An efficient one-pot synthesis of 6-alkoxy-8,9-dialkylpurines via reaction of 5-amino-4-chloro-6-alkylaminopyrimidines with N,N-dimethylalkaneamides and alkoxide ions

Article abstract of DOI:10.1016/S0040-4020(02)00867-0

The synthesis of a number of new 6-alkoxy-8,9-(disubstituted)purines has been accomplished by the cyclization of the corresponding intermediate 5-amino-4-chloro-6-(alkylamino)pyrimidines promoted by alkoxides and various N,N-dimethyl amides, where the latter act as solvent-reagents. By this three-component condensation reaction we are able to introduce an alkyl group in the 8 position of the purine ring with the concomitant nucleophilic replacement of the 6-chloro group with an alkoxy moiety.

Full text of DOI:10.1016/S0040-4020(02)00867-0

Tetrahedron 58 (2002) 7607–7611
An efficient one-pot synthesis of 6-alkoxy-8,9-dialkylpurines
via reaction of 5-amino-4-chloro-6-alkylaminopyrimidines
with N,N-dimethylalkaneamides and alkoxide ions
b
b
Pier Giovanni Baraldi,a Asier Unciti Broceta, Maria Jose Pineda de las Infantas,
,
*
`
` `
Juan Jose Dıaz Mochun, Antonio Espinosa and Romeo Romagnoli
b
b
a
a
`
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, via Fossato di Mortara 17/19, I-44100 Ferrara, Italy
bDepartamento de Quimica Organica y Farmaceutica, Facultad de Farmacia, Campus de Cartuja s/n, Granada, Spain
Received 24 April 2002; revised 28 June 2002; accepted 18 July 2002
Abstract—The synthesis of a number of new 6-alkoxy-8,9-(disubstituted)purines has been accomplished by the cyclization of the
corresponding intermediate 5-amino-4-chloro-6-(alkylamino)pyrimidines promoted by alkoxides and various N,N-dimethyl amides, where
the latter act as solvent–reagents. By this three-component condensation reaction we are able to introduce an alkyl group in the 8 position of
the purine ring with the concomitant nucleophilic replacement of the 6-chloro group with an alkoxy moiety. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
methodology suffers from drawbacks such as low overall
yield, long reaction times, cumbersome product-isolation
procedures and the limited availability of the appropriate
orthoester which allows the introduction of the substituent
in the 8 position of the purine ring. The preparation of
6-benzyloxypurine from 6-chloropurine by reaction with
benzyl alcohol under phase-transfer conditions has been
also reported.7,8 The subsequent N-alkylation of this
6-alkoxy purine with alkyl and benzyl halides furnished
an equimolar mixture of two N7 and N9 alkylated
regioisomer products. Recently, Dang and co-workers
reported that 6-chloro-8,9-dialkylsubstituted purine ana-
logues were efficiently synthesized in good yields and under
mild reaction conditions via cyclization of 4-alkylamino-5-
amino-6-chloropyrimidines and various aldehydes promoted
by FeCl3–SiO2.9
Purines are involved in a large number of biological
processes, and the purine scaffold is a component of
guanine and adenine, and therefore appears in nucleic acids
and cofactors that play an essential role in the modulation of
protein function and signal transduction.1 Over the past
years, purine derivatives substituted in position 9 with an
alkoxy group constitute an important class of pharmaco-
logically active compounds for which different targets can
be postulated, such as platelet activating factor (PAF)2 and
cyclin-dependent kinase (CDK)3 involved in asthma and
cancer, respectively.
The synthetic strategy for the synthesis of 6-alkoxy-8,9-
dialkyl purines involve a simple and straightforward three-
step approach which consists in the treatment of 4-alkyl-
amino-5-amino-6-chloropyrimidines with an alkyl ortho-
ester in presence of acetic anhydride,4 or catalytic amounts
of ethanesulfonic acid,5 to yield the corresponding 6-chloro-
8,9-dialkyl purines. These derivatives were subsequently
transformed in the 6-trimethylammonio, 6-[1-azabicyclo-
[2,2,2]octane] (quinuclidine) or 6-[[1,4-diazabicyclo-
[2,2,2]octane]] (DABCO) purines, which undergo facile
displacement reactions with alkoxides in dimethyl sulfoxide
to afford the corresponding 6-alkoxy purines.6 This
In this article, we report a new preparation of 6-alkoxy-8,9-
alkyl purines which were obtained in moderate yields by the
one-pot cyclocondensation reaction of 4-alkylamino-5-
amino-6-chloropyrimidines promoted by different combi-
nations of N,N-dimethylamides and alkoxides.
