Facile synthesis of 6-cyano-9-substituted-9H-purines and their ring expansion to 8-(arylamino)-4-imino-3-methylpyrimidino-[5,4-d]pyrimidines

Article abstract of DOI:10.1039/b106539b

6-Cyano-9-substituted-9H-purines were prepared in a high yielding, one-step process by refluxing triethyl orthoformate or triethyl orthopropionate with the corresponding (Z)-N₁-(aryl- or benzyl)-N₂-(2-amino-1,2-dicyanovinyl)formamidi

Full text of DOI:10.1039/b106539b

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Facile synthesis of 6-cyano-9-substituted-9H-purines and their
ring expansion to 8-(arylamino)-4-imino-3-methylpyrimidino-
[5,4-d]pyrimidines
1
Amal Al-Azmi,a Brian L. Booth,*a Robert A. Carpenter,a Alice Carvalho,b Elodie Marrelec,a
Robin G. Pritcharda and M. Fernanda J. R. P. Proençab
a Department of Chemistry, University of Manchester Institute of Science and Technology,
P.O. Box 88, Manchester, UK M60 1QD
b Department of Chemistry, University of Minho, Braga, Portugal
Received (in Cambridge, UK) 20th July 2001, Accepted 7th September 2001
First published as an Advance Article on the web 25th September 2001
6-Cyano-9-substituted-9H-purines were prepared in a high yielding, one-step process by refluxing triethyl
orthoformate or triethyl orthopropionate with the corresponding (Z)-N 1-(aryl- or benzyl)-N 2-(2-amino-1,2-
dicyanovinyl)formamidines. Attempted reaction of these cyanopurines with aqueous methylamine furnished
8-(arylamino)-4-imino-3-methylpyrimidino[5,4-d]pyrimidines, by attack at the imidazole ring rather than addition to
the 6-cyano group. All compounds have been fully characterised by spectroscopic data and an X-ray crystal structure
determination has been carried out on the 8-(4-methoxyanilino)-4-imino-3-methylpyrimidino[5,4-d]pyrimidine.
6-Methylamino-9-benzylpurines are reported1 to be potent
anti-epileptic agents, as well as showing anti-anginal and anti-
inflammatory activity. From structure–activity relationship
studies it has been established that both the 9-benzyl group and
a basic group in the 6 position are essential for activity. We were
interested in extending these studies to investigate the activities
of 9-aryl- and, particularly, 9-benzylpurines having a strongly
basic carboxamidino substituent in the 6-position.
A similar reaction of triethyl orthopropionate with 1a gave the
corresponding 2-ethyl-6-cyanopurine derivative 2i. The reac-
tions are summarised in Scheme 1. In the case of purines 2b, c
and d precipitation was induced by the addition of petroleum
ether to the cooled solution. This reaction offers a new, simple
route and high yield method for the preparation of 6-cyano-
purines. As far as we are aware all of the 6-cyanopurines iso-
lated are new compounds and they have been fully characterised
by elemental analysis, IR, 1H/13C NMR spectroscopy and mass
spectrometry and details are given in Tables 1–3.
There have been a number of previous reports of 6-amidino-
purines prepared by nucleophilic attack of a primary or
secondary amine on a 6-cyanopurine,2 or by treatment of
a 6-cyanopurine with a catalytic amount of sodium methoxide
in methanol to form an imidate intermediate, followed by
addition of ammonium chloride.3 The yields reported by this
last method are only a moderate 44–51%. 6-Cyanopurines4–12
can be synthesised by cyanide ion substitution of 6-iodo-,4
6-chloro,5–8 6-methylsulfonyl,9–11 6-tosyl-12 or 6-trimethyl-
ammonio-13 purine derivatives, or by dehydration of the 6-
oxime derivatives with acetic anhydride.14 More recently, work
in our group has established that 6-cyanopurines can also be
prepared either by reaction of 1-substituted-5-amino-4-(cyano-
formimidoyl)imidazoles with carboxylic acid anhydrides15 or
by the reaction of formamidines 1 with 1–3 equivalents of
dimethylformamide diethyl acetal in acetonitrile.16 Although
the last reaction can give good to excellent yields in many cases,
in some reactions it is not always easy to isolate the cyano-
purines in a pure state due either to by-product formation
or to the difficulties in handling the 5-amino-4-(cyanoform-
imidoyl)imidazoles.
