Bronsted Acid Catalyzed Cyclization of Inert N-Substituted Pyrroles to Benzo[ f ]pyrrolo[1,2- a ][1,4]diazepines

Article abstract of DOI:10.1055/a-1468-5725

Two approaches involving intramolecular and intermolecular cyclization, respectively, have been developed for the direct and practical construction of a series of important benzo[ f ]pyrrolo[1,2- a ][1,4]azepines by using Bronsted acid catalysts. Upon catalysis by TsOH, the intramolecular dehydroxylation/ring closure of 3-hydroxy-2-[2-(1 H -pyrrol-1-yl)benzyl]isoindolin-1-ones provided various racemic benzo[ f ]pyrrolo[1,2- a ][1,4]azepines in high yields. Furthermore, enantioenriched benzo[ f ]pyrrolo[1,2- a ][1,4]azepines were also obtained by chiral phosphoric acid catalyzed intermolecular addition of [2-(1 H -pyrrol-1-yl)phenyl]methanamines to 2-formylbenzoates under mild conditions.

Full text of DOI:10.1055/a-1468-5725

SYNLETT
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1
4
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4
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9
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 930–934
letter
930
en
Z. Gao et al.
Letter
Synlett
Brønsted Acid Catalyzed Cyclization of Inert N-Substituted
Pyrroles to Benzo[f]pyrrolo[1,2-a][1,4]diazepines
Zeng Gaoa,b
Jinlong Qiana
O
R1
R1
0
0
0
0
-
0
0
0
3
-
0
3
9
0
-
8
4
8
X
N
CHO
R
N
NH2
CPA
TsOH
Huameng Yanga
Jinlong Zhang*a
Gaoxi Jiang*a
+
N
N
R = H
N
CO2Me
OH
O
R
R1
Azepines
a State Key Laboratory for Oxo Synthesis and Selective Oxida-
tion, Center for Excellence in Molecular Synthesis, Suzhou
Research Institute of LICP, Lanzhou Institute of Chemical
Physics (LICP), Chinese Academy of Sciences, Lanzhou
730000, P. R. of China
R1
N
O
R1
O
P
Intramolecular
addition
intermolecular
addition
N
*
N
N
O
H
CBA
MeO
O
zhangjl@licp.cas.cn
gxjiang@licp.cas.cn
16 examples
5 examples
R
– H2O
b University of Chinese Academy of Sciences, Beijing 100049,
P. R. of China
791712373@qq.com
Corresponding Author
(a) Biologically active products containing pyrrole and azepine skeletons
Received: 14.12.2020
Me
Me
Accepted after revision: 27.03.2021
Published online: 27.03.2021
DOI: 10.1055/a-1468-5725; Art ID: st-2020-l0629-l
OH
H
H
OMe
H
Et
N
OH Me
Me
H
O
Me
OH
Me
O
OH
O
H
H
N
N
O
N
O
Abstract Two approaches involving intramolecular and intermolecu-
lar cyclization, respectively, have been developed for the direct and
practical construction of a series of important benzo[f]pyrrolo[1,2-
a][1,4]azepines by using Brønsted acid catalysts. Upon catalysis by
TsOH, the intramolecular dehydroxylation/ring closure of 3-hydroxy-2-
[2-(1H-pyrrol-1-yl)benzyl]isoindolin-1-ones provided various racemic
benzo[f]pyrrolo[1,2-a][1,4]azepines in high yields. Furthermore, enan-
tioenriched benzo[f]pyrrolo[1,2-a][1,4]azepines were also obtained by
chiral phosphoric acid catalyzed intermolecular addition of [2-(1H-pyr-
rol-1-yl)phenyl]methanamines to 2-formylbenzoates under mild condi-
tions.
