Synthesis of novel 2-aryl AICAR derivatives

Article abstract of DOI:10.1055/s-2004-831249

Novel 2-aryl AICAR (5-Amino-1-β-D-ribofuranosylimidazole-4- carboxamide) derivatives 8 were synthesized via the Suzuki-Miyaura cross-coupling reactions of 8-bromoadenosine. Following conversion of the adenine moiety of 4 to hypoxanthine (5) and the introduction of a MEM group, hydrolysis of 7 gave desired 2-aryl AICAR derivatives 8.

Full text of DOI:10.1055/s-2004-831249

PAPER
2799
Synthesis of Novel 2-Aryl AICAR Derivatives
Synthesis of
N
ove
a
l
2-Aryl AI
C
o
A
R
Derivat
k
ives i Kohyama, Tomoyuki Katashima, Yukio Yamamoto*
Graduate School of Human & Environmental Studies, Kyoto University, Sakyo-ku, Yoshida, Kyoto 606-8501, Japan
Fax +81(75)7536833; E-mail: yukio@fischer.jinkan.kyoto-u.ac.jp
Received 7 June 2004; revised 14 July 2004
non-toxic in contrast to organotin compounds used in the
Stille-type cross-coupling reactions.
Abstract: Novel 2-aryl AICAR (5-Amino-1-b-D-ribofuranosylimi-
dazole-4-carboxamide) derivatives 8 were synthesized via the Su-
zuki–Miyaura cross-coupling reactions of 8-bromoadenosine.
Following conversion of the adenine moiety of 4 to hypoxanthine
(5) and the introduction of a MEM group, hydrolysis of 7 gave de-
sired 2-aryl AICAR derivatives 8.
Since we had already established the facile synthesis of
AICAR from inosine,8 we examined the Suzuki coupling
reaction of 8-bromo-N-MEM-inosine first, but this reac-
tion did not proceed. Next, we changed the strategy of in-
troducing aryl groups to 8-bromoadenosine.
Key words: nucleosides, cross-coupling, palladium, inosine, ade-
nosine
By the action of bromine in NaOAc buffer, 8-bromoade-
nosine (2) was obtained from adenosine (1) in 81% yield.
The Suzuki coupling reaction of 2 was conducted using
Pd(Ph3P)4 as the catalyst and K2CO3 as the base in DME–
H2O (2:1) at 90 °C (Scheme 1). The yields of 8-arylade-
nosines 3 from 8-bromoadenosine (2) and several boronic
acids are given in Table 1.
A number of nucleotide analogues with modified purines
have been known as potent biologically active com-
pounds. Although 8-substituted purine derivatives are of
great interest because of their capacity of changing the
syn/anti conformation,1 purine derivatives with C-linked
substituents at position 8 were less reported than 2- or 6-
substituted purines. Among them, Verlinde et al. synthe-
sized 8-phenyladenosine and 8-(thien-2-yl)adenosine via
the Stille-type cross-coupling reactions of tri-O-acetyl-8-
bromoadenosine.2 Very recently, 8-arylguanosine and 8-
aryladenosines were synthesized via the Suzuki–Miyaura
cross-coupling reaction.3
The yields with boronic acids having the electron-rich
substituents (4-methoxyphenyl 3c) are relatively higher
than those with boronic acids having the electron-defi-
cient substituents (3-chlorophenyl 3d, phenylvinyl 3g)
and heterocyclic ones (thienyl 3e, furyl 3f). Due to the
lower solubility of compounds 3e–3g in CHCl3 and
MeOH, the column chromatography operation with them
was more difficult than that with 3a–3d. In order to in-
crease the solubility of 3 in organic solvents, we conduct-
ed the acetylation of the sugar hydroxy groups in the next
step.
AMP-activated protein kinase (AMPK)4 is considered to
be a master switch, regulating key proteins in metabolic
pathways, for example, hepatic fatty acid oxidation, lipo-
genesis, triglyceride synthesis and skeletal muscle fatty
acid oxidation.5 The activation of AMPK occurs under
conditions such as hypoxia, ischemia, heat shock, inhibi-
tion of glycolysis and muscle contraction.6 Because mus- R1
cle contraction in exercise brings anti-diabetic effects,
Table 1 Yields of the Intermediates for the Syntheses of 8a–8g (%)
2 → 3 3 → 4 4 → 5 5 → 6 6 → 8
a (Phenyl)
b (4-Fluorophenyl)
81
75
77
87
91
82
94
80
94
98
76
79
90
72
67
90
64
61
75
68
75
67
57
35
35
22
50
48
24
79
physical exercise is one of the most effective therapy in
the patients of type 2 diabetes. AMPK is considered to be
an important target for the treatment of type 2 diabetes
since this kinase is activated during physical exercise.7
c (4-Methoxyphenyl) 73
d (3-Chlorophenyl)
e (2-Thienyl)
63
40
26
47
5-Amino-1-b-D-ribofuranosylimidazole-4-carboxamide
(AICAR; R1 = H in 8) is a constituent of AICA-ribotide,
which is a biosynthetic precursor of purine nucleotides
(AMP, GMP). AICAR is receiving great attention since it
is an activatior of AMPK. In the course of exploring new
AICAR analogues, we planned to synthesize 2-aryl
AICAR derivatives that might provide a potential lead
compound to new types of drugs. From the viewpoint of
green chemistry, the Suzuki–Miyaura cross-coupling is
more suitable than the Stille-type cross-coupling because
boronic acid derivatives used in the Suzuki coupling are
f (2-Furyl)
g (Phenylvinyl)
Acetylation of 3 with Ac2O in pyridine gave more lipo-
philic tri-O-acetyladenosine derivatives 4 which were
easily handled in organic solvents. The oxidation reaction,
converting adenine moiety of 4 to hypoxanthine moiety,
with NaNO2 in HOAc gave tri-O-acetyl-8-arylinosines 5
without the deprotection of acetyl groups. In order to con-
vert hypoxanthine moiety of 5 to the desired 5-amino-4-
carboxamide-imidazole moiety, triacetate 5 was treated
SYNTHESIS 2004, No. 17, pp 2799–2804
x
x.
x
x
.
2
0
0
4
Advanced online publication: 29.09.2004
DOI: 10.1055/s-2004-831249; Art ID: F08404SS
© Georg Thieme Verlag Stuttgart · New York

2800
N. Kohyama et al.
PAPER
NH2
N
NH2
N
N
N
N
N
i
Br
O
O
N
N
HO
HO
HO OH
HO
OH
1
2
NH2
N
O
N
N
N
N
N
NH
ii
R1
O
iv
R1
O
N
RO
AcO
3; R= H
RO OR
AcO OAc
iii
4; R= Ac
5
O
O
OMe
N
N
N
N
O
NH2
NH2
R1
O
R1
v
vii
N
O
N
RO
HO
6; R= Ac
7; R= H
RO OR
HO OH
vi
8
Cl
a
e
b
f
c
g
d
F
MeO
S
O
a Reagents and conditions: (i) Br2, NaOAc buffer (81%); (ii) R1B(OH)2, K2CO3, Pd(Ph3P)4,
DME–H2O(2:1); (iii) Ac2O, pyridine; (iv) NaNO2, AcOH; (v) MEMCl, iPr2NEt, CH2Cl2; (vi)
NH3aq/MeOH; (vii) 0.2N-NaOHaq, reflux
Scheme 1
tion was then adjusted to 7 with 2 N NaOH. The resulting solids
were collected by filtration, successively washed with water and ac-
etone, and dried in vacuo to yield 2 (10.5 g, 81%).
