Efficient Syntheses of 2-Functionalized Thiophenes, Cyclopent[b]thiophenes, and Polysubstituted Benzo[b]thiophenes from 2-(Benzotriazol-1-ylmethyl)thiophenes

Article abstract of DOI:10.1021/jo970672g

Diverse 2-(functionalized-alkyl)- and 2-alkenylthiophenes 2a,b, 4a,b, and 6a-d are prepared via the side chain elaboration of 2-(benzotriazol-1-ylmethyl)thiophenes 3a,b, themselves readily available from the condensation of 1-(hydroxymethyl)benzotriazole with thiophenes 1a,b. Treatment of 2-(benzotriazol-1-ylmethyl)thiophenes 3b and 5g,j with styrenes in the presence of zinc bromide results in formal [3 + 2] cycloaddition to give in good yields substituted cyclopent[b]thiophenes 16a/17a, 16b/17b, and 18. Lithiation and 1,4-addition to a variety of α,β-unsaturated ketones and aldehydes, and subsequent acid-catalyzed intramolecular cyclization followed by debenzotri-azolylation-dehydration converts 3 and 5 to a range of polysubstituted benzo[b]thiophenes 19a-d and 25a-e in moderate to excellent yields. NOE difference spectroscopy and NMR ¹H-¹³C long-range correlation support structures of types 19 and 25 and exclude those of type 26, thus confirming the cyclization pathway.

Full text of DOI:10.1021/jo970672g

J . Org. Chem. 1997, 62, 6215-6221
6215
Efficien t Syn th eses of 2-F u n ction a lized Th iop h en es,
Cyclop en t[b]th iop h en es, a n d P olysu bstitu ted Ben zo[b]th iop h en es
fr om 2-(Ben zotr ia zol-1-ylm eth yl)th iop h en es
Alan R. Katritzky,* Larisa Serdyuk, Linghong Xie, and Ion Ghiviriga
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received April 15, 1997X
Diverse 2-(functionalized-alkyl)- and 2-alkenylthiophenes 2a ,b, 4a ,b, and 6a -d are prepared via
the side chain elaboration of 2-(benzotriazol-1-ylmethyl)thiophenes 3a ,b, themselves readily
available from the condensation of 1-(hydroxymethyl)benzotriazole with thiophenes 1a ,b. Treatment
of 2-(benzotriazol-1-ylmethyl)thiophenes 3b and 5g,j with styrenes in the presence of zinc bromide
results in formal [3 + 2] cycloaddition to give in good yields substituted cyclopent[b]thiophenes
16a /17a , 16b/17b, and 18. Lithiation and 1,4-addition to a variety of R,â-unsaturated ketones
and aldehydes, and subsequent acid-catalyzed intramolecular cyclization followed by debenzotri-
azolylation-dehydration converts 3 and 5 to a range of polysubstituted benzo[b]thiophenes 19a -d
1
and 25a -e in moderate to excellent yields. NOE difference spectroscopy and NMR H-13C long-
range correlation support structures of types 19 and 25 and exclude those of type 26, thus confirming
the cyclization pathway.
In tr od u ction
Resu lts a n d Discu ssion
P r ep a r a tion of 2-(Ben zotr ia zol-2-ylm eth yl)th io-
p h en es (3a ,b a n d 5a -j). 2-(Benzotriazol-1-ylmethyl)-
thiophenes 3a ,b were prepared according to our pre-
viously reported procedure from thiophenes and 1-
(hydroxymethyl)benzotriazole in refluxing acetic acid9
(Scheme 1). Novel compound 3a was characterized by
NMR and CHN analyses.
2-Substituted thiophenes are useful, inter alia as
dyestuffs, flavor agents, drugs, and inhibitors.1 Cyclo-
pent[b]thiophenes are of special interest as they consti-
tute heteroaromatic analogues of many biologically active
bicyclic compounds such as prostacyclin (PGI2)2 and
1-(dimethylamino)-3-phenylindane.3 Benzothiophenes
have attracted interest as potential biologically active
agents and as bioisosters of indoles; for example, numer-
ous benzo[b]thiophene analogs of biologically active in-
doles are agonists or antagonists of their indole conge-
ners.4
Side-chain metalation of thiophene derivatives is nor-
mally difficult to achieve because ring metalation is
predominant.10 However, due to the electron-withdraw-
ing ability of the benzotriazolyl group,5b compounds 3 can
easily be deprotonated exclusively at the side-chain CH2
R to the benzotriazolyl group. Accordingly, treatment of
3a ,b with n-butyllithium at -78 °C under argon in
tetrahydrofuran furnished deep green solutions of the
lithio derivatives. Reactions of these anions with phenyl
isocyanate, phenyl isothiocyanate, various alkyl halides,
or cyclohexanone gave the corresponding products
5a ,b,d ,f-j in good yields. Reaction of the anion of 3b
with benzaldehyde, followed by the addition of methyl
iodide, provided methyl ether derivative 5c in 87% yield.
Compounds 5a -d ,f-j were previously unknown and
were characterized by NMR spectroscopy and elemental
analyses. Compound 5e was prepared according to a
literature procedure11 from 2-methylthiophene and N-(1-
benzotriazolylalkyl)carbamate.
Syn th eses of 2-(F u n ction a lized -a lk yl)th iop h en es
6a -d a n d 2-Alk en ylth iop h en es (2a ,b a n d 4a ,b). The
C-2 side chain of thiophenes 5 should be capable of
further elaboration by the displacement of the benzotri-
azolyl moiety with nucleophiles (for reviews of benzotri-
azole as a leaving group, see ref 5). Indeed, treatment
of 5a ,b and 5d with zinc in refluxing acetic acid afforded,
as expected, the corresponding amides 6a ,d and thioa-
Previous work has demonstrated the versatility of
benzotriazole as a synthetic auxiliary in many transfor-
mations.5 We have recently described the benzotriazole-
assisted side-chain elaborations of indoles,6 pyrroles,7 and
benzenes.8 We have now extended this strategy to
provide facile and efficient routes to 2-(functionalized-
alkyl)- and 2-alkenylthiophenes, cyclopent[b]thiophenes,
and polysubstituted benzo[b]thiophenes all starting from
readily available 2-(benzotriazol-1-ylmethyl)thiophenes
3a ,b.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) Campaigne, E. In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984, p 910.
(2) (a) Cook, S.; Henderson, D.; Richardson, K. A.; Taylor, R. J . K.;
Saunders, J .; Strange, P. G. J . Chem. Soc., Perkin Trans. 1 1987, 1825.
(b) Richardson, K. A.; Saunders, J .; Taylor, R. J . K. Tetrahedron Lett.
1985, 26, 1171.
(3) Acheson, R. M.; MacPhee, K. E.; Philpott, P. G.; Barltrop, J . A.
J . Chem. Soc. 1956, 698.
(4) Campaigne, E. In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984, p 911.
(5) (a) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J . Tetrahedron
1991, 47, 2683. (b) Katritzky, A. R.; Yang, Z.; Cundy, D. J . Aldrichimica
Acta 1994, 27, 31. (c) Katritzky, A. R.; Lan, X. Chem. Soc. Rev. 1994,
363. (d) Katritzky, A. R.; Lan, X.; Fan, W.-Q. Synthesis 1994, 445.
(6) (a) Katritzky, A. R.; Li, J .; Stevens, C. V. J . Org. Chem. 1995,
60, 3401. (b) Katritzky, A. R.; Xie, L.; Cundy, D. Synth. Commun. 1995,
25, 539. (c) Katritzky, A. R.; Zhang, G.; Xie, L.; Ghiviriga, I. J . Org.
Chem. 1996, 61, 7558.
(9) Katritzky, A. R.; Toader, D.; Xie, L. J . Org. Chem. 1996, 61, 7571.
(10) Clarke, A. J .; McNamara, S.; Meth-Cohn, O. Tetrahedron Lett.
(7) (a) Katritzky, A. R.; Li, J . J . Org. Chem. 1996, 61, 1624. (b)
Katritzky, A. R.; Levell, J . R.; Li, J . Tetrahedron Lett. 1996, 37, 5641.
(8) Katritzky, A. R.; Zhang, G.; Xie, L. J . Org. Chem. 1997, 62, 721.
1974, 2373.
(11) Katritzky, A. R.; Xie, L.; Fan, W.-Q. J . Org. Chem. 1993, 58,
4376.
S0022-3263(97)00672-5 CCC: $14.00 © 1997 American Chemical Society

6216 J . Org. Chem., Vol. 62, No. 18, 1997
Katritzky et al.
