The Suzuki-Miyaura cross-coupling reactions of 2-, 6- or 8-halopurines with boronic acids leading to 2-, 6- or 8-aryl- and -alkenylpurine derivatives

Article abstract of DOI:10.1055/s-2001-16765

The Suzuki-Miyaura cross-coupling reactions of 9-benzyl-6-chloropurine, 9- or 3-benzyl-8-bromoadenine and 2,6-dihalopurines with boronic acids gave the corresponding 6-, 8- or 2-aryl- or -alkenylpurines in good yields. Anhydrous conditions in toluene were

Full text of DOI:10.1055/s-2001-16765

1704
PAPER
The Suzuki–Miyaura Cross-Coupling Reactions of 2-, 6- or 8-Halopurines
with Boronic Acids Leading to 2-, 6- or 8-Aryl- and -Alkenylpurine Derivatives
Synthesis of
Aryl- and
a
Alkenylpu
r
rines tina Havelková,a Dalimil Dvo ák,*a Michal Hocek*b
a
Department of Organic Chemistry, Prague Institute of Chemical Technology, 16628 Prague 6, Czech Republic
Fax +420(2)24354288; E-mail: dvorakd@vscht.cz
b
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague 6, Czech Republic
Fax +420(2)3111271; E-mail: hocek@uochb.cas.cz
Received 25 April 2001; revised 14 May 2001
introduction of simple alkyl groups,11,13 while cuprates are
superior for sec- and tert-alkyl14, alkynyl15 and
perfluoroalkyl11,16 groups. Our recent alternative
method17 consisting in the use of the Suzuki–Miyaura
Abstract: The Suzuki–Miyaura cross-coupling reactions of 9-ben-
zyl-6-chloropurine, 9- or 3-benzyl-8-bromoadenine and 2,6-diha-
lopurines with boronic acids gave the corresponding 6-, 8- or 2-aryl-
or -alkenylpurines in good yields. Anhydrous conditions in toluene
were superior for coupling of electron-rich boronic acids, while cross-coupling reactions of 6-halopurines with boronic
aqueous DME was used for electron-poor arylboronic acids as well
acids is applicable for the introduction of aryl and alkenyl
as for alkenylboronic acids. A good regioselectivity was observed
groups and overcomes most of the drawback of the previ-
for the coupling of 2,6-dihalopurines: 9-benzyl-2,6-dichloropurine
ous methods: many boronic acids are commercially avail-
reacted with one equivalent of phenyl boronic acid to give 9-benzyl-
able and inexpensive, they are non-toxic and they tolerate
2-chloro-6-phenylpurine, while an analogous reaction of 9-benzyl-
the presence of some unprotected functional groups. Since
our preliminary communication,17 this method has been
successfully applied for the synthesis of 6-arylpurine
bases and nucleosides5 as well as acyclic nucleotide
analogues11 and a significant cytostatic activity5 was
found in some 6-arylpurine ribonucleosides. In this full
paper we report in detail on the methodology of Suzuki–
Miyaura cross-coupling reactions of 2, 6 and 8-halopu-
rines with diverse types of aryl- and alkenylboronic acids
as well as on regioselectivity of coupling with 2,6-diha-
lopurines.
In our preliminary communication17 we reported on the
cross-coupling reactions of 6-halopurines with boronic
acids. Optimization of the procedure (catalytic systems,
bases, solvents and conditions) revealed the following re-
sults: i) Pd(PPh3)4 turned out to be the superior catalyst
[compared to other tested systems: Pd(dba)2/P(o-tol)3,
Pd(dba)2/AsPh3, PdCl2(PPh3)2]; ii) the use of potassium
carbonate as base resulted in very efficient coupling
[while other bases, i.e. Na2CO3, Cs2CO3, EtN(i-Pr)2,
NaOMe, did not give any reaction]; iii) the reactions are
significantly affected by the choice of solvent: while the
coupling of 7- or 9-benzyl-6-chloro- as well as of 9-ben-
zyl-6-iodopurine with electron rich arylboronic acids pro-
ceeds smoothly under anhydrous conditions [Method A:
100 °C, Pd(PPh3)4 (2.5–5 mol%), K2CO3/toluene at 100
°C], electron deficient arylboronic acids and alkenylbor-
onic acids required aqueous conditions in DME [Method
B: 85 °C, Pd(PPh3)4 (2.5–5 mol%), K2CO3/DME–H2O].
6-chloro-2-iodopurine gave selectively 9-benzyl-6-chloro-2-phe-
nylpurine.
Key words: purines, nucleobases, boronic acids, cross-coupling,
palladium
Purines bearing carbon substituents in positions 2, 6 or 8
possess a broad spectrum of biological activity. Thus 6-
methylpurine is highly cytotoxic,1 while 2-alkynylade-
nosines are an important class of adenosine receptors ag-
onists.2 Recently, a cytokinin activity of 6-(arylalkynyl)-,
6-(arylalkenyl)- and 6-(arylalkyl)purines,3 a cytostatic ac-
tivity of 6-(trifluoromethyl)purine riboside4 and of 6-
arylpurine ribonucleosides,5 a corticotropin-releasing hor-
mone antagonist activity of some 2,8,9-trisubstituted-6-
arylpurines6 and an antimycobacterial activity of 9-ben-
zyl-6-arylpurines7 were also reported.
Cross-coupling reactions of halopurines with organome-
tallics is an efficient approach for the preparation of pu-
rines bearing carbon substituents in the positions 2, 6 or 8.
