The Reaction of Hydrazine with α-Cyanocinnamate Esters: A Caveat

Article abstract of DOI:10.1081/SCC-120028648

α-Cyanocinnamate esters react with hydrazine to give initial products of conjugate addition that then undergo a fragmentation to give the azine of the carbonyl precursor to the starting ester, rather than intramolecular aminolysis to give the pyrazolidino

Full text of DOI:10.1081/SCC-120028648

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The Reaction of Hydrazine with α‐Cyanocinnamate
Esters: A Caveat
Paul J. Erdman a , Jimmy L. Gosse a , Jamey A. Jacobson a & David E. Lewis a
a Department of Chemistry , University of Wisconsin—Eau Claire , Eau Claire, Wisconsin,
54702‐4004, USA
Published online: 21 Aug 2006.
To cite this article: Paul J. Erdman , Jimmy L. Gosse , Jamey A. Jacobson & David E. Lewis (2004) The Reaction of
Hydrazine with α‐Cyanocinnamate Esters: A Caveat, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:6, 1163-1171, DOI: 10.1081/SCC-120028648
To link to this article: http://dx.doi.org/10.1081/SCC-120028648
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 1163–1171, 2004
The Reaction of Hydrazine with
a-Cyanocinnamate Esters:
A Caveat
Paul J. Erdman, Jimmy L. Gosse, Jamey A. Jacobson,
*
and David E. Lewis
Department of Chemistry, University of Wisconsin—Eau Claire,
Eau Claire, Wisconsin, USA
ABSTRACT
a-Cyanocinnamate esters react with hydrazine to give initial products of
conjugate addition that then undergo a fragmentation to give the azine of
the carbonyl precursor to the starting ester, rather than intramolecular
aminolysis to give the pyrazolidinone.
Key Words: Addition reactions; Retro reactions; Cleavage; Cyanocin-
namates; Hydrazine; Azines.
*
Correspondence: David E. Lewis, Department of Chemistry, University of
Wisconsin—Eau Claire, Eau Claire, WI 54702-4004, USA; E-mail: lewis@uwec.edu.
1163
DOI: 10.1081/SCC-120028648
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Erdman et al.
INTRODUCTION
Pyrazoles and pyrazolones have become increasingly popular as ligands
for metals in model systems for enzyme active sites, where the pyrazole
mimics the imidazole side chain of histidine. The synthesis of pyrazole
derivatives follows several well established strategies, all of which have been
extensively reviewed.[1–5] By far the most common route to these pyrazole
derivatives involves the well-established reaction between a 1,3-dicarbonyl
compound or its equivalent and hydrazine or a hydrazine derivative. In
particular, the reaction between acrylates and hydrazine or b-dicarbonyl
compounds and hydrazine gives derivatives of pyrazolone, and this has been a
major method for the synthesis of these heterocycles, which are especially
useful in the preparation of multidentate ligands.[6] More recently, the reaction
between hydrazine and an acetylenic carbonyl compound has been used in the
synthesis of pyrazoles lacking a substituent on either nitrogen.[7] To our
knowledge, there are no reports of fragmentation of the acrylate derivatives
during the synthesis of pyrazolones, although a similar fragmentation to that
observed here by us has recently been reported by Cardillo.[8] Herein, we
report that the reaction between hydrazine and a-cyanoacrylate esters gives
not the expected pyrazolinone, but the azine arising from what may be
characterized formally as a retro-Mannich or retro-ene fragmentation of the
intermediate b-hydrazinoester.
RESULTS AND DISCUSSION
The a-cyanocinnamate esters used in this study were all prepared
straightforwardly using the McElvain[9] or Vogel[10] procedure for the
Doebner modification of the Knoevenagel condensation of ethyl cyanoacetate
with the corresponding aromatic aldehyde. All the aldehydes used gave a only
the E-a-cyanocinnamate ester. All three esters prepared gave IR spectra with
;;
strong C N stretching vibrations.
On treatment with hydrazine in ethanol under reflux, the cyanocinnamate
1a gave a product whose spectra were not at all in accord with the spectrum
;;
expected for the pyrazolidinone. The IR spectrum lacked C55O and C
N
1
stretching vibrations. The H NMR spectrum showed no resonances for the
ethyl ester or amide groups, nor any of the resonances expected for the sp3
hybridized carbon atoms of the pyrazolidinone ring; the 13C NMR spectra
contained too few carbon resonances, lacking both the sp3 resonances of the
;;
ring and the C55O and C N resonances. Based on these spectroscopic data,
we were able to deduce that the major product of this reaction, isolated in well
over 80% yield in all cases, was the azine (5) of the aldehyde precursor of the

