The interaction of Bis(chloromethyl) isocyanatophosphinate with chiral -aminoalkylphosphonates: Stereoselective synthesis of 2,4-Dioxo-5-phenyl-1- phenylethylamino-4-phenoxy-1,3,4-diazaphospholidine

Article abstract of DOI:10.1080/10426500902930159

O,O-Diphenyl-(α-phenylethylamino)benzylphosphonate 6 was synthesized in racemic and enantiopure forms. Its interaction with bis(chloromethyl) isocyanatophosphinate 7 results in the formation of 2,4-dioxo-5-phenyl-1- phenylethylamino-4-phenoxy-1,3,4-diazap

Full text of DOI:10.1080/10426500902930159

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Phosphorus, Sulfur, and Silicon
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The Interaction of
Bis(chloromethyl)
isocyanatophosphinate
with Chiral α-
Aminoalkylphosphonates:
Stereoselective Synthesis
of 2,4-Dioxo-5-phenyl-1-
phenylethylamino-4-
phenoxy-1,3,4-
diazaphospholidine
Michael A. Pudovik a , Natalia A. Khailova a , Alfia A.
Shaimardanova a , Vladimir A. Alfonsov a & Olga N.
Kataeva a
a A. E. Arbuzov Institute of Organic and Physical
Chemistry , Kazan, Russia
Published online: 06 Jun 2009.
To cite this article: Michael A. Pudovik , Natalia A. Khailova , Alfia A.
Shaimardanova , Vladimir A. Alfonsov & Olga N. Kataeva (2009) The Interaction of
Bis(chloromethyl) isocyanatophosphinate with Chiral α-Aminoalkylphosphonates:
Stereoselective Synthesis of 2,4-Dioxo-5-phenyl-1-phenylethylamino-4-phenoxy-1,3,4-
diazaphospholidine, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:6,
1355-1362, DOI: 10.1080/10426500902930159
To link to this article: http://dx.doi.org/10.1080/10426500902930159

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Phosphorus, Sulfur, and Silicon, 184:1355–1362, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902930159
The Interaction of Bis(chloromethyl)
isocyanatophosphinate with Chiral
α-Aminoalkylphosphonates: Stereoselective Synthesis of
2,4-Dioxo-5-phenyl-1-phenylethylamino-4-phenoxy-1,3,4-
diazaphospholidine
Michael A. Pudovik, Natalia A. Khailova,
Alfia A. Shaimardanova, Vladimir A. Alfonsov,
and Olga N. Kataeva
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan,
Russia
O,O-Diphenyl-(α-phenylethylamino)benzylphosphonate 6 was synthesized in race-
mic and enantiopure forms. Its interaction with bis(chloromethyl)isocyanato-
phosphinate 7 results in the formation of 2,4-dioxo-5-phenyl-1-phenylethylamino-
4-phenoxy-1,3,4-diazaphospholidine 10.
Keywords α-Aminoalkylphosphonates; bis(chloromethyl)isocyanatophosphinate; di-
azaphospholidine; enantiomers; organophosphorus compounds
INTRODUCTION
Phosphorus-containing heterocycles with endocyclic P C bonds have
recently attracted significant interest. In particular, five-membered
phosphorus and element containing cyclic structures with P C bonds
revealing specific reactivity are of interest as pesticides, drugs, and
reagents in organic synthesis.1–3 One of the most convenient ap-
proaches to the synthesis of such phosphacyclanes is based on
Received 21 November 2007; accepted 23 March 2008.
Dedicated to Professor Marian Mikolꢀajczyk, CBMiM PAN in Lꢀ o´dz´, Poland, on the
occasion of his 70th birthday.
This work was supported by the Russian Foundation for Basic Research (grants no.
06-03-32085 and 07-03-00617).
Address correspondence to M. A. Pudovik, Institute of Organic and Physical Chem-
istry, Russian Academy of Sciences, 420088, Arbuzov Str., 8, Kazan, Russia. E-mail:
pudovik@iopc.knc.ru
1355

