Synthetic and Theoretical Studies on the Reduction of Electron Withdrawing Group Conjugated Olefins Using the Hantzsch 1,4-Dihydropyridine Ester

Article abstract of DOI:10.1021/jo034921e

The Hantzsch 1,4-dihydropyridine ester (1) has been observed to be a useful selective reducing agent for the reduction of electron-withdrawing conjugated double bonds. The rate of this reaction was observed to be dependent upon the nature of the conjugate

Full text of DOI:10.1021/jo034921e

Syn th etic a n d Th eor etica l Stu d ies on th e Red u ction of Electr on
With d r a w in g Gr ou p Con ju ga ted Olefin s Usin g th e Ha n tzsch
1,4-Dih yd r op yr id in e Ester
Simon J . Garden,* Cristiano Ruch Werneck Guimara˜es,† Marilza B. Corre´a,
Ce´sar Augusto Fernandes de Oliveira, Angelo da Cunha Pinto, and
Ricardo Bicca de Alencastro
Departamento de Qu´ımica Orgaˆnica, Instituto de Qu´ımica, Universidade Federal do Rio de J aneiro,
Cidade Universita´ria, CT, Bloco A, Rio de J aneiro, RJ 21949-900, Brasil
garden@iq.ufrj.br
Received J une 27, 2003
The Hantzsch 1,4-dihydropyridine ester (1) has been observed to be a useful selective reducing
agent for the reduction of electron-withdrawing conjugated double bonds. The rate of this reaction
was observed to be dependent upon the nature of the conjugated substituents and, consequently,
the electronic nature of the unsaturated double bond. Theoretical calculations confirmed the
importance of the HOMO-LUMO gap for this reaction and implicated a hydride transfer, agreeing
with the experimentally observed reaction rate order. The calculations also revealed the importance
of a boatlike structure of the 1,4-dihydropyridine nucleus as well as a trans arrangement of the
ester groups to facilitate the hydride transfer.
In tr od u ction
promise for application in asymmetric reductions17-23 as
well as in reductive aminations24 and the photoinduced
reduction of R,â-epoxyketones.25 In addition to the reduc-
tion of carbonyl compounds, Braude, Hannah, and Lin-
stead first showed that 1 could be employed for the
reduction of certain R,â-unsaturated compounds.26-28
Subsequent studies have further delineated the ap-
plicability of Hantzsch esters as hydrogen equivalents in
olefin reduction reactions.29-35
The natural product enzyme cofactors NAD(P) and
NAD(P)H1-6 have been a stimulus for the investigation
of the use of the Hantzsch ester (1) and other 1,4-
dihydropyridine derivatives, including 1-benzyl-1,4-di-
hydronicotinamide (BNAH) and 10-methyl-9,10-dihy-
droacridine (AcrH2), as attractive biomimetic reducing
agents for application in synthetic and physical organic
chemistry.6-8 These esters are known to reduce ketones9-13
and aldehydes14-16 to the respective alcohols in the
presence of Lewis acids, and some studies have shown
(14) Fukuzumi, S.; Ish-ikama, M.; Tanaka, T. Tetrahedron 1984,
42, 1021-1034.
* To whom correspondence may be addressed. Tel: 55-21-2562-7363.
Fax: 55-21-2562-7256.
(15) Gelbard, G.; Lin, J .; Roques, N. J . Org. Chem. 1992, 57, 1789-
1793.
† To whom correspondence regarding the theoretical calculations
may be addressed. Current address: Department of Chemistry, Yale
University, 225 Prospect St., New Haven, CT 06520-8107. Phone: (203)
432-6288. Fax: (203) 432-6144. E-mail: cris@ramana.chem.yale.edu.
(1) Bahnson, B. J .; Colby, T. D.; Chin, J . K.; Goldstein, B. M.;
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10.1021/jo034921e CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/21/2003
J . Org. Chem. 2003, 68, 8815-8822
8815

Garden et al.
SCHEME 1
TABLE 1. Id en tifica tion of Su bstr a te a n d P r od u ct
There has been considerable interest in the oxidation
mechanism of 1 and analogues, and this interest stems
from the biological role of NAD(P)H and the fact that
these dihydropyridine derivatives are potent drugs for
the treatment of hypertension.36-39 A number of mech-
anisms have been proposed based upon various experi-
mental findings. There is considerable evidence showing
that NADH and its model compounds may reduce their
substrates by a one-step hydride transfer or by a multi-
step electron-transfer-initiated hydride transfer, either
as an electron-proton-electron or electron-hydrogen
atom (e--H+-e- or e--H•). Experimental studies involv-
ing strong oxidants revealed an e--H+-e- mecha-
nism.40,41 Nevertheless, evidence supporting a one-step
hydride transfer was also reported when aldehydes and
ketones were employed as substrates, as in the majority
of bioreductions.42,43
Str u ctu r es
compound
R1
R2
R3
CO2Et
CN
CN
CO2Me
CO2Et
CO2allyl
N-piperidinyl
CN
CO2Et
CO2Et
CN
2a f 4a
2b f 4b
2c f 4c
2d f 4d
2e f 4e
2f f 4f
2g
3a f 5a
3b f 5b
3c
H
H
Me
H
H
H
H
H
H
H
CO2Et
CN
CN
CN
CN
CN
CO2Et
CN
CN
CO2Et
CN
3d f 5d
3e f 5e
3-MeO-4-HO
3-MeO-4-HO
CN
CO2Et
the initial loss of hydrogen from the 1-nitrogen in certain
oxidations of derivatives of 1.51,52
Recently, Zhu, Cheng, and co-workers described their
findings with respect to the oxidation mechanism of 1
by ethyl R-cyanocinnamates and benzylidenemalononi-
triles where they concluded that the reduction of the R,â-
unsaturated substrates was initiated by hydride transfer
from C-4 of 1.46 A hydride transfer was further substanti-
ated by obtaining cyclopropane products from appropri-
ately substituted benzylidenemalononitriles32,33 and other
cyclic products from appropriate precursors.48 Indepen-
dently of these workers, we found that the Hantzsch ester
was capable of reducing ethyl R-cyanocinnamates and
benzylidenemalononitriles as well as isatylidenemalonyl
derivatives (Scheme 1). Our experimental investigations
have found 1 to be a highly selective reducing agent for
the desired transformation, giving excellent yields.53 We
have observed that the velocity for the reaction between
1 and the methyleneoxindole derivatives in benzene/
ethanol varies with the nature of the substituents R2 and
R3, revealing the reactivity order CN/CN > CN/CO2Et
(diastereomeric mixture) > CO2Et/CO2Et, and that when
R2 and R3 are CO2Et and N-piperidinyl, no reaction with
1 was detected (Scheme 1, Tables 1 and 2). Thus, in this
work, we have probed the mechanism for the reaction
between 1 and the methyleneoxindole derivatives in a
theoretical study of the reactivity order obtained experi-
mentally.
