Synthesis of 2,5-disubstituted thienosultines and their thermal reactions with dienophiles and nucleophiles

Article abstract of DOI:10.1021/jo011122s

The 2,5-disubstituted thienosultines (5,7-disubstituted 1,4-dihydro-1H-3λ⁴-thieno[3,4-d][2,3]oxathiin-3-oxides) 5a-d were prepared from the corresponding dichlorides 4a-d with the commercially available Rongalite (sodium formaldehyde sulfoxylat

Full text of DOI:10.1021/jo011122s

Syn th esis of 2,5-Disu bstitu ted Th ien osu ltin es a n d Th eir Th er m a l
Rea ction s w ith Dien op h iles a n d Nu cleop h iles
Wen-Dar Liu, Chih-Chin Chi, I-Feng Pai, An-Tai Wu, and Wen-Sheng Chung*
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan 30050, ROC
wschung@cc.nctu.edu.tw
Received December 3, 2001
The 2,5-disubstituted thienosultines (5,7-disubstituted 1,4-dihydro-1H-3λ4-thieno[3,4-d][2,3]oxa-
thiin-3-oxides) 5a -d were prepared from the corresponding dichlorides 4a -d with the commercially
available Rongalite (sodium formaldehyde sulfoxylate) in 17-60% yields. When heated in the
presence of electron-poor dienophiles, sultines 5a -d underwent elimination of SO2, and the resulting
non-Kekule´ biradicals 7a -d were intercepted as the 1:1 adducts 8-12 in good to excellent yields.
The pyrolysis of sultines and sulfolenes with different concentrations of dienophiles revealed that
either a preequilibrium between starting reagents and biradical species or Diels-Alder and retro-
Diels-Alder reaction mechanisms may be involved; however, more work is necessary to establish
the proposed mechanisms. Reaction of sultine 5b with nBuLi was found to undergo a nucleophilic
ring-opening reaction to give sulfinyl alcohol 17 after H2O workup. When sultine 5a was heated in
benzene in a sealed tube in the presence of methanol, methanol-d4, or 2-mercaptoethanol, the
respective 1:1 trapping adducts 19-21 as well as the rearranged sulfolene 6a were isolated in
similar amounts. The isolation of adducts 19-21 may be explained by the involvement of either
biradical or ionic intermediates during the pyrolysis.
In tr od u ction
cyclobutenes are also useful precursors, but they often
come from other precursors;1h,i therefore, an extra step
in synthesis is usually required. Dihalides are useful in
thermal reactions; however, they usually require the
addition of other catalysts1a,e,i to enhance the reactivity.
We choose sultines3-5 as precursors for o-QDM because
they are usually stable above room temperature and yet
react thermally at milder conditions than sulfolenes.
Pioneering studies on benzosultine and derivatives as
o-QDM precursors had been explored by Durst et. al in
the last two decades,4 but further development of other
sultines was hampered by their tedious synthesis. The
successful application of Rongalite in the conversion of
The study of heterocyclic fused o-quinodimethane (o-
QDM, 1) has received considerable current interest,1 and
many methods have been developed for the generation
of o-QDM; for example, azo compounds, sulfolenes, ben-
(2) (a) Berson, J . A. Acc. Chem. Res. 1997, 30, 238. (b) In a study by
Lu et al. the thiophene diazene was unstable below -10 °C: Lu, H. S.
M.; Berson, J . A. J . Am. Chem. Soc. 1996, 118, 265. (c) The azo
precursor was reported to be stable only below -20 °C by Bush et al.:
Bush, L. C.; Heath, R. B.; Berson, J . A. J . Am. Chem. Soc. 1993, 115,
9830.
(3) (a) Wu, A.-T.; Liu, W.-D.; Chung, W.-S. J . Chin. Chem. Soc. 2002,
49, 77. (b) Liu, J .-H.; Wu, A.-T.; Huang, M.-H.; Wu, C.-W.; Chung, W.-
S. J . Org. Chem. 2000, 65, 3395. (c) Chung, W.-S.; Liu, J .-H. Chem.
Commun. 1997, 205. (d) Chung, W.-S.; Lin, W.-J .; Liu, W.-D.; Chen,
L.-G. J . Chem. Soc., Chem. Commun. 1995, 2537.
(4) For some earlier works on sultines, see: (a) King, J . F.; Rathore,
R. Tetrahedron Lett. 1989, 30, 2763. (b) Durst, T.; Charlton, J . L.;
Mount, D. B. Can. J . Chem. 1986, 64, 246. (c) Charlton, J . L.; Durst,
T. Tetrahedron Lett. 1984, 25, 5287. (d) J ung, F.; Molin, M.; Van Den
Elzen, R.; Durst, T. J . Am. Chem. Soc. 1974, 96, 935. (e) Connolly, T.
J .; Durst, T. Tetrahedron Lett. 1997, 38, 1337. (f) Sharma, N. K.; De
Reinach-Hirtzbach, F.; Durst, T. Can. J . Chem. 1976, 54, 3012. (g)
Roversi, E.; Monnat, F.; Schenk, K.; Vogel, P.; Bran˜a, P.; Sordo, J . A.
Chem.sEur. J . 2000, 6, 1858 and earlier references therein. (h)
Megevand, S.; Moore, J .; Schenk, K.; Vogel, P. Tetrahedron Lett. 2001,
42, 673.
zocyclobutenes, and dihalides are popular precursors.
Although azo compounds are popular for the generation
of o-QDMs because of their clean thermal and photo-
chemical reactions, they are notorious for their thermal
instability in thieno- and pyrrolo-fused diazenes.2b,c On
the contrary, sulfolenes are so stable that harsh reaction
conditions, such as flash vacuum pyrolysis or high-
temperature pyrolysis, are usually required.1c,d,g Benzo-
(1) For reviews of o-quinodimethanes, benzocyclobutenes, and re-
lated chemistry, see: (a) Segura, J . L.; Mart´ın, N. Chem. Rev. 1999,
99, 3199. (b) Collier, S. J .; Storr, R. C. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: New York,
1998; Vol. 10, pp 25-48. (c) Ando, K.; Kankake, M.; Suzuki, T.;
Takayama, H. Tetrahedron 1995, 51, 129. (d) Chou, T.-S. Rev.
Heteroatom Chem. 1993, 8, 65. (e) Mart´ın, N.; Seoane, C.; Hanack, M.
Org. Prep. Proced. Int. 1991, 23, 237. (f) Charlton, J . L.; Alauddin, M.
M. Tetrahedron 1987, 43, 2873. (g) Funk, R. L.; Vollhardt, K. P. C.
Chem. Soc. Rev. 1980, 9, 41. (h) Kametani, T. Pure Appl. Chem. 1979,
51, 747. (i) Oppolzer, W. Synthesis 1978, 793; Heterocycles 1980, 14,
1615.
(5) For a review of sultines, see: Dittmer, D. C.; Hoey, M. D. The
Chemistry of Sulphinic Acids, Esters, and Their Derivatives; Wiley:
Chichester, U.K., 1990; pp 239-273.
10.1021/jo011122s CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/04/2002
J . Org. Chem. 2002, 67, 9267-9275
9267

Liu et al.
SCHEME 1a
SCHEME 2
a
Reagents and conditions: (a) nBuLi, THF, 0 °C, 3 h; ZnCl2,
rt, 2 h; (b) PhBr, Pd(PPh3)4, THF, 55 °C, 24 h; (c) nBuLi, THF, 0
°C, 3 h; CH3I, 0 °C f rt, 24 h.
dihalides to sultines by Hoey and Dittmer5,6 makes it a
convenient precursor for o-QDM. Although the applica-
tion of sulfolenes and sultines as o-QDM precursors has
been popular, important questions remain to be answered
concerning their differences in reactivity and reaction
mechanisms. In their pyrolysis studies of sulfolenes with
alkenes, Takayama et al. reported1c,7 that Diels-Alder
reaction occurred first on the aromatic moiety, followed
by SO2 extrusion, then a second Diels-Alder reaction to
give 1:2 cycloadducts, and finally a retro-Diels-Alder
reaction to give the 1:1 fused adducts (vide infra).
We have been interested in the application of hetero-
cyclic fused o-QDM in Diels-Alder reactions,3 and in this
work R,R′-disubstituted thienosultines are synthesized to
find out whether sultines react through the mechanism
proposed by Takayama for sulfolenes or through a
biradical mechanism similar to those of diazenes.2 On one
hand, the bulky R,R′-disubstituents on thienosultines
may have two functions: (1) they hinder the direct
addition of dienophiles to R-positions of thiophene, and
(2) the phenyl group(s) may stabilize the thus formed
non-Kekule´ biradicals. Therefore, if the 1:1 fused adducts
are still formed with the bulky substituents, the biradical
mechanism may be involved. Furthermore, concentra-
tion-dependent trapping studies on the pyrolysis of
sulfolenes and sultines are carried out in the hope to
differentiate their reaction mechanisms on the basis of
whether their rate-determining steps are unimolecular
or bimolecular reactions. We herein report our explora-
tion of the scope of thienosultine derivatives and their
thermal reaction with various dienophiles and nucleo-
philes.
available. Butyllithium treatment of 2-phenylthiophene
(2)8a followed by methylation led to 2-methyl-5-phenyl-
thiophene (3c) in 97% yield. 2,5-Diphenylthiophene (3d )
was prepared by a known method using a palladium
catalyst.8b 2,5-Disubstituted 3,4-bis(chloromethyl)-
thiophenes 4a -d were prepared by chloromethylation of
the corresponding 2,5-disubstituted thiophenes 3a -d
adapted according to the procedures developed by Wyn-
berg et al. in the synthesis of the corresponding sulfones
6.9a,b The key step in the synthesis of sultines 5a -d is
the use of Rongalite (sodium formaldehyde sulfoxylate)
with the corresponding dichlorides 4a -d . Unfortunately,
the yields for the preparation of these sultines are
relatively poor compared to that of ca. 70% for the
preparation of benzosultine,5,6 and there is room for
further improvement of the thienosultine synthesis.
