Tetrahedron Letters 53 (2012) 2971–2975

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Tetrahedron Letters

journal homepage: www.elsevier .com/ locate/ tet le t

Effect of acid catalysis on the direct electrophilic fluorination of ketones, ketals,and enamides using Selectfluor™

Jack Liu a, Johann Chan a, Craig M. Bryant a, Petar A. Duspara a, Ernest E. Lee a, David Powell a, Hua Yang b,Ziping Liu b, Chris Walpole b, Edward Roberts b, Robert A. Batey a,⇑a Department of Chemistry, University of Toronto, 80, St. George Street, Toronto, Ontario, Canada M5S 3H6b AstraZeneca R&D Montreal, 7171 Frederick-Banting, Ville Saint-Laurent (Montreal) Quebec, Canada H4S 1Z9

a r t i c l e i n f o a b s t r a c t

Article history:Received 24 February 2012Revised 12 March 2012Accepted 20 March 2012Available online 27 March 2012

Keywords:FluorinationAcid catalystKetonesKetalsEnamidesMulti-component coupling reaction

0040-4039/$ - see front matter � 2012 Published byhttp://dx.doi.org/10.1016/j.tetlet.2012.03.074

⇑ Corresponding author.E-mail address: rbatey@chem.utoronto.ca (R.A. Ba

The fluorination of ketones, ketals, and enamides has been achieved using the electrophilic fluorinatingreagent Selectfluor™ (F-TEDA-BF4). For the reactions of ketones and ketals the use of sulfuric acid(0.1 equiv) as an additive was found to facilitate the reaction leading to more rapid product formation.This behavior is analogous to the known effects of acid catalysis on the bromination of ketones. The reac-tions were generally quite selective leading to the formation of monofluorinated products, and could beaccomplished on reaction scales up to 85 mmol using N-protected piperidone based substrates. Reactionsin the presence of MeOH led to the formation of the corresponding fluoroketones or fluoroketals depend-ing upon the substrate. The formation of the fluoroketals in this manner, as well as the fluorination ofcyclic enamides are examples of multi-component coupling reactions.

� 2012 Published by Elsevier Ltd.

NN

Cl

2BF4 NNOH

2BF4

Methods for the fluorination of organic molecules constitute animportant class of reactions, due to the presence of the C–F bond inmany medicinally and agrochemically important targets.1,2 Fluori-nation methods can be divided into two main classes, involvingeither nucleophilic or electrophilic fluorinating agents.1,3 In the lat-ter case, an organic nucleophile reacts with a formal source of F+.Many different electrophilic fluorinating agents are known, butelectrophilic N–F based reagents4 such as Selectfluor™ F-TEDA-BF4 1 and Accufluor™ NFTh 2 have emerged as being particularlyvaluable (Fig. 1).5 These reagents undergo reaction with a widerange of nucleophiles including electron-rich aromatic rings, eno-lates, alkenes, and alkynes. Particularly noteworthy are the reac-tions of enol esters and silyl enol ethers, which occur throughfluorine transfer to the more nucleophilic b-carbon. The overalltransformations can be considered as achieving a-fluorination ofcarbonyl compounds, with the enol derivatives serving as the cog-nate nucleophilic intermediates in the electrophilic fluorinationstep. For example, the fluorination of enol acetates using 2 givesa-fluoroketones.6 Selectfluor™ has also been used for fluorinationof enol acetates and silyl enol ethers.7,8 Stavber has shown thatenol acetates, styrenes, phenols, and enolizable 1,3-dicarbonylcompounds undergo fluorination reactions using 1 in water inthe presence of a surfactant at 60 �C.9 Selectfluor™ and NFSi

Elsevier Ltd.

tey).

