Pteridines. Part CXIX: A new pteridine - Purine transformation

Article abstract of DOI:10.1002/hlca.200890039

A variety of pyrimidine precursors 12-25 were converted into a series of new 7-hydroxylumazines (=7-hydroxypteridine-2,4(1H,3H)-diones) 26-35 which functioned as starting materials for the transformation into the corresponding 7-chlorolumazines 36-45. Subsequent reaction with hydrazine led to the 7-hydrazinolumazines 46-55 which gave on nitrosation the 7-azidolumazines 1 and 56-64. These compounds were subjected to short heating in xylene whereby 1 and 56-61 showed a new pteridine-purine interconversion in forming a new type of 1,3-disubstituted or 3-substituted xanthin-8-amine-derived nitrilium ylides (2,3,6,7-tetrahydro-N-methylidyne-2,6-dioxo-1H-purin-8-aminium ylides) 11 and 65-70. The presence of an additional 6-alkyl substituent in the 7-azidolumazines 63 and 64 or of an unsubstituted N(3) position in 62 caused further rearrangement to xanthine-9-carbonitriles 71-73. Prolonged heating of 7-azido-1,3-dimethyllumazine (1) also afforded theophylline-9-carbonitrile (=1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purine-9-carbonitrile; 5). The nitrilium ylide function was established by NMR and UV spectra as well as by elemental analyses. Confirmation of the nitrilium ylide structures was suggested by the result of the heating of 1,3-dimethyl-N-methylidynexanthin-8-aminium ylide 11 in EtOH or of 1 in pentan-1-ol leading to 8-aminotheophylline (=8-amino-3,7-dihydro-1,3-dimethyl-1H-purin-2,6-dione; 74).

Full text of DOI:10.1002/hlca.200890039

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Helvetica Chimica Acta – Vol. 91 (2008)
Pteridines
Part CXIX1)
A New Pteridine – Purine Transformation
by Wolfgang Pfleiderer*
Fachbereich Chemie, Universität Konstanz, Postfach 5560, D-78457 Konstanz
(phone: þ 497531-882279)
A variety of pyrimidine precursors 12 – 25 were converted into a series of new 7-hydroxylumazines
(¼ 7-hydroxypteridine-2,4(1H,3H)-diones) 26 – 35 which functioned as starting materials for the
transformation into the corresponding 7-chlorolumazines 36 – 45. Subsequent reaction with hydrazine
led to the 7-hydrazinolumazines 46 – 55 which gave on nitrosation the 7-azidolumazines 1 and 56 – 64.
These compounds were subjected to short heating in xylene whereby 1 and 56 – 61 showed a new
pteridine – purine interconversion in forming a new type of 1,3-disubstituted or 3-substituted xanthin-8-
amine-derived nitrilium ylides (2,3,6,7-tetrahydro-N-methylidyne-2,6-dioxo-1H-purin-8-aminium ylides)
11 and 65 – 70. The presence of an additional 6-alkyl substituent in the 7-azidolumazines 63 and 64 or of
an unsubstituted N(3) position in 62 caused further rearrangement to xanthine-9-carbonitriles 71 – 73.
Prolonged heating of 7-azido-1,3-dimethyllumazine (1) also afforded theophylline-9-carbonitrile
(¼1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purine-9-carbonitrile; 5). The nitrilium ylide function
was established by NMR and UV spectra as well as by elemental analyses. Confirmation of the nitrilium
ylide structures was suggested by the result of the heating of 1,3-dimethyl-N-methylidynexanthin-8-
aminium ylide 11 in EtOH or of 1 in pentan-1-ol leading to 8-aminotheophylline (¼ 8-amino-3,7-dihydro-
1,3-dimethyl-1H-purin-2,6-dione; 74).
1. Introduction. – The chemistry of nitrilium ylides [2] has been under investigation
for more then 40 years and revealed numerous syntheses which generate this reactive
function under a variety of conditions [3 – 6]. It is generally agreed that only in special
cases, a stable isolable nitrilium ylide can be expected due to the high reactivity of this
functionality in 1,3-dipolar cycloaddition reactions and towards nucleophiles. The
synthesis of a stable nitrilium ylide could be achieved by Janulis and Arduengo [7]
during photolysis of diazotetrakis(trifluoromethyl)cyclopentadiene in presence of
adamantane-1-carbonitrile to form adamantane-1-carbonitrilium 2,3,4,5-tetrakis(tri-
fluoromethyl)cyclopenta-2,4-dien-1-ylide (¼ N-(adamantan-1-ylmethylidyne)-2,3,4,5-
tetrakis(trifluoromethyl)cyclopenta-2,4-dien-1-aminium ylide) which was crystallized
and its structure established unequivocally by X-ray structure determination [8]. This
result is not unexpected in view of the anion-stabilizing ability of the tetrakis(tri-
fluoromethyl)cyclopentadienylide moiety as well as the steric bulk of the adamantyl
residue. The first example of a thermally generated nitrilium ylide is derived from 5-
1
)
Part CXVIII: [1].
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 91 (2008)
339
(tert-butyl)-2,3-dihydro-2,2,2-trimethoxy-3,3-bis(trifluoromethyl)-1,4,2,l5-oxazaphos-
phole by vacuum flash pyrolysis at 4008/10À3 Torr and matrix isolation at À 1968 [9].
Our interest in nitrilium ylides arose more or less accidentially during studies of
various 7-azidolumazine derivatives which turned out to rearrange in the solid state and
in inert solvents on heating [10]. We noticed that 7-azido-1,3-methyllumazine (¼ 7-
azidopteridine-2,4(1H,3H)-dione; 1) converts on drying at 1008 in the oven in a solid-
state reaction without change of its habitus into a new product which was identified as
theophylline-9-carbonitrile (¼1,3-dimethylxanthine-9-carbonitrile ¼ 1,2,3,6-tetrahy-
dro-1,3-dimethyl-2,6-dioxo-9H-purine-9-carbonitrile; 5) (Scheme 1). We assume that
this new pteridine – purine ring contraction proceeds most likely via the intermediate
nitrene 2 followed by a ꢁzwittazidoꢂ cleavage [11][12] to the intermediates 3 and 4
respectively, which can cyclize in one step to 1,3-dimethylxanthine-9-carbonitrile (5) or
via the 8-carbonitrile isomer 6 and a subsequent 1,5-sigmatropic shift of the functional
group.
Scheme 1
There are already some literature precedences of analogous ring contractions of 2-
azidopyrazines into 1H-imidazole-1-carbonitriles [13 – 15]. Ring expansion and ring
contraction of arylcarbenes and arylnitrenes is a subject of longstanding interest,
especially in the group of Wentrup [16][17] and others [18 – 20]. We will add to this
exiting field our results and describe here the experiments in detail which led to a new
type of stable nitrilium ylides [10].

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2. Syntheses and Results. – In a second experiment, we heated 7-azido-1,3-
dimethyllumazine (1) in xylene under reflux and obtained a relatively insoluble
material isomeric with 5 according to elemental analysis and the distinct differences in
UV and IR spectra. Treatment of this product in H2O or BuOH led to 8-amino-
theophylline (¼ 8-amino-1,3-dimethylxanthine) indicating that another pyrazine-ring
contraction has taken place on heating of 1 in an aprotic solvent. The NMR spectrum in
(D6)DMSO established that the structure of theophyllin-8-yl isocyanide (¼ 8-isocyano-
1,3-dimethylxanthine; 7) had to be excluded as a structural possibility due to the
presence of a s at d 8.58 which is rather a CH than a NH signal considering its stability in
a D2O-exchange experiment. Since heterocyclic azides [21 – 28] show a broad variety of
reactions, the structures of a cyclic carbodiimide 8, a condensed 1,3-diazeto[1,2-f]purine
derivative 9, a spiro compound 10, or a resonance-stabilized nitrilium ylide 11 could not
a priori be eliminated. It was obvious that the solution of this structural problem would
arise from spectral data and comparisons with model substances. From the IR spectrum
which exhibits a characteristic band at 2180 cmÀ1, we concluded that the cyclic
carbodiimide 8, the tricyclic ring system 9, and the spiro structure 10 were very much
unlikely, leaving the resonance-stabilized nitrilium ylide 11 as the most favourable
structure for the isomer of 5. The UV spectrum in MeOH shows two strong absorption
bands at 234 and 295 nm and a shoulder at 259 nm which resembled best the data of 8-
ethynyltheophylline [29] as the closest structural analog.
More 7-azidolumazines, i.e., 56 – 64, were synthesized by the same sequence of
reactions starting from the appropriate known and new 1-substituted and 1,3-
disubstituted 6-aminouracils (¼6-aminopyrimidine-2,4(1H,3H)-diones) 12 – 16 first
by nitrosation (!17 – 20), followed by reduction to the 5,6-diamino derivatives which
were condensed with ethyl or methyl glyoxylate (¼ethyl or methyl 2-oxoacetate)
(!21 – 25) and ethyl pyruvate (¼ethyl 2-oxopropanoate) forming, on ring closure, the
7-hydroxylumazines 26 – 35 (Scheme 2). Reaction with POCl3 led to the corresponding
7-chlorolumazines 36 – 45 which on treatment with hydrazine showed easy nucleophilic
displacement of the Cl-atom to give 46 – 55. Finally, NaNO2 treatment in acidic medium
yielded the 7-azidolumazines 1 and 56 – 64.

