Concise Synthesis of Spiro[indoline-3,2′-pyrrolidine] and 1-Azacarbazole Derivatives via Copper-Catalyzed Cyclization of Indoles

Article abstract of DOI:10.1002/adsc.201700073

A high-yielding, copper-catalyzed dearomatization reaction of indole from 2-methylindole-derived oxime acetates was realized, providing access to structurally novel spiro[indoline-3,2′-pyrrolidine] derivatives in 67–98% yields. When the C-2 position of the indole was not substituted, azacarbazole derivatives were obtained in moderate yields. This transformation provides an efficient approach to access nitrogen-containing spiroindolenine and azacarbazole derivatives with wide substrate scope. (Figure presented.).

Full text of DOI:10.1002/adsc.201700073

Title: Concise Synthesis of Spiro[indoline-3,2’-pyrrolidine] and 1-
Aza-carbazole Derivatives via Copper-Catalyzed Cyclization of
Indoles
Authors: Peng-Fei Wang, Chao Chen, Hui Chen, Li-Shuai Han, Liu Liu,
Hongbin Sun, Xiaoan Wen, and Qing-Long Xu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700073
Link to VoR: http://dx.doi.org/10.1002/adsc.201700073

10.1002/adsc.201700073
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Concise Synthesis of Spiro[indoline-3,2’-pyrrolidine] and 1-Aza-
carbazole Derivatives via Copper-Catalyzed Cyclization of
Indoles
Peng-Fei Wang,‡ Chao Chen,‡ Hui Chen, Li-Shuai Han, Liu Liu, Hongbin Sun, Xiaoan
Wen* and Qing-Long Xu*
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China
Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China
Fax: (+86)-25-8327-1050; E-mail: wxagj@cpu.edu.cn.com; qlxu@cpu.edu.cn
‡ These authors contributed equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
π-acidic catalyst.[8] Recently, Vincent and coworkers
Abstract.
A
high-yielding
copper-catalyzed
dearomatization reaction of indole from 2-methyl reported a straightforward access to spiroindoline
indole-derived oxime acetates was realized, providing
access to structurally novel spiro[indoline-3,2’-
pyrrolidine] derivatives in 67-98% yields. When the
C2-position of the indole was not substituted, aza-
carbazole derivatives were obtained in moderate
yields. This transformation provided an efficient
derivatives via the intramolecular hydroarylation of
N-Ac indoles mediated by FeCl3, which involves an
umpolung of the indole C2=C3 bond.[9] We recently
developed an intramolecular palladium-catalyzed
dearomative arylation reaction of indole via C-H
bond functionalization, providing access to
structurally novel spiroindolenines.[10] Owing to the
importance of spiroindolenine derivatives, the
development of new methods that afford novel spiro
structures with high efficiency is much desired.
approach
to
access
nitrogen-containing
spiroindolenine and aza-carbazole derivatives with
wide substrate scope.
Keywords: Copper-catalyzed; C-N bond formation;
spiroindoline; dearomatization;
The spiroindolenine and polycyclic indole
moieties are embedded in several classes of natural
products and biologically active compounds.[1] For
the past few years, great advances have been
achieved in the construction of these skeletons
bearing a quaternary stereocenter at C3 position of
the indole core. For the construction of these
important and valuable scaffolds, transition-metal
catalyzed dearomatization reactions of indole
derivatives have attracted considerable attention for
Scheme 1. Synthesis of spiro[indoline-3,2’-pyrrolidine]
derivatives.
