A large-scale low-cost preparation of n-benzylhydroxylamine hydrochloride

Article abstract of DOI:10.1055/s-0029-1216932

A high-yielding, practical two-step procedure for the preparation of N-benzylhydroxylamine starting from dibenzylamine is described. As specified in the detailed protocol, the reaction can be conveniently carried out on a > 0.5 mol laboratory scale.

Full text of DOI:10.1055/s-0029-1216932

3174
PRACTICAL SYNTHETIC PROCEDURES
A Large-Scale Low-Cost Preparation of N-Benzylhydroxylamine
Hydrochloride
N
-Benzylhydrox
h
ylamine
H
y
a
drochloridenh Binh Nguyen, Arnaud Martel, Robert Dhal, Gilles Dujardin*
Laboratoire de Synthèse Organique, UCO2M, UMR 6011 CNRS, Université du Maine,
72085 Le Mans, France
E-mail: gilles.dujardin@univ-lemans.fr
PSP
Received 22 April 2009; revised 8 June 2009
No168
Abstract: A high-yielding, practical two-step procedure for the preparation of N-benzylhydroxylamine starting from dibenzylamine is
described. As specified in the detailed protocol, the reaction can be conveniently carried out on a > 0.5 mol laboratory scale.
Key words: N-benzylhydroxylamine, N-benzylnitrones, 1,3-dipolar cycloaddition, secondary amine oxidation, nitrone hydrolysis
aq H2O2
Na2WO4
OHCCO2Et
NaOAc
CO2Et
HCl
Ph
N
O
Ph
Ph
N
H
Ph
Ph
NHOH.HCl
Ph
N
O
4
MeOH
92%
MeOH
H2O
3
2
1
72% (2 steps)
Scheme 1
N-Benzylhydroxylamine has become one of the most pop-
ular reagents in nitrone chemistry. Its condensation with
an aldehyde or a ketone1 and its addition to an activated
triple bond2 are among the most common methods to N-
benzylnitrones. 1,3-Dipolar cycloaddition of these ni-
trones with alkenes provides N-benzylisoxazolidines in
which the benzyl group can be easily removed from nitro-
gen in order to perform further manipulations at that atom.
The retail price of N-benzylhydroxylamine hydrochloride
(1) (approx. 5000 €/mol) is notably high for such a simple
molecule. During the course of our research on new meth-
odological developments concerning the 1,3-dipolar cy-
cloaddition of nitrones,1b,3 a large quantity of N-
benzylhydroxylamine was used as the starting material.
We considered the benefit of being able to prepare N-ben-
zylhydroxylamine on a large-scale by a cheap and reliable
procedure.
The preparation of N-benzylhydroxylamine6 by acid hy-
drolysis of nitrone 2 and subsequent neutralization attract-
ed our attention. Based on this result, we thought that
nitrone 2 could be an interesting precursor for 1, provided
that 2 could be obtained in a high-yielding and simple
way. Our attention was directed to the preparation of ni-
trone 2 by oxidation of dibenzylamine 3, given that 3 is
quite inexpensive (approx. 13 €/mol) as it can be easily
made by the reaction between NH3 and benzyl chloride in
industrial scale.
This transformation was previously carried out by using
H2O2 in the presence of a catalyst such as Na2WO4,7
SeO2,8 or MeReO3,9 or by using dimethyldioxirane,10 and
N-phenylsulfonyl-C-phenyloxaziridine.11 Among the
methods reported on a large-scale,7,9 Murahashi’s
procedure7 using Na2WO4 (2 mol%) seems to be the most
economic and practical as low-cost reagents (H2O2,
Na2WO4)12 and solvent (MeOH) were used, and the de-
sired nitrone could be obtained in excellent yield (85–96%
after recrystallization).
However, in the original Murahashi’s procedure,7 the
crude reaction mixture was subjected to methanol evapo-
ration without prior removal or treatment of the residual
oxidative agent H2O2. Despite the high yield, this method
seemed to be unsafe, especially for a larger scale synthe-
sis. Following our modified procedure, simple addition of
ice was found to precipitate the nitrone 2 from the crude
reaction mixture. By simple filtration, we could recover
the nitrone in high yield (~80%) and avoid hazardous ma-
nipulations.13 Moreover, this modification of the proce-
dure prevents the use of a large amount of CH2Cl2,
In the literature, some methods for the preparation of this