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341
Scheme 2
Thermolysis of 56 – 64 proceded in an analogous manner to that of 1, leading to the
nitrilium ylides 65 – 70 of which the 1-isopropyl-3-methyl-, the 1-neopentyl-3-methyl-,
the 1-neopentyl-3-octyl-, and the 1,3-dipropylxanthin-8-aminium ylides (¼ nitrilium
ylides) 67 – 70 showed much better solubilities than the 1,3-dimethyl-substituted 11,

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thus improving handling. The presence of an additional alkyl substituent at C(6) of the
7-azidolumazines 63 and 64 or the removal of the N(1) substituent such as in 62 did not
favor the nitrilium ylide formation but led to the corresponding xanthine-9-carbo-
nitriles 71 – 73.
In the case of 7-azido-1,3,6-trimethyllumazine (63), the formation of the
corresponding nitrilium ylide could only be detected on photolysis in MeOH as an
intermediate which was further hydrolyzed to give 8-aminotheophylline 74 (Scheme 3
and Fig.).
Scheme 3
More structural information was finally obtained from the 13C-NMR spectra which
were in excellent agreement with the proposed stable nitrilium ylide structures 11 and
65 – 70. The well-soluble nitrilium ylide 69, in a gated decoupling experiment in CDCl3,
exhibits a 1H,13C coupling constant of 246 Hz for the signal at d(C) 145.5 which is due
to the nitrilium moiety of the molecule, thus establishing directly this unusual structure.
Another long-range coupling (J ¼ 10 Hz) is observed for the signal at d(C) 110.1 which
has to be assigned logically to the C(8) atom. Comparisons of the 13C-NMR spectra of
the purinium betaine structures with those of the other xanthine derivatives (Table)
reveal the different electron distributions in both systems showing close similarities
only at C(2), C(4), and C(6), whereas in the zwitterion molecules, the chemical shifts of
C(5) are moved downfield to some extent, and C(8) is shifted tremendously upfield
indicating a relatively high electron density at this center.
Regarding the mechanism of the nitrilium ylide formation, we assume first cleavage
of the nitrene such as 2 to 3 which shows an electrocyclization to 8 followed by a
valence tautomerism to 9 and finally ring opening to 11.
3. Conclusions. – The unusually high thermodynamical stability of the new type of
heterocyclic nitrilium ylides is due to a strong resonance stabilization of the negatively
charged anion moiety of the molecules which can be described by a series of resonance
structures (Scheme 4).
With the zwitterions of type 11 we have isolated for the first time stable nitrilium
ylides which do not require a further bulky substituent at the nitrilium C-atom to
counteract secondary reactions.

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Figure. Photolysis of 7-azido-1,3,6-trimethyllumazine (63) in MeOH
Scheme 4

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Table. Spectral Data of Theophylline (75) and Purin-8-aminium Ylide Derivatives
UV (MeOH)
IR
13C-NMR ((D6)DMSO)
lmax [nm] log e [cmÀ1
]
C(6) C(2) C(4) C(8) C(5) XꢀC
75 270
4.02
154.0 150.9 147.5 139.9 106.1
230 (sh), 3.85, 2258
152.7 150.7 147.3 146.0 106.8 103.0
155.7 149.9 137.2 140.0 114.6 103.0
154.0 150.6 146.5 121.1 111.4 110.3
283
3.84
5
245,
260 (sh)
4.00, 2260
3.94
218,
296
4.38, 2220
4.12
222,
4.40, 2140
153.7 150.9 147.0 131.8 107.2
84.0,
73.5
246 (sh), 3.63,
294
4.25
11 234,
4.22, 2180
156.9 154.9 147.8 109.4 114.2 146.5
250 (sh), 3.95,
295
4.21
67 237,
4.19, 2200
4.19
156.9 154.9 147.8 109.4 114.2 146.6
250 (sh), 3.97,
296

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345
Table (cont.)
UV (MeOH)
IR
13C-NMR ((D6)DMSO)
lmax [nm] log e [cmÀ1
]
C(6) C(2) C(4) C(8) C(5) XꢀC
68 237,
4.19, 2129
157.6 154.1 149.1 109.5 114.3 146.8
250 (sh), 3.98,
297
4.19
69 228,
4.22, 2180
4.25
157.7 152.7 148.8 110.1 114.5 145.5
250 (sh), 3.98,
297
Experimental Part
General. TLC: precoated cellulose thin-layer sheets F 1440bLS 254 and silica gel thin-layer sheets F
1500 LS 254 from Schleicher & Schüll. Prep. TLC: silica gel 60 PF 254 from Merck. M.p.: Büchi-B-545
melting point apparatus; no corrections. pKa Values: measurements by the spectrophotometric method
[30]. UV: Perkin-Elmer-Lambda-15 spectrometer; lmax (log e) in nm, sh ¼ shoulder. 1H-NMR: Bruker-
WM-250 spectrometer; d in ppm rel. to Me4Si, J in Hz.
7-Azido-1,3-dimethylpteridine-2,4(1H,3H)-dione (1). To a suspension of 7-hydrazinyl-1,3-dime-
thylpteridine-2,4(1H,3H)-dione (46; 2.22 g, 10 mmol) in H2O (100 ml) was added NaNO2 (0.8 g,
11.6 mmol) with stirring and then dropwise conc. HCl soln. (2 ml). The solid was changing without the
intermediate formation of a soln. and was filtered off after 30 min, washed with EtOH and Et2O, and
dried in a vacuum desiccator: 1.9 g (81%) of 1. Crystal powder. M.p. 1558. UV (MeOH): 218 (4.24), 253
(4.14), 268 (sh, 3.98), 300 (3.46), 350 (4.18). 1H-NMR ((D6)DMSO): 8.25 (s, HÀC(6)); 3.51 (s,
MeÀN(1)); 3.31 (s, MeÀN(3)). Anal. calc. for C8H7N7O2 (233.2): C 41.20, H 3.03, N 42.05; found: C
41.38, H 3.34, N 42.09.
1,2,3,6-Tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purine-9-carbonitrile (5). A soln. of 1 (1.0 g, 4.3 mmol)
in abs. xylene (100 ml) was heated under reflux for 30 min. After 5 min refluxing, a brownish precipitate
started to separate, which was filtered off after cooling to give 0.45 g of 11. The filtrate was concentrated
and the residue recrystallized from EtOH (50 ml) with charcoal: 0.12 g (14%) of 5. Colorless needles.
M.p. 218 – 2208. UV (MeOH): 245 (4.00), 260 (sh, 3.94). 1H-NMR ((D6)DMSO): 8.53 (s, HÀC(8)); 3.66
(s, MeÀN(1)); 3.25 (s, MeÀN(3)). Anal. calc. for C8H7N5O2 (205.2): C 46.83, H 3.44, N 34.12; found: C
46.70, H 3.39, N 34.10.
2,3,6,7-Tetrahydro-1,3-dimethyl-N-methylidyne-2,6-dioxo-1H-purin-8-aminium Inner Salt (11). For
30 min, 1 (0.8 g, 3.4 mmol) was heated under reflux in dry xylene (30 ml). A precipitate separated from
the clear soln. after 5 – 10 min. The solid was collected from the hot soln., washed with Et2O and dried in a
vacuum desiccator: 0.49 g (70%) of 11. Crystal powder. M.p. 250 – 2538. UV (MeOH): 234 (4.22), 250
1
(sh, 3.95), 295 (4.21). H-NMR ((D6)DMSO): 8.62 (s, CÀH); 3.48 (s, MeÀN(3)); 3.36 (s, MeÀN(1)).
Anal. calc. for C8H7N5O2 (205.2): C 46.83, H 3.44, N 34.12; found: C 46.49, H 3.30, N 34.01.
6-Amino-1-isopropylpyrimidine-2,4(1H,3H)-dione (12) [31]. Isopropylurea (10.2 g, 0.1 mol) was
dissolved in 3n NaOEt soln. (100 ml) and heated under reflux. Then 2-cyanoacetic acid methyl ester
(11 ml, 0.11 mol) was added dropwise, and the mixture was heated for 4 h. After evaporation, the residue
was dissolved in H2O (100 ml), the soln. acidified with AcOH to pH 5 and continuously extracted with
AcOEt, the extract evaporated, and the residue recrystallized from acetone: 8.5 g (60%) of 12. Colorless

