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Synlett 2014; 25(08): 1145-1149
DOI: 10.1055/s-0033-1341069
letter
© Georg Thieme Verlag Stuttgart · New York

Phenylphosphonic Acid as Efficient and Recyclable Catalyst in the Synthesis of α-Aminophosphonates under Solvent-Free Conditions

Mercedes Bedolla-Medrano
a   Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, México   Fax: +52(777)3297997   Email: palacios@uaem.mx
,
Eugenio Hernández-Fernández
b   Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León, Pedro de Alba S/N, Ciudad Universitaria, 66400 San Nicolás de los Garza, Nuevo León, México
,
Mario Ordóñez*
a   Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, México   Fax: +52(777)3297997   Email: palacios@uaem.mx
› Author Affiliations
Further Information

Publication History

Received: 19 December 2013

Accepted after revision: 03 March 2014

Publication Date:
07 April 2014 (online)

 
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Abstract

Phenylphosphonic acid is an efficient, friendly and reusable heterogeneous catalyst for the synthesis of α-aminophosphonates through a ‘one-pot’ three-component reaction of amines, carbonyl compounds and dialkyl phosphites under solvent-free conditions. This methodology illustrates a very simple procedure, with wide applicability, extending the scope to aliphatic and aromatic amines, aliphatic and aromatic aldehydes and aliphatic ketones. It also enabled the synthesis of α-aminophosphonates in large scale, clean conversion, easy workup and purification. Excellent results were obtained in each case obtaining the desire compounds in moderate to good yields.


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Key words

α-aminophosphonates - phenylphosphonic acid catalyst - solvent-free conditions - heterogeneous catalysis

α-Aminophosphonates are probably the most important substitutes for the corresponding protein and nonprotein α-amino acids in biological systems, because these compounds are considered as stable mimetics of tetrahedral transition state of peptide hydrolysis,[1] and have wide applications in medicinal, bioorganic, agricultural and organic synthesis.[2] [3] [4] [5] Many α-aminophosphonates as well as their derivatives have applications as antibacterial,[6] anticancer,[7] anti-HIV,[8] antimalarial,[9] and antifungal agents,[10] and are also carriers of hydrophilic organic molecules across phospholipid bilayer membranes.[11] Some of them show also pesticidal, insecticidal and herbicidal activity,[12] and function as plant growth regulators.[13] The inert nature of the C–P bond in α-aminophosphonates as well as physical and structural similarity to the biologically important phosphate ester and carboxylic acid functionalities contribute a great deal to these activities. Additionally, the α-aminophosphonates have been used as key synthetic intermediates for the preparation of more complex compounds and as organocatalyst.[14] [15]

Due to the relevant properties exhibited by α-aminophosphonates and their derivatives, during the past decades numerous useful synthetic approaches have been developed for their preparation in both racemic and optically pure forms,[16] but certainly the Kabachnik–Fields reaction[17] is one of the most widely used methods for the synthesis of these compounds, which involves a ‘one-pot’ three-component reaction between aldehydes or ketones, amines and dialkyl or diaryl phosphites. For this reaction a wide spectrum of catalysts have been used including Brønsted and Lewis acids, organocatalysts, transition-metal oxides, heteropolyacids, polymer-supported catalysts, ionic liquids, nanocatalysts, and many more.[18] However, in spite of the potential utility of this reaction, the catalytic process suffers from one or more disadvantages such as the use of expensive or less available and stoichiometric amounts of catalyst, use of toxic catalysts, specialized handling techniques and tedious workup are necessary, long reaction times, vigorous reaction conditions, requirement of excess of reagents, use of flammable organic solvents, unsatisfactory yield and lack of generality. Furthermore, some of these catalysts can decompose or deactivate with the water generated during the imine formation. For these reasons, the introduction of an efficient, environmentally friendly, water-resistant and recyclable catalyst for the synthesis of α-aminophosphonates under solvent-free conditions is still a challenge.

Therefore, in connection with our program on the development of novel organic synthetic methodologies,[19] herein we report our investigation on the synthesis of α-aminophosphonates through a ‘one-pot’ three-component reaction between aldehydes and ketones, benzylamine and dimethyl phosphite in the presence of phosphorus acids as catalysts, which have also been used in the carbonylation of nitrobenzene,[20] three-component Ugi,[21] Biginelli,[22] and Pictet–Spengler reactions.[23] The use of these acidic catalysts displays several advantages such as operational simplicity, nontoxicity, reusability, low cost and easy isolation after completion of the reaction.