It is clear that during this reaction, cyclisation to an imid-
azole intermediate must occur and it is open to question
whether cyclisation occurs before reaction with the triethyl
ortho-formate or -propionate (path 1), or after reaction of these
reagents with the formamidine (path 2, Scheme 2). From
Scheme 2 it can be seen that both pathways would lead to a
common intermediate. From our extensive investigations on
formamidines of type 117,18 we know that cyclisation to a
5-amino-4-(cyanoformimidoyl)imidazole occurs easily under
base catalysis at room temperature, and that the NH of cyano-
formidoyl group reacts readily with electrophiles, such as acid
anhydrides. What is less certain is whether a similar reaction
can occur thermally in the absence of base and, if so, the rela-
tive rate for such a reaction. We have not carried out any kinetic
investigation of this reaction and this problem remains
unresolved. However, it has been established that conversion of
1a to imidazole 3a can be achieved in 91% yield after 3 h using
our reported procedure17 of addition of a catalytic amount of
DBU to an ethanol solution at room temperature. When 3 was
heated under reflux with an excess of triethyl orthopropionate
for 3 h, the 6-cyanopurine 2j was isolated in 65% yield. While
this experiment does not distinguish between path 1 and path 2
it does indicate that path 1 is feasible. This observation has led
to an alternative synthesis for 6-cyanopurines. Thus the acid
catalysed reaction of 3a and 3b with triethyl orthoformate gives
2a and 2j respectively in 91% yields (see Scheme 1).
Results and discussion
The formation of 6-cyanopurines from formamidines 1 with
dimethylformamide diethyl acetal suggested the possibility
that a more effective procedure might be to use trialkyl
orthoformates. Consequently, the previously reported17 form-
amidines 1a–e, together with the previously unreported form-
amidines 1f–h, were heated under reflux with an excess of
triethyl orthoformate and were found to give the 6-cyano-
purines 2a–h in good yields (see Table 1) by a clean precip-
itation after cooling the reaction mixture to room temperature.
In an effort to prepare a 6-(N-methylcarboxamido)purine
derivative 4 a similar procedure to that described by Higashino
et al.2 was followed and an equimolar quantity of 6-cyano-9-(4-
methoxyphenyl)-9H-purine 2a was caused to react with an
excess of aqueous methylamine in dichloromethane at room
2532
J. Chem. Soc., Perkin Trans. 1, 2001, 2532–2537
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106539b

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Table 1 Analytical and spectroscopic data for the compounds 1, 2, and 5
Compound
Yield (%)
Mp/ЊC
Molecular formula
Microanalytical data (%) found (calcd)
m/z (M ϩ 1)ϩ
M
1f
95
83
82
180–184
154–146
115–116
178–180
130–132
160–164
133
C12H9N6Br
C12H10N5F
C12H9N5F2
C13H9N5O
C14H11N5O
C14H11N5O2
C12H6N5F
C15H13N5O2
C13H7N6Br
C13H8N5F
C13H7N5F2
C15H13N5O
C13H6N6
C, 44.9 (45.5); H, 2.6 (2.8)
317
244
262
252
266
282
316
243
261
251
265
281
239
295
326
253
271
279
246
282
312
310
284
277
1g
1h
2a
2b
2c
2d
2e
2f
C, 58.1 (58.3); H, 3.9 (4.1); N, 28.3 (28.8)
C, 54.6 (54.2); H, 3.3 (3.5), N, 26.4 (26.8)
C, 61.6 (62.1); H, 4.0 (3.6); N, 28.5 (27.8)
C, 62.4 (63.2); H, 4.9 (4.2); N, 26.3 (26.4)
C, 59.0 (59.8); H, 4.4 (3.9), N, 24.8 (24.9)
C, 60.0 (60.2); H, 2.6 (2.5); N, 29.0 (29.3); F, 7.7 (7.9)
C, 61.0 (61.0); H, 4.6 (4.4); N, 23.4 (23.7)
C, 48.0 (47.8); H, 1.9 (2.1); N, 25.5 (25.7)
C, 61.6 (61.7); H, 3.4 (3.2); N, 27.7 (27.6)
C, 57.6 (57.6); H, 2.6 (2.6); N, 25.8 (25.8); F, 14.0 (13.6)
C, 64.4 (64.5); H, 4.6 (4.6); N, 25.0 (25.0)
C, 63.4 (63.3); H, 2.6 (2.4); N, 33.8 (34.1)
C, 59.6 (59.5); H, 5.1 (4.9); N, 29.7 (29.7)
Accurate mass 312.1338 (312.13346)g
80,a 91b
69
87
85
78
91
87
89
240
152
296, 38%c
327
195–198
104–105
142–143
161–162
228–229
250
168–170
180
190–192
Above 300
2g
2h
2i
254
272
96,a 65d
91b
86e, h
72e
98e
67e
99e
280
2j
246f
283
5a
5b
5c
5d
5e
C14H14N6O
C15H16N6O2
C16H18N6O
C14H13N6F
C14H11N7
313
311
C, 61.1 (61.9); H, 5.8 (5.8); N, 27.7 (27.1)
Accurate mass 284.1179 (284.11856)g
285
C, 60.75 (60.65); H, 3.91 (3.97); N, 35.33 (35.38)
277f
a Method A (direct from amidine 1a). b From imidazole 3 with acid catalysis. c (M Ϫ C6H2N5) 100%. d Method B (through imidazole 3). e Using
MeNH2 (aq) and dichloromethane. f By EI. g Despite many attempts these compounds could not be obtained analytically pure, probably due to
solvent association; they were both pure by TLC (1 : 1 CH2Cl2–EtOAc). h Excess MeNH2 gas in dichloromethane at 0 ЊC.
