Convertible’ isocyanide

Such a strategy follows the philosophy of resin capture, as introduced by Armstrong and Keating Keating TA, Armstrong RW. Postcondensation modifications of Ugi four-component condensation products 1-isocyano-cyclohexane as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 1996 118 2574-2583. See also Brown SD, Armstrong RW. Synthesis of tetrasubstituted ethylenes on solid support via resin capture. J Am Chem Soc 1996 118 6331-6332. 

Benzodiazepinediones 15 have been synthesized starting from anthranilic derivatives 13 and Armstrong convertible isocyanides 1. When the amino group of 13 is secondary, it does not interfere too much with the Ugi reaction, and the acid... 

Diketopiperazines 17 and ketopiperazines 19, which are important privileged structures, have been obtained by using various convertible isocyanides and by introducing the additional amino function, respectively, on the carboxylic [39] or amine component [33]. 

The use of convertible isocyanides is not always necessary in particular cases, also normal alkyl [32,40] or aryl [30] isocyanides have been employed for this task. For example, microwave irradiation of the Ugi adduct 16 (R = uBu) at 120°C in the presence of 10% CF3CO2H gave the desired diketopiperazines 17 in good yield, without the need to use more complex convertible isocyanides. However, for the synthesis of ketopiperazines 19, butyl isocyanide was found to be unsuitable. 

While in most reported cases the nucleophiles were amines, there were few examples involving heterocyclic nitrogens [40], alcoholic oxygens [27] or carbon nucleophiles [42, 43] too. Figure 4 shows a recent example of tandem Ugi-Dieckmann protocol [42]. Ugi convertible isocyanide 2, which requires a basic activation, was used, allowing a domino activation-cyclization of the intermediate 20 to give pyrrolidinediones (tetramic acids) 22. 

Although diketo- and ketopiperazines can be formed by coupling the Ugi reaction with an intramolecular acylation using convertible isocyanides, as described earlier, the approach that involves Sn2 reactions enables the introduction of an additional substituent R avoiding the loss of the diversity carried by the isocyanide. 

We have previously seen how cyclic lactams can be synthesized by installing a protected amine in one of the Ugi or Passerini components, followed by cyclization onto the isocyanide-derived amide, taking advantage of the particular reactivity of convertible isocyanides. The same type of compounds can be accessed through nucleophilic attack of the amine onto an ester moiety, suitably installed as additional function into another component. This strategy has been widely used for the preparation of diketopiperazines 104 (Fig. 22), a typical privileged structure, starting with... 

Keating TA, Armstrong RW (1995) Molecular diversity via a convertible isocyanide in the Ugi four-component condensation. J Am Chem Soc 117 7842-7843... 

Lindhorst T, Bock H, Ugi I (1999) A new class of convertible isocyanides in the Ugi four-component reaction. Tetrahedron 55 7411-7420... 

Gilley CB, Buller MJ, Kobayashi Y (2007) New entry to convertible isocyanides for the ugi reaction and its application to the stereocontrolled formal total synthesis of the proteasome inhibitor Omuralide. Org Lett 9 3631-3634... 

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... 

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 12 Use of a convertible isocyanide for synthesis of DKP s. Two examples of ketopiper-azlnes derived from use of convertible isocyanide and two representative 3D conformations of 72A (blue) and 72B (cyan). Yield shown represents yield over all steps...

Another macroarray study was described by Campbell et al. using an amino acid bound to the support via the carboxyl group 143 (Scheme 24) [47]. This allows for two more points of diversity as opposed to the above scaffold allowing for a substitution on the amino acid as well as an isocyanide, as the convertible isocyanide is no longer needed. Isolated yields were in the range of 82-99%. 

Dihydropyrazolo[l,5-a]pyrazine-4,7-diones 205 were synthesized by Nikulnikov et al. using tcrt-butyl isocyanide 209 as a convertible isocyanide [62]. The Ugi reaction of tert-butyl isocyanide and pyrazole-3-carboxylic acids 208 with various aldehydes 206 and amines 207 yields tert-butyl amides 210, which undergo cycli-zation into glacial acetic acid under microwave irradiation (Scheme 37). 

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... 

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... 

Keating, T. A. Armstrong, R. W. Postcondensation Modifications of Ugi Four-Component Condensation Products 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture, J. Am. Chem. Soc. 1996, 118, 257. 

The convertible isocyanide also enables transformation of the secondary amide in the Ugi product to a carboxylic acid, ester, or thioester, which is thus amenable to further functionalization. The aforementioned templates are all readily accessible via manufacture in 96-well plates using 96-well plate liquid handlers. The initial condensations are optimal with excess aldehyde (2 equiv.), which can be subsequently removed via a simple scavenging and filtration step with PS-TsNHNH2.18 Several universal resin-bound isocyanides have also been developed to exploit UDC methodology for the generation of the above heterocyclic products. 

