Isocyano amides

Among the a-acidic isocyanides, isocyano esters (1) (for the first isolated example of a-acidic isocyano ester see [24]), isocyano amides (2) (for the first isolated example of a-acidic isocyano amide see [25]), and arylsulfonyl methyl isocyanides (3) (for the first report of TosMlC see [26]) have been studied predominantly, and therefore this mini review will mainly focus on the MCRs involving these species. 

Fig. 3 General methods for the preparation of isocyano esters (1), isocyano amides (2), and arylsulfonyl methyl isocyanides (3) (R = afkyl and/or H)...

Monoalkylation of isocyano amides can be accomphshed by a Michael reaction with an ot,p-unsaturated ketone in the presence of a catalytic amount of tetrabuty-lammonium fluoride (TBAF) in THF, as indicated by Ito in 1989 [31]. In addition, Zhu recently reported the selective monoalkylation of isocyano amides by using Cs0H-H20 (1.5 eq.) in MeCN at 0°C [32]. A slight excess of alkylating agent (1.2 eq.) can be used under the optimized conditions, which generates the mono-alkylated products for a wide range of primary halides (X = Br or 1) after 24 h. 

Formamido esters and amides can be generated in two steps starting from (natural) a-amino acids (7). Owing to the wide availability of optically pure formamides, the s)mthesis of optically pure a-substituted a-acidic isocyano amides (2) and esters (1) has been envisioned using the dehydration route. 

The synthesis of a-chiral isocyano amides has also been reported using various dehydration methods [47, 53-66]. Because of the lower acidity of the a-proton in a-isocyano amides, high stereoinductions can be obtained using relatively harsh dehydration methods (POCls/EtsN, —20°C) [62]. However, the triphosgene/NMM protocol remains the method of choice [53]. 

Fig. 12 Formation of A-(cyanomethyl)amides in the MCR between primary isocyano amides, aldehydes/ketones, and amines...

Fig. 15 Formation of 5-iminooxazolines (42) by the MCR between a,a-disubstituted isocyano amides (41), aldehydes, and amines...

In 2007, Tron and Zhu reported the multicomponent synthesis of 5-iminoox-azolines (42) starting from a,a-disubstituted secondary isocyano amides (41), amines, and carbonyl components (see Fig. 15) [155]. The reaction presumably follows a similar mechanism as in the 2,4,5-trisubstituted oxazole MCR (described in Fig. 11) however, because of the absence of a-protons at the isocyano amide 41, the nonaromatized product is obtained. As in the 2,4,5-trisubstituted oxazole MCR, toluene was found to be the optimal solvent in combination with a weak Brpnsted acid. The reaction was studied for a range of aldehydes and secondary amines. In addition, a variety of functionalities such as acetate, free hydroxyl group, carbamate, and esters are tolerated. Clean conversions were observed for this MCR as indicated by NMR analysis of the crude products (isolated yield 50-68%). The... 

The structural diversity (and complexity) of the products obtained by the MCR between tertiary isocyano amides, aldehydes, and amines could be increased to various heterocyclic scaffolds by combining the initial 2,4,5-tiisubstituted oxazole MCR with in situ intramolecular tandem processes (Fig. 17). Most tandem processes reported are based on the reactivity of the oxazole ring toward C=C or C=C bonds in hetero Diels-Alder reactions followed by ring opening reactions generating the rather complex heterocyclic products with high degrees of variation. 

Fig. 18 Suggested reaction mechanism for the construction of pyrrolo[3,4-h]pyridme-5-ones (50) from the MCR between isocyano amides, aldehydes, amines, and acryloyl chloride derivatives...

Fig. 22 Possible reaction paths for the reaction between a-acidic isocyano amides (2 or 31), primary amines, and carbonyl components, including the Ag catalyzed formation of 2//-2-imidazolines (65)...

Recently, our group also contributed to CBD as a tool for DOS. By judicious selection of the reaction conditions, the 3CR between ot-acidic isocyanides 145 (isocyano amides and isocyano esters " ), carbonyl components 6 and primary amines 146 could be directed towards either 2//-2-imidazolines 150 or trisubsti-tuted oxazoles 152 (Scheme 13) [98]. 

It has to be noted that the formation of oxazoles using isocyano amides has been well studied by Zhu and co-workers (see [58, 59]). With the work of Elders et al. the oxazole MCR has been expanded with a wide range of isocyano esters. The MCR with isocyano amides can now also he directed to the 2-imidazolines. 

