Heck reactions of 6- and 2-halopurines

Article abstract of DOI:10.1002/ejoc.200800091

Under the conditions of the Heck reaction, 9-benzyl-6-iodopurine affords mainly the corresponding 6,6′-dimer, the Heck product being formed only in low yield (≤12%). With 7-benzyl-6-iodopurine the dimerization is suppressed and the Heck product is obtaine

Full text of DOI:10.1002/ejoc.200800091

FULL PAPER
DOI: 10.1002/ejoc.200800091
Heck Reactions of 6- and 2-Halopurines
[a]
[a]
ˇ
ˇ
Tomás Tobrman and Dalimil Dvorák*
Keywords: Nucleobases / Homogeneous catalysis / Nitrogen heterocycles / Heck reaction
Under the conditions of the Heck reaction, 9-benzyl-6-iodo-
purine affords mainly the corresponding 6,6Ј-dimer, the Heck
product being formed only in low yield (Յ12%). With 7-ben-
zyl-6-iodopurine the dimerization is suppressed and the
Heck product is obtained in 32–91% yield. 9-Substituted 6-
chloropurines in 71–97% isolated yields. The reaction pro-
ceeds with alkenes bearing electron-withdrawing substitu-
ents (like CO2Bu, COCH3, CN) and Ph, while vinyl acetate
and dodec-1-ene are unreactive.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
chloro-2-iodopurines react smoothly, giving 2-alkenyl-6- Germany, 2008)
have thus been prepared by Pd-catalyzed reactions between
Introduction
halopurines or O-tosylpurines and alkenylstannanes,[17]
alkenylzinc,[17c] or alkenylboron reagents.[18] An opposite
approach, involving coupling of 2-stanylated purines with
alkenyl halides, has also been described.[19] Heck reactions
of 6-vinylpurines were reported to produce 6-alkenyl-
purines.[4a]
Among a vast number of biologically active purine deriv-
atives, alkenylpurines play an important role.[1] 6-Alkenyl-
purines, for example, are associated with antimycobacte-
rial,[2] cytotoxic [3] and cytokinin[4] activity and with inhibi-
tion of 15-lipoxygenase.[5] Some 6-alkenylpurines have been
designed as covalent analogues of DNA base pairs[6] or
novel cross-linking agents,[7] and have also been used for
the synthesis of fluorescent nucleoside analogues.[8] More-
over, 2-alkenyladenosine derivatives have been reported to
function as inhibitors of adenosine receptors.[9]
Several methodologies have been used for the prepara-
tion of alkenylpurines. 6-Styrylpurine was first prepared by
condensation of 6-methylpurine with benzaldehyde in the
presence of HCl.[10] Another, more general, synthetic ap-
proach to 6-alkenylpurines, is based on Wittig reactions be-
tween 9-protected (purin-6-yl)methylene-triphenyl-λ5-phos-
phanes (Wittig reagents) and aldehydes or ketones.[11]
Cyclic 6-alkenyloxypurines have been prepared by intramo-
lecular cyclization of 6-(hydroxyalkyn-1-yl)purines,[12] while
6-enaminopurines are accessible by addition of amines to
6-alkynylpurines.[13] Partial hydrogenation of 2-alkynyl-[14]
and 8-alkynylpurines[15] to give the corresponding alkenes
has also been reported. Hydrogenation of 6-alkynylpurines
to 6-alkenylpurines was reported to proceed satisfactorily
only with 9-unprotected bases, with overhydrogenation tak-
ing place otherwise.[4a] However, the most versatile method-
ology for the preparation of alkenylpurines – nowadays
used almost without exception – is based on transition-
metal-catalyzed cross-coupling reactions.[16] Alkenylpurines
From this point of view it is interesting that Heck reac-
tions starting from halopurines have not yet been reported,
with the exception of the reaction between 8-bromocaffeine
and tert-butyl acrylate.[20] Heck reactions of halopurines
would be of key importance, since they would allow easy
introduction of alkenes bearing EWG substituents such as
CO2R, CO, or CN, cases in which the corresponding alken-
ylstannanes and boronic acids are not commonly accessible.
Recently, we have made attempts to perform Heck reactions
on 6-halopurines, but without success. No reactions were
observed under classical Heck conditions, whereas in the
presence of TlI or AgI acetates the formation of N1-substi-
tuted hypoxanthine derivatives was observed.[21] When the
reactions were run in the presence of hydride donors such
as triethylammonium formate, saturated products of “re-
ductive Heck reactions” were obtained.[22] Similarly, unsuc-
cessful attempted vinylation of 6-halopurines with vinyl
acetate under Heck conditions has been reported[4a]
Recently, as part of our continuing efforts to accomplish
Heck reactions of 6- and 2-halopurines, we observed the
formation of 6,6Ј-purine dimer 2 as a main product, but
together with a small amount of the desired Heck product
3, in the reaction between iodopurine 1 and butyl acrylate
in the presence of palladium catalyst without phosphane
ligand (Scheme 1).[23] Suppression of the dimerization
could, thus, possibly open an avenue to Heck reactions of
purine 6- and 2-halides. Purine dimers are highly polar
compounds, and they could easily have evaded detection
in previous research. Therefore, we reexamined the Heck
reactions of 6- and 2-halopurines from this point of view.
