“palladium and nickel-catalyzed carbon-carbon coupling …
TRANSCRIPT
INAUGURAL DISSERTATION
ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTLICHEN FAKULTÄT DER
KARL-FRANZENS UNIVERSITÄT
GRAZ, ÖSTERREICH
ZUM THEMA
“PALLADIUM AND NICKEL-CATALYZED
CARBON-CARBON COUPLING
REACTIONS FOR THE SYNTHESIS OF
QUINOLONE AND BISQUINOLONE
DERIVATIVES”
VORGELEGT VON
MAG. JAMSHED HASHIM
OKTOBER 2008
The work presented in this thesis was conducted at the Institute of Chemistry, Division of Organic and Bioorganic Chemsitry, at the Karl-Franzens University of Graz between November 2004 till October 2008. First of all, thanks to Allah for granting me the courage to fulfil my duties. I would like to thank the Higher Education Commission of Pakistan for a Ph.D. scholarship and the Austrian Exchange Service (ÖAD) for adminstrative help. I am cordially thankful to my supervisor Prof. Dr. C. Oliver Kappe for his encouraging and kind supervision. Special thanks to Prof. Dr. Georg Uray, Prof. Dr. Walter M. F. Fabian and Dr. Anne-Marie Kelterer for fluorescence, computational and enantioseparation studies in Chapter D. Thanks to Dr. Toma N. Glasnov for sharing results during the projects. I would like to thank the Prof. Dr. Wolfgang Stadlbauer for helpful discussions, Prof. Dr. Klaus Zanger and Bernhard Werner for recording numerous NMR Spectra, and Dr. Claudia Reidilinger for LC-MS analysis. My sincere and kind thanks to all my former and current colleagues and friends, especially to Jennifer, Nuzhat, Hana, Doris, Bimbisar, Mitra, Bernadett, Florian for all their support, discussions, help and making these years memorable for me. My parents, my brothers, sister, aunt and his family deserve special thanks for their support all through these years and making the possibility for acquiring the education. Big thank to my wife Nuzhat for her nice company and a son Hadi.
For my beloved parents. (Muhammad Hashim Khan & Firdous Hashim)
Table of Contents
A Introduction 1
1.1. Mechanistic Aspects of C-C Bond Forming Reactions 2
2. Types of Transition-Metal-Catalyzed C-C Coupling 3
Reactions.
2.1. The Suzuki-Miyaura Reaction 3
2.2. The Heck Reaction 4
2.3. The Sonogashira Coupling Reaction 6
2.4. The Stille Reaction 7
2.5. Ullmann-Type Reactions 7
3. Conclusion 9
4. References 10
B Symmetrical Bisquinolones via Metal-Catalyzed Cross- 12
Coupling and Homocoupling Reactions
1. Introduction 13
2. Results and Discussion 14
3. Conclusion 20
4. Experimental Section 20
5. References 28
C Symmetrical Bisquinolones via Nickel(0)-Catalyzed 30
Homocoupling of 4-Chloroquinolones
1. Introduction 31
2. Results and Discussion 33
3. Mechanistic Discussion 40
4. Conclusion 41
5. Experimental Section 41
6. References 47
D Bisquinolones as Chiral Fluorophores – A Combined 50
Experimental and Computational Study of Absorption
and Emission Characteristics
1. Introduction 51
2. Results and Discussion 52
2.1. Fluorescence 52
2.1.1. Computational Results 61
2.2. Separation of Enantiomers 65
3. Conclusion 68
4. Experimental Section 68
5. References 78
Appendix Summary 82
List of Publications
This thesis is based on the following publications:
1. Hashim, J.; Glasnov, T. N.; Kremsner, J. M.; Kappe, C. O.; Symmetrical
Bisquinolones via Metal-Ctalyzed Cross-Coupling and Homocoupling
Reactions. J. Org. Chem. 2006, 71, 1707-1710.
2. Hashim, J.; Kappe, C. O.; Synthesis of Symmetrical Bisquinolones via
Nickel(0)-Catalyzed Homocoupling of 4-Chloroquinolones. Adv. Synth.
Catal. 2007, 349, 2353-2360.
3. Hashim, J.; Kelterer, A.-M., Glasnov, T. N.; Kappe, C. O.; Uray, G.;
Fabian, W. M. F.; Bisquinolones as Chiral Fluorophores – A combined
Experimental and Computational Study of Absorption and Emission
Characteristics. Eur. J. Org. Chem. 2008, submitted for publication
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 1
A Transition-Metal-Catalyzed Carbon-Cabon Coupling
Reactions
1. Introduction
Transition-metal-catalyzed carbon-carbon coupling reactions belong to the most powerful and
flexible transformation known to organic chemists and have caused a real revolution in
organic synthesis in past decades.1 This art allowed cross-coupling of substrate in ways that
would have previously been thought impossible.2 In general, mild reaction conditions, high
functional group tolerance and broad availability of reagents have contributed to the growing
success of these C-C bond formation methods. Most C-C coupling protocols generally involve
the interaction of nucleophilic metallic reagents with electrophilic organohalides (or related
substrate)3 which are catalyzed by different transition-metals (as shown in Scheme 1).4
catalyst[M2] R1 R2R1M1 R2X+
M1 = Li (Murahashi)Mg (Kumada-Tamao, Corriu)B ( Suzuki-Miyaura)Al (Nozaki-Oshima, Negishi)Si (Tamao-Kumada, Hiyama-Hatanaka)Zn (Negishi)Sn (Migita-Kosugi, Stille).....
M2 = Fe, Ni, Cu, Pd, Rh,.......X = I, Br, Cl, OSO2R,......
Scheme 1. Different methodologies of C-C bond forming reactions.
In this context homogenous transition-metal catalysis has gained enormous relevance
in various C-C coupling reactions such as Heck, Stille, Suzuki and Sonagashira reactions.5
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 2 However, these reaction typically need hours or days for completion with traditional heating
under reflux condition.6 Besides the classical thermal activation mode, new methods have
emerged in the recent years. Such as 1) microwave, 2) ultrasound, 3) high pressure, 4)
micellar solutions, 5) microemulsions, 6) electrochemical activation, 7) nanofiltration, 8)
microreactors, 9) ball-milling conditions.4 Fortunately many of transition-metal-catalyzed
transformation can be significantly enhanced by microwave irradiation. Infact homogenous
transition metals catalyzed reactions represent one of the most important and best studied
reaction type in microwave-assisted organic synthesis.6 Further, It is appeared from the recent
literature that microwave irradiation mostly, not only results in a dramatic acceleration of
reaction, but also results in cleaner outcomes and increased yields.7
1.1. Mechanistic Aspects of C-C Bond Forming Reactions
Although carbon-carbon coupling reaction are catalyzed via different metals, e.g. palladium,
nickel, copper, iron (as shown in Scheme 1). However, a major part of the research in this
highly important area has been devoted to palladium catalysis. In general, carbon-carbon
coupling reaction catalyzed by palladium follow the usual reaction mechanism as shown for
coupling of organo metalics with organo halides of triflates in Scheme 2.5
Pd(0)
R1 Pd XR1 Pd R2
R1 R2 R1X
R2 MM X
oxidativeaddition
reductiveelimination
transmetallation
M = B, Sn, Si, Zn, Mg
Scheme 2. Major steps of palladium-catalyzed coupling reaction. (Catalytic cycle found in
textbooks).
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 3 2. Types of Transition-Metal-Catalyzed C-C Coupling
Reactions
Transition-metal-catalyzed reactions can be listed as follows:
1) Suzuki 2) Heck 3) Sonogashira 4) Stille 5) Ullmann
6)Fukuyama 7) Negishi 8) Kumada 9) Hiyama
In this overview some of the microwave-assisted transition-metal catalyzed reactions are
covered:
2.1. The Suzuki-Miyaura Reaction
The Suzuki-Miyaura coupling is basically the reaction of arylboronic acids with aryl halides
and triflates in the presence of palladium catalyst to form biaryl fragments, which are present
in many biologically active molecules. The advantages of employing the Suzuki-Miyaura
coupling include mild reaction conditions, tolerance to a wide range of functional groups, and
the availability of various boronic acids which are, in turn, generally low in toxicity and a
stable starting material.8 The Suzuki reaction is today arguably one of the most versatile tools
for cross-coupling reaction. As it is well-known fact that microwave (MW) heating has
emerged as a powerful technique by which reactions can be brought to completion in shorter
reaction times in a number of cases, so it is not surprising that carrying out high-speed Suzuki
reactions under controlled microwave conditions can be considered almost a routine synthetic
procedure today, given the enormous literature precedent for this transformation.9 The
reaction has also attracted the attention of several chemists involved in high-throughput
chemistry, as a large variety of boronic acids are commercially available.10
The first MW-promoted Suzuki couplings were published in 1996 (Scheme 3), which
is related to the coupling of phenylboronic acid with 4-methylphenyl bromide to give a fair
yield of product after a reaction time of less than 4 min under MW-irradiation. The same
reaction had previously reported with 4 h conventional heating time.11
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 4
Pd(PPh3)4, EtOH, DME, H2O
MW, 55 W, 2.8 min+
55%
Br
MeO (HO)2B MeO
Scheme 3. Suzuki coupling of phenylboronic acid with 4-methylphenyl bromide.
Recently, Hoornaert and co-workers have reported the microwave-assisted one-pot
synthesis of symmetrical highly functionalized 2(1H)-pyrazinones via Suzki-Miyaura-type
reaction (Scheme 4).12
N
N Pd(PPh3)4, K2CO3, dioxane
MW, 100 °C, 15-30 min
R1
Cl
R6
Cl
O
N
N
N
NO O
Cl
R6 R6
Cl
R1 R1
8 examples(49-68%)
OB
O
O
OB
Scheme 4. Suzuki-Miyaura-type homodimerization of 2(1H)-pyrazinones .
2.2. The Heck Reaction
The Heck reaction is broadly defined as Pd(0)-mediated coupling of an aryl or vinyl halide or
sulfonate with an alkene under basic conditions. Since its discovery, this methodology has
been found to be very versatile and applicable to a wide range of aryl species and a diverse
range of olefins.1f,4 This is generally a very mild reaction and does not require strict
anhydrous or inert conditions. Among aryl halide, iodides are very by far the most used, while
few examples of benzenesulfonate derivatives have also been reported.13 Solution-phase Heck
reactions were carried out successfully by microwave-assisted organic synthesis (MAOS) as
early as 1996.
In this context, the Heck arylation in Scheme 5 was the first example of a microwave-
assisted, palladium-catalyzed C-C bond formation. Thereby reducing reaction times from
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 5 several hours under conventional reflux conditions to sometimes less than five minutes.14 The
same high chemo and regioselectivity was found as in classical, oil bath heating (Scheme 5).11
Pd(OAc)2, Et3N, DMF
MW, 60 W, 4.8 min+
63%(oil bath, 100 °C, 17 h, 64%)
I
Br Br
Scheme 5. Chemoselective Heck coupling of 4-bromoiodobenzene and styrene.
A synthetically useful application of an intramolecular microwave-assisted Heck
reaction was described by Gracias et al (Scheme 6).15
Pd(OAc)2, PPh3, Et3N, MeCN
MW, 125 °C, 60 min
98%
I
N O
PhNHCH2Ph
O
MeO2C
PhNHCH2Ph
O
NO
MeO2C
Scheme 6. Intramolecular Heck reaction for the synthesis of seven-membered N-heterocycles.
Recently, Larhed and coworkers developed a general procedure for carrying out
oxidative Heck couplings, that is, the palladium(II)-catalyzed carbon-carbon coupling of
arylboronic acids with alkenes using copper(II) acetate as a reoxidant (Scheme 7),16 which is
another addition in already vast spectrum of MW-assisted heck chemistry.
Pd(OAc)2, Cu(OAc)2,LiOAc, DMF
MW, 100-140 °C, 5-30 min+
17 examples(45-81%)
B(OH)2
R
EWG
EWG
R
Scheme 7. Oxidative Heck-coupling of boronic acids and alkenes.
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 6 2.3. The Sonogashira Coupling Reaction
In this palladium-catalyzed reaction, aryl or vinyl halides or triflates couple to unactivated
terminal alkynes in the presence of a Cu(I) cocatalyst, usually delivered in the form of CuI.
Very mild conditions and tolerance to many other functional groups are among the advantages
of this procedure. Moreover, the triple bond can be converted into various new functionalities,
making this reaction very useful for combinatorial library generation.8
In 2001, Gogoll published the first pivotal work on the effect of directed microwave
activation on the efficiency and productivity in the Sonogashira coupling employing several
different aryl precursors (Scheme 8).17
Pd(PPh3)Cl2, CuI, Et2NH, DMF, LiCl
MW, 60 W, 4.8 min+
80-99%
ArX SiMe3
X = I, Br, Cl, OTfAr = carboaryl or heteroaryl
Ar SiMe3
Scheme 8. Palladium-catalyzed Sonogashira reaction with trimethylsilylacetylene.
Interestingly, new nickel18and copper19 catalyst systems have been introduced, even
“transition metal-free” reactions have been proposed.20 The solvent-free Sonogashira coupling
via Nickel is highly important as shown in Scheme 9. In this reaction sequence addition of
copper enhanced the reaction rate resulting in full conversion after irradiation for only 3
minutes in a domestic oven.
Ni(0), PPh3, CuI, KF, Al2O3
MW, 3 min+
53-75%
Br
BrR1
XR2
R1
R2
R1 = Cl, Br, MeR2 = NO2, COMe, OMe
Scheme 9. Solvent-free nickel-catalyzed Sonogashira reaction.
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 7 2.4. The Stille Reaction
The Stille coupling is a versatile reaction in which a variety of C-C bonds can be obtained by
reaction between stannanes and halides or pseudohalides.10 This base-free reaction is very
reliable, high yielding, and tolerant of many functionalities. The main drawback is the modest
reactivity of the organotin reactants and the formation of stoichiometric tin by-product which
is difficult to separate, but these limitations can be overcome by a judicious choice of
experimental conditions. The Stille reaction was one of the earliest transition metal-catalyzed
reactions to be accelerated with MW-assistance (Scheme 10).21
Pd2dba3, Ph3As, LiCl, NMP
MW, 50 W, 2.8 min+
68%Bu3Sn
OTf
O O
Scheme 10. Stille coupling with 4-acetylphenyl triflate.
One of the many applications reported is the Stille coupling of tin reagents with
fluorinated tags, in which the products and excess of the toxic tin-containing reagents can be
easily separated from the reaction mixture and, in the case of the reagents, be recycled.14 One
example of the tagged organostannanes is presented in Scheme 11.22
Pd(PPh3)2Cl2, LiCl, DMF
MW, 60 W, 2 min
63%
OTf
O
OMe
O
OMe
O(CH2CH2C6F13)3Sn+
O
Scheme 11. Stille-coupling with the tagged furan stannane reagent.
2.5. Ullmann-Type Reactions
The Ullmann-type reaction, that is, homocoupling of aryl or vinyl halides is conventionally
mediated by copper at high temperatures.23 Ullmann first reported this reaction in 1901.24
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 8 Although the coupling conditions that were first reported are still widely used, a host of
modifications have been made to the reaction. Some of these modifications have been made to
the reaction. Some of these modifications include the use of activated and alternative metals,
often resulting in much lower coupling temperatures. Nickel and palladium are the most
utilized source of alternative metals to effect this transformation.7 In recent years, Pd/C-
catalyzed Ullmann type coupling in the presence of reducing agents, such as sodium formate,
hydrogen, zinc, indium, or triethylamine has attracted increasing attention.5
To the best of our knowledge, very rare progress has been done in the use of Cu as a
catalyst for Ullmann reaction via using microwave irradiation. However, first report on the
controlled microwave mediated Ullmann-type N-arylation of N-H containing heteroarenes
with aryl bromide is reported in 2003 (Scheme 12).25
CuI, K2CO3, NMP
MW, 195 °C, 1-3 h
BrNH2
Me
+ NHHet NH2
MeNHet
9 examples(66-96%)
Scheme 12. Cu-catalyzed Ullmann-type N-arylation of N-H heteroarenes.
The introduction of Ni as an agent in the coupling of aryl halides represents a major
advance in the field.26 There have been rapid developments in the use of Ni-catalyzed
coupling reactions17,27 after the Semmelhack and co-workers 1971 report,28 where they used
Ni(cod)2 in DMF as an alternative to copper in the reductive homocoupling of aryl halides
(Scheme 13). Until now, there is very rare work reported on Ullmann-type Ni-catalyzed
homocoupling reaction via using microwave-irradiation.29
Ni(cod)2, DMF
52 °C82%
Br
Scheme 13. Ullmann-type homocoupling reaction via nickel-catalyst.
On the other hand, the relatively few palladium-mediated homocouplings reported to
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 9 date either are not general or, as with the nickel procedures, require inconvenient reaction
conditions to regenerate the active Pd(0) species.30 Few years ago, Lemaire and Rawal groups
published Pd-catalyzed Ullmann-type homocoupling reactions. Importantly Rawal and co-
workers reported a convenient and general protocol for aryl halides homocoupling towards
symmetrical biaryls, however, this procedure is conventional in heating mode (Scheme 14).31
Pd(OAc)2, P(o-tol)3 or As(o-tol)3,hydroquinone, Cs2CO3, DMA
25-100 °C, 1-48 h14 examples
(39-99%)
X
R R
R
Scheme 14. Palladium-catalyzed Ullmann-type reaction.
3. Conclusion
Now-a-days, transition metal-catalyzed carbon-carbon bond forming reactions belong
in the toolbox of synthetic organic chemist and cover an extremely wide range of
modifications and applications since first developed in 1970s. In all the methodologies
different activation modes have been utilized. But carrying out these cross/homo-coupling
reactions under controlled microwave irradiation can be considered today most effective. The
Suzuki-Miyaura and Stille protocols are two of the most versatile and well-investigated
microwave-assisted cross-coupling reactions in modern organic synthesis. It is indicative that
the combined approach of microwave irradiation and homogenous catalysis can offer a nearly
synergistic strategy in the sense that the combination has greater potential than its two
separate parts in isolation. In this Chapter the recent publications4,14,23 on carbon-carbon
coupling reactions were covered.
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 10 5. References
[1] a) Muci A. R.; Buchwald S. L. Top. Curr. Chem. 2002, 219, 131-209; b) Littke A.
F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176-4211; c) Prim, D.; Campagne,
J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041-2075; e) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633-9695; f) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-3066; g) Ley, S. V.; Thomas, A. W.
Angew. Chem. Int. Ed. 2003, 42, 5400-5449.
[2] a) Cross-coupling Reactions; Miyaura, N. A practical Guide; Ed.; Springer: Berlin,
2002; b) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F.,
Eds. 2nd ed.; Wiley-VCH: Weinheim, 2004.
[3] Prokopcova, H.; Kappe, C. O.; Angew. Chem. Int. Ed. 2008, 47, 3674-3676.
[4] Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61, 11771-11835.
[5] Yin, L.; liebscher, J. Chem. Rev. 2007, 107, 133-173.
[6] Kappe, C. O.; Angew. Chem. Int. Ed. 2004, 43, 6250-6284.
[7] Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem. 2008, 7, 1133-1155.
[8] Testero, S. A.; Mata, E. G. J. Comb. Chem. 2008, 10, 487-497.
[9] Homogenous transition-metal-catalysis: a) Larhed, M.; Moberg, C.; Hallberg, A.
Acc. Chem. Res. 2002, 35, 717-727; b) Olofsson, K.; Larhed, M.; In Microwave-
Assisted Organic Synthesis (Eds.: Lidström, P.; Tierney, J. P.), Blackwell, Oxford,
2004, Chap. 2.
