A new approach to the synthesis of 3-substituted 4-(diethoxyphosphoryl) isoxazoles from 3-azidoalka-l,3-dienylphosphonates

Article abstract of DOI:10.1055/s-0029-1216962

New 3-azidoalka-l,3-dienylphosphonates were synthesized by a convenient and efficient method. These compounds are useful as intermediates in the preparation of 3-(3-aryl-4,5-dihydroisoxazol-5-yl)- and 3-alkenyl-4- (diethoxyphosphoryl)isoxazoles.

Full text of DOI:10.1055/s-0029-1216962

PAPER
3405
A New Approach to the Synthesis of 3-Substituted 4-(Diethoxy-
phosphoryl)isoxazoles from 3-Azidoalka-1,3-dienylphosphonates
S
ynthesis of 3-Sub
a
stituted 4-(
l
D
ietho
e
xyphosphoryl)isoxa
y
zoles K. Brel*
Institute of Physiologically Active Compounds of Russian Academy of Sciences, Chernogolovka, Moscow region 142432,
Russian Federation
Fax +7(496)5249508; E-mail: brel@ipac.ac.ru
Received 11 March 2009; revised 22 May 2009
nates and the design of new phosphonoheterocycles, we
turned our attention towards development of synthesis 3-
substituted 4-(diethoxyphosphoryl)isoxazoles by using
phosphonoallenes as starting materials.
Abstract: New 3-azidoalka-1,3-dienylphosphonates were synthe-
sized by a convenient and efficient method. These compounds are
useful as intermediates in the preparation of 3-(3-aryl-4,5-di-
hydroisoxazol-5-yl)- and 3-alkenyl-4-(diethoxyphosphoryl)isox-
azoles.
General retrosynthetic analysis, illustrated for the synthe-
sis of target compounds 7 and 8, is given in Scheme 1. It
revealed that the 3,4-disubstituted isoxazoles might be
constructed by a simple and efficient three-step procedure
involving preparation of alkynols 1, their transformation
to 3-azidoalka-1,3-dienylphosphonates 5, synthesis of
4,5-dihydroisoxazolyl derivatives 6, and cyclization of 5
and 6 to give the final 3,4-disubstituted isoxazoles 7 and
8. The propargyl alcohols 1 were prepared in 80% yields
by a standard procedure, 11 starting from O-protected pro-
pargylic alcohol by using ethyl vinyl ether.12 Phosphory-
lated allenes 3 were synthesized directly from propargylic
alcohols 1 in ~70% yield by Horner–Mark [2,3]-sigmatro-
pic rearrangement of the unstable phosphates 213
(Scheme 2, Table 1). The treatment of compounds 3 with
a methanol solution in the presence of 4-toluenesulfonic
acid afforded unprotected allenic alcohols 4 in quantita-
tive yields.
Key words: allenes, azides, isoxazoles nitrile oxides, phosphorus
A 3,4-disubstituted isoxazole scaffold has frequently been
incorporated into the pharmacophore design for a wide
range of pharmaceutical agents.1 Some examples include
nonsteroidal anti-inflammatory drugs (NSAIDs),2 protein
kinase inhibitors,3 hypertensive agents.4 Isoxazole deriva-
tives form a part of many drugs used for antidepressant
therapy and the treatment osteoarthritis or rheumatoid ar-
thritis.5,6 The introduction of different functional groups
in the 3,4-positions of the isoxazole ring, makes it possi-
ble to expand the range reactions of 3,4-disubstituted
isoxazoles7,8 and to study their biological properties and,
in this context, the synthesis of 3-(3-aryl-4,5-dihydroisox-
azol-5-yl)- and 3-alkenyl-4-(diethoxyphosphoryl)isox-
azoles is of interest. However, this type of isoxazole has
not previously been described in the literature.
Table 1 Yields of Compounds 4–8
R
OH
(EtO)2(O)P
HO
4, 5, 7
R
Yield (%)
6, 8 Ar
Yield (%)
4
5
7
6
8
N3
ZO
Cl
a
b
c
H
5910
7510 70
a
b
c
Ph
63
79
82
85
80
79
84
79
84
Me 72
Pr 58
Bu 63
80
79
73
72
83
79
4-FC6H4
4-ClC6H4
4-MeC6H4
Ar
N
(EtO)2(O)P
R
O
R = -CH=CH-Alk,
d
d
e
N
O
4-MeOC6H4 80
Scheme 1
The reaction of phosphonates 4 with sodium azide at 40–
50 °C for two hours in N,N-dimethylformamide lead to the
formation of alka-1,3-dienes 5 with an E-double bond
configuration. Compounds 5 were isolated by flash chro-
matography on silica gel in 73–80% yields. Confirmation
of the E-structure of 3-azidoalka-1,3-dienes 5 was estab-
lished on the basis of their 1H and 13C NMR spectra. The
signals of H2 in 5 appears at the lowest field of the alka-
1,3-diene portion as a broad doublet at d = 6.61–6.92, cou-
pled to phosphorus (JH2,P = 1.8 Hz, only for 5a) as well as
H1trans (JH2,H1trans = 16.0–18.0 Hz). The signals of H1 in 5
As part of our research on the use of allenes as versatile
starting materials in organic synthesis9 we recently re-
ported their application to the synthesis of 2-(diethoxy-
phosphoryl)-3-(3-phenyl-4,5-dihydroisoxazol-5-yl)-2H-
azirines.10 In conjunction with our continuing study of the
chemical properties of polyfunctional alkadienylphospho-
SYNTHESIS 2009, No. 20, pp 3405–3410
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216962; Art ID: P03609SS
© Georg Thieme Verlag Stuttgart · New York

3406
V. K. Brel
PAPER
spection of the 1H NMR spectrum of the reaction mixture
showed the near quantitative conversion of azido alcohols
5 and 7 to the phosphonates 7 and 8. The 3,4-disubstituted
isoxazoles 7 and 8 are stable compounds and were isolat-
ed by column chromatography on silica gel, The structural
identity of isoxazole 7 and 8 was established by their 1H
and 13C NMR spectra.
OH
OP(OEt)2
Cl
b
a
ZO
ZO
Cl
R
1
2
R
R
H
2
R
Cl
(EtO)2(O)P
ZO
d
1
(EtO)2(O)P
C
3
H
In summary, we have described an easy and convenient
method for the preparation of new, synthetically valuable
3-(3-aryl-4,5-dihydroisoxazol-5-yl)- and 3-alkenyl-4-(di-
ethoxyphosphoryl)isoxazoles from 3-azidoalka-1,3-di-
enylphosphonates. Further studies on the reactivity of 3-
substituted 4-(diethoxyphosphoryl)isoxazoles and new
derivatives are currently in progress.
