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One-Pot, Three-Component Synthesis ofα-Amino Phosphonates Using NaHSO4-SiO2 as an Efficient and ReusableCatalystMalek Taher Maghsoodlou a , Reza Heydari a , Sayyed Mostafa Habibi-Khorassani a , Nourallah Hazeri a , Seyed Sajad Sajadikhah a , MohsenRostamizadeh a & Mojtaba Lashkari aa Department of Chemistry , Faculty of Science, University of Sistanand Baluchestan , Zahedan , IranAccepted author version posted online: 30 Jun 2011.Publishedonline: 14 Sep 2011.

To cite this article: Malek Taher Maghsoodlou , Reza Heydari , Sayyed Mostafa Habibi-Khorassani ,Nourallah Hazeri , Seyed Sajad Sajadikhah , Mohsen Rostamizadeh & Mojtaba Lashkari (2012) One-Pot,Three-Component Synthesis of α-Amino Phosphonates Using NaHSO4-SiO2 as an Efficient and ReusableCatalyst, Synthetic Communications: An International Journal for Rapid Communication of SyntheticOrganic Chemistry, 42:1, 136-143, DOI: 10.1080/00397911.2010.523153

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ONE-POT, THREE-COMPONENT SYNTHESIS OFa-AMINO PHOSPHONATES USING NaHSO4-SiO2

AS AN EFFICIENT AND REUSABLE CATALYST

Malek Taher Maghsoodlou, Reza Heydari,Sayyed Mostafa Habibi-Khorassani, Nourallah Hazeri,Seyed Sajad Sajadikhah, Mohsen Rostamizadeh, andMojtaba LashkariDepartment of Chemistry, Faculty of Science, University of Sistan andBaluchestan, Zahedan, Iran

GRAPHICAL ABSTRACT

Abstract A simple, efficient, and environmentally benign method has been developed for the

synthesis of a-amino phosphonates. One-pot, three-component reaction of aldehyds, amines,

and trialkylphosphite in the presence of silica-supported sodium hydrogen sulfate (NaHSO4-

SiO2) as an inexpensive and reusable catalyst under solvent-free conditions at 80�C affords

the corresponding a-amino phosphonates in good yields and short reaction times.

Keywords a-Amino phosphonates; heterogeneous catalyst; NaHSO4-SiO2; reusable

catalyst; trialkylphosphite

INTRODUCTION

Organophosphorus compounds have found a wide range of applications in theareas industrial, agricultural, and medicinal chemistry owing to their biological andphysical properties as well as their utility as synthetic intermediates.[1] In recent years,a-amino phosphonates have received attention as structural analogs of the corre-sponding a-amino acids. The activities of a-amino phosphonates as HIV protease,[2]

enzyme inhibitors,[3] antibiotics,[4] peptide mimics,[5] herbicide, insecticides andfungicides,[6] antitheromboticagents,[7] antimicrobial agents,[8] and inhibitors ofUDP-galactopyranose mutase[9] are reported in the literature.

Received May 26, 2010.

Address correspondence to Malek Taher Maghsoodlou, Department of Chemistry, Faculty of

Science, University of Sistan and Baluchestan, P. O. Box 98135-674, Zahedan, Iran. E-mail:

mt_maghsoodlou@yahoo.com

Synthetic Communications1, 42: 136–143, 2012

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397911.2010.523153

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Catalytic methods are currently used in synthetic organophosphorus chemistryto obtain various organophosphorus compounds, in particular, functionalizedphosphonates and phosphinates, which attract special attention because of theirbiological activities.[10] A large number of procedures have been developed for thesynthesis of a-amino phosphonates since the first synthesis by Fields.[11] Recently,one-pot, three-component synthesis starting from aldehydes, amines, and dialkylpho-sphites or trialkylphosphites has been reported using lanthanide triflate,[12] InCl3,

[13]

scandium tris(dodecyl sulfate),[14] lithium perchlorate,[15] CF3CO2H,[16] In(OTf)3,[17]

magnesium perchlorate,[18] PhNMe3Cl,[19] H3PW12O40,

[20] Amberlyst-15,[21]

Amberlite-IR 120,[22] sulfamic acid,[23] TiO2,[24] oxalic acid,[25] trifluoroethanol,[26] and

FeCl3 � tetrahydrofuran (THF).[27] However, many of these methods suffer from somedisadvantages such as long reaction times, environmental pollution caused by utiliza-tion of organic solvents, poor yields, stoichiometric amounts of catalysts, costly andmoisture-sensitive catalysts, highly toxic catalysts, and drastic reaction conditions.Therefore, there is a need to develop a facile one-pot synthesis of a-amino phospho-nates using mild reaction conditions and inexpensive or commercially availablereagents.

