Kabachnik-Fields reactions

Kabachnik-Fields reaction in synthesis and transformations of P-heterocycles 98UK940. 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

Scheme 42 The three-component Kabachnik-Fields reaction in the microreactor setup [89]...

This three-component coupling of a carbonyl, an amine and a hydrophosphoryl compound leads to a-aminophosphonates. The Kabachnik-Fields Reaction is very important in drug discovery research for generating peptidomimetic compounds. 

The pathway of the Kabachnik-Fields reaction depends on the nature of the substrates. The amine and hydrophosphoryl compound form a complex in which either one of the partners may react with the carbonyl compound. Often, the basicity of the amine determines the reaction pathway. Weakly basic amines such as anilines, which can act as proton donors, favour the formation cf an imine, whereas alkylamines such as cyclohexylamines do not form imines ... 

A more detailed discussion of the mechanism of the Kabachnik-Fields reaction, its synthetic potential and the biological activity of the a-aminophosphonates. 

As this example shows a high degree of complexity, one can imagine that the design of an enantioselective three-component reaction would be somewhat more difficult, and it is clear that some basic investigation into the stereocontrol of the Kabachnik-Fields reaction is still needed. 

Phosphorylated aminomethylindoles 98 were obtained from 3-formylindoles 97a,b, amines, and hydrophosphoryl compounds [99-101] in the Kabachnik-Fields reaction [233-235]. As shown by DTA, 3-(hydroxyamino)methylindole is formed initially in the case of secondary amines and then it reacts with dialkylphosphorous acid. In the case of ammonia and primary amines imine is formed at the first stage and then it adds dialkylphosphorous acid. 

Chiral carbonyl and aldimine substrates can give good diastereoselectivity in the Pudovik reaction.86 88,102 The Pudovik reaction of isolated imines generally proceeds in higher yield and de (where applicable) than if the imine is formed itt situ (the Kabachnik-Fields reaction, Section 7). 

The Kabachnik-Fields reaction is the three-component condensation of an aldehyde or ketone, an amine (secondary, primary, or ammonia) and a monobasic phosphorus(III) acid to yield an a-amino organophosphorus compound (a phos-phonate, phosphinate, or tertiary phosphine oxide) Scheme 28. It was discovered independently in 1952 by Kabachnik and Medved 120 and Fields,121 and may be regarded as a variant of the Pudovik reaction (Section 6), which was discovered contemporarily. The yields of the reaction tend to be only moderate (cf. Section 6), and are generally unsatisfactory with phosphinate reactants, but it is wide in scope and simple to perform. For a recent review of the Kabachnik-Fields reaction, including discussion of the mechanism (which usually proceeds via the imine), see Ref. 102. 

The original Kabachnik-Fields procedure employing ammonia as the amine component used ammonia in ethanol and the reactions were performed in sealed vessels at circa 100°C.90,123 This method avoids such conditions by using ammonium acetate as the source of ammonia, and it is also thought to act as an acid catalyst for imine formation other ammonium salts were unsatisfactory. Addition of water to produce a homogeneous reaction mixture resulted in diethyl 1-hydroxy-1-benzylphosphonate formation (i.e. from direct attack of diethyl phosphite 25 on benzaldehye, a common side reaction in the Kabachnik-Fields reaction). The yields of this reaction are serviceable, and better for aromatic than aliphatic aldehydes. The product 58 may be further purified by crystallization as the hydrochloride salt by treatment of 58 with hydrogen chloride in ethanol/diethyl ether.122... 

This procedure is Coveney, Whiting and co-workers synthesis of the hexaphos-phonic acid 61 by the Moedritzer-lrani reaction, the dodecasodium salt of which they investigated as a cement setting retarder. An attempt to synthesize the dodecaethyl ester of 61 using the Kabachnik-Fields reaction failed.128... 

Aminoalkyl and Related Acids. - Further development of the classical three component approach to aminoalkylphosphonates (the Kabachnik-Fields reaction) has been reported. The reaction of aldehydes, hydroxylamines and dimethyltrimethylsilyl phosphite using lithium perchlorate/diethyl ether as a catalyst gives N-trimethylsilyloxy-a-aminophosphonate derivatives. The catalytic activities of various lanthanide triflates as well as indium trichloride have been examined for the Kabachnik-Fields type reactions of aldehydes, amines and the phosphorus nucleophiles HP(0)(0Et)2 and P(OEt)3 in ionic liquids. TaCb-Si02 has been utilized as an efficient Lewis acid catalyst for the coupling of carbonyl compounds, aromatic amines and diethyl phosphite to produce a-... 

New y-ethoxycarbonyl- and ot-amino-alkyl-hydroxyphosphinic acid derivatives (366) and (367) were conveniently prepared by Michael addition or Kabachnik-Fields reaction of a new precursor, benzyloxymethyl hydrogen-phosphinate (368), with a,p-unsaturated esters or imines (Scheme 94). " Phosphinic acid inhibitors (369) of Cathepsin C were synthesized by addition of methyl acrylate to the appropriate a-amino phosphinic acid and by... 

The Kabachnik Fields reaction, which involves the hydrophosphonylation of phos phites with imines generated in situ from carbonyl compounds and amines, is an attractive method for the preparation of a amino phosphonates. Optically active a amino phosphonic acids and their phosphonate esters are an attractive class of compounds due to their potent biological activities as nonproteinogenic analogues of a amino acids. Therefore, considerable attention has been given to their enantio selective synthesis by hydrophosphonylation of preformed imines, using either metal based catalysts or organocatalysis [107]. 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

Scheme 3.53 Enantioselective synthesis of p branched a amino phosphonates by Kabachnik Fields reaction.

Keywords a-aminophosphonate, Kabachnik-Fields reaction, dimethyl phosphite... 

For further mention of (l-hydroxyalkyl)phosphonates in the context of the Kabachnik-Fields reaction, see Section 3.1.9. 

The Kabachnik-Fields Reaction in Ionic Liquids Using Microwave Heating... 

The Kabachnik-Fields reaction is an effective means of preparing biologically active a-amino phosphonates [64]. It involves the three component reaction of an aromatic aldehyde, an aniline, and diethylphosphite. The reaction has recently been performed using microwave irradiation with [BMIM]PF6, [BMIM]SbF6, [BMIM]BF4, and DMF as solvents and lanthanide triflates as catalysts (Scheme 7.18) [65]. The reactions were performed using a domestic microwave oven and pulsed irradiation. Catalyst activity in the ionic liquids was found to be higher than or comparable with that in DMF. It was also found that catalyst activity varied depending on the ionic liquid used. For example, Yb(OTf)3 was very active in [BMIM]BF4 but Sc(OTf)3 was more active in [BMIMjPFe. Excellent product yields were obtained. 

Scheme 7.18. The Kabachnik-Fields reaction using ionic liquids and microwave heating.

TMG (1) catalyses one-pot simultaneous reaction of indole-3-carboxaldehyde, a dialkyl- or diphenyl phosphite, and a primary amine to give the corresponding a-aminophosphonates in good yield (60-85%) (Scheme 4.10) [30], It is known as Kabachnik-Fields reaction. 

Other references related to the Kabachnik-Fields reaction are cited in the literature. 

This reaction is related to the Atherton-Todd Reaction and Kabachnik-Fields Reaction. 

Application of the microwave technique offered advantages in organo-phosphorus chemistry, such as in the Kabachnik-Fields reaction, in Diels-Alder cycloaddition and in an inverse Wittig-type reaction to synthesize phosphine oxide derivatives. ... 

---