compound have been reported. Direct benzylation of the
hydroxylamine results in a complex mixture of polyben-
zylated products, in which N,N-dibenzylhydroxylamine is
the major product.4 Reduction of benzaldoxime by
NaBH3CN in buffered diethyl ether solution affords the
desired N-benzylhydroxylamine in moderate and hardly
reproducible yields possibly due to a pH change during
the course of the process.5 Moreover, use of NaBH3CN is
highly toxic and can generate deleterious side products af-
ter workup.
SYNTHESIS 2009, No. 18, pp 3174–3176
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.08.2009
DOI: 10.1055/s-0029-1216932; Art ID: T08109SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
N-Benzylhydroxylamine Hydrochloride
3175
(the last trace of H2O could be removed by adding toluene and dis-
tilling). The residue was dried overnight in a vacuum desiccator to
afford pale yellow solid of crude BnNHOH·HCl (62 g) which was
purified by recrystallization from hot MeOH (120 mL) and then
Et2O (350 mL) to yield the pure desired product as white crystals
(57.4 g, 72%).
1H NMR (200 MHz, D2O): d = 11.9 (br, 2 H), 11.0 (br, 1 H), 7.57–
7.37 (m, 5 H), 4.31 (s, 2 H).
13C NMR (100 MHz, D2O): d = 131.6, 130.3, 129.1, 128.0, 62.2.
previously used for extraction of nitrone 2. Given that wa-
ter is not detrimental for the next reaction, we used the wet
nitrone directly in the subsequent acidic hydrolysis step.
Treatment of this crude mixture with an aqueous hydro-
chloric acid solution (20%) followed by steam distillation
under reduced pressure in order to eliminate PhCHO af-
forded pure BnNHOH·HCl 1 as colorless crystals after
only one recrystallization from hot methanol with good
overall yield (72%) (Scheme 1). This access to the hydro-
chloric salt 1 from nitrone 2 compares well with the pre-
vious synthesis of free N-benzylhydroxylamine by a
similar procedure6 or with the formation of relevant
oxalates via hydroxylaminolysis of nitrones.14 The purity
of 1 obtained by this procedure on a 0.5 mole scale was at-
tested by elemental analysis.
Anal. Calcd for C7H10ClNO (159.61): C, 52.67; H, 6.31; N, 8.78.
Found: C, 52.59; H, 6.40; N, 8.77.
Nitrone 4
A slurry of BnNHOH·HCl (3.20 g, 20 mmol) and anhydrous
NaOAc (2.18 g, 26 mmol) in MeOH (20 mL) was stirred for 10 min
at r.t. A solution of 50% ethyl glyoxylate in toluene (4.08 g, 20
mmol) was then added. After stirring for 3 h at r.t., the reaction mix-
ture was concentrated under vacuum. The white residue was parti-
tioned between CH2Cl2 (100 mL) and H2O (30 mL). The separated
aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The com-
bined organic phases were dried (MgSO4) and filtered through a
short pad of silica gel. The filtrate was concentrated under vacuum
to yield pure nitrone 4 as white crystals (4.10 g, 92%).
To exemplify the quality and utility of BnNHOH·HCl (1)
obtained by this simplified and safe procedure, we pre-
pared the activated nitrone 4, which is a pivotal synthon in
amino acid synthesis. By a highly simple procedure start-
ing from this salt and ethyl glyoxylate in an acetate-buff-
ered methanol solution, nitrone 4 was prepared in
excellent yield (92%) (Scheme 1). This procedure com- 1H NMR (200 MHz, CDCl3): d (E/Z = 3:1) = 7.58–7.33 (m, 5 Harom),
7.20 [s, 1 H, N=CH (E)], 7.05 [s, 1 H, N=CH (Z)], 5.70 [s, 2 H,
pares well with those previously described by condensing
3
CH2Ph (E)], 4.99 [s, 2 H, CH2Ph (Z)], 4.26 and 4.24 (q, J3,4 = 7.1
free BnNHOH and ethyl glyoxylate in the presence of
Hz, CH2CH3) 1.32 and 1.28 (t, 3J3,4 = 7.1 Hz, CH2CH3).
CaCl2 as catalyst.15
To conclude, we have described here a large-scale, sim-
Acknowledgment
ple, economic, and safe procedure for the preparation of
N-benzylhydroxylamine hydrochloride (1). This two-step
method requires only low-cost starting materials (Bn2NH,
H2O2, Na2WO4, HCl) and solvents (H2O, MeOH) with
highly simple purification (recrystallization, evaporation,
and steam distillation) in good overall yield.
