Synthesis and bioactivity of 6-bromo-2-(substituted)-3-(1-phenyl-ethyl)- 3,4-dihydro-1H- isophosphinoline 2-chalcogenides

Article abstract of DOI:10.1002/jhet.5570450319

(Chemical Equation Presented) Synthesis of 6-bromo-2-(substituted)-3-(1- phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-chalcogenides derivatives (6) were synthesized from 2-[(1-phenylethylamino)methyl]-4-bromophenol (1) by reaction with aryl/alkyl phosphoro dichloridates (2) in the presence of triethylamine at 55°C to 60°C to obtained the title compounds (6a-g). The title compounds (6h-j), were prepared via intermediate route. Few other title compounds (8a-c) were accomplished through a two step synthetic route involving 1 with dichlorophenyl phosphine (2a) and dichloroethyl phosphine (2a,b) in the presence of triethylamine in dry toluene under N₂ atmosphere to form the corresponding trivalent phosphorus intermediate (7). In the second step they were further converted to the corresponding chalcogenides 8a-c by reaction with hydrogen peroxide, sulfur and selenium respectively. They exhibited significant antibacterial, fungal and insecticidal activity.

Full text of DOI:10.1002/jhet.5570450319

May-Jun 2008
751
Synthesis and Bioactivity of 6-Bromo-2-(Substituted)-3-(1-Phenyl-
ethyl)- 3,4-Dihydro-1H- Isophosphinoline 2-Chalcogenides
K. Srinivasulua, B. Hari Babua, K. Suresh Kumara, C. Bhupendra Reddya, C. Naga Rajua*
and D. Roobab
aDepartment of Chemistry, Sri Venkateswara University, Tirupati-517502. India
bDepartment of Botany, Pachaiyappa's College, Madras University, Chennai-600001 India
e-mail: naga_raju04@yahoo.co.in
Received June 13, 2007
O
O
O
OH
H
O
O
P
R
P Cl
Cl2PR
(2)
POCl3 (3)
NH
CH3
Br
N
N
Toluene, Et3N
Br
Br
Toluene, Et3N
H
CH3
H
CH3
(1)
(4)
(6a-j)
55-60oC, N2
Toluene, Et3N, R-H (5),
X
P R
N
O
H
O
P R
H2O2/ S/ Se
Cl2PR (2a)
(1)
N
Br
Br
Toluene, Et3N
55-60oC, N2
CH3
H
CH3
(7)
(8a-c)
Synthesis of 6-bromo-2-(substituted)-3-(1-phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-chalco-
genides derivatives (6) were synthesized from 2-[(1-phenylethylamino)methyl]-4-bromophenol (1) by
reaction with aryl/alkyl phosphoro dichloridates (2) in the presence of triethylamine at 55°C to 60°C to
obtained the title compounds (6a-g). The title compounds (6h-j), were prepared via intermediate route.
Few other title compounds (8a-c) were accomplished through a two step synthetic route involving 1 with
dichlorophenyl phosphine (2a) and dichloroethyl phosphine (2a,b) in the presence of triethylamine in dry
toluene under N2 atmosphere to form the corresponding trivalent phosphorus intermediate (7). In the
second step they were further converted to the corresponding chalcogenides 8a-c by reaction with
hydrogen peroxide, sulfur and selenium respectively. They exhibited significant antibacterial, fungal and
insecticidal activity.
J. Heterocyclic Chem., 45, 75751 (2008).
INTRODUCTION
(2) in equimolar quantities in the presence of
triethylamine in dry toluene at 55-60°C produced the title
compounds (6a-g) (Scheme 1). The title compounds 6h-j
were prepared through intermediate (4). The reaction of
(1) with phosphorus oxychloride (3) in the presence of
triethylamine which was further treated with 4-
bromophenol, 1-phenylethylamine and indole to get 6h-j.
A few of the title compounds such as oxide, sulfide,
selenide (8a-c) were prepared through a two step synthetic
route involving (1) with dichlorophenyl phosphine in the
presence of triethylamine in dry toluene to form the
corresponding trivalent phosphorus intermediate (7), it
was further converted to the corresponding chalcogenides
by reaction with hydrogen peroxide, sulfur and selenium
respectively, under reflux conditions in the same vessel
(Scheme 2). In all the reactions, the title compounds
separated by removing the solvent from the filtrate. The
crude products were purified by recrystallization from
methanol, and characterized by elemental analysis, IR, 1H,
13C and 31P NMR and mass spectral data. [5-6] Reaction
yields, melting points, IR, 31P NMR data of (6a-j), (8a-c),
Discovery of an effective, target specific and eco-
friendly pesticides is an ever-persuing endeavor since
quality pesticides are required for crop protection, food
production and preservation. Pesticides currently in use
not only strike the targeted pest species but also affect the
non-target species and the environment. Polyhalogenated
hydrocarbon pesticides are banned due to their non-
biodegradability and toxic residues [1]. The phenolic
compounds are well-known bactericides and fungicides,
their use is restricted only to soil due to phytotoxicity [2].
Phosphorylation of phenols and amines with appropriate
phosphorus reagent has reduced their toxicity and
enhanced their bio-activity. Scientists were successful in
developing some organophosphorus systemic [3]
insecticides (e.g. Schradan), antibiotics [4] (e.g.
Phosfomycin, Phosfadecin), antiviral (Foscarnet) and
anticancer agents (Cyclophosphamide).
RESULTS AND DISCUSSION
Condensation of 2-[(1-phenylethylamino)methyl]-4-
bromophenol (1) with phenylphosphorodichloridates [5]
1
elemental analysis for (6a-j), (8a-c), H NMR data for

752
K. Srinivasulu, B. Hari Babu, K. Suresh Kumar, C. Bhupendra Reddy, C. Naga Raju and D. Rooba
Vol 45
(6a-j), (8a-c) and 13C NMR for (6a-h), (8a-c) and MS
data for (6a), (6b), (6g), (6i), (6j), (8b) and (8c) are
recorded.