2. Results and discussion
The purines with general formula 16 were prepared from 1
following the procedure outlined in Scheme 1. Amination of
commercially available 4,6-dichloro-5-nitropyrimidine 1
with ammonia or different alkyl amines in the presence of an
equimolar amount of sodium bicarbonate and THF as
Keywords: purine; cyclization; dimethylformamide dimethyl acetal;
one-pot reaction; amides.
*
Corresponding author. Tel.: þ39-532-291293; fax: þ39-532-291296;
e-mail: pgb@dns.unife.it
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00867-0

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P. G. Baraldi et al. / Tetrahedron 58 (2002) 7607–7611
Scheme 1.
solvent afforded the corresponding 4-alkylamino-5-nitro-6-
chloropyrimidines 2–8 in 45–65% yields, which were used
without purification for the next reaction. The subsequent
reduction of the nitro group using stannous chloride as
reductant furnished the corresponding 4-alkylamino-5-
amino-6-chloropyrimidines 9–15 which were cyclized by
treatment for 24 h at 958C with a mixture constituted from
the appropriate alkoxide (generate in situ by the correspond-
ing alcohol and sodium hydride) and a large excess of
the suitable N,N-dimethyl amide, to give exclusively the
corresponding 6-alkoxy-8,9-disubstituted alkyl purines
16a–m in acceptable yields. By this strategy, it is possible
to introduce simultaneously two different substituents in the
6 and 8 position of the purine ring. The structures of these
products were established by nuclear magnetic resonance
(NMR) spectra and mass spectra analysis.
The cyclization reaction that furnished 6,8,9-trisubstituted
purines 16a–m may proceed through the addition of the
6-chloro/alkoxy-4,5-diamino pyrimidine with the acetal of
the corresponding amide used (generated in situ by reaction
of the amide with the alkoxide). This hypothesis has been
corroborated by reference to the reaction of the 4-n-
pentylamino-5-amino-6-chloropyrimidine 13 with a strong
excess (50 equiv.) of dimethylformamide (DMF) at 958C for
24 h or with a mixture of DMF and ethanol (50 equiv. of
Scheme 2.

P. G. Baraldi et al. / Tetrahedron 58 (2002) 7607–7611
7609
each reagent)) at reflux for 24 h which failed to yield
3.3. General procedure for the preparation of
compounds (9–15)
the desired 6-chloropurine 17 and 6-ethoxypurine 16f,
respectively (Scheme 2). The failure of several amides to
yield the purine ring system starting from the derivative 13
led us to try the commercially available N,N-dimethyl-
formamide dimethyl acetal as a possible cyclizing agent, in
view of the successful synthesis of 6-chloro-8,9-disubsti-
tuted adenines via condensation of the 4-alkylamino-5-
amino-6-chloropyrimidines using alkylorthoesters. In fact,
when the compound 13 was treated with N,N-dimethyl-
formamide dimethyl acetal (10 equiv.) as solvent/reagent
at 958C for 24 h (Route A) or with a mixture of N,N-di-
methylformamide dimethyl acetal (5 equiv.) and DMF
(10 equiv.) at 1308C for 3 h (Route B), the 6-chloropurine
17 was formed with a 65 and 68% of yield, respectively.
Finally, the reaction of compound 13 with a ten-fold
excess both of N,N-dimethylformamide dimethyl acetal (as
solvent/reagent) and sodium ethoxide (generated in situ by
EtOH and NaH) at 958C for 24 h (Route C) afforded 16f in
good yield (57%).
