Preparation and Reactions of Benzofurano-, Indolo-, and Benzothieno-3-sulfolenes

Article abstract of DOI:10.1021/jo980044e

Benzofurano-, N-tosylindolo-, and benzothieno-3-sulfolenes have been prepared efficiently via their dihydro analogues. These fused 3-sulfolenes serve as ideal precursors for the corresponding heteroaromatic o-quinodimethanes. Derivatives of these 3-sulfolenes bearing bromo or alkyl group substitution from which substituted heteroaromatic o-quinodimethanes are generated have also been synthesized.

Full text of DOI:10.1021/jo980044e

J . Org. Chem. 1998, 63, 4645-4653
4645
P r ep a r a tion a n d Rea ction s of Ben zofu r a n o-, In d olo-, a n d
Ben zoth ien o-3-su lfolen es
Chung-Wen Ko and Ta-shue Chou*
Institute of Chemistry, Academia Sinica, Taipei, and Department of Chemistry,
National Taiwan University, Taipei, Taiwan, Republic of China
Received J anuary 8, 1998
Benzofurano-, N-tosylindolo-, and benzothieno-3-sulfolenes have been prepared efficiently via their
dihydro analogues. These fused 3-sulfolenes serve as ideal precursors for the corresponding
heteroaromatic o-quinodimethanes. Derivatives of these 3-sulfolenes bearing bromo or alkyl group
substitution from which substituted heteroaromatic o-quinodimethanes are generated have also
been synthesized.
In tr od u ction
olinone-,17 and indole-fused18 3-sulfolenes have been
synthesized. The extrusion of SO2 from most of these
molecules have been successful, and many of them can
be utilized in the synthesis of interesting heterocyclic
compounds. Since indole, benzofuran, and benzothiophene
skeletons are frequently found in nature and in synthetic
biologically active compounds, it is desirable to have
convenient accesses to the preparation of derivatives of
these heteroaromatics. The corresponding o-quinodi-
methanes, which are very reactive, appear to be useful
candidates for this purpose. Therefore, we wished to
explore the approaches toward the synthesis of benzofu-
ran-, indole-, and benzothiophene-fused 3-sulfolenes 3-5
and to examine their ability as precursors of benzofura-
no-,19 indolo-,20 and benzothieno-o-quinodimethanes21
6-8.
The chemistry of heteroaromatic o-quinodimethanes
(HAQD) 1 has drawn the increasing attention of organic
chemists recently.1 One general strategy toward the
generation of these reactive intermediates involves SO2
extrusion from heteroaromatic-fused 3-sulfolenes 2.2 The
advantages of this strategy include the ease of prepara-
tion and handling of these stable fused-3-sulfolenes, the
ease of derivatization of o-quinodimethanes, and the
possibility of synthetic applications via inter- and in-
tramolecular Diels-Alder reactions. To date, pyrrole-,3
thiophene-,4 furan-,5 thiazole-,6 isoxazole-,7 pyrazole-,8
oxazole-,9 isothiazole-,10 quinoxaline-,11 pyrazine-,12 py-
ridine-,13 pyrimidine-,14 pyrimidone-,15 quinoline-,16 quin-
(1) For a recent review, see: Chou, T. S. Rev. Heteroatom Chem.
1993, 8, 65.
(2) For reviews on the chemistry of 3-sulfolenes as precursors for
conjugated dienes, see: (a) Chou, T. S.; Tso, H. H. Org. Prep. Proc.
Int. 1989, 21, 257. (b) Chou, T. S.; Chou, S. S. P. J . Chin. Chem. Soc.
1992, 39, 625.
(3) (a) Chou, T. S.; Chang, R. C. J . Chem. Soc., Chem. Commun.
1992, 549. (b) Chou, T. S.; Tsai, C. Y. J . Chin. Chem. Soc. 1993, 40,
581.
(4) (a) Chou, T. S.; Tsai, C. Y. J . Chem. Soc., Chem. Commun. 1991,
1287. (b) Tso, H. H.; Tsay, H.; Li, J . H. Synth. Commun. 1995, 25,
3435. (c) Crew, A. P. A.; J enkins, G.; Storr, R. C.; Yelland, M.
Tetrahedron Lett. 1990, 31, 1491. (d) Chaloner, L. M.; Crew, A. P. A.;
O’Neill, P. M.; Storr, R. C. Tetrahedron 1992, 48, 8101. (e) Zwanenburg,
D. J .; de Haan, H.; Wynberg, H. J . Org. Chem. 1966, 31, 3363.
(5) Chou, T. S.; Tsai, C. Y. Heterocycles 1992, 34, 663.
(6) Chou, T. S.; Tsai, C. Y. Tetrahedron Lett. 1992, 33, 4201.
(7) (a) Chou, T. S.; Chang, R. C. Tetrahedron Lett. 1992, 33, 8121.
(b) Tso, H. H.; Yang, N. Y.; Chang, Y. M. J . Chem. Soc., Chem.
Commun. 1995, 1349.
(8) (a) Chou, T. S.; Chang, R. C. Heterocycles 1993, 36, 2839. (b)
Tso, H. H.; Chang, Y. M.; Tsay, H. Synth. Commun. 1996, 26, 569. (c)
Chauhan, P. M. S.; Crew, A. P. A.; J enkins, G.; Storr, R. C.; Walker,
S. M.; Yelland, M. Tetrahedron Lett. 1990, 31, 1487. (d) Chaloner, L.
M.; Crew, A. P. A.; Storr, R. C. Tetrahedron Lett. 1991, 32, 7609.
(9) Chou, T. S.; Chen, H. C.; Tsai, C. Y. J . Org. Chem. 1994, 59,
2241.
Furano-, pyrrolo-, and thieno-3-sulfolenes can be syn-
thesized by a 1,4-dicarbonyl approach3a from compound
9, or by a zincation/cyclization approach3b,4a,5 from com-
pound 10. Since neither of these two routes is suitable
for the synthesis of their benzo analogues 3-5, different
(18) Vice, S. F.; de Carvalho, H. N.; Taylor, N. G.; Dmitrienko, G. I.
Tetrahedron Lett. 1989, 30, 7289.
(19) (a) Bedford, S. B.; Begley, M. J .; Cornwall, P.; Knight, D. W.
Synlett 1991, 629. (b) Chou, C. H.; Trahanovsky, W. S. J . Org. Chem.
1986, 51, 4208.
(10) Tso, H. H.; Candraseharam, M. Tetrahedron Lett. 1996, 37,
4189.
(11) Chou, T. S.; Ko, C. W. Tetrahedron 1994, 50, 10721.
(12) Chou, T. S.; Ko, C. W. Molecules 1996, 1, 93.
(13) (a) Klemm, L. H.; J ohnson, W. O.; White, D. V. J . Heterocycl.
Chem. 1972, 9, 843. (b) Spinner, E.; Yeoh, G. B. J . Chem. Soc. B 1971,
289.
(20) For leading reviews, see: (a) Pindur, U.; Erfanian-Abdoust, H.
Chem. Rev. 1989, 89, 1681. (b) Magnus, P. Gallagher, T.; Brown, P.;
Pappalardo, P. Acc. Chem. Res. 1984, 17, 35.
(21) (a) Dyker, G.; Kreher, R. P. Chem. Ber. 1988, 121, 1203. (b)
The brief content of this paper has been recently published as a
communication, Ko, C. W.; Chou, T. S. Tetrahedron Lett. 1997, 38,
5315.
(14) Tome, A. C.; Cavaleiro, J . A. S.; Storr, R. C. Tetrahedron 1996,
52, 1735.
(15) (a) Tome, A. C.; O, Neill, P. M.; Storr, R. C.; Cavaleiro, J . A. S.
Synlett 1993, 347. (b) Tome, A. C.; Cavaleiro, J . A. S.; Storr, R. C.
Tetrahedron 1996, 52, 1723.
(16) White, L. A.; Storr, R. C. Tetrahedron 1996, 52, 3117.
(17) Chou, T. S.; Chen, H. C. Tetrahedron Lett. 1996, 37, 7823.
(22) Chou, T. S.; Hung, S. C.; Tso, H. H. J . Org. Chem. 1987, 52,
3394.
(23) Mason, K. G.; Smith, M. A.; Stern, E. S.; Elvidge, J . A. J . Chem.
Soc. C 1967, 2171.
(24) Hsu, C. T.; Wang, N. Y.; Latimer. L. H.; Sih, C. J . J . Am. Chem.
Soc. 1983, 105, 593.
(25) Harrington, P. J .; Difiore, K. A. Tetrahedron Lett. 1987, 28, 495.
S0022-3263(98)00044-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/18/1998

4646 J . Org. Chem., Vol. 63, No. 14, 1998
Ko and Chou
Sch em e 2
approaches needed to be developed. Toward this end, we
considered it convenient to prepare the dihydrobenzo-
heterocycle-fused sulfolanes 11-13 as the key intermedi-
ates. Subsequent oxidative aromatization would give the
final target molecules.
