Unexpected behaviour of 6-cyanopurines towards secondary amines

Article abstract of DOI:10.3987/COM-13-12695

Reaction of 6-cyanopurines with excess dimethylamine and excess piperidine at room temperature or by reflux-respectively-yielded a mixture of 6-purinecarboximidamides and N,N-dialkylpurines or piperidin-1-yl(purin-6-yl) methanimine and (piperidin-1-yl)-9H-purine, respectively. 6- Purinecarboximidamides were initially formed from the reaction, whereas N,N-dialkylpurines were detected in the mixture 30 min afterward. Both purines appeared to be generated from different mechanistic pathways.

Full text of DOI:10.3987/COM-13-12695

HETEROCYCLES, Vol. 87, No. 6, 2013
1301
HETEROCYCLES, Vol. 87, No. 6, 2013, pp. 1301 - 1309. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 6th March, 2013, Accepted, 9th April, 2013, Published online, 16th April, 2013
DOI: 10.3987/COM-13-12695
UNEXPECTED BEHAVIOUR OF 6-CYANOPURINES TOWARDS
SECONDARY AMINES
Amal Al-Azmi* and K. Anita Kumari
*Chemistry Department, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
E-mail: amal.alazemi@ku.edu.kw
Abstract - Reaction of 6-cyanopurines with excess dimethylamine and excess
piperidine at room temperature or by reflux-respectively-yielded a mixture of 6-
purinecarboximidamides and N,N-dialkylpurines or piperidin-1-yl(purin-6-
yl)methanimine
and
(piperidin-1-yl)-9H-purine,
respectively.
6-
Purinecarboximidamides were initially formed from the reaction, whereas N,N-
dialkylpurines were detected in the mixture 30 min afterward. Both purines
appeared to be generated from different mechanistic pathways.
Over the last few decades, a large number of 6-substituted purines, including N,N-dialkylpurine
derivatives, have been produced for their various biological activities1-23 with their activities depending
mainly on the type and position of substituents available. Several N,N-dialkylpurine derivatives have been
reported in the literature to act as anti-inflammatory, anti-allergic, and antirhinoviral agents whereas
others have been reported to act as antibacterial agents for Mycobacterium turberculosis strain H37Rv.
Other derivatives have been used successfully for the treatment of Alzheimer’s disease.24,25
R
N
R
N
N
NH2
NH
CN
N
N
N
CN
1
2

Proneça23,24 described two different synthetic routes for N,N-dialkylpurinederivatives: (1) reaction of 5-
amino-4-cyanoformimidoylimidazole 2 and N,N-dimethylformamide diethyl acetal followed by addition

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HETEROCYCLES, Vol. 87, No. 6, 2013
of excess secondary alkylamine or (2) treatment of 5-amino-4-cyanoformimidoylimidazole 2 with a
secondary alkylamine and then addition of either N,N-dimethylformamide diethyl acetal, salicyladehyde,
or 4-hydroxybenzaldehyde.
Over the last few years, our group has investigated the reactions of 6-cyanopurines with primary
amines.4,26 6-Cyanopurine 1 has proven to be a fruitful precursor for new and novel transformations
(Scheme 1).
RHN
N
N
RHN
N
N
N
excess R1C(OEt)3, reflux
N
N
NH
N
N
N
NH2
8
R1
9
NH2NH2·H2O, CH2Cl2,
rt
R
N
R
N
R
N
NH2OH·HCl, MeCO2Na
CH2Cl2, rt
N
N
N
R2OH, DBU, rt
N
N
N
N
N
N
CN
OR2
H2N
NOH
HN
4
1
3
R1NH2
MeNH2·HCl
R
N
N
N
RHN
N
N
RHN
N
reflux, ROH, CH2Cl2, THF
or CHCl3
N
N
N
N
H2N
NR1
N
NH
NHR1
N
R1
7
6
5
Scheme 1
However, to the best of our knowledge, the direct reaction of 6-cyanopurines with secondary amines has
yet to be examined. This paper describes the reaction of 6-cyanopurine 1 with dimethylamine and
piperidine.

