Rapid Syntheses of Heteroaryl-Substituted Imidazo[1,5-a]indole and Pyrrolo[1,2-c]imidazole via Aerobic C2-H Functionalizations

Article abstract of DOI:10.1021/acs.orglett.7b03596

Here we report an aerobic Pd(0) catalyzed C2-H functionalization of indoles and pyrroles with tethered N-methoxylamide as the directing group. A Pd(0)-initiated mechanism overcomes the directing or poisoning effect from a wide range of heterocycles including pyridine, pyrimidine, and thiazole. The imidazo[1,5-a]indole products are transformed to bioactive analogs after one-step manipulations, demonstrating the potential utility of this reaction in drug discovery.

Full text of DOI:10.1021/acs.orglett.7b03596

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rapid Syntheses of Heteroaryl-Substituted Imidazo[1,5‑a]indole and
Pyrrolo[1,2‑c]imidazole via Aerobic C2−H Functionalizations
Wei-Jun Kong,† Xingrong Chen,† Mingming Wang,† Hui-Xiong Dai,*,†,‡ and Jin-Quan Yu*,†,§
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, China
‡Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi,
Zhangjiang Hi-Tech Park, Shanghai, 201203, China
§Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: Here we report an aerobic Pd(0) catalyzed C2−H
functionalization of indoles and pyrroles with tethered N-
methoxylamide as the directing group. A Pd(0)-initiated
mechanism overcomes the directing or poisoning effect from a
wide range of heterocycles including pyridine, pyrimidine, and
thiazole. The imidazo[1,5-a]indole products are transformed to
bioactive analogs after one-step manipulations, demonstrating the
potential utility of this reaction in drug discovery.
midazo[1,5-a]indole and pyrrolo[1,2-c]imidazole derivatives
have been found to possess a wide range of biological
activities (Figure 1). A number of applications in medicinal
preparation of heteroarylated imidazo[1,5-a]indole and
pyrrolo[1,2-c]imidazoles.
I
Poor compatibility with heterocycles is a widespread problem
in Pd-catalyzed C−H functionalizations. First, heterocycles
could direct C−H activation at the undesired position; second,
heterocyles could sequester the Pd(II) catalyst via strong
coordination and render them inactive. Three major
approaches have been developed to overcome these undesired
heterocycle effects. Masking the coordinating atom by strong
acid or oxidizing the nitrogen to N-oxides has been employed
for allylic C(sp3)−H of acetoxylation.8 Alternatively, the use of
strongly coordinating bidentate directing groups can also
circumvent this problem to some extent. Especially, the
combination of a bidentate oxazoline-based directing group
and copper catalysts has demonstrated exceptional compati-
bility.9 The third approach involves design of directing groups
that can coordinate with a metal catalyst and also participate in
a subsequent bond forming event thereby outcompeting other
heterocycles.10
We have previously developed a catalytic system in which
Pd(0) is oxidized and sequestered by a N-methoxyl amide
directing group using air as the sole oxidant.10a Pd(II)
coordinated with the amide directing group is rapidly trapped
by isocyanide thereby overcoming interference from a wide
range of heterocycles (Scheme 1a). We wonder whether
analogous transformation can be developed for C2−H
functionalization of indole if the N-methoxylamide group is
Figure 1. Representative bioactive compounds of imidazo[1,5-
a]indole and pyrrolo[1,2-c]imidazole derivatives.
chemistry have been found by minor structural variations. For
example, structure a could be used as light-dependent tumor
necrosis factor-α (TNF-α) antagonists and antifungals.1
Compounds containing structure b can serve as central nervous
system (CNS) depressants, analgesics, and receptor antago-
nists.2 Compounds c are aldose reductase inhibitors (ARI) and
provide therapeutic possibility in the treatment of chronic
complications in diabetes.3 Directed C2−H functionalizations
of indole or pyrrole have been successfully exploited to
synthesize these polycyclic heterocycles.4,5 Recently, Cui and
others reported Rh(III)-catalyzed C2−H arylation using the
CONHOMe directing group5 previously developed in our
laboratory.6 However, substrates containing herteroaryls are not
described, presumably due to incompatibility. Considering the
importance of heterocycles in drug discovery,7 it is crucial to
develop catalytic systems that can functionalize heteroarylated
indoles and pyrroles to provide synthetic routes for the
Received: November 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03596
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
heteroaryl-substituted indoles and pyrroles (Scheme 2). N-
methoxyl aminocarbonyl (MeONHCO−) protected 3-methyl-
Scheme 1. Overcoming the Limitation of Heterocycle in
Pd(0) Catalyzed C−H Functionalizations
a
Scheme 2. Scope of Indoles and Pyrroles
tethered to indole via the urea linkage. If successful, a rapid
synthetic route can be established for the imidzao[1,5-a]indole
derivative (Scheme 1b). The anticipated compatibility of this
reaction with heteroatoms might provide access to diverse
imidzao[1,5-a]indole decorated with various heterocycles.
