Synthesis of N-vinyl 2,2-bisphosphonoaziridines from 1,1-bisphosphono-2- aza-1,3-dienes

Article abstract of DOI:10.1016/j.tetlet.2011.05.149

N-Vinyl 2,2-bisphosphonoaziridines are formed by treatment of 1,1-bisphosphono-2-aza-1,3-dienes with diazomethane. Depending on the substituents at the 4-position of the 1,1-bisphosphono-2-aza-1,3-dienes, exclusively 1-(ethenylamino)-2-phosphonoethenylpho

Full text of DOI:10.1016/j.tetlet.2011.05.149

Tetrahedron Letters 52 (2011) 4273–4276
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of N-vinyl 2,2-bisphosphonoaziridines
from 1,1-bisphosphono-2-aza-1,3-dienes
Pieter P. J. Mortier, Frederik E. A. Van Waes, Kurt G. R. Masschelein, Thomas S. A. Heugebaert,
⇑
Christian V. Stevens
Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653,
B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Vinyl 2,2-bisphosphonoaziridines are formed by treatment of 1,1-bisphosphono-2-aza-1,3-dienes with
diazomethane. Depending on the substituents at the 4-position of the 1,1-bisphosphono-2-aza-1,3-
dienes, exclusively 1-(ethenylamino)-2-phosphonoethenylphosphonates or mixtures of 1-(ethenylami-
no)-2-phosphonoethenylphosphonates and 2-imino-2-phosphonoethylphosphonates are obtained as
side products.
Received 6 April 2011
Revised 27 May 2011
Accepted 31 May 2011
Available online 16 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aminophosphonates
Azadienes
Aziridination
Bisphosphonates are a major class of drugs for the treatment of
bone diseases. They inhibit bone resorption by selective uptake
and adsorption to mineral surfaces in the bone, where they are
internalized by osteoclasts and interfere with specific biochemical
processes. Bisphosphonates can be classified according to their
mode of action. The more potent nitrogen-containing bisphospho-
nates or aminobisphosphonates act by inhibiting farnesyl diphos-
phate synthase, a key enzyme in the mevalonate pathway, and
affect cellular activity and cell survival by interfering with protein
prenylation and, therefore, the signaling functions of key regula-
tory proteins.1–5 Aminobisphosphonates have also effects beyond
the skeleton and are not selectively active on osteoclasts.6 As a re-
sult, these compounds display direct antitumor effects.5,7–11 Fur-
thermore, aminobisphosphonate drugs constitute an attractive
group as chemotherapeutic agents against protozoal diseases.12
Despite the importance of these aminobisphosphonates,
heterocyclic geminal bisphosphonates with the phosphonate
groups directly attached to the ring skeleton are scarcely reported
in the literature.13–18 During our ongoing efforts to further explore
the class of azaheterocyclic phosphonates,19,20 phosphonylated
azadienes have been shown to be interesting precursors of phos-
phonylated aziridines,21,22 phosphonylated b-lactams,23 phospho-
3-dienes 1, was synthesized by a 1,4-dehydrochlorination reaction
of in situ formed N-bisphosphonomethyl -chloroimines. These
latter compounds were obtained by a condensation reaction be-
a
tween tetraethyl aminomethylbisphosphonate and
a-chlorinated
aldehydes.26
Herein, we describe the use of these 1,1-bisphosphono-2-aza-
1,3-dienes 1 for the synthesis of N-vinyl 2,2-bisphosphonoaziri-
dines 3. To our knowledge, only one report has described
the synthesis of 2,2-bisphosphonoaziridines up to now. Aziridin-
ation of 1,1-bisphosphonoethylene was carried out using a cop-
per-catalyzed nitrogen transfer of a sulfonamide, mediated by
iodosylbenzene to afford the corresponding N-sulfonyl 2,2-
bisphosphonoaziridines.27
Besides the use of nitrenoids, the reaction between imines and
diazo compounds has already proven its importance in the forma-
tion of aziridines.28 As a consequence, this method was used for the
synthesis of 2-phosphonoaziridines, either by a reaction of a phos-
phonylated diazo compound with an imine29,30 or by a reaction
between a phosphonylated imine and a diazo compound.21,22
In this context, 1,1-bisphosphono-2-aza-1,3-diene 1b (R1 =
R2 = Et) was treated with an excess of diazomethane (5–10 equiv)
in Et2O. After stirring the reaction mixture for 19 h at room tem-
perature, all starting material was converted into three new prod-
ucts as was shown by 31P NMR. Continuation of the reaction for
about 25 h at room temperature resulted in a mixture of the same
products, however appearing in different ratios. Subsequently, the
solvent was evaporated in vacuo and the reaction products were
identified using NMR-techniques (Scheme 1).
nylated
c , and
-lactams,24 phosphonylated 2-oxazolidinones25
phosphonylated 2-imidazolidinones.25 Recently, a new class of
electron-deficient azadienes, that is, 1,1-bisphosphono-2-aza-1,
⇑
Corresponding author. Tel.: +32 9 264 58 60; fax: +32 9 264 62 43.
