Chemoselective addition of organometallics to oxime ethers

Article abstract of DOI:10.1016/j.jorganchem.2006.12.038

In this paper, an efficient method for preparation of various substituted hydroxylamines from aldehydes is reported. We first prepare O-trimethylsilyl oxime ether in 5 M solution of lithiumperchlorate in diethyl ether (LPDE 5M) from condensation reaction

Full text of DOI:10.1016/j.jorganchem.2006.12.038

Journal of Organometallic Chemistry 692 (2007) 1924–1927
www.elsevier.com/locate/jorganchem
Chemoselective addition of organometallics to oxime ethers
a,
a
b
Hossein Tavakol *, Saedeh Zakery , Akbar Heydari
a
Chemistry Department, Science Faculty, Zabol University, Zabol, Iran
Chemistry Department, Science Faculty, Tarbiat Modares University, Tehran, Iran
b
Received 1 June 2006; received in revised form 14 December 2006; accepted 22 December 2006
Available online 10 January 2007
Abstract
In this paper, an efficient method for preparation of various substituted hydroxylamines from aldehydes is reported. We first prepare
O-trimethylsilyl oxime ether in 5 M solution of lithiumperchlorate in diethyl ether (LPDE 5M) from condensation reaction between alde-
hyde and O-trimethylsilyl hydroxylamine, then add organosilane or organotin nucleophile in the same vessel to preparing the corre-
sponding a-substituted hydroxylamines in one-pot synthesis.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: Oximes; Organosilane; Chemoselective reactions; Lithiumperchlorate; Multicomponent reaction; Organotin
1. Introduction
compounds to oximes and oxime ethers. But the versatility
of these reactions is often limited by poor electrophilicity of
oximes [16] (vs. carbonyl or imines), tutomeric conversion
of substrate that contains a-Hydrogen to enamine-type
product, existence of geometric isomerisation (syn and
anti), liability of N–O bond, possibility of addition to both
carbon and nitrogen in C@N double bond, and formation
of byproducts such as aziridine, nitrile, and Beckmann
rearrangement products [17].
In recent years, there has been an increasing interest in
multicomponent reactions (MCRs) [1–3]. These reactions
are special types in synthetic organic chemistry, in which
three or more starting materials react in one vessel to give
one product. One of the most important MCRs is man-
nich-type reactions [4–7]. These three component reactions
are interesting and important, not only because of forming
two bonds in one reaction, but also because this methodol-
ogy would be useful for making a broad variety of nitro-
gen-containing compounds [8,9]. Although the original
mannich reaction was carried out with amines, these reac-
tions can be performed with other N-heterosubstituted
amines such as hydrazones and oximes [10–14].
Thus, it is very important that one procedure can pro-
duce only one of these products in high yield without major
formation of other byproducts.
2. Results and discussion
In other words, nucleophilic addition to oximes in man-
nich-type reactions is one of the namely devised methods
for preparation of substituted hydroxylamines (such as
similar addition to imines, hydrazones, and iminium salts)
[15]. If in these reactions the C–C bond is formed, the reac-
tion has a new synthetic importance. Therefore, this proce-
dure can be used for addition of organometallic
We first in situ prepared O-trimethylsilyl oxime ether
from condensation reaction between aldehyde and O-trim-
ethylsilyl hydroxylamine [18] in 5 M solution of lithium-
perchlorate in diethyl ether (that we named it LPDE 5M)
in 10 min [19], then in the same vessel, added ketene acetal
(1-methoxy-1-trimethylsilyloxy-2-methyl propene, 3) as a
nucleophile with trimethylsilyl chloride (TMSCl) for acti-
vating oxime ethers [20]. The reaction was completed
within 4 h. After this, we purified the product by column
chromatography and obtained 3-hydroxyamino esters in
*
Corresponding author. Fax: +98 542 2226765.
E-mail address: hosein_ta@yahoo.com (H. Tavakol).
0022-328X/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.12.038

H. Tavakol et al. / Journal of Organometallic Chemistry 692 (2007) 1924–1927
1925
H
OH
good yield (Scheme 1). These products are very important
because of their synthetic utility especially in b-lactam
synthesis.
O
N
O
4a
OTMS
OMe
H
OMe
1a
LPDE
+
Unfortunately, the reaction was only succeeded with ali-
phatic aldehydes and with aromatic aldehydes, only oxime
ethers produced from this and nucleophilic attack to aro-
matic oxime ethers can not be observed; because the car-
bon of C@N double bond in these compounds is less
electrophilic than the same carbon in aliphatic oxime
ethers. This problem can be arised from aromatic rings,
that show a good electron donor property in most case
and this property can lower the electrophilicity of C@N
double bond of oxime ethers. Therefore, we only succeed
at preparation of aliphatic 3-hyroxyamino esters via these
reactions.
