Rh(III)-Catalyzed Cascade Annulation/C-H Activation of o-Ethynylanilines with Diazo Compounds: One-Pot Synthesis of Benzo[a]carbazoles via 1,4-Rhodium Migration

Article abstract of DOI:10.1021/acs.orglett.6b02534

A Rh(III)-catalyzed cascade annulation/C-H activation of o-ethynylanilines with diazo compounds has been developed. This concise method allows for the rapid formation of a number of benzo[a]carbazoles in high yields, exhibiting good functional group toler

Full text of DOI:10.1021/acs.orglett.6b02534

Letter
pubs.acs.org/OrgLett
Rh(III)-Catalyzed Cascade Annulation/C−H Activation of
o‑Ethynylanilines with Diazo Compounds: One-Pot Synthesis of
Benzo[a]carbazoles via 1,4-Rhodium Migration
Songjin Guo, Kai Yuan, Meng Gu, Aijun Lin,* and Hequan Yao*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing, 210009, P. R. China
S
* Supporting Information
ABSTRACT: A Rh(III)-catalyzed cascade annulation/C−H
activation of o-ethynylanilines with diazo compounds has been
developed. This concise method allows for the rapid formation
of a number of benzo[a]carbazoles in high yields, exhibiting
good functional group tolerance and scalability. The key to the
success of this approach involves one C−N bond and two C−
C bond formation, and an aryl-to-aryl 1,4-rhodium migration.
enzo[a]carbazoles are privileged motifs found in natural
Scheme 1. Synthetic Approaches to Benzo[a]carbazoles
B
alkaloids and pharmaceutical molecules with anticancer
and antiangiogenic activities,1 as well as in organic photovoltaic
cells (OPVs), organic light-emitting diodes (OLEDs), and dye
sensitized solar cells (DSSCs) due to their unique electronic
and pronounced thermal stability properties (Figure 1).2
Figure 1. Alkaloids and photographic materials containing benzo[a]-
carbazoles.
Compared to previous work that mostly focused on the
construction of the single A ring or B ring to achieve
benzo[a]carbazoles, the simultaneous synthesis of A and B
rings has received increasing interest, because it not only brings
greatly improved synthetic efficiency but also enhances
aesthetic appeal for synthetic planning. Recently, Ohno11 and
Wu12 disclosed gold-, palladium-catalyzed or iodine-mediated
intramolecular cyclization of enediynes for the synthesis of
benzo[a]carbazoles (Scheme 1b). Liang13 and Gong14
developed a palladium- and gold-catalyzed intermolecular
tandem cyclization of two alkynes to synthesize benzo[a]-
Generally, the benzo[a]carbazoles could be synthesized relying
on the construction of ring A through photochemical
cyclization,3 palladium-, indium-, or copper-catalyzed cyclo-
aromatization,4 intramolecular Friedel−Crafts arylation,5
Diels−Alder reaction,6 and sequential propargylation/cyclo-
isomerization7 of preexisting indoles (Scheme 1a, left). On the
other hand, the method to the synthesis of benzo[a]carbazoles
also focused on the synthesis of ring B from amines or
arylhydrazine hydrochlorides via iridium-, palladium-, or
copper-catalyzed arylation/annulation,8 copper-promoted cy-
cloaddition,9 and oxidative cyclo-dehydrogenation (Scheme 1a,
right).10
Received: August 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02534
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Organic Letters
Letter
a b
,
carbazoles (Scheme 1b). From the step economy as well as the
functional group diversity point of view, the development of a
new method to construct benzo[a]carbazoles utilizing easily
prepared materials remains fascinating and challenging. Based
on our continuous interest in the synthesis of nitrogen
containing heterocycles,15 herein, we will report a rhodium-
catalyzed cascade annulation of o-ethynylanilines with diazo
compounds to construct benzo[a]carbazoles. In this reaction,
one C−N bond and two C−C bond formation was achieved
with a one-pot procedure, and an aryl-to-aryl 1,4-rhodium
migration was also involved (Scheme 1c).
