Smiles rearrangement spiro intermediate

Reversible double Smiles rearrangement through intermediate formation of tautomeric Meisenheimer spiro-complexes was observed in the system of l-methylamino-3-picryloxy-2-propanol [18] (Scheme 9). 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

As depicted in Scheme 53 the photo-Smiles rearrangement involves radical ion pairs. Intermediately the spiro-type Meisenheimer complex 277 is formed... 

Among the more recent approaches to phenoxazines and phenothiazines the reductive cyclization of 2-nitrodiphenyl ethers and sulfides with trialkyl phosphites is the most interesting. Here too a spiro intermediate is involved, produced by attack of an initially formed aryl nitrene on the second aromatic ring. The sulfide (252), for example, reacts with triethyl phosphite to yield 1-methylphenothiazine (253) and it is clear that in this case ring opening of the spiro intermediate also proceeds with a rearrangement of the Smiles type (Scheme 113) (75JCS(P1)2396). 

The reaction with pyridone (167) was interpreted as proceeding by the formation of the pyridone (168), followed by the Smiles rearrangement leading to the spiro compound (169), which by ring opening provides the pyrimidine derivative (170). In a subsequent cyclization step the pyrido-[1,2-aJpyrimidine skeleton (171) is formed, and finally hydrolysis of the imino group leads to the 6-oxo derivative (172). In the homologous imidazo-[l,2-n]pyridine series, the 5-iminoimidazo[l,2-c<]pyridine intermediate of type (171) could be isolated. 

To the best of our knowledge, the first indication that the Smiles rearrangement could be applied to olefination reactions emerged from the work of Hirai and coworkers [77] in 1972. These authors reported that anion generated from the thiazole-2-thiol derivatives 161 (R = H or Ph) (Scheme 52) and n-butyllithium (when R = H, two equivalents were used) reacted with ben-zaldehyde to provide, after chromatography, thiirane 162 and 1,3-thiazoHdin-2-one. Distillation of the thiirane gave the respective olefin 163 (which was also detected in the crude product). The authors realized that the reaction occurred through a spiro-bicyclic intermediate. 

In an interesting synthesis of 2-cyano-4,5-dihydro-3//-3,l-benzoxazepine 68 Besson el al. have found that reaction of 2-(aminophenyl)ethanol reacts with 4,5-dichloro-1,2,3-dithiazolium chloride to form a SchifFs base, the anion of which 66 undergoes rearrangement to form the above compound in a Smiles rearrangement involving the formation of the spiro-intermediate 67 (Scheme 7) <97SL704>. 

For a possible Smiles rearrangement of N-aryl sulfonamide involving a three-membered spiro intermediate see Muller, R Phuong, N.-T. M. Helv. Chim. Acta 1979, 62,494- 96. 

Bacque et al. have reported the first ever case of a radical Smiles rearrangement going through a four-membered spiro intermediate. The xanthate 133 upon reflux with peroxide in octane afforded the Smiles product 137 via the four-membered spiro intermediate 135 along with the symmetrical diarylethane 138. ... 

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