Benzazetidines are highly strained and inherently unstable heterocycles. There are only few methodologies for assembling these compounds. Here, a protocol is presented to trap an elusive cyclic, 4-membered hemiaminal structure. This method affords several benzazetidine in moderate to good yields (up to 81%), it uses inexpensive materials and does not require catalysts based on transition metals. The high ring strain energy of these benzazetidine systems was estimated by DFT calculations to be about 32 kcal mol-1. This synthesis can be applied also on gram scale with reaction yield essentially unchanged.

A common problem encountered in enantioselective organocatalysis is the aggregation of the catalyst, which can result in a relevant decrease of the efficiency and selectivity of the process. In the asymmetric synthesis of chiral benzofuranones, recently reported by us, we noted a remarkable increase of the reaction yield upon the addition of one of the reagents in a portionwise manner rather than in a single addition. We investigated this phenomenon by several experimental techniques such as 1D and 2D NMR experiments, UV-Vis spectroscopy, circular dichroism and dynamic light scattering. In addition, we studied the kinetic profile of this reaction using a simple numerical model and carried out in silico investigations. All these different approaches point to the conclusion that in the reaction medium a supramolecular polymerization/aggregation phenomenon, based on weak interactions, occurs and such a process is promoted by a quinone, which is one of the reagents of the benzofuranone synthesis. The portionwise mode of addition is a known strategy which can improve the performance of many synthetic procedures and this strategy is commonly adopted on account of empirical experience. However, our results provide an explanation, based on a chemical kinetic model, of the reason why the portionwise addition affects in such a dramatic way the yield of the benzofuranone synthesis catalyzed by Cinchona alkaloids.

The organocatalyzed addition of several malonates to 1,4-benzoquinones affords benzofuranones bearing a quaternary stereocenter with good enantioselectivity. This reaction is an intramolecular desymmetrization since it proceeds through the formation of an arylated achiral malonate that cyclizes to give the reaction product. The addition rate of the quinone dramatically affects the reaction yield which was originally low. The yield was considerably increased, in some cases, from less than 20 % to over 95 %, by adding the quinone in portions rather than at once, keeping similar enantioselectivity. A possible rationalization for the preferential formation of the indicated enantiomer has been investigated by DFT calculations.

Benzazetidines are a class of N‐heterocycles potentially very interesting for a variety of purposes, including biological applications and drug design. In the past, their high ring strain has hampered the development of trustable, general, and efficient synthetic methodologies for their preparation. In this review article, the aim is to disclose all the literature contributions about the synthesis of these compounds and the study of their reactivity, from the early examples to the most recent synthetic approaches. Recently, there has been a growth of interest for this heterocycle, driven by the publication of novel synthetic methodologies based on palladium‐catalyzed intramolecular C−H amination and organocatalyzed ring‐closure of 2‐(N‐Boc‐anilino)‐α‐ketoesters/amides.

4‐dimethylaminopyridine (DMAP) is an extremely versatile catalyst active in a large series of chemical transformations because of its relevant basicity and nucleophilicity. In this paper, we present the synthesis of two chiral DMAP derivatives starting from 4‐halopyridine and l‐proline benzyl ester. The key steps of these preparations are a ZnII‐coordinated dimer of proline ester and a variation of the Buchwald‐Hartwig promoted by copper(I) salts. The preparation of these compounds was achieved with the use of inexpensive materials and facile procedures and does not require the use of any catalyst based on transition metals. In addition, these procedures open up the way for the preparation of a large variety of chiral DMAP organocatalysts. Their catalytic activity was tested in t‐butoxycarbonyl transfer reactions, chosen as a benchmark because these transformations potentially profit from the presence of a nucleophilic catalyst. The kinetic resolution of alcohols and the enantioselective preparation of benzazetidines, in some experiments, was achieved with a noticeable enantiomeric ratio.