Cross-coupling reactions of halopurines with aryl- and alkyltrifluoroborates; the scope and limitations in the synthesis of modified purines

Article abstract of DOI:10.1055/s-0028-1088038

The scope and limitations of the use of the palladium-catalyzed cross-coupling reactions of diverse alkyl- and aryltrifluoroborates with halopurines have been studied. While aryl- and hetaryltrifluoroborates reacted readily with both 6-chloropurines and 8

Full text of DOI:10.1055/s-0028-1088038

PAPER
1309
Cross-Coupling Reactions of Halopurines with Aryl- and Alkyltrifluoro-
borates; The Scope and Limitations in the Synthesis of Modified Purines
C
ross-Coupling
b
Reactions
o
y
f
H
alopurine
n
s
w
ith
A
ryl-
ě
a
nd Alkyltr
k
ifluoroborate
s
Hasník, Radek Pohl, Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead & IOCB Research Center,
Flemingovo Nám. 2, 166 10 Prague 6, Czech Republic
Fax +420(220)183559; E-mail: hocek@uochb.cas.cz
Received 17 December 2008; revised 30 December 2008
reactive. Recently, a novel type of boron reagent, organ-
otrifluoroborates, is applied in these cross-coupling reac-
Abstract: The scope and limitations of the use of the palladium-
catalyzed cross-coupling reactions of diverse alkyl- and aryltrifluo-
roborates with halopurines have been studied. While aryl- and
hetaryltrifluoroborates reacted readily with both 6-chloropurines
tions.15
The
organotrifluoroborates
are
easily
crystallizable, air-stable16 and their reactivity is similar to
and 8-bromoadenines to give the corresponding 6- or 8-aryl deriva- boronic acids. After the primary investigation of the
cross-coupling of aryltrifluoroborates with aryl17 and alk-
tives in high yields, the alkyltrifluoroborates were much less reac-
enyl halides,18 it was also shown that various vinyl-19 and
tive and, even after thorough optimization, only methyl- and
cyclopropyltrifluoroborates gave moderate yields of the desired
alkyltrifluoroborates20,21 are stable enough to be success-
alkylated purines, while other alkyl-, dialkylaminomethyl- and
fully used in the cross-coupling. Molander et al. broad-
ethoxycarbonylethyltrifluoroborates did not give any reaction.
ened the application of alkyltrifluoroborates not only to
Key words: purines, cross-coupling reactions, organotrifluoro-
unfunctionalized species,22 but developed a convenient
borates, palladium, phosphine ligands
methodology for the preparation and application of alkyl-
trifluoroborates with diverse substituents in the a- or b-
position. They reported a cross-coupling reaction of b-
The 6- and 8-aryl-substituted purines represent an impor-
aminoethyltrifluoroborates with either electron-deficient
tant class of biologically active compounds.1 6-Aryl-
or electron-rich aryl bromides,23 explored the scope and
purine nucleosides possess cytostatic2 and anti-HCV3
limitations of this approach24 and also investigated the uti-
effects. 9-Alkyl-6-arylpurines exert antimycobacterial
lization of stable N,N-dialkylaminomethyltrifluoroborates
and antibacterial properties4 and corticotropine releasing
for the preparation of aromatic compounds with function-
hormone antagonist5 activity.6 8-Arylpurines7 and some
alized a-subtituents.25 They also focused on the prepara-
2,6-diarylpurines8 are antagonists of A1 and A2 adenosine
tion and application of various alkoxymethyl-
receptors. Also 6-alkylpurines are of interest: 6-methylpu-
trifluoroborates26 and trifluoroboratohomoenolates.27
rine is strongly cytotoxic9 and 6-cyclopropylpurine ribo-
Synthesis of a set of cycloalkyltrifluoroborates and cross-
nucleoside exerts10 interesting cytostatic activity. From
coupling of these species was reported recently, extending
the examples of alkyltrifluoroborates with b-hydrogens
functionalized derivatives, 6-hydroxymethyl-,11 6-fluo-
romethyl-12 and 6-dialkylaminomethylpurine13 nucleo-
on the alkyl chain.28,29 Because of the superior reactivity
sides are also promising cytostatics. While the 6-aryl- and
and wide tolerance to the presence of the functional
6-alkylpurines can be readily prepared by the classical
groups, the organotrifluoroborates seemed to be promis-
cross-coupling reactions14 of halopurines with arylboron-
ing reagents for the direct introduction of unfunctional-
ic acids or with alkylzinc, magnesium or aluminum orga-
ized and functionalized C-substituents to purines and so
nometallics, the synthesis of the latter functionalized
far no use of these regents in purine chemistry has been re-
derivatives is more challenging and requires multistep
ported. Here we report on the scope and limitations of the
functional group transformations12,13 of 6-hydroxymeth-
utilization of organotrifluoroborates in the synthesis of 6-
and 8-substituted purines as an alternative synthetic meth-
ylpurines.
The Suzuki–Miyaura cross-coupling is one of the most
important reactions in current organic chemistry and is
also widely used in purine chemistry. Usual substrates for
this reaction, boronic acids, are sometimes difficult to pu-
rify because of the lack of crystallization or the formation
of trimeric cyclic anhydrides (boroxines) – leading to dif-
ficulties in determining the stoichiometry of the boronic
acid added into the reaction. On the other hand, boronate
esters as alternative substrates are often unstable and less
odology to the standard Suzuki–Miyaura reaction.
Firstly we have tried to optimize the catalytic system and
reaction conditions on model reactions of 9-benzyl-6-
chloropurine (1) with phenyl- (2a) and methyltrifluorobo-
rates (2k) as examples of aryl and alkyl derivatives. Sev-
eral sources of palladium in combination with several
phosphine ligands successful in related cross-couplings of
boronates or trifluoroborates25b,27,28,30,31 (Figure 1) have
been used in these experiments. Results of the reactions of
6-chloropurine 1 with potassium phenyltrifluoroborate
(2a) are summarized in Table 1. Using conventional heat-
ing of the mixture in tetrahydrofuran–water (9:1) or tolu-
ene–water (3:1), Pd2(dba)3 with JohnPhos does not give
SYNTHESIS 2009, No. 8, pp 1309–1317
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088038; Art ID: Z28008SS
© Georg Thieme Verlag Stuttgart · New York

1310
Z. Hasník et al.
PAPER
any reaction, while Pd(OAc)2 with PPh3 gave a low yield
of the desired 6-phenylpurine 3a (entries 1 and 2). On the
other hand, the reaction in the presence of PdCl2(dppf)22
gave 3a in good yield (78%) and, quite surprisingly, sim-
ple Pd(PPh3)4 was the most efficient catalyst giving excel-
lent 88% yield of 3a (entries 3 and 4). We have also tested
the possibility of increasing the rate of the cross-coupling
reaction by microwave irradiation of the mixture, which is
known to increase the rate of the Suzuki–Miyaura cross-
coupling on purine systems.32 The optimum conditions
previously reported32 for boronic acids using Pd(OAc)2
with TPPTS in acetonitrile–water (1:2) were completely
inactive in this reaction. However, the use of PdCl2(dppf)
under microwave irradiation (5 min, 150 °C) was more ef-
ficient (63% yield), while the use of Pd(PPh3)4 gave quan-
titative conversion yielding 95% of the desired product 3a
(entries 7–9).
