Asymmetric synthesis of 2H-azirines derived from phosphine oxides using solid-supported amines. Ring opening of azirines with carboxylic acids

Article abstract of DOI:10.1021/jo025995d

A simple and efficient asymmetric synthesis of 2H-azirine-2-phosphine oxides 3 is described. The key step is a solid-phase bound achiral or chiral amine-mediated Neber reaction of β-ketoxime tosylates derived from phosphine oxides 1. Reaction of 2H-azirines 3 and 11 with carboxylic acids 4 gives phosphorylated ketamides 5 and 12. Ring closure of ketamides 5 and 12 with triphenylphosphine and hexachloroethane in the presence of triethylamine leads to the formation of phosphorylated oxazoles 8 and 13.

Full text of DOI:10.1021/jo025995d

Asym m etr ic Syn th esis of 2H-Azir in es Der ived fr om P h osp h in e
Oxid es Usin g Solid -Su p p or ted Am in es. Rin g Op en in g of Azir in es
w ith Ca r boxylic Acid s
Francisco Palacios,* Domitila Aparicio, Ana Mar´ıa Ochoa de Retana, J esu´s M. de los Santos,
J ose´ Ignacio Gil, and J ose´ Mar´ıa Alonso
Departamento de Quı´mica Orga´nica I, Facultad de Farmacia, Universidad del Pa´ıs Vasco, Apartado 450,
01080 Vitoria, Spain
qoppagaf@vf.ehu.es
Received May 31, 2002
A simple and efficient asymmetric synthesis of 2H-azirine-2-phosphine oxides 3 is described. The
key step is a solid-phase bound achiral or chiral amine-mediated Neber reaction of â-ketoxime
tosylates derived from phosphine oxides 1. Reaction of 2H-azirines 3 and 11 with carboxylic acids
4 gives phosphorylated ketamides 5 and 12. Ring closure of ketamides 5 and 12 with triphenylphos-
phine and hexachloroethane in the presence of triethylamine leads to the formation of phospho-
rylated oxazoles 8 and 13.
In tr od u ction
In the area of combinatorial chemistry and solid-phase
synthesis there is a constant need for new methodologies
which can be applied to the preparation of heterocycles
and small molecules.1,2 For this reason the development
of new polymer-supported reagents has attracted growing
interest in recent years. The highly strained 2H-azirine
ring systems, the smallest of the nitrogen-unsaturated
heterocycles, represent an important class of compounds
because of their high reactivity.3 Each of the three bonds
of the azirine ring can be cleaved, depending on the
experimental conditions used, and they can be used as
key intermediates in organic synthesis in the preparation
of acyclic functionalized amino derivatives4a-c and hetero-
cycles.4d-g In particular, 2H-azirines containing a car-
boxylic ester group I are excellent reagents for the
preparation of functionalized aziridines3,5 and R-5b,6a-d
and â-amino acid derivatives.5b,6e-g Furthermore, phos-
phorus substituents regulate many important biological
functions with molecular modifications influencing the
biological activity.7 For these reasons, functionalized 2H-
azirines containing a phosphorus substituent in the
F IGURE 1.
2-position (II, Figure 1) are expected to play a similar
role to that observed in the isosteric analogues I, in the
enantioselective synthesis of R- and â-aminophosphorus
derivatives. R-Aminophosphonates can be considered as
surrogates for R-amino acids,8a and have been used as
haptens for the generation of catalytic antibodies,8b as
(4) (a) Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 238-
264. (b) Bucher, C. B.; Heimgartner, H. Helv. Chim. Acta 1996, 79,
1903-1915. (c) Lehmann, J .; Linden, A.; Heimgartner, H. Tetrahedron
1999, 55, 5359-5376. (d) Pinho e Melo, T. M. V. D.; Lopes, C. S. J .;
d’A Rocha Gonzalves, A.; Be J a, J . A.; Paixao, A. M.; Silva, M. R.; Alte
da Veiga, L. J . Org. Chem. 2002, 67, 66-71. (e) Davis, F. A.; Liang, C.
H.; Liu, H. J . Org. Chem. 1997, 62, 3796-3797. (f) Ray, C. A.; Risberg,
E.; Somfai, P. Tetrahedron Lett. 2001, 42, 9289-9291. (g) Banert, K.;
Ho¨hler, F. Angew. Chem., Int. Ed. 2001, 40, 174-177.
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8, 1693-1715. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33,
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3857-3860. (b) Zwanengburg, B.; Thi J s, L. Pure Appl. Chem. 1996,
68, 735-738. (c) Davis, F. A.; Liu, H.; Reddy, C. V. Tetrahedron Lett.
1996, 37, 5473-5476. (d) Ploux, O.; Caruso, M.; Chassaing, G.;
Marquet, A. J . Org. Chem. 1988, 53, 3154-3158. (e) Righi, G.;
D’Achielle, R. Tetrahedron Lett. 1996, 37, 6893-6896. (f) Lim, Y.; Lee,
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(7) For reviews see: (a) Engel, R. In Handbook of Organophosphorus
Chemistry; M. Dekker, Inc.: New York, 1992. (b) Kafarski, P.; Lejczak,
B. Phosphorus Sulfur 1991, 63, 193-215. (c) Toy, A. D. F.; Walsh, E.
N. In Phosphorus Chemistry in Everyday Living; American Chemical
Society: Washington, DC, 1987; p 333.
(8) (a) Smith, A. B.; Yager, K. M.; Taylor, C. M. J . Am. Chem. Soc.
1995, 117, 10879-10888. (b) Hirschmann, R.; Smith, A. B.; Taylor, C.