After this, in order to evaluate the scope of this nucleo-
philic addition to oxime ethers, we decided to add allyltrib-
utyltin to oxime ethers with this methodology for synthesis
of homoallylic hydroxylamines. In this reaction, after pre-
paring O-trimethylsilyl oxime ethers from aldehydes and
O-trimethylsilyl hydroxylamine, we added equimolar
amount of allyltributyltin for in situ preparation of homo-
allylic hydroxylamines in 5–10 h with good yield (Scheme
2).
In Scheme 2, we see an interesting fact; these reactions
are only succeeded with aromatic aldehydes (contrary to
the reaction of Scheme 1). As a result, although these
two reactions are limited to aromatic or aliphatic alde-
hydes, but these limitations show the chemoselectivity of
these reactions. For proving this claim, we perform this
reaction with both aliphatic and aromatic oxime ethers
(that in situ prepared at one vessel), then both nucleophiles;
allyltributyltin and ketene acetal/TMSCl were added. After
completing the reaction and purification of products, we
obtain two major products: aliphatic 3-hyroxyamino esters
with aromatic homoallylic hydroxylamine and the amount
of aromatic 3-hyroxyamino esters and aliphatic homoally-
lic hydroxylamine is about zero. So that, we deduced that
allyltributyltin only react with aromatic oxime ethers and
ketene acetal/TMSCl only react with aliphatic oxime
ethers. This chemoselective double reaction is shown in
Scheme 3.
(2 eq)
1 eq TMSCl
H N-OTMS
+
Bu3Sn
OTMS
+
2
r.t, 5-10 hr
N
O
SnBu3
H
6f
1f
O2N
O2N
Scheme 3.
When we get these results, we decide to doing additional
experiments for examining this chemoselectivity.
First, we prepared and isolated oxime ethers 7a–h (both
aliphatic and aromatic) and react them separately with
both allyltributyltin and ketene acetal in some conven-
tional organic media with lewis acid such as LPDE 1M,
LPDE 5M and borontrifloride in dimethyl ether. The brief
results of these experiments are shown in Scheme 4.
As you see, results of Scheme 4 are perfectly consistent
with the results shown in Schemes 1 and 2. This means that
even we use pure oxime ether as an initial compound and
use various organic solvent and lewis acid, only aliphatic
oxime ethers react with ketene acetal and only aromatic
oxime ethers react with allyltributyltin to give correspond-
ing products. This results confirm our idea about this
chemoselectivity.
For completing our experiments, we make an experi-
ment with one aliphatic 7a and one aromatic 7f oxime ether
and both nucleophiles in some organic media (the same
with Scheme 4). This new experiment (Scheme 5) is the
same as experiment shown in Scheme 3 but we used pure
oxime ethers as an initial compound versus in situ synthesis
of them.
H
R
OH
OTMS
H
N
O
N
OTMS
OMe
a,b,c
TMSCl
OMe
+
+
R
r.t, 5-10 hr
a= LPDE 1M
b= LPDE 5M
7a-d
(3)
4a-d, 58%-90%
Bu3Sn OTMS
OTMS
c= BF3/OMe2
N
N
a,b,c
SnBu3
+
r.t, 5-10 hr
H
R
R
7e-h
(5)
6e-h, 41%-70%
1,4
R
Yield
Scheme 4.
H
R
OH
RCHO
(1)
OTMS
OMe
N
O
LPDE
a
b
c
d
i
-Pr 76%
-Pr 79%
-Bu 84%
-Hexyl 71%
TMSCl
+
+
r.t, 2hr
n
H2N-OTMS
OMe
t
(3)
(2)
(4)
c
Scheme 1.
Bu3Sn
OTMS
N
O
SnBu3
H
a= LPDE 1M
b= LPDE 5M
(5)
6f
O2N
a,b,c
O2N
1,6
R
Yield
7a
TMSCl
Bu3Sn
OTMS
+
+
O
RCHO
(1)
r.t, 5-10 hr
N
OTMS
OH
H
SnBu3
e
f
g
h
3-Pyridyl 64%
4-NO2-Ph 67%
3-NO2-Ph 57%
4-Me-Furyl 45%
LPDE
OTMS
N
N
+
4a
c= BF3/OMe2
r.t, 5-10 hr
R
H2N-OTMS
H
OMe
OMe
(6)
(5)
(2)
(3)
7f
Scheme 2.
Scheme 5.

