A highly regioselective amination of 6-aryl-2,4-dichloropyrimidine

Article abstract of DOI:10.1021/ol052578p

A highly regioselective amination of 6-aryl-2,4-dichloropyrimidine with aliphatic secondary amines and aromatic amines has been developed which strongly favors the formation of the C4-substituted product. The reactions with aliphatic amines are carried ou

Full text of DOI:10.1021/ol052578p

ORGANIC
LETTERS
2006
Vol. 8, No. 3
395-398
A Highly Regioselective Amination of
6-Aryl-2,4-dichloropyrimidine
Zhi-Hui Peng,* Michel Journet, and Guy Humphrey
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
zhihui_peng@merck.com
Received October 24, 2005
ABSTRACT
A highly regioselective amination of 6-aryl-2,4-dichloropyrimidine with aliphatic secondary amines and aromatic amines has been developed
which strongly favors the formation of the C4-substituted product. The reactions with aliphatic amines are carried out using LiHMDS as the
base and are catalyzed by Pd, while the aromatic amines require no catalyst.
Pyrimidines are widespread heterocyclic motifs found in
numerous natural products as well as synthetic pharmaco-
phores with antibacterial, antimicrobial, and antimycotic
activities.1 The highly electron-deficient nature of the pyri-
midine ring renders the nucleophilic aromatic substitution
reaction (SNAr) a general approach for the synthesis of a
large number of pyrimidine derivatives, especially from
readily available halopyrimidines.1 This feature also translates
to palladium-catalyzed cross-coupling reactions as even
pyrimidine chlorides are highly reactive substrates.2
The reactivity of each position of the pyrimidine halides
follows the general order C4(6) > C2 . C5. This order has
been observed for both palladium-catalyzed reactions and
SNAr displacements.1,2 In palladium-catalyzed C-C bond
formation reactions, Sonogashira reactions showed little
difference in reactivity between the C2 and C4 positions of
halopyrimidines,3 while a strong preference for the C4
position has been observed in Suzuki4 and Stille5 coupling
reactions such that the sequential introduction of different
substituents has been achieved.
The nucleophilic substitution reactions of 2,4-dichloropyri-
midines are generally only moderately selective toward the
formation of the C4-substituted product. For example, the
nucleophilic displacement of 2,4-dichloropyrimidines with
neutral nitrogen nucleophiles affords only 1:1 to 4:1 ratios
of the C4/C2 isomers (eq 1).6-8 This lack of regioselectivity
(4) (a) Gronowitz, S.; Hornfeldt, A.-B.; Kristjansson, V.; Musil, T. Chem.
Scr. 1986, 26, 305-309. (b) Cocuzza, A. J.; Hobbs, F. W.; Arnold, C. R.;
Chidester, D. R.; Yarem, J. A.; Culp, S.; Fitzgerald, L.; Gilligan, P. J. Bioorg.
Med. Chem. Lett. 1999, 9, 1057-1062. (c) Jiang, B.; Yang, C.-G.
Heterocycles 2000, 53, 1489-1498. (d) Gong, Y.; Pauls, H. W. Synlett
2000, 829-831. (e) Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66,
7125-7128.
(5) (a) Solberg, J.; Undheim, K. Acta Chem. Scand., Ser. B 1989, 43,
62-68. (b) Benneche, T. Acta Chem. Scand. 1990, 44, 927-931.
(6) For early examples, see: (a) Gabriel, S. Chem. Ber. 1901, 34, 3362-
3366. (b) Bu¨ttner, E. Chem. Ber. 1903, 36, 2227-2235. (c) Winkelmann,
W. J. Prakt. Chem. 1927, 115, 292-296. (d) Boon, W. R. J. Chem. Soc.
1952, 1532-1535.