[10] Ersmark, K.; Larhed, M.; Wannberg, J. Curr. Opin. Drug Discov. Devel. 2004, 7,
417-427.
[11] Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582-9584.
[12] De Borggraeve, W. M.; Appukkuttan, P.; Azzam, R.; Dehaen, W.; Compernolle, F.;
Van der Eycken, E.; Hoornaert, G.; Synlett 2005, 777-780.
[13] Yu, K.-L.; Deshpande, M. S.; Vyas, D. M. Tetrahedron Lett. 1994, 35, 8919-22.
[14] Kappe, C. O.; Stadler, A. Microwave in Organic and Medicinal Chemistry 2005, vol.
25, Wiley-VCH.
[15] Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 417-420.
[16] Andappan, M. M. S.; Nilsson, P.; Larhed, M. Mol. Diversity 2003, 7, 97-106.
[17] Erdelyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165-4169.
[18] Yan, J.; Wang, Z.; Wang, L. J. Chem. Res.(S) 2004, 1, 71-73.
[19] He, H.; Wu, Y. J. Tetrahedron Lett. 2004, 45, 3237-3239.
Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 11 [20] Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Eur. J. Org. Chem. 2003, 24,
4713-4716.
[21] Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996, 37, 8219-8222.
[22] Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg, A. J. Org. Chem.
1997, 62, 5583-5587.
[23] Loupy, A. Microwaves in Organic Synthesis 2006, vol. 2, Wiley-VCH.
[24] a) Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174-2185; b) Ullmann, F.; Meyer,
G. M.; Loewenthal, O.; Gilli, E. Liebigs Ann. Chem. 1904, 332, 38-81.
[25] Wu, Y.- J.; He, H.; LۥHeureux, A. Tetrahedron Lett. 2003, 44, 4217-4218.
[26] Knight, D. W.; Trost, B. M.; Fleming, I.; Pattenden, G. In Comprehensive Organic
Synthesis; Eds.; Pregamon: Oxford, 1991; vol. 3, p. 481.
[27] Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull. Chem. Soc. Jpn. 1990, 63,
80-87.
[28] Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. J. Am. Chem. Soc. 1971, 93, 5908-
5910.
[29] J. Hashim, T. N. Glasnov, J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2006, 71,
1707-1710.
[30] a) Tsuji, J. Palladium Reagents and catalysts; Wiley: New York, 1995; b) Torii, S.;
Tanaka, H.; Morisaki, K. Tetrahedron Lett. 1985, 26, 1655-1658.
[31] Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett. 1999, 1, 1205-1208.
Metal-Catalyzed Cross-Coupling and Homocoupling 12 B Symmetrical Bisquinolones via Metal-Catalyzed Cross-
Coupling and Homocoupling Reactions
Graphical Abstract
NR1
O
Cl
R2R3
R4
N OR1R2
R3
R4
NOR1 R2
R3
R4
Method A:
Method B:
PdCl2(dppf), [B(pin)]2, KOH, BuClMW, 130-145 °C, 35 min
NiCl2, PPh3, Zn, KI, DMFMW, 205 °C, 25 min
Abstract
Functionalized 4,4′-bisquinolones can be efficiently synthesized by microwave-assisted
palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling reactions, or via nickel(0)-
mediated homocouplings of 4-chloroquinolin-2(1H)-one precursors. Both methods are also
applicable to other types of symmetrical biaryls.
Metal-Catalyzed Cross-Coupling and Homocoupling 13 1. Introduction
Substituted biaryls play an important role in organic chemistry.1,2 Many natural products,
pharmaceuticals, herbicides and fine chemicals contain symmetrical or unsymmetrical biaryl
units. In addition, biaryls are applied as chiral ligands in catalysis, as liquid crystals or organic
conductors.1 Bis-heterocycles are also well-known in the literature and often display similarly
interesting biological and physical properties.2-5 Important structural motifs are, for example,
bipyridines,3 bithiophenes4, and bipyrroles.5
In the context of our ongoing interest in the chemistry of functionalized quinolin-
2(1H)-ones (carbostyrils),6 we became interested in the generation of the corresponding 4,4′-
bisquinolones of type 1. This novel class of bis-heterocycles are of interest both as aza-
analogues of biscoumarin natural products (e.g., 4,4′-biisofraxidin)7 and because of their
anticipated fluorescent properties as push-pull carbostyrils (R3 = R4 = OMe).8
N OR1R2
R3
R4
NOR1 R2
R3
R4
1; R1 = Me, Ph; R2 = H, alkylR3 = R4 = H, OMe
O OOMe
HO
MeO
OO OH
OMe
OMe
4,4'-biisofraxidin
Figure 1. Aza-analogues of biscoumarin natural products.
Here we report two different methods for the synthesis of bisquinolones of type 1 that
are based either on Pd(0)-catalyzed one-pot borylation/Suzuki cross-couplings or Ni(0)-
mediated homocouplings (Ullmann reaction) of 4-chloroquinolin-2(1H)-one precursors. Both
methods rapidly deliver bisquinolones in good to excellent yields employing controlled
microwave irradiation (MW) and are applicable not only toward the preparation of the desired
symmetrical bisquinolones but also as general methods for a symmetrical biaryl synthesis.
Several recently developed protocols for the preparation of symmetrical biaryls from
arylhalides via cross-coupling chemistry involve the use of bis(pinacolato)diboron as a
reagent.9−11 In these Pd(0)-catalyzed one-pot transformations, arylboronic esters are formed
Metal-Catalyzed Cross-Coupling and Homocoupling 14 as intermediates, which are not isolated, and undergo subsequent Suzuki coupling to directly
form the desired biaryls.9−11 The preferred catalyst for this transformation is PdCl2(dppf)
(dppf = diphenylphosphinoferrocene).9,11
2. Results and Discussion
As a starting point for the synthesis of bisquinolones 1, we investigated the one-pot
borylation/Suzuki cross-coupling of readily available 4-chloro-1-methylquinolin-2(1H)-one
2a6 as a model substrate (Table 1). All initial optimization studies were performed on a 0.25
mmol scale using automated sequential microwave processing to allow for shorter reaction
times and higher yields.10-12 An extensive optimization of the reaction parameters included
the amount of bis(pinacolato)diboron reagent, the type and the concentration of the Pd
catalyst, and the required base, solvent, reaction time, and temperature.
An initial attempt to adapt the previously reported protocols where aryl iodides,9
bromides,9,11 triflates,9 and reactive 2-chloroazaheterocycles10 have been employed as
precursors quickly demonstrated that the use of the suggested K2CO3 or KF base was not
successful. Under the published reaction conditions,9-11 only trace amounts of the desired
bisquinolone product 1a were obtained from the chloro precursor 2a, regardless of the
catalyst, solvent system and the reaction temperature. Gratifyingly, we discovered that the use
of the much stronger base KOH (4.5 equiv) in conjunction with PdCl2(dppf) as catalyst (10
mol%) provided excellent conversions (> 90%), depending on the solvent system used
(dioxane, 115 °C, 30 min).13
When several of the commonly used solvents for this type of transformation were
screened, such as DMSO, DMF or toluene, we noticed that, while the starting material was
consumed, the major reaction product with these solvents was the dehalogenated product, 1-
methylquinolin-2(1H)-one. Suitable solvents for the one-pot borylation/Suzuki cross-coupling
that minimized dehalogenation (<10 %) included dioxane, CH2Cl2, and 1,2-dichloroethane.
The best solvent identified in our studies, however, was 1-chlorobutane. Under optimized
reaction conditions (see Table 1, entry 3), full conversion to the bisquinolone 1a was achieved
within a 25 min reaction time, with only 3% of the dehalogenated product formed. It should
be noted that reducing the amount of KOH to, for example, 2.0 equiv also led to an increased
formation of the dehalogenated product.
Metal-Catalyzed Cross-Coupling and Homocoupling 15
Table 1. Catalyst/Ligand Screening for the Pd(0)-Catalyzed Bisquinolone Synthesisa
NMe
O
Cl
OB
O
O
OB
NMe
O
N OMe
2a
1a
[Pd], KOH, n-BuCl
MW, 130 °C, 30 min
entry catalyst
(mol%)
additive
(mol%)
product distribution
(%)b
1 PdCl2(dppf) (5) dppf (7) 22/61/17
2 PdCl2(dppf) (10) - 3/89/8
3 PdCl2(dppf) (10) dppf (7) 0/97/3c
4 Pd(OAc)2 (5) dppf (10) 0/92/8
5 Pd(PPh3)4 (8) - 1/91/8
6 palladacycled (2.5) dppf (10) 0/63/37
7 Pd2(dba)3 (2.5) - 0/60/40
8 Pd2(dba)3 (2.5) dppf (7) 0/84/16
9 Pd2(dba)3 (2.5) t-Bu3PHBF4
(5)
0/86/14
10 Pd2(dba)3 (2.5) PCy3 (5) 0/88/12
a Reaction conditions: 0.25 mmol chloroarene 2a, 4.5 equiv KOH, 0.7 equiv bis (pinacolato) diboron, 1.5 mL n-BuCl, sealed vessel, single mode, microwave irradiation at 130 °C for 30 min.
b Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215nm) traces: starting material/product/dehalogenated product.
c Product isolation by flash chromatography provided an 85% yield of bisquinolone 1a. d Herrmann’s palladacycle[trans-di(µ-acetato)bis[o-di-o-tolylphosphino)benzyl]dipalla- dium(II) .
Substantial efforts were made to identify the optimum catalyst, reaction temperature,
and time for this reaction (Table 1). After considerable experimentation, it was found that a
130 °C reaction temperature allowed the one-pot bisquinolone coupling to proceed within less
than half an hour. Whereas lower reaction temperatures resulted in longer reaction times,
Metal-Catalyzed Cross-Coupling and Homocoupling 16 higher temperatures produced more side and decomposition products. Among the many
catalysts tested, PdCl2(dppf) proved to be optimal. However, a 10 mol% loading of the
catalyst was required to achieve acceptable conversions. In fact, best results were obtained
upon the addition of a further amount of 7 mol% of free dppf ligand to slow catalyst
decomposition.9 Many other Pd catalyst/ligand systems proved significantly less efficient,
leading to a higher percentage of the dehalogenated product, although the use of
Pd(OAc)2/dppf or Pd(PPh3)4 furnished product yields that were also high (Table 1).
Importantly, the conversions determined by the HPLC monitoring of the crude
reaction mixtures (Table 1) nicely matched isolated product yields. From the experiment
described in entry 3, for example, an 85% yield of bisquinolone 1a was obtained after flash
chromatography. Our optimized one-pot borylation/Suzuki cross-coupling conditions were
applicable to a series of 4-chloroquinolin-2(1H)-one substrates, allowing the preparation of
various functionalized symmetrical bisquinolones (cf. Table 3).
The high costs of the required bis(pinacolato)diboron reagent and the Pd catalyst in the
above-mentioned cross-coupling protocols prompted us to explore an alternative
homocoupling method such as the Ullmann reaction,2 which would not require the use of an
additional cross-coupling partner. Among the many different available protocols for
successful bi(hetero)aryl synthesis via homocoupling methods,2-5 we were particularly
attracted by Ni-mediated reductive homocouplings, where the active Ni(0) complex is
prepared directly from an inexpensive Ni(II) salt and a reducing reagent such as Zn dust in the
presence of triphenylphosphine.2,14
As with the cross-coupling protocol, a careful optimization of the reaction conditions
with respect to the solvent, molar ratios (reagents and additives), time, and temperature was
performed for the homocoupling of chloroquinolone 2a (Table 2). Initial experiments
indicated that the general procedures for aryl halide homocouplings2,14,15 involving dry DMF
as the solvent, NiCl2 as the metal source, PPh3 as the ligand, and Zn dust as the reducing
reagent were also applicable to bisquinolone synthesis under microwave irradiation
conditions. Acceptable product yields of the homocoupled bisquinolone 1a were obtained
within 25 min at about a 205 °C reaction temperature; the only observed byproduct being
again the dehalogenated quinolone. As a result of the unreactive nature of the aryl chloride
precursor, it was necessary to use Ni in stoichiometric amounts (1.3 equiv). Lowering the
amount of Ni led to incomplete conversions. Similarly, we found that the presence of 1.3
equiv of Zn proved optimal for this transformation, with both lower and higher amounts of Zn
resulting in more dehalogenated product. Ligands such as PPh3 are essential in Ni-mediated
Metal-Catalyzed Cross-Coupling and Homocoupling 17 homocoupling reactions to stabilize the in situ generated Ni(0) catalyst and aryl Ni species
during the reaction sequence.15 In the present case, 4.0 equiv of PPh3 provided optimum
product yields.
Table 2. Effect of Iodide Additives on Ni(0)-Mediated Homocouplings of 4-
Chloroquinolonesa
NMe
O
Cl
NMe
O
N OMe
2a
1a
NiCl2, Zn, PPh3, DMFiodide additive
MW, 205 °C, 25 min
entry iodide additive
(equiv)
product distribution
(%)b
1 NaI (1.8) 0/88/12
2 KI (1.8) 1/95/4c
3 - 21/76/3
4 KI (1.0) 19/78/3
5 KI (1.6) 11/85/4
a Reaction conditions: 0.25 mmol chloroarene 2a, 1.3 equiv NiCl2, 1.3 equiv Zn dust, 4.0 equiv PPh3, iodide additive, 1.5 mL dry DMF, sealed vessel, single mode, microwave irraddiation at 205 °C for 25 min.
b Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215 nm) traces: starting material/product/dehalogenated product.
c Product isolation by flash chromatography provided a 90% yield of bisquinolone 1a.
Nevertheless, by applying the above-mentioned reagent mixtures, it proved difficult to
achieve high conversions in the desired short time frames. It is well-known that halide ions,
especially iodide, enhance the reaction rate of Ni-catalyzed homocoupling reactions.2,15 The
iodide ion is believed to function as a bridging ion between Ni and Zn in the electron transfer
process and/or as a donor ligand for the highly coordinatively unsaturated Ni(0) complex.15
The screening of several iodide sources in our model reaction finally resulted in the use of 1.8
Metal-Catalyzed Cross-Coupling and Homocoupling 18 equiv of KI as an additive (Table 2, entry 2). Under these optimized condition, the formation
of the dehalogenated byproduct could be kept to a minimum (ca. 4%), allowing the desired
bisquinolone homocoupling product 1a to be isolated in 90% yield after flash
chromatography.
Having two different optimized protocols for the efficient generation of symmetrical
bisquinolones from readily available 4-chloroquinolin-2(1H)-one substrates at hand, we next
proceeded to investigate the scope of these coupling procedures for (i) the preparation of a
variety of functionalized bisquinolones and (ii) the use of these methods as general high-
speed symmetrical biaryl coupling methods. Gratifyingly, both methods provided moderate to
excellent isolated product yields for all the quinolone systems, tested (entry 1-6, Table 3). For
the electron-rich mono- or disubstituted methoxy analogs (entry 4-6, Table 3), somewhat
higher reaction temperatures (145 °C) were applied in the cross-coupling protocol (Method A)
to achieve good yields.16 The required 4-chloroquinolone precursors were readily available
from the known 4-hydroxyquinolones by microwave-assisted chlorination using POCl3 as the
chlorinating reagent.6 For the examples displayed in Table 3, the Pd-catalyzed cross-coupling
method (Method A) proved to be somewhat more reliable, furnishing higher isolated product
yields (68-85%) as compared to those of the Ni-mediated homocoupling method (Method B,
39-90%). A clear disadvantage of the Ni method additionally lies in the required extensive
purification process, removing large quantities of the PPh3 ligand by flash chromatography.
We next attempted to synthesize 4,4′-biscoumarin starting from 4-chlorocoumarin using both
coupling methods. Biscoumarins are of considerable interest because of their physiological
properties and their presence as important structural units in a variety of biologically active
natural products (i.e., 4,4′-biisofraxidin).7 The generation of biscoumarins via cross-coupling
chemistry to our knowledge has not been reported in the literature.16,17 By changing to a
toluene/Cs2CO3 solvent/base system in the Pd-catalyzed one-pot borylation/Suzuki cross-
coupling (Method A), we achieved the preparation of 4,4′- biscoumarin in a moderate 67%
yield. The standard reaction conditions employing KOH as base furnished only very small
amounts of the desired product, presumably a result of the hydrolysis/destruction of the
sensitive coumarin heterocycle. When our base-free Ni(0)-mediated homocoupling protocol
was used, a near quantitative 98% yield of 4,4′-biscoumarin was obtained.17, 18
While both our protocols were optimized for the rather specific and comparatively
unreactive 4-chloroquinolin-2(1H)-one precursors (entry 1-6, Table 3), we were interested to
see if these procedures could also be used as general high-speed biaryl coupling methods.
Gratifyingly, we were pleased to find that both microwave-assisted coupling methods were
Metal-Catalyzed Cross-Coupling and Homocoupling 19 Table 3. Synthesis of Biaryls via Microwave-Assisted Cross- and Homocoupling of
(Hetero)aryl Chlorides and Bromides
Method A:PdCl2(dppf), [B(pin)]2, KOH, BuClMW, 130 °C, 35 min
Method B:NiCl2, Zn, PPh3, DMF, KIMW, 205 °C, 25 min
(Het)Ar-X
X = Cl, Br
(Het)Ar-Ar(Het)
entry substrate yield (%)a
Method Ab Method Bc
entry substrate yield (%)a
Method Ab Method Bc
1 NMe
O
Cl
85 90 6 NMe
O
Cl
MeO
MeO
82e 41
2 N O
Cl
68 68 7 O O
Cl
67f 98
3 N O
Cl
83d 39 8 N
Br
91e 94
4 NMe
O
ClMeO
83e 70 9 S
Br
89 65
5 NMe
O
Cl
MeO
70e 74 10 Br
91e 65
a Isolated yields of pure product. b Reaction conditions: 0.30 mmol substrate, 10 mol% PdCl2(dppf), 7 mol% dppf, 0.7 equiv bis(pinacolato)diboron, 4.5
equiv KOH, 2.0 mL n-BuCl, sealed-vessel, single-mode, microwave irradiation at 130 °C for 30 min. c Reaction conditions: 0.25 mmol substrate, 1.3 equiv NiCl2, 4.0 equiv PPh3, 1.3 equiv Zn, 1.8 equiv KI, 1.5 mL DMF,
sealed-vessel, single-mode, microwave irradiation at 205 °C for 25 min. d Reaction conditions: 10 mol% Pd(OAc)2, 20mol% dppf, 1.5 mL dioxane. e Reaction temperature: 145°C. f Reaction conditions: 6 mol% Pd(PPh3)4, 2.5 equiv CsCO3, 1.5 mL toluene.
also applicable to the more commonly used hetero(aryl) bromide substrates, such as 3-
bromoquinoline, 2-bromothiophene, and 1-bromonaphthalene (Table 3). Without any further
optimization, good to excellent yields of the corresponding bis(hetero)aryls were obtained.
Again, the Pd-catalyzed one-pot borylation/Suzuki cross-coupling conditions generally
provided somewhat higher product yields (ca. 90%) compared with those of the Ni-mediated
Ullmann homocoupling procedure.
Metal-Catalyzed Cross-Coupling and Homocoupling 20 3. Conclusion
In summary, we have developed two generally applicable high-speed methods for the
preparation of symmetrical (hetero)biaryls using either Pd(0)-catalyzed cross-coupling or
Ni(0)-mediated homocoupling principles. The procedures are particularly valuable for the
preparation of novel types of bisquinolones, which are presently under investigation as
fluorescent probes. Results from these studies will be published elsewhere. We are currently
investigating alternative catalytic cross- and homocoupling protocols to access
unsymmetrical bisquinolones.