4
H
HO
N3
3 Z = CH(Me)OEt
4 Z = H
5
c
e
f
H
R
N
O
Ar
(EtO)2(O)P
H
(EtO)2(O)P
HO
N
O
N3
NMR spectra were recorded on a Bruker CXP-200 spectrometer at
200 MHz (1H NMR), 81.01 MHz (31P NMR) and 50.3 MHz (13C
NMR) (1H 13C NMR relative to TMS as internal standard, 31P down-
field shifts are expressed with a positive sign, relative to external
85% H3PO4 in H2O). Benzaldehyde oximes are commercially avail-
able. Details of the synthesis 5-chloro-2-(diethoxyphosphoryl)pen-
ta-2,3-dien-1-ol (4a), and 3-azido-2-(diethoxyphosphoryl)penta-
2,4-dien-1-ol (5a) have been described in previous papers.10
7
6
f
Ar
N
O
(EtO)2(O)P
N
O
5-Chloro-2-(diethoxyphosphoryl)hexa-2,3-dien-1-ol (4b)
Following the typical procedure for 4a10 using 1b (2.2 g, 0.01 mol),
anhyd Et2O (90 mL), Et3N (1.52 g, 0.015 mol), and diethyl chloro-
phosphite (1.56 g, 0.01 mol) followed by column chromatography
(CHCl3–MeOH, 20:1) gave 4b (1.93 g, 72%) as an oil; Rf = 0.3.
8
Scheme 2 Reagents and conditions: (a) (EtO)2PCl, Et3N, Et2O, –25
°C; (b) r.t., 24 h; (c) MeOH, PTSA; (d) NaN3, DMF, 40–50 °C, 2 h;
(e) ArCCl=NOH, Et3N, Et2O, –40 °C; (f) MnO2, CHCl3, r.t., 24–48 h.
1H NMR (200 MHz, CDCl3): d = 5.80 (ddt, JH,H = 7.0 Hz, JH,H = 2.0
Hz, JH,P = 12.0 Hz, 1 H, =CH), 4.67 (ddq, JH,H = 7.0 Hz, JH,H = 2.0
Hz, JH,P = 1.5 Hz, 1 H, CHCl), 4.35 (dd, JH,H = 2.0 Hz, JH,P = 13.0
Hz, 2 H, CH2OH), 4.27–4.10 (m, 4 H, 2 POCH2CH3), 2.89 (br s, 1
H, OH), 1.68 (d, JH,H = 7.0 Hz, 3 H, CH3), 1.38 (t, JH,H = 7.0 Hz, 6
H, 2 POCH2CH3).
13C NMR (CDCl3): d = 206.6 (d, JC,P = 5.0 Hz, =C=), 99.04 (d,
JC,P = 186.0 Hz, =CP), 99.0 (d, JC,P = 15.0 Hz, =C), 63.4 (d,
JC,P = 6.0 Hz, POCH2CH3), 63.2 (d, JC,P = 6.0 Hz, POCH2CH3),
61.33 (d, JC,P = 5.0 Hz, CH2OH), 53.52 (d, JC,P = 7.0 Hz, CHCl),
appear as doublet, doublet, doublet (for 5a), doublet of
quartets (for 5b) and doublet of triplets (for 5c and 5d) at
d = 5.69–6.22 coupled to phosphorus (JH2,P = 1.8 Hz, only
for 5a) as well as H2trans (JH2,H1trans = 16.0–18.0 Hz). The
13C NMR spectra and, particularly, the DEPT experiment
further corroborated the proposed structure. Carbon atom
C2 forms a split doublet, which is coupled to phosphorus
(JC2,P = 4.0 or 5 Hz). The JC2,P value of 4.0 or 5 Hz is in
agreement with the cis arrangement of the phosphonate 25.23 (d, JC,P = 1.0 Hz, CH3), 16.8 (d, JC,P = 5.0 Hz, POCH2CH3),
group and C2.14 The quaternary C4, which carries the
phosphonate moiety, has the largest coupling constant
(JC4,P = 183.1–185 Hz).
16.65 (d, JC,P = 5.0 Hz, POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 16.02.
Anal. Calcd for C10H18ClO4P (268.677): C, 44.70; H, 6.75; P, 11.53.
Found: C, 44.73; H, 6.73; P, 11.70.
The next stage of our research entailed the synthesis of
4,5-dihydroisoxazoles from 3-azido-2-(diethoxyphospho-
ryl)penta-1,3-dien-5-ol (5a). The [3+2] cycloaddition of
the nitrile oxides to 5a was performed in diethyl ether at
–40 °C. In the optimized procedure, a solution of trieth-
ylamine in diethyl ether was added dropwise over two
hours to the mixture of arylhydroximoyl chloride and di-
polarophile 5a. 1,3-Diene 5a reacted smoothly with nitrile
oxides leading to 4,5-dihydroisoxazoles 6a–e in yields of
ca. 70–85%. Only the terminal double bond of alka-1,3-
diene 5a reacts with arylnitrile oxides; the diethoxyphos-
phoryl-substituted double bond does not react with arylni-
trile oxides.
5-Chloro-2-(diethoxyphosphoryl)octa-2,3-dien-1-ol (4c)
Following the typical procedure for 4a10 using 1c (2.48 g, 0.01 mol),
anhyd Et2O (90 mL), Et3N (1.52 g, 0.015 mol), and diethyl chloro-
phosphite (1.56 g, 0.01 mol) followed by column chromatography
(CHCl3–MeOH, 10:1) gave 4c (1.73 g, 58%) as an oil: Rf = 0.62.
1H NMR (200 MHz, CDCl3): d = 5.74 (ddt, JH,H = 8.0 Hz, JH,H = 2.0
Hz, JH,P = 11.0 Hz, 1 H, =CH), 4.67 (dq, JH,H = 7.0 Hz, JH,H = 5.0
Hz, 1 H, CHCl), 4.30 (dd, JH,H = 2.0 Hz, JH,P = 12.0 Hz, 2 H,
CH2OH), 4.25–4.10 (m, 4 H, 2 POCH2CH3), 2.64 (br s, 1 H, OH),
1.90 (dt, JH,H = 7.0 Hz, JH,H = 7.3 Hz, 2 H, CH2), 1.50 (m, 2 H, CH2),
1.37 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3), 0.98 (t, JH,H = 6.8 Hz, 3
H, CH3).
