Synthesis of novel oxime functionalized aldol products via Michael addition of oximes onto Baylis-Hillman adducts

Article abstract of DOI:10.1080/00397910500334132

Triphenylphosphine-catalyzed Michael addition of oximes 2 onto Baylis-Hillman (B-H) adducts 1 led to an easy access to a novel class of oxime functionalized aldol products 3. This demonstrates the first use of an oxygen-centered nucleophile in Michael addition to B-H adducts, without touching any other functional group. Deprotection of oxime in 3 was further demonstrated using molecular hydrogen (1 atm) and 10% Pd/C (cat.) to furnish functionalized 1,3-diols 4 as potentially useful synthons with optional backbone choice (R ³ and EWG). Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500334132

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Synthesis of Novel Oxime Functionalized
Aldol Products via Michael Addition of Oximes
Onto Baylis–Hillman Adducts
a
a
a
Debnath Bhuniya , Srinivas Gujjary & Sujata Sengupta
a
Metabolic Disorder (Chemistry) Group , Dr. Reddy's Laboratories
Ltd.—Discovery Research , Miyapur, Bollaram Road, Hyderabad, India
Published online: 15 Aug 2006.
To cite this article: Debnath Bhuniya , Srinivas Gujjary & Sujata Sengupta (2006) Synthesis of Novel Oxime
Functionalized Aldol Products via Michael Addition of Oximes Onto Baylis–Hillman Adducts, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:2,
151-164, DOI: 10.1080/00397910500334132
To link to this article: http://dx.doi.org/10.1080/00397910500334132
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Synthetic Communications , 36: 151–164, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500334132
Synthesis of Novel Oxime Functionalized
Aldol Products via Michael Addition
of Oximes Onto Baylis–Hillman Adducts
Debnath Bhuniya, Srinivas Gujjary, and Sujata Sengupta
Metabolic Disorder (Chemistry) Group, Dr. Reddy’s Laboratories
Ltd.—Discovery Research, Miyapur, Hyderabad, India
Abstract: Triphenylphosphine-catalyzed Michael addition of oximes 2 onto Baylis–
Hillman (B-H) adducts 1 led to an easy access to a novel class of oxime functionalized
aldol products 3. This demonstrates the first use of an oxygen-centered nucleophile in
Michael addition to B-H adducts, without touching any other functional group. Depro-
tection of oxime in 3 was further demonstrated using molecular hydrogen (1 atm) and
1
0% Pd/C (cat.) to furnish functionalized 1,3-diols 4 as potentially useful synthons
3
with optional backbone choice (R and EWG).
Keywords: Aldol products, Baylis–Hillman adducts, deprotection of oximes, 1,3-
diols, Michael addition, oximes, triphenylphosphine
INTRODUCTION
Recently our group has shown triphenylphosphine to be an effective catalyst
for the Michael addition reaction between oximes and commonly used
[
activated olefins. Baylis–Hillman (B-H) adducts 1 are also very attractive
1]
Michael acceptors, particularly because of their structural diversity.
Received in India July 14, 2005
DRL Publication No. 354. Part of these results was presented at Pharmacophore
2004, January 16–17, 2004, an international symposium organized by Dr. Reddy’s
Laboratories Ltd. on the occasion of its achievement in drug discovery.
Address correspondence to Debnath Bhuniya, Metabolic Disorder (Chemistry)
Group, Dr. Reddy’s Laboratories Ltd.—Discovery Research, Miyapur, Bollaram
Road, Hyderabad 500 049, India. Tel.: (þ91) 402 304 5439; Fax: (þ91) 402 304
5438; E-mail: debnathbhuniya@drreddys.com
1
51

1
52
D. Bhuniya, S. Gujjary, and S. Sengupta
Therefore, we opted to employ triphenylphosphine as a milder catalyst for the
Michael addition of oximes 2 onto B-H adducts 1. This, as one anticipates,
will lead to a novel class of highly functionalized aldol products 3. (Fig. 1,
Eq. 1).
The challenge was also to see whether dehydration of the B-H skeleton
could be avoided because the present catalyst is considered to be very mild.
It is worth mentioning here that there are many reports where attempts of
Michael addition to B-H adducts led to destruction of hydroxyl functionality
[2]
via an elimination or dehydration process (Fig. 1, Eq. 2). (For many such
instances, nicely captured in a recent review, please see Ref. 2(a). For a
recent related reference, see Ref. 2(b)).
Among the handful of literature reports where Michael additions onto
B-H adducts have been shown to produce functionalized aldol products as
[
3–5]
very useful synthons,
we did not find examples with oxygen-centered
nucleophiles. (For examples with sulfur as nucleophile, see, Ref. 3. For
carbon-centered nucleophile, see Ref. 4. For nitrogen-based nucleophile, see
Ref. 5). Thus, the proposed idea will also serve as the first example of
Michael addition of oxygen-centered nucleophile onto B-H adducts
to access a variety of oxime-functionalized aldol products. These oxime
derivatives may potentially be deprotected using a suitable reagent to access
1
,3-diols with choice of substitution at C1 and C2 positions. It is also worth
mentioning here that nitrile oxides, although not in a Michael fashion,
generated in situ from the respective oximes using NaOCl, have been
Figure 1. Proposed Michael Addition of 2 into 1; and deprotection of oxime in 3.