(7) For recent examples, see: (a) Mossini, F.; Maggiali, C.; Morini, G.;
Impicciatore, M.; Morini, G.; Molina, E. Farmaco, Ed. Sci. 1984, 39, 189-
199. (b) Delia, T. J.; Stark, D.; Glenn, S. K. J. Heterocycl. Chem. 1995,
32, 1177-1180. (c) Schomaker, J. M.; Delia, T. J. J. Heterocycl. Chem.
2000, 37, 1457-1462. (d) Luthin, D. R.; Hong, Y.; Tompkins, E.; Anderes,
K. L.; Paderes, G.; Kraynov, E. A.; Castro, M. A.; Nared-Hood, K. D.;
Castillo, R.; Gregory, M.; Vazir, H.; May, J. M.; Anderson, M. B. Bioorg.
Med. Chem. Lett. 2002, 12, 3635-3640. (e) Montebugnoli, D.; Bravo, P.;
Brenna, E.; Mioskowski, C.; Panzeri, W.; Viani, F.; Volonterio, A.; Wagner,
A.; Zanda, M. Tetrahedron 2003, 59, 7147-7156. (f) Joubran, L.; Jackson,
W. R.; Campi, E. M.; Robinson, A. J.; Wells, B. A.; Godfrey, P. D.;
Callaway, J. K.; Jarrott, B. Aust. J. Chem. 2003, 56, 597-606.
(1) (a) Hurst, D. T. In An Introduction to the Chemistry and Biochemistry
of Pyrimidines, Purines and Pteridines; Wiley: Chichester, 1980. (b) Brown,
D. J. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, Chapter 2.13. (c) Brown,
D. J. In The Pyrimidines; Interscience Publishers: New York, 1994.
(2) (a) Undheim, K.; Benneche, T. Heterocycles 1990, 30, 1155-1193.
(b) Undheim, K.; Benneche, T. In AdV. Heterocycl. Chem. 1995, 62, 305-
418. (c) Kalinin, K. N. Synthesis 1992, 413-432. (d) Littke, A. F.; Fu, G.
C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(3) Edo, K.; Yamanaka, H.; Sakamoto, T. Heterocycles 1978, 9, 271-
274.
10.1021/ol052578p CCC: $33.50
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makes these amination reactions of limited use synthetically
since the isomers are often difficult to separate. In support
of a recent development program, we required an efficient
C4 regioselective amination of 6-(4-fluorophenyl)-2,4-
dichloropyrimidine 3. During the course of our investigations,
we have discovered a highly regioselective amination
protocol of 6-aryl-2,4-dichloropyrimidines which strongly
favors the formation of the C4-isomer. In this paper, we
report our results of this unprecedented regioselective pal-
ladium-catalyzed amination reaction of 2,4-dichloropyrim-
idines.
slower and only afforded a 70:30 ratio of 4a/5a. This
dramatic difference was later attributed to the presence of
an impurity in the crystallized material, which was isolated
by careful chromatography and was determined by X-ray
crystallography to be the palladium adduct of 2,4,6-trichlo-
ropyrimidine 6 from the Suzuki coupling reaction (Figure
1). Complex 6 was a highly effective catalyst for the
Pyrimidine 3 was prepared via the Suzuki coupling
reaction of 2,4,6-trichloropyrimidine 1 with 4-fluorophenyl-
boronic acid 2 using a slightly modified literature procedure
(Scheme 1).4e The reaction of 3 with dibutylamine under the
Figure 1. ORTEP view of complex 6.
amination reaction. When the amination of the pure chro-
matographed 3 was carried out in the presence of 2 mol %
of 6, the reaction gave the same result as the crystallized
material (Scheme 1). A review of the literature revealed that
similar palladium-coordinated pyrimidine complexes have
been isolated and have shown catalytic activity in Stille
coupling reactions.5b Although chloro- and bromopyrimidines
have occasionally been employed as coupling partners in Pd-
catalyzed aminations,10,11 to the best of our knowledge, no
examples of regioselective palladium-catalyzed aminations
of 2,4-dichloropyrimidines have been reported.
