Synthesis of series of 1- and 3-differently substituted xanthines from imidazoles

Article abstract of DOI:10.1248/cpb.50.1379

A new and general method is described for the synthesis, in three steps and in good overall yields, of tetrasubstituted xanthines from an easily prepared imidazole precursor. The method is especially useful for the preparation in standardized conditions o

Full text of DOI:10.1248/cpb.50.1379

October 2002
Notes
Chem. Pharm. Bull. 50(10) 1379—1382 (2002)
1379
Synthesis of Series of 1- and 3-Differently Substituted Xanthines from
Imidazoles
Antonio Rodríguez HERGUETA,a María José FIGUEIRA,a Carmen LÓPEZ,a Olga CAAMAÑO,a
b
Franco FERNÁNDEZ, ,a and José Enrique RODRÍGUEZ-BORGES
*
a Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela; 15782-Santiago
b
de Compostela, Spain: and Departamento de Química, Faculdade de Ciências do Porto; Rua do Campo Alegre, 687–
4169007 Porto, Portugal. Received April 23, 2002; accepted June 26, 2002
A new and general method is described for the synthesis, in three steps and in good overall yields, of tetra-
substituted xanthines from an easily prepared imidazole precursor. The method is especially useful for the prepa-
ration in standardized conditions of series of xanthines combining a broad variety of primary or secondary
alkyl, benzyl or aryl groups at N1 and of alkyl or arylmethyl groups at N3, that are not readily available by other
methods.
Key words imidazole; xanthine; series; reductive amination; substituents combination
Xanthine derivatives play an important role in several bio- alkyl isocyanate in the presence of one equivalent of triethyl-
logical processes, including the inhibition of both calcium- amine in refluxing dry toluene led to the corresponding alky-
independent and calcium-dependent phosphodiesterases,1,2) lureas, 3a—g, in good-to-excellent yields; the reaction was
and the antagonism of adenosine receptors (ARs).3,4) Since completed within 72 h, and only traces of N,NЈ-dialkyureas
the characterization and cloning of the different subtypes of were observed when the crude reaction products were exam-
ARs,5—7) a large number of compounds with the xanthine ined by thin layer chromatography. Compound 2d (Chart 1),
framework have been synthesized in search of improved ac- however, failed to react even at high temperatures and pres-
tivity and selectivity.8—10)
sures and in the presence of a large excess of the isocyanate.
In connection with a search for novel antagonists of A2B Treatment of ureas 3a—g with KOH in refluxing ethanol re-
receptors, it was required a method for the preparation of sulted in ring closure, giving high post-isolation yields of 3-
some series of tetrasubstituted xanthines, each with a fixed substituted 1-alkylxanthines 4a—g (Chart 2).
set of substituents at N7 and C8 and a broad variety of sub-
When in an attempt to extend this method to the synthesis
stituents at N1 and N3. Though appropiated methods for the of 1-arylxanthines compounds 2a—c (Chart 1) were treated
preparation of tri- and tetrasubstituted xanthines are
known,11,12) they have in common that start from a mono- or
disubstituted aminopyrimidine precursor, so substitutents at
N1 and/or N3 of the final xanthine have to be introduced in
the early steps of the synthesis. This means the synthesis has
to be repeated almost from the very beginning for each com-
bination of substitutents at N1 and N3, making the procedure
poorly attractive for the mentioned purpose.
Our attention was turned at this point to a strategy, seldom
used and thus not well investigated, that has been reported to
produce very simple 1-monosubstituted xanthines in varying
yields.13—16) We have now developed the procedure described
herein that, starting from an aminoimidazole precursor, af-
fords differently tetrasubstituted xanthines, having a methyl
group (for example) at N7, a benzyl group at C8, a primary
alkyl group at N3 and an alkyl or aryl group at N1, and thus
substantially widening the scope of the partially similar pro-
cedure of Bridson16) for the preparation of 1-monosubstituted
xantines.