M.; Benkovic, P. A.; Taylor, S. D.; Yager, K. M.; Spengler, P. A.;
Benkovic, S. J . Science 1994, 265, 234-237.
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J . L. Tetrahedron Lett. 2001, 42, 4491-4494. (b) Georgiadis, D.; Dive,
V.; Yiotakis, A. J . Org. Chem. 2001, 66, 6604-6610. (c) Meyer, J . H.;
Bartlett, P. A. J . Am. Chem. Soc. 1998, 120, 4600-4609.
(1) For recent reviews see: (a) Nicolaou, K. C.; Pfefferkorn, J . A.
Biopolymers 2001, 60, 171-193. (b) Kauhaluoma, Y. Tetrahedron 2001,
57, 7053-7071. (c) Nefti, A.; Ostresh, J . M.; Houghten, R. A. In Solid-
Phase Synthesis; Kates, S. A., Albericio, F., Eds.; M. Dekker: New
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Olmstead, M. M.; Kurth, M. J . Org. Lett. 2002, 4, 741-744. (b) Nefti,
A.; Ostresh, J . M.; Houghten, R. A. Biopolymers 2001, 60, 212-219.
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A. Org. Lett. 2001, 3, 3341-3344. (e) Gopalsamy, A.; Yang, H. J . Comb.
Chem. 2001, 3, 278-283.
(3) For recent reviews on azirines see: (a) Palacios, F.; Ochoa de
Retana, A. M.; Mart´ınez de Marigorta, E.; de los Santos, J . M. Org.
Prep. Proced. Int. 2002, 34, 219-269. (b) Gilchrist, T. L. Aldrichim.
Acta 2001, 34, 51-55. (c) Palacios, F.; Ochoa de Retana, A. M.;
Mart´ınez de Marigorta, E.; de los Santos, J . M. Eur. J . Org. Chem.
2001, 2401-2414.
10.1021/jo025995d CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/14/2002
J . Org. Chem. 2002, 67, 7283-7288
7283

Palacios et al.
enzyme inhibitors9a,b and antibacterial agents,9c while
â-aminophosphonate derivatives, some of them naturally
occurring,10a have been used for the preparation of
peptide-based enzyme inhibitors10b,c and as agrochem-
icals10d or pharmaceuticals.10e,f
SCHEME 1
Optically active 2H-azirines with an asymmetric center
in the azirine cycle are present in some natural products,3
and enantiomerically enriched 2-alkoxycarbonyl-2H-azir-
ines I were previously prepared from chiral N-substituted
aziridine 2-carboxylic esters,11a,b and by using the Neber
reaction.11c,d Nevertheless, despite the potential interest
of 2H-azirines, these three-membered heterocycles di-
rectly substituted with a phosphorus-containing func-
tional group have received scarce attention.12 For this
reason, the development of new processes for asymmetric
synthesis of substituted 2H-azirines can represent an
important tool in organic synthesis. In this context, we
have described new methods for the preparation of five-
SCHEME 2
13
and six-membered14 phosphorus substituted nitrogen
heterocycles from functionalized phosphine oxides and
phosphonates and the synthetic uses of amino phospho-
rus derivatives as starting materials for the preparation
of acyclic compounds15 and phosphorus-containing het-
erocycles.16 Recently, we disclosed the first asymmetric
synthesis of 2H-azirines derived from phosphine oxides
by the alkaloid-mediated Neber reaction of tosyloximes.17,18
Continuing with our interest in the synthesis of new
phosphorus-substituted heterocycles we here report an
easy and high-yielding asymmetric synthesis of 2H-
azirine phosphine oxides (II, R ) Ph) from easily avail-
able tosyloximes containing a phosphine oxide (III, R )
Ph, Scheme 1) by means of solid-supported achiral and
chiral amines. The presence of the phosphorus substitu-
ent in these substrates increases the synthetic value of
these compounds because they may be used as building
blocks for the stereoselective construction of R- and
â-aminophosphorus derivatives.3a,c,8-10 Ring opening of
2H-azirines and the formation of phosphorylated oxazoles
(IV, Scheme 1) were also explored.
Resu lts a n d Discu ssion
(10) (a) Fields, S. F. Tetrahedron 1999, 55, 12237-12273. (b)
Hiratake, J .; Oda, J . Biosci. Biotechol. Biochem. 1997, 61, 211-218.
(c) Patel, D. V.; Schmidt, R. J .; Biller, S. A.; Gordon, E. M.; Robinson,
S. S.; Manne, V. J . Med. Chem. 1995, 38, 2906-2921. (d) Maier, L.;
Diel, P. J . Phosphorus, Sulfur Silicon 1994, 90, 259-279. (e) Gonella,
J .; Reiner, A. European Patent Application EP. 693,494, 1996 [Chem.
Abstr. 1996, 124, 261358k]. (f) Monaghan, D. T.; Bridges, R. J .; Cotman,
C. W. Annu. Rev. Pharmacol. Toxicol. 1989, 29, 365-402.
(11) (a) Davis, F. A.; Reddy, G. V.; Liu, H. J . Am. Chem. Soc. 1995,
117, 3651-3652. (b) Gentillucci, L.; Gri J zen, Y.; Thi J s, L.; Zwanen-
burg, B. Tetrahedron Lett. 1995, 36, 4665-4668. (c) Piskunova, I. P.;
Eremeev, A. V.; Mishnev, A. F.; Vosekalna, I. A. Tetrahedron 1993,
49, 4671-4676. (d) Verstappen, M. M. H.; Arians, G. J . A.; Zwanen-
burg, B. J . Am. Chem. Soc. 1996, 118, 8491-8492.
