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The Sommelet–Hauser rearrangement of X-benzylic onium ylides (X = heteroatom) is an interesting transformation in organic synthesis. This rearrangement proceeds via dearomative [2,3]-sigmatropic rearrangement, followed by aromatization to form a carbon(sp2)–carbon(sp3) bond. Few advances were made in studies performed around 2000 on this rearrangement because of several competitive side reactions and structural limitations. However, studies performed in the last 15 years on the rearrangement have remarkably expanded the substrate scope and synthetic applications. In this review, the utility of the Sommelet–Hauser rearrangement and recent advances for the generation of onium ylides are described.1 Introduction2 Base-Induced Rearrangement3 Transition-Metal-Catalyzed Rearrangement4 Light-Mediated Rearrangement5 Aryne-Induced Rearrangement6 Conclusions and Outlook

Site-selective nucleophilic ring-opening of 2 with Bu4NX proceeded at a much-substituted 2-position preferentially and produced tertiary alkyl halides 3.

A Tf2NH-catalyzed aza-Ferrier reaction of N,O-allenyl acetals was reported. This protocol provided various types of β-amino-α-methylene aldehydes as the products. The N,O-allenyl acetal substrates ...

The base-promoted α-alkylation of

The base-promoted aromatic [3,3] sigmatropic rearrangement of N-acyl-O-arylhydroxylamines giving α-(2-hydroxyphenyl)amides was successfully demonstrated. The substrates were prepared from N-substituted hydroxylamines by N-acylation followed by copper(I)-mediated O-arylation with boronic acids. Treatment of the substrates with lithium hexamethyldisilazide (LiHMDS) in THF at 0 °C to room temperature generated the corresponding amide enolates. The aromatic [3,3] rearrangement of the enolates provided the desired products in moderate to good yields. A crossover experiment produced only intramolecular products and clarified that the reaction proceeds via the aromatic [3,3] sigmatropic rearrangement, not a bond-cleavage–recombination process. Our method is a formal α-arylation of amides.

The base-induced Sommelet–Hauser (S–H) rearrangement of azetidine-2-carboxylic acid ester-derived ammonium salts into 2-aryl-substituted derivatives was demonstrated. The ring-strain of four-membered N-heterocycles enables efficient generation of the desired ylide intermediate and enhances the rate of the S–H rearrangement. The asymmetric version of the rearrangement was characterized by excellent levels of successive chirality transmissions. The regio- and stereo-controlled nucleophilic ring opening of the rearrangement products produced quaternary α-aryl amino acid esters with excellent enantiopurities.

The regioselective synthesis of secondary 1,3-dienamides 3 (1- N -acylamino-1,3-dienes) is successfully demonstrated by regiospecific base-promoted 1,4-elimination of ( Z )- or ( E )- N,N -di-Boc-4-methoxy-2-buten-1-ylamine 1 followed by mono-Boc elimination in situ.

The base-induced Sommelet–Hauser (S–H) rearrangement of N-(α-branched)benzylic glycine ester-derived ammonium salts 1 was investigated. When the α-branched substituent was a simple alkyl, such as a methyl or butyl, desired S–H rearrangement product 2 was obtained in low yield with formation of the [1,2] Stevens rearranged 4 and Hofmann eliminated products 5 and 6. However, when the α-branched substituent had a 2-oxy moiety, such as 2-acetoxyethyl or 2-benzoyloxyethyl, the yields of 2 were improved. These results could be explained by formation of chelated intermediate C that stabilizes the carbanionic ylide, and the subsequent initial dearomative [2,3] sigmatropic rearrangement would be accelerated. The existence of C was supported by mechanistic experiments. This enhancement effect is not very strong or effective; however, it will expand the synthetic usefulness of ammonium ylide rearrangements.

The base-promoted α-alkylation of N-((S)-1-phenylethyl)azetidine-2-carboxylic acid esters 1 was investigated. The use of diastereomerically pure borane complexes 3 as substrates, which are easily prepared from 1, dramatically improved the yields and diastereoselectivities of α-alkylated products 2. For example, the treatment of tert-butyl ester (1S,2S,1'S)-3a with 2.4 equivalents of lithium bis(trimethysilyl)amide (LiHMDS) at 0 °C followed by 2.6 equivalents of benzyl bromide afforded α-benzylated (2S,1'S)-2aa in 90% yield as almost a single diastereomer. Our method enables the production of optically active α-substituted azetidine-2-carboxylic acid esters starting from commercially available (S)-1-phenylethylamine, which is one of the least expensive chiral compounds.