Sch em e 1
Sch em e 2
Syn th esis of 2,6-Dim eth yl-4,8-d iisop r op ylben zo-
[1,2-b:4,5-b′]d ith iop h en e (11). Interestingly, when 5e
was refluxed in methylene chloride in the presence of zinc
bromide, the benzo[1,2-b:4,5-b′]dithiophene 11 was ob-
tained in 40% yield. This transformation is envisioned
to proceed via two successive nucleophilic substitutions
between two molecules of 5e to intermediate 10, which
then aromatized to give compound 11 (Scheme 2). How-
ever, in the cases of 5f-i, after similar refluxing in
methylene chloride with zinc bromide, although GC-MS
analyses showed the existence in the crude reaction
mixtures of the corresponding benzo[1,2-b:4,5-b′]dithio-
phenes, they could not be separated from oligomers of
similar polarity. Benzo[1,2-b:4,5-b′]dithiophenes have
previously been prepared via the reaction of dithienyl-
methanes with dichloromethyl alkyl ethers in the pres-
ence of tin(IV) chloride16 and also via a four-step sequence
starting from 3-bromo-2-thiophenecarboxaldehyde and
3-bromothiophene.17
Syn th esis of Cyclopen t[b]th ioph en es 16a/17a, 16b/
17b, a n d 18. Our previous work has included the facile
synthesis of 1-functionalized cyclopent[b]indoles from
3-(benzotriazol-1-ylmethyl)indole.6c Following a similar
protocol, we found that alkenes could function as nucleo-
philes to induce formal [2 + 3] cycloadditions with
2-(benzotriazol-1-ylmethyl)thiophenes 3b and 5g,j to
provide cyclopent[b]thiophenes. Thus, treatment of 3b
with zinc bromide, followed by the addition of 1,1-
diphenylethylene, afforded 1,1-diphenyl-5-methylcyclo-
pent[b]thiophene (18) in 52% yield via the addition of
cation 12 to 1,1-diphenylethylene and subsequent ring
closure of the intermediate benzylic cation 15 (Scheme
3). Similarly, 3-functionalized cyclopent[b]thiophenes
(16a /17a and 16b /17b ) were prepared from ZnBr2-
catalyzed reactions of 5 with styrenes. While 5g (derived
from 3b and n-propyl iodide) reacted with 4-methylsty-
rene to give a mixture of two diastereoisomeric cyclo-
pent[b]thiophenes (16a and 17a ) in yields of 85%, reac-
tion of 5j (prepared from 3b and cyclohexanone) with
R-methylstyrene provided a mixture of 16b and 17b in
mide 6b in 59-76% yields via the displacement of the
benzotriazolyl group with hydride. Again, when 5c was
treated with 2-methylfuran in the presence of zinc
bromide, the thienylfuryl compound 6c was produced as
a mixture of two diastereomers in 59% yield.
Importantly, if protons are present in side-chain E at
the â-position of the benzotriazolyl group in compounds
of type 5, debenzotriazolylation can occur upon heating
in the absence of nucleophiles to provide a variety of
2-alkenylthiophenes. Such reactions were accomplished
without the isolation of 5 as intermediates. Thus, the
anion of 3b underwent alkylation with alkyl halides to
give the alkylated intermediates, which without separa-
tion, upon refluxing in 1,4-dioxane in the presence of
Amberlyst-15 acidic resin, provided 2-alkenylthiophenes
2a ,b in good yields. Similar reactions of the 1,4-addition
products of the anion of 3b with R,â-unsaturated esters
gave 4a ,b. In the cases of 2a ,b, only trans isomers were
produced, while 4a ,b were each obtained as an insepa-
rable mixture of trans and cis isomers.
Previous preparations of 2-alkenylthiophenes have
included (i) reactions of 2-thiophenecarboxaldehydes12
and esters13 with phosphorus ylides, (ii) palladium-
catalyzed cross-coupling of 2-iodothiophene with diiso-
propyl (1-alkyl-1-alkenyl)boronates,14 and (iii) addition
of thiophene to acetylenes in the presence of Rh4(CO)12.15
The present one-pot approach, which is capable of leading
to functionalized 2-alkenylthiophenes directly from
thiophenes, complements the existing methods.
(12) Dopper, J . H.; Oudman, D.; Wynberg, H. J . Am. Chem. Soc.
1973, 95, 3692.
(13) Uijttewaal, A. P.; J onkers, F. L.; van der Gen, A. Tetrahedron
Lett. 1975, 1439.
(14) Satoh, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1986, 1329.
(15) Hong, P.; Cho, B.-R.; Yamazaki, H. Chem. Lett. 1980, 507.
(16) Ahmed, M.; Ashby, J .; Ayad, M.; Meth-Cohn, O. J . Chem. Soc.,
Perkin Trans. 1 1973, 1099.
(17) Beimling, P.; Koâmehl, G. Chem. Ber. 1986, 119, 3198.

Syntheses of 2-Functionalized Thiophenes
J . Org. Chem., Vol. 62, No. 18, 1997 6217
Sch em e 3
acidic conditions required for method iii, such as heating
in PPA, may limit its applicability.
Syn th esis of P olysu bstitu ted Ben zo[b]th iop h en es
(19a -d a n d 25a -e). We have previously reported
benzotriazole-mediated aromatic annulations to polysub-
stituted carbazoles6c and naphthalenes.8 Following a
similar protocol, polysubstituted benzo[b]thiophenes were
readily accessible. Thus, additions of the lithio deriva-
tives of 3 and 5 to R,â-unsaturated ketones or aldehydes,
followed by refluxing in 1,4-dioxane in the presence of
an acidic resin (Amberlyst-15), formed a variety of
polysubstituted benzo[b]thiophenes 25a -e and 19a -d
in moderate to excellent yields (Scheme 4). As exempli-
fied by the transformation sequence of 3 to 25 shown in
Scheme 4, the process is envisioned to proceed via
Michael addition, acid-catalyzed cyclization, and dehy-
drobenzotriazolylation.
The conditions required for the cyclizations 5 f 19 and
3 f 25 reflect that the reactivity of the thiophene ring is
intermediate between those of benzene and pyrrole.
Thus, while strong acidic conditions such as HBr + HOAc
or PPA were required for the cyclization in the case of a
benzene system,8 cyclization of 2-(benzotriazol-1-ylmeth-
yl)pyrroles was effected by refluxing in THF in the
presence of Amberlyst-15 acidic resin.7b In the case of
the present thiophenes, cyclization required refluxing in
the higher boiling 1,4-dioxane in the presence of Am-
berlyst-15 acidic resin.
83% yield. In both cases, the E isomers 16 are slightly
predominant (14:9 for 16a /17a , and 2:1 for 16b/17b). In
these reactions, zinc bromide is essential to the ionization
of 2-(benzotriazol-1-ylmethyl)thiophenes by coordinating
with the nitrogen atom on the benzotriazole ring.
Novel compounds 16-18 were characterized by el-
emental (C, H, N) analyses and NMR spectroscopy. Since
the thiophene 2-position is more nucleophilic than the
thiophene 3-position, the cyclization of cations 14 and 15
could possibly occur either at the 3-position or first at
the 2-position (ipso attack) to give spiro intermediates
of type 13 (Scheme 3), followed by the migration of one
of the two alkyl groups. Although the later pathway
seems unlikely, as only single regioisomers were ob-
tained, the regiochemistries of 16a /17a and 18 were
examined by NOE difference spectroscopy to confirm
structures 16-18. In the case of 18, irradiation of the
signal at 6.52 ppm (position 6) produced a positive NOE
on the methyl group at 2.44 ppm (position 5) and on the
phenyl signals at 7.20 ppm, which confirmed the regio-
chemistry assigned. The NOE difference experiments for
compounds 16a and 17a were run on the mixture (16a /
17a ). The regiochemistry was demonstrated by positive
NOE’s on the singlet in position 6 (6.34 and 6.29 ppm
correspondingly) and on the ortho protons on the phenyl
group (7.01 and 7.10 ppm correspondingly) when the
protons in position 1 at 4.21 ppm (16a ) or 4.12 ppm (17a )
were selectively irradiated.
The cis-trans stereochemistries of 16a and 17a were
also determined by NOE. The cis relationship of the
protons in positions 1 and 3 in 17a was evidenced by their
positive NOE’s upon irradiation of the proton at 2.98 ppm
(position 2). However, attempts to prove the regiochem-
istry and stereochemistry by NMR for 16b/17b failed due
to the overlap of the OH proton with the thiophene CH.
