Synthesis of 6-aryl-2,4-diamino-pyrimidines and triazines using palladium catalysed Suzuki cross-coupling reactions

Article abstract of DOI:10.1016/S0040-4020(01)00119-3

The high yielding synthesis of 6-aryl-2,4-diaminopyrimidines and triazines via palladium catalysed Suzuki cross-coupling reactions of commercially available 6-chloro-2,4-diaminopyrimidine 1 or 6-chloro-2,4-diaminotriazine 8 and aryl boronic acids are desc

Full text of DOI:10.1016/S0040-4020(01)00119-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2787±2789
Synthesis of 6-aryl-2,4-diamino-pyrimidines and triazines using
palladium catalysed Suzuki cross-coupling reactions
Graeme Cooke,a,p Hugues Augier de Cremiers,a,b Vincent M. Rotello,b Brian Tarbitc
and Petra E. Vanderstraetena
aDepartment of Chemistry, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, UK
bDepartment of Chemistry, University of Massachusetts, Amherst, MA 01003, USA
cSeal Sands Chemicals Ltd., Seal Sands, Middlesbrough, Cleveland TS2 1UB, UK
Received 26 October 2000; revised 2 January 2001; accepted 18 January 2001
AbstractÐThe high yielding synthesis of 6-aryl-2,4-diaminopyrimidines and triazines via palladium catalysed Suzuki cross-coupling
reactions of commercially available 6-chloro-2,4-diaminopyrimidine 1 or 6-chloro-2,4-diaminotriazine 8 and aryl boronic acids are
described. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
and medicinal4 properties. The synthesis of 6-aryl-2,4-
diaminopyrimidines are largely unexplored, however,
compound 2 has been previously synthesised by conden-
sation reactions of guanidine with acetophenone,5 3-phenyl-
propynenitrile6 or b-bromocinnamonitrile.7 The synthesis
of 6-aryl-2,4-diaminotriazines have been reported,8 and
typically involve the condensation of aryl-nitriles or esters
with dicyandiamide or biguanide, respectively. Clearly, it
would be advantageous to develop cross-coupling strategies
utilising Suzuki procedures to allow rapid and convenient
synthesis of a range of 6-aryl-2,4-diaminopyrimidines and
6-aryl-2,4-diaminotriazines from a common 6-halo-2,4-
diamino-pyrimidine or triazine building block.
The use of catalytic cross-coupling methodologies for
preparing aryl functionalised heterocycles with pharma-
ceutical, agrochemical, materials and supramolecular appli-
cations is a burgeoning ®eld of study.1 In particular, the
so-called Suzuki reaction,2 which involves the palladium
catalysed cross-coupling of heteroaryl-halides with aryl
boronic acids, has received considerable recent attention.
We are particularly interested in exploiting the versatility
of the Suzuki cross-coupling procedure to prepare 6-aryl-
2,4-diamino-pyrimidines and triazines, in view of their
potentially interesting molecular recognition,3 agrochemical
Scheme 1.
Keywords: triazines; Suzuki cross-coupling; tetrakis(triphenylphosphine)palladium; pyrimidines.
Corresponding author. Fax: 144-131-451-3180; e-mail: g.cooke@hw.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00119-3

2788
G. Cooke et al. / Tetrahedron 57 (2001) 2787±2789
2. Results and discussion
added and the suspension was placed in an ultrasonic
bath for a few minutes. The mixture was ®ltered, washed
thoroughly with THF and the ®ltrate was evaporated under
reduced pressure. The residue was puri®ed by column
chromatography on silica gel using ethyl acetate as eluent,
to afford 2 as a white solid (0.61 g, 73%); Rf (ethyl acetate)
