Bismuth(III) Chloride Mediated Michaelis-Arbuzov Reaction: A Facile Synthesis of Substituted Arylphosphonates/Phosphinates and Bioactivity Evaluation

Article abstract of DOI:10.1080/10426507.2015.1043048

BiCl₃ is economically affordable, less toxic and eco-friendly catalyst. A facile synthesis of substituted arylphosphonates/phosphinates in good yields was achieved using BiCl₃ catalyzed via Michaelis-Arbuzov reaction. 5-Iodovanillin/

Full text of DOI:10.1080/10426507.2015.1043048

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Phosphorus, Sulfur, and Silicon and the Related
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Bismuth(iii) Chloride Mediated Michaelis-Arbuzov
Reaction: A Facile Synthesis of Substituted
Arylphosphonates / Phosphinates and Bioactivity
Evaluation
b
a
a
a
a
Ch. Subramanyam , G. Madhava , S. K. Thaslim Basha , S. Rasheed , A. Uday Sankar & C.
a
Naga Raju
a
Department of Chemistry, Sri Venkateswara University, Tirupati – 517 502, India
b
Department of Biotechnology, Vikrama Simhapuri University, India
Accepted author version posted online: 13 May 2015.
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To cite this article: Ch. Subramanyam, G. Madhava, S. K. Thaslim Basha, S. Rasheed, A. Uday Sankar & C. Naga Raju (2015):
Bismuth(iii) Chloride Mediated Michaelis-Arbuzov Reaction: A Facile Synthesis of Substituted Arylphosphonates / Phosphinates
and Bioactivity Evaluation, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2015.1043048
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ACCEPTED MANUSCRIPT
BISMUTH(III) CHLORIDE MEDIATED MICHAELIS-ARBUZOV REACTION: A FACILE
SYNTHESIS OF SUBSTITUTED ARYLPHOSPHONATES / PHOSPHINATES AND
BIOACTIVITY EVALUATION
1
1
1
1
2
Ch. Subramanyam , G. Madhava , S. K. Thaslim Basha , S. Rasheed , A. Uday Sankar
1
*
and C. Naga Raju
1
Department of Chemistry, Sri Venkateswara University, Tirupati - 517 502, India
Department of Biotechnology, Vikrama Simhapuri University, India
2
Running head: BiCl
3
Catalyzed Synthesis of Substituted Arylphosphonates/Phosphinates
ABSTRACT BiCl
3
is economically affordable, less toxic and ecofriendly catalyst. A facile
synthesis of substituted arylphosphonates/phosphinates in good yields was achieved using BiCl
3
catalyzed via Michaelis-Arbuzov reaction. 5-Iodovanillin / 3,5-difluorobenzylbromide was
reacted with various phosphites and dimethyl phenylphosphonite in the presence of Lewis acid
catalyst BiCl
3
, under N
2
atmosphere at 40 °C to produce the corresponding
3
1
1
13
arylphosphonates/phosphinates. They were characterized by P, H and C NMR spectroscopy,
IR, mass spectrometry and elemental analysis. All title compounds were screened for their in
vitro antibacterial and antifungal activity. The compounds 5d, 3b, 5e, 5b exhibited good
antibacterial activity and the compounds 3a, 3b, 5a and 5d exhibited significant antifungal
activity compared to the standard bactericide Norfloxacin and fungicide Griseofulvin.
1
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O
OR2
R3
P
I
HO
HO
O
O
O
O
N , BiCl ,
phosphites/phosphonite
2
3
H
H
Antibacterial and
antifungal
THF, 40 ºC .
