Microwave-assisted Pd/Cu-catalyzed C-8 direct alkenylation of purines and related azoles: An alternative access to 6,8,9-trisubstituted purines

Article abstract of DOI:10.1021/jo201893h

An efficient microwave-assisted palladium/copper comediated C-8 direct alkenylation of purines with styryl bromides has been developed. The method is regioselective, functional group tolerant, rapid, and compatible with other related azoles. Combined with

Full text of DOI:10.1021/jo201893h

Note
pubs.acs.org/joc
Microwave-Assisted Pd/Cu-Catalyzed C-8 Direct Alkenylation of
Purines and Related Azoles: An Alternative Access to 6,8,9-
Trisubstituted Purines
Roxane Vabre,†,‡ Franciane Chevot,†,‡ Michel Legraverend,‡ and Sandrine Piguel*,†,‡
†Univ Paris-Sud, Orsay, F-91405, France
‡Institut Curie/CNRS, UMR 176, Bat
̂
. 110-112, Centre Universitaire, 91405 Orsay France
S
* Supporting Information
ABSTRACT: An efficient microwave-assisted palladium/
copper comediated C-8 direct alkenylation of purines with
styryl bromides has been developed. The method is
regioselective, functional group tolerant, rapid, and compatible
with other related azoles. Combined with subsequent
nucleophilic substitution, it provides an easy access to new 6,8,9-trisubstituted purines.
he purine scaffold is an ubiquitous feature in both
biological systems and synthetic compounds finding
direct alkenylation with various styryl bromides under micro-
T
wave conditions using a Pd/Cu cocatalyst system. Furthermore,
our process is feasible on a purine bearing a labile group in
position 6 that can be further functionalized on that position,
giving access to new 6,8,9-trisubstituted purines.
applications as biologically active compounds and fluorescent
probes.1−3 The broad spectrum of properties displayed by
purines is conferred by the number and diversity of substituents
that can be introduced on the seven peripheral atoms. As a
consequence, a plethora of methodologies for the construction
and functionalization of purines has been intensively ex-
plored.4−6 In the context of a medicinal chemistry program, we
were interested in generating a variety of C-8 vinyl-substituted
purines based on the direct alkenylation of a suitably
substituted purine, which could subsequently be used for
further functionalization on the other positions. Increasing
interest in C-8 substituted purines has driven the development
of more or less efficient methods for their elaboration, including
the heterocyclization of aminopyrimidine derivatives with
aldehydes,7 carboxylic acids8,9 or amides,10 metal-catalyzed
cross-coupling reactions of appropriate C-8-halogenated
purines,11−17 and direct metalation.18,19 A Pd-catalyzed allylic
substitution for the preparation of various C-8-alkenylated
purines has also been reported.20 In addition, transition-metal-
catalyzed C−H bond functionalization of purines has gained
significant attention in recent years. In particular, the direct
arylation21−26 and to a lesser extent direct alkenylation27 and
benzylation28 have been developed. A preliminary and single
example of microwave-assisted direct alkenylation of 9-
benzyladenine has been reported, requiring elevated temper-
ature (160 °C) and an excess of copper (2 equiv).29 Following
this work, the same group has examplified the direct
alkenylation process on caffeine and 9-benzyladenine with
various alkenyl halides; however, substantially modified
conditions and classical heating were used.27 Furthermore, no
E-styryl bromides bearing electron-withdrawing or electron-
donating groups were studied.
As the direct C-8 alkenylation of 6-chloropurine was
unsuccessful,30 we envisaged the use of the 6-benzylsulfanyl-
9-benzylpurine 1. Indeed, the thio-ether substituent is known to
be inert toward various conditions, including SNAr and cross-
coupling reactions, and as the results show, this motif is also
unreactive in the direct alkenylation conditions described
here.31 Furthermore, the sulfur atom could serve as a leaving
group after oxidation to the corresponding sulfone for
subsequent substitution with suitable nucleophiles, thus
providing new 6,8,9-trisubstituted purines. Compound 1 was
readily prepared in a two-step literature procedure starting from
6-chloropurine in an overall yield of 47%.31,32
In the pursuit of our program directed toward the
development of copper-catalyzed C−H bond functionalization
of azoles, we initially investigated the reaction between purine 1
and (E)-β-bromostyrene 2a by screening a series of copper/
ligand sources with LiOtBu as a base in dioxane at 120 °C
(Table 1).33−35 Unfortunately, despite extensive optimization,
we were unable to find an efficient copper-catalyzed protocol.
The yield of the alkenylated purine 3a did not exceed 20% with
CuI or CuBr·SMe2 in combination with phenantroline as
ligand, even after prolonged heating (Table 1, entries 1−2).
Other copper/ligand sources resulted in no conversion. Even
the system CuI/phenanthroline/K3PO4 used by You et al. for
the related direct arylation of caffeine failed.36 Adding a small
amount of palladium cocatalyst Pd(OAc)2 to the reaction
mixture, which previously had been effective,33 did not
significantly improve the yield (Table 1, entry 3, 22% yield).
