A practical strategy for the synthesis of 2-dialkylamino-4-arylamino-6-aminopyrimidines

Article abstract of DOI:10.1016/j.tetlet.2009.07.154

Starting from commercially available 4-amino-2,6-dichloropyrimidine, a practical four steps synthesis of 2-dialkylamino-4-arylamino-6-aminopyrimidines was developed. This strategy could introduce a diverse set of secondary amines and arylamines to displac

Full text of DOI:10.1016/j.tetlet.2009.07.154

Tetrahedron Letters 50 (2009) 5888–5893
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical strategy for the synthesis of
2-dialkylamino-4-arylamino-6-aminopyrimidines
*
Chaomin Li , Andrew Rosenau
Merck Research Laboratories-Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from commercially available 4-amino-2,6-dichloropyrimidine, a practical four steps synthesis of
2-dialkylamino-4-arylamino-6-aminopyrimidines was developed. This strategy could introduce a diverse
set of secondary amines and arylamines to displace the 2- and 4-chloro groups. The products of this route
are otherwise difficult to access. In addition, 6-amino arylation was carried out to demonstrate the reac-
tivity and utility of 2-dialkylamino-4-arylamino-6-aminopyrimidines as building blocks for assembling
interesting aminopyrimidine molecules.
Received 15 July 2009
Revised 29 July 2009
Accepted 30 July 2009
Available online 6 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Having presence in all naturally occurring nucleobases, pyrimi-
dines1 are arguably the most important diazines for living organ-
isms. Since the discovery of the first pyrimidine derivative in
1818,2 the use of pyrimidines as components in agrochemicals3
and pharmaceuticals has gained great interest.
to access 6a though an alternative route10 did not yield productive
outcomes.
Given the electron-rich nature imparted by two amino substitu-
tions in 7a, we anticipated that protection of the 7a amine with an
electronwithdrawing group such as tert-butoxycarbonyl (Boc)
could (1) block potential reactivity (dimerization) from the NH2
group at the 4-position, (2) enhance the reactivity of chloride in
C–N bond formation either through SNAr fashion or transition me-
tal catalyzed coupling reaction and (3) be easily removed following
the C–N bond formation. Herein, we report the development of
such a practical strategy for the preparation of 2-dialkylamino-4-
arylamino-6-aminopyrimidines (see Table 1).
The syntheses of the chloropyrimidine precursors 7 were
achieved following the known literature precedent11 by reacting
commercially available 4-amino-2,6-dichloropyrimidine 8 with
secondary amines 9 in nearly 90% yields. Bis-Boc protection12 of
7 was then realized with Boc2O (NaH, DMF) to the afforded inter-
mediates 10. To our delight, a C–N bond formation was readily
achieved when 10 was reacted with a wide range of arylamine sub-
strates under typical Buchwald coupling conditions.9 Ortho substi-
tutions (examples 6 and 7) on the arylamino building block were
tolerated. Encouragingly, heteroarylamines such as aminopyridine
(example 8), aminopyrimidines (example 9 and 10), aminothiazole
(example 11), and aminooxadiazole (example 12) all reacted to
give good yields. Final deprotection of the 4-amino group was, as
we expected, quantitative and led to the efficient production of a
diverse set of 2-dialkylamino-4-arylamino-6-aminopyrimidines
(see Scheme 1).
Aminopyrimidines, where one or more (up to four) pyrimidine
hydrogens are substituted with amino or functionalized amino
groups, can be found in a large number of natural products,4 such
as vitamine B1, and many pharmaceutical agents.5 Aminopyrimi-
dines are present in widely used classes of drugs including BCR-
ABL tyrosine kinase inhibitor imatinib (Gleevec, 1), dihydrofolate
reductase inhibitor trimethoprim (Triprim, 2), 5-HT 1A receptor
agonist Buspirone (Buspar, 3), HMG-CoA reductase inhibitor Rosu-
vastatin (Crestor, 4), and alpha-1 adrenergic receptor blocker
Doxazosin (Cardura, 5). As indicated in Figure 1, these aminopy-
rimidine therapeutics have a wide range of indications including
leukemia, bacterial infection, and hypertension management. In
addition, many pharmaceutical agents in development also contain
aminopyrimidine frameworks.6
During the course of a medicinal chemistry program, the syn-
thesis of an aminopyrimidine intermediate represented by 2-dial-
kylamino-4-arylamino-6-aminopyrimidine 6a (Fig. 2) became
important for further transformation. Despite the simple structural
feature of this compound and a literature report7 on the synthesis
of a related structure, our synthetic efforts toward 6a met with sig-
nificant setbacks. For example, the corresponding chloride precus-
or 7a failed to effectively produce product 6a in attempted direct
nucleophilic displacement reactions with aniline under either ba-
sic or acidic conditions.8 Transition metal catalyzed C–N coupling
with this substrate was also unsuccessful in our hands.9 Attempts
To further explore the utility of 6 in generating drug-like amino-
pyrimidine structures, we carried out Buchwald–Hartwig cou-
plings (Scheme 2) of representative compound 6a with a few
arylbromides. As can be seen from Table 2, the standard coupling
reactions gave regioselective coupling products with very high
* Corresponding author. Tel.: +1 617 992 3044; fax: +1 617 992 2403.
E-mail addresses: chaomin_li@merck.com, chaominl@gmail.com (C. Li).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.154

