Green synthetic method for 1,5-disubstituted carbohydrazones

Article abstract of DOI:10.1080/00397910600764600

A green synthetic method for 1,5-disubstituted carbohydrazones is described. The reaction of dimethyl carbonate with hydrazine hydrate first gave carbohydrazide, which further reacted with various aromatic aldehydes or aliphatic ketones under solvent-free conditions to efficiently afford 1,5-disubstituted carbohydrazone. This protocol has the advantages of using nontoxic dimethyl carbonate as starting material, no use of organic solvents, short reaction time, high yield, and simple workup procedure. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600764600

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Green Synthetic Method for 1,5‐Disubstituted
Carbohydrazones
Zheng Li a , Wei Zhu a , Jinlan Yu a , Xuelin Ma a , Zhong Lu a & Shuxiu Xiao a
a Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, China
Available online: 16 Feb 2007
To cite this article: Zheng Li, Wei Zhu, Jinlan Yu, Xuelin Ma, Zhong Lu & Shuxiu Xiao (2006): Green Synthetic
Method for 1,5‐Disubstituted Carbohydrazones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:18, 2613-2619
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Synthetic Communicationsw, 36: 2613–2619, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600764600
Green Synthetic Method for
1,5-Disubstituted Carbohydrazones
Zheng Li, Wei Zhu, Jinlan Yu, Xuelin Ma, Zhong Lu,
and Shuxiu Xiao
Gansu Key Laboratory of Polymer Materials, College of Chemistry
and Chemical Engineering, Northwest Normal University, Lanzhou,
Gansu, China
Abstract: A green synthetic method for 1,5-disubstituted carbohydrazones is
described. The reaction of dimethyl carbonate with hydrazine hydrate first gave carbo-
hydrazide, which further reacted with various aromatic aldehydes or aliphatic ketones
under solvent-free conditions to efficiently afford 1,5-disubstituted carbohydrazone.
This protocol has the advantages of using nontoxic dimethyl carbonate as starting
material, no use of organic solvents, short reaction time, high yield, and simple
workup procedure.
Keywords: Carbohydrazide, carbohydrazone, dimethyl carbonate, solvent-free
INTRODUCTION
Dimethyl carbonate (DMC) can be used as a carbonylating, methylating, and
methoxycarbonylating agent. Compared with general carbonylating or
methylating agents, such as phosgene, dimethyl sulfate, and methyl halides,
DMC is a nontoxic, environmentally benign reagent.[1] Therefore, it is
necessary to explore the application of DMC in organic synthesis.
Hydrazone derivatives are reported to possess a wide range of biological
activities, such as antituberculosis,[2] antimicrobial,[3] and anticonvulsant[4]
activities. However, to the best of our knowledge, carbohydrazone derivatives
Received in Japan January 15, 2006
Address correspondence to Zheng Li, Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, China. E-mail: lizheng@nwnu.edu.cn
2613

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Z. Li et al.
are not reported anywhere. In continuation of our effort to explore the utiliz-
ation of DMC and develop a green route for biologically active compounds,
herein we report the synthesis of a series of 1,5-disubstituted carbohydrazones
under solvent-free conditions using DMC as starting material.
RESULTS AND DISCUSSION
The commercially available DMC reacted with equivalent of hydrazine
hydrate for 4 h to first give methyl hydrazinoformate as an intermediate via
releasing methanol. After removing methanol from the reaction system, the
intermediate further reacted with excess of hydrazine hydrate for another
4 h to give carbohydrazide (1) in 86% yield. It is important to note that the
one-pot reaction of DMC with 2 equiv of hydrazine hydrate often leads to
low yield of product. Removal of formed methanol from the reaction
system is necessary for improving reaction yield.
The resulting carbohydrazide (1) was ground with aromatic aldehydes or
aliphatic ketones in a mortar with pestle at room temperature without any
solvents for 2–8 min to afford 1,5-disubstituted carbohydrazones (2a–q) in
very high yield (Scheme 1, Table 1).
It is noteworthy that the current method can be efficiently applied to all
aromatic aldehydes, although the reaction rates of liquid aldehydes (2a,
2c–f, and 2 k–n) are faster than solid ones (2b, 2g–j). For the aliphatic
aldehyde, such as formaldehyde and acetaldehyde, the reactions often lead
to products difficult to identify.
The current method can also be applied to aliphatic ketones. The less
sterically hindered aliphatic ketones can readily react with carbohydrazide
to give corresponding carbohydrazones in high yield (2o–q). However, the
more hindered aromatic ketones, such as acetophenone, 4-methoxyacetophe-
none, and 4-chloroacetophenone, cannot give any desired products under
similar conditions.
To compare the solvent-free method with solution method, the selected
reactions were investigated using the conventional refluxing method in a
solution of ethanol. However, the solution method takes much longer to
complete the reactions, and the yields are often lower than the corresponding
solvent-free reactions (Table 2).
The resulting compounds 2a–q are highly soluble in hot DMF, slightly
soluble in ethanol, and insoluble in acetone, chloroform, and dichloromethane.
Scheme 1.

