Direct Synthesis of Phosphonates and α-Amino-phosphonates from 1,3-Benzoxazines

A straightforward and novel method for transformation of readily available 1,3-benzoxazines to secondary phosphonates and α-aminophosphonates using boron trifluoride etherate as catalyst is developed. The formation of phosphonates proceeds through ortho-quinone methide (o-QM) generated in situ, followed by a phospha-Michael addition reaction. On the other hand, the α-aminophosphonates were obtained by iminium ion formation and the subsequence nucleophilic substitution of alkylphosphites. This method can be also used for the preparation of o-hydroxybenzyl ethers through oxa-Michael addition.

Considering the high value of these compounds and in connection with our recent work [33], we report herein an innovative methodology for the synthesis of secondary phosphonates and α-aminophosphonates from the reaction of 1,3-benzoxazines with diethyl or triethyl phosphite using catalytic amounts of boron trifluoride etherate. In addition, when the 1,3-benzoxazines was treated with alcohols under reflux conditions provided the corresponding ethers in good yields.

Results and Discussion
Initially, 1,3-benzoxazines 1a-h were prepared from the corresponding 2-(benzylamino)phenols following procedures described in the literature [34][35][36]. In the next step, the study of the reaction conditions for the synthesis of the phosphonate 2b and α-aminophosphonate 3b were started. For this purpose, the reaction of the 1,3-benzoxazine 1b and triethyl phosphite under different conditions (solvents, temperature and using boron trifluoride etherate as catalyst) was examined in order to find the best reaction conditions (Table 1). At first, the 1,3-benzoxazine 1b was treated with triethyl phosphite in ethanol obtaining the α-aminophosphonate 3b in 28% yield (Table 1, entry 1). In entry 2 was carried out the reaction at 26 • C in presence of catalytic amounts of boron trifluoride etherate (20 mol%) using DCM as solvent afforded the α-aminophosphonate 3b in 27% yield. On the other hand, using the same solvent at 40 • C and without catalysts the result was similar (3b; 28% yield, entry 3). In the next experiments, using MeCN as solvent at 26 and 82 • C without catalyst, product reaction was not formed (entries 4 and 5).
Alternatively, when MeCN was used in presence of catalytic amounts of boron trifluoride etherate (10 mol%) at 26 • C the phosphonate 2b in 18% yield was afforded (entry 6). On the other hand, from the reaction of the 1,3-benzoxazine 1b with triethyl phosphite and increasing amount of boron trifluoride etherate at 20 and 50 mol%, 2b in 28% yield was obtained in both cases (entries 7 and 8). Then 2.7 equivalents of triethyl phosphite were used and the phosphonate 2b was isolated in 28% yield (entry 9). In entry 10 the reaction mixture was refluxed in MeCN with the presence of boron trifluoride etherate (20 mol%), from these, the phosphonate 2b and α-aminophosphonate 3b in 30 and 47% yield respectively were afforded. catalytic amounts of boron trifluoride etherate. In addition, when the 1,3-benzoxazines was treated with alcohols under reflux conditions provided the corresponding ethers in good yields.