Herein, we report our efforts to expand the type of reactions
that can be used to functionalize the purine ring and especially
the C8-position through a rapid and functional group tolerant
Received: September 13, 2011
Published: October 17, 2011
© 2011 American Chemical Society
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Note
Table 1. Optimization of the Thermal Direct Alkenylation
Conditions
Table 2. Optimization of the Microwave-Assisted Direct
Alkenylation Conditions
a
a
b
entry
Pd source (5 mol %)
solvent
yield (%)
b
c
entry
reaction time (min)
yield (%)
1
2
3
4
5
6
7
8
9
10
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
16
c
1
2
3
4
5
6
7
30
60
15
30
30
30
30
74 (73)
70
61
18
22
Pd(OAc)2
Pd(OAc)2
PdCl2(CH3CN)2
Pd(acac)2
d
65
d
d
44
62
e
d
<5
42
f
de
,
52
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
51
g
d
35
38
d
a
toluene
THF
43
All reactions were performed at 0.2 M of purine (1 equiv) and styryl
bromide (2 equiv) in dioxane heated at 120 °C in a microwave reactor.
Isolated yields. Yield in parentheses was obtained for a reaction run
on a gram-scale. Reaction run at 100 °C. Cs2CO3 was used as base.
Only 10 mol % ligand were used. Thermal heating with premixing
f
37
b
c
a
All reactions were performed in a sealed tube at 0.2 M of purine (1
equiv), styryl bromide (2 equiv), t-BuOLi (2 equiv) in dioxane at 120
°C overnight; β-bromostyrene 2a was used as a mixture of E/Z: 8/2
isomers. Isolated yields. CuBr·SMe2 was used. Premixing CuI and
phenanthroline for 30 min. 10 and 5 mol % copper and ligand were
d
e
f
g
b
c
d
CuI and phenanthroline for 30 min.
e
f
%), phenanthroline (20 mol %), Pd(OAc)2 (5 mol %) in
dioxane at 120 °C under microwave irradiation for 30 min.
This optimized protocol was subsequently applied to the
direct C-8 alkenylation of purine 1 with various readily
accessible E-β-bromostyrenes (Scheme 1). These building
blocks were prepared in a two-step sequence starting from
the commercially available aldehydes via the Ramirez procedure
followed by the Hirao reduction.38,39 Both electron-rich and
electron-deficient β-bromostyrenes reacted at the C-8 position
of the purine in moderate to good yields. These conditions are
compatible with a range of functional groups including nitro,
cyano, and halides, which may be used for further trans-
formations. However, the dimethoxy substituent gave a
disappointing 24% yield. Noteworthy was the acetal group,
which survived the reaction conditions and underwent coupling
to afford the alkenylated purine 3j in a satisfactory 44% yield.
Unfortunately, related β-bromoalkenes bearing a simple alkyl
substituent were not reactive. Z-β-bromostyrenes, as illustrated
by the use of Z-β-bromo-4-methylstyrene, gave the expected
compound 3l in a 26% yield as an 8:2 mixture of Z/E isomers.
These results are still unclear at this stage.
used, respectively. P(o-tolyl)3 was used as ligand: Alami conditions.
Surprisingly, the problem was overcome by premixing the
copper source with phenanthroline for 30 min before adding
the rest of the reactants. In this way, the alkenylated product 3a
was isolated in 65% yield as the single E-stereoisomer (Table 1,
entry 4). A comparable result was obtained by using
PdCl2(CH3CN)2, whereas Pd(acac)2 gave the expected product
in a moderate 42% yield (Table 1, entries 5−6). Dioxane
proved to be the better solvent, as reactions in DMF or toluene
resulted in lower yields (Table 1, entries 8−9). In control
reactions, where the copper catalyst, the ligand, the palladium,
or the base was left out, only trace amounts of 3a were formed
(not shown). In addition, the reaction conditions reported by
Alami et al. for direct alkenylation between caffeine and alkenyl
halides were not suitable for our substrate, as the yield of our
target compound was low (Table 1, entry 10).27 These findings
are consistent with the majority of direct C−H bond
functionalization of purines, where a Pd/Cu cocatalyst is
generally required, although this is not always the case.34,36,37
Next, we turned our attention to the use of microwave
irradiation to shorten reaction times (Table 2). With
microwave heating, the targeted 8-styrylpurine 3a was cleanly
obtained in a slightly better yield, 74%, in only 30 min
compared to 16 h for conventional heating (Table 2, entry 1).
But more importantly, preactivation of the copper/ligand duet
was no longer needed. The yield of 3a remained unchanged
upon increasing the reaction time to 60 min (Table 2, entry 2),
whereas lower yields were obtained with a reaction time of 15
min or a temperature of 100 °C (Table 2, entries 3−4).
Replacing LiOtBu with Cs2CO3 was detrimental to the direct
alkenylation process, returning the starting material essentially
unchanged (Table 2, entry 5). Changing the ratio of CuI to
phenanthroline from 1:2 to 1:1 gave a negative effect, giving 3a
in 52% yield (Table 2, entry 6). For comparison, the same
reaction carried out for 30 min using traditional oil bath heating
afforded the alkenylated purine 3a in only 35% yield after 30
min premixing of the copper/ligand pair (Table 2, entry 7).
Thus, the optimum conditions were shown to be CuI (10 mol
An array of additional related azoles was also compatible with
the microwave-assisted catalyzed direct alkenylation conditions,
although varied reactivities were observed. Surprisingly, caffeine
coupled in a low 32% yield as well as 1,3,4-oxadiazole. Other
heterocycles such as 5-phenyloxazole, N-methylbenzimidazole,
benzothiazole, and 1,2,4-triazole gave moderate to good yields.
