《杂环合成》（英文版）Recent developments in indole ring synthesis—methodology and applications

5.1 0, B-Dinitrostyrene reductive cyclization Corey and co-workers have used the borchardt modification (Fe-HOAc-silica gel-tol-reflux)2of the reductive cyclization fo, B-dinitrostyrenes to prepare 6. 7-dimethoxyindole in a total ynthesis of aspidophytine. This modification was employed in he preparation of 7-acetoxy-6-methoxyindole and 4-acetoxy 5-methoxyindole, which were used in syntheses of gastropod indolequinones. Fukuyama and Chen have used this reduc tive cyclization to prepare a potential indole precursor to a NaBHa synthesis of hapalindole G. The synthesis of 5, 6-methylene- dioxindole by the catalytic reduction of the corresponding 73-75% o, B-dinitrostyrene proceeds in 94% yield. The very labile 5,6- dihydroxyindole can be synthesized using the Zn-controlled conditions shown in Scheme 52.95 All other conditions tried were unsatisfactory. R2-H. OMe Scheme 52 Scheme 49 5.2 Reissert indole svnthesis N2sCO2Me Nafion-H 50 mol% The classic Reissert indole synthesis, involving the reductive lization of o-nitrophenylpyruvic acid to indole-2-carboxylic toluene110° acid, was used by Shin and co-workers to prepare a series of 2-ethoxycarbonyl-4-alkoxymethylindoles in a synthesis of fragment E of nosiheptide, and by Sato en route to a series Meo f tricyclic indole derivatives. The modified Reissert reaction involving the reductive cyclization of an o-nitrophenyl- Meo acetaldehyde or o-nitrophenyl methyl ketone, has been adapted to solid-phase synthesis. Kraus and Selvakumar have employed the reductive cyclization of a nitro aldehyde to syn Scheme 50 hesize a tricyclic indole related to the pyrroloiminoquinone marine natural products. Related synthetic targets have been are minor products. Smith et al. have studied this cyclization to attacked by Joule and co-workers and a reductive cyclization doles and azetidin-2-ones 84 amidinesulfinic acid as a reducing agent in the reductive cyclin The ancient Sandmeyer isatin synthesis, which involves the ation of nitroketones to pyrroles and a tetrahydroindole electrophilic cyclization of an a-isonitrosoacetanilide, has Rawal and Kozmin have utilized a Reissert reaction in a been employed in a synthesis of the marine natural product synthesis of tabersonine that features an elegant construc convolutamydine A via 4.6-dibromoisatin. A new entry to tion of the requisite nitro ketone 44 using the new reagent 4, 5, 6-tetrahydro-2H-indol-2-ones involves 5-endo-trig cycliz- o-nitrophenylphenyliodonium fluoride (NPIF)to ation of a sulfoxide amide 42 in a Pummerer rearrangement o-nitrophenyl unit to silyl enol ether 43( Scheme 54).204, 20 Scheme 51). 8 Padwa et al. have developed elegant"domino Pummerer"cycloaddition7or cyclization protocols to con NaBH, NiCl2 OMe MeOH0° OMe OMe 2. 1M HCI THF TSOH SPh leO OM Scheme 53 CHaL 42 The reductive cyclization of o-nitrophenylacetic acids or Ar=2-bromophenyl esters leading to oxindoles has been employed by Williams and co-workers to prepare 6-hydroxy-7-meth dole in a syn- hesis of (+)-paraherquamide B, 06 and a similar reduction sequence yielded several chlorinated oxindoles and isatins. 207 Like the Fischer indole synthesis, and the Madelung cycliz 5.3 Leimgruber-Batcho indole synthesis ation and its modifications, and the numerous variations of The Leimgruber-Batcho indole synthesis involves the conver electrophilic cyclization to indoles, reductive cyclizat sion of an o-nitrotoluene to a B-dialkylamino-o-nitrostyrene of nitro aromatics is a powerful means of forming indoles, with dimethylformamide acetal, followed by reductive cycliz and several new developments have been described in recent ation to an indole Ochi and co-workers have used this protocol to prepare 6-bromo-5-methoxyindole for use in the synthesis of J. Chem. Soc. Perkin Trans. 2000. 1045-1075 1055

