Copper-catalyzed sulfenylation of pyrroles with disulfides or thiols: Directly synthesis of sulfenyl pyrroles

Article abstract of DOI:10.1016/j.tetlet.2012.04.094

We present here the synthesis of sulfenyl pyrroles by copper-catalyzed sulfenylation of pyrroles with organic disulfides or thiols. The direct sulfenylation of pyrroles with organic disulfides has been accomplished in the presence of 3 mol % of CuI in DMS

Full text of DOI:10.1016/j.tetlet.2012.04.094

Tetrahedron Letters 53 (2012) 3364–3368
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Copper-catalyzed sulfenylation of pyrroles with disulfides or thiols:
directly synthesis of sulfenyl pyrroles
⇑
Diego Alves , Renata G. Lara, Maria E. Contreira, Cátia S. Radatz, Luis F.B. Duarte, Gelson Perin
LASOL, CCQFA, Universidade Federal de Pelotas, UFPel, PO Box 354, 96010-900 Pelotas, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We present here the synthesis of sulfenyl pyrroles by copper-catalyzed sulfenylation of pyrroles with
organic disulfides or thiols. The direct sulfenylation of pyrroles with organic disulfides has been accom-
plished in the presence of 3 mol % of CuI in DMSO at 110 °C under air atmosphere. In the other hand,
sulfenylation of pyrroles with thiols were performed in the same solvent and temperature, however it
is necessary 5 mol % of CuI and nitrogen atmosphere. Using these protocols we were able to produce
2-sulfenyl pyrroles in good to excellent yields and with high selectivity without use of any ligand or
additive.
Received 9 April 2012
Accepted 19 April 2012
Available online 27 April 2012
Keywords:
Copper
Pyrroles
Disulfides
Thiols
Ó 2012 Elsevier Ltd. All rights reserved.
Sulfenyl pyrroles
R2
X
Diorganyl sulfides, particularly diaryl sulfides, represent special
structural units commonly found in many naturally occurring and
biologically active compounds1 as well as used as important inter-
mediates in organic synthesis.2 Thus, the development of efficient
and new methodologies for synthesis of these compounds has been
emerged in organic synthesis. Traditional methods for the forma-
tion of C–S bonds frequently require harsh reaction conditions.2
To overcome this limitations, considerable attention has been fo-
cused on the development of catalytic systems for the C–S bond
formation.3 In this line, transition metal-catalyzed protocols, espe-
cially copper-catalyzed reactions using specific ligands and addi-
tives, probably are the most important methods for the
preparation of diarylsulfides.3a,4 Copper-catalyzed protocols have
been extensively studied using organic disulfides or thiols as sulfur
source, and a range of sulfenyl arenes and sulfenyl heterocycles
was synthesized in good yields.3a,4 For example, Zhou and
co-workers developed an efficient and atom economical method
for synthesis of sulfenyl substituted azaheterocycles, by copper-
catalyzed sulfenylation of different azaheterocycles, such as
imidazopyridines, imidazopyrimidines, pyrrolo[2,3-b]pyridines
and indoles, with disulfides (Fig. 1).5
SR
R2
R3
X
N
R3
R4
R1
N
R1
N
R5
SR
X = CH, N
Figure 1. Sulfenyl substituted azaheterocycles.
+
R1SSR1
+
R1SH
N
R
N
R
CuI (3%)
DMSO, 110
20 h, air
CuI (5%)
SR1
N
R
°
C
DMSO, 110
°C
20 h, N2
majoritary
R = H, Me, Ph
R
1 = Aryl, Benzyl
In the context of azaheterocycles, pyrroles are an important
class of organic compounds which a variety of electronic and opti-
cal properties, used as a new materials, with naturally occurrence
and biological activities.6 There are different methods available in
the literature for the synthesis of functionalized pyrroles6a–c,7 and
the search of new methods still remain. Unfortunately, several
Scheme 1. General scheme of the reaction.
synthetic approaches to obtain functionalized pyrroles have some
disadvantages, such as, high temperatures and excess reagents.