In order to optimize the reaction conditions for the synthesis of α-aminophosphonates, different phosphorus compounds such as diphenylphosphinic acid (1), diphenylphosphate (2), phenylphosphinic acid (3), propylphosphonic acid (4), and phenylphosphonic acid (5) were tested as catalysts. Firstly, we carried out the reaction of benzaldehyde with benzylamine and dimethyl phosphite at 50 °C in the presence of 10 mol% of catalyst under solvent-free conditions (Table [1]),[24] and found that all catalysts 1–5 promoted the reaction affording the α-aminophosphonate 6a in good yield. The results in Table [1] show that the most efficient catalysts are the phenylphosphinic acid 3 and phenylphosphonic acid 5, which in only 30 minutes afforded the desired product with good yield (Table [1], entries 4 and 6), and the other catalysts could only equalize this performance with longer reaction times (Table [1], entries 2, 3 and 5). These results are in agreement with the pK a values described in the literature for these catalysts.[25] However, the reaction under catalyst- and solvent-free conditions at 80 °C gave 6a in only 37% yield after five hours (Table [1], entry 1). Decreasing the catalyst amount of 10 mol% to 5 mol% or 2.5 mol% resulted in lower yields.

Table 1 Identification of the Most Efficient Catalyst for the ‘One-Pot’ Three-Component Synthesis of α-Aminophosphonate 6a

Entry

Catalyst (10 mol%)

pK a

Time (h)

Yield (%)a

1

–

–

5.0

37

2

1

2.30

1.0

76

3

2

2.40

1.0

88

4

3

1.73

0.5

93

5

4

2.49

1.5

86

6

5

1.86

0.5

90

a Isolated yield after chromatographic purification.

With these results in hand and taking into account that phenylphosphinic acid 3 is an homogeneous catalyst, and considering that the phenylphosphonic acid (5) promotes the reaction as an heterogeneous catalyst, we proposed 5 as the best catalyst for the synthesis of α-aminophosphonates through ‘one-pot’ three-component conditions.

The ability to recycle and reuse 5 as well as its catalytic activity was studied in this system. In this context, 5 can be easily separated by filtration of the reaction mixture after dispersing in ethyl acetate. The recyclability of the heterogeneous catalytic system was also examined and can be reused for more than five successive times in new experiments without yield loss to generate 6a with purities similar to those obtained in the first run.

In order to compare the efficiency of phenylphosphonic acid 5 as catalyst, benzaldehyde, (S)-α-methylbenzylamine and dimethyl phosphite were allowed to react in the presence of 10 mol% of 5 at 50 °C, yielding the α-aminophosphonates 6b and 6c in 64% yield (Table [2], entry 1), but when the reaction was performed at 80 °C, the mixture of (R,S)- and (S,S)-6b was obtained in excellent yield with predominance of the R,S-diastereoisomer (Table [2], entry 2). Similar results were obtained using diethyl phosphite, giving α-aminophosphonates (R,S)- and (S,S)-6c (Table [2], entry 3). The diastereoisomeric ratio was determined by 31P NMR spectroscopy at 202 MHz, and the configuration was assigned by analogy with results reported in the literature.[26] [27] In the next screening, benzaldehyde was reacted with aniline and dimethyl and diethyl phosphite at 50 °C for one hour, affording the α-aminophosphonates 6d and 6e in excellent yield (Table [2], entries 4 and 5).

Table 2 Synthesis of α-Aminophosphonates 6b–e

Entry

R1

R2

Conditions

Yield (%)a

1

6b: (S)-CH(Me)Ph

Me

50 °C, 2.0 h

64b

2

6b: (S)-CH(Me)Ph

Me

80 °C, 1.5 h

92b

3

6c: (S)-CH(Me)Ph

Et

80 °C, 3.0 h

98c

4

6d: Ph

Me

50 °C, 1.0 h

98

5

6e: Ph

Et

50 °C, 1.0 h

96

a Isolated yield after chromatographic purification.

b The R,S- and S,S-diastereoisomers were obtained with 76:24 dr.

c The R,S- and S,S-diastereoisomers were obtained with 80:20 dr.

Next, to ensure the efficiency and fidelity of this procedure as a general methodology, we employed a series of aldehydes and ketones, benzylamine and dimethyl phosphite to obtain the desired α-aminophosphonates under the optimized conditions using 5 as catalyst. For this study benzylamine was selected because the benzyl fragment can be easily removed by hydrogenolysis to give the corresponding α-aminophosphonates which can be used as key building blocks.

