Palladium catalyzed ligand-free Suzuki cross-coupling reactions of benzylic halides with aryl boronic acids under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2004.07.073

A highly efficient Suzuki cross-coupling reaction between benzylic halides and aryl boronic acids using palladium chloride as catalyst in acetone:water (3:1) has been developed. High yields of products, mild reaction conditions and short reaction times in the absence of ligand are important features of this method. A highly efficient Suzuki cross-coupling reaction between benzylic halides and aryl boronic acids using palladium chloride as catalyst in acetone:water (3:1) as the solvent system has been developed. High yields of products, mild reaction conditions and short reaction times in the absence of ligand are important features of this method.

Full text of DOI:10.1016/j.tetlet.2004.07.073

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6959–6962
Palladium catalyzed ligand-free Suzuki cross-coupling reactions of
benzylic halides with aryl boronic acids under mild conditions
B. P. Bandgar,* Sampada V. Bettigeri and Jaywant Phopase
Organic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand Teerth Marathwada University,
Vishnupuri, Nanded 431 606, India
Received 29 April 2004; revised 7 July 2004; accepted 16 July 2004
Available online 10 August 2004
Abstract—A highly efficient Suzuki cross-coupling reaction between benzylic halides and aryl boronic acids using palladium chloride
as catalyst in acetone:water (3:1) as the solvent system has been developed. High yields of products, mild reaction conditions and
short reaction times in the absence of ligand are important features of this method.
Ó 2004 Elsevier Ltd. All rights reserved.
The palladium catalyzed Suzuki–Miyaura cross-cou-
pling reaction1 between aryl boronic acids and aryl
halides or triflates has proved to be a very popular
and versatile method for forming the carbon–carbon
single bonds of biaryls.2 Diarylmethane derivatives are
important building blocks in organic synthesis because
of their industrial applications. Organoboron reagents
exhibit greater functional group compatibility than
organozinc or Grignard reagents. Moreover, the innoc-
uous nature of boronic acids, which are generally non-
toxic and thermally air- and moisture-stable, is a
practical advantage of the Suzuki reaction relative to
other coupling processes. However, the procedure gen-
erally suffers from high catalyst loading due to the fast
decomposition of the catalyst. In recent years, several
thermally stable palladium catalysts have been success-
fully used for the Suzuki reaction,3 but most of the
results, which have been described with these catalysts
were obtained for the coupling of aryl halides. With
these catalysts, relatively few results have been reported
for the coupling of benzylic halides.4–6 Most of the
results described involve drastic conditions, specific
ligands4–6 and popular but unstable catalysts.5,6
anes via the corresponding benzylzinc bromides or ben-
zylmagnesium chlorides with aryl bromides or iodides.7
There are other instances in which Pd(0)-catalyzed cou-
plings of benzylic halides under Stille-type conditions
have been reported.8 Bransdsma and co-workers9 evalu-
ated benzyl–aryl cross-couplings for the synthesis of
various tetrachlorobenzyltoluenes using four different
transition metal catalysts with a number of different aryl
metal compounds. However, they did not employ Su-
zuki–Miyaura conditions. Longer reaction times (20–
48h), drastic conditions (130°C) and low yields are the
disadvantages associated with some of the reported
methods involving Suzuki cross-coupling reactions. In
this communication, we report ligand-free palladium
catalyzed cross-coupling reactions of aryl boronic acids
with benzyl halides in acetone:water (3:1) as the solvent
system at room temperature (Scheme 1).
The catalytic study (Table 1) showed that in the absence
of catalyst, there was no reaction even after stirring the
reaction mixture for 24h and benzyl iodide was quanti-
tatively recovered. Formation of a trace amount of the
corresponding diphenylmethane was observed when
the reaction was performed in the presence of 0.56 and
0.81mol% of PdCl2 as catalyst. Moderate yields (54%
and 66%) of the diphenylmethane were obtained in the
presence of 1.12 and 1.40mol% of PdCl2. However, with
1.69mol% of PdCl2 the reaction was complete in a short
time (0.8h) and an excellent yield of diphenylmethane
was obtained (97%). It is important to note that when
the amount of catalyst is increased from 1.69 to 2.25
or 2.82mol%, the yield of the product did not improve
Negishi and co-workers had earlier reported Pd(0)- and
Ni(0)-catalyzed syntheses of unsymmetrical diarylmeth-
Keywords: Suzuki cross-coupling reactions; Catalyst; Aryl boronic
acids; Benzylic halides; Diarylmethanes.
*
Corresponding author. Tel.: +91-2462-229242/3; fax: +91-2462-
229245; e-mail: bandgar_bp@yahoo.com
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.073