Recently, the use of solid acidic catalysts supported on silica has offered impor-tant advantages in organic synthesis, for example, operational simplicity, environmen-tal compatibility, lack of toxicity, reusability, low cost, and ease of preparation,handling, and isolation. Silica-supported sodium hydrogen sulfate (NaHSO4-SiO2)is well known as an efficient heterogeneous catalyst for many organic trasforma-tions.[28] This reagent can be prepared from NaHSO4 and silica gel.[28a] However,solvent-free reactions have received more attention in comparison with their homo-geneous counterparts because of economical and environmental demands, short reac-tion times, simple processes, increased product purities and yields, and precise controlof reaction parameters.[29] In the present article, we report a simple and effectiveprocedure for the one-pot, three-component synthesis of a-amino phosphonates deri-vatives from reaction of aldehydes, amines, and trialkylphosphite in the presence ofNaHSO4-SiO2 as an inexpensive and reusable catalyst under solvent-free conditionsat 80 �C (Scheme 1).

RESULTS AND DISCUSSION

First, to find out the optimum quantity of silica-supported sodium hydrogensulfate, the reaction of benzaldehyde (1mmol), aniline (1mmol), and trimethylpho-sphite (1mmol) was carried out using different quantities of NaHSO4-SiO2 undersolvent-free conditions at 80 �C (Table 1). As shown in Table 1, the use of 0.05 g

Scheme 1. Synthesis of a-amino phosphonates.

a-AMINO PHOSPHONATES SYNTHESIS 137

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of catalyst resulted in the greatest yield in 45min. Poor yield (43%) was obtainedwhen the reaction was carried out in the absence of NaHSO4-SiO2 at 80 �C undersolvent-free conditions for 24 h.

Thus, several reactions of different aldehydes, amines, and trialkylphosphitewere examined in the presence of NaHSO4-SiO2 (0.05 g) as a catalyst under solvent-free conditions at 80 �C. The results are summarized in Table 2. In all cases, theone-pot, three-component reaction proceeded smoothly to afford the correspondinga-amino phosphonates in good to excellent yields. As shown in Table 2, the reactionof anilines with a variety of aromatic aldehydes containing electron-deficient and=or

Table 1. Optimization amount of NaHSO4-SiO2 for the reaction of benzaldehyde,

aniline, and trimethylphosphite under solvent-free conditions at 80 �C

Entry Catalyst (g) Time (min) Yielda (%)

1 No catalyst 24 h 43

2 0.01 100 81

3 0.02 80 89

4 0.03 65 91

5 0.05 45 95

6 0.1 30 94

aYields refer to the pure isolated products.

Table 2. Preparation of a-amino phosphonates

Entry R1 R2 R3 Time (min) Yielda (%) Ref.b

1 Ph Ph Me 45 95 32

2 Ph Ph Et 120 94 38

3 4-NO2-C6H4 Ph Me 20 94 33

4 4-NO2-C6H4 Ph Et 60 91 36

5 4-NMe2-C6H4 Ph Me 50 93 35

6 4-F-C6H4 Ph Et 100 93 36

7 4-OH-C6H4 Ph Me 65 92 32

8 4-Me-C6H4 Ph Et 180 90 38

9 3-Cl-C6H4 Ph Me 45 94 35

10 3-Cl-C6H4 Ph Et 110 93 38

11 CH3CH2CH2 Ph Me 180 69 33

12 Ph PhCH2 Me 90 91 39

13 4-OMe-C6H4 CH3CH2CH2 Et 180 57 38

14 2,4-di-OMe-C6H3 4-OMe-C6H4 Me 50 95 —c

15 2,3-di-OMe-C6H3 2-F-C6H4 Me 55 96 —c

16 2,6-di-Cl-C6H3 4-Br-C6H4 Me 35 97 —c

17 2,3-di-OMe-C6H3 4-Br-C6H4 Me 55 96 —c

18 2,5-di-OMe-C6H3 4-Cl-C6H4 Me 55 96 —c

19 Ph 4-Cl-C6H4 Me 50 95 39

20 3-NO2-C6H4 3-NO2-C6H4 Et 120 92 30

21 4-NO2-C6H4 4-NO2-C6H4 Me 50 93 32

aYields refer to the pure isolated products.bAll known products have been reported previously in the literature andwere characterized by comparison

of IR and NMR spectra with authentic samples.cThe new compounds synthesized in this work.

