Tandem ring opening and oximation of ethyl 3-aroyl-1-cyano-4-hydroxy-2,4,6- triarylcyclohexanecarboxylate by hydroxylamine

Article abstract of DOI:10.1080/00397910701557713

The reaction of hydroxylamine hydrochloride with ethyl 3-aroyl-1-cyano-4- hydroxy-2,4,6-triarylcyclohexanecarboxylate has led to the formation of ethyl 2-[amino(hydroxyimino)methyl]-3-aryl-5-(hydroxyimino)-5-arylpentanoate via a tandem ring opening and ox

Full text of DOI:10.1080/00397910701557713

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Tandem Ring Opening and Oximation of Ethyl
3‐Aroyl‐1‐cyano‐4‐hydroxy‐2,4,6‐triarylcyclohexa
by Hydroxylamine
Sivaperuman Saravanan a , Heeralal Vignesh Babu a & Shanmugam
Muthusubramanian a
a Department of Organic Chemistry , Madurai Kamaraj University , Madurai,
India
Published online: 05 Oct 2007.
To cite this article: Sivaperuman Saravanan , Heeralal Vignesh Babu & Shanmugam Muthusubramanian (2007)
Tandem Ring Opening and Oximation of Ethyl 3‐Aroyl‐1‐cyano‐4‐hydroxy‐2,4,6‐triarylcyclohexanecarboxylate
by Hydroxylamine, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:20, 3635-3648, DOI: 10.1080/00397910701557713
To link to this article: http://dx.doi.org/10.1080/00397910701557713
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Synthetic Communicationsw, 37: 3635–3648, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557713
Tandem Ring Opening and Oximation
of Ethyl 3-Aroyl-1-cyano-4-hydroxy-2,4,6-
triarylcyclohexanecarboxylate
by Hydroxylamine
Sivaperuman Saravanan, Heeralal Vignesh Babu,
and Shanmugam Muthusubramanian
Department of Organic Chemistry, Madurai Kamaraj University,
Madurai, India
Abstract: The reaction of hydroxylamine hydrochloride with ethyl 3-aroyl-1-cyano-4-
hydroxy-2,4,6-triarylcyclohexanecarboxylate has led to the formation of ethyl 2-[ami-
no(hydroxyimino)methyl]-3-aryl-5-(hydroxyimino)-5-arylpentanoate via a tandem
ring opening and oximation process. The structures of the products are confirmed by
NMR and X-ray techniques, and the conformational features of the product arrived
at are compared with a molecular dynamics simulation study.
Keywords: 3-aroyl-1-cyano-4-hydroxy-2,4,6-triarylcyclohexanecarboxylate, NMR
analysis, PM3 calculation, tandem reaction, X-ray structure
1,2-Benzisoxazoles are a class of important heterocyclic compounds showing a
variety of biological and potential therapeutic activities. For example, some of
the derivatives of 1,2-benzisoxazoles have been found to exhibit neuroleptic[1]
antipsychotic-like activities[2] in mice and anti-inflammatory activity[3] in the
rat. (Z)-2-(1,2-Benzisoxazol-3-yl)-3-[2-(2-piperidinoethoxy)-phenyl]acryloni-
trile and their analogs having a methoxy substituent at C-5 of the benzoisoxa-
zole ring showed potent antispasmodic activities during in vitro and in vivo
Received in India March 13, 2007
Address correspondence to Shanmugam Muthusubramanian, Department of
Organic Chemistry, Madurai Kamaraj University, Madurai 625 021, India. E-mail:
muthumanian2001@yahoo.com
3635

3636
S. Saravanan, H. V. Babu, and S. Muthusubramanian
studies.[4] 3a,4,5,6,7,7a-Hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-
1,2-benzisoxazole was found to be an antibacterial agent in vivo.[5] We are
interested in the synthesis of new hydrogenated benzfused isoxazole from
easily available starting materials following a related reported route[6] and
expect the resultant compounds to be biologically interesting. The reaction
of hydroxylamine hydrochloride with ethyl 3-aroyl-1-cyano-4-hydroxy-
2,4,6-triarylcyclohexanecarboxylate (4) was carried out, ultimately aiming
at the targeted new hydrogenated benzfused isoxazole and pyrazole. This
attempt has ended up in the formation of an unexpected product 5 whose struc-
tural features are confirmed by NMR and X-ray studies.
The precursors for the present investigation, ethyl 3-aroyl-1-cyano-4-
hydroxy-2,4,6-triarylcyclohexanecarboxylates (4a–c), were obtained by the
1,4-addition of ethyl cyanoacetate (2) on substituted benzylideneacetophe-
none (1a–d) in the presence of a sodium ethoxide catalyst (Scheme 1).[7]
Compounds 1a to 1c reacted with 2 to give 4a–c in very good yield, but
under identical conditions 1d and 1e have led to the formation of 3d and 3e
in good yield. The reaction of excess hydroxylamine hydrochloride with
4a–4c in the presence of anhydrous sodium acetate in ethanol has been
carried out under reflux for 3 hours. The product (obtained in approximately
50% yield, with the rest being unreacted starting material) is not the oxime
derivative of the cyclic compound 4, but a different one (5a–c), the structural
features of which are described next.
Scheme 1.