PtBu2
P
P
SO3Na
3
XPhos
JohnPhos
TPPTS
P
P
i-PrO
Oi-Pr
cataCXium A
RuPhos
Figure 1 Ligands used during optimization
The second model reaction of 1 with methyltrifluorobo-
rate 2k showed completely different behavior (Table 2).
Firstly, we tried the conditions most successful in the phe-
nyltrifluoroborate 2a. However, all attempts to perform
the reaction with 2k in presence of Pd(PPh3)4 or PdCl2(dppf)
under both conventional heating or microwave totally
failed. Also unsuccessful was the use of Pd(OAc)2 with
XPhos or the use of Pd(PtBu3)2 (entries 1–4). Therefore,
we returned to the microwave irradiation32 in acetonitrile–
water using Pd(OAc)2–TPPTS which at least gave traces
of the desired product 3k. Then we further optimized
these conditions by increasing the amount of the catalyst,
using different bases and comparing microwave irradia-
tion with conventional heating (entries 6–12). Although
complete consumption of the starting chloropurine 1 was
observed in all cases, the isolated yields of 3k varied only
between 10–44%. The rest was a mixture of unidentified
chromatographically immobile side-products (presum-
ably products of degradation). It appears that the methyl-
trifluoroborate is much less reactive than the phenyl
derivative and its use for modification of purines will be
limited [the yield is much lower than the corresponding
methylation by cross-couplings with trimethylaluminum
or methylmagnesium chloride in the presence of
Fe(acac)3].33
The little success of the reaction with methyltrifluorobo-
rates did not discourage us from also testing other alkyl-
and dialkylaminomethyltrifluoroborates (Table 3). At
first we tried cyclopropyl- and cyclopentyltrifluorobo-
rates 2l and 2o. Standard procedure25b,28 using Pd(OAc)2
with XPhos did not work with cyclopropyltrifluoroborate
2l, however, the use of cataCXium A ligand28 in toluene–
water was successful giving 6-cyclopropylpurine 3l in
Table 1 Cross-Coupling of 1 with Phenyltrifluoroborate 2a
Cl
N
Ph
N
N
N
N
N
N
N
PhBF3K
2a
Bn
Bn
1
3a
Entry
Catalytic system
Pd (mol %) Base (3 equiv)
Conditions
Solvent
Yield of 3a (%)
1
2
3
4
5
6
7
8
9
Pd2(dba)3/JohnPhos
Pd(OAc)2/PPh3
PdCl2(dppf)
Pd(PPh3)4
2a
2
2
2
1
5
2
2
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
80 °C, 18 h
THF–H2O
THF–H2O
toluene–H2O
THF–H2O
THF–H2O
THF–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
0
14
78
88
39
73
0
80 °C, 18 h
80 °C, 18 h
80 °C, 18 h
Pd(PPh3)4
80 °C, 18 h
Pd(PPh3)4
80 °C, 18 h
Pd(OAc)2/TPPTS
PdCl2(dppf)
Pd(PPh3)4
mW, 150 °C, 5 min
mW, 150 °C, 5 min
mW, 150 °C, 5 min
63
95
a Mol% of Pd2(dba)3.
Synthesis 2009, No. 8, 1309–1317 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reactions of Halopurines with Aryl- and Alkyltrifluoroborates
1311
Table 2 Cross-Coupling of 1 with Methyltrifluoroborate 2k
Cl
N
Me
N
N
N
N
N
N
N
MeBF3K
2k
Bn
Bn
1
3k
Entry
Catalytic system
Pd(PPh3)4
Pd (mol%) Base (3 equiv) Conditions
Solvent
Yield of 3k (%)
1
2
3
4
2
2
5
5
K2CO3
Cs2CO3
Cs2CO3
K2CO3
80 °C, 18 h
80 °C, 18 h
80 °C, 18 h
THF–H2O or MeCN–H2O
THF–H2O or MeCN–H2O
THF–H2O or MeCN–H2O
THF–H2O or MeCN–H2O
0
0
0
0
PdCl2(dppf)
Pd(OAc)2/XPhos
Pd(PtBu3)2
80 °C, 18 h or
mW, 150 °C, 5 min
5
6
Pd(OAc)2/TPPTS
Pd(OAc)2/TPPTS
Pd(OAc)2/TPPTS
Pd(OAc)2/TPPTS
Pd(OAc)2/TPPTS
Pd(OAc)2/TPPTS
Pd(OAc)2/TPPTS
Pd(OAc)2/TPPTS
2
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
mW, 150 °C, 5 min
mW, 150 °C, 5 min
mW, 150 °C, 5 min
mW, 150 °C, 60 min
80 °C, 30 min
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
traces
30
7
10
5
44
8
39
9
5
10
10
11
12
5
80 °C, 2 h
20
5
mW, 150 °C, 5 min
mW, 150 °C, 5 min
18
5
27
75% yield (entry 2). On the other hand, the reaction with Electron-rich aryltrifluoroborates 2b and 2c reacted readi-
cyclopentyltrifluoroborate 2o was tested under diverse ly to give the desired compounds in quantitative yields,
conditions27–29 using JohnPhos,30 cataCXinium A,28 Ru- even when sterically hindered trifluoroborate 2c was used
34
Phos,27,29 TPPTS,31,32 and Pd(PPh3)4 without any suc- (entries 2 and 3). When electron-deficient arylborates 2d,f
cess (entries 3–8). The major advantage of the Molander were used, the conversions were not complete, but still we
protocol is the possibility using directly functionalized have obtained the desired substituted purines 3d,f in good
alkyltrifluoroborates in cross-coupling. Therefore, we fur- yields. In the case of hetaryltrifluoroborates, thiophenylb-
ther tested several attractive functionalized trifluoro- orates 2h,i reacted almost quantitatively, while in the re-
borates: dimethylaminomethyl- (2p), (piperidin-1- action with 2-furyltrifluoroborate (2g) the conversion was
yl)methyl-25b (2q), cyclohexylaminomethyl-35 (2r) and 2- only around 50% under standard conditions. However,
(ethoxycarbonyl)ethyl-27 (2s) trifluoroborates. Different when using a double portion of catalyst we have obtained
conditions from the literature and from our previous expe- the desired product 3g in excellent yield (entry 7). We
rience with phenyl- and methyltrifluoroborates both under have also tried the conditions developed for aromatic tri-
conventional heating and under microwave have been fluoroborates for vinyl- and allylborates (2j,m). While the
tested with all these reagents but no cross-coupling reac- vinylborate 2j reacted readily and gave the corresponding
tion was observed in any case (entries 7–23). Only in the product 3j in excellent yield, in the reaction of allylborate
case of cyclohexylaminomethyltrifluoroborate (2r), al- 2m isomerization occurred on the allyl system and we
most quantitative conversion was observed to give 9-ben- produced 6-(2-methylvinyl)purine 3n in a moderate yield
zyl-6-(N-cyclohexyl-N-methyl)aminopurine (3t) as a of 23% (entries 10 and 13).
product of N-arylation and deborylation of the reagent.
To explore the applicability of this procedure for function-
Apparently, unlike in other aryl and hetaryl halides,25b,27
alization of the purine ring in position 8 and to test the tol-
the functionalized alkyltrifluoroborates are not suitable
reagents for modification of halopurines.
erance to free amino group, we have studied the reactions
of 8-bromoadenine 4 with trifluoroborates 2a–l (Table 5).