13C NMR (CDCl3): d = 205.9 (d, JC,P = 5.0 Hz, =C=), 100.73 (d,
JC,P = 185.0 Hz, =CP), 99.0 (d, JC,P = 15.0 Hz, =C), 63.6 (d,
JC,P = 6.0 Hz, POCH2CH3), 63.4 (d, JC,P = 6.0 Hz, POCH2CH3),
The final step of the reaction of phosphonates 5 and 6 with
manganese dioxide at room temperature leads to forma-
tion of 3,4-disubstituted isoxazoles 7 and 8. The progress 61.42 (d, JC,P = 6.0 Hz, CH2OH), 53.32 (d, JC,P = 7.0 Hz, CHCl),
37.42 (d, JC,P = 1.5 Hz, CH2), 26.63 (d, JC,P = 1.0 Hz, CH2), 16.8 (d,
of condensation was monitored by TLC on silica gel. In-
Synthesis 2009, No. 20, 3405–3410 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 4-(Diethoxyphosphoryl)isoxazoles
3407
JC,P = 5.0 Hz, POCH2CH3), 16.65 (d, JC,P = 5.0 Hz, POCH2CH3),
Hz, CH2), 26.46 (s, CH2), 16.65 (d, JC,P = 6.0 Hz, 2 POCH2CH3),
9.35 (s, CH3).
14.24 (s, CH3),
31P NMR (81.01 MHz, CDCl3): d = 16.2.
31P NMR (81.01 MHz, CDCl3): d = 19.73.
Anal. Calcd for C12H22ClO4P (296.731): C, 48.57; H, 7.47; P, 10.44.
Found: C, 48.60; H, 7.48; P, 10.30.
3-Azido-2-(diethoxyphosphoryl)nona-2,4-diene-1-ol (5d)
Following the typical procedure for 5a10 using 4d (3.1 g, 0.01 mol),
NaN3 (1.63 g, 0.025 mol), and DMF (40 mL) followed by column
chromatography (CHCl3–MeOH, 20:1) gave 5d (2.31 g, 73%) as an
oil; Rf = 0.4.
1H NMR (200 MHz, CDCl3): d = 6.65 (ddt, JH,H = 16.0 Hz,
JH,H = 2.0 Hz, JH,H = 2.0 Hz, 1 H, =CH), 6.18 (dt, JH,H = 16.0 Hz,
JH,H = 7.0 Hz, 1 H, =CHCH2), 4.39 (br dd, JH,H = 3.5 Hz, JH,P = 16.0
Hz, 2 H, CH2OH), 4.17–4.02 (m, 4 H, 2 POCH2CH3), 3.34 (br t,
JH,H = 3.5 Hz, 1 H, OH), 2.25 (q, JH,H = 7.0 Hz, 2 H, CH2), 1.44 (m,
4 H, 2 CH2), 1.32 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3), 0.92 (t,
JH,H = 7.0 Hz, 3 H, CH3).
13C NMR (50.3 MHz, CDCl3): d = 148.70 (d, JC,P = 25.0
Hz, =CN3), 141.10 (d, JC,P = 2.0 Hz, =CH), 122.35 (d, JC,P = 4.0 Hz,
=CH), 116.20 (d, JC,P = 184.0 Hz, =CP), 62.35 (d, JC,P = 5.0 Hz, 2
POCH2CH3), 59.61 (d, JC,P = 7.0 Hz, CH2OH), 33.06 (s, CH2), 31.2
(s, CH2), 22.56 (s, CH2), 16.65 (d, JC,P = 6.0 Hz, 2 POCH2CH3),
14.24 (s, CH3),
5-Chloro-2-(diethoxyphosphoryl)nona-2,3-dien-1-ol (4d)
Following the typical procedure for 4a10 using 1d (2.62 g, 0.01
mol), anhyd Et2O (90 mL), Et3N (1.56 g, 0.01 mol), and diethyl
chlorophosphite (1.56 g, 0.01 mol) followed by column chromatog-
raphy (CHCl3–MeOH, 10:1) gave 4d (1.97 g, 63%) as an oil:
Rf = 0.5.
1H NMR (200 MHz, CDCl3): d = 5.70 (ddt, JH,H = 8.0 Hz, JH,H = 2.0
Hz, JH,P = 10.0 Hz, 1 H, =CH), 4.47 (dq, JH,H = 6.8 Hz, JH,H = 4.2
Hz, 1 H, CHCl), 4.32 (dd, JH,H = 2.0 Hz, JH,P = 13.0 Hz, 2 H,
CH2OH), 4.23–4.08 (m, 4 H, 2 POCH2CH3), 3.18 (br s, 1 H, OH),
1.88 (dt, JH,H = 6.8 Hz, JH,H = 7.3 Hz, 2 H, CH2), 1.46 (m, 4 H, 2
CH2), 1.35 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3), 0.93 (t, JH,H = 6.8
Hz, 3 H, CH3).
13C NMR (CDCl3): d = 205.0 (d, JC,P = 4.5 Hz, =C=), 100. 31 (d,
JC,P = 188.0 Hz, =CP), 99.8 (d, JC,P = 16.0 Hz, =C), 64.2 (d,
JC,P = 6.0 Hz, POCH2CH3), 63.4 (d, JC,P = 6.0 Hz, POCH2CH3),
61.02 (d, JC,P = 6.0 Hz, CH2OH), 51.25 (d, JC,P = 6.0 Hz, CHCl),
34.20 (d, JC,P = 1.5 Hz, CH2), 24.13 (d, JC,P = 1.0 Hz, CH2), 15.67
(s, CH2), 15.4 (d, JC,P = 5.0 Hz, POCH2CH3), 15.0 (d, JC,P = 5.0 Hz,
POCH2CH3), 7.32 (s, CH3).
31P NMR (81.01 MHz, CDCl3): d = 20.1.
5-[1-Azido-2-(diethoxyphosphoryl)-3-hydroxyprop-1-enyl)-3-
phenyl-4,5-dihydroisoxazole (6a); Typical Procedure
Alkadiene 5a (0.261 g, 0.001 mol) was dissolved in Et2O (10 mL).
PhCCl=NOH (0.233 g, 0.0015 mol) in Et2O (5 mL) was added at
–40 °C. Et3N (0.303 g, 0.003 mol) was added dropwise over 2 h.
Stirring was continued at –40 °C until the reaction was complete
(TLC, 2–3 h) and then at r.t. for 2 h. The reaction was quenched by
the addition of sat. NH4Cl (10 mL) The mixture was extracted with
Et2O, dried (Na2SO4), and the solvent was removed to give an oil
(0.4 g) that was purified by flash chromatography (CHCl3); yield:
0.238 g (63%); Rf = 0.73 (CHCl3–hexane, 50:1).
