Synthesis of potentially biologically active 6-(1,3-butadiynyl)purines

Article abstract of DOI:10.1002/jhet.1938

1,3-Alkadiynyl(trimethyl)silanes were prepared by the Negishi or Sonogashira reactions of bromoethynyl (trimethyl)silane with several terminal alkynes in 34-75% yield. However, the direct Hiyama coupling of these compounds with 6-iodopurine derivatives ha

Full text of DOI:10.1002/jhet.1938

40
Synthesis of Potentially Biologically Active 6-(1,3-Butadiynyl)purines
Vol 52
*
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M. Krovácek and D. Dvorák
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 52166 28 Prague 6,
Czech Republic
*
E-mail: dvorakd@vscht.cz
Received July 10, 2012
DOI 10.1002/jhet.1938
Published online 25 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
1,3-Alkadiynyl(trimethyl)silanes were prepared by the Negishi or Sonogashira reactions of bromoethynyl
(trimethyl)silane with several terminal alkynes in 34–75% yield. However, the direct Hiyama coupling of these
compounds with 6-iodopurine derivatives has not been successful. Therefore, a modified Sonogashira reaction
using TBAF or CsF for in situ removal of the trimethylsilyl group has been utilized. This methodology afforded
the desired 6-(1,3-butadiynyl)purines in 47–87% yield.
J. Heterocyclic Chem., 52, 40 (2015).
INTRODUCTION
Cadiot–Chodkiewicz reaction [9] have failed. Only forma-
tion of the symmetrical dimers, or in the case of the
Cadiot–Chodkiewicz reaction adduct of the propylamine
(used as the base) to the triple bond of the starting alkyne,
was observed. An alternative approach, coupling of 9-ben-
zyl-6-(2-haloethynyl)purine with alkyne, could not be used,
because all attempts to prepare starting 9-benzyl-6-(2-
haloethynyl)purines have been unsuccessful.
For that reason, we turned our attention to the coupling of
1-substituted buta-1,3-diynes with 6-halopurines. The syn-
thesis of the key intermediates, 1,3-alkadiynyl(trimethyl)
silanes 1, has been addressed first. Diynes 1 can, in principle,
be coupled directly with 6-halopurines using the Hyiama
reaction. Alternatively, Sonogashira or Negishi couplings
can be used after removal of the trimethylsilyl group. The
reaction of ethynyl(trimethyl)silane with 1-bromo-2-pheny-
lethyne under Cadiot–Chodkiewicz conditions [9] has not
been successful, probably because of the instability of the tri-
methylsilylgroup under the reaction conditions. Fortunately,
the Negishi coupling starting from phenylethyne 2a and
bromoethynyl(trimethyl)silane 3 was successful, giving the
desired 4-phenylbuta-1,3-diyn-1-yl(trimethyl)silane 1a in
63% yield (Scheme 1, Table 1, entry 1).
Many modified purines are biologically active [1].
Among them, 6-alkynyl derivatives play many important
roles, and are reported to be cytotoxic [2] and also exhibit
antimycobacterial [3] and cytokinin [4] activities. The
biological activities of 6-alkynylpurines can be ascribed to
their ability to undergo conjugate addition of a wide range
of nucleophiles to the triple C–C bond activated by strongly
electron-withdrawing purine nuclei [5]. Symmetrical bis
(purin-6-yl)diacetylenes, prepared by oxidative dimeriza-
tion of 6-alkynylpurines, were used for post-synthetic
modification of oligodeoxynucleotides [6] and were
designed and prepared as the covalent analogs of DNA base
pairs [7]. However, the synthesis and biological evaluation
of unsymmetrically substituted (purine-6-yl)buta-1,3-
diynes has remained, to the best of our knowledge, un-
known. Therefore, we developed the methodology for the
synthesis of these hitherto unknown compounds. This
new synthetic strategy can facilitate an access to the biolog-
ical evaluation of these new compounds.
RESULTS AND DISCUSSION
Alkynes bearing simple alkyl or diethylacetal groups
(Table 1, entries 2, 4) reacted with 3 similarly smoothly.
On the contrary, the alkynes bearing nitrogen-containing
substituents (Table 1, entries 3, 5) gave only low yields
of the desired diynes, presumably because of the formation
of hardly soluble lithium salts. Additives such as TMEDA
or HMPA had only limited influence on the yield in these
cases. Because butyllithium used for the deprotonation of
The first attempts to synthesize 6-(1,3-butadiynyl)purines
started from 9-benzyl-6-ethynylpurine, which is easily avail-
able by the Sonogashira coupling of 9-benzyl-6-chloropurine
[8] with ethynyl(trimethyl)silane followed by deprotection.
However, all attempts to couple 9-benzyl-6-ethynylpurine
with 1-bromo-2-phenylethyne or 1-iodo-2-phenylethyne
including Sonogashira coupling, Negishi coupling, and the
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Synthesis of Potentially Biologically Active 6-(1,3-Butadiynyl)purines
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Scheme 1. Preparation of alkadiynyl(trimethyl)silanes 1.
Scheme 2. Preparation of 6-diynylpurines 4a–g.
R
1. BuLi
2. ZnBr2
Br
Si(CH3)3
3
R
ZnBr
THF
-78 - r.t.
PdCl2(PPh3)2
THF, r.t.
R
3, Pd(dba)2,TFP, Et3N, CuI
THF, r.t.
H
2
Si(CH3)3
1
alkynes is not compatible with many functional groups, the
Sonogashira reaction of alkynes 2a–f with bromoethynyl
(trimethyl)silane (3) was also attempted. The yields were in
all cases, with the exception of phenylethyne (2a), somewhat
higher compared with the Negishi coupling. Improvement of
the yield was substantial in the case of imidazoyl derivative
1e (Table 1, entry 5). This approach also allowed coupling
of the propargyl acetate 2f (Table 1, entry 6).
Attempts to prepare the target 6-diynylpurines 4 directly
by Hiyama coupling of the prepared silylated diynes 1 with
iodopurine 6a were not successful. The reaction did not
proceed at all, or at higher temperatures, complete decom-
position of the diyne occurred. Therefore, a modified
Sonogashira reaction was used, and the unprotected diyne
was generated in situ from silanes 1 by gradual addition
of the solution of TBAF to the solution of iodopurine 6a,
silylated diyne 1, CuI, and the Pd catalyst in DMF
(Scheme 2). The yields of the desired 6-diynylpurines 4
varied approximately in the range 50% to 90% (Table 2).
Wihout the TBAF [10], the rection does not proceed. Isolation
of the imidazoylderivative 4e (Table 2, entry 5) was compli-
cated by similar RF of the product and TBAF. Therefore,
CsF was used as the base in this case. The acetoxydiynyl
derivative 4f was then deprotected by the methanolysis, giving
the hydroxymethyl derivative 4g in 90% yield.
The acetylated ribosides 5a–f have been prepared simi-
larly, starting with acetylated riboside 6b. The deprotection
by the methanolysis then gave the nucleosides 7a–e and
7g, in high isolated yield (Scheme 3, Table 3). In the case
of acetoxydiynyl derivative 5f, the acetoxygroup of the
diyne was deprotected simultaneously, giving the fully
deprotected nucleoside 7g in 90% yield (Table 3, entry 6).
CONCLUSIONS
The 6-butadiynylpurines can be easily prepared by the
Sonogashira coupling of the 6-iodopurine derivatives with
the substituted buta-1,3-diynes. The diynes are generated
in situ in the reaction mixture by the deprotection of the
Table 1
Preparation of alkadiynyl(trimethyl)silanes 1 (Scheme 1).
Negishia
Sonogashirab
(Yield %)
Entry
R
Product
(Yield %)
1
2
3
4
5
C6H5
C5H11
CH2N(CH3)2
CH(OC2H5)2
1a
1b
1c
1d
1e
63
75
55
74
48
70
34
41c,d
63
11c,e
6
CH2OCOCH3
1f
–
44
aReaction conditions: BuLi (1.25 eq.) and ZnBr2 (1.3 eq.) were added successively to the solution of alkyne (1.25 eq.) in THF at ꢀ78ꢁC. Then, bromoalkyne (1 eq.)
and PdCl2(PPh3)2 (2 mol.%) were added at room temperature.
bReaction conditions: The solution of bromoalkyne (1 eq.), alkyne (1.2 eq.), Et3N (3 eq.), CuI (2 mol.%.), Pd(dba)2 (2 mol.%), and TFP (4 mol.%) in THF
was stirred at room temperature.
cFormation of insoluble precipitate was observed.
dIn the presence of 1 eq. of TMEDA.
eIn the presence of 4 eq. of HMPA.