Chart 1
Ethyl 4-amino-2-benzyl-1-methylimidazole-5-carboxylate
(1),13) a precursor that can readily be prepared on a large
scale, was easily converted into secondary amines 2a—d at
room temperature by one-pot reductive amination: treatment
of 1 with two equivalents of the appropriate aldehyde, AcOH
and NaBH3CN in methanol afforded yields Ն80% with sim-
ple aliphatic and aromatic aldehydes, and a 67% yield of 2d
when applied to the sterically hindered pivalaldehyde (Chart
1).
Chart 2
Reaction of compounds 2a—c with one equivalent of an
* To whom correspondence should be addressed. e-mail: qofranco@usc.es
© 2002 Pharmaceutical Society of Japan

1380
Vol. 50, No. 10
Table 1. Yields, Physical, IR, 1H-NMR and MS Data for Amines 2a—d
Compound Yield (%) mp (°C)
IR (film) n (cmϪ1
)
1H-NMR (CDCl3) d (mult., na, J)
MS (70 eV) m/z (%)
2a
2b
90
80
Oil
Oil
3392 (NH), 1654 (CϭO) 0.98 (t, 3H, 7.3), 1.33 (t, 3H, 7.1), 1.33 (sex, 2H, 7.3),
3.41 (q, 2H, 6.6), 3.55 (s, 3H), 4.05 (s, 2H), 4.27 (q, 2H,
7.1), 5.59 (s, 1H), 7.13—7.34 (m, 5H)
301 (Mϩ, 27), 226 (100)
3375 (NH), 1651 (CϭO) 1.32 (t, 3H, 7.1), 3.58 (s, 3H), 4.06 (s, 2H), 4.27 (q, 2H,
7.1), 4.65 (d, 2H, 6.6), 5.81 (s, 1H), 6.24 (d, 1H, 3.0), 6.31
(dd, 1H, 1.8, 3.0), 7.29 (d, 1H, 1.8),7.19—7.35 (m, 5H)
3390 (NH), 1653 (CϭO) 1.32 (t, 3H, 7.1), 3.58 (s, 3H), 4.05 (s, 2H), 4.68 (q, 2H,
7.1), 4.68 (d, 2H, 8.0), 5.88 (s, 1H),7.13—7.42 (m, 10H)
3386 (NH), 1651 (CϭO) 1.06 (s, 9H), 1.34 (t, 3H, 7.1), 3.27 (d, 2H, 6.1), 3.56 (s,
3H), 4.05 (s, 2H), 4.28 (q, 2H, 7.1), 5.75 (s, 1H), 7.12—
7.42 (m, 5H)
339 (Mϩ, 100)
2c
93
67
Oil
Oil
349 (Mϩ, 100)
2d
329 (Mϩ, 15), 226 (100)
a) n, number of protons.
Table 2. Yields, Physical, IR, 1H-NMR and MS Data for Alkylureas 3a—g
IR (KBr) n (cmϪ1
Compound Yield (%) mp (°C)
)
1H-NMR (CDCl3) d (mult., na), J)
MS (70 eV) m/z (%)
3a
3b
3c
95
68
58
117—120 3324 (NH), 1701 (CϭO), 0.84 (t, 3H, 7.5), 0.89 (t, 3H, 7.3), 1.17 (t, 3H, 7.1), 1.33 386 (Mϩ, 34), 272 (100)
1640 (CϭO)
(sex, 2H, 7.3), 1.56 (sex, 2H, 7.5), 3.14 (q, 2H, 6.6),
3.64 (t, 3H, 7.5), 3.74 (s, 3H), 4.14 (s, 2H), 4.28 (q, 2H,
7.1), 4.70 (s, 1H), 7.15—7.35 (m, 5H)
127—130 3322 (NH), 1705 (CϭO), 0.88 (t, 3H, 7.5), 1.06 (d, 3H, 6.5), 1.14 (d, 3H, 6.5),
386 (Mϩ, 34), 272 (100)
426 (Mϩ, 23), 272 (100)
1636 (CϭO)
1.32 (t, 3H, 7.1), 1.57 (sex, 2H, 7.5), 3.61 (t, 2H, 7.5),
