δ and α SP3 C-H bond oxidation of sulfonamides with PhI(OAc)2/I2 under metal-free conditions

Article abstract of DOI:10.1021/jo7016982

(Chemical Equation Presented) An efficient δ and α sp ³ C-H bond oxidation of sulfonamides with PhI(OAc)₂/I ₂ under metal-free conditions has been reported. The reaction provides a useful route to pyrrolidines, N-sulfonyli

Full text of DOI:10.1021/jo7016982

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
rhfan@fudan.edu.cn
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,
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10.1021/jo7016982 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007
8994
J. Org. Chem. 2007, 72, 8994-8997

many oxidation procedures have been developed,8 certain
drawbacks of the approach, such as the requirement of an
additional metal catalyst or other additives, and low solubility
of oxidizer in organic solvent, limit the synthetic application
of such processes. N-Sulfonylimines are one of the few types
of stable electron-deficient imines and are of increasing
importance because they are versatile intermediates in organic
synthesis. Although there are a variety of methods developed
for the preparation of N-sulfonylimines,9 the direct oxidation
of sulfonamides to N-sulfonylimines remains an attractive
option.
The oxidation of N-benzyl-4-methylbenzenesulfonamide 3a
gave rise to N-sulfonylimines 4a 76% yield when AcOEt was
used as solvent (eq 2). Guo have used Pd(OAc)2 as catalyst in
the oxidation of 3a to 4a with O2, but the yield was very low
(16%).8a Control experiments indicated that no reaction occurred
in the absence of either PhI(OAc)2 or I2.
TABLE 1. Condition Screening Experiments for Intramolecular
Amination of N-Hexyl-4-methylbenzenesulfonamidea
entry
oxidation (equiv)
solvent
T (°C)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
PhI(OAc)2 (2)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 (4)/I2 (1)
PhI(OAc)2 (3)/I2 (0.5)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 3)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
PhI(OAc)2 (3)/I2 (1)
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
THF
DMF
t-BuOH
toluene
AcOEt
40
40
40
40
reflux
25
0
25
25
25
25
25
25
42
63
64
42
7
82
4
ndc
ndc
ndc
ndc
78
42
CH2Cl2
a All reactions were conducted on a 0.5 mmol scale. b Isolated yield.
c No product was detected.
SCHEME 1. Intramolecular C-H Bond Amination of
Amides
The aryl N-sulfonylimines formed in the oxidation reactions
were ready to undergo various subsequent addition reactions
without further purification. As shown in Table 2, entries 1-6,
cross-dehydrogenative-coupling (CDC) reactions between sul-
fonamide and malonate proceeded smoothly via the oxidations
of sulfonamides and the subsequent additions with malonate.10
In these procedures, the oxidation reaction and the nucleophilic
addition reaction were conducted in one flask, and generated
the corresponding CDC products in good yields. When allylzinc
bromide (Table 2, entries 8-11), allyltrimethylsilane (Table 2,
entry 12), diethyl phosphate (Table 2, entry 13), or dimethyl
acetylenedicarboxylate (eq 3) was used as nucleophile in the
subsequent addition reaction, a workup procedure for the
oxidation reaction mixture was necessary owing to the sensitivity
of nucleophilic reagent or catalyst to the oxidizer. The yields
in yield occurred when the reaction was warmed to reflux or
cooled to 0 °C. No product was detected when THF, DMF,
t-BuOH, or toluene was used as solvent, while the reaction could