A solution of 2–8 (5 mmol) in EtOH (10 mL) containing
SnCl2·2H2O (25 mmol, 5 equiv.) was refluxed for 1 h,
monitoring the reaction by TLC. The mixture was then
cooled at room temperature and NaHCO3 was added until
pH 8 was reached. After two extractions with EtOAc
(10 mL for each one), the organic phase was washed with an
aq. saturated solution of NaCl (2£5 mL) and dried on
Na2SO4. Evaporation under vacuum gave a solid that was
purified by column chromatography eluting with ethyl
acetate/petroleum ether solutions.
3.3.1. 4,5-Diamino-6-chloropyrimidine (9). Light tan
needles; yield 67%; mp 241–2428C (lit.10 mp 236–2388C).
3.3.2. 4-Ethylamino-5-amino-6-chloropyrimidine (10).
Yellow solid; yield 71%; mp 145–1478C (lit.11 mp 148–
1498C); dH (200 MHz, CD3OD): 7.72 (1H, s, NCHN), 3.12
(2H, m, NCH2CH3), 0.96 (3H, t, J¼7.1 Hz, NCH2CH3).
In conclusion, a one-step cyclization reaction with con-
comitant introduction of an alkoxy group in the 6-position
of 6-chloro-4,5-diaminopyrimidines with various amides as
solvent/reagent and by the presence of a ten-fold excess of
alkoxides was developed. This reaction is suitable for
synthesis of 6-alkoxy-8,9-disubstituted purines, and the
strategy described herein can be also utilized to generate
large combinatorial libraries containing the purine scaffold.
3.3.3. 4-n-Propylamino-5-amino-6-chloropyrimidine
(11). Light yellow solid; yield 68%; mp 111–1148C (lit.12
mp 113–1148C).
3.3.4. 4-n-Butylamino-5-amino-6-chloropyrimidine (12).
Yellow solid; yield 61%; mp 75–778C (lit.12 mp 80–818C);
n
max (KBr): 3310 cm21; dH (200 MHz, CDCl3): 7.71 (1H, s,
NCHN), 5.62 (1H, t, J¼7.1 Hz, NHCH2), 3.68 (2H, s, NH2),
3.31 (2H, m, NHCH2), 1.63 (4H, m, NCH2CH2CH2CH3),
0.86 (3H, t, J¼7.4 Hz, NCH2CH2CH2CH3).
3. Experimental
3.1. General
3.3.5. 4-n-Pentylamino-5-amino-6-chloropyrimidine
(13). Yellow solid; yield 66%; mp 81–838C (lit.12 mp
84–858C); nmax (KBr): 3330 cm21; dH (200 MHz, CDCl3):
8.05 (1H, s, NCHN), 5.06 (1H, t, J¼7.2 Hz, NHCH2), 3.41
(4H, m, NH2 and NHCH2), 1.61 (2H, m, NCH2CH2), 1.33
(4H, m, NCH2CH2CH2CH2CH3), 0.88 (3H, t, J¼7.2 Hz,
NCH2CH2CH2CH2CH3).
Reaction courses and product mixtures were routinely
monitored by TLC on silica gel (precoated F254 Merck
plates) and visualized with aqueous KMnO4. Chroma-
tography was performed with Merck 60–200 mesh silica
gel. Melting points were determined on a Buchi-Tottoli
apparatus and are uncorrected. 1H NMR spectra were
obtained in CD3OD, (CD3)2CO, CDCl3 or d6-DMSO
solutions on a Bruker AC 200 spectrometer. Infrared (IR)
spectra were measured with a Jasco A-102 diffraction
grating IR spectrometer. Chemical shifts (d) are given in
ppm upfield from tetramethylsilane. All products reported
3.3.6. 4-Isopropylamino-5-amino-6-chloropyrimidine
(14). Light yellow solid; yield 73%; mp 185–1868C (lit.13
mp 188–1898C); nmax (KBr): 3310 cm21; dH (200 MHz,
CD3OD): 7.76 (1H, s, NCHN), 4.28 (1H, m, CH(CH3)2),
1.26 (6H, d, J¼6.5 Hz, CH(CH3)2).
1
showed H and 13C NMR spectra in agreement with the
3.3.7. 4-Benzylamino-5-amino-6-chloropyrimidine (15).