1H NMR (200 MHz, CDCl3): d = 7.68 (m, 2 H, HPh), 7.42 (m, 3 H,
HPh), 6.33 (ddd, JH,H = 11.2 Hz, JH,H = 7.8 Hz, JH,P = 2.0 Hz, 1 H,
OCH), 4.33 (d, JH,H = 15.0 Hz, 2 H, CH2OH), 4.15 (dq, JH,H = 7.2
Hz, JH,P = 7.2 Hz, 4 H, 2 POCH2CH3), 3.66 (AB, JH,H = 11.2 Hz,
JH,P = 17.0 Hz, 1 H, CHH), 3.37 (AB, JH,H = 7.8 Hz, JH,P = 17.0 Hz,
1 H, CHH), 1.38 (t, JH,H = 7.2 Hz, 6 H, 2 POCH2CH3),
31P NMR (81.01 MHz, CDCl3): d = 16.3.
Anal. Calcd for C13H24ClO4P (310.758): C, 50.25; H, 7.78; P, 9.97.
Found: C, 50.51; H, 7.80; P, 9.80.
3-Azido-2-(diethoxyphosphoryl)hexa-2,4-diene-1-ol (5b)
Following the typical procedure for 5a10 with 4b (2.68 g, 0.01 mol),
NaN3 (1.63 g, 0.025 mol), and DMF (40 mL) followed by column
chromatography (CHCl3–MeOH, 20:1) gave 5b (2.2 g, 80%) as an
oil; Rf = 0.48.
1H NMR (200 MHz, CDCl3): d = 6.61 (dm, JH,H = 16.0 Hz, 1
H, =CH), 6.22 (dq, JH,H = 16.0 Hz, JH,H = 6.8 Hz, 1 H, =CHCH3),
4.40 (dd, JH,H = 6.0 Hz, JH,P = 17.0 Hz, 2 H, CH2OH), 4.14–4.05 (m,
4 H, 2 POCH2CH3), 3.19 (br s, 1 H, OH), 1.94 (d, JH,P = 6.8 Hz, 3
H, CH3), 1.33 (t, JH,H = 7.2 Hz, 6 H, 2 POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 148.72 (d, JC,P = 25.0
Hz, =CN3), 135.86 (d, JC,P = 1.5 Hz, =CH), 123.8 (d, JC,P = 4.0 Hz,
=CH), 116.01 (d, JC,P = 183.6 Hz, =CP), 62.38 (d, JC,P = 6.0 Hz, 2
POCH2CH3), 59.55 (d, JC,P = 6.0 Hz, CH2OH), 19.04 (s, CH3),
16.68 (d, JC,P = 6.0 Hz, 2 POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 156.17 (s, N=CPh), 156.07 (d,
JC,P = 18.1 Hz, =CN3), 130.84 (s, CPh), 129.22 (s, CPh), 129.17 (s,
CPh), 127.31 (s, CPh), 102.30 (d, JC,P = 198.2 Hz, =CP), 76.79 (d,
JC,P = 3.0 Hz, CH–O), 62.41 (d, JC,P = 6.0 Hz, POCH2CH3), 62.08
(d, JC,P = 6.0 Hz, POCH2CH3), 58.5 (d, JC,P = 5.5 Hz, CH2OH),
39.43 (s, CH2), 16.8 (d, JC,P = 6.0 Hz, 2 POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 19.82.
31P NMR (81.01 MHz, CDCl3): d = 19.48.
3-Azido-2-(diethoxyphosphoryl)octa-2,4-diene-1-ol (5c)
Following the typical procedure for 5a10 using 4c (2.96 g, 0.01 mol)
and NaN3 (1.63 g, 0.025 mol) followed by column chromatography
(CHCl3–MeOH, 20:1) gave 5c (2.4 g, 79%) as an oil; Rf = 0.45.
1H NMR (200 MHz, CDCl3): d = 6.69 (ddt, JH,H = 16.0 Hz,
JH,H = 2.0 Hz, JH,H = 2.0 Hz, 1 H, =CH), 6.22 (dt, JH,H = 16.0 Hz,
JH,H = 7.0 Hz, 1 H, =CHCH2), 4.42 (br dd, JH,H = 3.0 Hz, JH,P = 16.0
Hz, 2 H, CH2OH), 4.12–4.04 (m, 4 H, 2 POCH2CH3), 3.12 (br t,
JH,H = 3.0 Hz, 1 H, OH), 2.45 (q, JH,H = 7.0 Hz, 2 H, CH2), 2.11 (m,
2 H, CH2), 1.33 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3), 0.97 (t,
JH,H = 7.0 Hz, 3 H, CH3).
5-[1-Azido-2-(diethoxyphosphoryl)-3-hydroxyprop-1-enyl]-3-
(4-fluorophenyl)-4,5-dihydroisoxazole (6b)
Following the typical procedure for 6a with 5a (0.261 g, 0.001 mol),
4-FC6H4CCl=NOH (0.259 g, 0.0015 mol), and Et3N (0.303 g, 0.003
mol) followed by column chromatography (CHCl3–MeOH, 10:1)
gave 6b (0.314 g, 79%) as an oil; Rf = 0.61.
1H NMR (200 MHz, CDCl3): d = 7.83–7.76 (m, 2 H, Harom), 7.19–
7.10 (m, 2 H, Harom), 6.35 (dt, JH,P = 11.0 Hz, JH,H = 1.0 Hz, 1 H,
OCH), 4.38 (d, JH,P = 15.6 Hz, 2 H, CH2OH), 4.25–4.10 (m, 4 H, 2
POCH2CH3), 3.84 (AB, JH,H = 11.0 Hz, JH,P = 17.0 Hz, 1 H, CHH),
3.45 (AB, JH,H = 8.0 Hz, JH,P = 17.0 Hz, 1 H, CHH), 2.84 (br s, 1 H,
OH), 1.4 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3),
13C NMR (50.3 MHz, CDCl3): d = 163.77 (d, JC,F = 210.0 Hz,
Carom), 156.80 (s, N=CAr), 148.87 (d, JC,P = 25.0 Hz, =CN3), 128.75
(d, JC,F = 7.0 Hz, Carom), 125.12 (d, JC,F = 3.0 Hz, Carom), 115.95 (d,
13C NMR (50.3 MHz, CDCl3): d = 148.64 (d, JC,P = 25.0
Hz, =CN3), 141.00 (d, JC,P = 2.0 Hz, =CH), 124.15 (d, JC,P = 4.0 Hz,
=CH), 116.78 (d, JC,P = 185.0 Hz, =CP), 62.42 (d, JC,P = 6.0 Hz, 2
POCH2CH3), 59.31 (d, JC,P = 7.0 Hz, CH2OH), 35.06 (d, JC,P = 1.0
Synthesis 2009, No. 20, 3405–3410 © Thieme Stuttgart · New York

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V. K. Brel
PAPER
JC,F = 17.0 Hz, Carom), 118.10 (d, JC,P = 185.2 Hz, =CP), 79.18 (d,
JC,P = 5.0 Hz, CH–O), 62.71 (d, JC,P = 6.0 Hz, POCH2CH3), 62.50
(d, JC,P = 5.0 Hz, POCH2CH3), 59.03 (d, JC,P = 5.5 Hz, CH2OH),
40.53 (s, CH2), 16.50 (d, JC,P = 6.0 Hz, POCH2CH3), 16.42 (d,
JC,P = 7.0 Hz, POCH2CH3).
