Chemo-, regio- and stereospecific addition of adenine and 8-azaadenine to α,β-acetylenic γ-hydroxy nitriles: a short-cut to novel acyclic adenosine analogues

Article abstract of DOI:10.1016/j.tet.2010.01.015

Adenine (9H-purin-6-amine) adds readily to available α,β-acetylenic γ-hydroxy nitriles under mild conditions (molar ratio 1:1, K₂CO₃, DMF, rt, 10 min) to afford chemo-, regio- and stereospecifically (Z)-3-(6-amino-9H-purin-9-yl)-4-hydroxy-4-alkyl-2-alkenenitriles, novel functionalized acyclic nucleoside analogues (95-98% yield). Under similar conditions (K₂CO₃, DMF, rt, 1 h), 8-azaadenine (3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine) reacts with 4-hydroxy-4-methyl-2-pentynenitrile nonselectively at the 7-, 8- and 9-positions to give the corresponding adducts in a 1:10.5:9 ratio, the total yield being 81%. Chemo-, regio- and stereospecific addition of 8-azaadenine to the above α,β-acetylenic γ-hydroxy nitriles leading to (Z)-3-(7-amino-2H-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-4-hydroxy-4-alkyl-2-alkenenitriles in 44-90% yield is attained when the reaction is carried out without solvent in the presence of Et₃N (30 mol %), the molar ratio of 8-azaadenine:α,β-acetylenic nitriles being 1:2.0 (rt, 12-38 h).

Full text of DOI:10.1016/j.tet.2010.01.015

Tetrahedron 66 (2010) 1699–1705
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemo-, regio- and stereospecific addition of adenine and 8-azaadenine to
a,
b-acetylenic
g
-hydroxy nitriles: a short-cut to novel acyclic adenosine analogues
,
a
a
a
Boris A. Trofimova , Anastasiya G. Mal’kina , Valentina V. Nosyreva , Olesya A. Shemyakina ,
*
Angela P. Borisova a, Lyudmila I. Larina a, Olga N. Kazheva b, Grigorii G. Alexandrovc, Oleg A. Dyachenko b
a A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russia
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 Academician N. N. Semenov Str., Chernogolovka 142432, Russia
c N. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31 Leninskii Prosp., Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Adenine (9H-purin-6-amine) adds readily to available
a,b-acetylenic g-hydroxy nitriles under mild
Received 16 September 2009
Received in revised form 19 November 2009
Accepted 4 January 2010
conditions (molar ratio 1:1, K2CO3, DMF, rt, 10 min) to afford chemo-, regio- and stereospecifically (Z)-3-
(6-amino-9H-purin-9-yl)-4-hydroxy-4-alkyl-2-alkenenitriles, novel functionalized acyclic nucleoside
analogues (95–98% yield). Under similar conditions (K2CO3, DMF, rt, 1 h), 8-azaadenine (3H-[1,2,3]tri-
azolo[4,5-d]pyrimidin-7-amine) reacts with 4-hydroxy-4-methyl-2-pentynenitrile nonselectively at the
7-, 8- and 9-positions to give the corresponding adducts in a 1:10.5:9 ratio, the total yield being 81%.
Chemo-, regio- and stereospecific addition of 8-azaadenine to the above a,b-acetylenic g-hydroxy nitriles
leading to (Z)-3-(7-amino-2H-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-4-hydroxy-4-alkyl-2-alkenenitriles in
44–90% yield is attained when the reaction is carried out without solvent in the presence of Et3N
Available online 11 January 2010
Keywords:
Adenine
8-Azaadenine
a,b-Acetylenic g-hydroxy nitriles
(30 mol %), the molar ratio of 8-azaadenine:
a,b
-acetylenic nitriles being 1:2.0 (rt, 12–38 h).
Ó 2010 Elsevier Ltd. All rights reserved.
Nucleophilic addition
Nucleosides modification
Acyclic nucleoside analogues
1. Introduction
and its derivatives, possess significant biologically activity.5
Commonly, the preparation of such -branched derivatives by direct
a
Acyclic nucleoside analogues are currently used as antiviral
agents, e.g., for the treatment of human immunodeficiency virus
(HIV), hepatitis B (HBV), and herpes diseases.1–4 They are also
mentioned in the context of cancer therapy.5 Most of their ana-
logues represent modifications of the natural nucleosides in the
heterocyclic or in the ribose moieties.3,6 Usual structural alterations
relate to the sugar ring where 20- and 30-hydroxyl functions are
eliminated and the oxygen atom is replaced by a methylene group
(carbocyclic nucleosides).3,7,8 Also, 1,3-oxathiolanes3,9 (instead of
ribose derivatives) and their ring-opened congeners have been
synthesized.3,8 The latter, in some cases, were shown to be pro-
spective antiviral remedies.3,7 Among them are such important
antiherpetic drugs as acyclovir1,10 and ganciclovir,1,11 both de-
rivatives of guanine. Acyclic adenine analogues, namely, adefovir
and tenofovir are active against HBV and HIV infections.2 Attempts
to synthesize new more potent analogues of these drugs are cur-
rently being undertaken.2
alkylation of adenine encounters difficulties due to the competing
elimination reactions or low reactivity of the alkylation agent.5,12 The
reported syntheses include upto five steps starting from adenine with
total yield of the target adenosine analogues ranging 4–10%.5
Unsaturated acyclic adenosine congeners are convenient in-
termediates in the synthesis of the corresponding oligonucleo-
tides13 and polymeric analogues of nucleic acids.13b,14 Their
synthesis consists in relatively low-yield multistep procedures.13–15
The introduction of electron-withdrawing substituents into the
acyclic moiety of adenosine analogues was reported to be particu-
larly difficult.5 Much less is known about the application of acety-
lenic compounds in the synthesis of acyclic adenosine analogues.
Some propargyl halides were reported to alkylate adenine whilst
keeping the triple bond intact,16 whereas non-stereoselective ad-
dition of adenine to diethyl acetylenedicarboxylate led to a mixture
(2:1) of E- and Z-adducts in 65% yields.17 To the best of our knowl-
edge, this is the only example of adenine addition to the C^C bond.