A base-induced dearomative [2,3] sigmatropic rearrangement of amino acid ester-derived ammonium salts followed by 1,4-elimination produced α-(ortho-vinylphenyl)amino acid esters. The reaction of azetidine-2-carboxylic acid-derived ammonium salt, (1S,2S,1′R)-3b, proceeded with a perfect N-to-C chirality transfer to afford α-(ortho-vinylphenyl)azetidine-2-carboxylic acid ester, (R)-5 (99% ee). On the other hand, the reaction of glycine-derived ammonium salt (R)-6a, which involves an efficient chirality transfer from a chiral benzylic carbon to an α-carbon of an ester carbonyl giving the optically active α-(ortho-vinylphenyl)glycine ester, (R)-8a (85% ee), was demonstrated. Although this dearomative [2,3] rearrangement followed by 1,4-elimination has limitations with regard to the structures of the substrates, our method provides unique access to substituted α-arylamino acid derivatives.

Photoinduced electron transfer (PET) reactions promoted by 2-aryl substituted 1,3-dimethylbenzimidazolines (Ar-DMBIH) were investigated. Excited states of Ar-DMBIH, formed by irradiation using light above 360 nm, initiate PET reductions of various organic substrates, including transformations of epoxy ketones to aldols, free radical rearrangements such as the Dowd-Beckwith ring-expansion and 5- exo hexenyl cyclization, deprotection of N -sulfonyl-indols, and allylation of acyl formates. In these processes, Ar-DMBIH possessing 1-naphthyl, 2-naphthyl, 1-pyrenyl and 9-anthryl substituents formally act as two electron and one proton donors while the hydroxynaphthyl substituted derivative serves as a two electron and two proton donor. On the basis of the results of absorption spectroscopy studies, cyclic voltammetry and DFT calculation, a mechanistic sequence for these reduction reactions is proposed that involves initial photoexcitation of the aryl chromophore of the Ar-DMBIH followed by single electron transfer (SET) to the organic substrate to generate the radical cation of benzimidazoline and the radical anion of the substrate.

The copper-catalyzed regiospecific and 1,2-regioselective cyclopropanation of (1Z)-1-amino- and (1Z)-1-oxy-1,3-butadienyl derivatives, which could be prepared by Z-stereoselective 1,4-elimination with α-aryl diazoesters was successfully demonstrated. This successful regiospecific protocol enabled the preparation of the corresponding 1-amino- and 1-oxy-2-vinylcyclopropane derivatives as almost single stereoisomers.

The base-promoted 1,4-elimination reaction of N -Boc-1-amino-4-methoxy-2-alkene 1 is shown to proceed with perfect stereoselectivity to afford the corresponding N -Boc-1-amino-1,3-diene 2 in good yields. The reaction is highly stereospecific. The substrate E - 1 gave 1 Z - 2 by the ‘ Syn -Effect’ and Z - 1 gave 1 E - 2 via formation of a chelated intermediate. Our method is widely applicable to the preparation of various types of N -Boc-1-amino-1,3-dienes 2 .

Copper(II)–acid catalyzed cyclopropanation of electron-rich alkenes, such as 1,3-dienamides, with α-aryl diazoesters are described. The reaction could be performed without rare metal catalysts, excess substrate, or the need for the slow addition of the diazoesters.

A combination of 2-aryl substituted 1,3-dimethyl-benzimidazolines (DMBIHs) and tris(2,2′-bipyridine)ruthenium(II) chloride, Ru(bpy)3Cl2 was used to promote photoinduced electron-transfer (PET) reactions of α-halomethyl-substituted benzocyclic 1-alkanones. This photo-reagent system stimulates free radical forming, cleavage of both carbon–bromine and carbon–chlorine bonds that are not activated by carbonyl groups. The resulting free radicals undergo 5-exo hexenyl cyclization as well as sequential cyclization and ring-expansion (Dowd–Beckwith) reactions to form radicals that abstract hydrogen atoms from the radical cation of DMBIH to yield the observed products. The results of a study of the effects of substituents located on the 2-aryl ring of DMBIH suggest that steric and hydrogen-bonding interactions influence the nature of the reaction pathways followed by the radical intermediates. PET reactions using an iridium complex and DMBIH were also investigated.