1926
H. Tavakol et al. / Journal of Organometallic Chemistry 692 (2007) 1924–1927
The results of Scheme 5 confirm our belief about the
(189): C, 57.14; H, 10.05; N, 7.41; O, 25.40. Found: C,
57.27; H, 10.02; N, 7.35; O, 25.36%.
chemoselectivity of these reactions again, completely con-
sistent with Schemes 1–4, so that we named these reactions:
‘‘chemoselective’’ [21].
4.3. Methyl 3-(hydroxyamino)-2,2-dimethylhexanoate (4b)
Colorless oil, yield 0.298 g (79%); IR (KBr), m/cmÀ1
3. Conclusion
:
3270, 3195 (NH, OH), 2910 (CH), 1714 (C@O), 1447 (C–
N), 1380 (N–O). 1NMR (90 MHz, CDCl3) d: 1.03 (t,
J = 7 Hz, 3H, Me), 1.31 (s, 6H, 2Me), 1.21–1.63 (m, 2H,
H5), 2.03–2.41 (m, 2H, H4), 3.57 (t, J = 4 Hz, 1H, H3),
3.65 (s, 3H, OMe), 7.01–7.58 (bs, 2H, NH, OH). 13C
NMR (22.5 MHz, CDCl3) d: 13.3 (C6), 18.9 (C5), 21.8
(Me), 21.9 (Me), 31.2 (C4), 36.7 (C2), 52.0 (OMe), 55.3
(C3), 153.5 (C@O). Anal. Calc. for C9H19NO3 (189): C,
57.14; H, 10.05; N, 7.41; O, 25.40. Found: C, 57.29; H,
9.94; N, 7.42; O, 25.35%.
In summary, we wish to report, two chemoselective,
one-pot and three or four component reaction between
organometallic nucleophiles and oxime ethers for prepar-
ing aliphatic 3-hyroxyamino esters and aromatic homoally-
lic hydroxylamines. These reactions are very clean and the
procedures are very easy and consist of simple mixing of
the equimolar amounts of an aldehydes, O-trimethylsilyl
hydroxylamine, and organometallic nucleophiles.
4. Experimental
4.4. Methyl 3-(hydroxyamino)-2,2,4,4-
tetramethylpentanoate (4c)
Starting materials were obtained from Fluka and Merck
and were used without further purification. IR spectra were
determined as KBr pellets on a shimadzu model 470 spec-
trophotometer. 1NMR and 13C NMR spectra were
recorded using a JEOL FT-90 MHz spectrometer in CDCl3
with tetramethylsilane as internal standard. All yields refer
to isolated products after purification.
Yellow oil, yield 0.341 g (84%); IR (KBr), m/cmÀ1: 3420,
3285 (NH, OH), 2900 (CH), 1732 (C@O), 1448 (C–N),
1
1378 (N–O). H NMR (90 MHz, CDCl3) d: 1.22 (s, 9H,
t-Bu), 1.45 (s, 6H, 2Me), 2.14–2.72 (bs, 2H, NH, OH),
3.8 (s, 3H, OMe), 3.85 (s, 1H, H3); 13C NMR (22.5 MHz,
CDCl3) d: 20.2 (Me), 21.7 (Me), 27.4 (t-Bu), 33.6 (C4),
36.7 (C2), 52.2 (OMe), 55.95 (C3), 159.3 (C@O). Anal.
Calc. for C10H21NO3 (203): C, 59.11; H, 10.34; N, 6.90;
O, 23.65. Found: C, 59.26; H, 10.27; N, 6.85; O, 23.62%.
4.1. General procedure for preparation of 4a–d
To a mixture of aldehydes (2 mmol) in 5.0 M LPDE
(3 ml) was added or O-trimethylsilyl hydroxylamine
(2 mmol) at room temperature. After the mixture stirred
for 10 min, keteneacetal (2.2 mmol) and trimethylsilyl
chloride (2.5 mmol) was added. After this, the mixture
stirring at room temperature for 2 h. The reaction moni-
tored by TLC (1:1 hexane:ethyl acetate). Then the reac-
tion was quenched with saturated sodium bicarbonate
(until the pH of aqueous layer reach to 9) and then
extracted with dichloromethane. The organic extracts
were combined, dried over magnesium sulphate, and con-
centrated. The crude product was purred by column chro-
matography with silica gel using a hexane: ethyl acetate
4.5. Methyl 3-cyclohexyl-3-(hydroxyamino)-2,2-
dimethylpropanoate (4d)
Colorless oil, yield 0.325 g (71%); IR (KBr), m/cmÀ1
:
3260, 3160 (NH, OH), 2905 (CH), 1707 (C@O), 1440 (C–
N), 1307 (N–O). 1NMR (90 MHz, CDCl3) d: 0.92–1.53
(m, 6H, H6, H7), 1.34 (s, 6H, 2Me), 1.52–1.89 (m, 4H,
H5), 2.22 (m, 1H, H4), 3.45 (d, J = 9 Hz, 1H, H3), 3.73
(s, 3H, OMe), 8.11–8.87 (bs, 2H, NH, OH); 13C
NMR(22.5 MHz, CDCl3) d: 14.5 (C7), 21.7 (C6), 25.1
(Me), 25.3 (Me), 25.7 (C5), 29.9 (C4), 36.6 (C2), 52.5
(OMe), 55.7 (C3), 156 (C@O). Anal. Calc. for
C12H23NO3 (229): C, 62.88; H, 10.04; N, 6.11; O, 20.96.