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Scheme 1. Reaction between hydrazine and a-cyanocinnamates.
a-cyanocinnamate (Sch. 1). Ether extraction of the mother liquors from the
initial crystallization of the azine gave a colorless oil which was identified as
ethyl cyanoacetate. All the a-cyanocinnamates studied gave the same result.
The simpler rationalization (Sch. 2) for this reaction is that the initial
conjugate addition is followed by a base-promoted retro-Mannich reaction to
give the hydrazone and the enolate of ethyl cyanoacetate. Since the pKa of
ethyl cyanoacetate is 11, it is conceivable that the anion of this compound
could function as a leaving group under suitable circumstances. Sch. 2 also
shows one possible pathway for the hydrazone initially formed (6) to be
converted to the isolated azine by a disproportionation reaction. (For an
extensive discussion of keto-enol tautomerism in active mehtylene
compounds see: Ref.[11].)
The second rationalization (scheme 3) is that the b-hydrazinoester formed
in the initial step undergoes a retro-ene fragmentation through a six-membered
cyclic transition state to give the enol of ethyl cyanoacetate and the hydrazone
of the aldehyde. Ethyl cyanoacetate has a pKa of 11, so the enolate anion of the
ethyl cyanoacetate is a much weaker base than the anion of a simple ester or
nitrile. More importantly, ethyl cyanoacetate has 0.25% equilibrium enol
content in methanol solution.[12] Thus, in contrast to simple esters or nitriles,
ethyl cyanoacetate has a relatively low-energy enol, which should make it a

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Erdman et al.
Scheme 2. Base-promoted fragmentation of b-hydrazinoester.
better leaving group during the retro-ene reaction. This would, in turn,
facilitate the fragmentation to form the enol.
A third rationalization for the formation of the azine (Sch. 4), is that the b-
hydrazinoester 3 reacts with a second mole of the Michael acceptor to give the
dimeric species 7, prior to fragmentation to give the azine.
Each of these mechanisms predicts that ethyl cyanoacetate should be
formed in the reactions. It was therefore gratifying to find that ethyl cyano-
acetate was isolated from these reaction mixtures in yields commensurate with
that of the azine. This also lends support to the hypothesis that it is Michael
addition that initiates the reaction, since hydrazinolysis of the ester group
would lead to a hydrazide, which is not isolated. Interestingly, 2a does not
react with other nucleophiles which would appear to be equally suitable for
Michael addition. To date, we have found that the uncatalyzed reaction
Scheme 3. Retro-ene mechanism for fragmentation

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Reaction of Hydrazine with a-Cyanocinnamate Esters
1167
Scheme 4. Fragmentation of diester by ene mechanism.
between 2a and urea, thiourea, and phenylhydrazine fails to give any product
of a nucleophilic addition or substitution. This observation may lend support
to the mechanism in Sch. 4, since none of these nucleophiles would be capable
of forming the diester 7.
The fact that we have not been able to obtain definitive proof for the
presence of 3 in the reaction suggests that the fragmentation reaction proceeds
at least as rapidly as the initial addition. This may support the view that the
fragmentation more likely occurs by the retro-ene pathway in Sch. 3, since this
reaction is then unimolecular, with the hydrazone formation and the base-
promoted elimination reactions both being bimolecular. We do not, however,
hold this view without some equivocation.
Regardless of the mechanism of the fragmentation, these results sound a
caveat about conjugate addition reactions of primary amine nucleophiles to
Michael acceptors capable of eliminating the anion or the enol of an active
methylene compound after the Michael addition.
EXPERIMENTAL
General
Melting points were measured on a Fisher-Johns hotstage melting point
1
apparatus and are uncorrected. H NMR spectra were recorded as CDCl3
solutions using a JEOL Eclipse NMR spectrometer operating at 400 MHz;
peak positions are reported as d (ppm) downfield from internal Me4Si.
13C NMR spectra were recorded as CDCl3 solutions at 100 MHz; peak
positions are reported as d (ppm) relative to the center peak of CDCl3
(77.1 ppm) and peak multiplicities as singlet (s), doublet (d) triplet (t) or
quartet (q). Infrared spectra were recorded as KBr pellets using a Nicolet
Avatar 360 FTIR spectrophotometer. Thin layer chromatography (TLC) was

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Erdman et al.
carried out on Merck Kieselgel 60F254. Microanalyses were carried out by
Galbraith Laboratories, Knoxville, TN.
a-Cyanocinnamate Esters
These esters were prepared by a modification of the method of McElvain
and Lyle,[9] or by a modification of the method of Vogel.[10] Ethyl
cyanoacetate (1.0 eq), the aromatic aldehyde (1.0 eq), ammonium acetate
(0.4 eq) or piperidine (0.16 eq), and acetic acid (1.25 eq) were dissolved in
toluene (1 ml/mmol aldehyde), and the resultant solution was stirred under
reflux using a Dean-Stark water separator. During the reaction, a solid was
gradually formed. When no more water continued to accumulate, the reaction
mixture was cooled in ice and the solid deposited was collected by vacuum
filtration. The crude solid was recrystallized from methanol to give the pure
E-cyanocinnamate ester.
Ethyl E-2-cyano-3-(4-hydroxyphenyl)propenoate (2a) was prepared by
this method by heating ethyl cyanoacetate (5.70 g, 50.4 mmol), p-hydroxy-
benzaldehyde (6.11 g, 50.0 mmol), ammonium acetate (1.56 g, 20.2 mmol),
and acetic acid (5.40 g mL, 75 mmol) in toluene (50 mL) for 3 hr under reflux.
During the reaction, bright yellow crystals of 2a were deposited. Recrystal-
lization from methanol gave pure 2a (9.41 g, 87%) as a bright yellow solid,
m.p. 175–1788C.
n
max (KBr) 3228, 2234, 1732, 1714, 1587, 1519, 1443, 1292, 1270, 1176,
837, 762 cm21
.
1H NMR (CDCl3) d 8.17 (1H, s, ArCH ¼ ), 7.96 (2H, d J ¼ 8.4 Hz,
ArHC2,C6), 6.95 (2H, d J ¼ 8.4 Hz, ArHC3,C5), 4.37 (2H, q J ¼ 7.2 Hz,
CH2CH3), 1.39 (3H, t J ¼ 7.2 Hz, CH3) ppm.
13C NMR (CDCl3) d 162.7, 162.5, 154.2, 134.0 (2 C), 123.6, 116.4 (2 C),
116.1, 98.6, 62.0, 13.7 ppm.
Anal. Found: C, 66.57; H 5.08; N 6.50. C12H11NO3 req. C, 66.35; H, 5.10;
N, 6.45.
Ethyl E-2-cyano-3-(4-hydroxy-3-methoxyphenyl)-propenoate (2b) was
prepared by this method by heating ethyl cyanoacetate (21.29 g, 0.19 mol),
vanillin (24.36 g, 0.16 mol), piperidine (3 g, 35 mmol), and acetic acid
(13.23 g, 0.221 mol) in toluene (150 mL) for 18 hr under reflux. During the
reaction, bright yellow crystals of 2b were deposited. Recrystallization from
methanol gave pure 2b (34.57 g, 89%) as a bright yellow solid, m.p. 107–
1098C.
n
max (KBr) 3375, 3280, 2982, 2229, 1721, 1704, 1577, 1510, 1432, 1275,
.
1191, 1165, 1096, 1025, 856, 764, 760, 628, 569 cm21

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1H NMR (CDCl3) d 8.11 (1H, s, ArCH ¼ ), 7.83 (1H, d J ¼ 2.0–Hz,
ArHC2), 7.36 (1H, d J ¼ 8.2 Hz, of d, J ¼ 2.0 Hz, ArHC6), 6.96 (1H, d
J ¼ 8.2 Hz, ArHC5), 4.34 (2H, q J ¼ 7.3 Hz, OCH2CH3), 3.94 (3H, s, OCH3),
1.37 (3H, t J ¼ 7.3 Hz, CH2CH3) ppm.
13C NMR (CDCl3) d 163.3, 155.0, 151.1, 147.0, 128.8, 124.3, 116.5,
115.1, 111.3, 98.9, 62.5, 56.2, 50.8, 14.3 ppm.
Anal. Found: C, 62.89; H 5.30; N 5.64. C13H13NO4 req. C, 63.15; H, 5.30;
N, 5.67.
Ethyl E-2-cyano-3-(1-naphthyl)propenoate (2c) was prepared by this
method by heating ethyl cyanoacetate (20.36 g, 0.18 mol), 1-naphthaldehyde
(24.98 g, 0.16 mol), piperidine (3 g, 35 mmol), and acetic acid (13.24 g,
0.22 mol) in toluene (150 mL) for 15 hr under reflux. The reaction mixture was
evaporated under reduced pressure, and the off-white residue of 2c was
recrystallized from methanol gave pure 2c (20.5 g, 51%) as a white solid, m.p.
79.5–808C.
nmax (KBr) 2967, 2925, 2223, 1717, 1602, 1285, 1235, 1082, 781,
759 cm21
.
1H NMR (CD3COCH3) d 9.10 (1H, s, ArCH ¼ ), 8.23 (1H, d J ¼ 7.3 Hz,
ArHC2Ã), 8.15 (1H, d J ¼ 8.1 Hz, ArHC4Ã), 8.09 (1H, d J ¼ 8.4 Hz, ArHC5Ã),
8.03 (1H, d J ¼ 8.4 Hz, ArHC8Ã), 7.73–7.60 (4H, m, ArHC3,C6,C7), 4.4 (2H, q
J ¼ 7.0 Hz, CH2CH3), 1.40 (3H, t J ¼ 7.0 Hz, CH2CH3) ppm. Assignments of
Ã
peaks labeled may be interchanged.
13C NMR (CD3COCD3) d 161.9, 152.6, 133.7, 133.1, 131.5, 129.1, 128.9,
128.0, 127.9, 127.0, 125.4, 123.2, 114.9, 106.9, 62.5, 13.6 ppm.
Anal. Found: C, 76.25; H 5.30; N 5.64. C16H13NO2 req. C, 76.48; H, 5.21;
N, 5.57.
Reactions with Hydrazine
A mixture of the cyanocinnamate ester (1.0 eq) and hydrazine (1.1 eq) in
ethanol (5 mL/mmol ester) was heated under reflux for 6–10 hr and
monitored by TLC (CH2Cl2: EtOAc 95 : 5). When TLC analysis showed that
the starting ester had been consumed, heating was discontinued and the
ethanol was removed by evaporation under reduced pressure. Water (50 mL)
was added to the resultant yellow-brown oil, and the mixture was heated to
boiling. The solution was cooled in ice and the solid deposited was collected
by vacuum filtration, washed with water, and dried. The filtrate was extracted
with ether (3 Â 50 mL), and the ether extracts were combined, dried, and
evaporated to give an oil which was distilled under reduced pressure to give
ethyl cyanoacetate.

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Erdman et al.
p-Hydroxybenzaldehyde azine (5a, 1.80 g, 90%) was obtained by this
method from 2a (2.17 g, 10.0 mmol) and hydrazine (0.55 g, 11 mmol) in EtOH
(50 mL) as a pale yellow solid, m.p. 265–2678C (lit.[12] 2688C). Ethyl
cyanoacetate (0.41 g, 36%) was isolated from the filtrate as a colorless liquid,
b. 328C/0.05 mm Hg.
4-Hydroxy-3-methoxybenzaldehyde azine (5b, 1.32 g, 88%) was obtained
by this method from 2b (2.47 g, 10.0 mmol) and hydrazine (0.55 g, 11 mmol)
in EtOH (50 mL) as a pale yellow solid, m.p. 169–1718C (lit.[12] 174–176).
Ethyl cyanoacetate (0.54 g, 48%) was isolated from the filtrate as a colorless
liquid, b. 328C/0.05 mm Hg.
1-Naphthaldehyde azine (5c, 1.39 g, 90%) was obtained by this method
from 2c (2.51 g, 10 mmol) and hydrazine (0.55 g, 11 mmol) in EtOH (50 mL)
as a pale yellow solid, m.p. 152–1538C (lit.[13] 154–1558C). Ethyl cyano-
acetate (0.61 g, 54%) was isolated from the filtrate as a colorless liquid, b.
328C/0.05 mm Hg.
ACKNOWLEDGMENTS
The financial support of the National Institutes of Health (Grant #1 R15
DA013578-01), and the University of Wisconsin – Eau Claire Office of
Research and Sponsored Programs is gratefully acknowledged.
REFERENCES
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3. Kost, A.N.; Grandberg, I.I. Progress in pyrazole chemistry. In Advances
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4. Grimmett, M.R. Diazoles, triazoles, tetrazoles, and their benzo-
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Received in the USA October 16, 2003

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