Highly enantioselective synthesis of functionalized azepino[1,2-a] indoles via NHC-catalyzed [3+4] annulation

Article abstract of DOI:10.1039/c9cc01444f

The enantioselective [3+4] annulation of 3-formylindol-2-methyl-malonates with 2-bromoenals catalyzed by NHCs is described to afford functionalized azepino[1,2-a]indoles in high yields with excellent enantioselectivities. This method, in which the 3-formyl group in indoles acts as a necessary mediating group, provided cycloaddition products under mild conditions.

Full text of DOI:10.1039/c9cc01444f

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DOI: 10.1039/C9CC01444F
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COMMUNICATION
Highly enantioselective synthesis of functionalized azepino[1,2-
a]indoles via NHC-catalyzed [3+4] annulation
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
b
a,
Shi-Ya Zhu , Yuanzhen Zhang , Xin-Fa Chen , Jun Huang , Shi-Hui Shi , and Xin-Ping Hui *
DOI: 10.1039/x0xx00000x
Enantioselective [3+4] annulation of 3-formylindol-2-methyl- enals, isatin-derived enals with o-quinone methides, α,β-
malonates with 2-bromoenals catalyzed by NHCs is described to unsaturated ketones, and o-hydroxyphenyl substituted p-quin-
1
2d
afford functionalized azepino[1,2-a]indoles in high yields with one methides, respectively. In 2014, the group of Chi report-
excellent enantioselectivities. This method, in which the 3-formyl ed the stereoselective synthesis of dinitrogen-fused seven-
group in indoles acts as a necessary mediated group, provided membered heterocycles by NHC-catalyzed [3+4] cycloaddition
1
2e
12i
cycloaddition products under mild conditions.
of azomethine imines and enals. Glorius and our group
independently disclosed the NHC-catalyzed [3+4] annulations
to afford 1,2-diazepines. Enders et al. developed an enantio-
selective synthesis of spirobenzazepinones, spiro-1,2-diaze-
pinones and spiro-1,2-oxazepinones through NHC-catalyzed
The azepino[1,2-a]indole skeleton, which feature a fused
seven-membered ring through the N1-C2 connection, is an
important structural unit that occurs in several natural indole
alkaloids.1 In addition, many azepino[1,2-a]indoles exhibit
attractive pharmacological activities including antiprotozoal
properties,2a prostaglandin D2 receptor agonist, Hepatitis C
12g
[
3+4] cycloaddition of isatin-derived enals with in situ formed
aza-o-quinone methides, azoalkenes or nitrosoalkenes, res-
pecttively. In 2017, enantioenriched N−H-free 1,5-benzo-
thiazepines were synthesized by a formal [3+4] annulation of
2b
NS5B inhibitors2 and anti-cytokine inhibitors. The develop-
ment of efficient access through straightforward annulation
reaction to form azepino[1,2-a]indoles has drawn extensive
attention. Until now, some synthetic methods to this frame-
c-d
2e
12h
α,β-unsaturated acyl azoliums with 2-amino-benzenethiols
.
Additionally, NHC-catalyzed [3+4] annulation of α-bromoenals
with aryl 1,2-diamines was developed for highly enantio-
selective synthesis of 4-aryl N-H-free 1,5-benzodiazepin-2-
3
work have been reported, such as olefin metatheses, [2+5]
cycloadditions,4 radical cyclizations, and transition-metal-
5
12k-l
ones . Although asymmetric [3+4] annulations catalyzed by
6
catalyzed intramolecular cyclization cascade reactions.
NHCs have been utilized to synthesize some seven-membered
heterocycles, little effort has been focused on the enantio-
selective synthesis of azepino[1,2-a]indoles. Very recently, Chi
However, the reported investigations have so far been limited
to achiral or racemic derivatives.