C. Li, A. Rosenau / Tetrahedron Letters 50 (2009) 5888–5893
5889
Me
N
Me
H
N
N
N
NH2
N
N
N
O
N
O
OMe
N
N
N
N
HN
OMe
H2N
N
OMe
O
1: Gleevec
2: Triprim
3: Buspar
(cancer)
(antibiotic)
(anxiety disorder)
F
O
O
O
N
MeO
MeO
N
N
N
OH
COOH
N
N
N
O2S
OH
NH2
5: Cardura
4: Crestor
(LDL cholesterol)
(hypertension)
Figure 1. Drugs with aminopyrimidine framework.
H
yields. This reaction tolerated electron-donating groups (14b, 14c)
and ortho substitution (14c) on the benzene ring. More interest-
ingly, heteroarylbromides such as bromopyridines (14d, 14e) and
bromopyrimidine (14f) all reacted and gave high yielding
reactions.
H2N
N
H2N
N
Cl
N
N
N
N
N
In summary, a practical strategy for the synthesis of 2-dialkyla-
mino-4-arylamino-6-aminopyrimidines was developed. This strat-
egy uses commercially available 4-amino-2,6-dichloropyrimidine
as starting material and could introduce a diverse set of secondary
7a
6a
Figure 2.
Table 1
Yields for the synthesis of 2-dialkylamino-4-arylamino-6-aminopyrimidines starting from 4-amino-2,6-dichloropyrimidine
Entry
Secondary amines
Yields (%) for steps 8?7
and 7? 1013,14
Arylamines
Final products
Yields (%) for steps
10?1215
H
N
H2N
H
N
H2N
N
N
1
90/87
78
N
11a
9a
6a
H
N
H2N
H
N
H2N
H2N
H2N
N
N
2
3
4
90/87
91/87
90/85
71
92
N
11a
11a
11a
O
9b
O
6b
6c
6d
H
N
H2N
N
N
N
N
H
9c
N
H
N
H
N
H2N
N
75
N
9d
(continued on next page)

5890
C. Li, A. Rosenau / Tetrahedron Letters 50 (2009) 5888–5893
Table 1 (continued)
Entry
Secondary amines
Yields (%) for steps 8?7
Arylamines
Final products
Yields (%) for steps
and 7? 1013,14
10?1215
H
N
H2N
H2N
H2N
H2N
H2N
N
N
N
N
N
N
N
N
H
N
OMe
5
90/87
OMe
87
N
N
N
N
9a
9a
11b
6e
H
N
H
N
H2N
Me
Me
6
7
8
90/87
90/87
90/87
87
11c
6f
H
N
H2N
H
N
73
9a
9a
11d
11e
6g
6h
H
N
H
N
H2N
N
N
77
H
N
H2N
H
N
H2N
N
N
N
N
N
9
90/87
83
N
N
11f
9a
6i
H
N
H2N
H2N
H2N
N
H
N
H2N
N
N
N
N
N
N
N
N
N
10
11
12
90/87
90/87
90/87
85
78
77
N
N
N
N
11g
9a
9a
9a
6j
6k
6l
H
N
H
N
H2N
N
S
S
11h
H
N
N
N
H2N
N
H
N
O
N
O
11i