(12) (a) Alcaraz, G.; Wecker, U.; Baceiredo, A.; Dahan, F.; Bertrand,
G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1246-1248. (b) Piquet, V.;
Baceiredo, A.; Gornitzka, H.; Dahan, F.; Bertrand, G. Chem. Eur. J .
1997, 3, 1757-1264. (c) Russel, G. A.; Yao, C. F. J . Org. Chem. 1992,
57, 6508-6513.
(13) (a) Palacios, F.; Aparicio, D.; de los Santos, J . M.; Vicario, J .
Tetrahedron 2001, 57, 1961-1972. (b) Palacios, F.; Ochoa de Retana,
A. M.; Pagalday, J . Tetrahedron 1999, 55, 14451-14458. (c) Palacios,
F.; Pagalday, J .; Piquet, V.; Dahan, F.; Baceiredo, A.; Bertrand, G. J .
Org. Chem. 1997, 62, 292-296.
(14) (a) Palacios, F.; Aparicio, D.; Garc´ıa, J .; Vicario, J .; Ezpeleta,
J . M. Eur. J . Org. Chem. 2001, 3357-3365. (b) Palacios, F.; Ochoa de
Retana, A. M.; Oyarzabal, J . Tetrahedron 1999, 55, 5947-5964.
(15) (a) Palacios, F.; Oyarzabal, J .; Pascual, S.; Ochoa de Retana,
A. M. Org. Lett. 2002, 4, 769-772. (b) Palacios, F.; Alonso, C.; Amezua,
P.; Rubiales, G. J . Org. Chem. 2002, 67, 1941-1946. (c) Palacios, F.;
Aparicio, D.; Garc´ıa, J .; Rodr´ıguez, E.; Ferna´ndez, A. Tetrahedron 2001,
57, 3131-3141. (d) Palacios, F.; Herra´n, E.; Rubiales, G. J . Org. Chem.
1999, 64, 6239-6246.
(16) (a) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J . Tetra-
hedron 1999, 55, 3091-3104. (b) Barluenga, J .; Lo´pez, F.; Palacios, F.
Tetrahedron Lett. 1987, 28, 2875-2876.
(17) Palacios, F.; Ochoa de Retana, A. M.; Gil, J . I.; Ezpeleta, J . M.
J . Org. Chem. 2000, 65, 3213-3217.
Solid -P h a se Syn th esis of Azir in es 3. 2H-Azirines
3 (R1 ) CH3, C2H5) have been prepared in very good
yields by the modified Neber reaction of â-keto tosy-
loximes 1 with triethylamine or alkaloids.17 Now, we wish
to explore whether these heterocycles 3 could also be
prepared by using a resin-supported amine.19 2H-Azirine-
2-phosphine oxides 3a (R1 ) CH3) and 3b (R1 ) C2H5)
were generated in good yield and in a regioselective
fashion by thermal treatment in benzene at 50 °C of
â-ketoximes 1a ,b (R1 ) CH3, C2H5) with polymer-sup-
ported amines derived from diethylamine 2a 20 and mor-
pholine 2b20 (see Scheme 2, Table 1, entries 1-4). Resin-
supported amines 2a and 2b can be recovered after
handling of the resins with triethylamine (see Experi-
mental Section, Table 1, entry 2).
This process can also be extended to the asymmetric
synthesis of 2H-azirines 3, when chiral polymer-sup-
ported bases 2c derived from (S)-(+)-2-(methoxymethyl)-
pyrrolidine and 2d derived from (R)-(-)-2(methoxymethyl)-
pyrrolidine were used.20 These polystyrene chiral resins
2c and 2d were prepared by attachment of the chiral
secondary amines to solid supports with Merrifield resin.
Merrifield resin was reacted with (S)-(+)-2-(methoxym-
ethyl)pyrrolidine and (R)-( -)-2-(methoxymethyl)pyrro-
(19) For recent contributions on polymer-bound amine reactions
see: (a) Morgan, T.; Ray, N. C.; Parry, D. M. Org. Lett. 2002, 4, 597-
598. (b) Kilbrun, J . P.; Lau, J .; J ones, R. C. F. Tetrahedron 2002, 58,
1739-1743. (c) Zheng, C.; Combs, A. P. J . Comb. Chem. 2002, 4, 38-
43. (d) Larsen, S. D.; Dipaolo, B. A. Org. Lett. 2001, 3, 3341-3344. (e)
Dener, J . M.; Lease, T. G.; Novack, A. R.; Plunkett, M. J .; Hocker, M.
D.; Fantauzzi, P. P. J . Comb. Chem. 2001, 3, 590-597.
(20) Polymer-supported amines 2a and 2b are commercially avail-
able. Chiral resin-bound amines 2c,d were accomplished with use of
Merrifield resin (see text and Experimental Section).
(18) (a) For the asymmetric synthesis of 2H-azirine-2-phosphonates
from oximes see: Palacios, F.; Ochoa de Retana, A. M.; Gil, J . I.
Tetrahedron Lett. 2000, 41, 5363-5366. (b) For the asymmetric
synthesis of regioisomeric mixtures of 2H-azirine-2-phosphonates and
-3-phosphonates from aziridines see: Davis, F. A.; Wu, Y.; Yan, H.;
Prasad, K. R.; McCoull, W. Org. Lett. 2002, 4, 655-658. Davis, F. A.;
McCoull, W. Tetrahedron Lett. 1999, 40, 249-252.
