Organocatalyzed synthesis of α-(Substituted methyl)vinylphosphonates

Article abstract of DOI:10.1055/s-0030-1260176

α-(Substituted methyl)vinylphosphonates are obtained by a DABCO-catalyzed substitution reaction of diethyl α-(tert- butoxycarbonyloxymethyl)vinylphosphonate and (N-protected) amino- or soft pronucleophiles. The reactions are easily performed under mild co

Full text of DOI:10.1055/s-0030-1260176

PAPER
3109
Organocatalyzed Synthesis of a-(Substituted Methyl)vinylphosphonates
Cécile Garzon, Mireille Attolini,* Michel Maffei*
Aix-Marseille Université, Institut des Sciences Moléculaires de Marseille (iSm2), UMR CNRS 6263, équipe HIT, B.P. 551,
Campus scientifique de Saint Jérôme, 13397 Marseille Cedex 20, France
Fax +33(4)91289402; E-mail: michel.maffei@univ-cezanne.fr; E-mail: mireille.attolini@univ-cezanne.fr
Received 11 May 2011; revised 16 June 2011
According to the general trends for this reaction, 1 reacts
with DABCO to produce the ammonium salt A and tert-
butoxide anion (after CO2 extrusion), which will deproto-
nate the pronucleophile (NuH) to afford an activated spe-
Abstract: a-(Substituted methyl)vinylphosphonates are obtained
by a DABCO-catalyzed substitution reaction of diethyl a-(tert-
butoxycarbonyloxymethyl)vinylphosphonate and (N-protected)
amino- or soft pronucleophiles. The reactions are easily performed
under mild conditions (r.t., 1 h), and give good to excellent yields of cies (Nu–). The latter will react with A to yield finally the
the title compounds. A diphosphonate by-product was isolated in
expected product together with regeneration of DABCO
some examples, when the nucleophile has a less pronounced nu-
(Scheme 1).
cleophilic character.
Key words: a-(substituted methyl)vinylphosphonates, organoca-
O
EtO
talysis, diethyl a-(tert-butoxycarbonyloxymethyl)vinylphospho-
– CO2
–
NuH
P
t-BuO
N
nate, pronucleophiles, 1,4-diazabicyclo[2.2.2]octane
EtO
+
N
Functionalized vinylphosphonates constitute an important
class of building blocks for which numerous synthetic
methods have been reported.1 However, a-(substituted
methyl)vinylphosphonates have received less attention2
although they can be used for the preparation of biologi-
cally active b-aminophosphonic acid derivatives3 and 2,4-
disubstituted tetrahydrothiophenes.4 We recently reported
the synthesis of aminovinylphosphonates through an or-
ganocatalyzed displacement reaction of acetate by amines
in diethyl (a-acetoxymethyl)vinylphosphonate.5 Al-
though quite general, this method suffered from a lack of
selectivity when using primary amines, which yielded
mixtures of mono- and dialkylated products. Furthermore,
the use of other (less) nucleophilic reagents (e.g., soft car-
bon nucleophiles) did not give satisfactory results. Re-
cently, the organic Lewis base catalyzed substitution of O-
Boc Morita–Baylis–Hillman (MBH) adducts has emerged
as a powerful method for the synthesis of multifunctional
compounds in one step.6 In order to circumvent the above
limitations associated with the use of diethyl (a-acet-
oxymethyl)vinylphosphonate, we turned our attention to a
more reactive related substrate, namely, diethyl a-(tert-
butoxycarbonyloxymethyl)vinylphosphonate (1), in a
1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed sub-
stitution by amine derivatives and soft carbon nucleo-
philes (Equation 1).
A
1
t-BuOH
O
P
DABCO
EtO
EtO
–
Nu
+
N
N
O
EtO
EtO
P
Nu
Scheme 1
Vinylphosphonate 1 was obtained by treating diethyl (a-
hydroxymethyl)vinylphosphonate with di-tert-butyl di-
carbonate under standard conditions and was isolated as a
colorless oil, stable to air and moisture. In a first set of ex-
periments, N-protected primary amine equivalents were
used in order to set up a stereoselective synthesis of
monoalkylated
a-(aminomethyl)vinylphosphonates
(Table 1). Thus, N-tosylamides (Table 1, entries 1–4) as
well as succinimide (entry 5) or a chiral oxazolidinone
(entry 6) yielded the corresponding N-protected a-(ami-
nomethyl)vinylphosphonates as the sole products in very
good yields, the reactions being completed after one hour
at room temperature. Among the different solvents tested,
toluene was the most effective, whereas THF, dichlo-
romethane, and diethyl ether led to lower yields with for-
mation of unidentified by-products (as evidenced by 31P
NMR analysis of the crude products). Thus, this provides
a valuable selective synthesis of monoalkylated aminovi-
O
O
EtO
EtO
DABCO (20 mol%)
EtO
EtO
P
+
NuH
P
OBoc
Nu
toluene, r.t.
1 h
1
Equation 1
SYNTHESIS 2011, No. 19, pp 3109–3114
x
x.
x
x
.