J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1055 are minor products. Smith et al. have studied this cyclization to oxindoles as influenced by zeolite catalysts and they speculate that different carbenes are involved in the formation of oxin￾doles and azetidin-2-ones.184 The ancient Sandmeyer isatin synthesis, which involves the electrophilic cyclization of an α-isonitrosoacetanilide, has been employed in a synthesis of the marine natural product convolutamydine A via 4,6-dibromoisatin.185 A new entry to 1,4,5,6-tetrahydro-2H-indol-2-ones involves 5-endo-trig cycliz￾ation of a sulfoxide amide 42 in a Pummerer rearrangement (Scheme 51).186 Padwa et al. have developed elegant “domino Pummerer” cycloaddition187 or cyclization188 protocols to con￾struct complex oxindoles.189,190 5 Reductive cyclization Like the Fischer indole synthesis, and the Madelung cycliz￾ation and its modifications, and the numerous variations of electrophilic cyclization to indoles, reductive cyclization of nitro aromatics is a powerful means of forming indoles, and several new developments have been described in recent years. Scheme 49 Scheme 50 Scheme 51 5.1 o,
-Dinitrostyrene reductive cyclization Corey and co-workers 191 have used the Borchardt modification (Fe–HOAc–silica gel–tol–reflux) 192 of the reductive cyclization of o,β-dinitrostyrenes to prepare 6,7-dimethoxyindole in a total synthesis of aspidophytine. This modification was employed in the preparation of 7-acetoxy-6-methoxyindole and 4-acetoxy- 5-methoxyindole, which were used in syntheses of gastropod indolequinones.193 Fukuyama and Chen have used this reduc￾tive cyclization to prepare a potential indole precursor to a synthesis of hapalindole G.170 The synthesis of 5,6-methylene￾dioxyindole by the catalytic reduction of the corresponding o,β-dinitrostyrene proceeds in 94% yield.194 The very labile 5,6- dihydroxyindole can be synthesized using the Zn-controlled conditions shown in Scheme 52.195 All other conditions tried were unsatisfactory. 5.2 Reissert indole synthesis The classic Reissert indole synthesis, involving the reductive cyclization of o-nitrophenylpyruvic acid to indole-2-carboxylic acid, was used by Shin and co-workers to prepare a series of 2-ethoxycarbonyl-4-alkoxymethylindoles in a synthesis of fragment E of nosiheptide,196 and by Sato en route to a series of tricyclic indole derivatives.197 The modified Reissert reaction, involving the reductive cyclization of an o-nitrophenyl￾acetaldehyde or o-nitrophenyl methyl ketone, has been adapted to solid-phase synthesis.198 Kraus and Selvakumar have employed the reductive cyclization of a nitro aldehyde to syn￾thesize a tricyclic indole related to the pyrroloiminoquinone marine natural products.199 Related synthetic targets have been attacked by Joule and co-workers and a reductive cyclization step (Scheme 53) was used in a synthesis of several of these alkaloids.200–202 Zard and co-workers have used form￾amidinesulfinic acid as a reducing agent in the reductive cycliz￾ation of nitroketones to pyrroles and a tetrahydroindole.203 Rawal and Kozmin have utilized a Reissert reaction in a synthesis of tabersonine that features an elegant construc￾tion of the requisite nitro ketone 44 using the new reagent o-nitrophenylphenyliodonium fluoride (NPIF) to join the o-nitrophenyl unit to silyl enol ether 43 (Scheme 54).204,205 The reductive cyclization of o-nitrophenylacetic acids or esters leading to oxindoles has been employed by Williams and co-workers to prepare 6-hydroxy-7-methoxyoxindole in a syn￾thesis of ()-paraherquamide B,206 and a similar reduction sequence yielded several chlorinated oxindoles and isatins.207 5.3 Leimgruber–Batcho indole synthesis The Leimgruber–Batcho indole synthesis involves the conver￾sion of an o-nitrotoluene to a β-dialkylamino-o-nitrostyrene with dimethylformamide acetal, followed by reductive cycliz￾ation to an indole. Ochi and co-workers have used this protocol to prepare 6-bromo-5-methoxyindole for use in the synthesis of Scheme 52 Scheme 53