4. Experimental Section
General Methods All cross and homocoupling reactions involving air sensitive reagents were carried out under
an atmosphere of dry argon. Dry-flash chromatography was performed on Merck Silica gel 60
H (< 45 nm particle size). TLC analyses were performed on pre-coated (Merck Silica gel 60
HF254 ) plates. 1H NMR and 13C NMR spectra were recorded on a Bruker AMX360 and 500
instrument in CDCl3 or DMSO-d6 at 360 and at 90 MHz respectively. Melting points were
obtained on a Gallenkamp melting point apparatus, Model MFB-595 in open capillary tubes.
FTIR spectra were recorded on Perkin-Elmer 298 spectrophotometer using KBr pellets. Low
resolution mass spectra were obtained on an Hewlett-Packard LC/MSD Agilent 1100 series
instrument using atmospheric pressure chemical ionization (APCI) in positive or negative
mode. Analytical HPLC analysis was carried out on two different Shimadzu systems. The
Shimadzu LC-10 includes LC10-AT(VP) pumps, an autosampler (S-10AXL), and a dual
wavelength UV detector. The separations were carried out using a C18 reversed phase
analytical column, LiChrospher 100 (E. Merck, 100 x 3 mm, particle size 5 µm) at 25 °C and
a mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN and (B) 0.1 % TFA acid in MeCN
(all solvents were HPLC grade, Acros; TFA was analytical reagent grade, Aldrich). The
following gradient was applied: linear increase from solution 30 % B to 100% B in 7 min,
hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min. The Shimadzu LC-20
system includes a LC-20AD pump, a SIL-20A autosampler, a diode array detector (SPD-
M20A), a column oven (CTO-20A) and a degasser (DGU-20A5). The separations were
carried out using a Pathfinder®AS100 reversed phase analytical column (150 x 4.6 mm,
Metal-Catalyzed Cross-Coupling and Homocoupling 21 particle size 5 µm) at 25 °C and a mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN
and (B) 0.1 % TFA acid in MeCN (all solvents were HPLC grade, Acros; TFA was analytical
reagent grade, Aldrich). The following gradient was applied: linear increase from solution 20
% B to 100% B in 7 min, hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min.
The 4-hydroxyquinolin-2-one precursors required for the preparation of
chloroquinolones 1-6 were obtained from Aurora Feinchemie GmbH. Zn-powder (Merck
108789, < 60 μm particle size) was used for the Ni(0)-mediated homocouplings. All
anhydrous solvents (stored over molecular sieves), catalysts and ligands were obtained from
standard commercial vendors and were used without any further purification. Solvents for
column chromatography have been distilled prior to use.
Microwave Irradiation Experiments
Microwave-assisted synthesis was carried out in an Emrys™ Synthesizer or Initiator 8 single-
mode microwave instrument producing controlled irradiation at 2.450 GHz (Biotage AB,
Uppsala), including proprietary Workflow Manager Software (version 2.1). Experiments were
carried out in sealed microwave microwave (2 to 5 mL filling volume) process vials utilizing
the standard absorbance level (300 W maximum power). Reaction times under microwave
conditions refer to hold times at the temperatures indicated, not to total irradiation times. The
temperature was measured with an IR sensor on the outside of the reaction vessel.
General Procedure for the Preparation of 4-Chloroquinolin-2-ones 1-6 and
4-Chlorocoumarin.2 To 1.70 mmol of corresponding 4-hydroxyquinoline-2(1H)-one or 4-hydroxycoumarin,
respectively in a microwave process vial were added 520 mg (3.40 mmol, 320 µL) of POCl3
and 2 mL of anhydrous dioxane. The mixture was stirred for 2 min at room temperature to
allow complete homogenization. The sealed vial was heated by microwave irradiation for 25
min at 120 °C. After cooling to ambient temperature, the mixture was poured onto 20 mL of
ice water. The resulting solution was neutralized with 0.5 M KOH. After stirring for 20 min,
the neutral solution was extracted with 3 x 20 mL of diethyl ether. The organic layers were
combined, washed with 2 x 50 mL of water and dried over anhydrous MgSO4. The solvent
was removed under vacuum to produce the desired 4-chloroquinoline-2(1H)-ones (entry 1-6,
Table 3) and 4-chlorocoumarin, respectively. Samples of analytical purity were obtained by
recrystallization from ethanol. The physical and spectroscopic data of the known
Metal-Catalyzed Cross-Coupling and Homocoupling 22 chloroquinolones 1 (82% yield),6 2 (65% yield),19 3 (94% yield)19 and of 4-chlorocoumarin
(56% yield after flash chromatography)19 were in good agreement with literature data.
NMe
O
ClMeO
C11H10ClNO2
4-Chloro-6-methoxy-1-methylquinolin-2(1H)-one 4.
82% yield, mp 161–163 °C (ethanol); 1H-NMR (360 MHz, CDCl3): δ 3.69 (s, 3H), 3.90 (s,
3H), 6.90 (s, 1H), 7.24 (dd, J = 2.75 and 9.19 MHz, 1H), 7.32 (d, J = 9.20 Hz, 1H), 7.14 (d, J
= 2.73 Hz, 1H); 13C NMR (90 MHz, CDCl3)δ 29.7, 55.7, 107.8, 115.9, 120.0, 120.6, 121.4,
134.3, 143.5, 155.1, 160.5; MS (pos. APCI) m/z 223 (100, M), 188 (54, M – 35). Anal. Calcd.
for C11H10ClNO2: C, 59.07; H, 4.51; N, 6.26. Found: C, 59.04; H, 4.43; N, 6.05.
NMe
O
Cl
C11H10ClNO2MeO
4-Chloro-7-methoxy-1-methylquinolin-2(1H)-one 5.
77% yield, mp 123–125 °C (ethanol); 1H-NMR (360 MHz, CDCl3): δ 3.66 (s, 3H), 3.90 (s,
3H), 6.74 (s, 1H), 6.79 (s, 1H), 6.89 (d, J = 8.90 Hz, 1H), 7.91 (d, J = 8.90 Hz, 1H); 13C NMR
(90 MHz, CDCl3) δ 29.7, 55.7, 98.8, 110.1, 113.4, 117.8, 127.8, 141.4, 144.3, 161.5, 162.7;
MS (pos. APCI) m/z 223 (100, M), 188 (54, M – 35). Anal. Calcd. for C11H10ClNO2: C,
59.07; H, 4.51; N, 6.26. Found: C, 59.03; H, 4.57; N, 6.20.
NMe
O
Cl
C12H12ClNO3MeO
MeO
4-Chloro-6,7-dimethoxy-1-methylquinolin-2(1H)-one 6.
64% yield, mp 219–220 °C (ethanol); 1H-NMR (360 MHz, DMSO-d6): δ 3.63 (s, 3H), 3.85 (s,
3H), 3.96 (s, 3H), 6.74 (s, 1H), 7.03 (s, 1H), 7.27 (s, 1H); 13C NMR (90 MHz, DMSO-d6) δ
30.1, 56.6, 70.1, 99.0, 106.4, 111.5, 117.7, 135.9, 142.7, 145.6, 153.5, 160.2; MS (pos. APCI)
m/z 253 (100, M), 219 (47, M – 34). Anal. Calcd. for C12H12ClNO3: C, 56.82; H, 4.77; N,
Metal-Catalyzed Cross-Coupling and Homocoupling 23 5.52. Found: C, 56.83; H, 4.70; N, 5.41.
General Procedure for the One-Pot Borylation/Suzuki Cross Couling of
Haloarenes (Method A, Table 3). A mixture containing 0.30 mmol of the corresponding haloarene (Table 3), 24.5 mg (0.03
mmol, 10 mol%) of PdCl2(dppf), 11.6 mg (0.021 mmol, 7 mol%) of dppf, 53.3 mg (0.21
mmol, 0.7 equiv) of bis(pinacolato)diboron and 75.7 mg (1.35 mmol, 4.5 equiv) of finely
crushed KOH powder (analytical grade) was suspended in 2.0 mL of anhydrous 1-
chlorobutane under an argon atmosphere in a 5 mL microwave vial (Pyrex) equipped with a
magnetic stirring bar. The vial was sealed, stirred for 4 min at room temperature, and then
heated for 35 min at 130 °C (see Table 3 for deviations). Thereafter, the solvent was removed
under reduced pressure. The product was directly isolated by gradient dry flash
chromatography, using appropriate solvents. For yields, see Table 3.
General Procedure for the Homocoupling of Haloarenes (Method B, Table
3). A mixture containing 0.25 mmol of the corresponding haloarene (Table 3), 42.1 mg (0.325
mmol, 1.3 equiv) of anhydrous NiCl2, 262.3 mg (1 mmol, 4.0 equiv) of PPh3, 21.2 mg (0.324
mmol, 1.3 equiv) of Zn powder (<60 µm particle size), and 74.7 mg (0.45 mmol, 1.8 equiv) of
KI was dissolved in 1.5 mL anhydrous DMF under an argon atmosphere in a 5mL microwave
vial (Pyrex) equipped with a magnetic stirring bar. The vial was sealed, stirred for 4 min at
room temperature, and then heated for 25 min at 205 °C. Thereafter, the solvent was removed
under reduced pressure. The product was isolated by gradient dry flash chromatography,
using appropriate solvents. For yields, see Table 3.
NMe
O
N OMe
C20H16N2O2
4,4´-Bis-(1-methylquinolin-2(1H)-one) (Table 3, entry 1).
Metal-Catalyzed Cross-Coupling and Homocoupling 24 Mp 283-284°C (acetonitrile). IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ
3.71 (s, 6H), 6.67 (s, 2H), 7.11-7.17 (m, 4H), 7.64-7.67 (m , 4H); 13C NMR (90 MHz,
DMSO-d6) δ 29.8, 115.8, 119.6, 121.6, 122.7, 127.3, 131.8, 140.2, 146.1, 160.9; MS (pos.
APCI) m/z 317 (25, M + 1), 316 (100, M). Anal. Calcd for C20H16N2O2: C, 75.93; H, 5.10; N,
8.86. Found: C, 75.95; H, 4.98; N, 8.78.
N O
N O
C24H20N2O2
7,7´-Bis-(2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one) (Table 3, entry 2).
Mp 270°C dec. (acetonitrile); IR (KBr) νmax 1637 cm-1; 1H NMR (360 MHz, DMSO-d6) δ
2.02-2.13 (m, 4H), 2.99 (t, J = 5.8 Hz, 4H), 4.13 (t, J = 5.6 Hz, 4H), 6.62 (s, 2H), 6.96 (d, J =
7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 6.98 Hz, 2H); 13C NMR (90 MHz, DMSO-
d6) δ 20.6, 27.8, 42.6, 119.7, 121.4, 121.9, 125.3, 125.4, 130.5, 136.8, 146.4, 161.2; MS (pos.
APCI) m/z 368 (100, M).
N O
N O
C30H20N2O2
4,4´-Bis-(1-phenylquinolin-2(1H)-one) (Table 3, entry 3).
Mp > 400°C dec. (CCl4); IR (KBr) νmax 1661 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.81 (d, J
= 8.4 Hz, 2H), 6.91 (s, 2H), 7.14 (t, J = 7.57 Hz, 2H), 7.38-7.45 (m, 8H), 7.60 (t, J = 7.36 Hz,
2H), 7.68 (t, J = 7.62 Hz, 4H); 13C NMR (90 MHz, CDCl3) δ 116.6, 119.4, 122.4, 122.6,
127.0, 128.9, 129.2, 130.4, 130.9, 137.4, 141.2, 147.0, 161.5; MS (pos. APCI) m/z 441 (25, M
+ 1), 440 (100, M).
Metal-Catalyzed Cross-Coupling and Homocoupling 25
NMe
O
N OMe
MeOMeO
C22H20N2O4
4,4´-Bis-(6-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 4).
Mp 256-258°C (ethanol); IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ 3.58 (s,
6H), 3.69 (s, 6H), 6.57 (d, J = 2.8 Hz, 2H), 6.66 (s, 2H), 7.34 (dd, J = 9.25 and 2.8 Hz, 2H),
7.62 (d, J = 9.29 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ 29.8, 55.8, 110.0, 115.9, 119.4,
120.4, 122.5, 134.7, 145.5, 154.8, 161.1; MS (pos. APCI) m/z 377 (25, M + 1), 376 (100, M).
NMe
O
N OMe
MeO
MeO
C22H20N2O4
4,4´-Bis-(7-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 5).
Mp 232-234°C (ethanol); IR (KBr) νmax 1658 cm-1; 1H NMR (360 MHz, DMSO- d6) δ 3.67 (s,
6H), 3.89 (s, 6H), 6.45 (s, 2H), 6.76 (d, J = 8.67 Hz, 2H), 7.04-7.07 (m, 4H); 13C NMR (90
MHz, CDCl3) δ 29.8, 56.2, 99.7, 110.8, 113.5, 117.9, 128.8, 142.0, 146.3, 161.5, 162.3; MS
(pos. APCI) 377 (25, M + 1), 376 (100, M). Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36;
N, 7.44. Found: C, 70.23; H, 5.26; N, 7.37.
NMe
O
N OMe
MeO
MeO
C24H24N2O6
MeOMeO
4,4´-Bis-(6,7-dimethoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 6).
Mp 276-277 °C dec. (ethanol); IR (KBr) νmax 1642 cm-1; 1H NMR (360 MHz, DMSO-d6) δ
3.45 (s, 6H), 3.74 (s, 6H), 3.96 (s, 6H), 6.46 (s, 2H), 6.57 (s, 2H), 7.09 (s, 2H); 13C NMR (90
Metal-Catalyzed Cross-Coupling and Homocoupling 26 MHz, CDCl3) δ 30.0, 56.2, 56.4, 97.6, 108.2, 112.7, 119.1, 136.1, 145.2, 145.8, 152.8, 162.0;
MS (pos. APCI) m/z 437 (50, M + 1), 436 (100, M).
O O
O O
C18H10O4
4,4´-Bis-(2H-chromen-2-one) (Table 3, entry 7).
Mp 215-216°C (acetonitrile; lit.20 Mp 215 °C); 1H NMR (360 MHz, CDCl3) δ 6.50 (s, 2H),
7.22-7.24 (m, 4H), 7.47 (d, J = 8.42 Hz, 2H), 7.60-7.65 (m, 2H). MS (pos. APCI) m/z 291
(95, M + 1), 290 (45, M), 252 (100, M – 38), 236 (M – 54).
NC18H12N2N
3,3´-Bisquinoline (Table 3, entry 8).
Mp 269-271°C (ethanol) (lit.21 Mp 271 °C); 1H NMR (360 MHz, CDCl3) δ 7.70 (t, J = 7.25
Hz, 2H), 7.85 (t, J = 7.42 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 8.29 (d, J = 8.4 Hz, 2H), 8.57 (s,
2H), 9.33 (s, 2H). MS (pos. APCI) m/z 257 (20, M + 1), 256 (100, M).
C8H6S2S S
2,2´-Bisthiophene (Table 3, entry 9).
Mp 30-32 °C (diethyl ether) (lit.22 Mp 32-34 °C); 1H NMR (360 MHz, CDCl3) δ 7.02 (dd, J =
3.70 and 4.96 Hz, 2H), 7.19-7.24 (m, 4H). MS (pos. APCI) m/z 166 (100, M).
C20H14
1,1´-Bisnaphthalene (Table 3, entry 10).
Mp 158-159 °C (acetone) (lit.23,24 Mp 158.8-159 °C); 1H NMR (360 MHz, CDCl3) δ 7.29-7.32
Metal-Catalyzed Cross-Coupling and Homocoupling 27 (m, 2H), 7.40 (d, J = 8.38 Hz, 2H), 7.47-7.52 (m, 4H), 7.59-7.63 (m, 2H), 7.96 (dd, J = 2.97,
8.13 Hz, 4H).
Metal-Catalyzed Cross-Coupling and Homocoupling 28 5. References
[1] For reviews on biaryls, see: (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Shimizu, H.; Nagasaki, I.; Saito, T.
Tetrahedron 2005, 61, 5405. (c) Bringmann, G.; Price Mortimer, A. J.; Keller, P.
A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384.
[2] Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265.
[3] (a) Leadbeater, N. E.; Resouly, S. M. Tetrahedron Lett. 1999, 40, 4243. (b) Tiecco,
M.; Tingoli, M.; Testaferri, L.; Bartoli, D.; Chianelli, D. Tetrahedron 1989, 45,
2857.
[4] (a) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627. (b) Hassan, J.; Lavenot,L.;
Gozzi, Lemaire, M. Tetrahedron Lett. 1999, 40, 857.
[5] Grigg, R.; Johnson, R. W. J. Chem. Soc. 1964, 3315.
[6] Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70, 3864.
[7] (a) Pharkphoom, P.; Hiroshi, N.; Wanchai, D. E. Planta Med. 1998, 64, 774. (b) Lei,
J.-G.; Lin, G.-Q. Chin. J. Chem. 2002, 20, 1263.
[8] (a) Strohmeier, G.; Fabian, W. M. F.; Uray, G. Helv. Chim. Acta 2004, 87, 215. (b)
Lee, H.-K.; Cao, H.; Rana, T. M. J. Comb. Chem. 2005, 7, 279.
[9] (a) Nising, C. F.; Schmid, U. K.; Nieger, M.; Bräse, S. J. Org. Chem. 2004, 69,6830.
See also: (b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841. (c)
Ishiyama, T.; Murata, M.; Miyaura, N.; J. Org. Chem. 1995, 60, 7508. (d) Ishiyama,
T.; Itoh, Y.; Kitano, T.; Miyaura, N.; Tetrahedron Lett. 1997, 38, 3447.
[10] De Borggraeve, W. M.; Appukkuttan, P.; Azzam, R.; Dehaen, W.; Comper- nolle,F.;
Van der Eycken, E.; Hoornaert, G. Synlett 2005, 777.
[11] Melucci, M.; Barbarella, G.; Zambianchi, M.; Di Pietro, P.; Bongini, A. J. Org.
Chem. 2004, 69, 4821.
[12] Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
[13] The effect of stronger bases such as KOH probably lies in their stronger
nucleophilicity. For a detailed description of the reaction mechanism in these biaryl
formations and the role of the base, see ref. 9.
[14] (a) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Montanucci, M. Synthesis
1984, 736. (b) Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin Trans. 1
1997, 927. (c) For a recent report on iron-catalyzed homo- couplings, see: Cahiez,
G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005, 7, 1943.
Metal-Catalyzed Cross-Coupling and Homocoupling 29 [15] (a) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60, 176. (b)
Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060.
[16] Beletskaya, I. P.; Ganina, O. G.; Tsvetkov, A. V.; Fedorov, A. Y.; Finet, J.-P. Synlett
2004, 2797.
[17] For Suzuki and related cross-coupling reactions involving 4-sulfonyloxysubstituted
coumarins, see: (a) Boland, G. M.; Donnelly, D. M. X.; Finet, J.-P.; Rea, M. D. J.
Chem. Soc., Perkin Trans. 1 1996, 2591. (b) Donnelly, D. M. X.; Finet, J.-P.; Guiry,
P. J.; Rea, M. D. Synth. Commun. 1999, 29, 2719. (c) Yao, M.-L; Deng, M.-Z.
Heteroat. Chem. 2000, 11, 380. (d) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001,
66, 3642.
[18] For Ni-catalyzed homocouplings of 4-sulfonyloxy-substituted coumarins, see: Lei,
J.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2004, 2364.
[19] Stadlbauer, W. Monats. Chem. 1986, 117, 1305.
[20] Deshmukh, R. S. K.; Paradkar, M. V. Synth. Commun. 1988, 18, 589.
[21] (a) Uyeda, K. J. Pharm. Soc. Jpn. 1931, 51, 495. (b) Chem. Abstr. 1931, 25, 5427.
