February 1998
SYNLETT
181
The heating time and the amount of diethyl phosphite used for the
synthesis of 12a was strictly controlled in order to reduce the formation
of N-allyl-N-ethylaminomethyl phosphonate which was formed as a
side-product in the presence of an excess of diethyl phosphite.
as eluent. This solvent mixture gives excellent results with a variety of
organophosphonates. The loss of material during the purification of
these compounds is probably due to the partial hydrolysis of the
phosphonate to the corresponding mono ester or acid.
The N-allylaminomethyl phosphonates are powerful substrates because
they are easily accessible and possess four reactive centers (the allyl
moiety, the amino function, the active methylene function and the
phosphonate ester) which can be elaborated towards different end
products. In this report, the reactivity of the allyl moiety was exploited
in combination with the amino function for the synthesis of heterocyclic
phosphonates.
The phosphonylated aziridines are being evaluated as an easily
accessible substrate for the synthesis of other potentially physiologically
active heterocyclic phosphonates and their biological activity is being
tested as such and after hydrolysis to the corresponding α−
azaphosphonic acid.
In this paper we disclosed a straightforward, high yielding and easy
method for the synthesis of functionalized (aziridin-1-yl)methyl
phosphonates.
The addition of certain dialkyl phosphites to the hexahydrotriazine 11
led to good yields of the corresponding allylaminomethyl phosphonates
(purity >90%) although further purification by chromatography or
distillation gave a considerable loss of product. The reaction could not
be performed neither with dimethyl phosphite nor with diphenyl
phosphite. Using dimethyl phosphite, the reaction resulted in complex
reaction mixtures. The use of dimethyl trimethylsilyl phosphite
(prepared in situ from dimethyl phosphite, trimethylsilyl chloride and
triethylamine), did not give any positive result. Even the use of the
sodium salt of dimethyl phosphite (in order to generate the reactive
phosphorus(III) nucleophile in situ), did not result in the desired
dimethyl N-allylaminomethyl phosphonate. Even attempts to obtain the
dimethyl phosphonate by trans-esterification of the diethyl
References and Notes
◊
Research Leader of the Fund for Scientific Research - Flanders.
(1) Kafarski, B.; Lejczak, B. Phosphorus, Sulfur, and Silicon 1991,
63, 193 - 215.
(2) Dhawan, B.; Redmore, D. Phosphorus and Sulfur, 1987, 32, 119 -
144.
(3) De Lombaert, S.; Blanchard, L.; Tan, J.; Sakane, Y.; Berry, C.;
Ghai, R.D. Biorg. Med. Chem. Lett., 1995, 5, 145 - 150.
(4) De Lombaert, S.; Blanchard, L.; Berry, C.; Ghai, R.D.; Trapani
allylaminomethyl phosphonate with sodium methoxide led to
a
A.J., Biorg. Med. Chem. Lett., 1995, 5, 151 - 154.
complete loss of material during aqueous work-up of the reaction
mixture.
(5) Hamilton, G.S.; Huang, Z.; Yang, X.-Y.; Patch, R.J.; Narayanan,
B.A.; Ferkany, J.W. J. Org. Chem., 1993, 58, 7263 - 7270.
The use of diphenyl phosphite resulted in the isolation of almost
quantitative amounts of phenol indicating the hydrolysis of the
phosphonate during the synthesis. Therefore, the modified Kabachnik-
Fields reaction is quite limited to the use of dialkyl phosphites (which
also explains the minor use of the reaction compared to the Arbuzov
reaction) but leads to excellent results in the described cases.
(6) Engel, R. Chem. Rev., 1977, 77, 349 - 367.
(7) Öhler, E.; Kanzler, S. Liebigs Ann. Chem. 1994, 867 - 876.
(8) Fields, E.K. J. Am. Chem. Soc., 1952, 74, 1528 - 1531.
(9) Horning, D.E.; Muchowski, J.M. Can. J. Chem., 1974, 52, 1321 -
1330.
In order to brominate the allyl moiety, the amino function was first
protected as the hydrobromide salt by treating the allylaminomethyl
phosphonate with 48% aqueous hydrobromic acid, followed by reaction
with bromine in dichloromethane in a two-phase system. Protection of
the amino function is necessary since bromine is interacting otherwise
with the amino function, leading to very complex reaction mixtures
which were not further analyzed.