Scheme 1
Having established that Pd was required for high regiose-
lectivity, the reaction of 3 with dibutylamine was screened
with a number of phosphine ligands using Pd(OAc)2 as the
palladium source (Table 1). Unexpectedly, several of the
most general and highly active monodentate phosphine
ligands for the cross-coupling reactions, such as XPhos,12
Josiphos,13 and (t-Bu)3P,14 were poor catalyst systems for
the reaction. Not only were the reactions much slower, the
regioselectivities were also poor (entries 1-3). On the other
hand, the simple and inexpensive monodentate and bidentate
common SNAr conditions (K2CO3, DMAc) gave only a 70:
30 ratio of the C4 isomer 4a to the C2 isomer 5a (Scheme
1). In an effort to improve the regiochemisty of the reaction,
various solvents and bases were examined. Interestingly, very
different results were obtained for chromatographed 3 versus
crystallized9 3 when the reaction was carried out in THF
with LiHMDS as the base. The crystallized material gave
an impressive 99:1 ratio of 4a/5a, and the reaction was
completed in less than 0.5 h to afford 4a in 95% yield, while
the reaction of the chromatographed material was much
(10) For reviews on Pd-catalyzed aminations of aryl halides, see: (a)
Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A., Diederich, F., Eds.; John Wiley & Sons: Weinheim,
2004. (b) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002.
(11) For examples, see: (a) Charles, M. D.; Schultz, P.; Buchwald, S.
L. Org. Lett. 2005, 7, 3965-3968. (a) Kamenecka, T. M.; Lanza, T.; de
Laszlo, S. E.; Li, B.; McCauley, E. D.; Van Riper, G.; Egger, L. A.;
Kidambi, U.; Mumford, R. A.; Tong, S.; MacCoss, M.; Schmidt, J. A.;
Hagmann, W. K. Bioorg. Med. Chem. Lett. 2002, 12, 2205-2208. (b) Yin,
J. J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4,
3481-3484.
(8) Better regioselectivity has been obtained with N-sodium carbam-
ates: (a) Zanda, M.; Talaga, P.; Wagner, A.; Mioskowski, C. Tetrahedron
Lett. 2000, 41, 1757-1761. (b) Montebugnoli, D.; Bravo, P.; Corradi, E.;
Dettori, G.; Mioskowski, C.; Volonterio, A.; Wagner, A.; Zanda, M.
Tetrahedron 2002, 58, 2147-2154.
(9) Compound 3 could be isolated by crystallization from the crude
Suzuki coupling reaction mixture using MTBE-hexanes as the solvents.
(12) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655.
(13) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2005, 44, 1371-1375.
(14) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,
39, 617-620. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580.
396
Org. Lett., Vol. 8, No. 3, 2006

secondary amines were the best substrates, giving high
regioselectivity with all the effective catalyst systems shown
in Table 1 (entries 4-9). For the cyclic secondary amines,
however, complex 6 and Pd(OAc)2/dppb were the only
catalysts that produced high regioselectivities (Table 2,
entries 2-6). The mode of addition was also critical for the
more reactive cyclic amines to obtain high regioselectivity.