[22] Nishihara, Y.; Ikegashira, K.; Toriyama, F.; Mori, A.; Hiyama, T. Bull. Chem. Soc.
Jpn. 2000, 73, 985.
[23] Ibuki, E.; Ozasa, S.; Fujioka, Y.; Mizutani, H. Bull. Chem. Soc. Jpn. 1982, 55, 845.
[24] Collet, A.; Brienne, M. J.; Jacques, J. Bull. Chem. Soc. Jpn. 1972, 1, 127.
Nickel(0)-Catalyzed Homocoupling Reaction 30 C Symmetrical Bisquinolones via Nickel(0)-Catalyzed
Homocoupling of 4-Chloroquinolones
Graphical Abstract
NR1
O
Cl
N OR1
NOR1
0.25 equivs. NiCl2(PPh3)20.25 equivs. DPEphos
1.3 equivs. Zn, 1.8 equivs. KI
dioxane, MW, 130 °C, 30 min
R4
R3
R2
R2
R3
R4
R4
R3
Abstract
A method for the gram-scale preparation of functionalized 4,4´-bisquinolones using a
microwave-assisted Ullmann-type homocoupling reaction is described. The method is catalytic
in nickel(0) which is generated in situ by reduction from an inexpensive Ni(II) source and
utilizes readily available 4-chloroquinolin-2(1H)-ones as starting materials. In contrast to the
alternative palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling reaction, the new
method avoids the use of an expensive catalyst and cross-coupling partner such as
bis(pinacolato)diboron.
Nickel(0)-Catalyzed Homocoupling Reaction 31 1. Introduction
The structural sub-unit of symmetrical biaryls plays an important role in organic and medicinal
chemistry, and is found in a wide variety of natural products including alkaloids such as the
anti-HIV alkaloid michellamine B,[1] coumarins (4,4´-biisofraxidin),[2] polyketides[3] and
terpenes (Figure 1).[4] Compounds incorporating symmetrical biaryl moieties also find
applications as conductors for thin film transistor (e.g., 2,2′-bidithieno[3,2-b:2′,3′-d] thio-
phene),[5] as electronic and optoelectronic materials (e.g., indenofluorenes),[6] as chiral ligands
in catalysis (e.g., BINAP)[7] and in chiral or achiral liquid crystals (e.g., paracyclophanes).[8]
The biaryl subunit also constitutes an important structural motif in several pharmaceuticals
(e.g., in the laxative agent 4,4′-biphenol),[9] and in agrochemicals (e.g., in the non-selective
broad-spectrum herbicide Paraquat).[10] Related biaryl heterocycles are also well known in the
literature and often display similarly interesting biological and physical properties.[11]
O
O O
OO
O O
O
O O
S SS
S
S
S
PPh2PPh2
BINAPNH
OH
Me
OMeOH
OHOMe
Me
HN
OHMe
Me
Me OH
MeHO
OHHO N NMe Me
2 Cl
Michellamine B indenofluorenes
2,2´-bidithieno[3,2-b:2 ,́3 -́d]thiophene 4,4 -́biphenol Paraquat
++
_
paracyclophanes
Figure 1. Important symmetrical biaryl products.
In view of the substantial interest and broad application of symmetrical biaryls,[1-11]
considerable efforts have been undertaken to achieve efficient, economical, safe, and
Nickel(0)-Catalyzed Homocoupling Reaction 32 environmentally benign methods for their preparation in many academic and industrial
laboratories.[12] Since the first biaryl couplings performed by Ullmann over a century ago
applying stoichiometric amounts of copper metal,[13] the catalytic use of transition metals,
especially of palladium and nickel, in the formation of symmetrical biaryls is now well
established.[12] In this context we recently reported the first synthesis of 4,4′-bisquinolones of
type 1.[14] These novel, symmetrical bis-heterocycles are of considerable interest as aza-
analogues of biscoumarin natural products (e.g., 4,4′-biisofraxidin),[2] because of their
anticipated fluorescent properties as push–pull carbostyrils (1, R3 = R4= OMe),[15] and as
starting materials for the synthesis of novel aza-BINAP analogs (Figure 2).[16]
N OR1R2
R3
R4
NOR1 R2
R3
R4
O OOMe
OO OH
OMe
OMe
HO
MeO
N OR1
PPh2
N
Ph2P
OR1
4,4'-biisofraxidin1; R1 = Me, Ph; R2 = H, alkylR3 = R4 = H, OMe
"aza-BINAP"
R3
R4
R4
R3
Figure 2. 4,4′-Bisquinolones and 4,4′-biscoumarins.
In our recent publication we have outlined the generation of 4,4′-bisquinolones 1,
employing both a palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling method,
and a nickel(0)-mediated homocoupling protocol using the corresponding 4-chloroquinolin-
2(1H)-ones 2 as precursors.[14] Both methods did in fact allow the successful, high-yielding
preparation of a variety of bisquinolones of type 1, in addition to 4,4′-biscoumarin and a range
of other symmetrical bi(hetero)aryls. However, both procedures have severe disadvantages
that make them impractical for a larger scale synthesis required for our purposes: most
prominently, the borylation/Suzuki approach relied on the use of the rather expensive
bis(pinacolato)diboron cross-coupling reagent[17] and additionally required 10 mol% of the
costly palladium/ligand source PdCl2(dppf).[17] While the alternative homocoupling method
avoids the use of a cross-coupling partner and therefore appeares to be more favorably from
the standpoint of atom economy,[18] our original nickel-mediated method utilized
stoichiometric amounts of a nickel(II) source (1.3 equivalents of NiCl2) and required 4
Nickel(0)-Catalyzed Homocoupling Reaction 33 equivalents of triphenylphosphine as ligand.[14] The subsequent complex chromatographic
separation of the desired product from triphenylphosphine and its oxide impurity in fact only
allowed the preparation of quantities of bisquinolones 1 on a less than 50-mg scale.[19] We now
report an improved method for the homocoupling of 4-chloroquinolin-2(1H)-one 2 (see Table
1, Table 2 and Table 3) that utilizes a comparatively inexpensive combination of a nickel
catalyst [25 mol% of NiCl2(PPh3)2] and an additional bidentate ligand (25 mol% of
DPEphos).[17] Importantly, using this method good isolated product yields can be obtained
without purification by chromatography, allowing the preparation of bisquinolones 1 in gram-
scale quantities.
2. Results and Discussion
The main problem in the reported cross- and homocouplings involving 4-chloroquinolin-
2(1H)-ones[14] lies in the fact that these heteroaryl chlorides are comparatively unreactive as
coupling partners. It is well known that aryl chlorides, despite the fact that those substrates
would generally be the most useful ones because of their low cost and the wide availability,[20]
are comparatively unreactive as coupling partners in transition metal-catalyzed processes when
compared to aryl bromides and iodides.[20] General and efficient protocols employing aryl
chlorides as starting materials in such transformations have only recently emerged in the
literature.[20-23] The low reactivity of aryl chlorides is usually attributed to the strength of the
C-Cl bond (bond dissociation energies for Ph-X: Cl = 96 kcal mol-1; Br = 81 kcal mol-1; I = 65
kcal mol-1) which leads to a reluctance of aryl chlorides toward oxidative addition to transition
metal centers, a critical step in many transition metal-catalyzed coupling reactions.[20]
In our original nickel-mediated reductive homocoupling, the active nickel(0) complex
was generated from a nickel(II) salt and Zn dust as reducing agent in the presence of
triphenylphosphine as ligand.[14] In order to simplify and possibly to improve this procedure
we have now considered the direct use of a nickel(0) source. The successful use of the
commercially available zerovalent nickel complex Ni(COD)2 (COD = 1,5-cyclooctadiene) in
related homocoupling reactions of aryl bromides or iodides (Scheme 1)[24,25] prompted us to
apply these conditions also to the homocoupling of 4-chloro-1-methylquinolin-2-(1H)-one 2a
as a model substrate (Table 1).[24,25]
Nickel(0)-Catalyzed Homocoupling Reaction 34 Table 1. Reaction optimization for the nickel(0)-mediated reductive homocoupling of 4-
chloroquinolone 2a using Ni(COD)2.[a]
NMe
O
Cl
NMe
O
N OMe
2a
1a
Ni(COD)2, 2,2'-dipyridyl, solvent, KI
MW,120-195 °C, 25-35 min
entry Ni(COD)2
(equiv)
2,2´-dipyridyl
ligand (equiv)
KI additive
(equiv)
time [min] solvent / temp
[°C]
product
distribution
(%)[b]
1 0.50 1.0 - 25 DMF / 195 40/52/8
2 0.75 1.0 - 25 DMF / 195 0/97/3
3 0.75 - - 25 DMF / 195 20/75/5
4 0.75 1.0 - 35 dioxane / 130 10/90/0
5 0.75 1.0 0.5 35 dioxane / 130 0/99/1c
6 0.75 0.5 0.5 35 dioxane / 130 5/94/1
7 0.75 1.0 0.5 35 THF / 120 9/80/11
8 0.75 1.0 0.5 55 DMSO / 160 17/73/10 [a] Reaction conditions: 0.25 mmol chloroquinolone 2a, Ni(COD)2, 2,2´-dipyridyl, KI, 1.5 mL dry solvent, sealed vessel
single mode microwave irradiation. See the Experimental Section for further information. [b] Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215 nm) traces: starting material 2a
/product 1a/dehalogenated product. [c] Product isolation by filtration through Celite, evaporation, and subsequent recrystallization furnished a 93% yield of
bisquinolone 1a.
All optimization studies were performed on a 0.25 mmol scale using sealed vessel
microwave heating in order to extend the available temperature range above the boiling point
of the individual solvent.[27] An extensive optimization of the reaction parameters included the
amount of the nickel reagent, the type and concentration of additional ligands, the use of other
additives, different solvents, reaction time and temperature. While aryl bromides and iodides
have been shown to undergo this type of coupling of this type with relative ease,[24,25] only one
example of a reductive homocoupling which involves an aryl chloride is known, providing a
mere 14% product yield.[24] In these transformations, the oxidative addition generally is the
rate-limiting step (Scheme 1). Aryl halides which have comparatively small dissociation
energies (e.g., aryl iodides) will undergo faster oxidative addition to the metal center and
Nickel(0)-Catalyzed Homocoupling Reaction 35
L = solvent or COD- 2 L
LnNi(0) + ArX [LnNi ][ArX] Ni(I)X+ Ar
Ni(I)X + ArX ArNi(III)X2
ArNi(III)X2 + ArNi(III)X2 Ar2Ni(III)X + Ni(II)X2
Ar2Ni(III)X Ar-Ar + Ni(I)X
ArX + L4Ni(0) Ni(II)
X
Ar L
Lox. add.
Ni(II)
X
Ar L
L
+ ArX [ArNi(III)XL2] [ArX]chain start
chainpropagation
Scheme 1. Proposed mechanism of Ni(0)-mediated homocouplings of aryl halides using Ni(0)
species.[26]
ultimately will show a higher reactivity in the reductive homocoupling.[24] Since there is no
regeneration mechanism in this homocoupling, (stoichiometric amounts of Ni(COD)2 have
to be employed in order to achieve full conversion. In the case of 4-chloro-1-methylquinolin-
2-(1H)-one 2a the use of 0.75 equivs. of the sensitive Ni(COD)2 reagent (1.5 equivs. per biaryl
product) provided the best results. Lowering the amount of Ni(COD)2 led to incomplete
conversions (Table 1, entry 1), with the only observed by-product being the dehalogenated
quinolone.[14] Nickel(0)-mediated homocoupling reactions routinely rely on additional
ligands,[12,24-26,28] which stabilize the catalyst and the arylnickel species during the reaction
sequence and restrict decomposition. In the present case, 1.0 equivalent of 2,2′-dipyridyl
exhibited an optimum effect on the observed conversion (compare entries 2 and 3). Close to
quantitative conversions were observed by heating the reaction mixture in DMF at 195 °C for
25 min. Under these conditions, only very small amounts of the dehalogenated side-product,
1-methylquinolin-2-(1H)-one, were observed by HPLC monitoring. Ultimately, we found that
optimum results were achieved by switching to anhydrous dioxane as a solvent, which allowed
reduction of the reaction temperature to 130 °C. Further improvements were made by adding
0.5 equivalents of potassium iodide as an additive since it is known that iodide ions enhance
the reaction rate of nickel-catalyzed homocoupling reactions (compare entries 4 and 5).[28]
Under optimized reaction conditions (Table 1, entry 5), full conversion to bisquinolone 1a was
Nickel(0)-Catalyzed Homocoupling Reaction 36 observed within a 35 min reaction time with only 1% of the dehalogenated by-product formed.
Gratifyingly, product isolation in this case did not require chromatography and simply
involved filtration through a Celite pad, evaporation of solvent, and recrystallization of the
crude product from acetonitrile to provide a 93% isolated product yield of the desired
bisquinolone 1a. This protocol could be scaled to 1.0 mmol to provide 1a in ca. 100 mg
quantity. Despite this fact, the high cost and pronounced air sensitivity of the Ni(COD)2
reagent,[17] employed in almost stoichiometric amounts, precluded this method from being
used for the preparation of larger quantities of bisquinolones.
OPPh2 PPh2
PPh2
Ph2PFe
DPEphos dppf
Figure 3. Structures of bidentate ligands DPEphos and dppf.
We therefore turned our attention again to our original reductive homocoupling
protocol starting from a nickel(II) source in the hope to turn the stoichiometric method into a
catalytic version that would require less metal, and therefore also a smaller amount of the
reducing agent and, most importantly, less ligand which would greatly simplify the
purification process and thus make this method scalable. A number of examples involving the
Ni-mediated homocoupling of aryl chlorides to biphenyls have been reported in the
literature.[29,30] In this context, several sources of nickel(II) were evaluated under the originally
reported in situ reductive conditions using zinc dust.[14 In addition, in light of the results
obtained with Ni(COD)2, the solvent system was changed from DMF to dioxane. In our
originally reported protocol requiring stoichiometric amounts of an Ni source using DMF as
solvent,[14] we assume that the reductive elimination step is not favorable, therefore not
allowing the regeneration of the active Ni(0) species. The use of DMF or other coordinating
dipolar aprotic solvents will likely lead to de-coordination of ligands from the Ni(0) complex
and to the formation of undesired side products.[30] Employing dioxane as solvent, most of the
tested nickel(II) salts/complexes such as NiCl2, NiCl2(PPh3)2, NiCl2(dppe), NiCl2(dppf) and
Ni(acac)2 were effective in the desired homocoupling (Table 2). In all cases the only by-
product was the dehalogenated quinolone. By adding an additional amount of a bidentate
Nickel(0)-Catalyzed Homocoupling Reaction 37 Table 2. Catalyst/ligand screening for the nickel(0)-mediated reductive homocoupling of 4-
chloroquinolone using Ni(II) complexes.[a]
NMe
O
Cl
NMe
O
N OMe
2a
1a
Ni-catalyst, ligand, dioxane, Zn, KI
MW, 130 °C, 30 min
[a] Reaction conditions: 0.25 mmol chloroarene 2a, Ni-catalyst, ligand, 1.3 equivs. Zn dust, 1.8 equivs. KI, 1 mL dry dioxane, sealed vessel single mode microwave irradiation at 130 °C for 30 min.
entry catalyst (mol%) additive (mol%) Product
distribution(%)[b]
1 NiCl2(PPh3)2 (10) dppf (20) 0/61/39
2 NiCl2(PPh3)2 (20) dppf (10) 0/87/13
3 NiCl2(PPh3)2 (20) dppf (20) 0/91/9[c]
4 NiCl2(dppe) (20) dppf (20) 0/68/32
5 NiCl2(dppf) (25) dppf (25) 0/71/29
6 Ni(acac)2 (25) dppf (25) 1/65/34
7 NiCl2(PPh3)2 (25) DPEphos (25) 0/91/9[d]
[b] Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215 nm) traces: starting material 2a /product 1a/ dehalogenated product.
[c] Product isolation by flash chromatography provided a 86% yield of bisquinolone 1a. [d] For an 11-mmol run, product isolation by an extractive work-up and recrystalliza-tion led to 74%
yield of isolated pure product.
ligand (see mechanistic discussion below), such as bis(2-diphenylphosphinophenyl)ether
(DPEphos) or diphenylphosphinoferrocene (dppf) (Figure 3) to the reaction mixture, the
amount of the required nickel(II) complex could be reduced to 20 mol% and the
dehalogenation pathway could be largely suppressed (entries 3 and 7).
One of the best sets of conditions (entry 3) employed 20 mol% of NiCl2(PPh3)2 as
Ni(II) complex and 20 mol% of dppf as ligand employing the traditional reductive
environment (1.3 equivs. Zn dust, 1.8 equivs. KI). Microwave heating of the reaction mixture
at 130 °C for 30 min provided full conversion to the bisquinolone product with less than 10%
of the dehalogenated by-product being formed (86% isolated yield by flash chromatography).
Equally high selectivity and efficiency toward homocoupling was displayed employing
DPEphos as a ligand system, albeit using a 25 mol% catalyst and ligand loading (entry 7).
Nickel(0)-Catalyzed Homocoupling Reaction 38
While both methods required only 0.20-0.25 equivs. of the relatively inexpensive
nickel(II) complex NiCl2(PPh3)2 as catalyt,[17] the true advantage lies in the fact that here
chromatography is not required to separate triphenylphosphine and the additional
dppf/DPEphos ligands from the bisquinolone product. Notably, the use of DPEphos (entry 7)
provides equally high conversions as dppf (entry 3), but is the ligand of choice due to the
significantly lower cost.[17] We have therefore performed a ca. 40-fold scale-up of the
experiment described in entry 7 employing 11 mmol of chloroquinolone 2a as starting
material employing a larger microwave process vial (11-mL reaction volume). Gratifyingly,
monitoring the crude reaction mixture by HPLC demonstrated the full scalability of this
process: again, less then 10% of the unwanted dehalogenated quinolone was observed, with
HPLC traces being nearly indentical to those of the small scale experiment. In the purification
procedure, the dioxane solvent was evaporated under reduced pressure. After addition of
acetonitrile and warming to ca. 80 °C the crude reaction mixture was filtered through a pad of
Celite. Since DPEphos is nearly insoluble under those conditions, most of the ligand material
could be removed. Evaporation of the acetonitrile solvent furnished the crude bisquinolone
product which was subsequently dissolved in dichloromethane and washed three times with
saturated aqueous ammonium chloride solution. Evaporation of dichloromethane and
recrystallization of the crude material from acetonitrile provided bisquinolone 1a in 74% yield
(purity > 99% by HPLC at 215 nm).
In order to evaluate the general applicability of this homocoupling protocol, a number
of different 4-chloroquinolone substrates (in addition to 4-chlorocoumarin)[14] were subjected
to the optimized coupling protocol outlined above (Table 2). Utilizing the optimized catalytic
method detailed in Table 2 (entry 7), all substrates did undergo homocoupling to the respective
biaryl derivatives in >98% conversion and with very high selectivity. The amount of
dehalogenated by-products in most cases was below 5%. In fact, we find that this new protocol
involving catalytic amounts of NiCl2(PPh3)2 in combination with DPEphos as ligand provides
equally high isolated product yields (71-92%) compared to our previously published method
employing stoichiometric amounts of a Ni(II) source.[14] In most cases, the extractive work-
up/purification elaborated above specifically for bisquinolone 1a was also successful for other
biaryl derivatives, although the isolated yields using this non-chromatographic method were
not always as high as when using standard flash chromatography (Table 3).
