Synthesis of 2-aziridinyl phosphonates by modified Gabriel-Cromwell reaction and their antibacterial activities

Article abstract of DOI:10.1016/j.ejmech.2011.03.037

A set of new aziridinyl phosphonates (4a-g) were synthesized by using the Gabriel-Cromwell reaction and its modified version developed in this study and their structures confirmed by HRMS, IR, and NMR spectra. All the compounds were screened for their antibacterial activity. They all showed comparable moderate to good growth inhibitory activity in reference to ampicillin and streptomycin.

Full text of DOI:10.1016/j.ejmech.2011.03.037

European Journal of Medicinal Chemistry 46 (2011) 2485e2489
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 2-aziridinyl phosphonates by modified GabrieleCromwell reaction
and their antibacterial activities
a
,
a
b
b,1
*
ꢀ
Özdemir Dogan , Hakan Babiz , Ays¸e Gül Gözen , Songül Budak
a Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b Department of Biology, Middle East Technical University, 06531 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A set of new aziridinyl phosphonates (4aeg) were synthesized by using the GabrieleCromwell reaction
and its modified version developed in this study and their structures confirmed by HRMS, IR, and NMR
spectra. All the compounds were screened for their antibacterial activity. They all showed comparable
moderate to good growth inhibitory activity in reference to ampicillin and streptomycin.
Ó 2011 Elsevier Masson SAS. All rights reserved.
Received 15 December 2010
Received in revised form
9 March 2011
Accepted 16 March 2011
Available online 9 April 2011
Keywords:
Aziridinyl phosphonates
Antibacterial activity
1. Introduction
yielded aziridines in 14e45% [13]. In the study of Lesniak et al. 1,3-
dipolar cycloaddition of diazophosphonate with aryl imines
Aziridines are important small molecules that are found in the
structure of biologically active natural compounds and have many
applications in organic chemistry [1]. They are used as precursors to
amino acids, azomethine ylides, and amino alcohols. In addition
they are used as monomers for polymerization [2], chiral auxiliaries
[3], and chiral ligands [4]. Aziridinyl phosphonates are the precur-
produced aziridinyl phosphonates in 67e78% yield after a period of
15 days [14]. Very recently, Hodgson et al. reported aziridinyl
phosphonate synthesis by lithiation-induced phosphonyl migra-
tion from nitrogen to carbon in terminal aziridines [15]. Due to the
limited number of studies and also the limitations in the applica-
tion of some of the methods such as low yields, long reaction times,
or specific aziridine synthesis there is a need for the development
of more general methods for the synthesis of aziridinyl phospho-
nates. Our group has been involved in the synthesis of new azir-
idine derivatives to use them as chiral ligands for metal catalyzed
enantioselective synthesis of organic compounds [16]. As an
extention of previous studies, here in we report the synthesis of
new aziridinyl phosphonates by modified GabrieleCromwell
reaction and also their antibacterial activities.
sors of
a-amino phosphonates that find applications such as
enzyme inhibitors [5], as haptens for catalytic antibodies [6], as
antibacterial agents [7], and herbicides [8]. Although many studies
have been carried out for the synthesis of aziridine-2-carboxylate
esters, there are only limited number of studies reported for the
synthesis of aziridinyl phosphonates [9]. One of the methods
reported by Kim et al. involves the nitrene addition to cinnamoyl
phosphonate derivatives which produced N-tosyl-2-aziridinyl
phosphonates in 81e89% yield [10]. Another synthesis reported by
Stevens et al. gives rather specific N-vinylaziridinyl phosphonate
derivatives in 29e57% yield [11]. Davis et al. reported the synthesis
of chiral aziridinyl phosphonates in 76% yield by reacting
chiral sulfinimines with chloromethyl phosphonates [12]. Loreto
et al. also studied synthesis of aziridinyl phosphonates by (ethox-
2. Results and discussion
2.1. Chemistry
One of the commonly used methods for the aziridine synthesis
is the GabrieleCromwell reaction Scheme 1. A nice asymmetric
application of this method was reported by Garner et al. [17]. Berlin
et al. applied this method for the synthesis of diethyl 2-aziridinyl
phosphonate (4, R ¼ H) which was obtained in 62% yield by heating
dibromo compound 2 with ammonia in a sealed tube Scheme 1
[18]. This was the only aziridine reported by this group using the
ycarbonyl)nitrene addition to a,b-unsaturated phosphonates which
* Corresponding author. Tel.: þ90 312 210 5134; fax: þ90 312 210 3200.