The compounds (6a-j), (8a-c) showed absorption bands
in the region 3251, 1297-1202, 994-937, 1186-1167, 776,
632 cm-1 for P-NH, P=O, P-O and O-C of P-O-Carom and
P=S, P=Se respectively. [6]
The aromatic protons of (6a-j), (8a-c) resonated as
multiplets in the region δ 8.26-6.51. The proton attached
to the exocyclic chiral methine carbon exhibited a quartet
at δ 5.41-5.01 due to its coupling with the methyl group
attached to the same carbon. The C-4 methylene protons
resonated as multiplet at δ 4.37-4.04 indicating their non-
equivalence and coupling with phosphorus in the six
membered chair conformation of the isophosphinoline
2-oxide system.
ion in the expected ratio agreed well with the presence of
one bromine atom in the compound. [9]
Expulsion of C15H13BrNO3 radical from M+• formed the
ion at m/z 154 (100) as a base peak. The ions at m/z 383
(13), 289 (28), 105 (20) and 91 (11) were also observed in
the mass spectrum of 6a. The mass spectral data of the
representative compounds exhibited [M+2]+, M+. and ions
with substituted isophosphinoline moieties at appropriate
m/z values. Their mass spectral behavior is well in
agreement with that of similar organophosphorus (OP)
compounds [10-11].
Thus, the combined analytical, IR, NMR and mass
spectral data conclusively agreed with the proposed
structures for the title compounds (6a-j), (8a-c)
CONCLUSION
The 13C NMR spectra were recorded for 6a-h, and 8a-c.
13C NMR chemical shifts were interpreted based on the
additivity rules, coupling with phosphorus and intensity of
signals [7,9]. The endocyclic oxygen bonded to C-9, gave
signals as a doublet at δc 153.01-151.14 (J = 8-9 Hz). The
chiral carbon resonated as a doublet due to coupling with
phosphorus in the region δc 41.6-45.9 (d, J= 7.0-7.7 Hz).
The methylene carbon (C-4) gave signal in the region δc
48.5-54.4. The methyl carbon which is linked to the chiral
carbon resonated in the region δc 16.5-18.2.
In conclusion, we have evolved an effective and simple
route for the synthesis of novel Phenyl phos–phoro–
dichloridates linked Isophosphinoline 2-chalcogenides,
whose structures were supported by elemental and
spectral analyses. The reaction can be performed
smoothly in dry toluene in the presence of a base and the
products are relatively easy to isolate and purify. The
possible advantages of these new phosphorus heterocycles
are that they may be used as potential antibacterial fungal
and insecticides.
The 13C NMR chemical shifts for C-5 to C-10, C-1' to
C6' and C-1” to C-6” were observed in the expected range
[7]. The 31P NMR chemical shifts of compounds 6a-j
were observed in the region δp -3.65 to -4.63 other
compounds 8a-c, gave signals at 12.08, 78.04 and 89.19
respectively depending on the atoms present near
phosphorus. The observed chemical shifts are in
agreement with the literature values. [8]
EXPERIMENTAL
Melting points were determined in open capillary tubes on a
Mel-temp apparatus and are uncorrected. Microanalysis was
performed at Central Drug Research Institute, Lucknow, India
and Environmental Engineering Lab, S. V. University, Tirupati.
IR spectra were recorded as KBr pellets on a Perkin - Elmer 283
1
spectrophotometer. H and 13C NMR spectra were recorded on a
The compound 6 exhibited M+• ion at m/z 489 with 71
per cent intensity. Appearance of isotopic peak as M+• +2
Bruker AMX- 400 MHz spectrometer operating at 400 MHz for
1H and 100 MHz for 13C, and 161.9 MHz for 31P using
Scheme 1
O
O
O
O
OH
O
P
R
P Cl
(2)
Cl2PR
POCl3 (3)
NH
CH3
Br
N
N
Toluene, Et3N
Br
H
Br
Toluene, Et3N
H
CH3
H
CH3
(1)
(4)
(6a-j)
55-60oC, N2
Toluene, Et3N, R-H (5),
Scheme 2
X
O
H
O
P
R
P
N
R
H2O2/ S/ Se
Cl2PR (2a)
N
(1)
Br
Br
Toluene, Et3N
55-60oC, N2
CH3
H
CH3
(7)
(8a-c)
Compd.
R
Compd.
R
Compd.
R
Compd.
X
6g
6h
6i
4''-CH3CH2O
4''-BrC6H4O
C6H5(CH)CH3NH
C8H8N
8a
8b
8c
O
S
Se
6a
6b
6c
4''-NO2C6H4O
C6H5O
(ClCH2CH2)2N
6d
6e
6f
4''-ClC6H4O
2''-ClC6H4O
4''-CH3C6H4O
6j

May-Jun 2008
6-Bromo-2-(Substituted)-3-(1-Phenyl-ethyl)- 3,4-Dihydro-1H-Isophosphinoline 2-Chalcogenides
753
deuterochloroform. The 1H and 13C chemical shifts were
referenced to TMS and 31P chemical shifts to 85% H3PO4 (ortho-
phosphoric acid). FAB-Mass spectra were recorded on a Jeol SX
102 DA / 600 Mass spectrometer using Argon / Xenon (6 kV, 10
mA) as the FAB gas.
Compounds 8b-c were prepared by adopting the above
procedure.
Physical, Analytical and Spectral Data for the test
Compounds (6a-j), (8a-c).
Synthesis of 6-bromo-2-(Nitrophenoxy)-3-(1-phenyl-ethyl)-
3,4-dihydro-1H-isophosphinoline 2-oxide (6a). 4-Nitrophenyl
phosphorodichloridate (2) 0.51 g (2.0 mmole) in dry toluene (10
mL) was added dropwise to a stirred solution of (1) 0.61 g (2.0
mmole) and triethylamine 0.40 g (4.0 mmole) in 20 mL of dry
toluene at 0°C during 20 min. After the completion of the
addition, the reaction temperature was slowly raised to 55-60°C
and was maintained at this temperature for 5 h. Progress of the
reaction was monitored by TLC using hexne-ethyl acetate (3:1) as
mobile phase on silica gel (adsorbent). On separation of the
triethylamine hydrochloride by filtration, and evaporation of the
filtrate under reduced pressure, a solid residue was obtained. It
was washed with water and recrystallised from methanol to obtain
yield the compound 6a yield 0.66g (67.4%). mp. 148-150 °C.