[a] Department of Organic Chemistry, Institute of Chemical Tech-
nology, Prague
Technická 5, 2166 28 Prague 6, Czech Republic
Fax: +420-224-354-288
E-mail: Tomas.Tobrman@vscht.cz
dvorakd@vscht.cz
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 2923–2928
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2923

T. Tobrman, D. Dvorˇák
FULL PAPER
butyl acrylate (56 equiv.) increased the yield only slightly,
to 24%. The same result was obtained when the reaction
was performed in an excess of butyl acrylate serving at the
same time as solvent.
We next turned our attention to 7-benzyl-6-iodopurine
(4), in the expectation that the formation of the correspond-
ing 6,6Ј-dimer might be suppressed for steric reasons. Ad-
ditionally, the reported lower reactivities of 6-halo-7-ben-
zylpurines relative to their 9-benzyl analogues[17c] might be
disadvantageous for the dimer formation. To our delight,
the desired Heck product 5a was obtained in 53% yield
when the reaction was catalyzed by Pd(OAc)2 in the pres-
ence of iPr2NEt in DMF at 120 °C without phosphane li-
gand (Scheme 2, Table 1, Entry 1). To improve the yield, the
reaction was further optimized. Similar result was obtained
when Pd(dba)2 was used instead of Pd(OAc)2 (Table 1, En-
try 2). In contrast, replacement of iPr2NEt with K2CO3 or
the use of PdCl2(PPh3)2 as catalyst suppressed the reaction
(Table 1, Entries 3 and 4). The yield increased to 77%, how-
ever, in the presence of 1.1 equiv. of Tl2SO4 (Table 1, En-
try 5), while application of Na3PO4 as a base led to further
improvement and the reaction under phosphane-free condi-
tions gave 5a in 89% yield. The combination of Na3PO4
with diPheCy2P lowered the yield to 50% (Table 1, En-
tries 6 and 7), but a high yield of the Heck product was
obtained when Pd(OAc)2 was used in combination with bi-
PheCy2P and iPr2NEt (Table 1, Entry 8). Since in this case
the conversion of 4 was quantitative, which simplified sepa-
ration of the product, these conditions were used for Heck
reactions between 4 and other substrates. Under the above
conditions, acrylonitrile, methyl vinyl ketone, and styrene
Scheme 1. Reaction between 9-benzyl-6-iodopurine and butyl acryl-
ate under the conditions of the Heck reaction.
Results and Discussion
Repetition of the reaction between 9-benzyl-6-iodo-
purine (1) and butyl acrylate under the previously described
conditions[21] confirmed that in the presence of Pd(PPh3)2-
Cl2 or Pd(PPh3)4 only decomposition of starting com-
pounds takes place. However, when the reaction was per-
formed under phosphane-free conditions the dimer 2 be-
came the main product of the reaction, but accompanied
by a small amount of the desired Heck reaction product
3 (Scheme 1). The reaction between 1 and butyl acrylate
(4 equiv.) was then repeated in the presence of various bases
(Et3N, K2CO3, iPr2NEt, Ag2CO3) and solvents (NMP,
DMF, CH3CN) at different temperatures and with Pd-
(dba)2 or Pd(OAc)2 as a source of palladium, with the aim
of maximizing the formation of the Heck product. It ap-
peared that the reaction requires polar solvent and a tem-
perature above 100 °C, which excludes solvents such as
THF, acetonitrile, or toluene. The best results were ob-
tained in DMF at 120 °C; however, the yields of the Heck
product 3 did not exceed 12%. The use of a large excess of Scheme 2. Heck reactions of 7-benzyl-6-iodopurine.
