Aqueous-phase Suzuki-Miyaura cross-coupling reactions of free halopurine bases

Article abstract of DOI:10.1055/s-2006-950240

The Suzuki-Miyaura reaction of 9-unsubstituted 2-, 6-, and 8-halopurine bases with diverse aryl- and alkenylboronic acids in water-acetonitrile mixtures under microwave irradiation was used for the single-step synthesis of arylpurines. In most cases the p

Full text of DOI:10.1055/s-2006-950240

FEATURE ARTICLE
3515
Aqueous-Phase Suzuki–Miyaura Cross-Coupling Reactions of Free
Halopurine Bases
A
P
queous-Phas
e
e
Suzuki–M
t
iyaura
r
Cross-Couplin
Č
g
Reactions of
F
a
ree
H
alopu
p
rine Bases ek, Milan Vrábel, Zbyněk Hasník, Radek Pohl, Michal Hocek*
Gilead & IOCB Research Center, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Prague 6, 16610, Czech Republic
Fax +420(2)20183559; E-mail: hocek@uochb.cas.cz
Received 22 June 2006; revised 11 August 2006
Y
Abstract: The Suzuki–Miyaura reaction of 9-unsubstituted 2-, 6-,
X
and 8-halopurine bases with diverse aryl- and alkenylboronic acids
in water–acetonitrile mixtures under microwave irradiation was
used for the single-step synthesis of arylpurines. In most cases the
product crystallized directly from the reaction mixture in high
yields and good purity. The scope and limitations of these reactions
were studied.
Y
N
N
N
N
N
N
N
N
N
N
N
X
N
HO
HO
O
O
Ph
antimicrobial
1
2
2
2
2
2
2
2
Introduction
Results and Discussion
OH OH
cytostatic
NHR
OH OH
anti-HCV
.1
.2
.3
.4
.5
.6
Cross-Coupling Reactions of 6-Chloro-9H-purine
Cross-Coupling Reactions of 2-Amino-6-chloro-9H-purine
Cross-Coupling Reactions of 8-Bromoadenine
Cross-Coupling Reactions of 2-Chloroadenine
Cross-Coupling Reactions of 2,6-Dichloro-9H-purine
NMR Analysis of Arylpurines and Determination of
Regioselectivity
Conclusions
Experimental Section
References
O
N
H
N
N
N
N
X
N
N
O
N
X
adenosine receptor
antagonists
3
4
5
kinase inhibitors
Figure 1 Biologically active aryl- and hetarylpurines
Key words: purines, cross-coupling reactions, boronic acids, mi-
crowaves, water
actions are usually performed in organic solvents (e.g.,
toluene, dioxane, DMF, EtOH) or in mixtures of 1,2-
dimethoxyethane–water. The reaction performs very well
with all kinds of 9-substituted halopurines, including nu-
cleosides, however, the corresponding unsubstituted halo-
1
Introduction
12
2
-, 6-, and 8-Arylpurines represent an important class of 9H-purine bases are unreactive due to deprotonation at
1
biologically active compounds (Figure 1). 6-Arylpurine N9. In order to prepare 9-unsubstituted arylpurine bases,
2
3
nucleosides possess cytostatic and anti-HCV effects. 9- the cross coupling of 9-(tetrahydropyran-2-yl)purines is
Alkyl-6-arylpurines exert antimycobacterial and antibac- used2
a,16d,e
and the protecting group is removed at the end
4
terial properties and corticotropine releasing hormone of reaction sequence by treatment with acidic cation ex-
5
antagonist activity. Some 2-arylpurines are inhibitors of changer in ethanol (Scheme 1). Another problem in these
6
7
8
P38a MAP kinase and CDK. 8-Arylpurines and some reactions is the use of electron-poor arylboronic acids
9
2
,6-diarylpurines are antagonists of A and A adenosine
1 2
Ar-B(OH)2
Pd(PPh3)4, base
organic solvent
receptors. Related 8-benzylpurines are inhibitors of chap-
Cl
N
Ar
N
1
0
eron Hsp90.
N
N
N
N
The Suzuki–Miyaura cross-coupling reaction is common-
ly used for the introduction of an aryl group into the purine
N
H
N
H
1
1
moiety. This method is efficient, versatile, and biocom-
3
,4-dihydro-2H-
H+
2
,12,13
6,7,14
patible. Many examples of 6-,
2-,
and 8-
pyran, TsOH
deprotection
1
5
arylpurines have been prepared by this methodology
from the corresponding halopurines and several types of
Ar-B(OH)2
Pd(PPh3)4, base
organic solvent
Cl
N
Cl
N
1
6
di- and trisubstituted purines have been prepared by re-
gioselective reactions of di- and trihalopurines. The re-
N
N
N
N
1
7
N
N
THP
THP
SYNTHESIS 2006, No. 20, pp 3515–3526
1
7.
1
0
.
2
0
0
6
Scheme 1 Indirect synthesis of 6-aryl-9H-purines by the Suzuki–
Miyaura reaction
Advanced online publication: 10.10.2006
DOI: 10.1055/s-2006-950240; Art ID: T09206SS
Georg Thieme Verlag Stuttgart · New York
©

3
516
P. Čapek et al.
FEATURE ARTICLE
(
e.g., nitrophenyl, pyridyl, etc.) that usually require the Very recently, we have studied the application of the
1
2
18
use of aqueous conditions or special catalytic sys- aqueous phase Suzuki–Miyaura cross-coupling reaction
tems.
1
3a–d
19,20
for the introduction
of the phenylalanine moiety into
2
0
purine nucleosides and nucleotides and we have found
Biographical Sketches
Petr Čapek was born in chemistry, Academy of Sci- reactions in the synthesis of
979 in Prague. He graduat- ences of the Czech Republic purine–amino acid conju-
1
ed in organic chemistry under the supervision of Dr. gates. His current work is
from Charles University in M. Hocek. He has recently focused on the development
Prague in 2002. Since then defended his PhD thesis at of aqueous-phase cross-
he has performed his PhD Charles University. His coupling reactions of bio-
research at the Institute of PhD work dealt with the ap- molecules.
Organic Chemistry and Bio- plication of cross-coupling
Milan Vrábel was born in 2004. He is presently doing sion of Dr. M. Hocek. His
1981 in Šala (Slovak Re- his PhD research at the In- PhD work deals with the
public). He graduated in or- stitute of Organic Chemistry synthesis of modified nucle-
ganic chemistry from the and Biochemistry, Acade- osides and oligonucleotides
Slovak University of Tech- my of Sciences of the Czech utilizing cross-coupling re-
nology in Bratislava in Republic under the supervi- actions.
Zbyněk Hasník was born is presently doing his PhD M. Hocek. His PhD work
in 1982 in Zlín (Czech Re- research at the Institute of deals with the synthesis of
public). He graduated in or- Organic Chemistry and Bio- modified purine bases and
ganic chemistry from the chemistry, Academy of Sci- purine nucleosides utilizing
Institute of Chemical Tech- ences of the Czech Republic cross-coupling reactions.
nology Prague in 2005. He under the supervision of Dr.
Radek Pohl was born in his PhD degree in 2001. Af- tute of Organic Chemistry
1
972 in Prague. He graduat- ter his postdoctoral stay at and Biochemistry, Acade-
ed in organic chemistry the Center for Photochemi- my of Sciences of the Czech
from the Institute of Chemi- cal Sciences, Bowling Republic in Prague. His cur-
cal Technology Prague in Green State University in rent interest covers the ap-
1
996. He started his PhD re- the laboratory of P. Anzen- plication of modern NMR
search at the same institute bacher Jr., he returned to techniques and stereochem-
under the supervision of Prague and since has fo- ical and conformation anal-
Prof. J. Kuthan and obtained cused on NMR at the Insti- ysis.
Michal Hocek was born in Holý in 1996. In 1997 he un- Institute and an external lec-
1
969 in Benešov (former dertook postdoctoral re- turer at the Institute of
Czechoslovakia). He gradu- search with Prof. L. Ghosez Chemical Technology, Pra-
ated in organic and medici- at the Université Catholique gue. Since 1998 he has
nal chemistry from the de Louvain, Louvain-la- served as the Editor-in-
Institute of Chemical Tech- Neuve, Belgium. Since Chief of the journal Collec-
nology Prague in 1993. He 1998 he has begun indepen- tion of Czechoslovak Chem-
obtained his PhD at the In- dent research at the Institute ical Communications. His
stitute of Organic Chemistry of Organic Chemistry and research interests include
and Biochemistry, Acade- Biochemistry, Academy of the chemistry of purines and
my of Sciences of the Czech Sciences of the Czech Re- nucleosides, the application
Republic in Prague under public. Since 2003 he has of organometallics in organ-
the supervision of Prof. A. been a group leader at this ic synthesis, and bioorganic
and medicinal chemistry.
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

FEATURE ARTICLE
Aqueous-Phase Suzuki–Miyaura Cross-Coupling Reactions of Free Halopurine Bases
3517
that 9-unsubstituted purines, 6-chloropurine, and 8-bro-
moadenine also react very well with 4-(dihydroxybor-
yl)phenylalanine. This unexpected finding prompted us to
explore the scope of these aqueous-phase reactions of di-
verse halo-9H-purines and to verify its applicability in di-
rect single-step synthesis of arylpurine bases using
diverse types of boronic acid.
