Rhodium(III)-catalyzed direct selective C(5)-H oxidative annulations of 2-substituted imidazoles and alkynes by double C-H activation

Article abstract of DOI:10.1021/ol400537b

Double C-H activations of C(5)-H and Csp²-H of 2-substituted N-vinyl- or arylimidazoles were realized without heteroatom-directing assistance by rhodium(III) catalyst. A subsequent oxidative annulation reaction with alkynes efficiently produced aza-fused heterocycles with high molecular complexity in low to excellent yields.

Full text of DOI:10.1021/ol400537b

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed Direct Selective
C(5)ꢀH Oxidative Annulations
of 2‑Substituted Imidazoles and
Alkynes by Double CꢀH Activation
Ji-Rong Huang, Qian-Ru Zhang, Chuan-Hua Qu, Xun-Hao Sun, Lin Dong,* and
Ying-Chun Chen*
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry, Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
dongl@scu.edu.cn; ycchenhuaxi@yahoo.com.cn
Received February 26, 2013
ABSTRACT
Double CꢀH activations of C(5)ꢀH and Csp2ꢀH of 2-substituted N-vinyl- or arylimidazoles were realized without heteroatom-directing assistance
by rhodium(III) catalyst. A subsequent oxidative annulation reaction with alkynes efficiently produced aza-fused heterocycles with high molecular
complexity in low to excellent yields.
The transition-metal-catalyzed functionalization of CꢀH
bonds has been a highly intriguing research topic in the past
decade.1 Recently, direct CꢀH alkenylation and alkylation
of nitrogen heterocycles have been significantly developed,
which could be broadly grouped into different subfields.2ꢀ4
The most popular strategy was to introduce a directing
group into the substrate, assisting ortho CꢀH activa-
tion or roll-over CꢀH activation to form the active
metallacyclic complex.2 Another well-developed tool is
that sp2-hybridized nitrogen initially associates with
Rh catalyst and then affords an RhꢀNHC complex at
the ortho position.3 Nickel could also catalyze the
alkenylation of nitrogen heterocycles via the formation
of alkyne-coordinated Ni species.4 Very recently, Jiao
and co-workers reported the Pd-catalyzed oxidative
cycloaromatization of biaryls with alkynes through
dual activation of CꢀH bonds without directing groups
(Scheme 1, eq 1).5,6
(1) For selected recent reviews about CꢀH bond functionalizations,
see: (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (b)
Ackermann, L. Chem. Commun. 2010, 46, 4866. (c) Smith, A. M. R.; Hii,
K. K. Chem. Rev. 2011, 111, 1637. (d) Krause, N.; Winter, C. Chem. Rev.
2011, 111, 1994. (e) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem.
Rev. 2012, 112, 5879. (f) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev.
2012, 41, 3651. (g) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.;
Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236.
(2) For selected examples of CꢀH alkenylation and alkylation of
nitrogen heterocycles using directing groups, see: (a) Wang, L.; Huang,
J.; Peng, S.; Liu, H.; Jiang, X.; Wang, J. Angew. Chem., Int. Ed. 2013, 52,
1768. (b) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2010, 12, 2068. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (d) Shibata, T.; Takayasu, S.; Yuzawa, S.; Otani, T.
Org. Lett. 2012, 14, 5106. (e) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J.
Am. Chem. Soc. 2010, 132, 9602. (f) Engle, K. M.; Mei, T.-S.; Wasa, M.;
Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.
(4) (a) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem.
€
Soc. 2006, 128, 8146. (b) Kanyiva, K. S.; Lobermann, F.; Nakao, Y.;
Hiyama, T. Tetrahedron Lett. 2009, 50, 3463.
(5) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
7895.
(3) For selected examples containing RhꢀNHC complex, see: (a)
Ryu, J.; Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 3677. (b)
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (c) Wiedemann, S. H.; Lewis, J. C.; Ellman, J. A.; Bergman, R. G.
J. Am. Chem. Soc. 2006, 128, 2452. (d) Tan, K. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 3202. (e) Yotphan, S.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2010, 12, 2978.
