δ and r SP3 C-H Bond Oxidation of
Sulfonamides with PhI(OAc)2/I2 under
Metal-Free Conditions
applicablity in this synthetic module. We herein present an
efficient δ and R sp3 C-H bond oxidation of sulfonamides for
the synthesis of pyrrolidines and N-sulfonylimines with iodo-
benzene diacetate (PhI(OAc)2) and iodine (I2) under metal-free
conditions.
Renhua Fan,*,† Dongming Pu,† Fengqi Wen,† and Jie Wu†,‡
Amination of saturated C-H bonds provides a great potential
for the synthesis of amine derivatives.3 Intramolecular C-H
bond amination attracted more attention owing to its efficiency
and selectivity and to the synthetic significance of the hetero-
cycles.4 In most cases, a transition-metal catalyst is present to
promote the reaction. PhI(OAc)2 has been used as an oxidizing
reagent in the Rh- or Ru-catalyzed C-H amination for the
synthesis of five- or six-membered ring heterocycles. In these
procedures, a primary amide is oxidized with PhI(OAc)2 to an
iodimine, which is in turn decomposed by a metal complex to
generate the corresponding metallonitrene. The following cy-
clization occurs via C-H insertion to give the heterocycle as
product. Despite the great advantages of these approaches, there
are still certain limitations: (1) the secondary amides, which
cannot be oxidized to the corresponding iodimines, cannot take
place under the same conditions; (2) a transition-metal complex
is essential as catalyst in the reaction although it may cause
other concerns.
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai 200433, China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
ReceiVed August 2, 2007
As part of our program to develop the synthetic application
of sulfonamides,5 we found a δ-C-H insertion amination of
secondary amide, N-hexyl-4-methylbenzenesulfonamide 1a, with
PhI(OAc)2 and I2 under metal-free conditions (eq 1). The
reaction gave rise to a five-membered ring product, 2-ethyl-1-
tosylpyrrolidine 2a, in 12% yield. Control experiments indicated
that Rh2(OAc)4 could not catalyze the reaction. No cyclization
product 2a was formed in the absence of either PhI(OAc)2 or
I2.
An efficient δ and R sp3 C-H bond oxidation of sulfon-
amides with PhI(OAc)2/I2 under metal-free conditions has
been reported. The reaction provides a useful route to
pyrrolidines, N-sulfonylimines, and various sulfonamide
derivatives. The potential of this reaction system can be
evaluated by its mild condition and simple process.
Unactivated sp3 C-H bond oxidation and subsequent func-
tionalizations have attracted considerable interest in past
decades.1 The cleavage of an unactivated sp3 C-H bond has
proven difficult because it is kinetically and thermodynamically
unfavorable. Various transition-metal complexes have been used
in the oxidation of sp3 C-H bonds, and many excellent results
in this area have been reported in recent years.2 The oxidation
of sp3 C-H bonds, especially under metal-free conditions,
however, remains challenging because of a lack of universal
Subsequent investigations revealed that the desirable product
2a could be isolated in 63% yield when 3 equiv of PhI(OAc)2
was used (Table 1). A further increase of the amount of PhI-
(OAc)2 did not result in the improvement of yield. A 0.5 equiv
amount of I2 was not enough to complete the reaction. The
reaction was sensitive to the reaction temperature. While a best
yield (82%) was obtained at room temperature, a drastic decrease
† Fudan University.
‡ Shanghai Institute of Organic Chemistry.
(1) For selected reviews, see: (a) Bergman, R. G. Nature 2007, 446,
391. (b) Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683.
(c) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (d) Davies,
H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (e) Ritleng, V.;
Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (f) Labinger, J. A.;
Bercaw, J. E. Nature 2002, 417, 507. (g) Chen, H. Y.; Schlecht, S.; Semple,
T. C.; Hartwig, J. F. Science 2000, 287, 1995. (h) Shilov, A. E.; Shul′pin,
G. B. Chem. ReV. 1997, 97, 2879. (i) Arndtsen, B. A.; Bergman, R. G.;
Mobley, T. A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154.
(2) For selected examples, see: (a) Kloek, S. M.; Goldberg, K. I. J. Am.
Chem. Soc. 2007, 129, 3460. (b) Anstey, M. R.; Yung, C. M.; Du, J. N.;
Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 776. (c) Dong, C. G. Angew.
Chem., Int. Ed. 2006, 45, 2289. (d) Reddy, B. V. S.; Reddy, L. R.; Corey,
E. J. Org. Lett. 2006, 8, 3391. (e) Li, Z. P.; Li, C. J. J. Am. Chem. Soc.
2006, 128, 56. (f) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc.
2006, 128, 9048. (g) Brodsky, B. H.; Du Bois, J. J. Am. Chem. Soc. 2005,
127, 15391. (h) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc.
2004, 126, 6556. (i) Davies, H. M. L.; Jin, Q. H. Org. Lett. 2004, 6, 1769.
(j) Wong, M. K.; Chung, N. W.; He, L.; Yang, D. J. Am. Chem. Soc. 2003,
125, 158. (k) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc.
2001, 123, 8149.
(3) For selected reviews, see: (a) Davies, H. M. L.; Long, M. S. Angew.
Chem., Int. Ed. 2005, 44, 3518. (b) Mu¨ller, P.; Fruit, C. Chem. Rev. 2003,
103, 2905. (c) Dauban, P.; Dodd, R. H. Synlett 2003, 1571. (d) Breslow,
R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105, 6728.
(4) For selected examples, see: (a) Liang, C.; Robert-Peillard, F.; Fruit,
C.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. Angew. Chem., Int. Ed. 2006, 45,
4641. (b) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198. (c) Williams Fiori, K.; Fleming, J. J.; Du Bois, J. Angew. Chem.,
Int. Ed. 2004, 43, 4349. (d) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004,
43, 4210. (e) Fleming, J. J.; Williams Fiori, K.; Du Bois, J. J. Am. Chem.
Soc. 2003, 125, 2028. (f) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003,
125, 11510. (g) Davies, H. M. L.; Venkataramani, C. Org. Lett. 2003, 5,
1403. (h) Liang, J. L.; Yuan, S. X.; Huang, J. S.; Yu, W. Y.; Che, C. M.
Angew. Chem., Int. Ed. 2002, 41, 3465.
(5) (a) Fan, R.; Wang, W.; Pu, D.; Wu, J. J. Org. Chem. 2007, 72, 5905.
(b) Fan, R.; Pu, D.; Qin, L.; Wen, F.; Yao, G.; Wu, J. J. Org. Chem. 2007,
72, 3149.
10.1021/jo7016982 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007
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