Facile and general syntheses of 3- and/or 5-substituted 7-β-D- ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]purines as a new class of potential xanthine oxidase inhibitors

Article abstract of DOI:10.1055/s-1999-3437

Novel, general, and facile syntheses of 3- and/or 5-substituted 7-β-D- ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]purines (5-8) via compounds 4 as a new class of potential xanthine oxidase inhibitors are described. The key intermediates 4b-j were prepared by

Full text of DOI:10.1055/s-1999-3437

PAPER
655
Facile and General Syntheses of 3- and/or 5-Substituted 7-b-D-Ribofuranosyl-
7H-[1,2,4]triazolo[3,4-i]purines as a New Class of Potential Xanthine Oxidase
Inhibitors
Tomohisa Nagamatsu,*a Hiroo Yamasaki,a Toshihiko Akiyama,a Sachiko Hara,a Kenya Mori,b Hitoshi Kusakabeb
a Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700–8530, Japan
Fax +81(86)2517926; E-mail: nagamatsu@pheasant.pharm.okayama-u.ac.jp
b Research & Development Div., Yamasa Shoyu Co., Ltd., Choshi, Chiba 288–0056, Japan
Received 17 September 1998; revised 14 October 1998
Abstract: Novel, general, and facile syntheses of 3- and/or 5-sub-
stituted 7-b-D-ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]purines (5–8)
via compounds 4 as a new class of potential xanthine oxidase inhib-
itors are described. The key intermediates 4b–j were prepared by
oxidative cyclization of the aldehyde hydrazones 3a–i, derived
from 6-hydrazino-2-iodo-9-(2¢,3¢,5¢-tri-O-acetyl-b-D-ribofurano-
syl)-9H-purines (2) and an appropriate aldehyde, with diethyl
azodicarboxylate (DEAD) (Method A) or lead tetraacetate (Method
B) in good yields. The intermediates 4a–j were also synthesized
from heating of 2 with triethyl orthoesters (Method C) or with alde-
hydes and DEAD in one-pot reactions (Method D).
Key words: purine nucleosides, s-triazolo[3,4-i]purine nucleosides,
oxidative cyclization, xanthine oxidase inhibitor
In connection with ongoing work aimed at the synthesis
and biological evaluation of novel fused purine systems,1,2
we tried to prepare the angular type purine analogues, 7H-
[1,2,4]triazolo[3,4-i]purine nucleosides, which have very
recently been investigated as a new class of potential xan-
thine oxidase (XO) / xanthine dehydrogenase (XDH) in-
hibitors in our laboratory.3 Some of them showed more
potent bovine milk XO inhibitory activity than that of al-
lopurinol. Allopurinol and oxypurinol are known to inhib-
it xanthine oxidase,4 and allopurinol is now widely
employed in treatment of gout and hyperuricemia result-
ing from uric acid.5–7 Although XO / XDH inhibitory ac-
tivities have recently been discovered in some synthetic
compounds,8–12 no clinically effective XO inhibitors for
Method A: DEAD, MeCN, reflux, 5–10 h; Method B: Pb(OAc) , di-
4
oxane, reflux, 1–15 h; Method C: RC(OEt) , HOAc, 55–80 °C, 4–7
3
the treatment of hyperuricemia have been developed since
h; Method D: RCHO, MeCN, r.t., 5 h, then with DEAD, reflux, 5–
allopurinol was introduced for clinical use in 1963.4 Here
24 h
we report a new, convenient, and general synthesis of the
tricyclic purine compounds, 3- and/or 5-substituted 7-b-
D-ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]purines (5–8) as
Scheme 1
a new class of the xanthine oxidase inhibitors.
Since the first report13 on the synthesis of compounds hav-
ing a 7H-[1,2,4]triazolo[3,4-i]purine ring system in 1965,
Treatment of compound 1 with excess anhydrous hydra-
zine (2.3 mol equiv) in acetonitrile at room temperature
afforded 6-hydrazino-2-iodo-9-(2¢,3¢,5¢-tri-O-acetyl-b-D-
ribofuranosyl)-9H-purine (2) in 94% yield. The structure
which is of interest in view of the chemical and biological
properties, only two reports14, 15 have hitherto appeared in
was verified by satisfactory spectral and analytical data.
the literature. Halogenated purine nucleosides are good
In particular, the IR spectrum showed the characteristic
synthetic intermediates for the synthesis of a number of
N-H bands at nas = 3410, ns = 3360, n = 3260, and d = 1610
the purine nucleoside derivatives. Thus the availability
cm–1 for the NHNH2 group, and the structure was substan-
of 6-chloro-2-iodo-9-(2¢,3¢,5¢-tri-O-acetyl-b-D-ribofura-
tiated by the appearance of the molecular ion peak (MH+:
nosyl)-9H-purine (1)16 for the starting material enabled us
m/z = 535), which was attributable to the 6-hydrazino de-
to synthesize the tricyclic purine derivatives 4a–j as
shown in Scheme 1.
rivative 2 rather than 2-hydrazino derivative (MH+: m/z =
Synthesis 1999, No. 4, 655–663 ISSN 0039-7881 © Thieme Stuttgart · New York

656
T. Nagamatsu et al.
PAPER
Table 1 Formation and Physical Data of Compounds 3a–i
structures indicated (Table 4). Heating the hydrazones 3
thus obtained with diethyl azodicarboxylate (DEAD) (2.5
mol equiv) in anhydrous acetonitrile at reflux for 5–10 h
afforded the desired tricyclic purine derivatives, 5-iodo-7-
(2¢,3¢,5¢-tri-O-acetyl-b-D-ribofurano-syl)-7H-[1,2,4]triaz-
olo[3,4-i]purines 4, after isolation by column chromatog-
raphy (Merck Kieselgel 60, eluent: benzene/ethyl acetate,
1:1) in 70–79% yields as disclosed in the experimental ex-
amples 4d, f, i, j and indicated in the Table 2 (Method A).
The oxidative cyclization of the hydrazones 3 could also
be accomplished by heating at reflux for 1–15 h with lead
tetraacetate (2 mol equiv) in anhydrous dioxane and work
up in a similar manner as above to get the triazolopurines
4 in 66–73% yields as disclosed in the experimental ex-
amples 4b, c, e, g, h (Method B). Moreover, the triazol-
opurines 4 were obtained by heating the 6-hydrazino
derivative 2 with triethyl orthoesters (107 mol equiv) and
glacial acetic acid (5 parts) at 55–80 °C in 63–77% yields
as disclosed in the experimental examples 4a, b (Method
C). The present procedures were further simplified by the
following technique. Thus a solution of the hydrazinopu-
Prod-
ucta
Yieldb
(%)
mp (°C)c
Recrystalli-
zationd
Solvent
MS-
FABe
m/z MH+
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
92
85
89
90
93
87
92
81
85– 88
103–106
119–121
115–118
109–111
172–173
109–112
114–115
260–262
benzene
benzene
561
623
641
657, 659
701, 703
637
653
667
EtOH/H2O
DMF/H2O
DMF/H2O
EtOH/H2O
EtOAc
DMF/H2O
DMF/H2O
668
a Satisfactory microanalyses obtained: C ± 0.37, H ± 0.29, N ± 0.30.
b Yield based on the isolated product after column chromatography.
c Uncorrected.
d All products were obtained as colorless powder except for 3i
(yellow).
e FAB MS was measured with glycerol as a matrix.