Scheme 2. Substrate Scope
Initially, we began our investigation with 4-methyl-N-(2-
(phenylethynyl)phenyl)benzenesulfonamide 1a and ethyl 2-
diazo-3-oxobutanoate 2a as model substrates (Table 1). A
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
additive
solvent
yield (%)
59
1
2
3
4
5
6
7
8
9
10
[Cp*RhCl2]2
[RhCl(COD)]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
−
−
−
−
−
DMF
c
DMF
nd
THF
<5
70
33
61
70
81
66
45
91
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
CuCl2
CuO
CuBr
Cu(OAc)2
NaOAc
KOAc
Cu(OAc)2
Cu(OAc)2
−
d
11
d
c
12
nd
d
13
[Cp*RhCl2]2
75
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (5
mol %), additives (30 mol %), solvent (1.0 mL), at room temperature
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (5
mol %), Cu(OAc)2 (30 mol %), DMAC (1.0 mL), at 50 °C under Ar
b
c
under Ar atmosphere for 12 h, sealed tube. Isolated yields. nd = not
determined. The reaction was conducted at 50 °C.
b
c
for 12 h, sealed tube. Isolated yields. 3.0 mmol scale.
d
preliminary attempt with 5.0 mol % of [Cp*RhCl2]2 in 1.0 mL
DMF at room temperature led to the benzo[a]carbazole 3aa in
59% yield, and the structure was unambiguously identified by
single crystal X-ray analysis (entry 1). Replacing [Cp*RhCl2]2
with [RhCl(COD)]2 resulted in no product (entry 2). A brief
examination of solvents revealed that dipolar aprotic solvent
DMAC was an ideal choice, which afforded 3aa in 70% yield
(entry 4). The yield of 3aa increased to 81% in the presence of
Cu(OAc)2 when several copper salts were tested (entries 5−8).
Considering the anion may play an important role in the
reaction efficiency, several acetates were then tested and lower
yields were obtained compared with Cu(OAc)2 (entries 9−10).
By increasing the temperature to 50 °C, the yield could be
further increased to 91% (entry 11). Control experiments
indicated that [Cp*RhCl2]2 was indispensable to this reaction
(entries 12−13).
aniline ring afforded 3ba, 3da, and 3ea in 91%, 81%, and 71%
yields. The halogen and electron-withdrawing groups delivered
3ca, 3fa−ia in 46−79% yields. The phenyl ring bearing
electron-donating and -withdrawing groups at the meta- and
para-positions performed smoothly and afforded 3ka and 3la−
qa in moderate to good yields. Notably, to increase product
diversity, a heteroaryl-substituted substrate was also attempted.
4-Methyl-N-(2-(thiophen-2-ylethynyl)phenyl)-benzene-
sulfonamide 1r gave 3ra in 20% yield. When the ester group of
2a was altered from ethyl to methyl, tert-butyl, isopropyl, and
benzyl groups, 3ab−ae were obtained in 82−92% yields. By
changing the R3 group to n-propyl, cyclopropyl, and cyclohexyl
groups, 3af, 3ag, and 3ah were prepared in 84%, 87%, and 50%
yield, respectively. Ethyl 2-diazo-3-oxo-3-phenylpropanoate 2i
offered 3ai in 70% yield. When 3-diazopentane-2,4-dione 2j
was tested, the desired product 3aj was generated in 59% yield.
Unfortunately, no corresponding product could be obtained
when 2-diazo-1-morpholinobutane-1,3-dione 2k was used. To
improve the practicability of this reaction, a gram-scale reaction
was conducted and 3aa was isolated in 94% yield (1.29 g).
With the optimized conditions in hand, we then investigated
the substrate scope of the o-ethynylanilines and diazo
compounds to test the generality of this cascade cyclization,
and the results are summarized in Scheme 2. The presence of
methyl and methoxyl groups at C4- or C5-positions of the
B
DOI: 10.1021/acs.orglett.6b02534
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Organic Letters
Letter
With the aim to further evaluate the practicability of this
reaction, late-stage modification of 3aa was conducted and is
shown in Scheme 3. The sulfamide and ester group in 3aa
Rh(III) active species. In order to further illustrate the 1,4-
rhodium migration process, a deuterated labeling experiment
with [D]5-1a was conducted under the standard conditions
(Scheme 4c). The observed incorporation of hydrogen at the
C2 of indole 8 indicated the occurrence of 1,4-rhodium
migration (see Supporting Information (SI) for details).
Additionally, we examined the reaction of 1a in a 5:1 mixture
of DMAC/D2O solvent (Scheme 4d). The presence of D2O
provided deuterated [D]n-8 in 57% yield (see SI for details).
