Isonitrile convertible

Note that carbon monoxide inserts into the Zr-H bond of 1 (2 equiv.) to afford an T -formaldehydo-type complex [(Cp2ZrCl)]2(g-CH20) [200-202]. Iminoacyl zir-conocene complexes are formed after addition of 1 to isonitriles [203]. Carbon dioxide [183, 202] is reduced to formaldehyde with 1 (2 equiv.). C02-like molecules such as isocyanates RNCO [204], isothiocyanates RNCS [205], and carbodiimides RNCNR [204] are readily converted to the corresponding bidentate form-amido ligands. 

Reactions of iV-(a-aminoalkyl)benzotriazoles 898 with isonitriles catalyzed by boron trifluoride etherate give iV-(a-aminoalkylimidoyl)benzotriazoles 899 in high yield. Upon treatment with hydrochloric acid, derivatives 899 are conveniently converted to a-aminoamides 900 (Scheme 148) <2005JSC319>. 

The question of the constitution of hydrocyanic acid has already been considered (p. 139). Here it need only be remarked that the isonitriles are converted by hydrolysis into primary amines and formic acid no carbon monoxide is produced, although from the formula this might be expected. The reason for this is to be sought in the fact that the first stage in the reaction consists in the addition of water to the two free valencies of the carbon atom. The reaction must therefore be formulated thus ... 

In a dehydration reaction (Scheme 12.4), the IR band of the formamide carbonyl group at 1684 cm in (7) decreased and eventually converted to the isonitrile band at 2150 cm in (8) (Fig. 12.8). In a separate example (Scheme 12.5), the conversion of the IR band from the carbonate carbonyl group in (9) to the IR band of the carbamide carbonyl group in (10) can be monitored to assure the reaction completion (Fig. 12.9). Based on FTIR analysis, the reaction time course can be analyzed by integrating peak areas of the IR bands from the starting resin and the product. From the point of view of kinetics, the side reaction product formation can be excluded if the pseudo first order rates of the starting material consumption and the product formation are identical. 

Rikimaru K, Yanagisawa A, Kan T, Fukuyama T (2004) A versatile synthesis of a-amino acid derivatives via the ugi four-component condensation with a novel convertible isonitrile. Synlett 1 41-44... 

Linderman RJ, Binet S, Petrich SR (1999) Enhanced diastereoselectivity in the asymmetric Ugi reaction using a new convertible isonitrile. J Org Chem 64 336-337... 

Pirrung MC, Ghorai S (2006) Versatile, fragrant, convertible isonitriles. J Am Chem Soc 128 11772-11773... 

Pirrung MC, Ghorai S, Ibarra-Rivera TR (2009) Multicomponent reactions of convertible isonitriles. J Org Chem 74 4110-4117... 

Vamos M, Ozboya K, Kobayashi Y (2007) Synthesis of bicyclic pyroglutamic acid featuring the Ugi reaction and a unique stereoisomerization at the angular position by Grob fragmentation followed by a transannular ketene [2-1-2] cycloaddition reaction. Synlett 1595-1599. Kreye O, Westermann B, Wessjohann LA (2007) A stable, convertible isonitrile as a formic acid carbanion [-COOH] equivalent and its application in multicomponent reactions. S3mlett 20 3188-3192... 

Gilley CB, Kobayashi Y (2008) 2-nitrophenyl isocyanide as a versatile convertible isocyanide rapid access to a fused y-lactam (3-lactone bicycle. J Org Chem 73 4198 204 Chen JJ, Golebiowski A, Klopfenstein SR, West L (2002) The universal Rink-isonitrile resin applications in Ugi reactions. Tetrahedron Lett 43 4083 085 Hulme C, Peng J, Morton G, Salvino JM, Herpin T, Labaudiniere R (1998) Novel safety-catch linker and its application with a Ugi/De-BOC/Cyclization (UDC) strategy to access carboxylic acids, 1, 4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroqui-noxalinones. Tetrahedron Lett 39 7227-7230... 

Hulme C, Peng J, Tang S-Y, Bums CJ, Morize I, Labaudiniere R (1998) Improved procedure for the solution phase preparation of 1, 4-benzodiazepine-2, 5-dione libraries via Armstrong s convertible isonitrile and the Ugi reaction. J Org Chem 63 8021-8023... 

Hulme et al. describes the use of a convertible isonitrile for the generation of a ketopiperazine library (Scheme 12) [32]. Using a mono-A -Boc diamine 68 in the classical Ugi reaction followed by Boc deprotection and base-facilitated cyclization (3 steps, 1 pot) afforded the ketopiperazine 72 in relatively high yields. 