Derivatives of 8-azaadenine exhibit cytotoxic,18 antimicrobial,19
and mutagenic18c activities. On-going investigations into the
chemistry of 8-azaadenine is anticipated to be a potential source of
antitumor drugs.18b Of great importance is the free radical chem-
istry of these compounds, since tumor treatment involves both
chemo- and radiotherapy.18c There are fewer examples of acyclic
Special efforts have been directed toward the synthesis of
a-branched representatives of acyclicanalogues of adenosine, because
some of them, for example, erythro-9-(2-hydroxy-3-nonyl)adenine
* Corresponding author. Tel.: þ7 3952 421411; fax: þ7 3952 41 9346.
E-mail address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.015

1700
B.A. Trofimov et al. / Tetrahedron 66 (2010) 1699–1705
analogues of 8-azaadenine although their biological activity is
predicted to be promising.
the acetylenes 2 that led to chemo-, regio- and stereospecific for-
mation of the adducts 3a–d, (Z)-3-(6-amino-9H-purin-9-yl)-4-hy-
droxy-4-alkyl-2-alkenenitriles, in 95–98% yields.
Some selected results on the screening of catalysts and condi-
tions for the reaction under study are presented in Table 1. Among
them the following features draw attention:
In this paper, we report an original short-cut to novel func-
tionalized acyclic analogues of adenosine and its 8-azacongeners
basing on the direct addition of adenine and 8-azaadenine to
readily available
a,b-acetylenic g
-hydroxy nitriles.20
1. When carried out without catalyst and solvents (entries 1–3),
the reaction is preparatively much less efficient (conversions of 1
are 15–82%, yields of 3a are 62–72%) and takes much longer (up
to four days). The comparison of conversions and yields shows
that the non-catalytic reaction is not selective because some
amount of adenine is used up for side processes probably for the
addition to a second molecule of 2a by its other nitrogen atoms.
2. Triethylamine as a catalyst improves preparative characteris-
tics of the reaction increasing the conversion of adenine, yield
of adducts 3 and selectivity (entries 4–7), although the reaction
still is slow (from 16 h to two days) and not fully selective (cf.
conversions and yields). When an excess of acetylene is
employed (entries 4–7), 2,5-di(cyanomethylene)-1,4-dioxanes
4a,c, the dimers of starting acetylenes 2a,c previously de-
scribed25 are isolated in 16–30% yields (Scheme 2).
2. Results and discussion
Various NH-heterocycles are known to react readily with
-acetylenic -hydroxy nitriles (without transition metal
a
,b
g
catalysts or in the presence of bases) to afford the expected adducts
across the triple bond or their cyclic isomers, the corresponding
iminodihydrofurans.20c These heterocycles include imidazoles (no
catalyst and solvent, rt, 0.5–2 h),20c,21 benzimidazole [Et3N, 50 ꢀC,
4 h or MOH (M¼Na, K, Li), dioxane, 50 ꢀC, 1 h],20c,22 pyrazoles (no
catalyst and solvent, rt, 48–72 h),23 1,2,4-triazoles (no catalyst and
solvent, rt, 72 h)23 and tetrazole [MOH (M¼Na, K), THF (or DMSO),
20–40 ꢀC, 13–50 h].24 Therefore, it was a surprise that during our
diversified experiments adenine 1 turned out to be reluctant to
react efficiently with a,b-acetylenic g-hydroxy nitriles 2a–d under
the conditions valid for the above heterocycles. This was likely due,
at least partially, to a scarce solubility of this nucleobase in con-
ventional organic solvents. Our systematic screening of the cata-
lysts and conditions of the reaction allowed an efficient method of
CN
R2
O
Et3N
R2
R1
R1
the adenine addition to the a,b-acetylenic g-hydroxy nitriles to be
2a,c
developed. Eventually it was found that, when conducted at rt in
DMF with K2CO3 (13 mol %) as catalyst, the target reaction became
rapid, smooth and high-yielding (Scheme 1).
O
CN
4a,c
NH2
a: R1 = R2 = Me; c: R1- R2 =
NH2
N
N
R2
N
K2CO3 (13 mol%),DMF
rt, 10 min
Scheme 2.
N
N
R1
N
+
CN
CN
R2
R1
N
N
OH
3. Inferior results are obtained with alkaline metal hydroxides as
catalysts in water or water–ethanol mixture (entries 8–10). In
this case, along with adducts 3a,d, 5-amino-3(2H)-furanones
5a,d originating hydration of acetylene 2a and 2d as shown
in25c,26 are formed in 13–28% yields (Scheme 3).
H
OH
3a-d
1
2a-d
Isolated yield
Adduct
R1
R2
(%)
98
95
3a
3b
Me
Me
Me
E t
O
3c
3d
97
96
MOH, H2O
R2
R1
2a,d
NH2
O
5a,d
a: R1 = R2 = Me
d: R1 - R2 =
M = Li, Na
Scheme 1.
Despite the presence of five nucleophilic centers (nitrogen
atoms) in the molecule of adenine 1, potentially capable of attack-
ing the triple bond, only the imidazole nitrogen N-9 reacted with
Scheme 3.
Table 1
Synthesis of adducts 3a–d [adenine 1 (1 mmol), rt]
Entry
Acetylene, mmol
Catalyst, mol %
Solvent
Time
Conversion of 1 (%)
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
2a, 1.56
2a, 2.16
2a, 2.16
2a, 2.20
2b, 2.00
2c, 2.00
2d, 2.00
2a, 1.00
2a, 1.00
2d, 1.00
2a, 1.00
None
None
None
None
None
None
None
None
None
None
3 days
2 days
4 days
2 days
18 h
26 h
16 h
4 days
24 h
7 h
15
55
82
100
79
100
37
44
74
42
d
3a
3a
3a
3a
3b
3c
3d
3a
3a
3d
d
72
62
68
Et3N, 10
Et3N, 45
Et3N, 50
Et3N, 50
NaOH, 2.5
NaOH, 40
LiOH, 50
K2CO3, 10
81a
56
96a
72
H2O, 3 ml
H2O, 3 ml
EtOH–H2O 1:2, 4.5 ml
H2O, 4 ml
47b
39b
91c
db
9
10
11
24 days
2,5-Di(cyanomethylene)-1,4-dioxanes:25 4a (yield 16% for entry 4) and 4c (yield 30% for entry 6) are isolated, yields basing on acetylenes 2a,c.
