4- Nitroindoles, synthesis

PeUcey ET, Gribble GW (1999) Synthesis and reactions of N-protected 3-nitroindoles. Synthesis 1117-1122... 

A neat synthesis of 4-nitroindole depends on an acyladon-deacyladon sequence from 2-methyl-3-nitroaniline, as shown in Eq. 10.53. On the other hand, treatment of iV-protected indoles v/ith acetyl nitrate generated in sini at bw temperanire gives the correspondmg... 

S-nitroindoles in good yields The regioselecdve synthesis of nitroindoles is Lmportdnt for fiincdondlizddQn of indoles ... 

The previously unknown 2-nitroindoles have been conveniently prepared from o-nitroben-zaldehyde via the Sundberg indole synthesis fEq 10 61 ... 

Yang described the Pd-induced cyclization of an aryl bromide onto a pendant cyano group leading to y-carbolines and related compounds [488], Genet studied the use of chiral palladium complexes in the construction of the C-ring of ergot alkaloids, a study that culminated in a synthesis of (-)-chanoclavine I [489-491]. For example, nitroindole 388 is cyclized to 389 in 57% yield and with enantioselectivities of up to 95% using Pd(OAc)2 and (S)-(-)-BINAP. 

The Barton-Zard pyrrole synthesis <1990T7587> was applied in the syntheses of pyrrolo[3,4- ]indoles 423 from 3-nitroindoles 422. Treatment of appropriate alkyl 3-nitroindole-l-carboxylates 422a-c with ethyl isocyanoacetate and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the corresponding pyrrolo[3,4- ]indole 423a-c (Equation 12) <1997CC1873, 1999S1117>. 

This procedure illustrates the synthesis of 4-nitroindoles the present... 

The mechanism of the formation of 4-nitroindole parallels the Relssert indole synthesis and is discussed in references 2 and 3. 

Cyclization of 3-nitroindoles 127 with ethyl isocyanoacetate and DBU (conditions of Barton-Zard pyrrole synthesis) gave the corresponding pyrrolo 3,4-fc]indoles 128 (Scheme 22) [35],... 

This procedure illustrates the synthesis of 4-nitroindoles the present method can easily be extended to the 2-alkyl derivatives (using other ortho esters), 5-, 6- and/or 7-substituted derivatives and 1-alkyl derivatives (from... 

Only those indoles that are sufficiently basic to be protonated by acetic acid are reduced under these conditions. Thus, 5-nitroindole and 2,3-diphenylindole are recovered unchanged,whereas 5,6-dimeth-oxyindole is cleanly reduced to 5,6-dimethoxyindoline in 86% yield with NaBHsCN/HOAc. " This differential reactivity has been exploited by Cava and Rawal in their synthesis of CC-1065 analogs in which only the more basic double bond in (23) is reduced (equation 61).Indeed, this same tactic has since been utilized by Boger," Moodyand Sundberg, and their coworkers, in their respective synthetic efforts towards CC-1065 and the related phosphodiesterase inhibitors PDE-I and PDE-II. Likewise, Joule and coworkers have utilized NaBHsCN/HOAc in a chemoselective reduction of the more basic indole double bond in benzodipyrrole (24 equation 62). ... 

Treatment of an imidate which is placed ortho to a reactive methylene group with sodium hydroxide-DMSO results in the formation of a new pyrrole ring. Good to xcelient yields of 4-nitroindoles are obtained when 3-nitro-2-methyl-anilines (or acetanilides) are treated with diethyl oxalate in the presence of a strong base (cf. Madelung synthesis of indoles, p. 68). 

A direct benzylation step is used in the scaled-up synthesis of the asthma drug zasirulast. The reaction involves l-methyl-5-nitroindole and was done in the presence of CU2O (three equiv.). The product is obtained in 85% yield, along with two by-products, one of which is the 2,3-disubstituted product [81]. 

Moreover, a VNS was a key step in the first synthesis of pyrrolo[3,2-e]indole -a heterocyclic fragment of the antitumor antibiotic CC 1065. The a-cyano side chain is installed at the C-4 position on V-(benzyloxymethyl)-5-nitroindole 39 in good yield [25]. This intermediate (40) is then reductively cyclized using Pd(C) to produce the new ring system 41 in 69% yield however, the protecting group does not remain intact at 65°C. If this reaction is carried out at 45°C, the benzyloxy-methyl (BOM) group is left intact, and the pyrrolo[3,2-c]indole is isolated in 62%. 

Wojciechowski K, Makosza M (1989) Reactions of organic anions. Part 158. Vicarious nucleophilic substitution of hydrogen in 5- and 6-nitroindole derivatives. Synthesis 106-109... 

Roy S, Gribble GW (2005) A ctmvtmient synthesis of 2-nitroindoles. Tetrahedron Lett... 

Pelkey ET, Barden TC, Gribble GW (1999) Nucleophilic addition reactions of 2-nitro-l-(phenylsulfonyl)indole. A new synthesis of 3-substituted-2-nitroindoles. Tetrahedron Lett 40 7615-7619... 

Gribble GW, Pelkey ET et al (2000) Regioselective 1,3-dipolar cycloaddition reactions of unsymmetrical munchnones (l,3-oxazolium-5-olates) with 2- and 3-nitroindoles. A new synthesis of pyrrolo[3,4-b]indoles. Tetrahedron 56 10133-10140... 

Biolatto B, Kneeteman M et al (1999) Diels-Alder reactions of lV-tosyl-3-nitroindole and dienamides synthesis of intermediates of Aspidospermine alkaloids. Tetrahedron Lett... 

Kishbaugh TLS, Gribble GW (2001) Diels-Alder reactions of 2- and 3-nitroindoles. A simple hydroxycarbazole synthesis. Tetrahedron Lett 42 4783-4785... 

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