Purines. part XVI

Article abstract of DOI:10.1002/hlca.201000254

A series of N-substituted 8-aminoxanthines (=8-amino-3,7(or 3,9)-dihydro-1H-purine-2,6-diones) 8-16 and 34-37 were synthesized from the corresponding 8-nitroxanthines 1-7, 30-33, and 8-(phenylazo)xanthines 17 and 18 by catalytic reduction. Another approac

Full text of DOI:10.1002/hlca.201000254

Helvetica Chimica Acta – Vol. 93 (2010)
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Purines
Part XVI1)
Syntheses, Properties, and Reactions of 8-Aminoxanthines
by Mosselhi A. Mosselhi and Wolfgang Pfleiderer*
Fachbereich Chemie, Universitꢀt Konstanz, Postfach 5560, D-78457 Konstanz
(phone: þ 49-7531-882279; fax: þ 49-7531-883138; e-mail: Wolfgang.Pfleiderer@uni-konstanz.de)
A series of N-substituted 8-aminoxanthines (¼ 8-amino-3,7(or 3,9)-dihydro-1H-purine-2,6-diones)
8 – 16 and 34 – 37 were synthesized from the corresponding 8-nitroxanthines 1 – 7, 30 – 33, and 8-
(phenylazo)xanthines 17 and 18 by catalytic reduction. Another approach was derived from 6-amino-5-
(cyanoamino)uracils (¼ N-(6-amino-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)cyanamides) 23, 24, and
27 by base-catalyzed cyclization yielding 25 – 28. All 8-aminoxanthines 8 – 29 and 34 – 37 were acetylated
to the corresponding 8-(acetylamino)xanthines 40 – 57, and prolonged heating led to 8-(diacetylami-
no)xanthines 58 and 59. Several 8-aminoxanthines 8 – 13 were diazotized forming 8-diazoxanthines 60 –
64. Coupling reactions of isolated 62 and 64 and intermediary formed 8-diazoxanthines with 1,3-
dimethylbarbituric acid (¼1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione; 66) resulted in 5-[(xanthin-
8-yl)diazenyl]-1,3-dimethylbarbituric acids ¼ 3,7(or 3,9)-dihydro-8-[2-(1,2,3,4-tetrahydro-1,3-dimethyl-
2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-diones) 67 – 80. The newly synthesized xanthine deriv-
atives were characterized by the determination of their pKa values, the UV- and NMR spectra, as well as
elemental analyses.
Introduction. – Ever since the structural elucidation of the purine-ring system by
Emil Fischer in 1898 [2], this heterocycle [3] has attracted much attention due to its
wide distribution in nature in form of alkaloids, intermediates or end products of
metabolism, and nucleosides and nucleic acid components. Numerous purine
derivatives have been synthesized by the Traube synthesis [4] starting from
pyrimidine-5,6-diamines and fusing the imidazole moiety or by attachment of the
pyrimidine ring onto properly substituted imidazole derivatives [5]. In continuation of
our efforts in the purine field, we concentrated our interest, after the 8-nitroxanthines
[6], now on the little investigated 8-amino-N-methylxanthine derivatives. A few
derivatives of this type have been described in the literature [7 – 16], but no systematic
investigations of their properties and reactivities has been reported.
Synthesis. – The most straightforward syntheses of 8-aminoxanthines is the
catalytic reduction of the corresponding 8-nitroxanthines of type 12) [6]. Thus, we
obtained from 1 and its 1-methyl- (2), 3-methyl- (3), 3-benzyl- (4), 1,3-dimethyl- (5), 3-
benzyl-1-methyl- (6), and 1,3,7-trimethyl derivative 7 with Pd/C catalyst and H2 in a
1
)
)
Part XV: [1].
2
The xanthine structure has the same atom numbering as 1H-purine.
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Helvetica Chimica Acta – Vol. 93 (2010)
shaking apparatus in good yields the 8-aminoxanthines 8 – 14 (Scheme 1). Amino-
xanthine 8 was prepared earlier by Na2S2O4 reduction of 8-[(2,4-dichlorophenyl)azo]-
[10][12] and 8-[(4-chlorophenyl)azo]xanthine [15], and 8-aminotheophylline (12) was
synthesized from 8-chlorotheophylline with ethanolic ammonia [11] or by treatment of
Scheme 1

Helvetica Chimica Acta – Vol. 93 (2010)
2117
8-(benzylamino)theophylline in concentrated H2SO4 solution at room temperature
[16]. Aminoxanthine 14 was also obtained already in 1882 from 8-bromocaffeine in a
sealed tube at 1308 with saturated alcoholic ammonia [7]. The 8-amino-7-methylxan-
thine (15) [17] and 8-aminotheobromine (16) [18] resulted from catalytic reductions of
the corresponding 8-(phenylazo) derivatives 17 and 18, and 8-amino-1,7-dimethylxan-
thine (19) was obtained by three different routes: i) catalytic reduction of 8-azido-1,7-
dimethylxanthine (20), ii) treatment of 8-bromo-1,7-dimethylxanthine (21) with
methanolic ammonia in an autoclav at 1608, and iii) by reaction of 8-(benzylamino)-
1,7-dimethylxanthine (22) with concentrated H2SO4 solution at 508 giving the best
yield, i.e., 82%. Another approach to 8-aminoxanthines was achieved by base-catalyzed
cyclization of 6-amino-1-benzyl-5-[cyanomethylamino]uracil (¼6-amino-1-benzyl-5-
[cyano(methyl)amino]pyrimidine-2,4-(1H,3H)-dione ¼ N-(6-amino-1-benzyl-1,2,3,4-
tetrahydro-2,4-dioxopyrimidin-5-yl)-N-methylcyanamide; 23) and its 3-methyl deriv-
ative 24 on treatment with 1n NaOH at 808 to give 8-amino-3-benzyl-7-methyl- (25) and
8-amino-3-benzyl-1,7-dimethylxanthine (26). Aminoxanthine 26 could also be ob-
tained by methylation of 25 in DMF/K2CO3 with MeI. Analogously reacted 6-amino-1-
benzyl-5-[cyano(propyl)amino]uracil (27) and its 3-methyl derivative to 28 and 29.
Since the 8-nitro-9-methylxanthines 30 – 33 are easily available by nitration [6], the
corresponding 8-amino-9-methylxanthines 34 – 37 were prepared again by catalytic
reductions. Furthermore, 5-amino-1-methyl- (38) and 5-amino-1,3-dimethyl-6-(meth-
ylamino)uracil (39) yielded on treatment with bromocyan at pH 4.5 and room
temperature directly 36 and 37. All synthesized 8-aminoxanthines were converted into
the corresponding 8-(acetylamino) derivatives 40 – 57 by heating in Ac2O for a time
depending on the solubility of the starting material. Prolonged heating of 8-
aminocaffeine (14) and 8-amino-1,9-dimethylxanthine (35) yielded the 8-(diacetyl-
amino) derivatives 58 and 59, of which 58 is described in [19][20] but has never been
fully characterized.
Various 8-aminoxanthines have been applied to diazotization reactions which were
tried for the first time by Gomberg in 1900 [21] starting with 8-aminocaffeine (14) but
without success of isolation of the reaction product. More successful was H. Fischer [10]
in 1909 with 8-aminoxanthine (8) and Robins [15] in 1960 with 8-aminotheophylline
(12) isolating 8-diazoxanthine (60) and 8-diazotheophylline (64), respectively, as
yellowish solids. Analogously reacted 8 – 13 at low temperature to the corresponding 8-
diazoxanthines 60 – 65 in high yields (Scheme 2). According to the instability of the
diazofunction on heating, recrystallization of the reaction products was not possible,
but their characterization could be achieved by their UV and NMR spectra.
Coupling reactions of the 8-diazoxanthines 62 and 64 with 1,3-dimethylbarbituric
acid (¼1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione; 66) led to the corresponding
azo dyes 67 and 68 which exist most likely according to their NMR spectra in the (E)-
form stabilized by an intramolecular H-bond but also other tautomeric forms cannot be
excluded a priori. The 8-amino-7- and 8-amino-9-methylxanthines did not allow to
isolate the corresponding diazonium salts indicating that the imidazole moiety is
responsible for the stabilization of the zwitterion structures. To show that diazotizations
of 14 – 16, 19, 25, 26, 28, 29, and 34 – 37 took place in solution, the corresponding
diazonium salts were also coupled with 1,3-dimethylbarbituric acid (66) to give, in
analogy to 67 and 68, the azo dyes 69 – 80. The 8-diazoxanthines are stable in acidic

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2
solution but, in alkaline media, decomposition to unidentified products was observed.
Interestingly, diazotheophylline (64) reacted in MeOH within 2 days to give 8-
methoxy-1,3-dimethylxanthine [22] as shown in the Figure.
The UV spectra of 8-diazoxanthine (60) and 8-diazotheophylline (64) measured at
pH 11 by Jones and Robins [15] have to be revised (cf. Table 3) since the authors have
not realized the base lability of diazoxanthines leading to degradation.
Structures and Physical Properties. – The structures of the newly synthesized
xanthine derivatives were characterized by UV spectra based on the pKa values
(Tables 1 – 4), by NMR spectra, and C,H,N analyses. Aminoxanthine 8 shows in the
normal pH range one basic pKa value at 2.00 and two acidic pKa values at 8.48 and 12.01
describing the equilibria between cation (þ) and neutral form (0), neutral form and
monoanion ( – ) as well as monoanion and dianion (– –). The cations of all 8-
aminoxanthines show very similar UV spectra indicating that protonation takes place
in 7- or 9-position of the imidazole ring. The basic properties differ to some extent
depending on the position of the various substituents. The 9-methyl derivatives are
stronger bases than the 3-methyl- and 3-benzyl analogs which hinder partially the

Helvetica Chimica Acta – Vol. 93 (2010)
2119
Figure. Kinetics of 8-diazotheophylline (64) in MeOH in the dark
adjacent protonation site (see, e.g., 34 vs. 10 and 11). The first deprotonation step takes
place in the pyrimidine moiety at HꢀN(3) whereby a substituent at N(9) acidifies this
H-atom again for steric reasons. The second ionization in 8-aminoxanthine (8) takes
place at the NH of the imidazole ring as seen from the similarity of the second pKa
values of 9 – 11. If the imidazole moiety is substituted, a second acidic pKa value could
not been determined in the normal pH range. The ionization sequence in the
unsubstituted 8 can also be derived from the NMR spectra comparing the chemical
shifts of the HꢀN sites with those of the various N-methyl derivatives.