O
O
O
NH2
O
Stemoamide
(antihelminthic
activity)
Tetrapetalone A
(lipoxygenase inhibitor)
Anthramycin
(antitumor activity)
NHTf
NH
O
N
N
F
MeO
MeO
NH
N
anti-obesity drug
active ingredient
chiral base
R
Organocatalyst
(b) Meyers' lactamization to dibenz[c,e]azepines containing pyrrole via asymmetric induction
(Previous work)
Ph
R
N
R
Key words Brønsted acid catalysis, cyclization, pyrroles, intermolecu-
lar addition, azepines, asymmetric catalysis
N
(1.2 equiv)
H2N
OH
O
O
CO2Me
N
tBuCO2H (2.0 equiv)
Toluene (1 M), 150 °C
O
Ph
Two examples
R = Me, Bn
Five-membered pyrrole and seven-membered azepine
heterocycles are ubiquitous structural motifs, found in
many natural products and pharmaceuticals such as ste-
moamide, tetrapetalone A, and anthramycin (Scheme 1a).1
Among these molecules, dibenzo[c,e]azepines possess a
unique feature in that the conformation of the Ar–Ar stereo-
genic axis can be influenced by the adjacent stereogenic
center (axis-center stereochemical relay) to generate an ax-
ially chiral biaryl microstructure. As a family of important
chiral compounds that bear two kinds of chirality element
in most cases, these compounds have been synthesized as
anti-obesity drug analogues,2 chiral organocatalysts,3 and
chiral bases.4
(c) Preparation of benzo[f]pyrrolo[1,2-a][1,4]azepines (this work)
O
CHO
N
NH2
+
N
R
TsOH
CPA
N
N
N
R = H
CO2Me
R
HO
O
Scheme 1 Natural products containing ring-fused azepine moieties,
and two current strategies for constructing azepines containing fused
pyrroles
aryl is far less developed. In principle, the intramolecular
nucleophilic addition of pyrroles at the 2-position should
be an efficient and convenient method for preparing ben-
zo[f]pyrrolo[1,2-a][1,4]azepines with a center-axis stereo-
chemical relay. In 2013, the Levacher group realized an at-
roposelective synthesis of biaryl azepines through an asym-
metric induction based on the Meyers lactamization with
chiral 2-amino-2-phenylethanol under microwave irradia-
tion (Scheme 1b).7 However, the direct asymmetric alkyla-
In general, hydrogenation5 of various seven-membered
cyclic imines through transition-metal catalysis has been
widely used by the groups of Buchwald, Fan, Zhou, Turner,
and others as a valuable and useful strategy for obtaining
these synthetic targets.6 In sharp contrast, the construction
of azepine scaffolds containing an axially chiral heterobi-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 930–934
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

931
Z. Gao et al.
Letter
Synlett
tion of pyrroles remains underdeveloped because: (a) the
more-electron-rich N-containing heterocycle renders the
compound more vulnerable to attack by acid, base, or air;8
(b) catalytic mono C-alkylation of pyrrole is rather imprac-
tical due to several competing transformations such as
polyalkylation, ring opening, and polymerization;9 and (c)
compared with unprotected pyrroles that can be activated
by interaction with the N−H portion and which show less
steric hindrance,10 the inert N-substituted pyrroles are less
prone to undergo nucleophilic addition reactions because
of a lack of a free N–H moiety to interact with the catalyst
by hydrogen bonding or chelation.11 As part of our continu-
ing efforts to develop asymmetric cyclization of inert N-
substituted pyrroles,11m–p we report a straightforward and
practical preparation of biaryl azepines containing both
pyrrole and azepine skeletons by two different strategies in-
volving Brønsted acid catalyzed intramolecular or intermo-
lecular cyclizations, respectively, from simple starting ma-
terials (Scheme 1c).