The most preparatively efficient previous syntheses of
cyclopent[b]thiophenes include (i) the cyclization of acety-
lenic cyclic ketones,2 (ii) palladium-catalyzed cycloaddi-
tion of 2-iodothiophene, carbon monoxide and an olefin,18
and (iii) the ring-closure of 3-thienylpropionic acids.3,19
However, routes i and ii are not general and the strongly
Benzo[b]thiophenes 19a -d and 25a -e were all novel
and their structures were fully supported by elemental
analyses and NMR spectroscopy. As discussed above for
the ring closure of 14 and 15 in the synthesis of
cyclopent[b]thiophenes (Scheme 3), the ipso attack in the
cyclization of 21 was also taken into consideration. While
direct cyclization of 21 would give only the single regio-
isomers 25, possibly pathways via spiro intermediates
22 could furnish, in each case, two regioisomers 25 and
26 (Scheme 4). However, in all cases, single isomers
25a -e and 19a -d were obtained, suggesting that the
direct C-3 ring closure is operative under our reaction
conditions. However, structures of types 19 and 25 were
supported, and that of type 26 excluded, by NOE differ-
1
ence experiments together with H-13C long-range cor-
relations.
In the case of 19a , irradiation of the singlet at 6.93
ppm produced positive NOE’s on two methyl signals (2.42
and 2.44 ppm), identifying the proton on the thiophene
moiety and the methyl groups in positions 2 and 4.
Irradiation of the other deshielded singlet at 7.01 ppm
(on the benzene moiety) produced a positive NOE to the
same methyl group at 2.44 ppm (position 4) and not at
2.38 ppm (position 7). Structure 19b showed, as ex-
pected, positive NOE’s on both deshielded singlets at 6.97
and 7.04 ppm when the methyl group at 2.50 ppm was
irradiated. Irradiation of the other methyl signal (2.60
ppm) led to a positive NOE at 7.04 ppm. This allows the
assignment of the signals at 2.60, 7.04, 2.50, and 6.97
ppm to positions 2, 3, 4, and 5, respectively. Irradiation
of the methyl group in 19c (2.57 ppm) produced a positive
NOE on the singlet at 7.12 ppm, which was thus assigned
to position 3. Irradiation of the proton in position 3 led
(18) Grigg, R.; Khalil, H.; Levett, P.; Virica, J .; Sridharan, V.
Tetrahedron Lett. 1994, 35, 3197.
(19) (a) Dallemagne, P.; Rault, S.; Cugnon de Sevricourt, M.; Hassan,
Kh. M.; Robba, M. Tetrahedron Lett. 1986, 27, 2607. (b) Stanetty, P.
J . Chem. Res. (S) 1981, 99. (c) Frejd, T.; Karlsson, O. Tetrahedron 1979,
35, 2155. (d) Schneller, S. W.; Moore, D. R. J . Org. Chem. 1975, 40,
1840. (e) Meth-Cohn, O.; Gronowitz, S. Acta Chem. Scand. 1966, 20,
1577.

6218 J . Org. Chem., Vol. 62, No. 18, 1997
Katritzky et al.
Sch em e 4
signal which could be selectively irradiated, and this
irradiation produced a positive NOE on the signal at 7.65
ppm, corresponding to an ortho position on a phenyl ring.
No positive NOE at 7.31 or 7.41 ppm, as expected for a
structure of type 26, was observed.
Irradiation of the methyl signal in 25b (2.58 ppm)
produced a positive NOE on the singlet at 7.05 ppm,
which identified this signal as the one for the proton in
position 3. The regiochemistry of this compound was
proven by a positive NOE on a doublet at 7.60 ppm and
not a singlet as expected for a structure of type 26. In
25c, irradiation of the signal at 6.87 ppm produced
positive NOE’s on the methyl signal at 2.54 ppm (position
2) and on the singlet at 7.40 ppm, which is thus in
position 4. Irradiation of the methylene protons of the
ethyl group (2.59 ppm) produced a positive NOE on a
different singlet at 7.60 ppm, demonstrating that the
ethyl group is in position 6. The regiochemistry of 25d
was demonstrated by the positive NOE’s on the singlets
at 7.27 and 6.77 ppm upon irradiation of the methyl
group at 2.39. The proton ortho to the methyl group in
25e was identified as the one at 7.64 ppm by a positive
NOE upon irradiation at 2.37 ppm. Irradiation at 7.64
ppm produced a positive NOE on the doublet at 7.27 ppm,
which evidenced a structure of type 25.
Substituted benzo[b]thiophenes have previously usu-
ally been constructed by building a thiophene ring onto
a benzene nucleus20 and, less frequently, by the annu-
lation of a benzene ring onto a thiophene moiety.21
However, the latter approach is of special importance for
the preparation of benzothiophenes multisubstituted in
the benzene moiety. Building a benzene ring onto a
thiophene has been accomplished (i) from thiophenes
bearing two ortho substituents (one electrophilic and one
potentially nucleophilic) and Michael acceptors, followed
by intramolecular cyclization;21e this approach is useful
for the preparation of benzothiophenes with electron-
withdrawing substituents; (ii) Diels-Alder reactions of
thieno[2,3-c]furans with dienophiles,21c,d however, in
many cases the dienophile must be symmetrical in order
to control the regiochemistry; (iii) palladium-catalyzed
cyclocarbonylation of 3-(thienyl)allyl acetates,21a,b which
is restricted to the synthesis of benzothiophenes with an
acetoxy group; and (iv) condensations of â-metallo deriva-
tives of protected propanals [MCH2CH2CH(OR)2] with
2-thiophenecarboxaldehyde, followed by cyclization ef-
fected by dilute sulfuric acid,21f which are limited by the
availability of annulating reagents with suitable substi-
tution patterns.
to a positive NOE on the doublet at 7.55 ppm, demon-
strating that position 4 is a phenyl ring.
Con clu sion
Compound 19d displays 1H chemical shifts very similar
to those in 19c. When the doublet at 7.55 ppm was
irradiated, both singlets at 7.21 and 7.11 ppm showed a
positive NOE, thus discarding a structure of type 26. The
later signal was assigned to position 3, based on its
positive NOE upon irradiation of the methyl group in
position 2 (2.52 ppm).
In conclusion, general and efficient approaches to
2-substituted thiophenes, cyclopent[b]thiophenes, and
(20) (a) Buchwald, S. L.; Fang, Q. J . Org. Chem. 1989, 54, 2793. (b)
J ohnson, F.; Subramanian, R. J . Org. Chem. 1986, 51, 5040. (c) de
Groot, A.; J ansen, B. J . M. Synthesis 1985, 434. (d) Kitamura, T.;
Kawasato, H.; Kobayashi, S.; Taniguchi, H. Chem. Lett. 1986, 839. (e)
Kitamura, T.; Kobayashi, S.; Taniguchi, H. Chem. Lett. 1988, 1637.
(f) Bridges, A. J .; Lee, A.; Maduakor, E. C.; Schwartz, C. E. Tetrahedron
Lett. 1992, 33, 7499. (g) Russavskaya, N. V.; Korchevin, N. A.;
Sukhomazova, E. N.; Turchaninova, L. P.; Deryagina, E. N.; Voronkov,
M. G. J . Org. Chem. (USSR) 1991, 305. (h) Leardini, R.; Pedulli, G.
F.; Tundo, A.; Zanardi, G. J . Chem. Soc., Chem. Commun. 1985, 1390.
(i) Arnoldi, A.; Carughi, M. Synthesis 1988, 155.
In compound 25a , extensive overlapping of the proton
1
signals required H-13C direct and long-range correlation
for the identification of the chemical shifts of the protons
on the benzothiophene moiety. A HETCOR experiment
1
was run preserving the H-1H couplings in the proton
(21) (a) Iwasaki, M.; Kobayashi, Y.; Li, J .-P.; Matsuzaka, H.; Ishii,
Y.; Hidai, M. J . Org. Chem. 1991, 56, 1922. (b) Iwasaki, M.; Li, J .-P.;
Kobayashi, Y.; Matsuzaka, H.; Ishii, Y.; Hidai, M. Tetrahedron Lett.