The possibility of obtaining scaffold diversity by the MCR strategy has been further demonstrated using the M-(cyanomethyl)amide 3CR [60] (discussed earlier) as the primary MCR [103]. By applying the primary a-isocyano amide derivative of 176, this MCR could be connected to the Passerini, the Ugi and the Ugi Smiles [106, 107] MCRs resulting in various new scaffolds. 

Metal chelates that find use as aldol reaction catalysts are further exemplified hy the A1 complex of salen 60, which brings together a-isocyano amides and aldehyds to provide chiral 2-(a-hydroxyalkyl)-5-aminooxazoles. ... 

Stylotelline (23) is a constituent of a Stylotella sp. collected offshore in New Caledonia. 13C NMR spectra involving 2D NMR techniques provided the bulk of information leading to its structure. The absolute configuration was demonstrated after the tertiary isocyano group was removed to yield the known conjugated diene, ( + )-d-selinene (24). Optical rotation and spectral data of the transformation product were identical in all respects to those of the corresponding product obtained from eudesmols [42], Although neither the isothiocyanato nor the formamido compounds were isolated, the latter was prepared, which allowed an nOe observation between the axial C-3 and the amide protons. 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

Finally, isocyano esters can be converted to the corresponding amides upon treatment with an amine (typically just stirring in MeOH) [32, 43, 47, 67-71]. Although this procedure (path D) works well for a,a-unsubstituted isocyano esters and for a wide variety of primary and secondary amines, steric bulk around both the a-carbon and the amine component should be avoided. 

The same group further developed the asymmetric aldol reaction of A -methoxy-A -methyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Sch. 25). The reaction of the Weinreb amide 96 with acetaldehyde in the presence of 86c Au(I) catalyst gives the optically active tram-oxazoline 98 (E = CON(Me)OMe R = Me) with high diastereo- and enantioselectivities similar to those of 95 [49], The oxazoline can be transformed into A,0-protected /3-hydroxy-a-amino aldehydes or ketones. 

Some multicomponent syntheses of trisubstituted oxazoles were described. a-Isocyano-a-alkyl(aryl)acetamides, as 131 <05S161>, was demonstrated to be a useful starting material for a three-component reaction involving isoquinoline 129 <05SL532>. A four-component synthesis was also published starting from an aldehyde, a silylamide, an acyl chloride and a terminal acetylene derivative. The overall process is a modification of a four-component synthesis of a propargylic amide 134 which can be eventually isolated <05T 11317>. 

This consideration led us to perform the same reaction as described by Mat-sumoto but using a-isocyanoacetamide 23 [22] instead of the a-isocyanoacetate as a reaction partner. As shown in Scheme 15.10, the reaction indeed proceeded in a completely different way to afford 5-aminooxazole 24 in excellent yield [23]. We hypothesized that, under these mild conditions, the deprotonation of a-proton of amide 23 did not occur. Consequently, the sequence is initiated by a nucleophihc addition of the isocyano carbon to the in situ generated imine 19 and led to the nitrilium intermediate 25, which was in turn trapped by the amide oxygen to... 

Ganem and co-workers have developed the use of a Zn(OTf)2/TMSCl system to promote a variety of Passerini-type processes. The combination is active even for a,P-unsaturated aldehydes and usually problematic ketones. The promoter system was developed around a strategy of tethering nucleophilic functional groups to the isonitrile component to intercept the transient nitrilium species internally. Depending on the attached functionality either the a-hydroxy amide or a substituted oxazole could be obtained in high yield. For 1-isocyano-(2-morphilino)ethane (28), the reaction with... 

In an elegant work, Kobayashi s group introduced the 1 -isocyano-2-(2,2-dimethoxyethyl)benzene (indole-isonitrile) 90, as a convertible isonitrile in the Ugi-4C-3CR, and demonstrated the selective cleavage of the resulting C-terminal amide bond [75]. To this end, a mixtnre of ammonium acetate and a y- or 8-keto acid 89 was initially reacted (Scheme 7.37). Once the imine was formed, indole-isonitrile 90 was added so that the Ugi condensation products 91 were obtained (49-77%). Then, the Ugi product 91 was successfully con-... 

Sawamura M, Nakayama Y, Kato T, Ito Y (1995) Gold(I)-catalyzed asymmetric aldol reaction of JV-methoxy-JV-meihyl-alpha-isocyanoacetamide (alpha-isocyano Weinreb amide)—an efBcient synthesis of optically-active beta-hydroxy-alpha-amino aldehydes and ketones. J Org Chem 60 1727-1732... 

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