Ultrasound-promoted synthesis of biologically active α- hydroxyphosphonates/hydroxyphosphinates using 1,4-dimethylpiperazine as a catalyst

Article abstract of DOI:10.1080/10426507.2013.843002

A series of new α-hydroxyphosphonates/phosphinates was prepared using 1,4-dimethylpiperazine as a base catalyst under conventional as well as ultrasonic irradiation conditions by the reaction of 5-bromoindole-3- carboxaldehyde/2-nitrocinnamaldehyde with v

Full text of DOI:10.1080/10426507.2013.843002

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Phosphorus, Sulfur, and Silicon and the Related
Elements
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Ultrasound Promoted Synthesis of Biologically Active α-
Hydroxyphosphonates/Hydroxyphosphinates using 1,4-
Dimethylpiperazine as a Catalyst
S. Rasheed a , K. Venkata Ramana a , G. Madhava a , D. Subba Rao a & C. Naga Raju a
a Department of Chemistry , Sri Venkateswara University , Tirupati , 517 502 , Andhra
Pradesh , India
Accepted author version posted online: 23 Sep 2013.
To cite this article: Phosphorus, Sulfur, and Silicon and the Related Elements (2013): Ultrasound Promoted Synthesis of
Biologically Active α-Hydroxyphosphonates/Hydroxyphosphinates using 1,4-Dimethylpiperazine as a Catalyst, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2013.843002
To link to this article: http://dx.doi.org/10.1080/10426507.2013.843002
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ACCEPTED MANUSCRIPT
Ultrasound Promoted Synthesis of Biologically Active α-
Hydroxyphosphonates/Hydroxyphosphinates using 1,4-Dimethylpiperazine as a Catalyst
S. Rasheed, K. Venkata Ramana, G. Madhava, D. Subba Rao and C. Naga Raju*
Department of Chemistry, Sri Venkateswara University, Tirupati -517 502, Andhra Pradesh,
India.
ABSTRACT
A series of new α-hydroxyphosphonates/phosphinates were prepared using 1,4-
dimethylpiperazine as a base catalyst under conventional as well as ultrasonic irradiation
conditions by the reaction of 5-bromoindole-3-carboxaldehyde/2-nitrocinnamaldehyde with
various phosphonates/phosphinates. The high yields of α-hydroxyphosphonates/
hydroxyphosphinates were obtained in less reaction time under ultrasonic irradiation method as
compared with the conventional method. The synthesized compounds were screened for their in
vitro and in vivo antioxidant activity and the bio-screening data revealed that all the tested
compounds exhibited good antioxidant activity. Compound 8e exhibited potent antioxidant
activity both in in vitro and in vivo studies.
Br
Br
O
OH
O
H
Conventional
condition
P
R or R1
R2
N
H
N
H
NO2
OH
R2
1,4-Dimethylpiperazine
THF
O
NO2
O
P
H
R or R1
Ultrasonic
condition
Keywords: Ultrasound irradiation, 1,4-Dimethylpiperazine, α-Hydroxyphosphonates/hydroxy
phosphinates, Antioxidant activity.
Corresponding author Tel: +91-9703193375, E-mail address: rajuchamarthi10@gmail.com
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INTRODUCTION
Phosphorus molecules are important scaffolds in organic synthesis to biology.
