Pd-catalyzed allylic substitution of purin-8-yl(allyl) acetate: Route to (E)-Alkenylpurines

Article abstract of DOI:10.1135/cccc2011030

C⁸-Alkenylpurines were synthesized starting from purin-8-yl(allyl) acetates using Pdcatalyzed allylic substitution. The described protocol allows, by reaction of purin-8-yl(allyl) acetates with stabilized nucleophiles, an access to novel (E)-8-

Full text of DOI:10.1135/cccc2011030

Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
311
Pd-CATALYZED ALLYLIC SUBSTITUTION OF PURIN-8-YL(ALLYL)
ACETATE: ROUTE TO (E)-ALKENYLPURINES
1
2,
3
Miroslava TOBRMANOVÁ , Tomáš TOBRMAN * and Dalimil DVOŘÁK
Department of Organic Chemistry, Institute of Chemical Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic;
1
2
3
e-mail: mirka.tobrmanova@centrum.cz, tomas.tobrman@vscht.cz, dalimil.dvorak@vscht.cz
Received January 31, 2011
Accepted February 25, 2011
Published online March 17, 2011
Dedicated to Professor Pavel Kočovský on the occasion of his 60th birthday.
C8-Alkenylpurines were synthesized starting from purin-8-yl(allyl) acetates using Pd-
catalyzed allylic substitution. The described protocol allows, by reaction of purin-8-yl(allyl)
acetates with stabilized nucleophiles, an access to novel (E)-8-alkenylpurine derivatives un-
der Pd2dba3·CHCl3 catalysis in dry THF in yields ranging from 31 to 76%. A wide range of
nucleophiles showed exclusive E-alkene formation, however, ethyl nitroacetate gave mixture
of E/Z-alkenes. On contrary, purin-2-yl(allyl) acetates reacted smoothly only with dimethyl
malonate.
Keywords: Heterocycles; Palladium; Nucleophilic substitution.
A significance of C8-substituted purine derivatives has grown up within the
last decade. Especially, various guanine/guanosine and adenine/adenosine
derivatives bearing C8-sp2-carbon substituents have been prepared and
studied as fluorescent/photosensitive1–5 and electrochemical6,7 marks in
order to found a tool for the analysis of DNA or RNAs sequences. In addi-
tion, self-assebly of 8-aryl-2′-deoxyguanosine induced by the complexation
of metal cations such as K+ or Na+ to dendrimers and oligomers was de-
scribed8. Besides of photo- and electrochemical applications, C8-alkenyl/
arylpurines have been found as adducts that are formed by phenolic tox-
ins9, antagonist of the A3-adenosine receptor10, inhibitors of glycogen syn-
thase kinase11, ATP-competitive kinase12, fructose-1,6-bisphosphatase13,14
adenosine kinase15 and others16.
,
The importance of C8-substituted purine derivatives requires reliable
methods for the introduction of various functionalities at purine scaffold.
Up to now, several ways to the purines functionalized at the position 8
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 4, pp. 311–326
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2011030

312
Tobrmanová, Tobrman, Dvořák:
have been reported. Besides cyclization of the aminopyrimidine deriva-
tives11,12,14,16a,16b,17,18 cross-coupling reactions of 8-halopurines and alkenyl
or aryl organometallics have often been used. Thus, numerous examples of
the Sonogashira1,6,7,10,19, Stille2,13,20–23, Suzuki–Miyaura4,5,24 and Heck25 re-
actions have been utilized. Moreover, recently direct C–H arylation26 and
alkenylation27 have become methods of choice.
To the best of our knowledge, there has not been any report about Pd-
catalyzed allylic substitution of purinylallyl acetates in the literature. This
is somewhat surprising, since the allylic substitution is, in principle, very
general and may lead to the number of new structurally diverse purine
derivatives of a biological interest. The lack of synthetic applications of
palladium-catalyzed allylic substitution of purinyl(allyl) acetates led us to
an attempt to extend this synthetic methodology also to the purine de-
rivatives. We have started our study with purin-8-yl(allyl) acetate. The start-
ing compounds, the acetates 2a and 2b, are easily available via selective
C8-lithiation of 9-isopropyl-6-substituted purines 1a and 1b using n-butyl-
lithium at –80 °C (Scheme 1). Thus, the formed C8-lithiated derivatives
smoothly react with acroleine affording the allyl alcohols 2a and 2b in 69
and 61% yields, respectively. Subsequent acylation gave the desired acetates
2a and 2b in 53 and 28% overall isolated yields. The lower yield of 2b was
caused by tedious chromatographic separation from complex reaction mix-
ture in the acylation step.
1) BuLi (1.1 equiv.), THF, -80 °C
X
X
2) CH2=CHCHO (1.3 equiv.),-80 °C rt
N
N
N
N
N
N
3) AcCl (1.5 equiv.), Et3N (2.0 equiv.), rt
OAc
N
N
1a, X = OMe
1b, X = Cl
2a, X = OMe (53%, 2 steps)
2b, X = Cl (28%, 2 steps)
SCHEME 1
In order to develope a representative procedure, the acetate 2a was
treated with the dimethyl malonate enolate, which was generated from the
dimethyl malonate and sodium hydride in dry THF. The first experiments
with 5 mole % Pd(PPh3)4 and PdCl2(PPh3)4 catalysts at ambient tempera-
ture, turned out to be a successful choice furnishing the desired substitu-
tion products 3a and 4a as a mixture of Z- and E-stereoisomers in high
isolated yields (Table I, Entries 1, 2). When Pd2dba3·CHCl3 was used, single
(E)-alkenylpurine 4a has been obtained (Table I, Entry 3). With the same
catalyst, but in 2 mole % loading, the reaction time prolonged to 16 h
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Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
313
(Table I, Entry 4). A similar result was obtained, when Pd2dba3·CHCl3 was
used in combination with AsPh3 (Table I, Entry 5). The other tested
precatalysts and ligands lead to a mixture of E- and Z-stereoisomers with
isolated yields around 70% (Table I, Entries 6, 7, 8). Interestingly, the oppo-
site stereochemical outcome, exclusive formation of (Z)-alkenylpurine 3a,
was observed in the presence of Pd(OAc)2 and PCy3 (Table I, Entry 9).
In this case, the 3a was accompanied by the diallylated product 5a (Fig. 1)
in 14% isolated yield. It is worth mentioning, that the 5a was formed in
other cases as the by-product usually in less than 5% yield. The ability of
various alkenylpurines to readily undergo E/Z-isomerization has been re-
TABLE I
Optimization of Pd-catalyzed reaction of the allyl acetate 2a with diethyl malonate
MeO2C
OMe
N
OMe
N
CO2Me
CH2(CO2Me)2
Pd-cat.
