α-methylene β-amino phosphonic ester derivatives by amination of (1-trimethylsilanylmethyl-vinyl) phosphonic esters

Article abstract of DOI:10.1016/S0040-4020(01)00311-8

(1-Trimethylsilanylmethyl-vinyl)-phosphonic esters are synthesised via Wittig-Horner reactions starting from methylenediphosphonic esters. The reactions of (1-trimethylsilanylmethyl-vinyl)-phosphonic esters with NsONHCO₂Et and CaO, produce α-methylene N-(ethoxycarbonyl) β-amino phosphonic esters, isolated up to 60% yield, through addition of (ethoxycarbonyl) amine function on the double bond and silyl group elimination.

Full text of DOI:10.1016/S0040-4020(01)00311-8

TETRAHEDRON
Pergamon
Tetrahedron 57 &2001) 4423±4427
a-Methylene b-amino phosphonic ester derivatives by amination
of ꢀ1-trimethylsilanylmethyl-vinyl) phosphonic esters
M. Antonietta Loreto,a,p,² Clinio Pompilib and Paolo A. Tardellab
a
Á
Centro C.N.R. per lo Studio della Chimica delle Sostanze Organiche Naturali, c/o Dipartimento di Chimica, Universita `La Sapienza',
P.le A. Moro 5, I-00185 Roma, Italy
b
Á
Dipartimento di Chimica, Universita `La Sapienza', P.le Aldo Moro 5, I-00185 Roma, Italy
Received 10 January 2001; revised 19 February 2001; accepted 8 March 2001
AbstractÐ&1-Trimethylsilanylmethyl-vinyl)-phosphonic esters are synthesised via Wittig±Horner reactions starting from methylenedi-
phosphonic esters. The reactions of &1-trimethylsilanylmethyl-vinyl)-phosphonic esters with NsONHCO2Et and CaO, produce a-methylene
N-&ethoxycarbonyl) b-amino phosphonic esters, isolated up to 60% yield, through addition of &ethoxycarbonyl) amine function on the double
bond and silyl group elimination. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently starting from a,b-unsaturated phosphonic esters
we obtained N-&ethoxycarbonyl)aziridine phosphonate,
precursors of a or b-amino phosphonic acids.10
Amino phosphonic acids and their derivatives have
achieved an important role in many ®eldsof chemitsry.
1
Our previousexperience drove usto test the aziridination of
&1-trimethylsilanylmethyl-vinyl) phosphonic esters with
NsONHCO2Et. The aziridine ring after elimination of the
silyl group, would produce a-methylene b-amino phos-
phonic esters.
They show a large variety of biological activity and appli-
cationsin agriculture and medicine, and have been utilized
as herbicides or pesticides,2 antibacterial3 or antiviral
5
agents4 and asenzyme inhibitors.
A number of synthetic methods for the synthesis of a- or
b-amino alkylphosphonates is reported.6
2. Results and discussion
Recently we have focused our attention on the use of
the ethyl N-{[&4-nitrobenzene)sulphonyl]oxy}carbamate
&NsONHCO2Et) 1 to aminate electron poor ole®nsas a,b-
unsaturated esters7 and nitro ole®ns8 using an inorganic
insoluble base such as CaO in CH2Cl2.
We obtained substrates 3 by a Wittig±Horner reaction11
&Scheme 1) starting from trimethylsilanylmethyl- tetraethyl-
methylenediphosphonates 2 and the corresponding alde-
hyde.
The reaction of g-silylated a,b-unsaturated esters with 1
and CaO produced b,g-unsaturated N-&ethoxycarbonyl)
a-amino esters.9
2 wasobtained from tetraethylmethylenediphopshonate
alkylated by iodomethyltrimethylsilane in the presence of
NaH, according to the procedure used to alkylate the
Scheme 1. Synthesis of substrates 3.
Keywords: amination; aziridines; phosphonic acids and derivatives; silicon and compounds.