1989, 30, 95. (c) Schˆıning, A.; Friedrichsen, W. Tetrahedron Lett. 1988,
29, 1137. (d) Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.; Kondo,
K.; Iwasaki, T. J . Chem. Soc., Chem. Commun. 1991, 1635. (e)
Terpstra, J . W.; van Leusen, A. M. J . Org. Chem. 1986, 51, 230. (f)
Loozen, H. J . J .; Godefroi, E. F. J . Org. Chem. 1973, 38, 1056.
dimension. Singlets at 7.57 and 8.04 ppm correspond to
positions 5 and 7. The doublets at 7.31 and 7.41 ppm
are directly correlated to carbon signals of half the
intensity of those corresponding to positions ortho and
meta on the phenyl rings, thus they were assigned to
positions 2 and 3. The singlet at 8.04 ppm was the only

Syntheses of 2-Functionalized Thiophenes
J . Org. Chem., Vol. 62, No. 18, 1997 6219
1
109-110 °C; H NMR (DMSO-d6) δ 2.49 (s, 3H), 6.86 (d, J )
3.5 Hz, 1H), 7.27-7.52 (m, 7H), 7.64 (s, 1H), 7.85 (d, J ) 7.8
Hz, 2H), 8.07 (d, J ) 8.4 Hz, 1H), 12.39 (s, 1H); 13C NMR
(DMSO-d6) δ 15.0, 67.4, 111.5, 119.3, 123.2, 124.0, 125.1, 126.7,
127.4, 128.8, 129.9, 133.0, 133.1, 138.8, 142.4, 145.5, 194.9.
Anal. Calcd for C19H16N4S2: C, 62.61; H, 4.42. Found: C,
62.82; H, 4.77.
polysubstituted benzothiophenes have been developed, all
starting from readily available 2-(benzotriazol-1-ylmeth-
yl)thiophenes 3. While the cyclopent[b]thiophene con-
struction takes advantage of the ready introduction of
functionality into the 4-position of cyclopent[b]thiophenes,
the benzothiophene synthesis provides special opportuni-
ties for the introduction of substituents into the benzene
moiety of benzothiophenes. The main limitation of these
synthetic reactions is the acidic conditions required: thus
acid-sensitive substituents would not be tolerated.
1-Ben zotr ia zol-1-yl-1-(5-m eth ylth ien -2-yl)-2-m eth oxy-
2-p h en yleth a n e (5c) was purified by recrystallization from
Et2O to give a mixture of two diastereoisomers as an oil: yield
87% (1.52 g); one of the isomers was obtained as a colorless
solid in a pure state by washing the mixture with Et2O: mp
120-122 °C; 1H NMR (CDCl3) δ 2.34 (s, 3H), 3.19 (s, 3H), 5.35
(d, J ) 8.2 Hz, 1H), 6.13 (d, J ) 8.2 Hz, 1H), 6.42 (d, J ) 3.6
Hz, 1H), 6.63 (d, J ) 3.6 Hz, 1H), 7.20-7.39 (m, 6H), 7.45 (t,
J ) 7.2 Hz, 1H), 7.67 (d, J ) 8.3 Hz, 1H), 8.06 (d, J ) 8.3 Hz,
1H); 13C NMR (CDCl3) δ 15.1, 57.0, 64.6, 85.4, 110.5, 119.8,
123.7, 124.5, 127.0, 127.4, 127.5, 128.4, 128.5, 133.3, 135.2,
137.6, 140.9, 145.9. Anal. Calcd for C20H19N3OS: C, 68.74;
H, 5.48; N, 12.02. Found: C, 69.00; H, 5.57; N, 12.19.
N-P h en yl-2-ben zotr iazol-1-yl-2-th ien -2-ylacetam ide (5d)
was purified by recrystallization from EtOAc/hexane to give
Exp er im en ta l Section
Gen er a l. Melting points were determined with a hot-stage
apparatus and are uncorrected. NMR spectra were taken in
CDCl3 or DMSO-d6 with tetramethylsilane as the internal
1
standard for H (300 MHz) or solvent as the internal standard
for 13C (75 MHz). Tetrahydrofuran (THF) was distilled under
nitrogen immediately prior to use from sodium/benzophenone.
All reactions with air-sensitive compounds were carried out
under an argon atmosphere. Column chromatography was
conducted with silica gel 230-400 mesh. 2-(Benzotriazol-1-
ylmethyl)-5-methylthiophene (3b)9 and 2-(1-benzotriazol-1-yl-
2-methylpropyl)-5-methylthiophene (5e)11 were prepared ac-
cording to our previously reported procedure.
1
a colorless solid: yield 64% (1.1 g); mp 164-165 °C; H NMR
(DMSO-d6) δ 7.11-7.19 (m, 2H), 7.34-7.72 (m, 10H), 8.11 (d,
J ) 8.3 Hz, 1H), 10.82 (s, 1H); 13C NMR (DMSO-d6) δ 61.6,
111.7, 119.4, 119.7, 124.1, 124.3, 127.0, 127.6, 128.7, 128.9,
129.3, 132.5, 135.1, 138.0, 145.6, 164.4. Anal. Calcd for
C18H14N4OS: C, 64.65; H, 4.22; N, 16.75. Found: C, 64.46;
H, 4.28; N, 16.64.
P r ep a r a tion of 2-(Ben zotr ia zol-1-ylm eth yl)th iop h en e
(3a ). A mixture of 1-(hydroxymethyl)benzotriazole (30 mmol,
4.5 g), thiophene (180 mmol, 15.1 g), and p-toluenesulfonic acid
(0.1 g) in dioxane (20 mL) was refluxed for 3 days. The solvent
and an excess amount of thiophene were evaporated under
vacuum. To the oil residue was added sodium hydroxide (5%
aqueous, 10 mL) and chloroform (50 mL). The organic layer
was separated, washed with water (2 × 50 mL) and dried
(Na2SO4). Evaporation of the solvent gave the crude product
which was recrystallized from CH2Cl2/hexane to afford the
pure product as a colorless solid: yield 35% (2.23 g); mp 103-
104 °C; 1H NMR (CDCl3) δ 5.99 (s, 2H), 6.95 (dd, J ) 5.2 and
3.5 Hz, 1H), 7.10 (d, J ) 3.5 Hz, 1H), 7.24 (dd, J ) 5.2 and 1.3
Hz, 1H), 7.34 (t, J ) 7.4 Hz, 1H), 7.41-7.49 (m, 2H), 8.03 (d,
J ) 8.2 Hz, 1H); 13C NMR (CDCl3) δ 46.8, 109.5, 120.0, 124.0,
126.4, 127.1, 127.4, 127.5, 132.4, 136.6, 146.1. Anal. Calcd
for C11H9N3S: C, 61.37; H, 4.21; N, 19.52. Found: C, 61.38;
H, 4.26; N, 19.40.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-(1-Ben -
zotr iazol-1-ylalkyl)th ioph en es 5a-j. To a solution of 2-(ben-
zotriazol-1-ylmethyl)thiophene 3 (5 mmol) in dry THF (50 mL)
at -78 °C under argon was added n-BuLi (2 M, 2.8 mL, 5.5
mmol). After 1.5 h, the appropriate electrophile (5.5 mmol)
(phenyl isocyanate for 5a , phenyl isothiocyanate for 5b,
benzaldehyde for 5c, phenyl isocyanate for 5d , methyl iodide
for 5f, n-propyl iodide for 5g, n-butyl iodide for 5h , benzyl
bromide for 5i, and cyclohexanone for 5j) in THF (7 mL) was
added. The mixture was stirred at -78 °C for an additional 4
h and then at rt overnight. After being quenched with water
(50 mL), the mixture was extracted with Et2O (3 × 50 mL)
and the combined organic layer was dried (MgSO4). The
solvent was evaporated under vacuum and the residue purified
either by recrystallization or by column chromatography to
give the corresponding pure product 5. In the case of 5c, after
4 h of stirring at -78 °C, methyl iodide (0.7 g, 5 mmol) in
HMPA (10 mL) was added to protect the oxygen anion. The
mixture was stirred at this temperature for an additional 2 h
and then at rt overnight before workup.
2-(1-Ben zotr iazol-1-yleth yl)-5-m eth ylth ioph en e (5f) was
purified by column chromatography (hexane/EtOAc ) 10:1)
to give a colorless oil: yield 68% (0.82 g); H NMR (CDCl3) δ
1
2.15 (d, J ) 6.9 Hz, 3H), 2.39 (s, 3H), 6.33 (q, J ) 6.9 Hz, 1H),
6.60 (d, J ) 3.5 Hz, 1H), 6.85 (d, J ) 3.5 Hz, 1H), 7.29-7.42
(m, 3H), 8.06 (d, J ) 7.9 Hz, 1H); 13C NMR (CDCl3) δ 15.0,
21.1, 54.8, 110.1, 119.7, 123.7, 124.6, 125.2, 126.9, 131.7, 140.1,
140.2, 146.2. Anal. Calcd for C13H13N3S: C, 64.17; H, 5.39;
N, 17.27. Found: C, 63.80; H, 5.31; N, 17.31.