Strategies for the synthesis of pyrroles frequently involve the intro-
duction of a deactivating electron-withdrawing group that reduces
the electron-rich character of the pyrrole unit.7 Thus, 2-sulfenyl
⇑
Corresponding author.
E-mail address: diego.alves@ufpel.edu.br (D. Alves).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.094

D. Alves et al. / Tetrahedron Letters 53 (2012) 3364–3368
3365
Table 1
Sulfenyl pyrroles may be prepared, for example, by reaction of
pyrroles with sulfenyl chlorides,9 arylsulfenamides in the presence
of phosphorus(v) oxochloride,10 N-(aryl- and alkylthio)phthali-
mides11 and thiocyanate salts.6j,8b However, the basic problem in
these methods is the little stability of the sulfur starting materials.
Therefore, the development of a simple and general methodology
for the sulfenylation of pyrroles is attractive. To the best of our
knowledge, no copper-catalyzed coupling reactions of organic
disulfides or thiols with pyrroles have been described to form sulfe-
nyl pyrroles. Due to our continuous interest in the carbon–chalco-
gen bond formation under copper-catalyzed protocols12 prompted
us to explore a general procedure to obtain directly sulfenyl
pyrroles by copper-catalyzed coupling reactions of disulfides or thi-
ols with pyrroles (Scheme 1).
Our initial studies have focused on the development of an opti-
mum set of reaction conditions. Firstly, we reacted 1-methylpyr-
role 1a with diphenyl disulfide 2a, using CuI (10 mol %) as a
catalyst in DMSO at room temperature and under these conditions,
no product was observed.
To our satisfaction, increasing the temperature to 110 °C the
reaction proceeds smoothly, furnishing the desired 2-sulfenyl pyr-
role 3a in excellent yield with a little amount of 3-sulfenyl pyrrole
4a (Table 1; entry 1). We observed that the influence of the solvent
was important for the sulfenylation of pyrrole 1a. Reactions using
polar aprotic solvents, such as DMSO, DMF and CH3CN, furnishing
moderated to excellent results in the formation of product 3a (Ta-
ble 1; entries 1–3). However, when we use toluene as solvent,
product 3a was not formed (Table 1, entry 4).
Optimization of sulfenylation of pyrrole 1a using disulfides
SPh
Copper salt
+
PhSSPh
2a
+
SPh
N
Solvent, 110
20 h, air
°
C
N
N
Me
Me
Me
1a
3a
4a
Entry
Copper salt (mol %)
Solvent
Yield of 3a/4a (%)a,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CuI (10%)
CuI (10%)
CuI (10%)
CuI (10%)
DMSO
DMF
97
77
46
—
14
52
12
15
CH3CNc
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CuCl (10%)
CuBr (10%)
CuCN (10%)
CuO NPs (10%)
CuCl2 (10%)
CuBr2 (10%)
Cu(OAc)2 (10%)
Cu(acac)2 (10%)
CuI (7%)
16
48
5
6
96
CuI (5%)
CuI (3%)
CuI (1%)
96 (91)d
93 (56)d
80
a
Yields are given for isolated product.
Ratio 3a:4a (90:10) determined by GC/MS of the crude reaction mixture and
b
confirmed after isolation of pure products.
c
Reaction was performed at 80 °C.
Yields in parenthesis correspond to reactions performed using benzenethiol
d
under N2 atmosphere.