Nickel(0)-Catalyzed Homocoupling Reaction 39 Table 3. Nickel(0)-mediated reductive homocoupling of 4-chloroquinolone using
NiCl2(PPh3)2 and DPEphos.[a]
NiCl2(PPh3)2, DPEphos, Zn, KIdioxane
MW, 130 °C, 30 min(Het)Ar-Cl (Het)Ar-Ar(Het)
2 1
entry substrate yield [%][b]
1
NMe
O
Cl
85 (69)
2
N O
Cl
92 (39)
3
NMe
O
ClMeO
71 (−)[c]
4
NMe
O
Cl
MeO
79 (45)
5
NMe
O
Cl
MeO
MeO
83 (34)
6
O O
Cl
92 (73)
[a] Reaction conditions: 0.50 mmol chloroarene 2, 25 mol% NiCl2(PPh3)2, 25mol% DPEphos, 1.3 equivs. Zn dust, 1.8 equivs. KI, 0.8 mL dry dioxane, sealed vessel single mode microwave irradiation at 130 °C for 30 min.
[b] Isolated yields of pure product using flash chromatography. In parenthesis, isolated yields obtained by extractive work-up and recrystallization (see Experimental Section).
[c] Due to the insolubility of this material in acetonitrile, the extraction procedure was not successful in this case.
Nickel(0)-Catalyzed Homocoupling Reaction 40 3. Mechanistic Discussion
It is known that bidentate ligands such as dppf (Figure 3) increase the electron density on low-
valent transition metals, making the metal more nucleophilic, thus facilitating the oxidative
additionand reducing the propensity for reductive elimination.[26,31] The use of NiCl2(dppf) in
the presence of an additional amount of dppf (Table 2, entry 5) may lead to the formation of a
rather stable coordinatively saturated Ni(0) ligand complex (Figure 4) with tetrahedral
geometry having large ligand bite angles (dppf = 96°). This reduces the accessibility for
oxidative addition.[32] In contrast, a co-ordinatively unsaturated Ni(0) complex generated from
NiCl2(PPh3)2 and dppf (Figure 4) is more efficient toward oxidative addition and will enhance
the overall efficiency of the catalytic cycle.[32] In the specific homocoupling reaction described
in Table 2, NiCl2(PPh3)2 has proven to be more efficient and selective than the bidentate ligand
catalyst NiCl2(dppf) (compare entries 3 and 5). NiCl2(PPh3)2 is surrounded by monodentate
ligands and is thus more efficient to generate coordinatively reactive Ni(0) in situ in the
presence of an additional dppf ligand.
NiCl
Cl
P
P
Ph
PhPh
Ph
PhPh
(II)
NiCl2(PPh3)2
dppfNiPh3P
PP
co-ordinatively unsaturatedNi(0) complex
faster towardoxidative addition
NiCl
Cl
P
P
PhPh
PhPh(II)
NiCl2(dppf)
dppfNi
PP
co-ordinatively saturatedstable Ni(0) complex
slower towardoxidative addition
(0)
(0)PP
dppf
Fe
Figure 4. Difference in catalytic activity of coordinatively unsaturated and saturated Ni(0)
complexes.
Nickel(0)-Catalyzed Homocoupling Reaction 41 4. Conclusion
In summary, we have developed a Ni(0)-catalyzed reductive homocoupling reaction of easily
accessible 4-chloroquinolin-2(1H)-ones that provides 4,4′-bisquinolones in good yields. In
contrast to our previous protocol,[14] this new method only requires 0.25 equivalents of a
comparatively inexpensive Ni source and does not rely on chromatography for product
isolation. Key to the success was a change of solvent and the combined use of bidentate and
monodentate ligands providing more active Ni(0) catalytic species. The method is therefore
scalable and will allow us to further study the properties of these novel types of
bisheterocylces.
5. Experimental Section
General Methods All homocoupling reactions involving air-sensitive reagents were carried out under an
atmosphere of dry argon. Dry flash chromatography[33] was performed on Merck Silica gel 60
H (< 45 nm particle size). TLC analyses were performed on pre-coated (Merck Silica gel 60
HF254 ) plates. 1H NMR and 13C NMR spectra were recorded on a Bruker AMX360 and 500
instrument in CDCl3 or DMSO-d6 at 360 and at 90 MHz respectively. Melting points were
obtained on a Gallenkamp melting point apparatus, Model MFB-595 in open capillary tubes.
FT-IR spectra were recorded on Perkin-Elmer 298 spectrophotometer using KBr pellets. Low
resolution mass spectra were obtained on an Hewlett-Packard LC/MSD Agilent 1100 series
instrument using atmospheric pressure chemical ionization (APCI) in positive or negative
mode. Analytical HPLC analysis was carried out on two different Shimadzu systems. The
Shimadzu LC-10 includes LC10-AT(VP) pumps, an autosampler (S-10AXL), and a dual
wavelength UV detector. The separations were carried out using a C18 reversed phase
analytical column, LiChrospher 100 (E. Merck, 100 x 3 mm, particle size 5 µm) at 25 °C and a
mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN and (B) 0.1 % TFA acid in MeCN
(all solvents were HPLC grade, Acros; TFA was analytical reagent grade, Aldrich). The
following gradient was applied: linear increase from solution 30 % B to 100% B in 7 min,
hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min. The Shimadzu LC-20
system includes a LC-20AD pump, a SIL-20A autosampler, a diode array detector (SPD-
M20A), a column oven (CTO-20A) and a degasser (DGU-20A5). The separations were carried
Nickel(0)-Catalyzed Homocoupling Reaction 42 out using a Pathfinder®AS100 reversed phase analytical column (150 x 4.6 mm, particle size 5
µm) at 25 °C and a mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN and (B) 0.1 %
TFA acid in MeCN (all solvents were HPLC grade, Acros; TFA was analytical reagent grade,
Aldrich). The following gradient was applied: linear increase from solution 20 % B to 100%
B in 7 min, hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min.
The 4-hydroxyquinolin-2-one precursors required for the preparation of
chloroquinolones (Table 3, entry 1-6) were obtained from Aurora Feinchemie GmbH. Zn-
powder (Merck 108789, < 60 μm particle size) was used for the Ni(0)-mediated
homocouplings. All anhydrous solvents (stored over molecular sieves), catalysts and ligands
were obtained from standard commercial vendors and were used without any further
purification. Solvents for column chromatography have been distilled prior to use.
Microwave Irradiation Experiments
Microwave-assisted synthesis was carried out in an Emrys™ Synthesizer or Initiator 8 single-
mode microwave instrument producing controlled irradiation at 2.450 GHz (Biotage AB,
Uppsala), including proprietary Workflow Manager Software (version 2.1). Experiments were
carried out in sealed microwave microwave (2 to 5 mL filling volume) process vials utilizing
the standard absorbance level (300 W maximum power). Reaction times under microwave
conditions refer to hold times at the temperatures indicated, not to total irradiation times. The
temperature was measured with an IR sensor on the outside of the reaction vessel.
Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 2a using Bis(1,5-
cyclooctadiene)nickel(0) A mixture containing 48.4 mg (0.25 mmol) of 4-chloro-1-methylquinolin-2(1H)-one (2a),[34]
51.7 mg (0.188 mmol, 0.75 equivs.) of Ni(COD)2, 39.0 mg (0.25 mmol, 1.0 equiv.) of 2,2´-
dipyridyl, and 20.8 mg (0.125 mmol, 0.50 equivs.) of KI was suspended in 1.0 mL of
anhydrous dioxane under an argon atmosphere in a 5-mL Pyrex microwave vial equipped with
a magnetic stirring bar. The vial was sealed, stirred for 4 min at room temperature, and then
heated for 35 min at 130 °C. Thereafter, the solvent was removed under reduced pressure, the
remaining residue dissolved in CH2Cl2 and filtered through a small pad of Celite. Evaporation
of the solvent and recrystallization of the resulting crude material from acetonitrile delivered
pure bisquinolone 1a; yield: 36.8 mg (93%).
The reaction was also performed on a 1.0-mmol scale (130 °C for 55 min) providing
the same product yield.
Nickel(0)-Catalyzed Homocoupling Reaction 43 Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 2a using
Bis(triphenylphosphine)nickel(II) Dichloride and Diphenylphosphino-
ferrocene. A mixture containing 48.4 mg (0.25 mmol) of 4-chloro-1-methylquinolin-2(1H)-one (2a),
32.7 mg (0.05 mmol, 20 mol%) of NiCl2(PPh3)2, 27.7 mg (0.05 mmol, 20 mol%) of
diphenylphosphinoferrocene (dppf), 21.2 mg (0.324 mmol, 1.3 equivs.) of Zn powder and 74.7
mg (0.45 mmol, 1.8 equivs.) of KI was suspended in 1.0 mL anhydrous dioxane under an
argon atmosphere in a 5-mL Pyrex microwave process vial equipped with a magnetic stirring
bar. The vial was sealed, the mixture was stirred for 4 min at room temperature, and then
heated by microwave irradiation for 30 min at 130 °C. Thereafter, the solvent was removed
under reduced pressure. The product was isolated by gradient dry flash chromatography using
EtOAc/acetone as solvent mixture to obtain pure bisquinolone 1a; yield: 34.0 mg (86%).
Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 2a using
Bis(triphenylphosphine)nickel(II) Dichloride and DPEphos. A mixture containing 2.13 g (11 mmol) of 4-chloro-1-methylquinolin-2(1H)-one (2a), 1.8 g
(2.75 mmol, 25 mol%) of NiCl2(PPh3)2, 1.48 g (2.75 mmol, 25 mol%) of DPEphos, 935 mg
(14.3 mmol, 1.3 equivs.) of Zn powder and 3.29 g (19.82 mmol, 1.8 equivs.) of KI was
suspended in 11mL anhydrous dioxane under an argon atmosphere in a 20-mL Pyrex
microwave vial equipped with a magnetic stirring bar. The vial was sealed, the mixture was
stirred for 4 min at room temperature, and then heated for 30 min at 130 °C. In the purification
procedure, dioxane solvent was evaporated under reduced pressure. After addition of 60 mL of
acetonitrile and warming to ca. 80 °C the crude reaction mixture was filtered through a pad of
Celite to remove insoluble DPEphos ligand in addition to most of the triphenylphosphine
ligand. Evaporation of the acetonitrile solvent furnished the crude bisquinolone product
contaminated with small quantities of triphenylphosphine which was subsequently dissolved
in 400 mL of dichloromethane and washed three times with 150 mL of saturated aqueous
ammonium chloride solution (to remove inorganic potassium iodide). Drying of the organic
phase over anhydrous MgSO4, filtration through a pad of Celite, evaporation of
dichloromethane and subsequent recrystallization (2 times) from acetonitrile provided
bisquinolone 1a; yield: 1.28 g (74%, purity > 99% by HPLC at 215 nm).
Nickel(0)-Catalyzed Homocoupling Reaction 44 Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 1-5 using
Bis(triphenylphosphine)nickel(II) Dichloride and DPEphos A mixture containing 0.50 mmol of the corresponding Chloroarene (Table 3, entry 1-5), 81.8
mg (0.125 mmol, 25 mol%) of NiCl2(PPh3)2, 67.3 mg (0.125 mmol, 25 mol%) of DPEphos,
42.5 mg (0.65 mmol, 1.3 equivs.) of Zn powder and 149.4 mg (0.90 mmol, 1.8 equivs.) of KI
was suspended in 0.8 mL anhydrous dioxane under an argon atmosphere in a 5-mL Pyrex
microwave process vial equipped with a magnetic stirring bar. The vial was sealed, the
mixture was stirred for 4 min at room temperature, and then heated by microwave irradiation
for 30 min at 130 °C. Thereafter, the solvent was removed under reduced pressure. The
products were isolated by gradient dry flash chromatography using EtOAc/acetone as solvent
mixture to obtain the pure biaryls (Table 3, entry 1-5); yield: 71-92%.
Alternatively, products were isolated using an extractive work-up/purification
method as described above for compound 1a. Yields for both protocols are given in Table 3.
NMe
O
N OMe
C20H16N2O2
4,4´-Bis-(1-methylquinolin-2(1H)-one) (Table 3, entry 1):
Mp 283-284°C (acetonitrile). IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ 3.71
(s, 6H), 6.67 (s, 2H), 7.11-7.17 (m, 4H), 7.64-7.67 (m , 4H); 13C NMR (90 MHz, DMSO-d6)
δ 29.8, 115.8, 119.6, 121.6, 122.7, 127.3, 131.8, 140.2, 146.1, 160.9; MS (pos. APCI) m/z 317
(25, M + 1), 316 (100, M). Anal. Calcd for C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C,
75.95; H, 4.98; N, 8.78.
Nickel(0)-Catalyzed Homocoupling Reaction 45
N O
N O
C24H20N2O2
7,7´-Bis-(2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one) (Table 3, entry 2):
Mp 270°C dec. (acetonitrile); IR (KBr) νmax 1637 cm-1; 1H NMR (360 MHz, DMSO-d6) δ
2.02-2.13 (m, 4H), 2.99 (t, J = 5.8 Hz, 4H), 4.13 (t, J = 5.6 Hz, 4H), 6.62 (s, 2H), 6.96 (d, J =
7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 6.98 Hz, 2H); 13C NMR (90 MHz, DMSO-
d6) δ 20.6, 27.8, 42.6, 119.7, 121.4, 121.9, 125.3, 125.4, 130.5, 136.8, 146.4, 161.2; MS (pos.
APCI) m/z 368 (100, M).
NMe
O
N OMe
MeOMeO
C22H20N2O4
4,4´-Bis-(6-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 4):
Mp 256-258°C (ethanol); IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ 3.58 (s,
6H), 3.69 (s, 6H), 6.57 (d, J = 2.8 Hz, 2H), 6.66 (s, 2H), 7.34 (dd, J = 9.25 and 2.8 Hz, 2H),
7.62 (d, J = 9.29 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ 29.8, 55.8, 110.0, 115.9, 119.4,
120.4, 122.5, 134.7, 145.5, 154.8, 161.1; MS (pos. APCI) m/z 377 (25, M + 1), 376 (100, M).
NMe
O
N OMe
MeO
MeO
C22H20N2O4
4,4´-Bis-(7-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 5):
Mp 232-234°C (ethanol); IR (KBr) νmax 1658 cm-1; 1H NMR (360 MHz, DMSO- d6) δ 3.67 (s,
Nickel(0)-Catalyzed Homocoupling Reaction 46 6H), 3.89 (s, 6H), 6.45 (s, 2H), 6.76 (d, J = 8.67 Hz, 2H), 7.04-7.07 (m, 4H); 13C NMR (90
MHz, CDCl3) δ 29.8, 56.2, 99.7, 110.8, 113.5, 117.9, 128.8, 142.0, 146.3, 161.5, 162.3; MS
(pos. APCI) 377 (25, M + 1), 376 (100, M). Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36;
N, 7.44. Found: C, 70.23; H, 5.26; N, 7.37.
NMe
O
N OMe
MeO
MeO
MeOC24H24N2O6
MeO
4,4´-Bis-(6,7-dimethoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 6):
Mp 276-277 °C dec. (ethanol); IR (KBr) νmax 1642 cm-1; 1H NMR (360 MHz, DMSO-d6) δ
3.45 (s, 6H), 3.74 (s, 6H), 3.96 (s, 6H), 6.46 (s, 2H), 6.57 (s, 2H), 7.09 (s, 2H); 13C NMR (90
MHz, CDCl3) δ 30.0, 56.2, 56.4, 97.6, 108.2, 112.7, 119.1, 136.1, 145.2, 145.8, 152.8, 162.0;
MS (pos. APCI) m/z 437 (50, M + 1), 436 (100, M).
O O
O O
C18H10O4
4,4´-Bis-(2H-chromen-2-one) (Table 3, entry 7):
Mp 215-216°C (acetonitrile; lit.20 Mp 215 °C); 1H NMR (360 MHz, CDCl3) δ 6.50 (s,
2H), 7.22-7.24 (m, 4H), 7.47 (d, J = 8.42 Hz, 2H), 7.60-7.65 (m, 2H). MS (pos. APCI)
m/z 291 (95, M + 1), 290 (45, M), 252 (100, M – 38), 236 (M – 54).
Nickel(0)-Catalyzed Homocoupling Reaction 47 6. References
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Absorption and Emission Characteristics of Bisquinolones 50 D Bisquinolones as Chiral Fluorophores – A Combined
Experimental and Computational Study of
Absorption and Emission Characteristics
Graphical Abstract
NR1
O
X
N OR1
NOR1
R3
R2
R2
R3
R3
R2
NR1
O
R3
R2
R4
N
O
OCH3
N OCH3
O
O
O
O
NR1
O
NN
N
R3
R2
N O
R3
R2
R1
X = Cl, BrR1 = H, MeR2 = H, OMeR3 = H, OMe, CF3, OHR4 = H, OMe, CN
Absorption and Emission Characteristics of Bisquinolones 51 Abstract
Biscarbostyrils (4,4’-bisquinolones) can be synthesized from 4-chloro-2-quinolinones using a
Pd-catalyzed one-pot borylation/Suzuki cross-coupling protocol or via Ni(0)-mediated
reductive homocoupling. The electronic spectra of biscarbostyrils 4b-8 exhibit unusual
properties in comparison to the corresponding carbostyrils 1-3. Similar absorption spectra are
accompanied by red-shifted emission maxima up to 520 nm. Unsubstituted biscarbostyril 4b
displays the unusual property of a blueshift in dimethylsulfoxide as compared to water. For a
set of diversely substituted biscarbostyrils and related 4-aryl-2-quinolinones very selective
substitution patterns in order to increase fluorescence quantum yields are observed. In
bisquinolone 7, an additional diphenylphosphinoxide substitution in position 3 and 3´
increased the quantum yield to 0.2 and the epsilon value to 25000. A crown ether linkage
from position 6 to 6´ in biscarbostyrils improved the emission maximum from 470 to 500nm,
but the fluorescence quantum yield only from 0.03 to 0.06. Time-dependent density
functional calculations of absorption and emission spectra of selected derivatives show good
agreement with the corresponding experimental data. Especially, the large Stoke’s shift
observed for biscarbostyrils as well as their rather low fluorescence quantum yields can be
rationalized on the basis of these calculations. Like 1,1´ binaphthalenes the biscarbostyril
structures are axially chiral. Most of the enantiomers were baseline HPLC separated on the
Pirkle type ULMO column, with separation factors of up to 2.5. As expected for this π-acidic
chiral stationary phase electron donating methoxy substituents improve separation behavior.