E-mail address: chris.stevens@ugent.be (C.V. Stevens).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.149

4274
P. P. J. Mortier et al. / Tetrahedron Letters 52 (2011) 4273–4276
R2
Table 1
Reaction between 1,1-bisphosphono-2-aza-1,3-dienes
formation of N-vinyl 2,2-bisphosphono aziridines 3,1-(ethynylamino)-2-phospho-
noethenylphosphonates 4 and 2-imino-2-phosphonoethylphosphonates 5
1 and diazomethane with
(EtO)2(O)P
N
R1
(EtO)2(O)P
1
R2
(EtO)2(O)P
(EtO)2(O)P
N
CH2N2 (5-10 equiv)
Et2O, rt, 44 h
R1
R1 = R2 = Et
1
R1
R1
N
(OEt)2(O)P
R2
R2
H
CH2N2 (5-10 equiv)
Et2O, rt
R2
N
+
+
R1
(EtO)2(O)P
(EtO)2(O)P
N
N
(EtO)2(O)P
(EtO)2(O)P
(OEt)2(O)P
R1
N
R2
(EtO)2(O)P
R2
R2
H
(EtO)2(O)P
(EtO)2(O)P
N
2 (14 %)
3 (70 %)
4 (16 %)
R1
N
+
R1
N
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
Scheme 1. Treatment of 1,1-bisphosphono-2-aza-1,3-diene 1b with diazomethane.
5
3
4
Because it was assumed that 1,2,3-triazoline 2 was a direct pre-
cursor of aziridine 3, the other azadienes 1 were allowed to react
with diazomethane until no 1,2,3-triazoline 2 was left in the reac-
tion mixture, as was determined by 31P NMR. In all cases, together
with the formation of the N-vinyl 2,2-bisphosphonoaziridines 3,
the synthesis of the corresponding enamines 4 was observed. Per-
forming the reaction in the dark or in day light did not have any
influence on the reaction outcome. After evaporation of the solvent
in vacuo, the two endproducts, 3 and 4, were easily separated by
chromatography on silica gel. In case non-aromatic substituents
were present at the 4-position of the 1,1-bisphosphono-2-aza-
1,3-dienes (1a–c), the isolation of the enaminophosphonates
4a–c revealed the presence of small amounts of the corresponding
2-aza-1,3-dienes 5a–c, whereas aromatic substituents at the
4-position (1d–f) exclusively led to the isolation of the enam-
inophosphonates 4. Also noteworthy was the fact that the aromatic
1,1-bisphosphono-2-aza-1,3-dienes (1d–f) reacted markedly faster
with diazomethane in comparison to the non-aromatic ones (1a–c)
(Table 1).
R1
R2
Reaction time
(h)
3
4/5
Result Yielda
(%)
Result Yielda (%)
(ratio)b
Me Me 44
Et
(CH2)5
Ph
Ph
Cl
3a
3b
3c
3d
3e
3f
63
68
67
79
79
72
4a/5a
4b/5b 14 (86/14)
4c/5c 17 (77/23)
4d/5d 9 (100/0)
14 (80/20)
Et
44
90
Me 15
Ph
Ph
15
15
4e/5e
4f/5f
12 (100/0)
19 (100/0)
a
After chromatography (4+5).
Determined by 31P NMR.