7284 J . Org. Chem., Vol. 67, No. 21, 2002

Asymmetric Synthesis of 2H-Azirines
TABLE 1. Solid -P h a se Syn th esis of
2H-Azir in e-2-p h osp h in e Oxid es 3
SCHEME 3
entry
compd
base
R1
yield (%)
eec
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3a
3b
3a
3b
2a
2a
2a
2b
2c
2c
2d
2d
CH3
CH3
70a
66b
88a
66a
74a
65a
60a
89a
C2H5
C2H5
CH3
C2H5
CH3
16 (R)
37 (R)
37 (S)
15 (S)
C2H5
a
b
Yield of isolated purified compounds 3. Yield of isolated
purified compounds 3 from recovered amine 2a . c ee was deter-
mined by 31P NMR measurements, using a chiral shift reagent
(Yb(tfc)3).
lidine at 65 °C in DMF to afford new chiral resins 2c
and 2d .21 These chiral polymer-supported amines 2c and
2d were then used as chiral bases in the modified Neber
reaction of tosyl oximes 1, in a similar way to that
reported before for achiral resin amines (2a and 2b) to
give enantiomerically enriched 2H-azirines 3 (Scheme 2,
Table 1, entries 5-8). The enantiopurity of azirines
derived from phosphine oxide 3 (ee 15-37%) was deter-
mined by 31P NMR measurements in CDCl3 by using a
chiral shift reagent (Yb(tfc)3). The absolute configuration
of the azirines 3 was established before by reduction to
aziridines and formation of the enantiopure cis-N-(p-
toluenesulfinyl)aziridine-2-phosphine oxides.17
TABLE 2. r-Keta m id es 5 a n d 12 Obta in ed
entry
compd
R1
R2
yield (%)a
1
2
3
4
5
6
7
8
9
5a a
5a b
5a c
5a d
5a e
5bb
5bf
5bg
12a a
12a b
12bb
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
CH3
CH3
C2H5
CH3
C6H5
75
65
67
75
65
60
57
67
75
62
78
CH3OCH2
CH2dCH
CH2dCH(CH2)4
C6H5
HO2C-CH2
CH3O2C-CH2
CH3
10
11
C6H5
C6H5
Rin g-Op en in g of Azir in es w ith Ca r boxylic Acid s.
Cleavage of the N-C double bond of azirines can be
achieved with carboxylic acids,4a,22 and 3-amino-2H-
azirines have been widely used for elegant preparations
of linear peptides4a and depsipeptides.23 Given that, as
far as we know, no ring-opening reaction of azirines
containing phosphorus substituents has been reported as
giving acyclic compounds,24 we explored the reaction of
azirine-phosphine oxides with carboxylic acid. This
reaction can be used as a model of an acid-catalyzed ring-
opening reaction of these substrates and the functional-
ized ketamides generated could then be used for the
preparation of phosphorylated oxazoles.
Reaction of azirine 3a with acetic acid 4a (R2 ) CH3)
at room temperature led to the formation of R-ketamide
5a a (R1 ) R2 ) CH3) containing a phosphine oxide group
in the R-position (Scheme 3, Table 2, entry 1). Spectro-
scopic data were in agreement with the assigned struc-
ture of compound 5a a . Mass spectrometry of 5a a showed
the molecular ion peak (m/z 315, 2%), while in the 31P
NMR spectrum the phosphine oxide group resonated at
δP 31.2 ppm. The 13C NMR spectrum showed an absorp-
tion at δC 60.8 ppm as a doublet with coupling constant
1J PC ) 65.0 Hz for the carbon atom directly bonded to
the phosphine oxide moiety, as well as a singlet at δC
200.8 ppm for the carbonyl group. The formation of
a
Yield of isolated purified compounds 5 and 12.
adduct 5 could be explained by protonation of the
nitrogen atom of the azirine followed by nucleophilic
addition of the carboxylate to the azidinium ion to give
an unstable aziridine intermediate 6. Ring expansion of
aziridine 6 promoted by intramolecular nucleophilic
addition of the nitrogen pair to the carboxylic ester could
give the zwitterionic oxazolone 7, which underwent ring
opening to form ketamide 5. The scope of the reaction
was not limited to alkyl carboxylic acid 4a (R2 ) CH3),
given that not only benzoic acid 4b (R2 ) C6H5) but also
functionalized acids containing an ether linkage 4c (R2
) CH2OCH3) as well as olefinic groups 4d ,e (R2 ) CHd
CH2, (CH2)4CHdCH2) and malonic acid 4f (R2 ) CH2-
CO2H) also reacted with azirines 3 to give the corre-
sponding substituted R-ketamides 5 (Scheme 3, Table 2,
entries 2-7).
Rin g-Closu r e of r-Keta m id es 5 to P h osp h or u s-
Su bstitu ted Oxa zoles 8. Oxazoles are common hetero-
cycles in a wide variety of natural products possessing
biological activity and also are widely used intermediates
for functional transformations.25,26 Given that phosphorus
substituents regulate important biological functions, we
thought that ketamides 5 containing a phosphine oxide
substituent could be used for the preparation of oxazoles.
Different reaction conditions were used for the ring-
(21) Chiral resin-bound amines 2c,d were characterized by FTIR
and elemental analyses.
(22) (a) Heimgartner, H.; Obrecht, D. Helv. Chim. Acta 1987, 70,
102-115. (b) Vittorelli, P.; Heimgartner, H.; Schmid, H.; Hoet, P.;
Ghosez, L. Tetrahedron Lett. 1974, 30, 3737-3740.
(25) For recent reviews on oxazoles see: (a) Lewis, J . R. Nat. Prod.