MeO2C synthesize a series of N-hydroxyindoles and indoles, and to prepare several pyrrolo[4, 3, 2-delquinolines for use in the syn- thesis of the marine pyrroloiminoquinone alkaloids(Scheme DMSO THF 56). 7218 The selectivity observed in the nitro group reduction is noteworthy: shorter reduction periods lead to the cyano- TBSO quinolone, indicating that the less hindered nitro group is reduced first THF TiCI 89%NHOAC 1. PhOCHCN Meo.c Meo 2. (MeO)sO2 NaHCO3 acetone OMe 69%K, CO, MeCN bromoindoles, 2s and Showalter et al. synthesized 5-ethoxycarbonylindole and 6-amino-7-ethoxycarbon from the appropriate o-nitrotoluenes. The Leimgruber-Batcho method has been used to make c-4 substi- Meo PdCIz-Fe EtOH HOAC analogs of indolmycin, 0 and in a synthesis of arcyriacyanin Al1 It has been used in a large-scale synthesis of 6- bromoindole. An important extension of this indole ring Scheme 56 synthesis is the functionalization of the intermediate B- Makosza has also described the condensation of m-nitro- acylated this intermediate enamine to yield 45 which was con- aniline with ketones under strongly basic conditions to form verted to indole 46 after reductive cyclization(Scheme 55).213 4-and 6-nitroindoles.Remarkably, imines are not involved in Prashad and co-workers have also used this tactic to construct this reaction, but, rather, oxidative nucleophilic substitution 3-methoxycarbonylindoles by exposing the Leimgruber- of hydrogen by the ketone enolate occurs. Subsequent amine Batcho enamine to phosgene and then methanol, prior to carbonyl condensation yields the indole. The similarity of this reductive cyclization. 4 An enamine dimer was also identified oxidative substitution of hydrogen to the VNS reaction is clea In 6 Oxidative cyclization The Watanabe indole synthesis is the metal-catalyzed indole synthesis from anilines and glycols, or ethanolamines, and the elated intramolecular cyclization of o-aminophenethyl alco o, Me NCH(OMe hols to indoles. Watanabe. Shim. and co-workers have now DMF extended this reaction to the synthesis of N-alkylindoles in yields up to 78%(N-methylindole) from the reaction of N-alkyl- anilines with triethanolamine and the catalyst RuCl,- (PPh3)3. 21 This oxidative cyclization has also been used Et n PhH 50%6HO prepare a wide range of substituted indoles from ring substituted (methyl, methoxy, chloro, isopropyl, dimethyl, dimethoxy) anilines. Other catalysts have been studied in this reaction and CdBr2' 3KBr is particularly effective. The intramolecular version of this reaction occurs with ar aluminium orthophosphate-Pd syste Scheme 57).26This 225 and also with tetrakis( triphenylphosphine)palladium method also furnishes 4, 5,6, 7-tetrahydroindoles and pyrroles. a related electrolytic cyclization of o-nitrophenethylamines gives aq. EtoH THF reflux N-aminoalkylindoles. Scheme 55 Pd(Pha P)a Coe and co-workers have interru Batcho sequence by converting the int an o-nitrophenylacetaldehyde acetal N-alkylated, and then cyclized with ac c K2 CO3 MesBr reductively DMF 150C a series of l-alkyl-6-methoxycarbonylindole Scheme 57 5.4 Makosza indole svnthesis The essence of the Makosza indole synthesis is the vicariou 6.2 Knolker indole-carbazole synthesis nucleophilic substitution(VNS) 9, 14 of hydrogen to install the Over the past several years Knolker and co-workers have requisite side chain(usually acetonitrile) for reductive cycliz- parlayed the oxidative cyclization of tricarbonyliron-cyclo- ation onto a nitro group. Makosza has used this method hexadiene complexes into a remarkably versatile synthesis of 1056 J. Chem. Soc.. Perkin Trans. 1. 2000. 1045-1075

