Convenient preparation of 4-aryl-2-(heteroarylamino)pyrimidines and 4-anilino-2-(heteroarylamino)pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2010.04.062

4-Aryl-2-anilinopyrimidines and 2,4-dianilinopyrimidines are privileged structures found in many drug-like molecules and biologically active compounds. A method for the quick assembly of novel 4-aryl- and 4-anilino-2-(heteroarylamino)pyrimidines via Buchwald-Hartwig N-arylations at elevated temperatures under sealed tube conditions is reported. This method's convenience and practicality is demonstrated through the preparation of several novel non-nucleoside reverse transcriptase inhibitor (NNRTI) analogues.

Full text of DOI:10.1016/j.tetlet.2010.04.062

Tetrahedron Letters 51 (2010) 3259–3262
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient preparation of 4-aryl-2-(heteroarylamino)pyrimidines
and 4-anilino-2-(heteroarylamino)pyrimidines
*
Brian I. Bliss , Feryan Ahmed, Subashree Iyer, Weimin Lin, Joel Walker, He Zhao
Medicinal Chemistry Department, AMRI, 30 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Aryl-2-anilinopyrimidines and 2,4-dianilinopyrimidines are privileged structures found in many drug-
like molecules and biologically active compounds. A method for the quick assembly of novel 4-aryl- and
4-anilino-2-(heteroarylamino)pyrimidines via Buchwald–Hartwig N-arylations at elevated temperatures
under sealed tube conditions is reported. This method’s convenience and practicality is demonstrated
through the preparation of several novel non-nucleoside reverse transcriptase inhibitor (NNRTI)
analogues.
Received 29 January 2010
Revised 13 April 2010
Accepted 14 April 2010
Available online 18 April 2010
Dedicated to Asa John Livingston II
(1930–2003)—teacher, mentor, inspiration
and friend.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
dines with heteroarylamines under both thermal9f and micro-
wave9b,10 conditions. We also explored palladium-catalyzed
4-Aryl-2-anilinopyrimidines 1 and 2,4-dianilinopyrimidines 2
(i.e., DAPYs)1 represent privileged structures2 found in an ever
increasing number of drug-like molecules including VEGF and
CDK inhibitors,3 reverse transcriptase inhibitors (e.g., dapivirine
3),4 and tyrosine kinase inhibitors (e.g., GleevecÒ 4)5 ( Fig. 1).
Traditionally, 2,4-diamino pyrimidines have been prepared from
commercially available 2,4-dichloropyrimidine or 4-chloro-
2-(methylsufinyl)pyrimidine by either aromatic nucleophilic sub-
stitution (SNAr)6 or by palladium-catalyzed arylation/amination.7
Similarly, 2-amino-4-arylpyrimidines have been accessible via
SNAr or palladium-mediated amination of readily available
4-aryl-2-chloropyrimdines.8 However, chloride displacement in
4-amino- and 4-aryl-2-chloropyrimidines generally requires forc-
ing conditions which limits this chemistry to nucleophilic alkyl-
amines and anilines.3a
N-arylations7a,9c–e of heteroarylamines with 4-substituted-2-chlo-
ropyrimidines under standard Buchwald–Hartwig conditions
(refluxing dioxane, 12–18 h) which resulted in low conversions.
Next we examined conditions used to prepare 2-aminopyrimi-
dines via Buchwald–Hartwig N-arylations under microwave
conditions.7b,9a Examples in the literature utilized simple 2-chloro-
pyrimidines and relatively nucleophilic amines, in contrast to our
structurally more complex 4-substituted-2-chloropyrimidines
and non-nucleophilic heteroarylamines. With our substrates
6a–d, previously reported conditions routinely provided low
H
R1
N
R1
N
N
N
N
As a result, there are few examples of 4-aryl- or 4-anilino- 2-
(heteroarylamino)pyrimidines reported in the literature.7a,b,9
Our own research has prompted us to develop a synthetically
expedient method to generate novel 4-aryl- and 4-anilino-2-(het-
eroarylamino)pyrimidines 5 by functionalizing readily available
4-substituted-2-chloropyrimidines with a diverse set of heteroa-
rylamines (Fig. 2).