The cyclic secondary amines were premixed with LiHMDS
(1 M THF solution) and then added to the THF solution of
the pyrimidine and the catalyst to achieve the catalyzed
reaction. If the amine was added to the dichloropyrimidine
prior to premixing with LiHMDS (with or without the
catalyst), the neutral amine reacted quickly with the dichlo-
ropyrimidine through the SNAr pathway to give much lower
regioselectivities. Although LiHMDS is not basic enough
to fully deprotonate the secondary aliphatic amines,15 it may
complex with the amines to form the active species in the
palladium-catalyzed cycle.16 Unfortunately, the palladium-
catalyzed regioselective aminations was not suitable for the
aliphatic primary amines due to significant side reactions of
bis-arylation of the amines.17
Table 1. Catalyst Screening of the Amination of 3 with
Dibutylamine
ratio
yieldb of
entry
catalyst
time (4a:5a)a 4a (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2/X-phos (5 mol %)c
6 h
85:15
80:20
78:22
94:6
98:2
95:5
74
65
61
88
92
83
97
90
96
Pd(OAc)2/Josiphos (5 mol %)c 10 h
Pd(OAc)2P(t-Bu)3 (5 mol %)c 10 h
Pd(OAc)2/P(o-tol)3 (5 mol %)c
Pd(OAc)2/PPh3 (5 mol %)c
Pd(OAc)2/dppp (5 mol %)
Pd(OAc)2/dppb (1 mol %)
Pd(OAc)2/dpppe (5 mol %)
PdCl2(PPh3)2 (5 mol %)
2 h
30 min
1 h
5 min >99:1
1 h
97:3
99:1
5 min
a HPLC ratio. b HPLC assay yield. c 10 mol % of the ligand was used.
phenylphosphine ligands proved to be very effective (entries
4-8). The most active ligand was found to be the bidentate
ligand dppb (entry 7). With only 1 mol % catalyst loading,
the amination reaction was completed almost instantly at 0
°C to provide >99:1 selectivity for the C4-isomer 4a in high
yield. PdCl2(PPh3)2 was another active catalyst for this reac-
tion (entry 9). A screen of bases revealed that only LiHMDS
gave rapid reactions as well as high regioselectivity.
Previous studies of the nucleophilic substitution reactions
of anilines with 2,4,6-trichloropyrimidine gave rise to higher
regioselectivity for the C4-isomer (ca. 10:1) in polar solvents
such as ethanol.7c The nucleophilic substitution reaction of
3 with aniline, however, gave only 70:30 regioselectivity and
the reaction required forcing conditions to go to completion
due to the low nucleophilicity of aniline (Table 2, entry 7).
When the amination was carried out under the palladium
catalyzed conditions, the reaction was completed almost
instantaneously18 even at -60 °C to give a much better ratio
of 91:9 (Table 2, entry 7). We subsequently found that the
reaction gave the same result in the absence of the catalyst.
A plausible explanation was that the aniline was fully
deprotonated by LiHMDS to give the anionic anilide,15 and
direct nucleophilic substitution with the anilide was much
faster than the palladium-catalyzed reaction. Furthermore,
the secondary N-methylaniline gave an excellent 97:3 ratio
under the same conditions (Table 2, entry 8). Delia and co-
worker reported that the nucleophilic substitution reaction
of 2,4,6-trichloropyrimidine with the anionic phenolate ion
gave a good C4/C2 regioselectivity (90:10).19 This observa-
tion was explained by the reaction at C4 giving a more
favorable para-quinoid Meisenheimer intermediate than the
ortho-quinoid intermediate formed via the C2 substitution
pathway.
The palladium-catalyzed regioselective amination proved
to be general for a number of aliphatic secondary amines.
As shown in Table 2, while the SNAr reactions gave only
Table 2. Aminations of 3 with Aliphatic Secondary Amines
and Anilines
(15) The pKa values (in DMSO) for HN(SiMe)3, pyrrolidine, and aniline
are 30, 44, and 30.6, respectively.
(16) The anionic lithium amides of the aliphatic amines generated with
n-BuLi did not give as high regioselectivity.
(17) Buchwald reported that Pd/BINAP could minimize bis-arylations
for the aminations of primary amines with aryl bromides (Wolf, J. P.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-1157). Unfortunately, this
catalyst system provided the same result as our catalyst systems in the
aminations of primary amines with 3.
a HPLC ratio and HPLC assay yield. b Conditions A: K2CO3, DMAc,
rt, 1 h (entries 1-6) or BuOH, i-Pr2NEt, 125 °C, 24 h (entries 7 and 8).
c Conditions B: Pd(OAc)2/dppb (1-2 mol %) or 6 (2 mol %), LiHMDS,
THF, 0 °C, 1 h (entry 1) or -20 °C, 1 h (entries 2-6). d No catalyst, -60
°C, 0.5 h.
