Journal of the American Chemical Society
Page 6 of 8
D.; Ray, P. C.; Chauhan, Y. K.; Rao, K. B.; Reddy, N. M.; Reddy, D.
S. P. Patent WO2009125430, A2 20091015, 2009.
nities for its further functionalization. Finally, we examined
the reaction in gram scale to evaluate the practicability of the
reaction. More than five grams of diphenyl sulfoxide 1a with
acetonitrile 2a or pentanenitrile 2b were subjected to the reacꢀ
tion conditions (Scheme 4). These two scaleꢀup reactions proꢀ
ceeded smoothly to afford the respective desired products in
synthetically useful yields. The product 5aa could then be
simply converted into tricyclic compound 13 by a sequential
hydrolysis and FriedelꢀCrafts cyclization. 13 is a key precursor
for the synthesis of a commercial available antiꢀinflammatory
drug namely Zaltoprofen.29
1
2
3
4
5
6
7
8
(2) (a) Kukushkin, V. Y.; Pombeiro, A. J. L. Inorg. Chim. Acta
2005, 358, 1; (b) Xi, F.; Kamal, F.; Schenerman, M. A. Tetrahedron
Lett. 2002, 43, 1395; (c) Trivedi, B. K.; Holmes, A.; Stoeber, T. L.;
Blankey, C. J.; Roark, W. H.; Picard, J. A.; Shaw, M. K.; Essenburg,
A. D.; Stanfield, R. L.; Krause, B. R. J. Med. Chem. 1993, 36, 3300;
(d) Wong, Y.ꢀC.; Parthasarathy, K.; Cheng, C.ꢀH. Org. Lett. 2010, 12,
1736.
(3) Friedrich, K.; Wallenfels, K. The Chemistry of the Cyano
Group; WileyꢀInterscience: New York, 1970, pp. 341ꢀ421.
(4) (a) Chen, G.; Wang, Z.; Wu, J.; Ding, K. Org. Lett. 2008, 10,
4573; (b) Soli, E. D.; Manoso, A. S.; Patterson, M. C.; Deshong, P.;
Favor, D. A.; Hirschmann, R.; Smith, A. B. J. Org. Chem. 1999, 64,
3171.
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10
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12
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17
18
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
■ CONCLUSIONS
(5) Kurz, M. E.; Lapin, S. C.; Mariam, A.; Hagen, T. J.; Qian, X. Q.
J. Org. Chem. 1984, 49, 2728.
(6) Enthaler, S.; Inoue, S. Chem. Asian J. 2012, 7, 169.
In summary, we have developed a metal free αꢀarylation of
alkylnitirles by sequentially introducing Tf2O and a mild base
to the mixture of alkylnitriles and aryl sulfoxides. A variety of
αꢀarylated nitriles bearing a wide range of functional groups
have been chemoꢀ and regioselectively prepared under mild
conditions. NMR studies have identified an unprecedented
formation of the sulfonium imine 6ab and demonstrated the
importance of temperature on the formation and manipulation
of this highly unstable specie. Computational investigations
suggested that the reaction is likely to proceed through elecꢀ
trophilic assembling, and subsequent removal of HOTf, folꢀ
lowed by [3,3]ꢀsigmatropic rearrangement. We believe that the
advent of this arylation reaction will promote the development
of other “SꢀN” bond breaking induced [3,3]ꢀsigmatropic rearꢀ
rangements which are currently under investigation in our lab.
More efforts to the development of the chiral base induced
asymmetric αꢀarylation and the practical syntheses of high
value bioactive compounds are also underway.
(7) For αꢀarylation of unactivated alkylnitriles, see: (a) Culkin, D.
A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330; (b) You, J.;
Verkade, J. G. Angew. Chem. Int. Ed. 2003, 42, 5051; (c) Klapars, A.;
Waldman, J. H.; Campos, K. R.; Jensen, M. S.; Mclaughlin, M.;
Chung, J. Y. L.; Cvetovich, R. J.; Chen, C. J. Org. Chem. 2005, 70,
10186; (d) Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc.
2000, 122, 712; for αꢀarylation of activated alkylnitriles, see: (e)
Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 4641; (f) Xie, S. W.; Qin, P.; Li, M.; Zhang, X.
J.; Jiang, Y.; Ma, D. Tetrahedron Lett. 2013, 54, 3889; (g) Wu, L. Y.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
(8) (a) Nambo, M.; Yar, M.; Smith, J. D.; Crudden, C. M. Org. Lett.
2015, 17, 50; (b) Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134,
9102.
(9) (a) Shang, R.; Ji, D. S.; Chu, L.; Fu, Y.; Liu, L. Angew. Chem.
Int. Ed. 2011, 50, 4470; (b) Yeung, P. Y.; Chung, K. H.; Kwong, F. Y.