N
N
N
N
N
N
2a
+
iPr
4a
iPr
CO2Me
MeO2C
3a
3a:4a
3a + 4a
Entry
Catalysta
Time, h
Ratiob
Yieldc, %
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
3
3
58:42
55:45
0:100
0:100
0:100
57:43
56:44
32:68
100:0
73
81
70
71
61
81
75
87
65e
PdCl2(PPh3)2
Pd2dba3·CHCl3
Pd2dba3·CHCl3
5
16d
Pd2dba3·CHCl3, AsPh3
Pd(OAc)2, dppp
3
3
Pd2dba3·CHCl3, TFP
1.5
1.5
15
Pd2dba3·CHCl3, 2-Cy2Pbiphenyl
Pd(OAc)2, PCy3
a
Reaction conditions: dimethyl malonate (1.5 equiv.) was added to a suspension of NaH
(1.5 equiv.) in THF. The mixture was stirred 15 min at ambient temperature, then a solution
of Pd-cat. (5 mole %), phosphine ligands (10 mole %) and 2a (1.0 equiv.) in dry THF was
added. The resultant mixture was stirred at the room temperature. Isomeric purity was deter-
b
c
d
mined by 1H NMR. Obtained by 1H NMR. Overall isolated yield. 2 mole % of the cata-
e
lyst was used. Accompanied by 14% of the diallylated product 5a.
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314
Tobrmanová, Tobrman, Dvořák:
TABLE II
Pd-catalyzed reaction of the allyl acetates 2a and 2b with nucleophiles
X
X
Nu
N
N
N
N
Nucleophile, NaH
N
N
Pd2dba3 CHCl3, THF, rt
OAc
N
N
4
2
Entry Acetate
X
Nucleophilea
Time, h
5
Product (Yieldb, %)
O
1
2a
OMe
4b, 44
CO2Et
O
2
3
2a
2b
OMe
Cl
20
3
4c, 21
4d, 54
SO2Ph
Ph
MeO2C
CO2Me
4
5
6
2a
2a
2a
OMe
OMe
OMe
4a
4b
6
5a, 62
6
5b, 49
3e + 4e, 25:75c, 76
O2N
CO2Et
20
O
7
2a
OMe
24
5cd, 34
N
N
O
O
8
2a
2a
2b
2a
OMe
OMe
Cl
HCO2Nae
27
8
4f, 66
4g, 53
4h, 41
4ig, 35
9
PhSO2Nae,f
PhSO2Nae,f
AcONae
10
11
15
16
OMe
a
Reaction conditions: nucleophile (1.5 equiv.) was added to a suspension of NaH (1.5 equiv.)
in THF. The mixture was stirred 15 min at ambient temperature, then a solution of Pd-cat.
(5 mole %) and 2a or 2b (1.0 equiv.) in dry THF was added. The resultant mixture was
b
stirred at room temperature. Isomeric purity was determined by 1H NMR. Isolated yield.
c
A mixture of E- and Z-alkenes inseparable by column chromatography was obtained.
d
e
Diallylated product 5c was isolated as the only product. Reaction was performed without
f
g
NaH. Reaction was performed in dry DMF. Unreacted 2a (60%) was recovered.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 4, pp. 311–326

Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
315
cently reported25,28. However, in our case, compounds 3a and 4a have not
isomerized neither in the presence of Pd(OAc)2, PCy3 nor with TsOH 28
.
The ligandless condition developed for stereoselective formation of the
E-alkenylpurines has been used for the testing of the reactivity of 2a and 2b
with other nucleophiles. Ethyl acetoacetate and 2-(phenylsulfonyl)aceto-
phenone as examples of the C-stabilized nucleophiles furnished the ex-
pected E-alkenes 4b and 4c in moderates yields (Table II, Entries 1, 2).
Remarkably, acetate 2b, which possesses two reaction centers (allylacetate
and the halogen in the position 6), furnished exclusively the product of
allylic substitution 4d in 54% isolated yield (Table II, Entry 3). Nitroacetate,
as the only C-nucleophile, gave the mixture of Z- and E-isomers 3e and 4e
in 1:3 ratio (Table II, Entry 6). The ability of 4 to undergo further alkylation
was verified in case of 4a and 4b, which have been successfully alkylated
to afford diallylated products 5a and 5b (Fig. 1) in moderate yields (Table II,
Entries 4, 5). Surprisingly, 1,3-dimethylbarbituric acid formed the diallylated
product 5c (Fig. 1) as the only product (Table II, Entry 7). Additionally, so-
dium formate and sodium benzenesulfinate were sufficiently reactive, and
the expected allylpurines 4f, 4g and 4h were obtained (Table II, Entries 8, 9,
10). Tosylamide and 9-benzylhypoxanthine as examples of N-nucleophiles,
did not react with 2a under the tested conditions at ambient temperature.
Heating to 60 °C gave 6-methoxy-9-isopropyl-9-propenyl-9H-purine (4f) in
55% yield in this case, instead of the expected product of allylic substitu-
tion. When sodium acetate was used as nucleophile, partial rearrangement
to the isomeric acetate 4i was observed (Table II, Entry 11).
1) RuCl3 3H2O (5 mol %), NaIO4
MeCN, rt (67%)
2) CH2=CHMgCl (1.5 equiv.)
THF, -80 °C (58%)
Cl
Cl
N
N
N
N
N
N
N
3) AcCl (1.5 equiv.), Et3N (2.0 equiv.)
THF, 60 °C (34%)
OAc
N
7
13% 3 steps
Ph
6
Cl
N
Cl
1) DIBAL-H (3.0 equiv.),
THF, -80 °C (85%)
N
N
N
N
N
N
2) AcCl (1.5 equiv.), Et3N (2.0 equiv.)
THF, rt (100%)
N
BuO2C
8
9
OAc
85% 2 steps
SCHEME 2
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316
Tobrmanová, Tobrman, Dvořák:
The ability of acetate 2b to undergo Pd-catalyzed allylic substitution en-
couraged us to extend the scope of the above methodology to (purin-2-yl)-
propenyl acetate. Attemps to prepare acetate 7 by reaction of purinyl-
magnesium chloride29 with acroleine failed to give any isolable product.
Thus, the acetate 7 was prepared via sequence of the Heck reaction of
6-chloro-2-iodo-9-isopropyl-9H-purine with styrene30 giving styryl deriva-
tive 6 followed by RuCl3·3H2O catalyzed cleavage of double bond31
(Scheme 2). The isolated carbaldehyde was then treated with vinyl-
magnesium chloride and the subsequent acylation afforded the acetate 7.
The Heck reaction of 6-chloro-2-iodo-9-isopropyl-9H-purine with butyl
acrylate followed by the DIBAL-H reduction of the obtained ester 8 fol-
TABLE III
Pd-catalyzed reaction of the allyl acetates 2a and 2b with nucleophiles
Cl
N
Nucleophile, NaH
Pd-cat
N
7 or 9
Nu
N
N
10
Nucleophilea
Pd-cat.
Time, h
Product
Entry Acetate
(Yieldb, %)
1
2
9
9
9
9
9
9
9
7
9
9
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
PhSO2Na
Pd2dba3·CHCl3
Pd(OAc)2, PCy3
PdCl2(PPh3)2
Pd(PPh3)4
48
120
96
10a (13), 11 (12)
10a (26), 11 (40)
10a (39), 11 (6)
10a (16), 11 (10)
10a (26), 11 (20)
10a (92), 11 (<5)
10a (48), 11 (13)
10a (73), 11 (5)
10b (42), 11 (<5)
10c (40), 11 (<5)
3
4
72
5
Pd2dba3·CHCl3, 2-Cy2Pbiphenyl 120
c
6
Pd2dba3·CHCl3
24
168
3
c
7
Pd(OAc)2, PCy3
c
8
Pd2dba3·CHCl3
Pd2dba3·CHCl3
c
9
24
c
10
PhCOCH2SO2Ph Pd2dba3·CHCl3
24
a
Reaction conditions: dimethyl malonate (1.5 equiv.) was added to a suspension of NaH
(1.5 equiv.) in THF. The mixture was stirred 15 min at ambient temperature, then a solution
of Pd-cat. (5 mole %), phosphine ligand (10 mole %) and 7 or 9 (1.0 equiv.) in dry THF was
added. The resultant mixture was stirred at 60 °C. Isomeric purity was determined by 1H NMR.
b
c
Isolated yield. 3.0 Equivalents of dimethyl malonate and NaH were used.
