Efficient synthesis of nebularine and vidarabine via dehydrazination of (hetero)aromatics catalyzed by CuSO4 in water

Article abstract of DOI:10.1039/c3gc41658e

A simple dehydrazination reaction has been achieved in the presence of a catalytic amount of CuSO₄ for the first time. With CuSO₄ (2 mol%) as a catalyst and water as a solvent, the dehydrazination products were obtained in good yields (66-95%). Moreover, the drugs nebularine and vidarabine were afforded successfully, and vidarabine could be produced on a 0.923 kg scale, which shows good potential for industrial applications.

Full text of DOI:10.1039/c3gc41658e

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Efficient synthesis of nebularine and vidarabine via
dehydrazination of (hetero)aromatics catalyzed by
CuSO4 in water†
Cite this: Green Chem., 2014, 16,
1077
Received 14th August 2013,
Accepted 16th October 2013
Ran Xia,a,b Ming-Sheng Xie,b Hong-Ying Niu,b Gui-Rong Qu*a,b and
Hai-Ming Guo*a,b
DOI: 10.1039/c3gc41658e
www.rsc.org/greenchem
A simple dehydrazination reaction has been achieved in the pres-
ence of a catalytic amount of CuSO4 for the first time. With CuSO4
(2 mol%) as a catalyst and water as a solvent, the dehydrazination
products were obtained in good yields (66–95%). Moreover, the
drugs nebularine and vidarabine were afforded successfully, and
vidarabine could be produced on a 0.923 kg scale, which shows
good potential for industrial applications.
Hydrazine chemistry is an important area in organic syn-
thesis,1 and great endeavor has been devoted to the synthesis
of substituted hydrazine compounds (R–NHNH2) starting from
amines (R–NH2), haloalkanes (R–X) and others.2a–l In compari-
son, dehydrazination reactions have been less studied.2m,n The
advantages exhibited by the dehydrazination strategy are as
follows: (a) the desired dehydrazination products (R–H) can be
afforded directly, which is important for synthetic chemistry
applications; (b) the deuterated derivatives (R–D) can be effec-
tively synthesized; (c) the deamination and dehalogenation of
amines and haloalkanes can occur indirectly; and (d) the
product (R–H) can be further functionalized via C–H activation
strategies.3 In 1978, Chattopadhyaya and Reese reported the
dehydrazination of 8-hydrazinopurine derivatives catalyzed by
an excess amount of HgO (3.8 equiv.) (Scheme 1a).4 Recently,
Česnek et al. realized the dehydrazination of 6-hydrazino-
purine derivatives promoted by Ag2O (1.2 equiv.) (Scheme 1b).5
Later, Espinosa et al. introduced a strong base (2–6 equiv.) for
the dehydrazination of N-heteroarylhydrazines (Scheme 1b).6
Obviously, the high toxicity of HgO and the excess amount
of catalyst are not suitable for green and sustainable
Scheme 1 Different methods for dehydrazination.
Fig. 1 Examples of purine nucleosides possessing antiviral activities.
development. Meanwhile, some functional groups are not
tolerant of strong base conditions. Therefore, a green method
for dehydrazination with lower catalyst loading, mild reaction
conditions and a broad substrate scope is highly desirable.
Purine nucleosides and their analogues are an integral
component of RNA and DNA, and play a significant role in the
pharmaceutical industry.7 As shown in Fig. 1, nebularine is a
naturally occurring nucleoside that inhibits growth of the
mouse tumour Sarcoma 180 and mycobacteria, and can act as
a universal base to bind with all four of the nucleosides of
DNA.8 Vidarabine is an antiviral drug which is active against
aSchool of Environment, Henan Normal University, Xinxiang, Henan province
453007, People’s Republic of China. E-mail: guohm518@hotmail.com;
Fax: (+86) 373-3329276
bSchool of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical
Media and Reactions of Ministry of Education, Henan Normal University, 46 Jianshe
Road, Xinxiang, 453007, People’s Republic of China. E-mail: quguir@sina.com;
Fax: (+86) 373-3329276
†Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, and copies of 1H and 13C NMR spectra. See DOI:
10.1039/c3gc41658e
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herpes simplex and varicella zoster viruses.9 Famciclovir has reaction temperature was examined and the results showed that
been approved by the FDA for the treatment of herpes zoster 80 °C was the best choice (entries 7 vs. 11 and 12). A blank
(commonly known as shingles) and acute recurrent genital experiment carried out without a metal salt showed that the cata-
herpes.10 The industrial production of purine analogues is lyst was essential for the reaction to occur (entry 13). Meanwhile,
usually through a dehydrazination reaction promoted by HgO when the dehydrazination reaction was performed under N2,
(Scheme 1a). As mentioned earlier, toxic mercury residue pre- only a trace amount of dehydrazination product 2a was
sents a health risk to workers and can cause serious environ- observed, which indicated that air was crucial for the dehydra-
mental pollution. To date, no better alternative suitable for zination reaction to occur (entry 14). Therefore, the optimal reac-
industrial application has been developed. Thus, we wish to tion conditions were CuSO4 (2 mol%) in water under air at 80 °C
develop a green dehydrazination process that avoids the use for 6 h.