Br
O
OR2
P
R3
F
F
F
F
Keywords Michaelis-Arbuzov reaction, BiCl , 5-Iodovanillin, 3,5-difluorobenzylbromide,
3
arylphosphonates / phosphinates, antibacterial activity, antifungal activity
Corresponding author Tel: +91-9703193375, E-mail address: rajuchamarthi10@gmail.com
2
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INTRODUCTION
Phosphonates signify a class of stable organophosphorus compounds containing a single
carbon-phosphorus (C–P) bond, which makes them resistant to chemical and enzymatic
1
2
hydrolysis, thermal decomposition and photolysis. They have broad applications in flame
3
-4
5
6-7
retardancy, organic synthesis and biological applications. Synthetic phosphonates are now
8
a
8b
widely used as herbicides, stimulants for the latex production of Hevea brasiliensis,
9
10
11
12
13
pesticides, detergents, reagents for Wittig-Horner reactions, anti-bacterial, antiviral and
1
4
antitumor agents. A phosphonate motif is present in biomolecules which can act as inhibitors of
1
5
certain biosynthetic pathways and can be degraded only by some prokaryotic microorganisms.
The high chemical stability of phosphonates, together with their resistance to biodegradation,
makes this class of compounds of particular interest for the drug design. Phosphinates are also
1
6-17
proved to be superior transition state analogues for the preparation of catalytic antibodies
and
1
8
several arylphosphinates have been explored as potential therapeutics.
The Michaelis-Arbuzov rearrangement is one of the most extensively investigated
reactions in organophosphorus chemistry and is widely used to prepare phosphonates,
1
9
phosphinates and phosphine oxides. The mechanism of the Arbuzov reaction has been shown
to involve two nucleophilic attacks, i.e., the formation of a quasi-phosphonium salt by the
reaction of trialkyl phosphite with an alkyl halide and the dealkylation of this salt, accompanied
2
0
by rearrangement to a phosphonate. However, due to the resistance of aryl groups to
nucleophilic attack, the classic Arbuzov reaction was essentially limited to the preparation of
alkyl phosphonates. The synthesis of aryl phosphonates represents one early challenge. In this
3
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2
1–25
regard, the transition-metal catalyzed Arbuzov reaction has gained remarkable success.
Tavs
extended the classic Arbuzov reaction to the synthesis of dialkyl arylphosphonates by
2
1
phosphonylation of aryl halides with trialkyl phosphites catalyzed by nickel. Keglevich et al.
also synthesized arylphosphonates by the microwave-assisted Arbuzov reaction of triethyl
phosphite and aryl bromides in the presence of NiCl
2
as the catalyst under solvent-free
2
6
conditions. Rajeshwaran et al reported Lewis acid mediated Michaelis-Arbuzov reaction to
2
7
synthesize arylmethyl and heteroarylmethyl phosphonate esters at room temperature. In recent
2
8
29
years, economically affordable ecofriendly catalysts such as Cu(II) salts, Fe (II)/Fe(III) salts,
3
0,31
Ni salts and Bi(III) salts
bismuth trichloride (BiCl
low cost and relative insensitivity to air and to small amounts of moisture when compared with
received some interest in various organic reactions. Recently,
3
) has received attention in organic synthesis because of its low toxicity,
3
2
transition-metal complexes. Hua Li et al. developed a Bismuth(III) chloride-catalyzed one-pot
3
3
Mannich reaction for the synthesis of β-aminocarbonyl compounds. Zhan et al. reported the
BiCl catalyzed substitution reaction of propargylic alcohols with carbon and heteroatom-
centered nucleophiles such as allyl trimethylsilane, alcohols, aromatic compounds, thiols and
3
3
4
amides, leading to the construction of C–C, C–O, C–S and C–N bonds.
The possibility of broad applications of phosphonates as well as phosphinates and the
significance of BiCl as an ecofriendly catalyst prompted us to synthesize a series of novel
3
substituted aryl phosphonates/phosphinates catalyzed by Bismuth(III) chloride at 40 °C.
RESULTS AND DISCUSSION
4
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As part of the research programme in the development of new methodologies for the
synthesis of bioactive phosphonates and phosphinates, in this letter, we report the synthesis of
various substituted 5-formyl-2-hydroxy-3-methoxyphenylphosphonate/phosphinate (3a-e) and
substituted 3,5-difluorobenzylphosphonate/phosphinate (5a-e) in the presence of the efficient
catalyst Bismuth(III) chloride. To optimize the reaction conditions, 5-iodovanillin (1) and
trimethyl phosphite (TMP) (2a) were selected as substrates (Scheme 1).
