Regioselective synthesis of 4- and 5-oxazole-phosphine oxides and -phosphonates from 2H-azirines and acyl chlorides

Article abstract of DOI:10.1016/j.tet.2004.07.013

A simple and efficient regioselective synthesis of 4-oxazole-phosphine oxides 11 and -phosphonates 12 from 2H-azirine-phosphine oxides 1 and -phosphonates 6 is described. The key step for the synthesis of oxazoles 11 is a base-mediated ring closure of vin

Full text of DOI:10.1016/j.tet.2004.07.013

Tetrahedron 60 (2004) 8937–8947
Regioselective synthesis of 4- and 5-oxazole-phosphine oxides
and -phosphonates from 2H-azirines and acyl chlorides
*
Francisco Palacios, Ana M. Ochoa de Retana, Jose I. Gil and Jose M. Alonso
´
´
´ ´ ´
Departamento de Quımica Organica I, Facultad de Farmacia, Universidad del Paıs Vasco. Apartado 450, 01080 Vitoria, Spain
Received 11 May 2004; revised 2 July 2004; accepted 6 July 2004
Available online 18 August 2004
Abstract—A simple and efficient regioselective synthesis of 4-oxazole-phosphine oxides 11 and -phosphonates 12 from 2H-azirine-
phosphine oxides 1 and -phosphonates 6 is described. The key step for the synthesis of oxazoles 11 is a base-mediated ring closure of
vinylogous a-aminophosphorus compounds derived from phosphine oxides 4 and from phosphonates 8. These derivatives 4 and 8 are
obtained by reaction of functionalized azirines 1 and 6 with acyl chlorides 2 and subsequent acid-catalyzed ring opening of N-acylaziridine-
phosphine oxides 3 and -phosphonates 7. Regioselective thermal ring cleavage of N-acylaziridine-phosphine oxides 3 leads a-chloro-b-(N-
acylamido)-phosphine oxides 13 and their treatment with bases gives 5-oxazole-phosphine oxides 16.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
b-amino phosphorus derivatives12 as well as their dimeriza-
tion to phosphorylated pyrazines13 and the ring opening of
these azirines I with carboxylic acids followed by the
cyclization of the corresponding adducts II to oxazoles
containing phosphorus substituents in position 4 III through
the azirine-oxozolone methodology14 (Fig. 1). Furthermore,
the reaction of acyl halides with simple azirines to give
N-acylaziridines,15 oxazoles,16 or unsaturated N-acylimines17
has been described. However, the behaviour of phosphory-
lated azirines with acyl halides has not been reported. For
this reason and continuing with our interest in the synthesis
of new phosphorus substituted heterocycles, we here report
an easy and high yielding synthesis of 4- (III, Fig. 1) and
2H-Azirine ring systems represent an important class of
compounds because of their high reactivity1 in the
preparation of acyclic functionalized amino derivatives2a–c
and heterocycles.2d–h In particular, 2H-azirines containing a
carboxylic ester group are constituents of naturally
occurring antibiotics1a and are excellent reagents for the
preparation of functionalized aziridines1,3 and a-3b,4a–e and
b-amino acid derivatives,3b,4f–h while molecular modifi-
cations involving the introduction of organophosphorus
functionalities, replacing the carboxylic ester for an
isosteric phosphorus group, could increase the use of these
substrates as intermediates not only in organic synthesis but
also in medicinal chemistry.1,5 For this reason, we have
previously reported the preparation of 2H-azirine-phosphine
oxides6 and -phosphonates by a base-mediated Neber
reaction of tosyl oximes.7
In this context, we have also described new methods for the
preparation of five,8 and six9 membered phosphorus
substituted nitrogen heterocycles from functionalized phos-
phine oxides and phosphonates and the synthetic uses of
amino phosphorus derivatives as starting materials for the
preparation of acyclic compounds10 and phosphorus-
containing heterocycles.11 Recently, we described the use
of phosphorylated 2H-azirines for the synthesis of a- and
Keywords: Azirine phosphine oxide and phosphonate; Oxazole; Acyl
chloride.
* Corresponding author. Tel.: C34-945-013103; fax: C34-945-013049;
e-mail: qoppagaf@vf.ehu.es
Figure 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.013

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F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
5-(oxazolyl)-phosphorus derivatives (IV, Fig. 1) from easily
available azirines and acyl chlorides, as well as the
formation and isolation of their N-acyl-aziridine precursors.
Simple oxazoles are common units in a wide variety of
polyoxazole marine natural products possessing biological
activity,18 and oxazoles are also widely used intermediates
for functional transformations.19
agreement with the assigned structure of compound 3aa. In
the 31P NMR spectrum the phosphine oxide group of this
aziridine 3aa resonated at dPZ23.2 ppm, while well
resolved doublets at dZ3.32 ppm (2JPHZ23.0 Hz) for H-2
in the 1H NMR spectrum as well as at dCZ44.7 ppm
(1JPCZ96.2 Hz) and at dCZ59.8 ppm (2JPCZ5.5 Hz) for
C-2 and C-3 in the 13C NMR spectrum were observed. The
stereochemical assignment was based on NOE experiments.
The exclusive formation of trans-aziridine 3aa suggests that
the approach of the chloride to the cyclic compound from
the opposite position to the phosphine oxide group is more
favourable, due to the high exocyclic dihedral angle of
the saturated carbon and to the presence of the bulky
phosphorus group. The scope of the reaction was not limited
to acetyl chloride 2a (R2ZCH3), given that not only
benzoyl chloride 2b (R2ZPh), but also functionalized acyl
chlorides containing olefine groups 2c (R2Z(CH2)4-
CH]CH2), and 2d (R2ZCH]CH2) also reacted with
azirine 1a to give functionalized trans-(N-acylaziridines)
3ab-3ad (Scheme 1, Table 1, entries 2–4) in a regioselective
fashion. Likewise, 3-ethyl- 1b (R1ZC2H5) and 3-phenyl-
azirines 1c (R1ZPh) also reacted with acetyl chloride 2a
(R2ZCH3) to afford only trans-aziridinyl-phosphine oxides
3ba and 3ca (Scheme 1, Table 1, entries 5,6).
2. Results and discussion
2.1. Reaction of azirines 1 and 6 with acyl chlorides
2H-Azirines are ambident reagents and are capable of acting
in organic reactions not only as nucleophiles (N-1), but also
as electrophiles (C-3).1 Carboxylic acids can ring open these
strained three membered heterocycles I to give amides II by
means of acid-catalyzed addition of carboxylate nucleophile
and these amides II can be used for the preparation of
oxazoles III (Fig. 1). However, a different behaviour could
be expected in the case of other carboxylic derivatives such
as acyl chlorides, because in this case the acyl group could
act as electrophile. So, we initially explored the reaction of
acyl chlorides with phosphorylated azirines. Reaction of
azirine-phosphine oxide 1a (RZPh, R1ZCH3) with acetyl
chloride 2a (R2ZCH3) at room temperature led exclusively
to the formation of trans-(N-acyl-3-chloro-3-methyl-
aziridinyl-phosphine oxide) 3aa (RZPh, R1ZR2ZCH3)
(Scheme 1, Table 1, entry 1). No trace of the cis-aziridine
could be observed by 31P NMR. Spectroscopic data were in
Ring expansion of N-acylaziridines to five membered
heterocycles can be achieved by thermal treatment or in
the presence of acids,20 while no ring opening reaction of
N-acylaziridines containing phosphorus substituents has
been reported. We explored the reaction of azirine-
phosphine oxides because this reaction can be used as a
model of the influence of phosphorus substituents by the
ring opening reaction of these substrates and functionalized
amides generated could then be used for the preparation
of phosphorylated oxazoles. Treatment of functionalized
N-acylaziridines 3aa-ac with hydrogen chloride in THF
at room temperature led to the formation of vinylogous
a-amido-phosphine oxides 4aa-ac (Scheme 1, Table 2,
entries 1–3). Both conjugative addition of HCl to the
acryloyl group of N-acylaziridine 3ad (R2ZCH]CH2) and
the ring opening was observed when this aziridine 3ad was
treated with HCl to give a-amido-phosphine oxides 4ad
(R2ZCH2–CH2Cl) (Scheme 1, Table 2, entry 4). Spectro-
scopic data were in agreement with the assigned structure of
compounds 4. The formation of a-amido-phosphine oxides
4 could be explained by protonation of the nitrogen atom of
the N-acylaziridine followed by formation of the carbon–
carbon double bond and ring opening of activated
aziridinium ion 5. From a synthetic point of view, it is
noteworthy that the preparation of these a-amido-phosphine
oxides 4 can also be directly prepared from azirines 1
without the isolation of N-acylaziridines 3, when these
heterocycles 1 were treated with acyl chlorides 2 in a THF
solution containing hydrogen chloride (Scheme 1, Table 2,
entries 1–3). The use of azirines containing an ethyl group at
3-position 1b (R1ZC2H5) gave 4ba (R3ZCH3) (Scheme 1,
Table 2, entry 5) and allowed us to assign the Z-
configuration of the carbon–carbon double bond based on
NOE experiments.