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B. P. Bandgar et al. / Tetrahedron Letters 45 (2004) 6959–6962
B(OH)2
X
PdCl2 (1.69 mol%), r.t.
+
acetone:water (3:1)
R1
R2
R1= H, OMe, OCH2Ph, R2
R1
R2
= H, NO , F, Cl Br, I
,
X = Cl, Br, I
,
2
Scheme 1.
Table 1. Catalytic study of Suzuki cross-coupling reactions between
benzene boronic acids (1mmol) and benzyl iodide (1mmol)
Applying the optimized conditions, we studied the
Suzuki cross-coupling reaction of benzyl bromide with
phenyl boronic acid, which furnished an excellent yield
of diphenylmethane 2a (95%) in 2.5h (Table 2, entry
1). However, the coupling reaction of benzyl iodide with
phenyl boronic acid gave a better yield (97%) in a short-
er reaction time (0.8h) (entry 2). There was no coupling
reaction between benzyl chloride and phenyl boronic
acid even after stirring the reaction mixture for 24h
(entry 20). Next, the coupling reaction was examined
with several substituted benzyl bromides and substituted
aryl boronic acids in the presence of catalyst (Table 2).
Even o-xylene and p-xylene dibromides underwent
smooth Suzuki cross-couplings giving good to excellent
yields of products, although, longer reaction times were
required for the coupling of these dibromides with vari-
Entry
Catalyst, PdCl2
(mol%)
Reaction time
(h)
Yield
(%)
1
0
24––
24––
24––
2
0.56
0.81
24
3
41.12
54
5
6
7
8
9
1.40
1.69
2.25
2.25
2.82
24
66
97
96
0.8
0.8
2496
2496
even after stirring the reaction mixture for 24h (Table 1,
entries 7 and 8).
Table 2. Palladium catalyzed Suzuki cross-coupling reactions of aryl boronic acids with benzyl halides
Entry
Benzyl halide
Borornic acid
Product
Time (h)
2.5
Yielda (%)
95
(HO)2B
Br
1
2a
(HO)2B
I
2
3
4
0.8
97
2a
(HO)2B
(HO)2B
Br
Br
2.494
3.0
O2N
O2N
O2N
2b
92
95
O2N
2c
OMe
OMe
(HO)2B
(HO)2B
Br
5
6
2.0
4.0
O2N
OCH2Ph
O2N
OCH2Ph
2d
Br
85
84
Br
Br
2e
2f
OMe
(HO)2B
7
4.5
OMe
OMe
Br
Br
OCH2Ph
(HO)2B
(HO)2B
8
9
6.0
7.0
75
80
OCH2Ph
OCH2Ph
Br
2g
2h
Br
Br

B. P. Bandgar et al. / Tetrahedron Letters 45 (2004) 6959–6962
6961
Table 2 (continued)
Entry
Benzyl halide
Borornic acid
Product
Time (h)
10.0
Yielda (%)
OMe
OMe
(HO)2B
Br
Br
10
70
67
OMe
2i
2j
OCH2Ph
OCH2Ph
(HO)2B
Br
Br
11
15.0
OCH2Ph
(HO)2B
(HO)2B
Br
Br
Br
12
13
14
3.0
3.0
3.5
87
90
85
Cl
Cl
Cl
Cl
2k
Cl
OMe
OMe
2l
(HO)2B
Cl
2m
OCH2Ph
OCH2Ph
(HO)2B
(HO)2B
Br
15
16
17
18
19
20
21
3.0
1.0
91
93
94
88
92
F
2n
F
Br
Br
3a
Br
I
(HO)2B
(HO)2B
Br
0.5
Br
3a
OMe
Br
Br
1.25
1.5
Br
Br
Br
OMe
3b
(HO)2B
OCH2Ph
Br
OCH2Ph
3c
(HO)2B
(HO)2B
Cl
24N.R.
24N.R.
(CH2)3CH3
CH3(CH2)3Br
N.R.: No reaction.
a Yields of isolated, pure products.
ous aryl boronic acids (Table 2, entries 6–11). It is inter-
esting to note that benzyl bromides and iodides under-
went smooth coupling with aryl boronic acids whereas
halogens such F and Cl present on the aromatic ring re-
mained unaffected (Table 2, entries 12–15). However,
aromatic bromides and iodides underwent the Suzuki
cross-coupling reaction selectively in the presence of
benzyl bromides (Table 2, entries 16–19). Attempts to
react alkyl bromides with aryl boronic acids did not af-
ford any trace of the cross-coupled product even after
stirring the reaction mixture for 24h.
was stirred at room temperature until the reaction mix-
ture became homogeneous. Then, the mixture was
cooled in an ice bath and PdCl2 (3mg, 1.69mol%) was
added at 0°C under a nitrogen atmosphere. Stirring
was continued at room temperature until completion
of the reaction (TLC). The solvent was removed under
reduced pressure and the product was extracted with
diethyl ether. Removal of the solvent under vacuum fur-
nished a crude product, which was further purified by
column chromatography using silica gel and 100%
petroleum ether.
In conclusion, we have developed a highly efficient
method for the synthesis of diarylmethanes using a lig-
and-free Suzuki cross-coupling reaction.
2b: mp: 80°C; IR (KBr, neat): 854, 1103, 1407,
1535, 1608, 2855, 2922cmÀ1 1H NMR (300MHz,
;
CDCl3):
d 3.8 (s, 2H, Ar–CH2), 7.5 (d, 2H,
J = 8.6Hz, Ar–H), 7.8–7.9 (m, 5H, Ar–H), 8.2 (d, 2H,
J = 8.6Hz, Ar–H). Anal. Calcd for C13H11NO2: C,
73.22; N, 6.56; H, 5.19. Found: C, 73.09; N, 6.50; H,
5.19.
Typical procedure: A mixture of phenyl boronic acid
(1mmol), potassium carbonate (2.5mmol), 4-nitro-
benzyl iodide (1mmol) in acetone–water (3:1, 10mL)

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B. P. Bandgar et al. / Tetrahedron Letters 45 (2004) 6959–6962
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2004.07.073.
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