b
R1
R1
N
R2
R2
R2
CH2N2
(EtO)2(O)P
(EtO)2(O)P
N
R1
(EtO)2(O)P
(EtO)2(O)P
N
N
(EtO)2(O)P
N
(EtO)2(O)P
1
2
3
Keeping these observations in mind, a mechanism for the reac-
tion between the 1,1-bisphosphono-2-aza-1,3-dienes 1 and diazo-
methane was proposed. The 1,2,3-triazolines 2 are formed by a
1,3-dipolar cycloaddition of diazomethane and the C@N bond of
the 1,1-bisphosphono-2-aza-1,3-dienes 1. These intermediates 2
seem to be quite stable and are assumed to be the precursors for
either the aziridines 3 and the enamines 4. The formation of these
latter compounds 4 can be explained by a nitrogen-assisted elimi-
nation of a diethyl phosphite anion, followed by a nucleophilic at-
tack of this anion at the 4-position of the 1,2,3-triazolium ions 6,31
resulting in the elimination of nitrogen gas and formation of
2-aza-1,3-dienes 5. These azadienes 5 are susceptible to an
imine-enamine rearrangement, which results in the formation of
the corresponding enaminophosphonates 4. Clearly, the substitu-
ents at the 4-position of the azadienes 5 play a role in this
rearrangement. Because of the presence of an excess of diazometh-
ane in the reaction mixture, the aziridination of 2-aza-1,3-dienes 5
was considered as a competitive reaction, but the formation of
these N-vinyl 2-phosphono-3-phosphonomethylaziridines was
never observed. A possible alternative for the synthesis of the
enaminophosphonates 4 would be the monodephosphonylation
of the aziridines 3, resulting in the formation of the azirinium ions,
followed by a nucleophilic addition of the diethyl phosphite anion
at the 3-position of the azirinium ion. However, this reaction was
assumed to be quite unlikely to occur. Moreover, when one of
the aziridines (3a) was heated in boiling THF for 21 h, only starting
material was recovered, showing the thermal stability of the azir-
idines toward dephosphonylation reactions (Scheme 2).
X
R1
N
R2
R2
(EtO)2(O)P
R2
H
N
(EtO)2(O)P
(EtO)2(O)P
N
(EtO)2(O)P
R1
N
R1
N
(EtO)2(O)P
(EtO)2(O)P
6
5
4
Scheme 2. Plausible reaction mechanism.
was quite unexpected. Therefore, the synthesis of N-vinyl
2-ethoxycarbonyl-2-phosphonoaziridines was envisaged in order
to investigate if a similar reaction outcome was obtained when
1-ethoxycarbonyl-1-phosphono-2-aza-1,3-dienes were reacted
with diazomethane. The required 2-aza-1,3-diene 9 was synthe-
sized starting from a-chloro aldehyde 7 and ethyl amino(diethyl-
phosphono)acetate 832 (Scheme 3) using a similar method as
described for the formation of the 1,1-bisphosphono-2-aza-1,3-
dienes 1.26
Next, azadiene 9 was submitted to a reaction with an excess of
diazomethane. After 48 h of reaction at room temperature and
subsequent evaporation of the solvent in vacuo, a mixture of
compounds was recovered. With the help of 1H NMR and 31P
NMR spectra, these compounds were identified as starting material
9 (29%), mainly aziridine 10 (51%) and in lesser extent 2-aza-1,3-
diene 11 (20%) as an E/Z-mixture (major/minor: 83/17). There
were no signs of the corresponding enamine. Sampling of this
reaction mixture after 24 h had also revealed the presence of the
The presence of the enaminophosphonates 4 after reaction
of diazomethane with 1,1-bisphosphono-2-aza-1,3-dienes
1

P. P. J. Mortier et al. / Tetrahedron Letters 52 (2011) 4273–4276
4275
1. MgSO4 (0.5 equiv)
CH2Cl2, rt, 4 h
Aziridination of 1-ethoxycarbonyl-1-phosphono-2-aza-1,3-diene
9 with diazomethane revealed a similar reaction course. Other
diazo reagents, such as ethyl diazoacetate and trimethylsilyldia-
zomethane, were not reactive toward the 1,1-bisphosphono-2-
aza-1,3-dienes 1, neither at room temperature nor at elevated
temperatures. On the other hand, a thermal [1,5]-hydride shift of
the isomerizable azadiene 1b (R1 = R2 = Et) was observed.
O
Et
EtO2C
(EtO)2(O)P
8
Et
Et
EtO2C
N
+
H
NH2
Et
2. Et3N (1.1 equiv)
CH2Cl2, rt, 30'
Cl
(EtO)2(O)P
7
9 (67 %)
Scheme 3. Synthesis of 1-ethoxycarbonyl-1-phosphono-2-aza-1,3-diene 9.
Acknowledgments
Et
Financial support for this research from the BOF (Bijzonder
Onderzoeksfonds Universiteit Gent, Research Fund Ghent Univer-
sity) is gratefully acknowledged.
(EtO)2(O)P
EtO2C
N
Et
9
CH2N2 (5-10 equiv)
Et2O, rt
Supplementary data
Et
(EtO)2(O)P
Supplementary data (general information and spectroscopic
data of all compounds synthesized with complete peak assign-
ment. Copies of the 1H NMR spectra and 13C NMR spectra of all
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.05.149.
