A new synthesis of pteridines

Article abstract of DOI:10.1002/hlca.200690111

A new synthesis of pteridines possessing a (substituted) (Z)-3-hydroxyprop-1-enyl group at C(6) is based on the acylation of 4-amino-5-nitrosopyrimidines with dienoic acid chlorides, followed by a high-yielding intramolecular hetero-Diels-Alder cycloaddit

Full text of DOI:10.1002/hlca.200690111

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Helvetica Chimica Acta – Vol. 89 (2006)
A New Synthesis of Pteridines
by Ming Xu and Andrea Vasella*
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften,
ETH Zürich, CH-8093 Zürich
A new synthesis of pteridines possessing a (substituted) (Z)-3-hydroxyprop-1-enyl group at C(6) is
based on the acylation of 4-amino-5-nitrosopyrimidines with dienoic acid chlorides, followed by a high-
yielding intramolecular hetero-Diels–Alder cycloaddition and cleavage of the NꢀO bond leading to 4.
Thermolysis of the resulting pteridines 4 possessing a benzyloxy group at C(4) led to the products 5,
resulting from isomerisation of the 3-hydroxyprop-1-enyl to an 3-oxopropyl side chain, while the analo-
gous pteridine 8 possessing an NH2 group at C(4) remained unaffected.
Introduction. – Pteridines occur widely, play essential roles in growth processes and
the metabolism of one-carbon units [1–4], and are in clinical use as anticancer, antivi-
ral, antibacterial, and diuretic drugs [5]. A number of methods allow the synthesis of
pteridines either from pyrimidine or from pyrazine precursors [2][3]. 4-Amino-5-nitro-
sopyrimidines are common, crucial intermediates in the synthesis of purines and pter-
idines. They were reduced to 4,5-diaminopyrimidines, as in the Traube [6] and related
Pfleiderer purine syntheses [7], and in the Gabriel–Isay and Viscontini pteridine synthe-
ses [8][9], transformed to pyrimido-oxadiazinones that react with enamines or enol
ethers to form lumazines [10][11], or used directly, as in our improved modification
of the Traube purine synthesis [12] and in the Timmis condensation with carbonyl com-
pounds [13] that leads regioselectively to substituted pteridines. Recent years have seen
a rapid increase in studies devoted to pteridines1) while synthetic innovation has, with
few exceptions, been directed at improving known methods [10][11][27–33]. In the
context of our interest in 8-substituted guanines, we considered a new access to pteri-
dines. The high reactivity of nitroso (NO) groups as heterodienophiles in [4+2] cyclo-
additions [34] should allow a facile intramolecular hetero-Diels–Alder cycloaddition of
amides resulting from N-acylation of 4-amino-5-nitrosopyrimidines with penta-2,4-
dienoyl chlorides and lead regioselectively to C(6)- and/or C(7)-substituted pteridines.
As most naturally occurring pteridines, such as folic acids, biopterin, and neopterin, as
well as the anticancer drug methotrexate are substituted at C(6) [5], this would consti-
tute a potentially useful new synthesis of pteridines.
Results and Discussion. – We examined a few conditions for the acylation with
sorbyl chloride [35][36] of the poorly soluble 6-(benzyloxy)-5-nitrosopyrimidine-2,4-
1
)
See, e.g., [1][14–26]. A search in the Web of Science (January 2006) produced 352 references for the
period of 2000–2006.
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
1141
Scheme
a) RCH=CHꢀCH=CHꢀCOCl (R=Me, H, or Ph), pyridine; 60–70% of 2a–2c and 7. b) Suspension
in toluene, 1008; ca. 98% of 4a–4c and 8. c) Suspension in o-xylene, 1208; ca. 98% of 5a–5c.
diamine (1) [37] (Scheme) that we already used in our synthesis of 8-substituted purines.
We obtained satisfactory results, also for the acylation by penta-3,4-dienoyl [38] and 5-
phenylpenta-4,5-dienoyl chloride [39], by treating a pyridine solution of 1 at ꢀ108 with
a cold pyridine solution of 1.1 equiv. of the acyl chloride.