The influence of different copper catalysts was the next variable
studied (Table 1; entries 5–12). Analyzing the variety of tested cop-
per(I) and copper(II) salts, we observed that the best result was ob-
tained using 10 mol % of CuI, giving the desired product 3a in high
pyrroles have recently been demonstrated to activate the pyrrolic
ring and the utility of the activated pyrroles in acylation, nitration
and condensation reactions were established.8
Table 2
Scope and generality of the synthesis of the 2-sulfenyl pyrroles 3a–n from disulfides or thiolsa
SR1
R1SSR1
R1SH
2
5
+
SR1
N
R
N
R
N
R
N
R
Method A
Method B
1
3
4
1
Entry
Pyrrole
R1 (2 or 5)
Methoda
Product
Yieldb (%)
Ratio (3:4)c
Method A
Method B
93
30
90:10
90:10
S
N
+
S
S
Me
1a
1
N
a
N
Me
Me
3a + 4a
Me
Method A
Method B
85
81
85:15
85:15
Me
S
Me
N
+
Me
1a
2
3
N
b
N
Me
Me
3b + 4b
Me
Method A
Method B
74
85
80:20
80:20
S
N
+
S
Me
1a
Me
N
c
N
Me
Me
Me
3c + 4c
(continued on next page)

3366
D. Alves et al. / Tetrahedron Letters 53 (2012) 3364–3368
Table 2 (continued)
Entry
Pyrrole
R1 (2 or 5)
Methoda
Product
Yieldb (%)
Ratio (3:4)c
MeO
Method A
Method B
84
80
85:15
85:15
OMe
+
S
S
OMe
N
S
S
Me
1a
4
N
d
N
Me
Me
3d + 4d
Cl
Method A
Method B
72
70
95:5
95:5
Cl
Cl
N
+
Me
1a
5
6
N
e
N
Me
Me
3e + 4e
Method A
Method B
65
58
100:0
100:0
S
N
+
S
S
Me
1a
N
F
N
Me
Me
3f + 4f
S
Method A
Method B
78
75
80:20
75:25
N
+
N
7
8
Me
1a
N
g
Me
Me
3g + 4g
10
S
Method A
Method B
Traces
Traces
—
—
+
N
10
h
S
S
S
S
S
10
N
Me
1a
N
Me
Me
3h + 4h
Method A
Method B
95
87
90:10
90:10
S
S
S
S
N
+
H
1b
9
10
11
12
N
H
a
N
H
3i + 4i
Me
Method A
Method B
76
72
80:20
85:15
Me
Me
N
+
H
1b
N
H
b
N
H
3j + 4j
Cl
Method A
Method B
72
74
93:7
90:10
Cl
Cl
N
+
H
1b
N
H
e
N
H
3k + 4k
Method A
Method B
82
77
100:0
95:5
N
+
Ph
1c
N
a
N
Ph
Ph
3l + 4l

D. Alves et al. / Tetrahedron Letters 53 (2012) 3364–3368
3367
Table 2 (continued)
Entry
Pyrrole
R1 (2 or 5)
Methoda
Product
Yieldb (%)
Ratio (3:4)c
Me
Method A
Method B
74
86
75:25
75:25
Me
+
S
S
Me
N
S
S
Ph
1c
13
N
b
N
Ph
Ph
3m + 4m
Cl
Method A
Method B
79
84
85:15
85:15
Cl
Cl
N
+
Ph
14
N
e
N
1c
Ph
Ph
3n + 4n
a
Method A: Reactions are performed in the presence of pyrroles 1a–c (0.5 mmol), disulfides 2a–h (0.25 mmol) and 3 mol % of CuI in DMSO (0.5 mL), at 110 °C for 20 h under
air atmosphere. Method B: Reactions are performed in the presence of pyrroles 1a–c (0.5 mmol), thiols 5a–h (0.5 mmol) and 5 mol % of CuI in DMSO (0.5 mL), at 110 °C for
20 h under N2 atmosphere.
b
Yields are given for isolated products.
Determined by GC/MS of the crude reaction mixture and confirmed after isolation of pure products.
c
yield (Table 1, entry 1). Fortunately, when the amount of catalyst
was reduced from 10–3 mol %, excellent yields of product 3a were
obtained (Table 1; entries 13 and 15). However, in the reaction
using 1 mol % of CuI a little decrease in the yield of product 3a
was observed (Table 1; entry 16).