Phosphonates particularly α-hydroxyphosphonates have attained considerable attention since, α-
hydroxyphosphonic acids and their esters possesses a broad spectrum of biological and
pharmacological activities. It was found that α-hydroxyphosphonates exhibited promising
biological activities such as antiviral,1 antivaccina,2 antibacterial,3 anticancer,4 rennin
inhibition,5 pesticidal,6 HIV protease inhibitor,7 anti-HIV activity8 and also used as precursors
for the synthesis of α-halophosphonates, α-ketophosphonates, α-aminophosphonates, α-
thiocyanatophosphonates, α-azidophosphonates and α-carboxyphosphonates.9 Moreover, it was
found in the literature that α-hydroxyphosphonates act as potent radical scavengers.10 The
versatile biological and synthetic applications of α-hydroxyphosphonates led to considerable
attention for the development of new synthetic methodologies and interest to synthesize
structurally modified biologically active phosphonates. Several methods have been documented
in the literature for the synthesis of α-hydroxyphosphonates in the presence of base catalysts and
Lewis acid catalysts, as well as in ultrasonic and microwave irradiation conditions.11-13
Ultrasonication is an important technique and has been used to promote various organic
reactions in less time as compared with conventional conditions, and to synthesize bioactive
molecules.14-15 Hence, chemists have been focused considerable interest to carry out the
reactions under ultrasonication instead of conventional heating. The ultrasound effect on organic
reactions is attributed to formation, and growth of acoustic cavitations and impetus collapse of
bubbles in the liquid. Bubble collapse provides localized hot-spots with transient temperature of
5000-25000 oK of about 1800 atm and heating cooling rates in excess of 1010 Ks-1.16 The
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extreme conditions attained during bubble collapse, favors completion of organic reactions in
shorter times.
By considering the biological importance of α-hydroxyphosphonates and our continuous
research effort focused on ultrasound assisted reactions,17-18 we herein report new method for
the synthesis of α-hydroxyphosphonates/hydroxyphosphinates under ultrasound irradiation and
conventional conditions using 1,4-dimethylpiperazine as a base catalyst. The antioxidant activity
of the title compounds was evaluated.
RESULTS AND DISCUSSION
Chemistry: α-Hydroxyphosphonates/hydroxyphosphinates were prepared easily under
ultrasonication conditions using 1,4-dimethylpiperazine as base catalyst was depicted in Scheme
1. To prepare new title compounds, two alkyl phosphinates 3 a-b were synthesized primarily
from phenyl phosphinic acid (1) by treating with NaH in THF at 0-5 o C followed by reacting
with EtBr/ n-PrBr at 20-30 oC (Scheme S 1 Supplemental Materials).19
[Scheme 1]
To optimize the reaction conditions for the synthesis of α-hydroxyphosphonates/
phosphinates, 5-bromoindole -3-carboxaldehyde (4) and dimethyl phosphite (5a) were selected
as models. At first, the model reaction was carried out in THF at 60-65 oC under catalyst free
conditions to obtain diethyl (5-bromo-1H-indol-3-yl)(hydroxy)methylphosphonate (6a), even
after for long reaction time (16 h) low yield of the product 6a (38%) was observed (Table 1 entry
1). To improve the yield, the model reaction was progressed in different base catalysts, Et3N,
piperazine, 1,4-dimethylpiperazine and Lewis acid catalysts, CuCl2, FeCl3, ZnCl2 (Table 1 entry
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2-7). The high yield of the product 6a (78%) was observed in a short reaction time (4 h) using
1,4-dimethylpiperazine as a base catalyst (Table 1 entry 3). Further, to examine the solvent effect
on the reaction, the model reaction in the presence of 1,4-dimethylpiperazine was tested in
different solvents, CH3CN, C6H5CH3, CH2Cl2 and MeOH (Table 1 entry 8-11). Found that
good yield of the compound 6a was observed in THF solvent as compared with other used
solvents (Table 1 entry 3). To our delight, the effect of the amount of the catalyst was also
examined by altering the amount of the catalyst (Table 2 entry 1-5) results revealed that 30 mol%
of catalyst, 1,4-dimethylpiperazine is adequate to afford the high yield of the product 6a (Table 2
entry 5). However, the high amount of the catalyst (30 mol%), 1,4-dimethylpiperazine was used
to obtain good yield of the product and the catalyst was not reused due to homogeneity of the
catalyst. The proposed mechanism for the synthesis of α-hydroxy phosphonates in the presence
of 1,4-dimethylpiperazine catalyst was shown in Figure S 1. The generality of the optimized
conditions was checked by altering phosphites/synthesized phosphinates, aldehydes and the
products were obtained in good yields. The results are tabulated in Table 3.
[Insert Table 1 and Table 2]
In continuation of our endeavor and in search of alternative to conventional heating
methods, we attempted to carry out the optimized reaction condition under ultrasonication,
interestingly, the reaction was completed in very short reaction time (21 min) and afforded a high
yield of the product 6a (88%) at 60 oC in THF. The generality of the reaction was explored and
the results are summarized in Table 3.
