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Synthesis 2010(1): 57-62  
DOI: 10.1055/s-0029-1217091
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Tin(II) Compounds as Catalysts for the Kabachnik-Fields Reaction under Solvent-Free Conditions: Facile Synthesis of α-Aminophosphonates

Ricardo Gallardo-Macias, Kensaku Nakayama*
Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA
Fax: +1(562)9858557; e-Mail: nakayama@csulb.edu;

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Publication History

Received 13 July 2009
Publication Date:
26 October 2009 (online)

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Abstract

In the presence of a catalytic amount of tin(II) salts, the three-component Kabachnik-Fields reaction involving aldehydes, amines, and diethyl phosphite proceeded smoothly to afford the corresponding α-aminophosphonates in good to high yields. These reactions were carried out under solvent-free conditions.

Key words

α-aminophosphonates - catalysis - imines - Lewis acids - solvent-free

Since 1959, when Horiguchi and Kandatsu isolated 2-aminoethanephosphonic acid, [¹] aminophosphonates have attracted much attention due to their biological activity as enzyme inhibitors, [²] antibiotics, [³] peptide mimics, [4] herbicides, [5] and pharmacological agents. [6] As a result, several synthetic methodologies have been developed for their preparation. One method involves the coupling of dialkyl phosphite with imines (Pudovik reaction) in the presence of various Lewis acids such as BF3, [7] SnCl4, [8] ZrCl4, [9] tetra­(tert-butyl)phthalocyanine aluminum chloride (t-PcAlCl), [¹0] and AlCl3. [¹¹] However, this methodology possesses drawbacks such as moisture-sensitivity, long reaction times, multiple synthetic steps, and poor yields. [¹²]

In comparison to the Pudovik reaction, the Kabachnik-Fields reaction, [¹³] where an aldehyde, an amine, and a dialkyl phosphite are allowed to react in a three-component reaction, has enjoyed wider utilization in the synthesis of α-aminophosphonates due to its simplicity. Lewis acid catalysts such as Yb(OTf)3, [¹4] Cu(OTf)2, [¹5] phenyltrimethylammonium chloride, [¹6] InCl3, [¹7] SmI2, [¹8] lithium perchlorate, [¹9] alumina-supported reagents, [²0] TiO2, [²¹] and TaCl5-SiO2 [²²] have been employed. However, these methods need longer reaction times and require the use of solvents. More recently, methods involving new catalysts such as Mg(ClO4)2, [²³] metal triflates [M(OTf)n], [²4] as well as microwave synthesis, [²5] have been reported; these approaches follow the precepts of green chemistry in that they require no solvent and are energy efficient. [²6]

While the use of SnCl4 in an asymmetric Pudovik aminophosphonate synthesis in the presence of carbohydrate templates has been reported, [8] to our knowledge, a systematic investigation of the efficacy of other tin compounds in the Kabachnik-Fields reaction has not been carried out. Herein, we describe a simple, solvent-free Kabachnik-Fields protocol for the synthesis of α-aminophosphonates using catalytic amounts of tin(II) compounds under mild conditions. Based on previous reports where metal triflates served as effective catalysts in the Kabachnik-Fields reaction, we first screened Sn(OTf)2 (Equation  [¹] ).

Equation 1 Kabachnik-Fields Reaction Using Sn(OTf)2 as catalyst with dichloromethane as solvent

We were pleased to find that Sn(OTf)2 afforded the corresponding α-aminophosphonate 3a in 65% yield after 48 hours at room temperature using dichloromethane as the solvent. We then tested the effectiveness of Sn(OTf)2 as a catalyst under solvent-free conditions using the model system of benzaldehyde, aniline, and diethyl phosphite in the three-component reaction. To our delight, we found that Sn(OTf)2 served as a better catalyst for the Kabachnik­-Fields reaction under solvent-free conditions than with dichloromethane as solvent.

Next, we compared the efficacy of Sn(OTf)2 against other catalysts that have been reported in the synthesis of α-aminophosphonates under solvent-free conditions. In our hands, Sn(OTf)2 performed respectably when compared to other catalysts reported in the literature (Table  [¹] ).