temperature. The reaction was monitored carefully by TLC
(1 : 1 dichloromethane–ethyl acetate) and after 24 h the reaction
was complete and gave a 69% yield of 5a as a crystalline, white
solid. An improved yield of 5a (86%) was obtained by bubbling
methylamine gas through a solution of 2a in dichloromethane
at 0 ЊC. Reactions of the cyanopurines 2i, c, and g gave the
analogous products 5b–d also in high yields. Under the con-
ditions of method B, compound 2j reacts to give 5e in 94%
isolated yield after 18 h at room temperature. When this last
reaction was carried out in ethanol rather than dichloro-
methane the rate of reaction was slower, but an improved yield
of 99% of 5e was obtained. The analytical and spectroscopic
information on these products is given in Tables 1–3. The spec-
troscopic data showed several anomalies, which indicated that
Scheme 1 (i) Excess HC(OEt)3 or EtC(OEt)3 under reflux; (ii) either (a) excess MeNH2 (aq) in dichloromethane at rt or (b) excess MeNH2 (gas) in
dichloromethane at 0 ЊC; (iii) cat. DBU, ethanol, rt; (iv) either (a) excess EtC(OEt)3 under reflux or (b) HC(OEt)3 under reflux, Hϩ cat., CH3CN at rt.
J. Chem. Soc., Perkin Trans. 1, 2001, 2532–2537
2533

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Table 2 1H NMR spectroscopic data for the compounds 1, 2, and 5a
Compound
δH (ppm)
1fc
3.62 (br s, 2H, NH2), 6.7 (br s, 1H, NH), 7.68 (d, 2H, 3J 8.5 Hz, ArH), 7.85 (d, 2H, 3J 8.5 Hz, ArH), 8.26 (s, 1H, CH–)
4.56 (d, 2H, 3J6,NH 5.0 Hz, 6-H), 6.15 (s, 2H, NH2), 7.18 (m, 2H, ArH), 7.32 (ddd, 1H, 3JH,F 13.3, 3JH,H 7.5, 4JH,H 2 Hz, ArH), 7.44
(td, 1H, J 8, 2 Hz, ArH), 7.73 (d, 1H, 3J5,NH 4 Hz, 5-H), 8.17 (m, 1H, NH)
1gd, d
1hb, d
2ac
4.55 (d, 2H, 3J5,NH 5.5 Hz, 6-H), 6.44 (s, 2H, NH2), 7.08–7.36 (m, 3H, ArH), 7.74 (d, 1H, 3J5,NH 3.43 Hz, 5-H), 8.18 (m, 1H, NH)
3.98 (s, 3H, OMe), 7.2 (d, 2H, J 8 Hz, ArH), 7.63 (d, 2H, J 8 Hz, ArH), 8.6 (s, 1H, 8-H), 9.22 (s, 1H, 2-H)
3.8 (s, 3H, OMe), 5.38 (s, 2H, CH2), 6.9–7.96 (complex m, 4H, ArH), 8.3 (s, 1H, 8-H), 8.98 (s, 1H, 2-H)
3.98 (s, 3H, OMe), 4.00 (s, 3H, OMe), 7.00–7.20 (m, 3H, ArH), 8.5 (s, 1H, 8-H), 9.17 (s, 1H, 2-H)
7.45 (dd, J 9, 7.8 Hz, ArH), 7.82 (dd, J 9, 4.5 Hz, ArH), 8.5 (s, 1H, 8-H), 9.1 (s, 1H, 2-H)
2bc
2cc
2dd
2ec
3.86 (s, 3H, OMe), 3.90 (s, 3H, OMe), 5.45 (s, 2H, CH2), 6.80–7.00 (m, 3H, ArH), 8.3 (s, 1H, 8-H), 9.1 (s, 1H, 2-H)
2fb, c
2gb, d
7.88 (d, 2H, J 8.2 Hz, ArH), 8.09 (d, 2H, J 8.2 Hz, ArH), 8.89 (s, 1H, 8-H), 9.00 (s, 1H, H-C᎐N), 9.60 (s, 1H, 2-H)
᎐
5.74 (s, 2H, CH2), 7.11 (ddd, 1H, 3JH,F 9.4, 3JH,H 7.56, 4JH,H 2 Hz, ArH), 7.16 (ddd, 1H, 4JH,F 6, 3JH,H 7.56, 4JH,H 2 Hz, ArH), 7.36
(m, 1H, 3JH,H 7.56, 3JH,H 7.43, 4JH,F 5.8, 4JH,H 2 Hz, ArH), 7.45 (ddd, 1H, 3JH,H 7.43, 3JH,H 7.56, 4JH,H 2 Hz, ArH), 8.56 (s, 1H, 6-H),