Sch em e 3
Although molecules 11-13 can in principle be synthe-
sized by a number of methods, two very efficient ways
are shown in Scheme 1. These routes involve the
construction of heterocycles on a preexisting five-
membered, sulfone-containing molecule. In strategy A,
the carbon-heteroatom (C-X) bond is formed first, and
a cyclizative carbon-carbon (C-C) bond formation fol-
lows. Whereas in strategy B, the order of the formation
of the two bonds is reversed.
Sch em e 1
improved to 80% by using the diazonium salt 23,26
generated from o-anisidine 22.
Since route B had been successful for the preparation
of 11, we attempted to apply the same strategy to the
preparation of 12. However, neither o-iodoaniline 25 nor
N-tosyl-o-iodoaniline 26 gave the desired C-C bond
formation product upon treatment with 19 under the
same condition as that in Scheme 3, and only starting
material was recovered. The reactions of the diazonium
salts 28a -d , generated from the amines 27a -d , with 19
gave none of the desired products 29.
Syn th esis of Dih ydr oben zoh eter ocycle-Fu sed Su l-
fola n es 11-13. Attempts at preparing compound 11 by
using strategy A via 15 commenced with the introduction
of o-iodophenol 14 to a 2-sulfolene skeleton. Knowing
that phenoxide ion can induce the dehydrobromination
of 4-bromo-2-sulfolene and give thiophene dioxide 17
which dimerizes rapidly to produce compound 18,22 we
tried carefully to avoid basic conditions and used Mit-
sunobu coupling conditions. Hence, 2-sulfolen-4-ol 1623
was treated with 14 and diethyl azodicarboxylate (DEAD)
in the presence of PPh3 (Scheme 2).24 To our disappoint-
ment, the reaction only afforded compound 18 in 95%
yield. No direct substitution product 15 was detected.
We then turned our efforts to strategy B for the
preparation of 11. When iodoanisole 20 was treated with
19 in the presence of 1.1 equiv of Et3N and catalytic
amount of Pd(OAc)2 and Bu4NBr,25 the Pd-induced
coupling reaction proceeded smoothly to give 21 in 48%
yield (Scheme 3). Demethylation of 21 could be achieved
readily in concentrated aqueous HBr under reflux where
24 was produced in 78% yield. Cyclization of 24 in
saturated NaHCO3 gave 11 in 97% yield. If compound
21 was demethylated and cyclized without the isolation
of the intermediate 24, the overall yield of 11 (53%) was
appreciably lower. The yield of the preparation of
compound 21 by Pd-induced coupling reaction could be
Therefore, the preparation of 12 via strategy A was
examined. When 3,4-dibromosulfolane 3027 was treated
with excess of 25 in refluxing MeOH, the desired second-
ary amine 31 was obtained in 61% yield (Scheme 4). We
(26) Sengupta, S.; Bhattacharyya, S. Synth. Commun. 1996, 26, 231.
(27) Bailey, W. J .; Cummins, E. W. J . Am. Chem. Soc. 1954, 76,
1932.

Benzofurano-, Indolo-, and Benzothieno-3-sulfolenes
J . Org. Chem., Vol. 63, No. 14, 1998 4647
Sch em e 4
Sch em e 6
corresponding dihydro- and tetrahydroquinoxaline sys-
tems11 by DDQ or MnO2 oxidation, these oxidants were
tested at first. Disappointingly, neither of the oxidants
was found effective to aromatize 11-13 in refluxing
benzene. No higher temperatures were examined be-
cause N-acetylindolo-3-sulfolene18 is known to decompose
at 80-110 °C. An indirect method of aromatization was
therefore considered.
Sch em e 5
Thus, compound 11 was subject to radical bromination
condition (NBS, AIBN in refluxing benzene for 1 h) and
the desired benzofurano-3-sulfolene 3 was obtained in
74% yield, presumably via a sequence of radical bromi-
nation and dehydrobromination. The reaction time
should be kept short because prolonged heating resulted
in the formation of unseparable multibrominated prod-
ucts and poorer yield of 3 (eq 1).
found that this reaction requires at least 8 equiv of the
aniline 25. If 3 or 4 equiv of 25 was used, the yield of 31
was substantially lower. This is consistent with the
literature report that the reaction of aniline with 30 takes
place via a sequence of elimination and conjugate addi-
tion.22 Radical-initiated cyclization28 proceeded smoothly
when 31 was treated with Bu3SnH and AIBN in refluxing
benzene and 12a (R ) H) was obtained in 80% yield.
Attempts of one-step conversion from 31 to the indolo-
3-sulfolene (4a , R ) H) via Pd induced C-C bond
formation were not successful.
For the synthesis of (dihydrothieno)sulfolane 13, at-
tempts were made to prepare the intermediate 35. A
plausible method to prepare 35 involves a halosulfen-
ylation-dehydrohalogenation reaction sequence.29 When
compound 19 was treated with the sulfenyl bromide 33
(generated in situ from 2-bromothiophenol 32 and NBS)
at room temperature for 30 h, the addition reaction
proceeded smoothly to give 34 in 42% yield. Dehydro-
bromination of 34 by treatment with pyridine gave 35
in 91% yield (Scheme 5).
An alternative and simple route for the preparation of
35 involves the direct substitution of 4-bromo-2-sulfolene
3722 with a sulfur nucleophile. When o-bromophenothi-
olate 36, generated from 32 by treatment with NaOMe
in MeOH, was reacted with 37, the substituted product
35 was formed in 91% yield. Radical-initiated cyclization
(Bu3SnH, AIBN) of 35 in refluxing benzene yielded the
desired product 13 (Scheme 6).
When compound 3 was treated with excess of Br2 (3
equiv) in refluxing CH2Cl2 for 48 h, the starting material
was completely consumed, and a complex mixture was
obtained. Although the reaction was too complex to
analyze, the product mixture contains no SO2 functional-
ity. In the absence of Br2, compound 3 also gradually
lost SO2 and produced a complex mixture in refluxing
CH2Cl2. This is why the reaction time should not exceed
1 h during the conversion of 11 to 3. The ease of SO2
extrusion from 3 appeared to us somewhat unusual since
the SO2 extrusion requires temperatures higher than 140
°C for most heteroaromatic-fused 3-sulfolenes.1
Aromatization of 11 could also be achieved by treat-
ment with Br2 at 30 °C for 22 h (eq 2). In addition to
aromatizaion, one bromine atom was introduced onto the
benzene ring, and 38 was obtained in 82% yield. Appar-
ently, both radical bromination for aromatization of the
dihydrofuran moiety and ionic bromination of the ben-
zene ring occurred. When this reaction was carried out
at higher temperatures, a complex mixture of multibro-
minated products was formed and no trace of compound
3 was detected.
Ar om a tiza tion of Com p ou n d s 11-13. Oxidative
aromatization of heterocycles can be achieved by a
number of methods. However, care should be taken in
systems containing a 3-sulfolene moiety to avoid thermal
SO2 extrusion.2 Hence, the reaction temperatures for the
aromatization of 11-13 were carefully chosen. Since
quinoxaline-fused 3-sulfolene has been prepared from the
(28) For a leading reference, see: Motherwell, W. B.; Crich, D. Free
Radical Chain Reactions in Organic Synthesis; Academic Press: New
York, 1992.
(29) (a) Proteau, P. J .; Hopkins, P. B. J . Org. Chem. 1985, 50, 141.
(b) Hopkins, P. B.; Fuchs, P. L. J . Org. Chem. 1978, 43, 1208. (c)
Gundermann, K. D.; Holtman, P. Angew. Chem., Int. Ed. Engl. 1986,
5, 678.

4648 J . Org. Chem., Vol. 63, No. 14, 1998
Ko and Chou
Sch em e 7
Sch em e 8
Compound 3 could not have been the intermediate in
the reaction shown in eq 2. Otherwise at least some of
38 should have been produced when 3 was treated with
Br2 in refluxing CH2Cl2. Therefore, aromatic bromine
substitution of 11 must be faster than that of 3 upon
treatment with Br2. In other words, benzofuran is less
reactive than dihydrobenzofuran toward electrophilic
bromine substitution on the benzene ring. This may be
due to the weaker electron-donating ability of the furan
oxygen whose lone pair of electrons are more delocalized
than the dihydrofuran oxygen.
Initial attempts to aromatize compound 12a (R ) H)
to the corresponding indole 4a (R ) H) by NBS-induced
bromination failed (Scheme 7). When compound 12a (R
) H) was treated with NBS (1.3 equiv) and AIBN in
refluxing benzene, compound 39 was formed in 55% yield
along with 44% of recovered starting material. The ease
of aromatic bromination of compound 12a must be due
to the activating effect of the nitrogen atom. To avoid
aromatic bromination, compound 12a was partially de-
activated by conversion to sulfonamide 12b (R ) Ts). As
expected, the reaction of 12b with NBS/AIBN in refluxing
benzene for 2 h gave the indole 4b (R ) Ts) in 72% yield
(Scheme 7). Similar to the case of benzofurano-3-sul-
folene system, both aromatization and benzene ring
bromination occurred when compound 12b was treated
with excess of Br2 in CH2Cl2 under reflux where com-
pound 40 was produced in 75% yield.
intermediacy of the corresponding o-quinodimethanes 6,
7b (R ) Ts), and 8 was thus evidenced.
