Pd-catalyzed cross-coupling reactions of amides and aryl mesylates

Article abstract of DOI:10.1021/ol100720x

A catalyst, based on a biarylphosphine ligand, for the Pd-catalyzed cross-coupling reactions of amides and aryl mesylates is described. This system allows an array of aryl and heteroaryl mesylates to be transformed into the corresponding N-aryl amides in moderate to excellent yields.

Full text of DOI:10.1021/ol100720x

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2350-2353
Pd-Catalyzed Cross-Coupling Reactions
of Amides and Aryl Mesylates
Karin Dooleweerdt, Brett P. Fors, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received March 27, 2010
ABSTRACT
A catalyst, based on a biarylphosphine ligand, for the Pd-catalyzed cross-coupling reactions of amides and aryl mesylates is described. This
system allows an array of aryl and heteroaryl mesylates to be transformed into the corresponding N-aryl amides in moderate to excellent
yields.
Because of the ubiquity of N-aryl amides in biologically
active molecules, the development of efficient methods for
their synthesis has been an active area of research for many
years. The Goldberg-modified Ullman reaction was the first
cross-coupling protocol to synthesize these compounds
effectively from aryl iodides and amides using a stoichio-
metric quantity of copper.2 The utilization of diamines as
supporting ligands in these reactions has recently allowed
the use of catalytic quantities of copper, as well as extended
the scope of these processes to include aryl bromides.3 Pd
catalysts based on phosphine ligands have also been devel-
oped for these transformations. These systems have enabled
the coupling of amides with aryl bromides,4 chlorides,5
triflates,6 and tosylates.7
Although an array of aryl halides/pseudohalides have been
employed in these reactions, there have been no reports of
a catalyst system that can effectively couple amides with
aryl mesylates. Aryl mesylates are attractive substrates
because their use is more atom-economical than that of aryl
tosylates. Additionally, they are less expensive and more
stable than aryl triflates.8 Because of this, interest in aryl
mesylates as substrates has increased, and there have been
several reports of catalyst systems that allow their utilization
in both C-N9 and C-C10 cross-coupling processes.
(5) (a) Fors, B. P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L.
Tetrahedron 2009, 65, 6576. (b) Ikawa, T.; Barder, T. E.; Biscoe, M. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 13001. (c) Shen, Q.; Shekhar,
S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371.
(d) Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Revera-Ruiz, L. Org. Lett.
2003, 5, 2207.
(1) Montalbett, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827.
(2) Goldberg, I. Chem. Ber. 1906, 39, 1691.
(6) (a) Imbriglio, J. E.; DiRocco, D.; Raghavan, S.; Ball, R. G.; Tsou,
N.; Mosley, R. T.; Tata, J. R.; Colletti, S. Tetrahedron Lett. 2008, 49, 4897.
(b) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777. (c) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(3) (a) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 78. (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (c)
Kunz, K; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428. (d) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (e) Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421.
(4) (a) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734. (b)
Shi, F.; Smith, M. R.; Maleczka, R. E. Org. Lett. 2006, 8, 1411. (c) Yin, J.;
Buchwald, S. L. Org. Lett. 2000, 8, 1101.
(7) (a) Klapars, A.; Campos, K. R.; Chen, C.; Volante, R. P. Org. Lett.
2005, 7, 1185. (b) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(8) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754.
10.1021/ol100720x  2010 American Chemical Society
Published on Web 04/26/2010

Table 1. Optimization of the Pd-Catalyzed Cross-Coupling of
Amides and Aryl Mesylatesa
GC yield
entry
Pd source
base
solvent
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(OAc)2/H2O Act
Pd(OAc)2
(H3CCN)2PdCl2
(PhCN)2PdCl2
Pd(TFA)2
[(allyl)PdCl]2
Pd2(dba)3
Pd(dba)2
Pd(OAc)2/H2O Act
Pd(OAc)2/H2O Act
Pd(OAc)2/H2O Act
Pd(OAc)2/H2O Act
Pd(OAc)2/H2O Act
Pd(OAc)2/H2O Act
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
dioxane
toluene
DME
99
1
1
1
0
89
1
1
64
39
0
Figure 1. Biarylphosphine ligands.
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1
2
1
Herein, we report the first Pd-catalyzed amidation of aryl
mesylates. The use of a highly active catalyst system, based
on ligand 1, allows these reactions to proceed in good to
excellent yields using a diverse array of coupling partners
as substrates.
DMF
a Reaction conditions: ArOMs (1.0 mmol), benzamide (1.4 mmol), Pd
(1 mol %), 1 (2.2 mol %), base (1.4 mmol), solvent (2 mL/mmol), 110 °C,
1 h.
We started our studies by examining a catalyst comprised
of ligand 1 (Figure 1), which we have previously shown to
be effective for the coupling of amides with aryl chlorides.5a
We began with the reaction of benzamide and 4-tert-
butylphenyl methanesulfonate using various Pd sources,
bases, and solvents. By utilizing our water-mediated catalyst
preactiviation protocol11 with 1 mol % Pd(OAc)2, 2.2 mol
% 1, and Cs2CO3 in t-BuOH, the reaction gave a 99% yield
(GC) after 1 h at 110 °C (Table 1, entry 1). In contrast, using
Pd(OAc)2 without preactivation or other Pd(II) sources [i.e.,
(H3CCN)2PdCl2, (PhCN)2PdCl2, or Pd(TFA)2] only trace
product was observed (Table 1, entries 2-5). These results
emphasize the importance of efficiently forming the active
catalyst in these reactions. Further, when [(allyl)PdCl]2 was
used, which can be reduced via a nucleophile,12 a yield of
89% was obtained; this is only minimally less efficient than
the conventional preactivation protocol (Table 1, entry 6).
Employing Pd(0) sources such as Pd2(dba)3 or Pd(dba)2 in
this reaction resulted in a marked loss in activity (Table 1,
entries 7 and 8). Therefore, dba plays a non-innocent role in
this particular reaction, hindering catalysis.13 When the
reactions were run in the presence of K3PO4 or K2CO3,
instead of Cs2CO3, reduced yields of 69% and 39% were
obtained, respectively (Table 1, entries 9 and 10). Moreover,
the use of other solvents that are commonly used in C-N
cross-coupling reactions, such as dioxane, toluene, DME, or
DMF, lead to little or no product formation when used in
place of t-BuOH for these transformations (Table 1, entries
11-14).
With optimized reaction conditions in hand, we set out to
compare 1 to other biarylphosphine ligands that have
previously been employed in Pd-catalyzed C-N cross-
coupling reactions (Figure 2). By switching to a catalyst
comprised of 2, the dicyclohexylphosphino analogue of 1,
for the reaction of benzamide and 4-tert-butylphenyl meth-
anesulfonate, a slightly reduced yield of 84% was obtained.
This result was expected on the basis of earlier reports that
2formedanactivecatalystforbothC-NandSuzuki-Miyaura
(9) (a) So, C. M.; Zhou, Z.; Lau, C. P.; Kwong, F. Y. Angew. Chem.,
Int. Ed. 2008, 47, 6402. (b) Fors, B. P.; Watson, D. A.; Biscoe, M. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 13552.
(10) (a) Naber, J. R.; Fors, B. P.; Wu, X.; Gunn, J. T.; Buchwald, S. L.
Heterocycles 2010, 80, 1215. (b) Bhayana, B.; Fors, B. P.; Buchwald, S. L.
Org. Lett. 2009, 11, 3954. (c) So, C. M.; Lee, H. W.; Lau, C. P.; Kwong,
F. Y. Org. Lett. 2009, 11, 317. (d) Kuroda, J.; Inamoto, K.; Hiroya, K.;
Doi, T. Eur. J. Org. Chem. 2009, 2251. (e) So, C. M.; Lau, C. P.; Kwong,
F. Y. Angew. Chem., Int. Ed. 2008, 47, 8059.
(11) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett.
2008, 10, 3505.
Figure 2. Ligand comparison for the Pd-catalyzed amidation of
aryl mesylates.
(12) (a) Denmark, S. E.; Smith, R. C. Synlett 2006, 18, 2921. (b) Marion,
N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am.
Chem. Soc. 2006, 128, 4101.
Org. Lett., Vol. 12, No. 10, 2010
2351

Table 2. Pd-Catalyzed Cross-Coupling of Amides and Aryl
Table 3. Cross-Coupling Reactions of Heterocyclic Amides and
Heteroarylmesylates
Mesylatesa
a Reaction conditions: ArOMs (1.0 mmol), amide (1.2 mmol), Pd(OAc)2
(1 mol %), 1 (2.2 mol %), H2O (8 mol %), Cs2CO3 (1.4 mmol), t-BuOH (2
mL/mmol), 110 °C. b Isolated yields; average of 2 runs.
a Reaction conditions: ArOMs (1.0 mmol), amide (1.2 mmol), Pd(OAc)2
(1 mol %), 1 (2.2 mol %), H2O (8 mol %), Cs2CO3 (1.4 mmol), t-BuOH (2
mL/mmol), 110 °C. b Isolated yields; average of 2 runs.
cross-coupling reactions using aryl mesylates.9b,10b It is also
consistent with our prior finding that 1 was a more efficient
ligand for the Pd-catalyzed cross-coupling of amides and aryl
chlorides than 2.5a Employing ligand 3, which has been used
for amidation reactions of aryl tosylates,7b led to only trace
product formation. This illustrates the large differences in
reactivity between aryl tosylates and mesylates in cross-
coupling reactions. Further, substituting the 3-methoxy
substituent in 1 for a hydrogen or a methyl group (ligands 4
and 5) resulted in a drop in yield, demonstrating the influence
that the substituent in the 3-position of the ligand has on the
productivity of the catalyst.
rich aryl mesylates were transformed into the desired
N-arylamides in excellent yields with reaction times of less
than 4 h (Table 2, entries 1-5). Further, moderately electron-
deficient aryl mesylates proved to be highly efficient coupling
partners in these reactions (Table 2, entries 6 and 7). For
example, the reaction of 3-methoxyphenyl methanesulfonate
and benzamide resulted in a nearly quantitative yield in only
20 min. An o-methoxy on the aryl mesylate was well
tolerated (Table 2, entry 5); however, when the size of the
ortho substituent was increased (e.g., methyl), the reactions
did not proceed.
On the basis of these promising results we set out to
investigate more challenging substrates containing hetero-
cycles. Using a catalyst comprising 1, amides consisting of
heterocycles, such as 2-furamide, nicotinamide, or isonico-
tinamide, were coupled in good to excellent yields with
several different aryl mesylates (Table 3, entries 1-4). When
The scope of this reaction using a catalyst system based
on 1 was next explored. Both electron-neutral and electron-
(13) (a) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; McGlacken, G. P.;
Weissburger, F.; de Vries, A. H. M.; de Vondervoort, L. S. Chem.sEur. J.
2006, 12, 8750. (b) Mace, Y.; Kapdi, A. R.; Fairlamb, I. J. S.; Jutand, A.
Organometallics 2006, 25, 1795. (c) Amatore, C.; Jutand, A. Coord. Chem.
ReV. 1998, 178-180, 511.
2352
Org. Lett., Vol. 12, No. 10, 2010

an aryl mesylate that contained a non-nucleophilic hetero-
cycle [i.e., 4-(1H-pyrrol-1-yl)phenyl methanesulfonate] was
employed, the reaction gave a 94% yield (Table 3, entry 5).
However, when heteroaryl mesylates containing nucleophilic
groups were used, the yields of product were considerably
diminished and significant amounts of phenol formation were
observed (Table 3, entries 6 and 7). For example, the
coupling of 6-quinolinyl methanesulfonate and isobutyramide
yielded only 37% of the desired product. We postulated that
the heterocycles could be promoting phenol formation in two
ways. First, the aryl mesylates containing these heterocycles
are more electron-deficient, which could accelerate sulfonyl
transfer. This is consistent with the observation that when
the electron-deficient ethyl 3-[(methylsulfonyl)oxy]-benzoate
was employed as a substrate, a diminished yield of 67% was
obtained (Table 3, entry 4). Second, the heterocycles could
be acting as nucleophilic catalysts, assisting in desulfony-
lation. In support of this hypothesis, when 2-methyl-6-
quinolinyl methanesulfonate was used as the substrate, which
should be less nucleophilic than 6-quinolinyl methane-
sulfonate, the yield of the desired product was increased to
58% (Table 3, entry 8).
This system allows the coupling of electron-rich, -neutral,
and -deficient aryl mesylates in good to excellent yields.
Further, benzamides, aliphatic amides, and heterocyclic
amides all proved to be excellent coupling partners using
our new method. Finally, heteroaryl mesylates were also
successfully employed in these reactions, albeit with lower
yields than other substrates. Further studies to extend the
scope of these reactions to include secondary amides are
currently underway in our laboratories.
Acknowledgment. The authors thank the National Insti-
tutes of Health (NIH) for financial support of this project
(Grant GM-58160) and Merck, BASF (Pd compounds),
Chemetall (Cs2CO3), and Nippon Chemical for additional
support. B.P.F. thanks Boehringer Ingelheim and Merck for
fellowships. K.D. thanks the Department of Chemistry and
Interdisciplinary Nanoscience Center, University of Åarhus
for funding. The Varian NMR instrument used was supported
by the NSF (Grants CHE 9808061 and DBI 9729592).
Supporting Information Available: Procedural and spec-
tral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have developed a catalyst, based on ligand
1, for Pd-catalyzed amidation reactions using aryl mesylates.
OL100720X
Org. Lett., Vol. 12, No. 10, 2010
2353