1,5-Disubstituted Carbohydrazones
2615
Table 1. Green synthesis of compounds 2a–q
Yield
(%)a
Time
(min)
Mp
(8C)
Compound
R1
R2
2a
2b
2c
2d
2e
2f
2-HO-C6H4
4-HO-C6H4
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
96
94
97
97
97
92
94
93
90
92
95
96
96
95
2
6
3
3
4
3
6
7
8
7
5
4
4
5
235–236
220–224
210–212
197–198
187–188
212–214
244–246
247–245
235–236
236–237
198–200
148–150
112–114
184–186
2-CH3O-C6H4
3-CH3O-C6H4
2-Cl-C6H4
2g
2h
2i
4-Cl-C6H4
2,4-Cl2C6H3
3-CH3O-4-OH-C6H3
4-Br-C6H4
2j
2k
2l
4-C2H5O-C6H4
4-(n-C4H9O)-C6H4
4-(n-C6H13O)-C6H4
2m
2n
2o
2p
2q
CH3
–(CH2)4–
–(CH2)5–
CH3
99
97
96
4
4
5
126–128
208–210
180–181
aYields refer to isolated products.
1
All structures of the compounds 2a–q were identified by H NMR, IR, and
elemental analyses. The IR spectra of compounds 2a–q show the character-
istic absorptions at 3087–3229 cm21 for N-H and 1681–1718 cm21 for
1
C55O. The H NMR spectra of compounds 2a–q in DMSO-d6 show proton
peaks at d ¼ 9.32–10.84 for NH and d ¼ 8.10–8.25 for 55CH.
Table 2. Comparison of the solvent-free method with the solution method
Solution method
Solvent-free method
Time (min)
Yield (%)a
Compd.
Time (h)
Yield (%)a
2a
2d
2f
4
5
5
8
7
5
6
87
89
85
80
81
85
86
2
96
3
3
8
7
4
5
97
92
90
92
99
96
2i
2j
2o
2q
aYields refer to isolated products.

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Z. Li et al.
In conclusion, we have developed a green synthetic method for 1,5-disub-
stituted carbohydrazones in solvent-free conditions. This protocol has advan-
tages of using the green reagent DMC as starting material, no use of organic
solvents, mild reaction conditions, short reaction time, high yield, and simple
workup procedure.
EXPERIMENTAL
IR spectra were recorded using KBr pellets on a Digilab 300 FTIR spectropho-
tometer and 1H NMR spectra on a Mercury-400BB instrument using
(CD3)2SO as solvent and Me4Si as internal standard. Elemental analyses
were performed on a Vario E1 Elemental Analysis instrument. Mass spectra
were recorded on a QP-1000A GC-MS using the impact mode (70 eV).
Melting points were observed in an electrothermal melting-point apparatus
and uncorrected.
Preparation of Carbohydrazide (1)
The mixture of DMC (0.09 mol) and hydrazine hydrate (0.10 mol) was stirred
at 708C for 4 h. The reaction was monitored by TLC. Then the librated
methanol, water, and excess of DMC were removed under reduced pressure.
To the residue, additional hydrazine hydrate (0.22 mol) was added. The
mixture was stirred at 708C for another 4 h. Then the resulting solution was
distilled under reduced pressure until the white solid appeared; the residue
was cooled slowly and the formed crystal was collected by filtration and
dried to give product. Yield: 86%. Mp: 152–1538C.
General Procedure for the Preparation of 1,5-Disubstituted
Carbohydrazones (2a–q)
The mixture of carbohydrazide (1 mmol) and an appropriate aromatic
aldehyde or aliphatic ketone (2.2 mmol) was ground in a mortar by pestle at
room temperature. After 2–8 min, the mixture was washed with acetone,
and the solid was recrystallized from DMF-H2O to give the product.
Data
2a: IR (KBr, n, cm21): 3210, 3146 (N-H), 1700 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.77 (s, 2H, NH), 8.16 (s, 2H,55CH), 6.63–7.02 (m, 8H, Ar-H).
MS: m/z, 298 (Mþ). Anal. calcd. for C15H14N4O3: C, 60.40; H, 4.73; N, 18.78.
Found: C, 60.35; H, 4.68; N, 18.81.