3.74 (s, 3H), 3.93 (quint, 1H, 6.5), 4.14 (s, 2H), 4.27 (q,
2H, 7.1), 4.46 (s, 1H), 7.15—7.34 (m, 5H)
126—129 3321 (NH), 1706 (CϭO), 0.87 (t, 3H, 7.5), 0.96—1.24 (m, 4H), 1.31 (t, 3H, 7.1),
1635 (CϭO)
1.36—1.62 (m, 2H), 1.57 (sex, 2H, 7.5), 1.67—1.94 (m,
4H), 3.49—3.55 (m, 1H), 3.61 (t, 2H, 7.5), 3.73 (s, 3H),
4.13 (s, 2H), 4.26 (q, 2H, 7.1), 4.53 (s, 1H), 7.14—7.33
(m, 5H)
3d
3e
91
90
135—138 3319 (NH), 1700 (CϭO), 0.90 (t, 3H, 7.5), 1.29 (t, 3H, 7.1), 1.58 (sex, 2H, 7.5),
434 (Mϩ, 39), 272 (100)
424 (Mϩ, 14), 81 (100)
1643 (CϭO)
3.66 (t, 2H, 7.5), 3.70 (s, 3H), 4.10 (s, 2H), 4.24 (q, 2H,
7.1), 4.39 (d, 2H, 5.6), 4.98 (t, 1H, 5.6), 7.09—7.30 (m,
10H)
112—114 3324 (NH), 1708 (CϭO), 0.84 (t, 3H, 7.4), 1.28 (t, 3H, 7.1), 1.45 (sex, 2H, 6.9),
1642 (CϭO)
3.15 (q, 2H, 6.8), 3.69 (s, 3H), 4.10 (s, 2H), 4.20 (q,
2H, 7.1), 4.86 (s, 1H), 4.89 (s, 2H), 6.19 (d, 1H, 3.2),
6.23 (dd, 1H, 1.6, 3.2), 7.11 (d, 1H, 1.6), 7.21—7.31 (m,
5H)
3f
68
80
136—138 3340 (NH), 1706 (CϭO), 1.26 (t, 3H, 7.1), 3.66 (s, 3H), 4.07 (s, 2H), 4.18 (q, 2H, 472 (Mϩ, 28), 292 (100)
1640 (CϭO)
7.1), 4.42 (d, 2H, 5.5), 4.93 (s, 2H), 5.15 (d, 1H, 5.3),
6.20 (d, 1H, 3.0), 6.23 (dd, 1H, 1.8, 3.0), 7.05 (d, 1H,
1.8), 7.22—7.31 (m, 10H)
3g
87—88 3331 (NH), 1704 (CϭO), 0.83 (t, 3H, 7.4), 1.13 (t, 3H, 7.1), 1.47 (sex, 2H, 7.2),
434 (Mϩ, 8), 91 (100)
1640 (CϭO)
3.16 (t, 2H, 7.1), 3.64 (s, 3H), 4.07 (s, 2H), 4.19 (q, 2H,
7.1), 4.60 (s, 1H), 4.91 (s, 2H), 7.00—7.31 (m, 10H).
a) n, number of protons.
with one equivalent of an aryl isocyanate and triethylamine
In conclusion, an efficient and general synthetic procedure
under reaction conditions similar to those specified above, affording tetrasubstituted xanthines in good overall yields has
N,NЈ-diarylureas were isolated as the major products, and been developed. It is especially appropriate for the synthesis
only traces of the desired arylureas 3h—l were detected. under standardized conditions of series of xanthines combin-
However, 3h—l were successfully obtained by reacting ing a broad variety of primary or secondary alkyl, benzyl or
amines 2 with one equivalent of the appropriate aryl iso- aryl groups at N1 and of alkyl or arylmethyl groups at N3,
cyanate in refluxing dry toluene without any triethylamine. that are not readily available by other methods.
