Synthesis and molecular structure of substituted 4-[N-phenyl-N-(2- chloroethyl)amino]-1,4-dihydro-1,2,4λ5-diazaphosphorines

Article abstract of DOI:10.1007/s11176-005-0233-y

The reaction of 3-phenyl-2-phenylethynyl-1,3,2λ³- oxazaphospholidine with nitrilimines is a multistep process involving formation of the diazaphosphorine ring and cleavage of the oxazaphospholidine ring. The final products are the substituted 4

Full text of DOI:10.1007/s11176-005-0233-y

Russian Journal of General Chemistry, Vol. 75, No. 3, 2005, pp. 370 374. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 3, 2005,
pp. 406 410.
Original Russian Text Copyright
2005 by Trishin, Gonchar, Namestnikov, Stash, Zavodnik, Bel’skii
Synthesis and Molecular Structure of Substituted
4-[N-Phenyl-N-(2-chloroethyl)amino]-1,4-dihydro-
5
1,2,4 -diazaphosphorines
Yu. G. Trishin, T. V. Gonchar, V. I. Namestnikov,
A. I. Stash, V. E. Zavodnik, and V. K. Bel’skii
St. Petersburg State Technological University of Plant Polymers, St. Petersburg, Russia
Received June 25, 2004
Abstract The reaction of 3-phenyl-2-phenylethynyl-1,3,2 3-oxazaphospholidine with nitrilimines is a
multistep process involving formation of the diazaphosphorine ring and cleavage of the oxazaphospholidine
ring. The final products are the substituted 4-[N-phenyl-N-(2-chloroethyl)amino]-1,4-dihydro-1,2,4 5-diaza-
phosphorines. According to X-ray structural data obtained for 4-[N-phenyl-N-(2-chloroethyl)amino]-1,4-di-
hydro-1,5-diphenyl-3-ethoxycarbonyl-1,2,4 5-diazaphosphorine, the heteroring of these compounds has the
conformation of a flattened P-envelope.
We have shown recently [1] that 2-ethoxy-3-methyl-
1,3,2 -oxazaphospholidine reacts with nitrilimines
carbenium atom yielded substituted 4-[N-phenyl-N-
(2-chloroethyl)amino]-1,4-dihydro-1,2,4 -diazaphos-
3
5
(Huisgen 1,3-dipoles) to form alicyclic compounds
with a P C bond, which suggests the nucleophilic
attack of the nitrilimine carbenium atom nitrilimine
by the trivalent phosphorus atom, protonation of the
intermediate bipolar P+CNN ion by triethylamine
hydrohalide present in the reaction mixture, and
cleavage of the five-membered heterocycle across the
C O bond.
phorines II VIII.
The reaction probably starts with a nucleophilic
attack of the carbenium atom of nitrilimine by phos-
phorus (the nitrilimine was generated in situ from the
appropriate halohydrazones under the action of tri-
ethylamine). The arising bipolar ion IIa VIIIa under-
goes intramolecular nucleophilic addition to form the
cyclic ylide IIb VIIb, which is protonated with tri-
ethylamine hydrohalide to form the cyclic quasiphos-
phonium salt IIc VIIIc. The latter transforms into the
stable final product II VIII by the cleavage of the
oxazaphospholidine ring as a result of the attack of
the oxygen-bonded carbon atom of the five-membered
heterocycle by the halide ion. This reaction step is
similar to the second step of the classical Arbuzov
reaction. It yields the phosphoryl and N-phenyl-N-2-
haloethyl groups.
In this study we found that the introduction of an
acetylenic group instead of the ethoxy group at the
3
phosphorus atom in 1,3,2 -oxazaphospholidines
provides the formation of a six-membered diazaphos-
phorine heterocycle under the similar conditions, but
does not exclude the cleavage of the oxazaphosphol-
idine ring. In particular, the reactions of 3-phenyl-2-
3
phenylethynyl-1,3,2 -oxazaphospholidine
I
with
nitrilimines containing various substituents at the
+
R C(Hlg)=N NH Ar + Et3N
R C=N N Ar + Et3N HHlg
Ph
C=C
C=N
R
CH2
CH2
O
C C Ph
C=N N Ar
R
+
P
CH2
CH2
O
+
+
P
CH2
CH2
O
R C=N N Ar
N Ar
P C C Ph
N
N
N
Ph
Ph
Ph
I
IIa VIIIa
IIb VIIIb
1070-3632/05/7503-0370 2005 Pleiades Publishing, Inc.