HN
HN
R2
R2
1
2
CH3
N
N
H3C
CH3
N
N
HN
N
N
H
2. Results and discussion
N
N
CH3
H
HN
N
Our initial and unsuccessful attempts at preparing analogues of
5 involved simple SNAr substitution of 4-anilino-2-chloropyrimi-
O
CN
H3C
4 (Gleevec®)
3 (dapivirine)
* Corresponding author. Tel.: +1 518 512 2000.
E-mail address: brian.bliss@amriglobal.com (B.I. Bliss).
Figure 1. 4-Aryl-2-anilinopyrimidines 1 and 2,4-dianilinopyrimidines 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.062

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B. I. Bliss et al. / Tetrahedron Letters 51 (2010) 3259–3262
eroarylamino)pyrimidines 7–12 (Table 1) and 4-anilino-2-(hetero-
Heteroaryl = pyridine, pyridazine, pyrimidine,
pyrazine, oxazole, isoxazole, pyrazole,
imidazole, triazole, thiazole, etc.
arylamino)-pyrimidines 15–19 (Table 2).13
N
N
In preparing substrates 6a–d for the N-arylation chemistry, we
decided to include functionality that would allow us to probe the
electronic effects imparted by the substituent located at the pyrim-
idine 4-position. To that end we prepared compounds that con-
tained 4-aryl groups bearing electron-donating (–OCH3) and
HN
Heteroaryl
5
Figure 2. Novel 4-substituted-2-(heteroarylamino) pyrimidines 2.
electron-withdrawing substituents (–CO2CH3, –NO2). Table
1
summarizes our efforts to prepare 4-aryl-2-(heteroarylamino)-
pyrimidines 7–12. For example, 2-aminopyrazine and 2-chloropyr-
imidine 6b (Table 1, entry 3) were heated in the presence of
Pd2(dba)3 and Xantphos14 at 160 °C in a sealed tube for 6 h afford-
ing 9b in 38% yield. 4-Aryl groups bearing electron-rich substitu-
ents tended to give slightly higher yields of coupling product
than those bearing electron-withdrawing groups (Table 1). This
trend is in general agreement with the observations of Buchwald
and Hartwig.15 In comparing sealed tube reactions with microwave
reactions (Table 1, entries 1–3), we observed that sealed tube
conditions afforded higher conversion to product as observed by
LC–MS analysis, higher isolated yields and lower yields of homo-
coupling product 13. Surprisingly, not all amines examined
afforded product under either reaction conditions (e.g., 3-methylis-
oxazole-5-amine).
conversion (30–50%) by LC–MS analysis (UV @ 254 nm) when ex-
posed to microwave irradiation at 120 °C. Additionally, increasing
catalyst loading yielded greater amounts of unwanted homodi-
meric byproduct 13 (Table 1).
Based upon these initial results, we decided to focus our atten-
tion on Buchwald–Hartwig N-arylations at elevated temperature
and pressure under sealed tube conditions.11,12 Herein we describe
our protocol for the convenient preparation of novel 4-aryl-2-(het-
Table 1
N-Arylation of 4-aryl-2-chloropyrimidines 6a–d
X
X
Control experiments were performed to confirm that the mech-
anism of the reaction was palladium-mediated N-arylations and not
simply thermal substitutions. When 2-aminopyrazine, a relatively
X
Heteroaryl–NH2
N
N
+
N
N
N
HN
N
Heteroaryl
Cl
a–d
Table 2
2
N-Arylation of (substituted) 2-chloropyrimidines 14a–d
7–12
13
6
H
H
a: X = H
b: X = p-OCH3
c: X = p-CO2CH3
N
X
N
X
Heteroaryl–NH2
N
N
N
N
d
: X = m-NO2
HN
Cl
Heteroaryl
Sealed Tube (Δ): 1 equiv 2-chloropyrimidine; 1.2 equiv heteroarylamine;
2 equiv ; 0.1 equiv ; 0.3 equiv Xantphos;
K3PO4 Pd2(dba)3
14a–c
15–19
160 °C, 6 h; sealed tube.
