LaCl3.7H2O: An efficient catalyst for the synthesis of phosphinates (Michaelis-Arbuzov reaction) under neat conditions and their potential antimicrobial activity

Article abstract of DOI:10.1007/s12039-013-0550-3

An expeditious neat procedure was developed for the synthesis of a series of new methyl phenyl heterocyclic phosphinates (3a-l) through Michaelis-Arbuzov reaction by the reaction of various heterocyclic halides (Cl or Br) (1a-l) with dimethyl phenylphosphonite (2) under N₂ atmosphere using a heterogeneous catalyst, LaCl₃.7H₂O. The advantages of the developed procedure are good yields (80-89%) of the products, less reaction time (2-3 h), avoiding toxic catalysts and harmful solvents and easy work-up procedure. Further, antimicrobial activity of the synthesized compounds was evaluated at different concentrations 50, 100 and 150 μg/mL. Biological data revealed that compounds 3i, 3j and 3h, 3j exhibited potential antibacterial and antifungal activities, respectively, while the rest of the compounds showed moderate antimicrobial activity. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-013-0550-3

c
J. Chem. Sci. Vol. 126, No. 1, Month 2014, pp. 117–125. ꢀ Indian Academy of Sciences.
LaCl3.7H2O: An efficient catalyst for the synthesis of phosphinates
(Michaelis–Arbuzov reaction) under neat conditions and their potential
antimicrobial activity
MADHAVA GOLLAa, RASHEED SYEDa, VENKATA RAMANA KATLAa,
SUBBA RAO DEVINENIa, NARESH KONDAPALLIb and NAGA RAJU CHAMARTHIa,∗
aDepartment of Chemistry, bDepartment of Biochemistry, Sri Venkateswara University, Tirupati 517 502, India
e-mail: rajuchamarthi10@gmail.com
MS received 12 June 2013; revised 24 October 2013; accepted 31 October 2013
Abstract. An expeditious neat procedure was developed for the synthesis of a series of new methyl phenyl
heterocyclic phosphinates (3a–l) through Michaelis–Arbuzov reaction by the reaction of various heterocyclic
halides (Cl or Br) (1a–l) with dimethyl phenylphosphonite (2) under N2 atmosphere using a heterogeneous
catalyst, LaCl3.7H2O. The advantages of the developed procedure are good yields (80–89%) of the products,
less reaction time (2–3 h), avoiding toxic catalysts and harmful solvents and easy work-up procedure. Further,
antimicrobial activity of the synthesized compounds was evaluated at different concentrations 50, 100 and
150 μg/mL. Biological data revealed that compounds 3i, 3j and 3h, 3j exhibited potential antibacterial and
antifungal activities, respectively, while the rest of the compounds showed moderate antimicrobial activity.
Keywords. Michaelis–Arbuzov reaction; neat reaction; LaCl3.7H2O catalyst; antimicrobial activity.
1. Introduction
by the reaction of alkyl/aryl halides with trial-
kylphosphite.14 In the progress of the Michaelis–
Arbuzov reaction, chemists have been confronted some
deficiencies like elevated temperature required for
the activation of the reaction and prolonged heat-
ing which led to the decomposition of the start-
ing substrate resulting in limits to the applica-
tion of such reactions to sensitive substrates. The
reaction generates one equivalent of alkyl halide
which can react with phosphite under reaction con-
ditions to reduce the product and reaction efficiency.
Removal of the trialkyl phosphites used in a large
excess and weaker electrophiles aryl/heteroaryl halides
or vinyl halides giving lower yields are additional
problems.
It is well-known that organophosphorus compounds
bearing C–P bond, phosphonates/phosphinates have
wide range of applications in the fields of industry,
agriculture, medicine and synthetic chemistry as cata-
lysts and synthetic intermediates.1 Particularly, phos-
phinates are conveniently consist of C–P bond which is
formed by the reaction of trivalent phosphorus nucle-
ophile with an electrophilic carbon2 have been found in
many synthetic and biological applications. For exam-
ple, diarylphosphinate moieties have been found in var-
ious practical and scientific uses such as manufacturing
of flame retardants,3 advanced polymers,4 membranes,5
therapeutics6 and catalytic antibodies.7,8 As well as,
diaminophosphinates are powerful inhibitors of HIV-1
protease,9 monoaryl hydrogen phosphinates are useful
for an oxidation couplings,10 and hydrophosphinylation
of multiple bonds11 and aryl-phosphoindole acts as non-
nucleoside reverse transcriptase inhibitors.12 Hence,
researchers have focused their attention recently in the
synthesis of C–P linked organophosphorus compounds.