1H NMR (270 MHz, DMSO-d6): d = 8.11 (s, 1 H, H-2), 7.56 (br s,
2 H, NH2), 5.83 (d, J = 6.5 Hz, 1 H, 2¢-OH), 5.52 (dd, J = 8.6, 4.0
Hz, 1 H, 5¢-OH), 5.47 (d, H-1¢, J = 6.3 Hz, 1 H), 5.24 (d, J = 4.6 Hz,
1 H, 3¢-OH), 5.08 (dd, 1 H, H-2¢), 4.22–4.16 (m, 1 H, H-3¢), 3.98
(dd, J = 6.3, 4.0 Hz, 1 H, H-4¢), 3.74–3.46 (m, 2 H, H-5¢).
with 2-methoxyethoxymethyl chloride in the presence of
i-Pr2NEt in CH2Cl2.8 Compounds 6 were deacetylated to
increase the solubility in water since the final step reac-
tions should be conducted homogeneously in an aqueous
reaction medium. The hydrolysis reactions of 7 with 0.2 N
NaOH gave desired 2-aryl AICAR derivatives 8, which
were purified by column chromatography except 8g,
which was purified by crystallization.
8-Phenyladenosine (3a), Coupling Reaction; Typical Procedure
A mixture of 1,2-dimethoxyethane–water (2:1, 11 mL) was added
to a flask containing 8-bromoadenosine (1.0 g, 2.89 mmol), phenyl-
boronic acid (545 mg, 4.33 mmol), and K2CO3 (2.4 g, 17.3 mmol).
The mixture was stirred for 10 min at r.t. To the solution was added
Pd(PPh3)4 (334 mg, 0.29 mmol) and the mixture was stirred for 16
h at 90 °C. The reaction mixture was cooled to r.t. and filtered
through Celite. The solvent was evaporated and the residue was
chromatographed on silica gel (CHCl3–MeOH, 8:1) to give 3a (808
mg, 81%).
1H NMR (270 MHz, DMSO-d6): d = 8.16 (s, 1 H, H-2), 7.78–7.74
(m, 2 H, Ph), 7.61–7.58 (m, 3 H, Ph), 7.50 (br s, 2 H, NH2), 5.83–
5.73 (m, 2 H), 5.47 (d, J = 6.3 Hz, 1 H), 5.19 (dd, 1 H), 5.13 (d, J =
4.3 Hz, 1 H), 4.20–4.15 (m, 1 H), 3.94 (dd, 1 H), 3.74–3.66 (m, 1
H), 3.61–3.50 (m, 1 H).
2-Aryl AICAR derivatives 8 of completely novel type nu-
cleoside derivatives are expected to have interesting bio-
logical activities. The biological evaluation of these
compounds will be reported elsewhere.
1H NMR and 13C NMR spectra were recorded with an JEOL alpha-
500 (at 500 MHz for 1H and 126 MHz for 13C) and a JEOL-JNM-
EX-270 (at 270 MHz for 1H and 68 MHz for 13C). Chemical shifts
for 1H and 13C NMR are given in ppm (d) relative to TMS as internal
standard. J Values are given in Hz. Optical rotation was measured
with a JASCO DIP-1030 (with a 1 dm cell). HRMS were done with
a JEOL JMS-DX-300. TLC was carried out using Silica gel 60-F254
(Merck). Column chromatography was performed on silica gel
(Wako Pure Chemical Industries, Ltd. Wakogel C-300). Almost all
of reagents were purchased from Wako Pure Chemical Industries,
Ltd., Nacalai Tesque, Aldrich Chemical Company, Inc.
8-(4-Fluorophenyl)adenosine (3b)
Prepared from 2 and 4-fluorophenylboronic acid in 75% yield ac-
cording to the typical procedure for 3a.
8-Bromoadenosine (2); Typical Procedure
Saturated bromine–water (370 mL) was added slowly to a suspen-
sion of adenosine (10 g, 37.4 mmol) in NaOAc buffer (225 mL, 0.5
M, pH 4). The mixture was stirred at r.t. for 47 h. The solution was
decolorized by the addition of 5 N NaHSO3, and the pH of the solu-
1H NMR (270 MHz, DMSO-d6): d = 8.15 (s, 1 H, H-2), 7.85–7.76
(dd, J = 8.9, 5.6 Hz, 2 H, Ph), 7.51 (br s, 2 H, NH2), 7.49–7.40 (t,
J = 8.9 Hz, 2 H, Ph), 5.79 (dd, J = 8.9, 3.3 Hz, 1 H), 5.72 (d, J = 7.3
Synthesis 2004, No. 17, 2799–2804 © Thieme Stuttgart · New York

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Synthesis of Novel 2-Aryl AICAR Derivatives
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Hz, 1 H), 5.47 (d, J = 6.6 Hz, 1 H), 5.21–5.12 (m, 2 H), 4.20–4.14
(m, 1 H), 3.95 (dd, 1 H), 3.75–3.65 (m, 1 H), 3.61–3.50 (m, 1 H).
was added. The reaction mixture was stirred at r.t. for 16 h and then
the reaction was quenched by pouring into ice. The aqueous phase
was extracted with EtOAc (2 × 30 mL), washed with water (2 × 30
mL), dried (MgSO4), and concentrated in vacuo. Purification of the
crude product by flash chromatography (SiO2, EtOAc) yielded 4a
(847 mg, 77%).
8-(4-Methoxyphenyl)adenosine (3c)
Prepared from 2 and 4-methoxyphenylboronic acid in 73% yield ac-
cording to the typical procedure for 3a.
1H NMR (270 MHz, DMSO-d6): d = 8.13 (s, 1 H, H-2), 7.70 (d, J =
7.9 Hz, 2 H, Ph), 7.44 (br s, 2 H, NH2), 7.14 (d, J = 8.2 Hz, 2 H, Ph),
5.82 (dd, J = 9.0, 3.1 Hz, 1 H), 5.76 (d, J = 6.9 Hz, 1 H), 5.45 (d,
J = 6.3 Hz, 1 H), 5.18 (dd, 1 H), 5.12 (d, J = 4.3 Hz, 1 H), 4.22–4.14
(m, 1 H), 3.97–3.91 (m, 1 H), 3.75–3.64 (m, 1 H), 3.62–3.50 (m, 1
H), 3.32 (s, 3 H).
1H NMR (270 MHz, CHCl3): d = 8.38 (s, 1 H, H-2), 7.78–7.73 (m,
2 H, Ph), 7.60–7.54 (m, 3 H, Ph), 6.49 (dd, J = 6.1, 4.4 Hz, 1 H, H-
3¢), 6.02 (t, J = 5.8 Hz, 1 H, H-2¢), 5.96 (d, J = 4.3 Hz, 1 H, H-1¢),
5.71 (s, 2 H, NH2), 4.59–4.50 (m, 1 H, H-4¢), 4.42–4.30 (m, 2 H, H-
5¢), 2.10 (s, 3 H, acetyl), 2.07 (s, 3 H, acetyl), 2.02 (s, 3 H, acetyl).
2¢,3¢,5¢-Tri-O-acetyl-8-(4-fluorophenyl)adenosine (4b)
Prepared from 3b in 87% yield according to the typical procedure
for 4a.