(N-fluorobenzenesulfonimide) have also been employed for fluori-nations of enol acetates and enolizable 1,3-dicarbonyl compoundsusing solventless conditions.10 Glycals,5a,11 deoxyascorbic acidderivatives and tetronic acids12 are also known to undergo fluori-nation using 1. More nucleophilic enolate anions can also be fluo-rinated, although reagents such as NFSi rather than 1 or 2 areusually employed.13 Enamines are also known to undergo fluorina-tion by 1 to give a-mono- and difluoroketones.14 More recentlyamine catalyzed enantioselective fluorination reactions of carbonylcompounds using 1 have been developed.15 Analogous reactivity isalso known for electrophilic fluorinations of nucleophilic enam-ines, enamides, and indoles to generate b-fluoroamines.16,17

While these approaches have undoubtedly found widespreaduse, methods for the direct a-fluorination of carbonyl compounds,that do not require the prior formation of enol esters, silyl enolethers, or enolates, would constitute more efficient and practicalroutes than conventional methods. Some examples of this processare known, such as the use of Accufluor™ for the a-fluorination of

F F1 2

Figure 1. Electrophilic fluorinating reagents: Selectfluor™ F-TEDA-BF4 1 andAccufluor™ NFth 2.

Me

HMe

HOH

H H

F

O

OF

EtO

3b (85%) 3c (82%)

3d (70%) 3e (49%) 3f (71%)

R1

O

R2

1 (1.2 equiv)H2SO4 (0.1 equiv)

MeOH or MeCN50 C, 16 h

R1

O

R2

F

OF

3a (93%)

3

OF

F

O

O

F

Scheme 1. a-Fluoroketones 3 synthesized using direct fluorination by 1 andsulfuric acid.

2972 J. Liu et al. / Tetrahedron Letters 53 (2012) 2971–2975

ketones, which occurs at 80 �C in MeCN solvent,18 or in refluxingMeOH.19 The use of Selectfluor™ in the presence of a surfactanthas also been used for the fluorination of ketones at higher temper-atures.20 Selectfluor™ has also been used in combination with io-nic liquids21 and using flow synthesis techniques.22

To achieve direct electrophilic a-fluorination of ketones, initialformation of a nucleophilic enol intermediate must occur. Condi-tions that favor the formation of enols should therefore lead to im-proved rate and/or yield of the a-fluorinated products. Enolformation is known to be promoted under acidic conditions. In-deed, the rate of a-bromination of ketones (e.g., acetophenone)by Br2/MeOH under acid catalyzed conditions is known to be zer-oth order in bromine and first order in the ketone and acid.23,24

While this accelerating effect is well known for brominations, tothe best of our knowledge such an acid-catalyzed approach tothe direct fluorination of ketones by 1 or 2 has not been described.Our goal therefore was to establish whether acid catalysis wouldalso promote a-fluorination of ketones using the commerciallyavailable reagent Selectfluor™.

1-Tetralone was chosen as a test substrate for the reaction withSelectfluor™ (1.2 equiv) using H2SO4 (10 mol %) as a catalyst in avariety of solvents at 50 �C (Table 1). Reaction occurred most effi-ciently in methanol, with complete conversion achieved within 4 h(Table 1, entry 1). Reaction also occurred in acetonitrile and isopro-panol, although at a much slower rate. The addition of water as aco-solvent with either methanol or acetonitrile led to slower reac-tions.25 No reaction was observed in THF and EtOAc, althoughusing water as a co-solvent led to improved reactivity. Reactionat 50 �C in methanol in the absence of sulfuric acid occurred withonly 44% and 45% conversion after 4 h and 24 h, respectively. Reac-tion at room temperature using H2SO4 (10 mol %) in methanol oc-curred to give 3a with 58% and 71% conversion after 4 h and 24 h,respectively. In combination, these results show the practicaladvantage of using sulfuric acid as a catalyst at 50 �C to increaseyield and decrease reaction time. Finally, the use of a variety ofother acid catalysts led to lower reactivity relative to that achievedwith H2SO4. For example, use of 0.1 equiv of HCl, TsOH, or AcOHoccurred with 74%/95%, 89%/95%, and 83%/97% conversions,respectively (after 4 h/24 h). The use of pH 3 buffer was also possi-ble achieving 58%/94% conversions.