The UDC concept can be further extended by application of ethyl glyoxylate (a convertible aldehyde ). Simple reaction of 48 in the Ugi MCR with /V-Boc anthranilic acids, /V-Boc-rt-amino acids, mono-A-Boc diamines, and niono-A-Boc phenylenediamines, followed by acid treatment and in some cases proton scavenging, affords 1,4-benzodiazepines 49, diketopiperazines 50, ketopiperazines 51, and dihydroquinoxalinones 52, respectively.25 Note that products differ from those obtained from convertible isocyanides in that they contain an additional exocyclic amide... 

Cyclohexen-l-yl isocyanide 1 known as Armstrong convertible isocyanide has also been called universal isocyanide . It was prepared in 1963 by Ugi and Rose-ndahl [5] to be used as a synthetic equivalent of the unknown hydrogen isocyanide . The Ugi-4CR between 1, cyclohexanone N-benzylimine 2, and formic acid afforded N-cyclohexen-l-yl amide 3, which was cleaved in acidic medium to afford the primary a-acylamino amide 4 rather than the N-substituted amides usually obtained by the Ugi-4CR (Scheme 2.1). 

The Ugi group has designed a new class of convertible isocyanides, namely alkyl 2-isocyano-2-methylpropyl carbonates [7], prepared from commercially available 4,4-dimethyl-2-oxazoline. The Ugi-4CR of 11 afforded the expected products 12, which were converted into N-acyl a-amino acid esters 13 and N-acyl a-amino acids by in situ hydrolysis (Scheme 2.5) [7]. 

In general, the hydrolysis of amides requires conditions that are not compatible with the survival of several functional groups [10]. If the amide nitrogen is linked to an electron-withdrawing moiety, alkaline hydrolysis of the amide group is easier. Following this observation Martens and co-workers used 4-methoxy-2-nitrophenyl isocyanide 14 (or 2-methoxy-4-nitrophenyl isocyanide) as a convertible isocyanide for the preparation of Peptide Nucleic Acid (PNA) monomers [8a] (for another example, see Ref. [11]). The Ugi-4CR between isocyanide 14, carboxymethyl nucleo-... 

Another interesting convertible isocyanide, 2-(t-butyldimethylsilyloxymethyl)-phenyl isocyanide 21 was used by Linderman and co-workers [10] in a reaction with formic acid, benzylamine, and benzaldehyde to afford the Ugi adduct 22, which, upon acid treatment followed by basification, underwent O-desilylation and amide/ester exchange to afford the ester 23 (Scheme 2.8). A remarkable feature of 21 is the high diastereoselectivity observed when it is employed in combination with chiral aminosugar derivatives in Ugi-4CR [10]. 

The use of resin-bound convertible isocyanides such as the universal Rink isocyanide-resin [18], the safety-catch linker isocyanide-resin [8b, 19] the cyclo-hexenyl isocyanide-resin [8b], and the carbonate convertible isocyanide-resin [20] has found interesting applications in solid-phase Ugi-4CR and post-condensation transformations [21] (Scheme 2.9). 

Cyclohexenyl Isocyanide-resin Carbonate Convertible Isocyanide-resin... 

The Hulme group has reported two three-step, one-pot solution-phase procedures for the preparation of 2,5-diketopiperazines, based on the UDC strategy. The first method [74a] used ethyl glyoxylate as a bifunctional carbonyl input in an Ugi-4CR with amines, isocyanides, and N-Boc a-amino acids that afforded adducts 121, which were N-deprotected and cyclized to the desired products 122 (Scheme 2.44). The second method [8c] used Armstrong s convertible isocyanide 1 in a reaction with N-Boc a-amino acids, aldehydes, and amines that afforded products 123, which were deprotected and cyclized to diketopiperazines 124 (Scheme 2.44). 

The Kennedy group at Array BioPharma described an elegant synthesis of 2,5-diketopiperazines employing the resin-bound carbonate convertible isocyanide (CCI resin see Scheme 2.9) [20], Ugi products 133 were converted into esters 134 and then deprotected and transformed into diketopiperazines 135 (Scheme 2.48). 

Scheme 2.48. Diketopiperazines from carbonate convertible isocyanide resin.

Another example was reported by Ugi and co-workers in a study concerning the synthetic applications of convertible (jS-isocyanoethyl)alkyl carbonates [7a]. A solid-phase extension of the same procedure has been reported by the Kennedy group [20] at Array BioPharma who employed the resin-bound carbonate convertible isocyanide. 

A solid-phase extension of the UDC strategy for the preparation of highly pure and diverse arrays of l,4-benzodiazepine-2,5-diones has been reported. The method employed Wang resin-bound a-amino adds [75]. Another interesting solid-phase synthesis of l,4-benzodiazepine-2,5-diones was reported by Chen et al. [18b] that employed the Rink-isocyanide resin as the convertible isocyanide. 

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