Flash column chromatography of the crude product gave aryl-
ureas 3h—l that were not entirely free from N,NЈ-diaryl-
Experimental
ureas, and treatment of these mixtures with KOH in refluxing
ethanol then gave xanthines 4h—l in fair overall yields (54—
90%) from amines 2 (Chart 2).
Melting points were determined on a Reichert Kofler thermopan and are
uncorrected. The IR spectra of samples prepared in KBr discs (solids) or as
films between NaCl plates (oils) were recorded on a Perkin Elmer FTIR
1640 spectrometer. 1H- and 13C-NMR spectra were recorded in a Bruker
AMX-300 spectrometer at 300 and 75 MHz, respectively, with tetramethylsi-
lane (TMS) as internal standard. Mass spectra were recorded on a Kratos
MS-59 spectrometer. Silica gel (400 mesh) for flash chromatography (FC)
The structures of the new compounds were elucidated by
1
their IR, H-, 13C-NMR and electron impact-mass spectra
(EI-MS) data, which are summarized in Tables 1—6.

October 2002
1381
Table 3. Yields, Physical, IR, 1H-NMR and MS Data for 1,3-Disubstituted Xanthines 4a—l
Compound Yield (%)
mp (°C)
IR (KBr) n (cmϪ1
)
1H-NMR (CDCl3)a) d (mult., nb), J)
MS (70 eV) m/z (%)
4a
4b
4c
100
85
103—106 1701 (CϭO), 1654 (CϭO) 0.95 (t, 3H, 7.5), 0.98 (t, 3H, 7.4), 1.67 (sex, 2H, 7.5), 298 (Mϩ, 100)
1.81 (sex, 2H, 7.4), 3.79 (s, 3H), 3.95 (t, 2H, 7.5),
4.08 (t, 2H, 7.4), 4.15 (s, 2H), 7.16—7.34 (m, 5H)
Ͼ240
1699 (CϭO), 1652 (CϭO) 0.90 (t, 3H, 7.1), 1.54 (sex, 2H, 6.9), 1.90 (d, 6H, 6.6), 340 (Mϩ, 100)
3.78 (s, 3H), 3.81—3.95 (m, 1H), 3.89 (t, 2H, 7.1),
4.18 (s, 2H), 7.22—7.34 (m, 5H)
212—213 1699 (CϭO), 1636 (CϭO) 0.90 (t, 3H, 7.4), 0.95—1.24 (m, 4H), 1.31—1.43
(m, 2H), 1.55 (sex, 2H, 7.4), 1.61—1.85 (m, 4H),
70
380 (Mϩ, 6), 56 (100)
3.50—3.55 (m, 1H), 3.64 (t, 2H, 7.4), 3.78 (s, 3H),
4.19 (s, 2H), 7.21—7.49 (m, 5H)
4d
4e
4f
64
100
97
82—85
93—95
1699 (CϭO), 1652 (CϭO) 0.98 (t, 3H, 7.4), 1.81 (sex, 2H, 7.4), 3.78 (s, 3H),
4.08 (t, 2H, 7.4), 4.15 (s, 2H), 5.18 (s, 2H), 7.15—7.49
(m, 10H)
388 (Mϩ, 100)
1695 (CϭO), 1658 (CϭO) 0.93 (t, 3H, 7.5), 1.65 (sex, 2H, 7.5), 3.79 (s, 3H),
3.94 (t, 2H, 7.5), 4.17 (s, 2H), 5.29 (s, 2H), 6.30 (dd,
1H, 1.9, 3.1), 6.42 (d, 1H, 3.1), 7.18—7.34 (m, 6H)
378 (Mϩ, 56), 81 (100)
426 (Mϩ, 18), 81 (100)
388 (Mϩ, 67), 91 (100)
