crossover products in the Heck reaction has been examined
(Schemes 2 and 3).
Scheme 2. Retention and Crossover Heck Adducts from
4-Aryl-3-bromopyridinesa
Scheme 3. Heck Reactions of 2- and 4-Bromopyridines and
Other Biaryl Derivativesa
a Reagents and conditions: (a) H2CdCHCO2Et (3 equiv),
Pd(OAc)2 (0.1 equiv), (o-Tol)3P (0.2 equiv), NEt3 (5 equiv), MeCN,
125 °C (sealed tube), 20 h.
associated with biaryl derivatives has not been described
previously, although in a more general sense, processes
involving C-H activation6 are known to be associated with
Heck reaction conditions.7
Heck adducts 3a and 4a were formed in a 3:1 ratio, and
this raises a number of issues. First, what structural and/or
electronic factors determine the proportion of crossover
product generated? Second, can the migration pathway be
controlled and either suppressed or promoted? Although a
detailed mechanistic interpretation remains to be elucidated,
some of these questions have been addressed.
To examine the scope of this process, we have synthesized
a number of other biaryls, including the 4-aryl-3-bromopy-
ridines 1b and 1c (analogous to 1a). In addition, 2- and
4-bromopyridyl variants 5 and 10a/b have been prepared,
together with the series of simple substituted biaryl substrates
12a-c. These latter substrates incorporate an o-bromo moiety
but lack a heteroaryl component. The propensity of these
biaryl substrates to undergo Pd migration and to generate
a Reagents and conditions: (a) H2CdCHCO2Et (3 equiv),
Pd(OAc)2 (0.1 equiv), (o-Tol)3P (0.2 equiv), NEt3 (5 equiv), MeCN,
125 °C (sealed tube), 20 h.
It is clear that the crossover process, while the minor
pathway, is nevertheless general for 4-aryl-3-bromopyridines
(Scheme 2). Both 1b and 1c gave mixtures of retention and
crossover Heck products 3b/c and 4b/c, respectively. How-
ever, the proportion of crossover product increases as the
electron-withdrawing ability of the 4-aryl substitutent is
enhanced: R ) NO2 > H > OMe. Accordingly, the
4-nitrophenyl derivative 1a gave a 3:1 ratio (in favor of the
retention Heck product 3a), whereas 1b and 1c gave 7:1 and
10:1 ratios of 3b and 4b, and 3c and 4c, respectively.8
With 3-(4-nitrophenyl)-2-bromopyridine 5 (see Scheme 3),
neither retention nor crossover products 6 or 7a were
observed, but the reduced 2-alkyl product 8 was obtained in
9% yield. Reduction to give 3-(4-nitrophenyl)pyridine (9)
was the major pathway (29%), and a significant amount of
5 (59%) was recovered under the conditions used.9 Impor-
tantly, the formation of both Heck adducts 6 and 7 has been
achieved in a process that utilizes the crossover mechanism
(5) For a Heck reaction based on a simple biaryl, see: D´ıaz-Ortis, A.;
Prieto, P.; Vazquez, E. Synlett 1997, 269-270. By using 1a as a substrate
a variety of Heck conditions have been evaluated. Under Jeffrey conditions
[1a (1 equiv), Pd(OAc)2 (0.1 equiv), n-Bu4NI (2 equiv), NaOAc (5.5 eqiv),
ethyl acrylate (1.6 equiv), DMF, 100 °C, 4.5 days under N2] we observed
a small increase in crossover and obtained a 3:2 ratio of 3a and 4a. Under
either aqueous or strictly anhydrous conditions, we observed slow reactions,
and use of CsOAc or EtNi-Pr2 under our conditions gave no crossover
product.
(6) Ryabov, A. D. Chem. ReV. 1990, 90, 403-424. Dyker, G. Chem.
Ber. 1997, 130, 1567-1578. Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
1699-1712. Jia, C. G.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001,
34, 633-639. For insertion into aryl C-H via electrophilic substitution,
see: Markies, B. A.; Wijkens, P.; Kooijman, H.; Spek, A. L.; Boersma, J.;
van Koten G. J. Chem. Soc., Chem. Commun. 1992, 1420-1423. For the
effect of substituents on the rate of C-H, see: Catellani, M.; Chiusoli, G.
P. J. Organomet. Chem. 1992, 425, 151-154.
(7) de Meijere, A.; Bra¨se, S. J. Organomet. Chem. 1999, 576, 88-110.
Larock, R. C. J. Organomet. Chem. 1999, 576, 111-124. Ca´mpora, J.;
Lo´pez, J. A.; Palma, P.; Valerga, P.; Spillner, E.; Carmona, E. Angew.
Chem., Int. Ed. 1999, 38, 147-151. Catellani, M.; Motti, E.; Paterlini, L.;
Bocelli, G.; Righi, L. J. Organomet. Chem. 1999, 580, 191-196. Catellani,
M.; Motti, E.; Paterlini, L. J. Organomet. Chem. 2000, 594, 240-244.
Catellani, M.; Motti, E.; Baratta, S. Org. Lett. 2001, 3, 3611-3614. C-H
Activation via ortho-palladation has been used to mediate the Heck
reaction: Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586-1587.
(8) Intervention of the crossover pathway is not simply a function of
the alkene component, and reaction of 1a with styrene led to the
corresponding retention and crossover products in a 3:1 ratio.
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Org. Lett., Vol. 4, No. 18, 2002