Table 1. Heck reactions of 7-benzyl-6-iodopurine (4, Scheme 2).[a]
Entry
R
Catalyst
Ligand
Base
% Yield[b]
1
2
3
4
5
6
7
8
CO2Bu (5a)
CO2Bu (5a)
CO2Bu (5a)
CO2Bu (5a)
CO2Bu (5a)
CO2Bu (5a)
CO2Bu (5a)
CO2Bu (5a)
CN (5b)
Pd(OAc)2
Pd(dba)2
none
none
none
none
none
none
diPheCy2P
diPheCy2P
diPheCy2P
diPheCy2P
diPheCy2P
iPr2NEt
iPr2NEt
K2CO3
53[c]
51
Pd(OAc)2
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
trace
none
77[d]
89[c]
iPr2NEt
iPr2NEt
Na3PO4
Na3PO4
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
50[c]
86 (53[e])
49[e]
9
10
11
CH3CO (5c)
Ph (5d)
32[e]
47[e]
[a] Reaction conditions: a mixture of 4 with alkene (4 equiv.), base (2 equiv.), catalyst (5 mol-%), and DiPheCy2P (10 mol-%) in dry DMF
1
(5 mL per mmol of 4) was stirred under argon for 18 h at 120 °C. [b] The yields were established by H NMR with 2,3,5-trinitrobenzene
as internal standard. [c] Unreacted iodopurine 4 was present in the reaction mixture. [d] 1.1 Equiv. of Tl2SO4 was used as additive.
[e] Isolated yield.
2924
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2923–2928

Heck Reactions of 6- and 2-Halopurines
afforded the expected Heck-type products in fair yields ketone, and styrene proceeded with high yields (Entries 18–
(Table 1, Entries 9–11). In each case the (E) isomer of the 23), but electron-rich substrates – vinyl acetate and dodec-
product was obtained exclusively. Vinyl acetate, as an exam- 1-ene – were unreactive. Only traces (Յ3%) of the corre-
ple of an electron-rich alkene, gave only a dehalogenation sponding 2,2Ј-dimers were detected in the crude reaction
product – 7-benzylpurine. 6-Chloro-7-benzylpurine did not mixtures under ligand-free conditions or when TFP or o-
react under these conditions at all.
tolyl3P were used as ligands. When the reactions were cata-
We also examined the Heck reactions of 6-chloro-2-iodo lyzed with Pd(dba)2/BipheCy2P, formation of the 2,2Ј-dimer
derivatives 6a and 6b (Scheme 3). Since the chlorine in the was not observed.
6-position is not reactive, such reactions should selectively
lead to the 2-alkenyl-6-chloro derivatives. In this case there
is a possibility of further derivatization of such compounds
at the 6-position giving biologically relevant compounds.
The results are summarized in Table 2. As expected, the
products were obtained with exclusive 2-selectivity, the reac-
tion proceeding more easily than with 6-iododerivatives,
and the dimerization did not occur. The reaction of 6a was
optimized with the respect to the source of palladium, the
base used, the ligand, and the solvent. In DMF the yields
obtained span the range from 51 to 88%; again, phosphane-
free conditions and iPr2NEt gave the best results (Entries 4,
8, 12, 13). Unlike the reactions with 1 and 4, this reaction
proceeds even in acetonitrile at 60 °C, giving the desired
Scheme 3. Heck reactions of 6-chloro-2-iodopurine derivatives.
Heck product in 90% isolated yield after 3 h (Entry 15).
Other less polar solvents such as THF, EtOAc, DCE, and
toluene were less effective at this temperature, and only low
levels of conversion of 6a (2–9%) after prolonged reaction
The sterically more demanding methyl methacrylate gave
times were observed. To achieve acceptable reaction times low conversion and a substantial amount of the dimer in
with all substrates, acetonitrile as a solvent at 80 °C and the reaction with 6a at 80 °C in acetonitrile. A higher reac-
Pd(dba)2/iPr2NEt were used for the reactions of 6a and 6b tion temperature was required in this case. However, even
with other alkenes. Under these conditions, the reactions of 3 d heating at 120 °C in DMF led only to 54% yield of the
both substrates with acrylonitrile, butyl acrylate, ethyl vinyl desired product 7h (Table 2, Entry 23).
Table 2. Heck reactions of 2-iodopurines 6a and 6b (Scheme 3).[a]
Entry
R, R1, R2
Catalyst
Base
Solvent, temperature [°C]
% Yield[b]
1
2
3
4
5
6
7
8
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, CO2Bu
iPr, H, Ph
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2(PPh3)2
Pd(dba)2
(C3H5PdCl)2
Pd(dba)2/TFP
Pd(dba)2/o-tolyl3P
Pd(dba)2/BipheCy2P
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Na3PO4
K2CO3
Et3N
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 120
DMF, 100
DMF, 80
MeCN, 80
MeCN, 60
MeCN, 40
MeCN, 80
MeCN, 80
MeCN, 80
MeCN, 80
MeCN, 80
MeCN, 80
DMF, 120[d]
72
51
73
79
74
78
84
79
54
73
60
88
85
85
90
40[c]
87
97
80
71
78
82
54
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
iPr, H, CH3CO
iPr, H, CN
AcRf, H, CO2Bu
AcRf, H, Ph
AcRf, H, CH3CO
iPr, CH3, CO2Bu
Pd(dba)2
Pd(dba)2
Pd(dba)2/BipheCy2P
[a] Reaction conditions: a mixture of 6a or 6b with alkene (4 equiv.), base (2 equiv.), and catalyst (5 mol-%) in the indicated solvent (5 mL
per mmol of 6) was stirred under argon under the indicated conditions for three hours. [b] Isolated yield. [c] Unreacted 6a remains in
the reaction mixture. [d] Reaction time was 3 d.
