Kabachnik three-component

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. 

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. 

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-... 

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. 

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. 

The complex of iV,AT-dioxide (476) and Sc(III) has been applied in the three-component Kabachnik-Fields reaction of aldehydes, 2-aminophenol and diphenyl phosphite, giving the corresponding a-amino phosphonates (475) in good yields and high enantioselectivities (up to 87% ee) (Scheme 121). ... 

The synthesis of phosphinic peptides by a reverse sequence of P-C bond formation events (N+PC approach) is a less frequently applied strategy which may offer important diversification possibilities. In particular, an amidoalkylation condensation reaction between amides, aldehydes, and alkylphosphinic acids (the three-component Kabachnik-Fields reaction) affords in a single step the main pseudopeptidic backbone, thus facilitating fast screening of the nature of Pi position. In 1996, Chen and Coward observed that a mixture of benzyl carbamates, aldehydes, and alkylphosphinic acid 23 in AcCl can lead to Cbz-protected phosphinic pseudodipeptides 24 (Scheme 10a) [53]. This method was adjusted by Matziari et al. to the synthesis of Fmoc-protected phosphinic building blocks 25 and peptides thereof (Scheme 10b) [54]. 

A highly efficient solvent-free and catalyst-free method for the synthesis of a-aminophosphonates is a microwave-assisted three-component Kabachnik-Fields reaction involving aldehyde, amine, and dimethyl H-phosphonate [40]. 

Bhagat, S. and Chakraborti, A. K. 2007. An extremely efficient three-component reaction of aldehydes/ketones, amines, and phosphites (Kabachnik—Fields reaction) for the synthesis of a-aminophosphonates catalyzed by magnesium perchlorate. J. Org. Chem. 72(4) 1263-1270. 

Reductive amination of a-branched ketones and p-anisidine using Hantzsch ester as a hydride source and chiral Bronsted acid, TRIP, as a catalyst gave chiral p-branched amine (Scheme 5.17) [58]. This catalyst system was extended to three-component Kabachnik-Eields reaction, which uses phosphite as nucleophile instead of hydride, to give p-branched a-amino phosphonate [59]. Reductive ami-nation of p-keto ester or p-keto nitrile with trichlorosilane as a hydride source... 

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. 

It was not until 2011 when an enantioselective metal-catalyzed version of a real direct three-component one-pot Kabachnik-Fields reaction was published. Nakamura and Shibata developed an efficient method that allows the synthesis of chiral a-amino phosphonates 86 in good yield (up to 99%) with good enantioselectivity (up to 93% ee) using a... 

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. 

A facile and efficient one-pot three component reaction (Kabachnik-Fields reaction) for the synthesis of novel a-aminophosphonates by 1,4-dimethylpiperazine as a new catalyst. 

V. H. Tillu, D. K. Dumbre, R. D. Wakharkar, V. R. Choudhary, Tetrahedron Lett. 2011, 52, 863-866. One-pot three-component Kabachnik-Fields synthesis of a-aminophosphonates using H-beta zeolite catalyst. 

S. Rostamnia, H. Xin, N. Nouruzi, Microporous Mesoporous Mater. 2013, 179, 99-103. Metal-organic frameworks as a very suitable reaction inductor for selective solvent-free multicomponent reaction IRMOF-3 as a heterogeneous nanocatalyst for Kabachnik-Fields three-component reaction. 

N. Shibata, Adv. Synth. Catal. 2011, 353, 3285-3289. Diiect enantioselective three-component Kabachnik-Fields reaction catalyzed by chiral his(imidazoline)-zinc(II) catalysts. 

Jeong et al. reported cadmium perchlorate hydrate [CdlClOja xHjO] as a novel, expeditious catalyst for the three-component synthesis of a-amino-phosphonates via a one-pot reaction of an amine, a carbonyl (aldehyde/ ketone) and a H-phosphonate diester e.g. dimethylphosphite/diethylphos-phite) in open air in the absence of any solvent, with high yields (Scheme 17.15). This new methodology is the first example of a cadmium perchlorate hydrate-catalysed Kabachnik-Fields reaction. ... 

