Cross-coupling of benzylic acetates with arylboronic acids: One-pot transformation of benzylic alcohols to diarylmethanes

Article abstract of DOI:10.1039/b513372f

Benzylic acetates reacted with arylboronic acids in the presence of a DPEphos-[Pd(η³-C₃H₅)Cl]₂ catalyst when tert-amyl alcohol was used as a solvent, and the catalytic cross-couplings produced diarylmethanes in high yields (up to 94% isolated yield). The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b513372f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Cross-coupling of benzylic acetates with arylboronic acids: one-pot
transformation of benzylic alcohols to diarylmethanes{
Ryoichi Kuwano* and Masashi Yokogi
Received (in Cambridge, UK) 21st September 2005, Accepted 11th October 2005
First published as an Advance Article on the web 26th October 2005
DOI: 10.1039/b513372f
Benzylic acetates reacted with arylboronic acids in the presence
3
an alkoxide, benzylic acetates may be employed as an electrophilic
substrate. Based on this hypothesis, we attempted the reaction of
benzylic acetates with phenylboronic acid in alcoholic solvents. A
large amount of alcohol was expected to allow ligand exchange
between the acetate and the alkoxide on the palladium catalyst.
Various organic solvents were evaluated for the reaction of
anisyl acetate (4a) with phenylboronic acid (2a) at 80 uC in the
presence of 5 mol% DPPPent–palladium (Table 1). The consump-
tion of 4a was scarcely observed in either aprotic DMF or dioxane
solvent (entries 1 and 2). The use of methanol resulted in the
solvolysis of 4a and did not yield diarylmethane 3a (entry 3).
Isopropyl alcohol caused the palladium catalyst to decompose into
a black suspension (entry 4). Cross-coupling product 3a was
obtained successfully from the reaction using a tertiary alcohol
without the undesired solvolysis. tert-Amyl alcohol was the solvent
of our choice because it is liquid at room temperature (entry 5). In
a further evaluation of various palladium catalyst precursors,
ligands, and bases, the cross-coupling of 4a with 2a was found to
3 5 2
of a DPEphos–[Pd(g -C H )Cl] catalyst when tert-amyl
alcohol was used as a solvent, and the catalytic cross-couplings
produced diarylmethanes in high yields (up to 94% isolated
yield).
In organic synthesis, a basic method of C–C bond formation is the
palladium-catalysed cross-couplings of organohalides with orga-
1,2
nometallic compounds. The cross-coupling of benzylic halides
3–5
with aryl metal compounds yields diarylmethane skeletons,
which are often found in pharmacologically interesting com-
6
7
pounds and supramolecules. However, the use of benzylic cross-
coupling has been limited in organic synthesis because benzylic
halides are sometimes lachrymatory and are not always stable.
Recently, we reported the cross-coupling of benzylic carbonates
8
with arylboronic acids 2 (Scheme 1). The reaction proceeded
1
successfully in DMF with a DPPPent–palladium catalyst.
However, the optimal reaction conditions failed to trigger the
reaction of benzylic acetates 4, which were more accessible than
carbonates 1. The mechanism shown in Scheme 1 had been
proposed for the catalytic reaction. We assumed that the alkoxide
in intermediate A was advantageous for successive transmetalation
10
3
produce 3a in high yield when DPEphos –[Pd(g -C H )Cl] was
2
3
5
used as a catalyst (entry 6).{ Catalyst loading can be reduced to
2 mol% under optimal conditions. Moreover, 3a was obtained in
94% isolated yield (entry 7).§
9
with arylboronic acids and that (acetato)(benzyl)palladium
generated from benzyl acetate was inactive in the transmetalation.
However, if the acetate ligand on palladium can be replaced with
Table 1 Cross-coupling of 4a with 2a: optimization of reaction
conditions
a
b
Entry
Solvent
Ligand
Yield (%)
1
2
3
4
5
6
DMF
Dioxane
MeOH
i-PrOH
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
DPPPent
DPPPent
DPPPent
DPPPent
DPPPent
DPEphos
DPEphos
2 (2)
1
0
0
Scheme 1 Cross-coupling of benzylic carbonates (1) with arylboronic
acids (2) and its proposed mechanism.
19 (65)
32 (95)
94
c
d
7
Department of Chemistry, Graduate School of Sciences, Kyushu
University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
E-mail: rkuwascc@mbox.nc.kyushu-u.ac.jp; Fax: +81 92 642 2607;
Tel: +81 92 642 2572
a
3
Reactions were conducted on a 0.2 mmol scale in 1.0 cm of a
CO
)Cl] : ligand was 100 : 150 : 300 : 2.5 : 5.5. GC yield
solvent unless otherwise noted. The ratio of 4a : 2a : K
2
3
:
3
b
[Pd(g -C
3
H
5
after 3 h (average of two runs). GC yields after 24 h are given in
parentheses. The reaction was conducted on a 1 mmol scale (1.0 M)
{
Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and characterization data for products 3. See DOI:
0.1039/b513372f
c
d
for 72 h with 2 mol% palladium. Isolated yield.