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M. Krovácek and D. Dvorák
Vol 52
Table 2
Preparation of 6-diynylpurines 4a–ga (Scheme 2).
Table 3
Preparation of diynylpurine nucleosides 5a and 7b (Scheme 3).
Entry
R
Product
Yield %
Product
Product
Entry
R
(Yield %)
(Yield %)
1
2
3
4
5
C6H5
C5H11
CH2N(CH3)2
CH(OC2H5)2
4a
4b
4c
66
62
64
55
47
1
2
3
4
5
C6H5
C5H11
CH2N(CH3)2
CH(OC2H5)2
5a (87)
5b (59)
5c (70)
5d (76)
5e (72)
7a (86)
7b (75)
7c (83)
7d (87)
7e (95)
4d
4eb
6
7
CH2OCOCH3
CH2OH
4f
54
90
4gc
6
CH2OCOCH3
5f (69)
7g (89)
R = CH2OH
aReaction conditions: To the stirred mixture of iodopurine 6a, Pd(dba)2
(4 mol.%), TFP (8 mol.%), CuI (8 mol.%), and diyne 1 (1.5 eq.) in DMF
(2 mL/mmol), the solution of 0.5M TBAF∙3 H2O (1 eq.) was added
dropwise during 30 min at 40ꢁC. The mixture was stirred at this temper-
ature until all 6a was consumed (TLC). After evaporation of the DMF, the
product was isolated by chromatography.
aReaction conditions: To a stirred mixture of iodopurine 6b, Pd(dba)2
(4 mol.%), TFP (8 mol.%), CuI (8 mol.%), and diyne 1 (1.5 eq.) in DMF
(2 mL/mmol), the solution of 0.5M TBAF∙3 H2O (1 eq.) was added
dropwise during 30 min at 40ꢁC. The mixture was stirred at this temper-
ature until all 6b was consumed (TLC). After evaporation of the DMF, the
product was isolated by the chromatography.
bCsF was used instead of TBAF∙3 H2O.
cPreparation by methanolysis of 4f: The acetate 4f was dissolved in dry
MeOH (5 mL/mmol), MeONa (0.1 eq.) was added, and the solution was
stirred at room temperature until all 4f was consumed (TLC). After
quenching with AcOH (0.15 eq.) and evaporation of the solvent, 4g was
isolated by chromatography.
bReaction conditions: The riboside 5 was dissolved in dry MeOH (5 mL/
mmol), MeONa (0.1 eq.) was added, and the solution was stirred at room
temperature until all starting compound was consumed (TLC). After
quenching with AcOH (0.15 eq.) and evaporation of the solvent, pure 7
was isolated by chromatography.
Scheme 3. Preparation of diynylpurine nucleosides 7.
and Bruker DRX 500 Avance (1H 500MHz, 13C 125.77MHz)
spectrometers at 298K. Chemical shifts are given in ppm with tetra-
methylsilane as a reference compound; coupling constants J are
given in Hz. The unambiguous assignment of the signals (if noted)
is supported by 13C APT, 1H COSY, 13C(1H) HMQC, and 13C(1H)
HMBC spectra. High resolution mass spectra were recorded on an
LTQ Orbitrap Velos spectrometer (Thermo Scientific). IR spectra
were recorded on Nicolet FT-IR 740, Nicolet FT-IR 6700, and
Nicolet FT-IR iS10 (Thermo Scientific) spectrometers; wavenum-
bers are given in cmꢀ1
Bromoethynyl(trimethyl)silane (3).
.
Ethynyltrimethylsilane
corresponding buta-1,3-diynyl(trimethyl)silanes by TBAF
or CsF. Methanolysis of the acetylated ribosides 5 then
allows preparation of the unprotected nucleosides 7a–e,
g. Biological evaluation of the obtained diynylpurines 4
and 7 will be published elsewhere.
(2.95 g, 30 mmol) was dissolved in Et2O (20mL), the solution
was cooled to ꢀ78ꢁC, and BuLi (15mL of 2.0M solution) was
added dropwise. The reaction mixture was stirred at ꢀ78ꢁC for
30min, and the temperature was allowed to reach ꢀ40ꢁC.
Bromine (4.8 g, 30mmol) was added dropwise, and the
temperature was allowed to reach room temperature while stirring.
Subsequently, 10 mL of satd. NH4Cl and 10mL of satd. Na2S2O3
were added. The aqueous layer was extracted with Et2O
(2ꢂ 20mL), and the combined organic layers were dried over
MgSO4. After the careful removal of the solvents (0ꢁC), the
residue was purified by distillation under reduced pressure. It was
obtained 3.58 g (67%) of 3 as colorless liquid. Bp 61ꢁC/81Torr
EXPERIMENTAL
Unless stated otherwise, all reactions were performed in flame-
dried Schlenk flasks under argon. 9-Benzyl-6-iodopurine (6a) [11]
and 9-(O,O,O-triacetyl-b-D-ribofuranosyl)-6-iodopurine (6b) [12]
were prepared according to literature procedures. Other compounds
were purchased. Tetrahydrofurane was dried using the standard
benzophenone ketyl procedure, diethyl ether was distilled from
sodium, and DMF was distilled from P2O5. Other solvents were
purchased from Sigma-Aldrich or Acros Organics and used without
further purification. TLC analyses were performed on Fluka silica
plates (cat. no. 60778). Column chromatographies were performed
using Merck Silica Gel 60 (40–63 mm). Melting points were
measured on a Kofler bench and are not corrected. NMR spectra were
recorded on Varian Gemini 300 (1H 300.07MHz, 13C 75.46 MHz)
1
(lit. [13] 55ꢁC/55 Torr). H NMR (300 MHz, CDCl3): d 0.18 (s).
13C NMR (75MHz, CDCl3): d ꢀ0.3, 61.4, 86.9.
General procedure for preparation of alkadiynyl(trimethyl)
silanes
Method A (Negishi reaction)
Preparation of the organzinc reagent.
A solution of
alkyne 2 (1 eq.) in THF (2 mL per mmol of alkyne) was cooled to
ꢀ78ꢁC. Subsequently, BuLi (1.05 eq.) was added, and the mixture
was stirred for 10 min at ꢀ78ꢁC and then slowly warmed up to
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Synthesis of Potentially Biologically Active 6-(1,3-Butadiynyl)purines
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0ꢁC. After 5 min at 0ꢁC, the mixture was cooled down to ꢀ78ꢁC,
ZnBr2 (1.05 eq., as 1M solution in THF) was added, and the mixture
was warmed up to 0ꢁC.
(w), 1027 (w), 840 (s), 788 (w), 759 (w), 701 (w) cmꢀ1. HRMS
(EI): m/z [M]+ calcd for C10H17NSi 179.1130; found 179.1124.
(5,5-Diethoxypenta-1,3-diyn-1-yl)trimethylsilane (1d)
Reaction of organozinc reagents with bromoalkyne. Bro-
moethynyl(trimethyl)silane (3, 0.8 eq.) and PdCl2(PPh3)2 (2 mol.%)
were dissolved in THF (2 mL per mmol of 3), and solution of the
organozinc reagent was added dropwise during 30min while
stirring at room temperature. The reaction mixture was stirred at
room temperature for an additional 2 h, and satd. NH4Cl was added
(cca half the volume of the reaxtion mixture). The organic layer was
separated, and the aqueous layer was extracted twice with Et2O.
Combined organic layers were dried with MgSO4, and after the
removal of the solvents (max. 30ꢁC), the product was isolated using
column chromatography on silica gel.
Method A. From 3 (886 mg, 5.0 mmol) and 1,1-diethoxy-
prop-2-yne (2d, 769 mg, 6.0 mmol) was obtained after chroma-
tography (EtOAc–hexane 1:1, RF = 0.33) 461 mg (41%) of the
diyne 1d as light brown viscous oil.
Method B. From 3 (354 mg, 2.0 mmol) and 1,1-diethoxy-
prop-2-yne (2d, 200 mg, 2.4 mmol) was obtained after chroma-
tography (EtOAc–hexane 1:1, RF = 0.33) 173 mg (48%) of the
diyne 1d as light brown viscous oil.