Compounds 6b-g were prepared by adopting the above
procedure.
Characterization of 6-bromo-2-(4-nitrophenoxy)-3-(1-
phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6a)
yield 0.66g (66.8%). mp 148-150 °C. IR(KBr): νmax (cm-1), P=O
1277, P-O 941, O-C 1180. 31P NMR (CDCl3, 161.9 MHz) δ: -
4.45. 1H NMR (CDCl3, 400 MHz) δ: 8.26-6.84 (m, 12H, Ar-H),
4.01-3.81 (m, 2H, -CH2-), 5.32-5.15 (m, 1H, CH), 1.65 (d, J =
6.9 Hz, 3H, CH3). 13C NMR (CDCl3 100 MHz) δ: 53.8 (C-4),
132.2(C-5), 116.2 (C-6), 132.2 (C-7), 139.5 (C-8), 150.9 (d, 2J(P-
O-C endo)= 8.2 Hz, C-9), 124.0 (C-10), 121.3 (C-1'), 128.7 (C-2'&
C-6'), 128.3 (C-3'&C-5'), 127.1 (C-4'), 156.1 (C-1''), 120.2 (C-
2''), 124.1 (C-3''), 141.2 (C-4''), 124.1 (C-5''), 141.2 (C-6''), 42.9
(2Jpc= 7.4 Hz, C-CH3), 16.7 (C-CH3). FAB-MS m/z (%) : 491
[(77), M+ +2], 489 [(71), M+], 383 (13), 307 (46), 289 (28), 204
(8), 154 (100), 136 (52), 105 (20), 91(11). Anal. Calcd for
C21H18BrN2O5P: C 51.53, H 3.71, N 5.72; Found: C 51.61, H
3.65, N 5.70%.
Synthesis of the compounds 6h, through an intermediate
(4), 6-bromo-2-(chloro)-3-(1-phenyl-ethyl)-3,4-dihydro-1H-
isophosphinoline 2-oxide. A solution of phosphorus oxy-
chloride (3) 0.30 g (2.0 mmole) in 10 mL of dry toluene was
added drop wise to a stirred solution of (1) 0.61 g (2.0 mmole)
and triethylamine 0.40 g (4.0 mmole) in 20 mL of dry toluene at
0°C over a period of 30 min. After stirring for 4 h at 50-55°C,
formation of the intermediate 6-bromo-2-(chloro)-3-(1-phenyl-
ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (4) was ascer-
tained by TLC analysis. To the cooled (0-5°C) solution of (4) in
the same vessel additional quantity of triethylamine (2.0 mmole)
in 20 mL of dry toluene followed by 4-bromophenol/1-phenyl-
ethylamine/ indole (5) (2.0 mmole) in 20 mL of dry toluene
were added. The reaction mixture was stirred for 1 h at room
temperature and then for 4 h at 50-60°C. Progress of the reaction
was monitored by TLC. Triethylamine hydrochloride was
separated by filtration and the solvent was removed from the
filtrate in a rota-evaporator. The residue after washing with
water and recrystallisation from methanol afforded the
compounds, 6h respectively.
Characterization of 6-bromo-2-(phenoxy)-3-(1-phenyl-
ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6b) yield
0.69g (77.7%). mp 68-70 °C. IR(KBr): νmax (cm-1), P=O 1284, P-O
942 ,O-C 1183. 31P NMR (CDCl3, 161.9 MHz) δ: -4.18. 1H NMR
(CDCl3, 400 MHz) δ: 7.37-6.83 (m, 13H, Ar-H), 4.31-4.14 (m,
2H, -CH2-), 5.29-5.12 (m, 1H, CH), 1.61 (d, J = 6.8 Hz, 3H,
CH3). 13C NMR (CDCl3, 100 MHz) δ: 51.3 (C-4), 132.6 (C-5),
2
117.1 (C-6), 133.2 (C-7), 138.1 (C-8), 151.1 (d, J(P-O-C endo)= 8.1
Hz, C-9), 124.2 (C-10), 120.2 (C-1'), 128.4 (C-2'& C-6'), 128.1
(C-3'&C-5'), 126.1 (C-4'), 148.1 (C-1''), 129.1 (C-2''&C-6''),
128.9 (C-3''&C-5''), 125.0 (C-4''), 43.2 (2Jpc= 7.0 Hz, C-CH3),
17.1 (C-CH3). FAB-MS m/z(%): 446 [(80), M+ +2], 444 [(88),
M+], 340 (91), 306 (22), 202 (5), 154 (13), 105 (100), 102 (83).
Anal. Calcd for C21H19BrNO3P: C 56.77, H 4.03, N 3.15; Found:
C 56.83, H 4.09, N 3.21%.
Characterization of 6-bromo-2-(Bis-(2”-chloroethylam-ine)-
3-(1-phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide
(6c) yield 0.68g (69.5%). mp 97-99 °C. IR(KBr): νmax (cm-1), P=O
1273, P-O 982, O-C 1179. 31P NMR (CDCl3, 161.9 MHz) δ:
-4.88. 1H NMR (CDCl3, 400 MHz) δ: 7.87-6.51 (m, 8H, Ar-H),
4.62-4.42 (m, 2H, -CH2-), 5.32-5.10 (m, 1H, CH), 1.71 (d, J =
6.5, 3H, CH3), 4.37-4.11(m, 4H, NCH2), 3.30-3.27 (m, 4H, CH2
Cl). 13C NMR (CDCl3 100 MHz) δ: 52.9 (C-4), 129.0 (C-5),
Compounds 6i-j were prepared by adopting the above
procedure.
