Green Regioselective Synthesis of (Purin-6-yl)hydrazones

Article abstract of DOI:10.1134/S1070428019100178

Some unique purine hydrazinylidene derivatives were synthesized by the regioselective reaction of 2,6-dichloropurine with hydrazine hydrate, followed by condensation with commercially available 1,3-dicarbonyl compounds according to a green chemistry approach. The structures of the synthesized compounds were confirmed by ¹H and ¹³C NMR, IR, and mass spectra and elemental analyses. The regioselectivity of chlorine substitution in 2,6-dichloropurine was established by HMBC (Heteronuclear Multiple Bond Correlation) NMR technique.

Full text of DOI:10.1134/S1070428019100178

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 10, pp. 1575–1579. © Pleiades Publishing, Ltd., 2019.
Green Regioselective Synthesis of (Purin-6-yl)hydrazones
K. M. Kapadiyaa,* J. M. Dhalania, and B. Y. Patelb
a School of Science, Department of Chemistry, Bio-Research and Characterization Laboratory,
RK University, Rajkot, Gujarat, India
*e-mail: khushal_kapadiya06@yahoo.com
b B.V. Shah (Vadivihar) Science College, Department of Chemistry, C. U. Shah University,
Wadhwancity, Surendranagar, Gujarat, India
Received April 16, 2019; revised August 9, 2019; accepted August 16, 2019
Abstract—Some unique purine hydrazinylidene derivatives were synthesized by the regioselective reaction of
2,6-dichloropurine with hydrazine hydrate, followed by condensation with commercially available 1,3-di-
carbonyl compounds according to a green chemistry approach. The structures of the synthesized compounds
1
were confirmed by H and 13C NMR, IR, and mass spectra and elemental analyses. The regioselectivity of
chlorine substitution in 2,6-dichloropurine was established by HMBC (Heteronuclear Multiple Bond Correla-
tion) NMR technique.
Keywords: 2,6-dichloropurine, regioselective synthesis, green chemistry.
DOI: 10.1134/S1070428019100178
Nucleotides are among the most crucial cellular
components for plant growth, development, and
metabolism [1]. Purines, pyrimidines, nucleosides, and
nucleotides belong to a biologically important class of
compounds [2, 3]. Analysis of the U. S. FDA-ap-
proved drugs database reveals that 59% of small mole-
cule drugs contain a nitrogen heterocycle [4]. In recent
years, purine-fused aliphatic and aromatic derivatives
have attracted considerable attention because of their
valuable biological activities, medicinal properties, and
specific conjugated structures [5, 6]. Although great
endeavors have been devoted to the synthesis of
purine-fused non-cyclic derivatives, it still remains
an important and challenging goal for chemists since
only a few data are available on such syntheses involv-
ing several steps [7].
Traditional transition metal-catalyzed cross-cou-
pling reactions [8] (Pd, Pt, Sn, B, Mg, Si, etc.) have
contributed significantly to the formation of new
carbon–carbon bonds and to the synthesis of various
C6-substituted purine derivatives [9]. In addition, the
N9-position of synthetic purines has been substituted
by different (non)functionalized aromatic, aliphatic,
alicyclic, or heterocyclic moieties, and various bio-
logical properties of the resulting compounds have
been reported [10, 11].
compounds with highly variable substituents. Taking
into account a large number of available building
blocks such as amines, hydroxy compounds, terminal
and internal alkynes, cyclic and acyclic moieties, etc.
[12], we intended to use simple precursors. Herein, we
focused our efforts on the introduction of chemical
diversity into the purine scaffold in order to obtain
biologically active compounds..
