A new reaction of N-aryl-2-pyrimidinamines with triphosgene

Article abstract of DOI:10.1016/j.tetlet.2007.01.144

A new reaction of N-aryl-2-pyrimidinamines with triphosgene to afford N-aryl-N-(2-pyrimidinyl)-2-pyrimidinamine is described.

Full text of DOI:10.1016/j.tetlet.2007.01.144

Tetrahedron Letters 48 (2007) 2087–2089
A new reaction of N-aryl-2-pyrimidinamines with triphosgene
*
Mahavir Prashad, Bin Hu, Hong-Yong Kim, Denis Har,
Oljan Repi cˇ and Thomas J. Blacklock
Process Research and Development, Chemical and Analytical Development, Novartis Pharmaceuticals Corporation,
One Health Plaza, East Hanover, NJ 07936, USA
Received 3 November 2006; revised 23 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—A new reaction of N-aryl-2-pyrimidinamines with triphosgene to afford N-aryl-N-(2-pyrimidinyl)-2-pyrimidinamine is
described.
Ó 2007 Elsevier Ltd. All rights reserved.
In an ongoing program we needed to synthesize the sym-
metrical urea 3a (Scheme 1). We reasoned that 3a can be
easily prepared by a reaction of N-phenyl-2-pyrimidin-
withdrawing substituent in the phenyl ring (1c), gave
31% yield (62% of theory) of the desired product 2c (en-
try 3). In this case the symmetrical urea 3c was produced
in 8% yield (16% of theory). A phenyl substituent in the
pyrimidine ring (1d) also afforded the expected product
2d in 43.5% yield (87% of theory; entry 4). Reaction of
N-butyl-2-pyrimidinamine (1e) with triphosgene also
afforded the deaminated-self aminated product 2e in
24.5% yield (49% of theory) along with 10% (20% of
theory) of the symmetrical urea 3e (entry 5). Removal
of one of the nitrogen atoms from the pyrimidine ring,
as in N-phenyl-2-pyridinamine (1f), gave mainly the
unreacted starting material. Only 5% yield (10% of
theory; entry 6) of the desired product 2f was obtained.
To the best of our knowledge this method represents
the first synthesis of N-aryl-N-(2-pyrimidinyl)-2-
pyrimidinamines.
1
amine (1a) with 0.2 equiv of bis(trichloromethyl) car-
bonate (triphosgene), which is
a
less hazardous
2
–4
substitute for phosgene.
These conditions, however,
led to the unexpected N-phenyl-N-(2-pyrimidinyl)-2-
pyrimidinamine (2a). In this Letter, we report this new
deamination-self amination reaction of N-aryl-2-pyrim-
idinamines with triphosgene. Such a reaction of N-
aryl-2-pyrimidinamines with triphosgene has not been
5
,6
reported to the best of our knowledge.
Treatment7 of N-phenyl-2-pyrimidinamine (1a) with
0
.2 equiv of triphosgene in refluxing toluene yielded
the desired symmetrical urea 3a in only 1.5% yield (3%
of theory; Table 1, entry 1). N-Phenyl-N-(2-pyrimidin-
yl)-2-pyrimidinamine (2a) was isolated as the major
product in 36% yield (72% of theory). The structure of
A plausible mechanism for the deamination-self amina-
tion reaction of N-aryl-2-pyrimidinamines with triphos-
gene is illustrated in Scheme 2. The initially formed
imidoyl chloride intermediate (A) from the reaction of
N-aryl-2-pyrimidinamines (1) with triphosgene, could
undergo a nucleophilic displacement at 2-position by
another molecule of 1 to afford the deaminated-self ami-
nated product (2). Intermediate (A) could also undergo
a C–N bond cleavage reaction to afford intermediate
B, which then reacts with another molecule of 1 to yield
2
a was assigned based on spectroscopic data.8 This
deamination-self amination reaction of 1a with triphos-
gene represents a novel route to 2a. To examine the
scope, we next investigated this new reaction with sev-
eral substrates. The results are listed in Table 1. Reac-
tion of 1b, with an electron-donating group in the
phenyl ring, afforded the desired product 2b in 43% yield
(
86% of theory; entry 2). No symmetrical urea 3b was
observed in this reaction. Introduction of an electron-
2
. Intermediate B could also lead to the formation of
2-chloropyrimidine that can then react with another
molecule of 1 to afford 2. An HPLC analysis of the
reaction mixture at intervals did not indicate the pres-
ence of 2-chloropyrimidine. Additionally, treatment of
*
0
Corresponding author. Tel.: +1 862 778 3467; fax: +1 973 781 4384;
e-mail: mahavir.prashad@novartis.com
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.144