Table 1 Comparison of Catalysts in the Solvent-Free Kabachnik-Fields Reaction
Catalyst Yield (%) Time (h)
Mg(ClO4)2  50 4
Yb(OTf)3  93 3
Cu(OTf)2  90 4.5
Sn(OTf)2 100 0.5

Baghat and Chakraborti [²³] reported that they obtained the desired product in 98% yield after two minutes using 5 mol% of Mg(ClO4)2 as the catalyst. However, in our hands, the reaction mixture required heating at 50 ˚C for several hours in order to achieve this yield. Wu et al. [²7] have also reported that complete reaction is achieved with 5 mol% of Mg(ClO4)2 after five hours at 50 ˚C.

Next, we screened other tin(II) compounds as potential catalysts for the solvent-free Kabachnik-Fields reaction (Table  [²] ).

Table 2 Comparison of Tin Salts as Catalysts for the Solvent-Free Kabachnik-Fields Reaction
Catalyst Yield (%) Time (h)
Sn(OTf)2 100 0.5
SnCl2 100 0.5
SnBr2  94 2.5
SnI2 100 0.75
SnCl4 a  99 2.5
a A 1 M solution of SnCl4 in CH2Cl2 was used to prepare a mixture containing 10 mol% of the catalyst.

We found that all of the tin compounds catalyzed the formation of the desired product in high yields and in reasonable reaction times. These results compare favorably to the yields recently reported in the synthesis of 3a [¹7] [¹8] [²¹] [²7] and the reaction times were considerably shorter in many cases. We also screened several commercially available dialkyl phosphites and found that they all afforded the corresponding α-aminophosphonates in high yields (Table  [³] ). Based on these results and due to its low cost compared to other tin(II) compounds, SnCl2 was chosen as the catalyst for further studies in the solvent-free synthesis of α-aminophosphonates. The following trend was found between the amount of SnCl2 used versus reaction time: 1 mol% SnCl2: 12 h (73% yield); 5 mol% SnCl2: 7 h (100% yield); 10 mol% SnCl2: 0.5 h (100% yield). Therefore, we employed 10 mol% of the catalyst in all subsequent studies.

Table 3 SnCl2-Catalyzed Kabachnik-Fields Reaction Using Different Dialkyl Phosphites
Entry Phosphite Product Yield
(%) 		Time (h)
1 diethyl phosphite (DEP) 3a 100 0.5
2 dimethyl phosphite (DMP) 3b 100 2.5
3 di-n-butyl phosphite (DBP) 3c  92 2.5

The rate of imine formation was studied by allowing benz­aldehyde (1.0 mmol) and aniline (1.1 mmol) to react at room temperature under solvent-free conditions both with and without catalyst. The reaction progress was followed by GC-MS. It was established that the benzaldehyde was completely consumed under both conditions to form the imine after allowing the reaction to occur for one minute. This demonstrates that the rate-determining step is the reaction of the dialkyl phosphite with the imine intermediate and that the SnCl2 is catalyzing this step, at least in the case where aniline is the amine. These results also show that the catalyst does not affect the rate of imine formation.

We next examined a range of aromatic and aliphatic amines, as well as carbonyl compounds, as reactants in order­ to determine the scope of the SnCl2-catalyzed Kabachnik­-Fields reaction (Table  [4] ).

Table 4 SnCl2-Catalyzed Synthesis of α-Aminophosphonates Using Various Carbonyl Compounds, Amines and DMP/DEPa
Entry Carbonyl compound Amine Product Yield (%) Time (h)
 1 benzaldehyde p-anisidine 3d  57  8
 2 benzaldehyde p-nitroaniline 3e   64  6
 3 benzaldehyde piperidine 3f  43  0.5b
 4 benzaldehyde n-hexylamine 3g  68  5b
 5 benzaldehyde α-methylbenzylamine 3h  66  6
 6 4-hydroxybenzaldehyde aniline 3i 100  3
 7 p-anisaldehyde aniline 3j  83  6
 8 p-tolualdehyde aniline 3k 100  0.5
 9 2,4-dimethoxybenzaldehyde aniline 3l  75  1
10 2-furaldehyde aniline 3m 100   0.25
11 4-chlorobenzaldehyde aniline 3n  67  3.5
12 4-bromobenzaldehyde aniline 3o  77  3.5
13 4-nitrobenzaldehyde aniline 3p  55 27
14 2-naphthaldehyde aniline 3q  70 27
15 isobutyraldehyde aniline 3r  47  0.5b
16 isovaleraldehyde aniline 3s  46  1.5b
17 acetophenone aniline 3t  56  8c
a DMP = dimethyl phosphite; DEP = diethyl phosphite. All reactions were performed with DEP, except entries 3 and 15, which were carried out with DMP.
b The reaction was heated at 40 ˚C.
c The reaction was heated at 80 ˚C.

