Efficient synthesis of 6-substituted purine derivatives using Pd-catalyzed cross-coupling reactions with 2'-deoxyguanosine O6-tosylate

Article abstract of DOI:10.3987/COM-07-S(U)24

6-Substituted purine analogs function in a variety of biological activities including antiviral pathways. A number of studies have reported on the development of the efficient synthesis of these nucleoside analogs. We previously demonstrated that oligonucleotides containing 2-amino-6-vinylpurine derivatives react with the cytosine at the target site with extreme selectivity. This was the first finding that O⁶-tosylate derivative of guanosine worked as an efficient substrate for Pd(0)-catalyzed cross-coupling reaction with vinyltributylstannane to produce 2-amino-6-vinylpurine. In order to demonstrate usefulness of the tosylate precursor, in this study we investigated transition metal catalysts and ligands in achieving the cross-coupling reaction using boronic acids or Grignard reagents as a coupling partner.

Full text of DOI:10.3987/COM-07-S(U)24

HETEROCYCLES, Vol. 73, 2007
493
HETEROCYCLES, Vol. 73, 2007, pp. 493 - 501. © The Japan Institute of Heterocyclic Chemistry
Received, 21st June, 2007, Accepted, 23rd July, 2007, Published online, 25th July, 2007. COM-07-S(U)24
EFFICIENT SYNTHESIS OF 6-SUBSTITUTED PURINE DERIVATIVES
USING Pd-CATALYZED CROSS-COUPLING REACTIONS WITH
2’-DEOXYGUANOSINE O6-TOSYLATE
Fumi Nagatsugi,*1, 3 Yuki Ogata,2 Shuhei Imoto,1 and Shigeki Sasaki2, 3
1Institute of Multidiciplinary Research for Advanced Materials Tohoku University,
2
2-1-1 Katahira, Aoba-ku, Sendai-shi, Miyagi Japan, Graduate School of
Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku,
3
Fukuoka Japan, CREST, Japan Science and Technology Agency, 4-1-8 Honcho,
Kawaguchi, Saitama, Japan.
E-mail address: nagatugi@tagen.tohoku.ac.jp
Abstract 6-Substituted purine analogs function in a variety of biological
activities including antiviral pathways. A number of studies have reported on
the development of the efficient synthesis of these nucleoside analogs. We
previously
demonstrated
that
oligonucleotides
containing
2-amino-6-vinylpurine derivatives react with the cytosine at the target site with
extreme selectivity. This was the first finding that O6-tosylate derivative of
guanosine worked as an efficient substrate for Pd(0)-catalyzed cross-coupling
reaction with vinyltributylstannane to produce 2-amino-6-vinylpurine. In
order to demonstrate usefulness of the tosylate precursor, in this study we
investigated transition metal catalysts and ligands in achieving the
cross-coupling reaction using boronic acids or Grignard reagents as a coupling
partner.
INTRODUCTION
The involvement of modified purine analogues in multiple biological pathways has garnered considerable
interest in the synthesis of these compounds. For instance, several modified adenosine derivatives are