2
0
1
1
Advanced online publication: 18.08.2011
DOI: 10.1055/s-0030-1260176; Art ID: Z49111SS
© Georg Thieme Verlag Stuttgart · New York

3110
C. Garzon et al.
PAPER
Table 2 Synthesis of a-(Substituted Methyl)vinylphosphonates
Table 1 Synthesis of N-Protected a-(Aminomethyl)vinylphospho-
nates
Entry Pronucleophile
Product
Yield
(%)
Entry Pronucleophile
Product
Yield
(%)
O
P
CO2Me
EtO
O
P
O
O
1
8
9
CO2Me
CO2Me
83
84
O
O
O
EtO
EtO
S
S
CO2Me
HN
EtO
N
1
2
3
90
97
O
P
CO2Et
EtO
EtO
2
CO2Et
COMe
COMe
O
P
O
O
O
EtO
EtO
S
S
HN
N
2
O
P
3
10
11
99
79
EtO
EtO
O
O
O
O
P
O
CO2Et
CO2Et
O
EtO
EtO
HN
SO2
O
O
N
O
O
P
EtO
EtO
3
4
99
SO2
4
O
O
O
O
O
P
O
O
P
O
EtO
EtO
O
O
O
EtO
EtO
5
12
13
99
89
S
S
HN
N
4
5
5
6
94
96
O
O
P
NO2
EtO
EtO
6
NO2
CO2Et
CO2Et
O
P
O
O
EtO
EtO
HN
O
N
O
O
P
EtO
EtO
SO2
SO2
7
CH2(SO2Ph)2
14
99
O
P
O
O
EtO
EtO
HN
N
O
O
6
7
89
O
P
O
O
EtO
EtO
OEt
OEt
OEt
P
P
8
9
15
16
63
79
OEt
CO2Et
CO2Et
O
O
P
O
P
nylphosphonates upon removal of the protecting tosyl
group.
OEt
P
EtO
EtO
OEt
OEt
OEt
CN
CN
Next, our attention was turned to the use of carbon pronu-
cleophiles, which lead to a-(substituted methyl)vi-
nylphosphonates (Table 2) under the same experimental
conditions. Similar compounds were already prepared by
halogen substitution in 3-chloroprop-1-en-2-ylphospho-
nates, but these reactions were not selective, yielding mix-
tures of mono- and dialkylation products.2d Alternatively,
Horner–Wadsworth–Emmons olefination leads to analo-
gous derivatives.7
cyanomethylphosphonate (entry 9) led to somewhat lower
yields, and chromatographic purification allowed the iso-
lation of a by-product whose structure was assigned as 17
on the basis of its spectral data. We suspected that 17
could arise from the nucleophilic attack of tert-butoxide
onto 1, followed by reaction of the generated alkoxy anion
B with intermediate A (Scheme 2). This assumption was
supported by the presence of small amounts of diethyl (a-
hydroxymethyl)vinylphosphonate in the crude reaction
mixtures as evidenced by 31P NMR analysis.
In the reactions studied, very good to quantitative yields
were obtained with dimethyl malonate (Table 2, entry 1),
b-keto esters (entries 2 and 3), and b-diketones (entries 4
and 5). Ethyl nitroacetate (entry 6) and bis(phenylsulfo-
nyl)methane (entry 7) also gave good results. However,
the use of triethyl phosphonoacetate (entry 8) and diethyl
In order to check this hypothesis, 1 was submitted to the
DABCO-catalyzed reaction in the absence of pronucleo-
Synthesis 2011, No. 19, 3109–3114 © Thieme Stuttgart · New York

PAPER
Synthesis of a-(Substituted Methyl)vinylphosphonates
3111
1
proton signals of CDCl3 as an internal standard for H, the central
triplet of CDCl3 at 77.0 ppm for 13C, and H3PO4 as external standard
for 31P. Mass spectra (EI) were recorded with a QStar Elite spec-
trometer. Optical rotation was measured with a P-2000 JASCO
polarimeter. Diethyl (a-hydroxymethyl)vinylphosphonate was pre-
pared as already described.8 All other reagents were commercial
grades and used as received. The starting N-tosylamines were pre-
pared according to reported procedures.9
O
P
EtO
EtO
– CO2
–
t-BuO
N
1
+
N
A
O
1
t-BuO
Ot-Bu
Diethyl a-(tert-Butoxycarbonyloxymethyl)vinylphosphonate (1)
To a cooled (0 °C) and stirred solution of diethyl (a-hydroxymeth-
yl)vinylphosphonate (3 g, 15.5 mmol) and 4-dimethylaminopyri-
dine (0.094 g, 0.77 mmol, 0.05 equiv) in anhyd CH2Cl2 (30 mL) was
added dropwise a solution of di-tert-butyl dicarbonate (3.91 mL, 17
mmol, 1.1 equiv) in anhyd CH2Cl2 (25 mL). The mixture was then
stirred at r.t. overnight. Aq 5% HCl (10 mL) was added, and the lay-
ers were decanted. The organic layer was washed with aq 10%
NaHCO3 (10 mL), brine (20 mL), and dried (MgSO4). After filtra-
tion and removal of solvents in vacuo, the residue was purified by
flash chromatography on silica gel (EtOAc–MeOH, 95:5) to give 1
as a colorless oil; yield: 3.36 g (89%); Rf = 0.61 (EtOAc–MeOH,
95:5).
O
P
EtO
EtO
DABCO
–
O
B
N
+
O
N
P
EtO
EtO
O
O
EtO
OEt
OEt
P
P
EtO
O
1H NMR (300 MHz, CDCl3): d = 1.33 (t, 3JH,H = 7.2 Hz, 6 H, CH3),
17
1.48 (s, 9 H, t-C4H9), 4.10 (m, 4 H, OCH2), 4.71 (dt, 3JP,H = 8.1 Hz,
3
4JH,H = 1.5 Hz,
2
H, CH2), 6.10 (dq, JH,P = 45.9 Hz,
Scheme 2
2JH,H = 4JH,H = 1.5 Hz, 1 H, =CH2), 6.22 (dq, JH,P = 22.7 Hz,
3
2JH,H = 4JH,H = 1.5 Hz, 1 H, =CH2).
O
EtO
P
DABCO
O
O
P
3
13C NMR (75.47 MHz, CDCl3): d = 16.2 (d, JP,C = 6.3 Hz, CH3),
(20 mol%)
EtO
EtO
OEt
OEt
P
2
EtO
OBoc
27.7 [s, C(CH3)3], 62.1 (d, JP,C = 5.7 Hz, OCH2), 65.0 (d,
O
toluene, r.t.
1 h, 85%
2
2JP,C = 18.4 Hz, CH2), 82.5 [s, C(CH3)3], 130.9 (d, JP,C = 6.3
Hz, =CH2), 135.4 (d, 1JP,C = 177.3 Hz, PC=), 152.9 [s, OC(O)O].
