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SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2017, 49, 3801–3834reviewen
Recent Advances in the Synthesis of Hydrogenated Azocine-Containing MoleculesAnna V. Listratova Leonid G. Voskressensky* 0000-0002-9676-5846
RUDN University, Miklukho-Maklaya St. 6, Moscow, 117198, Russian [email protected]
Dedicated to the memory of Professor N. S. Prostakov (1917–2007) on the occasion of his 100th anniversary.
Received: 22.01.2017Accepted after revision: 05.04.2017Published online: 01.08.2017DOI: 10.1055/s-0036-1589500; Art ID: ss-2017-e0041-r
License terms:
Abstract This review covers recent advances in synthesis of azocine-containing systems. The most approaches towards azocines are dis-cussed.1 Introduction2 Ring-Expansion Reaction2.1 Ring-Expansion Reaction of Cyclopentane Containing the 1,4-
Diketone Moiety with Primary Amines (from 5 to 8)2.2 Ring-Expansion Reaction of Annulated Tetrahydropyridines under
the Action of Activated Alkynes (from 6 to 8)2.3 Reductive Ring-Expansion Reaction of Cyclic Oximes2.4 Other Ring-Expansion Reactions3 Heck Reaction4 Cycloaddition5 Ring-Closing Metathesis (RCM)6 Cyclization6.1 Metal-Catalyzed Cyclization6.2 Radical Cyclization6.3 Friedel–Crafts Cyclization6.4 Other Examples of Cyclizations7 Microwave- and Photo-Assisted Reactions8 Other Methods8.1 Cascade and Tandem Reactions8.2 Aldol Condensation8.3 Thermolysis8.4 Ring Opening8.5 Other Methods9 Conclusion
Key words azocine, ring-closing metathesis, cycloaddition, ring ex-pansion, Heck reaction, domino reaction
1 Introduction
The chemistry of annulated azocines has not been ex-plored in detail owing to the lack of efficient methods fortheir synthesis. The only exception is azocinoindoles, whichhave been investigated extensively due to the great numberof alkaloids with an azocinoindole fragment in their struc-ture. This review highlights most recent approaches to-wards annulated azocine derivatives published after theyear 2009; the previous review was published in 2008.1
Scheme 1 Synthesis of benzo[c]azocines
O
CO2R1
COPhR-NH2
N
O R
Ph
CO2R1 2a–c
Bi(NO3)2•5H2OTHF, 100 °C, 16 h
1a R1 = Me b R1 = Et
N
O R
Ph
CO2Et
THF, 100 °C, 16 h
2d–f
2a R = R1= Me; 28% b R = Me, R1 = Et; 40% c R = Bn, R1 = Et; 8%
2d R = Me; 38% e R = Bn; 21% f R = CH2CH2OEt; 15%
R-NH2
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2 Ring-Expansion Reactions
2.1 Ring-Expansion Reaction of Cyclopentane Con-taining the 1,4-Diketone Moiety with Primary Amines (from 5 to 8)
In 2006 the Cristoffers group2 discovered a novel bis-muth-catalyzed ring-expansion reaction of 1,4-diketoneswith primary amines that furnished an eight-memberedring. In 2011, they extended their relatively simple methodto the synthesis of annulated azocines. Thus, starting from
ethyl 1-oxo-indane-2-carboxylate 1, containing a 1,4-dike-tone motif, and primary amines under the bismuth-cata-lyzed ring-expansion reaction conditions gave benzo[c]azo-cine derivatives 2 in moderate yields (Scheme 1).3 It wasalso shown that, in some cases, the presence of bismuth ni-trate was not essential.3
A bismuth-free strategy of ring enlargement was alsosuccessful in the case of regioisomeric pyrido[c]azocines.4Synthesized from commercially available materials, threecyclopentapyridine derivatives 3, 6, and 9, containing β-oxo
Scheme 2 Synthesis of a pyrido[2,3-c]azocine
N CO2Me
Br
N CO2H
Br
(a) (b)
92% 68%
N CO2Me
CO2tBu
N CO2Me
CO2tBu
(d)
50%
NO
CO2tBu
NO
CO2tBu
COPhN N
O Me
Ph
CO2tBu
(f)
64%
3
4 5
(a) SOCl2, MeOH, 0–85 °C, 24 h; (b) CH2=CHCO2tBu, Pd(OAc)2, PPh3, Et3N, DMF, 110 °C, 18 h; (c) Pd/C (cat.), H2 (1 atm), iPrOH, 23 °C, 22 h; (d) NaH, THF, 0–50 °C, 1 h; (e) PhCOCH2Br, K2CO3, acetone, 40 °C, 2 h;(f) MeNH2, THF, 100 °C, 16 h.
(c)
92%
(e)
31%
Scheme 3 Synthesis of a pyrido[3,4-c]azocine
NCO2Et
Me
NCN
Me
(a) (b) (c)
83% 74% 47%
(d)
54%
N
O
CO2tBuN
O
CO2tBu
COPh
NN
O Me
Ph
CO2tBu
(f)
NCO2Et
CH(CO2Et)2
NCO2Et
Cl
NCO2Et
Me
O
59%
6 7
(g)
36%
8
(a) 1. H2SO4/H2O, 130 °C, 17 h; 2. EtOH, 80 °C, 4 h; (b) m-CPBA, CHCl3, 0-23 °C, 19 h; (c) TsCl, 1,4-dioxane, 100 °C, 1.5 h; (d) Na in EtOH, CH2(CO2Et)2, THF, 0-23 °C, 2 h; (e) Na, in EtOH, 65 °C, 2 h; (f) PhCOCH2Br, K2CO3, acetone, 40 °C, 3 h; (g) MeNH2, THF, 100 °C, 17 h.
(e)
50%
Biographical Sketches
Prof. Leonid G. Voskressenskywas born in 1968 in Moscow,Russia. He obtained his B.Sc. inchemistry from the Peoples’Friendship University of Russia(PFUR) in 1992, and his M.Sc. in1994. He obtained his Ph.D. inorganic chemistry from thesame university in 1999. In
2001 he joined the group ofProf. Cosimo Altomare (Universitadegli Studi di Bari, Italy) as apostdoctoral fellow in medicinalchemistry. In 2001, he becameassistant professor, in 2006associate professor, and in 2011full professor in the organicchemistry department at PFUR.
Since 2013 he has been theDean of the Science Faculty atPFUR. His group’s scientific in-terests focus mainly on dominoreaction methodology, newmulticomponent reactions, andmedicinal chemistry.
Dr. Anna Listratova was born inMoscow, Russia. She obtainedher B.Sc. in chemistry from thePeople’s Friendship University of
Russia (PFUR) in 2003, followedby an M.Sc. degree in 2005. Sheobtained the Ph.D. degree in or-ganic chemistry from the same
university in 2008 under guid-ance of Prof. L. G. Voskressenskyand remains a member of hisgroup.
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ester moieties, were alkylated with phenacyl bromide togive 1,4-diketones 4, 7, and 10. The latter were subjected toring-expansion reactions with methylamine giving pyri-do[2,3-c]azocine 5 (Scheme 2), pyrido[3,4-c]azocine 8(Scheme 3), and pyrido[3,2-c]azocine 11 (Scheme 4) in 36–64% yield.
In 2015, a six-step sequence for the synthesis of regio-isomeric thieno[c]azocines started from commerciallyavailable bromothiophenecarboxylic acids was workedout.5 Isopropyl esters of the bromothiophenecarboxylic ac-ids were subjected to Heck reaction followed by catalytichydrogenation and Dieckmann condensation giving the cy-clic β-oxo esters 12, 15, and 18, alkylation of which withphenacyl bromide led to 1,4-diketones 13, 16, and 19. Thefollowing step, a bismuth-catalyzed ring expansion of cy-clopentathiophene derivatives 13, 16, and 19 with methyl-amine, produced the target tetrahydrothieno[3,2-c]azocine14 (Scheme 5), tetrahydrothieno[3,4-c]azocine 17 (Scheme6), and tetrahydrothieno[2,3-c]azocine 20 (Scheme 7).Overall yields for the final products were 25%, 16%, and 12%,respectively.
2.2 Ring-Expansion Reaction of Annulated Tetrahy-dropyridines under the Action of Activated Alkynes (from 6 to 8)
In 2002, an alkyne-induced ring-expansion reaction ofannulated tetrahydropyridines leading to the formation ofazocine rings was found.6 It is presumed that ring-expan-sion reaction involves the Michael addition of the tertiaryN-atom in the (hetero)annulated pyridine system to the tri-
ple bond of the activated alkyne, followed by a nucleophilicsubstitution (SN) reaction in zwitterionic intermediate A(Scheme 8).
Over the last 8 years this method was successfully ap-plied to the synthesis of various annulated azocines: triazo-lopyrimido[4,5-d]azocines 21,7,8 tetrahydro[1]benzothie-no[3,2-d]azocines 22,9 hexahydropyrimido[4,5-d]azocines23 and -[5,4-d]azocines 24,10 tetrahydropyrimido[4,5-d]azo-cines 25,11 tetrahydrobenzofuro[3,2-d]azocine 26,12 tetra-hydrothieno[2,3-d]azocines 27,13 tetrahydroazocino[5,4-b]indoles 28,14,15 hexahydropyrimidothieno[3,2-d]azocines29,16,17 and benzo[d]azocines 30,18 including systems ob-tained for the first time, tetrahydrothieno[3,2-d]azocines3119 and tetrahydrochromeno[4,3-d]azocine 32 (Figure 1).20
Scheme 4 Synthesis of a pyrido[3,2-c]azocine
(c)
67%
(d)
74% N
O
CO2tBu
N
O
CO2tBu
COPh
N
N
O Me
Ph
CO2tBu
(f)
N
CO2Et
CH(CO2Et)2
N
CO2Et
ClN
CO2Et
Me
48%
11
Me
O
CO2Et
9
10
(a) 1. NH4OAc, toluene, 110 °C, 2 h; 2. CH2=CHCHO, 110 °C, 2.5 h; (b) DMF, trichloroisocyanuric acid, CH2Cl2, 23 °C, 16 h; (c) Na, in EtOH, CH2(CO2Et)2, THF, 0–23 °C, 4 h; (d) NaH, THF, 65 °C, 1 h; (e) PhCOCH2Br, K2CO3, acetone, 56 °C, 3 h; (f) MeNH2, THF, 100 °C, 15 h.
(a) (b)
34% 90%
(e)
71%
Scheme 5 Synthesis of a tetrahydrothieno[3,2-c]azocine
S Br
CO2H
S Br
CO2iPr
S
CO2iPr
S
CO2tBu
S
O
CO2tBu
COPh N
S
O Me
Ph
CO2tBu
(a) 1. SOCl2, reflux, 3.5 h, 2. DMAP (cat.), iPrOH, 90 °C, 20 h; (b) CH2=CHCO2tBu, Pd(PhCN)2Cl2, Me2NCH2CO2H, NaOAc, NMP, 130 °C, 20 h; (c) Pd/C (cat.), H2 (1 atm), iPrOH, 23 °C, 1 d; (d) tBuOK, THF, 0 °C, 45 min; (e) PhCOCH2Br, K2CO3, acetone, 40 °C, 23 h; (f) MeNH2, Bi(NO3)2•5H2O, THF, 120 °C, 4 d.
(a) (b)
(e)
94%
(f)
39%
CO2tBu
S
CO2iPr
CO2tBu
94% 85%
(c)
99%
O
(d)
54%
12
13 14
Scheme 6 Synthesis of a tetrahydrothieno[3,4-c]azocine
S
CO2H
S
CO2iPr
S
CO2iPr
S CO2tBu
S
O
CO2tBu
COPhN
S
O Me
Ph
CO2t-Bu(a) 1. SOCl2, reflux, 3 h, 2. DMAP (cat.), iPrOH, 90 °C, 15 h; (b) CH2=CHCO2tBu, Pd(OAc)2, Ph3P, Et3N, DMA, 130 °C, 21 h; (c) Pd/C (cat.), H2 (1 atm), iPrOH, 23 °C, 4 d; (d) tBuOK, THF, 0 °C, 45 min; (e) PhCOCH2Br, K2CO3, acetone, 40 °C, 19 h; (f) MeNH2, Bi(NO3)2•5H2O, THF, 120 °C, 4 d
(a) (b)
96% 91%
(c) (d)
86% 51%
16 17
Br Br CO2tBu
S
CO2iPr
CO2tBu
O
(e) (f)
82% 37%
15
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Attempts to combine the aforesaid ring expansion andUgi or Ugi-azide transformations into a single multicompo-nent reaction succeeded and provided thieno[3,2-d]azocine3321 (Scheme 9) and tetrazolyl-substituted benzo[d]azocine3418 (Scheme 10) in moderate yields.
2.3 Reductive Ring-Expansion Reaction of Cyclic Oximes
Using a method devised by Cho, Tokuyama, and co-workers, regiocontrolled reductive ring-expansion of cyclicoxime with diisobutylaluminum hydride gave benzo[b]azo-
Scheme 7 Synthesis of a tetrahydrothieno[2,3-c]azocine
S CO2H
Br
S CO2iPr
Br
S CO2iPr
CO2tBu
S CO2iPr
CO2tBu
S
O
CO2tBu
S
O
CO2tBu
COPh NS
O Me
Ph
CO2t-Bu
(a) 1. SOCl2, reflux, 3 h, 2. DMAP (cat.), iPrOH, 90 °C, 19 h;(b) CH2=CHCO2tBu, Pd(OAc)2, Ph3P, Et3N, DMA, 100 °C, 1 d; (c) Pd/C (cat.), H2 (1 atm), iPrOH, 23 °C, 1 d; (d) tBuOK, THF, 0 °C, 45 min; (e) PhCOCH2Br, K2CO3, acetone, 40 °C, 15 h; (f) MeNH2, Bi(NO3)2•5H2O, THF, 120 °C, 4 d.
