Indoles with oxalyl chloride

In 2001, Knaack and co-workers56 reported an application of the INADEQUATE experiment in the course of synthesizing and characterizing a biologically active 2-[l-(4-chlorobenzyl)-lH-indol-3-yl]-2-oxo-N-pyri-din-4-yl acetamide (6). Treatment of l-(4-chlorobenzyl)-lH-indole with oxalyl chloride afforded the corresponding oxoacetyl chloride that was finally subjected to aminolysis with 4-aminopyridine to afford the final product of the reaction scheme, 6. Although the NMR data supported the N-benzyl structure, a 1,1-ADEQUATE spectrum was acquired to provide additional confirmation of the structure of 6. 

EXTENSIONS AND COMMENTARY N-Methyltryptamine (monomethyltryptamine, NMT) is an alkaloid that has been found in the bark, shoots and leaves of several species of Virola, Acacia and Mimosa. However, the major snuffs associated with these plant have been shown to also contain 5-MeO-DMT and are discussed there. NMT has been synthesized in a number of ways. One can react 3-(2-bromoethyl)indole with methylamine. NMT can be isolated as the benzoyl derivative from the methylation of tryptamine with methyl iodide followed by reaction with benzoyl chloride, with the hydrolysis of this amide with alcoholic KOH. It can also be synthesized from indole with oxalyl chloride, with the resulting glyoxyl chloride reacting with methylamine in ether to give indol-3-yl N-methylglyoxalylamide (mp 223-224 °C from IPA) which is obtained in a 68% yield, which is reduced to NMT to give the amine hydrochloride (mp 175-177 °C from ) in a 75% yield. The most simple and direct synthesis is the formamide reduction given above. 

Some acyl halides are reactive enough to effect Friedel-Crafts acylation on the neutral heterocycles without a catalyst. For pyrrole such reactions are known, for example, with trifluoroacetyl chloride and trichloroacetyl chloride. Indole reacts smoothly in cold ether with oxalyl chloride and on heating with acetic anhydride. Some examples of these types of acylation are collected in Table 10. 

Acylation of the C3 position can also be accomplished with acid chlorides, as illustrated in the synthesis of indole 7.34, a drug for the treatment of depression. Reaction of indole 7.31 with oxalyl chloride affords C3-substituted product 7.32 even though the benzene ring is very electron-rich. Conversion to amide 7.33 is followed by reduction with lithium aluminium hydride which removes both carbonyl groups, affording the target indole 7.34. 

These bromides may be isolated in substance or worked up to give the free acid or the ester. Azulenes (e.g., isoguaiazulene) and olefins609 react in this way. Indoles react with oxalyl chloride by substitution at position 3.610... 

A sequence of bromination of a 3-indolyl acyl group followed by azide displacement and reduction, provides an effective route to 3-(a-aminoacyl)indoles <88JHC469>. Indoles react readily with oxalyl chloride at C-3 and the products have been used in combination with aryl acetic acid derivatives to generate indolyl-substituted maleic anhydrides and imides, as precursors for indolocarbazole antibiotics <90TL2353,93TL5623>. 

For instance, treatment of indole with bromine gives exclusively 3-bromoindole. In the same vein, Michael addition with nitroethene, ethyl acrylate, and the Vilsmeier reagent all take place at C3. The adduct between indole and the Vilsmeier reagent can be hydrolyzed under basic conditions to give 1//-indole-3-carbaldehyde. Meanwhile, nitration and treatment with oxalyl chloride all give rise to the C3 electrophilic substitution products. 

Greenhouse and colleagues have reported the regiospecific introduction of chlorine atoms into the 2-position of pyrrol-3-yl and indol-3-yl sulfoxides using oxalyl chloride [213]. For example, the pyrrol-3-yl sulfoxide (276), on treatment with oxalyl chloride followed by m-chloroperbenzoic acid oxidation (1.1 eq), gives the 2-chloro-substituted product (277) in 83% yield (Scheme 5.91). 