The Hantzsch ester (1) and analogues have been
employed as NADH models but not as frequently as
BNAH or AcrH2.44-48 This is probably due to there being
an additional mechanistic complexity regarding which of
the two different hydrogen atoms (from the 1- or 4-posi-
tions) is first transferred in the reduction process. A
number of isotope-labeling studies have pointed to initial
dehydrogenation taking place at the 4-position.30,44-46,49,50
However, there is also compelling evidence supporting
(30) Wallenfels, K.; Ertel, W.; Friedrich, K. Liebigs Ann. Chem. 1973,
1663-1674.
(31) Zhu, X. Q.; Liu, Y. C. J . Org. Chem. 1998, 63, 2786-2787.
(32) Li, J .; Liu, Y. C.; Deng, J . G. Tetrahedron: Asymmetry 1999,
10, 4343-4347.
(33) Li, J .; Liu, Y. C.; Deng, J . G.; Li, X. Z.; Cui, X.; Li, Z.
Tetrahedron: Asymmetry 2000, 11, 2677-2682.
(34) Lee, H. W.; Kim, B. Y.; Ahn, J . B.; Son, H. J .; Lee, J . W.; Ahn,
S. K.; Hong, C. I. Heterocycles 2002, 57, 2163-2173.
(35) Torchy, S.; Cordonnier, G.; Barbry, D.; Eynde, J . J . V. Molecules
2002, 7, 528-533.
(36) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed.
Engl. 1981, 20, 762-769.
(37) Thomas, R. E. In Burger’s Medicinal Chemistry and Drug
Discovery; Wolff, M. E., Ed.; J ohn Wiley and Sons Inc: New York, 1996;
Vol. 2, pp 214-217.
(38) Cheer, S. M.; McClellan, K. Drugs 2001, 61, 1777-1799.
(39) Tanaka, H.; Shigenobu, K. Cardiovasc. Drug Rev. 2002, 20, 81-
92.
(40) Sinha, A.; Bruice, T. C. J . Am. Chem. Soc. 1984, 106, 7291-
7292.
(41) Carlson, B. W.; Miller, L. L. J . Am. Chem. Soc. 1983, 105, 7453-
7454.
(42) Powell, M. F.; Bruice, T. C. J . Am. Chem. Soc. 1983, 105, 1014-
1021.
(43) Powell, M. F.; Bruice, T. C. J . Am. Chem. Soc. 1982, 104, 5834-
5836.
Resu lts a n d Discu ssion
Syn th etic Ap p lica tion of 1 for th e Red u ction of
r,â-Un sa tu r a ted Com p ou n d s. The Hantzsch ester (1)
(44) Zhao, B. J .; Zhu, X. Q.; Lu, Y.; Xia, C. Z.; Cheng, J . P.
Tetrahedron Lett. 2000, 41, 257-260.
(49) van Niel, J . C. G.; Pandit, U. K. J . Chem. Soc., Chem. Commun.
1983, 149-150.
(45) Zhu, X. Q.; Liu, Y. C.; Cheng, J . P. J . Org. Chem. 1999, 64,
8980-8981.
(50) Louis, H. P. M.; Pandit, U. K. J . Tetrahedron 1985, 41, 467-
472.
(46) Zhu, X. Q.; Zou, H. L.; Yuan, P. W.; Liu, Y.; Cao, L.; Cheng, J .
P. J . Chem. Soc., Perkin Trans. 2 2000, 1857-1861.
(47) Cheng, J . P.; Lu, Y.; Zhu, X. Q.; Sun, Y. K.; Bi, F.; He, J . Q. J .
Org. Chem. 2000, 65, 3853-3857.
(48) Zhu, X. Q.; Wang, H. Y.; Wang, J . S.; Liu, Y. C. J . Org. Chem.
2001, 66, 344-347.
(51) Xu, H.-J .; Deng, G.; Yu, Q. J . Chem. Soc., Chem. Commun.
1987, 916-917.
(52) Eynde, J .-J . V.; D’Orazic, R.; Haverbrke, Y. V. Tetrahedron
1994, 50, 2479-2484.
(53) Corre´a, M. B. M.Sc., Universidade Federal do Rio de J aneiro,
Brazil, 1998.
8816 J . Org. Chem., Vol. 68, No. 23, 2003

Studies Using the Hantzsch 1,4-Dihydropyridine Ester
TABLE 2. Red u ction of Isa tylid en e a n d Ben zylid en e
Com p ou n d s w ith th e Ha n tzsch Ester (1)
SCHEME 2
yield
entry substrate product
reaction conditions
(%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
4a
4b
4b
4c
benzene/EtOH (1:1) ∆ 3hr
EtOH, r.t., 15 min
benzene/AIBN, ∆ N2
EtOH, r.t., 15 min
benzene/EtOH 1 h (1:1), ∆
benzene/EtOH (1:1) r.t. 3hrs
benzene/EtOH (1:1) ∆ 1hr
benzene/EtOH (1:1) r.t. 1.5 hrs 75
benzene/EtOH (1:1), ∆
benzene
EtOH
benzene/EtOH (1:1)
EtOH
92
80
80
70
89
85
87
2b
2b
2c
2d b
2eb
2eb
2f
4d c
4ec
4ec
4fc
properties, also gave excellent isolated and purified yields
of reduced products (Table 2, entries 13 and 14).
2gb
3a
0
84
79
0
72
75
The structures of the oxindole products 4a -d were
confirmed by NMR, where the vicinal saturated methine
groups gave rise to two doublets in the 1H NMR (4-5
ppm) and corresponding signals for the respective carbon
atoms in the proton decoupled 13C PENDANT NMR
spectra. Mass spectra revealed a molecular ion consistent
with the incorporation of two hydrogen atoms in com-
parison with the respective spectra of the substrates. In
addition, the products proved to be identical to the
products obtained by reduction of 2 with zinc in ethyl
acetate/aqueous HCl or by catalytic hydrogenation with
Pd/C.
5a
5b
3b
3c
3d
3e
5d
5e
EtOH
a
b
Isolated purified yield. Mixture of geometric isomers. c Prod-
uct is a 1:1 mixture of two diastereoisomers.
was employed in stoichiometric quantities for the homo-
geneous reduction of isatylidenemalonyl derivatives (2a -
g), ethyl R-cyanocinnamates (3b ,e), and benzylidene-
malononitriles (3a ,d ) in ethanol or in benzene-ethanol
(Scheme 1, Table 1). Table 2 summarizes our findings.