0.1; mp 152±1568C (lit.5 mp 160±1618C); nmax (KBr) 3435,
3399, 3335, 3181, 1631; dH [400 MHz (CD3)2SO]: 7.94
(2H, d, Jˆ3.0 Hz, Ph), 7.46 (3H, t, Jˆ1.7 Hz, Ph), 6.40
(2H, s, NH2), 6.26 (1H, s, NvCH), 6.01 (2H, s, NH2); dC
[100 MHz (CD3)2SO]: 165, 163, 162, 138, 129, 128, 126,
91; MS (EI) 186 (M1, 100%). Found: C, 64.62; H, 5.42; N,
30.28. C10H10N4 requires C, 64.52; H, 5.38; N, 30.11%.
In the present work, we report the ®rst general, high
yielding synthesis of 6-aryl-2,4-diaminopyrimidines 2±7
via Suzuki cross-coupling reactions of commercially avail-
able 6-chloro-2,4-diaminopyrimidine 1 with aryl boronic
acids (Scheme 1).
We have extended our study to include the ®rst synthesis
6-aryl-2,4-diaminotriazines 9±12 using Suzuki method-
ology from commercially available 8 and aryl boronic
acids, which afforded the triazine derivatives 9±12 in
good yield (Scheme 2).
4.1.2. 2,4-Diamino-6-(4-methylphenyl)-pyrimidine 3.
This compound was synthesised analogously to 2 using 1
(1.0 g, 7 mmol), 4-methylphenylboronic acid (1.41 g,
10.4 mmol), Na2CO3 (2 M, 7.4 ml) and tetrakis(triphenyl-
phosphine)palladium (0.24 g, 0.19 mmol). Compound 3
was obtained as an off-white solid (1.02 g, 73%); Rf (ethyl
acetate) 0.15; mp 118±1208C; nmax (KBr) 3435, 3399, 3335,
3181, 1631; dH [400 MHz (CD3)2SO]: 7.80 (2H, d,
Jˆ8.3 Hz, Ph), 7.23 (2H, d, Jˆ7.9 Hz, Ph), 6.33 (2H, s,
NH2), 6.18 (1H, s, NvCH), 5.92 (2H, s, NH2), 2.33 (3H,
s, CH3); dC [100 MHz (CD3)2SO]: 165, 163, 162, 140, 135,
129, 126, 90, 21; MS (EI) 200 (M1, 100%). Found: C,
65.82; H, 5.98; N, 28.28. C11H12N4 requires C, 66.00; H,
6.00; N, 28.00%.
3. Conclusions
In summary, we describe a general, versatile, high yielding
method for preparing 6-aryl-2,4-diamino-pyrimidines and
an improved method of preparing 6-aryl-2,4-diaminotria-
zines. Building blocks 1 and 8 will be further exploited
to prepare highly functionalised pyrimidine and triazine
derivatives, and their synthesis will be reported in due
course.
4. Experimental
4.1. General
4.1.3. 2,4-Diamino-6-(4-methoxyphenyl)-pyrimidine 4.
This compound was synthesised analogously to 2 using 1
(1.0 g, 7 mmol), 4-methoxyphenylboronic acid (1.58 g,
10.4 mmol), Na2CO3 (2 M, 7.4 ml) and tetrakis(triphenyl-
phosphine)palladium (0.24 g, 0.19 mmol). Compound 4
was obtained as an off-white solid (1.18 g, 78%); Rf (ethyl
acetate) 0.11; mp 212±2158C; nmax (KBr) 3435, 3399, 3335,
3181, 1631; dH [400 MHz (CD3)2SO]: 7.95 (2H, d,
Jˆ2.9 Hz, Ph), 6.99 (2H, d, Jˆ2.9 Hz, Ph), 6.30 (2H, s,
NH2), 6.17 (1H, s, NvCH), 5.98 (2H, s, NH2), 3.76 (3H,
s, OCH3); dC [100 MHz (CD3)2SO]: 165, 164, 162, 160,
131, 128, 114, 90, 55; MS (EI) 216 (M1, 100%). Found:
All reagents were obtained from commercial suppliers and
were used without further puri®cation. DME was distilled
prior to use. Melting points were measured on a Reichert
hot-stage apparatus and are uncorrected. NMR spectra were
recorded on a Bruker DPX400 spectrometer. EI Mass spec-
tral data were obtained using a Finnigan MAT 900 XLT
mass spectrometer. Elemental analysis data were obtained
using an Exeter CE-440 elemental analyser.