The expected amides 2a–2c were obtained as green powders. They were not stable
in solution, as judged by a progressive colour change to yellow and the formation of
precipitates during chromatography, or in solution, and were not characterized. The
precipitates were very polar, insoluble in many organic solvents, and strongly fluores-
cent, suggesting a facile intramolecular [4+2] cycloaddition. The precipitates proved
complex mixtures. They were not separated. Fortunately, heating the crude acylation
products 2a–2c in toluene under reflux led almost quantitatively to the pure pteridines

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Helvetica Chimica Acta – Vol. 89 (2006)
4a–4c. The products 3a–3c of the expected [4+2] cycloaddition appear to undergo a
rapid eliminative cleavage of the weak NꢀO bond2), followed by tautomerisation.
The 5-nitrosopyrimidine-2,4,6-triamine (6) [41] was similarly acylated with sorbyl
chloride. Heating the resulting amide 7 in toluene induced a similar, more sluggish
transformation, leading to the diaminopteridine 8, again in high yields, as precipitates
that were purified by washing with H2O, AcOEt, and Et2O.
G
Remarkably, continued heating of 4a–4c3), best performed in boiling o-xylene, led
in high yields to the ketones 5a–5c3). The transformation of 4 to 5 is rationalised by a
[1,5]-sigmatropic H shift, followed by tautomerisation of the intermediate enol enam-
ine to the imino ketones 5. A precedent for such a transformation is found in the tau-
tomerisation reported by Coppola and Damon [42]. The diaminopteridine 8 did not
undergo such a transformation. Longer heating or higher temperatures led to its pro-
gressive decomposition.
The structure of the pteridine derivatives 4 and 8 follows unambiguously from their
spectroscopic data. Thus, the constitution of the secondary alcohol 4a is evidenced by
high-resolution MALDI-MS, elemental analysis, IR bands at 3420 cmꢀ1 (OH; NH
bands at 3323 and 3208 cmꢀ1), a comparison of their UV spectra with those of related
pteridines [27][43], and the 1H- and 13C-NMR data (Tables 1 and 2 in the Exper.Part ).
No 13C-NMR spectra of pteridin-7(8H)-ones were found by a Beilstein X-fire search.
The assignment of the 13C ss of 4 and 5 to the six quaternary C-atoms was first based
on the predictions of ChemDraw Ultra V. 9 and on a comparison, for C(2) and C(4),
with the C(2) and C(6) signals of O6-methylguanosines [44] and then revised – for
the assignment of C(2) and C(7) – on the basis of an HMBC spectrum of 4a. It
shows cross-peaks between the two ds of PhCH2 and the s at 164.51 ppm (C(4)),
between the s of NH2 and the ss at 164.51, 161.39 (C(8a)), and 150.62 ppm (C(2)),
and between the dd of HꢀC(1’) and the ss at 157.13 ppm (C(7)) and 146.08 (C(6)).
J(1’,2’) of the olefinic H-atom of 12.3 Hz is in keeping with the (Z)-configuration as evi-
denced by a comparison with the data of related 2-(3-hydroxyprop-1-enyl)pyridines
[45]. The structure of 8 is evidenced by the high-resolution MALDI mass spectrum,
an ATR-IR OH band at 3460 cmꢀ1, and broader NH bands at 3327 and 3175 cmꢀ1,
and the NMR spectra ((D6)DMSO) where the Me group resonates at 1.23 ppm as a
d (J=6.3 Hz), the olefinic H-atom at 6.56 (dd, J=12.0 and 1.2 Hz) and 5.87 ppm (dd,
J=12.0 and 7.8 Hz), and the allylic H-atom at 5.15 ppm (m), in keeping with a 13C q
at 22.43 ppm, and ds at 118.76, 144.01, and 63.07 ppm.
Also the structure of the ketones 5 follows unambiguously from their analytical
data. Thus, the 3-oxobutyl substituent of 5a is evidenced by the disappearance of the
2
)
)
See [40] for a base-promoted eliminative cleavage of a NꢀO bond.
3
In contact with air, the aldehyde 5b is easily oxidised to the corresponding (E)-configured a,b-unsa-
turated aldehyde 5d that was also formed in small amounts from 4b.