Analysis of Table 2 readily reveals a reactivity order,
which is dependent upon the nature of the substituents
R2 and R3. Barbry and co-workers recently revealed a
dependence of the electronic nature of the substituted
olefin in reductions with 1 in the presence of silica under
microwave irradiation as well as revealing a dependence
upon the structure of analogues of 1.35 The malonylnitrile
derivatives, 2b,c (Table 2, entries 2-4), are more readily
reduced, reaction occurring at room temperature or at
reflux in a few minutes, than the R-cyanoacetyl esters
(2d -f) which require several hours at room temperature
or 1 h under reflux (Table 2, entries 5-8). The R-cy-
anoacetyl esters are, in turn, more reactive than the
malonyl ester derivative, 2a (Table 2, entry 1). Further,
the introduction of a basic nitrogen conjugated with the
R,â-unsaturated system (2g) resulted in no observed
reaction even after refluxing for several hours (Table 2,
entry 9). In contrast to the reaction of 2a , compound 3c
was found to be unreactive toward 1 (Table 2, entries 1
and 12). As observed for compounds 2, although it was
necessary to perform all reactions under reflux, com-
pounds 3 also revealed similar differences in reactivity
(reactivity order, Table 2, entries 10, 13 > 11, 14 > 12).
The differences observed in the reactivity indicate that
the reactions are dependent upon the electronic nature
of the conjugated system or, more precisely, the HOMO-
LUMO gap of the reactants.
Compounds 2 (d , e, g) were obtained from the respec-
tive condensation reactions as mixtures of geometrical
isomers. Compound 2f was obtained as a single isomer.
1H NMR was used to determine the ratio of the isomers
of 2, before reduction with 1: 2d (2:1), 2e (6:1). Com-
pounds 4 (d , e, f) were obtained as 1:1 mixtures of two
diastereoisomeric products irrespective of the initial ratio
of the substrate isomers. The obtention of 1:1 mixtures
of diastereoisomeric products does not allow differentia-
tion between the possibility of a concerted (or pseudocon-
certed) transfer of hydrogen from 1 to the substrates,
which would have resulted in the preservation of the
initial diastereoisomeric ratios, or an initial hydride
transfer followed by subsequent protonation. This is the
result of the Hantzsch pyridine (6) being sufficiently basic
so as to catalyze the epimerization of the chiral
centers.55-58 This was confirmed when 4h was treated
with 6 in CDCl3 containing a couple of drops of MeOD-
d4 resulting in the product 4h -d2 (Scheme 2). When 4h
was solubilized in MeOD-d4, deuterium exchange oc-
curred even in the absence of 6. The 13C NMR revealed
the disappearance of the 1H decoupled signals corre-
sponding to the methines at 37.9 (diastereoisomer, 39.2)
and 44.88 ppm (44.94) and the appearance of multiplets
2
due to coupling of the 13C nuclei with the D nuclei.
The reduction of compounds 3 by 1 contrasts the
results of Shinkai, where the reduction of similar ben-
zylidene derivatives with N-benzyldihydronicotinamide
required the presence of Mg(ClO4)2 or acetic acid thus
revealing the greater reactivity of 1 for hydrogen dona-
tion.59
Th eor et ica l St u d ies of t h e R ed u ct ion of t h e
Meth ylen eoxin d ole Der iva tives by 1. Two QM/MM
studies verified that the reductions of pyruvate to L-
No evidence was found for the participation of a radical
reduction mechanism. The reactions were performed
under an air atmosphere with the exception of Table 2
entry 3 where the inclusion of AIBN and the use of an
inert atmosphere made no difference to the observed
reactivity or yield. The reaction of compound 2f (Table
2, entry 8) with 1 was also used to probe for the
possibility of a radical reaction though no evidence of
products arising from a radical cyclization reaction was
observed.54 In a similar manner, the phenolic substrates
3d and 3e, which could be expected to have antioxidant
(55) Roithova, J .; Exner, O. J . Phys. Org. Chem. 2001, 14, 752-
758.
(56) Hunter, E. P. L.; Lias, S. G. J . Phys. Chem. Ref. Data 1998,
27, 413-656.
(57) Condon, F. E. J . Am. Chem. Soc. 1965, 87, 4494-4496.
(58) Gero, A.; Markham, J . J . J . Org. Chem. 1951, 16, 1835-1838.
(59) Shinkai, S.; Kusano, Y.; Ide, T.; Sone, T.; Manabe, O. Bull.
Chem. Soc. J pn. 1978, 51, 3544-3548.
(54) Snider, B. B. Chem. Rev. 1996, 96, 339-363.
J . Org. Chem, Vol. 68, No. 23, 2003 8817

Garden et al.
F IGURE 1. Molecular electrostatic potential maps plotted at the Connolly surface: (a) 2b (R2 ) CN, R3 ) CN); (b) 2e (R2 ) CN,
R3 ) CO2Et); (c) 2e′ (R2 ) CO2Et, R3 ) CN); (d) 2a (R2 ) CO2Et, R3 ) CO2Et); (e) 2g′ (R2 ) N-piperidinyl, R3 ) CO2Et).
TABLE 3. HOMO a n d LUMO En er gies of 1 a n d
lactate in L-lactate dehydrogenase and oxaloacetate to
malate in malate dehydrogenase occur by a sequential
reaction of hydride transfer from NADH preceding a
Disu bstitu ted 3-Meth ylen eoxin d oles a n d HOMO/LUMO
En er gy Ga p sa
∆E
∆E
proton transfer from a His residue, and the rate-limiting
step is the hydride transfer.2,5 Kinetic and thermody-
namic studies of the reduction of ethyl R-cyanocinnama-
tes and benzylidenemalononitriles by 1 have shown
positive F values of 1.78 and 1.67, respectively, demon-
strating the electrophilic nature of the substrates and,
consequently, that the hydrogen lost from 1 must be a
hydride-like species.46 In addition, replacement of 1 by
1-4,4-d2 and 1-N-d in these reductions gave the observed
kinetic isotope effects of 5.3-6.0 and 1.2-1.3, respec-
tively.46 Using a different substrate, (Z)-ethyl R-cyano-
â-bromomethylcinnamate, Zhu and co-workers observed
similar kinetic isotope effects.45 These results suggest
that direct hydride transfer from the C4-position is the
rate-limiting step, followed by rapid proton transfer from
the nitrogen.44-46
In a first step to probe the mechanism of the reaction
between 1 and the methyleneoxindole derivatives, we
analyzed the energies of the HOMO and the LUMO for
each compound involved in the reaction (Table 3). The
calculated energy gaps between the LUMO of the meth-
yleneoxindole derivatives (2a , b, e, e′, and g′) and the
HOMO of 1 are smaller than the energy gaps between
the LUMO of 1 and the HOMO of the methyleneoxindole
derivatives. This result suggests that a hydride transfer
precedes a proton transfer from HEH, in agreement with
the previously cited literature. Moreover, the energy gaps
between the LUMO of 2a , b, e, e′, and g′ and the HOMO
of 1 agree with the experimental reactivity order, indicat-
ing that the hydride transfer is the rate-limiting step.