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Helvetica Chimica Acta – Vol. 91 (2008)
crystals. M.p. 2488. UV (MeOH): 269 (4.46). 1H-NMR ((D6)DMSO): 10.35 (br. s, HÀN(3)); 6.71 (br. s,
NH2): 4.69 (s, HÀC(5)); 4.48 (q, Me2CH); 1.41 (d, Me2CH). Anal. calc. for C7H11N3O2 (169.2): C 49.70, H
6.60, N 24.80; found: C 49.72, H 6.85, N 24.85.
6-Amino-1-isopropyl-3-methylpyrimidine-2,4(1H,3H)-dione (13) [32]. A soln. of 12 (1.69 g,
10 mmol) in 1n NaOH (10 ml) was treated at 358 dropwise with dimethyl sulfate (1.1 ml). After stirring
for 1 h, the precipitate was collected (0.85 g) and the filtrate extracted several times with CHCl3. The
CHCl3 layer was dried (Na2SO4), and concentrated and the residue combined with the first crop (0.85 g)
and recrystallized from H2O: 1.38 g (75%) of 13. Colorless crystals. M.p. 2088. ([32]: 210 – 2128). UV
(MeOH): 269 (4.48). 1H-NMR ((D6)DMSO): 6.70 (br. s, NH2); 4.68 (s, HÀC(5)); 4.50 (q, Me2CH); 3.03
(s, MeÀN(3)); 1.40 (d, Me2CH). Anal. calc. for C8H13N3O2 (183.2): C 52.45, H 7.15, N 22.93; found: C
52.74, H 8.05, N 22.93.
6-Amino-1-neopentylpyrimidine-2,4(1H,3H)-dione (14). Neopentylurea (13.0 g, 0.1 mol) was dis-
solved in 4n NaOEt soln. (100 ml) and heated under reflux. Then 2-cyanoacetic acid methyl ester (10 ml)
was added dropwise, and the mixture was heated for 4 h. After evaporation, the residue was dissolved in
hot H2O (100 ml) and the soln. acidified with AcOH to pH 5. The precipitate resulting on cooling was
collected and dried: 11.2 g (59%) of 14. Colorless crystals. M.p. 2678. UV (MeOH): 203 (4.02), 268
1
(4.32). H-NMR ((D6)DMSO): 10.29 (s, NH); 6.75 (s, NH2); 4.51 (s, HÀC(5)); 3.67 (s, CH2); 0.89 (s,
Me3C). Anal. calc. for C9H15N3O2 (197.2): C 54.81, H 7.67, N 21.30; found: C 54.25, H 7.81, N 21.07.
6-Amino-3-methyl-1-neopentylpyrimidine-2,4(1H,3H)-dione (15) [32]. A soln. of 14 (5.0 g,
0.025 mol) in 1n NaOH (50 ml) was treated at 358 dropwise with dimethyl sulfate (3.5 g, 0.035 mol).
During stirring for 1 h, a precipitate separated, which was filtered off and dried at 1008: 4.7 g (88%) of 15.
Colorless crystals. M.p. 2298. UV (MeOH): 203 (4.13), 268 (4.30). 1H-NMR ((D6)DMSO): 6.77 (s, NH2);
4.66 (s, HÀC(5)); 3.73 (br. s, CH2); 3.06 (s, MeÀN(3)); 0.89 (s, Me3C). Anal. calc. for C10H17N3O2
(211.3): C 56.85, H 8.11, N 19.89; found: C 56.70, H 8.55, N 19.91.
6-Amino-1-neopentyl-3-octylpyrimidine-2,4(1H,3H)-dione (16). To a soln. of 14 (10.0 g, 0.051 mol)
in DMF (200 ml) was added K2CO3 (20 g) and 1-bromooctane (12 g, 0.0625 mol). Then the mixture was
heated in an oil bath to 708 with stirring. After 3 h and cooling, the insoluble solid was filtered off and
discarded. The filtrate was evaporated and the residue purified by CC (CHCl3). The main fraction was
evaporated and the residue dried in a desiccator over P4O10: 11.2 g (72%) of 16. Colorless solid.
M.p. 1058. UV (MeOH): 203 (4.12), 269 (4.27). 1H-NMR ((D6)DMSO): 6.77 (s, NH2); 4.63 (s, HÀC(5));
3.68 (m, CH2ÀN(1), CH2ÀN(3); 1.43 (m, CH2CH2ÀN(3)); 1.21 (m, 5 CH2); 0.88 (s, Me3C); 0.84 (t,
Me(CH2)7). Anal. calc. for C17H31N3O2 (309.3): C 66.00, H 10.00, N 13.37; found: C 65.85, H 10.06, N
13.55.
6-Amino-1-isopropyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (17). To a soln. of 12 (16.9 g, 0.1 mol) in
EtOH/H2O 1:1 (500 ml) was added NaNO2 (10 g) and then dropwise with stirring AcOH (20 ml) at r.t.
After 3 h, the red precipitate was collected and dried at 1008: 18.0 g (91%) of 17. M.p. 2308. UV (MeOH):
1
227 (4.26), 317 (4.32). H-NMR ((D6)DMSO): 13.93 (br. s, 1 H, NH2ÀC(6)); 11.39 (s, HÀN(3)); 9.12
(br. s, 1 H, NH2ÀC(6)); 4.50 (m, Me2CH); 1.40 (d, Me2CH). Anal. calc. for C7H10N4O3 (198.2): C 42.40,
H 5.10, N 28.30; found: C 42.64, H 5.01, N 28.12.
6-Amino-1-isopropyl-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (18) [32]. To a soln. of 13
(18.3 g, 0.1 mol) in H2O (100 ml) was added at 508 NaNO2 (6.9 g, 0.1 mol), and under stirring dropwise
AcOH (20 ml). After cooling to r.t. and stirring for 1 h, the red precipitate was collected and dried at
1008: 17.1 g (80%) of 18. M.p. 2498. UV (MeOH): 227 (4.20), 317 (4.29). 1H-NMR ((D6)DMSO): 13.78
(br. s, 1 H, NH2ÀC(6)); 9.13 (br. s, 1 H, NH2ÀC(6)); 4.55 (m, Me2CH); 3.35 (s, MeN); 1.40 (d, Me2CH).
Anal. calc. for C8H12N4O3 (212.2): C 45.28, H 5.69, N 26.41; found: C 45.73, H 5.75, N 26.26.
6-Amino-3-methyl-1-neopentyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (19). As described for 18 with
15 (10.05 g, 0.05 mol): 9.8 g (86%) of 19. Dark red crystal. M.p. 2128. UV (MeOH): 227 (4.18), 317
(4.14). 1H-NMR ((D6)DMSO): 13.59 (br. s, 1 H, NH2ÀC(6)); 9.05 (br. s, 1 H, NH2ÀC(6)); 3.81 (s, CH2);
3.27 (s, MeÀN(3)); 0.89 (s, Me3C). Anal. calc. for C10H16N4O3 (240.3): C 49.99, H 6.71, N 23.32; found: C
50.25, H 6.75, N 23.31.
6-Amino-1-neopentyl-5-nitroso-3-octylpyrimidine-2,4(1H,3H)-dione (20). As described for 18, with
16 (15.45 g, 0.05 mol) in H2O/EtOH 1:1 (200 ml): 11.8 g (70%) of 20. Dark red crystals. M.p. 1628. UV
(MeOH): 228 (4.16), 317 (4.11). 1H-NMR ((D6)DMSO): 13.54 (br. s, 1 H, NH2ÀC(6)); 9.05 (br. s, 1 H,