Helvetica Chimica Acta – Vol. 89 (2006)
1143
signals corresponding to the olefinic C=C bond of 4a, a Me s at 2.07 ppm, and two trip-
let-like signals of an isolated ethylene group at 2.81 and 2.71 ppm. The PhCH2 of 5a res-
onate as a s at 5.43 ppm (13C-NMR: t at 67.42 ppm), while PhCH2 of 4a resonates as two
ds at 5.49 and 5.44 ppm. The C=O group of 5a is evidenced by a 13C s at 207.77 ppm and
an IR band at 1708 cmꢀ1. The ATR-IR OH/NH band of 4a at 3420 cmꢀ1 is replaced by a
much weaker NH band at 3427 cmꢀ1 for 5a.
This synthesis of pteridines possessing a configurationally defined 3-hydroxyprop-1-
enyl substituent at C(6) should allow a convenient access to naturally occurring pteri-
dines and their analogues; work towards this goal is in progress.
We thank the ETH Zürich and F.Hoffmann-La Roche , Basel, for generous support, Thomas Steinlin
for checking the transformations of 1 to 4a–4c and to 5a–5c, and for the UV spectra of these compounds,
and Dr. Bruno Bernet for checking the analytical data.
Experimental Part
General. See [46]. UV Spectra: MeOH, lmax (log e).
General Procedure for the Preparation of the Pteridin-7-ones 4a–4c and 8. A soln. of 1 [37] (245 mg,
1.0 mmol) or 6 [41] (154 mg, 1.0 mmol) in dry pyridine (10 ml) was cooled to ꢀ108, treated with the 2,4-
dienoyl chloride (1.1 mmol), and stirred for 12 h. The soln. was diluted with CH2Cl2 (50 ml), washed with
brine (3×20 ml), dried (MgSO4), and evaporated. FC (CH2Cl2/MeOH 100 :1) of the blue residue gave
green powders of 2a–2c and 7 (60–70%), resp. A suspension of 2a–2c and 7 (1 mmol) in toluene was
heated for 3–5 h to 1008, when a yellow suspension was formed. After evaporation, the solid yellow res-
idue was washed with H2O, AcOEt, and Et2O. Drying of the residue in vacuo (i.v.) gave 4a–4c and 8 (ca.
G
98%), resp. Yellow powders.
General Procedure for the Transformation of 4a–4c to the Carbonyl Compounds 5a–5c. A suspen-
sion of 4a–4c (1 mmol) in o-xylene was degassed, heated for 12 h to 1208, and evaporated. The solid yel-
low residue was washed with H2O and Et2
ders.
A
2-Amino-6-[(Z)-3-hydroxybut-1-enyl]-4-(phenylmethoxy)pteridin-7(8H)-one (4a). M.p. 2428 (dec.).
UV: 376 (4.18), 285 (3.84), 208 (4.46). IR (ATR): 3420m, 3323w, 3208m, 2834w, 2737w (br.), 1802w,
1670w, 1614s, 1560s, 1538m, 1496m, 1490m, 1464m, 1428s, 1387m, 1356s, 1327m, 1307m, 1182s, 1052s,
1
975m, 927m, 905m. H-NMR ((D6)DMSO, 300 MHz): see Table 1; additionally, 7.54–7.31 (m, 5 arom.
H); 5.49, 5.44 (2d, J=12.6, PhCH2). 13C-NMR ((D6)DMSO, 100 MHz; assignments based on a HSQC
and a HMBC spectrum): see Table 2; additionally, 136.31 (s); 128.23 (2d); 127.77 (d); 127.36 (2d);
67.32 (t, PhCH2). HR-MALDI-MS: 362.1223 (82, [M+Na]+, C17H17N5NaO3þ ; calc. 362.1229), 340.1402
(35, [M+H]+, C17H18N5O3þ ; calc. 340.1410), 322.1299 (100, [MꢀOH]+, C17H16N5Oþ2 ; calc. 322.1304).
Anal. calc. for C17H17N5O3 (339.35): C 60.17, H 5.05, N 20.64; found: C 60.38, H 5.15, N 20.50.
