Regioselective synthesis of mixed indole 2,3-bis(sulfides). A study of the mechanism of the second sulfenylation of indole

Article abstract of DOI:10.1021/jo951420n

Sulfenylation of indole using sulfenyl chlorides leads to the initial formation of a 3-indolyl sulfide, while excess reagent introduces a second sulfide at the 2-position of the ring. The mechanism of this second sulfenylation has not, to date, been rigor

Full text of DOI:10.1021/jo951420n

J . Org. Chem. 1996, 61, 1573-1577
1573
Regioselective Syn th esis of Mixed In d ole 2,3-Bis(su lfid es). A
Stu d y of th e Mech a n ism of th e Secon d Su lfen yla tion of In d ole
Pierre Hamel* and Patrice Pre´ville†
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval,
Que´bec, H9R 4P8 Canada
Received August 1, 1995X
Sulfenylation of indole using sulfenyl chlorides leads to the initial formation of a 3-indolyl sulfide,
while excess reagent introduces a second sulfide at the 2-position of the ring. The mechanism of
this second sulfenylation has not, to date, been rigorously elucidated. The development of the first,
regioselective synthesis of mixed indole 2,3-bis(sulfides) has allowed the study of the sulfenylation
of 3-indolyl sulfides using a different sulfenyl chloride. Our results afford evidence that the reaction
proceeds via an intermediate 3,3-disulfenylated indolenine species, with subsequent migration of
one of the sulfide groups to the 2-position.
Introduction of a sulfide group at the 3-position of
SR
SR
SR
indole can be accomplished in several ways. For in-
stance, indole can react with KI3, followed by thiourea,
with subsequent basic hydrolysis to generate in situ the
3-indolyl thiolate which may be alkylated.1 Alternatively,
3-indolyl sulfides may be obtained by sulfenylation, either
by reaction of indole anion with a disulfide2 or by the
action of a sulfenyl chloride on indole itself,3 this last
procedure being applicable also to N-substituted indoles.
The first two methods lead to exclusive introduction of
the sulfide into the 3-position, and no further sulfenyla-
tion occurs in the presence of excess reagents. However,
when sulfenyl chlorides are used, if the 2-position is
unsubstituted, excess reagent leads to a facile second
sulfenylation, affording indole 2,3-bis(sulfides).
(eq 1)
+
N
H
RS Cl
N
H
H
SR
SR
N
H
SR
+
S
R
N
H
H
The mechanism for the introduction of the second
sulfide group has, to date, not been rigorously elucidated.
Although it is possible to draw a mechanism which leads
to direct substitution at the 2-position (eq 1), a more
plausible pathway was proposed by Ottenheijm4 (eq 2),
where the second sulfenylation initially occurs at the
3-position, affording an intermediate 3,3-indolenine bis-
(sulfide). Since the presence of a sulfide at the 3-position
of the indole would not be expected to deactivate that
position, it is reasonable, barring steric factors, to propose
a second attack at that most nucleophilic position.
Migration of one of the sulfides to the 2-position promoted
by the positive charge on the indolenium cation is
proposed to occur via an episulfonium species.
In a very extensive and elegant series of experiments,
A. H. J ackson and co-workers5 provided convincing
evidence that alkylation of Grignard derivatives of 3-alky-
lindoles occurs by initial formation of 3,3-disubstituted
indolenines, followed by rearrangement to 2,3-dialkylin-
doles, and that this migration occurs in an intramolecular
fashion. In this paper, we supply evidence that the
sulfenylation of 3-indolyl sulfides also occurs predomi-
nantly, possibly completely, via a similar initial substitu-
tion at the 3-position, with subsequent migration.
RS Cl
SR
SR
SR
(eq 2)
+
N
N
H
H
Ma ter ia ls a n d Meth od s
In the process outlined in eq 2, the second sulfenylation
leads to a 3,3-bis(sulfide) in which the two groups are
identical so that migration of either one leads to the same
2,3-bis(sulfide). One apparently simple and obvious way
to resolve the mechanistic dilemma of direct vs indirect
introduction of the sulfide group into the 2-position would
be to perform the second sulfenylation of a 3-indolyl
sulfide using a different sulfenyl chloride. Thus, if direct
substitution were to occur as in eq 1, the second sulfide
should be introduced at the 2-position, resulting in a
single mixed bis(sulfide), whereas initial reaction at the
3-position would most likely lead to a mixture of two
mixed bis(sulfides), the composition of which would be
dictated by the relative propensities for migration of the
two sulfide moieties. This apparently simple concept
suffered from a major drawback: although we were
confident that the two isomers could be separated and
quantified, there remained the problem of structural
assignment, since there exist no examples of mixed indole
2,3-bis(sulfides) in the chemical literature to date.