The described methodology illustrates a very simple procedure, with wide applicability, extending the scope to aliphatic and aromatic aldehydes and aliphatic ketones. Thus, the α-aminophosphonates 6f–k were obtained in excellent yields using aromatic aldehydes bearing electron-donating groups (Table [3], entries 1–6), whereas aromatic aldehydes with electron-withdrawing groups gave the α-aminophosphonates 6l–n in moderate yields (Table [3], entries 7–9). The electron-donating or electron-withdrawing property of the aromatic aldehydes tested, showed to have a dramatic influence on the reaction course, which can be explained by a simple consideration of the electronic effect, whereas the heteroaromatic entities such as 3-indolecarboxaldehyde, 2-pyrrolecarboxaldehyde and furfural were also tested under this protocol, obtaining the α-aminophosphonates 6o–q in good yield, thus demonstrating that the procedure is quite suitable with this kind of compounds regardless of the unprotected heteroatoms (Table [3], entries 10–12). On the other hand, the reaction of aliphatic aldehydes with benzylamine and dimethyl phosphite produced the α-aminophosphonates 6r–u in good yields (Table [3], entries 13–16). Additionally, the reaction of cinnamaldehyde gave the α-aminophosphonate 6v in 86% yield (Table [3], entry 17).

Table 3 ‘One-Pot’ Three-Component Synthesis of α-Aminophosphonates 6f–z

Entry

R1

R2

Time (min)

Yield (%)a

Product

 1

3-HOC6H4

H

 50

79

6f

 2

3,4-(HO)2C6H3

H

 50

79

6g

 3

3,4-(MeO)2C6H3

H

 25

98

6h

 4

4-MeOC6H4

H

 70

82

6i

 5

2-MeO C6H4

H

 60

88

6j

 6

4-PhC6H4

H

 55

65b

6k

 7

4-MeO2CC6H4

H

 85

60b

6l

 8

4-ClC6H4

H

 60

63

6m

 9

4-F3CC6H4

H

 70

47b

6n

10

3-indole

H

 30

90

6o

11

2-pyrrole

H

 60

80

6p

12

2-furyl

H

 60

85

6q

13

n-Pr

H

 60

56

6r

14

i-Bu

H

 70

76

6s

15

i-Pr

H

 20

63

6t

16

t-Bu

H

 35

77

6u

17

(E)-PhHC=CH

H

100

86

6v

18

Me

Me

 20

75

6w

19

Et

Et

 20

76

6x

20

-(CH2)5-

 40

98

6y

a Isolated yield after chromatographic purification.

b Yield obtained with 20 mol% of catalyst.

Finally, the reaction of aliphatic ketones with benzylamine and dimethyl phosphite was tested, affording the quaternary α-aminophosphonates 6w–y in good to excellent yields (Table [3], entries 18–20). Additionally, the compound 6w was obtained on a five-gram scale, demonstrating that phenylphosphonic acid (5) can be used as catalyst in the large-scale synthesis of α-aminophosphonates. The formation of α-hydroxyphosphonates as a by-product was not observed in any of the reactions.

Based on the above results, we suggest a mechanism wherein the in situ formation of the imine intermediate, generated from condensation reaction of aldehyde or ketone and benzylamine, is activated by protonation giving a nine-membered transition state (Figure [1]), wherein 5 could play two roles: (1) the phenylphosphonic acid hydrogen activates the imine as a Brønsted acid; and (2) the phosphoryl oxygen activates the nucleophile by coordinating with the hydrogen of the phosphite as a Brønsted base, as has been proposed for chiral phosphonic acids.[28]

Zoom Image
Figure 1 Proposed mechanism for the synthesis of α-aminophosphonates catalyzed by phenylphosphonic acid

In conclusion, we have developed an efficient and facile method for the synthesis of tertiary and quaternary α-aminophosphonates in moderated to excellent yields, through the ‘one-pot’ three-component reaction of aldehydes and ketones with benzylamine and dimethyl phosphite in the presence of catalytic amount of phenylphosphonic acid under solvent-free conditions. Utilization of mild reaction conditions, large-scale synthesis, clean conversion, easy workup, purification of reaction products and reusable phenylphosphonic acid make this process extra attractive for the synthesis of α-aminophosphonates.