5-Amino-3(2H)-furanone25c,26 5a was formed, yield 13% – entry 8, 28% – entry 9, 80%dentry 11.
50–55 ꢀC, 5-amino-3(2H)-furanone 5d (yield 8%) was formed.
a
b
c

B.A. Trofimov et al. / Tetrahedron 66 (2010) 1699–1705
1701
4. In water, K2CO3 does not catalyze the reaction at all. Instead,
only hydration of starting acetylene occurs to give 5-amino-
3(2H)-furanone 5, for 2a the yield reaching 80% (entry 11).
formation of only one isomer. The Z-configuration of the isomers
follows from 2D (1H, 1H) NOESY spectra where a cross-peak be-
tween the olefinic proton and the methyl group protons is ob-
served. The configurational assignment and the substituent
location for the compounds 3a–d are also based on the values of
For the structure determination we have performed an X-ray
analysis of a single crystal of product 3a, which actually proves it to
be (Z)-3-(6-amino-9H-purin-9-yl)-4-hydroxy-4-methyl-2-pente-
nenitrile 3a (Fig. 1).
3
vicinal coupling constant JCH between olefinic proton H-11 and
carbon C-14 (3JCH¼3.6 Hz). In the 15N NMR spectra of the adducts
3a–d, as exemplified by the spectrum of 3b, four nitrogen signals of
heterocyclic fragment appear at ꢁ216.4 (N-9), ꢁ154.7 (N-3), ꢁ142.9
(N-1), and ꢁ137.7 (N-7) ppm, while nitrogen signals of CN and NH2
groups are in the region of ꢁ113.1 and ꢁ298.1 (1JNH¼90.3 Hz) ppm,
respectively.
In contrast to adenine 1, 8-azaadenine 6 reacted with acetylene
2a in the presence of K2CO3 in DMF non-selectively: all the three
nitrogen atoms of the triazole moiety were involved to give the
adducts 7–9 in the ratio 1:10.5:9 (1H NMR spectroscopic data),
respectively, the total yield being 81% (Scheme 4).
This result is in agreement with tautomeric equilibrium known
for 8-azaadenine.27
According to quantum chemical calculations (MP2/6-31*//HF/6-
31G8), the stability order for the tautomers A–C is as follows:
B>A>C.27 Alkylation4a,28 of 8-azaadenine 6 leads to a mixtures of
three4a or two28 isomers in ratios of N-9:N-8:N-7¼5:5.5:1 and
1:1.3:0. Thus, the isomer ratio obtained (Scheme 4) implies that
tautomers A–C add to the triple bond of acetylenes 2 with ap-
proximately equal rates under the conditions studied.
This turned out to be not the case for the reaction of 8-azaa-
denine 6 with a two-fold molar excess of acetylenes 2a–d in the
presence of Et3N (30 mol %, rt, 12–38 h). Under these conditions,
only nitrogen atom N-8 (tautomer B) happened to be active. As
a result, chemo-, regio- and stereospecific formation of isomers 8a–
d, (Z)-3-(7-amino-2H-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-4-hy-
droxy-4-alkyl-2-alkenenitriles, in 44–90% yields took place
(Scheme 5).
The high selectivity of the reaction observed in this case is likely
due to the tautomer reactivity change and shift of the tautomer
ratio in favor of tautomer B (Scheme 5). The quantum chemical
calculations27 predict the electrostatic effects in solution to be
important for the stability of tautomer B.
Figure 1. The conformation and designation of atoms in the adduct of 3a.
The crystalline structure is formed by one crystallographically
independent molecule taking the general position. The purine bi-
cycle is almost planar and the maximum deviation of atoms from
the plane does not exceed 0.01 Å. The deviation of N(4) and C(10)
atoms from the plane is also not higher than 0.01 Å. The purine
bicycle forms a dihedral angle (116.9ꢀ) with the plane of acryloni-
trile N(7)C(12)C(11). The torsion angles N(8)-C(10)-C(11)-C(12),
C(10)-C(11)-C(12)-N(7) and N(8)-C(10)-C(13)-O(1) are equal to
1.0(2)ꢀ, 153(5)ꢀ, and 165.1(1)ꢀ, respectively.
In the 1H NMR spectra of the adducts 8a–d, there is an olefinic
proton signal at 6.72–6.62 ppm, that is, indicative of the formation
of only one isomer. The vinyl moiety of 8a–d is manifested itself in
the 13C NMR spectra by the signals in the region 165.8–163.3 ppm
(C-10) and 100.6–98.6 ppm (C-11). The cyano C-atom resonates at
Multinuclear 1H, 13C, 15N, and 2D (NOESY, HMBC, HSQC) NMR
spectroscopy data as well as IR, UV, and MS investigation results of
the adducts 3a–d are in agreement with their structure.
In the 1H NMR spectra of the adducts 3a–d, there is an olefinic
proton signal (H-11) at 6.56–6.53 ppm, that is, indicative of the
NH2
NH2
NH2
Me
H
N
K2CO3, DMF
rt, 1 h
N
N
N
N
N
N
N
Me
CN
+
N
H
N
OH
N
N
N
H
N
N
2a
C
B
A
6
NH2
NH2
Me
N
N
N
NH
2Me
OH
N
CN
N
N
N
N
N
+
+
N
N
CN
N
N
Me
Me
CN
N
HO
Me
N
OH
Me
8
7
9
7:8:9=1:10.5:9
Scheme 4.