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Table 1. Physical Properties of 8-Aminoxanthines
Substitution
–
pKa
UV-Absorption spectraa)
pH
Molecular
form
lmax
log e
8
9
2.00
8.48
12.01
231, 278
4.05, 4.01
1.0
þ
0
–
– –
þ
0
[236], 287
218, [247], 293
[249], 294
233, 277
[3.66], 4.21
4.36, [3.75], 4.05
[3.75], 4.02
4.02, 4.07
6.0
11.0
2n NaOH
1.0
1-methyl
3-methyl
3-benzyl
2.12
8.88
12.44
[238], 287
216, [246], 291
[250], 293
235, 281
[3.60], 4.23
4.40, [3.75], 4.09
[3.72], 4.04
4.08, 4.09
7.0
11.0
14.0
ꢀ 1.0
7.0
11.0
2n KOH
ꢀ 1.0
5.0
11.0
14.3
ꢀ 1.0
6.0
12.0
ꢀ 1.0
6.0
–
– –
þ
0
10
11
1.29
9.77
12.72
[240], 289
214, [249], 292
[247], 290
234, 281
[3.66], 4.23
4.21, [3.71], 4.14
[3.70], 4.18
4.02, 4.07
–
– –
þ
0
1.10
9.42
12.66
[244], 290
208, [250], 292
228, 290
[3.55], 4.22
4.32, [3.64], 4.13
3.73, 4.13
–
– –
þ
0
15
34
12
13
19
16
25
28
35
36
26
7-methyl
1.58
8.97
232, 277
4.06, 4.05
[240], 289
218, [246], 292
233, 278
[3.63], 4.21
4.49, [3.64], 4.10
3.99, 4.03
–
9-methyl
2.31
6.59
þ
241, 288
4.00, 3.99
0
218, [246], 290
235, 282
4.33, 4.03, 3.95
3.96, 4.08
9.0
–
1,3-dimethyl
1.68
10.20
ꢀ 1.0
þ
[241], 289
212, [255], 292
234, 280
[3.56], 4.22
4.20, [3.67], 4.12
4.07, 4.15
6.0
0
13.0
ꢀ 1.0
6.0
13.0
ꢀ 1.0
6.0
12.0
ꢀ 1.0
6.0
13.0
ꢀ 1.0
6.0
13.0
ꢀ 1.0
6.0
13.0
ꢀ 1.0
6.0
–
3-benzyl-1-methyl
1,7-dimethyl
1.34
9.90
þ
[244], 290
212, [252], 294
233, 277
[3.52], 4.24
4.31, [3.66], 4.15
4.00, 4.02
0
–
1.85
9.10
þ
[240], 286
218, [250], 291
235, 281
[3.60], 4.18
4.47, [3.55], 4.07
4.04, 4.03
0
–
3,7-dimethyl
1.33
11.02
þ
[240], 286
214, [233], 285
235, 281
[3.70], 4.15
4.17, [3.82], 4.18
4.05, 4.09
0
–
3-benzyl-7-methyl
3-benzyl-7-propyl
1,9-dimethyl
0.99
10.80
þ
[244], 290
210, [234], 286
235, 282
[3.62], 4.23
4.52, [3.92], 4.21
4.04, 4.09
0
–
0.88
10.90
þ
[246], 290
210, [234], 287
234, 278
[3.59], 4.23
4.51, [3.94], 4.21
4.00, 4.09
0
–
3.26
6.74
þ
242, 287
4.02, 4.05
0
207, 248, 290
236, 283
4.41, 4.05, 3.99
4.03, 4.02
9.0
–
3,9-dimethyl
3.66
10.77
ꢀ 1.0
þ
242, 290
4.01, 3.95
6.0
0
213, 243, 284
236, 280
4.30, 3.94, 3.96
4.01, 4.07
9.0
–
3-benzyl-1,7-dimethyl
1.12
ꢀ 1.0
þ
[244], 289
[3.56], 4.21
6.0
0

Helvetica Chimica Acta – Vol. 93 (2010)
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Table 1 (cont.)
Substitution
pKa
UV-Absorption spectraa)
pH
Molecular
form
lmax
log e
29
14
37
3-benzyl-1-methyl-7-propyl
1.06
1.52
3.69
236, 281
[244], 290
236, 280
214, [245], 288
237, 283
244, 289
4.00, 4.07
[3.50], 4.20
3.97, 4.00
4.26, [3.54], 4.15
3.95, 3.97
3.92, 3.89
ꢀ 1.0
6.0
þ
0
1,3,7-trimethyl
1,3,9-trimethyl
ꢀ 1.0
þ
6.0
0
1.0
6.0
þ
0
a) Values within brackets are those of shoulders.
Similar conclusions can been drawn from the pKa values and UV spectra of the 8-
(acetylamino)xanthines 40 – 57 (Table 2). These xanthine derivatives are expectedly
weaker bases than their precursors due to the acetylation of the amino groups.
The 8-diazoxanthines show a similar pattern identifying 60 and 61 as stronger acids
as 62 indicating that the most acidic position is located at HꢀN(3). Anion formation at
this site is associated with a strong bathochromic shift of the long-wavelength
absorption band, whereas HꢀN(1) deprotonation in 62 causes a little red shift.
From a comparison of the pKa values and UV spectra of the 5-[(xanthin-8-
yl)diazenyl]-1,3-dimethylbarbituric acids 67 – 80 can be concluded that protonation in
the cations takes place again at the imidazole moiety due to the very similar shape of
the cation spectra (Table 4). The neutral molecular species are also very similar and
exist most likely in the intramolecularly H-bonded (E)-form which show a character-
istic signal in the NMR spectra at low field, at d(H) 14.00 – 14.20. The first acidic pKa in
all derivatives is due to deprotonation at the barbituric acid moiety leading to a
monoanion with an elongated chromophore associated with a red-shift of the long-
wavelength absorption band.
Experimental Part
General. Products were dried under high vacuum. The pKa values were determined by the
spectrophotometric method [23]. M.p.: Bꢀchi-B-545 melting-point apparatus; uncorrected. TLC:
precoated silica gel thin-layer sheets 60 F254 (SiO2; Merck) and cellulose sheets F 1440 LS 254 (Schleicher
& Schꢀll). Column chromatography (CC): SiO2 60 (Merck). Flash chromatography (FC): SiO2 (30 –
1
60 mm; Baker). UV/VIS: Perkin-Elmer Lambda 5; lmax (log e) in nm, sh ¼ shoulder. H-NMR: Bruker
AC 250; d in ppm rel. to Me4Si or CDCl3 ((D6)DMSO) as internal standard. Elemental analyses were
performed by the Analytical Laboratory of the Department of Chemistry, Konstanz University.
1. 8-Aminoxanthine (¼ 8-Amino-3,7-dihydro-1H-purine-2,6-dione; 8) [7][10][15]. A suspension of
8-nitroxanthine (1) [6] (0.6 g, 3.05 mmol) in H2O (100 ml) was dissolved by addition of conc. NH3 soln.
(4 ml). Then 10% Pd/C (50 mg) was added and reduction performed in a shaking apparatus under H2.
When H2 uptake stopped, the catalyst was filtered off and the filtrate acidified with AcOH (10 ml). The
formed precipitate was washed with H2O and dried to give 0.407 g (80%). Recrystallization from H2O
1
(900 ml) with charcoal gave 0.31 g (61%) of 8. Colorless solid. M.p. > 3008. H-NMR ((D6)DMSO):
10.30 (s, HꢀN(7)); 10.20 (br. s, HꢀN(1), HꢀN(3)); 6.30 (s, NH2). Anal. calc. for C5H5N5O2 · 0.5 H2O
(176.1): C 34.09, H 3.43, N 39.77; found: C 33.99, H 3.40, N 39.20.
2. 8-Amino-1-methylxanthine (¼ 8-Amino-3,7-dihydro-1-methyl-1H-purine-2,6-dione; 9). To a soln.
of 1-methyl-8-nitroxanthine (2) [6] (1.0 g, 4.74 mmol) in DMF (150 ml) was added 10% Pd/C (60 mg),

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Helvetica Chimica Acta – Vol. 93 (2010)
Table 2. Physical Properties of 8-(Acetylamino)xanthines
Substitution
–
pKa
UV-Absorption spectraa)
pH
Molecular
form
lmax
ꢀ 0.60 247, 278
log e
40
4.00, 4.22
ꢀ 3.0
4.0
9.0
13.0
ꢀ 3.0
4.0
þ
0
–
– –
þ
0
7.50 214, [241], 286 4.36, [3.79], 4.22
10.92 219, [257], 290 4.17, [3.90], 4.12
222, [248], 296 4.28, [4.03], 4.07
41 1-methyl
42 3-methyl
ꢀ 0.51 250, 278
3.94, 4.22
7.96 214, [240], 287 4.39, [3.71], 4.22
11.12 218, [232], 291 4.19, [4.11], 4.11
224, [240], 298 4.23, [4.19], 4.06
9.0
–
13.0
ꢀ 4.0
4.0
10.0
13.0
13.0
ꢀ 3.0
4.0
10.0
13.0
13.0
ꢀ 4.0
4.0
11.0
11.0
ꢀ 4.0
4.0
– –
þ
0
ꢀ 1.31 248, 281
4.03, 4.14
8.03 219, [244], 289 4.37, [3.76], 4.18
11.91 217, [252], 286 4.24, [3.79], 4.15
218, [236], 287 4.27, [3.92], 4.14
–
– –
– –
þ
0
43 3-benzyl
47 7-methyl
217, [235], 286 4.41, [4.00], 4.17
ꢀ 0.39 245, 277
8.32 210, 277
11.35 215, 290
218, 295
3.90, 4.23
4.30, 4.10
4.35, 3.98
4.33, 4.07
–
– –
– –
þ
0
–
–
54 9-methyl
44 1,3-dimethyl
216, 252, 286
4.27, 4.16, 4.16
4.06, 4.02, 4.18
ꢀ 1.07 218, 256, 282
8.16 219, [246], 289 4.42, [3.69], 4.22
217, [254], 286 4.27, [3.79], 4.16
217, [252], 286 4.29, [3.80], 4.14
45 3-benzyl-1-methyl
49 1,7-dimethyl
ꢀ 0.14 [244], 278
8.44 210, 277
216, 294
[3.86], 4.26
4.39, 4.14
4.41, 4.35
[3.93], 4.17
4.32, 4.10
þ
0
11.0
ꢀ 4.0
4.0
–
48 3,7-dimethyl
ꢀ 1.09 [250], 279
þ
9.39 212, 280
0
213, [235], 288 4.31, [4.01], 4.18
217, [236], 288 4.46, [3.97], 4.25
216, [237], 288 4.60, [4.00], 4.32
12.0
12.0
12.0
ꢀ 1.0
3.0
–
–
–
50 3-benzyl-7-methyl
52 3-benzyl-7-propyl
55 1,9-dimethyl
0.86 250, 278
3.98, 4.19
4.00, 4.09
4.05, 4.04
4.03, 4.06
4.00, 4.00
3.89, 4.07
4.40, 4.14
4.28, 4.22
4.39, 4.14
4.33, 4.29
[3.92], 4.22
4.40, 4.10
4.06, 4.14
4.05, 4.03
þ
5.59 243, 266
254, 279
0
8.0
–
56 3,9-dimethyl
0.10 255, 280
10.57 244, 269
ꢀ 1.0
þ
3.0
0
218, 251, 282
13.0
MeOH
13.0
MeOH
13.0
ꢀ 4.0
MeOH
ꢀ 2.0
MeOH
–
0
–
0
51 3-benzyl-1,7-dimethyl
53 3-benzyl-1-methyl-7-propyl
46 1,3,7-trimethyl
210, 279
223, 290
209, 278
223, 290
–
ꢀ 1.03 [248], 280
þ
214, 279
0
57 1,3,9-trimethyl
0.30 256, 280
245, 267
þ
0
a) Values within brackets are those of shoulders.