E-mail address: dogano@metu.edu.tr (H. Babiz).
1
Present address: Nigde University, Nigde, Turkey.
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.03.037

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Ö. Dogan et al / European Journal of Medicinal Chemistry 46 (2011) 2485e2489
2486
O
O
R
N
Table 1
Br
O
O
RNH2
(-HBr)
Br2
RNH2
P(OEt)2
P(OEt)2
P(OEt)2
Synthesis of 2-aziridinyl phosphonates.
P(OEt)2
Br
1
Br
2
3
4
Entry
Amine
Product
Yield (%)
Yield (%)
Method Aa
Method Bb
Scheme 1. Berlin’s synthesis of aziridinyl phosphonate by GabrieleCromwell reaction.
Ph
1
88 (86)
88 (62)
85
79
O
N
GabrieleCromwell reaction. The steps of this reaction involves
addition of Br2 to vinyl group to form compound 2. Then HBr
elimination by triethylamine or the amine used for aziridination
gives a-bromo phosphonate 3. Michael addition of another equiv-
alent of amine to 3 then SN2 displacement of bromide leads to the
aziridine 4.
However, the vinyl phosphonate 1 is difficult to synthesize [19]
and highly expensive. As an alternative to this method we planned
to start with acetyl phosphonate which can be synthesized easily
using the MichaeliseArbusow reaction [20]. After the synthesis of
acetyl phosphonate 5, the next step was the conversion of this
compound to tosylate 6 Scheme 2. Since it was necessary to have
NH2
P(OEt)2
4a
O
2
3
(CH3)2CHNH2
N
4b
P(OEt)2
89 (76)
96
NH2
O
N
4c
P(OEt)2
a good leaving group at
a-position of the phosphonate. This
conversion was made possible by treatment of acetyl phosphonate
with DBU and tosyl chloride.
NH2
O
O
4
5
50 (92)
65 (78)
73
91
O
N
4d
P(OEt)2
In order to synthesize compound 6 in high yield, it was neces-
sary to optimize the reaction conditions. For this reason, different
solvents (THF, DCM, CH3CN, MeOH, and CHCl3) were tried. Among
the solvents, CHCl3 and DCM gave similar results, and tosylate 6 was
obtained in about 50% yield. Product formation was not observed in
methanol and the highest yield (87%) was obtained with acetoni-
trile. In the case of THF, yield was 3e5% lower compared to aceto-
nitrile. We have tried two bases DBU and Et3N but almost no
product formation took place in Et3N. Therefore, DBU was chosen as
the base. After determining solvent and base, different reaction
times were tried. Increasing the reaction time from 3 h to 24 h
didn’t change the yield considerably. Change of reaction concen-
tration had a significant effect on the yield. The highest yield was
obtained when the concentration was about 0.2 M. Reactions
carried out at 0.5 M and 1.0 M gave the product in low yield. We
have also tried to synthesize mesylate instead of tosylate but the
yield was low. After determining the optimum conditions for the
synthesis of tosylate 6, the aziridine forming step was carried out
Scheme 2. Again, after doing some optimization studies by using
different solvents (THF, DCM, CHCl3, and CH3CN), different amine
concentrations and reaction times, it was found that the highest
yield could be obtained by stirring tosylate 6 with amine (1.4 equiv)
and DBU (1.0 equiv) at rt for 24 h in CH3CN. After optimizing the
reaction conditions, different amines were used to test the appli-
cability of this method. The same aziridines were also synthesized
by the GabrieleCromwell reaction (Method B, Scheme 1) in order to
compare the efficiency of two methods. The results of both
methods are summarized in Table 1. The absolute stereochemistry
at the aziridine chirality center of 4e, 4e’, 4f, and 4f’ were not
determined.
H
HO
HO
O
H
NH2
N
P(OEt)2
4e, 4e'
H
H
Me
Ph
Me
Ph
Ph
6
76 (82)
71
O
N
NH2
4f, f'
P(OEt)2
H
N
O
P
7
85
O
4g
N
OEt
P(OEt)2
OEt
a
Method A: Tosylate 6, amine (1.4 equiv), and DBU (1 equiv) were stirred at rt for
24 h. In parenthesis, values obtained using acetonitrile as the solvent after 48 h
stirring at rt.
b
Method B: Dibromide 2 and amine (3 equiv) were refluxed in acetonitrile for 3 h.