1356
M. A. Pudovik et al.
intramolecular cyclization of polyfunctional organophosphorus deriva-
tives containing substituted alkyl groups. 1,2-Azaphospholidines and
1,2-azaphosphorines were obtained by intramolecular cyclization of
haloalkylphosphonylated primary amines.4,5 A series of studies de-
voted to the synthesis of 1,2-thia- and 1,2-azaphosphacyclanes on
the basis of intramolecular alkylation of ω-haloalkyl substituted
compounds with thiophosphoryl- or imino-group was carried out.6–9
Synthesis of saturated and unsaturated polyheterophosphacyclanes
was performed by intramolecular cyclization of haloalkylphosphony-
lated ureas, thioureas, and uretanes.10–12 α-Aminoalkylphosphonates
and their N-substituted derivatives are of particular interest for
the creation of cyclic structures, since this class of compounds
shows wide and various biological activity.13 The transformation
of benzoylaminomethylphosphonate into 1,4,2-oxazaphospholine un-
der the action of phosphorus pentachloride was described.14 Com-
pounds containing a guanidine fragment in alkyl group of alkylphos-
phonates are cyclized to give 1,3,4-diazaphospholidines.15 It is
known that phosphonates with the cumulene system N=C=N in
alkyl group attach to secondary amines with subsequent cycliza-
tion of the adduct and formation of 1,3,4-diazaphospholines with 6-
coordinated phosphorus atom.16 Recently we have shown (Scheme 1)
that the addition of O,O-diphenyl(α-methylamino)benzylphosphonate
1 to phenylisocyanate 2a or phenylisothiocyanate 2b is easily car-
ried out in the presence of the catalytic quantities of triethy-
lamine with the formation of N,Nꢀ-disubstituted thioureas 3a–b,
which are cyclized to give diastereomeric 1,3,4-diazaphospholidines
4a–b.17
The processes of the cyclization in Scheme 1 are diastereoselective.
That provides the way to obtain stereoisomeric phosphacyclanes, in-
cluding enantiopure ones. In this respect, it is especially important to
use enantiopure aminoalkylphosphonates.
SCHEME 1

Stereoselective Synthesis of 1,3,4-Diazaphospholidine
1357
SCHEME 2
RESULTS AND DISCUSSION
As a preliminary study (Scheme 2), α-aminophosphonate 6 was ob-
tained by addition of diphenylphosphite to racemic benzalphenylethy-
lamine 5.
Owing to the presence of two chiral centers in 6, it is formed as a
mixture of two diastereomers characterized by two signals at 16.5 and
16.7 ppm in 31P NMR spectrum of the reaction mixture, and the ratio
is equal to 30:70. We did not succeed in separation of diastereomers
by fractional crystallization, though this separation method is often
successful. After each crystallization step, the ratio of diastereomers
became worse. The reason that it appeared impossible to separate the
diastereomers by fractional crystallization became clear after the X-
ray single crystal diffraction study had been carried out. Compound
6 crystallizes in the centrosymmetric space group P21/c as a racemic
mixture of two diastereomers.
Eventually we took a fraction of crystals with the diastereomeric
ratio 40:60 according to the NMR 1H and 31P spectra to study the
reactivity of aminophosphonate 6.
It appeared that in contrast to aminophosphonate 1, its analogue 6
at 20◦C does not react with iso(thio)cyanates 2a,2b, and the heating of
the reaction mixture results in its resinification. Such a result, appar-
ently, is caused by the steric factors, owing to the larger volume of the
substituent at nitrogen atom. However, the reaction with more reactive
bis(chloromethyl)isocyanate 7 proceeds slowly according to Scheme 3.
At the first stage, disubstituted urea 8 is formed as a result of the ad-
dition of aminophosphonate 6 to isocyanate 7. The former undergoes
intramolecular cyclization with elimination of phenol molecule and the
formation of phosphacyclane 9, containing endo- and exocyclic phos-
phorus atoms. Labile exocyclic P-N bond of 9 is cleaved upon the action
of phenol molecule to give final products diazaphospholidine 10 and
O-phenyl(chloromethyl)phosphinate 11.
One may expect the formation of four diastereomers in this reac-
tion, as the third chiral center at the phosphorus atom is formed
in phospholidine 10 upon cyclization. The 31P NMR spectrum of the

