Regioselective cycloadditions of β-substituted vinylphosphonate with nitrile oxides

Article abstract of DOI:10.1080/10426500802080717

Vinylphosphonates have been widely utilized in organic synthesis during the last two decades. In this article, a novel, highly regioselective cycloaddition utilizing nitrile oxides and vinylphosphonate for the synthesis of isoxazoline and fused isoxazolin

Full text of DOI:10.1080/10426500802080717

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Regioselective Cycloadditions
of β -Substituted
Vinylphosphonate with Nitrile
Oxides
Yong Ye a b , Li-bo Ma a b , Yong Luo b , Wen-hu Wang
b , Lun-zu Liu b & Yu-fen Zhao a
a Department of Chemistry, Key Laboratory
of Chemical Biology and Organic Chemistry ,
Zhengzhou University , Zhengzhou , China
b State Key Laboratory of Elemento-Organic
Chemistry , Institute of Elemento-Organic
Chemistry, Nankai University , Tianjin , China
Published online: 19 Dec 2008.
To cite this article: Yong Ye , Li-bo Ma , Yong Luo , Wen-hu Wang , Lun-zu Liu & Yu-
fen Zhao (2008) Regioselective Cycloadditions of β -Substituted Vinylphosphonate
with Nitrile Oxides, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:1,
135-140, DOI: 10.1080/10426500802080717
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Phosphorus, Sulfur, and Silicon, 184:135–140, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802080717
Regioselective Cycloadditions of β-Substituted
Vinylphosphonate with Nitrile Oxides
Yong Ye,1,2 Li-bo Ma,1,2 Yong Luo,2 Wen-hu Wang,2
Lun-zu Liu,2 and Yu-fen Zhao1
1Department of Chemistry, Key Laboratory of Chemical Biology
and Organic Chemistry, Zhengzhou University, Zhengzhou, China
2State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University, Tianjin, China
Vinylphosphonates have been widely utilized in organic synthesis during the last
two decades. In this article, a novel, highly regioselective cycloaddition utilizing
nitrile oxides and vinylphosphonate for the synthesis of isoxazoline and fused isox-
azoline rings was developed. The method has the advantages in that it tolerates a
wide variety of functional groups.
Keywords 1,3-Dipolar cycloadditions; isoxazoline; vinylphosphonates
INTRODUCTION
Vinylphosphonates have been widely utilized in organic synthesis dur-
ing the last two decades and became very useful for the construction of
functionalized organophosphorus compounds.1−2 In particular, cycload-
dition of nitrile oxides to vinylphosphonates is of considerable interest,
as the resulting isoxazolines are versatile intermediates in the synthe-
sis of a variety of natural products.3−4 Furthermore, the phosphonate
functional group has been thought to be usually stable under the vari-
ous transformations of isoxazolines including their reductive N O bond
cleavage.5
Recently, we have discovered that 3-diethylphosphonoethylene and
vinylphosphonate substituted at the α-position by phosphonyl or car-
bonyl groups react with nitrile oxides to afford only one regiospecific
Received 29 January 2008; 19 February 2008.
We thank the National Natural Science Foundation of China (No. 20602032), Educa-
tion Department of Henan Province, and Zhengzhou University.
Address correspondence to Yong Ye, Department of Chemistry, Key Laboratory of
Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou, 450052,
China. E-mail: yeyong03@mail.nankai.edu.cn
135

136
Y. Ye et al.
product, which is a valuable intermediate of the synthesis of variously
functionalized phosphonates.6,7 As a continuation of this study, we re-
port here the behavior of β-substituted vinylphosphonate with nitrile
oxides. The reaction has been explored with various substituted nitrile
oxide to achieve information on the influence of the substituent at the
β-position upon the regioselectivity and reactivity of the cycloaddition.
RESULTS AND DISCUSSION
The reaction of β-substituted vinylphosphonate with benzonitrile oxide
generated in situ from benzohydroximoyl chloride and triethylamine
in THF occurred smoothly at room temperature to afford the products
3 in good yield (shown in Scheme 1). The cycloadducts 3 characterized
1
by elemental analysis and H NMR spectra, in part also by 31P NMR.
Their related data are shown in Table I. Using the optimized conditions,
cycloaddition of vinylphosphonate with phenyl substituted was faster
than that of alkyl substituted. Reaction time was 12–18 h with 3e–g
and 24–48 h with 3a–d.
β-Substituted vinylphosphonate undergoes a highly regioselective
cycloaddition with nitrile oxide. The regioisomer was not detected by
TLC and isolated by column chromatography. The structures of the
adducts 3 rely upon the data of NMR. The regiochemistry follows from
the comparison of the spacings between the isoxazolinic hydrogens.
Previous NMR studies proved this technique to be useful for structural
assignment of isoxazoline derivatives,8,9 especially in the case of trans-
isomers. A proton in the 5-position absorbs lower field than a 4-proton,
owing to the paramagnetic shift caused by the adjacent oxygen atom. In
the case of the isoxazoline, ꢀδ5,4 (δ5–δ4) is always notably larger for the
4-isoxazoline (1.4–2 ppm) than for the 5-isomers (1 ppm).6 Because of
the higher deshielding effect of a relative to a phosphonyl substituent,
O
O
R
N
P(OEt)
_
+
ArC
2
N
O
+
R
Ar
(EtO) P
2
O
3
2
1
R=C6H13, Ph,4-NO2Ph-
SCHEME 1 Cycloaddition of β-substituted vinylphosphonate with aryl nitrile
oxides.