2-Amino-6-[(Z)-3-hydroxyprop-1-enyl]-4-(phenylmethoxy)pteridin-7(8H)-one (4b). M.p. 2208
(dec.). UV: 360 (3.91), 287 (3.70), 216 (4.43). IR (ATR): 3367m, 3330m, 3193m, 2888w, 2832w, 2766w
(br.), 1673m, 1650s, 1610s, 1561s, 1534s, 1489s, 1440s, 1388m, 1343s, 1325m, 1265m, 1189s, 1086m,
1064m, 1037m, 1016s, 950m, 913s. 1H-NMR ((D6)DMSO, 300 MHz): see Table 1; additionally,
7.50–7.31 (m, 5 arom. H); 5.49 (s, PhCH2); weak signals at 9.69 (d, J=7.8), 7.68 (d, J=16.2), and 7.12
(dd, J=16.2, 7.8) denote a contamination by 5 to 10% of 5d. 13C-NMR ((D6)DMSO, 100 MHz): see
Table 2; additionally, 136.58 (s); 128.42 (2d); 127.78 (d); 127.30 (2d); 67.10 (t, PhCH2). HR-MALDI-
MS: 348.1066 (43, [M+Na]+, C16
C
N5
U
H16
U
E
2-Amino-6-[(Z)-3-hydroxy-3-phenylprop-1-enyl]-4-(phenylmethoxy)pteridin-7(8H)-one (4c). M.p.
2058 (dec.). UV: 381 (4.16), 280 (3.91), 233 (4.22), 211 (4.55). IR (ATR): 3422w, 3323w, 3206m, 2734w
(br.), 1662m, 1613s, 1561s, 1487s, 1432s, 1394m, 1354s, 1326m, 1264m, 1178m, 1090m, 1046m, 1002m,
938m, 908m. 1H-NMR ((D6)DMSO, 300 MHz): see Table 1; additionally, 12.46 (s, HN(8)); 7.58–7.06

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Helvetica Chimica Acta – Vol. 89 (2006)
Table 1. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the Pteridin-7(8H)-ones
4a–4c, 5a–5c, and 8 in (D6)DMSO
4a
4b
4c
5a
5b
5c
8
HꢀN(8)
H2
12.40
7.24
6.61
5.95
5.15
4.89
1.20
12.3
1.2
12.38
7.20
6.68
6.09
4.53
4.92
–
12.46
12.34
7.08
2.81
2.71
–
12.37
7.09
2.90
2.76
9.73
–
–
6.6
–
12.35
7.06
2.99
3.40
–
–
–
6.6
–
12.12
7.29b)
6.56
5.87
5.15
4.81
1.23
12.0
1.2
a
NꢀC(2)
)
HꢀC(1’)
HꢀC(2’)
HꢀC(3’)
HOꢀC(3’)
Me(4’)
6.68
6.02
6.36
5.48
–
–
2.07
6.3
–
J(1’,2’)
J(1’,3’)
12.0
2.4
12.0
0
J(2’,3’)
J(3’,OH)
J(3’,4’)
7.5
4.2
6.3
5.4
)
–
9.0
4.2
–
–
–
–
1.2
–
–
–
–
–
7.8
4.5
6.3
c
a) Hidden by the arom. signals at 7.58–7.06 ppm. b) d(H2
ACHTREUNG
Table 2. Selected 13C-NMR Chemical Shifts [ppm] of the Pteridin-7(8H)-ones 4a–4c, 5a–5c, and 8 in
(D6)DMSO
4aa)
4b
4c
5a
5b
5cb)
8b)
C(2)
C(4)
C(4a)
C(6)
C(7)
C(8a)
C(1’)
C(2’)
C(3’)
C(4’)
150.62
164.51
107.54
146.08
157.13
161.39
118.56
145.75
63.45
150.65
164.53
107.71
146.52
157.17
161.37
119.18
142.63
60.28
151.01
164.61
107.56
145.83
157.26
161.41
118.50
142.50
67.45
151.92
164.25
106.70
151.17
157.02
161.17
26.64
38.25
207.77
30.16
151.72
164.27
106.82
151.27
157.03
161.18
25.17
39.18
202.53
–
152.03
164.14
106.71
151.13
157.01
161.06
26.44
34.17
199.01
–
148.88
160.63
106.49
143.68
157.79
162.20
118.76
144.01
63.07
22.26
–
–
22.43
a) Assignments based on a HSQC and a HMBC spectrum. b) Assignments based on a HSQC spectrum.
(m, 10 arom. H, NH2); 5.64, 5.43 (2d, J=12.6, PhCH2). 13C-NMR ((D6)DMSO, 100 MHz): see Table 2;
additionally, 144.33, 136.22 (2s); 128.41 (2d); 128.16 (2d); 127.97 (d); 127.70 (2d); 126.50 (d); 126.44
(2d); 67.52 (t, PhCH2). HR-MALDI-MS: 424.1376 (40, [M+Na]+, C22
A
N5
ACHTREUNG
402.1555 (45, [M+H]+, C22
384.1460).