Michaelis–Arbuzov reaction is very versatile and
widely used synthetic method for the synthesis of
phosphinates, phosphonates and phosphine oxides13
Catalytic methods play a special role in synthetic
organic chemistry for progress of the reactions in sim-
ple fashion. Therefore, researchers have developed var-
ious stress-free methods for C–P bond formation. A
small number of reports were found in the literature
on the formation of C–P bond in the presence of
Lewis acid catalysts such as BF3.Et2O,15 CuI,16 PdCl2
17
and NiCl218 via Michaelis–Arbuzov reaction. However,
these methods have some limitations in terms of reac-
tion time, temperature, reaction work-up and yields
of the products. BF3.Et2O catalysed Arbuzov reaction
took longer reaction time, copper-mediated reaction is
very rare16, and aryl and vinyl halides are involved in
∗For correspondence
117

118
Madhava Golla et al.
Arbuzov reaction at high temperature in the presence of catalyst was further washed with ethyl acetate (3 ×
PdCl2 and NiCl2.19,20
5 mL) and the combined organic layer was concentrated
In recent years, the usage of lanthanum (III) chlo- under reduced pressure to obtain the crude product,
ride as a catalyst has attracted the considerable atten- methyl phenyl (quinolin-3-yl)phosphinate (3a). The
tion due to its reusability, low cost, easy handling crude product was purified by column chromatogra-
and hence, a wide variety of reactions are effectively phy using ethyl acetate: hexane (1:3) as an eluent. The
catalysed with simple work-up procedures.21–23 There- same procedure was employed to synthesize further title
fore, we developed a neat procedure for the synthesis compounds 3(a–l) (table 4).
of new heterocyclic phosphinates by reacting various
heterocyclic halides with dimethyl phenylphosphonite
2.1a Methyl phenyl(quinolin-3-yl)phosphinate (3a):
through Michaelis-Arbuzov reaction in the presence
of an inexpensive heterogeneous catalyst, LaCl3.7H2O
under solvent-free conditions.
Brown solid, yield 72%, m.p 180–182◦C. IR (KBr,
υmax, cm−1): 1437 (P-CPh), 1385 (P-CHeterocyclic), 1267
(P = O), 1043 (P-O-CH3). 1H NMR (DMSO-d6): δ 8.61
(s, 1H, Ar-H), 7.94 (s, 1H, Ar-H), 7.90–7.40 (m, 9H,
Ar-H), 3.31 (s, 3H, -OCH3). 13C NMR (DMSO-d6): δ
151.3, 150.8, 136.4, 134.0, 132.5, 130.5, 129.4, 128.9,
128.6, 128.2, 128.0, 127.5, 127.0, 43.5 (d, J = 11.0
Hz). 31P NMR (DMSO-d6): δ 20.1. LC-MS m/z (%):
284 (M+H, 45)+, 270 (M+H−14, 100)+. Anal. Calcd.
for C16H14NO2P: C, 67.84; H, 4.98; N, 4.94; Found: C,
67.79; H, 4.93; N, 4.90.
2. Experimental
All chemicals were purchased from Sigma-Aldrich and
Merck, and used without further purification. Solvents
used for spectroscopic and other physical studies were
reagent grade and were further purified by literature
methods.24 Glassware was dried in oven at 150◦C prior
to use and all the reactions were conducted under nitro-
gen atmosphere. Melting points were examined in an
open capillary using GUNA digital melting point appa-
ratus and are uncorrected. IR spectra were recorded
on JASCO FT-IR spectrophotometer using KBr pel-
2.1b Methyl isoquinolin-4-yl(phenyl)phosphinate (3b):
Colourless solid, yield 70%, m.p 196–198◦C. IR (KBr,
υmax, cm−1): 1446 (P-CPh), 1404 (P-CHeterocyclic), 1269
(P = O), 1037 (P-O-CH3). 1H NMR (DMSO-d6): δ 9.53
(s, 1H, Ar-H), 8.68 (s, 1H, Ar-H), 8.29–7.87 (m, 9H,
Ar-H), 3.29 (s, 3H, -OCH3). 13C NMR (DMSO-d6): δ
155.3, 151.3, 143.7, 136.4, 131.5, 131.0, 130.7, 129.2,
128.6, 127.4, 125.7, 125.2, 39.9 (d, J = 12.0 Hz). 31P
NMR (DMSO-d6): δ 19.2. LC-MS m/z (%): 284 (M+H,
100)+. Anal. Calcd. for C16H14NO2P: C, 67.84; H, 4.98;
N, 4.94; Found: C, 67.72; H, 4.96; N, 4.81.