The ideal solution was to develop a method to obtain
authentic samples of these mixed bis(sulfides) through
selective synthesis which would allow unambiguous
assignment of the positions of the two sulfide groups.
† Mr. Patrice Pre´ville performed part of this work during a student
work term.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) Harris, R. L. N. Tetrahedron Lett. 1969, 51, 4465.
(2) Atkinson, J . G.; Hamel, P.; Girard, Y. Synthesis 1988, 480.
(3) Anzai, K. J . Heterocycl. Chem. 1979, 16, 567.
(4) Plate, R.; Nivard, R. J . F.; Ottenheijm, H. C. J . Tetrahedron 1986,
42, 4503.
(5) Biswas, K. M.; J ackson, A. H. Tetrahedron 1969, 25, 227 and
references therein.
0022-3263/96/1961-1573$12.00/0 © 1996 American Chemical Society

1574 J . Org. Chem., Vol. 61, No. 5, 1996
Hamel and Preville
Ta ble 1. Regioselective Syn th esis of Mixed In d ole
2,3-Bis(su lfid es)
Sch em e 1
SPh
SR2
R2SCl
(method A)
N
SCH3
SPh
(R2S)2
NaH, DMF
(method B)
H
N
H
SR1
N
H
SR1
CH3SCl
2a (2%)
N
H
1
2
SCH3
SPh
+
3a
yield of
2 (%)
N
H
example
method
R1
R2
a
b
c
d
e
f
A
A
A
A
A
A
B
B
CH3
Ph
Ph
4-MeOPh
4-MeOPh
4-NO2Ph
4-ClPh
4-MeOPh
Ph
CH3
4-MeOPh
Ph
4-NO2Ph
4-MeOPh
4-MeOPh
4-ClPh
89
80
73
82
84
80
81
88
2b (47%)
SPh
SCH3
+ 3a (35%)
SCH3
+
+
N
SPh
N
H
H
g
h
5 (4%)
4 (12%)
SCH3
2a (10%) + 2b (38%)
+ 4 (25%) + 5 (18%)
+ 3b (9%)
PhSCl
These compounds could then be used as standards for
the quantitation of the reaction mixtures by analytical
techniques, preferably HPLC, without the need to per-
form tedious separation of the isomers.
N
H
3b
The first regiospecific preparation of the mixed indole
2,3-bis(sulfides) was made possible by two recent syn-
theses of 2-indolyl sulfides: acid-catalyzed isomerization
of 3-indolyl sulfides6,7 and our recent method for selective
desulfenylation of indole 2,3-bis(sulfides).8 Sulfenylation
of 2-indolyl sulfides occurs as expected at the 3-position,
selectively affording mixed indole 2,3-bis(sulfides) in good
yields. We were thus able to synthesize a series of
complementary mixed bis(sulfides) (Table 1) to be used
in the mechanistic study of the second sulfenylation of
indole.
Sch em e 2
SCH3
SPh
SCH3
PhSCl
Cl–
+
N
H
SPh
N
SPh
H
2b
+CH3SCl
–CH3SCl
CH3SCl
4
3b
5
For the mechanistic study, we selected “matched sets”
of examples where the groups attached to sulfur had
significantly different electronic properties. For example,
the sulfenylation of 3-(phenylthio)indole with methane-
sulfenyl chloride was compared with the complementary
sulfenylation of 3-(methylthio)indole with benzenesulfe-
nyl chloride. In the event that the process should involve
transient generation of a 3,3-disubstituted species such
as in eq 2, both reactions might be expected to afford
similar ratios of the two mixed 2,3-bis(sulfides), resulting
from a common intermediate. Similar competitive stud-
ies with other substituents would be expected to afford
clues as to the relative migratory properties of the groups
involved in relation to their electronic character.