1-(2-Chloro-9H-purin-6-yl)hydrazine (2) was syn-
thesized in 98% yield by treatment of 2,6-dichloro-
purine (1) with hydrazine hydrate in the presence of
tetrabutylammonium bromide (TBAB) as phase-
transfer catalyst. The subsequent reaction of 2 with
various 1,3-dicarbonyl compounds 3a–3g in ethanol
under reflux afforded the corresponding hydrazones
4a–4g instead of expected pyrazole derivatives like 5
(Scheme 1). The reaction conditions were optimized
using the condensation of 2 and 3a as model reaction
(Table 1). The best result was achieved by heating the
reactants in boiling ethanol (80°C) for 3 h without any
catalyst (yield 92%, entry no. 1). When the reaction
was carried out in the presence of acid (concd. HCl,
TsOH, AcOH) or base catalyst [ethyl(diisopropyl)-
amine, DIPEA] in such solvents as ethanol, methanol,
THF, or DMF, the yield of 4a was poor (entry
nos. 2, 3) or no compound 4a was formed (entry
nos. 4, 5) despite prolonged reaction time (24 h). In no
case pyrazole 5 was detected in the reaction mixture.
Our goal was to develop a simple procedure
applicable for the quick preparation of diverse target
1575

KAPADIYA et al.
1576
Scheme 1.
R2
R1
R3
N
N
O
NH
N
O
O
R1
R3
N
H
Cl
NHNH2
Cl
N
N2H4·H2O
Bu4NBr, rt, 0.5 h
R2
EtOH, 80°C, 3 h
4a–4g
N
N
N
N
Unexpected Product
N
H
N
H
Cl
N
Cl
N
Me
1
2
N
OEt
N
N
N
N
Cl
N
H
5
Expected Product
R1 = Me (a, c, d, f, g), CN (b), CF3 (e); R2 = H (a–e), Me (f), F (g); R3 = OEt (a, b, d–g), pyrazin-2-yl (c), OMe (d).
The structure of hydrazones 4a–4g was confirmed
were also in agreement with the proposed hydrazone
structure.
1
by FT-IR, H and 13C NMR, and mass spectra. The
mass spectra of 4a–4g showed peaks of chlorine-con-
taining ions with an intensity ratio of 3:1 typical of the
presence of one chlorine atom. The IR spectra of
4a–4g contained absorption bands at about 3380 and
1730ꢀcm−1 assigned to stretching vibrations of the
secondary amino groups and carbonyl group, respec-
tively. The 8-H proton of the purine fragment
resonated in the 1H NMR spectrum of 4a at δ 8.4 ppm,
and no any other signal was observed in the aromatic
region, indicating the formation of hydrazone rather
than pyrazole structure. The signals at δ 12.2 and
11.1 ppm were assigned to the NH protons of the
purine (9-H) and hydrazone moieties, respectively.
Furthermore, two CH3 and two CH2 signals were
present in the aliphatic region. The 13C NMR spectra
Heteronuclear multiple-bond correlation (HMBC)
technique was utilized to determine the site of sub-
stitution of chlorine in the initial 2,6-dichloropurine
molecule. The HMBC spectrum of 4a is shown in
Fig. 1, and the observed correlations are listed in
Table 2. Only six types of protons showed correlations
with carbon nuclei. No correlations were observed for
the NH protons, whereas the 8-H proton (δ 8.41 ppm)
displayed couplings with C7, C6, and C10. The latter
correlation provides evidence for the substitution at C6.
1
The other H–13C correlations were also consistent
with the hydrazone structure of 4a.
In summary, a green chemistry procedure has been
developed for the synthesis of (2-chloro-9H-purin-6-
Table 1. Optimization of the reaction of (2-chloro-9H-purin-6-yl)hydrazine (2) with ethyl 3-oxobutanoate (3a)
Reaction time,
Yield
of 4a, %
Entry no.
Solvent/temperature, °C
Catalyst (mmol)
h
1
2
3
4
5
Ethanol/80
Ethanol/80
Methanol/70
THF/60
–
0.03.0
24
92
25
15
–
Concd. aq. HCl (0.01–0.2)
p-Toluenesulfonic acid (0.01–0.5)
Acetic acid (0.01–0.5)
24
24
DMF/110
Ethyl(diisopropyl)amine (DIPEA) (0.01–0.09)
24
–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

GREEN REGIOSELECTIVE SYNTHESIS OF (PURIN-6-YL)HYDRAZONES
1577
δC, ppm
0
40
80
120
160
200
14
12
10
8
6
4
2
δ, ppm
Fig. 1. 2D 1H–13C HMBC spectrum of 4a.