1358
M. A. Pudovik et al.
SCHEME 3
reaction mixture, recorded after 45 days, had a singlet signal of phenyl-
bis(chloromethyl)phosphinate 11 (δP 37.5 ppm), and two broad unre-
solved signals (at δP 20.8 and 21.5 ppm) assigned to diastereomers of
phospholidine 10 were observed. After crystallization from the reaction
mixture, solid product was obtained as a composition of three diastere-
omers in a 16:42:42 ratio. In the 1H NMR spectra, there are six doublet
signals: three of them in the region of 4.93–5.24 ppm assigned to the
protons of the CHP-fragments of three diastereomers and three oth-
ers at 1.52–1.84 ppm corresponding to the resonance of methyl group
of phenylethylamino-substituent. One of the diastereomers 10 with δP
21.50 ppm was isolated as a result of fractional crystallization, and its
molecular structure was determined by X-ray single crystal diffraction.
One of the enantiomers of this diastereomer is presented in
Figure 1 and has the following configurations of the chiral centers:
C5(R), C6(S), and P4(R). This diastereomer forms a racemic centrosym-
metric crystal. A heterocyclic fragment of a molecule of isolated di-
astereomer adopts a P-envelope, and the phosphorus atom is out of
plane C5N1C2N3 (0.02 Å) by 0,328 (2) Å. The orientation of phenyl group
at the C6 atom is orthogonal to a plane of the heterocycle that reduces an
opportunity of steric contacts. The phosphoryl substituent is in an equa-
torial position, and the phenoxy group occupies an axial position. In the
crystal molecules of compound 10, intermolecular hydrogen bonds N3–
H3. . . O2|[1-x,-y,-z] with the parameters are formed: N3–H3 0.68(4)Å,
H3. . . O2| 2.13(4)Å, N3. . . O2| 2.804(8)Å, (N3–H3. . . O2|) 177(5)◦.
The next step was to involve the enantiopure α-aminophosphonate
6A in the reaction with isocyanate 7. It is necessary to note that
the compound 6A was registered in reaction of catalytic addition of

Stereoselective Synthesis of 1,3,4-Diazaphospholidine
1359
FIGURE 1 Molecular structure of the diastereomer 10 in the crystal.
diphenylphosphite to (S)-(-)-benzal(1-phenyl)ethylamine 5A (catalyst
BF3) as a mixture of diastereomers by 31P NMR method18 without
separation. We obtained aminophosphonate in the same reaction, but
sodium phenolate was used as a catalyst. The reaction proceeds with
the formation of aminophosphonate diastereomers composition (74:26
ratio in the reaction mixture with δP 16.64 and 16.25 ppm). In con-
trast to the racemic sample, we succeed in fractional crystallization of
aminophosphonate diastereomers and isolated one of the isomers in
the enantiopure form ([α]2D0–53.7).
The reaction of aminophosphonate 6A with isocyanate 7 proceeds
stereoselectively. In the 31P NMR spectra of the reaction mixture, there
are two signals (δP21.5 and 22.8 ppm) of diazaphospholidines diastere-
omeric mixture 10A and 10B in rather good 83:17 ratio. 1-Phenyl-2,4-
dioxo-4-phenoxy-5-phenyl-1,3,4-diazaphospholidine 10A ([α]2D0+31.0◦)
was isolated by fractional crystallization.
Thus the reaction of enantiopure aminophosphonate with the chiral
inductor at nitrogen atom can be successfully used as a synton for
stereoselective cyclization reactions with the formation of enantiopure
phosphorus-nitrogen containing heterocycles.
EXPERIMENTAL
IR spectra were obtained using a UR-20 spectrophotometer. 1H,
13C, and 31P NMR spectra were recorded on a Bruker MSL-400

