Preparation of sulfenyl pyrroles

Article abstract of DOI:10.1055/s-0028-1087486

Sulfenyl groups are attracting interest as masking/protecting groups for pyrroles. A facile one-step synthesis of sulfenyl pyrroles, involving the reaction of pyrroles with N-(aryl- and alkylthio)phthalimides in the presence of MgBr₂, is reported and the methodology extends to include sulfinyl pyrroles. The one-step procedure gives good yields and is more efficient and practical than current multistep protocols to sulfenyl pyrroles that involve thiocyanato pyrrolic intermediates. A convenient procedure for the synthesis of N-(aryl- and alkylthio)phthalimides is also reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087486

112
LETTER
Preparation of Sulfenyl Pyrroles
Preparation of
Sul.
Ms
artin Gillis, Lana Greene, Alison Thompson*
Department of Chemistry, Dalhousie University, Halifax, NS, B3H 4J3, Canada
Fax +1(902)4941310; E-mail: Alison.Thompson@dal.ca
Received 2 February 2008
NaSCN
RMgBr
Abstract: Sulfenyl groups are attracting interest as masking/pro-
SCN
SR
N
tecting groups for pyrroles. A facile one-step synthesis of sulfenyl
pyrroles, involving the reaction of pyrroles with N-(aryl- and alkyl-
thio)phthalimides in the presence of MgBr2, is reported and the
methodology extends to include sulfinyl pyrroles. The one-step pro-
cedure gives good yields and is more efficient and practical than
current multistep protocols to sulfenyl pyrroles that involve thio-
cyanato pyrrolic intermediates. A convenient procedure for the syn-
thesis of N-(aryl- and alkylthio)phthalimides is also reported.
N
N
H
H
H
Scheme 1 2-Sulfenyl pyrroles via 2-thiocyanato pyrrole
3-thiocyanato pyrrole. These impracticalities prompted
our search for an improved, generalized route to a variety
of sulfenyl pyrroles.
Key words: pyrrole, thiophthalimide, magnesium bromide, sulfe-
3-Sulfenyl indoles may be prepared24 by reacting indoles
with thiols, in the presence of Selectfluor,™ which pre-
sumably acts to fluorinate the thiol and thus generate an
electrophilic sulfenylating agent. Furthermore, N-(phe-
nylthio)phthalimide,25–27 which has been used with eno-
lates, enamines, and oximes,28,29 has recently been utilized
in the preparation of 3-sulfenyl indoles.30 In this reaction,
catalytic amounts of MgBr2 (or alternative halide sources)
activate the reagent to generate the corresponding sulfenyl
bromide in situ, a process driven by concomitant loss of
the phthalimide anion. Thus, N-(phenylthio)phthalimide
is a stable and essentially odorless sulfenylating agent that
is activated, only upon demand, through halide catalysis.
nylation, sulfinylation
The preparation and manipulation of functionalized pyr-
roles is of increasing importance,1–6 with electronic, bio-
logical, and optical properties leading to their increasing
incorporation into new materials and improved pharma-
ceuticals.1,7–10 The synthesis of functionalized pyrroles is
challenging9,11,12 and traditionally involves high tempera-
tures, excess reagents, and harsh conditions. Successful
synthetic pyrrole chemistry is often achieved by the utili-
zation of 2-carboxylate pyrroles, whereby the electron-
withdrawing carboxylate group serves to temper the nu-
cleophility of the pyrrolic core.11 Recently, the sulfenyl
group has been shown to effectively mask the 2-position
of pyrroles,13,14 and the utility of 2-sulfenyl pyrroles in
acylation reactions, nitration reactions, and condensation
reactions with various aldehydes has highlighted the
sulfenyl group as a valuable pyrrole masking/protecting
group that can be removed using Raney nickel.14
Given the practical difficulties that we encountered using
2-thiocyanato pyrrole, we sought to investigate the utility
of phthalimide-based sulfenylating reagents for the prep-
aration of 2-sulfenyl pyrroles. We thus prepared a variety
of N-(aryl- and alkylthio)phthalimides and subsequently
reacted these sulfenylating reagents with several a- and b-
unsubstituted pyrroles to accordingly prepare a range of 2-
and 3-sulfenyl pyrroles.