Scheme 1.
Table 1. N-Acylaziridine-phosphine oxides 3 obtained
Entry
Compound
R1
R2
Yield (%)a
1
2
3
4
5
6
3aa
3ab
3ac
3ad
3ba
3ca
CH3
CH3
CH3
CH3
C2H5
Ph
CH3
Ph
(CH2)4CH]CH2
CH]CH2
CH3
76
81
43
96
85
80
These processes can be extended to azirines derived from
phosphonates 6. Treatment of 3-alkyl azirines 6a (RZOEt,
R1ZMe) and 6b (RZOEt, R1ZC2H5), with acetyl chloride
CH3
a
Yield of isolated purified compounds 3.

F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
8939
Table 2. Vinylogous amides 4 and 8 obtained
Table 3. 4-Oxazolyl-phosphine oxides 11 and -phosphonates 12 obtained
Entry
Compound
R
R2
R3
Yield (%)a
Entry
Compound
R
R1
R2
Yield (%)a
1
2
3
4
5
6
7
8
4aa
4ab
4ac
4ad
4ba
8aa
8ad
8ba
Ph
Ph
Ph
Ph
CH3
Ph
(CH2)4CH]CH2
CH2–CH2Cl
CH3
CH3
CH]CH2
CH3
H
H
H
H
CH3
H
H
CH3
96 (96)b
33 (42)b
22 (40)b
48
1
2
3
4
5
6
7
8
9
10
11aa
11ab
11ac
11ad
11ba
11ca
12aa
12ad
12ba
12ca
Ph
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
CH3
CH3
CH3
CH3
C2H5
Ph
CH3
CH3
C2H5
Ph
CH3
Ph
(CH2)4CH]CH2
CH]CH2
CH3
CH3
CH3
CH]CH2
CH3
CH3
87
82
71
52
67
58
59
63
65
92
Ph
58b
OEt
OEt
OEt
91
78
87
a
Yield of isolated purified compounds 4 and 8.
Yield of isolated compounds 4 obtained one pot from azirines 1.
b
a
Yield of isolated purified compounds 11 and 12.
2a (R2ZCH3) and acryloyl chloride 2d (R2ZCH]CH2)
gave vinylogous amides containing a diethoxyphosphoryl
group in the a-position 8aa (RZOEt, R2ZCH3, R3ZH),
8ad (RZOEt, R2ZCH]CH2, R3ZH) and 8ba (RZOEt,
R2ZCH3, R3ZCH3) (Scheme 1, Table 2, entries 6–8),
without the isolation of the N-acylaziridine precursors 7.
This strategy describes, as far as we know, the first synthesis
of vinylogous a-amido-phosphine oxides and -phospho-
nates. a-Aminophosphonates21 can be considered as
surrogates for a-aminoacids,22a and have been used as
haptens for the generation of catalytic antibodies,10b,c as
antibacterial agents,22d,e and as nucleoside,22f or as
phosphapeptide enzyme inhibitors.22g–k
biological functions,5 we thought that N-acylaziridines 3
or a-amido-phosphine oxides 4 could be used for the
preparation of oxazoles. Vinylogous amides 4 (RZPh, R3Z
H, CH3) were treated with 2 N aqueous NaOH solution in
dichloromethane to give 3-alkyl-oxazole phosphine oxides
11 (RZPh, R1ZCH3, C2H5) in good yields and in a
regioselective fashion (Scheme 2, Table 3, entries 1–5).
Formation of oxazoles 11 could be explained by cyclization
of intermediate 9 and subsequent loss of HCl from
dihydrooxazol 10. However, in the case of oxazoles
containing an aryl substituent, this 5-phenyl oxazole 11ca
(RZPh, R1ZPh) was directly obtained from 3-phenyl
azirine 1c by ring expansion with acetyl chloride and HCl
via an aziridinium cation (Scheme 2, Table 3, entry 6).
2.2. Formation of oxazoles 11, 12 and 16
Ring closure of a-amido-phosphonates 8 with 2 N aqueous
NaOH solution gave oxazole phosphonates 12 (Scheme 1,
Table 3, entries 7–9), and ring expansion of 3-phenyl azirine
6c (RZOEt, R1ZPh) with acetyl chloride 2a (R2ZCH3)
gave directly 5-phenyl oxazole phosphonate 12ca (RZOEt,
R1ZPh, R2ZCH3) (Scheme 2, Table 3, entry 10).
Oxazoles are common heterocycles in a wide variety of
natural products possessing biological activity and also are
widely used intermediates for functional transformations.18,19
Given that phosphorus substituents regulate important
Next, we also explored the behaviour of N-acylaziridines 3
when they were heated in the presence of a base, in order to
test whether these substrates could be opened in a different
regioselective fashion than before, with presence of acid.
Thermal treatment of N-acylaziridines 3aa (RZPh, R1Z
R2ZCH3), 3ab (RZPh, R1ZCH3, R2ZPh), 3ad (RZPh,
R1ZCH3, R2ZCH]CH2), 3ba (RZPh, R1ZC2H5, R2Z
CH3), in refluxing chlorobenzene and in the presence of
tributylamine led to the formation of vinylamides 13aa,
13ab, 13ad and 13ba in moderate yields (Scheme 3,
Table 4, entries 1–4) and a small proportion of oxazoles 11.
The formation of oxazoles 11 (minor components) can be
explained as before (Scheme 2) by regioselective ring
opening of the N–C2 bond followed by cyclization to the
five membered ring, while formation of major compounds
13 could be explained by regioselective ring opening of the
Table 4. Enamides 13 and 5-oxazolyl-phosphine oxides 16
Entry
Compound
R1
R2
Yield (%)a
1
2
3
4
5
6
7
13aa
13ab
13ad
13ba
16aa
16ab
16ba
CH3
CH3
CH3
C2H5
CH3
CH3
C2H5
CH3
Ph
CH]CH2
CH3
CH3
Ph
41
60
15
54
65
72
57
CH3
a
Yield of isolated purified compounds 13 and 16.
Scheme 2.

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F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
presence of HCl, while functionalised enamides 13 were
obtained by thermal treatment of N-acylaziridines 3. Ring
closure of vinylogous a-amides 4, 8 gives 4-oxazolyl-
phosphine oxides 11 and -phosphonates 12 while intramole-
cularcyclizationofenamides13affords5-oxazolyl-phosphine
oxides 16. Oxazoles18 are common compounds in a wide
variety of natural products possessing biological activity and
both oxazoles and a-aminophosphonates21 are widely used
intermediates in organic and medicinal chemistry.18,19,21,22
4. Experimental
4.1. General
Chemicals were purchased from Aldrich Chemical Com-
pany. Solvents for extraction and chromatography were
technical grade. All solvents used in reactions were freshly
distilled from appropriate drying agents before use. All
other reagents were recrystallized or distilled as necessary.
All reactions were performed under an atmosphere of dry
nitrogen. Analytical TLC was performed with Merck silica
gel 60 F254 plates. Visualization was accomplished by UV
light. Flash chromatography was carried out using Merck
silica gel 60 (230–400 mesh ASTM). Melting points were
determined with an Electrothermal IA9100 Digital Melting
Point Apparatus and are uncorrected. 1H (400, 300,
250 MHz), 13C (100, 75 MHz) and 31P NMR (120 MHz)
spectra were recorded on a Bruker Avance 400 MHZ and a
Varian Unity 300 MHz Plus spectrometer using CDCl3 or
CD3OD solutions with TMS as an internal reference (dZ
0.00 ppm) for 1H and 13C NMR spectra and phosphoric acid
(85%) (dZ0.0 ppm) for 31P NMR spectra. Chemical shifts
(d) are reported in ppm. Coupling constants (J) are reported
in Hertz. Low-resolution mass spectra (MS) were obtained
at 50–70 eV by electron impact (EIMS) on a Hewlett
Packard 5971 spectrometer or by chemical ionization (CI)
on a Hewlett Packard 1100 MSD spectrometer. Data are
reported in the form m/z (intensity relative to baseZ100).
