Direct, organocatalytic α-sulfenylation of aldehydes and ketones

Article abstract of DOI:10.1016/j.tetlet.2004.09.021

A method for direct sulfenylation of aldehydes and ketones, catalyzed by a novel pyrrolidine trifluoromethanesulfonamide organocatalyst, has been developed. This process serves as an efficient and mild approach to the preparation of α-phenylthio-ketones and -aldehydes.

Full text of DOI:10.1016/j.tetlet.2004.09.021

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8229–8231
Direct, organocatalytic a-sulfenylation of aldehydes and ketones
Wei Wang,a,* Hao Li,a Jian Wanga and Lixin Liaob
aDepartment of Chemistry, University of New Mexico, Albuquerque, NM 87131-0001, USA
bXinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi 830011, China
Received 13 August 2004; revised 2 September 2004; accepted 2 September 2004
Available online 21 September 2004
Abstract—A method for direct sulfenylation of aldehydes and ketones, catalyzed by a novel pyrrolidine trifluoromethanesulfon-
amide organocatalyst, has been developed. This process serves as an efficient and mild approach to the preparation of a-phenyl-
thio-ketones and -aldehydes.
ꢀ 2004 Elsevier Ltd. All rights reserved.
One of the important themes in contemporary organic
synthesis is the development of new reactions that pro-
duce versatile building blocks from simple and readily
available starting materials. a-Sulfenylated carbonyl
compounds are particularly attractive synthetic interme-
diates since they have been used for a variety of organic
transformations.1 Among the most common methods
used for the synthesis of these substrates are sulfenyl-
ation reactions of enolates2 and SN2 displacement reac-
tions of a-halogenated carbonyl compounds3 with
sulfides. Most methods, including those that use sulfenyl-
ation reactions of preformed enolates4 or enamines,5
require multistep preparative sequences. To our knowl-
edge, no direct, catalytic procedure for a-sulfenylation
of unmodified aldehydes and ketones has been
described. Recently we uncovered a simple, direct, and
efficient method for the preparation of a-selenoalde-
hydes and ketones from aldehydes and ketones.6,7 These
a-selenenylation reactions are promoted by the respec-
tive organocatalysts L-prolinamide and pyrrolidine
trifluoromethanesulfonamide I. In continuing efforts
directed at an exploration of a-oxidation reactions of
aldehydes and ketones, we observed the first examples
of high yielding aldehyde and ketone a-sulfenylations.
The reactions were efficiently catalyzed by the pyrrol-
idine trifluoromethanesulfonamide I,8 in which N-(phen-
ylthio)phthalimide serves as the phenylsulfenyl source.
In this communication, we report the results of a
detailed study of this process, which has led to the
development of a direct method for organocatalytic
a-sulfenylation of aldehydes and ketones.
The reaction conditions used earlier for a-selenenylation
of ketones were adapted to the a-sulfenylation process.7
Reactions of cyclohexanone with three commercially
available sulfenylating reagents, N-(phenylthio)phthal-
imide, dimethyldisulfide, and diphenyldisulfides in the
presence of 30mol% pyrrolidine trifluoromethanesul-
fonamide I as the organocatalyst were probed to evalu-
ate the sulfenylation reaction efficiencies (Table 1). The
Table 1. Effect of sulfenylating reagents on a-sulfenylation reactions
of cyclohexanonea
NHTf
O
N
H
O
I
SPh
30 mol%
CH2Cl2, RT
+
sulfenylating reagent
Entry
Sulfenylation reagent
t (h)
Yieldb (%)
1
2
3
N-(Phenylthio)phthalimide
PhSSPh
MeSSMe
23
48
48
89
<10
<10
a Reaction conditions: To a vial containing cyclohexanone (0.5mmol),
˚
0.5mL of anhydrous CH2Cl2 and 0.1g of 4A molecule sieves was
added catalyst I (0.075mmol) at room temperature. After 10min
vigorous stirring, sulfenylating reagent (0.25mmol) was added. Stir-
ring was continued for a certain period of time (see Table 1). The
reaction mixture was treated with water (5mL), then the solution was
extracted with CH2Cl2 (3 · 5mL). The combined extracts were dried
over MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by silica gel chromatography.
Keywords: a-Sulfenylation; Ketones; Aldehydes; Organocatalyst; Pyrr-
olidine sulfonamide.
*
Corresponding author. Tel.: +1 505 277 0756; fax: +1 505 277
2609; e-mail: wwang@unm.edu
b Isolated yield.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.021