Et
+
Et
N
EtO2C
N
(EtO)2(O)P
EtO2C
Et
10
11
Scheme 4. Reaction between 1-ethoxycarbonyl-1-phosphono-2-aza-1,3-diene
and diazomethane with formation of N-vinyl 2-(ethoxycarbonyl)-2-phosphonoaz-
iridine 10 and 1-(ethoxycarbonyl)-1-(phosphonomethyl)-2-aza-1,3-diene 11.
9
References and notes
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Scheme 5. Thermally induced [1,5]-hydride shift of 1,1-bisphosphono-2-aza-1,3-
diene 1b.
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intermediate 1,2,3-triazoline. Hence, a similar reaction course as
described for the aziridination of the 1,1-bisphosphono-2-aza-
1,3-dienes 1 (Scheme 2) was assumed to be plausible, with the
only difference that azadiene 11 was formed rather than the corre-
sponding enamine (Scheme 4).
In order to extend the scope of the aziridination of the 1,1-bis-
phosphono-2-aza-1,3-dienes 1, some other diazo reagents, such as
ethyl diazoacetate and trimethylsilyldiazomethane, were evalu-
ated. At room temperature, none of these reagents were active
toward azadiene 1b (R1 = R2 = Et). However, when the same reac-
tions were performed in toluene under reflux conditions, a trans-
formation of the starting product occurred, not into the expected
aziridine, but into 1-aza-1,3-diene 12. The presence of this latter
compound 12 could be rationalized by a thermal induced [1,5]-
hydride shift of 1,1-bisphosphono-2-aza-1,3-diene 1b. As ex-
pected, the formation of 12 was also observed when azadiene 1b
was heated in toluene without the presence of diazo reagents
(Scheme 5).
In conclusion, it was shown that 1-vinyl-2,2-bisphosphonoazir-
idines 3 are formed by treatment of 1,1-bisphosphono-2-aza-1,3-
dienes 1 with diazomethane33. As a side reaction, the formation
of 1-(ethenylamino)-2-phosphonoethenylphosphonates 4 was also
observed. Depending on the substituents at the 4-position of the
1,1-bisphosphono-2-aza-1,3-dienes, small amounts of the corre-
sponding 2-aza-1,3-dienes 5 were also observed. Because of the
particular reaction mechanism, it was not possible to drive the
reaction toward the synthesis of one single reaction product.
18. Olive, G.; Le Moigne, F.; Mercier, A.; Tordo, P. Synth. Commun. 2000, 30, 619–
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22. Vanderhoydonck, B.; Stevens, C. V. Synthesis 2004, 722–734.
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1338.
24. Vanderhoydonck, B.; Stevens, C. V. J. Org. Chem. 2005, 70, 191–198.
25. Vanderhoydonck, B.; Stevens, C. V. Tetrahedron 2007, 63, 7679–7689.
26. Masschelein, K. G. R.; Stevens, C. V. Tetrahedron Lett. 2008, 49, 4336–4338.
27. Inoue, S.; Okauchi, T.; Minami, T. Synthesis 2003, 1971–1976.
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31. Remark: To prove the presence of the 1,2,3-triazolium ions 6, dimethyl
phosphite was added (in 1, 20 and 120 equiv) to the reaction mixture of 1b
with diazomethane, after 4 h of reaction time. After completion of the reaction,
the correct mass of the mixed bisphosphonylated products could be observed
in minor amounts in LC–MS experiments (ES, Pos: 370 (M+H+, 100). However,
isolation of these mixed bisphosphonylated products was unsuccessful.
32. Hakimelahi, G. H.; Just, G. Synth. Commun. 1980, 10, 429–435.
33. General procedure for the synthesis of N-vinyl 2,2-bisphosphono-aziridines 3,1-
(ethenylamino)-2-phosphonoethenylphosphonates
4 and 2-imino-2-phospho-
noethylphosphonates 5: To a solution of a 1,1-bisphosphono-2-aza-1,3-diene26

4276
P. P. J. Mortier et al. / Tetrahedron Letters 52 (2011) 4273–4276
(0.50 mmol) in dry Et2O (2 ml) was added an excess of freshly prepared
diazomethane (2.5–5 mmol, 5–10 equiv), dissolved in dry Et2O. The mixture was
allowed to react at room temperature until completion as was determined by 31
Chromatography: CH2Cl2/CH3CN (6/4) Rf = 0.31. Yield: 63%. Diethyl (E)-2-
(diethoxyphosphoryl)-1-(2-methylprop-1-en-1-ylamino)ethenyl-phosphonate 4a.