1H NMR (270 MHz, CHCl3): d = 8.37 (s, 1 H, H-2), 7.79–7.72 (m,
2 H, Ph), 7.31–7.21 (m, 2 H, Ph), 6.48 (dd, J = 6.0, 4.3 Hz, 1 H, H-
3¢), 6.04 (t, J = 5.8 Hz, 1 H, H-2¢), 5.87 (d, J = 4.3 Hz, 1 H, H-1¢),
5.78 (s, 2 H, NH2), 4.58–4.49 (m, 1 H, H-4¢), 4.41–4.31 (m, 2 H, H-
5¢), 2.11 (s, 3 H, acetyl), 2.06 (s, 3 H, acetyl), 2.02 (s, 3 H, acetyl).
8-(3-Chlorophenyl)adenosine (3d)
Prepared from 2 and 3-chlorophenylboronic acid in 63% yield ac-
cording to the typical procedure for 3a.
1H NMR (270 MHz, DMSO-d6): d = 8.17 (s, 1 H, H-2), 7.82–7.59
(m, 4 H, Ph), 7.55 (br s, 2 H, NH2), 5.82–5.71 (m, 2 H), 5.50 (d, J =
6.3 Hz, 1 H), 5.21–5.11 (m, 2 H), 4.20–4.13 (m, 1 H), 4.00–3.93 (m,
1 H), 3.75–3.65 (m, 1 H), 3.65–3.50 (m, 1 H).
HRMS (FAB): m/z [M + H] calcd for C16H17ClN5O4: 378.0969;
found: 378.0956.
2¢,3¢,5¢-Tri-O-acetyl-8-(4-methoxyphenyl)adenosine (4c)
Prepared from 3c in 91% yield according to the typical procedure
for 4a.
1H NMR (270 MHz, CHCl3): d = 8.34 (s, 1 H, H-2), 7.79 (d, J = 8.6
Hz, 2 H, Ph), 7.06(d, J = 8.6 Hz, 2 H, Ph), 6.50 (dd, J = 5.8, 4.5 Hz,
1 H, H-3¢), 6.04 (t, J = 5.9 Hz, 1 H, H-2¢), 5.95 (d, 1 H, H-1¢), 5.94
(s, 2 H, NH2), 4.60–4.49 (m, 1 H, H-4¢), 4.42–4.30 (m, 2 H, H-5¢),
3.90 (s, 3 H, OCH3), 2.10 (s, 3 H, acetyl), 2.07 (s, 3 H, acetyl), 2.02
(s, 3 H, acetyl).
8-(2-Thienyl)adenosine (3e)
Prepared from 2 and 2-thienylboronic acid in 40% yield according
to the typical procedure for 3a.
1H NMR (270 MHz, DMSO-d6): d = 8.14 (s, 1 H, H-2), 7.87 (d, J =
5.3 Hz, 1 H, thienyl), 7.65 (d, J = 3.6 Hz, 1 H, thienyl), 7.51 (br s, 2
H, NH2), 7.29 (dd, J = 5.8, 4.5 Hz, 1 H, thienyl), 6.00 (d, J = 6.9 Hz),
5.79 (dd, J = 8.9, 3.6 Hz, 1 H), 5.52 (d, J = 6.3 Hz, 1 H), 5.25–5.15
(m, 2 H), 4.25–4.17 (m, 1 H), 3.99 (s, 1 H), 3.76–3.66 (m, 1 H),
3.65–3.51 (m, 1 H).
2¢,3¢,5¢-Tri-O-acetyl-8-(3-chlorophenyl)adenosine (4d)
Prepared from 3d in 82% yield according to the typical procedure
for 4a.
1H NMR (270 MHz, CHCl3): d = 8.38 (s, 1 H, H-2), 7.78–7.46 (m,
4 H, phenyl), 6.47 (dd, J = 6.0, 4.3 Hz, 1 H, H-3¢), 6.02 (t, J = 5.8
Hz, 1 H, H-2¢), 5.92 (d, J = 4.3 Hz, 1 H, H-1¢), 5.72 (s, 2 H, NH2),
4.59–4.49 (m, 1 H, H-4¢), 4.41–4.32 (m, 2 H, H-5¢), 2.11 (s, 3 H,
acetyl), 2.06 (s, 3 H, acetyl), 2.05 (s, 3 H, acetyl).
HRMS (FAB): m/z [M + H] calcd for C14H16N5O4S1: 350.0923;
found: 350.0920.
8-(2-Furyl)adenosine (3f)
Prepared from 2 and 2-furylboronic acid in 26% yield according to
the typical procedure for 3a.
1H NMR (270 MHz, DMSO-d6): d = 8.14 (s, 1 H, H-2), 8.01 (d, J =
1.0 Hz, 1 H, furyl), 7.55 (br s, 2 H, NH2), 7.14 (d, J = 3.3 Hz, 1 H,
furyl), 6.77 (dd, J = 3.3, 2.0 Hz, 1 H), 6.11 (d, J = 6.9 Hz, 1 H), 5.74
(dd, J = 8.9, 3.6 Hz, 1 H), 5.43 (d, J = 6.6 Hz, 1 H), 5.25–5.07 (m,
2 H), 4.21 (dd, J = 6.6, 4.6 Hz, 1 H), 4.00 (d, J = 2.3 Hz, 1 H), 3.76–
3.65 (m, 1 H), 3.61–3.47 (m, 1 H).
2¢,3¢,5¢-Tri-O-acetyl-8-(2-thienyl)adenosine (4e)
Prepared from 3e in 94% yield according to the typical procedure
for 4a.
1H NMR (270 MHz, CHCl3): d = 8.35 (s, 1 H, H-2), 7.58 (d, 2 H),
7.22 (t, 1 H), 6.65 (dd, J = 5.6, 4.3 Hz, 1 H, H-3¢), 6.16 (d, J = 4.3
Hz, 1 H, H-1¢), 6.06 (t, J = 5.6 Hz, 1 H, H-2¢), 5.98 (s, 2 H, NH2),
4.57–4.47 (m, 1 H, H-4¢), 4.44–4.32 (m, 2 H, H-5¢), 2.12 (s, 3 H,
acetyl), 2.05 (s, 3 H, acetyl), 2.04 (s, 3 H, acetyl).
HRMS (FAB): m/z [M + H] calcd for C14H16N5O5: 334.1151; found:
334.1151.
8-(2-Phenylvinyl)adenosine (3g)
Prepared from 2 and 2-phenylvinylboronic acid in 47% yield ac-
cording to the typical procedure for 3a.
2¢,3¢,5¢-Tri-O-acetyl-8-(2-furyl)adenosine (4f)
Prepared from 3f in 80% yield according to the typical procedure
for 4a.
1H NMR (270 MHz, CHCl3): d = 8.35 (s, 1 H, H-2), 7.68 (s, 1 H),
7.14 (d, J = 3.6 Hz, 1 H), 6.66–6.62 (m, 1 H), 6.57 (dd, J = 6.0, 4.3
Hz, 1 H, H-3¢), 6.42 (d, J = 4.0 Hz, 1 H, H-1¢), 6.06 (t, J = 5.9 Hz, 1
H, H-2¢), 5.78 (s, 2 H, NH2), 4.56–4.47 (m, 1 H, H-4¢), 4.45–4.30
(m, 2 H, H-5¢), 2.14 (s, 3 H, acetyl), 2.08 (s, 3 H, acetyl), 2.02 (s, 3
H, acetyl).
