One-pot synthesis of α-substituted hydroxylamine derivatives from aldehydes using lithium perchlorate/diethyl ether as a catalyst

Article abstract of DOI:10.1055/s-2003-41454

O-(Trimethylsilyl)oxime ethers, generated in situ by reaction of aldehydes and O-(trimethylsilyl)hydroxylamine in lithium perchlorate/diethyl ether solution, are highly reactive species and undergo facile reaction with silylated nucleophiles, such as trimethylsilyl cyanide and the binary reagent (MeO)₃P/Me₃SiCl, to give α-substituted hydroxylamine derivatives.

Full text of DOI:10.1055/s-2003-41454

1962
SHORT PAPER
One-Pot Synthesis of a-Substituted Hydroxylamine Derivatives from
Aldehydes Using Lithium Perchlorate/Diethyl Ether as a Catalyst
O
a
ne-Pot Synthesis
k
of
a
-Substitu
b
ted Hydrox
a
Chemistry Department, Tarbiat Modarres University, P. O. Box 14155-4838, Tehran, Iran
Fax +98(21)8006544; E-mail: akbar.heydari@gmx.de
b
Department of Phytochemistry, Shahid Beheshti University, Evin 1983963113, Tehran, Iran
Received 5 May 2003; revised 26 May 2003
thylsilyl)hydroxylamine, is submitted to a nucleophilic at-
tack with trimethylsilyl cyanide (Scheme 1). In all cases,
the desired products were obtained in high yields.
Abstract: O-(Trimethylsilyl)oxime ethers, generated in situ by re-
action of aldehydes and O-(trimethylsilyl)hydroxylamine in lithium
perchlorate/diethyl ether solution, are highly reactive species and
undergo facile reaction with silylated nucleophiles, such as trimeth-
ylsilyl cyanide and the binary reagent (MeO)3P/Me3SiCl, to give a-
substituted hydroxylamine derivatives.
Key words: lithium perchlorate, oximes, a-substituted hydroxy-
lamines
The addition of nucleophiles to a carbon–nitrogen double
bond has become an extremely useful process for the syn-
thesis of a variety of amines, a-amino acids, a-amino-
phosphonates, and other compounds of interest.1
Typically organometallic reagents can be utilized to
achieve this carbon–carbon bond formation reaction.2
Three factors which often diminish the versatility of these
reactions are poor electrophilicity of imines, enolization
of substrates that contain a-hydrogens, and the formation
of reductive coupling products.3 In many cases, these
problems can be overcome by using more activated imine
derivatives (iminium salts, acylimines, sulfonimines, ni-
trones, hydrazones and oximes) or less basic reagents.
With oximes the same problems are encountered since
oximes are often less electrophilic and less easily activat-
ed than the corresponding imine derivatives. The facile a-
deprotonation of oximes, the existence of mixtures of E-
and Z isomers of oximes, the lability of the nitrogen–oxy-
gen bond, and the poor oxime reactivity are the factors
that contribute to the complexity of the reaction.4 In addi-
tion, oximes having a quaternary carbon adjacent to the
carbonyl group are prone to undergo fragmentation as a
major reaction pathway, furnishing nitriles.5
Scheme 1
In order to evaluate the scope and limitations of this new
one-pot three-component reaction, the modification of the
structure of the nucleophiles was studied. As an analog of
a-(hydroxyamino)alkyl(aryl)carboxylic acids, a-(hy-
droxyamino)alkyl(aryl)phosphonic acids and their deriva-
tives are reported to show strong antibacterial activity.7
To the best of our knowledge, only a few examples of the
synthesis of a-(hydroxylamino)alkyl(aryl)phosphonic ac-
ids have been reported. These include the controlled re-
duction of a-nitroalkyl phosphonates with zinc and
ammonium chloride,8 addition of dialkyl phosphite to 1-
oxoaldoxime at elevated temperature,9 the nucleophilic
addition of lithium and potassium dialkyl phosphite an-
ions to N-glycosyl nitrone followed by glycoside cleavage
and hydrolysis,10 the condensation of a-(benzyloxyami-