The experiments were performed as follows: a solution
of the desired sulfenyl chloride (0.5 M) was prepared by
adding sulfuryl chloride (SO2Cl2) to a solution of the
appropriate disulfide in 1,2-dichloroethane.3 Then 0.525
mmol of this solution was added to a solution of a chosen
3-indolyl sulfide (0.5 mmol) in DMF. The reaction was
allowed to run at room temperature for 45 min and then
worked up as described in the Experimental Section. The
crude reaction mixtures were assayed by a combination
of TLC and HPLC analyses, and, in some cases, crude
chromatography was necessary to separate the mixture
into two fractions containing components which had
similar retention times by HPLC but different Rf’s on
silica gel, allowing quantitation by HPLC analysis of the
two separate fractions. Quantitation was effected by
comparison of peak areas with calibration curves ob-
tained using several concentrations of the different
standards. As will be seen, the study was complicated
by several side reactions affording multi component
mixtures. We quantified only components which were
present at concentrations greater than 5% of the total
mixtures. Each experiment was repeated twice, and the
results reported correspond to the average value observed
for each component.
Resu lts
Study Number 1: Methyl vs Phenyl (Scheme 1). When
3-(phenylthio)indole (3a ) was sulfenylated with a slight
excess of methanesulfenyl chloride as described above,
the results, as shown in Scheme 1, were quite surpris-
ing: along with a 35% recovery of 3a , the mixture
consisted of 2% of 2a and 47% of 2b, corresponding to a
2b/2a ratio of 23.5:1 in favor of the isomer in which the
phenylthio group present at the 3-position of the starting
material 3a has migrated to the 2-position. However,
the symmetrical 2,3-bis(phenylthio)indole (4) was present
(12%), as well as 2,3-bis (methylthio)indole (5) (4%).
The complementary sulfenylation of 3-(methylthio)-
indole (3b) with benzenesulfenyl chloride also afforded
a complex mixture of components. In this case 2a and
2b were obtained in 10 and 38% yields, respectively,
along with 9% of residual 3b, as well as the two
symmetrical bis(sulfides) 4 (25%) and 5 (18%). Although
the formation of the symmetrical bis(sulfides) may seem
surprising at first, they may be explained easily as
follows: the bis(sulfide) 2b may itself be subjected to
sulfenylation (Scheme 2), affording a 2,3,3-trisubstituted
transient species in which either of the two 3-substituents
(6) Plate, R.; Ottenheijm, H. C. J . Tetrahedron 1986, 42, 4511.
(7) Hamel, P.; Girard, Y.; Atkinson, J . G. J . Org. Chem. 1992, 57,
2694.
(8) Hamel, P.; Zajac, N.; Atkinson, J . G.; Girard, Y. J . Org. Chem.
1994, 59, 6372.

Mechanism of the Second Sulfenylation of Indole
J . Org. Chem., Vol. 61, No. 5, 1996 1575
Sch em e 3
Sch em e 4
SPh
S
S
NO2
N
S
OMe
H
N
OMe
H
4-MeOPhSCl
3a
4-NO2PhSCl
2d (38%)
3c
2e (46%)
S
OMe
S
OMe
NO2
+
+
N
SPh
H
N
H
S
2c (16%)
2f (0%)
S
OMe
S
NO2
+ 4 (21%) +
+ 6 (14%) +
N
H
S
OMe
N
+ 3c (23%)
H
6 (25%)
3d (17%)
S
OMe
PhSCl
S
NO2
2d (61%) + 2c (6%)
+ 4 (18%) + 6 (15%)
2e (63%) + 2f (0%)
4-MeOPhSCl
N
H
N
H
+ 6 (16%) + 3d (18%)
+ 3c (3%)
3c
3d
can be ejected, leading to 4 and/or 2b; if the CH3S group
is ejected, putatively as CH3SCl, it can react with the
starting material 3b to afford 2,3-bis(methylthio)indole
(5). In a control experiment when 2b was subjected to
benzenesulfenyl chloride, extensive transformation to 4
was confirmed by TLC and HPLC. This experiment
suggests that the 4 which is obtained in the original
mixture could result from initial formation of 2b, thus
greatly increasing the “formal” proportion of 2b/2a
resulting from the initial sulfenylation. Thus in both
experiments, the major mixed bis(sulfide) observed is the
one in which the phenylthio group is present at the
2-position.