The ring-brominated benzofurano-3-sulfolene 38 and
indolo-3-sulfolene 40 were also demonstrated to be
precursors for the corresponding o-quinodimethanes 46
and 47, respectively, by thermolysis and trapping reac-
tions with N-phenylmaleimide at 150 °C. The Diels-
Alder cycloadducts 48 (73%) and 49 (76%) were produced
accordingly.
N-Acetylindolo-3-sulfolene is known to lose SO2 at 80-
110 °C.18 In our study, the SO2 extrusion reaction of
benzofurano-3-sulfolene 3 takes place in refluxing CH2Cl2.
These thermolysis temperatures are substantially lower
than those required for furano-5 and pyrrolo-3-sulfolenes3
(about 160-180 °C), which in turn are lower than that
required for benzo-3-sulfolenes30 (210-230 °C). It is also
known that the thermolysis of pyrazino-12 and quinox-
alino-3-sulfolenes11 occurs only above 290 °C. It appears
that the aromaticity of the heterocycle fused to 3-sul-
folene has significant influence on the temperature
required for the extrusion of SO2. Since the conversion
of a fused-3-sulfolene to the corresponding o-quin-
odimethane involves the breakdown of the aromaticity
of the heterocycle, the energy barrier required for its SO2
extrusion reaction should be dependent on the loss of
stabilization during the process. Indeed, the order of the
temperatures required for SO2 extrusion from the above-
mentioned heteroaromatic-fused 3-sulfolenes is parallel
to the order of their aromatic stabilizing energies.31
A large number of derivatives of 3-sulfolenes have been
prepared by deprotonation-alkylation process. Thus,
compounds 3-5 were subject to this reaction sequence.
Aromatization of the benzothiophene system is the
easiest among the three systems. When compound 13
was treated with NBS and AIBN in benzene under reflux
for 1 h, the desired aromatic compound 5 was formed in
97% yield (eq 3).
(30) (a) Levy, L. A.; Sashikumar, V. P. J . Org. Chem. 1985, 50, 141.
(b) Oppolzer, W.; Roberts, D. A. Helv. Chim. Acta 1980, 63, 1703. (c)
Nicolaou, K. C.; Barnette, W. E.; Ma, P. J . Org. Chem. 1980, 45, 1463.
(31) (a) Chesnut, D. B. J . Comput. Chem. 1995, 16, 1227. (b)
Ve´szpremi, T.; Nyula´szi, L.; Va´rnai, P. J . Mol. Struct. (THEOCHEM)
1995, 358, 55. (c) Schleyer, P. von R.; Freeman, P. K.; J iao, H.;
Goldfuss, B. Angew. Chem., Int. Ed. Engl. 1995, 34, 337. (d) Schleyer,
P. von R.; Maerker, C.; Dransfeld, A.; J iao, H.; van Eikema Hommes,
J . R. J . Am. Chem. Soc. 1996, 118, 6317. (e) Chao, I.; Lu, H. F.; Chou,
T. S. J . Org. Chem. 1997, 62, 7882.
Rea ction s of Com p ou n d s 3-5. Compounds 3, 4b,
and 5 were treated with N-phenylmaleimide or dimethyl
fumarate, under thermal conditions (150 °C). In all
cases, SO2 was extruded, and the cycloadducts 41, 42,
43, 44, and 45 were obtained in 86%, 80%, 79%, 78%,
and 75% yield, respectively (Scheme 8). The transient

Benzofurano-, Indolo-, and Benzothieno-3-sulfolenes
J . Org. Chem., Vol. 63, No. 14, 1998 4649
Sch em e 9
When compound 5 was stirred with LiHMDS (0.9 equiv),
MeI (4 equiv), and HMPA (4 equiv) at -78 °C for 1 h,
the methylated product 50 was produced in 11% yield
along with recovered starting material 5 (35%), the
dimethylated product 51 (20%), and the trimethylated
product 52 (8%) (eq 4). Although deprotonation and
methylation reactions proceeded, rapid anion exchange
provides this complex product mixture.
Sch em e 10
To avoid multialkylation, we modified the experimental
procedure slightly by varying the reaction temperature
and the order of the addition of the reagents. Thus,
3-sulfolene 5 was first mixed with HMPA (2 equiv) in
THF at -105 °C, and then LiHMDS (0.5 equiv) was
added dropwise to generate the green-colored anion.
After the solution was warmed to -80 °C, MeI (2 equiv)
was added all at once. In this way, the monomethylated
product 50 was produced in 56% yield without multi-
methylation. Under the same condition, hexenylated
benzofurano-3-sulfolene 53 could also be prepared in 40%
yield (eq 5).
chemistry of methylation of 50 can therefore be deduced
unambiguously to be that shown in eq 5.
Deprotonation of 5 may lead to carbanion A or B.
Thermodynamically carbanion A is more stable than B
due to abundance of resonance structures (Scheme 9).
Kinetically, deprotonation at the 3-position leading to A
is also favored for steric reasons. Therefore, the first
deprotonation/methylation of 5 takes place selectively at
the 3-position to form product 50.
Benzofurano-3-sulfolene 3 behaved similarly in depro-
tonation/alkylation reactions. When 3 was stirred with
LiHMDS (0.9 equiv), MeI (4 equiv), and HMPA (4 equiv)
at -78 °C for 1 h, the dimethylated product 55 and
trimethylated product 56 were obtained in 11% and 29%
yield, respectively. Surprisingly, no monomethylated
product was detected under this reaction condition. On
the other hand, if MeI (4 equiv) was added all at once to
the preformed sulfolenyl carbanion (generated by depro-
tonation of 3 with LiHMDS in the presence of HMPA at
-105 °C and warmed to -80 °C), the monomethylated
product 54 was formed in 58% yield, along with 27% of
55 (Scheme 10). Apparently, anion exchange of the
sulfolenyl anions proceeded almost as fast as methylation
reactions.
The regiochemistry of these methylation reactions
involving 5 to 50 and 51 was determined by a 2D NMR
NOESY experiment of compound 51. This analysis
revealed an NOE correlation between the two protons
on the unsubstituted R-carbon (C-1) of the sulfone
functionality and one of the aromatic protons, indicating
they are in close proximity (Figure 1). Since mono-
methylated compound 50 must be the intermediate for
the formation of the dimethylated product 51, the regio-
The R-methylated sulfolenes also lose SO2 readily upon
thermolysis. When compounds 54 and 50 were heated
at 150 °C in the presence of dimethyl acetylenedicar-
boxylate followed by oxidation with DDQ, the dibenzo-
furan 57 and dibenzothiophene 58 were produced in 42%
F igu r e 1. NOE correlation in compound 51.

4650 J . Org. Chem., Vol. 63, No. 14, 1998
Ko and Chou
8.3 Hz, 1 H), 4.67-4.74 (m, 1 H), 5.34 (bs, 1 H), 6.74-6.81 (m,
3 H), 6.94 (t, J ) 7.8 Hz, 1 H), 7.11 (d, J ) 7.5 Hz, 1 H), 7.19
(t, J ) 7.7 Hz, 1 H); MS (m/z) 210 (M+), 193, 145, 131 (100%),
118, 103, 91, 77, 69. Anal. Calcd for C10H10O3S: C, 57.13; H,
4.79. Found: C, 57.06; H, 5.00.
Sch em e 11
1,3,3a ,8b-Tetr a h yd r oth ien o[3,4-b]ben zofu r a n 2,2-Di-
oxid e (11). To a solution of compound 24 (608 mg, 2.90 mmol)
in THF-H2O (1:1, 40 mL) was added solid NaHCO3 until
saturation, and the resulting mixture was stirred for 20 h. THF
was removed under reduced pressure, and the aqueous layer
extracted with CH2Cl2 (50 mL × 3). The combined organic
layers were dried with MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc, 2:1) to give 589 mg of 11 (97%) as a white
solid: mp 174-175 °C; IR (KBr) 3023, 2963, 1597, 1480, 1332,
1242, 1125, 1108, 970, 897, 749 cm-1; 1H NMR (CDCl3) δ 3.17
(dd, J ) 13.4, 7.7 Hz, 1 H), 3.43 (dd, J ) 14.2, 4.7 Hz, 1 H),
3.52-3.63 (m, 2 H), 4.30 (dd, J ) 16.9, 8.4 Hz, 1 H), 5.47 (ddd,
J ) 12.3, 7.4, 4.7 Hz, 1 H), 6.84 (d, J ) 8.0 Hz, 1 H), 6.95 (t,
J ) 7.4 Hz, 1 H), 7.18-7.27 (m, 2 H); MS (m/z) 210 (M+), 145,
131 (100%), 110, 103, 91, 77, 62. Anal. Calcd for C10H10O3S:
C, 57.13; H, 4.79. Found: C, 57.02; H, 4.83.
and 71%, respectively (Scheme 11), indicating the pres-
ence of the corresponding substituted o-quinodimethanes
59 and 60 as the intermediates.
In summary, we have demonstrated the success of
thermal generation and trapping of benzo-fused het-
eroaromatic o-quinodimethanes 6, 7, 8, 46, 47, 59, and
60 from the corresponding 3-sulfolenes. The efficient
preparation of 3-sulfolenes 3-5 and the ease of deriva-
tization make this approach useful for the construction
of multicyclic heteroaromatics.