In order to further explore the scope and limitations of this In aryltrifluoroborates, we have observed the same reac-
reaction for other types of trifluoroborates, we have cho- tivity of electron-rich trifluoroborates 2a–c,e and in-
sen a set of diverse aryl-, hetaryl- and the mentioned alkyl- creased reactivity of 3-carboxyphenyltrifluoroborate 2f
trifluoroborates 2a–m and used the optimized conditions leading to the desired derivatives 5a–c,e,f in excellent
for the preparation of desired 6-substituted purines start- yields. Only in the case of 3-nitrophenyltrifluoroborate 2d
ing from 6-chloropurine 1 (Table 4).
did we need to double the amount of the catalyst in order
to complete the conversion and get good yields of 5d (en-
Synthesis 2009, No. 8, 1309–1317 © Thieme Stuttgart · New York

1312
Z. Hasník et al.
PAPER
tries 1–6). For the preparation of the furyl derivative 5g, In conclusion, aryltrifluoroborates were found to be excel-
we again had to use a larger amount of Pd(PPh3)4 (4 lent reagents for the cross-coupling reactions with 6- or 8-
mol%) to reach complete conversion and to get good yield halopurines under Pd catalysis. These cross-couplings are
of 5g (73%). On the other hand, 3-thiophenetrifluorobo- fully comparable to the classical Suzuki–Miyaura cross-
rate 2h gave corresponding substituted adenine 5h in ex- coupling reactions of halopurines with arylboronic acids.
cellent yield even in the presence of 2 mol% of catalyst, However, similar to the low reactivity of alkylboronic
while in the case of 5-methyl-2-thiophenetrifluoroborate acids, alkyltrifluoroborates were found to be of very poor
2i, the lower yield was caused by incomplete conversion reactivity in cross-couplings with halopurines and only in
of starting material (entries 7–9). Position 8 on the purine the case of methyl- and cyclopropylborates, reasonable
moiety showed low reactivity in the cross-couplings with reactivity was observed to give the methyl- or cyclopropyl-
vinyl- and alkyltrifluoroborates 2j–l. Vinyl- and methyl- purines in moderate yields. Functionalized alkyltrifluoro-
trifluoroborate were completely unreactive (only the start- borates (substituted aminomethyl- and (ethoxycarbonyl-
ing material was recovered from the reaction mixture), ethyl)trifluoroborates) were totally unreactive in these re-
while potassium cyclopropyltrifluoroborate (2l) reacted actions and thus cannot be used for direct functionaliza-
with 8-bromoadenine 4 under catalysis with Pd(OAc)2 tion of purines. We have no explanation for the lack of
and cataCXium A giving 8-cyclopropyladenine 5l in a reactivity of these reagents in purines because other cross-
moderate yield of 48%.
couplings usually proceed in halopurines better than in
more electron-rich aryl halides.
Table 3 Attempts to Carry Out the Cross-Coupling of 1 with Unfunctionalised and Functionalised Alkylborates 2l–s
Cl
R
N
N
N
N
N
N
RBF3K
2l–s
N
N
Bn
Bn
3l,t
1
Entry Borate R
Catalyst
Base
Solvent
Methoda Yield
(%)
1
Pd(OAc)2/XPhos
Pd(OAc)2/cataCXium A Cs2CO3
K2CO3
THF–H2O
toluene–H2O
C
C
0
75
2l
2
3
4
5
6
7
8
Pd(OAc)2/TPPTS
Pd(PPh3)4
Pd(OAc)2/RuPhos
Pd2(dba)3/JohnPhos
Pd2(dba)3/TPPTS
Cs2CO3
MeCN–H2O
A
0
0
K2CO3 or Cs2CO3 MeCN–H2O, DMF–H2O or toluene–H2O A
K3PO4 or K2CO3 toluene–H2O A or B
K2CO3
0
2o
toluene–H2O, THF–H2O or MeCN–H2O
A
A
C
0b
0
K2CO3 or Cs2CO3 MeCN–H2O
Pd(OAc)2/cataCXium A Cs2CO3
toluene–H2O
0
9
10
11
12
Pd(OAc)2/TPPTS
Pd(PPh3)4
Pd(OAc)2/RuPhos
Cs2CO3
K2CO3
K3PO4
MeCN–H2O
MeCN–H2O
MeCN–H2O
toluene–H2O
A
A
A
C
dec.
dec.
dec.
dec.
2p
Me2N
Pd(OAc)2/cataCXium A Cs2CO3
13
14
Pd(OAc)2/TPPTS
Pd(OAc)2/cataCXium A Cs2CO3
K2CO3
toluene–H2O
toluene–H2O
C
C
0
dec.
N
2q
2r
0 (70)c
0 (85)c
0 (93)c
H
15
16
17
Pd(OAc)2/TPPTS
Pd(OAc)2/XPhos
Pd(PPh3)4
Cs2CO3
Cs2CO3
K2CO3
MeCN–H2O
MeCN–H2O
MeCN–H2O
A
A
A
N
MeCN–H2O
MeCN–H2O
toluene–H2O
toluene–H2O, MeCN–H2O, dioxane–H2O
or DMF–H2O
18
19
20
21
22
23
Pd(OAc)2/TPPTS
Pd(PPh3)4
Pd(OAc)2/RuPhos
Pd(OAc)2/TPPTS
Pd(PPh3)4
Cs2CO3
K2CO3
K3PO4
K2CO3
K2CO3
A
A
A
C
C
C
dec.
0
0
0
0
2s
EtOOC
THF–H2O, dioxane–H2O or DMF–H2O
toluene–H2O
Pd(OAc)2/cataCXium A Cs2CO3
0
a Method A: mW, 150 °C, 5 min; Method B: heating, 18 h, 125 °C; Method C: heating, 24 h, 80 °C.
b Decomposition in MeCN–H2O.
c Yield of 9-benzyl-6-(N-cyclohexyl-N-methyl)amino-9H-purine (3t).
Synthesis 2009, No. 8, 1309–1317 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reactions of Halopurines with Aryl- and Alkyltrifluoroborates
1313
Table 4 Cross-Coupling of 1 with Trifluoroborates 2a–m Table 5 Cross-Coupling of 4 with Trifluoroborates 2a–l
Cl
N
R
N
NH2
NH2
N
N
N
N
N
N
N
N
N
N
N
N
N
RBF3K
RBF3K
Br
R
2a–m
2a–l
N
Bn
Bn
5a–l
Bn
Bn
4
1
3a–n
Methoda Product (Yield, %)
Entry Borate R
Methoda Product (Yield, %)
Entry Borate R
1
2
2a
2b
A
A
5a (96)
5b (97)
1
2
3
2a
2b
2c
A
3a (95)
3b (95)
3c (94)
A
A
MeO
MeO
3
4
5
2c
2d
2e
A
A
A
5c (96)
OMe
OMe
O2N
O2N
5d (53, 90b)
5e (97)
4
5
2d
2e
A
A
3d (79)
3e (94)
HOOC
HOOC
6
7
8
9
2f
A
A
A
A
5f (99)
6
7
8
2f
A
A
A
3f (71)
O
S
O
S
2g
2h
3g (52, 95b)
3h (90)
2g
2h
2i
5g (51, 73b)
5h (96)
S
S
9
2i
A
3i (91)
5i (76)
10
11
12
2j
2k
2l
A
B
C
3j (97)
3k (44)
3l (75)
10
11
12
2j
2k
2l
A
B
C
5j (0)
5k (0)
5l (48)
Me
Me
a MethodA: 2 mol% Pd(PPh3)4, K2CO3, mW, 150 °C, 5 min, MeCN–
H2O; Method B: 10 mol% Pd(OAc)2/TPPTS, Cs2CO3, mW, 150 °C, 5
min, MeCN–H2O; Method C: 3 mol% Pd(OAc)2/cataCXium A,
Cs2CO3, toluene–H2O, 100 °C, 24 h.
