Synthesis of Four- to Seven-Membered Heterocycles by Ring Expansion: Ring Expansions of Thiiranes and Thietanes

Abstract

Thiiranes and thietanes are important intermediates in organic synthesis, just as their oxygen and nitrogen analogs (oxiranes and aziridines, and oxetanes and azetidines). They have been widely applied in the preparation of sulfur-containing compounds. Thiiranes undergo ring expansions to generate various four-, five-, six-, and seven-membered heterocyclic products, even larger heterocycles. Thietanes also undergo ring expansions to produce five-, six-, and seven-membered heterocyclic compounds, even larger heterocycles as well. The ring expansions include insertion, nucleophilic and electrophilic ring opening, and subsequent cyclization. The regioselectivities in nucleophilic ring-opening reactions of unsymmetrical thiiranes and thietanes are discussed. Generally, nucleophiles attack on the less substituted vicinal carbon atom to the sulfur in unsymmetrical thiiranes and thietanes, controlled by steric hindrance. In the presence of Lewis acids, the electronic effect significantly impacts the regioselectivity in ring-opening reactions. 2-Arylthiiranes and 2-alkenylthiiranes are attacked on their more substituted vicinal carbon atom with nucleophiles (the electronic effect control). For thietanes, electrophilic ring expansion is one of the major processes. Unsymmetrical thietanes undergo electrophilic ring expansion with carbenes and nitrenes through electrophilic attack and subsequent Stevens-type rearrangement, with the more substituted vicinal carbon shifting. Mechanisms on some of the most important ring expansions of thiiranes and thietanes are introduced.

Recent synthesis of thietanes

“…Synthesis of an optically active thietane nucleoside from diethyl L-tartrate (32). azaspiro [3.3]heptane was evaluated as inhibitor of kinases, insecticides, and acaricides, its sulfur analogue, 6-amino-2thiaspiro [3,3]heptane (28) was prepared from the cheap starting material 2,2-bis(bromo-methyl)propane-1,3-diol (11). Compound 11 was converted into 3-(tert-butoxycarbonyl)-1,1bis(hydroxymethyl)aminocyclobutane (25) in 6 steps.…”

“…Some pharmaceutical and biological thietane-containing compounds include thiaanalogue thietanose nucleosides 1 and 2 [3,4], and the spiroannulated glyco-thietane nucleoside 3 [5] of the antiviral (anti-HIV and HSV) drug oxetanocin A, the D-ring-modified thia derivatives 4 and 5 of the anticancer drug taxoids and docetaxels [6], thiathromboxane A2 6 [7], pesticide 7 [8], and the sweetener 8 [9] (Figure 1). Thietanes also serve as important and useful intermediates and versatile building blocks in organic synthesis for the preparation of sulfur-containing acyclic and heterocyclic compounds [10,11]. Several synthetic methods for thietanes have been developed and reviewed [12][13][14].…”

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

“…While the synthesis of 1,4-dithiane-type ring systems is not the primary focus of this review, the synthetic accessibility of these building blocks is of course an important consideration, and it impacts the utility of any building block-based strategy [19][20][21][22][23][24].…”

“…For a more detailed and extensive discussion of the synthesis of 1,4-dithiin derivatives, and the various strategies that are available, we refer to other reviews in this area [19][20][21][22][23][24]. In our hands, the ring expansion of 1,3-dithiolanes as pioneered by Parham is the most generally applicable and most versatile strategy, especially for substituted 1,4-dithiane ring systems, as a wide range of α-halocarbonyl starting materials can be used in this scheme.…”

“…In this review, we will focus on developments in the application of 1,4-dithiane building blocks, including their unsaturated and oxidized derivatives (Figure 1a). The chemistry of fully unsaturated 1,4-dithiins have received a good deal of attention in synthesis [19][20][21][22][23], in particular as these heterocycles constitute non-aromatic (and non-planar) analogues of thiophenes that find use in materials science applications. The properties, synthesis and materials applications of 1,4-dithiins have recently been reviewed by Etkind and Swager [24], and will not be extensively covered in this review.…”