494
HETEROCYCLES, Vol. 73, 2007
modulators of adenosine receptors1, and a number of 6-substituted purine derivatives show potent
cytokinin activity and stimulate plant cell growth and cell division.2 Recently, C-6 arylpurine
ribonucleosides have been shown to have cytostatic activity against selected transformed cell lines.3 We
previously reported that 2-amino-6-vinylpurine (1) exhibited efficient cross-linking reactivity to cytosine4,
and oligonucleotides containing 1 exhibited efficient antisense activity in the cell5.
Cross-coupling reactions are a powerful tool for the synthesis of these 6-substituted purine derivatives.
In many cases, 6-halopurines were used as cross-coupling substrates.6 We developed an efficient
method for the synthesis of 1, in which the O6-tosylate of guanosine derivative (2) acts as a good substrate
for cross-coupling reaction with vinylstannanes under catalysis by Pd(0).7
Scheme 1 Synthesis of 2-Amino-6-Vinylpurine (1) by Cross-Coupling Reaction with Vinylstannanes
OTs
Bu3Sn
N
N
N
N
N
N
TBDMSO
TBDMSO
N
NH2
N
NH2
O
O
Pd(PPh3)4(0.1 eq)
LiCl, dioxane, 100 C
94 %
2
1
OTBDMS
OTBDMS
Although cross-coupling reactions of aryl tosylates are more attractive because they are generated from
less expensive reagents and more stable than triflates, few studies have been reported on the
cross-coupling reaction using aryl sulfonates prior to our report. Recently, Lakshman and co-workers
demonstrated that 2’-deoxyguanosine O6-arylsulfonates can be utilized for Pd-catalyzed amination and
C-C coupling reactions with arylboronic acids.8 Aryl tosylates have been utilized for many types of
cross-coupling reactions as substrates in simpler aromatic systems.9 Interestingly, Hartwig and his
group have demonstrated that aryl and alkenyl tosylates can be efficiently coupled with aryl, alkenyl, and
alkyl Grignard reagents under catalysis by a combination of palladium and bulky ligand.10 These
reactions to 2’-deoxyguanosine O6-tosylates are potentially applicable for the generation of more highly
functionalized 6-substituted purines. In this paper, we describe our investigation in synthesizing of
2-amino-6-aryl, alkenyl and alkyl derivatives using palladium catalyzed cross-coupling reactions between
2’-deoxyguanosine O6-tosylate and Grignard reagents. Furthermore, we report the efficient synthesis of
2-amino-6-vinylpurine using vinylboronate ester by Suzuki-type cross-coupling.
RESULTS AND DISCUSSION
The cross-coupling reactions of 2’-deoxyguanosine O6-tosylate (2) with phenylmagnesium bromide
(PhMgBr) were initially investigated using hindered alkyl phosphine as ligands and palladium as catalysts.

HETEROCYCLES, Vol. 73, 2007
495
We found that the cross-coupling between 2 and PhMgBr proceeded smoothly under reflux conditions to
produce the desired coupling product (3) at a 30 % yield, along with dimer (4) at 31 % (Scheme 2). The
previous studies showed that Pd-catalyzed C-N bond formations were observed between C-6 halopurine
and amino group of C-6 aminopurine.11 Under reflux conditions, 3 reacted with O6-tosylate (2) to
generate the cross-coupling product (4). The N2-acetyl protected derivative as substrates did not produce
cross-coupling product under the same conditions, although the O6-tosylate derivative was consumed.
Scheme 2 Coupling of 2’-deoxyguanosine-O6-tosylate (2) with Phenylmagnesium Bromide
NH2
N
Ph
Ph
OTs
N
PhMgBr
N
N
N
N
N
N
+
R1
1 mol% Pd(dba)2
N
N
N
N
N
H
N
NH2
N
NH2
N
N
R1
P(tBu)2
R1
R1
1 mol%
3
4
PPh2
Fe
TBDMSO
Cp
R1:
O
31 %
30 %
reflux 30 min
OTBDMS
In attempting to improve the yield of 3, it was found that 2 mol% each of the catalyst and the ligand, 3
equivalents of PhMgBr, improved the product yield of 3 at room temperature significantly. The ratio of
the catalyst, the ligand and PhMgBr is very critical for the reaction yield, and lower yields were obtained
with PhMgBr of more or less than 3 equivalence (Table 1, entries 1-4). Using the same ratio, effects of
the combination of three catalysts, Pd(dba)2, (C6H5CN)2PdCl2, (dppf)NiCl2, and the four phosphine
ligands (L1-L4) on the yields were examined (Table 1).
Interestingly, the best results were obtained with a different combination of the catalyst and the ligand, i.e.
Pd(dba)2/L1 (entry 3), (C6H5CN)2PdCl2/ L2 (entry 9), and (dppf)NiCl2/L4 (entry 16).
Table 1 Coupling of 2’-deoxyguanosine-O6-tosylate (2) with Phenylmagnesium Bromide using
various combinations of catalysts and ligandsa
OTs
N
Ph
N
N
N
N
N
N
PhMgBr
TBDMSO
TBDMSO
N
NH
NH
2
2
O
O
catalyst
ligand
solvent
OTBDMS
OTBDMS