Synthesis of compound 8a. The compounds 8a were
prepared through a two step synthetic route. dichlorophenyl
phosphine (2a) 0.35 g (2.0 mmole) in dry toluene (10 mL) was
added drop wise to a stirred solution of (1) 0.61 g (2.0 mmole)
and triethylamine 0.40 g (4.0 mmole) in 20 mL of dry toluene at
0°C during 20 min under N2 atmosphere. After completion of the
addition, the reaction temperature was slowly raised to 55-60°C
and was maintained at this temperature for 4 h with stirring. The
completion of the reaction was monitored by TLC. After
completion of the reaction, the solid triethylamine hydrochloride
was removed by filtration, the filtrate contains trivalent
phosphorus intermediate (7), it was further converted to the
corresponding chalcogenides without isolation by reacting it
with hydrogen peroxide at 5 °C. After completion of the
addition, the temperature was raised to 50-60 °C and maintained
for 3 h with stirring. After completion of the reaction and on
evaporation of the filtrate using a rota-evaporator, a solid residue
was obtained. It was washed with water and recrystallised from
methanol to yield the title compounds 8a.
2
122.2 (C-6), 127.4 (C-7), 117.5 (C-8), 156.0 (d, J(P-O-C endo)= 8.3
Hz, C-9), 122.6 (C-10), 123.2 (C-1'), 128.5 (C-2'& C-6'), 128.2
(C-3'&C-5'), 129.1 (C-4'), 65.2 (s, 2C, C-1''), 43.2 (s, 2C, C-2''),
44.3 (2Jpc= 7.2 Hz, C-CH3), 17.8 (C-CH3). Anal. Calcd for C19
H22BrCl2N2O2P: C 46.36, H 4.50, N 5.69; Found: C 46.41, H
4.56, N 5.75%.
Characterization of 6-bromo-2-(4-chlorophenoxy)-3-(1-
phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6d)
yield 0.75g (78.4%). mp 95-97 °C. IR(KBr): νmax (cm-1), P=O
1297, P-O 973, O-C 1186. 31P NMR (CDCl3, 161.9 MHz) δ:
-4.19. 1H NMR (CDCl3, 400 MHz) δ: 7.42-6.84 (m, 12H, Ar-H),
4.29-4.16 (m, 2H, -CH2-), 5.30-5.17 (m, 1H, CH), 1.64 (d, J =
7.0 Hz, 3H, CH3). 13C NMR (CDCl3 100 MHz) δ: 53.1 (C-4),
128.1 (C-5), 123.2 (C-6), 127.0 (C-7), 116.1 (C-8), 152.9 (d,
2J(P-O-C endo)= 8.7 Hz, C-9), 123.2 (C-10), 119.3 (C-1'), 128.1 (C-
2'& C-6'), 128.1 (C-3'&C-5'), 126.0 (C-4'), 146.1 (C-1''), 118.3
(C-2''), 130.1 (C-3''), 120.0 (C-4''), 131.1 (C-5''), 116.1 (C-6''),
41.6 (2Jpc= 7.7 Hz, C-CH3), 16.9 (C-CH3). Anal. Calcd for

754
K. Srinivasulu, B. Hari Babu, K. Suresh Kumar, C. Bhupendra Reddy, C. Naga Raju and D. Rooba
Vol 45
C21H18BrClNO3P: C 52.69, H 3.78, N 2.63; Found: C 52.75, H,
3.73, N 2.70%.
MHz) δ: -3.65. 1H NMR (CDCl3, 400 MHz) δ: 7.60-6.72
(m,13H, Ar-H), 4.25-4.15 (m, 2H, -CH2-), 5.34-5.12 (m, 1H,
CH), 1.55 (d, J = 7.0 Hz, 3H, CH3), 3.65 (d, J = 8.0 Hz, 1H, -
NH-), 4.56-4.46 (m1H, CH), 1.68 (d, J = 6.0 Hz 3H, CH3).
FAB-MS m/z (%):473 [(83), M+ +2], 471 [(86), M+], 408
(27), 365 (16), 306 (61), 210 (30), 202 (8), 148 (30), 136 (13),
105 (100), 91 (11). Anal. Calcd for C23H24BrN2O2P: C, 58.64, H
5.13, N 5.94; Found: C 58.70, H 5.19, N 5.87%.
Characterization of 6-bromo-2-(4-indole)-3-(1-phenyl-
ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6j) yield
0.67g (71.7%). mp 135-137 °C. IR(KBr): νmax ( cm-1), P=O 1243,
P-O 956, O-C 1180. 31P NMR (CDCl3, 161.9 MHz) δ: -3.77. 1H
NMR (CDCl3, 400 MHz) δ: 7.64-6.87 (m, 14H, Ar-H), 4.29-4.13
(m, 2H, -CH2-), 5.21-5.02 (m, 1H, CH), 1.68 (d, J = 6.9 Hz, 3H,
CH3). FAB-MS m/z (%): 469 [(30), M+ +2], 467 [(33), M+],
386 (75), 325 (11), 307 (19), 282 (13), 154 (58), 136 (41), 105
(100) Anal. Calcd for C23H20BrNO2P: C 59.11, H 4.31, N 5.99;
Found: C 59.20, H 4.25, N 5.92%.
Characterization of 6-bromo-2-(2-chlorophenoxy)-3-(1-
phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6e)
yield 0.73g (76.3%). mp 78-81 °C. IR(KBr): νmax (cm-1), P=O 1287,
P-O 959, O-C 1185; 31P NMR (CDCL3, 161.9 MHz) δ: 1.82. 1H
NMR (CDCl3, 400 MHz) δ: 7.41-6.74 (m, 12H, Ar-H), 4.20-4.04
(m, 2H, -CH2-), 5.32-5.02 (m, 1H, -CH), 1.60 (d, J = 5.9 Hz, 3H,
CH3). 13C NMR (CDCL3 100 MHz) δ: 52.1 (C-4), 128.0 (C-5),
124.3 (C-6), 127.1 (C-7), 117.2 (C-8), 156.0 (d, 2J(P-O-C endo)= 9 Hz,
C-9), 125.0 (C-10), 121.2 (C-1'), 128.1 (C-2'& C-6'), 128.1 (C-
3'&C-5'), 122.1 (C-4'), 153.0 (C-1''), 125.2 (C-2''), 132.0 (C-3''),
121.3 (C-4''), 135.2 (C-5''), 117.3 (C-6''), 45.9 (2Jpc= 7.5 Hz,
C-CH3), 20.5 (C-CH3). Anal. Calcd for C21H18BrClNO3P: C
52.69, H 3.78, N 2.63; Found: C 52.76, H 3.74, N 2.69%.