[Insert Table 3]
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The chemical structures of all the synthesized compounds 6 a-e and 8 a-e were
characterized by NMR (31P, 1H, 13C), IR, mass spectral data and C, H, N analysis. In 31P
NMR spectra, the resonated signals appeared as singlet in the region 18.7-23.9 ppm.21 The P-C-
H protons resonated as a doublet due to its coupling with phosphorus atom in the region 4.80-
4.64 ppm. In 13C NMR, all the signals were observed in their respective regions. The
appearance of characteristic IR stretching absorptions in the regions of 3473-3300 cm-1, 1020-
1000 cm-1, 1260-1190 and 785-700 cm-1 confirmed the functionalities, -OH, P-O-C(butyl),
P=O, P-C (aliphatic) respectively in the title compounds.22
To avoid the mortality of the animals, an in vitro study was made as preliminary
screening method. In vitro non-enzymatic antioxidant activity of title α-hydroxyphosphonates/
phosphinates was evaluated using DPPH23 and superoxide radical scavenging24 methods (Table
S 1). Bio-screening data revealed that all the compounds showed potent to moderate antioxidant
activity, whereas compounds 6a, 6d, 8d and 8e exhibited potent antioxidant activity in both
methods and these results encouraged us to carry out in vivo studies. CATALASE activity25-26
of the title compounds (Figure S 1) was screened and the results indicated that 6a, 6d, 8d and 8e
compounds exhibited promising in vivo antioxidant activity. The biological data of the tested
compounds disclosed that compounds 6a, 6d, 8d and 8e exhibited promising activity in both
enzymatic and non-enzymatic assays. However, compound 8e exhibited scavenged maximum
free radicals at both concentrations when compared to the remaining title compounds and the
IC50 value of the compound 8e is very near to the standard ascorbic acid.
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CONCLUSION
In summary, a simple synthetic protocol was developed for the synthesis of
α-hydroxyphosphonates/phosphinates under ultrasonication and conventional conditions using
1,4-dimethylpiperazine as a base catalyst. The high yields of α-hydroxyphosphonates/
phosphinates were obtained in lower reaction times under ultrasonication method as compared
with conventional method. Further, in vitro and in vivo antioxidant activity was evaluated for the
title compounds and all the tested compounds exhibited potent to moderate antioxidant activity.
Compounds 6a, 6d, 8d and 8e exhibited promising radical scavenging activity. The variation in
scavenging capacity of the tested samples could be attributed to the effect of different
substitutions at the α-carbon. The antioxidant activity study of the synthesized compounds
provided an additional direction for structural optimization of the compounds for the
development of antioxidant nature with improved selectivity and reduced side effects.
EXPERIMENTAL
Thin layer chromatography was performed using silica gel 60 F-254 pre-coated plates
(0.25 mm) and visualized by iodine and UV irradiation. Sorbent silica gel (particle size 60-120
mesh) was used for column chromatography for purification of the synthesized compounds. 1H,
13C NMR and 31P NMR spectra were recorded in CDCl3 on a Bruker 400 MHz spectrometer
operating at 400 MHz for 1H, 100.25 MHz for 13C and 161.9 for 31P. TMS and 85% H3PO4
were used as internal standards in 1H NMR, 13C NMR and 31P NMR respectively. Mass spectra
were recorded in E.S.I Mode on API-3000 mass spectrometer. Elemental analysis was performed
on Thermo Finnigan Instrument at University of Hyderabad, Hyderabad.
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Sonication was performed using BANDELIN SONOREX® (Germany) with a frequency
of 35 kHz and a nominal power 200 W ultrasonic bath for ultrasonic irradiation with inbuilt
heating 30-80 (°C), which is thermostatically adjustable. The reaction vessel was placed inside
the ultrasonic bath containing water.
Synthesis of dimethyl (5-bromo-1H-indol-3-yl)(hydroxy)methylphosphonate (6a).