HETEROCYCLES, Vol. 87, No. 6, 2013
1303
When a mixture of 1a and excess dimethylamine was stirred at room temperature, formation of a product
occurred within 1 min to 2 min, as shown by TLC. Stirring was continued to drive the reaction to
completion. Approximately 30 min later, TLC again indicated the formation of another product. The
starting material was fully consumed within 5 d, and the two products were separated by column
chromatography. Reaction of 6-cyanopurine 1a with dimethylamine was carried out in an attempt to
isolate pyrimidine 10, as shown in Scheme 3, Route A. Dimethylamine was assumed to behave in a
manner similar to methylamine by opening the imidazole ring.4,15 IR and 13C NMR spectra of the isolated
solids showed the disappearance of the cyano group. Both products were fully characterised by
spectroscopic
analyses
and
identified
as
N6,N6-dimethyl-9-(4-methoxyphenyl)-9H-6-
purinecarboximidamide (Rf = 0.78) 11a, and N-[9-(4-methoxyphenyl)-9H-6-purinyl]-N,N-dimethylamine
12a (Rf = 0.53) in 2:1 (EtOAc:hexane). Another derivative, 1b, was also made to react with excess
dimethylamine, generating the purines 11b and 12b, as shown in Scheme 2, Table 1.
RHN
N
N
N
(Me)2N
CN
R
N
10
N
(Me)2NH
N
N
R
R
N
N
CN
N
N
N
+
, R = 4-MeOC H
1a
N
N
6
4
N
, R = 4-MeC H
b
6
4
N(Me)2
NH
(Me)2N
, R = 4-MeOC H
12a
, R = 4-MeOC H
11a
6
4
6
4
, R = 4-MeC H
b
, R = 4-MeC H
b
6
4
6
4
Scheme 2
Isolation of purines 11a and 11b suggested that the previously reported mechanism for the reaction of
methylamine with 6-cyanopurines could be interpreted via a different approach.
Previous papers4,15 reported that imidazole ring opening by methylamine and attack on the electrophilic
carbon of the cyano group are necessary to generate pyrimidopyrimidine. However, isolation of 11a and
11b indicated that the mechanism may actually start by nucleophilic attack of the amine on the cyano
group (Scheme 3, Route B).

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HETEROCYCLES, Vol. 87, No. 6, 2013
R
N
R
N
RHN
N
N
N
N
Route A
Route B
N
N
N
N
N
nucleophilic addition
(Me)2N
CN
CN
Me N
NH
1
Route A
Me
10
Route B
Route C
11
(Me)2NH
Ar
(SN
)
Route C
R
N
N
N
N
N
Me Me
12
Scheme 3
Purines 11 and 12 were clearly produced by two reaction intermediates. Formation of purine 11
represents an example of a nucleophilic addition reaction, whereas formation of purine 12 shows an
Ar
example of a typical SN reaction. Purines 12a and 12b were previously believed to form when excess
dimethylamine reacts with purines 11a and 11b, causing displacement of the carboximidine moiety.
Purines 11a and 11b were stirred with excess dimethylamine at room temperature for 7 d, and their
reaction was monitored by TLC. No change in the composition of the primary reaction mixture was
observed.
To generalise this observation, another two reactions were carried out and it was found that both purines
1a,b furnished the two expected products 13a,b and 14a,b, when refluxed with piperidine (Scheme 4,
Table 1).
R
N
R
N
N
N
R
N
N
H
N
N
N
N
N
+
N
reflux
N
N
N
NH
CN
, R = 4-MeOC H
14a
, R = 4-MeOC H
13a, R = 4-MeOC6H4
, R = 4-MeC H
13b
1a
6
4
6
4
, R = 4-MeC H
14b
, R = 4-MeC H
1b
6
4
6
4
6
4
Scheme 4