443 and 445), in the FAB mass spectrum. Subsequent rine 2 with an appropriate aldehyde (1.3 mol equiv) in an-
treatment of the 6-hydrazino derivative 2 with an appro- hydrous acetonitrile was stirred at r.t. for 5 h, followed by
priate alkylaldehyde (3 mol equiv) or arylaldehyde (1.3 heating with DEAD (3 mol equiv) at reflux for 5–24 h in
mol equiv) in acetonitrile at room temperature for 2–12 h one-pot reactions to yield the corresponding triazolopu-
gave the corresponding 6-aldehyde hydrazones 3a–i in rines 4c–j in 44–82% yields (Method D). The structures of
81–96% yields as shown in Table 1. All new compounds the tricyclic compounds 4a–j were confirmed by satisfac-
exhibited satisfactory elemental combustion analyses and tory analytical and spectral data as shown in Tables 2 and
1
MS, IR, and H NMR spectral data consistent with the 4. Especially, the 1H NMR spectra can be used to establish
Table 2 Preparation and Physical Data of Compounds 4a–j
Start-
ing
Mate-
rial
Methoda
Reaction Conditions
Prod-
uctb
Yieldc
(%)
mp (°C)d
(Appearance)
Recrystalliza-
tion Solvent
MS-
FABe
m/z MH+
Solvent
Temp
(°C)
Time
(h)
2
C
AcOH
55
4
4a
4b
4c
4d
4e
4f
77
180–182
(colorless powder)
119–121
(colorless powder)
126–130
(pale yellow powder)
192–195
(colorless powder)
174–177
(colorless powder)
113–115
(pale yellow powder)
106–109
(pale yellow powder)
146–148
EtOH
545
3a
2
3b
2
3c
2
3d
2
3e
2
3f
2
3g
2
3h
2
B
C
B
D
A
D
B
D
A
D
B
D
B
D
A
D
A
D
dioxane
AcOH
dioxane
MeCN
MeCN
MeCN
dioxane
MeCN
MeCN
MeCN
dioxane
MeCN
dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
reflux
80
1
7
5
18
10
17
10
24
8
66
63
73
82
79
63
73
79
70
53
68
44
71
75
73
65
75
61
EtOAc/benzene
EtOAc/benzene
EtOAc
559
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
621
639
benzene
655, 657
699, 701
635
EtOAc/benzene
EtOAc/benzene
EtOAc/benzene
EtOAc/benzene
EtOAc
5
15
24
12
16
5
6
10
17
4g
4h
4i
651
(pale yellow powder)
122–125
(pale yellow powder)
119–122
665
3i
2
4j
666
(pale yellow powder)
a Method A: DEAD; Method B: Pb(OAc)4; Method C: RC(OEt)3; Method D: RCHO, MeCN, r.t., then with DEAD, reflux.
b Satisfactory microanalyses obtained: C ± 0.36, H ± 0.34, N ± 0.31.
c Yield based on the isolated product after column chromatographic separation (Merck Kieselgel 60, eluent: benzene/EtOAc, 1:1).
d Uncorrected.
e FAB MS was measured with glycerol as a matrix.
Synthesis 1999, No. 4, 655–663 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Facile and General Syntheses of a New Class of Potential Xanthine Oxidase Inhibitors
657
the structures between the products 3 and 4. Namely, the ence of two multiplet signals at d = 3.83 and 3.91 for each
spectra of the products 3 in DMSO-d6 showed the pres- four protons attributable to CH2OCH2 and CH2NCH2 of
ence of two broad singlet signals, each one proton. The the morpholino, respectively, at the 5-position. Hydroly-
signal at d = 7.7–8.4 was attributable to the NHN=CH, sis of the iodo group of compounds 4 to get the desired 5-
while the other at d =11.6–12.2 was attributable to the oxo triazolopurine nucleosides 7a–c was achieved by
NHN=CH. On the other hand, such two broad singlet sig- treatment of compounds 4a, c, e (1 mmol) with 5% aque-
nals in the spectra of the products 4 disappeared.
ous potassium hydroxide (20 mL) at room temperature
and neutralization with 10% hydrochloric acid in 70–86%
yields. Moreover, heating the compounds 4a, c–e, h with
thiourea (2 mol equiv) in ethanol at 75 °C and then treat-
ment of the reaction residue with 10% aqueous sodium
hydroxide and 10% hydrochloric acid gave the corre-
sponding 5-thioxo triazolopurine nucleosides 8a–e in 50–
91% yields. The structures of new compounds 5–8 were
assigned on the basis of elemental analyses and satisfacto-
ry spectral data (Tables 3 and 4).
The iodo group of compounds 4 was easily displaced by
several nucleophiles, e.g. sodium methoxide, liquid
ammonia, aqueous potassium hydroxide, and thiourea to
afford the corresponding substituted triazolopurine nu-
cleosides 5–8 (Scheme 2). Namely, treatment of com-
pounds 4a, c–j with sodium methoxide (7 mol equiv)
in anhydrous methanol at 0–5 °C for 2 h and neutral-
ization with 10% hydrochloric acid afforded the corre-
sponding 5-methoxy-7-b-D-ribofuranosyl-7H-[1,2,4]tri-
azolo[3,4-i]purines (5a–i) in 67–95% yields (Table 3). Thus, we have demonstrated the first general syntheses of
Similarly reaction of compounds 4a, c with excess liquid 7H-[1,2,4]triazolo[3,4-i]purine nucleosides, namely, 3-
ammonia provided the corresponding 5-amino triazolopu- and/or 5-substituted 7-b-D-ribofuranosyl-7H-[1,2,4]triaz-
rine nucleosides 6a, b in 82–95% yields, while reaction of olo[3,4-i]purines via 6-hydrazino-2-iodo-9-(2¢,3¢,5¢-tri-O-
compound 4a with morpholine (4 mol equiv) and potassi- acetyl-b-D-ribofuranosyl)-9H-purines as a new class of
um carbonate (2 mol equiv) in dioxane at reflux for 20 h potential xanthine oxidase inhibitors. Some of them
yielded 5-morpholino derivative 6c in 49% yield. In the showed more potent bovine milk XO inhibitory activity
1H NMR spectra, the structures 5a–i and 6a, b were ascer- than that of allopurinol.3 Further investigations along this
tained explicitly by the presence of three protons singlet line are now in progress and the results of the inhibitory
signals at d = ca. 4.3 attributable to the methoxy group and activities of the compounds described in this paper will be
the presence of two protons singlet signals at d = ca. 7.9 reported elsewhere.
attributable to the amino group, respectively, at their 5-po-
sitions. While the structure 6c was ascertained by the pres-
Mps were obtained on a Yanagimoto micro melting point apparatus
and were uncorrected. Microanalyses were measured by Yanaco
Table 3 Preparation and Physical Data of Compounds 5a–i, 6a–c, 7a-c and 8a-e
Starting
Material
Reaction Conditions
Prod-
ucta
Yieldb
(%)
mp (°C)c
Recrystalli-
zation Sol-
vent
Appearance
MS-
FABd
m/z MH+
Solvent
Temp (°C)
Time
(h)
4a
4c
4d
4e
4f
4g
4h
4i
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
none
none
dioxane
H2O
H2O
H2O
0–5
0–5
0–5
0–5
0–5
0–5
0–5
0–5
0–5
r.t.
r.t.
reflux
r.t.
r.t.
r.t.