In all cases, the one-pot reaction proceeded cleanly to afford the corresponding α-aminophosphonate. The order of addition of the starting materials did not have any effect on the product yield. Extensive studies have been carried out on the mechanism of the Kabachnik-Fields reaction, and Scheme  [¹] is based on the studies by Cherkasov and Galkin involving aniline and its derivatives. [²8] [²9] In these cases, they reported that the imine formed from the aromatic amine and the benzaldehyde was the key intermediate in the product-forming pathway. In general, aromatic aldehydes with electron-donating groups afforded higher yields than those with electron-withdrawing groups. These results may be due to the substituent’s effects on the Lewis basicity of the nitrogen atom of the imine intermediate shown in the mechanism. Electron-donating groups on the aromatic ring would place greater electron density on the imine nitrogen and enhance the Lewis acid-base interaction between the tin catalyst and the imine, thus promoting the reaction. The use of aliphatic aldehydes and acetophenone resulted in lower yields. In these cases, the reaction required heating in order to shift the equilibrium towards product formation. In terms of the structural effects of the amines, substituted anilines resulted in lower yields while primary aliphatic amines gave moderate yields. Use of a secondary aliphatic amine resulted in lower yield. [³0]

Scheme 1 Mechanism for the tin(II)-catalyzed, three-component reaction between aniline, dialkyl phosphite, and benzaldehyde

In summary, commercially available tin(II) compounds, in particular SnCl2, were found to be good catalysts for the synthesis of α-aminophosphonates in a solvent-free, three-component reaction under atmospheric conditions. Further investigations, including the development of asymmetric variants of the Kabachnik-Fields reaction, are in progress and will be reported in due course.

¹H and ¹³C NMR spectra were obtained on a 400 MHz Tecmag spectrometer, with CDCl3 as solvent and TMS as internal reference. Thin layer chromatography was performed on aluminum-backed Silica gel TLC plates (250 µm layer) with UV visualization. Purification of products were performed by column chromatography using gravity grade silica gel (EtOAc-hexane, 70:30 → 50:50). All reactions were performed under solvent-free and atmospheric conditions at r.t., unless otherwise indicated. All solvents were purified using standard methods and stored over 3 Å molecular sieves. Mg(ClO4)2, Yb(OTf)2, Cu(OTf)2, Sn(OTf)2, SnCl2, SnBr2, SnI2, and SnCl4 (1 M in CH2Cl2), diethyl phosphite, dibutyl phosphite, di­methyl phosphite, most aromatic aldehydes, p-anisidine, p-nitro­aniline, hexylamine, piperidine, methylbenzylamine and aniline were purchased from Aldrich, Acros Organics, or Alfa Aesar and used without further purification. Benzaldehyde, p-anisaldehyde, 2-furaldehyde, isovaleraldehyde, isobutyraldehyde, and p-tolualdehyde were purified by simple distillation and stored over 3 Å molecular sieves under an argon atmosphere. LRMS were obtained on a Hewlett-Packard 5890 series II GC/MS. HRMS were obtained on an Agilent 6210 LCTOF instrument at the mass spectral facility in the Department of Chemistry at UC Riverside.

Solvent-Free, SnCl 2 -Catalyzed Kabachnik-Fields Reaction; General Procedure

A mixture of aldehyde (1 mmol), amine (1 mmol), dialkyl phosphite (1 mmol), and SnCl2 (0.1 mmol) was stirred at r.t. under atmospheric conditions until the reaction was complete. Brine (2.5 mL), H2O (2.5 mL) and EtOAc (5 mL) were added to quench the reaction, and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 5 mL) and the combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography on silica gel (EtOAc-hexane, 70:30 → 50:50) to afford the desired α-aminophosphonate.

Diethyl (Phenyl)( N -phenylamino)methylphosphonate (3a) [²³]

Obtained as a greenish-white solid.