(Kocuria spp) (Gram-positive) by performing disc diffusion assays
[21]. The Fs48, 30, and 24 were isolated from fresh water fish
surface mucus and identified at genus level with 16s ribosomal
DNA sequencing. Ampicillin and Streptomycin were used as the
reference drugs. The results were recorded for each tested
compound as the average diameter of inhibition zone of bacterial
growth around the disks in mm (Table 2).
Results of antibacterial screening studies revealed that all the
aziridinyl phosphonates showed moderate to good activity as
compared to reference antibiotics. As can be seen from Table 2
aziridinyl phosphonate 4b having benzyl group on the nitrogen
showed better activity than reference antibiotics against B. subtilis.
Aziridine 4e’ showed similar activity as amphicillin but better
activity than Streptomycin against the same bacteria. In the case of
E. coli, again, 4e’ showed the highest activity. Compounds 4b, 4c, 4d,
4e’, and 4f showed similar activity against Fs48, 4c showed the
highest activity against this bacteria. For Fs30, all the compounds
showed better activity than ampicillin and 4e showed the highest
inhibitory activity against this bacteria among the series of azir-
idinyl phosphonates. The compound 4e showed the highest activity
against Fs24 and the others 4a, 4b, 4c, 4e’, and 4f’ showed moderate
inhibitory activity against the same bacteria.
O
R
N
O
O
DBU
RNH2
P(OEt)2
P(OEt)2
P(OEt)2
4
TsCl, rt, 3h
DBU, rt, 24-48h
5
O
6
OTs
Scheme 2. Synthesis of aziridinyl phosphonate from acetyl phosphonate.
2.2. Antibacterial studies
The newly synthesized aziridinyl phosphonates 4aeg were
screened for their antibacterial activity against Bacillus subtilis
(Gram-positive), Escherichia coli DH5a (Gram-negative), and three
fresh water isolates, namely Fs48 (Gordonia spp) (Gram-positive to
variable), Fs30 (Brevundimonas spp) (Gram-negative), and Fs24

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Ö. Dogan et al / European Journal of Medicinal Chemistry 46 (2011) 2485e2489
2487
Table 2
Antibacterial activities of aziridinyl phosphonates.
Compounds
Inhibition zone diameters (mm)
Bacillus subtilis
Escherichia coli
Fs48 Gordonia spp
Fs30 Brevundimonas spp
Fs24 Kocuria spp
4a
4b
4c
4d
4e
4e’
4f
4f’
10 ꢃ 0
19.33 ꢃ 1.15
9.66 ꢃ 0.57
10.33 ꢃ 0.57
11 ꢃ 2
8 ꢃ 0
9 ꢃ 0
13 ꢃ 0
13.66 ꢃ 1.15
16 ꢃ 3.60
18 ꢃ 1.73
19 ꢃ 2.64
18.33 ꢃ 2.88
14.66 ꢃ 0.57
25 ꢃ 0
15.66 ꢃ 3.78
23.33 ꢃ 2.88
14.66 ꢃ 0.57
11 ꢃ 1.41
10 ꢃ 0
14.33 ꢃ 0.57
15 ꢃ 0
13.33 ꢃ 0.88
10.66 ꢃ 1.15
20 ꢃ 0
20 ꢃ 0
17 ꢃ 0
15.33 ꢃ 4.61
13.33 ꢃ 1.15
16.33 ꢃ 1.51
11.66 ꢃ 2.88
ND
13 ꢃ 3.46
18.66 ꢃ 1.51
12 ꢃ 2
10 ꢃ 0
13 ꢃ 1
13.66 ꢃ 1.15
13.33 ꢃ 0.57
12.33 ꢃ 2.51
10.67 ꢃ 0.57
29.33 ꢃ 0.57
11.66 ꢃ 1.15
11.33 ꢃ 2.30
17.33 ꢃ 2.3
14 ꢃ 0.0
12 ꢃ 0
19 ꢃ 1
4g
11.33 ꢃ 2.30
16.67 ꢃ 1.52
19.67 ꢃ 0.57
12.33 ꢃ 2.51
47.67 ꢃ 0.57
26 ꢃ 6.9
Ampicillin
Streptomycin
29 ꢃ 1.73
It is important to note that diastereomeric aziridines 4e and 4e’
behaved differently. While the first one showed highest activity
(highest of all) against Fs24 Kocuria spp, second one showed the
highest activity against E. coli. Also the diasteromers 4f and 4f’
showed parallel activities against the first four bacteria in Table 2
but different activities against Fs24 Kocuria spp. Aziridine 4g
having no substituent on the nitrogen showed a low but very
similar activity against all the bacteria. From these results it can be
concluded that the substituent on the nitrogen as well as the
stereochemistry of aziridine ring affects the antibacterial activity of
these compounds.