The use of the optimized conditions26 of 1.2 equiv of 1 and0.1 equiv of sulfuric acid at 50 �C led to the formation of 3a in93% isolated yield (Scheme 1). A range of other ketones could alsobe fluorinated using the Selectfluor™/sulfuric acid promoted con-ditions. Cyclic aryl ketones 3b and 3c were formed in high yields.Acyclic ketone 3d was formed in good yield, while reaction of

Table 1Synthesis of a-fluorotetralone 3a

O1 (1.2 equiv

H2SO4 (0.1 equiv

Entry Solvent Conversion after 4 ha (%)

1 MeOH P992 MeOH/H2O (9:1) 183 iPrOH 654 THF 655 THF/H2O (9:1) 116 EtOAc 657 EtOAc/H2O (9:1) 78 MeCN 119 MeCN/H2O (9:1) 5

a Conversion determined by 1H NMR.

para-ethoxyacetophenone afforded lower yields of the fluorinatedproduct 3e, with incomplete reaction conversions being obtained,even after reaction for extended periods and with the addition ofexcess 1. In addition, for the reaction in methanol some of the cor-responding dimethylketal of 3e was also observed in addition toketone 3e. Androsterone reacted to give 3f in 71% yield as a singleisolated diastereomer. Attempted reaction of other steroidalketones incorporating either aromatic rings (i.e., estrone), enones(i.e., progesterone and dydrogesterone) or alkenes (i.e., pregneno-lone) led to multiple fluorination products, suggesting that thesefunctionalities undergo competitive reaction under theseconditions.

Although the mechanism for formation of the fluoroketones 3has not been experimentally verified, it seems likely that reactionoccurs either via the corresponding nucleophilic enols or enolethers.27 The observation of the fluorinated dimethylketal side-product of 3e lends support to reaction occurring at least in partvia the methyl enol ethers. Dimethylketal adducts however werenot observed in the NMR of the crude reaction mixture of 3a. Theobservation of dimethylketal adducts of 3e presumably reflectsthe greater stability (equilibrium constant for formation) of aceto-phenone derived ketals.

We were also interested in the formation of fluorinated ketonesincorporating nitrogen heterocyclic rings, such as piperidones.8

Reaction of the free amines was considered unlikely to succeed,so N-protected piperidones were evaluated. Reaction of

OF.)

), 50 C

3a

Conversion after 24 ha (%) Conversion after 7 da (%)

— —93 9516 8865 —35 5065 —46 8085 9356 98

N

BnO O

FOO

N

BnO O

OO1 (3.0 equiv.)

MeCN / H2SO4 (0.1 equiv)50 C, 24 h, 88%

N

BnO O

O

HOOH

1 (1.3 equiv.)

MeCN / H2SO4 (0.1 equiv)50 C, 18 h, 81%

4d6

(2.0 equiv)

HOOH (2.0 equiv)

Scheme 3. Synthesis of spiroketal 4d.

OF

OHF(i)

(ii), (iii)

OHF

3a cis-7

trans-7

Scheme 4. Stereocontrolled synthesis of tetralone derived b-fluoroalcohols cis- andtrans-7. Reagents and conditions: (i) L-Selectride, THF, 0 �C then NaOH/H2O2 (72%yield); (ii) p-nitrobenzoic acid, PPh3, DEAD, THF, rt; (iii) NaOH, MeOH, THF (62%yield, over 2 steps).

J. Liu et al. / Tetrahedron Letters 53 (2012) 2971–2975 2973

N-protected piperidones in the presence of MeOH/MeCN (or meth-anol alone) led to the formation of the dimethyl ketals 4 ratherthan the expected ketones 5 (Scheme 2). Thus, 4a–c were formedin 70%, 83% and 94%, respectively on a 2–4 mmol scale.28 Reactionof N-Cbz piperidone on an 85 mmol scale afforded 4c in 80% iso-lated yield. These are interesting transformations since they areexamples of multicomponent coupling reactions,29 introducingthe fluorine substituent selectively b- to the amino functionality,and without the formation of multiply fluorinated products. Whilethe fluorination of acyclic and carbocyclic substrates led to the flu-oroketones 3a–f, the selective formation of fluoroketal adductsrather than fluoroketones products for the reactions of piperidonesis particularly noteworthy. This difference in behavior reflects theknown preference of the ketone group of 4-piperidones to reactto form stable ketals, hemiketals, and hydrates, and effect whichhas been attributed to the field effect of the piperidine nitrogen.30

The dimethylketals 4 could be readily deprotected to give the cor-responding ketones 5 using TFA/dichloromethane.31 The ketonescould also be formed directly by using acetonitrile rather than aMeOH based solvent system, affording 5b and 5c in 74% and 73%isolated yields, respectively on larger scale. The a-fluoropiperidoneproducts 5 incorporate fluorine substituent a- to the carbonyl andb- to the amino functionality.

