Indium triflate catalyzed reaction of diisopropyl diazomethylphosphonate with imines as a new approach to cis- and trans-aziridine-2-phosphonates

Article abstract of DOI:10.1016/j.tetlet.2007.05.042

A new and efficient synthesis of cis- and trans-aziridine-2-phosphonates by metal-catalyzed aziridination reaction of diisopropyl diazomethylphosphonate and substituted aryl imines is reported. By exploring the influence of different Lewis acids employed as catalysts, imine nitrogen substituents, and the solvent effects we conclude that the best results are obtained when N-diphenylmethyl-substituted benzylimines are reacted with diisopropyl diazomethylphosphonate in methylene chloride at 0 °C in the presence of In(OTf)₃ as catalyst.

Full text of DOI:10.1016/j.tetlet.2007.05.042

Tetrahedron Letters 48 (2007) 4911–4914
Indium triflate catalyzed reaction of diisopropyl
diazomethylphosphonate with imines as a new
approach to cis- and trans-aziridine-2-phosphonates
Roberto Pellicciari,a,* Laura Amori,a Natalia Kuznetsova,b
Simon Zlotskyb and Antimo Gioielloa
a
`
Dipartimento di Chimica e Tecnologia del Farmaco, Universita degli Studi di Perugia, Perugia 06123, Italy
bDepartment of Chemistry, Ufa State Technical University, Ufa, Russia
Received 4 April 2007; revised 2 May 2007; accepted 9 May 2007
Available online 16 May 2007
Abstract—A new and efficient synthesis of cis- and trans-aziridine-2-phosphonates by metal-catalyzed aziridination reaction of
diisopropyl diazomethylphosphonate and substituted aryl imines is reported. By exploring the influence of different Lewis acids
employed as catalysts, imine nitrogen substituents, and the solvent effects we conclude that the best results are obtained when
N-diphenylmethyl-substituted benzylimines are reacted with diisopropyl diazomethylphosphonate in methylene chloride at 0 °C
in the presence of In(OTf)3 as catalyst.
Ó 2007 Elsevier Ltd. All rights reserved.
2-EWG-substituted aziridines (Fig. 1) have emerged in
recent years as useful building blocks for the synthesis
of biologically important classes of compounds. Indeed,
aziridine-2-carboxylates are widely utilized for the prep-
aration of substituted a-aminoacids, diamine- and b-lac-
tam derivatives.1 Comparatively, less attention has been
devoted to aziridine-2-phosphonates,2 a bioisosterically
related class of compounds, also useful as intermediates
in the synthesis of biologically valuable molecules such
as a-aminophosphonates, important in medicine and
agriculture as enzyme inhibitors, antibiotics, clonal anti-
bodies, pesticides and herbicides.3
attracted considerable attention.4 In this Letter, we
describe the preparation of diisopropy-2-phosphonates
by an analogous approach, that is, the hitherto
unreported metal-catalyzed decomposition of
diazomethylphosphonate in the presence of aldimines.
a
In the planning of our work, we have made use of the
knowledge gained in the optimization of the EDA-imi-
nes aziridination reaction and, in particular, in the defi-
nition of the crucial role played by the catalyst in the
reaction outcome.4c–e,g,n,p In our case, in order to evalu-
ate the effect of the catalyst on the aziridination reac-
tion, we have investigated at first the reaction of
diisopropyl diazomethylphosphonate (DIDAMP 1)5
with N-benzylidene aniline 2a6 in the presence of cata-
lytic amounts of Lewis acids in methylene chloride both
at room temperature and at 0 °C (Table 1).7 The results
show that cis- and trans-aziridine-2-phosphonates 3a
and 4a can be formed in good to moderate yields with
a variable diastereoselectivity. In particular, the best re-
sult in terms of both yield and diastereoselectivity was
obtained when In(OTf)3 was used as catalyst. Indeed,
decomposition of DIDAMP 1 with 2a in methylene
chloride catalyzed by In(OTf)3 at 0 °C (entry 6) resulted
exclusively in the formation of diisopropyl cis-N-phenyl-
3-phenylaziridin-2-ylphosphonate 3a in 40% yield.
Cis-selectivity, albeit with lower yield (20%), has also
Among the strategies developed for the preparation of
aziridinyl-2-carboxylate derivatives, the metal-catalyzed
reaction of ethyl diazoacetate (EDA) with imines has
Figure 1. 2-EWG-substituted aziridine.
Keywords: Aziridines-2-phosphonates; Diisopropyl diazomethylphos-
phonate; In(Otf)3; Imines.
*
Corresponding author. Tel.: +39 075 5855120; fax: +39 075
5855124; e-mail: rp@unipg.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.042