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HETEROCYCLES, Vol. 73, 2007
Entry
Catalyst
Ligand
PhMgBr
Yield (%)
(equiv.)
1
2
Pd(dba)2
L1
L1
L1
L1
L2
L3
L4
L1
L2
L3
L4
L1
L2
L3
L4
L4
1
3
3
5
3
3
3
3
3
3
3
3
3
3
3
3
trace
72
76b
52
20
21
26
14
56
17
38
16
16
26
30
52b
Pd(dba)2
3
Pd(dba)2
4
Pd(dba)2
5
Pd(dba)2
6
Pd(dba)2
7
Pd(dba)2
8
(C6H5CN)2PdCl2
(C6H5CN)2PdCl2
(C6H5CN)2PdCl2
(C6H5CN)2PdCl2
(dppf)NiCl2
(dppf)NiCl2
(dppf)NiCl2
(dppf)NiCl2
(dppf)NiCl2
9
10
11
12
13
14
15
16
P(t-Bu)2
PCy2
PPh2
PCy2
Cp:
Cy:
PPh2
PCy2
PCy2
PPh2
Fe
Fe
Fe
Fe
Cp
Cp
Cp
Cp
L1
L2
L3
L4
aReaction conditions: Under argon, catalyst (2 mol %) and ligand (2 mol %) were added to a solution of 2 in toluene and the
mixture was degassed with argon for 30 min. PhMgBr (1.0 M THF) was added to the mixture and stirred for 24 h at r.t.
bToluene-THF (2:1) was used as solvent.
We next examined the cross-coupling reactions of the O6-tosylate (2) with several Grignard reagents
(Table 2). The reactions between the tosylate (2) and vinylmagnesium bromide to produce
2-amino-6-vinylpurine were investigated, but, unfortunately, the desired compound was obtained in low
yields (Table 2, entries 1-8). In contrast, 1-propenylmagnesium bromide generated a moderate product
yield (entry 9). This differs from our previous results in that the tributylstannane substrates of the vinyl
and the propenyl derivative produced the corresponding coupling product with Pd(PPh3)4 catalyst in a
similar yield.7 Reactions of allylmagnesium bromide with the tosylate (2) did not give the desired
product under any conditions (entries 10-13). The cross-coupling products were obtained in moderate
yields with the Pd(dba)2/L1 catalyst system for homoallylmagnesium bromide (entry 14), and with the
(dppe)PdCl2/L2 or (C6H5CN)2PdCl2/L2 system for alkylmagnesium bromide (entries 20, 25).

HETEROCYCLES, Vol. 73, 2007
497
Notably it may be a useful finding that 6-alkyl substituted derivatives of 2-aminopurine are prepared by
the coupling reaction between O6-tosylate (2) and the alkyl Grignard reagents with suitable combination
of the palladium catalysts and the phosphine ligands.
Table 2 Pd-Catalyzed Cross-coupling between Grignard Reagents and
2’-deoxyguanosine-O6-tosylate (2)a
OTs
N
R
N
N
N
N
N
N
RMgBr
TBDMSO
TBDMSO
N
NH2
NH2
O
O
catalyst
ligand
solvent
Yield
OTBDMS
Product
OTBDMS
Product
Entry
Grignard
Reagents
Catalyst/ligand
Yield
(%)
Grignard
Reagents
Catalyst/Ligand
Entry
(R=)
(%)
(R=)
7
1
2
3
4
5
6
7
8
9
1
Pd(dba)2/L1
Pd(dba)2/L2
-
14
15
16
17
18
19
20
21
Pd(dba)2/L1
Pd(dba)2/L2
54
31
36
BrMg
(vinyl)
36
16
10
-
(3-butenyl)
BrMg
Pd(dba)2/L3
(dppe)PdCl2/L2
Pd(dba)2/L4
(C6H5CN)2PdCl2/L2 26
(dppe)PdCl2/L1
(dppe)PdCl2/L2
(dppe)PdCl2/L3
(dppe)PdCl2/L4
Pd(dba)2/L1
8
Pd(dba)2/L1
Pd(dba)2/L2
46
58
61b
BrMg
14
20
11
71
(ethyl)
(dppe)PdCl2/L2
(C6H5CN)2PdCl2/L2 52
5
9
Pd(dba)2/L1
39
BrMg
BrMg
22
(1-propenyl)
6
(octyl)
BrMg
(CH2)6
10
11
12
13
Pd(dba)2/L1
Pd(dba)2/L2
-
-
-
-
23
24
Pd(dba)2/L2
34
50
(3-propenyl)
(dppe)PdCl2/L2
(dppe)PdCl2/L2
(C6H5CN)2PdCl2/L2 47
25
(C6H5CN)2PdCl2/L2
a Reaction conditions: Under argon, catalyst (2 mol %) and ligand (2 mol %) were added to a solution of 2 in toluene-THF
(2:1) and the mixture was degassed with argon for 30 min. Grignard reagents (3 equiv.) was added to the mixture and stirred
for 24 h at r.t. The structure of the ligands (L1-L4) are shown in the footnote of Table 1. b Reaction time was 2 h.
After several attempts for vinylation reactions with various organometallic reagents, including
magnesium, zinc, and indium derivatives, we found that vinylboronate ester by Suzuki-type
cross-coupling reaction with O6-tosylate (2) afforded the 6-vinylated compound (1) in good yield (Table
3). The use of the vinylboronate ester is superior to the previous method with the vinylstannane reagent,
as this method can be applied to a large scale synthesis and the vinylboronate ester is less toxic than the
vinylstannane reagent.