Helvetica Chimica Acta – Vol. 91 (2008)
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NH2ÀC(6)); 3.88 (m, CH2ÀN(1), CH2ÀN(3)); 1.57 (m, CH2CH2ÀN(3)); 1.26 (m, 5 CH2); 0.88 (s,
Me3C); 0.84 (t, Me(CH2)7). Anal. calc. for C17H30N4O3 (338.3): C 60.32, H 8.94, N 16.55; found: C 60.45,
H 9.09, N 16.43.
2-[(6-Amino-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)imino]acetic Acid Ethyl Esters 21 – 24: Gen-
eral Procedure 1 (G.P. 1). The appropriate 6-amino-5-nitrosopyrimidine-2,4(1H,3H)-dione 17 – 20
(0.02 mol) was treated with 20% aq. (NH4)2S soln. (50 ml) at 708 till the red color had disappeared.
Then the mixture was concentrated to half of the volume and the precipitate collected, washed with CS2
to remove some sulfur, and dried in a desiccator. Part of the obtained corresponding 5,6-
diaminopyrimidine-2,4(1H,3H)-dione (0.01 mol) was suspended in H2O (80 ml) and treated with ethyl
glyoxylate ethyl hemiacetal (1.8 g, 0.012 mol) at 508. After stirring for 1.5 h at r.t., the precipitate was
collected and dried at 1008.
2-[(6-Amino-1,2,3,4-tetrahydro-1-isopropyl-2,4-dioxopyrimidin-5-yl)imino]acetic Acid Ethyl Ester
(21). According to the G.P. 1 with 5,6-diamino-1-isopropylpyrimidine-2,4(1H,3H)-dione (1.84 g): 2.22 g
(83%) of 21. Pale yellow crystal powder. M.p. 2248. UV (MeOH): 277 (4.11), 352 (4.42). 1H-NMR
((D6)DMSO): 10.87 (s, HÀN(3)); 8.87 (s, CHCOOEt); 7.54 (br. s, NH2); 4.59 (m, Me2CH); 4.19 (q,
MeCH2); 1.44 (d, Me2CH); 1.25 (t, MeCH2). Anal. calc. for C11H16N4O4 (268.2): C 49.20, H 6.00, N 20.90;
found: C 49.18, H 5.75, N 20.90.
2-[(6-Amino-1,2,3,4-tetrahydro-1-isopropyl-3-methyl-2,4-dioxopyrimidin-5-yl)imino]acetic Acid
Ethyl Ester (22). According to the G.P. 1, with 5,6-diamino-1-isopropyl-3-methylpyrimidine-
2,4(1H,3H)-dione (1.98 g): 2.68 g (95%) of 22. Pale yellow crystal powder. M.p. 2048. UV (MeOH):
278 (4.05), 352 (4.37). 1H-NMR ((D6)DMSO): 8.88 (s, CHCOOEt); 7.56 (br. s, NH2); 4.63 (m, Me2CH);
4.20 (q, MeCH2); 3.10 (s, MeÀN(3)); 1.46 (d, Me2CH); 1.26 (t, MeCH2). Anal. calc. for C12H18N4O4 · H2O
(290.3): C 49.64, H 6.94, N 19.30; found: C 49.14, H 6.82, N 19.08.
2-[(6-Amino-1,2,3,4-tetrahydro-3-methyl-1-neopentyl-2,4-dioxopyrimidin-5-yl)imino]acetic Acid
Ethyl Ester (23). According to the G.P. 1 with 5,6-diamino-3-methyl-1-neopentylpyrimidine-
2,4(1H,3H)-dione (2.26 g): 2.79 g (90%) of 23. Pale yellow crystal powder. M.p. 2038. UV (MeOH):
205 (4.10), 277 (4.08), 352 (4.31). 1H-NMR ((D6)DMSO): 8.90 (s, CHCOOEt); 7.59 (br. s, NH2); 4.20 (q,
MeCH2); 3.91 (s, CH2); 3.14 (s, MeÀN(3)); 1.27 (t, MeCH2); 0.92 (s, Me3C). Anal. calc. for C14H22N4O4
(310.35): C 54.18, H 7.15, N 18.07; found: C 54.17, H 7.57, N 18.10.
2-[(6-Amino-1,2,3,4-tetrahydro-1-neopentyl-3-octyl-2,4-dioxopyrimidin-5-yl)imino]acetic Acid Ethyl
Ester (24). The nitroso derivative 20 (6.76 g, 0.02 mol) in EtOH (200 ml) was reduced catalytically with
PtO2 in a shaking apparatus under H2. After uptake of 900 ml of H2, the catalyst was filtered off, and
ethyl glyoxylate ethyl hemiacetal (10 g) was added to the filtrate. After stirring overnight, the solvent was
evaporated, the residue dissolved in AcOEt (20 ml), and hexane (50 ml) added to achieve crystallization.
After cooling in the icebox, the precipitate was collected and dried at 808: 6.28 g (77%) of 24. Pale yellow
crystal powder. M.p. 1748. UV (MeOH): 206 (4.11), 278 (4.07), 352 (4.29). 1H-NMR ((D6)DMSO): 8.90
(s, CHCOOEt); 7.60 (br. s, NH2); 4.21 (q, MeCH2); 3.92 (s, CH2ÀN(1)); 3.76 (t, CH2ÀN(3)); 1.48 (m,
CH2CH2ÀN(3)); 1.28 (t, MeCH2); 1.24 (m, 5 CH2); 0.91 (s, Me3C); 0.84 (t, Me(CH2)7). Anal. calc. for
C21H36N4O4 (408.5): C 61.20, H 8.80, N 13.60; found: C 61.35, H 8.82, N 13.60.
2-[(6-Amino-1,2,3,4-tetrahydro-2,4-dioxo-1,3-dipropylpyrimidin-5-yl)imino]acetic Acid Methyl Ester
(25). A suspension of 5,6-diamino-1,3-dipropylpyrimidine-2,4(1H,3H)-dione [33] (11.3 g, 0.05 mol) in
H2O (100 ml) and EtOH (50 ml) was treated under stirring with methyl glyoxalate ethyl hemiacetal
(12.0 g, 0.8 mol). The mixture was heated to 508 for 1 h, and then the precipitate was filtered off and dried
at 608: 13.5 g (87%) of 25. Yellowish crystal powder which was recrystallized from EtOH. M.p. 177 –
1788. UV (MeOH): 204 (4.00), 233 (4.08), 275 (4.03), 353 (4.26). 1H-NMR ((D6)DMSO): 8.19 (s,
CHCOOMe); 7.60 (br. s, NH2); 4.19 (t, CH2ÀN(1)); 3.91 (t, CH2ÀN(3)); 3.76 (s, MeO); 1.55 (m,
2 CH2CH2N); 0.92 (m, 2 MeCH2CH2N). Anal. calc. for C13H20N4O4 (296.4): C 52.68, H 6.80, N 18.91;
found: C 52.88, H 6.78, N 18.97.
1-Monosubstituted and 1,3-Disubstituted 7-Hydroxypteridine-2,4(1H,3H)-diones 26 – 35: General
Procedure 2 (G.P. 2). The appropriate [(6-amino-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)imino]ace-
tic acid ester 21 – 25 (0.01 mol) was heated under reflux in 1n NaHCO3 (40 ml) and EtOH (10 ml) for 1 h.
The mixture was carefully acidified with HCl to pH 0, and after cooling, the precipitate was collected and
dried at 1008.

