Direct C-N coupling of imidazoles with aromatic and benzylic compounds via electrooxidative C-H functionalization

Article abstract of DOI:10.1021/ja501093m

A method for the C-N coupling of imidazoles based on electrooxidative C-H functionalization of aromatic and benzylic compounds has been developed. The key to the success is the formation of protected imidazolium ions as initial products, avoiding overoxidation. Deprotection under nonoxidative conditions affords N-substituted imidazoles. Various functional groups are compatible with the present transformation. To demonstrate the power of the method, a P450 17 inhibiter and an antifungal agent having N-substituted imidazole structures were synthesized.

Full text of DOI:10.1021/ja501093m

Communication
pubs.acs.org/JACS
Direct C−N Coupling of Imidazoles with Aromatic and Benzylic
Compounds via Electrooxidative C−H Functionalization
Tatsuya Morofuji, Akihiro Shimizu, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto
615-8510, Japan
S
* Supporting Information
Although it serves as a powerful method for synthesizing N-
ABSTRACT: A method for the C−N coupling of
imidazoles based on electrooxidative C−H functionaliza-
tion of aromatic and benzylic compounds has been
developed. The key to the success is the formation of
protected imidazolium ions as initial products, avoiding
overoxidation. Deprotection under nonoxidative condi-
tions affords N-substituted imidazoles. Various functional
groups are compatible with the present transformation. To
demonstrate the power of the method, a P450 17 inhibiter
and an antifungal agent having N-substituted imidazole
structures were synthesized.
benzyl imidazoles, an excess amount of a benzylic compound is
required presumably because C−N coupling products are also
susceptible to H-atom abstraction.
Electrochemical oxidation8,9 serves as a powerful method for
functionalizing C−H bonds of benzylic10 and aromatic11
compounds by single electron transfer. Despite the usefulness
of the method, it suffers from overoxidation when a product is
also susceptible to electrochemical oxidation.12 This is indeed
the case when benzylic and aromatic compounds are
electrochemically oxidized in the presence of unprotected
imidazole (Figure 2a).
midazoles bearing organic substituents on the nitrogen atom
are important motifs in natural products and medicinal
compounds of various biological activities such as antiviral, anti-
I
inflammatory, anticancer, and antifungal activities (Figure 1).
Figure 2. Electrooxidative C−N cross-coupling of imidazoles with
benzylic and aromatic compounds. (a) Conventional approach. (b)
Present approach.
Here, we report a new approach to solve the problem; the
C−N coupling of protected imidazoles based on electro-
oxidative C−H functionalization of organic counterparts
(Figure 2b). This method is applicable not only to benzylic
but also to aromatic compounds. The initial products are N-
benzyl or N-arylimidazolium ions, which can be easily
converted to the corresponding N-benzyl or N-aryl imidazoles
by a subsequent nonoxidative removal of the protecting group.
The key to the success of the present approach is the
intermediacy of the electrooxidatively inactive imidazolium
ions, which avoids overoxidation. Therefore, the reaction does
not require an excess amount of a benzylic or aromatic
compound.
We first chose to use naphthalene (1a) because C−H
functionalization of 1a via the electrogenerated radical cation
intermediate is well known.13 Because the choice of an
appropriate protecting group of an imidazole is crucial for the
success of the present approach, the electrochemical reactions
of naphthalene in the presence of various N-protected
imidazoles were examined. The electrochemical reactions
Figure 1. Selected examples of N-substituted imidazoles.
Some N-substituted imidazoles are widely used as drugs.1 For
example, losartan is the first orally available angiotensin II
receptor antagonist and is used for treating hypertension.2
Although various protocols for C−N coupling of imidazole
derivatives and organic molecules have been developed, most of
them require prefunctionalization of organic molecules.3−5
Because direct C−N coupling6 between imidazoles and organic
compounds serves as a straightforward method for construction
of a wide variety of N-substituted imidazoles having intriguing
chemical and biological functions, development of efficient
methods for direct C−N coupling by C−H functionalization is
highly desired. Recently, direct C−N coupling by functionaliz-
ing benzylic C−H or a C−H bond adjacent to a heteroatom
based on radical H-atom abstraction has been reported.7
Received: January 31, 2014
Published: March 6, 2014
© 2014 American Chemical Society
4496
dx.doi.org/10.1021/ja501093m | J. Am. Chem. Soc. 2014, 136, 4496−4499

Journal of the American Chemical Society
Communication
Table 1. Optimization of the Protecting Groups
a
a
entry
protecting group
protecting group label
yield of 3a (%)
entry
5
protecting group
protecting group label
yield of 3a (%)
1
2
3
4
H
2a
2b
2c
2d
0
SO2C6H4-p-CH3
(Ts)
2e
71
COCH3
CO2NMe2
SO2NMe2
46
62
42
6
7
SO2CH3 (Ms)
SiMe3
2f
82
0
2g
a
Yields were determined by GC analysis using tridecane as an internal standard.
