Azide 1,3-dipolar cycloadditions to N-propynoyl and N-propenoyl (5R)-5-phenylmorpholin-2-one: Diastereocontrolled aziridine formation

Article abstract of DOI:10.1055/s-2008-1078595

N-Propynoyl (5R)-5-phenylmorpholin-2-one undergoes nonregioselective cycloaddition with aromatic azides to furnish mixtures of the corresponding triazoles, whereas N-propenoyl (5R)-5-phenylmorpholin-2-one reacts to furnish the corresponding diastereoisome

Full text of DOI:10.1055/s-2008-1078595

LETTER
2119
Azide 1,3-Dipolar Cycloadditions to N-Propynoyl and N-Propenoyl
(5R)-5-Phenylmorpholin-2-one: Diastereocontrolled Aziridine Formation
Diastereocontrolled
A
z
i
iridine
n
Formation dong Chen,1 Yu Gan, Laurence M. Harwood*
Department of Chemistry, University of Reading, Whiteknights Reading, RG6 6AD, UK
Fax +44(118)3786121; E-mail: l.m.harwood@reading.ac.uk
Received 22 May 2008
Dedicated to Professor Sir Jack Baldwin FRS on the occasion of his 70th birthday
Synthesis of N-propynoyl (5R)-5-phenyl-4-morpholin-2-
one (2) was readily achieved in 84% yield by condensa-
tion of 1 with propynoic acid using dicyclohexylcarbodi-
imide coupling and N-propenoyl (5R)-5-phenyl-4-
Abstract: N-Propynoyl (5R)-5-phenylmorpholin-2-one undergoes
nonregioselective cycloaddition with aromatic azides to furnish
mixtures of the corresponding triazoles, whereas N-propenoyl (5R)-
5-phenylmorpholin-2-one reacts to furnish the corresponding dia-
stereoisomerically pure aziridines in moderate to good yields, pre- morpholin-2-one (3) was prepared using propenoyl chlo-
ride–Et3N in 78% yield (Scheme 1).4
sumably via the intermediate triazolines.
Key words: (5R)-5-phenylmorpholin-2-one, triazole, triazoline,
aziridine
In 3 the boat conformation of the heterocyclic ring, planar
arrangement around the amide group and axial disposition
of the C-5 phenyl substituent were demonstrated by single
crystal X-ray diffraction analysis5 and this disposition of
the amide system is in keeping with previous observations
(Figure 1).6
In previous studies we have reported the application of the
(5R)-5-phenylmorpholin-2-one template (1) to the synthe-
sis of enantiomerically pure a-amino acids and enan-
tiopure long-chain threo-2-amino-3-hydroxyesters using
diastereocontrolled 1,3-dipolar cycloaddition of their
azomethine ylid derivatives and alkylation chemistry on
the 3,4-dehydro derivatives.2
1,3-Dipolar cycloaddition reaction of azides with dipo-
larophiles has resulted in a number of novel triazole and
triazoline scaffolds which are useful for the creation of di-
verse chemical libraries.3 In this letter we report the ther-
mal 1,3-dipolar cycloaddition reactions of aromatic azides
onto unsaturated amide derivatives 2 and 3 of (5R)-5-
phenylmorpholin-2-one (1) and the unexpectedly ready
extrusion of nitrogen from the triazoline adducts derived
from 3.
Figure 1 Single-crystal X-ray structure of propenamide 3
N
N
N
ArN
O
H
NAr
O
H
N
O
H
CO2H,
DCC, CH2Cl2
Ph
N
ArN3, toluene
reflux
Ph
N
O
Ph
N
O
O
O
O
O
H
H
N
4
2
Ph
H
O
O
NAr
O
O
H
O
H
1
Ph
N
Ph
N
ArN3, toluene
reflux
COCl
Et3N, CH2Cl2
O
O
O
5
3
Scheme 1
SYNLETT 2008, No. 14, pp 2119–2121
2
2
.0
8
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1078595; Art ID: D17208ST
© Georg Thieme Verlag Stuttgart · New York