13
2m
A
3n (23)c
m
n
a Method A: 2 mol% Pd(PPh3)4, K2CO3, mW, 150 °C, 5 min, MeCN–
H2O; Method B: 10 mol% Pd(OAc)2/TPPTS, Cs2CO3, mW, 150 °C, 5
min, MeCN–H2O; Method C: 3 mol% Pd(OAc)2/cataCXium A,
Cs2CO3, toluene–H2O, 100 °C, 24 h.
b 4 mol% of catalyst was used.
for 13C) in CDCl3 and DMSO-d6 (referenced to the residual solvent
signal). MS were measured on a ZAB-EQ (VG Analytical) spec-
trometer using FAB (ionization by Xe, accelerating voltage 8 kV,
glycerol+thioglycerol matrix). The H2O–MeCN mixture was de-
gassed in vacuo and stored under argon. Microwave-mediated reac-
tions 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).
b 4 mol% of catalyst was used.
c 9-Benzyl-6-[(E)-2-methylvinyl]-9H-purine (3n).
All chemicals were commercially available and used without fur-
ther purification. JohnPhos and cataCXium A were purchased from
Aldrich; TPPTS, XPhos and RuPhos from STREM Chemicals, Inc.
Trifluoroborates 2a–m,o were purchased from Aldrich, 2p,q,s from
Frontiers Scientific and trifluoroborate 2r was prepared according
to a previously published procedure.35 NMR spectra were measured
Cross-Coupling Reactions: General Procedure
A mixture of H2O–MeCN (2:1; 2 mL) was added through a septum
to an argon-purged vial containing 6-chloropurine 1 (122 mg, 0.5
on a Bruker Avance 400 (400 MHz for 1H and 100.6 MHz for 13
nuclei) and a Bruker Avance 500 (500 MHz for 1H and 125.8 MHz
C
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1314
Z. Hasník et al.
PAPER
mmol), trifluoroborate (0.6 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol)
and K2CO3 (207 mg, 3 mmol). The mixture was stirred under mi-
crowave irradiation heating at 150 °C for 5 min. The mixture was
filtered through Celite, evaporated to dryness and product was ob-
tained by silica gel column chromatography (EtOAc–hexanes).
Pure product was obtained by crystallization from CH2Cl2–heptane.
(s, 1 H, H-2), 9.06 (ddd, J6¢,5¢ = 7.9 Hz, J6¢,2¢ = 1.7 Hz, J6¢,4¢ = 1.4 Hz,
1 H, H-6¢), 9.47 (t, J2¢,4¢ = J2¢,6¢ = 1.7 Hz, 1 H, H-2¢), 13.20 (br s, 1 H,
COOH).
13C NMR (125.7 MHz, DMSO-d6): d = 46.78 (CH2Ph), 127.88 (CH-
o-Ph), 128.19 (CH-p-Ph), 129.03 (CH-m-Ph), 129.38 (CH-5¢),
130.53 (CH-2¢), 130.64 (C-5), 131.57 (C-3¢), 131.90 (CH-4¢),
133.60 (CH-6¢), 135.92 (C-1¢), 136.69 (C-ipso-Ph), 147.20 (CH-8),
151.84 (C-6), 152.74 (CH-2), 152.74 (C-4), 167.32 (COOH).
9-Benzyl-6-phenyl-9H-purine (3a)
Prepared from potassium phenyltrifluoroborate (2a; 55 mg) as
white crystals, yield 95%.
ESI-MS: m/z (%) = 331 (50) [M + 1].
1H NMR spectra were in accord with previously published data.36
HRMS (ESI): m/z calcd for C19H15N4O2: 331.1190; found:
331.1183.
9-Benzyl-6-(4-methoxyphenyl)-9H-purine (3b)
Prepared from potassium 4-methoxyphenyltrifluoroborate (2b;
128 mg) as yellowish crystals, yield 95%.
Anal. Calcd for C19H14N4O2 ·1/3 H2O (336.3): C, 67.85; H, 4.40; N,
16.66. Found: C, 67.67; H, 4.31; N, 16.37.
1H NMR spectra were in accord with previously published data.37
9-Benzyl-6-(furan-2-yl)-9H-purine (3g)
Prepared from potassium 2-furantrifluoroborate (2g; 104 mg) as
yellowish crystals, yield 52%. Using 4 mol% of Pd(PPh3)4 (22 mg,
0.02 mmol) the yield increased to 95%.
1H NMR spectra were in accord with previously published data.39
9-Benzyl-6-(2-methoxyphenyl)-9H-purine (3c)
Prepared from potassium 2-methoxyphenyltrifluoroborate (2c;
128 mg) as white crystals, yield 94%. 1H NMR spectra were in ac-
cord with previously published data.38
9-Benzyl-6-(thiophen-3-yl)-9H-purine (3h)
Prepared from potassium 5-methyl-2-thiophenetrifluoroborate (2h;
114 mg) as yellowish crystals, yield 91%.
1H NMR spectra were in accord with previously published data.38
9-Benzyl-6-(3-nitrophenyl)-9H-purine (3d)
Prepared from potassium 3-nitrophenyltrifluoroborate (2d; 137 mg)
1
as yellowish crystals, yield 95%. H NMR spectra were in accord
with previously published data.38
9-Benzyl-6-(5-methylthiophen-2-yl)-9H-purine (3i)
Prepared from potassium 3-thiophenetrifluoroborate (2i; 122 mg)
as yellowish crystals, yield 90%.
9-Benzyl-6-(2-naphthyl)-9H-purine (3e)
Prepared from potassium 2-naphthyltrifluoroborate (2e; 140 mg) as
white crystals, yield 94%.
Mp 167–169 °C (CH2Cl2–heptane).
IR (CHCl3): 2996, 1582, 1471, 1403, 1329, 1227 cm–1.
IR (CCl4): 3062, 1581, 1570, 1449, 1325, 1193 cm–1.
1H NMR (600 MHz, CDCl3): d = 5.50 (s, 2 H, CH2Ph), 7.32–7.40
(m, 5 H, H-o,m,p-Ph), 7.53 (ddd, J7,8 = 8.2 Hz, J7,6 = 6.8 Hz,
J7,5 = 1.4 Hz, 1 H, H-7-naphth), 7.56 (ddd, J6,5 = 8.2 Hz, J6,7 = 6.8
Hz, J6,8 = 1.4 Hz, 1 H, H-6-naphth), 7.90 (ddt, J5,6 = 8.2 Hz,
J5,7 = 1.4 Hz, J5,1 = J5,4 = 0.7 Hz, 1 H, H-5-naphth), 8.01 (dq,
J4,3 = 8.6 Hz, J5,1 = J4,5 = J4,8 = 0.7 Hz, 1 H, H-4-naphth), 8.06 (ddt,
J8,7 = 8.2 Hz, J8,6 = 1.4 Hz, J8,1 = J8,4 = 0.7 Hz, 1 H, H-8-naphth),
8.14 (s, 1 H, H-8), 8.88 (dd, J3,4 = 8.6 Hz, J3,1 = 1.7 Hz, 1 H, H-3-
naphth), 9.11 (s, 1 H, H-2), 9.42 (dq, 1 H, J1,3 = 1.7 Hz,
J1,4 = J1,5 = J1,8 = 0.7 Hz, H-1-naphth).