Conventional method
5-Bromoindole-3-carboxaldehyde (4) (1 mmol, 223 mg), dimethyl phosphite (5a) (1
mmol, 0.095 mL) and 1,4-dimethylpiperazine (30 mol%) were dissolved in THF (10 mL) in a
flask. The reaction mixture was stirred at 60-65oC for 4 h. Progress of the reaction was
checked by TLC using n-hexane and ethyl acetate (1:4) as an eluent. After completion of the
reaction, the reaction mixture was concentrated using a rota-evaporator and the crude product
was purified by column chromatography on silica gel (60–120 mesh) using n-hexane and ethyl
acetate (3:1) as an eluent to afford pure dimethyl (5-bromo-1H-indol-3-yl)(hydroxy)
methylphosphonate (6a) (84%).
Ultrasonication method
5-Bromoindole-3-carboxaldehyde (4) (1 mmol, 223 mg), dimethyl phosphite (5a) (1
mmol, 0.095 mL) and 1,4-dimethylpiperazine (30 mol%) were dissolved in THF (10 mL) in a
flask. The reaction mixture was stirred at 60 oC under ultrasonic irradiation for 21 min. Progress
of the reaction was checked by TLC using hexane and ethyl acetate (1:4) as an eluent. After the
completion of the reaction, the reaction mixture was concentrated in vacuum to obtain the crude
product and it was purified by column chromatography on silica gel (60-120 mesh) using hexane
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and ethyl acetate (3:1) as an eluent to afford pure dimethyl (5-bromo-1H-indol-3-
yl)(hydroxy)methylphosphonate (6a) (87%). The same experimental procedure was adopted for
the preparation of the remaining title compounds 6 b-e and 8 a-e.
Dimethyl (5-bromo-1H-indol-3-yl)(hydroxy)methylphosphonate (6a).
Pale yellow solid, mp: 67-69 oC. 31P NMR (CDCl3, 161.9 MHz): δ 19.1 ppm; 1H NMR
(CDCl3, 400 MHz): δ 3.86 (s, 6H), 4.49 (d, 1H, J = 7.3 Hz, P-C-H), 6.02 (s, -OH), 7.18 (s, 1H,
Ar-H), 7.78 (s, 1H, Ar-H), 7.30 (d, 1H, J = 4.8 Hz, Ar-H), 7.32 (d, J = 4.4 Hz, 1H, Ar-H), 8.17
(s, 1H, NH) ppm; IR (KBr) (vmax cm-1): 723 (P-C), 1022 (P-O-C(aliphatic)), 1195 (P=O),
3474 (-OH); E.S.I. mass m/z (%): 334 (100) [M+.], 336 (98) [M+.+2], 319 (55); Anal. cald. for
C11H13BrNO4P: C: 39.54, H: 3.92, N: 4.19. Found: C: 39.50, H: 3.89, N: 4.13.
(E)-Dimethyl 1-hydroxy-3-(2-nitrophenyl)allylphosphonate (8a).
Pale orange solid, mp: 84-86oC. 31P NMR (CDCl3, 161.9 MHz): δ 22.6 ppm; 1H NMR
(CDCl3, 400 MHz): δ 3.90 (s, 6H), 4.60 (d, 1H, J = 6.3 Hz, P-C-H), 5.20 (s, -OH), 6.40-6.50
(dd, 1H, J = 15.8, 7.0 Hz), 6.70 (d, 1H , J = 15.9 Hz), 7.30 - 7.60 (m, 3H), 8.00 (d, 1H , J = 14.0
Hz) ppm; IR (KBr) (vmax, cm-1): 740 (P-C), 1016 (P-O-C(aliphatic)), 1220 (P=O), 3460 (-OH);
E.S.I. mass m/z (%): 287 (100) [M+.], 257 (38), 179 (20), 135 (30); Anal. cald. for
C11H14NO6P: C: 46.00; H: 4.91; N: 4.88; Found: C: 46.10; H: 4.88; N: 4.91.
The Supplemental Materials contains additional characterization data for compounds 6b-e and
8b-eand sample spectra for compound 8d (Figures S 3 – S 5).
