Rh-Catalyzed Reactions of 3-Diazoindolin-2-imines: Synthesis of Pyridoindoles and Tetrahydrofuropyrroloindoles

Article abstract of DOI:10.1021/acs.orglett.5b01943

The rhodium-catalyzed reactions of 3-diazoindolin-2-imines with furans and dihydrofuran furnished 9H-pyrido[2,3-b]indoles and tetrahydrofuro[3′,2′:4,5]pyrrolo[2,3-b]indoles, respectively. A cascade reaction mechanism involving an α-imino rhodium carbene i

Full text of DOI:10.1021/acs.orglett.5b01943

Letter
pubs.acs.org/OrgLett
Rh-Catalyzed Reactions of 3‑Diazoindolin-2-imines: Synthesis of
Pyridoindoles and Tetrahydrofuropyrroloindoles
Chen Wang, Haojie Zhang, Bo Lang, Anni Ren, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
*
S Supporting Information
ABSTRACT: The rhodium-catalyzed reactions of 3-diazo-
indolin-2-imines with furans and dihydrofuran furnished 9H-
pyrido[2,3-b]indoles and tetrahydrofuro[3′,2′:4,5]pyrrolo[2,3-
b]indoles, respectively. A cascade reaction mechanism
involving an α-imino rhodium carbene intermediate is
proposed. The starting materials are readily available, and
the procedure is facile and efficient.
ndole and its derivatives are important scaffolds in naturally
Scheme 1. Preparation of Indole Derivations via α-Imino
Rhodium Carbenes
1
2
I
occurring compounds, pharmaceuticals, and optoelec-
3
tronics materials. Their unique functions and structural
diversities provide inspiration in the discovery of modern
synthetic methods, including the construction of indole
4
skeletons and the functionalization of indole rings.
Recently, α-imino rhodium carbene is becoming an
increasingly valuable intermediate in organic synthesis because
of the easy formation from 1-sulfonyl-1,2,3-trazole and various
effective transformations to a broad range of organic
5
6
7
8
9
compounds. Fokin, Gevorgyan, Murakami, Davies, Sar-
1
0
11
12
pong, Shi, and other groups have made significant
contributions in this chemistry. Inspired by the vivid reactivity
of α-imino rhodium carbenes and attracted by the importance
of indole ring systems, we recently demonstrated a class of
indole-embedded α-imino rhodium carbenes in situ generated
from 3-diazoindolin-2-imines in the presence of a rhodium
1
3
catalyst. Upon these specific rhodium carbenes, a series of
reactions had been realized, such as arylation, cyclopropanation,
1
3
N−H insertion, and transannulation (Scheme 1). These
transformations furnished a variety of indole derivatives. In
continuation of our study on this chemistry, we herein report a
rhodium-catalyzed synthesis of 9H-pyrido[2,3-b]indoles and
tetrahydrofuro[3′,2′:4,5]pyrrolo[2,3-b]indoles from 3-diazoin-
dolin-2-imines via an indole-embedded α-imino rhodium
carbene intermediate.
In consideration of the importance of 9H-pyrido[2,3-
14
b]indoles, also called α-carboline, in pharmaceuticals and
15
optoelectronics materials, we optimized the reaction con-
ditions for the preparation of 3a (Table S1; see Supporting
Information). The highest yield (64%) and the best selectivity
were approached when the reaction was carried out in DCE at
80 °C for 8 h (Table S1, entry 16).
Our initial trial was conducted between 3-diazo-indolin-2-
imine (1a) and 2,5-dimethylfuran (2a, 2 equiv) in the presence
of Rh (Oct) (1 mol %) in dichloroethane (DCE) at 80 °C for
Subsequently, we evaluated the effectiveness of the sulfonyl
group on 3-diazoindolin-2-imines 1 (Scheme 3). Reactions
were conducted under standard reaction conditions except for
the reaction time which was determined by thin layer
2
4
3
h. After workup, 9H-pyrido[2,3-b]indole (3a) and dihydro-
furo[3′,2′:4,5]pyrrolo[2,3-b]indole (4) were isolated in 36%
and 9% yields, respectively (Scheme 2). The structure of 3a was
16
established by the single crystal analysis of its analog 3d.
Further investigation demonstrated that 4 was unstable and
could be converted into 3a with or without a rhodium catalyst.
Received: July 8, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01943
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Organic Letters
Letter
Scheme 2. Formation and Conversion of 3a and 4
Scheme 3. Scope of Sulfonyl of 3-Diazo-indolin-2-imines
Figure 1. Scope of 3-Diazoindolin-2-imines.a a Reaction conditions: 1
(
8
0.2 mmol), 2a (2 mmol), Rh (Oct) (0.002 mmol), DCE (2 mL), N ,
0 °C, 8 h. Isolated yield. 18 h. 10 h. 24 h.
