A novel, one-pot synthesis of α-C-cyanohydrazines in the presence of lithium perchlorate/diethylether solution (5.0 M)

Article abstract of DOI:10.1246/cl.2002.368

Condensation of N,N-dimethylhydrazine, an aldehyde in lithium perchlorate/diethylether solution (5.0 M) gave N,N-dimethylhydrazone, which were treated with trimethylsilylcyanide to afford α-C-cyanohydrazine. These compounds are important precursors of nitrogen-substituted reagents.

Full text of DOI:10.1246/cl.2002.368

368
Chemistry Letters 2002
A Novel, One-Pot Synthesis of ꢀ-C-Cyanohydrazines in the Presence of
Lithium Perchlorate/Diethylether Solution (5.0 M)
Akbar Heydari,ꢀ Robabe Baharfar,y Mohsen Rezaie, and Saied M. Aslanzadeh
Chemistry Department, Tarbiat Modarres University, P. O. Box 14155-4838, Tehran, Iran
yChemistry Department, Mazandaran University, Babolsar, Iran
(Received November 14, 2001; CL-011151)
Condensation of N; N-dimethylhydrazine, an aldehyde in
hydrazine 2 and trimethylsilylcyanide 3 in LPDE (5.0M)
solution, which yield ꢀ-C-cyanohydrazines 4 in a one-pot
procedure, within 30min in high yields. 11 The N-N bond can
then be cleaved under reductive conditions to obtain the ꢀ-
aminonitriles. Hydrazones can therefore be regarded as stable
equivalents of imines derived from ammonia. ꢀ-C-Cyanohydra-
zines might be transformed further into ꢀ-hydrazino carboxylic-
acids and ꢀ-amino acids. To the best of our knowledge, only a few
synthesis of ꢀ-C-cyanohydrazines have been reported in the
literature: three-component condensation of carbonyl group,
sodium cyanide and N2H4. sulfate.12 Withoutlithium perchlorate/
diethylether solution, no product was observed even after 4 h.13
Several examples of the present three component coupling
reactions are summarized in Scheme 1.
lithium perchlorate/diethylether solution (5.0M) gave N; N-
dimethylhydrazone, which were treated with trimethylsilyl-
cyanide to afford ꢀ-C-cyanohydrazine. These compounds are
important precursors of nitrogen-substituted reagents.
The addition of nucleophilic reagents to the C¼N bonds of
imines or imine derivatives (iminium salts, acylimines, sulfoni-
mines, nitrones, oximes and hydrazones) is an old and well-
known reaction. In comparison to nucleophilic addition to
carbonyl compounds, the aza-analogous reaction has been
investigated much less. The poor electrophilicity of the imino
group, the abstraction of acidic ꢀ-protons forming an azaenolate,
are some general problems. To circumvent these problems, a
variety of methods have been developed. For example, activation
of the C¼N bond of imines or imines derivatives by coordination
of Lewis acid with the nitrogen lone pair or by addition of external
promoters.1 It would be difficult to extend the Lewis acids
catalyzed nucleophilic addition to imine derivatives. In addition it
cannot proceed a one-pot reaction from aldehydes and has to start
from imines because the amines and water that exist during imine
formation can decompose or deactivate many Lewis acids.2
Mannich-type reactions (a three-component condensation
reactions) is interesting and important, not only because two
bonds are formed in one-pot, but also because the methodology
would be useful for making a broad variety of compound
libraries.3 The classical intermolecular three-component Man-
nich reaction is, however, plagued by a number of serious
disadvantages:4 Due to the drastic reaction conditions unwanted
side reactions often take place. Major problems here are
deamination and formation of methylene bisketones. If one uses
a primary amine, reaction can continue until all the H atoms on the
nitrogen are replaced. Additionally, and with very few excepta-
tions, one can only use formaldehyde. Due to the very attractive
nature of Mannich bases, there have been many attempts to find
alternative synthetic routes to these compounds, which do not
suffer the severe drawbacks of the classical procedure. It has been
reported that the Mannich-type three-component condensation
reactions of aldehydes, N; N-dimethyltrimethylsilylamine and
nucleophiles such as diethylzinc take place in lithium perchlorate/