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HETEROCYCLES, Vol. 73, 2007
Table 3 Pd-Catalyzed Cross-coupling between 2,4,6-Trivinylcyclotriboroxane Pyridine and
2’-Deoxyguanosine-O6-tosylate (2)
OTs
Pd(PPh3)4 (0.1 eq)
B
N
N
N
N
N
N
O
B
O
B
.
+
TBDMSO
TBDMSO
additive
solvent
N
NH2
N
N
NH2
O
O
O
OTBDMS
OTBDMS
Entry
Additive
Solvent
Temperature
110 °C
Time
Yield (%)
1
2
3
4
5
6
LiBr, LiOH
LiCl, LiOH
LiBr, LiOH
LiCl, LiOH
dioxane /H2O
THF/H2O
2 h
8 h
84
68
54
75
75
46
60 °C to 80 °C
60 °C to 80 °C
110 °C
THF/H2O
8 h
dioxane/H2O
dioxane /H2O
dioxane /H2O
3.5 h
2 h
LiBr, K2CO3
LiI, LiOH
110 °C
110 °C
30 min
CONCLUSION
In conclusion, we developed the palladium catalyzed cross-coupling reactions with Grignard reagents and
O6-tosylated 2-aminopurine (2) using sterically hindered bisphosphine ligands to generate the
corresponding 6-aryl- and 6-alkyl-substituted 2-aminopurine products.
We further show that
2-amino-6-vinylpurine is obtained in good yield by palladium catalyzed cross-coupling reaction from 2
with vinylboronate ester. As O6-tosylated 2-aminopurine nucleoside derivative is easily prepared
compared to the corresponding 6-halogen derivatives, this may be a useful precursor for the
cross-coupling reaction to produce a variety of 6-alkyl or aryl-2-aminopurine derivatives.
EXPERIMENTAL
General
1H-NMR (400, or 500 MHz) spectra were recorded on a Varian UNITY-400, INOVA-500. 13C-NMR
(125 MHz) spectra were recorded on a Varian UNITY-400. IR spectra were obtained using a
SHIMADZU FTIR-8400 spectrophotometer. HRMS analyses were recorded on Applied Biosystems
Mariner System 5299 spectrometer using bradykinin, neurotensin and angiotensin as internal standards.
Representative Procedure for Palladium Catalyzed Cross-Coupling Reactions with Grignard
Reagents. Synthesis of 2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)