Yellow solid; yield 65%; mp 205–2068C (lit.14 mp 207–
2098C); nmax (KBr): 3330 cm21; dH (200 MHz, CD3OD):
7.71 (1H, s, NCHN), 7.30 (5H, m, Ph), 4.61 (2H, d, J¼
5.6 Hz, CH2Ph).
assigned structures. Mass spectra were obtained by electron
impact at 70 eV with a Fisons MD 800 instrument.
3.2. General procedure for the preparation of
compounds (2–8)
3.4. General procedure for the preparation of
compounds (16a–m)
To a stirred solution of commercially available 4,6-di-
chloro-5-nitropyrimidine 1 (10 mmol) in anhyd. THF
(15 mL) was added NaHCO3 (11 mmol, 1.1 equiv.). The
mixture was then heated to 558C and at this temperature the
appropriate amine (11 mmol, 1.1 equiv.) dissolved in THF
(5 mL) was added dropwise. After 1 h, the mixture was
cooled at room temperature, filtered and evaporated to give
a crude product, which was directly used for the next step
without purification.
A suspension of NaH (50%) in mineral oil (10 mmol,
10 equiv.) was dissolved in a mixture cooled at 08C
constituted both from the appropriate alcohol (10 mmol,
10 equiv.) and amide (50 mmol, 10 equiv.). The solution
was stirred at room temperature. for 30 min and then at 908C
for the same time. At 908C, compounds 9–15 (1 mmol)
dissolved in the appropriate amide (50 mmol, 50 equiv.)

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were added dropwise and the mixture heated for 24 h. The
reaction mixture, quenched to pH 7 with an aq saturated
NH4Cl solution, was then extracted with CH2Cl2 (3£
15 mL), the combined organic extracts dried (Na2SO4) and
the solvent evaporated. The residue was chromatographed
on silica gel using ethyl acetate/petroleum ether (3/1; v/v).
requires C, 61.52; H, 7.74; N, 23.91. Found: C, 61.36; H,
7.58; N, 23.77.
3.4.7. 6-Ethoxy-8-methyl-9-(ethyl)-9H-purine (16g).
Light brown solid; yield 39%; mp 145–1478C; dH
(200 MHz, CD3OD): 8.41 (1H, s, NCHN); 4.64 (2H, q,
J¼7.1 Hz, OCH2), 4.31 (2H, q, J¼7.2 Hz, NCH2CH3), 2.64
(3H, s, CCH3), 1.48 (3H, t, J¼7.1 Hz, OCH2CH3), 1.42 (3H,
t, J¼7.2 Hz, NCH2CH3). dC (75 MHz, CD3OD): 160.8,
154.2, 153.5, 142.3, 120.7, 64.1, 39.0, 15.1, 14.8, 13.6. MS
(70 eV) m/z (%): 206 (Mþ); 191; 162; 123; 107. C10H14N4O
requires C, 58.24; H, 6.84; N, 27.17. Found: C, 58.01; H,
6.67; N, 27.03.
3.4.1. 6-Ethoxy-9H-purine (16a). Colorless crystals; yield
34%; mp 228–2308C (lit.15 mp 223–2248C).
3.4.2. 6-Benzyloxy-9H-purine (16b). Light brown solid;
yield 39%; mp 170–1718C (lit.7 mp 170–1728C); dH
(200 MHz, d6-DMSO): 13.5 (1H, s, NH ), 8.52 (1H, s,
NCHN), 8.36 (1H, s, NHCHN), 7.42 (5H, m, Ph), 5.62 (2H,
s, CH2Ph). dC (75 MHz, d6-DMSO): 160.7, 154.6, 153.1,
142.4, 137.3, 130.2, 130.08, 129.5, 128.5, 128.3, 120.9,
64.5. MS (70 eV) m/z (%): 227.09 (Mþ1), 135.05.
C12H10N4O requires C, 63.71; H, 4.46; N, 24.77. Found:
C, 63.46; H 4.28; N, 24.77.
3.4.8. 6-Ethoxy-8-methyl-9-(n-propyl)-9H-purine (16h).