This result suggested that the aryl-to-aryl 1,4-Rh(III) migration
occurred in a concerted metalation−deprotonation/reprotona-
tion sequence (II to IV in Scheme 5).16
Scheme 3. Derivatization of Benzo[a]carbazole 3aa
Scheme 5. Proposed Reaction Mechanism
could be hydrolyzed, and the corresponding products 4 and 5
were obtained in 96% and 86% yields. After the hydrogenation
of 3aa, compound 6 with a hydroxyl group was obtained in 93%
yield. Besides, 6 could react with DPPA to provide the
benzo[a]carbazole 7 in 98% yield.
To gain some mechanistic insight into this transformation,
control experiments and deuterated labeling experiments were
carried out. 3aa could be obtained in 75% yield when
[Cp*RhCl2]2 was used as the sole catalyst, while only single
cyclic product 2-phenyl-1-tosyl-1H-indole 8 could be detected
with Cu(OAc)2 as the sole catalyst (Scheme 4a). Considering
Scheme 4. Mechanistic Experiments
Based on the above results and literature precedents,16−20
a
plausible reaction pathway of this Rh(III)-catalyzed cascade
annulation/C−H activation of o-ethynylanilines with diazo
compounds was proposed and is shown in Scheme 5.
Coordination of an alkyne to active Rh(III) species affords
intermediate I,18 which could increase the electrophilicity of the
triple bond. The nucleophilic attack of the nitrogen on the
triple bond generates the benzoheterocyclic Rh(III) species
II.19 An acetate promoted, concerted metalation−deprotona-
tion of II gives rhodacycle III, which could undergo acetolysis
to give IV.16 Subsequently, diazo compound 2a reacts with
intermediate IV to generate Rh-carbene intermediate V with
the release of N2 and Rh-carbene migratory insertion produces
intermediate VI.20 Upon protonation, intermediate VII could
be achieved along with the regeneration of the active
rhodium(III) species. Finally, intramolecular dehydration
condensation of VII yields the product 3aa.
In conclusion, we have developed a novel intermolecular
cascade annulation/C−H activation of o-ethynylanilines with
diazo compounds driven by the rhodium catalyst. The
benzo[a]carbazoles were obtained in high yields, exhibiting
good functional group tolerance and scalability. The reaction
proceeds through a catalytic cycle involving intramolecular
nucleophilic addition of o-ethynylanilines, aryl-to-aryl 1,4-
that indole 8 was the possible intermediate for this reaction, we
then examined the reaction between 8 and ethyl 2-diazo-3-
oxobutanoate 2a under the standard conditions (Scheme 4b);
no desired product 3aa was observed. These results suggested
that indole 8 as an intermediate was not involved in this
transformation. Moreover, the reaction was exclusively
catalyzed by Rh(III) active species and Cu(OAc)2 did not
take part in the catalytic cycle, but just helped to generate
C
DOI: 10.1021/acs.orglett.6b02534
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Wen, S. Adv. Synth. Catal. 2013, 355, 2172. (c) Kale, A. P.; Kumar, G.
S.; Mangadan, A. R. K.; Kapur, M. Org. Lett. 2015, 17, 1324.
(d) Suzuki, C.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2015, 17,
1597.
rhodium migration. In this strategy, one C−N bond and two
C−C bond formation was achieved with a one-pot procedure.
ASSOCIATED CONTENT
* Supporting Information
■
(9) Wang, J.; Li, J.; Zhu, Q. Org. Lett. 2015, 17, 5336.
S
(10) (a) Xiao, F.; Liao, Y.; Wu, M.; Deng, G.-J. Green Chem. 2012,
14, 3277. (b) Truax, N. J.; Mejia, F. B.; Kwansare, D. O.; Lafferty, M.
M.; Kean, M. H.; Pelkey, E. T. J. Org. Chem. 2016, 81, 6808.
(11) (a) Hirano, K.; Inaba, Y.; Watanabe, T.; Oishi, S.; Fujii, N.;
Ohno, H. Adv. Synth. Catal. 2010, 352, 368. (b) Hirano, K.; Inaba, Y.;
Takahashi, N.; Shimano, M.; Oishi, S.; Fujii, N.; Ohno, H. J. Org.
Chem. 2011, 76, 1212. (c) Hirano, K.; Inaba, Y.; Takasu, K.; Oishi, S.;
Takemoto, Y.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 9068.
(12) (a) Chen, C.-C.; Chin, L.-Y.; Yang, S.-C.; Wu, M.-J. Org. Lett.
2010, 12, 5652. (b) Chen, C.-C.; Yang, S.-C.; Wu, M.-J. J. Org. Chem.
2011, 76, 10269.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02534.
