Chapter Five - Cascade aza-Prins reactions

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Abstract

Saturated nitrogen-containing heterocycles are the basis of a plethora of natural products, including alkaloids and aza-sugars, and a recent survey also demonstrated that the piperidine ring is the most abundant nitrogen-containing heterocycle in FDA-approved pharmaceutically active and commercially available drugs, being found in 72 drugs. The aza-Prins and related reactions have emerged as a rapid and highly efficient method for the preparation of 6-membered nitrogen-containing heterocycles. This chapter reviews recent developments in the aza-Prins reaction, particularly focussing on reports since 2000.

Introduction

Historically, the Prins reaction developed from the Kriewitz reaction (Scheme 1A) and is the acid-promoted addition of alkenes to aldehydes and may give differing products depending on the exact nature and careful control of the reaction conditions (Scheme 1B). It was one of the early fundamental reactions for Csingle bondC bond formation and now numerous protic and Lewis acids are known to promote the reaction. A number of excellent reviews have traced the development of the Prins reaction (2010T413). The purpose of this chapter is not to review the development of the Prins or the aza-Prins reaction, but rather to update readers on the tremendous synthetic potential of the aza-Prins reaction in particular, and especially when coupled with other reactions in cascade processes.

It was thanks to investigations of reaction conditions and promoters for the Prins reaction by Hanschke and Gendorf, and by Stapp, that the synthesis of 3-alkyl-4-chlorotetrahydropyrans was observed, and thus the Prins cyclization was born (Scheme 1C). They also observed that homoallylic alcohols are key intermediates in forming tetrahydropyrans. This leads to the development of the modern Prins cyclization, which frequently commences with a homoallylic alcohol starting material and reacts with either an aldehyde/ketone, acetal, or epoxide, in the presence of a Brønsted or Lewis acid, to give, after nucleophile trapping, a tetrahydropyran (Scheme 1C). Many variations now exist, including a thia-Prins cyclization employing a thiol rather than an alcohol. There have been a number of excellent reviews on the development of the Prins reaction and the Prins cyclization (2010T413, 2012COC1277) including spirocyclizations (2017EJOC5484).

Given the success of the Prins cyclization reaction, the development of the analogous process involving a homoallylic amine was inevitable. However, in comparison with the Prins reaction, despite providing rapid access to a large number of synthetically important heterocycles and piperidines in particular, the aza-Prins is less well developed or reported. The development of the aza-Prins reaction falls into two classes: cyclization onto an iminium ion intermediate (often formed from a single-molecule precursor) or an analogous reaction to the Prins reaction whereby a homoallylic amine reacts with a carbonyl (or related) compound promoted by acid. This latter definition has been the key to the recent developments of the aza-Prins reaction and has four subclasses (Scheme 2): the aza-Prins reaction, the aza-alkyne-Prins reaction, the aza-silyl-Prins reaction, and the aza-acyliminium Prins reaction.

There have been a number of good reviews covering the synthesis of nonaromatic nitrogen heterocycles, which have included discussions of the aza-Prins reaction (2011COC1760, 2012COC1277, 2016AHC191, 2017EJOC5484, 2017JSOCJ340). A comprehensive review of cyclizations of N-acyliminium ions, including vinylsilanes, allylsilanes, and alkynyl silanes, has been published (2004CR1431).

The major drawback with the aza-Prins cyclization, which has prevented its adoption more widely, is the requirement for a sulfonamide group, particular N-tosyl (R = Ts, Ns, Bs in Schemes 2A and 4A), in order for the cyclization to proceed in high yields. Removal of the N-Ts group has been quite problematic, particularly in the presence of other functional groups in the heterocyclic product. This has generally not been an issue in the aza-silyl-Prins reaction, where R may be Bn, Ph, or alkyl.