Light brown solid; yield 29%; mp 163–1658C; dH
(200 MHz, CD3OD): 8.41 (1H, s, NCHN), 4.62 (2H, q,
J¼7.1 Hz, OCH2), 4.21 (2H, t, J¼7.4 Hz, NCH2CH2), 2.62
(3H, s, CCH3), 1.85 (2H, m, NCH2CH2), 1.47 (3H, t, J¼
7.1 Hz, OCH2CH3), 0.95 (3H, t, J¼7.4 Hz, NCH2CH2CH3).
dC (75 MHz, CD3OD): 160.8, 154.3, 153.7, 152.3, 120.7,
64.1, 45.5, 23.9, 14.8, 13.8, 11.3. MS (70 eV) m/z (%): 221.3
(Mþ1), 243.2. C11H16N4O requires C, 59.98; H, 7.32; N,
25.44. Found: C, 59.78; H, 7.04; N, 25.12.
3.4.3. 6-(Biphenyl-4-ylmethoxy)-9H-purine (16c). White
solid; yield 32%; mp 215–2168C; dH (200 MHz, d6-DMSO):
13.5 (1H, s, NH ), 8.53 (1H, s, NCHN), 8.40 (1H, s,
NHCHN), 7.66 (4H, m, CH2C6H4Ph), 7.44 (5H, m, Ph),
5.67 (2H, s, CH2C6H4). dC (75 MHz, d6-DMSO): 160.7,
154.5, 153.0, 142.4, 138.1, 137.8, 136.7, 131.3, 131.0, 130.2
130.0, 129.5, 129.4, 129.1, 128.9, 128.8, 120.9, 64.4. MS
(70 eV) m/z (%): 303.12 (Mþ1), 135.05. C18H14N4O
requires C, 71.51; H, 4.67; N, 18.53. Found: C, 71.25; H
4.59; N, 18.34.
3.4.9. 6-Ethoxy-8-methyl-9-(n-butyl)-9H-purine (16i).
Light yellow solid; yield 33%; mp 265–2678C; dH
(200 MHz, CD3OD): 8.41 (1H, s, NCHN), 4.61 (2H, q,
J¼7.1 Hz, OCH2), 4.23 (2H, t, J¼7.4 Hz, NCH2CH2), 2.60
(3H, s, CCH3), 1.78 (2H, m, NCH2CH2), 1.46 (3H, t, J¼
7.1 Hz, OCH2CH3), 1.36 (2H, m, NCH2CH2CH2CH3),
0.95 (3H, t, J¼7.4 Hz, NCH2CH2CH2CH3). dC (75 MHz,
CD3OD): 160.8, 154.3, 153.7, 152.3, 120.8, 64.1, 43.9, 32.7,
20.9, 14.8, 14.0, 13.9. MS (70 eV) m/z (%): 235.2 (Mþ1),
257.1, 229.1.C12H18N4O requires C, 61.52; H, 7.74; N,
23.91. Found: C, 61.28; H, 7.55; N, 23.78.
3.4.4. 6-Benzyloxy-9-(isopropyl)-9H-purine (16d). White
solid; yield 38%; mp 167–1698C; dH (200 MHz, CDCl3):
8.55 (1H, s, NCHN), 7.99 (1H, s, NHCHN); 7.54 (1H, m, 1H
of Ph), 7.34 (4H, m, 4H of Ph), 5.68 (2H, s, CH2C6H5),
4.90 (1H, d, J¼6.9 Hz, CH(CH3)2), 1.63 (6H, d, J¼6.9 Hz,
CH(CH3)2). dC (75 MHz, CDCl3): 160.7, 154.6, 153.1,
142.4, 137.2, 130.2, 130.1, 129.5, 128.5, 128.3, 120.9, 64.4,
13.6, 11.2, 10.9. MS (70 eV) m/z (%): 268.13 (Mþ1), 225.1,
177.08. C15H16N4O requires C, 67.15; H, 6.01; N, 20.88.
Found: C, 67.02; H, 5.89; N, 20.67.
3.4.10. 6-Ethoxy-8-methyl-9-(n-pentyl)-9H-purine (16j).