#

Acknowledgment

We gratefully acknowledge CONACyT of Mexico for financial support via project 181816. We thank Victoria Labastida-Galván for the technical assistance in MS and José Luis Viveros-Ceballos for the technical assistance in NMR. MBM also thanks CONACyT for the Graduate Scholarship 248554.

  • References and Notes

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  • 24 In a typical experiment, to a mixture of aldehyde or ketone (2.0 mmol) and benzylamine (2.0 mmol) was added the phenylphosphonic acid (5; 10 mol%). The reaction mixture was stirred at r.t. for 20 min. After this time, dimethyl phosphite (2.1 mmol) was added and the reaction mixture was stirred at 50 °C for the specific period of time (see Tables 1–3), and the progress of the reaction was monitored by TLC. The crude was directly subjected to silica gel flash chromatography eluting with EtOAc, obtaining the pure α-aminophosphonates. 1H NMR, 13C NMR, 31P NMR, and HRMS data for some newly obtained α-aminophosphonates are as follows. Compound 6g: yellow liquid. 1H NMR (400 MHz, CDCl3): δ = 3.48 [d, J = 10.5 Hz, 3 H, (MeO)2P], 3.52 (AB system, J = 13.3 Hz, 1 H, Bn), 3.78 (AB system, J = 13.3 Hz, 1 H, Bn), 3.79 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.89 (d, J = 20.1 Hz, 1 H, CHP), 6.63 (ddd, J = 8.0, 2.0, 2.0 Hz, 1 H, HAr), 6.77 (d, J = 8.0 Hz, 1 H, HAr), 7.11 (dd, J = 2.0, 2.0 Hz, 1 H, HAr), 7.20–7.31 (m, 5 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 50.8 (d, J = 17.6 Hz, Bn), 53.8 [d, J = 7.1 Hz, (MeO)2P], 54.1 [d, J = 7.6 Hz, (MeO)2P], 58.2 (d, J = 157.8 Hz, CHP), 114.7 (d, J = 5.0 Hz), 115.1, 121.0 (d, J = 8.1 Hz), 126.0, 127.2, 128.4 (2 × C), 139.0, 145.0 (2 × C). 31P NMR (161.9 MHz, CDCl3): δ = 26.62. HRMS (FAB+): m/z [M + H]+ calcd for C16H21NO5P: 338.1157; found: 338.1159. Compound 6k: white solid; mp 94–96 °C. 1H NMR (400 MHz, CDCl3): δ = 2.44 (br s, 1 H, NH), 3.58 (AB system, J = 13.3 Hz, 1 H, Bn), 3.58 [d, J = 10.5 Hz, 3 H, (MeO)2P], 3.75 [d, J HP = 10.6 Hz, 3 H, (MeO)2P], 3.84 (AB system, J = 13.3 Hz, 1 H, Bn), 4.10 (d, J = 20.2 Hz, 1 H, CHP), 7.22–7.36 (m, 6 H, HAr), 7.40–7.52 (m, 4 H, HAr), 7.59–7.64 (m, 4 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.3 (d, J = 17.4 Hz, Bn), 53.6 [d, J = 6.6 Hz, (MeO)2P], 53.9 [d, J = 6.6 Hz, (MeO)2P], 59.1 (d, J = 154.3 Hz, CHP), 127.1, 127.3, 127.4, 127.5, 128.5 (d, J = 6.7 Hz), 128.9, 129.1 (d, J = 5.5 Hz), 134.6, 139.3, 140.7, 140.9, 141.0. 31P NMR (161.9 MHz, CDCl3): δ = 23.05. HRMS (FAB+): m/z [M + H]+ calcd for C22H25NO3P: 382.1572; found: 382.1588. Compound 6l: colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 2.17 (br s, 1 H, NH), 3.52 (AB system, J = 13.3 Hz, 1 H, Bn), 3.58 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.74 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.80 (AB system, J = 13.3 Hz, 1 H, Bn), 3.93 (s, 3 H, MeO), 4.13 (d, J = 20.7 Hz, 1 H, CHP), 7.21–7.36 (m, 5 H, HAr), 7.52 (AA′BB′ system, J = 8.3, 2.2 Hz, 2 H, HAr), 8.06 (AA′BB′ system, J = 8.3 Hz, 2 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.5 (d, J = 17.3 Hz, Bn), 52.3 (MeO2C), 53.7 [d, J = 6.9 Hz, (MeO)2P], 54.0 [d, J = 6.9 Hz, (MeO)2P], 59.4 (d, J = 152.8 Hz, CHP), 127.5, 128.5, 128.7, 128.8 (d, J = 5.9 Hz), 130.0, 130.1, 138.9, 141.1, 166.9. 