diethylether solution5 (5.0M) to yield amines 6 respectively. This
method allows, at least in principle, all the limitations of the
classical Mannich reaction to be overcome. The level of
performance and the versatility of this method has already been
powerfully demonstrated in the synthesis of ꢀ-aminonitriles,7 ꢀ-
aminophosphonates,8 ꢀ-cyanohydroxylamine,9 N-trimethylsi-
lyl-oxy-ꢀ-aminophosphonates10 respectively. In this paper, we
report the condensation reactions of aldehydes 1, N; N-dimethyl-
Scheme 1.
This method seems to be a general synthetic route to ꢀ-
hydrazinonitriles. Unfortunately benzaldehyde, p-methoxy benz-
aldehyde, 3-pyridine carbaldehyde, furfural and cinnamaldehyde
are not amerable to the cyanation condition used in the one-pot
cyanohydrazination.14 Additionally, we found that cyanohydra-
zination of an aliphatic aldehyde rather than an aromatic was
performed in more than 99% selectivity. The reaction of
isobutyraldehyde, 3-pyridine carbaldehyde with N; N-dimethyl-
hydrazine and trimethylsilylcyanide in 5.0M LPDE solution give
ꢀ-C-cyanohydrazine 4 and 3-pyridinehydrazone 5, respectively.
In conclusion, we have observed a three-component
condensation reaction that offers an easy and effective one-pot
synthesis of ꢀ-C-Cyanohydrazines which are potentially might
be transformed further into ꢀ-hydrazino carboxylic acids and ꢀ-
amino acids. Further synthetic and asymmetric applications of the
reaction are now in progress in our laboratory.
Research supported by the National Research Council of
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
369
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I. R. Iran as a National Research project under the number 984.
6
7
References and Notes
1
2
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8
9
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3
4
5
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11 A typical experimental procedure, to a mixture of aldehyde
(2 mmol) in 5 M LPDE (4 ml) was added N; N-dimethyl-
hydrazine (2.2 mmol) at room temperature. The mixture was
stirred for 15 min. and trimethylsilylcyanide (2.2 mmol) was
added. The mixture was stirred for 15 min then water was
added and the product was extracted with CH2Cl2. The
organic phase was collected, dried (Na2SO4) and evaporated
to afford the crude product. The product was purified by flash
chromatography (hexan-ethyl acetate). 1H-NMR, 13C-NMR,
IR and MS spectra were entirely consistent with the assigned
structures. selected data as follow: 4a (R1 ¼ Methyl) 1H-
In recent years, lithium perchlorate in diethyl ether (LPDE)
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NMR (90MHz, CDCl Þ: ꢁ ¼ 3:8 (m, 1H, H1), 3.1 (bs, 1H,
3
NH), 2.6 (s, 6H, NCH3), 1.4 (d, JH-H ¼ 9 Hz, 3H, CH3); 13C-
NMR (22.5 MHz, CDCl3): ꢁ ¼ 121:26 (CN), 48.17 (NCH3),
45.64 (CH), 17.54(CH3); 4b (R1 ¼ Ethyl) 1H-NMR
2
(90MHz, CDCl 3): ꢁ ¼ 3:7 (t, JH-H ¼ 9 Hz, 1H, H1), 3.0
(bs, 1H, NH), 2.6 (s, 6H, NCH3), 1.8 (q, JH-H ¼ 9 Hz, 2H), 1.1
(t, JH-H ¼ 9 Hz, 3H); 13C-NMR (22.5 MHz, CDCl3): ꢁ ¼
120:7 (CN), 52.5 (CH), 48.3 (NCH3), 25.0(CH 2), 9.8 (CH3);
1
1
4c (R ¼ i-Propyl): H-NMR (90MHz, CDCl 3) ꢁ ¼ 3:5 (d,
JH-H ¼ 9 Hz, 1H, H1), 3.1 (bs, 1H, NH), 2.5 (s, 6H, NCH3),
1.9 (m, 1H, H2), 1.1 (d, JH-H ¼ 9 Hz, 3H, CH3Þ, 0.9 (d,
JH-H ¼ 9 Hz, 3H, CH3); 13C-NMR (22.5 MHz, CDCl3)
ꢁ ¼ 119:8 (CN), 57.6 (CH), 48.0(NCH ), 30.0 (CH), 19.1
3
(CH3), 18.0(CH 3).
12 C. G. Overberger, P.-T. Huang, and M. B. Berenbum, Organic
Synthesis, 4, 274 (1963), In the course of our studies a paper
appeared where hydrazones, generated in situ from aldehyde
and acylhydrazones in the presence of Lewis acids, were
condensed with allylsilane: S. Kobayashi, T. Hamada, and K.
Manabe, Synlett, 2001, 1140.
13 When a solution of aldehyde and N; N-dimethylhydrazine
was treated with trimethylsilylcyanide in diethylether atroom
temperature for 3 h, the corresponding hydrazone product was
obtained with high yield.
14 Cyanohydrazination of aldehydes (R1 ¼ Phenyl, p-MeO-
phenyl, 2-Furyl, 3-Pyridyl, trans-PhCH¼CH) afforded the
corresponding hydrazones in high yield.