Sch em e 5
S
OMe
N
H
3c
+4-NO2PhSCl
–4-NO2PhSCl
OMe
Cl–
S
Study Number 2: Phenyl vs 4-Methoxyphenyl (Scheme
3). The results of sulfenylation of 3-(phenylthio)indole
(3a ) with 4-methoxybenzenesulfenyl chloride were as
follows: 2c (16%) and 2d (38%) were obtained along with
significant amounts of the symmetrical bis(sulfides) 4
(21%) and 6 (25%). The same reasoning as in the
previous experiments can be used to explain the forma-
tion of these two components, and a control experiment
confirmed the displacement of the 3-phenylthio group
from 2d by 4-methoxybenzenesulfenyl chloride.
S
NO2
+
N
H
–4-MeOPhSCl
+4-MeOPhSCl
S
NO2
N
H
The results from the complementary sulfenylation of
3-((4-methoxyphenyl)thio)indole (3c) with benzenesulfe-
nyl chloride also showed a preponderance of 2d (61%)
over 2c (6%), along with the two symmetrical bis(sulfides)
4 (18%) and 6 (15%). In both studies, the major mixed
bis(sulfide) observed has the (4-methoxyphenyl)thio group
at the 2-position.
Study Number 3: 4-Methoxyphenyl vs 4-Nitrophenyl
(Scheme 4). In this study we compared an electron-rich
substituent with one which is strongly electron-deficient.
Reaction of 3-((4-methoxyphenyl)thio)indole (3c) with
4-nitrobenzenesulfenyl chloride led to puzzling results:
along with unreacted 3c (23%) there was obtained 2e
(46%), 2,3-bis((4-methoxyphenyl)thio)indole 6 (14%), and
3-((4-nitrophenyl)thio)indole (3d ) (17%)! No trace of 2f
was detected. Our explanation for the formation of 3d
is outlined in Scheme 5: Initial attack of the sulfenyl
chloride leads to the 3,3-disubstituted indolenine inter-
mediate. At this point, only partial migration occurs to
afford 2e, while a competing elimination of 4-methoxy-
benzenesulfenyl chloride leads to 3d . The nascent sulfe-
3d
nyl chloride can react in several ways: with the starting
material 3c, to afford 6; with 3d leading to the results
observed in the complementary experiment described
below; also it can react with 2e, in a displacement
reaction similar to Scheme 3, to also afford 6. This last
process was confirmed by a control reaction. It is not
surprising that, although 3d is produced in the mixture,
it does not suffer a second sulfenylation to afford bis((4-
nitrophenyl)thio)indole (7), since more vigorous condi-
tions are required to produce this second substitution (cf.
preparation of 7 in Experimental Section).
The identification of 3d in this experiment raises the
question as to the possibility that a process such as
outlined in Scheme 5 could have occurred in the previous
experiments. Indeed, minor peaks corresponding to the
complementary 3-indolyl sulfides were detected in the
HPLC tracings of all of the mixtures studied, suggesting
that such a displacement may have occurred.

1576 J . Org. Chem., Vol. 61, No. 5, 1996
Hamel and Preville
Exp er im en ta l Section
As a complementary experiment, 3-((4-nitrophenyl)-
thio)indole (3d ) was allowed to react with 4-methoxy-
benzenesulfenyl chloride, leading to the following mix-
ture: unreacted 3d (18%), 2e (63%), 6 (16%), and 3c (3%).
Once again, 2f was not detected in any significant
quantity.
All reactions were carried out under N2 atmosphere, al-
though this may not be necessary. Reagents and solvents from
commercial sources were used without further purification or
drying. Melting points were recorded in open capillary tubes
and are uncorrected. Infrared spectra were recorded using
KBr pellets, and the values reported correspond to the largest
or the most characteristic absorptions. The 300 MHz proton
NMR data were collected using a Bruker instrument. El-
emental analyses were provided by Guelph Chemical Labo-
ratories Ltd., Guelph, Ontario.
Sta r tin g Ma ter ia ls: 3-In d olyl Su lfid es. All of the 3-in-
dolyl sulfides used in this study have been previously re-
ported.2,7
2-In d olyl Su lfid es. All of the 2-indolyl sulfides used in
the preparation of the mixed bis(sulfides) have been reported7
except 1f.