2
4
2
b
c
d
chromatography. A slightly higher yield was observed for N-
benzenesulfonyl 3-diazoindolin-2-imine 1b, while p-fluoro-
benzenesulfonyl (1c), p-chlorobenzenesulfonyl (1d), 2-naph-
thalenesulfonyl (1e), and methanesulfonyl substituted 3-
diazoindolin-2-imines (1f) afforded 3a in decreased yields.
With the optimized reaction conditions in hand, we tested
the substrate scope of this transformation. First, we investigated
the scope of 3-diazoindolin-2-imines, and the results are
summarized in Figure 1. The substituent on the 1-position of 3-
diazoindolin-2-imines could be ethyl (1g), isopropyl (1h), allyl
(
1i), phenyl (1j), benzyl (1k), and H (1l). Thus, the
corresponding products 3b−g were obtained in yields varying
from 40% to 55%. The substituent on the 5-position of 3-diazo-
indolin-2-imine could be either an electron-donating group,
such as OMe (1m) and Me (1n), or an electron-withdrawing
group, such as F (1o), Cl (1p), and Br (1q). In these cases, the
reaction furnished the corresponding products 3h−n in 68%−
Figure 2. Scope of furans.a a Reaction conditions: 1 (0.2 mmol), 2 (2
mmol), Rh (Oct) (0.002 mmol), DCE (2 mL), N , 80 °C, 8 h;
2
4
2
b
Isolated yield. 30 h.
86% yields.
The scope of furans was also studied. Furan (2b) furnished
o−s in 33%−48% yields, while 2,5-diphenylfuran (2c)
occurs at the 2-position of furan to form intermediate B, which
undergoes a sequential ring-opening, 6π-electron ring closure
3
provided 3t and 3u in 47% and 49% yields, respectively
(6π-ERC) and E elimination to afford 3. In path B, the attack
2
(
Figure 2). For the unsymmetrical furans, such as 2-
methylfuran (2d), 2-ethylfuran (2e), 2-methyl-5-benzylfuran
2g), and 3-methylfuran (2h), the desired products 3va (38%),
wa (40%), 3ya (27%), and 3z (8%) were selectively yielded,
occurs at the 3-position of furan to generate intermediate E,
which undergoes an intramoleclular nucleophilic addition to
afford 4. 4 is unstable and can rearrange to 3 through a three-
membered ring intermediate G. For the monosubstituted
furans 2d, 2e, and 2h, Path A seems possible. However, for 2,5-
disubstituted furans, Path B should be more likely due to the
steric effect.
(
3
while their isomers 3vb, 3wb, and 3yb were determined to be
trace by H NMR (Scheme 4). In the case where 2-methyl-5-
phenylfuran (2f) was used as a substrate, the desired products
1
3
xa and 3xb were isolated in 18% yield for each.
Based on these results, we proposed a possible mechanism
The reactions between 3 and dihydrofuran (5) were also
studied. In the presence of a rhodium catalyst, 3a reacted with 5
in DCE at 80 °C for 4 h to provide tetrahydrofuro[3′,2′:4,5]-
pyrrolo[2,3-b]indole 6a (Figure 3) in 43% yield. The optimized
reaction conditions were established when the reaction of 1a
with 5 (2 equiv) was performed in the presence of Rh (Oct)
for the formation of 3 and 4 (Scheme 5). In the presence of a
rhodium(II) catalyst, 1a is converted into rhodium carbene A.
Then, 2 nucleophilically attacks the electron-deficient rhodium
carbene through two possible pathways. In path A, the attack
2
4
B
DOI: 10.1021/acs.orglett.5b01943
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Organic Letters
Letter
Scheme 4. Reaction of 1a with Asymmetrical Furans
Figure 3. Scope of 3-diazoindolin-2-imines for preparation of 6.
Reaction conditions: 1 (0.2 mmol), 5 (0.4 mmol), Rh (Oct) (0.002
2
4
mmol), CHCl (2 mL), N , 80 °C, 3 h. Isolated yield.
3
2
Scheme 5. Possible Mechanism for the Formation of 3 and 4
case where 1-unsubstituted 3-diazoindolin-2-imine 1l was used
as the substrate. The 5-substituted 3-diazoindolin-2-imines
furnished the corresponding products 6g−l in 44%−65% yields.
The sulfonyl group on 3-diazoindolin-2-imines 1 could be
methanesulfonyl (1f), benzenesulfonyl (1b), p-chlorobenzene-
sulfonyl (1d), and naphthalenesulfonyl (1e). In these cases, the
desired products 6m−p were obtained in 44%−59% yields.