31P NMR (161.9 MHz, CDCl3): δ = 22.15. HRMS (FAB+): m/z [M + H]+ calcd for C18H23NO5P: 364.1314; found: 364.1322. Compound 6n: white solid; mp 59–62 °C. 1H NMR (400 MHz, CDCl3): δ = 2.35 (br s, 1 H, NH), 3.52 (AB system, J = 13.2 Hz, 1 H, CH2Ph), 3.61 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.74 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.79 (AB system, J = 13.2 Hz, 1 H, CH2Ph), 4.12 (d, J = 20.6 Hz, 1 H, CHP), 7.21–7.35 (m, 5 H, HAr), 7.55 (AA′BB′ system, J = 8.1, 1.4 Hz, 2 H, HAr), 7.64 (AA′BB′ system, J = 8.1 Hz, 2 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.5 (d, J = 17.1 Hz, CH2Ph), 53.7 [d, J = 6.9 Hz, (MeO)2P], 54.0 [d, J = 7.0 Hz, (MeO)2P], 59.3 (d, J = 153.0 Hz, CHP), 124.3 (q, J = 275.0, CF3), 125.7 (dq, J = 3.6, 3.6 Hz), 127.6, 128.5, 128.7, 129.1 (d, J = 5.9 Hz), 130.4 (dq, J = 32.2, 2.9 Hz), 138.9, 140.1 (d, J = 3.5 Hz). 31P NMR (161.9 MHz, CDCl3): δ = 24.78 (q, J = 2.5 Hz). HRMS (FAB+): m/z [M + H]+ calcd for C17H20F3NO3P: 374.1133; found: 374.1035. Compound 6p: yellow liquid. 1H NMR (400 MHz, CDCl3): δ = 2.56 (br s, 1 H, NH), 3.43 [d, J = 10.4 Hz, 3 H, (MeO)2P], 3.60 (AB system, J = 13.4 Hz, 1 H, CH2Ph), 3.74 [d, J = 10.5 Hz, 3 H, (MeO)2P], 3.82 (AB system, J = 13.4 Hz, 1 H, CH2Ph), 4.09 (d, J = 20.2 Hz, 1 H, CHP), 6.10–6.17 (m, 2 H, HAr), 6.78 (ddd, J = 4.3, 2.6, 1.8 Hz, 1 H, HAr), 7.18–7.35 (m, 5 H, HAr), 9.71 (br s, 1 H, NH-pyrrole). 13C NMR (100 MHz, CDCl3): δ = 51.2 (d, J = 16.9 Hz, CH2Ph), 52.5 (d, J = 160.4 Hz, CHP), 53.5 [d, J = 6.9 Hz, (MeO)2P], 53.9 [d, J = 7.0 Hz, (MeO)2P], 108.1, 109.5 (d, J = 9.4 Hz), 119.0, 124.8 (d, J = 5.4 Hz), 127.2, 128.4, 128.5, 139.5. 31P NMR (161.9 MHz, CDCl3): δ = 22.70. HRMS (FAB+): m/z [M + H]+ calcd for C14H20N2O3P: 295.1212; found: 295.1224. Compound 6q: yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 1.94 (br s, 1 H, NH), 3.60 (AB system, J = 13.3 Hz, 1 H, Bn), 3.64 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.81 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.87 (AB system, J = 13.3 Hz, 1 H, Bn), 4.12 (d, J = 22.2 Hz, 1 H, CHP), 6.36–6.42 (m, 2 H, HAr), 7.22–7.35 (m, 5 H, HAr), 7.46 (ddd, J = 2.5, 1.8, 0.8 Hz, 1 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.3 (d, J = 16.4 Hz, CH2Ph), 52.7 (d, J = 162.5 Hz, CHP), 53.4 [d, J = 6.9 Hz, (MeO)2P], 53.9 [d, J = 6.8 Hz, (MeO)2P], 109.5 (d, J = 7.5 Hz), 110.6, 127.2, 128.4 (2 × C), 138.8, 142.7 (2 × C). 31P NMR (81 MHz, CDCl3): δ = 23.36. HRMS (FAB+): m/z [M + H]+ calcd for C14H19NO4P: 296.1052; found: 296.1039. Compound 6r: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H, Me), 1.31–1.43 (m, 1 H, CH2), 1.49–1.64 (m, 3 H, NH, CH2), 1.68–1.81 (m, 1 H, CH2), 2.91 (ddd, J = 12.2, 8.5, 4.6 Hz, 1 H, CHP), 3.77 [d, J = 9.9 Hz, 3 H, (MeO)2P], 3.80 [d, J = 9.9 Hz, 3 H, (MeO)2P], 3.87 (AB system, J = 13.1, 1.8 Hz, 1 H, Bn), 3.96 (AB system, J = 13.1 Hz, 1 H, Bn), 7.20–7.37 (m, 5 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 14.0 (Me), 19.4 (d, J = 10.9 Hz, CH2), 32.1 (CH2), 52.3 (d, J = 5.0 Hz, CH2Ph), 52.8 [d, J = 7.6 Hz, (MeO)2P], 53.0 [d, J = 6.4 Hz, (MeO)2P], 53.7 (d, J = 149.4 Hz, CHP), 127.2, 128.5 (2 × C), 140.1. 31P NMR (161.9 MHz, CDCl3): δ = 28.35. HRMS (FAB+): m/z [M + H]+ calcd for C13H23NO3P: 272.1416; found: 272.1415.
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  • References and Notes