Found: C, 62.98; H, 10.00; N, 6.07; O, 20.95%.
1
gradient from 3:2 to 1:1. H NMR, 13C NMR, and IR
spectra were entirely consistent with the assigned struc-
tures. The physical and spectra data of compounds 4a–
d are as follows.
4.6. General procedure for preparation of 6e–h
4.2. Methyl 3-(hydroxyamino)-2,2,4-trimethylpentanoate
(4a)
To a mixture of aldehyde (2 mmol) in 5.0 M LPDE
(3 ml) was added O-trimethylsilyl hydroxylamine (2 mmol)
at room temperature. After the mixture stirring for 10 min,
allyltributyltin (2 mmol) was added. After this, the mixture
was allowed to stir at room temperature for 4–5 h. The
reaction monitored by TLC (2:1 hexane:ethyl acetate).
Then the reaction was quenched with cooled brine and then
extracted with dichloromethane. The organic extracts were
combined, dried over magnesium sulphate, and concen-
trated. The crude product was purred by column chroma-
Yellow oil, yield 0.287 g (76%); IR (KBr), m/cmÀ1: 3395,
3185 (NH, OH), 2900 (CH), 1710 (C@O), 1450 (C–N),
1379 (N–O). 1H NMR (90 MHz, CDCl3) d: 1.11 (d,
J = 9 Hz, 6H, H5), 1.42 (s, 6H, 2Me), 2.89 (m, 1H, H4),
3.73 (s, 3H, OMe), 4.24 (d, J = 8 Hz, 1H, H3), 4.42–5.09
(bs, 2H, NH, OH). 13C NMR (22.5 MHz, CDCl3) d:
20.2, 21.8, 22.9, 23.0 (2Me, C5), 29.6 (C4), 36.7 (C2), 52.2
(OMe), 55.9 (C3), 158 (C@O). Anal. Calc. for C9H19NO3

H. Tavakol et al. / Journal of Organometallic Chemistry 692 (2007) 1924–1927
1927
tography with silicagel using a hexane:ethyl acetate gradi-
4.10. N-tributyltin-N-trimethylsilyloxy-1-(4-methyl-2-
furyl)but-3-en-1-amine (6h)
1
ent from 2:1 to 3:1. H NMR, 13C NMR, and IR spectra
were entirely consistent with the assigned structures. The
physical and spectra data of compounds 6a–d are as
follows.
Yellow oil, yield 0.475 g (45%); IR (KBr), m/cmÀ1: 1613
(aromatic ring), 1448 (C–N), 1375 (N–O); 1H NMR
(90 MHz, CDCl3) d: 0.4 (s, 9H, SiMe3), 0.7–1.6 (m, 27H,
SnBu3), 2.3 (s, 3H, Me), 2.4 (t, 2H,H2), 4.5–4.8 (m, 3H,
H1, H4), 5.6– 6.1 (m, 1H,H3), 5.9–6.5 (m, 2H, Ar); 13C
NMR (22.4 MHz, CDCl3) d: À0.9 (SiMe3), 10.2, 16.9,
29.1, 30.5 (SnBu3), 18.7 (Me), 44.2 (C2), 65.9 (C1), 108.2,
109.6, 114.4, 138.6, 140.3, 146.3 (C3, C4, Ar). Anal. Calc.
for C24 H47NO2 SiSn (528): C, 54.55; H, 8.90; N, 2.65; O,
6.06; Si, 5.30; Sn, 22.54. Found: C, 54.66; H, 8.83; N,
2.60; O, 6.15%.
4.7. N-tributyltin-N-trimethylsilyloxy-1-(3-pyridinyl)but-3-
en-1-amine (6e)
Yellow oil, yield 0.672 g (64%); IR (KBr) m/cmÀ1: 1648
(aromatic ring), 1434 (C–N), 1347 (N–O). 1H NMR
(90 MHz, CDCl3) d: 0.2 (s, 9H, SiMe3), 0.71–1.83 (m,
27H, SnBu3), 2.62 (2d, 2H, H2), 4.89 (dd, J = 9 Hz, 6 Hz,
1H, H1), 5.05–5.22 (m, 2H, H4), 5.63–6.14 (m, 1H, H3),
3
7.38–8.78 (m, 4H, aromatic ring); C NMR (125.8 MHz,
CDCl3) d: À1.0 (SiMe3), 13.6, 17.6, 26.9, 27.9 (SnBu3),
43.8 (C2), 70.9 (C1), 109.6 (C4), 123.6 (C3), 119.3, 123.7,
133.5, 146.7, 150.2 (aromatic ring). Anal. Calc. for
C24H46N2OSiSn (525): C, 54.86; H, 8.76; N, 5.33; O,
3.05; Si, 5.33; Sn, 22.67. Found: C, 54.97; H, 8.84; N,
5.290; O, 2.97%.
Acknowledgement
Research supported by Research Council of Zabol Uni-
versity, Research Council of Tarbiat Modares University,
and the National Research Council of I.R. Iran.
References
4.8. N-tributyltin-N-trimethylsilyloxy-1-(4-nitrophenyl)but-
3-en-1-amine (6f)
[1] L.F. Tietze, Chem. Rev. 96 (1996) 115.
[2] H. Bienayme, C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 6
(2000) 321.
Yellow oil, yield 0.762 g (67%); IR (KBr), m/cmÀ1: 1620
(aromatic ring), 1457 (C–N), 1342 (N–O), 740 (para-disub-
stituted benzene) 1H NMR (90 MHz, CDCl3) d: 0.4 (s, 9H,
SiMe3), 0.71–1.78 (m, 27H, SnBu3), 2.50 (2d, 2H, H2),
4.60–5.31 (m, 3H, H1, H4), 5.60 –6.12 (m, 1H, H3), 7.50
(d, J = 10 Hz, 2H, Ar), 8.1 (d, J = 10 Hz, 2H, Ar); 13C
NMR (125.8 MHz, CDCl3) d: À1.5 (SiMe3), 13.6, 15.0,
27.1, 27.8 (SnBu3), 43.9 (C2), 72.2 (C1), 116.9 (C4), 123.2
(C3), 123.5, 126.7, 135.2, 146.8 (Ar). Anal. Calc. for
C25H46N2O3 SiSn (569): C, 52.72; H, 8.08; N, 4.92; O,
8.44; Si, 4.92; Sn, 20.91. Found: C, 52.81; H, 8.13; N,
4.86; O, 8.48%.
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4.9. N-tributyltin-N-trimethylsilyloxy-1-(3-nitrophenyl)but-
3-en-1-amine (6g)
Yellow oil, yield 0.648 g (57%); IR (KBr), m/cmÀ1
:
1611 (aromatic ring), 1451(C–N), 1347 (N–O), 1071,
970, 871 (meta-disubstituted benzene); 1H NMR
(90 MHz, CDCl3) d: 0.3 (s, 9H, SiMe3), 0.8–1.9 (m,
27H, SnBu3), 2.5 (t, 2H, H2), 4.5–5.2 (m, 3H, H1, H4),
5.5– 6.2 (m, 1H, H3), 7.4–8.5 (m, 4H, Ar); 13C NMR
(22.4 MHz, CDCl3) d: À1.3 (SiMe3), 8.9, 13.5, 27.2,
28.8 (SnBu3), 43.9 (C2), 68.0 (C1), 109.4 (C4), 122.1
(C3), 124.5, 130.0, 132.9, 138.5, 147.8, 151.7 (Ar). Anal.
Calc. for C25H46N2O3 SiSn (569): C, 52.72; H, 8.08; N,
4.92; O, 8.44; Si, 4.92; Sn, 20.91. Found: C, 52.82; H,
8.11; N, 4.84; O, 8.47%.
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Tetrahedron Lett. 38 (1997) 1841.
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[19] We use O-trimethylsilyl hydroxylamine versus normal hydroxylamine
salts because of good solubility of it in various organic solvent and
fast syntheses of oxime ethers without needing to catalyst or pH
control.
[20] If we carried out the reaction without TMSCl, formation of desired
product was not being observed.
[21] We decide to complete these experiments by using allylsilane as a
nucleophile. But, unfortunately we don’t access to this compound for
doing this.