N-(1'-Benzotriazolylmethyl)-5-phenylmorpholin-2-one: A stable crystalline chiral azomethine ylid precursor

Article abstract of DOI:10.1055/s-2001-18763

The crystalline adduct of (5S)-5-phenylmorpholin-2-one with formaldehyde and benzotriazole on treatment with acid generates an azomethine ylid which may be trapped with a range of dipolarophiles in yields superior to those using in situ generation methodology.

Full text of DOI:10.1055/s-2001-18763

LETTER
1841
N-(1’-Benzotriazolylmethyl)-5-phenylmorpholin-2-one: A Stable Crystalline
Chiral Azomethine Ylid Precursor
N
-(1’
-
Benzotriazol
a
ylmethyl)
5
v
-phenylmorp
i
holin-2
d
-one J. Aldous,a,1 Estelle M.-N. Hamelin,b Laurence M. Harwood,*b Sukanthini Thurairatnama,1
a
Rhône Poulenc Rorer Limited, Rainham Road South, Dagenham, Essex RM10 7XS, UK
b
Department of Chemistry, University of Reading, Whiteknights, Reading, Berkshire RG6 6AD, UK
Fax +44(118)9316782; E-mail: l.m.harwood@reading.ac.uk
Received 23 August 2001
N
N
Abstract: The crystalline adduct of (5S)-5-phenylmorpholin-2-one
with formaldehyde and benzotriazole on treatment with acid gener-
ates an azomethine ylid which may be trapped with a range of dipo-
larophiles in yields superior to those using in situ generation
methodology.
N
H
H
N
H
Ph
Ph
N
O
a
O
O
O
Key words: chiral, azomethine ylid, benzotriazole, dipolar cy-
cloaddition
(1)
(4)
Scheme 2 a) benzotriazole, 32% aq HCHO, 1:1 EtOH:H2O, r.t., 24h
In a series of papers we have reported that (5S)-5-phenyl-
morpholin-2-one 1 reacts with aldehydes under both
thermal2a–l or Lewis acid catalysed conditions,3 generating
the azomethine ylid species 2 capable of undergoing high-
ly diastereoselective cycloadditions. In an effort to extend
the utility of this methodology we have pursued a pro-
gramme to identify stable substrates, which would furnish
2 under milder and experimentally more convenient con-
ditions. This has resulted in the identification of carbam-
ate derivative 3, which although it satisfied the chemical
and physical criteria, was not competitive with the direct
generation procedure in terms of yields of cycloadducts
(Scheme 1).4
In previous studies, N-phenylmaleimide and N-methyl-
maleimide have been found to be consistently the most ef-
fective dipolarophiles for cycloadditions onto azomethine
ylids derived from 1 and hence these were chosen to de-
termine optimal reaction conditions. A survey of various
alkylating, Lewis acid and Brønsted acid promoters such
as MeI, BF3 Et2O, trifluoroacetic acid, pyridinium para-
toluenesulfonate and para-toluenesulfonic acid in a series
of solvents and over a range of temperatures and reaction
times led to adoption of para-toluenesulfonic acid in re-
fluxing THF for 24 hours as the favoured conditions.8 Al-
though most combinations led to isolation of
cycloadducts, these optimal conditions gave combined
yields of exo- and endo-cycloadducts superior to the stan-
dard protocol in which the ylid is generated directly from
1 using paraformaldehyde in refluxing toluene. Applying
these optimised conditions to other dipolarophiles simi-
larly gave equal or superior yields to the standard protocol
(Scheme 3). Due to apparent incompatibility with the
standard thermal conditions, dimethyl fumarate had previ-
ously been found not to furnish any cycloadduct but mod-
ifying the optimised conditions with 4, using chloroform
as solvent, gave a single cycloadduct in 50% yield. In
keeping with previous observations, methyl propynoate
H
N
t
CO2 Bu
H
H
N
H
H
Ph
Ph
N
Ph
N
b
a
O
O
O
O
O
O
(3)
(1)
(2)
Scheme 1 a) (HCHO)n, toluene, reflux, –H2O; b) TFA, THF, r.t.
Aware of the comprehensive studies of Katritzky detail-
ing the reactivity profile of benzotriazole derivatives,5 we
decided to explore the potential of this functionality with-
in the context of azomethine ylid generation. According-
ly, following Katritzky’s procedure,6 (5S)-5-phenyl
morpholin-2-one 1 and benzotriazole were dissolved in
1:1 aqueous ethanol, aqueous formaldehyde added and the
mixture left at room temperature overnight. This resulted
in the precipitation of N-(1'-benzotriazolylmethyl)-5-phe-