Results and Discussion
Initially, 1,3-benzoxazines 1a-h were prepared from the corresponding 2-(benzylamino)phenols following procedures described in the literature [34][35][36]. In the next step, the study of the reaction conditions for the synthesis of the phosphonate 2b and α-aminophosphonate 3b were started. For this purpose, the reaction of the 1,3-benzoxazine 1b and triethyl phosphite under different conditions (solvents, temperature and using boron trifluoride etherate as catalyst) was examined in order to find the best reaction conditions (Table 1). At first, the 1,3-benzoxazine 1b was treated with triethyl phosphite in ethanol obtaining the α-aminophosphonate 3b in 28% yield (Table 1, entry 1). In entry 2 was carried out the reaction at 26 °C in presence of catalytic amounts of boron trifluoride etherate (20 mol%) using DCM as solvent afforded the α-aminophosphonate 3b in 27% yield. On the other hand, using the same solvent at 40 °C and without catalysts the result was similar (3b; 28% yield, entry 3). In the next experiments, using MeCN as solvent at 26 and 82 °C without catalyst, product reaction was not formed (entries 4 and 5).
Alternatively, when MeCN was used in presence of catalytic amounts of boron trifluoride etherate (10 mol%) at 26 °C the phosphonate 2b in 18% yield was afforded (entry 6). On the other hand, from the reaction of the 1,3-benzoxazine 1b with triethyl phosphite and increasing amount of boron trifluoride etherate at 20 and 50 mol%, 2b in 28% yield was obtained in both cases (entries 7 and 8). Then 2.7 equivalents of triethyl phosphite were used and the phosphonate 2b was isolated in 28% yield (entry 9). In entry 10 the reaction mixture was refluxed in MeCN with the presence of boron trifluoride etherate (20 mol%), from these, the phosphonate 2b and α-aminophosphonate 3b in 30 and 47% yield respectively were afforded. In another experiment, an increase to 3.5 equivalents of the triethyl phosphite under similar conditions did not improve the yield (entry 11). When hexane was used as solvent, no products were observed (Table 1, entry 12).
With these results the formation of the phosphonate was favored when triethyl phosphite, boron trifluoride etherate in catalytic quantities and a polar solvent as acetonitrile at room temperature were used, besides, the reaction was cleaner and the 1,3-benzoxazine that not reacted was recovered.  In another experiment, an increase to 3.5 equivalents of the triethyl phosphite under similar conditions did not improve the yield (entry 11). When hexane was used as solvent, no products were observed (Table 1, entry 12).
With these results the formation of the phosphonate was favored when triethyl phosphite, boron trifluoride etherate in catalytic quantities and a polar solvent as acetonitrile at room temperature were used, besides, the reaction was cleaner and the 1,3-benzoxazine that not reacted was recovered.

Scheme 1. Synthesis of phosphonates and -aminophosphonates from 1,3-benzoxazines.
The mechanism in Scheme 4 below shows an equilibrium in the ring-opening benzoxazines via iminium ion or o-Quinone Methide (o-QMs) intermediates. Considering that the stabilization of the iminium ions is directly affected by the steric effect of the substituent In order to study others phosphorus sources, the reaction of the 1,3-benzoxazines 1a-h, diethyl phosphite and boron trifluoride etherate as catalyst in MeCN were carried out (Scheme 2). To our satisfaction only the α-aminophosphonates 3a-h were detected in 24-96% yield. We found that the 1,3-benzoxazines 1a and 1b with hydrogen and methyl substituents show the best yields (96 and 80%, respectively), whereas, the 1,3-benzoxazines 1d, 1g and 1h with bulky substituents furnished the αaminophosphonates 3d, 3g and 3h in moderate yields (Scheme 2). Due to the fact benzyl and ohydroxylbenzyl groups are attached to the nitrogen atom, both move away from each other avoiding the steric hindrance, which causes them to be oriented towards the double bond of the iminium ion inhibiting the access of the phosphite. However, the 1,3-benzoxazine ring opening produces the reaction between the phenolate and hydrogen atom of diethyl phosphite tautomer (Ar-O − -H-O-P), this facilitate the attack to form the C-P bond, this effect does not occur when triethyl phosphite is used.