(a) (b)
99% 98%
(f)
47%
(c) (d) (e)
96% 68% 93%
18
19 20
Scheme 8 Plausible mechanism for the transformation of the tetrahy-dropyridine ring
N
Me
Me
MeR1
R2
N
Me
Me
Me
R2
R1
N
Me R2
R1
Me
MeA
Figure 1 Series of annulated azocines obtained by alkyne-induced ring-expansion reaction
N
N
NH
N
N NMeS
O R2
R
N
S R2
R1
R3
R
R1
HN
N
O R2
R1
RR3
NHN
N
O
CO2Me
Bn
R N
N
N
NR4R5 R2
RR3
N
O
Me
CO2Me
Me
NS
Ar R2
R1
Me
N
NH R2
Et
R3
R1 N
S
N
NR2
RO
R4 R1
R3N
O
R
R2
R1
N
NN
N R3
OMe
N
S
R
R1
R2
EtO2C
HN
N
O
O
AcO
Bn
CO2Me
R1 = H, CO2MeR2 = COMe, CO2Me
R3
O
21 22 23 24 25
26 27 28 29 30
31 32
Scheme 9 Combination of ring-expansion and Ugi reactions
NS
EtO2C
HN
MeO
CF3H
O MeHC O
OH
CN O Me
Me
MeCN–5 to 0 °C
N
S
EtO2C
HN
CF3O
Me
O
O
NH
O
Me
O
Me
Me
33 (32%)
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cine 35 and dibenzo[b,f]azocine 36 in high yields as a singleregioisomer with the nitrogen atom located in the positionneighboring the aromatic ring (Scheme 11).22–24
Based on this ring-expansion reaction of oximes, a con-cise synthesis of 17β-HSD3 inhibitor with a dibenzoazocineskeleton was carried out.25 All attempts to convert oximes37a,b into a single regioisomer failed, hence a mixture ofdibenzoazocines 38a and 39a in the ratio 2:1 or dibenzoazo-cines 38b and 39b in the ratio 6:1 was used. After acylationof dibenzoazocines 38 and 39 the obtained regioisomers 40and 41 were separated. Compound 40a was coupled underthe Suzuki–Miyaura coupling conditions to provide 17β-HSD3 inhibitor 42 in 70% yield. Desulfurization of 42 withRaney Ni gave also 17β-HSD3 inhibitor 43 (Scheme 12).Since 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3)is an enzyme involved in testosterone biosynthesis, inhibi-tors of 17β-HSD3 could provide new medicines for thetreatment of prostate cancer.
2.4 Other Ring-Expansion Reactions
Treatment of 1-vinyl-substituted indolinium salt 44 inrefluxing THF with the Hoveyda–Grubbs second-generationcatalyst (H-G II) resulted in allylic rearrangement to give azo-cino[5,4-b]indole 45, the product of ring expansion, in 44%yield (Scheme 13).26
A conceptually new and elegant strategy for the con-struction of 1H-azocino[5,4-b]indoles 47 and 48 via a gold-catalyzed ring expansion of 2-propargyl-β-tetrahydrocar-bolines 46 was developed by Zhang and co-workers.27 Theazocinoindoles 47 and 48 were obtained in moderate to ex-cellent yields. The method features mild conditions andwide functional group tolerance (Scheme 14).
Scheme 10 Combination of ring-expansion and Ugi-azide reactions
N
NO
Me
OMe
HC
CO2Me NC
Me
MeNaN3
MeOH–H2O
Me
CO2MeN
NN
N
O
MeO
R
R =
Me
Me
34 (38%)
Scheme 11 Synthesis of azocine systems via reductive ring-expansion reaction of cyclic oximes
HN
NH
1. DIBAL-H, CH2Cl2 0–5 °C
2. NaF
1. DIBAL-H, CH2Cl2 0–5 °C
2. NaF
35 (80%)
36 (73%)
N
NHO
HO
Scheme 12 A concise synthesis of 17β-HSD3 inhibitor
MeO2C
I
Br
5 steps
O HON
X
Br
X
Br
pyridine reflux
37a X = H; 90%37b X = SMe; 66%
NH
NH
X
Br
X
Br N N
X
Br
X
Br
OMe
OMe
N
X
Ph
OMe
DIBAL-H
CH2Cl2
38a X = H 39a X = H38b X = SMe 39b X = SMe
Ac2O, DMAP
Et3N, CH2Cl2, r.t.
40a X = H; 66% 41a X = H; 19%40b X = SMe; 70% 41b X = SMe; 11%
PhB(OH)2Pd(PPh3)4 (10 mol%)
K2CO3
THF–H2O, reflux
43 X = H; 70%42 X = SMe; 78%
Raney Ni, EtOH, reflux, 69%
+ +
NH2OH·H2O
40a,b
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Binaphthyl-azocines 50 were synthesized by the directcopper-catalyzed ring-expansion reaction of binaphthyl-azepines 49 and α-diazocarbonyl reagents.28 This transfor-mation is considered to be an example of a [1,2-]Stevens re-arrangement and presents a facile access to binaphthyl-azo-cines in moderate to high yields (Scheme 15).
Naphtho[1,8-ef]pyrimido[4,5-b]azocines 53 were pre-pared from acenaphthoquinone (51) and 6-aminouracil de-rivatives 52 in high yields.29 The ring expansion was carriedout as a one-pot process and included two steps: the addi-tion reaction of starting compounds and the subsequentoxidation cleavage of the intermediate in the presence ofPd(OAc)4 (Scheme 16).
Scheme 16 Synthesis of naphtho[1,8-ef]pyrimido[4,5-b]azocines
Azocine 55 and annulated azocine 57 were produced bya ring-expansion transformation of the piperidine ring ofcompounds 54 and 56 under the action of methyl propyn-oate and dimethyl butynedioate, respectively (Scheme17).30
3 Heck Reaction
The intramolecular Heck reaction is considered to beone of the most useful methods for the construction of me-dium-sized heterocycles due to its functional group toler-ance and high stereoselectivity. In 2009, the Majumdargroup developed an interesting and simple procedure forthe synthesis of various annulated azocines from unactivat-ed allylic substrates using a combination of two reactions,the aza-Claisen rearrangement and a palladium-catalyzedintramolecular Heck reaction. Thus, an appropriate sub-strate 59, prepared from N-allylanilines 58 by aza-Claisen
Scheme 13 Allyl rearrangement of 1-vinyl-substituted indolinium salt
N
N MeI
THF N
NMe
I
THF
N
NMe
N
N
45 (44%)
N NMes Mes
Ru
O
ClCl
H-G II =
44
H-G II
Scheme 14 Synthesis of 1H-azocino[5,4-b]indoles via a gold-catalyzed ring expansion of 2-propargyl-β-tetrahydrocarbolines; Au(I) = [AuNTf2(PPh3)]
N
N
R
R1
Au(I)toluene110 °C
N
N
R1
R
NH
N
R1
R
1. Au(I), toluene, 110 °C
2. NaBH(OAc)3, AcOH
46a R = CO2Me; R1 = Et; R2 = R3 = H46b R = CO2Me; R1 = CH2OTBDPS; R2 = R3 = H46c R = COPh; R1 = Et; R2 = R3 = H46d R = COMe; R1 = 4-MeOC6H4; R2 = R3 = H46e R = CO2Me; R1 = 4-O2NC6H4; R2 = R3 = H
R2
R2
R3
R3
47b 71%47c 45%
48a 92%48d 88%48e 87%
Scheme 15 Synthesis of binaphthyl-azocines
NCO2R1
R
CO2R1
N R
O
O
N2
O
OR1R1
Cu source
toluene 100 °C
R = Ph, 4-MeOC6H4, 4-MeC6H4, 4-BrC6H4, MeR1 = Me, Et
49 50 (61–93%)
Cu source = Cu(OTf)2 or CuI
O O
N
N
O
R
O
R1
H2N
HNO
NN
O
O
O
R1 R
1. EtOH/AcOH (10:1), 70 °C
2. Pb(OAc)4, r.t.
a R = R1 = Me; b R = H, R1 = Me; c R = R1 = H; d R = H, R1 = Bn; f R = H, R1 = Ph
51 52 53 (91–93%)
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rearrangement, tosylation, and alkylation with 2-bromo-benzyl bromides, was subjected to the intramolecular Heckreaction to give exo-Heck cyclized products, dibenzo[b,f]azo-cines 60, in 72–79% yields (Scheme 18).31
Scheme 18 Synthesis of dibenzo[b,f]azocines via the intramolecular Heck reaction
This strategy was successfully used for the synthesis ofdibenzo[b,f]azocinones.32 The precursors 61 for the Heckreaction were obtained from N-allyl-substituted anilines byaza-Claisen rearrangement, tosylation, and amidation with2-iodobenzoyl chloride. The products of the Heck reactiondepended on the conditions used. It was shown thatJeffrey’s two-phase protocol32 led to endocyclic product 63whereas phosphine-assisted standard conditions yieldedexocyclic products 62 (Scheme 19).
Scheme 19 Synthesis of dibenzo[b,f]azocines via the intramolecular Heck reaction
The same combined aza-Claisen rearrangement and in-tramolecular Heck reaction was successfully applied to thesynthesis of coumarin- or quinolone-annulated azocines6533 and pyrimidoazocines 67.34 The precursors 64 for theHeck reaction were synthesized using aza-Claisen rear-rangement of N-allylcoumarins or N-allylquinolones fol-lowed by alkylation with benzyl bromides. The intramolec-ular Heck reaction afforded azocine 65 in 75–79% yields(Scheme 20).
Scheme 20 Synthesis of coumarin- and quinolone-annulated azocines
In the case of pyrimido[5,4-b]azocines 67, the sub-strates 66 for the Heck reaction were prepared from 1,3-di-alkyl-5-bromouracils by reaction with allylamine, subse-quent aza-Claisen rearrangement, tosylation, and alkylationwith 2-bromobenzyl bromide. Pyrimidoazocines 67 wereobtained in high yields (Scheme 21).
The Majumdar group achieved another efficient andstraightforward method for the construction of dibenzoazo-cinones 72 and coumarin- and quinolone-annulated azoci-
Scheme 17 Synthesis of azocines via transformation of the piperidine ring
N
OH
O
Me
MeO2C
CO2Me
N
OH O
CO2Me
CO2MeMe
56 57 (23%)
N
OH O
N
Me
OHO
Me
CO2Me
CO2Me
54 55 (42%)
R
NH2
HN
NH2
R
R
R = 4-Me; 2-F; H
NH
R
Ts
N
R
Ts
R1
Br
Br R1
allyl bromide
DMF, K2CO3, reflux
BF3•Et2O
xylene, 140 °C
TsCl
Py, heat
N
Ts
R1
R
Pd(OAc)2 TBABKOAc
DMF, N2 90 °C
a R = 4-Me, R1 = H; b R = 2-F, R1 = H; c R = R1 = H; d R = 4-Me, R1 = OMe; e R = 2-F, R1 = OMe; f R = H, R1 = OMe
Br58
59 60
N
N
Ts
Pd(OAc)2, TBAB, KOAc
DMF, N2, 90 °C
Ts
O
I
N
Ts
Me
Pd(OAc)2, Ph3P, NaOAc
DMA, N2, 90 °C
R R
R1
a R = R1 = H; 59%; b R = F, R1 = H; 49%
a R = R1 = H; 82%; b R = F, R1 = H; 73%;c R = H, R1 = OMe; 82%; d R = H, R1 = Me; 76%;e R = Me, R1 = H; 79%
O O
61
62 63
R
R1
R1
X
O
NR
BrR1
64 65 (75–79%)
N
XOR
Me
R1
a X = O, R = Et, R1 = H; b X = O, R = Et, R1 = OMe; c X = O, R = Me, R1 = H; d X = O, R = Me, R1 = OMe;e X = NH, R = Me, R1 = H; f X = NH, R = Me, R1 = OMe
Pd(OAc)2 DMF, KOAc
Ph3P N2, 90 °C
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nones 73 via Pd-mediated reductive Mizoroki–Heck reac-tion.35 The starting N-methyl or N-ethyl o-substitutedamines 68 and 71 reacted with 2-iodophenylacetyl chloridegiving amides 69 and 72, which were subjected to Heck re-action producing the 8-exocyclized products 70 and 73 in42–60% yields (Scheme 22).
Kim and co-workers obtained tetracyclic azocine sys-tems 77 from indole derivatives 76 by applying the intra-molecular palladium-catalyzed Heck reaction.36 The re-quired starting materials were synthesized by the reactionof Baylis–Hillman acetates 74 and indoles 75 (Scheme 23).
Scheme 21 Synthesis of pyrimido[5,4-b]azocines
N
N
N
O
O
R1
R
N
R2
Br
N
N
Me
O
O
R1
R
R2Ts TsDMF
Pd(OAc)2 KOAc
TBAB, N2 90 °C
a R = R1 = Me, R2 = H; 85%; b R = R1 = Me, R2 = OMe; 83%;c R = R1 = Et, R2 = H; 80%; d R = R1 = Me, R2 = OMe; 81%;e R = Et, R1 = Me, R2 = OMe; 85%
66 67
Scheme 22 Construction of dibenzoazocinones and coumarin- and quinolone-annulated azocinones via Pd-mediated reductive Mizoroki–Heck reaction
PhHN
R
Ph
RHN
XO
PhN
R
OI
2-iodophenylacetyl chloride
CHCl3/H2O, TBAHS
2-iodophenylacetyl chloride
CHCl3/H2O, TBAHS
N
O
Ph
Pd(PPh3)4/HCOONa
DMF/H2O, 100 °C
PhRN
XO
OI
Pd(PPh3)4/HCOONa
DMF/H2O, 100 °C
X
N
Ph
O
R
O
70a R = H; 65%70b R = Me; 60%
73a X= O, R = Me; 55%73b X = O, R = Et; 56%73c X = NMe, R = Et; 45%73d X = NEt, R = Me, 42%
68 69
71 72
R
Scheme 23 Synthesis of tetracyclic azocine derivatives
Br
OAc
CO2Me
NH
R
R1 KOH
DMF, 0 °C
N
CO2Me
Br
RR1
Pd(OAc)2TBAB
K2CO3, DMF100 °C
N
CO2Me
R1
R
77a R = H, R1 = Me; 53%;77b R = R1 = Me; 60%
45–62%74 75
76
Scheme 24 Synthesis of benzo[4,5]azocino[3,2,1-hi]indoles
Br
OAc
CO2Me
NH
OKOH
DMF, r.t.