SYNTHESIS AND MOLECULAR STRUCTURE
Ph
371
Ph
CH=C
C=N
R
CH2
O
O
CH=C
C=N
R
+
P
Et3N HHlg
Et3N
Hlg
N Ar
CH2
N Ar
Hlg
P
CH2
N
N
CH2
Ph
Ph
IIc VIIIc
R = C(O)Me, Ar = Ph (II), C6H4Br-p (III); R = C(O)OEt, Ar = Ph (IV), C6H4Br-p (V), C6H4NO2-p (VI); Ar = Ph,
R = C(O)C6H4NO2-p (VII), Ph (VIII).
3
Note that 2-phenylethynyl-1,3,2 -dioxaphospho-
lane, the analog of compound I containing the oxygen
atom instead of the nitrogen atom in the five-
membered heterocycle, reacts with nitrilimines
similarly [2].
line compounds readily soluble in THF and acetone
and poorly soluble in hexane and ether. Their 31P
NMR spectra contain the signals in the range of
P
from 0.6 to 8.6 ppm, characteristic of substituted
1,2,4-diazaphosphorines [2, 4]. The signals are shifted
upfield by 8 10 ppm as compared to the related com-
pounds containing a 2-haloethoxy substituent at the P
atom [2]. This fact confirms the presence of the exo-
3
The starting 1,3,2 -oxazaphospholidine I was
prepared by the reaction of 3-phenyl-2-chloro-1,3,2 -
oxazaphospholidine with 2-phenylethynylmagnesium
bromide.
3
1
cyclic P N bond in II VIII. The H NMR spectra
contain the signals of the alkenyl proton at 5.69
3
6.06 ppm. The coupling constant JPH (0 3.3 Hz) in
CH2
CH2
O
P Cl + PhC CMgBr
I
many cases is close to zero, so that the signals appear
as singlets. The protons of the methylene groups
HlgCH2 and NCH2 are anisochronous. They give pairs
N
Ph
of multiplets at
3.62 4.51 and 3.51 3.63 ppm,
The signal of the phosphorus atom in the 31P NMR
respectively. In the IR spectra of II VIII, the absorp-
tion band characteristic of the C C bond is absent,
which additionally confirms its conversion. Note that
compounds II and III containing the acetyl group at
the C3 atom were obtained as mixtures of two dia-
stereomers A and B. This is indicated by the presence
of two signals in the 31P NMR spectra and by doubl-
ing of all the signals (primarily, of the alkenyl proton
signals) in the 1H NMR spectra (Table 2). The relative
content of the isomers changes in the course of re-
crystallization. The A : B ratio in the finally isolated
compounds II and III was 1:4 and 2:3, respectively.
spectrum of I ( 97.7 ppm) is shifted upfield as
P
compared to the signal of the related 2-phenylethynyl-
3
1,3,2 -dioxaphospholane ( 127.4 ppm) [2], in line
P
with the trend observed in going from amido esters to
1
O,O-diesters of trivalent phosphorus [3]. In the H
NMR spectrum, the OCH2 and NCH2 protons give
multiplets with
4.67 and 3.47 ppm, respectively.
The presence of the C C bond is confirmed by the IR
1
spectrum [ (C C) 2120 cm ].
Substituted diazaphosphorines II VIII were pre-
pared in 50 90% yield (Tables 1, 2). They are crystal-
Table 1. Yields, melting points, and elemental analyses of substituted 4-[N-phenyl-N(2-chloroethyl)amino]-1,4-dihydro-
1,2,4-diazaphosphorines II VIII
Found, %
H
Calculated, %
Comp.
no.
Yield,
%
R
Ar
mp,
C
Formula
C
P
C
H
P
II
C(O)Me
Ph
C6H4Br-p
Ph
C6H4Br-p
C6H4NO2-p 46
72
67
70
90
171 172 64.87 5.20 6.47 C25H23ClN3O2P
64.73 5.00 6.68
III
IV
V
C(O)Me
C(O)OEt
C(O)OEt
C(O)OEt
183 184 55.04 4.18 5.87 C25H32BrClN3O2P 55.32 4.09 5.71
180 182 63.01 5.02 6.11 C26H25ClN3O3P 63.22 5.10 6.27
161 162 54.68 4.32 5.65 C26H24BrClN3O3P 54.52 4.22 5.41
185 187 57.76 4.56 5.86 C26H24ClN4O5P
167 168 63.17 4.34 5.48 C30H24BrN4O4P
139 141 70.08 5.30 6.19 C29H25ClN3OP
VI
57.95 4.49 5.75
63.11 4.24 5.42
69.95 5.06 6.22
VII C(O)C6H4NO2-p Ph
VIII Ph Ph
75
52
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 3 2005

372
TRISHIN et al.
