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Chemistry Letters Vol.38, No.7 (2009)
ꢀ-Amidobenzylation of Aryl and Alkenyl Halides via Palladium-catalyzed
Suzuki–Miyaura Coupling with ꢀ-(Acylamino)benzylboronic Esters
Toshimichi Ohmura, Tomotsugu Awano, and Michinori Suginomeꢀ
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510
(Received April 7, 2009; CL-090345; E-mail: suginome@sbchem.kyoto-u.ac.jp)
The Suzuki–Miyaura coupling of ꢀ-(acetylamino)benzyl-
Table 1. The Suzuki–Miyaura coupling of ꢀ-(acylamino)ben-
zylboronic acid and their esters with 5aa
boronic esters with aryl and alkenyl halides has been achieved
using a Pd/P(t-Bu)3 catalyst with KF and H2O in 1,4-dioxane,
giving ꢀ-substituted benzylamines in high yields.
Pd(dba)2 (5 mol %)
Br
R1 R2
N
R1 R2
N
P(t-Bu)3 (10 mol %)
R1 R2
N
base (3 equiv)
+
+
Ph
B(OR3)2
Ph
H2O (2 equiv)
1,4-dioxane
110 °C, 3 h
Ph
Increasing attention has been paid to ꢀ-amino organoboronic
acids and their derivatives, because of their potential bioactivities
as analogues of amino acids.1 Much effort has therefore been de-
voted to development of their efficient synthetic methods includ-
ing Matteson’s asymmetric route, which involves homologation
of chiral organoboronic esters.2,3 In contrast, less attention has
been paid to the use of ꢀ-amino-substituted organoboron com-
pounds as intermediates in organic synthesis,4,5 despite recent
great advances in organoboron transformations, which include
the Suzuki–Miyaura coupling, the Miyaura conjugate addition,
and the Petasis reaction.6 Exploration of the methodology utiliz-
ing ꢀ-amino organoboron compounds would provide powerful
tools for synthesis of nitrogen-containing organic molecules.
The Suzuki–Miyaura coupling of ꢀ-amino-substituted orga-
noboron compounds with organic halides is an attractive strategy
that enables efficient access to functionalized amine derivatives.
Molander and co-workers have developed the coupling reaction
of potassium (dialkylaminomethyl)trifluoroborates for amino-
methylation of organic halides.5 While the reaction is applicable
to various organic halides such as aryl and alkenyl bromides, the
scope of the organoboron reagents is limited to unbranched,
aminomethylboron compounds.7 As far as we are aware, no suc-
cess has been achieved in the coupling of branched ꢀ-amino
alkylboranes. Herein, we describe the first application of
branched, ꢀ-amino-substituted organoboron compounds to the
Suzuki–Miyaura coupling, in which the protective group on
the amino nitrogen has a critical effect on the reaction efficiency.
Alkylboranes with an ꢀ-NH2 substituent are thermally un-
stable and tend to decompose via 1,2-boryl-rearrangement,
whereas their N-acylated derivatives are stable to handle.8 Thus,
we focused on a benzylboronic acid and its pinacol esters bear-
ing an acylamino group at the ꢀ-position of the boryl group as a
coupling reagent.9,10 Initial attempts at reaction of ꢀ-(acetyl-
amino)benzylboronic ester 1a with 4-bromotoluene (5a) en-
countered fast protodeborylation under the standard coupling
conditions such as those using Pd/PPh3 or Pd/DPPF catalysts
(see Supporting Information).11 After screening of Pd precursors,
ligands, bases, and solvents, we found the best conditions for the
coupling reaction, in which Pd(dba)2 (5 mol %), P(t-Bu)3
(10 mol %), KF (3 equiv), and H2O (2 equiv) were employed
in 1,4-dioxane at 110 ꢁC.7b Under these conditions, the reaction
of 1a with 5a (1.2 equiv) gave diarylmethanamine derivative
6a in 56% yield, although a small amount of benzylacetamide
(9, 6%) was also formed (Entry 1, Table 1). Reaction using other
9-11
1a, 2-4
5a
6a, 7, 8
Yield/%b
(1.2 equiv)
Boron compound
[NR1R2, B(OR3)2]
Entry
Base
Coupling
Protodeborylation
1
2
3
4
5
6
7
8
1a [NHAc, B(pin)]
1a
KF
CsF
56 (6a)
23 (6a)
39 (6a)
<1 (6a)
0 (6a)
6 (9)
67 (9)
38 (9)
88 (9)
88 (9)
62c (10)
0 (11)
53 (9)
1a
1a
K2CO3
K3PO4
NaOH
KF
1a
2 [NHBz, B(pin)]
3 [NMeAc, B(pin)]
4 [NHAc, B(OH)2]
23c (7)
KF
KF
0 (8)
9 (6a)
aPd(dba)2 (5 mol %), P(t-Bu)3 (10 mol %), organoboron compound (0.10
mmol), 5a (0.12 mmol), KF (3 equiv), and H2O (2 equiv) in 1,4-dioxane
(0.2 mL) were stirred at 110 ꢁC for 3 h. bGC yield based on organoboron
compound. cIsolated yield.
bases such as CsF, K2CO3, K3PO4, and NaOH gave poor results
because of preferential formation of 9 (Entries 2–5).12
Other ꢀ-aminobenzylboron compounds, bearing various
substituents on the nitrogen atom, were used in the reaction with
5a (Entries 6–8, Table 1). Reaction of ꢀ-(benzoylamino)benzyl-
boronic ester 2 gave coupling product 7 in low yield with major
formation of protodeborylation product 10 (Entry 6). In contrast,
no reaction took place with 3, which has an ꢀ-acetyl(methyl)-
amino group (Entry 7). Formation of 9 was found to be the major
reaction pathway in the reaction of boronic acid 4 (Entry 8). At-
tempts at using ꢀ-H2N- and ꢀ-Me2N-substituted benzylboronic
esters failed because of the instability of these organoboron com-
pounds.8 These results indicate that acetylamino-substituted
benzylboronic ester is the reagent of choice for the ꢀ-amido-
benzylation of aryl halides.
ꢀ-Amidobenzylation of aryl bromides 5 via the Suzuki–
Miyaura coupling of (ꢀ-acetylamino)benzylboronic esters 1
was carried out using an excess amount of 1 under the optimized
conditions (Table 2). The yield of 6a was improved to 70% when
the reaction was carried out with 1.5 equiv of 1a (Entry 1). Re-
action of 1a with electron-deficient aryl bromides 5d and 5e was
complete within 3 h to give 6d and 6e in high yields (Entries 4
and 5). In contrast, a longer reaction time was required for the
reaction with aryl bromides bearing an electron-donating me-
thoxy group (Entry 2). Sterically demanding 5f and 5g reacted
slowly to give the corresponding products in 78 and 70% yields,
respectively (Entries 6 and 7). Reaction of 3-pyridyl and 3-thien-
Copyright Ó 2009 The Chemical Society of Japan
Ohmura, Toshimichi