1H NMR (270 MHz, DMSO-d6): d = 8.10 (s, 1 H, H-2), 7.80–7.72
(m, 3 H, Ph, PhCH=CH), 7.56 (d, J = 16.2 Hz, 1 H, PhCH=CH),
7.45–7.33 (m, 5 H, Ph, NH2), 6.13 (d, J = 7.3 Hz, 1 H, H-1¢), 5.81
(dd, J = 7.4, 3.5 Hz, 1 H, 5¢-OH), 5.34 (d, J = 6.9 Hz, 1 H, 2¢-OH),
5.24 (d, J = 4.3 Hz, 1 H, 3¢-OH), 4.78–4.68 (m, 1 H, H-2¢), 4.25–
4.15 (m, 1 H, H-3¢), 4.07–3.98 (m, 1 H, H-4¢), 3.79–3.56 (m, 2 H,
H-5¢).
HRMS (FAB): m/z [M + H] calcd for C18H20N5O4: 370.1515; found:
370.1521.
2¢,3¢,5¢-Tri-O-acetyl-8-phenylvinyladenosine (4g)
Prepared from 3g in 94% yield according to the typical procedure
for 4a.
1H NMR (270 MHz, CHCl3): d = 8.33 (s, 1 H, H-2), 7.85 (d, J = 15.8
Hz, 1 H, PhCH=CH), 7.65–7.53 (m, 2 H, Ph), 7.47–7.36 (m, 3 H,
Ph), 7.11 (d, J = 15.5 Hz, 1 H, PhCH=CH), 6.42 (t, J = 5.3 Hz, 1 H,
2¢,3¢,5¢-Tri-O-acetyl-8-phenyladenosine (4a), Acetylation of
Sugar Moiety; Typical Procedure
A suspension of 8-phenyladenosine (800 mg, 2.33 mmol) in pyri-
dine (7 mL) was stirred at r.t., and then acetic anhydride (1.2 mL)
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N. Kohyama et al.
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H-3¢), 6.18 (d, J = 4.9 Hz, 1 H, H-1¢), 6.06 (t, J = 5.4 Hz, 1 H, H-2¢),
5.59 (s, 2 H, NH2), 4.55–4.33 (m, 3 H, H-4¢, H-5¢), 2.16 (s, 3 H,
acetyl), 2.08 (s, 3 H, acetyl), 1.99 (s, 3 H, acetyl).
2¢,3¢,5¢-Tri-O-acetyl-8-(2-furyl)inosine (5f)
Prepared from 4f in 67% yield according to the typical procedure
for 5a.
1H NMR (270 MHz, CHCl3): d = 12.9 (br s, 1 H, 1-NH), 8.17 (s, 1
H, H-2), 7.66–7.64 (m, 1 H), 7.31 (dd, 1 H), 6.67 (d, J = 4.3 Hz, 1
H, H-1¢), 6.64–6.61 (m, 1 H), 6.35 (dd, J = 6.0, 4.3 Hz, 1 H, H-3¢),
5.89 (t, J = 6.0 Hz, 1 H, H-2¢), 4.55–4.48 (m, 1 H, H-4¢), 4.44–4.28
(m, 2 H, H-5¢), 2.15 (s, 3 H, acetyl), 2.09 (s, 3 H, acetyl), 2.05 (s, 3
H, acetyl).
2¢,3¢,5¢-Tri-O-acetyl-8-(2-phenylvinyl)inosine (5a): Oxidative
Deamination; Typical Procedure
A solution of 2¢,3¢,5¢-tri-O-acetyl-8-phenyladenosine (4a; 840 mg,
1.79 mmol) in HOAc (27 mL) was stirred at r.t., and then NaNO2
(1.26 g) in H2O (9 mL) was added. After the reaction mixture was
stirred at r.t. for 19 h, the solvent was evaporated and water was add-
ed to the residue. The aqueous phase was extracted with EtOAc (2
× 30 mL). The combined organic layer was washed with sat. aq
NaHCO3 (2 × 30 mL) and sat. aq NaCl (2 × 30 mL), and dried
(MgSO4). Concentration in vacuo afforded 5a (826 mg, 98%).
1H NMR (270 MHz, CHCl3): d = 13.2 (br s, 1 H, 1-NH), 8.23 (s, 1
H, H-2), 7.77–7.62 (m, 2 H, Ph), 7.60–7.55 (m, 3 H, Ph), 6.42 (t,
J = 5.3 Hz, 1 H, H-3¢), 6.03 (d, J = 4.6 Hz, 1 H, H-1¢), 5.88 (t, J =
5.6 Hz, 1 H, H-2¢), 4.56–4.49 (m, 1 H, H-4¢), 4.40–4.33 (m, 2 H, H-
5¢), 2.10 (s, 3 H, acetyl), 2.09 (s, 3 H, acetyl), 2.03 (s, 3 H, acetyl).
HRMS (FAB): m/z [M + H] calcd for C20H21N4O9: 461.1308; found:
461.1305.
2¢,3¢,5¢-Tri-O-acetyl-8-(2-phenylvinyl)inosine (5g)
Prepared from 4g in 90% yield according to the typical procedure
for 5a.
1H NMR (270 MHz, CHCl3): d = 13.2 (br s, 1 H, 1-NH), 8.12 (s, 1
H, H-2), 8.09 (d, 1 H, PhCH=CH), 7.65–7.56 (m, 2 H, Ph), 7.47–
7.35 (m, 3 H, Ph), 7.06 (d, J = 15.8 Hz, 1 H, PhCH=CH), 6.31 (t,
J = 5.4 Hz, 1 H, H-3¢), 6.19 (d, J = 5.3 Hz, 1 H, H-1¢), 5.81 (t, J =
5.4 Hz, 1 H, H-2¢), 4.53–4.32 (m, 3 H, H-4¢, H-5¢), 2.17 (s, 3 H,
acetyl), 2.10 (s, 3 H, acetyl), 2.01 (s, 3 H, acetyl).
2¢,3¢,5¢-Tri-O-acetyl-8-(4-fluorophenyl)inosine (5b)
Prepared from 4b in 76% yield according to the typical procedure
for 5a.
HRMS (FAB): m/z [M + H] calcd for C24H25N4O8: 497.1672; found:
1H NMR (270 MHz, CHCl3): d = 13.1 (br s, 1 H, 1-NH), 8.27 (s, 1
H, H-2), 7.86–7.78 (m, 2 H, H-3¢¢, H-5¢¢), 7.30–7.22 (m, 2 H, H-2¢¢,
H-6¢¢), 6.40 (dd, J = 6.1, 4.4 Hz, 1 H, H-3¢), 5.94 (d, J = 4.6 Hz, 1
H, H-1¢), 5.90 (t, J = 5.7 Hz, 1 H, H-2¢), 4.56–4.47 (m, 1 H, H-4¢),
4.40–4.31 (m, 2 H, H-5¢), 2.11 (s, 3 H, acetyl), 2.06 (s, 3 H, acetyl),
2.04 (s, 3 H, acetyl).
497.1677.
2¢,3¢,5¢-Tri-O-acetyl-1-[(2-methoxyethoxy)methyl]-8-phenyl-
inosine (6a): Introduction of MEM Group; Typical Procedure
To a solution of 5a (1.09 g, 2.32 mmol) in CH2Cl2 (16 mL) was add-
ed N,N-diisopropylethylamine (605 mL, 3.48 mmol) at r.t,, and 2-
methoxyethoxymethyl chloride (317 mL, 2.78 mmol) was added
dropwise. The mixture was stirred at r.t. for 3.5 h, then quenched by
pouring over water. The aqueous phase was extracted with CHCl3
(2 × 30 mL), washed with 0.05 N HCl (2 × 30 mL) and sat. aq
NaHCO3 (2 × 30 mL), dried (MgSO4), and concentrated in vacuo.