Eur. J. Org. Chem. 2008, 2923–2928
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2925

T. Tobrman, D. Dvorˇák
FULL PAPER
Butyl 3-(7-Benzylpurine-6-yl)acrylate (5a): Purification of the crude
reaction mixture by flash chromatography with ethyl acetate/meth-
anol (20:1) gave the desired product 5a (45 mg, 54%) as a yellow
solid; m.p. 95–97 °C. 1H NMR (CDCl3): δ = 0.94 (t, J = 7.3 Hz,
CH3, 3 H), 1.38 (m, 2 H, CH2), 1.66 (m, 2 H, CH2), 4.19 (t, J =
6.4 Hz, 2 H, CH2O), 5.62 (s, 2 H, CH2Ph), 7.13 (m, 2 H, ArH),
7.20 (d, J = 15 Hz, 1 H, =CH), 7.35 (m, 3 H, ArH), 7.86 (d, J =
15 Hz, 1 H, =CH), 8.31 (s, 1 H, 8-H), 9.08 (s, 1 H, 2-H) ppm. 13C
NMR (CDCl3): δ = 13.6, 19.1, 30.6, 51.7, 64.9, 123.0, 126.5, 127.7,
129.0, 129.4, 133.8, 135.7, 144.6, 149.8, 153.2, 162.9, 165.8 ppm.
Conclusions
The Heck reactions of 9-substituted 6-iodopurines are
complicated by competitive dimerization, the Heck prod-
ucts being formed only in low yields. When 7-substituted 6-
iodopurine derivatives are used, however, the dimerization
is suppressed and the products of the Heck reaction can be
isolated in about 30–50% yields.[24] In contrast, the Heck
reactions of 9-substituted 6-chloro-2-iodopurines proceed
selectively at the 2-position, and the corresponding Heck
products are formed smoothly in high yields, accompanied
by only trace amounts of 2,2Ј-dimers. In most cases a cata-
lytic system without phosphane ligand using Pd(dba)2 [or a
combination of Pd(dba)2 with biPheCy2P] and iPr2NEt as
a base gave the best results.[25]
IR (CHCl ): ν = 2962, 2934, 1713, 1582, 1562, 1487, 1453, 1389,
˜
3
1369, 1336, 1302, 1284, 1158, 970 cm–1. HR MS (EI): calculated
for C19H20N4O2: 336.1586; found 336.1599.
3-(7-Benzylpurine-6-yl)acrylonitrile (5b): Chromatography with
EtOAc/methanol (20:1) gave 5b (32 mg, 49%) as a yellow solid;
1
m.p. 96–98 °C. H NMR (CDCl3): δ = 5.63 (s, 2 H, CH2), 6.85 (d,
J = 15.5 Hz, 1 H, =CH), 7.09 (m, 2 H, ArH), 7.39 (m, 3 H, ArH),
7.51 (d, J = 15.5 Hz, 1 H, =CH), 8.34 (s, 1 H, 8-H), 9.05 (s, 1 H,
8-H) ppm. 13C NMR (CDCl3): δ = 51.6, 116.9, 122.4, 126.2, 129.3,
Experimental Section
129.7, 133.5, 141.6, 142.3, 150.5, 153.0, 163.4 ppm. IR (CHCl ): ν
˜
3
General: All reactions were performed under nitrogen. NMR spec-
tra were measured on a Varian Gemini 300 (1H, 300.07 MHz; 13C,
75.46 MHz), a Bruker AMX3 400 (1H, 400.13 MHz and 13C,
100.62 MHz) or a Bruker DRX 500 Avance (1H, 500.13 MHz and
13C, 125.77 MHz) spectrometer at 298 K. Unambiguous assign-
ment of the NMR signals is based on 13C{1H}, 13C APT, COSY,
HMQC and 13C HMBC spectra. IR spectra were recorded on a
Nicolet 750 FT-IR instrument. Mass spectra were measured on a
ZAB-SEQ (VG Analytical) machine. The solvents were dried and
degassed by standard procedures; silica gel (ICN SiliTech, 32–63)
was used for column chromatography. 9-Benzyl-6-iodopurine[26]
(1), 7-benzyl-6-iodopurine[17c] (4), 9-benzyl-6-chloropurine,[3] 6-
chloro-2-iodo-9-isopropylpurine[27] (6a), and 6-chloro-2-iodo-9-
(O,O,O-triacetyl-β--ribofuranosyl)purine[28] (6b) were prepared by
the reported procedures; other compounds were purchased.