1
The H NMR spectra of sultines 5a -d deserve some
comments because they show two characteristic AB
quartets of the 1,4-hydrogens near oxathiin-3-oxide func-
tional groups. It has been reported that hydrogens on the
carbon R to the oxygen of an oxathiin-3-oxide (sultine)
have chemical shifts of 4.9-5.6 ppm, whereas hydrogens
on the carbon R to the sulfinyl of an oxathiin-3-oxide have
chemical shifts of 3.5-4.7 ppm.3-4,11b The four R-hydro-
gens of sulfolenes 6a -d have chemical shifts in the range
of 4.1-4.4 ppm and appear as singlets (except those for
6c, for which two singlets were observed) due to sym-
metry and lack of a nearby chiral center. In the five
thienosultines we have studied, the chemical shifts of
hydrogens in sultines 5a -d fell into two regions, 3.6-
4.4 and 4.9-5.5 ppm (see the Experimental Section),
which are in good agreement with the above description.
The magnitude of the geminal coupling constant of the
hydrogens R to the oxygen, J cd, is usually smaller than
that of hydrogens R to the sulfinyl group of a sultine (i.e.,
Resu lts a n d Discu ssion
The syntheses of 2,5-disubstituted thienosultines 5a -d
are shown in Schemes 1 and 2. 2,5-Dimethylthiophene
(3a ) and 2,5-dichlorothiophene (3b) are commercially
J
ab). The former are in the range of 13.6-14.9 Hz,
whereas the latter are in the range of 15.3-16.0 Hz (see
Table 1). The assignments of thienosultine 1H NMR
chemical shifts are based on previous assignments by
Pirkle on benzosultines11b and the known propensity of
(6) (a) Hoey, M. D.; Dittmer, D. C. J . Org. Chem. 1991, 56, 1947.
(b) J arvis, W. F.; Hoey, M. D.; Finocchio, A. L.; Dittmer, D. C. J . Org.
Chem. 1988, 53, 5750.
(7) (a) Ando, K.; Aakadegawa, N.; Takayama, H. J . Chem. Soc.,
Chem. Commun. 1991, 1765. (b) Ando, K.; Kankake, M.; Suzuki, T.;
Takayama, H. Synlett 1994, 741. (c) Konno, K.; Kawakami, Y.;
Hayashi, T.; Takayama, H. J . Chem. Soc., Perkin Trans. 1 1994, 1371.
(d) Chou, T.-S.; Tseng, H.-J . Tetrahedron Lett. 1995, 36, 7105. (e) Chou,
S.-S. P.; Lee, C.-S.; Cheng, M.-C.; Tai, H.-P. J . Org. Chem. 1994, 59,
2010.
(8) (a) Rossi, R.; Carpita, A.; Ciafalo, M.; Lippolis, V. Tetrahedron
1991, 47, 8443. (b) Campaigne, E.; Foye, W. J . Org. Chem. 1952, 17,
1405.
(9) (a) Wynberg, H.; Zwanenburg, D. J . J . Org. Chem. 1964, 29, 1919.
(b) Zwanenburg, D. J .; Wynberg, H. J . Org. Chem. 1969, 34, 333. (c)
Winn, M.; Bordwell, F. G. J . Org. Chem. 1967, 32, 1610.
9268 J . Org. Chem., Vol. 67, No. 26, 2002

Synthesis of 2,5-Disubstituted Thienosultines
TABLE 1. Ch a r a cter istic Hyd r ogen Ch em ica l Sh ifts a n d Gem in a l Cou p lin g Con sta n ts of Th ien osu ltin es 5a -d a n d Oth er
Heter ocyclic Su ltin es
a
Estimated accuracy for coupling constants is ca. (0.2 Hz. All measurements were done in CDCl3 in a 300 MHz NMR spectrometer.
protons cis to a sulfinyl oxygen to be deshielded; there-
fore, Hb is downfield shifted from Ha and Hd is downfield
shifted from Hc.11d
consistent with those reported by Takayama,1c,7a-c Chou,7d,e
and Wynberg9 in their early attempts. Furthermore, it
is interesting to observe the great similarity of our results
with sultines and those with diazenes reported by Berson
et al.2,10 For example, in the trapping experiments of
thiophene biradical 7e (X ) Y ) H) derived from a
diazene precursor,10 the sole adducts formed (85-100%)
had the fused structure (such as 8) but not the bridged
structure 13 (see Scheme 4).
The pyrolysis results of these sultines may be ex-
plained by at least three possible reaction mechanisms.
The most likely pathway is the formation of non-Kekule´
biradicals 7a -d , followed by the Diels-Alder reaction
with a dienophile to form either bridged adducts 13 or
fused adducts 8-12 (pathway A, Scheme 3). This mech-
anism resembles those proposed for thieno- or furano-
Sealed tube reaction of sultines 5a -d in benzene alone
gave the corresponding sulfolenes 6a -d in excellent
yields (83-94%). The Diels-Alder reactions of sultines
5a -d and sulfolenes 6a -d with typical electron-poor
dienophiles are presented in Scheme 3 and Table 2. For
example, when heated in benzene (sealed tube, 180 °C,
24 h) in the presence of 3 equiv of N-phenylmaleimide,
dimethyl fumarate, fumaronitrile, dimethyl acetylene-
dicarboxylate, or diethyl fumarate, the sultines 5a -d all
underwent extrusion of SO2, and the resulting non-
Kekule´ biradicals 7a -d were intercepted as the 1:1 fused
adducts 8-12 in 37-91% yields (entries 1-3, 5-7, 9-12,
and 14-17 of Table 2). In each case, small to substantial
amounts of sulfolenes 6a -d were also formed depending
on the power of the dienophiles; that is, stronger dieno-
philes led to higher yields of fused adducts and less
sulfolenes. It is important to note that sulfolenes 6a -d
did not react with any of these dienophiles under the
same reaction conditions (entries 4, 8, 13, and 18 of Table
2). The low reactivity of sulfolenes 6a -d is in sharp
contrast with the high reactivity of sultines 5a -d but is
(10) (a) Haider, K. W.; Clites, J . A.; Berson, J . A. Tetrahedron Lett.
1991, 32, 5305. (b) Stone, K. J .; Greenberg, M. M.; Blackstock, S. C.;
Berson, J . A. J . Am. Chem. Soc. 1989, 111, 3659. (c) Greenberg, M.
M.; Blackstock, S. C.; Berson, J . A. Tetrahedron Lett. 1987, 28, 4263.
(d) Reynolds, J . H.; Berson, J . A.; Kumashiro, K. K.; Duchamp, J . C.;
Zilm, K. W.; Scaiano, J . C.; Berinstain, A. B.; Rubello, A.; Vogel, P. J .
Am. Chem. Soc. 1993, 115, 8073. (e) Greenberg, M. M.; Blackstock, S.
C.; Berson, J . A. J . Am. Chem. Soc. 1989, 111, 3671. (f) Cichra, D.;
Platz, M. S.; Berson, J . A. J . Am. Chem. Soc. 1977, 99, 8507.
J . Org. Chem, Vol. 67, No. 26, 2002 9269

Liu et al.
SCHEME 3
SCHEME 4
(pathway B, Scheme 3). The third possible reaction
mechanism of thienosultines 5a -d is to undergo a Diels-
Alder reaction on the aromatic moieties first followed by
instantaneous SO2 elimination to give bridged adducts
13. Compounds 13 further react with another dienophile
to give the 1:2 adducts 15, and finally a retro-Diels-Alder
reaction of 15 would occur to form fused adducts 8-12
(Scheme 4). The latter mechanism was proposed by
Takayama to explain results with furano- and pyrrolosul-
folenes.1c,7
In the mechanisms involving biradical intermediates
(pathways A and B in Scheme 3), the rate will be
dependent only on the sultine concentration if the dieno-
phile concentration is kept high and a steady-state
approximation of the biradical concentration is satisfied.