¹H NMR (400 MHz, CDCl3): δ = 1.11 (t, J = 7.09 Hz, 3 H), 1.28 (t, J = 7.09 Hz, 3 H), 3.66 (m, 1 H), 3.93 (m, 1 H), 4.11 (m, 2 H), 4.72 (d, J = 7.7 Hz, 1 H), 4.78 (s, 1 H), 6.57-6.60 (m, 2 H), 6.67-6.71 (m, 1 H), 7.08-7.12 (m, 2 H), 7.31-7.35 (m, 3 H), 7.45-7.48 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.12, 16.17,16.35, 16.42, 55.35, 56.78, 63.10, 63.20, 63.23, 63.27, 113.82, 118.37, 127.75, 127.77, 127.83, 127.85, 127.88, 128.53, 128.55, 129, 129.11, 129.13, 135.82, 135.85, 146.15, 146.30.

LRMS (EI): m/z = 319 [M+], 182 [M - P(O)(OEt)2].

Dimethyl (Phenyl)( N -phenylamino)methylphosphonate (3b) [²³]

Obtained as a clear oil.

¹H NMR (400 MHz, CDCl3): δ = 3.47 (d, J = 10.52 Hz, 3 H), 3.76 (d, J = 10.7 Hz, 3 H), 4.80 (d, J = 24.3 Hz, 1 H), 6.58-6.61 (m, 2 H), 6.67-6.71 (m, 1 H), 7.07-7.12 (m, 2 H), 7.24-7.36 (m, 3 H), 7.45-7.48 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 53.42, 53.48, 53.54, 54.52, 56.03, 113.56, 118.14, 127.52, 127.58, 127.72, 127.75, 128.38, 128.40, 129.39, 129.69, 135.34, 135.36, 145.81, 145.96.

LRMS (EI): m/z = 291 [M+], 182 [M - P(O)(OMe)2].

Di- n -butyl (Phenyl)( N -phenylamino)methylphosphonate (3c)

Obtained as a green-brown oil.

¹H NMR (400 MHz, CDCl3): δ = 0.82 (t, J = 7.4 Hz, 3 H), 0.88 (t, J = 7.4 Hz, 3 H), 1.17-1.27 (m, 8 H), 3.54-4.14 (m, 5 H), 4.73 (d, J = 24.2 Hz, 1 H), 6.57-6.60 (m, 2 H), 6.66-6.70 (m, 1 H), 7.07-7.11 (m, 2 H), 7.30-7.33 (m, 3 H), 7.45-7.48 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 13.33, 13.37, 13.39, 18.35, 18.49, 18.55, 32.13, 32.2, 32.26, 32.33, 32.39, 55.13, 56.63, 65.28, 65.35, 66.65, 66.72, 66.74, 66.81, 113.66, 113.69, 118.16, 127.67, 127.72, 128.37, 128.43, 135.86, 135.88, 146.14, 146.28.

LRMS (EI): m/z = 375 [M+], 182 [M - P(O)(OBu)2].

HRMS: m/z [MH+] calcd for C21H30NO3P: 375.2036; found: 376.2035.

Diethyl [ N -(4-Methoxyphenyl)amino](phenyl)methylphosphonate (3d) [9]

Obtained as a dark solid.

¹H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.09 Hz, 3 H), 1.27 (t, J = 7.0 Hz, 3 H), 3.63-4.18 (m, 4 H), 3.66 (s, 3 H), 4.69 (d, J = 23.95 Hz, 1 H), 6.52-6.56 (m, 2 H), 6.65-6.69 (m, 2 H), 7.22-7.26 (m, 1 H), 7.31 (t, J = 7.4 Hz, 2 H), 7.44-7.47 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.02, 16.08, 16.27, 16.32, 55.47, 56.10, 57.60, 63.02, 63.09, 63.16, 114.58, 114.60, 115.11, 127.72, 127.73, 127.75, 127.79, 128.41, 128.44, 135.91, 135.93, 140.12, 140.27, 152.53, 157.46.

EIMS (EI): m/z  = 349 [M+], 212 [M - P(O)(OEt)2].

Diethyl [ N -(4-Nitrophenyl)amino](phenyl)methylphosphonate (3e) [²4]

Obtained as a yellow solid.