Oxime Functionalized Aldol Products
153
reacted with B-H adducts in a 1,3-dipolar cycloaddition fashion to obtain
[
highly substituted isoxazolines.
6]
RESULTS AND DISCUSSION
Initial results of triphenylphosphine-catalyzed Michael addition of oximes
onto B-H adducts are shown in Table 1. The model B-H adducts 1a–f,
which are the Michael acceptors here, have three different electron-
withdrawing groups (EWG) and were synthesized following the literature
[
7]
procedure. Using representative aldoximes 2a–b and ketoxime 2c, the
[1]
Michael reactions were studied following an optimized reaction condition
described in the Experimental section. In most of the cases the novel
oxime-derivatized aldol products 3 were obtained in good to very good
isolated yield. In cases of 3a, 3d, 3i, 3l, and 3n the expected syn and anti
products separated on TLC, hence they were characterized independently.
However, the other products were isolated as a mixture of syn/anti isomers.
Interestingly, for entries 3 and 6 (Table 1) the expected aldol products 3c
and 3f could not be obtained; instead, the corresponding retro-aldol
products were isolated in 30–40% yields.
We explain the formation of retro-aldol products in the following way:
1
Based on 400-MHz H NMR analysis, there was no significant stereose-
lectivity (to be precise, in the range of 40 : 60) observed for these aldol
products 3. The relative stereochemistry (syn and anti isomers) were tenta-
tively assigned based on a literature precedence for similarly substituted
[
8a]
1
aldol products.
Thus, in H NMR analysis, a coupling constant (J value)
of 6 Hz and above between C2–H and C3–H were assigned for anti-aldol.
Aldol products that had a relatively lower J value of ca. 5 Hz were assigned
as syn. A proposed stereochemical course of these reactions are presented
in Fig. 2.
To enquire about further generality in this reaction, selected oximes from
aliphatic aldehydes (e.g., iso butyraldehyde and cyclohexane carboxaldehyde)
were used for Michael addition with 1a. We observed that reactions were
bit slow and although 10–15% of products were obtainable, most of the
starting material 1a remained unreacted. This result supports our previous
observation that in general oximes derived from aliphatic carbonyl
[
1]
compounds are less reactive.
Obtained oxime-protected aldol derivatives as well as their corresponding
1
oxime-deprotected chiral 1,3-diols with optional R and EWG (Fig. 1, Eq. 3)

1
54
D. Bhuniya, S. Gujjary, and S. Sengupta
Table 1. Triphenylphosphine-catalyzed Michael addition of oximes 2 onto B-H adducts 1
1
R
2
R
a
b
Entry no.
EWG
CO Et
1
Y
2
3
% Yield
c
1
2
3
2
1a
1b
1c
H
H
H
2a 3a
2a 3b
2a 3c
60
82
CN
C(O)Me
d
—
c
4
5
6
CO Et
2
1a
1b
1c
H
H
H
2b 3d
66
75
CN
C(O)Me
2b
2b
3e
3f
d
—
c
7
8
9
CO Et
2
1a
1b
1c
Me 2c 3g
Me 2c 3h
65
78
45
CN
C(O)Me
c
Me 2c 3i
1
0
1
CO Et
2
1d
1d
H
2a
3j
56
68
1
CO
2
Et
Me 2c 3k
c
1
2
3
CO
CO
2
Et
Et
1e
1e
H
2a 3l
58
65
1
2
Me 2c 3m
c
1
4
5
CO
2
Et
1f
1f
H
2a 3n
68
72
1
CO Et
2
Me 2c
3o
a
Unless mentioned products were characterized after column chromatography as a
mixture of syn and anti isomers because they did not separete on TLC.
b
Isolated yield as a mixture of diastereomers or combined of isolated diastereomers.
Syn and anti products separated on TLC and hence they were purified and charac-
c
terized independently.
d
Instead of the expected aldol product, retro-aldol products were obtained.
[1,8]
would find various potential applications in organic synthesis.
For an
example of potential analoging of antibiotics Bu-2313, please see Ref. 8(a).
Also on analoging on carbapenem intermediates, please see Ref. 8(b).
Analoging of the methyl group (marked by star in the below structures)