N
CO2Me
Br
OO
Pd(OAc)2 TBAB
K2CO3 DMF, 100 °C
N
CO2Me
O
O
a R = H; 55%; b R = Cl; 50%
OR
R
R
81–87%74 78
79 80
Scheme 25 Synthesis of benzo[e]imidazo[4,5,1-kl][1]benzoazocines
Br
OAc
CO2Me KOH
MeCN, 0 °C
Pd(OAc)2, TBAB
K2CO3, DMF, 100 °C
83a R = Ph; 48%; 83b R = Me; 36%
N
NH
R
N
CO2Me
Br
NR
N
N
CO2Me
R
67–71%74 81
82
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Application of this protocol to compounds 79, 82, and85, derived from the reaction of Baylis–Hillman acetate 74with isatins 78, benzimidazoles 81, and carbazole 84, re-
spectively, resulted in the formation of tetra(penta)cyclicazocines, benzo[4,5]azocino[3,2,1-hi]indoles 80 (Scheme24), benzo[e]imidazo[4,5,1-kl][1]benzoazocines 83(Scheme 25), and benzo[4,5]azocino[1,2,3-jk]carbazole 86(Scheme 26).37
Martin and co-workers synthesized azocino[3,4,5-cd]in-doles 88 + 89 and 91 by Pd-catalyzed microwave-assistedHeck reaction from allylamine derivative 87 or enamine 90(Scheme 27).38
The unusual Heck product azocino[4,3-b]indole 93, re-sulting from an apparent 7-endo-cyclization with inversionof the ethylidene configuration, was obtained from cyclo-hepta[b]indole 92 in 43% yield (Scheme 28).39
A readily separable mixture (1.3:1.0) of bridged ben-zoazocines 95 and 96 was formed through an intramolecu-lar microwave-assisted Heck cyclization from azepine de-rivative 94 (Scheme 29).40
Dibenzo[b,f]azocine 98 was produced via microwave-assisted Heck coupling from bifunctional precursor 97 pre-pared by vinylation of bromobenzaldehyde and subsequentreductive imine condensation with the relevant 2-bro-moaniline.41 Dibenzo[b,f]azocine 98 was also synthesizedby a Suzuki–Heck cascade and also by a one-pot prepara-tion (Scheme 30).41
Starting from propargylamide 99, a novel protocol forthe tandem Heck–Suzuki reaction was used for the con-struction of the benzoazocines 100 and 101 (Scheme 31).42
Scheme 26 Synthesis of benzo[4,5]azocino[1,2,3-jk]carbazole
Br
OAc
CO2Me KOH
DMF, 0 °C
Pd(OAc)2 TBAB
K2CO3 DMF, 100 °C
NH
N
CO2Me
Br N
CO2Me
64%74 84
85 86 (68%)
Scheme 27 Synthesis of azocino[3,4,5-cd]indoles by Pd-catalyzed mi-crowave-assisted Heck reaction
N
Br CHO
Ts N
Br
Ts
Pd(OAc)2, P(o-Tol)3
Et3N, TBAC, MeCN120 °C, MW
N
Ts91 (72%)
1. allylamine, MS, THF; allylMgBr, –78 °C to rt; ClCO2Bn
2. Grubbs II, CH2Cl2 95%
NCbz
NCbz
90
N
Br CHO
Ts
N(TMS)2
TMSOTf, CH2Cl2
AcCl, OTMS
OMe
N
Br
Ts
N
CO2Me
Ac
Pd(OAc)2, Ph3P
Et3N, MeCN, 125 °C MW
N
N
CO2Me
Ac
N
N
CO2Me
Ac
Ts Ts
87
88 (83%) 89 (12%)
N NMes Mes
Ru
PCy3Cl
Cl
Ph
Grubbs II
Scheme 28 Synthesis of an azocino[4,3-b]indole
N
NMeO2C
I
Me
SO2Ph
N
SO2Ph
HN
Me
H
MeO2C
Pd(OAc)2, Ph3P, Ag2CO3
toluene, 80 °C
92 93 (43%)
Scheme 29 Synthesis of bridged azocines through an intramolecular microwave-assisted Heck reaction
N
Br
CbzPd(OAc)2 (10 mol%)P(o-Tol)3(20 mol%)
TBAC DIPEA
MeCN, MW79%
N NCbz Cbz
94 95 96
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4 Cycloaddition
In 2009, Rovis and co-workers developed the first enan-tioselective rhodium-catalyzed [4+2+2] cycloaddition ofterminal alkynes 102 and dienyl isocyanates 103 leading tothe formation of bicyclic azocines 104 and 105.43 Pyrro-lo[1,2-a]azocines 104 and 105 were obtained in good tohigh yields and excellent enantioselectivity (Scheme 32).The geometry of the diene moiety had a significant effecton the selectivity of the products and used pure (E)-dienewas used as the starting substrate.
A new and simple synthesis for azocine derivatives 108by [6+2] cycloaddition reaction was suggested by Saito andco-workers.44 Electron-deficient allenes 107 reacted with2-vinylazetidine 106 giving azocines 108 in moderatedyields (Scheme 33).
Louie and co-workers demonstrated in 2012 that azeti-din-3-ones 110 under the action of diynes 109 underwent aNi/IPr-catalyzed cycloaddition reaction leading to dihy-
Scheme 30 Synthesis of dibenzo[b,f]azocine by a Suzuki–Heck cascade
Br
CHO CHO
HN
Br
Br
H2Nsiloxane
TBAF NaCNBH3, ZnCl2 MeOH
NH
Pd(dba)2 SPhos
base 120 °C, MW
71%
SPhos =
OMe
PCy2
MeO
Br
HN
Clboroxine/K2CO3
Pd(dba)2
SPhos120 °C73%
Br
Br H2N
Cl
K2CO3, then boroxinePd(dba)2, SPhos
120 °C 33%
boroxine =B
OB
O
BO
N
97 98
Scheme 31 Synthesis of benzoazocines 100 and 101 via a Heck–Suzuki cascade
N
MeO
MeO
N
Br
PMB
O
Me
MeO
MeO
MePh O
PMB
N
MeO
MeO
MeO
PMB
PhB(OH)2
BF3K
Pd(PPh3)2Cl2K3PO4, DMF/H2O
110 °C, MW
Pd(PPh3)2Cl2K3PO4, DMF/H2O115 °C, MW
101 (59%)
100 (13%)
99
Scheme 32 Synthesis of pyrrolo[1,2-a]azocines
N
R
NC
O
R1R
R1
O
Hligand (10 mol%) PhMe, 110 °C
O
O O
P
O
Me
Me
Ar Ar
Ar Ar
Nligand =
102 103 104 R1 = H a R1 = H 105 R1 = Me b R1 = Me
Nn-Hex
O
H104a 74%, 99% ee 104b 69%, 99% ee
N
O
H
Cl
104c 65%, 99% ee 104d 82%, 99% ee
N
O
H
TIPSON
O
H
N
O
O
Nn-Hex
O
H
105a 62%, 99% ee 105b 51%, 99% ee
N
O
H
TIPSO
Me Me
Some examples:
[Rh(C2H4)2Cl2] (5 mol%)
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droazocinones 111 (Scheme 34).45 The method involves aCsp2–Csp3 bond-cleavage step that proceeds at low tem-peratures.
Scheme 34 Synthesis of dihydroazocinone derivatives
In 2013, Louie and co-workers reported the Ni/P(p-Tol)3-catalyzed cycloaddition of 1,3-dienes 112 and azeti-din-3-ones 113 yielding 1,4,7,8-tetrahydroazocin-2(3H)-ones 114 (Scheme 35).46
Bower and co-workers reported a direct approach tosubstituted azocinediones 116 by a Rh-catalyzed cycloaddi-tion–fragmentation process.47 Exposure of N-cyclopropyl-acrylamides 115 to phosphine-ligated cationic Rh(I) cata-
lyst systems under a CO atmosphere led to the formation ofrhodacyclopentanone intermediates. The subsequent inser-tion of the alkene fragment into the intermediates was fol-lowed by fragmentation to give azocinediones 116 (Scheme36). The overall process is considered to be equivalent to a[7+1]-cycloaddition–tautomerization sequence.
5 Ring-Closing Metathesis (RCM)
Another powerful method for the construction of medi-um-sized nitrogen-containing systems that has receivedconsiderable attention in recent years is ring-closing me-tathesis.
Li and co-workers reported a five-step sequence for theconstruction of dibenzo[b,f]azocinone 119 where the keystep was ruthenium-mediated ring-closing metathesis.48
Starting from methyl 4-amino-3-iodobenzoate (117) thesynthesis involved Stille coupling with tributyl(vinyl)stan-nane, followed by acylation with 2-vinylbenzoyl chloride,Boc protection, and RCM. Using Grubbs II catalyst, RCM ofcompound 118 resulted in dibenzo[b,f]azocinone 119(Scheme 37).
Starting from styryldiazoacetate 120, azocine 122 wasobtained by a sequence of two reactions: N–H insertion andRCM.49 It was also possible to combine the carbenoid N–Hinsertion and RCM reactions in a one-pot procedure for thesynthesis of methyl 1,2,5,6,7,8-hexahydroazocine-2-car-boxylate 122 (Scheme 38).
Scheme 33 Synthesis of azocine derivatives
N
Bn
•
R NBn
R
THF, rtovernight
106 107a R = Ac 108a R = Ac; 54% 107b R = COPh 108b R = COPh; 58%
N
Me
Y
R
N
O
R1
Y
O Me
R1
R
[Ni(cod)2] (10 mol%)IPr (20 mol%)
toluene, 0 °C
109 110 111
N
O Me
R1
Me
CO2Me
CO2Me
R1 = Boc; 88%R1 = CO2Me; 69%R1 = CHPh2; 92%
NY
O Me
Ph2HC
MeY = C(CH2CO2Me)2; 48%Y = O; 91%Y = NTs; 79%Y = C(SO2Ph)2; 59%
Some examples:
Scheme 35 Synthesis of 1,4,7,8-tetrahydroazocin-2(3H)-ones
X
R
R X
O O
R
R
[Ni(cod)2] (10 mol%)P(p-Tol)3 (25 mol%)
1,4-dioxane, 100 °C
112 113 114
a R = Me, X = NBoc; 79%b R = Bn, X = NBoc; 80%c R = CH2CH2Ph, X = NBoc; 82%, etc.
Scheme 36 Synthesis of azocinediones via a Rh-catalyzed cycloaddi-tion–fragmentation process
NBn
O
R1
R2
R
Conditions A:[Rh(cod)2]OTf (10 mol%)P[3,5-(CF3)2C6H3]3 (20 mol%)PhCN, CO, 150 °C
Conditions B:[Rh(cod)2]BARF (10 mol%)P[4-(CN)C6H4]3 (10 mol%)PhCN, CO, 150 °C
Rh
O
NBn O
R1
R2
NBn
O
O
Rh
R1
R2
NBn
O
O
R1
R2
R
R
R
115
116
116a R = R1 = R2 = H; 74% (A)116b R = R2 = H, R1 = Me; 67% (A)116c R = R2 = H, R1 = NPhth; 82% (A)116d R = R2 = H, R1 = PMP; 59% (A)116e R = R2 = H, R1 = Ph; 63% (A)116f R1 = R2 = Ph, R = Bu; 67% (B; trans-115f)116g R1 = R2 = Ph, R = Cy; 43% (B; trans-115g)116h R1 = R2 = Ph, R = Bn; 60% (B; trans-115h). etc.
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Carbamate 124, obtained through condensation of ami-nobenzaldehyde 123 with methylamine and subsequent insitu reaction with benzyl chloroformate and then allylzincbromide, underwent facile RCM in the presence of Grubbs IIcatalyst to give benzo[b]azocine 125 in 81% yield (Scheme39).38
The ring-closing metathesis approach was utilized toprepare novel 1,7-annulated azocino[3,2,1-hi]indole deriva-tives 129 starting from indoles 126 (Scheme 40).50,51
Formylation of indole 126 followed by allylation of the N-atom and condensation with nitromethane led to 1-allyl-7-(2-nitrovinyl)indole 127. Reaction of 1-allyl-7-(2-nitrovi-nyl)indole 127 with allylmagnesium bromide gave 1-allyl-7-[1-(nitromethyl)but-3-enyl]indole 128 that underwent
ring-closing metathesis to give azocinoindoles 129 in mod-erate yields.
