Pd(PPh3)4 was found to be an efficient catalyst in the
coupling of a number of electron deficient aryl bromides.
Ester (1a), cyano (1b), sulfonamide (1d), and formyl (1g)
substituted aryl bromides were all coupled in 1 h to give the
corresponding methylene-linked compounds in respectable
yields (Table 1, entries 1, 3, 6, and 10 respectively). Applying
the same reaction conditions to 4-chlorobenzonitrile 1c,
however, failed to give any product even after heating at 60
°C for 16 h. This prompted us to screen a range of palladium
sources. Briefly, combining Pd(OAc)2 with the recently
described SPhos (2-(dicyclohexylphosphino) dimethoxybi-
phenyl) ligand4 proved to be a superior system for Suzuki-
Miyaura coupling of B-benzyl-9-BBN to a wide range of
aryl halides. The latter were readily varied in terms of their
electronic and steric properties without detriment to the
coupling reaction. Anhydrous conditions were found to be
best with this Pd(OAc)2/SPhos system.
Table 2. Palladium-Catalyzed Coupling of Deactivated/
Sterically Hindered Aryl Halides/Triflates with
B-Benzyl-9-borabicyclo[3.3.1]nonane*
Pleasingly, 4-chlorobenzonitrile 1c was now coupled in 1
h to give the methylene-linked biphenyl using SPhos (4 mol
%) and Pd(OAc)2 (2 mol %) as the catalyst system. An
improved yield of the product 2c (89%) was obtained when
the catalyst loading was slightly increased (Table 1, entry
5). In general, the reactions were cleaner and yields improved
on using the more activated ligand system (Table 1, cf.
entries 1 and 2 and also entries 6 and 7).
In some cases, longer reaction times were required for
complete conversion of the aryl chloride compared to the
corresponding bromide (Table 1, entries 8 and 9). As can
be seen a range of functional groups (ester, formyl, sulfona-
mide, cyano) are well tolerated in the aryl halide coupling
partner. A number of heterocyclic halides were also suc-
cessfully derivatized to their benzyl-substituted analogues
(Table 1, entries 13 and 14).
The coupling reaction could also be carried out on ortho-
substituted sterically hindered substrates (Table 2, entries 1
and 2). Although reaction times were longer (16-18 h at
60 °C), this could be reduced by increasing the reaction
temperature as for the triisopropyl substituted aryl bromide
1n (Table 2, entry 3).
As can be seen from Table 2, electron-rich, and as such
deactivated, aryl halides can also be converted to the
methylene-linked diphenyls using this protocol. For example,
4-bromophenol (1o) was found to undergo the coupling
reaction in 2.5 h and gave the desired product (2l) in 83%
yield. Similarly, a methoxy substituent, on the aryl halide,
is well tolerated when it is para (Table 2, entry 5). A lower
yield results when the aryl bromide is ortho-substituted with
this group (Table 2, entry 8). Comparing the corresponding
bromide, chloride and triflate anisole (1p, 1q, 1r, respec-
tively), it was noted that the triflate has a much shorter
*Reaction conditions: (A) 1.0 equiv of aryl halide, 2.0 equiv of B-benzyl-
9-BBN, 3.0 equiv of K3PO4, cat. 4 mol % of Pd(PPh3)4, DMF, 1 mL of
water, 60 °C; (B) as in A but cat. 2 mol % of Pd(OAc)2 and 4 mol % of
SPhos ligand, anhydrous conditions. a Isolated yield. b Reaction carried out
at 100 °C. c 3 mol % of Pd(OAc)2 and 6 mol % of SPhos ligand used.
d THF was used as solvent.
coupling time (1 h vs 16 h for the bromide/chloride) and
gives a comparable yield to the bromide. As before,
increasing the temperature, to 100 °C, gave shorter reaction
times even for the sterically hindered, electron-rich aryl
bromide 1t which was coupled in excellent yield (80%, Table
2, entry 9).
As outlined below (Scheme 2), the benzylation reaction
was used to synthesize naturally occurring 2,4-bis(4-hy-
droxybenzyl)phenol14 (5) in two steps from commercially
available 2,4-dibromoanisole. Thus, dibenzylation of the
unactivated bisbromide (3) was achieved in a resonable yield
(13) General Procedure. K3PO4 (3 equiv) was added to the catalyst
Pd(PPh3)4 or Pd(OAc)2 and SPhos in THF or DMF (3 mL/mmol). When
Pd(PPh3)4 was used, H2O (1 mL/mmol) was added. The aryl halide/triflate
(1 equiv) was subsequently added along with the B-benzyl-9-BBN (2 equiv
of a 0.5 M solution in THF). The resulting mixture was heated with stirring
in a sealed tube until the reaction had reached completion, as judged by
LC/MS. The crude mixture was diluted with EtOAc, the organics washed
with 2 M NaOH, brine, dried (MgSO4) and concentrated in vacuo to yield
the crude product. Purification was carried out on silica gel using pentane/
ethyl acetate to give the desired methylene-linked biaryl product.
(14) Noda, N.; Kobayashi, Y.; Miyahara, K.; Fukahori, S. Phytochemistry
1995, 39, 1247-1248.
Org. Lett., Vol. 7, No. 22, 2005
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Flaherty, Alice