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). 

Scheme 13 Use of a convertible isonitrile to form a 2,5-DKP and two representative 3D conformations of 79A (blue) and 79B (cyan). Yield shown represents yield over all steps...

Hulme C, Morrissette MM, Volz FA, Bums CJ (1998) The solution phase synthesis of diketopiperazine libraries via the Ugi reaction novel application of Armstrong s convertible isonitrile. Tetrahedron Lett 39(10) 1113-1116... 

Fig. 3 The three most common modes to activate linear Ugi-products for cyclization, especially if the cyclization involves Ugi-reactive groups (e.g., acid, oxo-compound, or amine). Activation is mostly achieved with convertible isonitriles, i.e., activated amides (see text). Other MCRs follow similar concepts. With orthogonal second functionalities for cyclizations such deprotection and/or activation is not required (see below, e.g., RCM or cycloadditions)...

One of the pioneer works in the synthesis of DKPs through MCRs was reported by Hulme and coworkers in a three-step solution phase protocol based on UDC [33, 34]. They have obtained a series of different DKPs by reacting Armstrong s convertible isocyanide with aldehydes, M-Boc-protected amino acids as bifunctional acid component containing a protected internal amino nucleophile, and amines in methanol at room temperature. After Ugi-reaction, the isonitrile-derived amide is activated with acid (UAC) and allows cyclization to the DKP with the... 

Krasavin et al. described the synthesis of dihydropyrazol pyrazine diones via Ugi-4CR, employing ferf-butyl isocyanide as a convertible reagent [102], The authors reported that, under microwave irradiation, the ferf-butyl isocyanide behaves similar to Armstrong s isocyanide, furnishing the DKPs in good yields. It is noteworthy that the low priced isonitrile applied may be helpful for developing large-scale syntheses in the future (Scheme 6). 

Recently, a combination of the UAC and UDC protocols was reported by Wessjohann s group [40]. In this work, the acid-activated, well-behaved 1-iso-cyano-2-(2,2-dimethoxyethyl)-benzene was employed as convertible isocyanide in an Ugi-4CR [41]. The advantage of this one-pot procedure is the in situ deprotection of the W-protected amino acid along with the simultaneous activation of the isonitrile-bom carboxylate, enabling the nucleophilic attack of the free amine... 

The following are some examples of reactions which have produced vinylidene complexes but are either not of general application or have not been further developed. Oxygen atom transfer occurs in reactions of NbH (t] — OC — CPh2) Cp 2 with nitriles or isonitriles to give isocyanates and Nb(=C=CPh2)Cp 2 [260]. Metathesis of Ph(R) C=C=NPh (R = Me, aryl) with W(=CHPh)(CO)5 proceeds via W C(NPh=CHPh)=C (R)Ph (CO)s, which is converted to W =C=C(R)Ph (CO)5 by treatment with BF3. OMe2 [261]. 

The solid-supported reagent, 2, was subsequently used to convert isothiocyanates to isonitriles (Scheme 5.7). Primary, secondary and tertiary alkyl isocyanides, as well as aromatic analogues were synthesised using this microwave assisted methodology. Isocyamide products were produced in excellent yields and high purity in 30 min to 2 h at 140°C. 

NMR studies on Cp2Fe2(CO)2(CNMe)2 (186). As a consequence of these rules the six possible isomers of this complex (excluding optical isomers) (Fig. 3) should interconvert in two definite sets (26, 28, and 30 27, 29, and 31) in which it is not possible to convert members of the one set into members of the other set (assuming that there is no intermediate nonbridged structure with both isonitriles on the same metal atom). The NMR observations were in keeping with these predictions. 

According to Scheme 4 elimination of a proton from the iminodiazonium ion (I) forms the nitrile. Rearrangement of the ion (I) leads to formanilide. But there are no data available supporting these ideas. Another possible way for the formation of nitrile is a rearrangement of the iminocarbonium ion (II) of the type which occurs in the isomerization of isonitriles to nitriles". It was found that in 71.2-90.4% sulphuric acid, phenyl isocyanate is converted quantitatively into formanilide. For a better understanding of the... 

Ley and Taylor17 reported a polymer-supported oxazaphospholidine to convert isothiocyanides to isonitriles for subsequent application in Ugi three-component coupling reactions (entry 13). This method affords clean isonitriles and facilitates the handling of a toxic and unstable reactant. 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

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