30.2.3 O,P-Acetals (Update 2016)

α-Acetoxy phosphonates are prepared by reacting aldehydes with diethyl phosphite in the presence of acetic anhydride under solvent-free conditions using solid bases. The reactions of dialkyl phosphites with aldehydes in the presence of acetic anhydride and potassium carbonate under solvent-free conditions produce α-acetoxy phosphonates in one pot. This method is operationally simple, rapid, and generally gives high yields. Alkali metal carbonates (K₂CO₃ and Na₂CO₃) give better results than other solid bases such as magnesium oxide, calcium oxide, barium oxide, and alumina.^[1,2] Catalysts such as molybdenum(VI) dichloride dioxide (MoO₂Cl₂) or potassium phosphate (K₃PO₄) also effectively promote the hydrophosphonylation of aldehydes under solvent-free conditions to give α-hydroxy phosphonates in good yields (▶ Scheme 1).^[3,4]

Scheme 1 Preparation of α-Acetoxy and α-Hydroxy Phosphonates under Solvent-Free Conditions Using Solid Bases^[1–4]

The formation of α-hydroxy phosphonates from aldehydes and triethyl phosphite is accelerated by ultrasound under solvent-free conditions in the presence of potassium dihydrogen phosphate (KH₂PO₄) (▶ Scheme 2). A variety of aromatic, heteroaromatic, and α,β-unsaturated aldehydes can be used for this method, whereas low yields are obtained with aliphatic aldehydes, and no conversion occurs with ketones.^[5]

Scheme 2 Preparation of α-Hydroxy Phosphonates by Ultrasound Acceleration under Solvent-Free Conditions^[5]

α-Hydroxy phosphonates 1, derived from heterocyclic aldehydes or six-membered heterocyclic ketones, are effectively synthesized under solvent-free conditions using microwave irradiation (▶ Scheme 3). A wide range of heterocyclic compounds, including thiazoles, pyridines, and diazines, are tolerated on solid magnesium oxide supports and give satisfactory yields. The reaction yield is affected by the steric bulk of the phosphite used; see, for example, the reactions of aldehydes 2 and 3 (▶ Scheme 3).^[6]

Scheme 3 Preparation of α-Hydroxy Phosphonates from Heterocyclic Aldehydes and Ketones under Microwave Irradiation^[6]

Ar1	R1	Yield (%)	Ref
	H	83	[6]
	H	87	[6]
	H	84	[6]
	Me	80	[6]
	Me	80	[6]

Hydrophosphonylation of ketones is promoted by titanium(IV) isopropoxide under solvent-free conditions to produce quaternary α-hydroxy phosphonates efficiently in high yields (▶ Scheme 4).^[7] The substrate scope is broad, and functional groups of various types are tolerated. These are the first examples of ketone hydrophosphonylation using Lewis acid catalysts, although such catalysts are effective for hydrophosphonylation of aldehydes. Retro-hydrophosphonylation reactions and phospha-Brook reactions, which are often problematic with base-catalyzed ketone hydrophosphonylation, are avoided under these conditions.

Scheme 4 Preparation of α-Hydroxy Phosphonates from Ketones Mediated by Titanium(IV) Isopropoxide^[7]

R1	R2	Yield (%)	Ref
Ph	Me	98	[7]
		95	[7]
	Me	93	[7]
Cy	Me	81	[7]
4-ClC6H4	CH(OEt)2	87	[7]
Ph	(CH2)2Cl	86	[7]
Ph	CO2Me	86	[7]
CH(Bn)CO2Et	Me	93	[7]
	Me	89	[7]

Butyllithium serves as an efficient precatalyst for the hydrophosphonylation of aldehydes and unactivated ketones with dialkyl phosphites (▶ Scheme 5).^[8] Reduction of the catalyst loading (0.1 mol%) suppresses the reverse reaction (elimination of the dialkyl phosphite from the product) with ketone substrates. A broad range of substrates are tolerated to generate a series of α-hydroxy phosphonates in high yields in shortreaction times (generally within 5 min).