were carried out with 0.20 mmol of naphthalene (1a) and 0.6
mmol of a N-protected imidazole (2) in an H-type divided cell
equipped with an anode consisting of fine carbon fibers and a
platinum plate cathode using a 1.0 M solution of LiClO4 in
CH3CN at 20 °C under constant current conditions. In the
anodic chamber, 1a was oxidized, and in the cathodic chamber,
the proton was reduced to generate hydrogen. Trifluorome-
thanesulfonic acid was added to the cathodic chamber prior to
the electrolysis in order to promote the hydrogen generation.
After 2.5 F/mol of electricity was consumed, the reaction
mixture was treated with piperidine at 70 °C for 12 h. The
yields of the resulting C−N coupling product 3a were
determined by GC analysis.
Table 2. Robustness Screen of C−N Coupling of N-
a
Methylsulfonylimidazole with Naphthalene
The use of unprotected imidazole 2a gave no C−N coupling
product presumably because of the overoxidation (Table 1,
entry 1). In contrast, 1-acetylimidazole (2b) gave the C−N
coupling product 3a in 46% yield (entry 2). Among the
examined groups (entries 2−7), N-methylsulfonyl-protected
imidazole 2f (1-mesylimidazole) gave the product in the
highest yield (entry 6, 82%). The imidazolium intermediate 4f
could be characterized by NMR after electrolysis (see the
Supporting Information).
Various functional groups are compatible with the present
transformation. To demonstrate high chemoselectivity of the
present method, we applied a robustness screen that was
recently developed by Glorius group.14 The reactions were
performed in the presence of various compounds, having given
functional groups as additives. The conversion of naphthalene
(1a), the yield of the product 3a, and those of the unchanged
additives were determined by GC analysis (Table 2). Electron-
withdrawing groups such as ketone, ester, amide, cyano, and
nitro groups survived the reaction (entries 2−4), although
aldehydes could not tolerate the reaction conditions (entry 5).
Benzylic C−H bonds in non-electron-rich aromatic rings and
allylic C−H bonds were intact (entry 6). The observed
chemoselectivity sharply contrasts with that for the radical H-
atom abstraction.7 Aryl halides, which could be used for further
transformation, also survived the reaction (entry 7). Some
heterocycles such as coumarin, 2-acetylthiophene, and N-
tosylmorpholine survived, although N-tosylpyrrole and 2-
bromothiophene could not tolerate the reaction (entries 8−
12).
a
Yields of 3a, the additives, and naphthalene (1a) after reaction were
determined by GC analysis using tridecane as an internal standard.
Color coding should help the ready assessment of the data: green
(above 66%), yellow (34−66%), red (below 34%).
method could also be applied to other imidazole derivatives
such as N-methylsulfonyl-2-methylimidazole (2h) and N-
methylsulfonylbenzimidazole (2i), which gave the correspond-
ing C−N coupling products in good yields (entries 6−7).
Benzylic compounds are also effective for the C−N coupling
(entries 8−12). Notably, primary, secondary, and tertiary
benzylic C−H bonds were functionalized efficiently. The
regioselectivity of the reaction of 4-methoxy-1,2-dimethylben-
zene (1i) is interesting. The para methyl group was selectively
functionalized without affecting the meta methyl group (entry
11). 2-Methylimidazole and benzoimidazole could also be
introduced by the present C−N coupling (entries 12 and 13).
