Pd-catalyzed N-arylation of heteroarylamines

Article abstract of DOI:10.1021/ol0265923

(matrix presented) The palladium-catalyzed N-(hetero)arylation of a number of heteroarylamines including 2-aminopyridines, 2-aminothiazoles, and their analogues has been realized using Xantphos as the ligand. Weak bases such as Cs₂CO₃, Na₂CO₃, and K₃PO₄ were used in most cases to allow for the introduction of functional groups. Choice of the base and solvent was critical for the success of these reactions.

Full text of DOI:10.1021/ol0265923

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3481-3484
Pd-Catalyzed N-Arylation of
Heteroarylamines
Jingjun Yin,* Matthew M. Zhao, Mark A. Huffman, and James M. McNamara
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
jingjun_yin@merck.com
Received July 23, 2002
ABSTRACT
The palladium-catalyzed N-(hetero)arylation of a number of heteroarylamines including 2-aminopyridines, 2-aminothiazoles, and their analogues
has been realized using Xantphos as the ligand. Weak bases such as Cs2CO3, Na2CO3, and K PO4 were used in most cases to allow for the
3
introduction of functional groups. Choice of the base and solvent was critical for the success of these reactions.
Pd-catalyzed arylation of amines has attracted great attention
in the past few years.1 A wide range of aryl halides can be
coupled with primary and secondary amines or anilines under
mild conditions with excellent functional group compatibility.
However, few examples of Pd-catalyzed N-arylation of
heteroarylamines have been reported.2,3 Pd-catalyzed N-
arylation of aminopyridines2a-d and 3-aminothiophenes2e has
been achieved by using DPPP, BINAP, DPPF, or P(t-Bu)3
as ligand.4 However, the use of NaO-t-Bu as a strong base
limited the scope of these reactions. Recently, the arylation
of aminopyridines and analogous heteroarylamines using
BINAP and K2CO3 has been reported, but a large excess
(5-20 equiv) of the weak base was required.3 The scope of
the Pd-catalyzed N-arylation of heteroarylamines has been
mostly limited to aminopyridines and analogues, and no
examples with functional groups on the aryl halide or the
heteroarylamine have been reported. In addition, Pd-catalyzed
arylation of 2-aminothiazoles and analogues5,6 is previously
unreported despite the important biological activities of
2-arylaminothiazoles.5,7 Here, we wish to report our progress
in the Pd-catalyzed C-N bond-forming reactions between
(1) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (c) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (d) Yang, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (e) Muci, A. R.;
Buchwald, S. L. Practical Palladium Catalysts for C-N and C-O Bond
Formation. In Topics in Current Chemistry; Miyaura, N., Ed.; Springer-
Verlag: Berlin, 2002; Vol. 219, p 133.
(2) (a) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240. (b)
Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999,
1505. (c) Khan, M. M.; Ali, H.; van Lier, J. E. Tetrahedron Lett. 2001, 42,
1615. (d) Yang, J.-S.; Lin, Y.-H.; Yang, C.-S. Org. Lett. 2002, 4, 777. (e)
Ogawa, K.; Radke, K. R.; Rothstein, S. D.; Rasmussen, S. C. J. Org. Chem.
2001, 66, 9067. For an example of Ni- or Cu-catalyzed couplings between
a protected 5-iodouracil and heteroarylamines, see: (f) Arterburn, J. B.;
Pannala, M.; Gonzalez, A. M. Tetrahedron Lett. 2001, 42, 1475.
(3) (a) Jonckers, T. H. M.; Maes, B. U. W.; Lemie`re, G. L. F.; Dommisse,
R. Tetrahedron 2001, 57, 7027. (b) Kosˇmrlj, J.; Maes, B. U. W.; Lemie`re,
G. L. F.; Haemers, A. Synlett 2000, 1581.
(4) DPPP ) 1,3-bis(diphenylphosphino)propane; BINAP ) 2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl; DPPF ) 1,1′-bis(diphenylphosphino)-
ferrocene.
(5) Direct reaction of 2-aminothiazoles with highly activated aryl halides
in refluxing PhOH or EtOH has been very limited in scope and often resulted
in low yields in the absence of a 4-substituent on the thiazole. For examples,
see: (a) Sarkar, B. R.; Pathak, B.; Dutta, S.; Lahiri, S. C. J. Ind. Chem.
Soc. 1984, 61, 151. (b) Forlani, L.; Guastadisegni, G.; Raffellini, L.;
Todesco, P. E.; Foresti, E. Gazz. Chim. Ital. 1990, 120, 493. (c) Chauhan,
P. M. S.; Pratap, R.; Sharma, S. Ind. J. Chem. 1985, 15B, 1154. (d) El-
Bayouki, K. A. M.; Basyouni, W. M. Bull. Chem. Soc. Jpn. 1988, 61, 3794.
(e) Pande, A.; Pramilla, S.; Saxena, V. K.; Khan, M. N. A. A.; Verma, H.
N. Acta Pharm. Jugosl. 1984, 34, 61.
(6) For a Cu-catalyzed example, see ref 2f.
(7) Kim, K. S.; Kimball, D.; Cai, Z.-w.; Rawlins, D. B.; Misra, R. N.;
Poss, M. A.; Webster, K. R.; Hunt, J. T.; Ham, W.-C. U.S. Patent 6262096,
2001.
10.1021/ol0265923 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/05/2002