of toxic HgO. Following on from our previous work on the
To evaluate the generality of the reaction, a number of
modification of purine analogues,11,12 herein we carried out 6-hydrazinopurine derivatives with different substituents at N9
the dehydrazination reaction using a catalytic amount of were examined. As shown in Scheme 2, the corresponding
environmentally friendly and cheap CuSO4 for the first time, dehydrazination 6-H purine derivatives were obtained in good
with water as a solvent (Scheme 1c).
to excellent yields (71–95%). The purine rings bearing
Initially, we started our study by using 9-benzyl-6-hydrazino- different N9-substitutions such as benzyl, alkyl, allyl, ribosyl,
purine (1a) as a model substrate to optimize the reaction con- deoxyribosyl and arabinofuranosyl groups all furnished the
ditions (Table 1). When AgNO3 or Mn(OAc)3 were used as target dehydrazination 6-H purine products in good yields
catalysts, only a trace amount of product 2a was observed (2a–2h). In general, the benzyl, alkyl and allyl-substituted sub-
(entries 1 and 2). Other metal salts were then tested, and FeSO4 strates gave higher yields compared to the sugar-ring substi-
and K3Fe(CN)6 could afford the dehydrazination product 2a with tuted ones (2a–2c vs. 2d–2h). When a H atom was substituted
34% and 62% yield respectively (entries 3 and 4). We were happy
to observe that a 94% yield was obtained when CuSO4 (10 mol%)
was used as a catalyst (entry 5). Remarkably, the catalytic
efficiency was also satisfactory with a lower catalyst loading of
2 mol% (entry 6). The reaction time could be shortened to 6 h
and the yield was maintained (entry 7). When the catalyst
loading was further lowered to 1 mol%, the product 2a could
still be obtained with a slightly decreased yield (entry 8). Other
copper salts including CuCl2 and CuCl were also tested, but a
decreased yield was observed (entries 9 and 10). In addition, the
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
x [mol%]
Temp. [°C]
T [h]
Yieldb [%]
1
2
3
4
5
6
7
8
AgNO3
Mn(OAc)3
FeSO4
K3Fe(CN)6
CuSO4
CuSO4
CuSO4
CuSO4
CuCl2
10
10
10
10
10
2
2
1
2
2
80
80
80
80
80
80
80
80
80
80
100
60
80
80
10
10
10
10
10
10
6
20
6
6
6
6
6
6
Trace
Trace
43
62
94
93
93
87
76
16
90
63
0
9
10
11
12
13
14c
CuCl
CuSO4
CuSO4
None
2
2
CuSO4
2
Trace
Scheme 2 Dehydrazination reaction of various 6-hydrazinopurine deriva-
tives.[a,b] [a] Reaction conditions: 1a–1p (0.25 mmol), CuSO4 (0.005 mmol),
H2O (3.0 mL), oil bath, 80 °C, 6 h. [b] Isolated yield based on 1.
a Reaction conditions: 1a (0.25 mmol), H2O (3.0 mL), under air.
b Isolated yield based on 1a. c Under N2.
1078 | Green Chem., 2014, 16, 1077–1081
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Scheme 4 Selective synthesis of deuterium-labelled compounds.[a,b]
[a] Reaction conditions: 3a–3f (0.25 mmol), CuSO4 (0.005 mmol), H2O
(3.0 mL), oil bath, 80 °C, 6 h. [b] Isolated yield based on 3.
Scheme 3 Dehydrazination of heteroaromatic substrates.[a,b] [a] Reac-
tion conditions: 3a–3j (0.25 mmol), CuSO4 (0.005 mmol), H2O (3.0 mL),
oil bath, 80 °C, 6 h. [b] Isolated yield based on 3. [c] 20 h, GC-MS yield,
100% conversion.
with a Cl or F atom at C2 in the purine derivatives, the yields
of the dehydrazination products were almost unchanged (2a
vs. 2i, 2e vs. 2k, 2g vs. 2m). When a H atom at C2 in the purine
derivatives was substituted with an amino group, excellent, if
slightly reduced, yields could still be observed (2n and 2o).
These results indicated that the catalytic system could tolerate
different functional groups successfully. Moreover, the free
nucleobase could also proceed well through the dehydrazi-
nation reaction, giving the corresponding product in a good
yield (2p).
