3-Diazo-3/7-indole

Joseph Martinet first reported the conversion of anilines to dioxindoles upon combination with diethylmesoxalic ester in 1913 while earning a Ph.D. under the direction of A. Haller. He later went on the develop syntheses of indigols as well as develop practical methods for preparing diazo-indole dyes, which have been used industrially. ... 

AminothiaZoles. In contrast to the pyrazolones, pyridones, and indoles just described, aminotliiazoles are used as diazo components. As such they provide dyes that ate more bathochromic than their benzene analogues. Thus aminothiazoles are used chiefly to provide dyes in the red-blue shade areas. The most convenient synthesis of 2-aminothiazoles is by the condensation of thiourea with an a-chlorocarbonyl compound for example, 2-aminothiazole [96-50A-] (94) is prepared by condensing thiourea [62-56-6J with a-chloroacetaldehyde [107-20-0J both readily available intermediates. 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Diazo coupling occurs very readily between pyrroles and indoles and benzenediazonium salts. Reaction is much more rapid in alkaline solution when the species undergoing reaction... 

Aus Isatin-3-hydrazon (bzw. 3-Diazo-2-oxo-2,3-dihydro-indol) entsteht in waBriger Pufferlosung 3-Amino-2-oxo-2,3-dihydro-indol4. 

The matter was settled in 1994 in back-to-back communications by Gould [12] and Dmitrienko [13]. Gould showed that treatment of natural prekinamycin with dirhodium tetraacetate in methanol yielded the fluorene 16 (Scheme 3.1). The vinyl proton formed in this reaction (H-l) provided a critical spectroscopic handle and allowed unambiguous determination of the carbocyclic structure, excluding the presence of an indole heterocycle. In parallel, his research group obtained a high-quality crystal structure of a kinamycin derivative. The refined data set was shown to best accommodate a diazo rather than cyanamide (or isonitrile) function. 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

Alternatively, diazotization of ethyl indole-2-carboxylate (179) leads to formation of 2-carboethoxy-3-diazo-3H-indole (180) which undergoes rhodium-catalyzed alcohol O-H insertion reactions leading to 3-alkoxyindoles 181 <00TL6905>. 

Indolizine is much more basic than indole (p Ta = 3.9 vs. —3.5), and the stability of the cation makes it less reactive and resistant to acid-catalyzed polymerization. Protonation occurs at C-3, although 3-methylindolizine protonates also at C-l. Introduction of methyl groups raises the basicity of indolizines. Electrophilic substitutions such as acylation, Vilsmeyer formylation, and diazo-coupling all take place at C-3. Nitration of 2-methylindolizine under mild conditions results in substitution at C-3, but under strongly acidic conditions it takes place at C-l, presumably via attack on the indolizinium cation. However, the nitration of indolizines often can provoke oxidation processes. 

The formation of 3-diazo-37/-indoles from the reaction of indoles with tosyl azide is catalysed by the addition of benzyltriethylammonium chloride [22]. In the absence of the catalyst, 3,3 -azoindoles are formed to the complete exclusion of the diazoindoles. 

Aqueous NaOH (40%, 3 ml) is added dropwise to the indole (5.2 mmol), TosN, (1.02 g, 5.2 mmol) and TEBA-CI (30 mg, 0.13 mmol) in PhH (40 ml). The mixture is stirred at room temperature for 18 h in the dark and the organic phase is then separated, washed with H20 (3 x 30 ml), dried (Na2S04), and evaporated to yield the diazoindole, which can be purified by chromatography from silica [e.g. 3-diazo-2-phenyl-3//-indole, 75% 3-diazo-2-(2-pyridyl)-3//-indole, 87% 3-diazo-2-(2-thienyl)-3W-indole, 83%]. 

Photolysis of 59a in alcohols (ethanol or isopropanol) gave the corresponding indole 62 (R = H), by reductive diazo cleavage, together with acetaldehyde or acetone (66LA17). 

The behavior of the unconventional 3-diazo-2-oxoindoles 21c,d on photolysis and thermolysis needs to be mentioned separately because 21c,d show a reactivity that is somehow different from that observed in indole series. 

Compound 59a reacted with arylhydrazines to give complex mixtures as shown in Scheme 53 (70G745). The reaction presumably goes via an electron transfer process in which the diazo compound serves as electron acceptor. Similar reactions leading to even more complex mixtures were also observed with hydroxylamine, hydrazo compounds, and conjugate indole derivatives (70G757). 

The diazo group confers a broad spectrum of activity on the 2-substi-tuted indoles. In fact, 3-diazo-2-substituted indoles are effective against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi and Proteus vulgaris bacteria (65MI1), and 3-diazo-2-ethoxycarbo-nylindole inhibits sarcoma 180 in mice and rats (83KFZ1183). 

The perfluoroacetamide catalysts, rhodium(II) trifluoroacetamidate [Rh2(tfm)4] and rhodium(II) perfluorobutyramidate [Rh2(pfbm)4], are interesting hybrid molecules that combine the features of the amidate and perfluorinated ligands. In early studies, these catalysts were shown to prefer insertion over cycloaddition [30]. They also demonstrated a preference for oxindole formation via aromatic C-H insertion [31], even over other potential reactions [86]. In still another example, rhodium(II) perfluorobutyramidate showed a preference for aromatic C-H insertion over pyridinium ylide formation, in the synthesis of an indole nucleus [32]. Despite this demonstrated propensity for aromatic insertion, the perfluorobutyramidate was shown to be an efficient catalyst for the generation of isomtinchnones [33]. The chemoselectivity of this catalyst was further demonstrated in the cycloaddition with ethyl vinyl ethers [87] and its application to diversity-oriented synthesis [88]. However, it was demonstrated that while diazo imides do form isomtinchnones under these conditions, the selectivity was completely reversed from that observed with rhodium(II) acetate [89, 90]. 

The alternative regiochemical disposition of the diazo and tether of indole 260 failed to deliver any product upon addition of catalyst. Friedrichsen and co-workers (136) also applied this method to amine substituted tethers to generate polyaza-cyclic compounds (Scheme 4.70). The presence of the amino substituted furan subsequent to diazo-decomposition made it possible to cleave the ether bridge through the facility of the amino group formed to produce adduct 263. 

A recent example of this intramolecular tandem transformation is the Rh(ii)-catalyzed reaction of diazo keto ester 71. Depending on the structure of the diazo compound, a push-pull dipole intermediate derived from 71 can be trapped either by a tethered vinyl group (when n = 0) or by an indole 7r-bond (when n=l) (Equation (11)). This result clearly demonstrates a critical role of the conformation of the cycloaddition transition state. 

As part of a study of the reactions of arenesulfonyl azides with indoles, Bailey et al.lu obtained a compound from the action of tosyl azide on indoline-2-thione to which they ascribed structure 114 (R = H). In contrast, N-methylindoline-2-thione gave only a low yield of 114 (R = Me) under the same conditions. Diazo-transfer via an intermediate 115 is thought to be involved when R = H, facile loss of toluene-p-sulfonamide leads to 114a, but when R = Me, loss of the same fragment leads mainly to other products. 

---