nyl morpholin-2-one 4 as a colourless solid, isolated in
78% yield (Scheme 2).7
gave the regioisomer to be expected from LUMOdipole
–
HOMOdipolarophile frontier orbital interaction, whereas other
monoactivated dipolarophiles failed to react. The similar-
ity in yields, scope and limitation of this new approach
with those of the standard procedure leads us to conclude
that the reacting dipolar species are very similar under
both sets of reaction conditions and that the benzotriazole
must be totally divorced from the substrate before any sig-
nificant bonding interaction occurs with the dipolarophile.
In conclusion, we have demonstrated that (5S)-N-(1'-ben-
zotriazolylmethyl)-5-phenyl morpholin-2-one 4 satisfies
the criteria of providing a stable, solid material which gen-
erates azomethine ylid 2 under mild conditions which per-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1841,1842,ftx,en;G18401ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1842
D. J. Aldous et al.
LETTER
N
N
O
O
H
H
N
NR
O
NR
O
O
N
a
a
H
H
H
R
Ph
N
Ph
N
O
Ph
N
O
H
H
H
H
O
O
O
O
O
(4)
endo
exo
R
Me
Ph
MeO2C
CO2Me
CO2Me
35% (41%)
50% (45%)
33% (19%)
26% (13%)
MeO2C
a
CO2Me
b
H
CO2Me
H
H
CO2Me
CO2Me
H
CO2Me
H
CO2Me
H
Ph
N
O
CO2Me
Ph
N
O
CO2Me
Ph
N
Ph
N
H
H
H
H
O
H
O
H
O
H
O
O
O
endo
20% (20%)
exo
31% (30%)
50% (0%)
9% (6%)
Scheme 3 a) PTSA, THF, reflux, 24 h; b) PTSA, CHCl3, reflux, 24 h. Yields in parentheses are those obtained by generating the ylid directly
from morpholinone under standard thermal conditions.2a–d
Rachwal, B. J. Chem. Soc., Perkin Trans. 1 1987, 791.
(b) Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Chem. Soc.,
mit efficient trapping with a range of doubly activated
dipolarophiles.
Perkin Trans. 1 1987, 799. (c) Katritzky, A. R.;
Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi, L. J. Chem.
Soc., Perkin Trans. 1 1989, 225. (d) Subsequent to the
completion of our studies and following the publication of
our carbamate work (ref.4) we were contacted by Professor
Katritzky suggesting the very benzotriazole system we had
been investigating. We thank him for his interest in this
work.
Acknowledgement
E. M.-N. H. thanks Rhône Poulenc Rorer Limited for financial sup-
port.
(7) (5S)-N-(1’-Benzotriazolylmethyl)-5-phenylmorpholin-2-
one(4): (5S)-5-Phenylmorpholin-2-one 1 (474 mg, 2.7
mmol, 1 equiv) and benzotriazole (319 mg, 2.7 mmol, 1
equiv) were dissolved in water–ethanol 1:1 (5 mL).
Formaldehyde (37 wt% solution in water, 0.2 mL, 1 equiv)
was added via syringe and the resulting solution was stirred
at r.t. overnight. The solution was then cooled to 5 °C and the
resultant precipitate was filtered and washed with 1:1 aq
ethanol and dried in vacuo giving a colourless solid (645 mg,
78%), mp 112–113 °C; [ ]19D +82.0 (c 0.75, CHCl3); (Found
C, 65.92; H, 5.25; N, 17.94. C17H16N4O2 requires C, 66.22;
H, 5.23; N, 18.16%.); max (KBr disc): 175, 1456 cm–1; 1H
NMR (400 MHz, DMSO): = 8.05 (1 H, d, J = 8.2 Hz), 7.69
(1 H, d, J = 8.2 Hz), 7.55–7.38 (7 H, m), 5.64 (1 H, d, J =
14.7 Hz), 5.40 (1 H, d, J = 14.7 Hz), 4.30–4.46 (4 H, m), 3.66
(1 H, d, J = 16.8 Hz) ppm; 13C NMR (100 MHz, DMSO):
= 168.5, 144.6, 137.3, 133.5, 128.6, 128.3, 128.2, 128.0,
127.9, 123.9, 118.9, 110.4, 70.7, 63.9, 57.6, 50.2 ppm; MS
References
(1) Current address: Aventis Pharmaceuticals Inc., Mail Code:
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+
(C.I.): m/z 120 [C6H6N3 ], 90.
(8) General Method for the Preparation of Cycloadducts:
N-(1'-Benzotriazolylmethyl)-5-phenylmorpholin-2-one 4
(1 equiv), dipolarophile (3 equiv) and para-toluenesulfonic
acid (0.5 equiv) were dissolved in dry THF, or in the case of
dimethyl fumarate, in dry chloroform. Subsequently, the
mixture was refluxed for 24 h. Removal of solvent in vacuo
yielded the crude mixture of products along with excess
dipolarophile. The cycloadducts were then purified by
column chromatography on silica, eluting with toluene/
diethyl ether. Identification of the cycloadducts was carried
out by comparison with the known products.2
Synlett 2001, No. 12, 1841–1842 ISSN 0936-5214 © Thieme Stuttgart · New York