In an optimized reaction, N-methylpyrrole 1a (0.5 mmol), di-
phenyl disulfide 2a (0.25 mmol) and CuI (3 mol %) were dissolved
in DMSO (0.5 mL) and the heterogeneous reaction mixture was
stirred for 20 h at 110 °C under atmospheric air (Method A). Using
this reaction conditions, 2-sulfenyl pyrrole 3a was obtained in 93%
yield with a little amount of 3-sulfenyl pyrrole 4a [Ratio 3/4a
(90:10)].
tries 9–14). Good results of yields and selectivity were achieved
reacting pyrroles 1b and 1c with diaryl disulfides 2a, 2b and 2e
or aryl thiols 5a, 5b and 5e and to our satisfaction the reaction of
N-phenyl pyrrole 1c with diphenyl disulfide 2a produce exclu-
sively the product 3l in 82% yield (Table 2; entry 12; Method A).
Analyzing these results, we conclude that both methods provide
a general approach to prepare more complex 2-sulfenyl pyrroles
with good yields and selectivity.
In summary, a simple and selective methodology to synthesize
2-sulfenyl pyrroles was described by copper-catalyzed coupling of
organic disulfides or thiols with pyrroles. Using two independent
methodologies, a range of 2-sulfenyl pyrroles were obtained in
good to excellent yields and with high selectivity using catalytic
amount of CuI and without use of any ligand or additive.
The possibility of realize these reactions using organic thiols
was also studied. Thus, a mixture of N-methylpyrrole 1a, benzene-
thiol 5a and CuI (3 mol %) was reacted in DMSO at 110 °C under
atmospheric air for 20 h and the desired product 3a was obtained
in 40%. When the same reaction was performed under nitrogen
atmosphere, sulfenylation product 3a was achieved in 56%.
Different solvents and copper catalysts have been screened and
the best result was obtained when we performed the reaction at
110 °C for 20 h using DMSO as a solvent and CuI (5 mol %) as a cat-
alyst under nitrogen atmosphere (Method B). Using this reaction
conditions the desired product 3a was obtained in 91% yield with
a little amount of compound 4a [Ratio 3a/4a (90:10)].
To extend the scope of our methodology, the possibility of
performing the reaction with other pyrroles 1a–c with disulfides
2a–h or thiols 5a–h was investigated under our two developed
methodologies (Table 2).13 In most cases, the reaction proceeded
smoothly to give the 2-sulfenyl pyrroles 3a–n in good to excellent
yields using both methods. The reactions of N-methyl pyrrole 1a
with a range of substituted disulfides 2a–g gave the corresponding
2-sulfenyl pyrroles 3a–g in high yields and selectivity (Table 2;
entries 1–7; Method A). When the reactions were performed using
a range of thiols 5a–g, the yields and selectivity of obtained 2-sul-
fenyl pyrroles remained the same (Table 2; entries 1–7; Method B).
Gratifyingly, reactions of pyrrole 1a with b-naphthyl disulfide 2f or
b-naphthyl mercaptan 5f furnished the desired product 3f exclu-
sively in good yield (Table 2; entry 6; Methods A and B). However,
using both methods, no product of sulfenylation of N-methyl pyr-
role 1a was formed using dodecyl disulfide 2h or dodecanethiol 5h
(Table 2; entry 8). These reactions were also performed using
N-substituted pyrroles 1b and 1c using both methods (Table 2; en-
Acknowledgments
We are grateful to CAPES, CNPq and FAPERGS for the financial
support.
References and notes
1. (a) Gangjee, A.; Zeng, Y.; Talreja, T.; McGuire, J. J.; Kisliuk, R. L.; Queener, S. F. J.