(6) For selected examples of oxidative annulations of alkynes without
directing groups, see: (a) Tsuchimoto, T.; Matsubayashi, H.; Kaneko,
M.; Nagase, Y.; Miyamura, T.; Shirakawa, E. J. Am. Chem. Soc. 2008,
130, 15823. (b) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Shirakawa,
E.; Kawakami, Y. Angew. Chem., Int. Ed. 2005, 44, 1336.
r
10.1021/ol400537b
XXXX American Chemical Society

The assistance of adjacent π system might provide the
driving force to induce the activation of less reactive
C(5)ꢀH to give the five-membered metallacycle.11,12
Scheme 1. Transition-Metal-Catalyzed CꢀH Alkenylation and
Alkylation of Nitrogen Heterocycles
Table 1. Optimization of the Reaction Conditions for Synthesis
of 3aaa
entry
catalyst
oxidant
solvent yieldb (%)
1
2
3
4
5
6
7
8c
[Cp*RhCl2]2
Cu(OAc)2 H2O toluene
75
3
[RuCl2(p-cymene)]2 Cu(OAc)2 H2O toluene
12
3
(PPh3)3RhCl
Pd(OAc)2
toluene
N.R.
N.R.
65
Cu(OAc)2 H2O toluene
3
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
AgOAc
toluene
Nevertheless, Rh-catalyzed direct CꢀH activation of
nitrogen heterocycles without directing groups still re-
mains a huge challenge.7 Previously, we have demon-
strated that C(2)ꢀH of N-arylazoles could be utilized to
synthesize complex aza-fused quinolines via double CꢀH
activation.8,9 However, oxidative annulation reaction via
regioselective activation of the C(5)ꢀH bond of imidazoles
was still unrealized, for there was no extra directing group
or sp2-hybridized nitrogen to assist such a CꢀH activa-
tion.4b,7a Herein, we described an efficient protocol to
access complex aza-fused scaffolds by direct Rh(III)-
catalyzed double CꢀH activations of Csp2ꢀH (vinylic sp2
CꢀH or aryl Csp2ꢀH) and C(5)ꢀH of 2-substituted im-
idazoles and then coupling with alkynes (Scheme 1, eq 2).10
Cu(OAc)2 H2O DMF
18
3
Cu(OAc)2 H2O dioxane
65
3
Cu(OAc)2 H2O toluene
99
3
a Unless noted otherwise, reaction conditions were conducted with
0.1 mmol of 1a, 0.2 mmol of 2a, 5 mol % of catalyst, 0.12 mmol of
oxidant, 1 mL of solvent, 110 °C, under Ar atmosphere. b Isolated
products. c 1a:2a = 2.
We began our studies with the oxidative annulation of
2-methyl-N-vinylimidazole (1a) and diphenylacetylene
(2a). Gratifyingly, the desired product 3aa was formed
in 75% yield by using [Cp*RhCl2]2 as a catalyst and
Cu(OAc)2 H2O as an oxidant (Table 1, entry 1). However,
other transition metals such as [RuCl2(p-cymene)]2, (PPh3)3-
3
5,13
RhCl and Pd(OAc)2
showed much less or negative
(7) For selected examples of Rh-catalyzed oxidative annulations of
alkynes, see: (a) Umeda, N.; Hirano, K.; Satoh, T.; Shibata, N.; Sato, H.;
Miura, M. J. Org. Chem. 2011, 76, 13. (b) Satoh, T.; Miura, M. Chem.;
Eur. J. 2010, 16, 11212.
(8) Huang, J.-R.; Dong, L.; Han, B.; Peng, C.; Chen, Y.-C. Chem.;
Eur. J. 2012, 18, 8896.
catalytic activity (Table 1, entries 2ꢀ4). The yield was
reduced to 65% when AgOAc was used as an oxidant
(Table 1, entry 5). Inferior results were also obtained in
DMF or 1,4-dioxane (Table 1, entries 6 and 7). Pleasingly,
a quantitative yield was produced when excess imidazole
1a was used (Table 1, entry 8).13
With the established conditions in hand, we first exam-
ined various internal alkynes in place of 2a in the reactions
with imidazole 1a (Scheme 2). An array of diversely
substituted diarylacetylenes underwent the annulations
to afford the corresponding imidazo[1,5-R]pyridines
(3abꢀad) in moderate to excellent yields, even for hetero-
aryl- (2e) or alkyl-disubstituted (2f) alkynes. The present
catalytic system was also extended to unsymmetrically
disubstituted alkynes, could be utilized in the annulation
reaction, though the desired product 3aj was formed in low
regioselectivity. It was found that terminal alkynes were
not tolerated in this system.
(9) For selected examples on transition-metal-catalyzed C(2)ꢀH
activation of azoles, see: (a) Muto, K.; Yamaguchi, J.; Itami, K.
J. Am. Chem. Soc. 2012, 134, 169. (b) Nishino, M.; Hirano, K.; Satoh,
T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 6993. (c) Yamashita, M.;
Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
7481. (d) Lu, W.-J.; Jia, C.-G.; Kitamura, T.; Fujiwara, Y. Org. Lett.