proceed in AcOEt and CH2Cl2 with varied efficiency. Shono
reported the same conversion from 1a to 2a via an electro-
chemical oxidation, but the yield was only 22%.6
The reaction of N-octyl-4-methylbenzenesulfonamide 1b
proceeded smoothly and only gave expected five-membered ring
products in good yields.7 However, N-butyl-4-methylbenzene-
sulfonamide 1c did not react under the same conditions. A strong
electron-withdrawing group on nitrogen was essential for the
intramolecular amination. Sulfonamides 1e and 1f could be
converted into the corresponding pyrrolidines. By contrast,
benzamide 1h and trifluoroacetamide 1i were inactive in the
cyclization (Scheme 1).
(8) For selected examples, see: (a) Wang, J. R.; Fu, Y.; Zhang, B. B.;
Cui, X.; Liu, L.; Guo, Q. X. Tetrahedron Lett. 2006, 47, 8293. (b) Nicolaou,
K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126,
5192. (c) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2003, 42,
1480. (d) Sueda, T.; Kajishima, D.; Goto, S. J. Org. Chem. 2003, 68, 3307.
(e) Goti, A.; Romani, M. Tetrahedron Lett. 1994, 35, 6567. (f) Pratt, E. F.;
McGovern, T. P. J. Org. Chem. 1964, 29, 1540. (g) Yamaguchi, J.; Takeda,
T. Chem. Lett. 1992, 1933. (h) Larsen, J.; Jorgensen, K. A. J. Chem. Soc.,
Perkin Trans. 2 1992, 1213. (i) Maruyama, K.; Kusukawa, T.; Higuchi,
Y.; Nishinaga, A. Chem. Lett. 1991, 1093. (j) Nishinaga, A.; Yamazaki,
S.; Matsuura, T. Tetrahedron Lett. 1988, 29, 4115. (k) Keirs, D.; Overton,
K. J. Chem. Soc., Chem. Commun. 1987, 1660. (l) Cornejo, J. J.; Larson,
K. D.; Mendenhall, G. D. J. Org. Chem. 1985, 50, 5382. (m) Marino, J. P.;
Larsen, R. D. J. Am. Chem. Soc. 1981, 103, 4642. (n) Mu¨ller, P.; Gilabert,
D. M. Tetrahedron 1988, 44, 7171.
(9) (a) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131. (b) Wolfe, J.
P.; Ney, J. E. Org. Lett. 2003, 5, 4607. (c) Lee, K. Y.; Lee, C. G.; Kim, J.
N. Tetrahedron Lett. 2003, 44, 1231. (d) Chemla, F.; Hebbe, V.; Normant,
J. F. Synthesis 2000, 75. (e) Georg, G. I.; Harriman, G. C. B.; Peterson, S.
A. J. Org. Chem. 1995, 60, 7366. (f) Trost, B. M.; Marrs, C. J. Org. Chem.
1991, 56, 6468. (g) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org.
Synth. 1987, 66, 203.
For the reaction of N-propyl-4-methylbenzenesulfonamide,
the starting material disappeared, but no cyclization product was
isolated. Analysis of the unpurified reaction mixture by 1H NMR
spectroscopy indicated the formation of TsNH2 and propional-
dehyde, generated as the decomposition products of correspond-
ing sulfonimine.
The oxidation of a C-H bond R to nitrogen in secondary
amines is employed to synthesize imines from amines. Although
(10) For selected examples, see: (a) Zhang, Y. H.; Li, C. J. J. Am. Chem.
Soc. 2006, 128, 4242. (b) Li, Z.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 56.
(c) Li, Z.; Li, C. J. J. Am. Chem. Soc. 2005, 127, 6968. (d) DeBoef, B.;
Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556. (e) Murahashi,
S. I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312.
(f) Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003,
125, 1476. (g) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001,
34, 633.
(6) Shono, T.; Matsumura, Y.; Katoh, S.; Takeuchi, K.; Sasaki, K.;
Kamada, T.; Shimizu, R. J. Am. Chem. Soc. 1990, 112, 2368.
(7) (a) Togo, H.; Katohgi, M. Synlett 2001, 565. (b) de Armas, P.; Carrau,
R.; Concepcio´n, J. I.; Francisco, C. G.; Herna´ndez, R.; Sua´rez, T. L.
Tetrahedron Lett. 1985, 26, 2493.
J. Org. Chem, Vol. 72, No. 23, 2007 8995