Diaza [1,4] Wittig-type rearrangement of N-allylic-N-Boc-hydrazines into γ-amino-N-Boc-enamines was demonstrated. The scope and limitation, experimental mechanistic studies, and a proposed reaction mechanism were also described.

A photoreaction between benzoyl compounds, such as benzoylformate derivatives, and 2-( p -anisyl)-1,3-dimethylbenzimidazoline in the presence of allyl bromide was found to give various allylated alcohols. In the reaction of benzoylformates, α-hydroxy ester enolates, for which the negative charge occurs on the carbonyl carbon of benzoyl (umpolung reactivity), are proposed to be generated as intermediates by electron-transfer from benzimidazolines to the photoexcited benzoylformates; these species react with allyl bromide to produce α-allyl-α-hydroxy esters.

The 1,4-elimination reaction of (Z)-N-Boc-2-(4-methoxy-2-alkenyloxy)amines with Brønsted acids catalyzed aza-Ferrier reaction of the 1,4-eliminated product, thus obtained, afforded various β-amino-β,γ-unsaturated aldehydes. The scope and limitation of this sequential reaction are described.

Diaza [1,4] Wittig-type rearrangement of N-allylic-N-Boc-hydrazines into γ-amino-N-Boc-enamines was demonstrated. The scope and limitation, experimental mechanistic studies, and a proposed reaction mechanism were also described.

Oxidative ring-opening reactions of benzene-fused bicyclic cyclopropyl silyl ethers, promoted by copper(II) tetrafluoroborate, were investigated. The regioselectivity of cyclopropane ring-opening as well as product distributions were found to be highly dependent on the nature of the solvent. In alcohols, dimeric substances arising from external bond cleavage are major products. Radical rearrangement products are also formed in solvents such as ether and ethyl acetate. On the contrary, nucleophile addition to carbocation intermediates, generated by internal bond cleavage, occurs mainly in reactions taking place in acetonitrile. It is proposed that the observed solvent effects that govern the reaction pathways followed are a consequence of varying solvation of copper intermediates, which governs their reactivity and redox properties. In addition, the influence of counteranions of the copper salts, organonitriles, cyclic dienes, and substrate structures on the pathways followed in these reactions was also ex...

The regioselective synthesis of secondary 1,3-dienamides 3 (1- N -acylamino-1,3-dienes) is successfully demonstrated by regiospecific base-promoted 1,4-elimination of ( Z )- or ( E )- N,N -di-Boc-4-methoxy-2-buten-1-ylamine 1 followed by mono-Boc elimination in situ.

[5]Catenanes were synthesized by olefin metathesis dimerization. The reaction of pseudorotaxanes, which were derived from a [2]catenane and one equivalent of an ammonium salt bearing two terminal olefins in dichloromethane, with a catalytic amount of Grubbs catalyst afforded linear [5]catenanes in 12% yield. Intermolecular and intramolecular olefin metathesis reactions were controlled by the length of the alkyl chain of the ammonium salts.

Oxidative ring-opening reactions of benzene-fused bicyclic cyclopropyl silyl ethers, promoted by copper(II) tetrafluoroborate, were investigated. The regioselectivity of cyclopropane ring-opening as well as product distributions were found to be highly dependent on the nature of the solvent. In alcohols, dimeric substances arising from external bond cleavage are major products. Radical rearrangement products are also formed in solvents such as ether and ethyl acetate. On the contrary, nucleophile addition to carbocation intermediates, generated by internal bond cleavage, occurs mainly in reactions taking place in acetonitrile. It is proposed that the observed solvent effects that govern the reaction pathways followed are a consequence of varying solvation of copper intermediates, which governs their reactivity and redox properties. In addition, the influence of counteranions of the copper salts, organonitriles, cyclic dienes, and substrate structures on the pathways followed in these reactions was also examined.

