7-Deazaadenines: Synthesis of some new pyrrolo[2,3-d]pyrimidin-4-amines

Article abstract of DOI:10.1007/s00706-012-0847-9

New 2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines (derivatives of 7-deazaadenine) were prepared through cyclocondensation of 2-amino-1H-pyrrole-3- carbonitriles with aryl nitriles in the presence of potassium t-butoxide in boiling t-butanol. All synthesized

Full text of DOI:10.1007/s00706-012-0847-9

Monatsh Chem (2013) 144:677–680
DOI 10.1007/s00706-012-0847-9
ORIGINAL PAPER
7-Deazaadenines: synthesis of some new pyrrolo[2,3-d]-
pyrimidin-4-amines
•
Abolghasem Davoodnia Maryam Khashi
•
•
•
Niloofar Tavakoli-Hoseini Raheleh Moloudi
Hassan Ali Zamani
Received: 4 October 2011 / Accepted: 22 August 2012 / Published online: 28 September 2012
Ó Springer-Verlag 2012
Abstract New 2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines
(derivatives of 7-deazaadenine) were prepared through cyclo-
condensation of 2-amino-1H-pyrrole-3-carbonitriles with aryl
nitriles in the presence of potassium t-butoxide in boiling
t-butanol. All synthesized compounds were characterized on
the basis of their spectral and microanalytical data.
group and therefore can be named as 7-deazaadenines. A
number of these compounds are known to show anti-
inflammatory [11], antifungal [12], and antibacterial [12]
activities. Also, some 4-substituted aminopyrrolo[2,3-d]-
pyrimidine derivatives are selective A1-adenosine receptor
antagonists [13] (Fig. 1).
These findings encouraged us to synthesize some new
7-deazaadenine derivatives. Therefore, in continuation of
our previous works in the synthesis of new heterocyclic
compounds with potential biological activities [14–30],
in this paper we report a convenient synthesis of new
2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines (derivatives
of 7-deazaadenine) 3a–3f by reaction of 2-amino-1H-pyr-
role-3-carbonitriles 1a–1c [31] with aryl nitriles 2a–2c in
the presence of potassium t-butoxide in boiling t-butanol
(Scheme 1).
Keywords 2-Amino-1H-pyrrole-3-carbonitriles Á
Aryl nitriles Á 7-Deazaadenines Á
Pyrrolo[2,3-d]pyrimidin-4-amines
Introduction
In the last few decades, the chemistry of pyrrole and fused
heterocyclic pyrroles has received considerable attention
owing to their synthetic and effective biological impor-
tance [1–3]. Because of the presence of a pyrrolo[2,3-d]-
pyrimidine moiety in some important antibiotics [4–6] and
their structural resemblance to purines (A), interest has
arisen in the construction of such compounds. Moreover,
these compounds have been reported to possess significant
anti-HIV [7], antitumor [8], antimicrobial [9], and antian-
giogenic [10] activities. Pyrrolo[2,3-d]pyrimidin-4-amines
(C) may be regarded as analogues of adenine (B) in which
its N-7 (purine numbering) has been replaced by a CH
Results and discussion
Cyclocondensation of 2-amino-1H-pyrrole-3-carbonitriles
1a–1c with aryl nitriles 2a–2c in the presence of potassium
t-butoxide in t-butanol under reflux gave products identi-
fied as 2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines 3a–3f
(Table 1). The structures of new compounds 3a–3f were
deduced from their spectral and microanalytical data. For
1
example, the H NMR spectrum of 3d in CDCl3 did not
show the NH2 signal at d = 4.06 ppm belonging to
the precursor 1b, but instead showed a broad 2H signal at
5.05 ppm for an NH2 group as well as a sharp 3H signal at
2.50 ppm for methyl protons indicating the formation of
the bicyclic compound 3d. The IR spectrum was devoid of
the CN absorption band at 2,191 cm-1 of the precursor,
which shows the inclusion of the nitrile moiety in the
cyclocondensation process. Also this compound gave
A. Davoodnia (&) Á N. Tavakoli-Hoseini Á R. Moloudi Á
H. A. Zamani
Department of Chemistry, Mashhad Branch,
Islamic Azad University, Mashhad, Iran
e-mail: adavoodnia@yahoo.com; adavoodnia@mshdiau.ac.ir
M. Khashi
Young Researchers Club, Mashhad Branch,
Islamic Azad University, Mashhad, Iran
123