4.1.1. Synthesis of 1-(diethoxyphosphoryl) vinyl 4-
methylbenzenesulfonate (6)
To a dry two necked round bottom flask with a magnetic stir
bar under N2 atmosphere, diethyl acetyl phosphonate (100 L,
0.62 mmol) and 4-methylbenzene-1-sulfonyl chloride (176 mg,
m
0.923 mmol) in CH3CN (2.7 mL) was added. The reaction flask was
cooled to 0 ꢁC in an ice-water bath. Then, DBU (141
mL, 0.92 mmol)
was slowly added. The resulting mixture was stirred at rt for 3 h.
At the end of this time, water (10 mL) and CH2Cl2 (10 mL) was
added to the reaction flsk. Two layers were separated and aqueous
layer was extracted with CH2Cl2 (2 ꢂ 10 mL). The combined
organic layers were dried over MgSO4 and concentrated. The crude
product was purified by flash column chromatography on silica gel
(EtOAc, Rf ¼ 0.69) to give 6 in 87% yield (179 mg, 0.536 mmol) as
3. Conclusion
a light yellow solid. 1H NMR
d
7.77 (d, J ¼ 8.3 Hz, 2H), 7.28 (d,
A new method which can be considered as a modified Gabri-
eleCromwell reaction was developed for the synthesis of 2-azir-
idinyl phosphonates. Using this method eight new aziridines
including stereoisomers were synthesized in 70e92% yield. The
same aziridines were also synthesized by using classical Gabri-
eleCromwell reaction in 71e96% yield to compare the efficiency of
two methods. Basically both methods form the aziridinyl phos-
phonates in similar yields. The main advantages of the method
developed in this study are the ease of availability of the starting
material 6 and the fact that the aziridination reaction proceeds at rt.
The only disadvantage is the longer reaction times (24e48 h).
The antibacterial activities of synthesized aziridinyl phospho-
nates were tested for the first time in this study by performing disc
diffusion assays. These studies showed that aziridine derivatives
have different activities against different bacteria. The substituent
on the nitrogen has a significant effect on the activity. The stereo-
chemistry is also important, diasteromers 4e, 4e’ and 4f, 4f’ varied
in their activity against different bacteria. Especially for the dia-
stereomers 4e and 4e’, there is a significant difference in terms of
antibacterial activity.
J ¼ 8.1 Hz, 2H), 5.89 (ddd, J ¼ 12.8, 11.8, 2.6 Hz, 2H), 4.10e3.84 (m,
4H), 2.41 (s, 3H), 1.24 (t, J ¼ 7.1 Hz, 6H). 13C NMR
d 147.21 (Ar),
144.95 (Ar), 133.43 (CH2CP), 129.64 (Ar), 128.44 (Ar), 118.98 (d,
JPeC ¼ 23.16 Hz), 62.86 (CH2CH3), 62.81 (CH2CH3), 21.64 (CH3Ar),
16.18 (CH3CH2), 16.12 (CH3CH2). 31P NMR
d 5.24.
4.2. General procedure for the synthesis of aziridinyl phosphonates
4 (Method A)
To a stirred mixture of 1-(diethoxyphosphoryl)vinyl 4-methyl-
benzenesulfonate (6, 0.83 mmol) and DBU (0.83 mmol, 1.0 equiv)
was added amine (1.16 mmol, 2 equiv) at rt ad stirred for 24 h.
When the reactions were carried out in CH3CN, the concentration
was adjusted to w2 M with respect to amine. The resulting mixture
was stirred at this temperature for 48 h. The crude product was
purified by column chromatography using silica gel and hex-
ane:ethyl acetat (1:1 mixture) as the eluent.