1. Introduction
In addition to the traditional coumarin-based fluorophores,[1] comparatively few derivatives
of the structurally related quinolin-2(1H)-ones (carbostyrils) have found applications as
fluorescence markers.[2] Today, mainly “carbostyril 124” (7-amino-4-methylquinolin-2(1H)-
one) is known as fluorescent dye, whereas for enzymatic essays N-acylated versions of
“carbostyril 124” are used routinely. Recently, we have shown in a systematic study that
suitable functionalization of carbostyrils leads to derivatives with absorption and emission
characteristics comparable to those of coumarins.[3-5] For example, 4-trifluoromethyl
analogue 3b (Table 1) has an absorption maximum of 370 nm, an emission maximum of 440
nm, and a quantum yield of ca. 0.5,[4,8] which compares favorably with unsubstituted
Absorption and Emission Characteristics of Bisquinolones 52 carbostyril 1 and the 6,7-dimethoxy substituted analogue 2 (λmax(abs) 338 and 351 nm,
λmax(em) 396 and 402 nm, and fluorescence quantum yield 0.02 and 0.11). Carbostyrils are
more resistant towards pH changes (ring opening) and other thermal or chemical (oxidative
damage) bleaching reactions.[6] Moreover, they are easily functionalized, leading to versatile
fluorescent tags for proteins or polysaccharides.[7,8] Their photophysical properties and
chemical stability, thus, makes this class of compounds useful for bioconjugation in aqueous
media. Our group has also published a pH sensor measuring europium luminescence decay
time dependent on the protonation of bromothymol blue with a sol-gel embedded 3-
acylamino-4-trifluoromethyl-6,7-dimethoxycarbostyril europium complex.[9]
In recent years 4,4’-biscarbostyrils of type 4b, aza-analogues of biscoumarin natural
products (e.g., 4,4’-biisofraxidin[10]), have become readily available.[11] In view of the intense
long-wavelength fluorescence of photolabile bisisoquinolinones, e.g. for 6,6'-dimethoxy-2,2'-
diphenyl-2H,2'H-[4,4']biisoquinolinyl-3,3'-dione 4a[12] we wondered whether suitably
modified 4,4’-biscarbostyrils also would exhibit similar bathochromic shifts of their
absorption and emission bands. Furthermore, the anticipated axial chirality of these
derivatives offers the possibility for chiral recognition. Along similar lines, they also might
serve as ligands in asymmetric catalysis. Recently, biscarbostyril-based mono- and
diphosphine ligands of the aza-BINAP type have been reported.[13] Here we present a
combined experimental and computational study on 4,4’-biscarbostyrils 4–9b and compare
their photophysical properties with monomeric carbostyrils 1–3 and the isomeric 6,6'-
dimethoxy-2H,2'H-[4,4']biisoquinolinyl-3,3'-dione 4a. In addition, results for 4-aryl- (10a–
c), 4-heteroaryl- (11a–c), and 4-arylethinylcarbostyrils (12a,b) are presented. Experimental
absorption and fluorescence characteristics are also provided for the crown ether derivative
13 and the diphenyl phosphine- and phosphine oxide analogues as well as their bromine-
containing precursors 14–17c.[13] Since all investigated bisquinolones are axially chiral, a
HPLC study of enantioseparation effects on the Pirkle type chiral stationary phase (CSP)
ULMO is also presented.
2. Results and Discussion
2.1. Fluorescence: The first part in Table 1 shows fluorescence data of previously
investigated carbostyrils 1-3[4,5] compared with 4,4´-bisquinolones 4b-9b.[11] Due to the
synthetic protocol for the biscoupling reactions requiring previous N-methylation,[12] all
Absorption and Emission Characteristics of Bisquinolones 53 Table 1. Electronic spectra of all investigated compounds
Compound Solvent λmax e λmax exc λmax em Φ structure
1 DMSO 331 4250 340 380 0.023
H2O 326 4850 335 373 0.011
2 DMSO 351 5500 355 402 0.092
H2O 338 6000 343 396 0.071
3a DMSO 390 12400 400 436 0.610
H2O 380 11000 385 432 0.500
3b DMSO 370 9700 375 440 0.346
H2O 360 9700 365 430 0.331
4a DMF 505 28000 - 540 - O
N
NH3CO PhH3CO Ph
O
4b DMSO 340 11300 340 425 0.008
H2O 333 10800 330 470 0.016
5 DMSO 366 7800 370 475 0.028
H2O x quench
6 DMSO 350 8500 342 425 0.027
H2O 344 9500 330 458 0.009
7 DMSO 357 10000 360 495 0.039
H2O quench
8 DMSO 355 11900 358 500 0.052
DMSO* 340 8100 345 470 0.013
H2O 346 12200 520 0.006
9a DMSO 352 10500 360 505 0.003
9b
DMSO* 335 340 405 0.002
DMSO 335 9200 340 406 0.002
Absorption and Emission Characteristics of Bisquinolones 54
10a DMSO 355 9800 365 431 0.023
10b
H2O 346 350 431 0.008
DMSO 354 9200 365 428 0.027
10c
H2O 346 350 428 0.009
DMSO 363 9200 374 505 0.008
11a
H2O 360 360 470 0.006
DMSO 345 6200 352 411 0.016
11b DMSO 345 5800 350 415 0.020
11c DMSO 360 6500 365 450 0.185
12a DMSO 355 7700 355 425 0.005
12b DMSO 385 9000 385 460 0.057
13 DMSO 375 7900 380 500 0.060
Absorption and Emission Characteristics of Bisquinolones 55
14a
H2O 359 7500 350 500 0.001
DMSO 362 9700 362 437 0.010
14b DMSO 375 13200 375 438 0.001
15a DMSO 365 23900 365 430 0.002
15b DMSO 380 21000 400 470 0.008
15c
H2O 376 20400 400 490 0.001
DMSO 380 25600 395 470 0.189
16a DMSO 339 9800 340 430 0.002
16c DMSO 355 9300 354 430 0.016
17a
DMSO* 340 8800 340 420 0.005
DMSO 341 14000 341 420 0.003
17c DMSO 358 16600 360 415 0.015
* double maximum
Absorption and Emission Characteristics of Bisquinolones 56 carbostyrils with the exemption of 2 and 12b in the Table were prepared as the N1-
methylated species. Because of this synthetic requirement, they do not allow the formation
of the 2-OH tautomers. We have recently shown,[7,14] that absorption and emission maxima of
the N-alkylated derivatives are very similar to the NH varieties. Independent on the
substituent at N1, all carbostyrils exhibit a slight excitation and emission blue-shift in water
compared with DMSO. The recently published carbostyril 3a, having a cyano group in
position 4, had remarkable properties: it displayed an independence of emission maxima (ca
430 nm) and fluorescence quantum yields (about 0.5) in water, polar and apolar solvents.[8]
Interestingly, unsubstituted biscarbostyril 4b showed an absorption maximum of 340
nm in DMSO and 333 nm in water not much different from the parent carbostyril 1. To our
surprise, however, the (low yielding) emission maximum was 425 nm in DMSO and 470 nm
in water. Compound 1 had emitted at 380 and 373 nm, respectively. In water, 4b was red
shifted even compared with the best push-pull substituted 6,7-dimethoxycarbostyril 3a,
generally emitting at shorter wavelength than in DMSO.
As a consequence, we assumed that biscarbostyrils 5-9b would top all emission data
of simple 6,7-dimethoxycarbostyrils. However, this was only the case in terms of a somewhat
longer wavelength emission and hence larger Stoke´s shifts. Fluorescence quantum yields
were low even in DMSO and to our surprise methoxy substituents quenched emission in
water almost completely. This was not at all the case in the emission spectra of the above
mentioned 4-cyano analogue 3a,[8] and we had observed only an about 15-50% decrease in
300 350 400 450 500 550 600λ (nm)
Int (
au)
4b - exc 4b - em 8 - exc 8 - em 5 - exc 5 - em
Figure 1. Electronic spectra of unsubstituted biscarbostyril 4b, the mixed 6,7-dimethoxy/6,7-
H analogue 8 and the symmetrical 6,6´-dimethoxy-biscarbostyril 5.
Absorption and Emission Characteristics of Bisquinolones 57 the 4-CF3 series.[7] Studies of unsymmetrical biscarbostyril 8 in dichloromethane and in
glycerol at -30°C did not increase fluorescence, hence quenching is not affected by the
polarity or viscosity of the environment.
A remarkable feature of the mixed substitution in 8 and 9a is a fluorescence double
maximum representing both single carbostyril parts. This must be due to the perpendicular
arrangement of the carbostyril subunits and hence both parts behave just as single
chromophores. The symmetrical example 9b exhibits the characteristics of the shorter
wavelength absorbing trifluoromethyl part of 9a. The emission spectra of 8 can not be
completely separated but the mean emission wavelength is lowered to 470 nm if excitation
occurs at 340 nm, the maximum of the unsubstituted species 4b.
In order to investigate the effect of simple phenyl substitution in position 4, we
prepared 4-arlycarbostyril derivatives 10a-c applying standard Suzuki cross-coupling
chemistry.[15] To our disappointment, none of the investigated new compounds had a
fluorescence quantum yield exceeding 0.04. The emission maximum of 4-(p-cyanophenyl)-
carbostyril 10c is blue-shifted in water as in all monocarbostyrils, but contrasts the behavior
of biscarbostyrils 4b, 6 and 8. Interestingly, in DMSO 10c yielded even less fluorescence
compared with 10a and 10b. However, as expected, due to the electronegativity of the 4-
cyano substituent in DMSO a significant red shift to 505 nm was observed, exactly the value
found with mixed bisproduct 9a. We also investigated several 4-triazolo substituted
analogues. Interestingly, the fluorescence of the known[16] analogs 11a and isomer 11b did
not significantly surpass the fluorescence observed for carbostyril 1. We additionally
prepared the 6,7-dimethoxy substituted analogue of 11b, namely the 6,7-dimethoxy-1-
methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one 11c, using standard “Click”
chemistry as shown in Scheme 1.[16] Compound 11c was absorbing at 360 nm, almost at the
same wavelength as the CF3 model compound 3b and was found as an interesting candidate.
Scheme 1. Synthesis of 6,7-dimethoxy-1-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)quinolin-
2(1H)-one 11c.
Absorption and Emission Characteristics of Bisquinolones 58 It emitted at 430 nm with a fluorescence quantum yield 0.19, that is about 50% of the
quantum yield observed for 3b (fluorescence maximum 440nm).
In the light of these fairly low intensities the question arose if less steric demanding
substituents in position 4 would raise the quantum yield. We thus prepared 4-
phenylacetylene-substituted analogues 12a and 12b having an acetylene bridge between the
4-phenyl substituent and the carbostyril framework. The required 1-methyl-4-
(phenylethynyl)quinolin-2(1H)-one (12a) was prepared by Sonogashira cross-coupling
reaction of the corresponding bromide with phenylacetylene at room temperature (Scheme
2).[16] For the synthesis of 12b, a different synthetic route had to be taken since the synthesis
of the corresponding dimethoxy-derivatized 4-bromocarbostyril proved to be difficult.
Applying the Sonogashira conditions to a suitable bromo quinoline-N-oxide precursor[16] and
phenylacetylene led to the desired C-C coupling, providing the 6,7-dimethoxy-4-
(phenylethynyl)quinoline 1-oxide in good yield. The latter could be further converted into the
desired isomeric quinolone (12b) in a single synthetic step utilizing the known photochemical
rearrangement of quinoline-N-oxides to quinolin-2(1H)-ones (Scheme 2).[16]
Scheme 2. Synthesis of 1-methyl-4-(phenylethynyl)quinolin-2(1H)-one 12a and 6,7-
dimethoxy-4-(phenylethynyl)quinolin-2(1H)-one 12b.
Absorption and Emission Characteristics of Bisquinolones 59 Compared with carbostyril 10b the absorption wavelength maximum was red shifted in 12b
from 365nm to a double maximum at 385 and 410 nm (Stoke’s shift 3010 cm-1) and the
emission wavelength was shifted from 431 to 470 nm (Stoke’s shift e 1925 cm-1). Hence the
electronic spectra were well comparable with any long wavelength absorbing 6,7-dimethoxy-
substituted carbostyril. Disappointing was again the fluorescence quantum yield, although
with 5% somewhat better than all biscarbostyrils.
As a variation of the biscarbostyril series we next prepared macrocycle 13, a crown
ether bridged version of bis-6-methoxy-carbostyril 5. In recent years, crown ethers have
attracted much attention for their interesting binding properties with metal and organic
cations.[17,18] In general, crown ether macrocycles with two-dimensional circular cavities have
been widely studied[19] with respect to their complexation of predominantly alkali and
alkaline earth metals and ammonium salts.[20] In the present work we report the successful
synthesis of a mono cavity crown-ether based quinolone derivative 13.
N
NMe
Me
MeOMeO
O
O
N
NMe
Me
HOHO
O
O
Me
OOOO
N
NMe
O
O
O
O
O O
OTs OTs
5 18 13
BBr3, DCM
r.t., 16 h
K2CO3, DMF
90 °C, 16 h
Scheme 3. Synthesis of biscarbostyril crown ether 13.
The synthesis was achieved from methyl ether 5 by tribromoborane cleavage[21] to form the
6,6´-dihydroxy analogue 18. After reaction with tetraethylene glycol ditosylate[18,21] we
obtained 13 in 71% yield. We hoped not only to get more information about the steric change
conserving the same substitution pattern, but also to get complexation with alkali metal ions
shifting the absorption and emission wavelength by involvement of the lone pair of the 6,7
oxygens. On the one hand we succeeded in shifting the emission wavelength from 475 nm in
5 to 500 nm in crown ether 13. On the other hand, the fluorescence quantum yield was with
6% in DMSO the highest, topping all other bisquinolinones. Quenching in water was again
dominant. Disappointing was also that addition of Li, Na, K, and Cs ions[22,23] did not change
Absorption and Emission Characteristics of Bisquinolones 60 the absorbance and fluorescence values. Studies are ongoing to find response for organic
ammonium ions.
The investigated bisquinolinones display axial chirality and are potential catalysts to
be used as BINAP analogues.[13] Therefore we measured also the fluorescence of the
published diphenyl phosphine- and phosphine oxide analogues as well as of the brominated
precursors 14-17c.[13] Most of the compounds showed extremely weak fluorescence. To our
Table 2. Calculated (TDDFT-B3PW91/TZVP//BP86/SVP) absorption and emission
wavelengths λ (nm) and oscillator strengths in DMSO.
absorption emission
λ / nm f λ / nm f
1a 314 (308) 0.16 (0.16) 348 0.16
2a 339 (332) 0.29 (0.29) 376 0.25
3a 415 0.22 481 0.18
3ba 368 (360) 0.27 (0.27) 413 0.24
4b 332 0.08 399 0.07
5 366 0.01 492 0.03
6 342 0.11 399 0.06
7 379 0.14
8 382 0.02 479 0.02
10a 353 0.26
10b 351 0.29
10c 397 0.10
12b 412 0.23
4ab 437 (469) 0.14 (0.24) 471 (533) 0.03 (0.00)
[a] B3PW91/TZVP//B3LYP/6-31G(d) results in parentheses. [b] results for the second rotamer in parentheses; experimental values in DMF are λabs
= 485 nm and λflu = 530 nm; the calculations refer to the N1H model compound.
Absorption and Emission Characteristics of Bisquinolones 61 surprise, symmetrical diphenyl phosphine oxide 15c had with 0.19 the highest fluorescence
quantum yield of all investigated bisquinolinones. Also, the extinction coefficient 25600 is
2.5 times higher in comparison to parent compound 7. The UV maximum of 380 nm is 20 nm
red shifted and the fluorescence maximum of 470 nm is 20 nm blue shifted compared with 7.
This leads in combination with the fluorescence quantum yield to a total sensitivity and
Stoke´s shift well fitting to the class of substituted mono-coumarins and -carbostyrils.
2.1.1 Computational Results: To rationalize the experimental findings described above,
quantum chemical calculations (time-dependent density functional theory, TDDFT) have
been performed. Selected pertinent results of the TDDFT calculations are given in Table 2.
Also presented there is the computed influence of the solvent (DMSO, H2O) on the
absorption/emission characteristics. The TDDFT procedure has proven as a reliable tool for
the electronic features including absorption and emission characteristics of structurally
related coumarins dyes.[24] In simple carbostyril derivatives, TDDFT calculations using AM1
geometries had given quite good agreement between computed and experimental excitation
energies.[3-5] The situation is less satisfactory for bicarbostyrils. Here, the influence of
substituents on the long-wavelength absorption band is only poorly described when using
AM1 geometries. Apparently, there is little to choose between the two density functionals,
Figure 2. Plot of calculated (B3PW91/TZVP//BP86/SVP) vs. experimental absorption
maxima λabs (nm) in DMSO.
Absorption and Emission Characteristics of Bisquinolones 62 B3PW91 and PBE0, in terms of calculated trends; with respect to basis set, TZVP appears to
be preferable over 6-31G(d). Irrespective of the geometry, basis set and density functional
used, the largest deviations between experimental and calculated λmax–values are obtained for
compounds 7, 8, and 10c. For instance, omitting these three compounds increases the
correlation coefficient for B3PW91/TZVP//BP86/SVP – calculated λmax–values from R2 =
0.87 to R2 = 0.98 (Figure 2). Similarly, the largest discrepancy between experimental
fluorescence maxima and calculated S1 → S0 transition energies result for 7, 8, and 10c, e.g.
for B3PW91/TZVP longest wavelength transitions based on AM1 optimized S1 geometries,
R2 = 0.84, and R2 = 0.93 if 7, 8, and 10c are omitted from the correlation. BP86/SVP S1–
geometries for compounds 1 – 6, 8 result in R2 = 0.95 (PBE0/TZVP) and R2 = 0.96
(B3PW91/TZVP), respectively, to be compared with R2 = 0.90 obtained from AM1 CI=4
geometries (B3PW91/TZVP).
Some of these discrepancies, e.g. longest wavelength absorption of biscarbostyril 8,
can be rationalized on the basis of the nature of the involved electronic transitions.
Consequently, the following discussion of the relevant electronic features is based on
B3PW91/TZVP//BP86/SVP calculations in DMSO as solvent.
Figure 3. Plot of calculated (B3PW91/TZVP//BP86/SVP) vs. experimental Stokes’s shifts
Δν (cm–1) in DMSO (the regression line shown is results by taking into account both values
for 8).
Absorption and Emission Characteristics of Bisquinolones 63
The absorption spectra of biscarbostyrils do not differ significantly from their
monocarbostyril counterparts. In contrast, fluorescence maxima show a substantial
bathochromic shift (see Table 1). In Figure 3, a plot of the observed vs calculated
(B3PW91/TZVP/BP86/SVP) Stoke’s shift in DMSO is presented. With the exception of the
“mixed” derivative 8, the correlation is very good. However, experimental data suggest that
the observed absorption band actually is a superposition of two electronic transitions, see
below. Consequently, considerably better agreement between observed and calculated
Stoke’s shifts results when using the second calculated electronic transition [R2 = 0.61 (8/1)
vs R2 = 0.95 (8/2)].
In carbostyrils 1 – 3 the longest wavelength transition corresponds to the π (HOMO)
→ π* (LUMO) transition. Introduction of the methoxy groups at C6 and C7 preferentially
raises the HOMO and substitution by CF3 at C4 mainly affects the LUMO because of the node
of the HOMO at that position, Figure 4. The combined effects of both substituents, thus, result
in the observed bathochromic shift 1 → 2 → 3. Calculated oscillator strengths for this
transition are reasonably large, f = 0.16 – 0.27, in line with the experimentally found extinction
coefficients of ε = 4000 – 10000, Table 1. In the symmetric bicarbostyrils 4b, 5, and 7 but not
6, all electronic transitions occur pairwise at nearly the same wavelength. In the unsubstituted
4,4’-bicarbostyril 4b both calculated transitions with λ1 = 332 [π (HOMO) → π* (LUMO)]
and λ2 = 330 nm [π (NHOMO) → π* (LUMO)], have small but comparable oscillator
Figure 4. Orbitals involved in the first electronic transition of compound 3 (A) and 4b (B).
Absorption and Emission Characteristics of Bisquinolones 64 strengths f = 0.08 and f = 0.06. Thus, taken together, this explains the relatively large
absorption intensity, ε = 11000. In contrast, fluorescence occurs from the S1 state alone; hence
the very low quantum yields observed for 4,4’-bicarbostyrils. The low intensity of both
transitions can be rationalized in terms of the orbitals involved, Figure 4. Both the HOMO and
the NHOMO are mainly localized within one single carbostyril moiety, whereas the lowest
virtual orbital is of biphenyl-type; the concomitant poor overlap between these two orbitals,
NHOMO or HOMO and LUMO, respectively, leads to the small oscillator strength f. A
similar electronic structure description also holds for 5 and 7. The resulting two transitions, π
(HOMO) → π* (LUMO) and π (NHOMO) → π* (LUMO), at 365 nm are very weak, f = 0.01
and 0.03 and, thus, should be hidden below the much more intense (f = 0.18) π (HOMO) → π*
(NLUMO) absorption calculated at λ = 357 nm.