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7-Hydroxy-1-isopropylpteridine-2,4(1H,3H)-dione (28). According to the G.P. 2, with 21 (2.68 g):
2.18 g (91%) of 28. Colorless crystal powder. M.p. 2708. UV (MeOH): 206 (4.33), 264 (3.93), 325 (4.24).
1H-NMR ((D6)DMSO): 13.02 (br. s, OH); 11.55 (s, HÀN(3)); 7.96 (s, HÀC(6)); 5.51 (m, Me2CH); 1.46
(d, Me2CH). Anal. calc. for C9H10N4O3 · H2O (240.2): C 45.00, H 5.04, N 23.33; found: C 45.50, H 5.25, N
23.43.
7-Hydroxy-1-isopropyl-3-methylpteridine-2,4(1H,3H)-dione (29). According to the G.P. 2, with 22
(2.90 g): 2.15 g (91%) of 29. Colorless crystal powder. M.p. 2458. UV (MeOH): 209 (4.32), 264 (3.88),
325 (4.25). 1H-NMR ((D6)DMSO): 13.07 (br. s, OH); 8.00 (s, HÀC(6)); 5.47 (m, Me2CH); 3.29 (s,
MeÀN(3)); 1.48 (d, Me2CH). Anal. calc. for C10H12N4O3 (236.2): C 50.85, H 5.11, N 23.72; found: C 51.13,
H 5.46, N 23.90.
7-Hydroxy-3-methyl-1-neopentylpteridine-2,4(1H,3H)-dione (30). According to the G.P. 2, with 23
(3.10 g): 2.11 g (80%) of 30. Colorless crystal powder. M.p. 3008. UV (MeOH): 208 (4.37), 265 (3.84),
326 (4.12). 1H-NMR ((D6)DMSO): 12.97 (br. s, OH); 7.99 (s, HÀC(6)); 4.06 (s, CH2); 3.28 (s,
MeÀN(3)); 0.92 (s, Me3C). Anal. calc. for C12H16N4O3 (264.3): C 54.54, H 6.10, N 21.20; found: C 54.52,
H 6.53, N 21.27.
7-Hydroxy-1-neopentyl-3-octylpteridine-2,4(1H,3H)-dione (31). According to the G.P. 2, with 24
(4.1 g): 3.27 g (86%) of 31. Colorless crystal powder. M.p. 2558. UV (MeOH): 211 (4.36), 265 (3.85), 327
(4.14). 1H-NMR ((D6)DMSO): 13.05 (br. s, OH); 8.00 (s, HÀC(6)); 4.07 (s, CH2ÀN(1)); 3.90 (m,
CH2ÀN(3)); 1.55 (t, CH2CH2ÀN(3)); 1.24 (m, 5 CH2); 0.90 (s, Me3C); 0.83 (t, Me(CH2)7). Anal. calc. for
C19H30N4O3 · H2O (380.5): C 60.00, H 8.40, N 14.74; found: C 60.40, H 8.13, N 14.88.
7-Hydroxy-1,3-dipropylpteridine-2,4(1H,3H)-dione (32). According to the G.P. 2, with 25 (2.96 g):
2.0 g (76%) of 32. Colorless crystals. M.p. 2388. UV (MeOH): 210 (4.45), 270 (4.04), 326 (4.22).
1H-NMR ((D6)DMSO): 13.16 (br. s, OH); 8.00 (s, HÀC(6)); 4.06 (t, CH2ÀN(1)); 3.86 (t, CH2ÀN(3));
1.60 (m, CH2CH2ÀN(1), CH2CH2ÀN(3)); 0.90 (m, 2 MeCH2CH2N). Anal. calc. for C12H16N4O3 (264.3):
C 54.53, H 6.10, N 21.20; found: C 54.65, H 6.07, N 21.11.
7-Chloropteridine-2,4(1H,3H)-diones 36 – 45: General Procedure 3 (G.P. 3). Treatment of the
appropriate 7-hydroxypteridine-2,4(1H,3H)-dione 26 – 35 (0.04 mol) in POCl3 (200 ml) in presence of
KCl (10 g) for 5 h at 90 – 958 gave a clear soln. The POCl3 was evaporated and the residue treated with ice
(200 g) to give a colorless crystal powder which was washed with H2O and dried in a vacuum desiccator
over P4O10. The substances are chromatographically pure. Samples for elemental analysis were
recrystallized from H2O, EtOH, or H2O/EtOH.
7-Chloro-1,3-dimethylpteridine-2,4(1H,3H)-dione (36) [34]. According to the G.P. 3, with 7-
hydroxy-1,3-dimethylpteridine-2,4(1H,3H)-dione · H2O (26) [35] (9.04 g): 8.23 g (91%) of 36.
1
M.p. 1858. ([34]: 1848). UV (MeOH): 205 (4.15), 240 (4.14), 335 (3.99). H-NMR ((D6)DMSO): 8.68
(s, HÀC(6)); 3.49 (s, MeÀN(1)); 3.32 (s, MeÀN(3)).
7-Chloro-1-methylpteridine-2,4(1H,3H)-dione (37) [36]. According to the G.P. 3, with 7-hydroxy-1-
methylpteridine-2,4(1H,3H)-dione · H2O (27) [37] (8.48 g): 7.2 g (85%) of 37. M.p. 2858. ([36]: 284 –
1
2868). UV (MeOH): 203 (4.30), 237 (4.08), 335 (3.99). H-NMR ((D6)DMSO): 12.07 (s, NH); 8.63 (s,
HÀC(6)); 3.40 (s, MeÀN(1)). Anal. calc. for C7H5ClN4O2 (212.6): C 39.54, H 2.37, N 26.36; found: C
39.59, H 2.25, N 26.18.
7-Chloro-1-isopropylpteridine-2,4(1H,3H)-dione (38). According to the G.P. 3, with 28 (9.6 g): 7.49 g
(78%) of 38. M.p. 2268. UV (MeOH): 237 (4.09), 336 (4.13). 1H-NMR ((D6)DMSO): 11.95 (s, NH); 8.62
(s, HÀC(6)); 5.30 (m, Me2CH); 1.47 (d, Me2CH). Anal. calc. for C9H9ClN4O2 (240.6): C 44.92, H 3.77, N
23.29; found: C 44.96, H 3.64, N 23.01.
7-Chloro-1-isopropyl-3-methylpteridine-2,4(1H,3H)-dione (39). According to the G.P. 3, with 29
1
(9.44 g): 8.15 g (80%) of 39. M.p. 1818. UV (MeOH): 243 (4.16), 335 (4.10). H-NMR ((D6)DMSO):
8.67 (s, HÀC(6)); 5.39 (m, Me2CH); 3.30 (s, MeÀN(3)); 1.49 (d, Me2CH). Anal. calc. for C10H11ClN4O2
(254.6): C 47.16, H 4.35, N 22.00; found: C 47.46, H 4.63, N 22.31.
7-Chloro-3-methyl-1-neopentylpteridine-2,4(1H,3H)-dione (40). According to the G.P. 3, with 30
(10.56 g): 8.03 g (71%) of 40. M.p. 1668. UV (MeOH): 205 (4.22), 240 (4.17), 335 (3.96). 1H-NMR
((D6)DMSO): 8.67 (s, HÀC(6)); 4.07 (s, CH2ÀN(1)); 3.32 (s, MeÀN(3)); 0.93 (s, Me3C). Anal. calc. for
C12H15ClN4O2 (282.7): C 50.98, H 5.35, N 19.81; found: C 50.86, H 5.64, N 19.85.