As shown in Table 3, the present method can be applied to
other electron-rich aromatic compounds. Methoxybenzene
derivatives gave the corresponding C−N coupling products in
moderate to good yields (entries 2−4). In particular, para-
substituted methoxybenzenes gave single regioisomers. π-
Extended aromatic compounds such as phenanthrene (1e)
were effective in this reaction (entry 5). Furthermore, the
4497
dx.doi.org/10.1021/ja501093m | J. Am. Chem. Soc. 2014, 136, 4496−4499

Journal of the American Chemical Society
Communication
gave the cyclized N-benzylimidazole (entries 14 and 15). Only
the five-membered ring compound was formed, and a single
Table 3. C−N Coupling of Imidazole Derivatives with
a
Various Aromatic and Benzylic Compounds
1
diastereomer was observed by H NMR analysis of the crude
product. The stereochemistry was determined by JBCA16 and
NOE analyses and is consistent with a mechanism involving the
back-side attack to a benzylic cation stabilized by the cyclized
tosylamide group.10e
The electrochemical reaction is facilitated by an electron-
donating group such as a methoxy group on the aromatic ring.
The use of such an activating group gives us an added bonus
because a methoxy group can be used for further trans-
formations such as transition-metal-catalyzed coupling reac-
tions.17 For example, compound 3i synthesized by the present
electrochemical C−N coupling was reacted with PhMgBr in the
presence of a catalytic amount of NiCl2(PCy3)2 to give
compound 5, a P450 17 inhibiter,18 in 75% yield (Scheme 1).
Scheme 1. Synthesis of P450 17 Inhibitor 5 from 3i
Featuring Nickel Catalyzed C−O Bond Activation
The following synthesis of an antifungal agent,19 6, also
demonstrates the power of the present method (Scheme 2).
Scheme 2. Synthesis of Antifungal Agent 6 Using
Electrochemical C−N Coupling
Compound 7, which has two different benzylic positions, was
prepared from commercially available compounds in one
step.20 The present electrochemical method functionalized
the benzylic C−H bond next to the electron-rich aromatic ring
substituted by a methoxy group (highlighted in red) selectively
without affecting the benzylic C−H bond next to the relatively
electron poor aromatic ring substituted by two chloro groups
(highlighted in green). Thus, the electrochemical oxidation of 7
in the presence of 1-mesylimidazole 2f followed by treatment
with piperidine gave the desired 6 in 71% isolated yield.
In conclusion, we have developed a new electrooxidative C−
N coupling of N-mesylimidazole and its derivatives with
aromatic and benzylic compounds. The key to the success of
the present method is the formation of electrochemically
inactive imidazolium ions as initial products, which is converted
to the corresponding N-aryl- or N-benzylimidazoles by
subsequent treatment with piperidine. The method provides a
straightforward, highly chemoselective metal-free route to the
N-substituted imidazoles.
a
A total of 0.2 mmol of 1 was oxidized electrochemically in the
presence of 0.6 mmol of N-protected imidazole 2 using 2.5 F/mol of
electricity in a 1.0 M solution of LiClO4 in CH3CN at room
temperature. Isolated yields. A total of 1.0 mmol of N-protected
imidazole was used with 3.0 F/mol of electricity. The reaction was
carried out at 50 °C. Electrolysis was carried out in 0.1 M solution of
LiClO4 in 1,2-dimethoxyethane/dichloromethane (1/5). The reaction
was carried out at 0 °C with 2.2 F/mol of electricity. A total of 0.1
mmol of 1k and 0.5 mmol of 2f were used.
b
c
d
e
The present method can be integrated with electrooxidative
alkene-cyclization reactions.15 For example, the electrochemical
reaction of an alkene having a nucleophilic tosylamide group in
the presence of 2f followed by the treatment with piperidine
4498
dx.doi.org/10.1021/ja501093m | J. Am. Chem. Soc. 2014, 136, 4496−4499

Journal of the American Chemical Society
Communication
Y.; Atobe, M.; Fuchigami, T.; Inagi, S. ACS Macro Lett. 2012, 1, 656.
(d) Finney, E. E.; Ogawa, K. A.; Boydston, A. J. J. Am. Chem. Soc.