A large volume of work has been reported around employing different acids for the aza-Prins reaction, often as a means to influence the outcome of the cyclization and particularly with respect to the nucleophile trapping. This will be discussed in detail in Section 2.1. Initially, the reaction was studied employing either a Lewis acid or a Brønsted acid promotor. More recently, a Lewis acid/Brønsted acid promotor system of TiCl4/p-TsOH has been reported for the aza-Prins cyclization. This has been found to give piperidines in good to high yields and high diastereoselectivities for N-alkyl, N-aryl, and nonprotected homoallylic amines, thus removing the prerequisite for a sulfonamide group for a successful aza-Prins cyclization (2016JOC849). Using an N-p-methoxyphenyl (PMP) homoallylic amine preferentially gives the trans product, but free-NH2 homoallylic amines have the cis diastereoisomer as the major product. A supramolecular assembly metal (Ga)–ligand capsule of M4L6 stoichiometry has also been found to catalyze a bimolecular aza-Prins cyclization. The reaction occurs via binding inside the supramolecular cavity (2015JACS9202).

While the use of an N-sulfonamide is widely acknowledged and accepted for a successful aza-Prins reaction, Fache has shown that it is possible to hold the sulfonamide linkage within the homoallylic amine chain, and thus obtained δ-sultams in high yields via an aza-Prins cyclization (2013CEJ857). The cis isomer was the predominant δ-sultam formed (Scheme 3).

Historically, the Prins cyclization has also been used to prepare 1,3-dioxanes (Scheme 4A). In 2018, Zhong reported the first example of preparing 1,3-oxazinanes and oxazolidines using an aza-Prins cyclization and by utilizing dimethyl sulfoxide (DMSO) and disulfides developed the thia-aza-Prins method to give sulfenylated 1,3-oxazinanes (2018OL5899). Surprisingly, DMSO was found to act simultaneously as both solvent and surrogate for formaldehyde and that the CuBr2 catalyst and in situ-formed sulfinic acids meant that a synergistic Lewis acid–Brønsted acid catalytic process was occurring (Scheme 4B).

Rhee has reported a gold(I)-catalyzed cycloisomerization reaction of mixed N,O-acetals, themselves generated from homopropargylic amines, to highly substituted piperidines in what is formally an alkyne aza-Prins cyclization reaction (Scheme 5) (2009JACS14660).

Section snippets

Nucleophile trapping

By far the greatest work in the field of the aza-Prins has revolved around the nucleophile trapping of the intermediate secondary carbocation formed during the cyclization process, often leading to cascade reaction processes. A wide variety of nucleophiles are discussed in the following sections.

The aza-silyl-Prins and related reactions

The β-effect of silicon, whereby it is capable of stabilizing a β-carbocation via hyperconjugation, is a well-known and studied phenomenon (1985JACS1496, 1999ACR183). Given that the Prins reaction develops a secondary carbocation during the cyclization process, it is unsurprising that silicon has been incorporated into the starting materials in order to stabilize this intermediate. The development of the silyl-Prins reaction from the Prins reaction has already been described (Section 1), and it

Bi- and tricycle formation using the aza-Prins reaction

There are numerous examples of the aza-Prins reaction being employed in the synthesis of multiple fused ring systems via cascade processes.

Total syntheses involving cascade aza-Prins reactions

All the variations of the aza-Prins reaction that have been discussed have led to nitrogen-containing heterocycles. Such structures are the basis of a plethora of natural products, including alkaloids and aza-sugars, and a recent survey also demonstrated that the piperidine ring is the most abundant nitrogen-containing heterocycle in FDA-approved pharmaceutically active and commercially available drugs, being found in 72 drugs (2014JMC10257). Consequently, the aza-Prins reaction and its

Conclusions

This short review has demonstrated the development and the many uses and applications of the aza-Prins and related reactions. It is rapidly becoming an established synthetic method for the rapid and high-yielding synthesis of 6-membered ring nitrogen-containing heterocycles. When combined with other processes, it has become a very powerful synthetic tool and will continue to be expanded in scope and be utilized in total synthesis for many years to come.

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