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Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
317
lowed by acetylation gave the isomeric linear acetate 9 in 85% in two steps
(Scheme 2).
Due to easier access, the linear acetate 9 was used for the reaction with
dimethyl malonate under the same condition as 2. The optimized reaction
conditions for the formation of the E-alkene gave the target product 10a in
only 13% isolated yield along with 12% of the diallylated compound 11
(Fig. 1) accompanied with a chromatographically inseparable mixture of
degradation products (Table III, Entry 1). The reaction under palladium ace-
tate and tricyclohexylphospine catalysis furnished the primarily
diallylderivative 11 in 40% isolated yield (Table III, Entry 2). Further varia-
tion of the catalytic system did not affect the yield of 10a significantly (Ta-
ble III, Entries 3, 4, 5). However, the high yield of 10a was obtained when
3.0 equivalents of dimethyl malonate were used (Table III, Entry 6). Acetate
7, gave similar results as 9 but in shorter reaction time, which corresponds
with the expected higher reactivity of the acetate of the benzylic type (Ta-
ble III, Entry 8). On contrary, the yields of allylic substitution of acetate 9
with 2-(phenylsulfonyl)acetophenone and sodium benzenesulfinate, as ex-
amples of other nucleophiles, were low (40 and 42%), even when an excess
of nucleophiles was used (Table III, Entries 9, 10). The products were ac-
companied by chromatographically inseparable mixture of products of the
decomposition of the purine scaffold in this case.
In conclusion we have developed a method for Pd-catalyzed allylic substi-
tution of (6,9-disubstitutedpurin-8-yl)allyl acetates. The starting acetate 2a
OMe
MeO
OMe
MeO
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
EtO2C
COMe
MeO2C
CO2Me
5b
5a
O
OMe
MeO
Cl
Cl
N
N
N
N
N
O
N
N
N
N
MeO2C
CO2Me
N
N
N
N
O
N
N
N
N
N
11
5c
FIG. 1
Structures of the diallylated derivatives isolated in the course of the Pd-catalyzed allylic substi-
tution of allyl acetates 2a, 2b, 7 and 9
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 4, pp. 311–326

318
Tobrmanová, Tobrman, Dvořák:
and 2b react with various O- and C-stabilized nucleophiles in the presence
of Pd2dba3·CHCl3 in dry THF at room temperature to give novel (E)-8-
alkenylpurines. On contrary to preferential formation of E-alkenes of most
nucleophiles, ethyl nitroacetate gave mixture of E- and Z-alkenes insepara-
ble by column chromatography. The application of the reaction conditions
to (purin-2-yl)allyl acetate was successful only in case of dimethyl malonate.
The other tested nucleophiles afforded the final products in low yields ac-
companied by unidentified complex mixtures. Further studies including
the improvement of the reaction conditions at the position 2 of purine
moiety and the extension to the position 6 are ongoing in our laboratory.
EXPERIMENTAL
All reactions were performed under an argon atmosphere. NMR spectra (δ, ppm; J, Hz) were
measured on a Varian Gemini 300 (1H, 300.07 MHz; 13C, 75.46 MHz), a Bruker AMX3 400
(1H, 400.13 MHz; 13C, 100.62 MHz) or a Bruker DRX 500 Avance (1H, 500.13 MHz; 13C,
125.77 MHz) spectrometer at 298 K. Unambiguous assignment of the NMR signals is based
on 13C{1H}, 13C APT, COSY, HMQC and 13C HMBC spectra. IR spectra (ν, cm–1) were re-
corded on Nicolet 740 FT-IR. Mass spectra were measured on ZAB-SEQ (VG Analytical). The
solvents were dried and degassed by standard procedures, silica gel (Merck, Silica Gel 60,
40–63 µm) was used for column chromatography. 9-Isopropyl-6-methoxy-9H-purine32 (1a),
9-isopropyl-6-chloro-9H-purine33 (1b), 6-chloro-9-isopropyl-2-(2-phenylethenyl)-9H-purine30
(6) and butyl 3-(6-chloro-9-isopropylpurine-2-yl)acrylate30 (8) were prepared by the reported
procedures, other compounds were purchased.
8-(1-Acetoxyprop-2-enyl)-9-isopropyl-6-methoxy-9H-purine (2a)
A solution of BuLi (0.75 ml, 1.2 mmol, 1.6 M in hexane) was added to a solution of 1 (0.192 g,
1.0 mmol) in dry THF (10 ml) at –78 °C. Then the mixture was stirred 5 min at –78 °C fol-
lowed by addition of acroleine (0.09 ml, 1.3 mmol). The resultant mixture was stirred 1 h at
–80 °C and 1 h at 0 °C. Then the mixture was quenched by addition of saturated solution of
NH4Cl, extracted with dichloromethane (3 × 15 ml), dried over MgSO4, concentrated in
vacuo and column chromatography (silica gel, EtOAc–hexane, 2:1) afforded the correspond-
ing 1-(9-isopropyl-6-methoxy-9H-purin-8-yl)prop-2-en-1-ol. 1H NMR (300 MHz, CDCl3):
1.69 m, 6 H (CH3); 4.14 br s, 1 H (OH); 4.16 s, 3 H (CH3); 4.86 m, 1 H (CH); 5.36 d, 1 H,
3J = 13.4 (=CH); 5.43 d, 1 H, 3J = 17.16 (=CH); 5.52 d, 1 H, 3J = 4.32 (CH); 6.16 m, 1 H
(=CH); 8.49 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 20.8, 49.1, 54.0, 69.1, 117.6, 120.6,
136.5, 151.1, 153.2, 153.4, 160.5. IR: 3342, 2996, 2946, 1608, 1574, 1484, 1446, 1421, 1355,
1326, 1290, 1069, 1049. HRMS (EI): calculated for C12H16N4O2 248.1273, found 248.1273.
Isolated alcohol (0.323 g, 1.3 mmol) was dissolved in dry THF (10 ml) followed by addition
of triethylamine (0.36 ml, 2.6 mmol) and acetyl chloride (0.14 ml, 1.95 mmol). The resul-
tant mixture was stirred 2 h at ambient temperature, concentrated in vacuo and column
chromatography (silica gel, EtOAc–hexane, 2:1) gave the title compound (0.33 g, 87%) as
yellow amorphous solid. 1H NMR (300 MHz, CDCl3): 1.70 d, 6 H, 3J = 6.88 (CH3); 2.14 s,
3 H (CH3); 4.15 s, 3 H (CH3); 4.78 m, 1 H (CH); 5.36–5.44 m, 2 H (=CH2); 6.27 m, 1 H
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 4, pp. 311–326

Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
319
(=CH); 6.58 m, 1 H (CH-O); 8.50 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 20.50, 20.54,
20.75, 49.1, 53.6, 69.4, 119.3, 121.0, 132.2, 151.1, 149.1, 152.7, 160.6, 169.1. IR: 2996,
2947, 1743, 1608, 1574, 1485, 1447, 1409, 1372, 1357, 1326, 1292, 1265, 1070. HRMS (EI):
calculated for C14H18N4O3 290.1379, found 290.1369.