organic
chemists.[2]
Among
the
reported
Through the strategy of indole dearomatization
process, synthesis of the diazaspiroindolenine has
been reported rarely. In fact, preparation of
methodologies, the intramolecular allylic alkylation
of indole have been developed for preparation of
spiroindolenines using palladium,[3] iridium,[4] gold[5]
and ruthenium[6] as the catalysts. The cascade
transformation of indole-containing π-allyl species
has also been utilized to build spiroindolenine
derivatives in a direct manner.[3] The groups of You,
Xu and Liang recently reported a palladium catalyzed
spiro[indoline-3,2’-pyrrolidine] derivatives by
a
intramolecular SN2-type cyclization from β-3-indolyl
ketone oximes is the only reported example (Scheme
1).[11] On the other hand, copper-catalyzed N-O bond
cleavage of oxime ester has attracted considerable
interest, for construction of azaheterocycles.[12] As
part of our interest aimed at developing novel
synthetic methodologies for the rapid construction of
spirocyclic molecules,[10, 13] in this report we show
that spiro[indoline-3,2’-pyrrolidine] derivatives can
be efficiently obtained from β-3-indolyl ketone oxime
acetates via copper catalysis. The mechanism of this
dearomatizative
arylation
approach
to
spiroindolenines that involves an intramolecular
nucleophilic attack by the C3 position of indole of the
aryl palladium complex.[7] In a related process,
spiroindolenine derivatives were obtained through
electrophilic alkyne activation with a simple Lewis or
1
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10.1002/adsc.201700073
Advanced Synthesis & Catalysis
10
11 c
12
Cu(acac)2
-
Cs2CO3
Cs2CO3
K2CO3
Li2CO3
Et3N
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMSO
DMF
7
7
82
NR
86
80
66
66
41
74
39
76
66
51
57
reaction is different from that of the reported ones,
most of which exploit the nucleophilicity of indole
C3 position. Moreover, we found that under the
optimized reaction conditions indoles which lack
substitution at their C2 position furnished aza-
carbazole derivatives as major products.[14]
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
4
13
4
14
15 d
4
-
4
In our initial study, 2-methyl indole-derived
oxime acetate 1a was chosen as the model substrate
to investigate the copper-catalyzed intramolecular
cyclization reaction in toluene at 120 oC, using
Cs2CO3 as the base. To our delight, the desired
spiro[indoline-3,2’-pyrrolidine] derivative 2a was
obtained in 51% yield in the presence of CuBr under
argon condition (entry 1, Table 1). Encouraged by
this result, different copper complexes, including CuI,
CuCl, Cu2O, Cu(Ac)2, CuO, Cu(CH3CN)4PF6, CuSO4,
Cu(OTf)2, Cu(acac)2, were evaluated to determine
their impact on reaction efficiency (entries 2-10,
Table 1). We found that Cu(acac)2 was the most
efficient catalyst for this transformation, giving the
desired product 2a in 82% yield. A control
experiment established that no reaction occurs in the
absence of a copper catalyst (entry 11, Table 1). Next,
the examination of different bases such as K2CO3,
Li2CO3, Et3N revealed that the base played a critical
role in this reaction (entries 12-14, Table 1). K2CO3
was proved to be the best while the product yield was
decreased to 66% without base (entry 15, Table 1).
Different solvents such as DMSO, DMF, MeCN,
Dioxane were also investigated, and toluene was
found to be the optimal solvent (entries 16-19, Table
1). When the loading of the base or the copper
catalyst was decreased to 0.5 equiv. and 5 mol%,
respectively, the product was obtained in somewhat
lower yields (entries 20, 22, Table 1). When the
reaction was performed under air, the isolated yield
was 51% that indicated potential interference (entry
21, Table 1). Finally, the optimal reaction conditions
were determined as follows: substrate (1.0 equiv.),
K2CO3 (1.0 equiv.), Cu(acac)2 (10 mol%) in toluene
at 120 oC under argon condition.
16
K2CO3
K2CO3
K2CO3
2
17
6
18
MeCN
12
12
4
19
K2CO3 Dioxane
20 e
21 f
22 g
K2CO3
K2CO3
K2CO3
PhMe
PhMe
PhMe
12
7
a)
Reaction conditions: 1a (0.3 mmol), [Cu] (10 mol%),
base (1.0 equiv.), solvent, 120 oC, Ar. NR = no reaction.
b) Isolated yield.
c) No [Cu] catalyst was added.
d) No base was added.
e) Using 0.5 equiv. K2CO3.
f) Under Air condition.
g) Using 5 mol% Cu(acac)2.