2-(1-Ben zotr iazol-1-ylbu tyl)-5-m eth ylth ioph en e (5g) was
purified by column chromatography (hexane/EtOAc ) 2:1) to
give a colorless oil: yield 92% (1.29 g); 1H NMR (CDCl3) δ 0.95
(t, J ) 7.2 Hz, 3H), 1.18-1.44 (m, 2H), 2.39 (s, 3H), 2.40-2.52
(m, 1H), 2.59-2.72 (m, 1H), 6.11 (dd, J ) 9.3 and 6.3 Hz, 1H),
6.57 (d, J ) 3.5 Hz, 1H), 6.85 (d, J ) 3.5 Hz, 1H), 7.32 (t, J )
8.0 Hz, 1H), 7.40 (t, J ) 8.0 Hz, 1H), 7.49 (d, J ) 8.0 Hz, 1H),
8.05 (d, J ) 8.0 Hz, 1H); 13C NMR (CDCl3) δ 13.4, 15.2, 19.6,
37.0, 59.2, 110.1, 120.0, 123.8, 124.7, 125.7, 127.0, 132.0, 139.5,
140.3, 146.3. Anal. Calcd for C15H17N3S: C, 66.39; H, 6.31;
N, 15.48. Found: C, 65.97; H, 6.39; N, 15.53.
2-(1-Ben zotr ia zol-1-ylp en tyl)-5-m eth ylth iop h en e (5h )
was purified by column chromatography (hexane/EtOAc ) 2:1)
to give a colorless oil: yield 93% (1.32 g); H NMR (CDCl3) δ
1
0.84 (t, J ) 7.0 Hz, 3H), 1.11-1.25 (m, 1H), 1.25-1.90 (m, 3H),
2.38 (s, 3H), 2.41-2.56 (m, 1H), 2.58-2.72 (m, 1H), 6.07 (dd,
J ) 9.1 and 6.3 Hz, 1H), 6.56 (d, J ) 3.5 Hz, 1H), 6.84 (d, J )
3.5 Hz, 1H), 7.31 (t, J ) 8.0 Hz, 1H), 7.40 (t, J ) 8.0 Hz, 1H),
7.47 (d, J ) 8.0 Hz, 1H), 8.04 (d, J ) 8.0 Hz, 1H); 13C NMR
(CDCl3) δ 13.7, 15.2, 22.0, 28.5, 34.8, 59.6, 110.1, 120.0, 123.8,
124.7, 125.7, 127.0, 132.1, 139.5, 140.3, 146.3. Anal. Calcd
for C16H19N3S: N, 14.72. Found: N, 14.88.
2-[(1-Ben zotr ia zol-1-yl-2-p h en yl)m eth yl]-5-m eth ylth io-
p h en e (5i) was purified by recrystallization from EtOAc/
hexane to give a colorless solid: yield 87% (1.4 g); mp 118-
119 °C; 1H NMR (CDCl3) δ 2.40 (s, 3H), 3.78 (dd, J ) 13.9 and
6.4 Hz, 1H), 3.98 (dd, J ) 13.9 and 9.3 Hz, 1H), 6.24 (dd, J )
9.3 and 6.4 Hz, 1H), 6.56 (d, J ) 3.4 Hz, 1H), 6.84 (d, J ) 3.4
Hz, 1H), 7.01-7.03 (m, 2H), 7.03-7.15 (m, 3H), 7.25-7.37 (m,
3H), 8.01 (d, J ) 8.1 Hz, 1H); 13C NMR (CDCl3) δ 15.2, 41.7,
60.8, 109.7, 119.9, 123.7, 124.7, 125.9, 126.9, 127.1, 128.4,
128.8, 132.4, 136.5, 138.8, 140.6, 146.0. Anal. Calcd for
C19H17N3S: C, 71.44; H, 5.36; N, 13.15. Found: C, 71.34; H,
5.39; N, 13.19.
N-P h en yl-2-ben zotr ia zol-1-yl-2-(5-m eth ylth ien -2-yl)a c-
eta m id e (5a ) was purified by recrystallization from EtOAc/
hexane to give a colorless solid: yield 80% (1.39 g); mp 173-
1
175 °C; H NMR (DMSO-d6) δ 2.44 (s, 3H), 6.81 (d, J ) 3.5
Hz, 1H), 7.13 (t, J ) 7.4 Hz, 1H), 7.19 (d, J ) 3.5 Hz, 1H),
7.28-7.45 (m, 4H), 7.52 (t, J ) 8.2 Hz, 1H), 7.57-7.65 (m, 3H),
8.08 (d, J ) 8.2 Hz, 1H), 10.82 (s, 1H); 13C NMR (DMSO-d6) δ
14.1, 61.4, 111.2, 118.2, 118.7, 122.7, 123.2, 123.8, 126.2, 127.6,
131.6, 131.7, 136.9, 141.1, 145.0, 163.5; HRMS calcd for
C19H16N4OS 349.1123 (M + 1), found 349.1118.
2-[Ben zotr ia zol-1-yl(1-h yd r oxy-1-cycloh exyl)m eth yl]-
5-m eth ylth iop h en e (5j) was purified by column chromatog-
raphy (hexane/EtOAc ) 2:1) to give a colorless solid: yield 79%
(1.42 g); mp 145-146 °C; 1H NMR (CDCl3) δ 1.21-1.89 (m,
10H), 2.40 (s, 3H), 3.81 (s, 1H), 5.90 (s, 1H), 6.57 (d, J ) 3.3
N-P h en yl-2-b en zot r ia zol-1-yl-2-(5-m et h ylt h ien -2-yl)-
th ioa ceta m id e (5b) was purified by recrystallization from
EtOAc/hexane to give a colorless solid: yield 78% (1.41 g); mp

6220 J . Org. Chem., Vol. 62, No. 18, 1997
Katritzky et al.
Hz, 1H), 7.02 (d, J ) 3.3 Hz, 1H), 7.36 (t, J ) 8.0 Hz, 1H),
7.50 (t, J ) 8.0 Hz, 1H), 7.68 (d, J ) 8.0 Hz, 1H), 8.06 (d, J )
8.0 Hz, 1H); 13C NMR (CDCl3) δ 15.1, 21.6, 21.8, 25.4, 35.1,
35.6, 66.5, 74.2, 109.9, 120.1, 124.0, 124.2, 127.7, 128.4, 133.3,
134.2, 141.7, 145.2. Anal. Calcd for C18H21N3OS: N, 12.83.
Found: N, 12.67.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-F u n ction -
a lized Th iop h en es 7a ,b,d . A mixture of the corresponding
compound 5 (5a for 7a , 5b for 7b, and 5d for 7d ) (2 mmol),
zinc metal (2.6 g, 40 mmol) in acetic acid (10 mL), and dry
THF (20 mL) was refluxed for 3 days. On cooling the excess
amount of zinc metal was filtered off. To the solution was
added diethyl ether (50 mL) and the mixture was then washed
with water (3 × 50 mL) and dried (Na2SO4). The solvent was
removed under vacuum to give an oil which was separated by
column chromatography to give the pure product.
N-P h en yl-2-(5-m eth ylth ien -2-yl)a ceta m id e (6a ). Chlo-
roform was used as the eluent to give a colorless solid: yield
76% (0.35 g); mp 104-105 °C; 1H NMR (CDCl3) δ 2.50 (s, 3H),
3.87 (s, 2H), 6.69 (d, J ) 3.4 Hz, 1H), 6.82 (d, J ) 3.4 Hz, 1H),
7.11 (t, J ) 7.5 Hz, 1H), 7.31 (t, J ) 7.5 Hz, 2H), 7.38 (br s,
1H), 7.45 (d, J ) 7.5 Hz, 2H); 13C NMR (CDCl3) δ 15.0, 38.2,
119.8, 123.9, 124.8, 126.6, 128.5, 133.6, 137.9, 139.4, 168.4.
Anal. Calcd for C13H13NOS: C, 67.50; H, 5.66; N, 6.06.
Found: C, 67.57; H, 5.61; N, 5.92.