Oxazole itself was regioselectively alkenylated at the C-2
position (Scheme 2).
After having successfully alkenylated position 8 of the
functionalized purine, we were keen to investigate the
subsequent reaction at position 6 in order to check whether
the double bond would be compatible with the oxidation
conditions required for the activation of the 6-benzylsulfanyl
group. Pleasingly, selective activation of the sulfur atom was
then achieved by oxidation of compound 3a with m-CPBA in
CH2Cl2 to afford the corresponding sulfone in a quantitative
yield and that was sufficiently pure to be used in the next step
without further purification. This result is particularly note-
worthy, as it leaves the CC double bond untouched and
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Note
a
Scheme 1. Scope of Microwave-Assisted Direct Alkenylation of Purines with Alkenyl Bromides
a
Yields are calculated on isolated products (average of two runs).
b
Commercially available α-bromostyrene was used as coupling partner 2.
a
obtained in a two-step sequence from 3a with an overall yield
ranging from 48 to 79% (Scheme 3).
Scheme 2. Scope with Respect to the Heterocycles
In summary, a microwave-enhanced C-8 direct alkenylation
of purines and related azoles with various styryl bromides has
been developed, expanding the scope of previously described
methods. The high functional group tolerance and the speed of
the reaction render this method suitable for the combinatorial
synthesis of polyfunctionalized purines that is complementary
to existing methodologies. Subsequently, by combining with
nucleophilic substitution, the purine ring can now be
functionalized at positions 8 and 6, respectively, providing
access to new 6,8,9-trisubstituted purines that are actively being
investigated as valuable compounds for their biological and
physical properties. The presence of the benzylsulfanyl group
and its stability in the direct alkenylation conditions opens the
way to solid-phase synthesis of polyfunctionalized purines using
a sulfur-linked resin as a traceless linker.31
EXPERIMENTAL SECTION
■
General Experimental Methods. Commercially available re-
agents and solvents were used without further purification unless
otherwise stated. Yields refer to isolated and purified products.
Reactions were monitored by thin-layer chromatography carried out
on silica gel plates (60F-254) visualized under UV light. Column
chromatography was performed on silica gel 60, 40−63 μm. Chemical
shifts of 1H NMR and 13C NMR were reported in ppm (δ units), and
residual nondeuterated solvent was used as internal reference. The
following abbreviations were used to designate the multiplicities: s =
a
Yields are calculated on isolated products (average of two runs).
allows subsequent functionalization on the 6 position to access
new 6,8,9-trisubstituted purines of biological interest. Indeed,
the sulfone 11 underwent facile conversion to the compounds
12a−g upon reaction with the requisite amine in EtOH at 110
°C via SNAr. Thus, the 6-amino-8-styrylpurines 12a−g were
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Note
Scheme 3. Functionalization at Position 6 of the Purine via SNAr Displacement
singlet, d = doublet, t = triplet, q = quadruplet, bs = broad singlet, bd =
broad doublet, m = multiplet. Microwave irradiation was performed on
CEM Explorer (CEM Corporation). Temperature measurement of the
reaction mixture within the Discovery series was achieved by an IR
sensor. The method was set with a maximum power of 150 W with a
maximum pressure of 17 bar and used without powermax. Reaction
times refer to the hold time at the desired set temperature. Reaction
cooling was performed by compressed air after the heating period was
over.
0.018 mmol, 5 mol %), tBuOLi (57.8 mg, 0.722 mmol, 2 equiv),
distilled β-bromostyrene (132.2 mg, 0.722 mmol, 2 equiv), and
dioxane (2 mL). The tube was sealed with a rubber cap and heated to
120 °C for 30 min under microwave irradiation. The reaction mixture
was taken into EtOAc and washed with water, and the organic layer
was dried (MgSO4) and concentrated. The residue was purified by
flash chromatography on silica gel, eluting with cyclohexane/EtOAc
(100/0 → 85/15). The title compound was obtained as a yellow solid
(116.2 mg, 74%): mp = 148−150 °C; 1H NMR (300 MHz, CDCl3) δ
8.72 (s, 1H), 8.02 (d, J = 15.8 Hz, 1H), 7.51−7.47 (m, 4H), 7.34−7.21
(m, 11H), 6.96 (d, J = 15.8 Hz, 1H), 5.54 (s, 2H), 4.70 (s, 2H); 13C
NMR (75 MHz, CDCl3) δ 158.7, 151.4, 151.3, 150.0, 139.5, 137.5,
135.7, 135.4, 131.2, 129.6, 129.2, 129.1, 128.9, 128.5, 128.2, 127.5,
127.2, 126.8, 112.3, 45.7, 32.9. MS (ES+) m/z (%): 435.3 (30) [M +
H]+, 457.3 (100) [M + Na]+. HRMS (ESI) calcd for C27H23N4S [(M
+ H)+] 435.1643, found 435.1626.