Scheme 2. Direct conversion of 1,3-benzoxazines 1a-h to -aminophosphonates 3a-h.
With the results obtained in the phosphorylation of o-QMs, next we explored the direct transformation of 1,3-benzoxazine 1e. Thus, 1e was treated with 3-chloro-1-propanol at 70 °C for 12 h affording the oxa-Michael adduct 5a in 53 % yield. The ether product is a versatile intermediate to obtain more complex compounds [29,[39][40][41] (Scheme 3). In order to study others phosphorus sources, the reaction of the 1,3-benzoxazines 1a-h, diethyl phosphite and boron trifluoride etherate as catalyst in MeCN were carried out (Scheme 2). To our satisfaction only the α-aminophosphonates 3a-h were detected in 24-96% yield. We found that the 1,3-benzoxazines 1a and 1b with hydrogen and methyl substituents show the best yields (96 and 80%, respectively), whereas, the 1,3-benzoxazines 1d, 1g and 1h with bulky substituents furnished the α-aminophosphonates 3d, 3g and 3h in moderate yields (Scheme 2). Due to the fact benzyl and o-hydroxylbenzyl groups are attached to the nitrogen atom, both move away from each other avoiding the steric hindrance, which causes them to be oriented towards the double bond of the iminium ion inhibiting the access of the phosphite. However, the 1,3-benzoxazine ring opening produces the reaction between the phenolate and hydrogen atom of diethyl phosphite tautomer (Ar-O − -H-O-P), this facilitate the attack to form the C-P bond, this effect does not occur when triethyl phosphite is used. Under the optimized conditions, the 1,3-benzoxazines 1a-h were reacted with triethyl phosphite in presence of boron trifluoride etherate (20 mol%) in acetonitrile (Scheme 1). When the 1,3benzoxazines 1b, 1e and 1g were used, the o-hydroxybenzyl phosphonates 2b, 2e and 2g were formed in 28-40% yields. The o-hydroxybenzyl phosphonates are valuable building block for the synthesis of a wide range of compounds. [29,30,37,38]. From 1,3-benzoxazines 1a, 1d and 1h the α-aminophosphonates 3a, 3d and 3h were obtained in 6-89% yields (Scheme 1). In order to study others phosphorus sources, the reaction of the 1,3-benzoxazines 1a-h, diethyl phosphite and boron trifluoride etherate as catalyst in MeCN were carried out (Scheme 2). To our satisfaction only the α-aminophosphonates 3a-h were detected in 24-96% yield. We found that the 1,3-benzoxazines 1a and 1b with hydrogen and methyl substituents show the best yields (96 and 80%, respectively), whereas, the 1,3-benzoxazines 1d, 1g and 1h with bulky substituents furnished the αaminophosphonates 3d, 3g and 3h in moderate yields (Scheme 2). Due to the fact benzyl and ohydroxylbenzyl groups are attached to the nitrogen atom, both move away from each other avoiding the steric hindrance, which causes them to be oriented towards the double bond of the iminium ion inhibiting the access of the phosphite. However, the 1,3-benzoxazine ring opening produces the reaction between the phenolate and hydrogen atom of diethyl phosphite tautomer (Ar-O − -H-O-P), this facilitate the attack to form the C-P bond, this effect does not occur when triethyl phosphite is used.  A proposed reaction pathway is depicted in Scheme 4. The formation of -aminophosphonates can be explained through protonation of the oxygen by the hydrogen of diethyl phosphite which promotes the ring-opening generating the iminium ion, the subsequent phosphorylation provides the corresponding -aminophosphonates. On the other hand, when triethyl phosphite is used the electronic delocalization of electron pair of nitrogen could generate the ring opening of 1,3benzoxazines producing the iminium ion (path A) [42,43] which is attacked by the triethyl phosphite to give the -aminophosphonates. When the oxygen was activated (path B) it promoted o-QM formation following by phospha-Michael addition reaction [28] with P(OEt)3 to produce the corresponding phosphonates.

General Information
Reagents were obtained from commercial suppliers and were used without further purification. Melting points were determined in a Fischer Johns apparatus (Pittsburgh, PA, USA) and are uncorrected. NMR spectra were recorded on Varian System instrument (Palo Alto, CA, USA) at 400 MHz for 1 H-and 100 MHz for 13 C-and a Varian Gemini at 200 MHz for 1 H-and 50 MHz for 13 C-. The spectra were obtained in CDCl3 solutions using TMS as an internal reference. 31 P chemical shifts are reported relative to H3PO4 as an internal reference. High-resolution CI + and FAB + mass experiments were performed on a JEOL HRMStation JHRMS-700 (Akishima, Tokyo, Japan). The purification of all compounds was carried out by column chromatography using (silica gel 230-400 mesh). The dichloromethane and acetonitrile were refluxed on phosphorous pentoxide and hexane with sodium and benzophenone. Formaldehyde (30%) was used for the reactions. A proposed reaction pathway is depicted in Scheme 4. The formation of α-aminophosphonates can be explained through protonation of the oxygen by the hydrogen of diethyl phosphite which promotes the ring-opening generating the iminium ion, the subsequent phosphorylation provides the corresponding α-aminophosphonates. On the other hand, when triethyl phosphite is used the electronic delocalization of electron pair of nitrogen could generate the ring opening of 1,3-benzoxazines producing the iminium ion (path A) [42,43] which is attacked by the triethyl phosphite to give the α-aminophosphonates. When the oxygen was activated (path B) it promoted o-QM formation following by phospha-Michael addition reaction [28] with P(OEt) 3 to produce the corresponding phosphonates. A proposed reaction pathway is depicted in Scheme 4. The formation of -aminophosphonates can be explained through protonation of the oxygen by the hydrogen of diethyl phosphite which promotes the ring-opening generating the iminium ion, the subsequent phosphorylation provides the corresponding -aminophosphonates. On the other hand, when triethyl phosphite is used the electronic delocalization of electron pair of nitrogen could generate the ring opening of 1,3benzoxazines producing the iminium ion (path A) [42,43] which is attacked by the triethyl phosphite to give the -aminophosphonates. When the oxygen was activated (path B) it promoted o-QM formation following by phospha-Michael addition reaction [28] with P(OEt)3 to produce the corresponding phosphonates.