Initially, the reaction was performed using 5-iodovanillin (1) (1.2 mmol, 0.33 g) and
trimethyl phosphite (TMP) (2a) (1.8 mmol, 0.21 mL) in ethanol as solvent. Without catalyst
under refluxed conditions, it resulted in only trace amounts of the product 3a. Further, the effect
of the reaction was scrutinized with different catalysts (10 mol %) in EtOH to afford dimethyl 5-
formyl-2-hydroxy-3-methoxyphenylphosphonate (3a) as shown in Table 1, entry 1-5.
Remarkably, the good yield of compound 3a was observed with Bismuth(III) chloride. This
result attracted us to explore further the finest reaction conditions. Hence, the same reaction was
conducted in different solvents like THF, toluene and DCM (Table 1, entry 6-8). The best result
was obtained in THF (Table 1, entry 8). To our interest, the effect of the amount of the catalyst
on the reaction conditions was scrutinized by altering the amount of the catalyst (Table 1, entry
9
-14). The highest yield was observed at 20 mol% amount of the catalyst (Table 1, entry 12).
After optimization of the reaction conditions, to explore the scope and generality of this
method, various trialkyl phosphites (2b-d) and dimethyl phenylphosphonite (2e) (1.8 mmol)
were selected to undergo reaction with 5-iodovanillin (1) (1.2 mmol, 0.33 g) under the assigned
5
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conditions
methoxyphenylphosphonates
methoxyphenyl(phenyl)phosphinate (3e) (Scheme 2).
to
obtain
the
corresponding
substituted
methyl
5-formyl-2-hydroxy-3-
5-formyl-2-hydroxy-3-
(3b-d) and
Inspired by the above results, we further extended this process on 3,5-difluorobenzyl
bromide (4) (1.2 mmol, 0.17 mL) with various alkyl phosphites (2b-d) and dimethyl
phenylphosphonite (2e) (1.8 mmol) to afford the desired substituted 3,5-
difluorobenzylphosphonates (5a-d) and methyl 3,5-difluorobenzyl(phenyl)phosphinate (5e)
(
Scheme 3). The physical data of the synthesized compounds are presented in Table S2.
Spectroscopy
The chemical structure of the title compounds 3a-e and 5a-e are supported by spectral data
3
1
1
13
(
P, H and C NMR, IR and LC-MS), elemental analysis. The results are presented in the
3
1
Experimental section. Characteristic P NMR signals were observed in the region 39.2-17.5
1
ppm for all the compounds (3a–e, 5a-e). In H NMR spectra, the signals due to ArH protons
were observed in the region 7.92-7.63 ppm. The proton signals at 10.20-9.85 and 9.82-9.37 ppm
are assigned to CHO and OH functionalities of 3a-e. The signal due to P-CH proton signals
2
1
3
appeared at 3.63-3.47 ppm for 5a-e. C NMR chemical shifts were observed in the expected
regions. IR stretching absorptions for P=O, P-O-Calip were observed in the regions 1242-1230,
−1
1
029-1022 cm respectively. The absorptions due to OH, P-Caromatic were observed in the
−1
regions 3417-3411, 1463-1457 cm respectively for 3a-e. The characteristic absorption due to
6
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−1
+
P-Caliphatic stretching was observed in the region 736-724 cm for 5a-e. In their mass spectra, M
ions were observed for the expected m/z values.
Based on an overview and a literature survey, we propose a possible mechanism for the
mediated Michaelis-Arbuzov reaction (Figure S 1 Supplemental Materials). The alkyl
BiCl
3
halide and Lewis acid catalyst form a complex which enhances the electrophilic nature of the
alkyl halide and make it feasible to the S 2 attack of the lone pair electrons of the phosphorus of
N
trialkyl phosphite and determine the reaction pathway.
Biological activity
Antibacterial activity
The antibacterial activity of the title compounds was assayed against two Gram positive
3
5a,35b,35c
and two Gram negative bacteria by the agar well diffusion method.