Diverse types of organometallics have been used and each
type turned out to be superior for introduction of different
types of C-substituents. Thus Ni-catalyzed coupling reac-
tions of aryl- and alkylmagnesium halides with 6-halopu-
rines were used for the preparation of 6-aryl- and 6-
alkylpurines8. Pd-catalyzed cross-couplings of halopur-
ines with organostannanes were used for the introduction
of aryl, hetaryl, alkenyl or (less efficiently) alkyl groups9–
11 to positions 2, 6 and/or 8. Organozinc reagents, the most
versatile organometallics, were successfully used for the
attachment of alkyl, alkenyl, aryl or hetaryl groups10–12
into position 6. Trialkylaluminums could be used for the
Thus the reactions (Scheme 1) of 9-benzyl-6-chloropu-
rine (1a) with phenylboronic acids bearing electron-do-
nor, electroneutral and slightly electron-withdrawing
substituents under anhydrous conditions (Method A) gave
the corresponding 6-phenylpurines 2 in good yields
(Table 1, entries 1,2,5,6,12), the reactions with electron-
deficient phenylboronic acids, thienyl-, alkenyl- and alky-
lboronic acids gave only yields from moderate to very
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,MM,1704,1710,ftx,en;Z04401ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of Aryl- and Alkenylpurines
1705
NH2
N
Cl
N
R
N
RB(OH)2, Pd(PPh3)4
A: K2CO3, toluene, 100°C or
B: aq. K2CO3, DME, 85°C
NH2
NH2
PhCH2Cl,
K2CO3,
DMF
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
Br
+
Br
N
H
N
N
N
CH2Ph
CH2Ph
2a-2m
1
CH2Ph
3a
3b
CH2Ph
Scheme 1
RB(OH)2, Pd(PPh3)4
A: K2CO3, toluene, 100°C or
B: aq. K2CO3, DME, 85°C
low. On the other hand, when using aqueous conditions
(Method B), the yields of the reactions with electron-defi-
cient phenylboronic acids (nitro-, formyl- and acetylphe-
nyl), thienyl-, alkenylboronic acids were substantially
increased (Table 1, entries 3,4,7,8,10,11). The formyl de-
rivative 2g was accompanied by some difficult to isolate
NH2
NH2
N
N
N
N
R
R
N
N
N
N
CH2Ph
5a-5d
4a-4d
CH2Ph
impurities, probably as a result of instability of formyl de- Scheme 2
rivatives to aqueous base. Surprisingly, also 3-aminophe-
nylboronic acid afforded better results using Method B
(Table 1, entry 9). The use of aqueous conditions (Method
B) seems to be more versatile for introduction of various
types of substituents. On the other hand, the use of basic
aqueous solutions of K2CO3 is often incompatible with re-
active or labile functional and/or protective groups (e.g.
acyl protection of nucleosides).
Furthermore, the methodology of the Suzuki–Miyaura
cross-coupling reaction has been extended to the substitu-
tion at other positions of the purine ring. Thus 9-benzyl-
(3a) and 3-benzyl-8-bromoadenine (3b), the model com-
pounds for the study of reactivity of adenine derivatives
were prepared by benzylation of 8-bromoadenine18 with
benzyl chloride in the presence of K2CO3 in DMF at 120
°C in 60:40 ratio (Scheme 2). The compounds were sepa-
rated chromatographically and their structure was unam-
biguously identified on the basis 1H NMR, 13C NMR and
HMBC. The reactivity of 9-benzyl-8-bromoadenine (3a)
parallels that of 9-benzyl-6-chloropurine (1a). Phenylbo-
ronic acid coupled almost quantitatively to give the 8-phe-
nyladenine 4a no matter what method was used, while
Table 1 Reaction of 9-Benzyl-6-chloropurine (1a) with RB(OH)2
(1.2 equiv)
Entry Product
R
Reaction Methoda Yield
Time (h)
(%)
1
2a
C6H5
24
7
A
B
95
95
2
3
2b
2c
4-FC6H4
24
A
89
Table 2 Reaction of 9-benzyl-8-bromoadenine (3a) and 3-benzyl-
8-bromoadenine (3b) with RB(OH)2 (1.2 equiv)
(E)-C6H5CH=CH
24b
7.5
A
B
14
76
Entry Starting
Compound
Product
4a
R
Methoda Yield
(%)
4
2d
3-NO2C6H4
48b
7
A
B
19
66
1
2
3
4
5
6
7
8
3a
C6H5
4-FC6H4
A
B
96
96
5
6
2e
2f
2g
2h
2i
3-MeOC6H4
2-MeC6H4
4
24
23
24
24b
A
A
B
B
B
62
86
61
73
78
3a
3a
3a
3b
3b
3b
3b
4b
A
B
63
94
7
4-CHOC6H4
4-CH3COC6H4
3-NH2C6H4
2-thienyl
4c
(E)-
C6H5CH=CH
A
B
44
68
8
9
4d
3-NO2C6H4
C6H5
A
B
36
76
10
2j
24b
7b
A
B
39
87
5a
A
B
92
66
11
12
13
2k
2l
(E)-C5H11CH=CH 24b
A
B
18
98
8
5b
4-FC6H4
A
B
98
75
C4H9
C6F5
24b
24
A
B
18
0
5c
(E)-
C6H5CH=CH
A
B
41
77
2m
24
24
A
B
0
0
5d
3-NO2C6H4
A
B
95
89
a Method A: 2.5 mol% Pd(PPh3)4, K2CO3, toluene, 100 °C; Method
B: 2.5 mol% Pd(PPh3)4, 2 M aq K2CO3, DME, 85 °C.
b Unreacted 1a remains in the reaction mixture.
a Method A: 2.5 mol% Pd(PPh3)4, K2CO3, toluene–DMF 8:2,
100 °C, 24 h; Method B: 2.5 mol% Pd(PPh3)4, 2 M aq K2CO3,
DME, 85 °C, 24 h.
Synthesis 2001, No. 11, 1704–1710 ISSN 0039-7881 © Thieme Stuttgart · New York

1706
M. Havelková et al.
PAPER
styrylboronic and an electron-poor 3-nitrophenylboronic
acids afforded better yields of the corresponding 8-substi-
tuted adenines 4c and 4d when aqueous conditions (Meth-
od B) were used (Scheme 2, Table 2, entries 1,3,4).
Somewhat surprisingly also 4-fluorophenylboronic acid
gave better results using aqueous conditions (Table 2, en-
try 2). 3-Benzyl-8-bromoadenine (3b) reacted smoothly
with phenyl- and 4-fluorophenylboronic acids, giving the
corresponding 3-benzyl-8-phenyladenines 5a and 5b in
somewhat better yields under anhydrous conditions. Also
with styrylboronic acid the starting purine derivative 3b
was consumed in less than 24 hours. The yield of 5c was
in this case better with aqueous procedure (Table 2, entry
7). 3-Nitrophenylboronic acid reacted with 3-benzyl-8-
bromoadenine (3b) sluggishly under both aqueous and an-
hydrous conditions. In both cases however, high yields of
5d were achieved after prolonged reaction time (Table 2,
entry 8).
Ph
N
Cl
N
N
N
PhB(OH)2 (1 eq.)
77%
N
N
N
N
N
N
Cl
Cl
CH2Ph
CH2Ph
6
7
84%
Ph
N
PhB(OH)2 (3 eq.)
N
N
Ph
CH2Ph
PhB(OH)2 (3 eq.)
8
88%
Cl
Cl
N
N
N
N
N
(1 eq.)
PhB(OH)2
81%
I
N
Ph
N
CH2Ph
CH2Ph
9
10
Scheme 3
The Stille cross-coupling reactions of 9-benzyl-2,6-diha-
lopurines with organostannanes have been reported9i to
proceed with a good regioselectivity: the reaction with
one equivalent of organostannane gave the substitution in
the position 6, while the use of 6-chloro-2-iodopurine re-
sulted in the preferential substitution in the position 2.
Therefore we have studied the Suzuki–Miyaura coupling
reactions of 2,6-dihalopurines with phenylboronic acid
and the results were analogous. The reaction of 9-benzyl-
2,6-dichloropurine (6) with one equivalent of phenylbor-
onic acid under anhydrous conditions afforded smoothly
and selectively 9-benzyl-2-chloro-6-phenylpurine (7) in
77% yield, while with excess (3 equiv) of the phenylbo-
ronic acid both chlorine atoms were substituted to give 9-
benzyl-2,6-diphenylpurine (8) in 84% yield (Scheme 3).
On the other hand, the reaction of 9-benzyl-6-chloro-2-io-
or coupling reactions. This opens up an avenue to the syn-
thesis of a variety (a library) of potentially biologically ac-
tive purine derivatives bearing two different substituents
in positions 2 and 6. This study is now under way.
Melting points were determined on a Kofler block and are uncor-
rected. NMR spectra were measured on a Varian Gemini 300 (1H,
300.07 MHz; 13C, 75.46 MHz), a Bruker AMX3 400 (1H, 400.13
MHz and 13C, 100.62 MHz) or a Bruker DRX 500 Avance (1H,
500.13 MHz and 13C, 125.77 MHz) spectrometer at 298 K. Unam-
biguous assignment of the NMR signals is based on 13C{1H}, 13C
APT, COSY and 13C HMBC spectra. IR spectra were recorded on
Nicolet 750 FT-IR. Mass spectra were measured on ZAB-SEQ (VG
Analytical) The solvents were dried and degassed by standard pro-
cedures, silica gel (ICN SiliTech, 32-63) was used for column chro-
matography. 9-Benzyl-6-chloropurine10b (1), 9-benzyl-2,6-di-
dopurine (9) with one equivalent of the phenylboronic chloropurine9i (6) and 9-benzyl-6-chloro-2-iodopurine9i (9) were
prepared by the reported procedures.
acid under anhydrous conditions afforded selectively 9-
benzyl-6-chloro-2-phenylpurine (10) in 81% yield, while
the reaction with an excess of phenylboronic acid gave the
2,6-diphenylpurine 8 in 88% yield (Scheme 3). Although
Coupling of 9-Benzyl-6-chloropurine (1) with Boronic Acids;
General Procedure
Method A: Toluene (5 mL) was added through a septum to an argon
the reactivity of the iodine atom in the position 2 is appar-
ently higher that that of chlorine, the reactions of the 6-
chloro-2-iodopurine derivative 9 were substantially slow-
er (prolonged reaction times were required for completion
of the conversion) than the reactions of the 2,6-dichloro-
derivative 6 which is probably due to the fact that the leav-
ing iodide anion is more strongly complexed to palladium
thus slowing down the transmetallation with boric acid.
purged flask containing a 9-benzyl-6-chloropurine (1; 0.122 g, 0.5
mmol), boronic acid (0.75 mmol), anhyd K2CO3 (0.086 g, 0.625
mmol), Pd(PPh3)4 (0.014 g, 0.012 mmol) and the mixture was
stirred under argon at 100 °C until the reaction was completed
(TLC). The reaction mixture was cooled to r.t. and filtered through
Celite. The solvent was evaporated and the residue chromato-
graphed on silica gel (CHCl3–MeOH, 98:2). The crude product was
purified by crystallization from CH2Cl2–heptane.
Method B: The reaction under aqueous conditions was analogous,
except for the higher amount of K2CO3 (0.187 g, 1.35 mmol) togeth-
er with H2O (0.7 mL) in DME (5 mL) was used. The reaction mix-
ture was then stirred under argon at 85 °C. The workup was the
same as above.
In conclusion, we proved, that the Suzuki–Miyaura cross-
coupling reactions of halopurines with boronic acids is a
versatile, efficient and non-toxic alternative method for an
introduction of an aryl, hetaryl or alkenyl substituent into
positions 2, 6 or 8 of various purine derivatives. The ex-
cellent regioselectivity of the coupling reactions of 2,6-di-
halopurines allows, together with the previously known9i
regioselective Stille couplings, a selective and efficient
synthesis of 6-substituted 2-chloropurines or 2-substituted
6-chloropurines that could be used for further substitution
9-Benzyl-6-phenylpurine (2a)
Both Methods A and B afforded 95% yield; mp 124–126 °C (Lit.10b
mp 124–125 °C).
9-Benzyl-6-(4-fluorophenyl)purine (2b)
Yield: 89% (Method A), mp 127–129 °C.
Synthesis 2001, No. 11, 1704–1710 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Aryl- and Alkenylpurines
1707
1H NMR (300 MHz, CDCl3): = 5.48 (s, 2 H, CH2), 7.24 (m, 2 H,
ArH), 7.35 (m, 5 H, C6H5), 8.09 (s, 1 H, H-8 Pu), 8.86 (m, 2 H,
ArH), 9.03 (s, 1 H, H-2 Pu).
IR (CHCl3): = 2998, 1603, 1585, 1572, 1513, 1450, 1328 cm–1.
MS-EI: m/z (%) = 304 (M+, 100).
IR (CHCl3): = 3025, 3010, 1664, 1582, 1557, 1327, 1267 cm–1.
MS-EI: m/z (%) = 328 (M+, 69), 91 (100).
HRMS (EI): m/z Calcd for C20H16N4O 328.1324. Found: 328.1327.
Anal. Calcd for C20H16N4O (328.4): C, 73.15; H, 4.91; N, 17.06.
Found: C, 73.15; H, 5.23; N, 17.00.
HRMS (EI): m/z Calcd for C18H13FN4 304.1124. Found: 304.1119.
9-Benzyl-6-(3-aminophenyl)purine (2i)
Yield: 78% (Method B), mp 148–150 °C.
Anal. Calcd for C18H13FN4 (304.3): C, 71.04; H, 4.31; N, 18.41; F,
6.24. Found: C, 70.71; H, 4.75; N, 18.09; F, 6.33.
1H NMR (300 MHz, CDCl3): = 3.86 (s, 2 H, NH2), 5.48 (s, 2 H,
CH2), 6.85 (dd, J = 2.5, 7.9 Hz, 1 H, ArH), 7.35 (m, 6 H, C6H5 +
ArH), 8.09 (s, 1 H, H-8 Pu), 8.10 (m, 1 H, ArH), 8.22 (d, J = 7.7 Hz,
1 H, ArH), 9.04 (s, 1 H, H-2 Pu).
9-Benzyl-6-[(E)-styryl]purine (2c)
Yield: 14% (Method A), 82% (Method B); mp 127–129 °C (Lit.10b
mp 132–134 °C).
1H NMR (300 MHz, CDCl3): = 5.46 (s, 2 H, CH2), 7.37 (m, 8 H,
C6H5), 7.73 (m, 3 H, C6H5 + CH=CH), 8.05 (s, 1 H, H-8 Pu), 8.42
(d, J = 15.9 Hz, 2 H, CH=CH), 8.94 (s, 1 H, H-2 Pu).
IR (CHCl3): = 2997, 2927, 1621, 1582, 1571, 1327 cm–1.
MS (EI): m/z (%) = 301 (M+, 17), 91 (100).
Anal. Calcd for C18H15N5 (301.4): C, 71.74; H, 5.02; N, 23.24.
Found: C, 72.04; H, 5.50; N, 23.39.
9-Benzyl-6-(3-nitrophenyl)purine (2d)
Yield: 66% (Method B), 19% (Method A); mp 187–188 °C.
9-Benzyl-6-(2-thienyl)purine (2j)
1H NMR (300 MHz, CDCl3): = 5.51 (s, 2 H, CH2), 7.36 (m, 5 H,
C6H5), 7.73 (t, J = 8 Hz, 1 H, ArH), 8.16 (s, 1 H, H-8 Pu), 8.35 (m,
1 H, ArH), 9.10 (s, 1 H, H-2 Pu), 9.21 (m, 1 H, ArH), 9.75 (t, J = 2
Hz, 1 H, ArH).
Yield: 39% (Method A), 87% (Method B); mp 198–200 °C (Lit.10b
mp 198–200 °C).
9-Benzyl-6-((E)-hepten-1-yl)purine (2k)
Yield: 18% (Method A), 98% (Method B), mp 40–42 °C.
IR (CHCl3): = 3030, 3002, 1583, 1533, 1351 cm–1.
MS-EI: m/z (%) = 331 (M+, 15), 227 (100).
1H NMR (300 MHz, CDCl3): = 0.89 (m, 3 H, CH3), 1.36 (m, 4 H,
CH2), 1.57 (m, 2 H, CH2), 2.39 (dq, J = 7.1, 1.6 Hz, 2 H, CH2), 7.01
(dt, J = 15.9, 1.6 Hz, Pu-CH=CH), 7.23–7.40 (m, 5 H, C6H5), 7.63
(dt, J = 15.9, 7.1 Hz, Pu-CH=CH), 8.00 (s, 1 H, H-8 Pu), 8.89 (s, 1
H, H-2 Pu).
IR (CHCl3): = 2961, 2932, 1651, 1587, 1327 cm–1.
MS-EI: m/z (%) = 306 (M+, 49), 91 (100).
Anal. Calcd for C18H13N5O2 (331.3): C, 65.25; H, 3.95; N, 21.44.
Found: C, 65.25; H, 4.12; N, 21.17.
9-Benzyl-6-(3-methoxyphenyl)purine (2e)
Yield: 66% (Method A); mp 111–114 °C (Lit.10b mp 114–116 °C).
1H NMR (300 MHz, CDCl3): = 3.93 (s, 3 H, CH3), 5.49 (s, 2 H,
CH2), 7.08 (m, 1 H, ArH), 7.35 (m, 5 H, C6H5), 7.47 (t, J = 8 Hz, 1
H, ArH), 8.09 (s, 1 H, H-8 Pu), 8.36 (m, 1 H, ArH), 8.45 (m, 1 H,
ArH), 9.06 (s, 1 H, H-2 Pu).
HRMS (EI): m/z Calcd for C19H22N4 306.1896. Found: 306.1844.
9-Benzyl-6-butylpurine (2l)10b
Yield: 18% (Method A), oil.
9-Benzyl-6-(2-methylphenyl)purine (2f)
1H NMR (300 MHz, CDCl3): = 0.95 (t, J = 7.1 Hz, 3 H, CH3), 1.45
(m, 2 H, CH2), 1.88 (m, 2 H, CH2), 3.20 (t, J = 7.7 Hz, Pu-CH2), 5.43
(s, 2 H, CH2), 7.33 (m, 5 H, C6H5), 7.99 (s, 1 H, H-8 Pu), (s, 1 H, H-
2 Pu).
Yield: 89% (Method A); oil.
1H NMR (300 MHz, CDCl3): = 2.44 (s, 3 H, CH3), 5.49 (s, 2 H,
CH2), 7.35 (m, 8 H, C6H5 + ArH), 7.70 (m, 1 H, ArH), 8.06 (s, 1 H,
H-8 Pu), 9.08 (s, 1 H, H-2 Pu).
IR (CHCl3): = 2996, 1587, 1503, 1455, 1404, 1330 cm–1.
MS-EI: m/z (%) = 300 (M+, 28), 209 (100).
Benzylation of 8-Bromoadenine
A mixture of 8-bromoadenine (0.905 g, 4.23 mmol), K2CO3 (2.10
g, 14.8 mmol) and benzyl chloride (0.8 mL, 6.6 mmol) in DMF (40
mL) was heated to 120 °C for 9 h under argon. 1H NMR spectrum
of the crude reaction mixture showed formation of 3a and 3b in ap-
proximately 6:4 ratio. DMF was then evaporated in vacuum and the
residue chromatographed on silica gel (CHCl3–MeOH, 97:3) to
give 0.410 g of 9-benzyl-8-bromoadenine (3a) (more mobile) and
0.193 g of 3-benzyl-8-bromoadenine (3b) (less mobile). Analytical-
ly pure compounds were obtained by crystallization from EtOH.
HRMS (EI): m/z Calcd for C19H16N4 300.1374. Found: 300.1367.
Anal. Calcd for C19H16N4 (300.4): C, 75.98; H, 5.37; N, 18.65.
Found: C, 75.50; H, 5.48; N, 18.35.
9-Benzyl-6-(4-formylphenyl)purine (2g)
Yield: 61% (Method B), mp 161–164 °C.
1H NMR (300 MHz, CDCl3): = 5.51 (s, 2 H, CH2), 7.37 (m, 5 H,
C6H5), 8.06 (d, J = 8.2 Hz, 2 H, ArH), 8.16 (s, 1 H, H-8 Pu), 8.99 (s,
J = 8.2 Hz, 2 H, ArH), 9.11 (s, 1 H, H-2 Pu), 10.13 (s, 1 H, CHO).
IR (CHCl3): = 3024, 1706, 1583, 1561, 1328 cm–1.
MS (EI): m/z (%) = 314 (M+, 100).
9-Benzyl-8-bromoadenine (3a)
Yield: 32%, mp 226–227 °C.
1H NMR (500 MHz, DMSO-d6): = 5.35 (s, 2 H, CH2), 7.22 (d, 2
H, J = 7.1 Hz, C6H5), 7.29 (m, 1 H, C6H5), 7.34 (m, 2 H, C6H5), 7.45
(br s, 2 H, NH2), 8.16 (s, 1 H, H-2 Pu).
13C NMR (APT): = 46.6 (CH2), 119.0 (C-5), 126.5 (C-8), 127.1
(CH-Ph), 127.8 (CH-Ph), 128.7 (CH-Ph), 136.0 (C-Ph), 151.0 (C-
4), 153.1 (C-2), 154.8 (C-6).
HRMS (EI): m/z Calcd for C19H14N4O 314.1167 Found: 314.1161.
9-Benzyl-6-(4-acetylphenyl)purine (2h)
Yield: 73% (Method B), mp 137–139 °C.
1H NMR (300 MHz, CDCl3): = 2.67 (s, 3 H, CH3), 5.51 (s, 2 H,
CH2), 7.35 (m, 5 H, C6H5), 8.13 (d, J = 8.8 Hz, 2 H, ArH), 8.15 (s,
1 H, H-8 Pu), 8.91 (d, J = 8.8 Hz, 2 H, ArH), 9.10 (s, 1 H, H-2 Pu).
MS (EI): m/z (%) = 305 (M+, 17), 91 (100).
IR (KBr): = 3354, 3139, 1659, 1607, 1579, 1318, 1302 cm–1.
Synthesis 2001, No. 11, 1704–1710 ISSN 0039-7881 © Thieme Stuttgart · New York

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M. Havelková et al.
PAPER
Anal. Calcd for C12H10BrN5 (304.1): C, 47.39; H, 3.31; N, 23.03.
Found: C, 47.57; H, 3.62; N, 22.87.
1H NMR (300 MHz, DMSO-d6): = 5.62 (s, 2 H, CH2), 7.20–7.42
(m, 8 H, ArH), 7.48 (d, J = 15.9 Hz, 1 H, CH=CH), 7.70 (d, J = 7.1
Hz, ArH), 7.72 (d, J = 15.9 Hz, 1 H, CH=CH), 8.15 (s, 1 H, H-2 Pu).
3-Benzyl-8-bromoadenine (3b)
IR (KBr): = 3474, 3058, 1634, 1599, 1465, 1380, 1361 cm–1.
MS (EI): m/z (%) = 327 (M+, 64), 91 (100).
Yield: 15%; mp 239–240.5 °C (Lit.19 mp 206 °C).
1H NMR (400 MHz, DMSO-d6): = 5.47 (s, 2 H, CH2), 7.35 (m, 5
H, C6H5), 8.09 (br s, 1 H, NH2), 8.26 (br s, 1 H, NH2), 8.55 (s, 1 H,
H-2 Pu).
13C NMR (APT): = 52.0 (CH2), 121.5 (C-5), 127.8 (CH-Ph), 128.1
(CH-Ph), 128.7 (CH-Ph), 135.8 (C-Ph), 139.3 (C-8), 144.0 (C-2),
149.8 (C-4), 153.6 (C-6).
HRMS (EI): m/z Calcd 327.1483, found 327.1482.
Anal. Calcd for C20H17N5 (327.4): C, 73.37; H, 5.23; N, 21.39.
Found: C, 73.35; H, 5.22; N, 21.27.
9-Benzyl-8-(3-nitrophenyl)adenine (4d)
Yield: 36% (Method A), 76% (Method B); mp 178–179 °C.
1H NMR (300 MHz, DMSO-d6): = 5.58 (s, 2 H, CH2), 7.04 (m, 2
H, C6H5), 7.27 (m, 3 H, C6H5), 7.52 (br s, 2 H, NH2), 7.78 (m, 1 H,
ArH), 8.14 (m, 1 H, ArH), 8.23 (s, 1 H, H-2 Pu), 8.33 (m, 1 H, ArH),
8.49 (m, 1 H, ArH).
MS (EI ): m/z (%) = 305 (M+, 16), 91 (100).
IR (KBr): = 3442, 3088, 1665, 1620, 1455, 1432, 1242, 1219
cm–1.
Anal. Calcd for C12H10BrN5 (304.1): C, 47.39; H, 3.31; N, 23.03.
Found: C, 47.40; H, 3.37; N, 23.05.
MS (EI): m/z (%) = 346 (M+, 43), 91 (100).
IR (KBr): = 3140, 1641, 1601, 1535, 1352, 1300 cm–1.
Coupling of 9-Benzyl-8-bromoadenine (3a) and 3-Benzyl-8-
bromoadenine (3b) with Boronic acids; General Procedure
Method A: Toluene (5 mL) was added through a septum to an argon
purged flask containing a benzyl-8-bromoadenine (3a or 3b) (0.076
g, 0.25 mmol), boronic acid (0.375 mmol), anhyd K2CO3 (0.043 g,
0.312 mmol), Pd(PPh3)4 (0.007 g, 0.006 mmol) and the mixture was
stirred under argon at 100 °C until the reaction was completed
(TLC). The mixture was cooled to r.t. and filtered through Celite.
The solvent evaporated and chromatographed on silica gel [light pe-
troleum (bp 40–60 °C)–Et2O–acetone–MeOH, 50:30:17:3]. The
crude product was purified by crystallization from EtOAc–EtOH
(5:1).
Anal. Calcd for C18H14N6O2 (346.3): C, 62.42; H, 4.07; N, 24.26.
Found: C, 62.44; H, 4.06; N, 24.19.
3-Benzyl-8-phenyladenine (5a)
Yield: 92% (Method A), 66% (Method B), mp 254–256 °C.
1H NMR (400 MHz, DMSO-d6): = 5.57 (s, 2 H, CH2), 7.25–7.48
(m, 6 H, ArH), 7.53 (d, J = 7.2 Hz, 2 H, ArH), 7.90 (s, 2 H, NH2),
8.23 (d, J = 7.2 Hz, 2 H, ArH), 8.52 (s, 1 H, H-2 Pu).
IR (KBr): = 3437, 3133, 1662, 1620, 1599, 1439,1259 cm–1.
MS (EI): m/z (%) = 301 (M+, 93), 91 (100).
Method B: The reaction under aqueous conditions was analogous,
except that a higher amount of K2CO3 (0.093 g, 0.675 mmol) to-
gether with H2O (0.34 mL) and DME (2 mL) were used. The reac-
tion mixture was then stirred under argon at 85 °C. The workup was
the same as above.
Anal. Calcd for C18H15N5 (301.3): C, 71.74; H, 5.02; N, 23.24.
Found: C, 71.47; H, 5.46; N, 22.92.
3-Benzyl-8-(4-fluorophenyl)adenine (5b)
Yield: 98% (Method A), 75% (Method B), mp 236–238 °C.
1H NMR (400 MHz, DMSO-d6): = 5.59 (s, 2 H, CH2), 7.31–7.39
(m, 5 H, C6H5), 7.52 (d, J = 7.2 Hz, 2 H, ArH), 7.94 (br s, 2 H, NH2),
8.24 (dd, J = 5.5, 8.8 Hz, 2 H, ArH), 8.54 (s, 1 H, H-2 Pu).
IR (KBr): = 3307, 3162, 1648, 1623, 1523, 1449, 1217 cm–1.
MS (EI): m/z (%) = 319 (M+, 36), 91 (100).
9-Benzyl-8-phenyladenine (4a)
Yield: 96% (both Methods A and B); mp 102–104 °C.
1H NMR (300 MHz, DMSO-d6): = 5.49 (s, 2 H, CH2), 6.97 (m, 2
H, ArH), 7.25 (m, 3 H, ArH), 7.39 (br s, 2 H, NH2), 7.50 (m, 3 H,
ArH), 7.67 (m, 2 H, ArH), 8.18 (s, 1 H, H-2 Pu).
MS (EI): m/z (%) = 301 (M+, 39), 91 (100).
HRMS (EI): m/z Calcd 319.1233, found 319.1218.
HRMS (EI): m/z Calcd for C18H15N5 301.1327. Found: 301.1307.
Anal. Calcd for C18H14N5F H2O (337.4): C, 64.09; H, 4.78; N,
20.76. Found: C, 63.83; H, 4.81; N, 20.27.
IR (KBr): = 3318, 3140, 1656, 1597, 1475, 1372, 1331, 1298
cm–1.
3-Benzyl-8-[(E)-styryl]adenine (5c)
Yield: 41% (Method A), 77% (Method B); mp 264–266 °C.
1H NMR (300 MHz, DMSO-d6): = 5.55 (s, 2 H, CH2), 7.15–7.65
Anal. Calcd for C18H15N5 0.5H2O (310.4): C, 69.66; H, 5.20; N,
22.38. Found: C, 69.43; H, 5.43; N, 22.38.
(m, 12 H, C6H5 + CH=CH), 7.93 (s, 2 H, NH2), 8.49 (s, 1 H, H-2 Pu).
9-Benzyl-8-(4-fluorophenyl)adenine (4b)
Yield: 63% (Method A), 94% (Method B); mp 164–165 °C.
1H NMR (300 MHz, DMSO-d6): = 5.49 (s, 2 H, CH2), 6.97 (m, 2
H, C6H5), 7.25 (m, 3 H, C6H5), 7.34 (m, 2 H, ArH), 7.39 (br s, 2 H,
NH2), 7.72 (m, 2 H, ArH), 8.19 (s, 1 H, H-2 Pu).
IR (KBr): = 3251, 3059, 1678, 1621, 1445, 1312, 1229 cm–1.
MS (EI): m/z (%) = 327 (M+, 45), 91 (100).
HRMS (EI): m/z Calcd 327.1483, found 327.1494.
IR (KBr): = 3421, 3326, 3153, 1659, 1607, 1575, 1476, 1454,
1374, 1333, 1302, 1293 cm–1.
3-Benzyl-8-(3-nitrophenyl)adenine (5d)
Yield: 95% (Method A), 89% (Method B); mp 263–264 °C.
MS (EI) m/z (%) = 319 (M+, 61), 91 (100).
1H NMR (400 MHz, DMSO-d6): = 5.59 (s, 2 H, CH2), 7.28–7.40
(m, 3 H, C6H5), 7.52 (d, J = 7.4 Hz, 2 H, C6H5), 7.73 (t, J = 7.8 Hz,
1 H, ArH), 8.18 (br s, 2 H, NH2), 8.18 (d, J = 8 Hz, 1 H, ArH), 8.58
(s, 1 H, ArH), 8.60 (d, J = 7.7 Hz, 1 H, ArH), 9.00 (s, 1 H, H-2 Pu).
HRMS (EI): m/z Calcd 319.1233, found 319.1193.
Anal. Calcd for C18H14N5F H2O (337.4): C, 64.09; H, 4.78; N,
20.76. Found: C, 64.57; H, 4.71; N, 20.91.
IR (KBr): = 3436, 3154, 1659, 1610, 1532, 1350 cm–1.
MS (EI): m/z (%) = 346 (M+, 35%), 91 (100).
9-Benzyl-8-[(E)-styryl]adenine (4c)
Yield: 44% (Method A), 68% (Method B); mp 216–218 °C.
Synthesis 2001, No. 11, 1704–1710 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Aryl- and Alkenylpurines
1709
Anal. Calcd for C18H14N6O2 (346.3): C, 62.42; H, 4.07; N, 24.26.
Found: C, 62.19; H, 4.31; N, 23.96.
Acknowledgements
This work is a part of the research project Z4 055 905. It was further
supported by the Grant Agency of the Czech Republic (grant No.
203/00/0036) and by Prague Institute of Chemical Technology
(grant No. 110010015).
Cross-Coupling Reactions of 2,6-Dihalopurines with
Phenylboronic Acid; General Procedure
Toluene (5 mL) was added through a septum to an argon purged
flask containing a 2,6-dichloropurine (6; 138 mg, 0.5 mmol) or 2-
iodo-6-chloropurine (9; 0.186 g, 0.5 mmol), phenylboronic acid
(0.065 g, 0.54 mmol or 0.183 g, 1.5 mmol), K2CO3 (0.100 g, 0.72
mmol) and Pd(PPh3)4 (0.03 g, 0.026 mmol) and the mixture was
stirred at 100 °C for 8–20 h. After completion of the reaction (TLC
monitoring), the solvent was evaporated and the residue was chro-
matographed on a silica gel column [50 g, light petroleum (bp 40–
60 °C)–EtOAc, 2:1 to 1:1]. The crude products were crystallized
from CH2Cl2–heptane.
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9-Benzyl-2-chloro-6-phenylpurine (7)
Prepared from 6 with 1 equivalent of PhB(OH)2 (reaction time 8 h)
in 77% yield. Colorless needles; mp 143–146 °C (Lit.9i mp 150–151
°C).
1H NMR (500 MHz, CDCl3): = 5.44 (s, 2 H, CH2Ph), 7.32–7.40
(m, 5 H, C6H5), 7.54–7.57 (m, 3 H, C6H5), 8.04 (s, 1 H, H-8 Pu),
8.78–8.81 (m, 2 H, C6H5).
13C NMR (100 MHz, CDCl3): = 47.4 (CH2), 128.0, 128.7, 128.7,
129.2, 130.0 and 131.7 (CH-Ph), ca 130 (very weak, C-5), 134.5
and 134.7 (C-Ph), 144.6 (C-8), 154.2, 154.4 and 156.7 (C-2, C-4
and C-6).
FAB-MS: m/z (%) = 321 (46) [M + H], 91 (100).
Anal. Calcd for C18H13ClN4 (320.8): C, 67.40; H, 4.08; N, 17.47.
Found: C, 67.10; H, 4.13; N, 17.21.
(9) (a) Nair, V.; Turner, G. A.; Chamberlain, S. D. J. Am. Chem.
Soc. 1987, 109, 7223. (b) Nair, V.; Buenger, G. S. J. Am.
Chem. Soc. 1989, 111, 8502. (c) Nair, V.; Purdy, D. F.