Rep. 2001, 18, 95-128. (b) Roy, R. S.; Gehring, A. M.; Milne, J . C.;
Belshaw, P. J .; Walsh, C. T. Nat. Prod. Rep. 1999, 16, 249-263. (c)
Boyd, G. V. Prog. Heterocycl. Chem. 1999, 11, 213-229. (d) Rickborn,
B. Org. React. 1998, 53, 223-629. (e) Hartner, F. W. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Eds.; Elsevi-
er: Oxford, UK, 1996; Vol. 3, pp 261-318. (f) Wipf, P.; Venkatraman,
S. Synlett 1997, 1-10.
(23) (a) Koch, K. N.; Linden, A.; Heimgartner, H. Tetrahedron 2001,
57, 2311-2326. (b) Koch, K. N.; Heimgartner, H. Helv. Chim. Acta
2000, 83, 1881-1900. (c) Koch, K. N.; Linden, A.; Heimgartner, H.
Helv. Chim. Acta 2000, 83, 233-257.
(24) Ring expansion of phosphino-silyl-2H-azirine to four- and six-
membered phosphorus-containing heterocycles has been described.12b
J . Org. Chem, Vol. 67, No. 21, 2002 7285

Palacios et al.
SCHEME 4
SCHEME 5
SCHEME 6
TABLE 3. P h osp h or yla ted Oxa zoles 8 a n d 13 Obta in ed
substituted in the 2-position of the ring not only with
alkyl substituent 8a a (R2 ) CH3) but also with aryl
groups 8a b and 8bb (R2 ) C6H5) and ether 8a c (R2 )
CH3OCH2) or olefine groups 8a d (R2 ) CH2dCH) and
8a e (R2 ) CH2dCH(CH2)4). However, the ring closure
does not seem to be compatible with the presence of
carboxylic acid group in ketamide 5. Thus, oxazole 8bf
(R2 ) CH2CO2H) was not obtained by the reaction of
ketamide 5bf (R2 ) CH2CO2H), prepared by reaction of
azirine 3b and malonic acid 4f with triphenylphosphine
and hexachloroethane in the presence of triethylamine.
However, the corresponding functionalized oxazole 8bg
(R2 ) CH2CO2CH3) with the carboxylic acid protected
with an ester group was isolated by the reaction, in the
same conditions from the corresponding protected keta-
mide 5bg (R2 ) CH2CO2CH3), obtained by esterification
of ketamide 5bf (R2 ) CH2CO2H) with thionyl chloride
and methanol (see Scheme 5).
Finally, the formation of oxazoles was extended to
azirines derived from phosphonates 11.18a Heating azir-
ines 11a (R1 ) Me) and 11b (R1 ) Et) with acetic acid
4a (R2 ) Me) and benzoic acid 4b (R2 ) Ph) led to the
formation of R-ketamides containing a diethoxyphospho-
nyl group in the R-position 12a a -bb (Scheme 6, Table
2, entries 9-11).29 The formation of adducts 12 could be
explained as before (Scheme 3), by formal addition of the
carboxylic acid to the reactive carbon-nitrogen azirine
double bond to give an unstable aziridine intermediate,
followed by ring opening of zwitterionic oxazolone. Ket-
amides 12 were then treated with triphenylphosphine
and hexachloroethane in the presence of triethylamine
and oxazole phosphonates 13 were obtained (Scheme 6,
Table 3, entries 8-10). The formation of oxazoles 13 could
also be explained through a similar mechanism to that
reported for oxazoles 8.
entry
compd
R1
R2
yield (%)a
1
2
3
4
5
6
7
8
9
8a a
8a b
8a c
8a d
8a e
8bb
8bg
13a a
13a b
13bb
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
CH3
CH3
C2H5
CH3
C6H5
CH3OCH2
CH2dCH
CH2dCH(CH2)4
C6H5
CH3O2C-CH2
CH3
C6H5
C6H5
64
79
70
59
88
66
58
55
58
62
10
a
Yield of isolated purified compounds 8 and 13.
closure of ketamides 5, such as phosphorus pentachloride,
phosphorus oxychloride with sodium hydride, or phos-
phorus oxychloride with triethylamine, but the best
results were observed when a modified Wipf method27
was used replacing iodine for hexachloroethane. Keta-
mides 5 were treated with triphenylphosphine and
hexachloroethane in the presence of triethylamine in
THF to give oxazole phosphine oxides 8 in good yields
and in a regioselective fashion (Scheme 4, Table 3, entries
1-7). Spectroscopic data were in agreement with the
assigned structure of compounds 8. Mass spectrometry
of 8a a showed the molecular ion peak (m/z 297, 89%),
while in the 31P NMR spectrum the phosphinyl group
resonated at δP 18.8 ppm. The 13C NMR spectrum of
oxazole 8a a showed doublets at δC 126.5 ppm (1J PC
)
145.0 Hz) for C-4 and at δC 160.4 ppm (3J PC ) 19.2 Hz)
for C-2. The formation of oxazoles 8 could be explained
by deprotonation of ketamides 5 by means of dichloro-
triphenylphosphorane (Ph3PCl2), generated “in situ” from
triphenylphosphine and hexachloroethane,28 to give an
intermediate enamide 9 followed by the loss of triph-
enylphosphine oxide and ring closure of the reactive
carbene 10 formed, in a similar way to that reported for
simple oxazoles.27
Con clu sion s
The cyclization is quite general since oxazoles 8 derived
from phosphine oxides (4-position) can be prepared and
We have devised a simple, mild, and convenient
strategy for the asymmetric synthesis of 2H-azirines
substituted with a phosphine oxide group in the 2-posi-
tion of 3 from easily available oximes 1, using achiral or
chiral polymer-bound amines 2. These heterocycles are
very useful intermediates in the formation of R-ketamides
and phosphorus-substituted oxazoles. Substituted 2H-
(26) For recent contributions on oxazoles see: (a) Miller, R. A.;
Smith, R. M.; Karady, S.; Reamer, R. A. Tetrahedron Lett. 2002, 43,
935-938. (b) Berger, R.; Shoop, W. L.; Pivnichny, J . V.; Waarmke, L.