However, if the dienophile concentration is low, the rate
of reaction will be dependent not only on the concentra-
tion of sultines but also on the concentration of dieno-
philes.11e Alternatively, if a Diels-Alder reaction occurs
first on the aromatic part of sultine and it happens to be
the rate-determining step, the reaction would be second
order and first order with respect to both the sultine and
the dienophile. In the latter mechanism, the higher the
dienophile concentration the faster products are formed
and the faster starting sultines (or sulfolenes) are
consumed. Because thienosulfolenes 6a -d required a
much higher temperature to react with dienophiles, we
used furanosulfolene 163d instead and thienosultine 5a
for concentration-dependent kinetic studies.
TABLE 2. Sea led Tu be Rea ction s of 2,5-Disu bstitu ted
Th ien osu ltin es 5a -d a n d Su lfolen es 6a -d w ith Va r iou s
Dien op h iles (3 equ iv) in Ben zen ea
products
(yield, %)
total
yield, %
entry diene
dienophile
1
2
3
5a
5a
5a
6a
N-phenylmaleimide
dimethyl fumarate
fumaronitrile
6a (6) + 8a (91)
6a (49) + 9a (40)
6a (46) + 10a (43)
no reaction
97
89
89
0
4
various dienophilesb
5
6
7
8
5b N-phenylmaleimide
5b dimethyl fumarate
5b fumaronitrile
6b (7) + 8b (65)
6b (4) + 9b (64)
6b (16) + 10b (77)
no reaction
72
68
93
0
6b various dienophilesb
9
10
11
5c
5c
5c
N-phenylmaleimide
fumaronitrile
dimethyl
acetylenedicarboxylate
diethyl fumarate
various dienophilesb
6c (16) + 8c (76)
6c (13) + 10c (75)
6c (47) + 11c (37)
92
88
84
12
13
14
15
16
17
18
5c
6c
6c (23) + 12c (69)
no reaction
92
0
5d N-phenylmaleimide
5d dimethyl fumarate
5d fumaronitrile
6d (6) + 8d (82)
6d (12) + 9d (79)
6d (21) + 10d (75)
6d (30) + 12d (67)
no reaction
88
91
96
97
0
Concentration-dependent studies on the thermolysis of
thienosultine 5a (150 °C, 5 h) and furanosulfolene 16 (120
°C, 2 h) are shown in Figure 1. In the thermolysis of 5a ,
the yield of sulfolene 6a gradually decreased from 23%
to ca. 2% when the concentration of fumaronitrile in-
5d diethyl fumarate
6d various dienophilesb
a
All reactions were carried out in benzene solution in a sealed
b
tube at 180 °C for 24 h. All the dienophiles used in the table
were tested for sulfolenes 6a -d .
(11) (a) Andersen, K. K.; Foley, J .; Perkins, R.; Gaffield, W.;
Papanikalaou, N. J . Am. Chem. Soc. 1964, 86, 5637. (b) Pirkle, W. H.;
Hoekstra, M. S. J . Am. Chem. Soc. 1976, 98, 1832. (c) Harpp, D. N.;
Vines, S. M.; Montillier, J . P.; Chan, T. H. J . Org. Chem. 1976, 41,
3987. (d) Alternatively, one may envision that the lone pair electrons
on sulfur of a sulfinyl group could act to shield a proton cis-vicinal to
it. (e) For an excellent monograph on the kinetics of reactions involving
intermediates, see: Wentrup, C. Reactive Molecules; Wiley: New York,
1984; Chapter 1.
diazenes.2,10 Alternatively, sultines may undergo a one-
bond (carbon-oxygen bond) cleavage to form alkyl sulfinyl
biradicals of the type 7′a -d . The biradicals 7′a -d may
then undergo either an intramolecular rearrangement to
form sulfolenes 6a -d or an intermolecular trapping by
olefins to form after losing SO2 the 1:1 fused adducts
9270 J . Org. Chem., Vol. 67, No. 26, 2002

Synthesis of 2,5-Disubstituted Thienosultines
SCHEME 5
F IGURE 1. Product distributions of the sealed tube reactions
of sultine 5a and sulfolene 16 with various concentrations of
fumaronitrile: (a) 2,5-dimethylthienosultine 5a (16.5 mM in
toluene), reacted at 150 °C for 5 h, where closed circles indicate
the yield (%) of sulfolene 6a , open triangles indicate the yield
(%) of cycloadduct, and open squares indicate the yield (%) of
the recovered sultine; (b) furanosulfolene 16 (15.8 mM in
benzene), reacted at 120 °C for 2 h, where open circles indicate
the yield (%) of recovered sulfolene and open triangles indicate
the yield (%) of cycloadduct formed. All the reactions were
stopped far before completion.
Such an analysis would require direct spectroscopic
measurement as has been elegantly demonstrated in the
pyrolysis of a diazene.10f However, we lack a proper
thermostated optical cell for the in situ monitoring of
high-temperature kinetics. Although laser flash spec-
troscopy and matrix isolation would also provide valuable
information about the transient species, they are related
to photochemical and photophysical properties of these
sultines and may not be related to the thermolysis results
discussed here. Clearly more work is necessary to estab-
lish these proposed mechanisms.
creased from 0 to 0.25 M (Figure 1a). Concurrently, the
percentage yield of cycloadduct 10a increased when the
concentration of fumaronitrile increased. The results may
be rationalized easily if diradical intermediates are
invoked; that is, a competitive trapping of biradicals 7
by SO2 or dienophile determines the relative amount of
sulfolene 6a and cycloadduct 10a . A similar explanation
may be applied in the Diels-Alder and retro-Diels-Alder
reaction mechanism (Scheme 4), where a competitive
trapping of reactive diene 13 by dienophile or SO2
determines the relative product ratios. The consumption
rate of furanosulfolene 16 is shown to be concentration
dependent on both the sulfolene and fumaronitrile (Fig-
ure 1b). That is, higher dienophile (or sulfolene) concen-
tration led to faster consumption of sulfolene and faster
formation of cycloadducts. It would certainly be desirable
to differentiate the above mechanisms; however, more
accurate kinetic data are necessary for such an analysis.
It has long been known that the reaction of an optically
active reagent on sulfinate esters (sultines) will lead to
sulfoxides of high optical purity, the so-called Andersen
synthesis.11a These reactions are stereospecific and pro-
ceed with inversion at sulfur.11b Nucleophilic ring opening
of heterocyclic fused sultines, however, has rarely been
reported. Some of the few reported reactions of sultines
with Grignard reagents as well as organocopper-lithium
reagents11c were mainly with aliphatic sultines. Reaction
of sultine 5b with nBuLi gave the sulfinyl alcohol 17 after
workup by H2O; however, it gave a deuterated sulfinyl
alcohol, 18, as the main product if worked up by D2O
1
(Scheme 5). Careful inspection of the H NMR spectrum
of 18 revealed that deuterium appeared only on the
R-sulfinyl carbon, and no sign of deuterium scrambling
in other carbons was found. The isolation of 18 as the
J . Org. Chem, Vol. 67, No. 26, 2002 9271

Liu et al.
major product indicated that neighboring alkoxide might
have undergone a H abstraction from the R-carbon of the
sulfinyl group, giving hydroxyl and sulfinyl anion groups.
The sulfinyl anion group eventually abstracts either a
H from H2O or a deuterium from D2O to form 18 as the
finally observed product. Although yields for the nucleo-
philic attack of cyclic sulfinate esters (sultines) by nBuLi
are low (33-47%), they are comparable to the yields
reported (40-70%) for aliphatic sultines.11a-c
Sulfolenes are well-known to undergo alkylation readily
at their R-sulfonyl position upon deprotonation with
nBuLi followed by methyl iodide and ethyl, butyl, and
benzyl bromides, respectively.7 By contrast, sultines
undergo a nucleophilic attack if treated with a strong
base such as a Grignard reagent or nBuLi; therefore, the
synthesis of R-derivatives of sultines will not be straight-
forward. Reminiscences of the work done by Durst
indicated that sulfinyl alcohols 17 and 18 (so-called
δ-hydroxy sulfoxides)4d,f may be useful intermediates in
the synthesis of sultines.
with electron-poor alkenes, alkynes, radical trapping
agents, and nucleophiles. When heated in the presence
of electron-poor dienophiles, sultines 5a -d underwent
elimination of SO2, and the resulting biradicals (7a -d
or 7′a -d , Scheme 3) were intercepted as the 1:1 adducts
8-12 in good to excellent yields. In each case, small to
substantial amounts of sulfolenes 6a-d were also formed.
When sultine 5a was heated in benzene in a sealed tube
in the presence of methanol or 2-mercaptoethanol, the
respective trapping adducts 19-21 as well as the rear-
ranged sulfolene 6a were isolated. Reaction of sultine 5b
with nBuLi was found to undergo a nucleophilic ring-
opening reaction to give sulfoxide alcohol 17 after H2O
workup. Sulfoxide alcohols can be further transformed
into other sultine derivatives.4d,f Concentration-depend-
ent trapping of sultines and sulfolenes through thermoly-
sis revealed that different reaction mechanisms may be
involved. We are in the process of studying the photo-
chemistry and transient absorption spectroscopy of these
and other heterocyclic fused sultines,3 and the results will
be reported in due course.
