30.7.3 N, P-and P, P-Acetals (Update 2016)

T. Kimura

General Introduction

This update describes published methods for the synthesis and application of N, P-acetals and P, P-acetals reported between 2007 and 2014. Publications on this product class that appeared prior to 2006 are included in the previous contribution compiled by Yamashita in 2007 (see Section 30.7).

30.7.3.1 N, P-Acetals

The N—C—P structural motif is found in α-aminophosphonic acids and their derivatives. α-Aminophosphonic acids are structural analogues of α-amino acids wherein the carboxy group of the α-amino acid is replaced with a phosphoryl group. α-Aminophosphonic acid derivatives have a diverse range of biological activities including enzyme inhibitory, antiviral, antibacterial, and antitumor activities. Much effort has been devoted to developing novel synthetic methods for α-aminophosphonic acid derivatives, as well as to improving the previously known synthetic methods. Most of the synthetic methods for α-aminophosphonic acid derivatives are based on the hydrophosphorylation of imines or iminiums with phosphonates containing a P—H bond, and the generation of imines and iminium intermediates is key in the synthesis of α-aminophosphonic acid derivatives. Development of stereoselective synthetic methods for α-aminophosphonic acid derivatives possessing a chiral carbon center is another important subject, because the enantiomers have different biological activities. Excellent reviews of the synthesis of α-aminophosphonic acid derivatives have been published in recent years.^[1–4]

30.7.3.1.1 Synthesis of N, P-Acetals

30.7.3.1.1.1 Method 1: Cross Dehydrogenative Coupling of Amines and Phosphonates

Reaction of tertiary amines possessing an alkyl group with phosphonates containing a P—H bond in the presence of an oxidant gives α-aminophosphonates. A new C—P bond is formed between the C—H carbon atom adjacent to the nitrogen atom and the P—H phosphorus atom. This reaction is classified as a cross dehydrogenative coupling (CDC) reaction.^[5] In the cross dehydrogenative coupling reaction of amines and phosphonates, iminiums are initially generated in situ by the oxidation of amines, and the following hydrophosphorylation of the resulting iminiums with phosphonates gives α-aminophosphonates. Various types of metal and metal-free catalyst/co-oxidant systems and photoredox catalyst systems have been reported.^[6–19]

30.7.3.1.1.1.1 Variation 1: Using a Copper Catalyst under an Oxygen Atmosphere

The cross dehydrogenative coupling reaction of phosphonates 1 and N-aryltetrahydroisoquinolines 2 proceeds in the presence of a catalytic amount of copper(I) bromide under an oxygen atmosphere to give α-aminophosphonates 3 in good yield (▶ Scheme 1).^[6] The reaction occurs in a highly regioselective manner; i.e., a hydrogen atom at the position between the nitrogen atom and the aryl ring is selectively replaced with a phosphoryl group. This method advantageously uses an inexpensive copper salt as catalyst and molecular oxygen as a safe and abundant oxidant. Although the applicable substrates are limited to N-aryltetrahydroisoquinolines 2, it is noteworthy that the C—H bond is directly functionalized to a phosphoryl group.

Scheme 1 Copper-Catalyzed Cross Dehydrogenative Coupling of Tetrahydroisoquinolines and Phosphonates^[6]

Diethyl (2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (3, R¹ = Et; Ar¹ = Ph); Typical Procedure:^[6]

Phosphonate 1 (R¹ = Et; 51.5 μL, 0.4 mmol) was added to a mixture of CuBr (1.4 mg, 0.01 mmol) and tetrahydroisoquinoline 2 (Ar¹ = Ph; 42 mg, 0.2 mmol) in MeOH (0.6 mL). The 20-mL test tube containing the mixture was sealed and filled with O₂. The mixture was stirred at 60 °C for 16 h before being extracted with EtOAc. The extracts were filtered through a short layer of silica gel, which was eluted with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/EtOAc 1:1); yield: 79%.

30.7.3.1.1.1.2 Variation 2: Using an Iron Catalyst and tert-Butyl Hydroperoxide as Co-oxidant

Iron(II) chloride catalyzes the cross dehydrogenative coupling reaction of phosphonates 4 and N, N-dialkylanilines 5 to give α-aminophosphonates 6 (▶ Scheme 2).^[7,8] tert-Butyl hydroperoxide is used as a co-oxidant. The reaction gives α-aminophosphonates 6 in moderate to good yields and a variety of functional groups are tolerated under the reaction conditions. In the reaction of anilines bearing a methyl group and an ethyl group on the nitrogen atom (i.e., 5, R² = H; R³ = Et), the phosphoryl group is preferentially introduced onto the methyl group. When an excess of the dialkyl phosphonate is used for the reaction with N, N-dimethylanilines under reflux conditions, a second phosphorylation takes place at the remaining methyl group to give bis-phosphorylated products. This method features the use of inexpensive and non-toxic iron(II) chloride as a catalyst.