31P NMR (121.49 MHz, CDCl3): d = 16.1.
1
17
Equation 2
HRMS (EI): m/z calcd [M + H+] for C12H23O6P: 295.1305; found:
295.1304.
phile (Equation 2), which led to the formation of 17 in
85% yield.
Organocatalyzed Synthesis of a-(Substituted Methyl)vinylphos-
phonates; General Procedure
To a solution of 1 (0.1 g, 0.34 mmol) and the respective pronucleo-
phile (0.37 mmol, 1.1 equiv) in anhyd toluene (1.5 mL) was added
To our knowledge, this is the first report of such a side re-
action during an organocatalyzed reaction of a Boc deriv-
ative of a MBH adduct. The formation of 17 during some DABCO (0.0076 g, 0.068 mmol, 0.2 equiv) and the mixture was
stirred at r.t. for ca. 1 h. The progress of the reaction can be moni-
of the above reactions can be accounted for by the use of
tored by TLC (for eluents, see individual listings below) or by 31
NMR spectroscopy. After complete consumption of 1, the volatiles
were removed in vacuo, and the residue was purified by flash chro-
matography on silica gel (Tables 1 and 2).
P
less nucleophilic reagents (Table 2, entries 8 and 9) for
which the side reaction leading to 17 may occur to some
extent. Indeed, trace amounts of 17 were also detected in
the syntheses corresponding to entries 1–7 (Table 2).
Diethyl a-[(N-Allyl-N-tosyl)aminomethyl]vinylphosphonate (2)
Yield: 90%; colorless oil; Rf = 0.40 (EtOAc).
In conclusion, we have developed a general synthesis of
a-(substituted methyl)vinylphosphonates using a DAB-
CO-catalyzed substitution of the tert-butoxycarbonyloxy
moiety in 1 by amino and soft carbon nucleophiles. The
reactions are completed in usually one hour at room tem-
perature in the presence of 20 mol% of organocatalyst.
Despite the fact that a diphosphonate by-product is
formed in some experiments, its easy removal together
with the high yields of expected products still enable a
useful synthesis of the title compounds.
1H NMR (300 MHz, CDCl3): d = 1.31 (t, 3JH,H = 7.2 Hz, 6 H, CH3),
2.43 (s, 3 H, CH3), 3.80 (br d, 3JH,H = 6.6 Hz, 2 H, CH2), 3.94 (dt,
3JH,P = 5.7 Hz, 4JH,H = 1.7 Hz, 2 H, CH2), 4.07 (m, 4 H, OCH2), 5.08
3
(m, 2 H, =CH2), 5.51 (m, 1 H, CH=), 6.05 (dq, JH,P = 46.5 Hz,
3
2JH,H = 4JH,H = 1.7 Hz, 1 H, =CH2), 6.18 (dq, JH,P = 22.5 Hz,
3
2JH,H = 4JH,H = 1.7 Hz, 1 H, =CH2), 7.29 (br d, JH,H = 8.2 Hz, 2
Harom), 7.70 (br d, 3JH,H = 8.2 Hz, 2 Harom).
3
13C NMR (75.47 MHz, CDCl3): d = 16.3 (d, JP,C = 6.3 Hz, CH3),
21.5 (s, CH3), 47.2 (d, 2JP,C = 19.5 Hz, CH2), 50.7 (s, CH2), 62.1 (d,
2JP,C = 5.7 Hz, OCH2), 119.8 (s, =CH2), 127.2 (s, CHarom), 129.7 (s,
CHarom), 130.5 (d, 2JP,C = 7.5 Hz, =CH2), 131.9 (s, =CH), 134.5 (d,
1JP,C = 174.4 Hz, PC=), 137.0 (s, Carom), 143.5 (s, Carom).
Toluene was distilled from Na and CH2Cl2 from CaH2 immediately
before use. Analytical TLC analyses were performed on Merck sil-
ica gel 60 F254 plates. Visualization was accomplished by UV light
or by dipping in 2% KMnO4 aqueous solution. Flash chromatogra-
phy was carried out using Merck silica gel 60 (230–400 mesh).
NMR spectra were recorded on a Bruker Avance 300 spectrometer
(1H: 300 MHz, 13C: 75.47 MHz, 31P: 121.49 MHz) using residual
31P NMR (121.49 MHz, CDCl3): d = 17.3.
HRMS (EI): m/z calcd [M + H+] for C17H26NO5PS: 388.1342;
found: 388.1346.
Synthesis 2011, No. 19, 3109–3114 © Thieme Stuttgart · New York

3112
C. Garzon et al.
PAPER
3
Diethyl a-[(N-(But-3-enyl)-N-tosyl)aminomethyl]vinylphospho-
nate (3)
Yield: 97%; colorless oil; Rf = 0.54 (EtOAc).
13C NMR (75.47 MHz, CDCl3): d = 16.3 (d, JP,C = 6.3 Hz, CH3),
28.2 (s, CH2), 39.6 (d, 2JP,C = 16.1 Hz, CH2), 62.3 (d, 2JP,C = 5.2 Hz,
OCH2), 130.9 (d, 2JP,C = 8.0 Hz, =CH2), 132.9 (d, 1JP,C = 177.3 Hz,
PC=), 176.3 (s, C=O).
1H NMR (300 MHz, CDCl3): d = 1.33 (t, 3JH,H = 7.3 Hz, 6 H, CH3),
2.18 (q, 3JH,H = 7.5 Hz, 2 H, CH2), 2.42 (s, 3 H, CH3), 3.20 (m, 2 H,
31P NMR (121.49 MHz, CDCl3): d = 16.0.
3
CH2), 3.96 (br d, JH,P = 5.5 Hz, 2 H, CH2), 4.08 (m, 4 H, OCH2),
HRMS (EI): m/z calcd [M + H+] for C11H18NO5P: 276.0995; found:
3
4.98 (m, 2 H, =CH2), 5.62 (m, 1 H, CH=), 6.08 (br d, JH,P = 46.4
276.0994.