Tandem Ring Opening Oximation of Michael Adduct
3637
Figure 1. Fragment arrived at from the NMR data of 5.
The compound 5a is not freely soluble in chloroform, suggesting the
presence of more polar groups in the molecule. Only signals due to two aryl
systems, not four, can be observed in the proton and carbon-13 NMR
spectra (DMSO-d6). The presence of a -CH2-CH-CH(COOEt)-C(55X)-
grouping, as shown in Fig. 1, has been unambiguously established by two-
dimensional NMR connectivities. The signal at 3.38 ppm makes two intense
heteronuclear multiple bond correlation (HMBC) contours with the carbons
at 155.8 ppm and 136.3 ppm, the latter one being a quaternary carbon of an
aryl system. Thus the methylene end of the -CH2-CH-CH chain is
connected to an aryl ring (three-bond connection) and an sp2 hybridized
carbon with attached hetero atom (two-bond connection). It is surprising
that the other geminal hydrogen at 2.97 ppm has not exhibited this connec-
tivity in the HMBC spectrum. The presence of two slightly broadened
singlets at 9.38 ppm and 10.57 ppm, each accounting for one hydrogen and
another sharp singlet at 5.15 ppm accounting for two hydrogens, which are
all exchanging with D2O, prompted us to assign the structure of the product
formed (5a) to be an open chain analog with two hydroxy imino groups and
an amino group (Fig. 2). Bands at 3469, 3419, and 3370 cm21 in the IR
spectrum of 5a also confirm the presence of NH2 and OH groups.
It is clear that it is the mono-adduct that has undergone the addition of
hydroxylamine and not the bis adduct. Hence the formation of the product
5a–c can be explained by a mechanism (Scheme 2) involving retro-aldol
Figure 2. Structure of compound 5a.

3638
S. Saravanan, H. V. Babu, and S. Muthusubramanian
Scheme 2.
and Michael reactions to give the mono adduct in the first step of the reaction,
followed by the subsequent oximation reaction. The ring-opening process
requires hydroxylamine, proved by the fact that the simple treatment with
sodium acetate on 4 does not lead to any change under identical reaction con-
ditions. To prove the involvement of this tandem process, we have taken the
mono adduct ethyl 2-cyano-3-(2,4-dichlorophenyl)-5-oxo-5-arylpentanoate
(3d and 3e) and carried out the reaction under identical condition to get 5d
and 5e respectively in moderate yield. The single-crystal X-ray structural
analysis of 5d confirms the assigned structure (vide infra). The orientation
of the hydroxyl group of the two oximino functions, which are not clearly
inferred from the NMR data because the nuclear overhauser effect correlation
spectroscopy (NOESY) contours due to the hydroxyl groups are not clear,
have been unambiguously solved by molecular modeling and X-ray studies.
The results of X-ray analysis for 5d (Table 1) unambiguously proved the
structure assigned by NMR data. The ORTEP and packing diagrams are given
in Figs. 3 and 4. In the crystal structure of 5d, the 2,4-dichlorophenyl group is
gauche to the imino carbon in the conformational preference around the CH2-
CH bond and the two hydrogens of CH-CH bond prefer the anti position. The
conformational arrangement found around CH-CH and CH2-CH in the crystal
structure is in consonance with that observed in solution as revealed by the
coupling constants (Fig. 1). Crystal data have been deposited at the CCDC,
number 614664.
The PM3 molecular modeling method shows all four possible stereoche-
mical arrangements around C55N bond have comparable binding energy with
equally stable structures (Table 2). However, in the crystal structure of 5d, one
of the oximino group exists in cis-configuration with respect to the NH2 group,
and the other oximino group is trans to the phenyl group. It should be noted

Tandem Ring Opening Oximation of Michael Adduct
3639
Table 1. Crystal data and structural refinement for 5d
Parameters
5d
Empirical formula
Formula weight
Temperature
C20H21Cl2N3O4
438.30
293 (2) K
˚
0.71069 A
Wavelength
Crystal system, space group
Unit cell dimensions
Monoclinic, P 21/c
˚
˚
a ¼ 11.802 A; a ¼ 90.008; b ¼ 11.759 A;
˚
b ¼ 107.998 deg; c ¼ 16.754 A; g ¼ 90.008
3
˚
Z, volume
4, 2211.3 A
Density (calculated)
Absorption coefficient
F(000)
1.317 Mg/m3
0.323 mm21
912
Crystal size
0.18 ꢀ 0.16 ꢀ 0.14 mm
2.15 to 25.008
Theta range for data
collection
Index ranges
0 ꢁ h ꢁ 14, 21 ꢁ k ꢁ 13, 219 ꢁ l ꢁ 18
Reflections collected
Independent reflections
Absorption correction
Refinement method
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I . 2s(I)]
R indices (all data)
Largest diff. peak and hole
4519
3889 [Rint ¼ 0.0183]
Psi-scans
Full-matrix least-squares on F2
3889/0/271
1.027
R1 ¼ 0.0524, wR2 ¼ 0.1428
23
R1 ¼ 0.0938, wR2 ¼ 0.1696
˚
0.920 and 20.358 e A
.
that although compound 5d possesses a number of acidic hydrogens and a
variety of electron donor atoms, the molecule is not involved in intramolecular
hydrogen bonding; rather it exhibits intermolecular hydrogen bonding, even
though the oxime group exists in cis-configuration with respect to the NH2
group. The structure reveals intermolecular hydrogen bonding between
N8. . .N5 and O6. . .O9, forming an infinite chain of molecules along the crys-
tallographic axis c as shown in the packing diagram (Fig. 4). The linear chains
of molecule are additionally connected by classical R22(6) intermolecular
hydrogen bonding motif [O9. . .N9] and R22(12) intermolecular hydrogen
bonding motif [N8. . .O11], forming three-dimensional networks. Selected
hydrogen bond geometries are given in Table 3.
To explore the scope of this reaction, we carried out the same reaction
with the adduct formed from another nucleophile. Thus, the mono adduct 6
formed from benzyl cyanide and benzylideneacetophenone has been
subjected to hydroxylamine treatment as described (Scheme 3). In this case,
compound 7, similar to the one obtained in the previous reaction, has been

3640
S. Saravanan, H. V. Babu, and S. Muthusubramanian
Figure 3. ORTEP diagram of ethyl 2-[amino(hydroxyimino)methyl]-3-(2,4-dichloro-
phenyl)-5-(hydroxyimino)-5-phenylpentanoate (5d).
Figure 4. Packing diagram of ethyl 2-[amino(hydroxyimino)methyl]-3-(2,4-dichlor-
ophenyl)-5-(hydroxyimino)-5-phenylpentanoate (5d).

Tandem Ring Opening Oximation of Michael Adduct
3641
Table 2. Energy calculated by PM3 method for various orientation of hydroxylamine
groups for 5
Binding
energy
(kcal/mol)
Heat of
formation
(kcal/mol)
Dipole
moment
(Debye)
Orientation
of C55N-OH
Total energy
(kcal/mol)
5E-10Z
5E-10E
5Z-10Z
5Z-10E
2114950.4
2114949.1
2114950.5
2114949.2
25186.172
25184.91
25186.249
25184.999
239.01444
237.75183
239.09102
237.84047
1.531439
1.201498
1.604297
1.333146
obtained as evidenced by its IR and NMR spectra. In addition, another
product, 8, which is identified as the mono oxime of 6 by IR and NMR spec-
troscopy, has been obtained in which the cyanide group is not disturbed (IR
stretching at 2238 cm21) by the hydroxylamine, with only the carbonyl
group undergoing the reaction.
This study has demonstrated the unusual cleavage of the cyclic
compound, 3-aroyl-1-cyano-4-hydroxy-2,4,6-triarylcyclohexanecarboxylate,
under mild basic conditions to its monomer, ethyl 2-cyano-5-oxo-3,5-diaryl-
pentanoate, followed by the reaction of hydroxylamine with the ketone and
the cyanide functionalities. The structure and conformation of the obtained
product have been studied by NMR and X-ray crystallography.
EXPERIMENTAL
Melting points are uncorrected. One- and two-dimensional NMR spectra were
recorded on a Bruker 300-MHz instrument in DMSO-d6 using TMS as internal
standard. Chemical shifts are given in parts per million (d scale), and coupling
constants are given in hertz. IR spectra were recorded on a Jasco FT-IR
Table 3. Selected hydrogen-bonding geometry for 5d
D-H. . .A
(deg)
Symmetry
code
˚
D-H (A) H. . .A (A) D. . .A (A)
˚
˚
D-H. . . A
O9-H9. . .N9
0.89(5)
0.86
1.85 (5)
2.36
2.718 (3)
3.091 (4)
2.971 (3)
2.754 (4)
164 (4)
143.3
2x þ 1, 2y,
2z þ 1
N8-H8A. . .N5
x, 2y þ 1/2,
z þ 1/2
N8-H8B. . .O11 0.86
O6-H6. . .O9 0.71 (4)
2.16
156.5
2x þ 2, 2y,
2z þ 1
2.07 (4)
160 (5)
x, 2y þ 1/2,
z 2 1/2

3642
S. Saravanan, H. V. Babu, and S. Muthusubramanian
Scheme 3.
instrument (KBr pellet). Column chromatography was carried out in silica gel
(60–120 mesh) using petroleum ether–ethyl acetate as an eluent.
All the computational calculations for 5 were carried out on an MS
Windows 2000 platform with the software package of Hyperchem,[8]
version 7.0. The geometry optimization was performed with the Polak–
Ribiere algorithms included in the semi-empirical PM3 method.[9] Structure
was deemed to be minimized when the gradient root mean square was less
than 0.01 kcal/mol. This optimized structure was then subjected to confor-
mational search using a molecular dynamics simulation.
The single-crystal X-ray data for 5d were collected on a Nonius MACH3
˚
kappa diffractometer with MoKa radiation (l ¼ 0.71069 A). The structure
was solved by direct methods from SHELXA97[10] and refined by full-
matrix least squares on F2 by SHELXTL97.[11] Crystallographic data
(excluding structure factors) for the structure in this article have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 614664. Copies of the data can be obtained, free of
charge, by contacting the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK (E-mail: data_request@ccdc.cam.ac.uk; fax:
þ44 1223 336033).
General Procedure for the Preparation of Ethyl 3-Aroyl-1-cyano-4-
hydroxy-2,4,6-triarylcyclohexanecarboxylate (4a–c)
The adducts, ethyl 3-aroyl-1-cyano-4-hydroxy-2,4,6-triarylcyclohexanecar-
boxylates, have been prepared by a reported procedure.[7] Ethyl cyanoacetate

Tandem Ring Opening Oximation of Michael Adduct
3643
(0.0200 m) was added to different substituted chalcone (0.0200 m) in ether
solution in the presence of sodium ethoxide (0.0040 m) in ethanol, and the
reaction mixture was stirred at room temperature for about 24 h. The
product was purified by crystallization in ethanol. Compounds 4a and 4c
have already been reported.[7,12]
Ethyl 3-(4-Chlorobenzoyl)-4-(4-chlorophenyl)-1-cyano-4-hydroxy-
2,6-bis(4-methylphenyl)cyclohexanecarboxylate (4b)
Yield 78%, mp 2078C. Anal. calcd. for C37H33Cl2NO4: C, 70.93; H, 5.31; N,
2.24. Found: C, 70.97; H, 5.40; N, 2.31. IR (KBr pellet): nmax ¼ 3030, 2925,
2854, 2341, 1736, 1660, 1589, 1402, 1247 cm21 1H NMR (300 MHz,
.
CDCl3): d ¼ 0.76 (t, J ¼ 7.2 Hz, 3H); 2.11 (s, 3H); 2.13 (dd, J ¼ 12.6,
3.0 Hz, 1H); 2.30 (s, 3H); 2.84 (td, J ¼ 13.5, 2.4 Hz, 1H); 3.77 (q, J ¼ 7.2,
2H); 4.20 (dd, J ¼ 12.6, 3.0 Hz, 1H); 4.24 (d, J ¼ 12.3 Hz, 1H); 4.78
(d, J ¼ 12.3 Hz, 1H); 5.25 (d, J ¼ 2.1 Hz, 1H); 6.83 (d, J ¼ 8.1 Hz, 2H);
7.10–7.21 (m, 8H); 7.29–7.35 (m, 4H); 7.50 (d, J ¼ 8.4 Hz, 2H) ppm.
13C NMR (75 MHz, CDCl3): d ¼ 13.5, 20.9, 21.1, 41.7, 44.7, 48.7, 52.2,
59.9, 62.3, 117.8, 126.2, 128.2, 128.4, 128.5, 129.0, 129.3, 129.4, 131.3,
133.4, 134.6, 135.5, 137.9, 138.2, 140.2, 143.3, 166.3, 203.8 ppm.
General Procedure for the Preparation of Ethyl 2-Cyano-5-oxo-3,5-
diarylpentanoate (3d, 3e)
The adducts, ethyl 2-cyano-5-oxo-3,5-diarylpentanoates, have all been
prepared by the reported procedure. Ethyl cyanoacetate (0.0200 m) was
added to different chalcones (0.0200 m) in ether solution in the presence of
sodium ethoxide (0.0020 m) in ethanol, and the reaction mixture was stirred
at room temperature for about 24 h. The product was obtained by recrystalliza-
tion from ethanol.
Ethyl 2-Cyano-3-(2,4-dichlorophenyl)-5-oxo-5-phenylpentanoate (3d)
Yield 82%, mp 938C. Anal. calcd. for C20H17Cl2NO3: C, 61.55; H, 4.39; N,
3.59. Found: C, 61.61; H, 4.43; N, 3.61. IR (KBr pellet): nmax ¼ 3066,
2924, 2854, 2249, 1739, 1689, 1473, 1373, 1305, 1188, 1039 cm21
.
1H NMR (300 MHz, CDCl3): d ¼ 1.29 (t, J ¼ 7.2 Hz, 3H); 3.58 (dd,
J ¼ 18.0, 5.1 Hz, 1H); 3.85 (dd, J ¼ 18.0, 9.0 Hz, 1H); 3.98 (d, J ¼ 5.1 Hz,
1H); 4.26 (q, J ¼ 7.2 Hz, 2H); 4.69 (qui, J ¼ 5.1 Hz, 1H); 7.23 (dd,
J ¼ 8.4, 2.1 Hz, 1H); 7.32 (d, J ¼ 8.4 Hz, 1H); 7.45 (d, J ¼ 2.1 Hz, 1H);
7.49 (d, J ¼ 7.8 Hz, 2H); 7.60 (tt, J ¼ 7.8, 1.2 Hz, 1H); 7.95 (d, J ¼ 8.4 Hz,
2H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 13.9, 36.2, 38.8, 42.4, 63.3,

3644
S. Saravanan, H. V. Babu, and S. Muthusubramanian
114.9, 127.7, 128.0, 128.8, 130.0, 133.7, 133.8, 134.3, 134.5, 135.0, 136.0,
164.6, 195.7 ppm.
Ethyl 2-Cyano-3-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-
5-oxopentanoate (3e)
Yield 77%, mp 968C. Anal. calcd. for C21H19Cl2NO4: C, 60.01; H, 4.56; N,
3.33. Found: C, 60.05; H, 4.58; N, 3.36. IR (KBr pellet): nmax ¼ 3068,
2933, 2852, 2244, 1743, 1674, 1601, 1469, 1421, 1234, 1173, 1024 cm21
.
1H NMR (300 MHz, CDCl3): d ¼ 1.29 (t, J ¼ 7.2 Hz, 3H); 3.51 (dd,
J ¼ 17.7, 4.8 Hz, 1H); 3.74 (dd, J ¼ 17.7, 9.0 Hz, 1H); 3.87, (s, 3H); 3.98
(d, J ¼ 4.8 Hz, 1H); 4.26 (q, J ¼ 7.2 Hz, 2H); 4.68 (qui, J ¼ 4.8 Hz, 1H);
6.94 (d, J ¼ 9.0 Hz, 2H); 7.22 (dd, J ¼ 8.4, 2.1 Hz, 1H); 7.32
(d, J ¼ 8.4 Hz, 1H); 7.44 (d, J ¼ 2.1 Hz, 1H); 7.93 (d, J ¼ 9.0 Hz, 2H)
ppm. 13C NMR (75 MHz, CDCl3): d ¼ 14.3, 36.7, 38.8, 42.9, 55.9, 63.7,
114.3, 115.4, 128.1, 129.3, 129.6, 130.4, 130.8, 134.7, 135.0, 135.5, 164.4,
165.1, 194.6 ppm.
General Procedure for the Reaction of Ethyl 3-Aroyl-1-cyano-
4-hydroxy-2,4,6-triarylcyclohexanecarboxylate (4)/Ethyl 2-Cyano-
5-oxo-3,5-diarylpentanoate (3) with Hydroxylamine Hydrochloride
To a warm solution of 0.0040 m of ethyl 3-aroyl-1-cyano-4-hydroxy-2,4,6-
triarylcyclohexanecarboxylate (4)/ethyl 2-cyano-5-oxo-3,5-diarylpentanoate
(3) in 50 mL of ethanol, a solution of 1.85 g (0.0260 m) of hydroxylamine
hydrochloride and 2.18 g (0.0260 m) of anhydrous sodium acetate in 15 ml
of water was added by portions, and the reaction mixture was refluxed in a
water bath for 3 h. The reaction mixture was filtered off, and the filtrate was
poured onto crushed ice and extracted with chloroform. The product was
washed with petroleum ether and dried.
Ethyl 2-[Amino(hydroxyimino)methyl]-5-(hydroxyimino)-
3,5-diphenylpentanoate (5a)
Yield 50%, mp 1778C. Anal. calcd. for C20H23N3O4: C, 65.03; H, 6.28; N,
11.37. Found: C, 65.08; H, 6.26; N, 11.38. IR (KBr pellet): nmax ¼ 3469,
3419, 3370, 3249, 2981, 2927, 1724, 1666 cm21 1H NMR (300 MHz,
.
CDCl3): d ¼ 0.79 (t, J ¼ 7.2 Hz, 3H); 2.97 (dd, J ¼ 13.5, 3.6 Hz, 1H); 3.38
(dd, J ¼ 13.5, 11.7 Hz, 1H); 3.48 (d, J ¼ 11.7 Hz, 1H); 3.59 (td, J ¼ 11.7,
3.6 Hz, 1H); 3.76 (q, J ¼ 7.2 Hz, 2H); 5.15 (s, 2H); 6.98–7.02 (m, 2H);
7.07–7.09 (m, 3H); 7.22–7.30 (m, 5H); 9.38 (bs, 1H); 10.57 (bs, 1H) ppm.

Tandem Ring Opening Oximation of Michael Adduct
3645
13C NMR (75 MHz, CDCl3): d ¼ 13.5, 29.3, 43.4, 54.3, 60.6, 126.3, 126.8,
127.6, 127.9, 128.2, 128.3, 136.3, 139.5, 149.9, 155.8, 170.9 ppm.
Ethyl 2-[Amino(hydroxyimino)methyl]-5-(4-chlorophenyl)-
5-(hydroxyimino)-3-(4-methylphenyl)pentanoate (5b)
Yield 46%, mp 160–1628C. Anal. calcd. for C21H24ClN3O4: C, 60.36; H,
5.79; N, 10.06. Found: C, 60.40; H, 5.82; N, 10.09. IR (KBr pellet):
1
nmax ¼ 3444, 2925, 2856, 1736, 1760, 1589, 1248, 1093 cm21. H NMR
(300 MHz, CDCl3): d ¼ 0.83 (t, J ¼ 7.2 Hz, 3H); 2.22 (s, 3H); 2.89
(d, J ¼ 12.6 Hz, 1H); 3.36–3.61 (m, 3H); 3.77 (q, J ¼ 7.2 Hz, 2H); 5.25
(s, 2H); 6.89 (s, 4H); 7.22 (d, J ¼ 8.1 Hz, 2H); 7.27 (d, J ¼ 8.1 Hz, 2H);
9.53 (bs, 1H); 10.87 (bs, 1H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 12.5,
19.9, 28.1, 41.7, 53.2, 59.6, 126.7, 127.0 one carbon merges with the other,
127.9, 132.6, 133.9, 135.0, 135.3, 148.7, 153.7, 169.6 ppm.
Ethyl 2-[Amino(hydroxyimino)methyl]-5-(hydroxyimino)-
5-(4-methoxyphenyl)-3-phenylpentanoate (5c)
Yield 45%, mp 180–1828C. Anal. calcd. for C21H25N3O5: C, 63.14; H, 6.31;
N, 10.52. Found: C, 63.18; H, 6.36; N, 10.55. IR (KBr pellet): nmax ¼ 3413,
3292, 3236, 2933, 2837, 1722, 1637, 1606, 1514, 1304, 1248, 1188 cm21
.
1H NMR (300 MHz, CDCl3): d ¼ 0.86 (t, J ¼ 6.9 Hz, 3H); 2.85
(d, J ¼ 10.5 Hz, 1H); 3.26–3.59 (m, 3H); 3.75 (q, J ¼ 6.9 Hz, 2H); 3.79
(s, 3H); 5.22 (s, 2H); 6.79 (d, J ¼ 8.4 Hz, 2H); 6.93–7.07 (m, 5H); 7.31
(d, J ¼ 8.4 Hz, 2H); 9.48 (bs, 1H); 10.51 (bs, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d ¼ 12.5, 27.9, 41.6, 53.9, 57.8, 59.4, 112.2, 125.4, 126.3, 126.4,
127.2, 127.5, 138.8, 153.5, 158.3, 167.7, 168.2 ppm.
Ethyl 2-[Amino(hydroxyimino)methyl]-3-(2,4-dichlorophenyl)-
5-(hydroxyimino)-5-phenylpentanoate (5d)
Yield 55%, mp 1678C. Anal. calcd. for C20H21Cl2N3O4: C, 54.81; H, 4.83; N,
9.59. Found: C, 54.79; H, 4.85; N, 9.61. IR (KBr pellet): nmax ¼ 3446, 3361,
2987, 2906, 1726, 1670, 1475, 1315, 1174 cm21 1H NMR (300 MHz,
.
CDCl3): d ¼ 1.32 (t, J ¼ 7.2 Hz, 3H); 2.99 (dd, J ¼ 13.2, 4.5 Hz, 1H);
3.34–3.62 (m, 2H); 4.15–4.33 (m, 3H); 4.76 (s, 2H); 7.03 (d, J ¼ 8.1 Hz,
1H); 7.10 (d, J ¼ 2.4 Hz, 1H); 7.25–7.26 (m, 4H); 7.35–7.38 (m, 2H); 9.18
(bs, 1H); 10.81 (bs, 1H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 12.5, 27.7,
36.3, 51.1, 59.8, 124.5, 124.8, 126.4, 126.7, 129.7, 130.3, 133.2, 134.4,
134.7, 147.1, 152.7, 158.2, 169.2 ppm.

3646
S. Saravanan, H. V. Babu, and S. Muthusubramanian
Ethyl 2-[Amino(hydroxyimino)methyl]-3-(2,4-dichlorophenyl)-
5-(hydroxyimino)-5-(4-methoxyphenyl)pentanoate (5e)
Yield 49%, mp 152–1548C. Anal. calcd. for C21H23Cl2N3O5: C, 53.86; H,
4.95; N, 8.97. Found: C, 53.90; H, 4.96; N, 8.94. IR (KBr pellet):
nmax ¼ 3444, 3344, 3215, 2974, 2935, 2843, 1724, 1670, 1606, 1514, 1307,
1
1252, 1186 cm21. H NMR (300 MHz, CDCl3): d ¼ 1.31 (t, J ¼ 7.2 Hz,
3H); 2.94 (dd, J ¼ 13.2, 4.2 Hz, 1H); 3.35–3.58 (m, 2H); 3.78 (s, 3H);
4.16–4.32 (m, 3H); 4.85 (s, 2H); 6.77 (d, J ¼ 8.7 Hz, 2H); 7.05–7.14
(m, 2H); 7.31 (d, J ¼ 8.7 Hz, 2H); 7.40 (d, J ¼ 8.7 Hz, 1H); 9.09 (bs, 1H);
10.68 (bs, 1H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 12.8, 28.1, 36.8,
51.5, 53.9, 60.2, 112.1, 125.1, 126.1, 126.9, 127.2, 129.9, 130.8, 133.6,
134.9, 147.5, 152.6, 158.4, 169.6 ppm.
Procedure for Preparation of 3-(4-Methoxyphenyl)-5-(4-
methylphenyl)-5-oxo-2-phenyl-pentanenitrile (6)
The adduct, 3-(4-methoxyphenyl)-5-(4-methylphenyl)-5-oxo-2-phenyl-penta-
nenitrile, has been prepared by the reported procedure. Benzyl cyanide
(0.0160 m) was added to substituted chalcone (0.0160 m) in ether solution
in the presence of sodium ethoxide (0.0035 m) in ethanol, and the reaction
mixture was stirred at room temperature for about 24 h. The product was
obtained by recrystallization from ethanol.
3-(4-Methoxyphenyl)-5-(4-methylphenyl)-5-oxo-2-
phenylpentanenitrile (6)
Yield 89%, mp 1468C. Anal. calcd. for C25H23NO2: C, 81.27; H, 6.27; N, 3.79.
Found: C, 81.31; H, 6.29; N, 3.82. IR (KBr pellet): nmax ¼ 3014, 2929, 2841,
2242, 1674, 1608, 1513, 1456, 1301, 1246, 1180, 1032 cm21 1H NMR
.
(300 MHz, CDCl3): d ¼ 2.39 (s, 3H); 3.30 (dd, J ¼ 17.1, 5.1 Hz, 1H); 3.63
(dd, J ¼ 17.1, 9.0 Hz, 1H); 3.75 (s, 3H); 3.87–3.93 (m, 1H); 4.20
(d, J ¼ 5.7 Hz, 1H); 6.79 (d, J ¼ 8.9 Hz, 2H); 7.12 (d, J ¼ 8.9 Hz, 2H);
7.18–7.23 (m, 4H); 7.29–7.31 (m, 3H); 7.77 (d, J ¼ 8.1 Hz, 2H) ppm. 13C
NMR (75 MHz, CDCl3): d ¼ 21.6, 39.5, 44.0, 44.6, 55.1, 113.9, 119.8,
128.1, 128.2 one carbon merges with the other, 128.8, 129.0, 129.3, 131.4,
133.5, 134.1, 144.2, 158.8, 196.7 ppm.
Reaction of 3-(4-Methoxyphenyl)-5-(4-methylphenyl)-5-oxo-2-
phenylpentanenitrile (6) with Hydroxylamine
3-(4-Methoxyphenyl)-5-(4-methylphenyl)-5-oxo-2-phenylpentanenitrile (1.00 g,
0.0028 m was dissolved in 50 mL of ethanol by gentle warming. To this, a

Tandem Ring Opening Oximation of Michael Adduct
3647
solution of 1.36 g (0.0196 m) of hydroxylamine hydrochloride and 1.61 g
(0.0196 m) of anhydrous sodium acetate in 15 ml of water were added by
portions, and the reaction mixture was refluxed on a water bath for 3 h. The
reaction mixture was filtered off, and the filtrate was poured onto crushed
ice and extracted with chloroform. The crude mixture was subjected to
column chromatography to get two products, 7 and 8.
N0-hydroxy-5-(hydroxyimino)-3-(4-methoxyphenyl)-5-(4-
methylphenyl)-2-phenyl pentanimidamide (7)
Yield 55%, mp 1578C. Anal. calcd. for C25H27N3O3: C, 71.92; H, 6.52; N,
10.06. Found: C, 71.97; H, 6.55; N, 10.04. IR (KBr pellet): nmax ¼ 3384,
3029, 2924, 2860, 1660, 1610, 1514, 1450, 1250, 1180, 1034 cm21
.
1H NMR NMR spectrum recorded in acetone-d6 (300 MHz, CDCl3):
d ¼ 2.29 (s, 3H); 3.25 (dd, J ¼ 13.5, 3.6 Hz, 1H); 3.52–3.55 (m, 1H); 3.55
(s, 3H); 3.83–3.96 (m, 2H); 5.47 (s, 2H); 6.45 (d, J ¼ 8.7 Hz, 2H); 6.84
(d, J ¼ 8.7 Hz, 2H); 6.97 (tt, J ¼ 7.5, 1.2 Hz, 1H); 7.04 (d, J ¼ 7.5 Hz,
2H); 7.07 (d, J ¼ 8.1 Hz, 2H); 7.27 (d, J ¼ 7.5 Hz, 2H); 7.40
(d, J ¼ 8.1 Hz, 2H); 8.02 (bs, 1H); 10.65 (bs, 1H) ppm. 13C NMR NMR
spectrum recorded in acetone-d6 (75 MHz, CDCl3): d ¼ 21.6, 31.7, 44.8,
55.5, 55.6, 113.9, 127.5, 127.8, 129.0, 129.8, 130.0, 130.8, 134.3, 135.2,
138.9, 141.6, 156.3, 157.5, 159.1 ppm.
5-(Hydroxyimino)-3-(4-methoxyphenyl)-5-(4-methylphenyl)-2-
phenylpentanenitrile (8)
Yield 42%, mp 1468C. Anal. calcd. for C25H24N2O2: C, 78.10; H, 6.29; N,
7.29. Found: C, 78.13; H, 6.33; N, 7.28. IR (KBr pellet): nmax ¼ 3236,
3029, 2929, 2239, 1614, 1514, 1456, 1306, 1248, 1178, 1041 cm21
.
1H NMR NMR spectrum recorded in CDCl3 (300 MHz, CDCl3): d ¼ 2.33
(s, 3H); 3.15 (dd, J ¼ 13.5, 4.5 Hz, 1H); 3.37 (m, 1H); 3.60 (dd, J ¼ 13.5,
10.8 Hz, 1H); 3.71 (s, 3H); 3.96 (d, J ¼ 6.6 Hz, 1H); 6.65 (d, J ¼ 8.4 Hz,
2H); 6.90 (d, J ¼ 8.4 Hz, 2H); 7.01 (d, J ¼ 8.4 Hz, 2H); 7.06
(d, J ¼ 8.4 Hz, 2H); 7.14–7.18 (m, 1H); 7.26 (m, 4H); 8.65 (bs, 1H) ppm.
13C NMR NMR spectrum recorded in CDCl3 (75 MHz, CDCl3): d ¼ 21.2,
28.2, 44.6, 46.8, 55.1, 113.5, 119.8, 126.3, 128.0, 128.1, 128.6, 129.1,
129.2, 130.2, 132.2, 133.9, 139.1, 157.3, 158.8 ppm.
ACKNOWLEDGMENTS
The authors thank Department of Science and Technology (DST), New Delhi,
for the NMR facility under the Intensified Research in High Priority Area

3648
S. Saravanan, H. V. Babu, and S. Muthusubramanian
(IRHPA) program and DST (Funds for Improvement of Science and Technol-
ogy (FIST)), New Delhi, for the single-crystal X-ray diffractometer facility.
Financial support from Council of Scientific and Industrial Research
(CSIR), New Delhi, for S. Saravanan is gratefully acknowledged.
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