Helvetica Chimica Acta – Vol. 93 (2010)
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Table 3. Physical Properties of 8-Diazoxanthines
Substitution
pKa
UV-Absorption spectra
pH
Molecular
form
lmax
log e
60
61
62
–
7.68
7.72
9.37
234, 276, 366
222, 250, 290, 411
236, 282, 367
228, 253, 298, 415
237, 279, 371
212, 239, 274, 384
238, 280, 370
4.03, 3.52, 4.37
3.92, 4.07, 3.69, 4.08
3.87, 3.54, 4.25
3.81, 3.99, 3.64, 4.00
4.10, 3.59, 4.35
4.11, 3.81, 3.78, 4.19
4.14, 3.63, 4.31
5.0
10.0
5.0
10.0
5.0
12.0
5.0
0
–
0
–
0
–
0
0
0
1-methyl
3-methyl
63
64
65
3-benzyl
1,3-dimethyl
3-benzyl-1-methyl
239, 284, 372
239, 286, 372
4.03, 3.66, 4.31
4.08, 3.70, 4.29
7.0
7.0
for reduction under H2 in a shaking apparatus. After uptake of the theoretical amount of H2 (320 ml), the
catalyst was filtered off and the filtrate evaporated. The residue was washed with H2O and then
recrystallized from H2O: 0.592 g (69%) of 9. Colorless solid. M.p. > 3008. 1H-NMR ((D6)DMSO): 10.60
(s, HꢀN(7)); 10.20 (s, HꢀN(3)); 6.30 (s, NH2); 3.20 (s, MeꢀN(1)). Anal. calc. for C6H7N5O2 · 0.25 H2O
(185.2): C 38.81, H 3.94, N 37.72; found: C 39.05, H 3.83, N 37.77.
3. 8-Amino-3-methylxanthine (¼ 8-Amino-3,7-dihydro-3-methyl-1H-purine-2,6-dione; 10). As de-
scribed for 9, with 3-methyl-8-nitroxanthine (3) [6] (1.0 g, 4.74 mmol), DMF (100 ml), and 10% Pd/C
(60 mg): 0.496 g (58%) of 10. Colorless solid. M.p. > 3008. 1H-NMR ((D6)DMSO): 11.50 (s, HꢀN(7));
10.80 (s, HꢀN(1)); 6.45 (s, NH2); 3.40 (s, MeꢀN(1)). Anal. calc. for C6H7N5O2 (181.2): C 39.78, H 3.90, N
38.66; found: C 39.38, H 4.08, N 38.41.
4. 8-Amino-3-benzylxanthine (¼ 8-Amino-3-benzyl-3,7-dihydro-1H-purine-2,6-dione; 11). To a soln.
of 3-benzyl-8-nitroxanthine (4) [6] (1.5 g, 5.23 mmol) in H2O (300 ml) and conc. NH3 soln. (5 ml), 10%
Pd/C was added and reduction achieved under H2 in a shaking apparatus. When reduction stopped, the
catalyst was filtered off, and the filtrate evaporated. The residue was treated with H2O and filtered, and
the solid recrystallized from dil. AcOH with charcoal: 0.806 g (60%) of 11. Colorless crystals. M.p. 350 –
3528. 1H-NMR ((D6)DMSO): 11.29 (s, HꢀN(7)); 10.60 (s, HꢀN(1)); 7.35 – 7.25 (m, 5 arom. H); 6.45 (s,
NH2); 5.04 (s, CH2). Anal. calc. for C12H11N5O2 (257.3): C 56.02, H 4.31, N 27.23; found: C 55.70, H 4.63, N
26.82.
5. 8-Amino-1,3-dimethylxanthine (¼ 8-Amino-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 12)
[15][16]. i) As described for 11, with 8-nitrotheophylline (5) [6] (1.2 g, 5.33 mmol), Pd/C (80 mg),
H2O (200 ml) and conc. NH3 soln. (2 ml): 0.541 g (52%) of 12. Colorless powder. M.p. > 3108.
ii) A suspension of 5 (0.8 g, 3.56 mmol) in H2O (15 ml) was treated at 908 under stirring with
Na2S2O4 (2.0 g) by gradual addition. After 1 h, the soln. was cooled overnight, and the solid recrystallized
from dil. AcOH: 0.263 g (38%) of 12. Colorless crystals. M.p. > 3108. 1H-NMR ((D6)DMSO): 11.65 (s,
HꢀN(7)); 6.45 (s, NH2); 3.40 (s, MeꢀN(3)); 3.20 (s, MeꢀN(1)). Anal. calc. for C7H9N5O2 (195.2): C
43.02, H 4.64, N 35.88; found: C 43.06, H 4.46, N 35.49.
6. 8-Amino-3-benzyl-1-methylxanthine (¼ 8-Amino-3-benzyl-3,7-dihydro-1-methyl-1H-purine-2,6-
dione; 13). A soln. of 3-benzyl-1-methyl-8-nitroxanthine (6) [6] (0.5 g, 1.66 mmol) in H2O (50 ml) and
10% KOH soln. (2 ml) was treated with Pd/C (50 mg) and H2 in a shaking apparatus. After uptake of
110 ml of H2, the mixture was filtered and the filtrate neutralized by AcOH and partially concentrated.
The resulting precipitate was purified by dissolving in H2O (50 ml) and dil. H2SO4 soln., heating,
treatment with charcoal, and neutralization by NH3: 0.297 g (66%) of 13. Colorless crystals. M.p. 365 –
1
3688. H-NMR ((D6)DMSO): 9.80 (s, HꢀN(7)); 10.60 (s, HꢀN(1)); 7.35 – 7.25 (m, 5 arom. H); 6.49 (s,
NH2); 5.07 (s, CH2); 3.18 (s, MeꢀN(1)). Anal. calc. for C13H13N5O2 (271.3): C 57.56, H 4.80, N 25.83;
found: C 57.53, H 4.92, N 25.56.
7. 8-Amino-1,3,7-trimethylxanthine (¼ 8-Amino-3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione; 14)
[20]. A soln. of 8-nitrocaffeine (7) [6] (1.5 g, 6.28 mmol) in H2O/MeOH 1:1 (200 ml) was treated with

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Helvetica Chimica Acta – Vol. 93 (2010)
Table 4. Physical Properties of 5-[(Xanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acids
Substitution
pKa
UV-Absorption spectra
lmax
pH
Molecular
form
log e
67 3-methyl
ꢀ 1.95
230, 267, 386
5.26 224, 272, 411
4.02, 4.22, 4.28
4.06, 4.21, 4.27
ꢀ 4.0
0.0
þ
0
9.06 215, 235, 276, 408, 445 4.17, 4.12, 4.02, 4.29, 4.37
7.0
–
205, 240, 281, 394, 437
230, 266, 388
5.13 230, 272, 414
4.31, 4.04, 3.94, 4.37, 4.35
3.98, 4.19, 4.26
4.24, 4.02, 4.28
11.0
ꢀ 4.0
1.0
– –
þ
0
68 1,3-dimethyl
ꢀ 1.55
9.48 216, 240, 274, 416, 446 4.16, 4.10, 3.97, 4.30, 4.36
7.0
–
240, 282, 394, 436
211, 225, 290, 413
4.02, 3.92, 4.38, 4.33
4.14, 4.33, 4.02, 4.38
4.06, 4.24, 4.23
4.12, 4.13, 4.25
4.23, 4.07, 4.24, 4.31
3.98, 4.15, 4.29
13.0 – –
13.0 – –
70 7-methyl
77 9-methyl
ꢀ 0.22 228, 261, 384
4.29 238, 266, 409
233, 283, 428, 450
227, 266, 387
4.72 238, 270, 408
ꢀ 4.0
þ
0.0
0
7.0
–
72 1,7-dimethyl
71 3,7-dimethyl
ꢀ 1.13
ꢀ 3.0
þ
3.99, 4.10, 4.31
2.0
0
9.17 218, 235, 273, 405, 442 4.18, 4.12, 3.85, 4.44, 4.38
7.0
–
223, 248, 281, 418, 452
230, 269, 388
4.13 208, 232, 275, 408
4.34, 4.01, 3.88, 4.33, 4.36
4.01, 4.17, 4.27
4.25, 4.00, 4.13, 4.29
12.0 – –
ꢀ 1.74
ꢀ 4.0
þ
1.0
0
220, 242, 279, 406, 441 4.21, 4.08, 3.86, 4.43, 4.37
218, 253, 274, 410, 453 4.30, 4.04, 3.99, 4.47, 4.38
220, 250, 278, 410, 450 4.37, 4.15, 4.01, 4.48, 4.44
7.0
13.0 – –
13.0 – –
–
73 3-benzyl-7-methyl
75 3-benzyl-7-propyl
78 1,9-dimethyl
ꢀ 0.08 230, 260, 386
4.51 240, 266, 411
237, 282, 426, 461
4.05, 4.25, 4.25
4.14, 4.14, 4.30
4.20, 4.00, 4.25, 4.34
4.03, 4.26, 4.19
4.10, 4.16, 4.22
ꢀ 3.0
þ
2.0
0
7.0
–
79 3,9-dimethyl
ꢀ 0.54 234, 266, 386
ꢀ 4.0
þ
4.66 238, 271, 408
2.0
0
226, 237, 285, 403, 444 4.18, 4.15, 3.93, 4.34, 4.30
9.0
–
233, 249, 414, 455
ꢀ 2.35 230, 268, 390
4.10 242, 274, 410
4.15, 4.09, 3.86, 4.29, 4.38
4.04, 4.19, 4.28
4.00, 4.16, 4.30
13.0 – –
74 3-benzyl-1,7-
ꢀ 4.2
þ
dimethyl
2.0
0
218, 242, 280, 407, 445 4.25, 4.10, 3.88, 4.43, 4.39
7.0
–
76 3-benzyl-1-
ꢀ 2.19 232, 269, 394
4.87 241, 274, 413
248, 280, 407, 446
231, 268, 390
3.92 206, 239, 274, 410
4.02, 4.19, 4.27
4.01, 4.15, 4.30
4.07, 3.88, 4.41, 4.37
3.97, 4.13, 4.24
4.28, 3.97, 4.09, 4.27
ꢀ 4.0
þ
methyl-7-propyl
2.0
0
7.0
–
69 1,3,7-trimethyl
80 1,3,9-trimethyl
ꢀ 1.62
ꢀ 4.0
þ
1.0
0
220, 242, 278, 406, 444 4.15, 4.03, 3.77, 4.39, 4.33
7.0
–
ꢀ 0.36 234, 265, 388
4.03, 4.26, 4.20
4.01, 4.14, 4.23
ꢀ 3.0
þ
4.38 240, 272, 410
2.0
0
228, 236, 284, 404, 444 4.19, 4.16, 3.92, 4.33, 4.30
7.0
–
10% Pd/C (0.1 g) under H2 in a shaking apparatus. After uptake of H2 stopped, the catalyst was filtered
off, and the filtrate concentrated. The residue was purified by recrystallization from EtOH/AcOH:
0.563 g (43%) of 14. Colorless crystals. M.p. > 3008. 1H-NMR ((D6)DMSO): 6.80 (s, NH2); 3.60 (s,
MeꢀN(7)); 3.40 (s, MeꢀN(3)); 3.25 (s, MeꢀN(1)). Anal. calc. for C8H11N5O2 (209.2): C 45.93, H 5.30, N
33.48; found: C 46.01, H 5.42, N 32.90.