C. Li, A. Rosenau / Tetrahedron Letters 50 (2009) 5888–5893
5891
Boc
N
Cl
H2N
Boc
Cl
H2N
Cl
NaH, Boc2O
DMF
R2NH (9)
N
R
N
R
N
R
N
R
N
N
DIEA, iPrOH
75oC
N
N
Cl
10
8
7
Boc
N
H
N
H
H2N
N
Boc
Ar
Ar
TFA
N
R
N
R
ArNH2 (11), Pd2(dba)3, XPhos
N
R
N
R
Cs2CO3, DMF, 80oC
N
N
DCM
6
12
Scheme 1. Synthetic route toward 2-dialkylamino-4-arylamino-6-aminopyrimidines.
H
H2N
H
N
ArHN
N
ArBr (13), Pd2(dba)3, XPhos
N
N
N
N
Cs2CO3, DMF, 90oC
N
N
6a
14
Scheme 2. Synthesis of 2-dialkylamino-4,6-bisarylaminopyrimidines.
Table 2
Yields for coupling of 6a with aryl bromide16
Entry
Aryl bromide
Product
Yields (%)
H
N
H
N
N
N
1
94
90
94
NC
Br
CN
N
13a
14a
H
H
N
N
MeO
N
N
MeO
2
Br
N
13b
14b
H
N
H
N
N
N
3
Br
N
13c
13d
14c
14d
H
N
H
N
N
N
N
4
87
N
Br
N
(continued on next page)