126—128 1700 (CϭO), 1654 (CϭO) 3.78 (s, 3H), 4.17 (s, 2H), 5.17 (s, 2H), 5.29 (s, 2H),
6.30 (dd, 1H, 1.9, 3.1), 6.41 (d, 1H, 3.1), 7.17—7.48
(m, 11H)
1699 (CϭO), 1651 (CϭO) 0.93 (t, 3H, 7.5), 1.65 (sex, 2H, 7.5), 3.80 (s, 3H),
3.93 (t, 4H, 7,5), 4.15 (s, 2H), 5.28 (s, 2H), 7.18—7.54
(m, 10H)
4g
100
Ͼ330
4h
4i
90c)
154—156 1713 (CϭO), 1654 (CϭO) 1.00 (t, 3H, 7.4), 1.86 (sex, 2H, 7.4), 3.78 (s, 3H), 4.12 374 (Mϩ, 100)
(t, 2H, 7.4), 4.19 (s, 2H), 7.10—7.51 (m, 10H)
85c)
54d)
76d)
88e)
205—208 1709 (CϭO), 1654 (CϭO) 1.00 (t, 3H, 7.4), 1.85 (sex, 2H, 7.4), 3.78 (s, 3H), 4.11 392 (Mϩ, 23), 111 (100)
(t, 2H, 7.4), 4.19 (s, 2H), 7.05—7.36 (m, 9H)
4j
4k
4l
214—216 1713 (CϭO), 1664 (CϭO) 3.78 (s, 3H), 4.21 (s, 2H), 5.33 (s, 2H), 6.32 (dd, 1H,
1.9, 3.2), 6.45 (d, 1H, 3.2), 7.21—7.50 (m, 11H)
412 (Mϩ, 100)
205—207 1715 (CϭO), 1662 (CϭO) 3.78 (s, 3H), 4.21 (s, 2H), 5.32 (s, 2H), 6.32 (dd, 1H,
1.7, 3.1), 6.44 (d, 1H, 3.1), 7.02—7.40 (m, 10H)
430 (Mϩ, 45), 81 (100)
170—173 1708 (CϭO), 1659 (CϭO) 3.79 (s, 3H), 4.20 (s, 2H), 5.31 (s, 2H), 7.20—7.62 (m, 422 (Mϩ, 100)
15H)
a) 1H-NMR data for compounds 4b and 4c were obtained using CD3OD as solvent. b) n, number of protons. c) Overall yield from 2a. d) Overall yield from 2b.
e) Overall yield from 2c.
Table 4. 13C-NMR Shift Values for Amines 2a—d (CDCl3)
Compound
EtOCO
N–Me
CH2Ph
C-5
C-2
C-4
CH2R
11.8, 23.8, 44.9
40.4, 106.9, 110.6, 142.2, 161.7
47.2, 127.4, 128.8, 129.3, 140.6
27.6, 35.8, 54.7
2a
2b
2c
2d
15.0, 59.6, 161.8
15.0, 59.8, 167.1
15.0, 59.7, 161.8
15.5, 59.7, 162.1
33.1
33.1
33.1
33.1
34.1, 127.1, 128.5, 129.1, 136.1
34.1, 127.2, 128.6, 129.1, 136.6
34.0, 127.2, 128.6, 129.1, 136.6
34.0, 127.2, 128.5, 129.1, 136.5
102.0
102.7
102.3
101.7
149.6
149.2
149.6
149.4
157.0
153.8
156.6
153.2
Table 5. 13C-NMR Shift Values for Alkylureas 3a—g (CDCl3)
Compound
EtOCO
N–Me
33.5
33.4
33.4
33.4
33.4
33.4
33.4
CH2Ph
C-5
C-4
C-2
R3
R1NHCO
3a
3b
3c
3d
3e
3f
14.6, 61.1, 160.3
14.6, 61.2, 160.3
14.7, 61.2, 160.3
14.6, 61.2, 160.2
14.6, 61.2, 160.1
14.5, 61.3, 160.7
14.6, 61.2, 169.3
34.1, 127.5, 128.6,
129.4, 136.0
34.2, 127.5, 128.6,
129.4, 136.1
34.1, 127.5, 128.6,
129.3, 136.1
34.2, 127.5, 128.6,
129.4, 135.9
34.1, 127.5, 128.6,
129.3, 136.0
34.1, 127.5, 128.6,
129.3, 135.9
