halogen-metal exchange,6a,7 and oxidative addition of
metals to halothiophenes have been utilized.7a,8 However,
the ring-closure methods are generally not suitable for
preparation of thiophenes possessing sensitive substit-
uents, and thiophenes that can be synthesized by elec-
trophilic aromatic substitution are limited due to the
inherent activation of the 2- and 5-position and the
directing effects of substituents already present. Synthe-
sis of disubstituted thiophenes via proton-metal ex-
change is restricted to 2,5-disubstituted or 2,3-disubsti-
tuted thiophenes, and in the case of lithiation in the
3-position of 2-substituted thiophenes, low temperature
and specific ortho-directing groups have to be applied.6
Only a few disubstituted thiophenes have been synthe-
sized via halogen-metal exchange or oxidative addition
to dihalothiophenes, although regiospecific metalations
have been reported.6-8 Dihalothiophenes are commer-
cially available or can be prepared in good yields.9
The versatility of organoboron compounds in metal-
catalyzed coupling reactions has made arylboronic acids
or aryl boronates attractive nucleophiles.10 A number of
substituted aryl boronates have been synthesized by
metal-catalyzed borylations of substituted aryl halides
or triflates with dialkoxyhydroboranes11 or tetraalkoxy-
diboranes.12 These borylation reactions are compatible
with a wide range of functional groups, making these
methodologies useful for the preparation of functionalized
aryl boronates. However, only a few substituted thienyl
boronates have been synthesized by Pd(0)-catalyzed
Syn th esis of 2,3-Su bstitu ted Th ien ylbor on ic
Acid s a n d Ester s
Claus Christophersen,*,†,‡ Mikael Begtrup,‡
Søren Ebdrup,§ Henning Petersen,§ and Per Vedsø§
Novo Nordisk A/ S, Novo Alle´, DK-2880 Bagsværd, Denmark,
Department of Medicinal Chemistry, The Danish University
for Pharmaceutical Sciences, Universitetsparken 2,
DK-2200 Copenhagen N, Denmark, and Novo Nordisk A/ S,
Novo Nordisk Park, DK-2760 Måløv, Denmark
clcp@novonordisk.com
Received J une 27, 2003
Abstr a ct: A noncryogenic protocol for the synthesis of
2-substituted 3-thienylboronic acids and esters as well as
3-substituted 2-thienylboronic acids and esters has been
developed. Electrophiles were introduced regiospecifically in
the 2-position of 2,3-dibromothiophene and in the 3-position
of 2-bromo-3-iodothiophene by halogen-magnesium ex-
change followed by quenching with electrophiles. Palladium-
catalyzed borylation of the 2,3-substituted halothiophenes
with pinacolborane and P(t-Bu)3 as ligand for Pd produced
9 and 10. The borylation protocol was tolerated by a range
of functional groups; however, strongly electron-withdrawing
substituents decreased the stability of the thienylboronic
acids and esters.
Polyfunctionalized thiophenes are of interest in re-
search fields such as natural product synthesis,1 drug
design,2 and material science.3 Therefore, the ready
availability of suitable precursors such as disubstituted
thiophenes is of great importance. A number of methods
have been developed for the synthesis of disubstituted
thiophenes. In addition to ring-closure protocols,4 elec-
trophilic aromatic substitution,5 proton-metal exchange,6
(7) (a) Reinicke, M. G.; Pedaja, P. In The Chemistry of Heterocyclic
Compounds: Thiophene and Its Derivatives; Weissberger, A., Taylor,
E. C., Eds.; J ohn Wiley & Sons: New York, 1986; Vol. 44, Part 2, pp
159-522. (b) Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett.
1999, 40, 7449-7453. (c) Abarbri, M.; Thibonnet, L.; Be´rillon, F.;
Dehmel, F.; Rottla¨nder, M.; Knochel, P. J . Org. Chem. 2000, 65, 4618-
4638. (d) Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Lett.
2001, 42, 4841-4844.
