Photochemistry of diethynyl sulfides: A cycloaromatization for the formation of five-membered rings

Article abstract of DOI:10.1021/ol034266x

(Matrix presented) The first five-membered ring cycloaromatization reaction has been demonstrated. Photoirradiation of bis(phenylethynyl) sulfide in hexanes/1,4-cyclohexadiene produces 3,4-diphenylthiophene through the presumed intermediacy of 2,5-didehydrothiophene. In addition, phenylacetylene is produced in this reaction consistent with competing direct carbon-sulfur cleavage. For reactions in ethanol or 2-propanol production of the thiophene is accompanied by the formation of phenylacetylene and a thionoester of the corresponding alcohol. Thiophene products also result from the irradiation of other diethynyl sulfides.

Full text of DOI:10.1021/ol034266x

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2195-2197
Photochemistry of Diethynyl Sulfides: A
Cycloaromatization for the Formation of
Five-Membered Rings
Kevin D. Lewis, David L. Wenzler, and Adam J. Matzger*
Department of Chemistry and the Macromolecular Science and Engineering Program,
The UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
matzger@umich.edu
Received February 16, 2003 (Revised Manuscript Received May 20, 2003)
ABSTRACT
The first five-membered ring cycloaromatization reaction has been demonstrated. Photoirradiation of bis(phenylethynyl) sulfide in hexanes/
1,4-cyclohexadiene produces 3,4-diphenylthiophene through the presumed intermediacy of 2,5-didehydrothiophene. In addition, phenylacetylene
is produced in this reaction consistent with competing direct carbon−sulfur cleavage. For reactions in ethanol or 2-propanol production of the
thiophene is accompanied by the formation of phenylacetylene and a thionoester of the corresponding alcohol. Thiophene products also
result from the irradiation of other diethynyl sulfides.
The cycloaromatization of enediynes, the Bergman cycliza-
tion,1 has garnered much attention because two highly
reactive sp2 σ-radicals are generated under relatively mild
conditions (Scheme 1a). A number of natural products exploit
An alternative to thermal cycloaromatizations is the
“photo-Bergman” cyclization, which has been reported for
a number of enediyne derivatives.4 We report here an entirely
new variant of this cyclization, namely, the reaction of bis-
(phenylethynyl) sulfide (3a) and other diethynyl sulfide
derivatives; this constitutes the first five-membered ring
cycloaromatization reaction.5 The reaction course is consis-
tent with the intermediacy of a heretofore inaccessible 2,5-
didehydrothiophene,6 and the product is a 3,4-disubstituted
thiophene. As a five-membered ring analogue of the Bergman
cyclization (Scheme 1b), this is an important addition to the
area of cycloaromatization chemistry both for the potential
Scheme 1
this unique thermal isomerization in their mechanism of
action, and this has led to an explosion of research focused
on development of related antitumor agents.2 More recently,
this reaction has been recognized by the materials community
as a powerful methodology for the synthesis of conjugated
organic materials.3
(4) (a) Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.;
Cecil, T. L. J. Am. Chem. Soc. 1996, 118, 3291-3292. (b) Evenzahav, A.;
Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835-1841. (c) Clark, A. E.;
Davidson, E. R.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123, 2650-2657.
(5) (a) Matzger, A. J.; Lewis, K. D.; Rowe, M. P.; Wenzler, D. L.
Presented at the 223rd National Meeting of the American Chemical Society,
Orlando, FL, April 7-11, 2002. (b) Examples of nonaromatic five-
membered ring cyclizations have been reported. For a review concerning
the conversion of eneyne-allenes to fulvenes, see: Wang, K. K. Chem. ReV.
1996, 96, 207-222. (c) For a description of a diyne proceeding via a vinyl
diradical, see: Zimmerman, H. E.; Pincock, J. A. J. Am. Chem. Soc. 1973,
95, 3246-3250.
(1) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25-31.
(2) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci.
1993, 90, 5881-5888.
(3) (a) Tour, J. M. Chem. ReV. 1996, 96, 537-553. (b) Shah, H. V.;
Babb, D. A.; Smith, D. W. Polymer 2000, 41, 4415-4422. (c) Chen, X.
H.; Tolbert, L. M.; Hess, D. W.; Henderson, C. Macromolecules 2001, 34,
4104-4108.
(6) For isomeric didehydrothiophenes, see: (a) Reinecke, M. G. Tetra-
hedron 1982, 38, 427-498. (b) Teles, J. H.; Hess, B. A.; Schaad, L. J.
Chem. Ber. 1992, 125, 423-431.
10.1021/ol034266x CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/30/2003