Herein, we report an aerobic C2−H functionalization of
indoles and pyrroles containing a wide range of heterocycles,
which provides a new avenue to construct medicinally
important imidazo[1,5-a]indole and pyrrolo[1,2-c]imidazole
molecules.
We commenced the study with N-methoxy-1H-indole-1-
carboxamide 1a as the model substrate to explore the reaction
conditions. The proposed reaction could take place at 50 °C,
affording the desired product 2a in 60% yield, and the C3−H is
intact.11 However, 10% of byproduct 2a′ was also observed
(entries 2−4, Table 1). In order to improve the selectivity of 2a
ab
,
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 0.2 mmol 1a−1l, t-BuNC (2 equiv), Pd2(dba)3
b
(5 mol %), 35 mL sealed vial, 60 °C, 10 h; isolated yields. 1.0 mmol
scale. With 1-adamantyl isocyanide (2 equiv).
c
entry
temp (°C)
V (mL)
M (mol/L)
2a
2a′
1
2
3
4
5
6
7
8
rt
1
0.1
trace
60%
66%
64%
49%
66%
66%
69%
trace
10%
10%
10%
12%
5%
indole 1b, 3-phenylindole 1c, and phthalimide protected L-
phenylalanine methyl ester 1d gave the corresponding products
in moderate yields after a prolonged reaction time, which may
be due to steric hindrance (2b−2d). Meanwhile, a moderate
yield was obtained when the reaction was scaled up to 1.0
mmol (2a, conditions b). 1-Adamantyl isocyanide was also
applicable in this reaction, affording 2a1 in 62% yield. Various
electron-donating and -withdrawing substituents including
methyl (2m, 2q), methoxyl (2g, 2n, and 2r), fluoro (2i),
chloro (2e, 2j (confirmed by X-ray), and 2p), cyano (2l), and
ester (2g, 2h) at the 4-, 5-, 6-, and 7- position on indole were
tolerated in this reaction, affording the desired products in
moderate to good yields and excellent regiosectivity at the C2
position (65%−80% yields). A relatively reactive bromo group
was also well tolerated in this Pd(0) catalyzed reaction (2k and
2o), which can serve as a handle for further synthetic
elaborations. Pyrrole was applicable in this reaction as well,
furnishing product 2s in 66% yield. When the C3 position of
pyrrole was substituted with a methoxycarbonyl group
COOMe, C−H activation takes place at the less hindered C5
position exclusively in a yield of 66% (2t). It is worth noting
that 4- and 6-azaindoles 1u and 1v gave the corresponding
products 2u and 2v in 61% and 42% yields respectively,
demonstrating the compatibility of heterocycles.
50
60
70
60
60
60
60
60
1
0.1
1
0.1
1
0.1
0.5
2
0.2
0.05
0.033
0.02
0.04
3
4%
5
4%
c
d
9
5
70%
−
a
Reaction conditions: 0.1 mmol of 1a, t-BuNC (2 equiv), Pd2(dba)3
(5 mol %), 15 mL sealed vial, 10 h. Yield determined by H NMR
analysis of crude reaction mixture using CH2Br2 as an internal
standard. With 0.2 mmol of 1a, 35 mL sealed vial. Isolated yield.
b
1
c
d
to 2a′, reaction conditions were screened and it was found that
concentration played an important role in the formation of 2a′.
A lower concentration led to lower yields of 2a′ and a slight
improvement in the production of 2a (entries 5−8, Table 1).
When the concentration was less than 0.05 M, the yield of 2a′
could be reduced to lower than 5%. For the reason for
practicability, we chose 0.04 M as the optimal concentration for
further study (entry 9, Table 1).
