Armstrong convertible isocyanides

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... 

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). 

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. 

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

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). 

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 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 selected examples by Keating and Armstrong [59, 60] reported the synthesis of a small discrete solution library (eight compounds) of Ugi 4CC products and their further elaboration. The concerted mechanism of the Ugi 4CC is shown in Figure 7.5. The scarcity of commercial isocyanides encouraged the use of a convertible isocyanide [59, 60], which allowed its postcondensation transformations in other functional groups, which are shown in Figure 7.6. 

Figure 3-11 four-component Ugi reaction reported by Keating and Armstrong. A combinatorial mixture of the intermediate cyclohexenyl amide can be split into several portions, and each can be further reacted to give a variety of products, all of which will be combinatorial. (Reaction redrawn from description from Keating. T. A., and Armstrong. R. W Molecular diversity via a convertible isocyanide in the Ugi four-component condensation J. Am. Chem. Soc. 117 7842-7843. 1995.)... 

In 1995, Keating and Armstrong reported their combinatorial synthesis of benzodiaze pines by their convertible isocyanides [131]. An anthranilic acid reacts with cyclohexeny isocyanide, and an oxo-component by a U-4CR. Under acidic conditions, a Munchnom intermediate results and subsequently a benzodiazepine is formed. 

TA Keating, RW Armstrong. 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 118 2574-2583, 1996. 

A. M. Strocker, T. A. Keating, P. A. Tempest, R. W. Armstrong, Use of a convertible isocyanide for generation of Ugi reaction derivatives on solid support synthesis of a-acylaminoesters and pyrroles. Tetrahedron Lett. 1996, 37, 1149 1152. 

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