Hz, 1 H, =CH2), 6.18 (br d, 3JH,P = 22.6 Hz, 1 H, =CH2), 7.30 (br d,
3JH,H = 8.2 Hz, 2 Harom), 7.69 (br d, 3JH,H = 8.2 Hz, 2 Harom).
Diethyl (S)-3-(4-Benzyl-2-oxooxazolidin-3-yl)prop-1-en-2-yl-
phosphonate (7)
Yield: 89%; slightly yellow oil; Rf = 0.46 (EtOAc–MeOH, 95:5);
3
13C NMR (75.47 MHz, CDCl3): d = 16.3 (d, JP,C = 6.6 Hz, CH3),
21.5 (s, CH3), 32.4 (s, CH2), 48.2 (s, CH2), 49.0 (d, 2JP,C = 19.8 Hz,
2
CH2), 62.2 (d, JP,C = 5.5 Hz, OCH2), 117.2 (s, =CH2), 127.2 (s,
[a]D25 +7.3 (c 0.44, CH2Cl2).
2
CHarom), 129.7 (s, CHarom), 130.6 (d, JP,C = 7.1 Hz, =CH2), 134.4
3
1H NMR (300 MHz, CDCl3): d = 1.30 (2 t, JH,H = 7.0 Hz, 6 H,
1
(s, =CH), 134.9 (d, JP,C = 174.5 Hz, PC=), 136.8 (s, Carom), 143.5
CH3), 2.60 (dd, 2JH,H = 13.6 Hz, 3JH,H = 8.9 Hz, 1 H, CH2Ph), 3.05
(s, Carom).
2
3
(dd, JH,H = 13.6 Hz, JH,H = 4.5 Hz, 1 H, CH2Ph), 3.75 (m, 1 H,
CH2N), 4.00 (m, 2 H, CHN and 1 H of CH2O), 4.08 (m, 4 H, OCH2),
4.14 (m, 1 H, CH2O), 4.40 (m, 1 H, CH2N), 5.84 (br d, 3JH,P = 45.9
Hz, 1 H, =CH2), 6.17 (br d, 3JH,P = 21.6 Hz, 1 H, =CH2), 7.11 (m, 2
31P NMR (121.49 MHz, CDCl3): d = 17.0.
HRMS (EI): m/z calcd [M + H+] for C18H28NO5PS: 402.1499;
found: 402.1504.
Harom), 7.22 (m, 1 Harom), 7.27 (m, 2 Harom).
Diethyl a-[(N-tert-Butoxycarbonyl-N-tosyl)aminomethyl]vinyl-
phosphonate (4)
Yield: 99%; colorless oil; Rf = 0.63 (EtOAc).
1H NMR (300 MHz, CDCl3): d = 1.25 (t, 3JH,H = 5.7 Hz, 6 H, CH3),
1.25 (s, 9 H, t-C4H9), 2.34 (s, 3 H, CH3), 4.02 (m, 4 H, OCH2), 4.53
(dt, 3JH,P = 4.7 Hz, 4JH,H = 1.7 Hz, 2 H, CH2), 5.82 (br d, 3JH,P = 45.9
Hz, 1 H, =CH2), 6.11 (br d, 3JH,P = 22.8 Hz, 1 H, =CH2), 7.21 (br d,
3JH,H = 8.2 Hz, 2 Harom), 7.70 (br d, 3JH,H = 8.2 Hz, 2 Harom).
13C NMR (75.47 MHz, CDCl3): d = 16.0 (2 d, 3JP,C = 6.0 Hz, CH3),
38.2 (s, CH2), 43.6 (d, 2JP,C = 14.8 Hz, CH2), 55.4 (s, CHN), 62.0 (d,
2JPC = 6.0 Hz, OCH2), 66.8 (s, CH2), 126.9 (s, CHarom), 128.6 (s,
CHarom), 128.8 (s, CHarom), 131.8 (d, 2JP,C = 8.2 Hz, =CH2), 134.0 (d,
1JP,C = 175.6 Hz, PC=), 135.3 (s, Carom), 157.6 (s, C=O).
31P NMR (121.49 MHz, CDCl3): d = 16.6.
HRMS (EI): m/z calcd [M + H+] for C17H24NO5P: 354.1465; found:
354.1467.
3
13C NMR (75.47 MHz, CDCl3): d = 16.2 (d, JP,C = 6.3 Hz, CH3),
21.6 [s, C(CH3)3], 27.7 (s, CH3), 47.7 (d, 2JP,C = 21.8 Hz, CH2), 62.1
Dimethyl 2-[2-(Diethoxyphosphoryl)allyl]malonate (8)
Yield: 83%; yellow oil; Rf = 0.60 (EtOAc–MeOH, 95:5).
2
(d, JP,C = 5.2 Hz, OCH2), 84.5 [s, C(CH3)3], 128.1 (s, CHarom),
2
128.8 (d, JP,C = 7.5Hz, =CH2), 129.2 (s, CHarom), 135.1 (d,
1H NMR (300 MHz, CDCl3): d = 1.33 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
1JP,C = 173.2Hz, PC=), 136.7 (s, Carom), 144.5 (s, Carom), 150.4 [s,
3
3
2.86 (dd, JP,H = 15.1 Hz, JH,H = 7.8 Hz, 2 H, CH2), 3.73 (s, 6 H,
NC(O)O].
CH3), 3.84 (t, 3JH,H = 7.8 Hz, 1 H, CH), 4.08 (m, 4 H, OCH2), 5.82
(br d, JH,P = 47.2 Hz, 1 H, =CH2), 6.09 (br d, JH,P = 22.4 Hz, 1
HRMS (EI): m/z calcd [M + H+] for C19H30NO7PS: 448.1553;
3
3
found: 448.1551.
