Regioselectivity in cross-coupling reactions of 2,6,8-trichloro-9- (tetrahydropyran-2-yl)purine: Synthesis of 2,6,8-trisubstituted purine bases

Article abstract of DOI:10.1055/s-2004-834881

The regioselectivity of cross-coupling reactions (Pd-catalyzed Suzuki-Miyaura reactions with phenylboronic acid and Fe-catalyzed reactions with methylmagnesium chloride) of 2,6,8-trichloro-9-(tetrahydropyran-2-yl)purine with varying amounts of the organom

Full text of DOI:10.1055/s-2004-834881

PAPER
2869
Regioselectivity in Cross-Coupling Reactions of 2,6,8-Trichloro-9-(tetrahydro-
pyran-2-yl)purine: Synthesis of 2,6,8-Trisubstituted Purine Bases
S
ynthesis of 2,6,8-Tris
i
ubstitu
c
B
h
ases al Hocek,* Radek Pohl
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6,
Czech Republic
Fax +420(2)20183559; E-mail: hocek@uochb.cas.cz
Received 12 July 2004; revised 16 August 2004
thylmagnesium chloride. The aim of this study was to test
Abstract: The regioselectivity of cross-coupling reactions (Pd-cat-
whether the cross-couplings are suitable for consecutive
attachment of three different C-substituents onto purine
ring and to prepare 2,6,8-trisubstituted purine bases bear-
alyzed Suzuki–Miyaura reactions with phenylboronic acid and Fe-
catalyzed reactions with methylmagnesium chloride) of 2,6,8-
trichloro-9-(tetrahydropyran-2-yl)purine with varying amounts of
the organometallic reagent was studied. In general, the regioselec- ing the prominent methyl and/or phenyl substituents for
tivity of these reactions was quite low giving mixtures of isomers of
biological activity screening.
mono-, di- and trisubstituted products. Nevertheless, 2,6-dichloro-
8-methyl-9-THP-purine (1aab), 2-chloro-6,8-dimethyl-9-THP-pu-
rine (1abb) and 2,8-dichloro-6-phenyl-9-THP-purine (1aca) were
Cross-coupling reactions of 2,6- and 6,8-dihalopurines
are chemo- and regioselective.4–8,14 In general, the reac-
tions of 2,6- or 6,8-dichloropurines with one equivalent of
an organometallic reagent (arylboronic acid, arylstannane
or arylzinc halide) lead to regioselective substitution in
position 6. On the other hand, 2- or 8-iodo-6-chloropu-
rines react chemoselectively with organometallic reagents
at iodo substituted position 2 or 8. The only exception
from these gerenal rule is the recently reported8 Fe-cata-
lyzed reaction of 6,8-dichloropurines with methylmagne-
sium chloride giving preferentially 6-chloro-8-
methylpurines. So far, no study of regioselectivity of
cross-coupling reactions of 2,6,8-trichloropurines was re-
ported. Throughout the paper, the purines will be num-
bered in the form of 1xyz or 2xyz (x denotes substituent in
position 2, y in position 6 and z in position 8).
isolated in acceptable yields and used as intermediates for further
cross-coupling reactions giving a series of 2,6,8-trisubstituted
9-THP-purines that were deprotected to the corresponding purine
bases. Characteristic 13C NMR shifts of CH3 or ipso-Ph carbons in
different positions of the purine ring have been observed enabling
rapid and facile identification of the particular isomer.
Key words: purines, nucleobases, cross-coupling reactions, iron,
palladium
Biological activity and importance of 6-methylpurine1
and 6-phenylpurine2 bases and nucleosides have been re-
ported many times. This led us to the synthesis of their de-
rivatives bearing additional substituents in position 2 or 8
by regioselective cross-coupling reactions3 of 2,6- or 6,8-
dihalopurines. In this way, 2- and 8-substituted 6-phe-
nylpurine ribonucleosides,4,5 as well as 2-substituted 6-
methylpurines,6 2-substituted 6-phenylpurines,7 8-substi-
tuted 6-phenylpurines and 6-substituted 8-methylpurines8
were recently prepared.
THP-protected 2,6,8-trichloropurine 1aaa was the start-
ing compound of choice since the THP-group is stable un-
der standard cross-coupling conditions (neutral or basic)
and readily cleaved by acids. At first, we have tried to pre-
pare 2,6,8-trichloropurine from uric acid by the Fischer
deoxochlorination procedure15 (POCl3, N,N-dimethyl-
aniline or DMF) but this method was irreproducible in our
hands giving complex mixtures. Finally, we have suc-
ceeded in a one-pot 8-lithiation/chlorination sequence
(Scheme 1) starting from easily available 2,6-dichloro-9-
THP-purine (analogous to known16 8-halogenation of 6-
halopurines) giving the desired trichloropurine 1aaa in an
acceptable yield of 52%.
2,6,9-Tri- and 2,6,8,9-tetrasubstituted purines (usually
bearing N- or O-substituents in the positions 2, 6 and 8)
recently attracted attention as inhibitors of CDK,9 estro-
gen sulfotransferase10 and tubulin polymerization11 and as
antagonists of a corticotropin-releasing hormone.12 Com-
binatorial libraries of these compounds were prepared13
on solid-phase using highly regio- and chemoselective nu-
cleophilic substitutions of dihalopurines with N-, O- or S-
nucleophiles. However, a maximum of one C-substituent
was introduced by a cross-coupling reaction on the last re-
maining leaving group at the end of the synthesis. No re-
gioselective cross-coupling was ever used on solid
support. This paper reports on regioselectivity of cross-
coupling reactions of THP-protected 2,6,8-trichloropu-
rine with varying amounts of phenylboronic acids or me-
The protected trichloropurine 1aaa was subjected to a se-
ries of cross-coupling reactions: Fe-catalyzed reaction17
Cl
N
Cl
6
N
N
N
8
i)
N
N
Cl
2
N
Cl
Cl
N
THP
THP
1aaa
SYNTHESIS 2004, No. 17, pp 2869–2876
Advanced online publication: 15.10.2004
DOI: 10.1055/s-2004-834881; Art ID: T08304SS
x
x.
x
x
.