2
2
2
2
2
2
2
2
2
6
6
20
5
9
10
4
4
4
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
7a
7b
7c
8a
8b
8c
8d
8e
95
91
95
85
82
85
95
93
67
95
82
49
85
86
70
50
88
70
91
77
219–221
220–222
238–241
237–240
250–253
221–224
198–200
206–208
> 300
220–221
245–247
224–226
228–231
248–251
208–210
205–208
203–206
> 235 (dec)
200–203
222–225
EtOH
DMF/H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF/H2O
DMF/H2O
EtOH/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF
colorless needles
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
pale yellow crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
pale yellow crystals
pale grey crystals
pale grey crystals
colorless crystals
323
399
417
433, 435
477, 479
413
429
443
444
308
384
378
309
385
419, 421
325
401
4j
4a
4c
4a
4a
4c
4e
4a
4c
4d
4e
4h
EtOH
EtOH
EtOH
EtOH
EtOH
75
75
75
75
419
435, 437
431
DMF
DMF
75
4
a Satisfactory microanalyses obtained for 5: C ± 0.39, H ± 0.28, N ± 0.26, for 6: C ± 0.34, H ± 0.23, N ± 0.24, for 7: C ± 0.30, H ± 0.29,
N ± 0.33 and for 8: C ± 0.34, H ± 0.33, N ± 0.34.
b Yield based on the isolated product.
c Uncorrected.
d FAB MS was measured with 3-nitrobenzyl alcohol as a matrix and MH+ - H2O ion was observed in the spectra of compounds 6a,b, 7a–c
Synthesis 1999, No. 4, 655–663 ISSN 0039-7881 © Thieme Stuttgart · New York

658
T. Nagamatsu et al.
PAPER
1H NMR (DMSO-d6/TMS): d = 2.02 (s, 3H, 5¢-OCOMe), 2.04 (s,
3H, 3¢-OCOMe), 2.11 (s, 3H, 2¢-OCOMe), 4.22–4.27 (m, 1H, 5¢-
Ha), 4.33–4.40 (m, 2H, 4¢-H, 5¢-Hb), 4.60 (br s, 2H, NH2, exchange-
able with D2O), 5.57 (dd, 1H, J 2 ,3 = 5.6 Hz, J 3 ,4¢ = 5.1 Hz, 3¢-H),
¢
¢
¢
5.84 (dd, 1H, J 1 ,2 = 5.4 Hz, J 2 ,3 = 5.6 Hz, 2¢-H), 6.12 (d, 1H, J 1 ,2
¢
¢
¢
¢
¢ ¢
= 5.4 Hz, 1¢-H), 8.27 (s, 1H, 8-H), 9.43 (br s, 1H, NH, exchangeable
with D2O).
MS (FAB, glycerol matrix): m/z = 535 (MH+).
Anal. Calcd for C16H19I N6O7 (534.3): C 35.97, H 3.58, N 15.73.
Found: C 35.95, H 3.63, N 15.78.
6-Alkylidenehydrazino- and 6-Benzylidenehydrazino-2-iodo-9-
(2¢,3¢,5¢-tri-O-acetyl-b-D-ribofuranosyl)-9H-purines 3a–i;
General Procedure
A solution of the hydrazinopurine (2; 1.0 g, 1.87 mmol) and an ap-
propriate alkylaldehyde (5.6 mmol) or arylaldehyde (2.4 mmol) in
anhyd MeCN (60 mL) was stirred at r.t. for 2–12 h. All reactions
were monitored by analytical TLC (benzene/EtOH, 2:1 or CH2Cl2/
EtOAc, 1:1). After the reaction was complete, the solvent was evap-
orated in vacuo and the residue was subjected to column chroma-
tography on silica gel (eluent: benzene/EtOAc, 1:1) to give the
corresponding hydrazones 3a–i. The isolated products were recrys-
tallized from the solvents given in Table 1.
5-Iodo-7-(2¢,3¢,5¢-tri-O-acetyl-b-D-ribofuranosyl)-7H-[1,2,4]tri-
azolo[3,4-i]purine (4a) and its 3-Substituted Derivatives 4b–j;
General Procedure
Method A: A mixture of the hydrazone (3; 2.0 mmol) and DEAD
(0.87 g, 5.0 mmol) in anhyd MeCN (50 mL) was heated at reflux for
5–10 h. After the reaction was complete, the solvent was evaporated
in vacuo and the residue was subjected to column chromatography
on silica gel (eluent: benzene/EtOAc, 1:1) to give the corresponding
triazolopurines 4d, f, i, j. The isolated products were recrystallized
from the solvents given in Table 2.
a: MeONa, MeOH, 0–5 °C, 2 h, then 10% HCl; b: liquid NH3, r.t.,
6 h or morpholine, K2CO3, dioxane, reflux, 20 h; c: 5% aq KOH,
r.t., 5–10 h, then 10% HCl; d: (H N)2C=S, EtOH, 75 °C, 4 h, then
2
10% aq NaOH and 10% HCl
Method B: A mixture of the hydrazone (3; 1.8 mmol) and Pb(OAc)4
(1.6 g, 3.6 mmol) in anhyd dioxane (50 mL) was heated at reflux for
1–15 h. After the reaction was complete, the solvent was evaporated
in vacuo and the residue was subjected to column chromatography
on silica gel (eluent: benzene/EtOAc, 1:1) to give the corresponding
triazolopurines 4b, c, e, g, h (Tables 2 and 4).
Scheme 2
CHN Corder MT-5 apparatus. Mass spectra were recorded at 70 eV
ionizing voltage with FAB ionization using a VG-70SE spectrome-
ter. IR spectra were recorded on a JASCO IRA-102 spectrometer.
1H NMR spectra were obtained using a Varian VXR 500 MHz spec-
trometer with TMS as an internal standard. In all cases, chemical
shifts are in ppm downfield to TMS. J values are given in Hz and
signals are quoted as follows: s, singlet; d, doublet; t, triplet; q, quar-
tet; m, multiplet; br, broad. All reagents were of commercial quality
from freshly opened containers and were used without further puri-
fication. Organic solvents were dried by standard methods and dis-
tilled before use. Reaction progress was monitored by analytical
thin layer chromatography (TLC) on Merck silica gel 60 F254 plates
and products were visualized by UV light. Column chromatography
was run on Kieselgel 60 (70–230 mesh ASTM, Merck).
Method C: A mixture of the hydrazinopurine (2; 1.0 g, 1.87 mmol)
and triethyl orthoformate or triethyl orthoacetate (200 mmol) in gla-
cial HOAc (5 mL) was heated at 55–80 °C for 4–7 h. After cooling,
the formed precipitates were collected by filtration and washed with
anhyd EtOH to afford the corresponding triazolopurines 4a, b. Fur-
thermore, the filtrate was concentrated in vacuo and the residue was
subjected to column chromatography on silica gel (eluent: benzene/
EtOAc, 1:1) to yield the second crop of the triazolopurines 4a, b
(Tables 2 and 4).
Method D: A solution of the hydrazinopurine (2; 1.0 g, 1.87 mmol)
and an appropriate arylaldehyde (2.4 mmol) in anhyd MeCN (60
mL) was stirred at r.t. for 5 h, followed by heating the mixture with
DEAD (0.98 g, 5.6 mmol) at reflux for 5–24 h in one-pot reactions.
After the reaction was complete, the solvent was evaporated in vac-
uo and the residue was subjected to column chromatography on sil-
ica gel (eluent: benzene/EtOAc, 1:1) to give the corresponding
triazolopurines 4c–j (Tables 2 and 4).
6-Hydrazino-2-iodo-9-(2¢,3¢,5¢-tri-O-acetyl-b-D-ribofuranosyl)-
9H-purine (2)
To a solution of anhyd hydrazine (1.36 g, 42.7 mmol) in MeCN
(300 mL) was added 6-chloro-2-iodo-9-(2¢,3¢,5¢-tri-O-acetyl-b-D-
ribofuranosyl)-9H-purine16 (1; 10.0 g, 18.6 mmol) and the mixture
was stirred at r.t. for 2 h. The solvent was removed in vacuo and
crystallization of the residue from anhyd EtOH afforded the 6-hy-
drazinopurine nucleoside 2 as colorless crystals; yield: 9.32 g
(94%); mp 71–73 °C; TLC (benzene/EtOH, 2:1): Rf 0.60.
5-Methoxy-7-b-D-ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]purine
(5a) and its 3-Aryl Derivatives 5b–i; General Procedure
To a solution of MeONa prepared from Na (0.16 g, 7.0 mmol) and
anhyd MeOH (15 mL) was added an appropriate triazolopurine (4;
1.0 mmol) under cooling with ice-water. After stirring at 0–5 °C for
2 h, the deposited solid was collected by filtration, washed with an-
hyd MeOH, and recrystallized from EtOH or DMF to afford the cor-
IR (KBr): n = 3410 (as, NH2), 3360 (s, NH2), 3260 (NH), 1745
(C=O), 1730 sh (C=O) and d = 1610 cm–1 (NH2).