Purification of the crude product by flash chromatography (SiO2,
EtOAc–hexane, 4:1) yielded 6a (820 mg, 64%).
1H NMR (270 MHz, CDCl3): d = 8.17 (s, 1 H, H-2), 7.79–7.74 (m,
2 H, Ph), 7.57–7.51 (m, 3 H, Ph), 6.36 (dd, J = 5.9, 4.6 Hz, 1 H, H-
3¢), 5.99 (d, J = 4.6 Hz, 1 H, H-1¢), 5.86 (t, J = 5.4 Hz, 1 H, H-2¢),
5.59 (s, 2 H, NCH2O), 4.55–4.45 (m, 1 H, H-4¢), 4.40–4.31 (m, 2 H,
H-5¢), 3.86–3.81 (m, 2 H, OCH2CH2O), 3.57–3.52 (m, 2 H,
OCH2CH2O), 3.36 (s, 3 H, OCH3), 2.10 (s, 3 H, acetyl), 2.09 (s, 3
H, acetyl), 2.03 (s, 3 H, acetyl).
2¢,3¢,5¢-Tri-O-acetyl-8-(4-methoxyphenyl)inosine (5c)
Prepared from 4c in 79% yield according to the typical procedure
for 5a.
1H NMR (270 MHz, CHCl3): d = 12.9 (br s, 1 H, 1-NH), 8.15 (s, 1
H, H-2), 7.76 (d, J = 8.6 Hz, 2 H, H-3¢¢, H-5¢¢), 7.06 (d, J = 8.9 Hz,
2 H, Ph), 6.42 (dd, J = 5.9, 4.6 Hz, 1 H, H-3¢), 6.01 (d, J = 5.0 Hz,
1 H, H-1¢), 5.89 (t, J = 5.6 Hz, 1 H, H-2¢), 4.56–4.47 (m, 1 H, H-4¢),
4.40–4.31 (m, 2 H, H-5¢), 3.90 (s, 3 H, OCH3), 2.10 (s, 3 H, acetyl),
2.07 (s, 3 H, acetyl), 2.03 (s, 3 H, acetyl).
2¢,3¢,5¢-Tri-O-acetyl-8-(3-chlorophenyl)inosine (5d)
Prepared from 4d in 90% yield according to the typical procedure
for 5a.
13C NMR (68 MHz, CDCl3): d = 170.5, 169.4, 169.2 (CH3CO),
156.6 (C-6), 148.1, 147.0 (C-2), 133.1, 130.5, 129.8, 128.9, 128.7,
124.8, 88.0 (C-1¢), 80.0 (C-5¢), 75.3 (NCH2O), 72.3 (C-3¢), 71.6
(OCH2CH2O), 70.6 (C-2¢), 69.4 (OCH2CH2O), 63.3 (C-4¢), 59.2
(OCH3), 21.0, 20.7, 20.6 (CH3CO).
1H NMR (270 MHz, CHCl3): d = 13.0 (br s, 1 H, 1-NH), 8.19 (s, 1
H, H-2), 7.82 (t, 1 H), 7.81–7.71 (m, 1 H), 7.57–7.46 (m, 2 H), 6.38
(dd, J = 5.9, 4.6 Hz, 1 H, H-3¢), 5.98 (d, J = 4.6 Hz, 1 H, H-1¢), 5.87
(t, J = 5.6 Hz, 1 H, H-2¢), 4.57–4.47 (m, 1 H, H-4¢), 4.41–4.32 (m,
2 H, H-5¢), 2.12 (s, 3 H, acetyl), 2.07 (s, 3 H, acetyl), 2.05 (s, 3 H,
acetyl).
HRMS (FAB): m/z [M + H] calcd for C26H31N4O10: 559.2040;
found: 559.2058.
HRMS (FAB): m/z [M + H] calcd for C22H22ClN4O8: 507.1126;
found: 507.1107.
2¢,3¢,5¢-Tri-O-acetyl-8-(4-fluorophenyl)-1-[(2-methoxy-
ethoxy)methyl]inosine (6b)
Prepared from 5a in 61% yield according to the typical procedure
2¢,3¢,5¢-Tri-O-acetyl-8-(2-thienyl)inosine (5e)
Prepared from 4e in 72% yield according to the typical procedure
for 5a.
for 6a.
1H NMR (500 MHz, CDCl3): d = 8.17 (s, 1 H, H-2), 7.77 (dd, J =
8.5 Hz, 2 H, Ph), 7.23 (t, J = 8.5 Hz, 2 H, Ph), 6.35 (dd, J = 6.1, 4.6
Hz, 1 H, H-3¢), 5.90 (d, J = 4.3 Hz, 1 H, H-1¢), 5.87 (t, J = 5.8 Hz, 1
H, H-2¢), 5.59 (dd, 2 H, NCH2O), 4.52–4.48 (m, 1 H, H-4¢), 4.38–
4.33 (m, 2 H, H-5¢), 3.83 (dd, J = 3.7 Hz, 2 H, OCH2CH2O), 3.55–
3.53 (m, 2 H, OCH2CH2O), 3.37 (s, 3 H, OCH3), 2.11 (s, 3 H,
acetyl), 2.09 (s, 3 H, acetyl), 2.03 (s, 3 H, acetyl).
13C NMR (126 MHz, CDCl3): d = 170.5, 169.5, 169.3 (CH3CO),
165.1, 163.1, 156.6 (C-6), 150.7, 148.1, 147.1 (C-2), 131.9, 131.8
(Ph), 124.8, 116.2, 116.1 (Ph), 88.0 (C-1¢), 80.0 (C-5¢), 75.2
1H NMR (270 MHz, CHCl3): d = 13.1 (br s, 1 H, 1-NH), 8.26 (s, 1
H, H-2), 7.62–7.58 (m, 2 H), 7.21 (dd, J = 5.0, 4.0 Hz, 1 H), 6.54
(dd, J = 5.9, 4.6 Hz, 1 H, H-3¢), 6.23 (d, J = 4.6 Hz, 1 H, H-1¢), 5.91
(t, J = 5.6 Hz, 1 H, H-2¢), 4.54–4.46 (m, 1 H, H-4¢), 4.44–4.31 (m,
2 H, H-5¢), 2.13 (s, 3 H, acetyl), 2.07 (s, 3 H, acetyl), 2.05 (s, 3 H,
acetyl).
HRMS (FAB): m/z [M + H] calcd for C20H21N4O8S1: 477.1080;
found: 477.1085.
Synthesis 2004, No. 17, 2799–2804 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel 2-Aryl AICAR Derivatives
2803
(NCH2O), 72.3 (C-3¢), 71.5 (OCH2CH2O), 70.5 (C-2¢), 69.4
(OCH2CH2O), 63.1 (C-4¢), 59.0 (OCH3), 20.7, 20.5, 20.4 (CH3CO).
2¢,3¢,5¢-Tri-O-acetyl-8-(2-furyl)-1-[(2-methoxyethoxy)meth-
yl]inosine (6f)
Prepared from 5f in 67% yield according to the typical procedure
for 6a.
HRMS (FAB): m/z [M + H] calcd for C26H30N4O10F: 577.1946;
found: 577.1946.