Zhou, X., Sang, D., Zhang, Q., Lin, L., Liu, X., Feng, X. (2009). Enantioselective three-component Kabachnik-Fields reaction catalyzed by chiral Scandium(III)-A,A7-dioxide complexes. Organic Letters, 11, 1401-1404. 

E.D. Matveeva, T.A. Podrugina, E.V. TishkoVskvaya, L.G. Tomilova, N.S. Zefirov, Anovel catalytic three-component synthesis (Kabachnik-... 

Despite the chemical complexity of multicomponent reactions (MCRs), the dawn of MCRs was fairly early in the history of organic chemistry. The first MCR was the so-called Strecker reaction discovered in 1850 [1, 2], which generates amino acids via a three-component reactiOTi between amines, aldehydes (or ketones), and hydrogen cyanide (Scheme 1). Since then, organic chemists have devoted much effort to the discovery of additional MCRs. Thus, we now can find a number of MCRs, including the Biginelli reaction [3], the Gewald reaction [4], the van Leusen three-component reaction [5], the Hantzsch reaction [6], the Mannich reaction [7], the Kabachnik-Fields reaction [8, 9], the Passerini reaction [10], the Ugi reaction [11, 12] and numerous variations thereof [13]. 

In 2013, Fang et al. prepared and utilized a biodegradable SO3H-functionalized ionic liquid (IL), 3-(iV, N-dimethyldodecylammonium)pro-panesulfonic acid ([DDPA][HS04]), as an efficient catalyst for a one-pot, three-component synthesis of a-aminophosphonates (23) from aromatic aldehydes (21), aromatic amines (22), and triethylphosphite/diethyl-phosphite at room temperature through the Kabachnik-Fields reaction under solvent-free conditions or in aqueous media (Scheme 9). 

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. 

Very recently, Varalashmi et al. prepared a new class of diethyl(3,5-di-bromo-4-hydro3g henylamino)(substituted phenyl/heterocyclic)methylphos-phonates (52) by one-pot three-component Kabachnik-Fields reactions of 4-amino-2,6-dibromophenol (51), substituted heterocyclic/phenyl aldehydes (44) and diethylphosphite (2) using hydrated ceric chloride (5 mol%) under microwave irradiation in THF (Scheme 24). The reaction is rapid and highly efficient Moreover, the investigators evaluated in vitro... 

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. 

Very recently, Gangireddy et al. elaborated the synthetic scope for the 2-aminofluorene-substituted phosphonate derivatives (58) using a variety of aliphatic/alicyclic/aromatic aldehydes via three-component one-pot Kabachnik-Fields reactions under solvent-free microwave irradiation, just replacing the catalyst with polystyrene-supported p-toluenesulfonic acid (PS/PTSA). This procedure is also a simple, high yielding, straightforward, environmentally-friendly method for the synthesis of biologically relevant a-aminophosphonate scaffolds (Scheme 27). ... 

List and coworkers reported the three-component reaction of aldehyde 16, p-anisidine (17), and di(3-pentyl)phosphite 18, namely, the Kabachnik-Fields reaction, by means of chiral phosphoric acid (Scheme 11.6) [13]. An important feature of this reaction is that catalyst If with a bulky substituent (9-anthryl group) at the para-position of the 2,6-diisopropylphenyl group had a significant effect on the enantioselectivity. The desired product 19 was obtained in 86% yield with excellent... 

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]. 

Scheme 42.30 Domino three-component asymmetric Kabachnik-Fields reaction involving a dynamic kinetic resolution for a-branched aldehydes.

Scheme 42.31 Asymmetric domino three-component Kabachnik-Fields reaction using substituted benzaldehydes and cinnamaldehydes.

The one-pot, three-component, highly diastereoselective (95 5 dr) reaction of 2-formylbenzoic acid methyl ester (477) with (5)-(479) and (i )-(480) methylbenzylamine and dimethyl phosphite (478) (the Kabachnik-Fields reaction) proceeded under solvent and catalyst free-conditions to afford the corresponding chiral (3i ,105)-(481a) and (35 ,10i )-(481b) isoindolin-1-one-3-phosphonates in good yields and with high diastereoselectivity (Scheme 119). ... 

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