Corresponding author. Tel.: 139-6-4991-3668; fax: 139-6-490-631; e-mail: mariaantonietta.loreto@uniroma1.it
Associated to the National Institute of Chemistry of Biological Systems
p
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020&01)00311-8

4424
M. A. Loreto et al. / Tetrahedron 57 /2001) 4423±4427
Table 1. Synthesis of substrate 3: conditionsand yields
Entry
R
Method
Reaction time &h)
3 total yield &%)
Z/E
a
b
c
d
H
CH3
Ph
CH3&CH2)4
50% NaOH/CH2Cl2
50% NaOH/CH2Cl2 TBAI
50% NaOH/CH2Cl2
LDA/THF 2788C
6
24
6
84
49
53
69
±
60/40
30/70
58/42
2.5
triethylphosphonoacetate,12 and puri®ed by ¯ash chroma-
tography.
obtain &1-trimethylsilanylmethyl-vinyl) phosphonic esters;
these are allylsilanes, versatile intermediates utilised in
organic synthesis.15 Furthermore we have found a new
synthetic route employing NsONHCO2Et for the prepa-
ration of a-methylene b-&ethoxycarbonyl) amino alkyl-
phosphonates; these are important building blocks for the
synthesis of phosphonopeptides in which a-methylene
b-amino phosphonic acids are present, such as the antibiotic
A53868A.16 They could also be converted into b-amino
phosphonic acids having the a position, functionality
derived from a CyC double bond.
For 3a±c the Wittig±Horner reaction wascarried out in a
two-phase system using 50% aqueous NaOH as base in
CH2Cl2, for 3b tetrabutylammonium iodide &TBAI) was
necessary as a phase-transfer catalyst.
In the case of substrates 3d we needed LDA in dry THF to
obtain the desired product.13 In all cases we obtained a
mixture of Z and E isomers easily separated by ¯ash-
chromatography on silica gel with the reported ratio
&Table 1).
3. Experimental
3.1. General
The amination reactions on substrates 3 were carried out by
adding NsONHCO2Et and CaO portion wise reaching the
molar ratio and the time reported in Table 2. The reaction
producesthe aziridine ring 4 detected in the crude reaction
mixture by 1H NMR and GC-MS spectral data &Scheme 2).
GC analyses were performed on a HP 5890 Series II gas
chromatograph with a capillary column &methyl silicone,
length 12.5 m, internal diameter 0.2 mm, ®lm thickness
0.25 mm). GC-MS were done on a HP G1800A GCD system
with a capillary column &phenyl methyl silicone, length
30 m, internal diameter 0.25 mm, ®lm thickness 0.25 mm).
Microanalyses were carried out on a CE Instruments
By treating the crude reaction mixture with AcOH for 26 h,
the silyl group was eliminated and the a-methylene
b-amino phosphonic esters 5 were obtained.
1
EA1110. H NMR and 13C NMR spectra were obtained
The products were isolated by ¯ash-chromatography on
silica gel. The two isomers E and Z gave the same product;
the Z isomers have been shown to be more reactive. The
reaction of the Z isomers with NsONHCO2Et needed only
four equivalentsof reagent for the diasppearance of the
starting material and gave the isolated products 5 in higher
yields&Table 2).
in CDCl3 on a Gemini 200 spectrometer, with CHCl3 as
internal standard. 31P NMR spectra were obtained in
CDCl3 on a Bruker AC 300 spectrometer, with H3PO4 as
internal standard. IR spectra in CCl4 were done by a Perkin±
Elmer 1600 SeriesFTIR spectrometer.
3.2. Synthesis of [1-ꢀdiethoxy-phosphoryl)-2-trimethyl-
silanyl-ethyl]-phosphonic acid diethyl ester 2
The aziridination reactionsusing Et N in homogenoussolu-
3
tion of CH2Cl2,14 conditionsof generation of the &ethoxy-
carbonyl)nitrene, gave only tracesof aziridines.
To 60% NaH &0.88 g, 22 mmol; suspension in mineral oil)
in dry DME &12 mL), tetraethylmethylenediphosphonate
&5.8 g, 20 mmol) wasadded dropwise, under argon at 0 8C.
In summary, in this paper we have reported the route to
Table 2. Synthesis of 5: conditionsand yields
Entry
R
Substrate: NsONHCO2Et:CaO
Reaction time &h)
Substrate: AcOH
5 total yield &%)
a
H
CH3
CH3
Ph
Ph
CH3&CH2)4
CH3&CH2)4
1:4:4
1:4:4
1:8:8
1:10:10
1:10:10
1:4:4
4
5
24
30
24
5
1:8
1:8
1:10
1:10
1:10
1:8
60
51
42
35
22
61
41
b &Z)
b &E)
c&Z)
c&E)
d&Z)
d&E)
1:8:8
24
1:10
Scheme 2. Synthesis of a-methylene b-amino phosphonic esters 5.

