Synthesis of functionalized chiral phosphines and chlorothiophosphonates

Article abstract of DOI:10.1080/10426500601096609

N-alkyl-2/4-aminocycloiminium salts of pyridine on reaction with dichlorophenyl-phosphine in the presence of triethylamine generated a novel series of tricoordinated chiral halophosphines, which, through its asymmetric phosphorus atom, induced diastereoto

Full text of DOI:10.1080/10426500601096609

Phosphorus, Sulfur, and Silicon, 182:1093–1102, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601096609
Synthesis of Functionalized Chiral Phosphines and
Chlorothiophosphonates
Vijaya Kabra
Priti Kaushik
Suneeta Ojha
Department of Chemistry, University of Rajasthan, Jaipur, India
N-alkyl-2/4-aminocycloiminium salts of pyridine on reaction with dichlorophenyl-
phosphine in the presence of triethylamine generated a novel series of tricoordinated
chiral halophosphines, which, through its asymmetric phosphorus atom, induced
diastereotopicity in the geminal N-methylene group. Halophosphines have been syn-
thesized as a key precursor, which, in situ converted to stable tetracoordinated
phosphorus by oxidation with elemental sulfur to obtain a new series of synthon
compounds with an active chlorine atom. Chlorothiophosphonates have also ex-
hibited a similar chemical-shift nonequivalence of geminal protons of NCH . These
2
compounds have been used for generation of variety of chiral bisamidothiophospho-
nates and investigated for insecticidal activity against Holotrichia consanguinea
(whitegrub), which is an active pest of the crops of North India.
Keywords Prochirality; diastereotopicity; chlorophophines; chlorothiophosphonates
INTRODUCTION
The rich biological1,2 and synthetic3 profile of phosphorus-containing
chiral compounds has prompted the development of a new strategy for
their synthesis.4−7 Usually halophosphines incorporating a configura-
tionally stable tetrahedral center on the NMR time scale8 served as a
precursor for a catalyst in asymmetric synthesis and biologically ac-
tive molecules. In this study, we report a general synthetic route for a
novel series of functionalized halophosphines and chlorothiophospho-
nates with chiral phosphorus.
Received August 26, 2006; accepted October 11, 2006.
We are thankful to Department of Chemistry, University of Rajasthan, Jaipur, Panjab
University, Chandigarh, and CDRI, Lucknow, for different analysis.
Address correspondence to Vijaya Kabra, Department of Chemistry, University of
Rajasthan, Jaipur, 302 004 India. E-mail: sgkabra@sancharnet.in
1093

1094
V. Kabra et al.
SCHEME 1
RESULTS AND DISCUSSION
N-Alkyl-2-aminopyridinium halides 1, when reacted with dichloro
phenylphosphines (1 equivalent) and Et3N (1 equivalent) in a 2:1
mixture of toluene and methylene chloride, produced N-alkyl-2-
pyridinylidenamino(phenyl) chlorophosphines 2 (Scheme 1).
The products were moisture sensitive and stable only under a dry
1
nitrogen atmosphere, characterized by 31P and H NMR spectroscopy
(Table I). The reaction was monitored through 31P spectroscopy of the
reaction mixture where a signal of the reagents (PhPCl2) at δ 161 ppm
progressively disappeared with the appearance of the signal of products
2 in the range δ 107–123 ppm. This range is in well accordance with tri-
coordinated aminohalophosphines.9,10 These chiral synthons can serve
as good precursors for varities of asymmetric organophosphorus com-
pounds by simple substitution of chlorine by various nucleophiles.
In 1H spectroscopy, interesting nonequivalence of geminal methylene
protons was observed. Each proton appeared as a doublet at δ 4.25–
4.63 and 4.35–4.75 ppm due to geminal coupling (2 JHH= 15.0–17.0 Hz).
This unique phenomenon has been observed by different workers also
in chiral phosphorus derivatives.11,13 This anisochronous behavior of
methylene protons was due to a generated chiral phosphorus center
during phosphorylation, which was five bonds apart from the prochiral
carbon atom.
Halophosphines 2, on reaction with elemental sulfur in methy-
lene chloride, furnished another series of asymmetric active chlorine-
containing chlorothiophosphonates 3 (Scheme 2), which were stable
white to light-yellow colored crystalline solids and were characterized