Infrared spectra (IR) were taken on a Nicolet IRFT Magna
550 spectrometer, and were obtained as solids in KBr or as
neat oils. Peaks are reported in cmK1. Elemental analyses
were performed in a LECO CHNS-932 apparatus. Azirines
1 and 6 were prepared according to literature procedures.6,7
Scheme 3.
N–C1 single bond of the ring through an intermediate 14,
chloride rearrangement and formation of functionalized
acylimine 15 containing chloro and phosphine oxide groups
in the a position, followed by tautomerization.
Finally, base-mediated (NaH) ring closure of enamides 13
in THF reflux gave only 5-oxazolyl-phosphine oxides 16
(Scheme 4, Table 4, entries 5–7) in good yields and in a
regioselective fashion. The formation of oxazoles 16 can be
explained by deprotonation, sodium amidure salt formation
and intramolecular nucleophilic cyclization of intermediate
17 with the loss of NaCl. As far as we know, this process
describes the first synthesis of oxazole derivatives contain-
ing phosphorus substituent in position 5.
4.2. General procedure for the preparation of
N-acylaziridine-phosphine oxides 3
The corresponding acyl chloride 2 (5 mmol) was added to a
solution of 2H-azirine-2-diphenylphosphine oxide 1
(5 mmol) in benzene (10 mL) under a nitrogen atmosphere.
The mixture was stirred at room temperature until TLC
indicated the disappearance of azirine (1–38 h). Evaporation
of solvent under reduced pressure and chromatographic
purification by flash column chromatography with hexane/
ethyl acetate or crystallization afforded the corresponding
derivatives 3.
Scheme 4.
3. Conclusion
In conclusion, this account describes a simple, mild, and
convenient strategy for the preparation of oxazoles contain-
ing phosphorus substituents in position 4 and 5 from easily
available azirine-phosphine oxides 1 and -phosphonates 6
and acyl chlorides. N-Acylaziridines 3 can be isolated and
these strained heterocycles can be used for the preparation
of vinylogous a-amido-phosphine oxides 3 and phospho-
nates 8 when azirines were treated with acyl chlorides in the
4.2.1. trans-N-Acetyl-3-chloro-3-methyl-aziridin-2-yl
diphenyl phosphine oxide (3aa). The general procedure
was followed using 2H-azirine-2-diphenylphosphine oxide
1a (1.28 g, 5 mmol) and acetyl chloride 2a (0.38 mL,
5 mmol). Chromatographic purification and crystallization

F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
8941
from hexane/ethyl acetate gave 1.27 g (76%) of compound
3aa; mp 197–198 8C (hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3): d 2.06 (s, 3H), 2.23 (s, 3H), 3.32 (d,
2JPHZ23.0 Hz, 1H), 7.39–7.54 (m, 6H), 7.73–7.81 (m,
4H) ppm; 13C NMR (75 MHz, CDCl3): d 24.9, 25.0, 44.7 (d,
(MC, 33). Anal. Calcd for C18H17ClNO2P: C, 62.53; H, 4.96;
N, 4.05. Found: C, 62.44; H, 4.98; N, 4.07.
4.2.5. trans-N-Acetyl-3-chloro-3-ethyl-aziridin-2-yl
diphenyl phosphine oxide (3ba). The general procedure
was followed using 2H-azirine-2-diphenylphosphine oxide
1b (1.34 g, 5 mmol) and acetyl chloride 2a (0.38 mL,
5 mmol). Chromatographic purification and crystallization
from hexane/ethyl acetate gave 1.47 g (85%) of compound
3ba; mp 120–121 8C (hexane/ethyl acetate); 1H NMR
2
1JPCZ96.2 Hz), 59.8 (d, JPCZ5.5 Hz), 128.6–132.6 (m),
178.2 ppm; 31P NMR (120 MHz, CDCl3): d 23.2 ppm; IR
(KBr) nmax 3065, 1720, 1388, 1366, 1210 cmK1; MS (EI):
m/z 335 (MCC2, 21), 333 (MC, 62). Anal. Calcd for
C17H17ClNO2P: C, 61.18; H, 5.13; N, 4.20. Found: C,
61.35; H, 5.11; N, 4.21.
3
(300 MHz, CDCl3): d 1.17 (t, JHHZ7.3 Hz, 3H), 2.22 (m,
3
5
3JHHZ7.2 Hz, JHHgemZ7.2 Hz, 1H), 2.29 (d, JPH
Z
3
3
1.4 Hz, 3H), 2.47 (m, JHHZ7.2 Hz, JHHgemZ7.2 Hz,
4.2.2. trans-N-Benzoyl-3-chloro-3-methyl-aziridin-2-yl
diphenyl phosphine oxide (3ab). The general procedure
was followed using 2H-azirine-2-diphenylphosphine oxide
1a (1.28 g, 5 mmol) and benzoyl chloride 2b (0.58 mL,
5 mmol). Chromatographic purification and crystallization
from hexane/ethyl acetate gave 1.60 g (81%) of compound
2
1H), 3.43 (d, JPHZ23.2 Hz, 1H), 7.25–7.61 (m, 6H),
7.81–7.89 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3): d
1
2
10.2, 25.0, 30.8, 45.4 (d, JPCZ96.7 Hz), 65.4 (d, JPC
Z
P
4.5 Hz), 127.3–132.5 (m), 178.5 (d, 3JPCZ2.5 Hz) ppm; 31
NMR (120 MHz, CDCl3): d 22.7 ppm; IR (KBr) nmax 3058,
1666, 1434, 1374, 1199 cmK1; MS (CI): m/z 348 (MCC1,
90). Anal. Calcd for C18H19ClNO2P: C, 62.16; H, 5.51; N,
4.03. Found: C, 62.28; H, 5.50; N, 4.01.
3ab; mp 144–145 8C (hexane/ethyl acetate); 1H NMR
2
(300 MHz, CDCl3): d 2.20 (s, 3H), 3.57 (d, JPH
Z
22.7 Hz, 1H), 7.40–7.58 (m, 9H), 7.79–7.97 (m, 6H) ppm;
1
13C NMR (75 MHz, CDCl3): d 25.2, 44.2 (d, JPC
Z
2
4.2.6. trans-N-Acetyl-3-chloro-3-phenyl-aziridin-2-yl
diphenyl phosphine oxide (3ca). The general procedure
was followed using 2H-azirine-2-diphenylphosphine oxide
1c (1.59 g, 5 mmol) and acetyl chloride 2a (0.38 mL,
5 mmol). Chromatographic purification and crystallization
from hexane/ethyl acetate gave 1.58 g (80%) of compound
96.7 Hz), 61.6 (d, JPCZ5.0 Hz), 128.1–134.0 (m),
175.0 ppm; 31P NMR (120 MHz, CDCl3): d 23.5 ppm;
IR (KBr) nmax 3065, 1697, 1384, 1201 cmK1; MS (EI):
m/z 397 (MCC2, 18), 395 (MC, 55). Anal. Calcd for
C22H19ClNO2P: C, 66.76; H, 4.84; N, 3.54. Found: C,
66.56; H, 4.81; N, 3.54.
3ca; mp 97–98 8C (hexane/ethyl acetate); 1H NMR
2
(300 MHz, CDCl3): d 2.45 (s, 3H), 3.86 (d, JPH
Z
18.5 Hz, 1H), 7.12–7.58 (m, 13H), 7.79–7.86 (m,
4.2.3. trans-3-Chloro-3-methyl-N-(6-heptenoyl)-aziridin-
2-yl diphenyl phosphine oxide (3ac). The general
procedure was followed using 2H-azirine-2-diphenylphos-
phine oxide 1a (1.28 g, 5 mmol) and 6-heptenoyl chloride
2c (0.73 g, 5 mmol). Chromatographic purification and
crystallization from hexane/ethyl acetate gave 0.85 g (43%)
of compound 3ac; mp 153–154 8C (hexane/ethyl acetate);
2H) ppm; 13C NMR (75 MHz, CDCl3): d 25.1, 47.6 (d,
2
1JPCZ98.2 Hz), 61.3 (d, JPCZ5.5 Hz), 127.8–134.3 (m),
179.3 ppm; 31P NMR (120 MHz, CDCl3): d 22.6 ppm; IR
(KBr) nmax 3065, 1699, 1434, 1381, 1242 cmK1; MS (CI):
m/z 335 (MCC1, 40). Anal. Calcd for C22H19ClNO2P: C,
66.76; H, 4.84; N, 3.54. Found: C, 66.62; H, 4.85; N, 3.55.