2-Sulfenyl pyrroles may be prepared by reaction of pyr-
role with sulfenyl chlorides,15 although such sulfenylating
reagents are not ideal due to their limited stability. Alter-
natively, the reaction of pyrrole with thiocyanate salts
gives 2-thiocyanato pyrrole16–21 which may be reacted
with various Grignard reagents14,22 to give the correspond-
ing 2-sulfenyl pyrroles (Scheme 1). We prepared 2-thio-
cyanato pyrrole using an iodine-catalyzed reaction of
sodium thiocyanate and pyrrole in methanol.21 The result-
ing 2-thiocyanato pyrrole decomposed and it was neces-
sary that reactions using Grignard reagents were effected
immediately,23 with no purification of the thiocyanate.
Furthermore, even traces of 2-thiocyanato pyrrole passed
through multiple layers of latex gloves and caused stains
and discomfort of the skin,13 as noted previously18 for
N-(Phenylthio)phthalimide (1a) is commercially avail-
able and may also be readily prepared by the reaction of
phenylsulfenyl chloride (prepared in situ from thiophenol
and chlorine gas) and phthalimide,25,27 whereby varying
the thiol allows access to other N-(aryl- and alkyl-
thio)phthalimides. An alternative route to sulfenyl chlo-
rides involves the reaction of thiols or disulfides with sul-
furyl chloride.31,32 This approach permits the
stoichiometry of the reaction to be easily controlled, with-
out the need for time-consuming titrations that are re-
quired to ensure the desired stoichiometry when using
thiols and chlorine gas.25
Our initial efforts focused on the synthesis of 1a following
a similar procedure established using chlorine gas.27 Phe-
nylsulfenyl chloride was thus prepared by the reaction of
thiophenol with sulfuryl chloride in dichloromethane at 0
°C for 10 minutes (Scheme 2). The resulting solution was
then added dropwise to a solution of phthalimide and tri-
SYNLETT 2009, No. 1, pp 0112–0116
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087486; Art ID: S01408ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of Sulfenyl Pyrroles
113
O
For N-(arylthio)phthalimides 1a and 1f, sulfenylation of
electron-deficient pyrroles (2 and 3) and electron-rich
pyrroles (4 and 5) proceeded smoothly to give 2-arylsulfe-
nyl pyrroles 2a–5a and 2f–5f, respectively, in excellent
yields (Table 1, entries 1–4 and 15–18). Solvent and tem-
perature optimizations were conducted for the reaction of
1a with pyrroles 2 and 3. The use of DMAc30 gave higher
yields over DMF, and the optimal temperature for the re-
action was 90 °C with full conversion in one hour, com-
pared with 50% conversion in one hour at 50 °C. For the
reactions of 1a and 1f with pyrrole 5, the 2,5-bis-sulfeny-
lated 5a2 and 5f2 (ca. 10% isolated yield for each; see
Supporting Information for details) were also
observed and decreasing the stoichiometry of N-
(phenylthio)phthalimide 1a in the reaction with 5 did not
improve the yield of 5a (Table 1, entry 4).
phthalimide
Et3N
cat. Et3N
R1SH + SO2Cl2
R1SCl
N
SR1
0 °C to r.t.
0 °C to r.t.
O
1a, R1 = Ph, 83%
1b, R1 = Bn, 30%
1c, R1 = Et, 63%
1d, R1 = decyl, 70%
1e, R1 = t-Bu, 22%
1f, R1 = 4-MeOC6H4, 70%
Scheme 2 Synthesis of N-(aryl- and alkylthio)phthalimides
ethylamine in dichloromethane to effect an exothermic re-
action, and a mixture of products resulted. Repeating the
reaction at 0 °C gave 1a in only 22% yield, as compared
to 69% yield reported using chlorine gas.27 Similar results
were obtained when attempting to prepare N-(benzyl-
thio)phthalimide (1b)25 and N-(ethylthio)phthalimide
(1c).25 The problem seemed to lie in the synthesis of the
sulfenyl chloride and, as noted by others,31,32 the addition
of catalytic amounts of triethylamine improved the pro-
duction of phenylsulfenyl chloride and made a significant
overall improvement to provide 1a–d in good yields
(Scheme 2). However, both 1e25 and 1f were inaccessible
via this procedure but changing the solvents to hexanes
for the preparation of the sulfenyl chloride and DMF in
the second step provided 1e and 1f in acceptable yields.