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B.A. Trofimov et al. / Tetrahedron 66 (2010) 1699–1705
(1H, 13C) or nitromethane (15N). 1H–1H, 1H–13C and 1H–15N Coupling
NH2
constant (J in Hz) values approach to 0.1 Hz. NMR signals were
assigned using 2D NMR methods (HSQC or HMBC 1H–13C and
HMBC 1H–15N) and also with account data reported in Refs.30 IR
spectra were measured on a Bruker IFS-25 in KBr pellets. UV–vis
spectra were measured on a Perkin–Elmer Lambda 35 spectrometer
at rt (H2O, EtOH, d¼0.1, 0.3, 1.0 cm). Mass spectra were recorded on
a GC–MS-QP5050A spectrometer made by Shimadzu Company.
Chromatographic column parameters were as follows: SPBÔ-5,
length 60 m, internal diameter 0.25 mm, thickness of stationary
R2
N
CN
R1
N
N
Et3N (30 mol%)
rt, 12-38 h
R1
+
6
CN
N
N
OH
HO
R2
2a-d
8a-d
Yieds
(%)
90
72
Adduct
R1
R2
phase film 0.25 m
m; injector temperature 250 ꢀC, gas carrierdhe-
lium, flow rate 0.7 mL/min; detector temperature 250 ꢀC; mass
analyzer: quadrupole, electron ionization, electron energy: 70 eV,
ion source temperature 200 ꢀC; mass range 34–650 Da. All melting
points were taken on a Kofler micro hot stage. The reaction was
controlled by TLC on neutral Al2O3 (chloroform–benzene–ethanol,
20:4:1 as eluent). Adenine 1 and 8-azaadenine 6 are commercial
8a
8b
Me
Me
Me
E t
8c
8d
44
52
Scheme 5.
reagents (‘Merck’).
a,b-Acetylenic g-hydroxy nitriles 2a–d were
prepared according to a published method.20
115.4–114.8 ppm (C-12). The 2D (1H, 1H) NOESY spectra of the ad-
ducts 8a–d show cross-peaks between olefinic proton and methyl
group protons for compounds 8a and 8b, as well as between olefin
proton and protons of CH2 of the cycle substituent for compounds
8c and 8d.
4.2. X-ray diffraction
X-ray diffraction studies of 3a were carried out with an Bruker
SMART APEX2 CCD, diffractometer at rt (u/2q-scan mode, Mo-Ka
The configurational assignment and substituent location for the
compounds 8a–d have also been based on the values of vicinal
radiation, graphite monochromator). Crystalline structure was
solved by direct methods followed by Fourier synthesis using
SHELXS-97.31a The structure was refined using anisotropic full-
matrix approximation for all non-hydrogen atoms with SHELXL-
97.31b Coordinates of hydrogen atoms were defined experimentally
and refined isotropically. These data are available via
www.ccdc.cam.uk/contsretrieving.html (or from CCDC, 12 Union
CambrigeCB2 1EZ, UK, fax: þ44(0)1223 336 033; or e-mail:
deposit@ccdc.cam.ac.uk). Any request to the CCDC for data should
quote the full literature citation and CCDC reference number CCDC
743626.
3
coupling constant JCH between olefinic proton H-11 and carbon
3
C-14 (3JCH¼3.8–3.5 Hz). Since the trans-vicinal JCH value is always
larger than the corresponding cis-3JCH value, the H-11 atom is
located in the cis-position with respect to the C-14. Therefore,
compounds 8a–d are Z-isomers. Z-Stereospecificity of the additions
(Schemes 1 and 5) is expected from the known trans-mode of
concerted nucleophilic addition to acetylenes.29
In the 2D 1H–15N NMR spectra (HMBC) of compounds 8a–d, two
groups of nitrogen atom signals are observed: H-2 cross-peaks with
2
three nitrogen atoms N-1 [
d
ꢁ(147.1–146.8) ppm, JN–H¼16.4–
16.2 Hz], N-3 [
d
ꢁ(150.2–149.8) ppm, 2JN-H¼15.4–15.0 Hz], and N-9
4.2.1. Crystallographic data for 3a. C11H12N6O, M¼244.26, mono-
clinic, P21/n, a¼6.500(1) Å, b¼13.250(3) Å, c¼14.040(3) Å,
a
¼90ꢀ,
[
d
ꢁ(64.6–64.3) ppm], as well as olefinic proton cross-peaks both
b
¼93.60(3)ꢀ,
g
¼90ꢀ,
U¼1206.8(4) Å3,
Z¼4,
l
¼0.7107 Å,
with nitrogen atom of cyano group [
d
ꢁ(111.7–111.5) ppm] and N-8
Dcalcd¼1.34 g cmꢁ3
,
m
¼0.094 mmꢁ1
,
reflection observed/in-
atom of the triazole ring [
d
ꢁ(122.4–122.2) ppm].
dependent 11509/3227, 211 parameters refined, R¼0.048 for 2264
3. Conclusions
reflections with [F0>4s(F0)].
In summary, an original approach to the chemo-, regio- and
stereospecific modification of adenine and 8-azaadenine has been
developed. The approach consists in the nucleophilic addition of
4.3. The reaction of adenine 1 with
nitriles 2a–d
a,b-acetylenic g-hydroxy
adenine and 8-azaadenine to readily available
a,b-acetylenic
Method A. To a suspension of adenine 1 (135 mg, 1.0 mmol),
K2CO3 (18 mg, 13 mol %) in DMF (3 mL), the appropriate acetylenes
2a–d (1.0 mmol) in DMF (1 mL) was added at rt and stirred for
10 min. The resulting mixture was passed through neutral Al2O3
(0.5 cm, eluent: 3 mL of DMF) and then solvent was evaporated in
vacuo. The residue was washed with diethyl ether and dried in
vacuo to give (Z)-3-(6-amino-9H-purin-9-yl)-4-hydroxy-4-alkyl-2-
alkenenitriles 3a–d.
Method B. A mixture of adenine 1 (135 mg, 1.0 mmol) and
acetylene 2a (170 mg, 1.56 mmol) was stirred at rt for three days.