R1
O
N
R
TsOH (1.0 mol%)
CH2Cl2, r.t
N
N
N
R
R1
HO
O
2a–q
1a–q
Me
N
N
N
R
R
H
N
O
N
N
O
O
2a: 93%
2b: R = Me, 97%
2c: R = n-Bu, 89%
2d: R = Allyl, 94%
2e: R = Ph, 98%
2g: R = n-Pr, 99%
2h: R = Allyl, 93%
2i: R = Ph, 96%
2j: R = 4-MeOPh, 93%
2f: R = 4-MeOPh, 95%
stereogenic
axis
stereogenic
center
N
Cl
Ph
R1
N
Ph
N
O
N
O
2l: R = F, 97%
2m: R = Cl, 96%
X-ray structure of 2a
CCDC No. 1964245
2k: 94%
Br
N
N
Ph
N
Ph
Ph
MeO
MeO
N
O
N
N
Br
Cl
O
Initially, the intramolecular dehydroxylation/cyclization
O
2p: 96%
2n: 99%
2o: 95%
of
3-hydroxy-2-[2-(1H-pyrrol-1-yl)benzyl]isoindolin-1-
ones 1 catalyzed by TsOH was employed as an efficient
method for constructing azepines in CH2Cl2 at room tem-
perature (Scheme 2). Isoindolinones containing alkyl (Me,
Bu, or All) or aryl (Ph, 4-MeOC6H4) substituents were
amenable to this transformation and gave the correspond-
ing products 2a–f in high yields. The relative configuration
of product 2a was determined by X-ray single-crystal analy-
sis, which indicated the existence of a twisted C–N bond
(stereogenic axis) that was influenced by the adjacent ste-
reogenic center in the azepine. A methyl group at the 6-po-
sition of the substrate had no obvious influence on the re-
sults, and compounds 2g–k were obtained in yields of 93–
99%. Isoindolinones with a fluoro or chloro group at the 5-
position reacted smoothly to deliver the desired products 2l
and 2m in yields of 97 and 96%, respectively. Moreover,
polysubstituted products 2a and 2p were obtained from 1a
and 1p in yields of 95 and 96%, respectively.
Scheme 2 Substrate scope for racemic synthesis of benzo[f]pyrro-
lo[1,2-a][1,4]diazepines. Reagents and conditions: 1 (0.2 mmol), TsOH
(1.0 mol%), CH2Cl2 (2.0 mL), stirring, r.t., 1 h. The yields of the isolated
products are reported.
O
N
R
Cat A (5.0 mol%)
N
N
CH2Cl2, r.t.
N
R
HO
O
1a: R = H; 1e: R = Ph
2a, 2e
CF3
R
R
R
O
O
O
CF3
O
O
O
P
O
O
O
P
OH
P
OH
NHTf
O
O
O
P
NHTf
R
R
R
A8, R = 3,5-2iPrPh
A9, R = Phenanthyl
CF3
A4, R = Pyrenyl
A2, R = Pyrenyl
A3, R = 3,5-2iPrPh
A5, R = 1-Anthracenyl
A6, R = 3,5-2iPrPh
A7, R = Phenanthyl
A1
CF3
We then switched our attention to an investigation of
the asymmetric synthesis of these pyrroloazepines by using
a chiral Brønsted acid catalyst. However, treatment of the
typical substrates 1a and 1e with the chiral phosphoric am-
ide catalysts A1–A3 or the acid catalysts A4–A10 gave the
racemic products exclusively in all cases (Scheme 3).
Results for 2a
N
H
(iii) A1–A3: 70–89%, 0% ee
N
(iv) A4–A10: 20–40%, 0% ee
O
2a
O
O
P
O
OH
Result for 2e
N
Ph
(i) A1–A3: 46–80%, 0% ee
N
(ii) A4–A10: no reaction at r.t.–100 °C
The poor enantioselectivity toward the desired product
might have resulted from the high reactivity of the immo-
nium ion generated in situ or from the weak interaction in
the loose ion pair between the immonium ion and the cata-
lyst (Scheme 4; transition state A). With this understanding
of the reaction mechanism of the TsOH-catalyzed intramo-
lecular cyclization of isoindolinone 1a, we reasoned that
the imine formed in situ from amine 3a and aldehyde 4a
might be a potential reaction intermediate for the asym-
2e
O
A10
Scheme 3 Attempts at asymmetric reactions. Reactions were carried
out at a 0.2 mmol scale. Yields of the isolated products are reported.