Next, a variety of hydrazino-substituted purines and other
aromatic compounds were examined, and the results are sum-
marized in Scheme 3. 2-Hydrazinopyridine could be converted
to the corresponding pyridines in excellent yields (90% and
92%, 4a and 4b). It is worth noting that phenylhydrazines
bearing electron-withdrawing groups or electron-donating
groups could all be dehydrazinated with good yields (70–85%,
4c–4f). As far as we know, it is the first time that phenylhydra-
zines have been used as starting materials in the dehydrazina-
tion reaction. Other heteroaromatics such as benzothiazole
and pyrimidine also displayed good reaction activities (4g and
4h, 79% and 82% product yields). Removal of the hydrazino
group on the C2 or C8 position of purine nucleosides also gave
rise to the corresponding products in good yields (4i and 4j,
79% and 76%).
Scheme 5 (a) Synthesis of the drug nebularine; (b) Synthesis of the
drug vidarabine; (c) 1.5 kg scale synthesis of the drug vidarabine.
access to deuterium-labeled heteroaromatic and purine
derivatives.
This new green and efficient dehydrazination reaction was
also applied to the synthesis of nebularine and vidarabine
due to their significant antiviral activities. To our satisfac-
tion, the reaction proceeded smoothly to afford nebularine
(7) in a 73% yield (Scheme 5a) and vidarabine (9) in a 92%
yield (Scheme 5b). As shown in Scheme 5c, the reaction to
produce the drug vidarabine (9), when carried out on a
1.5 kg scale based on our method, resulted in good amounts
of the drug (0.923 kg, 71% yield, Scheme 5c). Compared to
the original industrial synthetic method that uses an excess
of HgO as the dehydrazination reagent, with Hg produced as
a side product and causing serious environmental pollu-
tion, this method shows good potential for industrial
applications.
Considering the importance of deuterium-labeled com-
pounds in mechanistic investigations, we attempted the syn-
thesis of deuterium-labeled compounds using the method
described here. When D2O was used as a solvent, the desired
deuterium-labeled compounds were obtained in good yields
(Scheme 4). Therefore, this method provides novel and rapid
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catalyst and water as a solvent, the synthesis of a series of
hydrazine-containing compounds proceeded well, affording
the dehydrazination products in good to excellent yields.
Furthermore, the catalytic system could tolerate different func-
tional groups including –F, –Cl, –NH2, alkyl, allyl, ribosyl, de-
oxyribosyl and arabinofuranosyl groups. More importantly, the
drugs nebularine and vidarabine could be obtained success-
fully, and vidarabine could even be obtained on a 0.923 kg
scale, which shows good potential for industrial applications.
In addition, deuterium-labelled compounds could be easily
obtained. This new rapid and efficient method, avoiding the
use of toxic solvents, represents a promising green route for
the dehydrazination reaction. Further studies into the mechan-
ism are currently underway.
We are grateful for financial support from the National
Natural Science Foundation of China (no. 21072047, 21172059,
21272059, 21202039, and 21372066), the Excellent Youth Foun-
dation of Henan Scientific Committee (no. 114100510012), the
Program for Innovative Research Team from the University of
Henan Province (2012IRTSTHN006), the Program for Chang-
jiang Scholars and Innovative Research Team in University
(IRT1061), the Research Fund for the Doctoral Program of
Higher Education of China (no. 20124104110006) and the
Program for Science & Technology Innovation Talents in Uni-
versities of Henan Province (no. 13HASTIT013).
Scheme 6 The isotope effects of H2O/D2O.
Finally, some experiments were designed to study the mech-
anism of the reaction. Firstly, a kinetic isotope effect (KIE)
experiment was performed (Scheme 6). The competition experi-
ments between 1a and H2O/D2O showed a primary KIE of
2.7 : 1, which indicates that the formation of C6–H in the
purine 1a is the rate-determining step of the reaction. When
the reaction to produce vidarabine (9) was performed on a
1.5 kg scale, a large amount of foam was observed (see ESI†
for details), and we propose that this foam contained N2 gas
released from the reaction. As air was crucial for the dehydrazi-
nation reaction to take place (Table 1, entry 14), the function
of air was tested. Under a N2 atmosphere, when air was
replaced by another oxidant such as K2S2O8, the reaction still
worked well (56% yield, see ESI† for details), which proved
that air functions as an oxidant. In addition, a blank exper-
iment was carried out in the absence of H2O and no product
was observed, which showed that the H atom of the C6–H
came from H2O (see ESI† for details). Although the reaction
proceeded well in the presence of excess amounts of the
radical scavenger TEMPO, the radical process could still not be
completely excluded (see ESI† for details).
Notes and references
1 B. A. Roden, “Hydrazine”, in Encyclopedia of Reagents for
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Based on the above results, a preliminary mechanism for
the dehydrazination reaction is proposed in Scheme 7. Firstly,
the hydrazine group is activated by the Cu(II) salt (Scheme 7,
A) and oxidized to the diazene intermediate B. Cu(II) is regene-
rated in the presence of air. The anion intermediate C is then
generated from diazene13 with the release of N2. Finally, the
C–H bond is formed between the anion intermediate C and
H2O to give the product 2a.
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Scheme 7 Preliminary proposal for the mechanism.
1080 | Green Chem., 2014, 16, 1077–1081
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