= 2224, 1580, 1562, 1488, 1451, 1391, 1369, 1335, 1165, 952 cm–1.
HR MS (EI): calculated for C15H19ClN4O2: 261.1014; found
261.1010.
7-Benzyl-6-(3-oxobut-1-enyl)purine (5c): Chromatography with
EtOAc/methanol (9:1) gave 5c (22 mg, 32%) as a yellow solid; m.p.
1
145–150 °C. H NMR (CDCl3): δ = 2.3 (s, 3 H, MeCO), 5.65 (s, 2
H, CH2Ph), 7.14 (d, J = 7.7 Hz, 2 H, ArH), 7.37 (m, 3 H, ArH),
7.53 (d, J = 15.1 Hz, 1 H, CH=), 7.68 (d, J = 15.1 Hz, 1 H, CH=),
8.35 (s, 1 H, 8-H), 9.12 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3): δ =
29.4, 51.7, 123.5, 126.4, 129.0, 129.5, 133.5, 133.6, 133.8, 144.8,
150.0, 153.2, 163.0, 197.1 ppm. IR (CHCl ): ν = 1695, 1580, 1488,
˜
3
1455, 1368, 1335 cm–1. HR MS (EI): calculated for C16H14N4O
278.1168; found 278.1176.
7-Benzyl-6-(2-phenylethenyl)purine (5d):[29] Chromatography with
EtOAc/methanol (9:1) gave 5d (37 mg, 47%) as a yellow solid; m.p.
179–182 °C. 1H NMR (CDCl3): δ = 5.67 (s, 2 H, CH2Ph), 7.15 (m,
3 H, 2H ArH and 1H CH=), 7.41 (m, 8 H, ArH), 8.23 (d, J =
14.6 Hz, 1 H, CH=), 8.32 (s, 1 H, 8-H), 9.09 (s, 1 H, 2-H) ppm.
13C NMR (CDCl3): δ = 51.5, 120.2, 122.2, 125.9, 127.7, 128.7,
128.8, 129.5, 134.9, 135.5, 138.8, 147.7, 149.2, 153.2, 162.2 ppm.
Butyl 3-(9-Benzylpurine-6-yl)acrylate (3): Dry DMF (0.5 mL), then
butyl acrylate (2 mL, 14 mmol) and iPr2NEt (65 mg, 0.5 mmol)
were added under argon to a mixture of 9-benzyl-6-iodopurine (1,
84 mg, 0.25 mmol) and Pd(dba)2 (7 mg, 0.0125 mmol). The re-
sulting mixture was then stirred at 120 °C for 18 h, silica (5 g) was
added, volatiles were evaporated, and flash chromatography with
EtOAc/hexane (2:1) afforded 3 (20 mg, 24%) as a colorless solid;
IR (CHCl ): ν = 1631, 1582, 1558, 1487, 1455, 1370 cm–1. HR MS
˜
3
m.p. 59–62 °C. 1H NMR (CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3 H, (EI): calculated for C20H16N4 312.1375; found 312.1352.
CH3), 1.42 (m, 2 H, CH2), 1.70 (m, 2 H, CH2), 4.24 (t, J = 6.5 Hz,
General Procedure for Heck Reactions of 6-Chloro-2-iodopurines 6a
2 H, O–CH2), 5.46 (s, 2 H, CH2), 7.33 (m, 5 H, ArH), 7.62 (d, J =
and 6b: Dry DMF or acetonitrile (3 mL per 0.25 mmol of iodo-
16.0 Hz, 1 H, =CH), 8.1 (s, 1 H, 8-H), 8.1 (d, J = 16.0 Hz, 1 H,
purine), then the alkene (4 equiv.) and iPr2NEt2 (2 equiv.) were
=CH), 9.0 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3): δ = 13.7, 19.1,
added under argon to a mixture of 6a or 6b (1 equiv.) and
30.6, 47.4, 64.8, 127.8, 128.7, 129.2, 132.0, 134.8, 138.0, 145.2,
Pd(dba)2 (0.05 equiv.). The resulting mixture was stirred for 3 h at
151.1, 152.5, 152.6, 166.2 ppm. IR (CHCl ): ν = 2962, 1713, 1583,
˜
3
the temperature given in Table 2. Silica (5 g) was added, volatiles
were evaporated, and a pure product was obtained by flash
chromatography.
1496, 1454, 1403, 1326, 1299, 1278 cm–1. HR MS (EI): calculated
for C19H20N4O2: 336.1586; found 336.1561.