To learn more about sultine chemistry and to deter-
mine the nature of the reactive intermediates, we further
explored the reaction of sultine 5a with radical trapping
reagents such as methanol, 1,4-cyclohexadiene, and
2-mercaptoethanol.12-14 In the presence of 2-mercapto-
ethanol in a sealed tube reaction in benzene, sultine 5a
underwent SO2 extrusion and gave a radical (or ionic)
trapping product, 19, as well as the rearranged sulfolene
6a in a ca. 2:3 ratio, with a total yield of 50%. Similar
trapping of the reactive intermediates by methanol gave
20 and sulfolene 6a in a ca. 1:1 ratio. The abstractions
of a hydrogen and a methoxy group in product 20 were
confirmed by a methanol-d4 trapping experiment, where
the disappearance of a methyl ether signal and a decrease
of the 3-methyl signal from an integration of three to two
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined on
a melting point apparatus and are uncorrected. 1H NMR
spectra were recorded at 300 MHz, 13C and DEPT NMR
spectra were recorded at 75.4 MHz, and the chemical shifts
are reported in parts per million (δ) relative to that of CDCl3
(δ ) 7.25 ppm for proton, and δ ) 77.00 ppm for carbon) or
tetramethylsilane as internal standard. Coupling constants are
reported in hertz (Hz). High-resolution mass spectra were
recorded on a spectrometer of the instrument center of either
National Tsing-Hua University or National Chung-Hsin Uni-
versity. C, H, and N combustion analyses were determined,
and all analyzed compounds are within (0.4% of the theoreti-
cal value unless otherwise indicated. Column chromatography
was performed on silica gel of 70-230 or 230-400 mesh. The
preparation of 2 followed a literature8a procedure. The syn-
thesis of dihalides 4a and 4b followed a literature procedure.9b,c
Da ta for 2-P h en ylth iop h en e (2): 98% yield; white solid;
1
protons were observed in H NMR spectra of adduct 21.
Although the formation of adducts 19-21 may be ex-
plained by a biradical trapping mechanism, alternatively,
it may also be explained by ionic intermediates similar
to those used by Myers in their trapping of R,3-dehydro-
toluene.13,14 The trapping of the reactive intermediate,
resulting from the pyrolysis of sultine 5a , by 1,4-cyclo-
hexadiene was found to be inefficient even though it has
been frequently used in the trapping of biradicals. The
results implied that the biradicals might have been
formed; however, they were either retrapped by SO2 (7a -
d ) or underwent intramolecular rearrangement (through
7′a -d ) to give only sulfolene 6a in 86% yield. Alterna-
tively, the latter results may favor the nucleophilic
displacement by methanol or mercaptoethanol on the
O-carbon atom to yield a sulfinic acid, which after losing
SO2 gives the observed products.15
1
mp 31-32 °C (lit.8a mp 36 °C); H NMR (300 MHz, CDCl3) δ
7.03-7.05 (1H, m), 7.23-7.37 (5H, m), 7.58-7.61 (2H, m); 13
C
NMR (75.4 MHz, CDCl3) δ 123.03 (CH), 124.75 (CH), 125.90
(CH), 127.41 (CH), 127.96 (CH), 128.84 (CH), 134.35 (Cq),
144.38 (Cq).
Syn th esis of 2-Meth yl-5-p h en ylth iop h en e (3c). To a
solution of 2 (4.36 g, 27.26 mmol) in THF (60 mL) at 0 °C was
slowly added n-butyllithium (2.5 M in hexane, 30 mmol) via
syringe under nitrogen. After the solution was stirred for 3 h,
methyl iodide (8.1 g, 54 mmol) in THF (4 mL) was added
dropwise with vigorous stirring. The reaction mixture was
gradually warmed to ambient temperature and stirred over-
night. The solution was poured into 50 mL of ice-water, the
two layers were separated, and the aqueous layer was ex-
tracted with ether (3 × 50 mL). The organic layers were
combined, dried over MgSO4, filtered, and concentrated. Flash
column chromatography on silica gel (hexane) gave 4.6 g (26
In conclusion, we have synthesized 2,5-disubstituted
thienosultines 5a -d and studied their thermal reactions
1
mmol, 97%) of 3c as a white solid: mp 39-41 °C; H NMR δ
2.47 (3H, s), 6.70-6.69 (1H, m), 7.07-7.08 (1H, m), 7.21-7.55
(5H, m); 13C NMR δ 15.45 (CH3), 122.85 (CH), 125.47 (CH),
126.16 (CH), 126.96 (CH), 128.78 (CH), 134.68 (Cq), 139.48 (Cq),
141.96 (Cq).
Syn th esis of 2,5-Dip h en ylth iop h en e (3d ). A hexane
solution of n-butyllithium (34.3 mmol) was added via syringe
to a stirred solution of 2-phenylthiophene (5.0 g, 31.2 mmol)
in anhydride THF (50 mL) at 0 °C under nitrogen. The mixture
was stirred at this temperature for 3 h, and then transferred
via syringe to a stirred solution of zinc chloride (4.68 g, 34.3
mmol) in 20 mL of anhydride THF at room temperature. The
(12) For examples of radical trapping by thiols, see: (a) Ottenheijm,
H. C. J . J . Org. Chem. 1981, 46, 5408. (b) Tome, A. C.; Cavaleiro, J . A.
S.; Storr, R. C. Tetrahedron 1996, 52, 1723.
(13) For efficient trapping of biradical intermediates using 1,4-
cyclohexadiene, see: (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J . Am.
Chem. Soc. 1989, 111, 8057. (b) Myers, A. G.; Dragovich, P. S.; Kuo,
E. Y. J . Am. Chem. Soc. 1992, 114, 9369.
(14) Storr et al. reported12b
a similar observation of conjugate
addition of thiol nucleophiles on the pyrimidin-4-ones generated from
the corresponding sulfolene with SO2 extrusion.
(15) We thank one of the reviewers for the suggestion of this
mechanism.
9272 J . Org. Chem., Vol. 67, No. 26, 2002

Synthesis of 2,5-Disubstituted Thienosultines
solution was stirred at ambient temperature for another 2 h
and then added via syringe to an oven-dried 250 mL round-
bottom flask containing tetrakis(triphenylphosphine)pal-
ladium (108 mg, 0.0936 mmol) and bromobenzene (5.0 g, 31.2
mmol) in 20 mL of dry THF. The reaction mixture was then
slowly heated to 55 °C and kept at this temperature for 24 h.
Dilute hydrochloric acid (0.1 N, 30 mL) was added to the cooled
reaction mixture. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 30 mL). The organic
layers were combined, washed with saturated sodium bicar-
bonate solution (30 mL) and water (3 × 30 mL), dried over
MgSO4, filtered, and concentrated. Recrystallization in hot
2-propanol gave 3.4 g (14.4 mmol, 46%) of 3d as a pale yellow
substituents are as follows: 60% for 5b, 17% for 5c and 5c′
(as a 1:1 mixture), and 25% for 5d .
Da t a for 5,7-Dim et h yl-1,4-d ih yd r o-1H-3λ4-t h ien o[3,4-
d ][2,3]oxa th iin -3-oxid e (Su ltin e 5a ): white solid; mp 70-
1
71 °C; H NMR δ 2.27 (6H, s), 3.58 (1H, A′B′, J ) 15.3 Hz),
3.88 (1H, A′B′, J ) 15.6 Hz), 4.93 (1H, AB, J ) 14.1 Hz), 5.16
(1H, AB, J ) 14.1 Hz); 13C NMR δ 12.11 (2 CH3), 50.92 (CH2),
58.73 (CH2), 119.13 (Cq), 125.40 (Cq), 128.72 (Cq), 133.15 (Cq);
MS (EI) m/z 202 (M+, 6.0), 138 (M+ - SO2, 100); HRMS m/z
calcd for C8H10O2S2 202.0122, found 202.0116. Anal. Calcd for
C8H10O2S2: C, 47.50; H, 4.98. Found: C, 47.29; H, 5.06.
Da ta for 5,7-Dich lor o-1,4-d ih yd r o-1H-3λ4-th ien o[3,4-d ]-
[2,3]oxa th iin -3-oxid e (Su ltin e 5b): white solid; mp 86-87
1
powder: mp 149-150 °C (lit.8b mp 149-150 °C); H NMR δ
1
°C; H NMR δ 3.66 (1H, A′B′, J ) 16.0 Hz), 3.73 (1H, A′B′, J
7.26-7.66 (12H, m); 13C NMR δ 123.97 (CH), 125.60 (CH),
127.50 (CH), 128.90 (CH), 134.27 (Cq), 143.58 (Cq); MS (EI)
m/z 237 (M+ + 1, 58), 236 (M+, 100), 202 (8).
) 16.1 Hz), 4.94 (1H, AB, J ) 14.9 Hz), 5.08 (1H, AB, J )
14.9 Hz); 13C NMR δ 49.50 (CH2), 57.04 (CH2), 120.44 (Cq),
121.23 (Cq), 125.51 (Cq), 126.36 (Cq); MS (EI) m/z 242 (M+,
11.4), 178 (M+ - SO2, 100); HRMS m/z calcd for C6H4Cl2O2S2
241.9030, found 241.9024. Anal. Calcd for C6H4Cl2O2S2: C,
29.64; H, 1.66. Found: C, 29.66; H, 1.94.