2120
M. Chen et al.
LETTER
N-Propynoyl (5R)-5-phenylmorpholin-2-one (2) under- As we were never able to isolate any triazolines arising
went ready 1,3-dipolar cycloaddition with a range of aro- from initial 1,3-dipolar cycloaddition with 3, an alterna-
matic azides (prepared according to literature tive pathway involving diastereocontrolled Michael-type
procedures7) in toluene at reflux. TLC monitoring showed addition followed by elimination of nitrogen cannot be
that the morpholinone starting material was consumed ruled out. For the same reason no conclusions can be
within two to four hours, to afford the corresponding tri- drawn about any regiocontrol in the 1,3-dipolar cycload-
azoles 4 in moderate to good yields as inseparable mix- dition if the triazolines 5 are intermediates. Nevertheless,
tures of regiosiomers in approximately equal proportions the ease of isolation of the aziridines and the complete di-
in each instance (Table 1).
astereocontrol in their formation is remarkable and un-
foreseen, permitting a synthetically useful means of
generating sophisticated molecular architectures.
However, when the propenamide derivative 3 was sub-
jected to the same cycloaddition reactions the expected
triazolines were not isolated but, instead, the aziridines 5
resulting from subsequent extrusion of nitrogen were ob-
tained as single diastereoisomers in consistently good
yields.8 In all cases spectroscopic data were consistent
with the structures assigned and, in addition the relative
stereochemistry was assigned unambiguously by single
crystal X-ray crystallographic analysis of 5a (Figure 2).5
Acknowledgment
MD thanks the China Scholarship Council, Ministry of Education
for financial support.
References and Notes
(1) Current address: Department of Environmental Science and
Engineering, Nanjing University of Information Science and
Technology, 210044, Nanjing, P. R. of China.
Such extrusion of nitrogen from triazolines has been ob-
served previously, but the facility with which it occurs in
this simple triazoline system was not expected, as it usu-
ally requires Brønsted acid or transition metal catalysis or
specific structural features in the substrate.9
(2) (a) Brome, V. A.; Harwood, L. M.; Osborn, H. M. I. Can. J.
Chem. 2006, 84, 1448. (b) Draffin, W. N.; Harwood, L. M.
Synlett 2006, 857. (c) Aldous, D. J.; Drew, M. G. B.;
Drafiin, W. N.; Hamelin, E. M.-N.; Harwood, L. M.
Synthesis 2005, 3271. (d) Aldous, D. J.; Drew, M. G. B.;
Hamelin, E. M.-N.; Harwood, L. M.; Jahans, A. B.;
Thurairatnam, S. Synlett 2001, 1841. (e) Aldous, D. J.;