Based on combined the aza-Claisen rearrangement andring-closing metathesis, the Majumdar group obtained pyr-imido[5,4-b]azocine derivatives 135 in excellent yields(Scheme 41).52 The starting 5-bromouracil derivatives 130reacted with allylamine to give 5-allyluracils 131, subse-quent catalyzed aza-Claisen rearrangement and tosylationled to tosyl derivatives 133. Reaction of 133 with homoallyl
Scheme 37 Synthesis of a dibenzo[b,f]azocinone
BocN
MeO
O
I
NH2
SnBu3
Pd(PPh3)4, K2CO3
toluene, EtOH, 90 °C
MeO
O
NH2
117
Cl
O
MeO
O
NH
O
Boc2O, Et3NDMAP, CH2Cl2
0 °C to rt
MeO
O
NBoc
O
MeOO
O
Grubbs II
toluene 120 °C
118 119 (69%)
Scheme 38 Synthesis of methyl 1,2,5,6,7,8-hexahydroazocine-2-car-boxylate
N
MeO
O
N2
Ph
MeO
O
N
Ph
Boc
NHBoc
CO2Me
Boc
i)
ii)
(i) Rh2(S-DOSP)4 (1 mol%), DCE, rt; (ii) Grubbs II or Hoveyda–Grubbs II (8–10 mol%), CH2Cl2, reflux
two-step 32%one-pot 30%
120 121
122
+
i), ii)
Scheme 39 Synthesis of a benzo[b]azocine
CHO
N
Ts
MeNH2, 4 Å MS
THF N
Ts
NMe
ClCO2BnTHF, 60 °C;
allylZnBr–78 °C to rt
83%
N
Ts
NMe
BnO
O
Grubbs II
CH2Cl2 81% N
Ts
NMe
BnO
O
124 125
123
Scheme 40 Synthesis of azocino[3,2,1-hi]indoles
NH
OMe
MeO
R
R1
POCl3 DMF
rtNH
OMe
MeO
R
R1
CHO
allyl bromide KOH
DMSO, rt
N
OMe
MeO
R
R1
CHO
MeNO2 NH4OAc
i-PrOH, reflux N
MeO
MeO
R
R1
NO2
allylMgBr
THF, rt N
OMe
MeO
R
R1
NO2
Grubbs catalyst
toluene, reflux
N
OMe
MeO
R
R1
O2N
66–96% 89–93%
79–98%
52–99% 40–61%
129a R = R1 = Ph129b R = 4-BrC6H4, R1 = H129c R = 4-ClC6H4, R1 = H129d R = 4-MeC6H4, R1 = H
126
127
128
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bromide provided the required precursor 134 for RCM us-ing the Grubbs first-generation catalyst (Grubbs I) to give135.
Scheme 41 Synthesis of pyrimido[5,4-b]azocine derivatives based on combined aza-Claisen rearrangement and RCM
Using the same concept, the Majumdar group preparedRCM precursors 137 and 140. Starting from aminonaphtha-lenes 136 and 139, reaction with allylamine, subsequentaza-Claisen rearrangement, tosylation, and alkylation withhomoallyl bromide gave 137 and 140. Under the RCM con-ditions, naphthalene derivatives 137 and 140 gave cyclizedproducts, naphtho[1,2-b]azocines 138 and naphtho[2,1-b]azocines 141, respectively, in good yields (Scheme 42).53
Lindsley and co-worker developed a novel six-step ap-proach for the rapid and enantioselective synthesis of pyr-rolo[1,2-a]azocines 147 and 152.54 Commercially availablealdehyde 142 was converted into (R)-N-sulfinylaldimine143, followed by indium-mediated allylation yielding 144.Subsequent alkenylation of 144 with 5-bromopent-1-eneprovides 145 which underwent RCM reaction with GrubbsII catalyst to deliver 146 in 70% yield for two steps. Hydro-genation, followed by a one-pot deprotection/acetal hydro-lysis/reductive amination sequence produced decahydropyr-rolo[1,2-a]azocine 147 in 87% yield for two steps and withmore than 98% ee (Scheme 43).
Pyrrolo[1,2-a]azocinone 152 was synthesized fromcommercial aldehyde 148, which was converted into (S)-N-sulfinylaldimine 149. Indium-mediated allylation of 149 togive 150 and subsequent deprotection gave a primaryamine that cyclized to give (S)-5-allylpyrrolidin-2-one 151.
The alkenylation of lactone 151 with 5-bromopent-1-ene,followed by RCM with Grubbs II catalyst afforded1,5,6,7,10,10a-hexahydropyrrolo[1,2-a]azocin-3(2H)-one152 in 73% yields for two steps (Scheme 44).
In 2013, using a modified strategy Lindsley and co-workers developed a rapid route to access pyrrolo[1,2-a]-,pyrido[1,2-a]-, and azepino[1,2-a]azocines 153–155(Scheme 45).55
Benedetti, Penoni, and co-workers obtained benzo[c]azo-cine derivative 158 in 69% yield from enyne 157, from 156using a Sonogashira reaction (Scheme 46).56
Hexahydroazocine 161 was formed by microwave-as-sisted RCM of an α-allyl-α-phenyl-α-amino acid 160 ob-tained in two steps from α-imino ester 159 (Scheme 47).57
N
N
R1
O
Br
R
O
allylamine
EtOH, reflux82–85%
N
N
R1
OHN
R
O
BF3•OEt2
xylene, 120 °C90–95%
N
N
R1
O
NH2
R
O
N
N
R1
O
NH
R
O
TsCl
Py, 80 °C97–97%
homoallyl bromide
K2CO3, acetone reflux
91–94%
N
N
R1
O
N
R
O
Ts
TsGrubbs I
CH2Cl2, rt85–89%
NN
N
R1
R
O
O Ts
a R = R1 = Me; b R = R1 = Et; c R = Et, R1 = Me
Ru
PCy3
PCy3
PhCl
Cl
Grubbs I =
130 131
132 133
134 135
Scheme 42 Synthesis of naphtho[1,2-b]azocines and naphtho[2,1-b]azocines
NH2
i
HN
ii
NH2
iii
NHTs
iv
NTs
NTs
v
136
137
138 (94%)
NH2 iHN ii
NH2iii NH
Ts
iv
N
Tsv
NTs
(i) allyl bromide, K2CO3, acetone; (i) BF3•OEt2, xylene, 140 °C;(iii) TsCl, Py, heat; (iv) homoallyl bromide, K2CO3, acetone, NaI; (v) Grubbs I (5 mol%), CH2Cl2, rt
139
140 141 (89%)
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Dash and co-workers constructed imidazo[1,5-a]azo-cine 163 from commercially available hydantoin 162 via afour-step procedure involving selective N-allylation and C5-alkylation and with the key step being RCM (Scheme 48).58
Moss reported the efficient synthesis of a range of het-erocycle-fused azocine derivatives 165–167 employing adirected metalation/ruthenium-catalyzed RCM approach.59
The RCM precursors 164 were synthesized from carboxylicacids or 2-chloro-4-iodopyridine in three to four steps(Scheme 49).
Rao and co-workers developed a common strategy forthe construction of polyhydroxy azocine derivatives, in-cluding a novel example, from D-1,5-gluconolactone 168,using an RCM protocol as the key step.60 D-1,5-Gluconolac-tone 168 was converted into compound 169 by a five-stepprocedure. Compound 169 was subjected to allylation withallyl chloride producing N-allyl derivative 170; subsequentdeprotection, oxidative cleavage, and reaction with vinyl-magnesium bromide gave 171. RCM of compound 171 af-forded the cyclized products 172 and 173. The final depro-tection and hydrogenation of azocines 172 and 173 provid-ed polyhydroxy azocine derivatives 174 and 175 in 72% and66% yields, respectively (Scheme 50).
Bertozzi and Sletten synthesized a novel strained azacy-clooctyne 181, which represents a new class of heterocyclicsubstrates for Cu-free click chemistry.61 The synthesis in-
Scheme 43 Synthesis of decahydropyrrolo[1,2-a]azocine
O
O
O
i
O
O
NS
O
O
O
HNS O
ii
O
O
NS
O
iii
ivN
SO
O
O
v–vi
N
H
147
(i) (R)-tert-butyl sulfinamide, CuSO4, CH2Cl2; (ii) In(0), allyl bromide, sat. aq NaBr, rt; (iii) LiHMDS, 5-bromopent-1-ene, DMF, –20 °C to rt; (iv) Grubbs II (5 mol%), CH2Cl2, 40 °C; (v) H2, Pd/C;(vi) 1. TFA/H2O (95:5), rt; 2. PS-BH(OAc)3
142 143 144
145 146
Scheme 44 Synthesis of 1,5,6,7,10,10a-hexahydropyrrolo[1,2-a]azo-cin-3(2H)-one
O
iHN
SO
ii iii
(i) (S)-tert-butyl sulfinamide, CuSO4, CH2Cl2; (ii) In(0), allyl bromide, sat. aq NaBr, rt; (iii) 1. HCl, MeOH, rt; 2. Na2CO3, CH2Cl2(iv) LiHMDS, 5-bromopent-1-ene, DMF, –20 °C to rt;(v) Grubbs II (5 mol%), CH2Cl2, 40 °C
MeO2C
N
MeO2C
S
O
MeO2C
NH
O
H iv, v
N
O
H
148 149 150
151 152
Scheme 45 Synthesis of pyrrolo[1,2-a]-, pyrido[1,2-a]-, and azepi-no[1,2-a]azocines
ClH
O
n
H2NS
O
CuSO4, rtCl
H
N
n
SO
Br
In(0), sat. NaBr
Cl
HN
n
SO
1. HCl/dioxane2. K2CO3, NaI, DMF MW, 120 °C
3. K2CO3, Br 3
N
n
1. TFA2. Grubbs II, toluene, MW, 100 °C N
Hn60–75%
n = 1–3153–155
Scheme 46 Synthesis of benzo[c]azocine
I
N
OSiMe3
PdCl2(PPh3)2CuI, Et3N, THF
1)
2) TBAF
N
O
H-G II (3 mol%)toluene, N2
70 °C
N
O
158 (69%)
53%
156 157
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volved nine steps beginning from 6-bromoglucopyranoside176. First, compound 176 was transformed into acyclic di-ene 177 via zinc reduction/reductive amination reactionfollowed by amide formation with methyl succinyl chloride.The eight-membered ring was constructed by RCM givingazocine 178, which was converted into ketone 179 by oxi-dation and subsequent hydrogenation. The condensation of179 with semicarbazide and then oxidation with seleniumdioxide led to selenadiazole 180. Subsequent thermal de-composition followed by saponification of the ester pro-duced azocine 181 (Scheme 51).
In 2011, Danheiser and co-workers showed that thecombination of ynamide-based benzannulation with RCMprovides an expeditious strategy for the assembly of benzo-fused nitrogen heterocycles including azocines 187–189.62
The precursors 184–186 for RCM were obtained viabenzannulation from cyclobutenones with ynamide 183,prepared by reaction of carbamate 182 with 5-bromopent-1-en-4-yne. RCM occurred in the presence of the Grubbs IIcatalyst in dichloromethane (Scheme 52).
The synthetic use of this strategy is illustrated in its ap-plication in a concise enantioselective route to the benzoazo-cine core 190 of the antitumor agents (+)-FR900482 and
Scheme 47 Synthesis of hexahydroazocine
Ph
N OMe
O
1. MgBr
THF, –78 °C to rt
2. (R)-DIFLUORPHOS (4.9 mol%)
[η3-C3H5PdCl]2 (7.5 mol%)
Ph OAc
–78 °C to rt
N
O
OMe
Ph
Ph
H-G II (5 mol%)
MW (100 W, 100 psi100 °C), toluene
N PMP
PhO
MeO
161 (95%)
OMe
OMe
159 160
Scheme 48 Synthesis of imidazo[1,5-a]azocine
NH
HNO
O
BnBr K2CO3
DMF, rt65%
NH
NO
O
Bn
N
NO
O
Bn
Br
K2CO3, DMF50 °C73%
162
N
NO
O
BnBr
LiHMDS
THF–20 °C to rt
46%
N
N
BnO
OGrubbs II
163 (47%)
Scheme 49 Synthesis of heterocycle-fused azocine derivatives
X
HetGrubbs II (5 mol%)
CH2Cl2, 45 °C
NR
NN
R
Cl165a R = H (60%)165b R = Me (81%)
NN
BocCl
O
166 (93%)
Y
HN
O
167a Y = S (60%)167b Y = O (79%)
164
Scheme 50 Synthesis of polyhydroxy azocine derivatives
O
HO
HOO
OH
OH
5 steps OO
OBn
NHCbzO
O
OO
OBn
NCbzO
O
allyl chlorideNaH, DMF
DMAP
0 °C to rt85%
HO
OBn
NCbzO
O
1. HIO5, anhyd Et2O 0 °C to rt
2. 0 °C to rt 65%
MgBr
Grubbs II
CH2Cl2, 40 °C 90% N
Cbz
HO
O
O
OBn NCbz
HOO
OBn
NH
HO
OH
OH
OHNH
HO
OH
OH
OH
1. PdCl2, H2 MeOH, rt2. 6 M HCl, rt3. DOWEX 5WX8-200 30% NH3 solution
174 (72%) 175 (66%)
O
168 169
170 171
172 173
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(+)-FR66979. The synthesis of the benzoazocine core 191and the completion of the formal total synthesis ofFR900482 and Fr66979 are shown in Scheme 53.
In 2013, Danheiser and co-workers employed the ‘sec-ond generation’ of benzannulation/RCM strategy, in whichα-diazo ketones 192 were employed as vinylketene sub-strates instead of cyclobutenones.63 Using this method hy-droxy-substituted naphtho[2,3-b]azocine 193 was obtainedin good yield (Scheme 54).
In their investigations to develop concise total synthesesof some indole alkaloids possessing the azocine ring,Bennasar and co-workers successfully applied the combina-tion of RCM and vinyl halide Heck cyclization for the con-struction of the azocinoindole moiety. The first unsuccess-ful attempt to work out the total synthesis of (±)-apparicineled to unexpected tetracycle 198.64 The required RCM sub-strates 195a,b, prepared from 2-vinylindole-3-carbalde-hyde 194 by reductive amination followed by N-acylation orsulfonylation, were subjected to RCM giving azocinoindoles196,b in acceptable yields. The removal of the Boc group inazocinoindole 196a, subsequent alkylation with (Z)-2-iodo-but-2-enyl tosylate and Heck cyclization yielded compound198 possessing a bridged azocine ring (Scheme 55).