9.26 (s, 1H, 2-H)
2hb, c
2ic
5.66 (s, 2H, CH2), 7.14–7.46 (m, 3H, ArH), 8.37 (s, 1H, 8-H), 9.09 (s, 1H, 2-H)
1.25 (t, 3H, J 7.4 Hz, Me), 3.07 (q, 2H, J 7.4 Hz, CH2), 3.83 (s, 3H, OMe), 7.08 (d, 2H, J 8 Hz, ArH), 7.56 (d, 2H, J 8 Hz, ArH), 8.36
(s, 1H, 8-H)
8.16 (d, 2H, J 9.0 Hz, ArH), 8.22 (d, 2H, J 9.0 Hz, ArH), 9.23 (s, 1H, 8-H), 9.46 (s, 1H, 2-H)
3.45 (s, 3H, NMe), 3.88 (s, 3H, OMe), 6.87 (d, 2H, J 8.5 Hz, ArH), 7.57 (d, 2H, J 8.5 Hz, ArH), 7.68 (s, 1H, 6-H), 8.18 (s, <2H,
NH2), 8.55 (s, 1H, 2-H)
1.34 (t, 3H, J 7.56 Hz, Me), 2.82 (q, 2H, J 7.56 Hz, CH2), 3.42 (s, 3H, NMe), 3.76 (s, 3H, OMe), 6.87 (d, 2H, J 9.0 Hz, ArH), 7.58
(s, 1H, 6-H), 7.71 (d, 2H, J 9.0 Hz, ArH), 8.10 (s, 1H, NH), 8.44 (br s, 1H, NH)
3.45 (s, 3H, NMe), 3.85 (s, 3H, OMe), 3.90 (s, 3H, OMe), 6.80 (d, 1H, J 8.64 Hz, ArH), 7.35 (dd, 1H, J 2.34, 8.8 Hz, ArH), 7.51
(d, 1H, J 2.34 Hz, ArH), 8.14 (s, 1H, 6-H), 8.46 (br s, 1H, NH), 8.5 (s, 1H, NH), 9.43 (s, 1H, 2-H)
3.54 (s, 3H, NMe), 4.83 (d, 2H, J 6 Hz, CH2), 5.60 (br s, 1H, NH), 6.80 (br s, 1H, NH), 7.35 (complex m, overlapping signals for 2H,
ArH), 7.27 (m, 1H, J 1.52, ∼6, 6.8 Hz, ArH), 7.39 (ddd, 1H, J 1.52, 7.47, 7.54 Hz, ArH), 7.70 (s, 1H, 6-H), 8.54 (s, 1H, 2-H)
3.82 (s, 3H, NMe), 7.87 (d, 2H, J 6.9 Hz, ArH), 8.25 (d, 2H, J 6.9 Hz, ArH), 8.81 (s, 1H, H-2), 8.91 (s, 1H, H-6), 10.10 (br s, 1H,
NH), 10.57 (s, 1H, NH), 10.81 (s, 1H, NH)
2jc
5ad
5bd
5cb, d
5dd
5ed
a All spectra were determined in CDCl3 except where stated. b In d6-DMSO. c Determined at 300 MHz. d Determined at 400 MHz.
Table 3 13C NMR spectroscopic data for the compounds 1, 2, and 5a
Compound
δC (ppm)
1fd
161.0 (6-C), 159.8 (5-C), 132.7 (Ar), 132.0 (Ar), 125.7 (Ar), 122.4 (1-C), 117.3 (4-C), 116.5 (3-C), 102.6 (2-C)
164.5 (d, 1JC–F 242.9 Hz, Ar), 154.5 (s, 5-C), 134.4 (d, 3JC,F 7.8 Hz, Ar), 133.3 (d, 3JC,F 4.1 Hz, Ar), 129.4 (d, 4JC,F 3.2 Hz, Ar), 128.3
(d, 2JC,F 14.1 Hz, Ar), 121.5 (s, 3-C), 120.3 (s, 4-C), 119.1 (d, 2JC,F 23.2 Hz, Ar), 119.1 (s, 2-C), 110.1 (s, 1-C), 42.1 (d, 3JC,F 3.8 Hz,
6-C)
1gb, e
1hb, c
161.6 (d, 1JC,F 241.8, 3JC,F 1.7 Hz, Ar), 161.0 (d, 1JC,F 239.0, 2JC,F 25.1 Hz, Ar), 131.6 (dd, 3JC,F 7.6, 3JC,F 7.5 Hz, Ar), 120.6 (dd, 2JC,F
24.4, 2JC,F 25.1 Hz, Ar), 119.4 (d, 2JC,F 24.2 Hz, Ar), 119.3 (d, 2JC,F 24.2 Hz, Ar), 119.1 (s, 4-C), 109.8 (s, 1-C), 100.9 (s, 1-C), 41.8
(d, 3JC,F 2.7 Hz, 6-C)
2ad
2bd
160.3 (Cp), 153.3 (2-C), 152.8 (4-C), 147.4 (8-C), 135.3 (6-C), 131.5 (5-C), 125.9 (Ci), 125.4 (Cm), 115.4 (Co), 114.9 (CN), 55.8 (OMe)
160.9 (Co), 152.1 (2-C), 150.3 (4-C), 148.1 (8-C), 133.3 (6-C), 131.2 (5-C), 129.0 (Cp), 126.9 (Co), 122.6 (Ci), 120.5 (Cm), 114.2 (CN),
113.3 (Cm), 58.9 (OMe), 46.2 (CH2)