Drew, M. G. B.; Hamelin, E. M.-N.; Harwood, L. M.;
Jahans, A. B.; Thurairatnam, S. Synlett 2001, 1836.
(f) Harwood, L. M.; Tyler, S. N. G.; Drew, M. G. B.; Jahans,
A.; MacGilp, I. G. ARKIVOC 2000, (v), 820. (g) Harwood,
L. M.; Tyler, S. N. G.; Anslow, A. S.; MacGilp, I. G.; Drew,
M. G. B. Tetrahedron: Asymmetry 1997, 8, 4007.
(3) (a) Vatmurge, N. S.; Hazra, B. G. Bioorg. Med. Chem. Lett.
2008, 18, 2043. (b) Aufort, M.; Herscovici, J.; Bouhours, P.;
Moreau, N.; Girard, C. Bioorg. Med. Chem. Lett. 2008, 18,
1195. (c) Ramakrishna, N. I.; Vedavati, P. G. Org. Biomol.
Chem. 2008, 779. (d) Nicholas, A. G.; Paramjit, A. S.
J. Org. Chem. 2007, 72, 9822. (e) Gullapalli, K.;
Table 1 Isolated Yields for Adducts 4 and 5
Ar
4
Yield (%)
5
Yield (%)
Ph
4a
4b
4c
4d
4e
4f
66
44
38
41
68
50
58
62
44
5a
5b
5c
5d
5e
5f
5g
5h
5i
67
45
49
57
77
75
78
73
66
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
3-BrC6H4
4-O2NC6H4
4g
4h
4i
Kukkadapu, A. J. Org. Chem. 2007, 72, 9822. (f) Chen, M.;
Zheng, Y.; Fan, S.; Gao, G.; Yang, L.; Tian, L.; Yiping, T.;
Feng, H. Synth. Commun. 2006, 36, 1063. (g) Furmeier, S.;
Metzger, J. O. Eur. J. Org. Chem. 2003, 649.
(h) Dvorakova, K.; Payne, C. M. Biochem. Pharmacol.
2000, 60, 749. (i) Burrage, T.; Kramer, E.; Brown, F.
Vaccine 2000, 18, 2454. (j) Chen, M.; Zheng, Y.; Fan, S.;
Gao, G.; Yang, L.; Tian, L.; Du, Y.; Tang, F.; Hua, W. Synth.
Commun. 2006, 36, 1063.
The diastereocontrol is presumably a consequence of the
axial phenyl substituent at C-5 of the morpholin-2-one
ring and the hindered rotation around the amide bond.
(4) Synthesis of N-Propynoyl (5R)-5-Phenylmorpholin-2-
one (2): To a solution of (5R)-5-phenylmorpholin-2-one
(0.53 g, 3 mmol) in anhyd CH2Cl2 (40 mL) was added
propynoic acid (0.21 g, 3 mmol), and then dicyclohexyl-
carbodiimide (0.68 g, 3.3 mmol) in anhyd CH2Cl2 (10 mL)
was added over 10 min. The resulting solution was stirred for
12 h. The solids were removed by filtration through a short
pad of Celite® and washed with CH2Cl2 (10 mL). The
solvent was removed under reduced pressure and the crude
material was purified by flash column chromatography on
silica, eluting with PE–EtOAc (3:1) to furnish the title
compound as colourless needles (1.81 g, 84%); mp 125–126
°C; [a]D20 –50.5 (c = 1.08, CHCl3). IR (film): 3243, 1738,
1635 cm–1. 1H NMR (250 MHz, CDCl3): d = 7.26–7.47 (m,
5 H), 5.60–5.66 (m, 1 H), 4.94 (d, J = 17.5 Hz, 0.5 H), 4.80
Figure 2 Single-crystal X-ray structure of aziridine adduct 5a
Synlett 2008, No. 14, 2119–2121 © Thieme Stuttgart · New York