Recentiy, glyoxylyl chlorides 3, formed in situ by direct glyoxylation of electron-rich heterocycles such as indoles and pyrroles with oxalyl chloride, have been coupled in the Cu-catalyzed Stephen-Castro reaction to terminal arylacetylenes [11]. The resulting heterocycHc ynediones 4 are valuable electrophihc building blocks for the synthesis of various pharmaceutically relevant compounds (Scheme 9.3). 

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

The early literature on the reactions of the indole Grignard reagents with the simple diacid chlorides, in particular with carbonyl chloride and oxalyl chloride (see Section III,C,4,b), is both conflicting and confusing and much of the work reported warrants repetition since the evidence presented in support of many of the structural assignments made is not entirel3 convincing. 

To 25 g indole (or 50 g 4-benzyloxyindole or 0.21 M other indole) in 1 L dry ether at 0° add a solution of 50 ml (75 g) oxalyl chloride in 1 L dry ether carefully and with good stirring a little at a time over Vi hour and stir until bubbling ceases (about one-half hour more). Some indoles require a longer reaction time (e.g., 4-Cl-indole requires fifteen hours refluxing) and some will not react (e.g., 4-Br-indole). Add portionwise, carefully with stirring at 0°, a solution of... 

SYNTHESIS (from indole) To a well stirred solution of 10 g of indole in 100 mL MTBE, cooled to 0 °C with an ice bath, there was added 8.6 g oxalyl chloride. The reaction mixture was stirred for 0.5 hr, and the solids removed by filtration and washed twice with 50 mL MTBE. This acid chloride was added to 20 mL anhydrous diisopropylamine. There was then added an excess of 2N HCI, the mixture cooled, and the resulting solids removed by filtration. These were recrystallized from MeOH to give, after air drying, 11.4 g (49%) indol-3-yl N,N-diisopropylglyoxylamide with a mp of 200-202 °C. 

There is the raw stuff potentially available to answer this question. There are a couple of compounds known with the sulfur in the 4-position, which is the location of the oxygen atom in psilocybin. The 4-thio analogues have been synthesized from 4-methylthio-indole, via the oxalyl chloride method and reaction with the appropriate amine. With dimethylamine, the indoleglyoxylamide was made in a 43% yield and had a mp 163-164 °C. With diisopropylamine, the amide was made in a 27% yield and had a mp 190-192 °C. The final amines were prepared by the reduction of these amides with LAH in THF. N,N-Dimethyl-4-thiotryptamine (4-MeS-DMT) was obtained in a 68% yield and melted at 108-110 °C N,N-diisopropyl-4-methylthiotryptamine (4-MeS-DIPT) was obtained in a 61% yield and melted at 92-94 °C. In animal studies of behavioral disruption with these three compounds, there was systematic drop of potency in going from the 5-MeS-DMT to 4-MeS-DMT to 4-MeS-DIPT. 

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... 

A soln of a (—)-4-nitrobenzyl [cyclohexyl(Fmoc-amino)methyl]phosphonic add (57 40.0 mg, 0.073 mmol) in CH2C12 (2mL) was cooled to 0°C, and dry DMF (6pL, 0.01 mmol) and oxalyl chloride (13 pL, 0.147 mmol) were added. The mixture was stirred for 0.5 h at 0°C, diluted with benzene (5mL), and concentrated. The phosphonochloridate was redissolved in benzene (2mL), and treated with TEA (20 pL, 0.147 mmol) followed by AgCN (29 mg, 0.217 mmol). After 5 min at rt, D-2-hydroxy-3-(l//-indol-3-yl)propanamide (22.4mg, 0.011 mmol) was introduced, and the mixture was heated at reflux for 2h, cooled to rt, filtered, and concentrated. The phosphonate diester was purified via flash chromatography (2% MeOH/CH2Cl2) to give a mixture of diastereomers (19.8mg, 37%), which were separated by RP-HPLC. For the minor diastereomer (4.5 mg, amorphous solid) [a]D +15 (c 0.47, EtOH). 

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