1
lets. H,13C and 31P NMR spectra were recorded on a
Bruker 400 MHz spectrometer operating at 400 MHz
1
for H NMR, 100 MHz for 13C NMR and 161.9 MHz
for 31P NMR in DMSO-d6 solvent. Tetramethylsilane
1
in H, 13C NMR and 85% H3PO4 in 31P NMR were
used as internal and external standards, respectively.
ESI mass spectra were recorded on a MLP 2103 mass
spectrometer. Elemental analysis was performed on
Thermo Finnigan FLASH EA 1112 instrument. Chemi-
cal shifts were recorded in parts per million (ppm) and
multiplicities are shown as the abbreviations: s (sin-
glet), brs (broad singlet), d (doublet), t (triplet), m
(multiplet).
2.1c Methyl phenyl(quinolin-2-yl)phosphinate (3c):
Pale yellow solid, yield 67%, m.p 186–188◦C. IR (KBr,
υmax, cm−1): 1440 (P-CPh), 1395 (P-CHeterocyclic), 1260
(P = O), 1045 (P-O-CH3). 1H NMR (DMSO-d6): δ 8.40
(d, 1H, J = 7.6 Hz, Ar-H), 7.98–7.44 (m, 9H, Ar-H),
7.25 (d, 1H, J = 7.2 Hz, Ar-H), 3.28 (s, 3H,-OCH3).
13C NMR (DMSO-d6): δ 156.2, 147.0, 136.0, 134.0,
132.1, 131.2, 130.6, 129.7, 128.7, 128.5, 128.0, 126.5,
122.0, 42.5 (d, J = 11.0 Hz). 31P NMR (DMSO-d6): δ
23.5; LC-MSm/z (%): 284 (M+H, 18)+, 270 (M+H-14,
100)+. Anal. Calcd. for C16H14NO2P: C, 67.84; H, 4.98;
N, 4.94; Found: C, 67.77; H, 4.95; N, 4.88.
2.1 General procedure for synthesis of the title
compounds (3a–l)
3-Bromoquinoline (1a) (0.20 mL, 0.001 mol), dimethyl
phenylphosphonite (0.23 mL, 0.001 mol) and Lewis
acid catalyst, LaCl3.7H2O (20 mol%) were taken into a
round bottom flask (50 mL) flushed with nitrogen. The
reaction mixture was stirred for 2 h at 50◦C under N2
atmosphere. The progress of the reaction was checked 2.1d Methyl 4-amino-6-chloropyrimidin-2-yl(phenyl)
by TLC using ethyl acetate: n-hexane (1:1) as an elu- phosphinate (3d): Colourless solid, yield 65%, m.p
ent. After completion of the reaction, the reaction mix- 178–180◦C. IR (KBr, υmax, cm−1): 1450 (P-CPh), 1390
1
ture was dissolved in 10 mL of ethyl acetate and then (P-CHeterocyclic), 1258 (P = O), 1050 (P-O-CH3). H
filtered-off to remove the catalyst. The residue i.e., NMR (DMSO-d6): δ 7.80–7.35 (m, 5H, Ar-H), 6.65

LaCl3.7H2O catalyst promoted Michaelis–Arbuzov reaction
119
131.8, 130.7, 128.2, 126.0, 39.4 (d, J = 10.0 Hz). 31P
NMR (DMSO-d6): δ 21.9. LC-MS m/z (%): 279 (M+H,
100)+. Anal. Calcd. for C12H11N2O4P: C, 51.81; H,
3.99; N, 10.07; Found: C, 51.75; H, 3.96; N, 10.02.
(s, 1H, Ar-H), 6.30 (s, 2H, Ar-NH2), 3.34 (s, 3H, -
OCH3). 13C NMR (DMSO-d6): δ 166.1, 164, 163.2,
133.9, 132.1, 130.5, 128.6, 106.5, 40.7 (d, J = 10.0 Hz).
31P NMR (DMSO-d6): δ 21.5. LC-MS m/z (%): 284
(M+H, 100)+, 286 (M+H+2, 32)+; Anal. Calcd. for
C11H11ClN3O2P: C, 46.58; H, 3.91; N, 14.81; Found: C,
46.52; H, 3.88; N, 14.76.
2.1i Methyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-
yl(phenyl)phosphinate (3i): Colour less solid, yield
65%, m.p 130–132◦C. IR (KBr, υmax, cm−1): 1440
(P-CPh), 1387 (P-CHeterocyclic), 1258 (P = O), 1065
2.1e Methyl 2-amino-4-hydroxy-6-methylpyrimidin-5-
yl(phenyl)phosphinate (3e): Colourless solid, yield
65%, m.p 66–68◦C. IR (KBr, υmax, cm−1): 1439 (P-
CPh), 1400 (P-CHeterocyclic), 1265 (P = O), 1030 (P-O-
1
(P-O-CH3). H NMR (DMSO-d6): δ 11.05 (s, 2H, -
NH), 7.90–7.50 (m, 6H, Ar-H), 3.37 (s, 3H, -OCH3).