1H NMR (270 MHz, CDCl3): d = 8.14 (s, 1 H, H-2), 7.62(s, 1 H),
7.26 (d, J = 3.3 Hz, 1 H), 6.61 (m, 2 H), 6.30 (dd, J = 5.9, 4.3 Hz, 1
H, H-3¢), 5.84 (t, J = 5.9 Hz, 1 H, H-2¢), 5.57 (s, 2 H, NCH2O), 4.49
(dd, 1 H, H-4¢), 4.42–4.28 (m, 2 H, H-5¢), 3.84–3.80 (m, 2 H,
OCH2CH2O), 3.55–3.51 (m, 2 H, OCH2CH2O), 3.36 (s, 3 H,
OCH3), 2.14 (s, 3 H, acetyl), 2.09 (s, 3 H, acetyl), 2.06 (s, 3 H,
acetyl).
13C NMR (68 MHz, CDCl3): d = 170.5, 169.4, 169.3 (CH3CO),
156.4 (C-6), 147.9, 147.0 (C-2), 144.4, 144.1, 142.0, 141.1, 114.5,
112.3, 88.2 (C-1¢), 80.0 (C-5¢), 75.3 (NCH2O), 72.8 (C-3¢), 71.6
(OCH2CH2O), 70.5 (C-2¢), 69.5 (OCH2CH2O), 63.5 (C-4¢), 59.2
(OCH3), 20.9, 20.8, 20.7 (CH3CO).
2¢,3¢,5¢-Tri-O-acetyl-1-[(2-methoxyethoxy)methyl]-8-(4-meth-
oxyphenyl)inosine (6c)
Prepared from 5c in 75% yield according to the typical procedure
for 6a.
1H NMR (270 MHz, CDCl3): d = 8.15 (s, 1 H, H-2), 7.72 (d, J = 8.9
Hz, 2 H, Ph), 7.04 (d, J = 8.9 Hz, 2 H, Ph), 6.36 (dd, J = 5.9, 5.0 Hz,
1 H, H-3¢), 5.98 (d, J = 4.6 Hz, 1 H, H-1¢), 5.87 (t, J = 5.6 Hz, 1 H,
H-2¢), 5.58 (s, 2 H, NCH2O), 4.54–4.46 (m, 1 H, H-4–), 4.39–4.31
(m, 2 H, H-5¢), 3.88 (s, 3 H, PhOCH3), 3.84–3.81 (m, 2 H,
OCH2CH2O), 3.56–3.52 (m, 2 H, OCH2CH2O), 3.36 (s, 3 H,
OCH3), 2.10 (s, 3 H, acetyl), 2.09 (s, 3 H, acetyl), 2.03 (s, 3 H,
acetyl).
13C NMR (68 MHz, CDCl3): d = 170.5, 169.4, 169.2 (CH3CO),
161.3, 156.6 (C-6), 151.6, 148.0, 146.7 (C-2), 131.3 (Ph), 124.7,
120.9, 114.3 (Ph), 87.9 (C-1¢), 80.0 (C-5¢), 75.2 (NCH2O), 72.3 (C-
3¢), 71.6 (OCH2CH2O), 70.6 (C-2¢), 69.4 (OCH2CH2O), 63.3 (C-4¢),
59.1 (OCH3), 55.6 (PhOCH3), 20.9, 20.7, 20.6 (CH3CO).
HRMS (FAB): m/z [M + H]calcd for C24H30N4O11: 549.1833;
found: 549.1821.
2¢,3¢,5¢-Tri-O-acetyl-1-[(2-methoxyethoxy)methyl]-8-(2-phenyl-
vinyl)inosine (6g)
Prepared from 5g in 57% yield according to the typical procedure
for 6a.
HRMS (FAB): m/z [M + H] calcd for C27H33N4O11: 589.2146;
found: 589.2166.
1H NMR (500 MHz, CDCl3): d = 8.11 (s, 1 H, H-2), 8.04 (d, J = 15.6
Hz, 1 H, PhCH=CH), 7.60–7.57 (m, 2 H, Ph), 7.43–7.35 (m, 3 H,
Ph), 7.02 (d, J = 15.9 Hz, 1 H, PhCH=CH), 6.28 (t, J = 5.3 Hz, 1 H,
H-2¢), 6.15 (d, J = 4.9 Hz, 1 H, H-1¢), 5.81 (t, J = 5.6 Hz, 1 H, H-3¢),
5.58 (dd, 2 H, NCH2O), 4.48 (dd, J = 3.7 Hz, 1 H, H-5¢), 4.44–4.40
(m, 1 H, H-4¢), 4.37–4.32 (m, 1 H, H-5¢), 3.84–3.81 (m, 2 H,
OCH2CH2O), 3.55–3.52 (m, 2 H, OCH2CH2O), 3.36 (s, 3 H,
OCH3), 2.17 (s, 3 H, acetyl), 2.10 (s, 3 H, acetyl), 2.03 (s, 3 H,
acetyl).
13C NMR (126 MHz, CDCl3): d = 170.6, 169.7, 169.5 (CH3CO),
156.6, 149.2, 147.9, 146.7 (C-2), 139.3 (PhCH=CH), 135.8, 129.6
(Ph), 129.0 (Ph), 127.6 (Ph), 125.1, 111.9 (PhCH=CH), 86.5 (C-1¢),
80.2 (C-4¢), 75.2 (NCH2O), 72.5 (C-2¢), 71.6 (OCH2CH2O), 70.5
(C-3¢), 69.5 (OCH2CH2O), 63.3 (C-5¢), 59.2 (OCH3), 20.8, 20.7,
20.6 (CH3CO).
2¢,3¢,5¢-Tri-O-acetyl-8-(3-chlorophenyl)-1-[(2-methoxy-
ethoxy)methyl]inosine (6d)
Prepared from 5d in 68% yield according to the typical procedure
for 6a.
1H NMR (270 MHz, CDCl3): d = 8.18 (s, 1 H, H-2), 7.78–7.44 (m,
4 H, Ph), 6.33 (dd, J = 5.9, 4.6 Hz, 1 H, H-3¢), 5.94 (d, J = 4.6 Hz,
1 H, H-1¢), 5.85 (t, J = 5.6 Hz, 1 H, H-2¢), 5.59 (s, 2 H, NCH2O),
4.55–4.45 (m, 1 H, H-4¢), 4.40–4.31 (m, 2 H, H-5¢), 3.85–3.80 (m,
2 H, OCH2CH2O), 3.57–3.52 (m, 2 H, OCH2CH2O), 3.36 (s, 3 H,
OCH3), 2.11 (s, 3 H, acetyl), 2.09 (s, 3 H, acetyl), 2.07 (s, 3 H,
acetyl).
13C NMR (68 MHz, CDCl3): d = 170.5, 169.4, 169.3 (CH3CO),
156.5 (C-6), 150.0, 148.2, 147.3 (C-2), 134.8, 130.6, 130.3, 130.2,
129.9, 127.9, 87.9 (C-1¢), 80.1 (C-5¢), 75.3 (NCH2O), 72.4 (C-3¢),
71.6 (OCH2CH2O), 70.5 (C-2¢), 69.5 (OCH2CH2O), 63.3 (C-4¢),
59.2 (OCH3), 20.9, 20.7, 20.6 (CH3CO).
HRMS (FAB): m/z [M + H] calcd for C28H34N4O10: 585.2196;
found: 585.2212.
5-Amino-2-phenyl-1-b-D-ribofuranosylimidazole-4-carboxam-
ide (8a): Ring-Opening Reaction; Typical Procedure
HRMS (FAB): m/z [M + H] calcd for C27H30ClN4O10: 593.1650;
found: 593.1637.