2012, 134, 12374. (e) Ashikari, Y.; Shimizu, A.; Nokami, T.; Yoshida,
J. J. Am. Chem. Soc. 2013, 135, 16070. (f) Kawa, K.; Saitoh, T.;
Nishiyama, S. Org. Lett. 2013, 15, 5484. (g) Yamaguchi, Y.; Okada, Y.;
Chiba, K. J. Org. Chem. 2013, 78, 2826. (h) Redden, A.; Perkins, R. J.;
Moeller, K. D. Angew. Chem., Int. Ed. 2013, 52, 12865. (i) Li, W.;
Zheng, C.; Hu, L.; Tian, H.; Little, R. D. Adv. Synth. Catal. 2013, 355,
2884.
(10) (a) Nokami, T.; Ohata, K.; Inoue, M.; Tsuyama, H.; Shibuya, A.;
Soga, K.; Okajima, M.; Suga, S.; Yoshida, J. J. Am. Chem. Soc. 2008,
130, 10864. (b) Okajima, M.; Soga, K.; Watanabe, T.; Terao, K.;
Nokami, T.; Suga, S.; Yoshida, J. Bull. Chem. Soc. Jpn. 2009, 82, 594.
(c) Srivastav, M. K.; Saraswat, A.; Singh, R. K. P. Orient. J. Chem. 2010,
26, 61. (d) Ashikari, Y.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc.
2011, 133, 11840. (e) Ashikari, Y.; Nokami, T.; Yoshida, J. Org. Lett.
2012, 14, 938.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectroscopic data of compounds
data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*J.-i. Yoshida. E-mail: yoshida@sbchem.kyoto-u.ac.jp.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Education, Culture, Sports, Science &
Technology, Japan, for the Grant-in-Aid for Scientific Research
on Innovative Areas, 2105. T.M. acknowledges JSPS for
financial support. We are also grateful to Ms. Eriko Kusaka of
Kyoto University for the NMR analyses.
(11) (a) Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.;
Urano, S.; Sato, M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009,
131, 11310. (b) Kirste, A.; Elsler, B.; Schnakenburg, G.; Waldvogel, S.
R. J. Am. Chem. Soc. 2012, 134, 3571. (c) Morofuji, T.; Shimizu, A.;
Yoshida, J. J. Am. Chem. Soc. 2013, 135, 5000.
(12) (a) Raoult, E.; Sarrazin, J.; Tallec, A. J. Appl. Electrochem. 1984,
14, 639. (b) Ogibin, Y. N.; Ilovaiskii, A. I.; Nikisin, G. I. Russ. Chem.
Bull. 1994, 43, 1536. (c) Purgato, F. L. S.; Ferreira, M. I. C.; Romero, J.
R. J. Mol. Catal. A: Chem. 2000, 161, 99. (d) Halas, S. M.; Okyne, K.;
Fry, A. J. Electrochim. Acta 2003, 48, 1837.
(13) (a) Nyberg, K. Acta Chem. Scand. 1971, 25, 3770. (b) Nyberg,
K. Acta Chem. Scand. 1973, 27, 503. (c) Morofuji, T.; Shimizu, A.;
Yoshida, J. Angew. Chem., Int. Ed. 2012, 51, 7259.
(14) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597.
(15) (a) Moeller, D. K.; Marzabadi, M. R.; New, D. G.; Chiang, M.
Y.; Keith, S. J. Am. Chem. Soc. 1990, 112, 6123. (b) Ashikari, Y.;
Nokami, T.; Yoshida, J. Org. Biomol. Chem. 2013, 11, 3322.
(c) Campbell, J. M.; Xu, H.; Moeller, K. D. J. Am. Chem. Soc. 2012,
134, 18388.
REFERENCES
■
(1) (a) Khanna, I. K.; Yu, Y.; Huff, R. M.; Weier, R. M.; Xu, X.;
Koszyk, F. J.; Collins, P. W.; Cogburn, J. N.; Lsakson, P. C.; Koboldt,
C. M.; Masferrer, J. L.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Yuan, J.; Yang, D.; Zhang, Y. Y. J. Med. Chem. 2000, 43, 3168. (b) Shin,
J.; Rho, J. R.; Seo, Y.; Lee, H. S.; Cho, K. W.; Kwon, H. J.; Sim, C. J.
Tetrahedron Lett. 2001, 42, 1965. (c) Newman, D. J.; Cragg, G. M.;
Snader, K. M. J. Nat. Prod. 2003, 66, 1022. (d) Pastor, I. M.; Yus, M.