Characterization of 6-bromo-2-(4-methylphenoxy)-3-(1-
phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6f)
yield 0.65g (70.9%). mp 98-100 °C. IR(KBr): νmax (Cm-1), P=O
1293, P-O 956, O-C 1169. 31P NMR (CDCl3, 161.9 MHz) δ:
-4.19. 1H NMR (CDCl3, 400 MHz) δ: 7.70-7.20 (m, 12H, Ar-H),
4.23-4.10 (m, 2H, -CH2-), 5.25-5.12 (m, 1H, CH), 1.71 (d, J =
6.2 Hz, 3H, CH3), 2.12-2.20 (s, 3H, 4''-CH3). 13C NMR (CDCl3
100 MHz) δ: 48.5 (C-4), 129.0 (C-5), 121.2 (C-6), 127.7 (C-7),
Characterization
ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (8a) yield
0.54g (63%). mp 140-142 °C. IR(KBr): νmax (cm-1), P=O 1202. 31
of
6-bromo-2-(phenyl)-3-(1-phenyl-
P
NMR (CDCl3, 161.9 MHz) δ: 12.08. 1H NMR (CDCl3, 400 MHz)
δ: 7.82-6.86 (m, 13H, Ar-H), 4.27-4.15 (m, 2H, -CH2-), 5.30-
5.12 (m, 1H, CH), 1.42 (d, J = 6.2 Hz, 3H, CH3). 13C NMR
(CDCl3 100 MHz) δ: 54.4 (C-4), 132.3 (C-5), 120.1 (C-6), 132.3
(C-7), 133.8 (C-8), 156.6 (C-9), 125.0 (C-10), 122.3 (C-1'),
128.6 (C-2'& C-6'), 128.1 (C-3'&C-5'), 126.1 (C-4'), 140.1 (C-
1''), 130.2 (C-2''&C-6''), 128.3 (C-3''& C-5''), 132.0 (C-4''), 42.4
(C-CH3), 16.9 (C-CH3). Anal. Calcd for C21H19BrNO2P: C 58.89,
H 4.46, N 3.27; Found: C 58.96, H 4.41, N 3.33%.
2
115.7 (C-8), 150.4 (d, J(P-O-C endo)= 8.5 Hz, C-9), 125.0 (C-10),
121.3 (C-1'), 128.8 (C-2'& C-6'), 128.3 (C-3'&C-5'), 122.0 (C-
4'), 153.2 (C-1''), 116.3 (C-2''), 130.2 (C-3''), 132.1 (C-4''), 132.1
(C-5''), 116.3 (C-6''), 22.9 (Ar-CH3), 41.6 (C-CH3), 20.0 (C-
CH3). Anal. Calcd for C22H21BrNO3P: C 57.66, H 4.61, N 3.06;
Found: C 57.71, H 4.58, N 3.12%.
Characterization
of
6-bromo-2-(ethoxy)-3-(1-phenyl-
ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6g) yield
0.54g (68.1%). mp 87-89 °C. IR(KBr): (cm-1), P=O 1252, P-O 994,
Characterization
of
6-bromo-2-(phenyl)-3-(1-phenyl-
ethyl)-3,4-dihydro-1H-isophosphinoline 2-sulfide (8b) yield
0.6g (67.5%). mp 130-132 °C. IR(KBr): νmax (cm-1), P=S 776. 31P
NMR (CDCl3, 161.9 MHz) δ: 78.04. 1H NMR (CDCl3, 400 MHz)
δ: 7.80-6.69 (m, 13H, Ar-H), 4.30-4.18 (m, 2H, -CH2-), 5.21-
5.10 (m, 1H, CH), 1.52 (d, J = 6.5 Hz, 3H, CH3). 13C NMR
(CDCl3 100 MHz) δ: 54.4 (C-4), 132.3 (C-5), 120.1 (C-6), 132.3
(C-7), 133.8 (C-8), 156.6 (d, 2J(P-O-C endo)= 8.8 Hz, C-9), 125.0 (C-
10), 122.29 (C-1'), 128.4 (C-2'& C-6'), 128.2 (C-3'&C-5'), 127.5
(C-4'), 140.1 (C-1''), 132.2 (C-2''&C-6''), 128.3 (C-3''& C-5''),
132.0 (C-4''), 42.4 (C-CH3), 16.9 (C-CH3). FAB-MS
m/z(%):446 [(94), M+ +2], 444 [(100), M+], 430 (11), 412 (19),
368 (8), 340 (83), 307 (16), 289 (13), 258 (38), 154 (50), 105
(75), 120 (8), 91 (11). Anal. Calcd for C21H19BrNOPS: C 56.76,
H 4.30, N 3.15; Found: C 56.81, H 4.34, N 3.23%.
1
O-C 1167. 31P NMR (CDCl3, 161.9 MHz) δ: -4.63. H NMR
(CDCl3, 400 MHz) δ: 7.84-6.79 (m, 8H, Ar-H), 4.37-4.24 (m,
2H, CH2), 5.30-5.10 (m, 1H, CH), 1.48 (d, J = 6.6 Hz, 3H, CH3),
3.57-3.40 (m, 2H, -CH2-), 1.90-1.50 (m, 3H, CH3). 13C NMR
(CDCl3 100 MHz) δ: 52.8 (C-4), 129.4 (C-5), 120.3 (C-6), 128.4
2
(C-7), 11.9 (C-8), 156.0 (d, J(P-O-C endo)= 8.1 Hz, C-9), 124.7 C-
10), 125.1 (C-1'), 128.6 (C-2'& C-6'), 128.3 (C-3'&C-5'), 127.0
1
2
(C-4'), 65.2 (d, Jpc= 8.6 Hz 1C, C-1''), 14.5 (d, Jpc= 6.3 Hz 1C,
C-2''), 42.8 (2Jpc= 7.6 Hz, C-CH3), 16.5 (C-CH3). FAB-MS m/z
398 [(8), M+ +2], 396 [(11), M+], 380 (2), 306 (100), 289 (13),
279 (2), 202 (11), 154 (91), 136 (58), 120 (11), 105 (77), 91
(13). Anal. Calcd for C17H19BrNO3P: C 51.53, H 4.82, N 3.53;
Found: C 51.60, H 4.86, N 3.60%.