Changing the cyclization site from 5,6-position to 4,5-position by using as a RCM precursor 2-allyl-3-[(allylami-no)methyl]indole 199 and introducing an additional isom-erization step before the Heck cyclization, they succeededin accomplishing the first total synthesis of (±)-apparicine(Scheme 56).64
The combination RCM/Heck cyclization successfully wasutilized for the synthesis of the upper-half of vinorelbine.65
Reductive amination of aldehyde 200 followed by Boc-pro-tection of the aliphatic nitrogen gave carbamate 201, whichsmoothly underwent RCM in the presence of the Grubbssecond-generation catalyst to give azocinoindole 202. Thesequence of N-Boc deprotection, alkylation with allylic bro-mide, N-indole-deprotection, and Heck cyclization gave theupper-half of vinorelbine 205 (Scheme 57).
RCM for the building of eight-membered nitrogen-con-taining cycle has also found application in the completionof the total synthesis of (–)-nakadomarin A, which showsinteresting cytotoxic and antibacterial activity. A concisediastereoselective total synthesis was completed in 21 stepsfrom D-pyroglutamic acid, wherein one of the key steps wasthe construction of the azocine ring via RCM (Scheme 58).66
6 Cyclization
6.1 Metal-Catalyzed Cyclization
Chowdhury and co-workers described an elegant meth-od for the synthesis of benzo[c][1,2,3]triazolo[1,5-a]azo-cines 208 via palladium/copper-catalyzed heterocycliza-tion.67 The starting ortho-iodo azides 206 were preparedfrom the corresponding alcohols by mesylation and subse-quent azidation. ortho-Iodo azides 206 underwent palladi-um/copper-catalyzed azide–alkyne cycloaddition with var-ious terminal acetylenes 207 followed by arylation of thetriazole to give azocine derivatives 208. Employing 1,3-di-ethynylbenzene (209) as a reactant, led to bis-heteroannu-lation giving azocine 210 in moderate yield (Scheme 59). Itis worth noting that the protocol included the formation ofone C–C and two C–N bonds in a one-pot reaction.
Benzo[5,6]azocino[3,4-b]indoles 215 were obtained infour steps from indole 211 through an intramolecular directarylation reaction as the key step.68 Indole 211 was firsttreated with amine 212 to give amide 213; N-Boc-protec-tion or N-methylation gave compounds 214. The cyclizationof 214 mediated by Pd(0) delivered benzo[5,6]azocino[3,4-b]indoles 215 (Scheme 60).
Pyrroloazocine 219 and azocinoindoles 217 were ob-tained via a palladium-catalyzed norbornene-mediatedtandem process involving the intramolecular ortho-alkyla-tion of an aromatic C–H bond followed by intramoleculardirect arylation reaction from compounds 216 and 218, re-spectively (Scheme 61).69
Scheme 51 Synthesis of a novel strained azacyclooctyne
OHOMeO
OMeOMe
Br 1. Zn, NaBH3CN
H2N
Cl
O
OMe
O
2.
70%
NO
OMeO
HO
MeO
MeO
Grubbs II
69%N O
OMeO
HO
MeO
MeO
1. PCC, 80%
2. H2, Pd/C, 89%
N O
OMeO
MeO
MeO
O
NO
OMeO
MeO
MeO
SeNN
H2N NH
O
NH3
Cl
1.
AcOH, aniline
2. SeO2 60%
1. 115 °C, 47%
2. LiOH, 66%
N O
OHO
MeO
MeO
181
176 177
178
179 180
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Scheme 52 Synthesis of benzo[b]azocines
CO2Me
N
H
N
CO2Me
1. KHMDS, CuI, pyr-THF2. Br
52%
OMe
MeO
OH
MeO
Me
N
CO2Me
CHCl3150 °C
OMe
MOMO
CHCl3150 °C
O
Bu
Cl
Cl
toluene135 °C
OH
Me
N
CO2Me
MOMO
OH
Bu
Me
N
CO2Me
Cl
45%60%62%
Grubbs IICH2Cl2, reflux
N
OH
MeO
MeCO2Me
N
OH
MeCO2Me
MOMON
OH
Bu
MeCO2Me
Cl
187 (86%) 188 (94%) 189 (87%)
Grubbs IICH2Cl2, reflux
Grubbs IICH2Cl2, reflux
182 183
184 185 186
Scheme 53 Synthesis of the benzoazocine core of (+)-FR900482 and the completion of the formal total synthesis of the antitumor agents (+)-FR900482 and (+)-FR66979; Teoc = [2-(trimethylsilyl)ethoxy]carbonyl
N
R
O
OTBS
OBn
NHR
Br OTBS
OBn
CuSO4, K3PO41,10-phenanthroline
toluene, 85 °C
68% 80–110 °Ctoluene83–90%
OH OTBSOBn
N
R
R1O
R1O
Grubbs II (5 mol%)CH2Cl2, reflux
80–89%
N
OH
MOMO
tBuO2C
OBnOTBS
190
OBn OTBSOBn
N
Teoc
BnO
Grubbs II (5 mol%)CH2Cl2, reflux
92%
n-Bu4NF, THF, rt
71–74%N
OBn
Teoc
OBnOTBS
NaH, BnBrDMF, rt80–92%
HN
OBn
OBnOH
NO NH
OHOH
R
OCONH2
R = CHO FR900482R = CH2OH FR66979
191OBn
R = CO2tBu, TeocR = CO2tBu; 68%R = Teoc; 78%
a R = CO2tBu; R1 = CH2OMe;b R = Teoc; R1 = Bn
for a
OBn
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The Van der Eycken group, in 2009, developed a shortand selective approach towards azocino[5,4-b]indoles 221using a microwave-assisted Hg(OTf)2-catalyzed intramolec-ular carbocyclization of amides 220 prepared from corre-sponding tryptamines and 3-substituted prop-2-ynoicacids (Scheme 62).70
In 2011, the Van der Eycken group elaborated a novelprocedure for the construction of the interesting azoci-no[cd]indoles 224 via a Pd-catalyzed intramolecular acety-lene hydroarylation.71 The required for the cyclization, sub-
strates 223 were synthesized by DCC-mediated amidationof suitable 4-bromotryptamines 222 and various propynoicacid derivatives. Microwave-assisted Pd-catalyzed cycliza-tion of indoles 223 proceeded smoothly leading to regio-and stereoselective azocino[4,5,6-cd]indole derivatives 224(Scheme 63).
The Van der Eycken group have also reported the syn-thesis of azocinoindoles via an efficient gold-catalyzedpost-Ugi intramolecular hydroarylation.72,73 Ugi-adducts225 and 227 underwent 8-endo-dig cyclization leading toazocino[5,4,3-cd]indoles 226 and azocino[5,4-b]indoles228, respectively. The merits of this method are good to ex-cellent yields, a wide range of functional groups introducedduring the Ugi reaction, and selectivity for 8-endo-dig cy-clization (Scheme 64).
Using a cationic gold-catalyzed intramolecular hydroa-rylation reaction of β-lactam-tethered allenyl indoles 229,Alcaide, Almendos, and co-workers obtained tetrahy-droazeto[1′,2′;1,2]azocino[3,4-b]indoles 230 as single iso-mers in good yields (Scheme 65).74 The formation of azo-cines 230 was rationalized through an 8-endo carbocycliza-tion of the indole group towards the terminal allene carbon.The gold-catalyzed cyclization allowed the regioselectiveformation of fused β-lactams without harming the sensi-tive four-membered heterocycle.
Pentacyclic azocine derivative 232 was generated ingood yield via a novel gold-catalyzed cascade cyclizationfrom N-[(2-azidophenyl)ethynyl]benzamides 231 (Scheme66).75
Scheme 54 Synthesis of naphtho[2,3-b]azocine 193
N
CO2Me
OTBS
Grubbs II (5 mol%)CH2Cl2
reflux76%
O N2
hν, CH2Cl2, rt
thentoluene, reflux
62–65%
HO
N
MeO2C
OTBS
HO
N
MeO2C
OTBS
192
193
Scheme 55 Synthesis of a tetracyclic azocine derivative
NMOM
CHOH2N1.
NaBH(OAc)3 AcOH, CH2Cl2, rt
2. Boc2O, MeOH, Et3N, refluxor TsCl, CH2Cl2, Et3N, rt
NMOM
N R
195a R = Boc, 70%195b R = Ts, 65%
Grubbs II
toluene, 60 °Cor CH2Cl2, reflux N
MOM
N
R
196a R = Boc, 70%196b R = Ts, 65%
from 196a
1. 1.2 M HCl/MeOH, rt
2.
K2CO3, MeCN, 70 °C
TsO
I
Me
NMOM
N
I
Me
NMOM
N
Me
197
198 (46%)
Pd(OAc)2, Ph3P AgCO3
toluene–Et3N 90 °C
194
60%
Scheme 56 The total synthesis of (±)-apparicine
NSO2Ph
N Boc
Me
MeGrubbs II
CH2Cl2 reflux NSO2Ph
N
Boc
Me
t-BuOK
THF, reflux
NH
N
Boc
Me
1. 1 M HCl/MeOH, rt
2.
DIPEA CH2Cl2/MeCN, rt
TsO
I
Me
90%
NH
N
Me30%
I
NH
N
CH2
Me
apparicine (15%)
Pd(OAc)2, Ph3P AgCO3
toluene–Et3N, 80 °C
199 Me
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Echavarren and co-workers reported the synthesis ofthe azocino[5,4-b]indole core skeleton of the lundurines bygold-catalyzed 8-endo-dig cyclization of an alkynylindole.76
The AuCl3-catalyzed cyclization of 2-[2-(2-ethynyl-5-oxo-pyrrolidino)ethyl]indole 233, prepared in seven steps from
Scheme 57 Synthesis of the upper-half of vinorelbine
NSO2Ph
CHO H2N1. NaBH(OAc)3
2. Boc2O, MeOHEt3N, reflux
65%NSO2Ph
NBoc
Grubbs II
CH2Cl2, reflux89% NSO2Ph
N
Boc
1. 1 HCl/MeOH, rt
2.Br Me
I
60%
NSO2Ph
N
Me
IL-Selectride
THF62%
NH
N
Me
I
Pd(PPh3)4Proton Sponge
K2CO3, toluenereflux
NH
N
Me
NH
N
Me
H
CO2MeN
N
OHCO2Me
OCOMe
HMe
MeO
Me
vinorelbine
200 201 202
203 204 205 (45%)
Scheme 58 The completion of the total synthesis of (–)-nakadomarin A
NH
OO
OH19 steps
N
O
O
N
O
H
H
Grubbs I
CH2Cl240 °C
NO
O
N
O
H
H
AlCl3LiAlH4
58%(2 steps)
NO
N
O
H
H
(–)-nakadomarin A
Scheme 59 Synthesis of benzo[c][1,2,3]triazolo[1,5-a]azocines and a bis-annulated azocine
I
OH
I
N3
1. MsCl, Et3N, CH2Cl2, 0–5 °C
2. NaN3, DMF, rt
R
Pd(PPh3)2Cl2, CuI, Et3N
DMF, 115–150 °C
N
NNR
206
207 208a R = Ph; 40%208b R = 4-MeO2CC6H4; 43% 208c R = 4-MeOC6H4; 38%
I
N3
206 209
N NN
N
NN
Pd(PPh3)2Cl2, CuI, Et3N
DMF, 115–150 °C
210 (27%)
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2-(1H-indol-3-yl)acetate, afforded azocinoindole 234 in55% isolated yield (Scheme 67); the feasibility of using oth-er gold complexes was considered.
6.2 Radical Cyclization
The Majumdar group developed a new efficient methodfor the synthesis of pyrimidoazocine derivatives 238 via thefirst example of an 8-endo-trig thiophenol-mediated radicalcyclization.77 The radical precursors 237 were prepared
from pyrimidines 235, products of the aza-Claisen rear-rangement of N-allyl-substituted pyrimidines, by tosylationand the subsequent reaction of intermediates 236 withpropargyl bromide. The alkenyl radicals were generatedfrom thiophenol initiated by benzoyl peroxide. The pyrimi-do[5,4-b]azocines 237 were obtained in excellent yields(Scheme 68).
Scheme 60 Synthesis of benzo[5,6]azocino[3,4-b]indoles; EOM = ethoxymethyl
N
EOM
CO2Me
I
HN
N
EOM
O
I
H2N
211 212
213
I
N
N
EOM
O
R
(i) DMAP, EDCI, CH2Cl2, 0 °C; 98%; (ii) Boc2O, DMAP, MeCN, rt; 99% or NaH, MeI, THF, rt; 99%; (iii) Pd(OAc)2, Ph3P, Ag2CO3, DMF, 140 °C
i
ii
214a R = Boc214b R = Me
iii
N
EOM
N
O
R
215a R = Boc; 97%215b R = Me; 47%
Scheme 61 Synthesis of dibenzo[c,f]pyrrolo[1,2-a]azocine and diben-zo[3,4:6,7]azocino[1,2-a]indoles
NN
RR
Br
Me R1
I
Me
R1
i
217a R = H, R1 = NO2; 24%217b R = CO2Me, R1 = NO2; 50%217c R = CO2Me, R1 = H; 50%
(i) PdCl2, P(2-furyl)3, Cs2CO3, norbornene, MeCN, 90 °C
N
Br
I
Me
NO2 N
MeNO2
i
216
218
219
Scheme 62 Synthesis of azocino[5,4-b]indoles
N
N
R3N
R1
N
R2
O
R3
O
R2
R1
Hg(OTf)2
CH2Cl2, MW
221a R1 = H, R2 = Bn, R3 = Me; 85%221b R1 = H, R2 = Bn, R3 = nPr; 82%221c R1 = H, R2 = PMB, R3 = Me; 59%221d R1 = H, R2 = Me, R3 = Me; 86%, etc.