34.1, 127.5, 128.9,
129.3, 135.9
117.4
117.4
117.0
117.3
117.6
117.4
117.3
145.7
145.5
145.8
145.3
144.6
145.1
145.3
149.7
149.6
149.6
149.7
149.6
149.7
149.6
11.8, 22.4, 51.1
11.8, 22.6, 51.1
11.8, 22.5, 51.1
11.8, 22.4, 51.3
11.8, 23.7, 42.8, 157.1
23.7, 23.9, 42.7, 155.0
25.3, 25.4, 26.1, 34.2,
34.4, 51.1, 156.4
45.1, 127.4, 127.9, 128.8,
140.1, 157.1
45.2, 108.7, 110.6,
142.2, 152.5
45.2, 108.8, 110.6,
142.3, 152.3
52.6, 127.3, 128.4,
128.5, 138.8
11.7, 23.7, 42.9, 156.8
45.2, 127.4, 128.0, 128.8,
139.8, 157.3
11.8, 23.7, 43.0, 157.2
3g

1382
Vol. 50, No. 10
Table 6. 13C-NMR Shift Values for 1,3-Disubstituted Xanthines 4a—l (CDCl3)a)
Compound
N–Me
32.3
33.2
33.4
32.4
32.4
32.4
32.3
32.4
32.4
32.4
32.4
32.4
CH2Ph
C-5
C-4
C-8
C-2
C-6
R3
R1
11.8, 21.7, 43.2
4a
4b
4c
4d
4e
4f
33.8, 127.6, 128.6,
129.4, 135.5
33.9, 129.2, 129.7,
129.8, 137.5
33.9, 127.8, 129.3,
129.8, 137.6
33.9, 127.6, 128.6,
129.4, 135.5
33.9, 127.6, 128.7,
129.3, 135.5
33.9, 127.7, 128.7,
129.3, 135.4
33.8, 127.6, 128.7,
129.3, 135.6
33.9, 127.7, 128.7,
129.4, 135.4
33.9, 127.7, 128.7,
129.4, 135.4
33.9, 127.7, 128.7,
129.4, 135.5
33.9, 127.7, 128.7,
129.4, 135.4
33.9, 127.7, 128.8,
129.4, 135.5
108.2
108.9
108.2
108.3
108.3
108.3
108.6
108.3
107.8
108.5
108.4
108.7
148.1
148.4
148.7
148.3
147.7
147.8
148.2
150.1
148.9
148.4
148.4
148.6
151.5
148.7
148.9
151.7
151.3
151.5
151.6
151.8
151.7
151.4
151.3
151.6
152.4
159.2
158.2
152.7
152.5
152.8
152.5
153.1
153.2
153.1
153.3
153.0
155.7
159.8
159.2
155.6
155.6
155.5
155.6
155.7
155.7
155.6
155.6
155.4
11.6, 21.8, 45.2
11.8, 22.9, 49.8
11.7, 22.4, 49.8
11.6, 21.8, 45.4
23.3, 23.6, 43.64
25.8, 26.7, 27.1,
34.2, 34.3
44.7, 127.8, 128.8,
129.2, 138.0
39.7, 109.7, 110.8,
142.7, 150.3
39.8, 109.7, 110.8,
142.7, 150.1
46.8, 128.1, 128.8,
129.3, 137.1
11.6, 21.8, 45.5
11.7, 21.7, 13.3
44.8, 127.8, 128.7,
129.4, 137.8
11.7, 21.7, 43.3
4g
4h
4i
128.9, 129.1, 129.7,
136.0
116.7 (d, Jϭ22 Hz),
130.9 (d, Jϭ9 Hz)
128.9, 129.2, 129.7,
135.8
116.7 (d, Jϭ23 Hz),
130.9 (d, Jϭ8 Hz)
129.0, 129.1, 129.8,
135.9
11.6, 21.8, 45.6
4j
39.9, 110.2, 110.9,
142.7, 150.0
39.9, 110.2, 110.9,
142.8, 149.9
47.7, 128.2, 128.8,
129.2, 137.0
4k
4l
a) 13C-NMR data for compounds 4b and 4c were obtained using CD3OD as solvent.