1H NMR (300 MHz, CDCl3): d 0.19 (s, 9 H, Si(CH3)3), 1.22
(t, J = 6.9, 6 H, CH3), 3.54–3.78 (m, 4 H, CH2), 5.28 (s, 1 H,
CH(OEt)2). 13C NMR (75 MHz, CDCl3): d ꢀ0.7, 14.9, 61.1,
69.9, 72.5, 86.7, 88.3, 91.3. IR (ATR): 2978 (m), 2932 (w),
2887 (w), 2111 (w), 1352 (w), 1326 (m), 1253 (w), 1089 (s),
1055 (s), 1016 (m), 916 (w), 866 (m), 845 (s), 761 (w), 702
(w), 634 (w) cmꢀ1. HRMS (EI): m/z [M]+ calcd for C12H20O2Si
224.3715; found 224.3720.
Method B (Sonogashira reaction).
A mixture of Pd(dba)2
(2 mol.%), TFP (4mol.%), CuI (2 mol.%), bromoethynyl
(trimethyl)silane 3 (1 eq.), terminal alkyne 2 (1.2 eq.), THF (2 mL
per mmol of 3), and Et3N (3 eq.) was stirred for 1 h at room
temperature. The solvents were then evaporated (max. 30ꢁC), and
the oily residue was column chromatographed on silica gel.
Trimethyl(4-phenylbuta-1,3-diyn-1-yl)silane (1a)
1-Methyl-5-(4-trimethylsilylbuta-1,3-diyn-1-yl)imidazole (1e)
Method A (modified). 1-Methyl-5-ethynylimidazole (2e,
106 mg, 1.0mmol) was dissolved in THF (4 mL), HMPA
(0.35 mL, 2 eq.) was added, and the solution was cooled to
ꢀ78ꢁC. Subsequently, LiHMDS (1.05 mL of 1M solution,
1.05 eq.) was added, and the reaction mixture was stirred for 1h at
ꢀ78ꢁC. The mixture was then allowed to warm to 0ꢁC, which led
to precipitation of a small amount of solid. Therefore, two more
equivalents of HMPA were added, which led to complete dissolu-
tion. Subsequently, ZnBr2 (1.05 mL of 1M solution in THF,
1.05 eq.) was added, and the reaction mixture was stirred for
30min at room temperature. Pd(P(t-Bu)3)2 (13mg, 2 mol.%) was
dissolved in THF (1 mL), and the solution was cooled to 0ꢁC with
stirring. Bromoethynyl(trimethyl)silane (3, 147 mg, 0.83 mmol)
was dissolved in THF (7 mL), and both the solution of 3 and the
solution of the organozinc were added simultaneously to the solu-
tion of the catalyst so that the added amount of both components
remained the same. The addition took approx. 30min. Subse-
quently, the water–ice bath was removed, and the reaction mixture
was stirred overnight at room temperature. The reaction was
quenched with satd. NH4Cl (5 mL), which led to precipitation of
solid material. Water (10mL) was added, which led to the dissolu-
tion of the anorganic salts. The mixture was extracted with DCM
(5ꢂ 30mL), and the combined organic layers were dried over
MgSO4. After the removal of the volatiles, the residue was column
chromatographed (EtOAc, RF = 0.3). It was obtained 18mg (11%)
of the diyne 1e as pale yellow amorphous solid.
Method A. From 3 (142 mg, 0.80 mmol) and phenylethyne
(2a, 102 mg, 1.0 mmol) was obtained after chromatography
(hexane, RF = 0.57) 97 mg (61%) of the diyne 1a as pale yellow
colorless viscous oil.
Method B. From 3 (177mg, 1.0mmol) and phenylethyne
(2a, 122 mg, 1.2mmol) was obtained after chromatography
(hexane, RF = 0.57) 109 mg (55%) of the diyne 1a as pale yellow
colorless viscous oil. 1H and 13C NMR spectra are in a good agree-
ment with published data [14].
Trimethyl(nona-1,3-diyn-1-yl)silane (1b)
Method A. From 3 (886 mg, 5.0 mmol) and hept-1-yne
(2b, 577 mg, 6 mmol) was obtained after chromatography (hexane,
RF = 0.61) 720 mg (75%) of the diyne 1b as colorless viscous oil.
Method B. From 3 (531 mg, 3.0 mmol) and hept-1-yne
(2b, 346 mg, 5 mmol) was obtained after chromatography
(hexane, RF = 0.61) 426 mg (74%) of the diyne 1b as colorless
viscous oil. 1H NMR (300 MHz, CDCl3): d 0.17 (s, 9 H, Si
(CH3)3), 0.89 (t, J = 7.0, 3 H, CH2CH3), 1.24–1.42 (m, 4 H, 2 ꢂ
CH2), 1.46–1.60 (m, 2 H, CH2), 2.26 (t, J = 7.0, 2 H, CꢃC–
CH2). 13C NMR (75 MHz, CDCl3): d ꢀ0.4, 13.9, 19.2, 22.1,
27.8, 30.9, 65.4, 80.2, 82.9, 88.4. IR (ATR): 2959 (m), 2933
(m), 2862 (w), 2225 (w), 2107 (w), 1722 (w), 1464 (w), 1426
(w), 1379 (w), 1328 (w), 1250 (m), 1182 (w), 1107 (w), 933
(w), 841 (s), 759 (w), 701 (w) cmꢀ1. HRMS (EI): m/z [M]+ calcd
for C12H20Si 192.1334; found 192.1326.
Method B. From 3 (334 mg, 1.9 mmol) and 1-methyl-5-ethy-
nylimidazole (2e, 106 mg, 1.6 mmol) was obtained after chroma-
tography (EtOAc, RF = 0.3) 110 mg (34%) of the diyne 1e as pale
yellow amorphous solid. 1H NMR (300 MHz, CDCl3): d 0.21 (s,
9 H, Si(CH3)3), 3.67 (s, 3 H, CH3), 7.36 (s, 1 H), 7.48 (s, 1 H).
13C NMR (75 MHz, CDCl3): d ꢀ0.6, 32.3, 63.9, 81.8, 87.0,
93.9, 115.2, 136.8, 138.7. IR (ATR): 3121 (w), 3088 (m), 2957
(m), 2898 (w), 2198 (s), 2105 (w), 1543 (w), 1490 (m), 1462
(w), 1414 (w), 1364 (w), 1289 (w), 1249 (s), 1242 (s), 1220
(w), 1127 (m), 1057 (w), 1031 (m), 1003 (w), 957 (w), 918
(m), 840 (s), 757 (m), 699 (w) cmꢀ1. HRMS (EI): m/z [M]+ calcd
for C11H14N2Si 202.0926; found 202.0926.
Dimethyl(5-(trimethylsilyl)penta-2,4-diyn-1-yl)amine (1c)
Method A. [note: 0.15 mL (1 eq.) TMEDA was added
prior to BuLi addition]. From 3 (149 mg, 0.8 mmol) and
dimethyl(prop-2-yn-1-yl)amine (2c, 83 mg, 1 mmol) was obtained
after chromatography (EtOAc–hexane, 1:1, RF = 0.33) 61 mg
(41%) of the diyne 1c as light brown viscous oil.