metric synthesis of pyrroloazepines by virtue of their mod-
erate reactivity and the stronger hydrogen bonding be-
tween the imine and the catalyst (Scheme 4; transition
state B). In addition, similar polycyclic azepines were also
obtained after a final annulation of intermediate 2a′.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 930–934

932
Z. Gao et al.
Letter
Synlett
Table 1 Optimization of the Enantioselective Reactiona
O
N
N
H
H
CPA
TsOH
N
N
NH
MeO
N
N
H
CHO
2a'
N
NH2
1a
2a
O
OH
Cat A (5.0 mol%)
O
+
N
toluene, 4 Å MS
r.t., 24 h
CPA
CO2Me
O
N
CHO
3a
4a
2a
O
O
P
N
*
CO2Me
O
N
N
H
Entry
Solvent
Catalyst
Yield (%)
ee (%)
+
4a
CBA
MeO
– H2O
1
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
50
61
53
44
73
46
69
49
65
64
70
n.r.d
61
65
61
70
72
64
70
69
69
62
35
2
10
27
54
76
48
74
54
67
67
71
–
O
N
NH2
Transition state A
Loose ion pair
High reactivity
Transition state B
H-bond interaction
Moderate reactivity
3a
3
Scheme 4 Developing a working hypothesis for improving the chiral
4
induction
5
6
With this idea in mind, we first investigated the catalyt-
ic activity of various catalysts A1–A10 for the model reac-
tion of amine 3a with ester 4a in toluene containing 4 Å
molecular sieve (4 Å MS) at room temperature for 24 hours.
As shown in Table 1, the designed cascade reaction took
place smoothly, and the desired product 5a was isolated in
yields of 44–73% yields and enantioselectivities of 2–76%
(Table 1, entries 1–10). Among the catalysts, A5 provided
the best outcome with a 76% ee of the desired product 2a
(entry 5). Examination of the solvent effect revealed that
toluene is the optimal choice (entries 5 and 11–18). The re-
action in THF gave rise to the imine product only, along
with a large amount of the starting materials 3a and 4a,
possibly due to the influence of the oxygen of the THF on
the hydrogen bond (entry 12). Changing the ratio of 3a to
4a had an obvious effect on the reaction, and an excess of
3a (3a/4a =1.5:1) was detrimental to enantioselectivity (en-
tries 19–20). The choice of the molecular sieve desiccant
did not have a significant effect on the results (entries 21
and 22), but the yield and enantioselectivity toward 5a dra-
matically decreased in its absence (entry 23).
Having established the optimal reaction conditions, we
next investigated the substrate scope of this cascade reac-
tion (Scheme 5). On using a tert-butyl (4b) or benzyl ester
(4c) instead of the methyl ester (4a), the enantioselectivity
toward adduct 2a improved slightly to 78% from the tert-
butyl ester, but only a trace of product was detected from
the benzyl ester. The 3-chloro-substituted product 2b was
also readily obtained in 65% yield and 76% ee. With a chloro
or fluoro group at the 4-position of amine substrate, the re-
action gave the corresponding product 2r or 2s exclusively
in a lower 36 and 46% ee, respectively. Only a 14% ee was
obtained for the methyl-substituted compound 2t.
7
8
9
10
11
12
13
14
15
16
17
18
19e
20f
21g
22h
23i
Et2O
71
73
71
68
73
72
56
0
CHCl3
CCl4
xylene
benzene
MTBE
toluene
toluene
toluene
toluene
toluene
72
70
40
a Reaction conditions: 3a (0.1 mmol), 4a (0.15 mmol, 1.5 equiv), CBA (5.0
mol%), 4 Å MS (100 mg), solvent (1.0 mL), stirring, 25 °C, 24 h.
b Yield of the isolated product.
c Determined by chiral HPLC.
d n.r. = no reaction.
e 0.1 mmol of 4a (3a:4a = 1:1) was used.
f 3a (0.15 mmol) and 4a (0.1 mmol) were used (3a:4a = 1.5:1).
g 3 Å MS.
h 5 Å MS.
i No desiccant.
synthesized from (pyrrolobenzyl)isoindolinones under
mild conditions.12 Additionally, enantioenriched pyrrole-
containing azepines with a flexible biaryl stereogenic axis
were obtained by a chiral phosphoric acid catalyzed inter-
molecular reaction of a pyrrolylbenzylamine and methyl 2-
formylbenzoate. This latter reaction has great potential for
the synthesis of pharmaceutically important molecules.
