Kabachnik-Fields reaction compounds

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 ... 

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. 

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. 

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]. 

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%. 

Kabachnik-Fields reaction is a three-component reaction between a carbonyl compound (ketone and aldehydes), an amine, and a dialkyl phosphite [144] to form a-aminoalkylphosphonates 79 (Scheme 12.26). It was first described in 1952 independently by Kabachnik [145] and Fields [ 146]. This reaction constitutes a general and effective method for the synthesis of a-amino phosphonates, which, in the last five decades, have danonstrated to be a kind of compounds of relevance. 

B. Saritha, S. J. Prakash, Synlett 2003, 505-506. Solvent and catalyst free three-component coupling of carbonyl compounds, amines and triethylphosphite a new synthesis of a-aminophosphonates. (c) M. M. Kabachnik, E. V. Zobnina, I. P. Beletskaya, Synlett 2005, 1393-1396. Catalyst-free microwave-assisted synthesis of a-aminophosphonates in a three-component system RjC(0)R2-(Et0)jP(0)H-RNH2. (d) X.-J. Mu, M.-Y. Lei, J.-P. Zou, W. Zhang, Tetrahedron Lett. 2006, 47, 1125-1127. Microwave-assisted solvent-free and catalyst-free Kabachnik-Fields reactions for a-amino phosphonates. (e) G. Keglevich, A. Szekrenyi, Lett. Org. Chem. 2008, 5, 616-622. Eco-friendly accomplishment of the extended Kabachnik-Eields reaction a solvent- and catalyst-free microwave-assisted synthesis of a-aminophos-phonates and a-aminophosphine oxides, (f) K. U. Maheswara Rao, G. R. Devi, N. J. Reddy, P. Santhipriya, C. S. Reddy, Phar. Chem. 2010, 2, 51-57. Uncatalyzed three component synthesis and anti-microbial activity of a-amino phosphonates. 

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. 

To furnish a convenient reaction platform, polymer chemists have explored the utility of non-isocyanide-based MCRs in order to avoid the use of isocyanides. For example, Tao and coworkers focused intensively on the employment of non-isocyanide MCRs such as the BigineUi reaction [70] and the three-compmient reaction between aldehydes, amines, and mercaptoacetic acid [71]. In additimi, the utility of the Kabachnik-Fields reaction was demonstrated independently by the groups of Theato [72] and Tao [73]. To be precise, Kakuchi and Theato showed that the Kabachnik-Fields post-polymerization modification reaction on poly(4-vinyl benzaldehyde) with amines and phosphites proceeded very efficiently to afford polymers featuring a-amino phosphonate pendant groups (Scheme 3) [72]. Furthermore, the group of Tao succeeded in synthesizing polymeric a-amino phosphonates via concurrent Kabachnik-Fields reactions of vinyl compounds and RAFT polymerization of the vinyl monomers in a one-pot process [73]. 

In the same year, Shaterian et al. also reported an eco-friendly and novel method for the synthesis of a series of such compounds from a one-pot three-component Kabachnik-Fields reaction employing nano-TiOz as an efficient and reusable heterogeneous catalyst under ambient and solvent-free conditions (Scheme 10). The method is effective and provides excellent yields of the products in a short reaction time, which makes this protocol a novel, environmentally friendly, and economically valuable process for the synthesis of this class of compounds. 

Rajasekhar et al. also synthesized a new class of diethyl a-aryl/2-thienyl-a-[2-(phenylthio)phenylamino]methylphosphonates (54) via a three-component Kabachnik-Fields reaction of 2-aminodiphenylsulfide (53), substituted phenyl/heterocyclic aldehydes (44), and diethyl-phosphate (2) in the presence of heterogeneous nano-silica-supported nano-BFs SiOa under solvent-free conditions under microwave irradiation (Scheme 25). The procedure has several advantages such as short reaction time, low loading of catalyst, good yields, and reusability of the heterogeneous silica-supported nano-catalyst. The title compounds were found to exhibit considerable in vitro antibacterial and antifungal activity. 

Cirandur and his group synthesized a new series of a-amino-phosphonates (56 and 58) via one-pot Kabachnik-Fields reactions using TiOa-SiOa as solid-supported catalyst from the reaction of naphthalene-2-amine (55)/2-aminofluorene (57), varying aldehydes and diethyl phosphate, in the absence of any solvent, under microwave irradiation (Scheme 26). The investigators screened all the synthesized compounds for their in vitro anticancer activity against two human cancer cell lines, HeLa and SK-BR-3, and a majority of them showed potent cytotoxic activity against the cancer cell lines tested. ... 