The reaction mixture was washed with diethyl ether and dried in
vacuo to give 148 mg of a solid consisting of adenine 1 (115 mg,
conversion 15%) and compound 3a (26 mg, 72%) (Table 1, entry 1).
Entries 2 and 3 (Table 1) were carried out under analogous
conditions, but at different molar ratio of start compounds (1:2,
1:2.16) and reaction time (two and four days).
g-hydroxy nitriles in a one-pot procedure at room temperature to
afford (Z)-3-(6-amino-9H-purin-9-yl)-4-hydroxy-4-alkyl-2-alke-
nenitriles 3a–d and (Z)-3-(7-amino-2H-[1,2,3]triazolo[4,5-d]pyr-
imidin-2-yl)-4-hydroxy-4-alkyl-2-alkenenitriles 8a–d in high
yields. The methodology allows the synthesis of novel families of
acyclic nucleosides with biologically important functionalities
(cyano, hydroxy, and vinyl groups). Such acyclic nucleosides are
potential pharmaceuticals and promising building blocks for drug
design.
4. Experimental
4.1. General
1H, 13C and 15N NMR spectra of the studied compounds were
recorded in DMSO-d6 at rt on Bruker DPX-400 and Bruker AV-400
spectrometers (400.13, 100.61, and 40.56 MHz, respectively). 1H,
Method C. To mixture of adenine 1 (135 mg, 1.0 mmol) and Et3N
(10 mg, 10 mol %), the acetylene 2a (240 mg, 2.2 mmol) were added
at rt and stirred for two days. The reaction mixture was sequentially
washed up acetone and diethyl ether, the residue was dried in
13C, and 15N chemical shifts (
d
in ppm) were measured with accu-
racy of 0.01, 0.02, and 0.1 ppm, respectively, and referred to HMDS

B.A. Trofimov et al. / Tetrahedron 66 (2010) 1699–1705
1703
vacuo to give compound 3a (191 mg). The combined organic layers
were evaporated in vacuo to give 182 mg of dark-red a residue. The
latter was washed with ethanol (2 mL) and diethyl ether (2 mL), the
resulting white powder (45 mg) consisting 6.5 mg of compound 3a
and 38.5 mg (16%) of 3,3,6,6-tetramethyl-1,4-dioxane 4a (1H NMR
data). 1H and 13C NMR spectra correspond to literature data.25 Total
yield 3a is 81% (Table 1, entry 4).
Anal. Calcd for C12H14N6O: C, 55.80; H, 5.46; N, 32.54. Found: C,
55.94; H, 5.76; N, 32.58.
4.3.3. (Z)-3-(6-Amino-9H-purin-9-yl)-3-(1-hydroxycyclopentyl)-2-
propenenitrile 3c. Method A: 262 mg, yield 97%; method C: 259 mg,
yield 96%; light beige crystals, mp 232–235 ꢀC; IR (KBr) 3432, 3321,
3257, 3154 (NH2, OH), 3061, 2985 (C]CH), 2225 (CN), 1662, 1640,
Under analogous conditions compounds 3b–d were obtained
1600 (NH2, C]C), 1573, 1511, 1482 (C]N) cmꢁ1
(400.13 MHz, DMSO-d6) d
;
1H NMR
8.18 (s, 1H), 8.17 (s, 1H), 7.40 (s, 2H), 6.53
(s, 1H), 5.77 (s, 1H), 1.29 (s, 8H); 13C NMR (100.61 MHz, DMSO-d6)
from adenine
1
(1.0 mmol), appropriate acetylenes 2b–d
(2.0 mmol) and Et3N (45–50 mol %) (Table 1, entries 5–7), but at
different molar ratio of start compounds (1:2, 1:2.0) and reaction
time (16–26 h).
d
160.7, 156.2, 153.3,150.1, 139.6, 117.9,114.9,100.0, 71.6, 27.7; MS m/
z (%) (EI): 270 (5) [M]þ, 229 (11), 201 (12), 135 (10), 67 (26), 66 (30),
Method D. To solution of adenine 1 (135 mg, 1.0 mmol), NaOH
(1.0 mg, 2.5 mol %) in water (3 mL), the acetylene 2a (109 mg,
1.0 mmol) was added and stirred at rt for four days. The water was
removed, the residue was washed with ethanol to result adenine 1
(76 mg, conversion 44%). Ethanol was removed in vacuo to give
mixture (177 mg) consisting of compound 3a (50 mg, 47%) and 5-
amino-2,2-dimethyl-3(2H)-furanone 5a (17 mg, 13%) (1H NMR
spectroscopic data). MS, 1H and 13C NMR spectra correspond to
literature data25c,26 (Table 1, entry 8).
65 (12), 59 (20), 54 (12), 53 (20), 52 (11), 43 (100), 42 (12), 41 (19),
40 (25); UV lmax (log 3) (ethanol): 209 (4.36), 258 (4.12) nm. Anal.
Calcd for C13H14N6O: C, 57.77; H, 5.22; N, 31.09. Found: C, 57.61; H,
5.42; N, 31.41.
4.3.4. (Z)-3-(6-Amino-9H-purin-9-yl)-3-(1-hydroxycyclohexyl)-2-
propenenitrile 3d. Method A: 273 mg, yield 96%; method C: 76 mg,
yield 72%; beige crystals, mp 236–240 ꢀC; IR (KBr) 3434, 3321, 3259,
3157 (NH2, OH), 3061 (C]CH), 2226 (CN), 1662, 1643, 1600 (NH2,
C]C), 1574, 1510, 1480 (C]N) cmꢁ1; 1H NMR (400.13 MHz, DMSO-
Entry 9 (Table 1) was carried out under analogous conditions,
but at 40 mol % of NaOH (24 h).