General Procedure As Illustrated for the Preparation of (E)-
4-(2-Bromovinyl)-1,1′-biphenyl (2c). To a solution of 4-(2,2-
dibromovinyl)-1,1′-biphenyl35 (507.2 mg, 1.838 mmol, 1 equiv) in
diethyl phosphonate (761.5 mg, 5.514 mmol, 3 equiv) was added
triethylamine (557.9 mg, 5.514 mL, 3 equiv). The reaction mixture
was stirred at room temperature for 1.5 h. Diethyl ether was added,
and the salts were removed by filtration. After evaporation of the
filtrate, the residue was purified by flash chromatography on silica gel,
eluting with cyclohexane to afford the title compound as a white solid
(E)-9-Benzyl-6-(benzylthio)-8-(4-methylstyryl)-9H-purine
1
(3b). A yellow solid (91.2 mg, 61%): mp = 162−164 °C; H NMR
1
(271 mg, 75%): H NMR (300 MHz, CDCl3) δ 7.58 (t, J = 7.7 Hz,
(300 MHz, CDCl3) δ 8.71 (s, 1H), 8.01 (d, J = 15.6 Hz, 1H), 7.51−
7.16 (m, 14H), 6.92 (d, J = 16.2 Hz, 1H), 5.54 (s, 2H), 4.70 (s, 2H),
2.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 151.6, 151.3,
150.0, 140.0, 139.6, 137.5, 135.7, 132.6, 131.3, 129.6, 129.2, 129.1,
128.5, 128.2, 127.5, 127.2, 126.8, 111.2, 45.7, 32.9, 21.5. MS (ES+) m/
z (%): 449.2 (100) [M + H]+, 471.2 (40) [M + Na]+. HRMS (ESI)
calcd for C28H25N4S [(M + H)+] 449.1800, found 449.1816.
4H), 7.47−7.36 (m, 5H), 7.14 (d, J = 14.0 Hz, 1H), 6.81 (d, J = 14.0
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 141.0, 140.4, 136.7, 134.9,
132.5, 131.9, 129.4, 128.8, 127.5, 127.4, 127.0, 126.9, 126.5, 106.5. MS
(ES+) m/z (%) 280.90 (100): [M + Na]+. HRMS (ESI) calcd for
C14H11BrNa [(M + Na)+] 280.9942, found 280.9947.
Compounds 2b,40 2d,41 2e,42 2f,43 2g,44 2h,45 2i,40 and 2l46 showed
satisfactory spectroscopic data in agreement with those reported in the
literature.
(E)-8-(2-([1,1′-Biphenyl]-4-yl)vinyl)-9-benzyl-6-(benzylthio)-
9H-purine (3c). A yellow solid (116 mg, 63%): mp = 172−174 °C;
1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.07 (d, J = 15.8 Hz,
1H), 7.60−7.21 (m, 19H), 7.00 (d, J = 15.8 Hz, 1H), 5.57 (s, 2H),
4.71 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 158.7, 151.4, 151.3,
150.0, 142.3, 140.2, 139.0, 137.5, 135.7, 134.3, 131.3, 129.2, 129.1,
128.9, 128.5, 128.2, 128.0, 127.7, 127.5, 127.2, 127.0, 126.8, 112.1,
45.7, 32.9. MS (ES+) m/z (%): 511.3 (85) [M + H]+, 533.3 (55) [M
+ Na]+. HRMS (ESI) calcd for C33H27N4S [(M + H)+] 511.1956,
found 511.1960.
(E)-1-(2-Bromovinyl)-4-(diethoxymethyl)benzene (2j). A
1
light yellow oil (857.7 mg, 73%): H NMR (300 MHz, CDCl3) δ
7.44 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 14.0 Hz,
1H), 6.78 (d, J = 14.0 Hz, 1H), 5.48 (s, 1H), 3.64−3.50 (m, 4H), 1.24
(t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 139.2, 136.9,
135.9, 127.1, 125.9, 106.8, 101.1, 61.0, 15.2. MS (ES+) m/z (%):
307.2 (90) [M + Na]+. HRMS (ESI) calcd for C13H17BrNaO2 [(M +
Na)+] 307.0310, found 307.0315.
1-Phenyl-1H-[1,2,4]triazole47 and 9-benzyl-6-chloro-9H-purine32
were prepared according to procedures described in the literature.
9-Benzyl-6-(benzylthio)-9H-purine (1). Benzylmercaptan (2.67
g, 21.46 mmol, 2.1 equiv) and triethylamine (2.17 g, 21.46 mmol, 2.1
equiv) were added to a solution of 9-benzyl-6-chloro-9H-purine (2.5 g,
10.22 mmol, 1 equiv) in EtOH (40 mL). The reaction mixture was
heated at 60 °C overnight. After evaporation, the residue was extracted
with DCM and washed with NH4Cl, and the organic layer was dried
(MgSO4) and concentrated. After purification by flash chromatog-
raphy on silica gel (DCM), the title compound was obtained as a white
solid (3.12 g, 92%): 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 7.92
(s, 1H), 7.47 (d, J = 6.8 Hz, 2H), 7.36−7.24 (m, 8H), 5.41 (s, 2H),
4.67 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 160.7, 152.1, 148.7,
142.5, 137.4, 135.1, 131.0, 129.2, 129.1, 128.6, 128.5, 127.8, 127.3,
47.3, 32.8. MS (ES+) m/z (%): 333.2 (100) [M + H]+. HRMS (ESI)
calcd for C19H17N4S [(M + H)+] 333.1174, found 333.1188.