Oxime Functionalized Aldol Products
155
Figure 2. Proposed mechanism of formation and stereochemistry assignment for 3
1
with optional substitution (R in present study coming from B-H component)
is a potential application of the present methodology.
Deprotection of oxime in 3 to obtain 1,3-diol 4 is therefore demonstrated here
[
9]
using Pd/C-catalyzed hydrogenation. (We did not see a literature report, as
a methodology, for conversion of O-alkyl derivatives of oximes into corre-
sponding alcohols using Pd/C-catalyzed hydrogenation way. However, for
a similar philosophy, please see Ref. 9(a)). Representative Michael adducts
3
p–s, obtained from respective B-H products, were synthesized following
the typical procedure described for 3d (see the Experimental section).
Except for the 3q, others were able to be isolated as pure diatereomers and
hence diatereomerically pure isomers were used for hydrogenation reaction.
Expected products 1,3-diols 4p–s were obtained in 75–95% isolated yield
(Table 2).
After realizing the potential use of this strategy of Michael addition of
oximes onto B-H adducts followed by deprotection of oximes to obtain
varieties of 1,3-diols, we opted to see whether unsubstituted hydroxylamine
could be used instead of aldoximes for making the Michael adducts. Interest-
ingly we observed that hydroxylamine reacted very smoothly with ethyl
acrylate, a representative activated olefin, through its nitrogen site, giving
quantitative yield of the dimmer 5 and not the desired product 6

1
56
D. Bhuniya, S. Gujjary, and S. Sengupta
Table 2. Deprotection of oximes in 3 into 1,3-diols 4 using Pd-catalyzed hydrogenation
3
4
% Yield
7
9
5
0
8
9
2
5
(
Scheme 1). However, hydroxyl amine failed to react with B-H adducts 1a and
d (chosen arbitrarily) even under heating conditions. Interestingly, triphenyl-
phosphine had no effect on these reactions.
1
Out of curiosity we wanted to see what happens when an oxime is allowed
to react with a B-H adducts in the presence of Lewis acids. As an outcome of
that screening, we were surprised to notice that in the presence of 0.5 equiv-
alent of Cu(II)Br , benzaldehyde oxime reacted with the B-H adduct 1a to
2
give 32% yield of isooxazoline 7 in two diastereomers, which were isolated
and characterized separately (Scheme 2). This result was otherwise
Scheme 1.

Oxime Functionalized Aldol Products
157
Scheme 2.
[6]
expected using NaOCl as described before. This new reaction condition is
being investigated in detail presently at our group.
CONCLUSION
In conclusion, Michael addition to B-H adducts, which is a sensitive reaction
with respect to 2,3 elimination reaction on the B-H backbone, has been
demonstrated here using a triphenylphosphine-catalyzed method. The
present methodology, in addition to our previous report, although specific to
oximes, thus shows further generality on Michael acceptors. This study also
demonstrates the first Michael addition reaction of an oxygen-centered
nucleophile onto B-H adducts. The oxime-functionalized aldol products
(3a–s) and their synthesis revealed in this communication are novel. In
addition, we have demonstrated a very convenient method for deprotection
of these oxime derivatives into their corresponding 1,3-diols (4p–s) using
Pd-catalyzed hydrogenation. Here also, we have not seen any direct literature
report where oxime-protected alcohols in general are being deprotected to the
corresponding alcohols. Knowing that the area of asymmetric B-H reactions is
advancing rapidly, the described protocol can be an option to access homo-
3
chiral 1,3-diols carrying an optional backbone (1-R and 2-EWG) coming
from B-H adducts. As reported in the past for similar cases, this new class
of oxime-functionalized aldols and 1,3-diols may find some potential appli-
cation in the area of medicinal chemistry.
EXPERIMENTAL
General
1
13
The melting points are uncorrected. H and C NMR spectra were recorded
on Mercury Plus (Varian 400 MHz), Unity Inova (Varian 500 MHz), and
Gemini-2000 (Varian 200 MHz) spectrometer in CDCl or DMSO-d6 with
3
TMS as internal standard: chemical shifts and J values are given in ppm
and Hz respectively. IR spectra were recorded on FT-IR spectrophotometer
from the Perkin Elmer 1600 series. The CI-mass spectra were recorded on
Hewlett Packard 5989 A using isobutane as chemical ionization gas (source