C
arom), 127.00 (s, Carom), 117.45 (d, JC,P = 187.0 Hz, =CP), 79.74 (d,
JC,P = 5.0 Hz, CH–O), 62.63 (d, JC,P = 6.0 Hz, POCH2CH3), 62.10
(d, JC,P = 5.0 Hz, POCH2CH3), 58.34 (d, JC,P = 6.0 Hz, CH2OH),
55.3 (s, OCH3), 45.53 (s, CH2), 16.42 (d, JC,P = 7.0 Hz, 2
POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 19.62.
31P NMR (81.01 MHz, CDCl3): d = 20.01.
5-[1-Azido-2-(diethoxyphosphoryl)-3-hydroxyprop-1-enyl]-3-
(4-chlorophenyl)-4,5-dihydroisoxazole (6c)
Following the typical procedure for 6a using 5a (0.261 g, 0.001
mol), 4-ClC6H4CCl=NOH (0.276 g, 0.0015 mol), and Et3N (0.303
g, 0.003 mol) followed by column chromatography (CHCl3–
MeOH, 10:1) gave 6c (0.339 g, 82%) as an oil; Rf = 0.59.
1H NMR (200 MHz, CDCl3): d = 7.74–7.62 (m, 2 H, Harom), 7.21–
7.10 (m, 2 H, Harom), 6.30 (dt, JH,P = 11.0 Hz, JH,H = 1.8 Hz, 1 H,
OCH), 4.36 (d, JH,P = 16.0 Hz, 2 H, CH2OH), 4.17–4.08 (m, 4 H, 2
POCH2CH3), 3.81 (AB, JH,H = 11.0 Hz, JH,P = 17.0 Hz, 1 H, CHH),
3.36 (AB, JH,H = 8.0 Hz, JH,P = 17.0 Hz, 1 H, CHH), 2.64 (br s, 1 H,
OH), 1.32 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3),
13C NMR (50.3 MHz, CDCl3): d = 159.47 (s, Carom), 156.63 (s,
N=CAr), 148.91 (d, JC,P = 25.0 Hz, =CN3), 128.34 (s, Carom), 125.10
(s, Carom), 115.34 (s, Carom), 117.10 (d, JC,P = 186.0 Hz, =CP), 79.01
(d, JC,P = 5.0 Hz, CH–O), 62.85 (d, JC,P = 6.0 Hz, POCH2CH3),
62.48 (d, JC,P = 5.0 Hz, POCH2CH3), 58.97 (d, JC,P = 5.0 Hz,
CH2OH), 40.54 (s, CH2), 16.26 (d, JC,P = 6.0 Hz, POCH2CH3),
16.34 (d, JC,P = 7.0 Hz, POCH2CH3).
4-(Diethoxyphosphoryl)-3-vinylisoxazole (7a); Typical Proce-
dure
Alkadiene 5a (0.261 g, 0.001 mol) was dissolved in CHCl3 (10 mL).
MnO2 (1.00 g) was added and the mixture was stirred at r.t. Stirring
was continued until the reaction was complete (TLC, 24–48 h). The
crude product was filtered through a pad of Celite and the residue
was washed with CHCl3. The solvent was removed to give an oil
that was purified by flash chromatography (CHCl3); yield: 0.162 g
(70%); Rf = 0.78.
1H NMR (200 MHz, CDCl3): d = 8.74 (d, JH,P = 1.5 Hz, 1 H,
OCH=), 6.76 (dd, JH,H = 11.0 Hz, JH,H = 18.0 Hz, 1 H, HC=CHH),
6.34 (d, JH,H = 18.0 Hz, 1 H, HC=CHH), 7.71 (d, JH,H = 11.0 Hz, 1
H, HC=CHH), 4.20–4.09 (m, 4 H, 2 POCH2CH3), 1.34 (t, JH,H = 7.0
Hz, 6 H, 2 POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.39 (d, JC,P = 23.0
Hz, =CHO), 159.81 (d, JC,P = 12.0 Hz, C=N), 124.72 (s, =CH),
123.25 (s, =CH), 107.69 (d, JC,P = 216.0 Hz, P–C=), 63.15 (d,
JC,P = 5.5 Hz,
POCH2CH3).
2 POCH2CH3), 16.65 (d, JC,P = 7.0 Hz, 2
31P NMR (81.01 MHz, CDCl3): d = 19.65.
31P NMR (81.01 MHz, CDCl3): d = 10.37.
Anal. Calcd for C9H14NO4P (231.188): C, 46.76; H, 6.10; P, 13.40.
Found: C, 46.90; H, 6.11; P, 13.29.
5-[1-Azido-2-(diethoxyphosphoryl)-3-hydroxyprop-1-enyl]-3-
(4-methylphenyl)-4,5-dihydroisoxazole (6d)
Following the typical procedure for 6a using 5a (0.261 g, 0.001
mol), 4-MeC6H4CCl=NOH (0.254 g, 0.0015 mol), and Et3N (0.303
g, 0.003 mol) followed by column chromatography (CHCl3–
MeOH, 10:1) gave 6d (0.335 g, 85%) as an oil; Rf = 0.57.