13C NMR (DMSO-d6): δ 163.5, 150.5, 141.8, 134.5,
132.6, 128.6, 128.4, 100.3, 43.5 (d, J = 12.0 Hz).
31P NMR (DMSO-d6): δ 19.5. LC-MS m/z (%): 267
(M+H, 100)+. Anal. Calcd. for C11H11N2O4P: C, 49.63;
H, 4.17; N, 10.52; Found: C, 49.55; H, 4.14; N,
10.47.
1
CH3). H NMR (DMSO-d6): δ 11.10 (s, 1H, Ar-OH),
7.86–7.30 (m, 5H, Ar-H), 6.35 (s, 2H, Ar-NH2), 3.38
(s, 3H, -OCH3), 2.32 (s, 3H, -CH3). 13C NMR (DMSO-
d6): δ 172.1, 167.4, 157.5, 134.0, 133.3, 130.5, 128.7,
113.4, 43.6 (d, J = 12.0 Hz), 21.8. 31P NMR (DMSO-
d6): δ 24.2. LC-MSm/z (%): 280 (M+H, 100)+. Anal.
Calcd. for C12H14N3O3P: C, 51.62; H, 5.05; N, 15.05;
Found: C, 51.56; H, 5.01; N, 15.00.
2.1j Methyl phenyl(pyrazin-2-yl)phosphinate (3j): Semi
solid, yield 65%. IR (KBr, υmax, cm−1): 1439 (P-CPh),
1395 (P-CHeterocyclic), 1262 (P = O), 1043 (P-O-CH3).
1H NMR (DMSO-d6): δ 8.80 (d, 2H, J = 8.0 Hz, Ar-
H), 8.56 (s, 1H, Ar-H), 7.87-7.34 (m, 5H, Ar-H), 3.32
(s, 3H, -OCH3). 13C NMR (DMSO-d6): δ 151.2, 148.2,
145.8, 144.0, 134.1, 132.2, 130.6, 128.7, 41.6 (d, J =
13.0 Hz). 31P NMR (DMSO-d6): δ 23.5. LC-MS m/z
(%): 235 (M+H, 100)+; Anal. Calcd. for C11H11N2O2P:
C, 56.41; H, 4.73; N, 11.96; Found: C, 56.36; H, 4.69;
N, 11.91.
2.1f Methyl 4,6-dimethoxy-1,3,5-triazin-2-yl(phenyl)
phosphinate (3f): Yellow solid, yield 68%, m.p 148–
150◦C. IR (KBr, υmax, cm−1): 1435 (P-CPh), 1395
1
(P-CHeterocyclic), 1260 (P = O), 1035 (P-O-CH3). H
NMR (DMSO-d6): δ 7.83–7.45 (m, 5H, Ar-H), 3.75
(s, 6H, Ar-OCH3), 3.32 (s, 3H, -OCH3). 13C NMR
(DMSO-d6): δ 175.0, 168.2, 134.0, 132.1, 130.3, 128.5,
53.2, 46.8 (d, J = 11.0 Hz). 31P NMR (DMSO-d6): δ
22.5. LC-MS m/z (%): 296 (M+H, 15)+, 282 (M+H-
14, 100)+. Anal. Calcd. for C12H14N3O4P: C, 48.82; H,
4.78; N, 14.23; Found: C, 48.75; H, 4.75; N, 14.18.
2.1k Methyl 4,6-dimethoxypyrimidin-2-yl(phenyl)
phosphinate (3k): Semi solid, yield 68%, IR (KBr,
υmax, cm−1): 1443 (P-CPh), 1379 (P-CHeterocyclic), 1253
1
2.1g Methyl phenyl(pyrimidin-2-yl)phosphinate (3g):
(P = O), 1035 (P-O-CH3). H NMR (DMSO-d6): δ
Brown solid, yield 72%, m.p 168–170◦C. IR (KBr, υmax
,
7.78–7.37 (m, 5H, Ar-H), 6.54 (s, 1H, Ar-H), 3.68
(s, 6H, Ar-OCH3), 3.36 (s, 3H, -OCH3). 13C NMR
(DMSO-d6): δ 170.5, 159.8, 133.9, 132.1, 130.4, 128.2,
87.4, 52.3, 42.8 (d, J = 14.0 Hz). 31P NMR (DMSO-
d6): δ 19.0 ppm; LC-MS m/z (%): 295 (M+H, 100)+.
