Indoles, reactions

Phosphorus trichloride in benzene is reported to effect mild and fast cydization. It has been used for synthesis of 2,3-dialkyl- and 2,3-diaryl-indoles[8-ll]. Table 7.2 presents some typical Fischer indolization reactions using both the traditional and more recently developed reaction conditions. 

A number of reaction pathways have been proposed for the Fischer indolization reaction. The mechanism proposed by Robinson and Robinson in 1918, which was extended by Allen and Wilson in 1943 and interpreted in light of modem electronic theory by Carlin and Fischer in 1948 is now generally accepted. The mechanism consists of three stages (I) hydrazone-ene-hydrazine equilibrium (II) formation of the new C-C bond via a [3,3]-sigmatropic rearrangement (III) generation of the indole nucleus by loss of... 

Imitrex (Sumatriptan) 82 is the first selective 5-HTid agonist developed by Glaxo for the treatment of migraine. The synthesis of Imitrex has been carried out by several different routes all of which involved a Fischer indolization reaction as the key step. Outlined below is one of the synthetic routes. 

LY311727 is an indole acetic acid based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) under development by Lilly as a potential treatment for sepsis. The synthesis of LY311727 involved a Nenitzescu indolization reaction as a key step. The Nenitzescu condensation of quinone 4 with the p-aminoacrylate 39 was carried out in CH3NO2 to provide the desired 5-hydroxylindole 40 in 83% yield. Protection of the 5-hydroxyl moiety in indole 40 was accomplished in H2O under phase transfer conditions in 80% yield. Lithium aluminum hydride mediated reduction of the ester functional group in 41 provided the alcohol 42 in 78% yield. 

We envisioned that improvement of the key Fisher indole reaction using diethyl 4-(N,N-dimethylamino)butanal (11) instead of diethyl 4-chlorobutanal (8) would lead to formation of the desired product directly. The approach would circumvent... 

The reaction tolerates a variety of functional groups, especially the acid-sensitive acetal (81b), carbamate (81c) and the benzyl triazole (81d-f, and 81h, j). These intermediates, which are unstable under the conditions of the traditional Fischer indole reaction, were conveniently synthesized using this method. The structurally... 

Reaction of phenyldiazonium chloride with 66 provides 6-phenylhydrazono derivative 72. Fischer indolization reaction of 72 in polyphosphoric acid gives pentacyclic 3-azarutecarpine derivatives 73 (Equation 3) <1996T7789>. 

McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2-substituded indoles <06T5109>. 

The required chirally substituted indoloazepine 219 was prepared by reaction of (5)-l-(l-naphthyl)ethylamine with the methiodide of 4-piper-idone (223), followed by a Fischer indole reaction leading to the V-carboline 224 (Scheme 56). Chlorination and reaction with thallium dimethylmalonate, followed by decarbomethoxylation of the resulting in-... 

Most indoles are synthesized by the Fischer indolization reaction. Here a phenylhydrazine is first reacted with an aldehyde, or ketone, carrying an a-methylene group (not acetaldehyde). The corresponding hydrazone is then treated with an acid, often hydrochloric acid. Ring closure occurs, through a [3,3]-sigmatropic change, and ammonia (as the ammonium cation) is lost (Scheme 7.14). 

An alternative synthesis from the Glaxo patents involves Fnedel-Crafts acylation of the 3-position of the indole intermediate 22 (Scheme 5) Reaction of hydrazine 10 with (phenylthio)acetaldehyde gave hydrazone 20, which was subjected to the Fischer indole reaction to give 3-thiophenylindole 21. It is noteworthy that this Fischer cyclization took place at room temperature because most require heat. Reductive desulfurization of 21 using Raney nickel provided indole 22. Acylation of the 3-position... 

The yield of the Fischer indole reaction was improved dramatically by employing 3-cyanopropanal diethylacetal as the aldehyde coupling partner (Scheme 10). Thus the hydrazone 33 was formed by reacting the hydrochloride salt of 31 with the diethylacetal in aqueous HCl. The hydrazone 33 was treated with polyphosphate ester in... 

Naratriptan was also prepared using the Fischer indole reaction (Scheme 15). Thus hydrazine 43 was condensed with Al-methyl-4-piperidineacetaldehyde in aqueous HCl to form hydrazone 44. Fischer indohzation was effected by treating 44 with polyphosphate ester in refluxing CHCI3 to provide naratriptan (3) in low yield. Higher yields may be attainable with the use of milder Fischer cyclization conditions (i.e. acetic acid or aqueous HCl). 

Scheme 15. Synthesis of naratriptan (3) using the Fischer indole reaction.

The Merck process group in Rahway has developed two syntheses of rizatriptan (4) utilizing palladium catalyzed indolization reactions (Schemes 19 and 20). Both routes start from the iodoaniline 51, which was prepared by reaction of 47 with iodine monochloride in the presence of CaCOa. " Palladium catalyzed coupling of iodoaniline 51 with bis-triethylsilyl protected butynol in the presence of NaaCOa provided a mixture of indoles 52a and 52b. This mixture was desilylated with aqueous HCl in MeOH to furnish the tryptophol 53 in 75% yield from 51. Protection of the alkyne prevented coupling at the terminal carbon of the alkyne and tnethylsilyl (TES) was found to be optimal because it offered the correct balance between reactivity (rate of coupling) and... 

Scheme 21. Synthesis of almotriptan (5) using the Grandberg modification of the Fischer indole reaction.

The Vilsmeier-Haack formylation procedure (Scheme 24) provides the most effective synthesis of formylpyrroles and indoles. Reaction of the heterocycles with the immonium cation (72), derived from DMF or (V-methylformanilide with an acid chloride, such as phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, benzoyl chloride or bromotriphenylphosphonium bromide, yields the intermediate heteroarylimmonium salt (73). Under suitable reaction conditions, this salt may be isolated from the reaction involving phosphorus oxychloride as an impure chlorophosphate (78TH30500) or precipitated from the reaction system as the thermally unstable perchlorate by the addition of sodium... 

Enamines derived from thiopyran-3-one, although tautomeric, tend to exist predominantly in conjugation with the sulfur atom the Fischer indole reaction, when applied to that ketone, affords solely the systems fused 2,3 on to the thiopyran (Scheme 10) (76CL5). 4-Amino-3,4-dihydro-2Ff-thiopyrans readily eliminate ammonia or amines on heating or treatment with acid, with formation of 2H- thiopyrans <78CR(C)(286)553). 

The reaction with dienophiles of the sulfur-substituted 3-vinylpyrrole, generated in situ by the alkylation of the 3-thioacetylpyrrole, has also been utilized to obtain indoles. Reactions with dimethyl maleate, dimethyl fumarate, methyl acrylate, acrylonitrile, and acrolein gave the corresponding cycloadducts which were directly transformed to the corresponding indoles by treatment with DDQ (91CPB489). 

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