Helvetica Chimica Acta – Vol. 93 (2010)
2125
8. 8-Amino-7-methylxanthine (¼ 8-Amino-3,7-dihydro-7-methyl-1H-purine-2,6-dione; 15). A soln. of
7-methyl-8-(phenylazo)xanthine (17; 0.5 g, 4.0 mmol) in H2O (200 ml) and 1n KOH (10 ml) was reduced
by 10% Pd/C (80 mg) under H2 in a shaking apparatus. The catalyst was filtered off, and the filtrate
acidified by AcOH. After evaporation to half of the volume, the formed precipitate was recrystallized
from dil. AcOH with charcoal: 0.521 g (72%) of 15. Colorless powder. M.p. > 3208. 1H-NMR
((D6)DMSO): 10.70 (br. s, HꢀN(3), HꢀN(1)); 6.54 (s, NH2); 3.60 (s, MeꢀN(7)). Anal. calc. for
C6H7N5O2 (181.2): C 39.78, H 3.90, N 38.66; found: C 39.80, H 3.90, N 38.65.
9. 8-Amino-3,7-dimethylxanthine (¼ 8-Amino-3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione; 16)
[18]. As described for 15, with 8-(phenylazo)theobromine (18; 1.4 g, 4.93 mmol) and 10% Pd/C
(75 mg) in H2O (400 ml) and 1n KOH (25 ml). The catalyst was filtered off after uptake of 220 ml of H2.
The filtrate was acidified by AcOH and then concentrated to half of the volume, and the formed
precipitate recrystallized from dil. AcOH (500 ml) with charcoal: 0.442 g (46%) of 16. Colorless crystals.
M.p. > 3008. 1H-NMR ((D6)DMSO): 10.40 (s, HꢀN(1)); 6.80 (s, NH2); 3.55 (s, MeꢀN(7)); 3.25 (s,
MeꢀN(3)). Anal. calc. for C7H9N5O2 (195.2): C 43.08, H 4.64, N 35.88; found: C 42.83, H 4.98, N 36.00.
10. 7-Methyl-8-(phenylazo)xanthine (¼ 3,7-Dihydro-7-methyl-8-(2-phenyldiazenyl)-1H-purine-2,6-
dione; 17). A mixture of 8-(phenylazo)xanthine [24] (2.6 g, 10.2 mmol), K2CO3 (1.41 g, 10.2 mmol), and
MeI (0.8 ml, 12.85 mmol) in DMF (100 ml) and dry acetone (100 ml) was stirred at r.t. for 12 h. After
evaporation to half of the volume and addition of H2O (300 ml) under stirring, the resulting precipitate
was recrystallized from AcOH (200 ml): 1.62 g (59%) of 17. Orange crystals. M.p. 307 – 3098. UV (pH 6):
230 (3.97), 260 (3.77), 310 (3.80), 398 (4.27), 450 (sh, 3.86). 1H-NMR ((D6)DMSO): 12.28 (s, HꢀN(3));
11.50 (s, HꢀN(1)); 8.30 – 7.69 (m, 5 arom. H); 4.41(s, MeꢀN(7)). Anal. calc. for C12H10N6O2 · 0.5 H2O
(279.3): C 51.61, H 3.94, N 30.11; found: C 51.20, H 4.20, N 29.71.
11. 3,7-Dimethyl-8-phenylazoxanthine (¼ 3,7-Dihydro-3,7-dimethyl-8-(2-phenyldiazenyl)-1H-pu-
rine-2,6-dione; 18). As described for 17, with 3-methyl-8-(phenylazo)xanthine (2.70 g, 10 mmol),
K2CO3 (1.38 g, 10 mmol), MeI (1 ml, 16 mmol), DMF (100 ml), and abs. acetone (200 ml). After stirring
for 12 h at r.t., the acetone was evaporated and the remaining soln. diluted with H2O (100 ml). The
precipitate was collected and recrystallized from AcOH (200 ml): 2.13 g (75%) of 18. Orange crystals.
M.p. 3128. UV (pH 7): 232 (4.04), 266 (sh, 3.87), 326 (3.91), 404 (4.26). 1H-NMR (CF3COOD): 8.20 – 7.5
(m, 5 arom. H); 4.55 (s, MeꢀN(7)); 3.80 (s, MeꢀN(3)). Anal. calc. for C13H12N6O2 (284.3): C 54.92, H
4.26, N 29.56; found: C 54.65, H 4.41, N 29.37.
12. 8-Amino-1,7-dimethylxanthine (¼ 8-Amino-3,7-dihydro-1,7-dimethyl-1H-purine-2,6-dione; 19).
i) A soln. of 8-azido-1,7-dimethylxanthine (20; 0.15 g, 0.68 mmol) in EtOH (100 ml) was catalytically
reduced by 10% Pd/C (75 mg) under H2 in a shaking apparatus. After stop of the H2-uptake, the mixture
was heated and filtered and the filtrate concentrated. The residue was recrystallized from 50% AcOH:
60 mg (45%) of 19. Colorless powder. M.p. > 3508.
ii) A mixture of 8-bromo-1,7-dimethylxanthine (21; 0.26 g, 1.0 mmol) in sat. methanolic ammonia
(20 ml) was heated in an autoclav to 1608 for 30 h. After cooling, the mixture was concentrated and the
residue recrystallized from 50% AcOH: 74 mg (38%) of 19.
iii) A soln. of 8-(benzylamino)-1,7-dimethylxanthine (22; 0.56 g, 1.97 mmol) in conc. H2SO4 soln.
(7 ml) was heated in an oilbath to 508 for 20 min. After cooling, the mixture was poured into ice water
(70 ml), and then the pH was adjusted to 6 – 7 with 10% KOH soln. The mixture was stirred overnight,
and the obtained precipitate recrystallized from AcOH/H2O 1:1 (100 ml): 0.314 g (82%) of 19. Colorless
crystals. M.p. > 3508. 1H-NMR ((D6)DMSO): 11.47 (s, HꢀN(3)); 6.68 (s, NH2); 3.52 (s, MeꢀN(7)); 3.12
(s, MeꢀN(1)). Anal. calc. for C7H9N5O2 (195.2): C 43.08, H 4.64, N 35.88; found: C 43.02, H 4.62, N 35.65.
13. 8-Hydrazino-1,7-dimethylxanthine [25]. A mixture of 8-bromo-1,7-dimethylxanthine (21; 1.0 g,
3.86 mmol) and 99% hydrazine hydrate (50 ml) was heated in an oilbath to 1008 with stirring for 30 min.
The precipitate formed was collected after cooling, washed with EtOH, and dried at 808: 0.64 g (79%) of
fine needles. M.p. 293 – 2958 (dec.). UV (pH 13): 216 (4.23), 236 (sh, 3.75), 288 (3.91). 1H-NMR
((D6)DMSO): 11.60 (s, HꢀN(3)); 8.01 (br. s, NHꢀC(8)); 4.30 (br. s, NH2); 3.49 (s, MeꢀN(7)); 3.10 (s,
MeꢀN(1)). Anal. calc. for C7H10N6O2 (210.2): C 40.00, H 4.80, N 39.99; found: C 40.17, H 4.76, N 39.40.
14. 8-Azido-1,7-dimethylxanthine (¼ 8-Azido-3,7-dihydro-1,7-dimethyl-1H-purine-2,6-dione; 20). A
soln. of 8-hydrazino-1,7-dimethylxanthine (0.4 g, 1.91 mmol) in 3% HCl soln. (40 ml) was cooled in ice to
0 – 58, and then under stirring, a soln. of NaNO2 (0.15 g, 2.17 mmol) in H2O (5 ml) was added dropwise.

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Helvetica Chimica Acta – Vol. 93 (2010)
After 30 min, the mixture was neutralized with 1n NaHCO3. The formed precipitate was recrystallized
from EtOH/H2O 2 :1 (60 ml): 0.219 g (52%) of 20. Yellowish crystals. M.p. 185 – 1908. UV (MeOH): 218
1
(3.99), 289 (4.11). H-NMR ((D6)DMSO): 11.95 (s, HꢀN(3)); 3.59 (s, MeꢀN(7)); 3.14 (s, MeꢀN(1)).
Anal. calc. for C7H7N7O2 (221.2): C 38.01, H 3.17, N 44.34; found: C 38.01, H 3.23, N 43.96.
15. 8-Bromo-1,7-dimethylxanthine (¼ 8-Bromo-3,7-dihydro-1,7-dimethyl-1H-purine-2,6-dione; 21).
To a warm soln. of 1,7-dimethylxanthine [26] (5.0 g, 27.78 mmol) in AcOH (50 ml) was dropwise added
bromine (3 ml, 51.8 mmol). Then, the mixture was heated to 808 for 2 h. After cooling, the mixture was
diluted with acetone (500 ml), and the formed precipitate purified by recrystallization from AcOH/
EtOH 1:2 (250 ml): 3.02 g (42%) of 21. Colorless crystals. M.p. 305 – 3078. UV (pH 13): 218 (4.49), 249
1
(sh, 3.84), 293 (3.98). H-NMR (CF3COOD): 4.10 (s, MeꢀN(7)); 3.50 (s, MeꢀN(1)). Anal. calc. for
C7H7BrN4O2 (259.1): C 32.45, H 2.72, N 21.63; found: C 32.66, H 2.76, N 21.85.
16. 8-(Benzylamino)-1,7-dimethylxanthine (¼ 8-(Benzylamino)-3,7-dihydro-1,7-dimethyl-1H-pu-
rine-2,6-dione; 22). A mixture of 21 (1.0 g, 3.86 mmol) in dist. benzylamine (10 ml) was heated in an
oilbath with stirring to 1308. After 1 h, the mixture was cooled, diluted with H2O (50 ml), and then
extracted with CHCl3. The CHCl3 extract was dried (Na2SO4) and concentrated, and the residue stirred
in Et2O for 30 min. The resulting solid was then recrystallized from EtOH (20 ml): 0.68 g (62%) of 22.
Slightly yellowish crystals. M.p. 223 – 2248. UV (pH 13): 222 (4.68), 297 (4.28). 1H-NMR ((D6)DMSO):
11.53 (s, HꢀN(3)); 7.52 (t, NHꢀC(8)); 7.31 – 7.22 (m, 5 arom. H); 4.50 (d, CH2); 3.58 (s, MeꢀN(7)); 3.09
(s, MeꢀN(1)). Anal. calc. for C14H15N5O2 (285.3): C 58.93, H 5.30, N 24.55; found: C 59.01, H 5.34, N
24.23.
17. 6-Amino-1-benzyl-5-[cyano(methyl)amino]uracil (¼ N-(6-Amino-1-benzyl-1,2,3,4-tetrahydro-
2,4-dioxopyrimidin-5-yl)-N-methylcyanamide; 23). To a soln. of 6-amino-1-benzyl-5-(methylamino)ur-
acil [26] (1.0 g, 4.07 mmol) in AcOH (10 ml) were added a soln. of NaHCO3 (0.8 g) in H2O (3 ml) and
then bromocyan (0.5 g, 4.72 mmol). After 1 h, H2O (10 ml) was added, and the mixture stirred overnight.
The obtained precipitate was washed with H2O and EtOH and dried under high vacuum: 1.0 g (91%) of
crude 23. Recrystallization from H2O/EtOH 1:1 (100 ml) gave 0.84 g (76%) of 23. Colorless crystals.
M.p. 287 – 2998. UV (MeOH): 203 (4.23), 264 (4.28). 1H-NMR ((D6)DMSO): 10.95 (s, HꢀN(3)); 7.37 –
7.16 (m, 5 arom. H, NH2); 5.06 (s, CH2); 2.90 (d, MeNꢀC(5)). Anal. calc. for C13H13N5O2 (271.3): C 57.55,
H 4.80, N 25.83; found: C 57.03, H 4.86, N 25.49.
18. 6-Amino-1-benzyl-5-[cyano(methyl)amino]-3-methyluracil (¼ N-(6-Amino-1-benzyl-1,2,3,4-tet-
rahydro-3-methyl-2,4-dioxopyrimidin-5-yl)-N-methylcyanamide; 24). As described for 23, with 6-amino-
1-benzyl-5-(methylamino)-3-methyluracil [26] (1.0 g, 3.85 mmol) and bromocyan (0.5 g, 4.72 mmol).
Recrystallization from EtOH (90 ml) gave 0.9 g (82%) of 24. Colorless crystals. M.p. 1958, solidifing and
1
a second m.p. at 2238. UV (MeOH): 203 (4.30), 264 (4.28). H-NMR ((D6)DMSO): 7.37 – 6.90 (m, 5
arom. H, NH2); 5.12 (s, CH2); 3.14 (s, MeꢀN(3)); 2.90 (d, MeNꢀC(5)). Anal. calc. for C14H15N5O2
(285.3): C 58.93, H 5.30, N 24.55; found: C 58.87, H 5.28, N 24.28.
19. 8-Amino-3-benzyl-7-methylxanthine (¼ 8-Amino-3-benzyl-3,7-dihydro-7-methyl-1H-purine-2,6-
dione; 25). A soln. of 23 (0.8 g, 2.95 mmol) in 1n NaOH (15 ml) was stirred at r.t. for 10 h and then
diluted with H2O (30 ml) and neutralized with AcOH. The resulting precipitate was washed with H2O
and dried to give 0.712 g (89%) of chromatographically pure 25. Recrystallization from H2O/EtOH 1:1
1
(100 ml) gave 0.84 g (76%) of 25. Colorless crystals. M.p. 305 – 3068. H-NMR ((D6)DMSO): 10.65 (s,
HꢀN(1)); 7.35 – 7.27 (m, 5 arom. H); 6.83 (s, NH2); 5.01 (s, CH2); 3.54 (s, MeꢀN(3)). Anal. calc. for
C13H13N5O2 (271.3): C 57.55, H 4.80, N 25.83; found: C 57.47, H 4.83, N 25.82.
20. 8-Amino-3-benzyl-1,7-dimethylxanthine (¼ 8-Amino-3-benzyl-3,7-dihydro-1,7-dimethyl-1H-pu-
rine-2,6-dione; 26). i) As described for 25 with 24 (0.8 g, 1.4 mmol) by boiling in 1n NaOH (20 ml) and
EtOH (20 ml) for 30 min. The mixture was neutralized with AcOH, and the precipitate recrystallized
from EtOH (40 ml): 0.52 g (65%) of 26. Colorless crystals. M.p. 224 – 2258.
ii) A mixture of 25 (0.2 g, 0.74 mmol), K2CO3 (0.1 g, 0.72 mmol), and MeI (0.2 ml) in DMF (20 ml)
was stirred at r.t. for 24 h and then concentrated. The residue was treated with H2O (50 ml), and the
resulting solid recrystallized from EtOH (15 ml): 0.12 g (57%) of 26. Colorless crystals. M.p. 224 – 2258.
1H-NMR ((D6)DMSO): 7.27 (m, 5 arom. H); 6.88 (s, NH2); 5.00 (s, CH2); 3.57 (s, MeꢀN(7)); 3.17 (s,
MeꢀN(1)). Anal. calc. for C14H15N5O2 (285.3): C 58.93, H 5.30, N 24.55; found: C 58.75, H 5.64, N 24.00.