Anal. Calcd. for C13H15N2O4P: C, 53.06; H, 5.14; N,
9.52; Found: C, 53.02; H, 5.11; N, 9.48.
cm−1): 1430 (P-CPh), 1385 (P-CHeterocyclic), 1268 (P =
O), 1045 (P-O-CH3). 1H NMR (DMSO-d6): δ 8.60 (d,
2H, J = 7.8 Hz, Ar-H), 7.75–7.35 (m, 6H, Ar-H), 3.29
(s, 3H, -OCH3). 13C NMR (DMSO-d6): δ 164.2, 157.0,
133.8, 132.0, 130.6, 128.7, 123.6, 42.8 (d, J = 14.0 Hz).
31P NMR (DMSO-d6): δ 25.2. LC-MSm/z (%): 235
(M+H, 100)+. Anal. Calcd. for C11H11N2O2P: C, 56.41;
H, 4.73; N, 11.96; Found: C, 56.35; H, 4.70; N,
11.91.
2.1l Methyl benzo[d]thiazol-2-yl(phenyl)phosphinate
(3l): Colourless solid, yield 70%, m.p 188–190◦C. IR
(KBr, υmax, cm−1): 1445 (P-CPh), 1400 (P-CHeterocyclic),
1
2.lh Methyl 5-nitropyridin-2-yl(phenyl)phosphinate
(3h): Brown solid, yield 73%, m.p 140–142◦C. IR
(KBr, υmax, cm−1): 1446 (P-CPh), 1394 (P-CHeterocyclic),
1264 (P = O), 1037 (P-O-CH3). 1H NMR (DMSO-d6):
δ 9.15 (s, 1H, Ar-H), 8.50 (d, 1H, J = 8.0 Hz, Ar-H),
7.85–7.40 (m, 6H, Ar-H), 3.36 (s, 3H, -OCH3). 13C
NMR (DMSO-d6): δ 162.0, 148.5, 146.1, 134.0, 132.4,
1258 (P = O), 1055 (P-O-CH3). H NMR (DMSO-
d6): δ 8.25 (d, 1H, J = 7.8 Hz, Ar-H), 8.10 (d, 1H,
J = 7.4 Hz, Ar-H), 7.78–7.35 (m, 7H, Ar-H), 3.35
(m, 3H, -OCH3). 13C NMR (DMSO-d6), 155.8, 153.3,
135.0, 133.7, 132.0, 130.9, 128.5, 125.2, 124.6, 121.6,
121.2, 44.6 (d, J = 12.0 Hz). 31P NMR (DMSO-d6): δ
19.8. LC-MS m/z (%): 290 (M+H, 30)+, 172 (M+H-

120
Madhava Golla et al.
MeO
O
Optimization of
reaction conditions
Br
Ph
P
P
Ph
MeX
+
+
MeO
OMe
N
1a
N
2
3a
Scheme 1. Model reaction for the optimization of Michaelis–Arbuzov reaction.
incubating for 24 h at 37◦C. The clear zones of inhi-
bition around the disc were measured (in mm). The
experiments were performed in triplicate and the aver-
age value was taken as final result. Also, the percentage
activity index for the compound was calculated using
the following formula.
118 100)+. Anal. Calcd. for C14H12NO2PS: C, 58.13; H,
4.18; N, 4.84; Found: C, 58.08; H, 4.15; N, 4.80.
2.2 Reusability of the catalyst, LaCl3.7H2O
The heterogeneous catalyst, LaCl3.7H2O was filtered-
off after the reaction was completed as residue. The iso-
lated catalyst was washed three to four times with ethyl
acetate to remove the tars on the catalyst and then dried
under vacuum at 60◦C for 10 h. The dried catalyst was
reused for monitoring the reaction up to 5 cycles.
%Activity Index
Zone of inhibition by test compound(diameter)
=
× 100.
Zone of inhibition by standard(diameter)
2.3b Antifungal screening test: The antifungal
screening of the synthesized compounds 3(a–l) was
evaluated against three pathogenic fungal strains
2.3 Biological activity
2.3a Antibacterial screening test: All the synthe- such as Aspergillus niger (MTCC-1881), Fusarium
sized compounds 3(a–l) were screened for their oxysporum (MTCC-1755) and Aspergillus foetidus
antibacterial activity against two Gram-positive strains, (NCIM-505) using poison food technique with some
Staphylococcus aureus (ATCC-19433), and Bacillus modifications.26 Ketoconazole was used as a standard
cereus (ATCC-11778) and two Gram-negative strains for comparison of the activity. Potato dextrose agar
such as Escherichia coli (ATCC-25922), and Proteus (PDA) was used as basal medium for the test of fungal
vulgaris (ATCC-29213) using filter paper disc diffu- activity. Glass petri dishes were sterilized and 15 mL of
sion method.25 Different concentrations (50, 100 and sterilized melted (∼45◦C) was poured into each petri
150 μg/mL) of test compounds and the standard, dish (90 mm). After solidification of the medium small
Ciprofloxacin were prepared in dimethylformamide portions of mycelium of each fungus were spread care-
(DMF) and DMF was used as negative control. The fully over the centre of each PDA plate with the help of
selected 24 h old bacteria cultured with 0.5 mL con- sterilized needles. The PDA plates were then incubated
taining 1 × 107CFU/mL in nutrient broth were spread at 25 2◦C for three days. The prepared discs of the
on nutrient broth-agar in Petri dishes. The paper discs test samples were placed gently on the solidified agar
(6 mm diameter, Whatman No. 2) were dried and plates freshly seeded with the test organisms with ster-
dipped in known concentration of the prepared test sam- ile forceps. Control discs were also placed on the test
ples. Then, these discs were placed on the culture and plates to compare the effect of solvent. The plates were
Table 1. Optimization of the catalyst and solvent effects for the synthesis of compound 3a.
Entry
Catalysts
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
No catalyst
CuCl2 (15 mol%)
FeCl3(15 mol%)
AlCl3(15 mol%)
THF
THF
THF
THF
THF
THF
THF
16.0
6.0
4.5
4.5
5.0
3.5
2.5
3.5
4.0
4.0
2.5
Trace
48.5
56.0
59.5
53.5
64.0
67.0
62.5
57.0
60.0
72.5
MgCl2(15 mol%)
CeCl3.7H2O (15 mol%)
LaCl3.7H2O (15 mol%)
LaCl3.7H2O (15 mol%)
LaCl3.7H2O (15 mol%)
LaCl3.7H2O (15 mol%)
LaCl3.7H2O (15 mol%)
Toluene
CH2Cl2
CH3CN
No solvent
9
10
11

LaCl3.7H2O catalyst promoted Michaelis–Arbuzov reaction
121
Table 2. Examination of the catalyst amount and temparature effects for the synthesis of compound 3a.
Entry
Catalyst loading
Temperature
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
LaCl3.7H2O (10 mol%)
LaCl3.7H2O (15 mol%)
LaCl3.7H2O (20 mol%)
LaCl3.7H2O (25 mol%)
LaCl3.7H2O (30 mol%)
LaCl3.7H2O (20 mol%)
LaCl3.7H2O (20 mol%)
LaCl3.7H2O (20 mol%)
LaCl3.7H2O (25 mol%)
LaCl3.7H2O (30 mol%)
50◦C
50◦C
50◦C
50◦C
50◦C
30◦C
40◦C
60◦C
50◦C
50◦C
3.5
2.5
2.5
2.5
2.5
4.5
3.0
2.5
2.5
2.5
66.0
72.5
78.0
78.5
78.5
58.0
68.0
79.0
79.0
80.5
then kept in a refrigerator at 40◦C for 24 h in order suggested that the reaction was progressed from mod-
to have sufficient time for materials to a considerable erate to good in the presence of these Lewis acid cat-
area of the plates. After, the plates were incubated at alysts (table 1 entry 2–7), although the high yield of
37◦C for 72 h. The inhibition zones were measured the product (67.0%) was detected in LaCl3.7H2O cata-
and compared with the controls. The experiments lyst (table 1 entry 7). Hence, LaCl3.7H2O catalyst was
were performed in triplicate and average value was preferred to synthesize the title compounds. The pre-
taken as final result. The percentage activity index was vious study has revealed that the efficacy of the reac-
calculated by the following equation.
tion also depends on solvent system. To our delight, the
model reaction was run in different solvents, toluene,
CH2Cl2, CH3CN and solvent-free conditions (table 1
entry 8–11). It was found that the highest yield (72.5%)
of the product 3a obtained in neat reaction conditions
as compared to other solvents (table 1 entry 11) in short
reaction time. In addition, other factors like amount of
the catalyst and the temperature are also influencing
the reaction. Hence, the reaction has also been inves-
tigated by loading the catalyst, LaCl3.7H2O in differ-
ent amounts (10, 15, 20, 25, 30%) (table 2 entry 1–5)
as well as the temperature effect was also examined at
different temperatures (30, 40, 50, 60◦C) (table 2 entry
5–10). The results showed that 20 mol% of the cata-
lyst and 50◦C are adequate to carry out the reaction
efficiently (table 2 entry 3). The excess use of catalyst
and adopting high temperature did not unveil significant
changes in the improvement of the reaction.
%Activity Index
Zone of inhibition by test compound(diameter)
=
× 100.