M.; Zakson-Aiken, M.; Owens, K. A.; de Montigny, P.; Schamatz, D.
M.; Wyvratt, M. J .; Fisher, M. H.; Meinke, P. T.; Coletti, S. L. Org.
Lett. 2001, 3, 3715-3718. (c) Wipf, P.; Methot, J . L. Org. Lett. 2001, 3,
1261-1264.
(27) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 3604-3606.
(28) Appel, R.; Scho¨ler, H. Chem. Ber. 1977, 110, 2382-2384.
(29) A small proportion of pyrazine phosphonates (<20%) was also
formed by dimerization of starting azirines 11.30
7286 J . Org. Chem., Vol. 67, No. 21, 2002

Asymmetric Synthesis of 2H-Azirines
(3-Meth yl-2H-a zir in -2-yl)p h osp h in e Oxid e (3a ). (A) As
described in the general procedure, 80.3 mg (70%) was
obtained as a white solid from (E)- and (Z)-2-(N-p-toluene-
sulfonyloximino)propyldiphenylphosphine oxide 1a and resin-
supported amine 2a . (B) As described in the general procedure,
75.7 mg (66%) was obtained as a white solid from (E)- and
(Z)-2-(N-p-toluenesulfonyloximino)propyldiphenylphosphine ox-
ide 1a and recovered resin-supported amine 2a : mp 97-98
azirines and oxazoles are important synthons in organic
synthesis3 and for the preparation of biologically active
compounds of interest in medicinal chemistry.3,25,26
Exp er im en ta l Section
Gen er a l Meth od s. Solvents for extraction and chromatog-
raphy were technical grade. All solvents used in reactions were
freshly distilled from appropriate drying agents before use:
CH2Cl2 (P2O5); n-hexane and diethyl ether (sodium benzophe-
none ketyl); ethyl acetate (K2CO3); CHCl3 (P2O5); toluene
(CaH2); dioxane (Na, benzophenone). All other reagents were
recrystallized or distilled as necessary. All reactions were
performed under an atmosphere of dry nitrogen. Analytical
TLC was performed with silica gel 60 F254 plates. Visualization
was accomplished by UV light and KMnO4 solution. Flash
chromatography was carried out with silica gel 60 (230-400
1
°C; H NMR (CDCl3) δ 7.88-7.36 (m, 10H), 2.38 (s, 3H), 2.18
(d, 2J PH ) 36.5 Hz, 1H) ppm; 13C NMR (CDCl3) δ 163.1 (d, 2J PC
) 3.5 Hz), 133.1-128.3 (m), 27.2 (d, 1J PC ) 111.8 Hz), 13.9 (d,
3J PC ) 1.5 Hz) ppm; 31P NMR (CDCl3) δ 29.8 ppm; IR (KBr)
3062, 1736, 1442, 1192 cm-1; MS (EI) m/z 255 (M+, 63), 201
(P(O)Ph2+, 36). Anal. Calcd for C15H14NOP: C, 70.58; H, 5.53;
N, 5.49. Found: C, 70.37; H, 5.52; N, 5.51.
(-)-(R)-(3-Meth yl-2H-azir in -2-yl)ph osph in e Oxide (3a).
As described in the general procedure, 84.9 mg (74%) was
obtained as a white solid from (E)- and (Z)-2-(N-p-toluene-
sulfonyloximino)propyldiphenylphosphine oxide 1a and resin-
supported amine 2c, ee 16%; [R]20D -8.0. For spectroscopic data
see above.
Gen er a l P r oced u r e for th e Syn th esis of r-Keta m id es
Der ived fr om P h osp h in es Oxid es (5). Method A: To a -80
°C solution of 2H-azirine 3 (5 mmol) in THF (5 mL) was added
a solution of carboxylic acid 4 (15 mmol) in THF (5 mL) under
nitrogen atmosphere. Then, the mixture was allowed to warm
to room temperature and was stirred for 1 to 4 days. The
solvent was evaporated under vacuum, and the crude product
was purified by flash chromatography (silica gel AcOEt).
Method B: The carboxilic acid 4 (5.5 mmol) was added under
nitrogen atmosphere and at room temperature to 2H-azirine
3 (5 mmol) without solvent. The mixture was stirred for 12-
20 h and then the crude residue was crystallized from diethyl
ether to yield products 5 as white solids.
1
mesh). Melting points are uncorrected. H (300 MHz), 13C (75
MHz), and 31P NMR (120 MHz) spectra were recorded with
use of tetramethylsilane (TMS) (0.00 ppm) or chloroform (7.26
ppm) as an internal reference in CDCl3 or D2O solutions for
1H NMR spectra or chloroform (77.0 ppm) as an internal
reference in CDCl3 solutions for 13C NMR, and phosphoric acid
(85%) for 31P NMR spectra. Chemical shifts (δ) are given in
ppm; multiplicities are indicated by s (singlet), d (doublet), dd
(double-doublet), t (triplet), q (quadruplet), or m (multiplet).