BIOLOGICAL ACTIVITY:
The in vitro antioxidant activity of the newly synthesized compounds 6 a-e and 8 a-e was
screened using DPPH, superoxide radical scavenging methods. The biological data revealed that
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all the compounds exhibited potent to moderate antioxidant activity. These results encouraged to
investigate in vivo antioxidant activity of the title compounds on catalase, which was carried out
after the examination of the acute toxicity of the title compounds. The results are summarized in
Table S 1 and Figure S 1 (See Supplemental Materials).
STATISTICAL ANALYSIS
All the values expressed as mean SD and data were analyzed by one-way ANOVA,
using Graph pad INSTAT. The post-hock analysis was carried out by Dunnet’s multiple
comparison tests to estimate the significance of difference between individual groups.
ACKNOWLEDGEMENTS
The author, S Rasheed express his thanks to University Grants Commission, New Delhi,
for awarding RFSMS Fellowship under the scheme of UGC-BSR Programme and G Madhava is
grateful to University Grants Commission, New Delhi, for the award of Senior Research
Fellowship (SRF). The authors also express their thanks to Mr. S. Adam for evaluating
antioxidant activity.
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REFERENCES
[1] Neyts, J.; De Clercq, E. Antimicrob. Agents. Chemother. 1997, 41, 2754-2756.
[2] Snoeck, R.; Holy, A.; Peeters, C. D.; Van Den O, J.; De Clercq, E.; Andrei, G. Antimicrob.
Agents. Chemother. 2002, 46, 3356-3361.
[3] Fleisch, H. Endocr. Rev. 1998, 19, 80-100.
[4] Lee, M. V.; Fong, E. M.; Singer, F. R.; Guenett, R. S. Cancer Res. 2001, 61, 2602-2608.
[5] Patel, D. V.; Gauvin, K. R.; Ryono, D. E.; Free, C. A.; Rogers, W. L.; Smith, S. A.; De
Forrest, J. M.; Oehl, R. S.; Petrillo, E. W. Jr. J. Med. Chem. 1995, 38, 4557-4569.
[6] Kafarski, P.; Lejczak, B. J. Mol. Catal. B: Enzym. 2004, 29, 99-104.
[7] Stowasser, B.; Budt, K. H.; Qi, L. J.; Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33,
6625-6628.
[8] Zheng, X.; Nair, V. Tetrahedron. 1999, 55, 11803-11818.
[9] Patel, D. V.; Gauvin, K. R.; Ryono, D. E. Tetrahedron Lett. 1990, 31, 5591-5594.
[10] Naidu, K. R. M.; Kumar, K. S.; Arulselvam, P.; Reddy, C. B.; Lasekan, O. Arch. Pharm.
Chem. Life Sci. 2012, 345, 957-963; (b) Rao, K. U. M.; Sundar, Ch. S.; Prasad, S. S.; Rani,
C. R.; Reddy C. S. Bull. Korean Chem. Soc. 2011, 32, 3343-3347.
[11] (a) Saito, B.; Katsuki, T. Angew. Chem. Int. Ed. 2005, 44, 4600-4602; (b) Duxbury, J. P.;
Cawley, A.; Thornton, M. P.; Wantz, L.; Warne, J. N. D.; Greatrex, R.; Brown, D.; Kee, T.
P. Tetrahedron Lett. 1999, 40, 4403-4406; (c) Duxbury, J. P.; Warne, J. N. D.; Mushtaq,
R.; Ward, C.; Thornton, M. P.; Jiang, M.; Greatrex, R.; Kee, T. P. Organometallics. 2000,
19, 4445-4457; (d) Arai, T.; Bongauchi, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1996,
61, 2926-2927; (e) Simoni, D.; Rondanin, R.; Morini, M.; Baruchello, R.; Lnvidiata, F. P.
10
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Tetrahedron Lett. 2000, 41, 1607-1610; (f) Alexander, C. W.; Albiniak, A. P.; Gibson, R.
L. Phosphorus, Sulfur and Silicon Relat. Elem. 2000, 167, 205-209; (g) Kaboudin, B.;
Nazari, R. J. Chem. Res. (S) 2002, 291-292; (h) Keglevich. G.; Tóth, V. R.; Drahos, L.