Zone of inhibition by standard(diameter)
3. Results and discussion
3.1 Chemistry
Various methods have been developed for the pro-
motion of the Michaelis–Arbuzov reaction effectively.
However, the developed procedures are associated with
some drawbacks. In order to develop a suitable condi-
tions for the formation of C–P bond through Michaelis–
Arbuzov reaction, we have established new method in
the part of our research programme using LaCl3.7H2O
catalyst under neat reaction conditions for the synthesis
of new methyl phenyl heterocyclic phosphinates 3(a–l).
The reaction conditions were optimized by taking 3-
bromoquinoline (1a) and dimethyl phenylphosphonite
(2) as models (scheme 1).
The reusability of the catalyst, LaCl3.7H2O was also
examined up to five cycles after purifying the used
Table 3. Screening of reusability of the catalyst,
LaCl3.7H2O (20 mol%) for the synthesis of compound 3a.
At first attempt, the model reaction was progressed
without catalyst by preserving N2 atmosphere result
trace amount of the product, methyl phenyl (quinolin-
3-yl) phosphinate (3a) (table 1 entry 1) was observed
after a long reaction time, 16 h even altering the reaction
temperature 30–65◦C. Further, to know the catalytic
effect on this reaction, the model reaction was examined
in THF using different catalysts, CuCl2, FeCl3, AlCl3,
MgCl2, CeCl3.7H2O and LaCl3.7H2O. The results
Entry
No. of runs
Time (h)
Yield (%)
1
2
3
4
5
1st
2nd
3rd
4th
5th
2.5
2.5
2.5
2.5
2.5
78.0
76.0
72.5
66.0
62.0

122
Madhava Golla et al.
catalyst (table 3 entry 1–5). It was observed that until as doublets in the region of δ 46.8–39.4 (d, J = 10.0–
to three cycles the catalyst did not loose its significant 14.0 Hz). In 31P NMR spectra, signals appeared as sin-
catalytic activity.
glets in the region of δ 19.1–25.4 ppm corresponding to
After optimization of the reaction conditions, var- ‘P’ atom in all the title compounds.27
ious title compounds were synthesized (scheme 2)
by altering heterocyclic halides and the results are
summarized in table 4. It was distinguished that
brominated materials involved in the reaction meritori-
ously and offered good yields as compared with chlo-
rinated material. Hopefully, we will continue further
related research to improve the catalytic nature of the
described catalyst by spreading on the solid support and
application of it to synthesize various organic molecules
in simple manner.
3.2 Biological activity
All the newly synthesized compounds were screened
for their antibacterial activity against two Gram-
positive bacterial strains such as S. aureus (ATCC-
19433), and B. cereus (ATCC-11778) and two Gram-
negative strains such as E. coli (ATCC-25922), and P.
vulgaris (ATCC-29213) using filter paper disc diffu-
sion method at different concentrations 50, 100 and
150 μg/mL and Ciprofloxacin was used as a stan-
The chemical structures of all the title compounds
(3a–l) were characterized by IR, NMR (1H, 13C, 31P), dard. The bacterial zone of inhibition values of the title
mass spectral data and elemental analysis. IR spec- compounds 3(a–l) in table S1 and the percentage of
tra of the title compounds (3a–l) gave absorption activity index in figures S1 and S2 (see supplementary
bands in the regions of 1269–1253 cm−1and 1055– information) are presented. The biological data revealed
1030 cm−1confirmed the functionalities P = O and P– that compounds 3i, 3j and 3h against S. aureus,
1
O–CH3, respectively. In H NMR spectra, aromatic compound 3j against B. cereus, compounds 3i and
protons of the title compounds (3a–l) gave chemi- 3h against E. coli and compound 3j against P. vul-
cal shift values in the region δ 8.29–7.34 ppm as garis showed promising activity. In overall antibacte-
complex multiplets and aliphatic –OCH3 protons reso- rial activity, the compounds 3i and 3j bearing uracil and
nated as singlets in the region of δ 3.37–3.28 ppm. 13
C
pyrazine pharmacophoric groups, respectively, showed
NMR spectral data of (3a–l) showed aromatic carbons high antibacterial activity nearly to the standard drug,
in their corresponding region and P–O–CH3 resonated Ciprofloxacin than that of the remaining compounds.
MeO
O
Ph
P
P
LaCl3 7H2O
Neat, N2
+
Ph
X
MeX
+
MeO
OMe
Heterocyclic
compounds
lic
ocyc
eter
H
nds
pou
com
50 0C, 2.5-4.5 h
2
1(a-l)
3(a-l)
X = Br (1a, 1b, 1e, 1g, 1h, 1i)
X = Cl (1c, 1d, 1f, 1j, 1k, 1l)
Heterocyclic compd.