Cl
N
R
N
base
Pd(OAc)2/L
N
N
N
N
+
R-B(OH)2
H O–MeCN
MW, 150 °C
2
N
H
N
H
2a–j
1
SO3Na
3a–j
L =
P
3
Scheme 2 The Suzuki–Miyaura reaction of 6-chloro-9H-purine
Table 1 The Suzuki–Miyaura Reaction of 6-Chloro-9H-purine
2
Results and Discussion
In our previous study of the Suzuki–Miyaura cross-cou-
pling reactions of halopurines with 4-(dihydroxybor-
yl)phenylalanine, the reactions were carried out in a
water–acetonitrile mixture (2:1) with sodium carbonate or
cesium carbonate as the base and a catalytic system con-
sisting of palladium(II) acetate and the water-soluble
phosphine ligand trisodium 4,4¢,4¢¢-phosphinetriyltriben-
Product Yielda
Entry Boronic
acid
R
Base
(%)
1
2
3
2a
2b
2c
Na CO
3a
3b
3c
73
83
60
2
3
3
3
Na CO
2
MeO
1
9,20
zenesulfonate [(3-NaO SC H ) P].
Both conventional
3
6
4 3
O N
2
Na CO
2
heating at 100 °C and microwave irradiation at 150 °C
were studied and compared. Whereas standard heating
was superior for the reaction of nucleosides and nucle-
otides (because of their instability during microwave irra-
diation), microwave heating was superior for the reaction
of free halopurine bases. It reduced the reaction time sig-
nificantly from several hours to minutes and also gave
better yields. Therefore, we began our investigation of the
Suzuki–Miyaura coupling of free halopurine bases using
these previously optimized conditions under microwave
irradiation.
77b
4
5
6
7
2d
2a
2b
2c
N
Na CO
3d
3a
3b
3c
2
3
Cs CO
82
84
53
2
3
Cs CO
2
3
MeO
2
O N
Cs CO
2
3
2
.1
Cross-Coupling Reactions of 6-Chloro-9H-
purine
8
9
2d
2e
N
Cs CO
3d
3e
85b
61
2
3
3
The first purine base we chose to examine was 6-chloro-
H-purine (1) and it is of interest because it allows entry
9
to biologically active 6-arylpurines. This purine base was
subjected to the cross-coupling reaction with a series of
aryl- and hetarylboronic acids under the conditions dis-
cussed above. The boronic acids of choice were phenylbo-
ronic acid (2a), electron-rich 4-methoxyphenylboronic
acid (2b), electron-deficient 3-nitrophenylboronic acid
Cs CO
H2N
2
1
0
2f
2g
2h
2i
Cs CO
3f
80
2
3
3
F
Cs CO
3g
3h
3i
12b
(51)
(
2c), and 3-pyridylboronic acid (2d) as an example of a 11
2
bc
N
S
hetaryl reagent (Scheme 2). The reactions were carried
out with sodium carbonate as the base for five minutes un-
der microwave-mediated heating at 150 °C. Full conver-
sion of the starting halopurine reagent 1 was observed in
1
2
Cs CO
61
2
3
3
all cases (TLC) and cross-coupling products 3a–d were 13
isolated in good yields (60–83%, Table 1, entries 1–4).
The 6-arylpurine products 3a–c crystallized directly from
S
Cs CO
2
27
(
40)d
1
4
2j
Cs CO
3j
78
2
3
the reaction mixture after cooling to ambient temperature
or to 4 °C; the pyridyl derivative 3d was exceptional and
isolated by preparative RP HPLC. As all of the other reac-
tion components (reagents, catalyst, and base) were solu-
ble in the water–acetonitrile mixture, the crude products
gave analytically pure samples after one recrystallization.
This facile and rapid isolation of cross-coupling products
was further shown to be applicable for most of the other
arylpurines prepared.
a
Unless otherwise stated, the products were isolated by crystalliza-
tion directly from the reaction mixture.
b
Product was isolated by preparative RP HPLC.
c
Pd(OAc) (0.1 equiv), microwave, 150 °C, 10 min.
2
d
Pd(OAc) (0.1 equiv), microwave, 150 °C, 20 min.
2
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

3
518
P. Čapek et al.
FEATURE ARTICLE
In the next set of reactions of 6-chloro-9H-purine (1) with Table 2 The Suzuki–Miyaura Reaction of 2-Amino-6-chloro-9H-
the same series of boronic acids 2a–d, sodium carbonate purine
was replaced by the more basic cesium carbonate, which
a
Entry Boronic acid
R
Product Yield (%)
was shown to be superior to sodium carbonate in our pre-
2
0
vious study. These reactions afforded 6-arylpurines 3a–
d in slightly higher yields compared to those from the re-
actions employing sodium carbonate, with the only excep-
tion of the 3-nitrophenyl derivative 3c (Table 1, entries 5–
1
2
3
2a
2b
2c
5a
5b
5c
88
83
82
MeO
8
). Therefore, cesium carbonate was the base of our
choice for all other reactions studied.
O N
2
The variety of arylboronic acids employed in reaction
with 6-chloropurine 1 was further extended to include oth-
er examples of electron-rich (3-aminophenyl, 2e) and elec-
tron-deficient (4-fluorophenyl, 2f) boronic acids. Both of
these showed very good reactivity and the corresponding
cross-coupling products were isolated by crystallization
from the reaction mixture in very good yields (Table 1,
entries 9 and 10). The hetarylboronic acids under study
were expanded to include another electron-deficient ex-
ample, 4-pyridylboronic acid (2g) and two examples of
electron-rich thienylboronic acids 2h,i. The reactivity of
the hetarylboronic acids differed significantly depending
on the regioisomer. While 3-pyridylboronic acid (2d)
gave arylpurine 3d in an excellent yield of 85% (Table 1,
32b
4
2d
N
5d
a
Unless otherwise stated, products were isolated by crystallization di-
rectly from the reaction mixture.
b
Product 5b crystallized from the reaction mixture was contaminated
by starting boronic acid.
5
d in poor yield (32%) accompanied by unreacted starting
halopurine 4 and boronic acid 2d (Table 2, entry 4).
entry 8), the reaction of 4-pyridylboronic acid (2g) was 2.3
very sluggish and gave product 3g in only 12% yield
Cross-Coupling Reactions of 8-Bromo-
adenine
(
Table 1, entry 11). The yield was improved to 51% by the
The reaction of boronic acids 2a–d with 8-bromoadenine
use of 10% of catalyst and prolonged reaction times. A
similar dichotomy in reactivity was observed with thie-
nylboronic acids 2h,i. 3-Thienylboronic acid reacted very
well to give 6-(3-thienyl)-9H-purine (3h) in a good yield
of 61% (Table 1, entry 12), while the isomeric 2-thienyl-
boronic acid (2i) reacted very poorly to give the desired
product 3i in 27% only (Table 1, entry 13). The yield was
slightly improved by using prolonged reaction times and
increasing the amount of catalyst. Finally, (E)-styrylbo-
ronic acid (2j) was employed in order to examine the re-
activity of alkenylboronic acids. The reaction proceeded
very well to give the corresponding product 3j in an excel-
lent yield of 78% (Table 1, entry 14).
(
6) (Scheme 4) was performed to study the efficiency of
the methodology for the introduction of aryl and hetaryl
substituents into position 8 of adenine. Reactions with all
four tested boronic acids 2a–d proceeded smoothly and
gave the corresponding products 7a–d in good to excel-
lent yields (Table 3, entries 1–4).
NH2
NH2
Cs2CO3
Pd(OAc)2/L
N
N
N
N
+
R-B(OH)2
Br
R
H O–MeCN
2
N
H
N
H
N
2a–d
N
MW, 150 °C
6
7a–d
Scheme 4 The Suzuki–Miyaura reactions of 8-bromoadenine
Table 3 The Suzuki–Miyaura Reactions of 8-Bromoadenine
2
.2
Cross-Coupling Reactions of 2-Amino-6-
chloro-9H-purine
a
Entry
1
Boronic acid R
Product Yield (%)
In order to extend the scope of the methodology to other
halopurine bases, we examined reactions of 2-amino-6-
chloropurine (4) with a series of boronic acids 2a–d
2a
7a
7b
7c
86
92
55
(
Scheme 3). Reactions with arylboronic acids 2a–c pro-
2
3
2b
ceeded smoothly to afford the desired products 5a–c in
excellent yields (Table 2, entries 1–3). On the other hand,
reaction of 4 with 3-pyridylboronic acid (2d) gave product
MeO
2c
2
O N
Cl
R
Cs2CO3
Pd(OAc)2/L
N
N
N
N
+
R-B(OH)2
4
2d
N
7d
76
H2O–MeCN
MW, 150 °C
N
H
N
H
H2N
N
2a–d
H2N
N
4
5a–d
a
Products were isolated by crystallization directly from the reaction
mixture.
Scheme 3 The Suzuki–Miyaura reaction of 2-amino-6-chloro-9H-
purine
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

FEATURE ARTICLE
Aqueous-Phase Suzuki–Miyaura Cross-Coupling Reactions of Free Halopurine Bases
3519
2
.4
Cross-Coupling Reactions of 2-Chloro-
adenine
electron distribution in the anion may be different from
that in the parent 9-substituted purine and, thus, this can
influence the regioselectivity. The first set of reactions of
dichloropurine 10 was performed with one equivalent of
boronic acid 2a–d. Reaction of 2d afforded 2-chloro-6-(3-
pyridyl)purine (11d) in high yield as a single product
The study of reactivity of various halopurine substrates
continued with 2-chloroadenine (8) as an example of a 2-
halopurine. The halogen atom in position 2 of the purine
ring is known to be the least reactive to cross-coupling re-
actions. The reactions of 8 with electron-rich phenyl- (2a)
and 4-methoxyphenylboronic acids (2b) proceeded well
with high yields (Scheme 5, Table 4, entries 1 and 2).
However, 3-nitrophenylboronic acid (2c) was significant-
ly less reactive and only traces of product 9c were ob-
served in the reaction mixture even after prolonged
reaction times and the amount of catalyst was increased
(
Scheme 6, Table 5, entry 4). However, the reactions of
all other boronic acids 2a–c gave mixtures of products
with 2-chloro-6-arylpurines 11 predominating (structural
assignment, vide infra) and minor amounts of disubstitut-
ed purines 12. The mixtures of products crystallized or
precipitated from the reaction mixture and the particular
products were either finally separated by preparative RP
HPLC or the major product was purified by recrystalliza-
tion (in the case of 11b).