β-Substituted Vinylphosphonate
137
TABLE I 1,3-Dipolar Cycloaddition Reaction of
β-Substituted Vinylphosphonate with
Benzonitrile Oxide
Product
R
Ar
Time (h) Yield*(%)
3a
3b
3c
3d
3e
3f
C6H13
C6H13
C6H13
C6H13
C6H5
4-FC6H4
4-ClC6H4
4-MeC6H4
C6H5
C6H5
4-MeC6H4
4-O2NC6H4
24
24
36
48
16
18
12
62.49
56.16
58.55
56.42
56.63
47.16
68.75
C6H5
4-O2NC6H4
3g
*Isolated yield based on substituted vinylphosphonate.
SCHEME 2 Cycloaddition of β-substituted vinylphosphonate with phosphonyl
nitrile oxides.
the spacing of a 4-phosphonyl substituted isoxazoline is larger than that
of the 5-phosphonyl regioisomer. The trend becomes more manifest in
the spectra of the isoxazolines carrying phenyl substituents.
Next, we examined the scope of β-substituted vinylphosphonate
with nitrile oxides. When β-substitute vinylphosphonate 1 reacted
with diisopropanyl phosphonyl nitrile oxides 4, only regioselec-
tively 2:1 addition product 5 was obtained (shown in Scheme 2).
The requisite nitrile oxides 4 were prepared according to the lit-
erature routes from the corresponding hydroximoyl bromides via
base induced dehydrobromidination.10 Meanwhile, when excessive β-
substitute vinylphosphonate 1 was added, only 2:1 cycloadduct was ob-
tained. A variety of β-substitute vinylphosphonate readily reacted with
phosphonyl nitrile oxides to produce the corresponding 2:1 cycloadduct
in moderate yields.

138
Y. Ye et al.
CONCLUSION
In conclusion, we have developed a novel 1,3-cyclic addition reaction
utilizing nitrile oxides and vinylphosphonate for the synthesis of 4-
phosphonyl isoxazoline and fused isoxazoline rings. The method has
advantages in that it tolerates a wide variety of functional groups,
is straightforward, and provides good yields of products from readily
accessible starting materials. Further study is underway to expand the
scope of this methodology, as well as to ascertain mechanistic details of
the cycloaddition process.
EXPERIMENTAL
General
All melting points are uncorrected. Elemental analyses were carried on
a Yanaco CHN Corder MT-3 apparatus. 1H and 31P NMR spectra were
measured by using a Bruker 300 spectrometer with TMS and 85%
H3PO4 as the internal and external reference respectively and with
CDCl3 as the solvent. Solvents used were purified and dried by stan-
dard procedures. Compounds 1 were synthesized according to Kiddle
and Babler11 and Monique et al.12 Benzonitrile oxides were prepared
efficiently from the corresponding hydroximoyl chlorides via base in-
duced dehydrochlorination.13
General Procedure for the Synthesis of 3a–g
To a stirred solution of compounds 1 (2.0 mmol) and hydroxamic
chlorides (2.2 mmol) in dry THF (15 mL) under N2, a solution of Et3N
(0.22 g, 2.2 mmol) in dry THF (15 mL) was added dropwise at −10◦.
The mixture was stirred at room temperature until the consumption of
vinylphosphonates, monitored by TLC. Then, the reaction mixture was
filtered to remove triethylamine hydrochloride, and the solvent was
evaporated in vacuum. The residue was chromatographed on a silica
gel column with petroleum ether/ethyl acetate 3:1(V:V) to give pure
3a–g as a solid or oil.
3a: 1H NMR: δ 0.85 (t, 3H); 1.14–1.80 (m, 16H); 3.60 (dd, 1H, J= 4.16,
19.8 Hz); 3.87–4.17 (m, 4H); 5.04 (m, 1H); 7.15 (m, 2H); 7.81(m, 2H);
31P NMR: 19.81; anal. calcd. for C19H29FNO4P: C, 59.21; H, 7.58; N,
3.63. Found C, 58.91; H, 7.68, N, 3.73.
3b: 1H NMR: δ 0.84 (t, 3H); 1.13–1.79 (m, 16H); 3.70 (dd, 1H, J= 4.06,
19.6 Hz); 3.9–4.2 (m, 4H); 5.1 (m, 1H); 7.33 (d, 2H, J= 8.84 Hz); 7.75
(d, 2H, J= 8.84 Hz); anal. calcd. for C19H29ClNO4P: C, 56.79; H, 7.27;
N, 3.49. Found C, 56.75; H, 7.17, N, 3.52.