1
Table 2. IR and H and 31P NMR data for substituted 4-[N-phenyl-N(2-chloroethyl)amino]-1,4-dihydro-1,2,4-diazaphos-
phorines II VIII
IR spectrum,
,
1H NMR spectrum, , ppm (J, Hz)
1
31P NMR
spectrum,
P, ppm
cm
Comp.
no.
HlgCH2,
two m
NCH2,
two m
other
groups
C=O
P=O
=CH, d (2JPh)
Ar H, m
II
1625
1700
1760
1766
1710
1760
1280 Isomer A: 6.06 (2.8) 4.48, 3.63 3.51, 3.58 7.02 7.85
Isomer B: 5.67 ( 0) 4.45, 3.82 3.52, 3.65 6.65 7.38
1240 Isomer A: 6.09 (3.4) 4.48, 3.72 3.51, 3.60 6.92 7.70
Isomer B: 5.69 ( 0) 4.46, 3.80 3.53, 3.67 6.60 7.30
2.65 s [C(O)Me]
2.38 s [C(O)Me]
2.64 s [C(O)Me]
2.39 s [C(O)Me]
1.43 t (Me),
4.42 m (OCH2)
1.43 t (Me),
4.42 m (OCH2)
0.6
7.4
1.1
7.8
7.3
III
IV
V
1250 5.64 ( 0)
1260 5.65 ( 0)
1245 5.74 ( 0)
4.53, 3.79 3.56, 3.63 6.61 7.35
4.51, 3.77 3.55, 3.62 6.50 7.30
4.51, 3.75 3.55, 3.62 6.82 7.95
4.57, 3.94 3.42, 3.58 6.55 8.18
7.8
8.6
VI
1.45
t (Me),
4.45 m (OCH2)
VII
VIII
1250 5.81 (3.3)
1260 5.45 (1.1)
4.12, 3.68 3.35, 3.40
6.65 8.18
The molecular structure of diazaphosphorines II
VIII was studied by single crystal X-ray diffraction
phorine IV as example (see figure; Tables 3, 4). We
found that all the atoms of the heterocycle except
for 4-[N-phenyl-N-(2-chloroethyl)amino]-1,4-dihydro- phosphorus are coplanar within 0.030 . The phos-
1,5-diphenyl-3-ethoxycarbonyl-1,2,4 5-diazaphos-
phorus atom deviates from this plane by 0.294
,
Cl
C25
C24
C26
C19
C21
C20
C23
N3
C22
O1
C17
C18
C13
C1
C2
P
O2
C16
C12
N1
C14
C4
C3
C15
N2
C7
O3
C11
C10
C5
C8
C6
C9
5
Molecular structure of 4-[N-phenyl-N-(2-chloroethyl)amino]-1,4-dihydro-1,5-diphenyl-3-ethoxycarbonyl-1,2,4 -diazaphos-
phorine IV.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 3 2005

SYNTHESIS AND MOLECULAR STRUCTURE
373
Table 3. Interatomic distances in the molecule of 4-[N-
phenyl-N-(2-chloroethyl)amino]-1,4-dihydro-1,5-diphenyl-
3-ethoxycarbonyl-1,2,4 5-diazaphosphorine IV
Table 4. Bond angles in the molecule of 4-[N-phenyl-N-
(2-chloroethyl)amino]-1,4-dihydro-1,5-diphenyl-3-ethoxy-
carbonyl-1,2,4 5-diazaphosphorine IV
Bond
d,
Bond
d,
Angle
, deg
Angle
, deg
Cl C20
1.780(6)
1.464(3)
1.662(4)
1.737(4)
1.786(4)
1.197(5)
1.314(5)
1.455(6)
1.340(4)
1.398(5)
1.448(5)
1.296(5)
1.419(5)
1.469(6)
1.341(6)
1.479(6)
1.492(6)
1.455(10)
1.359(7)
C7 C12
1.368(7)
1.375(7)
1.356(9)
1.361(8)
1.387(7)
1.380(6)
1.381(6)
1.378(7)
1.359(8)
1.374(8)
1.369(7)
1.509(9)
1.383(7)
1.386(7)
1.377(8)
1.345(8)
1.377(9)
1.357(8)
O1PN3
109.77(19)
118.1(2)
106.01(19)
114.32(19)
111.00(19)
96.8(2)
C8C7C12
120.4(5)
119.2(4)
120.3(4)
119.6(5)
120.6(6)
120.0(5)
119.9(5)
119.4(5)
118.6(4)
118.5(4)
122.8(4)
120.1(5)
120.9(5)
119.4(5)
120.3(5)
120.7(5)
110.4(4)
109.5(5)
117.4(5)
120.5(4)
122.0(4)
120.6(5)
121.1(6)
119.0(6)
120.8(5)
P O1
C8 C9
O1PC1
C8C7N1
P N3
C9 C10
N3PC1
C12C7N1
P C1
C10 C11
C11 C12
C13 C18
C13 C14
C14 C15