4-(2-Iod oa n ilin o)-2-su lfolen e (31). A solution of 3,4-
dibromosulfolane (0.91 g, 3.28 mmol) and 2-iodoaniline (5.75
g, 26.26 mmol) in dried MeOH (40 mL) was heated at reflux
in a dark-brown flask for 84 h. The solvent was removed
under reduced pressure, and the crude product was purified
by column chromatography (silica gel, hexane/EtOAc, 2:1) to
give 0.67 g of 31 in 61% yield as a light-yellow solid: mp 92-
Exp er im en ta l Section
Gen er a l P r oced u r e. 1H NMR spectra were determined
on a Bruker AC-300 NMR spectrometer as solutions in CDCl3.
IR spectra were determined on a Perkin-Elmer Paragon 1000
IR spectrophotometer. Mass spectra and high-resolution mass
spectra were determined on a VG 70-250S mass spectrometer.
Elemental analysis were performed on a Perkin-Elmer 240C
analyzer. Dichloromethane, THF, and toluene were freshly
distilled from CaH2, K, and Na, respectively, before use.
93 °C; IR (KBr) 3387, 3070, 1578, 1489, 1301, 1133, 738 cm-1
;
1H NMR (CDCl3) δ 3.15 (dd, J ) 13.5, 4.2 Hz, 1 H), 3.82 (dd,
J ) 13.5, 7.4 Hz, 1 H), 4.91-4.94 (m, 1 H), 5.15-5.23 (m, 1
H), 6.56 (t, J ) 7.5 Hz, 1 H), 6.90 (d, J ) 8.1 Hz, 1 H), 7.00 (s,
2 H), 7.28 (t, 7.6 Hz, 1 H), 7.72 (d, J ) 8.1 Hz, 1 H); 13C NMR
(acetone-d6) δ 53.4, 55.4, 86.1, 112.9, 121.0, 130.5, 134.7, 140.4,
140.6, 146.6; MS (m/z) 335 (M+) (100%), 271, 245, 207, 167,
144, 117, 91, 71; HRMS calcd for C10H10INO2S 334.9477, found
334.9478.
4-(2-Meth oxyp h en yl)-2-su lfolen e (21). Meth od I:
A
solution of 3-sulfolene 19 (271 mg, 2.29 mmol), 2-iodoanisole
20 (0.30 mL, 2.31 mmol), triethylamine (0.32 mL, 2.30 mmol),
tetrabutylammonium bromide (774 mg, 2.40 mmol), and Pd-
(OAc)2 (52 mg, 0.23 mmol) in dried benzene (15 mL) was
stirred in a foil-covered, stoppered flask at room temperature
for 20 h. The solvent was removed under reduced pressure,
and the crude product was purified by column chromatography
(silica gel, hexane/EtOAc, 2:1) to give 246 mg of 21 (48%) as a
white solid. Meth od II: A solution of NaNO2 (0.48 g, 6.96
mmol) in water (3 mL) was added dropwise to an ice-cold
mixture of o-anisidine 22 (0.70 mL, 6.21 mmol) in 47% HBF4
(3.50 mL, 15.56 mmol). Stirring was continued for 1 h at 0
°C, after which time the methanol (3 mL) solution of 3-sul-
folene 19 (1.03 g, 8.73 mmol) and Pd(OAc)2 (0.08 g, 0.36 mmol)
were added to the mixture. The resulting mixture was then
heated at reflux for 1 h. Water (5 mL) was added, and the
aqueous solution was extracted with CH2Cl2 (20 mL × 3). The
combined organic layers were dried with MgSO4 and concen-
trated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc, 2:1) to give
246 mg of 21 (80%): mp 79-81 °C; IR (KBr) 3085, 1585, 1454,
1434, 1241, 1111, 1016, 880, 753 cm-1; 1H NMR (CDCl3) δ 3.14
(dd, J ) 13.5, 5.2 Hz, 1 H), 3.68 (dd, J ) 13.5, 8.5 Hz, 1 H),
3.85 (s, 3 H), 4.68-4.74 (m, 1 H), 6.71-6.78 (m, 2 H), 6.91 (d,
J ) 8.5 Hz, 1 H), 6.95 (t, J ) 7.7 Hz, 1 H), 7.11 (d, J ) 7.7 Hz,
1 H), 7.30 (t, J ) 8.5 Hz, 1 H); MS (m/z) 224 (M+) (100%), 193,
159, 145, 129, 115, 91, 77, 62. Anal. Calcd for C11H12O3S: C,
58.91; H, 5.40. Found: C, 58.55; H, 5.63.
1,3,3a ,8b -Tet r a h yd r ot h ien o[3,4-b]in d ole 2,2-Dioxid e
(12a ). To a solution of compound 31 (128 mg, 0.38 mmol) in
dried benzene (20 mL) heated under reflux was added slowly
a solution of Bu3SnH (0.15 mL, 0.56 mmol) and AIBN (30 mg,
0.18 mmol) in MeOH (5 mL). The reaction mixture was
refluxed for 2 h after which time the solution was removed
under reduced pressure, the crude product was purified by
column chromatography (silica gel, hexane/EtOAc, 2:1) to give
64 mg of 12a (80%) as a white solid: mp 122-123 °C; IR (KBr)
3363, 3004, 2935, 1606, 1485, 1291, 1138, 754 cm-1; 1H NMR
(CDCl3) δ 3.14 (dd, J ) 13.4, 8.9 Hz, 1 H), 3.25 (dd, J ) 13.4,
5.2 Hz, 1 H), 3.38-3.50 (m, 2 H), 4.14 (dd, J ) 17.5, 8.8 Hz, 1
H), 4.68 (ddd, J ) 13.0, 7.6, 5.3 Hz, 1 H), 6.65 (d, J ) 7.7 Hz,
1 H), 6.78 (t, J ) 7.7 Hz, 1 H), 7.10 (t, J ) 7.4 Hz, 1 H), 7.10
(d, J ) 7.4 Hz, 1 H); 13C NMR (acetone-d6) δ 42.9, 55.0, 56.9,
59.2, 110.1, 119.3, 125.4, 129.2, 129.8, 151.5; MS (m/z) 209
(M+), 144, 130 (100%), 117, 103, 91, 77, 65; HRMS calcd for
C
10H11NO2S 209.0511, found 209.0504.
3-Br om o-4-(2-br om op h en ylth io)su lfola n e (34). To a
solution of NBS (6.1 g, 34.3 mmol) in CH2Cl2 (60 mL) was
added dropwise 2-bromothiophenol (4.0 mL, 33.3 mmol), and
the reaction mixture was stirred for 30 min. To this solution
was then added dropwise a solution of 3-sulfolene (4.0 g, 34.1
mmol) in CH2Cl2 (15 mL), and the resulting mixture was
stirred at room temperature for 30 h. After the solvent was
removed under reduced pressure, the crude product was
purified by column chromatography (silica gel, hexane/EtOAc,
2:1) to give 5.9 g of 34 (44%) as a white solid: mp 91-92 °C;
IR (KBr) 3009, 2950, 1444, 1402, 1311, 1182, 1121, 1019, 930,
4-(2-Hyd r oxyp h en yl)-2-su lfolen e (24). A solution of
compound 21 (937 mg, 4.20 mmol) in 47% HBr (20 mL) was
heated reflux for 3 h. The excess HBr was removed in vacuo,
and the residue was neutralized with saturated aqueous
NaHCO3. The aqueous layer was extracted with CH2Cl2 (20
mL × 3). The combined organic layers were dried with MgSO4
and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, hexane/EtOAc, 2:1) to give
688 mg of 24 (78%) as a white solid: mp 142-144 °C; IR (KBr)
1
842, 748 cm-1; H NMR (CDCl3) δ 3.22 (dd, J ) 13.9, 6.0 Hz,
1H), 3.52 (dd, J ) 14.2, 5.7 Hz, 1H), 3.80 (dd, J ) 13.9, 7.4
Hz, 1H), 4.03 (dd, J ) 14.2, 6.8 Hz, 1H), 4.24 (dd, J ) 13.3,
6.1 Hz, 1H), 4.48 (dd, J ) 12.3, 6.0 Hz, 1H), 7.26 (td, J ) 8.0,
1.4 Hz, 1H), 7.36 (td, J ) 7.4, 1.4 Hz, 1H), 7.59 (dd, J ) 7.4,
1.5 Hz, 1H), 7.69 (dd, J ) 8.0, 1.4 Hz, 1H); MS (m/z) 388 (M+
+ 4), 386 (M+ + 2), 384 (M+), 307, 305, 243, 241, 216, 214,
1
3410, 3105, 1596, 1451, 1267, 1101, 887, 750 cm-1; H NMR
(CDCl3) δ 3.23 (dd, J ) 13.4, 5.2 Hz, 1 H), 3.73 (dd, J ) 13.3,

Benzofurano-, Indolo-, and Benzothieno-3-sulfolenes
J . Org. Chem., Vol. 63, No. 14, 1998 4651
189, 187, 162, 135, 108 (100%), 69. Anal. Calcd for C10H10Br2-
O2S2: C, 31.11; H, 2.61. Found: C, 31.31; H, 2.63.
mmol) in dried benzene (6 mL) was heated at reflux for 1.5 h.