A possible mechanism for the formation of 6a is illustrated in
Scheme 6. Compound 6a might be formed through two
Scheme 6. Possible Mechanism for Formation of 6a
possible paths. In path A, nucleophilic addition of dihydrofuran
to the in situ generated rhodium carbene A forms intermediate
I, which undergoes an intramolecular nucleophilic addition to
afford 6a. Alternatively, the cyclopropanation of rhodium
carbine occurs to form intermediate J, which undergoes a
rearrangement to give 6a (path B).
In summary, we have developed a rhodium-catalyzed
synthesis of 9H-pyrido[2,3-b]indoles and tetrahydrofuro-
[3′,2′:4,5]pyrrolo[2,3-b]indoles by the reactions of 3-diazo-
indolin-2-imines with furans and dihydrofuran, respectively.
These transformations proceeded through an indole-embedded
(
1 mol %) in chloroform (2 mL) at 80 °C for 3 h (Table S2,
entry 2; see Supporting Information).
Under the optimized reaction conditions, we tested the
substrate diversity (Figure 3). Altering the substituent on the 1-
position of 3-diazoindolin-2-imines from methyl (1a) to ethyl
(1g), allyl (1i), benzyl (1k), and phenyl (1j) led to the
formation of the corresponding products 6b−e in 54%−62%
yields. The structure of 6c was determined by its single crystal
analysis. The highest yield (70%) was observed for 6f in the
1
6
C
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α-imino rhodium carbene intermediate. The cascade mecha-
nism for the formation of 9H-pyrido[2,3-b]indoles includes
nucleophilic addition of furan to rhodium carbene, 6π-electron
ring closure, and elimination−aromatization. Studies on the
synthetic applications of this methodology and further
exploration of the chemistry of 3-diazoindolin-2-imines are
currently underway in our laboratory.
Murakami, M. Angew. Chem., Int. Ed. 2013, 52, 3883. (c) Miura, T.;
Yamauchi, M.; Murakami, M. Chem. Commun. 2009, 1470.
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(
4
ASSOCIATED CONTENT
Supporting Information
(
■
*
S
Int. Ed. 2014, 53, 5142. (b) Jiang, Y.; Tang, X. Y.; Shi, M. Chem.
Commun. 2015, 51, 2122. (c) Tang, X. Y.; Zhang, Y. S.; He, L.; Wei,
Y.; Shi, M. Chem. Commun. 2015, 51, 133.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01943.
(12) For selected examples, see: (a) Ran, R. Q.; Xiu, S. D.; Li, C. Y.
Org. Lett. 2014, 16, 6394. (b) Medina, F.; Besnard, C.; Lacour, J. Org.
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Experimental procedures and characterization data for all
new compounds (PDF)
Crystallographic information for compound 3d (CIF)
Crystallographic information for compound 6c (CIF)
9
865. (f) Feng, J.; Wang, Y.; Li, Q.; Jiang, R.; Tang, Y. Tetrahedron
Lett. 2014, 55, 6455.
AUTHOR INFORMATION
Corresponding Authors
(13) (a) Sheng, G. R.; Huang, K.; Ma, S. C.; Qian, J.; Lu, P.; Wang, Y.
G. Chem. Commun. 2015, 51, 11056. (b) Xing, Y. P.; Sheng, G. R.;
Wang, J.; Lu, P.; Wang, Y. G. Org. Lett. 2014, 16, 1244. (c) Sheng, G.
R.; Huang, K.; Chi, Z. H.; Ding, H. L.; Xing, Y. P.; Lu, P.; Wang, Y. G.
Org. Lett. 2014, 16, 5096.
■
*
*
E-mail: pinglu@zju.edu.cn.
E-mail: orgwyg@zju.edu.cn.
Notes
(14) (a) Mahmoud, K. A.; Krug, M.; Wersig, T.; Slynko, I.;
Schachtele, C.; Totzke, F.; Sippl, W.; Hilgeroth, A. Bioorg. Med. Chem.
̈
Lett. 2014, 24, 1948. (b) Wadsworth, A. D.; Naysmith, B. J.; Brimble,
M. A. Eur. J. Med. Chem. 2015, 97, 816. (c) Yadav, A. K.; Verbeeck, S.;
Hostyn, S.; Franck, P.; Sergeyev, S.; Maes, B. U. W. Org. Lett. 2013, 15,
1060.
(15) (a) Han, J.; Thirupathaiah, B.; Kwon, G.; Kim, C.; Seo, S. Y.
Dyes Pigm. 2015, 114, 78. (b) Lee, C. W.; Im, Y.; Seo, J. A.; Lee, J. Y.
Org. Electron. 2013, 14, 2687. (c) Na, Y. J.; Song, W.; Lee, J. Y.;
Hwang, S. H. Org. Electron. 2015, 22, 92.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (Nos. 21472164, 21472173, and J1210042) for financial
support.
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