Intramolecular sulfoxide electrophilic sulfenylation in 2- and 3-indoleanilides

Article abstract of DOI:10.1016/j.tet.2007.09.050

When N-[2-(alkylsulfinyl)phenyl]-1H-indole-2-carboxamides with varying degrees of indolic and amidic N-alkylation are heated in an inert solvent or treated with trifluoroacetic anhydride; only compounds in which the amidic nitrogen is methylated cyclize t

Full text of DOI:10.1016/j.tet.2007.09.050

Tetrahedron 63 (2007) 12185–12194
Intramolecular sulfoxide electrophilic sulfenylation
in 2- and 3-indoleanilides
Mary E. Eggers,a,b Parag V. Joga,c and Dallas K. Batesa,
*
aDepartment of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
bSynovo GmbH, Paul Ehrlich Str. 15, 72076 Tu€bingen, Germany
cCalifornia Institute of Technology, Division of Chemistry and Chemical Engineering, 362 Crelin Laboratory,
1200 E California Blvd, Pasadena, CA 91125, USA
Received 17 May 2007; revised 18 September 2007; accepted 20 September 2007
Available online 26 September 2007
Abstract—When N-[2-(alkylsulfinyl)phenyl]-1H-indole-2-carboxamides with varying degrees of indolic and amidic N-alkylation are heated
in an inert solvent or treated with trifluoroacetic anhydride; only compounds in which the amidic nitrogen is methylated cyclize to indolo[3,2-
b]-1,5-benzothiazepinones (9, 10). Successful cyclization is attributed to the ability of N-Me amides to readily adopt a conformation conducive
to cyclization, which other derivatives are unable to achieve. The analogous 3-indoleanilide, N,N-dimethyl N-[2-(ethylsulfinyl)phenyl]-1H-
indole-3-carboxamide (17a), undergoes SES/rearrangement to produce 10 upon heating in p-xylene. An intermediate 3H-indolinium
spirocyclic species is proposed to account for this result.
Ó 2007 Elsevier Ltd. All rights reserved.
Ar
S
1. Introduction
CF3CO2
R
R'
Sulfoxides are widely used as electrophilic sulfenylating
agents. There are two general mechanistic pathways by
which sulfoxides become sulfenylating agents and both are
promoted by reagents and conditions typical for the Pum-
merer reaction.1 Many reported ‘anomalous’ Pummerer
reactions are electrophilic sulfenylation reactions, with the
‘anomalous’ pathway favored by the presence of a proximate
nucleophilic group2 or a non-acidic hydrogen atom on the
carbon a to the sulfoxide.3 This primary sulfenylation path-
way involves formation of a sulfonium salt by reaction at the
electrophilic sulfoxide sulfur in a species such as R2S–
O2CCF+3 or R2S–OH+. The sulfonium salt subsequently un-
dergoes dealkylation, either in situ or as a separate step, to
form the sulfenylation product. There are numerous exam-
ples of electrophilic sulfenylations of aromatics4 and hetero-
aromatics5 utilizing this approach and similar reactions
using sulfides and PIFA.6
Path A
Ar-H
O2CCF3
O
S
TFAA
S
S
R
R'
R
R'
R
Ar
CF3CO2
Path B
Ar-H
O
C
R
S
O
CF3
Scheme 1. Sulfenylation pathway depends upon the timing of events.
We have exploited sulfonium ions generated in situ from
sulfoxides (sulfoxide electrophilic sulfenylation—SES) fol-
lowed by variations in the mode of dealkylation to prepare
new N,S-heterocyclic systems: SES/displacement,11 SES/
ring enlargement,12 and SES/rearrangement (Eq. 1).13
O
O
N
H
The other pathway to sulfenylation involves a sulfenic acid
derivative formed from S–C bond cleavage in the sulfoxide.
Presumptive intermediates are a mixed anhydride of the sul-
fenic acid (RSOCOCF3, RSOAc, etc.) or a protonated sulfenic
acid (RSOH+2).7 There are also many examples of electro-
philic addition (with alkenes)8,9 and electrophilic substitution
(with arenes).10 The two pathways are shown in Scheme 1.
N
S
Et
O
S
Et
ð1Þ
O
O
S
N
N
S
Et
Keywords: Sulfoxide; Electrophilic sulfenylation; Spirocycle; Indole.
* Corresponding author. Tel.: +1 906 487 2048; fax: +1 906 487 2061;
e-mail: dbates@mtu.edu
In the latter process the unexpected rearrangement was not
the dominant pathway. We have sought to observe this
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.050

12186
M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
R
O
process in other systems, attempting to enhance the pathway
and to determine if the process is a general phenomenon. In
designing a system, the strong preference of indoles for elec-
trophilic attack at C-3 even when that position is already
substituted14 was an important consideration. We now report
that both 2- and 3-substituted indoles (A) and (B) produce
the same product under SES conditions.
R
R2
N
S
R2
N
S
N
N
R1
R1
O
O
R
1 = H R2 = H
R1 = H R2 = Me
1 = Me R2 = H
R1 = Me R2 = Me
1
3
5
7
2
4
6
8
R
Me
O
S
series a R = Et
Me
N
series b R = t-Bu
series c R = CH2CH2CN
N
Me
O
S
CO2Et
N
H
a
A
N
Me
O
1ab
2ab
N
Me
O
b
Me
O
Me
O
S
N
CO2H
N
H
c
O
O
4ab
3ab
5ab
N
Me
a or b
6ab
CO2H
c
B
N
Me
2. Results and discussion
2.1. Indoleanilides substituted at C-2
R = CH2CH2CN
O
7c
8abc
1ab
7ab
d
Indoleanilides substituted at C-2 (2, 4, 6, 8) were prepared
using standard methodologies (Scheme 2). Indole-2-carb-
oxylic acid chloride15 and a 2-(alkylthio)aniline16 produced
sulfides 1a–c in modest yields. Problems have been reported
with reactions of indole carboxylic acids with thionyl chlo-
ride17 and use of the unstable acid chloride (and consequent
low yield of amide) could be avoided by trimethylalumi-
num-catalyzed condensation18 of 2-(alkylthio)anilines and
ethyl indole-2-carboxylate. For example, 1a was obtained
in 92% yield by this approach. Oxidations were accom-
plished using standard methodologies: NaIO4 in CH2Cl2/
MeOH/H2O;3a OxoneÒ in THF/MeOH/H2O;19 or m-chloro-
perbenzoic acid (m-CPBA) in dichloromethane.20 Success
of the oxidations was insensitive to the reagent used; the
method selected was typically based on solubility of the
starting sulfide in the oxidation medium.
Scheme 2. Synthesis of 2-indoleanilides. Reagents and conditions (com-
pound number, % yield): (a) 2-ethylthioaniline, AlMe3, toluene, reflux
(1b 92%, 5a 84%); (b) SOCl2, Et2O, 2-(alkylthio)aniline, rt (1a, 32%, 1b
71%, 5b 59%); (c) SOCl2, Et2O, N-methyl-2-(alkylthio)aniline, rt (3a
38%, 3b 79%, 7c 27%); (d) 50% NaOH, CH3I, n-Bu4NHSO4, toluene (7a
82%, 7b 79%).
thermally (refluxing in chloroform or p-xylene)] clear pat-
terns of reactivity emerged when the sulfoxides were cy-
clized (Scheme 3). Conditions for cyclization were either
R
S
O
R2
S
N
N
R2
N
R1
N
R1
O
O
R
1 = H R2 = H
-
9
2ab
4ab
6ab
Monoalkylated compounds (4ab) bearing a methyl substitu-
ent on the amide nitrogen were prepared similarly, replacing
the aniline component with an N-methyl-2-(alkylthio)ani-
line21 followed by oxidation. Monoalkylated compounds
bearing the methyl substituent on the indole (6ab) were pre-
pared from alkylthioanilines and N-methylindole carboxylic
acid followed by oxidation.
R1 = H R2 = Me
R
1 = H R2 = Me
1 = Me R2 = Me
R1 = Me R2 = H
1 = Me R2 = Me
-
10
R
R
8abc
a series R = Et
b series R = t-Bu
c series R = CH2CH2CN
N,N0-Dimethylated compounds (8ab) were prepared by di-
alkylation of amides (1ab) by catalytic phase transfer methyl-
ation22 followed by oxidation. Sulfide 1c decomposed under
phase transfer conditions (retro-Michael) so compound 8c
was prepared in low yield by reaction of 1-methyl-1H-in-
dole-2-carboxylic acid chloride with 3-{[2-(methylamino)-
phenyl]thio}propanenitrile followed by oxidation.
Sulfoxide
Product, % yield
Sulfoxide Product, % yield
(TFAA, Thermal)
(TFAA, Thermal)
- (0, 0)
2a
2b
4a
4b
6a
6b
8a
8b
8c
- (0, 0)
- (0, 0)
- (0, 0)
9 (75, 56)
9 (100, 58)
10(90, 22)
10 (100, 66)
10 (50, 41)
When the sulfoxides were subjected to cyclization condi-
tions [either activation by electrophilic species (TFAA) or
Scheme 3. SES reactions of 2-indoleanilides.

M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
12187
thermal (refluxing in chloroform or p-xylene) or electro-
philic activation (TFAA). In successful reactions, tert-butyl
sulfoxide derivatives cyclize thermally in refluxing chloro-
form whereas ethyl sulfoxide derivatives require higher tem-
peratures (refluxing in p-xylene).23 In addition, a substituent
at the amidic nitrogen is essential for cyclization and the 1H
NMR spectrum (25 ꢀC) of every sulfoxide that successfully
cyclized is very poorly resolved. Poorly resolved spectra are
generally indicative of conformational interconversion be-
tween two or more rotomers on the NMR time scale. Record-
ing 1H NMR spectra at 100 ꢀC showed fewer, sharper peaks
as expected for an increased rate of interconversion in a
dynamic process.24
alternative isomer. In addition, 10 was synthesized via an
unambiguous route (Scheme 4) from 11, prepared using
methodology described by Atkinson et al.31 Refluxing 11
in toluene using SiO2 as catalyst32 gave 12, which upon
catalytic phase transfer dimethylation gave a product chro-
matographically and spectroscopically identical to the cycli-
zation product (10). This clearly establishes the sites of
attachment of the sulfur and carbonyl groups on the indole
ring of the SES product. Catalytic phase transfer methylation
of 9 also produced 10 (76%) confirming the structure of that
product as well.
c
10
9
N,N-Disubstituted amides have higher energy, non-planar
ground states compared to primary or secondary amides.25
They often exhibit broadened H NMR spectra due to the
H2N
1
a
S
low C(O)–N rotational barrier to cis-/trans-amide inter-
conversion. Disubstituted amides also exist predominately
in the cis-form.25b In our compounds this means the amidic
N-methyl substituted series is expected to exist primarily in a
conformation, which places the sulfoxide and indole entities
near one another and to possess conformational flexibility to
easily obtain a geometry conducive to indole p electron–
sulfoxide sulfur atom interaction for SES reaction.
CO2H
N
H
c
CO2H
N
H
11
S
b
11
N
H
N
H
O
12
Sulfoxides in the amidic N–H series (2ab, 6ab) either
produced decomposition products or were recovered un-
changed. The failure of compounds containing amidic N–H
to cyclize is attributable to factors preventing the sulfoxide
sulfur atom and the indole p-system from assuming a favor-
able conformation for cyclization: a formidable energy bar-
rier to interconversion of cis- and trans-amides, and a large
energy difference between the cis- and trans-amides with the
unfavorable (for cyclization) trans-isomer greatly preferred.
Me
O
N
S
N
Me
13
Scheme 4. Confirmation of structures of 9 and 10. Reagents and conditions:
(a) 2,20-diaminodiphenyldisulfide, NaH, DMF (93%); (b) SiO2, toluene,
reflux (63%); (c) n-Bu4NHSO4, 50% NaOH, CH3I, toluene, reflux [from
9 (76%), from 12 (89%)].
1
These factors are supported by the sharp, well-resolved H
NMR spectra of 2ab and 6ab in contrast to the severely
broadened H NMR spectra of compounds in which the
1
amidic nitrogen is methylated. Further restricting conforma-
tional flexibility of these compounds is a strong S]O/H–N
intramolecular hydrogen bond as evidenced by IR26 and 1H
NMR27 spectra.
2.2. Indoleanilides substituted at C-3
Syntheses of 3-indoleanilide sulfoxides (15a, 17ab) were
similar to those for the 2-substituted analogues. Reproduci-
bility problems were encountered with the reported33 prep-
aration of 3-indole carboxylic acid while preparing 14a, so
the tert-butyl analogue (14b) was prepared directly from
indole and 2-(tert-butylthio)aniline in the presence of tri-
phosgene and pyridine in 33% yield. Methylation and oxida-
tion provided 17b.
Compounds in which the amidic site is methylated (but still
contain an indolic N–H) (4ab) cyclize both thermally and
with TFAA activation to 10,11-dihydro-10-methyl-12H-in-
dolo[3,2-b]-1,5-benzothiazepin-11-one (9). Dimethylated
compounds 8abc react to give 10,11-dihydro-10,12-dime-
thylindolo[3,2-b]-1,5-benzothiazepin-11-one (10). Due to
competing side reactions, yields of 10 from 2-propanenitrile
compounds were inferior to both ethyl and tert-butyl sulf-
oxides and were not pursued further.
Cyclizations of sulfoxides 15a, 17ab were conducted under
both thermal and TFAA activation. As shown in Scheme 5,
results in this series were mixed. Like its 2-substituted indole
counterpart, the compound with an amidic N–H (15a) did
not cyclize under any conditions attempted. Compound
17a, which had a broad 1H NMR spectrum, gave a cyclized
product in good yield under thermal conditions, but decom-
posed to an intractable tar under TFAA activation. The tert-
butyl sulfoxide 17b, although it too had the 1H NMR and IR
patterns of successfully cyclized sulfoxides, decomposed
(under both thermal and TFAA activation).
As with product 9, spectral data for 10 clearly shows that cy-
clization was effected, however, additional proof of structure
was sought due to the possibility of migration of amide or
sulfur groups either during the reaction or subsequent equil-
ibration of products.28,29 Resultant isomeric compounds
would be expected to exhibit very similar spectral proper-
ties. Fortunately, rearrangement-scrambled product (13) is
a known compound. The UV spectrum and melting point
of our cyclization product differs considerably from that of
13 reported by Grandolini and co-workers30 ruling out this
The product obtained from heating 17a under reflux for
15 h in p-xylene (67% yield after chromatography) proved

12188
M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
intermediates have been proposed (for example, 1935 and
O
R
R
H
N
H
N
S
S
2036). However, the products observed derive from preferen-
tial sulfur migration in the 3H-indolium species. 3H-Indolic
S(IV)/ketone or amide spirocyclic intermediates have not
been invoked previously, although Hartke and Wendebourg5d
proposed 2H- and 3H-pyrrolium sulfonium dications as inter-
mediates in the acid-promoted sigmatropic [1,5] rearrange-
ment of 2-pyrrolylsulfonium salts to 3-pyrrolylsulfonium
salts.
O
O
a
N
N
H
H
15a R1 = H R2 = H
14ab
b
O
R
R
Me
Me
N
S
S
O
O
N
Me
N
a
CO2Me
SPh
O
O
S
N
N
Me
S
Et
N
H
Me
N
N
16ab
Me
17ab
18
19
20
see Table
a series R = Et
b series R = t-Bu
Formation of 10 via a spirocyclic intermediate requires
migration of the amide group to occur in preference to an
arylsulfonium group37 (or arylsulfanyl group if sulfur dealkyl-
ation precedes migration; the timing of events and the form of
the sulfur substituent are unknown). Both 3-acylindoles34 and
simple 3-alkylthio- and 3-arylthioindoles38 undergo acid-
catalyzed isomerization to their 2-substituted counterpart in
thermodynamically controlled processes (under significantly
more acidic conditions than used here). However, when both
acyl and sulfur groups are present at indole C-2/C-3, the ther-
modynamically more stable product cannot be determined by
inspection and, in this work, neither the product nor the alter-
native isomer is interconverted under the conditions of the
reaction. Thus, the product that forms predominately could
be a kinetic product derived by migration in a spirocyclic in-
termediate of the group having the greater migratory aptitude.
S
N
Me
N
Me
O
10
Product (% yield 1H NMR
Sulfoxide
υS=O
(cm-1)
1003
1014
1030
TFAA, thermal)
- (0, 0)
(rt)
15a
17a
17b
sharp
broad
broad
10 (0, 67%)
- (0, 0)
Scheme 5. Preparation and SES reactions of 3-indoleanilides. Reagents and
conditions: (a) m-CPBA, CH2Cl2, ꢂ10 ꢀC (15a 96%, 17a 72%, 17b 49%);
(b) n-Bu4HSO4, 50% NaOH, CH3I, toluene, reflux (16a 90%, 16b 73%).
2.3. A comment on the sulfenic acid pathway for SES
chemistry
to be identical to 10, the cyclization product from the
2-substituted indole sulfoxide. Mechanistically, there are
several possible explanations for this observation.
Sulfenylation of nucleophilic nitrogen via a sulfenic acid
generated from a sulfoxide is reported to occur under nearly
the same conditions reported here ((CCl3CO)2O/pyridine or
refluxing toluene/pyridine).39 Glucosulfinylpropanenitriles40
as well as tert-butyl alkyl sulfoxides,41 upon mild heating in
an inert solvent, generate transient sulfenic acids that have
been trapped.
ꢁ Migration of the amide group from C-3 to C-2 of indole
prior to cyclization (17a/8a/10). However, heating
the sulfide 16a (which cannot cyclize via SES) for
12 h in p-xylene showed no evidence of migration
(95% recovery of unchanged starting material). There
is literature precedence for acyl migration from C-3 to
C-2 in indoles but typically strongly acidic conditions
are required.34
ꢁ Initial formation of 13 by direct cyclization to C-2, fol-
lowed by rearrangement to 10 upon prolonged heating in
p-xylene, as we had observed previously in another in-
dolic system.28 However, authentic 13 (synthesized as
reported by Grandolini and co-workers)30 showed no
sign of rearrangement to 10 after 22 h in refluxing
p-xylene. Even an additional 24 h at reflux in 0.1%
TFA in p-xylene solution resulted in 92% recovery of
unchanged starting material.
To explore the possibility that 10 may also form via a tran-
sient sulfenic acid, we conducted thermal reactions of 8b
in the presence of a sulfenic acid trapping agent. When 8b
was refluxed in chloroform in the presence of 2-mercapto-
benzothiazole42 (1 M equiv) cyclization product 10 was ob-
tained in 32% yield (compared to 66% yield in the absence
of the trapping agent). This result demonstrates the reaction
does not require a sulfenic acid pathway. However, it does
not allow elimination of this pathway entirely, even though
the reduced yield may be due to the trapping agent interfer-
ing with sulfoxide activation in the SES pathway.
ꢁ Initial formation of a 3H-spirocyclic intermediate (such
as 18) during SES, followed by amide migration to C-2
and loss of a proton to give 10.
In some reactions of tert-butyl sulfoxides, small amounts of
21 and 22 were isolated in addition to cyclized product.
These compounds are indicative of sulfenic acid forma-
tion,43 but were never detected in reactions of ethyl sulfox-
ides. Yields of cyclized product from tert-butyl sulfoxides
Formation of product 10 via amide migration is unprece-
dented. Several examples of ketone/S(II)-based spirocyclic

M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
12189
were considerably lower when 21/22 were found in the crude
4.2. N-[2-(Ethylthio)phenyl]-1H-indole-2-carboxamide
(1a)
reaction product. In earlier work, we isolated sulfonium salts
from SES reactions.6a We believe sulfenic acids are not in-
termediates in SES sulfenylation reactions and, if formed,
produce side reactions.
4.2.1. Method A. To a well-stirred solution of indole-2-carb-
oxylic acid (10.0 g, 60 mmol) in Et2O (194 mL) at 0 ꢀC
under a drying tube was added dropwise, SOCl2 (9.6 mL,
140 mmol, 2.2 equiv) neat over 5 min. The mixture was
allowed to warm to room temperature. After stirring an
additional 2 h, volatiles were removed invacuo leaving a yel-
low solid, which was redissolved in Et2O (96 mL) and added
to a well-stirred solution of 2-(ethylthio)aniline (2 equiv,
18.4 g, 0.12 mol) in Et2O (96 mL) over 8 min at 0 ꢀC. The
resulting yellow slurry was stirred for 50 min at 0 ꢀC and
at room temperature for 30 min at which time the mixture
was diluted with EtOAc (100 mL). The combined organics
were washed with 5% aq HCl (3ꢃ150 mL), 5% aq NaHCO3
(3ꢃ150 mL), H2O (2ꢃ100 mL), dried (Na2SO4), and the
solvent evaporated in vacuo to yield a wet orange solid. Col-
umn chromatography (1:1 CHCl3/hexane) gave a yellow
solid, 1a (5.7 g, 32%). Analytically pure material could be
obtained by recrystallization from acetone. Mp 153–
S
S
N
N
N
N
N
Me
Me
Me
N
Me
O
O
21
S
S
O2
N
Me
Me
N
Me
O
O
Me
22
The difference in the two sulfenylation reaction pathways
(shown in Scheme 1) is in the timing of the departure of
the R0 substituent on the sulfoxide. It must be able to leave
easily for successful SES processes, but not so easily as to
depart prematurely (resulting sulfenic acid formation); it is
important to conduct reactions for 2-propanenitrile and
tert-butyl sulfoxides below the threshold for sulfenic acid
formation to obtain optimal yields of SES products.
1
155 ꢀC; IR 3350, 3298, 1654 cmꢂ1; H NMR (200 MHz)
d 10.09 (1H, d, J¼0.6 Hz), 9.51 (1H, s), 8.60 (1H, dd,
J¼1, 6 Hz), 7.65 (1H, dd, J¼0.6, 8 Hz), 7.53 (1H, dd,
J¼1, 6 Hz), 7.44 (1H, dd, J¼0.6, 8 Hz), 7.00–7.40 (5H,
m), 2.76 (2H, q, J¼7 Hz), 1.18 (3H, t, J¼7 Hz,); 13C NMR
d 160.2, 140.1, 137.6, 136.3, 131.5, 131.0, 128.1, 125.4,
124.6, 123.2, 122.6, 121.3, 120.4, 112.8, 103.4, 31.3, 15.3;
MS [m/z (relative intensity)] 296 (M+, 54), 235 (75), 153
(100). Anal. Calcd for C17H16N2OS: C, 68.90; H, 5.44; N,
9.45. Found: C, 68.70; H, 5.55; N, 9.34.
3. Conclusions
Both 2- and 3-indoleanilides (8abc and 17a) undergo cycli-
zation to produce the same product-indolo[3,2-b]-1,5-
benzothiazepin-11-one (10). For the 3-indoleanilides, the
possibility of indole substituent migration before or after
cyclization was eliminated and a 3H-indolinium spirocyclic
intermediate, with preferential migration of the amide-con-
taining moiety from C-3 to C-2, is proposed to rationalize
the rearrangement. We also discovered that successful cycli-
zation in this series requires the absence of an amidic hydro-
gen in the compounds. The lack of cyclization of compounds
containing an amidic hydrogen is attributed to N–H/O]S
hydrogen bonding, a low energy trans-amide conformation,
and a formidable rotational barrier to the cis-amide con-
formation, all of which enforce a molecular geometry that
precludes the sulfur atom from achieving an orientation con-
ducive to interaction with indole p-electrons. By extrapola-
tion, if cyclized compounds containing an amidic hydrogen
are synthetic targets, one should consider introducing an
easily removable amidic alkyl substituent (e.g., benzyl)
into the SES substrate.
4.2.2. Method B. To an N2-flushed flask containing toluene
(123 mL) was added trimethylaluminum (2.0 M in hexane,
21 mL, 42 mmol, 1.14 equiv) via a syringe dropwise. CAU-
TION: pyrophoric. This solution was cooled to 5 ꢀC and
2-(ethylthio)aniline (5.7 g, 37 mmol) in toluene (18 mL)
was added dropwise. After stirring 20 min at 5 ꢀC, the so-
lution was allowed to warm to room temperature over a 45-
min period. To the resulting solution was added dropwise
ethyl indole-2-carboxylate (7.0 g, 37 mmol) in toluene
(62 mL) and CH2Cl2 (18 mL). When the addition was
complete the reaction mixture was heated to reflux. After
refluxing 16 h, the cooled solution was hydrolyzed by
slow addition of 2% aq HCl (45 mL). The layers were sep-
arated and the aqueous layer extracted with EtOAc
(3ꢃ50 mL). The combined organics were washed with sat-
urated NaCl and then with H2O, dried (Na2SO4), and the
solvent evaporated in vacuo to yield a yellow solid
(9.8 g, 92%) as a single spot on TLC, which was identical
to the compound prepared above (1H NMR and mixed
melting point).
4. Experimental
4.1. General
4.3. N-[2-(Ethylsulfinyl)phenyl]-1H-indole-2-carb-
oxamide (2a)
To a well-stirred solution of 1a (0.5 g, 1.5 mmol) in THF/
MeOH (2.5 mL/1 mL) at 0 ꢀC was added all at once a solu-
tion of OxoneÒ in H2O (2.5 mL). The resulting mixture was
stirred at 0 ꢀC for 5 min then at room temperature for 2.5 h
then extracted with CH2Cl2 (2ꢃ10 mL). The combined
organics were washed with H2O, dried (Na2SO4), and the
solvent removed in vacuo to yield a light yellow solid, which
1
Melting points are uncorrected. H and 13C NMR spectra
were determined in CDCl3 solutions unless otherwise in-
dicated. IR spectra were recorded in KBr pellets for solid
samples and neat on NaCl plates for liquid samples. Mass
spectra were recorded at 70 eV (EI) unless indicated
otherwise.

12190
M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
1
was recrystallized in MeOH to yield a very pale yellow solid,
2a (0.3 g, 58%). Mp 156–157 ꢀC; IR 3289, 3168, 1662,
1009 cmꢂ1; 1H NMR (200 MHz) d 11.84 (1H, s, br), 10.29
(1H, s, br), 8.80 (1H, dd, J¼1, 8 Hz), 7.10–7.72 (8H, m, con-
taining 1H at d 7.45, dd, J¼1, 8 Hz), 3.07–3.19 (2H, dm),
1.26 (3H, t, J¼7 Hz); 13C NMR d 160.4, 141.6, 133.0,
131.2, 128.2, 127.7, 127.2, 127.1, 125.4, 125.1, 123.5,
122.9, 121.1, 112.4, 104.8, 48.9, 7.8; MS [m/z (relative
intensity)] 312 (M+, 63), 283 (20), 144 (100). Anal. Calcd
for C17H16N2O2S: C, 65.36; H, 5.16; N, 8.97. Found: C,
65.35; H, 5.33; N, 8.86.
290 ꢀC (dec); IR 3228, 1618 cmꢂ1; H NMR (200 MHz,
DMSO-d6) d 12.13 (1H, s, br), 7.15–7.67 (8H, m), 3.51
(3H, s); MS [m/z (relative intensity)] 280 (M+, 100). Anal.
Calcd for C16H12N2OS: C, 68.55; H, 4.31; N, 9.51. Found:
C, 68.63; H, 4.65; N, 9.91.
4.6.2. Method B (electrophilic activation). The reaction
was carried out as for 8a (see Section 4.7) with TFAA
(0.2 mL, 1.2 mmol, 3.75 equiv) in CH2Cl2 (2 mL), pyridine
(0.1 mL, 1.2 mmol, 4 equiv), and 4a (0.10 g, 0.3 mmol) in
CH2Cl2 (1 mL). Stirring at 0 ꢀC for 15 min, then at room
temperature for 0.5 h, yielded 9 as a yellow solid (0.3 g,
75%).
4.4. N-[2-(tert-Butylsulfinyl)phenyl]-N-methyl-
1H-indole-2-carboxamide (4b)
4.7. 10,11-Dihydro-10-methyl-12H-indolo[3,2-b]-1,5-
benzothiazepin-11-one (9) from 4b
To an ice-cooled solution of 3b (5.0 g, 14.8 mmol) in
CH2Cl2 (150 mL) was added slowly a solution of m-CPBA
(77%, 1.1 equiv, 21.1 mmol, 3.6 g) in CH2Cl2 (50 mL).
The resulting mixture was stirred at 0 ꢀC for 15 min and
then put it in a freezer (ꢂ8 ꢀC) overnight. The reaction mix-
ture was then poured into 5% NaHCO3 solution (150 mL)
and extracted with CH2Cl2 (200 mL). The combined organic
layer was washed with distilled water, dried, and concen-
trated in vacuo. Column chromatography (EtOAc/hexane,
9:1) gave a yellowish white solid, which was recrystallized
(hexane) to give a white solid (3.68 g, 70%). Mp 114–
4.7.1. Method A (thermal cyclization). A solution of 4b
(0.73 g, 2.1 mmol) in chloroform (75 mL) was heated under
reflux for 64 h. The solution was cooled to room temperature
precipitating a white solid (9, 0.33 g, 58%). Mp 295 ꢀC
1
(dec); IR 1619 cmꢂ1; H NMR d 10.61 (br, 1H), 7.56 (d,
J¼8.0 Hz, 1H), 7.42 (d, J¼8.0 Hz, 1H), 7.28 (d, J¼8.28 Hz,
1H), 7.17–7.19 (m, 2H), 7.11 (dt, J¼6.99, 1.07 Hz, 1H),
6.95–7.03 (m, 2H), 3.44 (s, 3H); MS [m/z (relative intensity)]
280 (M+, 100), 248 (27).
1
116 ꢀC; IR 3453, 1624 cmꢂ1; H NMR and 13C NMR was
not well-resolved due to presence of rotational isomers;
MS [m/z (relative intensity)] 144 (6), 56 (58), 41 (100).
4.7.2. Method B (electrophilic activation). The reaction
was carried out as for 8a (see Section 4.7) with TFAA
(0.45 g, 2.1 mmol, 3.75 equiv) in CH2Cl2 (20 mL), pyridine
(0.18 g, 2.3 mmol, 4 equiv), and 4b (0.20 g, 0.57 mmol) in
CH2Cl2 (15 mL). Stirring at 0 ꢀC for 15 min, then at room
temperature for 30 min, yielded 9 (0.16 g, 100%).
4.5. N-[2-(Ethylthio)phenyl]-N,1-dimethyl-1H-indole-
2-carboxamide (7a)
To a well-stirred suspension of 1a (5.2 g, 17 mmol) and
tetra-n-butylammonium sulfate (0.6 g, 2 mmol, 0.1 equiv)
in toluene (22 mL) was added 50% aq NaOH solution
(22 mL) in one portion. The resulting two-layer mixture
was heated to reflux and a solution of CH3I (5.4 g, 38
mmol, 2.2 equiv) in toluene (5 mL) added dropwise over
5 min. This mixture was refluxed for 24 h, cooled to room
temperature and the layers separated. The organic layer
was washed with H2O several times (until washings were
neutral to litmus), dried (Na2SO4), and the solvent evapo-
rated in vacuo to yield a brown solid, which was filtered
through a silica gel column (1:1 CHCl3/hexane) to give 7a
(4.7 g, 82%) as a white solid. Recrystallization (acetone)
4.8. 10,11-Dihydro-10,12-dimethylindolo[3,2-b]-
[1,5]benzothiazepin-11-one (10) from 8a
4.8.1. Method A (thermal cyclization). A solution of 8a
(1.0 g, 3 mmol) in p-xylene (35 mL) was heated under reflux
for 30 h. Solvent was removed in vacuo and the brown resi-
due was passed through a silica gel column (CHCl3) to give
10 (0.2 g, 22%). Mp 198–200 ꢀC; IR 1627 cmꢂ1; 1H NMR
(200 MHz) d 7.77 (1H, d, J¼0.9 Hz), 7.73 (1H, d, J¼
0.9 Hz), 7.08–7.58 (6H, m), 3.91 (3H, s), 3.62 (3H, s); 13C
NMR d 163.5, 146.0, 138.2, 137.4, 132.3, 131.0, 128.9,
126.2, 125.8, 125.5, 125.0, 120.6, 120.3, 117.5, 110.1,
38.6, 31.6; MS [m/z (relative intensity)] 294 (M+, 100).
Anal. Calcd for C17H14N2OS: C, 69.36; H, 4.79; N 9.52.
Found: C, 69.35; H, 4.89; N, 9.28.
1
gave pure 7a. Mp 127–128 ꢀC; IR 1635 cmꢂ1; H NMR
(200 MHz) d 6.95–7.38 (8H, m), 6.07 (1H, s), 3.97 (3H, s),
3.41 (3H, s), 2.80 (2H, apparent qd, J¼7.2, 4.9, 2.3 Hz,),
1.20 (2H, t, J¼7.3 Hz); 13C NMR d 164.6, 143.1, 138.4,
136.5, 132.3, 129.0, 128.8, 128.6, 127.9, 126.5, 123.7
122.2, 120.1, 110.1, 107.1, 37.2, 32.0, 26.4, 14.2; MS [m/z
(relative intensity)] 324 (M+, 2), 158 (100). Anal. Calcd
for C19H20N2OS: C, 70.34; H, 6.21; N, 8.63. Found: C,
70.27; H, 6.34; N, 8.58.
4.8.2. Method B (electrophilic activation). To a well-
stirred solution of TFAA (1.4 mL, 11 mmol, 3.75 equiv) in
CH2Cl2 (17 mL) at 0 ꢀC was added neat pyridine (1 mL,
12 mmol, 4 equiv) via syringe. To this solution was added,
8a (1 g, 3 mmol) in CH2Cl2 (9 mL), which had been previ-
ously cooled to 0 ꢀC. After stirring at 0 ꢀC for 15 min then
at room temperature for 3 h, the solution was poured into
a 10% aq Na2CO3 (30 mL) and stirred for 5 min. The layers
were separated and the aqueous layer washed with CH2Cl2
(1ꢃ30 mL). The combined organics were washed with 5%
HCl (3ꢃ40 mL), 10% aq Na2CO3 (1ꢃ40 mL), H2O, and
dried (Na2SO4). The solvent removal in vacuo gave a yellow
solid 10 (0.8 g, 90%). Mp 196–198 ꢀC.
4.6. 10,11-Dihydro-10-methyl-12H-indolo[3,2-b]-
[1,5]benzothiazepin-11-one (9) from 4a
4.6.1. Method A (thermal cyclization). A solution of 4a
(1.7 g, 5 mmol) in p-xylene (66 mL) was heated under reflux
for 12 h. Upon cooling to room temperature, the solution
was filtered to give a green solid, 9 (0.8 g, 56%). Mp

M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
12191
4.9. Trapping experiment
J¼1.4, 6.2 Hz), 7.25–7.48 (4H, m), 7.07 (1H, td, J¼1.4,
6.2 Hz), 2.78 (2H, q, J¼7 Hz), 1.20 (3H, t, J¼7 Hz); 13C
NMR d 165.4, 141.5, 138.2, 136.8, 131.0, 130.8, 125.8,
125.1, 124.4, 124.3, 123.3, 121.8, 121.2, 113.9, 113.5,
31.7, 16.1; MS [m/z (relative intensity)] 296 (M+, 12), 153
(100). Anal. Calcd for C17H16N2OS: C, 68.89; H, 5.44; N,
9.45. Found: C, 68.49; H, 5.62; N, 9.44.
To a solution of 8b (0.1 g, 0.27 mmol) in chloroform
(50 mL) was added 2-mercaptobenzothiazole (1.0 equiv,
0.27 mmol, 45.0 mg) and the resulting mixture was heated
under reflux for 72 h (until no starting material on TLC).
The solution was allowed to cool to room temperature
and the solvent was evaporated in vacuo to yield a brown
solid. Column chromatography (CH2Cl2) gave 10 (0.025 g,
32%).
4.13. N-[2-(tert-Butylthio)phenyl]-1H-indole-3-carb-
oxamide (14b)
4.10. 3-[(2-Aminophenyl)thio]-1H-indole-2-carboxylic
acid (11)
Triphosgene (1.1 g, 3.66 mmol) in toluene (5 mL) was
added to a well-stirred solution of indole (1.3 g, 11.0 mmol)
and pyridine (0.88 g, 11.0 mmol) in CH2Cl2 (40 mL) drop-
wise over 30 min at 25 ꢀC. The resulting dark red mixture
was stirred for 3.5 h at 25 ꢀC under drying tube. Solvent
was evaporated in vacuo to half of its volume and CH2Cl2
(10 mL) was added followed by a solution of 2-(tert-butyl-
thio)aniline (4.0 g, 22.1 mmol) in CH2Cl2 (25 mL) drop-
wise. The resulting dark green mixture was stirred at room
temperature under a drying tube for 4 h. The reaction mix-
ture was washed with 5% HCl (3ꢃ50 mL), 5% Na2CO3
(3ꢃ50 mL), H2O (50 mL). Drying (Na2SO4) and solvent
removal in vacuo and column chromatography (CH2Cl2)
gave a white solid (14b, 1.20 g, 33%). Mp 185–187 ꢀC; IR
To a well-stirred suspension of NaH (1.1 g, 45 mmol,
3.0 equiv) in dry DMF (30 mL) under N2 at room tempera-
ture was added dropwise a solution of indole-2-carboxylic
acid (2.4 g, 15 mmol) in DMF (10 mL). After the evolution
of H2 had ceased, a solution of 2,20-diaminodiphenyldisulfide
(15 mmol) in DMF (5 mL) was added dropwise and the dark
colored solution was heated at 50 ꢀC for 24 h, then poured
into H2O (75 mL) and extracted with Et2O (3ꢃ50 mL).
The aqueous layer was acidified to pHw5–6 precipitating
a light brown solid (11, 4.1 g, 93%). The solid was used in
the next step without purification.
1
3335, 1637 cmꢂ1; H NMR d 9.88 (br, 1H), 9.64 (br, 1H),
4.11. 10,11-Dihydro-10,12H-indolo[3,2-b][1,5]benzo-
thiazepin-11-one (12)
8.76 (d, J¼7.88 Hz, 1H), 8.46 (d, J¼7.88 Hz, 1H), 7.89 (d,
J¼2.64 Hz, 1H), 7.58 (d, J¼7.74 Hz, 1H), 7.46 (t, J¼
7.03 Hz, 2H), 7.32 (t, J¼7.03 Hz, 1H), 7.25 (t, J¼7.74 Hz,
1H), 7.08 (t, J¼7.74 Hz, 1H), 1.27 (s, 9H); 13C NMR
d 163.6, 142.1, 138.7, 136.8, 130.8, 129.5, 124.3, 123.0,
121.8, 120.3, 120.2, 120.0, 112.6, 112.4, 48.5, 31.0, 30.8;
MS [m/z (relative intensity)] 324 [M+, 13], 268 (6), 144
(100), 125 (24), 57 (5).
A suspension of 11 (5 g, 17.6 mmol) and SiO2 (column chro-
matographic grade, 20 g) in toluene (250 mL) was heated
under reflux for 13 h under a Dean–Stark trap. The partially
cooled reaction mixture was filtered through a sintered glass
funnel and the SiO2 washed with 1:1 CH2Cl2/MeOH
(50 mL) and then with MeOH (2ꢃ30 mL). The combined
organics were evaporated in vacuo and the light brown solid
recrystallized to produce 12 (2.95 g, 63%) as an off-white
solid. Mp 237–239 ꢀC (50% EtOH); IR 3414, 3197,
1654 cmꢂ1; 1H NMR (200 MHz) d 12.14 (1H, s, br), 10.46
(1H, s, br), 7.12–7.70 (8H, m); 13C NMR d 164.7, 142.3,
137.6, 133.0, 131.5, 130.6, 130.3, 127.0, 126.9, 126.8, 126.3,
125.2, 121.8, 120.8, 114.0; MS [m/z (relative intensity)]
266 (M+, 100). Anal. Calcd for C15H10N2OS: C, 67.65; H,
3.78; N, 10.52. Found: C, 67.48; H, 4.12; N, 10.42.
4.14. N-[2-(Ethylsulfinyl)phenyl]-1H-indole-3-carb-
oxamide (15a)
Yield 96%. Mp 60–61 ꢀC; IR 3217, 3168, 1652, 1003 cmꢂ1
;
1H NMR (200 MHz) d 11.15 (1H, s); 9.72 (1H, s), 8.71 (1H,
d, J¼8 Hz), 8.40–8.45 (1H, m), 7.90 (1H, d, J¼3 Hz), 7.06–
7.60 (6H, m), 3.02–3.24 (2H, dm), 1.18 (3H, t, J¼7 Hz); 13C
NMR d 164.9, 142.8, 137.8, 134.1, 128.8, 128.2, 127.3,
125.6, 124.4, 124.0, 123.8, 123.1, 122.7, 113.1, 113.0,
49.3, 8.8; MS [m/z (relative intensity)] 312 (M+, 15), 144
(100). Anal. Calcd for C17H16N2O2S: C, 65.36; H, 5.16;
N, 8.97. Found: C, 65.48; H, 5.23; N, 8.99.
4.12. N-[2-(Ethylthio)phenyl]-1H-indole-3-carboxamide
(14a)
To a magnetically stirred solution of indole-3-carboxylic
acid (1.5 g, 9 mmol) in THF (20 mL) at 0 ꢀC was added
dropwise neat oxalyl chloride (2.3 g, 18 mmol, 2 equiv). Af-
ter 12 h at room temperature, the solvent was evaporated in
vacuo and the yellow residue (in dichloroethane (40 mL))
was added to a mechanically stirred solution of 2-(ethylthio)-
aniline (2.8 g, 18 mmol, 2 equiv) in dichloroethane (30 mL).
After 5 h at room temperature, the mixture was washed with
5% HCl (3ꢃ50 mL), 5% NaHCO3 (3ꢃ50 mL), H2O, and
dried (Na2SO4). The solvent was evaporated in vacuo to
leave a dark brown oil. Column chromatography (CHCl3)
produced 14a as a faint brown solid (0.9 g, 35%). Mp
4.15. N-[2-(Ethylthio)phenyl]-N,1-dimethyl-1H-indole-
3-carboxamide (16a)
To a stirred suspension of 14a (1.8 g, 6.1 mmol) and tetra-
n-butylammonium sulfate in toluene (10 mL) was added
50% aq NaOH (7 mL) in one portion. After refluxing for
2 h, a solution of CH3I (1.9 g, 13.3 mmol, 2.2 equiv) in tol-
uene (2 mL) was added and the mixture heated under reflux
for an additional 17 h. The organics were collected, washed
with H2O until neutral to litmus, dried (Na2SO4), the
volatiles removed in vacuo, and the brown solid chromato-
graphed (CHCl3) to produce 16a (1.8 g, 90%) as an off-
1
103–105 ꢀC; IR 3352, 3216, 1638 cmꢂ1
;
1H NMR
white solid. Mp 172–173 ꢀC (acetone); IR 1621 cmꢂ1; H
(200 MHz) d 9.31 (1H, s), 8.66 (1H, dd, J¼1.3, 7 Hz),
NMR (200 MHz) d 8.41–8.46 (1H, m), 7.12–7.34 (7H, m),
6.06 (1H, d, J¼0.6 Hz), 3.49 (3H, s), 3.38 (3H, s), 2.90
8.31–8.36 (1H, m), 7.88 (1H, d, J¼3 Hz), 7.58 (1H, dd,

12192
M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
(2H, apparent qd, J¼7.1, 0.2 Hz), 1.27 (3H, t, J¼7.0 Hz);
13C NMR d 166.7, 143.6, 138.4, 136.8, 132.6, 130.3,
124.4, 124.2, 127.5, 126.7, 123.5, 123.2, 122.0, 110.0,
109.8, 37.3, 33.8, 26.2, 14.5; MS [m/z (relative intensity)]
324 (M+, 3), 158 (100). Anal. Calcd for C19H20N2OS:
C, 70.34; H, 6.21; N, 8.63. Found: C, 70.28; H, 6.41;
N, 8.69.
Acknowledgements
The authors thank the NSF for an equipment grant (CHE-
9512445). We would like to thank Professor G. Grandolini
(University of Parugia, Italy) for providing information
about the preparation and spectral properties of compound
13. P.V.J. thanks the Chemistry Department of Michigan
Technological University for financial support. The assis-
tance of Mr. Jerry L. Lutz (NMR instrumental assistance)
and Mr. Shane Crist (computer-related issues) is gratefully
acknowledged.
4.16. N-[2-(tert-Butylthio)phenyl]-N,1-dimethyl-1H-
indole-3-carboxamide (16b)
To a well-stirred suspension of 14b (1.1 g, 3.4 mmol) and
tetra-n-butylammonium hydrogensulfate (0.3 equiv, 1 mmol,
0.35 g) in toluene (100 mL) was added all at once 50% aq
NaOH solution (100 mL). The resulting two-layer mixture
was heated to reflux and a solution of iodomethane
(2.5 equiv, 8.5 mmol, 1.20 g) in toluene (10 mL) was added
dropwise over 5 min. The resulting two phase mixture
was maintained at reflux for 87 h. After cooling, the
organic layer was collected and washed with water several
times (until washings were neutral to litmus), dried over
Na2SO4, and evaporated in vacuo to yield an off-white solid.
Purification by column chromatography (chloroform/ether
9:1) gave16b as a white solid (0.87 g, 73%). Mp 156–
Supplementary data
Experimental procedures for 2-(ethylthio)-N-methylaniline,
2-(tert-butylthio)-N-methylaniline, ethyl N-methylindole-2-
carboxylate, 1b, 2b, 3ab, 4a, 5ab, 6ab, 7bc, 8abc, and the
1
thermal and TFAA-promoted cyclization of 8b; H NMR
and 13C NMR spectra for 1b–3b, 5b–8b, 7c, 10, 14b, and
16b; 1H NMR for 4b and 9. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.09.050.
158 ꢀC; IR 1630 cmꢂ1 1H NMR d 8.34–8.41 (m, 1H),
;
References and notes
7.59 (d, J¼7.72 Hz, 1H), 7.31–7.39 (m, 2H), 7.28 (ddd,
J¼7.71, 2.12 Hz, 1H), 7.17–7.22 (m, 2H), 7.10–7.16 (m,
1H), 5.81 (s, 1H), 3.43 (s, 6H), 1.29 (s, 9H); 13C
NMR d 166.1, 147.6, 136.5, 136.0, 131.6, 129.0, 128.9,
128.2, 127.3, 122.6, 122.3, 121.0, 109.8, 108.9, 46.7, 32.8,
31.6; MS [m/z (relative intensity)] 295 (12), 263 (21), 158
(100).
1. For recent reviews see: (a) Lucchi, O. D.; Miotti, U.; Modena,
G. Organic Reactions; Paquette, L. A., Ed.; Wiley: New York,
NY, 1991; Vol. 40, pp 157–405; (b) Padwa, A.; Gunn, D. E., Jr.;
Osterhout, M. H. Synthesis 1997, 1353–1377; (c) Padwa, A.;
Waterson, A. G. Curr. Org. Chem. 2000, 4, 175–203; (d)
Sano, T. Trends Heterocycl. Chem. 2001, 7, 117–142; (e)
Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401–2432.
2. (a) Pyne, S. G.; Hajipour, A. R. Tetrahedron 1994, 50, 13501–
13510; (b) Amat, M.; Hadida, S.; Pshenichnyi, G.; Bosch, J.
J. Org. Chem. 1997, 62, 3158–3175; (c) Arnone, A.; Bravo,
P.; Bruche, L.; Crucianelli, M.; Zanda, M.; Zappala, C.
J. Chem. Res., Synop. 1997, 416–417; (d) Kawasaki, T.;
Suzuki, H.; Sakaya, I.; Nakanishi, H.; Sakamoto, M.
Tetrahedron Lett. 1997, 38, 3251–3252; (e) Amat, M.; Llor,
N.; Coll, M. C.; Casamitjana, N.; Bosch, J. ARKIVOC 2004,
14–25; http://www.arkat-usa.org/ark/journal/2004/Melendez/
EM-755K/755K.pdf.
4.17. N-[2-(Ethylsulfinyl)phenyl]-N,1-dimethyl-1H-
indole-3-carboxamide (17a)
Yield 72%; mp 188–189 ꢀC (acetone); IR 1627, 1014 cmꢂ1
;
1H NMR (200 MHz, taken at 100 ꢀC in DMSO-d6) d 8.25–
8.31 (1H, m), 7.96–8.01 (1H, m), 7.19–7.60 (7H, m), 6.25
(1H, s), 3.54 (3H, s), 3.46 (3H, s), 2.56–2.80 (2H, m), 1.12
(3H, t, J¼6.6 Hz); 13C NMR d 167.0, 143.3, 143.1, 137.4,
133.5, 133.2, 133.0, 130.3, 121.9, 124.3, 123.7, 123.1,
123.0, 110.6, 110.5, 50.8, 49.5, 34.5, 7.3; MS [m/z (relative
intensity)] 340 (M+, 0.2), 158 (100). Anal. Calcd for
C19H20N2O2S: C, 67.03; H, 5.92; N, 8.23. Found: C,
67.25; H, 6.10; N, 8.27.
3. (a) Bates, D. K.; Sell, B. A.; Picard, J. A. Tetrahedron Lett.
1987, 28, 3535–3538.
4. (a) Wang, L. X.; Soczka-Guth, T.; Havinga, E.; Muellen, K.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1495–1497; (b)
Horiguchi, Y.; Sonobe, A.; Saitoh, T.; Toda, J.; Sano, T.
Chem. Pharm. Bull. 2001, 49, 1132–1137; (c) Becht, J.-M.;
Wagner, A.; Mioskowski, C. J. Org. Chem. 2003, 68, 5758–
5761.
5. (a) Hocker, J.; Ley, K.; Merten, R. Synthesis 1975, 334–335; (b)
Hartke, K.; Teuber, D.; Gerber, H.-D. Heterocycles 1986, 24,
2399–2402; (c) Hartke, K.; Teuber, D.; Gerber, H.-D.
Tetrahedron 1988, 44, 3261–3270; (d) Wendebourg, H. H.;
Hartke, K. Synthesis 1989, 329–331.
6. Feldman, K. S. Tetrahedron 2006, 62, 5003–5034. These chem-
istries have been compared on identical compounds (SES/sulf-
oxide6a,6b and PIFA/sulfide6c,6d); (a) Picard, J. A.; Chen, S.;
Bates, D. K. Heterocycles 1994, 38, 1775–1789; (b) Bates,
D. K.; Winters, R. T.; Picard, J. A. J. Org. Chem. 1992, 57,
3094–3097; (c) Huang, H.-Y.; Wang, H. M.; Kang, I.-J.;
4.18. N-[2-(tert-Butylsulfinyl)phenyl]-N,1-dimethyl-1H-
indole-3-carboxamide (17b)
To an ice-cooled solution of 16b (0.82 g, 2.30 mmol) in
CH2Cl2 (50 mL) was added slowly a solution of m-CPBA
(77%, 1.1 equiv, 3.32 mmol, 0.57 g) in CH2Cl2 (10 mL).
The resulting mixture was stirred at 0 ꢀC for 15 min and
then put it in a freezer (ꢂ8 ꢀC) overnight. The reaction mix-
ture was then poured into 5% aq NaHCO3 solution (50 mL)
and extracted with CH2Cl2 (50 mL). The combined organic
layer was washed with distilled water, dried, and concen-
trated in vacuo. Column chromatography (acetone/CH2Cl2,
1:1) gave white solid (0.42 g, 49%). Mp 159–160 ꢀC; IR
1
1631, 1030 cmꢂ1; H NMR and 13C NMR were not well-
resolved due to presence of rotational isomers; MS [m/z
(relative intensity)] 294 (35), 158 (100).

M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
12193
Chen, L.-C. J. Chin. Chem. Soc. 2003, 50, 1057–1060; (d)
Wang, H. M.; Lin, M. C.; Chen, L. C. J. Chin. Chem. Soc.
1994, 41, 217–220.
17. (a) Kermack, W. O.; Perkin, W. H., Jr.; Robinson, R. J. Chem.
Soc. 1921, 119, 1602–1642 (Chem. Abstr. 1921, 16, 367); (b)
Szmuszkovicz, J. J. Org. Chem. 1964, 29, 178–184; (c)
Boatman, R. J.; Whitlock, H. W. J. Org. Chem. 1976, 41,
3050–3051; (d) Bergman, J.; Carlsson, R.; Sjoberg, B.
J. Heterocycl. Chem. 1977, 14, 1123–1134.
18. Augelli-Szafran, C. E.; Blankley, C. J.; Roth, B. D.; Trivedi,
B. K.; Bousley, R. F.; Essenburg, A. D.; Hamelehle, K. L.;
Krause, B. R.; Stanfield, R. L. J. Med. Chem. 1993, 36,
2943–2949.
7. Chou, T. S.; Burgtorf, J. R.; Ellis, A. L.; Lammert, S. R.;
Kukolja, S. P. J. Am. Chem. Soc. 1974, 96, 1609–1610.
8. The most well studied example of this process is the Morin ring
expansion8a,b used to convert penam sulfoxides into cepham
antibiotics. Viehe et al.8c has reported a related intermolecular
counterpart that utilizes tert-butyl sulfoxides as latent sulfenyl
cations (via RSOCOCF3) for addition to alkenes. (a) Morin,
R. B.; Jackson, B. G.; Mueller, R. A.; Lavagnino, E. R.;
Scanlon, W. B.; Andrews, S. L. J. Am. Chem. Soc. 1963, 85,
1896–1897; (b) Morin, R. B.; Jackson, B. G.; Mueller, R. A.;
Lavagnino, E. R.; Scanlon, W. B.; Andrews, S. L. J. Am.
Chem. Soc. 1969, 91, 1401–1407; (c) Brichard, M. H.;
Musick, M.; Janousek, Z.; Viehe, H. G. Synth. Commun.
1990, 20, 2379–2386.
9. Some optically active sulfoxides have been shown to racemize
(even at room temperature) via a process of syn-b elimination
to an achiral sulfenic acid followed by recyclization to racemic
sulfoxide: (a) Stoodley, R. J.; Wilkins, R. B. J. Chem. Soc.,
Perkin Trans. 1 1974, 1572–1579; (b) Berges, D. A.; Taggert,
J. J. J. Org. Chem. 1985, 50, 413–415; See also: (c) Lee,
W. S.; Hahn, H. G.; Nam, K. D. J. Org. Chem. 1986, 51,
2789–2795.
10. (a) Hoard, D. W.; Luke, W. D. U.S. Patent 5,569,772, 1996;
Chem. Abstr. 1996, 126, 7983; (b) Hoard, D. W.; Luke, W. D.
U.S. Patent 5,514,826, 1996; Chem. Abstr. 1996, 125, 86485;
(c) Aikins, J. A.; Zhang, T. Y. Patent Application WO 96-
US9167 19960604, 1996; Chem. Abstr. 1996, 126, 117861;
(d) Hoard, D. W.; Luke, W. D.; Johnson, R. A. Book of
Abstracts, 214th ACS National Meeting, Las Vegas, NV,
September 7–11, 1997; ORGN-326; (e) Zhang, T. Y.;
O’Toole, J. C.; Aikins, J.; Sullivan, K. A. Book of Abstracts,
213th ACS National Meeting, San Francisco, CA, April 13–
17, 1997; ORGN-175.
19. Node, M.; Itoh, A.; Nishide, K.; Abe, H.; Kawabata, T.;
Masaki, Y.; Fuji, K. Synthesis 1992, 1119–1124.
20. (a) Terney, A. L., Jr.; Chasar, D. W.; Sax, M. J. Org. Chem.
1967, 32, 2465–2470; (b) Terney, A. L., Jr.; Ens, L.;
Herrmann, J.; Evans, S. J. Org. Chem. 1969, 34, 940–945.
21. (a) Alkyl¼Et, prepared using the general procedure of
Barluenga, J.; Bayon, A. M.; Asensio, G. J. Chem. Soc.,
Chem. Commun. 1984, 1334–1335; (b) See Section 4; (c)
Kuliev, A. M.; Agaeu, A. N.; Mamedov, F. A. Ser. Khim.