1H NMR (200 MHz, CDCl3): d = 7.72–7.68 (m, 2 H, Harom), 7.28–
7.24 (m, 2 H, Harom), 6.23 (dt, JH,P = 11.0 Hz, JH,H = 1.5 Hz, 1 H,
OCH), 4.32 (d, JH,P = 16.0 Hz, 2 H, CH2OH), 4.16–4.00 (m, 4 H, 2
POCH2CH3), 3.86 (AB, JH,H = 12.0 Hz, JH,P = 17.0 Hz, 1 H, CHH),
3.40 (AB, JH,H = 8.0 Hz, JH,P = 17.0 Hz, 1 H, CHH), 3.02 (br s, 1 H,
OH), 2.40 (s, 3 H, CH3), 1.38 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3).
4-(Diethoxyphosphoryl)-3-(prop-1-enyl)isoxazole (7b)
Following the typical procedure for 7a using 5b (0.275 g, 0.001
mol), MnO2 (1.00 g), and CHCl3 (10 mL), followed by column
chromatography (CHCl3) gave 7b (0.178 g, 72%) as an oil;
Rf = 0.69.
1H NMR (200 MHz, CDCl3): d = 8.69 (d, JH,P = 1.6 Hz, 1 H,
OCH=), 6.85 (dq, JH,H = 7.0 Hz, JH,H = 16.0 Hz, 1 H, =CHCH3),
6.44 (dq, JH,H = 16.0 Hz, JH,H = 2.0 Hz, 1 H, =CH), 4.24–4.04 (m, 4
H, 2 POCH2CH3), 1.94 (dd, JH,H = 7.0 Hz, JH,P = 2.0 Hz, 3 H, CH3),
1.35 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.02 (d, JC,P = 24.0
Hz, =CHO), 159.71 (d, JC,P = 13.0 Hz, C=N), 137.18 (s, =CH),
117.11 (s, =CH), 107.33 (d, JC,P = 216.0 Hz, P–C=), 63.02 (d,
JC,P = 5.5 Hz, 2 POCH2CH3), 19.38 (s, CH3), 16.62 (d, JC,P = 7.0 Hz,
2 POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 156.80 (s, N=CAr), 148.87 (d,
JC,P = 25.0 Hz, =CN3), 140.10 (s, CH3), 129.55 (s, Carom), 126.70 (s,
Carom), 126.03 (s, Carom), 118.10 (d, JC,P = 185.2 Hz, =CP), 79.18 (d,
JC,P = 5.0 Hz, CH–O), 62.71 (d, JC,P = 6.0 Hz, POCH2CH3), 62.50
(d, JC,P = 5.0 Hz, POCH2CH3), 59.03 (d, JC,P = 5.5 Hz, CH2OH),
40.53 (s, CH2), 21.38 (s, CH3), 16.42 (d, JC,P = 7.0 Hz, 2
POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 10.5.
31P NMR (81.01 MHz, CDCl3): d = 19.89.
Anal. Calcd for C10H16NO4P (245.215): C, 48.98; H, 6.58; P, 12.63.
Found: C, 49.18; H, 6.59; P, 12.51.
5-[1-Azido-2-(diethoxyphosphoryl)-3-hydroxyprop-1-enyl]-3-
(4-methoxyphenyl)-4,5-dihydroisoxazole (6e)
Following the typical procedure for 6a using 5a (0.261 g, 0.001
mol), 4-MeOC6H4CCl=NOH (0.270 g, 0.0015 mol), and Et3N
(0.303 g, 0.003 mol) followed by column chromatography (CHCl3–
MeOH, 10:1) gave 6e (0.328 g, 80%) as an oil; Rf = 0.5.
1H NMR (200 MHz, CDCl3): d = 7.76–7.60 (m, 2 H, Harom), 7.22–
7.13 (m, 2 H, Harom), 6.25 (dt JH,P = 12.0 Hz, JH,H = 2.0 Hz, 1 H,
OCH), 4.36 (d, JH,P = 16.0 Hz, 2 H, CH2OH), 4.20–4.11 (m, 4 H, 2
POCH2CH3), 3.87 (AB, JH,H = 12.0 Hz, JH,P = 17.0 Hz, 1 H, CHH),
3.84 (s, 3 H, OCH3), 3.42 (AB, JH,H = 8.0 Hz, JH,P = 17.0 Hz, 1 H,
CHH), 2.96 (br s, 1 H, OH), 1.3 (t, JH,H = 7.0 Hz, 6 H, 2
POCH2CH3).
4-(Diethoxyphosphoryl)-3-(pent-1-enyl)isoxazole (7c)
Following the typical procedure for 7a using 5c (0.304 g, 0.001
mol), MnO2 (1.00 g), and CHCl3 (10 mL), followed by column
chromatography (CHCl3) gave 7c (0.23 g, 83%) as an oil; Rf = 0.65.
1H NMR (200 MHz, CDCl3): d = 8.63 (d, JH,P = 1.5 Hz, 1
H, =CHO), 6.92 (dt, JH,H = 6.8 Hz, JH,H = 16.3 Hz, 1 H, =CHCH2),
6.46 (br d, JH,H = 16.3 Hz, 1 H, =CH), 4.22–4.05 (m, 4 H, 2
POCH2CH3), 2.37 (dt, JH,H = 7.0 Hz, JH,H = 6.8 Hz, 2 H, CH2), 1.67
(m, 2 H, CH2), 1.36 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3), 1.05 (t,
JH,H = 6.8 Hz, 3 H, CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.41 (d, JC,P = 23.0
Hz, =CHO), 160.23 (d, JC,P = 12.0 Hz, C=N), 142.61 (s, =CH),
115.77 (s, =CH), 107.83 (d, JC,P = 214.0 Hz, PC=), 63.12 (d,
13C NMR (50.3 MHz, CDCl3): d = 157.670 (s, N=CAr), 149.34 (d,
JC,P = 25.0 Hz, =CN3), 137.10 (s, Carom), 128.21 (s, Carom), 126.86 (s,
Synthesis 2009, No. 20, 3405–3410 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 4-(Diethoxyphosphoryl)isoxazoles
3409
JC,P = 6.0 Hz, 2 POCH2CH3), 33.73 (s, CH2), 29.40 (s, CH2), 16.76
(d, JC,P = 7.0 Hz, 2 POCH2CH3), 15.12 (s, CH3).
31P NMR (81.01 MHz, CDCl3): d = 11.03.
C
arom), 117.03 (d, JC,F = 17.0 Hz, Carom), 109.92 (d, JC,P = 219.3 Hz,
PC=), 74.52 (s, CH–O), 62.67 (d, JC,P = 6.0 Hz, 2 POCH2CH3),
39.83 (s, CH2), 16.52 (d, JC,P = 7.0 Hz, POCH2CH3), 16.76 (d,
JC,P = 7.0 Hz, POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 14.2.