C15 C16
C16 C17
C17 C18
C19 C20
C21 C26
C21 C22
C22 C23
C23 C24
C24 C25
C25 C26
O1PC3
C7C8C9
P C3
N3PC3
C10C9C8
O2 C4
O3 C4
O3 C5
N1 N2
N1 C2
N1 C7
N2 C3
N3 C21
N3 C19
C1 C2
C2 C13
C3 C4
C5 C6
C7 C8
C1PC3
C9C10C11
C10C11C12
C7C12C11
C18C13C14
C18C13C2
C14C13C2
C15C14C13
C16C15C14
C15C16C17
C18C17C16
C17C18C13
N3C19C20
C19C20Cl
C26C21C22
C26C21N3
C22C21N3
C23C22C21
C24C23C22
C23C24C25
C26C25C24
C4O3C5
N2N1C2
N2N1C7
C2N1C7
C3N2N1
C21N3C19
C21N3P
C19N3P
C2C1P
117.0(4)
124.2(3)
112.6(3)
123.2(3)
122.1(3)
118.2(4)
122.4(3)
119.5(3)
125.0(3)
122.1(4)
120.9(4)
117.0(3)
115.6(4)
126.8(3)
117.6(3)
124.5(4)
122.1(4)
113.3(4)
107.0(6)
121.1(5)
C1C2N1
C1C2C13
N1C2C13
N2C3C4
N2C3P
C4C3P
which allows the structure of the heterocycle to be
considered as a flattened P-envelope. The angle
between the phosphorus triangle (C1 P C3) and the
remaining part of the heterocycle is 14 . The angles
between the planes of the heterocycle and phenyl
rings C7 C12 and C13 C18 are 125.2 and 61.2 ,
respectively. The tetrahedral configuration of phos-
phorus is distorted; the XPY angles vary in the range
96.8 118.1 .
O2C4O3
O2C4C3
O3C4C3
O3C5C6
C25C26C21
chemical shift was measured against 85% phosphoric
acid.
Thus, by the reaction of 3-phenyl-2-phenylethynyl-
1,3,2 -oxazaphospholidine I with nitrilimines we pre-
A single crystal X-ray diffraction study of 4-[N-
phenyl-N-(2-chloroethyl)amino]-1,4-dihydro-1,5-di-
phenyl-3-ethoxycarbonyl-1,2,4 5-diazaphosphorine
IV was carried out on a CAD-4 diffractometer (MoK
radiation, /2 scanning). Triclinic crystals: C26H25
3
pared previously unknown substituted 1,4-dihydro-
5
1,2,4 -diazaphosphorines II VIII containing the
aminohalomethyl group at phosphorus. The presence
of this group in the molecules of organophosphorus
compounds is important for realization of their anti-
cancer propeties.
ClN3O3P; a 10.910(2), b 10.967(2), c 12.134(2)
,
;
3
72.52(3) , 68.21(3) , 67.54(3) , V 1224.4(4)
3
space group P1, Z 2, dcalc 1.340 g cm . The structure
was solved by the direct method, R 0.0538, RW 0.1387
[2394 reflections with I > 2 (I)]. The atomic
coordinates and their isotropic temperature factors are
deposited at the Cambridge Structural Database
(registry no. CCDC 235900).
EXPERIMENTAL
The IR spectra of I VIII were recorded on an IKS-
29 spectrometer in thin film (for I) or in KBr pellets
1
(for II VIII). The H NMR spectra were taken on a
3
Bruker AM-500 (500 MHz) spectrometer in CDCl3
with the internal stabilization by the resonance line of
2H. The 31P NMR spectra were measured on a Bruker
AC-200 spectrometer (81.4 MHz) in CDCl3. The
Synthesis of 3-phenyl-2-phenylethynyl-1,3,2 -
oxazaphospholidine I and its reactions with nitril-
imines were performed under dry argon in anhydrous
solvents.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 3 2005

374
TRISHIN et al.