1360
M. A. Pudovik et al.
spectrometer in CDCl3, and chemical shifts reported in ppm downfield
from TMS. MS were recorded on a TRACE MS Finnigan MAT mass
spectrometer.
The X-ray data for compound 10 were collected on a CAD-4 Enraf-
Nonius automatic diffractometer with graphite-monochromated Mo Kα
radiation at 20◦C. The stability of the crystal and of experimental con-
ditions was checked every 2 h using three control reflections, while
the orientation was monitored every 200 reflections by centering two
standards. Corrections for Lorentz and polarization effects were ap-
plied. Twenty five centered reflections were used to determine unit cell
dimensions.
The following programs were used: Data collection and reduction,
MoLEN19; structure solution, SHELXS-9720; and structure refinement
by full-matrix least-squares against F2 using, SHELXL-97.21
X-ray crystal data for 10: formula C22H21N2O3P, M = 392.38, col-
orless crystal 0.50 × 0.40 × 0.40 mm, a = 14.933(2), b = 10.476(3),
c = 14.003(2) Å, β = 110.80(1) V = 2047.8(7) Å3, ρcalc = 1.273 g cm−3
,
µ = 0.159 mm−1, empirical absorption correction (0.925 ≤ T ≤ 0.939),
Z = 4, monoclinic, space group P21/c (No. 14), λ = 0.71073 Å, T = 293
K, 5656 reflections collected, [(sinθ)/λ] = 0.60 Å−1, 3450 independent
(Rint = 0.096) and 1240 observed reflections [I ≥ 2 σ(I)], 257 refined pa-
rameters, R = 0.065, wR2 = 0.133, max. residual electron density 0.25
(−0.29) e Å−3, hydrogen atoms calculated and refined as riding atoms,
except the NH-group hydrogen, located from the difference Fourier map
and refined isotropically.
O,O-Diphenyl-(α-phenylethylamino)benzylphosphonate (6)
Benzalphenylethylamine (4.20 g, 20.1 mmol) was added to a solution of
diphenylphosphite (4.70 g, 20.1 mmol) and sodium phenolate (0.1 g) in
dry acetonitrile (20 mL), and the mixture was heated at 80◦C for 5 h.
The next day, acetonitrile was removed. White needles were obtained
after recrystallization from diethyl ether (5.9 g, 66%), mp 102–104◦C.
IR: 3320 (NH), 1590 (Ph), 1265 (P=O) cm–1; 1H NMR (acetone-d6): δ =
3
3
1.33 (d, JHH = 6.4 Hz, 3H, MeC), 1.36 (d, JHH = 6.4 Hz, 3H, MeC),
3.68 (major isomer) (q, 3JHH = 6.7 Hz, 1H, NCH), 4.00 (minor isomer) (q,
3JHH = 6.71 Hz, 1H, NCH), 4.11 (major isomer) (d, 2JPH = 23.6 Hz, 1H,
PCH), 4.57 (minor isomer) (d, 2JPH = 20.2 Hz, 1H, PCH), 7.15 (m, 20H,
Ph). 31P NMR (acetone-d6): δ = 16.5, 16.7. Anal. Calcd. for C27H26NO3P:
C, 73.12; H, 5.91; N, 3.16; P, 6.99. Found: C, 72.85; H, 6.07; N, 3.33; P,
6.88%.