HETEROCYCLES, Vol. 73, 2007
499
-6-phenylpurine (3) A solution of catalyst (2 µmol), ligand (2 µmol) and 2 (0.1 mmol) in toluene and
THF (5:1, 1.2 mL) was degassed with argon, followed by the addition of 1.0 M phenylmagnesium
bromide (THF solution, 0.3 mmol), then the mixture was stirred under argon at rt. After 24 h, the
reaction mixture was diluted with 20 % NH4Cl, extracted with EtOAc and the organic layer was washed
with saturated aqueous NaHCO3, brine. The organic layer was dried over Na2SO4 and evaporated to
give the crude product, which was chromatographed on a silica gel column (hexane:AcOEt=5:1 to 4.5:1)
to give 3 as a yellow syrup. FTIR (cm-1, neat): 2929, 1561, 1114; 1H-NMR (CDCl3) 8.63-8.61 (2H, m),
8.04 (1H, s), 7.52-7.43 (3H, m), 6.38 (1H, t, J=6.6 Hz), 5.13 (2H, s), 4.62-4.59 (1H, m), 4.01-3.98 (1H,
m), 3.82-3.73 (2H, m), 2.66-2.60 (1H, m), 2.40-2.34 (1H, m), 0.91 (9H, s), 0.89 (9H, s), 0.10 (6H, s), 0.06
(6H, s); 13C-NMR (125 MHz, CDCl3) -5.3, -5.1, -4.5, –4.4, 18.6, 26.2, 40.9, 63.1,72.4, 83.8, 88.0, 126.3,
128.7, 130.0, 130.8, 136.1, 140.0, 154.2, 156.1, 160.0; ESI-HRMS calcd for C28H46N5O3Si2 (M+H)+
556.3134, found 556.3144.
1
4: as a yelow syrup, FTIR (cm-1, neat): 2929, 1586; H-NMR (CDCl3) 8.84-8.81 (2H, m), 8.57 (1H, bs),
8.24 (1H, s), 7.92 (1H, s), 7.57-7.51 (3H, m), 6.54 (1H, dd, J=7.24, 6.6 Hz), 6.36 (1H, J=6.3 Hz), 5.01
(2H, s), 4.66-4.64 (1H, m), 4.63-4.60 (1H, m), 4.05-4.03 (1H, m), 4.02-3.99 (1H, m), 3.93 (1H, dd, J=5.1,
11.2 Hz), 3.85 (1H, dd, J=4.4, 11.2 Hz), 3.78 (1H, dd, J=3.2, 7.3 Hz), 3.76 (1H, dd, J=3.2, 7.3 Hz), 2.96
(1H, ddd, J=5.4, 7.6, 13.0. Hz), 2.64 (1H, ddd, J=5.8, 7.3, 13.0. Hz), 2.48 (1H, ddd, J=3.0, 5.9, 13.2. Hz),
2.39 (1H, ddd, J=3.2, 5.8, 13.1. Hz), 0.94 (9H, s), 0.93 (9H, s), 0.92 (9H, s), 0.90 (9H, s), 0.13 (6H, s),
0.12 (6H, s), 0.09 (6H, s), 0.07 (3H, s), 0.06 (3H, s), ESI-HRMS calcd for C50H85N10O6Si4 (M+H)+
1033.5725, found 1033.5695.
2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-6-(1-propenyl)purine (5)
1
FTIR (cm-1, neat): 2928, 1591, 1100; H-NMR (CDCl3) 7.99 (1H, s), 7.44 (0.6 H, dq, J=15.5, 6.9 Hz),
6.90 (0.4 H, dq, J=11.9, 2.0 Hz), 6.85 (0.6 H, dq, J=15.2, 1.7 Hz), 6.29 (0.4 H, dq, J=11.6, 7.3 Hz), 6.36
(1H, dd, J=5.6, 1.9 Hz), 4.89 (2H, bd), 4.60 (1H, q, J=3.0 Hz), 3.99 (1H, q, J=3.3 Hz), 3.82 (1H, dd,
J=11.1, 4.3 Hz), 3.75 (1H, dd, J=11.2, 3.6 Hz), 2.64-2.59 (1H, m), 2.40-2.31 (1H, m), 2.26 (1.2 H, dd,
J=7.3, 2.0 Hz), 2.02 (1.8 H, dd, J=6.9, 1.7 Hz), 0.92 (9H, s), 0.91 (9H, s), 0.11 (6H, s), 0.08 (3H, s), 0.07
(3H, s); ESI-HRMS calcd for C25H46N5O3Si2 (M+H)+ 520.3134, found 520.3114.
2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-6-(3-butenyl)purine (7)
1
FTIR (cm-1, neat): 2929, 1592; H-NMR (CDCl3) 7.93 (1H, s), 6.32 (1H, t, J=6.9 Hz), 5.88 (1H, ddt,
J=8.6, 10.6, 16.9 Hz), 5.06 (1H, dd, J=1.4, 16.9 Hz), 5.05 (2H, bs), 4.95 (1H, dd, J=10.6, 1.4 Hz),
4.59-4.56 (1H, m), 3.98-3.95 (1H, m), 3.80-3.71 (2H, m), 3.07 (2H, t, J=7.8 Hz), 2.65-2.54 (3H, m),
13
2.36-2.30 (1H, m), 0.90 (9H, s), 0.88 (9H, s), 0.09 (6H, s), 0.05 (6H, s); C-NMR (125 MHz, CDCl3)