Scheme 2 Iron-Catalyzed Cross Dehydrogenative Coupling of N, N-Dialkylanilines and Phosphonates^[8]

α-Aminophosphonates 6; General Procedure:^[8]

A 5.5 M soln of t-BuOOH in decane (0.47 mL, 2.5 mmol) was added dropwise to a mixture of FeCl₂ (13 mg, 10 mol%), aniline 5 (1.0 mmol), and phosphonate 4 (2.0 mmol) in MeOH (2.0 mL) over a period of 5 min under a N₂ atmosphere. The mixture was stirred at rt, at 60 °C, or under reflux for 14–36 h. The mixture was poured into brine (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, pentane/EtOAc/Et₃N).

30.7.3.1.1.2 Method 2: Aldehyde-Induced C—H Substitution with Phosphine Oxides

Direct functionalization of C—H bonds adjacent to the nitrogen atom in cyclic amines 9 with phosphine oxides 7 is achieved using aldehydes 8 and a catalytic amount of benzoic acid under microwave irradiation (▶ Scheme 3).^[20] The key intermediates in the reaction are azomethine ylides. As a competitive side reaction, the ordinary Kabachnik–Fields reaction of phosphine oxides 7, aldehydes 8, and amines 9 leads to the formation of structural isomers 11, but the use of benzoic acid suppresses the formation of isomers 11. The unreactive C—H bond is directly functionalized without the need for an oxidant and the only waste from the reaction is water. It should be noted that the reaction using cyclic amines other than pyrrolidines gives a mixture of the desired products 10 and the isomers 11.

Scheme 3 Benzoic Acid Catalyzed Aldehyde-Induced C—H Substitution of Cyclic Amines with Phosphine Oxides^[20]

α-Aminophosphine Oxides 10; General Procedure:^[20]

A microwave reaction tube containing a mixture of phosphine oxide 7 (0.6 mmol), aldehyde 8 (0.5 mmol), amine 9 (0.6 mmol), and BzOH (0.1 mmol) in toluene (1 mL) was sealed with a Teflon-lined snap cap and heated in a microwave reactor at 160–200 °C (200 W maximum, 30–80 psi) for 5–60 min. The mixture was directly purified by column chromatography (silica gel).

30.7.3.1.1.3 Method 3: Electrophilic Amination

Nucleophilic substitution of organophosphorus compounds possessing a leaving group at the α-position with nitrogen nucleophiles is a simple method for the synthesis of α-amino organophosphorus compounds.^[21] This synthetic route requires prefunctionalization of organophosphorus compounds. Another feature of organophosphorus compounds is that the acidic hydrogen atom at the α-position relative to the phosphorus atom can be removed by a base. The resulting carbanions are nucleophilic and are expected to react with electrophilic nitrogen sources to give α-amino organophosphorus compounds.^[22] Zinc–bisoxazoline catalyzed enantioselective electrophilic amination of β-keto phosphonates with azodicarboxylates has been reported.^[23]

The electrophilic α-amination of alkylphosphonates can be achieved using bis(2,2,6,6-tetramethylpiperidin-1-yl)zinc [Zn(tmp)₂] as a base, an O-benzoylhydroxylamine 14 as an electrophilic nitrogen source, and copper(II) chloride/2,2′-bipyridyl as a catalyst (▶ Scheme 4).^[24] Bis(α-phosphorylalkyl)zincs 13 are generated by the deprotonation of alkylphosphonates 12 with bis(2,2,6,6-tetramethylpiperidin-1-yl)zinc. The resulting organozincs 13 react with O-benzoylhydroxylamines 14 in the presence of a catalytic amount of copper(II) chloride and 2,2′-bipyridyl to give α-aminophosphonates 15 in high yield. Although the O-benzoylhydroxylamines 14 must first be prepared,^[25] electrophilic amination is a useful method because it is complementary to nucleophilic amination.

Scheme 4 Copper-Catalyzed Electrophilic Amination of Bis(α-phosphorylalkyl)zincs with O-Benzoylhydroxylamines^[25]

α-Aminophosphonates 15; General Procedure:^[25]

A mixture of 0.5 M Zn(tmp)₂ in toluene (0.4 mL, 0.2 mmol) and phosphonate 12 (0.42 mmol) was stirred at rt for 1 h. A mixture of O-benzoylhydroxylamine 14 (0.2 mmol), CuCl₂ (2.7 mg, 0.02 mmol), and bipy (6.2 mg, 0.04 mmol) in THF (1 mL) was added, and the mixture was stirred at rt for 2–6 h. The mixture was filtered through silica gel, which was washed with iPrOH. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel).