Gen er a l P r oced u r e for th e Syn th esis of 2,5-Disu bsti-
tu ted 3,4-Bis(ch lor om eth yl)th iop h en es 4a -d .9c The pro-
cedure for 4c is given as an example. Compound 3c (5.0 g,
28.7 mmol) was dissolved in carbon disulfide (10 mL), and
chloromethyl methyl ether (7.3 g, 86 mmol) was added. The
solution was cooled to 0 °C. A solution of tin tetrachloride (11.3
g, 43.05 mmol) in 10 mL of carbon disulfide was added
dropwise via an additional funnel under nitrogen. The mixture
turned dark green upon addition. The reaction mixture was
stirred at 0 °C for 1 h and then warmed to room temperature
for 2 h. The heterogeneous dark green mixture was poured
into ice-water (20 mL), and CH2Cl2 (40 mL) was added. After
the mixture was stirred for 10 min, the layers were separated
and the organic layer was washed with water (20 mL) and
dried over MgSO4. The solvent was distilled off in vacuo to
yield 3.7 g (1.37 mmol, 48%) of 4c as a viscous green oil.
Product 4c decomposed after chromatography on silica gel;
therefore, crude product was used without further purification.
The isolated yields based on starting materials 3a -c are as
follows: 4a , 41%; 4b, 69%; 4c, 48%; 4d , 64%.
Da ta for 7-Meth yl-5-p h en yl-1,4-d ih yd r o-1H-3λ4-th ien o-
[3,4-d ][2,3]oxa th iin -3-oxid e (Su ltin e 5c): pale yellow solid;
mp 91-92 °C; 1H NMR δ 2.41 (3H, s), 3.79 (1H, A′B′, J ) 15.5
Hz), 4.15 (1H, A′B′, J ) 15.5 Hz), 5.05 (1H, AB, J ) 14.0 Hz),
5.26 (1H, AB, J ) 14.0 Hz), 7.35-7.45 (5H, m); 13C NMR δ
12.71 (CH3), 51.59 (CH2), 58.81 (CH2), 121.02 (Cq), 126.42 (Cq),
127.79 (CH), 128.40 (CH), 128.94 (CH), 133.00 (Cq), 135.01 (Cq),
136.02 (Cq); MS (EI) m/z 264 (M+, 5), 200 (M+ - SO2, 96), 119
(96), 185 (M+
for C13H12O2S2 264.0279, found 264.0280. Anal. Calcd for
- SO2 - CH3, 100); HRMS m/z calcd
C
13H12O2S2: C, 59.07; H, 4.58. Found: C, 59.32; H, 4.71.
Da ta for 5-Meth yl-7-p h en yl-1,4-d ih yd r o-1H-3λ4-th ien o-
[3,4-d ][2,3]oxa th iin -3-oxid e (Su ltin e 5c′): pale yellow solid;
mp 95-97 °C; 1H NMR δ 2.37 (3H, s), 3.60 (1H, A′B′, J ) 15.6
Hz), 4.05 (1H, A′B′, J ) 15.6 Hz), 5.03 (1H, AB, J ) 14.1 Hz),
5.44 (1H, AB, J ) 14.1 Hz), 7.29-7.46 (5H, m); 13C NMR δ
12.59 (CH3), 51.54 (CH2), 58.75 (CH2), 121.04 (Cq), 126.42 (Cq),
127.71 (CH), 128.33 (CH), 128.86 (CH), 132.96 (Cq), 134.93 (Cq),
135.91 (Cq); MS (EI) m/z 264 (M+, 6), 200 (M+ - SO2, 78), 199
(100), 185 (75).
Da t a for 5,7-Dip h en yl-1,4-d ih yd r o-1H -3λ4-t h ien o[3,4-
d ][2,3]oxa th iin -3-oxid e (Su ltin e 5d ): clear crystal after
recrystallization from a solvent of CH2Cl2 and hexane; mp
176-177 °C; 1H NMR δ 3.80 (1H, A′B′, J ) 15.6 Hz), 4.36 (1H,
A′B′, J ) 15.6 Hz), 5.16 (1H, AB, J ) 14.0 Hz), 5.49 (1H, AB,
J ) 14.0 Hz), 7.37-7.49 (10H, m); 13C NMR δ 53.22 (CH2),
59.43 (CH2), 121.22 (Cq), 127.78 (Cq), 128.24 (CH), 128.31 (CH),
128.66 (CH), 128.95 (CH), 129.00 (CH), 129.05 (CH), 132.59
(Cq), 132.67 (Cq), 137.87 (Cq), 140.95 (Cq); MS (EI) m/z 326 (M+,
1.5), 262 (34), 261 (100), 228 (28); HRMS m/z calcd
for C18H14O2S2 326.0436, found 326.0433. Anal. Calcd for
Da ta for 3,4-Bis(ch lor om eth yl)-2,5-d im eth ylth iop h en e
1
(4a ): white solid; mp 59-61 °C; H NMR δ 2.40 (6H, s), 4.60
(4H, s); 13C NMR δ 12.75 (CH3), 37.23 (CH2), 131.95 (Cq),
135.91 (Cq). Anal. Calcd for C8H10Cl2S: C, 45.95; H, 4.82.
Found: C, 46.00; H, 4.85.
Da ta for 2,5-Dich lor o-3,4-bis(ch lor om eth yl)th iop h en e
(4b): white solid; mp 38-39 °C (lit.9b mp 41-42 °C); 1H NMR
δ 4.63 (4H, s); 13C NMR δ 35.66 (CH2), 126.94 (Cq), 132.88 (Cq).
Anal. Calcd for C6H4Cl4S: C, 28.83; H, 1.61. Found: C, 29.05;
H, 1.62.
Da t a for 3,4-Bis(ch lor om et h yl)-2-m et h yl-5-p h en yl-
1
th iop h en e (4c):2b viscous green oil; H NMR δ 2.48 (3H, s),
4.63 (2H, s), 4.69 (2H, s), 7.36-7.52 (5H, m); 13C NMR δ 12.96
(CH3), 37.12 (CH2), 38.55 (CH2), 128.21 (CH), 128.83 (CH),
129.02 (CH), 131.63 (Cq), 132.89 (Cq), 133.07 (Cq), 138.92 (Cq),
140.49 (Cq); MS (EI) m/z 272 (M+ + 2, 17), 271 (M+ + 1, 30),
270 (M+, 25), 269 (36), 234 (64), 185 (100).
C
18H14O2S2: C, 66.23; H, 4.32. Found: C, 66.18; H, 4.39.
Gen er a l P r oced u r e for th e Tr a p p in g Exp er im en ts of
2,5-Dim eth ylth ien osu ltin e 5a w ith Dien op h iles Su ch a s
N-P h en ylm a leim id e, Dim eth yl F u m a r a te, a n d F u m a -
r on itr ile. A solution of 2,5-dimethylthienosultine 5a (50 mg,
0.25 mmol), with or without the respective dienophiles (0.74
mmol), in benzene (3 mL) was kept in a sealed tube at 180 °C
for 24 h. The solvent was evaporated under vacuum, and the
residue was subjected to silica gel chromatography using
hexane/ethyl acetate (from 16:1 to 4:1) as the eluent. Sulfolene
6a was obtained in 90% yield (no quencher). For the trapping
by dienophiles, the respective yields are as follows: N-
phenylmaleimide, 6% 6a and 91% 8a ; dimethyl fumarate, 49%
6a and 40% 9a ; fumaronitrile, 46% 6a and 43% 10a .
Da t a for 4,6-Dim et h yl-1,3-d ih yd r o-1H-2λ6-t h ien o[3,4-
c]th iop h en e-2,2-d ion e (6a ): white solid; mp 187-188 °C; 1H
NMR δ 2.34 (6H, s), 4.11 (4H, s); 13C NMR δ 13.54 (CH3), 54.71
(CH2), 126.59 (Cq), 133.57 (Cq); MS (EI) m/z 202 (M+, 21.7),
138 (M+ - SO2, 100); HRMS m/z calcd for C8H10O2S2 202.0122,
found 202.0119. Anal. Calcd for C8H10O2S2: C, 47.50; H, 4.98.
Found: C, 47.29; H, 5.06.
Da ta for 3,4-Bis(ch lor om eth yl)-2,5-d ip h en ylth iop h en e
1
(4d ): white solid; 64% yield; mp 108.1-108.7 °C; H NMR δ
4.76 (4H, s), 7.42-7.61 (10H, m); 13C NMR δ 38.45 (CH2),
128.55 (CH), 128.94 (CH), 129.08 (CH), 132.50 (Cq), 132.58 (Cq),
143.22 (Cq); MS (EI) m/z 336 (M+ + 3, 4), 335 (M+ + 2, 7), 334
(M+ + 1, 27), 333 (M+, 17), 332 (42), 298 (20), 297 (47), 248
(100), 247 (62), 129 (69). Anal. Calcd for C18H14Cl2S: C, 64.87;
H, 4.23. Found: C, 64.70; H, 4.62.