Helvetica Chimica Acta – Vol. 91 (2008)
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7-Chloro-1-neopentyl-1-octylpteridine-2,4(1H,3H)-dione (41). According to the G.P. 3, with 31
(15.22 g): 13.0 g (86%) of 41. M.p. 858. UV (MeOH): 205 (4.26), 245 (4.17), 335 (3.97). 1H-NMR
(CDCl3): 8.45 (s, HÀC(6)); 4.21 (s, CH2ÀN(1)); 4.08 (t, CH2ÀN(3)); 1.30 (m, CH2CH2ÀN(3)); 1.23 (m,
5 CH2); 0.94 (s, Me3C); 0.85 (t, Me(CH2)7). 1H-NMR ((D6)DMSO): 8.66 (s, HÀC(6)); 4.07 (s,
CH2ÀN(1)); 3.94 (t, CH2ÀN(3)); 1.58 (t, CH2CH2ÀN(3)); 1.27 (m, 5 CH2); 0.92 (s, Me3C); 0.85 (t,
Me(CH2)7). Anal. calc. for C19H29ClN4O2 (380.7): C 59.88, H 7.62, N 14.70; found: C 60.08, H 7.85, N
14.77.
7-Chloro-1,3-dipropylpteridine-2,4(1H,3H)-dione (42). According to the G.P. 3, with 35 (10.56 g):
8.14 g (72%) of 42. M.p. 1168. UV (MeOH): 205 (4.08), 243 (4.07), 336 (3.92). 1H-NMR (CDCl3): 8.50
(s, HÀC(6)); 4.24 (s, CH2ÀN(1)); 4.08 (t, CH2ÀN(3)); 1.75 (m, CH2CH2ÀN(1), CH2CH2ÀN(3)); 0.98
(m, 2 MeCH2CH2N). Anal. calc. for C12H15ClN4O2 (282.7): C 50.98, H 5.35, N 19.82; found: C 50.94, H
5.32, N 19.80.
7-Chloro-3-methylpteridine-2,4(1H,3H)-dione (43) [36]. According to the G.P. 3, with 7-hydroxy-3-
methylpteridine-2,4(1H,3H)-dione · H2O (33) [37] (8.48 g): 7.23 g (85%) of 43. M.p. 306 – 3088 ([36]:
308 – 3108). UV (MeOH): 202 (4.24), 236 (4.12), 333 (4.00). 1H-NMR ((D6)DMSO): 12.48 (s, NH); 8.61
(s, HÀC(6)); 3.25 (s, MeN).
7-Chloro-1,3,6-trimethylpteridine-2,4(1H,3H)-dione (44) [36]. According to the G.P. 3, with 7-
hydroxy-1,3,6-trimethylpteridine-2,4(1H,3H)-dione (34) [38] (8.88 g): 8.83 g (92%) of 44. M.p. 1608.
([36]: 1618). UV (MeOH): 202 (4.25), 242 (4.21), 340 (4.01). 1H-NMR (CDCl3): 3.65 (s, MeÀN(1)); 3.50
(s, MeÀN(3)); 2.74 (s, MeÀC(6)).
7-Chloro-6-isopropyl-1,3-dimethylpteridine-2,4(1H,3H)-dione (45). According to the G.P. 3, with 7-
hydroxy-6-isopropyl-1,3-dimethylpteridine-2,4(1H,3H)-dione (35) [39] (10.0 g): 9.0 g (84%) of 45 which
1
was recrystallized from MeOH. M.p. 1478. UV (MeOH): 203 (4.23), 243 (4.23), 340 (4.01). H-NMR
((D6)DMSO): 3.51 (m, Me2CH); 3.47 (s, MeÀN(1)); 3.31 (s, MeÀN(3)); 1.27 (d, Me2CH). Anal. calc. for
C11H13ClN4O2 (269.7): C 48.98, H 4.86, N 20.78; found: C 49.17, H 4.83, N 20.93.
7-Hydrazinylpteridine-2,4(1H,3H)-diones 46 – 55: General Procedure 4 (G.P. 4). A suspension of the
appropriate 7-chloropteridine-2,4(1H,3H)-dione 36 – 45 (10 mmol) in EtOH (100 ml) was treated with
hydrazine hydrate (10 ml) by gentle warming to 508 to give a clear soln. from which, after a few minutes, a
yellowish precipitate separated out. After cooling to r.t. and stirring for 30 min, the solid was collected
and recrystallized from H2O or H2O/EtOH.
7-Hydrazinyl-1,3-dimethylpteridine-2,4(1H,3H)-dione (46) [40]. According to the G.P. 4, with 36
(2.26 g): 1.70 g (77%) of 46 which was recrystallized from DMF. Yellowish needles. M.p. 2708 ([40]:
2718). UV (MeOH): 218 (4.28), 282 (3.87), 343 (4.05). 1H-NMR ((D6)DMSO): 9.20 (s, NHNH2); 7.95 (s,
HÀC(6)); 4.73 (br. s, NHNH2); 3.45 (s, MeÀN(1)); 3.24 (s, MeÀN(3)).
7-Hydrazinyl-1-methylpteridine-2,4(1H,3H)-dione (47). According to the G.P. 4, with 37 (2.13 g):
1.70 g (77%) of 47. Yellowish needles. M.p. 2708. UV (MeOH): 218 (4.28), 282 (3.87), 343 (4.05).
1H-NMR ((D6)DMSO): 11.30 (s, NH); 9.40 (br. s, NHNH2); 7.95 (br. s, HÀC(6)); 4.75 (s, NHNH2); 3.38
(s, MeN). Anal. calc. for C7H8N6O2 (208.2): C 40.38, H 3.87, N 40.37; found: C 40.08, H 4.09, N 40.17.
7-Hydrazinyl-1-isopropylpteridine-2,4(1H,3H)-dione (48). According to the G.P. 4, with 38 (2.4 g):
1.87 g (79%) of 48. Yellowish needles. M.p. 2928. UV (MeOH): 219 (4.40), 281 (4.01), 342 (4.15).
1H-NMR ((D6)DMSO, 808): 10.86 (s, NH); 9.11 (s, NHNH2); 7.92 (br. s, HÀC(6)); 5.44 (s, Me2CH); 4.61
(br. s, NHNH2); 1.49 (d, Me2CH). Anal. calc. for C9H12N6O2 · H2O (254.2): C 42.51, H 5.55, N 33.06;
found: C 42.83, H 5.39, N 33.02.
7-Hydrazinyl-1-isopropyl-3-methylpteridine-2,4(1H,3H)-dione (49). According to the G.P. 4, with 39
(2.54 g): 1.78 g (71%) of 49. Yellowish needles. M.p. 256 – 2588. UV (MeOH): 220 (4.35), 281 (3.98), 341
1
(4.15). H-NMR ((D6)DMSO): 9.42 (s, NHNH2); 8.00 (br. s, HÀC(6)); 5.58 (s, Me2CH); 4.84 (br. s,
NHNH2); 3.23 (s, MeN); 1.47 (d, Me2CH). Anal. calc. for C10H14N6O2 (250.3): C 47.98, H 5.64, N 33.58;
found: C 47.92, H 5.52, N 33.55.
7-Hydrazinyl-3-methyl-1-neopentylpteridine-2,4(1H,3H)-dione (50). According to the G.P. 4, with
40 (2.83 g): 2.6 g (69%) of 50. Yellowish needles. M.p. 2968. UV (MeOH): 220 (4.32), 280 (3.97), 342
(4.14). 1H-NMR ((D6)DMSO): 9.20 (br. s, NHNH2); 7.94 (br. s, HÀC(6)); 4.71 (s, CH2ÀN(1)); 4.09 (br.
s, NHNH2); 3.25 (s, CH2ÀN(3)); 0.91 (s, Me3C). Anal. calc. for C12H18N6O2 (278.3): C 51.78, H 6.52, N
30.20; found: C 51.68, H 6.57, N 29.91.