Synthesis 1999, No. 4, 655–663 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Facile and General Syntheses of a New Class of Potential Xanthine Oxidase Inhibitors
659
Table 4 IR and1H NMR Spectral Data for the New Products 3a–i, 4a–j, 5a–i, 6a–c, 7a–c, and 8a–e Prepared
Product
IR (KBr)
1H NMR (500 MHz) (DMSO-d6/TMS)b
d, J (Hz)
n (cm-1)a
3a
3260 (NH); 1760,
1740, 1730 (C=O);
1210, 1090, 1040
(C-O-C)
1.96 (d, 3H, J = 5.37, CHMe), 2.03, 2.06, 2.12 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.26
(dd, 1H, Jgem = 13.1, J4’,5’a = 6.8, 5’-Ha), 4.38 (m, 2H, 4’-H, 5’-H2), 5.60 (dd, 1H, J2’,3’ = 5.7, J3’,4’
5.1, 3’-H), 5.86 (t, 1H, J = 5.6, 2’-H), 6.17 (d, 1H, J1’,2’ = 5.4, 1’-H), 7.70 (br s, 1H, CHMe), 8.38
=
(s, 1H, 8-H), 11.60 (s, 1H, NH, exchangeable with D2O)
3b
3c
3d
3e
3f
3260 (NH); 1760,
1750, 1740 (C=O);
1235, 1110, 1050
(C-O-C)
2.03, 2.06, 2.12 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.26 (dd, 1H, Jgem = 13.1, J4’,5’a = 6.8,
5’-Ha), 4.40 (m, 2H, 4’-H, 5’-Hb), 5.61 (dd, 1H, J2’,3’ = 5.9, J3’,4’ = 4.8, 3’-H), 5.88 (t, 1H, J = 5.6,
2’-H), 6.20 (d, 1H, J1’,2’ = 5.3, 1’-H), 7.46 (m, 3H, PhH), 7.76 (m, 2H, PhH), 8.30 (br s, 1H,
CHPh), 8.46 (s, 1H, 8-H) , 12.14 (s, 1 H, NH, exchangeable with D2O)
3270 (NH); 1760,
1745, 1730 (C=O);
1220, 1100, 1050
(C-O-C)
2.04, 2.07, 2.13 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.28 (dd, 1H, Jgem = 13.1, J4’,5’a = 6.8,
5’-Ha), 4.40 (m, 2H, 4’-H, 5’-Hb), 5.61 (dd, 1H, J2’,3’ = 5.8, J3’,4’ = 5.0, 3’-H), 5.89 (t, 1H, J = 5.6,
2’-H), 6.20 (d, 1H, J1’,2’ = 5.3, 1’-H), 7.31 (t, 2H, J = 8.8 Hz, Ar-mH), 7.82 (br t, 2H, Ar-oH),
8.30 (br s, 1H, CHAr), 8.47 (s, 1H, 8-H), 12.10 (br, 1H, NH, exchangeable with D2O)
3280 (NH); 1760,
1755, 1730 (C=O);
1240, 1095, 1055
(C-O-C)
2.03, 2.05, 2.12 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.27 (dd, 1H, Jgem = 13.3, J4’,5’a = 7.1,
5’-Ha), 4.39 (m, 2H, 4’-H, 5’-Hb), 5.60 (dd, 1H, J2’,3’ = 5.8, J3’,4’ = 4.8, 3’-H), 5.88 (t, 1H, J = 5.6,
2’-H), 6.19 (d, 1H, J1’,2’ = 5.3, 1’-H), 7.52 (d, 2H, J = 8.4, Ar-mH), 7.77 (d, 2H, J = 8.4, Ar-oH),
8.25 (br s, 1H, CHAr), 8.46 (s, 1H, 8-H), 12.10 (br, 1H, NH, exchangeable with D2O)
3260 (NH); 1755,
1740, 1725 (C=O);
1230, 1090, 1045
(C-O-C)
2.02, 2.05, 2.12 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.27 (dd, 1H, Jgem = 13.1, J4’,5’a = 6.9,
5’-Ha), 4.39 (m, 2H, 4’-H, 5’-Hb), 5.60 (dd, 1H, J2’,3’ = 5.7, J3’,4’ = 4.8, 3’-H), 5.88 (t, 1H, J = 5.6,
2’-H), 6.19 (d, 1H, J1’,2’ = 5.3, 1’-H), 7.65 (d, 2H, J = 7.9, Ar-mH), 7.70 (d, 2H, J = 7.9, Ar-oH),
8.25 (br s, 1H, CHAr), 8.47 (s, 1H, 8-H), 12.12 (br, 1H, NH, exchangeable with D2O)
3260 (NH); 1755,
1745, 1720 (C=O);
1230, 1090, 1050
(C-O-C)
2.03, 2.06, 2.12 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 2.34 (s, 3H, PhMe), 4.27 (dd, 1H, Jgem
= 13.2, J4’,5’a = 6.9, 5’-Ha), 4.39 (m, 2H, 4’-H, 5’-Hb), 5.60 (dd, 1H, J2’,3’ = 5.8, J3’,4’ = 5.0, 3’-H),
5.87 (t, 1H, J = 5.6 , 2’-H), 6.19 (d, 1H, J1’,2’ = 5.3, 1’-H), 7.26 (d, 2H, J = 7.9 , Ar-mH), 7.64 (d,
2H, J = 7.9 , Ar-oH), 8.26 (br, 1H, CHAr), 8.45 (s, 1H, 8-H), 12.10 (br, 1H, NH, exchangeable
with D2O)
3g
3h
3i
3270 (NH); 1755,
1745, 1720 (C=O);
1240, 1100, 1040
(C-O-C)
2.04, 2.07, 2.13 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 3.81 (3H, s, OMe), 4.28 (dd, 1H, Jgem
= 13.2, J4’,5’a = 6.8, 5’-Ha), 4.40 (m, 2H, 4’-H, 5’-Hb), 5.61 (dd, 1H, J2’,3’ = 5.9, J3’,4’ = 5.0, 3’-H),
5.89 (t, 1H, J = 5.6, 2’-H), 6.20 (d, 1H, J1’,2’ = 5.4, 1’-H), 7.03 (d, 2H, J = 8.3, Ar-mH), 7.70 (d,
2H, J = 8.3, Ar-oH), 8.25 (br, 1H, CHAr), 8.45 (s, 1H, 8-H) , 12.09 (br, 1 H, NH, exchangeable
with D2O)
3260 (NH); 1755,
1740, 1725 (C=O);
1230, 1090, 1035
(C-O-C)
2.03, 2.05, 2.12 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.26 (dd, 1H, Jgem = 13.1, J4’,5’a = 6.8,
5’-Ha), 4.39 (m, 2H, 4’-H, 5’-Hb), 5.59 (dd, 1H, J2’,3’ = 5.6, J3’,4’ = 4.9, 3’-H), 5.87 (t, 1H, J = 5.6,
2’-H), 6.08 (s, 2H, OCH2O), 6.18 (d, 1H, J1’,2’ = 5.3, 1’-H), 6.98 (d, 1H, J = 7.9, Ar-mH), 7.16 (dd,
1H, J = 1.8, 7.9, Ar-oH), 7.38 (s, 1H, J = 1.8, Ar-oH), 8.15 (br, 1H, CHAr), 8.45 (s, 1H, 8-H) ,
12.10 (br, 1H, NH, exchangeable with D2O)
3300 (NH); 1755,
1745, 1725 (C=O);
1230, 1105, 1060
(C-O-C)
2.04 , 2.07, 2.14 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.29 (dd, 1H, Jgem = 13.2, J4’,5’a = 6.9,
5’-Ha), 4.41 (m, 2H, 4’-H, 5’-Hb), 5.62 (dd, 1H, J2’,3’ = 5.6, J3’,4’ = 4.8, 3’-H), 5.90 (t, 1H, J = 5.6,