HETEROCYCLES, Vol. 87, No. 6, 2013
1305
Table 1. Reaction conditions used to synthesize compounds (11-14).
Entry
Reactant
Secondary
amine
Reaction Conditions
Product/ yield(%)
1
2
3
4
1a
1a
1b
1b
(Me)2NH
piperidine
(Me)2NH
piperidine
excess (Me)2NH, rt, 5 days
11a (33)/ 12a (36)
13a (29)/ 14a (38)
11b (39)/ 12b (54)
13b (12)/ 14b (69)
excess piperdine, reflux 1 h, CH2Cl2:hexane 1:4
excess (Me)2NH, rt, 3 days
excess piperdine, reflux 3 h, CH2Cl2:hexane 1:4
Ar
Like the previous reactions in Scheme 2, the SN products 14a,b were the major for both 1a and 1b.
In conclusion, this paper describes a mild, efficient, and direct method for preparing two 6-substituted
purines from easily made 6-cyanopurines. The products obtained showed the presence of two competing
reaction mechanisms, affording two different purines with acceptable yields.
EXPERIMENTAL
General
6-Cyanopurines 1a and 1b were prepared according to literature procedures.4 1H NMR spectra were
recorded on a Bruker DPX 400 spectrometer at 400 MHz. CDCl3 or DMSO-d6 was used as the solvent,
and tetramethylsilane was used as the internal standard. Chemical shifts are reported in  units (ppm). 13C
NMR spectra were obtained using a Bruker DPX 400 spectrometer at 100 MHz. Mass spectra were
recorded on a VG autospec Q spectrometer with digital data output. IR spectra were recorded on FTIR-
JASCO-FT/IR-6300 instrument using KBr discs. The (max) is recorded in cm-1. Melting points were
determined by a Gallenkamp melting point apparatus and are reported uncorrected. TLC was performed
on 0.25 mm pre-coated silica gel plates (Merck).
Reaction of 6-cyanopurine 1a with dimethylamine
Excess dimethylamine (20 mmol) was added to 6-cyanopurine 1a (0.28 g, 1.12 mmol), and the
suspension was stirred at room temperature. After a few minutes, the mixture yielded a clear solution.
TLC showed the presence of two products: one (Rf = 0.78) appearing 1 min to 2 min after stirring and the
other (Rf = 0.53) (EtOAc:hexane, 2:1) appearing 30 min later. Stirring was continued until TLC
indicated completion of the reaction 5 d. The resulting solids, which were composed of the two products,
were filtered off, and products were separated by column chromatography starting with a mobile phase of
1:9 EtOAc:hexane, gradually increasing to 100% EtOAc.

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HETEROCYCLES, Vol. 87, No. 6, 2013
N6,N6-Dimethyl-9-(4-methoxyphenyl)-9H-6-purinecarboximidamide 11a: Yellow needles (0.11 g, 0.37
mmol, 33%), mp 160-163 C [Found accurate mass: 296.1380; m/z (EI) (M+) 296, 100%; C15H16N6O
requires: 296.1380; M 296]; H 400 MHz (DMSO-d6, TMS) 3.32 (s, 6H, N(CH3)2), 3.75 (s, 3H, OCH3),
6.93 (d, 2H, J 8.8 Hz, ArH), 7.85 (d, 2H, J 9.2 Hz, ArH), 8.50 (s, 1H, CH), 8.53 (s, 1H, CH), 9.82 (s, 1H,
NH); C 100 MHz (DMSO-d6, TMS) 158.30, 156.69, 155.63, 153.51, 151.80, 134.12, 133.07, 131.65,
123.01, 113.70, 55.24, 40.82; max: (KBr) 3318, 2925, 1605, 1541, 1411, 1240, 1180, 1008, 835 cm−1.
N-[9-(4-Methoxyphenyl)-9H-6-purinyl]-N,N-dimethylamine 12a: Cream powder (0.11 g, 0.40 mmol,
36%), mp 166-169 C [Found accurate mass: 269.1271; m/z (EI) (M+) 269, 100%; C14H15N5O requires:
269.1271; M 269]; H 400 MHz (DMSO-d6, TMS) 3.32 (s, 6H, N(CH3)2), 3.82 (s, 3H, OCH3), 7.12 (d,
2H, J 9.2 Hz, ArH), 7.71 (d, 2H, J 9.2 Hz, ArH), 8.24 (s, 1H, CH), 8.46 (s, 1H, CH); C 100 MHz
(DMSO-d6, TMS) 158.56, 154.48, 152.35, 150.08, 138.77, 127.88, 125.08, 119.56, 114.58, 55.54, 40.93;