138 M. T. MAGHSOODLOU ET AL.

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electron-releasing groups and trimethyl=triethylphosphite proceeded to afforda-amino phosphonates in good to excellent yields. On the basis of experimentalresults, the rates of all reactions in the presence of triethylphosphite were reducedin comparison with trimethylphosphite under constant conditions. We have alsoprepared five new analogs of these compounds in excellent yields (Table 2, entries14–18). These new compounds were characterized by elemental analyses, meltingpoint, infrared (IR), NMR (1H, 13C and 31P), and mass spectroscopies. In addition,the reaction of benzaldehyde, aniline, and triphenylphosphite was checked in thepresence of NaHSO4-SiO2 under solvent-free conditions at 80

�C for 24 h, but unfor-tunately the expected corresponding a-amino phosphonate was not obtained.

The feasibility of reusing the catalyst was also examined by treating benzal-dehyde with aniline and trimethylphosphite in the presence of NaHSO4-SiO2 undersolvent-free conditions at 80 �C. The separated catalyst was reused after beingwashed with methanol and dried at 100 �C for 60min. The results showed that thecatalyst can be used five times without significant loss of its activity (Table 3).

CONCLUSION

In conclusion, silica-supported sodium hydrogen sulfate was found to be anefficient, commercially available, environmentally friendly, and reusable catalystfor the one-pot, three-component reaction of aldehydes, amines, and trialkylpho-sphite to afford a-amino phosphonates in good to excellent yields. The reactions werecarried out under thermal solvent-free conditions with short reaction times. The ther-mal solvent-free green procedure offer advantages including shorter reaction times,environmentally friendliness, simple workup, good yields, and cost-effective recoveryand reusability of catalyst for a few times without significant loss of its activity.

EXPERIMENTAL

Melting points and IR spectra of all compounds were measured on an Electro-thermal 9100 apparatus and a Shimadzu IR-460 spectrometer respectively. The 1H,13C, and 31P NMR spectra were obtained on Bruker DRX-250 and 400 Avanceinstruments with CDCl3 as a solvent. Elemental analyses were performed using aHeraeus CHN-O-Rapid analyzer. Mass spectra were recorded on an AgilentTechnology (HP) spectrometer operating at an ionization potential of 70 eV. All

Table 3. Investigation of reusability of the

catalyst in the reaction of benzaldehyde with

aniline and trimethylphosphite

Run Yielda (%)

1 95

2 94

3 91

4 87

5 86

aYields refer to the pure recovered catalyst.

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reagents and solvents obtained from Fluka and Merck were used without furtherpurification.

General Procedure for the Synthesis of a-Amino Phosphonates

The mixture of aldehyde (1mmol), amine (1mmol), and NaHSO4-SiO2 (0.05 g)were stirred for a few minutes. Then trimethyl=triethylphosphite (1mmol) wasadded, and the mixture was stirred at 80 �C in oil bath for the appropriate time(see Table 2). After completion of the reaction (monitored by thin-layer chromato-graohy, TLC), the reaction mixture was cooled and EtOAc (15mL) was added toseparate the catalyst by simple filtration. The filtrate was washed with distilled water(10mL� 3). The organic layer was dried over anhydrous Na2SO4 and evaporated.The crude product was purified by silica-gel column chromatography with themixture of n-hexane=EtOAc (7:3) as eluant to provide pure a-amino phosphonates.Spectral data for new products are given.