1
58
D. Bhuniya, S. Gujjary, and S. Sengupta
temp. 2508C and quadruple temp. 1008C). The ES-mass data were generated
using a triple quadruple mass spectrometer (Perkin Elmer Sciex Model API
3
000) with capillary voltage at þ5000 V. Elemental analysis was done on a
Perkin Elmer II series.
Ethyl 2-(3-Nitrobenzylideneaminoxymethyl)-3-hydroxy-3-
(
4-nitrophenyl)propanoate (3d); Typical Procedure for Synthesis of 3
A mixture of B-H adduct 1a (301 mg, 1.2 mmol), aldoxime 2b (200 mg,
.2 mmol), and triphenylphosphine (63 mg, 0.24 mmol) was stirred in dry
1
acetonitrile (600 L) at rt for 16 h. The reaction was guided by TLC. The
solvent was removed (rotavapor) and the crude was purified by column
chromatography (silica gel 100–200, ethyl acetate/hexanes) to obtain syn
isomer of the aldol product 3d as a faster eluting compound (150 mg).
Further elution gave the anti-3d (180 mg).
Characterization of Syn-3d
1
R : 0.25 (30% ethyl acetate in hexanes). Mp: 99–1008C. H NMR (CDCl ,
f
3
4
00 MHz): 1.20 (t, J ¼ 7.2 Hz, 3H); 3.27 (dt, J ¼ 7, 5.4 Hz, 1H); 3.35
(
d, J ¼ 3.4 Hz, –OH); 4.16 (q, J ¼ 7.2 Hz, 2H); 4.46 (dd, J ¼ 11.2, 5.4 Hz,
1
H); 4.63 (dd, J ¼ 11.2, 7 Hz, 1H); 5.27 (dd, J ¼ 5.4, 3.4 Hz, 1H); 7.56
(
(
(
t, J ¼ 8 Hz, 1H); 7.60 (d, J ¼ 8.8 Hz, 2H); 7.79 (dt, J ¼ 8, 2 Hz, 1H); 7.96
s, 1H); 8.19–8.23 (aromatics, 1H); 8.21 (d, J ¼ 8.8 Hz, 2H); 8.38
1
3
t, J ¼ 2 Hz, 1H). C NMR (CDCl , 50 MHz): 13.97, 52.34, 61.31, 71.32,
3
7
1
1
4
1.58, 121.46, 123.44 (2C), 124.38, 127.15 (2C), 129.76, 132.58, 133.33,
21
47.01, 147.21, 148.47, 148.65, 172.37. IR (neat, cm ): 3505 (br), 2925,
728 (ester), 1528, 1349. Mass m/z (ES): 400.1 [M-OH], 418.1 [M þ 1],
þ
35.4 [M þ NH ], 440.1 [M þ Na], 857.5 [M þ Na]. Anal. calcd. for
4
2
C H N O : C, 54.68; H, 4.59; N, 10.07. Found C, 54.64; H, 4.61; N, 10.03.
9 19 3 8
1
Characterization of Anti-3d
R : 0.20 (30% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz): 1.19
1
f
3
(
t, J ¼ 7.2 Hz, 3H); 3.21 (q, J ¼ 6 Hz, 1H); 3.67 (bs, –OH); 4.18
q, J ¼ 7.2 Hz, 2H); 4.35 (dd, J ¼ 11.2, 6.4 Hz, 1H); 4.52 (dd, J ¼ 11.2,
(
5
.6 Hz, 1H); 5.20 (d, J ¼ 6 Hz, 1H); 7.55–7.61 (aromatics, 1H); 7.58
(
(
(
d, J ¼ 8.8 Hz, 2H); 7.86 (dt, J ¼ 7.6, 2 Hz, 1H); 8.13 (s, 1H); 8.21–8.26
1
3
aromatics, 1H); 8.23 (d, J ¼ 8.8 Hz, 2H); 8.44 (t, J ¼ 2 Hz, 1H). C NMR
CDCl , 50 MHz): 13.97, 52.34, 61.36, 71.10, 72.40, 121.52, 123.57 (2C),
3
1
1
24.42, 127.12 (2C), 129.79, 132.66, 133.41, 147.26, 147.44, 148.45,
2
48.65, 172.37. IR (neat, cm ): 3476 (br), 2925, 1727 (ester), 1528, 1349.
1
þ
Mass m/z (ES): 400.3 [M-OH], 418.1 [M þ 1], 435.4 [M þ NH ], 440.1
4
[
M þ Na], 857.5 [M þ Na].
2