An analogous approach could be used to form the spiroketal 4din good yield using 1 and ethylene glycol (Scheme 3). The spirok-etal 4d was also prepared in 88% yield (on a 30 mmol scale) fromthe spiroketal 6. Again there was no evidence for the formationof other fluorinated products in these reactions. The successfultransformation of 6 into 4d suggests an acid promoted ring-opening of the ketal to give an intermediate enol ether which thenundergoes fluorination followed by ring-closure to regenerate thespiroketal ring. Formation of 4d could also be achieved by thedirect fluoroketalization of the corresponding piperidone in 81%yield. Again this illustrates the potential of using fluorination reac-tions to achieve multi-component couplings.

The product a-fluoroketones 3 are useful synthetic precursorsand can be utilized for the synthesis of a variety of other fluori-nated products. For example, reduction of the fluorotetralone 3awith L-Selectride afforded the cis-substituted b-fluoroalcoholcis-7 in 72% yield as a single diastereomer (P98:2 d.r.) (Scheme4). Sodium borohydride reduction (MeOH, 0 �C or rt) gave a lowercis:trans diastereomeric ratio of 4:1, whereas the use of DIBAL-H(THF, �78 �C) gave a reversed 1:3 selectivity favoring the trans-7diastereomer. The alcohol trans-7 could also be obtained as a singlediastereoisomer via a two-step Mitsunobu/hydrolysis protocol in

N

R O

O

N

R O

F

N

R O

OF

MeO OMe4a (R = p-ClC6H4) 70%4b (R = p-CN-C6H4) 83%4c (R = OBn) 94%(80% on an 85 mmol scale)

5a (R = p-ClC6H4)5b (R = p-CN-C6H4)5c (R = OBn)

1 (1.5-2.2 equiv)H2SO4 (0.1 equiv)

MeOH / MeCN60 C, 16 h

TFA / CH2Cl2 (1:1)r.t., 1 h

5b 74% (on a 26 mmol scale)5c 80%(73% on a 10 mmol scale)

1 (1.5 equiv)H2SO4 (0.1 equiv)MeCN50 C, 24 h

5a 77%5b 91%5c 93%

Scheme 2. Formation of a-fluoropiperidones 5 and the corresponding ketals 4using 1 and sulfuric acid.

62% yield from cis-7. The b-fluoroalcohols can also be convertedto b-fluoroamines via Mitsunobu reaction, as for example in thereaction of cis-6 with MeNHTs to give 8 (Scheme 5). The a-fluoro-piperidones 5 and their ketals 4 are also valuable synthetic precur-sors as exemplified in an approach to spirocyclic fluoroamidineiNOS selective inhibitors.32

Encouraged by the success of the a-fluorination of ketones viaan intermediate enol ether and the known reactivity of glycals,we also wished to test whether similar reactivity could be achievedin the reactions of suitably protected cyclic enamines or vinylogousamides (Scheme 6).16 Previous studies had demonstrated that ena-mides can be halogenated at the b-position under electrophilicconditions, as for example in the b-iodination of carbamate pro-tected 2-pyrrolines.33 Reaction of N-Cbz-dihydropyridinone with1 in MeOH afforded the b-fluoropiperidine 9 in 52% yield. Similarreaction of N-Cbz-pyrroline with 1 in water/MeCN afforded theb-fluoropyrrolidine 10 in 92% yield as a mixture of diastereomers.

Similar reaction of N-Cbz-pyrroline with 1 in MeOH/MeCNafforded the CBz-protected b-fluoroamine derivative 11 in 80%yield as a mixture of diastereomers (Scheme 7). Allylation at the2-position could be achieved using N-acyliminium ion chemistryby the reaction of 11 with allyltrimethylsilane and BF3�OEt2, to give12 in excellent yield as a mixture of diastereomers. A hydrobora-tion/oxidation sequence gave alcohol 13. Conversion to the fluoro-pyrrolizidine 14 was achieved by catalytic TPAP oxidation to thecorresponding aldehyde, and then treatment under catalytichydrogenation conditions, via Cbz-deprotection/reductiveamination.