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7-Hydrazinyl-1-neopentyl-3-octylpteridine-2,4(1H,3H)-dione (51). According to the G.P. 4, with 41
(3.8 g): 1.8 g (65%) of 51. Yellowish needles. M.p. 2388. UV (MeOH): 221 (4.38), 282 (4.01), 343 (4.24).
1H-NMR ((D6)DMSO): 9.38 (br. s, NHNH2); 7.96 (br. s, HÀC(6)); 4.73 (s, CH2ÀN(1)); 4.09 (br. s,
NHNH2); 3.87 (t, CH2ÀN(3)); 1.53 (m, CH2CH2ÀN(3)); 1.24 (m, 5 CH2); 0.90 (s, Me3C); 0.83 (t,
Me(CH2)7). Anal. calc. for C19H32N6O2 (377.5): C 60.45, H 8.54, N 22.26; found: C 60.67, H 8.54, N 22.48.
7-Hydrazinyl-1,3-dipropylpteridine-2,4(1H,3H)-dione (52). According to the G.P. 4, with 42 (2.83 g):
1.85 g (67%) of 52. Yellowish needles. M.p. 2708. UV (MeOH): 220 (4.38), 281 (4.01), 342 (4.19).
1H-NMR ((D6)DMSO): 8.22 (br. s, NHNH2); 7.56 (s, HÀC(6)); 4.75 (br. s, NHNH2); 4.10 (m,
CH2ÀN(1)); 3.84 (m, CH2ÀN(3)); 1.58 (m, 2 CH2CH2N); 0.86 (m, 2 MeCH2CH2N). Anal. calc. for
C12H18N6O2 (276.3): C 52.16, H 6.57, N 30.42; found: C 52.23, H 6.57, N 30.39.
7-Hydrazinyl-3-methylpteridine-2,4(1H,3H)-dione (53). According to the G.P. 4, with 43 (2.13 g,
10 mmol): 1.90 g (91%) of 53 which was recrystallized from H2O. Yellowish needles. M.p. > 3008. UV
(MeOH): 215 (4.41), 279 (4.01), 340 (4.15). 1H-NMR ((D6)DMSO): 11.57 (s, NH); 9.31 (s, NHNH2); 7.86
(s, HÀC(6)); 4.66 (br. s, NHNH2); 3.18 (s, MeN). Anal. calc. for C7H8N6O2 (208.2): C 40.38, H 3.87, N
40.37; found: C 40.13, H 4.01, N 39.84
7-Hydrazinyl-1,3,6-trimethylpteridine-2,4(1H,3H)-dione (54) [40]. According to the G.P. 4, with 44
(2.4 g, 10 mmol): 1.90 g (81%) of 54 which was recrystallized from H2O. Yellowish needles. M.p. 2768.
UV (MeOH): 217 (4.36), 281 (3.93), 339 (4.19). 1H-NMR ((D6)DMSO): 9.25 (s, NHNH2); 4.84 (s,
NHNH2); 3.34 (s, MeÀN(3)); 3.25 (s, MeÀN(1)); 2.29 (s, MeÀC(6)).
7-Hydrazinyl-6-isopropyl-1,3-dimethylpteridine-2,4(1H,3H)-dione (55). According to the G.P. 4,
with 45 (2.7 g, 10 mmol): 1.98 g (75%) of 55 which was recrystallized from H2O. Yellowish needles.
1
M.p. 2698. UV (MeOH): 216 (4.29), 281 (3.86), 338 (4.14). H-NMR ((D6)DMSO): 9.21 (s, NHNH2);
4.86 (s, NHNH2); 3.52 (s, MeÀN(1)); 3.25 (s, MeÀN(3)); 3.15 (m, Me2CH); 1.14 (d, Me2CH). Anal. calc.
for C11H16N6O2 (264.3): C 49.99, H 6.10, N 31.80; found: C 49.88, H 6.05, N 31.76.
7-Azidopteridine-2,4(1H,3H)-diones 56 – 64: General Procedure 5 (G.P. 5). To a suspension of the
appropriate 7-hydrazinylpteridine-2,4(1H,3H)-dione 46 – 55 (10 mmol) in H2O (100 ml) was added
NaNO2 (0.8 g, 11.6 mmol) with stirring, and then dropwise conc. HCl soln. (2 ml). The solid was changing
without the intermediate formation of a soln. and was filtered off after 30 min, washed with EtOH and
Et2O, and dried in a vacuum desiccator: slightly brownish crystal powder. Recrystallization was achieved
from H2O, EtOH, or DMF.
7-Azido-1-methylpteridine-2,4(1H,3H)-dione (56). According to the G.P. 5, with 47 (2.08 g): 1.75 g
(80%) of 56. Yellowish crystals. M.p. > 3208. UV (MeOH): 212 (4.22), 250 (4.12), (262 (sh, 4.09), 344
(4.20). 1H-NMR ((D6)DMSO): 11.94 (s, HÀN(3)); 8.20 (s, HÀC(6)); 3.42 (s, MeÀN(1)). Anal. calc. for
C7H5N7O2 (219.2): C 38.35, H 2.30, N 44.73; found: C 38.39, H 2.45, N 44.07.
7-Azido-1-isopropylpteridine-2,4(1H,3H)-dione (57). According to the G.P. 5, with 48 (2.36 g):
1.44 g (58%) of 57. Yellowish crystals. M.p. 216 – 2188. UV (MeOH): 217 (4.29), 253 (4.14), 264 (sh,
4.11), 349 (4.23). 1H-NMR ((D6)DMSO): 11.27 (s, HÀN(3)); 8.30 (s, HÀC(6)); 5.30 (m, Me2CH); 1.45
(s, Me2CH). Anal. calc. for C9H9N7O2 (247.2): C 43.73, H 3.67, N 39.66; found: C 43.95, H 3.69, N 39.36.
7-Azido-1-isopropyl-3-methylpteridine-2,4(1H,3H)-dione (58). According to the G.P. 5, with 49
(2.5 g): 2.1 g (80%) of 58. Yellowish crystals. M.p. 1468. UV (MeOH): 216 (4.26), 250 (4.17), 266 (sh,
4.02), 357 (4.22). 1H-NMR ((D6)DMSO): 8.24 (s, HÀC(6)); 5.43 (m, Me2CH); 3.20 (s, MeÀN(3)); 1.52
(s, Me2CH). Anal. calc. for C10H11N7O2 (261.3): C 45.96, H 4.24, N 37.53; found: C 46.23, H 4.35, N 37.45.
7-Azido-3-methyl-1-neopentylpteridine-2,4(1H,3H)-dione (59). According to the G.P. 5, with 50
(2.78 g): 2.6 g (90%) of 59. Yellowish crystals. M.p. 1598. UV (MeOH): 217 (4.23), 252 (4.15), 268 (sh,
1
3.99), 348 (4.20). H-NMR ((D6)DMSO): 8.24 (s, HÀC(6)); 4.10 (s, CH2ÀN(1)); 3.32 (s, MeÀN(3));
0.94 (s, Me3C). Anal. calc. for C12H15N7O2 (289.3): C 49.82, H 5.23, N 33.89; found: C 49.94, H 5.20, N
33.57.
7-Azido-1-neopentyl-3-octylpteridine-2,4(1H,3H)-dione (60). According to the G.P. 5, with 51
(1.88 g, 0.05 mmol): 1.45 g (75%) of 60. Yellowish crystals. M.p. 1608. UV (MeOH): 219 (4.26), 252
(4.06), 271 (sh, 3.94), 347 (4.20). 1H-NMR ((D6)DMSO): 8.23 (s, HÀC(6)); 4.10 (s, CH2ÀN(1)); 3.91 (m,
CH2ÀN(3)); 1.57 (m, CH2CH2ÀN(3)); 1.23 (m, 5 CH2); 0.92 (s, Me3C); 0.84 (t, Me(CH2)7). Anal. calc.
for C19H29N7O2 (387.5): C 60.29, H 7.54, N 25.30; found: C 60.12, H 7.55, N 25.14.

Helvetica Chimica Acta – Vol. 91 (2008)
351
7-Azido-1,3-dipropylpteridine-2,4(1H,3H)-dione (61). According to the G.P. 5, with 52 (2.76 g,
10 mmol): 1.97 g (68%) of 61. Yellowish crystals. M.p. 1048. UV (MeOH): 216 (4.18), 251 (4.11), 268 (sh,
1
3.94), 348 (4.19). H-NMR ((D6)DMSO): 8.25 (s, HÀC(6)); 4.10 (t, CH2ÀN(1)); 3.90 (t, CH2ÀN(3));
1.68 (m, 2 CH2CH2N); 0.91 (m, 2 MeCH2CH2N). Anal. calc. for C12H15N7O2 (289.3): C 49.82, H 5.23, N
33.89; found: C 49.80, H 5.37, N 33.68.
7-Azido-3-methylpteridine-2,4(1H,3H)-dione (62). According to the G.P. 5, with 53 (2.08 g): 1.8 g
(86%) of 62. M.p. > 3208. UV (MeOH): 211 (4.27), 245 (4.06), 260 (sh, 3.90), 346 (4.22). 1H-NMR
((D6)DMSO): 12.31 (s, HÀN(1)); 8.19 (s, HÀC(6)); 3.24 (s, MeÀN(3)). Anal. calc. for C7H5N7O2
(219.2): C 38.35, H 2.30, N 44.73; found: C 38.16, H 2.10, N 44.88.
7-Azido-1,3,6-trimethylpteridine-2,4(1H,3H)-dione (63). According to the G.P. 5, with 54 (2.47 g):
2.0 g (86%) of 63. M.p. 1438 (dec.). UV (MeOH): 214 (4.19), 251 (4.18), 264 (sh, 4.03), 354 (4.15).
1H-NMR ((D6)DMSO): 3.50 (s, MeÀN(1)); 3.31 (s, MeÀN(3)); 2.41 (s, MeÀC(6)). Anal. calc. for
C9H9N7O2 (247.2): C 43.73, H 3.67, N 39.67; found: C 43.59, H 3.82, N 39.57.
7-Azido-6-isopropyl-1,3-dimethylpteridine-2,4(1H,3H)-dione (64). According to the G.P. 5, with 55
(2.64 g): 2.41 g (87%) of 64. M.p. 1368 (dec.). UV (MeOH): 214 (4.23), 251 (4.22), 264 (sh, 4.05), 353
(4.18). 1H-NMR ((D6)DMSO): 3.50 (s, MeÀN(1)); 3.30 (s, MeÀN(3)); 3.24 (m, Me2CH); 1.22 (s,
Me2CH). Anal. calc. for C11H13N7O2 (275.3): C 47.99, H 4.76, N 35.62; found: C 48.15, H 4.89, N 35.30.
2,3,6,7-Tetrahydro-3-methyl-N-methylidyne-2,6-dioxo-1H-purin-3-aminium Inner Salt (65). A soln.
of 56 (0.219 g, 1 mmol) in xylene (6 ml) was heated under reflux for 20 min. After cooling, the precipitate
was collected, washed with MeOH and Et2O, and dried at 608: 0.145 g (76%) of 65. Yellowish crystal
powder. M.p. > 3208. UV (MeOH): 233 (4.17), 250 (sh, 3.98), 299 (4.20); pKa 2.37. UV (pH 0): 231
1
(4.17), 289 (4.06), UV (pH 5): 231 (4.18), 260 (sh, 3.82), 306 (4.14). H-NMR ((D6)DMSO): 11.66 (s,
NH); 8.35 (s, CHꢀNþ); 3.28 (s, MeÀN(3)). Anal. calc. for C7H5N5O2 · H2O (209.2): C 40.20, H 3.37, N
33.49; found: C 40.10, H 3.62, N 33.47.
2,3,6,7-Tetrahydro-3-isopropyl-N-methylidyne-2,6-dioxo-1H-purin-8-aminium Inner Salt (66). As
described for 65, with 57 (0.247 g, 1 mmol) in xylene (5 ml) for 10 min: 0.145 g (66%) of 66. Yellowish
crystals. M.p. 2078. UV (MeOH): 235 (4.15), 254 (sh, 3.85), 302 (4.07). 1H-NMR ((D6)DMSO): 11.50 (s,
NH); 8.41 (s, CHꢀNþ); 5.30 (q, Me2CH): 1.41 (d, Me2CH). Anal. calc. for C9H9N5O2 (219.2): C 49.31, H
4.14, N 31.95; found: C 49.44, 4.08, N 31.75.
2,3,6,7-Tetrahydro-3-isopropyl-1-methyl-N-methylidyne-2,6-dioxo-1H-purin-8-aminium Inner Salt
(67). A soln. of 58 (0.261 g, 1 mmol) in xylene (4 ml) was heated under reflux for 10 min. After
cooling, little MeOH and Et2O were added, and the precipitate was collected and dried: 0.15 g (64%) of
67. Yellowish crystals. M.p. 1768. UV (MeOH): 237 (4.19), 250 (sh, 3.97), 296 (4.19). 1H-NMR
((D6)DMSO): 8.58 (s, CHꢀNþ); 5.35 (q, Me2CH): 3.43 (s, MeÀN(1)); 1.42 (d, Me2CH). Anal. calc. for
C10H11N5O2 (233.2): C 51.49, H 4.75, N 30.03; found: C 51.38, H 5.07, N 29.97.
2,3,6,7-Tetrahydro-3-neopentyl-1-methyl-N-methylidyne-2,6-dioxo-1H-purin-8-aminium Inner Salt
(68). As described for 67, with 59 (0.289 g) in xylene (6 ml) for 15 min. Drying at 608 gave 0.18 g
(69%) of 68. M.p. 1758. UV (MeOH): 237 (4.19), 250 (sh, 3.98), 297 (4.19). 1H-NMR ((D6)DMSO): 8.60
(s, CHꢀNþ); 3.99 (s, CH2); 3.46 (s, MeÀN(1)); 0.93 (s, Me3C). Anal. calc. for C12H15N5O2 (261.3): C
55.15, H 5.79, N 26,80; found: C 54.95, H 5.63, N 26.58.
2,3,6,7-Tetrahydro-3-neopentyl-1-octyl-N-methylidyne-2,6-dioxo-1H-purin-8-aminium Inner Salt
(69). A soln. of 60 (0.196 g, 0.5 mmol) in xylene (3 ml) was heated under reflux for 15 min. After
cooling, hexane (3 ml) was added, and the resulting precipitate was collected and dried in a vacuum
desiccator: 0.115 g (64%) of 69. Yellowish crystals. M.p. 1738. UV (MeOH): 228 (4.22), 250 (sh, 3.98),
297 (4.25). 1H-NMR ((D6)DMSO): 8.58 (s, CHꢀNþ); 3.98 (s, CH2ÀN(3)); 3.95 (t, CH2ÀN(1)); 1.68 (t,
CH2CH2ÀN(1)); 1.24 (m, 5 CH2); 0.92 (s, Me3C); 0.85 (t, Me(CH2)7). Anal. calc. for C19H29N5O2 (359.5):
C 63.48, H 8.13, N 19.48; found: C 63.45, H 8.10, N 19.41.
2,3,6,7-Tetrahydro-1,3-dipropyl-N-methylidyne-2,6-dioxo-1H-purin-8-aminium Inner Salt (70). A
soln. of 61 (0.5 g, 1.73 mmol) in xylene (5 ml) was heated under reflux for 10 min. After cooling, the
mixture was evaporated and the resulting residue treated with Et2O to give a precipitate. The solid was
collected and recrystallized from little AcOEt to give, after drying in a vacuum desiccator, 0.15 g (33%)
of 70. Yellowish crystals. M.p. 1658. UV (MeOH): 236 (4.27), 251 (sh, 4.06), 294 (4.28). 1H-NMR
((D6)DMSO): 8.60 (s, CHꢀNþ); 3.93 (m, 2 CH2N); 1.75 – 1.55 (m, 2 CH2CH2N); 0.90 (m,

