Synthesis of β-aminovinylphosphonates by organocatalytic nucleophilic displacement of acetate with amines

Article abstract of DOI:10.1016/j.tetlet.2010.05.050

The synthesis of diethyl β-aminovinylphosphonates 2 from acetoxy phosphonate 1 is described. The reaction entails an organocatalyzed substitution of the acetoxy group by primary or secondary amines. The use of a catalytic amount of DABCO is necessary if the amine is not nucleophilic enough, otherwise a strong nucleophilic amine can react without organocatalyst. The reaction led to a series of functionalized title compounds in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.05.050

Tetrahedron Letters 51 (2010) 3772–3774
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of b-aminovinylphosphonates by organocatalytic nucleophilic
displacement of acetate with amines
*
*
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
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of diethyl b-aminovinylphosphonates 2 from acetoxy phosphonate 1 is described. The
reaction entails an organocatalyzed substitution of the acetoxy group by primary or secondary amines.
The use of a catalytic amount of DABCO is necessary if the amine is not nucleophilic enough, otherwise a
strong nucleophilic amine can react without organocatalyst. The reaction led to a series of functionalized
title compounds in good to excellent yields.
Received 25 March 2010
Revised 10 May 2010
Accepted 12 May 2010
Available online 20 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
b-Aminovinylphosphonates
Organocatalysis
Morita–Baylis–Hillman derivatives
1,4-Diazabicyclo[2.2.2] octane
Diethyl (a-acetoxymethyl)
vinylphosphonate
Functionalized vinylphosphonates constitute an important class
of building blocks for which numerous synthetic methods have been
reported.1 In this area, b-aminovinylphosphonates, although much
less studied, have received attention due to their use for the prepa-
ration of b-aminophosphonic acid derivatives2 which display
diverse biological activities such as antibiotics,3 enzymes inhibi-
tors,4 anti HIV5 and anti inflammatory agents.6 In addition, they
1-cycloalkenylphosphonates has also been reported using an
amine-induced cyclization of
-halo alkynylphosphonates.16
We wish to describe here an alternate synthesis of diethyl
aminovinylphosphonates 2 using a displacement reaction of the
x
acetate group in diethyl (a-acetoxymethyl) vinylphosphonate 1
by amines (Scheme 1). The reaction may occur spontaneously or
in the presence of 20 mol % of DABCO (1,4-diazabicyclo[2.2.2] oc-
tane) as organocatalyst,17 depending on the nature of the nucleo-
philic amine.
are used for the synthesis of hydroxyphosphonates or
a-aminoest-
ers7 and 2,4-disubstituted tetrahydrothiophenes.8
b-Aminovinylphosphonates have been obtained via Mannich
reactions9 or from dimethyl 3-chloropropene phosphonate.10 On
the other hand, N-(alkoxycarbonyl) b-aminovinylphosphonates
were prepared by aziridination of dialkyl (1-trimethylsilanylmeth-
yl-vinyl)phosphonates followed by silyl group elimination and aziri-
dine ring opening,11 by aldol-type addition of ethylphosphonate to
trifluoromethyl-substituted imines followed by treatment with
m-chloroperbenzoic acid,12 from N-Boc aminoethylidene-1,1-bis-
phosphonates13 and very recently by SN2 displacement of 1,2-dibro-
mo-2-propene followed by a nickel-catalyzed Arbusov reaction.14
Finally, Krische and co-workers15 reported a triphenylphosphine-
catalyzed allylic substitution of Morita–Baylis–Hillman (MBH)
2-(diethylphosphonyl)-substituted allylic acetates with 4,5-
dichlorophthalimide as the nucleophile. The synthesis of 2-amino-
Compound 1 was obtained by standard acetylation18 of diethyl
(a
-hydroxymethyl) vinylphosphonate19 and formally corresponds
to the acetylated MBH adduct of diethyl vinylphosphonate and
formaldehyde.
As shown in Table 1, several primary and secondary amines re-
acted with 1 in THF at room temperature in the presence of
20 mol % DABCO, leading to b-aminovinylphosphonates 2 in good
to excellent yields.
The DABCO-induced substitution of allylic MBH acetates is the
subject of numerous reports,20 and involves the DABCO-acetate
O
P
EtO
EtO
O
P
EtO
EtO
R
DABCO (0.2 equiv)
THF, rt.
OAc
HN
+
NRR'
R'
* Corresponding authors. Tel.: +33 4 91 28 27 03; fax: +33 4 91 28 94 02 (M.M.);
tel.: +33 4 91 28 83 04; fax: +33 4 91 28 94 02 (M.A.).
2
1
E-mail addresses: mireille.attolini@univ-cezanne.fr (M. Attolini), michel.maf
fei@univ-cezanne.fr (M. Maffei).
Scheme 1. Synthesis of b-aminovinyl phosphonates 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.050