Although the results of these last two experiments
were complicated by several side reactions, it is signifi-
cant that the only mixed bis(sulfide) observed was 2e,
having the (4-methoxyphenyl)thio group at the 2-position,
in both experiments, with no trace of the isomeric 2f.
Discu ssion
From careful examination of the mechanism outlined
in eq 2, it should be possible to predict which of the two
sulfide groups would be most likely to migrate to the
2-position. Since this migration is promoted by the
positive charge on the indole nitrogen, it is reasonable
to suggest that the sulfur bearing the substituent with
the highest electron density would have a greater pro-
pensity to migrate. The results of the above series of
experiments appear to support this hypothesis, as in each
case the major mixed bis(sulfide) formed is the one in
which the sulfide bearing the most electron-donating
substituent occupies the 2-position of the indole ring.
2-((4-Nitr op h en yl)th io)in d ole (1f) was obtained by tri-
fluoroacetic acid (TFA)- catalyzed isomerization7 of 3-((4-
nitrophenyl)thio)indole (3d ): 253 mg of the 3-indolyl sulfide
(1 mmol) and 8 mL of TFA were refluxed for 1.5 h. After
cooling, the TFA was evaporated. The residue was dissolved
in ether, and the solution was washed several times with
water, dried over MgSO4, and evaporated down to a mixture
which was chromatographed on silica gel, eluting with 10%
EtOAc in toluene to afford, as the least polar component, 152
mg of 1f as a yellow solid (60%), mp 104-106 °C. IR: 3420-
(NH), 1570, 1505 and 1330 (NO2) cm-1
.
1H NMR (acetone-
d6): δ 6.98 (s, 1H), 7.13 (m, 1H), 7.26 (m, lH), 7.30 (d, J ) 9.1
Hz, 2H), 7.47 (d, J ) 8.3 Hz, 1H), 7.67 (d, J ) 8 Hz, 1H), 8.15
(d, J ) 9.1 Hz, 2H), 10.8 (NH).
Anal. Calcd for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36;
S, 11.86. Found: C, 62.36; H, 3.76; N, 10.47; S, 12.15. There
was also obtained, as a more polar component, 68 mg of the
bis(sulfide) 7 (see below for preparation).
Although an array of side reactions made analysis of
the reaction mixtures more tedious than was expected,
it is important to point out that all of these reactions
appear to be due to attack at the 3-position already
bearing a sulfide group. This observation supports the
premise that this position remains the most reactive on
the ring and greatly enhances the probability that the
mechanism outlined in eq 2 is, at the very least, pre-
dominant. In fact, a process such as described in Scheme
2, which represents a third sulfenylation, should have
been expected to happen, on the basis of our working
hypothesis.
Sym m etr ica l In d ole 2,3-Bis(su lfid es). The bis sulfides
4, 5 and 6 have been previously reported.8
2,3-Bis((4-n itr op h en yl)th io)in d ole (7). To a suspension
of 2.31 g of 4-nitrophenyl disulfide (7.5 mmol) in 20 mL of 1,2-
dichloroethane there was added 0.57 mL of sulfuryl chloride
(945 mg, 7 mmol), and the resulting mixture was refluxed for
30 min. After cooling, the dark yellow solution was added
slowly at rt to a solution of 585 mg of indole (5 mmol) in 10
mL of DMF. The resulting mixture was refluxed for 30 min.
After cooling, the dichloroethane was evaporated away. The
residual DMF solution was diluted with water and extracted
twice with ether. These extracts were washed twice with
water, dried, and evaporated to a residue which was chroma-
trographed on silica gel, eluting with a 1:5 mixture of EtOAc
and hexane to afford 1.09 g of 7 as a yellow solid, mp 163-
The complexity of the reaction mixtures suggests that
variations in the relative proportions of the reagents, as
well as in the reaction times, should lead to mixtures
where the relative proportions of components would differ
from those that we have obtained. However, we feel that
it is reasonable to assume that similar trends would be
observed and that the results would lead to the same
conclusions.
1
165 °C. IR: 3380 (NH), 1575, 1510 and 1335 (NO2) cm-1. H
NMR (acetone-d6): δ 7.24 (d, J ) 9 Hz, 2H), 7.25 (m, 1H), 7.38
(d, J ) 9 Hz, 2H), 7.40 (m, 1H), 7.56 (d, J ) 8 Hz, 1H), 7.63 (d,
J ) 8.3 Hz, 1H), 8.03 (d, J ) 9 Hz, 2H), 8.10 (d, J ) 9 Hz, 2H).
