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30 Acetals: O/N, S/S, S/N, and N/N and Higher Heteroatom Analogues

DOI: 10.1055/sos-SD-030-00001

Otera, J.Science of Synthesis, (2007301.

General Introduction

This volume is concerned with the synthesis of acetal-type compounds involving two carbonheteroatom bonds at the geminal position, mainly focusing on heteroatoms heavier than oxygen. The combinations of heteroatoms covered in this volume are diverse, including O/N, O/P, S/P, S/S, S/N, S/Se, S/Te, Se/Se, Se/Te, Se/N, Se/P, Te/Te, Te/N, Te/P, N/N, N/P, and P/P. These are summarized in Table 1 together with the sections in which they appear.

Table 1 Classes of Acetals Covered in Volume 30

Product Class Subclass Section
O,N-acetals 30.1
acyclic 30.1.1
cyclic 30.1.2
carbohydrate derivatives (including nucleosides) 30.1.3
O,P- and S,P-acetals 30.2
S,S-acetals 30.3
acyclic S,S-acetals 30.3.1
1,3-dithietanes 30.3.2
1,3-dithiolanes 30.3.3
1,3-dithianes 30.3.4
1,3-dithiepanes 30.3.5
S,S-acetal S-oxides and S,S-dioxides 30.3.6
deprotection of S,S-acetals 30.3.7
S,N-acetals 30.4
Se- and Te-containing acetals 30.5
N,N-acetals 30.6
N,P- and P,P-acetals 30.7

Among them, the S,S-acetals play the most important roles because of both availability as protecting groups and versatility as acyl anion equivalents to effect facile CC bond formation. They have been employed extensively in organic synthesis and thus Section 30.3, which deals with this subject, occupies more than half of this volume. In this context, special introductory comments have been included in Section 30.3 so that this important class of compounds can be specifically summarized. As a result, this introduction will outline the other product classes.

Section 30.1 deals with O,N-acetals, in which an sp3-carbon is bonded to nitrogen and oxygen. The simplest form is derived from combination of amino and alkoxy groups leading to O,N-acetals 1. In sharp contrast to O,O-acetals, the hemiacetals of which are usually very unstable, the oxygen function can be a hydroxy group to give aminals 2. The cyclic derivatives are also available in three forms: 3, 4, and 5 (Scheme 1). Essentially the same methods are employed for synthesis of both acyclic and cyclic compounds. Addition of amines to carbonyl compounds is the most common way,[‌1‌] while hydride addition to amides is also useful. Transacetalization between O,O-acetals with amines is feasible. In particular, this method is employable for the synthesis of cyclic O,N-acetals. For this class of compounds, direct acetalization of carbonyls with chiral amino alcohols is also of great use to provide various building blocks for asymmetric synthesis.

Scheme 1 Structures of Acyclic and Cyclic O,N-Acetals

Aminals or O,N-acetals undergo facile CO bond cleavage to give rise to subsequent CC bond formation on the acetal carbon. The reaction is induced by Lewis acids and proceeds via a carbocation, which is stabilized by the contribution of an iminium structure (Scheme 2).[‌1‌‌3‌] CC bond formation is also catalyzed by some transition-metal catalysts.

Scheme 2 Lewis Acid Promoted CC Bond Formation of O,N-Acetals[‌1‌‌3‌]

The synthetic utility of O,N-acetals is highlighted for carbohydrate derivatives with particular emphasis on nucleosides and N-glycoproteins in Section 30.1.3

The synthesis of O,P- and S,P-acetals is described in Section 30.2. One of the characteristic features of this class of compounds is facile formation by addition of a PH bond to carbonyl groups (Scheme 3).[‌4‌] A variety of phosphorus-containing acetals are available using this strategy, irrespective of the use of phosphorus(III) or phosphorus(V). The reaction is utilized successfully for the synthesis of phosphorus-containing carbohydrates.[‌5‌] Another versatile method is to use addition of phosphorus anions to carbonyl compounds.[‌6‌,‌7‌] Again, this protocol is applicable for both phosphorus(III) and phosphorus(V). The S,P-acetals are obtained basically by the same methodology.

Scheme 3 Addition of a PH Bond to a Carbonyl Group[‌4‌]

Combination of S- and N-functions is the subject of Section 30.4. S,N-Acetals, of general structures 6 and 7, are not only useful building blocks in organic synthesis but also include sulfur-containing bicyclic β-lactams 8 and 9 (Scheme 4).