1H and 13C NMR spectra for all new compounds (PDF)
X-ray crystallographic data for 3aa (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
(13) Xia, X.-F.; Wang, N.; Zhang, L.-L.; Song, X.-R.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2012, 77, 9163.
(14) Li, N.; Lian, X.-L.; Li, Y.-H.; Wang, T.-Y.; Han, Z.-Y.; Zhang, L.;
*E-mail: ajlin@cpu.edu.cn.
*E-mail: hyao@cpu.edu.cn; cpuhyao@126.com.
Notes
Gong, L.-Z. Org. Lett. 2016, 18, 4178.
The authors declare no competing financial interest.
(15) (a) Zhao, L.; Li, Z.; Chang, L.; Xu, J.; Yao, H.; Wu, X. Org. Lett.
2012, 14, 2066. (b) Su, Y.; Zhou, H.; Chen, J.; Xu, J.; Wu, X.; Lin, A.;
Yao, H. Org. Lett. 2014, 16, 4884. (c) Jiang, H.; Gao, S.; Xu, J.; Wu, X.;
Lin, A.; Yao, H. Adv. Synth. Catal. 2016, 358, 188. (d) Sun, P.; Wu, Y.;
Yang, T.; Wu, X.; Xu, J.; Lin, A.; Yao, H. Adv. Synth. Catal. 2015, 357,
2469. (e) Li, X.; Gai, K.; Yuan, Z.; Wu, J.; Lin, A.; Yao, H. Adv. Synth.
Catal. 2015, 357, 3479. (f) Wu, Y.; Sun, P.; Zhang, K.; Yang, T.; Yao,
H.; Lin, A. J. Org. Chem. 2016, 81, 2166. (g) Sun, P.; Wu, Y.; Huang,
Y.; Wu, X.; Xu, J.; Yao, H.; Lin, A. Org. Chem. Front. 2016, 3, 91.
(16) For selected examples of 1,4-rhodium migration reactions, see:
(a) Ma, S.; Gu, Z. Angew. Chem., Int. Ed. 2005, 44, 7512. (b) Seiser, T.;
Roth, O. A.; Cramer, N. Angew. Chem., Int. Ed. 2009, 48, 6320.
(c) Souillart, L.; Cramer, N. Chem. Sci. 2014, 5, 837. (d) Burns, D. J.;
Lam, H. W. Angew. Chem., Int. Ed. 2014, 53, 9931. (e) Burns, D. J.;
Best, D.; Wieczysty, M. D.; Lam, H. W. Angew. Chem., Int. Ed. 2015,
54, 9958. (f) Korkis, S. E.; Burns, D. J.; Lam, H. W. J. Am. Chem. Soc.
2016, 138, 12252.
(17) For selected examples, see: (a) Yamabe, H.; Mizuno, A.;
Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2005, 127, 3248.
́
(b) Partridge, B. M.; Gonzalez, J. S.; Lam, H. W. Angew. Chem., Int. Ed.
2014, 53, 6523. (c) Wang, M.; Zhang, X.; Zhuang, Y.-X.; Xu, Y.-H.;
Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 1341. (d) Hu, T.-J.; Zhang, G.;
Chen, Y.-H.; Feng, C.-G.; Lin, G.-Q. J. Am. Chem. Soc. 2016, 138,
2897.
ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC21272276 and NSFC21502232),
the Natural Science Foundation of Jiangsu Province
(BK20140655), the Foundation of State Key Laboratory of
Natural Medicines (ZZYQ201605), and the Innovative
Research Team in University (IRT_15R63) is gratefully
acknowledged.
REFERENCES
■
(1) For selected examples, see: (a) Knolker, H. J.; Reddy, K. R. Chem.
Rev. 2002, 102, 4303. (b) Peifer, C.; Stoiber, T.; Unger, E.; Totzke, F.;
̈
Schachtele, C.; Marme,
Dannhardt, G. J. Med. Chem. 2006, 49, 1271. (c) Routier, S.; Merour,
́
D.; Brenk, R.; Klebe, G.; Schollmeyer, D.;
̈
́
J.-Y.; Dias, N.; Lansiaux, A.; Bailly, C.; Lozach, O.; Meijer, L. J. Med.
Chem. 2006, 49, 789. (d) Wang, Y.-Q.; Li, X.-H.; He, Q.; Chen, Y.;
Xie, Y.-Y.; Ding, J.; Miao, Z.-H.; Yang, C.-H. Eur. J. Med. Chem. 2011,
46, 5878. (e) Schmidt, A. W.; Reddy, K. R.; Knolker, H.-J. Chem. Rev.
