Phase-transfer catalysis for the synthesis of hydroxylamines from oximes using benzyltriethylammonium borohydride in methanol and under solid-phase conditions

Article abstract of DOI:10.1070/MC2006v016n01ABEH002213

Effective phase-transfer catalysis methodologies for the reduction of oximes to hydroxylamines by a selective and versatile reducing agent, benzyltriethylammonium borohydride (BTEABH), in methanol and under solid-phase conditions are presented.

Full text of DOI:10.1070/MC2006v016n01ABEH002213

Mendeleev
Communications
Mendeleev Commun., 2006, 16(1), 50–51
Phase-transfer catalysis for the synthesis of hydroxylamines from oximes using
benzyltriethylammonium borohydride in methanol and under solid-phase conditions
Mannathusamy Gopalakrishnan,* Thirunavukkarasu Anandabaskaran, Purusothaman Sureshkumar,
Jayaraman Thanusu, Arumugam K. Kumaran and Vijayakumar Kanagarajan
Department of Chemistry, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India.
E-mail: emgeekk@yahoo.co.in
DOI: 10.1070/MC2006v016n01ABEH002213
Effective phase-transfer catalysis methodologies for the reduction of oximes to hydroxylamines by a selective and versatile
reducing agent, benzyltriethylammonium borohydride (BTEABH), in methanol and under solid-phase conditions are presented.
The modification of sodium borohydride1–5 has attracted a great
Table 1 Selective reduction of 4-methoxybenzaldoxime with BTEABH
deal of attention in synthetic organic chemistry since it has led
to selective reduction of functional groups, which are otherwise
inert to sodium borohydride alone. For instance, the reductions
of acid chlorides to aldehydes6 or alkenes to saturated hydro-
carbons7 can be achieved using a combination of sodium boro-
hydride with CuI or CoII, respectively.
(1 mmol scale) at room temperature.
Entry
Solvent
t/min
Yielda (%)
1
None
Methanol
None
16
38
16
38
86
75
84
73
2
3b
4b
The Borsch method utilising sodium cyanoborohydride8 and
zinc borohydride9 is currently the most popular way of converting
oximes into hydroxylamines. Other methods include the use of
sodium borohydride and trifluoroacetic acid10 or aqueous sulfuric
acid,11 zinc borohydride,12 zinc modified cyanoborohydride13
and 1-benzyl-1-azonia-4-azabicyclo[2.2.2]octane tetraborate.14
Butyltriphenylphosphonium tetraborate15 was used as a selective
reducing agent for the reduction of oximes, enamines and imines
under solid-phase conditions. However, phosphonium salts are
expensive, and by-products are harmful to the environment.
Hydroxylamines are known as anti-bacterial, antifungal and
antileukemic agents; N-hydroxyurea is an effective antineou-
plasmic agent,16 and cyclopiroxolamine has a broad-spectrum
antifungal activity.17
Methanol
aIsolated yield of the reduced product. bThe reaction was carried out in
100 mmol scale using BTEABH (33 g).
A model reaction was performed by reducing 4-methoxy-
benzaldoxime with BTEABH. The use of 330 mg (1 mmol) of
BTEABH was found sufficient for the highly effective and selec-
tive reduction of 4-methoxybenzaldoxime to a corresponding
hydroxylamine in 86% yield in a 1 mmol scale experiment
at room temperature for 16 min under solid-phase conditions
(Table 1, entry 1), by simple grinding with a pestle and a mortar
(P/M). The reduction of the oxime with the reducing agent in
methanol proceeded smoothly in 75% yield at room temperature
for 38 min in solution (entry 2) with stirring with a magnetic
stirrer. Moreover, a quantitative conversion (84% yield) was
accomplished in a 100 mmol scale experiment using 33 g of
BTEABH and 15.1 g of an oxime after P/M grinding at room
temperature for 10 min (entry 3). The reduction in methanol pro-
ceeded with quantitative conversion (73% yield) in a 100 mmol
scale experiment during 38 min at room temperature (entry 4).
As can be seen in Table 2, oximes are cleanly reduced to the
corresponding hydroxylamines‡ in good to excellent yields in
We found benzyltriethylammonium borohydride† (BTEABH)
as an efficient phase-transfer catalyst for the synthesis of these
biologically significant compounds. In continuation of the
development of environmentally benign methods using solid
supports,18–20 we have developed an environmentally safe and
clean synthesis of hydroxylamines using methanol as a solvent
or grinding in a mortar (Scheme 1).
†
Synthesis of BTEABH. Sodium borohydride (3.78 g, 100 mmol) was
added to a solution of benzyltriethylammonium chloride (39.94 g,