C. Garzon et al. / Tetrahedron Letters 51 (2010) 3772–3774
3773
Table 1
Synthesis of b-aminovinylphosphonates 2 from acetoxyphosphonate 1a
Table 2
Synthesis of novel functionalized b-aminovinylphosphonates 2 from 1a
Entry
Amine
Yield (%)
With DABCO (0.2 equiv)
Entry
1
Amine
DABCOb (equiv)
Yield (%)
Without DABCO
10b
CH3
N
H
—
99
93
NH2
N
H2N
1
2
98
91
N
S
2
3
0.2
0.2
CH3
H
N
CH3
No reaction
O
H2N
H3C
NH2
N
76
2b
95
N
3
4
CH3
CH3O
CH3
NH2
c
93
4
5
—
—
98
82
NH2
c
5
6
(n-Bu)2NH
i-BuNH2
83
68d
71e
OH
OH
O
N
H
c
7
8
98
N
H
CH3
60f
67g
6
7
—
87
81
NH2
HN
a
CH3
Reactions were carried out with 1 (100 mg; 0.42 mmol), amine (0.47 mmol,
1.1 equiv) and DABCO (9.5 mg; 0.085 mmol, 0.2 equiv) in THF (1.5 mL) at rt for 24 h.
OH
H
Conversion measured by 31P NMR.
b
HO
HO
HO
N
c
CH3
0.2
Not performed.
Dialkylated product 3 was also obtained (25% yield).
Dialkylated product 3 was also obtained (18% yield).
Dialkylated product 4 was also obtained (35% yield).
d
e
f
OH OH
g
CH3
Dialkylated product 4 was also obtained (21% yield).
8
—
—
83
N
H
OH OH
H
H3C
9c
60d
N
N
CH3
O
O
O
O
H
NH2
(EtO)2P
P(OEt)2
(EtO)2P
P(OEt)2
N
N
10c
—
58d
N
H
3
4
a
Reactions were carried out with 1 (100 mg; 0.42 mmol), amine (0.47 mmol,
Figure 1.
1.1 equiv) and DABCO (9.5 mg; 0.085 mmol, 0.2 equiv) in THF (1.5 mL) at rt for 24 h.
b
DABCO was used if necessary.
Reactions were carried out in the presence of 2 equiv of 1.
Yield of bisphosphonate (dialkylated product).
c
d
salt intermediate which further yields the substitution product
with regeneration of DABCO. The organocatalyst DABCO is essen-
tial for aromatic amines, that is, aniline (entry 1) which gives
98% yield of aminophosphonate (vs 10% conversion without DAB-
CO), N-methyl aniline which does not react in the absence of
organocatalyst (entry 2) and for anisidine (entry 3).
However, we found that the use of DABCO is not essential in the
case of aliphatic amines which led to the expected amin-
ovinylphosphonates by simple reaction with 1 (entries 4–8). This
feature can be accounted for by a higher nucleophilic character
of the amine and is due to the direct substitution of allylic MBH
acetates by amines (or azides) in the absence of organocatalyst.21
Furthermore, the formation of bisphosphonates 3 and 4 (Fig. 1)
as a result of the dialkylation reaction was encountered in the case
of isobutylamine (entry 6) and allylamine (entry 7), respectively.
O
P
EtO
EtO
-
O
P
EtO
ArNH2
AcO
+
DABCO
-
1
NHAr
(
)
+
AcO
+
DABCO-H
EtO
N
N
2
O
P
EtO
EtO
+
+
DABCO
NH2Ar
(regenerated)
-
AcO
Scheme 2. Mechanism for the synthesis of 2.