1
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 5899–5901 | 5899

View Article Online
The scope of the cross couplings of benzylic acetates 4 with
arylboronic acids 2 is summarised in Table 2. Electron-poor
benzylic acetate 4c as well as electron-rich 4a reacted with 2a to
produce a cross-coupling product 3c in high yield (entry 2). The
electronic property of 2 barely affected the rate of the catalytic
reaction and the yield of diarylmethane (entries 6 and 7). Some
reactive functional groups, e.g. ester (entry 3), chloro (entry 4), and
hydroxy (entry 8), were tolerable for the cross-coupling. As the
reaction proceeded, the reaction of 4a with 2d formed a gel, and
the gelation appeared to produce a low yield of 3i. However, this
problem was solved by conducting the reaction in a mixture of
tert-amyl alcohol and DMF. The ortho-phenyl substituent of 2e
hardly hampered the formation of diarylmethane 3j (entry 9).
(2-naphthyl)methyl acetate with 2a yielded the desired diaryl-
methanes in ,10% yield (GC) at 24 h.
The one-pot transformation of benzylic alcohol 5a into
diarylmethane 3a was attempted by means of the above-mentioned
catalytic reaction (Scheme 2). The acetylation of 5a was conducted
in tert-amyl alcohol with acetic anhydride and triethylamine.
Benzylic acetate 4a was selectively obtained with no formation of
tert-amyl acetate. Potassium carbonate, the palladium catalyst,
and 2a were successively added to the mixture, which was then
heated at 80 uC. The one-pot reaction produced diarylmethane 3a
in 75% isolated yield. The other benzylic alcohols, 5b and 5c, were
successfully transformed into 3c and 3d in good yields, respectively.
We have demonstrated that benzylic acetates function as
electrophilic substrates in palladium-catalysed cross-coupling with
organoboron compounds. To our knowledge, this is the first
reaction involving the activation of the benzylic C–O bond of
(Naphthyl)methyl esters exhibited
a
considerably higher
reactivity than benzyl ester in the palladium-catalyzed benzylic
1
1
substitutions with soft nucleophiles, while the cross-coupling of
a
Table 2 Cross-coupling of benzylic acetates (4) with arylboronic acids (2)
b
Entry
1
4
2
Time/h
96
Product (3)
Yield (%)
83
2
3
2a
2a
24
72
86
85
c
4
2a
2a
72
48
48
65
80
92
d
5
6
d
7
4a
48
89
e
8
4a
4a
48
24
3
92
86
9
a
3
Reactions were conducted on a 1 mmol scale in tert-amyl alcohol (1.0 cm ) unless otherwise noted. The ratio of 4 : 2 : K
2
CO
3
: [Pd(g -
b
c
: DPEphos was 100 : 110 : 220 : 1.0 : 2.2. Isolated yield. The reaction was conducted on a 0.5 mmol scale with 1.5 molar
C
equivalents of 2a and 5 mol% palladium. The reactions were conducted in 2.0 cm of tert-amyl alcohol. The reaction was conducted in a
3
H
5
)Cl]
2
d
3
e
3
mixture of tert-amyl alcohol (3.0 cm ) and DMF (0.5 cm ).
3
5
900 | Chem. Commun., 2005, 5899–5901
This journal is ß The Royal Society of Chemistry 2005

View Article Online
Chem., Int. Ed., 2005, 44, 674; K. C. Nicolaou, P. G. Bulger and
D. Sarlah, Angew. Chem., Int. Ed., 2005, 44, 4442.
2
3
Recent examples: W. Su, S. Urgaonkar, P. A. McLaughlin and
J. G. Verkade, J. Am. Chem. Soc., 2004, 126, 16433; K. W. Anderson
and S. L. Buchwald, Angew. Chem., Int. Ed., 2005, 44, 6137.
Example: D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1979, 101,
4992; E.-i. Negishi, H. Matsushita and N. Okukado, Tetrahedron Lett.,
1981, 22, 2715; R.-J. de Lang, M. J. C. M. van Hooijdonk, L. Brandsma,
H. Kramer and W. Seinen, Tetrahedron, 1998, 54, 2953; S. Chowdhury
and P. E. Georghiou, Tetrahedron Lett., 1999, 40, 7599; L. Chahen,
H. Doucet and M. Santelli, Synlett, 2003, 1668; S. Langle, M. Abarbri
and A. Duch eˆ ne, Tetrahedron Lett., 2003, 44, 9255.
4
5
C. Vanier, F. Lorg e´ , A. Wagner and C. Mioskowski, Angew. Chem., Int.
Ed., 2000, 39, 1679.
E.-i. Negishi, A. O. King and N. Okukado, J. Org. Chem., 1977, 42,
Scheme 2 One-pot transformation of 5 to 3.
1821; M. Piber, A. E. Jensen, M. Rottlander and P. Knochel, Org. Lett.,
1
999, 1, 1323; G. A. Molander and T. Ito, Org. Lett., 2001, 3, 393;
12,13
benzyl acetate with homogeneous catalysis.