Table 1. Evaluation of the Reaction Conditions. a
time yield
(h)
entry
[Cu]
base
solvent
(%) b
51
1
2
3
4
5
6
7
8
9
CuBr
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
7
7
58
CuCl
7
62
Cu2O
7
39
Cu(OAc)2
CuO
7
50
7
79
Cu(CH3CN)4PF6 Cs2CO3
7
61
CuSO4
Cs2CO3
Cs2CO3
7
42
Cu(OTf)2
7
67
2
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10.1002/adsc.201700073
Advanced Synthesis & Catalysis
a) Reaction conditions: 1 (0.3 mmol), Cu(acac)2 (10 mol%),
Meanwhile, the substrate bearing hydrogen at C2
position of the indole ring could provide aza-
carbazole derivative 4 as the major product, therefore,
further exploration of the substrate scope was
performed as shown in Scheme 3. We found that
reaction of C2-unsubstituted indole derivatives (3)
could smoothly provide aza-carbazole derivatives 4a-
4g in good yields (51-70%) under the optimized
reaction conditions. Next, substrates bearing a para
substituent (4-OMe, 4-Cl, 4-Br) on the phenyl ring
adjacent to the oxime acetate moiety were
investigated. The corresponding fused pyridine
products (4h-4j) were obtained in moderate yields
(38-52%). Together, this protocol provides a new
approach to aza-carbazole derivatives.
K2CO3 ( 1.0 equiv.), toluene, 120 oC, Ar.
Scheme 2. Substrate scope for synthesis of spirocycles. a
With the optimal reaction conditions in hand, we
then investigated the scope of the ketoxime acetates
and the results were shown in Scheme 2. Different
substituents on the benzene ring of the indole core
such as methyl, methoxyl, chloro were all well-
tolerated and the corresponding products were
obtained in good isolated yields (2a-2d). The
substrate 1e bearing a ethyl group at the C2-position
of the indole moiety also worked well to afford the
product 2e in 67% yield. Interestingly, when a phenyl
moiety was introduced at the C2 position of the
indole, product 2f was obtained in excellent yield
(93%). Next, the substitution pattern on the aromatic
ring adjacent to the oxime moiety was varied (e.g., 4-
OMe, 4-Br, 4-Cl) and we found that regardless of the
electronic properties of this ring, all of the substrates
could be smoothly converted to the corresponding
products in reasonable yields (74-81%). Likewise,
varying the substituents on the indole core did not
have a dramatic impact on the course of the
spirocyclization process and the corresponding
products (2j-2q) were obtained in good to excellent
yields (74-98%). In addition to structurally diverse
aryl groups, alkyl groups are also well-tolerated
adjacent to the oxime acetate moiety as substrate 1n,
bearing an ethyl group, furnished the desired product
2n in 98% yield under the standard reaction
conditions. Through exploring the substrate scope,
we found that the substrates with phenyl group at the
C2-position of the indole moiety afforded the desired
products in higher yields, probably due to the
favorable stability of the corresponding radical
intermediates.
To further demonstrate the utility of this efficient
spirocyclization, the reaction of 1a was performed on
a 1.0 mmol scale and product 2a was isolated in 82%
yield. Compound 2a could be easily reduced with
NaBH4 to provide spiroindoline 2a’ in 85% yield
(Scheme 4), and the relative configuration was
confirmed by the NOE spectra (see the supporting
information for details).
Scheme 4. Practical preparation and transformation of 2a.