(
Table 4, entry 3). 3-Pyridylboronic acid (2d) gave prod-
uct 9d in moderate yield (Table 4, entry 4) and no im-
Monosubstituted 2-chloro-6-phenylpurine (11a) was pre-
pared by the reaction of 10 with phenylboronic acid (2a)
in 55% yield accompanied by minor amount of diphen-
ylpurine 12a (Table 5, entry 1). Similarly, reaction of 2b
afforded a mixture of monoaryl- and diarylpurine prod-
ucts 11b and 12b (the ratio of products was determined by
NMR and pure 11b was isolated by recrystallization). On
the other hand, a complex mixture was obtained from the
reaction of 10 with 3-nitrophenylboronic acid (2c) and the
expected 6-aryl-2-chloropurine 11c was isolated by
HPLC in low yield. All these reactions clearly show that
the aqueous-phase cross-coupling reaction of 2,6-dichlo-
ro-9H-purine (10) also takes place preferentially in posi-
tion 6. However, the regioselectivity is significantly lower
compared to the reactions of 9-substituted 2,6-dihalopu-
rines in organic solvents. Apparently, the synthetic appli-
cability of such aqueous-phase reactions to the synthesis
of 2,6-disubstituted purines is rather limited.
provement was observed after longer reaction times.
NH2
NH2
Cs2CO3
Pd(OAc)2/L
N
N
N
N
+
R-B(OH)2
H2O–MeCN
MW, 150 °C
N
H
N
H
Cl
N
2a–d
R
N
8
9a–d
Scheme 5 The Suzuki–Miyaura reaction of 2-chloroadenine
Table 4 The Suzuki–Miyaura Reaction of 2-Chloroadenine
a
Entry Boronic acid R
Product Yield (%)
1
2
3
2a
2b
2c
9a
9b
9c
67
90
MeO
2
O N
traces
Cl
R
R-B(OH)2
2a–d
N
N
N
N
4
2d
N
9d
47 (48)b
1 equiv
N
H
N
H
Cl
N
Cl
N
1
0
11a–d
major product
a
Unless otherwise stated, products were isolated by crystallization di-
R
rectly from the reaction mixture.
R-B(OH)2
2a–d
b
Microwave, 150 °C, 10 min.
N
N
3
equiv
N
R
N
H
2
.5
Cross-Coupling Reactions of 2,6-Dichloro-
H-purine
12a–d
major product
9
Scheme 6 The Suzuki–Miyaura reactions of 2,6-dichloro-9H-
purine
Finally, the reaction of 2,6-dichloropurine (10) with one
or three equivalents of boronic acids was examined in or-
der to address the regioselectivity of such aqueous-phase
cross-coupling reactions. Standard cross-coupling reac- The reactions of 2,6-dichloropurine 10 with three equiva-
tions of 9-substituted 2,6-dichloropurines with one equiv- lents of boronic acids 2a–d gave the expected 2,6-di-
alent of an arylboronic acid in organic solvents occur1
2b
arylpurines 12a, 12b, and 12d in high yields (Table 5,
regioselectively in position 6 and they are often used for entries 5, 6, and 8). Only the in case of 3-nitrophenylbo-
preparation of 2,6-disubstituted purine derivatives.16 In ronic acid (2c) was a complex mixture obtained from
aqueous-phase cross-coupling reactions under basic con- which both mono- and disubstituted products 11c and 12c
ditions, the purine is apparently deprotonated and the were isolated in very low yields (Table 5, entry 7).
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

3
520
P. Čapek et al.
FEATURE ARTICLE
Table 5 The Suzuki–Miyaura Reactions of 2,6-Dichloro-9H-purine tinctive correlation between H8 and C6 or C2, we decided
to provide a chemical proof of the regioselectivity. The re-
Entry Boronic R
acid
Equiv Product
Yielda
(%)
action of 2-chloro-6-phenyl-9H-purine (11a) with tri-
methylaluminum catalyzed by tetrakis(triphenylphosphine)
palladium(0) in anhydrous tetrahydrofuran afforded the
2-methyl-6-phenyl-9H-purine (13) in 81% yield
b
1
2
3
2a
2b
2c
1
1
1
11a
2a
55
5
b
1
1
15
(
Scheme 7). The H– N HMBC experiment with com-
11b
12b
57c
6
pound 13 revealed cross-peaks of the methyl group in the
position 2 to the nitrogens N1 and N3, while the hydrogen
H8 gave correlations to nitrogens N7 and N9 respectively.
This was the final definitive proof that the arylation of
MeO
26d
O N
2
11c
2
,6-dichloro-9H-purine (10) with one equivalent of a bo-
ronic acid proceeds regioselectively in position 6.
4
2d
N
1
11d
70
5
6
7
2a
2b
2c
3
3
3
12a
12b
11c
92
91
N
5 equiv AlMe3
N
N
N
H
Pd(PPh3)4
THF
MeO
Cl
N
N
H
N
H
H3C
N
1
1a
81%
1
3
b
2
O N
25
14
b
1H,15N HMBC correlations
1
2c
1
15
Scheme 7 Derivatization of 11a and H– N HMBC correlation in
product
8
2d
N
3
12d
89
3
Conclusions
a
Unless otherwise stated, products were isolated by crystallization di-
rectly from the reaction mixture.
Mono- and disubstituted products were separated from crude co-
crystals by RP HPLC.
b
In conclusion, the aqueous-phase Suzuki–Miyaura cross-
coupling reactions of free halopurine bases with diverse
c
Monosubstituted product was isolated from crude co-crystals by re- aryl- and alkenylboronic acids proceeds very well to give
crystallization.
the corresponding aryl- or alkenylpurines in a single step.
In most cases the products crystallized from the reaction
mixtures and were isolated by simple recrystallization in
d
Accompanied by unidentified byproducts.
2
.6
NMR Analysis of Arylpurines and Determi-
nation of Regioselectivity
high yields. This methodology is superior to the laborious
protection–coupling–deprotection sequence used in the
synthesis of arylpurine bases in the past. The scope and
limitations of these reactions have been studied to show
that they are fairly general and are applicable to a wide
range of boronic acids and for several types of 2-, 6-, or 8-
halopurines. The most reactive are electron-rich phenyl-
boronic acids, while the reactions of some hetarylboronic
acids are less efficient. The reactions of 6-chloropurine
and 8-bromoadenine proceeded generally very well, while
the reactions of 2-chloroadenine with electron-poor aryl-
boronic acids were the most problematic. On the other
In general, NMR analysis of purine bases is not trivial due
to 7H/9H tautomerism. Direct observation of some 13
C
NMR signals, i.e. C4, C5, and CH-8, is often difficult.
Therefore HMBC experiments served as a tool for the as-
signment of carbon signals. In all the compounds studied,
the ipso carbon signals of the aryl groups in positions 2, 6,
and 8 follow the same rule we have already observed for
1
6e
phenyl-substituted purines (arranged in the order of de-
creasing chemical shift ipso-C2 > ipso-C6 > ipso-C8).
As previously discussed, cross-coupling reactions of 2,6- hand, we have found that these aqueous-phase reactions
dichloropurine 10 under alkaline aqueous conditions may are not suitable for regioselective synthesis of 2,6-disub-
not necessarily have the same regioselectivity as the cor- stituted purines from 2,6-dichloropurine. This study is an
1
2b
responding 9-protected 2,6-dihalopurines, therefore we example of the power of the aqueous-phase cross-cou-
required independent proof. At first we studied compound pling reactions1 that, apart from environmental aspects,
8a
1
1a, which was formed as the major product in the reac- can very often offer higher reactivity of some substrates
tion of 10 with one equivalent of phenylboronic acid compared to organic solvents. The use of microwave irra-
1
13
(
Table 5, entry 1). H– C HMBC experiments with com- diation significantly shortened reaction times, which
pound 11a revealed a broad signal for the phenyl ortho- made this methodology even more efficient. Undoubted-
hydrogens (d = 8.73) which gave a weak cross peak to a ly, aqueous-phase cross-coupling reactions will find fur-
carbon at d = 152.73 (this could be either C2 or C6 de- ther broad application in organic synthesis and industrial
pending on the regioselectivity). Since there was no dis- processes.
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

FEATURE ARTICLE
Aqueous-Phase Suzuki–Miyaura Cross-Coupling Reactions of Free Halopurine Bases
6-(3-Pyridyl)-9H-purine (3d)
3521
NMR spectra were measured on a Bruker Avance 400 (400 MHz for
1
13
H and 100.6 MHz for C nuclei) and a Bruker Avance 500 (500
Prepared from 6-chloro-9H-purine (1) and boronic acid 2d. Product
3d (140 mg, 85%) was isolated from the crude reaction mixture by
RP HPLC. White crystals of 3d were obtained after recrystallization
1
13
MHz for H and 125.8 MHz for C) in DMSO-d (referenced to the
6
residual solvent signal). In the assignment of NMR signals, the at-
oms of aryl groups are numbered with ¢, while in diaryl compounds
(H
O–MeOH); mp 287–291 °C.
2
1
2a–d, the aryl in position 6 is numbered with ¢ and the aryl in po-
IR (KBr): 3103, 3070, 2982, 2809, 2692, 2573, 1600, 1582, 1470,
sition 2 with ¢¢. MS were measured on a ZAB-EQ (VG Analytical)
spectrometer using FAB (ionization by Xe, accelerating voltage 8
–1
1
443, 1380, 1326, 921, 860, 799, 703, 640 cm .