Selected Data

Compound 14 (Table 2, Entry 14). Yellow solid, mp 131–133 �C. 1H NMR(CDCl3, 250MHz) d: 3.45 (3H, d, 3JPH¼ 10.5Hz, P-OCH3), 3.67 (3H, s, OCH3),3.75 (3H, s, OCH3), 3.80 (3H, d, 3JPH¼ 10.7Hz, P-OCH3), 3.89 (3H, s, OCH3),4.18 (1H, br, NH), 5.25 (1H, d, 2JPH¼ 24.0Hz, CHP), 6.44–6.70 (6H, m, Ar),7.34–7.38 (1H, m, Ar); 13C NMR (CDCl3, 62.9MHz) d: 48.12 (d, 1JPC¼ 157.3Hz),53.68 (d, 2JPC¼ 6.9Hz), 53.84 (d, 2JPC¼ 6.9Hz), 55.27, 55.61, 55.79, 98.52, 104.90(d, J¼ 2.5Hz), 114.67, 115.05, 116.40, 128.97 (d, J¼ 5.0Hz), 140.02 (d, J¼ 15.7Hz),152.61, 158.18 (d, J¼ 6.9Hz), 160.51; 31P NMR (CDCl3, 101MHz) d: 26.41; IR(KBr) t: 3320 (NH), 1235 (P¼O), 1060, 1039 (P–O�Me); MS m=z (%): 381 (Mþ,14), 272 (100), 259 (10), 257 (11), 149 (88), 123 (53), 121 (69), 109 (6), 92 (10), 79(18), 77 (17). Anal. calcd. for C18H24NO6P: C, 56.69; H, 6.34; N, 3.67. Found: C,56.83; H, 6.49; N, 3.75.

Compound 15 (Table 2, Entry 15). White solid, mp 84–85 �C. 1H NMR(CDCl3, 250MHz) d: 3.54 (3H, d, 3JPH¼ 10.5Hz, P-OCH3), 3.83 (3H, d, 3JPH¼10.3Hz, P-OCH3), 3.85 (3H, s, OCH3), 3.98 (3H, s, OCH3), 4.63 (1H, br, NH),5.43 (1H, d, 2JPH¼ 24.0Hz, CHP), 6.56–7.11 (7H, m, Ar); 13C NMR (CDCl3,62.9MHz) d: 47.74 (d, 2JPC¼ 157.4Hz), 53.68 (d, 2JPC¼ 6.9Hz), 53.90 (d, 2JPC¼6.9Hz), 55.65, 60.94, 112.16 (d, J¼ 2.5Hz), 113.34 (d, J¼ 2.8Hz), 114.54 (d,J¼ 18.5Hz), 118.02 (d, J¼ 7.0Hz), 119.70 (d, J¼ 4.0Hz), 124.31 (d, J¼ 2.6Hz),124.53 (d, J¼ 3.5Hz), 129.27, 134.42 (dd, J¼ 14.7Hz, J¼ 11.4Hz), 147.03 (d,J¼ 7.4Hz), 151.90 (d, 1JFC¼ 237.8Hz), 152.33 (d, J¼ 1.7Hz); 31P NMR (CDCl3,101MHz) d: 25.17; 19F NMR (CDCl3, 376.5MHz) d: �135.22; IR (KBr) t: 3316(NH), 1240 (P¼O), 1052, 1030 (P�O�Me); MS m=z (%): 369 (Mþ, 6), 260 (100),245 (10), 135 (16), 123 (13), 122 (11), 111 (21), 109 (10), 95 (8), 79 (10). Anal. calcd.for C17H21FNO5P: C, 55.29; H, 5.73; N, 3.79. Found: C, 55.41; H, 5.70; N, 3.76.

Compound 16 (Table 2, Entry 16). White solid, mp 94–96 �C. 1H NMR(250MHz, CDCl3) d: 3.62 (3H, d, 3JPH¼ 10.8Hz, P-OCH3), 3.86 (3H, d, 3JPH¼ 10.9Hz,P-OCH3), 4.62 (1H, br, NH), 5.80 (1H, d, 2JPH¼ 28.8Hz, CHP), 6.49–6.54 (2H, m, Ar),