4.2.1. Diethyl 1-benzylaziridin-2-ylphosphonate (4a)
Colorless oil, (EtOAc, Rf ¼ 0.1), yield 88% (197 mg, 0.732 mmol);
1H NMR
d
7.40e7.07 (m, 5H), 4.14e3.71 (m, 4H), 3.55 (d, J ¼ 13.0 Hz,
4. Experimental
1H), 3.24 (d, J ¼ 13.0 Hz, 1H), 2.12 (dd, J ¼ 9.2, 3.5 Hz, 1H), 1.77e1.39
(m, 2H), 1.20 (t, J ¼ 7.0 Hz, 3H), 1.13 (t, J ¼ 7.1 Hz, 3H). 13C NMR
4.1. Chemistry
d 137.78 (CH), 128.38 (CH), 128.28 (CH), 127.34 (CH), 65.27 (d,
J ¼ 7.3 Hz, CH2Ph), 62.29 (d, J ¼ 6.2 Hz, CH2CH3), 61.96 (d, J ¼ 6.1 Hz,
IR spectra were recorded on FT-IR Shimadzu 8300 spectropho-
tometer. 1H, 13C, and 31P NMR spectra were recorded on a Bruker
400 MHz spectrometer in CDCl3eCCl4 using tetramethylsilane as
CH2CH3), 31.92 (d, J ¼ 5.3 Hz, CH2N), 31.71 (d, JPeC ¼ 216.9 Hz, PCH),
16.39 (CH3), 16.33 (CH3). 31P NMR
d
22.48. IR (neat, cmꢀ1) 3062,
2981, 2930, 2906, 1454, 1019, 766. HRMS-EI (m/z): calcd for
internal standard and chemical shifts are reported in d units. HRMS
C13H21NO3P (M þ Hþ): 270.1259; found: 270.1254.
were recorded on a Waters Micromass Q-TOF instrument in ESþ
mode. Thin layer chromatography was performed on pre-coated
silica plates (Merck Kiesegel 60 F254) and column chromatography
using silica gel (mesh 230ꢀ400). Phosphomolybdic acid in ethanol
and ninhydrin was used as visualizing agents.
4.2.2. Diethyl 1-isopropylaziridin-2-ylphosphonate (4b)
Colorless oil, (EtOAc, Rf
0.746 mmol); 1H NMR
4.17e3.94 (m, 4H), 2.00 (ddd, J ¼ 8.9, 3.5,
1.0 Hz, 1H), 1.45 (td, J ¼ 7.1, 1.1 Hz, 1H), 1.41e1.32 (m, 2H), 1.27 (t,
¼
0.14), yield 88.4% (165 mg,
d

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Ö. Dogan et al / European Journal of Medicinal Chemistry 46 (2011) 2485e2489
2488
J ¼ 7.1 Hz, 6H), 1.10 (d, J ¼ 8.9 Hz, 3H), 1.08 (d, J ¼ 8.9 Hz, 3H). 13
C
4.21e4.01 (m, 4H), 2.35 (q, J ¼ 6.5 Hz, 1H), 1.97 (dd, J ¼ 8.9, 3.3 Hz,
1H), 1.55 (ddd, J ¼ 19.3, 6.8, 3.6 Hz, 1H), 1.45 (t, J ¼ 7.0 Hz, 1H), 1.39
NMR
d
62.36 (d, J ¼ 7.1 Hz, CH(CH3)2), 62.18 (d, J ¼ 6.4 Hz, CH2CH3),
61.67 (d, J ¼ 6.3 Hz, CH2CH3), 31.36 (d, JPeC ¼ 219.3 Hz, PCH), 31.07
(d, J ¼ 5.2 Hz, CH2N), 21.87 (C), 16.36 (CH3), 16.30 (CH3), 16.23 (CH3).
(d, J ¼ 6.5 Hz, 3H), 1.29 (t, J ¼ 7.0 Hz, 6H). 13C NMR
d 143.79 (Ph),
128.28 (Ph), 127.14 (Ph), 126.58 (Ph), 70.97 (d, J ¼ 7.1 Hz, CHPh),
62.41 (d, J ¼ 6.5 Hz, CH2OP), 62.19 (d, J ¼ 6.3 Hz, CH2OP), 32.59 (d,
JPeC ¼ 218.6 Hz, CHP), 31.53 (d, J ¼ 5.2 Hz, CH2N), 23.54 (CH3CH),
31P NMR 23.11. IR(neat, cmꢀ1) 3345, 2970, 2931, 2874, 1370, 1234,
d
1024, 970. HRMS-EI (m/z): calcd for C9H21NO3P (M þ Hþ):
222.1259; found: 222.1251.