Nauk. 1971, 32–36 (Chem. Abstr. 1984, 77, 151594).
22. Gajda, T.; Zwierzak, A. Synthesis 1981, 1005–1008.
23. Both 2-cyanoethyl and tert-butyl sulfoxides are known to
undergo both SES-type reactions and sulfenic acid formation
at much lower temperatures than methyl or ethyl sulfoxides:
Shelton, J. R.; Davis, K. E. Int. J. Sulfur Chem. 1973, 3,
205–216.
24. Jog, P. V.; Brown, R. E.; Bates, D. K. J. Org. Chem. 2003, 68,
8240–8243.
25. (a) Oki, M. Applications of Dynamic NMR Spectroscopy to
Organic Chemistry; VCH: Deerfield Beach, FL, 1985; (b)
Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem.
1995, 60, 4715–4720.
26. Sulfoxide bands in the IR spectra of 2ab and 6ab appear
at lower frequency than those of compounds in the amidic
NH series: Furukawa, N.; Fujihara, H. The Chemistry of
Sulfones and Sulfoxides; Patai, S., Rappoport, Z., Stirling,
C. J. M., Eds.; John Wiley and Sons: New York, NY, 1988;
pp 541–565.
11. Bates, D. K.; Tafel, K. A.; Xu, J. Heterocycl. Commun. 1996, 2,
115–116.
12. Bates, D. K.; Xia, M. J. Org. Chem. 1998, 63, 9190–9196.
13. Bates, D. K.; Tafel, K. A. J. Org. Chem. 1994, 59, 8076–
8080.
27. 1H NMR data suggesting intramolecular N–H/O]S hydro-
gen bonding is as follows. Oxidation of 3a to 4a (and 1a to
2a) results in a chemical shift change ofw0.2 ppm (downfield)
in the indolic N–H signal whereas oxidation of 5a to 6a (and 1a
to 2a) results in a chemical shift change of w2.2 ppm (down-
field) in the amidic N–H signal (in CDCl3 solution).
Comparing 1H NMR spectra recorded in CDCl3 to spectra
recorded in DMSO-d6 for compounds 2a, 9, and 12 indicates
that DMSO causes a small (w0.4 ppm) upfield shift in the ami-
dic N–H signal and a larger (w2.7 ppm) downfield shift in the
indolic N–H. Additionally, the temperature dependence values
for the amidic and indolic N–H signals (DdNH/DT, CDCl3
solution in the range 290–365 K) are ꢂ1.0 and ꢂ5.5 ppb/K,
respectively: (a) Soth, M. J.; Nowick, J. S. J. Org. Chem.
1999, 64, 276–281; (b) Gung, B. W.; Zhu, Z.; Everingham, B.
J. Org. Chem. 1997, 62, 3436–3437; (c) Kessler, H. Angew.
Chem., Int. Ed. Engl. 1982, 21, 512–523.
14. 3,3-Spirocyclic and other 3,3-disubstituted-3H-indolinium
species resulting from indole/electrophile interactions are
a common occurrence throughout indole chemistry: (a)
Jackson, A. H.; Smith, A. E. Tetrahedron 1965, 21, 989–
1000; (b) Jackson, A. H.; Naidoo, B.; Smith, P.
Tetrahedron 1968, 24, 6119–6129; (c) Jackson, A. H.;
Smith, A. E. Tetrahedron 1968, 24, 403–413; (d) Biswas,
K. M.; Jackson, A. H. Tetrahedron 1969, 25, 227–241;
(e) Jackson, A. H.; Naidoo, B. J. Chem. Soc., Perkin
Trans. 2 1973, 548–551; (f) Hallett, D. J.; Gerhard, U.;
Goodacre, S. C.; Hitzel, L.; Sparey, T. J.; Thomas, S.;
Rowly, M.; Ball, R. G. J. Org. Chem. 2000, 65, 4984–
4993; (g) Decker, M.; Faust, R.; Wedig, M.; Nieger, M.;
Holzgrabe, U.; Lehmann, J. Heterocycles 2001, 55, 1455–
1466.
28. Bates, D. K.; Habib, Q. A. J. Heterocycl. Chem. 1995, 32,
1477–1481.
29. Hamel, P.; Girard, M.; Tsou, N. N. J. Heterocycl. Chem. 1999,
36, 643–652.
30. Ambrogi, V.; Furlani, A.; Grandolini, G.; Papaioannou, A.;
Perioli, L.; Scarcia, V.; Tuttobello, L. Eur. J. Med. Chem.
1993, 28, 659–667.
15. Nippon Chemiphar Co. Ltd, Japanese Patent JP 59,27,870,
1971; Chem. Abstr. 1984, 101, 110729f.
16. (a) Alkyl¼Et: Nieforth, K. A. J. Pharm. Sci. 1963, 52, 1136–
1139; (b) Alkyl¼CH2CH2CN: Lankin, D. C.; Petterson,
R. C.; Velazquez, R. A. J. Org. Chem. 1974, 39, 2801–2803;
(c) Alkyl¼tert-Bu: Courtin, A.; von Tobel, H.-R.; Auerbach,
G. Helv. Chim. Acta 1980, 63, 1412–1419.
31. Atkinson, J. G.; Hamel, P.; Girard, Y. Synthesis 1988, 480–481.

12194
M. E. Eggers et al. / Tetrahedron 63 (2007) 12185–12194
32. Blade-Font, A. Tetrahedron Lett. 1980, 21, 2443–2446.
33. Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Sauders, J.;
Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.;
Waitling, K. J. Med. Chem. 1991, 34, 140–151.
J. Chem. Soc., Chem. Commun. 1989, 63–65; (d) Hamel, P.;
Girard, Y.; Atkinson, J. G. J. Org. Chem. 1992, 57, 2694–2699.
39. Wright, S. W.; Abelman, M. M.; Bostrom, L. L.; Corbett, R. L.
Tetrahedron Lett. 1992, 33, 153–156.
34. Jackson, A. H.; Naidoo, B.; Smith, A. E.; Bailey, A. S.;
Vandrevala, M. H. J. Chem. Soc., Chem. Commun. 1978,
779–781.
40. Aucagne, V.; Aversa, M. C.; Batattucci, A.; Bonacorsi, P.;
Giannetto, P.; Rollin, P.; Tatibouet, A. J. Org. Chem. 2002,
67, 6925–6930.
35. Engqvist, R.; Bergman, J. Tetrahedron 2003, 59, 9649–9653.
36. Nagarajan, K.; Arya, V. P.; Parthasarathy, T. N.; Shenoy, S. J.;
Shah, R. K.; Kulkarni, Y. S. Indian J. Chem. Soc., Sect. B 1981,
20, 672–679.
37. The migratory aptitude of an alkylsulfonium species in pyrro-
les5a appears to be roughly the same as an alkylthio group under
the same conditions: Kakushima, M.; Frenette, R. J. Org.
Chem. 1984, 49, 2025–2027.
41. (a) Bell, R.; Cottam, P. D.; Davies, J.; Jones, D. N. J. Chem.
Soc., Perkin Trans. 1 1981, 2106–2115; (b) Shelton, J. R.;
Davis, K. E. Int. J. Sulfur Chem. 1973, 3, 197–204.
42. (a) Kamiya, T.; Teraji, T.; Saito, Y.; Hashimoto, M.;
Nakaguchi, O.; Oku, T. Tetrahedron Lett. 1973, 3001–3004;
(b) See also: Micetich, R. G.; Maiti, S. N.; Singh, M. P.;
Tanaka, M.; Yamazaki, T.; Ogawa, K. Tetrahedron Lett.
1985, 26, 5971–5977.
38. (a) Harris, R. L. N.; McFadden, H. G. Aust. J. Chem. 1986, 39,
887–892; (b) Plate, R.; Ottenheijm, H. C. J. Tetrahedron 1986,
42, 4511–4516; (c) Hamel, P.; Girard, Y.; Atkinson, J. G.
43. (a) Block, E.; O’Connor, J. J. Am. Chem. Soc. 1974, 96, 3929–
3944; (b) Koch, P.; Ciuffarin, E.; Fava, A. J. Am. Chem. Soc.
1970, 92, 5971–5977.