Med. Chem. 2007, 50, 3046; (b) Hu, W.; Guo, Z.; Chu, F.; Bai, A.; Yi, X.; Cheng, G.;
Li, J. Bioorg. Med. Chem. Lett. 2003, 13, 1153; (c) Caboni, P.; Sammelson, R. E.;
Casida, J. E. J. Agric. Food Chem. 2003, 24, 7055; (d) Wang, Y.; Chackalamannil,
S.; Hu, Z.; Clader, J. W.; Greenlee, W.; Billard, W.; Binch, H. I. I. I.; Crosby, G.;
Ruperto, V.; Duffy, R. A.; McQuade, R.; Lachowicz, J. Bioorg. Med. Chem. Lett.
2000, 10, 2247; (e) Nielson, S. F.; Nielson, E. O.; Olsen, G. M.; Liljefors, T.; Peters,
D. J. Med. Chem. 2000, 43, 2217; (f) De Martino, G.; Edler, M. C.; La Regina, G.;
Cosuccia, A.; Barbera, M. C.; Barrow, D.; Nicholson, R. I.; Chiosis, G.; Brancale,
A.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2006, 49, 947.
2. (a) Metzner, P.; Thuillier, A. In Sulfur Reagents in Organic Synthesis; Katritzky, A.
R., MethCohn, O., Rees, C. W., Eds.; Academic Press: San Diego, 1994; (b) Kondo,
T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205; (c) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400.
3. (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596; (b) Ananikov, V.
P.; Zalesskiy, S. S.; Beletskaya, I. P. Curr. Org. Synth. 2011, 8, 2.
4. Some Examples: (a) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett.
2002, 4, 2803; (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517; (c)
Bates, C. G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D. Org. Lett. 2004, 6,
5005; (d) Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X. Synlett 2004, 1254;
(e) Fukuzawa, S.; Shimizu, E.; Atsuumi, Y.; Haga, M.; Ogata, K. Tetrahedron Lett.
2009, 50, 2374; (f) Zhu, D.; Xu, L.; Wu, F.; Wan, B. S. Tetrahedron Lett. 2006, 47,
5781; (g) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org. Chem. 2008,
640; (h) Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. J. Org.
Chem. 2008, 73, 5625; (i) Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.;
Mandal, S.; Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org. Chem. 1971, 2009, 74.

3368
D. Alves et al. / Tetrahedron Letters 53 (2012) 3364–3368
5. Li, Z.; Hong, J.; Zhou, X. Tetrahedron 2011, 67, 3690.
12. (a) Alves, D.; Santos, C. G.; Paixão, M. W.; Soares, L. C.; Souza, D.; Rodrigues, O.
E. D.; Braga, A. L. Tetrahedron Lett. 2009, 50, 6635; (b) Alves, D.; Pena, J. M.;
Vieira, A. S.; Botteselle, G. V.; Guadagnin, R. C.; Stefani, H. A. J. Braz. Chem. Soc.
2009, 20, 988; (c) Gonçalves, L. C.; Fiss, G. F.; Perin, G.; Alves, D.; Jacob, R. G.;
Lenardão, E. J. Tetrahedron Lett. 2010, 51, 6772; (d) Ricordi, V. G.; Freitas, C. S.;
Perin, G.; Lenardão, E. J.; Jacob, R. G.; Savegnago, L.; Alves, D. Green Chem. 2012,
1030, 14.
6. (a)Pyrroles; Taylor, E. C., Jones, R. A., Eds.; John Wiley & Sons: New York, 1990;
(b) Ketcha, D. M. In Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist,
T. L., Eds.; Pergamon Press: New York, 2001; Vol. 13, (c)The Chemistry of
Pyrroles; Jones, A. R., Bean, G. P., Eds.; Academic Press: London, 1977; (d)
Sternberg, E. D.; Dolphin, D.; Brückner, C. Tetrahedron 1998, 54, 4151; (e)
Melvin, M. S.; Tomlinson, J. T.; Saluta, G. R.; Kucera, G. L.; Lindquist, N.;
Manderville, R. A. J. Am. Chem. Soc. 2000, 122, 6333; (f) Fürstner, A. Angew.