In contrast to 4, 5, and 7, there is a quite substantial splitting of the first two singlet
states in 7,7’-dimethoxy-4,4’-biscarbosytil 6, with calculated (B3PW91/TZVP//BP86/SVP,
DMSO) absorption maxima at λ1 = 342 [π (HOMO) → π* (LUMO)] and λ2 = 333 nm [π
(NHOMO) → π* (LUMO)]. A third transition, π (HOMO) → π* (NLUMO) results at λ2 =
320 nm. The first and this latter one appear to be quite intense, f = 0.11 and f = 0.28. All
biscarbostyrils show a long wavelength shoulder in their experimental absorption band; in 6
this shoulder is clearly resolved resulting in two well-separated maxima (DMSO) at λ1 = 350
nm and λ2 = 336 nm with ε1 = 8500 and ε2 = 10400. Obviously, this second band has to be
assigned to the third calculated electronic transition.
The calculated (B3PW91/TZVP//BP86/SVP, DMSO) longest wavelength transition
in 8, λ1 = 382 nm, f = 0.02, is a pure charge transfer (CT) π (HOMO) → π* (LUMO)
transition where the HOMO and LUMO are localized at the 6,7-dimethoxy substituted and
the unsubstituted carbostyril moiety. The second transition, λ2 = 346 nm, is governed by the
π (HOMO) → π* (NLUMO) excitation describing a locally excited state within the 6,7-
dimethoxy substituted carbostyril fragment. Hence the quite large calculated intensity f =
0.27. This also explains the large discrepancy between experimental and calculated longest
wavelength absorption of 8: actually it is the second electronic transition which is responsible
for the observed absorption band.
Although the oscillator strength is just one factor contributing to fluorescence
quantum yields, the present calculations reveal the intrinsic low φF-values of the investigated
biscarbostyrils. Thus, as described above, no observable quantum yield effect of temperature,
viscosity or less polar solvent could be observed. In p-quaterphenyl fluorophores where the
Absorption and Emission Characteristics of Bisquinolones 65 dihedral angle τ between the two central rings is constrained by dialkoxy spacers, a clear
correlation between τ and the rate constant for radiationless transitions has been observed.[25]
Here, we do not find a correlation between the torsion of the two carbostyril moieties and the
fluorescence quantum yield. Although 4-aryl derivatives 10a-c show larger calculated
oscillator strengths, these derivatives still have rather low quantum yields. Since radiationless
deactivation by phenyl twisting might be a possible reason, we have separated the phenyl
group from the carbostyril moiety by the steric less demanding acetylene moiety, compound
12b. Compared with the 4-phenyl derivative 10a a bathochromic shift of both absorption and
fluorescence can be observed, Δλexp(abs) = 30 nm and Δλexp(flu) = 29 nm (DMSO).
Somewhat larger effects are predicted by the calculations, Δλcalc(abs) = 50 nm and Δλcalc(flu)
= 83 nm (DMSO) based on AM1 geometries. However, quantum yields are still fairly low, φF
= 0.06. Thus, we have not pursued this type of structural modification any further. In
contrast, according to the calculations, directly connecting the cyano group at C4, compound
3a, should lead to absorption and emission at reasonably long wavelengths, λcalc(abs) = 411
nm and λcalc(flu) = 449 nm (DMSO) with rather large oscillator strengths, Table 2. Indeed,
compound 3a has been found to be highly fluorescent, φF = 0.61 in DMSO,[8] with
experimental absorption and emission maxima in good agreement with the theoretical
predictions.
2.2. Separation of Enantiomers
In order to separate bisquinolone enantiomers we have chosen ULMO as a Pirkle type chiral
stationary phase separating enantiomers of π-electron rich aromatic compounds particularly
well.[26] Also axial chiral binaphthol derivatives have been previously resolved on this chiral
stationary phase (CSP). Results are collected in Table 3 showing chiral recognition of all
investigated axially chiral compounds using the same mobile phase, n-heptane/dioxane 1:1.
Already enantiomers of simple biscarbostyril 4b are separated on the 125 mm column with
almost sufficient resolution (1.43). As expected for this type of CSP, methoxy substituents
increase chiral discrimination. 3,3´-Dibromo derivative 15a is best resolved (5.62) and has
the large separation factor α 2.42. Interestingly, crown ether 13 is better resolved than the
6,6´-dimethoxy analogue 5 (3.81 vs 2.23). Retention of the first eluting enantiomer is equal
but the CSP interaction of the second enantiomer of the crown ether is intensified (Figure 5).
Looking closer at results in Table 3, some interesting trends can be extracted. 6-Alkyloxy
Absorption and Emission Characteristics of Bisquinolones 66 Table 3. HPLC Enantiomer Separation of Bisquinolin-2-ones on an ULMO Chiral Stationary
Phase.
Compound k1 k2 α res Structure
4b 1.70 2.04 1.20 1.43
5 3.26 5.42 1.66 2.23
6 2.32 3.02 1.30 1.95
7 6.66 10.28 1.54 2.05
9a 1.93 2.67 1.38 1.69
9b 0.67 0.72 1.08 0.53
13 3.76 7.02 1.87 3.81
14a 4.21 8.12 1.93 3.63
15a 3.30 7.98 2.42 5.82
16a 0.70 0.73 1.04 0.21
17a 0.64 0.81 1.26 1.13
substituents increase non-specific interactions most, which is reflected in prolonged retention
and hence large k1 values (5, 14a). 3-Bromo substituents decrease k1 hence non-specific
Absorption and Emission Characteristics of Bisquinolones 67 interactions and elute the better retained enantiomer with similar k2 parameters as observed
with 7 and 13. Therefore, bromides 14a-17a are better separated than other analogues in this series.
0 5 t (min) 10
4b
13
Figure 5. Enantiomer separation of compound 4b and crown ether 13 on the ULMO Chiral
Stationary Phase
Resolution of biscarbostyrils containing only electron withdrawing trifluoromethyl
substituents is poor (9b, 16a, 17a). In terms of retention trifluoromethyl substituents in
position 6 inhibit interaction with the CSP and both k values are small leading to small
separation factors. Investigating 9b on the π-basic D-naphthylalanine CSP which should
better interact with electron deficient aromatic rings, however, no chiral recognition at all was
observed (k = 0.50). Also the simple biscarbostyril 4b was not separated (k = 1.20). In short,
chiral recognition on ULMO could be achieved for all investigated biscarbostyrils and the
most promising candidate to get liquid chromatographic separation in a preparative scale was
the 3,3-dibromo compound 15a, which is the potential precursor for an enantiopure diphenyl
phosphine catalyst.[13]
Absorption and Emission Characteristics of Bisquinolones 68 3. Conclusion
Absorption and emission maxima of selected mono- and biscarbostyrils, calculated by time-
dependent density functional theory, show good agreement with the corresponding
experimental data, especially with the B3PW91/TZVP//BP86/SVP procedure. The largest
deviations, irrespective of the geometries, basis set, or density functional used, are found for
compounds 7, 8, and 10c. In compound 8 the experimentally observed absorption/emission
maxima apparently are a superposition of two electronic transitions, hence the discrepancy
with the calculated results. Calculated Stokes’s shifts also nicely correlate with the
experimental ones, again with the exception of 8 for which exact experimental
absorption/emission maxima are difficult to obtain. Furthermore, the S1→S0 transitions in
biscarbostirys are characterized by very low oscillator strengths, responsible for their low
fluorescence quantum yields.
4. Experimental Section
General Methods 1H NMR and 13C NMR spectra were recorded on a 360 MHz instrument at 360 and at 90
MHz respectively. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal
standard. The letters s, d, t, q and m are used to indicate singlet, doublet, triplet, quadruplet
and multiplet. FTIR spectra were recorded using KBr pellets. Low resolution mass spectra
were obtained on a LC/MS instrument using atmospheric pressure chemical ionization
(APCI) in positive or negative mode. Analytical HPLC analysis was carried out on a C18
reversed-phase (RP) analytical column (119 × 3 mm, particle size 5 mm) or a reversed-phase
column (150 × 4.6 mm, particle size 5 µm) at 25 °C using a mobile phase A
(water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow rate of
0.5 mL/min. The following gradient was applied: linear increase from solution 30% B to 100
% B in 8 min, hold at 100% solution B for 7 min. The synthesized compounds were purified
on a Biotage SP1 automated flash chromatography system using cartridges packed with KP-
SIL, 60 Å (32-63 µm particle size). Melting points were obtained on a standard melting point
apparatus in open capillary tubes. TLC analyses were performed on pre-coated (silica gel 60
HF254) plates. All anhydrous solvents (stored over molecular sieves), and chemicals were
obtained from standard commercial vendors and were used without any further purification.
Absorption and Emission Characteristics of Bisquinolones 69
Carbostyril 1 is commercially available (Alfa Aesar), whilst
carbostyrils/biscarbostyrils 2,[4] 3a-b,[8] 4-7,[11] 9b,[13] 11a,b[16] and 14-17[13] have been
previously reported from our laboratories.
Microwave Irradiation Experiments
Microwave-assisted synthesis was carried out in an Emrys™ Synthesizer or Initiator 8 single-
mode microwave instrument producing controlled irradiation at 2.450 GHz (Biotage AB,
Uppsala), including proprietary Workflow Manager Software (version 2.1). Experiments were
carried out in sealed microwave microwave (2 to 5 mL filling volume) process vials utilizing
the standard absorbance level (300 W maximum power). Reaction times under microwave
conditions refer to hold times at the temperatures indicated, not to total irradiation times. The
temperature was measured with an IR sensor on the outside of the reaction vessel.
Electronic Spectra 1cm cells were used for all experiments. UV/Vis spectra were recorded using a Shimadzu
UV/Vis scanning spectrophotometer UV-2101 PC; concentration: 10-4 mol/L. Standard
excitation and emission spectra were recorded using a Perkin-Elmer LS50B luminescence
spectrometer at ambient temperature, standard slit width 3 or, if compounds were very
weakly fluorescent, 5 or even 10 nm; concentration was between 0.5 and 1 × 10-6 M,
adjusting for an average absorption value 0.1 at the excitation wavelength. For measurements
in water, a 10-2 M stock solution in DMSO was used. Approximate -30 °C measurements
were done using a freezer and placing the cells into a dry argon atmosphere. Also degassing
with ultrasound/argon did not significantly change emission intensities. Relative fluorescence
quantum yields were calculated from the fluorescence areas using quinine sulfate at pH1 as a
standard (0.560); DMSO values were corrected with the factor (nH2O/nsolvent)2. DMSO was of
purest grade (Sigma Aldrich, Buchs, Switzerland) and checked for intrinsic fluorescence.
Computational Details Electronic transition energies (absorption and emission) were calculated by time-dependent
density functional theory (TDDFT)[27] using various density functionals (B3LYP,[28]
B3PW91,[29] PBE0,[30] and BP86[31]) and basis sets [6-31G(d), [32] SVP,[33] and TZVP[34]).
Geometries were optimized by the semiempirical AM1 method[35] (CI = 4 for S1
optimization) or by density functional theory calculations [BP86/SVP for S0 and S1 states; for
S0 also B3LYP/6-31G(d) was used]. Solvent effects (dimethylsulfoxide, water) were
Absorption and Emission Characteristics of Bisquinolones 70 approximated by the IEF-PCM procedure.[36] To investigate excited states including electron
correlation post-Hartree-Fock methods using multiple Slater determinants can be used.
Coupled Cluster (CC) methods are exact, but time-consuming methods. In order to save
computer time at a low loss of accuracy, the Coupled Cluster Singles Doubles CCSD
equations can be approximated to be correct only through first order, using the singles as
zeroth-order parameter (CC2[37]). Programs used were AMPAC,[38] TURBOMOLE,[39] and
Gaussian 03.[40] Visualization was done by MOLDEN[41] and MOLEKEL.[42]
Chiral Separations Chiral HPLC measurements were performed using a HEWLETT PACKARD series HP1050
instrument consisting of a pumping system, a multiple wavelength detector and an
autosampler and the HPChemstation software. The chiral stationary phases (CSPs) were an
(S,S)-ULMO column (125x4mm) and a covalent D-naphthylalanine column (250x4mm)
from REGIS, Morton Grove, Ill, USA. Mobile phase solvents were of HPLC grade
(MERCK, Darmstadt, Germany). The mobile phase was n-heptane/dioxane 1:1. 5µl of a
sample solution (concentration about 0.05mg/mL) was injected. All runs were performed at
25 °C and wavelength was adjusted according to absorption maxima (Table 1).
6,7-Dimethoxy-1,1'-dimethyl-4,4'-biquinolin-2,2'(1H,1'H)-dione) (8):
A mixture of 76.1 mg (0.30 mmol) of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-
one,[11] 58.1 mg (0.30 mmol, 1.0 equiv) of 1-methyl-4-chloroquinolin-2(1H)-one,[11] 49.0 mg
(0.060 mmol, 10.0 mol%) of PdCl2(dppf)2, 23.3 mg (0.042 mmol, 7 mol%) of dppf, 106.6 mg
(0.42 mmol, 0.7 equiv) of bis-(pinacolato)diboron, 151.5 mg (2.7 mmol, 4.5 equiv) of finely
crushed KOH powder (analytical grade), and 2.0 mL of n-BuCl, in a 2 mL Pyrex microwave
vial was equipped with a magnetic stirring bar and sealed. The resulting mixture was stirred
for 5 min at room temperature under Ar and then heated for 30 min at 145 °C via single-
mode microwave irradiation. After cooling to ambient conditions, the solvent was removed
under reduced pressure and the product directly purified by automated flash chromatography
Absorption and Emission Characteristics of Bisquinolones 71 using petroleum ether/EtOAc as eluent to 56.5 mg (50%) of 6,7-dimethoxy-1,1'-dimethyl-
4,4'-biquinolin-2,2'(1H,1'H)-dione) (8) as a colorless solid, mp 155-157 °C (ethanol); IR
(KBr) νmax 3435, 1650, 1258 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.59 (s, 3H), 3.84 (s, 6H),
4.04 (s, 3H), 6.61 (d, J = 7.4 Hz, 2H), 6.75 (s, 1H), 6.88 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.28
(d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H); 13C NMR (90 MHz,
CDCl3) δ: 29.7, 29.9, 56.3, 97.5, 108.2, 112.9, 114.7, 119.2, 119.6, 121.7, 122.4, 127.5,
131.4, 136.1, 140.1, 145.2, 145.4, 146.5, 152.7, 161.6; MS (pos. APCI) m/z 376 (100, M),
377 (20, M + 1). The known symmetrical bisquinolones 7[11] and 4[11] were isolated in 17%
and 10% yield, respectively, as by-products.
6,7-Dimethoxy-1,1'-dimethyl-6'-(trifluoromethyl)-4,4'-biquinolin-2,2'(1H,1'H)-dione
(9a):
A mixture of 76.1 mg (0.30 mmol) of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-
one,[11] 78.5 mg (0.30 mmol, 1.0 equiv) of 4-chloro-1-methyl-6-(trifluoromethyl)quinolin-
2(1H)-one,[13] 49.0 mg (0.060 mmol, 10.0 mol%) of PdCl2(dppf)2, 23.3 mg (0.042 mmol, 7
mol%) of dppf, 106.6 mg (0.42 mmol, 0.7 equiv) of bis-(pinacolato)diboron, 293.2 mg (0.9
mmol, 4.5 equiv) of finely crushed KOH powder (analytical grade), and 2.0 mL of n-BuCl, in
a 2 mL Pyrex microwave vial was equipped with a magnetic stirring bar and sealed. The
resulting mixture was stirred for 5 min at room temperature under Ar and then heated for 30
min at 145 °C via single-mode microwave irradiation. After cooling to ambient conditions,
the solvent was removed under reduced pressure and the product directly purified by
automated flash chromatography using petroleum ether/EtOAc as eluent to 22.7 mg (17%) of
9a as orange solid, mp 237-239 °C (ethanol); IR (KBr) νmax 3436, 1649, 1309 cm–1; 1H-NMR
(360 MHz, CDCl3) δ: 3.62 (s, 3H), 3.86 (s, 6H), 4.06 (s, 3H), 6.55 (s, 1H), 6.62 (s, 1H), 6.83
(s, 1H), 6.91 (s, 1H), 7.53 (s, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H); 13C
NMR (90 MHz, CDCl3) δ: 29.9, 30.0, 56.3, 97.7, 107.8, 112.4, 115.3, 119.3, 119.4, 123.2,
124.6, 124.9, 125.1, 127.8, 136.3, 142.2, 144.2, 145.4, 146.2, 153.0, 161.3; MS (pos. APCI)
m/z 444 (100, M), 445 (25, M + 1). The known symmetrical bisquinolones 9b[13] and 7[11]
were isolated in 4% and 76% yields, respectively, as by-products.
Absorption and Emission Characteristics of Bisquinolones 72
6,7-Dimethoxy-1-methyl-4-phenylquinolin-2(1H)-one (10a):
A mixture of 76.1 mg (0.30 mmol) of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-
one),[11] 36.6 mg (0.30 mmol, 1.0 equiv) of phenylboronic acid, 0.7 mg (0.003 mmol, 1.0
mol%) of Pd(OAc)2, 2.7 mg (0.012 mmol, 4 mol%) of PPh3, 91.1 mg (0.9 mmol, 125 µL, 3.0
equiv) of Et3N, and 2.0 mL of DME/H2O (3:1), in a 2 mL Pyrex microwave vial was
equipped with a magnetic stirring bar and sealed. The resulting mixture was stirred for 5 min
at room temperature and then heated for 30 min at 150 °C via single-mode microwave
irradiation. After cooling to ambient conditions, the solvent was removed under reduced
pressure and the product directly purified by flash chromatography using petroleum
ether/EtOAc as eluent to 82.4 mg (93%) of 10a as a white solid, mp 135-137 °C (ethanol); IR
(KBr) νmax 3435, 1649, 1422, 1257 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.75 (s, 3H), 3.79
(s, 3H), 4.04 (s, 3H), 6.59 (s, 1H), 6.87 (s, 1H), 6.99 (s, 1H), 7.43-7.56 (m, 6H); 13C NMR
(90 MHz, CDCl3) δ: 29.8, 56.2, 97.4, 108.8, 113.6, 118.8, 128.6, 128.7, 128.8, 136.1, 137.6,
144.8, 150.4, 152.1, 162.0; MS (pos. APCI) m/z 295 (100, M), 296 (40, M + 1).
6,7-Dimethoxy-4-(4-methoxyphenyl)-1-methylquinolin-2(1H)-one (10b):
This material was prepared in an analogous fashion as described for 10a above, except that
45.6 mg (0.30 mmol, 1.0 equiv) of 4-methoxyphenylboronic acid is used to produce 83.9 mg
(86%) of 10b as light yellow crystals, mp 178-180 °C (ethanol); IR (KBr) νmax 3436, 1661,
1258, 822 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.77 (s, 3H), 3.79 (s, 3H), 3.89 (s, 3H), 4.04
(s, 3H), 6.56 (s, 1H), 6.85 (s, 1H), 7.03 (d, J = 8.9 Hz, 3H), 7.39 (d, J = 8.6 Hz, 2H); 13C
NMR (90 MHz, CDCl3) δ: 29.8, 55.4, 56.2, 97.4, 108.8, 114.1, 118.6, 128.6, 130.1, 132.0,
136.1, 144.8, 150.1, 151.9, 159.9, 162.1; MS (pos. APCI) m/z 325 (100, M+1).