Stereoselective Synthesis of 1,3,4-Diazaphospholidine
1361
O,O-Diphenyl-(α-phenylethylamino)benzylphosphonate (6A)
Compound 6A was obtained from diphenylphosphite (4.9 g, 20.9 mmol)
and (S)-(-)-benzalphenylethylamine (4.37 g, 20.9 mmol) as described
for phosphonate 6, yield: (1.3 g, 14%); mp 122–123 ◦C; [α]D20 −53.7◦(c =
1.22, CH3CN). IR: 3325 (NH), 1590 (Ph), 1275 (P=O) cm–1. H NMR
1
3
3
(acetone-d6): δ = 1.41 (d, JHH = 6.3 Hz, 3H, MeC), 3.73 (q, JHH
=
6.7 Hz, 1H, NCH), 4.16 (d, 2JPH = 23.6 Hz, 1H, PCH), 7.3 (m, 20H, Ph).
31P NMR (acetone-d6): δ = 16.2. Anal. Calcd. for C27H26NO3P: C, 73.12;
H 5.91; N 3.16; P, 6.99. Found: C, 72.93; H, 5.88; N, 3.22; P, 6.76%.
2,4-Dioxo-5-phenyl-1-phenylethylamino-4-phenoxy-1,3,4
-diazaphospholidine (10)
Isocyanate 7 (0.89 g, 2 mmol) was added to a solution aminophospho-
nate 6 (0.38 g, 2 mmol) in acetonitrile (20 mL). In 45 days, crystalline
product 10 (0.30 g, 38%) was separated, mp 201–207 ◦C. IR: 1190,
–1
1210 (POPh), 1278 (P=O), 1590 (Ph), 1700 (C=O), 3080 (NH) cm
.
1H NMR (acetone-d6): δ = 1.10 (d, JHH = 5.9 Hz, 3H, MeC), 1.22 (d,
3
3JHH = 7.4 Hz, 3H, MeC), 1.34 (d, JHH = 7.1 Hz, 3H, MeC), 4.45 (d,
3
2JPH = 21.1 Hz, 1H, PCH), 4.67 (d, JPH = 21.5, 1H, PCH), 4.86 (d,
2
2JPH = 29.3 Hz, 1H, PCH), 5.6 (m, 1H, NCH), 5.33 (m, 1H, NCH), 7.01
(m, 15H, Ph).31P NMR (acetone-d6): δ = 21.5, 20.8. MS: m/z (%) 392.36
(M+). Anal. Calcd. for C22H21N2O3P: C, 67.33; H, 5.39; N, 7.13; P, 7.89.
Found: C, 67.14; H, 5.11; N, 6.98; P, 7.67%.
2,4-Dioxo-5-phenyl-1-phenylethylamino-4-phenoxy-1,3,4
-diazaphospholidine (10A)
Compound 10A was obtained similarly from aminophosphonate 6A
(0.45 g, 1.0 mmol) and isocyanate 7 (0.19 g, 1.0 mmol). Yield: (0.18 g,
46%); mp 182–183◦C. [α]D 31.0◦ (c = 1.09, CH3CN). IR: 1190, 1215
(POPh), 1255 (P=O), 1595 (Ph), 1695 (C=O), 3070 (NH). 1H NMR
3
3
(acetone-d6): δ = 1.62 (d, JHH = 4.6 Hz, 3H, MeC), 4.86 (q, JHH
=
2
5.0 Hz, 1H, NCH), 5.07 (d, JPH = 13.1 Hz, 1H, PCH), 7.2 (m, 15H,
Ph), 8.54 (s, 1H, NH). 31P-NMR (acetone-d6): δ = 21.6. Anal. Calcd. for
C22H21N2O3P: C, 67.33; H, 5.39; N, 7.13; P, 7.89. Found: C, 67.05; H,
5.16; N, 6.80; P, 7.72%.
REFERENCES
[1] F. Mathey, Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain
(Pergamon, 2001), p. 670.

