Ugi-type reaction

De Mello et al. have constructed a so-called pSYNTAS (miniaturized synthesis and total analysis system). The system was used to perform an Ugi-type reaction to form several a-aminoacetamides from amines, isocyanates and formaldehyde in the presence of water (Scheme 25) [56-58]. The reported system consists of a glass/silicon nanoreactor [59] in connection to a TOF-MS for the real-time online analysis of the reaction stream. Reactions were conducted in the 600 nl volume chip under continuous flow of 20-2 pl/min flow rate. Reduced flow rates resulted in increased outputs. The analyzed outlet flow showed high yields of the desired products with small quantities of starting materials and intermediates (no exact yields were reported). 

Using an efficient IBX-mediated Ugi-type reaction, Zhu and co-workers reported the synthesis of a series of 1,2-disubstituted tetrahydroisoquinolines 143 in moderate to high yields <07AG(I)5775>. To the best of the author s knowledge, this is the first example of dual acylation at the Cl position and at the N-H group of tetrahydroisoquinoline. 

A highly flexible and efficient microwave-assisted Ugi-type reaction was described by Guchhait and co-workers [139] for the generation of a library of A -fused aminoimidazoles 101 in excellent yields. A heterocyclic amidine or 2-aminopyridine was reacted with an aldehyde and an isocyanide using zirconium (IV)chloride as the catalyst and PEG-400 as the solvent. The reaction is very tolerant to the nature of the substituents of the aldehyde (Scheme 78). 

Inhibitors may also be generated by the use of molecular evolution. This technology has been successfully applied to thrombin [29]. In brief, a synthetic scheme is chosen that potentially enables the synthesis of a very large combinatorial library in this case, a three-component Ugi-type reaction was selected. A small set of molecules is synthesized with a random choice of components and tested... 

Polymer-bound isonitrile (423), obtained from TentaGel-NH2 through treatment of the resin with formic acid and acetic anhydride, followed by dehydration of the resulting formamide with tosyl chloride and pyridine, has been employed in the preparation of N-substituted amino add ester [349]. Thus, Ugi MCR, performed in the presence of an alcohol instead of the carboxylic component, gave rise to an imino-ether spedes (426). Several Lewis acids were tested in searching for optimal reaction conditions. Boron trifluoride etherate displayed the better yields in term of desired product of the Ugi-type reaction. Amino acid methyl esters (427) were thus obtained when using methanol as the alcohol component, after deavage from the resin of the intermediate imino-ethers by an acetone/water mixture (Scheme 87). 

For other selected examples of Ugi-type reactions staring from 1, n-diamines see (a) Shaabani, A. Maleki, A. Moghimi-Rad, J. (2007) Journal of Organic Chemistry, 72, 6309-6311. (b) Krasavin, M. Parchinsky, V. (2008) Synlett, 645-648 (c) Kysil, V. Tkachenko, S. Khvat, A. Williams, C. Tsirulnikov, S. Churakova, M. Ivachtchenko, A. (2007) Tetrahedron Letters, 48, 6239-6244. 

Scheme 24.25 Catatytic as54iunetric Ugi-type reaction with acyclic azomethine imines.

The Smiles rearrangement was recendy involved in an Ugi-type reaction described by El Kaim... 

New synthetic methods for benzodiazepine synthesis involving Ugi-type multicomponent/post-Ugi cyclization reactions continue to be of interest. Ugi reactions of indole-2-carboxaldehydes, isocyanides, amines, and 2-iodobenzoic acid derivatives led to intermediates which, with copper(I) catalysis, underwent intramolecular indole N-arylation to produce indolo-fused benzodiazepinones, such as 134 (13CC2894). 2-Azido-benzaldehyde, isocyanides, propargylamines, and nitrophenols underwent Ugi-type reaction, Smiles-type rearrangement, and intramolecular azide-alkyne cyclization to afford triazolo-fused benzodiazepinones such as 135... 

In this sense, in 2007, Suginome and coworkers developed a pioneering example of a free acid Ugi-type reaction nsing the aminoborane 1 that yielded the final amides (Scheme 7.1) [14]. In this methodology, a number of aldehydes, secondary amines, and isocyanides were mixed in the presence of aminoborane 1 at room temperature, giving the corresponding a-amino amides... 

Y. Tanaka, T. Hasui, M. Suginome, Org. Lett. 2007, 9, 4407-4410. Acid-free, aminoborane-mediated Ugi-type reaction leading to general utilization of secondary amines. 

G. Jiang, J. Chen, J.-S. Huang, C.-M. Che, Org. Lett. 2009,11, 4568 571. Highly efficient oxidation of amines to imines by singlet oxygen and its application in Ugi-type reactions. 

T. Hashimoto, H. Kimura, Y. Kawamata, K. Marnoka, Angew. Chem. Int. Ed. 2012, 51, 7279-7281. A catalytic asymmetric Ugi-type reaction with acyclic azomethine imines. 

The only reaction which allowed introducing fluorine atom at position 5 of indoli-zine ring was the Ugi-type reaction [48], The resulting 5-fluoroinolizine 58 was sensitive to nucleophiles giving rise to mini-library of 5-subsituted derivatives. 

A four component Ugi-type reaction was employed for the synthesis of a range of dipeptides 383 with diastereomeric excesses of 92 to >99%, although the compounds described all retained the sugar auxiliary (Scheme 60). ... 

Ddmling and coworkers adapted a four-component Ugi-type reaction sequence to the synthesis of highly substituted 3-pyrrolin-2-ones (Scheme 104 20040L39). The combination of aUyl isocyanide (395), primary amine 396, a-phosphonoacetic acid 397, and a-ketoaldehyde 398 gives the 5-carboxamido-3-pyrrolin-2-one 399. The two-step process involves an Ugi multicomponent reaction followed by an intramolecular Homer/ Wadsworth/Emmons cycHzation. 

To overcome this limitation, we have reasoned that a compound (which we write in the generic format as Z-X) composed of an electrophile (Z) and a nucleophilic group (X) could essentially perform the same function as the carboxylic acid in an Ugi-type reaction (Scheme 11.7). Based on this hypothesis, we have previously developed a chlorosilane-promoted addition reaction of isocyanides... 

Toward the synthesis of heterocycles utilizing isocyanide, this concept was expanded to the intramolecular trapping of the nitrilium intermediate in the Ugi-type reaction. When a molecule contains both an electrophile (C=N) and a potential nucleophilic group (Nu ), intramolecular trapping of the nitrilium intermediate could be readily realized relative to the intermolecular version (Scheme 11.8). Based on this hypothesis, we chose A -acyl azomethine imine as an isocyano-phile, which is an extended conjugated 1,3-dipole and could function as a 1,5-dipole to afford the corresponding heterocycles (Figure 11.7). 

A three-component Ugi-type reaction using A/ -alkylbenzohydrazide (instead of amine) has been catalysed by an axially chiral binaphthyl dicarboxylic acid and found to proceed with up to 93% ee with an acyclic azomethine imine. Stereoselectivity of a Ugi reaction starting from an oxanorbornenone / -amino acid, R CHO, and RNC has been improved through solvent selection. ... 

---