The Kabachnik-Fields reaction is a three-component hydrophosphonylation of imines formed in the reaction mixture from carbonyl compounds and amines [75]. In 2008, List and coworkers reported on such a reaction catalyzed by chiral phosphoric acids that combines a dynamic kinetic resolution with the concomitant generation of a new stereogenic center (Scheme 42.30). The resolution is possible when chiral racemic aldehydes 135 are used. This is because the imine formed in the first step of the reaction is in equilibrium with its achiral enamine tautomer, thereby racemizing the starting material continuously. Since one of the two enantiomers is selectively activated by the chiral phosphoric acid catalyst, the addition of phosphite 136 affords the exclusive formation of one diastereomer. All phos-phonate products 137 were obtained with good yields and moderate to excellent diastereo- and enantioselectivity [76]. 

Addition of Phosphorus Nucleophiles to Imines As the Pudovik and the Abramov reactions constitute phosphorus analogs of the aldol reaction, there is also a phosphorus equivalent for the Mannich reaction, namely, the Kabachnik-Fields reaction (see Scheme 47.7). In this process, phosphorus nucleophiles add to imines to produce a-aminophosphonate derivatives, which can be considered amino acid analogs. These compounds by themselves, or when incorporated into short peptides, find applications as enzyme inhibitors or as antibacterial and antifungal agents. However, in only a few instances were optically pure derivatives prepared for biological and pharmaceutical applications. Examples include the synthesis of antibiotic ala-fosfalin 82, penicillopepsin 83, and HIV protease... 

The reaction between ammonia (or a primary or secondary amine), formaldehyde and phosphorous acid is only one particular case of the Kabachnik-Medved -Fields reaction, consisting of the aminomethylation of a phosphorus species possessing a reactive P(0)H group, and so is of the Mannich type. The involvement of ammonia leads only to 226 and the intermediate aminomethylphosphonic 227 (R = H) and aminobis(methylene)bisphos-phonic acid 228 (R = H) are not isolable although they are detectable by NMR spectroscopy the sequence can be stopped at the earlier stages if a primary or secondary amine is used The use of a,co-diaminoalkanes leads to complexones of type 229 . Ethanolamine affords the related bis(phosphonic acid) 230 and diethanolamine yields 231 under similar conditions acidolysis of the linear compounds brings about their cyclization... 

The Keglevich group has continued to deal with environmentally friendly and P-heterocyclic chemistry. The solid liquid phase alkylation of P=0-functionalised CH acidic compounds was accomplished under phase transfer catalytic and microwave (MW) conditions." a-Hydroxy-benzylphosphine oxides were synthesized by the addition of diphenylphosphine oxide to the carbonyl group of substituted benzaldehydes under MW conditions." The double Kabachnik-Fields (phospha-Mannich) reaction was utilized in the preparation of bis(phosphinoxidomethyl)amines. The Diels Alder cycloadditions of 1,2-dihydrophosphinine oxides and subsequent... 

Shingare and co-workers have presented for the first time a successful implementation of ultrasound irradiation for the rapid synthesis of a-hydroxy phosphonates (521) and a-amino phosphonates (525) under solvent-free conditions from triethyl phosphite (524), aromatic aldehydes (523) and amines (522) using camphor sulfonic acid (CSA) (Scheme 130). One-pot, three-component Kabachnik-Fields synthesis of a-aminophos-phonates (529) from carbonyl compounds (526), primary amines (527), and dibenzyl/dimethyl/diethyl substituted phosphites (528) has been carried out in high yields, using H-beta zeolite as a reusable catalyst (Scheme 131). Zhang and co-workers have developed the nickel-catalysed Arbuzov type phosphonylation to afford phenyl substituted phosphonates (532) in the reaction of aryl triflates (530) with triethyl phosphite (531), in which KBr, as an additive, promoted the Sn2 catalytic step (Scheme 132). ... 

The formation of dialkyl (a-aminoalkyl)phosphonothioates (33) through the Kabachnik-Medved -Fields interaction of dialkyl hydrogenphosphonothioates and carbonyl compounds in the presence of anmionia was established in the early days of the study of that reaction, as was the formation of dialkyl [a-(arylamino)arylmethyl]phos-phonothioates (34) by the addition of (RO)2P(S)H to anils (Scheme... 

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