H, =CH2).
13C NMR (75.47 MHz, CDCl3): d = 16.3 (d, JP,C = 6.3 Hz, CH3),
3
Diethyl a-{[(N-(Pent-4-enyl)-N-tosyl]aminomethyl}vinylphos-
phonate (5)
Yield: 94%; colorless oil; Rf = 0.57 (EtOAc).
31.6 (d, 2JP,C = 11.5 Hz, CH2), 50.3 (d, 3JP,C = 4.0 Hz, CH), 52.6 (s,
3
2
CH3), 62.0 (d, JP,C = 5.7 Hz, OCH2), 132.0 (d, JP,C = 9.2
Hz, =CH2), 135.5 (d, 1JP,C = 175.5 Hz, PC=), 168.9 (s, CO2).
1H NMR (300 MHz, CDCl3): d = 1.33 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
31P NMR (121.49 MHz, CDCl3): d = 18.1.
HRMS (EI): m/z calcd [M + H+] for C12H21O7P: 309.1098; found:
3
3
1.54 (qt, JH,H = 7.5 Hz, 2 H, CH2), 1.96 (q, JH,H = 7.5 Hz, 2 H,
3
CH2), 2.43 (s, 3 H, CH3), 3.12 (m, 2 H, CH2), 3.94 (dt, JH,P = 5.3
Hz, JH,H = 1.5 Hz, 2 H, CH2), 4.09 (m, 4 H, OCH2), 4.95 (m, 2
4
309.1097.
H, =CH2), 5.68 (m, 1 H, CH=), 6.09 (m, 1 H, =CH2), 6.18 (m, 1
H, =CH2), 7.30 (br d, 3JH,H = 8.2 Hz, 2 Harom), 7.69 (br d, 3JH,H = 8.2
Hz, 2 Harom).
Ethyl 2-Acetyl-4-(diethoxyphosphoryl)pent-4-enoate (9)
Yield: 84%; slightly yellow oil; Rf = 0.37 (EtOAc).
1H NMR (300 MHz, CDCl3): d = 1.18 (t, 3JH,H = 7.0 Hz, 3 H, CH3),
3
13C NMR (75.47 MHz, CDCl3): d = 16.3 (d, JP,C = 6.0 Hz, CH3),
1.26 (t, 3JH,H = 7.0 Hz, 6 H, CH3), 2.18 (s, 3 H, OCH3), 2.71 (m, 2
21.5 (s, CH3), 27.1 (s, CH2), 30.7 (s, CH2), 48.5 (s, CH2), 48.7 (d,
3
2
2JP,C = 17.0 Hz, CH2), 62.1 (d, JP,C = 6.0 Hz, OCH2), 115.4
H, CH2), 3.88 (t, JH,H = 7.3 Hz, 1 H, CH), 4.01 (m, 4 H, OCH2),
3
3
(s, =CH2), 127.1 (s, CHarom), 129.7 (s, CHarom), 130.5 (d, 2JP,C = 7.7
Hz, =CH2), 135.0 (d, 1JP,C = 174.0 Hz, PC=), 136.7 (s, =CH), 137.1
(s, Carom), 143.4 (s, Carom).
4.10 (q, JH,H = 7.0 Hz, 2 H, OCH2), 5.72 (br d, JH,P = 47.4 Hz, 1
H, =CH2), 5.96 (br d, 3JH,P = 22.6 Hz, 1 H, =CH2).
3
13C NMR (75.47 MHz, CDCl3): d = 16.1 (d, JP,C = 6.6 Hz, CH3),
18.9 (s, CH3), 29.4 (s, CH3), 30.7 (d, 2JP,C = 11.5 Hz, CH2), 57.5 (d,
31P NMR (121.49 MHz, CDCl3): d = 17.1.
HRMS (EI): m/z calcd [M + H+] for C19H30NO5PS: 416.1655;
2
3JP,C = 3.8 Hz, CH), 61.3 (s, OCH2), 61.9 (2 d, JP,C = 5.5 Hz,
OCH2), 131.6 (d, 2JP,C = 9.3 Hz, =CH2), 135.5 (d, 1JP,C = 174.0 Hz,
found: 416.1654.
PC=), 168.5 (s, CO2), 201.7 (s, C=O).
31P NMR (121.49 MHz, CDCl3): d = 18.2.
HRMS (EI): m/z calcd [M + H+] for C13H23O6P: 307.1305; found:
Diethyl a-[(2,5-Dioxopyrrolidin-1-yl)methyl]vinylphosphonate
(6)
Yield: 96%; colorless oil; Rf = 0.31 (EtOAc–MeOH, 95:5).
307.1307.
1H NMR (300 MHz, CDCl3): d = 1.34 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
3
Ethyl 2-Benzoyl-4-(diethoxyphosphoryl)pent-4-enoate (10)
Yield: 99%; colorless oil; Rf = 0.50 (EtOAc).
2.75 (s, 4 H, CH2), 4.09 (m, 4 H, CH2), 4.29 (dt, JH,P = 9.3 Hz,
4JH,H = 1.5 Hz, 2 H, OCH2), 5.76 (br d, 3JH,P = 45.4 Hz, 1 H, =CH2),
6.16 (br d, 3JH,P = 21.2 Hz, 1 H, =CH2).
Synthesis 2011, No. 19, 3109–3114 © Thieme Stuttgart · New York

PAPER
Synthesis of a-(Substituted Methyl)vinylphosphonates
3113
1H NMR (300 MHz, CDCl3): d = 1.08 (t, 3JH,H = 7.0 Hz, 3 H, CH3),
Ethyl 4-(Diethoxyphosphoryl)-2-nitropent-4-enoate (13)
Yield: 89%; orange oil; Rf = 0.56 (EtOAc).
