Organic Letters
Letter
(3) (a) Sridhar, S. K.; Saravanan, M.; Ramesh, A. Eur. J. Med. Chem.
2001, 36, 615−625. (b) Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq,
E. Farmaco 1999, 54, 624−628. (c) Bamnela, R.; Shrivastava, S. P. Indian
J. Chem. B 2014, 53, 1128−1135.
formation of trace amounts of N-demethylated product (1′) from
the amine was inevitable with all of the different amides and
imides employed in the reaction. To understand its formation, a
control experiment of 1b was carried out in the absence of amide,
wherein a mixture of products, 4-chloro-N-methylaniline (1b′)
and N-(4-chlorophenyl)-N-methylformamide (13), were ob-
tained in 25 and 75% yields, respectively (Scheme 7 (3)). This is
consistent with the previous observation by Miura et al., who
reportedtheformationofthesetwoproductsduringtheoxidation
of amine with [Fe(salen)]OAc and suggested oxygen insertion in
to the alkyl radical of N,N-dimethylaniline as the most probable
pathway leading to their formation.23a,29
(4) Jarrahpour, A.; Khalili, D.; De Clercq, E.; Salmi, C.; Brunel, J. M.
Molecules 2007, 12, 1720−1730.
(5) Bal, T. R.; Anand, B.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem.
Lett. 2005, 15, 4451−4455.
(6) (a) Sridhar, S. K.; Ramesh, A. Biol. Pharm. Bull. 2001, 24, 1149−
1152. (b) Panda, J. Pharma Sci. Monitor 2012, 3, 2304−2313.
(7) Khan, S.; Haque, S.; Imran, M.; Siddiqui, N. J. Pharm. Res. 2006, 5,
61−64.
(8) Zhou, W.; Li, S. L.; Lu, W. Q.; Yuan, J.; Xu, Y. F.; Li, H. L.; Huang, J.;
Zhao, Z. J. MedChemComm 2016, 7, 292−296.
On the basis of these experimental findings and the available
literature, a plausible mechanism for the reaction has been
(9) (a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048−9049. (b) Shrestha, R.; Mukherjee, P.; Tan, Y.; Litman, Z. C.;
Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 8480−8483. (c) Banerjee, D.;
Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2014, 53, 1630−1635.
(10)(a)Jeong,T.;Han,S.;Mishra,N.K.;Sharma, S.;Lee,S.Y.;Oh,J.S.;
Kwak, J. H.; Jung, Y. H.; Kim, I. S. J. Org. Chem. 2015, 80, 7243−7250.
(b) Jia, X. F.; Han, J. J. Org. Chem. 2014, 79, 4180−4185.
(11) (a) Lin, H.;Li, S. S.;Dong, L. Org. Biomol. Chem. 2015, 13, 11228−
11234. (b) Muralirajan, K.; Parthasarathy, K.; Cheng, C. H. Org. Lett.
2012, 14, 4262−4265.
In conclusion, we have developed an unprecedented copper-
catalyzed direct sp3 α-C−H amidation/imidation of N,N-
dimethylarylamines with aromatic heterocyclic amides/imides
under ambient conditions using air as the oxidant. A wide range of
substrates including oxindoles, isatins, phthalimides, and aryl
amides as well as cyclic amides/imides respond to this C−N bond
formation and furnish the biologically useful amidated/imidated
heterocycles in good to high yields. The reaction is believed to
follow a radical pathway involving an iminium ion intermediate.
The protocol is atom-economic, does not require toxic oxidants
or additives, and can be executed efficiently at ambient
temperature.
(12) Shirakawa, E.; Uchiyama, N.; Hayashi, T. J. Org. Chem. 2011, 76,
25−34.
(13)Yang, F.;Li,J.;Xie,J.;Huang, Z.-Z. Org.Lett. 2010,12,5214−5217.
(14) Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.;
DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960−19965.
(15) Wang, L.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Chem. - Eur. J. 2008, 14,
10722−10726.
(16) Jang, S. S.; Youn, S. W. Org. Biomol. Chem. 2016, 14, 2200−2204.
(17) (a) Zhang, Y.; Feng, B. N.; Zhu, C. J. Org. Biomol. Chem. 2012, 10,
9137−9141. (b) Vemula, S. R.; Kumar, D.; Cook, G. R. ACS Catal. 2016,
6, 5295−5301. (c) Wu, X. S.; Yang, K.;Zhao, Y.; Sun, H.; Li, G. G.; Ge, H.
