Cyclopropanation of 1,2-dibromoethylphosphonate: A synthesis of β-aminocyclopropylphosphonic acid and derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.09.035

Diethyl (1,2-dibromoethyl)phosphonate was found to undergo cyclopropanation with nitromethane in good yield. The resulting trans β-nitrocyclopropylphosphonate was converted to the trans N-protected aminocyclopropylphosphonate through a reduction-protection sequence. Subsequent hydrolysis gave the free β-aminocyclopropylphosphonic acid without any formation of ring-opening byproduct. Cyclopropanation of 1,2-dibromoethylphosphonates with nitroalkanes and their reduction are also discussed.

Full text of DOI:10.1016/j.tetlet.2014.09.035

Tetrahedron Letters 55 (2014) 6068–6071
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cyclopropanation of 1,2-dibromoethylphosphonate: a synthesis of
b-aminocyclopropylphosphonic acid and derivatives
⇑
Nicolas Rabasso, Antoine Fadel
Laboratoire de Méthodologie, Synthèse et Molécules Thérapeutiques, ICMMO, UMR-CNRS 8182, Bât. 410, Université Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2014
Revised 2 September 2014
Accepted 8 September 2014
Available online 16 September 2014
Diethyl (1,2-dibromoethyl)phosphonate was found to undergo cyclopropanation with nitromethane in
good yield. The resulting trans b-nitrocyclopropylphosphonate was converted to the trans N-protected
aminocyclopropylphosphonate through a reduction–protection sequence. Subsequent hydrolysis gave
the free b-aminocyclopropylphosphonic acid without any formation of ring-opening byproduct. Cyclo-
propanation of 1,2-dibromoethylphosphonates with nitroalkanes and their reduction are also discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
b-Aminophosphonic acids
b-Nitrocyclopropylphosphonates
Bromovinylphosphonates
Aminophosphonates
Cyclopropanation
Introduction
Ph
O
P
O
P
OH
OH
HO
HO
R
Aminocyclopropylphosphonic acids and their derivatives have
attracted considerable attention due to their interesting synthetic
studies and their useful biological activities.1–3 These molecular
structures combine several interesting features: (i) the cyclopro-
pane motif is found in many naturally occurring and biologically
active compounds.4 In addition the cyclopropane ring often acts
as a molecular subunit inducing particular biological activities.5
(ii) There is a long standing interest in phosphonic acids and deriv-
atives as analogs of natural organo-phosphates.6
H2N
NH2
( )-1
(-)-2
Figure 1. b-Aminocyclopropylphosphonic acids.
cyclopropanation of vinylphosphonates with sulfoxonium ylides
(path b), as key-step, and a subsequent Curtius rearrangement
(Fig. 2).12 Very recently, Charette and co-workers13 reported a
stereoselective synthesis of b-phthalimidocyclopropylphosphonate
by rhodium-catalyzed cyclopropanation of alkenes with a diazo
compound (path c). However, in the latter case no conversion to
Aminophosphonic acids display promising antibacterial7 and
anti-cancer properties.8 They are also potent neuromodulators,
plant growth regulators, and herbicides.9 Although,
a
-aminocyclo-
the free b-aminocyclopropylphosphonic acid
1 is reported.
propylphosphonic acids (
a-ACPPs) have been extensively studied
Moreover, synthesis of racemic b-aminocyclopropylbisphosphonate
1 (R = P(O)(OEt)2) was reported by Couthon and co-workers14
involving a Michael type addition of ethyl 2-bromoacetate on
vinylidene-1,1-bisphosphonate (path d), followed by an intramolec-
ular cyclization and a Curtius rearrangement (Fig. 2).
This context prompted us to search for an efficient and concise
synthesis of b-aminocyclopropylphosphonic acids 1 for which the
amino group would be introduced without the use of a Curtius
rearrangement. Indeed, to date, most of the reported procedures
to access such compounds involve the use of this rearrangement.
Few years ago we reported a short and efficient synthesis of
as analogs of natural and non-natural amino acids,10 b-aminocyclo-
propylphosphonic acids (b-ACPPs) 1 and derivatives have received
less attention. Hanessian and co-workers have reported the first
and unique synthesis of the enantiopure b-amino-3-phenylcyclo-
propylphosphonic acid (À)-2, a constrained analog of the GABAB
antagonist (Fig. 1).11
Their approach is based on a conjugate addition of the chiral
chlorophosphonamide anion to
by a Curtius rearrangement (path a). Later, Mikolajczyk and Midura
reported the preparation of the other enantiomer (+)-2 by
a,b-unsaturated esters, followed
a
-ACPPs from cyclopropanone acetals through a Kabachnik–Fields
reaction.15–18 The biological evaluation of these compounds
showed some interesting activities as ACC-Oxidase inhibitor.3
⇑
Corresponding author. Tel.: +33 (0)1 6915 3239; fax: +33 (0)1 6915 4679.
