A facile and efficient synthesis of thieno[2,3-c]furans and furo[3,4-b]indoles via a Pummerer-induced cyclization reaction

Article abstract of DOI:10.1021/jo9607929

The α-thiocarbocation generated from the Pummerer reaction of an o-heteroaroyl-substituted sulfoxide is intercepted by the adjacent keto group to produce an α-thio-substituted heteroaromatic isobenzofuran. In the presence of a suitable dienophile, the reactive o-xylylene undergoes a Diels-Alder cycloaddition followed by an acid-catalyzed ring-opening and aromatization to give heteroaromatic naphthalene derivatives. This one-pot procedure occurs smoothly with electron-deficient dienophiles. The tandem Pummerer cyclization-cycloaddition sequence also occurs intramolecularly using unactivated alkenyl tethers of variable length. With acetylenic dienophiles, the primary cycloadducts undergo in situ ring-opening to produce hydroxynaphthalene derivatives. In the absence of a dienophile, it was possible to prepare 4-(ethylthio)-6-phenylthieno[2,3-c]furan and 1-ethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole. Various synthetic approaches were used for the preparation of the requisite thiophene- and indole-derived sulfoxide precursors. The facility of the tandem Pummerer-Diels-Alder reaction was very dependent on the experimental conditions used to promote the reaction. The best results were achieved by employing a mixture of acetic anhydride and toluene which contained a catalytic quantity of p-toluenesulfonic acid. The presence of the acid effectively drives the reaction in the desired direction by preventing formation of the acetoxy sulfide, which corresponds to the normal Pummerer product.

Full text of DOI:10.1021/jo9607929

6166
J . Org. Chem. 1996, 61, 6166-6174
A F a cile a n d Efficien t Syn th esis of Th ien o[2,3-c]fu r a n s a n d
F u r o[3,4-b]in d oles via a P u m m er er -In d u ced Cycliza tion Rea ction †
C. Oliver Kappe and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received April 30, 1996X
The R-thiocarbocation generated from the Pummerer reaction of an o-heteroaroyl-substituted
sulfoxide is intercepted by the adjacent keto group to produce an R-thio-substituted heteroaromatic
isobenzofuran. In the presence of a suitable dienophile, the reactive o-xylylene undergoes a Diels-
Alder cycloaddition followed by an acid-catalyzed ring-opening and aromatization to give hetero-
aromatic naphthalene derivatives. This one-pot procedure occurs smoothly with electron-deficient
dienophiles. The tandem Pummerer cyclization-cycloaddition sequence also occurs intramolecularly
using unactivated alkenyl tethers of variable length. With acetylenic dienophiles, the primary
cycloadducts undergo in situ ring-opening to produce hydroxynaphthalene derivatives. In the
absence of a dienophile, it was possible to prepare 4-(ethylthio)-6-phenylthieno[2,3-c]furan and
1-ethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole. Various synthetic approaches were used for the
preparation of the requisite thiophene- and indole-derived sulfoxide precursors. The facility of the
tandem Pummerer-Diels-Alder reaction was very dependent on the experimental conditions used
to promote the reaction. The best results were achieved by employing a mixture of acetic anhydride
and toluene which contained a catalytic quantity of p-toluenesulfonic acid. The presence of the
acid effectively drives the reaction in the desired direction by preventing formation of the acetoxy
sulfide, which corresponds to the normal Pummerer product.
o-Quinodimethanes are highly reactive diene compo-
and have been the focus of considerable interest in both
the synthetic and theoretical communities.18,19 As highly
reactive heteroaromatic o-xylylenes, they readily partici-
pate in inter- and intramolecular 4+2-cycloaddition reac-
tions.18,19 Further synthetic manipulation of the initially
formed oxo-bridged cycloadduct usually provides an easy
entry into naphthalene derivatives and related polycyclic
aromatic ring systems. In many instances, the reactive
isobenzofuran derivative is generated in the presence of
a suitable dienophile. By comparison, heteroaromatic
isobenzofuran analogs, in particular five-membered het-
eroaromatic derivatives, have not been extensively stud-
ied and only a few examples of synthetically useful
Diels-Alder reactions of such species are known.20-27
Most notable among the heteroaromatic isobenzofurans
(2) reported in recent years are the furo[3,4-b]furans,20
thieno[2,3-c]furans,21,22 furo[3,4-d]isoxazoles,23 and furo-
nents that have been extensively utilized for the as-
sembly of a variety of polycyclic aromatic compounds.1
Heterocyclic analogs of o-xylylene are of considerable
interest for their potential in organic synthesis. Recently,
there has been an increasing number of reports on the
generation and reactivity of various heterocyclic o-xylyl-
enes containing one, two, or three heteroatoms.2-17
Isobenzofurans 1 correspond to one of the more interest-
ing members of the o-quinodimethane family of dienes
† This paper is dedicated to Professor Philip E. Eaton on the occasion
of his 60th birthday.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
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S0022-3263(96)00792-X CCC: $12.00 © 1996 American Chemical Society

Synthesis of Thieno[2,3-c]furans and Furo[3,4-b]indoles
J . Org. Chem., Vol. 61, No. 18, 1996 6167
Resu lts a n d Discu ssion
The classical Pummerer reaction can be initiated by a
variety of electrophilic reagents (Pummerer promoters).30
Acetic anhydride is by far the most commonly used
reagent and is often utilized as the solvent at reflux
temperature or in combination with other solvents or
cocatalysts. The more electrophilic trifluoroacetic anhy-
dride has also been employed since it allows the reaction
to proceed under very mild conditions in the presence of
basic (e.g. pyridine, triethylamine) or Lewis acid catalysts
(e.g. SnCl4). Another very useful promoter is trimethyl-
silyl trifluoromethanesulfonate (TMSOTf) since this re-
agent permits the reaction to be carried out at temper-
atures well below 0 °C. The latter two reagents are
frequently used if attack by the nucleophilic “counterion”
on the Pummerer intermediate is to be avoided.30 In our
earlier studies, we have successfully employed neat acetic
anhydride as the Pummerer promoter since we found it
to be highly effective for inducing the Pummerer reaction
in the isobenzofuran system. However, when thiophene-
or indolo-derived sulfoxides (vide infra) were used, the
desired cycloadducts were obtained in much lower yield
(10-20%), with the major product in most cases being
acetoxy sulfides of type 9.30 It became evident, therefore,
that a modified triggering protocol had to be developed
in order to achieve acceptable yields of the desired
heterocyclic cycloadducts. After considerable experimen-
tation with a variety of Pummerer promoters and co-
catalysts, we found that the highest yield of cycloaddition
that could be obtained from the cascade process utilized
a mixture of toluene and acetic anhydride which also
contained a catalytic quantity of p-toluenesulfonic acid
(p-TsOH).31 These conditions, whereby the sulfoxide is
[3,4-b]indoles.24-27 These 10π-systems are isoelectronic
with the pentalene dianion and have been of some
theoretical interest.20 MO calculations on these hetero-
isobenzofurans indicate that they possess little or no
aromatic character, and this is reflected in their high
chemical reactivity.20 Over the years, most of the studies
reported in the literature for these systems center on
their use as dienes in inter- and intramolecular Diels-
Alder reactions.20-27 Such cycloaddition processes allow
for a rapid entry into complex polyheterocyclic rings and
makes these compounds potentially useful for natural
product synthesis.
The vast majority of 2,3-methylene heteroaromatics
have been prepared by flash vacuum pyrolysis or by 1,4-
elimination from suitable precursors. One limitation of
these methods is that the precursors are sometimes not
easily available. Recently, we reported on the Pum-
merer-induced cyclization of keto sulfoxides28 as a method
to prepare thio-substituted isobenzofurans of type 4. The
R-thiocarbocation generated from the Pummerer reaction
of an o-benzoyl substituted sulfoxide is intercepted by the
adjacent keto group to produce isobenzofuran 4 as a
transient intermediate which undergoes a subsequent
Diels-Alder cycloaddition with an added dienophile. The
resulting cycloadduct 5 can be readily converted to
representatives of several types of arylnaphthalene lig-
nans.29 In a continuation of our studies in this general
area, we now report on an extension of the tandem
Pummerer-Diels-Alder sequence for the synthesis of
several thieno[2,3-c]furans and furo[3,4-b]indoles. The
results of these studies are described herein.
slowly added to a refluxing mixture of toluene, acetic
anhydride (10 equiv), p-TsOH (catalyst), and the ap-
propriate dienophile (2-3 equiv) gave consistently the
best results (>80% yields), both for inter- and intramo-
lecular cycloaddition reactions (vide infra). It should be
noted that when p-TsOH was used alone, the tandem
cascade process did not occur.30 Other standard Pum-
merer promoters such as trifluoroacetic anhydride or
TMSOTf were also ineffective and afforded in most cases
(23) Aâmann, L.; Palm, L.; Zander, M.; Friedrichsen, W. Chem. Ber.
1991, 124, 2481. Aâmann, L.; Friedrichsen, W. Heterocycles 1989, 29,
1003. Aâmann, Debaerdemaeker, T.; Friedrichsen, W. Tetrahedron
Lett. 1991, 32, 1161.
(24) Gribble, G. W.; Keavy, D. J .; Davis, D. A.; Saulnier, M. G.;
Pelcman, B.; Barden, T. C.; Sibi, M. P.; Olson, E. R.; BelBruno, J . J . J .
Org. Chem. 1992, 57, 5878 and references therein.
(25) Miki, Y.; Hachiken, H. Synlett 1993, 333.
(26) Shiue, J .-S.; Fang, J .-M. J . Chem. Soc., Chem. Commun. 1993,
1277.
(27) Nagel, J .; Friedrichsen, W.; Debaerdemaeker, T. Z. Naturforsch.
1993, B48, 213.
(28) Cochran, J . E.; Padwa, A. Tetrahedron Lett. 1995, 36, 3495.
(29) Cochran, J . E.; Padwa, A. J . Org. Chem. 1995, 60, 3938. Padwa,
A.; Cochran, J . E.; Kappe, C. O. J . Org. Chem. 1996, 61, 3706.
(30) For a review of the Pummerer reaction and different triggering
methods, see: DeLucchi, O.; Miotti, U.; Modena, G. Organic Reactions;
Paquette, L. A., Ed.; J ohn Wiley: 1991; Chapter 3, pp 157-184.
(31) Watanabe, M.; Nakamori, S.; Hasegawa, H.; Shirai, K.; Kuma-
moto, T. Bull. Chem. Soc. J pn. 1981, 57, 817.

6168 J . Org. Chem., Vol. 61, No. 18, 1996
Kappe and Padwa
Sch em e 1a
only the classical Pummerer products of type 9. The
presence of p-TsOH as a cocatalyst dramatically acceler-
ated the rate in which sulfoxides of type 7 undergo the
Pummerer transformation (7 f 8) as compared to reac-
tions carried out without any p-TsOH. The initially
formed thionium ion 8 can either be captured internally
by the adjacent carbonyl group32 to give, after proton loss,
the isobenzofuran intermediate 10 or it can react in the
traditional sense with an external nucleophile (i.e., AcO-)
to furnish the acetoxy sulfide 9. The presence of p-TsOH
effectively drives the reaction in the desired direction (8
f 10) either by preventing the formation of the acetoxy
sulfide 9 or by assisting the ejection of the acetoxy group
(9 f 8), should 9 be formed. Indeed, control experiments
with the thiophene-derived acetoxy sulfides of type 9
support the latter suggestion (vide infra). The presence
of p-TsOH also promotes the conversion of the primary
cycloadduct 11 into the aromatized product 12, thereby
adding another step to this series of cascade reactions.
In order to establish the feasibility of an intramolecular
Diels-Alder cycloaddition in the R-thio isobenzofuran
series, we first prepared sulfoxides 16 and 17 which
contain an alkenyl tether attached to the keto group.
Weinreb’s amide 1333 was treated with the appropriate
a
Reagents: (a) SOCl2, (b) MeNHOMe, (c) NBS, (d) EtSH, (e)
PhMgBr, (f) NaIO4/MeOH, (g) Ac2O/p-TsOH, (h) N-phenylmale-
imide or maleic anhydride/catalytic p-TsOH, (i) methyl acrylate.
lecular tandem Pummerer-Diels-Alder transformation
when subjected to the acetic anhydride/p-TsOH condi-
tions. It should be noted that bimolecular Diels-Alder
reactions of R-thioisobenzofurans with unactivated π-sys-
tems (e.g. cyclohexene) only proceed in low yield or not
at all.28 The high yielding intramolecular Diels-Alder
cycloaddition reaction of 18 and 19 is certainly related
to entropic factors which place the tethered double bond
in close proximity to the diene system. The products
isolated correspond to the thionaphthalene derivatives
22 and 23. Structures 22 and 23 were established by
spectroscopic methods and this was further confirmed by
desulfurization with Raney-Ni to give cyclopenta[a]-
naphthalene 2435 and tetrahydrophenanthrene 25,36
respectively.
We next turned our attention to the thiophene analogs
(Scheme 1). Thiophene-2-carboxylic acid 26 was con-
verted to the Weinreb amide 27 following standard
procedures.33 The (ethylthio)methyl functionality was
then introduced by NBS bromination and subsequent
displacement of bromide with ethanethiol.37 The result-
ing sulfide 28 was treated with phenylmagnesium bro-
Grignard reagent to give the corresponding acetophe-
none-derived sulfides 14 and 15, which were subse-
quently oxidized with sodium periodate34 in methanol to
produce sulfoxides 16 and 17 in good overall yield.
Although both sulfoxides 16 and 17 bear an unactivated
alkenyl tether, they smoothly underwent the intramo-
(32) DeGroot, A.; J ansen, B. J . M. J . Org. Chem. 1984, 49, 2034.
J ansen, B. J . M.; Bouwman, C. T.; DeGroot, A. Tetrahedron Lett. 1994,
35, 2977. J ommi, G.; Pagliarin, R.; Sisti, M.; Tavecchia, P. Synth.
Commun. 1989, 2467.
(33) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. For
a review of the chemistry of Weinreb amides, see: Sibi, M., P. Org.
Prep. Proced. Int. 1993, 25, 15.
(35) Seipioi, J .; Kawalek, B.; Mirek, J . Synthesis 1977, 701.
(36) Durland, J . R.; Adkins, H. J . Am. Chem. Soc. 1938, 60, 1501.
Ernst, R.; Stolle, R. Magn. Res. Chem. 1989, 27, 796.
(34) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282.
(37) Ono, N.; Miyake, H.; Saito, T.; Kaji, A. Synthesis 1980, 952.

Synthesis of Thieno[2,3-c]furans and Furo[3,4-b]indoles
J . Org. Chem., Vol. 61, No. 18, 1996 6169
mide to produce ketone 29, which in turn was oxidized
with sodium periodate to give sulfoxide 30. Treatment
of 30 with N-phenylmaleimide or maleic anhydride under
the tandem Pummerer-Diels-Alder conditions provided
benzo[b]thiophene derivatives 35 and 36 in excellent
yield. The initially formed primary cycloadducts 32 and
33 could not be isolated or observed. However, when the
reaction was carried out in the absence of a dienophile,
we were able to isolate thieno[2,3-c]furan 31 in 79% yield.
This isobenzofuran analog proved to be surprisingly
stable, and to the best of our knowledge corresponds to
the second example of a stable thieno[2,3-c]furan reported
in the literature.21 As expected, 31 cleanly afforded
thienoisoindole 35 (80%) when treated with N-phenyl-
maleimide in toluene in the presence of catalytic amounts
of p-TsOH at room temperature. It should be noted that
thienofuran 31 also underwent the Diels-Alder reaction
when the less reactive methyl acrylate was used as the
dienophile. Thus, treatment of 31 with methyl acrylate
in the presence of scandium(III) trifluoromethane-
sulfonate [Sc(OTf)3]38 for 2 days gave rise to benzo[b]-
thiophene 37 in 78% yield. This reaction also proceeded
in the absence of Sc(OTf)3 but in much lower yield.
Analysis of the crude reaction mixture by 1H-NMR failed
to reveal the presence of the alternate regioisomer. The
position of the ester group in 37 was determined by NOE
experiments, which showed a significant enhancement
of the signal for H5 upon irradiation of the CH3 and CH2
multiplets of the adjacent ethylthio group. The ethylthio
group plays a significant role in terms of influencing the
regiochemistry of the Diels-Alder reaction, since the
corresponding diphenyl derivative (i.e., 4,6-diphenyl-
thieno[2,3-c]furan) showed no regioselectivity, producing
a 1:1 mixture of regioisomeric cycloadducts when treated
with methyl acrylate.21 The formation of adduct 37 as a
single regioisomer is consistent with FMO theory. The
most favorable interaction is between the HOMO of the
thieno[2,3-c]furan and the LUMO of methyl propiolate.
The atomic coefficient at the ethylthio-substituted posi-
tion in the furan ring is larger than at the phenyl position
in the HOMO and this nicely accommodates the high
regioselectivity encountered.
Since furo[3,4-b]indoles have recently been employed
as intermediates in the synthesis of some naturally
occurring carbazole derivatives (e.g., ellipticine24 and
murrayaquinone A25), we decided to explore the potential
of the tandem Pummerer-Diels-Alder strategy toward
the synthesis of several substituted carbazoles. The
required sulfoxide 45 was prepared in the standard
manner as outlined below. The readily available N-
As was mentioned above, the use of the toluene/acetic
anhydride/p-TsOH reaction medium is critical for the
success of the reaction. Subjection of sulfoxide 30 to
standard Pummerer conditions (i.e., refluxing acetic
anhydride) led to a mixture of thienofuran 31 (23%) and
to an acetoxy sulfide (64%). This acetoxy sulfide could
be converted back to 31 by treatment with p-TsOH in
toluene, and then trapped with N-phenylmaleimide to
ultimately give cycloadduct 35.
(phenylsulfonyl)indole-2-carbaldehyde 4240 was first pro-
tected as an imine by treating it with tert-butylamine.
The resulting imine was subsequently brominated with
NBS to give bromomethyl derivative 43. Nucleophilic
displacement of the bromide by ethanethiol followed by
acidic hydrolysis of the imine produced aldehyde 44.
Oxidation of the sulfide in the usual manner gave
sulfoxide 45 in 58% overall yield (five steps).
Treatment of 45 with either N-phenylmaleimide or
maleic anhydride utilizing the Pummerer-Diels-Alder
conditions afforded the fused carbazoles 47 and 48 in
excellent yield. When the reaction was carried out in the
absence of a dienophile, it was possible to isolate furo-
The intramolecular variation of the tandem Pum-
merer-Diels-Alder sequence also occurred in the
thiophene series.21b,c The tethered sulfoxide 39 was
prepared by reaction of Weinreb’s amide 28 with pent-
enylmagnesium bromide followed by oxidation of the
resulting sulfide with sodium periodate. Subjection of
39 to the acetic anhydride/p-TsOH conditions led to
indeno[4,5-b]thiophene 41 in 85% yield. Here, the in-
tramolecular Diels-Alder sequence of 39 to 41 provides
an easy entry into this polycyclic ring system which is
far superior to the previously reported multistep prepa-
ration of related indeno[4,5-b]thiophenes.39
(39) Pailer, M.; Gruenhaus, H. Monatsh. Chem. 1974, 105, 1362.
Gruenhaus, H.; Pailer. M.; Stof, S. J . Heterocycl. Chem. 1976, 13, 1161.
(40) Benzies, D. W. M.; Fresneda, P. M.; J ones, R. A. Synth.
Commun. 1986, 16, 1799.
(38) For a review on the use of Sc(OTf)3 as catalyst in Diels-Alder
reactions, see: Kobayashi, S. Synlett 1994, 689.

6170 J . Org. Chem., Vol. 61, No. 18, 1996
Kappe and Padwa
[3,4-b]indole 46 in 78% yield. Although 46 is not as
stable as thienofuran 31, it could be obtained in a high
state of purity by rapid workup and chromatographic
purification of the reaction mixture. However, if kept at
room temperature, significant decomposition of 46 oc-
curred within days. As expected, a pure sample of
furoindole 46 readily reacts with N-phenylmaleimide in
the presence of p-TsOH to give pyrrolocarbazole 47.
Addition of dimethyl acetylenedicarboxylate (DMAD)
to furoindole 46 afforded carbazole diester 50 in 67%
yield. Here, the in situ ring-opening of the oxobridge in
Interestingly, with this regioisomer, the yields of cyclo-
adducts 56 and 57 were significantly lower (ca. 50%) as
compared to cycloadducts 47 and 48. Evidently, the
formation of furoindole 55 (36% yield from 54) is not as
efficient as in the case of the isomeric furoindole 46,
although the reasons for this are not fully understood at
the moment.
In conclusion, we have demonstrated that the tandem
Pummerer-Diels-Alder reaction sequence can be used
to efficiently synthesize a variety of polyheterocyclic ring
systems. The key intermediates in these cascade proc-
esses are R-thioisobenzofurans, which in some cases can
be isolated and independently reacted with an appropri-
ate dienophile to give 4+2-cycloadducts. We found it to
be most convenient to carry out these reactions in an all-
tandem fashion. Our results clearly indicate that the
tandem-cascade process is a powerful method for the
construction of complex heteroaromatic o-quino-
dimethanes. This area of research is currently being
pursued in more detail in our laboratories.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
residue was chromatographed on a silica gel column using an
ethyl acetate-hexane mixture as the eluent unless specified
otherwise.
intermediate 49 occurs even in the absence of an acidic
catalyst. Presumably, the ring-opening reaction is as-
sisted by the lone pair of electrons on the neighboring
sulfur atom. This assumption is supported by the fact
that some related oxo-bridged cycloadducts, where the
ethylthio group is replaced by a phenyl group, are quite
stable.24
In an extension of these studies, we have also inves-
tigated the reaction of the regioisomeric indolosulfoxide
54. The synthesis of 54 exactly parallels the preparation
1-(2-((Eth ylth io)m eth yl)p h en yl)h ex-5-en -1-on e (14). To
a stirred solution containing 2.39 g (10 mmol) of amide 1333
in 30 mL of dry THF was added dropwise via transfer syringe
a solution of pent-4-en-1-ylmagnesium bromide [prepared from
4.47 g (30 mmol) of 5-bromo-1-pentene and 0.77 g (32 mmol)
of Mg in 30 mL of dry THF] at 0 °C under argon. After stirring
at rt for 4 h, the mixture was poured into 5% HCl/ice-water
and extracted with ether. The combined organic layer was
washed with water, dried over Na2SO4, and concentrated
under reduced pressure. The resulting oil was purified by
flash silica gel chromatography to give 1.83 g (74%) of sulfide
14 as a colorless oil: IR (neat) 2925, 1687, 1438, 1232, 990,
and 755 cm-1 1H-NMR (CDCl3) δ 1.19 (t, 3H, J ) 7.5 Hz),
;
1.84 (quint, 2H, J ) 7.2 Hz), 2.15 (q, 2H, J ) 7.2 Hz), 2.42 (q,
2H, J ) 7.5 Hz), 2.92 (t, 2H, J ) 7.2 Hz), 3.98 (s, 2H), 5.01 (m,
2H), 5.79 (m, 1H), 7.26-7.39 (m, 3H), and 7.56 (d, 1H, J ) 7.2
Hz); 13C-NMR (CDCl3) δ 14.4, 23.0, 25.8, 33.0, 33.5, 40.9, 115.1,
126.7, 128.2, 130.5, 130.9, 138.0, 138.3, 138.6, and 204.7; MS
m/ e 248 (M+), 219, 186, 151, 145, 131, 119 (base), and 91;
HRMS (EI) calcd for C15H20OS 248.1235, found 248.1240.
1-(2-((Eth ylth io)m eth yl)ph en yl)h ept-6-en -1-on e (15) was
prepared by a similar method starting from 2.39 g (10 mmol)
amide 1333 and 6-bromo-1-hexene in 68% yield: IR (neat) 2926,
1
1685, 1439, 1221, and 904 cm-1; H-NMR (CDCl3) δ 1.20 (t,
3H, J ) 7.5 Hz), 1.50 (m, 2H), 1.74 (m, 2H), 2.10 (q, 2H, J )
7.2 Hz), 2.43 (q, 2H, J ) 7.5 Hz), 2.92 (t, 2H, J ) 7.5 Hz), 3.98
(s, 2H), 4.98 (m, 2H), 5.81 (m, 1H), 7.27-7.39 (m, 3H), and
7.57 (d, 1H, J ) 7.4 Hz); 13C-NMR (CDCl3) δ 14.5, 23.6, 25.9,
28.4, 33.5, 33.6, 41.6, 114.5, 126.8, 128.2, 130.5, 131.0, 138.4,
138.5, 138.7, and 204.9; MS m/ e 262 (M+), 233, 179, 151, 131,
119 (base), and 91; HRMS (EI) calcd for C16H22OS 262.1391,
found 262.1383.
1-(2-((Eth ylsu lfin yl)m eth yl)ph en yl)h ex-5-en -1-on e (16).
To a solution containing 2.08 g (8.4 mmol) of sulfide 14 in 50
mL of methanol was added 1.93 g (9 mmol) of sodium periodate
at 0 °C. Water was added to the mixture until the solution
began to turn cloudy (ca. 5-10 mL). After stirring for 5 h at
rt, water and CH2Cl2 were added to the reaction mixture. The
aqueous layer was extracted with CH2Cl2, and the combined
organic layer was washed with water, dried, and concentrated
under reduced pressure. The crude sulfoxide was purified by
flash silica gel chromatography to give 2.02 g (91%) of sulfoxide
of 45 as described above. In this case, the overall yield
of sulfoxide 54 starting from indole 5141 was 58%.
(41) Rubiralta, M.; Diez, A.; Vila, C.; Troin, Y.; Miguel, D. Hetero-
cycles 1991, 32, 1341.

Synthesis of Thieno[2,3-c]furans and Furo[3,4-b]indoles
16 as a pale yellow oil: IR (neat) 2932, 1680, 1445, 1225, 1040,
J . Org. Chem., Vol. 61, No. 18, 1996 6171
2H), 7.58 (d, 1H, J ) 8.4 Hz), 7.76 (d, 1H, J ) 8.4 Hz), and
7.93 (d, 1H, J ) 8.4 Hz); 13C-NMR (CDCl3) δ 22.9, 23.2, 25.7,
30.4, 122.7, 124.6, 125.6, 125.7, 128.2, 128.3, 131.5, 132.0,
132.5, and 134.3; MS m/ e 182 (M+, base), 165, 154, and 141.
N -Me t h oxy-N -m e t h yl-3-m e t h ylt h iop h e n e -2-ca r b ox-
a m id e (27). To a mixture containing 14.2 g (0.1 mol) of acid
26 and 200 mL of dry benzene was added 23.8 g (0.2 mol) of
thionyl chloride. The mixture was stirred for 24 h at 50 °C.
After the reaction was complete, the solvent and excess reagent
were removed under reduced pressure and the crude acid
chloride was dried under vacuum. The crude compound was
dissolved in 400 mL of dry CH2Cl2, and 10.72 g (0.11 mol) of
N,O-dimethylhydroxylamine hydrochloride was added. The
mixture was stirred under argon at 0 °C while 18.2 g (0.23
mol) of pyridine was added dropwise via syringe. Stirring was
continued for 2 h at rt, and then the mixture was washed with
brine and extracted with ether. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure to give
15.9 g (86%) of 27 as a colorless oil which was used without
further purification in the next step: IR (neat) 1631, 1413,
1355, 1200, and 977 cm-1; 1H-NMR (CDCl3) δ 2.55 (s, 3H), 3.33
(s, 3H), 3.71 (s, 3H), 6.90 (d, 1H, J ) 5.0 Hz), and 7.37 (d, 1H,
J ) 5.0 Hz); 13C-NMR (CDCl3) δ 16.8, 33.1, 61.5, 124.8, 128.9,
130.7, 146.2, and 164.0; MS m/ e 185 (M+), 125 (base), 97, 69,
53, and 45; HRMS (EI) calcd for C8H11NO2S 185.0511, found
185.0512.
N-Meth oxy-N-m eth yl-3-((eth ylth io)m eth yl)th iop h en e-
2-ca r boxa m id e (28). A mixture containing 9.25 g (50 mmol)
of amide 27, 9.79 g (55 mmol) of N-bromosuccinimide, 200 mg
of benzoyl peroxide, and 200 mL of carbon tetrachloride was
heated at reflux under argon for 1 h. The mixture was cooled
to rt and was filtered from the precipitated succinimide.
Evaporation of the solvent under reduced pressure left the
crude bromomethyl intermediate as a clear oil: 1H-NMR
(CDCl3) δ 3.37 (s, 3H), 3.72 (s, 3H), 4.98 (s, 2H), 7.18 (d, 1H,
J ) 5.0 Hz), and 7.45 (d, 1H, J ) 5.0 Hz). This material was
used in the next step without further purification.
1
1018, and 762 cm-1; H-NMR (CDCl3) δ 1.26 (t, 3H, J ) 7.5
Hz), 1.71 (quint, 2H, J ) 7.2 Hz), 2.03 (q, 2H, J ) 7.2 Hz),
2.57-2.77 (m, 2H), 2.87 (m, 2H), 3.84 (d, 1H, J ) 12.3 Hz),
4.52 (d, 1H, J ) 12.3 Hz), 4.91 (m, 2H), 5.71 (m, 1H), 7.29-
7.41 (m, 3H), and 7.72 (d, 1H, J ) 6.9 Hz); 13C-NMR (CDCl3)
δ 6.4, 22.8, 32.6, 39.7, 45.1, 56.4, 114.9, 127.9, 129.1, 130.8,
131.5, 132.8, 136.8, 137.5, and 203.2.
1-(2-((Eth ylsu lfin yl)m eth yl)ph en yl)h ept-6-en -1-on e (17).
A 2.20 g (8.4 mmol) sample of sulfide 15 was oxidized in a
manner similar to that described above using sulfide 14 and
sodium periodate/methanol to give 17 (88%) as a pale yellow
oil: IR (neat) 2931, 1680, 1443, 1221, 1041, 1017, and 904
cm-1 1H-NMR (CDCl3) δ 1.36 (t, 3H, J ) 7.5 Hz), 1.44 (m,
;
2H), 2.07 (m, 2H), 2.76 (m, 2H), 2.97 (t, 2H, J ) 7.5 Hz), 3.88
(d, 1H, J ) 12.0 Hz), 4.64 (d, 1H, J ) 12.0 Hz), 4.98 (m, 2H),
5.76 (m, 1H), 7.37-7.51 (m, 3H), and 7.82 (d, 1H, J ) 7.4 Hz);
13C-NMR (CDCl3) δ 6.4, 23.4, 28.0, 33.2, 40.4, 45.1, 56.6, 114.3,
127.9, 129.2, 131.0, 131.6, 132.8, 136.8, 138.0, and 203.3;
HRMS (EI) calcd for C16H22O2S 278.1341, found 278.1331.
Gen er a l P r oced u r e for t h e Ta n d em P u m m er er -
Diels-Ald er Rea ction Sequ en ce. A mixture of dry toluene
(10 mL), acetic anhydride (0.5 mL), and the appropriate
dienophile (1 mmol) containing a catalytic amount of p-
toluenesulfonic acid (ca. 1 mg) was heated at reflux under
argon. To this mixture was added dropwise a solution of the
appropriate sulfoxide (0.5 mmol) in dry toluene (5 mL) via
syringe over a 20 min period. For the intramolecular cyclo-
additions, the addition was carried out over a 1 h interval
using 25 mL of solvent. After the addition was complete, the
solution was heated at reflux for an additional 20 min until
no more sulfoxide was detected by TLC. The mixture was
evaporated to dryness and the crude residue was purified by
flash silica gel chromatography or by recrystallization.
5-(E t h ylt h io)-2,3-d ih yd r o-1H -cyclop en t a [a ]n a p h t h a -
len e (22) was obtained from 132 mg (0.5 mmol) sulfoxide 16
in 84% yield as a colorless oil: IR (neat) 2926, 1582, 1440,
1
1367, and 751 cm-1; H-NMR (CDCl3) δ 1.27 (t, 3H, J ) 7.5
To a solution containing 3.10 g (50 mmol) of ethanethiol in
200 mL of dry benzene was added dropwise 7.60 g (50 mmol)
of DBU. After stirring at 25 °C for 20 min, a solution of the
above bromomethyl derivative in 70 mL of dry benzene was
added dropwise within 30 min. After stirring for 2 h at rt,
the precipitated hydrobromide salt was filtered, and the
remaining solution was concentrated under reduced pressure
to leave behind an oil which was purified by flash silica gel
chromatography to give 8.70 g (71%) of 28 as a colorless oil:
Hz), 2.20 (quint, 2H, J ) 7.2 Hz), 2.93 (q, 2H, J ) 7.5 Hz),
3.06 (t, 2H, J ) 7.2 Hz), 3.20 (t, 2H, J ) 7.2 Hz), 7.44 (m, 2H),
7.56 (s, 1H), 7.76 (m, 1H), and 8.44 (m, 1H); 13C-NMR (CDCl3)
δ 14.5, 24.3, 29.0, 31.1, 33.7, 124.9, 125.0, 126.0, 126.8, 130.9,
131.4, 132.2, 139.1, and 140.7; MS m/ e 228 (M+, base), 199,
165, and 152; HRMS (EI) calcd for C15H16S 228.0973, found
228.0983.
9-(Eth ylth io)-1,2,3,4-tetr a h yd r op h en a n th r en e (23) was
obtained from 139 mg (0.5 mmol) of sulfoxide 17 in 81% yield
as a colorless oil: IR (neat) 2925, 1584, 1445, 1370, and 751
IR (neat) 1626, 1519, 1452, 1418, and 1360 cm-1
;
1H-NMR
(CDCl3) δ 1.23 (t, 3H, J ) 7.5 Hz), 2.52 (q, 2H, J ) 7.5 Hz),
3.34 (s, 3H), 3.70 (s, 3H), 4.18 (s, 2H), 7.14 (d, 1H, J ) 5.0
Hz), and 7.41 (d, 1H, J ) 5.0 Hz); 13C-NMR (CDCl3) δ 14.3,
25.59, 29.4, 32.9, 61.3, 125.6, 129.0, 129.5, 146.7, and 163.1;
MS m/ e 245 (M+), 214, 185, 157 (base), 153, 125, 96, 70, and
45; HRMS (EI) calcd for C10H15NO2S2 245.0544, found 245.0539.
2-Ben zoyl-3-((et h ylt h io)m et h yl)t h iop h en e (29). To a
solution containing 2.45 g (10 mmol) of amide 28 in 30 mL of
dry THF was added dropwise via syringe a solution of
phenylmagnesium Grignard (25 mmol, 25 mL of 1M THF
solution) at 0 °C under argon. After stirring for 2 h at 0 °C,
the mixture was poured into 5% HCl/ice and was extracted
with ether. The combined organic layer was washed with
water, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash silica gel chro-
matography to give 2.20 g (84%) of sulfide 29 as a colorless
oil: IR (neat) 1632, 1402, 1269, and 692 cm-1; 1H-NMR (CDCl3)
δ 1.19 (t, 3H, J ) 7.5 Hz), 2.47 (q, 2H, J ) 7.5 Hz), 4.07 (s,
2H), 7.25 (d, 1H, J ) 5.0 Hz), 7.42-7.55 (m, 4H), and 7.83
(dd, 2H, J ) 7.8 and 1.2 Hz); 13C-NMR (CDCl3) δ 14.4, 25.8,
29.3, 128.0, 129.0, 130.8, 131.1, 132.2, 135.1, 139.5, 146.7, and
189.0; MS m/ e 262 (M+), 233, 216, 202, 201 (base), 200, 199,
183, 171, 105, and 77; HRMS (EI) calcd for C14H14OS2
262.0486, found 262.0484.
1
cm-1; H-NMR (CDCl3) δ 1.39 (t, 3H, J ) 7.5 Hz), 1.90-2.00
(m, 4H), 2.95 (t, 2H, J ) 6 Hz), 3.02 (q, 2H, J ) 7.5 Hz), 3.13
(t, 2H, J ) 6 Hz), 7.43 (s, 1H), 7.59 (m, 2H), 8.02 (m, 1H), and
8.54 (m, 1H); 13C-NMR (CDCl3) δ 14.5, 22.8, 23.1, 25.5, 28.7,
30.3, 123.2, 125.0, 126.0, 125.9, 130.3, 131.1, 131.4, 131.8,
133.1, and 134.1; MS m/ e 242 (M+, base), 213, 181, and 165;
HRMS (EI) calcd for C16H18S 242.1129, found 242.1130.
2,3-Dih ydr o-1H-cyclop en ta [a ]n a p h th a len e (24). A mix-
ture of 228 mg (1 mmol) of 22, 25 mL of ethanol, 5 mL of water,
and 1 mL of Raney-Ni (50% slurry in water) was heated at
reflux for 48 h. After the sulfide had been consumed, the
mixture was filtered, and the catalyst was washed with warm
ethanol. The clear solution was concentrated under reduced
pressure and the residue was purified by flash silica gel
chromatography to give the known35 cyclopenta[a]naphthalene
24 (92%) as a colorless oil: 1H-NMR (CDCl3) δ 2.13 (quint,
2H, J ) 7.4 Hz), 3.02 (t, 2H, J ) 7.4 Hz), 3.15 (t, 2H, J ) 7.4
Hz), 7.30-7.43 (m, 3H), 7.60 (d, 1H, J ) 8.3 Hz), 7.71 (d, 1H,
J ) 8.1 Hz), and 7.77 (d, 1H, J ) 7.9 Hz); 13C-NMR (CDCl3) δ
24.5, 31.0, 33.7, 123.2, 124.2, 125.7, 126.6, 128.3, 130.4, 132.5,
139.3, and 140.8; MS m/ e 168 (M+, base), 167, 165, 152, and
115.
1,2,3,4-Tetr a h yd r op h en a n th r en e (25) was prepared in
an analogous fashion by treating 242 mg (1 mmol) of 23 with
Raney-Ni to give the known tetrahydrophenanthrene 25 (92%)
as a white solid: mp 32-34 °C (lit.36 mp 34-35 °C); 1H-NMR
(CDCl3) δ 1.85 (m, 2H), 1.94 (m, 2H), 2.88 (t, 2H, J ) 6 Hz),
3.08 (t, 2H, J ) 6 Hz), 7.17 (d, 1H, J ) 8.4 Hz), 7.37-7.48 (m,
2-Ben zoyl-3-((eth ylsu lfin yl)m eth yl)th iop h en e (30). A
262 mg (1 mmol) sample of sulfide 29 was oxidized in a manner
similar to that described with 14 using sodium periodate as
the oxidant to give 30 (88%) as a white solid: mp 86-87 °C;
IR (KBr) 1633, 1401, 1273, 1047, 1019, and 693 cm-1; 1H-NMR

6172 J . Org. Chem., Vol. 61, No. 18, 1996
Kappe and Padwa
(CDCl3) δ 1.36 (t, 3H, J ) 7.5 Hz), 2.76 (m, 2H), 4.29 (d, 1H,
J ) 12.8 Hz), 4.63 (d, 1H, J ) 12.8 Hz), 7.33 (d, 1H, J ) 5.0
Hz), 7.49 (dd, 2H, J ) 7.8 and 7.8Hz), 7.60 (dd, 1H, J ) 7.8
and 7.8 Hz), 7.62 (d, 1H, J ) 5.0 Hz), and 7.85 (dd, 2H, J )
7.8 and 1.2 Hz); 13C-NMR (CDCl3) δ 6.7, 45.2, 51.6, 128.2,
129.0, 131.6, 132.0, 132.5, 136.2, 138.3, 139.3, and 188.9. Anal.
Calcd for C14H14O2S2: C, 60.40; H, 5.07. Found: C, 60.34; H,
5.07.
22 mg (23%) of thienofuran 31 (fraction 1) and 73 mg (64%) of
acetic acid [[2-(2-benzoylthiophene-3-yl)ethyl]thio]methyl ester
(cf. 9) (fraction 2) as a yellow oil. The latter was 90% pure:
IR (neat) 1743, 1640, 1518, 1410, and 1260 cm-1
;
1H-NMR
(CDCl3) δ 1.28 (t, 3H, J ) 7.5 Hz), 2.08 (s, 3H), 2.68-2.86 (m,
2H), 7.36 (d, 1H, J ) 5.1 Hz), 7.43-7.59 (m, 4H), 7.61 (s, 1H),
and 7.85 (d, 2H, J ) 8.1 Hz). Prolonged standing at room
temperature led to decomposition, and consequently, the
product was used without further purification in the next step.
A mixture of 5 mL of dry toluene and 76 mg (0.44 mmol) of
N-phenylmaleimide containing a catalytic amount of p-tolu-
enesulfonic acid was heated at reflux under argon. A solution
containing 73 mg (0.22 mmol) of the above acetoxy sulfide in
2 mL of dry toluene was added dropwise via syringe within
20 min. After the addition was complete, the solution was
heated at reflux for an additional 5 min. The mixture was
evaporated to dryness and the resulting oil was purified by
flash silica gel chromatography to give 54 mg (60%) of pure
35, identical in all respects with the material obtained in the
tandem reaction described above.
1-(3-((E t h ylt h io)m e t h yl)t h iop h e n e -2-yl)h e x-5-e n -1-
on e (38). To a solution containing 2.45 g (10 mmol) of amide
28 in 30 mL of dry THF was added dropwise via syringe a
solution of pent-4-en-1-ylmagnesium bromide [prepared from
4.47 g (30 mmol) of 5-bromo-1-pentene and 0.77 g (32 mmol)
of Mg in 30 mL of dry THF] at 0 °C under argon. After stirring
for 2 h at 0 °C, the mixture was poured into 5% HCl/ice water
and was extracted with ether. The combined organic layer
4-(Eth ylth io)-6,8-d ip h en ylth ien o[2,3-f]isoin d ole-5,7-d i-
on e (35) was prepared from 139 mg (0.5 mmol) of sulfoxide
30 and 173 mg (1 mmol) of N-phenyl maleimide in 91% yield
as a pale yellow solid: mp 144-145 °C; IR (KBr) 1755, 1710,
1500, 1373, 1118, 759, and 693 cm-1; 1H-NMR (CDCl3) δ 1.29
(t, 3H, J ) 7.5 Hz), 3.25 (q, 2H, J ) 7.5 Hz), 7.34-7.59 (m,
10H), 7.75 (d, 1H, J ) 5.0 Hz), and 8.07 (d, 1H, J ) 5.0 Hz);
13C-NMR (CDCl3) δ 15.2, 30.9, 123.5, 126.0, 126.7, 127.8, 128.3,
128.5, 128.8, 129.0, 130.4, 131.7, 132.3, 134.6, 136.0, 146.3,
147.5, 165.8, and 165.9. Anal. Calcd for C24H17NO2S2: C,
69.37; H, 4.12; N, 3.37. Found: C, 69.25; H, 4.15; N, 3.36.
4-(Eth ylth io)-8-p h en ylth ien o[2,3-f]isoben zofu r a n -5,7-
d ion e (36) was prepared from 139 mg (0.5 mmol) of sulfoxide
30 and 98 mg (1 mmol) of maleic anhydride in 89% yield as a
pale yellow solid: mp 166-167 °C; IR (KBr) 1830, 1773, 1340,
1216, 1135, and 916 cm-1; 1H-NMR (CDCl3) δ 1.30 (t, 3H, J )
7.5 Hz), 3.26 (q, 2H, J ) 7.5 Hz), 7.58 (s, 5H), 7.90 (d, 1H, J )
5.0 Hz), and 8.09 (d, 1H, J ) 7.5 Hz); 13C-NMR (CDCl3) δ 15.2,
30.8, 122.5, 125.9, 127.7, 128.7, 129.0, 132.7, 133.5, 134.3,
137.6, 147.5, 148.4, 161.4, and 161.5. Anal. Calcd for
C18H12O3S2: C, 63.51; H, 3.55. Found: C, 63.58; H, 3.64.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of H et er o-
cyclic Isoben zofu r a n s 31, 46, a n d 55. A mixture containing
dry toluene (10 mL), acetic anhydride (0.5 mL), and a catalytic
amount of p-toluenesulfonic acid (ca. 1 mg) was heated at
reflux under argon. A solution of the appropriate sulfoxide
(0.5 mmol) in dry toluene (5 mL) was added dropwise via
syringe over a 20 min interval. After the addition was
complete, the solution was heated at reflux for an additional
10-15 min. The mixture was concentrated in vacuo to ca. 20%
of its original volume. The resulting toluene solution was
placed on a flash silica gel column and eluted first with hexane,
followed by a 6:1 hexane/ethyl acetate mixture. Using this
method the following compounds were prepared.
was washed with water, dried over Na2
SO4, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to give 2.06 g (81%) of sulfide 38 as
a colorless oil: IR (neat) 2924, 1665, 1519, 1408, 1234, and
909 cm-1 1H-NMR (CDCl3) δ 1.23 (t, 3H, J ) 7.5 Hz), 1.86
;
(m, 2H), 2.14 (m, 2H), 2.50 (q, 2H, J ) 7.5 Hz), 2.87 (t, 2H, J
) 7.4 Hz), 4.18 (s, 2H), 5.04 (m, 2H), 5.81 (m, 1H), 7.19 (d,
1H, J ) 5.0 Hz), and 7.41 (d, 1H, J ) 5.0 Hz); 13C-NMR (CDCl3)
δ 14.6, 23.5, 25.9, 29.4, 33.0, 41.2, 115.2, 129.2, 131.7, 135.7,
137.9, 146.2, and 193.6; MS m/ e 254 (M+), 194, 165, 157, 151,
140, 125 (base), 97, and 41; HRMS (EI) calcd for C13H18OS2
254.0799, found 254.0802.
1-(3-((Eth ylsu lfin yl)m eth yl)th iop h en e-2-yl)h ex-5-en -1-
on e (39). A 254 mg (1 mmol) sample of sulfide 38 was oxidized
in a manner similar to that described for sulfide 14 using
sodium periodate/methanol to give 39 (79%) as a pale yellow
oil: IR (neat) 2933, 1660, 1514, 1410, and 1051 cm-1; 1H-NMR
(CDCl3) δ 1.35 (t, 3H, J ) 7.5 Hz), 1.83 (m, 2H), 2.14 (m, 2H),
2.71 (m, 2H), 2.89 (t, 2H, J ) 7.2 Hz), 4.30 (d, 1H, J ) 12.3
Hz), 4.65 (d, 1H, J ) 12.3 Hz), 5.02 (m, 2H), 5.81 (m, 1H),
7.22 (d, 1H, J ) 5.0 Hz), and 7.52 (d, 1H, J ) 5.0 Hz); 13C-
NMR (CDCl3) δ 6.5, 23.2, 32.7, 40.8, 45.0, 51.4, 45.2, 129.6,
132.3, 136.5, 137.0, 137.3, and 193.5; HRMS (FAB) calcd for
C13H18LiO2S2 277.0908, found 277.0909 (M + Li)+.
4-(E t h ylt h io)-7,8-d ih yd r o-6H -in d en o[4,5-b]t h iop h en e
(41) was obtained from 135 mg (0.5 mmol) of sulfoxide 39 as
a colorless solid in 85% yield: mp 35-36 °C; IR (KBr) 1582,
1439, 1365, and 847 cm-1; 1H-NMR (CDCl3) δ 1.28 (t, 3H J )
7.5 Hz), 2.20 (m, 2H), 2.94 (q, 2H, J ) 7.5 Hz), 3.04 (m, 4H),
7.31 (s, 1H), 7.37 (d, 1H, J ) 5.0 Hz), and 7.60 (d, 1H, J ) 5.0
Hz); 13C-NMR (CDCl3) δ 14.7, 25.0, 29.0, 32.2, 33.2, 123.7,
125.1, 128.3, 136.1, 139.4, and 140.7; MS m/ e 234 (M+, base),
205, and 171. Anal. Calcd for C13H14S2: C, 66.62; H, 6.02.
Found: C, 66.60, H, 6.03.
3-((Eth ylth io)m eth yl)-1-(p h en ylsu lfon yl)-1H-in d ole-2-
ca r ba ld eh yd e (44). To a solution containing 8.97 g (30 mmol)
of aldehyde 4240 and 7.30 g (100 mmol) of distilled tert-
butylamine in 100 mL of dry CH2Cl2 was added 6 g of
molecular sieves (4 Å, activated). The mixture was heated at
reflux for 4 h, and then additional sieves were added to the
reaction mixture. After heating for an additional 12 h, the
resulting mixture was filtered, and the solvent was removed
under reduced pressure to give 10.3 g (97%) of the correspond-
ing imine: mp 142-143 °C; IR (KBr) 2960, 1632, 1445, 1362,
1218, and 1174 cm-1; 1H-NMR (CDCl3) δ 1.39 (s, 9H), 2.36 (s,
3H), 7.20-7.43 (m, 6H), 7.64 (m, 2H), 8.14 (m, 1H), and 8.74
(s, 1H); 13C-NMR (CDCl3) δ 9.9, 29.6, 58.5, 115.0, 119.9, 123.1,
123.9, 125.9, 126.5, 128.9, 131.9, 132.7, 133.5, 136.3, 137.5,
4-(Eth ylth io)-6-p h en ylth ien o[2,3-c]fu r a n (31) was ob-
tained from 139 mg (0.5 mmol) of sulfoxide 30 as a colorless
oil in 79% yield: IR (neat) 1597, 1481, 1447, 1253, 977, and
760 cm-1; 1H-NMR (CDCl3) δ 1.30 (t, 3H, J ) 7.5 Hz), 2.84 (q,
2H, J ) 7.5 Hz), 6.85 (d, 1H, J ) 5.0 Hz), 7.11 (d, 1H, J ) 5.0
Hz), 7.24 (dd, 1H, J ) 7.6 and 7.6 Hz), 7.43 (dd, 2H, J ) 7.6
and 7.6 Hz), and 7.63 (dd, 2H, J ) 7.6 and 1.2 Hz); 13C-NMR
(CDCl3) δ 15.5, 31.3, 115.2, 122.6, 123.6, 126.9, 128.8, 129.8,
132.7, 133.3, 142.2, and 145.1; MS m/ e 260 (M+), 231 (base),
203, 199, and 77; HRMS (EI) calcd for C14H12OS2 260.0330,
found 260.0326.
Met h yl 4-(et h ylt h io)-7-p h en ylb en zo[b]t h iop h en e-6-
ca r boxyla te (37). A mixture containing 66 mg (0.25 mmol)
of 31, 215 mg (2.5 mmol) of methyl acrylate, 12 mg (0.025
mmol) of Sc(OTf)3, and 10 mL of dry THF was stirred under
argon at 25 °C for 2 days. Evaporation of the solvent under
reduced pressure followed by silica gel chromatography gave
64 mg (78%) of cycloadduct 37 as a pale yellow oil: IR (neat)
1
1718, 1432, 1248, and 1127 cm-1; H-NMR (CDCl3) δ 1.39 (t,
3H, J ) 7.5 Hz), 3.10 (q, 2H, J ) 7.5 Hz), 3.63 (s, 3H), 7.39-
7.48 (m, 5H), 7.62 (m, 2H), and 7.90 (s, 1H); 13C-NMR (CDCl3)
δ 14.4, 27.9, 52.0, 123.1, 125.8, 126.2, 128.0, 128.3, 128.4, 130.8,
136.2, 139.6, 141.6, 142.4, and 168.0; MS m/ e 328 (M+, base),
299, 267, 240, 208, 196, 162, and 112; HRMS (EI) calcd for
C18H16O2S2 328.0592, found 328.0583.
Gen er a tion a n d Cycloa d d ition of th e Nor m a l P u m -
m er er P r od u ct Der ived fr om Th iop h en e Su lfoxid e 30.
A solution of 100 mg (0.36 mmol) of sulfoxide 30 in 10 mL of
acetic anhydride was heated at reflux under argon for 1 h.