Scheme 5 Preparation of α-Hydroxy Phosphonates Mediated by Butyllithium^[8]

R1	R2	R3	Yield (%)	Ref
Ph	H	Et	>99	[8]
2-MeOC6H4	H	Et	>99	[8]
2-ClC6H4	H	Et	>99	[8]
3-O2NC6H4	H	Et	>99	[8]
1-naphthyl	H	Et	>99	[8]
2-furyl	H	Et	90	[8]
Pr	H	Et	97	[8]
Ph	H	iPr	99	[8]
Ph	Me	Et	95	[8]
2-ClC6H4	Me	Et	79	[8]
2-BrC6H4	Me	Et	59	[8]
3-O2NC6H4	Me	Et	99	[8]
3-pyridyl	Me	Et	96	[8]
Ph	Ph	Et	97	[8]
2-furyl	Me	Et	69	[8]
Ph	(CH2)10Me	Et	40	[8]
Ph	Bz	Et	55	[8]
		Et	93	[8]
(CH2)5		Et	95	[8]
Ph	Me	iPr	85	[8]

Several lanthanide complexes have been used as highly efficient catalysts for hydrophosphonylation reactions (▶ Scheme 6).^[9–11] A lanthanide amide {[(TMS)₂N)]₃La(μ-Cl)Li(THF)₃}^[9]and amino-coordinated lithium-bridged bis(indolyl)lanthanide amide 4^[10] catalyze the hydrophosphonylation of aldehydes with diethyl or diphenyl phosphite. Reactions using 4 are performed neat and high yields (ca. 99%) are achieved. Lanthanide anilido complex 5 catalyzes the hydrophosphonylation of ketones, as well as aldehydes, with diethyl phosphite in hexane.^[11] Under these reaction conditions, a low catalyst loading (0.1 mol%) is sufficient and excellent yields (ca. 99%) are obtained.

Scheme 6 Preparation of α-Hydroxy Phosphonates Mediated by Lanthanide Complexes^[10,11]

Ammonium metavanadate (NH₄VO₃), which is a water-soluble inorganic acid, also promotes the hydrophosphonylation of aryl- or hetarylaldehydes with triethyl phosphite (▶ Scheme 7; 18 examples, up to 94% yield). This method involves solvent-free conditions at room temperature and short reaction times. Aliphatic aldehydes and aromatic ketones are not converted by this reaction. In these cases no reaction occurs, even on increasing the concentration of the catalyst.^[12]

Scheme 7 Preparation of α-Hydroxy Phosphonates Mediated by Ammonium Metavanadate^[12]

Immobilized catalysts have been developed for hydrophosphonylation reactions. Such methods are environmentally benign because of the solvent-free conditions and simple workup.

The first example of this type of catalyst is polymer-bound phosphazene base 6, 2-(tert-butylimino)-2-(diethylamino)-1,3-dimethyl-1,3,2-diazaphosphinane supported on polystyrene (PS-BEMP); it promotes hydrophosphonylation of aromatic and aliphatic aldehydes. The process can be performed on a large scale using a continuous-flow procedure (▶ Scheme 8).^[13]

Scheme 8 Preparation of α-Hydroxy Phosphonates Mediated by a Polymer-Bound Phosphazene Base^[13]

The second example is magnetic nanoparticle (γ-Fe₂O₃) immobilized 1,5,7-triazabicyclo[4.4.0]dec-5-ene 8 (MNP-TBD). Oxindolyl α-hydroxy phosphonates are synthesized from isatins 7 and dimethyl or diethyl phosphite; the substrate scope is wide (▶ Scheme 9). The catalyst is easily recovered using an external magnet and can be reused (6 times) without any significant loss of activity.^[14]

Scheme 9 Preparation of α-Hydroxy Phosphonates Mediated by a Nanoparticle Catalyst^[14]

Diethyl Hydroxy(4-methylthiazol-5-yl)methylphosphonate (1, Ar¹ = 4-Methylthiazol-5-yl; R¹ = H); Typical Procedure:^[6]

4-Methylthiazole-5-carbaldehyde (0.381 g, 3 mmol), diethyl phosphite (0.414 g, 3 mmol), and MgO (0.484 g, 12 mmol) were mixed and exposed to microwave irradiation. The heating was intermittent (every 2 min), and the mixture was stirred. The reaction was monitored by TLC, and was stopped at 6 min. Then, CHCl₃ (2 × 10 mL) was poured into the container and MgO was removed by filtration. The solvent was evaporated under reduced pressure and the residue was recrystallized (EtOAc/petroleum ether) to afford the pure product as a white solid; yield: 83%.

