Keto-indoles

Tietcheu, C., Garcia, C., Gardette, D., Dugat, D., and Gramain, J.-C. (2002) Efficient photochemical synthesis of tricyclic keto-indoles. Journal of Heterocyclic Chemistry, 39, 965-973. 

Irradiation of the paracyclophane (24) - in 1,2-dichloroethane solution in the presence of iodine - is reported to give an 80% yield of the novel quinolinophane-2(lH)-one (25) (Aly, Chapter 4). Tricyclic keto-indoles (27) are reported to be formed in good to excellent yields from the readily accessible enaminones (26) (Tietcheu et al. Chapter 4). The reaction occurs under various conditions, but the best results are obtained in the presence of sodium methoxide in benzene-methanol solution. 

The key intermediate in the Joule syntheses (251) in this series is the pyridyl keto indole 604, which was prepared by Scheme 37. Standard reactions gave the y-amino enone, 605. Reaction of 605 with the salt of dimethyl sulfoxide and acetic acid-catalyzed rearrangement of the tetracyclic intermediate 606 gave dasycarpidone (607) and 3-epidasycarpidone (608) via the iminium 609. Dasycarpidone was converted to uleine (610) by the Wittig reaction, but 3-epidasycarpidone required somewhat different conditions for conversion to 3-epiuleine (611 Scheme 37). 

As we have seen, a large number of pyrrole indole dehydrogenations involved the use of abenzoquinone, usually DDQ, and a selection of the substrates that were converted to indoles is sununarized in Schane 4 [20-29]. In each case the compound shown afforded the fully aromatic indole in some cases the yields were not reported. The oxidation of trifluoro alcohol 9 afforded the keto indole. Space does not permit the illustration of the syntheses of the substrates shown in Schane 4. 

An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acld in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acrtophenone phenylhydrazone (I) gives 2-phenyllndole (I V). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction ... 

The keto arylhydrazone 22 indolized to give only the 3-H substituted indole 23 upon treatment under the cyclization conditions. Indolization had occurred toward the more substituted carbon atom. ... 

Many 3-substituted indoles have also been prepared with the use of a-alkyl or a-aryl-p-keto sulfides. Thus indolization of aniline 5 with 3-methylthio-2-butanone 27 furnished indolenine 28, presumably via the same mechanism discussed earlier. The indolenine 28 was relatively unstable and reduced to the indole 29 without purification. Tetrahydrocarbazole 32 was prepared in 58% overall yield. Smith et al. made excellent use of the Gassman process in the total synthesis of (-i-)-paspalicine and (+)-paspalinine. ... 

On saponification l-(2-methoxycarbonylphenyl)pyrrole yields l-(2-carboxyphenyl)pyrrole, m.p. 106-107°, which on reaction with polyphosphoric acid at 70° is cyclized to 9-keto-9H-pyrrolo-(l,2-a)indole in 28-32% yield. Through the choice of the appropriate amine and acetal components, the substituted l-(2-meth-oxycarbonylphenyl)pyrroles become readily available intermediates in the preparation of a variety of derivatives of the pyrrolo( 1,2-a) indole ring system. 

Finally, 1-ethyl-2-methyl indole was reacted111 with pyromellitic anhydride to give a mixture of keto acids, as in Scheme 12, which was then treated with diphenylamines to yield bisphthalides such as 33 and 34. These color formers produce orange images on development, as also do those in which the indole residue is replaced by a 4-dialkylaminophenyl group. 

It has been known for sometime that 2-(2-bromoanilino)enones undergo Heck-type cyclizations to form indoles and carbazoles. Thus, Kibayashi reported the synthesis of 4-keto-l,2,3,4-tetrahydrocarbazoles in this manner [362], and Rapoport employed this reaction (296 to 297) to achieve an improved synthesis of 7-methoxymitosene [363]. A series of related mitosene analogs has been crafted using Pd chemistry by Michael and co-workers [364], They found that P(o-tol)3 was far superior to PPh3 in conjunction with Pd(OAc)2. 

The mechanism of this elegant, surprising, and widely applicable synthesis of indole derivatives was only explained recently (R. Robinson). It must be assumed that the keto-phenylhydrazones, in tautomeric hydrazo-form, undergo a species of benzidine rearrangement which, like the latter, can often occur even in dilute acid solution, e.g. with the phenylhydrazone of pyruvic acid. 

Finally, indole ring formation is via condensation of the amino and keto functions. This is analogous to imine formation, as seen in part (a), but dehydration produces the aromatic pyrrole ring rather than an imine. Alternatively, one could write imine formation followed by tautomerism to the aromatic enamine. 

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-f>]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). 

The synthesis of cyclic ethers 137 was achieved by a Fischer indole synthesis starting from cyclic keto arylhydrazones generated in situ from 4-(hydroxy-methylene)-3,4-dihydrobenzo[ 7]oxepin-5(2H)-one 136 and the corresponding diazonium salt (Equation (20), 1993JHC1481). 

The study (05ZOR89) showed that thenoines actively react with thiols in acidic media at room temperature to give /1-keto sulfides 250 in good yields. On alkaline hydrolysis, the latter compounds are readily cleaved to ketones 251, which are valuable intermediates for subsequent syntheses. In 06MI2, they were involved in a Fischer reaction and indole- bridged dithienylethenes 252 and 253 were obtained. Hence, a convenient procedure was developed for the transformation of readily available acyloins into photochromic indole-bridged dithienylethenes (Scheme 71). 

The key step in this synthesis is an intramolecular nucleophilic attack on the electron-rich indole nucleus by the carbocation derived from the p-keto sulfoxide in the presence of acid. Finally, the intermediate tetrahydrocarbazole aromatizes by elimination of methanethiol under the conditions of the reaction to produce the hydroxycarbazole (511) (Scheme 5.12). 

Muthusamy found that with the simple cyclohexyl keto-ylide derived from 189 (Ri = H) and an electron-withdrawing group protecting the indole nitrogen, that the indole would add in a regioreversed fashion producing the other possible... 

A recent example of this intramolecular tandem transformation is the Rh(ii)-catalyzed reaction of diazo keto ester 71. Depending on the structure of the diazo compound, a push-pull dipole intermediate derived from 71 can be trapped either by a tethered vinyl group (when n = 0) or by an indole 7r-bond (when n=l) (Equation (11)). This result clearly demonstrates a critical role of the conformation of the cycloaddition transition state. 

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