1095

1096

Chiral Phosphines and Chlorothiophosphonates
1097
SCHEME 2
by elemental analysis, 31P, 1H, (Table I) and 13C NMR; and mass spec-
troscopy. Here, the phenomenon of diastereotopicity can also be ob-
served for NCH2 protons in 1H spectrum, which gave two doublets due
to geminal coupling in the range δ 4.65–4.72 and 4.91–5.02 ppm with
coupling constant (2 JHH= 15.0–17.0 Hz).
These stable active chlorine-containing chiral synthons obtained as
the racemic mixture also can act as precursors for various chiral thio-
phosphonates via substitution through different nucleophiles.
Further confirmation of 3b has been done by 13C NMR. The ipso-
carbon of the phenyl group attached to phosphorus showed a doublet
with a high coupling constant in the range (1 J = 213.7 Hz) due to a
CP
nearby electronegative chlorine atom14 (Table II).
TABLE II Mass Spectrum and 13C NMR data of 3b
Compound
m/z (%)
δ (ppm) J (Hz)
3b
354 (M+, 22); 356 (M+2, 7); 320
(6); 321 (10); 181 (100); 165 (10);
163 (73); 136 (56); 135 (53); 107
(22)
14.5 (OCH2CH3); 53.0 (NCH2);
62.3 (OCH2CH3); 110.2 (C-5);
120.0 (d, 2
128.0 (d, 3
J
= 12.1 Hz, C-3);
CP
J
= 16.2 Hz,
CP
C
meta ); 130.0 (Cpara);130.5 (d,
2 J = 12.4 Hz, Cortho ); 139.6
CP
(C-4); 140.6 (C-6); 140.7
(d, 1
J
= 213.7 Hz, Cipso,);
CP
157.5 (d, 2
J
CP
= 11.3 Hz, C-2);
160 (C=O)
Relative abundances have been given in parentheses.

1098
V. Kabra et al.
SCHEME 3
Mass spectrum of N-(2-ethoxy-2-oxoethyl)-2-pyridinylidenamido
(phenyl)chloro thiophosphonate 3b has been shown in Table II. The
molecular ion peak appeared at m/z 354 with 22% abundance together
with an M+2 peak at m/z 356 approximately one-third of the intensity
of the molecular ion peak (7%) because of the presence of 37Cl isotope,
which further splitted in a different ion peak at m/z 320, 321, 181, 136,
135, 107, 165, and 163. A base peak was found at m/z 181 with 100%
abundance.
Similarly, N-alkyl-4-aminopyridinium halides 4 yielded the cor-
responding N-alkyl-4-pyridinylidenamido(phenyl) chlorothiophospho-
nate 5 (Scheme 3). As expected, in this compound geminal protons of
N-methylene groups were equivalent because the stereogenic phospho-
rus centre is very far away (Table I); hence, we observed a singlet for
N-methylene protons in the region δ 2.37 ppm.
INSECTICIDAL ACTIVITY
As reported by Hartly,15 chirality enchances the bioactivity of the com-
pounds; asymmetrical chlorothiophosphonates 3a–d were also found
to be active against whitegrubs Holotrichia consanguinea (Coleoptera:
Scarabacidae) when subjected to insecticidal activity by the soil drench-
ing method.16 The first instar stage of whitegrub at 50-ppm v/v dose
has been selected for this study. Percent mortality of the insect in each
replicate was calculated by counting the number of dead insects. The
percentage figures then converted to the angular transformed values,

Chiral Phosphines and Chlorothiophosphonates
1099
TABLE III Percent Mortality of First Instar Holotrichia
consanguinea Grubs 2, 6, and 10 Days After the Treatment by the Soil
Drenching Method
Percent Mortality
Days After Treatment
S. No
Treatments
N-(2-Methoxy-2-
2 Days
6 Days
10 Days
3a
32.50
45
70
-oxoethyl)-2-pyridinyliden-
amido(phenyl)chlorothiophosphonates
N-(2-Ethoxy-2-oxoethyl)-
2-pyridinyliden-
amido(phenyl)chlorothiophosphonates
N-Methyl-2-
(34.71)
(42.05)
(56.97)
3b
3c
30
(33.05)
37.50
(37.72)
62.50
(52.27)
15
25
42.50
pyridinylidenamido(phenyl)
chloroth-
(22.50)
(29.88)
(40.67)
iophosphonates
3d
N-Benzyl-2-
25
32.50
55
pyridinylidenamido(phenyl)
chlorothiophosphonates
Control
(32.38)
(34.71)
(47.88)
0.00
4.32
13.00
0.00
2.12
6.36
0.00
5.60
7.13
Standard Error Mean
.
Critical Difference at 5 %
FIGURE 4 Percent mortality of first instar Holotrichia consanguinea grubs 2,
6, and 10 days after the treatment.