Helvetica Chimica Acta – Vol. 93 (2010)
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21. 6-Amino-1-benzyl-5-(propylamino)uracil ( ¼ 6-Amino-1-benzyl-5-(propylamino)pyrimidine-
2,4(1H,3H)-dione). A suspension of 6-amino-1-benzyl-5-bromouracil [26] (15.4 g, 52.03 mmol) in 50%
aq. propylamine (50 ml) was heated in an autoklav to 808 for 5 h. After cooling, the formed precipitate
was washed with MeOH (20 ml) and Et2O (20 ml) and dried in a vacuum desiccator: 9.27 g of crude
product. Recrystallization from PrOH (500 ml) gave 7.84 g (55%) of a yellowish powder. M.p. 204 – 2068.
1H-NMR ((D6)DMSO): 10.58 (br. s, HꢀN(3)); 7.35 – 7.10 (m, 5 arom. H); 6.33 (s, NH2); 5.00 (s, CH2N);
2.75 (br. s, NHꢀC(5)); 2.60 (t, MeCH2CH2N); 1.45 – 1.20 (m, MeCH2CH2N); 0.80 – 0.60 (t, MeCH2CH2).
Anal. calc. for C14H18N4O2 (274.3): C 61.30, H 6.61, N 20.43; found: C 61.12, H 6.50, N 20.28.
22. 6-Amino-1-benzyl-5-[cyano(propyl)amino]uracil (¼ N-(6-Amino-1-benzyl-1,2,3,4-tetrahydro-
2,4-dioxopyrimidin-5-yl)-N-propylcyanamide; 27). A suspension of 6-amino-1-benzyl-5-(propylami-
no)uracil (4.0 g, 14.6 mmol) in 1n AcOH/0.5m AcONa (100 ml; pH 4.5) was treated with bromocyan
(2.0 g, 18.80 mmol) at r.t. for 15 h. The obtained precipitate was recrystallized from EtOH (200 ml): 3.0 g
(69%) of 27. Colorless crystals. M.p. 259 – 2608. UV (MeOH): 203 (4.25), 265 (4.29). 1H-NMR
((D6)DMSO): 10.90 (br. s, HꢀN(3)); 7.29 – 7.00 (m, 5 arom. H, NH2); 5.09 (s, CH2N(1)); 3.21 – 2.89 (br. t,
MeCH2CH2N); 1.63 – 1.38 (m, MeCH2CH2N); 0.97 – 0.80 (br. t, MeCH2CH2). Anal. calc. for C15H17N5O2
(299.3): C 60.20, H 5.69, N 23.41; found: C 60.14, H 5.66, N 23.60.
23. 8-Amino-3-benzyl-7-propylxanthine (¼ 8-Amino-3-benzyl-3,7-dihydro-7-propyl-1H-purine-2,6-
dione; 28). Addition of 27 (2.0 g, 6.69 mmol) to 1n NaOH (100 ml) under stirring gave a soln. from
which, after 5 min, a solid precipitated. The suspension was stirred at r.t. for 2 h and then acidified with
AcOH (30 ml). The formed precipitate was washed with H2O and EtOH, dried, and then recrystallized
from EtOH/H2O 4 :1 (100 ml): 1.6 g (80%) of 28. Colorless crystals. M.p. 263 – 2648. 1H-NMR
((D6)DMSO): 10.80 (br. s, HꢀN(3)); 7.35 – 7.25 (m, 5 arom. H); 6.90 (s, NH2); 5.02 (s, CH2N(3)); 4.20 –
3.90 (t, MeCH2CH2N); 1.90 – 1.60 (m, MeCH2CH2N); 0.90 (br. t, MeCH2CH2). Anal. calc. for C15H17N5O2
(299.3): C 60.20, H 5.69, N 23.41; found: C 60.32, H 5.74, N 23.53.
24. 8-Amino-3-benzyl-1-methyl-7-propylxanthine (¼ 8-Amino-3-benzyl-3,7-dihydro-1-methyl-7-
propyl-1H-purine-2,6-dione; 29). A soln. of 28 (0.8 g, 2.68 mmol) in 1n NaOH (20 ml) was heated to
408, and then Me2SO4 (0.4 ml, 4.22 mmol) was added dropwise. The mixture was stirred for 15 h at r.t.,
and the formed precipitate washed with H2O and dried: 0.5 g (60%) of crude 29. Recrystallization from
EtOH (40 ml) gave 0.377 g (45%) of 29. Colorless crystals. M.p. 209 – 2108. 1H-NMR ((D6)DMSO):
7.30 – 7.25 (m, 5 arom. H); 6.84 (s, NH2); 5.03 (s, CH2N(3)); 3.99 – 3.41 (t, MeCH2CH2N); 3.14 (s,
MeꢀN(1); 1.66 – 1.50 (m, MeCH2CH2N); 0.88 – 0.72 (t, MeCH2CH2). Anal. calc. for C16H19N5O2 (313.4):
C 61.32, H 6.11, N 22.35; found: C 61.35, H 6.16, N 22.30.
25. 8-Amino-9-methylxanthine (¼ 8-Amino-3,9-dihydro-9-methyl-1H-purine-2,6-dione; 34) [15]. A
soln. of 9-methyl-8-nitroxanthine (30) [15] (0.75 g, 3.55 mmol) in H2O (100 ml) and conc. NH3 soln.
(5 ml) was reduced with 10% Pd/C (45 mg) under H2 in a shaking apparatus. After uptake of 230 ml of
H2, the catalyst was filtered off, and the filtrate concentrated. The residue was recrystallized from H2O
1
(500 ml) with charcoal: 0.373 g (58%) of 34. Colorless powder. M.p. > 3008. H-NMR ((D6)DMSO):
11.80 (s, HꢀN(3)); 10.60 (s, HꢀN(1)); 6.10 (s, NH2); 3.50 (s, MeꢀN(9)). Anal. calc. for C6H7N5O2 ·
0.25 H2O (185.7): C 38.80, H 4.04, N 37.72; found: C 38.74, H 4.25, N 37.11.
26. 8-Amino-1,9-dimethylxanthine (¼ 8-Amino-3,9-dihydro-1,9-dimethyl-1H-purine-2,6-dione; 35).
As described for 34, with 1,9-dimethyl-8-nitroxanthine (31) [15] (1.0 g, 4.44 mmol), 10% Pd/C (60 mg)
and H2. The crude product was recrystallized from H2O/AcOH 4 :1 (250 ml): 0.581 g (67%) of 35.
Colorless powder. M.p. > 3008. 1H-NMR ((D6)DMSO): 12.40 (s, HꢀN(3)); 6.20 (s, NH2); 3.50 (s,
MeꢀN(9)); 3.20 (s, MeꢀN(1)). Anal. calc. for C7H9N5O2 (195.2): C 43.08, H 4.54, N 35.88; found: C
43.01, H 4.57, N 35.93.
27. 8-Amino-3,9-dimethylxanthine (¼ 8-Amino-3,9-dihydro-3,9-dimethyl-1H-purine-2,6-dione; 36). i)
As described for 34, with 3,9-dimethyl-8-nitroxanthine (32) [15] (0.3 g, 0.134 mmol), 10% Pd/C (30 mg),
and H2. The crude product was recrystallized from H2O/AcOH 1:1 (50 ml): 0.136 g (52%) of 36.
Colorless powder. M.p. 320 – 3228.
ii) A suspension of 1-methyl-6-(methylamino)-5-nitrosouracil [27] (3.0 g, 16.03 mmol) in (NH4)2S
soln. (20 ml) was heated to 708 for 20 min, and after cooling, the formed precipitate 38 was dissolved in 1n
AcOH/0.5m AcONa (20 ml, pH 4.5). Then bromocyan (0.8 g, 7.55 mmol) was added, and the mixture
stirred at r.t. overnight. The formed precipitate was purified by recrystallization from H2O (400 ml) with

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Helvetica Chimica Acta – Vol. 93 (2010)
charcoal: 0.447 g (39%) of 36. Colorless crystals. M.p. 320 – 3228. 1H-NMR ((D6)DMSO): 10.80 (s,
HꢀN(1)); 5.99 (s, NH2); 3.60 (s, MeꢀN(9)); 3.55 (s, MeꢀN(3)). Anal. calc. for C7H9N5O2 (195.2): C
43.08, H 4.54, N 35.88; found: C 42.83, H 4.81, N 35.66.
28. 8-Amino-1,3,9-trimethylxanthine (¼ 8-Amino-3,9-dihydro-1,3,9-trimethyl-1H-purine-2,6-dione;
37). i) A soln. of 1,3,9-trimethyl-8-nitroxanthine (33) [15] (0.3 g, 0.134 mmol) in DMF (50 ml) was
reduced with 10% Pd/C (30 mg) under H2 in a shaking apparatus. After filtration of the catalyst, the
filtrate was concentrated, and the residue treated with H2O (20 ml), filtered, and recrystallized from
EtOH/H2O 1:1 (40 ml): 0.56 g (60%) of 37. Colorless crystals. M.p. 319 – 3208.
ii) A suspension of 1,3-dimethyl-6-(methylamino)-5-nitrosouracil [27] (3.0 g, 16.03 mmol) and
Raney-Ni (1.5 g) in MeOH (50 ml) was reduced under H2 in a shaking apparatus. After filtration, the
mixture was evaporated, and the residue 39 dried in a vacuum desiccator. A soln. of 39 (0.9 g, 4.89 mmol)
in 1n AcOH/0.5m AcONa (30 ml, pH 4.5) was then treated with bromocyan (0.6 g, 5.66 mmol) under
stirring at r.t. for 3 h. The resulting precipitate was purified by recrystallization from EtOH/H2O 1:1
(150 ml) with charcoal: 0.45 g (44%) of 37. Colorless crystals. M.p. 3208. 1H-NMR ((D6)DMSO): 6.00 (s,
NH2); 3.60 (s, MeꢀN(9)); 3.58 (s, MeꢀN(3)); 3.20 (s, MeꢀN(1)). Anal. calc. for C8H11N5O2 (209.2): C
45.93, H 5.30, N 33.48; found: C 45.90, H 5.10, N 33.07.
29. 8-(Acetylamino)xanthine (¼ N-(3,7-Dihydro-2,6-dioxo-1H-purin-8-yl)acetamide; 40). A suspen-
sion of 8 (0.1 g, 0.6 mmol) in Ac2O (10 ml) was heated under reflux for 5 h. The precipitate was collected
after cooling and washed with H2O and EtOH. The solid was dissolved in hot DMSO (20 ml), and then
H2O was added slowly until a precipitate started to separate. After cooling, the mixture was filtered, and
the solid washed and dried at 1008: 70 mg (56%) of 40. Colorless powder. M.p. > 3208. 1H-NMR
((D6)DMSO): 11.83 (s, HꢀN(7)); 11.49 (br. s, HꢀN(1), HꢀN(3)); 10.05 (s, NHꢀC(8)); 2.10 (s, MeCO).
Anal. calc. for C7H7N5O3 (209.2): C 40.16, H 3.35, N 33.46; found: C 40.03, H 3.49, N 32.82.
30. 8-(Acetylamino)-1-methylxanthine (¼ N-(3,7-Dihydro-1-methyl-2,6-dioxo-1H-purin-8-yl)acet-
amide; 41). As described for 40, with 9 (0.15 g, 0.83 mmol) and Ac2O (5 ml) for 4 h. The precipitate
was collected after cooling, washed with H2O and EtOH, and purified by recrystallization from dil.
AcOH: 0.113 g (61%) of 41. Colorless crystals. M.p. > 3008. 1H-NMR ((D6)DMSO): 11.81 (s, HꢀN(7),
HꢀN(3)); 11.76 (s, NHꢀC(8)); 3.15 (s, MeꢀN(1)); 2.10 (s, MeCO). Anal. calc. for C8H9N5O3 (223.2): C
43.05, H 4.06, N 31.38; found: C 43.10, H 4.07, N 31.50.
31. 8-(Acetylamino)-3-methylxanthine (¼ N-(3,7-Dihydro-3-methyl-2,6-dioxo-1H-purin-8-yl)acet-
amide; 42). As described for 40, with 10 (0.1 g, 0.55 mmol) and Ac2O (5 ml) for 4 h. The precipitate
was collected after cooling and washed with H2O and EtOH. Partial evaporation of the filtrate gave a
second crop. Both solids were purified by recrystallization from dil. AcOH: 0.086 g (70%) of 42.
Colorless crystals. M.p. > 3508. 1H-NMR ((D6)DMSO): 12.40 (s, HꢀN(7)); 12.00 (s, HꢀN(1)); 11.30 (s,
NHꢀC(8)); 3.35 (s, MeꢀN(3)); 2.10 (s, MeCO). Anal. calc. for C8H9N5O3 (223.2): C 43.05, H 4.06, N
31.38; found: C 43.05, H 4.17, N 31.20.
32. 8-(Acetylamino)-3-benzylxanthine (¼ N-(3-Benzyl-3,7-dihydro-2,6-dioxo-1H-purin-8-yl)acet-
amide; 43). As described for 40, with 11 (0.1 g, 0.39 mmol) in AcOH (2 ml) and Ac2O (3 ml) for 3 h.
After cooling, the precipitate was collected, washed with H2O and EtOH, and purified by recrystalliza-
tion from H2O/AcOH 3 :1 (20 ml): 0.07 g (60%) of 43. Colorless crystals. M.p. 317 – 3188. 1H-NMR
((D6)DMSO): 12.11 (s, HꢀN(7)); 11.64 (s, HꢀN(1)); 11.05 (s, NHꢀC(8)); 7.28 (m, 5 arom. H); 5.07 (s,
CH2N); 2.08 (s, MeCO). Anal. calc. for C14H13N5O3 · 0.5 H2O (223.2): C 54.55, H 4.54, N 22.73; found: C
54.70, H 4.92, N 22.53.
33. 8-(Acetylamino)-1,3-dimethylxanthine (¼ N-(3,7-Dihydro-1,3-dimethyl-2,6-dioxo-1H-purin-8-
yl)acetamide; 44). As described for 40, with 12 (0.5 g, 2.56 mmol) and Ac2O (10 ml) for 2 h. After
evaporation, the solid was washed with H2O and EtOH and then purified by recrystallization from H2O
1
(200 ml) with charcoal: 0.405 g (67%) of 44. Colorless crystals. M.p. > 3308. H-NMR ((D6)DMSO):
12.00 (br. s, HꢀN(7), NHꢀC(8)); 3.40 (s, MeꢀN(3)); 3.25 (s, MeꢀN(1)); 2.10 (s, MeCO). Anal. calc. for
C9H11N5O3 (237.2): C 45.57, H 4.67, N 29.53; found: C 45.58, H 4.73, N 29.63.
34. 8-(Acetylamino)-3-benzyl-1-methylxanthine (¼ N-(3-Benzyl-3,7-dihydro-1-methyl-2,6-dioxo-1H-
purin-8-yl)acetamide; 45). As described for 40, with 13 (0.2 g, 0.74 mmol) and Ac2O (3 ml) for 1 h. After
cooling, H2O (5 ml) was added and the mixture heated for 30 min and then cooled. The formed
precipitate was recrystallized from EtOH/H2O 5 :1 (60 ml): 0.141 g (61%) of 45. Colorless crystals. M.p.

