Smiles rearrangements

Intramolecular nucleophilic aromatic rearrangement. General scheme  

Smiles, S. J. Chem. Soc. 1935, 181. Samuel Smiles began his career at King s College London as an assistant professor. He later became professor and chair there. He was elected Fellow of the Royal Society (FRS) in 1918. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 238, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applicatitms, DOI 10.1007/978-3-3I9-03979-4 255, Springer International Publishing Switzerland 2014 

Raju Ranjith Kumar and Subbu Perumal 1.3.7.1 Description 

For example, 3 undergoes Smiles rearrangement to afford 4, in which S02Ar is the leaving group, ArO is the nucleophile and the nitro group serves to activate its ortho position. 

The Smiles rearrangement occurs via an intramolecular nucleophilic aromatic substitution as shown below.  

The Smiles rearrangement followed by intramolecular cyclization of 2-(3-cyanopropoxy)-6-methylpyridine-3-carbonitrile (13) in the presence of potassium tert-butoxide in dioxane afforded 5-amino-8-methyl-l,2-dihydrofuro[2,3-/ ][l,6]naphthyridine (14) in 83% yield. The structure of 14 was assigned with the help of spectroscopic data and elemental analysis. The precursor 13, in turn, was obtained from the reaction of 6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (12) with 4-bromobutyronitrile in DMF. 

Weidner ef alP described a one-pot Smiles rearrangement method for the synthesis of various aminoquinolines from the corresponding hydroxyquinolines and showed that the tendency for the conversion depends on the electron-deficient nature of the quinolines. In a specific example, the reaction of 15 with (i) 2-bromo-2-methylpropionamide, 3 equiv. each of NaH and cesium carbonate in dioxane at reflux for 16 h and (ii) N-methylpyrrolidinone (NMP), l,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidinone (DMPU) (10 1 ratio) and 1 equiv. of NaH at 150 C for 72 h afforded the amine 16. 

Quaternary protoberberinium salts react with primary and secondary amines to generate aminated protoberberine salts. Oxygenated substituents at C-9 or C-11 are efficiently replaced with nitrogen by this procedure. The use of hindered secondary amines leads to side products due to competing 0-de-methylation of the C-9 or C-11 methoxyls. 

acyi base NaOH, KOH, RONa, RLi, K2CO3/DMSO 

The first step of the reaction is the formation of the nucleophile by deprotonation. The substrate then has to adopt the reactive conformation in which the plane of the migrating ring is perpendicular to the Z-Z bond. The nucleophile attacks the ring in an Ipso fashion to form a five-membered transition state that affords the product. 

The total synthesis of the lichen diphenyl ether epiphorellic acid 1 was achieved in the laboratory of J.A. Elix using the Smiles rearrangement as the key step. The diaryl phenolic ester substrate was heated in dry DMSO in the presence of potassium carbonate, which brought about the rearrangement. The resulting carboxylic acid was converted to the methyl ester with diazomethane and was debenzylated under catalytic hydrogenation conditions. 

Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase, dipyrido[2,3-/)]diazepinones, were prepared by J.R. Proudfoot and co-workers.These compounds are isomeric to the potent inhibitor nevirapine and available via the Smiles rearrangement of substrates that are intermediates used for the synthesis of nevarpine analogs. The deprotonated amide functionality in the rearrangement products displaces the chlorine at the 2-position to give the desired heterocycles in moderate to good yield. 

A one-pot procedure was developed for the preparation of aromatic amines from phenols via a one-pot Smiles rearrangement by N.P. Peet et al.° This new approach can be considered as an alternative of the Bucherer reaction which only works well for naphthalene derivatives and gives very poor yields for substituted benzene derivatives. In the current procedure, the phenol was reacted with 2-bromo-2-methylpropionamide to give 2-aryloxy-2-methylpropionamide which upon treatment with base underwent the Smiles rearrangement. The hydrolysis of the resulting A/-aryl-2-hydroxypropionamide afforded the aromatic amine. 

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Thiophene, 2-methyl-5-(mesitylsulfonyl)-Truce-Smiles rearrangement, 4, 825 Thiophene, 2-methyl-3-nitro-acidity, 4, 799... 

