Synthesis and characterization of novel phospholane heterocycles

Article abstract of DOI:10.1080/10426500601161056

Phospholanes are a unique class of cyclic organophosphorus compounds, which have marked applicability in medicinal science, agroscience, and catalytical chemistry. Using phosphorus trichloride as a phosphorylating agent, fourteen novel chiral cyclic organ

Full text of DOI:10.1080/10426500601161056

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Synthesis and Characterization
of Novel Phospholane
Heterocycles
Vijaya Kabra a , Arpana Meel a , Ritu Mathur a & Priti
Kaushik a
a Department of Chemistry , University of
Rajasthan , Jaipur, India
Published online: 29 Aug 2007.
To cite this article: Vijaya Kabra , Arpana Meel , Ritu Mathur & Priti Kaushik
(2007) Synthesis and Characterization of Novel Phospholane Heterocycles,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:6, 1403-1412, DOI:
10.1080/10426500601161056
To link to this article: http://dx.doi.org/10.1080/10426500601161056
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Phosphorus, Sulfur, and Silicon, 182:1403–1412, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601161056
Synthesis and Characterization of Novel
Phospholane Heterocycles
Vijaya Kabra
Arpana Meel
Ritu Mathur
Priti Kaushik
Department of Chemistry, University of Rajasthan, Jaipur, India
Phospholanes are a unique class of cyclic organophosphorus compounds, which
have marked applicability in medicinal science, agroscience, and catalytical
chemistry. Using phosphorus trichloride as a phosphorylating agent, fourteen
novel chiral cyclic organophosphorus derivatives were achieved using different 2-
aminocycloimines as starting material. The resulting five-membered cyclic deriva-
tives have shown the ABCX3 system associated with one phosphorus nucleus in 1
H
NMR. The present study thus describes a novel synthetic strategy for phospholanes,
which are analogous to cyclophosphamides.
Keywords Bifunctional nucleophiles; cyclophosphamides; phospholane; phosphoryla-
tion
INTRODUCTION
A novel synthetic strategy for five-membered cyclophosphamide analo-
gous has been developed using 2-aminocycloimines as starting material
this piece of research work is the extension of our previous work, which
has furnished different series of organophosphorus derivatives incorpo-
rating different heterocyclic nuclei.1−5 As has been reported, cyclophos-
phamides and its analogous are of continuing interest based upon their
chemical use in the treatment of cancer,6 hence, this research will be of
general application to scientists.
Different synthetic routes have been described in the literature,
where cyclic organophosphorus compounds including dioxaphosphori-
nane and related phosphoramides were synthesized by Wadsworth and
Received October 30, 2006; accepted December 4, 2006.
We are highly grateful to the Head, Department of Chemistry, University of Rajasthan,
for recording a number of spectra and for providing all of the necessary facilities.
Address correspondence to Vijaya Kabra, Department of Chemistry, University of
Rajasthan, Jaipur, 302004, India. E-mail: sgkabra@sancharnet.in
1403

1404
V. Kabra et al.
Emmons7 and Edmundson and Mitchell.8 The basic idea for our re-
cent developed synthetic route has been developed from the synthetic
procedure of Mundt and Riese;9 these scientists have used phosphorus
trichloride as a phosphorylating agent, which has been reacted with
bifunctional nucleophiles and thus successfully generated a variety of
cyclic and heterocyclic dichlorophosphanyl compounds.9−11 Interesting
31P NMR spectrum has been described by these workers. Wink et al.
using a different technology generated a new chiral auxillaries. The au-
thor has suggested the important use of these molecules in asymmetric
catalysis.12
Ramirez et al.13 has described the another synthetic route and the
geometry of dioxaphosphorane. Detailed stereochemistry has also been
discussed in his article.
RESULTS AND DISCUSSION
Under
a nitrogen atmosphere, the N-alkyl-2-aminopyridinium/
thiazolium/benzothiazolium halides (3) have been reacted with an
equimolar amount of phosphorus trichloride and two equivalents
of triethylamine at 0–5◦C in methylene chloride to generate corre-
sponding iminodichlorophosphines. These intermediates have been
oxidized in situ with elemental sulfur (1/8 equivalents) at ambient
temperature generating cycloiminylidenamidothiophosphoryl dichlo-
rides, which, on substitution with racemic 1,2-propanediol/1-phenyl-
1,2-ethanediol, gave corresponding phospholanes (6a–j) in which phos-
phorus was in its more stable tetracoordinated state. While in the syn-
thesis of 5a–d, the corresponding iminodichlorophosphines directly re-
acted with diol moiety (4) without oxidation with sulfur; thus in 5a–d,
the phosphorus was in its comparatively less stable tricoordinated state
(Scheme 1).
The products were white crystalline solids with sharp melting points.
1
All the products were characterized by H and 31P NMR techniques.
The results have been reported in Table I.
Compouds 6a–j were obtained as diastereomers in which sulfur at
position 2 and methyl/phenyl at position 4 were in trans configuration,
which has provided more stability to these molecules. The most inter-
esting feature in 1 H NMR spectra of 6a, 6c, 6e, 6f, 6j, 5b, and 5d was
the appearance of protons from the diol component as ABCX3 system
associated with a phosphorus nucleus. Here 5-CH2 and 4-H protons of
the phospholane ring comprised the ABC part of the system, and 4-CH3
group formed the X3 part (Figure 1).