The corresponding-6,6Ј-dimer 2 is not eluted under these condi-
tions and was not isolated. The presence of 6 in large amounts in
the crude reaction mixture could, however, be shown by H NMR
Butyl 3-(6-Chloro-9-isopropylpurine-2-yl)acrylate (7a): Use of the
General Procedure starting from 6a (81 mg, 0.25 mmol), Pd(dba)2
(7 mg, 0.0125 mmol), butyl acrylate (128 mg, 1 mmol), and
iPr2NEt (65 mg, 0.5 mmol), with heating at 60 °C in dry acetoni-
trile (3 mL) and chromatography with EtOAc/hexane (2:1), gave 7a
(73 mg, 90%) as a yellow solid; m.p. 69–74 °C. 1H NMR (CDCl3):
δ = 0.98 (t, J = 7.4 Hz, 3 H, CH3), 1.46 (m, 2 H, CH2), 1.69 (d, J
= 6.8 Hz, 6 H, CH3), 1.74 (m, 2 H, CH2), 4.25 (t, J = 6.6 Hz, 2 H,
O–CH2), 4.95 (m, 1 H, CHMe2), 7.26 (d, J = 15.7 Hz, 1 H, =CH),
7.73 (d, J = 15.7 Hz, 1 H, =CH), 8.19 (s, 1 H, 8-H) ppm. 13C NMR
(CDCl3): δ = 13.7, 19.2, 22.5, 30.7, 48.3, 64. 8, 127.4, 131.3, 141.8,
1
[(CDCl3, 300 MHz): δ = 5.54 (s, 4 H, CH2Ph), 7.36 (br. s, 10 H,
ArH), 8.23 (s, 2 H, H-8), 9.31 (s, 2 H, H-2) ppm.[23]
General Procedure for Heck Reactions of 7-Benzyl-6-iodopurine (4):
Dry DMF (3 mL), then the alkene (1 mmol) and iPr2NEt (65 mg,
0.5 mmol) were added under argon to a mixture of 7-benzyl-6-
iodopurine (4, 84 mg, 0.25 mmol), Pd(OAc)2 (3 mg, 0.0125 mmol),
and DiPheCy2P (9 mg, 0.025 mmol). The resulting mixture was
stirred at 120 °C for 18 h, silica (5 g) was added, volatiles were evap-
orated, and the product was obtained by flash chromatography.
143.8, 150. 8, 151.8, 156.5, 166.3 ppm. IR (CHCl ): ν = 2964, 2937,
˜
3
2926
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2923–2928

Heck Reactions of 6- and 2-Halopurines
2877, 1714, 1652, 1588, 1555, 1487, 1460, 1426, 1392, 1298, 1283,
6-Chloro-2-(2-phenylethenyl)-9-(O-triacetyl-β-D-ribofuranosyl)-
1250, 1171 cm–1. HR MS (EI): calculated for C15H19ClN4O2 purine (7f): Use of the General Procedure starting from 6b (159 mg,
322.1197; found 322.1199.
0.30 mmol), Pd(dba)2 (6 mg, 0.011 mmol), styrene (125 mg,
1.2 mmol), and iPr2NEt (78 mg, 0.6 mmol), with heating at 80 °C
in dry acetonitrile (3 mL) and chromatography with EtOAc/hexane
3-(6-Chloro-9-isopropylpurine-2-yl)acrylonitrile (7b): Use of the Ge-
neral Procedure starting from 6a (162 mg, 0.5 mmol), Pd(dba)2
(14 mg, 0.025 mmol), acrylonitrile (106 mg, 2 mmol), and iPr2NEt
(130 mg, 1 mmol), with heating at 120 °C in dry DMF (6 mL) and
chromatography with EtOAc/hexane (2:1), afforded 7b 99 mg
1
(2:1), gave 7f (120 mg, 78%) as a white foam. H NMR (CDCl3):
δ = 2.05 (s, 3 H, COCH3), 2.14 (s, 3 H, COCH3), 2.20 (s, 3 H,
COCH3), 4.37 (dd, J1 = 5.1, J2 = 13.1 Hz, 1 H, CH2OAc), 4.49 (m,
2 H, 1H CH and 1H CH2OAc), 5.89 (t, J = 5.5 Hz, 1 H, AcO–
CH), 6.09 (t, J = 4.6 Hz, 1 H, AcO–CH), 6.20 (d, J = 4.4 Hz, 1 H,
O–CH), 7.30 (d, J = 16.0 Hz, 1 H, =CH), 7.37 (m, 1 H, ArH), 7.42
(m, 2 H, ArH), 7.69 (d, J = 7.3 Hz, 2 H, ArH), 8.10 (d, J = 16.0 Hz,
1 H, =CH), 8.20 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = 20.4,
20.6, 20.7, 62.6, 70.1, 73.2, 80.1, 87.2, 126.0, 127.8, 128.8, 129.3,
130.4, 135.8, 139.3, 143.5, 151.2, 151.7, 160.1, 69.4, 169.5,
1
(80%) as a yellow solid; m.p. 185–190 °C. H NMR (CDCl3): δ =
1.69 (d, J = 6.8 Hz, 6 H, CH3), 4.94 (m, 1 H, CHMe2), 6.85 (d, J
= 16.1 Hz, 1 H, =CH), 7.51 (d, J = 16.2 Hz, 1 H, =CH), 8.23 (s, 1
H, 8-H) ppm. 13C NMR (CDCl3): δ = 22.5, 48.4, 105.6, 117.1,
131.8, 144.3, 147.8, 151.1, 151.7, 154.7 ppm. IR (CHCl ): ν = 2226,
˜
3
1586, 1553, 1485, 1461, 1390, 1340, 1322, 1173, 1147, 967,
917 cm–1. HR MS (EI): calculated for C11H10ClN5 247.0625; found
247.0628.