2000, 2, 2927. (e) Ding, Z.; Yoshikai, N. Angew. Chem., Int. Ed. 2012, 51,
4698. (f) Kandukuri, S. R.; Schiffner, J. A.; Oestreich, M. Angew. Chem.,
Int. Ed. 2012, 51, 12047. (g) Dong, J.; Huang, Y.; Qin, X.; Cheng, Y.;
Hao, J.; Wan, D.; Li, W.; Liu, X.; You, J. Chem.;Eur. J. 2012, 18, 6158.
(10) For selected recent examples on Rh(III)-catalyzed vinylic sp2
CꢀH activation, see: (a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am.
Chem. Soc. 2010, 132, 9585. (b) Hyster, T. K.; Rovis, T. Chem. Sci 2011,
2, 1606. (c) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew.
Chem., Int. Ed. 2011, 50, 1338. (d) Lian, Y. J.; Huber, T.; Hesp, K. D.;
Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2013, 52, 629. (e)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 3645.
(11) For selected examples of five-membered metallacycles, see: (a)
Ackermann, L. Chem. Rev. 2011, 111, 1315. (b) Davies, D. L.; Al-Duaij,
O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.; Russell, D. R. Dalton
Trans. 2003, 4132. (c) Davies, D. L.; Donald, S. M. A.; Al-Duaij, O.;
Next we investigated the scope of N-substituted imida-
zoles (Scheme 3). Various substituents such as alkyl, aryl,
€
Macgregor, S. A.; Polleth, M. J. Am. Chem. Soc. 2006, 128, 4210. (d) Li,
L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130, 12414.
(e) Boutadla, Y.; Al-Duaij, O.; Davies, D. L.; Griffith, G. A.; Singh, K.
Organometallics 2009, 28, 433. (f) Han, Y.-F.; Li, H.; Hu, P.; Jin, G.-X.
Organometallics 2011, 30, 905. (g) Boutadla, Y.; Davies, D. L.; Jones,
R. C.; Singh, K. Chem.;Eur. J. 2011, 17, 3438. (h) Kisenyi, J. M.;
Sunley, G. J.; Cabeza, J. A.; Smith, A. J.; Adams, H.; Salt, N. J.; Maitlis,
P. M. J. Chem. Soc., Dalton Trans. 1987, 2459.
(12) The reaction did not give the desired product when 2-methyl-N-
CH3-imidazole was used as a substrate. Almost all starting materials
were recycled, which might support the assistance of adjacent π system
to induce the C(5)ꢀH activation to give the five-membered metallacycle.
(13) For more details of condition screenings, see the Supporting
Imformation.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Substrate Scope of Alkynesa
Scheme 3. Scope and Limitations of N-Substituted Imidazolesa
a Unless noted otherwise, reaction conditions were conducted with
0.2 mmol of 1a, 0.1 mmol of 2, 5 mol % of [Cp*RhCl2]2, 0.12 mmol of
Cu(OAc)2 H2O, 1 mL of toluene, 110 °C, under Ar atmosphere. Yields
3
are reported for the isolated products. Ratios of regioisomers are given
in parentheses and were determined by 1H NMR analysis. Major
isomers are shown.
and ester groups on N-alkenyl moiety were well tolerated,
and the corresponding imidazo[1,5-R]pyridines (3baꢀda)
were constructed effectively. An imidazole with a disub-
stituted alkenyl group also proceeded smoothly leading to
the highly substituted pyridine derivative3ea albeitin a fair
yield. To our delight, an N-phenylimidazole exhibited the
similar CꢀH activation pattern toward thiscatalyst system
and the corresponding imidazo[1,5-R]quinoline product
(3fa) was obtained in 82% yield. In addition, imidazoles
bearing either electron-donating or -withdrawing groups
at the para-position of the N-aryl ring showed good
reactivity to give products 3ga and 3ha in 73% and 77%
yield, respectively. However, an ortho-substituted aryl
substrate only produced the corresponding tricycle 3ia in
25% yield, probably because of steric hindrance. A mix-
ture of regioisomers (3ja and 3ja0) was generated by
employing an imidazole with a meta-cyanophenyl group.
Fortunately, imidazoles bearing N-heteroaryl group were
also compatible, producing 3ka and 3la in good isolated
yields.