(E)-9-Benzyl-6-(benzylthio)-8-(3,4-dimethoxystyryl)-9H-pu-
rine (3d). After crystallization from cyclohexane/Et2O, the title
compound was obtained as a yellow solid (42 mg, 24%): mp = 132−
134 °C; 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 7.96 (d, J = 15.8
Hz, 1H), 7.50 (d, J = 6.9 Hz, 2H), 7.34−7.20 (m, 8H), 7.09 (d, J = 8.3
Hz, 1H), 6.96 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 15.8 Hz,
1H), 5.55 (s, 2H), 4.70 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 158.3, 151.7, 151.3, 150.6, 150.1, 149.1, 139.3,
137.5, 135.8, 131.3, 129.2, 129.1, 128.5, 128.2, 127.2, 126.8, 121.5,
111.1, 110.3, 109.6, 56.0, 55.9, 45.7, 32.9. MS (ES+) m/z (%): 495.3
(100) [M + H]+, 517.3 (20) [M + Na]+. HRMS (ESI) calcd for
C29H27N4O2S [(M + H)+] 495.1855, found 495.1842.
(E)-9-Benzyl-6-(benzylthio)-8-(3-fluorostyryl)-9H-purine
1
(3e). A yellow solid (116 mg, 71%): mp = 168−170 °C; H NMR
(300 MHz, CDCl3) δ 8.73 (s, 1H), 7.98 (d, J = 15.8 Hz, 1H), 7.50 (d,
J = 6.8 Hz, 2H), 7.36−7.14 (m, 11H), 7.03 (td, J = 8.4, 2.9 Hz, 1H),
6.95 (d, J = 15.8 Hz, 1H), 5.55 (s, 2H), 4.70 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 164.7, 161.4, 159.0, 151.6, 150.7, 150.0, 138.1, 138.0,
137.7, 137.6, 137.4, 135.6, 131.2, 130.4, 129.22, 129.16, 128.5, 128.3,
127.3, 126.8, 123.7, 123.6, 116.6, 116.3, 113.7, 113.6, 113.4, 45.7, 32.9.
MS (ES+) m/z (%) 453.3 (45) [M + H]+, 475.3 (100) [M + Na]+.
General Procedure for the Direct Alkenylation As Illustrated
for the Preparation of (E)-9-Benzyl-6-(benzylthio)-8-styryl-9H-
purine (3a). A flame-dried tube filled with argon was charged with 1
(120 mg, 0.361 mmol, 1 equiv), CuI (6.9 mg, 0.036 mmol, 10 mol %),
phenanthroline (13 mg, 0.072 mmol, 20 mol %), Pd(OAc)2 (4.1 mg,
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Note
HRMS (ESI) calcd for C27H22FN4S [(M + H)+] 453.1549, found
453.1558.
128.5, 128.0, 127.3, 127.1, 114.6, 46.1, 33.0, 21.4. MS (ES+) m/z (%):
449.5 (100) [M + H]+. HRMS (ESI) calcd for C28H25N4S [(M + H)+]
449.1800, found 449.1801.
(E)-9-Benzyl-6-(benzylthio)-8-(4-(trifluoromethyl)styryl)-9H-
1
Compounds 4,33 5,27 6,48 7,33 9,33 and 1049 showed satisfactory
spectroscopic data in agreement with those reported in the literature.
(E)-2-Phenyl-5-styryl-1,3,4-oxadiazole (8). A brown solid (98
mg, 29%): mp = 134−136 °C; 1H NMR (300 MHz, CDCl3) δ 8.14−
8.11 (m, 2H), 7.66−7.53 (m, 6H), 7.44−7.39 (m, 3H), 7.11 (d, J =
16.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.3, 164.0, 138.9,
134.8, 131.8, 130.0, 129.09, 129.05, 127.5, 127.0, 123.8, 110.0. MS (ES
+) m/z (%) 271.1 (100) [M + Na]+. HRMS (ESI) calcd for
C16H13N2O [(M + H)+] 249.1028, found 249.1027.
purine (3f). A yellow solid (57 mg, 44%): mp = 174−176 °C; H
NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.03 (d, J = 15.9 Hz, 1H),
7.63−7.55 (m, 4H), 7.50 (d, J = 6.9 Hz, 2H), 7.35−7.19 (m, 8H), 7.02
(d, J = 15.8 Hz, 1H), 5.57 (s, 2H), 4.70 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 159.3, 151.8, 150.5, 150.0, 138.7, 137.5, 137.4, 135.6, 131.2,
130.8, 129.22, 129.19, 128.5, 128.4, 127.6, 127.3, 126.8, 125.9, 125.8,
122.1, 114.8, 45.8, 32.9. MS (ES+) m/z (%) 503.3 (35) [M + H]+,
525.3 (100) [M + Na]+. HRMS (ESI) C28H22F3N4S calcd for [(M +
H)+] 503.1517, found 503.1497.
(E)-9-Benzyl-6-(benzylthio)-8-(3-bromostyryl)-9H-purine
General Procedure for the Amination As Illustrated for the
Preparation of (E)-N,9-Dibenzyl-8-styryl-9H-purin-6-amine
(12a). A solution of m-CPBA (162.9 mg, 0.944 mmol, 2.2 equiv) in
DCM (1.5 mL) was dried on MgSO4 and added dropwise to a
solution of 3a (186 mg, 0.429 mmol, 1 equiv) in DCM (15 mL) at 0
°C. The reaction mixture was stirred for 2 h in an ice bath and then
quenched by the addition of a saturated solution of Ca(OH)2. This
mixture was extracted with DCM and washed with water, and the
organic layer was dried (MgSO4) and evaporated under reduced
pressure. A solution of the resulting sulfone, sufficiently pure to be
used directly in the next step, and benzylamine (115 mg, 1.073 mmol,
2.5 equiv) in EtOH (2 mL) was introduced in a sealed tube and heated
at 110 °C until the reaction mixture became clear (2 h). After
evaporation, the residue was purified by flash column chromatography
on silica gel (cyclohexane/EtOAc 100/0 → 80/20) to afford the title
1
(3g). A yellow solid (107 mg, 57%): mp = 182−184 °C; H NMR
(300 MHz, CDCl3) δ 8.73 (s, 1H), 7.93 (d, J = 15.8 Hz, 1H), 7.60 (s,
1H), 7.51−7.44 (m, 3H), 7.39−7.19 (m, 10H), 6.94 (d, J = 15.8 Hz,
1H), 5.56 (s, 2H), 4.70 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 159.1,
151.6, 150.7, 150.0, 137.7, 137.5, 137.4, 135.5, 132.3, 131.2, 130.4,
129.9, 129.21, 129.16, 128.5, 128.3, 127.3, 126.8, 126.3, 123.0, 113.7,
45.7, 32.9. MS (ES+) m/z (%) 513.2 (65) [M + H]+, 537.2 (50) [M +
Na]+. HRMS (ESI) calcd for C27H22BrN4S [(M + H)+] 513.0749,
found 513.0757.
(E)-4-(2-(9-Benzyl-6-(benzylthio)-9H-purin-8-yl)vinyl)-
benzonitrile (3h). A yellow solid (105 mg, 63%): mp = 206−208
°C; 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.00 (d, J = 15.8 Hz,
1H), 7.65 (d, J = 8.3 Hz, 2H), 7.56−7.48 (m, 4H), 7.35−7.28 (m,
6H), 7.21−7.18 (m, 2H), 7.03 (d, J = 15.8 Hz, 1H), 5.57 (s, 2H), 4.70
(s, 2H); 13C NMR (75 MHz, CDCl3) δ 159.5, 151.9, 150.1, 149.9,
139.6, 137.4, 136.9, 135.5, 132.6, 131.2, 129.2, 128.5, 128.4, 127.8,
127.3, 126.7, 118.5, 115.8, 112.5, 45.8, 32.9. MS (ES+) m/z (%) 460.3
(100) [M + H]+. HRMS (ESI) calcd for C28H22N5S [(M + H)+]
460.1596, found 460.1589.
1
compound as a yellow solid (133.7 mg, 74%): H NMR (300 MHz,
CDCl3) δ 8.44 (s, 1H), 7.76 (d, J = 15.9 Hz, 1H), 7.47−7.22 (m,
15H), 6.96 (d, J = 15.9 Hz, 1H), 6.14 (bs, 1H), 5.51 (s, 2H), 4.91 (bs,
2H); 13C NMR (75 MHz, CDCl3) δ 154.0, 153.0, 150.5, 148.4, 138.5,
136.8, 136.1, 135.6, 129.2, 129.0, 128.9, 128.7, 128.1, 127.9, 127.5,
127.2, 126.8, 119.8, 113.1, 45.6, 44.8. MS (ES+) m/z (%): 418.3 (100)
[M + H]+. HRMS (ESI) calcd for C27H24N5 [(M + H)+] 418.2032,
found 418.2041.
(E)-9-Benzyl-6-(benzylthio)-8-(3-nitrostyryl)-9H-purine (3i).
1
A yellow solid (101.5 mg, 58%): mp = 186−188 °C; H NMR (300
MHz, CDCl3) δ 8.75 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H),
8.04 (d, J = 15.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.0 Hz,
1H), 7.50 (d, J = 7.0 Hz, 2H), 7.34−7.23 (m, 8H), 7.07 (d, J = 15.8
Hz, 1H), 5.59 (s, 2H), 4.70 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
159.5, 151.8, 150.1, 150.0, 148.7, 137.4, 137.1, 136.4, 135.5, 133.5,
131.2, 130.0, 129.2, 128.5, 128.4, 127.3, 126.8, 123.8, 121.3, 115.4,
45.8, 32.9. MS (ES+) m/z (%) 480.2 (100) [M + H]+, 502.3 (60) [M
+ Na]+. HRMS (ESI) calcd for C27H22N5O2S [(M + H)+] 480.1494,
found 480.1487.
(E)-9-Benzyl-N-propyl-8-styryl-9H-purin-6-amine (12b). Pro-
pylamine was distilled before use. Reaction time: 1 h. A yellow oil
1
(125.2 mg, 79%): H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 7.77
(d, J = 15.9 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.37−7.23 (m, 8H),
6.96 (d, J = 15.9 Hz, 1H), 5.99 (bs, 1H), 5.50 (s, 2H), 3.66 (bs, 2H),
1.79−1.72 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 154.3, 153.0, 148.1, 136.7, 136.1, 135.7, 129.2, 129.0, 128.9,
128.1, 127.2, 126.8, 119.6, 113.2, 45.6, 42.7, 23.0, 11.5. MS (ES+) m/z
(%): 370.5 (100) [M + H]+, 392.5 (25) [M + Na]+. HRMS (ESI)
calcd for C23H24N5 [(M + H)+] 370.2032, found 370.2031.
(E)-9-Benzyl-N-(2-methoxyethyl)-8-styryl-9H-purin-6-amine
(12c). 2-Methoxyethylamine was distilled before use. Reaction time: 2
h. A yellow oil (124 mg, 75%): 1H NMR (300 MHz, CDCl3) δ 8.40 (s,
1H), 7.79 (d, J = 15.9 Hz, 1H), 7.47 (d, J = 6.4 Hz, 2H), 7.36−7.20
(m, 8H), 6.95 (d, J = 15.9 Hz, 1H), 6.29 (bs, 1H), 5.50 (s, 2H), 3.90
(bs, 2H), 3.66 (t, J = 5.2 Hz, 2H), 3.41 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 154.2, 152.8, 148.3, 136.8, 136.1, 135.7, 129.2, 129.0, 128.9,
128.0, 127.2, 126.8, 119.8, 113.2, 71.3, 58.9, 45.6. MS (ES+) m/z (%):
386.8 (100) [M + H]+, 408.8 (50) [M + Na]+. HRMS (ESI) calcd for
C23H24N5O [(M + H)+] 386.1981, found 386.1992.
(E)-9-Benzyl-6-(benzylthio)-8-(4-(diethoxymethyl)styryl)-9H-
purine (3j). A yellow oil (86 mg, 44%): 1H NMR (300 MHz,
CDCl3) δ 8.72 (s, 1H), 8.03 (d, J = 15.8 Hz, 1H), 7.48 (s, 6H), 7.34−
7.20 (m, 8H), 6.97 (d, J = 15.8 Hz, 1H), 5.55 (s, 2H), 5.50 (s, 1H),
4.70 (s, 2H), 3.64−3.51 (m, 4H), 1.28−1.18 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 158.7, 151.5, 151.3, 150.0, 140.7, 139.1, 137.5, 135.7,
135.4, 131.3, 129.2, 129.1, 128.5, 128.3, 127.4, 127.2, 126.8, 112.5,
101.1, 61.1, 45.7, 32.9, 15.2. MS (ES+) m/z (%) 537.4 (100) [M +
H]+, 559.4 (80) [M + Na]+. HRMS (ESI) calcd for C32H33N4O2S [(M
+ H)+] 537.2324, found 537.2305.
9-Benzyl-6-(benzylthio)-8-(1-phenylvinyl)-9H-purine (3k). α-
Bromostyrene was distilled before use. A yellow solid (79 mg, 50%):
mp = 128−130 °C; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 7.50
(d, J = 7.0 Hz, 2H), 7.33−7.18 (m, 11H), 6.95−6.92 (m, 2H), 5.93 (s,
1H), 5.75 (s, 1H), 5.08 (s, 2H), 4.70 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 159.9, 153.4, 151.9, 150.2, 138.7, 137.6, 137.0, 135.7, 130.7,
129.2, 128.9, 128.8, 128.53, 128.49, 127.8, 127.2, 126.8, 123.2, 46.7,
32.8. MS (ES+) m/z (%) 435.2 (100) [M + H]+, 457.1 (70) [M +
Na]+. HRMS (ESI) calcd for C27H23N4S [(M + H)+] 435.1643, found
435.1627.
(E)-9-Benzyl-6-(pyrrolidin-1-yl)-8-styryl-9H-purine (12d). Re-
1
action time: 30 min. A yellow solid (124.3 mg, 76%): H NMR (300
MHz, CDCl3) δ 8.37 (s, 1H), 7.76 (d, J = 15.9 Hz, 1H), 7.47 (d, J =
7.3 Hz, 2H), 7.38−7.19 (m, 8H), 6.96 (d, J = 15.9 Hz, 1H), 5.51 (s,
2H), 4.29 (bs, 2H), 3.81 (bs, 2H), 2.06 (bs, 4H); 13C NMR (75 MHz,
CDCl3) δ 152.7, 152.6, 151.5, 147.0, 136.4, 136.0, 135.7, 128.95,
128.88, 128.8, 127.9, 127.1, 126.7, 120.5, 113.6, 45.4, 29.7. MS (ES+)
m/z (%): 382.6 (100) [M + H]+. HRMS (ESI) calcd for C24H24N5
[(M + H)+] 382.2032, found 382.2045.
(Z)-9-Benzyl-6-(benzylthio)-8-(4-methylstyryl)-9H-purine
(3l). A yellow oil obtained as an inseparable mixture of E/Z (2:8)
isomers (42.1 mg, 26%): 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H),
7.49 (d, J = 7.0 Hz, 2H), 7.40−7.23 (m, 9H), 7.08−7.05 (m, 4H), 6.93
(d, J = 12.6 Hz, 1H), 6.35 (d, J = 12.6 Hz, 1H), 5.16 (s, 2H), 4.69 (s,
2H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.6, 151.8, 150.4,
149.6, 139.6, 139.5, 137.6, 135.8, 132.4, 131.0, 129.33, 129.26, 128.8,
(E)-N,9-Dibenzyl-N-methyl-8-styryl-9H-purin-6-amine
(12e). N-Methyl-1-phenylmethan-amine was distilled before use.