Characterization of 6-bromo-2-(4-bromophenoxy)-3-(1-
phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6h)
yield 0.67g (67%) mp 110-112 °C IR(KBr): νmax (cm-1), P=O 1262,
P-O 982, O-C 1167. 31P NMR (CDCl3, 161.9 MHz) δ: -4.45. 1H
NMR (CDCl3, 400 MHz) δ: 7.50-6.80 (m, 12H, Ar-H), 4.52-4.23
(m, 2H, -CH2-), 5.42-5.25 (m, 1H, CH), 1.60 (d, J = 6.8 Hz, 3H,
CH3). 13C NMR (CDCl3 100 MHz) δ: 49.1 (C-4), 128.3 (C-5),
123.7 (C-6), 127.5 (C-7), 116.1 (C-8), 150.8 (C-9), 124.9 (C-
10), 121.3 (C-1'), 128.4 (C-2'& C-6'), 128.1 (C-3'&C-5'), 128.6
(C-4'), 155.3 (C-1''), 118.2 (C-2''), 132.2 (C-3''), 116.1 (C-4''),
132.1 (C-5''), 118.2 (C-6''), 40.6 (C-CH3), 16.1 (C-CH3). Anal.
Calcd for C21H18Br2NO3P: C 48.21, H 3.46, N 2.67; Found: C
48.15, H 3.40, N 2.72%.
Characterization of 6-bromo-2-(phenyl)-3-(1-phenyl-ethyl)-
3,4-dihydro-1H-isophosphinoline 2-Selenide (8c) yield 0.68g
(69.2%). mp 100-102 °C; IR(KBr): νmax (cm-1), P=Se 632. 31P NMR
(CDCl3, 161.9 MHz) δ: 89.19.1H NMR (CDCl3, 400 MHz) δ: 7.81-
6.97 (m, 12H, Ar-H), 4.30-4.20 (m, 2H, -CH2-), 5.48-5.39 (m, 1H,
CH), 1.57 (d, J = 6.2 Hz, 3H, CH3). 13C NMR (CDCl3 100 MHz)
δ: 52.6 (C-4), 129.3 (C-5), 127.3 (C-6), 132.5 (C-7), 133.6 (C-8),
2
156.2 (d, J(P-O-C endo)= 8.0 Hz, C-9), 125.2 (C-10), 118.2 (C-1'),
128.5 (C-2'& C-6'), 128.1 (C-3'&C-5'), 125.6 (C-4'), 138.1 (C-1''),
130.1 (C-2''&C-6''), 129.5 (C-3''& C-5''), 127.4 (C-4''), 43.4 (C-
CH3), 19.1 (C-CH3). GC-MS m/z (%):493 [(5), M+ +2], 491
[(12), M+], 414 (9), 307 (13), 301 (100), 158 (8), 146 (58), 128
(5), 105 (6). Anal. Calcd for C21H19BrNOPSe: C, 51.34, H, 3.89, N
2.85; Found: C, 51.39, H, 3.94, N 2.90%.
Characterization of 6-bromo-2-(1-phenylethylamine)-3-(1-
phenyl-ethyl)-3,4-dihydro-1H-isophosphinoline 2-oxide (6i)
yield 0.66g (70%). mp 123-124 °C. IR(KBr): νmax (cm-1), P=O
1243, P-O 937, O-C 1181, P-NH 3251. 31P NMR (CDCl3, 161.9
Bioassays. The experiments were carried out on the
laboratory
mulberrysilkworm); epilachna vigintioctopun- ctata F (adults,
cultures of Bombyx mori
L
(eggs,

May-Jun 2008
6-Bromo-2-(Substituted)-3-(1-Phenyl-ethyl)- 3,4-Dihydro-1H-Isophosphinoline 2-Chalcogenides
755
brinjal epilachna beetle); Bacillus subtilis, Escherichia coli,
Aspergillus niger and Alternaria alternata.
the test solution consists of 100 µg of test compound. Sterile
Whatman No.1 filter paper discs of 3 mm diameter were
impregnated with definite amount of test compound by adding
desired volume of test solution on to the disc drop by drop with
a time lag to facilitate solvent evaporation. Control filter paper
discs were impregnated with solvent only. Using disc diffusion
method the sensitivity of test organisms grown on media in the
title and reference compound Aeromycin was determined by
measuring the diameter of the zone of inhibition after 24 h. The
results are given in (Table 4).
Insecticidal Activity. The egg hatching of Bombyx mori was
treated with different concentrations of test compounds and their
effect on egg hatching had statistically significance. Egg
hatching of Bombyx mori was greatly affected in compounds
(6a), (6j) and (8a) which were on par with thiodicarb and the
effect of the carbamate was comparable with Helicoverpa
armigera on cotton. The compound (6g), (6f), (6e), (6i), (6b),
and (8a) even at 11.5 times lesser concentration (30 mg/L)
exhibited significant insecticidal activity on Epilachna beetle as
compared to thiodicarb at 40 mg/L. These insecticidal efficacies
of the new test compounds would be attributed to their novel
chemical structural features. Another example to prove the
insecticidal activity of the test compound by using the
Scirpophaga incertulas.