The NH proton was not observed.
Con clu sion
Gen er a l P r oced u r es for th e Syn th esis of Mixed In d ole
2,3-Bis(su lfid es). Meth od A:32-(Meth ylth io)-3-(p h en ylth -
io)in d ole (2a ). To a solution of 196 mg of diphenyl disulfide
(0.9 mmol) in 2 mL of 1,2-dichloroethane at room temperature
there was added 61 µL of sulfuryl chloride (101 mg, 0.75
mmol). The resulting yellow solution, after being stirred for
5 min, was added to a solution of 196 mg of 2-(methylthio)-
indole (1a ) (1.2 mmol) in 2 mL of DMF. The resulting mixture
was stirred for 1 h, the reaction was quenched with water,
and the solution was extracted three times with ether. The
organic phase was washed twice with water, dried over Mg-
SO4, filtered, and evaporated to a residue which was chro-
matographed on silica gel, eluting with a 1:5 mixture of ethyl
acetate and hexane. There was obtained 289 mg of 2a (89%)
We have developed an efficient, facile regioselective
synthesis of mixed indole 2,3-bis(sulfides). The avail-
ability of these compounds allowed us to perform a study
of the mechanism of the second sulfenylation of indole,
which demonstrates that this process occurs predomi-
nantly, if not completely, by initial substitution at the
3-position of the ring, leading to a 3,3-disubstituted
indolenine intermediate, followed by migration of one of
the sulfide groups to the 2-position, as has been suggested
by Ottenheijm.4 The mechanism of this migration,
proposed to occur in an intramolecular fashion via a
transient episulfonium species, remains to be demon-
strated. Although our data may be considered to be
compatible with this hypothesis, we cannot rule out at
this time the possibility of a more complex, intermolecu-
lar process.
as a beige solid, mp 87-89 °C. IR: 3442, 1475, 1435, 743 cm-1
.
1H NMR (CDCl3): δ 2.47 (s, 3H), 7.05-7.25 (m, 7H), 7.38 (d,
J ) 8.1 Hz, 1H), 7.54 (dd, J ) 0.8 and 7.7 Hz, 1H), 8.48 (br,
NH). Anal. Calcd for C15H13NS2: C, 66.38; H, 4.83; N, 5.16;
S, 23.63. Found: C, 66.15; H, 5.00; N, 5.00; S, 23.32.

Mechanism of the Second Sulfenylation of Indole
J . Org. Chem., Vol. 61, No. 5, 1996 1577
1240, cm-1
.
1H NMR (CDCl3) δ 3.80 (s, 3H), 6.83 (d, J ) 8.9
Hz, 2H), 6.98 (d, J ) 8.6 Hz, 2H), 7.10 (d, J ) 8.6 Hz, 2H),
7.08-7.30 (m, 3H), 7.37 (d, J ) 8.9 Hz, 2H), 7.51 (d, J ) 8.0
Hz, 1H), 8.16 (br, NH). Anal. Calcd for C21H16ClNOS2: C,
63.38; H, 4.05; N, 3.52: S, 16.11; Cl, 8.91. Found: C, 63.59;
H, 4.13; N, 3.48; S, 15.97; Cl, 9.26.
Gen er a l P r oced u r e for Su lfen yla tion of 3-In d olyl
Su lfid es w ith Su lfen yl Ch lor id es. Su lfen yla tion of 3-((4-
n itr op h en yl)th io)in d ole (3d ) w ith 4-m eth oxyben zen e-
su lfen yl Ch lor id e. To a solution of 167 mg of 4-methox-
yphenyl disulfide (0.6 mmol) in 2 mL of 1,2-dichloroethane
there was added 41 µL of sulfuryl chloride (0.5 mmol). The
resulting yellow orange solution was stirred at room temper-
ature for 10 min, assuming formation of a 0.5 M solution of
the sulfenyl chloride. From this solution, 1.05 mL (0.525
mmol) was added to a solution of 135 mg of 3d (0.5 mmol) in
1 mL of DMF. The mixture was stirred at room temperature
for 45 min, the reaction was quenched with water, and the
solution was extracted twice with EtOAc. The organic phase
was washed three times with water, dried over MgSO4, and
evaporated down to a residue which was analyzed by HPLC.
