Synthesis of substituted 1-thia-3-aza-λ5-phosphacyclohex- 2-ene

Article abstract of DOI:10.1007/s11172-005-0024-y

The addition of dimethylamine to O-phenyl 2- chloropropylisothiocyanatophosphonate afforded the six-membered cyclic product, viz., 1-thia-3-aza-4λ⁵-phosphacyclohex-2-ene.

Full text of DOI:10.1007/s11172-005-0024-y

1722
Russian Chemical Bulletin, International Edition, Vol. 53, No. 8, pp. 1722—1725, August, 2004
Synthesis of substituted 1ꢀthiaꢀ3ꢀazaꢀ4λ5ꢀphosphacyclohexꢀ2ꢀene
ꢀ
M. A. Pudovik, S. A. Terent´eva, N. A. Khailova, R. Z. Musin, N. M. Azancheev,
O. N. Kataeva, I. A. Litvinov, A. B. Dobrynin, and A. N. Pudovik
A. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843 2) 75 2253. Eꢀmail: pudovik@iopc.knc.ru
The addition of dimethylamine to Oꢀphenyl 2ꢀchloropropylisothiocyanatophosphonate
5
afforded the sixꢀmembered cyclic product, viz., 1ꢀthiaꢀ3ꢀazaꢀ4λ ꢀphosphacyclohexꢀ2ꢀene.
Key words: chloroalkylphosphonates, functionalization, heterocyclization, thiaazaꢀ
phosphacyclohexene.
Earlier, we have found1 that in the presence of bases,
phosphorylated thioureas in which the phosphorus atom
is bound to the chloromethyl group can undergo cyclizaꢀ
tion to give 1,3,4ꢀthiaazaphospholines. With the aim of
examining the possibility of the synthesis of large rings, in
particular, sixꢀmembered rings, according to this proceꢀ
dure, we introduced the 2ꢀchloroalkyl group instead of
the chloromethyl fragment at the P atom. Taking into
account the published data,2 we prepared tris(2ꢀchloroꢀ
propyl) phosphite (1) by the reaction of phosphorus
trichloride with propylene oxide. Compound 1 was
isomerized to bis(2ꢀchloropropyl) 2ꢀchloropropylphosꢀ
phonate (2) on prolonged heating (Scheme 1). Chlorinaꢀ
tion of the latter with PCl5 afforded the target product,
viz., 2ꢀchloropropylphosphonyl dichloride (3).
Scheme 2
pound 5 was used without additional purification because
it decomposes in the course of vacuum distillation.
After passing an excess of dimethylamine through a
benzene solution of isothiocyanatophosphonate 5, coꢀ
crystals of cyclic product 7 and Me2NH•HCl formed
(Scheme 3). Cyclization occurs, apparently, through the
intermediate formation of phosphorylated thiourea 6,
which is rapidly transformed into the final product 7.
Since the reaction was carried out in the presence of an
excess of dimethylamine, we hypothesize that the most
probable cyclization mechanism involves the initial forꢀ
mation of the complex between the base (dimethylamine)
and thiourea, which is accompanied by weakening of
the N—H bond, to give, presumably, the ion pair
6–•Me2NH2+. The subsequent nucleophilic attack of the
S atom of the thiourea fragment on the Cβ atom of the
chloropropyl group is accompanied by the simultaneous
displacement of the Cl atom from the latter group to form
a cyclic system. We have proposed3 an analogous reaction
mechanism for the formation of fiveꢀmembered heteroꢀ
cycles from the corresponding chloromethylphosphorylꢀ
thioureas based on the results of calculations by the
semiempirical MNDO and ab initio HF/6ꢀ31G* methods
and the density functional theory (DFT/PBE/TZ2P).
Triple recrystallization of the precipitate from benꢀ
zene afforded individual phosphacyclane 7 as one diaꢀ
Scheme 1
The reaction of equimolar amounts of dichloride 3
and phenol produced monochlorophosphonate 4, which
was transformed into isothiocyanatophosphonate 5 on
heating in the presence of KSCN over a long period of
time (Scheme 2).
According to the 31P NMR spectroscopic data, prodꢀ
ucts 4 and 5 containing two chiral centers exist as two
diastereomers in an approximately equal amounts. Comꢀ
1
stereomer (δP 15.74). In the H NMR spectrum of comꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1657—1659, August, 2004.
1066ꢀ5285/04/5308ꢀ1722 © 2004 Springer Science+Business Media, Inc.