5892
C. Li, A. Rosenau / Tetrahedron Letters 50 (2009) 5888–5893
Table 2 (continued)
Entry
Aryl bromide
Product
Yields (%)
H
N
H
N
N
N
N
N
5
98
Br
N
13e
14e
H
H
N
N
N
N
N
N
N
N
6
87
Br
N
13f
14f
12. Bis-Boc protection was chosen over Mono-Boc due to the attempted Mono-Boc
protection giving a mixture of both products and starting material. In terms of
reactivity for the subsequent coupling reaction, Mono-Boc protected 7a
showed a comparable reactivity with 10a.
amines and arylamines to displace the 2- and 4-chloro groups
which are otherwise difficult to access. In addition, 6-amino aryla-
tion was carried out to demonstrate the reactivity and utility of 2-
dialkylamino-4-arylamino-6-aminopyrimidines as building blocks
for assembling interesting aminopyrimidine molecules.
13. Representative procedure for the synthesis of chloroaminopyrimidine 7: 6-chloro-
2-(piperidin-1-yl)pyrimidin-4-amine (7a). To a solution of dichloride 8 (5.0 g,
30.5 mmol) in anhydrous 2-propanol (30.5 mL) were added N,N0-
diisopropylethylamine (26.6 mL, 152 mmol) and piperidine (3.62 mL,
36.6 mmol). The resulting solution was heated to 75 °C and stirred for 16 h.
The reaction mixture was allowed to cool to room temperature before being
diluted with water (100 mL), and extracted with ethyl acetate (100 mL). The
organic extract was washed with water (100 mL ꢀ 2) and brine (100 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the
crude product. The product was then purified by flash chromatography
(0?100% ethyl acetate in hexanes over 10 column volumes) to yield pure 7a
(5.85 g, 90.2%). 1H NMR (600 MHz, CDCl3) d 5.69 (s, 1H), 4.55 (s, 2H), 3.71–3.66
(m, 4H), 1.64–1.58 (m, 2H), 1.57–1.50 (m, 4H). ESIMS (m/z): 213 (M+H).
14. Representative procedure for the synthesis of bis-bocaminopyrimidine 10: di-tert-
butyl [6-chloro-2-(piperidin-1-yl)pyrimidin-4-yl]imidodicarbonate (10a). To a
solution of 7a (1 g, 4.70 mmol) in anhydrous N,N-dimethylformamide
(23.5 mL), at 0 °C, was added sodium hydride (1.128 g, 28.2 mmol, 60%). The
resulting solution was allowed to stir for 10 min before di-tert-butyl
dicarbonate (4.10 g, 18.81 mmol) was added along with additional N,N-
dimethylformamide (23.5 mL) to facilitate stirring of the foamy mixture. The
solution was allowed to stir overnight while warming to ambient temperature.
The reaction mixture was cooled to 0 °C before water was added very carefully
to quench the remaining sodium hydride, after which ethyl acetate (100 mL)
was used to extract the product. The extract was washed with water
(2 ꢀ 100 mL) before being concentrated in vacuo. The residue was
redissolved in dichloromethane (20 mL) and water (20 mL) before potassium
carbonate (3.90 g, 28.2 mmol) and 2-(aminomethyl)pyridine (4.81 mL,
47.0 mmol) were added. The mixture was stirred for 30 min to allow
complete reaction with the remaining Boc2O (otherwise it is very difficult to
separate the product from Boc2O using silica gel chromatography). More DCM
was added and the organic layer was washed with water (100 mL) and brine
(100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (0?30% ethyl acetate
in hexanes over 15 column volumes) to yield 10a (1.43 g, 86.8%). 1H NMR
(600 MHz, CDCl3) d 6.89 (s, 1H), 3.67 (m, 4H), 1.69–1.47 (m, 24H). ESIMS (m/z):
413 (M+H).
Acknowledgments
We are grateful to B. Adams and B. Becker for help in NMR anal-
ysis and to J. Methot and C. Dinsmore for proofreading the draft
and for helpful discussions.
References and notes
1. For a review on the recent advances in pyrimidine synthesis, see: Hill, M. D.;
Movassaghi, M. Chem. Eur. J. 2008, 14, 6836–6844.
2. Brugnatelli, G. Ann. Chim. Phys. 1818, 8, 201–206.
3. Lamberth, C. Heterocycles 2006, 68, 561–603.
4. Lagoja, I. M. Chem. Biodiversity 2005, 2, 1–50.
5. Roth, B.; Cheng, C. C. Prog. Med. Chem. 1982, 19, 268–330.
6. Selected recent examples: (a) Altenbach, R. J.; Adair, R. M.; Bettencourt, B. M.;
Black, L. A.; Fix-Stenzel, S. R.; Gopalakrishnan, S. M.; Hsieh, G. C.; Liu, H.; Marsh,
K. C.; McPherson, M. J.; Milicic, I.; Miller, T. R.; Vortherms, T. A.; Warrior, U.;
Wetter, J. M.; Wishart, N.; Witte, D. G.; Honore, P.; Esbenshade, T. A.; Hancock,
A. A.; Brioni, J. D.; Cowart, M. D. J. Med. Chem. 2008, 51, 6571–6580; (b)
Bingham, A. H.; Davenport, R. J.; Fosbeary, R.; Gowers, L.; Knight, R. L.; Lowe, C.;
Owen, D. A.; Parry, D. A.; Pitt, W. R. Bioorg. Med. Chem. Lett. 2008, 18, 3622–
3627; (c) Lum, C.; Kahl, J.; Kessler, L.; Kucharski, J.; Lundstrom, J.; Miller, S.;
Nakanishi, H.; Pei, Y.; Pryor, K.; Roberts, E.; Sebo, L.; Sullivan, R.; Urban, J.;
Wang, Z. Bioorg. Med. Chem. Lett. 2008, 18, 3578–3581.
7. A related structure was prepared in moderate yield in: Bundy, G. L.; Banitt, L. S.;
Dobrowolsky, P. J.; Palmer, J. R.; Schwartz, T. M.; Zimmermann, D. C.; Lipton, M.
F.; Mauragis, M. A.; Veley, M. F.; Appell, R. B.; Clouse, R. C.; Daugs, E. D. Org.
Process Res. Dev. 2001, 5, 144–151.
15. Representative procedure for the synthesis of 2-dialkylamino-4-arylamino-6-
amino pyrimidines 6: N-phenyl-2-(piperidin-1-yl)pyrimidine-4,6-diamine
H2N
N
H2N
Cl
(6a). To
dimethylformamide (1.62 mL), under an atmosphere of nitrogen, were added
cesium carbonate (237 mg, 0.727 mmol), aniline (11a) (33.2 L, 0.363 mmol),
a solution of 10a (100 mg, 0.242 mmol) in anhydrous N,N-
N
H
N
N
N
N
l
reflux, 18 h
52 %
XPhos (34.6 mg, 0.073 mmol), and tris(dibenzylideneacetone) dipalladium
(24.39 mg, 0.027 mmol). The resulting solution was heated to 80 °C for 3 h
before being allowed to cool to ambient temperature. Sat. ammonium chloride
(40 mL) was added to quench the reaction before the product was extracted
into ethyl acetate (50 mL). The organic extract was washed with satd
ammonium chloride (2 ꢀ 50 mL) and brine (50 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to afford the crude bis-Boc
protected product. The residue was purified by flash chromatography (0?80%
ethyl acetate in hexanes over 10 column volumes) to yield pure bis-Boc
product 12a (88.7 mg, 77.8%). 1H NMR (600 MHz, DMSO) d 9.26 (s, 1H), 7.56 (d,
J = 7.9 Hz, 2H), 7.25 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 6.22 (s, 1H), 3.63–
3.58 (m, 4H), 1.56 (dd, J = 12.4, 5.7 Hz, 2H), 1.44 (m, 22H). ESIMS (m/z): 470
(M+H).The bis-Boc product (100 mg) was redissolved in dichloromethane
(1.42 mL) along with trifluoroacetic acid (1.64 mL, 21.30 mmol). The resulting
solution was allowed to stir for 1 h before satd sodium bicarbonate was added
N
Cl
.
8. (a) Koppel, H. C.; O‘Brien, D. E.; Robins, R. K. J. Am. Chem. Soc. 1959, 81, 3046–
3051; (b) Debi, M. J. Indian Chem. Soc. 1987, 4, 612–615.
9. Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–6361.
10. (a) Sabat, M.; VanRens, J.; Laufersweiler, M. J.; Brugel, T. A.; Maier, J.;
Golebiowski, A.; De, B.; Easwaran, V.; Hsieh, L. C.; Walter, R. L.; Mekel, M. J.;
Evdokimov, A.; Janusz, M. Bioorg. Med. Chem. Lett. 2006, 16, 5973–5977; (b)
Guillier, F.; Roussel, P.; Moser, H.; Kane, P.; Bradley, M. Chem. Eur. J. 1999, 5,
3450.
11. Montebugnoli, D.; Bravo, P.; Brenna, E.; Mioskowski, C.; Panzer, W.; Viani, F.;
Volonterio, A.; Wagner, A.; Zanda, M. Tetrahedron 2003, 59, 7147–7156. The
regiochemistry of 7a was also confirmed by NOE study.