With the reaction conditions established, it is crucial to
examine the scope of indoles, especially the compatibility with
B
DOI: 10.1021/acs.orglett.7b03596
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
After exploring the generality with common indoles and
pyrroles, we then extensively investigated the compatibility of
heterocycles in this reaction (Scheme 3). In particular, we
Scheme 4. Proposed Mechanism for the Formation of 2a
Scheme 3. Overcome the Limitation of Heterocycles in C−H
a
Functionalization of Indoles and Pyrroles
To demonstrate the utility of the imidazo[1,5-a]indole
products, a number of transformations were carried out. 2a was
converted to the aforementioned bioactive molecule analogs
through simple manipulations (Scheme 5). The N-methoxyl
Scheme 5. Transformations of Product 2a
a
Reaction conditions: 0.2 mmol of 3a−3l, t-BuNC (2 equiv),
Pd2(dba)3 (5 mol %), 35 mL sealed vial, 60 °C, 10 h; isolated yields.
examined the presence of heterocycles that can potentially
direct C−H activation at other sites leading to scrambling of
regioselectivity. When pyridine was installed at the C4 or C5
position of indoles, no detrimental effects were observed in this
reaction. Importantly, no ortho-C−H activation directed by
pyridine was observed with 3a−3c. Pyrimidine, pyrazine, and
quinoline tethered at the C5 position of indole were well
tolerated, giving corresponding products in moderate to
excellent yields (4d−4f). Substrates bearing five-membered
nitrogen containing heterocycles including pyrazole, oxazoline,
and thiazole at the C5 position were well tolerated (3g−3i).
The C−H bonds of electron-rich furan and thiophene can
potentially be activated by Pd(II) in a nondirected fashion to
give undesired side products.12 Under our standard conditions,
the reaction produced the desired products 4j and 4k efficiently
without side reactions occurring on the furan and thiophene
rings. When the C3 position of pyrrole is substituted with a
pyridyl group, C5−H was functionalized exclusively due to
steric hindrance in 60% yield (4l). This result also suggests that
the directing effect of pyridyl group is completely outcompeted.
Based on our previous mechanistic study on this catalytic
system,10a we propose a plausible mechanism for this reaction
(Scheme 4). In the presence of air and 1a, Pd(0) is oxidized to
Pd(II) A, followed by 1,1-insertion of t-BuNC into the Pd−N
bond to afford B. Acyl migration of B gives intermediate C, in
which the C2−H is activated to give the six membered
cyclopalladium(II) complex D. Reductive elimination of D
furnishes the target product 2a and releases active Pd(0).
imido group of 2a was reduced to afford analogous CNS
depressant 5a under hydrogen with Pd/C as catalyst. When
treated with sulfuric acid in methanol, the N-methoxyl imido
group could be hydrolyzed to give dicarboximide 5b in 66%
yield. Switching the solvent to tetrahydrofuran led to the
removal of the tert-butyl group, affording 1H-imidazo[1,5-
a]indole-1,3(2H)-dione 5b′. Interestingly, reflux in trifluoro-
acetic acid can deprotect the tert-butyl group of 2a selectively to
give 5c in 97% yield. Finally, treatment of 2a with sodium
hydroxide in mixed solvents of water and n-propanol furnished
5d in nearly quantitative yield.
In summary, we have reported palladium(0) catalyzed
isocyanide insertive C2−H functionalization of N-methoxylcar-
bonyl protected indoles and pyrroles to afford imidazo[1,5-
a]indole and pyrrolo[1,2-c]imidazole derivatives. This reaction
is compatible with various functional groups. The amide
directing group overrides the directing or poisoning effect of
diverse strongly coordinating heterocycles. The resulting
imidazo[1,5-a]indoles could be transformed to bioactive
analogs via simple synthetic manipulations.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03596.
C
DOI: 10.1021/acs.orglett.7b03596
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and spectra data for all new
Letter
(9) Shang, M.; Wang, M.-M.; Saint-Denis, T. G.; Li, M.-H.; Dai, H.-
X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 5317−5321.