Heteroat. Chem. 2011, 22, 15-17; (i) Kaboudin, B.; Fallahai, M. Tetrahedron Lett. 2011,
52, 4346-4347 (j) Xia, M.; Lu, Y. D. Ultrason. Sonochem. 2007, 14, 235-240.
[12] (a) Boullet, F. T.; Lequitte, M. Tetrahedron Lett. 1986, 27, 3515-3516; (b) Gawron, O.;
Grelecki, C.; Reilly, W.; Sands, J. J. Am. Chem. Soc. 1953, 75, 3591-3592; (c) Smaardijk,
A. Ab.; Noorda, S.; Bolhuis, F. V.; Wynberg, H. Tetrahedron Lett. 1985, 26, 493-496; (d)
Blazis, V. J.; Koeller, K. J.; Spilling, C. D. J. Org. Chem. 1995, 60, 931-940; (e) Sardarian,
A.R.; Kaboudin, B. Synth. Commun. 1997, 27, 543-551; (f) Venugopal, T.; Chung H. K.
Bull. Korean Chem. Soc. 2008, 29, 1781-1783; (g) Pàmies, O.; Bäckvall, J. E. J. Org.
Chem. 2003, 6, 4815-4818; (h) Kumar, K. S.; Reddy, B. C.; Reddy, V. N.; Rani C. R.;
Reddy, C. S. Org. Commun. 2012, 5, 50-57.
[13] (a) Boullet, F. T.; Foucaud, A.; Synthesis, 1982, 11, 916; (b) Yokomatsu, T.; Yamagishi,
T.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1997, 1, 1527-1533; (c) Azizi, N.; Saidi, M.
R. Phosphorus, Sulfur, Silicon Relat. Elem. 2003, 178, 1255-1259; (d) Razumov, A. I.;
Moskva, V. V. Russ J Gen Chem., 1974, 44, 2586.
[14] Mason, T. J. Chem. Soc. Rev. 1997, 26, 443-451.
[15] (a) Luche, J. L. Synthetic organic sonochemistry; Plenum Press: New York, 1998; (b)
Mason, T. J. Advances in sonochemistry; JAI Press: London and Greenwich, CT, 1990.
[16] Li, H.; Ni, Y. H.; Hong, J. Scr. Mater. 2009, 60, 524-527.
11
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[17] Rao, V. K.; Reddy, S. S.; Krishna, B. S.; Naidu, K. R. M.; Ghosh, S. K. Green Chem Lett
and Rev. 2010, 3, 217-223.
[18] Rasheed, S.; Ramana, K. V.; Sekhar, K. C.; Fareeda, G.; Raju, C. N.; Arch. Pharm. Chem.
Life Sci. 2012, 345, 294-301.
[19] Volle, J. N.; Fillippini, D.; Midrier, C.; Sobecki, M.; Drag, M.; Virieux, D.; Pirat, J. L.
Synthesis. 2011, 15, 2490-2494.
[20] Kaboudin, B.; Faghini, M.R. Synthesis. 2010, 10, 1736-1740.
[21] Kabachnik, M. M.; Minaeva, L. I.; Beletskaya, L. P. Russ. J. Org. Chem. 2009, 45, 1119-
1122.
[22] Thomas, L. C. The Interpretation of the Infrared Spectra of Organic Phosphorus
Compounds, Heyden and Sons, London, 1974, 129.
[23] Akowuah, G. A.; Ismail, Z.; Norhayati, I.; Sadikun, A. Food Chem. 2005, 93, 311-317.
[24] Vani, T.; Rajani, M.; Sarkar, S.; Shishoo, C. J. Inter. J. Pharmacog., 1997, 35, 313-317.
[25] Aebi, H. Methods Enzymol. 1984, 105, 121-126.
[26] Sinha, K. A. Anal. Biochem. 1972, 47, 389-394.