Substituted 1ꢀthiaꢀ3ꢀazaꢀ4λ5ꢀphosphacyclohexꢀ2ꢀene Russ.Chem.Bull., Int.Ed., Vol. 53, No. 8, August, 2004
1723
Scheme 3
C(8)
C(7)
C(2)
N(2)
S(1)
N(3)
P(4)
C(6)
C(15)
C(5)
O(4)
O(5)
O(4)´
C(9)
C(10)
C(11)
C(14)
C(13)
pound 7, the signal of the Me group at the C atom appears
3
4
as a doublet of doublets (δ 1.36, JH,H = 6.8 Hz, JH,P
=
C(12)
2.7 Hz). The composition and structure of product 7 were
confirmed also by the results of EI mass spectrometry and
elemental analysis. In the mass spectrum of phosphaꢀ
cyclane 7, the peak at m/z 284 corresponds to the moꢀ
lecular ion [M]•+. The first step of fragmentation of molꢀ
ecule 7 under EI is associated with elimination of the Me
group from the dimethylamino fragment resulting in the
appearance of the ion peak [M – Me]+ at m/z 269. Elimiꢀ
nation of the dimethylamino group gives rise to the ion
peak [M – NMe2]+ at m/z 240. The cleavage of the C—S
and P—C bonds in the phosphorusꢀcontaining heteroꢀ
cycle gives rise to the [M – C3H6]+ ion at m/z 242. The
ion peak [M – OPh]+ at m/z 191 is, apparently, attributꢀ
able to the cleavage of the P—O bond with localization of
the charge on the phosphorusꢀcontaining fragment. Subꢀ
sequent fragmentation of this ion accompanied by the
cleavage of the C—S and P—C bonds in the heterocycle
affords the [M – OPh – C3H6]+ ion at m/z 149, which is
the most abundant ion in the mass spectrum of comꢀ
pound 7. The presence of other fragment ions at small
Fig. 1. Molecular geometry of compound 7 in the crystal and
C—H...O hydrogen bonds (indicated by dashed lines).
m/z in the mass spectrum of compound 7 is, apparently,
associated with successive fragmentation of the aboveꢀ
mentioned ions under EI.
According to the results of Xꢀray diffraction study,
molecule
7 adopts a chair conformation. The
S(1)—C(2)—N(3)—P(4) fragment is planar (within
0.02(1) Å), and the C(5) and C(6) atoms deviate from
this plane by 0.440(7) and –0.380(6) Å, respectively, i.e.,
in opposite directions from the planar fragment (Fig. 1,
Table 1). The chiral P(4) and C(6) atoms have an
R configuration. The O atom of the phosphoryl group is
in an equatorial position and the phenoxy group is in an
axial position. The methyl group at the chiral C atom is in
an equatorial position. The P=O and exocyclic P—O bond
lengths (1.468(4) and 1.601(4) Å, respectively) have stanꢀ
Table 1. Selected bond lengths (d) and bond angles (ω) in compound 7
Bond
d/Å
Angle
ω/deg
Angle
ω/deg
S(1)—C(2)
S(1)—C(6)
P(4)—O(4)
P(4)—O(5)
P(4)—N(3)
P(4)—C(5)
O(5)—C(9)
N(2)—C(2)
N(2)—C(7)
N(2)—C(8)
N(3)—C(2)
C(5)—C(6)
C(6)—C(15)
1.772(7)
1.818(6)
1.468(4)
1.601(4)
1.619(4)
1.795(7)
1.410(6)
1.333(8)
1.440(9)
1.439(8)
1.292(7)
1.534(8)
1.493(9)
C(2)—S(1)—C(6)
O(4)—P(4)—O(5)
O(4)—P(4)—N(3)
O(4)—P(4)—C(5)
O(5)—P(4)—N(3)
O(5)—P(4)—C(5)
N(3)—P(4)—C(5)
P(4)—O(5)—C(9)
C(2)—N(2)—C(7)
C(2)—N(2)—C(8)
C(7)—N(2)—C(8)
P(4)—N(3)—C(2)
S(1)—C(2)—N(2)
S(1)—C(2)—N(3)
104.7(3)
113.0(2)
114.6(2)
113.3(3)
102.0(2)
105.0(3)
107.9(3)
119.7(3)
119.1(5)
124.0(5)
116.8(5)
129.1(4)
113.5(4)
126.0(5)
N(2)—C(2)—N(3)
P(4)—C(5)—C(6)
S(1)—C(6)—C(5)
120.4(6)
111.3(4)
111.5(4)
122.0(6)
118.9(6)
120.5(6)
106.7(4)
112.3(5)
116.2(5)
121.4(5)
122.4(6)
117.7(6)
118.5(6)
C(10)—C(11)—C(12)
C(11)—C(12)—C(13)
C(12)—C(13)—C(14)
S(1)—C(6)—C(15)
C(5)—C(6)—C(15)
O(5)—C(9)—C(10)
O(5)—C(9)—C(14)
C(10)—C(9)—C(14)
C(9)—C(10)—C(11)
C(9)—C(14)—C(13)