1,5-Disubstituted Carbohydrazones
2617
2b: IR (KBr, n, cm21): 3214, 3151 (N-H), 1703 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.78 (s, 2H, NH), 8.17 (s, 2H,55CH), 6.63–7.03 (m, 8H, Ar-H).
MS: m/z, 298 (Mþ). Anal. calcd. for C15H14N4O3: C, 60.40; H, 4.73; N, 18.78.
Found: C, 60.45; H, 4.66; N, 18.74.
2c: IR (KBr, n, cm21): 3202, 3134 (N-H), 1695 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.74 (s, 2H, NH), 8.12 (s, 2H, 55CH), 6.60–7.00 (m, 10H, Ar-
H). MS: m/z, 266 (Mþ). Anal. calcd. for C15H14N4O: C, 67.65; H, 5.30; N,
21.04. Found: C, 67.58; H, 5.27; N, 21.10.
2d: IR (KBr, n, cm21): 3220, 3158 (N-H), 1707 (C55O). 1H NMR
(400 MHz, DMSO-d6) d 10.75 (s, 2H, NH), 8.15 (s, 2H, 55CH), 6.90–
7.35 (m, 8H, Ar-H), 3.79 (s, 6H, OCH3). MS: m/z, 326 (Mþ). Anal. calcd.
for C17H18N4O3: C, 62.57; H, 5.56; N, 17.17. Found: C, 62.51; H, 5.50;
N, 17.22.
2e: IR (KBr, n, cm21): 3218, 3156 (N-H), 1706 (C55O). 1H NMR
(400 MHz, DMSO-d6) d 10.74 (s, 2H, NH), 8.14 (s, 2H, 55CH), 6.92–
7.34 (m, 8H, Ar-H), 3.78 (s, 6H, OCH3). MS: m/z, 326 (Mþ). Anal.
calcd. for C17H18N4O3: C, 62.57; H, 5.56; N, 17.17. Found: C, 62.64; H,
5.59; N, 17.12.
2f: IR (KBr, n, cm21): 3216, 3153 (N-H), 1705 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.79 (s, 2H, NH), 8.18 (s, 2H,55CH), 6.64–7.05 (m, 8H, Ar-H).
MS: m/z, 334 (Mþ). Anal. calcd. for C15H12Cl2N4O: C, 53.75; H, 3.61; N,
16.72. Found: C, 53.67; H, 3.66; N, 16.68.
2g: IR (KBr, n, cm21): 3217, 3154 (N-H), 1706 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.79 (s, 2H, NH), 8.19 (s, 2H,55CH), 6.65–7.06 (m, 8H, Ar-H).
MS: m/z, 334 (Mþ). Anal. calcd. for C15H12Cl2N4O: C, 53.75; H, 3.61; N,
16.72. Found: C, 53.84; H, 3.57; N, 16.77.
2h: IR (KBr, n, cm21): 3229, 3166 (N-H), 1718 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.84 (s, 2H, NH), 8.25 (s, 2H,55CH), 6.67–7.09 (m, 6H, Ar-H).
MS: m/z, 402 (Mþ). Anal. calcd. for C15H10Cl4N4O: C, 44.59; H, 2.49; N,
13.87. Found: C, 44.51; H, 2.53; N, 13.93.
2i: IR (KBr, n, cm21): 3227, 3166 (N-H), 1715 (C55O). 1H NMR
(400 MHz, DMSO-d6) d 10.80 (s, 2H, NH), 8.20 (s, 2H, 55CH), 6.95–
7.37 (m, 6H, Ar-H), 3.84 (s, 6H, OCH3). MS: m/z, 358 (Mþ). Anal.
calcd. for C17H18N4O5: C, 56.98; H, 5.06; N, 15.63. Found: C, 56.91; H,
5.09; N, 15.57.
2j: IR (KBr, n, cm21): 3223, 3160 (N-H), 1712 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.81 (s, 2H, NH), 8.22 (s, 2H,55CH), 6.66–7.07 (m, 8H, Ar-H).