d6)
d
8.20 (s, 1H), 8.19 (s, 1H), 7.46 (s, 2H), 6.54 (s, 1H), 5.60 (s, 1H),
161.1, 156.6,
Method E. Solution of adenine 1 (135 mg, 1.0 mmol), LiOH
(12 mg, 50 mol %) in water (3 mL) was stirred and heated to
50–55 ꢀC, then solution of acetylene 2d (109 mg, 1.0 mmol) in
ethanol (1.5 mL) was added. The resulting mixture was stirred at
50–55 ꢀC for 7 h. The solvents were removed in vacuo to result
255 mg of a solid consisting of adenine 1 (78 mg, conversion 42%),
compound 3d (110 mg, 91%), and 2-amino-1-oxaspiro[4.5]dec-2-
en-4-one 5d (14 mg, 8%) (1H NMR spectroscopic data). 1H NMR for
1.59–1.16 (m, 10H); 13C NMR (100.61 MHz, DMSO-d6)
d
153.6, 150.5, 139.9, 118.2, 115.4, 100.7, 72.9, 34.5, 24.9, 21.2; MS m/z
(%) (EI): 284 (34) [M]þ, 267 (42), 266 (27), 265 (20), 256 (22), 241
(14), 229 (14), 228 (19), 227 (29), 216 (15), 214 (29), 213 (39), 200
(23), 188 (28), 187 (53), 186 (38), 175 (15), 160 (16), 159 (34), 134
(94), 135 (100), 132 (22), 119 (19), 108 (40), 105 (18), 93 (15), 92 (26),
81 (31), 79 (19), 67 (58), 66 (49), 65 (22), 57 (18), 55 (56), 54 (24), 53
(31), 52 (19), 45 (19); UV lmax (log 3) (ethanol): 209 (4.57), 261
5d (400.13 MHz, DMSO-d6)
d
4.24 (s, 1H), 1.87–1.44 (m, 10H); MS m/
(4.37) nm. Anal. Calcd for C14H16N6O: C, 59.14; H, 5.67; N, 29.56.
Found: C, 59.49; H, 5.46; N, 29.37.
z (%) (EI) for 5d: 167 (38) [M]þ,126 (16),112 (93), 99 (15), 86 (27), 81
(35), 79 (13), 69 (33), 68 (14), 67 (14), 55 (22), 54 (12), 53 (14), 44
(18), 43 (24), 42 (20), 41 (100), 40 (18), 39 (31) (Table 1, entry 10).
4.4. Reaction of 8-azaadenine 6 with
nitriles 2a–d
a,b-acetylenic g-hydroxy
4.3.1. (Z)-3-(6-Amino-9H-purin-9-yl)-4-hydroxy-4-methyl-2-pente-
nenitrile 3a. Method A: 239 mg, yield 98%; method B: 26 mg, yield
72% (Table 1, entry 1); 84 mg, yield 62% (Table 1, entry 2); 137 mg,
yield 68% (Table 1, entry 3); method C: 197 mg, yield 81%; yellow
crystals; mp 220–222 ꢀC (ethanol); IR (KBr) 3432, 3321, 3264, 3157
(NH2, OH), 3061 (C]CH), 2225 (CN), 1662, 1643, 1600 (NH2, C]C),
4.4.1. General method. To mixture of 8-azaadenine 6 (136 mg,
1.0 mmol) and Et3N (30 mg, 30 mol %), the appropriate acetylenes
2a–d (2.0 mmol) were added at rt and stirred for 12–38 h. The re-
action mixture was sequentially treated acetone and diethyl ether,
the residue was dried in vacuo to give compounds 8a–d.
1573, 1510, 1482 (C]N) cmꢁ1
;
1H NMR (400.13 MHz, DMSO-d6)
d
8.19 (s, 1H), 8.17 (s, 1H), 7.41 (s, 2H), 6.53 (s, 1H), 5.79 (s, 1H), 1.29
4.4.1.1. (Z)-3-(7-Amino-2H-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-
4-hydroxy-4-methyl-2-pentenenitrile 8a. Yield 220 mg, 90%, white
powder, mp 222–224 ꢀC (decomp.); IR (KBr) 3434, 3378, 3346 (NH2,
OH), 3051 (C]CH), 2228 (CN), 1671, 1641, 1603 (NH2, C]C), 1577,
(s, 6H); 13C NMR (100.61 MHz, DMSO-d6)
d 160.7,156.3,153.4,150.2,
139.6, 117.9, 114.9, 100.1, 71.6, 27.7; MS m/z (%) (EI): 244 (26) [M]þ,
230 (13), 229 (97), 202 (22), 201 (100), 187 (21), 186 (49), 159 (44),
136 (23), 135 (29), 119 (13), 108 (18), 92 (17), 81 (31), 67 (40), 66
(41), 65 (18), 59 (38), 54 (16), 53 (17), 52 (17); UV lmax (log 3)
(ethanol): 208 (4.41), 258 (4.19) nm. Anal. Calcd for C11H12N6O: C,
54.09; H, 4.95; N, 34.41. Found: C, 53.79; H, 5.05; N, 34.26.
1482 (C]N) cmꢁ1; 1H NMR (400.13 MHz, DMSO-d6)
d
8.59 (s, 1H),
8.40 (s, 1H), 8.38 (s, 1H), 6.67 (s, 1H), 5.99 (s, 1H), 1.43 (s, 6H); 13C
NMR (100.61 MHz, DMSO-d6) 165.8, 158.9, 158.3, 157.6, 127.7,
115.2, 98.6, 72.7, 28.8; 15N NMR (40.56 MHz, DMSO-d6)
d
d
ꢁ150.1,
ꢁ147.0, ꢁ122.3, ꢁ111.5, ꢁ64.3; MS m/z (%) (EI): 245 (6) [M]þ, 230
(10), 217 (14), 159 (10), 132 (18), 110 (100), 105 (11), 82 (22), 81 (11),
67 (36), 66 (38), 65 (14), 61 (10), 59 (47), 55 (19), 54 (21), 53 (26), 52
(16), 45 (10), 44 (23), 43 (93), 42 (20), 41 (38), 40 (40); UV lmax
4.3.2. (Z)-3-(6-Amino-9H-purin-9-yl)-4-hydroxy-4-methyl-2-hex-
enenitrile 3b. Method A: 245 mg, yield 95%; method C: 115 mg,
yield 56%, light beige crystals; mp 208–214 ꢀC; IR (KBr) 3430, 3321,
3264, 3174 (NH2, OH), 3066 (C]CH), 2225 (CN), 1661, 1638, 1600
(log 3) (ethanol): 207 (4.40), 240 (4.14), 279 (4.00), 309 (4.02) nm.