All newly
synthesized compounds exhibited moderate to good activity against both Gram positive and
Gram negative bacteria. Especially 5d, 3b, 5e and 5b exhibited good antibacterial activity
against both Gram positive and Gram negative bacteria when compared to that of standard drugs.
The data are presented in Table S 1 (Supplemental Materials).
Antifungal activity
The antifungal activity of the newly synthesized compounds was screened against two
3
6
fungi, Aspergillus niger and Fusarium oxysporum by the poison plate technique. All
compounds exhibited moderate to good antifungal activity against the two fungi. Especially 3a,
7
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3b, 5a and 5d exhibited better activities than the remaining compounds. The data are presented
in Table S 2.
EXPERIMENTAL
Materials and methods
All chemicals used were purchased from Sigma-Aldrich and Merck. Solvents were
distilled from the appropriate drying agents and stored under N . The reactions were monitored
2
by thin layer chromatography (TLC) on Merck precoated silica GF254 plates. Melting points were
determined in open capillaries on a Guna melting point apparatus and are uncorrected. IR
1
13
31
Spectra were recorded as KBr discs on a Nicolet 380 FT-IR spectrophotometer. H, C and P
NMR spectra were recorded in DMSO-d
6
on a Bruker AMX 400 MHz spectrometer operating at
1
13
31
4
00 MHz for H, 100 MHz for C and 161.9 for P NMR. TMS was used as the internal
1
13
31
standard for H and C NMR spectra and H
3
PO as the external standard for P NMR spectra.
4
Chemical shifts were expressed in ppm. LC-MS spectra were recorded on a SHIMADZU 2010A
mass spectrometer. Elemental analysis was performed on Thermo Finnigan Flash 1112
instrument at the University of Hyderabad, Hyderabad. Silica gel (100-200 mesh) was used in
column chromatography (CC) for purification of the synthesized compounds. Multiplicities are
shown as the abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet) and J in Hz. The
structures of the products, and sample spectroscopic characterizations for 3d and 5d are shown in
Table S 3 and Figures S 2 – S 5 (Supplemental Materials)
General synthesis of compounds 3a-d
8
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5
-Iodovanillin (1) (1.2 mmol, 0.33 g) and trimethyl phosphite (2a) (1.8 mmol, 0.21 mL) in
dry THF (20 mL) were taken in a flat bottomed flask. To this mixture, BiCl (20 mol%) was
added and the reaction mixture was stirred vigorously at 40 °C under a N atmosphere for 4 h.
3
2
The progress of the reaction was monitored by TLC (EtOAc: hexane, 2:1). After completion of
the reaction, the reaction mixture was filtered to separate the catalyst. The solvent from the
filtrate and the byproducts were removed under reduced pressure to get the crude product. The
resulting crude product was purified by CC (EtOAc-hexane 1:1 as eluent) to afford pure
dimethyl 5-formyl-2-hydroxy-3-methoxyphenylphosphonate (3a). The remaining title
compounds (3b-d) were prepared by adopting the above described procedure.
Methyl
Iodovanillin (1) (1.2 mmol, 0.33 g) was treated with dimethyl phenylphosphonite (2e) (1.8
mmol) in dry THF in the presence of BiCl as catalyst at 40 °C under N for 4 h. The crude
5-formyl-2-hydroxy-3-methoxyphenyl(phenyl)-phosphinate
(3e).
5-
3
2
product was purified by CC to obtain pure 3e.
General Synthesis of 5a-d
3
,5-Difluorobenzyl bromide (4) (1.2 mmol, 0.17 mL) and trimethyl phosphite (2a) (1.8
mmol, 0.21 mL) in dry THF (20 mL) were taken in a flat bottomed flask. To this mixture, BiCl
20 mol%) was added and the reaction mixture was stirred vigorously at 40 °C under N for 4 h.
3
(
2
The progress of the reaction was monitored by TLC (EtOAc/hexane, 2:1). After completion of
the reaction, the reaction mixture was filtered to separate the catalyst. The solvent from the
filtrate and the byproducts were removed under reduced pressure. The resulting crude product
was purified by CC (EtOAc/hexane 1:1 as eluent to afford pure dimethyl 3,5-
9
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difluorobenzylphosphonate (5a). The remaining title compounds (5b-d) were prepared by
adopting the above described procedure.