A solution of 6a (820 mg, 1.47 mmol) in MeOH (15 mL) was stirred
at r.t., and then aq NH3 (3 mL) was added. The reaction mixture was
stirred at r.t. for 17 h and concentrated in vacuo to give white solid.
Successively, the solid was suspended with 0.2 N aq NaOH and
heated under reflux for 1 h. After cooling, the reaction mixture was
neutralized with 3 N HCl, and concentrated in vacuo. The residue
was extracted with hot EtOH, filtered, and concentrated in vacuo.
Purification of the crude product by flash chromatography (SiO2,
2¢,3¢,5¢-Tri-O-acetyl-1-[(2-methoxyethoxy)methyl]-8-(2-thie-
nyl)inosine (6e)
Prepared from 5e in 75% yield according to the typical procedure
for 6a.
1H NMR (270 MHz, CDCl3): d = 8.15 (s, 1 H, H-2), 7.59–7.54 (m,
2 H), 7.21 (dd, 1 H), 6.46 (dd, J = 5.9, 5.0 Hz, 1 H, H-3¢), 6.19 (d,
J = 4.6 Hz, 1 H, H-1¢), 5.87 (t, J = 5.6 Hz, 1 H, H-2¢), 5.58 (s, 2 H,
NCH2O), 4.51–4.30 (m, 3 H, H-4¢, H-5¢), 3.84–3.80 (m, 2 H,
OCH2CH2O), 3.55–3.51 (m, 2 H, OCH2CH2O), 3.36 (s, 3 H,
OCH3), 2.16 (s, 3 H, acetyl), 2.12 (s, 3 H, acetyl), 2.07 (s, 3 H,
acetyl).
13C NMR (68 MHz, CDCl3): d = 170.5, 169.4, 169.2 (CH3CO),
156.4 (C-6), 148.2, 147.1 (C-2), 145.9, 130.2, 129.8, 129.7, 127.8,
124.9, 87.8 (C-1¢), 80.2 (C-5¢), 75.3 (NCH2O), 72.2 (C-3¢), 71.6
(OCH2CH2O), 70.7 (C-2¢), 69.5 (OCH2CH2O), 63.3 (C-4¢), 59.2
(OCH3), 21.0, 20.8, 20.7 (CH3CO).
25
CHCl3–MeOH, 7:1) yielded 1a (171 mg, 35% for 2 steps); [a]D
–8.4 (c = 0.5, MeOH).
1H NMR (500 MHz, DMSO-d6): d = 7.60–7.56 (m, 2 H, Ph), 7.49–
7.42 (m, 3 H, Ph), 6.80 (br d, 2 H, CONH2), 6.27 (s, 2 H, NH2), 5.66
(s, 1 H, 5¢-OH), 5.59 (d, J = 6.4 Hz, 1 H, 2¢-OH), 5.53 (d, J = 5.8 Hz,
1 H, H-1¢), 5.10 (s, 1 H, 3¢-OH), 4.66 (dd, J = 9.2, 5.8 Hz, 1 H, H-
2¢), 4.07 (s, 1 H, H-3¢), 3.85 (s, 1 H, H-4¢), 3.68–3.60 (m, 2 H, H-5¢).
13C NMR (126 MHz, DMSO-d6): d = 166.9 (CONH2), 144.2 (C-4),
139.7 (C-2), 130.3 (Ph), 129.2 (Ph), 128.4 (Ph), 112.3 (C-5), 88.9
(C-1¢), 85.5 (C-4¢), 70.3 (C-3¢), 69.6 (C-2¢), 61.0 (C-5¢).
HRMS (FAB): m/z [M + H] calcd for C24H29N4O10S: 565.1604;
found: 565.1606.
HRMS (FAB): m/z [M + H] calcd for C15H19N4O5: 335.1355; found:
335.1349.
Synthesis 2004, No. 17, 2799–2804 © Thieme Stuttgart · New York

2804
N. Kohyama et al.
PAPER
5-Amino-2-(4-fluorophenyl)-1-b-D-ribofuranosylimidazole-4-
carboxamide (8b)
Prepared from 6b in 35% yield (for 2 steps) according to the typical
procedure for 8a.
H, H-2¢), 4.09 (s, 1 H, H-3¢), 3.89 (s, 1 H, H-4¢), 3.68–3.63 (m, 2 H,
H-5¢).
13C NMR (126 MHz, DMSO-d6): d = 166.6 (CONH2), 144.4 (C-4),
133.3 (C-2), 131.8(thienyl), 127.8(thienyl), 127.5 (thienyl), 127.4
(thienyl), 112.3 (C-5), 88.5 (C-1¢), 85.7 (C-4¢), 70.3 (C-3¢), 70.1 (C-
2¢), 60.9 (C-5¢).
[a]D25 –16 (c = 0.2, MeOH).
1H NMR (500 MHz, DMSO-d6): d = 7.61 (dd, J = 8.6, 5.5 Hz, 2 H,
Ph), 7.31 (t, J = 8.8 Hz, 2 H, Ph), 6.73 (br d, 2 H, CONH2), 6.26 (s,
2 H, NH2), 5.64 (s, 1 H, 5¢-OH), 5.54 (s, 1 H, 2¢-OH), 5.52 (s, 1 H,
H-1¢), 5.09 (s, 1 H, 3¢-OH), 4.63 (dd, J = 6.9, 6.6 Hz, 1 H, H-2¢), 4.06
(dd, 1 H, H-3¢), 3.85 (d, 1 H, H-4¢), 3.67–3.60 (m, 2 H, H-5¢).
13C NMR (126 MHz, DMSO-d6): d = 166.8 (CONH2), 161.2 (C-4¢¢),
144.2 (C-4), 138.7 (C-2), 131.4 (Ph), 126.8 (C-1¢¢), 115.4 (Ph),
112.2 (C-5), 88.8 (C-1¢), 85.6 (C-4¢), 70.2 (C-3¢), 69.7 (C-2¢), 60.9
(C-5¢).
HRMS (FAB): m/z [M + H] calcd for C13H17N4O5S1: 341.0920;
found: 341.0912.
5-Amino-2-(2-furyl)-1-b-D-ribofuranosylimidazole-4-carbox-
amide (8f)
Prepared from 6f in 24% yield (for 2 steps) according to the typical
procedure for 8a.
[a]D25 –10 (c = 0.31, MeOH).
HRMS (FAB): m/z [M + H] calcd for C15H18FN4O5: 353.1261;
found: 353.1270.
1H NMR (500 MHz, DMSO-d6): d = 7.80 (s, 1 H, furyl), 6.90 (br d,
2 H, CONH2), 6.76 (d, J = 3.0 Hz, 1 H, furyl), 6.62 (m, 1 H, furyl),
6.34 (s, 2 H, NH2), 5.79 (d, J = 7.3 Hz, 1 H, H-1¢), 5.66 (t, J = 4.1
Hz, 1 H, 5¢-OH), 5.47 (d, J = 6.6 Hz, 1 H, 2¢-OH), 5.15 (d, J = 4.3
Hz, 1 H, 3¢-OH), 4.52 (dd, J = 6.6 Hz, 1 H, H-2¢), 4.08 (s, 1 H, H-
3¢), 3.90 (s, 1 H, H-4¢), 3.68–3.63 (m, 2 H, H-5¢).