2088
M. Prashad et al. / Tetrahedron Letters 48 (2007) 2087–2089
Main Products
R
R
R'
triphosgene
(0.2 equiv)
N
H
N
N
N
N
N
N
N
toluene
reflux
+
O
N
N
N
R
R'
N
N
N
R'
R'
R'
R
1
1
a: R = H
R' = H
2a: R = H
R' = H
3a: R = H
R' = H
b: R = OCH R' = H
2b: R = OCH R' = H
3b: R = OCH R' = H
3
3
3
1
c: R = CF3 R' = H
2c: R = CF3 R' = H
2d: R = H
3c: R = CF3 R' = H
3d: R = H
1
d: R = H
R' = Phenyl
R' = Phenyl
R' = Phenyl
CH3
triphosgene
(0.2 equiv)
N
CH3
H
N
N
N
N
N
N
N
N
N
+
+
O
N
toluene
reflux
N
N
CH3
2e
N
1e
CH3
3
e
triphosgene
H
N
N
(
0.2 equiv)
N
N
N
toluene
reflux
O
N
N
N
N
2
f
1f
3f
Scheme 1.
Table 1. Reaction of N-aryl-2-pyrimidinamines with triphosgene
0
Entry
Starting
material
R
R
Product (s)
% Isolated yield
(% of theory)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
H
H
H
2a
a
36 (72)
1.5 (3)
3
OCH
3
2b
3
43 (86)
Not detected
b
CF
H
3
2c
3
31 (62)
8 (16)
c
Phenyl
—
2d
3
43.5 (87)
Not detected
d
—
—
2e
3
24.5 (49)
10 (20)
e
—
2f
5 (10)
3
f
Not detected
2
-chloropyrimidine with 1a in refluxing toluene did not
lead to the formation of 2a. These results suggest that
-chloropyrimidine is not an intermediate in this reac-
tion. An LC–MS analysis of the reaction mixture from
ther of which was detected by LC–MS. Such a deamina-
tion-self amination reaction was not observed by a
reaction of 1b with p-nitrophenyl chloroformate.
2
1
2
a indicated the formation of intermediate (A), product
a, and aniline (E). Aniline (E) could be formed either
In summary, a new deamination-self amination reaction
of N-aryl-2-pyrimidinamines with triphosgene to afford
N-aryl-N-(2-pyrimidinyl)-2-pyrimidinamine is described.
via phenyl isocyanate (C) or imidoyl chloride (D), nei-