¹H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.0 Hz, 3 H), 1.30 (t, J = 7.0 Hz, 3 H), 3.56-3.66 (m, 1 H), 3.87-3.96 (m, 1 H), 4.08-4.19 (m, 2 H), 4.8 (d, J = 23.8 Hz, 1 H), 6.56-6.59 (m, 2 H), 7.33-7.45 (m, 5 H), 7.99-8.02 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.07, 16.13, 16.34, 16.4, 54.69, 56.20, 63.24, 63.31, 63.77, 63.84, 112.34, 125.99, 127.69, 127.71, 127.74, 128.42, 128.45, 128.81, 128.84, 128.86, 134.53, 134.56, 138.85, 151.86, 152.00, 152.02.

LRMS (EI): m/z = 364 [M+], 227 [M - P(O)(OEt)2].

Dimethyl (Phenyl)(piperidin-1-yl)methylphosphonate (3f) [³¹]

The reaction was heated at 40 ˚C to give the product as a white solid.

¹H NMR (400 MHz, CDCl3): δ = 1.31 (t, J = 5.6 Hz, 2 H), 1.55-1.61 (m, 4 H), 2.41 (m, 2 H), 2.82 (m, 2 H), 3.47 (d, J = 10.5 Hz, 3 H), 3.90 (d, J = 10.4 Hz, 3 H), 3.97 (d, J = 23.2 Hz, 1 H), 7.29-7.48 (m, 5 H).

¹³C NMR (100 MHz, CDCl3): δ = 23.80, 26.17, 52.30, 52.38, 52.51, 52.59, 54.01, 54.09, 67.46, 69.07, 127.95, 128.0, 130.40, 130.49.

LRMS (EI): m/z = 283 [M+], 174 [M - P(O)(OMe)2].

Diethyl ( n- Hexylamino)(phenyl)methylphosphonate (3g) [9]

The reaction was heated at 40 ˚C to give the product as a clear oil.

¹H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.09 Hz, 3 H), 1.13 (t, J = 6.5 Hz, 3 H), 1.24-1.29 (m, 9 H), 1.44 (q, J = 6.9 Hz, 2 H), 2.41-2.56 (m, 3 H), 3.77-3.87 (m, 1 H), 3.91-4.13 (m, 4 H), 7.27-7.29 (m, 1 H), 7.32-7.35 (t, J = 7.3 Hz, 2 H), 7.41-7.42 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 13.75, 15.93, 15.98, 16.11, 16.16, 22.31, 26.53, 29.47, 31.39, 47.66, 47.83, 60.07, 61.59, 62.48, 62.55, 62.63, 62.70, 127.49, 127.52, 128.07, 128.10, 128.19, 128.24, 128.25, 135.82, 135.86.

LRMS (EI): m/z = 327 [M+], 190 [M - P(O)(OEt)2].

Diethyl (Phenyl)[ N -(1-phenylethyl)amino]methylphosphonate (3h) [¹4]

Obtained as a clear oil.

¹H NMR (400 MHz, CDCl3): δ = 1.02-1.10 (m, 3 H), 1.21-1.34 (m, 6 H), 2.01 (s, 1 H), 3.64-3.76 (m, 1 H), 3.82-3.97 (m, 1 H), 4.03-4.24 (m, 4 H), 7.16-7.35 (m, 10 H).

¹³C NMR (100 MHz, CDCl3): δ = 15.96, 16.02, 16.28, 16.29, 16.33, 22.15, 22.16, 24.64, 54.98, 55.10, 57.21, 58.71, 60.11, 62.47, 62.54, 62.68, 62.76, 62.80, 126.52, 126.81, 126.85, 126.95, 127.48, 127.51, 128.14, 128.16, 128.19, 128.22, 128.24, 128.36, 128.42, 136.35, 136.36, 143.90, 145.00.

LRMS (EI): m/z = 346 [M+], 210 [M - P(O)(OEt)2].

Diethyl (4-Hydroxyphenyl)( N -phenylamino)methylphosphonate (3i) [²¹]

Obtained as an orange solid.