Oxime Functionalized Aldol Products
159
Characterization of Ethyl 2-(4-Nitrobenzylideneaminoxymethyl)-
3
-hydroxy-3-(4-nitrophenyl)propanoate (3a)
1
Syn-3a: R : 0.4 (30% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz):
f
3
1
.19 (t, J ¼ 7.1 Hz, 3H); 3.25 (dt, J ¼ 6, 5.3 Hz, 1H); 3.33 (d, J ¼ 3.3 Hz,
OH); 4.15 (q, J ¼ 7.1 Hz, 2H); 4.47 (dd, J ¼ 11.6, 5.4 Hz, 1H); 4.64 (dd,
J ¼ 11.6, 7 Hz, 1H); 5.27 (dd, J ¼ 5.3, 3.3 Hz, 1H); 7.59 (d, J ¼ 8.3 Hz,
–
2
H); 7.67 (d, J ¼ 8.8 Hz, 2H); 7.94 (s, 1H); 8.20 (d, J ¼ 8.8 Hz, 2H); 8.22
1
3
(
d, J ¼ 8.8 Hz, 2H). C NMR (CDCl , 50 MHz): 14.07, 52.31, 61.42,
2
47.25 (2C), 148.35, 172.18. IR (neat, cm ): 3476 (br), 2926, 1728 (ester),
3
7
1
1
1.37, 71.67, 123.56 (2C), 124.05 (2C), 127.15 (2C), 127.65 (2C), 138.00,
1
520, 1347. Mass m/z (ES): 400.4 [M-OH], 418.3 [M þ 1], 435.3
þ
þ
4
[M þ NH ], 440.5 [M þ Na], 852.7 [M þ NH ], 857.5 [M þ Na].
4
2
2
1
Anti-3a: R : 0.35 (30% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz):
f
3
1
.17 (t, J ¼ 7.2 Hz, 3H); 3.21 (apparent q, J ¼ 6 Hz, 1H); 3.65 (d, J ¼ 6.4 Hz,
OH); 4.16(q, J ¼ 7.2 Hz, 2H); 4.37 (dd, J ¼ 11.3, 6.2 Hz, 1H); 4.53
–
(
dd, J ¼ 11.2, 5.6 Hz, 1H); 5.19 (apparent t, J ¼ 6.3 Hz, 1H); 7.57 (d,
J ¼ 8.6 Hz, 2H); 7.73 (d, J ¼ 8.8 Hz, 2H); 8.12 (s, 1H); 8.22 (d, J ¼ 8.6 Hz,
1
3
2
5
H); 8.24 (d, J ¼ 8.8 Hz, 2H). C NMR (CDCl , 50 MHz)_: 14.05,
3
2.34, 61.45, 71.19, 72.62, 123.67 (2C), 124.06 (2C), 127.12 (2C), 127.72
2
1
(
2C), 137.68, 147.49 (2C), 148.59, 172.36. IR (neat, cm ): 3476 (br),
926, 1728 (ester), 1520, 1347. Mass m/z (ES): 400.4 [M-OH], 418.3
2
þ
þ
[
[
M þ 1], 435.3 [M þ NH ], 440.4 [M þ Na], 852.7 [M þ NH ], 857.5
2
4
2
4
M þ Na].
Characterization of 2-(1-Phenylethylideneaminoxymethyl)-
-hydroxy-3-(4-nitrophenyl)propanoate (3i)
3
1
Syn-3i: R : 0.70 (30% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz):
f
3
2
.11 (s, 3H); 2.22 (s, 3H); 3.35 (dt, J ¼ 6.5, 4.9 Hz, 1H); 3.75 (d, J ¼ 3 Hz,
OH); 4.43 (dd, J ¼ 11.6, 4.9 Hz, 1H); 4.56 (dd, J ¼ 11.8, 6.4 Hz, 1H);
.28 (dd, J ¼ 5.1, 3 Hz, 1H); 7.35–7.38 (aromatics, 3H); 7.54–7.60
–
5
2
1
(
aromatics, 4H); 8.21 (d, J ¼ 8.6 Hz, 2H). IR (neat, cm ): 3391 (br), 2924,
709 (carbonyl), 1520, 1347. Mass m/z (ES): 357.0 [M þ 1], 379.0
M þ Na], 735.5 [M þ Na].
1
[
2
1
Anti-3i: R : 0.65 (30% ethyl acetate in hexanes) H NMR (CDCl , 400 MHz):
f
3
2
.19 (s, 3H); 2.21 (s, 3H); 3.33 (dt, J ¼ 6.6, 5.0 Hz, 1H); 3.67 (d, J ¼ 5.6 Hz,
–
OH); 4.29 (dd, J ¼ 11.6, 6.3 Hz, 1H); 4.41 (dd, J ¼ 11.3, 4.9 Hz, 1H); 5.17
(
apparent, J ¼ 5.9 Hz, 1H); 7.35–7.40 (aromatics, 3H); 7.55–7.60 (aromatics,
2
1
4
H); 8.22 (d, J ¼ 8.8 Hz, 2H). IR (neat, cm ): 3454 (br), 2924, 1710
(
carbonyl), 1520, 1346. Mass m/z (ES): 357.0 [M þ 1], 379.0 [M þ Na],
7
35.5 [M þ Na].
2