Anal. Calcd for C12H20NO4P (273.269): C, 52.74; H, 7.38; P, 11.33.
Found: C, 52.85; H, 7.38; P, 11.34.
Anal. Calcd for C16H18FN2O5P (368.301): C, 52.18; H, 4.93; P,
8.41. Found: C, 52.30; H, 4.94; P, 8.38.
4-(Diethoxyphosphoryl)-3-(hex-1-enyl)isoxazole (7d)
Following the typical procedure for 7a using 5d (0.318 g, 0.001
mol), MnO2 (1.00 g), and CHCl3 (10 mL), followed by column
chromatography (CHCl3) gave 7d (0.224 g, 79%) as an oil;
Rf = 0.63.
1H NMR (200 MHz, CDCl3): d = 8.72 (d, JH,P = 1.5 Hz, 1
H, =CHO), 6.87 (dt, JH,H = 6.8 Hz, JH,H = 16.3 Hz, 1 H, =CHCH3),
6.43 (br d, JH,H = 16.3 Hz, 1 H, =CH), 4.27–4.06 (m, 4 H, 2
POCH2CH3), 2.31 (dt, JH,H = 7.0 Hz, JH,H = 6.8 Hz, 2 H, CH2), 1.48
(m, 4 H, 2 CH2), 1.37 (t, JH,H = 7.0 Hz, 6 H, 2 POCH2CH3), 0.95 (t,
JH,H = 6.8 Hz, 3 H, CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.72 (d, JC,P = 23.0
Hz, =CHO), 160.00 (d, JC,P = 12.0 Hz, C=N), 142.49 (s, =CH),
115.71 (s, =CH), 107.38 (d, JC,P = 216.0 Hz, PC=), 63.00 (d,
JC,P = 6.0 Hz, 2 POCH2CH3), 33.44 (s, CH2), 31.08 (s, CH2), 22.60
(s, CH2), 16.72 (d, JC,P = 7.0 Hz, 2 POCH2CH3), 14.29 (s, CH3).
3-[3-(4-Chlorophenyl)-4,5-dihydroisoxazol-5-yl]-4-(diethoxy-
phosphoryl)isoxazole (8c)
Following the typical procedure for 7a using 6c (0.415 g, 0.001
mol), MnO2 (1.00 g), and CHCl3 (10 mL), followed by column
chromatography (CHCl3) gave 8c (0.323 g, 84%) as an oil;
Rf = 0.45.
1H NMR (200 MHz, CDCl3): d = 8.75 (d, JH,P = 1.5 Hz, 1
H, =CHO), 7.73–7.61 (m, 2 H, Harom), 7.26–7.12 (m, 2 H, Harom),
6.10 (dd, JH,H = 11.5 Hz, JH,H = 7.0 Hz, 1 H, OCH), 4.30–4.12 (m, 4
H, 2 POCH2CH3), 4.10 (AB, JH,H = 11.5 Hz, JH,P = 17.0 Hz, 1 H,
CHH), 3.47 (AB, JH,H = 7.0 Hz, JH,P = 17.0 Hz, 1 H, CHH), 1.39 (t,
JH,H = 7.0 Hz, 3 H, POCH2CH3), 1.35 (t, JH,H = 7.0 Hz, 3 H,
POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.10 (d, JC,P = 22.5 Hz, =CH–
O), 159.12 (s, Carom), 161.74 (d, JC,P = 12.5 Hz, C=N), 128.51 (s,
Carom), 124.30 (s, Carom), 115.74 (s, Carom), 106.22 (d, JC,P = 218.6
Hz, PC=), 74.61 (s, CH–O), 62.44 (d, JC,P = 6.0 Hz, 2 POCH2CH3),
39.62 (s, CH2), 16.73 (d, JC,P = 7.0 Hz, POCH2CH3), 16.45 (d,
JC,P = 7.0 Hz, POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 1.0.
Anal. Calcd for C13H22NO4P (287.296): C, 54.35; H, 7.72; P, 10.78.
Found: C, 54.51; H, 7.73; P, 10.61.
4-(Diethoxyphosphoryl)-3-(3-phenyl-4,5-dihydroisoxazol-5-yl)-
isoxazole (8a)
31P NMR (81.01 MHz, CDCl3): d = 14.7.
Following the typical procedure for 7a using 6a (0.38 g, 0.001 mol),
MnO2 (1.00 g), and CHCl3 (10 mL), followed by column chroma-
tography (CHCl3) gave 8a (0.28 g, 80%) as an oil; Rf = 0.48.
1H NMR (200 MHz, CDCl3): d = 8.75 (d, JH,P = 1.5 Hz, 1
H, =CHO), 7.42–7.69 (m, 2 H, HPh), 7.44–7.41 (m, 3 H, HPh), 6.01
(dd, JH,H = 11.0 Hz, JH,H = 7.4 Hz, 1 H, OCH), 4.32–4.15 (m, 4 H, 2
POCH2CH3), 4.03 (AB, JH,H = 11.0 Hz, JH,P = 17.0 Hz, 1 H, CHH),
3.69 (AB, JH,H = 7.4 Hz, JH,P = 17.0 Hz, 1 H, CHH), 1.39 (t,
JH,H = 7.0 Hz, 3 H, POCH2CH3), 1.35 (t, JH,H = 7.0 Hz, 3 H,
POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.43 (d, JC,P = 22.0
Hz, =CHO), 161.35 (d, JC,P = 13.0 Hz, C=N), 157.36 (s, CPh),
130.86 (s, CPh), 129.27 (s, CPh), 127.37 (s, CPh), 108.69 (d,
JC,P = 218.0 Hz, PC=), 74.21 (s, CH–O), 63.45 (d, JC,P = 6.0 Hz, 2
POCH2CH3), 39.54 (s, CH2), 16.76 (d, JC,P = 7.0 Hz, POCH2CH3),
16.69 (d, JC,P = 7.0 Hz, POCH2CH3).
Anal. Calcd for C16H18ClN2O5P (384.756): C, 49.95; H, 4.72; P,
8.05. Found: C, 49.82; H, 4.76; P, 8.21.
4-(Diethoxyphosphoryl)-3-[3-(4-methylphenyl)-4,5-dihydro-
isoxazol-5-yl]isoxazole (8d)
Following the typical procedure for 7a using 6d (0.356 g, 0.001
mol), MnO2 (1.00 g), and CHCl3 (10 mL), followed by column
chromatography (CHCl3) gave 8d (0.29 g, 79%) as an oil; Rf = 0.40.