In the Schmidt reaction of fluonnated dicarboxyhc acids, the appropnate amides can be obtained in fairly good yield [48] Complications arise from possible cychzation if the fluorine atom is in the 8 position relative to the newly formed amino group [/] Fluonnated aromatic ethers, upon heating in dimethylformamide, undergo Smiles rearrangement to give diarylamines [49, 50] (equation 11)... 

Smiles rearrangement was observed also in base-catalyzed cyclization of 2-hydroxy-2 -nitrodiphenylsulfones leading to low yields (about 5%) of phenoxathiine 10,10-dioxides (34JCS422, 56JA5357). However, this type of compounds can be easily prepared by other methods (05CB1411, 06CB1340). 

Use of some pyridinium oxides in this reaction was also described and the formed azaphenoxathiin /V-oxides can be easily converted to their mother heterocycles (80JHC989, 87JHC211). When 3-chloro-4-nitropyridine 1-oxide (271) was used, small amounts of products of Smiles rearrangement were... 

Chloro-5-nitrobenzaldehyde, -acetophenone, or -benzophenone derivatives treated with 2-aminothiophenol under alkaline conditions provided good yields of the corresponding dibenzo[(3,/][l,4]thiepins. Similar treatment of 2-chloro-3,5-dinitrobenzophenone (318) provided 58% of dibenzo[(3,/][l,4]thiepin 321 and 20% of phenothiazine 323. Its formation can be easily explain by the Smiles rearrangement of the initially formed intermediate 320 into diphenylamine derivative 322, followed by denitrocyclization reaction leading to the corresponding product of denitrocyclization 323 (Scheme 49). When the reaction was done in pyridine, only this product was isolated in 50% yield (57JCS3818). 

The Smiles rearrangement of sulfones 352 led to intermediates 353 the final ring closure was done in glacial acetic acid to provide the corresponding products of denitrocyclization 354 in 66% yield (Scheme 54) (72JHC699). 

Intramolecular cyclization can yield fluorinated phenoxazines by a Smiles rearrangement (86IZV1855) and 2,3-dihydro-l,4-benzodioxins by a base-induced reaction [81JFC(18)483]. 

Both cis- and rrans-l-arylsulfonyl-2-arylsulfenyl propenes (56) underwent a Smiles rearrangement under electron impact at 20 and 70 eV and formed a diarylsulfide ion [M — 104]+ (equation 27a)39 through a process where a bond between the R C H group and the sulfide sulfur is formed and a rearomatization occurs by a loss of the neutral thiirene dioxide or a simultaneous expulsion of SOz and propyne. The ion m/z 148 was also obtained from all of the sulfonyl-sulfides, 56 (equation 27b) and here the loss of R2 seemed to be related to the bond strength39. In addition to the above compounds 56 exhibited some simple cleavages before and after sulfone-sulfinate rearrangements. 

A Smiles rearrangement (equation 28) was also responsible for the secondary loss of SOz in the El induced fragmentation of 2-(p-chlorophenoxymethyl)-3-arylsulfonylmethyl-5-chlorobenzo(h)thiophenes (59) but not in their 3-alkylsulfonylmethyl derivatives33. In the latter, the loss of RS02 from the molecular ions and those of RS02 and RSOH from the [M — C1C6H40] + ions are the predominant routes of fragmentation. 

Nucleophilic substitutions of halogen by the addition-elimination pathway in electron-deficient six-membered hetarenes by sulfinate anions under formation of sulfones have been described earlier120. The corresponding electron-poor arenes behave similarly121 (equation 30). A special type of this reaction represents the inverse Smiles rearrangement in equation 31122. 

Coats and Gibson250 have reported that sulfmic acids obtained from the rearrangement of o-hydroxy sulfones can be reconverted to the original sulfones. This reaction, which has been designated as the reverse Smiles rearrangement, took place readily when the sulfinic... 

In reducing media, a synthetically useful variation of the Smiles rearrangement, which leads to the formation of fused ring systems, has been observed (equation 77)251. In this reaction, rearrangement is followed by displacement of the sulfinate anion by a nucleophilic o -substituent. 

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