Palladium-catalyzed direct intermolecular α-arylation of amides with aryl chlorides

Article abstract of DOI:10.1021/ol4019002

An efficient catalytic system for the direct intermolecular α-arylation of acetamide derivatives with aryl chlorides is presented. Chemoselectivities up to 10:1 in the mono-and diarylation of acetamides were achieved by careful selection of bases, solvent

Full text of DOI:10.1021/ol4019002

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Direct Intermolecular
r‑Arylation of Amides with Aryl Chlorides
Bing Zheng,†,‡ Tiezheng Jia,‡ and Patrick J. Walsh*,‡
Department of Applied Chemistry, China Agricultural University, Beijing 100193,
P. R. China, Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for
High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania,
231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
pwalsh@sas.upenn.edu
Received July 6, 2013
ABSTRACT
An efficient catalytic system for the direct intermolecular R-arylation of acetamide derivatives with aryl chlorides is presented. Chemoselectivities
up to 10:1 in the mono- and diarylation of acetamides were achieved by careful selection of bases, solvents, and stoichiometry. Bis-arylated
amides were prepared in up to 95% yield.
Amides are ubiquitous building blocks for fine chem-
icals1 and pharmaceuticals2 and are common subunits
in natural products.3 The direct cross-coupling of
unfunctionalized amides with aryl bromides to form
CÀC bonds is a synthetically efficient and straightforward
approach to their elaboration4 and has generated consid-
erable interest.5
† China Agricultural University.
In pioneering studies on the arylation of amides,
the Hartwig group described a (BINAP)Pd-based catalyst
for the R-arylation of acetamides with aryl bromides
(Scheme 1A). Yields up to 72% were obtained despite
competing formation of diarylated byproducts.5c They
also demonstrated that the mechanism of oxidative
addition of aryl chlorides proceeded through a palladium
species bearing a single monodentate phosphine in the intra-
molecular R-arylation of amides to produce oxindoles.6
Palladium catalysts ligated with bidentate ligands will acti-
vate aryl chlorides at temperatures around 100 °C.7 Hartwig
and co-workers later developed a general procedure for
amide R-arylation by R-deprotonation, transmetalation to
zinc, and cross-coupling with aryl bromides (Scheme 1B).5a
Contrary to the successful application of aryl bromides to
amide R-arylation, the intermolecular R-arylation of amides
with aryl chlorides is unknown to our knowledge.
Aryl chlorides are generally less reactive than aryl bro-
mides in oxidative additions.8 Nonetheless, aryl chlorides
are less expensive and more readily accessible than aryl
‡ University of Pennsylvania.
(1) Haag, B. A.; Zhang, Z.-G.; Li, J.-S.; Knochel, P. Angew. Chem.,
Int. Ed. 2010, 49, 9513.
(2) Liu, X.-Y.; Fang, Z.-Z.; Dong, P.-P.; Shi, X.-H.; Teng, Y.-J.; Sun,
X.-Y. Pharmazie 2012, 67, 804.
(3) Kantorova, M.; Kolinska, R.; Pazoutova, S.; Honzatko, A.;
Havlicek, V.; Flieger, M. J. Nat. Prod. 2002, 65, 1039.
(4) (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (b)
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Rev. 2003, 36, 234. (c) Bellina,
F.; Rossi, R. Chem. Rev. 2010, 110, 1082. (d) Johansson, C. C. C.;
Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676. (e) Novak, P.;
Martin, R. Curr. Org. Chem. 2011, 15, 3233. (f) Cho, G. Y.; Bolm, C.
Org. Lett. 2005, 7, 1351. (g) You, J.; Verkade, J. G. Angew. Chem., Int.
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2006, 128, 4976. (b) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F.
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B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546. (d) Wu, L.; Falivene,
L.; Drinkel, E.; Grant, S.; Linden, A.; Cavallo, L.; Dorta, R. Angew.
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(f) Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743.
(g) Kuendig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G. Angew.