Methyl 3,5-difluorobenzyl(phenyl)phosphinate (5e). 3,5-Difluorobenzyl bromide (4) (1.2
mmol, 0.17 mL) was reacted with dimethyl phenylphosphonite (2e) (1.8 mmol) in dry THF in
the presence of BiCl
3
as catalyst at 40 °C under N for 4 h. The crude product was purified by
2
CC to obtain pure 5e.
The synthetic protocol for the compounds (3a-e) and (5a-e) is shown in Scheme 2 Scheme
3
.
Physical, analytical and spectral data of 3a-e and 5a-e
Dimethyl 5-formyl-2-hydroxy-3-methoxyphenylphosphonate (3a). Semi solid, Yield
3
1
1
7
7
3
5%. P NMR: δ 21.5; H NMR: δ 10.20 (s, 1H, CHO), 9.85 (s, 1H, OH), 7.76 (s, 1H, ArH),
1
3
.35 (s, 1H, ArH), 3.79 (s, 3H, OCH
3
), 3.40 (s, 6H, OCH ); C NMR: δ 192.1 (C-7), 154.7 (C-
3
), 147.8 (C-2), 133.0 (C-5), 126.9 (C-6), 125.1 (C-1), 117.8 (C-4), 56.4 (C-8), 54.1 (C-9, C-9′);
+
IR: 3417 (OH), 1463 (P-Car), 1240 (P=O), 1028 (P-O-Calip); LCMS m/z, (%): 261 (100) [M+H] .
Calcd. for C10
H
13
6
O P (260); C, 46.16; H, 5.04%; found: C, 46.10; H, 5.09%.
Diethyl 5-formyl-2-hydroxy-3-methoxyphenylphosphonate (3b). Semi solid, Yield
3
1
1
8
7
0%. P NMR: δ 22.3; H NMR: δ 10.12 (s, 1H, CHO), 9.82 (s, 1H, OH), 7.82 (s, 1H, ArH),
1
3
.42 (s, 1H, ArH), 4.01 (m, 4H, OCH
2
CH
3
), 3.75 (s, 3H, OCH
3
), 1.15 (t, 6H, OCH
2
CH ); C
3
NMR: δ 190.2 (C-7), 153.5 (C-3), 152.1 (C-2), 131.3 (C-5), 127.4 (C-6), 117.3 (C-1), 116.2 (C-
), 61.6 (C-9, C-9′), 56.3 (C-8), 16.2 (C-10, C-10′); IR: 3415 (OH), 1460 (P-Car), 1238 (P=O),
4
1
0
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+
1
5
027 (P-O-Calip); LCMS m/z (%): 289 (100) [M+H] . Calcd. for C12
H
17
6
O P (288): C, 50.00; H,
.94%), found: C, 50.05; H, 5.89%.
Diisopropyl 5-formyl-2-hydroxy-3-methoxyphenylphosphonate (3c). Semi solid,
3
1
1
Yield 77%. P NMR: δ 20.3; H NMR: δ 10.03 (s, 1H, CHO), 9.78 (s, 1H, OH), 7.83 (s, 1H,
ArH), 7.41 (s, 1H, ArH), 4.52 (m, 2H, OCH (CH ), 3.80 (s, 3H, OCH ), 1.21 (t, 12H,
); C NMR: δ 191.5 (C-7), 159.9 (C-3), 135.4 (C-2), 127.7 (C-5), 126.5 (C-6), 120.6
C-1), 117.6 (C-4), 71.6 (C-9, C-9′), 56.5 (C-8), 23.9 (C-10, C-10′, C-10′′, C-10′′′); IR: 3415
3
)
2
3
1
3
3 2
OCH(CH )
(
(
+
OH), 1458 (P-Car), 1235 (P=O), 1026 (P-O-Calip); LCMS m/z (%): 317 (100) [M+H] . Calcd. for
P (316): C, 53.16; H, 6.69%; found: C, 53.10; H, 6.62%.