1
60
D. Bhuniya, S. Gujjary, and S. Sengupta
Characterization of Ethyl 2-(4-Nitrobenzylideneaminoxymethyl)-
-hydroxy-3-(thiophen-3-yl)propanoate (3l)
3
1
Anti-3l: R : 0.30 (20% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz):
f
3
1
.15 (t, J ¼ 7.2 Hz, 3H); 2.96 (d, J ¼ 3 Hz, 1H, –OH); 3.24–3.29 (m, 1H, 2C-
H); 4.12 (q, J ¼ 7.2 Hz, 2H); 4.53 (dd, J ¼ 11.2, 4.8 Hz, 1H); 4.67 (dd,
J ¼ 11.2, 7.6 Hz, 1H); 5.19 (dd, J ¼ 6, 3 Hz, 1H); 7.09 (dd, J ¼ 5.2, 1.6 Hz,
1
8
6
1
H); 7.27–7.32 (aromatics, 2H); 7.71 (d, J ¼ 8.8 Hz, 2H); 8.07 (s, 1H);
1
3
.22 (d, J ¼ 8.8 Hz, 2H). C NMR (CDCl , 100 MHz): 14.02, 52.47, 61.00,
3
9.17, 72.52, 121.84, 123.98 (2C), 125.61, 126.16, 127.64 (2C), 138.04,
2
42.46, 147.00, 148.47, 172.42. IR (neat, cm ): 3431 (br), 2927, 1726
1
(
ester), 1519, 1345. Mass m/z (CI): 361 [M 2 17], 379 [M þ 1].
1
Syn-3l: R : 0.25 (20% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz):
f
3
1
.20 (t, J ¼ 7.2 Hz, 3H); 3.23–3.28 (m, 2H, 2C-H and –OH); 4.13–4.21
m, 2H); 4.43 (d, J ¼ 6.4 Hz, 2H); 5.13 (d, J ¼ 4.8 Hz, 1H); 7.10 (dd,
J ¼ 5.2, 1.6 Hz, 1H); 7.25–7.27 (aromatics, 1H); 7.33 (dd, J ¼ 5.1, 3 Hz,
(
1
3
1
H); 7.72 (d, J ¼ 8.8 Hz, 2H); 8.10 (s, 1H); 8.23 (d, J ¼ 8.8 Hz, 2H).
C
NMR (CDCl , 50 MHz): 14.07, 52.34, 61.12, 68.75, 73.10, 121.84, 123.99
3
(
2C), 125.54, 126.46, 127.66 (2C), 137.95, 142.75, 147.11, 148.20, 172.93.
2
1
IR (neat, cm ): 3477 (br), 2927, 1727 (ester), 1520, 1345. Mass m/z (CI):
61 [M 2 17], 379 [M þ 1].
3
General Procedure for Hydrogenation; Conversion of 3p–s to 4p–s
3
p–s (1 mmol) were hydrogenated under molecular hydrogen (1 atm) in
presence of 10% Pd/C (300 mg) in solvents of choice (10 mL of AcOH for
p–q, alternatively 30 mL AcOEt for 3p–s) at rt for 4–5 h (TLC guided).
3
Reaction mixture was filtered through celite and washed with ethyl acetate.
Filtrate was condensed (for AcOH solvent, a base workup was done),
and the crude mass was purified by column chromatography (silica gel
100–200, ethyl acetate and hexanes) to obtain the 1,3-diols 4p–s. Originally
AcOH was used as solvent. However, it was observed later that EtOAc was a
more convenient solvent.
Characterization of Anti-Ethyl 2-(hydroxymethyl)-3-hydroxy-
-(4-fluorophenyl)propanoate (Anti-4p)
3
1
R : 0.2 (40% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz): 1.24
f
3
(
t, J ¼ 7.1 Hz, 3H); 2.18 (dd, J ¼ 7, 5.1 Hz, –OH); 2.87 (dt, J ¼ 6.7,
4
.7 Hz, 1H); 3.24 (d, J ¼ 5.4 Hz, –OH); 3.64–3.72 (m, 1H); 3.83–3.89
(
m, 1H); 4.20 (q, J ¼ 7.1 Hz, 2H); 5.10 (t, J ¼ 5.9 Hz, 1H); 7.05
1
3
(
t, J ¼ 8.6 Hz, 2H); 7.36 (dd, J ¼ 8.6, 5.4 Hz, 2H). C NMR (CDCl ,
3
5
0 MHz): 14.05, 54.35, 61.19, 61.54, 72.34, 115.35 (d, J ¼ 21 Hz, 2C),