Equally important, in order to facilitate successful purifi-
cations using recrystallization, unreacted phthalimide was
easily removed by treatment of a dichloromethane solu-
tion of the crude material with 1 M NaOH. While these
yields are somewhat lower than those involving chlorine
gas, this procedure offers a rapid and convenient access to
a variety of N-(aryl- and alkylthio)phthalimides in reason-
able quantities (e.g., 50 mmol) and acceptable yields with
minimal effort. Furthermore, unlike the sulfenyl chlo-
rides, all examples were crystalline and displayed no sign
of decomposition after more than six months of storage in
a sealed bottle (in air) at room temperature.
For N-(alkylthio)phthalimides 1b–e, sulfenylation of
electron-deficient pyrroles (2 and 3) and electron-rich
pyrroles (4 and 5) proceeded, but with noticeable differ-
ences across the series. For example, reaction of 4 with
1b–d occurred in excellent yield (Table 1, entries 7, 11,
and 14), but no reaction occurred with the more steric de-
manding 1e. Furthermore, 1b reacted smoothly with pyr-
roles 4 and 5 (Table 1, entries 7 and 8), 1c with 3 and 4
(Table 1, entries 9 and 10), and 1d with 3 and 4 (Table 1,
entries 13 and 14); however, reactions of 1b with 2 or 3,
and 1c and 1d with 2 proceeded with incomplete conver-
sions (Table 1, entries 5, 6, 9, and 12). Even when using a
procedure developed for sluggish reactions and/or utiliz-
ing longer reaction times,30 incomplete conversions were
observed. In addition, reactions of 1c and 1d with 5 gave
a mixture of products sulfenylated at the 2-, 3-, and/or 5-
positions (see Supporting Information for details). In or-
der to investigate the functional group tolerability of this
approach, pyrroles 6–9 were reacted with N-(phenyl-
thio)phthalimide (1a). Pyrroles 6, 7, and 9 reacted
smoothly to provide the corresponding sulfenylated prod-
ucts in good to excellent isolated yields (Table 1, entries
19, 20, and 22); however, pyrrole 8 (Table 1, entry 21)
provided only 36% yield of 3-sulfenylated pyrrole 8a.
With a range of N-(aryl- and alkylthio)phthalimides in
hand, we investigated the sulfenylation of benzyl 3,5-di-
methyl-pyrrole-2-carboxylate (2), ethyl 3,5-dimethyl-pyr-
role-2-carboxylate (3), kryptopyrrole (4), pyrrole (5),
ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate (6), diketo-
pyrrole (7), 1H-pyrrole-2-carbaldehyde (8), and (R)-
BINOL ester pyrrole (9). The earlier method described for
the isolation of 3-sulfenyl indoles,30 prepared using 1a, in-
volved precipitation upon the addition of water. We
adopted a basic aqueous workup procedure whereby the
reaction mixture was diluted with ethyl acetate and
washed several times with 1 M NaOH. This treatment
gave improved yields of the sulfenylated pyrrole over pre-
cipitation, and allowed for the removal of the unreacted N-
(aryl- and alkylthio)phthalimide, via hydrolysis, permit-
ting chromatographic purification.
Compared to the preparation of sulfenyl pyrroles via de-
rivatization of thiocyanato pyrroles with Grignard re-
agents, the method reported here gives clean products,
with facile workup and isolation procedures, that would
otherwise be difficult to attain. In particular, in our hands
5a prepared using 2-thiocyanato pyrrole and phenylmag-
nesium bromide is unstable in air, even after extensive
chromatographic purification, and must be either used im-
mediately or N-protected with an electron-withdrawing
group.23 In contrast, 5a prepared via the phthalimide route
described herein is bench-stable, with no sign of decom-
position after more than three months. The reaction of
pyrrole with N-(phenylthio)phthalimide was performed
on a large scale to produce 6.3 mmol of 5a in 62% isolated
yield. With direct access to large quantities of sulfenyl
pyrroles, this method should find several applications in
other synthetic endeavors.
Synlett 2009, No. 1, 112–116 © Thieme Stuttgart · New York

114
H. M. Gillis et al.
LETTER
Table 1 Sulfenylation of Pyrroles
R3
R4
R1S
R3
R4
CO2R
R2
CO2R
R2
SR1
N
H
N
N
H
N
H
H
2a–f
3a–f
4a–f
5a–f
2 R = Bn
3 R = Et
4 R2 = R4 = Me, R3 = Et
5 R2 = R3 = R4 = H
R
O
O
O
O
O
NH
NH
N
SR1
R6
R7
R6
R7
R
9 R = H
O
9a R = SR1
R5
R5
SR1
N
N
MgBr2
DMAc
90 °C
1 h
H
H
6a R6 = CO2Et, R5 = R7 = Me
6 R6 = CO2Et, R5 = R7 = Me
7a R6 = C(O)(CH2)4C(O)Me, R5 = R7 = Mee
8 R5 = CHO, R6 = SPh, R7 = SR1 = H
7 R6 = C(O)(CH2)4C(O)Me, R5 = R7 = Me
8 R5 = CHO, R6 = R7 = H
Entrya
1
Pyrrole
R1
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Et
Product
2a
Yield (%)
>95
>95
>95
62b,c
41d,e
71d,f
89
2
3
4
5
2
3
4
5
2
3
4
2
3
4
3
3
4
5
6
7
8
2
3a
3
4a
5a14,22
4
5
2b
6
3b
7
4b
8
5b
40g
9
2c
56h,i
10
11
12
13
14
15
16
17
18
19
20
21
Et
3c
93
Et
4c
90
decyl
2d
3d
4d
2f
54d,j,k
>95l
95
decyl
decyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
89
3f
>95
>95
62
4f
5f
6a
7a
8a
88
Ph
>95
36
Ph
22
9
Ph
9a
67
a Unless otherwise noted, all reactions were conducted using 0.44 mmol of the pyrrole with 1.0 equiv of the thiophthalimide reagent and 0.01
equiv of MgBr2.
b Conditions: 10 mmol of pyrrole.
c The amounts of 0.75 or 1.0 equiv of thiophthalimide reagent gave similar results.
d Conditions: 1.6 equiv of thiophthalimide, 0.7 equiv of Et3N and 0.5 equiv of MgBr2; reaction stirred for 3 d.
e Conversion: 43%.
f Conversion: 73%.
g Isolated as a 2.2:1 inseparable mixture of 5b (40%) and 2,5-bis-sulfenylated material 5b2 (18%).
h Conversion: 60%.
i Isolated as a 1.5:1 inseparable mixture of 2c (56%) and starting material 2 (37%).
j Conversion: 57%.
k Reaction stirred for 6 h.
l Reaction stirred for 3 h.
Synlett 2009, No. 1, 112–116 © Thieme Stuttgart · New York

LETTER
Preparation of Sulfenyl Pyrroles
115
dried to give crude product that was purified by recrystallization.
For samples with appreciable amounts of phthalimide present, the
crude was treated as previously described (vide supra).
This approach to pyrroles substituted with sulfur-contain-
ing moieties was extended to include the preparation of
sulfoxide-substituted pyrroles (Scheme 3). For example,
reaction of N-(phenylsulfinyl)phthalimide27,33 with pyr-
role 3 in the presence of MgBr2 provided 10 in 25% unop-
timized isolated yield (70% yield based on recovered
starting material).