max: (KBr) 3090, 2921, 1598, 1521, 1430, 1258, 1183, 1070, 970, 821 cm−1.
Reaction of 6-cyanopurine 1b with dimethylamine
A methanolic solution of dimethylamine (10 mL, 20 mmol) was added to 6-cyanopurine 1b (0.47 g, 2.0
mmol), and the suspension was stirred at room temperature. After 10 min to 15 min, the reaction mixture
yielded a light brown clear solution. Stirring was continued until the reaction reached completion,
approximately 2 d to 3 d. The reaction mixture revealed the presence of two solids. Addition of MeOH
dissolved one of the solids, leaving the other product undissolved for collection by filtration. The second
product was obtained by concentration of the MeOH layer followed by crystallisation from acetone.
N6,N6-Dimethyl-9-(4-methylphenyl)-9H-6-purinecarboximidamide 11b: Light brown crystals, (0.22 g,
0.78 mmol, 39%), mp 161-165 C [Found accurate mass: 280.1430; m/z (EI) (M+) 280, 100%; C15H16N6
requires: 280.1430; M 280]; H 400 MHz (DMSO-d6, TMS) 2.29 (s, 3H, CH3), 3.35 (s, 6H, N(CH3)2),
7.16 (d, 2H, J 8.4 Hz, ArH), 7.85 (d, 2H, J 8.4 Hz, ArH), 8.52 (s, 1H, CH), 8.53 (s, 1H, CH), 9.78 (s, 1H,
NH); C 100 MHz (DMSO-d6, TMS) 158.26, 156.67, 153.56, 151.67, 136.11, 134.10, 133.11, 132.60,
128.97, 121.18, 40.86, 20.55; max: (KBr) 3329, 1598, 1576, 1525, 1447, 1409, 1359, 1234, 1003, 822,
626 cm−1.
N,N-Dimethyl-N-[9-(4-methylphenyl)-9H-6-purinyl]amine 12b: Off-white powder (0.27 g, 1.06 mmol,
54%), mp 136-139 C [Found accurate mass: 253.1321; m/z (EI) (M+) 253, 100%; C14H15N5 requires:
253.1321; M 253]; H 400 MHz (DMSO-d6, TMS) 2.38 (s, 3H, CH3), 3.35 (s, 6H, N(CH3)2), 7.37 (d, 2H,

HETEROCYCLES, Vol. 87, No. 6, 2013
1307
J 8.4 Hz, ArH), 7.71 (d, 2H, J 8.4 Hz, ArH), 8.25 (s, 1H, CH), 8.51 (s, 1H, CH); C 100 MHz (DMSO-d6,
TMS) 154.48, 152.39, 149.99, 138.58, 137.10, 132.54, 129.86, 123.23, 121.21, 119.72, 37.96, 20.64;