1H NMR (300 MHz, CDCl3): d 1.43 (m, 2H), 1.69 (m, 2H),
3
2.06 (m, 2H), 2.11 (m, 3H), 2.58 (m, 2H), 3.40 (d, JPH
Z
4.3. General procedure for the preparation of a-
amidophosphine oxides 4
24.0 Hz, 1H), 4.97 (m, 2H), 5.78 (m, 1H), 7.45–7.63 (m,
6H), 7.81–7.88 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3):
d 23.7, 25.1, 28.1, 33.3, 37.8, 44.2 (d, 1JPCZ97.0 Hz), 60.1
A solution of the corresponding N-acylaziridine-phosphine
oxide 3 (5 mmol) in THF (10 mL) was saturated with
hydrogen chloride and the mixture was stirred at room
temperature under a nitrogen atmosphere until the formation
of a precipitate (4 h). Evaporation of solvent under reduced
pressure and crystallization from ethyl acetate afforded
compounds 4.
2
(d, JPCZ5.6 Hz), 114.7, 128.5–132.5 (m), 138.2,
181.1 ppm; 31P NMR (120 MHz, CDCl3): d 23.3 ppm; IR
(KBr) nmax 3060, 1700, 1200 cmK1; MS (EI): m/z 403
(MCC2, 21), 401 (MC, 68). Anal. Calcd for C22H25ClNO2P:
C, 65.75; H, 6.27; N, 3.49. Found: C, 65.60; H, 6.29; N, 3.48.
4.2.4. trans-N-Acryloyl-3-chloro-3-methyl-aziridin-2-yl
diphenyl phosphine oxide (3ad). The general procedure
was followed using 2H-azirine-2-diphenylphosphine oxide
1a (1.28 g, 5 mmol) and acryloyl chloride 2d (0.41 mL,
5 mmol). Chromatographic purification and crystallization
from hexane/ethyl acetate gave 1.66 g (96%) of compound
4.3.1. N-[2-Chloro-1-(diphenylphosphinyl)-allyl]-aceta-
mide (4aa). The general procedure was followed using
N-acylaziridinephosphine oxide 3aa (1.67 g, 5 mmol).
Crystallization from ethyl acetate gave 1.60 g (96%) of
1
compound 4aa; mp 228–229 8C (hexane/ethyl acetate); H
3ad; mp 113–114 8C (hexane/ethyl acetate); 1H NMR
NMR (300 MHz, CDCl3): d 1.96 (s, 3H), 5.29 (d, 2JHHgem
Z
2
(300 MHz, CDCl3): d 2.10 (m, 3H), 3.40 (d, JPH
Z
2.1 Hz, 1H), 5.48 (dd, 2JHHgemZ2.1 Hz, 4JPHZ2.2 Hz, 1H),
3
2
2 3
22.6 Hz, 1H), 5.89 (dd, JHHcisZ9.5 Hz, JHHgemZ3.8 Hz,
5.77 (dd, JPHZ7.4 Hz, JHHZ9.8 Hz, 1H), 7.47–7.56 (m,
1H), 6.35 (m, 3JHHcisZ9.5 Hz, 2JHHgemZ3.8 Hz, 3JHHtrans
Z
6H), 7.65 (d, JHHZ9.8 Hz, 1H), 7.74–7.86 (m, 4H) ppm;
3
1.7 Hz, 2H), 7.40–7.56 (m, 6H), 7.76–7.83 (m, 4H) ppm; 13C
NMR (75 MHz, CDCl3): d 25.1, 44.3 (d, 1JPCZ96.2 Hz), 60.5
(d, 2JPCZ5.5 Hz), 128.6–132.6 (m), 131.1, 131.4, 173.3 ppm;
31P NMR (120 MHz, CDCl3): d 23.4 ppm; IR (KBr) nmax
3060, 1705, 1187 cmK1; MS (EI): m/z 347 (MCC2, 11), 345
13C NMR (75 MHz, CDCl3): d 22.8, 53.9 (d, JPC
Z
1
76.0 Hz), 118.1 (d, 3JPCZ6.5 Hz), 128.5–132.5 (m), 135.5,
169.7 ppm; 31P NMR (120 MHz, CDCl3): d 31.7 ppm; IR
(KBr) nmax 3227, 3180, 3060, 1670, 1205 cmK1; MS (EI):
m/z 335 (MCC2, 15), 333 (MC, 42). Anal. Calcd for

8942
F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
3
C17H17ClNO2P: C, 61.18; H, 5.13; N, 4.20. Found: C,
61.39; H, 5.12; N, 4.21.
NMR (300 MHz, CDCl3): d 2.68 (t, JHHZ6.6 Hz, 2H),
3.62 (t, 3JHHZ6.6 Hz, 2H), 5.29 (d, 2JHHgemZ2.1 Hz, 1H),
2
2
5.47 (d, JHHgemZ2.1 Hz, 1H), 5.74 (dd, JPHZ9.5 Hz,
The compound 4aa was obtained directly (1.60 g, 96%)
when 2H-azirine-2-diphenylphosphine oxide 1a (1.28 g,
5 mmol) was added to a solution of acetyl chloride 2a
(0.38 mL, 5 mmol) in benzene (10 mL) saturated of
hydrogen chloride and the mixture was stirred at room
temperature for 2 h.
3JHHZ7.1 Hz, 1H), 7.46–7.53 (m, 6H), 7.73–7.83 (m, 4H),
7.91 (d, JHHZ7.1 Hz, 1H) ppm; 13C NMR (75 MHz,
3
1
CDCl3): d 38.2, 39.0, 54.3 (d, JPCZ76.0 Hz), 119.7 (d,
3JPCZ7.5 Hz), 129.0–133.7 (m), 131.4 (d, 2JPCZ10.0 Hz),
172.3 (d, 3JPCZ5.5 Hz) ppm; 31P NMR (120 MHz, CDCl3):
d 31.7 ppm; IR (KBr) nmax 3231, 3065, 1672, 1189 cmK1
;
MS (EI): m/z 384 (MCC3, 16), 382 (MCC1, 18). Anal.
Calcd for C18H18Cl2NO2P: C, 56.56; H, 4.75; N, 3.66.
Found: C, 56.76; H, 4.76; N, 3.67.
4.3.2. N-[2-Chloro-1-(diphenylphosphinyl)-allyl]-benza-
mide (4ab). The general procedure was followed using
N-acylaziridinephosphine oxide 3ab (1.98 g, 5 mmol).
Crystallization from ethyl acetate gave 0.65 g (33%) of
4.3.5. N-[2-Chloro-1-(diphenylphosphinyl)-buten-2-
enyl]-acetamide (4ba). This compound 4ba was obtained
directly when 2H-azirine-2-diphenylphosphine oxide 1b
(1.34 g, 5 mmol) was added to a solution of acetyl chloride
2a (0.38 mL, 5 mmol) in benzene (10 mL) saturated of
hydrogen chloride and the mixture was stirred at room
temperature for 5 h. Crystallization from ethyl acetate gave
1.01 g (58%) of compound 4ba; mp 231–232 8C (hexane/
1
compound 4ab; mp 223–224 8C (hexane/ethyl acetate); H
NMR (300 MHz, CDCl3): d 5.36 (d, 2JHHgemZ2.1 Hz, 1H),
2
2
5.50 (d, JHHgemZ2.1 Hz, 1H), 5.91 (dd, JPHZ9.3 Hz,
3JHHZ8.1 Hz, 1H), 7.37–7.57 (m, 11H), 7.69 (d, JHH
Z
3
7.5 Hz, 1H), 7.81–7.90 (m, 4H) ppm; 13C NMR (75 MHz,
CDCl3): d 54.4 (d, 1JPCZ75.0 Hz), 118.2 (d, 3JPCZ6.6 Hz),
127.2–133.3 (m), 135.5, 166.8 ppm; 31P NMR (120 MHz,
CDCl3): d 31.8 ppm; IR (KBr) nmax 3204, 3065, 1646,
1200 cmK1; MS (EI): m/z 398 (MCC3, 15), 396 (MCC1,
73). Anal. Calcd for C22H19ClNO2P: C, 66.76; H, 4.84; N,
3.54. Found: C, 66.98; H, 4.78; N, 3.55.
1
ethyl acetate); H NMR (300 MHz, CDCl3): d 1.43 (m,
5JPHZ6.4 Hz, JHHZ3.0 Hz, 3H), 1.92 (s, 3H), 5.71 (dd,
3
2JPHZ9.9 Hz, JHHZ7.0 Hz, 1H), 5.82 (m, JPHZ6.6 Hz,
3JHHZ3.2 Hz, 1H), 7.21–7.80 (m, 10H), 8.00 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3): d 14.0, 22.6 (d, 4JPCZ3.0 Hz),
3
4
The compound 4ab was obtained directly (1.60 g, 96%)
when 2H-azirine-2-diphenylphosphine oxide 1a (1.28 g,
5 mmol) was added to a solution of benzoyl chloride 2b
(0.58 mL, 5 mmol) in benzene (10 mL) saturated of
hydrogen chloride and the mixture was stirred at room
temperature for 2 h.