(10) De Smaele, D.; De Kimpe, N. J. Chem. Soc., Chem. Commun.,
1995, 2029 -2030.
(11) De Kimpe, N.; De Smaele, D. Tetrahedron, 1995, 51, 5465 -
5478.
(12) Zaripov, R.K.; Shamgunov, K.Sh. Tr. Khim. -Metall. Inst., Akad.
Nauk, Kaz. SSR, 1973, 20, 51 - 54. Chem. Abstr. , 1974, 81,
136228k.
After stirring the mixture for five hours at room temperature,
triethylamine was added and the dibromo derivatives 13 were isolated
after extraction with dichloromethane. The dibrominated amines could
be purified by flash chromatography but were mostly used as such
because of some loss of material during flash chromatography. After
bromination, no spontaneous cyclization or other side reactions were
observed.
(13) Spectral data of the allylaminomethyl phosphonate 12a; IR (neat):
-1
1
3450 (br.), 2990, 1240, 1032, 970 cm ; H-NMR (270
max
MHz, CDCl ) : 1.34 (t, 6H, J = 6.9 Hz, Me), 1.58 (br.s., 1H, NH),
3
2.97 (2H, d, J = 12.5 Hz, NCH P), 3.32 (dxd, J = 6.3 Hz, J =
H-P
2
1
2
1.3 Hz, CHCH N), 4.15 (m, 4H, OCH ), 5.16 (m, 2H, CH =),
2
2
2
13
5.83 (m, 1H, CH=). C-NMR (68 MHz, CDCl ) : 15.80 (Me, J
3
C-
= 4.9 Hz), 43.46 (NCH P, J
= 155.0 Hz), 52.66 (CHCH N,
P
2
C-P
2
The cyclization of the dibromoaminomethyl phosphonate 13 was
preferentially performed with sodium borohydride in methanol leading
to [[2-(bromomethyl)aziridin-1-yl]methyl]phosphonates 14 after
J
= 15.9 Hz), 61.27 (CH O, J
= 6.1 Hz), 115.97 (CH=),
C-P
2
C-P
+
135.29 (CH =); MS m/z (%) 207(M , 14), 139(14), 125(14),
2
111(15), 83(16), 82(15), 71(15), 70(100), 69(28), 68(30), 65(14),
56(15), 41(49).
13
aqueous work-up and extraction with dichloromethane. The use of
other bases gave complex reaction mixtures or much lower yields of the
(aziridin-1-yl)methyl phosphonates. It seems that sodium borohydride
has the optimal base strength in order to deprotonate the amino function
without inducing any side reactions.
Spectral data of the [(2,3-dibromopropylamino)methyl]-
-1
1
phosphonate 13a; IR (neat) :
3400 cm (br, NH) ; H-NMR
max
(270 MHz, CDCl ) : 1.35 (t, 6H, J = 6.9 Hz, Me), 1.80 (br.s., 1H,
3
NH), 3.01 and 3.12 (dxdxd, 2H, J = 14.8 Hz, J
= 12.5 Hz,
H1-P
AB
Although the corresponding brominated azetidines can be formed
theoretically, the cyclization exclusively leads to the aziridines due to
the lower energy barrier for ring closure forming three membered ring
systems compared to four membered ring systems.
J
= 11.5 Hz), 3.14 and 3.31 (dxdxd, 2H, J = 13.5 Hz, J
AB H1-Hc
H2-P
= 3.6 Hz, J
= 6.6 Hz, CH N), 3.81 (m, 2H, CH Br), 4.17 (m,
2 2
H2-Hc
13
4H, OCH ), 4.22 (m, 1H, CHBr). C-NMR (68 MHz, CDCl ) :
16.49 (Me), 16.58 (Me), 33.35 (CH Br), 44.89 (NCH P, J
2
3
=
2
2
C-P
The aziridines were obtained as pure oils after flash chromatography
using preferentially chloroform / acetonitrile / triethylamine (79 / 20 / 1)
155.0 Hz), 51.93 (CHBr), 54.16 (CH N, J
= 13.4 Hz), 62.18
2
C-P
(CH O, J = 6.1 Hz), 62.23 (CH O, J = 6.1 Hz); MS m/z (%)
2
C-P
2
C-P