Oxime Functionalized Aldol Products
161
1
27.84 (d, J ¼ 8 Hz, 2C), 137.14, 162.4 (d, J ¼ 245Hz), 173.55. IR (neat,
2
1
cm ): 3419 (br), 2938, 1717 (carbonyl), 1605. Mass m/z (ES): 260.3
M þ 18], 265.1 [M þ 23], 507.1 [M þ 23].
[
2
Characterization of Ethyl 2-(Hydroxymethyl)-3-hydroxy-3-(pyridin-3-yl)-
propanoate (4q)
Isolated as a 60 : 40 mixture of anti and syn diastereomers. For clarity, NMR
data are given for the major diastereomer. R : 0.4 (80% ethyl acetate in
f
1
hexanes). H NMR (CDCl , 400 MHz): 1.14 (t, J ¼ 7.1 Hz, 3H); 2.87 (dt,
3
J ¼ 6.2, 4.7 Hz, 1H); 3.71 (dd, J ¼ 11.3, 5 Hz, 1H); 3.90 (dd, J ¼ 11.3,
4
.8 Hz, 1H); 4.10 (q, J ¼ 7.1 Hz, 2H); 5.28 (d, J ¼ 6.4 Hz, 1H); 7.30 (dd,
J ¼ 8, 5.1 Hz, 1H); 7.75 (dt, J ¼ 5.6, 1.8 Hz, 1H); 8.47 (d, J ¼ 5 Hz, 1H);
1
3
8
6
.53 (d, J ¼ 1.8 Hz, 1H). C NMR (CDCl , 50 MHz): 13.92, 53.81, 61.06,
3
1.17, 71.76, 123.51, 134.38, 137.68, 147.67, 148.68, 172.26. Mass m/z
(CI): 226 [M þ 1].
Characterization of Anti-ethyl 2-(hydroxymethyl)-3-hydroxy-3-
4-aminoophenyl)propanoate (Anti-4r)
(
1
Mp: 1148C. R : 0.2 (50% ethyl acetate in hexanes). H NMR (DMSO-d ,
f
6
4
00 MHz): 1.26 (t, J ¼ 7.1 Hz, 3H); 2.86 (dt, J ¼ 8.3, 4.9 Hz, 1H); 3.40–
.46 (m, 1H); 3.53–3.60 (m, 1H); 3.99 (t, J ¼ 5.3 Hz, –OH); 4.12 (bs,
3
–
NH2); 4.17 (q, J ¼ 7.1 Hz, 2H); 4.55 (d, J ¼ 4.5 Hz, –OH); 4.73 (dd,
J ¼ 8.3, 4.3 Hz, 1H); 6.62 (d, J ¼ 8.3 Hz, 2H); 7.08 (d, J ¼ 8.3 Hz, 2H).
1
3
C NMR (DMSO-d , 50 MHz): 13.43, 55.44, 59.35, 60.05, 71.54, 113.64
6
2
2C), 126.58 (2C), 130.82, 145.95, 172.89. IR (neat, cm ): 3375 (br),
1
(
2
926, 1715 (carbonyl), 1615. Mass m/z (ES): 222.1 [M 2 17], 240.1
[
M þ 1], 262.3 [M þ 23], 501.4 [M þ 23]. Anal. calcd. for C H NO : C,
2
12 17
4
6
0.24; H, 7.16; N, 5.85. Found C, 60.21; H, 7.21; N, 5.82.
Characterization of Anti-ethyl 2-(hydroxymethyl)-3-hydroxy-3-
2-phenethyl)propanoate (Anti-4s)
(
1
R : 0.2 (30% ethyl acetate in hexanes). H NMR (CDCl , 400 MHz): 1.28
f
3
(
t, J ¼ 7.1 Hz, 3H); 1.74–1.84 (m, 1H); 1.90–2.00 (m, 1H); 2.55
q, J ¼ 4.3 Hz, 1H); 2.65–2.74 (m, 1H); 2.85–2.94 (m, 1H); 4.00 (dd,
(
J ¼ 11.5, 4 Hz, 1H); 4.06 (dd, J ¼ 11.5, 4.3 Hz, 1H); 4.13–4.18 (m, 1H);
4
2
7
2
.21 (q, J ¼ 7.1 Hz, 2H); 7.17–7.23 (aromatics, 3H); 7.26–7.32 (aromatics,
1
3
H). C NMR (CDCl , 50 MHz): 14.09, 32.05, 36.76, 51.70, 60.91, 61.00,
3
2
0.95, 125.87, 128.36 (4C), 141.53, 173.60. IR (neat, cm ): 3418 (br),
1
938, 1722 (carbonyl), 1195. Mass m/z (ES): 253.3 [M þ 1], 275.1
[
M þ 23], 527.3 [M þ 23].
2