Based on the results outlined above and also on
work already reported, we propose a radical
mechanism for this transformation (Scheme 5). In the
first step an imino radical is generated when Cu(I)
initiates a reductive N-O bond cleavage of the
ketoxime acetate A. Next, an intramolecular 5-exo-
trig radical cyclization of intermediate A gives rise to
intermediate B. Finally, single-electron oxidation of
intermediate
corresponding
B
by Cu(II) species forms the
product spiro[indoline-3,2’-
pyrrolidine] derivative and the Cu(I) catalyst is
regenerated. To understand the mechanism of the
reaction, we added radical scavengers to the reaction,
and found that when TEMPO (20 mol%) was added,
the reaction could still proceed but the product was
obtained in a much lower yield (20%).[15] However,
When substrate 3a (R = H) was employed in this
transformation, the unstable spiroindole was
obtained, then 1,2-migration would be taken place,
and many related processes via 1,2-migration have
[8b, 16]
been reported in the literatures,
affording
intermediate C, a double bond is formed by oxidizing
the intermedate C to produce the product 4a.
a) Reaction conditions: 3 (0.3 mmol), Cu(acac)2 (10 mol%),
K2CO3 (1.0 equiv.), toluene, 120 oC.
Scheme 3. Substrate scope for synthesis of aza-carbazole
derivatives. a
3
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10.1002/adsc.201700073
Advanced Synthesis & Catalysis
[2] For recent reviews, see: a) S. P. Roche, J. A. Porco, Jr.
Angew. Chem. 2011, 123, 4154-4179; Angew. Chem.,
Int. Ed. 2011, 50, 4068-4093. b) C.-X. Zhuo, W.
Zhang, S.-L. You, Angew. Chem. 2012, 124, 12834-
12858; Angew. Chem., Int. Ed. 2012, 51, 12662-
12686. c) C.-X. Zhuo, C. Zheng, S.-L. You, Acc.
Chem. Res. 2014, 47, 2558-2573. d) N. Denizot, T.
Tomakinian, R. Beaud, C. Kouklovsky, G. Vincent,
Tetrahedron Lett. 2015, 46, 4413-4429. e) M. J.
James, P. O’Brien, R. J. K. Taylor, W. P. Unsworth,
Chem. Eur. J. 2016, 22, 2856.
[3] For palladium catalysis, see: a) M. Bandini, A. Melloni,
F. Piccinelli, R. Sinisi, S. Tommasi, A. Umani-
Ronchi, J. Am. Chem. Soc. 2006, 128, 1424-1425. b)
T. D. Montgomery, A. E. Nibbs, Y. Zhu, V. H. Rawal,
Org. Lett. 2014, 16, 3480-3483. c) R.-D. Gao, C. Liu,
L.-X. Dai, W. Zhang, S.-L. You, Org. Lett. 2014, 16,
3919-3921. d) A. E. Nibbs, T. D. Montgomery, Y.
Zhu, V. H. Rawal, J. Org. Chem. 2015, 80, 4928-
4941. e) Z.-S. Liu, W.-K. Li, T.-R. Kang, L. He, Q.-Z.
Liu, Org. Lett. 2015, 17, 150-153.
[4] For iridium catalysis, see: a) Q.-F. Wu, H. He, W.-B.
Liu, S.-L. You, J. Am. Chem. Soc. 2010, 132, 11418-
11419. b) Q.-F. Wu, C. Zheng, S.-L. You, Angew.
Chem. 2012, 124, 1712-1715; Angew. Chem., Int. Ed.
2012, 51, 1680-1683. c) C.-X. Zhuo, Q.-F. Wu, Q.
Zhao, Q.-L. Xu, S.-L. You, J. Am. Chem. Soc. 2013,
135, 8169-8172. d) X. Zhang, L. Han, S.-L. You,
Chem. Sci. 2014, 5, 1059-1063. e) Q.-F. Wu, C.
Zheng, C.-X. Zhuo, S.-L. You, Chem. Sci. 2016, 7,
4453-4459.
[5] For gold catalysis, see: a) G. Cera, P. Crispino, M.
Monari, M. Bandini, Chem. Commun. 2011, 47,
7803-7805. b) G. Cera, M. Chiarucci, A. Mazzanti,
M. Mancinelli, M. Bandini, Org. Lett. 2012, 14,
1350-1353.
