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An efficient synthesis of α-hydroxyphosphonates
and α-aminophosphonates in the presence of
chlorotrimethylsilane
Rajkumar U. Pokalwar a , Sandip A. Sadaphal a , Amol H. Kategaonkar a , Bapurao B.
Shingate a & Murlidhar S. Shingare a
a Department of Chemistry, Dr. Babasahe
b Ambedkar Marathwada University, Aurangabad,
431004, India
Available online: 18 Jan 2010
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INDUSTRY LETTER
An efficient synthesis of a -hydroxyphosphonates and a -aminophosphonates in the presence
of chlorotrimethylsilane
Rajkumar U.Pokalwar,Sandip A.Sadaphal,Amol H.Kategaonkar,Bapurao B.Shingate and
Murlidhar S.Shingare*
Department of Chemistry,Dr.Babasaheb Ambedkar Marathwada University,Aurangabad 431004,India
(Received 31March 2009;final version received 13October 2009)
Solvent free,and quantitative yielding synthesis of a -hydroxyphosphonates (2a Áh)from 2-chloroquinolin-3-carbaldehyde (1a Áh)and a -aminophosphonates (4a Áp)from imines (3a Áp),obtained from 2-chloroquinoline-3-carbaldehyde by using triethylphosphite in the presence of chlorotrimethylsilane at room temperature in short time.
P OCH 2CH 3OCH 2CH 3
31a–h
2a–h
R R 2CH 32CH
3
3a–p
reaction to a book or an article4a–p
3Keywords:2-chloroquinoline-3-carbaldehyde;a -hydroxyphosphonate;imines;a -aminophosphonate;TMSCl
Introduction
Quinolines (1Á3)are an important class of hetero-cyclic compounds and have been screened for several biological activities such as bactericidal (4),antitu-mor (5),anti-inflammatory (6),and antimalarial (7).Quinolines such as 2-chloroquinoline-3-carbaldehyde occupy a prominent position as they are key inter-mediates for further annelation and for various functional group interconversions (8,9).It is also reported that organophosphates are potent pesticides which have wide variety of application (10).Recently,some new vinyl phosphates have been reported as potent inhibitors of phosphatase (11Á13)and phos-phodiesterase (14,15).
There are only a few reports on the synthesis and bioactivity of C ÁP bonds which have been found to
have insecticidal (16)and antifungal (17)activities.Also a -hydroxyphosphonates (18)and a -aminopho-
sphonates are important biologically active com-pounds (19,20).a -Aminophosphonates,due to their structural analogy to amino acids,have been the subject of considerable current interest.They act as peptide mimics (21),enzyme inhibitors (22,23),anti-biotics,and pharmacological agents (24,25).
Green Chemistry Letters and Reviews Vol.3,No.1,March 2010,33Á38
D o w n l o a d e d  b y  [222.168.48.68] a t  17:46 08 A u g u s t  2011
a -Hydroxyphosphonates may serve as precursors for the synthesis of a -amino-phosphonates which are analogs of amino acids.A number of synthetic methods for the synthesis of a -hydroxyphosphonates have been reported (26Á29).But the disadvantage associated with the existing methodologies is either long reaction times or the requirement of drastic conditions.
In the literature,a -hydroxyphosphonates have been prepared using:quinine catalyst in toluene as solvent (30),DBU or n-BuLi in THF (31),HCl:ether media in DCM (32),LiClO 4:diethyl ether solution in the presence of trimethylsilyl chloride (TMSCl)(33),toluene and Ti(OiPr)4(34),hydroxyphosphorylation of aldehydes catalyzed by guanidine hydrochloride in water (35),herate and AlCl 3(36),and TFA or TfOH (37).