Helvetica Chimica Acta – Vol. 93 (2010)
2129
286 – 2888. 1H-NMR ((D6)DMSO): 12.09 (s, HꢀN(7)); 11.66 (s, NHꢀC(8)); 7.28 (m, 5 arom. H); 5.12 (s,
CH2N); 3.23 (s, MeꢀN(1)); 2.09 (s, MeCO). Anal. calc. for C15H15N5O3 (313.3): C 57.51, H 4.79, N 22.36;
found: C 57.40, H 4.98, N 22.20.
35. 8-(Acetylamino)-1,3,7-trimethylxanthine (¼ N-(3,7-Dihydro-1,3,7-trimethyl-2,6-dioxo-1H-purin-
8-yl)acetamide; 46). As described for 40, with 14 (0.21 g, 1.0 mmol) and Ac2O (3 ml) for 2 h.
Recrystallization from H2O (120 ml) gave 0.141 g (56%) of 46. Colorless crystals. M.p. 265 – 2668.
1H-NMR ((D6)DMSO): 9.80 (s, NHꢀC(8)); 3.70 (s, MeꢀN(7)); 3.30 (s, MeꢀN(3)); 3.00 (s, MeꢀN(1));
2.10 (s, MeCO). Anal. calc. for C10H13N5O3 (251.2): C 47.80, H 5.21, N 27.88; found: C 47.83, H 5.24, N
27.16.
36. 8-(Acetylamino)-7-methylxanthine (¼ N-(3,7-Dihydro-7-methyl-2,6-dioxo-1H-purin-8-yl)acet-
amide; 47). As described for 40, with 15 (0.1 g, 0.55 mmol) and Ac2O (3 ml) for 1.5 h. After evaporation,
H2O (20 ml) was added, and the mixture stirred at r.t. for 1 h. The precipitate was purified by
recrystallization from H2O (10 ml): 73 mg (59%) of 47. Colorless crystals. M.p. 358 – 3608. 1H-NMR
((D6)DMSO): 11.46 (s, HꢀN(3)); 10.76 (s, HꢀN(1)); 10.55 (s, NHꢀC(8)); 3.60 (s, MeꢀN(7)); 2.09 (s,
MeCO). Anal. calc. for C8H9N5O3 · 0.5 H2O (232.2): C 41.35, H 4.31, N 30.15; found: C 41.56, H 4.63, N
29.92.
37. 8-(Acetylamino)-3,7-dimethylxanthine (¼ N-(3,7-Dihydro-3,7-dimethyl-2,6-dioxo-1H-purin-8-
yl)acetamide; 48). As described for 40, with 16 (0.1 g, 0.52 mmol) and Ac2O (5 ml) for 2 h.
Recrystallization from H2O (10 ml) gave 91 mg (75%) of 48. Colorless crystals. M.p. 3158. 1H-NMR
((D6)DMSO): 10.20 (s, HꢀN(1)); 9.85 (s, NHꢀC(8)); 3.60 (s, MeꢀN(7)); 3.35 (s, MeꢀN(3)); 2.00 (s,
MeCO). Anal. calc. for C9H11N5O3 (237.2): C 45.57, H 4.67, N 29.53; found: C 45.20, H 4.85, N 29.22.
38. 8-(Acetylamino)-1,7-dimethylxanthine (¼ N-(3,7-Dihydro-1,7-dimethyl-2,6-dioxo-1H-purin-8-
yl)acetamide; 49). As described for 40, with 19 (0.2 g, 1.0 mmol) and Ac2O (6 ml) for 2 h.
Recrystallization from H2O/AcOH 1:1 (40 ml) gave 0.136 g (59%) of 49. Colorless crystals. M.p.
350 – 3548. 1H-NMR ((D6)DMSO): 11.80 (s, HꢀN(3)); 10.56 (s, NHꢀC(8)); 3.63 (s, MeꢀN(7)); 3.16 (s,
MeꢀN(1)); 2.10 (s, MeCO). Anal. calc. for C9H11N5O3 (237.2): C 45.57, H 4.67, N 29.53; found: C 45.52, H
4.59, N 29.45.
39. 8-(Acetylamino)-3-benzyl-7-methylxanthine (¼ N-(3-Benzyl-3,7-dihydro-7-methyl-2,6-dioxo-1H-
purin-8-yl)acetamide; 50). As described for 40, with 25 (0.25 g, 0.92 mmol) and Ac2O (5 ml) for 3 h.
Recrystallization from H2O/EtOH 1:1 (20 ml) gave 0.159 g (55%) of 50. Colorless crystals. M.p. 259 –
2608. 1H-NMR ((D6)DMSO): 11.17 (s, HꢀN(1)); 10.76 (s, NHꢀC(8)); 7.28 (m, 5 arom. H); 5.05 (s,
CH2N); 3.62 (s, MeꢀN(7)); 2.08 (s, MeCO). Anal. calc. for C15H15N5O3 (313.3): C 57.51, H 4.79, N 22.36;
found: C 57.50, H 4.85, N 22.28.
40. 8-(Acetylamino)-3-benzyl-1,7-dimethylxanthine (¼ N-(3-Benzyl-3,7-dihydro-1,7-dimethyl-2,6-di-
oxo-1H-purin-8-yl)acetamide; 51). As described for 40, with 26 (0.3 g, 1.03 mmol) in AcOH (10 ml) and
Ac2O (2 ml) for 2 h. Recrystallization from MeOH (15 ml) gave 0.138 g (40%) of 51. Colorless crystals.
M.p. 216 – 2178. 1H-NMR ((D6)DMSO): 10.72 (s, NHꢀC(8)); 7.20 (m, 5 arom. H); 5.11 (s, CH2N); 3.65
(s, MeꢀN(7)); 3.23 (s, MeꢀN(1)); 2.08 (s, MeCO). Anal. calc. for C16H17N5O3 (327.3): C 58.70, H 5.24, N
21.40; found: C 58.68, H 5.36, N 21.38.
41. 8-(Acetylamino)-3-benzyl-7-propylxanthine (¼ N-(3-Benzyl-3,7-dihydro-2,6-dioxo-7-propyl-1H-
purin-8-yl)acetamide; 52). As described for 40, with 28 (0.3 g, 1.03 mmol) in AcOH (10 ml) and Ac2O
(2 ml) for 2 h. Recrystallization from EtOH (30 ml) gave 0.216 g (63%) of 52. Colorless crystals. M.p.
2618. 1H-NMR ((D6)DMSO): 11.17 (s, HꢀN(1)); 10.51 (s, NHꢀC(8)); 7.28 (m, 5 arom. H); 5.05 (s,
CH2N); 4.00 (t, CH2ꢀN(7)); 2.07 (s, MeCO); 1.74 – 1.58 (m, CH2CH2N); 0.85 – 0.69 (t, MeCH2CH2).
Anal. calc. for C17H19N5O3 (341.4): C 59.82, H 5.57, N 20.53; found: C 59.76, H 5.64, N 20.41.
42. 8-(Acetylamino)-3-benzyl-1-methyl-7-propylxanthine (¼ N-(3-Benzyl-3,7-dihydro-1-methyl-2,6-
dioxo-7-propyl-1H-purin-8-yl)acetamide; 53). As described for 40, with 29 (0.1 g, 0.32 mmol) in AcOH
(10 ml) and Ac2O (2 ml) for 2 h. Recrystallization from EtOH (20 ml) gave 65 mg (58%) of 53. Colorless
1
crystals. M.p. 2348. H-NMR ((D6)DMSO): 11.17 (s, HꢀN(1)); 10.60 (s, NHꢀC(8)); 7.31 – 7.23 (m, 5
arom. H); 5.11 (s, CH2N); 4.02 (t, CH2ꢀN(7)); 3.23 (s, MeꢀN(1)); 2.08 (s, MeCO); 1.75 – 1.66 (m,
CH2CH2N); 0.81 – 0.75 (t, MeCH2CH2). Anal. calc. for C18H21N5O3 (355.4): C 60.84, H 5.92, N 19.72;
found: C 61.06, H 5.88, N 19.72.