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R. Pellicciari et al. / Tetrahedron Letters 48 (2007) 4911–4914
Table 1. Aziridine-2-phosphonates from DIDAMP 1 and N-benzyl-
idene aniline 2a catalyzed by various Lewis acids
We assume that this diminished catalytic power of the
metal can be ascribed to the solvating properties of
THF.
Having established that the best conditions for aziridin-
ation reaction with DIDAMP 1 involved the use of
In(OTf)3 as catalyst in methylene chloride at 0 °C, we
decided to apply this system to study the effect on the
reaction rate of diverse para-substituents at the benzylic
moiety of imine.6 The results reported in Table 3 indi-
cate that the aziridines were formed in high overall
yields (77–91%), and the reaction rate was influenced
by the nature of the substituent at the benzylic group.
In particular, we found out that compounds 2g–i reacted
faster with respect to unsubstituted benzylimine 2d,
while pMe-benzylimine 2e reacted significantly slower
(24 h). This behaviour could reflect a positive effect of
electron-withdrawing substituents and a negative influ-
ence of electron-donor substituents on the benzylimine
reactivity. The best yield (91%) and diastereoselectivity
(6:1) was obtained for 2g (Table 3, entry 4).
Entry
Lewis acida
Temp
Yieldb (%)
Cis/trans
(3a/4a)b
1
2
3
4
5
6
Zn(OTf)2
Cu(OTf)2
In(OTf)3
Zn(OTf)2
Cu(OTf)2
In(OTf)3
rt
rt
rt
0 °C
0 °C
0 °C
66
>5
39
64
20
40
1/1
n.d.c
13/1
4/1
Cis only
Cis only
a 10 mol % with respect to imine.
b Determined by 1H NMR analysis of the crude reaction mixture.
c n.d. = not determined.
been achieved when 2a was reacted with DIDAMP 1 in
the presence of 10% Cu(OTf)2 at 0 ° C (entry 5).
Two different mechanisms have been proposed for the
metal-catalyzed aziridination reaction with EDA and
imines depending on the properties of the metal.4g In
the case of copper and rhodium catalysts the metal
reacts with EDA to form a metal-carbene complex that
attacks the imine nitrogen and affords the final aziri-
dines through a planar azomethine ylide intermediate.
Differently, Zn(OTf)2, BF3, AlCl3 and TiCl4 act as Lewis
acids by activating imine for a nucleophilic attack by
EDA at the a-carbon atom (most likely the rate-deter-
mining step) and the aziridine products are obtained
after a second nucleophilic substitution with N2 as the
leaving group.4f It is noteworthy that some experimental
evidences that we found in the reaction of DIDAMP 1
with aldimines in the presence of In(OTf)3 as catalyst,
such as the lack of DIDAMP dimers formation (prod-
ucts derived from carbene coupling), the isolation of
On the basis of these results, we then decided to use
In(OTf)3 as catalyst in order to examine both the influ-
ence of imines N-substitution and the solvent effect on
the reaction outcome. Thus, a number of N-benzylidene
amines 2b–d6 were reacted with 1 in the presence of 10%
In(OTf)3 in methylene chloride at 0 °C. As summarized
in Table 2, the formation of cis-aziridines was again
favoured. In particular, the aziridination reaction of
N-(pMeOPh)- and N-(pCF3Bn)-benzylimines 2b and 2c
(entries 1 and 2) yielded diastereoselectively the corre-
sponding cis-aziridines 3b and 3c in similar yields,
whereas 2d (entry 3) afforded both cis- and trans-azir-
idines 3d and 4d in 4/1 ratio and in higher overall yields.
The influence of the solvent in the In(OTf)3-catalyzed
aziridination of DIDAMP 1 and (N-benzyhydryl)-benz-
ylimine 2d was explored next (Table 2). While the use
of toluene (entry 4) led to similar results with respect
to methylene chloride (entry 3), when the reaction was
performed in THF longer reaction times were required
(70 h vs 6 h) and a lower overall yield was obtained.
Table 3. Influence of various substituents at the benzyl moiety of the
imine in the aziridination reaction
Table 2. In(OTf)3-catalyzed aziridination reaction of DIDAMP 1 with
differently N-substituted imines and solvents
Entry
2
R
Solvent
Cis/transa
Isolated
yieldb
(%)
Entry
2
R
Time (h)
Cis/trans
Isolated
yieldb
(%)
(3/4)
3
4
(3/4)a
3
4
1
2
3
4
5
b
c
pMeOPh
pCF3Bn
CHPh2
CHPh2
CHPh2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
1/1
42
40
64
60
39
1
2
3
4
5
6
d
e
f
H
6
24
4
3
2.5
2.5
4/1
4/1
4/1
6/1
2/1
2/1
58
40
68
79
54
53
19
16
18
12
28
27
n.d.c
13/1
4/1
pMe
pAcO
pCl
pCF3
pNO2
d
d
d
19
15
11
g
h
i
Cis only
a Determined by 1H NMR analysis of the crude reaction mixture.
b Calculated after purification by flash chromatography on silica gel.
c n.d. = not determined.
a Determined by 1H NMR analysis of the crude reaction mixture.
b Calculated after purification by flash chromatography on silica gel.

R. Pellicciari et al. / Tetrahedron Letters 48 (2007) 4911–4914
4913
in methylene chloride at 0 °C. The utilization of the
methodology above described for the preparation of
aziridine-2-phosphonates of pharmaceutical interest is
under way and the results will be reported in due time.
Acknowledgement
This study was co-financed by MIUR funds (PRIN
2004).
Supplementary data
Scheme 1. Proposed mechanism for the In(OTf)3 catalyzed aziridin-
ation reaction of aldimines with DIDAMP.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.05.042.
enamines as by-products, as well as the imine nitrogen
substituent effect on the reaction rate could be compat-
ible with the latter mechanism (Scheme 1). Moreover,
those factors weakening the catalytic efficacy of the me-
tal salt, such as the metal cation solvatation, were found
to negatively affected the yield and the rate of the
reaction.
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4914
R. Pellicciari et al. / Tetrahedron Letters 48 (2007) 4911–4914
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