Our initial studies were focused on a search for optimal
reaction conditions including reaction temperature, solvent,
and nickel precursors for the arylation of benzaldehyde (1a)
with 4-bromoanisole (2a), producing diarylcarbinol 3a. The
reaction temperature is important for the selectivity and yield.
At refluxing temperature of THF, the arylation reaction is
slow, giving 3a in 52% yield. Significant amount of pinacol
5 (22%) was formed via the reductive homo coupling of
benzaldehyde. At 110 °C the yield of 5 decreased greatly
and diarylcarbinol 3a in 67% yield was obtained. In addition,
a new product, diaryl ketone 6 in 23% yield, was formed.
The optimum temperature with respect to selectivity and
yield was ca. 75 °C.
(diphenylphosphino)ethane (dppe) ligand provided clean
chemistry with 4-bromoanisole at 75 °C, giving 91% of 3a.
Nitrogen-containing ligands, 2,2′-bipyridyl and 1,10-phenan-
throline, did not give any expected product; however,
bisoxazoline 48 provided 3a in 82% yield although no
chirality was observed (entry 16). Solvents also play a crucial
role in the reaction. The use of highly polar solvents, DMF
and acetonitrile, caused low yields along with several
byproducts (entries 11-12). In a low polarity solvent, 1,2-
dichloroethane or toluene, the reaction was incomplete even
after 48 h and gave poor yields (entries 13 and 15). An ether-
type solvent is most suitable for this nickel-catalyzed
reaction. The reaction afforded 3a in 56% yield in 1,2-
dimethoxyethane and 91% in THF (entries 10 and 14).
The catalytic arylation also nicely applied to a set of aryl
bromides and aldehydes. As shown in Table 2, 4-bromoani-
sole and 4-bromotoluene reacted smoothly with benzaldehyde
to give the corresponding diarylcarbinols in high yields.9 Aryl
bromides with Cl, MeCONH-, MeCO- substituents reacted
with benzaldehyde slowly and afforded low yields of the
corresponding diarylcarbinol 3 (entries 9-11). 4-Nitrobromo-
benzene and 4-cyanobromobenzene did not give any aryla-
tion product. The position of substituent on aryl bromide
influences greatly the yield of the reaction. Ortho-substituted
aryl bromides are generally less reactive and give lower
yields of diarylcarbinols than the corresponding para-
substituted ones (entries 1 and 8). An ortho effect was
markedly observed in the case of 2-bromo-m-xylene and
2-bromomesitylene; no arylation product was detected even
after 48 h.
The nature of phosphine ligands influences drastically the
rate of reaction and product yields (Table 1). Several
Table 1. Reaction of 4-bromoanisole with Benzaldehyde under
Various Conditionsa
entry
catalyst
solvent
isolated yield (%)
In contrast to the behavior of aryl bromides, electron-
donating substituents on the aromatic ring of aldehydes
reduces the yields of diarylcarbinol 3, while electron-
withdrawing groups favor formation of these products. The
reaction of 4-methoxybenzaldehyde with 4-bromoanisole
gives product 3c in 57% yield. When 2,4-dimethoxybenzal-
dehyde was treated with 4-bromoanisole, the corresponding
carbinol 3l was isolated in only 12% and no arylation product
was detected when 3,4,5-trimethoxybenzaldehyde was used.
On the other hand, the reaction of 4-cyanobenzadehyde and
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
no
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
DMF
toluene
DME
DCE
THF
0
Ni(PPh3)2Br2
Ni(PnBu3)2Br2
Ni(PPh2Me)Br2
Ni(BINAP)Cl2
Ni(BINAP)Br2
Ni(dppp)Br2
Ni(chiraphos)Br2
Ni(dppb)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
trace
0
0
0
8
22
32
18
91
43
38
6
56
8
82
(5) Reviews: (a) Cintas, P. Synthesis 1992, 248. (b) Saccomano, N. A.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 1, pp 173-209. Synthesis of natural
products: (a) Kishi, Y. Pure Appl. Chem. 1992, 64, 343. (b) Nicolaou, K.
C.; Sorensen, E. J. Classics in Total Synthesis; VCH Publishers Inc.:
Weinheim, 1996; pp 712-717 and references therein.
(6) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281. (b) Furstner, A.; Shi, N. J. Am. Chem.
Soc. 1996, 118, 12349.
Ni(dppe)Br2
Ni(bisoxazoline)Br2
a Reactions of 4-bromoanisole (1.25 mmol) with benzaldehyde (1.00
mmol) were carried out at 75 °C for 48 h in 4 mL of solvent by using 10
mol % of Ni-catalysts and Zn (2.75 mmol). Isolated yields are based on
benzaldehyde used.
(7) Grigg, R.; Putnikovic, B.; Urch, C. J. Tetrahedron Lett. 1997, 38,
6307.
(8) Honda, Y.; Date, T.; Hiramatsu, H.; Yamauchi, M. Chem. Commun.
1997, 1411.
(9) General procedure for the arylation of aldehydes: Ni(dppe)Br2
(62 mg, 0.1 mmol) and Zn (180 mg, 2.75 mmol) were placed in a screw-
capped vial. The vial was sealed with septum and flashed several times
with N2. 4-Bromoanisole (234 mg, 1.25 mmol), benzaldehyde (106 mg,
1.0 mmol), and THF (4 mL) were added to the reaction mixture via syringe.
The septum was removed, and the vial was sealed with a screw cap quickly
under N2. The reaction mixture was stirred at 75 °C for 24 h. The crude
reaction mixture was diluted with ether, filtered through a thin Celite pad,
and washed several times with ether. The solution was concentrated in
vacuo. The residue was chromatographed on a silica gel column (hexane/
EtOAc ) 85/15) to give 195 mg (91%) of 3a.
monodentate phosphine complexes, Ni(PPh3)2Br2, Ni(Pn-
Bu3)2Br2, Ni(PPh2Me)2Br2, and Ni(PCy3)2Br2, were tested as
catalysts for the reaction. Either no arylation product or a
trace of 3a was detected using these nickel complexes. In
contrast, the reaction was efficiently catalyzed by nickel(II)
complexes bearing a bidentate phosphine ligand, such as Ni-
(dppp)Br2, Ni(dppb)Br2, Ni(chiraphos)Br2, and Ni(dppe)Br2
(Table 1, entries 7-15). The catalyst containing 1,2-bis-
2296
Org. Lett., Vol. 2, No. 15, 2000