Scheme 4 S,N-Acetals and Sulfur-Containing Bicyclic β-Lactams

In addition to the orthodox S,N-acetalization method of carbonyl compounds, these compounds can be obtained by various specific reactions based on strong nucleophilicity or reactivity of the sulfur functions. Upon exposure to Grignard or organolithium reagents, the CS bond is cleaved preferentially to the CN bond, affording a variety of alkylamines (Scheme 5).[‌8‌,‌9‌]

Scheme 5 Reaction of N-Aryl-N-[(phenylsulfanyl)methyl]methylamine with Grignard and Organolithium Reagents[‌8‌,‌9‌]

When the nitrogen is bonded to aromatic or electron-withdrawing groups, normal deprotonation occurs at the acetal carbon with butyllithium (Scheme 6).[‌10‌]

Scheme 6 Lithiation at the Acetal Carbon Followed by Alkylation[‌10‌]

The heaviest acetals containing selenium and tellurium functions are described in Section 30.5, including S,Se-, S,Te-, Se,Se-, Se,Te-, Te,Te-, Se,N-, Se,P-, Te,N-, and Te,P-acetals. Because both elements are heavier members of the same group as sulfur in the periodic table, essentially the same methods used to prepare sulfur-containing acetals can be employed for the selenium and tellurium analogues. As expected, these acetals behave similarly to their oxygen and sulfur analogues in some cases. For example, Se,Se-acetals can be readily metalated by treatment with metal amides, and the resulting α-metallo Se,Se-acetals are useful precursors to substituted Se,Se-acetals;[‌11‌‌14‌] they are also found to be valuable acyl anion equivalents. On the other hand, these heavier derivatives also exhibit characteristic reactivities different from the sulfur-containing acetals, thus occupying a unique position in organic synthesis. The CSe and CTe bonds of the acetals are easily cleaved homolytically or heterolytically and useful intermediates such as α-organoselanyl carbanions, α-selanylcarbenium ions, and α-selanyl- or non-selanyl carbon radicals are feasible. α-(Organoselanyl)alkyllithiums bearing alkyl and aryl groups can be generated by seleniumlithium exchange of Se,Se-acetals or triselenoortho esters with butyllithium in tetrahydrofuran/hexane, accompanied by loss of a butyl selenide (Scheme 7).[‌11‌] In particular, the reactions of selenium-stabilized carbanions with electrophiles such as allylic alcohols, epoxides, alkenes, and ketones can provide a wide variety of organoselanyl or non-selanyl compounds.

Scheme 7 Generation of α-(Organoselanyl)alkyllithiums Followed by Reaction with an Electrophile[‌11‌]

The Se,Se-acetals can provide α-selanyl carbocations, which are good electrophiles in Lewis acid mediated CC bond formation (Scheme 8). Applications of this technology to cationic intramolecular cyclization lead to various carbocycles[‌15‌,‌16‌] or heterocycles.[‌17‌,‌18‌]

Scheme 8 Generation of α-Organoselanyl Carbocations Followed by Reaction with a Nucleophile[‌15‌‌18‌]

The final active species are the carbon-centered radicals produced by the homolytic cleavage of the CSe bond with tributyltin hydride/triethylborane or 2,2-azobisisobutyronitrile (Scheme 9).[‌19‌] Such versatilities exemplify the synthetic potential of the Se- and Te-containing acetals.

Scheme 9 Homolytic Cleavage of CSe Bonds[‌19‌]

In Section 30.6, N,N-acetals are described. These compounds serve as good protecting groups for carbonyls because they are relatively stable but readily cleaved under acidic conditions. The compounds are most conveniently prepared by N,N-acetalization of aldehydes with amines (Scheme 10).[‌20‌‌23‌] Synthetic utilization of this class of compounds is limited, but a few examples are given in this section.

Scheme 10 N,N-Acetalization of Aldehydes with Amines[‌20‌‌23‌]

The final subjects, N,P- and P,P-acetals, are described in Section 30.7. The methods employed for the synthesis of these compounds are somewhat similar to those for the O,P- and S,P-acetals in Section 30.2. Addition of a PH bond to a carbonyl group in the presence of amine is effective, and direct addition to imines is also useful. Reaction of phosphorus anions with (α-haloalkyl)amines is also available. Essentially similar methods can be employed for the synthesis of P,P-acetals. All of these protocols are applicable to both phosphorus(III) and phosphorus(V) reagents.