2
0
0
4
Scheme 1 Reagents and conditions: i. 1) LDA, THF, –78 °C; 2)
C2Cl6 (54%)
© Georg Thieme Verlag Stuttgart · New York

2870
M. Hocek, R. Pohl
PAPER
with methylmagnesium chloride and Pd-catalyzed Suzu- The Suzuki–Miyaura reaction of 1aaa under Pd(PPh3)4
ki–Miyaura reaction18 with phenylboronic acid catalysis in toluene with one equivalent of PhB(OH)2 gave
(Scheme 2, Table 1). The molar ratios of 1aaa and orga- a mixture, from which 2,8-dichloro-6-phenylpurine 1aca
nometallics varied from 1:1 to large excess of the reagent was isolated in a reasonable yield of 46% (entry 6). The
in order to achieve selective mono-, di- or trisubstitution. same reaction using an excess of the boronic acids (entries
Unfortunately, both types of reactions appeared to be 7 and 8) gave only inseparable complex mixtures contain-
much less selective than those of 2,6- or even 6,8-dichlo- ing mono-, di- and triphenylpurines, as well as some prod-
ropurines giving rather complex mixtures of products and ucts of partial dechlorination. Fractional crystallization of
isomers.
these mixtures gave pure 1ccc in low yields (ca. 10–20%),
but attempts to isolate any other product in pure form
failed. Again, even the use of a large excess of the boronic
acid (entry 8) did not lead to complete conversion to the
2,6,8-triphenylpurine 1ccc. In order to enhance the reac-
tivity we turned our attention to the Lakshman18c modified
conditions: Pd(OAc)2, 2-(dicyclohexylphosphino)biphe-
nyl (biphenPCy2) and K3PO4 in THF. Under these condi-
tions the reaction of 1aaa with two equivalents of the
boronic acid gave again inseparable mixture (entry 9), but
the reaction with an excess of PhB(OH)2 gave finally
complete conversion to 1ccc (entry 10).
In the case of the Grignard reagent, the reaction of 1aaa
with 1–1.5 equivalents of MeMgCl gave conversions of
50–62% affording chromatographically separable mix-
tures of 8-methyl- and 6,8-dimethylpurines 1aab and
1abb in moderate yields (Table 1, entries 1 and 2) accom-
panied by inseparable mixture of minor isomers (in both
cases substantial amount of the unreacted starting 1aaa
was recovered and reused). When using 2.1 equivalents of
MeMgCl, the conversion was higher but the mixture of
products even more complex (entry 3). In this case, also
minor isomers 1aba and 1bab were isolated and charac-
terized. On the other hand, even the use of a large excess Despite the low selectivity and moderate yields, 2,6-
(12 equiv) of the reagent did not lead to complete conver- dichloro-8-methyl-9-THP-purine (1aab), 2-chloro-6,8-
sion to 2,6,8-trimethylpurine 1bbb (entry 4). In order to dimethyl-9-THP-purine (1abb) and 2,8-dichloro-6-phe-
selectively and efficiently prepare the trimethylpurine nyl-9-THP-purine (1aca) were chromatographically iso-
1bbb the Pd-catalyzed reaction with trimethylaluminum19 lated in sufficient amounts and used as intermediates for
was used giving virtually complete conversion and good further cross-coupling reactions. The Suzuki–Miyaura re-
yield of 1bbb (entry 5).
action of 2,6-dichloro-8-methylpurine 1aab with three
CH3
N
N
N
N
CH3
H3C
N
THP
1bbb
CH3
CH3
N
N
N
N
ii)
iii)
N
CH3
CH3
Cl
N
Ph
N
THP
THP
1cbb
1abb
Ph
Cl
Cl
N
N
N
N
iii)
N
N
N
N
N
N
N
N
i)
N
CH3
CH3
CH3
CH3
Cl
30 h
iii)
Ph
Cl
N
Cl
Cl
N
Cl
N
THP
THP
1aab
1ccb
iii)
iv)
THP
1aaa
Ph
Ph
6 h
i)
N
N
N
N
Cl
N
1aca
N
THP
THP
1acb
ii)
Ph
Ph
N
N
N
N
Ph
Ph
N
H3C
N
THP
THP
1ccc
1bcb
Scheme 2 Reagents and conditions: i) MeMgCl, Fe(acac)3, THP, NMP, r.t.; ii) Me3Al, Pd(PPh3)4, THF, 80 °C; iii) PhB(OH)2, K2CO3,
Pd(PPh3)4, toluene, 90 °C; iv) PhB(OH)2, K3PO4, Pd(OAc)2, biphenPCy2, THF, 80 °C
Synthesis 2004, No. 17, 2869–2876 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,6,8-Trisubstituted Purine Bases
2871
Table 1 Cross-Coupling Reactions of Chloropurines 1aaa, 1aab, 1abb and 1aca
Entry
Starting
Compd
Reagent
Ratio
Condnsa
Products (Yield)b
1
2
1aaa
1aaa
1aaa
1aaa
1aaa
1aaa
1aaa
1aaa
1aaa
1aaa
1aab
1aab
1abb
1aca
1aca
MeMgCl
MeMgCl
MeMgCl
MeMgCl
Me3Al
1:1.1
1:1.5
1:2.1
1:12
1:6
A
A
A
A
B
1aab (14%), 1abb (11%), recovered 1aaa (50%)
1aab (23%), 1abb (16%), recovered 1aaa (38%)
3
1aab (16%), 1abb (36%), 1aba (3%), 1bab (3%), recovered 1aaa (10%)
4
1abb (40%), 1bbb (57%)
1bbb (80%)
5
6
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
MeMgCl
Me3Al
1:1
C
1aca (46%) + complex mixture of other products
inseparable complex mixturec
inseparable complex mixturec
inseparable complex mixturec
1ccc (87%)
7
1:2
C
8
1:6
C
9
1:2
D
D
Cd
Ce
C
10
11
12
13
14
15
1:8.3
1:3
1acb (69%)
1:4.5
1:4
1ccb (85%)
1cbb (96%)
1:3
A
B
1acb (79%)
1:4
1bcb (98%)
a Conditions: (A) MeMgCl, Fe(acac)3, THF, NMP, r.t.; (B) Me3Al, Pd(PPh3)4, THF, 80 °C; (C) PhB(OH)2, Pd(PPh3)4, K2CO3, toluene, 90 °C;
(D) PhB(OH)2, Pd(OAc)2, biphenPCy2, K3PO4, THF, 80 °C.
b Isolated yields (average of 2–3 identical experiments).
c Compound 1ccc was isolated by fractional crystallization in low yields (ca. 10–20%).
d Reaction time 6 h.
e Reaction time 30 h.