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A. Davoodnia et al.
Fig. 1 Purine core (A),
adenine (B), and its 7-deaza
analogue (C)
H2N
5
H2N
6
6
4
3
1
1
5
N
N
N
7
7
5
N
N
2
2
2
8
8
N
3
N
3
6
N
N
4
4
N
N
H
9
1
H
9
H
7
A
B
C
H2N
Ph
Ph
CN
Ph
CN
N
NH2
Ar
t-BuOH
Ar
+
ArCN
N
t-BuOK
reflux
N
Ph
Ph
NH2
Ph
N
N
R
N
R
R
1a 1c
2a 2c
4
3a 3f
-
-
-
1a: R = Me
1b:
3a: R = Me, Ar = Ph
3b:
R = C6H11
R = C6H11, Ar = Ph
1c: R = CH2Ph
3c: R = C6H11, Ar = 4-ClC6H4
2a: Ar = Ph
3d: R = C6H11, Ar = 3-MeC6H4
2b:
3e:
Ar = 4-ClC6H4
R = CH2Ph, Ar = Ph
3f: R = CH2Ph, Ar = 3-MeC6H4
2c: Ar = 3-MeC6H4
Scheme 1
Table 1 Synthesis of 2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines 3a–3f
(Scheme 1)
Experimental
Entry
R
Ar
Product Time/h Yield/%a M.p./°C
Melting points were recorded on a Stuart SMP3 melting
point apparatus. The IR spectra were obtained using a
1
2
3
4
5
6
a
Methyl
C6H5
3a
3b
6
8
8
8
7
7
71
79
67
66
72
65
232–233
206–207
207–209
261–262
245–247
164–167
1
Bruker Tensor 27 spectrophotometer from KBr disks. H
Cyclohexyl C6H5
NMR (500 MHz) spectra were recorded with a Bruker
500 MHz spectrometer. 13C NMR (100 MHz) spectra were
recorded with a Bruker 400 MHz spectrometer. Mass
spectra were obtained using a Finnigan-MAT 8430 mass
spectrometer operating at an ionization potential of 70 eV.
Elemental analysis was performed on a Thermo Finnigan
Flash EA microanalyzer.
Cyclohexyl 4-ClC6H4 3c
Cyclohexyl 3-MeC6H4 3d
Benzyl
Benzyl
C6H5
3e
3-MeC6H4 3f
Isolated yields
satisfactory elemental analysis data corresponding to the
molecular formula C31H30N4. The formation of the prod-
ucts 3a–3f is assumed to proceed via the intermediates 4
prepared by initial nucleophilic attack of the amino group
in the 2-position of pyrrole on the cyano group of aryl
nitriles. However, under these conditions, attempts to iso-
late these intermediates failed after careful monitoring of
the reactions.
General procedure for the preparation of 2-aryl-7H-
pyrrolo[2,3-d]pyrimidin-4-amines 3a–3f
To a solution of 5 mmol 2-amino-1H-pyrrole-3-carbonitr-
iles 1a–1c and 1 mmol potassium t-butoxide in 25 cm3
t-butanol, 5.5 mmol aryl nitriles 2a–2c was added.
The reaction mixture was heated under reflux for 6–8 h.
The reaction was monitored by TLC. Upon completion, the
solvent was evaporated in vacuo, the residue was dissolved
in 25 cm3 water, and subsequently neutralized by 1 N HCl.
The crude product was collected and recrystallized from
In conclusion, we have reported a facile synthesis of
some new pyrrolo[2,3-d]pyrimidin-4-amines (7-deazaade-
nines) in good yields by cyclocondensation of 2-amino-1H-
pyrrole-3-carbonitriles with aryl nitriles in the presence of
potassium t-butoxide in boiling t-butanol.
123