no)alkylphosphonic acid with O-alkylisourea followed by
subsequent treatment with boron tris(trifluoroacetate)11
and the controlled reduction of a-(hydroxylimi-
no)alkyl(aryl)phosphosphonates with borane-pyridine
complex.12 Unfortunately, these methods are limited by a
narrow scope, by competition with other reactions, and
difficulties in the preparation of the starting materials. In
this paper, we wish to report a facile synthesis of a-(hy-
Recently, we have demonstrated the synthetic utility of
lithium perchlorate/diethyl ether (LPDE) solution (1.0–
5.0 M) in the preparation of several nitrogen-containing
compounds.6 We have now focused our attention on the
use of LPDE medium for oxime activation. In this paper
we wish to report a mild, simple and efficient conversion
of aldehydes 1 to a-cyano(silyloxy)amines 4 in LPDE me-
dium. In this reaction an oxime trimethylsilyl ether,
formed in situ from a mixture of aldehyde and O-(trime-
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 10 09 2003.
Art Id.1437-210X,E;2003,0,13,1962,1964,ftx,en;Z05903SS.pdf.
DOI: 10.1055/s-2003-41454
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
One-Pot Synthesis of a-Substituted Hydroxylamine
1963
a-(Hydroxylamino)alkyl(aryl)phosphonates 7; General Proce-
dure
droxyamino)alkyl(aryl)phosphonates 7 in good yields by
a new three-component synthesis in which an O-trimeth-
ylsilyl oxime ether [generated in situ from aldehyde 1 and
O-(trimethylsilyl)hydroxylamine (2)] is reacted with the
binary reagent (MeO)3P/Me3SiCl in LPDE solution (5.0
M) at room temperature within 1 hour. Examples are
shown in Scheme 2.13
To a mixture of aldehyde (2 mmol) in 5 M LPDE (4 mL) was added
O-(trimethylsilyl)hydroxylamine (232 mg, 2.2 mmol) at r.t. The
mixture was stirred for 15 min and a mixture of trimethyl phosphite/
trimethylsilyl chloride (2.2 mmol) was added. After the mixture was
stirred for 1 h, H2O (10 mL) was added. The H2O layer was extract-
ed with CH2Cl2 (3 × 30 mL), and the combined organics were
washed with sat. aq NaHCO3 solution (20 mL) and brine (30 mL),
dried (Na2SO4), and concentrated. The product was purified by
1
flash chromatography (hexane–EtOAc). H NMR, 13C NMR, IR
and MS spectra of all the products were entirely consistent with the
assigned structures. Selected data are given below.
7c (R1 = t-Bu)
3
1H NMR (500 MHz, CDCl3): d = 3.76 (d, JP-H = 10 Hz, 3 H,
OCH3), 3.74 (d, 3JP-H = 10 Hz, 3 H, OCH3), 3.57 (d, 2JP-H = 10 Hz,
1 H, H-1), 3.4–3.2(br s, 2 H, NH, OH), 1.05 (s, 9 H, CH3).
2
13C NMR (125 MHz, CDCl3): d = 75.6 (d, JP-C = 158 Hz, C-1),
53.14 (d, 3JP-C = 6.3 Hz, OCH3), 52.7 (d, 3JP-C = 7 Hz, OCH3), 34.55
(s, CH), 26.4 (s, CH3).
7d (R1 = Ph)
1H NMR (90 MHz, CDCl3): d = 7.6–7.2 (m, 5 H, ArH), 5.09 (d,
3
2JP-H = 16 Hz, 1 H, H-1), 3.78 (d, JP-H = 10 Hz, 3 H, OCH3), 3.74
(d, 3JP-H = 10 Hz, 3 H, OCH3), 3.5–3.3 (br s, 2 H, NH, OH).
13C NMR (125 MHz, CDCl3): d = 136.21 (C), 128.47 (CH, Ar),
Scheme 2
2
128.35 (CH, Ar), 127.01 (CH, Ar), 70.6 (d, JP-C = 159 Hz, C-1),
54.04 (d, 3JP-C = 7.5 Hz, OCH3), 52.7 (d, 3JP-C = 7.5 Hz, OCH3).
In summary, three-component reactions between alde-
hydes, O-(trimethylsilyl)hydroxylamine, and silylated nu-
cleophiles (the formation of dimethyltrimethylsilyl
phosphite has been postulated14) have been successfully
carried out by using LPDE solution to afford a-substituted
hydroxylamine derivatives 4 and 7 in high yields. The re-
actions are very clean and the procedure is very easy; sim-
ple mixing almost equimolar amounts of an aldehyde, O-
(trimethylsilyl)hydroxylamine, and the nucleophile.
Acknowledgment
This research was supported by the National Research Council of I.
R. Iran as a National Research project under the number 984.
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Synthesis 2003, No. 13, 1962–1964 ISSN 1234-567-89 © Thieme Stuttgart · New York