To prepare test solution of the compounds (6a-j), (8a-c) 5 mg
of test compound was dissolved in 1 mL of ethanol and the
volume was made up to 10 mL with sterile water. 1 mL of this test
solution was spread over the surface of artificial diet of 4 g taken
in a polyethylene cup for rearing rise stem borer Scirpophaga
incertulas. Twenty, 15 day-old larvae of S.incertulas were
released on to the diet. Observations were made to evaluate the
effect of test compounds on survival of the larvae. The live and
the dead larvae of Scirpophaga incertulas were counted after 10
days. In order to record the insecticidal effect of the test
compounds on the hatchability of the eggs of Scirpophaga
incertulas, 25 eggs of S. incertulas were placed on the diet. The
Effect on Hatchability of Eggs. Eggs of Bombyx mori were
collected from local grainage and were stored at laboratory
conditions. Solutions of the respective treatments (6a-j) and
(8a-c), were prepared in 0.2% ethanol in distilled water to get a
concentration of 40 mgL-1 and thiodicarb was used as reference
compound at 500 mgL-1. Three sets of eggs (20 eggs/set) of the
test insect were soaked in respective treatments for 30 min. The
treated eggs were air dried and maintained at temperature 30
(±2) °C under laboratory conditions in glass tubes for hatching.
The unhatched eggs were counted on 2nd and 3rd days to
determine cumulative reduction in hatching in the respective
treatments. Distilled water without the test compound was used
as a control (Table 1).
Mortality of Brinjal Epilachna Beetles.
From the
laboratory culture, 2-day-old adult beetles were collected and
starved for 12 h before their exposure to the respective
treatments. Brinjal leaf discs (4 cm diameter) were soaked in
respective treatments with concentration given in 2.3.1 for 10
min and were then air dried. The treated leaf discs of respective
treatments were placed in individual petri plates. Ten adult test
insects were introduced onto treated leaf materials. Three
replications were maintained for each treatment. Average
mortality of beetles in each treatment was recorded after 24 hrs
of feeding with respective treatments. The treated leaf discs
were replaced with untreated fresh material and mortality of
beetles were recorded on 2nd, 3rd and 4th days after treatment.
The data on egg hatching and natural control of beetles, which
corrected values and reference to the check were computed and
statistical inference [12-13] was drawn (Table 1).
Antimicrobial Properties. The antibacterial and antifungal
properties of the test compounds were evaluated by the agar
diffusion method [14] their effect was compared to antibiotics
like gentamycin and nystatin. Methanolic solutions of the test
compounds were used for testing microbial activity. The
bacterial cultures were grown overnight in agar nutrient broth at
37°C and the fungal cultures were grown in potato dextrose
broth for one week. The bacterial lawns were prepared by spread
plating and fungal lawns were prepared by pour plating. The
samples were loaded in the wells, the test plates were incubated
and the zone of inhibition was measured. Bacterial strains used:
Bacillus subtilis (Gram positive), Escherichia coli (Gram
negative). Fungal cultures used: Aspergillus niger, Alternaria
alternata (Table 3).
Table 1
Effect of (6a-j), (8a-c) at 40 mgL-1 on Egg Hatching and Adult Mortality
Compd
Unhatched eggs Corrected adult mortality
of Bombyxmori
(%) @
of Henosepilachna
vigintioctopunctata (%)#
13.33 (17.68)
06.76 (08.16)
36.00 (34.85)
12.38 (14.40)
24.03 (21.04)
11.06 (15.86)
13.33 (17.68)
18.98 (12.42)
12.38 (14.40)
27.15 (25.86)
11.22 (18.68)
18.30 (21.02)
18.30 (21.02)
96.82 (73.33)
22.86 (22.60)
**
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
8a
8b
8c
65.00 (52.00)
23.38 (27.80)
75.00 (58.92)
23.38 (27.80)
45.07 (42.08)
23.08 (27.92)
24.76 (28.97)
36.07 (36.93)
23.38 (27.80)
53.30 (46.92)
10.00 (14.17)
36.76 (36.83)
36.76 (36.83)
84.01 (70.66)
40.00 (38.26)
**
Antimicrobial Activity. The antimicrobial activity of the
compounds was comparable to the commercial antibiotics like
gentamycin and nystatin. Test compounds were found to inhibit
the growth of bacteria Bacillus subtilis and Escherichia coli and
fungi of species Aspergillus niger, Alternaria alternata
respectively. The compounds (6a), (6f) and (8a) were more
effective in inhibiting the growth of Gram-positive Bacillus as
compared to Gram-negative E. coli. Compound 8c exhibited
moderate antifungal activity whereas compound 6f showed equal
activity when compared to that of Nystatin against A. niger.
Antibacterial Activity. Compounds (6a-j), (8a-c) were
screened for their antibacterial activity by the method of Vincent
and Vincent [15] employing Pseudomonas solanacearum,
Xanthomonas campestris and Agrobacterium tumefaciens. The
stock solutions of the test compounds were prepared by
dissolving 1 mg of the compound in 0.6 mL of ethanol and the
final volume was made up to 1 mL with sterile water, 0.1 mL of
Thidocarb
Generalmean
Fest
CD(P=005)
1556
2391
Figures in parenthesis are angular transformed values; @ With
reference to treated eggs in water soaking; # Corrected with reference
to natural mortality in untreated leaf bite regions; ** 'F' test
significance at 1% level; CD-Critical difference

756
K. Srinivasulu, B. Hari Babu, K. Suresh Kumar, C. Bhupendra Reddy, C. Naga Raju and D. Rooba
Vol 45
number of larvae hatched in the diet after 10 days were recorded.
[16-17] The results are shown in (Table-2) and compared with
untreated control. In each test three replications were maintained.
Acknowledgement. The authors express thanks to Prof.
C. Devendranath Reddy and Dr. C. Suresh Reddy, Dept.
of Chemistry, S.V. University, Tirupati, India for
encouragement and helpful discussion and Director,
CDRI, Lucknow and Chairman SIF, IISc Bangalore, India
for the C, H analysis, NMR and Mass spectral data.
Table 2
Antimicrobial activity of compounds (6a-j), (8a-c) at 150 µg/L Zone
of inhibition (mm)
Bacteria
B.
subtilis
Fungi
REFERENCES
Compd
E.
coli
A.
