yield (entry 8). Another example of the beneficial effect of
Zn(OAc)2 was observed in the reaction of 2-(methylthio)-
pyrazine (entry 10). Under the standard conditions in the
presence of 4% of Pd catalyst and 1.2 equiv of copper
carboxylate, reaction of 2-(methylthio)pyrazine with 3,4-
methylenedioxyphenylboronic acid returned the starting
thioether unchanged. However, addition of 1.2 equiv of Zn-
(OAc)2 to the reaction mixture led to formation of the desired
product in 64% yield.
Table 1. Heteroaryl Thioether-Boronic Acid Cross-Couplinga
Presumably, the Zn(OAc)2 may function to tie up basic
nitrogen atoms that potentially interfere with the reaction
system. In the case of 3-pyridylboronic acid, which appar-
ently exists in a zwitterionic form, Zn(OAc)2 could bind to
the 3-pyridinyl nitrogen and prevent deprotonation of the
boronic acid. The latter is known to interfere with CuI
carboxylate-mediated thiol ester-boronic acid coupling.6 Zn-
(OAc)2 was also effective in the case of the 2-(methylmer-
capto)pyrazine (entry 10), perhaps by tying up the pyrazine
4-nitrogen and preventing it from interfering with catalysis
(by coordination of Cu(I) or by deprotonation of the boronic
acid).
In contrast to 2-(methylthio)pyrazine (entry 10, Table 1),
2-bromopyrazine did not react with boronic acids under the
current reaction conditions. Similarly, while 2-methylthio-
3-nitropyridine easily reacted with 3,4-dimethoxyphenylbo-
ronic acid giving the desired coupling product in 87% yield
(entry 3, Table 1), the 2-chloro derivative provided only
traces of product under the same conditions. Conversely, no
reaction was observed (starting material was recovered) when
heterocyclic thioethers were subjected to typical Suzuki-
Miyaura reaction conditions (2-methylthiobenzothiazole, 2%
Pd(PPh3)4, K2CO3, dioxane, 60 °C, 18 h). This comparison
underscores the difference between the Suzuki-Miyaura
protocol and the base-free CuTC-mediated reaction system
described here. In accord with previously reported observa-
tions,6 addition of halides (NaI, LiBr, LiCl, NaCl, Bu4NBr)
to the CuTC-mediated process had a negative impact on the
reaction outcome, stopping the reaction even when sub-
stoichiometric amounts were used.
Simple aryl thioethers showed limited reactivity in the
current cross-coupling system: only those with electron-
withdrawing substituents provided cross-coupling products,
and only in low yields. Suspecting a sluggish oxidative
addition to palladium by the relatively electron-rich aryl
thioethers (in contrast to the more electron-deficient het-
eroaryl thioethers), nickel catalysts were explored. Unfor-
tunately, although a low-valent nickel catalyst is competent
at oxidative addition to aromatic thioethers,8 simply switching
from a palladium to a nickel catalyst did not solve the
reactivity problem for the boronic acid-aromatic thioether
coupling.
Comparison of the cross-coupling of thioorganic substrates
using the current palladium-catalyzed, nonnucleophilic, base-
free boronic acid system with that using the more potent
organomagnesium9 and -zinc10 reagents in either a nickel-
or palladium-catalyzed protocol is appropriate. The success
a Thioether (0.50 mmol), boronic acid (0.55 mmol), Pd catalyst, CuTC,
and, where indicated, Zn(OAc)2 were placed in reaction vessel. After
flushing with argon, THF was added and the reaction mixture was stirred
at 50 °C for 18 h. b 4% Pd2dba3-16% TFP, 1.3 equiv of CuTC. c 1%
Pd2dba3-8% TFP, 1.2 equiv of CuTC, 1.2 equiv of Zn(OAc)2.
examples in entries 6 and 9 also benefited from the use of
the thioglycolamide pendant. The modifiable leaving group
feature of this system suggests possible applications ranging
from solid support-based reagents to pendant-driven substrate
recognition.
Zn(OAc)2 was an essential additive in some cases. For
example, treatment of 2-(methylthio)benzothiazole with
3-pyridylboronic acid, 1.6 equiv of CuTC, and 5% of Pd
catalyst in THF at 50 °C yielded only starting material.
Fortunately, the addition of Zn(OAc)2 (1.2 equiv) to the
reaction mixture dramatically changed the reaction outcome;
the desired cross-coupling product was generated in 53%
(8) Osakada, K.; Maeda, M.; Nakamura, Y.; Yamamoto, T.; Yamamoto,
A. J. Chem. Soc., Chem. Commun. 1986, 442-443.
980
Org. Lett., Vol. 4, No. 6, 2002