170.3 ppm. IR (CHCl ): ν = 3051, 1752, 1594, 1554, 1498, 1452,
˜
3
1390, 1266 cm–1. HR MS (EI): calculated for C24H23ClN4O7
6-Chloro-9-isopropyl-2-(2-phenylethenyl)purine (7c): Use of the Ge-
neral Procedure starting from 6a (81 mg, 0.25 mmol), Pd(dba)2
(7 mg, 0.0125 mmol), styrene (104 mg, 1 mmol), and iPr2NEt
(65 mg, 0.5 mmol), with heating at 80 °C in dry acetonitrile (3 mL)
and chromatography with EtOAc/hexane (2:1), gave 7c (65 mg,
514.1255; found 514.1277.
6-Chloro-2-(3-oxobut-2-enyl)-9-(O-triacetyl-β-D-ribofuranosyl)-
purine (7g): Use of the General Procedure starting from 6b (159 mg,
0.30 mmol), Pd(dba)2 (9 mg, 0.015 mmol), methyl vinyl ketone
(84 mg, 1.2 mmol), and iPr2NEt (78 mg, 0.6 mmol), with heating at
80 °C in dry acetonitrile (3 mL) and chromatography with EtOAc/
hexane (2:1), afforded 7g (119 mg, 82%) as a white foam. 1H NMR
(CDCl3): δ = 2.09 (s, 3 H, COCH3), 2.11 (s, 3 H, COCH3), 2.19 (s,
3 H, COCH3), 2.47 (s, 3 H, COCH3), 4.36–4.52 (m, 3 H, 2H
CH2OAc and 1H CH), 5.73 (t, J = 5.5 Hz, 1 H, AcO–CH), 6.09
(t, J = 5.1 Hz, 1 H, AcO–CH), 6.23 (d, J = 4.5 Hz, 1 H, O–CH),
7.49 (d, J = 16.0 Hz, 1 H, =CH), 7.57 (d, J = 16.0 Hz, 1 H, =CH),
8.32 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = 20.4, 20.5, 20.7,
28.0, 62.8, 70.3, 73.2, 80.3, 86.9, 131.6, 135.4, 139.8, 144.4, 151.5,
1
87%) as a yellow solid; m.p. 147–149 °C. H NMR (CDCl3): δ =
1.69 (d, J = 6.8 Hz, 6 H, CH3), 4.98 (m, 1 H, CHMe2), 7.29 (d, J
= 15.7 Hz, 1 H, =CH), 7.35 (m, 1 H, ArH), 7.41 (m, 2 H, ArH),
7.65 (d, J = 7.4 Hz, 2 H, ArH), 8.04 (d, J = 15.9 Hz, 1 H, =CH),
8.13 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = 22.6, 47.8, 126.6,
127.6, 128.8, 129.1, 130.1, 136.0, 138.2, 142.7, 150.5, 152.0,
159.1 ppm. IR (CHCl ): ν = 2931, 2857, 1639, 1591, 1551, 1495,
˜
3
1454, 1425, 1388, 1344, 1323, 1281 cm–1. HR MS (EI): calculated
for C16H15ClN4 298.0985; found: 298.0981.
6-Chloro-9-isopropyl-2-(3-oxobut-1-enyl)purine (7d): Use of the Ge-
neral Procedure starting from 6a (81 mg, 0.25 mmol), Pd(dba)2
(7 mg, 0.0125 mmol), methyl vinyl ketone (70 mg, 1 mmol), and
iPr2NEt (65 mg, 0.5 mmol), with stirring at 80 °C in dry acetoni-
trile (3 mL) and chromatography with EtOAc/hexane (2:1), af-
forded 7d (64 mg, 97%) as a yellow solid; m.p. 183–187 °C. 1H
NMR (CDCl3): δ = 1.69 (d, J = 6.8 Hz, 6 H, CH3), 2.46 (s, 3 H,
COCH3), 4.95 (m, 1 H, CHMe2), 7.44 (d, J = 16.0 Hz, 1 H, =CH),
7.57 (d, J = 16.0 Hz, 1 H, =CH), 8.21 (s, 1 H, 8-H) ppm. 13C NMR
(CDCl3): δ = 22.5, 27.8, 48.4, 131.4, 134.8, 140.6, 144.0, 150.8,
151.6, 157.6, 169.3, 169.5, 170.2, 198.4 ppm. IR (CHCl ): ν = 1753,
˜
3
1678, 1557, 1390, 1368, 1266, 1226 cm–1. HR MS (EI): calculated
for C20H21ClN4O8 480.1048; found 480.1057.
