Selective addition of amines to 5-trifluoromethyl-2,4-dichloropyrimidine induced by Lewis acids

Article abstract of DOI:10.1016/j.tetlet.2013.06.025

A variety of 2,4-diamino-pyrimidine systems can be prepared from the corresponding 2,4-dichloro-pyrimidine by sequential addition of two amines, the first adding selectively to the 4-position. In contrast it was found that 2,4-dichloro-5-trifluoromethyl-p

Full text of DOI:10.1016/j.tetlet.2013.06.025

Tetrahedron Letters 54 (2013) 4610–4612
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective addition of amines to 5-trifluoromethyl-2,4-dichloropy-
rimidine induced by Lewis acids
a
b
b
b
Daniel T. Richter a, , John C. Kath , Michael J. Luzzio , Nandell Keene , Martin A. Berliner ,
⇑
Matthew D. Wessel b
a Pfizer Global R&D, 10614 Science Center Drive, La Jolla, CA 92121, United States
b Pfizer Global R&D, Eastern Point Road, Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 2,4-diamino-pyrimidine systems can be prepared from the corresponding 2,4-dichloro-
pyrimidine by sequential addition of two amines, the first adding selectively to the 4-position. In contrast
it was found that 2,4-dichloro-5-trifluoromethyl-pyrimidine yields a 1:1 mixture of the two possible iso-
mers. Lewis acids were employed to increase the ratio of isomers to >10:1 in favor of the 2-addition prod-
uct. Optimization of the effect of Lewis acid additives on this and other dichloropyrimidine systems will
be discussed.
Received 17 May 2013
Revised 3 June 2013
Accepted 6 June 2013
Available online 13 June 2013
Keywords:
Dichloropyrimidine
Lewis acid
Ó 2013 Elsevier Ltd. All rights reserved.
Addition
Diaminopyrimidine
Selective
The 2,4-diaminopyrimidine moiety (1) plays a critical role in a
variety of molecules that display a rich diversity of pharmacologi-
cal activity. Kinase inhibitors,1 CRF antagonists,2 5HT antagonists,3
and HIV reverse transcriptase inhibitors4 are some of the many
classes of drugs that contain this structural motif. The synthesis
of 2,4-diaminopyrimidines (Fig. 1) commonly starts with the cou-
pling of a pyrimidine intermediate (2a–f) and one equivalent of an
amine (3) It is well documented that for the vast majority of pyrim-
idines (2) and amines (3), this first amine addition occurs preferen-
tially (or exclusively) at the more reactive pyrimidine 4-position to
provide amino-pyrimidine (4).5 The primary factors that influence
the selectivity of this addition are the stereoelectronic effects asso-
ciated with substituents in both 2 and 3 and to a lesser extent the
reaction solvent.5 Subsequent heating of 4 with a second amine (5)
provides diaminopyrimidine (1).
Interestingly, 5-trifluoromethyl-2-chloro-4-aminopyrimidines
prepared from 5-trifluoromethyl-2,4-dichloropyrimidine (6),
unlike the analogous 5-substituted pyrimidines 2a–f provided a
nearly equivalent mixture of two pyrimidine isomers 7:8 as op-
posed to a >10:1 mixture favoring the more polar 2-chloro-4-ami-
nopyrimidine 8. While it was possible to separate the mixture of
7:8 by reverse phase preparative HPLC, this process was difficult
and tedious at best, yielding less than 50% of each regioisomer. This
issue coupled with the relatively lower yields of desired isomer
obtained severely limits the utility of these intermediates. As
exemplified in Table 1, lack of selectivity in the 5-trifluoromethyl
series is a surprising anomaly in the reactivity of these heterocyclic
systems. When this substitution is desired, this unusual behavior
represents a huge hurdle to preparation of compounds of this
type.6 Yields of <50% for the first step of a synthesis are not desir-
able, especially in a case where the chemistry is traditionally very
high yielding and versatile. Therefore a regioselective route for the
preparation of these molecules was desired.
Initially minor adjustments to the reaction conditions were
investigated using 4-methylaniline as the amine control. A series
of reactions were carried out over a temperature range of À78 °C
to ambient temperature as well as screening a variety of solvents.
Temperature modifications yielded only extended reaction times
with no increase in selectivity. Additionally in those cases where
the temperature was below 0 °C, reagents became insoluble such
that no reaction occurred until the reaction was warmed to room
temperature. Results from a solvent screen were equally unpro-
ductive. Using a wide range of anhydrous solvents (tetrahydrofu-
ran, 1,2-dichloroethane, t-butanol, ether, methylene chloride,
acetonitrile, methanol, ethanol, 2-propanol, dioxane, 1,2-dime-
thoxyethane, toluene, chloroform, ethyl acetate, or a mixture of
1:1 DCE/t-butanol) afforded no discernible changes to the reaction
results.
Due to the lack of success altering reaction conditions, it be-
came apparent that other means of influencing the selectivity
would be necessary. Additives such as protic and Lewis acids
⇑
Corresponding author. Tel.: +1 8586226008.
E-mail address: daniel.richter@pfizer.com (D.T. Richter).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.025