Gen er a l P r oced u r e for th e Syn th esis of 5,7-Disu bsti-
t u t ed 1,4-Dih yd r o-1H -3λ4-t h ien o[3,4-d ][2,3]oxa t h iin -3-
oxid es (Su ltin es) 5a -d . A solution of 4a -d (0.30 g for 4a ,
1.43 mmol), Rongalite (0.44 g, 2.86 mmol), and TBAB (0.69 g,
2.15 mmol) in DMF (50 mL) was stirred at room temperature
for 2 h. The mixture was diluted with H2O (40 mL) and
extracted three times (3 × 20 mL) with ether. The organic
layer was dried over MgSO4, concentrated, and purified by
column chromatography (25-5:1 hexane/ethyl acetate) to give
0.14 g (0.67 mmol, 47%) of 5a . Corresponding yields for other
J . Org. Chem, Vol. 67, No. 26, 2002 9273

Liu et al.
Da ta for 1,3-Dim eth yl-6-p h en yl-4a ,5,6,7,7a ,8-h exa h y-
ylen ed ica r boxyla te, a n d Dieth yl F u m a r a te. A solution of
2-methyl-5-phenylthienosultine 5c (50 mg, 0.189 mmol), with
or without the respective dienophiles (0.567 mmol), in toluene
(3 mL) was kept in a sealed tube at 180 °C for 24 h. The solvent
was evaporated under vacuum, and the residue was subjected
to silica gel chromatography using hexane/ethyl acetate (from
6:1 to 4:1) as the eluent. Sulfolene 6c was obtained in 98%
yield (no quencher). For the trapping by dienophiles, the
respective yields are as follows: N-phenylmaleimide, 16% 6c
and 76% 8c; fumaronitrile, 13% 6c and 75% 10c; dimethyl
acetylenedicarboxylate, 47% 6c and 37% 11c; diethyl fuma-
rate, 23% 6c and 69% 12c.
Da ta for 4-Meth yl-6-p h en yl-1,3-d ih yd r o-1H-2λ6-th ien o-
[3,4-c]th iop h en e-2,2-d ion e (6c): clear crystal; mp 197-198
°C (CH2Cl2/hexane); 1H NMR δ 2.44 (3H, s), 4.17 (2H, s), 4.38
(2H, s), 7.44-7.32 (5H, m); 13C NMR δ 13.89 (CH3), 53.89
(CH2), 56.21 (CH2), 125.69 (Cq), 126.88 (CH), 127.98 (CH),
128.37 (Cq), 129.13 (CH), 132.94 (Cq), 133.78 (Cq), 136.67 (Cq);
MS (EI) m/z 265 (M+ + 1, 3), 264 (M+, 25), 200 (M+ - SO2,
100), 199 (80), 185 (M+ - SO2 - CH3, 64), 184 (53); HRMS
m/z calcd for C13H12O2S2 264.0279, found 264.0278. Anal. Calcd
for C13H12O2S2: C, 59.07; H, 4.58. Found: C, 59.13; H, 4.67.
Da ta for 1-Meth yl-3,6-d ip h en yl-4a ,5,6,7,7a ,8-h exa h y-
d r o-4H-th ien o[3,4-f]isoin d ole-5,7-d ion e (8c): yellow oil; 1H
NMR δ 2.38 (3H, s), 2.76-2.88 (2H, m), 3.29-3.58 (4H, m),
6.95-6.98 (2H, m), 7.29-7.42 (8H, m); 13C NMR δ 12.37 (CH3),
24.32 (CH2), 24.94 (CH2), 40.11 (CH), 126.33 (CH), 127.26 (CH),
128.60 (CH), 128.68 (CH), 129.04 (CH), 130.46 (Cq), 131.77 (Cq),
131.95 (Cq), 132.30 (Cq), 133.60 (Cq), 134.89 (Cq), 178.54 (Cq),
178.63 (Cq); MS (EI) m/z 374 (M+ + 1, 18), 373 (M+, 100), 225
(40), 187 (14); HRMS m/z calcd for C23H19NO2S 373.1137, found
373.1136.
d r o-4H-th ien o[3,4-f]isoin d ole-5,7-d ion e (8a ): white solid;
1
mp 149-151 °C; H NMR δ 2.20 (6H, s), 2.57-2.63 (2H, m),
3.12-3.18 (2H, m), 3.20-3.30 (2H, m), 6.82-6.86 (2H, m),
7.24-7.33 (3H, m); 13C NMR δ 12.14 (CH3), 24.47 (CH2), 40.23
(CH), 126.38 (CH), 128.51 (CH), 129.01 (CH), 129.24 (Cq),
130.64 (Cq), 131.78 (Cq), 178.77 (Cq); MS (EI) m/z 311 (M+, 100),
163 (60); HRMS m/z calcd for C18H17NO2S 311.0980, found
311.0984.
Da ta for Dim eth yl (5R*,6R*)-1,3-Dim eth yl-4,5,6,7-tet-
r a h yd r oben zo[c]th iop h en e-5,6-d ica r boxyla te (9a ): white
solid; mp 106-108 °C; 1H NMR δ 2.17 (6H, s), 2.21-2.48 (2H,
m), 2.84-2.97 (4H, m), 3.66 (6H, s); 13C NMR δ 12.46 (CH3),
27.70 (CH2), 42.68 (CH), 50.00 (CH3), 128.37 (Cq), 130.58 (Cq),
175.13 (Cq); MS (EI) m/z 282 (M+, 71.0), 222 (67), 163 (100);
HRMS m/z calcd for C14H18O4S 282.0926, found 282.0921.
Anal. Calcd for C14H18O4S: C, 59.55; H, 6.43. Found: C, 59.19;
H, 6.38.
Da ta for (5R*,6R*)-1,3-Dim eth yl-4,5,6,7-tetr a h yd r oben -
zo[c]t h iop h en e-5,6-d ica r b on it r ile (10a ): white solid; mp
214-215 °C; 1H NMR δ 2.92 (6H, s), 2.87-2.95 (2H, m), 3.11-
3.27 (4H, m); 13C NMR δ 12.58 (CH3), 26.74 (CH2), 28.87 (CH3),
118.55 (Cq), 126.30 (Cq), 130.58 (Cq); MS (EI) m/z 216 (M+,
21.7), 138 (100); HRMS m/z calcd for C12H12N2S 216.0727,
found 216.0722.
Gen er a l P r oced u r e for th e Tr a p p in g Exp er im en ts of
2,5-Dich lor oth ien osu ltin e 5b w ith Dien op h iles Su ch a s
N-P h en ylm a leim id e, Dim eth yl F u m a r a te, a n d F u m a -
r on itr ile. A solution of 2,5-dichlorothienosultine 5b (50 mg,
0.21 mmol), with or without the respective dienophiles (0.62
mmol), in benzene (3 mL) was kept in a sealed tube at 180 °C
for 24 h. The solvent was evaporated under vacuum, and the
residue was subjected to silica gel chromatography using 25:1
hexane/ethyl acetate as the eluent. Sulfolene 6b was obtained
in 95% yield (no quencher). For the trapping by dienophiles,
the respective yields are as follows: N-phenylmaleimide, 7%
6b and 65% 8b; dimethyl fumarate, 4% 6b and 64% 9b;
fumaronitrile, 16% 6b and 77% 10b.
Da ta for (5R*,6R*)-1-Meth yl-3-p h en yl-4,5,6,7-tetr a h y-
d r oben zo[c]th iop h en e-5,6-d ica r bon itr ile (10c): pale yel-
1
low solid; mp 158.2-160.0 °C; H NMR δ 2.37 (3H, s), 2.97-
3.40 (6H, m), 7.26-7.45 (5H, m); 13C NMR δ 12.87 (CH3), 26.81
(CH2), 28.10 (CH2), 28.76 (CH), 29.03 (CH), 118.32 (Cq), 118.55
(Cq), 126.40 (Cq), 127.39 (Cq), 127.63 (CH), 128.44 (CH), 128.82
(CH), 133.38 (Cq), 133.68 (Cq), 135.75 (Cq); MS (EI) m/z 278
(M+, 100), 199 (57), 185 (45), 165 (26); HRMS m/z calcd for
Da ta for 4,6-Dich lor o-1,3-d ih yd r o-1H-2λ6-th ien o[3,4-c]-
1
th iop h en e-2,2-d ion e (6b): white solid; mp 157-160 °C; H
NMR δ 4.22 (4H, s); 13C NMR δ 55.09 (CH2), 123.07 (Cq), 128.05
(Cq); MS (EI) m/z 242 (M+, 18.5), 178 (M+ - SO2, 100); HRMS
m/z calcd for C6H4Cl2O2S2 241.9030, found 241.9039. Anal.
Calcd for C6H4Cl2O2S2: C, 29.64; H, 1.66. Found: C, 29.66;
H, 1.94.
C
17H14N2S 278.0879, found 278.0871.