4.1.1. 2,4-Diamino-6-phenylpyrimidine 2. To a mixture
6-chloro-2,4-diaminopyrimidine 1 (0.65 g, 4.5 mmol) and
tetrakis(triphenylphosphine)palladium (0.16 g, 0.13 mmol)
in DME (10 ml) was added phenylboronic acid (0.823 g,
6.75 mmol) immediately followed by aqueous Na2CO3
(2 M, 4.7 ml). The mixture was ¯ushed with N2 for 5 min
and the reaction mixture was then heated under re¯ux for
48 h. After cooling, the reaction mixture was evaporated
under reduced pressure to dryness. THF (100 ml) was
C, 61.22; H, 5.52; N, 26.17. C11H12N4O requires C, 61.11;
H, 5.55; N, 25.93%.
4.1.4. 2,4-Diamino-6-(4-¯uorophenyl)-pyrimidine 5. This
compound was synthesised analogously to 2 using 1 (0.69 g,
4.76 mmol), 4-¯uorophenylboronic acid (1.0 g, 7.14 mmol),
Na2CO3 (2 M, 5 ml) and tetrakis(triphenyl-phosphine)
Scheme 2.

G. Cooke et al. / Tetrahedron 57 (2001) 2787±2789
2789
palladium (0.16 g, 0.13 mmol). Compound 5 was obtained
as an off-white solid (0.84 g, 86%); Rf (ethyl acetate) 0.26;
mp 233±2368C; nmax (KBr) 3435, 3399, 3335, 3188, 2287,
1635; dH [400 MHz (CD3)2SO]: 7.92 (2H, q, Jˆ2.9 Hz, Ph),
7.31 (2H, t, Jˆ6.7 Hz, Ph), 7.21 (2H, s, NH2), 6.83 (2H, s,
NH2), 6.25 (1H, s, NvCH); dC [100 MHz (CD3)2SO]: 165,
164, 162, 130, 116, 92; MS (EI) 204 (M1, 100%). Found: C,
58.90; H, 4.42; N, 27.32. C10H9N4F requires C, 58.82; H,
4.41; N, 27.50%.
Jˆ8.3, Ph), 7.20 (2H, d, Jˆ7.9, Ph), 3.70 (4H, s, NH2), 2.30
(3H, s, CH3); MS (EI) 201 (M1). Found: C, 59.62; H, 5.48;
N, 34.78. C10H11N5 requires C, 59.70; H, 5.47; N, 34.82%.
4.1.9. 2,4-Diamino-6-(4-methoxyphenyl)-1,3,5-triazine
11. This compound was synthesised analogously to 2
using 8 (0.25 g, 1.72 mmol), 4-methoxyphenylboronic
acid (0.39 g, 2.58 mmol), tetrakis(triphenylphosphine)palla-
dium (0.09 g, 0.08 mmol) and Na2CO3 (2 M, 2 ml).
Compound 11 was obtained as a white solid (0.28 g,
76%); Rf (ethyl acetate) 0.1; mp.2008C; dH [400 MHz
(CD3)2SO]: 8.42 (2H, d, Jˆ9.0 Hz, Ph), 6.99 (2H, d,
Jˆ9.0 Hz, Ph), 3.90 (3H, s, OCH3), 3.70 (4H, s, NH2);
MS (EI) 217 (M1). Found: C, 55.59; H, 5.00; N, 32.38.
C10H11N5O requires C, 55.30; H, 5.07; N, 32.26%.