8-(1-Acetoxyprop-2-enyl)-6-chloro-9-isopropyl-9H-purine (2b)
A solution of LDA (2.2 mmol, prepared from diisopropylamine (0.31 ml, 2.2 mmol) and
BuLi (1.38 ml, 2.2 mmol, 1.6 M solution in hexane) at –80 °C) in dry THF (5 ml) was added
to a solution of 1 (0.393 g, 2.0 mmol) at –78 °C. Then the mixture was stirred 5 min at
–78 °C followed by addition of acroleine (0.18 ml, 2.5 mmol). The resultant mixture was
stirred 1 h at –78 °C and 1 h at 0 °C. Then the mixture was quenched by addtion of satu-
rated solution of NH4Cl, extracted with dichloromethane (3 × 15 ml), dried over MgSO4,
concentrated in vacuo and column chromatography (silica gel, EtOAc–hexane, 2:1) afforded
corresponding 1-(6-chloro-9-isopropyl-9H-purin-8-yl)prop-2-en-1-ol (0.466 g, 69%) as color-
less oil. 1H NMR (300 MHz, CDCl3): 1.69 d, 6 H, 3J = 6.9 (CH3); 3.94 d, 1 H, 3J = 6.3 (OH);
4.93 m, 1 H (CH); 5.41 d, 1 H, 3J = 10.5 (=CH2); 5.48 d, 1 H, 3J = 17.3 (=CH2); 5.60 m, 1 H
(CH-O); 6.13 m, 1 H (=CH); 8.68 s, 1 H (H-2). HRMS (EI): calculated for C11H13ClN4O
252.0778, found 252.0779. Isolated alcohol (0.466 g, 1.84 mmol) was dissolved in dry THF
(10 ml) followed by addition of triethylamine (0.51 ml, 3.68 mmol) and acetyl chloride
(0.20 ml, 2.77 mmol). The resultant mixture was stirred 2 h at ambient temperature, con-
centrated in vacuo and column chromatography (silica gel, EtOAc–hexane, 1:2) gave the ti-
tle compound (0.22 g, 41%) as colorless oil. 1H NMR (300 MHz, CDCl3): 1.75 d, 6 H, 3J =
6.74 (CH3); 2.19 s, 3 H (CH3); 4.88 m, 1 H (CH); 5.44 d, 1 H, 3J = 17.3 (=CH2); 5.49 d, 1 H,
3J = 10.5 (=CH2); 6.26 m, 1 H (=CH); 6.64 d, 1 H, 3J = 6.0 (CH); 8.71 s, 1 H (H-8). 13C NMR
(75 MHz, CDCl3): 20.6, 20.8, 20.9, 50.1, 69.9, 120.2, 131.3, 132.1, 151.2, 150.9, 152.8,
152.9, 169.3. IR: 2942, 1747, 1595, 1561, 1444, 1400, 1372, 1351, 1224, 1183, 1155, 1106,
1023, 988. HRMS (EI): calculated for C13H15ClN4O2 294.0884, found 294.0881.
1-(6-Chloro-9-isopropyl-9H-purin-2-yl)prop-2-enyl acetate (7)
Water (20 ml) and acetonitrile (30 ml) was added to a mixture of 6 (1.0 g, 3.35 mmol),
RuCl3·3H2O (0.044 g, 0.17 mmol) and sodium periodate (2.145 g, 10.04 mmol). The mixture
was stirred 10 min at ambient temperature, diluted with saturated solution of Na2S2O3 and
extracted with EtOAc (3 × 20 ml). Collected organic phases were dried over MgSO4, concen-
trated in vacuo and column chromatography (silica gel, EtOAc–hexan 2:1) gave 6-chloro-
9-isopropyl-9H-purin-2-carbaldehyde (0.506 g, 67%) as white solid; m.p. 151–155 °C
(CH2Cl2–hexane). 1H NMR (300 MHz, CDCl3): 1.63 d, 6 H, 3J = 6.9 (CH3); 5.02 m, 1 H (CH);
8.40 s, 1 H (H-8); 10.00 s, 1 H (CHO). 13C NMR (75 MHz, CDCl3): 22.7, 48.5, 128.8, 133.3,
152.7, 151.8, 153.0, 189.4. IR (CHCl3): 2928, 2854, 1723, 1583, 1554, 1481, 1393, 1350,
1320, 1292, 1172, 1147, 982, 967, 909, 883, 847. HRMS (EI): calculated for C9H9ClN4O
224.0454, found 224.0465. The isolated carbaldehyde (0.660 g, 3.0 mmol) was dissolved in
dry THF (50 ml), cooled to –78 °C, followed by addition of vinylmagnesium chloride
(2.75 ml, 4.4 mmol, 1.6 M solution in THF). The mixture was stirred 2 h at –78 °C, quenched
by addition of AcOH (2 ml, 4 mmol, 2 M solution in methanol), concentrated in vacuo and
column chromatography (silica gel, EtOAc) gave 1-(6-chloro-9-isopropyl-9H-purin-2-yl)prop-
2-enol (0.480 g, 58%) as white amorphous solid. 1H NMR (300 MHz, CDCl3): 1.63 d, 6 H,
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Tobrmanová, Tobrman, Dvořák:
3J = 6.9 (CH3); 4.92 m, 1 H (CH); 5.22 td, 1 H, 3J = 1.7, 10.2 (=CH2); 5.36 td,1 H, 3J = 1.7,
4.9 (CH-O); 5.52 td, 1 H, 3J = 1.7, 17.0 (=CH2); 6.60 m, 1 H (=CH); 8.39 s, 1 H (H-8).
13C NMR (75 Mz, CDCl3): 22.5, 48.1, 74.2, 115.8, 130.6, 138.2, 143.1, 151.1, 151.6, 163.5.
IR (CHCl3): 3487, 1593, 1561, 1493, 1459, 1393, 1374, 1329, 1084, 1059, 976, 932, 880.
HRMS (EI): calculated for C11H13ClN4O 252.0778, found 252.0786. Finally, obtained alcohol
(0.226 g, 0.89 mmol) and DMAP (0.022 g, 0.18 mmol) was dissolved in dry THF (20 ml).
Then triethylamine (0.25 ml, 1.79 mmol) and acetyl chloride (0.10 ml, 1.34 mmol),
the mixture was stirred 24 h at 60 °C, concentrated in vacuo and column chromatography
(silica gel, EtOAc–hexane, 2:1) gave the title compound (0.090 g, 34%) as yellow oil.
1H NMR (300 MHz, CDCl3): 1.64 m, 6 H (CH3); 2.20 s, 3 H (CH3); 4.91 m, 1 H (CH); 5.35 td,
1 H, 3J = 1.4, 10.2 (=CH2); 5.51 td, 1 H, 3J = 1.4, 17.0 (=CH2); 6.20 m, 1 H (=CH); 6.31 m,
1 H (CH-O); 8.14 s, 1 H (H-8). 13C NMR (75 MHz, CDCl3): 21.0, 22.3, 22.4, 48.0, 76.8, 118.7,
130.7, 133.7, 143.1, 150.9, 151.7, 160.4, 170.0. IR (CHCl3): 1741, 1593, 1560, 1492, 1459,
1392, 1373, 1147, 1139, 1114, 1025, 985, 941, 881. HRMS (EI): calculated for C13H15ClN4O2
294.0884, found 294.0891.