(1:1) to give a colorless solid: 40% (0.60 g); mp 288-289 °C;
1H NMR (CDCl3) δ 1.53 (d, J ) 7.1 Hz, 12 H), 2.60 (s, 6H),
3.58 (m, 2H), 7.22 (s, 2H); 13C NMR (CDCl3) δ 16.5, 21.3, 33.9,
120.0, 120.1, 132.8, 134.9, 138.7. Anal. Calcd for C18H22S2:
C, 71.47; H, 7.33. Found: C, 71.60; H, 7.37.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Alk en yl-
th iop h en es 2a ,b a n d 4a ,b. To a stirred solution of 2-(ben-
zotriazol-1-ylmethyl)-5-methylthiophene (3b) (1.2 g, 5 mmol)
in THF (45 mL) was added n-BuLi (2.0 M, 2.5 mL, 5.5 mmol)
under argon at -78 °C. After 1 h, an appropriate electrophile
(benzyl bromide for 2a , n-butyl bromide for 2b, ethyl cin-
namate for 4a , and ethyl crotonate for 4b) (5.5 mmol) in THF
(10 mL) was added. The mixture was stirred at -78 °C for
an additional 3 h and was allowed to warm to rt overnight. (i)
In the cases of 2a and 2b, Amberlyst-15 resin (10 g) was added
and the mixture was refluxed under argon for 5 h. (ii) In the
cases of 4a and 4b, THF was distilled off, and Amberlyst-15
resin (15 g) and 1,4-dioxane (50 mL) were added. The mixture
was refluxed under argon for 3 days. Upon cooling, the resin
was filtered off and the solvent evaporated. Methylene
chloride (50 mL) was added to the residue and the solution
was washed with NaOH (2 N, 30 mL) and water (30 mL). The
organic layer was separated and dried (NaSO4). After the
solvent was removed, the crude product was purified by
column chromatography to give the pure product.
tr a n s-1-(5-Meth ylth ien -2-yl)-2-p h en yleth en e (2a ). Et-
OAc/hexane (1:4) was used as the eluent to give a colorless
N-P h en yl-2-(5-m et h ylt h ien -2-yl)t h ioa cet a m id e (6b ).
Et2O/hexane (1:2) was used as the eluent to give a colorless
oil: yield 67% (0.31 g); H NMR (CDCl3) δ 2.51 (s, 3H), 4.40
1
solid: 92% (0.91 g); mp 79-80 °C (lit.22 mp 85 °C); H NMR
1
(CDCl3) δ 2.49 (s, 3H), 6.64-6.66 (m, 1H), 6.80 (d, J ) 16.0
Hz, 1H), 6.85 (d, J ) 3.3 Hz, 1H), 7.15 (d, J ) 16.0 Hz, 1H),
7.23 (t, J ) 8.0 Hz, 1H), 7.33 (t, J ) 8.0 Hz, 2H), 7.44 (d, J )
8.0 Hz, 2H); 13C NMR (CDCl3) δ 15.6, 122.2, 125.8, 126.2,
126.3, 127.1, 127.3, 128.6, 137.2, 139.3, 140.9.
(s, 2H), 6.72 (d, J ) 3.0 Hz, 1H), 6.86 (d, J ) 3.0 Hz, 1H), 7.27
(t, J ) 7.7 Hz, 1H), 7.38 (t, J ) 7.7 Hz, 2H), 7.62 (d, J ) 7.7
Hz, 2H), 8.87 (br s, 1H); 13C NMR (CDCl3) δ 15.3, 48.6, 123.5,
125.6, 127.0, 128.4, 128.8, 133.4, 138.3, 141.4, 199.7. Anal.
Calcd for C13H12NS2: C, 63.12; H, 5.30; N, 5.66. Found: C,
63.16; H, 5.55; N, 5.68.
tr a n s-1-(5-Meth ylth ien -2-yl)p en ten e (2b). EtOAc/hex-
ane (1:8) was used as the eluent to give a colorless oil: 90%
(0.74 g); 1H NMR (CDCl3) δ 0.94 (t, J ) 7.4 Hz, 3H), 1.42-
1.56 (m, 2H), 2.09-2.17 (m, 2H), 2.44 (s, 3H), 5.84 (dt, J )
15.7 and 6.9 Hz, 1H), 6.41 (d, J ) 15.7 Hz, 1H), 6.51-6.58 (m,
1H), 6.64 (d, J ) 3.3 Hz, 1H); 13C NMR (CDCl3) δ 13.7, 15.4,
22.5, 34.9, 123.5, 124.1, 125.2, 129.7, 137.6, 141.1. Anal. Calcd
for C10H14S: C, 72.25; H, 8.50. Found: C, 72.47; H, 8.55.
Eth yl 4-(5-Meth ylth ien -2-yl)-3-p h en yl-3-bu ten a te (4a ).
EtOAc/hexane (1:8) was used as the eluent to give a colorless
oil as a mixture of cis and trans isomers: 71% (1.02 g); 1H
NMR (CDCl3) (signals for the minor isomer are in square
brackets) δ 1.17 (t, J ) 7.1 Hz, 3H) [1.19 (t, J ) 7.2 Hz, 3H)],
2.26 (s, 3H) [2.49 (s, 3H)], 3.40 (s, 2H) [3.87 (s, 2H)], 4.08 (q,
J ) 7.1 Hz, 2H) [4.14 (q, J ) 7.2 Hz, 2H)], 6.47 (d, J ) 3.5 Hz,
1H) [6.70 (d, J ) 3.5 Hz, 1H)], 6.62 (d, J ) 3.5 Hz, 1H) [6.94
(d, J ) 3.5 Hz, 1H)], 6.65 (s, 1H) [6.99 (s, 1H)], 7.23-7.47 (m,
5H); 13C NMR (CDCl3) (signals for minor isomers are in square
brackets) δ 14.1, 15.2 [15.3], 45.9 [37.5], 60.7 [60.9], 124.3
[124.2], 124.3 [125.5], 126.1, 127.9 [127.3], 128.4, 129.0 [128.9],
131.9, 138.0 [138.1], 139.8, 140.4 [140.6], 170.9. Anal. Calcd
for C17H18SO2: C, 71.30; H, 6.34. Found: C, 71.64; H, 6.35.
Eth yl 4-(5-Meth ylth ien -2-yl)-3-m eth yl-3-bu ten a te (4b).
EtOAc/hexane (1:8) was used as the eluent to give a colorless
oil as a mixture of cis and trans isomers: 62% (0.69 g); 1H
NMR (CDCl3) (signals for the minor isomer are in square
brackets) δ 1.28 (t, J ) 7.1 Hz, 3H), 2.05 (s, 3H) [1.97 (s, 3H)],
2.48 (s, 3H) [2.46 (s, 3H)], 3.16 (s, 2H) [3.39 (s, 2H)], 4.18 (q,
J ) 7.1 Hz, 2H), 6.43 (s, 1H) [6.51 (s, 1H)], 6.63-6.69 (m, 1H),
6.76-6.81 (m, 1H); 13C NMR (CDCl3) (signals for minor
isomers are in square brackets) δ 14.1, 15.1, 18.5, 46.1 [39.1],
60.5, 122.5 [121.9], 124.8 [125.1], 126.9 [126.4], 128.5, 138.4,
139.3, 171.3; HRMS calcd for C12H16O2S 224.0871 (M+), found
224.0907.
N-P h en yl-2-th ien -2-yla ceta m id e (6d ). Chloroform was
used as the eluent to give a colorless solid: yield 59% (0.26 g);
mp 116-117 °C; H NMR (CDCl3) δ 3.89 (s, 2H), 6.90-7.01
1
(m, 2H), 7.06 (t, J ) 7.1 Hz, 1H), 7.21 (d, J ) 4.6 Hz, 1H),
7.27 (t, J ) 7.7 Hz, 2H), 7.58 (d, J ) 7.7 Hz, 2H), 9.39 (br s,
1H); 13C NMR (CDCl3) δ 37.6, 119.4, 123.3, 124.3, 126.0, 126.3,
128.2, 136.2, 138.1, 167.9. Anal. Calcd for C12H11NOS: C,
66.33; H, 5.10; N, 6.45. Found: C, 66.23; H, 5.18; N, 6.38.
P r ep a r a tion of 1-(5-Meth ylth ien -2-yl)-1-(5-m eth ylfu -
r a n -2-yl)-2-m eth oxy-2-p h en yleth a n e (6c). A mixture of
1-benzotriazol-1-yl-1-(5-methylthien-2-yl)-2-methoxy-2-phen-
ylethane (5c) (1.6 g, 4.6 mmol), 2-methylfuran (0.41 g, 5 mmol),
and ZnBr2 (2.5 g, 11 mmol) in methylene chloride (40 mL) was
stirred at rt for 5 days. The solid was filtered and water (50
mL) was added to the solution. After separation, the aqueous
layer was extracted with Et2O (2 × 50 mL) and dried (Na2SO4).