Microwave (μW): 1 equiv 2-chloropyrimidine; 1.5–2.0equiv heteroarylamine;
2 equiv ; 0.1 equiv ; 0.3 equiv Xantphos;
a
: X = H
b: X = F
c: X = NO2
K3PO4 Pd2(dba)3
1 h at T < 120 °C, 300 W.
Sealed Tube (
Δ):1 equiv 2-chloropyrimidine; 1.2 equiv heteroarylamine;
2 equiv ; 0.1equiv ; 0.3 equiv Xantphos;
Entry
1
Heteroaryl
Product
D
(Yld %)a
l
W (Yld %)a
K3PO4
160°C, 6 h; sealed tube.
W):1 equiv 2-chloropyrimidine; 1.5–2.0 equiv heteroarylamine;
Pd2(dba)3
7a
7b
7c
62%
41%
30%
42%
CH3
33%b
Microwave (
μ
2 equiv
; 0.1 equiv
; 0.3 equiv Xantphos;
Pd2(dba)3
K3PO4
1 h at T < 120 °C, 300 W.
N
7d
Trace
(Yld %)a
l
W (Yld %)a
8a
8b
8c
46%
48%
35%
21%
14%
Entry
1
Heteroaryl
Product
D
N
N
S
15a
15b
15c
75%
81%
51%
2
CH3
65%
57%
8d
Trace
Et
N
9a
9b
9c
45%
38%
Trace
NR
16a
16b
16c
Trace
Trace
Trace
N
N
N
2
3
3
4
5
N
72%
9d
17a
17b
17c
63%
40%
45%
10a
10b
10c
10d
30%
22%
Trace
24%
57%
37%
N
OCH3
N
N
OCH3
CH3
N
N
18a
18b
18c
45%
49%
51%
11a
11b
11c
11d
45%
52%
Trace
Trace
4
O
CH3
CH3
H3C
N
N
N
12a
12b
12c
12d
47%
25%
52%
39%
19a
19b
19c
41%
27%
54%
6
5
N
41%
Bn
Bn
a
Isolated yields.
Used rac-BINAP versus Xantphos.
b
a
Isolated yields.

B. I. Bliss et al. / Tetrahedron Letters 51 (2010) 3259–3262
3261
nucleophilic amine,16 was heated with 2-chloropyrimidine 6b (Ta-
ble 1, entry 3) under sealed tube reaction conditions, omitting
Pd2dba3 yielded approximately 10% conversion to product 9b as
detected by LC–MS after 6 h at 160 °C.17 Furthermore, when 2-ami-
nopyrazine was heated with 2-chloropyrimidine 6b and cesium
carbonate in n-butanol at 160 °C for 6 h, no reaction was observed.
These results indicate that the primary mode of reactivity for the
formation of 9b is via palladium-mediated N-arylation chemistry
and that with our substrates 6a–d, SNAr plays a minor mechanistic
role in overall product yields. Similar observations and mechanistic
conclusions under microwave conditions have been reported.7b
We also prepared related substrates 4-anilino-2-chloropyrimi-
dines 14a–c and examined the palladium-mediated N-arylation
chemistry with heteroarylamines to afford 4-anilino-2-(heteroa-
rylamino)pyrimidines 15–19 (Table 2).
To our surprise, during the N-arylation reactions of 4-anilino-2-
chloropyrimidines 14a–c (Table 2), homodimeric byproduct for-
mation was not observed by LC–MS analysis. Furthermore, with
the noteworthy exception of 16c (Table 2, entry 2),18 we observed
little significant advantage in terms of yield for either the thermal
or microwave conditions. As was the case in Table 1, not all hetero-
arylamines underwent N-arylation with substrates 14a–c under
thermal conditions (e.g., 2-aminothiazole-4-carboxylic acid). Addi-
tionally, the electronics of the para-position substituent on 14a–c
had minimal impact on reaction yields (e.g., Table 2, entries 3
and 4). We surmise that the dominant electronic effect of the 4-
anilino moiety is only marginally modulated by the presence of
either electron-donating or electron-withdrawing groups on the
aniline ring.