¹H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.09 Hz, 3 H), 1.24 (t, J = 7.09 Hz, 3 H), 3.66-3.76 (m, 1 H), 3.88-3.98 (m, 1 H), 4.01-4.16 (m, 2 H), 4.71 (d, J = 24.03 Hz, 1 H), 6.58-6.60 (m, 2 H), 6.67 (t, J = 7.4 Hz, 1 H), 6.73 (d, J = 8.24 Hz, 2 H), 7.08 (t, J = 8.46 Hz, 2 H), 7.21-7.23 (m, 2 H), 8.51 (s, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.04, 16.10, 16.21, 16.27, 54.26, 55.90, 63.43, 63.50, 63.57, 113.85, 115.81, 115.83, 118.34, 125.67, 125.7, 128.79, 128.84, 129.02, 146.02, 146.17, 156.64, 156.67.

Diethyl (4-Methoxyphenyl)( N -phenylamino)methylphosphonate (3j) [9]

Obtained as a white solid.

¹H NMR (400 MHz, CDCl3): δ = 1.13 (t, J = 7.01 Hz, 3 H), 1.27 (t, J = 7.09 Hz, 3 H), 3.64-4.17 (m, 4 H), 3.76 (s, 3 H), 4.71 (d, J = 23.8 Hz, 1 H), 6.57-6.60 (m, 2 H), 6.66-6.70 (m, 1 H), 6.84-6.87 (m, 2 H), 7.07-7.12 (m, 2 H), 7.36-7.40 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.16, 16.21, 16.32, 16.4, 54.54, 55.14, 56.05, 63.07, 63.11, 63.14, 63.18, 113.82, 113.96, 113.98, 118.27, 127.58, 127.63, 128.85, 128.91, 129.06, 146.20, 146.34, 159.20, 159.23.

LRMS (EI): m/z = 349 [M+], 212 [M - P(O)(OEt)2].

Diethyl (4-Methylphenyl)( N -phenylamino)methylphosphonate (3k) [9]

Obtained as a white-yellow solid.

¹H NMR (400 MHz, CDCl3): δ = 1.12 (t, J = 7.09 Hz, 3 H), 1.27 (t, J = 7.09 Hz, 3 H), 2.29 (s, 3 H), 3.63-4.16 (m, 4 H), 4.73 (d, J = 24.1 Hz, 1 H), 6.59 (d, J = 7.7 Hz, 2 H), 6.67 (t, J = 7.4 Hz, 1 H), 7.06-7.13 (m, 3 H), 7.33-7.35 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.08, 16.14, 16.29, 16.35, 21.07, 21.02, 22.71, 22.73, 54.86, 56.36, 63.05, 63.07, 63.09, 63.14, 63.17, 113.74, 118.19, 127.59, 127.62, 127.64, 129.02, 129.16, 129.18, 129.20, 132.59, 132.62, 137.44, 137.47, 146.20, 146.36.

LRMS (EI): m/z = 333 [M+], 196 [M - P(O)(OEt)2].

Diethyl (2,4-Dimethoxyphenyl)( N -phenylamino)methylphosphonate (3l)

Obtained as a white-pink solid; mp 100-103 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 1.06 (t, J = 7.09 Hz, 3 H), 1.30 (t, J = 7.09 Hz, 3 H), 3.59-3.68 (m, 1 H), 3.75 (s, 3 H), 3.85-3.95 (m, 1 H), 3.89 (s, 3 H), 4.12-4.21 (m, 2 H), 4.78 (br s, 1 H), 5.28 (d, J = 24.26 Hz, 1 H), 6.42-6.45 (m, 2 H), 6.57-6.67 (m, 3 H), 7.05-7.11 (m, 2 H), 7.35-7.38 (m, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.08, 16.10, 16.33, 55.19, 55.62, 62.84, 62.91, 62.96, 63.04, 96.4, 98.31, 98.33, 104.7, 104.73, 113.51, 116.67, 117.97, 128.81, 129, 129.02, 146.17, 146.32, 158.12, 160.37, 160.40.

LRMS (EI): m/z = 379 [M+], 241 [M - P(O)(OEt)2].

HRMS: m/z [MH+] calcd for C19H26NO5P: 379.1621; found: 380.1619.

Diethyl (2-Furanyl)( N -phenylamino)methylphosphonate (3m) [²4]

Obtained as a red-purple oil.