7-Deazaadenines: synthesis of some new pyrrolo[2,3-d]pyrimidin-4-amines
679
(M?, 15), 376 (100), 259 (11), 241 (10), 125 (14), 111 (21),
97 (30), 83 (32), 71 (35), 69 (30), 57 (57), 55 (54).
ethanol to give compounds 3a–3f in 65–79 % yields
(Table 1).
7-Benzyl-2,5,6-triphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
amine (3e, C31H24N4)
7-Methyl-2,5,6-triphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
amine (3a, C25H20N4)
1H NMR (CDCl3): d = 5.16 (s, 2H, NH2), 5.52 (s, 2H, CH2),
6.95–7.65 (m, 18H, Har), 8.60-8.65 (m, 2H, Har) ppm; 13C
NMR (100 MHz, CDCl3): d = 46.14, 100.53, 114.21,
126.86, 127.24, 127.65, 128.01, 128.25, 128.28, 128.38,
128.53, 129.16, 129.35, 130.53, 130.87, 131.22, 134.69,
135.34, 138.35, 139.22, 152.32, 156.91, 158.24 ppm; IR
(KBr): vꢀ = 3,285, 3,158 (NH2) cm-1; MS: m/z (%) = 452
(M?, 100), 375 (10), 361 (49), 257 (16), 241 (8), 214 (9), 187
(12), 128 (15), 104 (55), 91 (81), 77 (36), 59 (91), 57 (40).
1H NMR (500 MHz, CDCl3): d = 3.84 (s, 3H, CH3), 5.15
(s, 2H, NH2), 7.27–7.55 (m, 13H, Har), 8.50–8.55 (m, 2H,
Har) ppm; 13C NMR (100 MHz, CDCl3): d = 29.87,
100.54, 113.56, 126.86, 127.90, 128.13, 128.29, 128.39,
128.58, 129.30, 130.54, 130.80, 130.87, 134.84, 135.44,
139.22, 152.24, 156.73, 158.16 ppm; IR (KBr): ¯vꢀ = 3,286,
3,162 (NH2) cm-1; MS: m/z (%) = 376 (M?, 71), 257
(15), 256 (22), 214 (14), 189 (12), 118 (14), 104 (88), 91
(19), 77 (100), 69 (37), 57 (62), 55 (62).
7-Benzyl-2-(3-methylphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine (3f, C32H26N4)
7-Cyclohexyl-2,5,6-triphenyl-7H-pyrrolo[2,3-d]pyrimidin-
4-amine (3b, C30H28N4)
1H NMR(CDCl3):d = 2.49 (s, 3H, CH3), 5.18 (br s, 2H, NH2),
5.52 (s, 2H, CH2), 7.05–7.45 (m, 17H, Har), 8.33 (d, 2H,
J = 7.0 Hz, Har) ppm; 13C NMR (100 MHz, CDCl3):
d = 21.65, 46.13, 100.48, 114.18, 125.18, 126.82, 126.83,
127.21, 127.68, 128.22, 128.34, 128.51, 128.56, 128.57,
130.15, 130.51, 130.88, 131.21, 134.69, 135.30, 137.77,
138.36, 139.12, 152.33, 156.81, 158.38 ppm; IR (KBr):
vꢀ = 3,305, 3,134 (NH2) cm-1; MS: m/z (%) = 466 (M?,
100), 389 (11), 375 (61), 257 (18), 241 (9), 214 (8), 194 (11),
128 (14), 118 (41), 104 (9), 91 (91), 77 (16), 57 (28), 55 (24).
1H NMR (CDCl3): d = 1.20–2.00 (m, 8H, cyclohexyl),
2.90–3.05 (m, 2H, cyclohexyl), 4.00–4.10 (m, 1H, CH–N),
5.09 (br s, 2H, NH2), 7.25–7.70 (m, 13H, Har), 8.53 (d, 2H,
J = 8.2 Hz, Har) ppm; 13C NMR (100 MHz, CDCl3):
d = 25.60, 26.38, 31.44, 56.81, 101.12, 113.33, 126.67,
127.84, 128.15, 128.25, 128.30, 128.39, 129.18, 130.58,
131.11, 131.55, 135.09, 135.52, 139.41, 151.67, 156.82,
156.87 ppm; IR (KBr): vꢀ = 3,292, 3,169 (NH2) cm-1; MS:
m/z (%) = 444 (M?, 92), 362 (100), 259 (16), 257 (16),
241 (21), 214 (12), 128 (10), 104 (36), 83 (12), 77 (18), 67
(14), 57 (9), 55 (31).
Acknowledgments The authors express their gratitude to the Isla-
mic Azad University, Mashhad Branch for its financial support.
2-(4-Chlorophenyl)-7-cyclohexyl-5,6-diphenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-amine (3c, C30H27ClN4)
1H NMR (CDCl3): d = 1.20–2.00 (m, 8H, cyclohexyl),
2.85–3.00 (m, 2H, cyclohexyl), 4.00–4.10 (m, 1H, CH–N),
5.04 (br s, 2H, NH2), 7.20–7.50 (m, 12H, Har), 8.46 (d, 2H,
J = 8.6 Hz, Har) ppm; 13C NMR (100 MHz, CDCl3):
d = 25.61, 26.34, 31.46, 56.80, 101.19, 113.35, 126.72,
128.20, 128.31, 128.37, 128.40, 129.13, 130.56, 131.07,
131.43, 134.97, 135.08, 135.68, 137.98, 151.52, 155.89,
156.79 ppm; IR (KBr): ¯vꢀ = 3,306, 3,145 (NH2) cm-1; MS:
m/z (%) = 480 (M??2, 28), 478 (M?, 85), 396 (100), 259
(33), 257 (26), 241 (47), 214 (28), 189 (18), 155 (35), 138
(59), 128 (32), 104 (26), 83 (34), 77 (35), 57 (37), 55 (79).
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