C
14
H
21
O
6
Dibutyl 5-formyl-2-hydroxy-3-methoxyphenylphosphonate (3d). Semi solid, Yield
31
1
7
8%. P NMR: δ 17.5; H NMR: δ 9.94 (s, 1H, CHO), 9.75 (s, 1H, OH), 7.88 (s, 1H, ArH), 7.41
s, 1H, ArH), 3.95 (m, 4H, OCH CH CH CH ), 3.89 (s, 3H, OCH ), 1.62 (m, 4H,
), 1.34 (m, 4H, OCH CH CH CH ), 1.05 (t, 6H, OCH
(
2
2
2
3
3
1
3
OCH
2
CH
2
CH
2
CH
3
2
2
2
3
2
CH
2
CH
2
CH
3
);
C
NMR: δ 190.1 (C-7), 152.1 (C-3), 147.3 (C-2), 134.7 (C-5), 130.0 (C-6), 115.5 (C-1), 112.8 (C-
ˈ
4
3
), 79.3 (C-9 & C-9 ), 54.6 (C-8), 32.4 (C-10, C-10′), 19.5 (C-11, C-11′), 14.4 (C-12, C-12′); IR:
+
413 (OH), 1457 (P-Car), 1232 (P=O), 1024 (P-O-Calip); LCMS m/z, (%): 345 (100) [M+H] ;
Calcd. For C16
H
25
O
6
P (344): C, 55.81; H, 7.32; found: C, 55.73; H, 7.26%.
Methyl 5-formyl-2-hydroxy-3-methoxyphenyl(phenyl)phosphinate (3e). Semi solid,
3
1
1
Yield 71%. P NMR: δ 31.2; H NMR: δ 9.85 (s, 1H, CHO), 9.37 (s, 1H, OH), 7.92-7.41 (m,
1
3
7
1
1
H, Ar-H), 3.80 (s, 3H, OCH
3
), 3.47 (s, 3H, POCH ); C NMR: δ 191.8 (C-7), 157.8 (C-3),
3
51.6 (C-2), 135.8 (C-10), 132.2 (C-5), 131.2 (C-12, C-12′), 128.4 (C-6), 124.5 (C-1), 121.5 (C-
3), 118.4 (C-11, C-11′), 112.6 (C-4), 56.0 (C-8), 52.9 (C-9); IR: 3411 (OH), 1458 (P-Car), 1230
1
1
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+
(
P=O), 1025 (P-O-Calip); LCMS m/z (%): 307 (100) [M+H] . Calcd. for C15
H
15
5
O P (306): C,
58.83; H, 4.94%; found: C, 58.88; H, 4.89%.
3
1
Dimethyl 3,5-difluorobenzylphosphonate (5a). Semi solid, Yield 76%. P NMR: δ 28.2;
1
13
H NMR: δ 6.71-6.65 (m, 3H, ArH), 3.61 (d, J = 6.5 Hz, 2H, PCH
2
), 3.49 (s, 6H, OCH ); C
3
NMR: δ 165.6 (C-3, C-5), 133.8 (C-1), 112.4 (C-2, C-6), 103.4 (C-4), 53.9 (C-7), 29.7 (C-8, C-
+
8
′); IR: 1242 (P=O), 1029 (P-O-Calip), 735 (P-Calip); LCMS m/z (%): 237 (100) [M+H] . Calcd.
for C
9
H
11
F
2
3
O P (236): C, 45.77; H, 4.69%; found: C, 45.85; H, 4.62%.
3
1
1
Diethyl 3,5-difluorobenzylphosphonate (5b). Semi solid, Yield 79%. P NMR: δ 25.0; H
NMR: δ 6.82-6.73 (m, 3H, ArH), 3.94 (m, 4H, OCH CH ), 3.63 (d, J = 6.4 Hz, 2H, PCH ), 1.28
); C NMR: δ 166.1 (C-3, C-5), 140.6 (C-1), 114.2 (C-2, C-6),
04.7 (C-4), 66.6 (C-8, C-8′), 38.9 (C-7), 16.3 (C-9, C-9′); IR: 1238 (P=O), 1028 (P-O-Calip), 728
2
3
2
13
(
t, J = 5.6 Hz, 6H, OCH
2
CH
3
1
+
(
P-Calip); LCMS m/z (%): 265 (100) [M+H] . Calcd. for C11
H
15
F
2
3
O P (264): C, 50.01; H, 5.72%;
found: C, 50.08; H, 5.67%.