Curr. Chem. Bio. 2009, 3, 385. (e) Kon, Y.; Kubota, T.; Shibazaki, A.;
Gonoi, T.; Kobayashi, J. Bioorg. Med. Chem. Lett. 2010, 20, 4569.
(f) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (g) Gupta, V.; Kant, V. Sci.
Intl. 2013, 1, 253. (h) Zhang, L.; Peng, X.; Damu, G. L. V.; Geng, R.;
Zhou, C. Med. Res. Rev. 2014, 34, 340.
(2) Sica, D. A.; Gehr, T. W.; Ghosh, S. Clin. Pharmacokinet. 2005, 44,
797.
(16) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 397.
(3) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(b) Bariwal, J.; Eycken, E. V. Chem. Soc. Rev. 2013, 42, 9283.
(4) N-Arylation of imidazoles using aryl halides: (a) Antilla, J. C.;
Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578. (b) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779.
(c) Zhu, L.; Li, G.; Luo, L.; Guo, P.; Lan, J.; You, J. J. Org. Chem. 2009,
74, 2200. (d) Chen, H.; Wang, D.; Wang, X.; Huang, W.; Cai, Q.;
Ding, K. Synthesis 2010, 1505.
(5) N-Arylation of imidazoles using arylboronic acids: (a) Lam, P. Y.
S.; Clark, C. G.; Saubem, S.; Adams, J.; Winters, M. P.; Chan, D. M.
T.; Cobs, A. Tetrahedron Lett. 1998, 39, 2941. (b) Kantam, M. L.;
Venkanna, G. T.; Sridhar, C.; Sreedhar, B.; Choudary, B. M. J. Org.
Chem. 2006, 71, 9522. (c) Sreedhar, B.; Venkanna, G. T.; Kumar, K. B.
S.; Balasubrahmanyam, V. Synthesis 2008, 795.
(17) (a) Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428.
(b) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486. (c) Li,
B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem.Eur. J. 2011, 17, 1728.
(d) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346.
(18) Zhuang, Y.; Wachall, B. G.; Hartmann, R. W. Bioorg. Med. Chem.
2000, 8, 1245.
(19) Massa, M. A.; Santo, R. D.; Costi, R.; Retico, A.; Apuzzo, G.;
Simonetti, N. Eur. J. Med. Chem. 1993, 28, 715.
(20) (a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc.
2010, 132, 920. (b) Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am.
Chem. Soc. 2012, 134, 6146.
(6) (a) Collet, F.; Dodd, R.; Dauban, P. Chem. Commun. 2009, 5061.
(b) Wencel-Delord, J.; Drcģ e, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem.
Soc. Rev. 2011, 40, 5068. (d) Tang, C.; Yuan, Y.; Cui, Y.; Jiao, N. Eur. J.
Org. Chem. 2013, 7480.
(7) (a) Xia, Q.; Chen, W.; Qiu, H. J. Org. Chem. 2011, 76, 7577.
(b) Pan, S.; Liu, J.; Wang, Z.; Guo, X.; Li, Z. Org. Lett. 2010, 12, 1932.
(c) Xiang, L.; Yongxin, C.; Kangining, L.; Don, W.; Baohua, C. Chin. J.
Chem. 2012, 30, 2285. (d) Xia, Q.; Chen, W. J. Org. Chem. 2012, 77,
9366. (e) Xue, Q.; Xie, J.; Li, H.; Cheng, Y.; Zhu, C. Chem. Commun.
2013, 49, 3700.
(8) (a) Moeller, K. D. Tetrahedron 2000, 56, 9527. (b) Sperry, J. B.;
Wright, D. L. Chem. Soc. Rev. 2006, 35, 605. (c) Yoshida, J.; Kataoka,
K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265.
(9) Recent examples: (a) Kashiwagi, T.; Amemiya, F.; Fuchigami, T.;
Atobe, M. Chem. Commun. 2012, 48, 2806. (b) Mitsudo, K.;
Kamimoto, N.; Murakami, H.; Mandai, H.; Wakamiya, A.; Murata,
Y.; Suga, S. Org. Biomol. Chem. 2012, 10, 9562. (c) Shida, N.; Ishiguro,
4499
dx.doi.org/10.1021/ja501093m | J. Am. Chem. Soc. 2014, 136, 4496−4499