Methyl 3-(6-Chloro-9-isopropylpurine-2-yl)methacrylate (7h): Dry
DMF (3 mL), then methyl methacrylate (100 mg,1 mmol) and
iPr2NEt (65 mg, 0.5 mmol) were added under argon to a mixture
of 6a (81 mg, 0.25 mmol), Pd(dba)2 (7 mg, 0.0125 mmol) and Di-
PheCy2P (9 mg, 0.025 mmol). The resulting mixture was stirred at
120 °C for 3 d. Purification by flash chromatography with EtOAc/
151.9, 156.7, 198.5 ppm. IR (CHCl ): ν = 3051, 1677, 1628, 1588,
1
˜
3
hexane (2:1) gave 9 (38 mg, 54%) as a bright yellow oil. H NMR
1554, 1424, 1389, 1266 cm–1. HR MS (EI): calculated for
(CDCl3): δ = 1.69 (d, J = 6.8 Hz, 6 H, CH3), 2.53 (s, 3 H, CH3),
3.85 (s, 3 H, OCH3), 4.91 (m, 1 H, CHMe2), 7.74 (s, 1 H, =CH),
8.19 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = 14.5, 22.4, 48.4,
52.3, 130.2, 135.2, 136.5, 143.8, 150.2, 151.5, 157.8, 168.8 ppm. IR
C12H13ClN4O 264.0778; found 264.0772.
Butyl [6-Chloro-9-(O-triacetyl-β-D-ribofuranosyl)purine-2-yl]acryl-
ate (7e): Use of the General Procedure starting from 6b (180 mg,
0.25 mmol), Pd(dba)2 (7 mg, 0.0125 mmol), acrylonitrile (128 mg,
1 mmol), and iPr2NEt (65 mg, 0.5 mmol), with heating at 80 °C in
dry acetonitrile (3 mL) and chromatography with EtOAc/hexane
(CHCl ): ν = 2955, 2856, 1714, 1590, 1554, 1489, 1460, 1438, 1393,
˜
3
1378, 1345, 1277, 1172, 1145, 1122 cm–1. HR MS (EI): calculated
for C13H15ClN4O2 294.0884; found 294.0888.
1
(2:1), gave 7e (127 mg, 94%) as a white foam. H NMR (CDCl3):
Supporting Information (see also the footnote on the first page of
δ = 0.98 (t, J = 7.4 Hz, 3 H, CH3), 1.46 (m, 2 H, CH2), 1.70 (m, 2
H, CH2), 2.10 (s, 6 H, COCH3), 2.19 (s, 3 H, COCH3), 4.25 (t, J
= 6.6 Hz, 2 H, O–CH2), 4.38 (dd, J1 = 4.1, J2 = 12.4 Hz, 1 H,
CH2O), 4.45 (dd, J1 = 2.9, J2 = 12.3 Hz, 1 H, CH2OAc), 4.5 (m, 1
H, CH), 5.68 (t, J = 5.2 Hz, 1 H, AcO–CH), 5.92 (t, J = 5.2 Hz, 1
H, AcO–CH), 6.24 (d, J = 4.9 Hz, 1 H, O–CH), 7.27 (d, J =
15.7 Hz, 1 H, =CH), 7.72 (d, J = 15.7 Hz, 1 H, =CH), 8.31 (s, 1
H, 8-H) ppm. 13C NMR (CDCl3): δ = 13.7, 19.2, 20.4, 20.5, 20.7,
30.7, 62.8, 64.9, 70.3, 73.3, 80.4, 86.7, 128.3, 131.5, 141.2, 144.1,
1
this article): H and 13C NMR spectra of compounds 3, 5a–d, and
7a–h.
Acknowledgments
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, by the MSM6046137301 research project of the
same Ministry, and by the Grant Agency of the Czech Republic
(grant No. 203/06/0888).
151.5, 151.6, 157.4, 166.1, 169.3, 169.5, 170.2 ppm. IR (CHCl ): ν
˜
3
= 2964, 2937, 1753, 1715, 1591, 1557, 1390, 1298, 1284, 1171 cm–1.
HR MS (EI): calculated for C23H27ClN4O9 538.1467; found
538.1489.
Eur. J. Org. Chem. 2008, 2923–2928
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2927

T. Tobrman, D. Dvorˇák
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5d.
Received: January 25, 2008
Published Online: April 30, 2008
2928
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2923–2928