Method B. From 3 (354 mg, 2.0 mmol) and dimethyl(prop-2-
yn-1-yl)amine (2c, 200 mg, 2.4 mmol) was obtained after chroma-
tography (EtOAc–hexane, 1:1, RF = 0.33) 173 mg (48%) of the
diyne 1c as light brown viscous oil. 1H NMR (300 MHz, CDCl3):
d 0.19 (s, 9 H, Si(CH3)3), 2.30 (s, 6 H, N(CH3)2), 3.36 (s, 2 H,
CH2). 13C NMR (75 MHz, CDCl3): d ꢀ0.4, 44.0, 48.3, 70.3,
74.1, 85.1, 87.7. IR (ATR): 2958 (w), 2944 (w), 2902 (w), 2862
(w), 2824 (w), 2775 (w), 2212 (w), 2104 (w), 1455 (w), 1419
(w), 1536 (w), 1322 (w), 1251 (m), 1155 (w), 1097 (w), 1034
5-Trimethylsilylpenta-2,4-diyn-1-yl acetate (1f)
Method B. From 3 (531 mg, 3.0 mmol) and propargyl acetate
(2f, 353 mg, 3.6 mmol) was obtained after chromatography
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M. Krovácek and D. Dvorák
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(EtOAc–hexane, 1:10, RF = 0.5) 257 mg (44%) of the diyne 1f as
pale yellow viscous oil. 1H NMR (300 MHz, CDCl3): d 0.16 (s, 9
H, Si(CH3)3), 2.06 (s, 3 H, CH3), 4.69 (s, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d ꢀ0.7, 20.5, 52.2, 71.2, 71.4,
86.8, 88.0, 169.8. IR (ATR): 2961 (w), 2112 (m), 1746 (s),
1430 (w), 1376 (w), 1358 (w), 1251 (m), 1214 (s), 1026 (m),
969 (w), 840 (s), 759 (m), 703 (w), 634 (w), 603 (w), 539 (w),
489 (w) cmꢀ1. HRMS (EI): m/z [M]+ calcd for C10H14O2Si
194.0763; found 194.0754.
Reaction of butadiynyl(trimethyl)silanes with 6-iodopurines—
general procedure. A solution of 6-iodopurine 6 (1ekv.), Pd(dba)2
(4 mol.%), TFP (8 mol.%), CuI (8 mol.%), and silylated diyne 1
(1.5 eq.) in DMF (2mL per mmol of 6) was stirred at 40ꢁC. A
0.5M solution of TBAF∙3 H2O in DMF (1eq.) was added
dropwise during approx. 30min, and the reaction mixture was
stirred at 40ꢁC until the conversion was complete according to
TLC. The solvent was then evaporated, and the residue was
column chromatographed on silica gel.
129.1 (CHPh), 134.6 (CPqh), 135.1 (C-5), 140.4 (C-6), 145.5 (C-8),
151.6 (C-4), 152.6 (C-2). IR (ATR): 3059 (w), 2938 (w), 2778
(w), 2233 (w), 1574 (s), 1496 (w), 1439 (w), 1402 (w), 1319 (m),
1247 (w), 1213 (w), 1142 (w), 1028 (w), 974 (w), 908 (w), 804
(w), 725 (m), 697 (w), 642 (w), 544 (w) cmꢀ1. HRMS (ESI): m/z
[M+ Na]+ calcd for C19H17N5Na 338.1382; found 338.1381.
9-Benzyl-6-(5,5-diethoxypenta-1,3-diyn-1-yl)purine (4d). From
9-benzyl-6-iodopurine (6a, 168mg, 0.50 mmol) and diyne 1d
(135mg, 0.60 mmol) was obtained after chromatography (hexane–
EtOAc 1:1, RF = 0.53) 100mg (55%) of 4d as light brown, waxy
1
solid. H NMR (300 MHz, CDCl3): d 1.25 (t, J = 7.2, 6 H, CH3),
3.58–3.84 (m, 4 H, CH2), 5.39 (s, 1 H, CH(OEt)2), 5.44 (s, 2 H,
CH2Ph), 7.27–7.38 (m, 5 H, Ph), 8.10 (s, 1 H, H-8), 8.96 (s, 1 H,
H-2). 13C NMR (75MHz, CDCl3): d 15.0 (CH3), 47.5 (CH2Ph),
61.4 (OCH2), 69.0 (CꢃC), 72.7 (CꢃC), 80.8 (CꢃC), 81.4
(CꢃC), 91.4 (CH(OEt)2), 127.9 (CHPh), 128.8 (CHPh), 129.2
(CHPh), 134.6 (CPqh), 135.3 (C-5), 140.0 (C-6), 145.6 (C-8), 151.8
(C-4), 152.7 (C-2). IR (ATR): 3063 (w), 2977 (m), 2926 (m),
2159 (w), 1577 (s), 1491 (w), 1451 (m), 1395 (m), 1332 (s), 1242
(w), 1160 (m), 1101 (m), 1059 (s), 1014 (m), 978 (m), 912 (w),
802 (w), 724 (m), 699 (m), 644 (m), 540 (w) cmꢀ1. HRMS (ESI):
m/z [M+ Na]+ calcd for C21H20N4O2Na 383.1484; found 383.1475.
9-Benzyl-6-(4-(1-methylimidazol-5-yl)buta-1,3-diyn-1-yl)purine (4e)
9-Benzyl-6-(4-phenylbuta-1,3-diyn-1-yl)purine (4a). From 9-
benzyl-6-iodopurine (6a, 67 mg, 0.20 mmol) and diyne 1a
(60 mg, 0.30 mmol) was obtained after chromatography
(hexane–EtOAc 2:1, RF = 0.24) 44 mg (66%) of 4a as yellow
solid. Crystallization (hexane–EtOAc) afforded yellow needles,
1
mp 151ꢁC. H NMR (300 MHz, CDCl3): d 5.44 (s, 2 H, CH2),
Modification: CsF (same molar amount) was used instead
7.26–7.40 (m, 8 H, Ph), 7.46–7.58 (m, 2 H, Ph), 8.11 (s, 1 H,
H-8), 8.96 (s, 1 H, H-2). 13C NMR (75 MHz, CDCl3): d 47.4
(CH2Ph), 73.4 (CꢃC), 75.2 (CꢃC), 82.4 (CꢃC), 85.7 (CꢃC),
120.7 (CqPh), 127.8 (CHPh), 128.4 (CHPh), 128.7 (CHPh), 129.1
(CHPh), 129.9 (CHPh), 132.8 (CHPh), 134.6 (CPqh), 135.1 (C-5),
140.5 (C-6), 145.4 (C-8), 151.6 (C-4), 152.7 (C-2). IR (ATR):
3092 (w), 3047 (w), 2947 (w), 2208 (s), 1799 (w), 1745 (w),
1568 (s), 1491 (m), 1434 (m), 1402 (m), 1317 (m), 1263 (w),
1226 (w), 1193 (m), 1142 (w), 1078 (w), 1027 (w), 950 (w),
910 (w), 858 (w), 753 (m), 719 (m), 681 (m), 668 (m), 640 (m),
594 (w), 529 (w), 470 (w) cmꢀ1. HRMS (ESI): m/z [M + Na]+
calcd for C22H14N4Na 357.1116; found 357.1108.
of TBAF.
From 9-benzyl-6-iodopurine (6a, 51mg, 0.15 mmol)
and diyne 1e (30mg, 0.15mmol) was obtained after chromatogra-
phy (EtOAc–MeOH 9:1, RF = 0.2) 24 mg (47%) of 4e as white
powder, mp >160ꢁC (dec.). 1H NMR (500MHz, C2D2Cl4,
373 K): d 3.75 (s, 3 H, CH3), 5.47 (s, 2 H, CH2), 7.28–7.45 (m, 5
H, Ph), 7.51 (s, 1 H, H-20 or H-40), 7.54 (s, 1 H, H-20 or H-40),
8.10 (s, 1 H, H-8), 9.00 (s, 1 H, H-2). 13C NMR (125MHz,
C2D2Cl4, 373K): d 31.9 (CH3), 47.3 (CH2Ph), 77.7 (CꢃC), 78.9
(CꢃC), 81.17 (CꢃC), 81.23 (CꢃC), 114.6 (C-50), 127.6 (CHPh),
128.5 (CHPh), 129.0 (CHPh), 134.5 (C-5 or CqPh), 134.8 (C-5 or CqPh),
138.4 (C-20 or C-40), 139.3 (C-20 or C-40), 140.0 (C-6), 145.2 (C-8),
151.8 (C-4), 152.6 (C-2). IR (ATR): 3348 (m), 3087 (w), 3042 (w),
2924 (w), 2210 (s), 1736 (w), 1680 (w), 1582 (s), 1546 (w), 1492
(m), 1438 (m), 1404 (m), 1367 (w), 1327 (m), 1278 (w), 1242
(w), 1225 (w), 1200 (m), 1119 (m), 1080 (w), 1058 (w), 967 (w),
938 (w), 902 (w), 858 (w), 843 (w), 802 (w), 774 (w), 735 (w),
700 (w) cmꢀ1. HRMS (EI): m/z [M]+ calcd for C20H14N6
338.1280; found 338.1288.
9-Benzyl-6-(nona-1,3-diyn-1-yl)purine (4b). From 9-benzyl-6-
iodopurine (6a, 67 mg, 0.20mmol) and diyne 1b (57 mg,
0.30mmol) was obtained after chromatography (hexane–EtOAc
2:1, RF = 0.32) 41 mg (62%) of 4b as pale yellow amorphous
1
solid. H NMR (300 MHz, CDCl3): d 0.89 (t, J = 7.5, 3 H, CH3),
1.25–1.42 (m, 4 H, CH2), 1.52–1.62 (m, 2 H, CH2), 2.37
(t, J = 7.2, 2 H, CꢃC–CH2), 5.43 (s, 2 H, CH2Ph), 7.27–7.37
(m, 5 H, Ph), 8.08 (s, 1 H, H-8), 8.92 (s, 1 H, H-2). 13C NMR
(75 MHz, CDCl3): d 13.9 (CH3), 19.6 (CH2), 22.1 (CH2), 27.6
(CH2), 30.9 (CH2), 47.4 (CH2Ph), 64.9 (CꢃC), 68.5 (CꢃC), 83.4
(CꢃC), 89.9 (CꢃC), 127.8 (CHPh), 128.7 (CHPh), 129.2 (CHPh),
134.7, 135.1, 141.0, 145.2, 151.5, 152.7. IR (ATR): 3057 (w),
2928 (m), 2859 (w), 2233 (m), 1573 (s), 1496 (w), 1438 (w),
1402 (w), 1323 (m), 1212 (w), 1162 (w), 1142 (w), 1078 (w),
979 (w), 803 (w), 722 (w), 696 (w), 640 (w) cmꢀ1. HRMS
(ESI): m/z [M + Na]+ calcd for C21H20N4Na 351.1586; found:
351.1572.
5-(9-Benzylpurin-6-yl)penta-2,4-diyn-1-yl acetate (4f). From 9-
benzyl-6-iodopurine (6a, 168mg, 0.50mmol) and diyne 1f (97 mg,
0.50 mmol) was obtained after chromatography (hexane–EtOAc
1
1:1, RF = 0.34) 90 mg (54%) of 4f as yellow waxy solid. H NMR
(300 MHz, CDCl3): d 2.12 (s, 3 H, CH3), 4.83 (s, 2 H, CH2OAc),
5.44 (s, 2 H, CH2Ph), 7.28–7.39 (m, 5 H, Ph), 8.10 (s, 1 H, H-8),
8.96 (s, 1 H, H-2). 13C NMR (75MHz, CDCl3): d 20.6 (CH3), 47.5
(CH2Ph), 52.2 (OCH2), 70.4 (CꢃC), 72.4 (CꢃC), 80.4 (CꢃC),
81.0 (CꢃC), 127.9 (CHPh), 128.8 (CHPh), 129.2 (CHPh), 134.6
(CPqh), 135.3 (C-5), 140.0 (C-6), 145.6 (C-8), 151.8 (C-4), 152.8 (C-
2), 169.9 (C=O). IR (ATR): 3104 (w), 3033 (w), 2923 (w), 2851
(w), 2242 (w), 2164 (w), 1742 (s), 1578 (s), 1491 (m), 1457 (w),
1445 (w), 1427 (w), 1399 (m), 1367 (m), 1358 (m), 1323 (s), 1249
(m), 1214 (m), 1168 (m), 1078 (w), 1016 (m), 982 (m), 903 (w),
883 (w), 825 (w), 732 (m), 697 (w), 641 (m), 595 (w), 549 (w),
526 (w), 459 (w), 417 (w) cmꢀ1. HRMS (ESI): m/z [M + H]+
calcd for C19H15N4O2 331.1195; found 331.1189.
9-Benzyl-6-(5-dimethylaminopenta-1,3-diyn-1-yl)purine (4c).
From 9-benzyl-6-iodopurine (6a, 67mg, 0.20 mmol) and diyne 1c
(51mg, 0.25 mmol) was obtained after chromatography (EtOAc–
MeOH–Et3N, 18:2:1, RF = 0.67) 40 mg (64%) of 4c as brown,
1
waxy solid. H NMR (300 MHz, CDCl3): d 2.33 (s, 6 H, CH3),
3.48 (s, 2 H, CH2N), 5.44 (s, 2 H, CH2Ph), 7.25–7.38 (m, 5 H,
Ph), 8.09 (s, 1 H, H-8), 8.94 (s, 1 H, H-2). 13C NMR (75 MHz,
CDCl3): d 43.9 (CH3), 47.4 (CH2), 48.5 (CH2), 69.5 (CꢃC), 70.1
(CꢃC), 82.1 (CꢃC), 83.7 (CꢃC), 127.8 (CHPh), 128.7 (CHPh),
9-(O,O,O-Triacetyl-b-D-ribofuranosyl)-6-(4-phenylbuta-1,3-
diyn-1-yl)purine (5a). From 9-(O,O,O-triacetyl-b-D-ribofuranosyl)-
6-iodopurine (6b, 106mg, 0.21 mmol) and diyne 1a (50 mg,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2015
Synthesis of Potentially Biologically Active 6-(1,3-Butadiynyl)purines
45
0.25mmol) was obtained after chromatography (hexane–EtOAc
1:1, RF = 0.29) 92mg (87%) of 5a as pale yellow waxy solid. H
ranosyl)-6-iodopurine (6b, 160 mg, 0.32 mmol) and diyne 1d
(85 mg, 0.38 mmol) was obtained after chromatography (EtOAc–
hexane 1:1) 127 mg (76%) of 5d as colorless waxy solid. 1H
NMR (300 MHz, CDCl3): d 1.23 (t, J = 7.2, CH3), 2.06 (s, 3 H,
COCH3), 2.10 (s, 3 H, COCH3), 2.13 (s, 3 H, COCH3), 3.57–3.81
(m, 4 H, CH2), 4.32–4.48 (m, 3 H, 2ꢂ H-50 + H-40), 5.38 (s, 1 H,
CH(OEt)2), 5.63 (t, J = 5.1, 1 H, H-30), 5.93 (t, J = 5.4, 1 H, H-20),
6.22 (d, J = 5.3, 1 H, H-10), 8.28 (s, 1 H, H-8), 8.93 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d 15.0 (CH2CH3), 20.3 (COCH3),
20.5 (COCH3), 20.7 (COCH3), 61.4 (CH2CH3), 62.8 (C-50), 68.8
(CꢃC), 70.4 (C-30), 72.4 (CꢃC), 73.0 (C-20), 80.4 (C-40), 81.2
(CꢃC), 81.8 (CꢃC), 86.5 (C-10), 91.4 (CH(OEt)2), 136.0 (C-5),
140.5 (C-6), 144.1 (C-8), 151.2 (C-4), 152.8 (C-2), 169.3 (C=O),
169.5 (C=O), 170.2 (C=O). IR (ATR): 2978 (w), 2934 (w), 2158
(w), 1754 (s), 1581 (m), 1493 (w), 1441 (w), 1404 (w), 1371 (w),
1331 (w), 1220 (s), 1140 (w), 1087 (m), 1050 (m), 902 (w), 804
(w) cmꢀ1. HRMS (ESI): m/z [M + Na]+ calcd for C25H28N4O9Na
551.1754; found 551.1742.
1
NMR (300 MHz, CDCl3): d 2.07 (s, 3 H, COCH3), 2.11 (s, 3 H,
COCH3), 2.14 (s, 3 H, COCH3), 4.35–4.50 (m, 3 H, 2 ꢂ H-50 + H-
40), 5.65 (t, J = 4.7, 1 H, H-30), 5.95 (t, J = 5.3, 1 H, H-20), 6.24
(d, J = 5.3, 1 H, H-10), 7.30–7.46 (m, 3 H, Ph), 7.54–7.60 (m, 2 H,
Ph), 8.31 (s, 1 H, H-8), 8.95 (s, 1 H, H-2). 13C NMR (75 MHz,
CDCl3): d 20.3 (COCH3), 20.5 (COCH3), 20.7 (COCH3), 62.9
(C-50), 70.5 (C-30), 73.0 (C-20), 73.3 (CꢃC), 74.9 (CꢃC), 80.4
(C-40), 83.0 (CꢃC), 86.1 (CꢃC), 86.5 (C-10), 120.7 (CPqh), 128.5
(CHPh), 130.1 (CHPh), 132.8 (CHPh), 135.9 (C-5), 141.1 (C-6),
143.9 (C-8), 151.1 (C-4), 152.9 (C-2), 169.3 (C=O), 169.5 (C=O),
170.2 (C=O). IR (ATR): 2921 (w), 2850 (w), 2213 (m), 1744 (s),
1575 (s), 1490 (w), 1438 (m), 1370 (m), 1321 (w), 1202 (s), 1151
(m), 1090 (m), 1063 (m), 1003 (m), 951 (w), 915 (w), 860 (w),
785 (w), 762 (w), 729 (w), 690 (w), 634 (w), 532 (w), 470 cmꢀ1
.
HRMS (ESI): m/z [M+ Na]+ calcd for C26H22N4O7Na 525.1386;
found 525.1369.
9-(O,O,O-Triacetyl-b-D-ribofuranosyl)-6-(nona-1,3-diyn-1-
yl)purine (5b). From 9-(O,O,O-triacetyl-b-D-ribofuranosyl)-6-
iodopurine (6b, 88 mg, 0.18 mmol) and diyne 1b (40 mg,
0.21 mmol) was obtained after chromatography (hexane–EtOAc
9-(O,O,O-Triacetyl-b-D-ribofuranosyl)-6-(4-(1-methylimidazol-
5-yl)buta-1,3-diyn-1-yl)purine (5e). From 9-(O,O,O-triacetyl-b-D-
ribofuranosyl)-6-iodopurine (6b, 160mg, 0.32 mmol) and diyne
1e (64 mg, 0.32 mmol) was obtained after chromatography
(EtOAc–MeOH 20:1) 115 mg (72%) of 5e as yellow waxy solid.
1H NMR (500 MHz, C2D2Cl4, 373K): d 2.09 (s, 3 H, COCH3),
2.11 (s, 3 H, COCH3), 2.17 (s, 3 H, COCH3), 3.76 (s, 3 H,
NCH3), 4.38–4.50 (m, 3 H, 2 ꢂ H-50 + H-40), 5.66 (m, 1 H, H-30),
5.99 (m, 1 H, H-20), 6.25 (d, J = 5.1, 1 H, H-10), 7.53 (s, 1 H, H-
200 or H-400), 7.58 (s, 1 H, H-200 or H-400), 8.30 (s, 1 H, H-8), 8.97
(s, 1 H, H-2). 13C NMR (125 MHz, C2D2Cl4, 373 K): d 19.9
(COCH3), 20.0 (COCH3), 20.2 (COCH3), 32.0 (NCH3), 62.6
(C-50), 70.5 (C-30), 72.8 (C-20), 78.6 (CꢃC), 80.5 (C-40), 81.2
(CꢃC), 81.7 (CꢃC), 86.6 (C-10), 114.4 (C-500), 135.4 (C-5),
138.5 (C-200 or C-400), 139.3 (C-200 or C-400), 140.5 (C-6), 143.9
(C-8), 151.2 (C-4), 152.6 (C-2), 168.9 (C=O), 169.1 (C=O),
169.7 (C=O). IR (ATR): 3114 (w), 2949 (w), 2208 (m), 1745
(s), 1578 (s), 1539 (w), 1491 (w), 1439 (w), 1405 (w), 1373
(w), 1332 (w), 1242 (s), 1122 (m), 1098 (w), 1050 (m), 927
(w), 857 (w), 824 (w), 804 (w), 732 (w) cmꢀ1. HRMS (EI):
m/z [M]+ calcd for C24H22N6O7 506.1550; found 506.1556.
5-(9-(O,O,O-Triacetyl-b-D-ribofuranosyl)purin-6-yl)penta-
2,4-diyn-1-yl acetate (5f). From 9-(O,O,O-triacetyl-b-D-ribofura
nosyl)-6-iodopurine (6b, 101 mg, 0.20 mmol) and diyne 1f
(50 mg, 0.26 mmol) was obtained after chromatography (EtOAc–
hexane 2:1, RF = 0.57) 69 mg (69%) of 5f as pale yellow waxy
solid. 1H NMR (300 MHz, CDCl3): d 2.07 (s, 3 H, COCH3), 2.11
(s, 3 H, COCH3), 2.12 (s, 3 H, COCH3), 2.14 (s, 3 H, COCH3),
4.33–4.49 (m, 3 H, 2 ꢂ H-50 + H-40), 4.83 (s, 2 H, CꢃC–CH2),
5.64 (t, J = 5.1, 1 H, H-30), 5.94 (t, J = 5.3, 1 H, H-20), 6.22
(d, J = 5.0, H-10), 8.28 (s, 1 H, H-8), 8.94 (s, 1 H, H-2). 13C NMR
(75 MHz, CDCl3): d 20.4 (COCH3), 20.5 (COCH3), 20.6
(COCH3), 20.7 (COCH3), 52.2 (CꢃC–CH2), 62.9 (C-50), 70.3
(CꢃC), 70.5 (C-30), 72.0 (CꢃC), 73.0 (C-20), 80.5 (C-40), 80.8
(CꢃC), 81.5 (CꢃC), 86.6 (C-10), 136.0 (C-5), 140.6 (C-6), 144.1
(C-8), 151.2 (C-4), 152.8 (C-2), 169.3 (C=O), 169.5 (C=O), 169.9
(C=O), 170.2 (C=O). IR (ATR): 2939 (w), 2243 (w), 2162 (w),
1739 (s), 1577 (m), 1492 (w), 1429 (w), 1372 (w), 1332 (w),
1209 (s), 1144 (w), 1093 (w), 1029 (m), 909 (w), 804 (w), 730
(w), 638 (w) cmꢀ1. HRMS (ESI): m/z [M + Na]+ calcd for
C23H22N4O9Na 521.1284; found 521.1276.
1
1:1, RF = 0.47) 51 mg (59%) of 5b as colorless waxy solid. H
NMR (300 MHz, CDCl3): d 0.88 (t, J = 7.0, 3 H, CH2CH3),
1.24–1.44 (m, 4 H, CH2), 1.57 (m, 2 H, CH2), 2.05 (s, 3 H,
COCH3), 2.09 (s, 3 H, COCH3), 2.12 (s, 3 H, COCH3), 2.38
(t, J = 7.0, 2 H, CꢃC–CH2), 4.32–4.48 (m, 3 H, 2 ꢂ H-50 +H-40),
5.63 (t, J = 5.3, 1 H, H-30), 5.93 (t, J = 5.3, 1 H, H-20), 6.21
(d, J = 5.3, 1 H, H-10), 8.26 (s, 1 H, H-8), 8.96 (s, 1 H, H-2). 13C
NMR (75MHz, CDCl3): d 13.8 (CH2CH3), 19.6 (CH2), 20.3
(COCH3), 20.4 (COCH3), 20.7 (COCH3), 22.0 (CH2), 27.5
(CH2), 30.9 (CH2), 62.8 (C-50), 64.7 (CꢃC), 68.2 (CꢃC), 70.4
(C-30), 73.0 (C-20), 80.4 (C-40), 83.8 (CꢃC), 86.4 (C-10), 90.3
(CꢃC), 135.8 (C-5), 141.5 (C-6), 143.7 (C-8), 151.0 (C-4), 152.7
(C-2), 169.2 (C=O), 169.5 (C=O), 170.2 (C=O). IR (ATR): 2930
(w), 2860 (w), 2235 (m), 1744 (s), 1576 (s), 1493 (w), 1440 (w),
1369 (w), 1330 (w), 1209 (s), 1093 (w), 1045 (m), 900 (w), 804
(w), 638 (w), 595 (w) cmꢀ1. HRMS (ESI): m/z [M+ Na]+ calcd
for C25H28N4O7Na 519.1856; found 519.1840.
9-(O,O,O-Triacetyl-b-D-ribofuranosyl)-6-(5-dimethylamino
penta-1,3-diyn-1-yl)purine (5c). From 9-(O,O,O-triacetyl-b-D-
ribofuranosyl)-6-iodopurine (6b, 202 mg, 0.40 mmol) and diyne
1c (90 mg, 0.5 mmol) was obtained after chromatography
(EtOAc–MeOH–Et3N, 40:2:1, RF = 0.45) 136 mg (70%) of 5c as
1
unstable brown wax. H NMR (300 MHz, CDCl3): d 1.98 (s, 3
H, COCH3), 2.02 (s, 3 H, COCH3), 2.06 (s, 3 H, COCH3), 2.25
(s, 6 H, N(CH3)2), 3.40 (s, 2 H, CH2N), 4.24–4.43 (m, 3 H,
2 ꢂ H-50 + H-40), 5.57 (t, J = 5.1, 1 H, H-30), 5.87 (t, J = 5.3, 1
H, H-20), 6.16 (d, J = 5.1, 1 H, H-10), 8.25 (s, 1 H, H-8), 8.84
(s, 1 H, H-2). 13C NMR (75 MHz, CDCl3): d 20.1 (COCH3),
20.3 (COCH3), 20.5 (COCH3), 43.8 (NCH3), 48.3 (NCH2),
62.7 (C-50), 69.2 (CꢃC), 69.7 (CꢃC), 70.2 (C-30), 72.8 (C-20),
80.2 (C-40), 82.3 (CꢃC), 84.0 (CꢃC), 86.3 (C-10), 135.7 (C-5),
140.8 (C-6), 143.9 (C-8), 150.9 (C-4), 152.5 (C-2), 169.1
(C=O), 169.3 (C=O), 170.0 (C=O). IR (ATR): 2943 (w), 2826
(w), 2780 (w), 2232 (w), 2150 (w), 1743 (s), 1576 (s), 1493
(w), 1439 (w), 1405 (w), 1369 (m), 1329 (w), 1210 (s), 1095
(m), 1041 (m), 906 (w), 804 (w), 730 (w), 639 (w), 601 (w)
cmꢀ1. HRMS (ESI): m/z [M + H]+ calcd for C23H26N5O7
484.1832; found 484.1824.
General procedure of methanolysis of ribosides 5a–f and
9-(O,O,O-Triacetyl-b-D-ribofuranosyl)-6-(5,5-diethoxypenta-
1,3-diyn-1-yl)purine (5d). From 9-(O,O,O-triacetyl-b-D-ribofu
diynyl acetate 4f.
dissolved in dry MeOH (5 mL per mmol), then MeONa (0.1 eq.,
Acetylated riboside 5a–f (acetate 4g) was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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46
M. Krovácek and D. Dvorák
Vol 52
as 0.1M solution in MeOH) was added and the reaction mixture
was stirred at room temperature until the conversion was
complete (TLC). Subsequently, AcOH (0.15 eq., as 0.1M
solution in MeOH) was added, and after evaporation of the
volatiles, the residue was chromatographed.
5.22 (m, 2 H), 5.40 (s, 1 H, CH(OEt)2), 6.00 (d, J = 6.4, 1 H,
H-10), 8.43 (s, 1 H, H-8), 8.76 (s, 1 H, H-2). 13C NMR (75MHz,
CDCl3): d 15.0, 61.7, 62.7, 68.5, 71.8, 72.0, 74.1, 82.2, 82.7,
87.3, 90.9, 91.4, 136.1, 139.9, 146.3, 150.3, 151.9. IR (ATR):
3312 (s), 3107 (m), 2976 (m), 2929 (m), 2886 (m), 2241 (w),
2155 (w), 1579 (s), 1492 (m), 1443 (m), 1400 (m), 1328 (m),
1256 (w), 1211 (m), 1179 (w), 1114 (m), 1080 (s), 1044 (s), 977
(m), 899 (m), 864 (w), 802 (w), 740 (w), 702 (w), 636 (w), 596
(w), 551 (w), 494 (w) cmꢀ1. HRMS (ESI): m/z [M + Na]+ calcd
for C19H22N4O6Na 425.1437; found 425.1431.
9-b-D-Ribofuranosyl-6-(4-phenylbuta-1,3-diyn-1-yl)purine (7a).
From 5a (51 mg, 0.10 mmol) was obtained after chromatography
(EtOAc–MeOH 20:1, RF = 0.43) 33 mg (86%) of 7a as beige
amorphous powder. 1H NMR (300 MHz, DMSO): d 3.53–3.63
(m, 1 H, H-50), 3.64–3.74 (m, 1 H, H-50), 3.98 (m, 1 H, H-40), 4.19
(m, 1 H, H-30), 4.60 (m, 1 H, H-20), 5.09 (t, J= 5.3, 1 H, OH-
50), 5.25 (d, J= 5.3, 1 H, OH), 5.56 (d, J= 5.9, 1 H, OH), 6.04
(d, J= 5.3, 1 H, H-10), 7.42–7.57 (m, 3 H, Ph), 7.68–7.73 (m, 2
H, Ph), 8.96 (s, 2 H, H-8 + H-2). 13C NMR (75 MHz, DMSO):
d 61.3, 70.3, 72.7, 74.1, 76.3, 80.4, 85.8, 85.9, 88.1, 119.6,
129.3, 131.1, 133.1, 135.8, 138.6, 146.7, 151.7, 152.5. IR
(ATR): 3626 (w), 3296 (m), 3091 (m), 3055 (m), 2936 (m),
2212 (s), 1580 (s), 1494 (w), 1450 (m), 1443 (m), 1409 (w),
1389 (w), 1329 (m), 1211 (m), 1130 (w), 1095 (m), 1064 (m),
1025 (w), 983 (w), 950 (w), 866 (w), 852 (w), 809 (w), 762
9-b-D-Ribofuranosyl-6-(4-(1-methylimidazol-5-yl)buta-1,3-diyn-
1-yl)purin (7e). From 5e (45mg, 0.09mmol) was obtained after
chromatography (EtOAc–MeOH 9:1) 32mg (95%) of 7e as pale
1
yellow amorphous solid. H NMR (DMSO, 373K): d 3.61–3.66
(m, 1 H, H-50), 3.71–3.74 (m, 1 H, H-50), 3.75 (s, 3 H, CH3),
4.01–4.06 (m, 1 H, H-40), 4.23–4.27 (m, 1 H, H-30), 4.62–4.66
(m, 1 H, H-20), 6.07 (d, J = 5.2, 1 H, H-10), 7.58 (s, 1 H, H-400),
7.82 (s, 1 H, H-200), 8.87 (s, 1 H, H-8), 8.94 (s, 1 H, H-2). 13C
NMR (DMSO, 373 K): d 31.5 (CH3), 60.9 (C-50), 69.9 (C-30),
73.6 (C-20), 73.8 (CꢃC), 78.9 (CꢃC), 79.7 (CꢃC), 79.8 (CꢃC),
85.5 (C-40), 87.9 (C-10), 113.4 (C-500), 135.5 (C-5), 138.2 (C-6),
138.4 (C-400), 140.6 (C-200), 145.9 (C-8), 151.7 (C-2 or C-4),
151.9 (C-2 or C-4). IR (ATR): 3110 (s), 3091 (s), 2925 (m), 2871
(m), 2214 (s), 1882 (w), 1758 (w), 1678 (w), 1584 (s), 1545 (w),
1493 (m), 1461 (m), 1439 (m), 1418 (m), 1400 (m), 1331 (s),
1277 (m), 1253 (m), 1223 (s), 1201 (s), 1178 (m), 1124 (s), 1079
(s), 1059 (s), 941 (w), 901 (w), 857 (m), 840 (w), 803 (w), 736
(w), 709 (w), 686 (w) cmꢀ1. HRMS (EI): m/z [M]+ calcd for
C18H16N6O4 380.1233; found 380.1236.
(w), 687 (w), 636 (w), 593 (w), 528 (w), 475 (w) cmꢀ1
.
HRMS (ESI): m/z [M + Na]+ calcd for C20H16N4O4Na 399.1069;
found 399.1055.
9-b-D-Ribofuranosyl-6-(nona-1,3-diyn-1-yl)purin (7b). From
5b (32 mg, 0.064 mmol) was obtained after chromatography
(EtOAc–MeOH 9:1, RF = 0.58) 18mg (75%) of 7b as white
amorphous powder. 1H NMR (300 MHz, DMSO): d 0.87
(t, J = 7.0, 3 H, CH3), 1.26–1.42 (m, 4 H, CH2), 1.50–1.60 (m, 2
H, CH2), 2.51 (t, J=7.0, 2 H, CꢃC–CH2), 3.51–3.61 (m, 1 H, H-50),
3.63–3.73 (m, 1 H, H-50), 3.96 (m, 1 H, H-40), 4.17 (m, 1 H, H-30),
4.58 (m, 1 H, H-20), 5.09 (t, J = 5.3, 1 H, OH-50), 5.25 (d, J = 5.0,
1 H, OH), 5.56 (d, J = 5.6, 1 H, OH), 6.01 (d, J = 5.3, 1 H, H-10),
8.91 (s, 1 H, H-2 or H-8), 8.92 (s, 1 H, H-2 or H-8). 13C NMR
(75MHz, DMSO): d 14.0, 19.0, 21.8, 27.2, 30.7, 61.3, 64.2, 69.5,
70.3, 74.0, 81.4, 85.9, 88.0, 91.0, 135.8, 139.1, 146.5, 151.6,
152.4. IR (ATR): 3285 (s), 2927 (s), 2858 (s), 2233 (s), 1578 (s),
1492 (w), 1444 (m), 1403 (m), 1329 (m), 1211 (m), 1093 (m),
1058 (m), 981 (w), 866 (w), 802 (w), 724 (w), 637 (w), 593 (w)
cmꢀ1. HRMS (ESI): m/z [M + Na]+ calcd for C19H22N4O4Na
393.1539; found 393.1534.
5-(9-b-D-Ribofuranosylpurin-6-yl)penta-2,4-diyn-1-ol (7g).
From 5f (75mg, 0.15mmol) was obtained after chromatography
(EtOAc–MeOH 20:1, RF = 0.20) 44mg (89%) of 7g as white
amorphous solid. 1H NMR (300MHz, DMSO): d 3.54–3.75 (m, 2
H, H-50), 3.97 (m, 1 H, H-50), 4.18 (m, 1 H, H-40), 4.34
(d, J =6.2, 2 H, CꢃC–CH2), 4.58 (m, 1 H, H-30), 5.09 (t, J = 5.3,
OH-50), 5.24 (d, J = 5.3, 1 H, OH), 5.56 (d, J = 5.9, 1 H, OH),
5.63 (t, J = 6.4, 1 H, OH), 6.03 (d, J = 5.3, 1 H, H-10), 8.94 (s, 1
H, H-2 or H-8), 8.942 (s, 1 H, H-2 or H-8). 13C NMR (75 MHz,
DMSO): d 49.8 (CꢃC–CH2), 61.2 (C-50), 67.3 (CꢃC), 70.3
(C-30), 72.1 (CꢃC), 74.1 (C-20), 80.3 (CꢃC), 85.9 (C-40), 88.0
(C-10), 88.6 (CꢃC), 135.8 (C-5), 138.7 (C-6), 146.6 (C-8), 151.7
(C-4), 152.4 (C-2). IR (ATR): 3273 (s), 3104 (s), 2923 (m), 2237
(m), 2153 (w), 1730 (w), 1580 (s), 1491 (m), 1445 (m), 1402 (m),
1330 (m), 1256 (w), 1211 (m), 1111 (m), 1081 (m), 1056 (m),
1025 (m), 979 (m), 892 (w), 864 (w), 815 (w), 802 (w), 748 (w),
706 (w), 635 (w), 595 (w), 535 (w), 471 (w) cmꢀ1. HRMS (ESI):
m/z [M+ Na]+ calcd for C15H14N4O5Na 353.0862; found 353.0859.
5-(9-Benzylpurin-6-yl)penta-2,4-diyn-1-ol (4g). From 4f
(66 mg, 0.2 mmol) was obtained after chromatography (EtOAc)
9-b-D-Ribofuranosyl-6-(5-(dimethylamino)penta-1,3-diynyl)
purine (7c). From 5c (107 mg, 0.22 mmol) was obtained after
chromatography (EtOAc–MeOH–Et3N 18:2:1) 66 mg (83%) of 7c
as unstable light brown waxy solid. 1H NMR (300 MHz, DMSO):
d 2.23 (s, 6 H, N(CH3)2), 3.50–3.76 (m, 2 H, H-50), 3.97 (m, 1 H,
H-40), 4.18 (m, 1 H, H-30), 4.58 (m, 1 H, H-20), 5.2 (br s, 3 H,
3 ꢂ OH), 6.02 (d, J = 5.1, 1 H, H-10), 8.93 (s, 1 H, H-2 or H-8),
8.94 (s, 1 H, H-2 or H-8). 13C NMR (75 MHz, DMSO): d 44.3,
48.4, 61.7, 69.0, 70.8, 71.3, 74.5, 81.0, 86.0, 86.4, 88.5, 136.3,
139.2, 147.1, 152.1, 152.9. IR (ATR): 3268 (m), 3104 (m), 2924
(m), 2871 (m), 2783 (m), 2234 (w), 2149 (w), 1641 (w), 1576 (s),
1491 (m), 1441 (m), 1400 (m), 1327 (m), 1257 (w), 1211 (m),
1110 (m), 1082 (m), 1053 (m), 978 (w), 893 (w), 863 (w), 838
1
52 mg (90%) of 4g as white powder, mp >150ꢁC (dec.). H NMR
(300 MHz, DMSO) d 4.33 (d, J=6.2, 2 H, CH2OH), 5.50 (s, 2 H,
CH2Ph), 5.63 (t, J= 6.2, 1 H, OH), 7.22–7.36 (m, 5 H, Ph), 8.84 (s,
1 H, H-2 or H-8), 8.91 (s, 1 H, H-2 or H-8). 13C NMR (75MHz,
DMSO) d 46.9 (CH2Ph), 49.8 (CH2OH), 67.3 (CꢃC), 72.2 (CꢃC),
80.1 (CꢃC), 88.4 (CꢃC), 127.9 (CHPh), 128.2 (CHPh), 129.0
(CHPh), 135.3 (C-5), 136.3 (CPqh), 138.5 (C-6), 148.4 (C-8), 151.8
(C-4), 152.4 (C-2). IR (ATR): 3193 (m), 3065 (m), 2925 (w), 2852
(w), 2229 (m), 1577 (s), 1499 (m), 1450 (m), 1431 (m), 1403 (m),
1333 (m), 1321 (m), 1249 (m), 1217 (m), 1166 (m), 1031 (m), 983
(m), 963 (w), 884 (w), 804 (w), 731 (m), 694 (m), 639 (m), 596
(w), 552 (w), 537 (w), 455 (w) cmꢀ1. HRMS (ESI): m/z [M + Na]+
calcd for C17H12N4ONa 311.0909; found 311.0917.
(w), 803 (w), 744 (w), 705 (w), 639 (w), 556 (w), 477 (w) cmꢀ1
.
HRMS (ESI): m/z [M+ Na]+ calcd for C17H19N5O4Na 380.1335;
found 380.1324.
9-b-D-Ribofuranosyl-6-(5,5-diethoxypenta-1,3-diyn-1-yl)purine
(7d). From 5d (71 mg, 0.13 mmol) was obtained after
chromatography (EtOAc–MeOH 9:1) 47 mg (87%) of 7d as pale
yellow waxy solid. 1H NMR (300 MHz, CDCl3): d 1.24
(dt, J = 1.8, 7.2, 6 H, CH3), 3.57–3.82 (m, 5 H), 3.94 (m, 1 H),
4.11 (m, 1 H), 4.31 (m, 1 H), 4.51 (d, J = 4.1, 1 H), 4.97 (m, 1 H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2015
Synthesis of Potentially Biologically Active 6-(1,3-Butadiynyl)purines
47
ꢀ
[5] Kuchar, M.; Pohl, R.; Votruba, I.; Hocek, M. Eur J Org Chem
2006, 5083.
[6] Mikawa, N.; Ono, Y.; Matsuda, A. J Am Chem Soc 2003, 125,
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[7] a) Hocek, M.; Votruba, I. Bioorg Med Chem Lett 2002, 12,
Acknowledgments. This project was supported by the Research
Center “The Structure and Synthetic Applications of Transition
Metal Complexes-LC06070” of the Ministry of Education,
Youth and Sports of the Czech Republic, by the grant
MSM6046137301 of the same Ministry, and by the Grant
Agency of the Czech Republic (grant no. 203/09/1552).
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1055–1058; b) Naus, P.; Votruba, I.; Hocek, M. Collect Czech Chem
Commun 2004, 69, 1955.
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[8] Hocek, M.; Stará, I. G.; Starý, I.; Dvoráková, H. Collect Czech
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REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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