The solvent was removed under vacuum to give an oil which
was purified by column chromatography (hexane/EtOAc ) 4:1)
to give the pure product as a mixture of two disteroisomers:
colorless oil; 59% (0.84 g); 1H NMR (CDCl3) (signals for the
minor isomer are in square brackets) δ 2.19 (s, 3H) [2.27 (s,
3H)], 2.45 (s, 3H) [2.34 (s, 3H)], 3.24 (s, 3H) [3.21 (s, 3H)], 4.35
(d, J ) 7.7 Hz, 1H) [4.41 (d, J ) 8.3 Hz, 1H)], 4.66 (d, J ) 7.7
Hz, 1H) [4.60 (d, J ) 8.3 Hz, 1H)], 5.71 (d, J ) 3.5 Hz, 1H)
[5.79 (d, J ) 3.0 Hz, 1H)], 5.90 (d, J ) 3.0 Hz, 1H) [6.10 (d, J
) 3.5 Hz, 1H)], 6.33 (d, J ) 3.3 Hz, 1H) [6.39 (d, J ) 3.0 Hz,
1H)], 6.55 (d, J ) 3.5 Hz, 1H) [6.60 (d, J ) 3.3 Hz, 1H)], 7.11-
7.27 (m, 5H); 13C NMR (CDCl3) (signals for the minor isomer
are in square brackets) δ 13.5 [13.6], 15.3 [15.2], 48.5 [48.3],
57.2, 86.0 [86.3], 105.9 [106.2], 107.9 [107.4], 124.1 [124.3],
125.7 [125.5], 127.1, 127.5, 127.6, 127.9 [128.0], 138.7 [138.5],
140.1 [139.9], 150.6, 152.1 [152.5]. Anal. Calcd for C19H20O2-
S: C, 73.04; H, 6.45. Found: C, 72.89; H, 6.35.
Gen er a l P r oced u r e for th e P r ep a r a tion of Cyclop en t-
[b]th iop h en es 16-18. To a solution of 2-(benzotriazol-1-
ylmethyl)thiophene 3 or 5 (3b for 18, 5g for 16/17a , and 5j
for 16/17b) (4 mmol) in methylene chloride (50 mL) was added
ZnBr2 (2.7 g, 12 mmol) at rt under nitrogen. After 15 min, an
appropriate styrene (1,1-diphenylethylene for 18, 4-methyl-
styrene for 16/17a , and R-methylstyrene for 16/17b) (4.4 mmol)
P r ep a r a tion of 2,6-Dim eth yl-4,8-bis(1-m eth yleth yl)-
ben zo[1,2-b:4,5-b′]d ith iop h en e (11). A mixture of 2-(1-
benzotriazol-1-yl-2-methylpropyl)-5-methylthiophene (5e) (1.3
g, 5 mmol) and ZnCl2 (0.7 g, 5 mmol) in methylene chloride
(50 mL) was refluxed overnight and then ice water (50 mL)
was added. After separation, the aqueous layer was extracted
with chloroform (2 × 30 mL) and the combined organic extracts
were washed with NaOH (aqueous 3%, 40 mL) and water (50
mL). On drying (NaSO4), the solvent was evaporated to give
an oil which was washed with a mixture of Et2O and hexane
(22) Tominaga, Y.; Tedjamulia, M. L.; Castle, R. N.; Lee, M. L. J .
Heterocycl. Chem. 1983, 20, 487.

Syntheses of 2-Functionalized Thiophenes
J . Org. Chem., Vol. 62, No. 18, 1997 6221
in methylene chloride (5 mL) was added. On cooling, ZnBr2
was filtered off and NaOH (1 N, 20 mL) was added. The
organic layer was separated and the aqueous layer was
extracted with Et2O (2 × 40 mL). The combined organic
extracts were washed with water (60 mL) and dried (Na2SO4).
After the solvent was evaporated under vacuum, the residue
was separated by column chromatography to give the pure
product.
2H), 2.54 (s, 3H), 2.62 (s, 3H), 2.75 (t, J ) 7.9 Hz, 2H), 7.01 (s,
1H), 7.06 (s, 1H), 7.30-7.43 (m, 5H); 13C NMR (CDCl3) δ 14.4,
16.3, 19.2, 22.8, 34.5, 120.3, 126.6, 127.8, 127.9, 128.9, 129.5,
131.1, 136.8, 139.2, 140.1, 140.3, 142.2. Anal. Calcd for
C19H20S: C, 81.38; H, 7.19. Found: C, 81.34; H, 7.41.
2-Meth yl-4,6-d ip h en yl-7-bu tylben zo[b]th iop h en e (19c).
Hexane/EtOAc (40:1) was used as the eluent to give the pure
product as a colorless oil: 42% (0.73 g); 1H NMR (CDCl3) δ
0.84 (t, J ) 7.3 Hz, 3H), 1.27-1.39 (m, 2H), 1.63-1.73 (m, 2H),
2.58 (s, 3H), 2.87 (t, J ) 8.2 Hz, 2H), 7.15 (s, 1H), 7.23 (s, 1H),
7.32-7.47 (m, 8H), 7.57 (d, J ) 7.3 Hz, 2H); 13C NMR (CDCl3)
δ 13.7, 16.3, 22.9, 31.5, 32.2, 121.5, 126.7, 127.1, 127.7, 128.0,
128.4, 129.1, 129.6, 133.0, 134.2, 136.9, 137.8, 140.6, 141.0,
141.1, 141.9. Anal. Calcd for C25H24S: C, 84.22; H, 6.79.
Found: C, 83.97; H, 7.08.
2-Meth yl-4,6-diph en yl-7-pr opylben zo[b]th ioph en e (19d).
Hexane was used as the eluent to give the pure product as a
colorless oil: 36% (0.62 g); 1H NMR (CDCl3) δ 0.90 (t, J ) 7.3
Hz, 3H), 1.64-1.77 (m, 2H), 2.57 (s, 3H), 2.81-2.86 (m, 2H),
7.16 (s, 1H), 7.24 (s, 1H), 7.32-7.47 (m, 8H), 7.58 (t, J ) 8.1
Hz, 2H); 13C NMR (CDCl3) δ 14.4, 16.2, 22.7, 34.7, 121.5, 126.7,
127.0, 127.7, 128.0, 128.4, 129.1, 129.6, 132.8, 134.2, 137.0,
137.8, 140.5, 141.0, 141.1, 141.9. Anal. Calcd for C24H22S: C,
84.16; H, 6.47. Found: C, 83.91; H, 6.88.
4,6-Dip h en ylben zo[b]th iop h en e (25a ). Hexane/EtOAc
(4:1) was used as the eluent to give the pure product as a
colorless solid: 90% (1.35 g); 1H NMR (CDCl3) δ 7.31-7.54
(m, 8H), 7.58-7.71 (m, 3H), 7.69 (d, J ) 7.5 Hz, 2H), 8.08 (s,
1H); 13C NMR (CDCl3) δ 119.8, 123.1, 124.5, 126.6, 127.3,
127.4, 127.5, 128.5, 128.8, 129.1, 137.1, 137.8, 138.0, 140.9,
141.2. Anal. Calcd for C20H14S: C, 83.88; H, 4.93. Found:
C, 83.61; H, 4.89.
1,1-Diph en yl-5-m eth ylcyclopen t[b]th ioph en e (18). Hex-
ane/EtOAc (30:1) was used as the eluent to give a colorless
1
solid: 52% (0.76 g); mp 109-110 °C; H NMR (CDCl3) δ 2.48
(s, 3H), 2.90-2.96 (m, 2H), 3.04-3.09 (m, 2H), 6.55 (s, 1H),
7.15-7.30 (m, 10H); 13C NMR (CDCl3) δ 16.3, 28.1, 46.6, 59.0,
120.9, 125.9, 127.6, 128.0, 139.4, 142.6, 148.1, 150.6. Anal.
Calcd for C20H18S: C, 82.71; H, 6.25. Found: C, 83.11; H, 6.62.