30.7.3.1.1.4 Method 4: Aldehyde-Induced Decarboxylative Coupling of α-Amino Acids and Phosphonates

α-Aminophosphonic acids are analogues of α-amino acids and the direct conversion of α-amino acids into α-aminophosphonic acids by substitution of a carboxy group with a phosphoryl group is an attractive synthetic method. One example of the decarboxylative coupling of N-benzyl-L-proline and diphenylphosphine oxide was reported in 2011,^[26]and aldehyde-induced decarboxylative coupling has been developed. This reaction takes place in the presence of catalysts such as copper(I) iodide/N, N-diisopropylethylamine,^[27]cerium(IV) oxide,^[28] and (diacetoxyiodo)benzene/iodine,^[29] as well as under catalyst-free conditions.^[30] This method is environmentally benign because the byproducts of the reaction are only water and carbon dioxide.

30.7.3.1.1.4.1 Variation 1: Using Copper/N, N-Diisopropylethylamine Catalyst

The carboxy group of α-amino acids 17 is replaced with a phosphoryl group in a copper/N, N-diisopropylethylamine catalyzed, aldehyde-induced decarboxylative coupling reaction (▶ Scheme 5).^[27] The reaction of α-amino acids 17 with aldehydes 18 generates azomethine ylides, which react with phosphonates 16 to give α-aminophosphonates 19. Both acyclic and cyclic α-amino acid derivatives are applicable substrates. In this method, readily available α-amino acid derivatives 17 are used as starting materials, and inexpensive copper(I) iodide is used as the catalyst.

Scheme 5 Copper/N, N-Diisopropylethylamine Catalyzed, Aldehyde-Induced Decarboxylative Coupling of α-Amino Acids and Phosphonates^[27]

Diethyl [1-(4-Cyanobenzyl)pyrrolidin-2-yl]phosphonate [19, R¹ = OEt; R², R³ =(CH₂)₃; Ar¹ = 4-NCC₆H₄]; Typical Procedure:^[27]

CuI (17.0 mg, 0.09 mmol) was added to a soln of proline [17, R², R³ =(CH₂)₃; 52.0 mg, 0.45 mmol] in toluene (2.5 mL), and the mixture was stirred at rt for 10 min. iPr₂NEt (15.7 μL, 11.6 mg, 0.09 mmol), aldehyde 18 (Ar¹ = 4-NCC₆H₄; 55.0 mg, 0.42 mmol), and phosphonate 16 (R¹ = OEt; 38.4 μL, 0.3 mmol) were added and the mixture was stirred in an oil bath at 130 °C for 20 h. The resulting suspension was diluted with CH₂Cl₂, washed with H₂O, and extracted with CH₂Cl₂, and the extracts were dried (Na₂SO₄). After the solvent had been removed under reduced pressure, the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1 to 1:1) to give the product as a yellowish oil; yield: 83%.

30.7.3.1.1.4.2 Variation 2: Without Catalyst

The aldehyde-induced decarboxylative coupling also occurs in the absence of catalysts and bases, although the products are obtained in only moderate yield (▶ Scheme 6)_.^[30] The reaction of phosphonates 20, α-amino acids 21, and aldehydes 22 in toluene under reflux gives α-aminophosphonates 23. It is important to add the aldehyde to the reaction mixture in small portions over several hours to avoid the formation of regioisomeric side products.

Scheme 6 Catalyst-Free Aldehyde-Induced Decarboxylative Coupling of α-Amino Acids and Phosphonates^[30]

α-Aminophosphonates 23; General Procedure:^[30]

Phosphonate 20 (1 mmol) was added to a mixture of α-amino acid 21 (1.5 mmol) and toluene (2 mL) under reflux. Aldehyde 22 (1.5 mmol) was added to the mixture in small portions over a period of 1–5 h. The resulting soln was diluted with H₂O (30 mL) and extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine (30 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc 9:1 to 6:4).

30.7.3.1.1.5 Method 5: Substitution of α-Hydroxyphosphonates with Amines

α-Hydroxy organophosphorus compounds can be readily prepared by the hydrophosphorylation of carbonyl compounds with organophosphorus compounds possessing a P—H bond. This is referred to as the Pudovik reaction [see Science of Synthesis, Vol. 30 (Section 30.2.1.1.1) and Science of Synthesis: Stereoselective Synthesis, Vol. 2 (Section 2.11.3)].^[31]Conversion of the hydroxy group of α-hydroxy organophosphorus compounds into a leaving group and subsequent nucleophilic substitution with nitrogen nucleophiles is often used for the synthesis of α-amino organophosphorus compounds.^[21,32] For instance, tosylation of the hydroxy group of an α-hydroxyphosphinate and the subsequent nucleophilic substitution of the toluenesulfonate group with amines gives α-aminophosphinates.^[21]Treatment of α-hydroxyphosphinates under Mitsunobu conditions also gives α-aminophosphinates.^[21] The hydroxy group in α-hydroxy organophosphorus compounds can also be directly substituted with amines.^[33] This substitution reaction is accelerated by microwave irradiation^[34] and the use of trifluoromethanesulfonic acid.^[35] Retro-hydrophosphorylation of α-hydroxyphosphonates, the formation of imines from the resulting carbonyl compounds with amines, and re-hydrophosphorylation of imines is a possible mechanism for the formation of α-aminophosphonates.