Da ta for Dim eth yl 1-Meth yl-3-p h en yl-4,7-d ih yd r oben -
zo[c]th iop h en e-5,6-d ica r boxyla te (11c): yellow solid; mp
1
101-102 °C; H NMR δ 2.40 (3H, s), 3.54-3.75 (4H, m), 3.79
(3H, s), 3.83 (3H, s), 7.28-7.45 (5H, m); 13C NMR δ 12.95
(CH3), 27.25 (CH2), 29.00 (CH2), 52.42 (CH3), 127.12 (CH),
128.41 (CH), 128.71 (CH), 129.80 (Cq), 131.78 (Cq), 131.93 (Cq),
133.84 (Cq), 134.23 (Cq), 168.19 (Cq), 168.71 (Cq); MS (EI) m/z
342 (M+, 77), 310 (100), 309 (65), 282 (34), 251 (44), 224 (87);
HRMS m/z calcd for C19H18O4S 342.0926, found 342.0929.
Da ta for 1,3-Dich lor o-6-p h en yl-4a ,5,6,7,7a ,8-h exa h y-
d r o-4H-th ien o[3,4-f]isoin d ole-5,7-d ion e (8b): white solid;
mp 195-196 °C; 1H NMR δ 2.77-2.85 (2H, m), 3.31-3.46 (4H,
m), 7.06-7.09 (2H, m), 7.36-7.45 (3H, m); 13C NMR δ 24.06
(CH2), 39.24 (CH), 121.26 (Cq), 126.18 (CH), 128.69 (CH),
129.10 (CH), 131.49 (Cq), 131.84 (Cq), 177.52 (Cq); MS (EI) m/z
Da ta for Dieth yl (5R*,6R*)-1-Meth yl-3-p h en yl-4,5,6,7-
tetr ah ydr oben zo[c]th ioph en e-5,6-dicar boxylate (12c): pale
yellow solid; mp 72-73 °C; 1H NMR δ 1.19-1.32 (6H, m), 2.34
(3H, s), 2.83-3.18 (6H, m), 4.10-4.23 (4H, m), 7.27-7.40 (5H,
m); 13C NMR δ 12.82 (CH3), 14.09 (CH3), 14.15 (CH3), 27.70
(CH2), 29.41 (CH2), 42.70 (CH), 43.08 (CH), 60.82 (CH2), 126.93
(CH), 128.37 (CH), 128.57 (CH), 130.93 (Cq), 131.65 (Cq), 131.87
(Cq), 133.48 (Cq), 134.29 (Cq), 174.56 (Cq), 174.63 (Cq); MS (EI)
m/z 372 (M+, 46), 327 (11), 298 (20), 225 (100); HRMS m/z calcd
for C21H24O4S 372.1395, found 372.1395.
Gen er a l P r oced u r e for th e Tr a p p in g Exp er im en ts of
2,5-Dip h en ylth ien osu ltin e 5d w ith Dien op h iles Su ch a s
N-P h en ylm a leim id e, Dim eth yl F u m a r a te, F u m a r on i-
t r ile, a n d Diet h yl F u m a r a t e. A solution of 2,5-diphenyl-
thienosultine 5d (50 mg, 0.153 mmol), with or without the
respective dienophiles (0.459 mmol), in toluene (3 mL) was
kept in a sealed tube at 180 °C for 24 h. The solvent was
evaporated under vacuum, and the residue was subjected to
silica gel chromatography using hexane/ethyl acetate (from
10:1 to 6:1) as the eluent. Sulfolene 6d was obtained in 94%
yield (no quencher). For the trapping by dienophiles, the
respective yields are as follows: N-phenylmaleimide, 6% 6d
351 (M+, 100), 169 (52), 134 (47); HRMS m/z calcd for C16H11
-
SO2Cl2N 350.9987, found 350.9887. Anal. Calcd for C16H11SO2-
Cl2N: C, 54.56; H, 3.15; N, 3.98. Found: C, 54.57; H, 3.54; N,
4.09.
Da ta for Dim eth yl (5R*,6R*)-1,3-Dich lor o-4,5,6,7-tet-
r a h yd r oben zo[c]th iop h en e-5,6-d ica r boxyla te (9b): white
solid; mp 88-89 °C; 1H NMR δ 2.52-2.71 (2H, m), 2.93-3.15
(4H, m), 3.75 (6H, s); 13C NMR δ 26.77 (CH2), 41.57 (CH), 52.23
(CH3), 120.56 (Cq), 131.81 (Cq), 174.03 (Cq); MS (EI) m/z 322
(M+, 55.1), 262 (100), 203 (99), 168 (74); HRMS m/z calcd for
C12H12SO4Cl2 321.9833, found 321.9828. Anal. Calcd for C12H12
SO4Cl2: C, 44.60; H, 3.74. Found: C, 44.65; H, 3.89.
-
Da ta for (5R*,6R*)-1,3-Dich lor o-4,5,6,7-tetr a h yd r oben -
zo[c]t h iop h en e-5,6-d ica r b on it r ile (10b ): white solid; mp
192-194 °C; 1H NMR δ 3.00-3.21 (4H, m), 3.35-3.39 (2H, m);
13C NMR δ 25.84 (CH2), 27.86 (CH), 117.53 (Cq), 123.02 (Cq),
127.72 (Cq); MS (EI) m/z 256 (M+, 85.4), 178 (100); HRMS m/z
calcd for C10H6Cl2N2S 255.9629, found 255.9633.
Gen er a l P r oced u r e for th e Tr a p p in g Exp er im en ts of
2-Meth yl-5-ph en ylth ien osu ltin e 5c with Dien oph iles Su ch
a s N-P h en ylm a leim id e, F u m a r on itr ile, Dim eth yl Acet-
9274 J . Org. Chem., Vol. 67, No. 26, 2002

Synthesis of 2,5-Disubstituted Thienosultines
and 82% 8d ; dimethyl fumarate, 21% 6d and 75% 9d ;
fumaronitrile, 12% 6d and 79% 10d ; diethyl fumarate, 30%
6d and 67% 12d .
Da ta for 4-[(Bu tylsu lfin yl)m eth yl-d 1]-2,5-d ich lor o-3-
th ien ylm eth a n ol (18): 47% yield; white solid; mp 88-90 °C;
1H NMR δ 0.95 (3H, t, J ) 7.2 Hz), 1.54-1.55 (2H, m); 1.73-
1.83 (2H, m); 2.74 (2H, t, J ) 7.8 Hz), 3.96, 4.08 (1H, AB, J )
Da t a for 4,6-Dip h en yl-1,3-d ih yd r o-1H -2λ6-t h ien o[3,4-
c]th iop h en e-2,2-d ion e (6d ): white solid; mp 214-215 °C; 1H
NMR δ 4.41 (4H, s), 7.35-7.46 (10H, m); 13C NMR δ 55.29
(CH2), 127.10 (CH), 127.23 (Cq), 128.40 (CH), 129.22 (CH),
13.8 Hz), 4.47 (2H, d, J ) 6.6 Hz), 4.70 (1H, t, J ) 6.6 Hz); 13
C
NMR δ 13.63 (CH3), 21.99 (CH2), 24.55 (CH2), 48.39 (t, C-D),
51.13 (CH2), 55.56 (CH2), 125.83 (Cq), 126.15 (Cq), 127.09 (Cq),
138.71 (Cq); MS (EI) m/z 302 (M+ + 1, 4), 117 (100); Rf ) 0.1
(hexane:ethyl acetate ) 4:1).
132.58 (Cq), 138.44 (Cq); MS (EI) m/z 326 (M+, 9), 262 (M+
-
SO2, 16), 261 (100), 228 (20); HRMS m/z calcd for C18H14O2S2
326.0436, found 326.0434. Anal. Calcd for C18H14O2S2: C,
66.23; H, 4.32. Found: C, 66.01; H, 4.44.
Gen er a l P r oced u r e for th e Tr a p p in g Exp er im en ts of
2,5-Dim eth ylth ien osu ltin e 5a by Radical Tr appin g Agen ts
Su ch a s 2-Mer ca p toeth a n ol, Meth a n ol, Meth a n ol-d 4, a n d
1,4-Cycloh exa d ien e. A solution of 5a (50 mg, 0.25 mmol)
with the respective radical trapping agents (each 1 mL except
0.5 mL for 1,4-cyclohexadiene) in benzene (2 mL) was kept in
a sealed tube at 180 °C for 24 h. The solvent was evaporated
under vacuum, and the residue was subjected to silica gel
chromatography using hexane/ethyl acetate (from 16:1 to 1:1)
as the eluent. The trapping yields are as follows: 21% 19 and
30% 6a by 2-mercaptoethanol, 19% 20 and 20% 6a by
methanol, 37% 21 and 26% 6a by methanol-d4, and 86%
sulfolene 6a by 1,4-cyclohexadiene.