3
3
1.26 (t, JH,H = 7.0 Hz, 6 H, CH3), 2.89 (dd, JH,P = 16.1 Hz,
3JH,H = 7.3 Hz, 2 H, CH2), 4.00 (m, 4 H, OCH2), 4.05 (q, 3JH,H = 7.0
1H NMR (300 MHz, CDCl3): d = 1.30 (t, 3JH,H = 7.2 Hz, 3 H, CH3),
3
Hz, 2 H, OCH2), 4.82 (t, JH,H = 7.3 Hz, 1 H, CH), 5.79 (br d,
1.35 (t, 3JH,H = 7.0 Hz, 6 H, CH3), 3.17 (m, 2 H, CH2), 4.10 (m, 4 H,
3JH,P = 47.4 Hz, 1 H, =CH2), 5.96 (br d, 3JH,P = 22.3 Hz, 1 H, =CH2),
7.40 (t, 3JH,H = 7.3 Hz, 2 Harom), 7.51 (t, 3JH,H = 7.3 Hz, 1 Harom), 7.97
(d, 3JH,H = 7.3 Hz, 2 Harom).
3
4
OCH2), 4.29 (m, 2 H, OCH2), 5.59 (dd, JH,H = 9.6 Hz, JH,P = 5.5
3
Hz, 1 H, CH), 5.88 (br d, JH,P = 45.9 Hz, 1 H, =CH2), 6.12 (br d,
3JH,P = 21.7 Hz, 1 H, =CH2).
13C NMR (75.47 MHz, CDCl3): d = 13.8 (s, CH3), 16.1 (d,
13C NMR (75.47 MHz, CDCl3): d = 13.9 (s, CH3), 16.3 (d,
2
3JP,C = 6.6 Hz, CH3), 31.9 (d, JP,C = 11.5 Hz, CH2), 52.2 (d,
2
3JP,C = 6.3 Hz, CH3), 33.9 (d, JP,C = 11.5 Hz, CH2), 62.4 (2 d,
2
3JP,C = 3.3 Hz, CH), 61.3 (s, OCH2), 61.8 (2 d, JP,C = 6.0 Hz,
2JP,C = 5.7 Hz, OCH2), 63.3 (s, OCH2), 86.5 (s, CH), 132.7 (d,
2
OCH2), 128.5 (s, CHarom), 128.6 (s, CHarom), 132.2 (d, JP,C = 9.3
2
1JP,C = 177.3 Hz, PC=), 134.1 (d, JP,C = 8.6 Hz, =CH2), 163.8 (s,
1
Hz, =CH2), 133.5 (s, CHarom), 135.3 (d, JP,C = 174.0 Hz, PC=),
CO2).
135.8 (s, Carom), 168.7 (s, CO2), 194.3 (s, C=O).
31P NMR (121.49 MHz, CDCl3): d = 18.4.
HRMS (EI): m/z calcd [M + H+] for C18H25O6P: 369.1462; found:
369.1461.
31P NMR (121.49 MHz, CDCl3): d = 16.8.
HRMS (EI): m/z calcd [M + H+] for C11H20NO7P: 310.1050; found:
310.1052.
Diethyl 4,4-Bis(phenylsulfonyl)but-1-en-2-ylphosphonate (14)
Yield: 99%; colorless oil; Rf = 0.40 (EtOAc).
Diethyl (4-Acetyl-5-oxo)hex-1-en-2-ylphosphonate (11)
Yield: 79%; yellow oil; Rf = 0.43 (EtOAc–MeOH, 95:5).
1H NMR (300 MHz, CDCl3): d = 1.21 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
3.18 (dd, 3JH,P = 16.8 Hz, 3JH,H = 6.0 Hz, 2 H, CH2), 3.95 (m, 4 H,
OCH2), 5.63 (t, 3JH,H = 6.0 Hz, 1 H, CH), 5.84 (br d, 3JH,P = 45.3 Hz,
1H NMR (300 MHz, CDCl3): d = 1.27 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
3
3
1.98 (s, 6 H, CH3), 2.71 (dd, JH,P = 15.1 Hz, JH,H = 7.2 Hz, 2 H,
CH2), 4.03 (m, 4 H, OCH2), 4.11 (t, 3JH,H = 7.2 Hz, 1 H, CH), 5.69
(dq, 3JH,P = 47.2 Hz, 2JH,H = 4JH,H = 1.3 Hz, 1 H, =CH2), 6.20 (br d,
3JH,P = 22.1 Hz, 1 H, =CH2).
3
1 H, =CH2), 5.91 (br d, JH,P = 21.3 Hz, 1 H, =CH2), 7.47 (m, 4
Harom), 7.59 (m, 2 Harom), 7.84 (m, 4 Harom).
3
13C NMR (75.47 MHz, CDCl3): d = 16.1 (d, JP,C = 6.6 Hz, CH3),
29.4 (d, 2JP,C = 13.2 Hz, CH2), 62.2 (d, 2JP,C = 6.0 Hz, OCH2), 79.8
(d, 3JP,C = 1.6 Hz, CH), 128.8 (s, CHarom), 129.1 (s, CHarom), 132.6
(d, 1JP,C = 178.4 Hz, PC=), 133.0 (d, 2JP,C = 8.2 Hz, =CH2), 134.2 (s,
CHarom), 138.2 (s, Carom).
3
13C NMR (75.47 MHz, CDCl3): d = 16.7 (d, JP,C = 6.0 Hz, CH3),
22.6 (s, CH3), 30.8 (d, 2JP,C = 12.1 Hz, CH2), 62.0 (d, 2JP,C = 6.0 Hz,
3
2
OCH2), 65.9 (d, JP,C = 3.8 Hz, CH), 131.4 (d, JP,C = 8.8
Hz, =CH2), 135.6 (d, 1JP,C = 175.1 Hz, PC=), 202.8 (s, C=O).
31P NMR (121.49 MHz, CDCl3): d = 18.3.
HRMS (EI): m/z calcd [M + H+] for C12H21O5P: 277.1199; found:
31P NMR (121.49 MHz, CDCl3): d = 17.1.