6-Chloro-9-isopropyl-2-(3-acetoxypropenyl)-9H-purine (9)
DIBAL-H (15.3 ml, 15.3 mmol, 1.0 M solution in toluene) was added to a solution of 8 (1.65 g,
5.11 mmol) in dry THF (60 ml) at –80 °C. The resultant mixture was stirred 40 min at –80 °C,
quenched by addition of Na2SO4·10H2O (6.6 g, 20.45 mmol), warmed to r.t., concentrated
in vacuo and flash chromatography (silica gel, EtOAc) gave the alcohol (1.04 g, 81%) as yel-
low solid; m.p. 111–116 °C (CH2Cl2–hexane). 1H NMR (300 MHz, CDCl3): 1.65 d, 6 H, 3J =
6.9 (CH3); 4.46 m, 2 H (CH2); 4.91 m, 1 H (CH); 6.83 td, 1 H, 3J = 1.7, 15.7 (=CH); 7.32 td,
1 H, 3J = 4.8, 11.0 (=CH); 8.10 s, 1 H (H-8). 13C NMR (75 MHz, CDCl3): 22.4, 47.8, 62.5,
127.9, 129.9, 140.0, 142.8, 150.3, 151.8, 158.4. IR (CHCl3): 3612, 3392, 1661, 1592, 1553,
1490, 1459, 1427, 1391, 1319, 1090, 981, 926, 904, 882. HRMS (EI): calculated for
C
11H13ClN4O 252.0778, found 252.0789. Isolated alcohol (1.04 g, 4.12 mmol) was dissolved
in dry THF (60 ml) followed by addition of triethylamine (1.45 ml, 8.23 mmol) and acetyl
chloride (0.43 ml, 6.17 mmol). The resultant mixture was stirred 0.5 h at ambient tempera-
ture, concentrated in vacuo and column chromatography (silica gel, EtOAc–hexane, 2:1)
gave the title compound (1.21 g, 99%) as white solid; m.p. 115–118 °C (CH2Cl2). 1H NMR
(CDCl3): 1.66 d, 6 H, 3J = 6.9 (CH3); 2.15 s, 3 H (CH3); 4.85 dd, 2 H, 3J = 1.7, 5.5 (CH2);
4.92 m, 1 H (CH); 6.72 td, 1 H, 3J = 1.6, 15.7 (=CH); 7.25 m, 1 H (=CH); 8.13 s, 1 H (H-8).
13C NMR (CDCl3): 20.8, 22.5, 47.8, 63.6, 130.3, 130.4, 133.8, 142.9, 150.5, 151.8, 157.8,
170.5. IR (CHCl3): 3683, 3616, 2400, 2361, 2334, 1736, 1592, 1553, 1425, 1390, 1321, 1084,
1029, 979, 928. HRMS (EI): calculated for C13H15ClN4O2 294.0884, found 294.0886.
Pd-Catalyzed Allylic Substitution of Acetates 2a, 2b, 7 and 9. General Procedure
Dimethyl malonate (1.5 equiv.) was added to a suspension of NaH (1.5 equiv.) in dry THF
(10 ml per mmol of dimethyl malonate). The mixture was stirred 15 min at ambient temper-
ature, then a solution of acetates 2a, 2b, 7, 9 and Pd-cat. (5 mole %) in dry THF (5 ml per
mmol of acetates) was added. The resultant mixture was stirred at room temperature. The
finished reaction mixture was concentrated in vacuo and final products were isolated by col-
umn chromatography.
Dimethyl (Z)-2-[3-(9-isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]malonate (3a): A reaction
mixture, prepared according the general procedure, starting from dimethyl malonate (0.06 ml,
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Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
321
0.53 mmol), NaH (0.021 g, 0.53 mmol, 60% suspension in mineral oil), 2a (0.101 g,
0.35 mmol), Pd(OAc)2 (0.004 g, 0.018 mmol) and PCy3 (0.01 g, 0.036 mmol) was stirred
15 h at ambient temperature. Column chromatography (silica gel, EtOAc–hexane, 2:1) gave
the title compound (0.082 g, 65%) as white amorphous solid, that was ≥98% Z determined
by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.67 d, 6 H, 3J = 6.80 (CH3); 3.34 t, 2 H, 3J = 6.9
(CH2); 3.71 m, 7 H, 6 H (CH3) + 1 H (CH); 4.18 s, 3 H (O-CH3); 4.84 m, 1 H (CH); 6.20 m,
1 H (=CH); 6.50 d, 1 H, 3J = 11.8 (=CH); 8.47 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 21.4,
28.6, 48.2, 51.0, 52.5, 54.0, 117.7, 121.6, 138.0, 148.3, 150.9, 152.4, 160.6, 169.3.
IR (CDCl3): 2994, 2956, 1734, 1603, 1571, 1482, 1438, 1338, 1327, 1297, 1160, 1068, 1047.
HRMS (EI): calculated for C17H22N4O5 362.1590, found 362.1590.
Dimethyl (E)-2-[3-(9-isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]malonate (4a): A reaction
mixture, prepared according the general procedure, starting from dimethyl malonate (0.07 ml,
0.65 mmol), NaH (0.026 g, 0.65 mmol), 2a (0.125 g, 0.43 mmol) and Pd2dba3·CHCl3 (0.022 g,
0.022 mmol) was stirred 5 h at ambient temperature. Column chromatography (silica gel,
EtOAc–hexane, 2:1) gave the title compound (0.109 g, 70%) as white amorphous solid, that
was ≥98% E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.67 d, 6 H, 3J = 6.9 (CH3);
2.92 t, 2 H, 3J = 7.1 (CH2); 3.58 t, 1 H, 3J = 7.4 (CH); 3.74 s, 6 H (CH3); 4.15 s, 3 H (CH3);
4.88 m, 1 H (CH); 6.60 d, 1 H, 3J = 15.3 (=CH); 7.08 m, 1 H (=CH); 8.44 s, 1 H (H-2).
13C NMR (75 MHz, CDCl3): 21.6, 32.3, 47.9, 50.8, 52.5, 53.9, 119.0, 121.5, 136.9, 149.1,
150.7, 152.8, 160.3, 168.8. IR (CDCl3): 3022, 2995, 2957, 1752, 1735, 1604, 1571, 1483,
1438, 1359, 1328, 1289, 1159, 1071, 1049. HRMS (EI): calculated for C17H22N4O5 362.1590,
found 362.1586.
Ethyl (E)-2-[3-(9-isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]acetoacetate (4b): A reaction
mixture, prepared according the general procedure, starting from ethyl acetoacetate (0.10 ml,
0.75 mmol), NaH (0.030 g, 0.75 mmol), 2a (0.145 g, 0.50 mmol) and Pd2dba3·CHCl3 (0.026 g,
0.025 mmol) was stirred 5 h at ambient temperature. Column chromatography (silica gel,
EtOAc–hexane, 2:1) gave the title compound (0.080 g, 44%) as yellow amorphous solid, that
was ≥98% E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.28 t, 3 H, 3J = 7.0 (CH3);
1.68 d, 6 H, 3J = 7.0 (CH3); 2.29 s, 3 H (CH3); 2.86 t, 2 H, 3J = 7.0 (CH2); 3.67 t, 1 H, 3J = 7.3
(CH); 4.17 s, 3 H (CH3); 4.21 m, 2 H (CH2); 4.89 m, 1 H (CH); 6.59 d, 1 H, 3J = 15.4 (=CH);
7.07 m, 1 H (=CH); 8.46 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 14.0, 21.5, 29.4, 31.4,
47.8, 53.9, 58.5, 61.7, 118.8, 121.5, 137.4, 149.2, 150.7, 152.8, 160.3, 168.7, 201.5.