Chem., Int. Ed. 2003, 42, 3582; (g) O’Hagen, D. Nat. Prod. Rep. 2000, 17, 435; (h)
Sato, A.; McNulty, L.; Cox, K.; Kim, S.; Scott, A.; Daniell, K.; Summerville, K.;
Price, C.; Hudson, S.; Kiakos, K.; Hartley, J. A.; Asao, T.; Lee, M. J. Med. Chem.
2005, 48, 3903; (i) D’Alessio, R.; Margiotti, A.; Carlini, O.; Colotta, F.; Ferrari, M.;
Gnocchi, P.; Isetta, A. M.; Mongelli, N.; Motta, P.; Rossi, A.; Rossi, M.; Tibolla, M.;
Vanotti, E. J. Med. Chem. 2000, 43, 2557; (j) Campiani, G.; Nacci, V.; Bechelli, S.;
Ciani, S. M.; Garofalo, A.; Fiorini, I.; Wikström, H.; de Boer, P.; Liao, Y.; Tepper, P.
G.; Cagnotto, A.; Mennini, T. J. Med. Chem. 1998, 41, 3763.
7. (a) Paine, J. B., III In The Porphyrins; Dolphin, D., Ed.; Academic Press: London,
1978; Vol. I,. Chapter 4 (b) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.;
Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411; (c) Jolicoeur,
B.; Chapman, E. E.; Thompson, A.; Lubell, W. D. Tetrahedron 2006, 62, 11531.
8. (a) Garabatos-Perera, J. R.; Rotstein, B. H.; Thompson, A. J. Org. Chem. 2007, 72,
7382; (b) Thamyongkit, P.; Bhise, A. D.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem.
2006, 71, 903.
13. General procedure for the copper-catalyzed directly synthesis of sulfenyl pyrroles:
Method A: To
a round-bottomed flask containing organic disulfide
(0.25 mmol), appropriate pyrrole (0.5 mmol), CuI (3 mol %), was added DMSO
(0.5 mL). The reaction mixture was allowed to stir at 110 °C for 20 h under
atmospheric air. Method B: To a round-bottomed flask containing organic thiol
(0.5 mmol), appropriate pyrrole (0.5 mmol), CuI (5 mol %), was added DMSO
(0.5 mL). The reaction mixture was allowed to stir at 110 °C under a nitrogen
atmosphere for 20 h.
After stirring the reactions under these two methods, independently, the
solutions were cooled to room temperature, diluted with ethyl acetate (10 mL),
and washed with water (3 Â 10 mL). The organic phases were separated, dried
over MgSO4, and concentrated under vacuum. The residues were purified by
flash chromatography on silica gel using ethyl acetate/hexane as the eluent.
Selected spectral and analytical data for 1-phenyl-2-(phenylthio)-1H-pyrrole
3l: Yield: 0.128 g (82%). 1H NMR (CDCl3, 300 MHz): d 7.32–7.27 (m, 3H), 7.22–
19 (m, 2H), 7.16–7.12 (m, 2H), 7.08–7.02 (m, 2H), 6.94–6.92 (m, 2H), 6.73 (dd,
J = 3.6, 1.7 Hz, 1H), 6.38 (dd, J = 3.6, 3.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d
139.48, 139.36, 128.72, 128.58, 127.39, 126.47, 126.34, 126.09, 125.22, 121.37,
118.49, 109.57. MS: m/z (rel. int.) 251 (100), 218 (16), 173 (12), 77 (30), 51
(18).
9. Thompson, A.; Butler, R. J.; Grundy, M. N.; Laltoo, A. B. E.; Robertson, K. N.;
Cameron, T. S. J. Org. Chem. 2005, 70, 3753.
10. Antipin, R. L.; Chernysheva, A. N.; Beloglazkina, E. K.; Zyk, N. V. Chem.
Heterocycl. Compd. 2010, 1071, 46.
11. Gillis, H. M.; Greene, L.; Thompson, A. Synlett 2009, 112.