LETTER
(d, J = 17.5 Hz, 0.5 H), 4.69–4.76 (m, 2 H), 4.33 (d, J = 17.5
Diastereocontrolled Aziridine Formation
2121
deposited at the Cambridge Crystallographic Data Centre,
deposition numbers CCDC 689449 (3), CCDC 689448 (5a)
and copies of these data can be obtained by applying to
CCDC, University Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW, UK; [fax: +44(1223)336033; email:
deposit@ccdc.cam.ac.uk).
Hz, 0.5 H), 4.16 (d, J = 17.5 Hz, 0.5 H), 3.29 (s, 0.5 H), 3.08
(s, 0.5 H). MS: m/z = 230 [M + 1]+, 178, 148, 104, 99, 45.
Synthesis ofN-Propenoyl(5R)-5-Phenylmorpholin-2-one
(3): To a mixture of (5R)-5-phenylmorpholin-2-one (0.531
g, 3 mmol), Et3N (9 mmol) and anhyd CH2Cl2 (40 mL),
propenoyl chloride (0.408 g, 4.5 mmol) was added dropwise
over 10 min. The resulting solution was stirred for 5 h under
an atmosphere of nitrogen. The reaction was quenched by
the addition of sat. Na2CO3 (40 mL), the aqueous phase was
extracted with Et2O (2 × 30 mL) and the combined extracts
were dried over MgSO4. The solvent was removed under
reduced pressure and the crude material was purified by
flash column chromatography on silica, eluting with PE–
Et2O (1:5) to furnish the title compound as an oil.
(6) For instance, see: (a) Drew, M. G. B.; Harwood, L. M.; Park,
G.; Price, D. W.; Tyler, S. N. G.; Park, C. R.; Cho, S. G.
Tetrahedron 2001, 57, 5641. (b) Dellaria, J. F.; Satarsiero,
B. D. J. Org. Chem. 1989, 54, 3916.
(7) For instance, see: (a) Diez-Gonzalez, S.; Correa, A.;
Cavallo, L.; Nolan, S. P. Chem. Eur. J. 2006, 12, 7558.
(b) Benati, L.; Bencivenni, G.; Leardini, R.; Minozzi, M.;
Nanni, D.; Scialpi, R.; Spagnolo, P.; Zanardi, G. J. Org.
Chem. 2006, 71, 5822.
Crystallization from Et2O produced colourless crystals (0.54
g 78%); mp 51–52 °C; [a]D20 –69.9 (c = 4.65, CHCl3). IR
(film): 1747, 1651 cm–1. 1H NMR (250 MHz, CDCl3): d =
7.28–7.51 (m, 7 H), 6.50 (m, 1 H), 6.01 (m, 1 H), 4.02–4.50
(m, 4 H). MS: m/z = 231, 178, 148, 104, 99, 45.
(8) Synthesis of Aziridine Adducts 5: A solution of N-
propenoyl (5R)-5-phenylmorpholin-2-one (3; 231 mg, 1
mmol) and the requisite aryl azide (1.5 mol) in toluene was
heated to reflux for 2–3 h until TLC analysis indicated the
absence of dipolarophile. Solvent was removed under
reduced pressure and the crude material was purified by
flash column chromatography on silica, eluting with PE–
Et2O (1:7) to furnish the compounds 5 as colourless solids.
Analytical Data for 5a: mp 67–69 °C; [a]D20 –112.7 (c =
1.0, CHCl3). IR (film): 1762, 1663 cm–1. 1H NMR (250
MHz, CDCl3): d = 7.10–7.50 (m, 5 H), 6.80–7.05 (m, 3 H),
6.20 (d, J = 7.5 Hz, 2 H), 5.35 (br t, J = 5.0 Hz, 1 H), 4.89 (d,
J = 17.5 Hz, 1 H), 4.69 (dd, J = 11.0 Hz, J¢ = 3.0 Hz, 1 H),
4.35–4.60 (m, 2 H), 2.50–2.70 (m, 2 H), 2.10–2.25 (m, 1 H).
MS: m/z = 323 [M + 1]+, 178, 148, 104, 99, 45.
(5) X-ray data of 3: C13H13NO3, MW = 231.2; T = 293(3) K;
monoclinic, P2(1), a = 7.0336(1), b = 7.1121(6), c =
11.7883(7) Å; b = 91.464(7)°; Z = 2; Dx = 1.303 g·cm–3;
F(000) = 244; m(Mo–Ka) = 0.093 mm–1. The number of
independent reflections used in the analysis was 1860 with
I ≥ 2s(I). Data were measured (qmax = 30.13°) on an Oxford
Diffraction Gemini S Ultra instrument using Mo–Ka
radiation; final R1 = 3.12, wR2 = 7.78. 5a: C19H18N2O3, M =
322.3; T = 293 (3) K; monoclinic, P2(1), a = 7.2342(1), b =
11.7560(2), c = 9.9218(2) Å; b = 106.408(2)°; Z = 2; Dx =
1.321 g⋅cm–3; F(000) = 340; m(Cu–Ka) = 0.735 mm–1. The
number of independent reflections used in the analysis was
2107 with I ≥ 2s(I). Data were measured (qmax = 66.13°) on
an Oxford Diffraction Gemini S Ultra instrument using
CuKa radiation; final R1 = 2.44, wR2 = 6.81. Atomic
coordinates and further crystallographic details have been
(9) (a) Fantauzzi, S.; Gallo, E.; Caselli, A.; Piangiolino, C.;
Ragaini, F.; Cenini, S. Eur. J. Org. Chem. 2007, 36, 6053.
(b) Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am.
Chem. Soc. 2005, 127, 1354. (c) Lin, Z.; Kadapa, P. K.
J. Heterocycl. Chem. 1997, 34, 1645.
Synlett 2008, No. 14, 2119–2121 © Thieme Stuttgart · New York

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