54.0 (d, 1JPCZ78.1 Hz), 127.3–132.6 (m), 170.0 (d, 3JPC
Z
6.4 Hz) ppm; 31P NMR (120 MHz, CDCl3): d 32.6 ppm; IR
(KBr) nmax 3230, 3184, 3051, 1660, 1182 cmK1; MS (CI):
m/z 348 (MCC1, 100). Anal. Calcd for C18H19ClNO2P: C,
62.16; H, 5.51; N, 4.03. Found: C, 62.30; H, 5.52; N, 4.02.
4.4. General procedure for the preparation of diethyl
a-amidophosphonate 8
4.3.3. N-[2-Chloro-1-(diphenylphosphinyl)-allyl]-hepten-
amide (4ac). The general procedure was followed using
N-acylaziridinephosphine oxide 3ac (2.01 g, 5 mmol).
Crystallization from ethyl acetate gave 0.44 g (22%) of
compound 4ac; mp 187–188 8C (ethyl acetate); H NMR
(300 MHz, CDCl3): d 1.16–1.26 (m, 2H), 1.31–1.51 (m,
2H), 1.91–1.98 (m, 2H), 2.09–2.29 (m, 2H), 4.90–4.98 (m,
The corresponding acyl chloride 2 (5 mmol) was added to a
solution of the corresponding 2H-azirine-phosphonate 6
(5 mmol) in benzene (10 mL) under a nitrogen atmosphere.
The mixture was stirred at room temperature until TLC
indicated the disappearance of azirine (1–36 h). Evaporation
of solvent under reduced pressure and chromatographic
purification by flash column chromatography with hexane/
ethyl acetate afforded the corresponding derivatives 8.
1
4
4
2H), 5.30 (d, JPHZ0.5 Hz, 1H), 5.45 (d, JPHZ0.5 Hz,
2
3
1H), 5.68 (m, 1H), 5.77 (dd, JPHZ9.9 Hz, JHHZ7.5 Hz,
1H), 7.35 (d, 3JHHZ7.5 Hz, 1H), 7.44–7.58 (m, 6H), 7.75–
7.87 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3): d 25.0,
1
28.1, 33.3, 36.1, 53.6 (d, JPCZ76.0 Hz), 114.6, 118.1 (d,
4.4.1. Diethyl (1-acetylamino-2-chloro-allyl)-phospho-
nate (8aa). The general procedure was followed 2H-
azirine-phosphonate 6a (0.96 g, 5 mmol) and acetyl chloride
2a (0.38 mL, 5 mmol). Chromatographic purification and
crystallization from hexane/ethyl acetate gave 1.35 g (91%)
of compound 8aa as an oil; Rf 0.65 (ethyl acetate/methanol
5%); 1H NMR (300 MHz, CDCl3): d 1.27 (m, 6H), 2.01 (s,
3H), 4.15 (m, 4H), 5.15 (dd, 2JPHZ21.4 Hz, 3JHHZ9.3 Hz,
3JPCZ6.6 Hz), 128.5–132.5 (m), 135.5, 138.3, 172.6 ppm;
31P NMR (120 MHz, CDCl3): d 31.7 ppm; IR (KBr) nmax
3220, 3065, 1660, 1195 cmK1; MS (EI): m/z 404 (MCC3,
1), 402 (MCC1, 3). Anal. Calcd for C22H25ClNO2P: C,
65.75; H, 6.27; N, 3.49. Found: C, 65.82; H, 6.23; N, 3.46.
The compound 4ac was obtained directly (0.80 g, 40%)
when 2H-azirine-2-diphenylphosphine oxide 1a (1.28 g,
5 mmol) was added to a solution of 6-heptenoyl chloride 2c
(0.73 g, 5 mmol) in benzene (10 mL) saturated of hydrogen
chloride and the mixture was stirred at room temperature for
2 h.
3
1H), 5.41 (m, 1H), 5.53 (m, 1H), 6.70 (d, JHHZ9.3 Hz,
1H) ppm; 13C NMR (75 MHz, CDCl3): d 16.1, 22.5, 51.8 (d,
1JPC2Z159.3 Hz), 63.3, 63.6, 117.1 (d, 3JPCZ9.1 Hz), 135.3
3
(d, JPCZ4.0 Hz), 169.7 (d, JPCZ7.5 Hz) ppm; 31P NMR
(120 MHz, CDCl3): d 19.1 ppm; IR (NaCl) nmax 3258, 1666,
1186, 1097 cmK1; MS (EI): m/z 271 (MCC2, 27), 269
(MC, 42). Anal. Calcd for C9H17ClNO4P: C, 40.09; H, 6.35;
N, 5.19. Found: C, 40.28; H, 6.33; N, 5.20.
4.3.4. 3-Chloro-N-[2-chloro-1-(diphenylphosphinyl)-
allyl]-propionamide (4ad). The general procedure was
followed using N-acylaziridinephosphine oxide 3ad (1.75 g,
5 mmol). Crystallization from ethyl acetate gave 0.92 g
(48%) of compound 4ad; mp 236–237 8C (ethyl acetate); 1H
4.4.2. Diethyl (1-acryloylamino-2-chloro-allyl)-phospho-
nate (8ad). The general procedure was followed

F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
8943
2H-azirine-phosphonate 6a (0.96 g, 5 mmol) and acryloyl
chloride 2d (0.41 mL, 5 mmol). Chromatographic purifi-
cation and crystallization from hexane/ethyl acetate gave
1.10 g (78%) of compound 8ad as an oil; Rf 0.51 (ethyl
4.5.2. 5-Methyl-2-phenyl-oxazol-4-yl diphenylphosphine
oxide (11ab). The general procedure was followed using
a-amidophosphine oxide 4ab (1.98 g, 5 mmol). Chromato-
graphic separation (hexane/ethyl acetate) gave 1.47 g (82%)
of compound 11ab as a white solid; mp 134–135 8C
(hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): d
1
3
acetate); H NMR (300 MHz, CDCl3): d 1.26 (m, JHH
7.3 Hz, 6H), 4.11 (m, 4H), 5.25 (dd, 2JPHZ21.5 Hz, 3JHH
9.5 Hz, 1H), 5.41 (m, 1H), 5.59 (m, 1H), 5.65 (dd, JPH
Z
Z
Z
5
4
2.65 (d, JPHZ1.9 Hz, 3H), 7.35–7.96 (m, 15H) ppm; 13C
3
2.4 Hz, JHHcisZ9.3 Hz), 6.27 (m, 2H), 7.28 (s, 1H) ppm;
NMR (75 MHz, CDCl3): d 11.9, 126.5–133.8 (m), 159.0 (d,
13C NMR (75 MHz, CDCl3): d 16.2 (d, 3JPCZ5.5 Hz), 16.3
2JPCZ27.0 Hz), 160.7 (d, JPCZ18.29 Hz) ppm; 31P NMR
3
(d, 3JPCZ3.5 Hz), 51.9 (d, 1JPCZ159.1 Hz), 63.5 (d, 2JPC
Z
(120 MHz, CDCl3): d 18.9 ppm; IR (KBr) nmax 3070, 1780,
1585, 1442, 1187 cmK1; MS (EI): m/z 359 (MC, 56). Anal.
Calcd for C22H18NO2P: C, 73.53; H, 5.05; N, 3.90. Found:
C, 73.43; H, 5.06; N, 3.91.
2
3
7.0 Hz), 63.7 (d, JPCZ7.0 Hz), 117.4 (d, JPCZ8.6 Hz),
127.8, 129.9, 135.2, 165.0 (d, 3JPCZ8.1 Hz) ppm; 31P NMR
(120 MHz, CDCl3): d 18.3 ppm; IR (NaCl) nmax 3257, 1679,
1533, 1241, 1029 cmK1; MS (EI): m/z 281 (MC, 70). Anal.
Calcd for C10H17ClNO4P: C, 42.64; H, 6.08; N, 4.97.
Found: C, 42.50; H, 6.10; N, 4.95.
4.5.3. 2-(Hex-5-enyl)-5-methyl-oxazol-4-yl diphenylphos-
phine oxide (11ac). The general procedure was followed
using a-amidophosphine oxide 4ac (2.01 g, 5 mmol).