of creating new therapeutics and as a novel route to
polythiophene materials.
3a may hinder bond formation in the transition state,10 these
effects are not evident in the starting diethynyl sulfides.
Although thermal reaction below 240 °C led exclusively
to recovered starting material,11 irradiation of 3a at 300 nm
in hexanes in the presence of 1,4-cyclohexadiene (CHD, 2
mM) as the trapping agent consistently results in the
production of two species: 3,4-diphenylthiophene (4a) and
phenylacetylene (5a) in yields of 16 and 33%, respectively.
A substantial increase in the concentration of CHD leads to
lower yields of 4a while leaving that of 5a relatively
unchanged. Substituting γ-terpinene as the trapping agent
results in similar yields of both 4a and 5a compared to CHD.
In addition, irradiation of 3a at 350 nm leads to similar yields
and ratios of products, but with a slower rate of reaction
(see Supporting Information). A precipitate that forms during
the reaction displays broad peaks in the proton NMR
spectrum (7.0-8.0 ppm in CDCl3), and LDI-TOF MS
analysis is consistent with oligomerization occurring as a
major side reaction.
Both computation and experiment have demonstrated that
the carbon-carbon distance of the enediyne systems sub-
stantially affects the barrier of six-membered ring cycloaro-
matizations.7 In the simplest enediyne system, hex-3-ene-
1,5-diyne (1), the a-b distance is 2.93 Å, while the c-d
distance is 4.32 Å as determined by microwave spectros-
copy.8 The first microwave and crystal structures of free
diethynyl sulfides were recently obtained, revealing the
carbon-carbon distances critical for bond formation to obtain
the 2,5-didehydrothiophene intermediate (Figure 1).9 The
Utilization of an alcohol to function as both solvent and
trapping agent in the irradiation of 3a results in the formation
of three products: 4a, 5a, and the appropriately substituted
thionoester 6a or 6c (Scheme 2). The yield of 4a in ethanol
and 2-propanol was 11 and 8%, respectively. The yield of
5a in both solvents was approximately 30%, and the
thionoesters were produced in 20% yield. Triplet sensitization
(acetophenone or xanthone) in these solvents leads to
modestly decreased yields of 4a. The use of alcohols that
are poorer hydrogen atom donors, methanol and t-butanol,
results in drastically reduced yields of all products consistent
with competing polymerization processes.
To explore the generality of this five-membered ring
cycloaromatization, a diethynyl sulfide with two propyl
substituents (3b) and one with both a propyl and a phenyl
substituent (3c) were examined. Irradiation of 3b at 300 nm
in hexanes with CHD results in the formation of 3,4-
dipropylthiophene (4b) in 2% yield, reflecting a reduced
efficiency of the cyclization with alkyl substituents on the
diethynyl sulfide. These effects are still evident in 3c, which
produces 3-phenyl-4-propylthiophene (4c) in 3% yield. The
rate of consumption of 3b during irradiation is approximately
five times slower when compared to the other substrates and
is likely due to the lack of an efficient chromophore.
Figure 1. Key structural parameters for the precursors to six- and
five-membered ring cycloaromatization reactions determined by
microwave spectroscopy (1, 2) and X-ray diffraction (3a).
a-b distances in diethynyl sulfides are shorter than those in
enediynes, and the c-d distances are slightly longer. For
the parent diethynyl sulfide (2), microwave spectroscopy
determines these values to be 2.64 and 4.66 Å, respectively.
X-ray crystallographic studies on the bis(phenyl) derivative
(3a) find that the a-b distance is 2.62 Å, while the c-d
distance is 4.57 Å. Though the bulk of the substituents in
Scheme 2
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Org. Lett., Vol. 5, No. 13, 2003