E-mail address: antoine.fadel@u-psud.fr (A. Fadel).
http://dx.doi.org/10.1016/j.tetlet.2014.09.035
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

N. Rabasso, A. Fadel / Tetrahedron Letters 55 (2014) 6068–6071
6069
Table 1
O
S
O
H3C
H3C
CO2R1
Preparation of nitrocyclopropylphosphonate 6a from dibromophosphonate 4a
O
P
P(OR2)2
Tolp
CO2R1
N
N
Cl
O
P
O
P
Hanessian
path a
Midura
path b
H
OEt
OEt
OEt
OEt
S
K2CO3 (3 equiv)
H
+
Br
O
O
P
DMSO-THF (5:1)
82%
O2N
5a
OH
OH
R
O2N
Br
4
( )-6a
O
H2N
O
O
N
1
O
P(OR2)2
P(OR2)2
Entry
Time (h)
[c] mol/L
6a (yield %)
Br
Couthon
path d
CO2R1
(R2O)2P
O
CN
1
2
3
4
5
24
24
20
24
5
1.00
0.20
0.14
0.10
0.14
30
Charette
path c
73
this
N2
R
NO2
81b
81
work
O
82c
P(OR2)2
Br
a
Reaction conditions: dibromo 4, methane 5a (1.2 equiv) K2CO3 (3 equiv),
Br
DMSO–THF (5:1), rt.
b
Isolated yield for reaction in DMSO.
Reaction carried out under sonication.
c
Figure 2. Synthetic routes toward b-aminocyclopropylphosphonic acids.
O
P
O
P
O
P
5a
K2CO3 (3 equiv)
O
H
NO2
O
P
OH
OH
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
H
K2CO3 (2 equiv)
H
10 h, 35°C
DMSO-THF
93%
P
5a
4
Br
DMSO-THF
H2N
O2N
Br
O2N
Br
90%
7
trans-( )-6a
4
6a
3a
Scheme 2. Formation of 6a from bromovinylphosphonate 7.
Scheme 1. Synthetic sequence of b-aminocyclopropylphosphonic acid.
Continuing our efforts in this field we extended our interest to
the preparation of heterocyclic
O
P
O
P
1) TMSI (3 equiv)
CH2Cl2, 3 h, rt
a
-aminophosphonic acids19–22
OH
OH
3
(
OEt
OEt
H
H
and their incorporation into peptides.23 In the present work, we
now turn our attention to the synthesis of non-substituted b-
aminophosphonic acid 1, which to date remains unknown. Exten-
sion to b-alkylated counterparts is also reported. Our approach for
the synthesis of the racemic ACPP 3a is depicted in Scheme 1. The
ACPP 3a would be prepared from the nitrophosphonate 6a through
reduction and hydrolysis. The latter would be obtained from the
cyclopropanation24 of the (1,2-dibromoethyl)phosphonate 4 with
nitromethane 5a (Scheme 1).
2
1
2) EtOH,
O
O2N
O2N
)-6a
(
)-8a
88%
Scheme 3. Synthesis of nitrocyclopropylphosphonic acid 8a.
observed. Indeed, treatment of dibromophosphonate 4, with
K2CO3 in DMSO–THF in the absence of nitromethane, furnished
the bromovinylphosphonate 7 in excellent yield (93%). Then, the
latter underwent an attack by nitromethane 5a through
a
sequence involving a Michael addition, followed by an intramolec-
ular SN2 alkylation to form the expected aminophosphonate
6a in 90% yield (Scheme 2). As a consequence, we postulate that
the formation of the vinylphosphonate 7 precedes the possible
competitive nucleophilic reaction of nitromethane on the dib-
romophosphonate 4. Then the Michael addition of nitromethane
to the vinylphosphonate 7 gives the intermediate 1-bromo-3-
nitropropylphosphonate, which is not observed. The latter
Results and discussion
The (1,2-dibromoethyl)phosphonate 4 was easily prepared
from the bromination of the commercially available diethyl vinyl-
phosphonate according to the procedure reported by Sainz-Diaz
and co-workers.25
The one-pot double alkylation was performed at room temper-
ature by a slow addition of nitromethane 5a to a stirred solution
of dibromophosphonate 4 and 3 equiv of potassium carbonate in
a mixture of DMSO and THF (5:1), to give the desired nitro-
cyclopropylphosphonate 6a in good yields (Table 1, entries 1–4).
We observed that when the concentration of the reaction med-
ium was ranging from 0.14 M to 0.10 M, the yield of the reaction
was deeply increased (compare entries 3 and 4 to entry 1). In
addition under the same conditions, the use of sonication
decreased the reaction time from 24 h to 5 h (entry 5, 82% yield).