Chromatographic separation (hexane/ethyl acetate) gave
1.30 g (71%) of compound 11ac as a white solid; mp 77–
78 8C (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3):
4.4.3. Diethyl (1-acetylamino-2-chloro-but-2-enyl)-phos-
phonate (8ba). The general procedure was followed 2H-
azirine-phosphonate 6b (1.03 g, 5 mmol) and acetyl chloride
2a (0.38 mL, 5 mmol). Chromatographic purification and
crystallization from hexane/ethyl acetate gave 1.23 g (87%)
of compound 8ba as an oil; Rf 0.45 (ethyl acetate); 1H NMR
(300 MHz, CDCl3): d 1.26 (m, 6H), 1.72 (dd, 5JPHZ6.7 Hz,
3JHHZ4.4 Hz, 3H), 2.01 (s, 3H), 4.09 (m, 4H), 5.17 (dd,
2JPHZ21.7 Hz, 3JHHZ9.5 Hz, 1H), 5.97 (m, 4JPHZ6.7 Hz,
3
3
d 1.44 (tt, JHHZ7.5 Hz, JHHZ7.5 Hz, 2H), 1.75 (tt,
3
3
3JHHZ7.5 Hz, JHHZ7.5 Hz, 2H), 2.12 (dt, JHHZ7.5 Hz,
3JHHZ7.5 Hz, 2H), 2.58 (d, JPHZ2.1 Hz, 3H), 2.73 (t,
4
3JHHZ7.5 Hz, 2H), 4.98 (m, 2H), 5.78 (m, 1H), 7.41–7.89
(m, 10H) ppm; 13C NMR (75 MHz, CDCl3): d 11.6, 26.3,
1
27.7, 28.2, 29.6, 114.7, 126.0 (d, JPCZ145.0 Hz), 128.2–
3
3JHHZ3.5 Hz, 1H), 6.94 (d, JHHZ9.0 Hz, 1H) ppm; 13C
133.9 (m), 138.3, 158.6 (d, 2JPCZ26.7 Hz), 163.8 (d, 3JPC
Z
3
NMR (75 MHz, CDCl3): d 14.1, 16.3 (d, JPCZ5.0 Hz),
17.6 Hz) ppm; 31P NMR (120 MHz, CDCl3): d 18.3 ppm;
IR (KBr) nmax 3070, 1686, 1600, 1434, 1195 cmK1; MS
(EI): m/z 365 (MC, 100). Anal. Calcd for C22H24NO2P: C,
72.31; H, 6.62; N, 3.83. Found: C, 72.41; H, 6.60; N, 3.83.
1
2
23.0, 52.3 (d, JPCZ160.6 Hz), 63.3 (d, JPCZ7.0 Hz),
126.7 (d, 3JPCZ10.1 Hz), 128.2 (d, 2JPCZ1.5 Hz), 169.3 (d,
3JPCZ7.5 Hz) ppm; 31P NMR (120 MHz, CDCl3): d
19.8 ppm; IR (NaCl) nmax 3482, 2979, 1712, 1454, 1261,
1016 cmK1; MS (CI): m/z 284 (MCC1, 40). Anal. Calcd for
C10H19ClNO4P: C, 42.34; H, 6.75; N, 4.94. Found: C,
42.48; H, 6.77; N, 4.93.
4.5.4. 5-Methyl-2-vinyl-oxazol-4-yl diphenylphosphine
oxide (11ad). The general procedure was followed using
a-amidophosphine oxide 4ad (1.91 g, 5 mmol). Chromato-
graphic separation (hexane/ethyl acetate) gave 0.80 g (52%)
of compound 11ad as a white solid; mp 100–101 8C
(hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): d
4.5. General procedure for the preparation of
4-oxazolyl-phosphine oxides 11 and -phosphonates 12
4
2
2.61 (d, JPHZ2.1 Hz, 3H), 5.58 (dd, JHHgemZ0.9 Hz,
2
To a solution of the corresponding vinylogous amide 4
(5 mmol) in dichloromethane (20 mL) a 2 N aqueous NaOH
solution (0.95 mL, 25 mmol) was added and the hetero-
geneous mixture was stirred at room temperature for 2 days.
The crude was extracted with dichloromethane and the
organic layer was dried with anhidrous magnesium sulfate.
Evaporation of solvent under reduced pressure afforded a
mixture that was chromatographied on silica gel to give
compounds 11 and 12.
3JHHcisZ11.1 Hz, 1H), 6.10 (dd, JHHgemZ0.9 Hz,
3JHHtransZ17.7 Hz, 1H), 6.50 (dd, JHHcisZ11.1 Hz,
3
3JHHtransZ17.7 Hz, 1H), 7.38–7.86 (m, 10H) ppm; 13C
NMR (75 MHz, CDCl3): d 11,7, 122.4, 123.0, 126.4 (d,
1JPCZ145.0 Hz), 128.3–133.4 (m), 158.9 (d, JPC
Z
2
26.7 Hz), 159.9 (d, JPCZ18.2 Hz) ppm; 31P NMR
(120 MHz, CDCl3): d 18.9 ppm; IR (KBr) nmax 3065,
1750, 1600, 1180 cmK1; MS (EI): m/z 310(MCC1, 26).
Anal. Calcd for C18H16NO2P: C, 69.90; H, 5.21; N, 4.53.
Found: C, 69.75; H, 5.19; N, 4.55.
3
4.5.1. 2,5-Dimethyl-oxazol-4-yl diphenylphosphine oxide
(11aa). The general procedure was followed using a-
amidophosphine oxide 4aa (1.67 g, 5 mmol). Chromato-
graphic separation (hexane/ethyl acetate) gave 1.29 g (87%)
of compound 11aa as a white solid; mp 117–118 8C
(hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): d
4.5.5. 5-Ethyl-2-methyl- oxazol-4-yl diphenylphosphine
oxide (11ba). The general procedure was followed using
a-amidophosphine oxide 4ba (1.73 g, 5 mmol). Chromato-
graphic separation (hexane/ethyl acetate) gave 1.04 g (67%)
of compound 11ba as a white solid; mp 78–79 8C (hexane/
ethyl acetate); 1H NMR (300 MHz, CDCl3): d 1.23 (t,
4
2.42 (s, 3H), 2.59 (d, JPHZ1.8 Hz, 3H), 7.41–7.88 (m,
10H) ppm; 13C NMR (75 MHz, CDCl3): d 11.6, 13.8, 126.5
3JHHZ7.5 Hz, 3H), 2.43 (s, 3H), 3.04 (q, JPHZ1.2 Hz,
4
1
2
(d, JPCZ145.0 Hz), 128.3–133.8 (m), 158.9 (d, JPC
Z
3JHHZ7.5 Hz, 2H), 7.41–7.87 (m, 10H) ppm; 13C NMR
26.1 Hz), 160.4 (d, JPCZ19.2 Hz) ppm; 31P NMR
(120 MHz, CDCl3): d 18.8 ppm; IR (KBr) nmax 3070,
1590, 1447, 1195 cmK1; MS (EI): m/z 297 (MC, 89). Anal.
Calcd for C17H16NO2P: C, 68.68; H, 5.42; N, 4.71. Found:
C, 68.88; H, 5.40; N, 4.69.
Z
3
1
(75 MHz, CDCl3): d 12.8, 13.8, 19.2, 125.4 (d, JPC
3
142.5 Hz), 128.2–133.8 (m), 160.4 (d, JPCZ18.1 Hz);
2
163.7 (d, JPCZ27.2 Hz) ppm; 31P NMR (120 MHz,
CDCl3): d 19.0 ppm; IR (KBr) nmax 3059, 1586, 1440,
1196 cmK1; MS (EI): m/z 311 (MC, 100). Anal. Calcd for

8944
F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
C18H18NO2P: C, 69.45; H, 5.83; N, 4.50. Found: C, 69.48;
H, 5.84; N, 4.48.
4JPCZ7.0 Hz), 20.0, 61.5, 129.8 (d, 1JPCZ221.1 Hz), 160.4
2 3
(d, JPCZ33.2 Hz), 161.7 (d, JPCZ19.1 Hz) ppm; 31P
NMR (120 MHz, CD3OD): d 5.0 ppm; IR (NaCl) nmax
2985, 2925, 1666, 1586, 1434, 1049 cmK1; MS (EI): m/z
247 (MC, 34). Anal. Calcd for C10H18NO4P: C, 48.58; H,
7.34; N, 5.67. Found: C, 48.71; H, 7.32; N, 5.69.