D. T. Richter et al. / Tetrahedron Letters 54 (2013) 4610–4612
4611
3
5
R1
R2
R1
R2
N
H
X
N
X
X
N
N
H
N
R1
R1
R1
Δ
Base
N
R2
N
1
N
R2
Cl
N
N
R2
Cl
N
Cl
4
R= H, F, Cl, Br, Me, OMe
2a-f
R1
R2
CF3
N
H
CF3
Cl
CF3
N
N
N
R1
R1
Cl
N
N
Base
N
R2
N
7
Cl
N
6
Cl
R2
8
1:1 Mixture
Figure 1. 2,4-Diaminopyrimidine synthesis.
(LA) appeared to be the only viable solution. Initially, protic acids
(HCl or Acetic acid) were employed, both as an additive and by pre-
paring amine salts. However, due to the diminished solubility of
these salts the reactions were slow or did not occur at all. Upon
the addition of base, the reaction would proceed but only give
the same 1:1 mixture of isomers observed previously. This result
led us to investigate Lewis acids, which also have the potential to
coordinate with the nitrogens of the pyrimidine. If coordination oc-
curs to the pyrimidine it was believed to favor substitution at the
less sterically hindered C-2 position.
While these results were quite exciting there were a few ani-
lines that did not show any changes in selectivity. Most notably,
p-methoxyaniline gave an 8:1 ratio while o-methoxyaniline gave
only a 1:1 ratio (Table 2). In this case it was believed that the o-
methoxy aniline was involved in a chelating effect with the LA such
that coordination to the pyrimidine was not occurring. Upon addi-
tion of 2 equiv of LA the selectivity increased from 1:1 to 9:1.
A similar result was obtained for 4-dimethylaminoaniline which
went from 1:1 to 11:1 (Table 2). As a result anilines with any sub-
stitution capable of complexing with the zinc or forming a chelate
as in the o-methoxy case can be added selectively with additional
equivalents of LA.
These positive results suggested that the effect could carry over
to more nucleophilic alkyl amines which also did not show any in-
creased selectivity with 1 equiv of LA. Because of the increased
nucleophilicity of these amines the initial attempts with 1 equiv
of ZnCl2 were unsuccessful. With 2 equiv of LA, the complex
formed crashes out of solution immediately. However, the reaction
takes 24 h to reach completion compared to the typical 2–4 h seen
with anilines while the selectivity increased to only 5:1 (Table 2).
Yet, this moderate selectivity is quite useful since these analogs
can be isolated via crystallization.
Initially it was believed that the Lewis acid was complexing
with the pyrimidine and thus directing the chemistry to the less
hindered site, however attempts at isolating a pyrimidine/LA com-
plex were unsuccessful and no discernable effects could be seen in
the Fluorine NMR when ZnCl2 was present. Since precipitate
formed when the two reagents were combined, it was believed
that the Lewis acid was instead coordinating with the amine. Since
zinc is capable of coordinating with two coordinating nitrogens it
was expected that this selectivity would be seen with fewer than
1 equiv of Lewis acid, and that is indeed the case. Increased selec-
tivity was observed with as little as 0.25 equiv of ZnCl2 although
optimal results were obtained when sufficient LA was present to
moderate the reaction.
With the conditions optimized, it was of interest to see if ZnCl2
could be used to alter the selectivity of additions to other dichloro-
pyrimidines. The results from a small set of pyrimidines showed
that 5-H and 5-Me were both shifted from approximately 9:1 to
nearly 1:1, 5-Cl experienced no change (see Table 1). This repre-