IR (CDCl3): 2991, 2944, 1740, 1716, 1653, 1604, 1571, 1483, 1458, 1442, 1358, 1327, 1270,
1170, 1158, 1070, 1049, 1017, 964. HRMS (EI): calculated for C18H24N4O4 360.1798, found
360.1794.
(E)-2-[3-(9-Isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]-2-(phenylsulfonyl)acetophenone (4c):
A reaction mixture, prepared according the general procedure, starting from 2-(phenyl-
sulfonyl)acetophenone (0.159 g, 0.61 mmol), NaH (0.024 g, 0.61 mmol), 2a (0.118 g,
0.41 mmol) and Pd2dba3·CHCl3 (0.021 g, 0.020 mmol) was stirred 20 h at ambient tempera-
ture. Column chromatography (silica gel, EtOAc–hexane, 2:1) gave the title compound
(0.094 g, 31%) as white foam, that was 98% E determined by 1H NMR. 1H NMR (300 MHz,
CDCl3): 1.55 dd, 6 H, 3J = 6.3 (CH3); 3.13 m, 2 H (CH); 4.11 s, 3 H (CH3); 4.69 m, 1 H (CH);
5.27 dd, 1 H, 3J = 1.7, 4.7 (CH); 6.47 d, 1 H, 3J = 15.3 (=CH); 6.89 m, 1 H (=CH); 7.44 m,
2 H (ArH); 7.57 m, 3 H (ArH); 7.67 m, 1 H (ArH); 7.78 m, 2 H (ArH); 7.94 m, 2 H (ArH);
8.41 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 21.5, 31.5, 47.9, 53.9, 68.5, 120.1, 121.4,
128.8, 129.1, 129.2, 129.8, 134.3, 134.4, 134.5, 136.1, 136.6, 150.8, 148.6, 152.7, 160.3,
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322
Tobrmanová, Tobrman, Dvořák:
191.1. IR (CDCl3): 1681, 1604, 1571, 1523, 1484, 1449, 1441, 1421, 1358, 1328, 1311, 1135,
1084, 1071, 973, 931. M+ (EI): 490.
Dimethyl (E)-2-[3-(6-chloro-9-isopropyl-9H-purin-8-yl)prop-2-enyl]malonate (4d): A reaction
mixture, prepared according the general procedure, starting from dimethyl malonate (0.17 ml,
1.45 mmol), NaH (0.058 g, 1.45 mmol), 2b (0.248 g, 0.96 mmol), and Pd2dba3·CHCl3
(0.050 g, 0.048 mmol) was stirred 3 h at ambient temperature. Column chromatography
(silica gel, EtOAc–hexane, 2:1) gave the title compound (0.191 g, 54%) as yellow oil, that
was ≥98% E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.71 d, 6 H, 3J = 6.9 (CH3);
2.97 t, 2 H, 3J = 7.3 (CH2); 3.63 m, 1 H (CH); 3.77 s, 6 H (CH3); 4.92 m, 1 H (CH); 6.66 d,
1 H, 3J = 15.3 (=CH); 7.22 m, 1 H (=CH); 8.64 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 21.4,
32.3, 48.5, 50.5, 52.8, 118.5, 131.6, 139.8, 150.5, 149.3, 152.3, 152.7, 168.7.
Ethyl (Z)-2-[3-(9-isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]-2-nitroacetate (3e) and ethyl
(E)-2-[3-(9-isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]-2-nitroacetate (4e): A reaction mix-
ture, prepared according the general procedure, starting from ethyl nitroacetate (0.07 ml,
1.45 mmol), NaH (0.058 g, 0.64 mmol), 2a (0.124 g, 0.43 mmol) and Pd2dba3·CHCl3 (0.022 g,
0.022 mmol) was stirred 20 h at ambient temperature. Column chromatography (silica gel,
EtOAc–hexane, 2:1) gave inseparable mixture of Z- and E-stereoisomers (Z–E, 25:75, 0.125 g,
76%) characterized as the mixture. 1H NMR (CDCl3): 1.31 t, 3 H, 3J = 7.2 (CH3); 1.33 t, 3 H,
3J = 7.1 (CH3); 1.67 d, 6 H, 3J = 7.2 (CH3); 1.69 d, 6 H, 3J = 6.9 (CH3); 3.15–3.30 m, 2 H
(CH2); 3.68 m, 2 H (CH2); 4.17 s, 3 H (CH3); 4.18 s, 3 H (CH3); 4.32 m, 2 H (CH2); 4.33 m,
2 H (CH2); 4.87 m, 1 H (CH); 4.89 m, 1 H (CH); 5.29 dd, 1 H, 3J = 1.7, 5.4 (CH); 5.58 t, 1 H,
3J = 7.2 (CH); 6.16 m, 1 H (=CH); 6.65 d, 1 H, 3J = 11.6 (=CH); 6.68 d, 1 H, 3J = 15.3 (=CH);
7.08 m, 1 H (=CH); 8.48 s, 1 H (H-2); 8.50 s, 1 H (H-2). 13C NMR (CDCl3): 13.9, 21.5, 21.6,
30.1, 33.7, 48.0, 48.3, 54.0, 54.1, 63.0, 63.4, 86.7, 87.1, 116.3, 121.2, 121.5, 121.6, 132.5,
133.6, 151.0, 151.3, 147.6, 148.4, 152.4, 152.8, 160.5, 160.8, 163.6, 164.2. IR (CDCl3): 2988,
1752, 1604, 1567, 1483, 1459, 1442, 1358, 1327, 1260, 1071, 1049, 1022. HRMS (EI): calcu-
lated for C16H21N5O5 363.1543, found 363.1550.
9-Isopropyl-6-methoxy-8-propenyl-9H-purine (4f): A reaction mixture, prepared according the
general procedure, starting from sodium formate (0.159 g, 1.04 mmol), 2a (0.151 g, 0.52 mmol)
and Pd2dba3·CHCl3 (0.027 g, 0.026 mmol) was stirred 27 h at ambient temperature. Column
chromatography (silica gel, EtOAc–hexane, 2:1) gave the title compound (0.080 g, 66%) as
colorless oil, that was ≥98% E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.65 d,
6 H, 3J = 6.9 (CH3); 1.97 dd, 3 H, 3J = 1.7, 6.9 (CH3); 4.13 s, 3 H (CH3); 4.86 m, 1 H (CH);
6.47 d, 1 H, 3J = 15.5 (=CH); 7.19 m, 1 H (=CH); 8.42 s, 1 H (H-2). 13C NMR (75 MHz,
CDCl3): 18.9, 21.4, 47.7, 53.8, 117.1, 121.4, 138.0, 150.0, 150.3, 152.7, 160.0. IR: 2979,
2941, 1656, 1601, 1570, 1481, 1448, 1419, 1397, 1351, 1324, 1290, 1171, 1159, 1136, 1092,
1069, 1048, 983, 959, 943, 897, 801. HRMS (ESI): calculated for C12H16N4O [M + H]+
233.13967, found 233.13919.