Light brown solid; yield 29%; mp 153–1558C; dH
(200 MHz, CD3OD): 8.42 (1H, s, NCHN), 4.63 (2H, q,
J¼7.1 Hz, OCH2), 4.24 (2H, t, J¼7.4 Hz, NCH2CH2), 2.62
(3H, s, CCH3), 1.82 (2H, m, NCH2CH2), 1.48 (3H, t, J¼
7.1 Hz, OCH2CH3), 1.35 (4H, m, NCH2CH2CH2CH2CH3),
0.91 (3H, t, J¼6.9 Hz, NCH2CH2CH2CH2CH3). dC (75 MHz,
CD3OD): 160.7, 154.2, 153.6, 152.3, 120.7, 64.1, 44.1, 30.3,
29.9, 23.3, 14.9, 14.2, 13.8. MS (70 eV) m/z (%): 248 (Mþ);
233; 219; 205; 191; 177; 163; 149; 134; 123. C13H20N4O
requires C, 62.88; H, 8.12; N, 22.56. Found: C, 62.67; H,
8.00; N, 22.44.
3.4.5. 6-Benzyloxy-9-(benzyl)-9H-purine (16e). White
solid; yield 28%; mp 125–1278C (lit.8 mp 127–1288C);
dH (200 MHz, CD3OD): 8.55 (1H, s, NCHN), 8.34 (1H, s,
NHCHN), 7.53 (2H, m, 2H of Ph), 7.35 (8H, m, 3H of Ph
and 5H of the other Ph), 5.67 (2H, s, OCH2C6H4), 5.52 (2H,
s, NCH2C6H4). dC (75 MHz, CD3OD): 161.7, 155.4, 153.3,
144.8, 137.6, 137.4, 130.0, 129.8, 129.5, 129.5, 129.4,
129.4, 129.2, 129.1, 128.9, 128.8, 121.9, 69.7, 48.4. MS
(70 eV) m/z (%): 317.36 (Mþ1), 339.15. C19H16N4O
requires C, 72.13; H, 5.10; N, 17.71. Found: C, 71.89; H,
4.86; N, 17.52.
3.4.11. 6-Ethoxy-8-methyl-9-(benzyl)-9H-purine (16k).
Light brown solid; yield 34%; mp 294–2958C; dH
(200 MHz, CD3OD): 8.49 (1H, s, NCHN), 7.34 (5H, m,
Ph); 5.52 (2H, s, NCH2Ph), 4.68 (2H, q, J¼7.1 Hz,
OCH2CH3), 2.52 (3H, s, CCH3), 1.51 (3H, t, J¼7.1 Hz,
OCH2CH3). dC (75 MHz, CD3OD): 160.9, 154.6, 153.9,
152.7, 137.2, 130.1, 130.0, 129.1, 128.1, 127.9, 120.8, 64.3,
46.9, 14.8, 14.0. MS (70 eV) m/z (%): 268 (Mþ); 253; 149;
131; 103; 91. C15H16N4O requires C, 67.15; H, 6.01; N,
20.88. Found: C, 66.97; H, 5.89; N, 20.77.
3.4.6. 6-Ethoxy-9-(n-pentyl)-9H-purine (16f). Light yellow
viscous oil; yield 32%; oil; dH (200 MHz, CD3OD): 8.42
(1H, s, NCHN), 7.77 (1H, s, NCHN), 4.63 (2H, q, J¼7.1 Hz,
OCH2), 4.22 (2H, t, J¼7.2 Hz, NCH2), 1.80 (2H, m,
NCH2CH2), 1.49 (3H, t, J¼7.1 Hz, OCH2CH3), 1.34
(4H, m, NCH2CH2CH2CH3), 0.91 (3H, t, J¼7.2 Hz,
NCH2CH2CH2CH3). dC (75 MHz, CD3OD): 160.6, 154.3,
153.5, 152.3, 120.6, 64.2, 44.16, 30.2, 29.8, 23.2, 14.8, 14.3.
MS (70 eV) m/z (%): 235.15 (Mþ1), 206.1. C12H18N4O
3.4.12. 6-Ethoxy-8-ethyl-9-(isopropyl)-9H-purine (16l).