30.2.3.1.1 Variation 1: Diastereoselective Hydrophosphonylation

The reactions of optically pure chiral 2-azanorbornane aldehydes exo–9 and endo–9 with silylated phosphorus esters are highly diastereoselective. (S)-α-Hydroxy phosphonic acid 10A is obtained from exo–9, and the R-diastereomer 10B is obtained from endo–9 (▶ Scheme 10).^[15]

Scheme 10 Hydrophosphonylation of Chiral 2-Azanorbornane Aldehydes with a Silylated Phosphorus Ester^[15]

Highly diastereoselective hydrophosphonylation is observed in the reactions of tetraaryl-2,2-dimethyldioxolane-4,5-dimethanol (TADDOL) derived H-phosphonate 11 and aldehydes. The chiral auxiliary can be removed by two different procedures to give (α-hydroxyalkyl)phosphonic acids in good yields (▶ Scheme 11).^[16]

Scheme 11 Reactions of a TADDOL-Containing H-Phosphonate and Aldehydes^[16]

30.2.3.1.2 Variation 2: Enantioselective, Metal-Catalyzed Addition of Phosphites to Aldehydes (Pudovik Reaction)

The optically active aluminum(salalen) complex 12, bearing a new optically active salalen ligand derived from (1R,2R)-cyclohexane-1,2-diamine, catalyzes enantioselective hydrophosphonylation of aldehydes to give the corresponding α-hydroxy phosphonates 14 with high enantioselectivities; however, the reaction is slow, and a high catalyst loading of 10 mol% and long reaction times are required.^[17] Aluminum(salalen) 13, which has tert-hexyl groups in place of tert-butyl groups, was developed in the same laboratory. Catalyst 13 needs a lower catalyst loading and gives improved yields, product enantioselectivities, and reaction times (▶ Scheme 12).^[18]

Scheme 12 Asymmetric Catalytic Hydrophosphonylation of Aldehydes by Aluminum–Salalen Complexes^[17,18]

Catalysts with chiral binaphthyl skeletons also have significant potential. The aluminum–binaphthyl Schiff base complex 15 obtained from 1,1′-binaphthalene-2,2′-diamine is a good catalyst for enantioselective hydrophosphonylation of aldehydes, and high selectivities are obtained in the reactions of both aromatic and aliphatic aldehydes (▶ Scheme 13).^[19]

Scheme 13 Asymmetric Catalytic Hydrophosphonylation of Aldehydes by an Aluminum–Binaphthyl Schiff Base Complex^[19]

A bifunctional chiral aluminum complex of 1,1′-binaphthalene-2,2′-diol (BINOL) derivative 16, which has tertiary amine groups at the 3- and 3′-positions of BINOL, promotes enantioselective hydrophosphonylation of aldehydes. The enantioselectivity is usually moderate to good (up to 87% ee), and a wide variety of aromatic, heteroaromatic, α,β-unsaturated, and aliphatic aldehydes can be used in this method (▶ Scheme 14).^[20]

Scheme 14 Asymmetric Catalytic Hydrophosphonylation of Aldehydes by a Bifunctional Binaphthyl Aluminum Complex^[20]

The metal–organic self-assembly of substituted binaphthalenediols 17/18 and cinchona alkaloid 19 in combination with titanium(IV) isopropoxide catalyzes asymmetric hydrophosphonylation of aldehydes with high enantioselectivities. BINOL ligand 17 is the best choice for aromatic aldehydes, whereas BINOL 18 gives the best results for aliphatic aldehydes (▶ Scheme 15).^[21]

Scheme 15 Asymmetric Catalytic Hydrophosphonylation of Aldehydes by Titanium Complexes^[21]

Enantioselective Pudovik reactions of bis(2,2,2-trifluoroethyl)phosphite with aldehydes are catalyzed by the tethered bis(8-quinolinolato) (TBOx) aluminum complex 20 (▶ Scheme 16).^[22] The reaction proceeds even with a low catalyst loading (0.5–1 mol%). The obtained chiral α-hydroxy phosphonates 21 can be converted into α-hydroxy phosphonic acids without loss of enantiopurity.

Scheme 16 Asymmetric Catalytic Hydrophosphonylation of Aldehydes by a Tethered Bis(8-quinolinolato)–Aluminum Complex^[22]

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