NF

OHF MeNHTs / PPh3

DEAD / THF59%

H3C Ts

cis-7 8

Scheme 5. Synthesis of a b-fluoroamine 8 using a Mitsunobu reaction of cis-7.

NCbz

1 (1.1 equiv)

H2O / MeCN4 C r.t., 92%

NCbz

F

OR

N

BnO O

O

N

BnO O

MeO OMe1 (1.5 equiv)H2SO4 (0.1 equiv)

MeOH50 C, 52%

F

OMe9

10

Scheme 6. Synthesis of b-fluoroamines using electrophilic fluorination.

NCbz

1, MeOH / MeCN

80% NCbz

F

OMeSiMe3

BF3 OEt2, CH2Cl2-78 C

NCbz

F(i) BH3 THF / THF

(ii) H2O2, NaOH NCbz

FOH

N

F(i) Pr4N+ RuO4 (0.5 mol%),NMO, 4Å MS, CH2Cl2

(ii) H2, Pd, EtOH

60%

60%

99%

11

12 13

14

Scheme 7. Application of electrophilic fluorination to the synthesis of afluoropyrrolizidine 14.

2974 J. Liu et al. / Tetrahedron Letters 53 (2012) 2971–2975

In conclusion, the use of sulfuric acid as a catalyst has beendemonstrated to facilitate the direct fluorination of ketones usingthe commercially available electrophilic fluorinating reagentSelectfluor™. Methanol or acetonitrile were shown to be the bestsolvents for the reaction. In the case of reaction in the presenceof methanol, a-fluoroketone or ketal products could be observeddepending upon the ketone substrate employed. Further kineticand mechanistic studies will be necessary to more fully establishthe mechanism for the transformation, but by analogy with bro-mination reactions, reaction presumably occurs through eitherthe corresponding enols or enol ethers, with the sulfuric acid pro-moting the formation of these nucleophilic intermediates. Thereactions generally occurred in good yields and with excellentselectivity for the formation of the monofluorinated products. Ena-mides could also be fluorinated using Selectfluor™, although thegreater nucleophilic character of these compounds was such thata sulfuric acid catalyst was unnecessary.

Acknowledgments

We thank the Natural Sciences and Engineering Research Coun-cil (NSERC) of Canada, AstraZeneca and the Ontario Research andDevelopment Fund for financial support. We thank Dr. A.B. Youngfor MS analyses.

References and notes

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3. For reviews of enantioselective fluorinations, see: (a) Lectard, S.; Hamashima,Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352, 2708–2732; (b) Ma, J.-A.; Cahard, D.Chem. Rev. 2008, 108, PR1–PR43; (c) Prakash, G. K. S.; Beirer, P. Angew. Chem.,Int. Ed. 2006, 45, 2172–2174; (d) Bobbio, C.; Gouverneur, V. Org. Biomol. Chem.2006, 4, 2065–2075; (e) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146.

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Reydellet-Casey, V.; Knoechel, D. J.; Herrinton, P. M. Org. Process Res. Dev.1997, 1, 217–221; (c) Hoffman, R. V.; Tao, J. J. Org. Chem. 1999, 64, 126–132; (d) Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479–3486; (e) Armstrong, A.; Dominguez-Fernandez, B.; Tsuchiya, T.Tetrahedron 2006, 62, 6614–6620; (f) Li, Y.; Mao, S.; Hager, M. W.;Becnel, K. D.; Schinazi, R. F.; Liotta, D. C. Bioorg. Med. Chem. Lett. 2007,17, 3398–3401.

8. For fluorinations of silyl enol ethers of piperidones, see for example: (a) Planty,B.; Pujol, C.; Lamothe, M.; Maraval, C.; Horn, C.; Le Grand, B.; Perez, M. Bioorg.Med. Chem. Lett. 2010, 20, 1735–1739; (b) Sum, A. M.; Lankin, D. C.; Hardcastle,K.; Snyder, J. P. Chem. Eur. J. 2005, 11, 1579–1591; (c) Armstrong, A.; Ahmed, G.;Dominguez-Fernandez, B.; Hayter, B. R.; Wailes, J. S. J. Org. Chem. 2002, 67,8610–8617; (d) van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.; Cheng,S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A. M.; Morrison, D.;Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russel, M. G. N.; Sohal, B.;Stanton, J. A.; Thomas, S.; Verrier, H.; Watt, A. P.; Castro, L. J. J. Med. Chem. 1999,42, 2087–2104.