13C NMR (151 MHz, CDCl3): d = 47.28 (CH2Ph), 125.96 (CH-3-
naphth), 126.26 (CH-7-naphth), 127.47 (CH-6-naphth), 127.69
(CH-5-naphth), 127.80 (CH-o-Ph), 128.26 (CH-4-naphth), 128.58
(CH-p-Ph), 129.16 (CH-m-Ph), 129.47 (CH-8-naphth), 130.82
(CH-1-naphth), 131.15 (C-5), 133.05 (C-8a-naphth), 133.22 (C-2-
naphth), 134.65 (C-4a-naphth), 135.17 (C-ipso-Ph), 144.15 (CH-8),
152.58 (C-4), 152.61 (CH-2), 154.77 (C-6).
1H NMR (400 MHz, CDCl3): d = 2.58 (s, 3 H, Me), 5.43 (s, 2 H,
CH2-9), 6.90 (d, J = 3.6 Hz, 1 H, H-4¢), 7.25–7.39 (m, 5 H, Ph), 8.02
(s, 1 H, H-8), 8.45 (d, J = 3.6 Hz, 1 H, H-3¢), 8.87 (s, 1 H, H-2).
13C NMR (100.6 MHz, CDCl3): d = 15.77 (CH3), 47.18 (CH2Ph),
127.36 (CH-4¢), 127.74 (CH-o-Ph), 128.50 (CH-p-Ph), 129.08 (CH-
m-Ph), 133.12 (CH-3¢), 135.20 (C-ipso-Ph), 137.42 (C-2¢), 143.71
(CH-8), 146.35 (C-5¢), 150.30 (C-5), 151.81 (C-4), 152.62 (CH-2),
153.61 (C-6).
ESI-MS: m/z (%) = 307 (100) [M + 1].
HRMS (ESI): m/z calcd for C17H15N4S:307.1012; found: 307.1009.
Anal. Calcd for C17H14N4S (306.4): C, 66.64; H, 4.69; N, 18.29;
Found: C, 66.37; H, 4.69; N, 18.13.
9-Benzyl-6-vinyl-9H-purine (3j)
Prepared from potassium vinyltrifluoroborate (2j; 80 mg) as a white
solid, yield 97%.
1H NMR spectra were in accord with previously published data.37
ESI-MS: m/z (%) = 337 (100) [M + 1].
HRMS (ESI): m/z calcd for C22H17N4: 337.1448; found: 337.1445.
Anal. Calcd for C22H16N4·1/6 H2O (339.4): C, 77.86; H, 4.85; N,
16.51. Found: C, 77.81; H, 4.77; N, 16.50.
9-Benzyl-6-methyl-9H-purine (3k)
A mixture of H2O–MeCN (2:1; 2 mL) was added through a septum
to an argon-purged vial containing 6-chloropurine 1 (122 mg, 0.5
mmol), potassium methyltrifluoroborate (2k, 73 mg, 0.6 mmol),
Pd(OAc)2 (11 mg, 0.05 mmol), TPPTS (71 mg, 0.125 mmol) and
Cs2CO3 (488 mg, 1.5 mmol). The mixture was stirred under micro-
wave irradiation heating at 150 °C for 5 min. The mixture was fil-
tered through Celite, evaporated to dryness and product was
obtained by silica gel column chromatography (EtOAc–hexanes).
Pure product was obtained by crystallization from CH2Cl2–heptane
to obtain 25 mg (44% yield) of 3k as white crystals.
9-Benzyl-6-(3-carboxyphenyl)-9H-purine (3f)
Prepared from potassium 3-carboxyphenyltrifluoroborate (2f;
137 mg) as white crystals, yield 71%. Mp 233–235 °C (CH2Cl2–
heptane).
IR (KBr): 3075, 2537, 1687, 1567, 1433, 1325, 1296 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 5.58 (s, 2 H, CH2Ph), 7.30 (m,
1 H, H-p-Ph), 7.36 (m, 2 H, H-m-Ph), 7.39 (m, 2 H, H-o-Ph), 7.74
(dd, J5¢,6' = 7.9 Hz, J5¢,4¢ = 7.7 Hz, 1H, H-5¢), 8.13 (ddd, J4¢,5¢ = 7.7
Hz, J4¢,2¢ = 1.7 Hz, J4¢,6¢ = 1.4 Hz, 1 H, H-4¢), 8.89 (s, 1 H, H-8), 9.04
1H NMR spectra were in accord with previously published data.37
Synthesis 2009, No. 8, 1309–1317 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reactions of Halopurines with Aryl- and Alkyltrifluoroborates
1315
9-Benzyl-6-cyclopropyl-9H-purine (3l)
6¢), 7.52 (ddd, J4¢,3¢ = 8.4 Hz, J4¢,5¢ = 7.5 Hz, J4¢,6¢ = 1.8 Hz, 1 H, H-
4¢), 8.17 (s, 1 H, H-2).
A mixture of toluene–H2O (10:1; 2 mL) was added through a sep-
tum to an argon-purged vial containing 6-chloropurine 1 (122 mg,
0.5 mmol), potassium cyclopropyltrifluoroborate (2l, 85 mg, 0.6
mmol), Pd(OAc)2 (3.3 mg, 0.015 mmol), cataCXium A (8 mg,
0.022 mmol) and Cs2CO3 (488 mg, 1.5 mmol). The mixture was
stirred at 100 °C for 24 h. The reaction was quenched with H2O and
extracted with CHCl3 (3 × 20 mL), collected organic layers were
dried (MgSO4), filtered and the solvent was evaporated. The residue
was chromatographed on a silica gel column (EtOAc–hexane). Pure
product was obtained by crystallization from CH2Cl2–heptane to
obtain 94 mg (75% yield) of 3l as yellowish crystals.
13C NMR (125.7 MHz, DMSO-d6): d = 46.04 (CH2Ph), 55.54
(CH3O), 111.73 (CH-3¢), 118.73 (C-5), 119.17 (C-1¢), 120.07 (CH-
5¢), 127.01 (CH-o-Ph), 127.44 (CH-p-Ph), 128.48 (CH-m-Ph),
131.94 (CH-6¢), 132.07 (CH-4¢), 137.00 (C-ipso-Ph), 148.25 (C-8),
150.78 (C-4), 152.74 (CH-2), 155.87 (C-6), 157.32 (C-2¢).
ESI-MS: m/z (%) = 332 (100) [M + 1].
HRMS (ESI): m/z calcd for C19H18N5O:332.1506; found; 332.1506.
Anal. Calcd for C19H17N5O·1/3 H2O (337.4): C, 67.64; H, 5.28; N,
20.76. Found: C, 67.68; H, 5.14; N, 20.76.
1H NMR spectra were in accord with previously published data.10
9-Benzyl-8-(3-nitrophenyl)adenine (5d)
9-Benzyl-6-(2-methylvinyl)-9H-purine (3n)
Prepared from potassium allyltrifluoroborate (2m; 89 mg) as yel-
lowish crystals, yield 23%.
1H NMR spectra were in accord with previously published data.40
Prepared from potassium 3-nitrophenyltrifluoroborate (2d; 137 mg)
as yellowish crystals, yield 53%. Using 4 mol% of Pd(PPh3)4 (22
mg, 0.02 mmol) the yield increased to 90%.