Also prepared in the same manner were the following.
3-(Meth ylth io)-2-(p h en ylth io)in d ole (2b): beige solid,
mp 49-51 °C. IR: 3380, 1475, 1440, 735 cm-1
.
1H NMR
(CDCl3): δ 2.34 (s, 3H), 7.19-7.31 (m, 8H), 7.78 (dd, J ) 1.5
and 8.5 Hz, 1H), 8.22 (br, NH). Anal. Calcd for C15H13 NS2:
C, 66.38; H, 4.83; N, 5.16; S, 23.63. Found: C, 66.45; H, 4.93;
N, 4.93; S, 23.24.
3-((4-Met h oxyp h en yl)t h io)-2-(p h en ylt h io)in d ole (2c):
off-white solid, mp 107-110 °C. IR: 3380, 1478, 1230, 740
cm-1 1H NMR (CDCl3): δ 3.73 (s, CH3), 6.71 (d, J ) 8.8 Hz,
.
2H), 7.12-7.32 (m, 8H), 7.17 (d, J ) 8.8 Hz, 2H), 7.62 (dd, J
) 0.7 and 8.9 Hz, 1H), 8.30 (br, NH). Anal. Calcd for C21H17
NOS2: C, 69.39; H, 4.71: N, 3.85; S, 17.64. Found: C, 68.99,
H, 4.97; N, 3.70; S, 17.96.
-
2-((4-Met h oxyp h en ylt h io)-3-p h en ylt h io)in d ole (2d ):
cream-colored solid, mp 113-115 °C. IR: 3380, 1490, 1245,
735 cm-1 1H NMR (CDCl3): δ 3.80 (S, 3H), 6.84 (d, J ) 8.8
.
Hz, 2H), 7.06-7.30 (m, 8H), 7.38 (d, J ) 8.8 Hz, 2H), 7.54 (d,
J ) 7.8 Hz, 1H) 8.13 (br, NH). Anal. Calcd for C21H17 NOS2:
C, 69.39: H, 4.71; N, 3.85: S, 17.64. Found: C, 68.99; H, 4.83;
N, 3.73; S, 17.63.
2-((4-Met h oxyp h en yl)t h io)-3-((4-n it r op h en yl)t h io)in -
d ole (2e). For the preparation of 4-nitrobenzenesulfenyl
chloride, the mixture of disulfide and SO2Cl2 in 1,2-dichloro-
ethane was refluxed for 30 min and then cooled down and used
as such. The 2e was obtained as an orange solid, mp 114-
Gen er a l P r oced u r e for th e An a lysis of Su lfen yla tion
Mixtu r es by HP LC. Mixtures were analyzed using a C18
reverse-phase column. The eluent in all cases was a 60:40
mixture of acetonitrile and deionized water, at a flow rate of
1 mL/min. UV detector wavelength was set at 254 nm. Stock
solutions of the various standards were made up in CH3CN,
at four different concentrations, and calibration curves were
obtained relating peak areas to concentrations.
Crude sulfenylation mixtures, all from 0.5 mM scale reac-
tions, were dissolved in 250 mL of CH3CN, and this solution
was again dissolved by a factor of 50, affording an “assumed”
40 mM mixture. From this, 25 µL was injected onto the
column. Retention times and peak areas were correlated with
the appropriate compounds and concentrations, allowing the
quantitation of each component. Results in the schemes
represent the relative proportions of major constituents of the
mixtures.
In study no. 2, the retention times of 2d and 4 were the
same; this was also the case for 2c and 6. However, these
pairs of compounds had different Rf’s on TLC. In both
experiments, the crude sulfenylation mixture was initially
chromatographed on three preparative TLC plates, eluting
twice with a 1:5 mixture of EtOAc and hexane. The plate area
was separated in two, and the silica was extracted separately
with EtOAc, affording two mixtures, one containing 2d and
6, the other containing 2c and 4. The two mixtures were
analyzed separately, allowing quantitation of the compounds
which had similar retention times in the original mixture.