Y
equivalents of phenylboronic acid under standard condi-
tions in six hours gave selectively the 2-chloro-6-phenyl
derivative 1acb in relatively good yield (entry 11), while
when using a larger excess and prolonged reaction time
(30 hours), the 2,6-diphenyl derivative 1ccb was obtained
in very good yield (entry 12). Analogous reaction of 2-
chloro-6,8-dimethylpurine 1abb gave the 2-phenyl deriv-
ative 1cbb in excellent yield (entry 13). 2,8-Dichloro-6-
phenylpurine 1aca reacted with excess of MeMgCl under
Fe catalysis to give selectively 8-monomethyl derivative
1acb in good yield, while the reaction with trimethylalu-
minum gave quantitatively 2,8-dimethyl-6-phenylpurine
1bcb.
Y
i)
N
N
N
N
N
Z
Z
N
H
X
N
2xyz
X
N
1xyz
THP
x, y or z
X, Y or Z
Cl
a
CH3
Ph
b
c
Scheme 3 i) Dowex 50X8 (H+ form), EtOH, reflux
stituents. In the cases where an 8-substituent was present,
the NOE signal enhancement for methyl or o-H-Ph was
observed after irradiation of the OCH proton from the 9-
THP substituent. An assignment of quaternary purine car-
bons as another tool for determination of the position of
substituents was based on the measurement of H,C-long-
range correlations of OCH protons of THP (cross-peaks to
C-4 and C-8), CH3 and o-H-Ph protons. For example, the
H,C-HMBC spectrum of 6,8-dimethyl-2-phenyl-9-THP-
purine 1cbb shows cross-peaks of OCH of THP (5.87
ppm) to C-4 (152.32 ppm) and C-8 (153.26 ppm), of CH3-
8 (2.79 ppm) to C-8 (153.26 ppm), of CH3-6 (2.86 ppm)
Nine examples of THP-protected 2,6,8-trisubstituted pu-
rine derivatives 1xyz obtained in sufficient amounts were
deprotected under standard conditions (reflux in EtOH in
presence of acidic cation exchanger)20 to give the corre-
sponding free trisubstituted purine bases 2xyz in very
good yields of 85–96% (Scheme 3, Table 2).
The regioselectivity of cross-coupling reactions was de-
termined by NMR spectroscopy. H,C-HMBC and DPFG-
NOE experiments were performed for all the prepared
compounds to verify the position of methyl or phenyl sub-
Synthesis 2004, No. 17, 2869–2876 © Thieme Stuttgart · New York

2872
M. Hocek, R. Pohl
PAPER
Table 3 Characteristic 13C Chemical Shifts (d) of CH3 or i-Carom
Carbons at Different Positions of the Purine Ring
Table 2 Deprotection of 9-THP-purines 1xyz
Entry
Starting Compd
1aab
Product
2aab
2abb
2bbb
2aca
2bcb
2cbb
2ccb
Yield (%)a
Compound
CH3 or i-Caroma in Position, d
1
2
3
4
5
6
7
8
9
85
96
91
89
85
88
92
94
88
2
–
–
6
8
–
1abb
1aba
1aab
1bab
1abb
1bbb
1aca
1ccc
19.35
1bbb
–
–
16.49
16.39
16.45
16.38
1aca
25.68
26.05
1bcb
19.32
19.36
1cbb
1ccb
–
133.99
136.37
134.75
19.63
–
1acb
2acb
2ccc
138.59
–
130.31
16.68
16.26
16.50
16.55
–
1ccc
1acb
1cbb
1ccb
1bcb
1aba
a Isolated yields after crystallization.
138.45
138.58
26.20
–
136.44
136.18
19.35
to C-5 (130.53 ppm) and C-6 (156.95 ppm) and of o-H-
Ph-2 (8.50 ppm) to C-2 (157.96 ppm). The substitution
pattern of each trisubstituted purine 1xyz is apparent just
from 13C NMR shifts of methyl or i-C-Ph carbons
(Table 3). The carbon signals of methyl group in the posi-
tion 8 appear at ca. 16 ppm, in the position 6 at ca. 19,
while in the position 2 at ca. 26 ppm for all compounds.
Analogously, the ipso-carbons of Ph groups resonate at
ca. 130, 134–136 and 138 in the positions 8, 6 and 2, re-
spectively. The same behavior was observed in the series
of free purine bases 2xyz and also in previously
published6–8 2,6- and 6,8-disubstituted purines. Free bases
2xyz exhibit tautomerism21 that results in very weak and
in some cases missing quaternary carbons in 13C NMR
spectra. However, the missing carbons could be in several
cases observed indirectly from HMBC spectra.
a Chemical shifts of CH3 groups are in normal type, shifts of i-Carom
are in italics.
Unless otherwise stated, solvents were evaporated at 40 °C/2kPa
and compounds were dried at 60 °C/2kPa. Melting points were de-
termined on a Kofler block and are uncorrected. Mass spectra were
measured on a ZAB-EQ (VG Analytical) spectrometer. NMR spec-
tra were measured on Bruker Avance 500 MHz spectrometer (1H at
500, 13C at 125.7 MHz) and Bruker Avance 400 MHz spectrometer
(1H at 400, 13C at 100.6 MHz). Chemical shifts (in ppm, d scale)
were referenced to TMS as internal standard; coupling constants (J)
are given in Hz. H,C-HMBC and DPFG-NOE experiments were
performed for complete assignement of all signals and to verify the
position of substituents.
In conclusion, cross-coupling reactions of 2,6,8-trichloro-
9-THP-purine 1aaa proceed with low selectivity but still
basically follow the same rules as for 6,8-dichloropurines.
The Fe-catalyzed reaction with methylmagnesium chlo-
ride occurs preferentially in position 8 while the Suzuki–
Miyaura reaction with phenylboronic acid in position 6. It
is also quite difficult, and modified methods must be used
in order to achieve complete persubstitution. Three types
of partly substituted derivatives could be isolated in suffi-
cient amounts and used for another cross-coupling step.
