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Indoles - Sundberg R.J.

Sundberg R.J. Indoles - Academic press, 1996. - 95 p.
ISBN 0-12-676945-1
Download (direct link): indoles1996.djvu
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The final step can involve introduction of the amino group or of the carbonyl group. oNitrobenzyl aldehydes and ketones are useful intermediates which undergo cyclization and aromatization upon reduction. The carbonyl group can also be introduced by oxidation of alcohols or alkenes or by ozonolysis. There are also examples of preparing indoles from oaminophcnyl-acetonitriles by partial reduction of the cyano group.
One route to onitrobenzyl ketones is by acylation of carbon nucleophiles by onitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonate[l], methyl acetoacetate[2], Meldrum’s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of onitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to onitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7]. Deformylation and reduction leads to 2-sub-stituted indoles.
2.3 CONDENSATION OF o-AMlNOBENZYL ALDEHYDES AND KETONES
15
Q=CR
(2.3)
Acylation of the Leimgruber Batcho enamines with phosgene followed by methanolysis and reductive cyclization generates methyl indole-3-carb-oxylates[8]
The rcactant corresponding to retrosynthetic path b in Scheme 2.2 can be obtained by Meerwein arylation of vinyl acetate with onitrophenyldiazonium ions[9], Retrosynthetic path с involves oxidation of a 2-(o-nitrophenyl)ethanol. This transformation has also been realized for 2-(oaminophenyl)ethanols. For the latter reaction the best catalyst is Ru(PPh3)2Cl2. The reaction proceeds with evolution of hydrogen and has been shown to be applicable to a variety of ring-substituted 2-(o-aminophenyl)ethanols[10],
x
^ч^-сн2сн20н Ru(PPh3)2ci2
WNH2 <2-5>
H
This method has been successfully applied to the substituted indole 2.6B, an analogue of the teleocidin type of protein kinase activators[ll].
C2H502CNH C2H502CNH
-CH2CH2OH Ru(PPh3)2CI2
NH2 toluene, 105° — , (2.6)
_ H
2.6A 2.6B
2-(o-Nitrophenyl)ethanols can be converted directly to indoles by use of a binary catalyst consisting of Pd/C or Rh/C and Ru(PPh3)2Cl2[10], The starting materials can be obtained by condensation of an o-nitrotoluene with formaldehyde. An illustrative procedure is given below for 4-chloro-indole.
The oxidative generation of o-aminophenylacetaldehydes can be done by ozonolysis (retrosynthetic path d in Scheme 2.2) but this requires an elec-
16
2 CATEGORY la CYCLIZATIONS
tron-attracting substituent either on nitrogen or the ring to prevent further oxidation. An early example was reported by Plieninger[12] and the method has subsequently been used to prepare 4-substituted indoles[13] as in the case of an intermediate in the synthesis of the natural product rivularin D[14],
Retrosynthetic path e in Scheme 2.2 requires a regioselective oxidation of an o-nitrostyrene to the corresponding phenylacetaldehyde. This transformation has been accomplished hy Wacker oxidation carried out in such a way as to ensure the desired regioselectivity. The required o-nitrostyrenes can be prepared by Heck vinylation. One procedure for oxidation uses 1,3-propanediol to trap the product as a i,3-dioxane[15]. These can then be hydrogenated over Rh/C and cyclized by treatment with dilute HC1.
CH2=CH2 rH _P~\
Pd(QAc)2 ^ хр^СИ=СИг PdCI2. CuCI 2_<0V
^Ao2 p<‘°b 1200 ^N02 HO(CH2)3OH ^no2
1) H2, Rh/C xiT,:V^
2) HCI (2.8)
H
An alternative procedure involves use of alkyl nitrites and traps the desired product as an acetal[16], o-Nitrobenzyl cyanides are also potential indole precursors. Reduction of the nitrilc to the iminc level and of the nitro group to the amine level permits cyclization and aromatization to indoles. Reduction has been carried out both in a single slep[l 7 19] or by a two-step sequence[20]. One route to the o-nitrobenzyl cyanide starting materials is by the ‘vicarious nucleophilic substitution’ route developed by Makosza[18] which starts with a nitrobenzene. The cyanides can also be alkylated at the benzylic position so that it is also possible to introduce a 3-substituent as in the synthesis of 5-benzyloxy-3-methylindole[20].
2.3 CONDENSATION OF o-AMlNOBENZYL ALDEHYDES AND KETONES
17
PhCH20
ArOCH2CN
PhCH20
,ch2cn
KO-t-Bu, DMF
CH3l,K2C03 phCH20
CH3
.CHCN
1)РЮ2, H2 -►
PhCH20
CH3
18-crown-6
2) DiBAIH
i
H
(2.9)
The reduction of onitrophenyl acetic acids or esters leads to cyclization to oxindoles. Several routes to o-nitrophenylacetic acid derivatives are available, including nitroarylation of carbanions with o-nitroaryl halides[21,22] or trif-late[23] and acylation of o-nitrotoluenes with diethyl oxalate followed by oxidation of the resulting 3-(onitrophenyl)pyruvate[24-26].
Procedures
Ethyl 4-(2-nitrophenyl)acetoacetate[3]
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