H20
N5
U
A
N
ACHTREUNG
2-Amino-6-(3-oxobutyl)-4-(phenylmethoxy)pteridin-7(8H)-one (5a). M.p. 2458 (dec.). UV: 343
(4.08), 284 (3.78), 212 (4.40). IR (ATR): 3427w, 3322w, 3202w, 2900w, 2835w, 2760w (br.), 1708w,
1666m, 1615s, 1557s, 1498m, 1431s, 1391m, 1354s, 1307m, 1253m, 1178m, 1087m, 1058m, 978m, 930m,
1
911m. H-NMR ((D6)DMSO, 300 MHz): see Table 1; additionally, 7.51–7.32 (m, 5 arom. H); 5.44 (s,
PhCH2). 13C-NMR ((D6)DMSO, 100 MHz): see Table 2; additionally, 136.34 (s); 128.42 (2d); 128.38
(2d); 128.10 (d); 67.42 (t, PhCH2). HR-MALDI-MS: 362.1222 (49, [M+Na]+, C17H17N5NaO3þ ; calc.
362.1229), 340.1398 (100, [M+H]+, C17H18N5O3þ ; calc. 340.1410).
2-Amino-6-(3-oxopropyl)-4-(phenylmethoxy)pteridin-7(8H)-one (5b). M.p. 2108 (dec.). UV: 345
(3.89), 282 (3.74), 209 (4.37). 1H-NMR ((D6)DMSO, 300 MHz): see Table 1; additionally, 7.49–7.31

Helvetica Chimica Acta – Vol. 89 (2006)
1145
(m, 5 arom. H); 5.43 (s, PhCH2). 13C-NMR ((D6)DMSO, 100 MHz): see Table 2; additionally, 136.46 (s);
128.41 (2d); 128.12 (2d); 127.98 (d); 67.20 (t, PhCH2). HR-MALDI-MS: 348.1067 (31, [M+Na]+,
C16H15N5NaOþ3 ; calc. 348.1073), 326.1249 (79, [M+H]+, C16H16N5Oþ3 ; calc. 326.1253).
2-Amino-6-(3-oxo-3-phenylpropyl)-4-(phenylmethoxy)pteridin-7(8H)-one (5c). M.p. 2558 (dec.).
UV: 343 (3.57), 279 (3.35), 235 (3.75), 204 (4.19). IR (ATR): 3414w, 3322w, 3204w, 2916w, 2831w,
2736w (br.), 1684m, 1662m, 1644s, 1619s, 1559s, 1511m, 1497m, 1433s, 1392m, 1355s, 1298s, 1205m,
1183s, 1088m, 1055s, 987m, 920m. 1H-NMR ((D6)DMSO, 300 MHz): see Table 1; additionally,
7.98–7.29 (m, 10 arom. H); 5.38 (s, PhCH2). 13C-NMR ((D6)DMSO, 125 MHz; assignments based on
HSQC spectrum): see Table 2; additionally, 136.81, 136.33 (2s); 132.83 (d); 128.51 (2d); 128.21 (2d);
127.78 (3d); 127.72 (2d); 66.96 (t, PhCH2). HR-MALDI-MS: 424.1380 (59, [M+Na]+, C22
A
G
U
calc. 424.1386), 402.1563 (100, [M+H]+, C22 O3þ ; calc. 402.1566).
G
N
ACHTREUNG
2,4-Diamino-6-[(Z)-3-hydroxybut-1-enyl)pteridin-7(8H)-one (8). M.p. 2108 (dec.). IR (ATR): 3460w,
3327m, 3175m, 2969w, 2924w, 2847w, 2721w (br.), 1826w, 1615s, 1556s, 1530s, 1480s, 1454s, 1401s, 1323m,
1257m, 1153m, 1108m, 1048s, 930m, 903m. 1H-NMR ((D6)DMSO, 300 MHz): see Table 1. 13C-NMR
((D6)DMSO, 100 MHz; assignments based on HSQC spectrum): see Table 2. HR-MALDI-MS:
271.0914 (26, [M+Na]+, C10
C
N6
U
H13
U
G
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Received February 16, 2006