Solvent-controlled Csp2→O silyl migration: The "one-pot" synthesis of 2,3-disubsituted thiophenes

Article abstract of DOI:10.1021/ol702149c

(Chemical Equation Presented) An effective "one-pot" synthesis of disubstituted thiophene derivatives employing 3-bromo-2-silyl thiophenes has been developed. A solvent-controlled [1,4] C^sp2→O silyl migration was involved as the key step in thi

Full text of DOI:10.1021/ol702149c

ORGANIC
LETTERS
Solvent-Controlled Csp2fO Silyl
Migration: The “One-Pot” Synthesis of
2,3-Disubsituted Thiophenes
2007
Vol. 9, No. 22
4655-4658
Nelmi O. Devarie-Baez, Brian J. Shuhler, Hua Wang, and Ming Xian*
Department of Chemistry, Washington State UniVersity, Pullman, Washington 99164
mxian@wsu.edu
Received August 31, 2007
ABSTRACT
An effective “one-pot” synthesis of disubstituted thiophene derivatives employing 3-bromo-2-silyl thiophenes has been developed. A solvent-
controlled [1,4] Csp2fO silyl migration was involved as the key step in this process.
Substituted thiophenes are of interest in drug discovery and
material science.1 Although a number of methods have been
developed for their syntheses,2 current methods to prepare
multisubstituted thiophenes still rely on multistep manipula-
tions to install substituents one by one, which is inefficient
and time-consuming. A “one-step” strategy to install multiple
substituents on a thiophene ring is still a challenging goal.3
We envisioned that the silyl group on a thiophene ring could
serve as a carbanion precursor if triggered by the anionic
CfO silyl migration to precipitate tandem C-C bond
formations. Hence, multisubstituted thiophenes could be
prepared from silylthiophenes in a “one-pot” fashion.
Anionic CfO silyl migration4 is a mild way to generate
synthetically useful carbanions, and significant progress has
been made in the utility of this migration in tandem
reactions.5 These tandem reactions usually involve the silyl
migration from an sp3 carbon to oxygen.6 In contrast, there
has been very limited synthetic application of silyl migration
from an sp2 carbon to oxygen. Takeda reported the copper-
(I)-alkoxide promoted CfO silyl migration of vinylsilanes
and subsequent reaction of the resulting vinylcopper species.7
Moser investigated the addition of organolithium species to
an o-trimethylsilylbenzaldehyde-Cr(CO)3 complex and the
reactions of aryl anions generated by silyl migration.8 Herein,
we report that silylthiophenes can be used to carry out silyl-
migration mediated tandem reactions to introduce multiple
(1) (a) Bhlmann, F.; Zedero, C. In Thiophenes and Its DeriVatiVes;
Gronowitz, S., Ed.; The Chemistry of Heterocyclic Compounds, Vol. 44;
John Wiley & Sons: New York, 1985; part 1, p 261. (b) Press, J. B. In
Thiophenes and Its DeriVatiVes; Gronowitz, S., Ed.; The Chemistry of
Heterocyclic Compounds, Vol. 44; John Wiley & Sons: New York, 1991;
part 1, p 397. (c) Roncali, J. Chem. ReV. 1992, 92, 711. (d) Schopf, G.;
Komehl, G. In AdVances in Polymer Science: Polythiophenes-Electrically
ConductiVe Polymers; Abel, A., Ed.; Springer-Verlag: Berlin, Heidelberg,
New York, 1997; Vol. 129.
(2) For selected reviews, see: (a) Ila, H.; Baron, O.; Wagner, A. J.;
Knochel, P. Chem. Commun. 2006, 583. (b) Guernion, N. J. L.; Hayes, W.
Curr. Org. Chem. 2004, 8, 637. (c) Weissberger, A.; Taylor, E. C. In
Thiophenes and Its DeriVatiVes; Gronowitz, S., Ed.; The Chemistry of
Heterocyclic Compounds, Vol. 44; John Wiley & Sons: New York, 1985;
Part 1, pp 1.
(4) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
(5) For reviews, see: (a) Moser, W. H. Tetrahedron 2001, 57, 2065. (b)
Schaumann, E.; Kirschining, A. Synlett 2007, 177.
(6) For selected examples: (a) Fischer, M. R.; Kirschning, A.; Michel,
T.; Schaumann, E. Angew. Chem., Int. Ed. Engl. 1994, 33, 217. (b) Smith,
A. B., III; Kim, D.-S.; Xian, M. Org. Lett. 2007, 9, 3307. (c) Tietze, L. F.;
Geissler, H.; Gewart, J. A.; Jakobi, U. Synlett 1994, 511. (d) Nakai, Y.;
Kawahata, M.; Yamaguchi, K.; Takeda, K. J. Org. Chem. 2007, 72, 1379.
(e) Kirschning, A.; Kujat, C. Luiken, S.; Schaumann, E. Eur. J. Org. Chem.
2007, 2387. (f) Jones, P. F.; Lappert, M. F.; Szary, A. C. J. Chem. Soc.,
Perkin Trans. 1 1973, 2272. (g) Hale, K. J.; Hummersone, M. G.; Bhatia,
G. S. Org. Lett. 2000, 2, 2189.
(3) For selected examples, see: (a) Mitsudo, K.; Thansandote, P.;
Wilhelm, T.; Mariampillai, B.; Lautens, M. Org. Lett. 2006, 8, 3939. (b)
Ye, X. S.; Li, W. K.; Wong, H. N. C. J. Am. Chem. Soc. 1996, 118, 2511.
(c) Fattuoni, C.; Usai, M.; Cabiddu, M. G.; Cadoni, E.; De Montis, S.;
Cabiddu, S. Synthesis 2006, 3855.
(7) Tsubouchi, A.; Onishi, K.; Takeda, T. J. Am. Chem. Soc. 2006, 128,
14268 and references therein.
(8) (a) Moser, W. H.; Endsley, K. E.; Colyer, J. T. Org. Lett. 2000, 2,
717. (b) Moser, W. H.; Zhang, J.; Lecher, C. S.; Frazier, T. L.; Pink, M.
Org. Lett. 2002, 4, 1981.
10.1021/ol702149c CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/04/2007