(10) (a) Liu, Y.-J.; Xu, H.; Kong, W.-J.; Shang, M.; Dai, H.-X.; Yu, J.-
Q. Nature 2014, 515, 389−393. (b) Kong, W.-J.; Liu, Y.-J.; Xu, H.;
Chen, Y.-Q.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 2146−
2149. (c) Wang, H.; Lorion, M. M.; Ackermann, L. Angew. Chem., Int.
Ed. 2016, 55, 10386−10390.
compounds (PDF)
Accession Codes
CCDC 1573949 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(11) (a) Hu, Z.; Liang, D.; Zhao, J.; Huang, J.; Zhu, Q. Chem.
Commun. 2012, 48, 7371−7373. (b) Xu, S.; Huang, X.; Hong, X.; Xu,
B. Org. Lett. 2012, 14, 4614−4617.
(12) Yang, Y.; Lan, J.; You, J. Chem. Rev. 2017, 117, 8787−8863.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hxdai@simm.ac.cn (H.-X.D.).
*E-mail: yu200@scripps.edu (J.-Q.Y.)
ORCID
Hui-Xiong Dai: 0000-0002-2937-6146
Jin-Quan Yu: 0000-0003-3560-5774
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, the CAS/SAFEA
International Partnership Program for Creative Research
Teams, NSFC-21121062, NSFC-21472211, NSFC-21421091,
Youth Innovation Promotion Association CAS (No. 2014229),
and The Recruitment Program of Global Experts for financial
support. We gratefully acknowledge The Scripps Research
Institute and the NIH (NIGMS, 1R01 GM102265) for their
financial support.
REFERENCES
■
(1) (a) Voss, M. E.; Carter, P. H.; Tebben, A. J.; Scherle, P. A.;
Brown, G. D.; Thompson, L. A.; Xu, M.; Lo, Y. C.; Yang, G.; Liu, R.-Q.
Bioorg. Med. Chem. Lett. 2003, 13, 533−538. (b) Kutschy, P.; Suchy,
́
M.; Dzurilla, M.; Takasugi, M.; Kovac
Commun. 2000, 65, 1163−1172.
́ ̌
ik, V. Collect. Czech. Chem.
(2) (a) Wright, W. B. US Patent, 3565902; Chem. Abstr. 1971, 75,
36033. (b) Varasi, M.; Heidempergher, F.; Caccia, C.; Salvati, P. PCT
Int. Appl., WO 9532209; Chem. Abstr. 1995, 124, 232456.
(3) (a) Ogawa, K.; Yamawaki, I.; Matsushita, Y. Jpn. Kokai. Patent JP,
04297478; Chem. Abstr. 1992, 118, 234056. (b) Yamawaki, I.;
Matsushita, Y.; Asaka, N.; Ohmori, K.; Nomura, N.; Ogawa, K. Eur.
J. Med. Chem. 1993, 28, 481−498.
(4) Katritzky, A. R.; Singh, S. K.; Bobrov, S. J. Org. Chem. 2004, 69,
9313−9315.
(5) (a) Zheng, J.; Zhang, Y.; Cui, S. Org. Lett. 2014, 16, 3560−3563.
(b) Wu, Z. J.; Li, Y. Q.; Huang, Z. Z. Eur. J. Org. Chem. 2016, 2016,
5399−5404. (c) Zhang, Y.; Zheng, J.; Cui, S. J. Org. Chem. 2014, 79,
6490−6500.
(6) (a) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc.
2008, 130, 7190−7191. (b) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2016, 55, 10578−10599; Angew. Chem.
2016, 128, 10734−10756.
(7) (a) Dalvie, D.; Kang, P.; Loi, C.-M.; Goulet, L.; Nair, S.
Metabolism, Pharmacokinetics and Toxicity of Functional Groups; Royal
Society of Chemistry: Cambridge, U.K., 2010; p 328. (b) Gibson, S.;
McGuire, R.; Rees, D. C. J. Med. Chem. 1996, 39, 4065−4072.
(c) Broughton, H. B.; Watson, I. A. J. Mol. Graphics Modell. 2004, 23,
51−58.
(8) Malik, H. A.; Taylor, B. L.; Kerrigan, J. R.; Grob, J. E.; Houk, K.;
Du Bois, J.; Hamann, L. G.; Patterson, A. W. Chem. Sci. 2014, 5,
2352−2361.
D
DOI: 10.1021/acs.orglett.7b03596
Org. Lett. XXXX, XXX, XXX−XXX