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A. A.; Tartakovsky, V. A. J. Org. Chem. 2010, 75, 5367–5370; (b) Rudler, H.;Parlier, A.; Hamon, L.; Herson, P.; Chaquin, P.; Daran, J.-C. Tetrahedron 2009, 65,5552–5562; (c) Alkhathlan, H. Z. Tetrahedron 2003, 59, 8163–8170.

17. For examples fluorination of indoles, see: (a) Shibata, N.; Tarui, T.; Doi, Y.; Kirk,K. L. Angew. Chem., Int. Ed. 2001, 40, 4461–4463; (b) Baudoux, J.; Salit, A.-F.;Cahard, D.; Plaquevent, J.-C. Tetrahedron Lett. 2002, 43, 6573–6574; (c)Fujiwara, T.; Yin, B.; Jin, M.; Kirk, K. L.; Takeuchi, Y. J. Fluorine Chem. 2008,129, 829–835; (d) Lozano, O.; Blessley, G.; Martinez del Campo, T.; Thompson,A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur, V. Angew.Chem., Int. Ed. 2011, 50, 8105–8109; (e) Lin, R.; Ding, S.; Shi, Z.; Jiao, N. Org. Lett.2011, 13, 4498–4501.

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Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2002, 2609–2615.20. Stavber, G.; Zupan, M.; Stavber, S. Synlett 2009, 589–594.21. Pavlinac, J.; Zupan, M.; Stavber, S. Molecules 2007, 14, 2394–2409.22. Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahedron 2009, 65,

6611–6625.23. Toullec, J.; El-Alaoui, M. J. Org. Chem. 1986, 51, 4054–4061.24. For a review, see: Toullec, J. Adv. Phys. Org. Chem. 1982, 18, 1–77.25. Similar observations have been made for a-bromination reactions, see Ref.23

and Cohen, I. J. Am. Chem. Soc. 1930, 52, 2827–2835.26. Representative experimental procedure for the formation of fluorotetralone 3a: To

1-tetralone (1.33 mL, 10.0 mmol) and Selectfluor™ (4.25 g, 12.0 mmol) inMeOH (5.0 mL), was treated concd H2SO4 (53 lL, 1.00 mmol). The mixture wasstirred under N2 at 50 �C overnight, filtered and the solvent was removed invacuo. Ether was added and washed with water and brine and dried overMgSO4. The crude product was purified by flash chromatography (10% of EtOAcin hexane) to afford fluorotetralone 3a (1.44 g, 93%). 1H NMR (400 MHz, CDCl3)d 8.07 (d, J = 8.0 Hz, 1H), 7.53 (m, 1H), 7.36 (dd, J = 8.0, 8.0 Hz, 1H), 7.27 (d,J = 8.0 Hz, 1H), 5.15 (ddd, J = 47.5, 13.0, 5.0 Hz, 1H), 3.14 (m, 2H), 2.62–2.54 (m,1H), 2.41–2.33 (m, 1H). 19F NMR (400 MHz, CDCl3) d �190.6 (dm, J = 47.5 Hz).

27. For a discussion of the effects controlling a-bromination via either enol etheror enol intermediates, see Refs.23–25

28. Representative experimental procedure for the formation of 4-(3-fluoro-4,4-dimethoxypiperidine-1-carbonyl)benzonitrile 4b: To 4-(4-oxopiperidine-1-