The copper-catalyzed regiospecific and 1,2-regioselective cyclopropanation of (1Z)-1-amino- and (1Z)-1-oxy-1,3-butadienyl derivatives, which could be prepared by Z-stereoselective 1,4-elimination with α-aryl diazoesters was successfully demonstrated. This successful regiospecific protocol enabled the preparation of the corresponding 1-amino- and 1-oxy-2-vinylcyclopropane derivatives as almost single stereoisomers.

Selective amine de-alkylation enables the conversion of Sommelet–Hauser rearrangement products into 2-aryl-2-bromoacetic acid derivatives. These compounds are valuable synthetic intermediates in the synthesis of α-aryl-α-amino or α-aryl-β-amino acid derivatives. The method presented herein is a formal de-N,N-dialkylation of Sommelet–Hauser rearrangement products.

Asymmetric α-2-tosylethenylation of (S)-2-(pyrrolidin-1-yl)propanoic acid esters was shown to produce good yields with high enantioselectivities. The reaction proceeds via the formation of a non-racemic ammonium enolate without an external source of chirality.

Aza-Prins cyclization reaction of N -tosyl-3-butenylamine with aliphatic and aromatic aldehydes was performed using a combination of FeCl 3 and 1-butyl-3-methylimidazolium hexafluorophosphate (BmimPF 6 ) or 1-butyl-3-methylimidazolium tetrachloroferrate (BmimFeCl 4 ) in benzotrifluoride (BTF). The desired N -tosyl-4-chloro-2-substituted piperidines were obtained from aliphatic aldehydes in comparable yields to those for the previously reported reactions in which FeCl 3 was used in CH 2 Cl 2 . On the other hand, significant progress for the piperidine synthesis from aromatic aldehydes has been achieved, particularly when BmimFeCl 4 was used with FeCl 3 in BTF.

A solution of potassium tert-butoxide in THF was shown to remarkably enhance the base-induced Sommelet–Hauser rearrangement of N-benzylic amino acid-derived ammonium ylides.

The optical resolution of N-chiral, amino acid-derived quaternary ammonium salts is demonstrated by using chiral BINOL as a complexing agent. Determination of the enantiopurities and absolute configurations of the resolved N-chiral tetraalkylammonium salts are described. The [1,2] Stevens rearrangement of N-chiral ammonium salts is shown to proceed with N-to-C chirality transmission to afford optically active 3-substituted morpholin-2-one derivatives., NOTICE: this is the author’s version of a work that was accepted for publication in . Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in PUBLICATION, [VOL20, ISSUE22, (2009-11)] DOI:10.1016/j.tetasy.2009.10.025

[5]Catenanes were synthesized by olefin metathesis dimerization. The reaction of pseudorotaxanes, which were derived from a [2]catenane and one equivalent of an ammonium salt bearing two terminal olefins in dichloromethane, with a catalytic amount of Grubbs catalyst afforded linear [5]catenanes in 12% yield. Intermolecular and intramolecular olefin metathesis reactions were controlled by the length of the alkyl chain of the ammonium salts.

The Sommelet-Hauser rearrangement of N-benzylic ammonium ylides generated from ammonium salts is an interesting and useful transformation that enables one to convert a readily accessible C-N bond into a new C-C bond to an aromatic ring. The rearrangement was discovered by Sommelet in 1937, studied in detail by Hauser, and applied to organic synthesis by Sato until 1999. Further studies have not advanced because several competitive side reactions and structural limitations of the products severely limit the substrate scope and synthetic applications. In this Personal Account, a history of the research in problem solving and recent advances in the base-induced Sommelet-Hauser rearrangement are described. This synthetic method developed by my group provides efficient access to various types of α-aryl-α-amino acid and α-aryl-β-amino acid derivatives.

A sequential treatment of 1,2-trans disubstituted oxiranes (I) with BF3·OEt2 and dimethylbenzimidazole (DMB) produces β-hydroxyketones (II) as main products.

N-Boc-1-amino-1,3-dienes are obtained with perfect stereoselectivity by base-promoted 1,4-elimination reactions of N-Boc-1-amino-4-methoxy-2-alkenes.