substitutents on a thiophene ring in “one-pot”. To the best
of our knowledge, this is the first synthetic application of
the solvent-controlled Csp2fO silyl migration.
The silylthiophenes employed in our study were 3-bromo-
2-silyl-thiophenes 1. Our design is described in Scheme 1:
have caused a limitation in this coupling step. To our delight,
after several attempts we were able to find a suitable
condition for this step: when the 3-thienyllithium of 1
generated via lithium-bromine exchange was treated with
1.0 equiv of aldehydes in Et2O at -78 °C, desired products
3a-3f were obtained in very high yields (Scheme 3 and
Scheme 1
Scheme 3
Table 1). No ring-opening product was observed. Silyl
subsitutents and aldehyde varients had little effect on the
yields of the coupling reaction. This set up a good base for
the designed tandem reaction.
the carbanion 2 generated from 1 via metal-bromine
exchange will react with an aldehyde to provide alkoxide 3,
which in turn will undergo a [1,4] Csp2fO silyl migration to
result in a new carbanion 4. Finally, 4 will be trapped by
electrophiles to furnish disubsituted thiophene 5. As such,
3-bromo-2-silyl-thiophenes 1 could serve as 2,3-thienyldi-
anion equivalents for the assembly of two different sub-
situtents on the thiophene ring in one step.
Table 1. Alkylation of 3-Bromo-2-silylthiophene with
Aldehydes
3-Bromo-2-silyl-thiophene substrates were prepared from
3-bromothiophene 6 via 2-lithiation and subseqent quenching
with chlorosilanes (Scheme 2). In order to study the effect
Scheme 2
With a series of 3-hydroxyalkyl-2-silylthiophenes (3) in
hand, we next examined the Csp2fO silyl migration and
subsequent coupling reactions. In fact, Keay et al. did some
pioneering work in this area.11 They studied the silyl
migration of several silylthiophene substrates and found the
use of lithium bases resulted in the recovery of starting
material. Silyl migration occurred only when sodium or
potassium bases were used. However, they were not able to
trap the carbanion formed by the migration with any
electrophiles except protons. They concluded that any
reactive species at the arene ring formed by silyl migration
will be rapidly protonated during the reaction, which
precluded further C-C bond formation.
of silyl subsitutents on each step of the tandem reaction, three
silyl variants, 1a, 1b, and 1c, were prepared in almost
quantitive yield.
The first step of the tandem reaction is the coupling
reaction between 1 and aldehydes. Organolithiums and
organomagnesiums have been used to promote the reactions
of some 3-bromothiophenes with aldehydes to form 3-hy-
droxyalkylthiophenes.9 We are particularly interested in using
organolithiums in our design since lithium counterions can
be transmetalated to other metals such as Mg, Zn, Cu, etc.
Such process could either facilitate the silyl migration or
expand the reaction scope of carbanions generated from the
silyl migration. However, the silyl group at the 2-position
has been reported to markedly increase the tendency toward
ring-opening of the 2-silyl 3-thienyllithiums,10 which may
The results of Csp2fO silyl migration using our substrates
are shown in Scheme 4 and Table 2. Compound 3e was used
to investigate the migration conditions. Similar to the Keay’s
(9) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(10) Gronowitz, S.; Frejd, T.; Karlsson, O.; Lawitz, K.; Pedeja, P.;
Petterson, K. Chem. Scr. 1981, 18, 192.
(11) (a) Bures, E.; Spinazze, P. G.; Beese, G.; Hunt, I. R.; Rogers, C.;
Keay, B. A. J. Org. Chem. 1997, 62, 8741. (b) Spinazze, P. G.; Keay, B.
A. Tetrahedron Lett. 1989, 30, 1765.
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Org. Lett., Vol. 9, No. 22, 2007