We thank the French Ministry of Research for the PhD grant to
T.B.N.
References
(1) (a) Inouye, Y.; Hara, J.; Kakisawa, H. Chem. Lett. 1980,
1407. (b) Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G.
J. Org. Chem. 2008, 73, 2621. (c) Dondoni, A.; Franco, S.;
Junquera, F.; Merchan, F.; Merino, P.; Tejero, T. Synth.
Commun. 1994, 24, 2537.
(2) (a) Winterfeldt, E.; Krohn, W.; Stracke, H. Chem. Ber. 1969,
102, 2346. (b) Nguyen, T. B.; Martel, A.; Dhal, R.;
Dujardin, G. Org. Lett. 2008, 10, 4493.
All reagents and solvents were used as received without any further
purification. 1H NMR spectra were recorded on a Bruker DPX-200
spectrometer in D2O for 1 and CDCl3 for 4 using TMS as a refer-
ence.
BnNHOH·HCl (1)
In a 2-L, three-necked, round-bottomed flask equipped with a 500-
mL pressure-equalizing dropping funnel, a thermometer, and a
magnetic stirring bar were placed Na2WO4·2H2O (2.94 g, 10
mmol), Bn2NH (98.5 g, 0.5 mol) and MeOH (0.5 L). The flask was
cooled with an ice bath to 0–5 °C (internal temperature) and 30% aq
H2O2 (170 mL, 1.5 mol) was added dropwise over a period of ca. 2
h. During the period of addition, the reaction mixture should be
carefully kept at a temperature below 5 °C. The cooling bath was re-
moved 2 h after the end of the addition of H2O2, and the mixture was
stirred for 18 h at r.t. The contents of the flask were first transferred
to a 5 L beaker and then crushed ice (3 kg) was next added to the
mixture with vigorous stirring. The white precipitate of nitrone 2
was filtered, washed with ice water until the filtrate gave a negative
result with peroxide test (ca. 0.5 L of H2O was needed). The wet
crude nitrone 2 was then placed in a 2-L round-bottomed flask con-
taining aq 20% HCl (1 L). The flask was fitted to a rotary evaporator
keeping the water bath temperature at 70 °C with slow rotation un-
der atmospheric pressure. After 30 min, the pressure was carefully
reduced to 100 mmHg while benzaldehyde was distilled off with
H2O. When the total volume remained 130 mL, the flask was re-
moved from the rotary evaporator. The semi-solid mixture was
washed with toluene (3 × 100 mL) and then concentrated in vacuo
(3) (a) Nguyen, T. B.; Gaulon, C.; Chapin, T.; Tardy, S.;
Tatibouet, A.; Rollin, P.; Dhal, R.; Martel, A.; Dujardin, G.
Synlett 2006, 3255. (b) Nguyen, T. B.; Martel, A.; Dhal, R.;
Dujardin, G. Synlett 2008, 2041. (c) Nguyen, T. B.; Vuong,
T. M. H.; Martel, A.; Dhal, R.; Dujardin, G. Tetrahedron:
Asymmetry 2008, 19, 2084. (d) Nguyen, T. B.; Martel, A.;
Dhal, R.; Dujardin, G. Synlett 2009, in press.
(4) Jones, L. W.; Sneed, M. C. J. Am. Chem. Soc. 1917, 39, 677.
(5) Feuer, H.; Vincent, B. F.; Bartlett, R. S. J. Org. Chem. 1965,
30, 2877.
(6) Nakajima, M.; Anselme, J. P. J. Org. Chem. 1983, 48, 1444.
(7) (a) Murahashi, S. I.; Mitsui, H.; Shiota, T.; Tsuda, T.;
Watanabe, S. J. Org. Chem. 1990, 55, 1736. (b) Murahashi,
S.-I.; Shiota, T.; Imada, Y. Org. Synth. Coll. Vol. 9; Wiley:
New York, 1998, 632.
(8) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28,
2383.
(9) Goti, A.; Cardona, A.; Soldaini, G. Org. Synth. 2005, 81,
204.
(10) Murray, R. W.; Singh, M. J. Org. Chem. 1990, 55, 2954.
(11) Zajac, W. W. Jr.; Walters, T. R.; Darcy, M. G. J. Org. Chem.
1988, 53, 5856.
Synthesis 2009, No. 18, 3174–3176 © Thieme Stuttgart · New York

3176
T. B. Nguyen et al.
PRACTICAL SYNTHETIC PROCEDURES
(12) The cost of the tungstate catalyst, used at a 2 mol%, is
approximately 60 €/mol.
(13) Evaporation of the solvent (MeOH) at reduced pressure in
the presence of large quantities of aqueous H2O2, as
described in reference 7.
T.; Fukuyama, T. Synthesis 2000, 1299. (b) Tokuyama, H.;
Kuboyama, T.; Fukuyama, T. Org. Synth. 2003, 80, 207.
(c) Coskun, N.; Parlar, A. Synth. Commun. 2005, 35, 2445.
(15) Inouye, Y.; Watanabe, S.; Kakisawa, H. Bull. Chem. Soc.
Jpn. 1979, 52, 3763.
(14) (a) Tokuyama, H.; Kuboyama, T.; Amano, A.; Yamashita,
Synthesis 2009, No. 18, 3174–3176 © Thieme Stuttgart · New York