2-(4-Methoxyphenyl)isoindoline-1,3-dione (1f)
Recrystallization from 75% EtOAc in hexanes gave the title com-
pound as a yellow solid (7.4 g, 70%); mp 203–204 °C (75% EtOAc
in hexanes). 1H NMR (500 MHz, CDCl3): d = 7.87 (2 H, dd, J = 3.0,
5.5 Hz), 7.76 (2 H, d, J = 9.0 Hz), 7.75–7.72 (2 H, dd, J = 3.0, 5.5
Hz), 6.84 (2 H, d, J = 9.0 Hz), 3.78 (3 H, s). 13C NMR (125 MHz,
CDCl3): d = 168.0 (2 × s), 161.6 (s), 136.8 (2 × d), 134.7 (2 × d),
132.2 (2 × s), 125.7 (s), 124.0 (2 × d), 114.9 (2 × d), 55.6 (q).
HRMS (ESI+): m/z calcd for C15H11NO3S: 285.0460 {308.0357 for
[M + Na]}; found: 308.0352.
O
O
Ph
S
MgBr2
DMAc
O
+
N
S
CO2Et
CO2Et
90 °C
3 h
N
H
N
H
Ph
Sulfenylated Pyrroles 2a,c,f, 3a,c,d,f, 4a–d,f,
5a,a2,b,b2,c2,c2¢,c3,d,d2,d2¢,d3,f,f2, 6a, 7a, 9a, 10
O
3
10
A stirred suspension of the pyrrole (0.44 mmol), thiophthalimide
sulfenylating reagent (1.0 equiv), and MgBr2 (0.01 equiv) in de-
gassed N,N-dimethylacetamide (1 mL) was heated at 90 °C for 1 h.
After cooling to r.t., the solution was diluted with EtOAc, extracted
with 1 M NaOH (3×) before being dried over Na2SO4, and then con-
centrated to give crude product that was purified using flash column
chromatography (FCC).
Scheme 3 Sulfinylation of 3
In summary, N-(aryl- and alkylthio)phthalimides may be
used for the sulfenylation and sulfinylation of pyrroles.
Furthermore, we have optimized the workup procedure
for the sulfenylation reaction such that the current route to
sulfenyl pyrroles is amenable to scale-up and gives prod-
ucts that are not susceptible to degradation, unlike the
route involving thiocyanato pyrrole.
3-Ethyl-2,4-dimethyl-5-(phenylthio)-1H-pyrrole (4a)
Flash column chromatography (5% Et2O in hexanes) gave the title
1
compound as a purple solid (99 mg, >95%). H NMR (500 MHz,
CDCl3): d = 7.65 (1 H, br s), 7.21–7.17 (2 H, m), 7.08–7.05 (1 H,
m), 6.96–6.95 (2 H, m), 2.43 (2 H, q, J = 7.0 Hz), 2.19 (3 H, s), 2.07
(3 H, s), 1.09 (3 H, t, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3): d =
140.2 (s), 129.1 (2 × d), 127.1 (s), 126.9 (s), 125.6 (2 × d), 125.0
(d), 122.7 (s), 109.1 (s), 18.2 (t), 15.7 (q), 11.6 (q), 10.1 (q). HRMS
(ESI–): m/z calcd for C14H17NS: 231.1082 {230.1003 for [M – H]};
found: 230.1009.
General Procedures and Representative Data
Sulfenylating Reagents 1a–d
Sulfuryl chloride (1.0 equiv; ca. 5 M in CH2Cl2) was added drop-
wise via a dropping funnel to a solution of thiol (0.05 mol; ca. 1 M
in CH2Cl2) and Et3N (0.1 mL) at 0 °C. After stirring for 15 min, the
mixture was warmed to r.t. for 30 min and then cooled to 0 °C. The
resulting solution was transferred dropwise via cannula to a solution
of phthalimide (1.0 equiv; ca. 1 M in CH2Cl2) and Et3N (1.3 equiv)
at 0 °C, and the mixture was then warmed to r.t. over 1 h. The solu-
tion was diluted with H2O, extracted with CH2Cl2 (3×) before being
dried over Na2SO4, and then concentrated to give crude product that
was purified using recrystallization. For samples with appreciable
amounts of phthalimide present, the crude was dissolved with
CH2Cl2, diluted with 1 M NaOH, extracted with CH2Cl2 (3×) before
being dried over Na2SO4, then concentrated before being purified
by recrystallization.