With these results in hand, we then examined the silyl
migration-alkylation of 3 with a series of electrophiles
(Scheme 5 and Table 3). As such, a solution of 3 in THF/
Scheme 4
Scheme 5
results, the [1,4] silyl migration proceeded nicely when
NaHMDS and KHMDS were used as the base, whereas the
migration completely stopped when a lithium base such as
t-BuLi was used in a series of solvents: THF, Et2O, and
DMPU was treated with t-BuLi at -30 °C, followed by the
addition of electrophiles and warming to rt. In constrast to
Keay’s results,11 the carbanion intermediates formed under
our conditions were able to react with alkyl halides,
Table 2. Silyl Migration of 3-Hydroxyalkyl-2-silylthiophenes
Table 3. Silyl Migration/Alkylations of
3-Hydroxyalkyl-2-silylthiophenes
DME. Since we were particularly interested in using lithium
base in the first step of the tandem reaction, we tested a series
of solvent additives to explore the solvent-controlled condi-
tions for the migration. The addition of TMEDA, HMPA,
or crown ether to the reaction mixture did not help the
migration as only the starting material was recovered (entry
6) or a small amount of migration product was obtained
(entries 7, 8). Surprisingly, when DMPU was added to the
mixture, the silyl migration occurred smoothly at low
temperature (-30-0 °C) and the desired migration product
was obtained in almost quantative yield (entry 9). This
condition was then applied to other substrates including 3b,
3c, 3d, and 3f. All gave excellent results (entries 10-13).
To establish the mode of silyl migration under this condition,
we carried out a crossover experiment, wherein an equimolar
mixture of 3e and 3c was treated with t-BuLi in THF/DMPU
solvent (Scheme 4). No crossover products were observed.
Thus, the silyl migration occurred intramolecularly.
aldehydes, and ketones to introduce substituents at the
2-position of the thiophene. As shown in Table 3, both
Org. Lett., Vol. 9, No. 22, 2007
4657

ketone carbonyl groups in these cases. It is worth noting that
the silyl subsitutents on the thiophene have little effect on
the reaction, since TMS, TES, and TBS substrates all gave
similar yields.
Table 4. “One-Pot” Synthesis of 2,3-Disubstituted Thiophenes
Encouraged by these results, we turned to the development
of a one-flask three-component coupling protocol, employing
3-bromo-2-silyl-thiophenes 1, aldehydes, and a series of
electrophiles (Scheme 6 and Table 4). Optimal conditions
Scheme 6
entail Li-Br exchange of 1 in Et2O at -78 °C for 30 min,
followed by the addition of a solution of an aldehyde in Et2O.
Completion of the first alkylation was achieved in ca. 60
min at -78 to -20 °C (TLC). Addition of the second
electrophile, premixed with THF/DMPU, completed the
reaction sequence. In general, the yields of desired three-
component coupling products are good (Table 4). Alkyl
halides, aldehydes, and nonenolizable ketones served as
suitable electrophiles in this reaction sequence.
In summary, an effective one-pot synthesis of disubstituted
thiophene derivatives employing 3-bromo-2-silyl thiophenes
as 2,3-thienyldianion equivalents has been developed. A [1,4]
C
sp2fO silyl migration was involved as the key step in this
process. To the best of our knowledge, this is the first
example of solvent-controlled Csp2fO silyl migration. Given
the potential to extend this tactic to other mono- or
multisubstituted silyl thiophenes and other arylheterocycles,
this “one-pot” strategy will greatly enhance our capability
to synthesize polyfunctionalized heterocycles. Studies di-
rected at these applications continue in our laboratory.
alkyl aldehydes and aryl aldehydes were good electrophiles
to give the desired coupling products in good yields.
Compounds 5b, 5f-5h, and 5j,5k were obtained as an
inseparable 1:1 mixture of diastereomers.
Nonenolizable ketones such as benzophenone are also
good electrophiles for this reaction. However, alkyl ketones
such as acetone and cyclohexanone only gave a trace amount
of desired products (data not shown). Presumably, the
carbanion protonation was faster than the addition to the
Acknowledgment. This work has been supported by the
Washington State University.
Supporting Information Available: Synthetic proce-
dures, spectroscopic data, and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702149C
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