155.4, 155.1 (Cp, Cm), 151.9 (2-C), 150.2 (4-C), 148.2 (8-C), 142.5 (Ci), 135.2 (6-C), 130.2 (5-C), 117.5 (Co), 116.5 (Cm), 116.2 (Co),
113.5 (CN), 53.3 (OMe), 51.2 (OMe)
163.5 (d, J 243 Hz, Cp), 153.3 (2-C), 152.1 (4-C), 147.0 (8-C), 135.2 (6-C), 135.0 (d, J 2.2 Hz, Ci), 131.8 (5-C), 131.5 (d, J 7.5 Hz, Co),
121.2 (d, J 21.5 Hz, Cm), 113.4 (CN)
154.2, 154.4 (Cp, Cm), 152.9 (2-C), 152.2 (4-C), 148.0 (8-C), 135.0 (6-C), 132.6 (Ci), 130.7 (5-C), 126.3 (Co), 115.6 (Co), 115.3 (Cm),
113.7 (CN), 56.0 (OMe), 55.9 (OMe), 47.9 (CH2)
2cd
2de
2ed
2fb, d
2gb, e
2hb, d
167.8 (C᎐N), 152.6 (2-C), 152.4 (4-C), 147.8 (8-C), 136.5 (Ci), 134.6 (6-C), 132.7 (Cm), 129.7 (5-C), 128.3 (Cp), 124.2 (Co), 114.3
᎐
(CN)
160.9 (d, 1JC,F 247.7 Hz, Ar), 153.2 (s, 2-C), 152.9 (s, 4-C), 148.1 (s, 8-C), 134.8 (s, 6-C), 131.4 (d, 3JC,F 8.2 Hz), 131.1 (d, 3JC,F 3.5 Hz,
Ar), 124.9 (d, 4JC,F 3.7 Hz, Ar), 121.3 (d, 2JC,F 14.6 Hz, Ar), 116.1 (d, 2JC,F 21.1 Hz, Ar), 113.6 (CN), 41.9 (d, 3JC,F 4.1 Hz, CH2)
162.9 (dd, 1JC,F 249, 3JC,F 7.5 Hz, Ar), 159.6 (dd, 1JC,F 249, 3JC,F 7.5 Hz, Ar), 159.0 (s, 2-C), 151.0 (s, 4-C), 132.0 (dd, 2JC,F 22.7, 4JC,F
3.8 Hz, Ar), 131.7 (dd, 2JC,F 22.7, 4JC,F 3.8 Hz, Ar), 129.3 (s, 5-C), 114.5 (CN), 112.4 (dd, 2JC,F 22.7, 3JC,F 7.5 Hz, Ar), 111.2 (t, 2JC,F
22.7 Hz, Ar), 42.1 (d, 3JC,F 3.8 Hz, CH2)
2id
160.0 (Cp), 153.6 (2-C), 152.4 (4-C), 146.6 (8-C), 135.9 (6-C), 129.1 (5-C), 125.2 (Ci), 123.8 (Cm), 115.3 (Co), 114.9 (CN), 55.7
(OMe), 22.6 (CH2), 11.2 (Me)
153.0 (2-C), 152.6 (4-C), 149.1 (8-C), 137.4 (Ar), 135.8 (6-C), 133.9 (Ar), 129.4 (5-C), 123.9 (Ar), 118.1 (CN), 114.1 (CN), 110.9
(Ar)
167.6 (8-C), 156.7 (Cp), 153.3 (4-C), 153.0 (6-C), 147.3 (2-C), 138.3 (4a-C), 131.1 (8a-C), 125.7 (Ci), 122.5 (Co), 114.4 (Cm), 55.6
(OMe), 34.7 (NMe)
169.3 (8-C), 156.8 (Cp), 152.7 (4-C), 150.2 (6-C), 146.2 (2-C), 136.2 (4a-C), 131.8 (8a-C), 123.3 (Ci), 121.2 (Co), 114.1 (Cm), 55.5
(OMe), 36.1 (NMe), 32.7 (Me), 12.5 (CH2)
168.7 (8-C), 156.2, 155.9 (Cm, Cp), 152.2 (4-C), 151.7 (6-C), 148.5 (2-C), 141.5 (Ci), 135.5 (4a-C), 129.2 (8a-C), 116.6 (Co), 116.3
(Cm), 115.2 (Co), 59.5, 59.3 (2 × OMe), 39.3 (NMe)
166.8 (8-C), 159.3 (d, J 246.3 Hz, Co), 153.5 (4-C), 151.4 (6-C), 147.9 (2-C), 138.4 (4a-C), 130.4 (d, J 3.4 Hz, Co), 129.9 (8a-C), 129.8
(d, J 8.4 Hz, Cp), 125.8 (d, J 14.6 Hz, Ci), 124.7 (d, J 3.6 Hz, Cm), 116.0 (d, J 21.4 Hz, Cm), 39.1 (d, J 8.64 Hz, CH2), 36.6 (NMe)
156.4 (4-CЈ), 156.3 (2-C), 155.2 (8-C), 147.0 (6-C), 142.4 (8a-C), 134.4 (CЈ), 132.9 (Cm), 128.7 (4a-C), 121.9 (Co), 119.0 (CN), 106.0
(Cp)
2jb, d
5ae
5be
5cb, e
5de
5ec, e
a Except where stated all spectra were determined in CDCl3. b In d6-DMSO. c In d6-DMSO–TFA. d Determined at 70 MHz. e Determined at 100
MHz.