Novel Phospholane Heterocycles
1405
SCHEME 1
In the ABC part, the most upfield signal at δ 2.14–3.99 ppm corre-
sponding to HA was assigned to that proton of the 5-CH2 moiety, which
is cis to CH3 group. This signal was a typical doublet of a doublet of a
doublet due to the geminal coupling with HC, vicinal coupling with trans
HB, and three bond coupling with phosphorus, but in some compounds
FIGURE 1

1406

1407

1408

Novel Phospholane Heterocycles
1409
it was a typical multiplet due to four-bond coupling also with the 4-CH3
group.
The other proton HC of the 5-CH2 group formed the C-part, and its
signal appeared at δ 3.46–4.79 ppm and could be identified as a doublet
of a doublet of a doublet of a quartet due to geminal coupling with 5-
HA, vicinal coupling with HB, three-bond coupling with phosphorus,
and four-bond coupling with trans 4-CH3 protons.
The 4-HB proton appeared at δ 2.95–4.60 ppm and formed the B part
of the system. This could be identified as a doublet of a doublet of a
quartet of a doublet. It showed vicinal coupling with trans HA and cis
HC, three-bond coupling with 4-CH3 protons, and three-bond coupling
with phosphorus.
The 4-CH3 group (the X3 part) appeared as a multiplet and could be
identified as a doublet of a doublet at δ 1.08–1.47 ppm due to three-bond
coupling with HB and long range coupling with HC.
In 6b, 6d, 6g, 5a, 5c, and 6h, the phenyl ring was present in place
of the methyl group, and hence less multiplicity was observed. Instead
these phenyl protons appeared in the aromatic region. The effect of
deshielding due to this phenyl ring on HA, HB, and HC was also ob-
served, and HA proton was most deshielded and appeared in the most
downfield region, while HC appeared in most upfield region.
All the aromatic protons of the heterocyclic ring appeared in the
expected aromatic region with expected multiplicities. The 31P NMR
values were observed in a particular range for tri- and tetracoordinated
phosphorus depending upon the nature of the nuclei (Table I).
CONCLUSION
A novel synthetic route has been developed for the synthesis of phos-
pholanes including the pyridine/benzothiazole/thiazole nucleus. These
molecules have resemblance with cyclophosphamides and hence should
be highly bioactive and a potential antitumour agent.
EXPERIMENTAL
All the reactions were performed under an inert atmosphere of dry ni-
trogen using freshly dried solvents and reagents. Glasswares were also
placed in oven before use for 2–3 h at a high temperature. The standard
syringe technique was applied to transfer dry solvents and reagents.
The diols 1,2-propanediol and 1-phenyl-1,2-ethanediol used in the re-
actions were racemates. The synthesized products were also stored un-
der a nitrogen atmosphere until characterization. Their melting points
were determined by the capillary method. 31P spectra were recorded