Tetrahedron 1991, 47, 365. (d) Mamos, P.; Van Aerschot,
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1992, 33, 2413. (e) Van Aerschot, A. A.; Mamos, P.;
Weyns, N. J.; Ikeda, S.; De Clercq, E.; Herdewijn, P. J. Med.
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K. Tetrahedron Lett. 1990, 31, 5877. (h) Gundersen, L. L.
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9-Benzyl-6-chloro-2-phenylpurine (10)
Prepared from 9 with 1 equivalent of PhB(OH)2 (reaction time 20 h)
in 81% yield. Colorless needles; mp 143–144 °C (Lit.9i mp 158–160
°C).
1H NMR (500 MHz, CDCl3): = 5.48 (s, 2 H, CH2Ph), 7.37 (br s, 5
H, C6H5), 7.48–7.51 (m, 3 H, C6H5), 8.03 (s, 1 H, H-8 Pu), 8.52–
8.54 (m, 2 H, C6H5).
13C NMR (100 MHz, CDCl3): = 47.8 (CH2), 128.1, 128.5, 128.6,
128.8, 129.22 and 131.8 (CH-Ph), 129.9 (C-5), 134.9 and 136.6 (C-
Ph), 144.8 (C-8), 151.0, 152.6 and 159.4 (C-2, C-4 and C-6).
Gundersen, L. L.; Rise, F. Tetrahedron 1996, 52, 5625.
(10) (a) Gundersen, L. L.; Langli, G.; Rise, F. Tetrahedron Lett.
1995, 36, 1945. (b) Gundersen, L. L.; Bakkestuen, A. K.;
Aasen, A. J.; Øveras, H.; Rise, F. Tetrahedron 1994, 50,
9743. (c) Nolsøe, J. M. J.; Gundersen, L. L.; Rise, F. Acta
Chem. Scand. 1999, 53, 366. (d) Hocek, M.; Masojídková,
M.; Holý, A. Tetrahedron 1997, 53, 2291. (e) Hocek, M.;
Masojídková, M.; Holý, A. Collect. Czech. Chem. Commun.
1997, 62, 136.
FAB-MS: m/z (%) = 321 (35) [M + H], 91 (100).
Anal. Calcd for C18H13ClN4 (320.8): C, 67.40; H, 4.08; N, 17.47.
Found: C, 67.08; H, 4.16; N, 17.68.
9-Benzyl-2,6-diphenylpurine (8)
Prepared from 6 (reaction time 8 h) or from 9 (reaction time 20 h)
with 3 equivalents of PhB(OH)2 in 84% (from 6) or 88% (from 9)
yields; colorless needles; mp 166–168 °C.
(11) esnek, M.; Hocek, M.; Holý, A. Collect. Czech. Chem.
Commun. 2000, 65, 1357.
(12) Hassan, A. E. A.; Abou-Elkair, R. A. I.; Montgomery, J. A.;
Secrist, J. A. III. Nucleosides, Nucleotides, Nucleic Acids
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1992, 57, 5268.
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1996, 37, 1285. (b) Dvo áková, H.; Dvo ák, D.; Holý, A.
Collect. Czech. Chem. Commun. 1998, 63, 2065.
1H NMR (500 MHz, CDCl3): = 5.51 (s, 2 H, CH2Ph), 7.32–7.40
(m, 5 H, C6H5), 7.46–7.60 (m, 6 H, ArH), 8.05 (s, 1 H, H-8), 8.70
(d, 2 H, J = 7.3, Ho-C6H5), 8.94 (d, 2 H, J = 7.3, Ho-C6H5).
13C NMR (100 MHz, CDCl3): = 47.2 (CH2), 128.0, 128.3, 128.4,
128.5, 128.6 and 129.1 (CH-Ph), 129.6 (C-5), 129.6, 130.1 and
130.8 (CH-Ph), 135.6, 136.2 and 138.4 (C-Ph), 144.1 (C-8), 153.5,
154.3 and 158.7 (C-2, C-4 and C-6).
FAB-MS: m/z (%) = 363 (100) [M + H].
Anal. Calcd for C24H18N4 (362.4): C, 79.54; H, 5.01; N, 15.46.
Found: C, 79.21; H, 5.04; N, 15.26.
(15) Examples: (a) position 2: Harada, H.; Asano, O.; Hoshino,
Y.; Yoshikawa, S.; Matsukura, M.; Kabasawa, Y.; Niijima,
J.; Kotake, Y.; Watanabe, N.; Kawata, T.; Inoue, T.;
Horizoe, T.; Yasuda, N.; Minami, H.; Nagata, K.;
Synthesis 2001, No. 11, 1704–1710 ISSN 0039-7881 © Thieme Stuttgart · New York

1710
M. Havelková et al.
PAPER
Murakami, M.; Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe,
S. J. Med. Chem. 2001, 44, 170 and references cited therein.
(b) position 6: Tanji, K.; Higashino, T. Chem. Pharm. Bull
1988, 36, 1935 and references cited therein. (c) position 8:
Gunji, H.; Vasella, A. Helv. Chim. Acta 2000, 83, 2975 and
references cited therein.
(17) Havelková, M.; Hocek, M.; esnek, M.; Dvo ák, D. Synlett
1999, 1145.
(18) (a) Janeba, Z.; Holý, A.; Masojídková, M. Collect. Czech.
Chem. Commun. 2000, 65, 1126. (b) Mezsárosová, K.;
Holý, A.; Masojídková, M. Collect. Czech. Chem. Commun.
2000, 65, 1109.
(16) Hocek, M.; Holý, A. Collect. Czech. Chem. Commun. 1999,
64, 229.
(19) Ishino, M.; Sakaguchi, T.; Morimoto, I.; Okitsu, T. Chem.
Pharm. Bull. 1981, 29, 2403.
Synthesis 2001, No. 11, 1704–1710 ISSN 0039-7881 © Thieme Stuttgart · New York