M. A. Loreto et al. / Tetrahedron 57 /2001) 4423±4427
4425
After 0.5 h at room temperature, a solution of iodomethyl-
trimethylsilane &3.4 mL, 23 mmol) in DME &6 mL) was
added and the resulting mixture was heated to 708C. After
being stirred for 3 h the mixture was poured into dilute
aqueousammonium chloride &60 mL) and the aqueous
phase was extracted with diethyl ether. The combined
organic phases were washed with brine and dried
&Na2SO4). After evaporation of solvent the reaction mixture
was puri®ed by ¯ash chromatography on silica gel &hexane:
acetoneˆ7:3) to obtain 2 asa yellowish oil &5g, 67% yield).
GC-MS m/z: 374 &M1 0.3), 359&14), 237&100), 210&39),
165&64), 121&20), 109&20), 73&22); Anal. Calcd. for
C13H32O6P2Si: C 41.70, H 8.61, Found: C 41.62, H 8.88;
IR: nPyO 1250 cm21; 1H NMR d: 0.00 &s, 9 H, SiCH3), 1.08
&td, 2 H, SiCH2, JHHˆ6.6 Hz, JHPˆ18 Hz), 1.28 &t, 12 H,
CH2CH3), 2.28 &tt, 1 H, CH, JHHˆ6.6 Hz, JHPˆ24.0 Hz),
4.02±4.22 &m, 8 H, OCH2); 13C NMR d: 21.0 &SiCH3),
54.0 Hz); 13C NMR d: 21.4 &SiCH3), 16.2 &d, CH2CH3,
JCCOPˆ6.5 Hz), 16.3 &d, yCHCH3, JCCCPˆ7.6 Hz), 24.1 &d,
CH2Si, JCCPˆ12.5 Hz), 60.4 &d, OCH2, JCOPˆ6.0 Hz), 127.0
&d, yC, JCPˆ171.1 Hz), 139.2 &d, yCH, JCCPˆ11.5 Hz); 31
NMR d: 20.4.
P
3.3.3.
ꢀE)-ꢀ1-Trimethylsilanylmethyl-propenyl)-phos-
phonic acid diethyl ester 3b. Pale yellow oil, GC-MS
m/z: 264 &M1, 3), 250 &13), 248 &89), 221 &31), 205 &17),
193 &97), 191 &25), 187 &18), 177 &14), 165 &13), 154 &28),
153 &15), 139 &46), 138 &18), 137 &15), 123 &33), 121 &100),
83 &13), 77 &14), 75 &48), 73 &67), 53 &13), 45 &27); IR: nPyO
1250; nCyC 1622 cm21; Anal. Calcd. for C11H25O3PSi: C
49.97, H 9.53. Found: C 49.88, H 9.46.1H NMR: 0.05 &s,
9 H, SiCH3), 1.35 &t, 6 H, CH2CH3, JHHˆ7.3 Hz), 1.65±1.82
&m, 5 H, CHCH3, SiCH2), 3.98±4.20 &m, 4 H, OCH2), 6.50
&dq, 1 H, yCH, JHHˆ6.6 Hz, JHP cisˆ27.0 Hz); 13C NMR d:
20.5 &SiCH3), 14.9 &d, yCHCH3, JCCCPˆ20.8 Hz), 16.3 &d,
CH2CH3, JCCOPˆ6.4 Hz), 17.5 &d, SiCH2, JCCPˆ11.4 Hz)
61.3 &OCH2, JCOPˆ6.0 Hz), 128.3 &d, yCP, JCPˆ
178.7 Hz), 137.2 &d, yCH, JCCPˆ11.4 Hz); 31P NMR d:
22.7.
11.2 &d, CH2Si, JCCPˆ6.1 Hz), 16.4 &d, CH2CH3, JCCOP
ˆ
6.1 Hz), 32.0 &t, CH, JCPˆ134.3 Hz), 62.4 &d, OCH2,
JCOPˆ6.1 Hz); 31P NMR d: 25.7.
3.3. Synthesis of 3a±c
3.3.4.