Anal. Calcd for C10H11N7O: C, 48.98; H, 4.52; N, 39.98. Found: C,
48.65; H, 4.79; N, 39.72.
(NH2, C]C), 1571, 1506, 1480 (C]N) cmꢁ1
DMSO-d6)
;
1H NMR (400.13 MHz,
d
8.17 (s, 1H), 8.16 (s, 1H), 7.40 (s, 2H), 6.49 (s, 1H), 5.62
(s, 1H), 1.56–1.49 (m, 1H), 1.47–1.40 (m, 1H), 1.30 (s, 3H), 0.86 (t,
J¼7.3 Hz, 3H); 13C NMR (100.61 MHz, DMSO-d6)
d
159.9, 156.3,
4.4.1.2. (Z)-3-(7-Amino-2H-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-
4-hydroxy-4-methyl-2-hexenenitrile 8b. Yield 186 mg, 72%, white
powder, mp 210–212 ꢀC (decomp.); IR (KBr) 3387, 3338, 3126 (NH2,
OH), 3064 (C]CH), 2225 (CN), 1673, 1638, 1604 (NH2, C]C), 1572
153.3, 150.1, 139.5, 117.9, 115.0, 100.7, 74.1, 32.1, 25.1, 7.7; 15N NMR
(40.56 MHz, DMSO-d6)
d
ꢁ298.1 (1JNH¼90.3 Hz), ꢁ216.4, ꢁ154.7,
ꢁ142.9, ꢁ137.7, ꢁ113.1; MS m/z (%) (EI): 258 (2) [M]þ, 229 (18), 215
(17),136 (11), 135 (23), 108 (14), 67 (37), 66 (36), 65 (15), 55 (23), 54
(21), 53 (35), 52 (18), 51 (10), 45 (14), 44 (12), 43 (100), 42 (14), 41
(C]N) cmꢁ1; 1H NMR (400.13 MHz, DMSO-d6)
d 8.59 (s,1H), 8.39 (s,
1H), 8.38 (s, 1H), 6.62 (s, 1H), 5.86 (s, 1H), 1.80–1.75 (m, 1H), 1.68–
(16), 40 (66); UV lmax (log
3
) (ethanol): 208 (4.44), 258 (4.20) nm.
1.61 (m, 1H), 1.38 (s, 3H), 0.86 (t, J¼7.2 Hz, 3H); 13C NMR

1704
B.A. Trofimov et al. / Tetrahedron 66 (2010) 1699–1705
(100.61 MHz, DMSO-d6)
d
164.1, 158.5, 157.8, 157.1, 127.3, 114.8, 99.2,
References and notes
74.8, 32.5, 26.7, 7.9; 15N NMR (40.56 MHz, DMSO-d6)
d
ꢁ150.2,
ꢁ147.0, ꢁ122.4, ꢁ111.7, ꢁ64.6; MS m/z (%) (EI): 259 (3) [M]þ, 230
1. Guillarme, S.; Legoupy, S.; Bourgougnon, N.; Aubertinc, A.-M.; Hueta, F. Tetra-
hedron 2003, 59, 9635 and references therein.
2. Kotian, P. L.; Satish Kumar, V.; Lin, T.-H.; El-Kattan, Y.; Ghosh, A.; Wu, M.; Cheng,
X.; Bantia, S.; Babu, Y. S.; Chand, P. Nucleosides, Nucleotides, Nucleic Acids 2006,
25, 121.
(19), 67 (12), 66 (10), 55 (20), 54 (19), 53 (44), 52 (11), 43 (100), 42
(13), 41 (11), 40 (19); UV lmax (log 3) (ethanol): 207 (4.26), 240
(4.05), 279 (3.88), 309 (3.91) nm. Anal. Calcd for C11H13N7O: C,
50.96; H, 5.05; N, 37.82. Found: C, 51.29; H, 4.95; N, 37.46.
3. Canoa, P.; Gonzalez-Moa, M. J.; Teijeira, M.; Teran, C.; Uriarte, E.; Pannecouque,
C.; De Clercq, E. Chem. Pharm. Bull. 2006, 54, 1418.
4. (a) Holy, A.; Dvorakova, N.; Jindrich, J.; Mazojidkova, M.; Budesinsky, M.; Bal-
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Zemlicka, J. Nucleosides, Nucleotides, Nucleic Acids 2007, 26, 391.
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4.4.1.3. (Z)-3-(7-Amino-2H-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-
3-(1-hydroxycyclopentyl)-2-propenenitrile 8c. Yield 119 mg, 44%,
white powder, mp 214–217 ꢀC (decomp.); IR (KBr) 3361, 3181, 3161
(NH2, OH), 3051 (C]CH), 2232 (CN), 1670, 1640, 1593 (NH2, C]C),
1566 (C]N) cmꢁ1
;
1H NMR (400.13 MHz, DMSO-d6)
d
8.57 (s, 1H),
8.40 (s, 1H), 8.38 (s, 1H), 6.70 (s, 1H), 5.73 (s, 1H), 1.95–1.59 (m, 8H);
13C NMR (100.61 MHz, DMSO-d6)
164.2, 158.8, 158.2, 157.5, 127.7,
7. Marquez, V. In Advances in Antiviral Drug Design; De Clercq, E., Ed.; JAI:
Greenwich, 1996; Vol. 2, pp 89–146.
d
115.2, 99.1, 82.5, 24.2; 15N NMR (40.56 MHz, DMSO-d6)
d
ꢁ149.8,
8. Agrofoglio, L. A.; Challand, S. R. In Acyclic, Carbocyclic and L-Nucleosides;
Townsend, L. B., Ed.; Klumer Academis: Dordrecht, 1998; Vol. 3.
