Diethyl(benzamido(diisopropoxyphosphoryl)methyl)phosphonate

: Bisphosphonates are widely used in medicine and related areas, mainly for the treatment of bone diseases, such as osteoporosis. However, their synthesis is usually performed under harsh reaction conditions. In order to overcome this limitation, the present work illustrates a new synthetic route to access the title α -aminobisphosphonate in milder reaction conditions using α -phosphorylated imines as key intermediates. Abstract: Bisphosphonates are widely used in medicine and related areas, mainly for the treatment of bone diseases, such as osteoporosis. However, their synthesis is usually performed under harsh reaction conditions. In order to overcome this limitation, the present work illustrates a new synthetic route to access the title α-aminobisphosphonate in milder reaction conditions using α-phosphory-lated imines as key intermediates.


Scheme 2.
Our proposal to access amino bisphosphonates.

Results
The proposed synthesis requires two base-catalyzed steps. For this reason, we initially tested the direct addition of diethyl phosphite 2 to α-bromo aminophosphonate 1 in presence of an excess of triethylamine, which is known to promote the elimination of hydrobromic acid as well as to act as a catalyst in the Pudovik reaction. In order to demonstrate the formation of the α-iminophosphonate intermediate 4, the reaction was monitored by 31 P NMR ( 31 P NMR of α-iminophosphonate 4 (δ = 1.7 ppm)). The addition of the phosphite 2 with 0.1 equivalents of trimethylamine afforded the bisphosphonate product 3. However, the low stability of α-iminophosphonates makes this two-step procedure less efficient. Therefore, the synthesis of 3 was performed using a single-step procedure, affording the bisphosphonate 3 in 76% yield after purification (Scheme 3). In this context, α-iminophosphonates have emerged as promising substrates to access α-aminophosphonate derivatives [20,21] that allow phosphorylated imine intermediates and make them suitable for subsequent transformations [22][23][24]. It should be noted that all those methodologies require milder reaction conditions when compared with the previously known strategies (Scheme 1B,C). Over the last decade, our group has been working on the synthesis of organophosphorus compounds [22,[25][26][27][28][29][30]. Based on Steglich's [31] and Kobayashi´s reports [32][33][34], as well as our previous experience with nucleophilic additions to imines [22,26,28,35,36], in this case, we propose the synthesis of chiral diethyl (benzami-do (diisopropoxyphosphoryl) methyl) phosphonate through a Pudovik reaction using α-bromo aminophosphonates as the starting material of the corresponding imine (Scheme 2).

Scheme 2.
Our proposal to access amino bisphosphonates.

Results
The proposed synthesis requires two base-catalyzed steps. For this reason, we initially tested the direct addition of diethyl phosphite 2 to α-bromo aminophosphonate 1 in presence of an excess of triethylamine, which is known to promote the elimination of hydrobromic acid as well as to act as a catalyst in the Pudovik reaction. In order to demonstrate the formation of the α-iminophosphonate intermediate 4, the reaction was monitored by 31 P NMR ( 31 P NMR of α-iminophosphonate 4 (δ = 1.7 ppm)). The addition of the phosphite 2 with 0.1 equivalents of trimethylamine afforded the bisphosphonate product 3. However, the low stability of α-iminophosphonates makes this two-step procedure less efficient. Therefore, the synthesis of 3 was performed using a single-step procedure, affording the bisphosphonate 3 in 76% yield after purification (Scheme 3).

Scheme 2.
Our proposal to access amino bisphosphonates.