β-Substituted Vinylphosphonate
139
1
3c: H NMR: δ 0.86 (t, 3H); 1.12–1.82 (m, 16H); 2.33 (s, 3H); 3.61
(dd, 1H, J= 4.12, 19.7 Hz); 3.86–4.16 (m, 4H); 5.06 (m, 1H); 7.20 (d, 2H,
J= 8.12 Hz); 7.68 (d, 2H, J= 8.12 Hz); anal. calcd. for C20H32NO4P: C,
62.98; H, 8.45; N, 3.67. Found C, 63.02; H, 8.20, N, 3.76.
3d: 1H NMR: δ 0.85 (t, 3H); 1.12–1.79 (m, 16H); 3.71 (dd, 1H, J= 4.14,
19.82 Hz); 3.89–4.2 (m, 4H); 5.1 (m, 1H); 7.37 (m, 3H); 7.79 (m, 2H);
anal. calcd. for C19H30NO4P: C, 62.11; H, 8.23; N, 3.81. Found C, 62.03;
H, 8.17, N, 3.92.
1
3e: H NMR: δ 1.17–1.31 (m, 6H); 3.92–4.15 (m, 5H); 6.09 (dd, 1H,
J= 5.22, 20.84 Hz); 7.23–7.38 (m, 6H); 7.77–7.80 (m, 4H); anal. calcd.
for C19H22NO4P: C, 63.50; H, 6.17; N, 3.90. Found C, 63.31; H, 6.04, N,
3.94.
1
3f: H NMR: δ 1.13–1.24 (m, 6H); 2.25 (s, 3H); 3.91–4.14 (m, 5H);
5.98 (dd, 1H, J= 4.18, 20.86 Hz); 7.08 (d, 2H, J= 8.34 Hz); 7.60 (d, 2H,
J= 8.34 Hz); anal. calcd. for C20H24NO4P: C, 64.33; H, 6.48; N, 3.75.
Found C, 64.36; H, 6.25, N, 3.53.
1
3g: yellow solid, mp 144–146◦. H NMR: δ 1.21–1.37 (m, 6H); 3.93
(dd, 1H, J= 5.22, 19.82 Hz); 4.03–4.18 (m, 4H); 6.23 (dd, 1H, J= 5.22,
21.9 Hz); 7.53 (d, 2H, J= 8.83 Hz); 7.98 (d, 2H, J= 9.04 Hz); 8.23 (d,
4H, J= 8.8 Hz); anal. calcd. for C19H20N3O8P: C, 50.79; H, 4.49; N,
9.35. Found C, 50.94; H, 4.30, N, 9.24. HRMS (ESI): m/z calcd. for
C19H20N3O8P: 449.0988; found: 449.0995.
General Procedure for the Synthesis of 5
To A stirred solution of phosphonyl hydroximoyl bromides (0.432 g,
1.5 mmol) and β-substituted vinylphosphonate (15 mmol) in dry ether
(10 mL), a solution of Et3N (0.2 g, 2 mmol) in dry ether (10 mL) was
added dropwise at −10◦. After half an hour, the solution ascends to
ambient temperature. The reaction mixture was stirred continue for
three days. After filtered, the solvent was evaporated in vacuum. The
residue was chromatographed on a silica gel column with petroleum
ether/ethyl acetate 1:3 to give pure 5a–c as an oil.
5a: yield 19.6%, 1H NMR: δ 7.32 (m, 5H), 5.89–6.03 (dd, 1H),
4.69(m,4H), 4.12–4.22 (m, 5H), 1.20–1.39 (m, 30H), 31P NMR: δ 0.89
(αP), –3.25(βP), 18.53 (γP); anal. calcd. for it, found(calcd): C47.72
(47.71), H6.79 (6.93), N 4.29(4.28).
1
5b: yield 31.4%, H NMR: δ 4.65–4.75 (m, 5H), 3.99–4.10 (m, 5H),
1.08–1.41 (m, 40H), 0.73–0.76 (m, 3H), 31P NMR: δ 1.08 (αP), –3.14
(βP), 19.2 (γP).; anal. calcd. for it, found(calcd): C46.98 (47.13) 8.13(8.06)
4.28(4.23).
5c: yield 56.1%, 1H NMR: δ 8.19–8.23 (d, 2H), 7.51–7.55 (d, 2H), 6.06
(dd, 1H), 4.83 (m, 4H), 4.21 (m, 5H), 1.23–1.37 (m, 30H), 31P NMR: δ 0.53

140
Y. Ye et al.
(αP), –3.32 (βP), 17.68 (γP); anal. calcd. for it, found (calcd): 44.59(44.64)
6.35(6.34) 5.98(6.01).
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