NH2
N
N
N
N
Cl
N
3a
3b
3c
3d
OH
N
OMe
N
N
N
N
O2N
H2N
N
CH3
MeO
N
N
N
3e
3f
3g
3h
O
OMe
S
N
HN
N
N
O
N
H
MeO
N
3i
3j
3k
3l
Scheme 2. Neat and LaCl3.7H2O catalysed synthesis for new methyl phenyl hetero/heteroarylphosphinates (3a–l).

LaCl3.7H2O catalyst promoted Michaelis–Arbuzov reaction
123
A. niger (MTCC-1881), F. oxysporum (MTCC-1755) disclosed that compound 3j showed potent activity and
and A. foetidus (NCIM-505) fungal strains were used to compounds3hand3lshowedgoodactivityagainstallthe
screen the antifungal activity of the synthesized com- tested fungal strains which were closer to the standard
pounds 3(a–l) fusing poison plate method at different drug, Ketoconazole. Thefungalzoneofinhibitionvalues
concentrations 50, 100 and 150 μg/mL and Ketocona- are given in table S2 and the results of percentage
zole was used as a standard. The bio-screening data inhibition of the title compounds 3(a–l) are given in
Table 4. Physical data for the synthesized title phosphinate derivatives 3(a–l).
Compd.
Product
Time (h)
2.5
Yield (%)
78.0
m.p (◦C)
MeO
O
P
Ph
N
3a
180–182
O
P
MeO
Ph
N
3b
3c
2.5
3.0
74.5
70.0
196–198
186–188
OMe
O
N
P
Ph
NH2
N
OMe
Cl
N
P
Ph
O
3d
3e
3f
3.5
4.0
3.5
71.5
72.0
72.0
178–180
66–68
OMe
OH
O
P
N
N
Ph
CH3
H2N
MeO
N
OMe
N
OMe
O
N
P
Ph
148–150
N
OMe
P
N
O
N
Ph
3g
3h
2.5
3.0
79.0
81.5
168–170
140–142
MeO
P
O
O2N
Ph
O
OMe
P
O
HN
O
Ph
N
H
3i
3j
3.0
4.5
70.5
73.0
130–132
–
N
N
OMe
O
P
Ph
OMe
N
OMe
O
MeO
N
P
Ph
3k
3l
3.5
3.5
75.5
71.5
–
OMe
S
P
O
N
Ph
188–190

124
Madhava Golla et al.
1652; (c) Malachowski W P and Coward J K 1994 J.
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2007 Fluid Phase. Equilibr. 258 99
figure S3(seesupplementaryinformation). Overall, com-
pound 3j showed potent antibacterial and antifungal
activities.
4. Lligadas G, Ronda J C, Galia M and Cadiz V J 2006
Polym. Sci. Part A: Polym. Chem. 44 5630
5. Hwang M, Ha H Y and Kim D J 2008 Membr. Sci. 325
4. Conclusion
647
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In summary, we conclude that LaCl3.7H2O was found
to be an efficient heterogeneous catalyst for the syn-
thesis of new methyl phenyl heterocyclic phosphi-
nates under neat reaction conditions through Michaelis–
Arbuzov reaction. The method has several advantages:
low cost, readily available, reusability of the catalyst,
avoidance of toxic solvents, neat reaction conditions,
easy work-up procedure, low reaction time, high yields
of the products and significant generality. The in vitro
antimicrobial activity of the newly synthesized com-
pounds was evaluated against four bacterial strains and
three fungal strains. Compound 3j exhibited potent
antibacterial as well as antifungal activities, neverthe-
less all the remaining compounds showed good to mod-
erate activity. The present methodology could be use-
ful in future for the synthesis of organic bio-active
molecules/intermediates.
12. Francois R A, Agnes A, Stephanie B, Catherine C,
Thierry C, Jocelyn J, Chiara M, Barbara P, Luana V,
Michel L, Arlene R, Maria S, David S, Richard S and
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organophosphorus compounds (New York: Wiley); (b)
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81 415
Supplementary information
The electronic supplementary information consists of
antibacterial data (table S1, figures S1 and S2) and anti-
fungal data (table S2 and figure S3) can be seen in www.
ias.ac.in/chemsci.
14. (a) Michaelis A and Kaehene R 1898 Cheme. Ber. 31
1408; (b) Arbuzov A E 1906 J. Russ. Phys. Chem. Soc.
38 687
Acknowledgements
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The author, GM thanks the University Grants Commis-
sion (UGC), New Delhi, for the award of UGC-Junior
Research Fellowship (JRF). SR, and DSR are thankful
to the UGC, New Delhi, for awarding Junior Research
Fellowship (JRF) under the scheme of Basic Scientific
Research Programme (BSR).
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