Table 2. Correlations in the 1H–13C HMBC spectrum of 4a
6
4
Me
N
2
NH
Me
N
N
10
NH
9
3
O
5
O
N
7
6
N
N
11
3
1
8
O
O
4
N
N
H
2
H1
Cl
N
Cl
N
7
5
Me
Me
1H
13C
Carbon no.
δC, ppm
Proton no.
δ, ppm
HMBC Correlations
01
02
03
04
05
06
07
08
09
10
11
145.65
060.44
043.17
016.58
014.03
151.87
108.81
151.24
149.61
161.70
170.15
1
2
3
4
5
6
7
12.232
11.108
08.411
–
–
8.41↔108.81, 8.41↔151.87, 8.41↔161.7
4.12↔14.03, 4.16↔170.15
4.103–4.156
03.719
3.72↔14.03, 3.71↔151.98, 3.71↔145.65, 3.71↔170.15
2.03↔43.17, 2.03↔145.65, 2.03↔151.24, 2.03↔170.15
1.23↔60.44
02.035
1.20–1.23
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

KAPADIYA et al.
1578
yl)hydrazones of various 1,3-dicarbonyl compounds in
89–95% yield. Spectroscopic data have confirmed the
formation of hydrazones rather than expected pyrazole
derivatives, and the regioselectivity of chlorine sub-
stitution in 2,6-dichloro-9H-purine by hydrazine has
been determined by using HMBC technique.
(C=Carom), 1367 (C–N), 1245 (C–O), 930 (δC–Harom),
788 (C–Cl). 1H NMR spectrum, δ, ppm: 12.32 s (1H,
9-H), 11.08 s (1H, 6-NH), 8.41 s (1H, 8-H), 4.12 q
(2H, OCH2), 3.71 s (2H, CH2), 2.03 s (3H, CH3), 1.23–
1.20 t (3H, CH2CH3). 13C NMR spectrum, δC, ppm:
166.97, 154.27, 149.37, 147.37, 144.36, 128.87, 127.09,
61.18, 36.37. Mass spectrum: m/z: 296.71 [M]+.
Found: C 44.54; H 4.46; Cl 11.90; N 28.32; O 10.78.
C11H13ClN6O2. Calculated, %: C 44.53; H 4.42;
Cl 11.95; N 28.32; O 10.78.
EXPERIMENTAL
All chemicals and solvents were purchased from
Sigma–Aldrich, Merck, Finar, and Spectrochem Ltd.
and were used without further purification. Thin-layer
chromatography was accomplished on 0.2-mm pre-
coated Silica gel G60 F254 plates (Merck); visualiza-
tion was made under UV light (λ 254 and 365 nm).
The IR spectra were recorded on a Shimadzu IR
Ethyl 3-[2-(2-chloro-9H-purin-6-yl)hydrazinyli-
dene]-3-cyanopropanoate (4b). Yield 93%, light
yellow powder, mp 151–154°C. IR spectrum, ν, cm–1:
3376 (N–H), 3120 (C–Harom), 2984 (C–Haliph), 2359
(C≡N), 1738 (C=O), 1628 (C=Carom), 1373 (C–N),
1
1233 (C–O), 943 (δC–Harom), 781 (C–Cl). H NMR
1
Affinity-1S spectrometer. The H and 13C NMR spec-
spectrum, δ, ppm: 12.35 s (1H, 9-H), 11.10 s (1H,
6-NH), 8.45 s (1H, 8-H), 4.09 q (2H, OCH2), 3.70 s
(2H, CH2), 1.27–1.23 t (3H, CH2CH3). 13C NMR spec-
trum, δC, ppm: 168.28, 159.27, 146.37, 143.37, 141.36,
123.09, 63.18, 35.37. Mass spectrum: m/z 307.70 [M]+.
Found: C 42.97; H 3.21; Cl 11.51; N 31.89; O 10.42.
C11H10ClN7O2. Calculated, %: C 42.94; H 3.28;
Cl 11.52; N 31.86; O 10.40.
tra were recorded on a Bruker Avance II spectrometer
at 400 and 101.1 MHz, respectively, using DMSO-d6
as solvent; the chemical shifts are referenced to tetra-
methylsilane. The mass spectra were obtained on
an Agilent 7820A/5977B GC/MS-QP instrument. Sol-
vents were evaporated with a Roteva rotary evaporator.