General Information
Reagents were obtained from commercial suppliers and were used without further purification. Melting points were determined in a Fischer Johns apparatus (Pittsburgh, PA, USA) and are uncorrected. NMR spectra were recorded on Varian System instrument (Palo Alto, CA, USA) at 400 MHz for 1 H-and 100 MHz for 13 C-and a Varian Gemini at 200 MHz for 1 H-and 50 MHz for 13 C-. The spectra were obtained in CDCl3 solutions using TMS as an internal reference. 31 P chemical shifts are reported relative to H3PO4 as an internal reference. High-resolution CI + and FAB + mass experiments were performed on a JEOL HRMStation JHRMS-700 (Akishima, Tokyo, Japan). The purification of all compounds was carried out by column chromatography using (silica gel 230-400 mesh). The dichloromethane and acetonitrile were refluxed on phosphorous pentoxide and hexane with sodium and benzophenone. Formaldehyde (30%) was used for the reactions. Scheme 4. Proposed reaction pathway for the ring-opening of 1,3-benzoxazines to generated phosphonates and α-aminophosphonates.

General Information
Reagents were obtained from commercial suppliers and were used without further purifification. Melting points were determined in a Fischer Johns apparatus (Pittsburgh, PA, USA) and are uncorrected. NMR spectra were recorded on Varian System instrument (Palo Alto, CA, USA) at 400 MHz for 1 Hand 100 MHz for 13 C-and a Varian Gemini at 200 MHz for 1 H-and 50 MHz for 13 C-. The spectra were obtained in CDCl 3 solutions using TMS as an internal reference. 31 P chemical shifts are reported relative to H 3 PO 4 as an internal reference. High-resolution CI + and FAB + mass experiments were performed on a JEOL HRMStation JHRMS-700 (Akishima, Tokyo, Japan). The purifification of all compounds was carried out by column chromatography using (silica gel 230-400 mesh). The dichloromethane and acetonitrile were reflfluxed on phosphorous pentoxide and hexane with sodium and benzophenone. Formaldehyde (30%) was used for the reactions.

General Procedure to Obtain the 1,3-benzoxazines 1a-h
A mixture of 2-(benzylamino)-phenol (1.0 eq.) and formaldehyde solution (1.3 eq.) in dichloromethane was stirred at 37 • C for 1 h using a modified Dean-Stark tramp. The crude product was purified by flash chromatography using hexane:EtOAc (99:01) or by recrystallization in methanol.
The 1 H-and 13 C-NMR data for the compound 1a were identical to those reported in the literature [36].

Conclusions
We have developed a novel "one-pot" method for the synthesis of secondary benzyl phosphonates and α-aminophosphonates from 1,3-benzoxazines. The phosphonates were obtained through direct o-QM formation, followed by a phospha-Michael addition reaction and the α-aminophosphonates by iminium ion formation and the subsequent alkylphophites addition. In addition, this synthetic methodology was used to the preparation a valuable o-hydroxybenzyl ether derivative, which makes it a useful and efficient method for the synthesis of phosphonates, α-aminophosphonates and benzyl ethers.