¹H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.01 Hz, 3 H), 1.25 (t, J = 7.01 Hz, 3 H), 3.80-4.20 (m, 4 H), 4.91 (d, J = 23.88 Hz, 1 H), 6.28 (t, J = 3.12 Hz, 1 H), 6.38 (t, J = 3.2 Hz, 1 H), 6.65-6.73 (m, 4 H), 7.09-7.14 (m, 2 H), 7.34 (s, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 15.89, 15.95, 16.03, 16.08, 49.04, 50.63, 62.95, 63.02, 63.17, 63.24, 108.44, 108.50, 110.45, 110.47, 113.61, 113.63, 118.53, 128.83, 128.85, 142.12, 142.50, 145.7, 146.88, 149.08, 149.10.

LRMS (EI): m/z = 309 [M+], 172 [M - P(O)(OEt)2].

Diethyl (4-Chlorophenyl)( N -phenylamino)methylphosphonate (3n) [²4]

Obtained as a yellow-brown solid.

¹H NMR (400 MHz, CDCl3): δ = 1.15 (t, J = 7.09 Hz, 3 H), 1.28 (t, J = 7.09 Hz, 3 H), 3.72-4.18 (m, 4 H), 4.73 (d, J = 24.49 Hz, 1 H), 6.54-6.57 (m, 2 H), 6.68-6.72 (m, 1 H), 7.07-7.12 (m, 2 H), 7.29-7.31 (m, 2 H), 7.39-7.42 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.16, 16.21, 16.33, 63.23, 53.43, 54.72, 56.22, 63.30, 63.33, 63.40, 113.78, 118.60, 118.74, 128.71, 128.74, 129.06, 129.11, 129.16, 129.36, 133.66, 134.53, 134.56, 145.89, 146.03, 152.64.

LRMS (EI): m/z = 353 [M+], 216 [M - P(O)(OEt)2].

Diethyl (4-Bromophenyl)( N -phenylamino)methylphosphonate (3o) [³²]

Obtained as a grayish solid.

¹H NMR (400 MHz, CDCl3): δ = 1.16 (t, J = 7.0 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3 H), 3.73-4.18 (m, 4 H), 4.71 (d, J = 24.8 Hz, 1 H), 6.53-6.56 (m, 2 H), 6.69-6.73 (m, 1 H), 7.08-7.13 (m, 2 H), 7.33-7.36 (m, 2 H), 7.44-7.47 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.15, 16.21, 16.33, 16.39, 54.80, 56.29, 63.23, 63.30, 63.33, 63.39, 113.77, 118.59, 118.61, 121.75, 121.80, 129.16, 129.37, 129.39, 129.44, 131.62, 131.64, 131.67, 135.08, 135.11, 145.86, 146.01.

LRMS (EI): m/z = 397 [M+], 260 [M - P(O)(OEt)2].

Diethyl (4-Nitrophenyl)( N -phenylamino)methylphosphonate (3p) [²¹]

Obtained as an orange solid.

¹H NMR (400 MHz, CDCl3): δ = 1.18 (t, J = 7.09 Hz, 3 H), 1.29 (t, J = 7.0 Hz, 3 H), 3.83-4.21 (m, 4 H), 4.86 (d, J = 25.48 Hz, 1 H), 6.52-6.55 (m, 2 H), 6.71-6.75 (m, 1 H), 7.08-7.13 (m, 2 H), 7.64-7.68 (m, 2 H), 8.17-8.21 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.16, 16.34, 16.38, 16.4, 54.84, 55.23, 56.73, 63.16, 63.41, 63.48, 63.69, 63.75, 113.77, 119.05, 123.69, 128.58, 128.61, 128.63, 129.30, 129.32, 129.39, 141.29, 144, 144.04, 145.52, 145.66, 147.58.

LRMS (EI): m/z = 364 [M+], 227 [M - P(O)(OEt)2].

Diethyl (2-Naphthyl)( N -phenylamino)methylphosphonate (3q) [9]

Obtained as a yellowish solid.