1H NMR spectra were in accord with previously published data.41
Cross-Coupling Reactions of Adenines; General Procedure
A mixture of H2O–MeCN (2:1; 2 mL) was added through a septum
to an argon-purged vial containing 8-bromoadenine 4 (152 mg, 0.5
mmol), trifluoroborate (0.6 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol)
and K2CO3 (207 mg, 3 mmol). The mixture was stirred under mi-
crowave irradiation heating at 150 °C for 5 min. The mixture was
filtered through Celite, evaporated to dryness and product was ob-
tained by silica gel column chromatography (EtOAc–hexanes).
Pure product was obtained by crystallization from CH2Cl2–heptane.
9-Benzyl-8-(2-naphthyl)adenine (5e)
Prepared from potassium 2-naphthyltrifluoroborate (2f; 140 mg) as
a white solid, yield 97%.
Mp 188–191 °C (CH2Cl2–heptane).
IR (CHCl3): 3412, 2984, 1636, 1588, 1466, 1329 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 5.61 (s, 2 H, CH2Ph), 7.02 (m,
2 H, H-o-Ph), 7.20 (m, 1 H, H-p-Ph), 7.25 (m, 2 H, H-m-Ph), 7.41
(br s, 2 H, NH2), 7.58 (ddd, J7,8 = 8.6 Hz, J7,6 = 6.9 Hz, J7,5 = 1.7 Hz,
1 H, H-7-naphth), 7.60 (ddd, J6,5 = 8.6 Hz, J6,7 = 6.9 Hz, J6,8 = 1.7
Hz, 1 H, H-6-naphth), 7.84 (dd, J3,4 = 8.5 Hz, J3,1 = 1.8 Hz, 1 H, H-
3-naphth), 7.89 (dd, J8,7 = 8.6 Hz, J8,6 = 1.7 Hz, 1 H, H-8-naphth),
7.98 (dd, J5,6 = 8.6 Hz, J5,7 = 1.7 Hz, 1 H, H-5-naphth), 8.02 (d,
J4,3 = 8.5 Hz, 1 H, H-4-naphth), 8.22 (s, 1 H, H-2), 8.23 (d, 1 H,
J1,3 = 1.8 Hz, H-1-naphth).
9-Benzyl-8-phenyladenine (5a)
Prepared from potassium phenyltrifluoroborate (2a; 55 mg) as
white crystals, yield 96%.
1H NMR spectra were in accord with previously published data.41
9-Benzyl-8-(4-methoxyphenyl)adenine (5b)
Prepared from potassium 4-methoxyphenyltrifluoroborate (2b;
128 mg) as white crystals, yield 97%. Mp 152–154 °C (CH2Cl2–
heptane).
13C NMR (125.7 MHz, DMSO-d6): d = 46.50 (CH2Ph), 118.89 (C-
5), 126.05 (CH-3-naphth), 126.60 (CH-o-Ph), 127.16 (CH-7-
naphth), 127.40 (C-2-naphth), 127.62 (CH-6-naphth), 127.70 (CH-
p-Ph), 127.92 (CH-5-naphth), 128.53 (CH-4-naphth), 128.56 (CH-
8-naphth), 128.59 (CH-1-naphth), 128.92 (CH-m-Ph), 132.57 (C-
8a-naphth), 133.30 (C-4a-naphth), 137.31 (C-ipso-Ph), 149.93 (C-
8), 151.79 (C-4), 153.12 (CH-2), 156.10 (C-6).
IR (CCl4): 3419, 1630, 1480, 1353, 1254, 1177 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 3.80 (s, 3 H, CH3O), 5.48 (s, 2
H, CH2Ph), 6.99 (m, 2 H, H-o-Ph), 7.04 (m, 2 H, H-m-C6H4OMe),
7.22 (m, 1 H, H-p-Ph), 7.27 (m, 2 H, H-m-Ph), 7.35 (br s, 2 H, NH2),
7.62 (m, 2 H, H-o-C6H4OMe), 8.15 (s, 1 H, H-2).
ESI-MS: m/z (%) = 352 (100) [M + 1].
HRMS (ESI): m/z calcd for C22H18N5; 352.1557; found: 352.1553.
13C NMR (125.7 MHz, DMSO-d6): d = 46.31 (CH2Ph), 55.51
(CH3O), 114.38 (CH-m-C6H4OMe), 118.64 (C-5), 122.24 (C-i-
C6H4OMe), 126.41 (CH-o-Ph), 127.62 (CH-p-Ph), 128.93 (CH-m-
Ph), 130.43 (CH-o-C6H4OMe), 137.31 (C-ipso-Ph), 149.99 (C-8),
151.56 (C-4), 152.75 (CH-2), 155.86 (C-6), 160.58 (C-p-
C6H4OMe).
Anal. Calcd for C22H17N5·1/2 H2O (357.4): C, 73.31; H, 5.03; N,
19.43. Found: C, 73.46; H, 4.83; N, 19.32.
9-Benzyl-6-(3-carboxyphenyl)adenine (5f)
Prepared from potassium 3-carboxyphenyltrifluoroborate (2f;
137 mg) as a white solid, yield 99%.
ESI-MS: m/z (%) = 332 (100) [M + 1].
Mp > 260 °C (CH2Cl2–heptane).
HRMS (ESI): m/z calcd for C19H18N5O:332.1506; found: 332.1504.
IR (KBr): 3318, 3180, 1638, 1567, 1399, 1331, 1298 cm–1.
Anal. Calcd for C19H17N5O·1/2 H2O (340.4): C, 67.04; H, 5.33; N,
20.58. Found: C, 66.60; H, 5.17; N, 20.23%.
1H NMR (500 MHz, DMSO-d6): d = 5.52 (s, 2 H, CH2Ph), 6.94 (m,
2 H, H-o-Ph), 7.17 (m, 1 H, H-p-Ph), 7.21 (m, 2 H, H-m-Ph), 7.40
(t, J5¢,4¢ = J5¢,6¢ = 7.6 Hz, 1 H, H-5¢), 7.41 (br s, 2 H, NH2), 7.62 (ddd,
9-Benzyl-8-(2-methoxyphenyl)adenine (5c)
Prepared from potassium 2-methoxyphenyltrifluoroborate (2c;
128 mg) as brownish crystals, yield 96%.
IR (CCl4): 3420, 2927, 1742, 1631, 1466, 1293 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 3.68 (s, 3 H, CH3O), 5.19 (s, 2
H, CH2Ph), 6.86 (m, 2 H, H-o-Ph), 7.03 (td, J5¢,4¢ = J5¢,6¢ = 7.5 Hz,
J
6¢,5¢ = 7.6 Hz, J6¢,2¢ = 1.7 Hz, J6¢,4¢ = 1.4 Hz, 1 H, H-6¢), 8.05 (ddd,
4¢,5¢ = 7.6 Hz, J4¢,2¢ = 1.7 Hz, J4¢,6¢ = 1.4 Hz, 1 H, H-4¢), 8.17 (s, 1 H,
J
H-2), 8.42 (t, J2¢,4¢ = J2¢,6¢ = 1.7 Hz, 1 H, H-2¢).