1100
V. Kabra et al.
which have been subjected to a complete randomized technique17 (Table
III and Figure 1).
CONCLUSION
The present work evolved an economical synthetic strategy for few
chiral molecules. Furthermore, insecticidal analysis showed that com-
pounds 3a and 3b, having electron-withdrawing (phenyl and ester)
groups in the vicinity of a phosphorus atom, were found to be best
with 56.97% and 52.27% grub mortality. Compound 3d was observed
with 47.88% mortality. 3c with 40.67% was found to be inferior to the
other three compounds. In the control, there was no grub mortality.
These results confirmed the previous reported18 finding that bulky and
electron-withdrawing substituent enhance the bioactivity, and hence
3a, 3b, and 3d were found to be superior in insecticidal activity.
EXPERIMENTAL
All experiments were performed in an atmosphere of dry nitrogen using
schlenk technique. Solvents were distilled and dried by common meth-
ods before use. The melting points were determined on an electric tempo
instrument by the capillary method. All the glasswares were dried in
an electric oven at a high temperature for 2–3 h. 31P NMR spectra were
recorded on an FT NMR spectrometer Jeol AL 300 at 121.50 MHz (obset
156 KHz), 1H NMR were recorded on Jeol AL 300 at 300.40 MHz (obset
130 KHz), and 13C NMR spectra were recorded on Jeol FT NMR sys-
tem AL 300 at 75.45 MHz (obset 124 KHz). Elemental analyses were
carried out on a Heraeus Carlo Erba 1108 analyzer. FAB mass spec-
trum was recorded on a Jeol SX 102/DA–6000 mass spectrometer/data
system using Argon/Xenon (6 KV, 10 mA) as the FAB gas.
N-Alkyl-2-pyridinylidenamino(phenyl)chlorophosphines
(2a–c): General procedure
To a well-stirred suspension of N-alkyl-2-aminopyridinium halides
(3.81 g, 15 mmoles) in toluene (10 mL) was added triethylamine
(4.29 mL, 30 mmoles) with stirring at 0–5◦C. A solution of
dichlorophenylphosphines (2.12 mL, 15 mmoles) in a mixture 2:1 of
toluene and methylene chloride (30:15 mL) was added dropwise with
constant stirring. After stirring for 2–3 days at r.t., the reaction mixture
was filtered, and the solvent was removed from the filterate under re-
duced pressure. The residue thus obtained was extracted with diethyl

Chiral Phosphines and Chlorothiophosphonates
1101
ether (2 × 50 mL). Combined ethereal extracts were concentrated up
to 30% and left in a refrigerator, whereupon a white solid deposited,
which was filtered, dried, and recrystallized from methylene chloride.
N-Alkyl-2/4-pyridinylidenamido(phenyl)chlorothio
phosphonates (3a–d and 5a) General procedure
N-alkyl-2/4-aminocycloiminium halides (3.81 g, 15 mmoles) was sus-
pended in toluene (10 mL), and triethylamine (4.29 mL, 30 mmoles)
was added slowly with stirring at 0–5oC , followed by a solution of
dichlorophenylphosphines (2.12 mL, 15 mmoles) in a mixture 2:1 of
toluene and Methylene chloride (30:15 mL), which was added dropwise
with constant stirring. After 2 h. of stirring, the reaction mixture was
brought to r.t., and sulfur powder (0.49 g, 15 mmoles) was added to
it. The resulting mixture was left for 2–3 days and then was filtered,
and solvent was removed from the filterate in vacuo. The residue thus
obtained was extracted with diethyl ether (2 × 50 mL). Combined ethe-
real extracts were concentrated up to 30% and left in a refrigerator,
whereupon a white to light-yellow solid deposited, which was filtered,
dried, and recrystallized from methylene chloride.
BIOACTIVITY
A dose of 5 kg/hectare was computed for soil bioassay. 50 cc (∼60 g) of
air-dried soil was taken in each plastic container (length = 8 cm and
diameter = 5 cm) with 12 mL of stock solution (75 mg of compound dis-
solved in little quantity of acetone and diluted with 120 mL of water). In
these containers one test grub was introduced with some millet roots.
For control, (soil, water, and acetone mixture) grub and millet root have
been taken. Ten such replicates were prepared for each compound, and
percent mortality of the insect in each replicate was calculated. The per-
centage figures were then converted to the angular transformed values,
which were subjected to the statistical analysis of Completely Random-
ized Design (CRD) technique.17
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