100 mmol) in methanol (100 ml). The reaction mixture was stirred at
room temperature for 90 min; the resulting white solid product was
collected, washed with water (200 ml) and dried in a vacuum desiccator
over calcium chloride to yield a white solid product (41.2 g, 98%),
mp 140–143 °C. 1H NMR (CDCl3) d: 7.58–7.57 (m, HAr), 4.45 (s, 2H),
OH
OH
N
HN
R1
i or ii
+ BTEABH
R1
R2
R2
R1 = Ar, aliphatic
R2 = H, aliphatic
1
2
3.28 (q, 2H), 1.43 (t, 3H), HBH did not appeared in the spectrum.
4
13C NMR (CDCl3) d: 9.74 (Me), 54.95 (CH2), 62.63 (benzylic C), 135.0–
131.9 (CAr), 149 (ipso-C). IR: (KBr, n/cm–1): 3471, 3403, 2979, 2832,
1598, 1258.
Scheme 1 Selective reduction of oximes to hydroxylamines using BTEABH.
Reagents and conditions: i, pestle and mortar, solid-phase; ii, magnetic
stirrer, methanol.
50 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(1), 50–51
In conclusion, we have demonstrated the utility of BTEABH
as a selective and versatile phase-transfer catalyst for the reduc-
tion of oximes to the corresponding hydroxylamines both under
solid-phase conditions and in methanol without the environ-
mental disadvantages of toxic butyltriphenylphosphonium tetra-
borate.15 In the reduction of oximes with this reducing agent, no
trace of over reduction to the amine was observed.
Table 2 Selective reduction of oximes to hydroxylamines with BTEABH
in methanol and under solid-phase conditions.
Under solid-phase
conditions
Product 2a
In methanol
Entry
R1
Ph
R2 t/min Yield (%)b t/min Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
30
29
27
31
30
33
30
29
35
32
35
33
38
40
42
45
32
35
25
23
82
79
80
78
79
80
78
71
78
73
72
70
75
70
69
65
80
79
72
74
80
81
82
80
78
80
78
76
73
70
8
95
88
89
85
86
85
88
90
86
88
84
80
86
79
76
76
93
90
82
84
89
87
90
89
87
89
85
86
84
81
3-NO2C6H4
4-NO2C6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
4-MeC6H4
4-HOC6H4
4-MeOC6H4
2-MeO-4-HOC6H3
3,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
furan-2-yl
thiophen-2-yl
R1 + R2 = (CH2)4
R1 + R2 = (CH2)5
Ph
10
11
13
12
14
13
11
13
12
16
15
16
18
20
22
9
12
11
11
13
12
11
14
12
10
15
17
18
20
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Me 35
Me 32
Me 33
Me 30
Me 35
Me 33
Me 40
Me 38
Me 42
4-FC6H4
4-ClC6H4
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
4-MeC6H4
4-HOC6H4
4-MeOC6H4
2-MeO-4-HOC6H3 Me 45
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aAll the products are characterised on the basis of IR, 1H NMR and MS
spectral data as well as by comparing with authentic samples prepared
according to literature. bIsolated yields of products.
the presence of BTEABH both under solid-phase conditions
and in the presence of methanol. The former method makes use
of local heat produced by the P/M grinding of oximes in the
presence of BTEABH for driving the chemical reactions. The
latter method employs simple stirring of BTEABH and oximes
in methanol. Note that various structurally diverse benzaldoximes
and ketoximes are selectively reduced to the corresponding
hydroxylamines probably due to the efficiency of the reducing
agent.
‡
Typical experimental procedure for the synthesis of N-benzylhydroxyl-
amine (2, R1 = Ph, R2 = H).
(A) With a pestle and a mortar (P/M) under solid-phase conditions.
A mixture of benzaldoxime (1 mmol) and BTEABH (1 mmol) was P/M
ground for 8 min. On completion of the reaction, as monitored by TLC,
the reaction mixture was taken up in ethyl acetate (2×15 ml) and dried
over anhydrous Na2SO4 followed by evaporation of the solvent in vacuo
to furnish the corresponding reduction product. It was purified by column
chromatography on silica gel using a mixture of ethyl acetate and light
petroleum (20:80) as an eluent, yield 95%.
(B) Stirring with a magnetic stirrer in solution. Benzaldoxime (1 mmol)
was added to a stirred solution of BTEABH (1 mmol) in methanol
(15 ml). The mixture was stirred at room temperature with a magnetic
stirrer for 30 min and then the mixture was worked up and purified as
described above. IR spectra were recorded with a Nicolet Avatar-360
FT-IR spectrophotometer in KBr pellets. 1H NMR spectra were recorded
on a Bruker AMX-400 spectrometer (400 MHz) in CDCl3 using TMS as
an internal standard. 13C NMR spectra were recorded on a Bruker AMX-
400 spectrometer (100 MHz) in CDCl3. Mass spectra were recorded on a
Finnigan MAT 8230 mass spectrometer.
Received: 12th July 2005; Com. 05/2546
Mendeleev Commun. 2006 51