Gassman synthesis of indoles

In 1974, Gassman et al. reported a general method for the synthesis of indoles. For example, aniline 5 was reacted sequentially with r-BuOCl, methylthio-2-propanone 6 and triethylamine to yield methylthioindole 7 in 69% yield. The Raney-nickel mediated desulfurization of 7 then provided 2-methylindole 8 in 79% yield. The scope and mechanism of the process were discussed in the same report by Gassman and coworkers as well. 

Ilac Gassman method for synthesis of indoles from /V-haloanilines 3.06.3.4.3... 

In 1974, Paul Gassman and co-workers recognized the potential of the described rearrangement and reported a one-pot, general method for the synthesis of indoles based on the rearrangement of the nonisolable aza-sulfonium ylides. In the very first example of this method, aniline 4 was treated sequentially with f-BuOCl, methylthio-2-propanone 5 and triethylamine to provide methylthioindole 6 in 69% yield. Raney-nickel-mediated desulfuriza-tion afforded 2-methylindole 7 in 79% yield. 

In 1981, Wierenga first introduced a modification of Gassman oxindole synthesis for the synthesis of indole derivative 34, part of the left-hand segment of the antitumor agent CC-1065. In accordance to that, addition of derivative 30 in a equimolar amount of the hindered base, [1,8-bis(dimethylamino)naphthylene (R3N), to the chloride complex of ethyl-a-(mercaptomethyl)propionate 31, followed by a triethylamine catalyzed Sommelet-Hauser rearrangement and an acid-induced cyclization gave oxindole 32. Treatment of 32 with excess BH3 SMei at room temperature afforded 33 in 95% yield. 

The Gassman method has proven to be adaptable to complex structures, such as the intermediate 7.20B used in the synthesis of the indole diterpenes paspalicine and pasalinine[5]. Table 7.5 gives some other examples. 

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. ... 

The Gassman indole synthesis has one serious limitation. Attempts to use anilines with an ortho/para- methoxy moiety failed to indolize. One means to overcome this was synthesis of the corresponding oxindoles followed by reduction to the indoles. ... 

Indok synthesis. Gassman and van Bergen have used a modification of the above-mentioned procedure for synthesis of 2-substituted indoles from anilines. The aniline IS treated as above with a chlorinating reagent at — 65° and then an equivalent of methyl-thio-2-propanone at the same temperature. An equivalent of a base (usually triethyl-amine) is added. Workup affords the indole derivative (2) in 60-70% yield. The thio-methyl group is removed with Raney nickel (>70% yield). The keto sulfide can be varied thus nse of methyl phenacyl sulfide [CH3SCH2C(=0)C5H5]4 in the synthesis leads to 2-phenylindoles. 

A total synthesis of (+)-paspalicine and (+)-paspalinine took advantage of the Gassman indole synthesis. The thiomethyl ketone was treated with A-chloroaniline (prepared by mixing aniline with t-butyl hypochlorite) to afford the azasulfonium salt, which was transformed into anilinylsulfide upon treatment with triethylamine. Desulfurization with Raney nickel was followed by the acid-catalyzed cyclization to give the hexacyclic indole intermediate. 

In the synthesis of an indoloquinolone antibacterial, the Gassman indole synthesis was explored to serve as the central operation. Therefore, difluoroaniline was selectively monobrominated. Although the Fischer indole cyclization for the resulting 2-bromo-4,5-difluoroaniline only gave the indole in poor yield, the Gassman indole synthesis worked well in one pot. Thus, treatment of the aniline with r-butyl hypochlorite was followed by addition of ethylthio-2-propanone and treatment with triethylamine to produce the indole in excellent yield. 

The most extensively used approach is route A (Scheme 1). Some of the more commonly employed indole syntheses, such as the Fischer, Bischler, Nenitzescu and the Gassman procedures, also fall into this category.Of these, the Fischer indole synthesis (Scheme 2) has been most widely applied. However, the requirement of properly substituted starting materials, which can often be difficult to fulfil, and/or the lack of regio-selectivity in the cyclizative step, limit its utility. An example of the use of the Fischer indole synthesis in the synthesis of a carbazole alkaloid is given in Scheme 3. 

Although isatins having adjacent carbonyls of very different reactivity— amide vs. ketone—undergo a variety of chenucal reactions [86,87], the focus here is on synthetic transformations to indoles. Accordingly, isatins can be reduced directly to indoles (Scheme 11, equations 1-7) [16,89-93]. Given the availability of isatins from aromatic amines (e.g., Sandmeyer synthesis [86], Gassman synthesis [88]), the reduction of isatins to indoles can be an important alternative to other methods. 

Generally, the reaction works well for electron-deficient anilines. A modified approach using in situ prepared chlorosulfonium salts is preferred for more electron-rich anilines. Substituted thiol derivatives can be used to produce 3-oxindoles, which can be further reduced to 3-indole derivatives that are not available via the Gassman indole synthesis. The reaction is equally useful for the preparation of isatin derivatives vide infra). Historically, the Gassman oxindole synthesis has found applications in the preparation of heterocycles with medical or insecticidal properties. The reaction also has potential applications for the synthesis of oxindole containing natural products. ... 

The indole nucleus is present in various bioactive molecules and many selective protocols for its construction have been developed. Classical methods for the indole synthesis include the Fischer indole synthesis, the Batcho-Leimgruber synthesis from o-nitrotoluenes and dimethylformamide acetals, the Gassman synthesis from N-haloanilines, the reductive cyclization of o-nitrobenzyl ketones, and the Madelung cyclization of A/ -acyl-o-toluidines [42,43]. 

The Gassman indole synthesis involves an one-pot process in which hypohalite, a P-carbonyl sulfide derivative 2, and a base are added sequentially to an aniline or a substituted aniline 1 to provide 3-thioalkoxyindoles 3. Raney nickel-mediated desulfurization of 3 then produces the parent indole... 

The Gassman indole synthesis provides a single regioisomer when ortho/para substituted anilines are employed, the yields of which are quite good generally. This provides some advantage in the preparation of 7-substituted indoles compared to other methods which normally give low yields, that is, the Fischer indole process. ... 

The mechanism of the Gassman indole synthesis bears some resemblance to that of the Fischer indole reaction. An Sn2 displacement of the TV-chlorinated aniline with the a-keto sulfide gives rise to a sulfonium ion. After deprotonation, a [2,3]-sigmatropic rearrangement (Sommelet-Hauser rearrangement) takes place where the weak N-S bond is broken and a strong C-C bond is formed. Similar to the Fischer indole reaction, the resulting imine was transformed into indole after re-aromatization and cyclization. 

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