3-Diazo-3//-indoles, synthesis

Some other modifications of the Bischler indole synthesis have been developed. One such modification is that of Moody and coworkers, who employed rhodium to effect N-H insertion of an a-diazo-p-ketoester to an aniline (Scheme 5, equations 1 and 2) [58-60]. The so-formed arylamino P-ketoester 16 was smoothly converted to indole 17 with the ion-exchange resin Amberlyst 15 or in somewhat lower yield with boron trifluoride etherate [59]. These workers extended the method to the synthesis of A-unsubstituted indoles using the novel A-protecting groups, A-(2-ethoxycarbonylethyl)... 

After copper and palladium, rhodium is the third most important transition metal for the synthesis of the indole ring. For a 2007 review on this reaction, see Patil and Paiil [1], Some early examples (Scheme 1) are Alper s rhodium reaction of 2-aryl-2/7-azirines to give 2-styiylindoles (equation 1) [2], Watanabe s Rh-catalyzed Fischer indole synthesis (equation 2) [3], Ucciani s 3-methylindole synthesis via the hydroformylation of o-nitrostyrene (equation 3) [4], and Burst s preparation of 3-acetyl-2-hydrox-yindoles from the Rh-catalyzed decomposition and carbenoid aromatic C-H bond insertion (equation 4) [5]. Narasaka extended Alper s 2-aryl-2//-azirine reaction to a Rh(II)-catalyzed synthesis of 2,3-disubstituted indoles [6], and both Cenini [7] and Alper [8] stretched the deoxygenation of o-nitrostyrenes to give indoles. Burst s Rh-catalyzed decomposition of a-diazo carbonyl compounds was used by Bauban [9] and Jha [10] in the synthesis of substituted oxindoles. 

In 1981, Nordlander demonstrated that acetals 22 can be used as reactants in the Bischler-Mdhlau indole synthesis, providing 2,3-unsubstituted indoles in good yield. Subsequent modification was made by Sundberg in 1984. From 1998 to 2002, Moody and co-workers developed a modified Bischler indole synthesis by using rhodium(II) acetate to catalyze the reaction of N-methylanilines with a-diazo-P-ketoesters via an N-H insertion reaction of a rhodium carbenoid. The resulting a-(A -arylamino)ketones cyclize to give indoles upon treatment with BF3 or an acidic ion exchange resin. ... 

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. 

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]. 

It was proposed to synthesize 6-phosphorylated indoles 174 [189] by the Japp-Klingemann reaction. Diazotization of m- di hydroxyphosphoryl)aniline followed by the reaction of the diazo compound with ethylacetoacetic ester gave w-phosphorylphenylhydrazone of ethyl a-ketobutyrate, which was used for the synthesis of the desired compound 174. 

This sequence was recently used in the synthesis of the alkaloid (+ )-aspidophytine (19). The key sequence of reactions was initiated by treatment of diazo ketoester 15 with Rh2(OAc)4 to generate a transient metallocarbene that reacted with the proximal imido carbonyl group to form dipole 16 (06OL3275). A subsequent 1,3-dipolar cycloaddition across the tethered indole n-bond gave cycloadduct 17 in 97% yield. Oxabicycle 17 was then converted into 18 by the action of BF3 OEt2 in 70% yield and this compound was eventually converted into ( )-aspidophytine (19). 

The 3-acetyl group on an indole can be transformed into an a-diazoketone by a deformylative diazo transfer process, involving treatment with base and trifluoroacetylation followed by base-catalyzed reaction with mesylazide (Scheme 136) <90JOC1959>. This methodology has been used in a synthesis of the oxazolyl indole alkaloid pimprinine <9481021 >. 

As indicated previously, in similar fashion, indole analog 520 undergoes a smooth cycloaddition, via an isomunchnone intermediate, to adduct 521 (Fig. 4.156). Unfortunately, attempts to apply this chemistry to a synthesis of the alkaloid vallesamidine 534 were not successful (Fig. 4.161). Thus diazo imides 533 failed to cyclize onto the indole double bond via the corresponding isomunchnone. 

Hashimoto and coworkers [69] have recently begun to explore the use of chiral rhodium catalysts in the intramolecular dipolar cycloadditirai reactions of indoles, and have applied their methodology to the synthesis of the Aspidosperma ring system. Thus, the cycloaddition of the cyclopropyl carbonyl ylides derived from cyclopropyl diazo-5-imido-3-ketoesters 135 upon treatment with dirhodium (11) tetrakis[Af-tetrachlorophthaloyl-(5)-ferf-leucinate] gave cycloadducts 136 along with the spiro[2.3]hexanes 137 in only moderate yields (Scheme 34). Although the reaction proceeds with exclusive endo diastereoselectivity, only moderate enantioselectivities of up to 66% enantiomeric excess (ee) could be obtained. 

The synthesis of l,2-cyclopropapyrrolo[l,2-a]indoles devised by Moody and Jones [54] was based on 1,3-dipolar addition of a diazo group to an alkene (Scheme 24). In this synthesis, indole-2-carboxaldehyde 169 was alkylated with allyl bromide in the presence of sodium hydride and then condensed with tosylhydrazine to give 170. The sodium salt of 170 underwent [3 + 2] cycloaddition, affording 171, when it was heated in benzene. Further heating in refluxing... 

The total synthesis of several members of the vinca and tacaman class of indole alkaloids has also been accompHshed using push-pull dipoles in the critical cycloaddition step (2007OL3249, 2008JOC2792). The central step in the synthesis consists of an intramolecular [3-F2]-cycloaddition reaction of an a-diazo indoloamide (i.e., 19), which delivers the pentacyclic skeleton of the natural product in excellent yield (Scheme 6). The acid lability of... 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

The Amdt-Eistert homologation is equally applicable to the synthesis of alkaloids. For example, Stoltz demonstrated its application to the first synthesis of the bis-indole alkaloid dragmacidin D (38). In the final steps of the synthesis, carboxylic acid 36 was homologated to the diazo ketone, which was subsequently exposed to hydrobromic acid. This gave a-bromo ketone 37, which was elaborated to racemic dragmacidin D (38). 

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