1
H NMR (500 MHz, DMSO-d ): d = 7.64 (ddd, J = 8.0 Hz,
kV, glycerol + thioglycerol matrix). The H O–MeCN mixture was
6
5¢,4¢
2
J5¢,6¢ = 4.8, J5¢,2¢ = 1.0 Hz, 1 H, H-5¢), 8.70 (s, 1 H, H-8), 8.74 (dd,
J6¢,5¢ = 4.8 Hz, J6¢,4¢ = 1.7 Hz, 1 H, H-6¢), 9.00 (s, 1 H, H-2), 9.06 (dt,
degassed in vacuo and stored under argon. Preparative HPLC sepa-
rations were performed on a column packed with 10 mm C18 re-
versed phase [Phenomenex, Luna C18(2)]. Microwave-mediated
reactions were performed in a microwave reactor Initiator (Biotage,
Inc.), operated in mode with priority of temperature (microwave
source performance changes automatically to maintain the set tem-
perature in the course of the reaction).
J4¢,5¢ = 8.0 Hz, J4¢,2¢ = 2.3 Hz, J = 1.7 Hz, 1 H, H-4¢), 9.91 (br d,
4¢,6¢
J2¢,4¢ = 2.3 Hz, 1 H, H-2¢).
1
3
C NMR (125.8 MHz, DMSO-d ): d = 124.05 (CH-5¢), 129.92 (C-
6
5), 131.56 (C-3¢), 136.48 (CH-4¢), 145.91 (CH-8), 150.08 (C-6),
150.31 (CH-2¢), 151.52 (CH-6¢), 152.15 (CH-2), 154.17 (C-4).
MS (FAB): m/z = 197 [M + H]+.
Cross-Coupling Reactions; General Procedure
+
A mixture of H O–MeCN (2:1, 5 mL) was added through a septum
HRMS (FAB): m/z [M + H] calcd for C10
H
8
N
5
: 198.0780; found:
2
1
98.0779.
to an argon-purged vial containing halopurine (0.8 mmol), boronic
acid (1 mmol), Pd(OAc) (9 mg, 0.04 mmol), (3-NaO SC H ) P
2
3
6
4 3
Anal. Calcd for C H N ·0.5H O (206.2): C, 58.25; H, 3.91; N,
33.96. Found: C, 58.62; H, 3.55; N, 34.31.
1
0
7
5
2
(
114 mg, 0.2 mmol), and Cs CO (782 mg, 2.4 mmol). The mixture
2 3
was stirred under microwave irradiation heating at 150 °C for 5
min. The product crystallized directly from the mixture after cool-
ing to 4 °C or it was isolated from the crude mixture by HPLC (C18
6
-(3-Aminophenyl)-9H-purine (3e)
Prepared from 6-chloro-9H-purine (1) and boronic acid 2e. Product
3e (107 mg, 61%) was isolated by crystallization from the reaction
mixture as yellowish crystals; mp 285–288 °C.
column, linear gradient of 0.3% AcOH–H O to 0.3% AcOH–
2
MeOH). An analytical sample of the products was recrystallized
(
H O–MeOH or EtOH mixtures).
2
IR (KBr): 3051, 2809, 1588, 1559, 1496, 1474, 1436, 1362, 1327,
–
1
1
282, 1168, 993, 946, 818, 780 cm .
6
-Phenyl-9H-purine (3a)
Prepared from 6-chloro-9H-purine (1) and boronic acid 2a. Product
a (128 mg, 82%) was isolated by crystallization from the reaction
mixture as yellow crystals. All analytical and spectral data were in
1
H NMR (400 MHz, DMSO-d ): d = 5.29 (br s, 2 H, NH ), 6.74
6
2
3
(ddd, J4 = 8.0 Hz, J = 2.3 Hz, J = 1.2 Hz, 1 H, H-4¢), 7.21 (t,
¢,5¢ 4¢,2¢ 4¢,6¢
J5¢,4¢ = J5¢,6¢ = 8.0 Hz, 1 H, H-5¢), 7.97–8.04 (br m, 2 H, H-2¢, H-6¢),
2
a
accord with previously published data.
8.60 (s, 1 H, H-8), 8.90 (s, 1 H, H-2), 13.50 (br s, 1 H, NH).
1
3
C NMR (100.6 MHz, DMSO-d ): d = 114.50 (CH-2¢), 116.64
6
6
-(4-Methoxyphenyl)-9H-purine (3b)
Prepared from 6-chloro-9H-purine (1) and boronic acid 2b. Product
b (152 mg, 84%) was isolated by crystallization from the reaction
mixture as yellow crystals. All analytical and spectral data were in
(
1
1
CH-4¢), 117.57 (CH-6¢), 129.15 (CH-5¢), 129.40 (C-5), 136.40 (C-
¢), 144.87 (CH-8), 149.02 (C-3¢), 151.83 (CH-2), 153.04 (C-6),
3
54.20 (C-4).
+
2
1
MS (FAB): m/z (%) = 212 [M + H] (100).
accord with previously published data.
+
HRMS (FAB): m/z [M + H] calcd for C H N : 212.0936; found:
1
1
10
5
6
-(3-Nitrophenyl)-9H-purine (3c)
2
12.0944.
Prepared from 6-chloro-9H-purine (1) and boronic acid 2c using
Na CO as the base. Product 3c (115 mg, 60%) was isolated by crys-
Anal. Calcd for C H N ·0.5H O (220.1): C, 59.99; H, 4.58; N,
1.80. Found: C, 59.62; H, 4.46; N, 31.43.
1
1
9
5
2
2
3
3
tallization from the reaction mixture as yellowish crystals; mp
300 °C.
>
6
-(4-Fluorophenyl)-9H-purine (3f)
IR (KBr): 3093, 1602, 1585, 1520, 1355, 1320, 1306, 1241, 1102,
Prepared from 6-chloro-9H-purine (1) and boronic acid 2f. Product
f (137 mg, 80%) was isolated by crystallization from the reaction
mixture as yellow crystals. All analytical and spectral data were in
–
1
9
21, 892, 805, 735, 688, 638 cm .
3
1
H NMR (400 MHz, DMSO-d ): d = 7.90 (t, J5¢,4¢ = 8.2 Hz,
6
2
a
accord with previously published data.
J5¢,6¢ = 7.9 Hz, 1 H, H-5¢), 8.40 (ddd, J4¢,5¢ = 8.2 Hz, J4¢,2¢ = 2.4 Hz,
J4¢,6¢ = 1.1 Hz, 1 H, H-4¢), 8.75 (s, 1 H, H-8), 9.02 (s, 1 H, H-2), 9.23
(
6
-(4-Pyridyl)-9H-purine (3g)
dt, J6¢,5¢ = 7.9 Hz, J = 1.7 Hz, J = 1.1 Hz, 1 H, H-6¢), 9.71 (t,
6¢,2¢ 6¢,4¢
Prepared from 6-chloro-9H-purine (1) and boronic acid 2g. The
amount of catalyst and reaction time were doubled. Product 3g (80
mg, 51%) was isolated from the crude reaction mixture by RP
HPLC. Yellowish crystals of 3g were obtained after recrystalliza-
J2¢,4¢ = 2.4 Hz, J2¢,6¢ = 1.7 Hz, 1 H, H-2¢), 13.80 (br s, 1 H, NH).
1
3
C NMR (100.6 MHz, DMSO-d ): d = 123.86 (CH-2¢), 125.44
6
(
1
1
CH-4¢), 130.14 (C-5), 130.58 (CH-5¢), 135.21 (CH-6¢), 137.33 (C-
¢), 146.12 (CH-8), 148.34 (C-3¢), 149.38 (C-6), 152.02 (CH-2),
tion (H O–MeOH). All analytical and spectral data were in accord
2
54.28 (C-4).
22
with previously published data.
MS (FAB): m/z = 242 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C H N O : 242.0678;
found: 242.0682.
6-(3-Thienyl)-9H-purine (3h)
Prepared from 6-chloro-9H-purine (1) and boronic acid 2h. Product
1
1
8
5
2
3
h (99 mg, 61%) was isolated by crystallization from the reaction
Anal. Calcd for C H N O (241.2): C, 54.77; H, 2.93; N, 29.03.
1
1
7
5
2
mixture as yellow crystals; mp 282–294 °C.
Found: C, 54.72; H, 2.84; N, 28.69.
IR (KBr): 3100, 2977, 2813, 1602, 1584, 1523, 1413, 1323, 1075,
–
1
9
27, 841, 792, 643 cm .
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

3
522
P. Čapek et al.
FEATURE ARTICLE
1
13
H NMR (500 MHz, DMSO-d ): d = 7.74 (dd, J = 5.1 Hz,
C NMR (125.8 MHz, DMSO-d ): d = 123.41 (CH-2¢), 124.10 (C-
6
5¢,4¢
6
J5¢,2¢ = 3.0 Hz, 1 H, H-5¢), 8.24 (dd, J4¢,5¢ = 5.1 Hz, J4¢,2¢ = 1.2 Hz, 1
H, H-4¢), 8.62 (s, 1 H, H-8), 8.88 (s, 1 H, H-2), 8.94 (dd, J2¢,5¢ = 3.0,
J2¢,4¢ = 1.2 Hz, 1 H, H-2¢).
5), 124.94 (CH-4¢), 130.26 (CH-5¢), 135.30 (CH-6¢), 138.01 (C-1¢),
141.95 (CH-8), 148.25 (C-3¢), 150.10 (C-6), 156.30 (C-4), 160.40
(C-2).
1
3
+
C NMR (125.8 MHz, DMSO-d ): d = 127.17 (CH-5¢), 127.58
MS (FAB): m/z (%) = 257 [M + H] (60), 133 (100).
6
(
8
CH-4¢), 128.65 (C-5), 130.43 (CH-2¢), 138.41 (C-3¢), 145.10 (CH-
), 148.78 (C-6), 152.19 (CH-2), 153.57 (C-4).
HRMS (FAB): m/z [M + H]+ calcd for C H N O : 257.0787;
1
1
8
6
2
found: 257.0780.
+
MS (FAB): m/z (%) = 203 [M + H] (100).