2534
J. Chem. Soc., Perkin Trans. 1, 2001, 2532–2537

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Table 4 Selected bond lengths (Å) and angles (Њ) for the compound
8-(4-methoxyanilino)-4-imino-3-methylpyrimidino[5,4-d]pyrimidine
Bond lengths/Å
Bond angles/Њ
N(1)–C(2)
N(1)–C(6)
N(1)–C(11)
N(3)–C(2)
N(3)–C(3A)
N(7)–C(8)
1.370(5)
1.413(4)
1.467(5)
1.277(4)
1.388(5)
1.311(5)
1.367(5)
1.360(5)
1.283(4)
1.357(5)
1.360(7)
1.360(7)
1.361(5)
1.382(5)
1.410(5)
1.458(5)
1.386(6)
1.396(5)
1.381(6)
1.387(6)
1.378(7)
1.365(6)
C(2)–N(1)–C(6)
120.7(3)
120.5(3)
118.6(3)
116.0(3)
114.0(3)
115.0(3)
132.0(4)
119.1(5)
126.7(4)
123.3(3)
117.1(3)
119.6(3)
118.6(3)
113.7(3)
122.9(3)
117.6(3)
119.5(3)
129.6(4)
120.1(3)
121.4(4)
118.5(3)
118.4(4)
125.1(4)
116.6(4)
120.4(5)
121.0(4)
116.3(5)
125.5(4)
118.2(4)
121.5(5)
120.6(4)
C(2)–N(1)–C(11)
C(6)–N(1)–C(11)
C(2)–N(3)–C(3A)
C(8)–N(7)–C(7A)
C(8)–N(9)–C(8)
C(10)–N(13)–C(14)
C(21)–O(20)–C(17)
N(3)–C(2)–N(1)
N(7)–C(7A)
N(9)–C(8)
N(12)–C(6)
N(13)–C(10)
O(20)–C(21)
O(20)–C(21)
O(20)–C(17)
C(3A)–C(7A)
C(3A)–C(10)
C(6)–C(7A)
C(14)–C(15)
C(14)–C(19)
C(15)–C(16)
C(16)–C(17)
C(17)–C(18)
C(18)–C(19)
C(7A)–C(3A)–N(3)
C(7A)–C(3A)–C(10)
N(3)–C(3A)–C(10)
N(12)–C(6)–N(1)
N(12)–C(6)–C(7A)
N(7)–C(7A)–C(3A)
N(7)–C(7A)–C(6)
C(3A)–C(7A)–C(6)
N(7)–C(8)–N(9)
N(9)–C(10)–N(13)
N(9)–C(10)–C(3A)
N(13)–C(10)–C(3A)
C(15)–C(14)–C(19)
C(15)–C(14)–N(13)
C(19)–C(14)–N(13)
C(16)–C(15)–C(14)
C(15)–C(16)–C(17)
O(20)–C(17)–C(18)
O(20)–C(17)–C(16)
C(18)–C(17)–C(16)
C(19)–C(18)–C(17)
C(18)–C(19)–C(14)
Scheme 2 Possible mechanisms for 6-cyanopurine formation.