1
62
D. Bhuniya, S. Gujjary, and S. Sengupta
Synthesis and Characterization of N,N-bis-
2-(Ethylcarboxylato)ethyl]hydroxylamine (5)
[
A mixture of hydroxylamine (1.0 g, 30 mmol), ethyl acrylate (1 mL, 10 mmol),
and triphenylphosphine (500 mg, 2.0 mmol) in acetonitrile (5 mL) was stirred
at rt for 15 min. The reaction mixture was condensed and the pure product 5
was isolated as thick oil (quantitative yield) from the crude mass using
column chromatography (silica gel 100–200, ethyl acetate and hexanes).
1
H NMR (CDCl , 400 MHz): 1.25 (t, J ¼ 7.1 Hz, 6H); 2.59 (t, J ¼ 6.9 Hz,
3
4
1
H); 2.99 (t, J ¼ 6.9 Hz, 4H); 4.14 (t, J ¼ 7.1 Hz, 4H); 5.80 (bs, –OH).
3
C NMR (CDCl , 50 MHz): 13.77, 31.65, 55.14, 60.23, 171.93. IR
3
2
1
(
neat, cm ): 3426 (br), 2984, 1735 (carbonyl), 1183. Mass m/z (CI): 234
M þ 1].
[
Synthesis and Characterization of Ethyl 5-[1-Hydroxy-2-(4-
nitrophenyl)ethyl]-3-phenyl-4,5-dihydroisoxazolo-5-carboxylate (7)
A mixture of 1a (600 mg, 2.39 mmol), benzaldehyde oxime (290 mg,
2
.39 mmol), and anhydrous CuBr (266 mg, 1.19 mmol, 0.5 eq.) in dry aceto-
2
nitrile solvent (2.4 mL) was heated at 60–658C for 24 h. The reaction mixture
was condensed to obtain the crude mass, which on column chromatography
(silica gel 100–200, ethyl acetate and hexanes) yielded two the diastereomers
of 7. Combined yield: 32%. (200 and 120 mg for faster and slower eluting
diastereomers respectively).
1
R : 0.4 (20% ethyl acetate in hexanes, double run). H NMR (CDCl3,
f
4
00 MHz): 1.33 (t, J ¼ 7.2 Hz, 3H); 3.40 (bs, 1H, –OH); 3.94 (d,
J ¼ 10.5 Hz, 1H); 3.99 (d, J ¼ 10.5 Hz, 1H); 4.27–4.37 (m, 2H); 5.52
(
(
s, 1H); 7.48 (t, J ¼ 7.6 Hz, 2H); 7.62 (t, J ¼ 7.4 Hz, 1H); 7.81
1
3
d, J ¼ 8.9 Hz, 2H); 8.12 (d, J ¼ 8.1 Hz, 2H); 8.22 (d, J ¼ 8.9 Hz, 2H).
C
NMR (CDCl , 50 MHz): 13.83, 33.80, 63.42, 65.39, 75.34, 122.92 (2C),
3
1
1
28.47 (2C), 129.26, 129.69 (2C), 130.19 (2C), 133.76, 144.84, 148.03,
67.61, 171.59. Mass m/z (ES): 371.3 [M þ 1], 393.3 [M þ 23], 758.3
[
M þ 18].
2
1
R : 0.2 (20% ethyl acetate in hexanes, double run). H NMR (CDCl3,
f
4
00 MHz): 1.29 (t, J ¼ 7.2 Hz, 3H); 3.21 (d, J ¼ 4 Hz, 1H, –OH); 3.65
(
d, J ¼ 3.2 Hz, 2H); 4.26 (q, J ¼ 7.2 Hz, 2H); 5.41 (d, J ¼ 4 Hz, 1H); 7.38–
7
.44 (aromatics, 3H); 7.60–7.70 (aromatics, 4H); 8.22 (d, J ¼ 8.8 Hz, 2H).
1
3
C NMR (CDCl , 50 MHz): 14.00, 38.15, 62.71, 73.54, 91.97, 123.56 (2C),
3
1
1
26.90 (2C), 127.75 (2C), 128.74, 128.84 (2C), 130.82, 144.30, 147.96,
57.31, 169.67. Mass m/z (ES): 371.3 [M þ 1], 393.3 [M þ 23], 758.3
[
M þ 18].
2

Oxime Functionalized Aldol Products
ACKNOWLEDGMENTS
163
We are thankful to the management of Discovery Research, DRL, for overall
support. Analytical Research Department of Discovery Research SBU is
especially acknowledged for providing us with the data to characterize all
the compounds.
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