TABLE 2. Oxidation Reactions of Sulfonamides and Subsequent
Addition Reactionsa
entry
1c
Ar
nucleophile (equiv) and conditions
5b (%)
Ph
p-CH3C6H4
CH2(COOEt)2 (2), t-BuOK (2),
t-BuOH, rt
CH2(COOEt)2 (2), t-BuOK (2),
t-BuOH, rt
5a (82)
2c
3c
4c
5c
6c
5b (78)
5c (73)
5d (79)
5e (83)
5f (81)
p-CH3OC6H4 CH2(COOEt)2 (2), t-BuOK (2),
t-BuOH, rt
o-ClC6H4
CH2(COOEt)2 (2), t-BuOK (2),
t-BuOH, rt
CH2(COOEt)2 (2), t-BuOK (2),
t-BuOH, rt
CH2(COOEt)2 (2), t-BuOK (2),
t-BuOH, rt
CH2dCHCH2ZnBr (3), THF, rt
CH2dCHCH2ZnBr (3), THF, rt
CH2dCHCH2ZnBr (3), THF, r.t.
p-FC6H4
o-CF3C6H4
7c
8d
Ph
Ph
5g (0)
FIGURE 1. Tentative mechanism for the δ and R sp3 C-H bond
oxidation of sulfonamides with PhI(OAc)2/I2.
5g (84)
5h (81)
5i (80)
5j (82)
9d
p-CH3C6H4
10d
11d
12d
p-CH3OC6H4 CH2dCHCH2ZnBr (3), THF, rt
p-FC6H4
SCHEME 2. Oxidation of 4-Methylbenzenesulfinamides 1d
and 7
CH2dCHCH2ZnBr (3), THF, r.t.
CH2dCHCH2SiMe3 (3), Bu4NF (0.1), 5j (78)
Ph
THF, rt
HPO(OEt)2 (3), K2CO3 (1),
ClCH2CH2Cl, rt
13d
Ph
5k (82)
a Reactions were conducted on a 1 mmol scale. b Isolated yield. c After
the oxidation reaction, nucleophilic reagent was added into directly. d The
oxidation reaction was quenched with Me2S (3 equiv), and after a workup
with satd Na2S2O3, the resulted concentrated crude product was treated with
nucleophilic reagents under the corresponding conditions.
of these two-step reactions were not affected by the additional
workup operation.
of W - hV or ultrasonic irradiation resulted in the decomposition
of the formed N-sulfonylimines.
A tentative mechanism for the products formation is proposed
in Figure 1. The reaction of PhI(OAc)2 and iodine generated
iodobenzene and acetyl hypoiodite. Sulfonamides then reacted
with acetyl hypoiodite to form sulfonamidyl radicals.11d In the
cases of N-hexylsulfonamides, sulfonamidyl radicals underwent
a 1, 5-H shift to form δ carbon radicals, which was a very easily
oxidizable species. After an oxidation to carbocation and the
subsequent cyclization, five-membered ring products were
generated.12 Sulfonamidyl radicals with benzyl groups were
converted into R carbon radicals via a 1,2-H shift. Aryl
sulfonimines were obtained as the result of the following
oxidation and deprotonation.8d
Further experiments showed that the oxidation and a tandem
Knoevenagel-Michael addition of resulted N-sulfonylimine
with diethyl malonate5 could be conducted in one flask (eq 4).
When (S)-N-hexyl-4-methylbenzenesulfinamide 1d was used
as the starting material, sulfinamide was oxidized to sulfon-
amide, and 2-ethyl-1-tosylpyrrolidine 2a was formed as the final
product. The oxidation of (S)-N-benzyl-4-methylbenzenesul-
finamide 7 under the same conditions gave sulfonamide 3a and
N-sulfonylimines 4a as the products, and no sulfinimine 8 was
detected from the reaction (Scheme 2).
The PhI(OAc)2/I2 system has been used as a radical precursor
to form sulfonamidyl radicals.11 In these processes, however,
photochemical treatments or ultrasonic irradiations were es-
sential to promote the reactions. In our reaction conditions, extra
hV or ultrasonic irradiation were not necessary. On the contrary,
in the cases of formation of N-sulfonylimines, the utilization
(11) For selected examples, see: (a) Lu, H. J.; Chen, Q.; Li, C. Z. J.
Org. Chem. 2007, 72, 2564. (b) Togo, H.; Kotohgi, M. Synlett 2001, 565.
(c) Katohgi, M.; Togo, H. Tetrahedron 2001, 57, 7481. (d) Madsen, J.;
Viuf, C.; Bols, M. Chem. Eur. J. 2000, 6, 1140. (e) Togo, H.; Harada, Y.;
Yokoyama, M. J. Org. Chem. 2000, 65, 926. (f) Boto, A.; Hernandez, R.;
Suarez, E. J. Org. Chem. 2000, 65, 4930. (g) Katohgi, M.; Togo, H.;
Yamaguchi, K.; Yokoyama, M. Tetrahedron 1999, 55, 14885. (h) Togo,
H.; Hoshina, Y.; Muraki, T.; Nakayama, H.; Yokoyama, M. J. Org. Chem.
1998, 63, 5193. (i) Francisco, C. G.; Gonzalez, M. C.; Suarez, E. J. Org.
Chem. 1998, 63, 8092.
(12) (a) Tanner, D. D.; Arhart, R.; Meintzer, C. P. Tetrahedron 1985,
41, 4261. (b) Nikishin, G. I.; Troyansky, E. Z.; Lazareva, M. Z. Tetrahedron
1985, 41, 4279. (c) Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1960,
82, 1657.
8996 J. Org. Chem., Vol. 72, No. 23, 2007