The solvent was removed under reduced pressure. The crude
product was purified by column chromatography (silica gel,
hexane/EtOAc, 4:1) to give 17.7 mg of 39 (55%) as a white
solid: mp 184-186 °C; IR (KBr) 3382, 3064, 3005, 2950, 2907,
4-(2-Br om op h en ylth io)-2-su lfolen e (35). Meth od I: To
a solution of NaOMe [prepared from Na metal (40 mg, 1.74
mmol)] in dried MeOH (10 mL) at 0 °C was added dropwise
2-bromothiophene (0.28 mL, 2.33 mmol), and the reaction
mixture was stirred at 0 °C for 10 min. To this thiophenoxide
solution was then added dropwise a solution of 4-bromo-2-
sulfolene 37 (381 mg, 1.93 mmol) in dried MeOH (8 mL), and
the resulting mixture was stirred at room temperature for 24
h. After the solvent was removed under reduced pressure, the
crude product was purified by column chromatography (silica
gel, hexane/EtOAc, 2:1) to give 437 mg of 35 (91%) as a white
solid. Meth od II: To a solution of compound 34 (0.63 g, 1.63
mmol) in dried CH2Cl2 was added pyridine (0.33 mL, 4.08
mmol), and the resulting mixture was refluxed for 3 days. After
the solvent was removed under reduced pressure, the crude
product was purified by column chromatography (silica gel,
hexane/EtOAc, 2:1) to give 0.45 g of 35 (91%) as a white solid:
mp 65-66 °C; IR (KBr) 3093, 2949, 1443, 1292, 1149, 1014,
881 cm-1; 1H NMR (CDCl3) δ 3.28 (dd, J ) 14.2, 3.5 Hz, 1 H),
3.87 (dd, J ) 14.2, 8.1 Hz, 1 H), 4.92-4.96 (m, 1 H), 6.94-
7.03 (m, 2 H), 7.26 (td, J ) 7.6, 1.5 Hz, 1 H), 7.43 (td, J ) 7.6,
1.2 Hz, 1 H), 7.63 (dd, J ) 7.9, 1.5 Hz, 1 H), 7.69 (dd, J ) 7.9,
1.2 Hz, 1 H); MS (m/z) 306 (M+ + 2), 304 (M+), 242, 240, 188,
161, 128, 108 (100%), 85, 69. Anal. Calcd for C10H9BrO2S2:
C, 39.35; H, 2.97. Found: C, 39.35; H, 2.88.
1,3,3a ,8b-Tetr a h yd r oth ien o[3,4-b]ben zoth iop h en e 2,2-
Dioxid e (13). To a solution of compound 35 (450 mg, 1.48
mmol) in dried benzene (40 mL) heated under reflux was added
slowly a solution of Bu3SnH (0.6 mL, 2.23 mmol) and AIBN
(117 mg, 0.71 mmol) in anhydrous benzene (10 mL). The
reaction mixture was heated at reflux for 2 h after which time
the solution was removed under reduced pressure. The crude
product was purified by column chromatography (silica gel,
hexane/EtOAc, 2:1) to give 202 mg of 13 (61%) as a white
solid: 121-122 °C; IR (KBr) 2999, 2942, 1440, 1394, 1275,
1092, 905, 734 cm-1; 1H NMR (CDCl3) δ 3.28 (dd, J ) 9.1, 5.4
Hz, 1 H), 3.43 (dd, J ) 8.9, 5.4 Hz, 1 H), 3.46-3.60 (m, 2 H),
4.34 (dd, J ) 16.1, 8.2 Hz, 1 H), 4.54 (dd, J ) 16.1, 8.2 Hz, 1
H), 7.14 (s, 1 H), 7.15 (s, 1 H), 7.19-7.24 (m, 2 H); MS (m/z)
226 (M+), 162, 147 (100%), 134, 129, 91, 71. Anal. Calcd for
1
1604, 1570, 1472, 1295, 1246, 1156, 1125, 864, 682 cm-1; H
NMR (CDCl3) δ 3.15 (dd, J ) 14.1, 9.7 Hz, 1H), 3.31 (dd, J )
13.7, 5.4 Hz, 1H), 3.41-3.53 (m, 2H), 4.26 (dd, J ) 17.8, 8.9
Hz, 1H), 4.43 (bs, 1H), 4.70-4.85 (m, 1H), 7.15 (s, 1H), 7.40
(d, J ) 1.7 Hz, 1H); 13C NMR (acetone-d6) δ 43.6, 54.6, 56.3,
58.6, 102.6, 109.5, 127.8, 133.5, 133.6, 140.4; MS (m/z) 369 (M+
+ 4), 367 (M+ + 2), 365 (M+), 288 (100%), 286, 221, 195, 149,
115, 89; HRMS calcd for C10H9Br2NO2S 364.8721, found
364.8716.
4-Tolu en esu lfon yl-1,3,3a ,8b-tetr a h yd r oth ien o[3,4-b]in -
d ole 2,2-Dioxid e (12b). A solution of compound 12a (468 mg,
2.24 mmol), Et3N (0.78 mL, 5.60 mmol), and TsCl (676 mg,
3.55 mmol) in dried CH2Cl2 (30 mL) was heated at reflux for
45 h. After the solvent was removed under reduced pressure,
the crude product was purified by column chromatography
(silica gel, hexane/EtOAc, 2:1) to give 725 mg of 12b (89%) as
a white solid: mp 178-180 °C; IR (KBr) 3020, 2951, 1593,
1456, 1345, 1299, 1155, 749 cm-1; 1H NMR (CDCl3) δ 2.38 (s,
3 H), 3.07 (dd, J ) 13.3, 8.6 Hz, 1 H), 3.42-3.52 (m, 2 H), 3.72
(ddd, J ) 14.2, 8.0, 2.3 Hz, 1 H), 4.04 (dd, J ) 18.2, 8.8 Hz, 1
H), 4.83 (dd, J ) 17.6, 7.8 Hz, 1 H), 7.04-7.11 (m, 2 H), 7.25
(d, J ) 8.3 Hz, 2 H), 7.26-7.33 (m, 1 H), 7.63-7.70 (m, 1 H),
7.65 (d, J ) 8.2 Hz, 2 H); MS (m/z) 363 (M+), 299, 208, 155,
144 (100%), 130, 117, 91, 77, 65. Anal. Calcd for C17H17
-
NO4S2: C, 56.18; H, 4.71; N, 3.85. Found: C, 55.90; H, 4.68;
N, 3.72.
4-Tolu en esu lfon yl-1,3-d ih yd r oth ien o[3,4-b]in d ole 2,2-
Dioxid e (4b). A solution of compound 12b (102 mg, 0.28
mmol), NBS (75 mg, 0.42 mmol), and AIBN (46 mg, 0.28 mmol)
in dried benzene (20 mL) was heated at reflux for 1 h. The
solvent was removed under reduced pressure. The crude
product was purified by column chromatography (silica gel,
hexane/EtOAc, 4:1) to give 81 mg of 4b (80%) as a white solid:
mp 143-145 °C; IR (KBr) 2980, 1371, 1314, 1174, 1114, 753
cm-1; 1H NMR (CDCl3) δ 2.37 (s, 3 H), 4.34 (s, 2 H), 4.68 (s, 2
H), 7.25-7.44 (m, 5 H), 7.71 (d, J ) 8.5 Hz, 2 H), 8.10 (d, J )
8.3 Hz, 1 H); 13C NMR (CDCl3) δ 29.7, 54.1, 56.0, 113.7, 114.4,
119.6, 124.4, 125.9, 126.1, 126.1, 128.0, 130.3, 134.7, 137.0,
145.9; MS (m/z) 361 (M+), 297, 232, 142 (100%); HRMS calcd
for C17H15NO4S2 361.0444, found 361.0446.
C
10H10O2S2: C, 53.07; H, 4.45. Found: C, 53.14; H, 4.35.
1,3-Dih yd r oth ien o[3,4-b]ben zofu r a n 2,2-Dioxid e (3). A
solution of compound 11 (208 mg, 0.99 mmol), NBS (230 mg,
1.29 mmol), and AIBN (83 mg, 0.51 mmol) in dried benzene
(30 mL) was heated at reflux for 1.5 h after which the solvent
was removed under reduced pressure. The crude product was
purified by column chromatography (silica gel, hexane/EtOAc,
4:1) to give 152 mg of 3 (74%) as a white solid: 137-138 °C;
7-Br om o-4-tolu en esu lfon yl-1,3-d ih yd r oth ien o[3,4-b]in -
d ole 2,2-Dioxid e (40). A solution of compound 12b (53 mg,
0.15 mmol) and bromine (0.02 mL, 0.39 mmol) in CH2Cl2 (10
mL) was heated at reflux for 24 h. To the reaction mixture
was added saturated aqueous Na2S2O3 (5 mL) and extracted
with CH2Cl2 (20 mL × 3). The combined organic layers were
dried with MgSO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography
(silica gel, hexane/EtOAc, 4:1) to give 48 mg of 40 (75%) as a
white solid: 38-39 °C; IR (KBr) 3104, 3069, 2975, 2925, 1589,
IR (KBr) 2974, 1445, 1292, 1225, 1112, 749 cm-1 1H NMR
;
(CDCl3) δ 4.43 (s, 4 H), 7.32 (t, J ) 7.3 Hz, 1 H), 7.39 (t, J )
7.3 Hz, 1 H), 7.47 (d, J ) 7.3 Hz, 1 H), 7.55 (d, J ) 7.3 Hz, 1
H); 13C NMR (CDCl3) δ 53.9, 55.5, 110.7, 112.1, 119.7, 124.0,
124.3, 125.5, 145.8, 156.8; MS (m/z) 208 (M+), 144 (100%), 115,
89, 63, 51; HRMS calcd for C10H8O3S 208.0194, found 208.0202.