On the other hand, cross-coupling reactions of protected
2,6-dichloro-8-methylpurine 1aab and 2,8-dichloro-6-
phenylpurine 1aca are regioselective and modified condi-
tions or prolonged reaction times must be used in order to
achieve complete disubstitutions. Obviously, this method-
2,6,8-Trichloro-9-(tetrahydropyran-2-yl)purine (1aaa)
LDA (2 M solution in heptane–THF–benzene, 7 mL, 14 mmol) was
added dropwise to a stirred solution of 2,6-dichloro-9-(tetrahydro-
pyran-2-yl)purine (2.75 g, 10 mmol) in THF (40 mL) under argon
at –78 °C during 30 min and the solution was stirred at –78 °C for 1
h. Then a solution of hexachloroethane (5 g, 21 mmol) in THF (20
mL) was added dropwise and stirring at –78 °C was continued for 2
h. Then sat. aq NH4Cl (4 mL) was added and after 5 min, the organic
phase was separated. It was evaporated and co-distilled with tolu-
ene. The residue was chromatographed on a silica gel column (200
g, EtOAc–heptane, 1:4 to 1:1) to give the product that was recrys-
tallized from CH2Cl2–heptane; yield: 1.6 g (52%); yellowish crys-
tals; mp 114–116 °C (Lit.22 mp 117–119 °C).
1H NMR (400 MHz, CDCl3): d = 1.61–1.96 (m, 4 H, CH2), 2.15 and
ology is not suitable for regioselective solid-phase synthe- 2.90 (2 m, 2 × 1 H, CH2), 3.74 (td, 1 H, J = 11.8, 2.3 Hz, bCH2O),
4.19 (ddt, 1 H, Jgem = 11.8, 4.9, 1.9 Hz, aCH2O), 5.74 (dd, 1 H,
sis but a series of nine different 2,6,8-trisubstituted
purines were prepared after deprotection of the corre-
sponding THP-derivatives. None of the final purines 2xyz
showed any considerable cytostatic activity (L1210,
HL60, HeLa S3 and CCRF-CEM cell-lines).
J = 11.4, 2.5 Hz, OCH).
13C NMR (100.6 MHz, CDCl3): d = 23.02, 24.48 and 28.68 (CH2),
69.28 (CH2O), 84.25 (OCH), 129.48 (C-5), 144.47 (C-8), 150.39
(C-6), 152.96 (C-2), 153.30 (C-4).
FAB-MS: m/z (%) = 307 (100, M + H+).
Synthesis 2004, No. 17, 2869–2876 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,6,8-Trisubstituted Purine Bases
2873
Anal. Calcd for C10H9Cl3N4O (307.6): C, 39.05; H, 2.95; Cl, 34.58;
N, 18.22. Found: C, 39.01; H, 2.96; Cl, 34.34; N, 17.98.
EI-HRMS: m/z calcd for C11H12Cl2N4O: 286.0388; found:
286.0392.
General Procedures
Cross-Coupling Reactions of Chloropurines with Methylmag-
nesium Chloride
2,8-Dichloro-6-methyl-9-(tetrahydropyran-2-yl)purine (1aba)
Colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.57–1.94 (m, 4 H, CH2), 2.14 (m,
1 H, CH2), 2.78 (s, 3 H, CH3-6), 2.91 (m, 1 H, CH2), 3.74 (td, 1 H,
J = 11.8, 2.3 Hz, bCH2O), 4.18 (ddt, 1 H, Jgem = 11.8 Hz, J = 4.3,
1.8 Hz, aCH2O), 5.73 (dd, 1 H, J = 11.4, 2.5 Hz, OCH).
13C NMR (100.6 MHz, CDCl3): d = 19.35 (CH3-6), 23.12, 24.58 and
28.74 (CH2), 69.22 (CH2O), 83.73 (OCH), 130.77 (C-5), 142.61 (C-
8), 152.51 (C-4), 153.79 (C-2), 160.52 (C-6).
Method A: MeMgCl (3 M solution in THF, amounts varying from
0.33 mL, 1 mmol up to 4 mL, 12 mmol) was added dropwise to a
stirred solution of a chloropurine (1 mmol) and Fe(acac)3 (103 mg,
0.29 mmol) in THF (10 mL) and NMP (0.5 mL) under argon and the
resulting reaction mixture was stirred at r.t. for 8 h. It was then
poured onto a mixture of ice (ca. 100 mL) and NH4Cl (1 g) and the
products were extracted with CHCl3 (3 × 100 mL). Evaporation of
the organic phase followed by column chromatography on siliga gel
(100 g, EtOAc–hexanes (1:1) → EtOAc → EtOAc–MeOH, 9:1) af-
forded the products (Tables 1 and 2).
EI-MS: m/z (%) = 286 (2, M+), 203 (8), 85 (100).
EI-HRMS: m/z calcd for C11H12Cl2N4O: 286.0388; found:
286.0400.
Cross-Coupling Reactions of Chloropurines with Trimethylalu-
minum
2-Chloro-6,8-dimethyl-9-(tetrahydropyran-2-yl)purine (1abb)
Colorless oil.
Method B: Me3Al (2 M solution in toluene, 2 mL, 4 mmol or 3 mL,
6 mmol) was added dropwise to a stirred solution of a chloropurine
(1 mmol) and Pd(PPh3)4 (60 mg, 0.05 mmol) in THF (10 mL) under
argon and the resulting reaction mixture was stirred at 75 °C for 8
h. The workup and isolation was the same as in Method A (Tables 1
and 2).
1H NMR (400 MHz, CDCl3): d = 1.60–1.85 (m, 3 H, CH2), 1.92,
2.10 and 2.35 (3 m, 3 × 1 H, CH2), 2.78 (s, 3 H, CH3-8), 2.79 (s, 3
H, CH3-6), 3.74 (td, 1 H, J = 11.7, 2.6 Hz, bCH2O), 4.18 (ddt, 1 H,
Jgem = 11.7 Hz, J = 4.3, 1.9 Hz, aCH2O), 5.79 (dd, 1 H, J = 11.3, 2.6
Hz, OCH).
13C NMR (100.6 MHz, CDCl3): d = 16.45 (CH3-8), 19.32 (CH3-6),
22.96, 24.84 and 30.24 (CH2), 69.08 (CH2O), 82.58 (OCH), 130.94
(C-5), 152.71 (C-2), 152.95 (C-4), 154.14 (C-8), 159.43 (C-6).
Cross-Coupling Reactions of Chloropurines with Phenylboron-
ic Acid
Method C: Toluene (10 mL) was added to an argon-purged flask
containing a chloropurine (1 mmol), K2CO3 (200 mg, 1.5 mmol),
phenylboronic acid (amounts from 122 mg, 1 mmol up to 732 mg,
6 mmol) and Pd(PPh3)4 (59 mg, 0.05 mmol) and the mixture was
stirred under argon at 100 °C for 8 h. After cooling to r.t., the sol-
vent was evaporated in vacuo and the residue was chromatographed
as in Method A (Tables 1 and 2).