4.5.6. 2-Methyl-5-phenyl-oxazol-4-yl diphenylphosphine
oxide (11ca). The compound 11ca was obtained directly
when 2H-azirine-2-diphenylphosphine oxide 1c (1.58 g,
5 mmol) was added to a solution of acetyl chloride 2a
(0.38 mL, 5 mmol) in benzene (10 mL) saturated of
hydrogen chloride and the mixture was stirred at room
temperature for 24 h. Chromatographic separation (hexane/
ethyl acetate) gave 1.04 g (58%)of compound 11ca as a
white solid; mp 134–135 8C (hexane/ethyl acetate); 1H
4.5.10. Diethyl (2-methyl-5-phenyl-oxazol-4-yl)-phos-
phonate (12ca). The compound 12ca was obtained directly
when 2H-azirinephosphonate 6c (1.27 g, 5 mmol) was
added to a solution of acetyl chloride 2a (0.38 mL,
5 mmol) in benzene (10 mL) and the mixture was stirred
at room temperature for 24 h. Chromatographic separation
(hexane/ethyl acetate) gave 1.36 g (92%) of compound 12ca
as a colorless oil; Rf 0.51 (ethyl acetate); 1H NMR
3
NMR (300 MHz, CDCl3): d 2.51 (t, JHHZ7.5 Hz, 3H),
7.32–8.09 (m, 10H) ppm; 13C NMR (75 MHz, CDCl3): d
2
14.1, 128.3–132.2 (m), 159.0 (d, JPCZ25.2 Hz), 160.5 (d,
3JPCZ20.0 Hz) ppm; 31P NMR (120 MHz, CDCl3): d
(300 MHz, CDCl3): d 1.31 (t, JHHZ7.1 Hz, 6H), 2.55 (d,
3
19.6 ppm; IR (KBr) nmax 3051, 1580, 1481, 1202 cmK1
;
5JPHZ0.5 Hz, 3H), 4.18 (m, 4H), 7.43 (m, 3H), 8.0 (m,
2H) ppm; 13C NMR (75 MHz, CDCl3): d 13.4, 15.9 (d,
MS (CI): m/z 360 (MCC1, 100). Anal. Calcd for
C22H18NO2P: C, 73.53; H, 5.05; N, 3.90. Found: C, 73.68;
H, 5.04; N, 3.91.
2
1
4JPCZ6.6 Hz), 62.4 (d, JPCZ5.5 Hz), 123.9 (d, JPC
Z
2
226.8 Hz), 126.0–129.5 (m), 157.1 (d, JPCZ37.8 Hz),
160.4 (d, JPCZ22.7 Hz) ppm; 31P NMR (120 MHz,
3
CDCl3): d 10.0 ppm; IR (NaCl) nmax 3065, 2979, 1580,
1487, 1023 cmK1; MS (EI): m/z 295 (MC, 24). Anal. Calcd
for C14H18NO4P: C, 56.95; H, 6.14; N, 4.74. Found: C,
57.10; H, 6.16; N, 4.73.
4.5.7. Diethyl 2,5-(dimethyl-oxazol-4-yl) phosphonate
(12aa). The general procedure was followed using diethyl
a-amidophosphonate 8aa (1.35 g, 5 mmol). Chromato-
graphic separation (hexane/ethyl acetate) gave 0.69 g
(59%) of compound 12aa as a colorless oil; Rf 0.34 (ethyl
1
3
acetate); H NMR (300 MHz, CDCl3): d 1.35 (t, JHH
7.1 Hz, 6H), 2.44 (s, 3H), 2.54 (d, 4JPHZ2.4 Hz, 3H), 4.16
(m, 4H) ppm; 13C NMR (75 MHz, CDCl3): d 11.5, 16.4 (d,
Z
4.6. General procedure for the preparation of N-
vinylamides 13
2
1
3JPCZ6.6 Hz), 62.5 (d, JPCZ5.5 Hz), 127.0 (d, JPC
Z
Z
A solution of the corresponding N-acylaziridine-phosphine
oxide 3 (5 mmol) and tributylamine (1.15 mL, 5 mmol) in
chlorobenzene (10 mL) was refluxing in an atmosphere of
nitrogen until TLC indicated the disappearance of N-acyl-
aziridine. The crude was washed with HCl 2 N watery
solution. The organic layer was dried with anhidrous
magnesium sulfate. Evaporation of solvent under reduced
pressure afforded a mixture that was chromatographied on
silica gel to give compounds 13.
2
3
243.7 Hz), 158.5 (d, JPCZ39.8 Hz), 160.9 (d, JPC
22.2 Hz) ppm; 31P NMR (120 MHz, CDCl3): d 10.0 ppm;
IR (NaCl) nmax 2985, 1730, 1600, 1440, 1029 cmK1; MS
(EI): m/z 233 (MC, 28). Anal. Calcd for C9H16NO4P: C,
46.35; H, 6.92; N, 6.01. Found: C, 46.50; H, 6.94; N, 5.99.
4.5.8. Diethyl (5-methyl-2-vinyl-oxazol-4-yl)-phospho-
nate (12ad). The general procedure was followed using
diethyl a-amidophosphonate 8ad, (1.40 g, 5 mmol). Chro-
matographic separation (hexane/ethyl acetate) gave 0.77 g
(63%) of compound 12ad as a colorless oil; Rf 0.51 (ethyl
4.6.1. cis-N-[2-Chloro-1-methyl-2-(diphenylphosphinyl)-
vinyl)-acetamide (13aa). The general procedure was
followed using N-acylaziridinephosphine oxide 3aa
(1.67 g, 5 mmol). Chromatographic separation (hexane/
ethyl acetate) gave 0.68 g (41%) of compound 13aa as a
white solid; mp 130–131 8C (hexane/ethyl acetate); 1H
1
3
acetate); H NMR (300 MHz, CDCl3): d 1.28 (t, JHH
6.4 Hz, 6H), 2.53 (d, 4JPHZ2.3 Hz, 3H), 4.10 (m, 4H), 5.59
Z
3
2
(d, JHHcisZ11.1 Hz, 1H), 6.04 (t, JHHgemZ0.8 Hz,
3JHHtransZ17.6 Hz, 1H), 6.50 (dd, JHHcisZ11.3 Hz,
3
4
3JHHtransZ17.7 Hz, 1H) ppm; 13C NMR (75 MHz,
NMR (300 MHz, CDCl3): d 2.12 (d, JPHZ2.4 Hz, 3H),
3
2
6
CDCl3): d 11.5, 16.3 (d, JPCZ6.6 Hz), 62.6 (d, JPC
Z
2.63 (d, JPHZ0.9 Hz, 3H), 7.49–7.85 (m, 10H), 11.64 (s,
2
3
5.5 Hz), 122.6, 122.9, 158.5 (d, JPCZ39.8 Hz), 160.2 (d,
1H) ppm; 13C NMR (75 MHz, CDCl3): d 18.5 (d, JPC
Z
3JPCZ22.2 Hz) ppm; 31P NMR (120 MHz, CDCl3): d
6.0 Hz), 25.3, 100.4 (d, 1JPCZ114.0 Hz), 125.0–132.9 (m),
9.6 ppm; IR (NaCl) nmax 2979, 1739, 1593, 1023 cmK1
;
155.0 (d, JPCZ7.5 Hz), 168.7 ppm; 31P NMR (120 MHz,
2
MS (EI): m/z 245 (MC, 42). Anal. Calcd for C10H16NO4P:
C, 48.98; H, 6.58; N, 5.71. Found: C, 49.10; H, 6.56; N,
5.72.
CDCl3): d 35.6 ppm; IR (KBr) nmax 3158, 3065, 1706, 1630,
1328, 1175 cmK1; MS (EI): m/z 335 (MCC2, 10), 333
(MC, 30). Anal. Calcd for C17H17ClNO2P: C, 61.18; H,
5.13; N, 4.20. Found: C, 61.39; H, 5.10; N, 4.25.
