TABLE 1. Coupling of Arylboronic Esters with
4-Morpholinecarbonyl Chloridea
Synthesis of Tertiary Benzamides via
Pd-Catalyzed Coupling of Arylboronic
Esters and Carbamoyl Chlorides
Morten Lyse´n, Susan Kelleher, Mikael Begtrup, and
Jesper Langgaard Kristensen*
Department of Medicinal Chemistry, Danish University of
Pharmaceutical Sciences, Universitetsparken 2, DK-2100
Copenhagen, Denmark
entry
boronic ester
R
product
isolated yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
H
F
3a
3b
3c
3d
3e
3f
79
87
94
87
76
86
79
Cl
CN
Ph
Received March 9, 2005
OMe
NHBoc
1g
3g
a Reaction conditions: arylboronic ester (2 mmol), 4-morpholi-
necarbonyl chloride (4 mmol), CsF (4 mmol), PdCl2(PPh3)2 (0.06
mmol) in THF (8 mL), reflux 16 h.
We chose to examine the coupling of neopentylglycol
arylboronic esters instead of free arylboronic acids, as this
makes it possible to monitor the progress of the reactions
via GC-MS.5 A series of ortho-substituted arylboronic
esters (1a-g, Table 1) with different electronic and steric
properties were selected.6 As carbamoyl chloride coupling
partner we chose 4-morpholinecarbonyl chloride (2) as
the resulting amides (3a-g) serve as cheap alternatives
to Weinreb amides,7 making them very useful intermedi-
ates for further transformation.
Testing different bases, Pd catalysts, and solvents
revealed that the use of CsF8 as base in combination with
PdCl2(PPh3)2 in THF or dioxane did indeed induce the
coupling to give the desired amides, and we settled on
the following conditions: 2 equiv of carbamoyl chloride,
2 equiv of CsF, 3% PdCl2(PPh3)2 in THF at reflux. Excess
of the carbamoyl chloride is nesccessary as it is slowly
converted to the corresponding carbamoyl fluoride during
the course of the reaction. As seen in Table 1, the coupling
of a series of ortho-substituted neopentylglycol arylbo-
ronic esters with 2 gave the desired morpholinamides in
good to excellent yield.
Ortho-substituted arylboronic esters are efficiently coupled
with carbamoyl chlorides under Pd-catalysis to give tertiary
benzamides.
The benzamides are a very important class of com-
pounds with a wide range of applications. They are
usually prepared via the addition of an amine to an
activated benzoic acid derivative, e.g., an acid chloride
(route A in Figure 1). An alternative and much less used
approach to benzamides is the addition of a metalated-
benzene derivative to a carbamoyl chloride (route B in
Figure 1).
FIGURE 1. Different synthetic routes to benzamides.
Lemoucheux et al. reported the synthesis of tertiary
amides via Ni-catalyzed addition of Grignard reagents
to carbamoyl chlorides and the direct addition of orga-
nocuprates to carbomoyl chlorides.1 Earlier reports de-
scribe the Pd-catalyzed coupling of carbamoyl chlorides
with stannanes.2 The Pd-catalyzed coupling of arylbo-
ronic derivatives with organohalides, the Suzuki-
Miyaura coupling,3 has become widespread for the con-
struction of C-C bonds. We were intrigued by the
prospect of preparing benzamides via the coupling of
arylboronic derivatives with carbamoyl chlorides and set
out to explore this possibility.4
(4) During the preparation of this manuscript, a paper appeared
describing the coupling of para-substituted arylboronic acids with N,N-
dibutyl chloroformate; see: Duan, Y.-Z.; Deng, M.-Z. Synlett 2005, 355.
(5) Neopentylglycol arylboronic esters can be prepared very conve-
niently from the parent arylboronic acids in the following way:
Equimolar amounts of arylboronic acid and neopentylglycol are stirred
in CH2Cl2 (3-5 mL/mmol) at rt. Initially, the mixture is heterogeneous
as arylboronic acids are generally not very soluble in CH2Cl2. After
approximately 1 h, the mixture becomes clear, indicating that the
reaction is complete. The CH2Cl2 phase is washed with water and brine,
dried over Na2SO4, filtered, and the solvent is removed, leaving the
neopentylglycol arylboronic esters. See also: Kristensen, J. L.; Lyse´n,
M.; Vedsø, P.; Begtrup, M. Org. Synth. 2005, 81, 134.
(6) 1a: Bowie, R. A.; Musgrave, O. C.; J. Chem. Soc. C 1963, 3945.
1b-d: Kristensen, J.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett.
2001, 3, 1435. 1e: Bowie, R. A.; Musgrave , O. C. J. Chem. Soc. C,
1966, 566. 1f: Chaumeil, H.; Signorella, S.; Le Drian, C. Tetrahedron
2000, 56, 9655. 1g: Eskildsen, J.; Østergaard, N.; Vedsø, P.; Begtrup,
M. Tetrahedron 2002, 58, 7635.
(1) (a) Lemoucheux, L.; Rouden, J.; Lasne, M.-C. Tetrahedron Lett.
2000, 41, 9997. (b) Lemoucheux, L.; Seitz, T.; Rouden, J.; Lasne, M.-
C. Org. Lett. 2004, 6, 3703.
(7) Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J. Org.
Chem. 2002, 67, 5032 and references therein.
(8) K2CO3, Na2CO3, K3PO4, NaF, and KF all gave inferior results.
Fluoride activation in Suzki couplings: (a) Ichikawa, J.; Moriya, T.;
Sonoda, T.; Kobayashi, H. Chem. Lett. 1991, 961. (b) Wright, S. W.;
Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59, 6095.
(2) (a) Balas, L.; Jousseaume, B.; Shin, H.; Verlhac, J.-B.; Wallian,
F. Organometallics 1991, 10, 366. (b) Jousseaume, B.; Kwon, H.;
Verlhac, J.-B.; Denat, F.; Dubac, J. Synlett 1993, 117. (c) Murakami,
M.; Hoshino, Y.; Ito, H.; Ito, Y. Chem. Lett. 1998, 163.
(3) Miyaura, M.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
10.1021/jo050459h CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/21/2005
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J. Org. Chem. 2005, 70, 5342-5343