3774
C. Garzon et al. / Tetrahedron Letters 51 (2010) 3772–3774
Supplementary data
P(OEt)2
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.050.
NH
O
O
P(OEt)2
CH3
P(OEt)2
N
References and notes
N
O
N
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H3C
P(OEt)2
5
6
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Figure 2.
The presence of DABCO in these cases did not improve notably the
selectivity.
Using 1.1 equiv of nucleophilic amine is sufficient to drive the
reaction to completion. This suggests that even if the nucleophilic
amine is partially consumed by evolved acetic acid to give the cor-
responding salt, it can be regenerated by proton exchange with the
reaction product 2 already formed, thus leading to the acetate salt
of 2, together with liberated amine. When using aromatic amines
where DABCO must be present, the substitution of the DABCO salt
by amine regenerates DABCO along with acetic acid. According to
the pKa values for aniline and DABCO, one might expect a selective
protonation of DABCO which should be deactivated. However, the
higher concentration of 2 (compared to that of [DABCOÀH]+) pre-
sumably helps in shifting the equilibrium towards the regeneration
of DABCO from its acetate salt (Scheme 2).
Encouraged by these results, we were interested in expanding
the scope of the reaction to the synthesis of more complex b-amin-
ovinylphosphonates by using different primary and secondary
amines (Table 2), the reactions being carried out in the presence
of DABCO, if necessary.
Thus, the reaction led to a facile route to heterocyclic deriva-
tives 2 (entries 1–3), whereas enantiopure amine (entry 4) or ami-
noalcohols (entries 5–8) yielded chiral derivatives. In the case of
diamines, the reaction led to unseparable complex mixtures, pre-
sumably mono- and bisphosphonates together with other byprod-
ucts. However, bisphosphonates 5 and 6 (Fig. 2) could eventually
be obtained in satisfactory yields when the reactions were per-
formed with 2 equiv of 1 (entries 9 and 10).
11. Loretto, M. A.; Pompili, C.; Tardella, P. A. Tetrahedron 2001, 57, 4423–4427.
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16, 28–48.
18. Synthesis of 1: To a cooled (0 °C) solution of diethyl 3-hydroxyprop-1-en-2-
ylphosphonate (1 g, 5.15 mmol), dimethylaminopyridine (0.038 g, 0.31 mmol,
0.06 equiv)
and
triethylamine
(1.1 mL,
7.7 mmol,
1.5 equiv)
in
dichloromethane (10 mL) was added dropwise a solution of acetic anhydride
(0.54 mL, 5.7 mmol, 1.1 equiv) in dichloromethane (30 mL) and the mixture
was stirred at room temperature for 3 h. It was then washed with 15% Na2CO3
until pH 9, with 5% HCl (pH 2) and brine. After drying over MgSO4, filtration
and removal of solvents, the residue was purified by flash chromatography
(ethyl acetate/methanol, 95:5) to furnish 1 as a colourless oil (1.02 g, 84%
yield). 1H NMR (300 MHz, CDCl3) d 1.32 (t, 3JHH = 7.0 Hz, 6H), 2.10 (s, 3H), 4.10
In summary, we have shown that functionalized b-amin-
ovinylphosphonates can be easily obtained from 1 by an organo-
catalyzed substitution reaction of acetate by amines. This can
lead to functionalized derivatives as well as chiral compounds,
the reaction being performed at room temperature, using only a
slight excess of amine, this feature being interesting in the case
of amines whose preparation is multistep and time consuming.
Depending on the nucleophilic character of this amine, using a cat-
alytic amount of DABCO as the initiator is necessary, but a strong
nucleophilic amine can react alone.
3
3
4
(qt, JHH
6.05 (dq, JHP = 46.0 Hz, JHH
2JHH
=
3JHP = 7.1 Hz, 4H), 4.72 (dt, JHP = 8.8 Hz, JHH’
=
4JHH = 1,5 Hz, 2H),
3
2
3
=
4JHH = 1.5 Hz, 1H), 6.20 (dq, JHP = 22.5 Hz,
=
4JHH = 1.5 Hz, 1H). 13C NMR (75.47 MHz, CDCl3) d: 16.3 (d,
2 2
3JPC = 6.3 Hz), 20.8 (s, CH3), 62.1 (d, JPC = 5.7 Hz), 62.8 (d, JPC = 17.8 Hz),
130.9 (d, JPC’ = 6.9 Hz), 134.6 (d, JPC’ = 177.8 Hz), 170.2 (s, C@O). 31P NMR
2
1
(121.49 MHz, CDCl3): 17.0 ppm.
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Acknowledgements
Financial support as a ‘Ministère de la Recherche et de la Tech-
nologie’ grant to Cécile Garzon and from C.N.R.S. is gratefully
acknowledged.