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228; (d) Trofimov, B. A.; Andriyankova, L. V.; Mal’kina, A. G.; Belyaeva, K. V.;
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26. (a) Andriyankova, L. V.; Abramova, N. D.; Mal’kina, A. G.; Skvortsov, Y. M. Izv.
Acad. Nauk SSSR. Ser. Khim. 1989, 1421; (b) Abramova, N. D.; Andriyankova, L. V.;
Mal’kina, A. G.; Bel’ski, V. K.; Kositsyna, E. I.; Skvortsov, Y. M. Izv. Acad. Nauk
SSSR. Ser. Khim. 1989, 2344; (c) Trofimov, B. A.; Mal’kina, A. G.; Shemyakina, O.
A.; Borisova, A. P.; Nosyreva, V. V.; Dyachenko, O. A.; Kazheva, O. N.; Alexan-
drov, G. G. Synthesis 2007, 2641; (d) Trofimov, B. A.; Mal’kina, A. G.; Shemya-
kina, O. A.; Nosyreva, V. V.; Borisova, A. P.; Albanov, A. I.; Kazheva, O. N.;
Alexandrov, G. G.; Chekhlov, A. N.; Dyachenko, O. A. Tetrahedron 2009, 65, 2472.
ꢁ146.8, ꢁ122.2, ꢁ111.7, ꢁ64.3; MS m/z (%) (EI): 271 (5) [M]þ, 136
(34), 81 (41), 67 (32), 66 (28), 65 (23), 56 (10), 55 (39), 54 (50), 53
(100), 52 (20), 51 (15), 43 (98), 42 (63), 41 (94), 40 (55); UV lmax
(log 3) (ethanol): 209 (4.34), 240 (4.08), 309 (3.93) nm. Anal. Calcd
for C12H13N7O: C, 53.13; H, 4.83; N, 36.14. Found: C, 53.09; H, 4.96;
N, 36.28.
4.4.1.4. (Z)-3-(7-Amino-2H-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-
3-(1-hydroxycyclohexyl)-2-propenenitrile 8d. Yield 148 mg, 52%,
white powder, mp 216–220 ꢀC (decomp.); IR (KBr) 3437, 3335, 3190
(NH2, OH), 3066 (C]CH), 2227 (CN), 1671, 1643, 1605 (NH2, C]C),
1573 (C]N) cmꢁ1
;
1H NMR (400.13 MHz, DMSO-d6)
d
8.58 (s, 1H),
8.38 (s, 1H), 8.36 (s, 1H), 6.72 (s, 1H), 5.70 (s, 1H), 1.71–1.47 (m, 10H);
13C NMR (100.61 MHz, DMSO-d6)
163.3, 158.9, 158.7, 158.6, 127.8,
115.4, 100.6, 74.3, 34.8, 25.2, 21.4; 15N NMR (40.56 MHz, DMSO-d6)
d
d
ꢁ149.8, ꢁ146.8, ꢁ122.2, ꢁ111.7, ꢁ64.3; MS m/z (%) (EI): 285 (3)
[M]þ, 136 (11), 110 (10), 81 (26), 67 (22), 66 (33), 65 (12), 56 (11), 55
(44), 54 (28), 53 (62), 52 (10), 51 (10), 44 (16), 43 (51), 42 (28), 41
(79), 40 (100); UV lmax (log 3) (ethanol): 209 (4.23), 240 (3.90), 300
(3.79) nm. Anal. Calcd for C13H15N7O: C, 54.73; H, 5.30; N, 34.37.
Found: C, 54.87; H, 5.44; N, 34.43.
4.4.1.5. Reaction of the 8-azaadenine 6 with acetylene 2a in the
presence of K2CO3 in DMF. To a suspension of 8-azaadenine 6
(137 mg, 1.0 mmol), K2CO3 (11 mg, 8 mol %) in DMF (1.5 mL), the
acetylene 2a (109 mg, 1.0 mmol) in DMF (1.5 mL) was added at rt.
The reaction mixture was stirred for 1 h. The resulting mixture was
passed through neutral Al2O3 (0.5 cm, eluent: 3 mL of DMF) and
then solvent was evaporated in vacuo. The residue was treated with
diethyl ether and dried in vacuo to give 210 mg of crude product
consisting from N-8d(Z)-3-(7-amino-2H-[1,2,3]triazolo[4,5-d]pyr-
imidin-2-yl)-4-hydroxy-4-methyl-2-pentenenitrile 8a (41.5%),
N-9d(Z)-3-(7-amino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-
hydroxy-4-methyl-2-pentenenitrile 9 (35.5%) and N-7d(Z)-3-(7-
amino-1H-[1,2,3]triazolo[4,5-d]pyrimidin-1-yl)-4-hydroxy-4-methyl-
2-pentenenitrile 7 (4%) (1H NMR data), total yield 81%.
For 7: 1H NMR (400.13 MHz, DMSO-d6)
s, 1H), 8.38 (s, 1H), 6.65 (s, 1H), 5.93 (s, 1H), 1.33 (s, 6H).
For 9: 1H NMR (400.13 MHz, DMSO-d6)
8.68 (br s, 1H), 8.38 (s,
1H), 8.34 (br s, 1H), 6.70 (s, 1H), 5.93 (s, 1H), 1.33 (s, 6H); 13C NMR
(100.61 MHz, DMSO-d6) 161.8, 158.1, 156.6, 150.1, 123.1, 114.6,
d 8.68 (br s, 1H), 8.44 (br
d
d
101.1, 72.4, 28.0; 15N NMR (40.56 MHz, DMSO-d6)
d
ꢁ163.1
(2JNH¼15.9 Hz), ꢁ149.8, ꢁ144.9 (2JNH¼16.4 Hz), ꢁ122.0, ꢁ112.1.
Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (Grant No. 08-03-00156), Presidium of RAS (Program
15.9), Presidium of Department of Chemical Sciences and Materials
RAS (Grant No. 5.1.3.) and Integration Projects No. 93, 5.

B.A. Trofimov et al. / Tetrahedron 66 (2010) 1699–1705
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