Asymmetric syntheses that use N-heterocyclic carbenes
12m
and co-workers
reported enantioselective synthesis of
(
NHCs) as catalysts have been studied extensively and are an
azepino[1,2-a]indoles by NHC and sulfinate co-catalyzed inter-
molecular Rauhut–Currier reaction between enals and nitro-
vinyl indoles. Therefore, it is of widespread interest to develop
new entries to synthesize chiral azepino[1,2-a]indoles. As our
important method for asymmetric carbon-carbon bond forma-
7
8-11
tion. The annulation reactions
synthesis of diverse chiral cyclic compounds. The asymmetric
3+4] annulations are efficient approaches for the synthesis of
optically enriched seven-membered heterocyclic compounds.
have been applied for the
[
13
group works on the NHC-catalyzed asymmetric reactions, we
aim to develop a straightforward [3+4] annulation method for
synthesis of chiral azepino[1,2-a]indoles catalyzed by NHCs
under mild conditions. As anticipated, the asymmetric [3+4]
annulation of 2-((3-formyl-1H-indol-2-yl)methyl)malonate with
1
2a-c, 12f
Among them, asymmetric synthesis of fused ε-lactones
and spirocyclic oxindole-ε-lactones was demonstrated by
1
2j
several groups through NHC-catalyzed [3+4] annulations of
2
-bromoenals proceeded smoothly (Scheme 1) and the desired
aState Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China E-mail:
huixp@lzu.edu.cn
Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry
and Chemical Engineering, Yan’an University, Yan’an 716000, Shaanxi, P. R. China
CHO
CO2Me
CHO
R1
CHO
O
N
H
CO2Me
R1
2
CO Me
b
R2
NHC
R2
NEt3
N
CO2Me
Br
NHC
O
R2
Electronic Supplementary Information (ESI) available: Crystallographic data, a
detailed protocol, NMR and HPLC data of the synthesized compounds are Scheme 1 NHC-Catalyzed enantioselective [3+4] annulation.
provided. CCDC 1897738. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1 Optimization of reaction conditionsa
Table 2 Substrates scope of the NHC-catalyzed [3+4] annulation
a
View Article Online
CHO
CHO
OHC
CHO
DOI: 10.1039/C9CC01444F
COOMe
COOMe
CO Me
CO2Me
2
D
CO2Me
CHO cat. (10 mol %)
CHO NHC (10 mol %)
R2
2
CO Me
R1
+
Ph
+
2
CO Me
NH CO2Me
N
O
NEt3, DCM, rt
R1
N
O
R2
base, solvent, rt
Ph
N
Br
Br
2a
H
1a
2a-2r
3
a
-
1a 1c
3a-3t
O
O
O
Et
O
N
N
N
N BF4
time yield
ee
(%)
N
N
entry R1
R2
N
N
N
N
N
Mes
b
c
N
(h)
24
24
18
12
24
24
12
12
12
18
24
(%)
Ph
Ar
Cl
Cl
BF4
cat. A
Ar = C6F5
Et
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
H (1a)
Ph (2a)
88 (3a) 98
84 (3b) 98
89 (3c) 91
91 (3d) 96
89 (3e) 97
88 (3f) 96
90 (3g) 96
92 (3h) 96
cat. B
cat. C
cat. D
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
2-BrC
3-BrC
4-BrC
4-MeC
3-MeC
3-ClC
4-ClC
4-FC
3-FC
6
6
6
H
H
H
4
(2b)
(2c)
(2d)
entry catal. base
solvent time (h) yield (%)b ee (%)c
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
A
B
C
NEt
NEt
NEt
NEt
3
3
3
3
toluene 24
toluene 24
toluene 24
toluene 24
toluene 48
21
–
26
34
–
31
19
24
55
36
34
56
85
88
80
70
75
85
–
93
92
–
88
94
94
98
95
97
97
97
98
95
95
96
4
d
6
H
4
(2e)
(2f)
6
H
4
D
D
D
D
D
D
D
D
D
D
D
D
D
D
6
H
H
4
(2g)
(2h)
(2i)
(2j)
2 3
Cs CO
DABCO toluene 24
DMAP
DIPEA
6
4
6
H
H
4
91 (3i)
87 (3j)
97
96
toluene 24
toluene 24
0
1
2
3
4
5
6
7
8
9
0
6
4
4-O
2
NC
6
H
4
(2k)
85 (3k) 98
92 (3l) 99
NEt
NEt
NEt
NEt
NEt
NEt
NEt
NEt
NEt
3
3
3
3
3
3
3
3
3
DCM
THF
DCE
24
48
48
48
24
24
24
24
24
4-methyl formate (2l) 12
0
1
2
3
4
5
6
7
1-naphthyl (2m)
2-naphthyl (2n)
3,4-Cl
2-thienyl (2p)
CH (2q)
Cy (2r)
12
12
12
18
24
24
12
18
91 (3m) 98
94 (3n) >99
90 (3o) 98
89 (3p) 76
67 (3q) 93
12 (3r) 93
91 (3s) 98
87 (3t) 88
CHCl
DCM
DCM
DCM
DCM
DCM
3
2 6 3
C H (2o)
d
e
3
f
eg
eh
5-Cl (1b) Ph (2a)
5-CH (1c) Ph (2a)
3
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol, 1 equiv), base
a
Reaction conditions: 1 (0.1 mmol), 2 (0.14 mmol, 1.4 equiv), NEt
3
b
c
(
0.11 mmol, 1 equiv). Isolated yield. Determined by chiral HPLC
b
(
0.154 mmol, 1.54 equiv), NHC D (0.01 mmol). Isolated yield.