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Helvetica Chimica Acta – Vol. 93 (2010)
43. 8-(Acetylamino)-9-methylxanthine (¼ N-(3,9-Dihydro-9-methyl-2,6-dioxo-1H-purin-8-yl)acet-
amide; 54). As described for 40, with 34 (0.1 g, 0.55 mmol) and Ac2O (5 ml) for 4 h. After cooling, the
formed precipitate was washed with H2O and EtOH, dried, and recrystallized from H2O (20 ml) with
charcoal: 62 mg (50%) of 54. Colorless crystals. M.p. > 3508. 1H-NMR ((D6)DMSO): 11.93 (s,
HꢀN(3)); 10.77 (s, HꢀN(1)); 10.33 (s, NHꢀC(8)); 3.36 (s, MeꢀN(9)); 2.04 (s, MeCO). Anal. calc. for
C8H9N5O3 · 0.125 H2O (225.6): C 42.58, H 4.10, N 31.05; found: C 43.03, H 4.17, N 30.82.
44. 8-(Acetylamino)-1,9-dimethylxanthine (¼ N-(3,9-Dihydro-1,9-dimethyl-2,6-dioxo-1H-purin-8-
yl)acetamide; 55). i) As described for 40, with 35 (0.195 g, 1 mmol) in AcOH (10 ml) and Ac2O (4 ml)
for 1 h. After cooling, the formed precipitate was washed with H2O and EtOH and recrystallized from
EtOH/H2O 1:1 (30 ml): 0.161 g (68%) of 55. Colorless crystals. M.p. > 3108.
ii) A soln. of 8-(diacetylamino)-1,9-dimethylxanthine (59; 0.1 g, 0.36 mmol) in H2O (10 ml) was
heated under reflux for 1.5 h. After cooling, the colorless crystals were washed with H2O and dried at
1008: 50 mg (59%) of 55. M.p. > 3108. 1H-NMR ((D6)DMSO): 12.20 (s, HꢀN(3)); 10.31 (s, NHꢀC(8));
3.40 (s, MeꢀN(9)); 3.18 (s, MeꢀN(1)); 2.12 (s, MeCO). Anal. calc. for C9H11N5O3 (237.2): C 45.57, H 4.67,
N 29.53; found: C 45.43, H 4.77, N 29.75.
45. 8-(Acetylamino)-3,9-dimethylxanthine (¼ N-(3,9-Dihydro-3,9-dimethyl-2,6-dioxo-1H-purin-8-
yl)acetamide; 56). As described for 55 (i), with 36 (0.195 g, 1 mmol): 0.118 g (49%) of 56. Colorless
crystals. M.p. 310 – 3118. 1H-NMR ((D6)DMSO): 11.07 (s, HꢀN(1)); 10.27 (s, NHꢀC(8)); 3.62 (s,
MeꢀN(9)); 3.58 (s, MeꢀN(3)); 2.05 (s, MeCO). Anal. calc. for C9H11N5O3 · 0.25 H2O (241.7): C 44.68, H
4.65, N 28.96; found: C 44.60, H 4.85, N 28.71.
46. 8-(Acetylamino)-1,3,9-trimethylxanthine (¼ N-(3,9-Dihydro-1,3,9-trimethyl-2,6-dioxo-1H-purin-
8-yl)acetamide; 57). As described for 40, with 37 (0.1 g, 0.48 mmol) in AcOH (5 ml) and Ac2O (1 ml) for
40 min. After cooling, the mixture was evaporated and the residue heated in H2O (5 ml) for 30 min.
Evaporation and recrystallization of the solid from EtOH (10 ml) gave 76 mg (63%) of 57. Colorless
crystals. M.p. 262 – 2638. 1H-NMR ((D6)DMSO): 10.30 (s, NHꢀC(8)); 3.66 (s, MeꢀN(9)); 3.65 (s,
MeꢀN(3)); 3.21 (s, MeꢀN(1)); 2.05 (s, MeCO). Anal. calc. for C10H13N5O3 (251.2): C 47.80, H 5.21, N
27.88; found: C 47.94, H 5.13, N 27.66.
47. 8-(Diacetylamino)-1,3,7-trimethylxanthine (¼ N-Acetyl-N-(3,7-dihydro-1,3,7-trimethyl-2,6-dioxo-
1H-purin-8-yl)acetamide; 58) [20]. As described for 40, with 14 (0.2 g, 0.96 mmol) and Ac2O (10 ml) for
5 h. The mixture was concentrated, and the residue treated with Et2O for 1 h at r.t. The precipitate was
dissolved again in hot Ac2O (5 ml), and after cooling, the soln. was diluted with Et2O (3 ml): 0.1 g (36%)
of 58. Colorless crystals. M.p. 144 – 1458. 1H-NMR (CDCl3): 4.10 (s, MeꢀN(7)); 3.80 (s, MeꢀN(3)); 3.70
(s, MeꢀN(1)); 2.80 (s, 2 Ac). Anal. calc. for C12H15N5O4 (293.3): C 49.14, H 5.16, N 23.88; found: C 49.20,
H 5.10, N 23.71.
48. 8-(Diacetylamino)-1,9-dimethylxanthine (¼ N-Acetyl-N-(3,9-dihydro-1,9-dimethyl-2,6-dioxo-1H-
purin-8-yl)acetamide; 59). As described for 40, with 35 (0.2 g, 1.03 mmol) and Ac2O (8 ml) for 3 h. After
evaporation, the residue was stirred in H2O (20 ml) for 30 min, and then the solid collected.
Recrystallization from Ac2O (40 ml) and drying in a desiccator over KOH gave 0.178 g (62%) of 59.
Colorless crystals. 1H-NMR ((D6)DMSO): 12.40 (s, NH); 3.43 (s, MeꢀN(9)); 3.20 (s, MeꢀN(1)); 2.24 (s,
2 Ac). Anal. calc. for C11H13N5O4 (279.3): C 47.31, H 4.69, N 25.08; found: C 47.07, H 4.79, N 25.25.
49. 8-Diazoxanthine (¼ 8-Diazo-3,8-dihydro-1H-purine-2,6-dione; 60) [15]. To a soln. of 8 (0.1 g,
0.6 mmol) in 5% KOH soln. (10 ml), NaNO2 (43 mg, 0.62 mmol) was added, and then the mixture cooled
in an ice bath (0 – 58). Under stirring in the dark, conc. HCl soln. (5 ml) was added dropwise, and after
1 h, the resulting precipitate was washed with H2O and MeOH and dried in a vacuum desiccator over
P4O10: 97 mg (91%) of 60. Yellowish solid. M.p. 1458 (dec.). 1H-NMR ((D6)DMSO): 11.75 (s, HꢀN(3));
11.16 (s, HꢀN(1)). Anal. calc. for C5H2N6O2 (178.1): C 33.72, H 1.13, N 47.19; found: C 33.62, H 1.20, N
47.01.
50. 8-Diazo-1-methylxanthine (¼ 8-Diazo-3,8-dihydro-1-methyl-1H-purine-2,6-dione; 61). As de-
scribed for 60, with 9 (0.15 g, 0.83 mmol), 5% KOH soln. (8 ml), NaNO2 (60 mg, 0.87 mmol), and conc.
HCl soln. (3 ml): 0.14 g (88%) of 61. Yellowish solid. M.p. 1548 (dec.). 1H-NMR ((D6)DMSO): 12.01 (s,
HꢀN(3)); 3.19 (s, MeꢀN(1)). Anal. calc. for C6H4N6O2 · 0.25 H2O (192.7): C 36.61, H 2.16, N 42.71;
found: C 36.70, H 2.28, N 42.62.

Helvetica Chimica Acta – Vol. 93 (2010)
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51. 8-Diazo-3-methylxanthine (¼ 8-Diazo-3,8-dihydro-3-methyl-1H-purine-2,6-dione; 62). As de-
scribed for 60, with 10 (0.181 g, 1 mmol), 5% KOH soln. (10 ml), NaNO2 (0.1 g, 1.45 mmol), and conc.
HCl soln. (3 ml): 0.15 g (78%) of 62. Yellowish solid. M.p. 1568 (dec.). 1H-NMR ((D6)DMSO): 11.43 (s,
HꢀN(1)); 3.32 (s, MeꢀN(3)). Anal. calc. for C6H4N6O2 · 0.25 H2O (192.7): C 36.61, H 2.16, N 42.71;
found: C 36.60, H 2.08, N 42.23.
52. 3-Benzyl-8-diazoxanthine (¼ 3-Benzyl-8-diazo-3,8-dihydro-1H-purine-2,6-dione; 63). As de-
scribed for 60, with 11 (0.26 g, 1 mmol), 5% KOH soln. (10 ml), NaNO2 (0.1 g, 1.45 mmol), and conc.
HCl soln. (5 ml): 0.23 g (85%) of 63. Yellowish solid. M.p. 1308 (dec.). 1H-NMR ((D6)DMSO): 11.51 (s,
HꢀN(1)); 7.30 (m, 5 arom. H); 5.06 (s, CH2N). Anal. calc. for C12H8N6O2 (268.3): C 53.73, H 2.99, N
31.34; found: C 54.00, H 3.09, N 31.13.
53. 8-Diazo-1,3-dimethylxanthine (¼ 8-Diazo-3,8-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 64)
[15]. A soln. of 12 (0.4 g, 2.05 mmol) in 5% HCl soln. (20 ml) was cooled to 0 – 58, and then NaNO2
(0.16 g, 2.32 mmol) was added in four portions. The mixture was stirred for 1.5 h, and the resulting
precipitate washed with H2O and MeOH and dried in a vacuum desiccator: 0.38 g (90%) of 64. Yellowish
powder. M.p. 1558 (dec.). 1H-NMR ((D6)DMSO): 3.41 (s, MeꢀN(3)); 3.24 (s, MeꢀN(1)). Anal. calc. for
C6H6N6O2 (194.2): C 37.11, H 3.11, N 43.28; found: C 37.20, H 3.00, N 43.11.
54. 3-Benzyl-8-diazo-1-methylxanthine (¼ 3-Benyzl-8-diazo-3,8-dihydro-1-methyl-1H-purine-2,6-di-
one; 65). As described for 64, with 13 (0.12 g, 0.44 mmol), 5% HCl soln. (20 ml), and NaNO2 (40 mg,
0.58 mmol): 0.11 g (89%) of 65. Yellowish powder. M.p. 1208 (dec.). 1H-NMR ((D6)DMSO): 7.32 – 7.25
(m, 5 arom. H); 5.13 (s, CH2N); 3.27 (s, MeꢀN(1)). Anal. calc. for C13H10N6O2 · 0.25 H2O (286.7): C
54.45, H 3.57, N 29.29; found: C 55.09, H 3.63, N 29.00.
55. 5-[(3-Methylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,7-Dihydro-3-methyl-8-[2-
(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-dione; 67).
To a soln. of 1,3-dimethylbarbituric acid (66; 81 mg, 0.52 mmol) in buffer pH 8 (10 ml) was added
under stirring 62 (0.1 g, 0.52 mmol) to form a reddish precipitate. After 5 min, the mixture was acidified
by 1n HCl to pH 2 – 3, and stirring was continued for 30 min. The precipitate was washed with H2O
(10 ml) and EtOH (10 ml) and dried at 1008: 0.17 g (94%) of 67. Light red solid. M.p. > 3508. 1H-NMR
((D6)DMSO): 14.00 (br. s, HOꢀC(6), HꢀN(7’)); 11.05 (s, HꢀN(1’)); 3.23 (s, MeꢀN(3’)); 3.20 (s,
2 MeN). Anal. calc. for C12H12N8O5 (348.3): C 41.38, H 3.45, N 32.18; found: C 41.57, H 3.68, N 31.91.
56. 5-[(1,3-Dimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,7-Dihydro-1,3-dimeth-
yl-8-[2-(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-di-
one; 68). As described for 67, with 66 (45 mg, 0.29 mmol) and 64 (60 mg, 0.29 mmol): 94 mg (90%) of 68.
Red powder. M.p. 328 – 3308. Recrystallization from DMF (8 ml) gave 83 mg (79%). 1H-NMR
((D6)DMSO): 14.10 (br. s, HOꢀC(6)); 14.00 (s, HꢀN(7’)); 3.42 (s, MeꢀN(3’)); 3.21 (s, MeꢀN(1’)); 3.20
(s, 2 MeN). Anal. calc. for C13H14N8O5 · 0.5 H2O (371.3): C 42.00, H 3.90, N 30.02; found: C 41.90, H 4.12,
N 30.00.
57. 5-[(1,3,7-Trimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,7-Dihydro-1,3,7-tri-
methyl-8-[2-(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-
2,6-dione; 69). A soln. of 14 (0.1 g, 0.48 mmol) in 5% HCl soln. (15 ml) was cooled in an ice bath to 0 – 58.
Then, NaNO2 (35 mg, 0.51 mmol) was added under stirring, and after 1 h, the yellow soln. was dropwise
added to a cold soln. of 66 (75 mg, 0.48 mmol) in 1n NaOH (15 ml). The pH was adjusted to 8, and after
stirring for 10 min, the mixture was acidified with 1n HCl to pH 1 – 2. The precipitate was washed with
H2O (10 ml) and MeOH (10 ml), and the red solid recrystallized from AcOH (8 ml): 70 mg (39%) of 69.
Light red crystals. M.p. 3208. 1H-NMR ((D6)DMSO): 14.19 (br. s, HOꢀC(6)); 3.95 (s, MeꢀN(7’)); 3.40
(s, MeꢀN(3’)); 3.20 (s, MeꢀN(1’)); 3.18 (s, 2 MeN). Anal. calc. for C14H16N8O5 (376.3): C 44.68, H 4.25,
N 29.78; found: C 44.25, H 4.27, N 29.24.
58. 5-[(7-Methylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,7-Dihydro-7-methyl-8-[2-
(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-dione; 70).
A soln. of 15 (0.15 g, 0.83 mmol) in 5% KOH soln. (30 ml) was cooled in an ice bath to 0 – 58, then,
NaNO2 (60 mg, 0.87 mmol) was added and the soln. acidified by dropwise addition of conc. HCl soln.
(5 ml). After 15 min stirring, the yellow soln. was dropwise added to 66 (0.13 g, 0.83 mmol) in cold 5%
KOH soln. (30 ml), the pH adjusted to 8, and stirring continued for another 15 min. The mixture was
then acidified by 1n HCl (10 ml) and stirred at r.t. for 30 min. The formed precipitate was recrystallized