ꢀZ)-ꢀ2-Phenyl-1-trimethylsilanylmethyl-vinyl-)-
To a stirred solution of the substrate 2 &5.35 mmol) in an
heterogenousmixture of 50% aqueousosdium hydroxide
&6 mL) and dichloromethane &6 mL), the aldehyde
&5.50 mmol) wasadded dropwise. For 3a a 30% formalde-
hyde aqueoussolution wasadded. For 3b the reaction was
performed adding quaternary ammonium salt tetrabutyl-
ammonium iodide &TBAI) in catalytic amounts. The
mixture was stirred for several hours, as reported in Table
1, then extracted with dichloromethane. The organic layer
phosphonic acid diethyl ester 3c. Pale yellow oil, GC-
MS m/z: 326 &M1, 13), 325 &20), 255 &13), 253 &14), 154
&15), 153 &12), 145 &48), 144 &16), 139 &21), 129 &18), 121
&45), 117 &13), 116 &31), 115 &100), 75 &32), 73 &54), 45&17);
Anal. Calcd. for C16H27O3PSi: C 58.87, H 8.34. Found: C
58.77, H 8.44. IR: nPyO 1239 cm21; 1H NMR d: 0.15 &s, 9 H,
SiCH3), 1.10 &t, 6 H, CH2CH3, JHHˆ7.3 Hz), 1.95±2.10 &d, 2
H, JHPˆ18 Hz, CH2Si), 3.75±4.00 &m, 4 H, OCH2CH3), 7.00
&d, 1 H, yCH, JHP transˆ49 Hz), 7.22±7.55 &m, 5 H, Ph); 13
C
wasdried &Na SO4) and evaporated under vacuum. The
2
NMR d: ±1.3 &SiCH3), 15.9 &d, CH2CH3, JCCOPˆ7.0 Hz),
mixture was puri®ed by ¯ash-chromatography on silica
gel &hexane: ethylacetateˆ6:4) to yield the pure Z and E
isomers in the ratio reported in Table 1.
26.4 &d, SiCH2, JCCPˆ12.4 Hz), 61.2 &d, OCH2, JCOP
ˆ
7.0 Hz), 127.5 &CH arom), 128.9 &d, yCP, JCPˆ172.1 Hz),
129.0 &CH arom.), 136.9 &d, C arom. JCCCPˆ7.7 Hz), 140.6
&d, yCH, JCCPˆ9.7 Hz); 31P NMR d: 18.7.
3.3.1. ꢀ1-Trimethylsilanylmethyl-vinyl)-phosphonic acid
diethyl ester 3a. Pale yellow oil, GC-MS m/z: 250 &M1 2),
235 &21), 207 &18), 193 &13), 182 &17), 179 &92), 177 &19),
167 &13), 165 &19), 155 &31), 153 &29), 139 &56), 138 &23),
137 &22), 123 &38), 122 &14), 120 &100), 75 &36), 73 &49), 45
&20); Anal. Calcd. for C10H23O3PSi: C 47.98, H 9.26. Found:
C 47.79, H 9.29. IR: nPyO 1251, nCyC 1556 cm21; 1H NMR
d: 0.04 &s, 9 H, SiCH3), 1.30 &t, 6 H, CH2CH3), 1.72 &d, 2 H,
CH2Si, JHPˆ16.1 Hz), 4.05 &m, 4 H, OCH2CH3), 5.54 &d, 1
3.3.5.
ꢀE)-ꢀ2-Phenyl-1-trimethylsilanylmethyl-vinyl)-
phosphonic acid diethyl ester 3c. Pale yellow oil, GC-
MS m/z: 326 &M1, 16), 325 &26), 311 &14), 255 &18), 253
&17), 154 &15), 145 &49), 144 &17), 138 &22), 129 &18), 121
&46), 117 &16), 116 &35), 115 &100), 75 &32), 73 &49), 45 &16),
43 &13); Anal. Calcd. for C17H27O3PSi: C 58.87, H 8.34.