Org. Lett. 2011, 13, 2912.
(10) (a) Lýpez, R.; Palomo, C. Angew. Chem. Int. Ed. 2015, 54,
13170; (b) Nerush, N.; Vogt, M.; Gellrich, U.; Leitus, G.; BenꢀDavid,
Y.; Milstein, D. J. Am. Chem. Soc. 2016, 138, 6985.
ASSOCIATED CONTENT
Supporting Information
(11) For recent reviews, see: (a) Pulis, A. P.; Procter, D. J. Angew.
Chem. Int. Ed. 2016, 55, 9842; (b) Shafir, A. Tetrahedron Lett. 2016,
57, 2673; (c) Huang, X.; Klimczyk, S.; Maulide, N. Synthesis 2012,
44, 175; for reactions of aryl sulfoniums with nucleophiles, see: (d)
Akai, S.; Kawashita, N.; Satoh, H.; Wada, Y.; Kakiguchi, K.; Kuꢀ
riwaki, I.; Kita, Y. Org. Lett. 2004, 6, 3793; (e) Akai, S.; Morita, N.;
Iio, K.; Nakamura, Y.; Kita, Y. Org. Lett. 2000, 2, 2279; (f) Akai, S.;
Kawashita, N.; Morita, N.; Nakamura, Y;. Iio, K.; Kita, Y. Heterocy-
cles 2002, 58, 75; (g) Akai, S.; Kawashita, N.; Satoh, H.; Wada, Y.;
Kakiguchi, K.; Kuriwaki, I.; Kita, Y. Org. Lett. 2004, 6, 3793; (h)
Padwa, A.; Nara, S.; Wang, Q. Tetrahedron. Lett. 2006, 29, 595; (i)
Huang, X.; Maulide, N. J. Am. Chem. Soc. 2011, 133, 8510; (j) Huang,
Full experimental details, characterization datas, NMR and
DFT studies, NMR spectra for all new compounds. This
material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
*pengbo@zjnu.cn
̀
X.; Patil, N.; Fares, C.; Thiel, W.; Maulide, N. J. Am. Chem. Soc.
̀
Author Contributions
2013, 135, 7312; (k) Eberhart, A. J.; Procter, D. J. Angew. Chem. Int.
Ed. 2013, 52, 4008; (l) Eberhart, A; Cicoira, C.; Procter, D. J. Org.
Lett. 2013, 15, 3994; (m) Eberhart, A. J.; Shrives, H. J.; Ýlvarez, A.;
Carrër, A.; Zhang, Y. T.; Procter, D. J. Chem. Eur. J. 2015, 21, 7428;
(n) Eberhart, A. J.; Imbriglio, J. E.; Procter, D. J. Org. Lett. 2011, 13,
5882; (o) Eberhart, A. J.; Shrives, H.; Zhang, Y. T.; Carrër, A.; Parry,
A. V. S.; Tate, D. J.; Turner, M. L.; Procter, D. J. Chem. Sci. 2016, 7,
1281; (p) FernándezꢀSalas, J.; Pulis, A. P.; Procter, D. J. Chem.
Commun. 2016, 52, 12364; for other elegant examples of sulfonium
salts reacting with nucleophiles, see: (q) Yoshida, S.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2009, 11, 2185; (r) Kobatake, T.; Fujino, D.;
Yoshida, S.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2010, 132,
11838; (s) Ookubo, Y.; Wakamiya, A.; Yorimitsu, H.; Osuka, A.
Chem. Eur. J. 2012, 18, 12690; (t) Murakami, K.; Yorimitsu, H.;
Osuka, A. Angew. Chem. Int. Ed. 2014, 53, 7510; (u) Hu, G.; Xu, J.;
Li, P. Org. Lett. 2014, 16, 6036.
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work is supported by Zhejiang Normal University,
National Natural Science Foundation of Chinaꢀ21502171
and the State Key Laboratory of Fine Chemicals (KF
1512). Chang, Y.H. thanks for the support of NSFCꢀ
21266007. Thomas, A. A. and Eey, S. T.ꢀC. are acknowlꢀ
edged for helpful discussion.
REFERENCES
(12) For reactions of aryl sulfoxides with electrophilic species, see:
(a) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160; (b)
Lu, B.; Li, Y.; Wang, Y.; Aue, D. H.; Luo, Y.; Zhang, L. J. Am. Chem.
Soc. 2013, 135, 8512; (c) Lau, V. M.; Gorin, C. F.; Kanan, M. W.
(1) (a) Baker, D.; Burce, M.; Cahn, A.; Thomas, M. Patent
WO2010097114, A1 20100902, 2010; (b) Kuwata, K.; Kimura, T.;
Muto, J. Pantent WO2010131717, A1 20101118, 2010; (c) Tyagi, O.
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