(hetero)aryl halides and heteroarylamines including 2-ami-
nopyridines, 2-aminothiazoles, and their analogues.
The reaction between 2-aminopyridine and electron-neutral
5-bromo-m-xylene was first studied to establish the most
effective conditions (Table 1). In addition to DPPF and
of DPPF or BINAP, the reaction only reached 67% conver-
sion in the same amount of time (Table 1, entries 5 and 6),
showing that Xantphos is a much better ligand for this
reaction.10,11
Using the above optimized conditions, i.e., Xantphos as
the ligand, Cs2CO3 as the base, and dioxane as the solvent,
a variety of heteroarylamines was reacted with (hetero)aryl
halides (Table 2). The amino group attached to a pyridine,
Table 1. Optimization of Conditionsa
Table 2. N-Arylation of 2-Aminopyridines and Othersa
entry
% Pd
ligand
base
conv (%)
B/Ab
1
2
3
4
5
6
7
8
9
4
8
8
8
8
8
8
4
4
1
Xantphos
Xantphos
Xantphos
DPPF
DPPF
BINAP
NaO-t-Bu
K3PO4
100c,d
100
100
46c
67
67
74e
100
100f
100f
0
0.30
0.30
0.05
0.04
0.19
0.14
0.12
0.08
0.01
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
BINAP
Xantphos
Xantphos
Xantphos
10
a Reaction conditions: 1.0 mmol of ArBr, 1.05 mmol of Ar′NH2, L/Pd
) 1.5, 1.2-1.4 equiv of base, 2.0-2.5 mL of dioxane, 100 °C, 15-20 h.
b Uncorrected LC ratio. c Toluene as the solvent. d 1.2 mmol of ArBr and
1.0 mmol of Ar′NH2 were used. e L/Pd ) 1. f L/Pd ) 1.1.
BINAP, which were typically used in previous reports for
this type of reaction,2,3 Xantphos8 was also tested as the
ligand. With Xantphos as the ligand and NaO-t-Bu as a
strong base, the reaction went smoothly without any forma-
tion of the undesired 2-anilinopyridine (B) (Table 1, entry
1).
However, when weaker bases such as K3PO4 and Cs2CO3
were used for potential functional group compatibility (Table
1, entries 2 and 3), significant amounts of byproduct B
formed.9 The amount of undesired aryl group transfer product
B decreased with decreasing amounts of Xantphos (Table
1, entries 3 and 8-10). We were pleased to find that the
reaction went to completion in 15 h with just 1% of Pd and
1.1% of Xantphos, limiting the byproduct to ∼1% (Table 1,
entry 10). On the other hand, even with 8% of Pd and 12%
a Reaction conditions: 1.0 mmol of aryl halide, 1.05-1.4 equiv of
Ar′NH2, 1.4 equiv of Cs2CO3, 0.5-2 mol % of Pd2(dba)3 (1 mol % of Pd
refers to 0.5 mol % of Pd2(dba)3), 1.1-4.4 mol % of Xantphos (L/Pd )
1.1), 4 mL (2 mL for entries 1, 2, 4, and 5) 1,4-dioxane, 100 °C, 15-23 h.
Isolated yields are reported. b 1 mol % of BINAP was used as ligand.
c Values in parentheses are from Xantphos. LC yield is given (82%
conversion). d L/Pd ) 1.5. e 1.0 equiv of KO-t-Bu was added to neutralize
the HCl salt of 4-chloropyridine; 1.4 equiv of K3PO4 was used instead of
Cs2CO3.
(8) First developed by van Leeuwen: (a) Kranenburg, M.; van der Burgt,
Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Organometallics
1995, 14, 3081. For previous examples using Xantphos in Pd-catalyzed
C-N bond forming reactions, see: (b) Guari, Y.; van Es, D. S.; Reek, J.
N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Tetrahedron Lett. 1999,
40, 3789. (c) Harris, M. C.; Geis, O.; Buchwald, S. L. J. Org. Chem. 1999,
64, 6019. (d) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (e)
Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
10251. (f) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (g) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (h) Cacchi, S.; Fabrizi,
G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539. (i) Artamkina,
G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381.
(j) Browning, R. G.; Mahmud, H.; Badarinarayana, V.; Lovely, C. J.
Tetrahedron Lett. 2001, 42, 7155. (k) Anbazhagan, M.; Stephens, C. E.;
Boykin, D. W. Tetrahedron Lett. 2002, 43, 4221.
pyrimidine, pyrazine, triazine, pyrazole, or thiophene ring
could be arylated with electron-neutral (Table 2, entries 1
and 9) and electron-rich aryl bromides (Table 2, entry 5) as
well as 2-, 3-, or 4-halopyridines. An ortho-substituted aryl
bromide (2-bromotoluene) was also coupled with amino-
(10) For other examples where the use of Xantphos provides better results
than the use of BINAP or DPPF, see ref 8e-j.
(9) It formed likely via exchange between the aryl group of ArBr bound
to Pd and the phenyl group of Xantphos. For similar observations, see: (a)
Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 3694-3703.
(b) Reference 8f,g,i. For a mechanistic study, see: (c) Goodson, F. E.;
Wallow, T. I.; Novak, B. M. J. Am. Chem. Soc. 1997, 119, 12441.
(11) For discussions of its unique trans-coordination to Pd, see: (a)
Reference 8g. (b) Guari, Y.; van Strijdonck, G. P. F.; Boele, M. D. K.;
Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Chem. Eur. J.
2001, 7, 475. (c) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N.
H. Acc. Chem. Res. 2001, 34, 895.
3482
Org. Lett., Vol. 4, No. 20, 2002