d
analysis. 1a (0.1 mmol), 2a (0.13 mmol, 1.3 equiv), NEt
3
(0.143
c
d
Determined by chiral HPLC analysis. The scale-up synthesis of
compound 3e was performed (1a, 1.73 mmol) and compound 3e
was obtained in 85% yield and 96% ee.
e
mmol, 1.43 equiv). 1a (0.1 mmol), 2a (0.14 mmol, 1.4 equiv), NEt
3
f
(0.154 mmol, 1.54 equiv). 1a (0.1 mmol), 2a (0.15 mmol, 1.5
g
equiv), NEt
added. 50 mol % LiCl was added.
3
(0.165 mmol, 1.65 equiv). 50 mol % PhCOOH was
h
9
8% ee when 1.4 equiv of the 2-bromoenal 2a was used (entry
4). Further screening of additives, such as PhCO H and LiCl,
failed to improve the yield (entries 16–17).
1
2
azepino[1,2-a]indole products were obtained in high yield and
excellent enantioselectivity.
Having established the optimized conditions, the substrate
scopes with regard to 2-bromoenals were investigated. As
shown in Table 2, a range of 2-bromoenals 2a–2n with both
electron-withdrawing and electron-donating groups reacted
smoothly with 1a and products 3a–3n were obtained in high
yields and excellent enantioselectivities (entries 1–14). When
the reaction of 2-bromoenal 2l bearing methyl formate and 1a
was examined, product 3l was obtained in excellent yield and
enantioselectivity (entry 12). A switch of substituents from
substituted phenyl groups to 1-naphthyl or 2-naphthyl groups,
the asymmetric annulation conducted well and gave excellent
yields and enantioselectivities (entries 13–14). In addition, 3,4-
dichlorophenyl substituted 2-bromoenal 2o was found to be
readily participated in the asymmetric [3+4] annulation and
afforded products 3o with excellent yield and enantio-
selectivity (entry 15). However, 2-bromoenal with electron-
riched heteroaromatic ring delivered the product 3p in high
yield and moderate enantioselectivity (entry 16). For (Z)-2-
bromobut-2-enal (2q), product 3q was formed in 67% yield
and 93% ee (entry 17). Steric hindrance was proved obviously,
and cyclohexyl substituted 2-bromoenal 2r resulted in poor
yield (entry 18). Finally, the asymmetric annulation of sub-
We started our investigation with the reaction of dimethyl
2
-((3-formyl-1H-indol-2-yl)methyl)malonate (1a) with (Z)-2-
bromo-3-phenylacrylaldehyde (2a) in the presence of 10 mol %
of NHC precatalyst and 1.1 equiv of NEt in toluene (Table 1).
3
The reaction using precatalyst A gave the desired [3+4]
annulation product 3a in 21% yield and 85% ee (entry 1).
However, when precatalyst B was used under the same
conditions, the product 3a wasn’t formed (entry 2). Additional
studies found that chiral triazolium precatalyst C afforded 3a
with 26% yield and 93% ee (entry 3). The use of precatalyst D
with N-mesityl substituent led to 3a with 34% yield and 92% ee
entry 4). Subsequently, several bases were examined and the
results showed that organic bases like DMAP and DIPEA gave
compound 3a with lower yields and slightly high ee values
entries 7–8). A switch of solvent from toluene to DCM
resulted in a moderate yield (55%) and excellent ee (98%)
entry 9). Other solvents (THF, DCE) were screened, but the
yield and enantioselectivity decreased (entries 10–11). In
contrast, chloroform gave similar results for the asymmetric
annulation (entry 12). To increase the yield of the reaction, the
molar ratio of the substrates 1a and 2a were optimized
(
(
(
(
entries 13–15). The product 3a was obtained in 88% yield and
2
| J. Name., 2012, 00, 1-3
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strates 1b–1c with 2-bromoenal 2a was evaluated. As
expected, the desired product 3s was obtained in 91% yield
and 98% ee (entry 19). When 5-methyl substituted substrate
View Article Online
DOI: 10.1039/C9CC01444F
1
c was employed, the product 3t was obtained in slightly lower
yield and enantioselectivity (entry 20).