̈
2012, 112, 3193.
(2) For selected examples, see: (a) Qian, X.; Zhu, Y.-Z.; Chang, W.-
Y.; Song, J.; Pan, B.; Lu, L.; Gao, H.-H.; Zheng, J.-Y. ACS Appl. Mater.
Interfaces 2015, 7, 9015. (b) Paramasivam, M.; Chitumalla, R. K.;
Singh, S. P.; Islam, A.; Han, L.; Rao, V. J.; Bhanuprakash, K. J. Phys.
Chem. C 2015, 119, 17053. (c) Ivaniuk, K.; Cherpak, V.; Stakhira, P.;
Hotra, Z.; Minaev, B.; Baryshnikov, G.; Stromylo, E.; Volyniuk, D.;
Grazulevicius, J. V.; Lazauskas, A.; Tamulevicius, S.; Witulski, B.; Light,
M. E.; Gawrys, P.; Whitby, R. J.; Wiosna-Salyga, G.; Luszczynska, B. J.
Phys. Chem. C 2016, 120, 6206.
(18) For selected examples, see: (a) Seoane, A.; Casanova, N.;
Quinones, N.; Mascarenas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014,
̃
̃
136, 834. (b) Zheng, J.; Zhang, Y.; Cui, S. Org. Lett. 2014, 16, 3560.
(c) Park, J.; Mishra, N. K.; Sharma, S.; Han, S.; Shin, Y.; Jeong, T.; Oh,
J. S.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. J. Org. Chem. 2015, 80, 1818.
(19) For selected examples, see: (a) Mizukami, A.; Ise, Y.; Kimachi,
T.; Inamoto, K. Org. Lett. 2016, 18, 748. (b) Hu, Z.; Tong, X.; Liu, G.
Org. Lett. 2016, 18, 2058.
(3) (a) Protti, S.; Palmieri, A.; Petrini, M.; Fagnoni, M.; Ballini, R.;
Albini, A. Adv. Synth. Catal. 2013, 355, 643. (b) Li, Y.; Pang, Z.;
Zhang, T.; Yang, J.; Yu, W. Tetrahedron 2015, 71, 3351.
(4) (a) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Nagase, Y.;
Miyamura, T.; Shirakawa, E. J. Am. Chem. Soc. 2008, 130, 15823.
(b) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
7895. (c) Xie, R.; Ling, Y.; Fu, H. Chem. Commun. 2012, 48, 12210.
(d) Bhunia, S. K.; Polley, A.; Natarajan, R.; Jana, R. Chem. - Eur. J.
2015, 21, 16786.
(20) For selected examples of carbene migratory insertion, see:
(a) Shi, Z.; Koester, D. C.; Boultadakis-Arapinis, M.; Glorius, F. J. Am.
Chem. Soc. 2013, 135, 12204. (b) Xia, Y.; Liu, Z.; Liu, Z.; Ge, R.; Ye,
F.; Hossain, M.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2014, 136, 3013.
(c) Yu, S.; Liu, S.; Lan, Y.; Wan, B.; Li, X. J. Am. Chem. Soc. 2015, 137,
1623. (d) Zhao, D.; Kim, J. H.; Stegemann, L.; Strassert, C. A.;
Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 4508. (e) Chen, X.; Hu, X.;
Bai, S.; Deng, Y.; Jiang, H.; Zeng, W. Org. Lett. 2016, 18, 192.
(5) Zhou, J.; Yang, W.; Wang, B.; Ren, H. Angew. Chem., Int. Ed.
2012, 51, 12293.
(6) (a) Tao, Y.; Zhang, F.; Tang, C.-Y.; Wu, X.-Y.; Sha, F. Asian J.
Org. Chem. 2014, 3, 1292. (b) Sha, F.; Tao, Y.; Tang, C.-Y.; Zhang, F.;
Wu, X.-Y. J. Org. Chem. 2015, 80, 8122.
(7) Reddy, C. R.; Valleti, R. R.; Dilipkumar, U. Chem. - Eur. J. 2016,
22, 2501.
(8) (a) Ca,
́
N. D.; Sassi, G.; Catellania, M. Adv. Synth. Catal. 2008,
350, 2179. (b) Zhu, D.; Liu, Q.; Luo, B.; Chen, M.; Pi, R.; Huang, P.;
D
DOI: 10.1021/acs.orglett.6b02534
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