In summary, we report here an efficient δ and R sp3 C-H
bond oxidation of sulfonamides with PhI(OAc)2/I2 under a
metal-free condition. The reaction provides a useful route to
pyrrolidines, N-sulfonylimines and various sulfonamide deriva-
tives. The potential of this reaction system can be demonstrated
by its mild condition and simple process. The reaction mech-
anism, scope, and synthetic application are ongoing and will
be reported in due course.
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to provide the
desired product. 2-Ethyl-1-tosylpyrrolidine 2a: H NMR (400 MHz,
CDCl3) δ 7.70 (d, J ) 8.2 Hz, 2H), 7.29 (d, J ) 8.2 Hz, 2H),
3.50-3.55 (m, 1H), 3.32-3.37 (m, 1H), 3.16-3.20 (m, 1H), 2.41
(s, 3H), 1.81-1.88 (m, 1H), 1.72-1.80 (m, 1H), 1.41-1.61 (m,
4H), 0.90 (t, J ) 7.2 Hz, 3H). The spectral data are consistent with
those reported in the literature.6
1
Acknowledgment. Financial support from National Natural
Science Foundation of China (20642006, 20502004), the
Shanghai Rising-Star Program (07QA14007), and Fudan Uni-
versity is gratefully acknowledged.
Experimental Section
General Procedure for δ C-H Amination Cyclization of
Sulfonamides. A Schlenk tube was charged with PhI(OAc)2 (483
mg, 1.5 mmol) and sulfonamide (0.5 mmol), evacuated, and
backfilled with argon. I2 (127 mg, 0.5 mmol) and DCE (2 mL)
were successively added. Then the reaction mixture was stirred at
room temperature until the sulfonamide disappeared monitored by
TLC. The mixture was quenched with saturated Na2S2O3 and
extracted by ethyl acetate (100 mL × 3). The organic layer was
Supporting Information Available: Experimental procedures,
characterization data, and copies of 1H and 13C NMR of new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO7016982
J. Org. Chem, Vol. 72, No. 23, 2007 8997