220a–d
NH
N
R1
NH
OHg(OTf)2
CH2Cl2, MW
220e–g 221e R1 = Me; 75%221f R1 = Et; 71%221g R1 = Ph; 58%
N
O
R1
NH
N
R1NH
OHg(OTf)2
CH2Cl2, MW
220h,i 221h R1 = Me; 78%221i R1 = n-Am; 71%
N
O
R1
CH2OTIPSTIPSOH2C Bn
Bn
Scheme 63 Synthesis of azocino[4,5,6-cd]indole derivatives
NH
BrNH
R1 R
OH
O
DCC, DMAPCH2Cl2, 25 °C
57–72%222 223
NH
NO
R1
RPd(PPh3)4 (3 mol%)
HCOONa
DMF/H2O, MW, 110 °C
224a R = Me, R1 = PMB; 77%224b R = Et, R1 = PMB; 75%224c R = Pr, R1 = PMB; 67%224d R = Pent, R1 = H; 46%224e R = Ph, R1 = H; 26%, etc.
NH
Br
N
O
R R1
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On developing the total synthesis of (±)-apparacine,Bennasar and co-workers prepared azocino[4,3-b]indole242 via radical cyclization.64 The synthesis of compounds
242 began with the preparation of selenoester 241 as theradical precursor. Selenoester 241 was prepared by reduc-tive amination of aldehyde 239, followed by Boc protectionof the resulting secondary amine, and phenylselenenationof the corresponding carboxylic acid. The treatment ofselenoester 241 with Bu3SnH as the radical mediate andEt3B as the initiator led to the formation of azocinoindole242. The reaction of 242 with methyllithium followed by
Scheme 64 Synthesis of azocino[5,4,3-cd]indoles and azocino[5,4-b]indoles
N
R
COOH
CNR1
H2NR2
MeOH
50 °C62–98% N
NNH
O
R1
R2
O
(IPr)AuCl (10 mol%)AgNTf2
DCE, 100 °C
N
NO
HN
R2 O
R
R
R1
225
226a R = Me, R1 = tBu, R2 = PMB, R3 = H; 78%226b R = Me, R1 = Cy, R2 = PMB, R3 = H; 68%226c R = Et, R1 = tBu, R2 = PMB, R3 = H; 76%, etc.
R3
R3
R3
NH
R
COOHCN
R1
OHCR2
MeOH
50 °C62–98%
NH
O
Au(PPh3)OTf (5 mol%)
CDCl3, rt
NH
R
228a R = Me, R1 = tBu, R2 = 4-MeOC6H4, R3 = H; 85% 228b R = Me, R1 = tBu, R2 = Cy, R3 = H; 84%228c R = Me, R1 = tBu, R2 = tBu, R3 = H; 90% etc.
NH2
N
R2
O
HN
R1
N
R
O
R2 HN
O
R3
R3
227
R3
R1
Scheme 65 Synthesis of tetrahydroazeto[1′,2′;1,2]azocino[3,4-b]in-doles
N
NO
•
MeO H H
Me
R
N
N
O
Me
MeOH H
R
(IPr)AuCl (5 mol%)AgSbF6 (5 mol%)
DCE, 90 °C, MW
229 230a R = H; 59%230b R = Cl; 70%230c R = OMe; 53%
Scheme 66 Synthesis of a pentacyclic azocine derivative
N3
N
Ph
Ts[LAuCl/AgOTf]
(1 mol%)
MeCN, 50 °C
NH
N
Ts
231 232 (51%)L = P(4-F3CC6H4)3
Scheme 67 Synthesis of the azocino[5,4-b]indole core skeleton of the lundurines
NH
NO
AuCl3 (5 mol%)
CH2Cl2, rtNH
N
O
233 234 (55%)
N
N
O
MeO
CO2Me
lundurine A
Scheme 68 Synthesis of pyrimido[5,4-b]azocines
N
N
R1
O
O
NH2
R
TsCl Py
80 °C90–98%
N
N
R1
O
O
NH
R
Tspropargyl bromide
K2CO3
acetone90–93%
N
N
R1
O
O
N
R
Ts
N
N
NO
O
R1
R
Ts SPh
H
a R = R1 = Me; b R = R1 = Et; c R = Et, R1 = Me; d R = Et, R1 = H
tBuOH, PhSH
benzoyl peroxidereflux
237 238 (70–85%)
235 236
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dehydration of the intermediate tertiary alcohol providedazocinoindole 243 (Scheme 69), which successfully used inthe synthesis of (±)-apparacine (see Scheme 55).
In their investigations, Li and co-workers generated azo-cine derivatives 245 and 247 starting from diesters 244 and246 by a sequence of reactions in which the azocine-forma-tion step was radical cyclization.78 In the case of azocine245 it was a Mn(III)-mediated oxidative radical process,whereas the azocine system 247 was obtained by a reduc-tive radical process (Scheme 70).
Diaba, Bonjoch, and co-worker obtained morphan com-pounds 249 via the first intramolecular atom transfer radi-cal process between trichloroacetamide and enol acetateused as a radical acceptor.79 The reaction was promoted byGrubbs II catalyst, thus expending the scope of these cata-lysts beyond the metathesis reaction (Scheme 71).
This reaction enabled the construction of the tricyclicskeleton of the immunosuppressant FR901483. The re-quired proradical trichloroacetamide 251 was synthesizedin five steps starting from azaspirodecane 250. The treat-ment of ketone 251 with isopropenyl acetate gave a regio-isomeric mixture of enol acetate 252 in a 1.8:1 ratio, theunseparated mixture was treated with Grubbs II catalyst af-fording the diazatricyclic derivative 253, its epimer 254,and unexpected mixture of enones 255. The reaction ofcompound 253 with zinc led to dechlorinated derivative256, possessing the tricyclic skeleton of immunosuppres-sant FR901483, in 58% yield (Scheme 72).79
Li and co-workers used a route based on the iodine-atom-transfer radical 8-endo cyclization to synthesize anumber of azocine derivatives.80 Thus, N-acyloxazolidin-
ones 257 underwent 8-endo cyclization promoted byBF3·OEt2/H2O leading to the formation of oxazoloazocine258 in high yields with excellent regio- and stereoselectivi-ty (Scheme 73). It is interesting to note that the productconfiguration was changed from 3,8-trans to 3,8-cis.
Li and co-workers also showed that in the presence ofMg(ClO4)2 and a bis(oxazoline) ligand, N-ethoxycarbonyl-substituted 2-iodo-N-(pent-4-enyl)alkanamides 259 under-went 8-endo cyclization giving only 3,5-trans-substitutedazocan-2-ones 260 in excellent yields (Scheme 74).
Similarly, the BF3·OEt2/H2O promote reaction of N-(2-al-lylaryl)-N-(ethoxycarbonyl)-2-iodoalkanamides 261 afford-ed benzo[b]azocines 262 with cis-3,5-configuration in highyields (Scheme 75).
Scheme 69 Synthesis an azocino[4,3-b]indole
NH
OMe
O
CHO
H2NBr
1.
NaBH(OAc)3 AcOH, CH2Cl2, rt
2. Boc2O dioxane, rt 76%
NH
OMe
O
N
BocBr
1. LiOH, THF–H2O then HCl
2. Et3N, Bu3P PhSeCl 90%
NH
SePh
O
N
BocBr
Bu3SnH, Et3B
benzene, rt
NH
N
Boc
O
54%
NH
N
Boc
1. MeLi, THF, –10 °C
2. TsOH, MeCN, rt
239 240
241
242 243 (70%)
Scheme 70 Synthesis of bridged azocine derivatives
N
CO2Et
CO2Et
Br
K2CO3 MeCN
reflux95%
N CO2EtCO2Et
tBuOH toluenereflux
75%
N
OH
CO2Et Mn(OAc)3, DMSO22 °C
78% N
CO2Et
O
245
244
N
CO2Et
CO2Et
Br
K2CO3 MeCN
reflux94%
N CO2Et
CO2Et
t-BuOHtoluenereflux
75%
N
OH
CO2Et
N
O
CO2Et
Br
NBS, DMSO22 °C
95%
Bu3SnH AIBN
benzene
reflux50%
N
CO2Et
O
247
246
Scheme 71 Synthesis of morphan compounds
OAc
N O
CCl2R
Bn
Grubbs II
toluene, 155 °C
N OH
H
Cl
R
Bn
O
N OH
H
CO2Et
Cl
Bn
O249a R = Cl; 68% epi-249a 249b R = CO2Et and epi-249b 50%
248
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6.3 Friedel–Crafts Cyclization
Azocino[3,4-b]indol-1-ones 264 were obtained via acid-catalyzed intramolecular Friedel–Crafts cyclization of 1-methyl-N-(4-oxobutyl)indole-2-carboxamides 263 in lowyields (Scheme 76).81
Pandey and co-workers developed a general route forthe synthesis of azocino[5,4-b]indoles 269 starting from al-lyl bromide 265 which prepared from Morita–Baylis–Hillman adducts.82 The reaction of tryptamine with allylbromide 265 gives 266, protection of the nitrogen atoms in
266 gives 267, and saponification of the ester group in 267gave indoles 268 which underwent Friedel–Crafts intramo-lecular cyclization affording azocino[5,4-b]indoles 269 ingood yields (Scheme 77).
Kim and Seo used the Friedel–Crafts reaction as the keystep for the construction of azocine ring in the tetracycliccompound 274.83 Aminoacrylate 271, prepared from 3,4-di-methoxyphenethylamine via amidation reaction with 2-io-dobenzoic acid and subsequent Michael addition of ethylpropynoate, was subjected to the Heck reaction giving iso-indole 272. The hydrogenation of isoindole 272 followed byhydrolysis provide derivative 273 which by the action ofpolyphosphoric acid was converted into tetracyclic com-pound 274 (Scheme 78).
Scheme 72 Synthesis of tricyclic skeleton of immunosuppressant FR901483
N
I
Bn
O O 5 steps
N
NMe
CO2Me
CCl3
O OAc
TsOH reflux93%
N
NMe
CO2Me
CCl3
O
O OAc252a (3α)252b (3β)
(1.8:1)
Grubbs II
toluene155 °C
O
N
OCl
ClN
CO2Me
Me
253254 (epimer at C2)
2
N
NMe
CO2Me
CHCl2
O
O54%
255a (3α)255b (3β)
26%
N
HO
O
N
CO2Me
Me
ZnNH4Cl
256 (58%)
N
HOPO(OH)2
N
CO2Me
Me
OH
PMB
FR901483
250 251
Scheme 73 Synthesis of oxazoloazocines
I NO
OOR
(Bu3Sn)2BF3•OEt2/H2O
CH2Cl2, hν, rt
NO
OOR
I
257 258 (70–87%)
a R = Me; b R = Et; c R = Bu; d R = C6H13; e R = iPr, etc.
Scheme 74 Synthesis of azocan-2-ones
I N
OOR
Mg(ClO4)2, ligandEt3B, O2
CH2Cl2, rt
NOEt
OOR
I
259 260
a R = Me; 92%b R = Et; 87%c R = Bu; 80%d R = C6H13; 83%, etc.
OEt
N
O
N
O
Me Me
Me MeMe
Me
ligand =
Scheme 75 Synthesis of benzo[b]azocines
I
N
O
O
RBF3•OEt2, H2O
Et3B, O2
CH2Cl2, rt
N
OEtO
O
R
I
a R = Me, R1 = H; b R = Et, R1 = H; c R = tBu, R1 = H; d R = Me, R1 = 6-Me, etc.
OEt
R1
261 cis-262 (69–80%)
R1
Scheme 76 Synthesis of azocino[3,4-b]indol-1-ones via acid-catalyzed intramolecular Friedel–Crafts cyclization
R
R1 N
N
O
R2
O
R3
R
R1 N
N
Me MeO
R3
R2MeCN
a R = R1 = OMe, R2 = H, R3 = nBu b R = R1 = H, R2 = 4-MeOC6H4, R3 = Me
263 264 (10–21%)
TFA
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The same sequence of reactions was used in the case ofthe synthesis of an azocine alkaloid, magallanesine(Scheme 79).83
Scheme 79 Synthesis of magallanesine
6.4 Other Examples of Cyclization
In a new synthetic route for the synthesis of thedasycarpidone skeleton and for the total synthesis of (±)-uleine, Patir and Uludag used acid-catalyzed intramolecularcyclization to construct the azocino[4,3-b]indole core.84 Re-duction of ketoamide 275 with borane–dimethyl sulfidecomplex and the subsequent acidification of the resulted al-cohol 276 with TFA led to 277, which was treated in situwith DDQ furnishing the desired tetracyclic compounds278 in good yield. Four further steps were required to com-plete the total synthesis of (±)-uleine from azocinoindole278 (Scheme 80).
Azocinoindoles 280 and 283 were obtained by Hamadaand co-workers via a novel acid-promoted skeletal rear-rangement of 2- or 3-alkylideneindolenium cations gener-ated from compounds 279 and 282.85,86 A reaction cascadeleading to the azocine system involved intramolecular ipso-Friedel–Crafts alkylation of phenols, rearomatization of the
Scheme 77 Synthesis of azocino[5,4-b]indoles
NH
NH2 Br
MeO2CAr
Et3N, CH2Cl2
0 °C to rt70–85%
NH
NH
MeO2CAr
N
N
MeO2CAr
SO2Ph
SO2Ph
NaOH TBAHS
PhSO2Cl 0 °C to rt66–85%
N
N
HO2CAr
SO2Ph
SO2Ph
LiOH
THF–H2O, rt55–68%
N
SO2Ph
N
SO2Ph
O
Ar
1. SOCl2, toluene, reflux
2. AlCl3, toluene, 0 °C to rt 73–89%
265
269a Ar = Ph269b Ar = 4-O2NC6H4269c Ar = 4-MeC6H4269d Ar = 4-F3CC6H4, etc.