7-Br om o-1,3-d ih yd r ot h ien o[3,4-b]b en zofu r a n 2,2-Di-
oxid e (38). A solution of compound 11 (133 mg, 0.63 mmol)
and bromine (0.07 mL, 1.37 mmol) in CH2Cl2 (15 mL) was
stirred at 30-35 °C for 22 h. To the reaction mixture was
added saturated aqueous Na2S2O3 (5 mL). The layers were
separated, and the aqueous layers were extracted with CH2-
Cl2 (20 mL × 3). The combined organic phase was dried with
MgSO4 and concentrated under reduced pressure. The crude
product was purified by column chromatography (silica gel,
hexane/EtOAc, 4:1) to give 148 mg of 38 (82%) as a white
solid: mp 139-140 °C; IR (KBr) 2977, 1432, 1303, 1225, 1117,
974, 802, 759 cm-1; 1H NMR (CDCl3) δ 4.40 (s, 2 H), 4.44 (s, 2
H), 7.43 (d, J ) 8.8 Hz, 1 H), 7.49 (dd, J ) 8.8, 1.9 Hz, 1 H),
7.62 (d, J ) 1.9 Hz, 1 H); MS (m/z) 288 (M+ + 2), 286 (M+),
224 (100%), 222, 198, 177, 149, 115, 62. Anal. Calcd for C10H7-
BrO3S: C, 41.83; H, 2.46. Found: C, 41.45; H, 2.40.
1367, 1298, 1167, 1114, 988, 927, 809, 771 cm-1 1H NMR
;
(CDCl3) δ 2.38 (s, 3 H), 4.30 (s, 2 H), 4.66 (s, 2 H), 7.28 (d, J
) 8.3 Hz, 2 H), 7.51 (d, J ) 8.8 Hz, 1 H), 7.53 (s, 1 H), 7.69 (d,
J ) 8.4 Hz, 2 H), 7.97 (d, J ) 8.7 Hz, 1 H); MS (m/z) 377 (M+
+ 2 - SO2), 375(M+ - SO2), 222, 220, 141, 91, 64 (100%). Anal.
Calcd for C17H14BrNO4S2: C, 46.37; H, 3.20; N, 3.18. Found:
C, 46.33; H, 3.09; N, 2.78.
1,3-Dih yd r oth ien o[3,4-b]ben zoth iop h en e 2,2-Dioxid e
(5). A solution of compound 13 (27 mg, 0.12 mmol), NBS (30
mg, 0.17 mmol), and AIBN (5 mg, 0.03 mmol) in dried benzene
(10 mL) was refluxed for 1.5 h. The solvent was removed
under reduced pressure. The crude product was purified by
column chromatography (silica gel, hexane/EtOAc, 4:1) to give
26 mg of 5 (97%) as a white solid: mp 164 °C (dec); IR (KBr)
2975, 2927, 1431, 1315, 1255, 1133, 1116, 763 cm-1; 1H NMR
(CDCl3) δ 4.45 (s, 2 H), 4.52 (s, 2 H), 7.40-7.48 (m, 2 H), 7.57-
7.61 (m, 1 H), 7.86-7.89 (m, 1 H); MS (m/z) 224 (M+), 160,
137 (100%), 120 107. Anal. Calcd for C10H8O2S2: C, 53.55;
H, 3.60. Found: C, 53.31; H, 3.47.
5,7-Dibr om o-1,3,3a,8b-tetr ah ydr oth ien o[3,4-b]in dole 2,2-
Dioxid e (39). A solution of compound 12a (18.3 mg, 0.09
mmol), NBS (21.6 mg, 0.12 mmol), and AIBN (5.0 mg, 0.03

4652 J . Org. Chem., Vol. 63, No. 14, 1998
Ko and Chou
Gen er a l P r oced u r e for th e Diels-Ald er Rea ction of
Heter oa r om a tic-F u sed 3-Su lfolen es 3, 4b, 5, 38, a n d 40.
A solution of a heteroaromatic-fused 3-sulfolene (0.1 mmol)
and dienophile (0.8 mmol) in toluene (4 mL) was heated in a
sealed tube at 150 °C for 2 h after which time the solvent was
removed under reduced pressure. The crude product was
purified by column chromatography (silica gel, hexane/EtOAc,
4:1) to give the cycloadduct.
z) 397 (M+ + 2), 395 (M+), 186 (100%), 171, 149, 115, 91, 77;
HRMS calcd for C20H14BrNO3 395.0157, found 395.0151.
6-Br om o-5-tolu en esu lfon yl-2-p h en yl-3aâ,4,10,10a â-tet-
r ah ydr o-2H,5H-pyr r olo[3,4-b]car bazole-1,3-dion e (49): ob-
tained from the reaction of compound 40 and N-phenylmale-
imide in 76% yield as a white solid: 203-205 °C; IR (KBr)
2920, 1690, 1362, 1164, 900, 750, 685, 660 cm-1 1H NMR
;
(CDCl3) δ 2.26 (s, 3 H), 2.90 (ddd, J ) 16.2, 8.1, 1.8 Hz, 1 H),
3.26-3.33 (m, 1 H), 3.35 (d, J ) 16.1 Hz, 1 H), 3.54 (td, J )
17.0, 9.3 Hz, 1 H), 3.55 (td, J ) 16.9, 8.9 Hz, 1 H), 4.1 (dd, J
) 17.6, 2.1 Hz, 1 H), 6.91-6.94 (m, 2 H), 7.1 (d, J ) 8.2 Hz, 2
H), 7.32-7.43 (m, 4 H), 7.55 (d, J )2.0 Hz, 1 H), 7.7 (d, J )
9.2 Hz, 2 H), 8.0 (d, J ) 8.9 Hz, 1 H); MS (m/z) 550 (M+), 548,
391, 363, 307, 261, 167, 149 (100%), 136, 107. Anal. Calcd
for C27H21BrN2O4S: C, 59.02; H, 3.85; N, 5.10. Found: C,
58.99; H, 3.77; N, 4.95.
2-P h en yl-3a â,4,10,10a â-tetr a h yd r o-2H,5H-p yr r olo[3,4-
b]d iben zofu r a n -1,3-d ion e (41): obtained from the reaction
of compound 3 and N-phenylmaleimide in 86% yield as a white
solid: mp 170-172 °C; IR (KBr) 2928, 1700, 1445, 1387, 1191,
1
1155, 742, 690 cm-1; H NMR (CDCl3) δ 3.15 (dd, J ) 16.1,
7.9 Hz, 1 H), 3.23 (dd, J ) 17.9, 9.1 Hz, 1 H), 3.35 (dd, J )
16.2, 3.5 Hz, 1 H), 3.45 (dd, J ) 17.9, 2.8 Hz, 1 H), 3.55 (td, J
) 8.9, 3.7 Hz, 1 H), 3.65 (td, J ) 8.9, 3.1 Hz, 1 H), 7.20-7.29
(m, 4 H), 7.35-7.48 (m, 5 H); 13C NMR (CDCl3) δ 20.3, 21.8,
38.6, 39.5, 110.6, 111.2, 118.6, 122.7, 124.0, 126.2, 127.3, 128.6,
129.1, 131.7, 150.5, 154.6, 177.9, 178.1; MS (m/z) 317 (M+),
3-Meth yl-1,3-d ih yd r oth ien o[3,4-b]ben zoth iop h en e 2,2-
Dioxid e (50). Meth od I: To a solution of compound 5 (108
mg, 0.49 mmol) and hexamethyl phosphoramide (0.17 mL, 0.98
mmol) in THF (10 mL) cooled at -105 °C was slowly added a
solution of lithium hexamethyldisilazide (LiHMDS,0.2 M, 0.23
mmol). After the solution was warmed to -80 °C, methyl
iodide (0.06 mL, 0.96 mmol) was added at once. The stirring
was continued for 2 h after which time the reaction was
quenched by EtOAc. The solvent was removed under reduced
pressure and the crude product was purified by HPLC (hexane/
EtOAc, 4:1) to give 31 mg of 50 (56%) as a white solid: mp
186, 171, 149, 128, 115, 84, 49 (100%); HRMS calcd for C20H15
NO3 317.1052, found 317.1049.