Anal. Calcd for C H N O ·HCl·0.5H O (301.7): C, 43.79; H, 3.34;
1
1
8
6
2
2
+
HRMS (FAB): m/z [M + H] calcd for C H N S: 203.0391; found:
N, 27.86. Found: C, 42.12; H, 2.90; N, 28.50.
9
7
4
2
03.0384.
2
-Amino-6-(3-pyridyl)-9H-purine (5d)
Prepared from 2-amino-6-chloro-9H-purine (4) and boronic acid
d. Isolated by crystallization from the reaction mixture to give 5d
55 mg, 32%) as a brown solid. According to NMR spectra, the
Anal. Calcd for C H N S (202.2): C, 53.45; H, 2.99; N, 27.70.
Found: C, 53.79; H, 2.95; N, 27.44.
9
6
4
2
(
6
-(2-Thienyl)-9H-purine (3i)
crude product was contaminated by 3-pyridylboronic acid. An ana-
lytical sample was purified by HPLC, white crystals; mp >300 °C.
Prepared from 6-chloro-9H-purine (1) and boronic acid 2i. The
amount of catalyst was doubled and the reaction time was increased
to 20 min. Product 3i (65 mg, 40%) was isolated by crystallization
from the reaction mixture as yellow crystals. All analytical and
IR (KBr): 3409, 3200, 2361, 1616, 1577, 1374, 1290, 1027, 933,
905, 793 cm .
–
1
2
2
spectral data were in accord with previously published data.
1
H NMR (400 MHz, DMSO-d ): d = 6.47 (br s, 2 H, NH ), 7.58 (dd,
6
2
J5¢,4¢ = 8.0 Hz, J = 4.8 Hz, J = 0.9 Hz, 1 H, H-5¢), 8.16 (s, 1 H,
5¢,6¢
5¢,2¢
(
E)-6-Styryl-9H-purine (3j)
Prepared from 6-chloro-9H-purine (1) and boronic acid 2j. Product
j (139 mg, 78%) was isolated by crystallization from the reaction
mixture as yellow crystals. All analytical and spectral data were in
H-8), 8.69 (dd, J6¢,5¢ = 4.8 Hz, J6¢,4¢ = 1.7 Hz, 1 H, H-6¢), 8.96 (dt,
J4¢,5¢ = 8.0 Hz, J4¢,2¢ = 2.1 Hz, J4¢,6¢ = 1.7 Hz, 1 H, H-4¢), 9.81 (br d,
J2¢,4¢ = 2.1 Hz, 1 H, H-2¢), 12.70 (br s, 1 H, NH).
3
1
3
2
3
C NMR (125.8 MHz, DMSO-d ): d = 123.49 (CH-5¢), 123.79 (C-
accord with previously published data.
6
5
1
), 131.73 (C-3¢), 135.94 (CH-4¢), 141.45 (CH-8), 149.91 (CH-2¢),
50.52 (C-6), 150.78 (CH-6¢), 155.75 (C-4), (C-2 not observed).
2
-Amino-6-phenyl-9H-purine (5a)
Prepared from 2-amino-6-chloro-9H-purine (4) and boronic acid
a. Isolated by crystallization from the reaction mixture to give 5a
149 mg, 88%) as yellow crystals. All analytical and spectral data
+
MS (FAB): m/z (%) = 213 [M + H] (100).
2
(
+
HRMS (FAB): m/z [M + H] calcd for C H N 213.0889; found:
213.0892.
1
0
8
6:
2
a
were in accord with previously published data.
8
-Phenyladenine (7a)
2
-Amino-6-(4-methoxyphenyl)-9H-purine (5b)
Prepared from 2-amino-6-chloro-9H-purine (4) and boronic acid
b. Isolated by crystallization from the reaction mixture to give 5b
160 mg, 83%) as yellowish crystals; mp 233–236 °C.
Prepared from 8-bromoadenine (6) and boronic acid 2a. Isolated by
crystallization from the reaction mixture to give 7a (145 mg, 86%)
as white crystals. NMR spectra were in accord with previously pub-
2
(
2
4
lished data; mp >300 °C.
IR (KBr): 3468, 3433, 3306, 3173, 2835, 1605, 1568, 1516, 1462,
1
–
1
IR (KBr): 3471, 3395, 3306, 2972, 2868, 1653, 1598, 1492, 1301,
9
MS (FAB): m/z = 212 [M + H]+.
381, 1258, 1179, 1031, 903, 630 cm .
–
1
46, 705 cm .
1
H NMR (400 MHz, DMSO-d ): d = 3.84 (s, 3 H, CH O), 6.29 (br
6
3
s, 2 H, NH ), 7.08 (m, 2 H, H-3¢, H-5¢), 8.07 (s, 1 H, H-8), 8.74 (m,
2
2
+
H, H-2¢, H-6¢), 12.58 (br s, 1 H, NH).
HRMS (FAB): m/z [M + H] calcd for C11
212.0943.
H
10
N
5
: 212.0936; found:
1
3
C NMR (100.6 MHz, DMSO-d ): d = 55.45 (CH O), 113.83 (CH-
6
3
3
1
¢, CH-5¢), 123.47 (C-5), 128.89 (C-1¢), 130.90 (CH-2¢, CH-6¢),
Anal. Calcd for C11H N ·0.25H O: C, 61.24; H, 4.44; N, 32.46.
9 5 2
Found: C, 61.70; H, 4.13; N, 32.47.
40.32 (CH-8), 152.88 (C-6), 155.38 (C-4), 160.22 (C-2), 161.22
(
C-4¢).
8-(4-Methoxyphenyl)adenine (7b)25
Prepared from 8-bromoadenine (6) and boronic acid 2b. Isolated by
crystallization from the reaction mixture to give 7b (177 mg, 92%)
as white crystals; mp >300 °C.
+
MS (FAB): m/z (%) = 242 [M + H] (100).
HRMS (FAB): m/z [M + H]+ calcd for C H N O: 242.1042;
found: 242.1038.
1
2
12
5
Anal. Calcd for C H N O·0.5H O (250.1): C, 57.59; H, 4.83; N,
12
11
5
2
IR (KBr): 3476, 3062, 3104, 1652, 1594, 1483, 1296, 1254, 1178,
2
7.98. Found: C, 57.53; H, 4.53; N, 27.78.
–1
1
030, 837 cm .
1
H NMR (400 MHz, DMSO-d ): d = 3.83 (s, 3 H, CH O), 7.05 (br
6
3
2
-Amino-6-(3-nitrophenyl)-9H-purine (5c)
s, 2 H, NH ), 7.10 (m, 2 H, H-3¢, H-5¢), 8.08 (m, 2 H, H-2¢, H-6¢),
2
Prepared from 2-amino-6-chloro-9H-purine (4) and boronic acid
8
.10 (s, 1 H, H-2), 13.15 (br s, 1 H, NH).
13C NMR (100.6 MHz, DMSO-d
): d = 55.53 (CH
3¢, CH-5¢), 122.56 (C-1¢), 127.98 (CH-2¢, CH-6¢), 148.72 (C-8),
2
c. Isolated from the reaction mixture by neutralization with 2 M
HCl to give 5c as its hydrochloride hemihydrate (198 mg, 82%) as
6
O), 114.56 (CH-
3
a brown precipitate; mp >300 °C.
1
52.34 (CH-2), 155.02 (C-6), 160.79 (C-4¢), (C-4 and C-5 not ob-
IR (KBr): 3486, 3369, 1635, 1520, 1459, 1351, 1302, 1261, 1095,
–1
served).
9
24, 797 cm .
MS (FAB): m/z = 242 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C12
1
H NMR (500 MHz, DMSO-d ): d = 6.57 (br s, 2 H, NH ), 7.86 (t,
6
2
J5¢,4¢ = 8.1 Hz, J = 7.9 Hz, 1 H, H-5¢), 8.22 (s, 1 H, H-8), 8.37
(
(
H N O: 242.1042;
12 5
5¢,6¢
ddd, J4¢,5¢ = 8.1 Hz, J4¢,2¢ = 2.4 Hz, J4¢,6¢ = 1.1 Hz, 1 H, H-4¢), 9.21
ddd, J6¢,5¢ = 7.9 Hz, J6¢,2¢ = 1.5 Hz, J6¢,4¢ = 1.1 Hz, 1 H, H-6¢), 9.60 (t,
found: 242.1039.
J2¢,4¢ = 2.4 Hz, J2¢,6¢ = 1.5 Hz, 1 H, H-2¢), 12.80 (br s, 1 H, NH).
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

FEATURE ARTICLE
Aqueous-Phase Suzuki–Miyaura Cross-Coupling Reactions of Free Halopurine Bases
3523
Anal. Calcd for C H N O (241.3): C, 59.74; H, 4.60; N, 29.03.
Found: C, 59.91; H, 4.43; N, 29.08.
2-(4-Methoxyphenyl)adenine (9b)
Prepared from 6-amino-2-chloro-9H-purine (8) and boronic acid
b. Isolated from the reaction mixture by crystallization to give 9b
1
2
11
5
2
2
7
8
-(3-Nitrophenyl)adenine (7c)
(173 mg, 90%) as a yellow solid; mp 295–298 °C (Lit. 304–
Prepared from 8-bromoadenine (6) and boronic acid 2c. Isolated by
crystallization from the reaction mixture to give 7c (113 mg, 55%)
as yellowish crystals; mp >300 °C.
305 °C).
IR (KBr): 3315, 3104, 1652, 1606, 1520, 1388, 1257, 1169, 1028,
–1
9
42, 799 cm .
IR (KBr): 3468, 3300, 3092, 2978, 2742, 1655, 1593, 1532, 1353,
1
H NMR (400 MHz, DMSO-d ): d = 3.81 (s, 3 H, CH O), 6.99 (m,
–
1
6
3
1
295, 1126, 961, 875, 787, 705 cm .
2
H, H-3¢, H-5¢), 7.00 (br s, 2 H, NH ), 8.28 (m, 2 H, H-2¢, H-6¢),
2
1
H NMR (400 MHz, DMSO-d ): d = 7.33 (br s, 2 H, NH ), 7.85 (t,
8.31 (s, 1 H, H-8).
13
6
2
J5¢,4¢ = 8.3 Hz, J = 7.8 Hz, 1 H, H-5¢), 8.16 (s, 1 H, H-2), 8.32
5¢,6¢
C NMR (100.6 MHz, DMSO-d ): d = 55.35 (CH O), 113.60 (CH-
6
3
(
(
(
1
ddd, J4¢,5¢ = 8.3 Hz, J4¢,2¢ = 2.4 Hz, J4¢,6¢ = 1.1 Hz, 1 H, H-4¢), 8.53
ddd, J6¢,5¢ = 8.3 Hz, J6¢,2¢ = 1.7 Hz, J6¢,4¢ = 1.1 Hz, 1 H, H-6¢), 9.02
t, J2¢,4¢ = 2.4 Hz, J2¢,6¢ = 1.7 Hz, 1 H, H-2¢), 13.65 (br s, 1 H, NH).
3
3
1
(
¢, CH-5¢), 116.78 (C-5), 129.11 (CH-2¢, CH-6¢), 131.83 (C-1¢),
40.86 (CH-8), 153.58 (C-4), 155.07 (C-6), 157.31 (C-2), 160.43
C-4¢).
C NMR (100.6 MHz, DMSO-d ): d = 120.98 (CH-2¢), 124.31
+
6
MS (FAB): m/z (%) = 242 [M + H] (100).
HRMS (FAB): m/z [M + H]+ calcd for C H N O: 242.1041;
found: 242.1053.
(
8
CH-4¢), 130.92 (CH-5¢), 131.72 (C-1¢), 132.18 (CH-6¢), 146.59 (C-
), 148.56 (C-3¢), 152.25 (C-4), 153.22 (CH-2), 155.80 (C-6), (C-5
12 12
5
not observed).
MS (FAB): m/z = 257 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C H N O : 257.0787;
Anal. Calcd for C H N O·2H O (277.3): C, 51.98; H, 5.45; N,
12 11
5
2
2
5.26. Found: C, 52.10; H, 4.60; N, 25.90.
1
1
8
6
2
found: 257.0780.
2
-(3-Pyridyl)adenine (9d)
Prepared from 2-chloroadenine (8) and boronic acid 2d. Isolated by
neutralization with 1 M HCl followed by crystallization from the re-
action mixture to give 9d (79 mg, 47%); mp >300 °C.
8
-(3-Pyridyl)adenine (7d)
Prepared from 8-bromoadenine (6) and boronic acid 2d. Isolated by
crystallization from the reaction mixture to give 7d (129 mg, 76%)
as white crystals; mp > 300 °C.
IR (KBr): 3482, 3414, 3329, 3192, 2704, 1661, 1639, 1598, 1384,
–
1
1
281, 1029, 943, 924, 796, 722, 634 cm .
IR (KBr): 3401, 3320, 3076, 2973, 2705, 1648, 1599, 1298, 1106,
1
1
–
1
H NMR (400 MHz, DMSO-d ): d = 7.29 (br s, 2 H, NH ), 7.49 (dd,
6 2
026, 946, 795, 706 cm .
J5¢,4¢ = 8.0 Hz, J5¢,6¢ = 4.8 Hz, 1 H, H-5¢), 8.16 (s, 1 H, H-8), 8.58 (dt,
1
H NMR (400 MHz, DMSO-d ): d = 7.26 (br s, 2 H, NH ), 7.58
6
2
J4¢,5¢ = 8.0 Hz, J4¢,2¢ = J = 1.8 Hz, 1 H, H-4¢), 8.61 (br m, 1 H, H-
4¢,6¢
(
1
ddd, J5 = 8.0 Hz, J = 4.8 Hz, J = 0.8 Hz, 1 H, H-5¢), 8.15 (s,
¢,4¢ 5¢,6¢ 5¢,2¢
6
¢), 9.46 (br m, 1 H, H-2¢), 12.96 (br s, 1 H, NH).
H, H-2), 8.44 (ddd, J4¢,5¢ = 8.0 Hz, J4¢,2¢ = 2.3 Hz, J = 1.6 Hz, 1
4¢,6¢
1
3
C NMR (100.6 MHz, DMSO-d ): d = 117.34 (C-5), 123.62 (CH-
H, H-4¢), 8.67 (dd, J = 4.8 Hz, J6¢,4¢ = 1.6 Hz, 1 H, H-6¢), 9.31 (dd,
6
6
¢,5¢
5
1
¢), 134.25 (C-3¢), 134.89 (CH-4¢), 140.23 (CH-8), 148.98 (CH-2¢),
50.16 (CH-6¢), 152.02 (C-4), 156.04 (C-2 and C-6).
J
= 2.3 Hz, J = 0.8 Hz, 1 H, H-2¢), 13.53 (br s, 1 H, NH).
2¢,5¢
2
¢,4¢
1
3
C NMR (100.6 MHz, DMSO-d ): d = 119.67 (C-5), 124.18 (CH-
6
MS (FAB): m/z = 213 [M + H]+.
5
1
¢), 126.09 (C-3¢), 133.63 (CH-4¢), 146.13 (C-8), 147.48 (CH-2¢),
50.65 (CH-6¢), 152.12 (C-4), 153.03 (CH-2), 155.61 (C-6).
+
HRMS (FAB): m/z [M + H] calcd for C H N : 213.0889; found:
1
0
9
6
MS (FAB): m/z = 213 [M + H]+.
213.0895.
+
HRMS (FAB): m/z [M + H] calcd for C H N : 213.0889; found:
1
0
9
6
2
-Chloro-6-phenyl-9H-purine (11a)
2
13.0894.
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2a (1
equiv). Isolated by neutralization with 1 M HCl followed by crys-
tallization from the reaction mixture. Separation on RP-HPLC af-
forded 11a (101 mg, 55%) and 12a (11 mg, 5%) as white crystals.
Anal. Calcd for C H N ·0.5H O: C, 54.29; H, 4.10; N, 37.99.
Found: C, 54.78; H, 3.86; N, 37.25.
1
0
8
6
2
2
-Phenyladenine (9a)
Prepared from 6-amino-2-chloro-9H-purine (8) and boronic acid
a. Isolated from the reaction mixture by crystallization to give 9a
2-Chloro-6-phenyl-9H-purine (11a)28
Mp 265–273 °C.
2
2
6
(
114 mg, 67%) as yellow crystals; mp >300 °C (Lit. 321–322 °C).
IR (KBr): 3093, 2993, 1602, 1581, 1564, 1328, 1262, 1167, 887,
–
1
IR (KBr): 3476, 3100, 1647, 1591, 1386, 1333, 1278, 932, 778, 719
cm .
764, 681, 623 cm .
–
1
1
H NMR (500 MHz, DMSO-d ): d = 7.58–7.65 (m, 3 H, H-3¢, H-4¢,
6
1
H NMR (400 MHz, DMSO-d ): d = 7.15 (br s, 2 H, NH ), 7.38–
H-5¢), 8.70 (s, 1 H, H-8), 8.73 (m, 2 H, H-2¢, H-6¢), 13.80 (br s, 1 H,
NH).
6
2
7
2
.48 (m, 3 H, H-3¢, H-4¢, H-5¢), 8.12 (s, 1 H, H-8), 8.33 (m, 2 H, H-
¢, H-6¢), 12.88 (br s, 1 H, NH).
13
C NMR (125.8 MHz, DMSO-d ): d = 128.75 (C-5), 129.02 (CH-
6
1
3
C NMR (100.6 MHz, DMSO-d ): d = 117.62 (C-5), 127.70 (CH-
3¢, CH-5¢), 129.58 (CH-2¢, CH-6¢), 131.83 (CH-4¢), 134.55 (C-1¢),
146.59 (CH-8), 152.73 (C-2), 154.02 (C-6), 156.29 (C-4).
MS (FAB): m/z = 231 [M + H]+.
6
2
1
¢, CH-6¢), 128.33 (CH-3¢, CH-5¢), 129.48 (C-4¢), 138.97 (C-1¢),
39.82 (CH-8), 151.33 (C-4), 157.85 (C-2), (C-6 not observed).
+
MS (FAB): m/z (%) = 212 [M + H] (100).
+
HRMS (FAB): m/z [M + H] calcd for C H ClN : 231.0438; found:
1
1
8
4
+
HRMS (FAB): m/z [M + H] calcd for C H N : 212.0936; found:
231.0439.
1
1
10
5
2
12.0944.
Anal. Calcd for C H ClN Cl·0.2H O: C, 56.40; H, 3.18; N, 23.92.
1
1
7
4
2
Anal. Calcd for C H N ·0.5H O (220.2): C, 59.99; H, 4.58; N,
Found: C, 56.72; H, 2.92; N, 23.41.
11
9
5
2
3
1.80. Found: C, 59.81; H, 4.24; N, 32.38.
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

3
524
P. Čapek et al.
FEATURE ARTICLE
2
-Chloro-6-(4-methoxyphenyl)-9H-purine (11b)
2,6-Diphenyl-9H-purine (12a)
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2b (1
equiv). Isolated by neutralization with 1 M HCl followed by crys-
tallization from the reaction mixture. Separation on RP-HPLC af-
forded only a mixture of 11b and 12b in 10:1 ratio (according to
NMR) as white crystals. Further recrystallization of this mixture
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2a (3
equiv). Isolated by crystallization from the reaction mixture to give
12a (200 mg, 92%); mp 280–294 °C.
IR (KBr): 3437, 3062, 2995, 2830, 1611, 1587, 1561, 1413, 1372,
–1
1
249, 1126, 879, 763, 690, 631 cm .
(EtOH–H O) gave pure 11b (118 mg, 57%); mp 287–291 °C.
2
1
H NMR (400 MHz, DMSO-d ): d = 7.49–7.67 (m, 6 H, H-3¢, H-4¢,
6
IR (KBr): 3436, 3093, 2930, 1595, 1560, 1517, 1310, 1261, 1160,
1
H-5¢, H-3¢¢, H-4¢¢, H-5¢¢), 8.57 (m, 2 H, H-2¢¢, H-6¢¢), 8.65 (s, 1 H, H-
8
–
1
032, 889, 796, 589 cm .
), 8.96 (m, 2 H, H-2¢, H-6¢), 13.65 (br s, 1 H, NH).
1
H NMR (400 MHz, DMSO-d ): d = 3.87 (s, 3 H, CH O), 7.15 (m,
13
6
3
C NMR (100.6 MHz, DMSO-d ): d = 127.90 (CH-2¢¢, CH-6¢¢),
6
2
H, H-3¢, H-5¢), 8.64 (s, 1 H, H-8), 8.75 (m, 2 H, H-2¢, H-6¢), 13.70
1
1
28.83 (C-5), 128.83 and 128.87 (CH-3¢, CH-5¢, CH-3¢¢, CH-5¢¢),
29.53 (CH-2¢, CH-6¢), 130.22 (CH-4¢¢), 131.12 (CH-4¢), 136.07
(
br s, 1 H, NH).
1
3
C NMR (100.6 MHz, DMSO-d ): d = 55.63 (CH O), 114.45 (CH-
(C-1¢), 138.24 (C-1¢¢), 145.61 (CH-8), 152.04 (C-6), 155.07 (C-4),
157.31 (C-2).
MS (FAB): m/z = 273 [M + H]+.
6
3
3
1
¢, CH-5¢), 126.98 (C-1¢), 128.26 (C-5), 131.47 (CH-2¢, CH-6¢),
45.79 (CH-8), 152.72 (C-2), 153.95 (C-6), 155.75 (C-4), 162.28
(
C-4¢).
HRMS (FAB): m/z calcd for C H N : 273.1140; found: 273.1145.
MS (FAB): m/z = 261 [M + H]+.
17
13
4
Anal. Calcd for C H N (272.3): C, 74.98; H, 4.44; N, 20.58.
+
17 12
4
HRMS (FAB): m/z [M + H] calcd for C H ClN O: 261.0543;
found: 261.0540.
1
2
10
4
Found: C, 74.42; H, 4.22; N, 20.52.
Anal. Calcd for C H ClN O (260.7): C, 55.29; H, 3.48; N, 21.49.
2,6-Bis(4-methoxyphenyl)-9H-purine (12b)
1
2
9
4
Found: C, 55.17; H, 3.36; N, 21.58.
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2b (3
equiv). Isolated by crystallization from the reaction mixture to give
12b (242 mg, 91%); mp 250–252 °C.
2
-Chloro-6-(3-nitrophenyl)-9H-purine (11c)
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2c (1
equiv). Isolated from the reaction mixture by HPLC to give 11c (57
mg, 26%) as white crystals; mp 310–314 °C.
IR (KBr): 3429, 2960, 2907, 2837, 1603, 1562, 1514, 1374, 1252,
–1
1
167, 1031, 805, 560 cm .
1
H NMR (500 MHz, DMSO-d ): d = 3.85 (s, 3 H, CH O-2), 3.88 (s,
6
3
IR (KBr): 3400, 3086, 1603, 1580, 1524, 1354, 1249, 1100, 918,
3
8
H, CH O-6), 7.10 (m, 2 H, H-3¢¢, H-5¢¢), 7.18 (m, 2 H, H-3¢, H-5¢),
–
1
3
8
00 cm .
.49 (m, 2 H, H-2¢¢, H-6¢¢), 8.54 (s, 1 H, H-8), 8.96 (m, 2 H, H-2¢,
1
H NMR (400 MHz, DMSO-d ): d = 7.91 (t, J5¢,4¢ = 8.2 Hz,
H-6¢), 13.50 (br s, 1 H, NH).
6
J5¢,6¢ = 7.9 Hz, 1 H, H-5¢), 8.44 (ddd, J4¢,5¢ = 8.2 Hz, J4¢,2¢ = 2.4 Hz,
13
C NMR (125.8 MHz, DMSO-d ): d = 55.45 (CH O-2), 55.55
3
6
3
J4¢,6¢ = 1.1 Hz, 1 H, H-4¢), 8.77 (s, 1 H, H-8), 9.13 (dt, J = 7.9 Hz,
6¢,5¢
(
(
1
CH O-6), 114.11 (CH-3¢¢, CH-5¢¢), 114.25 (CH-3¢, CH-5¢), 127.85
J6¢,2¢ = 1.6 Hz, J = 1.1 Hz, 1 H, H-6¢), 9.60 (t, J2¢,4¢ = 2.4 Hz,
6¢,4¢
C-5), 128.65 (C-1¢), 129.42 (CH-2¢¢, CH-6¢¢), 130.94 (C-1¢¢),
J2¢,6¢ = 1.6 Hz, 1 H, H-2¢).
31.24 (CH-2¢, CH-6¢), 144.55 (CH-8), 151.82 (C-6), 154.73 (C-4),
1
3
C NMR (100.6 MHz, DMSO-d ): d = 124.00 (CH-2¢), 126.09
157.25 (C-2), 161.06 (C-4¢¢), 161.67 (C-4¢).
6
(
1
1
CH-4¢), 129.69 (C-5), 130.80 (CH-5¢), 135.32 (CH-6¢), 136.11 (C-
MS (FAB): m/z = 333 [M + H]+.
¢), 147.74 (CH-8), 148.36 (C-3¢), 151.10 (C-6), 152.56 (C-2),
HRMS (FAB): m/z calcd for C H N O : 333.1352; found:
56.78 (C-4).
19 17
4
2
3
33.1342.
+
MS (FAB): m/z (%) = 276 [M + H] (5).
Anal Calcd for C H N O (332.4): C, 68.66; H, 4.85; N, 16.86.
1
9
16
4
2
HRMS (FAB): m/z calcd for C H ClN O : 276.0288; found:
1
1
7
5
2
Found: C, 68.42; H, 4.67; N, 16.65.
2
76.0279.
Anal. Calcd for C H ClN O (275.7): C, 47.93; H, 2.18; N, 25.03.
2,6-Bis(3-nitrophenyl)-9H-purine (12c)
11
6
5
2
Found: C, 47.44; H, 2.14; N, 24.95.
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2c (3
equiv). Isolated from the complex reaction mixture by HPLC to
give 12c (40 mg, 14%) as white crystals; mp >300 °C.
2
-Chloro-6-(3-pyridyl)-9H-purine (11d)
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2d (1
equiv). Isolated from the reaction mixture by HPLC to give 11d
IR (KBr): 3431, 1604, 1581, 1526, 1354, 1249, 1101, 918, 800
cm .
–1
(
130 mg, 70%) as white crystals; mp >300 °C.
1
H NMR (400 MHz, DMSO-d ): d = 7.83 (t, J
= 8.2 Hz,
6
5¢¢,4¢¢
IR (KBr): 3413, 3099, 1600, 1583, 1373, 1312, 1255, 1030, 991,
J5¢¢,6¢¢ = 7.8 Hz, 1 H, H-5¢¢), 7.92 (t, J = 8.2 Hz, J = 8.0 Hz, 1 H,
–
1
5¢,4¢
5¢,6¢
8
79 cm .
H-5¢), 8.27 (ddd, J6¢¢,5¢¢ = 7.8 Hz, J6¢¢,2¢¢ = 1.6 Hz, J6¢¢,4¢¢ = 1.0 Hz, 1 H,
H-6¢¢), 8.30 (ddd, J4¢¢,5¢¢ = 8.2 Hz, J4¢¢,2¢¢ = 2.3 Hz, J4¢¢,6¢¢ = 1.0 Hz, 1 H,
H-4¢¢), 8.45 (ddd, J4¢,5¢ = 8.2 Hz, J4¢,2¢ = 2.4 Hz, J4¢,6¢ = 1.1 Hz, 1 H,
H-4¢), 8.57 (t, J2¢¢,4¢¢ = 2.4 Hz, J2¢¢,6¢¢ = 1.6 Hz, 1 H, H-2¢¢), 8.79 (s, 1
H, H-8), 9.14 (dt, J = 8.0 Hz, J6¢,2¢ = 1.2 Hz, J = 1.1 Hz, 1 H,
1
H NMR (500 MHz, DMSO-d ): d = 7.66 (ddd, J = 8.0 Hz,
6
5¢,4¢
J5¢,6¢ = 4.8 Hz, J = 0.8 Hz, 1 H, H-5¢), 8.75 (s, 1 H, H-8), 8.78 (dd,
5¢,2¢
J6¢,5¢ = 4.8 Hz, J6¢,4¢ = 1.8 Hz, 1 H, H-6¢), 8.98 (br m, 1 H, H-4¢), 9.85
(
br m, 1 H, H-2¢), 13.95 (br s, 1 H, NH).
6
¢,5¢
6¢,4¢
1
3
H-6¢), 9.61 (t, J2¢,4¢ = 2.4 Hz, J2¢,6¢ = 1.2 Hz, 1 H, H-2¢).
C NMR (125.8 MHz, DMSO-d ): d = 124.26 (CH-5¢), 129.87 (C-
6
1
3
5
1
), 130.47 (C-3¢), 136.71 (CH-4¢), 146.91 (CH-8), 150.31 (CH-2¢),
52.10 (CH-6¢), 152.82 (C-2), 155.73 (C-4), (C-6 not observed).
C NMR (100.6 MHz, DMSO-d ): d = 121.99 (CH-2¢¢), 123.40
6
(CH-4¢¢), 124.01 (CH-2¢), 126.12 (CH-4¢), 129.62 (C-5), 130.80 and
130.92 (CH-5¢ and CH-5¢¢), 133.91 (CH-6¢¢), 135.31 (CH-6¢),
+
MS (FAB): m/z (%) = 232 [M + H] (15).
1
36.05 (C-1¢), 139.64 (C-1¢¢), 147.43 (CH-8), 148.37 (C-3¢), 148.68
HRMS (FAB): m/z calcd for C H ClN : 232.038; found: 232.038.
1
0
7
5
(C-3¢¢), 151.21 (C-6), 152.62 (C-2), 156.50 (C-4).
Anal. Calcd for C H ClN ·1.5H O (258.7): C, 46.43; H, 3.51; N,
+
1
0
6
5
2
MS (FAB): m/z (%) = 263 [M + H] (100).
2
7.08. Found: C, 46.04; H, 3.35; N, 26.51.
Synthesis 2006, No. 20, 3515–3526 © Thieme Stuttgart · New York

FEATURE ARTICLE
Aqueous-Phase Suzuki–Miyaura Cross-Coupling Reactions of Free Halopurine Bases
3525
+
HRMS (FAB): m/z [M + H] calcd for C H N O : 263.0836;
found: 263.0838.
(4) (a) Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Liu, F.;
Nolsøe, J. M. J. Bioorg. Med. Chem. Lett. 2000, 10, 1207.
b) Andresen, G.; Gundersen, L.-L.; Nissen-Meyer, J.; Rise,
F.; Spilsberg, B. Bioorg. Med. Chem. Lett. 2002, 12, 567.
c) Gundersen, L.-L.; Nissen-Meyer, J.; Spilsberg, B. J.
1
7
11
6
4
(
Anal. Calcd for C H N O ·2H O (398.3): C, 51.26; H, 3.54; N,
1.10. Found: C, 51.08; H, 2.67; N, 20.35.
1
7
10
6
4
2
2
(
Med. Chem. 2002, 45, 1383. (d) Bakkestuen, A. K.;
Gundersen, L.-L.; Utenova, B. T. J. Med. Chem. 2005, 48,
2
,6-Di-3-pyridyl-9H-purine (12d)
Prepared from 2,6-dichloro-9H-purine (10) and boronic acid 2d (3
equiv). Isolated from the reaction mixture to give 12d (195 mg,
8
2710.
1
3
(5) Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.;
Gilligan, P. Bioorg. Med. Chem. Lett. 1999, 9, 1063.
6) Wan, Z.; Boehm, J. C.; Bower, M. J.; Kassis, S.; Lee, J. C.;
9%) as a white solid, mp >300 °C. Due to its low solubility,
C
NMR of 12d could not be measured.
(
IR (KBr): 3438, 2505, 1612, 1594, 1560, 1373, 1286, 1187, 1029,
8
Zhao, B.; Adams, J. L. Bioorg. Med. Chem. Lett. 2003, 13,
–1
71, 795 cm .
1191.
1
(7) Vandromme, L.; Piguel, S.; Lozach, O.; Meijer, L.;
H NMR (500 MHz, DMSO-d ): d = 7.59 (dd, J5¢¢,4¢¢ = 8.0 Hz,
6
Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. Lett.
J5¢¢,6¢¢ = 4.7 Hz, J
= 0.9 Hz, 1 H, H-5¢¢), 7.67 (dd, J5¢,4¢ = 8.0 Hz,
5¢¢,2¢¢
2006, 16, 3144.
J5¢,6¢ = 4.8 Hz, J5¢,2¢ = 0.9 Hz, 1 H, H-5¢), 8.68 (s, 1 H, H-8), 8.70 (dd,
J6¢¢,5¢¢ = 4.7 Hz, J6¢¢,4¢¢ = 1.7 Hz, 1 H, H-6¢¢), 8.77 (dd, J = 4.8 Hz,
J6¢,4¢ = 1.7 Hz, 1 H, H-6¢), 8.86 (dt, J4¢¢,5¢¢ = 8.0 Hz, J4¢¢,2¢¢ = 2.2 Hz,
J4¢¢,6¢¢ = 1.7 Hz, 1 H, H-4¢¢), 9.24 (dt, J4¢,5¢ = 8.0 Hz, J4¢,2¢ = 2.2 Hz,
J4¢,6¢ = 1.7 Hz, 1 H, H-4¢), 9.70 (dd, J2¢¢,4¢¢ = 2.2 Hz, J2¢¢,5¢¢ = 0.9 Hz, 1
H, H-2¢¢), 10.08 (br d, J2¢,4¢ = 2.2 Hz, 1 H, H-2¢).
(
8) (a) Cristalli, G.; Lambertucci, C.; Taffi, S.; Vittori, S.;
6¢,5¢
Volpini, R. Curr. Top. Med. Chem. 2003, 3, 387.
(
(
b) Müller, C. E. Curr. Top. Med. Chem. 2003, 3, 445.
c) Kim, Y. C.; Ji, X.; Melman, N.; Linden, J.; Jacobson, K.
A. J. Med. Chem. 2000, 43, 1165. (d) Kim, S. A.; Marshall,
M. A.; Melman, N.; Kim, H. S.; Müller, C. E.; Linden, J.;
Jacobson, K. A. J. Med. Chem. 2002, 45, 2131. (e) Baraldi,
P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.; Fruttarolo, F.;
Romagnoli, R.; Moorman, A. R.; Gessi, S.; Merighi, S.;
Varani, K.; Borea, P. A. Bioorg. Med. Chem. Lett. 2004, 14,
+
MS (FAB): m/z (%) = 275 [M + H] (35), 197 (95).
+
HRMS (FAB): m/z [M + H] calcd for C H N : 275.1045; found:
2
1
5
11
6
75.1039.
Anal. Calcd for C H N ·0.5H O (283.3): C, 63.60; H, 3.91; N,
2
15
10
6
2
3607.
9.67. Found: C, 63.75; H, 3.54; N, 29.68.
(
9) Chang, L. C. W.; Spanjersberg, R. F.; von Frijtag Drabbe
Kunzel, J. K.; Mulder-Krieger, T.; Brussee, J.; IJzerman, A.
P. J. Med. Chem. 2006, 49, 2861.
10) (a) He, H.; Zatorska, D.; Kim, J.; Aguirre, J.; Llauger, L.;
She, Y.; Wu, N.; Immormino, R. M.; Gewirth, D. T.;
2
-Methyl-6-phenyl-9H-purine (13)
Dry THF (3 mL) was added through septum to a mixture of 2-chlo-
(
(
ro-6-phenyl-9H-purine (11a; 100 mg, 0.43 mmol) and Pd(PPh3)4
(
25 mg, 5 mol%) under argon. Then 2 M AlMe in toluene (1.1 mL,
3
Chiosis, G. J. Med. Chem. 2006, 49, 381. (b)Vilenchik, M.;
Solit, D.; Basso, A.; Huezo, H.; Lucas, B.; He, H.; Rosen, N.;
Spampinato, C.; Modrich, P.; Chiosis, G. Chem. Biol. 2004,
2
.2 mmol) was added dropwise and the mixture was stirred at 75 °C
for 8 h. The crude mixture was poured into iced NH Cl and extract-
ed with CHCl . The product 13 was isolated by column chromatog-
raphy (silica gel) as white crystals (74 mg, 81%); mp 240–244 °C.
4
3
11, 787.
11) Reviews: (a) Hocek, M. Eur. J. Org. Chem. 2003, 245.
(b) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.
1
H NMR (500 MHz, DMSO-d ): d = 2.74 (s, 3 H, CH ), 7.52–7.60
6
3
(
6
m, 3 H, H-3¢, H-4¢, H-5¢), 8.53 (s, 1 H, H-8), 8.80 (m, 2 H, H-2¢, H-
2
2
003, 103, 1875. (c) Lakshman, M. K. J. Organomet. Chem.
002, 653, 234.
¢), 13.35 (br s, 1 H, NH).
1
3
C NMR (125.8 MHz, DMSO-d ): d = 26.04 (CH ), 128.00 (C-5),
(12) (a) Havelková, M.; Hocek, M.; Česnek, M.; Dvořák, D.
Synlett 1999, 1145. (b) Havelková, M.; Dvořák, D.; Hocek,
M. Synthesis 2001, 1704.
(13) (a) Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J.
C.; Dinh, Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am.
Chem. Soc. 2001, 123, 7779. (b) Lakshman, M. K.;
Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.; Sevova, N.;
Boggess, B. Org. Lett. 2002, 4, 1479. (c) Gunda, P.;
Russon, L. M.; Lakshman, M. K. Angew. Chem. Int. Ed.
6
3
1
1
28.80 (CH-3¢, CH-5¢), 129.50 (CH-4¢), 130.96 (CH-2¢, CH-6¢),
36.01 (C-1¢), 144.36 (CH-8), 152.00 (C-6), 154.67 (C-4), 160.92
(
C-2).
MS (FAB): m/z = 211 [M + H]+.
+
HRMS (FAB): m/z [M + H] calcd for C H N : 211.0984; found:
2
1
2
11
4
11.0981.
2
004, 43, 6372. (d) Lakshman, M. K.; Gunda, P.; Prandhan,
Acknowledgment
P. J. Org. Chem. 2005, 70, 10329. (e) Liu, J.; Robins, M. J.
Org. Lett. 2004, 6, 3421. (f) Liu, J.; Robins, M. J. Org. Lett.
This work is a part of the research project Z4 055 0506. It was sup-
ported by the Grant Agency of the Czech Republic (023/05/0043)
and by Gilead Sciences, Inc. (Foster City, CA, USA).
2
005, 7, 1149.
14) (a) Hocek, M.; Dvořáková, H. J. Org. Chem. 2003, 68,
773. (b) Ding, S.; Gray, N. S.; Ding, Q.; Schultz, P. G.
(
5
Tetrahedron Lett. 2001, 42, 8751.
15) (a) Amann, N.; Wagenknecht, H.-A. Synlett 2002, 687.
(
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