2’-H), 6.23 (d, 1H, J1’2’= 5.3, 1’-H), 8.02 (d, 2H, J = 8.9, Ar-mH), 8.32 (d, 2H, J = 8.9, Ar-oH),
8.38 (br, 1H, CHAr), 8.53 (s, 1H, 8-H) ) , 12.15 (br, 1 H, NH, exchangeable with D2O)
4a
4b
4c
4d
1750, 1740, 1720
(C=O); 1225, 1100,
1040 (C-O-C)
2.03, 2.07, 2.14 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.29 (dd, 1H, Jgem = 12.8, J4’,5’a = 5.3,
5’-Ha), 4.43 (m, 2H, 4’-H, 5’-Hb), 5.66 (t, 1H, J = 5.4, 3’-H), 5.90 (t, 1H, J = 5.5, 2’-H), 6.34 (d,
1H, J1’,2’ = 5.0, 1’-H), 8.59 (s, 1H, 8-H), 9.46 (s, 1H, 3-H)
1760, 1740, 1730
(C=O); 1230, 1100,
1045 (C-O-C)
2.04, 2.08, 2.14 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 3.05 (s, 3H, 3-Me), 4.29 (dd, 1H, Jgem
= 12.8, J4’,5’a = 6.5, 5’-Ha), 4.43 (m, 2H, 4’-H, 5’-Hb), 5.66 (t, 1H, J = 5.5, 3’-H), 5.88 (t, 1H, J =
5.4, 2’-H), 6.31 (d, 1H, J1’,2’ = 4.9, 1’-H), 8.51 (s, 1H, 8-H)
1760, 1745, 1725
(C=O); 1230, 1090,
1045 (C-O-C)
2.01, 2.06, 2.11 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.26 (dd, 1H, Jgem = 12.8, J4’,5’a = 6.2,
5’-Ha), 4.41 (m, 2H, 4’-H, 5’-Hb), 5.62 (t, 1H, J = 5.4, 3’-H), 5.88 (t, 1H, J = 5.5, 2’-H), 6.33 (d,
1H, J1’,2’ = 4.9, 1’-H), 7.57 (m, 3H, PhH), 7.65 (m, 2H, PhH), 8.57 (s, 1H, 8-H)
1755, 1745, 1725
(C=O); 1220, 1080,
1040 (C-O-C)
2.01, 2.06, 2.11 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.25 (dd, 1H, Jgem = 12.9, J4’,5’a = 6.3,
5’-Ha), 4.42 (m, 2H, 4’-H, 5’-Hb), 5.62 (t, 1H, J = 5.6, 3’-H), 5.87 (t, 1H, J = 5.5, 2’-H), 6.33 (d,
1H, J1’,2’ = 4.9, 1’-H), 7.43 (t, 2H, J = 8.9, Ar-mH), 7.44 (dd, 2H, JH,F = 5.5, JH,H = 8.6, Ar-oH),
8.57 (s, 1H, 8-H)
Synthesis 1999, No. 4, 655–663 ISSN 0039-7881 © Thieme Stuttgart · New York

660
T. Nagamatsu et al.
PAPER
Table 4 (continued)
Product
IR (KBr)
1H NMR (500 MHz) (DMSO-d6/TMS)b
d, J (Hz)
n (cm-1)a
4e
1755, 1745, 1725
(C=O); 1230, 1090,
1045 (C-O-C)
2.01, 2.06, 2.11 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.26 (dd, 1H, Jgem = 12.9, J4’,5’a = 6.2,
5’-H2), 4.41 (m, 2H, 4’-H, 5’-Hb), 5.62 (t, 1H, J = 5.7, 3’-H), 5.87 (t, 1H, J = 5.4, 2’-H), 6.33 (d, 1H,
J1’,2’ = 4.9, 1’-H), 7.66 (d, 2H, J = 8.5, Ar-mH), 7.72 (d, 2H, J = 8.5, Ar-oH), 8.58 (s, 1H, 8-H)
4f
1760, 1750, 1730,
(C=O); 1230, 1100,
1045 (C-O-C)
2.01, 2.06, 2.11 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.25 (dd, 1H, Jgem = 12.9, J4’,5’a = 6.2,
5’-Ha), 4.41 (m, 2H, 4’-H, 5’-Hb), 5.61 (t, 1H, J = 5.6, 3’-H), 5.87 (t, 1H, J = 5.5, 2’-H), 6.32 (d, 1H,
J1’,2’ = 4.9, 1’-H), 7.64 (d, 2H, J = 8.4, Ar-mH), 7.80 (d, 2H, J = 8.4, Ar-oH), 8.58 (s, 1H, 8-H)
4g
1750, 1740, 1720
(C=O); 1220, 1090,
1040 (C-O-C)
2.01, 2.06, 2.11 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 2.42 (s, 3H, PhMe), 4.26 (dd, 1H, Jgem
= 12.8, J4’,5’a = 6.1, 5’-Ha), 4.41 (m, 2H, 4’-H, 5’-Hb), 5.61 (t, 1H, J = 5.6, 3’-H), 5.87 (t, 1H, J = 5.5,
2’-H), 6.32 (d, 1H, J1’,2’ = 4.8, 1’-H), 7.38 (d, 2H, J = 8.1, Ar-mH), 7.54 (d, 2H, J = 8.1, Ar-oH),
8.57 (s, 1H, 8-H)
4h
4i
1755, 1745, 1720
(C=O); 1230, 1100,
1045 (C-O-C)
2.01, 2.06, 2.11 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 3.05 (s, 3H, OMe), 4.25 (dd, 1H, Jgem
= 12.8, J4’,5’a = 6.1, 5’-Ha), 4.40 (m, 2H, 4’-H, 5’-Hb), 5.61 (t, 1H, J = 5.6, 3’-H), 5.87 (t, 1H, J =
5.5, 2’-H), 6.32 (d, 1H, J1’,2’ = 4.9, 1’-H), 7.12 (d, 2H, J = 8.7, Ar-mH), 7.57 (d, 2H, J = 8.7, Ar-
oH), 8.56 (s, 1H, 8-H)
1750, 1740, 1725
(C=O); 1230, 1100,
1030 (C-O-C)
2.03, 2.07, 2.12 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.27 (dd, 1H, Jgem = 12.8, J4’,5’a = 6.2,
5’-Ha), 4.42 (m, 2H, 4’-H, 5’-Hb), 5.63 (t, 1H, J = 5.6, 3’-H), 5.88 (t, 1H, J = 5.4, 2’-H), 6.16 (s, 2H,
OCH2O), 6.33 (d, 1H, J1’,2’ = 4.9, 1’-H), 7.11 (d, 1H, J = 8.1, Ar-mH), 7.15 (dd, 1H, J = 1.7, 8.1,
Ar-oH), 7.23 (d, 1H, J = 1.7, Ar-oH), 8.57 (s, 1H, 8-H)
4j
1755, 1740, 1725
(C=O); 1220, 1090,
1040 (C-O-C)
2.02, 2.07, 2.11 (each s, each 3H, 5’-, 3’- and 2’-OCOMe), 4.26 (dd, 1H, Jgem = 12.8, J4’,5’a = 6.1,
5’-Ha), 4.42 (m, 2H, 4’-H, 5’-Hb), 5.62 (t, 1H, J = 5.6, 3’-H), 5.88 (t, 1H, J = 5.4, 2’-H), 6.34 (d,
1H, J1’,2’ = 4.9, 1’-H), 8.03 (d, 2H, J = 8.8, Ar-mH), 8.45 (d, 2H, J = 8.8, Ar-oH), 8.60 (s, 1H, 8-H)
5a
3360, 1100, 1050
(OH)
3.59 [br dd (dd after addition of D2O, Jgem = 11.8, J4’,5’a = 4.4), 1H, 5’-Ha], 3.69 [br dd (dd after
addition of D2O, Jgem = 11.8, J4’,5’b = 4.3), 1H, 5’-Hb], 3.97 (q, 1H, J = 3.9, 4’-H), 4.24 [t (dd after