By comparison, similar double alkylation was already reported,
under basic conditions starting from 1,2-dibromoethylcarbzoxy-
late, yielding nitrocyclopropylcarboxylate in only 59% after
48 h.26 On the other hand, in order to facilitate the work-up pro-
cedure for this reaction, we tried to lower the amount of DMSO
used, by introducing a co-solvent. We found that in DMSO or in
a mixture of DMSO/THF (5:1) the reaction occurred in comparable
yields. However, in THF only the vinylphosphonate intermediate
7 was formed.
undergoes
a fast intramolecular cyclization to provide the
nitrocyclopropylphosphonate 6a.
Next, the hydrolysis of phosphonates 6a was accomplished by
treatment with 3 equiv of a freshly opened bottle of trimethylsilyl
iodide in dichloromethane at room temperature,16 followed by the
addition of propylene oxide in ethanol to provide the b-nitrocyclo-
propylphosphonic acid 8a in 88% (Scheme 3). It is noteworthy that
lowering the amount of TMSI for the reaction, or using instead
TMSBr, resulted in the formation of about 10–30% of the monopho-
sphonate intermediate.
Next, we investigated the reduction of the nitro group to the free
amine. Precedents in the literature highlighted, during reduction of
nitrocyclopropylcarboxylate, the ability of the resulting aminocy-
clopropylcarboxylate to undergo a ring opening, due to the push–
pull effect, leading to c
-aminobutyric acid (GABA).27–29 Taking into
account this phenomena, several mild methods for the reduction of
the nitro group to the free amine were investigated. Known
reagents such as Zn/AcOH, Zn/HClaq,
30 or NiCl2/NaBH4 did not give
It is noteworthy that in this reaction the formation of a small
amount of diethyl 1-bromovinylphosphonate 7 resulting from
the dehydrobromination of dibromophosphonate 4 was always
satisfactory results: no reaction, many TLC spots, or 5% yield of
undesired product 10a were obtained, respectively. Moreover,

6070
N. Rabasso, A. Fadel / Tetrahedron Letters 55 (2014) 6068–6071
Table 2
O
P
O
P
Preparation of nitrocyclopropylphosphonates 6b–d from dibromophosphonate 4a
OEt
OEt
O
P
OEt
OEt
reduction
H2N
OEt
OEt
N
HO
6a
H2N
+
+
O
P
R
OEt
OEt
K2CO3 (3 equiv)
R
9a
11a
--
20%
10%
10a
4
+
DMSO-THF (5:1)
rt, 20 h
O2N
5b-e
Raney nickel, EtOH
20% Pd(OH)2/C, NaBH4
H2, 5% Pd/C, EtOH
--
--
--
25%
60%
45%
O2N
( )-6b-e
Entry
R
[c] mol/L
Product 6
Yield
Scheme 4. Attempts to reduce the nitro group into free amine.
1
2
3
4
Me
Et
CH2OTBS
CH2OH
0.12
0.14
0.14
0.14
6b
6c
6d
6e
72 (67)b
71
68
NRc
O
P
O
P
H2, Raney Ni
pH 7 buffer
R'2O, rt, 4 h
1) 9 N HCl
reflux, 5 h
OH
OH
OEt
OEt
a
H
H
Reaction conditions: dibromo 4, nitroalkane
DMSO–THF (5:1), rt.
5 (1.2 equiv) K2CO3 (3 equiv),
6a
2) EtOH,
O
b
H2N
R' NH
Value in parentheses, isolated yield for reaction in DMSO.
NR: no reaction.
3a
c
12a
13a
R' = Boc
R' = Bz
90%
69%
80%
88%
Scheme 5. Preparation of the free b-aminocyclopropylphosphonic acid 3a.
O
P
O
P
1) TMSI (3 equiv)
CH2Cl2, 3 h, rt
OH
OH
OEt
OEt
R
R
reduction over an excess of T-1 Raney nickel in EtOH only afforded
2) EtOH,
O
O2N
O2N
25% of the undesired ring-opening product 10a.31–33
6b
6c
R = Me
R = Et
8b 83%
8c 79%
34
However, reduction over Pd(OH)2/C with NaBH4 furnished
R = Me
X
Raney Ni
60% yield of ring opening product 10a, along with a 20% of a mix-
ture of cis/trans oxime 11a.35 Reduction of 6a under hydrogen with
a catalytic amount of 5% Pd/C in EtOH gave roughly the same
results. All attempts to prepare the free amine 9a were unsuccess-
ful (Scheme 4).