1H NMR (200 MHz, CDCl3): d = 8.70 (d, JH,P = 2.0 Hz, 1
H, =CHO), 7.70–7.77 (m, 2 H, Harom), 7.29–7.26 (m, 2 H, Harom),
6.12 (dd, JH,H = 12.0 Hz, JH,H = 7.0 Hz, 1 H, OCH), 4.25–4.10 (m, 4
H, 2 POCH2CH3), 4.08 (AB, JH,H = 12.0 Hz, JH,P = 17.0 Hz, 1 H,
CHH), 3.49 (AB, JH,H = 7.0 Hz, JH,P = 17.0 Hz, 1 H, CHH), 2.43 (s,
3 H, CH3), 1.30 (t, JH,H = 7.0 Hz, 3 H, POCH2CH3), 1.35 (t,
JH,H = 7.0 Hz, 3 H, POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.83 (d, JC,P = 22.0 Hz,
=CH–O), 161.55 (d, JC,P = 13.0 Hz, C=N), 140.41 (s, Carom), 129.65
(s, Carom), 126.78 (s, Carom), 126.13 (s, Carom), 107.54 (d, JC,P = 218.5
Hz, PC=), 74.67 (s, CH–O), 63.54 (d, JC,P = 6.0 Hz, 2 POCH2CH3),
39.56 (s, CH2), 16.76 (d, JC,P = 7.0 Hz, POCH2CH3), 21.38 (s, CH3),
16.43 (d, JC,P = 7.0 Hz, POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 15.3.
Anal. Calcd for C16H19N2O5P (350.311): C, 54.86; H, 5.47; P, 8.84.
Found: C, 54.92; H, 5.46; P, 8.92.
4-(Diethoxyphosphoryl)-3-[3-(4-fluorophenyl)-4,5-dihydroisox-
azol-5-yl]-isoxazole (8b)
31P NMR (81.01 MHz, CDCl3): d = 12.5.
Following the typical procedure for 7a using 6b (0.4 g, 0.001 mol),
MnO2 (1.00 g), and CHCl3 (10 mL), followed by column chroma-
tography (CHCl3) gave 8b (0.29 g, 79%) as an oil; Rf = 0.48.
1H NMR (200 MHz, CDCl3): d = 8.75 (d, JH,P = 1.5 Hz, 1
H, =CHO), 7.80–7.75 (m, 2 H, Harom), 7.20–7.10 (m, 2 H, Harom),
6.08 (dd, JH,H = 11.0 Hz, JH,H = 7.0 Hz, 1 H, OCH), 4.33–4.16 (m, 4
H, 2 POCH2CH3), 4.01 (AB, JH,H = 11.0 Hz, JH,P = 17.0 Hz, 1 H,
CHH), 3.68 (AB, JH,H = 7.0 Hz, JH,P = 17.0 Hz, 1 H, CHH), 1.38 (t,
JH,H = 7.0 Hz, 3 H, POCH2CH3), 1.34 (t, JH,H = 7.0 Hz, 3 H,
POCH2CH3).
Anal. Calcd for C17H21N2O5P (364.339): C, 56.04; H, 5.81; P, 8.50.
Found: C, 56.20; H, 5.82; P, 8.49.
4-(Diethoxyphosphoryl)-3-[3-(4-methoxyphenyl)-4,5-dihydro-
isoxazol-5-yl]isoxazole (8e)
Following the typical procedure for 7a using 6e (0.372 g, 0.001
mol), MnO2 (1.00 g), and CHCl3 (10 mL), followed by column
chromatography (CHCl3) gave 8e (0.319 g, 84%) as an oil;
Rf = 0.48.
1H NMR (200 MHz, CDCl3): d = 8.75 (d, JH,P = 2.0 Hz, 1
H, =CHO), 7.78–7.54 (m, 2 H, Harom), 7.28–7.15 (m, 2 H, Harom),
6.18 (dd, JH,H = 12.0 Hz, JH,H = 7.0 Hz, 1 H, OCH), 4.22–4.14 (m, 4
H, 2 POCH2CH3), 4.06 (AB, JH,H = 12.0 Hz, JH,P = 17.0 Hz, 1 H,
13C NMR (50.3 MHz, CDCl3): d = 166.10 (d, JC,P = 22.5
Hz, =CHO), 164.0 (d, JC,F = 212.0 Hz, Carom), 161.65 (d, JC,P = 13.0
Hz, C=N), 128.61 (d, JC,F = 7.0 Hz, Carom), 125.72 (d, JC,F = 3.0 Hz,
Synthesis 2009, No. 20, 3405–3410 © Thieme Stuttgart · New York

3410
V. K. Brel
PAPER
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1999, 463.
(13) Mark, V. Tetrahedron Lett. 1962, 3, 281.
(14) Brel, V. K.; Belsky, V. K.; Stash, A. I.; Zavodnik, V. E.;
Stang, P. J. Eur. J. Org. Chem. 2005, 512.
CHH), 3.84 (s, 3 H, OCH3), 3.43 (AB, JH,H = 7.0 Hz, JH,P = 17.0 Hz,
1 H, CHH), 1.29 (t, JH,H = 7.0 Hz, 3 H, POCH2CH3), 1.31 (t,
JH,H = 7.0 Hz, 3 H, POCH2CH3).
13C NMR (50.3 MHz, CDCl3): d = 166.64 (d, JC,P = 22.0
Hz, =CHO), 161.55 (d, JC,P = 12.5 Hz, C=N), 137.50 (s, Carom),
128.67 (s, Carom), 126.96 (s, Carom), 127.22 (s, Carom), 107.74 (d,
JC,P = 218.0 Hz, PC=), 74.82 (s, CH–O), 63.76 (d, JC,P = 6.0 Hz, 2
POCH2CH3), 55.8 (s, OCH3), 39.26 (s, CH2), 16.82 (d, JC,P = 7.0
Hz, POCH2CH3), 16.43 (d, JC,P = 7.0 Hz, POCH2CH3).
31P NMR (81.01 MHz, CDCl3): d = 14.0.
Anal. Calcd for C17H21NO6P (380.337): C, 53.69; H, 5.57; P, 8.14.
Found: C, 53.72; H, 5.59; P, 8.16.
Acknowledgment
This work was supported by the Russian Foundation for Basic
Research, project: 09-03-00099.
References
(1) Dileep Kurman, J. S.; Ho, M. M.; Leung, J. M.; Toyokuni,
T. Adv. Synth. Catal. 2002, 344, 1146.
Synthesis 2009, No. 20, 3405–3410 © Thieme Stuttgart · New York