To further support the hydride transfer as the rate-
limiting step, we derived molecular electrostatic potential
(MEP) maps plotted at the Connolly surface of each
methyleneoxindole derivative (Figure 1).60 Blue and red
colors represent the most repulsive and attractive inter-
HOMO
energy
LUMO
energy
(LUMO -
(LUMO -
compoundb
HOMO)c
HOMO)d
1
-8.460
-9.281
-9.175
-9.159
-9.059
-8.662
-0.353
-2.039
-1.718
-1.688
-1.349
-0.936
2b
2e′
2e
2a
2g
6.421
6.742
6.772
7.111
7.524
8.928
8.822
8.806
8.706
8.309
a
b
Values in eV. 2b (R2 ) CN, R3 ) CN), 2e (R2 ) CN, R3
)
CO2Et), 2e′ (R2 ) CO2Et, R3 ) CN), 2a (R2 ) CO2Et, R3 ) CO2Et),
2g′ (R2 ) N-piperidinyl, R3 ) CO2Et). c LUMO of disubstituted
d
3-methyleneoxindoles and HOMO of 1. HOMO of disubstituted
3-methyleneoxindoles and LUMO of 1.
actions with a positive probe charge, respectively. Figure
1 shows that while the most reactive compound (2b ,
R2 ) R3 ) CN) and the diasteromeric mixture (com-
pounds 2e, e′) have predominant green and yellow colors,
respectively, at the exocyclic double bond, the least
reactive of those substrates that react (2a , R2 ) R3 ) CO2-
Et) and the unreactive derivative (2g′) have a highly
negative region (red color) at the exocyclic double bond.
The color gradation suggests that if the methyleneoxin-
dole derivatives are attacked by a hydride ion, compound
2b would be the most reactive, followed by the diastero-
meric mixture, compounds 2e and 2e′. This reactivity
order agrees with the experimental order and, again,
indicates that the hydride transfer precedes the proton
transfer and is the rate-limiting step.
To determine whether the hydride is transferred from
the 4-position (Ha) or the 1-position (Hb), we analyzed
the HOMO eigenvector of the hydride donor, 1, and the
charges derived from the MEP, Figure 2. Table 4 shows
(60) Connolly, M. L. Science 1983, 221, 709-713.
8818 J . Org. Chem., Vol. 68, No. 23, 2003

Studies Using the Hantzsch 1,4-Dihydropyridine Ester
the TS for the reaction will also be stabilized by the
conjugative effects observed in the respective intermedi-
ate.
The mechanism and TS features of hydride transfer
mediated by NAD+ and NADH have been extensively
investigated using theoretical methods.61-66 Several im-
portant conclusions from these previous calculations, that
have implications in this present study, can be sum-
marized as follows: (1) the 1,4-dihydronicotinamide ring
is slightly puckered in a boatlike conformation, but the
ring is quite flexible with small barriers to inversion;62,66
(2) for hydride transfer from 1,4-dihydronicotinamide to
protonated nicotinamide, there is a strong preference for
a syn or stacking arrangement for the two pyridine rings
in TSs.61 The same arrangement was observed for other
hydride-transfer TSs of molecules with extended unsat-
uration.63,64 The syn preference can be attributed to the
maximized overlap between the LUMOs of hydride
acceptor and hydride donor; (3) the 3-amide group of 1,4-
dihydronicotinamide activates the hydride transfer when
it is in a trans conformation in transition structures.61,65
The three-dimensional models for the reactants and
for the intermediates were constructed. These consisted
of HEH, one of the disubstituted 3-methyleneoxindoles
(2a , b, e, e′, or g), and three ethanol molecules. Besides
simulating part of the solvent effects in the reaction, the
ethanol molecules were included so as to avoid undesir-
able intermolecular hydrogen bonds between HEH and
the substrates, which hindered an adequate geometry for
the hydride transfer. Basically, two ethanol molecules are
hydrogen bonded to the ester groups of the Hantzsch
ester and one ethanol molecule is hydrogen bonded to
the carbonyl of the amide group of the disubstituted
3-methyleneoxindoles. The complexes were constructed
in such a manner so that 1 was always oriented in a syn
arrangement with respect to the exocyclic double bond
of the derivatives, for studies of hydride transfer to C2
or C3 (Figure 3). It can be noted that after the hydride
transfer to one of the carbon atoms of the exocyclic double
bond, the syn arrangement also facilitates the proton
transfer from the 1-position of 1 to the other carbon in
the second step of the reduction, without the need for
major structural rearrangement. The energy of the
complexes and intermediates, and consequently the rela-
tive rate constants, is highly dependent on the conforma-
tion and orientation of the ethanol molecules. Therefore,
we tried to obtain energy-minimized structures for all
reactants and intermediates with equivalent orientation
and conformation for the solvent molecules regardless of
the substituents. As in previous theoretical studies,61,65
where it was found that the hydride transfer from 1,4-
dihydronicotinamide was activated by a trans conforma-
tion of the 3-amide group, we also found in this study
that the trans ester configuration was essential for
hydride transfer (Figure 3). The trans ester conformation
F IGURE 2. Schematic representation of the possible reactions
of 1 with compounds 2.
TABLE 4. HOMO Coefficien ts of 1 (Ha a n d Hb), LUMO
Coefficien ts of th e Disu bstitu ted 3-Meth ylen eoxin d oles
(C2 a n d C3), a n d Ch a r ges Der ived fr om th e Molecu la r
Electr osta tic P oten tia l
compounda
atom
coefficients
charges
1
Ha
Hb
C3
C2
C3
C2
C3
C2
C3
C2
C3
C2
0.2325
-0.0001
0.5145
0.4913
0.5336
0.4721
0.5387
0.4697
0.5593
0.4414
0.5663
0.3974
0.06
0.25
-0.18
0.06
-0.28
0.16
-0.26
0.15
2b
2e′
2e
2a
-0.31
0.14
0.06
2g′
-0.16
a
2b (R2 ) CN, R3 ) CN), 2e (R2 ) CN, R3 ) CO2Et), 2e′ (R2
CO2Et, R3 ) CN), 2a (R2 ) CO2Et, R3 ) CO2Et), 2g′ (R2
N-piperidinyl, R3 ) CO2Et).
)
)
that Ha has a significant HOMO component, while Hb
has a negligible one. Moreover, Ha has a less positive
MEP-derived charge than Hb. These results indicate that
the disubstituted 3-methyleneoxindoles are reduced by
a hydride ion from the 4-position of 1. To determine which
carbon atom (C2 or C3) of the exocyclic double bond is
attacked by the hydride ion of 1, we analyzed the LUMO
eigenvector of the methyleneoxindole derivatives and,
again, the charges derived from the MEP, Figure 2. The
results show that, except for the unreactive derivative
(compound 2g′), it was not possible to determine precisely
which carbon atom would be attacked by the hydride ion,
since despite having a greater LUMO component than
C2, C3 has a more negative MEP-derived charge for all
the reactive compounds (Table 4).
To distinguish which carbon atom is attacked by the
hydride ion and evaluate the influence of the substituents
on the reactivity, we built three-dimensional models for
the reactants before the hydride transfer to C2 and C3
and for the intermediates generated after the reaction.
The reason for using intermediate structures instead of
transition structures (TS) was due to nonconvergence in
the calculations performed to obtain the TS. However,
our theoretical results for the hydride transfer to both
C2 and C3 indicated endothermic reactions for all deriva-
tives. Thus, we can safely assume by using the Hammond
postulate that the TS in each case is closer in energy,
and in structure, to the respective intermediate than to
the reactants. This supports the hydride transfer from
the 4-position of 1 relative to the 1-position, as it
generates an aromatic compound as an intermediate, the
protonated Hantszch pyridine. As the hydride transfer
from 1 is an endothermic reaction, we can expect that
(61) Wu, Y.-D.; Lai, D. K. W.; Houk, K. N. J . Am. Chem. Soc. 1995,
117, 7, 4100-4108.
(62) Wu, Y.-D.; Houk, K. N. J . Am. Chem. Soc. 1991, 113, 2353-
2358.
(63) Wu, Y.-D.; Houk, K. N. J . Am. Chem. Soc. 1987, 109, 2226-
2227.
(64) Wu, Y.-D.; Houk, K. N. J . Am. Chem. Soc. 1987, 109, 906-
908.
(65) Donkersloot, M. C. A.; Buck, H. M. J . Am. Chem. Soc. 1981,
103, 6554-6558.
(66) Young, L.; Post, C. B. J . Am. Chem. Soc. 1993, 115, 1964-1970.
J . Org. Chem, Vol. 68, No. 23, 2003 8819

Garden et al.
TABLE 5. En th a lp y of F or m a tion of th e Rea cta n t a n d
In ter m ed ia te Mod els for th e Hyd r id e Tr a n sfer to C2, a n d
Rela tive Rea ctivity to th e F a stest Rea ction a
∆Hf°
∆Hf°
complexc
(reactants) (intermediates) ∆∆Hf° ln(ka/kx)b
1 and 2b
1 and 2e′
1 and 2e
1 and 2a
1 and 2g′
-263.32
-390.64
-392.72
-511.30
-437.89
-229.30
-351.38
-353.01
-469.07
-393.56
34.02
39.26
39.71
42.23
44.33
0
8.85
9.61
13.86
17.41
a
b
Values in kcal/mol. See equation in the text for details.
c Complex between 1 and 2b (R2 ) CN, R3 ) CN), 2e′ (R2 ) CO2Et,
R3 ) CN), 2e (R2 ) CN, R3 ) CO2Et), 2a (R2 ) CO2Et, R3
CO2Et), 2g′ (R2 ) N-piperidinyl, R3 ) CO2Et).
)
TABLE 6. En th a lp y of F or m a tion of th e Rea cta n t a n d
In ter m ed ia te Mod els for th e Hyd r id e Tr a n sfer to C3 a n d
Rela tive Rea ctivity to th e F a stest Rea ction a
∆Hf°
∆Hf°
complexc
(reactants) (intermediates) ∆∆Hf° ln(ka/kx)b
1 and 2b
1 and 2e′
1 and 2e
1 and 2a
1 and 2g′
-261.48
-386.18
-382.27
-508.41
-435.49
-238.04
-360.28
-356.57
-480.07
-397.68
23.44
25.90
25.70
28.34
37.81
0
4.15
3.82
8.27
24.27
F IGURE 3. Selected PM3 energy-optimized three-dimen-
sional models of reactants and intermediates: (a) hydride
transfer from 1 to C2 of 2b (R2 ) R3 ) CN); (b) hydride transfer
from 1 to C3 of 2e′ (R2 ) CO2Et, R3 ) CN). The hydrogen atom
that is transferred to the exocyclic double bond is colored in
yellow.
a
b
Values in kcal/mol. See equation in the text for details.
c Complex between 1 and 2b (R2 ) CN, R3 ) CN), 2e′ (R2 ) CO2Et,
R3 ) CN), 2e (R2 ) CN, R3 ) CO2Et), 2a (R2 ) CO2Et, R3
CO2Et), 2g′ (R2 ) N-piperidinyl, R3 ) CO2Et).
)
model for the hydride transfer to C2 and C3, respectively,
and the relative rate constant with respect to the fastest
reaction, calculated using eq 1. The theoretical reactivity
order was found to be the same as the experimentally
observed order for both mechanisms. Table 5 shows that
the hydride transfer to C2 of compound 2b is ap-
proximately 7 × 103 times more reactive than that of
compound 2e′ (R2 ) CO2Et, R3 ) CN) and approximately
15 × 103 times more reactive than that of compound 2e
(R2 ) CN, R3 ) CO2Et). Thus, as shown experimentally,
compound 2b is more reactive than the diastereomeric
mixture. Compound 2b is also approximately 1 × 106
times more reactive than compound 2a and 36 × 106
times more reactive than compound 2g′, which is unre-
active. This last result does not justify the nonreactivity
of 2g′, as it is only 36 times less reactive than 2a . On
the other hand, Table 6 shows that for the hydride
transfer to C3, 2b is roughly 60 and 45 times more
reactive than compounds 2e′ and 2e and 4 × 103 times
more reactive than 2a . Furthermore, compound 2b is 3
× 1010 times more reactive than compound 2g′, which
does not react. The theoretical reactivity order for the
hydride transfer to C3 is more in line with the experi-
mental reactivity order, as it explains the nonreactivity
of compound 2g′. Moreover, considering only the enthalpy
contribution involved in achieving the TS and, as we
discussed before, that the structure and energy of the TS
resemble that of the intermediate, the difference in
enthalpy of formation between reactants and intermedi-
ates suggests that the hydride transfer to C3 is faster
than the hydride transfer to C2 regardless of the sub-
stituents. This should be expected due to the strong
stabilization by delocalizing excess electronic charge over
the oxindol ring; the intermediate generated by the
hydride transfer to C3 is more stable than the one
activated the hydride by orienting it in the proper
configuration for attack at either C2 or C3, depending
upon the model, of the exocyclic double bond.
The intermediates were obtained through the transfer
of one of the Ha hydrogens of 1 to the carbon atoms C2
and C3. Parts a and b of Figure 3 show the three-
dimensional structures of the PM3 energy-optimized
models of reactants and intermediates for the hydride
transfer to C2 when R2 ) R3 ) CN and for the hydride
transfer to C3 when R2 ) CO2Et and R3 ) CN, respec-
tively. The hydrogen atom that is transferred to the
exocyclic double bond is colored yellow. Figure 3 reveals
that the six-membered ring of 1 is slightly boatlike in
the reactants, as was previously found in other theoreti-
cal studies.61,63,66 The same observation was made for the
other substituents.
As reliable theoretical entropies are unlikely to be
obtainied by the PM3 method, we assumed that the
entropic variation for the formation of the TS is similar
for all substituents. Thus, the relative rate constant may
be written as shown in eq 1 where ka is the rate constant
for the fastest reaction (R2 ) R3 ) CN), kx is the rate
constant for the reactions with the other substituents, R
is the gas constant, T is the absolute temperature,
∆Hf°int x is the standard enthalpy of formation of the
intermediate x and ∆Hf °x is the standard enthalpy of
formation of the reactants x.
ka
1
ln
=
(∆Hf°int x - ∆Hf°x - ∆Hf°int a + ∆Hf°a)
kx RT
(1)
Tables 5 and 6 show the calculated values of the
enthalpies of formation of each reactant and intermediate
8820 J . Org. Chem., Vol. 68, No. 23, 2003

Studies Using the Hantzsch 1,4-Dihydropyridine Ester
nilin with malononitrile or ethyl cyanoacetate and basic
alumina (Merck cat. 1097).70 Benzaldehyde was condensed
with diethyl malonate in ethanol in the presence of a catalytic
quantity of piperidine to give 3c.
Gen er a l P r oced u r e for Red u ction w ith th e Ha n tzsch
Ester . Unsaturated substrate (1.00 mmol) and Hantzsch ester
(1.05 mmol) were combined in EtOH or EtOH/benzene (15 mL)
and left stirring at room temperature or heated to reflux as
indicated in Table 2.
The reaction products were isolated by evaporating the
solvent, taking up the residue in ethyl acetate, and extracting
with aqueous HCl (1.0 mol L-1). The crude product after drying
over Na2SO4, filtration, and evaporation of the solvent was
filtered through a short column of silica eluting with hexane/
ethyl acetate (1:1 v/v).
generated by the hydride transfer to C2. The same
argument follows for the TS of both mechanisms due to
the Hammond postulate. Finally, we may conclude that
the experimental reactivity order is affected by electronic
effects of the substituents in the exocyclic double bond,
as characterized by the HOMO-LUMO gaps and the
MEP maps. However, steric effects probably play a
significant role in the hydride transfer as the reactivity
of the disubstituted 3-methyleneoxindoles decreases with
the size of the substituents.
Con clu sion s
The Hantzsch 1,4-dihydropyridine ester (1) has proved
to be a versatile reducing agent for the reduction of ethyl
R-cyanocinnamates, benzylidenemalononitriles, and ma-
lonylisatylidene derivatives. Experimentally, no evidence
was found for reactions involving radical intermediates
and the rates of reaction were observed to be dependent
upon the nature of the conjugated substituents. The
mechanism for oxidation of 1 by disubstituted 3-meth-
yleneoxindoles (2) was clarified by semiempirical calcula-
tions employing the PM3 Hamiltonian. In agreement
with other studies,2,5,44-46,61 we verified through compari-
son of the experimental and theoretical reactivity orders
that the reduction of the methyleneoxindole derivatives
occurs via a hydride transfer from the C4-position of 1
to the C3 carbon atom of the exocyclic double bond,
followed by a proton transfer from the protonated pyri-
dine intermediate to C2. The calculated energy differ-
ences between HOMO (1) and LUMO (2) molecular
orbitals were found to be consistent with the observed
reaction rate order, which are in turn correlated with the
nature of the substituents in compounds 2.
Com p u ta tion a l Deta ils. All calculations were performed
with the PM3 Hamiltonian71,72 within the MOPAC 93 pro-
gram73 on a Silicon Graphics O2 R10000 workstation under
an IRIX operational system. All structures were fully opti-
mized in the gas phase using the keywords GNORM)0.1 and
PRECISE. The InsightII program was employed as a graphic
interface for the construction and visualization of molecular
structures.
Ch a r a cter iza tion of th e Red u ced P r od u cts. Dieth yl-
2-(2-oxo-2,3-dih ydr o-1H-3-in dolyl)m alon ate (4a). Mp: 128-
130 °C. IR (ν ( 4 cm-1): 3386, 2984, 1736, 1616, 1474, 749.
1H NMR (CDCl3): δ 1.01 [3H, t, J 7.0]; 1.26 [3H, t, J 7.0]; 4.07
[2H, m]; 4.07 [1H, d, J 3.6]; 4.23 [1H, d, J 3.6]; 6.89 [1H, d, J
7.5]; 4.26 [2H, m]; 6.99 [1H, td, J 7.5; J 0.9]; 7.21 [1H, td, J
7.5, J 0.9]; 7.37 [1H, d, J 7.5]; 8.99[NH, bs]. 13C NMR: 13.8
[CH3]; 14.1 [CH3]; 45.4 [CH]; 52.4 [CH]; 61.9 [CH2]; 62.1 [CH2];
110.0 [CH]; 122.6 [CH]; 125.3 [CH]; 126.4 [C]; 128.8 [CH];
142.2 [C]; 167.2 [CdO ester]; 168.2 [CdO, ester]; 178.0 [CdO,
amide]. Mass C15H17NO5 (m/z [% abundance]): 291 [20]; 245
[15]; 218 [28]; 172 [100].
2-(2-Oxo-2,3-d ih yd r o-1H-3-in d olyl)m a lon on itr ile (4b).
Mp: 189-200 °C. IR (ν ( 4 cm-1): 3202, 2893, 2219, 1702,
1
1618, 1473, 754. H NMR (CDCl3/DMSO-d6): δ 4.00 [1H, d, J
4.3]; 5.20 [1H, d, J 4.3]; 6.98 [1H, d, J 7.8]; 7.08 [1H, t, J 7.6];
7.32 [1H, t, J 7.7]; 7.53 [1H, d, J 7.5]; 10.79 [1H, s]. 13C NMR:
24.1 [CH]; 44.6 [CH]; 110.5 [CH]; 111.4 [CN]; 112.2 [CN]; 122.4
[CH]; 123.0 [C]; 124.5 [CH]; 129.9 [CH]; 143.1 [C]; 173.2 [Cd
O, amide]. Mass C11H7N3O (m/z [% abundance]): 197 [22], 132
[100].
2-(1-Meth yl-2-oxo-2,3-d ih yd r o-1H-3-in d olyl)m a lon on i-
tr ile (4c). Mp: 138-139 °C. IR (ν ( 4 cm-1): 3065, 2865, 1694,
1613, 759. 1H NMR (CDCl3/DMSO-d6): δ 3.28 [3H, s]; 3.96 [1H,
d, J 3.7]; 4.57 [1H, d, J 3.7]; 6.96 [1H, d, J 7.5]; 7.22 [1H, t, J
7.5]; 7.47 [1H, t, J 7.5]; 7.66 [1H, d, J 7.5]. 13C NMR: 24.7
[CH]; 27.0 [CH3]; 45.1 [CH]; 109.5 [CH]; 109.7 [CN]; 111.7
[CN]; 121.6 [C]; 124.0 [CH]; 124.8 [CH]; 130.9 [CH]; 144.9 [C];
171.0 [CdO, amide]. Mass C12H9N3O (m/z [% abundance]): 211
[18], 146 [100].
Meth yl-2-cya n o-2(2-oxo-2,3-d ih yd r o-1H-3-in d olyl)a ce-
ta te (4d ). (Diastereoisomeric mixture, ratio 1:1.) Mp: 128-
129 °C. IR (ν ( 4 cm-1): 3286, 3095, 3027, 2958, 2900, 2253,
1749, 1720, 753. 1H NMR (CDCl3): δ 3.66, 3.94 [2 × 3H, s];
3.99, 4.15, 4.38, 4.45 [4 × 1H, d, J 3.8]; 6.92, 6.94 [2 × 1H, d,
J 7.5]; 7.05, 7.06 [2 × 1H, t, J 7.5]; 7.19 [1H, d, 7.5]; 7.26 [2 ×
1H, t, J 7.5]; 7.48 [1H, 1d, J 7.5]; 9.19 and 9.23 [2 × NH, bs].
13C NMR: 37.7, 38.8 [CH]; 45.3, 45.5 [CH]; 54.0, 54.3 [CH3];
110.7, 110.9 [CH]; 113.6, 115.3 [CN]; 123.1, 123.3 [CH]; 124.2
[CH]; 124.4 [C]; 124.8 [CH]; 129.7, 129.9 [CH]; 142.0, 142.1
[C]; 164.1, 165.3 [CdO, ester]; 175.9 [CdO, amide]. Mass
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded in CDCl3
using 300- and 200-MHz (1H) spectrometers and are referenced
to CHCl3. Coupling constants are quoted in Hz. Assignments
in 13C spectra were based upon analysis of PENDANT spectra.
Mass spectra were recorded by GC-MS or by direct insertion.
IR spectra were recorded using either KBr or KCl disks.
Melting points were recorded using a capillary melting point
aparatus and are reported as uncorrected values.
The Hantzsch ester (1) was prepared using a literature
procedure.67
P r ep a r a tion of th e Ma lon ylisa tin ylid en e Der iva tives.
The isatinylidene derivatives (2a -c, e) were prepared by
condensing diethyl malonate, malononitrile, or ethyl cyano-
acetate with isatin or N-methylisatin in ethanol.68,69 Compound
2d was obtained when isatin and ethylcyanoacetate were
combined in MeOH in the presence of a catalytic quantity of
piperidine. Compound 2f was obtained in a manner similar
to compound 2e except that allyl alcohol was used as the
solvent for condensing allyl cyanoacetate with isatin in the
presence of a catalytic quantity of piperidine. Compound 2g
was obtained when isatin was treated with ethyl nitroacetate
in the presence of an excess of piperidine in refluxing ethanol.
P r ep a r a tion of th e Ben zylid en e Der iva tives. The ben-
zylidene derivatives 3(a , b, d , and e) were prepared by
condensing stoichiometric quantities of benzaldehyde or va-
C
12H10N2O3 (m/z [% abundance]): 230 [20]; 171 [100]; 132 [30].
(70) Texeir-Boullet, F.; Foucaud, A. Tetrahedron Lett. 1982, 23,
4927-4928.
(71) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220.
(72) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 221-264.
(73) Stewart, J . J . P.; MOPAC93-Revision Number 2 ed.; Fujistu
Limited: 1993.
(67) Singer, A.; McElvain, S. M. In Organic Syntheses; J ohn Wiley
and Sons: New York, 1943; Vol. 2, pp 214-216.
(68) da Silva, J . F. M.; Garden, S. J .; Pinto, A. C. J . Braz. Chem.
Soc. 2001, 12, 273-324.
(69) Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1.
J . Org. Chem, Vol. 68, No. 23, 2003 8821

Garden et al.
Eth yl 2-Cya n o-2-(2-oxo-2,3-d ih yd r o-1H-3-in d olyl)a ce-
ta te (4e).74 (Diastereoisomeric mixture, ratio 1:1.) Mp: 105-
110 °C. IR (ν ( 4 cm-1): 3280, 2986, 2905, 2256, 1724, 1621,
1472, 754. 1H NMR (CDCl3): δ 1.07, 1.38 [2 × 3H, t, J 7.1];
3.98 [1H, d, J 2.5]; 4.14 and 4.35 [1H, d, J 3.8], 4.08 [2H, m];
4.15 [1H, d, J 3.5]; 4.37 [3H, m]; 4.45 [1H, d, J 3.2]; 6.94 [2 ×
1H, m]; 7.05 [2 × 1H, m]; 7.24 [3 × 1H, m]; 7.49 [1H, d, J 7.4];
9.41, 9.44 [2 × NH, bs]. 13C NMR: 13.6, 14.0 [CH3]; 37.8, 38.9
[CH]; 45.4 [CH]; 63.4, 63.8 [CH2]; 110.6, 110.8 [CH]; 113.7,
115.5 [CN]; 122.9, 123.1 [CH]; 124.1 [CH]; 124.2, 124.4 [C];
124.7 [CH]; 129.6, 129.7 [CH]; 142.1, 142.2 [C]; 163.5, 164.7
[CdO ester]; 176.0 [CdO amide]. Mass C13H12N2O3 (m/z [%
abundance]): 244 [32], 171 [100], 132 [30].
Allyl-2-cya n o-2-(2-oxo-2,3-d ih yd r o-1H -3-in d olyl)a ce-
ta te (4f). (Diastereoisomeric mixture, ratio 1:1.) Oil. IR (ν (
4 cm-1): 3265, 3093, 2896, 2255, 1747, 1721, 1621, 1472, 753,
733. 1H NMR (CDCl3):δ 3.99 [1H, d, J 3.1]; 4.18 [1H, d, J 3.7];
4.37 [1H, d, J 3.8]; 4.44 [1H, d, J 3.2]; 4.53 [2H, d, J 5.8]; 4.83
[2H, d, J 5.8]; 5.16-5.47 [4H, m]; 5.65 [1H,m]; 5.97 [1H,m];
6.92 [1H, d, J 8.3]; 6.95 [1H, d, J 8.6]; 7.06 [1H, t, J 7.5]; 7.08
[1H, t, J 7.3]; 7.22 [1H, d, J 7.4]; 7.29 [1H, t, J 7.8]; 7.30 [1H,
t, J 7.7]; 7.51 [1H, d, J 7.5]; 8.76 [1H, bs]; 8.81 [1H, bs]. 13C
NMR: 37.9, 39.1 [CH]; 45.4, 45.5 [CH]; 67.8, 68.1 [CH2]; 110.7,
110.8 [CH]; 113.5, 115.3 [CN]; 120.0, 120.5 [C], 123.3, 123.4
[CH], 124.2 [C], 124.4, 125.1 [CH], 129.8, 130.0 [CH], 130.4,
130.6 [CH], 141.9, 142.1 [C], 163.3, 164.6 [CdO], 175.6 [Cd
O]. Mass C14H12N2O3 (m/z [% abundance]): 256 [10], 171 [100],
132 [20].
1H NMR (CDCl3): δ 1.28 [3H, t, J 7.1]; 3.25 [2H, m]; 3.73 [1H,
m]; 4.24 [2H, q, J 7.1]; 7.32 [5H, m]. 13C NMR: 14.2 [CH3];
35.9 [CH2], 39.8 [CH], 63.0 [CH2], 116.3 [CN], 127.9 [CH], 129.0
[CH], 129.2 [CH], 135.4 [C], 141.13 [CH], 165.6 [CdO]. Mass
C
12H13NO2 (m/z [% abundance]): 203 [15], 130 [20], 91 [100].
2-(4-H yd r oxy-3-m et h oxyb en zyl)m a lon on it r ile (5d ).
Mp: 86-87. IR (ν ( 4 cm-1): 3450, 3057, 3000, 2948, 2259,
1
1626, 1576, 1447, 960, 757, 689. H NMR (CDCl3/DMSO-d6):
δ 3.19 [2H, d J 6.8]; 3.88 [3H, s]; 4.41 [1H, t, J 6.8]; 4.77 [1H,
bs]; 6.78 [1H, dd, J 8.0, 2.0], 6.85 [1H, d, J 2.0], 6.87 [1H, d, J
8.0]. 13C NMR: 24.7 [CH]; 35.8 [CH2]; 55.5 [CH3]; 112.1 [CH];
112.7 [CN]; 115.2 [CH]; 121.6 [CH]; 124.2 [C]; 146.2 [C]; 147.3
[C]. Mass C11H10N2O2 (m/z [% abundance]): 202 [15], 137 [100],
122 [10].
E t h y l-2-c y a n o -3-(4-h y d r o x y -3-m e t h o x y h e n y l)p r o -
p a n oa te (5e). Oil. IR (ν ( 4 cm-1): 3440, 2983, 2940, 2844,
1
2252, 1743, 1602, 1518, 1273, 1033. H NMR (CDCl3): δ 1.28
[3H, t, J 7.1]; 3.12 [1H, dd, J 13.9, 8.2]; 3.20 [1H, dd, J 13.9,
5.7]; 3.69 [1H, dd, J 8.2, 5.7]; 3.88 [3H, s]; 4.23 [2H, q, J 7.1];
5.77 [1H, s]; 6.74 [1H, dd, 8.0, 1.8]; 6.79 [1H, d, J 1.8]; 6.86
[1H, d, J 8.0]. 13C NMR: 14.1 [CH3]; 35.8 [CH2]; 40.2 [CH];
56.1 [CH3]; 63.1 [CH2]; 109.0 [CH]; 111.8 [CH]; 114.8 [CH];
116.5 [CN]; 122.1 [CH]; 127.3 [C]; 145.5 [C]; 146.8 [C]; 165.8
[CdO]. Mass C13H15NO4 (m/z [% abundance]): 249 [12], 206
[14], 151 [26], 137 [100].
Ack n ow led gm en t. The authors gratefully acknowl-
edge financial support from the Brazilian agencies
CNPq, FUJ B, and FAPERJ . S.J .G. also thanks the
Fundac¸a˜o Fiocruz, Farmanguinhos, Rio de J aneiro, for
financial support from the PAPES II program, and
C.R.W.G. acknowledges CNPq/Brazil (Conselho Nacio-
nal de Desenvolvimento Cient´ıfico e Tecnolo´gico) for a
postdoctoral fellowship.
2-Ben zylm a lon on itr ile (5a ).46 Mp: 80-81. IR (ν ( 4
cm-1): 3067, 3030, 2914, 2258, 1496, 1454, 749, 701. 1H NMR
(CDCl3):δ 3.28 [2H, d, J 6.9]; 3.91 [1H, d, J 6.9]; 7.32 [2H, m];
7.42 [3H, m]. 13C NMR: 25.2 [CH]; 36.8 [CH2]; 112.4 [CN];
129.0 [CH]; 129.3 [CH]; 129.5 [CH]; 133.1 [C]. Mass C10H8N2
(m/z [% abundance]): 156 [15], 91 [100].
Eth yl 2-Cya n o-3-p h en ylp r op a n oa te (5b).46 Oil. IR (ν (
4 cm-1): 3089, 3065, 3032, 2984, 2939, 2908, 2251, 1745, 1259.
Su p p or tin g In for m a tion Ava ila ble: Tables of atomic
coordinates for key calculated structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(74) Harley-Mason, J .; Ingleby, R. F. J . J . Chem. Soc., 1958, 3639-
3642.
J O034921E
8822 J . Org. Chem., Vol. 68, No. 23, 2003