1362
M. A. Pudovik et al.
[2] M. A. Pudovik, V. V. Ovchinikov, R. A. Cherkasov, and A. N. Pudovik, Uspechi Khim.,
52, 640 (1983).
[3] R. A. Cherkasov and M. A. Pudovik, Uspechi Khim., 63, 1087 (1994).
[4] D. G. Hewitt and G. L. Newland, Aust. J. Chem., 30, 579 (1977).
[5] D. J. Collins, J. W. Heterington, and J. M. Swan, Aust. J. Chem., 27, 1759 (1974).
[6] I. M. Aladzheva, O. V. Bykhovskaya, D. I. Lobanov, P. V. Petrovsky, K. A. Lyssenko,
and T. A. Mastryukova, Chem. Heterocyclic Compounds, 1, 105 (2002).
[7] I. M. Aladzheva, O. V. Bykhovskaya, D. I. Lobanov, K. A. Lyssenko, M. Yu. Antipin,
T. A. Mastryukova, and M. I. Kabachnik, Mendeleev Commun., 48, 48 (1996).
[8] I. M. Aladzheva, O. V. Bykhovskaya, D. I. Lobanov, P. V. Petrovsky, K. A. Lyssenko,
T. A. Mastryukova, and M. I. Kabachnik, Zh. Obshch. Khim., 68, 1421 (1998).
[9] I. M. Aladzheva, D. I. Lobanov, P. V. Petrovsky, K. A. Lysenko, M. Yu. Antipin, and
T. A. Mastryukova, Heteroatom. Chem., 14, 1 (2003).
[10] G. A. Chmutova, V. V. Zverev, M. A. Pudovik, N. A. Khailova, and A. N. Pudovik.
Zh. Obshch. Khim., 73, 1793 (2003).
[11] N. A. Khailova, N. E. Krepysheva, G. M. Saakyan, R. Kh. Bagautdinova, A. A.
Shaimardanova, N. M. Azancheev, I. A. Litvinov, A. T. Gubaidullin, M. A. Pudovik,
and A. N. Pudovik, Zh. Obshch. Khim., 72, 1145 (2002).
[12] M. A. Pudovik, S. A. Terenteva, R. Z. Musin, N. A. Khailova, O. N. Kataeva, I. A.
Litvinov, and A. N. Pudovik,. Izv. Akad. Nauk. Ser. Khim., 1657 (2004).
[13] V. P. Kukhar and H. R. Hudson, Aminophosphonic and Aminophosphinic Acids:
Chemistry and Biological Activity (Wiley, New York, 2000), p. 634.
[14] H. J. Cristau, J. M. Lambert, A. Sarris, and J. L. Pirat, Phosphorus, Sulfur, and
Silicon, 111, 125 (1996).
[15] A. Yu. Aksinenko, V. B Sokolov, O. V. Koreichenko, A. N. Pushin, and I. V. Martynov,
Izv. Akad. Nauk. Ser. Khim., 1688 (1988).
[16] A. N. Chekhlov, A. Yu. Aksinenko, V. B. Sokolov, and A. N. Pushin, Dokl. Akad.
Nauk SSSR., Ser. Khim., 297, 1132 (1987).
[17] N. A. Khailova, A. A. Shaimardanova, G. M. Saakyan, T. A. Ziablikova, N. M.
Azancheev, I. A Litvinov, A. T. Gubaidullin, D. B. Krivolapov, R. Z. Musin, G. A.
Chmutova, M. A. Pudovik, and A. N. Pudovik, Zh. Obshch. Khim., 73, 1284 (2003).
[18] C Yuan and C. Cui, Phosphorus, Sulfur, and Silicon, 55, 159 (1991).
[19] L. H. Straver and A. J. Schierbeek, MolEN. Structure Determination System (Nonius
B.V., Delft, Netherlands), 1 and 2 (1994).
[20] G. M. Sheldrick, Acta Cryst., A46, 467 (1990).
[21] G. M. Sheldrick, Universita¨t Go¨ttingen, 1997; graphics SCHAKAL, E. Keller, Uni-
versita¨t Freiburg, 1997.