3-Phenyl-2-phenylethynyl-1,3,2 3-oxazaphos-
20 ml of benzene was refluxed for 2 h. A small
amount of triethylamine hydrochloride (14 20%) was
filtered off. In the case of V and VIII, the residue was
a solid which was crystallized from 1:1 acetone
hexane. In the case of IV, VI, and VII, the residue
was an oily substance which was treated with diethyl
ether (compounds IV and VI) or with 2:1 ether
hexane mixture (VII). The crystalline products were
filtered off and crystallized from 3:1 hexane benzene
(compound IV), 1:1 acetone hexane (compound VI),
or 2:1 hexane benzene (compound VII).
pholidine I. A solution of phenylethynylmagnesium
bromide prepared from 4.0 g of magnesium, 14.2 g
of ethyl bromide, and 14.0 g of phenylacetylene in
40 ml of THF was added dropwise with vigorous stir-
ring at 60 C to a solution of 24.9 g of 2-chloro-3-
3
phenyl-1,3,2 -oxazaphospholidine [5] in 200 ml of
THF. After that the reaction mixture was gradually
heated to 20 C, stirred for 30 min, and then 50 ml of
pyridine was added. The resulting precipitate was
filtered off, THF was distilled off at reduced pressure,
and the residue was extracted with diethyl ether (3
100 ml). The ether was removed in a vacuum, and the
residue was crystallized on cooling to 0 5 C to obtain
ACKNOWLEDGMENTS
3
24.7 g (77%) of 3-phenyl-2-phenylethynyl-1,3,2 -
The study was financially supported by the Russian
Foundation for Basic Research (project no. 03-03-
32905).
oxazaphospholidine I, mp 67 70 C. IR spectrum,
1
1
, cm : 2120 (C=C), 1010 (P O C). H NMR spec-
trum (CDCl3), , ppm: 3.47 m (2H, NCH2), 4.67 m
(2H, OCH2), 6.90 7.52 m (10H, Ph). 31P NMR spec-
REFERENCES
trum:
97.7 ppm. Found, %: C 71.78; H 5.39; P
P
11.45. C16H14NOP. Calculated, %: C 71.90; H 5.28;
P 11.59.
1. Trishin, Yu.G., Gonchar, T.V., and Namestnikov, V.I.,
Zh. Obshch. Khim., 2004, vol. 74, no. 10, p. 1752.
2. Senyukh, S.V., Namestnikov, V.I., Trishin, Yu.G., and
Chistokletov, V.N., Zh. Obshch. Khim., 1990, vol. 60,
no. 10, p. 1926.
Substituted 4-[N-phenyl-N-(2-chloroethyl)-
amino]-1,4-dihydro-1,2,4 5-diazaphosphorines II
and III. A solution of 0.005 mol of 3-phenyl-2-phe-
3
3. Nifant’ev, E.E. and Vasyanina, L.K., Spektroskopiya
YaMR 31P (31P NMR Spectroscopy), Moscow: Mosk.
Gos. Ped. Inst., 1986.
nylethynyl-1,3,2 -oxazaphospholidine I, 0.005 mol
of appropriate hydrazonoyl chloride, and 2 ml of tri-
ethylamine in 20 ml of benzene was refluxed for 2 h.
The abundant precipitate that formed after cooling to
20 C was filtered off, washed with water (2 50 ml)
to remove an impurity of triethylamine hydrochloride,
and crystallized from 1:1 acetone hexane (compound
II) or benzene (compound III).
4. Erofeeva, M.P., Trishin, Yu.G., and Chistokletov, V.N.,
Zh. Obshch. Khim., 1989, vol. 59, no. 9, p. 2146;
Namestnikov, V.I., Trishin, Yu.G., Tamm, L.A., and
Chistokletov, V.N., Zh. Obshch. Khim., 1990, vol. 60,
vol. 3, p. 510; Trishin, Yu.G., Afanasov, A.F., Litvi-
nov, I.A., Naumov, V.A., and Chistokletov, V.N., Zh.
Obshch. Khim., 1990, vol. 60, no. 11, p. 2446.
Substituted 4-N-[N-phenyl-N-(2-chloroethyl)]-
5
1,4-dihydro-1,2,4 -diazaphosphorines IV VIII. A
solution of 0.005 mol of 3-phenyl-2-phenylethynyl-
1,3,2 -oxazaphospholidine I, 0.005 mol of appropri-
ate hydrazonoyl halide, and 2 ml of triethylamine in
5. Pudovik, A.N., Pudovik, M.A., Shulyndina, O.S., and
Nagaeva, Kh.Kh., Zh. Obshch. Khim., 1970, vol. 40,
no. 7, p. 1477.
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 3 2005