Palladium-catalyzed synthesis of arylacetamides from arylboronic acids

Article abstract of DOI:10.1016/S0040-4039(03)00586-0

Aryl amides were synthesized by the palladium catalyzed cross-coupling reaction of α-bromoacetamides with arylboronic acids in good yields. Both electron-donating and electron-withdrawing substituents on the aromatic ring are found to be compatible. The a

Full text of DOI:10.1016/S0040-4039(03)00586-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3423–3426
Palladium-catalyzed synthesis of arylacetamides from arylboronic
acids
Ya-Zhen Duan and Min-Zhi Deng*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
Received 17 December 2002; revised 9 February 2003; accepted 12 February 2003
Abstract—Aryl amides were synthesized by the palladium catalyzed cross-coupling reaction of a-bromoacetamides with aryl-
boronic acids in good yields. Both electron-donating and electron-withdrawing substituents on the aromatic ring are found to be
compatible. The addition of Cu2O and PPh3 was found to be essential for good reaction yields. © 2003 Elsevier Science Ltd. All
rights reserved.
Among the various methodologies of palladium-cata-
lyzed coupling of organic electrophiles with
organometallic compounds to form carbon–carbon
bonds, the Suzuki-type reaction has attracted much
interest due to its attractive features (high yields, mild
conditions, tolerance for many functional groups and
solvent moisture, etc.).1 The electrophilic sites in these
cross-coupling reactions are usually sp2-carbons
attached to a good leaving group (e.g. aryl and vinyl
halides or triflates). In contrast, general methods to
cross-couple electrophiles having C(sp3)ꢀX bonds with
organoboronic acids are scarce, presumably because
of their slow oxidative addition to palladium cata-
lysts.2 Suzuki and co-workers have reported only one
such example—the cross-coupling of ethyl bromo-
acetate with phenylboronate using (the highly toxic)
Tl2CO3 as a base.3 Recently, Gooßen reported that
the palladium-catalyzed cross-coupling of bromoacetic
acid derivatives with arylboronic acids was accom-
plished using a special ligand, P(a-Nap)3.4 We have
been also interested in this kind of reaction and ear-
lier found that Cu2O could promote the Suzuki-type
cross-coupling of ethyl bromoacetate with arylboronic
acids without recourse to any special ligand.5 To
expand the scope of electrophiles we investigated the
cross-coupling of bromoacetamides with arylboronic
acids.
Amides are useful building blocks both for laboratory
synthesis as well as industrial manufacturing.6
A
number of elegant routes to amides have been devel-
oped.7 Some of which utilize carbon monoxide as the
carbonyl source, and the reaction were carried out
under a CO atmosphere.8 Herein, we report an alter-
native route to arylacetamides via the Suzuki-type
coupling of arylboronic acids with bromoacetamides.
The cross-coupling reactions were initially carried out
using 3-methylphenylboronic acid and N,N-dibutyl
bromoacetamide as the starting materials to optimize
the conditions (Table 1). Under traditional Suzuki
conditions, only 29% yield of coupling product was
obtained (entry 1). We then turned our attention to
the use of Cu2O as an additive because its beneficial
effect on the cross-coupling of ethyl bromoacetate
with arylboronic acids was noted by us earlier.5 How-
ever, in the present case the use of catalytic amount
of Cu2O alone still did not give satisfactory results
though the yield of the cross-coupled acetamide
product increased somewhat (entry 2). In view that
PPh3 is expected to react with a-bromoacetamides to
give the corresponding phosphonium salts,9 the elec-
* Corresponding author. Tel.: 86-21-64163300-3425; fax: 86-21-
64166128; e-mail: dengmz@pub.sioc.ac.cn
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00586-0