  • 1 Mucha A, Kafarski P, Berlicki Y. J. Med. Chem. 2011; 54: 5955
    CrossrefPubMedSearch in Google Scholar
  • 2 Aminophosphinic and Aminophosphonic Acids: Chemistry and Biological Activity. Kukhar VP, Hudson HR. John Wiley & Sons; New York: 2000
    Search in Google Scholar
  • 3 Prasada GS, Rao GN. J. Modern. Med. Chem. 2013; 1: 49
    Search in Google Scholar
  • 5 Sienczyk M, Oleksyszyn J. Curr. Med. Chem. 2009; 16: 1673
    CrossrefSearch in Google Scholar
  • 9 Sivaraman KK, Paiardini A, Sieńczyk M, Ruggeri C, Oellig CA, Dalton JP, Scammells PJ, Drag M, McGowan S. J. Med. Chem. 2013; 56: 5213 ; and references therein
    CrossrefSearch in Google Scholar
  • 10 Devineni SR, Doddaga S, Donka R, Chamarthi NR. Chin. Chem. Lett. 2013; 24: 759 ; and references therein
    CrossrefSearch in Google Scholar
  • 11 Danila DC, Wang X, Hubble H, Antipin IS, Pinkhassik E. Bioorg. Med. Chem. Lett. 2008; 18: 2320
    CrossrefSearch in Google Scholar
  • 17 Kabachnik MI, Medved T. Dokl. Acad. Nauk. SSSR 1952; 83: 689
    Search in Google Scholar
  • 19 Tibhe GD, Bedolla-Medrano M, Cativiela C, Ordóñez M. Synlett 2012; 23: 1931
    Thieme ConnectSearch in Google Scholar
  • 20 Ragaini F, Cognolato C, Gasperini M, Cenini S. Angew. Chem. Int. Ed. 2003; 42: 2886
    CrossrefSearch in Google Scholar
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  • 24 In a typical experiment, to a mixture of aldehyde or ketone (2.0 mmol) and benzylamine (2.0 mmol) was added the phenylphosphonic acid (5; 10 mol%). The reaction mixture was stirred at r.t. for 20 min. After this time, dimethyl phosphite (2.1 mmol) was added and the reaction mixture was stirred at 50 °C for the specific period of time (see Tables 1–3), and the progress of the reaction was monitored by TLC. The crude was directly subjected to silica gel flash chromatography eluting with EtOAc, obtaining the pure α-aminophosphonates. 1H NMR, 13C NMR, 31P NMR, and HRMS data for some newly obtained α-aminophosphonates are as follows. Compound 6g: yellow liquid. 1H NMR (400 MHz, CDCl3): δ = 3.48 [d, J = 10.5 Hz, 3 H, (MeO)2P], 3.52 (AB system, J = 13.3 Hz, 1 H, Bn), 3.78 (AB system, J = 13.3 Hz, 1 H, Bn), 3.79 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.89 (d, J = 20.1 Hz, 1 H, CHP), 6.63 (ddd, J = 8.0, 2.0, 2.0 Hz, 1 H, HAr), 6.77 (d, J = 8.0 Hz, 1 H, HAr), 7.11 (dd, J = 2.0, 2.0 Hz, 1 H, HAr), 7.20–7.31 (m, 5 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 50.8 (d, J = 17.6 Hz, Bn), 53.8 [d, J = 7.1 Hz, (MeO)2P], 54.1 [d, J = 7.6 Hz, (MeO)2P], 58.2 (d, J = 157.8 Hz, CHP), 114.7 (d, J = 5.0 Hz), 115.1, 121.0 (d, J = 8.1 Hz), 126.0, 127.2, 128.4 (2 × C), 139.0, 145.0 (2 × C). 