Boc2O
O
P
O
O
OEt
OEt
OEt
P
OEt
P
OEt
OEt
Boc NH
O
Boc
NH
15b (78%)
12 (0%)
14b (75%)
On the other hand, to overcome this problem, the nitrophosph-
onate 6a was subjected to a one-pot reduction–protection sequence
with a catalytic amount of Raney nickel in ethanol under hydrogen
atmosphere in the presence of a pH 7 phosphate buffer solution.36
The free amine hence formed, is in situ protected as a carbamate
with the use of 3 equiv of Boc2O or as an amide with Bz2O to give
N-Boc aminophosphonate 12a or N-Bz 13a in 90% or 69% yields,
respectively (Scheme 5). Finally, the acidic hydrolysis of the pro-
tected aminophosphonates 12a and 13a with 9 N HCl at reflux for
5 h followed by propylene oxide treatment gave the same desired
aminophosphonic acid 3a in good yield. It is noteworthy that, in
comparison to their carboxylate counterparts,27–29 the b-amin-
ocyclopropylphosphonates can be hydrolyzed without any forma-
tion of ring-opening products (Scheme 5).
Scheme 6. Reduction and hydrolysis of substituted nitrophosphonates 6b–c.
3JP,C = 2.8 Hz
3JP,C = 2.3 Hz
3JP,C = 3.0 Hz
O
P
O
P
O
P
OEt
OEt
OEt
OEt
OH
OH
H3C
TBSO
O2N
H3C
O2N
δc = 20.7 ppm O2N
δc = 22.4 ppm
δc = 24.7 ppm
1JP,C = 190.7 Hz
1JP,C = 192.2 Hz
1JP,C = 180.8 Hz
6c
8b
6d
Figure 3. NMR data for cyclopropanes trans-6 and trans-8 (dC values [ppm] and 3JC,P
cis coupling constants [Hz]).
Scope and limitations: The double alkylation of dibromophosph-
onate 4 was then applied to other nitroalkanes 5b–d and provided
trans-nitrophosphonates 6b–d in good yields (Table 2, entries 1–3).
However, it has to be noted that the presence of a free alcohol 5e
inhibits the double alkylation reaction, and does not give the
desired product 6e (entry 4).
in 13C NMR spectroscopy between the phosphorus atom and the
carbon atom bound to the b-position (Fig. 3). The classical range of
3
3
values is JP–C cis = 2.0–4.5 Hz for the trans isomers and JP–C
=
trans
0–1.2 Hz for the cis isomers, as reported in the literature.12,16,39 The
analysis of the 1H NMR spectra of compounds 6a and 8a showed that
the H-2 proton has a trans relationship to H-1 and H-3 (J2,1 = 3.6–3.8
and J2,3 = 3.6–3.8 Hz). Moreover, the magnitude of the coupling
constants observed for J1,3 is ca. 11–12 Hz for the cis and 7–8 Hz
for the trans relationship, respectively (see Supplementary mate-
rial). These characteristic values are in agreement with those
reported for trans nitrocyclopropane isomers.40
Next, the hydrolysis of phosphonates 6b–c was accomplished
by treatment with 3 equiv of trimethylsilyl iodide in dichlorometh-
ane at room temperature,16 followed by the addition of propylene
oxide in ethanol to provide the b-nitrocyclopropylphosphonic
acids 8b, and 8c in 83% and 79%, respectively (Scheme 6).
In contrast, the reduction–protection sequence of 6b (R – H)
under the same conditions used above (Raney Ni/H2, Boc2O, pH 7
phosphate buffer solution) did not yield the expected product 12,
only ketone 14b37 was isolated in 75% yield. The latter resulted
from the reduction of the nitro group, followed by a cyclopropane
ring-opening into an imine intermediate, which is then hydro-
lyzed. Moreover, the reduction–protection sequence of 6b with
NiCl2/NaBH4 in EtOH, in the presence of Boc2O (3 equiv) gave only
the protected ring-opening product 15b38 in 78% yield (Scheme 6).
Finally, the stereochemical study showed that all these nitro-
cyclopropylphosphonates 6a–d and derivatives have the complete
trans configuration. This stereochemistry was determined by the
This trans selectivity is in agreement with the results reported
by de Meijere et co-workers for the formation of b-nitrocyclopro-
pane-carboxylates.26 This selectivity is probably not the result of
simple steric repulsions as illustrated by compounds 6c and 6d
and comes almost probably for stereoelectronic factor.
Conclusion
In conclusion, we have developed an efficient cyclopropanation
reaction of dibromoethylphosphonate with nitroalkanes. This
procedure affords b-nitrocyclopropylphosphonates with exclusive
trans selectivity. The hydrolysis of the phosphonate moiety leads
3
analysis of the JP–C = 2.0–3.0 Hz coupling constants as observed

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6071
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hydrogen atmosphere, must be done with a concomitant protec-
tion of the free amine as an amide or a carbamate, to prevent the
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The authors thank the CNRS and the University Paris-Sud for
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