-
5-Tolu en esu lfon yl-2-p h en yl-3a â,4,10,10a â-tetr a h yd r o-
2H,5H-p yr r olo[3,4-b]ca r ba zole-1,3-d ion e (42): obtained
from the reaction of compound 4b and N-phenylmaleimide in
80% yield as a white solid: mp 199-201 °C; IR (KBr) 2928,
1708, 1451, 1371, 1174, 1089, 963, 757 cm-1; 1H NMR (CDCl3)
δ 2.26 (s, 3 H) 2.92-3.01 (m, 1 H), 3.30-3.41 (m, 2 H), 3.46-
3.62 (m, 2 H), 4.11 (dd, J ) 17.5, 2.0 Hz, 1 H), 6.94-6.98 (m,
2 H), 7.08 (d, J ) 8.3 Hz, 2 H), 7.22-7.44 (m, 6 H), 7.70 (d, J
) 10.2 Hz, 2 H), 8.19 (d, J ) 8.1 Hz, 1 H); MS (m/z) 470 (M+),
315, 168 (100%), 143, 91, 65. Anal. Calcd for C27H22N2O4S:
C, 68.92; H, 4.71; N, 5.95. Found: C, 68.53; H, 4.84; N, 5.68.
2-P h en yl-3a â,4,10,10a â-tetr a h yd r o-2H,5H-p yr r olo[3,4-
b]d iben zoth iop h en e-1,3-d ion e (43): obtained from the
reaction of compound 5 and N-phenylmaleimide in 79% yield
as a white solid: mp 142-143 °C; IR (KBr) 2926, 1704, 1494,
154-155 °C; IR (KBr) 2960, 2911, 2352, 1303, 1131, 758 cm-1
;
1H NMR (CDCl3) δ 1.72 (d, J ) 7.0 Hz, 3 H), 4.43 (s, 2H), 4.54
(q, J ) 7.0 Hz, 1 H), 7.39-7.48 (m, 2 H), 7.59 (dd, J ) 6.0, 2.3
Hz, 1 H), 7.88 (dd, J ) 6.8, 3.1 Hz, 1 H); MS (m/z) 238 (M+),
174 (100%), 147, 129, 115. Anal. Calcd for C11H10O2S2: C,
55.44; H, 4.23. Found: C, 55.46; H, 4.28. Meth od II: To a
solution of compound 5 (60 mg, 0.27 mmol), methyl iodide (0.07
mL, 1.12 mmol), and hexamethyl phosphoramide (0.20 mL,
1.15 mmol) in THF (10 mL) cooled at -78 °C was slowly added
a solution of lithium hexamethyldisilazide (LiHMDS, 0.26
mmol) in THF (2 mL). The stirring was continued for 2 h after
which time the reaction was quenched by EtOAc. The solvent
was removed under reduced pressure, and the crude product
was purified by HPLC (hexane/EtOAc, 4:1). Under this
condition, compounds 50 (11%), 51 (20%), and 52 (8%) were
obtained.
1
1383, 1182, 754 cm-1; H NMR (CDCl3) δ 2.98 (dd, J ) 16.0,
5.7 Hz, 1 H), 3.18 (dd, J ) 15.4, 5.2 Hz, 1 H), 3.52 (d, J ) 16.9
Hz, 1 H), 3.58-3.64 (m, 3 H), 7.01 (d, J ) 7.9 Hz, 2 H), 7.27-
7.39 (m, 5 H), 7.68 (d, J ) 7.8 Hz, 1 H), 7.79 (d, J ) 7.8 Hz, 1
H); MS (m/z) 333 (M+), 185, 136, 120, 107. Anal. Calcd for
C
20H15NO2S: C, 72.05; H, 4.53; N, 4.20. Found: C, 71.80; H,
4.51; N, 4.05.
2,3-Bis(m eth oxyca r bon yl)-1,2,3,4-tetr a h yd r od iben zo-
fu r a n (44): obtained from the reaction of compound 3 and
dimethyl fumarate in 78% yield as a white solid: mp 95-97
°C; IR (KBr) 2964, 2850, 1734, 1437, 1350, 1297, 1221, 1170,
3,3-Dim et h yl-1,3-d ih yd r ot h ien o[3,4-b]b en zot h io-
p h en e 2,2-Dioxid e (51): mp 164-166 °C; IR (KBr) 2926,
1
2362, 1298, 1121, 753 cm-1; H NMR (CDCl3) δ 1.75 (s, 6H),
4.41 (s, 2H), 7.37-7.47 (m, 2H), 7.59 (dd, J ) 6.5, 2.0 Hz, 1H),
7.87 (dd, J ) 6.9, 2.3 Hz, 1H); 13C NMR (CDCl3) δ 23.9, 53.0,
65.0, 122.0, 123.0, 123.3, 125.3, 125.4, 135.2, 139.7, 143.8; MS
(m/z) 252 (M+), 188 (100%), 173, 147, 129; HRMS calcd for
1
1104, 1001, 908, 747 cm-1; H NMR (CDCl3) δ 2.78-3.38 (m,
6H), 3.75 (s, 6H), 7.16-7.28 (m, 2H), 7.37-7.43 (m, 2H); 13C
NMR (CDCl3) δ 22.9, 25.4, 41.5, 41.7, 52.1, 52.2, 110.9, 118.4,
122.5, 123.6, 127.6, 150.6, 154.7, 173.9, 174.3; MS (m/z) 288
(M+), 257, 228, 196, 169 (100%), 144, 115; HRMS calcd for
C
12H12O2S2 252.0280, found 252.0278.
1,3,3-Tr im et h yl-1,3-d ih yd r ot h ien o[3,4-b]b en zot h io-
C
16H16O5 288.0998, found 288.0999.
2,3-Bis(m et h oxyca r b on yl)-1,2,3,4-t et r a h yd r od ib en -
p h en e 2,2-Dioxid e (52): mp 168-169 °C; IR (KBr) 2981,
2933, 1446, 1297, 1120, 767 cm-1; 1H NMR (CDCl3) δ 1.59 (s,
6H), 1.78 (d, J ) 7.1 Hz, 3H), 4.51 (q, J ) 7.2 Hz, 1H), 7.39
(td, J ) 7.3, 1.9 Hz, 1H), 7.44 (td, J ) 7.3, 1.5 Hz, 1H), 7.68
(d, J ) 7.7 Hz, 1H), 7.88 (d, J ) 7.8 Hz, 1H); 13C NMR (CDCl3)
δ 15.1, 23.6, 25.9, 59.6, 63.9, 121.8, 123.3, 125.0, 125.1, 128.5,
134.8, 139.9, 142.7; MS (m/z) 266 (M+), 202, 187 (100%), 172,
147, 128, 115; HRMS calcd for C13H14O2S2 266.0436, found
266.0428.
zoth iop h en e (45): obtained from the reaction of compound
5 and dimethyl fumarate in 75% yield as a white solid: mp
99-100 °C; IR (KBr) 2954, 1731, 1439, 1174, 753 cm-1 1H
;
NMR (CDCl3) δ 2.85-2.95 (m, 1H), 3.04-3.11 (m, 1H), 3.17-
3.31 (m, 2H), 3.75 (s, 3H), 3.77 (s, 3H), 7.26-7.38 (m, 2H), 7.56
(d, J ) 7.8 Hz, 1H), 7.76 (dd, J ) 7.59, 1.3 Hz, 1H); 13C NMR
(CDCl3) δ 26.2, 27.9, 41.4, 42.4, 52.2, 104.4, 120.6, 122.4, 124.2,
127.2, 134.0, 138.6, 138.8, 174.2, 174.6; MS (m/z) 304 (M+),
273, 244, 185 (100%), 160, 139, 115, 92; HRMS calcd for
3-(5-H exen yl)-1,3-d ih yd r ot h ien o[3,4-b]b en zot h io-
p h en e 2,2-Dioxid e (53). To a solution of compound 5 (60
mg, 0.27 mmol) and hexamethyl phosphoramide (0.2 mL, 1.15
mmol) in THF (10 mL) cooled at -105 °C was slowly added a
solution of lithium hexamethyldisilazide (LiHMDS, 0.2 M, 0.23
mmol). After the solution was warmed to -80 °C, 6-iodo-1-
hexene (240 mg, 1.14 mmol) was added at once. The stirring
was continued for 2 h after which time the reaction was
quenched by EtOAc. The solvent was removed under reduced
pressure, and the crude product was purified by HPLC
(hexane/EtOAc, 4:1) to give 28 mg of 53 (40%) as a white
C
16H16O4S 304.0770, found 304.0777.