sents an encouraging breakthrough in the chemistry of these sys-
tems, as the two isomers formed are easily separable by normal
phase chromatography. Other LA may be able to shift the product
distribution even more significantly to the typically unfavored
isomers.
For this initial study, 6 was combined with 1.1 equiv of a com-
mercially available Lewis acid prior to addition of 4-methylaniline
(1.0 equiv) followed by the triethylamine base (1.1 equiv). The
crude reaction mixtures from this screen were analyzed by HPLC
to determine the isomeric ratio of 7 to 8. Using the original reaction
conditions (THF, RT, 1 equiv Et3N), a screen of 18 readily available
Lewis acids was employed (ZnCl2, Zn(OAc)2, BF3–Et2O, Mg(OTf)2,
MgCl2, MgBr2, CuCl, CuCl2, SnCl2, SnCl4, LiCl, LiOAc, AgNO3, AgOTf,
TiCl4, EtAlCl2, DIP-Cl, BCl3, 1.1 equiv). Initial results offered some
small improvements, in particular zinc salts were most effective
followed by CuCl2 and AgOTf. ZnCl2 exhibited the best improve-
ment of selectivity with a 4:1 ratio of 7 to 8. A more detailed inves-
tigation involving ZnCl2 as an additive and some minor
optimization of reaction conditions provided a 10-fold increase in
selectivity from the initial 1:1 ratio seen with no Lewis Acid
(Table 2). By switching to a solvent mixture of DCE/t-BuOH and
allowing the Lewis acid to complex with the amine and pyrimidine
before the addition of the base (which eliminated the need for
cooling reactions to 0 °C) >10:1 selectivity could be obtained. Com-
parison of this data with the isomeric ratio of the substitution reac-
tion run in the absence of an additive, provided evidence
suggesting that the addition of zinc chloride enhanced the selectiv-
ity ratio of 7:8 in favor of the less polar isomer 7. Additionally,
these simple changes applied to a wide variety of substituted ani-
lines, including those with electron withdrawing (EWG) and
donating groups (EDG), demonstrated that the selectivity in some
cases could be increased up to 17:1 (Table 2).
Table 1
Percent isomer ratios for selected pyrimidines reacted with 4-methylaniline
Pyrimidine
X
4-Isomer
2-Isomer
2a
2c
2e
6
H
CH3
Cl
95 (49)
95 (58)
100 (100)
40 (5)
5 (51)
<5 (28)
0 (0)
The addition of Lewis acids, most notably ZnCl2, to amine sub-
stitution reactions on 2,4-dichloro-5-trifluoromethylpyrimidine
CF3
60 (95)
⁄
Results in parenthesis are with ZnCl2.

4612
D. T. Richter et al. / Tetrahedron Letters 54 (2013) 4610–4612
Table 2
Selectivity of substitution as a result of ZnCl2 addition for various amines
Amine
Ratio of 7:8 (1.0 equiv ZnCl2)
Ratio of 7:8 (2.0 equiv ZnCl2)
—
Isolated yield of 7
15:1
87
NH2
O
8:1
—
—
72
95
NH2
Cl
17:1
NH2
10:1
1:1
—
78
28
N
H
O
9:1
NH2
N
1:1
11:1
73
NH2
NH2
1:1
1:1
1:1
5:1
5:1
5:1
33
33
30
NH2
NH
⁄ All reactions carried out on 500 mg scale at ambient temperature, C-2 isomer isolated by crystallization from MeOH/water. Ratios calculated from HPLC of crude reaction.
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heavily favored with 0.25–1 equiv of ZnCl2 with isomerically pure
products easily isolated via recrystallization. In addition, alkyl
amines can also be added selectively in a 5:1 ratio with 2 equiv
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5-Me-2,4-dichloropyrimidines. This breakthrough affords the
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.025.
References and notes
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