Found: C 58.86, H 8.40. IR: nPyO 1237 cm21, nCyC
ring
1596 cm21; H NMR d: 0.02 &s, 9 H, SiCH3), 1.35 &t, 6 H,
1
H, yCH, JHP transˆ49.8 Hz), 5.88 &d, 1 H, yCH, JHP cis
ˆ
22.7 Hz); 13C NMR d: 21.3 &SiCH3), 16.3 &d, CH2CH3,
JCCOPˆ6.3 Hz), 21.9 &d, CH2Si, JCCPˆ10.6 Hz), 61.6 &d,
OCH2CH3, JCOPˆ6.0 Hz), 126.9 &d, yCH2, JCCPˆ10.0 Hz),
136.6 &d, yC, JCPˆ171.5 Hz); 31P NMR d: 20.6.
CH2CH3, JHHˆ7.3 Hz), 2.04±2.18 &d, 2 H, SiCH2, JHPˆ
22.0 Hz), 4.04±4.22 &m, 4 H, OCH2CH3), 7.22±7.40 &m, 6
H, Ph and CH); 13C NMR d: 20,5 &SiCH3), 16.3 &d,
CH2CH3, JCCOPˆ6.3 Hz), 18.2 &d, SiCH2, JCCPˆ9.7 Hz),
61.5 &d, OCH2, JCOPˆ6.0 Hz), 127.8 &CH arom.), 128.2
&CH arom.), 129.3 &d, yCP, JCPˆ175.4Hz), 136.3 &d, C
arom. JCCCPˆ24.4 Hz), 138.5 &d, yCH, JCCPˆ12.2 Hz);
31P NMR d: 23.2.
3.3.2.
ꢀZ)-ꢀ1-Trimethylsilanylmethyl-propenyl)-phos-
phonic acid diethyl ester 3b. Pale yellow oil, GC-MS
m/z: 264 &M1, 3), 250 &13), 249 &84), 221 &30), 205 &16),
193 &96), 191&27), 187 &17), 155 &28),153 &15), 139 &46),138
&18), 137 &15), 135 &15), 123 &31), 121 &100), 83 &14),
77&13), 75 &47), 73 &76), 53 &16), 45 &29); Anal. Calcd. for
C11H25O3PSi: C 49.97, H 9.53. Found: C 49.85, H 9.52. IR:
3.4. Preparation of 3d
To a stirred solution of a 2M LDA &1.32 mL, 2.64 mmol) in
dry THF &1.45 mL), 900 mg &2.4 mmol) of 2 in dry THF
&0.80 mL) were added, under argon at ±788C. After 5 min
the bath washeated to 2208C and exanal &0.32 mL,
2.6 mmol) in dry THF &0.80 mL) wasadded dropwies.
1
nPyO 1253, nCyC 1622 cm21; H NMR d: 0.00 &s, 9H,
SiCH3), 1.30 &t, 6H, CH2CH3, JHHˆ7.3 Hz), 1.70 &d, 2 H,
SiCH2, JHPˆ16.7 Hz), 2.00 &m, 3 H, yCHCH3), 4.10 &m, 4
H, OCH2), 6.08 &dq, 1 H, yCH, JHHˆ7.3 Hz, JHP
ˆ
trans

4426
M. A. Loreto et al. / Tetrahedron 57 /2001) 4423±4427
The mixture wasstirred for 2.5 h at room temperature then
treated with water &5 mL) and the aqueousphaes was
extracted with diethyl ether. The organic layer wasdried
&Na2SO4) and evaporated under vacuum. The mixture was
puri®ed by ¯ash-chromatography on silica gel &hexane:
ethylacetateˆ7:3) to yield the pure Z and E isomers in the
ratio reported in Table 1.
chromatography on silica gel &hexane: acetoneˆ7:3) in the
yield reported in Table 2.
3.5.1.