Table 3. N-Arylation of 2-Aminothiazoles and Analoguesa
a Reaction conditions: 1.0 mmol of aryl halide, 1.05-1.4 equiv of Ar′NH2, 1.1-2.4 equiv of base, 1-4 mol % of Pd2(dba)3, 3-12 mol % of Xantphos
(L/Pd ) 1.5), toluene (4-8 mL/mmol ArX), 100 °C, 15-16 h. Isolated yields are reported. b 1.0 equiv of H2O was added. c 1,4-Dioxane as the solvent.
d L/Pd ) 1.1.
pyrazine (Table 2, entry 6) and even 2-amino-3-methyl-
-pyridine (Table 2, entry 3). Relatively low levels of catalyst
loading (1-2% of Pd except for the hindered substrates in
entry 3) were required, which was also important to lower
the amounts of the undesired N-phenyl heteroarylamines
when inactivated aryl halides were used. With the use of
just 1.4 equiv of Cs2CO3 as a weak base, functional groups
such as aldehyde and methyl/ethyl ester groups are tolerated
(Table 2, entries 4, 7, and 9). A secondary aminopyridine
(2-methylaminopyridine) also underwent the cross-coupling
reactions using the weak base. Interestingly, BINAP was a
better ligand for the reaction between 2-aminopyridine and
2-chloropyridine (Table 2, entry 2).12
Unfortunately, under the above optimized conditions, the
reactions between 2-chloropyridines and 2-aminothiazoles
gave very little products. In addition, reactions between
2-chloropyridine and 2-aminothiazole/2-aminobenzothiazole
did not proceed at all under previously reported conditions
(EtOH, NEt3, 100 °C, 16 h) for direct nucleophilic attack of
2-aminothiazoles to highly activated aryl halides without
catalysts.5c,d After an extensive screening of reaction variables
including the base, solvent, additive, and ligand, we found
Xantphos was still the best ligand among those commonly
used for Pd-catalyzed aminations. The key to the success of
these reactions, however, was to use Na2CO3 or K3PO4
instead of Cs2CO3 as the base and toluene as the solvent in
many cases. The results of arylation of 2-aminothiazoles and
analogues are summarized in Table 3.13
2-Aminothiazoles with various substituents reacted with
2-chloropyridines, 2-chloropyrimidine, chloropyrazine, 2-chlo-
roquinoline, and 4-nitrochlorobenzene in good to excellent
yields (Table 3, entries 1-5). No 4-substituents on the
thiazole were required for a successful reaction (Table 3,
entries 1-3).5 Functional groups such as nitro and ester
groups were tolerated. 2-Amino-1,3,4-thiadiazole and 2-ami-
nobenzothiazole also reacted with 2-chloropyridine under
these conditions (Table 3, entries 6 and 7). In a few reactions,
0.5-1 equiv of H2O was added to help push the reaction to
