Palladium-catalyzed cross-coupling between 8-substituted 6-thiophenyl purines and boronic acids

Article abstract of DOI:10.1055/s-0033-1340734

A palladium(II)-catalyzed, copper(I)-mediated Liebeskind-Srogl cross-coupling for the C-6 arylation/alkenylation on purine scaffold is reported. Various boronic acids reacted readily with 8-substituted 6-thiophenylpurines. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340734

PAPER
▌933
paper
Palladium-Catalyzed Cross-Coupling between 8-Substituted 6-Thiophenyl-
purines and Boronic Acids
Pd-Catalyzed Cross-Coupling Reactions on Purines
Roxane Vabre,a,b Julien Couradin,a,b Delphine Naud-Martin,b Michel Legraverend,b Sandrine Piguel*a,b
a
Univ Paris-Sud, 91405 Orsay, France
b
UMR 176, Institut Curie/CNRS, Bât 110 Centre Universitaire, 91405 Orsay, France
Fax +33(1)69075381; E-mail: sandrine.piguel@curie.fr
Received: 14.11. 2013; Accepted after revision: 12.01.2014
the formation of C–C bond on the purine ring, a few ex-
Abstract: A
palladium(II)-catalyzed,
copper(I)-mediated
amples have been reported. In 1985, Takei reported a
cross-coupling between 6-(methylsulfanyl)purine deriva-
tives and Grignard reagents with a nickel-phosphine com-
plex.14 Robins later described a reaction between 6-
sulfanylpurine and boronic acids, using Pd(OAc)2, a car-
bene ligand [1,3-bis(2,6-diisopropylphenyl)imidazoline-
2-ylidene], and K3PO4 in toluene at 90 °C for eight
hours.15 Good yields were obtained but only three exam-
ples were presented. Fukuyama detailed a single example
of a cross-coupling reaction between a 6-sulfanylpurine
and an organozinc compound using Pd(dppf)Cl2 in tolu-
ene at 50 °C over two hours.16 Very recently, Hocek
described the cross-coupling reaction of a 8-(phenylsulfa-
nyl)purine with phenylboronic acid or stannanes.17
Liebeskind–Srogl cross-coupling for the C-6 arylation/alkenylation
on purine scaffold is reported. Various boronic acids reacted readily
with 8-substituted 6-thiophenylpurines.
Key words: purine, cross-coupling, sulfur, copper, palladium
Purine is the most widely distributed N-heterocycle scaf-
fold in nature and its synthetic derivatives are well known
for their biological and more recently fluorescent proper-
ties.1 These characteristics are linked to the diversity of
substituents that can be introduced, especially on the C-2,
C-6, C-8, and N-9 positions. Although many strategies
have been described for the elaboration and functionaliza-
tion of purines, the development of new methods for rapid
functionalization is still of great synthetic interest.2
In our previous work on Pd-catalyzed amidation and ami-
nation of 8-iodopurine, the first example of Liebeskind–
Srogl reaction between 6-thiophenyl-8-phenylaminopu-
rine and (4-methoxyphenyl)boronic acid using Pd(0) and
Cu(I) complexes as catalysts under neutral conditions was
also disclosed.3b,18 Thus, we were keen to optimize this
method in order to discover the scope of reactivity of var-
ious 8-substituted 6-thioetherpurines in the Liebeskind–
Srogl reaction.
During our precedent work on functionalization at the C-
8 position of purines, a major drawback was the undesired
reactivity of the C–Cl bond at the 6-position of the purine
scaffold during Buchwald–Hartwig and direct C–H alke-
nylation reactions.3 Indeed, 6-chloropurines are well
known to be reactive under various conditions such as
SNAr and metal-catalyzed cross-coupling reactions.4 To
circumvent this problem, we chose to replace the chloro
atom at the 6-position of the purine ring by a thiophenyl
group that would be initially inert under the studied reac-
tion conditions to allow the C-8 functionalization of pu-
rines, but that would be subsequently reactive enough to
introduce various substituents on the C-6 position of the
purine ring.
In this context, we report the palladium-catalyzed cross-
coupling of various 8-substituted 6-thioetherpurines with
a range of boronic acids that widens the type of reactions,
which can be used to functionalize the purine ring. We
also took advantage of the stability of the C–S bond under
a variety of metal-catalyzed reactions including Suzuki,
Buchwald–Hartwig, and direct C–H alkenylation and al-
kynylation conditions to synthesize 6,8,9-trisubstituted
purines, with an efficient Liebeskind–Srogl cross-cou-
pling as the last step.
Over the last decade, the reactivity of the C–S bond has
gained significant attention as organosulfur compounds
provide a good alternative to the use of halogenated
reagents in metal-catalyzed reactions5 including cross-
coupling reactions between thioethers and alkynyl,6 or-
ganotin,7 organomagnesium,8 organozinc,9 organosili-
con,10 organoindium,11 and to a larger extent organoboron12
compounds.
The Liebeskind–Srogl cross-coupling optimization was
initially performed with an easily accessible substrate, pu-
rine 1, and the commercially available (4-methoxyphe-
nyl)boronic acid (Table 1). The first attempt was carried
out using the standard Liebeskind–Srogl conditions, with
copper(I) thiophene-2-carboxylate (CuTC), Pd2(dba)3,
and tri(2-furyl)phosphine as the ligand in THF at 50 °C
(Table 1, entry 1).18b After 16 hours of reaction, the prod-
uct 2a was obtained in a promising yield of 50%. When
this catalyst system was replaced by Pd(PPh3)4, a similar
yield of 42% was observed (entry 2).18c But when
Pd(dppf)Cl2 was used in 1,4-dioxane, the isolated yield
In purine chemistry, the reactivity of C–S bond has been
mostly studied through sulfur atom oxidation of 6-thio-
aryl(alkyl)purines followed by nucleophilic aromatic sub-
stitution.3a,13 Regarding C–S bond functionalization for
SYNTHESIS 2014, 46, 0933–0942
Advanced online publication: 11.02.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340734; Art ID: SS-2013-Z0743-OP
© Georg Thieme Verlag Stuttgart · New York

934
R. Vabre et al.
PAPER
leapt to 79% (entry 3).19 It is clear that the reaction pro- traces of product were observed when CuTC was replaced
ceeds very rapidly, since a comparable yield of 73% was with copper(I) 3-methylsalicylate (CuMeSal) and com-
observed when the heating time was reduced to only 15 plete absence of CuTC was fatal to the reaction (entries
minutes (entry 4). Heating under microwave irradiation 11, 12). Thus, the optimum conditions were found to be
raised the yield of 2a to 83% (entry 5); however, fewer Pd(dppf)Cl2 (2 mol%) and CuTC (2 equiv) in 1,4-dioxane
equivalents of CuTC resulted in a considerable decrease at 120 °C for 15 minutes under classical heating.