[1-ꢀEthoxycarbonylamino-methyl)-vinyl]-phos-
phonic acid diethyl ester 5a. Colorless oil, GC-MS m/z:
265 &M1, 14), 220 &26), 192 &65), 177 &28), 164 &84), 156
&38), 149 &20), 148 &18), 146 &20), 137 &32), 136 &100), 135
&13), 129 &14), 128 &31), 121 &42), 120 &31), 118 &54), 109
&44), 107 &18), 100 &16), 91 &13), 84 &20), 82 &33), 81 &39),
65 &27), 57 &28), 56 &40), 55 &22), 54 &21); Anal. Calcd. for
C10H20NO5P: C 45.28, H 7.60, N 5.28. Found: C 45.01, H
7.72, N 5.15; IR: nNH 3446, nCyO 1727, nPyO 1254 cm21; 1H
NMR d: 1.13±1.34 &2 t, 9 H, CH3), 3.82±4.20 &m, 8 H,
OCH2, NCH2), 5.34 &br, 1 H, NH), 5.90 &d, 1 H, yCH2,
JHP transˆ46.9 Hz), 6.05 &d, 1 H, yCH2, JHP cisˆ22.0 Hz);
3.4.1. ꢀZ)-ꢀ1-Trimethylsilanylmethyl-hept-1-enyl)phos-
phonic acid diethyl ester 3d. Pale yellow oil, GC-MS
m/z: 320 &M1, 3), 305 &26),291 &28), 278 &14), 277 &47),
264 &32), 263 &37), 250 &189), 249 &100); 247 &20), 235
&14), 221 &15), 210 &27), 204 &26), 191 &45), 183 &17), 182
&15), 154 &15), 139 &20), 122 &24), 120 &81), 109 &18), 81
&13), 75&38), 73&82), 67&19), 45&17); Anal. Calcd. for
C15H33O3PSi: C 56.22, H 10.38. Found: C 56.34, H 10.52.
IR: nPyO 1246, nCyC 1618 cm21; 1H NMR d: 20.01 &s, 9 H,
SiCH3), 0.82 &t, 3 H, CH2CH3, JHHˆ7.3 Hz), 1.20±1.42 &m,
12 H, 3 CH2, 2 OCH2CH3), 1.65 &d, 2 H, CH2Si,
JHPˆ16.1 Hz), 2.40 &m, 2 H, CH2CHˆ), 4.00 &m, 4 H,
OCH2), 5.90 &dt, 1 H, yCH, JHHˆ6.6 Hz, JHP transˆ51.3 Hz);
13C NMR d: 14.4 &CH2CH3), 16.1 &d, CH2CH3, JCCOP
ˆ
6.3 Hz), 42.2 &d, NCH2, JCCPˆ15.2 Hz), 60.8 &OCH2),
62.0 &d, OCH2, JCOPˆ5.7 Hz), 129.7 &d, yCH2, JCCP
ˆ
7.7 Hz), 136.3 &d, yC, JCPˆ172.6 Hz), 156.3 &CyO); 31P
NMR d: 18.0.
13C
NMR d: 21.4 &SiCH3), 13.9 &CH2CH3), 16.2
3.5.2.
ꢀ2-Ethoxycarbonylamino-1-methylene-propyl)-
&d,OCH2CH3, JCCOPˆ6.6 Hz), 22.4 &CH2), 24.1 &d, CH2Si,
phosphonic acid diethyl ester 5b. Colorless oil, GC-MS
m/z: 279 &M1, 2), 264 &100), 218 &13), 206 &38), 192 &22),
164 &24), 137 &30), 136 &48), 135 &33), 120 &17), 117 &22),
109 &23), 82 &14), 81 &15), 53 &16), 44 &18); Anal. Calcd. for
C11H22NO5P: C 47.31, H 7.94, N 5.02. Found: C 47.25, H
7.96, N 4.91; IR: n NH 3440, nCyO 1722, nPyO 1250 cm21; 1H
NMR d: 1.20±1.48 &m, 12 H, CH3), 4.00±4.20 &m, 6H,
OCH2), 4.40±4.70 &m, 1 H, CH), 5.32 &br, 1 H, NH),
JCCPˆ12.8 Hz), 29.3 &CH2), 30.3 &d, CH2CHˆ, JCCCP
ˆ
6.9 Hz), 31.4 &CH2), 60.9 &d, OCH2, JCOPˆ5.8 Hz), 128.6
&d, yC, JCPˆ171.6 Hz), 145.6 &d, yCH, JCCPˆ12.2 Hz).
3.4.2. ꢀE)-ꢀ1-Trimethylsilanylmethyl-hept-1-enyl)phos-
phonic acid diethyl ester 3d. Pale yellow oil, GC-MS
&m/z): 320 &M1, 3); 305 &26); 291 &28); 278 &14); 277
&47); 264 &33); 263 &38); 250 &18); 249 &100); 235 &14);
221 &15); 210 &28); 204 &20); 191 &44); 183 &18); 182
&16); 154 &16); 139 &22); 122 &28); 120 &94); 109 &14); 81
&15); 77 &13); 75 &48); 73 &91); 67 &20); 53 &13); 45 &21); 41
&13); Anal. Calcd. for C15H33O3PSi: C 56.22, H 10.38.