2618
Z. Li et al.
MS: m/z, 422 (Mþ). Anal. calcd. for C15H12Br2N4O: C, 42.48; H, 2.85; N,
13.21. Found: C, 42.55; H, 2.91; N, 13.16.
2k: IR (KBr, n, cm21): 3219, 3157 (N-H), 1706 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.74 (s, 2H, NH), 8.14 (s, 2H,55CH), 6.88–7.33 (m, 8H, Ar-H),
3
3
4.04 (q, 4H, J ¼ 6.8 Hz, OCH2), 1.34 (t, 4H, J ¼ 6.8 Hz, CH3). MS: m/z,
354 (Mþ). Anal. calcd. for C19H22N4O3: C, 64.39; H, 6.26; N, 15.81.
Found: C, 64.44; H, 6.20; N, 15.77.
2l: IR (KBr, n, cm21): 3217, 3155 (N-H), 1704 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.72 (s, 2H, NH), 8.12 (s, 2H,55CH), 6.85–7.30 (m, 8H, Ar-H),
4.00 (t, 4H, OCH2), 1.34–1.73 (m, 8H, CH2), 0.98 (t, 6H, CH3). MS: m/z, 410
(Mþ). Anal. calcd. for C23H30N4O3: C, 67.29; H, 7.37; N, 13.65. Found: C,
67.21; H, 7.43; N, 13.71.
2m: IR (KBr, n, cm21): 3214, 3152 (N-H), 1702 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.70 (s, 2H, NH), 8.10 (s, 2H,55CH), 6.83–7.28 (m, 8H, Ar-H),
3.97 (t, 4H, OCH2), 1.30–1.72 (m, 16H, CH2), 0.97 (t, 6H, CH3). MS: m/z,
466 (Mþ). Anal. calcd. for C27H38N4O3: C, 69.50; H, 8.21; N, 12.01.
Found: C, 69.43; H, 8.14; N, 12.10.
2n: IR (KBr, n, cm21): 3203, 3135 (N-H), 1696 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 10.75 (s, 2H, NH), 8.13 (s, 2H,55CH), 6.31–7.01 (m, 6H, Fu-H).
MS: m/z, 246 (Mþ). Anal. calcd. for C11H10N4O3: C, 53.66; H, 4.09; N, 22.75.
Found: C, 53.58; H, 4.13; N, 22.83.
2o: IR (KBr, n, cm21): 3197, 3094 (N-H), 1688 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 9.39 (s, 2H, NH), 0.94 (s, 12H, CH3). MS: m/z, 170 (Mþ). Anal.
calcd. for C7H14N4O: C, 49.39; H, 8.29; N, 32.92. Found: C, 49.47; H, 8.33; N,
32.89.
2p: IR (KBr, n, cm21): 3194, 3090 (N-H), 1686 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 9.37 (s, 2H, NH), 1.05–1.57 (m, 16H, CH2). MS: m/z, 222 (Mþ).
Anal. calcd. for C11H18N4O: C, 59.44; H, 8.16; N, 25.20. Found: C, 59.38; H,
8.20; N, 25.16.
2q: IR (KBr, n, cm21): 3191, 3087 (N-H), 1681 (C55O). 1H NMR (400 MHz,
DMSO-d6) d 9.32 (s, 2H, NH), 1.01–1.61 (m, 20H, CH2). MS: m/z, 250 (Mþ).
Anal. calcd. for C13H22N4O: C, 62.37; H, 8.86; N, 22.38. Found: C, 62.33; H,
8.82; N, 22.41.
ACKNOWLEDGMENT
The authors thank the Chunhui Project of Ministry of Education of China
(Z2004-1-62034) for the financial support of this work.

1,5-Disubstituted Carbohydrazones
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