Further explorations of the efficient asymmetric synthesis,
as well as an examination of the biological activities of the
useful products, are ongoing in our laboratory.
In conclusion, we have developed two strategies involv-
ing an intramolecular annulation and an intermolecular re-
action, respectively, for the efficient and practical construc-
tion of pyrroloazepines. By catalysis with TsOH, a series of
racemic benzo[f]pyrrolo[1,2-a][1,4]azepines were readily
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 930–934

933
Z. Gao et al.
Letter
Synlett
3890. (h) Guo, R.-N.; Gao, K.; Ye, Z.-S.; Shi, L.; Li, Y.; Zhou, Y.-G.
Pure Appl. Chem. 2013, 85, 843. (i) Shen, H.-Q.; Gao, X.; Liu, C.;
Hu, S.-B.; Zhou, Y.-G. Org. Lett. 2016, 18, 5920. (j) Balakrishna,
B.; Bauzá, A.; Frontera, A.; Vidal-Ferran, A. Chem. Eur. J. 2016, 22,
10607. (k) Wang, J. Tetrahedron Lett. 2013, 54, 5956. (l) Li, P.;
Huang, Y.; Hu, X.; Dong, X.-Q.; Zhang, X. Org. Lett. 2017, 19,
3855. (m) Rueping, M.; Merino, E.; Koenigs, R. M. Adv. Synth.
Catal. 2010, 352, 2629. (n) Zawodny, W.; Montgomery, S. L.;
Marshall, J. R.; Finnigan, J. D.; Turner, N. J.; Clayden, J. J. Am.
Chem. Soc. 2018, 140, 17872. (o) Ding, Z.-Y.; Chen, F.; Qin, J.; He,
Y.-M.; Fan, Q.-H. Angew. Chem. Int. Ed. 2012, 51, 5706. (p) Yang,
Z.; Ding, Z.; Chen, F.; He, Y.-M.; Yang, N.; Fan, Q.-H. Eur. J. Org.
Chem. 2017, 1973. (q) Miao, T.; Ma, B.; Ding, Z.; Liu, Y.; He, Y.-
M.; Fan, Q.-H. Asian J. Org. Chem. 2017, 1219. (r) Liu, Y.; Chen, F.;
He, Y.-M.; Li, C.; Fan, Q.-H. Org. Biomol. Chem. 2019, 17, 5099.
(6) (a) Cheetham, C. A.; Massey, R. S.; Pira, S. L.; Pritchard, R. G.;
Wallace, T. W. Org. Biomol. Chem. 2011, 9, 1831. (b) France, S. P.;
Aleku, G. A.; Sharma, M.; Mangas-Sanchez, J.; Howard, R. M.;
Steflik, J.; Kumar, R.; Adams, R. W.; Slabu, I.; Crook, R.; Grogan,
G.; Wallace, T. W.; Turner, N. J. Angew. Chem. Int. Ed. 2017, 56,
15589. (c) Liu, J.; Yang, X.; Zuo, Z.; Nan, J.; Wang, Y.; Luan, X.
Org. Lett. 2018, 20, 244. (d) Yang, T.; Guo, X.; Yin, Q.; Zhang, X.
Chem. Sci. 2019, 10, 2473.
(7) Postikova, S.; Sabbah, M.; Wightman, D.; Nguyen, I. T.;
Sanselme, M.; Besson, T.; Brière, J. F.; Oudeyer, S.; Levacher, V.