30.7.3.1.1.5.1 Variation 1: Under Microwave Irradiation

The substitution reaction of α-hydroxybenzylphosphonates 24 with primary amines 25 is normally slow and gives α-aminophosphonates 26 in low yield, but microwave irradiation is effective in promoting the reaction (▶ Scheme 7).^[34] The reaction can be performed without solvent or catalyst.

Scheme 7 Microwave-Assisted Substitution of α-Hydroxybenzylphosphonates with Amines^[34]

α-Aminophosphonates 26; General Procedure:^[34]

A mixture of α-hydroxyphosphonate 24 (0.10 g, 4.1 mmol) and amine 25 (12.3 mmol) in a sealed tube was irradiated in a microwave reactor equipped with a pressure controller at 100–110 °C for 10–60 min. The volatile materials were removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, MeOH/CHCl₃).

30.7.3.1.1.5.2 Variation 2: Using Trifluoromethanesulfonic Acid

α-Hydroxyalkylphosphonates 27 undergo substitution with sulfonamides 28 in the presence of trifluoromethanesulfonic acid to give α-aminophosphonates 29 (▶ Scheme 8).^[35]The reaction can be performed at room temperature without exclusion of air or moisture. Although a stoichiometric amount of trifluoromethanesulfonic acid is necessary for the reaction because of the low nucleophilicity of sulfonamides 28, the use of crystalline sulfonamides, which are stable and easy to handle, is advantageous compared to the reaction employing odorous amines (▶ Section 30.7.3.1.1.5.2).

Scheme 8 Trifluoromethanesulfonic Acid Mediated Substitution of α-Hydroxyalkylphosphonates with Sulfonamides^[35]

Diethyl {(4-Methoxyphenyl)[(4-methylphenyl)sulfonamido]methyl}phosphonate (29, Ar¹ = 4-MeOC₆H₄; R¹ = 4-Tol; R² = H); Typical Procedure:^[35]

TfOH (0.16 mL, 1.824 mmol) was added to a soln of α-hydroxyphosphonate 27 (Ar¹ = 4-MeOC₆H₄; 0.5 g, 1.824 mmol) and sulfonamide 28 (R¹ = 4-Tol; R² = H; 0.31 g, 1.824 mmol) in 1,4-dioxane (4 mL), and the mixture was stirred at rt for 5 h. The reaction was quenched with ice-cold H₂O, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/petroleum ether) to give a white solid; yield: 0.733 g (94%).

30.7.3.1.1.6 Method 6: Substitution of α-Amido Sulfones with Organophosphorus Compounds

The sulfonyl group of α-amido sulfones is substituted with a phosphoryl group through reaction with organophosphorus nucleophiles.^[36,37] α-Amido sulfones are readily prepared from aldehydes, carbamates, and sodium arenesulfinates.^[38] The substitution reaction of α-amido sulfones 30 with dimethyl phosphonate occurs in the presence of 5 mol% of a hydroquinine derivative 31 and potassium hydroxide to give optically active α-amido phosphonates 32 in good yield with good enantioselectivity (▶ Scheme 9).^[37] The reaction proceeds via the asymmetric hydrophosphorylation of in situ generated imines. It is noteworthy that sulfones derived from aliphatic aldehydes, especially linear unbranched sulfones, are successfully substituted, because the resulting aliphatic imines are generally unstable. The reaction with sulfones derived from aromatic aldehydes results in the formation of racemic products. tert-Butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) protecting groups on the nitrogen atom are deprotected by standard deprotection methods without a significant loss of enantiomeric excess.

Scheme 9 Asymmetric Hydrophosphorylation of Imines Generated from α-Amido Sulfones^[37]

α-Amidophosphonates 32; General Procedure:^[37]

Dimethyl phosphonate (14 μL, 0.15 mmol for N-Boc α-amido sulfones; 28 μL, 0.30 mmol for N-Cbz α-amido sulfones) was added to a mixture of α-amido sulfone 30 (0.10 mmol) and hydroquinine 31 (2.6 mg, 0.005 mmol) in toluene (1 mL). Finely ground KOH (17 mg, 0.30 mmol), weighed in an oven-dried vial, was added to the mixture at –78 °C in one portion. The mixture was stirred at –78 °C for 60 h. Sat. aq NH₄Cl (~2 mL) was added and the mixture was allowed to warm to rt. The organic layer was separated, and the aqueous layer was extracted with toluene (2 × 1 mL). The combined organic extracts were directly purified by column chromatography (silica gel, hexane/EtOAc/acetone 5:3:2).

30.7.3.1.1.7 Method 7: Substitution of Dichloromethane with Tertiary Amines and Organophosphorus Compounds

α-Aminophosphonates are synthesized via consecutive substitution of two chloro groups in dichloromethane with nitrogen nucleophiles and phosphorus nucleophiles (▶ Scheme 10).^[39] The reaction of amines 34 with dichloromethane gives (chloromethyl)ammonium chlorides, which decompose to iminium chlorides and organic chlorides. Hydrophosphorylation of the resulting iminium intermediates with phosphonates 33 gives α-aminophosphonates 35. The C—N (or H—N) bond cleavage priority (N—R⁴, N—R³, and N—R²) follows an order of H > t-Bu > allyl > Bn > Me > primary and secondary alkyl. A diverse range of α-aminophosphonates can be synthesized using this three-component coupling.