31P NMR (161.9 MHz, CDCl3): δ = 26.62. HRMS (FAB+): m/z [M + H]+ calcd for C16H21NO5P: 338.1157; found: 338.1159. Compound 6k: white solid; mp 94–96 °C. 1H NMR (400 MHz, CDCl3): δ = 2.44 (br s, 1 H, NH), 3.58 (AB system, J = 13.3 Hz, 1 H, Bn), 3.58 [d, J = 10.5 Hz, 3 H, (MeO)2P], 3.75 [d, J HP = 10.6 Hz, 3 H, (MeO)2P], 3.84 (AB system, J = 13.3 Hz, 1 H, Bn), 4.10 (d, J = 20.2 Hz, 1 H, CHP), 7.22–7.36 (m, 6 H, HAr), 7.40–7.52 (m, 4 H, HAr), 7.59–7.64 (m, 4 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.3 (d, J = 17.4 Hz, Bn), 53.6 [d, J = 6.6 Hz, (MeO)2P], 53.9 [d, J = 6.6 Hz, (MeO)2P], 59.1 (d, J = 154.3 Hz, CHP), 127.1, 127.3, 127.4, 127.5, 128.5 (d, J = 6.7 Hz), 128.9, 129.1 (d, J = 5.5 Hz), 134.6, 139.3, 140.7, 140.9, 141.0. 31P NMR (161.9 MHz, CDCl3): δ = 23.05. HRMS (FAB+): m/z [M + H]+ calcd for C22H25NO3P: 382.1572; found: 382.1588. Compound 6l: colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 2.17 (br s, 1 H, NH), 3.52 (AB system, J = 13.3 Hz, 1 H, Bn), 3.58 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.74 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.80 (AB system, J = 13.3 Hz, 1 H, Bn), 3.93 (s, 3 H, MeO), 4.13 (d, J = 20.7 Hz, 1 H, CHP), 7.21–7.36 (m, 5 H, HAr), 7.52 (AA′BB′ system, J = 8.3, 2.2 Hz, 2 H, HAr), 8.06 (AA′BB′ system, J = 8.3 Hz, 2 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.5 (d, J = 17.3 Hz, Bn), 52.3 (MeO2C), 53.7 [d, J = 6.9 Hz, (MeO)2P], 54.0 [d, J = 6.9 Hz, (MeO)2P], 59.4 (d, J = 152.8 Hz, CHP), 127.5, 128.5, 128.7, 128.8 (d, J = 5.9 Hz), 130.0, 130.1, 138.9, 141.1, 166.9. 31P NMR (161.9 MHz, CDCl3): δ = 22.15. HRMS (FAB+): m/z [M + H]+ calcd for C18H23NO5P: 364.1314; found: 364.1322. Compound 6n: white solid; mp 59–62 °C. 1H NMR (400 MHz, CDCl3): δ = 2.35 (br s, 1 H, NH), 3.52 (AB system, J = 13.2 Hz, 1 H, CH2Ph), 3.61 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.74 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.79 (AB system, J = 13.2 Hz, 1 H, CH2Ph), 4.12 (d, J = 20.6 Hz, 1 H, CHP), 7.21–7.35 (m, 5 H, HAr), 7.55 (AA′BB′ system, J = 8.1, 1.4 Hz, 2 H, HAr), 7.64 (AA′BB′ system, J = 8.1 Hz, 2 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.5 (d, J = 17.1 Hz, CH2Ph), 53.7 [d, J = 6.9 Hz, (MeO)2P], 54.0 [d, J = 7.0 Hz, (MeO)2P], 59.3 (d, J = 153.0 Hz, CHP), 124.3 (q, J = 275.0, CF3), 125.7 (dq, J = 3.6, 3.6 Hz), 127.6, 128.5, 128.7, 129.1 (d, J = 5.9 Hz), 130.4 (dq, J = 32.2, 2.9 Hz), 138.9, 140.1 (d, J = 3.5 Hz). 