4.5.9. Diethyl (5-ethyl-2-methyl-oxazol-4-yl)-phospho-
nate (12ba). The general procedure was followed diethyl
a-amidophosphonate 8ba, (1.41 g, 5 mmol). Chromato-
graphic separation (hexane/ethyl acetate) gave 0.76 g
(65%) of compound 12ba as a colorless oil; Rf 0.44 (ethyl
4.6.2. cis-N-[2-Chloro-1-methyl-2-(diphenylphosphinyl)-
vinyl]-benzamide (13ab). The general procedure was
followed using N-acylaziridinephosphine oxide 3ab
(1.98 g, 5 mmol). Chromatographic separation (hexane/
ethyl acetate) gave 1.19 g (60%) of compound 13ab as a
white solid; mp 136–137 8C (hexane/ethyl acetate); 1H
1
3
acetate); H NMR (300 MHz, CD3OD): d 1.08 (m, JHH
Z
4
7.0 Hz, 9H) Hz, 2.24 (s, 3H), 2.78 (dq, JPHZ1.5 Hz,
3
4
3JHHZ7.5 Hz, 2H), 3.71 (m, JHHZ7.8 Hz, 4H) ppm; 13C
NMR (300 MHz, CDCl3): d 2.27 (d, JPHZ1.5 Hz, 3H),
NMR (75 MHz, CD3OD): d 13.3 (d, 3JPCZ4.1 Hz), 17.0 (d,
7.38–8.04 (m, 15H), 12.53 (s, 1H) ppm; 13C NMR (75 MHz,

F. Palacios et al. / Tetrahedron 60 (2004) 8937–8947
8945
3
1
1
2
CDCl3): d 19.0 (d, JPCZ6.5 Hz), 101.1 (d, JPC
Z
(d, JPCZ134.4 Hz), 149.5 (d, JPCZ18.1 Hz), 164.9 (d,
3JPCZ10.1 Hz) ppm; 31P NMR (120 MHz, CDCl3): d
16.6 ppm; IR (KBr) nmax 3065, 1593, 1441, 1315,
1202 cmK1; MS (EI): m/z 297 (MC, 100). Anal. Calcd for
C17H16NO2P: C, 68.68; H, 5.42; N, 4.71. Found: C, 68.88;
H, 5.40; N, 4.73.
2
115.0 Hz), 127.0–134.1 (m), 155.0 (d, JPCZ7.5 Hz),
165.1 ppm; 31P NMR (120 MHz, CDCl3): d 35.8 ppm; IR
(KBr) nmax 3120, 1689, 1310, 1154 cmK1; MS (EI): m/z 397
(MCC2, 7), 395 (MC, 17). Anal. Calcd for C22H19ClNO2P:
C, 66.76; H, 4.84; N, 3.54. Found: C, 66.80; H, 4.85; N,
3.50.
4.7.2. 4-Methyl-2-phenyl-oxazol-5-yl diphenylphosphine
oxide (16ab). The general procedure was followed using
N-vinylamide 13ab (1.98 g, 5 mmol). Chromatographic
separation (hexane/ethyl acetate) gave 1.29 g (72%) of
compound 16ab as a white solid; mp 158–159 8C (hexane/
ethyl acetate); 1H NMR (300 MHz, CDCl3): d 2.44 (d,
4.6.3. cis-N-[2-Chloro-1-methyl-2-(diphenylphosphinyl)-
vinyl]-acrylamide (13ad). The general procedure was
followed using N-acylaziridinephosphine oxide 3ad
(1.75 g, 5 mmol). Chromatographic separation (hexane/
ethyl acetate) gave 0.26 g (15%) of compound 13ad as a
1
4JPHZ1.8 Hz, 3H), 7.48–8.04 (m, 15H) ppm; 13C NMR
white solid; mp 97–98 8C (hexane/ethyl acetate); H NMR
4
1
(75 MHz, CDCl3): d 12.9, 126.5–132.5, 138.1 (d, JPC
(300 MHz, CDCl3): d 2.69 (d, JPHZ1.8 Hz, 3H), 5.75
Z
Z
3
2
2
3
(dd, JHHcisZ10.2 Hz, JHHgemZ1.2 Hz, 1H), 6.20 (dd,
133.0 Hz), 150.7 (d, JPCZ18.0 Hz), 164.2 (d, JPC
3JHHcisZ10.2 Hz, JHHtransZ17.1 Hz, 1H), 6.39 (dd,
3
10.1 Hz) ppm; 31P NMR (120 MHz, CDCl3): d 16.6 ppm;
IR (KBr) nmax 3070, 3020, 1699, 1205 cmK1; MS (EI): m/z
359 (MC, 60). Anal. Calcd for C22H18NO2P: C, 73.53; H,
5.05; N, 3.90. Found: C, 73.36; H, 5.03; N, 3.91.
3JHHtransZ17.1 Hz, JHHgemZ1.2 Hz, 1H), 7.49–7.83 (m,
2
10H), 11.96 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3): d
3
1
18.6 (d, JPCZ6.0 Hz), 101.1 (d, JPCZ114.0 Hz), 127.8,
128.5–132.7 (m), 155.0 (d, JPCZ8.0 Hz), 163.6 ppm; 31P
2
NMR (120 MHz, CDCl3): d 35.6 ppm; IR (KBr) nmax 3140,
1700, 1515, 1333, 1192 cmK1; MS (EI): m/z 347 (MCC2,
17), 345 (MC, 54). Anal. Calcd for C18H17ClNO2P: C,
62.53; H, 4.96; N, 4.05. Found: C, 62.36; H, 5.00; N, 4.06.
4.7.3. 4-Ethyl-2-methyl-oxazol-5-yl diphenylphosphine
oxide (16ba). The general procedure was followed using
N-vinylamide 13ba. Chromatographic separation (hexane/
ethyl acetate) gave 0.89 g (57%) of compound 16ba as a
1
white solid; mp 75–76 8C (hexane/ethyl acetate); H NMR
3
4.6.4. cis-N-[2-Chloro-2-(diphenylphosphinyl)-1-ethyl-
vinyl)-acetamide (13ba). The general procedure was
followed using N-acylaziridinephosphine oxide 3ba
(1.73 g, 5 mmol). Chromatographic separation (hexane/
ethyl acetate) gave 0.94 g (54%) of compound 13ba as a
(300 MHz, CDCl3): d 1.09 (t, JHHZ7.5 Hz, 3H), 2.39 (d,
3
5JPHZ0.8 Hz, 3H), 2.55 (q, JHHZ7.6 Hz, 2H), 7.40–7.70
(m, 10H) ppm; 13C NMR (75 MHz, CDCl3): d 13.4, 14.1,
1
19.9, 128.5–132.4, 137.2 (d, JPCZ134.5 Hz), 155.0 (d,
3
2JPCZ18.1 Hz), 165.1 (d, JPCZ10.6 Hz) ppm; 31P NMR
1
white solid; mp 73–74 8C (hexane/ethyl acetate); H NMR
(120 MHz, CDCl3): d 16.3 ppm; IR (KBr) nmax 3058, 1719,
1585, 1427, 1202 cmK1; MS (EI): m/z 311 (MC, 100). Anal.
Calcd for C18H18NO2P: C, 69.45; H, 5.83; N, 4.50. Found:
C, 69.57; H, 5.84; N, 4.51.
(300 MHz, CDCl3): d 0.72 (m, 3H), 1.97 (s, 3H), 3.02 (q,
3JHHZ7.32 Hz, 2H), 7.33–7.65 (m, 10H), 11.42 (s,
1H) ppm; 13C NMR (75 MHz, CDCl3): d 11.8, 24.1 (d,
1
3JPCZ5.5 Hz), 25.4, 100.2 (d, JPCZ113.8 Hz), 128.2–
2
132.9 (m), 160.4 (d, JPCZ6.6 Hz), 168.1 ppm; 31P NMR
(120 MHz, CDCl3): d 35.7 ppm; IR (KBr) nmax 3124, 3032,
1706, 1606, 1374, 1248 cmK1; MS (CI): m/z 348 (MCC1,
53). Anal. Calcd for C18H19ClNO2P: C, 62.16; H, 5.51; N,
4.03. Found: C, 62.30; H, 5.52; N, 4.04.
Acknowledgements
´
The authors thank the Direccion General de Investigacion
del Ministerio de Ciencia y Tecnologıa (MCYT, Madrid
´
´
´
DGI, PPQ2003-00910) and the Universidad del Paıs Vasco
(UPV, GC/ 2002) for supporting this work. J. M. Alonso
4.7. General procedure for the preparation of
5-oxazolyl-phosphine oxides 16
´
thanks the Ministerio de Educacion y Cultura (Madrid) for a
predoctoral fellowship and J. I. Gil thanks the Direccion
´
A solution of the corresponding N-vinylamide 13 (5 mmol)
in THF (20 mL) was added to a 0 8C suspension of NaH
(0.24 g, 6 mmol) in THF (15 mL). The mixture was refluxed
in nitrogen atmosphere until TLC indicated the disappear-
ance of N-vinylamide. Ice was added and the mixture was
extracted with dichlorometane. The organic layer was dried
with anhidrous magnesium sulfate. Evaporation of solvent
under reduced pressure afforded a mixture that was
chromatographied on silica gel to give compounds 16.
´
General de Investigacion del Ministerio de Ciencia y
Tecnologıa (MCYT, Madrid) for postdoctoral support.
´
References and notes
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´
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4
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