3
1
Di-isopropyl-3,5-difluorobenzylphosphonate (5c): Semi solid, Yield 73%. P NMR: δ
1
2
5.3; H NMR: δ 6.92-6.70 (m, 3H, ArH), 4.20 (m, 2H, OCH(CH
3
2
) ), 3.54 (d, J= 6.0 Hz, 2H,
1
3
PCH ), 1.10 (d, J = 5.8 Hz, 12H); C NMR: δ 164.3 (C-3, C-5), 136.9 (C-1), 113.3 (C-2, C-6),
2
102.7 (C-4), 70.6 (C-8, C-8′), 33.4 (C-7), 24.5 (C-9, C-9′, C-9′′, C-9′′′); IR: 1233 (P=O), 1024 (P-
+
O-Calip), 727 (P-Calip); LCMS m/z (%): 293 [M+H] . Calcd. for C13
H
19
F
2
3
O P (292): C, 53.42; H,
6.55%; found: C, 53.50; H, 6.60%.
3
1
Dibutyl 3,5-difluorobenzylphosphonate (5d): Semi solid, Yield 75%. P NMR: δ 21.8;
1
H NMR: δ 6.89-6.73 (m, 3H, ArH), 3.99 (m, 4H, OCH
2
CH
2
CH
2
CH ), 3.56 (d, J = 6.2 Hz, 2H,
3
1
2
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PCH
OCH
9.1 (C-8, C-8′), 34.5 (C-7), 32.6 (C-9, C-9′), 19.7 (C-10, C-10′), 14.6 (C-11, C-11′); IR: 1230
2
), 1.63 (m, 4H, OCH
2
CH
2
CH
2
CH
3
), 1.35 (m, 4H, OCH
2
CH
2
CH
2
CH ), 1.10 (t, 6H,
3
1
3
2
CH
2
CH
2
CH
3
); C NMR: δ 164.3 (C-3, C-5), 136.1 (C-1), 112.5 (C-2, C-6), 102.4 (C-4),
7
+
(
(
P=O), 1022 (P-O-Calip), 724 (P-Calip); LCMS m/z (%): 321 [M+H] . Calcd. for C15
H
23
F
2
3
O P
320): C, 56.25; H, 7.24%; found: C, 56.31; H, 7.29%.
3
1
Methyl 3,5-difluorobenzyl(phenyl)phosphinate (5e): Semi solid, Yield 77%. P NMR: δ
1
3
9.2; H NMR: δ 7.48-6.63 (m, 8H, ArH), 3.84 (d, J = 6.4 Hz, 2H, PCH
2
), 3.47 (s, 3H, POCH );
3
1
3
C NMR: δ 166.1 (C-3, C-5), 136.2 (C-9), 134.5 (C-1), 132.0 (C-11, C-11′), 129.1 (C-12), 128.5
(
C-10, C-10′), 113.8 (C-2, C-6), 104.7 (C-4), 50.3 (C-8), 28.9 (C-7); IR: 1237 (P=O), 1029 (P-O-
+
C
alip), 736 (P-Calip); LCMS m/z (%): 283 (100) [M+H] . Calcd. for C14
H
13
F
2
2
O P (282): C, 59.58;
H, 4.64%; found: C, 59.52; H, 4.68%.).
Statistical analysis
Data of antimicrobial activity were expressed as means ± S.D. of three replicates. On the
basis of the calculated value by using ANOVA method, it has been observed that the difference
below 0.05 level (P<0.05) were considered as statistically significant.