[6] X. Zhang, W.-B. Liu, Q.-F. Wu, S.-L. You, Org. Lett.
2013, 15, 3746-3749.
[7] a) K.-J. Wu, L.-X. Dai, S.-L. You, Org. Lett. 2012, 14,
3772-3775. b) X.-X. Wu, Y. Shen, W.-L. Chen, S.
Chen, P.-F. Xu, Y. -M. Liang, Chem. Commun. 2015,
51, 16798-16801.
[8] a) S. G. Modha, A. Kumar, D. D. Vachhani, J. Jacobs,
S. K. Sharma, V. S. Parmar, L. Van Meervelt, E. V.
Van der Eycken, Angew. Chem. 2012, 124, 9710-
9713; Angew. Chem., Int. Ed. 2012, 51, 9572-9575. b)
V. A. Peshkov, O. P. Pereshivko, E. V. Van der
Eycken, Adv. Synth. Catal. 2012, 354, 2841-2848. c)
M. J. James, J. D. Cuthbertson, P. O’Brien, R. J. K.
Taylor, W. P. Unsworth, Angew. Chem. 2015, 127,
7750-7753; Angew. Chem., Int. Ed. 2015, 54, 7640-
7643. d) F. Schrꢀder, U. K. Sharma, M. Mertens, F.
Devred, D. P. Debecker, R. Luque, E. V. Van der
Eycken, ACS Catal. 2016, 6, 8156-8161.
Scheme 5. Proposed mechanism.
In summary, we have developed a novel and highly
efficient
copper-catalyzed
intramolecular
dearomatization reaction of C3-substituted indoles,
which allows the construction of both spiro[indoline-
3,2’-pyrrolidine] and aza-carbazole derivatives by
varying the substituents at the C2 position of the
indole nucleus. Further work to expand the scope of
this novel spirocyclization strategy and to better
understand the reaction mechanism are currently
ongoing in our laboratory and results will be reported
in due course.
Experimental Section
To a solution of 1 or 3 (0.3 mmol) in dry toluene (3.0 mL)
was add K2CO3 (0.3 mmol) and Cu(acac)2 (0.03 mmol) into
Schlenk flask under argon, and then the reaction mixture
was stirred at 120 °C until complete consumption as
monitored by TLC. The solvents were removed under
reduced pressure, and flash chromatography was used to
give the desired product.
Acknowledgements
Financial support from National Natural Science Foundation of
China (grants 81373303, 81473080, 81573299 and 21502230) is
gratefully acknowledged. This project was also supported by the
Jiangsu Province Natural Science Foundation (BK20150688),
the “111 Project” from the Ministry of Education of China, the
State Administration of Foreign Expert Affairs of China (No. 111-
2-07) and program for Changjiang Scholars and Innovative
Research Team in University (IRT1193), Project Program of
State Key Laboratory of Natural Medicines, China
Pharmaceutical University (No. SKLNMZZYQ201607).
References
[1] a) R. T. Brown, Indoles, The Monoterpenoid Indole
Alkaloids. In The Chemistry of Heterocyclic
Compounds; J. E. Saxton, A. Weissberger, E. C.
Taylor, Eds.; Wiley: New York, 1983; Vol. 25, Part 4,
p 85. b) J. E. Saxton, In The Alkaloids, Chemistry and
Biology; G. A. Cordell, Ed.; Academic Press: San
Diego, 1998; Vol. 51, p 1. c) P. M. Dewick, In
[9] R. K. Nandi, R. Guillot, C. Kouklovsky, G. Vincent,
Org. Lett. 2016, 18, 1716-1719.
[10] X. Lei, H.-Y. Xie, C. Xu, X. Liu, X. Wen, H. Sun, Q.-
L. Xu, Adv. Synth. Catal. 2016, 358, 1892-1896.
[11] K. Tanaka, Y. Mori, K. Narasaka, Chem. Lett. 2004,
33, 26-27.