Scheme 10 Substitution of Dichloromethane with Amines and Phosphonates^[39]

α-Aminophosphonates 35; General Procedure:^[39]

A mixture of phosphonate 33 (0.5 mmol), CH₂Cl₂ (0.5 mL), and amine 34 (1.5 mmol) in DMF (0.5 mL) was stirred at 75 °C (for primary and secondary amines) or 100 °C (for tertiary amines) for 12 h under a N₂ atmosphere. Sat. aq Na₂CO₃ (10 mL) was added to the mixture, which was then extracted with EtOAc. The combined organic layer was dried (Na₂SO₄)and concentrated under reduced pressure. The resulting residue was purified by short column chromatography (silica gel) or preparative GPC.

30.7.3.1.1.8 Method 8: Asymmetric Hydrogenation of α-Enamido Phosphonates

Rhodium-catalyzed asymmetric hydrogenation of α,β-unsaturated α-aminophosphonates, also referred to as α-enamido phosphonates, is performed as a benchmark reaction to demonstrate the stereocontrolling ability of chiral ligands.^[40–48] The development of efficient synthetic methods for α-enamido phosphonates [see Science of Synthesis, Vol. 24 (Section 24.2.18)] makes this synthetic route attractive. The asymmetric hydrogenation of α-enamido phosphonates 37 using a rhodium(I)–monodentate phosphoramidite (36; DpenPhos) catalyst gives α-aminophosphonates 38 with excellent enantioselectivity (▶ Scheme 11).^[47] The reaction proceeds at room temperature within 1 hour under hydrogen at ambient pressure.

Scheme 11 Asymmetric Hydrogenation of α-Enamido Phosphonates Using a Chiral Rhodium–Phosphoramidite Catalyst^[47]

^α-Aminophosphonates 38; General Procedure:^[47]

(S, S)-DpenPhos (36; 0.005 mmol) and [Rh(cod)₂]BF₄ (1.0 mg, 0.0025 mmol) were added to a Schlenk tube under an argon atmosphere. A balloon filled with H₂ was attached to the Schlenk tube, and the system was purged three times with H₂ to remove the argon. CH₂Cl₂ (0.6 mL) was added to the tube, and the resulting mixture was stirred at rt for 10 min. A soln of phosphonate 37 (0.25 mmol) in CH₂Cl₂ (0.6 mL) was added, and the mixture was stirred for 1 h. H₂ gas was released in a hood. The mixture was filtered through a short pad of silica gel and eluted with petroleum ether/EtOAc.

30.7.3.1.1.9 Method 9: Reduction of α-Iminophosphonates

In addition to the hydrogenation of α-enamido phosphonates (▶ Section 30.7.3.1.1.8), the reduction of α-iminophosphonates is an alternative method for the synthesis of α-aminophosphonates through reduction. Reducing agents such as sodium borohydride,^[49] borane–dimethyl sulfide,^[50] and catecholborane^[51] reportedly reduce the imino group of α-iminophosphonates to give α-aminophosphonates. α-Iminophosphonates are also reduced to α-aminophosphonates by palladium-catalyzed hydrogenation.^[52,53]

N-Hydroxy-α-iminophosphonates 39 can be prepared by condensation of acylphosphonates and hydroxylamine. N-Hydroxy-α-iminophosphonates 39 are hydrogenated in the presence of catalytic amounts of palladium(II) acetate, (R)-BINAP, and (1S)(+)-10-camphorsulfonic acid (CSA) under an atmosphere of hydrogen to give optically active N-hydroxy-α-aminophosphonates 40 (▶ Scheme 12).^[53] In the presence of the chiral ligand (R)-BINAP, the N-hydroxy-α-aminophosphonates 40 are obtained in good yield and with good enantioselectivity. A catalytic amount of 10-camphorsulfonic acid is necessary as a Brønsted acid to enhance the reactivity of (E)-N-hydroxy-α-iminophosphonates 39. The hydroxy group on the nitrogen atom in the product 40 can be removed by hydrogenation in the presence of Pearlman’s catalyst [Pd(OH)₂/C].