5.82±6.14 &t, 2 H, yCH2, JHP
ˆ45.4 Hz, JHP
ˆ
trans
cis
21.2 Hz); 13C NMR d: 14.6 &CHCH3), 16.2 &d, CH2CH3,
JCCOPˆ6.1 Hz), 21.3 &CH2CH3), 50.0 &d, CH, JCCP
ˆ
12.9 Hz), 60.7 &OCH2), 62.0 &d, OCH2, JCOPˆ6.0 Hz),
129.7 &yCH2), 136.8 &d, yC, JCPˆ170.0 Hz), 156.1 &CO);
31P NMR d: 18.0.
Found:
C 56.22, H 10.50. IR: nPyO 1251, nCyC
1612 cm21; H NMR d: 0.01 &s, 9 H, SiCH3), 0.85 &t, 3 H,
CH2CH3, JHHˆ7.3 Hz), 1.18±1.46 &m, 12 H, 3 CH2, 2
OCH2CH3), 1.68 &d, 2 H, CH2Si, JHPˆ20.5 Hz), 2.02 &m,
2 H, CH2CHy), 4.00 &m, 4 H, OCH2), 6.35 &dt, 1 H, yCH,
JHHˆ6.6 Hz, JHP cisˆ23.4 Hz); 13C NMR d: 20.5 &SiCH3),
13.9 &CH2CH3), 16.2 &d, OCH2CH3, JCCOPˆ6.4 Hz), 17.7 &d,
CH2Si, JCCPˆ11.5 Hz), 22.4 &CH2), 28.2 &CH2), 29.1 &d,
CH2CHˆ, JCCCPˆ19.6 Hz), 31.5 &CH2), 61.2 &d, OCH2,
JCOPˆ5.9 Hz), 126.8 &d, yC, JCPˆ177.4 Hz), 143.0 &d,
yCH, JCCPˆ10.4 Hz).
1
3.5.3. [1-ꢀEthoxycarbonylamino-phenyl-methyl)-vinyl]-
phosphonic acid diethyl ester 5c. Colorless oil, GC-MS
m/z: 341 &M1, 26); 295 &22); 294 &21); 269 &13); 268
&100); 240 &15); 238 &13); 212 &13); 204 &14); 196 &19);
193 &22); 179 &15); 178 &47); 158 &14); 156 &18); 137
&32); 136 &30); 132 &25); 131 &19); 130 &31); 116 &25);
109 &35); 107 &16); 106 &30); 104 &14); 103 &24); 91 &19),
82 &20), 80 &24), 79 &18), 77 &36), 45 &16), 44 &85); Anal.
Calcd. for C16H24NO5P: C 56.30, H 7.09, N 4.10. Found: C
56.52, H 7.31, N 4.08; IR: nNH 3358, nCyO 1733, nPyO
1
1254 cm21, H NMR d: 1.05 &t, 3 H, CH2CH3), 1.20±1.38
3.5. Reaction of 3 with NsONHCO2Et
&m, 6 H, CH2CH3), 3.60±4.20 &m, 6 H, OCH2), 5.60 &dd, 1
H, CH, JHHˆ8.0 Hz, JHPˆ17.6 Hz), 5.90 &br, 1 H, NH), 6.08
&d, 1 H, yCH2, JHP transˆ44.7 Hz), 6.18 &d, 1 H, yCH2, JHP
To a stirred solution of the substrate 3 &5.0 mmol) in CH2Cl2
&2.5 mL), NsONHCO2Et &5.0 mmol, 1 equiv.) and CaO
&5.0 mmol, 1 equiv.), were added, every 30 min, reaching
the molar ratio substrate: reagent reported in Table 2.