Encouraged by the good tolerance toward various func-
tional groups, the scope of various C2-substituted imida-
zoles was further examined. The results are summarized in
Scheme 4. An imidazole with a bulky isopropyl group
provided the desired 3ma in a high yield. Aryl and vinyl
moieties on C2 position were compatible with the reaction
system and the corresponding imidazo[1,5-R]quinolines
3na and 3oa were produced exclusively, albeit with mod-
erate yields. Interestingly, an imidazole with an acetyl
group could react with 2a to afford 3pa albeit in low yield
due to some side reactions, while excellent yield was
obtained for 3qa with a benzoyl group. In addition,
imidazoles bearing a cyano or sulfonyl group exhibited
the similar reactivity, giving 3ra or 3sa, respectively, in
moderate yields. Notably, the thioether functional group
a Unless noted otherwise, reaction conditions were conducted with
0.2 mmol of 1, 0.1 mmol of 2a, 5 mol % of [Cp*RhCl2]2, 0.12 mmol of
Cu(OAc)2 H2O, 1 mL of toluene, 110 °C, under Ar atmosphere. Yields
3
are reported for the isolated products. b 0.1 mmol of 1i and 0.2 mmol of
2a were used.
did not affect the catalytic activity, and high yields were
achieved for products 3ta and 3ua. Moreover, even an
imidazole with a 2-Cl group could be applied, though the
product 3va was obtained in a fair yield. 2,4-disubstituted
imidazole also proceeded well in the reaction with 2a to
produce 3wa in 40% yield, and the yield could be improved
to76%yield by changingtheratioofthe startingmaterials.
On the other hand, it was pleasing that R-CꢀH bond of
N-aryl pyrroles 4 could also be activated under the same
catalytic system, an array of pyrrolo[1,2-R]quinoline deriv-
atives (5aꢀe) were smoothly produced in low to good
yields.14
We further carried out some deuterium experiments to
gain some insights into the catalytic mechanism. The
C(5)ꢀH kinetic isotopic effects were determined to be
1.5, however, DKIE in Csp2ꢀH of 1.0 was obtained, thus
indicating that cleavage of C(5)ꢀH bond in imidazole
might be involved in the rate-determining step (Scheme 5,
eqs 3 and 4).15
(14) For selected examples of R-CꢀH activation of pyrroles, see: (a)
Ref. (9i). (b) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami,
Y. Chem. Commun. 2003, 2454. (c) Blaszykowski, C.; Aktoudianakis, E.;
Bressy, C.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 2043. (d) Wang,
X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (e) Rieth,
R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett. 2004, 6,
3981.
(15) We conducted deuterium exchange and competition reactions to
gain some insights into the mechanism. For more details, see the
Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Annulation Reactions of Diverse Imidazoles and
Pyrrolesa
Scheme 5. Kinetic Isotopic Effects
and pyridines with high molecular complexity. This cata-
lytic strategy was also applicable to the double CꢀH
activation of N-arylpyrrole substrates to access pyrrolo-
[1,2-R]quinoline scaffolds. Further investigation of the
catalytic mechanism and synthetic application of this
reaction is underway in this laboratory.
Scheme 6. Plausible Mechanism
a Unless noted otherwise, reaction conditions were conducted with
0.2 mmol of 1 or 4, 0.1 mmol of 2a, 5 mol % of [Cp*RhCl2]2, 0.12 mmol
of Cu(OAc)2 H2O, 1 mL of toluene, 110 °C, under Ar atmosphere.
3
Yields are reported for the isolated products. b 0.1 mmol of 1, 0.2 mmol
of 2a.
A plausible mechanism for the oxidative annulation was
proposed (Scheme 6). C(5)ꢀH first undergoes insertion by
Rh(III) catalyst to give intermediate I, presumably facili-
tated by the assistance of adjacent π system.12 Then the
following vinylic sp2 CꢀH activation event occurs to
afford the five-membered rhodacycle intermediate II. Sub-
sequently, alkyne coordinates to Rh(III) to yield inter-
mediate III. Regioselective insertion of the alkyne into the
RhꢀC bond gives an alkyne-coordinating seven-membered
ring intermediate IV, which would subsequent reductive
elimination to give product 3aa.
In conclusion, we have successfully developed a Rh(III)-
catalyzed double CꢀH activation of C(5)ꢀH of 2-substi-
tuted imidazole substrates and Csp2ꢀH without hetero-
atom directing assistance, followed by an annulation
reaction with alkynes to give diverse aza-fused quinolines
Acknowledgment. We are grateful for financial support
from the NSFC (21202106), Sichuan University Scientific
Research Foundation, Sichuan University “985 project-
Science and technology innovation platform for novel
drug development”, and the Open Research Fund from
State Key Laboratory of Breeding Base of Systematic
Research, Development and Utilization of Chinese Med-
icine Resources.
Supporting Information Available. Experimental pro-
cedures, structural proofs, and NMR spectra of the
products. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX