Palladium-catalyzed amidation of 2-chloropyrimidines

Article abstract of DOI:10.1016/j.tetlet.2010.12.088

A mild and efficient Pd-catalyzed coupling of amides with 2-chloropyrimidines is described. The use of bidentate phosphines, such as Xantphos (7), as supporting ligands was found to be crucial for providing high yields of 2-(N-acylamino)pyrimidine couplin

Full text of DOI:10.1016/j.tetlet.2010.12.088

Tetrahedron Letters 52 (2011) 1020–1022
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed amidation of 2-chloropyrimidines
⇑
Marc Vimolratana, Jillian L. Simard, Sean P. Brown
Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient Pd-catalyzed coupling of amides with 2-chloropyrimidines is described. The use of
bidentate phosphines, such as Xantphos (7), as supporting ligands was found to be crucial for providing
high yields of 2-(N-acylamino)pyrimidine coupling products 1.
Received 12 November 2010
Revised 15 December 2010
Accepted 19 December 2010
Available online 29 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Table 1
The Pd-catalyzed cross-coupling of amides with aryl halides has
emerged as a powerful method for the construction of (N-acyla-
mino)arenes.1 Efficient couplings of both primary and secondary
amides with various aryl halides2 and sulfonates3 have been
reported. In the course of our medicinal chemistry efforts, we
The effect of ligand on the Pd-catalyzed amidation of 2-chloropyrimidine
O
N
Pd2(dba)3, ligand
O
N
Ph
N
H
N
8
Ph
NH2
Cl
Cs2CO3, dioxane, 100 °C
N
required access to substituted 2-(N-acylamino)pyrimidines
1
Entrya
Ligand
Pd2(dba)3 (%)
Yieidb (%)
(Fig. 1). However, to our knowledge, there have been no reports
of C–N cross-coupling reactions between amides and 2-halopyrim-
idines.4 Inspired by the broad functional group tolerance and
robust nature of Pd-catalyzed processes, we set out to develop a re-
lated protocol for the synthesis of diverse pyrimidines 1. In this
Letter, we describe a method for the N-arylation of amides with
2-chloropyrimidines using a Pd catalyst derived from the bidentate
phosphine ligand Xantphos (7) (Fig. 1).
1
2
3
4
5
6
7
8
None
None
XPhos (2)
XPhos (2)
0
5
5
5
2
2
29
43c
35
3
BrettPhos (3)
Me4tBuXPhos (4)
Me4tBuXPhos (4)
BINAP (5)
5
5
5
5
5
5
5
5
1
41d
89
89
92c
94
91c
82
9
dppf (6)
dppf (6)
Xantphos (7)
Xantphos (7)
Xantphos (7)
10
11
12
13
Me
R
a
Me
Me
Reaction conditions: 2-chloropyrimidine (1.2 equiv), benzamide (1 equiv),
Pd2(dba)3 (5 mol % or as otherwise indicated), ligand (1.5 equiv to Pd), Cs2CO3
R
i-Pr
PCy2
i-Pr
O
N
(1.4 equiv), 1,4-dioxane (0.5 M), 100 °C.
Me
i-Pr
P(t-Bu)2
i-Pr
b
Yields refer to pure isolated product after a reaction time of 16 h and are
R
N
H
N
unoptimized.
c
Toluene and 110 °C were used instead of dioxane and 100 °C, respectively.
K3PO4 and t-BuOH was used instead of Cs2CO3 and dioxane, respectively.
d
2-(N-acylamino)pyrimidine
i-Pr
i-Pr
1
2
4
R=H, XPhos ( )
Me4tBuXPhos ( )
In our initial studies, we sought to define suitable conditions for
the Pd-catalyzed coupling of benzamide with 2-chloropyrimidine
(Table 1). Recently, Buchwald and co-workers have demonstrated
the utility of monodentate biaryl phosphine ligands, such as XPhos
(2), BrettPhos (3), and Me4tBuXPhos (4) (Fig. 1), in the Pd-catalyzed
amidation of aryl halides and sulfonates.2b–e,3b–e Unfortunately, in
our hands, Pd catalysts derived from these ligands performed
poorly in the amidation of 2-chloropyrimidine (entries 3, 5, and
6). Given this surprising result, we hypothesized that the amida-
tion product 8 may be interfering with catalyst turnover by pro-
moting the formation of an inactive Pd-chelate complex. We,
therefore, surmised that switching to bidentate phosphine ligands
would prove beneficial. To our delight, Pd catalysts derived from
3
R=OMe, BrettPhos ( )
Me Me
PPh2
Fe
PPh2
PPh2
PPh2
O
PPh2
PPh2
5
6
dppf ( )
Xantphos (7)
BINAP ( )
Figure 1. 2-(N-Acylamino)pyrimidine architecture and phosphine ligands.
⇑
Corresponding author. Tel.: +1 650 244 2258; fax: +1 650 244 2015.
E-mail address: sebrown@amgen.com (S.P. Brown).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.088

M. Vimolratana et al. / Tetrahedron Letters 52 (2011) 1020–1022
1021
Table 3
several bidentate phosphines, including BINAP (5), dppf (6), and
The Pd-catalyzed coupling of benzamide with representative halopyrimidines
Xantphos (7), all afforded excellent yields of the coupled product
8 (entries 8, 9, and 11).5,6 Xantphos (7), in particular, has been
widely employed as a supporting ligand in Pd-catalyzed amidation
reactions2a,3a,3h,7 and, on this basis, was chosen for further evalua-
tion in this process.
N
X
N
O
Pd2(dba)3, Xantphos
O
R
R
Ph
N
H
N
Ph
NH2
N
Cs2CO3, dioxane, 100 °C
Entrya
Azine
Product
Yieldb (%)
94
We next examined the scope of the amide component in the Pd-
catalyzed amidation of 2-chloropyrimidine (Table 2). A variety of
amides, including aromatic, aliphatic, and cyclic derivatives, partic-
ipated in the coupling reaction. Notably, electron-rich, electron-
deficient, and ortho-substituted benzamides all coupled efficiently
(entries 2–4). Considerable variation in the steric requirement of
primary aliphatic amides was readily accommodated (entries 5
and 6). In fact, coupling of the sterically encumbered substrate piv-
alamide furnished the expected acylaminopyrimidine in nearly
quantitative yield (entry 6). A cyclic secondary amide (or lactam)
also reacted efficiently (entry 7). However, in accordance with pre-
vious disclosures, acyclic secondary amides proved to be reluctant
coupling partners (entries 8 and 9).2a
N
O
O
N
N
1
Cl
N
N
Ph
Ph
N
H
N
N
N
2
3
71
65
N
H
Br
Et
Et
O
O
O
O
N
N
N
N
N
Ph
Ph
Ph
Ph
N
H
N
N
N
N
Cl
N
N
N
N
N
4
5
6
96
82
27
Cl
N
H
CF3
OMe
Me
CF3
N
Table 2
The Pd-catalyzed coupling of 2-chloropyrimidine with representative amides
Cl
N
H
OMe
Me
O
O
N
N
N
Pd2(dba)3, Xantphos
Cs2CO3, dioxane, 100 °C
Product
R1
NH
R2
R1
N
N
Cl
N
Cl
N
H
R2
Entrya
Amide
Yieidb (%)
a
Reaction conditions: ArX (1.2 equiv), amide (1 equiv), Pd2(dba)3 (5 mol %),
Xantphos (15 mol %), Cs2CO3 (1.4 equiv), 1,4-dioxane (0.5 M), 100 °C.
Yields refer to pure isolated product after a reaction time of 16 h and are
unoptimized.
O
O
N
b
1
2
94
NH2
N
H
N
O
O
N
Significant variation in the halopyrimidine component of the
amidation reaction was also permitted (Table 3). Both 2-chloro-
and 2-bromopyrimidine were suitable substrates for amidation
with benzamide (entries 1 and 2). In general, substitution of the
halopyrimidine nucleus with electron-withdrawing or electron-
donating functional groups did not appreciably alter the efficiency
of the reaction (entries 3–5). It is worth noting, however, that
couplings of 2-chloro-4-methylpyrimidine (entry 6) and 2-
chloro-4,6-dimethylpyrimidine (not shown) did not proceed to full
conversion. We suspect that the poor reactivity of chloropyrimi-
dines bearing methyl substituents at the 4- or 6-positions may
be attributable to the relative acidity of the conjugated pseudo-
benzylic protons.
In conclusion, we have described a mild and efficient Pd-cata-
lyzed coupling of amides with 2-chloropyrimidines for the forma-
tion of diverse 2-(N-acylamino)pyrimidines 1. The use of bidentate
phosphines, such as Xantphos (7), as supporting ligands was found
to be important for achieving high yields of coupled products.
Studies to evaluate the scope of 2-haloazine component of the ami-
dation reaction are underway.
NH2
NH2
N
N
71
87
80
H
F3C
F3C
O
O
N
3
4
N
N
H
MeO
MeO
O
N
O
NH2
N
H
N
Me
Me
O
N
O
5
6
7
8
91
96
93
38
Me
NH2
O
Me
N
H
N
N
O
Me
Me
Me
Me
NH2
N
H
N
Me
Me
O
N
O
NH
N
O
N
Supplementary data
O
N
Me
NH
Me
Me
N
Me
O
N
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.088.
O
References and notes
9
32
NH
Me
N
Me
N
1. For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400; (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428; (c) Ma, D.; Cai, Q.
Acc. Chem. Res. 2008, 41, 1450; (d) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed
Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds., 2nd ed.; Wiley-VCH:
Weinheim, Germany, 2004; (e) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 6338; (f) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
a
Reaction conditions: ArCl (1.2 equiv), amide (1 equiv), Pd2(dba)3 (5 mol %),
Xantphos (15 mol %), Cs2CO3 (1.4 equiv), 1,4-dioxane (0.5 M), 100 °C.
Yields refer to pure isolated product after a reaction time of 16 h and are
unoptimized.
b

1022
M. Vimolratana et al. / Tetrahedron Letters 52 (2011) 1020–1022
2. (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101; (b) Hicks, J. D.; Hyde, A. M.;
Martinez Cuezva, A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 16720; (c)
Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
13001; (d) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10,
3505; (e) Fors, B. P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. Tetrahedron 2009,
65, 6576; (f) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani, M.; Larsen, R. D.; Faul,
M. M. Org. Lett. 2008, 10, 2609; (g) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6,
2433; (h) Audisio, D.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.
Tetrahedron Lett. 2007, 48, 6928; (i) Messaoudi, S.; Audisio, D.; Brion, J.-D.;
Alami, M. Tetrahedron 2007, 63, 10202; (j) Artamkina, G. A.; Sergeev, A. G.;
Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381; (k) Hartwig, J. F.; Kawatsura,
M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
5575; (l) Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz, L. Org. Lett. 2003,
5, 2207; (m) Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. J. Org.
Chem. 2006, 71, 375; (n) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett.
2006, 8, 3311; (o) Ye, W.; Mo, J.; Zhao, T.; Xu, B. Chem. Commun. 2009, 3246; (p)
Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734; (q) Shi, F.; Smith, M. R.;
Maleczka, R. E. Org. Lett. 2006, 8, 1411; (r) Shen, Q.; Shekhar, S.; Stambuli, J. P.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371; (s) Kotecki, B. J.; Fernando, D.
P.; Haight, A. R.; Lukin, K. A. Org. Lett. 2009, 11, 947.
R.; Chen, C.; Volante, R. P. Org. Lett. 2005, 7, 1185; (h) 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.
4. Example of amidation of 2-chloropyridopyrimidines and 3-chloropurine,
respectively: (a) Tikad, A.; Routier, S.; Akssira, M.; Leger, J.; Jarry, C.;
Guillaumet, G. Synthesis 2009, 14, 2379; (b) Vilarrasa, J.; Caner, J. J. Org. Chem.
2010, 75, 4880.
5. Typical procedure for Pd-catalyzed amidation of 2-chloropyrimidines. A screw-cap
vial was charged with benzamide (121 mg, 1.00 mmol), Cs2CO3 (456 mg,
1.40 mmol), Xantphos (87 mg, 0.15 mmol), Pd2(dba)3 (46 mg, 0.050 mmol), 2-
chloropyrimidine (137 mg, 1.20 mmol), and 1,4-dioxane (2 mL). The mixture
was sparged with nitrogen for 3 min, stirred for 16 h at 100 °C, and cooled to
room temperature. The residue was diluted with dichloromethane, filtered
through celite, and concentrated. The crude product was purified by silica gel
flash chromatography (40–100% ethylacetate/hexanes) to provide N-(pyrimidin-
2-yl)benzamide (188 mg, 0.85 mmol, 94% yield) as an amorphous solid (Table 1,
entry 8).
6. The reaction efficiency observed with dppf (6) as a supporting ligand and
toluene as solvent (Table 1, entry 10) is in discord with results disclosed in Ref.
4b pertaining to the amidation of a 3-chloropurine derivative (0% yield). The
disparity between these two results accentuates the reactivity variation often
observed among differing heterocyclic architectures.
3. (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043; (b) Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 6653; (c) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754; (d) Dooleweerdt, K.; Fors, B. P.; Buchwald, S. L. Org. Lett.
2010, 12, 2350; (e) Willis, M. C.; Brace, G. N.; Holmes, I. P. Synthesis 2005, 3229;
(f) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777; (g) Klapars, A.; Campos, K.
7. Example of amidation of 2-iodopurines: (a) Vandromme, L.; Legraverend, M.;
Kreimerman, S.; Lozach, O.; Meijer, L.; Grierson, D. S. Bioorg. Med. Chem. 2007,
15, 130; (b) Piguel, S.; Legraverend, M. J. Org. Chem. 2007, 72, 7026.