Scheme 12 Palladium-Catalyzed Asymmetric Hydrogenation of N-Hydroxy-α-iminophosphonates^[53]

Diethyl {[N-(Hydroxy)amino](phenyl)methyl}phosphonate (40, R¹ = Et; Ar¹ = Ph); Typical Procedure:^[53]

A mixture of Pd(OAc)₂ (1.6 mg, 7 μmol), (R)-BINAP (4.5 mg, 7 μmol), and CF₃CH₂OH (4 mL) was stirred at 70 °C under an argon atmosphere until the (R)-BINAP had completely dissolved. After the mixture had been cooled, phosphonate 39 (R¹ = Et; Ar¹ = Ph; 37.0 mg, 0.144 mmol) and CSA (3.2 mg, 14 μmol) were added, and the mixture was stirred until complete homogenization. The mixture was transferred into a steel autoclave with a glass inlet using a syringe, and the autoclave was filled with dry argon. The autoclave was sealed and pressurized with H₂ to 50 atm. The mixture was stirred at 60 °C for 1 h. Solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, CH₂Cl₂/MeOH 40:1) to give a white solid; yield: 92%.

30.7.3.1.1.10 Method 10: 1,4-Addition of Aryltrifluoroborates to α-Enamido Phosphonates

The 1,4-addition of potassium aryltrifluoroborates to α-enamido phosphonates 42 occurs in propan-2-ol in the presence of a chiral DIFLUORPHOS (41)/rhodium catalyst and sodium hydrogen carbonate to give α-aminophosphonates 43 in good yields with high enantioselectivity (▶ Scheme 13).^[54] The reaction appears to proceed via carbometalation and subsequent enantioselective protonation. The reaction with phenylboronic acid in place of the aryltrifluoroborate also gives the α-aminophosphonate 43 (Ar¹ = Ph).

Scheme 13 Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryltrifluoroborates to α-Enamido Phosphonates^[54]

α-Aminophosphonates 43; General Procedure:^[54]

Degassed iPrOH (1.4 mL) was added to a mixture of phosphonate 42 (0.34 mmol), the aryltrifluoroborate (0.68 mmol), {RhCl(CH₂=CH₂)₂}₂ (2 mg, 1.5 mol%), (S)-DIFLUORPHOS (41; 7.7 mg, 3.3 mol%), and NaHCO₃ (28.6 mg, 0.34 mmol) under an argon atmosphere. The mixture was stirred in an oil bath at 90 °C for 20 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography.

30.7.3.1.1.11 Method 11: Addition of Carbon Nucleophiles to α-Iminophosphonates

The addition of carbon nucleophiles, such as silicon enolates and allylsilanes, to the imino group of α-iminophosphonates in the presence of a chiral copper catalyst gives optically active α-aminophosphonates.^[55,56] Terminal alkynes,^[57,58] cyanide,^[59] and nitromethane^[60] are also used as carbon nucleophiles in the addition to α-iminophosphonates in the presence of chiral catalysts, and α-aminophosphonates possessing a tertiary or quaternary chiral carbon atom are formed with good levels of enantioselectivity.

30.7.3.1.1.11.1 Variation 1: Using Terminal Alkynes

In addition to the three-component coupling reaction of formylphosphonate hydrate, p- anisidine, and terminal alkynes in the presence of a silver(I) trifluoromethanesulfonate catalyst,^[57] α-aminopropargylphosphonates 46 can also be synthesized from α-iminophosphonates 44 and terminal alkynes (▶ Scheme 14).^[58] This reaction occurs in the presence of 2 mol% of a copper(I) trifluoromethanesulfonate/pybox 45 catalyst at room temperature without a base, and α-aminopropargylphosphonates 46 are obtained in good yield with moderate enantioselectivity. The four phenyl groups on the dihydrooxazole rings in the pybox ligand 45 are important in controlling the orientation of the substrates.

Scheme 14 Asymmetric Synthesis of α-Aminopropargylphosphonates from Terminal Alkynes and α-Iminophosphonates^[58]

α-Aminopropargylphosphonates 46; General Procedure:^[58]

A mixture of (CuOTf)₂·toluene (0.01 mmol, 2.0 mol%) and pybox 45 (7.0 mg, 0.011 mmol, 2.1 mol%) in CHCl₃ (3.0 mL) was stirred at rt for 2 h. A soln of phosphonate 44 (136.0 mg, 0.50 mmol) in CHCl₃ (0.5 mL) was added to the mixture, followed immediately by a terminal alkyne (1.5 mmol). The mixture was stirred at rt for 10 h. After the solvent had been removed under reduced pressure, the residue was purified by flash column chromatography (silica gel, hexane/EtOAc 3:2).

30.7.3.1.1.11.2 Variation 2: Using Pyruvonitrile

The asymmetric addition of carbon nucleophiles to ketimines is not easy because of the latter’s low reactivity and difficult enantiofacial discrimination compared to aldimines. Nevertheless, α-amino-α-phosphorylnitriles 49 are synthesized through asymmetric cyanation of α-ketiminophosphonates 47 catalyzed by cinchonidine (48) (▶ Scheme 15).^[59]α-Ketiminophosphonates 47 are prepared by N-chlorination of α-aminophosphonates with trichloroisocyanuric acid and subsequent β-elimination using poly(4-vinylpyridine). Cyanation of α-ketiminophosphonates 47 with pyruvonitrile (acetyl cyanide) proceeds in the presence of 10 mol% of cinchonidine (48) and gives α-amino-α-phosphorylnitriles 49 with good enantioselectivity.