9-Isopropyl-6-methoxy-8-[3-(phenylsulfonyl)propenyl]-9H-purine (4g): Dry DMF (4 ml) was
added to a mixture of 2a (0.093 g, 0.32 mmol), sodium benzenesulfinate (0.079 g, 0.48 mmol)
and Pd2dba3·CHCl3 (0.017 g, 0.016 mmol). The resultant mixture was stirred 8 h at ambient
temperature, concentrated in vacuo and column chromatography (silica gel, EtOAc–MeOH,
9:1) gave the title compound (0.063 g, 53%) as yellow amorphous solid, that was ≥98% E
determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.63 d, 6 H, 3J = 6.9 (CH3); 4.07 d, 2 H,
3J = 7.8 (CH2); 4.18 s, 3 H (CH3); 4.79 m, 1 H (CH); 6.63 d, 1 H, 3J = 15.4 (=CH); 6.98 m,
1 H (=CH); 7.56 m, 2 H (ArH); 7.66 m, 1 H (ArH); 7.91 m, 2 H (ArH); 8.48 s, 1 H (H-2).
13C NMR (75 MHz, CDCl3): 21.6, 48.0, 54.1, 59.9, 121.7, 124.8, 125.7, 128.4, 129.3, 134.0,
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Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
323
138.4, 151.2, 147.7, 152.7, 160.6. IR (CDCl3): 2996, 2944, 2872, 1603, 1572, 1483, 1448,
1356, 1326, 1310, 1155, 1087, 1071, 1049. HRMS (EI): calculated for C18H20N4O3S 372.1256,
found 372.1259.
6-Chloro-9-Isopropyl-8-[3-(phenylsulfonyl)propenyl]-9H-purine (4h): Dry DMF (4 ml) was
added to a mixture of 2b (0.104 g, 0.35 mmol), sodium benzenesulfinate (0.087 g, 0.53 mmol)
and Pd2dba3·CHCl3 (0.019 g, 0.018 mmol). The resultant mixture was stirred 15 h at ambi-
ent temperature, concentrated in vacuo and column chromatography (silica gel, EtOAc–
hexane, 2:1) gave the title compound (0.055 g, 41%) as yellow foam, that was 98% E deter-
mined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.66 d, 6 H, 3J = 6.9 (CH3); 4.09 d, 2 H, 3J =
7.8 (CH2); 4.81 m, 1 H (CH); 6.69 d, 1 H, 3J = 15.3 (=CH); 7.08 m, 1 H (=CH); 7.57–7.71 m,
3 H (ArH); 7.92 d, 2 H, 3J = 8.2 (ArH); 8.66 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 21.5,
48.8, 59.8, 124.2, 128.1, 128.4, 129.4, 131.7, 134.1, 138.5, 151.0, 150.1, 150.9, 152.7.
IR (CDCl3): 3069, 2930, 2857, 1590, 1560, 1447, 1397, 1352, 1325, 1252, 1153, 1086, 997.
HRMS (EI): calculated for C17H17ClN4O2S 376.0761, found 376.0767.
2-(3-Acetoxypropenyl)-9-isopropyl-6-methoxy-9H-purine (4i): Dry THF (5 ml) was added to
a
mixture of 2a (0.152 g, 0.52 mmol), sodium acetate (0.064 g, 0.78 mmol) and
Pd2dba3·CHCl3 (0.027 g, 0.026 mmol). The resultant mixture was stirred 16 h at 50 °C, con-
centrated in vacuo and column chromatography (silica gel, EtOAc–hexane, 2:1) gave the ti-
tle compound (0.053 g, 35%) as yellow foam, that was ≥98% E determined by 1H NMR.
1H NMR (300 MHz, CDCl3): 1.71 d, 6 H, 3J = 6.9 (CH3); 2.15 s, 3 H (CH3); 4.18 s, 3 H (CH3);
4.85 d, 2 H, 3J = 4.6 (CH2); 4.90 m, 1 H (CH); 6.74 d, 1 H, 3J = 15.4 (=CH); 7.22 m, 1 H
(=CH); 8.48 s, 1 H (H-2). 13C NMR (75 MHz, CDCl3): 20.8, 21.6, 48.0, 54.0, 63.6, 118.0,
121.6, 134.4, 150.9, 148.7, 152.8, 160.5, 170.4. IR: 2993, 2945, 1743, 1604, 1572, 1484,
1458, 1441, 1363, 1351, 1327, 1231, 1070. HRMS (EI): calculated for C14H18N4O3 290.1379,
found 290.1366.
Dimethyl (E)-2,2-bis[3-(9-isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]malonate (5a): A reac-
tion mixture, prepared according the general procedure, starting from 4a (0.144 g,
0.40 mmol), NaH (0.016 g, 0.40 mmol), 2a (0.183 g, 0.63 mmol), and Pd2dba3·CHCl3
(0.021 g, 0.020 mmol) was stirred 5 h at ambient temperature. Column chromatography
(silica gel, EtOAc–MeOH, 9:1) gave the title compound (0.145 g, 62%) as yellow foam, that
was ≥98% E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.66 d, 12 H, 3J = 6.9
(CH3); 3.00 t, 2 H, 3J = 7.4 (CH2); 3.76 s, 6 H (CH3); 4.17 s, 6 H (CH3); 4.89 m, 2 H (CH);
6.62 d, 2 H, 3J = 15.1 (=CH); 7.06 m, 2 H (=CH); 8.46 s, 2 H (H-2). 13C NMR (75 MHz,
CDCl3): 21.6, 37.1, 47.9, 52.8, 54.0, 57.7, 120.4, 121.5, 135.2, 149.0, 150.8, 152.8, 160.3,
170.4. IR: 2994, 2939, 1735, 1603, 1571, 1483, 1440, 1359, 1327, 1292, 1174, 1137, 1070,
1049. HRMS (EI): calculated for C29H36N8O6 592.2787, found 592.2758.
(E)-5,5-bis[3-(9-Isopropyl-6-methoxy-9H-purin-8-yl)prop-2-enyl]-1,3-dimethylbarbituric acid (5c):
A reaction mixture, prepared according the general procedure, starting from 1,3-dimethyl-
barbituric acid (0.091 g, 0.58 mmol), NaH (0.023 g, 0.58 mmol), 2a (0.113 g, 0.39 mmol)
and Pd2dba3·CHCl3 (0.020 g, 0.020 mmol) was stirred 24 h at ambient temperature. Column
chromatography (silica gel, EtOAc–MeOH, 9:1) gave the title compound (0.080 g, 34%) as
yellow oil, that was ≥98% E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.68 d,
12 H, 3J = 6.8 (CH3); 3.05 d, 4 H, 3J = 7.8 (CH2); 3.26 s, 6 H (CH3); 4.17 s, 6 H (CH3);
4.88 m, 2 H (CH); 6.60 d, 2 H, 3J = 15.4 (=CH); 6.90 m, 2 H (=CH); 8.46 s, 2 H (H-2).
13C NMR (75 MHz, CDCl3): 21.6, 28.7, 42.6, 47.8, 54.0, 56.6, 121.8, 132.5, 151.0, 148.2,
152.7, 160.4, 169.9, 170.5. IR (CDCl3): 2994, 2942, 1684, 1604, 1572, 1483, 1443, 1422,
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Tobrmanová, Tobrman, Dvořák:
1382, 1358, 1328, 1290, 1251, 1070. HRMS (EI): calculated for C30H36N10O5 616.2870,
found 616.2851.
Dimethyl (E)-2-[3-(6-chloro-9-isopropyl-9H-purin-2-yl)prop-2-enyl]malonate (10a): A reaction
mixture, prepared according the general procedure, starting from dimethyl malonate
(0.054 ml, 0.51 mmol), NaH (0.020 g, 0.51 mmol, 60% suspension in mineral oil), 9
(0.050 g, 0.17 mmol) and Pd2dba3·CHCl3 (0.009 g, 0.0085 mmol) was stirred 24 h at 60 °C.
Column chromatography (silica gel, EtOAc) gave the title compound (0.057 g, 92%) as yel-
low oil, that was ≥98% E determined by 1H NMR. 1H NMR (CDCl3): 1.62 d, 6 H, 3J = 6.5
(CH3); 2.90 dt, 2 H, 3J = 1.4, 7.3 (CH2); 3.61 t, 1 H, 3J = 7.4 (CH); 3.75 s, 6 H (CH3); 4.89 m,
1 H (CH); 6.64 td, 1 H, 3J = 1.4, 15.4 (=CH); 7.11 m, 1 H (=CH); 8.09 s, 1 H (H-8). 13C NMR
(CDCl3): 22.5, 31.6, 47.7, 51.0, 52.7, 130.1, 131.4, 136.3, 142.6, 150.4, 151.8, 158.2, 169.0.
IR (CHCl3): 1734, 1591, 1552, 1490, 1458, 1436, 1391, 1319, 987, 908. HRMS (EI): calculated
for C16H19ClN4O4 366.1111, found 366.1095.
(E)-6-Chloro-9-Isopropyl-2-[3-(phenylsulfonyl)propenyl]-9H-purine (10b): Dry DMF (4 ml) was
added to a mixture of 9 (0.150 g, 0.508 mmol), sodium benzenesulfinate (0.251 g,
1.53 mmol) and Pd2dba3·CHCl3 (0.026 g, 0.025 mmol). The resultant mixture was stirred
24 h at ambient temperature, concentrated in vacuo and column chromatography (silica gel,
EtOAc–hexane, 4:1) gave the title compound (0.080 g, 42%) as yellow foam, that was ≥98%
E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.63 d, 6 H, 3J = 6.6 (CH3); 4.04 d,
2 H, 3J = 7.5 (CH2); 4.89 m, 1 H (CH); 6.59 d, 1 H, 3J = 15.6 (=CH); 7.10 m, 1 H (=CH);
7.51–7.67 m, 3 H (ArH); 7.90 d, 2 H, 3J = 8.40 (ArH); 8.13 s, 1 H (H-2). 13C NMR (75 MHz,
CDCl3): 22.4, 47.9, 59.9, 125.3, 128.3, 129.1, 130.5, 133.9, 137.0, 138.3, 143.3, 150.4, 151.7,
156.7. IR: 3063, 3020, 2982, 2921, 2849, 1687, 1589, 1551, 1490, 1459, 1447, 1425, 1391,
1319, 1309, 1217, 1172, 1151, 1085, 1025, 999, 976, 922, 881, 752, 705, 688, 667. HRMS
(ESI): calculated for C17H18O2N4ClS [M + H]+ 377.08334, found 377.08289.
(E)-2-[3-(6-Chloro-9-isopropyl-9H-purin-2-yl)prop-2-enyl]-2-(phenylsulfonyl)acetophenone (10c):
A reaction mixture, prepared according the general procedure, starting from 2-(phenyl-
sulfonyl)acetophenone (0.398 g, 1.53 mmol), NaH (0.024 g, 1.53 mmol), 9 (0.150 g,
0.51 mmol) and Pd2dba3·CHCl3 (0.026 g, 0.0254 mmol) was stirred 24 h at 60 °C. Column
chromatography (silica gel, EtOAc–hexane, 2:1) gave the title compound (0.100 g, 40%) as
yellow foam, that was ≥98% E determined by 1H NMR. 1H NMR (300 MHz, CDCl3): 1.54 d,
6 H, 3J = 6.9 (CH3); 3.08 t, 2 H, 3J = 7.5 (CH2); 4.80 m, 1 H (CH); 5.25 m, 1 H (CH); 6.55 d,
1 H, 3J = 15.6 (=CH); 6.91 dt, 1 H, 3J = 7.5, 15.0 (=CH); 7.40 m, 2 H (ArH); 7.50 m, 3 H
(ArH); 7.60 m, 1 H (ArH); 7.55 m, 2 H (ArH); 7.90 m, 2 H (ArH); 8.05 s, 1 H (H-8). 13C NMR
(75 MHz, CDCl3): 22.3, 47.7, 63.5, 68.8, 128.6, 128.9, 129.0, 129.5, 132.5, 134.0, 134.3,
136.2, 136.6, 142.8, 150.1, 151.6, 157.5, 191.2. IR: 3117, 3065, 2982, 2935, 1738, 1681,
1591, 1550, 1490, 1448, 1426, 1391, 1321, 1310, 1277, 1220, 1150, 1111, 1084, 1027, 999,
977, 938, 904, 882, 837, 753, 687, 666. HRMS (ESI): calculated for C25H23O3N4ClS [M + H]+
495.1252, found 495.12414.
Dimethyl (E)-2,2-bis[3-(6-chloro-9-isopropyl-9H-purin-2-yl)prop-2-enyl]malonate (11): A reac-
tion mixture, prepared according the general procedure, starting from dimethyl malonate
(0.054 ml, 0.51 mmol), NaH (0.020 g, 0.51 mmol, 60% suspension in mineral oil), 9 (0.050 g,
0.17 mmol), Pd(OAc)2 (0.0019 g, 0.0085 mmol) and PCy3 (0.0048 g, 0.017 mmol) was stirred
120 h at 60 °C. Column chromatography (silica gel, EtOAc) gave the title compound (0.057 g,
92%) as brown foam, that was ≥98% E determined by 1H NMR. 1H NMR (CDCl3): 1.65 d,
12 H, 3J = 6.9 (CH3); 3.00 d, 4 H, 3J = 7.7 (CH2); 3.80 s, 6 H (CH3); 4.94 m, 2 H (CH); 6.71 d,
1 H, 3J = 15.4 (=CH); 7.08 m, 1 H (=CH); 8.12 s, 1 H (H-8). 13C NMR (CDCl3): 22.6, 36.0,
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Pd-catalyzed Allylic Substitution of Purin-8-yl(allyl) Acetate
325
47.6, 52.8, 58.0, 130.2, 133.1, 134.4, 142.7, 150.4, 151.8, 158.0, 170.7. IR (CHCl3): 1733,
1591, 1552, 1490, 1458, 1436, 1390, 1319, 978, 911, 880. HRMS (EI): calculated for
C
27H30Cl2N8O4 600.1767, found 600.1788.
This project was supported by the Research Centre “The Structure and Synthetic Applications of
Transition Metal Complexes-LC06070” of the Ministry of Education, Youth and Sports of the Czech
Republic and by the Czech Science Foundation (grant no. 203/09/1552).
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