8230
W. Wang et al. / Tetrahedron Letters 45 (2004) 8229–8231
Table 2. Effect of solvents on a-sulfenylation reaction of cyclohexa-
none with Ia
Reactions in CH2Cl2, CH3CN, EtOAc, and THF,
proceeded in high yields, while using solvents such as
1,4-dioxane, DMSO, and DMF, were less efficient. As
a result, CH3CN was selected as the solvent of choice
for the subsequent studies.
O
O
O
N
O
SPh
20 mol% catalyst I
+
SPh
solvent, RT
Entry
Solvent
t (h)
Yieldb (%)
Table 4. Pyrrolidine sulfonamide I catalyzed a-sulfenylation reactions
1
2
3
4
5
6
7
CH2Cl2
CH3CN
THF
24
4
81
83
78
70
58
39
39
of ketones and aldehydesa
12
11
10
24
24
O
O
O
EtOAc
1,4-Dioxane
DMSO
20-30 mol% catalyst I
SPh
N SPh
+
R1
CH3CN, RT
R2
R1 R2
O
DMF
Entry
1
Product
t (h)
Yieldb (%)
a Reaction conditions (see footnote in Table 1).
b Isolated yield.
O
SPh
4
83c
yield of the reaction using N-(phenylthio)phthalimide
was found to be superior to those with the other two
sulfenylating reagents. Therefore, this reagent was used
in subsequent reactions.
O
SPh
SPh
2
3
6
88c
As the data in Table 2 demonstrate, the reaction med-
ium had a great impact on the a-sulfenylation process.
O
O
24
60c
Table 3. Catalyst screening for a-sulfenylation reaction of cyclohexa-
nonea
N
Me
O
O
O
N
O
O
SPh
organocatalyst
CH3CN, RT
SPh
SPh
4
5
24
56d
+
SPh
H
H
O
O
Entry
Catalyst (mol%)
t (h)
Yieldb (%)
ND
SPh
SPh
56d,e
H
36
1
2
3
4
5
6
7
8
24
CONH2
(20)
N
H
7.4 : 1
O
O
O
SPh
SPh
6
7
36
42d,e
H
H
H
SPh
10
4
66
83
CO2H
N
H
n-Bu
n-Bu
(20)
(20)
20 : 1
O
SPh
SPh
36
52d,e
NHTf
H
SPh
N
H
I
n-C5H11
n-C5H11
23 : 1
O
NHTf
(10)
24
24
48
SPh
8
9
30
36
66d
63d
N
H
H
n-C6H13
O
O
NHTf
(5)
12
SPh
N
H
H
H
n-C7H15
O
NHSO2C6F5
(20)
SPh
SPh
24
24
24
<10
<10
<10
36
72
57d,e
H
N
H
10
11
SPh
n-C8H18
n-C8H17
7.4 : 1
O
46d
SPh
N
H
(20)
(20)
H
a Reaction conditions (see footnote in Table 1).
b Isolated yield.
N
H
c 20mol% I used.
d 30mol% I used.
a Reaction conditions (see footnote in Table 1).
b Isolated yields.
e Molar ratio determined by 1H NMR.

W. Wang et al. / Tetrahedron Letters 45 (2004) 8229–8231
8231
A catalyst screening study of the a-sulfenylation reac-
tion of cyclohexanone with N-(phenylthio)phthalimide
was performed next. A wide range of reaction yields
were obtained when the pyrrolidine derivatives, shown
in Table 3, were used. L-Prolinamide, which is an effec-
tive catalyst for a-selenenylation of aldehydes, displayed
poor activity (Table 3, entry 1), whereas the reaction
promoted by L-proline took place in a 66% yield after
10h (entry 2). Reactions employing other organocata-
lyst, including piperidine, pyrrolidine, and pyrrolidine
pentafluorophenylsulfonamide (entries 6–8), were also
inefficient. Pyrrolidine trifluoromethanesulfonamide I
showed the highest catalytic activity (entry 3). In this
case, the reaction proceeded rapidly when a 20mol%
catalyst loading was used and a 83% yield was achieved.
However, when the loading of I was reduced to 5–
10mol%, the reaction rates were significantly lowered.
and aldehydes. The full scope of this process and its
mechanistic intricacies are currently being investigated.
Acknowledgements
Financial support for this effort came from the Depart-
ment of Chemistry, University of New Mexico. We
thank Professor Patrick S. Mariano for making critical
editorial comments about the manuscript.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2004.09.021.
References and notes
To demonstrate the scope of this new a-sulfenylation
reaction, we probed reactions of various ketones pro-
moted by 20mol% pyrrolidine trifluoromethanesulfona-
mide I. Generally, high yields (60–88%) were obtained
for reactions of cyclic ketones (Table 4, entries 1–3).
Unfortunately, a-sulfenylation reactions of acyclic
ketone substrates were sluggish and complex product
mixtures were produced.
1. (a) Trost, B. M. Chem. Rev. 1978, 78, 363–382; (b) Trost, B.
M. Acc. Chem. Res. 1978, 11, 453–461.
2. (a) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem.
Soc. 1976, 98, 4887–4902; (b) Trost, B. M.; Massiot, G. S.
J. Am. Chem. Soc. 1977, 99, 4405–4412; (c) Groenewegen,
P.; Kallenberg, H.; van der Gen, A. Tetrahedron Lett. 1979,
20, 2817–2820; (d) Coates, R. M.; Pigott, H. D.; Ollinger, J.
Tetrahedron Lett. 1974, 15, 3955–3958; (e) Seebach, D.;
Teschner, M. Tetrahedron Lett. 1973, 14, 5113–5116; (f)
Seebach, D.; Teschner, M. Chem. Ber. 1976, 109, 1601–
1616; (g) Huang, C.-H.; Liao, K.-S.; De, S. K.; Tsai, Y.-M.
Tetrahedron Lett. 2002, 41, 3911–3914.
3. (a) Asinger, F.; Thiel, M.; Kalzendorf, I. Justus Liebigs
Ann. Chem. 1957, 610, 25–32; (b) Asinger, F.; Schaefer, W.;
Triem, H. Monatsh. Chem. 1966, 97, 1510–1522; (c) Truce,
W. E.; Knospe, R. H. J. Am. Chem. Soc. 1955, 77, 5063–
5067.
This direct, catalytic a-sulfenylation reaction is not re-
stricted to cyclic ketones since it also is applicable to
aldehydes (Table 4, entries 4–11). Variations in the steric
demand of aldehydes had only a minor effect on the a-
sulfenylation reaction efficiency. Generally, high reac-
tion yields were obtained regardless of the length and
degree of branching of the aldehyde chain. Interestingly,
in some cases (Table 4, entries 5–7 and 10), bis-addition
products were formed in variable, minor amounts
4. Murai, S.; Kuroki, Y.; Hasegawa, K.; Tsutsumi, S. Chem.
Commun. 1972, 946–947.
5. Kuehen, M. E. J. Org. Chem. 1963, 28, 2124–2128.
6. Wang, W.; Wang, J.; Li, H. Org. Lett. 2004, 6, 2817–2820.
7. Wang, W.; Wang, J.; Li, H. Chem. Commun., submitted for
publication.
1
(by H NMR analysis of the crude product mixtures),
however the mono- and bis-products cannot be sepa-
rated by silica gel column chromatography.
In summary, a pyrrolidine sulfonamide I organocata-
lytic procedure for direct a-sulfenylation reactions of
ketones and aldehydes has been developed. This reac-
tion, which produces a-sulfeno-aldehyde and -ketone
products, is applicable to a wide range of cyclic ketones
8. This catalyst showed high catalytic activities for a-amin-
oxylation and the Mannich-type reactions: (a) Wang, W.;
Wang, J.; Li, H. Tetrahedron Lett. 2004, 45, 7235–7238; (b)
Wang, W.; Wang, J.; Li, H. Tetrahedron Lett. 2004, 45,
7243–7246.