1
Reaction time: 16 h. A yellow oil (89.6 mg, 48%): H NMR (300
MHz, CDCl3) δ 8.41 (s, 1H), 7.76 (d, J = 15.9 Hz, 1H), 7.47 (d, J =
7.1 Hz, 2H), 7.38−7.24 (m, 13H), 6.97 (d, J = 15.8 Hz, 1H), 5.55 (s,
2H), 3.53 (bs, 2H), 1.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
9546
dx.doi.org/10.1021/jo201893h|J. Org. Chem. 2011, 76, 9542−9547

The Journal of Organic Chemistry
Note
154.3, 152.3, 152.1, 146.7, 138.1, 136.4, 136.2, 135.9, 129.0, 128.8,
128.6, 128.0, 127.9, 127.3, 127.2, 126.8, 120.2, 113.4, 53.5, 45.5, 43.5.
MS (ES+) m/z (%): 432.5 (100) [M + H]+, 454.5 (40) [M + Na]+.
HRMS (ESI) calcd for C28H26N5 [(M + H)+] 432.2188, found
432.2201.
(14) Vrabel, M.; Pohl, R.; Klepetarova, B.; Votruba, I.; Hocek, M.
Org. Biomol. Chem. 2007, 5, 2849.
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2008, 350, 602.
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2011, 52, 491 and references cited therein.
́ ̌ ̌ ́
́
(17) Sedlacek, O.; Brehova, P.; Pohl, R.; Holy, A.; Janeba, Z. Can. J.
́
́
̌
́
(E)-9-Benzyl-N-(4-methoxybenzyl)-8-styryl-9H-purin-6-
1
amine (12f). Reaction time: 1 h. A yellow oil (150.1 mg, 78%): H
NMR (300 MHz, CDCl3) δ 8.44 (s, 1H), 7.76 (d, J = 15.9 Hz, 1H),
7.45 (d, J = 6.8 Hz, 2H), 7.37−7.21 (m, 10H), 6.95 (d, J = 15.9 Hz,
1H), 6.89 (d, J = 8.5 Hz, 2H), 6.04 (bs, 1H), 5.51 (s, 2H), 4.84 (bs,
2H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0, 153.9, 153.0,
150.6, 148.3, 136.8, 136.1, 135.6, 130.5, 129.3, 129.2, 129.0, 128.9,
128.1, 127.2, 126.8, 119.8, 114.0, 113.1, 55.3, 45.6, 44.3. MS (ES+) m/
z (%): 448.5 (100) [M + H]+, 470.6 (80) [M + Na]+. HRMS (ESI)
calcd for C28H26N5O [(M + H)+] 448.2137, found 448.2131.
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M.; Tobrman, T.; Dvorak, D. Collect. Czech.
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(E)-N 1-(9-Benzyl-8-styryl-9H-purin-6-yl)-N 2,N2-diethyl-
ethane-1,2-diamine (12g). N,N-Diethylethylenediamine was dis-
tilled before use. Reaction time: 30 min. The residue was purified by
flash column chromatography on silica gel (DCM/EtOH 100/0 →
80/20) to afford the title compound as a yellow oil (127.7 mg, 66%):
1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.80 (d, J = 15.9 Hz,
(23) Storr, T. E.; Strohmeier, J. A.; Baumann, C. G.; Fairlamb, I. J. S.
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̌
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1H), 7.48 (d, J = 6.4 Hz, 2H), 7.37−7.22 (m, 8H), 6.96 (d, J = 15.9
Hz, 1H), 6.35 (bs, 1H), 5.51 (s, 2H), 3.76 (bs, 2H), 2.78 (t, J = 6.2 Hz,
2H), 2.65 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 154.3, 153.0, 148.1, 136.7, 136.2, 135.8, 129.2, 129.0,
128.9, 128.0, 127.2, 126.8, 119.9, 113.3, 51.7, 46.7, 45.6, 29.7, 11.5. MS
(ES+) m/z (%): 427.6 (100) [M + H]+. HRMS (ESI) calcd for
C26H31N6 [(M + H)+] 427.2610, found 427.2609.
(26) Van
2011, 13, 496.
̌ ́ ̌ ́ ́ ̌
kova, B.; Krchnak, V.; Soural, M.; Hlavac, J. ACS Comb. Sci.
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(30) Indeed, the substitution of the chloro atom by the t-BuOLi was
predominant, meaning that this reaction is much faster than the direct
alkenylation.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C for all compounds 1, 2c, 2j, 3a−l, 4−10,
and 12a−g. This material is available free of charge via the
Internet at http://pubs.acs.org..
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58, 7911.
(32) Lu, W; Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. J.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sandrine.piguel@curie.u-psud.fr.
■
Org. Chem. 2007, 72, 5012.
(33) Besseliev
Org. Lett. 2008, 10, 4029.
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re, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D.
̀
ACKNOWLEDGMENTS
R.V. and F.C. thank the Minister
et de la Recherche for doctoral fellowships. Marianne Bombled
is acknowledged for obtaining MS data.
■
̀
̀
e de l′Enseignement Super
́
ieur
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