HRMS (EI): m/z calcd [M + H+] for C20H25O7PS2: 473.0852; found:
277.1198.
473.0854.
Enol Form of 11
The enol form of 11 displayed specific chemical shifts.
Ethyl 2,4-Bis(diethoxyphosphoryl)pent-4-enoate (15)
Yield: 63%; yellow oil; Rf = 0.43 (EtOAc–MeOH, 90:10).
1H NMR (300 MHz, CDCl3): d = 1.27 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
1H NMR (300 MHz, CDCl3): d = 1.21 (t, 3JH,H = 7.2 Hz, 3 H, CH3),
1.29 (m, 12 H, CH3), 2.75 (m, 2 H, CH2), 3.36 (ddd, 2JH,P = 23.2 Hz,
3JH,H = 11.9 Hz, 4JH,P = 3.0 Hz, 1 H, CH), 4.04 (m, 2 H, OCH2), 4.13
(m, 8 H, OCH2), 5.79 (dq, 3JH,P = 47.4 Hz, 2JH,H = 4JH,H = 1.5 Hz, 1
H, =CH2), 6.04 (br d, 3JH,P = 22.5 Hz, 1 H, =CH2).
3
1.98 (s, 3 H, CH3), 2.13 (s, 3 H, CH3), 3.12 (dt, JH,P = 6.4 Hz,
4JH,H = 4JH,H = 1.9 Hz, 2 H, CH2), 4.03 (m, 4 H, OCH2), 5.54 (dq,
3JH,P = 47.8 Hz, JH,H = 4JH,H = 1.9 Hz, 1 H, =CH2), 6.01 (br d,
2
3JH,P = 22.3 Hz, 1 H, =CH2).
13C NMR (75.47 MHz, CDCl3): d = 16.7 (d, JP,C = 6.0 Hz, CH3),
3
13C NMR (75.47 MHz, CDCl3): d = 13.9 (s, CH3), 16.1 (d,
22.6 (s, CH3), 29.5 (s, CH3), 29.6 (d, 2JP,C = 13.2 Hz, CH2), 61.8 (d,
3
3JP,C = 6.0 Hz, CH3), 16.1 (d, JP,C = 6.0 Hz, CH3), 29.6 (dd,
2JP,C = 6.0
Hz,
OCH2),
105.2
(s, =C),
127.9
(d,
2JP,C = 11.8 Hz, 2JP,C = 3.6 Hz, CH2), 43.9 (dd, 1JP,C = 129.0 Hz,
2JP,C = 9.9Hz, =CH2), 137.6 (d, JP,C = 172.9 Hz, PC=), 191.8
1
2
3JP,C = 4.4 Hz, CH), 61.3 (s, OCH2), 61.8 (2 d, JP,C = 6.0 Hz,
(s, =COH), 202.8 (s, C=O).
31P NMR (121.49 MHz, CDCl3): d = 18.9.
2
2
OCH2), 62.7 (2 d, JP,C = 6.6 Hz, OCH2), 131.3 (d, JP,C = 9.3
1
3
Hz, =CH2), 135.9 (dd, JP,C = 174.5 Hz, JP,C = 17.0 Hz, PC=),
168.0 (s, CO2).
Diethyl a-(2,6-Dioxocyclohexylmethyl)vinylphosphonate (12)
Yield: 99%; orange oil; Rf = 0.23 (EtOAc–MeOH, 95:5).
31P NMR (121.49 MHz, CDCl3): d = 18.4, 21.8.
HRMS (EI): m/z calcd [M + H+] for C15H30O8P2: 401.1489; found:
1H NMR (300 MHz, CDCl3): d = 1.32 (t, 3JH,H = 7.1 Hz, 6 H, CH3),
401.1491.
3
3
1.97 (qt, JH,H = 6.4 Hz, 2 H, CH2), 2.53 (t, JH,H = 6.4 Hz, 4 H,
3
CH2), 3.22 (d, JH,P = 12.6 Hz,
2 H, CH2), 4.08 (qt,
Tetraethyl 1-Cyanobut-3-ene-1,3-diyldiphosphonate (16)
Yield: 79%; yellow oil; Rf = 0.35 (EtOAc–MeOH, 95:5).
3JH,H = 3JH,P = 7.1 Hz, 4 H, OCH2), 5.86 (br d, JH,P = 22.3 Hz, 1
3
H, =CH2), 5.91 (br d, 3JH,P = 48.3 Hz, 1 H, =CH2).
1H NMR (300 MHz, CDCl3): d = 1.34 (t, 3JH,H = 7.0 Hz, 6 H, CH3),
1.38 (m, 6 H, CH3), 2.65 (m, 1 H, CH2), 2.89 (m, 1 H, CH2), 3.49
(ddd, 2JH,P = 23.2 Hz, 3JH,H = 11.9 Hz, 4JH,P = 3.8 Hz, 1 H, CH), 4.10
(m, 4 H, OCH2), 4.25 (m, 4 H, CH2), 6.00 (br d, 3JH,P = 46.1 Hz, 1
H, =CH2), 6.19 (br d, 3JH,P = 21.5 Hz, 1 H, =CH2).
3
13C NMR (75.47 MHz, CDCl3): d = 15.7 (d, JP,C = 6.6 Hz, CH3),
19.8 (s, CH2), 23.6 (d, 2JP,C = 12.6 Hz, CH2), 31.4 (s, CH2), 64.4 (d,
3
2JP,C = 6.6 Hz, OCH2), 112.3 (d, JP,C = 7.7 Hz, =C), 132.4 (d,
1
2JP,C = 8.8 Hz, =CH2), 132.8 (d, JP,C = 176.2 Hz, PC=), 195.7 (s,
C=O).
13C NMR (75.47 MHz, CDCl3): d = 16.2 (m, CH3), 29.6 (dd,
31P NMR (121.49 MHz, CDCl3): d = 21.4.