4.1.5. 2,4-Diamino-6-(4-cyanophenyl)-pyrimidine 6. This
compound was synthesised analogously to 2 using 1 (0.69 g,
4.76 mmol),
4-cyanophenylboronic
acid
(1.05 g,
7.14 mmol), Na2CO3 (2 M, 5 ml) and tetrakis(triphenyl-
phosphine)palladium (0.16 g, 0.13 mmol). Compound 6
was obtained as an off-white solid (0.86 g, 86%); Rf (ethyl
acetate) 0.24; mp 220±2248C (dec). nmax (KBr) 3435, 3399,
3335, 3181, 1631; dH [400 MHz (CD3)2SO]: 8.05 (2H, d,
Jˆ8.0 Hz, Ph), 7.93 (2H, d, Jˆ8.0 Hz, Ph), 6.47 (2H, s
NH2), 6.26 (1H, s, NvCH), 6.06 (2H, s, NH2); dC
[100 MHz (CD3)2SO]: 165, 164, 160, 143, 132, 127, 119,
112, 92; MS (EI) 211 (M1, 100%). Found: C, 62.56; H,
4.27; N, 32.28. C11H9N5 requires C, 62.56; H, 4.27; N,
33.18%.
4.1.10. 2,4-Diamino-6-(4-¯uorophenyl)-1,3,5-triazine 12.
This compound was synthesised analogously to 2 using 8
(0.25 g, 1.72 mmol), 4-¯uorophenylboronic acid (0.36 g,
2.58 mmol), tetrakis(triphenylphosphine)palladium (0.09 g,
0.08 mmol) and Na2CO3 (2 M, 2 ml). Compound 12 was
obtained as a white solid (0.27 g, 77%); Rf (ethyl acetate)
0.1; mp.2008C; dH [400 MHz (CD3)2SO]: 8.27 (2H, t,
Jˆ9.0 Hz, Ph), 7.28 (2H, t, Jˆ9.0 Hz, Ph), 6.76 (4H, s
NH2); MS (EI) 205 (M1). Found: C, 52.62; H, 3.98; N,
34.28. C9H8N5F requires C, 52.68; H, 3.90; N, 34.15%.
4.1.6. 2,4-Diamino-6-(3-nitrophenyl)-pyrimidine 7.
This compound was synthesised analogously to 2 using 1
(0.50 g, 3.46 mmol), 3-nitrophenyl boronic acid (0.87 g,
5.19 mmol), Na2CO3 (2 M, 3.6 ml) and tetrakis(triphenyl-
phosphine)palladium (0.12 g, 0.095 mmol). Compound 7
was obtained as an off-white solid (0.70 g, 82%); Rf (ethyl
acetate) 0.33; mp 213±2168C; nmax (KBr) 3435, 3399, 3335,
3181, 1631; dH [400 MHz (CD3)2SO]: 8.76 (1H, s Ph), 8.30
(2H, d, Jˆ1.3 Hz, Ph), 7.72 (1H, t, Jˆ8.0 Hz, Ph), 6.51 (2H,
s NH2), 6.34 (1H, s, NvCH), 6.14 (2H, s, NH2); dC
[100 MHz (CD3)2SO]: 165, 164, 159, 148, 140, 132, 130,
124, 121, 91; MS (EI) 231 (M1, 100%). Found: C, 51.72; H,
3.90; N, 30.38. C10H9N5O2 requires C, 51.95; H, 3.90; N,
30.30%.
Acknowledgements
The authors thank the Royal Society of Chemistry, National
Science Foundation (US) (V. M. R.) and the Royal Society
for ®nancial support and the EPSRC National Mass
Spectrometry Service Centre, Swansea, for performing
mass spectral analysis.
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4.1.7. 2,4-Diamino-6-phenyl-1,3,5-triazine 9. This compound
was synthesised analogously to 2 using 8 (1.0 g, 6.87 mmol),
phenylboronic acid (1.25 g, 10.3 mmol), tetrakis(triphenyl-
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7.2 ml). Compound 9 was obtained as a white solid (0.90 g,
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57.62; H, 4.98; N, 37.28. C9H9N5 requires C, 57.75; H, 4.81;
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