these products were not 6-carboxamidinopurines of type 4. In
the 1H NMR spectrum (see Table 2) for the compounds 5a and
b there is a distinct upfield shift of the ortho protons of the
4-methoxyphenyl ring, when compared with the equivalent
cyanopurine 2a and this cannot be explained on the basis of
minor functional group changes in the 6-position, also there are
substantial changes in the chemical shifts of the heterocyclic
ring protons which are unexpected. The literature on the reac-
tions of 6-cyanopurines with amines is confusing in that, as
mentioned previously, Higashino et al.2 report that 9-phenyl-
9H-purine-6-carbonitrile reacts with butylamine and piperidine
to give around a 50% yield of the corresponding N-butyl-
9-phenyl-9H-purine-6-carboxamidine and 9-phenyl-6-(piper-
idinylcarboximidoyl)-9H-purine by nucleophilic attack on the
cyano group. Conversely, the Robins group11,19,20 have shown
that reaction of 9-(2,3,5-tri-O-acetyl-β--ribofuranosyl)purine-
6-carbonitrile with methanolic ammonia results in attack at the
imidazole ring with rearrangement to give a 4-amino-8-(β--
ribofuranosylamino)pyrimidino[5,4-d]pyrimidine in unspeci-
fied yield, and a similar rearrangement in around 17% yield has
been noted by Mabry et al.21 during the reaction of 9-(3,5-di-
O-benzoyl-2,2-difluoro-2-deoxy-α/β--ribofuranosyl)purine-6-
carbonitrile with ammonium hydroxide in methanol. This
follows an earlier patent by Cook and Berry22 which describes
the isolation of ribofuranosylpyrimidino[5,4-d]pyrimidines in
75% yield on reaction of the corresponding purine-6-carbo-
nitrile with methanolic ammonia in a pressure vessel at 0–18 ЊC.
Thus the product from the reaction with methylamine could be
either the 6-carboxamidine derivative 4 or the pyrimidino[5,4-d]-
pyrimidine derivative 5. These compounds are constitutional
isomers and cannot be distinguished by elemental analysis or
mass spectrometry and it is difficult to distinguish between the
Fig. 1
two possibilities by spectroscopic methods. A single crystal
X-ray structure determination on the compound 5a confirmed
that the compound was the rearrangement product 8-(4-meth-
oxyanilino)-4-imino-3-methylpyrimidino[5,4-d]pyrimidine (Fig.
1, Table 4) arising by initial opening of the imidazole ring as
shown in Scheme 3. Our observations lead to the conclusion
that the reactions of 9-aryl-9H-purine-6-carbonitriles with
aqueous methylamine lead invariably to the pyrimidino[5,4-d]-
pyrimidine rearrangement products with no evidence for the
formation of a 6-carboxamidinopurine derivative by nucleo-
philic attack on the 6-cyano group.
These results, together with the earlier work referred to
above, throw into question the reports of Higashino et al.,2 as it
would appear unlikely that purine-6-carboxamidine derivatives
can be prepared from 6-cyanopurines by direct reaction with
ammonia or amine nucleophiles, although the Hocek pro-
cedure3 via the imidate does appear to be a reliable method for
the synthesis of 6-amidinopurines.
J. Chem. Soc., Perkin Trans. 1, 2001, 2532–2537
2535

View Article Online
13.3 mmol) and 4-bromobenzaldehyde (2.44 g, 13.3 mmol) were
stirred at room temperature in methanol (15 cm3) for 50 min to
give the title compound 1f (4.0 g, 12.6 mmol, 95%) as a yellow
powder.
Synthesis of (Z )-N 1-(2-fluorobenzyl)-N 2-(amino-1,2-dicyano-
vinyl)formamidine 1g
2-Fluorobenzylamine (3.81 g, 30.48 mmol) was added dropwise
to a suspension of pure ethyl (Z)-N-(2-amino-1,2-dicyano-
vinyl)formimidate (5.0 g, 30.48 mmol) in dry ethanol (20 ml)
containing a catalytic amount of anilinium hydrochloride (0.02
g). After approximately 1 h a pale orange solid precipitated and
stirring was continued for a further 3 hours when TLC (1 : 1
EtOAc–hexane) confirmed that all the starting material had
disappeared. The precipitate was filtered, washed with diethyl
ether and dried under vacuum to give 1g (6.18 g, 25.43 mmol,
83%).
Synthesis of (Z )-N 1-(2,6-difluorobenzyl)-N 2-(2-amino-1,2-
dicyanovinyl)formamidine 1h
Scheme
3
Mechanism of formation of 8-(arylamino)-4-imino-3-
methylpyrimidino[5,4-d]pyrimidine.
Following the procedure described above 2,6-difluorobenzyl-
amine (3.96 ml, 30.40 mmol), ethyl (Z)-N-(2-amino-1,2-
dicyanovinyl)formimidate (4.98 g, 30.40 mmol) and anilinium
hydrochloride (0.02 g) stirred for 18 h at room temperature in
ethanol (20 ml) gave a fine, cream precipitate. This was filtered
and treated as previously to give 1h (5.07 g, 19.43 mmol, 64%).
In conclusion we report a facile synthesis of 6-cyanopurines
and we have established that in the case of the N 9-aryl and
benzyl derivatives the reaction of a simple amine, such as
methylamine, occurs by opening of the imidazole ring leading
to pyrimidine[5,4-d]pyrimidines in good yields.