1410
V. Kabra et al.
on Jeol AL300 at 121.50 MHz (Obset 156 KHz) using 85% H3PO4 as
an external standard, and 1 H spectra were recorded on Jeol AL300 at
300.4 MHz (Obset 130 KHz) using TMS as an internal standard.
2-(N-AIkylpyridin-2ꢀ-ylidenamido)-4-methyI/phenyl-1,3,2-
dioxaza-phospholanes-2-sulfides (6a–e): General Procedure
To the suspension of N-alkyl-2-aminopyridinium halides (12.7 mmoles)
in methylene chloride, addition of triethylamine (25.4 mmoles) and
phosphorus trichloride (12.7 mmoles) was done at 0–5◦C. After con-
tinuous stirring of 2–4 h at ambient temperature, sulfur powder (12.7
mmoles) was added. After continuous stirring of 24 h, triethylamine
(25.4 mmoles) and racemic 1,2-propanediol (12.7 mmoles)/1-phenyl 1,2-
ethanediol (12.7 mmoles) in methylene chloride was added at 0–5◦C.
The stirring was allowed for 3 days. After that the solvent was removed
under vacuo, and residue was extracted with ether and left in a refrig-
erator, whereupon a white solid separated out, which was filtered and
dried.
2-(N-Alkylbenzothiazol-2ꢀ-ylidenamido)-4-methyl/phenyl-
1,3,2-dioxaphospholanes-2-sulfides (6f–g): General Procedure
To a well-stirred suspension of N-alkyl-2-aminobenzothiazolium
halides (10.3 mmoles) in methylene chloride (20 mL), at 0–5◦C was
added phosphorus trichloride (10.3 mmoles) followed by dropwise addi-
tion of a solution of triethylamine (20.5 mmoles) in methylene chloride
(30 mL) under a nitrogen atmosphere. After 2–4 h of stirring at room
temperature, sulfur powder (10.3 mmoles) was added to it. The result-
ing mixture was allowed to stir for 24 h, after which triethylamine
(20.5 mmoles) and racemic 1,2-propanediol/(10.3 mmoles)/1-phenyl-1,
2-ehtanediol (10.3 mmoles) in methylene chloride were added dropwise
at 0–5◦C, and the stirring was allowed for the next three days. After
that the solvent was removed under vacuo, and the residue was ex-
tracted with ether and kept in a refrigerator (0◦C), whereupon a white
solid was separated out, which was filtered and dried.
2-(N-Alkylthiazol-2ꢀ-ylidenamido)-4-methyl/phenyl-1,3,2-
dioxaphospholanes-2-sulfides (6h–j): General Procedure
A very similar procedure for 6a–g was followed. To the suspension of
N-alkyl-2-aminothiazolium halide (12.4 mmoles) in methylene chloride
(20 mL), at 0–5◦C phosphorus trichloride (12.4 mmoles) was added
followed by dropwise addition of triethylamines (24.8 mmoles), the

Novel Phospholane Heterocycles
1411
resulting mixture was allowed to stir for the next 2–4 hours. After
that sulfur powder (12.4 mmoles) was added to this at room temper-
ature, and the stirring was continued for the next 24 h. After that
triethylamine (24.8 mmoles) was added followed by dropwise addition
of racemic 1,2-propanediol (12.4 mmoles)/1-phenyl-1,2-ethanediol (12.4
mmoles) in methylene chloride at 01–5◦C, and stirring was continued
for the next 3 days, after which the solvent was removed under vacuo,
and the residue was extracted with ether and left in a refrigerator (0◦C).
A white solid was separated out and dried under vacuo.
2-(N-Alkylbenzothiazol-2ꢀ-ylidenamido)-4-methyl/phenyl-
1,2,2-dioxaphospholane (5a–b): General Procedure
To the suspension of N-alkyl-2-aminobenzothiazolium halide (10.3
mmoles) in methylene chloride (20 mL), phosphorus trichloride (10.3
mmoles) was added, followed by a dropwise addition of triethylamine
(20.5 mmoles) at 0–5◦C. After 24 h of stirring, racemic 1,2-propanediol
(10.3 mmoles)/1-phenyl-1,2-ethanediol (10.3 mmoles) in methylene
chloride was added dropwise in the presence of triethylamine (20.5
mmoles) and left for stirring for the next two days. After that the sol-
vent was dried under vacuo and residue was extracted with ether. A
white solid was separated out and dried.
2-(N-Alkylthiazol-2ꢀ-ylidenamido)-4-methyl/phenyl-1,3,2-
dioxaphospholanes (5c–d): General Procedure
To a well-stirred suspension of N-alkyl-2-aminothiazolium halide (12.4
mmoles) in methylene chloride (20 mL), phosphorus trichloride (12.4
mmoles) was added, followed by a dropwise addition of triethylamine
(24.8 mmoles) in methylene chloride (10 mL) at 0–5◦C. The result-
ing mixture was allowed to stirr for 24 h: after that, racemic 1,2-
propanediol (12.4 mmoles)/1-phenyl-1,2-ehtanediol (12.4 mmoles) in
methylene chloride (50 mL) was added dropwise in the presence of tri-
ethylamine (24.8 mmoles) at 0–5◦C, and stirring was continued for the
next two days. After that, the solvent was removed under vacuo, and
residue was extracted with ether and left in a refrigerator. A solid was
separated out, and it was dried.
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V. Kabra et al.
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