8-Br om o-2-ph en yl-3a â,4,10,10a â-tetr ah ydr o-2H,5H-pyr -
r olo[3,4-b]d iben zofu r a n -1,3-d ion e (48): obtained from the
reaction of compound 38 and N-phenylmaleimide in 73% yield
as a white solid: mp 175-177 °C; IR (KBr) 1704, 1447, 1386,
1200, 1178, 798, 746, 693 cm-1; 1H NMR (CDCl3) δ 3.10 (dd, J
) 16.3, 8.3 Hz, 1 H), 3.22 (dd, J ) 17.5, 8.9 Hz, 1 H), 3.28 (dd,
J ) 16.1, 4.0 Hz, 1 H), 3.41 (dd, J ) 20.4, 3.4 Hz, 1 H), 3.54
(td, J ) 8.2, 3.3 Hz, 1 H), 3.65 (td, J ) 8.9, 3.2 Hz, 1 H), 7.19-
7.46 (m, 7 H), 7.58 (d, J ) 1.9 Hz, 1 H); 13C NMR (CDCl3) δ
20.1, 21.9, 38.5, 39.4, 110.3, 112.7, 115.9, 121.5, 126.2, 126.8,
128.7, 129.1, 129.3, 131.7, 152.1, 153.4, 177.7, 177.8; MS (m/
solid: mp 83-85 °C; IR (KBr) 2925, 2361, 1306, 1134 cm-1
;
1H NMR (CDCl3) δ 1.40-1.51 (m, 2 H), 1.59-1.65 (m, 2 H),
1.70-1.94 (m, 1 H), 2.01-2.18 (m, 3 H), 4.27-4.38 (m, 1 H),

Benzofurano-, Indolo-, and Benzothieno-3-sulfolenes
J . Org. Chem., Vol. 63, No. 14, 1998 4653
4.33 (s, 2 H), 4.88-5.00 (m, 2 H), 5.68-5.82 (m, 1 H), 7.30-
7.40 (m, 2 H), 7.48-7.53 (m, 1 H), 7.76-7.83 (m, 1 H); 13C NMR
(CDCl3) δ 26.2, 28.5, 30.2, 33.2, 54.8, 66.1, 114.8, 122.0, 123.0,
125.2, 125.4, 125.5, 134.8, 136.0, 138.2, 140.3; MS (m/z) 306
(M+), 242 (100%), 185, 173, 160, 147, 129, 115, 64; HRMS calcd
for C16H18O2S2 306.0749, found 306.0754.
δ 14.4, 22.0, 22.2, 59.4, 61.8, 112.2, 119.4, 123.7, 124.3, 125.2,
137.4, 154.7, 156.3; MS (m/z) 250 (M+), 218, 203, 186, 171, 84,
49 (100%); HRMS calcd for C13H14O3S 250.0664, found 250.0661.
2,3-Bis(m eth oxyca r bon yl)-4-m eth yld iben zofu r a n (57).
A solution of compound 54 (17 mg, 0.08 mmol) and dimethyl
acetylenedicarboxylate (0.07 mL, 0.57 mmol) in benzene (5 mL)
was heated at 150 °C for 2 h. Then DDQ (140 mg, 0.62 mmol)
was added and heated at 150 °C for 3 h. After the solvent
was removed under reduced pressure, the crude product was
purified by column chromatography (silica gel, hexane/EtOAc,
4:1) to give 10 mg of 57 (42%) as a white solid: mp 98-100
°C; IR (KBr) 2955, 1731, 1439, 1358, 1276, 1237, 1204, 1146,
3-Meth yl-1,3-d ih yd r oth ien o[3,4-b]ben zofu r a n 2,2-Di-
oxid e (54) a n d 3,3-Dim eth yl-1,3-d ih yd r oth ien o[3,4-b]-
ben zofu r a n 2,2-Dioxid e (55). To a solution of compound 3
(80 mg, 0.38 mmol) and hexamethyl phosphoramide (0.20 mL,
1.15 mmol) in THF (10 mL) cooled at -105 °C was slowly
added a solution of lithium hexamethyldisilazide (LiHMDS,
0.09 M, 0.19 mmol). After the solution was warmed to -80
°C, methyl iodide (0.10 mL, 1.46 mmol) was added at once.
The stirring was continued for 2 h after which time the
reaction was quenched by EtOAc. The solvent was removed
under reduced pressure and the crude product was purified
by HPLC (hexane/EtOAc, 4:1) to give 24 mg of 54 (58%) and
12 mg of 55 (27%). Compound 54: a white solid, mp 78-80
°C; IR (KBr) 2921, 2361, 1450, 1307, 1116, 748 cm-1; 1H NMR
(CDCl3) δ 1.71 (d, J ) 6.7 Hz, 3H), 4.31-4.44 (m, 1H), 4.39 (s,
2H), 7.31 (td, J ) 7.2, 1.3 Hz, 1H), 7.38 (td, J ) 7.5, 1.4 Hz,
1H), 7.46 (d, J ) 7.2 Hz, 1H), 7.54 (d, J ) 7.5 Hz, 1H); 13C
NMR (CDCl3) δ 12.8, 54.3, 58.5, 108.7, 112.1, 119.7, 123.9,
124.3, 125.4, 150.9, 156.5; MS (m/z) 222 (M+), 158 (100%), 131,
115, 102, 77, 64; HRMS calcd for C11H10O3S 222.0351, found
222.0348. Compound 55: a white solid, mp 93-95 °C; IR
(KBr) 2970, 2931, 2361, 1298, 1227, 1117, 751 cm-1; 1H NMR
(CDCl3) δ 1.73 (s, 6H), 4.36 (s, 2H), 7.31 (t, J ) 7.4 Hz, 1H),
7.37 (td, J ) 7.3, 1.3 Hz, 1H), 7.47 (d, J ) 8.1 Hz, 1H), 7.54 (d,
J ) 8.0 Hz, 1H); 13C NMR (CDCl3) δ 21.4, 52.8, 62.1, 106.4,
112.0, 119.7, 123.7, 124.4, 125.2, 155.4, 156.1; MS (m/z) 236
(M+), 172 (100%), 157, 128, 115, 102, 77, 63; HRMS calcd for
1
1050, 758; H NMR (CDCl3) δ 2.57 (s, 3H), 3.95 (s, 3H), 4.00
(s, 3H), 7.40 (t, J ) 7.5 Hz, 1H), 7.52 (t, J ) 7.7 Hz, 1H), 7.62
(d, J ) 8.5 Hz, 1H), 7.98 (d, J ) 7.5 Hz, 1H), 8.48 (s, 1H); 13
C
NMR (CDCl3) δ 29.7, 52.5, 52.7, 112.0, 120.3, 120.9, 121.2,
122.8, 123.5, 123.6, 124.0, 128.2, 134.4, 157.1, 166.3, 169.4;
MS (m/z) 298 (M+), 267 (100%), 251, 224, 208, 180, 152; HRMS
calcd for C17H14O5 298.0841, found 298.0829.
2,3-Bis(m et h oxyca r b on yl)-4-m et h yld ib en zot h io-
p h en e (58). A solution of compound 50 (34 mg, 0.14 mmol)
and dimethyl acetylenedicarboxylate (0.14 mL, 1.14 mmol) in
benzene (5 mL) was heated at 150 °C for 2 h. Then DDQ (260
mg, 1.14 mmol) was added and heated at 150 °C for 3 h. After
the solvent was removed under reduced pressure, the crude
product was purified by column chromatography (silica gel,
hexane/EtOAc, 4:1) to give 32 mg of 58 (71%) as a white solid:
mp 128-130 °C; IR (KBr) 2957, 1723, 1589, 1548, 1400, 1340,
1272, 1235, 1193, 1160, 1115, 1021, 765, 739; 1H NMR (CDCl3)
δ 2.57 (s, 3H), 3.97 (s, 3H), 4.01 (s, 3H), 7.50-7.53 (m, 2H),
7.87-7.90 (m, 1H), 8.19-8.23 (m, 1H), 8.65 (s, 1H); 13C NMR
(CDCl3) δ 18.0, 52.6, 52.7, 121.2, 122.3, 122.9, 124.6, 125.1,
127.7, 129.8, 132.4, 135.3, 139.8, 145.0, 166.4, 169.7, 185.8;
MS (m/z) 314 (M+), 300, 282, 269, 224 (100%), 196, 139; HRMS
calcd for C17H14O4S 314.0613, found 314.0618.
C
12H12O3S 236.0507, found 236.0509.
1,3,3-Tr im eth yl-1,3-dih ydr oth ien o[3,4-b]ben zofu r an 2,2-
Dioxid e (56). To a solution of compound 3 (35 mg, 0.17
mmol), methyl iodide (0.05 mL, 0.80 mmol), and hexamethyl
phosphoramide (0.12 mL, 0.69 mmol) in THF (5 mL) cooled at
-78 °C was slowly added a solution of lithium hexamethyl-
disilazide (LiHMDS, 0.07 M, 0.15 mmol). The stirring was
continued for 2 h after which time the reaction was quenched
by EtOAc. The solvent was removed under reduced pressure,
and the crude product was purified by HPLC (hexane/EtOAc,
4:1) to give compounds 55 (11%) and 56 (29%). Compound
56: white solid, mp 91-93 °C; IR (KBr) 2923, 1448, 1311,
Ack n ow led gm en t. We thank the National Science
Council for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
all compounds and 13C NMR for compounds 3, 4b, 12a , 31,
42, 44, 47, 48, 51, 54-61 (51 pages). This material is
contained in libraries on microfiche, immediately 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.
1
1102, 748 cm-1; H NMR (CDCl3) δ 1.71-1.76 (m, 9H), 4.48
(q, J ) 7.0 Hz, 1H), 7.30 (td, J ) 7.3, 1.2 Hz, 1H), 7.37 (td, J
) 7.4, 1.4 Hz, 1H), 7.53 (t, J ) 7.8 Hz, 2H); 13C NMR (CDCl3)
J O980044E