Coupling constants (J ) are reported in hertz. Low-resolution
mass spectra (MS) were obtained at 50-70 eV by electron
impact (EI) or chemical ionization (CI). Data are reported in
the form m/z (intensity relative to base ) 100). Infrared spectra
(IR) were taken on a IRFT spectrometer, and were obtained
as solids in KBr or as neat oils in NaCl. Peaks are reported in
cm-1. [R]20D were taken on a polarimeter with a Na/HaI lamp.
Oximes 1a ,b,17 morpholinomethyl polystyrene resin 2b,31 and
2H-azirine-2-phosphonates 1118a were synthesized according
to literature procedures.
N-[1-(Dip h en ylp h osp h in oyl)-2-oxop r op yl]a cet a m id e
(5a a ). 5a a (1.18 g, 75%) was obtained as a white solid from
2H-azirine 3a (1.28 g, 5 mmol) and acetic acid glacial 4a (0.32
g, 5 mmol) as described in the general procedure Method B:
mp 193-194 °C; 1H NMR (CDCl3) δ 7.97-7.46 (m, 10H), 7.13
Gen er a l P r oced u r e for th e P r ep a r a tion of P olym er -
Su p p or ted Am in es (2c a n d 2d ). A suspension of Merrifield
resin (4 mmol, 1 mmol of Cl/g of resin, 4 g) in DMF (32 mL)
was treated with (S)-(+)-2-(methoxymethyl)pyrrolidine or (R)-
(-)-2-(methoxymethyl)pyrrolidine32 (16 mmol, 2 mL). The
resulting mixture was shaken at 65 °C for 18 h under N2
atmosphere and then allowed to stand at room temperature
24 h. After the solution was cooled to room temperature, the
resin was filtered and washed successively with MeOH, DMF,
MeOH, CH2Cl2, MeOH, CH2Cl2, MeOH, AcOEt, and pentane.
The resulting polymer-supported amine was dried at 20 °C
under vacuum for 12 h and stored in tightly sealed bottles.
(S)-(+)-2-(Meth oxym eth yl)p yr r olid in om eth yl P olysty-
r en e Resin (2c). IR (KBr) 2805 (OMe st), 1109 (C-O-C st)
cm-1. Anal. Found: C, 91.98; H, 8.93; N, 1.51.
Gen er a l P r oced u r e for th e Syn th esis of 2H-Azir in e-
2-p h osp h in e Oxid es (3). To a suspension of resin-supported
amine 2a -c (ca. 0.5 mmol, 1.1 equiv) in benzene (8.0 mL) was
added tosyl oxime 1 (0.45 mmol, 1 equiv). The mixture was
shaken at 50 °C for 3 to 4 days under N2 atmosphere after
which time the polymer was filtered and washed with CH2Cl2
(5 mL), Et2O (5 mL), CH2Cl2 (5 mL), and Et2O (5 mL). The
filtrate was evaporated under vacuum. Purification of the
crude product by flash chromatography (silica gel AcOEt-
hexanes 4:1) afforded an oil that was precipitated with Et2O
and recrystallized from AcOEt-hexanes to yield compounds
3. Resin-supported amines 2a -c were recovered by washing
successively with MeOH, TEA, CH2Cl2, MeOH, TEA, CH2Cl2,
MeOH, TEA, and CH2Cl2.
3
2
3
(d, J HH ) 9.0 Hz, 1H), 5.85 (dd, J PH ) 11.4 Hz, J HH ) 9.0
Hz, 1H), 2.15 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (CDCl3) δ
1
200.8, 169.3, 133.2-128.1 (m), 60.8 (d, J PC ) 65.0 Hz), 29.9,
22.7 ppm; 31P NMR (CDCl3) δ 31.2 ppm; IR (KBr) 3190, 3032,
3022, 1720, 1680 cm-1; MS (EI) m/z 315 (M+ + 2), 201 (P(O)-
Ph2+, 40). Anal. Calcd for C17H18NO3P: C, 64.76; H, 5.75; N,
4.44. Found: C, 64.58; H, 5.74; N, 4.47.
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zoles
(8). To a room temperature solution of triphenyl phosphine
(1.70 g, 6.5 mmol) and hexachloroethane (1.54 g, 6.5 mmol) in
THF (20 mL) was added a solution of R-ketamide 5 (5 mmol)
in THF (5 mL) under nitrogen atmosphere. The mixture was
stirred at room temperature for 5 min. After that, triethy-
lamine (2.10 mL, 15 mmol) was dropped for 10 min. The
mixture was heated at THF reflux for 20 h. The solvent was
evaporated under vacuum and the residue was diluted with
water and extracted with CH2Cl2. The organic layers where
dried over anhydrous magnesium sulfate, filtered, and con-
centrated under vacuum. The crude residue was purified by
flash chromatography (silica gel AcOEt).
4-(Dip h en ylp h osp h in oyl)-2,5-d im eth yloxa zole (8a a ).
8a a (0.95 g, 64%) was obtained as a white solid from R-keta-
mide 5a a (1.58 g, 5 mmol) as described in the general
procedure: mp 117-118 °C; 1H NMR (CDCl3) δ 7.88-7.41 (m,
4
10H), 2.59 (d, J PH ) 1.8 Hz, 3H), 2.42 (s, 3H) ppm; 13C NMR
(CDCl3) δ 160.4 (d, 3J PC ) 19.2 Hz,), 158.9 (d, 2J PC ) 26.1 Hz),
1
133.2-128.3 (m), 126.5 (d, J PC ) 145.0 Hz), 13.8, 11.6 ppm;
31P NMR (CDCl3) δ 18.8 ppm; IR (KBr) 3070,1590, 1195 cm-1
;
MS (EI) m/z 297 (M+, 89). Anal. Calcd for C17H16NO2P: C,
(30) Palacios, F.; Ochoa de Retana, A. M.; Gil, J . I.; Lo´pez de Munain,
R. Org. Lett. 2002, 4, 2405-2408.
68.68; H, 5.42; N, 4.71. Found: C, 68.88; H, 5.40; N, 4.72.