Con tr ol Exp er im en ts: Rea ction of 2b w ith Ben zen e-
su lfen yl Ch lor id e. Benzenesulfenyl chloride was prepared
as described above from Ph2S2 and SO2Cl2 in 1,2-dichloroet-
hane. A volume equivalent to 0.12 mmol was added to a
solution of 27 mg of 2b (0.1 mmol) in 0.3 mL of DMF. The
mixture was stirred at r.t. A TLC taken after 5 min showed
extensive transformation to 4; the mixture was worked up
after 30 min, and HPLC analysis showed a 4/2b ratio of 5:1.
116 °C (EtOH). IR: 3380, 1575, 1510, 1330 cm-1
.
1H NMR
(CDCl3) δ 3.78 (s, 3H), 6.83 (d, J ) 8.8 Hz, 2H), 7.07 (d, J )
9.0 Hz, 2H), 7.13-7.36 (m, 3H), 7.39 (d, J ) 8.8 Hz, 2H), 7.47
(d, J ) 7.7 Hz, 1H), 7.98 (d, J ) 9.0 Hz, 2H), 8.29 (br, NH).
Anal. Calcd for C21H16N2O3S2: C, 61.75; H, 3.95; N, 6.86; S,
15.70. Found: C, 61.68; H, 3.87; N, 6.92; S, 15.44.
3-((4-Met h oxyp h en yl)t h io)-2-((4-n it r op h en yl)t h io)in -
d ole (2f): yellow crystals, mp 153-155 °C (EtOH). IR: 3375
(br), 1575, 1508, 1330 cm-1 1H NMR (CDCl3): δ 3.71 (s, 3H),
.
6.66 (d, J ) 9 Hz, 2H), 7.06 (d, J ) 9 Hz, 2H), 7.15 (d, J ) 9
Hz, 2H), 7.21-7.44 (m, 3H), 7.73 (d, J ) 7.9 Hz, 1H), 7.99 (d,
J ) 9 Hz, 2H), 8.50 (br, NH). Anal. Calcd for C21H16N2O3S2:
C, 61.75; H, 3.95; N, 6.86; S, 15.70. Found: C, 61.43; H, 3.81;
N, 6.84; S, 15.78.
Met h od B2. 2-((4-Ch lor op h en yl)t h io)-3-((4-m et h oxy-
p h en yl)th io)in d ole (2g). To a suspension of 16 mg of 97%
NaH (0.67 mmol) in 1.5 mL of DMF there was added 130 mg
of 2-((4-chlorophenyl)thio)indole (1g) (0.5 mmol), and the
resulting mixture was stirred at room temperature under an
N2 atmosphere until gassing subsided (30 min). There was
added 167 mg of 4-methoxyphenyl disulfide (0.6 mmol) and
the mixture was stirred at room temperature overnight. The
reaction was quenched with saturated aqueous NH4Cl, and
the solution was diluted with water and extracted twice with
ether. The crude product from the organic phase was chro-
matographed on silica gel, eluting with a 1:5 mixture of EtOAc
and hexane, to afford 160 mg of 2g (80%) as an oil which
solidified. Crystallization from ether-hexane gave cubic
crystals, mp 99-101 °C. IR: 3265, 1490, 1470, 1250 cm-1. 1H
NMR (CDCl3): δ 3.73 (s, 3H), 6.69 (d, J ) 8.8 Hz, 2H), 7.08-
7.19 (m, 7H), 7.29 (m, 2H), 7.65 (d, J ) 7.9 Hz, 1H) 8.32 (br,
NH). Anal. Calcd for C21H16 ClNOS2: C, 63.38; H, 4.05; N,
3.52; S, 16.11; Cl, 8.91. Found: C, 63.50; H, 4.18; N, 3.47; S,
16.18; Cl, 9.21.
Rea ction of 2d w ith 4-Meth oxyben zen esu lfen yl Ch lo-
r id e. A similar reaction on 2d , reacting with 4-methoxyben-
zenesulfenyl chloride, worked up after 45 min, afforded a 6/2d
ratio of ca. 2:1.
3-((4-Ch lor op h en yl)th io)-2-((4-m eth oxyp h en yl)th io)in -
d ole (2h ) was prepared in the same fashion from 2-((4-
methoxyphenyl)thio)indole and 4-chlorophenyl disulfide: white
rosettes, mp 92-94 °C (ether-hexane). IR: 3430, 1490, 1470,
J O951420N