140 M. T. MAGHSOODLOU ET AL.

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7.14–7.37 (5H, m, Ar); 13C NMR (CDCl3, 62.9MHz) d: 52.74 (d, 1JPC¼ 157.9Hz), 53.63(d, 2JPC¼ 6.9Hz), 53.93 (d, 2JPC¼ 7.5Hz), 110.79, 115.26, 128.55 (d, J¼ 1.3Hz), 129.66(d, J¼ 3.1Hz), 130.58 (d, J¼ 2.5Hz), 130.68, 132.06, 134.75 (d, J¼ 5.0Hz), 136.66 (d,J¼ 6.9Hz), 144.57 (d, J¼ 15.7Hz); 31P NMR (CDCl3, 101MHz) d: 22.54; IR (KBr)t: 3324 (NH), 1255 (P¼O), 1061, 1017 (P�O�Me); MS m=z (%): 443 (Mþþ 4, 5), 441(Mþþ 2, 12), 439 (Mþ, 8), 332 (80), 330 (100), 328 (86), 294 (9), 249 (8), 184 (14), 157(13), 155 (13), 109 (6), 76 (18). Anal. calcd. for C15H15BrCl2NO3P: C, 41.03; H, 3.44;N, 3.19. Found: C, 41.20; H, 3.49; N, 3.28.

Compound 17 (Table 2, Entry 17). White solid, mp 136–137 �C. 1H NMR(250MHz, CDCl3) d: 3.48 (3H, d, 3JPH¼ 10.5Hz, P-OCH3), 3.82 (3H, d, 3JPH¼10.7Hz, P-OCH3), 3.86 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.26 (1H, br, NH),5.35 (1H, d, 2JPH¼ 24.0Hz, CHP), 6.54 (2H, d, J¼ 8.8Hz, Ar), 6.82–7.08 (3H, m,Ar), 7.17 (2H, d, J¼ 8.8Hz); 13C NMR (CDCl3, 62.9MHz) d: 48.06 (d, 1JPC¼156.6Hz), 53.80 (d, 2JPC¼ 6.9Hz), 53.85 (d, 2JPC¼ 6.9Hz), 55.67, 60.94, 110.40,112.18 (d, J¼ 2.5Hz), 115.48, 119.64 (d, J¼ 4.4Hz), 124.34 (d, J¼ 2.5Hz), 129.00,131.92, 144.88 (d, J¼ 15.1Hz), 146.95, 152.33; 31P NMR (CDCl3, 101MHz) d:25.42; IR (KBr) t: 3317 (NH), 1267 (P¼O), 1054, 1018 (P�O�Me); MS m=z (%):431 (Mþ 2, 6), 429 (Mþ, 7), 322 (100), 320 (89), 241 (6), 154 (8), 135 (13), 121 (9),109 (9), 91 (6), 79 (8). Anal. calcd. for C17H21BrNO5P: C, 47.46; H, 4.92; N 3.26.Found: C, 47.41; H, 4.97; N, 3.24.

Compound 18 (Table 2, Entry 18). Brownish solid, mp 112–114 �C. 1HNMR (250MHz, CDCl3) d: 3.46 (3H, d, 3JPH¼ 10.5Hz, P-OCH3), 3.70 (3H, s,OCH3), 3.80 (3H, d, 3JPH¼ 10.6Hz, P-OCH3), 3.88 (3H, s, OCH3), 4.25 (1H, br,NH), 5.32 (1H, d, 2JPH¼ 24.8Hz, CHP), 6.51–7.04 (7H, m, Ar); 13C NMR (CDCl3,62.9MHz) d: 47.93 (d, 2JPC¼ 155.4Hz), 53.70 (d, 2JPC¼ 6.9Hz), 53.87 (d, 2JPC¼6.9Hz), 55.63, 56.37, 111.78, 113.96, 114.79, 123.04, 124.74, 128.99, 144.59 (d,J¼ 15.1Hz), 151.44; 31P NMR (CDCl3, 101MHz) d: 25.47; IR (KBr) t: 3310(NH), 1252 (P¼O), 1040, 1024 (P�O�Me); MS m=z (%): 385 (Mþ, 9), 276 (100),261 (37), 246 (30), 149 (21), 140 (18), 111 (16), 109 (8), 79 (11). Anal. calcd. forC17H21ClNO5P: C, 52.93; H, 5.49; N, 3.63. Found: C, 53.04; H, 5.45; N, 3.71.

ACKNOWLEDGMENT

We gratefully acknowledge financial support from the Research Council of theUniversity of Sistan and Baluchestan.

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