Reactions of 3c in alcohols led to the competitive production
of both the alkyl- (R ) n-propyl) and aryl- (R ) phenyl)
substituted thionoesters (6b or 6d) of the corresponding
alcohols (see Supporting Information).
butyl phenylethynyl sulfide (9) at 300 nm in 2-propanol
(Scheme 4)14 to yield 5a (2%) and 6a (17%). The increased
Scheme 4
A mechanism consistent with the above results is outlined
in Scheme 2. Irradiation of the diethynyl sulfide results in
competing cycloaromatization to the 2,5-didehydrothiophene
or cleavage of a σ-bond between an sp-carbon and sulfur.
The five-membered ring diradical intermediate is trapped by
a hydrogen donor to form the thiophene product (4).12 The
substituted ethynyl radical that results from the carbon-sulfur
bond cleavage is trapped to provide a terminal alkyne (5).
The thiyl radical (7) abstracts hydrogen from the solvent and
is trapped as the thionoester (6), likely via the corresponding
alkyl- or phenylthioketene. Photoreduction of the triple bond,
as observed in much alkyne photochemistry,4b,5c does not
take place for 3a (Scheme 3).13 Furthermore, because
yield of the thionoester relative to phenylacetylene is
consistent with preferential cleavage of the weaker sulfur-
butyl bond under these conditions to form 7a and its
subsequent conversion to 6a.
In summary, the first five-membered ring cycloaromati-
zation has been demonstrated for the formation of thiophenes
and has considerable potential in organic and materials
synthesis. This is the first in a potentially general series of
reactions that can include cycloaromatizations leading to
furans, pyrroles, and phospholes. Studies along these lines
are currently underway.
Scheme 3
Acknowledgment. The authors would like to thank the
ACS-PRF, the Oak Ridge Associated Universities (Ralph
E. Powe Award), and the University of Michigan for funding.
K.D.L. is a fellow of the NSF sponsored IGERT program
for Molecularly Designed Electronic, Photonic, and Nano-
structured Materials at the University of Michigan.
Supporting Information Available: Synthetic proce-
dures, spectral and analytical data, and tables containing
photochemical yields. This material is available free of charge
via the Internet at http://pubs.acs.org.
independently synthesized trans,trans-bis(2-phenylvinyl) sul-
fide and trans-(2-phenylvinyl)-2-phenylethynyl sulfide are
not rapidly consumed under these reaction conditions, either
alone or in the presence of 3a, the absence of the vinyl
species indicates that photoreduction is not an important
pathway in this system. Support for competing cycloaroma-
tization and direct σ-cleavage is provided by irradiation of
OL034266X
(11) (a) Higher temperatures led to a mixture of products consistent with
a radical chain process where 4a was only a minor product. (b) Recently
published computational results for enthalpies of the thermal cyclization
depicted in Scheme 1b indicate a barrier of 55.8 kcal/mol and endothermicity
of 19.3 kcal/mol: Kawatkar, S. P.; Schreiner, P. R. Org. Lett. 2002, 4,
3643-3646.
(12) Photoirradiation of 2,5-diiodo-3,4-diphenylthiophene in hexanes in
the absence of trapping agent exclusively yields 4a, indicating that formation
of 5 or 7 from a thiophene monoradical is not facile.
(13) Vinyl diradical (8) is not trapped in the experiment, suggesting that
either it does not form or that reactions competing with its trapping are
more rapid than in the analogous hydrocarbon in ref 5c.
(14) Acetylenic ether photochemistry has also been proposed to involve
cleavage of the weaker heteroatom-carbon bond; see: Smith, B. A.;
Callinan, A. J.; Swenton, J. S. Tetrahedron Lett. 1994, 35, 2283-2286.
(7) (a) Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184-4190. (b)
Nicolaou, K. C.; Zuccarello, G.; Riemer, C.; Estevez, V. A.; Dai, W. M. J.
Am. Chem. Soc. 1992, 114, 7360-7371.
(8) McMahon, R. J.; Halter, R. J.; Fimmen, R. L.; Wilson, R. J.; Peebles,
S. A.; Kuczkowski, R. L.; Stanton, J. F. J. Am. Chem. Soc. 2000, 122,
939-949.
(9) Matzger, A. J.; Lewis, K. D.; Nathan, C. E.; Peebles, S. A.; Peebles,
R. A.; Kuczkowski, R. L.; Stanton, J. F.; Oh, J. J. J. Phys. Chem. A 2002,
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