EI-MS: m/z (%) = 266 (16, M+), 183 (56), 85 (100).
EI-HRMS): m/z calcd for C12H15ClN4O: 266.0934; found:
266.0939.
6-Chloro-2,8-dimethyl-9-(tetrahydropyran-2-yl)purine (1bab)
Colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.63–1.96 (m, 4 H, CH2), 2.12 and
2.45 (2 m, 2 × 1 H, CH2), 2.77 (s, 3 H, CH3-2), 2.80 (s, 3 H, CH3-8),
3.76 (td, 1 H, J = 11.6, 2.5 Hz, bCH2O), 4.21 (ddt, 1 H, Jgem = 11.6
Hz, J = 4.2, 1.4 Hz, aCH2O), 5.80 (dd, 1 H, J = 11.3, 2.6 Hz, OCH).
13C NMR (100.6 MHz, CDCl3): d = 16.39 (CH3-8), 22.92 and 24.90
(CH2), 25.68 (CH3-2), 30.18 (CH2), 69.16 (CH2O), 82.89 (OCH),
128.29 (C-5), 148.40 (C-6), 153.22 (C-4), 154.46 (C-8), 161.48 (C-
2).
Cross-Coupling Reactions of Chloropurines with Phenylboron-
ic Acid
Method D: THF (10 mL) was added to an argon-purged flask con-
taining a chloropurine (1 mmol), K3PO4 (300 mg, 1.4 mmol), phe-
nylboronic acid (244 mg, 2 mmol or 1 g, 8.3 mmol), Pd(OAc)2 (22
mg, 0.1 mmol) and biphenPCy2 (70 mg, 0.2 mmol) and the mixture
was stirred under argon at 75 °C for 8 h. After cooling to r.t., the sol-
vent was evaporated in vacuo and the residue was chromatographed
as in Method A (Tables 1 and 2).
EI-MS: m/z (%) = 266 (5, M+), 183 (34), 85 (100).
EI-HRMS: m/z calcd for C12H15ClN4O: 266.0934; found: 266.0915.
Cleavage of THP-Protected Purines
Method E: A mixture of a THP-protected base 1xyz (0.6–0.8 mmol),
Dowex 50 X 8 (H+) (ca. 300 mg), EtOH (50 mL) and H2O (1 mL)
was refluxed for 1 h, then filtered while hot and the resin was
washed with hot EtOH (2 × 50 mL). The combined filtrates were
evaporated and the residue co-distilled with toluene. Crystallization
of the residue from MeOH–toluene with addition of heptane afford-
ed the free bases 2xyz.
2,6,8-Trimethyl-9-(tetrahydropyran-2-yl)purine (1bbb)
Foam that crystallized on standing; mp 104–107 °C.
1H NMR (400 MHz, CDCl3): d = 1.62–1.93 (m, 4 H, CH2), 2.09 and
2.44 (2 m, 2 × 1 H, CH2), 2.75 (s, 3 H, CH3-2), 2.76 (s, 6 H, CH3-6
and CH3-8), 3.76 (td, 1 H, J = 11.9, 2.5 Hz, bCH2O-THP), 4.19 (ddt,
1 H, Jgem = 11.9 Hz, J = 4.7, 1.9 Hz, aCH2O), 5.80 (dd, 1 H,
J = 11.3, 2.6 Hz, OCH).
2,6-Dichloro-8-methyl-9-(tetrahydropyran-2-yl)purine (1aab)
Foam that crystallized on standing; mp 109–112 °C.
13C NMR (100.6 MHz, CDCl3): d = 16.38 (CH3-8), 19.36 (CH3-6),
23.25 and 25.08 (CH2), 26.05 (CH3-2), 30.33 (CH2), 69.11 (CH2O),
82.49 (OCH), 129.74 (C-5), 152.19 (C-4), 152.52 (C-8), 156.70 (C-
6), 161.02 (C-2).
1H NMR (400 MHz, CDCl3): d = 1.62–1.85 (m, 3 H, CH2), 1.94,
2.11 and 2.36 (3 m, 3 × 1 H, CH2), 2.81 (s, 3 H, CH3-8), 3.74 (td, 1
H, J = 11.6, 2.6 Hz, bCH2O), 4.20 (ddt, 1 H, Jgem = 11.6 Hz, J = 4.2,
1.9 Hz, aCH2O), 5.78 (dd, 1 H, J = 11.3, 2.6 Hz, OCH).
13C NMR (100.6 MHz, CDCl3): d = 16.49 (CH3-8), 22.86, 24.72 and
30.14 (CH2), 69.15 (CH2O), 83.10 (OCH), 129.63 (C-5), 149.47 (C-
6), 151.79 (C-2), 153.78 (C-4), 156.13 (C-6).
EI-MS: m/z (%): 246 (26, M+), 162 (100), 85 (22).
EI-HRMS: m/z calcd for C13H18N4O: 246.1481; found: 246.1475.
Anal. Calcd for C13H18N4O (246.3): C, 63.39; H, 7.37; N, 22.75.
Found: C, 63.03; H, 7.37; N, 22.42.
EI-MS: m/z (%) = 286 (2, M+), 203 (8), 85 (100).
2,8-Dichloro-6-phenyl-9-(tetrahydropyran-2-yl)purine (1aca)
Foam that crystallized on standing; mp 172–175 °C.
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PAPER
EI-MS: m/z (%) = 308 (12, M+), 224 (100), 183 (20), 85 (16).
1H NMR (400 MHz, CDCl3): d = 1.60–1.96 (m, 4 H, CH2), 2.15 and
2.91 (2 m, 2 × 1 H, CH2), 3.75 (td, 1 H, J = 11.8, 2.3 Hz, bCH2O),
4.20 (ddt, 1 H, Jgem = 11.8 Hz, J = 4.6, 1.6 Hz, aCH2O), 5.81 (dd, 1
H, J = 11.4, 2.6 Hz, CHO), 7.51–7.57 (m, 3 H, m- and p-H-Ph), 8.71
(m, 2 H, o-H-Ph ).
13C NMR (100.6 MHz, CDCl3): d = 23.15, 24.62 and 28.84 (CH2),
69.27 (CH2O), 83.62 (OCH), 128.68 (C-5), 128.73 (m-CH-Ph),
129.94 (o-CH-Ph), 131.84 (p-CH-Ph), 133.99 (i-C-Ph), 143.06 (C-
8), 154.09 (C-2), 154.46 (C-4), 155.46 (C-6).