Melting points were measured in open capillaries and
are uncorrected. Supplementary data containing FID
files and spectra of the representative compounds are
available from the authors.
3-[2-(2-Chloro-9H-purin-6-yl)hydrazinylidene]-
1-(pyrazin-2-yl)butan-1-one (4c). Yield 95%, dark
yellow powder, mp 156–159°C. IR spectrum, ν, cm–1:
3372 (N–H), 3121 (C–Harom), 2998 (C–Haliph), 1724
(C=O), 1687 (C=N), 1623 (C=Carom), 1361 (C–N), 913
(δC–Harom), 785 (C–Cl). 1H NMR spectrum, δ, ppm:
12.29 s (1H, 9H), 11.11 s (1H, 6-NH); 8.97 s, 8.69 d,
and 8.61 d (1H each, pyrazine); 8.43 s (1H, 8-H),
3.78 s (2H, CH2), 2.13 s (3H, CH3). 13C NMR
spectrum, δC, ppm: 182.82, 166.97, 153.27, 148.37,
147.20, 144.86, 128.97, 126.99, 55.18, 26.37. Mass
spectrum: m/z: 330.73 [M]+. Found, %: C 47.20;
H 3.30; Cl 10.74; N 33.86; O 4.90. C13H11ClN8O.
Calculated, %: C 47.21; H 3.35; Cl 10.72; N 33.88;
O 4.84.
1-(2-Chloro-9H-purin-6-yl)hydrazine (2). A mix-
ture of 2,6-dichloro-9H-purine (0.5 mmol), hydrazine
hydrate (0.98 mL), and tetrabutylammonium bromide
(TBAB) (0.003 mmol) was stirred at room temperature
for 30 min. The originally light yellow colour changed
to dark yellow after reaction completion (TLC, ethyl
acetate–hexane, 3:7). The mixture was poured into ice
water and stirred at room temperature for 20 min, and
1
the precipitate was filtered off and dried. H NMR
spectrum, δ, ppm: 12.50 br.s (1H, 9-H), 9.16 s (1H,
6-NH), 8.12 s (8-H), 5.00–4.59 br.s (2H, NH2). Mass
spectrum: m/z 184.59 [M]+.
Compounds 4a–4g (general procedure). A mixture
of 2 (0.54 mmol) and 1,3-dicarbonyl compound 3a–3g
(0.54 mmol) in ethanol was stirred at 80°C for 3 h.
After completion of the reaction (TLC), the mixture
was poured into ice water, and the solid was filtered
off, dried, and purified by silica gel column chroma-
tography (60–120 mesh) using ethyl acetate–hexane
(2:8) as eluent.
Methyl 3-[2-(2-chloro-9H-purin-6-yl)hydra-
zinylidene]butanoate (4d). Yield 89%, dark yellow
powder, mp 148–149°C. IR spectrum, ν, cm–1: 3396
(N–H), 3114 (C–Harom), 2978 (C–Haliph), 1727 (C=O),
1620 (C=Carom), 1373 (C–N), 1236 (C–O), 1141
1
(C–O), 925 (δC–Harom), 785 (C–Cl). H NMR spec-
trum, δ, ppm: 12.38 s (1H, 9-H), 11.07 s (1H, 6-NH),
8.43 s (1H, 8-H), 3.73 s (2H, CH2), 2.13 s (3H, CH3),
1.18–1.10 s (3H, OCH3). 13C NMR spectrum, δC, ppm:
167.97, 156.17, 150.27, 145.21, 144.96, 129.83,
123.29, 62.88, 35.48. Mass spectrum: m/z 282.69 [M]+.