During the addition the ¯ask was cooled in water bath to
avoid overheating, asthe reaction isexothermic. After
stirring &4±24 h, Table 2), 100 mL of a pentane±CH2Cl2
mixture &2:1) wasadded. After ®ltration, the organic
phase was concentrated in vacuo and treated with AcOH
&8±10 equiv., Table 2) for 26 h. The mixture waswashed
with aqueousosdium bicarbonate, then extracted with
CH2Cl2 and dried &Na2SO4). The solvent was evaporated
under vacuum and the products 5 were isolated by ¯ash-
ˆ21.2 Hz), 7.20±7.42 &m, 5 H, Ph); 13C NMR d: 15.5
cis
&CH3), 16.1 &d, CH3, JCCOPˆ5.8 Hz), 57.6 &d, CH, JCCP
ˆ
13.4 Hz), 61,1 &OCH2), 61.9 &d, OCH2, JCOPˆ6.1 Hz),
126.9 &CH arom.), 127.7 &CH arom.), 128.5 &CH arom.),
129.5 &d, yC, JCPˆ170.9 Hz), 139.2 &yCH2), 155.6
&CyO); 31P NMR d: 17.2.
3.5.4.
ꢀ2-Ethoxycarbonylamino-1-methylene-heptyl)-
phosphonic acid diethyl ester 5d. Colorless oil, GC-MS
m/z: 335 &M1, 0.08), 264 &100), 218 &13), 192 &20), 164 &18),
145 &12), 136 &26), 117 &25), 109 &14); Anal. Calcd. for
C15H30NO5P: C 53.72, H 9.02, N 4.18. Found: C 53.73, H

M. A. Loreto et al. / Tetrahedron 57 /2001) 4423±4427
4427
8.94, N 4.14; IR: nNH 3444, nCyO1722, nPyO1248 cm21; 1H
NMR d: 0.88 &t, 3 H, CH3), 1.15±1.42 &m, 15 H, 3 CH2, 3
CH3), 1.55±1.80 &m, 2 H, CH2), 3.85±4.49 &m, 7 H, 3 OCH2,
3. Allen, J. G.; Atherton, F. R.; Hall, M. J. Nature 1978, 272, 56±
58.
4. Stowasser, B.; Budt, K. H.; Jian-Qi, L.; Peyman, A.; Ruppert,
D. Tetrahedron Lett. 1992, 33, 6625±6628.
CH), 5.42 &br, 1 H, NH), 5.91 &d, 1 H, yCH2, JHP trans
ˆ
46.1 Hz), 6.00 &d, 1 H, yCH2, JHP cisˆ21.2 Hz); 13C NMR
d: 14.0 &CH3), 15.5 &CH3), 16.1 &d, CH3, JCCOPˆ6.6 Hz),
22.4 &CH2), 25.7 &CH2), 31.3 &CH2), 34.6 &CH2), 55.0 &d,
CH, JCCPˆ11.6 Hz), 60.6 &OCH2), 62.0 &d, OCH2, JCOPˆ6.0
HZ), 130.2 &d, yCH2, JCCPˆ9.4 Hz), 139.9 &d, yC, JCPˆ
169.6 Hz); 155.8 &CyO).
5. &a) Bergnes, G.; Daouk, R. K. Bioorg. Med. Chem. Lett. 1997,
1021±1026. &b) Warthon, C. J.; Wrigglesworth, R. J. Chem.
Soc., Perkin Trans. 1 1981, 433±436. &c) Patel, D. V.; Rielly-
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Acknowledgements
6. Fields, S. C. Tetrahedron 1999, 55, 12237±12273.
7. Carducci, M.; Fioravanti, S.; Loreto, M. A.; Pellacani, L.;
Tardella, P. A. Tetrahedron Lett. 1996, 37, 3777±3778.
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9. Loreto, M. A.; Pompei, F.; Tardella, P. A.; Tofani, D.
Tetrahedron 1997, 53, 15853±15858.
We thank Dott. M. Bassetti for his assistance in the 31P
NMR spectra, the Italian Ministero dell'Universita e della
Ricerca Scienti®ca e Tecnologica &MURST), the University
`La Sapienza' of Rome &National Project `Stereoselezione
in Sintesi Organica. Metodologie ed Applicazioni') and the
Consiglio Nazionale delle Ricerche &CNR) for ®nancial
support.
Á
10. Fazio, A.; Loreto, M. A.; Tardella, P. A. Tetrahedron Lett.
2001, 42, 2185±2187.
11. &a) Piechucki, C. Synthesis 1974, 869±870. &b) Mikolajczyk,
M.; Grzejszczak, S.; Midura, W.; Zatorski, A. Synthesis 1976,
396±398.
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