Absorption and Emission Characteristics of Bisquinolones 73
6,7-Dimethoxy-4-(4-cyanophenyl)-1-methylquinolin-2(1H)-one) (10c):
This material was prepared in an analogous fashion as described for 10a above, except that
44.1 mg (0.30 mmol, 1.0 equiv) of 4-cyanophenyl boronic acid is used to produce 64.4 mg
(67%) 10c as a yellow solid, mp 223-225 °C (ethanol); IR (KBr) νmax 3476, 2227, 1652,
1424, 1260, 840 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.76 (s, 3H), 3.81 (s, 3H), 4.05 (s, 3H),
6.56 (s, 1H), 6.78 (s, 1H), 6.88 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H); 13C
NMR (90 MHz, CDCl3) δ: 29.9, 56.2, 97.6, 107.9, 112.6, 112.8, 118.3, 119.1, 129.6, 132.5,
136.3, 142.3, 145.2, 148.3, 152.6, 161.6; MS (pos. APCI) m/z 320 (100, M), 321 (20, M + 1).
6,7-Dimethoxy-1-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (11c):
Into a 25 mL round bottom flask, equipped with a magnetic stirring bar, 500 mg (1.97 mmol)
of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-one,[11] and 386 mg (3 equiv, 5.94 mmol)
of fresh sodium azide together with 10 mL DMF were added. The reaction mixture was then
heated at 100 °C for 16h. After the reaction was completed the solvent was removed under
reduced pressure and the residue purified by dry-flash chromatography with EtOAc as eluent.
The solvent was removed under reduced pressure to provide 292 mg (57%) of 4-azido-6,7-
dimethoxy-1-methylquinolin-2(1H)-one as a colorless solid, mp 163-164 °C (decomp.)
(ethyl acetate); IR (KBr) νmax 3429, 2120, 1631, 1427, 1259 cm–1; 1H-NMR (360 MHz,
CDCl3) δ: 3.70 (s, 3H), 3.95 (s, 3H), 4.02 (s, 3H), 6.37 (s, 1H), 6.76 (s, 1H), 7.20 (s, 1H); 13C
NMR (90 MHz, CDCl3) δ: 29.6, 56.2, 97.1, 104.1, 104.5, 108.8, 135.9, 145.1, 147.8, 153.1,
162.0; MS (pos. APCI) m/z 260 (100, M), 261 (15, M + 1). Into a 5 mL microwave glass
vial, equipped with a magnetic stirring bar, 312 mg (1.2 mmol) of the above mentioned azide,
30 mg (0.1 equiv, 0.12 mmol) CuSO4.5H2O and 24 mg (0.1 equiv, 0.12 mmol) sodium
Absorption and Emission Characteristics of Bisquinolones 74 ascorbate together with 2 mL of DMF were added, followed by 145 µL (135 mg, 1.1 equiv,
1.32 mmol) of phenylacetylene. The reaction mixture was sealed and stirred for 5 min.
Thereafter, the vial was heated at 110 °C for 20 min in a Biotage Initiator microwave
instrument. After the reaction was completed the resulted mixture was poured onto 100 mL
of ice-water and stirred for an additional 1 h. The formed solids were filtered off on a
Büchner funnel and washed extensively with additional 2 x 500 mL portions of water to give
237 mg (55%) of pure 11c, mp 234-235 °C (ethanol); IR (KBr) νmax 3436, 3132, 1641, 1584,
1462, 1264, 1017 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.79 (s, 3H), 3.84 (s, 3H), 4.05 (s,
3H), 6.71 (s, 1H), 6.87 (s, 1H), 7.30 (s, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.47-7.51 (m, 2H), 7.94
(d, J = 7.2 Hz, 2H), 8.19 (s, 1H); 13C NMR (90 MHz, CDCl3) δ: 30.2, 56.3, 97.4, 106.1,
109.0, 113.3, 121.0, 125.9, 128.9, 129.1, 129.5, 136.8, 142.7, 145.8, 148.1, 153.5, 161.4; MS
(pos. APCI) m/z 362 (100, M), 363 (20, M + 1), 334 (85, M – 28).
1-Methyl-4-(phenylethynyl)quinolin-2(1H)-one (12a):
Into a 10 mL round bottom flask, equipped with a magnetic stirring bar, 200 mg (0.84 mmol)
of 1-methyl-4-bromoquinolin-2(1H)-one,[16] 102 µL (1.1 equiv, 95 mg, 0.93 mmol) of
phenylacetylene, 59 mg (0.084 mmol, 10 mol%) of Pd(PPh3)2Cl2, 16 mg (0.084 mmol, 10
mol%) of CuI, 165 µL (1.1 equiv, 120 mg, 0.93 mmol) of N-ethyldiisopropylamine and 5.0
mL of dioxane were added. The resulting reaction mixture was stirred for 2 hrs at room
temperature. Thereafter, the solvent was removed under reduced pressure and the crude
residue purified by dry-flash chromatography using petroleum ether/EtOAc (1:2) as eluent to
yield 199 mg (91%) of 12a as a colorless solid mp 106-107 °C (ethanol); IR (KBr) νmax 3434,
2923, 2852, 1654, 750 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.76 (s, 3H), 6.99 (s, 1H), 7.32-
7.45 (m, 5H), 7.62-7.68 (m, 3H), 8.16 (d, J = 7.9 Hz, 1H); 13C NMR (90 MHz,
CDCl3) δ: 29.5, 84.0, 98.7, 114.3, 120.1, 121.9, 122.3, 124.5, 127.5, 128.6, 129.5, 131.1,
132.0, 132.5, 139.9, 161.5; MS (pos. APCI) m/z 259 (100, M), 260 (20, M + 1).
Absorption and Emission Characteristics of Bisquinolones 75
6,7-Dimethoxy-4-(phenylethynyl)quinolin-2(1H)-one (12b):
Into a 10 mL round bottom flask equipped with a magnetic stirring bar, 500 mg (1.76 mmol)
of 4-bromo-6,7-dimethoxyquinoline 1-oxide,[16] 213 µL (1.1 equiv, 198 mg, 1.94 mmol) of
phenylacetylene, 124 mg (0.18 mmol, 10 mol%) of Pd(PPh3)2Cl2, 34 mg (0.084 mmol, 10
mol%) of CuI, 437 µL (1.5 equiv, 342 mg, 2.64 mmol) of N-ethyldiisopropylamine and 5.0
mL of dioxane were added. The resulting reaction mixture was stirred for 2h at room
temperature. Thereafter, the solvent was removed under reduced pressure and the crude
residue purified by dry-flash chromatography using petroleum ether/EtOAc (1:2) as eluent to
yield 377 mg (70%) of 6,7-dimethoxy-4-(phenylethynyl)quinoline 1-oxide as a colorless
solid, mp 185-186 °C (EtOAc); IR (KBr) νmax 3436, 2784, 2200, 1659, 1513, 1420, 1264,
1145, 855 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 4.06 (s, 3H), 4.07 (s, 3H), 7.32 (d, J = 6.44,
1H), 7.39-7.4 (m, 3H), 7.53 (s, 1H), 7.53-7.59 (m, 2H), 8.04 (s, 1H), 8.33 (d, J = 6.41, 1H); 13C NMR (90 MHz, CDCl3) δ: 56.0, 56.1, 84.8, 98.3, 98.5, 106.7, 111.7, 121.5, 121.9, 129.4,
130.4, 132.2, 132.4, 135.0, 145.6, 152.9, 161.3; MS (pos. APCI) m/z 306 (100, M), 290 (18,
M - 16). A stirred solution of 405 mg (1.33 mmol) of the above quinoline 1-oxide in 25 mL
of MeOH, placed in a crystallization dish, was irradiated with an OSRAM Ultra-Vitalux®
300W lamp for 90 min. The addition of a several 5 mL portions of MeOH is needed to
prevent the reaction mixture from running dry. After the rearrangement is complete, the
reaction mixture is concentrated under vacuum and the residue is poured onto cold water,
stirred for 15 min and filtered to give 363 mg (89%) of 12b as a light yellow solid, mp 269-
271 °C (ethanol); IR (KBr) νmax 3436, 2784, 2200, 1659, 1513, 1420, 1264, 1145 cm–1; 1H-
NMR (360 MHz, CDCl3) δ: 3.85 (s, 3H), 3.88 (s, 3H), 6.62 (s, 1H), 6.92 (s, 1H), 7.34 (s, 1H),
7.52-7.53 (m, 3H), 7.73-7.74 (m, 2H), 11.79 (s, 2H); 13C NMR (90 MHz, CDCl3) δ: 57.3,
85.5, 98.3, 107.0, 112.5, 116.0, 121.5, 129.4, 131.0, 132.2, 133.0, 133.5, 135.0, 146.5, 153.5,
161.2; MS (pos. APCI) m/z 305 (100, M).
Absorption and Emission Characteristics of Bisquinolones 76
NCH3
O
NCH3
O
HOHO
6,6'-Dihydroxy-1,1'-dimethyl-4,4'-biquinolin-2,2'(1H,1'H)-dione (18):
A mixture of 229.6 mg (0.61 mmol) of biscarbostiryl 5[11] in a 10 mL Pyrex microwave vial
was equipped with a magnetic stirring bar and sealed. After purging with Ar for 5 minutes
and the addition of 3.0 mL of DCM, 536.16 mg (2.14 mmol, 206 µL, 3.5 equiv) of BBr3 was
added under ice cooling. The resulting mixture was stirred for 16 h at room temperature. The
resulting mixture was poured onto ice water and after stirring for 20-30 minutes, the required
product is collected by filtration to yield 204 mg (96%) of 18 as a yellowish solid, mp >300
°C (ethanol); IR (KBr) νmax 3432, 3268, 1638, 1565 cm–1; 1H-NMR (360 MHz, DMSO-d6) δ:
3.67 (s, 6H), 6.51 (d, J = 2.6 Hz, 2H), 7.13 (dd, J = 9.1 Hz, 2.7 Hz, 2H), 7.52 (d, J = 9.1 Hz,
2H), 9.45 (s, 2H); 13C NMR (90 MHz, DMSO-d6) δ: 29.7, 111.1, 117.1, 120.4, 120.9, 121.7,
133.7, 145.6, 152.8, 160.3; MS (neg. APCI) m/z 348 (100, M), 349 (20, M + 1), 347 (10, M –
1), 346 (30, M - 2).
6,6'-(Tetraethyleneoxy)-1,1'-dimethyl-4,4'-biquinolin-2,2'(1H,1'H)-dione (13):
A mixture of 52.3 mg (0.15 mmol) of 6,6'-dihydroxy-1,1'-dimethyl-4,4'-biquinolin-
2,2'(1H,1'H)-dione (18) in a 50 mL round bottom flask was equipped with a magnetic stirring
bar and sealed. After purging with Ar for 5 min 5.0 mL of a DMF-K2CO3 (K2CO3, 82.9 mg,
0.60 mmol, 4.0 equiv) suspension was added dropwise at 90 °C under Ar. After an additional
30 min 90.5 mg of tetraethylene glycol ditosylate (0.18 mmol, 72 µL, 1.2 equiv) was added
dropwise. The resulting mixture was stirred for 16 h at 90 °C under Ar. After removal of the
solvent under reduced pressure the crude product was purified on a SP1 automatic flash
chromatography system using DCM/acetone as eluent to yield 53.9 mg (71%) of crown ether
13 as a yellowish solid, mp 262-263 °C (ethanol); IR (KBr) νmax 3436, 2924, 2856, 1654 cm–
Absorption and Emission Characteristics of Bisquinolones 77 1; 1H-NMR (360 MHz, DMSO-d6) δ: 3.39-3.45 (m, 8H),3.52-3.54 (m, 4H), 3.69 (s, 6H),
3.81-3.85 (m, 2H), 4.08-4.12 (m, 2H), 6.56 (d, J = 2.6 Hz, 2H), 6.68 (s, 2H), 7.36 (dd, J = 9.2
Hz, 2.7 Hz, 2H), 7.62 (d, J = 9.3 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ: 29.8, 68.0, 68.7,
70.2, 70.4, 111.5, 117.1, 119.2, 120.1, 122.7, 134.6, 145.8, 153.6, 160.6; MS (pos. APCI) m/z
506 (100, M), 507 (45, M + 1).
Absorption and Emission Characteristics of Bisquinolones 78 5. References
[1] a) G. Zheng, Y.-M. Guo, W.-H. Li, J. Am. Chem. Soc. 2007, 129, 10616-10617; b)
E. K. Feuster, T. E. Glass, J. Am. Chem. Soc. 2003, 125, 16174-16175; c) E. P.
Diamandis, Analyst 1992, 117, 1879-1884; d) F. Badalassi, P. Crotti, G. Klein, J.-
L. Reymond, Eur. J. Org. Chem. 2004, 2557-2566; e) S. R. Trenor, A. R. Shultz,
B. J. Love, T. E. Long, Chem. Rev. 2004, 104, 3059-3078; f) M.-S. Schiedel, C. A.
Briehn, P. Bauerle, Angew. Chem. Int. Ed. 2001, 40, 4677-4680; g) M. Kozlov, V.
Bergendahl, R. Burgess, A. Goldfarb, A. Mustaev, Anal. Biochem. 2005, 342, 206-
213.
[2] a) P. Ge, P. R. Selvin, Bioconjugate Chem. 2008, 19, 1105-1111; b) D. J. Williams,
M. Gilmore, L. Steward, M. Verhagen, K. R. Aoki, US Patent 2006, 2006063221;
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Summary 82 Summary
The thesis is divided into 4 chapters which include an overview of transition-metal catalyzed
carbon-carbon cross-coupling and homocoupling reactions based on highly functionalized
novel quinolones. In addition, some recent literature related to C-C coupling reactions is
discussed.
Chapter A is a summary on transition-metal-catalyzed carbon-carbon coupling reactions.
Transition-metal-catalyzed carbon-carbon bond formations have caused a real revolution in
organic syntheses in the past decades. Aryl-aryl bond formation has been known for more
than a century and was one of the first reactions involving a transition metal. This protocol
has been substantially improved and expanded over the past 30 years, providing an
indispensable and simple methodology for preparative organic chemists. Recent
developments in the cross-coupling of substrates are noteworthy and has previously been
thought impossible. Owing to their widespread applications in the organic synthesis a plethora
of literature has been published. The following are the well-known transition-metal-catalyzed
reactions: Suzuki, Heck, Sonogashira, Stille, Ullmann, Fukuyama, Negishi, Kumada, and
Hiyama cross-couplings.
Now-a-days, transition metal-catalyzed carbon-carbon bond forming reactions are
powerful tools in the toolbox of synthetic organic chemist and cover a extremely wide range
of modifications and applications since first developed in 1970s. In all the methodologies
different activation modes have been utilized. Carrying out these cross/homo-coupling
reactions under controlled microwave irradiation can be considered today as a very effective
way. It is indicative that the combined approach of microwave irradiation and homogenous
catalysis can offer a nearly synergistic strategy in the sense that the combination has greater
potential than its two separate parts in isolation.
Chapter B is focused on the efficient synthesis of functionalized 4,4′-bisquinolones by
microwave-assisted palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling
reactions, or via nickel(0)-mediated homocouplings (Ullmann reaction) of 4-chloroquinolin-
2(1H)-one precursors. Substituted biaryls play an important role in organic chemistry. Many
natural products, pharmaceuticals, herbicides and fine chemicals contain symmetrical or
unsymmetrical biaryl units. Important structural motifs are, for example, bipyridines,
Summary 83 bithiophenes, and bipyrroles. The synthesized novel class of bis-heterocycles are of interest
both as aza-analogues of biscoumarin natural products (e.g., 4,4′-biisofraxidin). Both methods
rapidly deliver bisquinolones in good to excellent yields employing controlled microwave
irradiation (MW) and are applicable not only toward the preparation of the desired
symmetrical bisquinolones but also as general methods for other types of symmetrical biaryl
synthesis. The procedures are particularly valuable for the preparation of novel types of
bisquinolones, which are presently under investigation as fluorescent probes.
In chapter C, a method for the gram-scale preparation of functionalized 4,4´-
bisquinolones using a microwave-assisted Ullmann-type homocoupling reaction is described.
The method is catalytic in nickel(0) which is generated in situ by reduction from an
inexpensive Ni(II) source and utilizes readily available 4-chloroquinolin-2(1H)-ones as starting
materials. In contrast to the alternative palladium(0)-catalyzed one-pot borylation/Suzuki
cross-coupling reaction, the new method avoids the use of an expensive catalyst and cross-
coupling partner such as bis(pinacolato)diboron. The structural sub-unit of symmetrical biaryls
plays an important role in organic and medicinal chemistry, and is found in a wide variety of
natural products including alkaloids such as the anti-HIV alkaloid michellamine B, coumarins,
polyketides and terpenes. Compounds incorporating symmetrical biaryl moieties also find
applications as conductors for thin film transistor applications, as electronic and optoelectronic
materials, as chiral ligands in catalysis (e.g., BINAP) and in chiral or achiral liquid crystals. In
view of the substantial interest and broad application of symmetrical biaryls, considerable
efforts have been undertaken to achieve efficient, economical, safe, and environmentally
benign methods for their preparation in many academic and industrial laboratories. Since the
first biaryl couplings performed by Ullmann over a century ago applying stoichiometric
amounts of copper metal, the catalytic use of transition metals, especially of palladium and
nickel, in the formation of symmetrical biaryls is now well established. We have developed a
Ni(0)-catalyzed reductive homocoupling reaction of easily accessible 4-chloroquinolin-2(1H)-
ones that provides 4,4′-bisquinolones in good yields. In contrast to our previous protocol, this
new method only requires 0.25 equivalents of a comparatively inexpensive Ni source and does
not rely on chromatography for product isolation. Key to the success was a change of solvent
and the combined use of bidentate and monodentate ligands providing more active Ni(0)
catalytic species. The method is therefore scalable and will allow us to further study the
properties of these novel types of bisheterocylces.
Chapter D comprises the fluorescent and computational studies of quinolones and
bisquinolones derivatives. The electronic spectra of biscarbostyrils exhibit unusual properties
Summary 84 in comparison to the corresponding carbostyrils. Similar absorption spectra are accompanied
by red-shifted emission maxima up to 520 nm. Unsubstituted biscarbostyril displays the
unusual property of a blueshift in dimethylsulfoxide as compared to water. For a set of
diversely substituted biscarbostyrils and related 4-aryl-2-quinolinones very selective
substitution patterns in order to increase fluorescence quantum yields are observed. In
addition to the traditional coumarin-based fluorophores, comparatively few derivatives of the
structurally related quinolin-2(1H)-ones (carbostyrils) have found applications as fluorescence
markers. Carbostyrils are more resistant towards pH changes (ring opening) and other thermal
or chemical (oxidative damage) bleaching reactions. Moreover, they are easily functionalized,
leading to versatile fluorescent tags for proteins or polysaccharides. Their photophysical
properties and chemical stability, thus, makes this class of compounds useful for
bioconjugation in aqueous media. In chapter D a combined experimental and computational
study on photophysical properties of 4,4’-biscarbostyrils is presented. In addition, results for
4-aryl-, 4-hetaryl-, and 4-arylethinylcarbostyrils are also discussed. Experimental absorption
and fluorescence characteristics are also provided for the crown ether derivative and the
diphenyl phosphine- and phosphine oxide analogues as well as their bromine-containing
precursors. Since all investigated bisquinolones are axially chiral, a HPLC study of
enantioseparation effects on the Pirkle type chiral stationary phase (CSP) ULMO is also
presented. Absorption and emission maxima of selected mono- and biscarbostyrils, calculated
by time-dependent density functional theory, show good agreement with the corresponding
experimental data, especially with the B3PW91/TZVP//BP86/SVP procedure. Calculated
Stokes’s shifts also nicely correlate with the experimental ones, again with the exception of
only one compound. Furthermore, transitions in biscarbostirys are characterized by very low
oscillator strengths, responsible for their low fluorescence quantum yields.