General procedure for the reaction of (Z )-N 1-(2-amino-1,2-
dicyanovinyl)-N 2-aryl/benzylformamidines 1a–h with triethyl
ortho-formate or -propionate
Experimental
The (Z)-N 1-(2-amino-1,2-dicyanovinyl)-N 2-aryl and -benzyl-
formamidines and the 5-amino-1-aryl-4-(cyanoformimidoyl)-
imidazole used in this work were prepared from previously
described procedures.16,17 1H NMR spectra were recorded on
either a Bruker AC 300 or 400 spectrometer at 300 or 400 MHz
respectively. 13C NMR spectra were recorded on either a Bruker
AC 300 or 400 spectrometer at 75 or 100 MHz respectively.
Mass spectra (FAB) were recorded on a Kratos MS-45 instru-
ment with a digital data output. Melting points were deter-
mined using a Gallenkamp melting point apparatus and are
uncorrected. TLC was performed using Camlab polygram C245
pre-coated silica gel plates (Fluka).
Method A. Triethyl orthoformate (15.0 cm3, 90 mmol) or tri-
ethyl orthopropionate (12.0 cm3, 59.6 mmol) was added to the
formamidines 1a–h (6.0 mmol) and the resulting suspension
was heated under reflux for 1.5–3 hours. The resulted brown
solution was cooled to room temperature. The 6-cyanopurine
products either precipitated out after cooling (2a, c, i and f) or
precipitated upon addition of petroleum ether (2b, d, e, g, h and
j), and the solid was filtered off under vacuum, washed with
petroleum ether (bp 40–60 ЊC) and dried under vacuum.
Method B. Triethyl orthoformate (3 cm3, 17.43 mmol) was
added to a suspension of imidazole 3a or 3j (4.34 mmol) in
acetonitrile (50 cm3) and a catalytic amount of sulfuric acid
(1 drop) was added. The reaction mixture was stirred at room
temperature until the TLC (1 : 1 EtOAc–hexane) showed that
all the starting material had been consumed. The off-white solid
in suspension was filtered and washed with ethanol and diethyl
ether. A second crop of the same product was isolated when the
mother liquor was concentrated in the rotary evaporator.
Crystallography
The crystals were mounted on a glass fibre. All measurements
were performed on a Rigaku AFC6S diffractometer employing
graphite monochromated Cu-Kα radiation. The data were col-
lected at a temperature of 20 1 ЊC using the ω scanning tech-
nique to a maximum of a 2θ value of 65.17Њ. The structures
were solved by direct methods using SHELX8623 and refined by
full-matrix least squares based on F using SHELX93.24 Non-
hydrogens were refined anisotropically. Hydrogen atoms were
located geometrically and were refined isotropically.
Synthesis of 8-(arylamino)-4-imino-3-methylpyrimidino[5,4-d]-
pyrimidines 5a–e
The cyanopurine (8.0 mmol) was dissolved in dichloromethane
(20.0 cm3) and to this, aqueous methylamine (7.0 equiv.) was
added. The solution was stirred at room temperature for 24 h or
until TLC (1 : 1 CH2Cl2–EtOAc) showed the absence of starting
material. The solvent was then removed under vacuum to give
a solid residue, which was washed with ethanol, to give an
insoluble white solid. Isolation of the solid by filtration under
vacuum, followed by washing several times with 95% ethanol
(3 × 5 cm3) gave a white powder, which could be purified by
recrystallisation from hot ethanol to give white crystals.
Crystal data.† C14H14N6O, M = 283.31, orthorhombic, a =
30.542(9), b = 12.114(2), c = 7.3571(10) Å, V = 2722.1(10) Å3,
space group Pbca, Z = 8, Dx = 1.378 g cmϪ3. Crystal dimensions
0.35 × 0.35 × 0.02 mm3, µ(Mo-Kα) = 0.767 mmϪ1, 4659 reflec-
tions measured, 2317 unique (Rint = 0.1181) which were used in
all calculations, and 1019 reflections [I > 2σ(I )]. The final
ωR(F 2) was 0.1656 (all data).
Synthesis of (Z )-N 1-(4-bromobenzylidene)-N 2-(2-amino-1,2-
dicyanovinyl)formamidrazone 1f
(Z)-N-(2-Amino-1,2-dicyanovinyl)formamidrazone25 (2.0 g,
Acknowledgements
Thanks are due to the University of Kuwait for financial
support to one of us (Amal Al-Azmi) and to the PRAXIS/C/
QUI/10101/1998 for a grant.
† CCDC reference number 167808. See http://www.rsc.org/suppdata/
p1/b1/b106539b/ for crystallographic files in .cif or other electronic
format.
2536
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15 B. L. Booth, R. D. Coster and M. F. Proença, Synthesis, 1988, 8,
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2537