J. Org. Chem. 2013, 78, 8191.
(8) (a) Reinecke, M. G.; Johnson, H. W.; Sebastian, J. F. J. Am. Chem.
Soc. 1963, 85, 2859. (b) Belen’kii, L. I. Heterocycles 1994, 37,
2029.
(9) (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, 3rd
ed; Chapman and Hall: London, 1995, 231. (b) Schofield, K.
Hetero-Aromatic Nitrogen Compounds: Pyrroles and Pyridines;
Plenum Press: New York, 1967. (c) Jorapur, Y. R.; Lee, C.-H.; Chi,
D. Y. Org. Lett. 2005, 7, 1231.
CHO
N
N
NH2
R
H
A5 (5.0 mol%)
+
toluene, 4 Å MS
r.t., 24 h
CO2R
N
R
4a: R = Me; 4b: R = tBu
4c: R = Bn
O
3
2a, 2q–t
N
N
H
H
N
Me
N
N
H
R
N
H
Cl
O
O
2a,
N
N
2r, R = Cl, 61%, 36% ee
2s, R = F, 68%, 46% ee
73%, 76% ee (from 4a)
71%, 78% ee (from 4b)
trace (from 4c)b
O
O
2q, 65%, 76% ee
2t, 60%, 14% ee
Scheme 5 Substrate scope for the asymmetric cascade reaction. Re-
agents and conditions: 3 (0.1 mmol), 4 (0.15 mmol, 1.5 equiv), A5 (5.0
mol%), 4 Å MS (100 mg), toluene (1.0 mL), stirring, 25 °C, 24 h. Yields of
the isolated products are reported. The ee values were determined by
chiral HPLC analysis. a Detected by 1H NMR.
Conflict of Interest
The authors declare no conflict of interest
Funding Information
Financial support from the National Natural Science Foundation of
China (21602231) and the Natural Science Foundation of Jiangsu
Province (BK20191197 and BK20181373) is gratefully acknowledged.
N
ati
o
n
a
l
N
a
t
ura
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e
n
c
e
F
o
u
n
dati
o
n
o
f
C
h
i
na(2
1
6
0
2
2
3
1)
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atura
l
S
c
i
e
nc
e
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o
u
n
dati
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o
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Ji
a
n
gs
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Pro
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i
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c
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K
2
0
1
9
1
1
9
7
)
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atura
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nc
e
F
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it
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Supporting Information
(10) For asymmetric addition of unprotected pyrroles, see: (a) Trost,
B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438. (b) Sheng, Y.-
F.; Gu, Q.; Zhang, A.-J.; You, S.-L. J. Org. Chem. 2009, 74, 6899.
(c) Sheng, Y.-F.; Li, G.-Q.; Kang, Q.; Zhang, A.-J.; You, S.-L. Chem.
Eur. J. 2009, 15, 3351. (d) Hong, L.; Sun, W.; Liu, C.; Wang, L.;
Wong, K.; Wang, R. Chem. Eur. J. 2009, 15, 11105. (e) Yokoyama,
N.; Arai, T. Chem. Commun. 2009, 3285. (f) Hong, L.; Liu, C.; Sun,
W.; Wang, L.; Wong, K.; Wang, R. Org. Lett. 2009, 11, 2177.
(g) Blay, G.; Fernández, I.; Monleón, A.; Pedro, J. R.; Vila, C. Org.
Lett. 2009, 11, 441. (h) Singh, P. K.; Singh, V. K. Org. Lett. 2010,
12, 80. (i) Blay, G.; Fernández, I.; Muñoz, M. C.; Pedro, J. R.;
Recuenco, A.; Vila, C. J. Org. Chem. 2011, 76, 6286. (j) Zhang, K.-
F.; Nie, J.; Guo, R.; Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2013,
355, 3497; corrigendum: Adv. Synth. Catal. 2014, 356, 2133.
(k) Hua, Y.-Z.; Han, X.-W.; Yang, X.-C.; Song, X.; Wang, M.-C.;
Chang, J.-B. J. Org. Chem. 2014, 79, 11690. (l) Li, C.; Guo, F.; Xu,
K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Org. Lett. 2014, 16, 3192.