Scheme 15 Asymmetric Cyanation of α-Ketiminophosphonates Catalyzed by Cinchonidine^[59]

α-Amino-α-phosphorylnitriles 49; General Procedure:^[59]

AcCN (71 mL, 1 mmol) was added to a soln of phosphonate 47 (0.5 mmol) and cinchonidine (48; 10 mol%) in CHCl₃ under a N₂ atmosphere at –45 or 0 °C. The mixture was stirred at –45 or 0 °C for 72 h. The resulting soln was concentrated under reduced pressure, and the residue was purified by crystallization (EtOH).

30.7.3.1.1.12 Method 12: Hydrophosphorylation of Imines (Pudovik Reaction)

The addition of phosphonates possessing a P—H bond to imines is known as the Pudovik reaction.^[1–4,31] The Pudovik reaction is one of the most popular methods for the synthesis of α-aminophosphonates [see Science of Synthesis: Stereoselective Synthesis, Vol. 2 (Section 2.11.3)]. Much effort has been devoted to developing efficient Brønsted acid catalysts and Lewis acid catalysts. Chiral catalysts such as heterobimetallic complexes,^[61] thioureas,^[62]and phosphoric acids^[63] have successfully been applied to the asymmetric Pudovik reaction of imines with phosphonates. As a continuation of efforts to develop more active and stereoselective chiral catalysts, a variety of chiral metal catalysts and organocatalysts have emerged.^[64–76] The diastereoselective synthesis of α-aminophosphonates using chiral auxiliaries has also been reported.^[77–81]

30.7.3.1.1.12.1 Variation 1: Using a Chiral Aluminum–Salalen Catalyst

Hydrophosphorylation of aromatic aldimines 50 with dimethyl phosphonate occurs in the presence of a catalytic amount of a chiral aluminum–salalen complex 51 to give optically active α-aminophosphonates 52 in high yield with good enantioselectivity (▶ Scheme 16).^[64] The 4-methoxy-3-methylphenyl group on the nitrogen atom of imines 50 is important to successfully achieve an enantioselective reaction. The 4-methoxy-3-methylphenyl group in the product 52 can be removed by anodic oxidation. Because aliphatic aldimines are difficult to isolate due to their instability, they are generated in situ from aliphatic aldehydes and amines in the presence of 4-Å molecular sieves. Subsequent hydrophosphorylation of the in situ generated aldimines also gives optically active α-aminophosphonates.

Scheme 16 Chiral Aluminum–Salalen Catalyzed Hydrophosphorylation of Aldimines^[64]

α-Aminophosphonates 52; General Procedure:^[64]

Dimethyl phosphonate (27.5 μL, 0.30 mmol) was added to a soln of Al(salalen) complex 51 (12.5 mg, 0.020 mmol) and imine 50 (0.20 mmol) in THF (1 mL) at –15 °C under a N₂ atmosphere, and the mixture was stirred for 24 h. The reaction was quenched with H₂O, and the mixture was extracted with EtOAc (3 × 1 mL). The combined organic layers were passed through a pad of Celite and Na₂SO₄. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/EtOAc 7:3 to 3:7).

The reaction of bis(2,2,2-trifluoroethyl) phosphonate with N-(diphenylphosphoryl)imines 53 proceeds in the presence of the chiral aluminum catalyst 54 (TBOxAlCl), prepared from the chiral tethered bis(quinolin-8-olato) (TBOxH) ligand and diethylaluminum chloride, to give α-aminophosphonates 55 in high yield and high enantiomeric excess (▶ Scheme 17).^[66] Although the chiral ligand must be prepared, the reaction proceeds with very low catalyst loading, and the ligand can be recovered and reused without any loss of efficiency. The products can be converted into α-aminophosphonic acids upon treatment with methanolic, concentrated hydrogen chloride under reflux conditions.

Scheme 17 Hydrophosphorylation of Imines Catalyzed by a Chiral Tethered Bis(quinolin-8-olato)aluminum Complex^[66]

α-Aminophosphonates 55; General Procedure:^[66]

The ligand TBOxH (8.8 mg, 0.01 mmol) was added to a flame-dried flask, and the flask was purged with argon (3 ×). CH₂Cl₂ (1 mL) was added to the flask, and a 1.0 M soln of Et₂AlCl in hexanes (10 μL, 0.01 mmol) was added to the resulting soln. The soln was stirred for 5 min. After all of the volatiles were removed under reduced pressure, the flask was evacuated and purged with argon (3 ×). Hexanes (10 mL) and bis(2,2,2-trifluoroethyl) phosphonate (270 mg, 1.1 mmol) were added to the residue, and the mixture was stirred for 5 min. Imine 53 (1.0 mmol) was added to the mixture, which was then stirred at rt for 1 h. The reaction was quenched with 1.0 M aq HCl (10 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with H₂O (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexanes to recover TBOxH and then acetone/hexanes) to give the product 55.