266 267
268
Scheme 78 Synthesis of benzo[5,6]azocino[2,1-a]isoindole
MeO
MeO
NH2
I
HO2C
EDCI, DMAP99%
MeO
MeOHN O
I
O
OEt
CsCO3, DMF97%
MeO
MeO
N
CO2Et
I
OPd(OAc)2Bu4NCl
NaHCO3DMF, 50 °C
99%
MeO
MeO
N
CO2Et
O
1. H2, Pd/C, 97%
2. NaOH, 82%
MeO
MeO
N
CO2H
O
PPA, 70 °C
75%
MeO
MeO
N
O 274
273
272
270
271
O
NH2
I
HO2C
CO2Et
1. Pd(OAc)22. H2/Pd
3. KOH/EtOH 79%
N
CO2H
O
1. TFAA
2. BF3•OEt2 76%
N
O
O
O
O
OMe
OMe1.
chloridomethyltriazine4-methylmorpholine
98%
2.
99%
N
CO2Et
I
O
O
O
OMe
OMe
O
O
OMe
OMe
O
O
OMe
OMe DDQdioxane–MeCN
110 °C57%
N
O
O
O
O
OMe
OMe
magallanesine
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spirocyclohexadienone unit, and iso-Pictet–Spengler reac-tion. In addition to the targeted azocinoindoles, pyrrolidinederivatives 281 and 284 were isolated as the major byprod-ucts (Scheme 81).
Azocino[4,3-b]indoles 287 were synthesized by the oxi-dative cyclization of [3-(3-oxopiperidin-2-yl)indol-2-yl]malonates 286 obtained in four steps from dimethyl ordi-tert-butyl malonates 285.87 Furthermore, these azoci-no[4,3-b]indoles were successfully used for the total syn-thesis of (±)- and (–)-actinophyllic acid (Scheme 82).
Reitz and co-workers have prepared benzo[d]azocines294 and 295 which are formally analogues of Phe-Ala orAla-Phe dipeptides joined together on their side chains.88
The synthesis began with the conversion of the N-Boc-pro-tected 2′-iodo-L-phenylalanine 288 into N-Fmoc derivative289. Negishi coupling of 289 with either Boc-(β-I)-D-Ala-OMe or Boc-(β-I)-L-Ala-OMe gave dipeptides 290 and 291,respectively. Removals of Boc- and benzyl ester groups ofbis-amino acids 290 and 291 and amide formation and cy-clization with 1-hydroxy-7-azabenzotriazole (HOAt) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexa-fluorophosphate (HATU) provided azocines 292 and 293.
Fmoc-deprotection followed by simultaneous amidolysis ofthe ester with methylamine and acetylation led to dipep-tides 294 and 295 (Scheme 83).
Scheme 80 Synthesis of a tetracyclic azocine system with the dasycar-pidone skeleton
NH
O
S
S
MeCONHMe
1) Me2S•BH3
2) AcOH
NH
HO
S
S
MeCONHMe
H
NH
S
S
N
Me O
H
HMe
DDQ
61%NH
S
S
N
Me O
H
HMe
NH
N
Me O
H
HMe
CH2
4 steps
(±)-uleine
NH
N
Me O
H
HMe
O
dasycarpidone
275
276 277
278
Scheme 81 Acid-promoted skeletal rearrangement of 2- or 3-alkylidene-indolenium cations
N
Boc
HO
N
Ts
TFA
CH2Cl2, 0 °C
N
Boc
N
OMe
Ts
MeO280 (30%)
N
Boc
NTs
281
N
Ts
NTs
OMe
HO
TFA
CH2Cl2, rt
N
Ts
N
Ts
OMe
N
Ts
N
Ts282
283 (31%)
284
279
Scheme 82 Synthesis of azocino[4,3-b]indoles
CO2RRO2C4 steps
NH
CO2R
CO2R
NBocO
LDA[Fe(DMF)3Cl2][FeCl4]
THF, –78 °C to rtNH
N
O
CO2RCO2R
Boc
a R = Me; b R = tBu
285
286
rac-287 (63–73%)
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Hexahydrochromeno[3,4-c]azocine 297 was obtainedfrom chromene 296 by cyclization which occurred duringDuff formylation, but the yield of the cyclic product waspoor at only 9% (Scheme 84).89
7 Microwave- and Photo-Assisted Reactions
Alcaide, Almendos, and co-workers developed a methodfor the synthesis of structurally novel bicyclic azocine-fused β-lactams 299 and 300 in the absence of any metalcatalyst.90 This was the first example of metal-free prepara-tion of eight-membered rings by the thermolysis of non-conjugated azetidin-2-one-tethered bis(allenes) 298 on ap-plication of microwave irradiation. Azocines 299 and 300were isolated as single regio- and diastereoisomers(Scheme 85).
The Van der Eycken group elaborated a new approachtowards the construction of 5,6,7,8-tetrahydrodiben-zo[c,e]azocines 303 via a microwave-assisted copper-cata-lyzed intramolecular A3-coupling reaction.91 Formed in situby Boc deprotection of biaryl compounds 301, biaryl deriv-atives 302 with both amino and aldehyde groups reactedwith the suitable alkynes in the presence of CuBr under fo-cused microwave irradiation thus forming dibenzo[c,e]azo-cines 303 in good to excellent yields (Scheme 86).
Yudin and Cheung found that N-vinyl-β-lactams 304underwent microwave-assisted ring-expansion, resultingfrom [3,3]-sigmatropic rearrangement between two strate-gically placed alkene moieties on the β-lactam, giving azo-cines 305 in yields of 8–86% (Scheme 87).92,93
On irradiation of 4-diazo-4H-imidazole 306 in hexafluo-robenzene gave the unusual imidazo[3,4-a]azocine 307 in51% yield (Scheme 88).94
Kutateladze and co-workers synthesized epoxybenzoazo-cines 309 and 311 from aniline derivatives 308 and 310, re-spectively, by photo-generation of azaxylylenes and theirsubsequent intramolecular [4+4] cycloaddition with a fu-
Scheme 83 Synthesis of benzo[d]azocines; NEM = N-ethylmorpholine
I
BocHN CO2Bn
I
FmocHN CO2Bn
FmocHN CO2Bn
MeO2C NHBoc
FmocHN CO2Bn
MeO2C NHBoc
NH
O
FmocHN CO2MeNH
O
FmocHN CO2Me
NH
O
FmocHNNHMe
ONH
O
FmocHNNHMe
O
294 (67%) 295 (77%)
290 291
i, ii
iv iii
v–viiv–vii
viii, ixviii, ix
(i) 4 M HCl, dioxane, quant.; (ii) Fmoc-OSu, NEM, THF, 94%; (iii) Zn, I2, Boc-(β-I)-L-Ala-OMe, DMF, Pd[P(o-tolyl)3]2Cl2, 47%; (iv) Zn, I2, Boc-(β-I)-D-Ala-OMe, DMF, Pd[P(o-tolyl)3]2Cl2, 42%; (v) H2, Pd/C (10% dry), MeOH; (vi) 4 N HCl, dioxane, quant.; (vii) HOAt, HATU, NEM, DMF 33%; (viii) MeNH2, EtOH, quant.; (ix) Ac2O, PS-CH2NMe2
288 289
292 293
Scheme 84 Synthesis of hexahydrochromeno[3,4-c]azocine; HMTA = hexamethylenetetramine
OO
HO
NHAlloc
OO
HO
N Alloc
CHO
1) Ac2O Py, MeCN
2) HMTA TFA, 75 °Cacidic workup
296 297 (9%)
Scheme 85 Synthesis of novel bicyclic azocine-fused β-lactams
NO
RO•
R1
•
H HR2O
tolueneMW, 175–250 °C
R1 = Me, R2 = HN
O
RO
O MeH H
299a R = Me; 25%299b R = Ph; 23%
tolueneMW, 175–250 °C
NO
RO
R2OH H
R1
300 (42–61%)a R = R1 = R2 = Me; b R = R2 = Me, R1 = Ph; c R = R2 = Me, R1 = PMP etc.
298
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ran-containing pendant tethered either via the aniline ni-trogen or through the carbonyl-group-containing fragment(Scheme 89).95
8 Other Methods
8.1 Cascade and Tandem Reactions
Nakamura and co-workers elaborated an efficient syn-thesis of azocine derivatives 313 from O-propargylic oximes312 in good to excellent yields by the means of a Rh-cata-
lyzed 2,3-rearrangement/heterocyclization cascade se-quence.96 It is noteworthy that the chirality of the substratewas maintained throughout the cascade process to affordoptically active azocines 313d (Scheme 90).
Scheme 90 Synthesis of azocine derivatives
Scheme 86 Synthesis of 5,6,7,8-tetrahydrodibenzo[c,e]azocines
N
O
MeO
OMe
A
Boc
R
TFA–CH2Cl2(1:3)
0 °CNH
O
MeO
OMe
A
R
R1
CuBr (10 mol%)100 °C, MW
MeO
MeO
A
NR
R1
303 (48–95%)
a R = PMB, R1 = Ph, A = benzene; b R = PMB, R1 = PMP,A = benzene; c R = PMB, R1 = Cy, A = benzene etc.
301 302
Scheme 87 [3,3]-Sigmatropic rearrangement of N-vinyl-β-lactams
NO
Me
R
DMF
MW, 160–200 °C
HN
Me
O R
a R = Ph, R1 = H; b R = 4-O2NC6H4, R1 = H; c R = 4-NCC6H4, R1 = H; d R = 4-MeOC6H4, R1 = H; e R = H, R1 = Me, etc.
R1 R1
304 305 (8–86%)
Scheme 88 Synthesis of imidazo[3,4-a]azocine
N
NPh
N2
O
O
C6F6
hνN
NPh
O
O
F
FF
F
F
F
306 307
Scheme 89 Synthesis of epoxybenzoazocines
NH2
O R
O NH
OH R
O
hν
HN
R
HO
O
azaxylylene
HN
HO
O
N
O2N
HN
HO
O
O2N S
HN
HO
O
O2N
Some examples
308
309 (21–76%)
X
O
NHO
R
hνX N
OH
O
R
a X = CH, R = H; b X = CH, R = Cl; c X = CH, R = Br; d X = N, R = H
310 311 (40–62%)
R1
O
R
N
[RhCl(cod)]2 (2.5 mol%)P(4-F3CC6H4)3 (10 mol%)
0.1 M MeCN, 80 °C
N
R1
R
O
a R = R1 = Ph; b R = 4-MeOC6H4, R1 = Ph; c R = 4-ClC6H4, R1 = Ph
R1
O
R
N
BnO [RhCl(cod)]2 (2.5 mol%)
P(4-F3CC6H4)3 (10 mol%)
0.1 M MeCN, 80 °C
N
R1
R
O
BnO
*
(R,Z)-trans 99% ee
45%, 70% ee
312 313 (34–94%)
312d 313d
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She, Xie, and co-workers accomplished a gold-catalyzed1,2-acyloxy migration/intramolecular [3+2]-cycloadditioncascade reaction for the construction of unsaturated azo-cines 315 starting from enynyl esters 314 (Scheme 91).97
Scheme 91 A gold-catalyzed 1,2-acyloxy migration/intramolecular [3+2]-cycloaddition cascade reaction
In 2016, She, Xie, and co-workers subsequently expand-ed this gold-catalyzed 1,2-acyloxy migration/intramolecu-lar [3+2]-cycloaddition cascade reaction to the synthesis ofbenzo[d]azocines 317 from 1,9-enynyl esters 316. The reac-tion proceeded under mild conditions leading to benzoazo-cines 317 in good to excellent yields of 55–82% (Scheme92).98
Scheme 92 Synthesis of benzo[d]azocines 317
Kumar and co-workers synthesized benzo[b]azocines318 through an unprecedented one-pot, triflic acid mediat-ed, tandem Michael addition–Fries rearrangement of sorbyl-anilides 319.99 The reaction is proposed to proceed via a δ-lactam intermediate, earlier considered unreactive for theFries rearrangement (Scheme 93).
In their research concerning the total synthesis of (±)-actinophyllic acid, Martin and co-workers constructed thetetracyclic core of the natural compound in a single chemi-cal operation via a novel Lewis acid catalyzed cascade of re-actions involving stabilized carbocations and π-nucleop-hiles.100 The treatment of a mixture of electrophile precur-sor indole 320 and π-nucleophiles 321 with TMSOTf in thepresence of 2,6-di-tert-butylpyridine, followed by addition
of NaOMe in MeOH at –78 °C gave tetracyclic systems 322in 53–80% yields (Scheme 94).
8.2 Aldol Condensation
In their work on the total syntheses of (–)-FR901483and (+)-8-epi-FR901483, Huang and co-workers successful-ly used the aldol condensation for the construction of theazocine ring.101,102 Starting from the known chiron (R)-1-al-lyl-3-benzyloxypiperidine-2,5-dione, piperidin-3-ol 324was obtained in four steps. The oxidation of 323 gave a ke-tone that underwent an intramolecular aldol ring-closurereaction forming azocine derivative 324 (Scheme 95).