The Sommelet-Hauser rearrangement of N-benzylic ammonium ylides generated from ammonium salts is an interesting and useful transformation that enables one to convert a readily accessible C-N bond into a new C-C bond to an aromatic ring. The rearrangement was discovered by Sommelet in 1937, studied in detail by Hauser, and applied to organic synthesis by Sato until 1999. Further studies have not advanced because several competitive side reactions and structural limitations of the products severely limit the substrate scope and synthetic applications. In this Personal Account, a history of the research in problem solving and recent advances in the base-induced Sommelet-Hauser rearrangement are described. This synthetic method developed by my group provides efficient access to various types of α-aryl-α-amino acid and α-aryl-β-amino acid derivatives.

A new sequential, one-pot protocol for transforming 1,3-disubstituted 2,3-epoxy ketones to β-hydroxy ketones and α-methylene ketones has been developed. Reaction of epoxy ketones with boron trifluoride etherate (BF3·OEt2) generates the cationic intermediates by regioselective epoxide ring opening and an acyl shift. Then, a treatment of these cations with 2-aryl-1,3-dimethylbenzimidazolines (DMBIH) results in formation of 1,2-disubstituted 3-hydroxy ketones. DMBIH serves as a hydride donor in the second step of this process. Finally, the β-hydroxy ketones can be converted to 1,2-disubstituted 2-methylene ketones by treatment with methanesulfonic acid or a combination of methanesulfonyl chloride and triethylamine. Importantly, the sequential steps involved in formation of the α-methylene ketone products can be carried out in one pot.

Treatment of 1-alkoxy-4-methoxy-(2Z)-alkenes or 1-siloxy-4-methoxy-(2Z)-alkenes with n-butyllithium in diethyl ether is shown to afford the corresponding (1Z,3E)-dienyl, alkyl or silyl ethers, respectively, in high stereoselectivity via a facile 1,4-elimination. The scope and the regio- and stereochemical features of the synthetic method are described.

Treatment of 1-alkoxy-4-methoxy-(2Z)-alkenes or 1-sil-oxy-4-methoxy-(2Z)-alkenes with n-butyllithium in diethyl ether is shown to afford the corresponding (1Z,3E)-dienyl, alkyl or silyl ethers, respectively, in high stereoselectivity via a facile 1,4-elimination. The scope and the regio- and stereochemical features of the synthetic method are described.

The asymmetric [2,3] Stevens rearrangement of epimeric mixtures of N-allylic ammonium salts derived from (5R)-5-phenyl-1,4-oxazin-2-one is shown to proceed with efficient kinetic resolution to afford the unnatural α-amino acid derivatives in high enantio-purities.

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its ability to recognize the chirality of beta-branched primary alkyl halides, which provides impressive levels of kinetic resolution and double stereodifferentiation during the alkylation, allowing for two alpha- and gamma-stereocenters to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether (CPME), this system offers a facile access to structurally diverse optically active vicinal diamines. Furthermore, the optically active alpha-amino acid Weinreb amide 11 can be efficiently converted to the corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and alkylation of the optically active alpha-amino ketone into both syn and anti alpha-amino alcohols with almost complete relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the present approach renders both enantiomers of alpha-amino amides including Weinreb amides readily available with enormous structural variation and also establishes a general and practical route to vicinal diamines, alpha-amino ketones, and alpha-amino alcohols with the desired stereochemistry.

The intermolecular aromatic substitution of N,N-dialkylanilines and alkoxybenzenes with diazoesters is shown to proceed in the presence of catalytic amounts of both copper(II) salt and acid (Lewis or Bronsted). This method is a mild and rare metal-free C–C bond formation reaction between aromatic (sp2) and aliphatic (sp3) carbons.

A new protecting group, 1,2-dimethoxy-4,5-dimethylene, for acyclic amino acid derivatives could be introduced by N , N -dialkylation with 1,2-bis(bromomethyl)-4,5-dimethoxybenzene ( 1 ) and removed via amine de-alkylation with acyl chlorides. The method can be used with base-induced [2,3] and [1,2] Stevens rearrangement products.