Chem., Int. Ed. 2007, 46, 8484. (h) Jia, Y.-X.; Hillgren, J. M.; Watson,
E. L.; Marsden, S. P.; Kundig, E. P. Chem. Commun. 2008, 4040. (i)
Luan, X.; Mariz, R.; Robert, C.; Gatti, M.; Blumentritt, S.; Linden, A.;
Dorta, R. Org. Lett. 2008, 10, 5569. (j) Ackermann, L.; Vicente, R.;
Hofmann, N. Org. Lett. 2009, 11, 4274. (k) Taylor, A. M.; Altman,
R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900. (l) Wuertz, S.;
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r
10.1021/ol4019002
XXXX American Chemical Society

bromides, making their use in cross-coupling reactions
highly desirable.
Under these conditions, however, only a 25% yield
of the monoarylated amide 3aa was obtained (Table 1,
entry 1). Based on our previous experience with the aryla-
tion of sulfoxides with aryl chlorides,12 we hypothesized
that catalyst activation might be problematic. We, there-
fore, turned to the Buchwald-type precatalysts (Figure 1),
which readily form active catalysts.15,16 As shown in
Table 1, four common solvents [toluene, cyclopentyl
methyl ether (CPME), dioxane, and dimethoxyethane
(DME)] were screened using the second generation palla-
dium dimer L115,16 with Kwong’s indole-based phosphine
(L; see Scheme 1C). CPME was determined to be the most
effective solvent, providing a mixture of the mono- and bis-
arylated products in a 5:1 ratio (entries 2À5, Table 1).
From these reactions, the monoarylated 3aa was isolated
in up to 63% yield (Table 1, entry 3). The other solvents
(toluene, dioxane, and DME) led to generation of 3aa in
lower yields(15À59%) and with inferior ratios of mono- to
bis-arylated products (Table 1, entry 3 vs 2, 4, and 5).
Further screening of six bases [LiOtBu, NaOtBu, KOtBu,
LiN(SiMe3)2, NaN(SiMe3)2, and KN(SiMe3)2] resulted in
yields from 6À63% of monoarylated 3aa and 2:1 to 5:1
ratios of monoarylated 3aa to bis-arylated 4aa (Table 1,
entries 3 and 6À10). To improve the yield and selectivity
for 3aa, Buchwald’s third generation palladium dimerL217
and the third generation indole-based precatalyst L317
(Figure 1) were investigated with chlorobenzene 1a and
N,N-diethylacetamide 2a. Unfortunately, the ratio of
monoarylation 3aa to bis-arylation 4aa dropped below
3:1 (Table 1, entries 11 and 12). Our best conditions for mono-
arylation of acetamides with aryl chlorides were, therefore,
2.5 mol % second generation palladium dimer L1 and 10 mol %
L with 3 equiv of LiOtBu in CPME at 110 °C for 12 h.
With our optimized reaction conditions, we examined
the scope of aryl chlorides in the monoarylation with 2a
(Table 2). Phenyl chloride (1a) provided a 5:1 ratio of
mono-/bis-arylated products from which the monoaryl-
ated product 3aa was isolated in 63% yield (Table 2,
entry 1). Likewise, alkyl substituted aryl chlorides, such
as 4-tert-butyl chlorobenzene (1b), 4-chlorotoluene (1c),
and 3-chlorotoluene (1d) coupled with 2a in moderate to
good selectivities (5:1À10:1 mono-/bis-arylated product)
in 63À70% yield of the major products (entries 2À4). Aryl
chlorides with ortho-substitution, such as 2-chlorotoluene
and 1-chloronaphthalene, were poor substrates (<10%
yield) in this reaction. This appears to be a limitation of the
palladium catalyst with Kwong’s indole-based phosphine.
Aryl chlorides bearing electron donating groups,
such as 3-chloro-N,N-dimethylaniline (1e) or 1-chloro-4-
methoxybenzene (1f), gave the monocoupled products in
70À72% yield with 7:1 to 10:1 selectivity (entries 5À6).
Lower selectivities(3:1À5:1), however, wereobserved when
We have been interested in the catalytic functionaliza-
tion of weakly acidic sp3-hybridized CÀH bonds9 (pKa’s
28À35 in DMSO) and have recently developed methods for
the in situ deprotonation and coupling of diarylmethanes,10
sulfones,11 sulfoxides,12 and chromium-activated benzylic
amines.9
Based on these advances, we hypothesized that a
palladium-catalyzed deprotonative cross-coupling process
(DCCP) for the arylation of amides (pKa >35) with aryl
chlorides should be possible (Scheme 1C). Herein we
report the first chemoselective mono- and bis-arylation
of N,N-dialkyl acetamide derivatives with aryl chlorides.
The palladium catalyst identified for this challenging
reaction is based on Kwong’s indole phosphine13 and
alkoxide bases.
Scheme 1. Palladium-Catalyzed R-Arylation of Amides
We initiated studies of the R-arylation of amides with
aryl chlorides employing the same catalyst and conditions
we developed for the palladium-catalyzed arylation of
sulfones with aryl bromides11 (PhSO2CH3, pKa 29).14
(8) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(d) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555.
(9) (a) McGrew, G. I.; Temaismithi, J.; Carroll, P. J.; Walsh, P. J.
Angew. Chem., Int. Ed. 2010, 49, 5541. (b) Zhang, J.; Stanciu, C.; Wang,
B.; Hussain, M. M.; Da, C.-S.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J.
J. Am. Chem. Soc. 2011, 133, 20552. (c) McGrew, G. I.; Stanciu, C.;
Zhang, J.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J. Angew. Chem., Int.
Ed. 2012, 51, 11510.
(10) (a) Zhang, J.; Bellomo, A.; Creamer, A. D.; Dreher, S. D.;
Walsh, P. J. J. Am. Chem. Soc. 2012, 134, 13765. (b) Bellomo, A.;
Zhang, J.; Trongsiriwat, N.; Walsh, P. J. Chem. Sci. 2013, 4, 849.
(11) Zheng, B.; Jia, T.; Walsh, P. J. Org. Lett. 2013, 15, 1690.
(12) Jia, T.; Bellomo, A.; EL Baina, K.; Dreher, S. D.; Walsh, P. J.
J. Am. Chem. Soc. 2013, 135, 3740.
(13) (a) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007, 9, 2795.
(b) Lee, H. W.; Lam, F. L.; So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong,
F. Y. Angew. Chem., Int. Ed. 2009, 48, 7436.
(14) Matthews, W. S.; Bares, J.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCallum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006.
(15) (a) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073. (b) Shu, W.; Buchwald, S. L. Chem. Sci. 2011, 2, 2321. (c) Yang,
Y.; Oldenhius, N. J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 615.
(16) (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686. (b) Albert, J.; D’Andrea, L.; Granell, J.; Zafrilla, J.;
Font-Bardia, M.; Solans, X. J. Organomet. Chem. 2007, 692, 4895.
(17) (a) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013,
4, 916. (b) Bruno, N. C.; Buchwald, S. L. Org. Lett. 2013, 15, 2876.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the R-Arylation of N,N-Diethylacet-
amide 2a with Chlorobenzene 1aa
Table 2. Substrate Scope of Aryl Chlorides in the R-Arylation
of 2a to Give 3a
isolated
3aa
NMR yield
(%)
4aa
NMR yield
(%)
entry
ArÀCl
product
ratiob
yield (%)
1
2
3
4
5
6
7
8
PhÀCl
3aa
3ab
3ac
3ad
3ae
3af
5:1
10:1
5:1
63
68
63
70
72
70
65
72
entry
base
solvent
4-tBuÀC6H4ÀCl
4-MeÀC6H4ÀCl
3-MeÀC6H4ÀCl
3-Me2NÀC6H4ÀCl
4-CH3OÀC6H4ÀCl
4-FÀC6H4ÀCl
1b
2
LiOtBu
toluene
toluene
CPME
dioxane
DME
25
59
63c
34
15
45
50
12
15
6
trace
14
LiOtBu
7:1
3
LiOtBu
12
7:1
4
LiOtBu
14
10:1
3:1
5
LiOtBu
3
3ag
3ah
6
NaOtBu
KOtBu
CPME
CPME
CPME
CPME
CPME
CPME
CPME
20
3-CF3ÀC6H4ÀCl
5:1
7
14
a Reactions performed using 1.0 equiv of 1, 2.0 equiv of 2a on
8
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
LiOtBu
trace
trace
trace
14
0.2 mmol scale. b Ratio is between mono- and bis-arylated product.
9
10
11d
12e
36
29
LiOtBu
15
a Reactions performed using 1.0 equiv of 1a, 2.0 equiv of 2a, and
3.0 equiv of base on a 0.2 mmol scale. b 20 mol % L used. c Isolated yield.
d 2.5 mol % L2 and 10 mol % L used. e 5.0 mol % L3 used.
Table 3. Optimization of the Diarylation of N,N-Diethylaceta-
mide 2a with 1aa
NMR
entry
[Pd]
base
yield (%)
1b
2b
3
L3
L3
L2
L2
L1
L1
NaOtBu
KOtBu
NaOtBu
KOtBu
NaOtBu
KOtBu
84
69
69
50
64
56
Figure 1. Buchwald’s second and third generation dimeric pre-
catalysts and the third generation precatalyst bound to Kwong’s
indole-based phosphine (L).
4
5
6
a Reactions performed using 2.0 equiv of 1a, 1.0 equiv of 2a on
a 0.2 mmol scale. b 0 mol % additional L used.
aryl chlorides bearing electron-withdrawing substituents,
such as 1-chloro-4-fluorobenzene (1g) and 1-chloro-
3-(trifluoromethyl)benzene (1h, entries 7À8). The higher
percentages of diarylated products could be due to the
increased acidity of the monoarylated products. None-
theless, the yields of these substrates (63À72%) were
comparable to others in Table 2. Other sensitive functional
groups, such as nitro, cyano, or esters, were incompatible
with our reaction conditions.
Our starting point for the optimization of the bis-
arylation of acetamides with aryl chlorides was entry 6 of
Table 1, where NaOtBu was employed as the base in
CPME and the bis-arylated 4aa was formed in 20% yield.
We found that the third generation indole phophine-based
precatalyst L3 was the best palladium source in terms of
yield (84%) in combination with CPME (Table 3, entry 1
vs entries 3 and 5). In general, NaOtBu was more effective
than KOtBu with different palladium sources (entries 1, 3,
5 vs2, 4 and 6), soit wasemployed in the bis-arylation of 2a
with aryl chlorides.
Under the optimized conditions of entry 1 in Table 3, the
diarylation of N,N-diethylacetamide 2a with a variety
of aryl chlorides and 5 mol % third generation indole-
based precatalyst was investigated. As shown in Table 4,
70%À80% isolated yields were achieved in the diarylation.
Chlorobenzene (1a), 4-tert-butyl chlorobenzene (1b), and
3-chlorotoluene (1d) furnished products 4aa, 4bb, and 4dd
in 80%, 76%, and 70% yields, respectively. Electron-rich
4-chloroanisole (1f) afforded the double-coupled product 4ff
in 72% yield. Electron-deficient 1-chloro-4-fluorobenzene
(1g) underwent coupling in 72% yield to provide 4gg.