addition of D2O, J2,3’ = 4.9, J3’,4’ = 3.9), 1H, J = 4.3, 3’-H], 4.28 (s, 3H, OMe), 4.64 (t, 1H, J = 5.3,
2’-H), 5.07 (br, 1H, 5’-OH, exchangeable with D2O), 5.40 (br, 1H, 3’-OH, exchangeable with
D2O), 5.65 (br, 1H, 2’-OH, exchangeable with D2O), 6.00 (d, 1H, J1’,2’ = 5.6, 1’-H), 8.54 (s, 2H, 3-
H, 8-H)
5b
5c
3350, 1115, 1050
(OH)
3.59 [m (dd after addition of D2O, Jgem = 11.8, J4’,5’a = 4.4), 1H, 5’-Ha], 3.69 [m (dd after addition
of D2O, Jgem = 11.8, J4’,5’b = 4.3), 1H, 5’-Hb], 3.97 (q, 1H, J = 4.1, 4’-H), 4.23 [q (dd after addition
of D2O, J2’,3’ = 4.9, J3’,4’ = 3.9), 1H, J = 4.6, 3’-H], 4.29 (s, 3H, OMe), 4.65 [q (t after addition of
D2O, J = 5.3), 1H, J = 5.6, 2’-H], 5.01 (t, 1H, J5’,OH = 5.4, 5’-OH, exchangeable with D2O), 5.29
(d, 1H, J3’,OH = 5.0, 3’-OH, exchangeable with D2O), 5.54 (d, 1H, J2’,OH = 6.1, 2’-OH, exchangeable
with D2O), 6.00 (d, 1H, J1’,2’ = 5.7, 1’-H), 7.55 (m, 3H, PhH), 8.25 (m, 2H, PhH), 8.54 (s, 1H, 8-H)
3400, 1110, 1060
(OH)
3.59 [br dd (dd after addition of D2O, Jgem = 11.8, J4’,5’a = 4.4), 1H, 5’-Ha], 3.66 [br dd (dd after
addition of D2O, Jgem = 11.8, J4’,5’b = 4.3), 1H, 5’-Hb], 3.96 (q, 1H, J = 3.9, 4’-H), 4.22 (t, 1H, J =
4.3, 3’-H), 4.29 (s, 3H, OMe), 4.63 (t, 1H, J = 5.4, 2’-H), 5.08 (br, 1H, 5’-OH, exchangeable with
D2O), 5.36 (br, 1H, 3’-OH, exchangeable with D2O), 5.50 (br, 1H, 2’-OH, exchangeable with
D2O), 6.00 (d, 1H, J1’,2’ = 5.8, 1’-H), 7.40 (t, 2H, J = 8.9, Ar-mH), 8.25 (dd, 2H, JH,F = 5.7, JH,H
8.4, Ar-oH), 8.54 (s, 1H, 8-H)
=
5d
5e
3350, 1090, 1060
(OH)
3.60 (dd, 1H, Jgem = 11.9, J4’,5’a = 4.4, 5’-Ha), 3.70 (dd, 1H, Jgem = 11.9, J4’,5’b = 4.3, 5’-Hb), 3.98 (q,
1H, J = 4.0, 4’-H), 4.24 (t, 1H, J = 4.4, 3’-H), 4.30 (s, 3H, OMe), 4.65 (t, 1H, J = 5.3, 2’-H), 5.03
(br, 1H, 5’-OH, exchangeable with D2O), 5.40 (br, 1H, 3’-OH, exchangeable with D2O), 5.50 (br,
1H, 2’-OH, exchangeable with D2O), 6.00 (d, 1H, J1’,2’ = 5.7, 1’-H), 7.64 (d, 2H, J = 8.5, Ar-mH),
8.27 (d, 2H, J = 8.5, Ar-oH), 8.56 (s, 1H, 8-H)
3400, 1120, 1070
(OH)
3.60 (dd, 1H, Jgem = 11.9, J4’,5’a = 4.3, 5’-Ha), 3.70 (dd, 1H, Jgem = 11.9, J4’,5’b = 4.3, 5’-Hb), 3.98 (q,
1H, J = 3.9, 4’-H), 4.23 (t, 1H, J = 4.2, 3’-H), 4.30 (s, 3H, OMe), 4.65 (t, 1H, J = 5.2, 2’-H), 5.05
(br, 1H, 5’-OH, exchangeable with D2O), 5.39 (br, 1H, 3’-OH, exchangeable with D2O), 5.53 (br,
1H, 2’-OH, exchangeable with D2O), 6.01 (d, 1H, J1’,2’ = 5.8, 1’-H), 7.78 (d, 2H, J = 8.5, Ar-mH),
8.20 (d, 2H, J = 8.5, Ar-oH), 8.56 (s, 1H, 8-H)
Synthesis 1999, No. 4, 655–663 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Facile and General Syntheses of a New Class of Potential Xanthine Oxidase Inhibitors
661
Table 4 (continued)
Product
IR (KBr)
1H NMR (500 MHz) (DMSO-d6/TMS)b
d, J (Hz)
n (cm-1)a
5f
3350, 1100, 1050
(OH)
3.59 [br dd (dd after addition of D2O, Jgem = 11.8, J4’,5’a = 4.4), 1H, 5’-Ha], 3.69 [br dd (dd after
addition of D2O, Jgem = 11.8, J 4’,5’b = 4.3), 1H, 5’-Hb], 3.98 (q, 1H, J = 4.0, 4’-H), 4.25 (t, 1H, J =
4.3, 3’-H), 4.30 (s, 3H, OMe), 4.65 (t, 1H, J = 5.3, 2’-H), 5.08 (br, 1H, 5’-OH, exchangeable with
D2O), 5.42 (br, 1H, 3’-OH, exchangeable with D2O), 5.56 (br, 1H, 2’-OH, exchangeable with
D2O), 6.00 (d, 1H, J1’,2’ = 5.6, 1’-H), 7.38 (d, 2H, J = 8.1, Ar-mH), 8.15 (d, 2H, J = 8.1, Ar-oH),
8.55 (s, 1H, 8-H)
5g
3300, 1100, 1050
(OH)
3.60 [m (dd after addition of D2O, Jgem = 11.8, J4’,5’a = 4.4), 1H, 5’-Ha], 3.69 [m (dd after addition
of D2O, Jgem = 11.8, J4’, 5 ’b = 4.3), 1H, 5’-Hb], 3.85 (s, 3H, Ar-OMe), 3.98 (q, 1H, J = 3.8, 4’-H), 4.24
[q (t after addition of D2O, J = 4.3), 1H, J = 4.5, 3’-H], 4.30 (s, 3H, 5-OMe), 4.66 [q (t after addi-
tion of D2O, J = 5.3), 1H, J = 5.6, 2’-H], 5.06 (t, 1H, J5’,OH = 5.4, 5’-OH, exchangeable with D2O),
5.33 (d, 1H, J3’,OH = 4.8, 3’-OH, exchangeable with D2O), 5.59 (d, 1H, J2’,OH = 6.0, 2’-OH, ex-
changeable with D2O), 6.00 (d, 1H, J1’,2’ = 5.7, 1’-H), 7.12 (d, 2H, J = 8.8, Ar-mH), 8.20 (d, 2H, J
= 8.8, Ar-oH), 8.54 (s, 1H, 8-H)
5h
5i
3400, 1090, 1040
(OH)
3.60 (dd, 1H, Jgem = 11.9, J4’,5’a = 4.3, 5’-Ha), 3.69 (dd, 1H, Jgem = 11.9, J4’,5’b = 4.3, 5’-Hb), 3.97 (q,
1H, J = 4.0, 4’-H), 4.23 (t, 1H, J = 4.3, 3’-H), 4.29 (s, 3H, OMe), 4.65 (t, 1H, J = 5.3, 2’-H), 5.04
(br, 1H, 5’-OH, exchangeable with D2O), 5.40 (br, 1H, 3’-OH, exchangeable with D2O), 5.50 (br,
1H, 2’-OH, exchangeable with D2O), 6.00 (d, 1H, J 1’,2’ = 5.6, 1’-H), 6.14 (s, 2H, OCH2O), 7.10 (d,
1H, J = 8.2, Ar-mH), 7.68 (d, 1H, J = 1.6, Ar-oH), 7.83 (dd, 1H, J = 1.6, 8.2, Ar-oH), 8.54 (s, 1H,