16.52 (d, JPeC ¼ 5.7 Hz, CH3CH2),16.46 (d, JPeC ¼ 5.8 Hz, CH3CH2). 31
P
NMR
d
22.76. IR(neat, cmꢀ1) 3060, 2978, 2929, 2906, 1245, 1021,
4.2.3. Diethyl 1-cyclohexylaziridin-2-ylphosphonate (4c)
961. HRMS-EI (m/z): calcd for C14H21NO3PNa (M þ Naþ): 306.1235;
21
Colorless oil, (EtOAc, Rf ¼ 0.29), yield 89% (210 mg, 0.804 mmol);
found: 306.1237. 4f’: Colorless oil, [
a
]
D
¼ þ26 (c, 0.1, CH2Cl2),
1H NMR
d
4.15e3.99 (m, 4H), 2.04e1.95 (m, 1H), 1.73 (m, 4H),
(EtOAc, Rf ¼ 0.14), yield 32.6% (149 mg, 0.526 mmol); 1H NMR
1.58e1.31 (m, 5H), 1.27 (t, J ¼ 7.0 Hz, 3H), 1.26 (t, J ¼ 7.0 Hz, 3H),
d
7.40e7.10 (m, 5H), 3.96e3.54 (m, 4H), 2.32 (q, J ¼ 6.5 Hz, 1H), 2.19
1.21e0.97 (m, 4H). 13C NMR
d
70.08 (d, J ¼ 6.7 Hz, CHNCHP), 62.29
(dd, J ¼ 9.1, 3.6 Hz,1H),1.60 (t, J ¼ 7.0 Hz,1H),1.52e1.42 (m,1H),1.40
(d, J ¼ 6.3 Hz, CH2CH3), 61.82 (d, J ¼ 6.3 Hz, CH2CH3), 32.41
(CH2CHCH2), 30.78 (d, JPeC ¼ 219.2 Hz, PCH), 30.59 (d, J ¼ 5.2 Hz,
CH2NCH), 25.93 (CH2CH2CH), 24.46 (CH2CH2CH2CH), 16.45 (d,
(d, J ¼ 6.6 Hz, 3H), 1.12 (t, J ¼ 7.1 Hz, 3H), 1.03 (t, J ¼ 7.1 Hz, 3H). 13C
NMR
d 143.21 (Ph), 128.23 (Ph), 127.34 (Ph), 127.13 (Ph), 71.42 (d,
J ¼ 6.9 Hz, CH3CH), 62.14 (d, J ¼ 6.2 Hz, CH2CH3), 61.48 (d, J ¼ 6.0 Hz,
J ¼ 6.1 Hz, CH3CH2), 16.36 (d, J ¼ 6.2 Hz, CH3CH2). 31P NMR
d 23.36.
CH2CH3), 31.97 (d, J ¼ 5.2 Hz, CH2N), 31.28 (d, JPeC ¼ 216.4 Hz, CHP),
IR(neat, cmꢀ1) 2980, 2927, 2854, 1449, 1245, 1022, 961. HRMS-EI
22.93 (CH3CH), 16.30 (CH3CH2), 16.23 (CH3CH2). 31P NMR
d 21.49. IR
(m/z): calcd for C12H25NO3P (M þ Hþ): 262.1572; found: 262.1569.
(neat, cmꢀ1) 3060, 2978, 2929, 2906, 1246, 1022, 954. HRMS-EI (m/
z): calcd for C14H21NO3PNa (M þ Naþ): 306.1235; found: 306.1225.