of the yield (entry 6). As there was no significant micro-
In order to explore the scope of this method, these opti-
wave effect, the influence of the reaction temperature was
mized conditions were next applied to couple 8-substitut-
investigated under thermal heating. The yield dramatical-
ed purines with a range of boronic acids (Table 2). 8-
ly decreased when the reaction was performed at room
Unsubstituted purines were efficiently reactive as elec-
temperature even after 24 hours (entry 7). Indeed, the
tron-deficient and electron-rich aromatic and vinyl groups
higher the temperature of the reaction, the better the yield
were introduced from the corresponding boronic acids in
was (entries 4, 8 and 9) peaking at 86% for reaction at
yields ranging from 59 to 86% (Table 2, entries 1–3). In
120 °C (entry 9). However, reducing the amount of boron-
the case of 8-chloropurine, the reaction was chemoselec-
ic acid decreased the yield by half (entry 10). Finally, only
tive but a low yield was observed despite total conversion
(entry 4). Unfortunately, the reaction did not take place
with 8-iodopurine (entry 5). In spite of total conversion,
only traces of 8,8′-purine dimer (~10%) and product de-
rived from a Suzuki reaction in position 8 (<5%) were iso-
lated. In this case, the carboxylate counterion (from
CuTC) could act as a base allowing the Suzuki reaction to
proceed. Thus, under Liebeskind–Srogl conditions, the
C–I bond seems to interfere with the reactivity of the C–S
bond. This behavior was in agreement with the work of
Dvorak on the dimerization of iodopurines in the presence
of CuTC.20 However, it was quite in contrast with the
work of Neumann or Wipf on the orthogonal selectivity of
the Liebeskind–Srogl coupling versus the Suzuki–Miyaura
reaction on bromopyrimidinones18c and quinazolines,18c,21
respectively. Noteworthy was the C–S bond, which was
stable under metal-catalyzed reaction conditions includ-
ing the Buchwald–Hartwig coupling used during the syn-
thesis of starting material 9 and direct C–H bond
alkenylation and alkynylation for the synthesis of com-
pounds 10 and 11. Whilst phenylamino, styryl, and
alkynyl22 groups were well tolerated on the position 8 of
the purine scaffold under the optimized Liebeskind–Srogl
conditions (entries 6–9) it should be noted, however, that
some purines were degraded at 120 °C and required a low-
er heating temperature of 80 °C (entries 4, 6–8). Regretta-
bly, boronic acids bearing a simple alkyl substituent were
unreactive.
Table 1 Optimization of Liebeskind–Srogl Conditions with Purine
1 and (4-Methoxyphenyl)boronic Acida
OMe
SPh
N
OMe
Pd source (2 mol%)
CuTC (2 equiv)
N
N
N
N
N
N
+
N
THP
THP
B(OH)2
1
2a
(2 equiv)
Entry Pd source
Solvent
Temp/Time
Yield
(%)b
1
2
Pd2(dba)3
THF
50 °C, 16 h
50 °C, 16 h
80 °C, 16 h
50c
42d
79
Pd(PPh3)4
THF
3
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
4
80 °C, 15 min
80 °C, 15 min
80 °C, 15 min
25 °C, 15 min
100 °C, 15 min
120 °C, 15 min
120 °C, 15 min
120 °C, 15 min
120 °C, 15 min
73
5
83e
63e,f
16g
79
6
7
8
9
86
Then, we were interested in studying the scope of our op-
timized Liebeskind–Srogl conditions on 8-styrylpurine 10
that has been previously developed in our laboratory via a
direct C–H bond functionalization reaction (Table 3).3a,23
Compound 1 reacted with bromostyrene through direct al-
kenylation, using a Pd/Cu co-catalysis under microwave
irradiation, to afford compound 10. Then, the Liebeskind–
Srogl reaction proceeded well with a range of electron-
rich and electron-poor boronic acids. These optimized
conditions are compatible with functional groups such as
nitro or halogen that can undergo subsequent transforma-
tions. Nevertheless, in the case of (4-cyanophenyl)boron-
ic acid and propenylboronic acid, purification problems
were encountered and the products were contaminated
with starting material 10. It should be noted that products
5c, 5e, and 5g, were inclined to isomerization on silica gel,
10
11
12
42h
<5i
0j
a Substrate 1 (1 equiv), 4(-methoxyphenyl)boronic acid (2 equiv), and
CuTC (2 equiv) were heated in a sealed tube in the presence of [Pd]
(2 mol%).
b Isolated yields.
c Four mol% of Pd2(dba)3 and 16 mol% of TFP.
d Five mol% of Pd source.
e Microwave heating.
f CuTC used: 1.2 equiv.
g Yield obtained when the reaction was run for 24 h: 24%.
h (4-Methoxyphenyl)boronic acid used: 1.2 equiv.
i CuMeSal was used.
j No CuTC.
Synthesis 2014, 46, 933–942
© Georg Thieme Verlag Stuttgart · New York

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Pd-Catalyzed Cross-Coupling Reactions on Purines
935
a phenomenon previously observed by Lakshman during lowed by the optimized Liebeskind–Srogl reaction led to
a Heck reaction on nucleosides.24 Finally, a two-step se- new 6-aryl/alkenyl-8-stryrylpurines.
quence involving direct C–H bond functionalization fol-
Table 2 Scope of Palladium-Catalyzed Copper-Mediated Cross-Coupling between 6-Thioetherpurines and Boronic Acids under Classical
Heating
Entry
Substrate
Product
Yield (%)a
OMe
SPh
N
N
N
N
1
1
2a
86
N
N
N
N
THP
THP
CF3
SPh
N
N
N
N
2
3
4
1
2b
2c
3a
65
N
N
N
N
THP
THP
SPh
N
N
N
N
N
N
1
59
N
N
THP
THP
OMe
SPh
N
N
N
N
Cl
8a
30b
N
N
N
N
Cl
THP
THP
OMe
SPh
N
N
N
N
I
5
8b
3b
0
N
N
N
N
I
THP
THP
OMe
SPh
N
N
N
N
6
NHPh
9
4a
54b
N
N
N
N
NHPh
THP
THP
© Georg Thieme Verlag Stuttgart · New York
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936
R. Vabre et al.
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Table 2 Scope of Palladium-Catalyzed Copper-Mediated Cross-Coupling between 6-Thioetherpurines and Boronic Acids under Classical
Heating (continued)
Entry
Substrate
Product
Yield (%)a
CF3
SPh
N
N
N
N
7
9
4b
47c,d
NHPh
N
N
N
N
NHPh
THP
THP
OMe
SPh
Ph
N
N
N
N
8
10
5a
72d
Ph
N
N
N
N
THP
THP
OMe
SPh
N
N
N
N
5522
Ph
9
11
6
N
N
N
N
Ph
THP
THP
a Isolated yields. Average of two runs.
b Conditions: 80 °C, 15 min.
c Starting material recovered: 30%.
d Conditions: 80 °C, 30 min.
Having in hand the 8-iodo-6-thiophenylpurine 8b, we fur- tive alternative for the rapid, stepwise functionalization of
ther tested its useful synthetic application. First, Suzuki purine derivatives.
conditions, using phenylboronic acid, Pd(PPh3)4, and
In conclusion, optimized Liebeskind–Srogl cross-
K2CO3 in 1,4-dioxane–water, were successfully applied to
coupling conditions could be applied to various 8-substi-
give 8-phenylpurine 12. Interestingly, the C–S bond was
tuted 6-thiophenylpurines with boronic acids, expanding
the scope of the limited described examples. The func-
not reactive as only traces of 6,8-diphenylpurine were de-
tected. Thus, the C–I bond appears to be more reactive
tional group tolerance and the speed of this optimized
than the C–S bond regardless of the conditions applied,
Liebeskind–Srogl reaction render this method suitable for
the combinatorial synthesis of new polyfunctionalized pu-
rines that is complementary to existing methods.
highlighting the orthogonal reactivity of compound 8b as
already observed in other heterocyclic series.21,25 Then,
purine 12 reacted smoothly with both electron-rich and
electron-poor boronic acids at the 6-position with moder-
ate to good yields to give 6,8-diarylpurines 7a–h (Table
4). As with the 8-styrylpurine, reaction with phenylboron-
ic acid led to an average 39% yield and separation be-
Commercially available reagents and solvents were used without
further purification, unless otherwise stated. Yields refer to isolated
and purified products. Reactions were monitored by TLC carried
out on silica gel plates (60F-254) and visualized under UV light.
tween the product and the substrate 12 remained difficult
when (4-cyanophenyl)boronic acid was used. However,
6-propenylpurine was obtained in a good yield of 75%.
Column chromatography was performed on silica gel 60, 40–63
1
μm. Chemical shifts of H NMR and 13C NMR were reported in
ppm (δ units) and residual nondeuterated solvent was used as inter-
nal reference. Standard abbreviations were used to designate the
multiplicities. Microwave irradiation was performed on CEM Ex-
plorer (CEM Corporation). Temperature measurement of the reac-
tion mixture within the Discovery series was achieved by an IR
sensor. The method was set with maximum power of 150 W, with
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.
Although 6,8-diarylpurines can be potentially synthesized
in a two-step sequence by regioselective Suzuki coupling
from 6,8-dihalogenated purines as already described for
compound 7g4d or by combination of Suzuki coupling/di-
rect C–H arylation,26 the purine derivatives 7a–f and 7h
were newly synthesized. Therefore, these double C–I/C–
S cross-coupling reactions represent a viable chemoselec-
Synthesis 2014, 46, 933–942
© Georg Thieme Verlag Stuttgart · New York

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Pd-Catalyzed Cross-Coupling Reactions on Purines
937
Table 3 Scope of 8-Styrylpurines
CuI (10 mol%)
SPh
R
SPh
N
Pd(OAc)2 (5 mol%)
Pd(dppf)Cl2 (2 mol%)
Ph
N
N
N
N
phenanthroline (20 mol%)
Ph
CuTC (2 equiv)
N
N
N
N
N
H
bromostyrene (2 equiv)
t-BuOLi (2 equiv)
1,4-dioxane, 120 °C
MW, 30 min
RB(OH)2 (2 equiv)
1,4-dioxane, 80 °C, 30 min
N
N
THP
THP
5a–h
THP
1
10
54%
Product
R
Yield (%)a
5a
5b
5c
5d
5e
5f
4-MeOC6H4
72
4-Me2NC6H4
4-F3CC6H4
4-NCC6H4
3-O2NC6H4
3-ClC6H4
66
68b,c
54d
81e,f
54
5g
5h
Ph
46g
60d
(E)-MeCH=CH
a Isolated yields. Average of two runs.
b Reaction time: 15 min.
c Isolated as an E/Z 8:2 mixture.
d NMR yield.
e Reaction time: 1 h.
f Isolated as an E/Z 95:5 mixture.
g Isolated as an E/Z 86:14 mixture.
Table 4 Scope of 8-Phenylpurines
SPh
SPh
R
Pd(PPh3)4 (10 mol%)
Pd(dppf)Cl2 (2 mol%)
CuTC (2 equiv)
N
N
N
K2CO3 (3 equiv)
N
N
N
I
Ph
Ph
N
PhB(OH)2 (1.5 equiv)
1,4-dioxane–H2O (4:1)
RB(OH)2 (2 equiv)
1,4-dioxane, 80 °C, 30 min
N
N
N
N
N
THP
THP
THP
100 °C, 16 h
63%
8b
12
7a–h
Product
R
Yield (%)a
7a
7b
7c
7d
7e
7f
4-MeOC6H4
4-Me2NC6H4
4-F3CC6H4
4-NCC6H4
3-O2NC6H4
3-ClC6H4
60
43b
56
20c
56
57
39
75
7g
7h
Ph
(E)-MeCH=CH
a Isolated yields. Average of two runs.
b Reaction time: 1 h.
c NMR yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 933–942

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R. Vabre et al.
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Compounds 1,3b 4a,3b 7g,4d 8b,3b and 93b showed satisfactory spec-
troscopic data in agreement with those reported in the literature. 1H
NMR for compound 2a was already described.27
13C NMR (75 MHz, CDCl3): δ = 162.2, 153.5, 153.1, 152.4, 142.1,
131.6, 129.4, 127.9, 114.2, 84.0, 69.5, 55.5, 29.0, 24.8, 23.4.
MS (ES+): m/z (%) = 345.3 (100, [M + H]+), 261.2 (60, [M –
THP]+).
Thioether-Boronic Acid Coupling; 6-(4-Methoxyphenyl)-9-(tet-
rahydro-2H-pyran-2-yl)-9H-purine (2a); Typical Procedure
A flame-dried tube filled with argon was charged with 1 (80 mg,
0.256 mmol, 1 equiv), Pd(dppf)Cl2 (3.7 mg, 0.005 mmol, 2 mol%),
CuTC (97.7 mg, 0.512 mmol, 2 equiv), and 4-methoxyphenylbo-
ronic acid (77.8 mg, 0.512 mmol, 2 equiv) in anhydrous 1,4-dioxane
(1.5 mL). The sealed tube was placed in a preheated oil bath at
120 °C for 15 min. The reaction mixture was taken up in EtOAc (20
mL), washed with 10% NH4OH (10 mL), and the organic layer was
dried (MgSO4), and concentrated. The residue was purified by flash
chromatography on silica gel eluting with CH2Cl2–EtOH (100:0 →
99:1). The title compound was obtained as a beige solid (68.3 mg,
86%); mp 154–156 °C.
1H NMR (300 MHz, CDCl3): δ = 8.97 (s, 1 H), 8.81 (d, J = 9.0 Hz,
2 H), 8.31 (s, 1 H), 7.07 (d, J = 9.0 Hz, 2 H), 5.84 (dd, J = 9.9, 2.6
Hz, 1 H), 4.20 (d, J = 13.2 Hz, 1 H), 3.90 (s, 3 H), 3.85–3.77 (m, 1
H), 2.29–2.02 (m, 3 H), 1.89–1.65 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.1, 154.7, 152.5, 151.6, 141.6,
131.6, 130.6, 128.4, 114.2, 82.0, 69.0, 55.5, 32.0, 25.0, 22.9.
HRMS (ESI): m/z calcd for C17H18ClN4O2 [(M + H)+]: 345.1118;
found: 345.1117.
N-Phenyl-9-(tetrahydro-2H-pyran-2-yl)-6-[4-(trifluorometh-
yl)phenyl]-9H-purin-8-amine (4b)
Reaction conditions: 80 °C, 30 min; yield: 25.4 mg (47%); white
solid; mp 146–148 °C.
1H NMR (300 MHz, CDCl3): δ = 8.93 (d, J = 8.1 Hz, 2 H), 8.79 (s,
1 H), 8.22 (s, 1 H), 7.79 (t, J = 7.9 Hz, 4 H), 7.44 (t, J = 8.0 Hz, 2
H), 7.14 (t, J = 7.4 Hz, 1 H), 6.01 (dd, J = 9.9, 3.1 Hz, 1 H), 4.39 (d,
J = 11.3 Hz, 1 H), 3.86 (br s, 1 H), 2.03 (m, 3 H), 1.78 (br s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.3, 150.7, 149.7, 146.6, 139.8,
138.6, 129.5, 129.4, 125.5, 125.4, 123.4, 118.8, 83.7, 69.9, 30.8,
25.4, 22.5.
MS (ES+): m/z (%) = 440.2 (100, [M + H]+).
HRMS (ESI): m/z calcd for C23H21F3N5O [(M + H)+]: 440.1698,
found: 440.1717.
MS (ES+): m/z (%) = 311.1 (100, [M + H]+), 227.1 [M – THP]+.
HRMS (ESI): m/z calcd for C17H19N4O2 [(M + H)+]: 311.1508;
(E)-6-(4-Methoxyphenyl)-8-styryl-9-(tetrahydro-2H-pyran-2-
yl)-9H-purine (5a)
Reaction conditions: 80 °C, 30 min; yield: 71.6 mg (72%); yellow
oil.
found: 311.1505.
9-(Tetrahydro-2H-pyran-2-yl)-6-[4-(trifluoromethyl)phenyl]-
9H-purine (2b)
Reaction conditions: 120 °C, 15 min; yield: 43.8 mg (65%); white
solid; mp 170–172 °C.
1H NMR (300 MHz, CDCl3): δ = 9.06 (s, 1 H), 8.93 (d, J = 8.1 Hz,
2 H), 8.38 (s, 1 H), 7.81 (d, J = 8.3 Hz, 2 H), 5.87 (dd, J = 10.0, 2.3
Hz, 1 H), 4.22 (d, J = 11.2 Hz, 1 H), 3.87–3.78 (m, 1 H), 2.22–2.04
(m, 3 H), 1.90–1.67 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.1, 152.5, 152.1, 142.8, 139.0,
132.6, 132.2, 131.5, 130.2, 125.9, 125.61, 125.56, 122.3, 82.2, 69.0,
32.0, 25.0, 22.9.
1H NMR (300 MHz, CDCl3): δ = 8.92 (d, J = 9.1 Hz, 2 H), 8.89 (s,
1 H), 8.10 (d, J = 16.0 Hz, 1 H), 7.68–7.65 (m, 2 H), 7.57 (d, J =
16.0 Hz, 1 H), 7.46–7.37 (m, 3 H), 7.10 (d, J = 9.0 Hz, 2 H), 6.08
(dd, J = 11.2, 2.4 Hz, 1 H), 4.32 (dd, J = 11.1, 3.2 Hz, 1 H), 3.83–
3.78 (s, 3 H), 3.83 (m, 1 H), 2.39–2.26 (m, 1 H), 2.11–2.04 (m, 1 H),
1.87–1.68 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 162.0, 153.0, 152.9, 152.2, 151.7,
138.8, 136.1, 131.7, 130.5, 129.6, 129.1, 128.8, 127.8, 115.7, 114.2,
82.7, 69.5, 55.5, 31.9, 25.4, 23.4.
MS (ES+): m/z (%) = 413.1 (100, [M + H]+), 429.1 (50, [M –
THP]+).
MS (ES+): m/z (%) = 349.1 (100, [M + H]+).
HRMS (ESI): m/z calcd for C17H16F3N4O [(M + H)+]: 349.1276;
HRMS (ESI): m/z calcd for C25H25N4O2 [(M + H)+]: 413.1978;
found: 413.1978.
found: 349.1271.
(E)-N,N-Dimethyl-4-[8-styryl-9-(tetrahydro-2H-pyran-2-yl)-
9H-purin-6-yl]aniline (5b)
Reaction conditions: 80 °C, 30 min; yield: 67.7 mg (66%); dark
green solid; mp 202–204 °C.
1H NMR (300 MHz, CDCl3): δ = 8.89–8.84 (m, 3 H), 8.08 (d, J =
16.0 Hz, 1 H), 7.66 (d, J = 7.1 Hz, 2 H), 7.57 (d, J = 16.0 Hz, 1 H),
7.47–7.36 (m, 3 H), 6.87 (d, J = 9.0 Hz, 2 H), 6.07 (d, J = 9.2 Hz, 1
H), 4.32 (d, J = 11.1 Hz, 1 H), 3.83 (t, J = 11.1 Hz, 1 H), 3.09 (s, 6
H), 2.38–2.25 (m, 1 H), 2.09 (s, 1 H), 1.96–1.71 (m, 4 H).
(E)-6-(Prop-1-en-1-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-pu-
rine (2c)
Reaction conditions: 120 °C, 15 min; yield: 27.8 mg (59%); dark
yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.86 (s, 1 H), 8.25 (s, 1 H), 7.68–
7.56 (m, 1 H), 7.02 (d, J = 15.5 Hz, 1 H), 5.80 (dd, J = 9.6, 2.3 Hz,
1 H), 4.19 (d, J = 12.2 Hz, 1 H), 3.80 (td, J = 11.4, 2.6 Hz, 1 H),
2.17–2.06 (m, 3 H), 1.89–1.68 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.6, 152.5, 152.2, 151.6, 151.3,
138.1, 136.1, 131.3, 129.9, 129.4, 129.0, 127.6, 123.6, 115.8, 111.7,
82.5, 69.4, 40.2, 31.8, 25.4, 23.3.
13C NMR (75 MHz, CDCl3): δ = 154.3, 152.5, 151.0, 141.7, 140.2,
130.6, 126.6, 81.9, 68.9, 31.9, 24.9, 22.9, 19.3.
MS (ES+): m/z (%) = 245.1 (100, [M + H]+).
HRMS (ESI): m/z calcd for C13H17N4O [(M + H)+]: 245.1402;
MS (ES+): m/z (%) = 426.3 (100, [M + H]+), 342.2 (35, [M –
THP]+).
found: 245.1398.
HRMS (ESI): m/z calcd for C26H28N5O [(M + H)+]: 426.2294;
8-Chloro-6-(4-methoxyphenyl)-9-(tetrahydro-2H-pyran-2-yl)-
9H-purine (3a)
Reaction conditions: 80 °C, 15 min; yield: 24.3 mg (30%); brown
solid; mp 128–130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.94 (s, 1 H), 8.73 (d, J = 8.9 Hz,
2 H), 7.06 (d, J = 8.9 Hz, 2 H), 5.81 (dd, J = 11.3, 2.2 Hz, 1 H), 4.23
(d, J = 11.4 Hz, 1 H), 3.89 (s, 3 H), 3.75 (t, J = 11.8 Hz, 1 H), 3.03
(qd, J = 12.5, 4.0 Hz, 1 H), 2.15 (m, 1 H), 1.93–1.66 (m, 4 H).
found: 426.2276.
(E)-8-Styryl-9-(tetrahydro-2H-pyran-2-yl)-6-[4-(trifluoro-
methyl)phenyl]-9H-purine (5c)
Reaction conditions: 80 °C, 15 min; yield: 73.9 mg (68%); E/Z =
8:2; light brown solid; mp 122–124 °C.
1H NMR (300 MHz, CDCl3): δ = 9.03–8.97 (m, 3 H, E), 8.77 (d, J =
7.8 Hz, 0.54 H, Z), 8.13 (d, J = 15.8 Hz, 1 H, E), 7.84 (d, J = 8.3 Hz,
2 H, E), 7.68 (d, J = 7.0 Hz, 2 H, E), 7.58 (d, J = 16.0 Hz, 1 H, E),
7.49–7.41 (m, 3 H, E), 7.18 (d, J = 12.9 Hz, 0.27 H, Z), 6.96 (d, J =
Synthesis 2014, 46, 933–942
© Georg Thieme Verlag Stuttgart · New York

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Pd-Catalyzed Cross-Coupling Reactions on Purines
939
12.5 Hz, 0.27 H, Z), 6.10 (d, J = 11.1 Hz, 1 H, E), 5.89 (d, J = 11.4
Hz, 0.27 H, Z), 4.34 (d, J = 10.4 Hz, 1 H, E), 4.23 (d, J = 10.3 Hz,
0.27 H, Z), 3.84 (t, J = 11.2 Hz, 1 H, E), 3.76–3.69 (m, 0.27 H, Z),
2.65–2.53 (m, 0.27 H, Z), 2.41–2.30 (m, 1 H, E), 2.12 (m, 1 H, E),
1.96 (d, J = 14.2 Hz, 1 H, E), 1.89–1.63 (m, 4 H, E/Z).
13C NMR (75 MHz, CDCl3): δ = 153.4, 153.3, 152.1, 151.7, 151.6,
151.2, 140.4, 139.6, 139.4, 135.8, 132.3, 131.9, 131.4, 130.1, 130.0,
129.8, 129.7, 129.1, 128.9, 128.2, 127.8, 126.1, 125.5, 125.3, 122.5,
116.9, 115.3, 83.2, 82.8, 69.5, 31.8, 30.7, 25.3, 25.0, 23.3.
HRMS (ESI): m/z calcd for C24H23N4O [(M + H)+]: 383.1872;
found: 383.1863.
6-(4-Methoxyphenyl)-8-(phenylethynyl)-9-(tetrahydro-2H-py-
ran-2-yl)-9H-purine (6)
Reaction conditions: 120 °C, 15 min; yield: 16.6 mg (55%); light
brown solid; mp 130–132 °C.
1H NMR (300 MHz, CDCl3): δ = 8.98 (s, 1 H), 8.83 (d, J = 8.5 Hz,
2 H), 7.71–7.68 (m, 2 H), 7.46 (m, 3 H), 7.07 (d, J = 8.5 Hz, 2 H),
5.98 (dd, J = 11.3, 2.3 Hz, 1 H), 4.28 (d, J = 11.9 Hz, 1 H), 3.90 (s,
3 H), 3.80 (t, J = 11.7 Hz, 1 H), 3.07 (qd, J = 12.6, 4.4 Hz, 1 H),
2.17–2.14 (m, 1 H), 1.98–1.65 (m, 4 H).
MS (ES+): m/z (%) = 473.2 (100, [M + Na]+).
HRMS (ESI): m/z calcd for C25H22F3N4O [(M + H)+]: 451.1746;
13C NMR (75 MHz, CDCl3): δ = 162.2, 154.5, 153.1, 152.0, 137.5,
132.3, 131.8, 130.6, 130.4, 128.8, 128.3, 121.0, 114.2, 96.7, 83.8,
79.5, 69.5, 55.5, 29.7, 25.1, 23.6.
found: 451.1753.
(E)-6-(3-Nitrophenyl)-8-styryl-9-(tetrahydro-2H-pyran-2-yl)-
9H-purine (5e)
Reaction conditions: 80 °C, 1 h; yield: 50.3 mg (81%); E/Z = 95:5;
MS (ES+): m/z (%) = 411.1 (100, [M + H]+), 327.1 (90, [M –
yellow oil.
THP]+).
1H NMR (300 MHz, CDCl3): δ = 9.81 (s, 1 H), 9.29 (d, J = 7.9 Hz,
1 H), 8.96 (s, 1 H), 8.34 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 15.9 Hz, 1
H), 7.76–7.67 (m, 3 H), 7.56 (d, J = 16.0 Hz, 1 H), 7.49–7.41 (m, 3
H), 6.10 (d, J = 10.8 Hz, 1 H), 4.35 (d, J = 10.9 Hz, 1 H), 3.85 (t, J =
10.5 Hz, 1 H), 2.42–2.30 (m, 1 H), 2.13 (m, 1 H), 2.00–1.76 (m, 4
H).
13C NMR (75 MHz, CDCl3): δ = 153.6, 151.6, 149.9, 148.8, 140.0,
137.9, 135.6, 131.3, 130.0, 129.7, 129.1, 127.9, 125.1, 124.8, 115.1,
82.8, 69.6, 31.8, 25.4, 23.3.
HRMS (ESI): m/z calcd for C25H23N4O2 [(M + H)+] 411.1821;
found: 411.1811.
6-(4-Methoxyphenyl)-8-phenyl-9-(tetrahydro-2H-pyran-2-yl)-
9H-purine (7a)
Reaction conditions: 80 °C, 30 min; yield: 38.5 mg (60%); beige
solid; mp 158–160 °C.
1H NMR (300 MHz, CDCl3): δ = 8.99 (s, 1 H), 8.89 (d, J = 9.0 Hz,
2 H), 7.96–7.93 (m, 2 H), 7.59–7.57 (m, 3 H), 7.06 (d, J = 9.0 Hz, 2
H), 5.64 (d, J = 9.3 Hz, 1 H), 4.28 (d, J = 9.4 Hz, 1 H), 3.89 (s, 3 H),
3.70 (t, J = 11.3 Hz, 1 H), 3.13 (qd, J = 13.1, 4.0 Hz, 1 H), 2.08–2.01
(m, 1 H), 1.86–1.61 (m, 4 H).
MS (ES+): m/z (%) = 428.4 (80, [M + H]+).
HRMS (ESI): m/z calcd for C24H22N5O3 [(M + H)+]: 428.1723;
13C NMR (75 MHz, CDCl3): δ = 161.9, 154.9, 154.0, 152.0, 131.7,
130.8, 130.6, 130.2, 130.1, 128.8, 128.6, 114.1, 84.2, 69.1, 55.5,
28.7, 24.3, 23.6.
found: 428.1732.
(E)-6-(3-Chlorophenyl)-8-styryl-9-(tetrahydro-2H-pyran-2-yl)-
9H-purine (5f)
Reaction conditions: 80 °C, 30 min; yield: 54.3 mg (54%); yellow
oil.