Generally,a -aminophosphonates are prepared in the presence of Lewis acids or bases by the addition of phosphorous nucleophiles to the imines.Lewis acids such as SnCl 4,SnCl 2,ZrCl 4,ZnCl 2,and MgBr 2have been used as catalysts for such reactions (38Á40).Recently,Lewis and Bronsted acids such as LiClO 4(41),InCl 3(42),lanthanide triflates (43),TaCl 5ÁSiO 2(44),montmorillonite clay-MW (45),Al 2O 3-MW (46),and CF 3COOH (47)were found to be effective in the preparation of a -aminophosphonates.How-ever,many of these procedures require expensive reagents,long reaction times and suffer from poor yields.These reactions cannot be carried out in one step by the reaction between a carbonyl compounds,an amine and dialkylphosphite because the amine and water present during imine formation can decompose or deactivate the Lewis acid (48).In continuation of our work on phosphorus chemistry (49Á52),herein we wish to report the solvent free synthesis of a -hydroxyphosphonates and a -aminophosphonates at room temperature in quantitative yield.Results and discussion
We have reported the synthesis of a -hydroxypho-sphonates (51)from 2-chloroquinolin-3-carbaldehyde at reflux temperature in toluene;while at reflux temperature,TMSCl was added.To add TMSCl at the reflux temperature is not ecofriendly because it
emits gases during addition.Azizi et al.(33)reported that for the same system at room temperature costly moisture sensitive reagents such as LiClO 4and diethyl ether media could be used.To overcome these difficulties we have developed a new method for the synthesis of a -hydroxyphosphonate from 2-chloroquinolin-3-carbaldehyde.Herein we wish to report the newer method which is economically viable,solvent free,and carried out at room tem-perature in quantitative yield.
To the mixture of triethylphosphite and 2-chlor-oquinolin-3-carbaldehyde (1a Á
h )TMSCl was added in stirring at room temperature.During addition,we observed that the reaction was exothermic (temperature rise from 25to 408C).2-Chloroquino-lin-3-carbaldehyde has two reaction centers:chlorine at the second and a formyl group at the third position of quinoline ring.However,the formyl group has higher reactivity in the presence of TMSCl.TMSCl reacts with the formyl group to generate a carbonium ion and a TMS protected hydroxyl group.Triethyl-phosphite attacks the generated carbonium ion and the mentioned compound rearranges to a -trimethyl-silyloxyphophonate.
By adding methanol,unreacted TMSCl was reacted with methanol and generates gaseous HCl which yielded desired product (2a Á
h )(Scheme 1,Table 1).Through this method,there was significant improvement in the yields of the products.The reported yields of a -hydroxyphosphonates in the presence of solvent and at higher temperature were 76Á83%(51).The yields of the a -hydroxypho-sphonates using this new process are now in the range of 95Á97%.Here we have synthesized eight com-pounds by applying the same procedure and obtained each in quantitative yield.All the synthesized com-pounds are characterized by spectral analysis,physi-cal constants,and compared with their authentic.Previously we have synthesized a -aminophospho-nates (52)containing highly bioactive quinoline moiety in two steps.In the first step,imines of 2-chloroquinoline-3-carbaldehyde were synthesized and converted to a -aminophosphonates using TMSCl and triethylphosphite in acetonitrile at reflux in the next step.Herein we report a newer method which is economically viable,solvent free and carried out at
P OCH 2CH 3OCH 2CH 3
31a –h
2a –h
34R.U.Pokalwar et al .
D o w n l o a d e d  b y  [222.168.48.68] a t  17:46 08 A u g u s t  2011
room temperature in quantitative yield.Imines (3a Á
p )(Scheme 2)were prepared at room temperature from derivatives of 2-chloroquinoline-3-carbaldehyde and 3-fluoroaniline or 2-methylaniline in ethanol using a catalytic amount of acetic acid in excellent yields and were characterized by mass spectra.a -Aminopho-sphonates (4a Á
p )(Scheme 2,Table 2)were then prepared in quantitative yields by reacting imines (3a Á
p )with triethylphosphite in the presence of TMSCl at room temperature.After completion of the reaction,the excess TMSCl was removed using methanol.The reported yields of a -aminophospho-nates in the presence of solvent and at higher temperature were 89Á93%(52).The yields of the a -aminophosphonates using this new process are now in the range of 95Á98%.Here we have synthesize
d 16compounds by applying the same procedure and obtained each in quantitative yield.All the com-pounds synthesized were unequivocally characterized on the basis of analytical data.