Encouraged by the results of the diarylation with aryl
chlorides, we next examined the arylation of arylacetamides
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Substrate Scope of Aryl Chlorides in the Diarylation of 2aa
Table 6. Substrate Scope of Aryl Chlorides in the R-Arylation of
Arylacetamides 3a
isolated
isolated
entry
R1
R2
R3
yield (%)
entry
ArÀCl
product
yield (%)
1
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
90
95
93
90
88
91
90
90
93
83
77
1
2
3
4
5
PhÀCl
4aa
4bb
4dd
4ff
80
76
70
72
72
4-tBu
4-tBuÀC6H4ÀCl
3-MeÀC6H4ÀCl
4-MeOÀC6H4ÀCl
4-FÀC6H4ÀCl
2
3
3-Me
4
3-Me2N
4-MeO
4-pyrrol
4-F
4-tBu
4-tBu
4-tBu
4-tBu
5
4gg
6
a Reactions performed using 2.0 equiv of 1, 1.0 equiv of 2a on a
0.2 mmol scale.
7
8
pyrrolidine
piperidine
Et
9
10
11
3-pyridyl
to yield diarylated products 4 bearing two different aryl
groups. As summarized in Table 5, a short survey of
Buchwald-type precatalysts led to the choice of the third
generation indole-based precatalyst L3, which generated
95% yield of the product 4aa when 1.5 equiv of chlorobenzene
was employed (Table 5, entry 1). Decreasing the loading of
precatalyst from 5.0 to 2.5 mol % also led to a satisfactory
yield (91%, entry 2). The second and third generation palla-
dium dimers were also examined in the arylation of 3aa with
chlorobenzene, but gave lower yields (Table 5, entries 3 and 4).
3-thiophenyl
Et
a Reactions performed using 1.5 equiv of 1, 1.0 equiv of 3, and
3.0 equiv of base on a 0.2 mmol scale.
Electron-rich 4-chloroanisole (1f) and 4-pyrrole chloro-
benzene (1i) were successfully coupled with 3aa to afford
4af and 4ai in 88% and 91% yield, respectively. Likewise,
1-chloro-4-fluorobenzene (1g) reacted smoothly to give
4ag in 90% yield.
Changing the substituents on the amide nitrogen of the
substrates had little impact on the reactivity in the aryla-
tion. Pyrrolidine (3ba) and piperidine (3ca) acetamide
derivatives gave arylation products 4ba and 4ca in 90%
and 93% yield, respectively (Table 6). Substrates that bear
heteroaryl groups on the acetamide, such as 3-pyridyl (3aj)
and 3-thiophene (3ak), were also suitable substrates under
the optimized conditions, providing 4aj and 4ak in 83%
and 77% yield, respectively.
Table 5. Optimization of the Arylation of 3aa with 1aa
In summary, we report the first deprotonative cross-
coupling process for the intermolecular arylation of
amides with aryl chlorides. Buchwald-type precatalysts
formed with Kowng’s indole-based ligand effectively cat-
alyzes the direct R-arylation of acetamides with aryl chlo-
rides. It is noteworthy that the chemoselectivity between
mono- and bis-arylated products was effectively controlled
by base and solvent combinations.
catalyst/
mol %
NMR
entry
[Pd]
yield (%)
1b
2b
3
L3
L3
L2
L1
5
95
91
85
76
2.5
2.5
2.5
4
a Reactions performed using 1.5 equiv of 1a, 1.0 equiv of 3aa on a
0.2 mmol scale. b 0 mol % L used.
Acknowledgment. We thank the National Science
Foundation [CHE-0848460 (GOALI) and 1152488] for
financial support. B.Z. thanks the China Scholarship
Council [2011635137] for financial support.
Our optimal conditions employed NaOtBu as a base in
CPME with 2.5 mol % of the indole-based precatalyst L3
at 110 °C. Under these conditions, various aryl chlorides
were examined (Table 6). The alkyl substituted 4-tert-butyl
chlorobenzene (1b) and 3-chlorotoluene (1d) gave diaryl-
acetamides 4ab and 4ad in 95% and 93% yield, respec-
tively. 3-Chloro-N,N-dimethylaniline (1e) reacted smoothy
to give the product 4ae in 90% yield.
Supporting Information Available. Procedures, charac-
terization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX