Selective synthesis of E-isomers of aldoximes via a domino aza-Michael/retro-Michael reaction

Article abstract of DOI:10.2478/s11696-012-0137-3

A highly stereoselective synthesis of E-isomer of aldoximes was developed through a base-catalysed domino aza-Michael/retro-Michael reaction of hydroxylamine and 2-(R-benzylidene)malononitrile. This reaction generates (E)-aldoxime diastereomer in high yie

Full text of DOI:10.2478/s11696-012-0137-3

Chemical Papers 66 (4) 308–311 (2012)
DOI: 10.2478/s11696-012-0137-3
SHORT COMMUNICATION
Selective synthesis of -isomers of aldoximes via a domino
aza-Michael/retro-Michael reaction
a
a
b
aWei Chen, Wei-Guo Yu, Hai-Bo Shi, Xiao-Yan Lu*
aZhejiang Pharmaceutical College, 315100 Ningbo, China
bNingbo No. 2 Hospital, 315010 Ningbo, China
Received 6 August 2011; Revised 23 November 2011; Accepted 1 December 2011
A highly stereoselective synthesis of E-isomer of aldoximes was developed through a base-
catalysed domino aza-Michael/retro-Michael reaction of hydroxylamine and 2-(R-benzylidene)malo-
nonitrile. This reaction generates (E)-aldoxime diastereomer in high yields (eight examples, isolated
yields of 82–93 %), excellent diastereomeric purity (diastereomeric ratio higher than 95 : 5 by 1H
NMR), and proceeds under mild reaction conditions (aqueous NaOH, pH 12, room temperature,
4 h).
c
ꢀ 2012 Institute of Chemistry, Slovak Academy of Sciences
Keywords: isomer, aldoxime, hydroxylamine, 2-benzylidenemalononitrile
Oxime compounds frequently exhibit satisfactory
insecticidal, fungicidal, or herbicidal activity. A re-
cent study of molecular design, synthesis, and bio-
logical activity of oxime compounds has attracted a
great deal of attention (Song et al., 2005). The addi-
tion of hydroxylamine to aromatic aldehyde to yield
aldoximes is not only one of the best understood exam-
ples of a non-enzymatic addition-elimination reaction
(Jencks, 1959), but also an important reaction in or-
ganic synthesis (Sandler & Karo, 1983). Two isomeric
aldoximes (Z and E) are usually produced with dif-
ferent physical properties and biological activities and
which should be separated by chromatography or re-
crystallisation. The classical methods of the synthesis
of aldoximes usually give a mixture of the two geo-
metric isomers (Z : E ratio of 85 : 15 to 1 : 1) (Sharghi
& Hosseini, 2002; Sharghi & Sarvari, 2001; Guo et al.,
2001).
which have been used for the oximation of aldehy-
des also catalyse the inter-conversion of Z/E-isomers.
The rate of equilibration of a mixture of Z/E-isomers
and the position of the equilibrium is temperature-
dependent (Smith & Antoniades, 1960). Recently, con-
siderable attention has been paid to a selective syn-
thesis of E- and Z-isomers of oximes (Sharghi & Sar-
vari, 2001). However, isolation of the (E)-oxime us-
ing the methodology described is not practical, as it
must be carried out at 0◦C to prevent formation of
the Z-diastereomer. These classical methods are de-
pendent on temperature or acidic conditions hence are
not practical for process-scale synthesis. Although our
method requires an additional step, it effectively de-
livers the desired (E)-aldoximes under alkaline condi-
tions at room temperature, providing a selective syn-
thesis of (E)-aldoximes for acid-sensitive substrates.
Aldoxime formation proceeds through the forma-
tion of a tetrahedral intermediate followed by an acid-
catalysed dehydration step (Uno et al., 1994). The for-
mation of a mixture of isomers (Z and E) suggests
an E1 elimination of water and a proton (Bruckner,
2002). We recently reported that the electron-deficient
α,α-dicyanoalkenes could act as versatile direct viny-
Very few methods are available for the synthesis
of exclusively E-isomer of aldoximes (Zvilichovsky &
Heller, 1972; Uno et al., 1994). In many cases, E-
isomers have been obtained from the Z forms by the
hydrochloride method or by purification by column
chromatography (Furniss et al., 1989). The reagents
*Corresponding author, e-mail: xiaoyanlu@yahoo.cn

W. Chen et al./Chemical Papers 66 (4) 308–311 (2012)
309
Fig. 1. Proposed formation of aldoximes via domino aza-Michael/retro-Michael addition reactions. Reaction conditions: i)
CH2(CN)2; ii) H2NOH · HCl, aza-Michael addition; iii) splitting off (CN)2CH− and HB, retro-Michael addition, E2
elimination.
Table 1. Characterisation data of prepared (E)-aldoximes
Compound
R
Yielda/%
M.p.a/◦C
M.p.b/◦C
IIa
IIb
IIc
IId
IIe
IIf
H
4-Me
4-Cl
3-Cl
2-Cl
3-Me
3-OMe
4-Br
92
90
93
91
84
85
82
92
33
32
79–80
110
71–72
75
60
40
115–116
76–78
107–109
72–73
75–76
60–61
39–40
114–115
IIg
IIh
a) Yields and m.p. of crystalline products obtained after chromatography; b) values reported in literature (Sharghi & Sarvari, 2001;
Crawford & Woo, 1965; Dalton & Foley, 1973; Guo et al., 2001).
logous donors in asymmetric Michael addition reac-
tions of nitroalkenes and α,β-unsaturated aldehydes
with excellent chemical- and stereo-selectivity (Xue
et al., 2005; Xie et al., 2006). Our report on the
sequential Michael/retro-Michael addition reactions
between α,α-dicyanoalkenes and α,β-unsaturated ke-
tones (Xie et al., 2007) lead us to speculate that
2-benzylidenemalononitrile could be applied succes-
sively as Michael acceptor and retro-Michael donor
in some domino sequences. In this respect, we en-
visaged that sequential aza-Michael/retro-Michael ad-
dition reactions between 2-benzylidenemalononitrile
and hydroxylamine would be possible, as outlined in
Fig. 1, to provide a straightforward protocol for the se-
lective synthesis of (E)-aldoximes via E2 elimination.
All reagents were commercially available products
(Sigma–Aldrich Co., China) and were used without
further purification. 2-(R-benzylidene)malononitriles
(Ia–Ih) were prepared as previously published (Chang
et al., 2005). 1H (400 MHz) and 13C (100 MHz) NMR
spectra were recorded on a Bruker 400 spectrometer
using CDCl3 as a solvent and TMS as an internal stan-
dard. ESI-HRMS spectra (70 eV) were measured with
a Finnigan LCQDECA ion trap mass spectrometer.
(E)-Aldoximes (IIa–IIh) were synthesised in accor-
dance with the general method as follows: an aque-
ous solution of NaOH (1 M, 6 mL) was added to
a solution of hydroxylamine hydrochloride (5 mmol)
in H2O (5 mL) under stirring at room tempera-
ture until the pH value reached 12. Next, 2-(R-
benzylidene)malononitrile (I, 1 mmol) was added and
the mixture was stirred for 4 h followed by extraction
of the product with CH2Cl2 (3 × 10 mL). The organic
layer was washed with water (3 × 30 mL), dried with
Na2SO4 and the solvent evaporated to give the crude
(E)-aldoxime II in almost quantitative yield. The pure
product was obtained by flash chromatography on sil-
ica gel using EtOAc/petroleum ether (ϕr = 1 : 9). The
isolated yields and m.p. of all compounds II are given
in Table 1 and the spectral data are summarised in
Table 2.
In an initial investigation, we tested the reaction
of 2-benzylidenemalononitrile with hydroxylamine hy-
drochloride in the presence of 1 M NaOH solu-
tion at room temperature. The desired crude (E)-
aldoxime was isolated after 4 h in almost quanti-

310
W. Chen et al./Chemical Papers 66 (4) 308–311 (2012)
Table 2. Spectral data of newly prepared compounds
Compound
Spectral dataa
IIa
IIb
IIc
IId
IIe
1H NMR (CDCl3), δ: 9.18 (brs, 1H), 8.17 (s, 1H), 7.58–7.55 (m, 2H), 7.40–7.37 (m, 3H)
13C NMR (CDCl3), δ: 150.4, 131.9, 130.1, 128.8, 127.1
ESI-HRMS, m/z (found/calc.): 122.0599/122.0606 ([M + H]+, C7H7NO + H)
1H NMR (CDCl3), δ: 9.03 (brs, 1H), 8.14 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H)
13C NMR (CDCl3), δ: 150.2, 140.3, 129.5, 129.0, 126.9, 21.4
ESI-HRMS, m/z (found/calc.): 136.0757/136.0762 ([M + H]+, C8H9NO + H)
1H NMR (CDCl3), δ: 8.74 (s, 1H), 8.13 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H)
13C NMR (CDCl3), δ: 149.3, 136.0, 130.3, 129.0, 128.2
ESI-HRMS, m/z (found/calc.): 156.0214/156.0216 ([M + H]+, C7H6ClNO + H)
1H NMR (CDCl3), δ: 9.06–8.77 (m, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.43–7.30 (m, 2H)
13C NMR (CDCl3), δ: 149.2, 134.8, 133.5, 130.1, 130.0, 126.8, 125.2
ESI-HRMS, m/z (found/calc.): 156.0211/156.0216 ([M + H]+, C7H6ClNO + H)
1H NMR (CDCl3), δ: 8.88–8.67 (m, 1H), 8.59 (s, 1H), 7.82 (dd, J = 7.6 Hz, J = 1.5 Hz, 1H), 7.40 (dd, J = 7.9 Hz,
J = 1.0 Hz, 1H), 7.36–7.24 (m, 2H)
13C NMR (CDCl3), δ: 147.6, 133.9, 131.1, 129.9, 129.6, 127.1, 127.0
ESI-HRMS, m/z (found/calc.): 156.0212/156.0216 ([M + H]+, C7H6ClNO + H)
IIf
IIg
IIg
1H NMR (CDCl3), δ: 9.90 (s, 1H), 8.24 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.25 (d, J =
7.5 Hz, 1H), 2.41 (s, 3H)
13C NMR (CDCl3), δ: 150.5, 138.4, 131.6, 130.9, 128.6, 127.5, 124.2, 21.2
ESI-HRMS, m/z (found/calc.): 136.0759/136.0762 ([M + H]+, C8H9NO + H)
1H NMR (CDCl3), δ: 9.80 (s, 1H), 8.15 (s, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.20–7.08 (m, 2H), 6.93 (d, J = 8.2 Hz,
1H), 3.78 (s, 3H)
13C NMR (CDCl3), δ: 159.6, 150.4, 132.9, 129.7, 120.1, 116.4, 111.1, 55.1
ESI-HRMS, m/z (found/calc.): 152.0716/152.0712 ([M + H]+, C8H9NO2 + H)
1H NMR (CDCl3), δ: 8.56 (s, 1H), 8.11 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H)
13C NMR (CDCl3), δ: 149.4, 132.1, 130.8, 128.5, 124.3
ESI-HRMS, m/z (found/calc.): 199.9715/199.9711 ([M + H]+, C7H6BrNO + H)
a) NMR data are in good agreement with the published data (Crandall & Reix, 1992; Gordon et al., 1984; Danoff et al., 1979;
Edwards et al., 2007).
Table 3. Selected crystallographic dataa and structure refine-
ment for compound IIh
Empirical formula
C7H6BrNO
Formula mass
Temperature, T (K)
200.04
296(2)
Crystal system, space group Monoclinic, P21/c
˚
a (A)
6.1929(4)
4.7875(3)
25.4600(13)
752.75(8)
4
˚
b (A)
˚
c (A)
3
˚
Unit-cell volume, V (A )
Formula per unit cell, Z
Absorption coefficient,
µ (mm−1
Fig. 2. A perspective drawing of IIh structure.
5.386
)
Crystal size (mm)
Diffractometer
Reflections collected
Independent reflections (Rint) 1690 (0.0300)
Refinement method
0.46 × 0.27 × 0.1
Siemens P4
5969
tative yield. In further experiments, various 2-(R-
benzylidene)malononitriles (possessing electron-dona-
ting or electron-withdrawing groups in the benzene
ring) analogously underwent a condensation reaction
with hydroxylamine at room temperature, giving the
corresponding (E)-aldoximes in high yields (Table 1).
Full-matrix least-squares on F2
1690/0/91
1.028
R1 = 0.0312, wR2 = 0.0808
0.626 and −0.411
Data/restraints/parameters
Goodness-of-fit on F2
R indices [I > 2σ(l)]
Largest difference peak
1
The absence of Z-isomer was confirmed by H NMR
−3
˚
spectral data (Table 2). In addition, the E configura-
tion was confirmed by a single-crystal X-ray diffrac-
tion of 2-(4-bromobenzylidene)malononitrile (IIh) (see
Fig. 2 and Table 3).
and hole (e A
)
a) Standard deviations in parentheses.
In conclusion, the domino aza-Michael/retro-Mi-
chael addition reactions using 2-benzylidenemalono-
nitrile strategy under alkaline conditions provides a
straightforward protocol for the selective synthesis of
(E)-aldoximes in high yields. Further work to extend

W. Chen et al./Chemical Papers 66 (4) 308–311 (2012)
311
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Acknowledgements. The authors gratefully acknowledge fi-
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