C. Li, A. Rosenau / Tetrahedron Letters 50 (2009) 5888–5893
5893
slowly to the reaction to quench the remaining acid (2 mL). Ethyl acetate was
added to extract the product before being washed with satd sodium
bicarbonate (2 ꢀ 50 mL) and brine (50 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated to yield the desired deprotected product 6a
(57.4 mg, quantitative). 1H NMR (600 MHz, DMSO) d 8.50 (s, 1H), 7.46 (d,
J = 7.9 Hz, 2H), 7.18 (t, J = 7.8 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 5.84 (s, 2H), 5.14
(s, 1H), 3.66–3.54 (m, 4H), 1.55 (d, J = 5.1 Hz, 2H), 1.43 (m, 4H). ESIMS (m/z):
270 (M+H).
bromobenzonitrile (24.3 mg, 0.134 mmol), XPhos (13.3 mg, 0.028 mmol), and
tris(dibenzylideneacetone) dipalladium (10.2 mg, 0.011 mmol). The resulting
solution was heated to 90 °C for 3 h before being allowed to cool to ambient
temperature. Satd ammonium chloride was added to quench the reaction
before the product was extracted into ethyl acetate. The organic extract was
washed with satd ammonium chloride and brine, dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to afford the crude product. The
residue was purified by flash chromatography (0?60% ethyl acetate in hexanes
over 12 column volumes) to yield 14a (39 mg, 94 %). 1H NMR (600 MHz,
DMSO) d 9.22 (s, 1H, NH), 8.89 (s, 1H, NH), 8.22 (s, 1H), 7.72 (dd, J = 1.8, 7.8 Hz,
1H), 7.54 (d, J = 7.2 Hz, 2H), 7.45 (m, 1 H), 7.29 (m, 3H), 6.92 (m, 1H), 5.52 (s,
1H, pyrimidine CH), 3.71 (m, 4H), 1.64 (m, 2H), 1.54 (m, 4H). ESIMS (m/z): 371
(M+H).
16. Representative procedure for the synthesis of 2-dialkylamino-4-arylamino-6-
arylamino pyrimidines 14: 3-{[6-(phenylamino)-2-(piperidin-1-yl)pyrimidin-4-
yl]amino}benzonitrile (14a). To
a solution of 6a (30 mg, 0.111 mmol) in
anhydrous N,N-dimethylformamide (1.0 mL), under an atmosphere of
nitrogen, were added cesium carbonate (72.6 mg, 0.223 mmol), 3-