8-H)
3400, 1100, 1050
(OH)
3.60 [m (dd after addition of D2O, Jgem = 11.8, J4’,5’a = 4.4), 1H, 5’-Ha], 3.70 [m (dd after addition
of D2O, Jgem = 11.8, J4’,5’b = 4.3), 1H, 5’-Hb], 3.98 (q, 1H, J = 3.9, 4’-H), 4.25 (t , 1H, J = 4.2, 1H,
3’-H), 4.32 (s, 3H, OMe), 4.65 (t , 1H, J = 5.0, 2’-H), 5.10 (br, 1H, 5’-OH, exchangeable with D2O),
5.44 (br, 1H, 3’-OH, exchangeable with D2O), 5.70 (br, 1H, 2’-OH, exchangeable with D2O), 6.02
(d, 1H, J1’,2’ = 5.6, 1’-H), 8.43 (d, 2H, J = 8.9, Ar-mH), 8.53 (d, 2H, J = 8.9, Ar-oH), 8.59 (s, 1H,
8-H)
6a
3300, 1095, 1055
(OH); 3150, 3100,
1640 (NH2)
3.56 [m (dd after addition of D2O, Jgem = 11.9, J4’,5’a = 4.2), 1H, 5’-Ha], 3.66 [m (dd after addition
of D2O, Jgem = 11.9, J4’,5’b = 4.2), 1H, 5’-Hb], 3.92 (q, 1H, J = 4.0, 4’-H), 4.15 [q (t after addition of
D2O, J = 4.3), 1H, J = 4.5, 3’-H], 4.49 [q (t after addition of D2O, J = 5.4), 1H, J = 5.5, 2’-H], 5.04
(t, 1H, J5’,OH = 5.5, 5’-OH, exchangeable with D2O), 5.19 (d, 1H, J3’,OH = 4.8, 3’-OH, exchangeable
with D2O), 5.47 (d, 1H, J2’,OH = 6.0, 2’-OH, exchangeable with D2O), 5.88 (d, 1H, J1’,2’ = 5.7, 1’-
H), 7.98 (s, 2H, NH2, exchangeable with D2O), 8.23 (s, 1H, 8-H), 9.30 (s, 1H, 3-H)
6b
6c
3300, 1110, 1050
(OH); 3200, 3150,
1620 (NH2)
3.57 (dd, 1H, Jgem = 11.9, J4’,5’a = 4.1, 5’-Ha), 3.66 (dd, 1H, Jgem = 11.9, J4’,5’b = 4.2, 5’-Hb), 3.93 (q,
1H, J = 3.9, 4’-H), 4.15 (t, 1H, J = 4.3, 3’-H), 4.51 (t, 1H, J = 5.4, 2’-H), 5.05 (br, 1H, 5’-OH, ex-
changeable with D2O), 5.20 (br, 1H, 3’-OH, exchangeable with D2O), 5.48 (br, 1H, 2’-OH, ex-
changeable with D2O), 5.93 (d, 1H, J1’,2’ = 5.9, 1’-H), 7.56 (m, 3H, PhH), 7.87 (s, 2H, NH2,
exchangeable with D2O), 8.27 (m, 2H, PhH), 8.35 (s, 1H, 8-H)
3400, 1118, 1070
(OH)
3.57 [m (dd after addition of D2O, Jgem = 11.9, J 4’,5’a = 4.2), 1H, 5’-Ha], 3.67 [m (dd after addition
of D2O, Jgem = 11.9, J4’,5’b = 4.2), 1H, 5’-H2], 3.83 (m, 4H, CH2OCH2), 3.91 (m, 4H, CH2NCH2),
3.95 (q, 1H, J = 4.1, 4’-H), 4.20 [q (t after addition of D2O, J = 4.3), 1H, J = 4.6, 3’-H], 4.62 [q (t
after addition of D2O, J = 5.3), 1H, J = 5.6, 2’-H], 5.00 (t, 1H, J 5’,OH = 5.4, 5’-OH, exchangeable
with D2O), 5.27 (d, 1H, J3’,OH = 5.0, 3’-OH, exchangeable with D2O), 5.49 (d, 1H, J 2’,OH = 6.1, 2’-
OH, exchangeable with D2O), 5.97 (d, 1H, J1’,2’ = 5.6, 1’-H), 8.45 (s, 1H, 8-H), 8.52 (s, 1H, 3-H)
7a
7b
7c
3350, 1090, 1060
(OH); 3130 (NH);
1655 (C=O)
3.52 (dd, 1H, Jgem = 12.3, J4’,5’a = 2.7, 5’-Ha), 3.66 (dd, 1H, Jgem = 12.3, J4’,5’b = 2.6, 5’-Hb), 3.95 (q,
1H, J = 2.5, 4’-H), 4.11 (dd, 1H, J2’,3’ = 5.0, J3’,4’ = 2.5, 3’-H), 4.64 (dd, 1H, J1’,2’ = 6.7, J2’,3’ = 5.0,
2’-H), 5.00 (br, 1H, 5’-OH, exchangeable with D2O), 5.16 (br, 1H, 3’-OH, exchangeable with
D2O), 5.45 (br, 1H, 2’-OH, exchangeable with D2O), 5.70 (d, 1H, J1’,2’ = 6.7, 1’-H), 7.79 (s, 1H, 8-
H), 7.98 (s, 1H, 3-H)
3300, 1070, 1045
(OH); 3100 (NH);
1657 (C=O)
3.53 (dd, 1H, Jgem = 12.4, J4’,5’a = 2.6, 5’-Ha), 3.67 (dd, 1H, Jgem = 12.4, J4’,5’b = 2.5, 5’-Hb), 3.96 (q,
1H, J = 2.4, 4’-H), 4.11 (dd, 1H, J2’,3’ = 4.9, J3’,4’= 2.5, 3’-H), 4.61 (t, 1H, J = 5.0, 2’-H), 5.07 (br,
1H, 5’-OH, exchangeable with D2O), 5.10 (br, 1H, 3’-OH, exchangeable with D2O), 5.49 (br, 1H,
2’-OH, exchangeable with D2O), 5.69 (d, 1H, J 1’,2’ = 6.7, 1’-H), 7.05 (m, 3H, PhH), 7.78 (s, 1H,
8-H), 8.11 (m, 2H, PhH)
3300, 1080, 1060
(OH); 3120 (NH);
1655 (C=O)
3.55 (dd, 1H, Jgem = 12.4, J4’,5’a = 2.6, 5’-Ha), 3.69 (dd, 1H, Jgem = 12.4, J4’,5’b = 2.5, 5’-Hb), 4.07 (q,
1H, J = 2.4, 4’-H), 4.14 (dd, 1H, J2’,3’ = 5.0, J3’,4’ = 2.4, 3’-H), 4.39 (dd, 1H, J1’,2’ = 6.7, J2’,3’ = 5.0,
2’-H), 5.02 (br, 1H, 5’-OH, exchangeable with D2O), 5.07 (br, 1H, 3’-OH, exchangeable with
D2O), 5.51 (br, 1H, 2’-OH, exchangeable with D2O), 5.91 (d, 1H, J1’,2’ = 6.7, 1’-H), 7.62 (d, 2H, J
= 8.5, Ar-mH), 8.14 (s, 1H, 8-H), 8.21 (d, 2H, J = 8.5, Ar-oH)
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PAPER
Table 4 (continued)
Product
IR (KBr)
1H NMR (500 MHz) (DMSO-d6/TMS)b
d, J (Hz)
n (cm-1)a
8a
3350, 1085, 1060
(OH); 3120 (NH);
1225 (C=S)
3.68 (m, 1H, 5’-Ha), 3.71 (m, 1H, 5’-Hb), 4.06 (q, 1H, J = 2.5, 4’-H), 4.15 (dd, 1H, J2’,3’ = 5.0, J3’,4’
= 2.7, 3’-H), 4.40 (dd, 1H, J1’,2’= 5.9, J2’,3’ = 5.0, 2’-H), 5.30 (br, 1H, 5’-OH, exchangeable with
D2O), 5.78 (br, 1H, 3’-OH, exchangeable with D2O), 6.10 (d, 1H, J1’,2’ = 5.9, 1’-H), 6.25 (br, 1H,
2’-OH, exchangeable with D2O), 8.43 (s, 1H, 8-H), 8.54 (s, 1H, 3-H)
8b
3300, 1070, 1060
(OH); 3100 (NH);
1210 (C=S)
3.71 (m, 2H, 5’-Ha, 5’-Hb), 4.07 (q, 1H, J = 2.7, 4’-H), 4.15 (dd, 1H, J2’,3’ = 5.1, J3’,4’ = 2.8, 3’-H),
4.22 (dd, 1H, J1’,2’ = 5.9, J2’,3’ = 5.1, 2’-H), 5.60 (br, 1H, 5’-OH, exchangeable with D2O), 5.82 (br,
1H, 3’-OH, exchangeable with D2O), 6.11 (d, 1H, J1’,2’ = 5.9, 1’-H), 6.22 (br, 1H, 2’-OH, exchange-
able with D2O), 7.58 (m, 3H, PhH), 8.25 (m, 2H, PhH), 8.43 (s, 1H, 8-H)
8c
3350, 1090, 1050
(OH); 3100 (NH);
1220 (C=S)
4.33 (m, 2H, 5’-Ha, 5’-Hb), 4.67 (q, 1H, J = 2.4, 4’-H), 4.99 (t, 1H, J = 5.3, 3’-H), 5.23 (t, 1H,
J = 4.9, 2’-H), 6.61 (d, 1H, J1’,2’ = 4.5, 1’-H), 7.39 (m, 2H, Ar-mH), 8.33 (m, 2H, Ar-oH), 9.35
(s, 1H, 8-H)
8d
3330, 1080, 1050
(OH); 3130 (NH);
1215 (C=S)
3.69 (m, 2H, 5’-Ha, 5’-Hb), 4.10 (q, 1H, J = 2.4, 4’-H), 4.15 (dd, 1H, J2’,3’ = 4.9, J3’,4’ = 2.3, 3’-H),
4.43 (t, 1H, J = 5.1, 2’-H), 5.56 (br s, 1H, 5’-OH, exchangeable with D2O), 5.81 (br s, 1H, 3’-OH,
exchangeable with D2O), 5.94 (d, 1H, J1’,2’ = 6.7, 1’-H), 6.25 (br s, 1H, 2’-OH, exchangeable with
D2O), 7.63 (d, 2H, J = 8.6, Ar-mH), 8.21 (d, 2H, J = 8.6, Ar-oH), 8.67 (s, 1H, 8-H)
8e
3370, 1080, 1060
(OH); 3140 (NH);
1250 (C=S)
3.69 (dd, 1H, Jgem = 11.8, J4’,5’a = 2.4, 5’-Ha), 3.74 (dd, 1H, Jgem = 11.8, J4’,5’b = 2.7, 5’-Hb), 4.08
(q, 1H, J = 2.6, 4’-H), 4.15 (dd, 1H, J2’,3’ = 4.7, J3’,4’ = 2.7, 3’-H), 4.40 (t, 1H, J = 5.5, 2’-H), 5.50
(br, 1H, 5’-OH, exchangeable with D2O), 5.83 (br, 1H, 3’-OH, exchangeable with D2O), 6.10
(d, 1H, J1’,2’ = 6.3, 1’-H), 6.22 (br, 1H, 2’-OH, exchangeable with D2O), 7.13 (d, 2H, J = 8.8,
Ar-mH), 8.18 (d, 2H, J = 8.8, Ar-oH), 8.41 (s, 1H, 8-H)
a The values in italics refer to wave numbers at which shoulders or inflexions occur in the absorption.
b All products were measured in DMSO-d6 as the measurement solvent except for product 8c (trifluoroacetic acid-d).
responding 5-methoxy derivatives 5a–i (Tables
Furthermore, the filtrate was neutralized with 10% HCl to yield a
second crop of the 5-methoxy derivatives 5a–i.
3
and 4).
7-b-D-Ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]purine-5(6H)-
thione (8a) and its 3-Aryl Derivatives 8b–e; General Procedure
A mixture of an appropriate triazolopurine (4; 1.0 mmol) with thio-
urea (0.15 g, 2.0 mmol) in anhyd EtOH (50 mL) was heated at 75
°C for 4 h. After the reaction was complete, the solution was con-
centrated in vacuo and stirred with 10% aq NaOH (20 mL) at r.t. for
30 min. Then, the solution was adjusted to pH 1 with 10% HCl to
afford the precipitates, which were filtered by suction, washed with
cold H2O, and recrystallized from DMF to get the corresponding
pure the 5-thioxo derivatives 8a–e (Tables 3 and 4).
5-Amino-7-b-D-ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]purine
(6a) and its 3-Phenyl Derivative 6b; General Procedure
An appropriate triazolopurine (4; 1.0 mmol) was transfered to a 200
mL stainless steel cylinder, and the reaction cylinder was cooled to
– 78 °C. Then anhyd liquid NH3 (30 mL) was added to the cylinder
and the sealed mixture was allowed to warm to r.t. After standing at
r.t. for 6 h, the residual solid was collected by filtration, washed with
anhyd EtOH, and recrystallized from DMF/H2O to afford the corre-
sponding 5-amino derivatives 6a, b (Tables 3 and 4).
Acknowledgement
We are grateful to the SC-NMR Laboratory of Okayama University
for 500-MHz 1H NMR experiments. This study was financially as-
sisted in part by Grant-in-Aid for Scientific Research (No.
07672267 and 09680570) from the Ministry of Education, Science,
Sports, and Culture, Japan.
5-Morpholino-7-b-D-ribofuranosyl-7H-[1,2,4]triazolo[3,4-i]pu-
rine (6c)
A mixture of the triazolopurine (4a; 1.0 g, 1.84 mmol), morpholine
(0.64g, 7.35 mmol), and K2CO3 (0.51 g, 3.68 mmol) in dioxane (20
mL) was refluxed for 20 h. After the reaction was complete, the sol-
vent was evaporated in vacuo and the residual oil was triturated with
EtOAc. The formed crystals were collected by filtration and recrys-
tallized from EtOH/H2O to give the 5-morpholino derivative 6c as
colorless crystals (Tables 3 and 4).
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PAPER
Facile and General Syntheses of a New Class of Potential Xanthine Oxidase Inhibitors
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Synthesis 1999, No. 4, 655–663 ISSN 0039-7881 © Thieme Stuttgart · New York