13C NMR (125.7 MHz, DMSO-d6): d = 46.40 (CH2Ph), 118.82 (C-
5), 126.65 (CH-o-Ph), 127.70 (CH-p-Ph), 128.09 (CH-5¢), 128.92
(CH-m-Ph), 129.30 (C-3¢), 129.82 (CH-6¢), 130.48 (CH-2¢), 130.91
(CH-4¢), 137.15 (C-ipso-Ph), 138.91 (C-1¢), 150.23 (C-8), 151.57
(C-4), 153.01 (CH-2), 156.08 (C-6), 171.04 (COOH).
J
5¢,3¢ = 1.0 Hz, 1 H, H-5¢), 7.13–7.20 (m, 4 H, H-3¢ and H-m,p-Ph),
7.26 (br s, 2 H, NH2), 7.31 (dd, J6¢,5¢ = 7.5 Hz, J6¢,4¢ = 1.8 Hz, 1 H, H-
ESI-MS: m/z (%) = 346 (100) [M + 1].
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1316
Z. Hasník et al.
PAPER
HRMS (ESI): m/z calcd for C19H16N5O2: 346.1299; found:
129.62 (C-2-thienyl), 136.87 (C-ipso-Ph), 143.26 (C-5-thienyl),
346.1295.
144.37 (C-8), 151.76 (C-4), 153.04 (CH-2), 155.66 (C-6).
ESI-MS: m/z (%) = 322 (100) [M + 1].
9-Benzyl-8-(furan-2-yl)adenine (5g)
HRMS (ESI): m/z calcd for C17H16N5S:322.1121; found: 322.1121.
Prepared from potassium 2-furantrifluoroborate (2g; 104 mg) as
white crystals, yield 51%. Using 4 mol% of Pd(PPh3)4 (22 mg, 0.02
mmol) the yield increased to 73%.
Anal. Calcd for C17H15N5S (321.4): C, 63.53; H, 4.70; N, 21.79.
Found: C, 63.25; H, 4.75; N, 21.79.
Mp 153–157 °C (CH2Cl2–heptane).
9-Benzyl-8-cyclopropyladenine (5l)
IR (CHCl3): 3525, 3412, 2989, 2360, 1636, 1581, 1468, 1331, 1295
cm–1.
A mixture of toluene–H2O (10:1; 2 mL) was added through a sep-
tum to an argon-purged vial containing 8-bromoadenine 4 (152 mg,
0.5 mmol), potassium cyclopropyltrifluoroborate (2l, 85 mg, 0.6
mmol), Pd(OAc)2 (3.3 mg, 0.015 mmol), cataCXium A (8 mg,
0.022 mmol) and Cs2CO3 (488 mg, 1.5 mmol). The mixture was
stirred at 100 °C for 24 h. The reaction was quenched with H2O and
extracted with CHCl3 (3 × 20 mL), collected organic layers were
dried (MgSO4), filtered and the solvent was evaporated. The residue
was chromatographed on a silica gel column (EtOAc–MeOH). Pure
product was obtained by crystallization from CH2Cl2–heptane to
obtain 64 mg (48% yield) of 3l as yellowish crystals.
1H NMR (500 MHz, DMSO-d6): d = 5.66 (s, 2 H, CH2Ph), 6.68 (dd,
J4,3 = 3.5 Hz, J4,5 = 1.8 Hz, 1 H, H-4-furyl), 7.01 (dd, J3,4 = 3.5 Hz,
J3,5 = 0.8 Hz, 1 H, H-4-furyl), 7.12 (m, 2 H, H-o-Ph), 7.23 (m, 1 H,
H-p-Ph), 7.29 (m, 2 H, H-m-Ph), 7.46 (br s, 2 H, NH2), 7.92 (dd, 1
H, J5,4 = 1.8 Hz, J5,3 = 0.8 Hz, H-5-furyl), 8.19 (s, 1 H, H-2).
13C NMR (125.7 MHz, DMSO-d6): d = 46.24 (CH2Ph), 112.41 and
112.42 (CH-3,4-furyl), 118.72 (C-5), 126.70 (CH-o-Ph), 127.71
(CH-p-Ph), 128.92 (CH-m-Ph), 137.21 (C-ipso-Ph), 140.81 (C-8),
144.44 (C-2-furyl), 145.17 (CH-5-furyl), 151.14 (C-4), 153.27
(CH-2), 156.01 (C-6).
IR (i-PrOH): 1652 cm–1.
ESI-MS: m/z (%) = 292 (100) [M + 1].
1H NMR (500 MHz, DMSO-d6): d = 0.94–1.00 (m, 4 H, H-2,3-c-
Pr), 2.16 (m, 1 H, H-1-c-Pr), 5.47 (s, 2 H, CH2Ph), 6.99 (br s, 2 H,
NH2), 7.23 (m, 2 H, H-o-Ph), 7.27 (m, 1 H, H-p-Ph), 7.33 (m, 2 H,
H-m-Ph), 8.10 (s, 1 H, H-2).
13C NMR (125.7 MHz, DMSO-d6): d = 7.81 (CH-1-c-Pr), 8.39
(CH2-2,3-c-Pr), 44.91 (CH2Ph), 117.60 (C-5), 127.22 (CH-o-Ph),
127.72 (CH-p-Ph), 128.86 (CH-m-Ph), 137.28 (C-ipso-Ph), 150.97
(C-4), 151.92 (CH-2), 153.57 (C-8), 155.10 (C-6).
HRMS (ESI): m/z calcd for C16H14N5O: 292.1193; found:
292.1194.
Anal. Calcd for C16H13N5O·3/4 H2O (304.8): C, 63.04; H, 4.79; N,
22.98. Found: C, 63.05; H, 4.71; N, 22.82.
9-Benzyl-8-(thiophen-3-yl)adenine (5h)
Prepared from potassium 3-thiophenetrifluoroborate (2h; 114 mg)
as brown crystals, yield 96%.
ESI-MS: m/z (%) = 266 (100) [M + 1].
Mp 164–168 °C (CH2Cl2–heptane).
HRMS (ESI): m/z calcd for C15H16N5: 266.1400; found: 266.1401.
IR (KBr): 3317, 3115, 1665, 1601, 1453, 1301 cm–1.
Anal. Calcd for C15H15N5 (271.3): C, 66.40; H, 5.82; N, 25.81.
Found: C, 66.30; H, 5.62; N, 25.63.
1H NMR (500 MHz, DMSO-d6): d = 5.60 (s, 2 H, CH2Ph), 7.01 (m,
2 H, H-o-Ph), 7.23 (m, 1 H, H-p-Ph), 7.28 (m, 2 H, H-m-Ph), 7.37
(br s, 2 H, NH2), 7.52 (dd, J4,5 = 5.1 Hz, J4,2 = 1.3 Hz, 1 H, H-4-thie-
nyl), 7.69 (dd, J5,4 = 5.1 Hz, J5,2 = 2.9 Hz, 1 H, H-5-thienyl), 7.92
(dd, J2,5 = 2.9 Hz, J2,4 = 1.3 Hz, 1 H, H-2-thienyl), 8.17 (s, 1 H, H-
2).
13C NMR (125.7 MHz, DMSO-d6): d = 46.03 (CH2Ph), 118.49 (C-
5), 126.44 (CH-o-Ph), 126.82 (CH-2-thienyl), 127.56 (CH-5-thie-
nyl), 127.73 (CH-p-Ph), 128.04 (CH-4-thienyl), 129.04 (CH-m-Ph),
130.72 (C-3-thienyl), 137.09 (C-ipso-Ph), 145.84 (C-8), 151.44 (C-
4), 153.04 (CH-2), 155.94 (C-6).