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 8, August, 2004
Pudovik et al.
Cl, 54.12; P, 15.54. C3H6Cl3OP. Calculated (%): Cl, 54.47;
P, 15.86. 31P NMR, δ: 44.22.
dard values. The N atom in the dimethylamino group
adopts a planarꢀtrigonal configuration (the sum of the
bond angles is 360(1)°). Analysis of intermolecular interꢀ
actions, which was carried out using the PLATON proꢀ
gram,4 demonstrated that the molecular packing in the
crystal is stabilized by weak C—H...O hydrogen bonds.
The molecules are linked to each other through the biꢀ
furcate C(6)—H(6)...O(4)´ (1 + x, y, z) (C(6)—H(6),
1.04 Å; H(6)...O(4)´, 2.24 Å; C(6)...O(4)´, 3.145(7) Å;
C(6)—H(6)—O(4)´, 145°) and C(10)—H(10)...O(4)´
(1 + x, y, z) hydrogen bonds (C(10)—H(10), 0.99 Å;
H(10)...O(4)´, 2.38 Å; C(10)...O(4)´, 3.362(7) Å;
C(10)—H(10)—O(4)´, 172°) to form infinite chains along
the 0a axis. The molecules are also linked in infinite zigꢀ
zag chains along the 0c axis through the intermolecular
C(12)—H(12)...O(4)´ hydrogen bonds (–x, –1/2 + y, –z)
(C(12)—H(12), 0.98 Å; H(12)...O(4)´, 2.51 Å;
C(12)...O(4)´, 3.427(7) Å; C(12)—H(12)—O(4)´, 154°).
These two types of chains form together a twoꢀdimenꢀ
sional network. It should be noted that compound 7 crysꢀ
tallizes in the chiral polar space group P21, and the molꢀ
ecule is chiral. We established its absolute configuration
in the crystal. The crystals of compound 7 can be considꢀ
ered as a conglomerate, i.e., crystallization leads to
spontaneous resolution of enantiomers.
OꢀPhenyl 2ꢀchloropropylchlorophosphonate (4). A mixture
of dichloride 3 (7.7 g, 39.4 mmol) and phenol (3.7 g, 39.4 mmol)
was heated at 160 °C for 18 h, and compound 4 was obtained
by fractionation in a yield of 4 g (40%), b.p. 105—110 °C
(0.06 Torr). Found (%): Cl, 28.04; P, 12.90. C9H11Cl2O2P.
Calculated (%): Cl, 28.06; P, 12.25. 31P NMR (C6H6), δ:
32.07, 33.08.
2ꢀDimethylaminoꢀ6ꢀmethylꢀ4ꢀoxoꢀ4ꢀphenoxyꢀ1ꢀthiaꢀ3ꢀazaꢀ
4λ ꢀphosphacyclohexꢀ2ꢀene (7). A mixture of acid chloride 4
5
(2 g, 7.9 mmol) and KSCN (0.77 g, 7.9 mmol) in anhydrous
MeCN (5 mL) was heated at 80 °C for 10 h. Potassium chloride
was separated from a solution of product 5 (δ 8.03, 9.86) in a
P
yield of 0.58 g (100%). Then MeCN was removed, the residue
was dissolved in anhydrous benzene (5 mL), and an excess of
Me2NH was passed through the solution. After 24 h, product 7
was filtered off, recrystallized three times from benzene, and
dried in vacuo. The yield was 1.2 g (53%), m.p. 200—202 °C.
Found (%): C, 51.15; H, 6.00; N, 10.13; P, 10.86; S, 10.86.
C12H17N2O2PS. Calculated (%): C, 50.70; H, 5.98; N, 9.85;
P, 10.91; S, 11.26. IR, ν/cm–1: 1580 (C=N), 1250 (P=O).
3
4
1H NMR, δ: 1.36 (dd, MeC, JH,H = 6.8 Hz, JH,P = 2.7 Hz);
1.71 and 2.28 (both m, HA, HB, CH2); 3.07 (br.s, MeN); 3.60
(m, CHS); 7.00—7.30 (m, Ph). 31P NMR (DMSOꢀd6), δ: 15.03.
Xꢀray diffraction study of compound 7. Paleꢀyellow crystals
of compound 7 (from DMF) (C12H17N2O2PS, M = 284.31) are
monoclinic, space group P21, a = 6.1513(8) Å, b = 7.749(2) Å,
c = 14.470(2) Å, β = 97.99(1)°, V = 683.1(2) Å3, Z = 2, dcalc
=
Therefore, cyclization of 2ꢀchloropropylphosphonylꢀ
substituted thiourea afforded a new representative of
P,N,Sꢀcontaining unsaturated sixꢀmembered heteroꢀ
cycles, viz., substituted 1ꢀthiaꢀ3ꢀazaꢀ4λ5ꢀphosphacycloꢀ
hexꢀ2ꢀene.