Found, %: C 42.47; H 3.95; Cl 12.56; N 29.70;
Ethyl 3-[2-(2-chloro-9H-purin-6-yl)hydrazinyli-
dene]butanoate (4a). Yield 95%, light yellow powder,
mp 146–148°C. IR spectrum, ν, cm–1: 3486 (N–H),
3124 (C–Harom), 2978 (C–Haliph), 1778 (C=O), 1638
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

GREEN REGIOSELECTIVE SYNTHESIS OF (PURIN-6-YL)HYDRAZONES
O 11.32. C10H11ClN6O2. Calculated, %: C 42.49;
1579
ACKNOWLEDGMENTS
H 3.92; Cl 12.54; N 29.73; O 11.32.
This work was supported by RK University, Rajkot and
C. U. Shah University, Wadhwancity, as a collaboration of
faculty exchange program.
Ethyl 3-[2-(2-chloro-9H-purin-6-yl)hydrazinyli-
dene]-4,4,4-trifluorobutanoate (4e). Yield 94%, light
yellow powder, mp 157–160°C. IR spectrum, ν, cm–1:
3376 (N–H), 3111 (C–Harom), 2982 (C–Haliph), 1725
(C=O), 1628 (C=Carom), 1375 (C–F), 1361 (C–N),
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
1
1236 (C–O), 930 (δC–Harom), 785 (C–Cl). H NMR
spectrum, δ, ppm: 12.31 s (1H, 9-H), 11.18 s (1H,
6-NH), 8.43 s (1H, 8-H), 4.16 q (2H, OCH2), 3.69 s
(2H, CH2), 1.25–1.21 t (3H, CH2CH3). 13C NMR spec-
trum, δC, ppm: 170.25, 153.27, 151.47, 145.97, 142.76,
129.07, 126.19, 61.18, 46.37. Mass spectrum:
m/z 350.68 [M]+. Found, %: C 37.68; H 2.82; Cl 10.19;
F 16.22; N 23.94; O 9.15. C11H10ClF3N6O2. Cal-
culated, %: C 37.67; H 2.87; Cl 10.11; F 16.25;
N 23.96; O 9.12.
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Ethyl 3-[2-(2-chloro-9H-purin-6-yl)hydrazinyli-
dene]-2-methylbutanoate (4f). Yield 92%, dark
yellow powder, mp 145–148°C. IR spectrum, ν, cm–1:
3387 (N–H), 3109 (C–Harom), 2972 (C–Haliph), 1718
(C=O), 1613 (C=Carom), 1376 (C–N), 1232 (C–O), 925
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1
(δC–Harom), 785 (C–Cl). H NMR spectrum, δ, ppm:
12.29 s (1H, 9-H), 11.07 s (1H, 6-NH), 8.45 s (1H,
8-H), 4.16 q (2H, OCH2), 3.76 q (1H, CH), 2.09 s
(3H, CH3), 1.55 d (3H, CH3), 1.24 t (3H, CH2CH3).
13C NMR spectrum, δC, ppm: 177.63, 166.27, 154.21,
149.57, 149.87, 143.66, 129.87, 128.09, 61.18, 41.34,
36.37. Mass spectrum: m/z 310.74 [M]+. Found, %:
C 46.40; H 4.86; Cl 11.42; N 27.01; O 10.31.
C12H15ClN6O2. Calculated, %: C 46.38; H 4.87;
Cl 11.41; N 27.05; O 10.30.
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Ethyl 3-[2-(2-chloro-9H-purin-6-yl)hydrazinyli-
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3386 (N–H), 3119 (C–Harom), 2982 (C–Haliph), 1718
(C=O), 1620 (C=Carom), 1373 (C–N), 1352 (C–F),
1
1232 (C–O), 933 (δC–Harom), 786 (C–Cl). H NMR
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6-NH), 8.39 s (1H, 8-H), 4.15 q (2H, OCH2), 3.77 s
(1H, CH), 2.03 s (3H, CH3), 1.23 t (3H, CH2CH3).
13C NMR spectrum, δC, ppm: 170.45, 165.97, 154.77,
149.57, 147.27, 145.96, 129.27, 121.92, 61.28, 36.47.
Mass spectrum: m/z 314.70 [M]+. Found: C 41.97;
H 3.84; Cl 11.29; F 6.02; N 26.72; O 10.16.
C11H12ClFN6O2. Calculated, %: C 41.98; H 3.84;
Cl 11.27; F 6.04; N 26.70; O 10.17.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019