As such, overall coupling yields are not materially affected by
the nature of the aniline substituent in 14a–c.
Although it is difficult to rationalize the excellent yields ob-
tained for 16c (Table 2, entry 2) under microwave conditions and
the absence of homodimeric byproduct formation for substrates
14a–c, our results in Tables 1 and 2 demonstrate N-arylations at
elevated temperatures under sealed tube conditions are a general
and practical set of conditions for the N-arylation of both 4-aryl-
and 4-anilino-2-chloropyrimidines.
To illustrate the utility of our method, we prepared several ana-
logues of the non-nucleoside reverse transcriptase inhibitor
(NNRTI) dapivirine (3). Dapivirine is currently in Phase II clinical
trials for the prevention of HIV infections and is expected to enter
Phase III clinical trials in late 2009.19 Novel dapivirine analogues
21–25 containing various 2-(heteroarylamines) can be prepared
in two steps from the commercially available 2,4-dichloropyrimi-
dine via readily accessible 2-chloro-N-mesitylpyrimidin-4-amine
(20)20 (Table 3).
In conclusion, we have demonstrated that non-nucleophilic het-
eroaryl amines can undergo Buchwald–Hartwig N-arylation with
4-aryl and 4-anilino-2-chloropyrimidines at elevated temperatures
under sealed tube conditions to afford novel 4-aryl-2-(heteroaryla-
mino)pyrimidines and 4-anilino-2-(heteroarylamino)pyrimidines.
This method allows for the rapid, convenient construction, and
diversification of 4-substituted-2-chloropyrimidines which is an
important privileged structure found in many drug-like molecules.
This method provides reproducible results in modest to good
yields, affords generally higher conversion to product with 4-anili-
no-2-chloropyrimidines compared to previously reported Buch-
wald–Hartwig N-arylations under microwave conditions, and is
easily amendable to parallel synthesis. The advantages and utility
of this method were illustrated by the synthesis of 21–25 which
are novel analogues of the non-nucleoside reverse transcriptase
inhibitor (NNRTI) dapivirine (3).
Table 3
Preparation of novel dapivirine analogues (21–25)
CH3
CH3
Heteroaryl–NH2
Acknowledgments
H3C
CH3
H3C
N
CH3
NH
NH
The authors wish to acknowledge and thank AMRI for their
financial support, Dr. Jolicia Gauuan for her encouragement and
helpful discussions during the early stages of this work, and Mrs.
Meagan Slater for her critical review of this Letter.
N
N
N
HN
Cl
Heteroaryl
20
21–25
Sealed Tube: 1 equiv 2-chloropyrimidine; 1.2 equiv heteroarylamine;
2 equiv ; 0.1 equiv ; 0.3 equiv Xantphos;
Supplementary data
K3PO4
Pd2(dba)3
160 °C, 6 h; sealed tube.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.062.
Entry
1
Heteroaryl
Product
Yielda (%)
26%
CH3
References and notes
21
N
1. DAPY is
a commonly used abbreviation in the literature for 2,4-
dianilinopyrimidines.
2
3
4
2220
60%
42%
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N
OCH3
CH3
CH3
N
N
23
H3C
CH3
Et
S
24
25
Trace
43%
N
N
N
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N
Bn
a
Isolated yields.

3262
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procedure.
Preparation
of
10-mL sealed tube was equipped
N2-(6-methoxypyridin-3-yl)-N4-
phenylpyrimdine-2,4-diamine (17a):
A
with a magnetic stirbar, septum, and purged with nitrogen. The sealed tube
was charged with 2-chloro-N-phenylpyrimidin-4-amine (6a, 0.100 g,
0.50 mmol), 6-methoxypyridin-3-amine (0.074 g, 0.60 mmol), Pd2(dba)3
(0.046 g, 0.050 mmol), Xantphos (0.080 g, 0.15 mmol), anhydrous K3PO4
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