Da t a for 1,3,6-Tr ip h en yl-4a ,5,6,7,7a ,8-h exa h yd r o-4H-
th ien o[3,4-f]isoin d ole-5,7-d ion e (8d ): white solid; mp 214-
217 °C; 1H NMR δ 2.87-2.96 (2H, m), 3.47-3.49 (2H, m),
3.59-3.64 (2H, dd, J ) 14.7, 6 Hz), 6.99-7.02 (2H, m), 7.34-
7.52 (13H, m); 13C NMR δ 24.91 (CH2), 40.16 (CH), 126.42
(CH), 127.75 (CH), 128.74 (CH), 128.88 (CH), 129.24 (CH),
131.55 (Cq), 131.77 (Cq), 133.32 (Cq), 137.85 (Cq), 178.58 (Cq);
MS (EI) m/z 436 (M+ + 1, 11), 435 (M+, 100), 287 (16), 286
(20), 261 (13); HRMS m/z calcd for C28H21NO2S 435.1294, found
435.1285. Anal. Calcd for C28H21NO2S: C, 77.22; H, 4.86; N,
3.22. Found: C, 77.20; H, 5.04; N, 3.41.
Da ta for 2-[(2,4,5-Tr im eth yl-3-th ien yl)m eth yl]su lfa n yl-
Da ta for Dim eth yl (5R*,6R*)-1,3-Dip h en yl-4,5,6,7-tet-
r a h yd r oben zo[c]th iop h en e-5,6-d ica r boxyla te (9d ): white
1
1-eth a n ol (19): colorless liquid; H NMR δ 2.14 (3H, s), 2.28
(3H, s), 2.35 (3H, s), 2.69 (2H, t, J ) 5.7 Hz); 3.60 (2H, s),
3.68-3.88 (2H, br s); 13C NMR δ 12.43 (CH3), 13.05 (CH3),
13.16 (CH3), 27.79 (CH2), 34.93 (CH2), 60.45 (CH2), 129.21 (Cq),
131.28 (Cq), 132.27 (Cq); MS (EI) m/z 216 (M+, 10), 139 (100);
HRMS m/z calcd for C10H16OS2 216.0643, found 216.0639.
Da ta for 3-(Meth oxym eth yl)-2,4,5-tr im eth ylth iop h en e
(20): colorless liquid; 1H NMR δ 2.07 (3H, s), 2.27 (3H, s), 2.38
(3H, s), 3.33 (3H, s), 4.27 (2H, s); 13C NMR δ 12.10 (CH3), 12.80
(CH3), 12.89 (CH3), 57.56 (CH3), 66.27 (CH2) 128.74 (Cq), 132.93
(Cq), 133.49 (Cq), 133.58 (Cq); MS (EI) m/z 170 (M+, 1), 138
(100); HRMS m/z calcd for C9H14OS 170.0765, found 170.0763.
Da ta for 3-(Meth oxy-d 3-m eth yl)-2,5-d im eth yl-4-m eth yl-
d 1-th iop h en e (21): colorless liquid; 1H NMR δ 2.05 (2 H, t, J
) 2.1 Hz), 2.27 (3H, s), 2.38 (3H, s), 4.26 (2H, s); 13C NMR δ
11.88 (t, J CD ) 20 Hz, CH2D), 12.84 (CH3), 12.93 (CH3), 66.19
(CH2) 128.78 (Cq), 132.91 (Cq), 133.53 (Cq); MS (EI) m/z 174
(M+, 23), 139 (60), 84 (100); HRMS m/z calcd for C9H10D4OS
174.1017, found 170.1017.
1
solid; mp 184-185 °C; H NMR δ 2.90-3.05 (4H, m), 3.24-
3.30 (2H, m), 3.71 (6H, s), 7.29-7.49 (10H, m); 13C NMR δ
29.14 (CH2), 42.79 (CH), 52.08 (CH3), 127.42 (CH), 128.52 (CH),
128.66 (CH), 131.57 (Cq), 133.88 (Cq), 136.52 (Cq), 174.89 (Cq);
MS (EI) m/z 406 (M+, 34), 346 (10), 287 (100), 252 (34); HRMS
m/z calcd for C24H22O4S 406.1240, found 406.1243. Anal. Calcd
for C24H22O4S: C, 70.91; H, 5.45. Found: C, 71.10; H, 5.49.
Da ta for (5R*,6R*)-1,3-Dip h en yl-4,5,6,7-tetr a h yd r oben -
zo[c]th iop h en e-5,6-d ica r bon itr ile (10d ): due to the severe
overlap of 10d with 6d in column chromatography, we
obtained only proton NMR data, δ 3.19-3.48 (6H, m), 7.36-
7.49 (10H, m).
Da ta for Dieth yl (5R,6R)-1,3-Dip h en yl-4,5,6,7-tetr a h y-
dr oben zo[c]th ioph en e-5,6-dicar boxylate (12d): white solid;
mp 145-146 °C; 1H NMR δ 1.25 (6H, t, J ) 7.1 Hz), 2.90-
3.04 (4H, m), 3.24-3.29 (2H, dd, J ) 15, 2.7 Hz), 4.17 (4H, q,
J ) 7.1 Hz), 7.32-7.49 (10H, m); 13C NMR δ 14.07 (CH3), 29.16
(CH2), 42.95 (CH), 60.85 (CH2), 127.38 (CH), 128.52 (CH),
128.65 (CH), 131.74 (Cq), 133.95 (Cq), 136.45 (Cq), 174.43 (Cq);
MS (EI) m/z 435 (M+ + 1, 9), 434 (M+, 59), 287 (100), 286 (79),
253 (46); HRMS m/z calcd for C26H26O4S 434.1553, found
434.1553. Anal. Calcd for C26H26O4S: C, 71.86; H, 6.03.
Found: C, 72.07, H, 6.14.
Rea ction of 5b w ith n -Bu Li F ollow ed by Qu en ch in g
w ith H2O or D2O To Give P r od u cts 17 a n d 18. To a 25 mL
two-necked bottle were added 100 mg (0.42 mmol) of 5b and
5 mL of dry THF. The solution was cooled to -78 °C, 248 µL
(0.62 mmol) of nBuLi was added via syringe, and the resulting
solution was stirred at this temperature for 1 h. It was then
stirred at 0 °C for 1 h and at rt for another 1 h. The solution
was quenched with either brine (1 mL) or D2O (1 mL) in an
ice bath, and the product was extracted with ethyl ether (3 ×
5 mL). The combined organic extracts were washed with water
(2 × 5 mL) and brine (5 mL) and then dried with MgSO4. The
solvent was evaporated under vacuum, and the residue was
subjected to silica gel chromatography using hexane/ethyl
acetate (4:1) as the eluent to yield 42 mg (0.14 mmol) of 17 or
60 mg (0.20 mmol) of 18.
P r oced u r e for th e Con cen tr a tion -Dep en d en t Tr a p -
p in g of Th ien osu lt in e 5a a n d F u r a n osu lfolen e 16 b y
F u m a r on itr ile. Stock solutions of 5a and 16 were first
prepared by adding 60 mg (0.30 mmol) of 5a to 18 mL of
toluene or 45 mg (0.28 mmol) of 16 to 18 mL of benzene. The
stock solution was then equally divided into six thick-walled
tubes, and each contained a 3 mL solution of 5a (16.5 mM) in
toluene or 16 (15.8 mM) in benzene. Tubes a and b were
without fumaronitrile, and tubes c-f were with different
amounts of fumaronitrile: (c) 4 mg (0.05 mmol, 16.7 mM), (d)
20 mg (0.26 mmol), (e) 40 mg (0.51 mmol), (f) 60 mg (0.77
mmol). After three cycles of freeze-pump-thaw, these tubes
were sealed under vacuum, all reacted at the same time in an
oil bath thermostated at (1) 150 ( 2 °C, 5 h for 5a , and (2)
120 ( 2 °C, 2 h for 16, and then cooled to room temperature.
The solvent of these tubes was removed by rotary evaporation,
and to each of them was added 1 mL of CDCl3 with 50 mM
1
N-phenylmaleimide as internal standard for H NMR analysis.
The data shown in Figure 1 are the average of at least two
runs.
Da ta for 4-[(Bu tylsu lfin yl)m eth yl]-2,5-d ich lor o-3-th i-
en ylm eth a n ol (17): 33% yield; white solid; mp 85-86 °C; 1H
NMR δ 0.98 (3H, t, J ) 7.5 Hz), 1.46-1.60 (2H, m); 1.73-1.84
(2H, m); 2.47 (2H, t, J ) 7.2 Hz), 3.94, 4.10 (2H, AB, J ) 14.0
Hz), 4.49 (2H, d, J ) 6.9 Hz), 4.70 (1H, t, J ) 6.6 Hz); 13C
NMR δ 13.63 (CH3), 21.99 (CH2), 24.55 (CH2), 48.59 (CH2),
51.07 (CH2), 55.50 (CH2), 125.80 (Cq), 126.18 (Cq), 127.06 (Cq),
138.68 (Cq); MS (EI) m/z 301 (M+ + 1, 7), 117 (100); HRMS
m/z calcd for C10H14S2O2Cl2 299.9812, found 299.9804; Rf )
0.1 (hexane:ethyl acetate ) 4:1).
Ack n ow led gm en t. We thank the National Science
Council of the Republic of China for financial support
(Grant No. NSC89-2113-M-009-026).
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C (or
DEPT) NMR spectra for compounds 8a , 8c, 10a -d , 11c, 12c,
and 17-21. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O011122S
J . Org. Chem, Vol. 67, No. 26, 2002 9275