The catalytic cross-
K. Itami, M. Mineno, T. Kamei and J. Yoshida, Org. Lett., 2002, 4,
3635.
coupling was significantly accelerated by the tertiary alcohol
solvent. Although the observation is consistent with our working
hypothesis, it is unclear whether or not tert-amyl alcohol
accelerates the transmetalation step. Mechanistic investigations
focusing on the effect of alcoholic solvents are in progress.
This work was supported by the Tokuyama Science Foundation
and Grant-in-Aids (Nos. 16685011 and 17035062) from MEXT.
6
J. S. Wai, M. S. Egbertson, L. S. Payne, T. E. Fisher, M. W. Embrey,
L. O. Tran, J. Y. Melamed, H. M. Langford, J. P. Guare, L. Zhuang,
V. E. Grey, J. P. Vacca, M. K. Holloway, A. M. Naylor-Olsen,
D. J. Hazuda, P. J. Felock, A. L. Wolfe, K. A. Stillmock, W. A. Schleif,
L. J. Gabryelski and S. D. Young, J. Med. Chem., 2000, 43, 4923;
Y.-Q. Long, X.-H. Jiang, R. Dayam, T. Sanchez, R. Shoemaker, S. Sei
and N. Neamati, J. Med. Chem., 2004, 47, 2561.
D. Philp and J. F. Stoddart, Angew. Chem., Int. Ed. Engl., 1996, 35,
1154; M. M. Conn and J. Rebek, Jr., Chem. Rev., 1997, 97, 1647;
A. Jasat and J. C. Sherman, Chem. Rev., 1999, 99, 931.
R. Kuwano and M. Yokogi, Org. Lett., 2005, 7, 945.
7
8
Notes and references
{
(
The yield of 3a was significantly affected by ligand. Use of PPh
t-Bu) P?HBF , DPPE, and DPPB gave 3a in 0%, 0%, 0%, and 8% yield,
respectively. When Pd(OAc)
reaction produced 3a in 11% yield after 3 h.
General procedure for the cross-coupling of benzylic acetates with
arylboronic acids: under a nitrogen atmosphere, a benzylic acetate 4
1.0 mmol) was added to a suspension of an arylboronic acid 2 (1.1 mmol),
3
,
9 N. Miyaura, K. Yamada, H. Suginome and A. Suzuki, J. Am. Chem.
Soc., 1985, 107, 972; R. Kakino, I. Shimizu and A. Yamamoto, Bull.
Chem. Soc. Jpn., 2001, 72, 371.
10 M. Kranenburg, Y. E. M. van der Burgt, P. C. J. Kamer,
P. W. N. M. van Leeuwen, K. Goubitz and J. Fraanje,
Organometallics, 1995, 14, 3081.
11 R. Kuwano, Y. Kondo and Y. Matsuyama, J. Am. Chem. Soc., 2003,
125, 12104; R. Kuwano and Y. Kondo, Org. Lett., 2004, 6, 3545;
R. Kuwano, Y. Kondo and T. Shirahama, Org. Lett., 2005, 7, 2973.
12 Examples of catalytic reaction involving the cleavage of C–O bond in
(naphthyl)methyl acetates: J. M. Baird, J. R. Kern, G. R. Lee,
D. J. Morgans and M. L. Sparacino, J. Org. Chem., 1991, 56, 1928;
J.-Y. Legros and J.-C. Fiaud, Tetrahedron Lett., 1992, 33, 2509;
J.-Y. Legros, M. Toffano and J.-C. Fiaud, Tetrahedron, 1995, 51, 3235;
M. Assi e´ , J.-Y. Legros and J.-C. Fiaud, Tetrahedron: Asymmetry, 2005,
3
4
3
2
3 5 2
was used in place of [Pd(g -C H )Cl] , the
§
(
3
potassium carbonate (304 mg, 2.2 mmol), [Pd(g -C
0 mmol), and DPEphos (11.8 mg, 22 mmol) in tert-amyl alcohol (1.0 cm ).
The suspension was stirred at 80 uC until 4 was completely consumed
monitored by GC). After brine was added, the mixture was extracted
several times with hexane. The combined organic layer was dried with
MgSO , and was evaporated under reduced pressure. The residue was
3 5 2
H )Cl] (3.6 mg,
3
1
(
4
purified by a flash column chromatography (EtOAc–hexane) to give the
desired product.
16, 1183.
1
Recent reviews: A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed.,
002, 41, 4176; S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron,
002, 58, 9633; J. Tsuji, in Palladium Reagents and Catalysts, John Wiley
Sons, West Sussex, 2004, p. 105; A. C. Frisch and M. Beller, Angew.
13 Examples of catalytic reaction involving the cleavage of C–O bond in
benzyl trifluoroacetate: K. Nagayama, I. Shimizu and A. Yamamoto,
Bull. Chem. Soc. Jpn., 1999, 72, 799; H. Narahashi, A. Yamamoto and
I. Shimizu, Chem. Lett., 2004, 33, 348.
2
2
&
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 5899–5901 | 5901