The mixture was evaporated to dryness and the resulting oil
was dissolved in CH2Cl2. The solution was washed with
saturated aqueous NaHCO3, dried over Na2SO4, and concen-
trated under reduced pressure. The remaining oil was im-
mediately purified by flash silica gel chromatography to give

Synthesis of Thieno[2,3-c]furans and Furo[3,4-b]indoles
J . Org. Chem., Vol. 61, No. 18, 1996 6173
and 149.6. This compound was used directly in the next step
without further purification.
Calcd for C22H15NO5S2: C, 60.40; H, 3.46; N, 3.20. Found: C,
60.33; H, 3.52; N, 3.23.
A mixture of 3.54 g (10 mmol) of the above imine, 1.96 g
(11 mmol) of N-bromosuccinimide, 100 mg of benzoyl peroxide,
and 120 mL of carbon tetrachloride was heated at 65-70 °C
(bath temperature) with irradiation (150 W lamp) under argon.
The reaction was stopped immediately after all the NBS had
been consumed and succinimide was floating on the surface
(ca. 30 min) by rapid immersion of the reaction flask in an ice
bath. After filtration, the solvent was removed under reduced
pressure and the residue was crystallized to give 3.8 g (88%)
of the bromomethyl imine 43: mp 109-110 °C; IR (KBr) 2966,
1-(Eth ylth io)-4-(p h en ylsu lfon yl)-4H-fu r o[3,4-b]in d ole
(46) was obtained from 188 mg (0.5 mmol) of sulfoxide 45 as
a clear oil in 78% yield: IR (neat) 1448, 1368, 1134, and 956
cm-1; 1H-NMR (CDCl3) δ 1.22 (t, 3H, J ) 7.5 Hz), 2.84 (q, 2H,
J ) 7.5 Hz), 7.22-7.51 (m, 5H), 7.75 (d, 1H, J ) 7.5 Hz), 7.82
(m, 3H), and 7.96 (d, 1H, J ) 8.4 Hz); 13C-NMR (CDCl3) δ 15.3,
30.4, 114.8, 121.8, 122.2, 124.4, 125.6, 126.7, 126.9, 127.7,
128.9, 133.6, 133.9, 134.4, 136.5, 144.0; MS m/ e 357 (M+), 328,
216, 188, 141, and 77; HRMS (EI) calcd for C18H15NO3S2
357.0493, found 357.0492.
1
1627, 1445, 1373, and 1174 cm-1; H-NMR (CDCl3) δ 1.40 (s,
Dim eth yl 4-(eth ylth io)-1-h yd r oxy-9-(p h en ylsu lfon yl)-
ca r ba zole-2,3-d ica r boxyla te (50). A solution containing 60
mg (0.17 mmol) of furoindole 46 and 57 mg (0.48 mmol) of
dimethyl acetylenedicarboxylate in 10 mL of dry benzene was
heated at reflux under argon for 2 h. The benzene solution
was passed through a plug of silica gel and was concentrated
under reduced pressure. The crude material was purified by
silica gel chromatography to give 67 mg (67%) of 50 as a pale
yellow solid: mp 161-162 °C; IR (KBr) 1733, 1668, 1437, 1362,
9H), 4.94 (s, 2H), 7.31-7.68 (m, 8H), 8.16 (m, 1H), and 8.77
(s, 1H). This compound was used immediately in the next step
without further purification.
To a solution containing 310 mg (5 mmol) of ethanethiol in
50 mL of dry benzene was added dropwise 760 mg (5 mmol)
of DBU. After stirring at rt for 20 min, a filtered solution
containing 2.16 g (5 mmol) of imine 43 in 25 mL of dry benzene
was added dropwise. The mixture was stirred for 2 h at rt
and the precipitated hydrobromide salt was filtered and the
remaining solution was concentrated under reduced pressure.
The crude imine was dissolved in 20 mL of acetone and
hydrolyzed by the addition of 20 mL of 2 N HCl. After stirring
at rt for 30 min, the acetone was removed under reduced
pressure, and the resulting solid was filtered to give 1.33 g
(74%) of aldehyde 44 as a colorless solid: mp 113-114 °C; IR
1
and 1330 cm-1; H-NMR (CDCl3) δ 1.14 (t, 3H, J ) 7.5 Hz),
2.78 (q, 2H, J ) 7.5 Hz), 3.93 (s, 3H), 3.95 (s, 3H), 7.43-7.63
(m, 5H), 7.92 (dd, 2H, J ) 8.4 and 1.2 Hz), 8.42 (d, 1H, J )
8.4 Hz), 9.03 (d, 1H, J ) 8.4 Hz), and 11.97 (s, 1H); 13C-NMR
(CDCl3) δ 14.2, 31.1, 52.4, 53.2, 108.0, 116.5, 117.0, 124.3,
124.4, 126.0, 127.0, 128.2, 128.7, 129.3, 133.4, 135.2, 139.6,
139.7, 142.4, 152.0, 168.0, and 169.4. Anal. Calcd for
C24H21NO7S2: C, 57.70; H, 4.24; N, 2.80. Found: C, 57.55; H
4.30; N, 2.84.
(KBr) 1677, 1547, 1365, and 1178 cm-1
;
1H-NMR (CDCl3) δ
1.13 (t, 3H, J ) 7.5 Hz), 2.29 (q, 2H, J ) 7.5 Hz), 4.13 (s, 2H),
7.34-7.73 (m, 8H), 8.24 (m, 1H), and 10.60 (s, 1H); 13C-NMR
(CDCl3) δ 14.4, 24.4, 25.5, 115.9, 122.2, 124.9, 126.6, 129.1,
132.5, 132.9, 134.2, 136.7, 137.7, 140.4, and 184.8. Anal.
Calcd for C18H17NO3S2 C, 60.15; H, 4.77; N, 3.90. Found: C,
60.21; H, 4.80; N, 3.87.
2-((Eth ylth io)m eth yl)-1-(p h en ylsu lfon yl)-1H-in d ole-3-
ca r ba ld eh yd e (53). A sample of aldehyde 5141 (8.97 g, 30
mmol) was allowed to react with excess tert-butylamine in the
same manner as described above for aldehyde 42 to give 10.2
g (96%) of the corresponding tert-butylimine as a colorless solid,
mp 117-118 °C (lit.41 mp 113-114 °C). The imine was used
without further purification in the next step.
A mixture containing 3.54 g (10 mmol) of the above imine,
1.96 g (11 mmol) of N-bromosuccinimide, 100 mg of benzoyl
peroxide, and 120 mL of carbon tetrachloride was heated at
reflux under argon for 1.5 h. After cooling to rt, the mixture
was filtered and the solvent was removed under reduced
pressure. Crystallization of the residue gave 3.84 g (89%) of
N-tert-butyl-2-bromomethyl-1-(phenylsulfonyl)-1H-indole-3-
methanimine (52) as a colorless solid: mp 134-135 °C; IR
(KBr) 2970, 1643, 1450, 1364, and 1164 cm-1; 1H-NMR (CDCl3)
δ 1.34 (s, 9H), 5.37 (s, 2H), 7.32-7.58 (m, 5H), 7.96 (m, 2H),
8.13 (m, 1H), 8.34 (m, 1H), and 8.62 (s, 1H); 13C-NMR (CDCl3)
δ 22.0, 29.6, 58.4, 114.4, 120.5, 122.5, 124.5, 126.2, 127.0, 127.5,
129.2, 134.1, 136.6, 136.9, 138.5, and 147.2. Anal. Calcd for
C20H21BrN2O2S: C, 55.43; H, 4.88; N, 6.46. Found: C, 55.35;
H, 4.85; N, 6.43.
3-((Eth ylsu lfin yl)m eth yl)-1-(ph en ylsu lfon yl)-1H-in dole-
2-ca r b a ld eh yd e (45). To a solution containing 718 mg (2
mmol) of sulfide 44 in 15 mL of dioxane was added a solution
of 470 mg (2.2 mmol) of sodium periodate in 5 mL of water.
After the mixture was stirred for 24 h at rt, water and CH2Cl2
were added. The aqueous phase was extracted with CH2Cl2
and the combined organic layer was washed with water and
dried over Na2SO4. The organic layer was concentrated under
reduced pressure and the crude sulfoxide was purified by flash
silica gel chromatography to give 700 mg (92%) of pure 45 as
a white solid: mp 119-120 °C; IR (KBr) 1672, 1544, 1373,
1
and 1179 cm-1; H-NMR (CDCl3) δ 1.28 (t, 3H, J ) 7.5 Hz),
2.57 (m, 2H), 4.31 (d, 1H, J ) 12.9 Hz), 4.54 (d, 1H, J ) 12.9
Hz), 7.36-7.77 (m, 8H), 8.22 (m, 1H), and 10.64 (s, 1H); 13C-
NMR (CDCl3) δ 6.8, 45.2, 48.0, 115.3, 122.7, 124.6, 125.3, 126.4,
129.2, 129.4, 129.7, 133.5, 134.4, 136.7, 137.1, and 184.7. Anal.
Calcd for C18H17NO4S2: C, 57.58; H, 4.56; N, 3.73. Found: C,
57.51; H, 4.58; N, 3.78.
Bromomethyl imine 52 was converted into aldehyde 53
following the procedure previously described for 43, affording
1.40 g (78%) of 53: mp 91-92 °C; IR (KBr) 1654, 1546, 1379,
10-(Eth ylth io)-2-ph en yl-5-(ph en ylsu lfon yl)-5H-pyr r olo-
[3,4-b]ca r ba zole-1,3-d ion e (47) was obtained from 188 mg
(0.5 mmol) of sulfoxide 45 and 173 mg (1 mmol) of N-
phenylmaleimide as a colorless solid in 90% yield: mp 249-
1
and 1191 cm-1; H-NMR (CDCl3) δ 1.24 (t, 3H, J ) 7.5 Hz),
1
250 °C; IR (KBr) 1760, 1708, 1370, and 1350 cm-1; H-NMR
2.61 (q, 2H, J ) 7.5 Hz), 4.59 (s, 2H), 7.32-7.59 (m, 6H), 8.03
(m, 2H), 8.25 (m, 1H), and 10.31 (s, 1H); 13C-NMR (CDCl3) δ
14.2, 25.3, 26.5, 114.3, 119.4, 121.3, 125.1, 125.8, 125.9, 127.1,
129.3, 134.4, 135.7, 138.2, 147.5, and 185.1; MS m/ e 359 (M+),
218, 204, 190, 158, 156, 128, 117, 102, and 77. Anal. Calcd
for C18H17NO3S2: C, 60.15; H, 4.77; N, 3.90. Found: C, 59.89;
H, 4.83; N, 3.76.
2-((Eth ylsu lfin yl)m eth yl)-1-(ph en ylsu lfon yl)-1H-in dole-
3-ca r ba ld eh yd e (54). A 718 mg (2 mmol) sample of sulfide
53 was oxidized in a manner similar to that outlined for sulfide
44 using sodium periodate/dioxane to give 54 in 92% yield,
(CDCl3) δ 1.25 (t, 3H J ) 7.5 Hz), 3.21 (q, 2H, J ) 7.5 Hz),
7.39-7.69 (m, 10H), 7.91 (d, 2H, J ) 7.8 Hz), 8.46 (d, 1H, J )
8.4 Hz), 8.92 (s, 1H), and 9.27 (d, 1H, J ) 8.1 Hz); 13C-NMR
(CDCl3) δ 15.0, 31.3, 110.0, 114.6, 124.4, 125.4, 125.7, 126.5,
126.6, 127.2, 128.0, 129.0, 129.3, 129.5, 131.6, 131.7, 131.9,
132.8, 134.5, 137.4, 139.6, 141.1, 165.9, and 166.2. Anal.
Cacld for C28H20N2O4S2: C, 65.61; H, 3.93; N, 5.47. Found:
C, 65.67; H, 3.96; N, 5.46.
10-(E t h ylt h io)-5-(p h en ylsu lfon yl)-5H -fu r o[3,4-b]ca r -
ba zole-1,3-d ion e (48) was obtained from 188 mg (0.5 mmol)
of sulfoxide 45 and 98 mg (1 mmol) of maleic anhydride as a
colorless solid in 89% yield: mp 209-210 °C; IR (KBr) 1839,
mp 119-120 °C; IR (KBr) 1670, 1444, 1385, and 1186 cm-1
;
1H-NMR (CDCl3) δ 1.41 (t, 3H, J ) 7.5 Hz), 2.88 (m, 2H), 4.80
(d, 1H, J ) 13.8 Hz), 4.96 (d, 1H, J ) 13.8 Hz), 7.35-7.64 (m,
5H), 7.85 (m, 2H), 8.07 (m, 1H), 8.32 (m, 1H), and 10.19 (s,
1H); 13C-NMR (CDCl3) δ 6.8, 46.1, 48.3, 114.1, 121.7, 123.5,
125.3, 126.0, 126.3, 126.4, 129.5, 134.7, 135.8, 137.5, 138.2,
and 185.7. Anal. Calcd for C18H17NO4S2: C, 57.58; H, 4.56;
N, 3.74. Found: C, 57.68; H, 4.57; N, 3.68.
1
1805, 1771, and 1272 cm-1; H-NMR (CDCl3) δ 1.25 (t, 3H, J
) 7.5 Hz), 3.22 (q, 2H, J ) 7.5 Hz), 7.44-7.73 (m, 6H), 7.91
(d, 2H, J ) 7.5 Hz), 8.46 (d, 1H, J ) 8.4 Hz), 8.92 (s, 1H), and
9.17 (d, 1H, J ) 8.1 Hz); 13C-NMR (CDCl3) δ 15.1, 31.2, 111.0,
114.6, 124.8, 124.9, 125.6, 126.5, 126.6, 129.6, 130.2, 130.4,
134.1, 134.2, 134.9, 137.2, 140.0, 141.9, 161.1, and 162.5. Anal.

6174 J . Org. Chem., Vol. 61, No. 18, 1996
Kappe and Padwa
4-(Eth ylth io)-2-p h en yl-5-(p h en ylsu lfon yl)-5H-p yr r olo-
[3,4-b]ca r ba zole-1,3-d ion e (56) was prepared from 188 mg
(0.5 mmol) of sulfoxide 54 and 173 mg (1 mmol) of N-
phenylmaleimide as a colorless solid in 51% yield: mp 251-
2H, J ) 8.1 Hz), and 8.16 (d, 1H, J ) 8.5 Hz); 13C-NMR (CDCl3)
δ 15.3, 30.3, 116.3, 121.4, 122.0, 124.0, 124.6, 127.4, 127.5,
127.6, 128.9, 132.9, 133.7, 134.2, 137.1, and 145.7; HRMS (EI)
calcd for C18H15NO3S2 357.0493, found 357.0504.
1
252 °C; IR (KBr) 1767, 1708, 1363, and 1174 cm-1; H-NMR
(CDCl3) δ 1.00 (t, 3H, J ) 7.5 Hz), 2.99 (q, 2H, J ) 7.5 Hz),
7.25-7.56 (m, 12H), 7.85 (d, 1H, J ) 7.8 Hz), 8.16 (d, 1H, J )
8.4 Hz), and 8.26 (s, 1H); 13C-NMR (CDCl3) δ 14.2, 31.7, 113.6,
118.8, 121.0, 125.8, 126.2, 126.6, 126.9, 128.0, 128.4, 128.8,
129.0, 129.3, 130.7, 131.0, 131.6, 133.5, 134.7, 137.0, 142.7,
146.3, 165.6, and 166.2. Anal. Calcd for C28H20N2O4S2: C,
65.61; H, 3.93; N, 5.47. Found: C, 65.34; H, 3.97; N, 5.42.
4-(E t h ylt h io)-5-(p h e n ylsu lfon yl)-5H -fu r o[3,4-b]ca r -
ba zole-1,3-d ion e (57) was prepared from 188 mg (0.5 mmol)
of sulfoxide 54 and 98 mg (1 mmol) of maleic anhydride as a
colorless solid in 53% yield: mp 224-225 °C; IR (KBr) 1838,
1775, 1607, 1444, 1363, 1263, and 1173 cm-1; 1H-NMR (CDCl3)
δ 0.98 (t, 3H, J ) 7.5 Hz), 2.96 (q, 2H, J ) 7.5 Hz), 7.28-7.63
(m, 7H), 8.16 (d, 1H, J ) 7.5 Hz), 8.16 (d, J ) 8.4 Hz), and
8.27 (s, 1H). Anal. Calcd for C22H15NO5S2: C, 60.44; H, 3.46;
N, 3.20. Found: C, 60.24; H, 3.49; N, 3.16.
Ack n ow led gm en t. We gratefully acknowledge the
National Science Foundation and the National Cancer
Institute (CA-26750), DHEW, for generous support of
this work. We also thank Bobby L. Williamson for some
experimental assistance. C.O.K. wishes to acknowledge
the Austrian Science Foundation (FWF) for an Erwin-
Schro¨dinger-Postdoctoral Fellowship. Use of high-field
NMR spectrometer used in these studies was made
possible through equipment grants from the NIH and
NSF.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR and 13C-
NMR spectra for new compounds lacking analyses (15 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
3-(Eth ylth io)-4-(p h en ylsu lfon yl)-4H-fu r o[3,4-b]in d ole
(55) was prepared from 188 mg (0.5 mmol) of sulfoxide 54 as
a colorless oil in 36% yield: IR (neat) 1449, 1373, 1260, and
1
1091 cm-1; H-NMR (CDCl3) δ 1.31 (t, 3H, J ) 7.5 Hz), 2.99
(q, 2H, J ) 7.5 Hz), 7.24-7.54 (m, 6H), 7.68 (s, 1H), 7.87 (d,
J O9607929