was from Merck. Reagents and solvents were of commercial grade (Aldrich
Chemical Co.).
Acknowledgments The authors thank the Spanish Government CICYT
(SAF98-0148-C04-04 and 1FD97-2371-C03-02) for financial support of this
General Procedure for the Preparation of Amines 2a—d The appro- work. A.R.H. also thanks the Spanish Ministry of Education and Culture
priate aldehyde (2 mmol) was added to a solution of imidazole 1 (1 mmol) (DGESIC) for a research contract.
and AcOH (0.15 ml, 2 mmol) in dry MeOH (10 ml), and this mixture was
stirred for 1 h at room temperature. NaCNBH3 was added and stirring was References
continued for a further 24 h. After evaporation of the solvent in vacuo, the
residue was purified by flash column chromatography (10—40% EtOAc in
hexane), affording the desired amine 2.
General Procedure for the Preparation of Alkylureas 3a—g A mix-
ture of the corresponding amine 2 (1 mmol), Et3N (0.14 ml, 1 mmol) and the
appropriate isocyanate (1 mmol) in dry toluene (10 ml) was heated under re-
flux for 18 h. More isocyanate (1 mmol) was then added, and heating was
continued for a further 48 h. After evaporation of the solvent in vacuo, the
residue was purified by flash column chromatography (30—60% EtOAc in
hexane), affording the desired alkylurea 3.
General Procedure for the Preparation of 3-Substituted 1-Alkylxan-
thines 4a—g 1N KOH (2 ml) was added to a solution of the corresponding
alkylurea 3 (1 mmol) in EtOH (5 ml), and the mixture was heated under re-
flux for 2 h and then neutralized with 0.5N HCl. The solvent was evaporated
in vacuo, and the residue was purified by flash column chromatography (0—
10% hexane in EtOAc), yielding the desired xanthine 4a—g.
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General Procedure for the Preparation of 3-Substituted 1-Arylxan- 10) Kim Y. C., Ji X., Melman N., Linden J., Jacobson K. A., J. Med.
thines 4h—l A mixture of the corresponding amine 2 (1 mmol) and the Chem., 43, 1165—1172 (2000).
appropriate aryl isocyanate (1 mmol) in dry toluene (10 ml) was heated 11) Müller C. E., Shi D., Manning M., Jr., Daly J. W., J. Med. Chem., 36,
under reflux for 72 h. After evaporation of the solvent in vacuo, the residue 3341—3349 (1993).
was purified by flash column chromatography (10% EtOAc in hexane), af- 12) Müller C. E., Sandoval-Ramirez J., Synthesis, 1295—1299 (1995).
fording an arylurea 3 mixed with traces of an N,NЈ-diarylurea. This mixture 13) Cook A. H., Thomas G. H., J. Chem. Soc., 1950, 1884—1888 (1950).
was dissolved in EtOH (5 ml), and after addition of 1N KOH (2 ml) was
heated under reflux for 2 h and neutralized with 0.5N HCl. The solvent was
14) Bader H., Downer J. D., Driver P., J. Chem. Soc., 1950, 2775—2784
(1950).
evaporated in vacuo, and the residue was purified by flash column chro- 15) Edenhofer A., Helv. Chim. Acta, 58, 2192—2209 (1975).
matography (10—30% EtOAc in hexane), giving the desired xanthine 4h—l. 16) Bridson P. K., Wang X., Synthesis, 1995, 855—858 (1995).