¹H NMR (400 MHz, CDCl3): δ = 1.07 (t, J = 7.09 Hz, 3 H), 1.27 (t, J = 7.0 Hz, 3 H), 3.61-4.18 (m, 4 H), 4.92 (d, J = 24.18 Hz, 1 H), 6.61-6.68 (m, 3 H), 7.04-7.09 (m, 2 H), 7.40-7.46 (m, 2 H), 7.58-7.61 (m, 1 H), 7.77-7.82 (m, 3 H), 7.93 (s, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.06, 16.12, 16.30, 16.36, 55.48, 56.96, 63.16, 63.23, 65.72, 113.79, 118.34, 125.50, 125.54, 125.93, 125.94, 126.07, 126.77, 126.84, 127.55, 127.57, 127.86, 128.24, 128.26, 129.07, 132.96, 132.98, 133.15, 133.18, 133.40, 133.44, 146.17, 146.31.

LRMS (EI): m/z = 369 [M+], 232 [M - P(O)(OEt)2].

Dimethyl 2-Methyl-1-( N -phenylamino)propylphosphonate (3r) [²³]

The reaction was heated at 40 ˚C to give the product as a white solid.

¹H NMR (400 MHz, CDCl3): δ = 1.05 (d, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 2.19-2.29 (m, 1 H), 3.65 (d, J = 10.22 Hz, 3 H), 3.72 (d, J = 10.6 Hz, 3 H), 3.9 (br s, 1 H), 6.65-6.72 (m, 3 H), 7.14-7.18 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 17.90, 17.95, 20.36, 20.48, 29.75, 29.80, 52.17, 52.24, 53.16, 53.22, 55.14, 56.65, 113.07, 117.85, 129.20, 147.34, 147.39.

LRMS (EI): m/z = 257 [M+], 148 [M - P(O)(OMe)2].

Diethyl 3-Methyl-1-( N -phenylamino)butylphosphonate (3s) [²¹]

The reaction was heated at 40 ˚C to give the product as a white solid.

¹H NMR (400 MHz, CDCl3): δ = 0.87 (d, J = 6.56 Hz, 3 H), 0.94 (d, J = 6.71 Hz, 3 H), 1.15 (t, J = 7.09 Hz, 3 H), 1.27 (t, J = 7.09 Hz, 3 H), 1.66 (dd, J = 6.71, 7.7 Hz, 2 H), 1.80-1.89 (m, 1 H), 3.64-3.78 (m, 2 H), 3.89-3.97 (m, 1 H), 4.04-4.14 (m, 3 H), 6.64-6.70 (m, 3 H), 7.12-7.16 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.18, 16.24, 16.28, 21.33, 23.14, 24.06, 24.19, 39.50, 39.53, 48.2, 49.76, 61.63, 61.78, 62.66, 62.67, 112.91, 117.57, 129.02, 147.11, 147.13.

LRMS (EI): m/z = 299 [M+], 162 [M - P(O)(OEt)2].

Diethyl 1-Phenyl-1-( N -phenylamino)ethylphosphonate (3t) [²³]

The reaction was heated at 80 ˚C to give the product as a white solid.

¹H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.99 (d, J = 16.4 Hz, 3 H), 3.74-4.07 (m, 4 H), 6.39 (d, J = 7.7 Hz, 2 H), 6.66 (t, J = 7.3 Hz, 1 H), 7.00 (dt, J = 1.0, 7.4 Hz, 2 H), 7.24-7.36 (m, 3 H), 7.59-7.62 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 16.19, 16.20, 16.24, 19.89, 20.0, 20.03, 58.75, 60.24, 63.28, 63.35, 63.42, 63.49, 116.52, 166.54, 118.22, 127.22, 127.26, 127.99, 128.01, 128.04, 128.11, 128.14, 128.52, 128.54, 138.35, 138.42, 144.52, 144.68.

LRMS (EI): m/z = 333 [M+], 196 [M - P(O)(OEt)2].

Acknowledgment

Financial support from the CSULB Provost Summer Research Scholarship and CSULB Scholarly and Creative Activity Program are gratefully acknowledged.

30

Lewis acids such as SnCl2 may not be necessary in the formation of aminophosphonate 3f, which involves piperidine, a secondary aliphatic amine. We are currently investigating the synthesis of α-aminophosphonates from secondary aliphatic amines.

30

Lewis acids such as SnCl2 may not be necessary in the formation of aminophosphonate 3f, which involves piperidine, a secondary aliphatic amine. We are currently investigating the synthesis of α-aminophosphonates from secondary aliphatic amines.

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Scheme 1 Mechanism for the tin(II)-catalyzed, three-component reaction between aniline, dialkyl phosphite, and benzaldehyde