(m) Wu, K.; Zhuo, M.-H.; Sha, D.; Fan, Y.-S.; An, D.; Jiang, Y.-J.;
Zhang, S. Chem. Commun. 2015, 51, 8054. (n) Hu, Y.; Li, Y.;
Zhang, S.; Li, C.; Li, L.; Zha, Z.; Wang, Z. Org. Lett. 2015, 17, 4018.
(o) Nakamura, S.; Matsuda, N.; Ohara, M. Chem. Eur. J. 2016, 22,
9478. (p) Lou, H.; Wang, Y.; Jin, E.; Lin, X. J. Org. Chem. 2016, 81,
2019. (q) Sun, J.; Hu, Y.; Li, Y.; Zhang, S.; Zha, Z.; Wang, Z. J. Org.
Chem. 2017, 82, 5102. (r) Gui, Y.; Li, Y.; Sun, J.; Zha, Z.; Wang, Z.
J. Org. Chem. 2018, 83, 7491.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1468-5725.
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References and Notes
(1) (a) Snow, G. A. Bacteriol. Rev. 1970, 34, 99. (b) Lin, W.-H.; Ye, Y.;
Xu, R.-S. J. Nat. Prod. 1992, 55, 571. (c) Thurston, D. E.; Bose, D. S.
Chem. Rev. 1994, 94, 433. (d) Murakami, S.; Takemoto, T.;
Shimizu, Z. J. Pharm. Soc. Jpn. 1953, 73, 1026.
(2) Hall, I. H.; Murthy, A. R. K.; Wyrick, S. D. J. Pharm. Sci. 1986, 75,
622.
(3) (a) Page, P. C. B.; Bartlett, C. J.; Chan, Y.; Day, D.; Parker, P.;
Buckley, B. R.; Rassias, G. A.; Slawin, A. M. Z.; Allin, S. M.; Lacour,
J.; Pinto, A. J. Org. Chem. 2012, 77, 6128. (b) Kano, T.; Sugimoto,
H.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 18130. (c) Page, P. C.
B.; Pearce, C. A.; Chan, Y.; Parker, P.; Buckley, B. R.; Rassias, G. A.;
Elsegood, M. R. J. J. Org. Chem. 2015, 80, 8036.
(4) Saudan, L. A.; Bernardinelli, G.; Kündig, E. P. Synlett 2000, 483.
(5) (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
8952. (b) Chang, M.; Li, W.; Hou, G.; Zhang, X. Adv. Synth. Catal.
2010, 352, 3121. (c) Zhang, Y.; Kong, D.; Wang, R.; Hou, G. Org.
Biomol. Chem. 2017, 15, 3006. (d) Guo, C.; Sun, D.-W.; Yang, S.;
Mao, S.-J.; Xu, X.-H.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc.
2015, 137, 90. (e) Chen, F.; Ding, Z.; Qin, J.; Wang, T.; He, Y.; Fan,
Q.-H. Org. Lett. 2011, 13, 4348. (f) Gao, K.; Yu, C.-B.; Li, W.; Zhou,
Y.-G.; Zhang, X. Chem. Commun. 2011, 47, 7845. (g) Gao, K.; Wu,
B.; Yu, C.-B.; Chen, Q.-A.; Ye, Z.-S.; Zhou, Y.-G. Org. Lett. 2012, 14,
(11) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
4370. (b) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org.
Lett. 2007, 9, 4065. (c) Cao, C.-L.; Zhou, Y.-Y.; Sun, X.-L.; Tang, Y.
Tetrahedron 2008, 64, 10676. (d) Sibi, M. P.; Coulomb, J.; Stanley,
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 930–934

934
Z. Gao et al.
Letter
Synlett
L. M. Angew. Chem. Int. Ed. 2008, 47, 9913. (e) Huang, Y.;
Tokunaga, E.; Suzuki, S.; Shiro, M.; Shibata, N. Org. Lett. 2010, 12,
1136; corrigendum: Org. Lett. 2010, 12, 3570. (f) He, Y.; Lin, M.;
Li, Z.; Liang, X.; Li, G.; Antilla, J. C. Org. Lett. 2011, 13, 4490.
