Indoles carbon dioxide reaction with

The in situ generation of the carbon dioxide adduct of an indole provides sufficient protection and activation of an indole for metalation at C-2 with r-butyl-lithium. The lithium reagent can be quenched with an electrophile, and quenching of the reaction with water releases the carbon dioxide. ... 

Oddo and Sessa claimed that 1-carboxyindole (375) was obtained on treatment of indole magnesium iodide with gaseous carbon dioxide. Majima and Kotake later reported that 3-carboxyindole (376) and not 375 was the main product obtained in this reaction improved yields of 376 were obtained when the reaction was carried out in anisole instead of ether.Subsequently, several workers have employed essentially this procedure, for the synthesis of 376. It has recently been shown, however, that both the acids 375 and 376 are formed in approximately equal amounts by the carbonation of the indole Grignard reagent (Kasparek and Hea-cook ). 

Pyrano-[4,2-b]-pyrrol-5-ones (40) and pyrano-[4,3-b]-pyrrol-6-ones (41) (Figure 2.4) are stable cyclic analogs of pyrrole 2,3-quinodimethane and undergo Diels Alder reaction [40, 41] with various dienophiles to afford indole derivatives after loss of carbon dioxide. 

Flynn et al., also described the synthesis of the fused indoles [73]. The o-iodotrifluoroacetanilide 110 was coupled to aryl alkyne 111 under Sono-gashira conditions followed by subsequent reaction with aryl iodide, 107 with gaseous carbon dioxide produced the fused indole 158. Lewis acid dealkylation with aluminum trichloride produced the deprotected alcohol 159. 

Cycloadditions have been carried out to 37/-indoles (222, 223) (125,126), N-arylmaleimides (224) (127,128), l,2), -azaphospholes (225) (129), 5(47/)-oxazo-lones (226) (130), and 4,5-dihydrooxazoles (230) (131). The primary cycloadducts from the reaction of oxazolones (e.g., 226 with diaryl nitrile imines), derived from tetrazoles in refluxing anisole, do not survive. They appear to lose carbon dioxide and undergo a dimerization-fragmentation sequence to give the triazole 228 and the diarylethene 229 as the isolated products (130). In cases where the two aryl substituents on the oxazole are not the same, then, due to tautomerism, isomeric mixtures of products are obtained. 

The magnesium bromide salt of indole gives the 3-carboxy derivatives in about 30% yield on reaction with carbon dioxide (56JCS2853). Ethyl indole-3-carboxylate can be obtained directly, but in modest yield, using ethyl chloroformate (62JOC496, 6602805). Indole-2-carboxylic acid derivatives can be obtained via the benzenesulfonyl-protected 2-lithio derivative (equation 181) (73JOC3324). 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

To exploit the reactions of the C-lithio derivatives of N-unsubstituted pyrroles and indoles, N-protecting/masking groups such as ferf-butoxycarbonyl, terZ-biitylcarbamoyl, benzenesulfonyl, dimethylamino, and dimethylaminomethyl must be used. This is illustrated by a route to G-acylated pyrroles 441. Another very useful process involves N-lithiation, N-carbonation, and lithiation of the resulting indol-l-ylcarboxylate at C(2) reaction with an electrophile and loss of carbon dioxide during work-up give N-unsubstituted 2-substituted indoles, for example, 2-haloindoles in excellent yields. 

Many compounds [olehns, alcohols, and carboxyhc acids (or other carbonyl chemistry)] will undergo dimerization reactions. Figure A15-7 shows how carboxylic acids can react with an alcohol to form a dimer [6] (note that it should be loss of water and not carbon dioxide). In RP-UPLC under basic conditions, the elution order would be dihunisal in its ionized form < descarboxydiflunisal < the dimer. Indoles have been shown to dimerize under acidic conditions, and phenols have shown to dimerize under free radical initiated oxidative conditions, usually ortho-phenols [1]. Due to the low bond dissociation energy of the benzylic C-H bond and ease of radical formation, dimerization can occur at the benzylic center. Nalidixic acid undergoes dimerization under thermolysis conditions to produce a dimeric structure [26]. 

Activity Tests with Model Compounds. Activity tests with model compounds were also carried out for the fresh, regenerated, and aged catalysts in a fixed bed reactor under a vapor phase condition at 5.0 MPa. 3 cm of crushed catalyst (0.35 - 0.5mm) was diluted with 9 cm of inactive alumina particles. Catalyst activities, such as hydrodesulfurization (HDS), hydrodenitrogenation (HDN), and hydrogenation (HG), were measured, feeding a mixture of 1 wt% carbon dioxide, lwt% dibenzothiophene, 1 wt% indole, and 1 wt% naphthalene in n-heptane. The catalysts were presulfided with a 5% H2S/H2 mixture at 400 °C for two hours and aged with a liquid feed at a reaction condition for 24 hours. Tests for HDS and HDN reactions were conducted at 275 °C, while those for a HG reaction were done at 325 °C. Condensed liquid products were analyzed with gas chromatography. Since all the reactions took place with the crashed catalysts in the vapor phase, we assumed that effectiveness factors were unity (9). 

One of the most convenient iV-protecting gronps in indole a-lithiations is carbon dioxide becanse the iV-protecting gronp is installed in situ and, fnrther, falls off during normal work-up. This technique has been nsed to prepared 2-halo-indoles and to introdnce a variety of substitnents by reaction with appropriate electrophiles - aldehydes, ketones, chloroformates, etc. ... 

A dihydro version of the pyranoindoI-3-one has also been used as a precursor of an indole quinodimethane, as the result of thermal loss of carbon dioxide <89TL7289, 93T439>. The dihydro compounds can be prepared effectively from the pyranoindolones by a sequence of lactone hydrolysis, carbonyl reduction and relactonization. They can then be decomposed thermally in the presence of suitable dienophiles such as maleimides, quinones, or unsaturated ketones or esters. For example, the dihydroindolone (309) in its thermal reaction with iV-phenylmaleimide gives the tetracyclic adduct (310) (Scheme 93). 

Gribble and coworkers [90, 91] have shown that munchnones 220 undergo dipolar cycloadditions with 2- or 3-nitro-substituted A -protected indoles 219 to give, after loss of carbon dioxide from the initial cycloadduct 221, the corresponding pyrroloindoles 222. These products are synthetic equivalents of indole 2,3-quino-dimethanes and in turn have been used as dienes in subsequent Diels-Alder reactions (see the following chapter). For munchnones that provide unsymmetrically substituted pyrroles (i.e.. Re and R7 are not same), good regioselectivity is observed in the cycloaddition reactions (Scheme 60). 

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