Yellow viscous oil; yield 29%; viscous oil; dH (200 MHz,

P. G. Baraldi et al. / Tetrahedron 58 (2002) 7607–7611
7611
CD3OD): 8.35 (1H, s, NCHN), 4.80 (1H, d, J¼6.8 Hz,
NCH(CH3)2), 4.58 (2H, q, J¼7.1 Hz, OCH2CH3), 2.94
(2H, q, J¼7.5 Hz, CCH2CH3), 1.67 (6H, d, J¼6.8 Hz,
NCH(CH3)2), 1.42 (3H, t, J¼7.1 Hz, OCH2CH3), 1.36 (3H,
t, J¼7.5 Hz, CCH2CH3). dC (75 MHz, CD3OD): 160.5,
155.8, 154.6, 150.8, 121.8, 62.8, 48.9, 22.0, 21.2, 21.0, 14.8,
11.8. MS (70 eV) m/z (%): 235.1 (Mþ1), 257.1. C12H18N4O
requires C, 61.52; H, 7.74; N, 23.91. Found: C, 61.44; H,
7.62; N, 23.77.
amide dimethyl acetal (1.34 mL, 1.19 g, 10 mmol,
10 equiv.). The reaction was stirred at room temperature
for 30 min and at the same temperature, compound 13
(215 mg, 1 mmol) dissolved in DMF-dimethylacetal (1 mL)
was added dropwise and the mixture heated for 24 h at 958C.
The reaction quenched to pH 7 with an aqueous saturated
NH4Cl solution was then extracted with CH2Cl2 (3£15 mL),
the combined organic extracts dried (Na2SO4) and the
solvent evaporated. The residue chromatographed on silica
gel using ethyl acetate/petroleum ether (3/1; v/v) as solvent
furnished 16f as a viscous oil (133 mg, 57% yield).
3.4.13. 6-Ethoxy-8-ethyl-9-(n-butyl)-9H-purine (16m).
Yellow viscous oil; yield 31%; viscous oil; dH (200 MHz,
CD3OD): 8.42 (1H, s, NCHN), 4.59 (2H, q, J¼7.1 Hz,
OCH2CH3), 4.23 (t, J¼7.4 Hz, 2H), 2.93 (2H, q, J¼7.5 Hz,
CCH2CH3), 1.79 (2H, m, NCH2CH2), 1.43 (3H, t, J¼
7.1 Hz, OCH2CH3), 1.39 (3H, t, J¼7.5 Hz, CCH2CH3), 1.38
(2H, m, 2H, NCH2CH2CH2), 0.93 (3H, t, J¼7.4 Hz,
NCH2CH2CH2CH3). dC (75 MHz, CD3OD): 160.3, 156.3,
154.7, 151.4, 121.1, 62.9, 42.9, 32.5, 21.3, 20.5, 14.8, 13.9,
11.4. MS (70 eV) m/z (%): 249.2 (Mþ1); 271.1; 221.1.
C13H20N4O requires C, 62.88; H, 8.12; N, 22.56. Found: C,
62.76; H, 8.01; N, 22.48.
References
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3.4.14. Synthesis of 6-chloro-9-(n-pentyl)-9H-purine
(17). Route A. A mixture of 4-n-pentylamino-5-amino-6-
chloro-pyrimidine 13 (214 mg, 1 mmol) and N,N-dimethyl-
formamide dimethyl acetal (1.34 mL, 1.19 g, 10 mmol,
10 equiv.) was heated at 958C for 24 h. The solution was
evaporated and the residue purified by flash chromatography
(eluent EtOAc/petroleum ether, 4/1, v/v) furnished the
compound 17 as yellow viscous oil (146 mg, 65% yield); dH
(CDCl3): 8.31 (1H, s, NCHN), 7.68 (1H, s, NCHNCH2),
4.12 (2H, t, J¼7.4 Hz, NCH2), 1.84 (2H, m, NCH2CH2),
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Route B. A mixture of the compound 13 (214 mg, 1 mmol),
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5 mmol, 5 equiv.) and DMF (0.77 mL, 730 mg, 10 mmol,
10 equiv.) was heated at 1308C for 3 h. After this time, the
work-up of the reaction and the purification of the crude
product was performed following the same procedure as
reported in Route A. The compound 17 was isolated as
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3.4.15. Synthesis of 6-ethoxy-9-n-pentylamino-9H-purine
(compound 16f) using DMF-dimethylacetal and sodium
ethoxide. Route C. A suspension of NaH (50%) in mineral
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(0.58 mL, 10 mmol, 10 equiv.) and N,N-dimethylform-
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