(18) Two equivalents of LiHMDS was required.
(19) Delia, T. J.; Nagarajan, A. J. Heterocycl. Chem. 1998, 35, 269-
273.
2:1 to 4:1 regioselectivities, the Pd-catalyzed reactions gave
>30:1 ratio for all the secondary amines studied. The acyclic
Org. Lett., Vol. 8, No. 3, 2006
397

To investigate the electronic effect of the C6 substituent
on the amination reaction, the 6-phenyl- and 6-(4-methoxy-
phenyl)-substituted 2,4-dichloropyrimidines 7 and 10 were
synthesized using the analogous Suzuki reactions as shown
in Scheme 1. The electron-neutral C6-phenyl-substituted
pyrimidine 7 gave the same high reactivity and high
regioselectivity as 3 in the Pd-catalyzed amination reactions
with aliphatic amines (Table 3, entries 1-3). The electron-
amine complex and insertion of the resultant Pd-imine
complex.20 To study whether epimerization was possible in
our palladium-catalyzed amination, the chiral 2-methyl
piperazine 13 was subjected to the amination reaction with
7 using Pd(OAc)2/dppb (2 mol %) as the catalyst. As shown
in eq 2, the reaction gave the C4-substituted product 14 with
a 99:1 regioselectivity and essentially no loss of enantiomeric
purity. Presumably, the generation of the Pd-amide inter-
mediate and the following reductive elimination in the
general catalytic cycle10 was much faster than â-hydride
elimination.
Table 3. Aminations of 6-Phenyl- and
6-(4-Methoxyphenyl)-2,4-dichloropyrimidines
In summary, we have developed a highly regioselective
Pd-catalyzed amination of 6-aryl-2,4-dichloropyrimidine
which strongly favors the formation of the C4-isomer. One
of the most effective Pd catalysts for the reaction is the
complex arising from oxidative addition of Pd with 2,4,6-
trichloropyrimidine. The scope of the coupling reaction is
currently limited to aliphatic secondary amines and anilines.
Both electron-withdrawing and electron-donating C6-aryl
groups give high regioselectivity with low catalyst loading.
We have also discovered that the reactions of aromatic
amines require no catalyst and also give high regioselectivity.
a 0 °C, 1 h. b -20 °C, 1 h. c No catalyst, -60 °C, 0.5 h. d HPLC assay
yield.
Acknowledgment. We thank Dr. Arlene McKeown for
X-ray crystallographic analyses, Mirlinda Biba for chiral
HPLC analyses, and Bob Reamer for NMR analyses.
donating C6-(4-methoxyphenyl)-substituted pyrimidine 10
showed slightly lower reactivity and diminished, but still
high, regioselectivity (Table 3, entries 1-3). Complex 6 and
Pd(OAc)2/dppb were still the most effective catalysts for both
substrates. Similar to 3, the catalyst was not required for the
reactions with N-methylaniline (Table 3, entry 4).
Note Added after ASAP Publication. Due to a produc-
tion error, the Cl at the 4 position of the starting material in
the abstract graphic was cut off in the version published
ASAP January 12, 2006; the corrected version was published
ASAP January 13, 2006.
In the previously reported Pd-catalyzed amination reactions
of amines with a R-chiral center, epimerization occurred
through a sequence of the â-hydride elimination of the Pd-
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(20) (a) Zhao, S.-H.; Miller, A. K.; Berger, J.; Flippin, L. A. Tetrahedron
Lett. 1996, 37, 4463-4466. (b) Tanatani, A.; Mio, M. J.; Moore, J. S. J.
Am. Chem. Soc. 2001, 123, 1792-1793.
OL052578P
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