3424
Y.-Z. Duan, M.-Z. Deng / Tetrahedron Letters 44 (2003) 3423–3426
Table 1. Effects of the reaction conditions on the cross-coupling reactiona
Entry
Additive
Yieldb (%)
1
2
3
4
5
6
K3PO4·3H2O
K3PO4·3H2O, Cu2O (6 mol%)
K3PO4·3H2O, PPh3 (6 mol%)
K3PO4·3H2O, Cu2O (6 mol%), PPh3 (6 mol%)
K2CO3, Cu2O (6 mol%), PPh3 (6 mol%)
K3PO4·3H2O, Cu2O (6 mol%), AsPh3 (6 mol%)
29
41
73
79
62
79
a Reactions were carried out at 90°C for 24 h using a mixture of 3-methylphenylboronic acid (0.6 mmol), N,N-dibutyl bromoacetamide (0.5
mmol), 3 mol% Pd(PPh3)4, and base (3.3 equiv.) in 4 mL of toluene.
b Isolated yields.
In summary, it was found for the first time that
Cu2O and PPh3 can efficiently promote the Suzuki-
type coupling reaction of arylboronic acids with bro-
moacetamides to afford arylacetamides in good yields.
The conditions are mild that many functional groups
may be tolerated. The procedure is suitable for
preparing various arylacetamides and may be useful
for a wide range of applications in medicinal chem-
istry in particular because amides are a common class
of organic compounds. A detailed mechanistic study
as well as an examination of the scope of the reaction
are currently underway in our laboratory.
trophilicity of which would be considerably stronger
than that of a-bromoacetamides themselves, the effect
of PPh3 as an additive was also examined. To our
delight,
a much improved reaction was indeed
observed (entry 3). The combined effect of Cu2O and
PPh3 was noticeable, though not substantial, and
after considerable experimentation, the best result
(entry 4) was obtained for our model reaction with 6
mol% each of Cu2O and PPh3 added to a reaction
mixture containing K3PO4·3H2O (3.3 equiv.), 3-
methylphenylboronic acid (1.2 equiv.), N,N-dibutylac-
etamide (1.0 equiv,) and Pd(PPh3)4 (3 mol%).
Although AsPh3 was as effective as PPh3 (entry 6),
the latter is preferred for obvious reasons.
Acknowledgements
The coupling reactions of various arylboronic acids
with bromoacetamides were carried out under opti-
mized conditions10 and the results are collected in
Table 2.
We thank the NNSF of China and State Key Labo-
ratory of Organometallic Chemistry, Chinese
Academy of Sciences, for financial support. A gener-
ous supply of arylboronic acids from Inc. of Frontier
Scientific is also gratefully acknowledged.
As can be seen in Table 2, the cross-coupling reac-
tions of arylboronic acids with various N,N-dialkyl-
bromoacetamides proceed readily to give the
corresponding arylacetamides in good yields (entries
1–9). In the case of N-alkylacetamides, the yields of
cross-coupling are somewhat lower than that of N,N-
dialkyl bromoacetamides (entries 10–12 versus entries
1–9). When bromoacetamide was used for coupling
with 3-methylboronic acid, no cross-coupling product
was obtained (entry 13). This process tolerates a
number of functional groups on the aromatic ring
(entries 4–7). While an electron-donating substituent
on the arylboronic acid decreases the cross-coupling
yield (entry 5), electron-withdrawing substituents
increase the yield (entries 6 and 7).
References
1. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457;
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (c)
Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359.
2. (a) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. Rev.
2000, 100, 3187; (b) Ca´rdenas, D. J. Angew. Chem., Int.
Ed. 1999, 38, 3018.
3. Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989,
1405.
4. Gooßen, L. J. Chem. Commun. 2001, 669.

Y.-Z. Duan, M.-Z. Deng / Tetrahedron Letters 44 (2003) 3423–3426
3425
Table 2. Palladium-catalyzed cross-coupling reactions of arylboronic acids with various bromoacetamidesa

3426
Y.-Z. Duan, M.-Z. Deng / Tetrahedron Letters 44 (2003) 3423–3426
5. Liu, X.-X.; Deng, M.-Z. Chem. Commun. 2002, 6, 622.
mL) and bromoacetamide 2a (125 mg, 0.5 mmol) were
added and the reaction mixture was stirred at 90°C for 24
h. The reaction mixture was allowed to cool to rt, and
H2O (5 mL) was added. The mixture was then extracted
with diethyl ether (10 mL×3). The combined organic
layer was washed with brine (10 mL×3), dried over
MgSO4 and concentrated. The residue was chro-
matographed on silica gel (elution with hexanes/ethyl
acetate=5:1) to afford the corresponding arylacetamide
6. (a) Lewis, J. R. Nat. Prod. Rep. 2002, 19, 223; (b) Jin, Z.;
Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19, 454.
7. Benz, G. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 6, p. 381.
8. (a) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39,
3327; (b) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar,
G. Tetrahedron Lett. 1986, 27, 2931; (c) Lee, S. L.; Son,
S. U.; Chung, Y. K. Chem. Commun. 2002, 1310.
9. Bordwell, F. G.; Zhang, S.-Z.; Zhang, X.-M.; Liu, W.-Z.
J. Am. Chem. Soc. 1995, 27, 7092.
10. Typical experimental procedure for the synthesis of N,N-
dibutyl-2-(3-methylphenyl)acetamide (3a): Arylboronic
acid 1a (82 mg, 0.55 mmol), Pd(PPh3)4 (18 mg, 0.016
mmol), Cu2O (4 mg, 0.028 mmol), PPh3 (8 mg, 0.030
mmol), K3PO4·3H2O (439 mg, 1.65 mmol, 3.3 equiv.)
were placed in a flask under Ar atmosphere. Toluene (4
1
3a. H NMR (300 MHz, CDCl3–TMS) l 7.20 (d, J=7.7
Hz, 1H), 7.03–7.07 (m, 3H), 3.65 (s, 2H), 3.32(t, J=7.7
Hz, 2H), 3.19 (t, J=7.7 Hz, 2H), 2.32 (s, 3H), 1.41–1.54
(m, 4H), 1.23–1.33 (m, 4H), 0.88–0.95 (m, 6H) ppm;
EIMS m/z 261 (M+, 36), 57 (100), 105 (74), 86 (74), 156
(70), 100 (44), 261 (36), 41 (26), 106 (17); IR (neat) 2960,
2932, 2874, 1643, 1608, 1458, 1425, 766 cm−1; Anal. cald
for C17H27NO: C, 78.11; H, 10.41; N, 5.36. Found: C,
77.78; H, 10.07; N, 5.17.