MS (ES+): m/z (%) = 387.1 (100, [M + H]+), 303.1 (40, [M –
THP]+).
1H NMR (300 MHz, CDCl3): δ = 8.94 (s, 1 H), 8.88–8.85 (m, 2 H),
8.13 (d, J = 16.0 Hz, 1 H), 7.67 (d, J = 6.7 Hz, 2 H), 7.60–7.40 (m,
6 H), 6.09 (dd, J = 11.2, 2.1 Hz, 1 H), 4.33 (d, J = 10.9 Hz, 1 H),
3.83 (t, J = 10.4 Hz, 1 H), 2.39–2.28 (m, 1 H), 2.12 (m, 1 H), 1.97–
1.75 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 153.3, 153.1, 151.5, 151.4, 139.5,
137.9, 135.8, 134.7, 131.1, 130.7, 130.0, 129.7, 129.6, 129.0, 128.3,
128.2, 127.8, 115.3, 82.7, 69.5, 53.6, 31.8, 25.3, 23.3.
HRMS (ESI): m/z calcd for C23H23N4O2 [(M + H)+]: 387.1821;
found: 387.1808.
N,N-Dimethyl-4-[8-phenyl-9-(tetrahydro-2H-pyran-2-yl)-9H-
purin-6-yl]aniline (7b)
Reaction conditions: 80 °C, 1 h; yield: 44.2 mg (43%); dark green
solid; mp 208–210 °C.
1H NMR (300 MHz, CDCl3): δ = 8.93 (s, 1 H), 8.86 (d, J = 9.1 Hz,
2 H), 7.97–7.93 (m, 2 H), 7.58–7.56 (m, 3 H), 6.82 (d, J = 9.2 Hz, 2
H), 5.64 (dd, J = 11.3, 2.1 Hz, 1 H), 4.27 (d, J = 9.6 Hz, 1 H), 3.70
(t, J = 10.9 Hz, 1 H), 3.07 (s, 6 H), 2.05–2.01 (m, 1 H), 1.86–1.61
(m, 5 H).
MS (ES+): m/z (%) = 417.2 (100, [M + H]+), 333.1 (50, [M –
THP]+).
HRMS (ESI): m/z calcd for C24H22ClN4O [(M + H)+]: 417.1482;
13C NMR (75 MHz, CDCl3): δ = 154.6, 154.2, 153.7, 152.3, 152.1,
131.4, 130.6, 130.5, 130.1, 128.8, 123.6, 111.7, 84.2, 69.1, 40.3,
29.8, 28.7, 24.9, 23.6.
found: 417.1475.
(E)-6-Phenyl-8-styryl-9-(tetrahydro-2H-pyran-2-yl)-9H-pu-
rine (5g)
Reaction conditions: 80 °C, 30 min; yield: 42.4 mg (46%); E/Z =
MS (ES+): m/z (%) = 400.4 (100, [M + H]+).
86:14; yellow oil.
HRMS (ESI): m/z calcd for C24H26N5O [(M + H)+]: 400.2137;
1H NMR (300 MHz, CDCl3): δ = 8.95–8.87 (m, 3 H, E), 8.67 (s,
0.30 H), 8.13 (d, J = 16.0 Hz, 1 H, E), 7.68–7.36 (m, 9 H, E), 7.14
(d, J = 12.4 Hz, 0.30 H, Z), 6.95 (d, J = 13.1 Hz, 0.15 H, Z), 6.09 (d,
J = 11.0 Hz, 1 H, E), 5.86 (d, J = 11.6 Hz, 0.15 H, Z), 4.33 (d, J =
10.8 Hz, 1 H, E), 4.21 (d, J = 14.3 Hz, 0.15 H, Z), 3.84 (t, J = 10.4
Hz, 1.15 H, E/Z), 2.65–2.53 (m, 0.15 H, Z), 2.40–2.28 (m, 1 H, E),
2.11 (m, 1.15 H, E/Z), 1.95 (d, J = 14.2 Hz, 1.15 H, E/Z), 1.88–1.68
(m, 3.45 H, E/Z).
found: 400.2140.
8-Phenyl-9-(tetrahydro-2H-pyran-2-yl)-6-[4-(trifluorometh-
yl)phenyl]-9H-purine (7c)
Reaction conditions: 80 °C, 30 min; yield: 61.2 mg (56%); white
solid; mp 142–144 °C.
1H NMR (300 MHz, CDCl3): δ = 9.08 (s, 1 H), 9.00 (d, J = 8.4 Hz,
2 H), 7.96–7.93 (m, 2 H), 7.80 (d, J = 8.1 Hz, 2 H), 7.61–7.59 (m, 3
H), 5.66 (d, J = 11.7 Hz, 1 H), 4.29 (d, J = 8.9 Hz, 1 H), 3.71 (t, J =
11.2 Hz, 1 H), 3.22–3.11 (m, 1 H), 2.08 (s, 1 H), 1.89–1.63 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 156.2, 154.5, 152.4, 152.0, 139.3,
132.4, 132.0, 131.5, 131.1, 130.2, 130.1, 129.9, 128.9, 126.0, 125.6,
125.5, 122.4, 84.4, 69.1, 28.6, 24.8, 23.6.
13C NMR (75 MHz, CDCl3): δ = 153.2, 153.1, 152.7, 151.6, 139.1,
136.1, 135.9, 130.8, 130.0, 129.9, 129.8, 129.6, 129.0, 128.7, 128.6,
128.4, 128.2, 127.8, 115.5, 82.7, 69.5, 31.8, 29.8, 25.4, 23.3.
MS (ES+): m/z (%) = 383.4 (70, [M + H]+), 299.3 (50, [M – THP]+).
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MS (ES+): m/z (%) = 425.3 (100, [M + H]+), 341.2 (70, [M –
HRMS (ESI): m/z calcd for C19H21N4O [(M + H)+]: 321.1715;
found: 321.1705.
THP]+).
HRMS (ESI): m/z calcd for C23H20F3N4O [(M + H)+]: 425.1589;
found: 425.1577.
8-Chloro-6-(phenylthio)-9-(tetrahydro-2H-pyran-2-yl)-9H-pu-
rine (8a)
In a dry flask, a solution of lithium diisopropylamide (LDA) was
prepared in situ from 1.6 M n-BuLi in hexane (5 mL, 8 mmol, 5
equiv) and i-Pr2NH (1.1 mL, 8 mmol, 5 equiv) in freshly distilled
THF (10 mL) and stirred for 30 min at –78 °C under argon. A solu-
tion of 1 (500 mg, 1.6 mmol, 1 equiv) in freshly distilled THF (10
mL) was added dropwise and the solution was stirred at –78 °C for
1 h. Then, a solution of hexachloroethane (0.91 mL, 8 mmol, 5
equiv) in freshly distilled THF (10 mL) was added dropwise and the
solution was stirred at –78 °C for 15 min, warmed to r.t., and stirred
for 1 h. Sat. aq NH4Cl (10 mL) was added and the resulting mixture
was extracted with EtOAc (2 × 20 mL). The organic layers were
combined, dried (MgSO4), filtered, and concentrated. The residue
was purified by flash chromatography on silica gel eluting with cy-
clohexane–EtOAc (100:0 → 90:10) to afford the title compound as
a beige solid; yield: 456.3 mg (82%); mp 128–130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.51 (s, 1 H), 7.56–7.53 (m, 2 H),
7.38–7.36 (m, 3 H), 5.64 (dd, J = 11.2, 1.9 Hz, 1 H), 4.11 (d, J =
11.6 Hz, 1 H), 3.64 (t, J = 11.7 Hz, 1 H), 2.89 (qd, J = 12.4, 3.9 Hz,
1 H), 2.05–1.96 (m, 1 H), 1.81–1.51 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 159.7, 152.3, 149.6, 141.4, 135.7,
129.6, 129.9, 129.4, 126.9, 84.1, 69.4, 29.0, 24.7, 23.3.
6-(3-Nitrophenyl)-8-phenyl-9-(tetrahydro-2H-pyran-2-yl)-9H-
purine (7e)
Reaction conditions: 80 °C, 30 min; yield: 57.9 mg (56%); brown
solid; mp 150–152 °C.
1H NMR (300 MHz, CDCl3): δ = 9.75 (s, 1 H), 9.30 (d, J = 7.8 Hz,
1 H), 9.09 (s, 1 H), 8.34 (d, J = 8.1 Hz, 1 H), 7.97 (m, 2 H), 7.72 (t,
J = 8.0 Hz, 1 H), 7.62–7.57 (m, 3 H), 5.67 (dd, J = 11.2, 2.0 Hz, 1
H), 4.29 (d, J = 11.4 Hz, 1 H), 3.72 (t, J = 11.1 Hz, 1 H), 3.25–3.11
(m, 1 H), 2.08–2.05 (m, 1 H), 1.90–1.63 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 156.4, 154.6, 151.9, 151.0, 148.6,
137.6, 135.8, 131.1, 130.0, 129.6, 128.9, 125.0, 124.5, 84.4, 69.1,
28.6, 24.8, 23.5.
MS (ES+): m/z (%) = 402.3 (85 [M + H]+), 318.3 [M – THP]+.
HRMS (ESI): m/z calcd for C22H20N5O3 [(M + H)+]: 402.1566;
found: 402.1563.
6-(3-Chlorophenyl)-8-phenyl-9-(tetrahydro-2H-pyran-2-yl)-
9H-purine (7f)
Reaction conditions: 80 °C, 30 min; yield: 57.7 mg (57%); beige
solid; mp 126–128 °C.
1H NMR (300 MHz, CDCl3): δ = 9.05 (s, 1 H), 8.84 (m, 2 H), 7.95
(m, 2 H), 7.60 (m, 3 H), 7.48 (m, 2 H), 5.65 (dd, J = 11.3, 2.1 Hz, 1
H), 4.28 (d, J = 10.1 Hz, 1 H), 3.71 (t, J = 11.0 Hz, 1 H), 3.23–3.09
(m, 1 H), 2.08–2.05 (m, 1 H), 1.89–1.62 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 155.9, 154.4, 152.6, 151.9, 137.7,
134.8, 131.2, 131.0, 130.8, 130.1, 130.0, 129.9, 129.6, 128.9, 128.4,
84.4, 69.1, 28.6, 24.8, 23.6.
MS (ES+): m/z (%) = 347.2 (80, [M + H]+), 263.1 (100, [M –
THP]+).
HRMS (ESI): m/z calcd for C16H16ClN4OS [(M + H)+]: 347.0733;
found: 347.0730.
(E)-6-(Phenylthio)-8-styryl-9-(tetrahydro-2H-pyran-2-yl)-9H-
purine (10)
A flame-dried tube filled with argon was charged with 1 (450 mg,
1.44 mmol, 1 equiv), CuI (27.4 mg, 0.144 mmol, 10 mol%), phen-
anthroline (51.9 mg, 0.288 mmol, 20 mol%), Pd(OAc)2 (16.2 mg,
0.072 mmol, 5 mol%), t-BuOLi (57.8 mg, 0.722 mmol, 2 equiv),
and a solution of distilled β-bromostyrene (527.5 mg, 2.88 mmol, 2
equiv) in 1,4-dioxane (3 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 up in EtOAc (15 mL) and washed with
H2O (10 mL). The organic layer was dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with cyclohexane–EtOAc (100:0 → 90:10). The ti-
tle compound was obtained as a white solid; yield: 325.4 mg (54%);
mp 210–212 °C.
MS (ES+): m/z (%) = 391.3 (100, [M + H]+), 307.2 (90, [M –
THP]+).
HRMS (ESI): m/z calcd for C16H16ClN4OS [(M + H)+]: 391.1326;
found: 391.1320.
6,8-Diphenyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (7g)
Reaction conditions: 80 °C, 30 min; yield: 35.8 mg (39%); white
solid; mp 162–164 °C.
1H NMR (300 MHz, CDCl3): δ = 9.05 (s, 1 H), 8.86 (d, J = 6.5 Hz,
1 H), 7.96–7.93 (m, 2 H), 7.59–7.50 (m, 6 H), 5.65 (dd, J = 11.3, 2.1
Hz, 1 H), 4.28 (d, J = 9.4 Hz, 1 H), 3.70 (t, J = 11.0 Hz, 1 H), 3.15
(qd, J = 12.9, 4.2 Hz, 1 H), 2.06–2.02 (m, 1 H), 1.88–1.61 (m, 4 H).
1H NMR (300 MHz, CDCl3): δ = 8.56 (s, 1 H), 8.06 (d, J = 16.0 Hz,
1 H), 7.69–7.62 (m, 4 H), 7.49–7.38 (m, 6 H), 5.97 (d, J = 11.2 Hz,
1 H), 4.31 (d, J = 12.3 Hz, 1 H), 3.80 (t, J = 11.5 Hz, 1 H), 2.32 (m,
1 H), 2.07 (m, 1 H), 1.92–1.81 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 158.6, 151.6, 151.4, 149.3, 138.9,
135.7, 135.5, 130.5, 129.4, 129.3, 129.2, 128.8, 127.5, 114.9, 82.6,
69.2, 31.5, 25.1, 23.1.
13C NMR (75 MHz, CDCl3): δ = 155.5, 154.3, 154.2, 152.0, 135.9,
131.2, 130.9, 130.1, 130.0, 128.9, 128.7, 84.3, 69.1, 28.7, 24.8,
23.6.
MS (ES+): m/z (%) = 357.3 (90, [M + H]+).
HRMS (ESI): m/z calcd for C22H21N4O [(M + H)+]: 357.1715;
found: 357.1705.
MS (ES+): m/z (%) = 415.1 (100, [M + H]+).
HRMS (ESI): m/z calcd for C24H23N4OS [(M + H)+]: 415.1593;
(E)-8-Phenyl-6-(prop-1-en-1-yl)-9-(tetrahydro-2H-pyran-2-yl)-
9H-purine (7h)
Reaction conditions: 80 °C, 30 min; yield: 61.9 mg (75%); light
brown oil.
found: 415.1589.
1H NMR (300 MHz, CDCl3): δ = 8.88 (s, 1 H), 7.88 (m, 2 H), 7.66–
7.56 (m, 4 H), 7.10 (d, J = 15.7 Hz, 1 H), 5.57 (dd, J = 11.2, 1.9 Hz,
1 H), 4.26 (d, J = 9.4 Hz, 1 H), 3.68 (t, J = 11.1 Hz, 1 H), 3.12 (qd,
J = 12.7, 3.7 Hz, 1 H), 2.07–2.01 (m, 4 H), 1.85–1.59 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 155.1, 153.7, 153.4, 152.1, 139.5,
130.8, 130.0, 129.9, 128.8, 126.5, 84.2, 69.0, 28.6, 24.8, 23.5, 19.2.
8-(Phenylethynyl)-6-(phenylthio)-9-(tetrahydro-2H-pyran-2-
yl)-9H-purine (11)
A flame-dried tube filled with argon was charged with 1 (100 mg,
0.320 mmol, 1 equiv), CuBr·SMe2 (9.9 mg, 0.048 mmol, 15 mol%),
DPEPhos (25.9 mg, 0.048 mmol, 15 mol%), t-BuOLi (51.3 mg,
0.640 mmol, 2 equiv), and a solution of bromophenylacetylene
(144.9 mg, 0.800 mmol, 2.5 equiv) in 1,4-dioxane (2 mL). The tube
was placed in a preheated oil bath at 120 °C for 1 h. The reaction
mixture was taken up in EtOAc (15 mL), washed with H2O (10 mL),
and the organic layer was dried (MgSO4), filtered, and concentrat-
MS (ES+): m/z (%) = 321.3 (80, [M + H]+), 237.3 (100, [M –
THP]+).
Synthesis 2014, 46, 933–942
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Pd-Catalyzed Cross-Coupling Reactions on Purines
941
ed. The residue was purified by flash chromatography on silica gel
eluting with cyclohexane–EtOAc (100:0 → 80:20). The title com-
pound was obtained as a beige solid; yield: 49.3 mg (37%); mp
>230 °C (dec.).
1H NMR (300 MHz, CDCl3): δ = 8.64 (s, 1 H), 7.67 (m, 4 H), 7.45
(m, 6 H), 5.90 (d, J = 11.3 Hz, 1 H), 4.26 (d, J = 13.0 Hz, 1 H), 3.77
(t, J = 11.8 Hz, 1 H), 3.01 (qd, J = 12.3, 4.0 Hz, 1 H), 2.14 (d, J =
11.0 Hz, 1 H), 1.95–1.64 (m, 4 H).
and references cited therein. (h) Kokatla, H. P.; Lakshman,
M. K. Org. Lett. 2010, 12, 4478; and references cited therein.
(i) Čerňa, I.; Pohl, R.; Klepetárŏvá, B.; Hocek, M. J. Org.
Chem. 2010, 75, 2302; and references cited therein.
(j) Vaňková, B.; Krchňák, V.; Soural, M.; Hlaváč, J. ACS
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D.; Crestey, F. O.; Carell, T.; Knochel, P. Org. Lett. 2011,
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2012, 44, 610; and references cited therein. (m) Crestey, F.;
Zimdars, S.; Knochel, P. Synthesis 2013, 45, 3029; and
references cited therein.
13C NMR (75 MHz, CDCl3): δ = 160.7, 152.9, 148.6, 136.8, 135.7,
132.3, 130.7, 130.4, 129.7, 129.4, 128.8, 127.2, 120.8, 96.8, 84.0,
79.0, 69.4, 29.7, 25.0, 23.4.
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D.; Dvořáková, H. Synthesis 2004, 889. (e) Piguel, S.;
Legraverend, M. J. Org. Chem. 2007, 72, 7026. (f) Ibrahim,
N.; Legraverend, M. J. Comb. Chem. 2009, 11, 658.
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MS (ES+): m/z (%) = 413.1 (100, [M + H]+), 329.1 (750, [M –
THP]+).
HRMS (ESI): m/z calcd for C24H21N4OS [(M + H)+]: 413.1436;
found. 413.1437.
8-Phenyl-6-(phenylthio)-9-(tetrahydro-2H-pyran-2-yl)-9H-pu-
rine (12)
In a 100 mL round-bottomed flask were introduced 8b (1.41 g, 3.22
mmol, 1 equiv), phenylboronic acid (588.9 mg, 4.83 mmol, 1.5
equiv), K2CO3 (1.34 g, 9.66 mmol, 3 equiv), Pd(PPh3)4 (372 mg,
0.322 mmol, 10 mol%), and 1,4-dioxane–H2O (4:1, 33 mL). The
mixture was placed in a preheated oil bath at 100 °C and stirred
overnight. Then, the reaction mixture was diluted with EtOAc (10
mL) and washed with H2O (2 × 10 mL). The organic layer was dried
(MgSO4), filtered, and concentrated. The residue was purified by
column chromatography on silica gel eluting with cyclohexane–
EtOAc (100:0 → 85:15) to afford a beige solid; yield: 782 mg
(63%); mp 186–188 °C.
1H NMR (300 MHz, CDCl3): δ = 8.65 (s, 1 H), 7.88 (m, 2 H), 7.68
(m, 2 H), 7.57–7.46 (m, 6 H), 5.55 (dd, J = 11.2, 1.7 Hz, 1 H), 4.25
(d, J = 8.6 Hz, 1 H), 3.66 (t, J = 11.1 Hz, 1 H), 3.10 (qd, J = 13.0,
4.1 Hz, 1 H), 2.05–2.00 (m, 1 H), 1.84–1.58 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 160.1, 154.5, 152.0, 150.5, 135.7,
130.8, 130.0, 129.8, 129.5, 129.4, 128.8, 127.6, 84.4, 69.0, 28.7,
24.8, 23.5.
MS (ES+): m/z (%) = 389.1 (100, [M + H]+).
HRMS (ESI): m/z calcd for C22H21N4OS [(M + H)+]: 389.1436;
(9) (a) Metzger, A.; Melzig, L.; Despotopoulou, C.; Knochel, P.
Org. Lett. 2009, 11, 4228. (b) Melzig, L.; Metzger, A.;
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found: 389.1437.
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Acknowledgment
(13) (a) Ding, S.; Gray, N. S.; Ding, Q.; Schultz, P. G. J. Org.
Chem. 2001, 66, 8273. (b) Fu, R.; Xu, X.; Dang, Q.; Bai, X.
J. Org. Chem. 2005, 70, 10810. (c) Liu, J.; Dang, Q.; Wei,
Z.; Shi, F.; Bai, X. J. Comb. Chem. 2006, 8, 410. (d) Oxoby,
M.; Moreau, F.; Durant, L.; Denis, A.; Genevard, J.-M.;
Vongsouthi, V.; Escaich, S.; Gerusz, V. Bioorg. Med. Chem.
Lett. 2010, 20, 3486.
R.V. thanks the Ministère de l’Enseignement Supérieur et de la Re-
cherche for a doctoral fellowship. Marianne Bombled is thanked for
recording the mass spectra.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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942
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Synthesis 2014, 46, 933–942
© Georg Thieme Verlag Stuttgart · New York