Pd-Catalyzed Aryl-Aryl Cross-Coupling Reaction
TABLE 2. Palladium-Catalyzed Cross-Coupling Reaction of
ortho-Fluorinated Triarylindium Organometallics with Aryl
Electrophilesa
SCHEME 2
coupling compounds 15a and 16a in good yields, 74 and 86%,
respectively (Table 1, entries 11 and 13). Remarkably, the results
obtained in the synthesis of heterobiaryls improved the previ-
ously reported synthesis using other organometalics.9 This set
of results demonstrates the important synthetic utility of indium
reagents and their high efficiency in the directed ortho-
metallation-transmetallation-cross-coupling nexus.
In a new step forward, taking advantage of the different
groups that can be used in the directed ortho-metallation, we
extended our methodology to other substituted arenes. For this
purpose, we tried the O-aryl carbamate functionality, which can
act not only as DMG but also as a leaving group in nickel-
catalyzed cross-coupling reactions with Grignard reagents.10
Under the previous experimental conditions, the ortho-metal-
lation and transmetallation sequence with the O-arylcarbamate
2 also proceeded cleanly, and the palladium-catalyzed cross-
coupling reactions with all the electrophiles tested before gave
the corresponding aryl-aryl and aryl-heteroaryl coupling
products in good to excellent yields (70-99%, Table 1, entries
2, 4, 6, 8, 10, 12, and 14).
a Reactions were performed using 0.4 equiv of R3In and 1 equiv of
Ar′-X. PMDTA: N,N,N′,N′,N′′-pentamethyldiethylenetriamine. b Isolated
yield.
TMEDA (1.2 equiv), followed by transmetallation to indium
by the addition of InCl3 (0.4 equiv), and reaction with
4-iodotoluene (3, 1 equiv), in the presence of Pd(PPh3)2Cl2 (4%)
as catalyst, afforded the ortho-substituted biaryl product 10a in
58% yield after 4 h. Optimizing the reaction conditions, we
observed that the use of other palladium catalysts such as Pd-
(PPh3)4 gave similar yields, but interestingly, the reaction in
the presence of Pd(dppf)Cl2 (4%) improved the yield up to 96%
in just 1 h (Table 1, entry 1). In this process, the high efficiency
of the transmetallation step together with the relatively mild
reaction conditions (THF, reflux), short reaction times, and high
atom economy are noteworthy since the three methoxyphenyl
groups attached to the indium were transferred.
After this encouraging result, the previous optimized reaction
conditions were applied to other organic electrophiles. To our
delight, we observed that tri-(2-methoxyphenyl)indium reacted
chemoselectively with 4-bromoacetophenone (4a), providing the
ortho-substituted biphenyl 11a in 88% yield within 1 h (Table
1, entry 3). A similar yield was obtained using aryl triflate 4b
as electrophile (85%).
One of the most important challenges in the aryl-aryl cross-
coupling reaction is the use of heteroaryls either as nucleophiles
or as electrophiles. For this reason, we studied the reactivity of
tri-(2-methoxyphenyl)indium with electron-deficient aromatic
heterocycles such as halopyridines or haloquinolines. Thus, the
cross-coupling reaction of tri-(2-methoxyphenyl)indium with
2-bromo-5-nitropyridine (5), 3-bromopyridine (6), and 3-bro-
moquinoline (7) gave the corresponding cross-coupling products
12a (78%), 13a (81%), and 14a (91%), respectively, in good
yields (Table 1, entries 5, 7, and 9). In addition, the cross-
coupling reaction of the same triorganoindium reagent with
electron-rich heterocyclic halides, such as 2-bromothiophene (8)
or 2-bromothiazole (9), also provided the aryl-heteroaryl
As a directing metallation group, we also employed the fluoro
group in benzene derivatives. The regioselective metallation of
1-fluoro-4-methoxybenzene (17a) under Schlosser’s condi-
tions,11 in the ortho-position to the fluorine atom,12 followed
by transmetallation to indium, and palladium-catalyzed cross-
coupling with the aryl halides 3 and 4a and triflate 4b, afforded
the corresponding fluorobiaryls 18 and 19 in excellent yields
(87-94%, Table 2, entries 1-3). In addition, the regioselective
metallation of 1-fluoro-2-methoxybenzene (17b), in the ortho-
position to the fluorine atom,12 under the same conditions as
before, followed by transmetallation to indium and palladium-
catalyzed cross-coupling with aryl iodide 3, aryl bromide 4a,
or aryl triflate 4b, afforded the corresponding fluorobiaryls 20
and 21 in high yields (88-96%, Table 2, entries 4-6).
The excellent results obtained in the cross-coupling reactions
of ortho-substituted arylindium organometallics with aryl and
heteroaryl electrophiles led us to extend the scope of these
reactions by studying their reactivity with nonaromatic elec-
trophiles such as vinyl triflates, which are useful electrophiles
(9) (a) Sonesson, C.; Lindborg, J. Tetrahedron Lett. 1994, 35, 9063-
9066. (b) Mongin, F.; Mojovic, L.; Guillamet, B.; Tre´court, F.; Que´guiner,
G. J. Org. Chem. 2002, 67, 8991-8994. (c) Ishikura, M.; Oda, I.; Terashima,
M. Heterocycles 1985, 23, 2375-2386. (d) Xia, M.; Chen, Z.-C. Synth.
Commun. 1999, 29, 2457-2465. (e) Jensen, J.; Skjaerbaek, N.; Vedso, P.
Synthesis 2001, 128-134.
(10) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V.
J. Org. Chem. 1992, 57, 4066-4068.
(11) Katsoulos, G.; Takagishi, S.; Schlosser, M. Synlett 1991, 731-732.
(12) The regioselectivity in the metallation of 17a and 17b was confirmed
by reaction of the metallated species with CO2. For further details, see the
Supporting Information.
J. Org. Chem, Vol. 72, No. 4, 2007 1273