B. Nat. Commun. 2015, 6, 6462.
ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
(18) (a) Pelletier, G.; Powell, D. A. Org. Lett. 2006, 8, 6031−6034.
(b) Tran, B. L.; Li, B. J.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc. 2014,
136,2555−2563. (c)Teng, F.;Sun, S.;Jiang,Y.;Yu,J.-T.;Cheng,J. Chem.
Commun. 2015, 51, 5902−5905.
Experimental procedures and spectroscopic data of all new
X-ray crystal structure data for compound 8d (CIF)
(19) (a) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813−
3816. (b) Liu, X. W.; Zhang, Y. M.; Wang, L.; Fu, H.; Jiang, Y. Y.; Zhao, Y.
F. J. Org. Chem. 2008, 73, 6207−6212. (c) Zhu, F.; Lu, B.; Sun, H. M.;
Shen, Q. Tetrahedron Lett. 2016, 57, 4152−4156.
(20) Khan, K. M.; Khan, M.; Ambreen, N.; Taha, M.; Rahim, F.;
Rasheed, S.;Saied, S.;Shafi, H.;Perveen, S.;Choudhary, M. I. Med. Chem.
2013, 9, 681−688.
AUTHOR INFORMATION
■
Corresponding Author
ORCID
(21) Bogdanov, A. V.; Vazykhova, A. M.; Khasiyatullina, N. R.;
Krivolapov, D. B.; Dobrynin, A. B.; Voloshina, A. D.; Mironov, V. F.
Chem. Heterocycl. Compd. 2016, 52, 25−30.
Author Contributions
†S.K.S. and N.C. contributed equally.
(22) (a) Meunier, B.; de Visser, S. P.; Shaik, S. Chem. Rev. 2004, 104,
3947−3980. (b) Denisov, I. G.; Makris, T. M.; Sligar, S. G.; Schlichting, I.
Chem. Rev. 2005, 105, 2253−2277.
Notes
The authors declare no competing financial interest.
(23) (a) Murata, S.; Miura, M.; Nomura, M. J. Chem. Soc., Chem.
Commun. 1989, 116−118. (b) Murata, S.; Miura, M.; Nomura, M. J. Org.
Chem. 1989, 54, 4700−4702.
ACKNOWLEDGMENTS
■
(24) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem.
Soc. 2008, 130, 11005−11012. (b)Murahashi, S. I.; Komiya, N.;Terai, H.
Angew. Chem., Int. Ed. 2005, 44, 6931−6933.
S.K.S. thanks MHRD, IIT Delhi, for his graduate fellowship. N.C.
thanks DST for a SERB. We thank CSIR, India (02(180)/14/
EMR-II), for financially supporting this work, DST-FIST for
funding the ESI-HRMS, and the SCXRD facility at IIT Delhi.
(25) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U. S. A. 2006, 103,
8928−8933.
(26) Kochi, J. K. J. Am. Chem. Soc. 1962, 84, 3271−3277.
(27) (a) Shono, T.; Toda, T.; Oshino, N. J. Am. Chem. Soc. 1982, 104,
2639−2641. (b) Miwa, G. T.; Garland, W. A.; Hodshon, B. J.; Lu, A. Y.
H.; Northrop, D. B. J. Biol. Chem. 1980, 255, 6049−6054.
(28) Heimbrook, D. C.; Murray, R. I.; Egeberg, K. D.; Sligar, S. G.; Nee,
M. W.; Bruice, T. C. J. Am. Chem. Soc. 1984, 106, 1514−1515.
(29) Murata, S.; Suzuki, K.; Tamatani, A.; Miura, M.; Nomura, M. J.
Chem. Soc., Perkin Trans. 1 1992, 1387−1391.
REFERENCES
■
(1) (a) Abdulghani, A. J.; Abbas, N. M. Bioinorg. Chem. Appl. 2011,
2011, 1. (b) Akdemir, A.; Guzel-Akdemir, O.; Karali, N.; Supuran, C. T.
Bioorg. Med. Chem. 2016, 24, 1648−1652.
(2)(a)Vej-Hansen, B.;Bundgaard, H. Arch. Pharm. Chem. Sci. Ed. 1979,
7, 65−77. (b) Bundgaard, H.; Johansen, M. J. Pharm. Sci. 1980, 69, 44−
46.
D
Org. Lett. XXXX, XXX, XXX−XXX