352
Helvetica Chimica Acta – Vol. 91 (2008)
2 MeCH2CH2N). Anal. calc. for C12H15N5O2 (261.3): C 55.16, H 5.79, N 26.80; found: C 55.16, H 5.80, N
26.76.
1,2,3,6-Tetrahydro-1,3,8-trimethyl-2,6-dioxo-9H-purine-9-carbonitrile (71). a) A soln. of 63 (0.233 g,
1 mmol) in xylene (5 ml) was heated under reflux for 10 min. The solvent was evaporated and the residue
recrystallized from MeOH to give, after drying, 0.13 g (60%) of 71. Colorless crystals. M.p. 1488.
b) In an oven, 63 (0.233 g, 1 mmol) was heated to 1008 and kept at this temp. for 9 days. The solid was
recrystallized from EtOH to give 1.64 g (75%) of 71. Colorless crystals. M.p. 1488. UV (MeOH): 204
(4.10), 245 (4.02), 266 (sh, 3.85). 1H-NMR ((D6)DMSO): 3.66 (s, MeÀN(3)); 3.23 (s, MeÀN(1)); 2.54 (s,
MeÀC(8)). 13C-NMR ((D6)DMSO): 155.64; 149.85; 145.30; 140.19; 113.57; 103.39; 30.27; 28.20; 13.01.
Anal. calc. for C9H9N5O2 (219.2): C 49.31, H 4.14, N 31.95; found: C 48.96, H 4.15, N 32.03
1,2,3,6-Tetrahydro-8-isopropyl-1,3-dimethyl-2,6-dioxo-9H-purine-9-carbonitrile (72). A soln. of 64
(0.275 g, 1 mmol) in xylene (5 ml) was heated under reflux for 5 min. The solvent was evaporated and the
residue recrystallized from MeOH to give, after drying, 0.18 g (73%) of 72. Colorless crystals. M.p. 1748.
UV (MeOH): 247 (4.10), 270 (sh, 3.89). 1H-NMR ((D6)DMSO): 3.71 (s, MeÀN(3)); 3.21 (s, MeÀN(1));
3.19 (m, Me2CH); 1.33 (d, Me2CH). 13C-NMR ((D6)DMSO): 155.80; 152.77; 149.90; 140.35; 113.34;
103.35; 30.32; 28.22; 26.86; 20.14. Anal. calc. for C11H13N5O2 (247.3): C 53.43, H 5.30, N 28.33; found: C
53.53, H 5.42, N 28.52.
1,2,3,6-Tetrahydro-1-methyl-2,6-dioxo-9H-purine-9-carbonitrile (73). A suspension of 62 (0.219 g,
1 mmol) in dry xylene (100 ml) was heated under reflux for 1 h. The precipitate was filtered off the warm
soln., washed with EtOH and Et2O, and dried at 1008 in the oven: 0.115 g (60%) of 73. Colorless crystals.
M.p. > 3208. UV (MeOH): 250 (3.98), 262 (sh, 3.94). IR: 2245. 1H-NMR ((D6)DMSO): 11.85 (s,
HÀN(3)); 8.36 (s, HÀC(8)); 3.18 (s, MeÀN(1)). Anal. calc. for C7H5N5O2 (191.15): C 43.98, H 2.64, N
36,64; found: C 43.89, H 2.74, N 36.43.
8-Amino-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione (74). a) A suspension of 11 (0.12 g,
0.58 mmol) in EtOH (50 ml) was heated under reflux for 2 h. The precipitate was collected after
1
cooling: 94 mg (83%) of 74, identical with authentic material by UV and H-NMR. Colorless crystals.
M.p. > 3008 ([41]: > 3008). UV (MeOH): 211 (4.39), 289 (4.22). 1H-NMR ((D6)DMSO): 11.37 (s, NH);
6.52 (s, NH2); 3.32 (s, MeÀN(3)); 3.17 (s, MeÀN(1)).
b) A soln. of 1 (0.47 g, 0.2 mmol) in pentan-1-ol (10 ml) was heated under reflux for 20 min. From
the clear soln. separated, after ca. 5 min, a precipitate which was collected after cooling. Purification was
achieved by dissolution in dil. HCl soln., treatment with charcoal, filtration, and neutralization of the hot
filtrate by ammonia: 0.18 g (46%) of 74. Colorless crystal powder. M.p. > 3008.
3,7-Dihydro-1,3-dimethyl-1H-purine-2,6-dione (¼ Theophylline; 75). a) A soln. of 5 (0.102 g,
0.5 mmol) in H2O (15 ml) was heated under reflux for 60 min. The solvent was evaporated and the
residue recrystallized from EtOH: 75 mg (77%) of 75. Colorless crystals. M.p. 2708 ([42]: 268 – 2708).
b) A soln. of 1 (0.205 g, 1 mmol) in N,N-dimethylacetamide (5 ml) was heated under reflux for
15 min. The solvent was evaporated and the residue recrystallized from EtOH with little charcoal: 90 mg
(50%) of 75. Colorless crystals. M.p. 2708.
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Received October 22, 2007