Versatile Scope of a Masked Aldehyde Nitrone in 1,3-Dipolar Cycloadditions

Abstract

A new masked aldehyde-containing nitrone 1 that is easily available through a facile one-step procedure has been developed. It undergoes a [3 + 2]-thermal cycloaddition with a wide range of dipolarophiles, affording isoxazolidine cycloadducts that are suitable for versatile postcycloaddition modifications. The acetal cycloadducts are acid-stable, but allow for acetal hydrolysis under mildly basic conditions. The isoxazolidine ring can be opened via an efficient one-pot procedure to give amine-protected γ-alcohols that can be further converted to furanose derivatives.

1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides with Carbonyl Dipolarophiles Yielding Oxazolidine Derivatives

“…Cycloaddition of trans-azomethine ylide 24, generated from 2-benzoylaziridines 23, to aldehydes 2. When trichloroacetaldehyde (2g) was used as the dipolarophile, the corresponding trans-4,5-oxazolidines 25k-o were obtained exclusively (Table 2, Entries [11][12][13][14][15]. The orientation of the addition was confirmed by specific deuterium-labelling experiments, and the preference for the trans-4,5-isomer was rationalized by considering that the intermediate cis-and trans-azomethine ylides had time to equilibrate to mostly the more stable trans-azomethine ylide 24 prior to addition (owing to the sluggish dipolarophilic activity of the carbonyl bond).…”

“…The reaction involves the addition of 1,3-dipoles, such as azides, nitrones, carbonyl ylides, nitrile oxides, nitrile imines and azomethine ylides to unsaturated double or triple bonds (1,2-dipolarophiles) [8][9][10][11][12][13][14][15]. Azomethine ylides 1, which contain four electrons distributed over the π orbitals of a C-N-C group, are examples of the bent allyl anion-type of 1,3-dipole [16][17][18].…”

“…Furthermore, hydrolysis of the oxazolidine products 6 leads to 1,2-ethanolamines 8, the substructure of which can be found in a wide array of compounds of natural and synthetic origins, e.g., halostochine (9), epinephrine (10) and salbutamol (11) (Figure 1a) [43][44][45]. Finally, the oxazolidine ring is a core substructure of bioactive compounds of pharmaceutical and agrichemical interest, such as cycloclenbuterol (12), famoxadone (13) and anacetrapib (14) (Figure 1b) [46][47][48]. Herein, we provide a comprehensive review of the 1,3-dipolar cycloaddition reactions of azomethine ylides and carbonyl dipolarophiles and note interesting reactions of the oxazolidine products.…”

Beyond the Alternatives that Switch the Mechanism of the 1,3-Dipolar CyCloadditions from Concerted to Stepwise or Vice Versa: A Literature Review

“…About five years later, Ueber (alkyl azides) [19], and Pechmann (diazoalkanes) [20], in two separate works, reported two new 1,3-dipolar cycloadditions. Beckmann (1890) [21], and Werner and Buss (1894) [22], discovered azomethine oxides (nitrones), and nitrile oxides, respectively, which were then widely applied as 1,3-dipoles, in the dipolar reactions (for example [23,24]). Forty years later, by publishing the first review on the 1,3-dipolar cycloaddition in 1938, Smith widely introduced this reaction as a new approach for synthesising five-membered ring heterocyclic compounds [25], however, the applicability of the 1,3-dipolar reaction as an approach to synthesis was limited [26].…”

Five-Membered Ring Systems With O and N Atoms

“…Nitrone 76, a stable solid compound that can be easily prepared on a multigram scale, smoothly reacts with alkenes to give isoxazolidines featuring a masked aldehyde group at C-3 position such as 77 (15OL5550). Tricyclic isoxazolidine 79 was synthesized through a highly regio-and diastereoselective tandem nitrone formation/intramolecular 1,3-DC starting from piperidinone 78 and then converted into the rigid scaffold 80 containing three points of diversity.…”