13C NMR (126 MHz, DMSO-d6): d = 166.6 (CONH2), 144.1 (C-4),
143.8 (C-2), 143.6 (furyl), 130.6, 112.5, 111.4 (furyl), 110.9 (furyl),
88.8 (C-1¢), 85.6 (C-4¢), 70.2 (C-3¢), 70.1 (C-2¢), 60.8 (C-5¢).
5-Amino-2-(4-methoxyphenyl)-1-b-D-ribofuranosylimidazole-
4-carboxamide (8c)
Prepared from 6c in 22% yield (for 2 steps) according to the typical
procedure for 8a.
[a]D25 –5.7 (c = 0.5, MeOH).
1H NMR (270 MHz, DMSO-d6): d = 7.49 (d, J = 7.9 Hz, 2 H, Ph),
7.02 (d, J = 7.9 Hz, 2 H, Ph), 6.76 (br d, 2 H, CONH2), 6.20 (s, 2 H,
NH2), 5.63 (s, 1 H, 5¢-OH), 5.55 (d, J = 7.6 Hz, 1 H, H-1¢), 5.49 (d,
J = 6.3 Hz, 1 H, 2¢-OH), 5.09 (d, J = 4.3 Hz, 1 H, 3¢-OH), 4.63 (m,
1 H, H-2¢), 4.07 (m, 1 H, H-3¢), 3.85–3.81 (m, 1 H, H-4¢), 3.80 (s, 3
H, OCH3), 3.64 (m, 2 H, H-5¢).
13C NMR (126 MHz, DMSO-d6): d = 166.9 (CONH2), 159.5 (Ph),
144.0 (C-4), 140.0 (C-2), 130.7 (Ph), 122.6 (Ph), 113.8 (Ph), 112.0
(C-5), 88.8 (C-1¢), 85.4 (C-4¢), 70.2 (C-3¢), 69.6 (C-2¢), 61.0 (C-5¢),
55.2 (OCH3).
HRMS (FAB): m/z [M + H] calcd for C13H17N4O6: 325.1148; found:
325.1146.
5-Amino-2-(2-phenylvinyl)-1-b-D-ribofuranosylimidazole-4-
carboxamide (8g)
Prepared from 6g in 79% yield (for 2 steps) according to the typical
procedure for 8a.
[a]D25 +60 (c = 0.15, MeOH).
1H NMR (500 MHz, DMSO-d6): d = 7.62, (d, 2 H, Ph), 7.38–7.18
(m, 5 H, Ph, PhCH=CH, PhCH=CH), 6.81 (br d, 2 H, CONH2), 6.23
(s, 2 H, NH2), 5.98 (br s, 2 H, OH), 5.82 (d, J = 7.3 Hz, 1 H, H-1¢),
5.81 (br s, 1 H, OH), 4.30 (t, J = 6.8 Hz, 1 H, H-2¢), 4.10 (dd, J =
6.2, 2.8, 1 H, H-3¢), 3.93 (d, J = 2.4 Hz, 1 H, H-4¢), 3.73–3.64 (m, 2
H, H-5¢).
13C NMR (126 MHz, DMSO-d6): d = 166.5 (CONH2), 144.3, 137.1,
136.7, 130.0, 128.7 (Ph), 127.8, 126.7 (Ph), 115.0, 112.5, 87.7 (C-
1¢), 86.0 (C-4¢), 71.8 (C-2¢), 69.6 (C-3¢), 60.8 (C-5¢).
HRMS (FAB): m/z [M + H] calcd for C16H21N4O6: 365.1461; found:
365.1467.
5-Amino-2-(3-chlorophenyl)-1-b-D-ribofuranosylimidazole-4-
carboxamide (8d)
Prepared from 6d in 50% yield (for 2 steps) according to the typical
procedure for 8a.
[a]D25 –5.0 (c 0.6, MeOH).
1H NMR (500 MHz, DMSO-d6): d = 7.65–7.48 (m, 4 H, Ph), 6.86
(br d, 2 H, CONH2), 6.34 (s, 2 H, NH2), 5.72 (d, J = 6.7 Hz, 1 H,
2¢-OH), 5.69 (s, 1 H, 5¢-OH), 5.59 (d, J = 7.6 Hz, 1 H, H-2¢), 5.30–
5.00 (m, 1 H, 3¢-OH), 4.63 (t, J = 6.6 Hz, 1 H, H-2¢), 4.07 (d, J = 3.6
Hz, 1 H, H-3¢), 3.88 (d, J = 1.8 Hz, 1 H, H-4¢), 3.70–3.60 (m, 2 H,
H-5¢).
13C NMR (126 MHz, DMSO-d6): d = 166.7 (CONH2), 144.5 (C-4),
138.1 (C-2), 133.2, 132.2, 130.4, 128.7, 128.4, 127.6, 112.6 (C-5),
88.8 (C-1¢), 85.7 (C-4¢), 70.3 (C-3¢), 69.8 (C-2¢), 61.0 (C-5¢).
HRMS (FAB): m/z [M + H] calcd for C17H21N4O5: 361.1512; found:
361.1513.
References
(1) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003,
103, 1875; and references cited therein.
(2) Verlinde, C. L. M. J.; Callens, M.; Calenbergh, S. V.;
Aerschot, A. V.; Herdewijn, P.; Hannaert, V.; Michels, P. A.
M.; Opperdoes, F. R.; Hol, W. G. J. J. Med. Chem. 1994, 37,
3605.
(3) (a) Amann, N.; Wagenknecht, H.-A. Synlett 2002, 687.
(b) Western, E. C.; Daft, J. R.; Johnson, E. M.; Gannett, P.
M.; Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767.
(4) Rutter, G. A.; Silva Xavier, G.; Leclerc, I. Biochem. J. 2003,
375, 1.
(5) Song, X. M.; Fiedler, M.; Galuska, D.; Ryder, J. W.;
Fernström, M.; Chibalin, A. V.; Wallberg-Henriksson, H.;
Zierath, J. R. Diabetologia 2002, 45, 56.
HRMS (FAB): m/z [M + H] calcd for C15H18ClN4O5: 369.0966;
found: 369.0960.
5-Amino-1-b-D-ribofuranosylimidazole-2-(2-thienyl)-4-carbox-
amide (8e)
Prepared from 6e in 48% yield (for 2 steps) according to the typical
procedure for 8a.
[a]D25 +12 (c = 0.24, MeOH).
1H NMR (500 MHz, DMSO-d6): d = 7.64 (d, J = 5.2 Hz, 1 H, thie-
nyl), 7.36 (d, J = 3.7 Hz, 1 H, thienyl), 7.15 (t, J = 4.4 Hz, 1 H, thie-
nyl), 6.79 (br d, 2 H, CONH2), 6.34 (s, 2 H, NH2), 5.80 (d, J = 7.6
Hz, 1 H, H-1¢), 5.69 (t, J = 4.0 Hz, 1 H, 5¢-OH), 5.59 (d, J = 6.1 Hz,
1 H, 2¢-OH), 5.16 (d, J = 4.0, 1 H, 3¢-OH), 4.58 (dd, J = 6.4 Hz, 1
(6) Hayashi, T.; Hirshman, M. F.; Fujii, N.; Habinowski, S. A.;
Witters, L. A.; Goodyear, L. J. Diabetes 2000, 49, 527.
(7) Musi, N.; Goodyear, L. J. Curr. Drug Targets: Immune,
Endocr. Metab. Disord. 2002, 2, 119.
(8) Kohyama, N.; Yamamoto, Y. Synthesis 2003, 2639.
Synthesis 2004, No. 17, 2799–2804 © Thieme Stuttgart · New York