In order to further explore the scope of substrates, the
enantioselective [3+4] annulations of 1a with cinnamaldehyde,
cinnamic acid, 3-phenylpropanoic acid were carried out,
respectively. It is worth noting that compound 3a could also be
obtained by the annulation of 1a with cinnamaldehyde (4)
catalyzed by NHC precatalyst D in the presence of oxidant
Figure 1 X-Ray crystallography of compound 3d.
(
Scheme 2). However, when carboxylic acids were used, the
CHO
CHO
cat. D (10 mol %)
CO2Me
2
CO Me
reactions did not occur. The cycloaddition product can readily
undergo further transformation. Treatment of compound 3e
with NaBH
CHO
NEt3 (1.54 equiv)
+
Ph
(eq. 1)
N
O
N
DCM, rt, 48 h
Br
Ph
H
o
6
2a (1.4 equiv)
in THF at 0 C, the reductive product 5 was
(0.1 mmol, 1 equiv)
7
4
MeO2C
afforded in 88% yield and 92% ee (Scheme 3).
MeO2C
CO2Me
Ph
cat. D (10 mol %)
NEt3 (1.54 equiv)
The absolute configuration of the product was determined
to be (R)-3d by using X-ray crystal analysis (Figure 1). Other
product configurations were assigned tentatively by analogy.
To understand the mechanism further, some control ex-
periments were carried out (Scheme 4). Treatment of methyl
CO2Me
CHO
Ph
+
N
(eq. 2)
(eq. 3)
DCM, rt, 16 h
51% yield
N
Br
H
O
8 (0.1 mmol, 1 equiv)
2a (1.4 equiv)
9
R
R
cat. D (10 mol %)
CHO NEt3 (1.54 equiv)
2
CO Me
CO2Me
CO2Me
+
Ph
DCM, rt, 48 h
N
O
NH CO2Me
Br
a (1.4 equiv)
Ph
3
-(3-formyl-1H-indol-2-yl)propanoate (6) with 2-bromoenal 2a
2
(
0.1 mmol, 1 equiv)
R = NO2 (1d), CH3 (1e)
in the optimal conditions, the desired compound 7 wasn’t
formed (eqn. (1)). We next examined the reaction of dimethyl
Scheme 4 Control experiments
.
2
-((1H-indol-2-yl)methyl)malonate (8) with 2a and product (E)-
dimethyl 2-((1-cinnamoyl-1H-indol-2-yl)methyl)malonate (9)
was afforded in 51% yield (eq. (2)). Furthermore, the reaction
of substrates 1d and 1e with 2a were tested, and the results
showed that the desired products could not be formed (eqn
CHO
O
CO2Me
CO2Me
N
CHO
R
N
N
N
O
Mes
Br
Ar
2
3
Mes
(
3)). The above results showed that the 3-formyl group in the
CHO
N
N
OH
N
CO2Me
indole moiety was required for this annulation.
CO2Me
N
On the basis of the above control experiments and relevant
Br
R
Ar
O
O
1
4
calculated results , a possible mechanism is proposed in
Figure 2. Initially, NHC catalyst combines with 2-bromoenal 2
generated Breslow intermediate I. Subsequently, α,β-unsa-
turated acylazolium II is formed through tautomerization and
debromination of intermediate I. Next, deprotonation and
proton transfer of the substrate 1a to the 1a’ in the presence
O
Mes
N
CHO
I
N
N
NEt3
V
N
N
O
H
CO Me
CO2Me
2
MeO C
2
MeO2C
1a
Mes
O
N
R
N
CHO
N
HO
MeO
O
O
of NEt
3
is possibly involved in this process. The Michael
CO2Me
CO2Me
Ar
OMe
O
addition of 1a’ to intermediate II from the re-face (III) gives the
enolate IV. Finally, the intermediate IV undergoes proton
transfer, tautomerization and intramolecular lactamization to
form the desired product 3 with release of the NHC catalyst.