Mixture of diethyl (E)-2-(diethoxyphosphoryl)-1-(2-methylprop-1-en-1-
ylamino)-ethenylphosphonate 4a and diethyl 2-(diethoxyphosphoryl)-1-(2-
methylprop-1-en-1-ylimino)ethylphosphonate 5a (ratio 4a/5a:80/20). 1H
NMR (300 MHz, CDCl3) d: 1.32 (6H, t, J = 7.2 Hz, 2 Â CH2CH3), 1.37 (6H, t,
J = 7.2 Hz, 2 Â CH2CH3), 1.67 (6H, br s, 2 Â HC@CCH3), 3.98–4.27 (8H, m,
4 Â CH2CH3), 4.79 (1H, dd, JHP = 19.3 Hz, JHP = 12.1 Hz, PCH), 6.42 (1H, d,
J = 11.6 Hz, HC@CCH3), 9.27 (1H, dd, J = 33.0 Hz, J = 11.6 Hz, NH). 13C NMR
(75 MHz, CDCl3) d: 16.1 (HC@CCH3), 16.3 (d, 3JCP = 6.9 Hz, 2 Â CH2CH3), 16.4 (d,
P
NMR (for reaction time, see Table 1). After evaporation of the solvent in vacuo, a
mixture of compounds was obtained, which were easily separated by
chromatography on silica gel. In case of azadienes 1a–c, small amounts of the
corresponding 2-aza-1,3-dienes 5a–c were also isolated together with the
enaminophosphonates 4a–c. Diethyl [2-(diethoxyphosphoryl)-1-(2-methylprop-
1-en-1-yl)aziridin-2-yl]phosphonate 3a. 1H NMR (300 MHz, CDCl3) d: 1.33 (6H, t,
J = 7.2 Hz, 2 Â CH2CH3), 1.34 (6H, t, J = 7.2 Hz, 2 Â CH2CH3), 1.64 (3H, br s,
HC@CCH3), 1.82 (3H, br s, HC@CCH3), 2.63 (2H, t, 3JHP = 7.4 Hz, NCH2), 4.12–4.28
(8H, m, 4 Â CH2CH3), 5.75 (1H, br s, HC@CCH3). 13C NMR (75 MHz, CDCl3) d: 16.5
2
3JCP = 6.9 Hz, 2 Â CH2CH3), 22.5 (HC@CCH3), 61.8 (d, JCP = 4.6 Hz, 2 Â CH2CH3),
63.2 (d, 2JCP = 5.8 Hz, 2 Â CH2CH3), 85.2 (dd, 1JCP = 181.1 Hz, 2JCP = 13.9 Hz, PCH),
1
1
(br s, 4 Â CH2CH3), 17.3 (CH3), 22.2 (CH3), 35.9 (t, JCP = 180.0 Hz, CP2), 38.3
111.8 (HC@CCH3), 121.4 (d, JCP = 3.5 Hz, NCH), 148.5 (dd, JCP = 181.1 Hz,
(NCH2), 62.88 (d, 2JCP = 3.5 Hz, CH2CH3), 62.92 (d, 2JCP = 3.5 Hz, CH2CH3), 63.26 (d,
2JCP = 3.5 Hz, NCP). 31P NMR (121 MHz, CDCl3) d: 10.93 (3JPP = 83.4 Hz), 23.15
2JCP = 3.5 Hz, CH2CH3), 63.30 (d, 2JCP = 3.5 Hz, CH2CH3), 127.5 (HC@CCH3), 131.1
(3JPP = 83.4 Hz). IR (cmÀ1
) mmax: 1025 (br, P–O), 1248 (P@O). MS m/z (%): (ES, Pos)
(t, 3JCP = 5.8 Hz, HC@CCH3). 31P NMR (121 MHz, CDCl3) d: 18.79. IR (cmÀ1
)
mmax
:
370 (M+H+, 100). Elem. Anal. Calcd for C14H29NO6P2: C, 45.53; H, 7.91; N, 3.79.
Found: C, 45.41; H, 7.88; N, 3.80. Chromatography: EtOAc (100%) Rf = 0.56. Yield:
14%.
1016 (br, P–O), 1248 (P@O). MS m/z (%): (ES, Pos) 370 (M+H+, 100). Elem. Anal.
Calcd for C14H29NO6P2: C, 45.53; H, 7.91; N, 3.79. Found:C, 45.67; H, 7.93; N, 3.79.