Sulfenylated Pyrroles 2b,d, 3b, 8a
A stirred suspension of the pyrrole (0.44 mmol), thiophthalimide
sulfenylating reagent (1.6 equiv), Et3N (0.7 equiv), and MgBr2 (0.5
equiv) in degassed N,N-dimethylacetamide (1 mL) was heated at 90
°C for 1 d. After cooling to r.t., the solution was diluted with EtOAc,
extracted with 1 M NaOH (3×) before being dried over Na2SO4, and
then concentrated to give crude product that was purified using FCC
or preparative thin-layer chromatography (PTLC).
Ethyl 4-(benzylthio)-3,5-dimethyl-1H-pyrrole-2-carboxylate
(3b)
2-(Phenylthio)isoindoline-1,3-dione (1a)25–27
Reaction stirred for 3 d; FCC (70–100% CH2Cl2 in hexanes) gave
1
the title compound as a beige solid (90 mg, 71%). H NMR (500
Recrystallization from EtOH gave the title compound as a yellow
1
MHz, CDCl3): d = 8.76 (1 H, br s), 7.22–7.16 (3 H, m), 7.00–6.96
(2 H, m), 4.30 (2 H, q, J = 7.0 Hz), 3.60 (2 H, s), 2.28 (3 H, s), 1.86
(3 H, s), 1.36 (3 H, t, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3): d =
161.7 (s), 139.0 (s), 138.4 (s), 132.6 (s), 129.2 (2 × d), 128.4 (2 × d),
126.9 (d), 117.9 (s), 111.8 (s), 60.2 (t), 41.0 (t), 14.8 (q), 11.6 (q),
11.3 (q). HRMS (ESI+): m/z calcd for C16H19NO2S: 289.1136
{312.1034 for [M + Na]}; found: 312.1029.
solid (9.6 g, 83%); mp 163–164 °C (EtOH). H NMR (500 MHz,
CDCl3): d = 7.93 (2 H, dd, J = 3.0, 5.5 Hz), 7.78 (2 H, dd, J = 3.0,
5.5 Hz), 7.62–7.58 (2 H, m), 7.33–7.25 (3 H, m). 13C NMR (125
MHz, CDCl3): d = 167.9 (2 × s), 135.3 (s), 134.9 (2 × d), 132.2
(2 × s), 131.2 (2 × d), 129.5 (3 × d), 124.3 (2 × d). HRMS (ESI+):
m/z calcd for C14H9NO2S: 255.0354 {278.0252 for [M + Na]};
found: 278.0246.
Sulfenylating Reagents 1e and 1f
Supporting Information for this article is available online at
Sulfuryl chloride (1.0 equiv; ca. 5 M in hexanes) was added drop-
wise via a dropping funnel to a solution of thiol (0.05 mol; ca. 1 M
in hexanes) and Et3N (0.1 mL) at 0 °C. After stirring for 15 min, the
mixture was warmed to r.t. for 30 min and then cooled to 0 °C. The
resulting solution was transferred dropwise via cannula to a solution
of phthalimide (1.0 equiv; ca. 1 M in DMF) and Et3N (1.3 equiv),
and stirring was continued at r.t. for 1 h. The solution was trans-
ferred to a beaker containing ice-cold water, the resulting suspen-
sion was filtered, and then washed with ice-cold water before being
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the Natural Sciences and Engineering
Research Council of Canada (NSERC) and AstraZeneca. The au-
thors thank James Cai for conducting preliminary experiments and
Sarah Bennett for supplying pyrroles 6 and 7.
Synlett 2009, No. 1, 112–116 © Thieme Stuttgart · New York

116
H. M. Gillis et al.
LETTER
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