CONCLUSION
In conclusion, we have synthesized a series of novel alkyl substituted aryl
phosphonates/phosphinates by Michaelis-Arbuzov rearrangement at 40 °C with high yields by
the reaction of an aryl halide with various trialkyl phosphites and dimethyl phenylphosphonite in
the presence of inexpensive, economically affordable and ecofriendly catalyst, Bismuth(III)
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3
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chloride which has proved to be a superior catalyst in this reaction. The majority of the newly
synthesized compounds exhibited good antibacterial and antifungal activity when compared to
the standard drug.
ACKNOWLEDGMENT
The authors G. Madhava and S. K. Thaslim Basha acknowledge the University Grants
Commission for the award of Senior Research Fellow (SRF). Also, the authors express their
thanks to Hyderabad Central University and Osmania University for providing instrumentation
facilities for recording the spectra.
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4
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a
Table 1. Optimization of reaction conditions for the synthesis of 3a
b
Entry
Catalyst (mol%)
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
Toluene
DCM
Time
24h
24h
6h
Temperature
Yield (%)
1
2
3
4
5
6
7
8
9
No Catalyst
reflux
reflux
55
Trace
30
Et
·Et
·7H
BiCl
BiCl
BiCl
3
N
BF
3
2
O (10)
O (10)
58
CeCl
3
2
5h
50
56
3
(10)
(10)
(10)
5h
40
63
3
5h
40
62
3
5h
40
63
BiCl (10)
3
THF
THF
THF
THF
THF
THF
THF
4h
4h
4h
4h
4h
4h
4h
40
40
40
40
40
40
40
68
69
70
72
75
75
75
BiCl
BiCl
BiCl
BiCl
BiCl
BiCl
3
(12.5)
1
1
1
1
1
0
1
2
3
4
3
(15)
3
(17.5)
3
(20)
3
(22.5)
3
(25)
a
The reaction was performed using 5-iodovanillin (1.2 mmol) and trimethyl phosphite (1.8
b
mmol); Isolated yields.
1
8
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O
O
I
Optimization of
the reaction conditions
P
O
HO
O
HO
O
O
P
O
O
O
O
H
1
2a
3a
H
Scheme 1: Model reaction for the optimization of the reaction conditions
1
9
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O
OR2
P
I
1
R3
OR2
N , BiCl3
HO
HO
O
2
2
6
R1 X
P
R
1
O
7
5
O
O
R3
THF, 40 ºC .
O
3
4
8
H
H
1
2a-e
3a-e
R1
R2
CH
R
3
a
b
CH3
O CH
3
1
3
9
9
H
C
2
H
C
9
2
H2
CH3
CH3
O C CH
3
1
1
10
9
10
1
1
0
10
H CH
H CH
H CH3
O C
3
3
c
d
C
C
9
9
1
CH3
CH
CH
3
111
3
1
1
1
0
1
0
H2
C
H2
C
H2
C
9
H2
H2
H2
C1
1
1
1
0
12
10
12
C
O C
1
9
C
CH
3
C
11 CH
3
C
11 CH
3
H
H
H
2
2
2
1
1
11
1
2
e
10
CH3
CH
13
3
9
11
12
Scheme 2: Synthesis of substituted 5-formyl-2-hydroxy-3-methoxyphenylphosphonates (3a-
d)/phosphinate (3e)
2
0
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O
Br
OR2
P
7
OR2
R
N , BiCl3
2
3
1
R O
P
1
2
6
R1
X
R3
THF, 40 ºC .
F
F
F
3
5
F
4
4
2a-e
5a-e
R1
R2
R3
a
b
CH3
CH
O CH
3
3
1
8
8
H2
C
H2
C
8
H
2
CH
CH
9
3
3
O
C
C1 H3
1
8
9
1
9
9
H CH3
H CH3
H CH3
c
d
C
C
O C
8
1
CH3
CH
3
8
CH
3
1
1
111
9
9
H2
C
H2
C
H2
C
8
H2
C
H2
H2
C
1
1
9
11
9
11
O C
C
H
CH3
C
H
10 CH3
8
1
C
H
10
1
CH3
2
2
2
1
1
10
11
e
9
CH3
C8 H3
12
11
1
0
Scheme 3: Synthesis of substituted 3,5-difluorobenzylphosphonates (5a-d)/phosphinate (5e).
2
1
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