Uludag and co-workers ring-closed 1-oxo-1,2,3,4-tetra-hydrocarbazole 325 by a NaH-promoted intramolecular al-dol condensation to give the azocino[4,3-b]indole system326 (Scheme 96).103
8.3 Thermolysis
Thermolysis of hydrazine 327 in m-xylene under refluxled to the impressive cyclopropa[3,4]azocino[1,2-a]benz-imidazole 328 in a poor yield of 11% with the two otherproducts 329 and 330 in higher yields of 22% and 33%(Scheme 97).104
N
O
tBuO
Ts
Au(PPh3)Cl (5 mol%)AgSbF6 (5 mol%)
CH2Cl2, rt NR
Ts
OH
H
OtBu
Me
O
R
314 315 (61–74%)
a R = H; b R = iPr; c R = Cy; d R = CH2CH2Ph
NO R3
O
Ts
Au(PPh3)Cl (5 mol%)AgSbF6 (5 mol%)
40 °C, DCE N Ts
OHO
R3
Me O
R1
316 317 (55–82%)
a R = R1 = R2 = H, R3 = tBu; b R = 5-Me, R1 = R2 = H, R3 = tBu; c R = 5-F, R1 = R2 = H, R3 = tBu; d R = 4-F, R1 = R2 = H, R3 = tBu, etc.
R2
R1
R
R
R2
Scheme 93 Synthesis of benzo[b]azocines via tandem Michael addi-tion–Fries rearrangement
R
HN
O
Me TfOH
DCE, rt
N
O
Me
R
HN
R
Me
O318
319 (52–90%)
a R = 4-Me; b R = H; c R = 4-Cl; d R = 4-OMe, etc.
Scheme 94 Synthesis of tetracyclic azocinoindoles
NH
OAc
BnO
OBn N
RO
O
TIPSO
1) 2,6-di-tert-butylpyridine TMSOTf, CH2Cl2, –78 °C
2) NaOMe, MeOH, –78 °C
NH
OTIPS
OBnOBn
NRO2C
a R = Bn; b R = Me; c R = Allyl
320 321
322 (53–80%)
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Thermolysis of the 12-membered ring aza-enediyne331 in benzene in the presence of catalytic amounts of p-toluenesulfonic acid produced the addition-dehydration
product, naphtho[2,3-b]azocine 332 in 18% yield, however,the major product of this reaction was N-tosyl lactam 333in 28% yield (Scheme 98).105
8.4 Ring Opening
Tetracyclic azocine derivative 336 possessing a paullone-like structural framework was obtained in a single stepfrom a novel 2,2′-spirobi[indolin]-3-one 335 prepared byCu-mediated intramolecular cascade reaction of cyclopen-ta[b]indole 334.106 Compound 335 when treated withmethanolic KOH underwent demesylation followed by ringopening and subsequent aromatization to give 336 in 90%yield (Scheme 99).
Scheme 99 Synthesis of a tetracyclic azocine derivative
Yavari and Seyfi found that furo[2′,3′:2,3]cyclopen-ta[1,2-b]pyrroles 338, obtained by Wittig reaction from oxo-indeno[1,2-b]pyrroles 337 and DMAD, underwent Et3N-mediated ring opening thus affording tetrahydroben-zo[c]furo[3,2-e]azocines 339 in good yields (Scheme100).107
Scheme 95 Synthesis of bridged azocine derivatives
NO O
OBn4 steps
N
O
O
OH
(COCl)2 DMSOCH2Cl2
Et3N
–78 °C, 90%
N
O
O
O
N
O
O
OH
4 M HClTHF, rt
CSA, tolueneHOCH2CH2OH
90 °C 53%
323
324
Scheme 96 Synthesis of a bridged azocino[4,3-b]indole
NH
NMeO2C
CHO
O
NaH
THF, rt85% N
HO
N
MeO2C
H
H
OH
325 326
Scheme 97 Synthesis of cyclopropa[3,4]azocino[1,2-a]benzimidazole
N
NMe
Me H
N N
Ph
Ph
m-xylenereflux
N
NMe
Me N
NMe
Me
N
NMe
Me
Me
327
328 (11%)
330 (33%)
329 (22%)
Scheme 98 Thermolysis of a 12-membered ring aza-enediyne
N
OH
Ts
3 TsOH
benzene, 60 °C
N
Ts
Ph
N
OTs
3
331
332 (18%)
333 (28%)
NH
HNS
OO
Me CuI (10 mol%)air
DMF–H2O120 °C66%
N
N
O S
OO
Me
H
5% KOH/MeOH
reflux, 90%
HN
HNO
336
334 335
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Scheme 100 Synthesis of tetrahydrobenzo[c]furo[3,2-e]azocines
8.5 Other Methods
Waghmode and co-workers synthesized epoxy-bridgedbenzo[d]azocines 342 in good to excellent yields from 1-(bromomethyl)-3-(tosyloxy)chromane 340 via nucleophilicsubstitution with various benzylamine derivatives 341(Scheme 101).108
Scheme 101 Synthesis of epoxy-bridged benzoazocines via nucleo-philic substitution
Jia and co-workers elaborated a highly enantioselectivepalladium/L-proline-catalyzed α-arylative desymmetriza-tion of cyclohexanones 343 leading to a series of opticallyactive morphan derivatives 344 with α-carbonyl tertiarystereocenters in good yields (Scheme 102).109
Scheme 102 Synthesis of a series of optically active morphan deriva-tives
Xu, Li, and co-workers have designed and synthesizednovel neonicotinoid analogues 346–348 with an aza-bridged azocine fragment.110 Azocine derivatives 346–348were prepared by reaction of imidazole 345 with glutaral-dehyde and a primary amine hydrochloride (aliphaticamines, phenylhydrazines, and anilines) (Scheme 103).
Azocine derivative 350 was obtained in 16% yield viacationic aza-Cope rearrangement of aminoketal 349(Scheme 104).111
Yao, Wu, and co-workers developed a novel facile andefficient route for the synthesis of benzo[b]naphtha[2,3-d]azocinones 353 through a palladium-catalyzed reactionof 2-alkynylanilines 351 with 2-(2-bromobenzylidene)cy-clobutanones 352.112 During the reaction process, doublecarbometalation resulting in the formation of three newbonds was involved (Scheme 105).
Boeckman and co-workers obtained azocine derivatives355 and 357 using a one-pot, aza-Wittig/retro-aza-Claisensequence from 2-vinylcyclobutanecarbaldehydes 354 and356, respectively.113 The rearrangement sequence proceed-ed under mild conditions affording azocines 355 and 357 in75–92% yields (Scheme 106).
Modification of a previously reported procedure114 al-lowed Raffa and co-workers obtain the polycyclic system,5,7:7,12-dimethanopyrazolo[3,4-b]pyrazolo[3′,4′:2,3]aze-pino[4,5-f]azocine 360.115 Methylaminopyrazoles 358 andhexane-2,5-dione (359) reacted in refluxing 1,4-dioxane inthe presence of p-toluenesulfonic acid thus leading to com-pounds 360 in 10–37% yields (Scheme 107).
Systematically investigating the reactivity of the pallad-acycles obtained in their studies, Vicente, Saura-Llamas,and co-workers synthesized various azocine-containingsystems. Thus, heating of complex 361 in the presence ofTlOTf and 2,4-dimethylphenyl isocyanide gave azocine 363through insertion of isocyanide and C–N coupling process(Scheme 108).116
The treatment of eight-membered palladacycles 364and palladacycles 366 with CO afforded benzo[d]azocine-2,4-(1H,3H)-diones 365117 or hexahydrobenzo[d]azocin-ones 367,118 which resulted from the insertion of a mole-cule of CO into the Pd–C bond and subsequent C–N reduc-tive coupling (Scheme 109).
These methods were extended to the preparation ofdibenzo[c,e]azocines 369/370 and 371 via insertion of COand isocyanide, respectively (Scheme 110).119
9 Conclusion
In recent years, many new pathways towards eight-membered azaheterocycles have been elaborated includingdomino approaches, MCRs, metal-catalyzed cyclizations,RCM, and ring-expansion strategies. These approaches pro-vide environmentally friendly and step-economical accesstowards several annulated azocines with substantial biolog-
CO2Me
CO2Me N
CO2Me
CO2Me
O
R
Ph3P CH2Cl2
rt74–88%
N
CO2Me
CO2MeR
O
MeO2CCO2Me
OH
HO
HO
Et3N, EtOH
refluxN
O
O
CO2Me
MeO2C
R
CO2Me
CO2Me
337
338 339 (75–86%)
a R = Ph; b R = Bn; c R = 2-ClC6H4CH2; d R = 4-MeOC6H4CH2
O
OMe
OMe
Br
OTs
NH2 K2CO3
MeCN 80 °C
O
OMe
OMe
N
340 342 (71–90%)
341
a R = Ph; b R = 3,4-Cl2C6H3; c R = 2-ClC6H4; d R = 4-FC6H4, etc.
R
R
N
Br
R
O
R1
R1
N
O
H
H
R
L-proline (10 mol%)Pd(OAc)2 (5 mol%)
Ph3P (12 mol%)
AcOH, K3PO4, MeOH
343344a R = Bn, R1 = H; 91%, 97% ee344b R = Bn, R1 = 8-OMe, 85%, 99% ee344c R = Bn, R1 = 8-F; 92%, 98% ee344d R = Bn, R1 = 9-OMe; 95%, 97% ee, etc.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3801–3834
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ical activity and natural compounds. However, much workremains to be done to elaborate general synthetic strategytowards medium-sized nitrogen heterocycles includingazocines.
Scheme 103 Synthesis of novel neonicotinoid analogues
NCl
N NH
NO2
O O
R-NH2·HCl
NCl
N N
O2NN
R
NCl
N N
O2NN
NCl
N N
O2NN
HN
R
R
345
a R = Me; 52%b R = Et; 20%c R = iPr; 3%d R = Pr; 5%
NH2
R ·HCl
a R = H; 17%b R = 4-Me; 34%c R = 2-Me; 42%d R = 4-Br; 29%e R = 2-F; 22%f R = 4-Cl; 32%
NH
R ·HCl
H2N
a R = H; 42%b R = 4-Me; 46%c R = 4-F; 43%d R = 2-Cl; 67%
346
348
347
Scheme 104 Cationic aza-Cope rearrangement of an aminoketal
N
O
O
HN
Ph
H
41) TFA, dimedone morpholine, 120 °C
2) CbzCl, Na2CO3 CHCl3, 22 °C
H
Ph
Cbz
349 350 (16%)
Scheme 105 Synthesis of benzo[b]naphtha[2,3-d]azocinones
NH2
R1
R
Br
R2
O
Pd(OAc)2 (5 mol%)Cy3P (10 mol%)
K2CO3, dioxane, reflux
HN
O
R
R2
R1
351 352
353 (41–88%)
a R = H, R1 = Ph, R2 = H; b R = H, R1 = 4-MeC6H4, R2 = H; c R = H, R1 = 4-ClC6H4, R2 = H; d R = H, R1 = 4-FC6H4, R2 = H, etc.
Scheme 106 Synthesis of azocine derivatives
O
R
CHOOHC Ph3P, R1N3
toluene, reflux
N
CHO
R1
354
a R1 = Bn; b R1 = (CH2)2CO2Et; c R1 = Bu
O
SO2Ph
R1
CHO
R1
PhO2S Ph3P, BnN3
toluene, reflux
N
SO2Ph
R1 Bn
a R = R1 = H; b R = Me, R1 = H; c R = H, R1 = Me; d R = R1 = Me, etc.
R
R
R
356
355 (87–89%)
357 (75–92%)
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3801–3834
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A. V. Listratova, L. G. Voskressensky ReviewSyn thesis
Funding Information
This publication was supported by the Ministry of Education andScience of the Russian Federation (Agreement number
02.a03.21.0008). The financial support of the Russian Foundation forBasic Research (Grant # 17-03-00605) is gratefully acknowledged.Ministry of Education and Science of the Russian Federation (02.a03.21.0008)Russian Foundation for Basic Research (17-03-00605)
References
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Scheme 107 Synthesis of 5,7:7,12-dimethanopyrazolo[3,4-b]pyrazo-lo[3′,4′:2,3]azepino[4,5-f]azocine
NN
R
NH
Me
R1
O
MeMe
Odioxane, reflux
NN
R
N
R1
Me
Me
N
N
N
R
R1
MeMe
358
359
360 (10–37%)
a R = Me, R1 = H; b R = Ph, R1 = H; c R = Me, R1 = 3-Cl
TsOH
Scheme 109 Synthesis of benzo[d]azocinediones or hexahydroben-zo[d]azocinones
NMe2
Pd
Me2N
O NRHX
Y
OPd
NMe2
Me2N
NRH
X
Y
364
CO
N
O R
X
Y
365 (57–94%)
a R = H, X = Y = Ph; b R = H, X = Y = Et; c R = H, X = Ph, Y = Me
Pd
NH2
R R
X
R2
366 367 (52–73%)
NH
R R
R2
O
R1
R1
2
COR1
R1
a R = H, R1 = OMe, R2 = CO2Et; b R = H, R1 = OMe, R2 = Ac c R = Me, R1 = H, R2 = CO2Et; d R = Me, R1 = H, R2 = Ac
X = Br or Cl
O
OTf OTf
Scheme 108 Synthesis of iminobenzo[d]azocine
Pd
NH2
Me Me
Cl
CNXy
CO2Et361
NH
Me Me
CO2Et
NXy
Pd
NH2
Me Me
CNXy
CNXy
CO2Et
XyNC, TlOTf
363 (58%)
OTf
Δ
362
Xy = 2,4-Me2C6H3
Scheme 110 Synthesis of dibenzo[c,e]azocines
Pd
NH2
R R
X
NH
NHXy
R1
R1
2
MeO
MeO
2 XyNCMeO
MeO
NH2Br
CNXy
NXy
1. TlOTf2. Δ
370 (45%)
1. TlOTf, XyNC 2. Δ
NH
NHXy
369 (90%)
X = Cl
1/2
368
Pd
NH2
R R
X
R1
R1
2
1/2
368
CO NH
O
R1
R1
RR
371
R1 = OMe, R = H; 70%R1 = H, R = Me; 40%
TfOTfO
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3801–3834
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A. V. Listratova, L. G. Voskressensky ReviewSyn thesis
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