Results
The proposed synthesis requires two base-catalyzed steps. For this reason, we initially tested the direct addition of diethyl phosphite 2 to α-bromo aminophosphonate 1 in presence of an excess of triethylamine, which is known to promote the elimination of hydrobromic acid as well as to act as a catalyst in the Pudovik reaction. In order to demonstrate the formation of the α-iminophosphonate intermediate 4, the reaction was monitored by 31 P NMR ( 31 P NMR of α-iminophosphonate 4 (δ = 1.7 ppm)). The addition of the phosphite 2 with 0.1 equivalents of trimethylamine afforded the bisphosphonate product 3. However, the low stability of α-iminophosphonates makes this two-step procedure less efficient. Therefore, the synthesis of 3 was performed using a single-step procedure, affording the bisphosphonate 3 in 76% yield after purification (Scheme 3). The most relevant signal of compound 3 in the 1 H NMR spectrum (CDCl3) is the proton corresponding to the P-CH-P moiety, which is seen as a representative triplet doublet at δH = 5.19 ppm ( 2 JPH = 21.5 Hz and 3 JHH = 10.2 Hz), the result of the coupling between CH and the NH of the amide moiety and the coupling of CH with each of the contiguous phosphonates. In addition, due to the low interchange ratio of the NH belonging to the amide group, a doublet is observed at 6.54 ppm, showing coupling only with the neighboring CH moiety ( 3 JHH = 10.2 Hz). Likewise, in the 13 C NMR spectrum of phosphorylated The most relevant signal of compound 3 in the 1 H NMR spectrum (CDCl 3 ) is the proton corresponding to the P-CH-P moiety, which is seen as a representative triplet doublet at δ H = 5.19 ppm ( 2 J PH = 21.5 Hz and 3 J HH = 10.2 Hz), the result of the coupling between CH and the NH of the amide moiety and the coupling of CH with each of the contiguous phosphonates. In addition, due to the low interchange ratio of the NH belonging to the amide group, a doublet is observed at 6.54 ppm, showing coupling only with the neighboring CH moiety ( 3 J HH = 10.2 Hz). Likewise, in the 13 C NMR spectrum of phosphorylated derivative 3, the two doublets corresponding to the two diastereotopic CH carbons of the iso-propyl moiety appear at δ C = 72.8 ppm ( 2 J CP = 17.4 Hz) and δ C = 72.7 ppm ( 2 J CP = 17.7 Hz). The methylene carbons corresponding to the two ethoxy groups can be also detected as two doublets with chemical shifts at δ C = 63.7 ppm (d, 2 J CP = 29.3 Hz) and δ C = 63.6 ppm (d, 2 J CP = 29.7 Hz). A very characteristic signal corresponding to the CH carbon appears as a double doublet at δ C = 44.9 ppm with strong coupling with the two adjacent phosphorus atoms ( 1 J CP = 148.4 Hz and 1 J CP = 146.6 Hz). Finally, due to the presence of a chiral center in the structure, the two carbons corresponding to the four methyl groups at the isopropyl moieties appear as two doublets at 24.7 ppm ( 3 J CP = 3.3 Hz) and 23.9 ppm ( 3 J CP = 5.4 Hz) for isopropyl groups. However, both methyl groups of the ethoxy group appear overlapped as one doublet at 16.5 ppm ( 3 J CP = 6.0 Hz). As expected, the 31 P NMR spectrum of substrate 3 shows two doublets at δ P = 16.5 and 14.3 ppm ( 2 J PP = 31.3 Hz).
The FTIR spectrum of compound 3 shows a stretching vibration around ν = 3218 cm −1 , which is typical for N-H moiety. In addition, several absorptions within the interval ν = 3056-2986 cm −1 correspond to the stretching vibration of aromatic and aliphatic C-H bonds. One of the most relevant absorption signals observed in the IR spectrum corresponds to the stretching vibration of the amide C=O bond at ν = 1657 cm −1 . The vibration of the P=O bonds corresponding to the ethyl and isopropyl phosphonates results in moderate absorption bands at ν = 1258 cm −1 and ν = 1163 cm −1 . Due to the presence of the phosphorylated groups, the IR spectrum shows two signals at ν = 1144 cm −1 and ν = 1109 cm −1 which correspond to the P-O-C stretching bonds of both phosphonate moieties.
The high-resolution mass spectrometry (HRMS (ESI-TOF) m/z) experiment shows a peak corresponding to the molecular ion with an exact mass of 436.1642 (M + H) + that fits with the predicted mass ((M + H) + = 436.1654) of the calculated molecular formula (C 18 H 32 NO 7 P 2 ) far within the standard tolerated deviation.

General Experimental Information
Solvents used for extraction and chromatography were technical grade. All the solvents used in reactions were freshly distilled from appropriate drying agents before use. All other reagents were recrystallized or distilled as necessary. All reactions were performed under an atmosphere of dry nitrogen. Analytical TLC was performed with silica gel 60 F254 plates. Visualization was accomplished by UV light. 1 H and 13 C-NMR spectra were recorded on a Varian Unity Plus (Varian Inc., NMR Systems, Palo Alto, Santa Clara, CA, USA) (at 300 MHz, 75 MHz, 120 MHz and 282 MHz) and on a Bruker Avance 400 (Bruker BioSpin GmbH, Rheinstetten, Germany) (at 400 MHz for 1 H and 100 MHz for 13 C). Chemical shifts (δ) were reported in ppm relative to residual CHCl3 (δ = 7.26 ppm for 1 H and δ = 77.16 ppm for 13 C NMR). Coupling constants (J) were reported in Hertz. Data for 1 H NMR spectra were reported as follows: chemical shift, multiplicity, coupling constant and integration. Multiplicity abbreviations were as follows: s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet. 13 C-NMR peak assignments were supported by distortionless enhanced polarization transfer (DEPT). High resolution mass spectra (HRMS) were obtained by positive-ion electrospray ionization (ESI). Data were reported in the form m/z (intensity relative to base = 100). Infrared spectra (IR) were taken in a Nicolet iS10 Thermo Scientific spectrometer (Thermo Scientific Inc., Waltham, MA, USA) as neat solids. Peaks were reported in cm −1 .

Conclusions
The synthesis of bisphosphonate derivative 3 was accomplished by the direct addition of diethyl phosphite 2 to a solution of α-bromo aminophosphonate 1 under the presence of an excess of triethylamine. 1 H, 13 C, 31 P and 2D-NMR, and FTIR and HRMS experiments unequivocally confirm the structure of the obtained compound.