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Conventional Br
condition
Br
OH
O
O
O
R or R1
H
P
P
+
H
R or R1
R2
THF 1,4-DMP
))))
R2
N
H
N
H
Ultrasonic
condition
6 a-e
3a-b & 5 a-c
4
Conventional
condition
NO2
OH
O
NO2
O
O
R or R1
P
P
R2
+
H
THF
H
1,4-DMP
))))
R2
R1 ro R
Ultrasonic
condition
7
3 a-b & 5 a-c
8 a-e
R
R1
R2
Phosphinate/phosphite Product
S. No
1
2
3
OMe
OEt
OBut
Ph
OMe
5a
5b
5c
3a
6a
6b
6c
6d
OEt
OBut
4
OEt
5
6
OPri
3b
6e
Ph
OMe
OEt
OMe
OEt
5a
5b
5c
3a
8a
8b
8c
8d
8e
7
OBut
OBt
Ph
8
9
OEt
3b
OPri
10
Ph
Scheme 1. Synthesis of α-hydroxyphosphonates/phosphinates under conventional and ultra-
sonication conditions.
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Table 1. Optimization of the catalyst and solvent for the synthesis of α-
hydroxyphosphonates/phosphinates.a
Entry
Catalyst
No catalyst
Solvent
THF
Temperature (oC) Time (h) Yield (%)
1
2
60-65
60-65
16.0
7.0
38
49
Et3N (25 mol%)
THF
1,4-Dimethylpiperazine
(25 mol%)
3
THF
60-65
4.0
78
4
5
6
7
Piperazine (25%)
CuCl2 (25 mol%)
FeCl3 (25 mol%)
ZnCl2 (25 mol%)
THF
THF
THF
THF
60-65
60-65
60-65
60-65
4.0
4.0
4.0
4.0
75
69
71
71
1,4-Dimethylpiperazine
(25 mol%)
8
9
CH3CN
75-80
80-90
30-40
60-65
4.0
4.0
4.0
4.0
69
70
65
68
1,4-Dimethylpiperazine C6H5CH
3
(25 mol%)
1,4-Dimethylpiperazine
(25 mol%)
10
11
DCM
1,4-Dimethylpiperazine
(25 mol%)
EtOH
aThe model reaction was carried out using 5-bromoindole -3-carboxaldehyde (4) (1 mmol)
and dimethyl phosphite (5a).
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Table 2. Amount of catalyst, 1,4-dimethylpiperazine effect on the synthesis of α-hydroxy
phosphonates/phosphinates.a
Yield
Catalyst
Time
Entry
mol (%)
2.5
5
(%)b
46
1
2
4.0 h
4.0 h
53
3
10
4.0 h
58
4
20
4.0 h
65
5
30
4.0 h
84
6
40
4.0 h
84
7c
30
21 minc
88
aThe model reaction was carried out using 5-bromoindole -3-carboxaldehyde (4) (1 mmol) and
dimethyl phosphite (1 mmol) (5a). bIsolated yields. cThe model reaction was carried out in ultra-
sonication using 30 mol% of 1,4-dimethyl piperazine as a catalyst.
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Table 3 Synthesis of α-hydroxyphosphonates/phosphinates under conventional and ultra-
sonication using 30 mol% of DMP catalyst.
Timea (h)/
Compd
6a
Structure
Yielda/b (%)
84/88
b (min)
Br
OH
O
P
4.0/21
OMe
MeO
N
H
Br
OH
O
P
6b
6c
4.0/21
4.5/21
86/90
86/86
OEt
EtO
N
H
Br
OH
O
P
OBu
BuO
OH
N
H
Br
O
P
6d
6e
5.0/21
5.0/21
83/87
85/85
Ph
Ph
EtO
N
H
Br
OH
O
P
PrO
N
H
NO2
OH
O
8a
8b
4.5/21
4.5/21
80/85
81/87
P
OMe
MeO
OH
NO2
O
P
OEt
EtO
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NO2
OH
O
8c
8d
8e
5.0/21
5.0/21
5.0/21
81/87
82/83
79/84
P
OBu
BuO
NO2
OH
O
P
P
Ph
EtO
OH
NO2
O
Ph
PrO
aTime and isolated yields of the reaction was carried out under conventional conditions. bTime
and isolated yields of the reaction was carried out under ultra-sonication conditions.
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