4.2.4. Diethyl 1-(furan-2-ylmethyl)aziridin-2-ylphosphonate (4d)
Colorless oil, (EtOAc, Rf ¼ 0.24), yield 50% (108 mg, 0.415 mmol);
4.3. Aziridin-2-ylphosphonate (4g)
1H NMR
d
7.29 (dd, J ¼ 1.8, 0.8 Hz, 1H), 6.25 (dd, J ¼ 3.2, 1.8 Hz, 1H),
6.21 (d, J ¼ 3.2 Hz, 1H), 4.07e3.92 (m, 4H), 3.62 (d, J ¼ 13.9 Hz, 1H),
3.29 (d, J ¼ 13.9 Hz, 1H), 2.09 (ddd, J ¼ 9.2, 3.2, 1.2 Hz, 1H), 1.70e1.56
(m, 2H), 1.24 (t, J ¼ 7.1 Hz, 3H), 1.19 (t, J ¼ 7.1 Hz, 3H). 13C NMR
Diethyl 1-benzylaziridin-2-ylphosphonate (4a, 50 mg, 0.19 mmol)
and PdeC (25 mg 10%) was stirred in CH3OH (0.63 mL) under N2
atmosphere. Then H2 gas filled into the reaction flask having a baloon
attached to it. After stirring for 30 min tlc analysis showed no starting
material. The reaction mixture was filtered through celite and the
solvent was removed by rotary evaporator to give pure compound 4g
(28.6 mg, 0.160 mmol) in 85% yield as a colorless oil. 1H NMR
d
151.22 (OCCH), 142.09 (OCHCH), 110.25 (CHCO), 108.35 (CHCHO),
62.33 (d, J ¼ 6.2 Hz, CH2CH3), 62.01 (d, J ¼ 6.1 Hz, CH2CH3), 56.27 (d,
J ¼ 7.5 Hz, CH2CCH), 31.23 (d, J ¼ 5.4 Hz, CH2CHP), 31.03 (d,
JPeC ¼ 216.7 Hz), 16.43 (CH3), 16.37 (CH3). 31P NMR
d 22.40. IR(neat,
cmꢀ1) 3113, 2983, 2931, 2908, 1505, 1243,1017, 796. HRMS-EI (m/z):
calcd for C11H19NO4P (M þ Hþ): 260.1052; found: 260.1058.
d
4.11e3.91 (m, 4H), 1.89 (d, J ¼ 11.1 Hz, 1H), 1.79e1.61 (m, 2H),
1.30e1.15 (m, 6H).13C NMR
d
62.03 (t, J ¼ 5.5 Hz), 22.54 (d, J ¼ 2.4 Hz),
21.97 (d, JPeC ¼ 195.6 Hz),16.38 (CH3),16.32 (CH3). 31P NMR
d 27.15. IR
(neat, cmꢀ1) 3450, 3256, 2983, 2909,1235,1018, 958. HRMS-EI (m/z):
calcd for C6H15NO3P (M þ Hþ): 180.0783; found: 180.0789.
4.2.5. Diethyl (1-(1-hydroxybutan-2-yl)aziridin-2-yl)phosphonate
(4e and 4e’)
21
4e: Colorless oil,
[a
]
¼ þ38 (c, 0.1, CH2Cl2), (EtOAc/
D
MeOH ¼ 10:1, Rf ¼ 0.32), yield 33% (69 mg, 0.274 mmol); 1H NMR
4.4. Synthesis of 1,2-dibromoethylphosphonate (2)
d
4.20e4.01 (m, 4H), 3.68e3.53 (m, 2H), 3.33 (s, 1H), 2.01
(dd, J ¼ 8.9, 3.6 Hz, 1H), 1.72 (ddd, J ¼ 20.5, 6.6, 3.6 Hz, 1H), 1.57
(t, J ¼ 7.1 Hz, 1H), 1.50e1.42 (m, 2H), 1.37e1.32 (m, 1H), 1.30
(t, J ¼ 7.1 Hz, 3H), 1.26 (t, J ¼ 7.1 Hz, 3H), 0.88 (t, J ¼ 7.5 Hz, 3H). 13C
Diethyl vinylphosphonate (1, 0.2 mL, 1.24 mmol) was added into
a pre-dried two necked flask and was dissolved in CH2Cl2 (13 mL)
and the reaction mixture cooled to 0 ꢁC Br2 (0.830 mL,1.67 mmol, in
2.4 mL CH2Cl2) was added to this solution. After 30 min stirring at
rt, tlc showed no starting material. The reaction mixture was
applied directly to column chromatography (EtOAc) to yield 2
(382 mg, 1.18 mmol) in 95% yield as a light yellow oil. 1H NMR
NMR
d
72.52 (d, J ¼ 6.8 Hz, CHCH2OH), 65.52 (CH2OH), 63.01
(d, J ¼ 6.0 Hz, CH2CH3), 62.08 (d, J ¼ 6.6 Hz, CH2CH3), 31.11