(31) Booth, R. H.; Hodges, J . C. J . Am. Chem. Soc. 1997, 119, 4882-
Gen er a l P r oced u r e for Syn th esis of r-Keta m id es De-
r ived fr om P h osp h on a tes (12). The carboxylic acid 4 (7.5
mmol) was added to 2H-azirinephosphonate 11 (5 mmol)
4886.
(32) Enders, D.; Fey, P.; Kipphardt, H. Organic Syntheses; Wiley:
New York, 1993; Collect. Vol. VIII, pp 26-31.
J . Org. Chem, Vol. 67, No. 21, 2002 7287

Palacios et al.
without solvent, under nitrogen atmosphere, at room temper-
ature, and with continuous stirring. The mixture was heated
at 70 °C for 2 h. Then, the crude residue was purified by flash
chromatography (silica gel AcOEt/hexanes) affording R-keta-
mides 12 and a small proportion (15-20%) of pyrazine
phosphonates.30
Dieth yl (2,5-Dim eth yloxa zol-4-yl)p h osp h on a te (13a a ).
13a a (0.64 g, 55%) was obtained as a colorless oil from
R-ketamide 12a a (1.26 g, 5 mmol) as described in the general
method: Rf 0.34 (AcOEt); 1H NMR (CDCl3) δ 4.16 (m, 4H),
4
3
2.54 (d, J PH ) 2.3 Hz, 3H), 2.44 (s, 3H), 1.35 (t, J HH ) 7.1
3
Hz, 6H); 13C NMR (CDCl3) δ 160.9 (d, J PC ) 22.2 Hz), 158.5
2
1
2
Diethyl(1-Acetylam in o-2-oxopr opyl)ph osph on ate (12aa).
12a a (0.94 g, 75%) was obtained as an oil from 2H-azirine-
phosphonate 11a (0.96 g, 5 mmol) and acetic acid 4a (0.45 g,
7.5 mmol) as described in the general procedure: Rf 0.51
(d, J PC ) 39.8 Hz), 127 (d, J PC ) 243.7), 62.5 (d, J PC ) 5.5
Hz), 16.4 (d, 3J PC ) 6.6 Hz), 11.5; 31P NMR (CDCl3) δ 10.0 ppm;
IR (NaCl) 2985, 2919, 1730, 1600,1440, 1029, 970 cm-1; MS
(EI) m/z 233 (M+, 28). Anal. Calcd for C9H16NO4P: C, 46.35;
H, 6.92; N, 6.01. Found: C, 46.20; H, 6.89; N, 5.99.
3
(AcOEt); 1H NMR (CDCl3) δ 6.48 (d, J HH ) 8.4 Hz, 1H), 5.25
2
3
(dd, J PH ) 23.3 Hz, J HH ) 8.4 Hz, 1H), 4.11 (m, 4H), 2.36 (s,
3H), 2.01 (s, 3H), 1.28 (m, 6H) ppm; 13C NMR (CDCl3) δ 199.9,
3
2
1
Ack n ow led gm en t. The authors thank the Direccio´n
General de Investigacio´n del Ministerio de Ciencia y
Tecnolog´ıa (MCYT, Madrid DGI, BQU2000-0217) and
the Universidad del Pa´ıs Vasco (UPV, G11/ 99) for
supporting this work. J .I.G. and J .M.A. thank the
Universidad del Pa´ıs Vasco and the Ministerio de
Educacio´n y Cultura (Madrid) for predoctoral fellow-
ships.
169.4 (d, J PC ) 5.0 Hz), 63.5 (d, J PC ) 6.1 Hz), 57.9 (d, J PC
) 141.0 Hz), 29.0, 22.8, 16.2 ppm; 31P NMR (CDCl3) δ 16.2
ppm; IR (NaCl) 3262, 3040, 1731, 1678 cm-1; MS (EI) m/z 252
(M+ + 1, 4). Anal. Calcd for C9H18NO5P: C, 43.03; H, 7.22; N,
5.58. Found: C, 43.14; H, 7.20; N, 5.60.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dieth yl
(2,4-Dia lk yloxa zol-4-yl)p h osp h on a tes (13). To a room tem-
perature solution of triphenylphosphine (1.70 g, 6.5 mmol) and
hexachloroethane (1.54 g, 6.5 mmol) in toluene (20 mL) was
added a solution of R-ketamide 12 (5 mmol) in toluene (5 mL)
under nitrogen atmosphere. The mixture was stirred at that
temperature for 5 min. After that, triethylamine (2.10 mL, 15
mmol) was dropped for 10 min. The subsequent mixture was
heated at toluene reflux for 20 h. The solvent was evaporated
under vacuum and the residue was purified by precipitation
in cold ethyl ether. The organic layers were concentrated under
vacuum and the subsequent residue was ground with cold
water and filtered. The aqueous layer was concentrated,
affording compounds 13 as colorless oils.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data (1H NMR, 13C NMR, 31P
NMR, IR, and MS) for all new compounds (-)-2d , 3b, (-)-3b,
(+)-3a , (+)-3b, 5a b, 5a c, 5a d , 5a e, 5bb, 5bf, 5bg, 8a b, 8a c,
8a d , 8a e, 8bb, 8bg, 12a b, 12bb, 13a b, and 13bb. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O025995D
7288 J . Org. Chem., Vol. 67, No. 21, 2002