1-(4-Meth ylph en yl)-3-pr opyl-5-m eth ylcyclopen t[b]th io-
p h en e (16/17a ). Hexane/EtOAc (40:1) was used as the eluent
to give a colorless oil as a mixture of two disteroisomers (trans:
cis ) 14:9 based on GC-MS of crude product, trans:cis ) 1:1
1
after column): 83% (0.89 g); H NMR (CDCl3) (signals for cis
isomer are in square brackets) δ 0.91-0.99 (m, 3H), 1.36-
1.72 (m, 4H), 1.77-1.86 (m, 1H) [2.92-3.02 (m, 1H)], 2.30 (s,
3H) [2.32 (s, 3H)], 2.41 (s, 3H), 2.43-2.55 (m, 1H), 3.12-3.22
(m, 1H) [3.22-3.35 (m, 1H)], 4.11 (t, J ) 8.3 Hz, 1H) [4.21 (t,
J ) 6.1 Hz, 1H)], 6.29 (s, 1H) [6.33 (s, 1H)], 6.95-7.11 (m,
4H); 3C NMR (CDCl3) δ 14.2, 16.2, 21.0, 21.1 [21.3], 38.9 [39.3],
41.6 [42.3], 46.2 [47.1], 47.1 [47.6], 120.2, 127.1 [127.4], 129.1,
135.5 [135.6], 142.2 [142.5], 142.7 [143.0], 144.7 [145.0], 147.4.
Anal. Calcd for C18H22S: C, 79.95; H, 8.20. Found: C, 79.74;
H, 8.39.
1,5-Dim eth yl-1-p h en yl-3-(1-h yd r oxycycloh exyl)cyclo-
p en t[b]th iop h en e (16/17b). Hexane/EtOAc (20:1) was used
as the eluent to give a colorless oil as a mixture of two
disteroisomers (trans:cis ) 2:1 based on GC-MS of crude
2-Meth yl-4,6-d ip h en ylben zo[b]th iop h en e (25b). Hex-
ane/EtOAc (30:1) was used as the eluent to give the pure
1
product, trans:cis ) 2:1 after column): 85% (1.3 g); H NMR
1
product as a colorless solid: 45% (0.67 g); mp 86-87 °C; H
(CDCl3) (signals for cis isomer are in square brackets) δ 0.75-
1.50 (m, 5H), 1.54 (s, 3H) [1.62 (s, 3H)], 1.62-1.82 (m, 6H),
2.44 (s, 3H), 2.53-2.59 (m, 2H), 3.50 (t, J ) 9.9 Hz, 1H) [3.06
(dd, J ) 13 and 6.3 Hz, 1H)], 6.61 (s, 1H) [6.57 (s, 1H)], 7.18-
NMR (CDCl3) δ 2.56 (s, 3H), 7.10 (s, 1H), 7.31-7.52 (m, 6H),
7.55 (s, 1H), 7.60 (d, J ) 7.5 Hz, 2H), 7.67 (d, J ) 7.5 Hz, 2H),
7.95 (s, 1H); 13C NMR (CDCl3) δ 16.3, 119.4, 120.8, 124.3,
127.1, 127.3, 128.5, 128.8, 129.0, 136.9, 137.0, 137.8, 141.1,
141.2, 141.3. Anal. Calcd for C21H16S: C, 83.96; H, 5.37.
Found: C, 83.94; H, 5.45.
3
7.26 (m, 1H), 7.29-7.38 (m, 2H), 7.52 (d, J ) 7.5 Hz, 2H); C
NMR (CDCl3) δ 15.2, 22.0 [21.7], 23.4 [23.3], 25.8, 31.9 [33.8],
32.4 [32.5], 38.2 [37.0], 45.3 [45.8], 50.7 [49.7], 81.6 [82.1], 84.1
[83.8], 124.5 [124.3], 124.5 [124.6], 124.7 [124.9], 126.2 [126.3],
128.0 [127.9], 137.8 [137.7], 140.0, 150.6 [149.5]. Anal. Calcd
for C21H26OS: C, 77.25; H, 8.03. Found: C, 77.33; H, 8.29.
Gen er a l P r oced u r e for th e P r ep a r a tion of P olysu b-
stitu ted Ben zoth iop h en es 19a -d a n d 25a -e. To a stirred
solution of an appropriate 2-(1-benzotriazol-1-ylalkyl)thiophene
3 or 5 (5 mmol) in THF (45 mL) was added n-BuLi (1.6 M, 3.2
mL, 5.5 mmol) at -78 °C under argon. After 1 h, an
appropriate R,â-unsaturated aldehyde or ketone (5.5 mmol)
in THF (10 mL) was added. The mixture was stirred at -78
°C for an additional 3 h and then allowed to warm to rt
overnight. The THF was distilled off, and Amberlyst-15 acidic
resin (13 g) and 1,4-dioxane (50 mL) were added. The mixture
was refluxed for 3 h under argon. After the resin was filtered
off, the solvent was evaporated, and water (50 mL) and
methylene chloride (50 mL) were added to the residue. After
separation, the aqueous layer was extracted with Et2O (2 ×
40 mL). The combined organic extracts were washed with
NaOH (2 N, 30 mL) and water (50 mL). On drying (NaSO4),
the solvent was evaporated and the crude product was purified
by column chromatography to give the pure compound.
2,4,7-Tr im eth yl-6-ph en ylben zo[b]th ioph en e (19a). Hex-
ane was used as the eluent to give the pure product as a
2-Met h yl-5-p h en yl-6-et h ylb en zo[b]t h iop h en e (25c).
Hexane/EtOAc (40:1) was used as the eluent to give the pure
product as a colorless oil: 69% (0.87 g); 1H NMR (CDCl3) δ
1.11 (t, J ) 7.5 Hz, 3H), 2.55 (s, 3H), 2.66 (q, J ) 7.5 Hz, 2H),
6.89 (s, 1H), 7.30-7.43 (m, 5H), 7.46 (s, 1H), 7.65 (s, 1H); 13
C
NMR (CDCl3) δ 15.6, 16.1, 26.4, 121.2, 121.3, 123.6, 126.7,
128.0, 129.5, 137.5, 138.5, 138.6, 139.2, 140.4, 142.2. Anal.
Calcd for C17H16S: C, 80.91; H, 6.39. Found: C, 80.96; H, 6.43.
2,4-Dim eth yl-6-p h en ylben zo[b]th iop h en e (25d ). Hex-
ane/EtOAc (20:1) was used as the eluent to give the pure
product as a colorless oil: 74% (0.88 g); 1H NMR (CDCl3) δ
2.60 (s, 6H), 7.02 (s, 1H), 7.28-7.34 (m, 2H), 7.42 (t, J ) 7.6
Hz, 2H), 7.62 (d, J ) 7.6 Hz, 2H), 7.79 (s, 1H); 13C NMR
(CDCl3) δ 16.3, 19.7, 118.0, 119.7, 124.4, 126.9, 127.2, 128.7,
131.9, 136.8, 139.1, 140.4, 140.7, 141.4; HRMS calcd for
C16H14S 238.0816 (M+), found 238.0800.
5-Meth yl-6-(4-ter t-bu tylph en yl)ben zo[b]th ioph en e (25e).
Hexane/EtOAc (40:1) was used as the eluent to give the pure
1
product as a colorless solid: 77% (1.08 g); mp 99-100 °C; H
NMR (CDCl3) δ 1.39 (s, 9H), 2.39 (s, 3H), 7.26-7.35 (m, 3H),
7.39-7.48 (m, 3H), 7.73 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3)
δ 20.9, 31.4, 34.6, 123.3, 124.5, 125.0, 126.4, 129.0, 132.1, 137.4,
138.9, 139.1, 149.7. Anal. Calcd for C19H20S: C, 81.38; H,
7.19. Found: C, 81.32; H, 7.30.
1
colorless solid: 81% (1.01 g); mp 61-62 °C; H NMR (CDCl3)
δ 2.42 (s, 3H), 2.54 (s, 3H), 2.61 (s, 3H), 7.06 (s, 1H), 7.07 (s,
1H), 7.29-7.43 (m, 5H); 13C NMR (CDCl3) δ 16.3, 18.3, 19.2,
120.5, 125.8, 126.5, 127.4, 127.9, 128.9, 129.7, 136.7, 138.7,
140.2, 141.0, 141.8. Anal. Calcd for C17H16S: C, 80.91; H,
6.39. Found: C, 80.63; H, 6.83.
2,4-Dim e t h yl-6-p h e n yl-7-p r op ylb e n zo[b]t h iop h e n e
(19b). Hexane/EtOAc (40:1) was used as the eluent to give
the pure product as a colorless solid: 64% (0.89 g); mp 72-73
°C; 1H NMR (CDCl3) δ 0.85 (t, J ) 7.5 Hz, 3H), 1.57-1.70 (m,
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 5a , 4b, and 25d (6 pages). This material is
contained in libraries on microfiche, immediately followed this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O970672G