31P NMR (161.9 MHz, CDCl3): δ = 24.78 (q, J = 2.5 Hz). HRMS (FAB+): m/z [M + H]+ calcd for C17H20F3NO3P: 374.1133; found: 374.1035. Compound 6p: yellow liquid. 1H NMR (400 MHz, CDCl3): δ = 2.56 (br s, 1 H, NH), 3.43 [d, J = 10.4 Hz, 3 H, (MeO)2P], 3.60 (AB system, J = 13.4 Hz, 1 H, CH2Ph), 3.74 [d, J = 10.5 Hz, 3 H, (MeO)2P], 3.82 (AB system, J = 13.4 Hz, 1 H, CH2Ph), 4.09 (d, J = 20.2 Hz, 1 H, CHP), 6.10–6.17 (m, 2 H, HAr), 6.78 (ddd, J = 4.3, 2.6, 1.8 Hz, 1 H, HAr), 7.18–7.35 (m, 5 H, HAr), 9.71 (br s, 1 H, NH-pyrrole). 13C NMR (100 MHz, CDCl3): δ = 51.2 (d, J = 16.9 Hz, CH2Ph), 52.5 (d, J = 160.4 Hz, CHP), 53.5 [d, J = 6.9 Hz, (MeO)2P], 53.9 [d, J = 7.0 Hz, (MeO)2P], 108.1, 109.5 (d, J = 9.4 Hz), 119.0, 124.8 (d, J = 5.4 Hz), 127.2, 128.4, 128.5, 139.5. 31P NMR (161.9 MHz, CDCl3): δ = 22.70. HRMS (FAB+): m/z [M + H]+ calcd for C14H20N2O3P: 295.1212; found: 295.1224. Compound 6q: yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 1.94 (br s, 1 H, NH), 3.60 (AB system, J = 13.3 Hz, 1 H, Bn), 3.64 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.81 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.87 (AB system, J = 13.3 Hz, 1 H, Bn), 4.12 (d, J = 22.2 Hz, 1 H, CHP), 6.36–6.42 (m, 2 H, HAr), 7.22–7.35 (m, 5 H, HAr), 7.46 (ddd, J = 2.5, 1.8, 0.8 Hz, 1 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.3 (d, J = 16.4 Hz, CH2Ph), 52.7 (d, J = 162.5 Hz, CHP), 53.4 [d, J = 6.9 Hz, (MeO)2P], 53.9 [d, J = 6.8 Hz, (MeO)2P], 109.5 (d, J = 7.5 Hz), 110.6, 127.2, 128.4 (2 × C), 138.8, 142.7 (2 × C). 31P NMR (81 MHz, CDCl3): δ = 23.36. HRMS (FAB+): m/z [M + H]+ calcd for C14H19NO4P: 296.1052; found: 296.1039. Compound 6r: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H, Me), 1.31–1.43 (m, 1 H, CH2), 1.49–1.64 (m, 3 H, NH, CH2), 1.68–1.81 (m, 1 H, CH2), 2.91 (ddd, J = 12.2, 8.5, 4.6 Hz, 1 H, CHP), 3.77 [d, J = 9.9 Hz, 3 H, (MeO)2P], 3.80 [d, J = 9.9 Hz, 3 H, (MeO)2P], 3.87 (AB system, J = 13.1, 1.8 Hz, 1 H, Bn), 3.96 (AB system, J = 13.1 Hz, 1 H, Bn), 7.20–7.37 (m, 5 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 14.0 (Me), 19.4 (d, J = 10.9 Hz, CH2), 32.1 (CH2), 52.3 (d, J = 5.0 Hz, CH2Ph), 52.8 [d, J = 7.6 Hz, (MeO)2P], 53.0 [d, J = 6.4 Hz, (MeO)2P], 53.7 (d, J = 149.4 Hz, CHP), 127.2, 128.5 (2 × C), 140.1. 31P NMR (161.9 MHz, CDCl3): δ = 28.35. HRMS (FAB+): m/z [M + H]+ calcd for C13H23NO3P: 272.1416; found: 272.1415.
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Figure 1 Proposed mechanism for the synthesis of α-aminophosphonates catalyzed by phenylphosphonic acid