HRMS (EI): m/z calcd [M + H+] for C13H21O5P: 289.1199; found:
3
2
1JC,P = 142.4 Hz, JC,P = 2.5 Hz, CH), 30.9 (dd, JC,P = 12.1 Hz,
2
2JC,P = 3.3 Hz, CH2), 62.3 (2 d, JP,C = 6.0 Hz, OCH2), 64.0 (2 d,
2
289.1197.
2JP,C = 6.6 Hz, OCH2), 133.4 (d, JP,C = 9.3 Hz, =CH2), 133.9 (dd,
Synthesis 2011, No. 19, 3109–3114 © Thieme Stuttgart · New York

3114
C. Garzon et al.
PAPER
J. Org. Chem. 2006, 71, 7892. (h) Gajda, A.; Gajda, T.
1JP,C = 177.0 Hz, JP,C = 15.1 Hz, PC=), 115.4 (d, JP,C = 9.3 Hz,
3
2
C≡N).
Tetrahedron 2008, 64, 1233. (i) Rabasso, N.; Fadel, A.
Tetrahedron Lett. 2010, 51, 60.
31P NMR (121.49 MHz, CDCl3): d = 17.2, 17.3.
(3) For reviews on the synthesis and biological activities of b-
aminophosphonates, see : (a) Stowasser, B.; Budt, K.-H.;
Qi, L. J.; Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992,
33, 6625. (b) Wester, R. T.; Chambers, R. J.; Green, M. D.;
Murphy, W. R. Bioorg. Med. Chem. Lett. 1994, 4, 2005.
(c) Patel, D. V.; Reilly-Gauvin, K.; Ryono, D. E.; Free, C.
A.; Rogers, W. L.; Smith, S. A.; DeForrest, J. M.; Oehl, R.
S.; Petrillo, E. W. Jr. J. Med. Chem. 1995, 38, 4557.
(d) Zygmunt, J.; Gancarz, R.; Lejczak, B.; Wieczorek, P.;
Kafarski, P. Bioorg. Med. Chem. Lett. 1996, 6, 2989.
(e) Tao, M.; Bihovsky, R.; Wells, G. J.; Mallamo, J. P.
J. Med. Chem. 1998, 41, 3912. (f) Aminophosphonic and
Aminophosphinic Acids; Kukhar, V. P.; Hudson, H. R., Eds.;
Wiley: New York, 2000. (g) Palacios, F.; Alonso, C.;
de Los Santos, J. M. Chem. Rev. 2005, 105, 899.
(h) Whitteck, J. T.; Ni, W.; Griffin, B. M.; Eliot, A. C.;
Thomas, P. M.; Kelleher, N. L.; Metcalf, W. W.;
van der Donk, W. A. Angew. Chem. In. Ed. Engl. 2007, 46,
9089. (i) Al Quntar, A. A. A.; Gallily, R.; Katzavian, G.;
Srebnik, M. Eur. J. Pharm. 2007, 556, 9.
HRMS (EI): m/z calcd [M + H+] for C13H25NO6P2: 354.1230; found:
354.1229.
Diethyl a-[2-(Diethoxyphosphoryl)allyloxymethyl]vinylphos-
phonate (17)
This compound was obtained following the general procedure ex-
cept that no pronucleophile was added; yield: 85%; colorless oil;
Rf = 0.49 (EtOAc–MeOH, 90:10).
3
1H NMR (300 MHz, CDCl3): d = 1.29 (t, JH,H = 7.0 Hz, 12 H,
3
CH3), 4.06 (m, 8 H, OCH2), 4.14 (br d, JH,P = 7.5 Hz, 4 H, CH2),
6.09 (br d, 3JH,P = 46.7 Hz, 2 H, =CH2), 6.14 (br d, 3JH,P = 22.8 Hz,
2 H, =CH2).
3
13C NMR (75.47 MHz, CDCl3): d = 16.3 (d, JP,C = 6.9Hz, CH3),
62.0 (d, 2JP,C = 5.7 Hz, CH2), 69.2 (d, 2JP,C = 17.8 Hz, OCH2), 129.7
(d, 2JP,C = 6.3 Hz, =CH2), 136.1 (d, 1JP,C = 175.5 Hz, PC=).
31P NMR (121.49 MHz, CDCl3): d = 16.8.
HRMS (EI): m/z calcd [M + H+] for C15H31O7P2: 371.1383; found:
371.1378.
(4) M’rabet, H.; M’hamed, M. O.; Efrit, M. L. Synth. Commun.
2009, 39, 1655.
(5) Garzon, C.; Attolini, M.; Maffei, M. Tetrahedron Lett. 2010,
51, 3772.
Acknowledgment
Financial support as a ‘Ministère de la Recherche et de la Techno-
logie’ grant to Cécile Garzon as well as from C.N.R.S. is gratefully
acknowledged.
(6) For selected examples, see : (a) Du, Y.; Han, X.; Lu, X.
Tetrahedron Lett. 2004, 45, 4967. (b) Zheng, S.; Lu, X.
Org. Lett. 2008, 10, 4481. (c) Cui, H. L.; Huang, J. R.; Lei,
J.; Wang, Z. F.; Chen, S.; Wu, S.; Chen, Y. C. Org. Lett.
2010, 12, 720. (d) Lei, J.; Cui, H. L.; Li, R.; Wu, L.; Ding, Z.
Y.; Chen, Y. C. Org. Biomol. Chem. 2010, 8, 2840.
(e) Hong, L.; Sun, W.; Liu, C.; Zhao, D.; Wang, R. Chem.
Commun. 2010, 46, 2856. (f) Peng, J.; Huang, X.; Cui, H.
L.; Chen, Y. C. Org. Lett. 2010, 12, 4260. (g) Basavaiah,
D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447.
(7) Capuzzi, M.; Perdicchia, D.; Jorgensen, K. A. Chem. Eur. J.
2008, 14, 128.
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Synthesis 2011, No. 19, 3109–3114 © Thieme Stuttgart · New York