J. Liu et al. / Tetrahedron Letters 53 (2012) 2971–2975 2975

carbonyl)benzonitrile (0.952 g, 4.17 mmol) in MeOH/MeCN (30 mL) was addedconcentrated sulfuric acid (50 lL, 0.94 mmol), followed by Selectfluor� (3.25 g,9.22 mmol). The mixture was heated at 60 �C under a nitrogen atmosphere for16 h. Saturated aq NH4Cl was added, and the mixture extracted with EtOAc(3 � 50 mL). The resulting solution was washed with brine, and dried overdried over magnesium sulfate. The crude product was purified by flashchromatography (50:50 EtOAc/heptane) to give 4b (1.01 g, 83%). 1H NMR(500 MHz, toluene-d8, 110 �C): d 7.18 (4H, m), 4.20 (1H, d, J = 47.6 Hz), 3.98(2H, br m), 3.11–3.00 (7H, m), 2.72 (1H, m), 1.83 (1H, m), 1.61 (1H, m). 19F NMR(470 MHz, toluene-d8, 110 �C) d �198.7 (dm, J = 47.2 Hz). 13C NMR (125 MHz,MHz, toluene-d8, 110 �C) d 169.0, 140.9, 137.8, 132.2, 118.2, 114.5, 98.2 (d,J = 21.2 Hz), 85.8 (d, J = 167.5 Hz), 47.9, 47.5, 47.0 (br), 41.0 (br), 28.5. LRMS (EI)m/z 292 (14), 262 (29), 241 (16), 130 (100), 101 (67). HRMS (EI) m/z calcd forC15H17FN2O3 [M]+ 292.1228, found 292.1223.

29. For a review of multi-component coupling reactions, see: MulticomponentReactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA:Weinheim, Germany, 2005.

30. (a) Brookes, P.; Walker, J. J. Chem. Soc. 1957, 37, 3173–3175; (b) Yagami, C.;Sugiura, M.; Tamura, K.; Takao, N. Chem. Pharm. Bull. 1980, 28, 2653–2657; (c)Yagami, C.; Sugiura, M.; Takao, N. Chem. Pharm. Bull. 1980, 28, 3665–3669; (d)Lyle, R. E.; Adel, R. E.; Lyle, G. G. J. Org. Chem. 1959, 24, 342–345; (e) Conroy, J.L.; Sanders, T. C.; Seto, C. T. J. Am. Chem. Soc. 1997, 119, 4285–4291.

31. Representative experimental procedure for the formation of 4 4-(3-fluoro-4-oxopiperidine-1-carbonyl)benzonitrile 5b: To 4-(3-fluoro-4,4-dimethoxypiperidine-1-carbonyl)benzonitrile 4b (0.292 g, 1.00 mmol) in dichloromethane (4 mL) undera nitrogen atmosphere was added trifluoroacetic acid (4 mL). The reactionmixture was stirred at room temperature for 1 h. The reaction was quenchedwith aq NaHCO3 (40 mL), and extracted with EtOAc (3 � 40 mL). The resultingsolution was washed with brine, and dried over dried over magnesium sulfate.The crude product was purified by flash chromatography (70:30 EtOAc/heptane) to give 5b (0.242 g, 91%). 1H NMR (500 MHz, toluene-d8, 110 �C): d(rotamers) 7.14 (2H, s), 7.06 (2H, s), 4.24 (1H, d, J = 48.5 Hz), 3.60 (1H, br s),3.29 (3H, br s), 2.30 (1H, s), 1.94 (1H, s). 19F NMR (470 MHz, toluene-d8, 110 �C)d (rotamers) �193.6, 196.0. 13C NMR (125 MHz, MHz, toluene-d8, 110 �C) d199.3, 169.0, 139.4, 137.8, 132.4, 117.7, 115.8, 90.0 (d, J = 237.5 Hz), 49.7 (d,J = 33.7 Hz), 44.3, 39.5 LRMS (EI) m/z 246 (46), 218 (23), 171 (8), 130 (100), 102(42), 75 (7). HRMS (EI) m/z calcd for C13H11FN2O2 [M]+ 246.0798, found246.0805.

32. Walpole, C.; Liu, Z.; Lee, E. E.; Yang, H.; Zhou, F.; Mackintosh, N.; Sjogren, M.;Taylor, D.; Shen, J.; Batey, R. A. Tetrahedron Lett. 2012, 53, 2942–2947.

33. (a) Norton Matos, M. R. P.; Afonso, C. A. M.; Batey, R. A. Tetrahedron Lett. 2001,42, 7007–7010; (b) Norton Matos, M. R. P.; Afonso, C. A. M.; McGarvey, T.; Lee,P.; Batey, R. A. Tetrahedron Lett. 1999, 40, 9189–9193.