30.7.3.1.1.12.3 Variation 3: Using Cinchona Alkaloid Catalysts

Optically active N-sulfonyl-α-aminophosphonates 58, with a chiral quaternary carbon atom, are synthesized by asymmetric hydrophosphorylation of N-sulfonylketimines 56, which are prepared from 2,4,6-trimethylbenzenesulfonamide and ketones, using diphenyl phosphonate in the presence of a catalytic amount of hydroquinine (57) (▶ Scheme 18).^[69]The antipodal stereoisomers can also be synthesized with same order of enantioselectivity using hydroquinidine in place of hydroquinine. The 2,4,6-trimethylbenzenesulfonyl group on the nitrogen atom in the product 58 can be removed upon treatment with methanesulfonic acid in trifluoroacetic acid/anisole. Although a long reaction time is needed to complete the reaction, the asymmetric hydrophosphorylation of ketimines, which are more challenging substrates compared to aldimines, has been achieved using commercially available cinchona alkaloids.

Scheme 18 Cinchona Alkaloid Catalyzed Asymmetric Hydrophosphorylation of Ketimines^[69]

R1	R2	ee (%)	Yield (%)	Ref
Ph	Me	97	99	[69]
Ph	Et	97	96	[69]
4-MeOC6H4	Me	97	99	[69]
(CH2)2Ph	Me	55	98	[69]
Cy	Me	75	97	[69]
		89	93	[69]

α-Aminophosphonates 58; General Procedure:^[69]

Diphenyl phosphonate (0.10 mmol) was added to a soln of imine 56 (0.033 mmol), hydroquinine (57; 0.0007 mmol), and Na₂CO₃ (0.050 mmol) in toluene (0.33 mL) at –20 °C, and the mixture was stirred for 3–5 d. After the mixture had been warmed to rt, H₂O was added. The mixture was extracted with CH₂Cl₂, and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel).

30.7.3.1.1.12.4 Variation 4: Using a Chiral Copper Catalyst

Asymmetric hydrophosphorylation of aromatic and aliphatic N-thiophosphorylketimines 60 with phosphonates 59 occurs in the presence of a catalytic amount of a chiral bisphosphine–copper complex at room temperature to give enantioenriched N-thiophosphoryl-α-aminophosphonates 61 (▶ Scheme 19).^[74] α-Aminophosphonates 61, possessing a chiral quaternary carbon center, are obtained with high enantiomeric excess. The thiophosphoryl group on the nitrogen atom in the product 61 is removed by treatment with perchloric acid. Reaction under neat conditions, gram-scale synthesis, and recovery and reuse of the catalyst are possible with this method.

Scheme 19 Catalytic Asymmetric Hydrophosphorylation of N-Thiophosphoryl Ketimines^[74]

Diethyl 1-[(Diphenylphosphorothioyl)amino]-1-phenylethylphosphonate (61, R¹ = Et; R² = Ph; R³ = Me); Typical Procedure:^[74]

A mixture of [Cu(NCMe)₄]PF₆ (3.7 mg, 0.01 mmol), 1,2-bis[(2R,5R)-2,5-diphenylpyrrolidin-1-yl]ethane (5.1 mg, 0.01 mmol), and THF (2.0 mL) was stirred for 1 h. Et₃N (70 μL, 0.50 mmol) was then added to the mixture under an argon atmosphere. The mixture was stirred for 1 h to give the catalyst soln [copper(I) complex: 0.005 M; Et₃N: 0.25 M]. The catalyst soln (0.2 mL) containing the copper(I) complex (0.001 mmol) and Et₃N (0.05 mmol) was added to the imine 60 (R² = Ph; R³ = Me; 67.0 mg, 0.2 mmol) under an argon atmosphere. Phosphonate 59 (R¹ = Et; 51.6 μL, 0.4 mmol) was added, and the resulting mixture was stirred at rt for 72 h. The mixture was purified by preparative TLC (hexane/EtOAc 1:1); yield: 85.2 mg (90%).

30.7.3.1.1.12.5 Variation 5: Using a Chiral Auxiliary

The diastereoselective addition of phosphonates to chiral imines or chiral phosphonates to imines is an alternative method for the synthesis of optically active α-aminophosphonates via hydrophosphorylation of imines.^[77–81] In this method, the diastereomer separation process and the removal of chiral auxiliaries are key issues. The hydrophosphorylation of optically active N-(tert-butylsulfinyl)imines 62 with dimethyl phosphonate occurs at room temperature in the presence of potassium carbonate to give N-(tert-butylsulfinyl)-α-aminophosphonates 63 in good yield and diastereoselectivity (▶ Scheme 20).^[78] The N–tert-butylsulfinyl group activates the imines and serves as a chiral directing group. The major diastereomers are separated by flash column chromatography on silica gel, and the N–tert-butylsulfinyl group is removed from the products 63 by treatment with hydrochloric acid.

Scheme 20 Diastereoselective Hydrophosphorylation of N–tert-Butylsulfinylimines^[78]

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