(g) You, Y.; Cui, B.-D.; Zhou, M.-Q.; Zuo, J.; Zhao, J.-Q.; Xu, X.-Y.;
Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2015, 80, 5951.
(h) Majer, J.; Kwiatkowski, P.; Jurczak, J. Org. Lett. 2011, 13,
5944. (i) Gutierrez, E. G.; Wong, C. J.; Sahin, A. H.; Franz, A. K.
Org. Lett. 2011, 13, 5754. (j) Cai, Y.; Tang, Y.; Atodiresei, I.;
Rueping, M. Angew. Chem. Int. Ed. 2016, 55, 14126. (k) Li, H.;
Tong, R.; Sun, J. Angew. Chem. Int. Ed. 2016, 55, 15125. (l) Gade,
A. B.; Patil, N. T. Synlett 2017, 28, 1096. (m) Gao, Z.; Zhang, J.;
Yang, H.; Jiang, G. J. Org. Chem. 2018, 83, 11407. (n) Wei, Z.;
Zhang, J.; Yang, H.; Jiang, G. Adv. Synth. Catal. 2019, 361, 3694.
(o) Wei, Z.; Zhang, J.; Yang, H.; Jiang, G. Org. Lett. 2019, 21, 2790.
(p) Gao, Z.; Wang, F.; Qian, J.; Yang, H.; Xia, C.; Zhang, J.; Jiang, G.
Org. Lett. 2021, 23, 1181.
hexane–EtOAc).
9H-Isoindolo[1,2-c]pyrrolo[1,2-a][1,4]benzodiazepin-
11(15bH)-ones 2a, 2q–t; General Procedure (Intermolecular
Reaction)
The appropriate amine 3 (0.1 mmol, 1.0 equiv), methyl 2-form-
ylbenzoate (4a, 0.15 mmol, 1.5 equiv), chiral phosphoric acid A5
(5.0 mol%), and 4 Å MS (100 mg) were stirred in toluene (1.0
mL) at r.t. under N2. Upon completion of the reaction, the
solvent was removed and the crude mixture was purified by
flash column chromatography.
9H-Isoindolo[1,2-c]pyrrolo[1,2-a][1,4]benzodiazepin-
11(15bH)-one (2a)
White solid; yield: 53.2 mg (93%); mp 192-195 °C. 1H NMR (400
MHz, CDCl3):  = 7.91 (d, J = 7.5 Hz, 1 H), 7.64–7.44 (m, 6 H),
7.35 (t, J = 7.4 Hz, 1 H), 7.10 (d, J = 2.9 Hz, 1 H), 6.26 (t, J = 3.3 Hz,
1 H), 5.94 (d, J = 3.5 Hz, 1 H), 5.40 (s, 1 H), 5.06 (d, J = 13.9 Hz, 1
H), 4.17 (d, J = 13.9 Hz, 1 H). 13C NMR (101 MHz, CDCl3):  =
167.0, 141.7, 140.2, 133.6, 131.5, 131.2, 130.0, 128.9, 128.5,
127.3, 124.0, 123.6, 121.8, 109.5, 107.2, 56.4, 44.6.
(12) 9H-Isoindolo[1,2-c]pyrrolo[1,2-a][1,4]benzodiazepin-
11(15bH)-ones 2a–q; General Procedure (Intramolecular
Reaction)
CCDC 1964245 contains the supplementary crystallographic
data for compound 2a. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
The appropriate isoindolone 1 (0.2 mmol, 1.0 equiv) and TsOH
(1 mol%) were stirred in CH2Cl2 (1 mL) at r.t. When the reaction
was complete, the solvent was removed and the crude mixture
was purified by flash column chromatography (silica gel,
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 930–934