1.382 g cm–3, F(000) = 284. The intensities of 2423 reflections
were measured on an Enraf Nonius CADꢀ4 diffractometer at
20 °C (λ(MoꢀKα), ω/2θ scanning technique, 2θ
< 27.8°), of
max
which 1385 reflections were with I > 3σ. The intensities of three
check reflections showed no decrease in the course of Xꢀray data
collection. Because of a low value of the coefficient (µ(Mo) =
3.29 cm–1), absorption was ignored. The structure was solved by
direct methods using the SIR program6 and refined first isoꢀ
tropically and then anisotropically. All H atoms were revealed
from difference electron density syntheses. Their contributions
to the structure factors were taken into account in the final step
of the refinement with fixed positional and thermal parameters.
With the aim of establishing the absolute structure and, conseꢀ
quently, the absolute configuration of the molecule, the direct
and inverted structures were refined taking into account anomaꢀ
lous scattering by all nonhydrogen atoms. The reliability factors
were as follows: R = 0.04488, Rw = 0.04981 for the direct strucꢀ
ture, and R = 0.04496, Rw = 0.04992 for the inverted structure
based on 1303 independent reflections for 162 refinement paꢀ
rameters. All calculations were carried out using the MOLEN
complex program7 on an AlphaStation 200 computer. Accordꢀ
ing to the Hamilton test,8 the direct structure corresponds to the
absolute structure with the probability of 95%. The final reliꢀ
ability factors were R = 0.045, Rw = 0.050 based on 1303 indeꢀ
pendent reflections with F2 ≥ 3σ. The complete tables of the
atomic coordinates, bond lengths, and bond angles were deposꢀ
ited with the Cambridge Structural Database.
Experimental
The 1H NMR spectrum was recorded on a Bruker WMꢀ250
instrument (250 MHz) in a mixture of CDCl3 and C6D6 (1 : 1).
The 31P NMR spectra were measured on a CXPꢀ90 instrument
(36.47 MHz) with 85% H3PO4 as the external standard. The IR
spectrum of heterocycle 7 was recorded on a URꢀ20 spectromꢀ
eter in the frequency range of 400—3600 cm–1 in Nujol mulls.
The mass spectra (EI) were obtained on a TRACE MS Finnigan
MAT instrument with direct inlet of the sample into the ion
source; the energy of ionizing electrons was 70 eV; the temperaꢀ
ture of the ion source was 200 °C. The evaporator tube was
heated in programmed mode from 35 to 150 °C with a step of
35 °C min–1. The massꢀspectrometric data were processed using
the Xcalibur program.
Phosphite 1 and phosphonate 2 were synthesized according
to known procedures.2,5
2ꢀChloropropylphosphonyl dichloride (3). Phosphorus pentaꢀ
chloride (49.5 g, 236 mmol) was added gradually with stirring to
compound 2 (37 g, 118 mmol), which was heated to 140 °C, in
the presence of catalytic amounts (0.3 g) of CuCl. The reaction
mixture was kept at 140 °C for 3 h, volatile compounds were
removed, and compound 3 was obtained by fractionation in a
yield of 10 g (43%), b.p. 70—74 °C (0.06 Torr). Found (%):
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 03ꢀ03ꢀ
33064).

Substituted 1ꢀthiaꢀ3ꢀazaꢀ4λ5ꢀphosphacyclohexꢀ2ꢀene Russ.Chem.Bull., Int.Ed., Vol. 53, No. 8, August, 2004
1725
4. A. L. Spek, PLATON for Windows, Version 98, Acta Crystallogr.,
Sect. A, 1998, 46, 34.
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Received July 17, 2003;
in revised form January 20, 2004