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HETEROCYCLES, Vol. 73, 2007
-5.5, -5.4 -4.8, -4.7, 18.0, 18.3, 25.7, 25.9, 32.2, 32.4, 40.6, 62.9, 72.1, 83.5, 87.7, 115.1, 127.1, 137.5,
139.2, 152.3, 159.5, 162.9; ESI-HRMS calcd for C26H48N5O3Si2 (M+H)+ 534.3290, found 534.3300.
2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-6-ethylpurine (8)
1
Yellow caramel; FTIR (cm-1, neat): 2929, 1592; H-NMR (CDCl3) 7.93 (1H, s), 6.31 (1H, t, J=6.9 Hz),
4.94 (2H, s), 4.59-4.56 (1H, m), 3.98-3.95 (1H, m), 3.81-3.71 (2H, m), 3.00 (2H, q, J=7.8 Hz), 2.64-2.58
(1H, m), 2.36-2.30 (1H, m), 1.35 (3H, t, J=7.8 Hz), 0.90 (9H, s), 0.88 (9H, s), 0.09 (6H, s), 0.05 (6H, s);
13C-NMR (125 MHz, CDCl3) -5.5, -5.4 -4.8, -4.7, 12.6, 18.0, 18.4, 25.8, 25.9, 26.5, 40.6, 62.9, 72.2, 83.6,
87.7, 126.9, 139.1, 152.2, 160.0, 164.9; ESI-HRMS calcd for C24H46N5O3Si2 (M+H)+ 508.3134, found
508.3112.
2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-6-octylpurine (9)
1
Orange oil; FTIR (cm-1, neat): 2928, 1591; H-NMR (CDCl3) 7.94 (1H, s), 6.34 (1H, t, J=6.7 Hz), 4.90
(2H, s), 4.62-4.57 (1H, m), 4.01-3.98 (1H, m), 3.80 (1H, dd, J=4.1, 11.2 Hz), 3.75 (1H, dd, J=3.1, 11.0
Hz), 2.98 (2H, t, J=7.9 Hz), 2.64 (1H, ddd, J=5.8, 7.3, 13.0 Hz), 2.35 (1H, ddd, J=3.4, 6.1, 13.0 Hz),
1.84-1.78 (2H, m), 0.93-0.91 (10H, m), 0.87 (3H, t, J=.7.1 Hz), 0.90 (9H, s), 0.88 (9H, s), 0.09 (6H, s),
13
0.05 (6H, s); C-NMR (125 MHz, CDCl3) -5.5, -5.4, -4.8, -4.7, 14.1, 18.0, 18.4, 25.8, 25.9, 28.7, 29.2,
29.4, 29.7, 30.2, 31.8, 33.4, 40.5, 62.9, 72.2, 83.9, 87.7, 126.9, 140.2, 152.2, 159.4, 164.1; ESI-HRMS
calcd for C30H58N5O3Si2 (M+H)+ 592.4073, found 592.4086.
ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for Scientific Research from Japan Society for the Promotion
of Science (JSPS), CREST from Japan Science and Technology Corporation and Advanced and
Innovational Research Program in Life Sciences from the Ministry of Education, Culture, Sports, Science
and Technology, the Japanese Government.
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