EI-HRMS: m/z calcd for C18H20N4O: 308.1637, found: 308.1648.
6,8-Dimethyl-2-phenyl-9-(tetrahydropyran-2-yl)purine (1cbb)
Foam that crystallized on standing; mp 58–62 °C.
1H NMR (400 MHz, CDCl3): d = 1.63–1.89 (m, 3 H, CH2), 1.98,
2.14 and 2.60 (3 m, 3 × 1 H, CH2), 2.79 (s, 3 H, CH3-8), 2.86 (s, 3
H, CH3-6), 3.78 (td, 1 H, J = 11.7, 2.4 Hz, bCH2O), 4.20 (ddt, 1 H,
Jgem = 11.7 Hz, J = 4.3, 1.8 Hz, aCH2O), 5.87 (dd, 1 H, J = 11.2, 2.5
Hz, OCH), 7.40–7.55 (m, 3 H, m- and p-H-Ph), 8.50 (m, 2 H, o-H-
Ph).
13C NMR (100.6 MHz, CDCl3): d = 16.26 (CH3-8), 19.63 (CH3-6),
23.27, 25.04 and 30.17 (CH2), 69.01 (CH2O), 82.70 (OCH), 128.13
(m-CH-Ph), 128.35 (o-CH-Ph), 129.68 (p-CH-Ph), 130.53 (C-5),
138.45 (i-C-Ph), 152.32 (C-4), 153.26 (C-8), 156.95 (C-6), 157.96
(C-2).
EI-MS: m/z (%) = 348 (7, M+), 265 (90), 229 (40), 85 (100).
EI-HRMS: m/z calcd for C16H14Cl2N4O: 348.0545, found:
348.0542.
2,6,8-Triphenyl-9-(tetrahydropyran-2-yl)purine (1ccc)
Yellowish crystals from EtOAc–heptane; mp 185–188 °C.
EI-MS: m/z (%) = 432 (8, M+), 348 (100), 85 (18).
EI-MS: m/z (%) = 308 (14, M+), 224 (100), 85 (12).
1H NMR (400 MHz, CDCl3): d = 1.56–1.70 (m, 2 H, CH2), 1.76–
1.94 (m, 2 H, CH2), 2.09 and 3.32 (2 m, 2 × 1 H, CH2), 3.74 (td, 1
H, J = 12.4, 2.3 Hz, bCH2O), 4.29 (ddt, 1 H, Jgem = 12.4 Hz, J = 5.0,
1.6 Hz, aCH2O), 5.70 (dd, 1 H, J = 11.3, 2.4 Hz, OCH), 7.45–7.62
(m, 9 H, 3 × m- and p-H-Ph), 7.99 (m, 2 H, o-H-Ph-8), 8.70 (m, 2
H, o-H-Ph-2), 9.02 (m, 2 H, o-H-Ph-6).
13C NMR (100.6 MHz, CDCl3): d = 23.62, 24.97 and 28.62 (CH2),
68.78 (CH2O), 84.05 (OCHO), 128.36, 128.50 and 128.68 (CH-Ph),
129.82 (C-5), 129.90 and 129.99 (CH-Ph), 130.31 (i-C-Ph-8),
130.60 and 130.62 (CH-Ph), 136.37 (i-C-Ph-6), 138.59 (i-C-Ph-2),
153.63 (C-6), 155.12 and 155.50 (C-8 and C-4), 157.99 (C-2).
EI-HRMS: m/z calcd for C18H20N4O: 308.1637; found: 308.1636.
8-Methyl-2,6-diphenyl-9-(tetrahydropyran-2-yl)purine (1ccb)
Colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.65–1.91 (m, 3 H, CH2), 2.01,
2.15 and 2.58 (3 m, 3 × 1 H, CH2), 2.84 (s, 3 H, CH3-8), 3.80 (td, 1
H, J = 11.7, 2.5 Hz, bCH2O), 4.23 (ddt, 1 H, Jgem = 11.7 Hz, J = 4.3,
1.9 Hz, aCH2O), 5.97 (dd, 1 H, J = 11.3, 2.4 Hz, OCH), 7.42–7.63
(m, 6 H, 2 × m- and p-H-Ph), 8.65 (m, 2 H, o-H-Ph-2), 8.90 (m, 2
H, o-H-Ph-6).
EI-HRMS: m/z calcd for C28H24N4O: 432.1950; found: 432.1941.
13C NMR (100.6 MHz, CDCl3): d = 16.50 (CH3), 23.33, 25.10 and
30.32 (CH2), 69.09 (CH2O), 82.68 (OCH), 128.20, 128.34 and
128.52 (CH-Ph), 129.93 (C-5), 129.66, 129.78 and 130.43 (CH-Ph),
136.44 (i-C-Ph-6), 138.58 (i-C-Ph-2), 152.45 (C-6), 154.02 (C-8),
154.43 (C-4), 157.59 (C-2).
Anal. Calcd for C28H24N4O (432.5): C, 77.75; H, 5.59; N, 12.95.
Found: C, 77.38; H, 5.57; N, 12.61.
2-Chloro-8-methyl-6-phenyl-9-(tetrahydropyran-2-yl)purine
(1acb)
EI-MS: m/z (%) = 370 (17, M+), 286 (100), 245 (10), 85 (11).
Foam that crystallized on standing; mp 200–203 °C.
EI-HRMS: m/z calcd for C23H22N4O: 370.1794; found: 370.1809.
1H NMR (400 MHz, CDCl3): d = 1.62–1.88 (m, 3 H, CH2), 1.95,
2.10 and 2.33 (3 m, 3 × 1 H, CH2), 2.83 (s, 3 H, CH3-8), 3.76 (td, 1
H, J = 11.8, 2.6 Hz, bCH2O), 4.20 (ddt, 1 H, Jgem = 11.8 Hz, J = 4.4,
1.9 Hz, aCH2O), 5.88 (dd, 1 H, J = 11.3, 2.6 Hz, OCH), 7.49–7.58
(m, 3 H, m- and p-H-Ph), 8.74 (m, 2 H, o-H-Ph).
13C NMR (100.6 MHz, CDCl3): d = 16.68 (CH3-8), 23.00, 24.92 and
30.39 (CH2), 69.14 (CH2O), 82.52 (OCH), 128.63 (m-CH-Ph),
129.14 (C-5), 129.86 (o-CH-Ph), 131.26 (p-CH-Ph), 134.75 (i-C-
Ph), 153.05 (C-2), 154.72 (C-4), 154.76 (C-8), 155.01 (C-6).
2,6-Dichloro-8-methylpurine (2aab)
Colorless crystals from MeOH–toluene–heptane; mp 230–234 °C
(Lit.23 mp 245–249 °C).
1H NMR (500 MHz, CDCl3 + MeOD): d = 2.67 (s, 3 H, CH3-8).
13C NMR (125.7 MHz, CDCl3 + MeOD): d = 15.00 (CH3-8), 151.63
(C-2), 157.15 (C-8). Note: C-4, C-5 and C-6 signals did not appear.
EI-MS: m/z (%) = 202 (100, M+), 167 (23), 131 (19).
EI-MS: m/z (%) = 328 (12, M+), 244 (100), 209 (20), 85 (39).
EI-HRMS: m/z calcd for C6H6Cl2N4: 201.9813; found: 201.9823.
Anal. Calcd for C6H4Cl2N4 (203.0): C, 35.49; H, 1.99; N, 27.60.
Found: C, 35.64; H, 2.02; N, 27.22.
EI-HRMS: m/z calcd for C17H17ClN4O: 328.1091; found: 328.1093.
Anal. Calcd for C17H17ClN4O (328.8): C, 62.10; H, 5.21; N, 17.04.
Found: C, 62.10; H, 5.18; N, 16.77.
2-Chloro-6,8-dimethylpurine (2abb)
Colorless crystals from MeOH–toluene–heptane; mp 220 °C (dec.).
1H NMR (500 MHz, CDCl3 +MeOD): d = 2.66 (s, 3 H, CH3-8); 2.77
(s, 3 H, CH3-6).
13C NMR (125.7 MHz, CDCl3 + MeOD): d = 14.82 (CH3-8), 19.01
(CH3-6), 130.84 (C-5), 152.34 (C-2), 155.23 (C-8), 157.71 (C-6).
Note: C-4 signal did not appear.
2,8-Dimethyl-6-phenyl-9-(tetrahydropyran-2-yl)purine (1bcb)
Colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.61–1.97 (m, 4 H, CH2), 2.10 and
2.42 (2 m, 2 × 1 H, CH2), 2.81 (s, 3 H, CH3-8), 2.84 (s, 3 H, CH3-2),
3.78 (td, 1 H, J = 11.8, 2.6 Hz, bCH2O), 4.20 (ddt, 1 H, Jgem = 11.8
Hz, J = 4.4, 1.9 Hz, aCH2O), 5.90 (dd, 1 H, J = 11.3, 2.6 Hz, OCH),
7.47 (m, 1 H, p-H-Ph), 7.53 (m, 2 H, m-H-Ph), 8.67 (m, 2 H, o-H-
Ph).
13C NMR (100.6 MHz, CDCl3): d = 16.55 (CH3-8), 23.19 and 25.02
(CH2), 26.20 (CH3-2), 30.34 (CH2), 69.10 (CH2O), 82.29 (OCH),
128.09 (C-5), 128.53 (m-CH-Ph), 129.52 (o-CH-Ph), 130.25 (p-
CH-Ph), 136.18 (i-C-Ph), 152.70 (C-6), 153.18 (C-8), 154.04 (C-4),
160.99 (C-2).
EI MS: m/z (%) = 182 (100, M+), 147 (13), 106 (6).
EI-HRMS: m/z calcd for C7H7ClN4: 182.0359; found: 182.0363.
Anal. Calcd for C7H7ClN4 (182.6): C, 46.04; H, 3.86; N, 30.68.
Found: C, 45.69; H, 3.83; N, 30.36.
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Synthesis of 2,6,8-Trisubstituted Purine Bases
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2,6,8-Trimethylpurine (2bbb)
13C NMR (100.6 MHz, CDCl3 + MeOD): d = 14.93 (CH3-8), 25.34
(CH3-2), 128.47 (m-CH-Ph), 129.45 (p-CH-Ph), 130.43 (o-CH-Ph),
135.60 (i-C-Ph), 152.92 (C-6), 153.65 (C-8), 160.40 (C-2). Note: C-
4 and C-5 signals did not appear.
Colorless crystals from EtOAc–heptane; mp 209–211 °C (Lit.24 mp
220–222 °C).
1H NMR (400 MHz, CDCl3 + MeOD): d = 2.63 (s, 3 H, CH3-8),
2.73 (s, 3 H, CH3-2), 2.76 (s, 3 H, CH3-6).
EI-MS: m/z (%) = 224 (100, M+), 183 (58).
13C NMR (100.6 MHz, CDCl3 + MeOD): d = 14.90 (CH3-8), 18.97
(CH3-6), 25.08 (CH3-2), 130.72 (C-5), 152.46 (C-4), 152.88 (C-8),
156.71 (C-6), 160.29 (C-2).
EI-HRMS: m/z calcd for C13H12N4: 224.1062; found: 224.1069.
Anal. Calcd for C13H12N4 (224.3): C, 69.62; H, 5.39; N, 24.98.
Found: C, 69.25; H, 5.33; N, 24.77.
EI-MS: m/z (%) = 162 (100, M+), 147 (5), 121 (7).
6,8-Dimethyl-2-phenylpurine (2cbb)
Colorless crystals from EtOAc–heptane; mp 258–262 °C (dec.).
EI-HRMS: m/z calcd for C8H10N4: 162.0905; found: 162.0902.
Anal. Calcd for C8H10N4 (162.2): C, 59.24; H, 6.21; N, 34.54.
Found: C, 58.89; H, 6.14; N, 34.22.
1H NMR (500 MHz, CDCl3 + MeOD): d = 2.60 (s, 3 H, CH3-8),
2.87 (br s, 3 H, CH3-6), 7.42–7.53 (m, 3 H, m- and p-H-Ph), 8.35 (br
m, 2 H, o-H-Ph).
13C NMR (125.7 MHz, CDCl3 + MeOD): d = 13.96 (CH3-8), 19.48
(CH3-6), 128.03 (m-CH-Ph), 128.46 (o-CH-Ph), 129.76 (p-CH-Ph),
131.62 (C-5), 138.24 (i-C-Ph), 153.40 (C-8), 157.20 (C-6), 158.36
(C-2). Note: C-4 signal did not appear.
2,8-Dichloro-6-phenylpurine (2aca)
Colorless crystals from EtOAc–heptane; mp 260–262 °C.
1H NMR (400 MHz, DMSO-d6): d = 7.55–7.67 (m, 3 H, m- and p-
H-Ph), 8.59 (br m, 2 H, o-H-Ph), ca. 14.80 (br s, 1 H, NH).
13C NMR (100.6 MHz, DMSO-d6): d = 129.07 (m-CH-Ph), 129.40
(o-CH-Ph), 131.97 (p-CH-Ph), 133.98 (i-C-Ph), 152.83 (C-6).
Note: C-2, C-4, C-5 and C-8 signals did not appear.
EI-MS: m/z (%) = 224 (100, M+), 209 (5), 183 (6).
EI-HRMS: m/z calcd for C13H12N4: 224.1062; found: 224.1069.
EI-MS: m/z (%) = 264 (100, M+), 229 (72).
Anal. Calcd for C13H12N4 (224.3): C, 69.62; H, 5.39; N, 24.98.
Found: C, 69.23; H, 5.45; N, 24.95.
EI-HRMS: m/z calcd for C11H6Cl2N4: 263.9970; found: 263.9987.
Anal. Calcd for C11H6Cl2N4 (264.0): C, 49.84; H, 2.28; N, 21.13.
Found: C, 49.48; H, 2.21; N, 20.82.
2,6-Diphenyl-8-methylpurine (2ccb)
Colorless crystals from EtOAc–heptane; mp 229–230 °C.
1H NMR (400 MHz, CDCl3 + MeOD): d = 2.63 (s, 3 H, CH3-8),
7.45–7.63 (m, 6 H, m- and p-H-Ph), 8.52 (m, 2 H, o-H-Ph-2), 8.84
(br m, 2 H, o-H-Ph-6).
13C NMR (100.6 MHz, CDCl3 + MeOD): d = 13.99 (CH3-8),
128.06, 128.46, 128.50, 129.58, 129.85 and 130.55 (CH-Ph),
136.12 (i-C-Ph-6), 138.38 (i-C-Ph-2), 152.66 (C-6), 153.99 (C-8),
155.08 (C-4), 157.90 (C-2). Note: C-5 signal did not appear.
2,6,8-Triphenylpurine (2ccc)
Colorless crystals from EtOAc–heptane; mp 212–214 °C.
1H NMR (400 MHz, CDCl3 + MeOD): d = 7.35–7.65 (m, 9 H, m-
and p-H-Ph), 8.10 (m, 2 H, o-H-Ph-8), 8.52 (m, 2 H, o-H-Ph-2),
9.06 (m, 2 H, o-H-Ph-6).
13C NMR (100.6 MHz, CDCl3 + MeOD): d = 127.06, 128.18,
128.47 and 128.83 (CH-Ph), 128.87 (i-C-Ph-8), 129.91, 129.94,
130.77 and 130.89 (CH-Ph), 136.16 (i-C-Ph-6), 138.37 (i-C-Ph-2),
153.23 (C-6), 153.63 (C-8), 155.53 (C-4), 158.26 (C-2). Note: C-5
signal did not appear.
EI-MS: m/z (%) = 286 (100, M+), 245 (17), 183 (19).
EI-HRMS: m/z calcd for C18H14N4: 286.1218; found: 286.1212.
Anal. Calcd for C18H14N4 (286.3): C, 75.50; H, 4.94; N, 19.57.
Found: C, 75.12; H, 4.89; N, 19.47.
EI-MS: m/z (%) = 348 (100, M+), 244 (11), 174 (6), 115 (11).
EI-HRMS: m/z calcd for C23H16N4: 348.1375; found: 348.1376.
Anal. calcd for C23H16N4 (348.4): C, 79.29; H, 4.63; N, 16.08.
Found: C, 78.96; H, 4.55; N, 15.79.
Acknowledgment
This work is part of research project Z4 055 905. It was supported
by the Grant Agency of the Academy of Sciences of the Czech Re-
public (grant No. B4055201) and by Sumika Fine Chemicals, Co.
Ltd. (Osaka, Japan). The authors also thank Mrs. Kamila Havlíková
for technical assistance and Dr. Ivan Votruba for cytostatic activity
screening.
2-Chloro-8-methyl-6-phenylpurine (2acb)
Colorless crystals from EtOAc–heptane; mp >290 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.60 (s, 3 H, CH3-8), 7.53–7.64
(m, 3 H, m- and p-H-Ph), 8.66 (br m, 2 H, o-H-Ph-2), ca. 13.60 (br
s, 1 H, NH).
13C NMR (100.6 MHz, DMSO-d6): d = 15.41 (CH3-8), 128.92 (m-
CH-Ph), 129.34 (o-CH-Ph), 131.45 (p-CH-Ph), 134.67 (i-C-Ph),
151.85 (C-2), 156.31 (C-6), 156.57 (C-8). Note: C-4 and C-5 sig-
nals did not appear.
References
(1) (a) Montgomery, J. A.; Hewson, K. J. Med. Chem. 1968, 11,
48. (b) Parker, W. B.; King, S. A.; Allan, P. W.; Bennett, L.
L. Jr.; Secrist, J. A.; Montgomery, J. A.; Gilbert, K. S.;
Waud, W. R.; Wells, A. H.; Gillespie, G. Y.; Sorscher, E. J.
Hum. Gene Ther. 1997, 8, 1637. (c) Parker, W. B.; Allan, P.
W.; Shaddix, S. C.; Rose, L. M.; Speegle, H. F.; Gillespie,
G. Y.; Bennett, L. L. Jr. Biochem. Pharmacol. 1998, 55,
1673. (d) Hassan, A. E. A.; Abou-Elkair, R. A. I.;
EI-MS: m/z (%) = 244 (100, M+), 230 (10), 209 (60), 168 (12).
EI-HRMS: m/z calcd for C12H9ClN4: 244.0516; found: 244.0519.
Anal. Calcd for C12H9ClN4 (244.7): C, 58.90; H, 3.71; N, 22.90.
Found: C, 58.59; H, 3.60; N, 22.62.
2,8-Dimethyl-6-phenylpurine (2bcb)
Colorless crystals from EtOAc–heptane; mp 285–288 °C (dec.).
Montgomery, J. A.; Secrist, J. A. III Nucleosides,
Nucleotides, Nucleic Acids 2000, 19, 1123.
1H NMR (400 MHz, CDCl3 +MeOD): d = 2.67 (s, 3 H, CH3-8), 2.83
(s, 3 H, CH3-2), 7.46–7.60 (m, 3 H, m- and p-H-Ph), 8.55 (br m, 2
H, o-H-Ph).
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PAPER
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