The Kabachnik-Fields reaction

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 

Caution Carry out all protocols in an efficient hood and wear disposable vinyl or latex gloves and chemical-resistant safety goggles at all times. 

Charge a one-necked round-bottomed flask (500 mL), equipped with a magnetic stirrer bar and fitted with a water condenser, with a solution of ammonium acetate (7.70 g, 0.10 mol) in ethanol (200 mL). Add 3 A molecular sieves (2.0 g), benzaldehyde (10.61 g, 0.10 mol) and diethyl phosphite 25 (13.81 g, 0.10 mol) at room temperature. 

Stir the reaction mixture and heat at 60°C for 44 h and then cool to room temperature. 

Raise the pH of the aqueous solution to 11 with 2 M aqueous sodium hydroxide solution and extract with dichloromethane (3 x 200 mL). 

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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... 

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. 

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-... 

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]. 

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.

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

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. ... 

One of the very first methods for the preparation of a-aminophosphonic acids appears to be the one described by Kabachnik and Medved [8]. The Kabachnik-Fields reaction is still very useful, especially for the preparation of dialkyl 1-aminoalkanephosphonates. According to this method, a-aminophosphonates were obtained reacting ammonia, carbonyl compounds (aldehydes and ketones), and dialkyl H-phosphonate. A little later. Fields [9] presented a method of synthesis of 1-aminoalkylphosphonic acids by replacing ammonia with amine—reacting both (aldehydes and ketones) with ammonia, or amine and dialkyl H-phosphonate to give dialkyl esters of 1-aminoalkylphosphonic acid (see Appendix). Hydrolysis of the esters produced free aminoalkylphosphonic acids. Yields of aminophosphonates vary from 40 to 47%. 

Experimental results revealed that the first stage of the Kabachnik-Fields reaction, namely, the formation of a dialkyl H-phosphonate-amine complex is of critical importance for further reaction direction. Depending on the acidity-basicity relationship between the dialkyl H-phosphonate and the amine, the complex can have a structure like 1 or 2 with mutually opposite polarization of the reagents, or a relatively symmetrical and readily polarizable structure like 3 [12c],... 

The reaction rate of the Kabachnik-Fields reaction by the first mechanism (route a) can be given by the following equation ... 

An alternative reaction mechanism suggests the formation of methylenediamine in the first stage of the Kabachnik-Fields reaction [8],... 

It has been established that higher yields in the Kabachnik-Fields reaction can be achieved when secondary amines are employed. The yield of N-substituted aminomethyl phosphonates is considerably lower with primary amines because of the participation of the reaction product in further aminomethylation, leading to the substitution of the second N-H hydrogen atom with a methylphosphonate functionality [8]. 

A simple and general method for asymmetric synthesis of a-aminophosphonic acids has been introdnced, based on the Kabachnik-Fields reaction of dimethyl H-phosphonate with 2-phenyl elhanolamine [15]. 

Another interesting application is the use of the Kabachnik-Fields reaction for the preparation of cyclic aminophosphonates-l,2-oxaphospholanes and 1,2-oxaphosphori-nanes [37]. 3-Amino-3-methyl-2-ethoxy-2-oxo-l,2-oxaphosphorinane is obtained by aminophosphonylation of 5-hydroxy-2-pentanone. 

This reaction has fonnd nnmerons synthetic applications. An example of its use in polymer chemistry is shown in Scheme 12.27 [151]. The Kabachnik-Fields reaction is involved, together with a reversible addition fragmentation chain transfer (RAFT) polymerization in a one-pot system that allows the efficient preparation of poly(aminophosphonate)s under controlled radical polymerization (CRP) [152]. 

It worth to mention that despite the importance of the Kabachnik-Fields reaction, stereoselective versions for the synthesis of enantioenriched a-aminophosphonates are scarce [212, 213], and only few enantioselective examples have been published to date (for reviews on enantioselective catalytic direct hydrophosphonylations of imines, see Refs. [162a-c]). Organocatalytic examples use well-known chiral binol-derived phosphoric acid organocatalysts (Fig. 12.6,80 and 81) [214], and regarding metal catalysis, chiral scandium(III)-A,A -dioxide and... 

R. A. Cherkasov, V. I. Galkin, Russ. Chem. Rev. 1998, 67, 857-882. The Kabachnik-Fields reaction synthetic potential and the problem of the mechanism. 

Y. Zhang, Y. Zhao, B. Yang, C. Zhu, Y. Wei, L. Tao, Polym. Chem. 2014, 5, 1857-1862. One pot synthesis of well-defined poly(aminophosphonate)s time for the Kabachnik-Fields reaction on the stage of polymer chemistry. 

R. Karpowicz, J. Lewkowski, E. Mi ko, M. Zielinski, Heteroat. Chem 2014, 25, 163-170. The Kabachnik-Fields reaction accelerated in external magnetic field. 

R. Gallardo-Macias, K. Nakayama, Synthesis 2010, 57-62. Tin(II) compounds as catalysts for the Kabachnik-Fields reaction under solvent-free conditions facile synthesis of a-aminophosphonates. 

Aminoalkyl acids and their derivatives. Montchamp and coworkers have synthesized new / ,A -heterocyclic frameworks [3-hydroxy-1,3-azaphospholane (121) and 3-hydroxy-l,3-azaphosphorinane-3-oxides (122)] from readily available oo-amino-Zf-phosphinates (123)-(124) and aldehydes or ketones via the intramolecular Kabachnik-Fields reaction under thermal or microwave heating. The heterocycles constitute novel analogues of a-amino acids, which might be useful in preparation of peptidomimetics. The Kabachnik-Fields reaction has been also employed in the one-pot and solvent-free synthesis of a-aminophosphonates using commercially available titanium oxide (Ti02) as an extremely efficient catalyst. " ... 

Substituent and solvent effects on the Kabachnik-Fields reaction of the dialkyl hydrogenphosphite-cyclohexylamine-benzaldehyde system have been reported kinetic analysis shows evidence of a hydroxyphosphonate intermediate. Kinetics are also reported for several substituted benzaldehydes, probing for evidence of an alternative imine intermediate, and for salicylaldehyde, which does proceed via an imine (as the hydroxyphosphonate is unstable). When the dialkyl hydrogenphosphonate reactant is changed to a phosphonate, the rate and mechanism of the reaction are significantly altered. ... 

SCHEME 18 A heterocyclic variation of the Kabachnik-Fields reaction using cyclic amines. 

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