(d, JPeC ¼ 218.3 Hz), 29.53 (d, J ¼ 5.9 Hz, CH2N), 24.65 (CH2CHN),
16.35 (d, J ¼ 2.8 Hz, CH3CH2O), 16.30 (d, J ¼ 2.2 Hz, CH3CH2O), 10.47
(CH3CH2CH). 31P NMR
d
23.84. IR(neat, cmꢀ1) 3403, 2977, 2933,
d
4.26e4.12 (m, 4H), 4.03e3.88 (m, 2H), 3.61e3.48 (m, 1H), 1.33 (t,
2877, 1233, 1019, 965, 795. HRMS-EI (m/z): calcd for C10H23NO4P
(M
Hþ): 252.1364; found: 252.1359. 4e’: Colorless oil,
¼ þ44 (c, 0.1, CH2Cl2), (EtOAc/MeOH ¼ 10:1 Rf ¼ 0.25), yield
45% (94 mg, 0.374 mmol); 1H NMR
4.15e4.00 (m, 4H), 3.68e3.55
J ¼ 7.0 Hz, 6H). 13C NMR
d
64.01 (d, J ¼ 7.0 Hz, CH2CH3), 63.70 (d,
þ
21
J ¼ 6.9 Hz, CH2CH3), 41.88 (d, JPeC ¼ 150.8 Hz), 31.72 (CH2Br), 16.37
[a]
D
(CH3CH2), 16.32 (CH3CH2). 31P NMR
d 15.27.
d
(m, 2H), 2.37 (s, 1H), 2.09 (dd, J ¼ 9.1, 3.6 Hz, 1H), 1.67 (t, J ¼ 7.1 Hz,
1H), 1.64e1.57 (m, 1H), 1.55e1.43 (m, 2H), 1.37e1.31 (m, 1H),
1.31e1.28 (m, 3H), 1.28e1.24 (m, 3H), 0.89 (t, J ¼ 7.5 Hz, 3H). 13C
4.5. Synthesis of aziridinyl phosphonates 4ae4g by (Method B)
NMR
d
73.08 (d, J ¼ 6.7 Hz, CHCH2OH), 63.85 (CH2OH), 62.52 (d,
Diethyl 1,2-dibromoethylphosphonate (2, 329 mg, 1.02 mmol)
was weighed into a pre-dried two necked flask and dissolved by
adding CH3CN (1.85 mL). After adding Et3N (0.170 mL,1.22 mmol) at
rt, white solids were observed. Then the amine (3.05 mmol) was
added and the resulting mixture was refluxed at 80e85 ꢁC for 3 h.
At the end of this time, the reaction mixture was treated with 0.1 N
HCl (10 mL) and CH2Cl2 (10 mL) was added. Two layers were
separated, and the aqueous layer was extracted with CH2Cl2
(2 ꢂ 10 mL). The combined organic layers were dried over Na2SO4,
concentrated under reduced pressure, and purified by flash column
chromatography on silica gel using hexane:ethyl acetat (1:1
mixture) as the eluent.
J ¼ 6.4 Hz, CH2O), 62.00 (d, J ¼ 6.3 Hz, CH2O), 31.34 (CH2N), 29.73 (d,
JPeC ¼ 219.5 Hz), 23.93 (CH2CHN), 16.45 (d, JPeC ¼ 5.9 Hz, CH3CH2),
16.39 (d, JPeC ¼ 6.1 Hz, CH3CH2), 10.26 (CH3CH2CH). 31P NMR
d
22.86. IR(neat, cmꢀ1) 3394, 2979, 2931, 2878,1233, 1019, 964, 795.
HRMS-EI (m/z): calcd for C10H23NO4P (M þ Hþ): 252.1364; found:
252.1354.
4.2.6. Diethyl 1-(1-phenylethyl) aziridin-2-ylphosphonate (4f and
4f’)
21
4f: Colorless oil, [
a
]
D
¼ þ44 (c, 0.1, CH2Cl2), (EtOAc, Rf ¼ 0.38),
7.34e7.08 (m, 5H),
yield 49.2% (225 mg, 0.794 mmol); 1H NMR
d

ꢀ
Ö. Dogan et al / European Journal of Medicinal Chemistry 46 (2011) 2485e2489
2489
See also;
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Acknowledgments
The authors thank the Scientific and Technical Research Council
of Turkey (TUBITAK, Grant No. TBAG 110T073) and the Middle East
Technical University Research Foundations for the financial
support.
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