M. Prashad et al. / Tetrahedron Letters 48 (2007) 2087–2089
2089
H
N
N
N
R
1
triphosgene
(
0.2 equiv)
Cl
O
Cl
O
N
N
N
N
or
N
N
1
R
R
(
A)
1
NCO
-
R
+ Cl
NH2
R
N
(C)
1
[
(C) or (D) ]
+
N
+
R
or
N
N
N
(B)
[
E]
NHCOCl
N
N
(
E)
2
(
D)
R
Scheme 2.
1
3
References and notes
J = 4.7 Hz); C NMR (DMSO-d
6
, d) 55.6, 114.7, 116.6,
+
1
29.1, 136.4, 157.7, 158.7, 162.8; MS (ESI) 280.2 (MH ).
Compound 2c: mp 184–186 °C; H NMR (CD
t, 2H, J = 4.9 Hz), 7.33 (d, 2H, J = 8.4 Hz), 7.68 (d, 2H,
1
1
. Hirota, H.; Sekiya, T.; Hishikura, A.; Endo, H.;
Hamada, Y.; Ito, Y. Bull. Chem. Soc. Jpn. 1980, 53,
3
OD, d) 7.20
(
1
3
J = 8.4 Hz), 8.60 (d, 4H, J = 4.9 Hz); C NMR (DMSO-
= 270.0 Hz), 125.1, 125.5, 126.4,
7
17–719.
. Eckert, H.; Forster, B. Angew. Chem. Int. Ed. Engl. 1987,
6, 894–895.
. Pasquato, L.; Modena, G.; Cotarca, L.; Delogu, P.;
Mantovani, S. J. Org. Chem. 2000, 65, 8224–8228.
2
3
4
5
d6, d) 117.7, 124.6 (q, J
C–F
+
1
27.0, 130.0, 147.3, 159.0, 162.3; MS (ESI) 318.2 (MH ).
1
Compound 2d: mp 140–142 °C; H NMR (DMSO-d
.26–7.28 (m, 3H), 7.39–7.50 (m, 8H), 7.77 (d, 2H,
J = 5.3 Hz), 7.99–8.02 (m, 4H), 8.70 (d, 2H, J = 5.3 Hz);
C NMR (DMSO-d
36.3, 143.6, 159.6, 162.9, 164.3; MS (ESI) 402.3 (MH ).
2
6
, d)
7
. Majer, P.; Randad, R. S. J. Org. Chem. 1994, 59, 1937–
1
3
1
938.
. Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Synthesis
996, 553–576.
. Krishnaswamy, D. Synlett 2000, 1860.
. Typical procedure: A mixture of 1a–f (5.0 mmol), triphos-
gene (0.83 mmol), and toluene (20.0 mL) was refluxed
6
, d) 112.3, 126.0, 127.4, 129.3, 131.5,
+
1
1
Compound 2e: oil; H NMR (CD OD, d) 0.91 (t, 3H,
J = 7.4 Hz), 1.21–1.41 (m, 2H), 1.63–1.73 (m, 2H), 4.29 (t,
1
3
6
7
2
H, J = 7.5 Hz), 7.06 (t, 2H, J = 4.9 Hz), 8.57 (d, 4H,
13
J = 4.9 Hz); C NMR (CD
3
OD, d) 14.6, 21.5, 25.8, 32.1,
+
1
17.0, 159.9, 163.5; MS (ESI) 230.2 (MH ). Compound 2f:
(
110 °C internal temperature) for 8 h. A second portion of
1
mp 83–85 °C; H NMR (CD OD, d) 6.94–6.97 (m, 2H),
.02–7.06 (m, 2H), 7.11–7.14 (m, 2H), 7.20–7.25 (m, 1H),
.32–7.41 (m, 2H), 7.60–7.72 (m, 2H), 8.13–8.21 (m, 2H);
3
triphosgene (0.166 mmol) was added and the refluxing was
continued for an additional 16 h. The reaction mixture was
cooled to room temperature and basified with 2 N sodium
hydroxide (14.0 mL). The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate
7
7
1
3
C NMR (CD OD, d) 119.3, 120.4, 127.4, 128.6, 131.4,
3
1
1
40.2, 146.5, 149.4, 159.8; H NMR (CD
3
OD, d). Com-
, d) 7.10–7.15 (m, 6H),
.16–7.23 (m, 2H), 7.26–7.32 (m, 4H), 8.54 (d, 4H,
1
pound 3a: H NMR (DMSO-d
6
(
20.0 mL). The combined organic layers were dried and
concentrated. The crude material was purified by silica gel
7
+
J = 4.9 Hz); MS (ESI) 369.3 (MH ). Compound 3c: mp
chromatography.
1
1
2
7
4
3
15–218 °C; H NMR (CD OD, d) 7.14 (t, 2H, J = 4.9 Hz),
8
. Compound 2a: mp 164–166 °C; H NMR (DMSO-d
6
, d)
.38 (d, 4H, J = 8.3 Hz), 7.60 (d, 4H, J = 8.5 Hz), 8.54 (d,
7
.1–7.25 (m, 5H), 7.37 (t, 2H, J = 4.7 Hz), 8.61 (d, 4H,
+
13
H, J = 4.9 Hz); MS (ESI) 505.1 (MH ). Compound 3e:
oil; H NMR (CD
.43 (m, 4H), 1.65–1.79 (m, 4H), 4.07 (t, 4H, J = 7.3 Hz),
.75 (t, 2H, J = 4.9 Hz), 8.26 (d, 4H, J = 4.9 Hz); MS (ESI)
J = 4.7 Hz); C NMR (DMSO-d
6
, d) 117.3, 125.9, 127.3,
+
1
1
29.4, 143.7, 158.8, 162.7: MS (ESI) 250.2 (MH ). Com-
3
OD, d) 0.94 (t, 6H, J = 7.4 Hz), 1.36–
1
1
6
3
pound 2b: mp 129–130 °C; H NMR (DMSO-d
H), 6.93 (dd, 2H, J = 6.8 and 2.3 Hz), 7.06 (dd, 2H,
J = 6.8 and 2.3 Hz), 7.13 (t, 2H, J = 4.7 Hz), 8.58 (d, 4H,
6
, d) 3.76 (s,
3
+
29.1 (MH ).