completion (Table 3, entries 1, 3, and 4).14 Relatively higher
levels of catalyst loading (2-8% of Pd) were required, and
it was necessary to run these reactions at lower concentrations
(13) Typical Procedure (Table 3, Entry 4). A re-sealable Schlenk tube
was charged with Pd2(dba)3 (18.4 mg, 0.02 mmol, 4 mol % Pd), Xantphos
(34.7 mg, 0.06 mmol), 2-amino-4-methylthiazole (140 mg, 1.2 mmol), Na2-
CO3 (fine powder, 149 mg, 1.4 mmol), chloropyrazine (0.091 mL, 1.0
mmol), and degassed toluene (4 mL). While the mixture was being stirred,
H2O (18 mg, 1.0 mmol) was added dropwise. The Schlenk tube was capped
and carefully subjected to three cycles of evacuation-backfilling with N2.
It was then sealed and immersed into a 100 °C oil bath. After 15 h, the
mixture was cooled, diluted with THF, filtered, concentrated, and chro-
matographed on an SiO2 flash column to give a crude product. It was then
sonicated in 3 mL of toluene-hexanes (1:1), filtered, and dried to give the
pure product as a white solid (167 mg, 87%).
(12) In this work, we found that BINAP was a better ligand only for
reactions between 2-halopyridines and 2-aminopyridine/pyrimidines.
(14) The exact role of water is unclear. One possibility is that it helped
solubilize the inorganic base to increase the reaction rate.
Org. Lett., Vol. 4, No. 20, 2002
3483

(4-8 mL of solvent/mmol ArX).15 When an electron-neutral
aryl halide was used, 2-aminothiazole itself failed to give
the desired reaction under various conditions, but 2-
aminobenzothiazole and 2-amino-1-methylbenzimidazole
were arylated using NaO-t-Bu as the base (Table 3, entries
8 and 9).
In summary, we have developed a protocol for the
N-(hetero)arylation of a number of heteroarylamines includ-
ing 2-aminopyridines and their analogues using Xantphos
as the ligand, Cs2CO3 as the base, and dioxane as the solvent.
Aryl halides with various electronic and steric properties
could be used, and functional groups were well tolerated.
The first Pd-catalyzed arylation of 2-aminothiazoles and
analogues was also accomplished with the use of Xantphos
as the ligand. Na2CO3 and K3PO4 had to be used instead of
Cs2CO3 for the reactions with activated (hetero)aryl halides,
and NaO-t-Bu was required for inactivated aryl halides.
Acknowledgment. We thank Bob Reamer for NMR
assistance.
Supporting Information Available: Experimental pro-
cedures and characterization data for arylation products
(Tables 2 and 3). This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) For a discussion of the concentration effect, see ref 8g.
OL0265923
3484
Org. Lett., Vol. 4, No. 20, 2002