Acknowledgment
This work is a part of the research project Z4 055 0506. It was sup-
ported by the ‘Centre for New Antivirals and Antineoplastics’
(1M0508), by the Programme for Targeted Research
(1QS400550501) and by Gilead Sciences, Inc.
References
(1) Review: Legraverend, M.; Grierson, D. S. Bioorg. Med.
Chem. 2006, 14, 3987.
(2) (a) Hocek, M.; Holý, A.; Votruba, I.; Dvořáková, H. J. Med.
Chem. 2000, 43, 1817. (b) Hocek, M.; Holý, A.; Votruba, I.;
Dvořáková, H. Collect. Czech. Chem. Commun. 2001, 66,
483.
ESI-MS: : m/z (%) = 308 (100) [M + 1].
HRMS (ESI): m/z calcd for C16H14N5S:308.0964; found: 308.0963.
Anal. Calcd for C16H13N5S·4/5 H2O (321.8): C, 59.72; H, 4.57; N,
21.76. Found: C, 59.46; H, 4.56; N, 21.46.
(3) Hocek, M.; Nauš, P.; Pohl, R.; Votruba, I.; Furman, P. A.;
Tharnish, P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 5869.
(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. Med. Chem. 2002, 45, 1383. (d) Bakkestuen, A. K.;
Gundersen, L.-L.; Utenova, B. T. J. Med. Chem. 2005, 48,
2710.
(5) Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.;
Gilligan, P. Bioorg. Med. Chem. Lett. 1999, 9, 1063.
(6) Vandromme, L.; Piguel, S.; Lozach, O.; Meijer, L.;
Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. Lett.
2006, 16, 3144.
9-Benzyl-8-(5-methylthiophen-2-yl)adenine (5i)
Prepared from potassium 5-methyl-2-thiophenetrifluoroborate (2i;
122 mg) as a yellowish powder, yield 76%.
Mp 208–213 °C (CH2Cl2–heptane).
IR (CHCl3): 3413, 2988, 1632, 1590, 1464, 1294 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 2.45 (d, JCH3,4 = 1.1 Hz, 3 H,
CH3), 5.63 (s, 2 H, CH2Ph), 6.83 (dq, J4,3 = 3.7 Hz, J4,CH3 = 1.1 Hz,
1 H,H-4), 7.05 (m, 2 H, H-o-Ph), 7.23 (d, J3,4 = 3.7 Hz, 1 H, H-3),
7.25 (m, 1 H, H-p-Ph), 7.31 (m, 2 H, H-m-Ph), 7.37 (br s, 2 H, NH2),
8.15 (s, 1 H, H-2).
13C NMR (125.7 MHz, DMSO-d6): d = 15.17 (CH3), 46.07
(CH2Ph), 118.55 (C-5), 126.22 (CH-o-Ph), 127.07 (CH-4-thienyl),
127.71 (CH-3-thienyl), 128.01 (CH-p-Ph), 129.09 (CH-m-Ph),
Synthesis 2009, No. 8, 1309–1317 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reactions of Halopurines with Aryl- and Alkyltrifluoroborates
1317
(7) (a) Cristalli, G.; Lambertucci, C.; Taffi, S.; Vittori, S.;
Volpini, R. Curr. Top. Med. Chem. 2003, 3, 387.
(21) For review of cross-coupling reactions of
alkyltrifluoroborates, see: Doucet, H. Eur. J. Org. Chem.
2008, 2013.
(22) Molander, G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B.
J. Org. Chem. 2003, 68, 5534.
(23) Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203.
(24) Molander, G. A.; Jean-Gérard, L. J. Org. Chem. 2007, 72,
8422.
(25) (a) Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9,
1597. (b) Molander, G. A.; Dormisky, P. E.; Sandrock, D. L.
J. Org. Chem. 2008, 73, 2052.
(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,
3607.
(8) Chang, L. C. W.; Spanjersberg, R. F.;
(26) Molander, G. A.; Canturk, B. Org. Lett. 2008, 10, 2135.
(27) Molander, G. A.; Petrillo, D. A. Org. Lett. 2008, 10, 1795.
(28) Molander, G. A.; Gormisky, P. E. J. Org. Chem. 2008, 73,
7481.
(29) van den Hoogenband, A.; Lange, J. H. M.; Terpstra, J. W.;
Koch, M.; Visser, G. M.; Korstanje, T. J.; Jastrzebski, J. B.
H. Tetrahedron Lett. 2008, 49, 4122.
(30) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 9550.
(31) Shaughnessy, K. H. Eur. J. Org. Chem. 2006, 1827.
(32) Čapek, P.; Vrábel, M.; Hasník, Z.; Pohl, R.; Hocek, M.
Synthesis 2006, 3515.
(33) (a) Hocek, M.; Dvořáková, H. J. Org. Chem. 2003, 68,
5773. (b) Hocek, M.; Hocková, D.; Dvořáková, H. Synthesis
2004, 889.
(34) Suzuki, A. Chem. Commun. 2005, 4759.
(35) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031.
(36) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam,
V.; Knochel, P. Tetrahedron 1997, 53, 7237.
(37) Gundersen, L.-L.; Bakkestuen, A. K.; Aasen, A. J.; Øverås,
H.; Rise, F. Tetrahedron 1994, 50, 9743.
von Frijtag Drabbe Kunzel, J. K.; Mulder-Krieger, T.;
Brussee, J.; IJzerman, A. P. J. Med. Chem. 2006, 49, 2861.
(9) Montgomery, J. A.; Hewson, K. J. Med. Chem. 1968, 11, 48.
(10) Kuchař, M.; Pohl, R.; Klepetářová, B.; Votruba, I.; Hocek,
M. Org. Biomol. Chem. 2008, 6, 2377.
(11) (a) Šilhár, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Lett.
2004, 6, 3225. (b) Šilhár, P.; Pohl, R.; Votruba, I.; Hocek,
M. Collect. Czech. Chem. Commun. 2005, 70, 1669.
(12) Šilhár, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Biomol.
Chem. 2005, 3, 3001.
(13) Šilhár, P.; Hocek, M.; Pohl, R.; Votruba, I.; Shih, I.; Mabery,
E.; Mackman, R. Bioorg. Med. Chem. 2008, 16, 2329.
(14) Reviews: (a) Hocek, M. Eur. J. Org. Chem. 2003, 245.
(b) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.
2003, 103, 1875. (c) Lakshman, M. K. J. Organomet. Chem.
2002, 653, 234.
(15) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(16) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020.
(17) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68,
4302. (b) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6,
2649.
(38) Brændvang, M.; Gundersen, L.-L. Bioorg. Med. Chem.
2005, 13, 6360.
(18) Molander, G. A.; Fumagalli, T. J. Org. Chem. 2006, 71,
5743.
(19) Molander, G. A.; Bernardi, C. J. Org. Chem. 2002, 67, 8416.
(20) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393.
(39) Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Liu, F.;
Nolsøe, J. M. J. Bioorg. Med. Chem. Lett. 2000, 10, 1207.
(40) Klečka, M.; Tobrman, T.; Dvořák, D. Collect. Czech. Chem.
Commun. 2006, 71, 1221.
(41) Havelková, M.; Dvořák, D.; Hocek, M. Synthesis 2001,
1704.
Synthesis 2009, No. 8, 1309–1317 © Thieme Stuttgart · New York