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Helvetica Chimica Acta – Vol. 93 (2010)
from AcOH (15 ml): 104 mg (36%) of 70. Light red crystals. M.p. > 3508. 1H-NMR ((D6)DMSO): 14.00
(br. s, HOꢀC(6)); 12.10 (s, HꢀN(3’)); 10.80 (s, HꢀN(1’)); 3.91 (s, MeꢀN(7’)); 3.21 (s, 2 MeN). Anal.
calc. for C12H12N8O5 · 0.5 H2O (357.3): C 40.29, H 3.49, N 31.33; found: C 40.30, H 3.20, N 30.85.
59. 5-[(3,7-Dimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,7-Dihydro-3,7-dimeth-
yl-8-[2-(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-di-
one; 71). As described for 70, with 16 (0.1 g, 0.51 mmol), 5% KOH soln. (5 ml), NaNO2 (40 mg,
0.58 mmol), and conc. HCl soln. (3 ml). The diazonium salt soln. was dropwise added to 66 (80 mg,
0.51 mmol) in buffer soln. of pH 8 (15 ml). Acidification and stirring for 5 h gave a red solid.
Recrystallization from AcOH (5 ml) gave 71 mg (38%) of 71. Light red solid. M.p. 3378. 1H-NMR
((D6)DMSO): 14.12 (br. s, HOꢀC(6)); 11.21 (s, HꢀN(1’)); 3.92 (s, MeꢀN(7’)); 3.32 (s, MeꢀN(3’)); 3.21
(s, 2 MeN). Anal. calc. for C13H14N8O5 (362.3): C 43.09, H 3.87, N 30.94; found: C 42.95, H 3.89, N 30.74.
60. 5-[(1,7-Dimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,7-Dihydro-1,7-dimeth-
yl-8-[2-(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-di-
one; 72). As described for 70, with 19 (0.1 g, 0.51 mmol), NaNO2 (40 mg, 0.58 mmol), and 66 (80 mg,
0.51 mmol). Recrystallization from AcOH (5 ml) gave 50 mg (27%) of 72. Reddish crystals. M.p. 3308.
1H-NMR ((D6)DMSO): 14.20 (br. s, HOꢀC(6)); 12.01 (s, HꢀN(3’)); 3.92 (s, MeꢀN(7’)); 3.21 (s,
2 MeN); 3.17 (s, MeꢀN(1’)). Anal. calc. for C13H14N8O5 · 0.25 AcOH (377.3): C 42.97, H 4.00, N 29.70;
found: C 42.97, H 4.06, N 29.53.
61. 5-[(3-Benzyl-7-methylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3-Benzyl-3,7-dihy-
dro-7-methyl-8-[2-(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-pu-
rine-2,6-dione; 73). As described for 70, with 25 (0.14 g, 0.51 mmol) in 5% KOH soln. (10 ml), NaNO2
(40 mg, 0.58 mmol), and 66 (80 mg, 0.51 mmol). After final stirring for 3 h, the formed solid was
recrystallized from AcOH (10 ml): 91 mg (41%) of 73. Light red crystals. M.p. 3308. 1H-NMR
((D6)DMSO): 14.18 (br. s, HOꢀC(6)); 7.30 (m, 5 arom. H); 5.09 (s, CH2N); 3.96 (s, MeꢀN(7’)); 3.21 (s,
2 MeN). Anal. calc. for C19H18N8O5 (438.4): C 52.06, H 4.13, N 25.56; found: C 51.92, H 4.07, N 25.31.
62. 5-[(3-Benzyl-1,7-dimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3-Benzyl-3,7-
dihydro-1,7-dimethyl-8-[(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-
1H-purine-2,6-dione; 74). A soln. of 26 (0.1 g, 0.35 mmol) in 15% HCl soln. (10 ml) was cooled to 0 – 58.
Then, NaNO2 (30 mg, 0.43 mmol) was added in small portions, and the mixture stirred for 15 min. The
yellow soln. was added dropwise to 66 (55 mg, 0.35 mmol) in 5% KOH soln. (10 ml) and, after
acidification with 1n HCl, stirred for 3 h. The formed precipitate was recrystallized from AcOH/MeOH
1:1 (10 ml): 71 mg (45%) of 74. Light red crystals. M.p. 276 – 2778. 1H-NMR ((D6)DMSO): 14.20 (br. s,
HOꢀC(6)); 7.37 – 7.30 (m, 5 arom. H); 5.16 (s, CH2N); 4.00 (s, MeꢀN(7’)); 3.23 (s, MeꢀN(1’)); 3.21 (s,
2 MeN). Anal. calc. for C20H20N8O5 (452.4): C 53.10, H 4.42, N 24.78; found: C 53.03, H 4.37, N 24.76.
63. 5-[(3-Benzyl-7-propylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3-Benzyl-3,7-dihy-
dro-7-propyl-8-[2-(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-pu-
rine-2,6-dione; 75). To a soln. of 28 (0.2 g, 0.57 mmol) and NaNO2 (50 mg, 0.72 mmol) in 5% KOH soln.
(10 ml) was added dropwise under cooling and stirring conc. HCl soln. (4 ml). After 30 min, the yellow
diazonium salt soln. was added to a soln. of 66 (104 mg, 0.67 mmol) in buffer pH 8 (30 ml). Then, the
mixture was acidified with HCl to pH 2 and stirred at r.t. overnight. The orange precipitate was
recrystallized from AcOH/MeOH 1:1 (10 ml): 0.1 g (32%) of 75. Orange crystals. M.p. 2958. 1H-NMR
((D6)DMSO): 14.20 (br. s, HOꢀC(6)); 11.29 (s, HꢀN(1’)); 7.30 – 7.27 (m, 5 arom. H); 5.08 (s, CH2N);
4.33 (t, MeCH2CH2N); 4.00 (s, MeꢀN(7’)); 3.20 (s, 2 MeN); 1.89 – 1.75 (m, MeCH2CH2N); 0.93 (t,
MeCH2). Anal. calc. for C21H22N8O5 (466.4): C 54.08, H 4.72, N 24.03; found: C 54.08, H 4.75, N 23.82.
64. 5-[(3-Benzyl-1-methyl-7-propylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3-Benzyl-
3,7-dihydro-1-methyl-7-propyl-8-[2-(1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)-
diazenyl]-1H-purine-2,6-dione; 76). To a cold soln. of 29 (0.2 g 0.64 mmol) in dioxane (20 ml) and conc.
HCl soln. (2 ml) was added NaNO2 (50 mg, 0.72 mmol) in H2O (2 ml) dropwise with stirring, and after
10 min, this soln. was added to a soln. of 66 (0.1 g, 0.64 mol) in dioxane (20 ml) and AcONa (0.6 g,
0.74 mmol). After addition and stirring for 15 min, the mixture was acidified with HCl to pH 3 and the
precipitate collected after another 2 h of stirring at r.t. Recrystallization from AcOH/MeOH 1:2 (15 ml)
1
gave 61 mg (20%) of 76. Orange crystals. M.p. 2058. H-NMR ((D6)DMSO): 14.16 (br. s, HOꢀC(6));
7.32 – 7.28 (m, 5 arom. H); 5.15 (s, CH2N); 4.41 (t, MeCH2CH2N); 3.23 (s, MeꢀN(1’)); 3.20 (s, 2 MeN);

Helvetica Chimica Acta – Vol. 93 (2010)
2133
1.82 – 1.79 (m, MeCH2CH2N); 0.89 (t, MeCH2). Anal. calc. for C22H24N8O5 · 0.5 AcOH (510.4): C 54.12, H
5.10, N 21.96; found: C 53.98, H 5.04, N 21.96.
65. 5-[(9-Methylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,9-Dihydro-9-methyl-8-[2-
(1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-dione; 77). A soln. of
34 (0.1 g, 0.55 mmol) and NaNO2 (40 mg, 0.68 mmol) in 5% KOH soln. (10 ml) was cooled with ice to 0 –
58, and then conc. HCl soln. (3 ml) was dropwise added. After stirring for 10 min, this soln. was added
slowly to 66 (86 mg, 0.55 mmol) in 5% KOH soln. (20 ml), and then the pH was adjusted to 7 – 8. After
another 10 min, the soln. was acidified to pH 1 – 2 and stirred at r.t. for 3 h. The precipitate was washed
with H2O (10 ml) and MeOH (10 ml) and recrystallized from AcOH (5 ml): 77 mg (40%) of 77. Orange
powder. M.p. > 3508. 1H-NMR ((D6)DMSO): 14.00 (br. s, HOꢀC(6)); 12.11 (s, HꢀN(3’)); 10.90 (s,
HꢀN(1’)); 3.70 (s, MeꢀN(9’)); 3.21 (s, 2 MeN). Anal. calc. for C12H12N8O5 (348.3): C 41.38, H 3.45, N
32.18; found: C 41.40, H 3.53, N 31.70.
66. 5-[(1,9-Dimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,9-Dihydro-1,9-dimeth-
yl-8-[2-(1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-dione; 78). As
described for 77, with 35 (0.1 mg, 0.51 mmol) and NaNO2 (40 mg, 0.58 mmol). The diazonium salt soln.
was added to 66 (80 mg, 0.51 mmol) and finally stirred for 3 h. The precipitate was recrystallized from
AcOH/MeOH 1:1 (10 ml): 57 mg (32%) of 78. Orange powder. M.p. 327 – 3288. 1H-NMR ((D6)DMSO):
14.10 (br. s, HOꢀC(6)); 12.70 (s, HꢀN(3’)); 3.69 (s, MeꢀN(9’)); 3.18 (s, MeꢀN(1’)); 3.20 (s, 2 MeN).
Anal. calc. for C13H14N8O5 · H2O (380.3): C 41.05, H 4.15, N 29.47; found: C 41.25, H 3.94, N 29.25.
67. 5-[(3,9-Dimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,9-Dihydro-3,9-dimeth-
yl-8-[2-(1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-dione; 79). As
described for 77, with 36 (0.1 mg, 0.51 mmol) and NaNO2 (40 mg, 0.58 mmol). The diazonium salt soln.
was added to 66 (80 mg, 0.51 mmol) and finally stirred for 3 h. The precipitate was recrystallized from
AcOH/MeOH 1:1 (10 ml): 62 mg (33%) of 79. Orange powder. M.p. 290 – 2918. 1H-NMR ((D6)DMSO):
14.00 (br. s, HOꢀC(6)); 11.25 (s, HꢀN(1’)); 3.80 (s, MeꢀN(9’)); 3.61 (s, MeꢀN(3’)); 3.21 (s, 2 MeN).
Anal. calc. for C13H14N8O5 · 0.25 AcOH (377.3): C 42.97, H 4.00, N 29.70; found: C 43.17, H 4.16, N 29.29.
68. 5-[(1,3,9-Trimethylxanthin-8-yl)diazenyl]-1,3-dimethylbarbituric Acid (¼ 3,9-Dihydro-1,3,9-tri-
methyl-8-[2-(1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidin-5-yl)diazenyl]-1H-purine-2,6-dione;
80). To a cooled soln. of 37 (0.1 mg, 0.48 mmol) in 5% HCl soln. (15 ml) was added in small portions
NaNO2 (35 mg, 0.48 mmol). After stirring for 1 h, this soln. was added dropwise to 66 (75 mg, 0.48 mmol)
in 1n NaOH (15 ml). The pH was adjusted to 8, and after 15 min, the mixture was acidified by 1n HCl
(10 ml) and stirred for another 30 min. The precipitate was recrystallized from AcOH (5 ml): 80 mg
(44%) of 80. Light red crystals. M.p. 289 – 2908. 1H-NMR ((D6)DMSO): 14.00 (br. s, HOꢀC(6)); 3.87 (s,
MeꢀN(9’)); 3.69 (s, MeꢀN(3’)); 3.21 (s, MeꢀN(1’)); 3.20 (s, 2 MeN). Anal. calc. for C14H16N8O5 (376.3):
C 44.68, H 4.25, N 29.79; found: C 44.27, H 4.42, N 29.58.
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[3] J. H. Lister, ꢃPurinesꢄ, Wiley – Interscience, New York, 1971.
[4] J. H. Lister, ꢃPurinesꢄ, Wiley – Interscience, New York, 1971, p. 31; W. Traube, Ber. Dtsch. Chem. Ges.
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Received July 6, 2010