(8) (a) Steinkopf, W.; Schmitt, H. F.; Friedler, H. J ustus Liebigs.
Ann. Chem. 1937, 527, 237-261. (b) Lawesson, S.-O. Arkiv Kemi 1957,
11, 337-343. (c) Gronowitz, S.; Petterson, K. J . Heterocycl. Chem. 1976,
13, 1099-1100. (d) Lawesson, S.-O. Arkiv Kemi 1957, 11, 317-324.
(e) Lawesson, S.-O. Arkiv Kemi 1957, 11, 325-336. (f) Kim, S.-H.;
Rieke, R. D. Tetrahedron Lett. 1997, 38, 993-996. (g) Rieke, R. D.;
Kim, S.-H.; Wu, X. J . Org. Chem. 1997, 62, 6921-6927.
† Novo Nordisk A/S, Novo Alle´.
‡ The Danish University for Pharmaceutical Sciences.
§ Novo Nordisk A/S, Novo Nordisk Park.
(1) (a) Bohlmann, F.; Zdero, C. In The Chemistry of Heterocyclic
Compounds: Thiophenes and Its Derivatives; Gronowitz, S., Ed.; J ohn
Wiley & Sons: New York, 1985; Vol. 44, Part 1, pp 261-323. (b) Pelkey,
E. T. Prog. Heterocycl. Chem. 1998, 10, 87-108.
(2) Press, J . B. In The Chemistry of Heterocyclic Compounds:
Thiophene and Its Derivatives; Gronowitz, S., Ed.; J ohn Wiley &
Sons: New York, 1991; Vol. 44, Part 4, pp 397-502. (b) Negwer
Nominum 2000, International Drug Directory; Swiss Pharmaceutical
Society, Ed.; Medpharm Scientific Publishers: Stuttgart, 2000.
(3) (a) Roncali, J . Chem. Rev. 1992, 92, 711-738. (b) Schopf, G.;
Koâmehl, G. In Advances in Polymer Science: Polythiophenes -
Electrically Conductive Polymers; Abel, A., Ed.; Springer-Verlag:
Berlin, Heidelberg, New York, 1997; Vol. 129.
(4) Weissberger, A.; Taylor, E. C. In The Chemistry of Heterocyclic
Compounds: Thiophene and Its Derivatives; Gronowitz, S., Ed.; J ohn
Wiley & Sons: New York, 1985; Vol. 44, Part 1, pp 1-213.
(5) Weissberger, A.; Taylor, E. C. In The Chemistry of Heterocyclic
Compounds: Thiophene and Its Derivatives; Gronowitz, S., Ed.; J ohn
Wiley & Sons: New York, 1986; Vol. 44, Part 2, pp 1-117.
(6) (a) Frejd, T. In The Chemistry of Heterocyclic Compounds:
Thiophene and Its Derivatives; Weissberger, A., Taylor, E. C., Eds.;
J ohn Wiley & Sons: New York, 1992; Vol. 44, Part 5, pp 257-754. (b)
Carpenter, A. J .; Chadwick, D. J . J . Chem. Soc., Perkin Trans. 1 1985,
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(9) The three isomeric dibromothiophenes are commercially avail-
able. 2-Bromo-3-iodothiophene can be prepared according to ref 8c.
2-Bromo-4-iodothiophene can be prepared according to: Gronowitz, S.;
Holm, B. Acta Chem. Scand. 1976, B30, 505-511. 3-Bromo-2-chloro-
thiophene can be prepared according to: Gronowitz, S.; Holm, B. Acta
Chem. Scand. 1976, B30, 423-429. 4-Bromo-2-chlorothiophene can be
prepared according to: Dettmeier, U.; Eichler, K.; Ku¨hlein, K.; Leupold,
E. I.; Litterer, H. Angew. Chem., Int. Ed. Engl. 1987, 26, 468-469.
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10.1021/jo034919n CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003
J . Org. Chem. 2003, 68, 9513-9516
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