Niger
A.
alternata
[1] Srivastava, R. P.; Saxena, R. C.; Text book of insect
toxicology, Himachal Publications, Udaipur, India, pp. 165 1989.
[2] Perry, A. S.; Yamamoto, I.; Ishaye, I.; Perry, R.; Insecticides
in agriculture and environment retrospect and prospects, Narosa
Publishing House, New Delhi, p. 261, 1998.
[3] White-Stevens Robert, Pesticides in the Environment, Part I,
Vol. I, Marcel Dekker Inc., New York, pp. 4, 1971.
[4] Hendlin, D.; Stapley, E. O.; Jackson, M.; Wallick, H.; Miller,
A. K.; Wolf, F. J.; Miller, T. W.; Chaiet, L.; Kahan, F. M.; Foltz, E. L.;
Woodruff, H. B.; Mata, J. M.; Hernandez, S.; Mochales, S.;
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
8a
8b
8c
9
3
4
6
5
10
3
6
2
3
3
2
8
9
-
6
2
3
4
3
5
2
3
1
1
-
-
-
-
2
2
-
2
-
-
2
-
2
2
2
8
2
-
1
-
3
1
5
-
-
3
1
6
-
Phosphonomycin,
a
New Antibiotic Produced by Strains of
-
Streptomyces, Science, 1969, 166, 122.
3
14
-
[5] White, D. W.; Gibbs, D. E.; Verkade, J. G.; Solution
Stereochemistry of Cyclophosphamide and Rigid Model Analogues, J.
Am. Chem. Soc. 1979, 101, 1937.
Gentamcin
Nystatin
(-) No activity
8
11
[6] The Interpretation of the Infrared Spectra of Organophos-
phorus Compounds, Heydon and Sons Ltd, London 1974.
[7] (a) Silverstein, R. M.; Webster, F. X.; Spectrometric
Identification of Organic Compounds, 6th ed., John Wiley, New York,
1998. (b) Hari Babu, Y.; Srinivasulu, K.; Suresh Reddy, C.;
Devendranath Reddy, C.; Arkivoc, 2007, 15, 97. (c) Vasu Govardhana
Reddy, P.; Kiran, Y. B.; Suresh Reddy, C.; Devendranath Reddy, C .;
Chem Pharm Bull 2004, 52(3), 307.
[8] Quin, L. D.; Verkade, J. G.; Phosphorus 31 NMR Spectral
Properties in Composund Characterization and Structural Analysis,
VCH Publishers, New York, 1994.
[9] Vasugovardhana Reddy, P.; Suresh Reddy, C.; and
Venugopal, M.; Heteroatom Chem. 2003, 14(6), 509.
[10] Hari Babu, Y.; Vasugovardhana Reddy, P.; Suresh Reddy,
C., Devendranath Reddy C.; and Umamaheswari Devi, P.; J. Heterocycl.
Chem. 2002, 39 1039.
[11] Devendranath Reddy, C.; and Rao, C. V. N.; Org Mass
Spectrom, 1982, 17, 598.
[12] Busvine, J. R.; A Critical Review on the Techniques for
Testing Insecticides, 6th ed., CAB, Slough, England, pp. 345, 1971.
[13] Snedecor, G. W.; Cochran, W.G.; Statistical Methods, Iowa
State University Press, Iowa, pp. 533, 1968.
Table 3
Insecticidal Activity of (6a-j), (8a-c)
Compd
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
8a
8b
8c
Control
+
#
43.8
13.6
44.2
18.6
36.6
14.5
21.4
23.6
16.6
40.1
12.2
25.2
34.2
00.0
21.5
62.9
23.6
38.5
34.4
53.5
44.6
46.8
56.8
20.2
61.8
42.2
32.1
94.0
+ % of mortality on 10 days adult larvae of Scirpophaga
incertulas. # % of hatched eggs of Scirpophaga incertulas
Table 4
Antibacterial Activity of Compound (6a-j), (8a-c)
Diameter of zone of inhibition in millimeters
Xanthomonas campestris
Pseudomonas solanacearum
Agrobacterium tumefaciens
Compd
50
µg/disc
16
5
100
µg/disc
16
5
150
µg/disc
20
6
50
µg/disc
19
8
19
11
13
12
13
14
12
18
8
100
µg/disc
19
9
22
14
16
14
15
16
13
19
10
150
µg/disc
22
11
26
16
18
15
17
18
15
22
12
50
100
µg/disc
21
11
24
16
17
16
17
18
15
21
12
17
18
150
µg/disc
23
13
27
18
19
17
19
20
17
24
14
19
20
µg/disc
20
10
21
13
15
14
15
16
14
20
10
16
17
26
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
8a
8b
8c
17
10
14
9
11
11
10
15
5
19
12
16
11
12
14
10
18
5
21
13
17
12
14
16
12
19
7
11
12
19
13
14
21
16
17
23
14
15
22
15
16
24
18
19
26
Aeromycin
28
30

May-Jun 2008
6-Bromo-2-(Substituted)-3-(1-Phenyl-ethyl)- 3,4-Dihydro-1H-Isophosphinoline 2-Chalcogenides
757
[14] Deans, S.; G.; Richie, G.; Antibacterial Properties of Plant
Essential oils, International J Food Microbiol, 1987, 5, 165.
[15] Amanlou, M.; Fazeli, M. R.; Arvin, A.; Amin, H. G.; and
Farsan, H.; Fitoterapia 2004, 75, 768.
G.; Tikar, S. N.; Nimbalkar, S. A.; Efficacy of some Insecticide against
Helicoverpa armigera (Hub), Pestology, 2000, 34, 65.
[17] Tsushima Kazunori, Yano Toshihiko, Umeda Kimitoshi,
Nortiadamatsuo, Hisano Masachika & Nobuoohno, Pest Sci, 1989, 25,
17.
[16] Manne, P. N.; Deshmukh, S. D.; Rao, N. G. V.; Dodale, H.