N
II
H
N
O
1a'
Mes
N
Mes
N
N
N
N
CO2Me
N
Ar N
O
O
IV
O
O
H
CHO
OMe
OH
OHC
cat. D (10 mol %)
CO2Me
CO2Me
Ph
CO2Me
NEt3 (0.2 equiv), DCM
III
CHO
+
tBu
tBu
Ph
N
O
NH CO Me
2
4
(1.4 equiv)
O
O
Figure 2 Possible catalytic cycle.
1a (0.1 mmol, 1 equiv)
tBu
tBu
61% yield, 98% ee
oxidant (1.5 equiv)
3a
Scheme 2. Application of cinnamaldehyde for synthesis of 3a.
Conclusions
CHO
CH2OH
In summary, we have reported an efficiently enantio-
selective [3+4] annulation for the synthesis of functionalized
azepino[1,2-a]indoles. The cycloaddition products were
achieved in good yields with excellent enantioselectivities. Our
studies suggest that the 3-formyl group in the indoles plays a
CO2Me
CO2Me
CO Me
2
NaBH , THF
4
2
CO Me
N
O
N
O
0
°C
Me
Me
3e
88% yield, 92% ee
5
Scheme 3 Reduction reaction of compound 3e
.
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Journal Name
G. E. Hutson, R. C. Johnston, E. O. McCusker, P.VHiew.-YA.rtiCclhe eOonlninge
necessary mediated group for this [3+4] annulation. Future
studies will aim to develop asymmetric [n+4] annulations.
We are grateful for the financial support of the National
Natural Science Foundation (21372106), Natural Science Basic
Research Plan in Shaanxi Province (2018JQ2063) and Scientific
Research Program Funded by Shaanxi Provincial Education
Department (18JK0883).
and K. A. Scheidt, J. Am. Chem. Soc., 2014, 136, 76; (d) C. Guo,
DOI: 10.1039/C9CC01444F
M. Schedler, C. G. Daniliuc and F. Glorius, Angew. Chem., Int.
Ed., 2014, 53, 10232; (e) X. Wu, B. Liu, Y. Zhang, M. Jeret, H.
Wang, P. Zheng, S. Yang, B.-A. Song and Y. R. Chi, Angew.
Chem., Int. Ed., 2016, 55, 12280; (f) X.-Y. Chen, J.-W. Xiong, Q.
Liu, S. Li, H. Sheng, C. von Essen, K. Rissanen and D. Enders,
Angew. Chem., Int. Ed., 2018, 57, 300.
1
0 For recent examples, see: (a) J. Mahatthananchai, J. Kaeo-
bamrung and J. W. Bode, ACS Catal., 2012, 2, 494; (b) A. G.
Kravina, J. Mahatthananchai and J. W. Bode, Angew. Chem.,
Int. Ed., 2012, 51, 9433; (c) C. Guo, M. Fleige, D. Janssen-
Müller, C. G. Daniliuc and F. Glorius, Nat. Chem., 2015, 7, 842;
Conflicts of interest
There are no conflicts to declare.
(d) D. Xie, L. Yang, Y. Lin, Z. Zhang, D. Chen, X. Zeng and G.
Zhong, Org. Lett., 2015, 17, 2318; (e) S. R. Yetra, S. Mondal, S.
Mukherjee, R. G. Gonnade and A. T. Biju, Angew. Chem., Int.
Ed., 2016, 55, 268; (f) G.-T. Li, Z.-K. Li, Q. Gu and S.-L. You, Org.
Lett., 2017, 19, 1318; (g) B. Liu, W. Wang, R. Huang, J. Yan, J.
Wu, W. Xue, S. Yang, Z. Jin and Y. R. Chi, Org. Lett., 2018, 20,
Notes and references
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2
60.
1
1
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DOI: 10.1039/C9CC01444F
Table of Contents Entry
CHO
O
CHO
N
CO2Me
CO2Me
R2
CHO cat. D (10 mol %)
N
N
+
R2
N
Mes
NEt3 (1.1 equiv)
DCM, rt
Cl
N
CO2Me
Br
R1
R1
H
O
2
MeO2C
cat. D
0 examples
up to 94% yield, > 99% ee
Enantioselective [3+4] annulation of 3-formylindol-2-methylmalonates with 2-bromoenals catalyzed by NHCs is described to
efficient synthesis of functionalized azepino[1,2-a]indoles.
1