max: (KBr) 3100, 2923, 1598, 1517, 1421, 1296, 974, 810, 641 cm−1.
Reaction of 6-cyanopurine 1a and 1b with piperidine
Excess of piperidine was added to 6-cyanopurine 1a (0.6 g, 2.39 mmol), or 1b (0.52 g, 2.21 mmol). The
mixture was refluxed for 1 h (1a) and 3 h (1b). Two new spots were detected using TLC and the reaction
reached completion. The mixture was concentrated and the residue was dissolved with a minimum
amount of DCM, then excess of hexane and left to precipitate (24 h). The solids formed were filtered off,
and separated by column chromatography starting with a mobile phase of hexane, and gradually
increasing to 100% EtOAc.
(9-(4-Methoxyphenyl)-9H-purin-6-yl)(piperidin-1-yl)methanimine 13a: Cream powder (0.23 g, 0.68
mmol, 29%), mp 173-176 C [Found accurate mass: 336.1694; m/z (EI) (M+) 336, 42%; C18H20N6O
requires: 336.1693; M 336]; H 400 MHz (DMSO-d6, TMS) 1.65 (s, 6H, 3CH2), 3.76 (s, 3H, OCH3), 4.35
(s, 4H, 2CH2), 6.94 (d, 2H, J 8.8 Hz, ArH), 7.85 (d, 2H, J 9.2 Hz, ArH), 8.50 (s, 1H, CH), 8.53 (s, 1H,
CH), 9.85 (s, 1H, NH); C 100 MHz (DMSO-d6, TMS) 157.50, 156.91, 155.65, 153.54, 151.78, 134.40,
132.94, 131.59, 123.05, 113.68, 55.23, 48.04, 26.01, 24.19; max: (KBr) 3447, 3344, 3102, 3043, 3019,
2940, 2917, 2853, 1601, 1578, 1543, 1517, 1505 cm−1.
9-(4-Methoxyphenyl)-6-(piperidin-1-yl)-9H-purine 14a: light red crystals (0.28 g, 0.9 mmol, 38%), mp
151-155 C [Found accurate mass: 309.1583; m/z (EI) (M+) 309, 100%; C17H19N5O requires: 309.1584;
M 309]; H 400 MHz (DMSO-d6, TMS) 1.56 (m, 4H, 2CH2), 1.65 (m, 2H, CH2), 3.83 (s, 3H, OCH3),
4.23 (s, 4H, 2CH2), 7.11 (d, 2H, J 8.8 Hz, ArH), 7.70 (d, 2H, J 8.8 Hz, ArH), 8.24 (s, 1H, CH), 8.45 (s,
1H, CH), C 100 MHz (DMSO-d6, TMS) 158.56, 153.30, 152.40, 150.32, 138.65, 127.82, 125.12, 119.22,
114.54, 55.51, 45.72, 25.72, 24.29; max: (KBr) 3445, 3103, 3073, 3023, 2978, 2927, 2915, 2847, 1921,
1888, 1698, 1650, 1576, 1558, 1521 cm−1.
Piperidin-1-yl(9-p-tolyl-9H-purin-6-yl)methanimine 13b: off-white powder (0.082 g, 0.25 mmol, 12%),
mp 169-172 C [Found accurate mass: 320.1743; m/z (EI) (M+) 320, 100%; C18H20N6 requires: 320.1743;
M 320]; H 400 MHz (DMSO-d6, TMS) 1.64 (m, 6H, 3CH2), 2.29 (s, 3H, CH3), 4.33 (s, 4H, 2CH2), 7.16
(d, 2H, J 8.4 Hz, ArH), 7.85 (d, 2H, J 8.4 Hz, ArH), 8.52 (s, 1H, CH), 8.53 (s, 1H, CH), 9.81 (s, 1H, NH);
C 100 MHz (DMSO-d6, TMS) 157.48, 156.90, 153.59, 151.66, 136.03, 134.38, 132.99, 132.64, 128.92,

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HETEROCYCLES, Vol. 87, No. 6, 2013
121.24, 48.03, 26.00, 24.15, 20.51; max: (KBr) 3349, 3038, 2963, 2919, 2855, 1902, 1598, 1536, 1443
cm−1.
6-(Piperidin-1-yl)-9-p-tolyl-9H-purine 14b: light yellow powder (0.44 g, 1.5 mmol, 69%), mp 141-145
C [Found accurate mass: 293.1634; m/z (EI) (M+) 293, 100%; C17H19N5 requires: 293.1634; M 293]; H
400 MHz (DMSO-d6, TMS) 1.60 (m, 4H, 2CH2), 1.69 (m, 2H, CH2), 2.39 (s, 3H, CH3), 4.23 (s, 4H,
2CH2), 7.37 (d, 2H, J 8 Hz, ArH), 7.71 (d, 2H, J 8.4 Hz, ArH), 8.26 (s, 1H, CH), 8.51 (s, 1H, CH); C 100
MHz (DMSO-d6, TMS) 153.31, 152.45, 150.24, 138.49, 137.12, 132.47, 129.82, 123.31, 119.36, 45.66,
25.72, 24.28, 20.62; max: (KBr) 3447, 3106, 3081, 3044, 3021, 2924, 2862, 2848, 1590, 1578, 1554,
1524 cm−1.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Kuwait University and SAF Facility for financially supporting their
work through Research Grant No. SC04/09 and Project Nos. GS 01/01 and GS 03/01.
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