Medicinal Natural Products:
A
Biosynthetic
Approach, 2nd ed.; Wiley: Chichester, 2001; p 350. d)
S. E. O’Connor, E. McCoy, Recent Adv. Phytochem.
2006, 40, 1-22. e) S. E. O’Connor, In Comprehensive
Natural Products II; L. Mander, H.-W. Liu, Eds.;
Elsevier: Amsterdam, 2010; Vol. 1, p 977.
[12] Selected recent examples, see: a) Y. Lian, T. Huber, K.
D. Hesp, R. G. Bergman, J. A. Ellman, Angew. Chem.
4
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10.1002/adsc.201700073
Advanced Synthesis & Catalysis
2013, 125, 657-661; Angew. Chem., Int. Ed. 2013, 52,
629-633. b) Z. Shi, D. C. Koester, M. Boultadakis-
Arapinis, F. Glorius, J. Am. Chem. Soc. 2013, 135,
12204-12207. c) J. C. Walton, Acc. Chem. Res. 2014,
47, 1406-1416. d) C. Chen, L. Hou, M. Cheng, J. Su,
X. Tong, Angew. Chem. 2015, 127, 3135-3139;
Angew. Chem., Int. Ed. 2015, 54, 3092-3096. e) H.
Huang, J. Cai, X. Ji, F. Xiao, Y. Chen, G.-J. Deng,
Angew. Chem. 2016, 128, 315-319; Angew. Chem.,
Int. Ed. 2016, 55, 307-311.
[13] P.-F. Wang, C.-H. Jiang, X. Wen, Q.-L. Xu, H. Sun, J.
Org. Chem. 2015, 80, 1155-1162.
[14] Selected examples, see: a) F. Portela-Cubillo, J. S.
Scott, J. C. Walton, J. Org. Chem. 2008, 73, 5558-
5565. b) F. Portela-Cubillo, B. A. Surgenor, R. Alan
Aitken, J. C. Walton, J. Org. Chem. 2008, 73, 8124-
8127.
[15] Meanwhile, other radical scavengers were examined,
when BHT (20 mol%) and DIAD (20 mol%) were
used, the reaction only gave mixture products.
[16] Selected examples on 1,2-migration, see: a) K. G.
Liu, A. J. Robichaud, J. R. Lo, J. F. Mattes, Y. Cai,
Org. Lett. 2006, 8, 5769-5771. b) X. Zhang, S. Sarkar,
R. C. Larock, J. Org. Chem. 2006, 71, 236-243. c) C.
Zheng, Q.-F. Wu, S.-L. You, J. Org. Chem. 2013, 78,
4357-4365. d) S. J. Heffernan, J. P. Tellam, M. E.
Queru, A. C. Silvanus, D. Benito, M. F. Mahon, A. J.
Hennessy, B. I. Andrews, D. R. Carbery, Adv. Synth.
Catal. 2013, 355, 1149-1159. e) M. J. James, R. E.
Clubley, K. Y. Palate, T. J. Procter, A. C. Wyton, P.
O’Brien, R. J. K. Taylor, W. P. Unsworth, Org. Lett.
2015, 17, 4372-4375. f) J. T. R. Liddon, M. J. James,
A. K. Clarke, P. O'Brien, R. J. K. Taylor, W. P.
Unsworth, Chem. Eur. J. 2016, 22, 8777-8780. g) T.-
H. Yang, C.-W. Kuo, V. Kavala, A. Konala, C.-Y.
Huang, C.-F. Yao, Chem. Commun. 2017, DOI:
10.1039/C6CC09468F.
5
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10.1002/adsc.201700073
Advanced Synthesis & Catalysis
COMMUNICATION
Concise
Synthesis
of
Spiro[indoline-3,2’-
pyrrolidine] Derivatives via Copper-catalyzed
Dearomatization of Indoles
Adv. Synth. Catal. Year, Volume, Page – Page
Peng-Fei Wang,‡ Chao Chen,‡ Hui Chen, Li-Shuai Han,
Liu Liu, Hongbin Sun, Xiaoan Wen* and Qing-Long Xu
*
6
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