The mechanism of the formation of a -hydroxy-phosphonates and a -aminophosphonates in the pre-sence of TMSCl have shown in Figures 1and 2,respectively.
Experimental
2-Chloroquinoline-3-carbaldehydes were prepared in the laboratory by the reported method (53).Triethyl-phosphite and chlorotrimethylsilane were procured
from Lancaster;methanol and N,N -dimethylforma-mide (DMF)were procured from S.D.Fine-chem.All melting points were determined in open capillaries on Kumar’s melting point apparatus.The products were characterized by their spectral data.1H NMR spectra were recorded on Varian Gemini in CDCl 3at 400MHz using TMS as an internal standard.IR spectra were recorded on a Perkin ÁElmer FTIR using KBr discs.Mass spectra were recorded on Micromass Quatrro-II using electrospray Ionization technique,showing (m '1)peak as a molecular ion peak.The test for the purity of products and the progress of the reactions was accomplished by TLC on Merck silica gel plates.General procedure
(2a)Diethyl (2-chloro-quinolin-3-yl)(hydroxy)methylphosphonate
To the mixture of 2-chloroquinoline-3-carbaldehyde (0.95gm,5mmol),triethylphosphite (1.66gm,10mmol),and chlorotrimethylsilane (1.08gm,10mmol)were added dropwise and stirred at room temperature.The progress of the reaction was monitored by TLC using hexane:ethyl acetate (7:3)as the solvent system.After completion of the reaction (25min),the reaction mixture was dissolved in methanol for the quenching of excess TMSCl and removal of the residual silyl ester linkages.This methanolic solution was concentrated to get crude product.Further purification was achieved by
Table 1.TMSCl facilitated synthesis of a -hydroxyphosphonates.Entry R 1R 2R 3Time (min)
Yield (%)
Yield (51)(%)
MP (8C)2a H H H 259676.4124Á1262b CH 3H H 309680.6145Á1472c H CH 3H 249681.4126Á1282d H H CH 3259580.6141Á1432e OCH 3H H 309583.3170Á1722f H
OCH 3H 259780.3154Á1562g OC 2H 5H H 259579.2168Á1702h
H
H
C 2H 5
30
97
77.1
145Á147
R R 2CH 32CH
3
3a –p
4a –p
3Green Chemistry Letters and Reviews
35
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dissolving the crude compound in dichloromethane and precipitated by hexane.The solid obtained was stirred for 15min and filtered,washed with hexane and dried at 408C (1.56gm,yield 96%,m.p.124Á1268C).IR (KBr ),cm  1:3246((OH);1218((P 0O);1033((P ÁO ÁC).1H NMR (CDCl 3),d ;ppm:  1.2(t,3H,O ÁCH 2ÁCH 3);1.3(t,3H,O ÁCH 2ÁCH 3);2.0(s,1H,(CH ÁOH);4.0(m,4H,O ÁCH 2ÁCH 3and O ÁCH 2ÁCH 3);5.6(d,1H,(CH ÁP 0O);7.5(t,1H,Ar ÁH,C 6);7.7(t,1H,Ar ÁH,C 7);7.8(d,1H,Ar ÁH,C 5);8.0(d,1H,Ar ÁH,C 8);8.6(s,1H,Ar ÁH,C 4).ES Á
MS :m/z 330(m '1)and 331.9(m '3).
Elemental analysis:C 14H 17ClNO 4P calculated:C:51.00%,H:5.20%,N:4.25%;found:C:51.027%,H:5.393%,N:4.35%.
(4a)Diethyl (3-fluorophenylamino)(2-chloroquinolin-3-yl)methylphosphonate
To a mixture of N -((2-chloroquinolin-3-yl-methyl-ene)-3-fluorobenzenamine (1.12gm,4mmol)and triethylphosphite (1.66gm,10mmol)was added TMSCl (1.08gm,10mmol).The progress of the reaction was monitored by TLC using hexane:ethyl acetate (8:2)as the solvent system.After the comple-tion of the reaction,the reaction mixture was
Table 2.TMSCl facilitated synthesis of a -aminophosphonates.Entry R 1R 2R 3R 4R 5Time (min)Yield (%)Yield (52)(%)
MP (8C)4a H H H H F 309692.1146Á1484b CH 3H H H F 259890.1136Á1384c H CH 3H H F 309692.5163Á1654d H H CH 3H F 309789.2113Á1154e OCH 3H H H F 259791.0153Á1554f H
OCH 3H H F 309593.3155Á1574g OC 2H 5H H H F 309791.0160Á1624h H H C 2H 5H F 309592.2159Á1614i H H H CH 3H 259690.0139Á1414j CH 3H H CH 3H 259889.5104Á1064k H CH 3H CH 3H 309692.0143Á1454l H H CH 3CH 3H 309592.0160Á1624m OCH 3H H CH 3H 259790.098Á1004n H
OCH 3H CH 3H 309792.0126Á1284o OC 2H 5H H CH 3H 309690.5146Á1484p
H
H
C 2H 5
CH 3
H
30
98
91.2
133Á135
N
Cl
Ar =
P O O
O Ar
OH
P O O O
–EtOH
–TMS–OH
R 1R 2
R 3
36R.U.Pokalwar et al .
D o w n l o a d e d  b y  [222.168.48.68] a t  17:46 08 A u g u s t  2011
dissolved in methanol for the quenching of excess TMSCl and removal of the residual silyl ester linkages.This methanolic solution was concentrated to get crude product.The solid was further recrys-tallized from DMF and water mixture,dried in an oven at508C for8.0h(dry wt.01.59gm,yield96%). IR(KBr):3311cm(1((NH);1234cm(1((P0O); 1032cm(1((PÁOÁC).1H NMR(CDCl3,d;ppm): 1.05(t,3H,OÁCH2ÁCH3,J08Hz);  1.35(t,3H, OÁCH2ÁCH3,J08Hz);3.7(m,1H,OÁCH2ÁCH3);
3.9(m,1H,OÁCH2ÁCH3);
4.2(m,2H,OÁCH2ÁCH3);
5.4(d,1H,ÁNHÁCHÁP0O,J024Hz);
6.3Á6.5(m,3H,PhÁH,C2,C4,C6);
7.0(dd,1H,PhÁH, C5,J08Hz);7.5(t,1H,Quinolin-H,C5,J08Hz);
7.69(t,1H,Quinolin-H,C6,J08Hz);7.75(d,1H, Quinolin-H,C7,J08Hz);7.99(d,1H,Quinolin-H, C8,J08Hz);8.34(d,1H,Quinolin-H,C4,J08 Hz).ESÁMS:m/z423.1(m'1)and425.1(m'3). Elemental analysis:C20H21ClFN2O3P calculated:C: 56.81%,H:5.01%,N:6.63%;found:C:56.72%,H: 4.95%,N:6.65%.
Conclusion
In conclusion,a new methodology was developed for the synthesis of a-hydroxyphosphonates2aÁh from2-chloroquinolin-3-carbaldehyde1aÁh by using triethylphosphite in the presence of TMSCl at room temperature in quantitative yields.Also a new methodology was developed for the synthesis of a-
Á2-chloroquinoline-3-carbaldehydes for the first time using TMSCl at room temperature.All the reactions were performed under mild reaction conditions, shorter reaction times and in quantitative yields (Tables1and2).The methodology developed will be of much use to combinatorial chemist. Ackno
wledgements
Authors are thankful to the Head,Department of Chem-istry,Dr.B.A.M.University,Aurangabad for providing laboratory facilities.
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P
O
O
O
Ar =
Ar′ =
R
R
Figure2.Mechanism of the synthesis of a-aminophosphonates.
Green Chemistry Letters and Reviews37 D
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