1056 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 marine bromoindoles,208 and Showalter et al. synthesized 6-amino-5-ethoxycarbonylindole and 6-amino-7-ethoxycarbon￾ylindole from the appropriate o-nitrotoluenes.209 The Leimgruber–Batcho method has been used to make C-4 substi￾tuted indoles for elaboration to conformationally-restricted analogs of indolmycin,210 and in a synthesis of arcyriacyanin A.211 It has been used in a large-scale synthesis of 6- bromoindole.212 An important extension of this indole ring synthesis is the functionalization of the intermediate β- dialkylamino-o-styrene. Thus, Clark and co-workers have acylated this intermediate enamine to yield 45 which was con￾verted to indole 46 after reductive cyclization (Scheme 55).213 Prashad and co-workers have also used this tactic to construct 3-methoxycarbonylindoles by exposing the Leimgruber– Batcho enamine to phosgene and then methanol, prior to reductive cyclization.214 An enamine dimer was also identified in this study. Coe and co-workers have interrupted the Leimgruber– Batcho sequence by converting the intermediate enamine to an o-nitrophenylacetaldehyde acetal, which was reductively N-alkylated, and then cyclized with acid to give a series of 1-alkyl-6-methoxycarbonylindoles.215 5.4 Makosza indole synthesis The essence of the Makosza indole synthesis is the vicarious nucleophilic substitution (VNS) 139,140 of hydrogen to install the requisite side chain (usually acetonitrile) for reductive cycliz￾ation onto a nitro group. Makosza has used this method to Scheme 54 Scheme 55 synthesize a series of N-hydroxyindoles and indoles,216 and to prepare several pyrrolo[4,3,2-de]quinolines for use in the syn￾thesis of the marine pyrroloiminoquinone alkaloids (Scheme 56).217,218 The selectivity observed in the nitro group reduction is noteworthy; shorter reduction periods lead to the cyano￾quinolone, indicating that the less hindered nitro group is reduced first. Makosza has also described the condensation of m-nitro￾aniline with ketones under strongly basic conditions to form 4- and 6-nitroindoles.219 Remarkably, imines are not involved in this reaction, but, rather, oxidative nucleophilic substitution of hydrogen by the ketone enolate occurs. Subsequent amine carbonyl condensation yields the indole. The similarity of this oxidative substitution of hydrogen to the VNS reaction is clear. 6 Oxidative cyclization 6.1 Watanabe indole synthesis The Watanabe indole synthesis is the metal-catalyzed indole synthesis from anilines and glycols, or ethanolamines, and the related intramolecular cyclization of o-aminophenethyl alco￾hols to indoles. Watanabe, Shim, and co-workers have now extended this reaction to the synthesis of N-alkylindoles in yields up to 78% (N-methylindole) from the reaction of N-alkyl￾anilines with triethanolamine and the catalyst RuCl2- (PPh3)3. 220,221 This oxidative cyclization has also been used to prepare a wide range of substituted indoles from ring￾substituted (methyl, methoxy, chloro, isopropyl, dimethyl, dimethoxy) anilines.222 Other catalysts have been studied in this reaction and CdBr2
3KBr is particularly effective.223,224 The intramolecular version of this reaction occurs with an aluminium orthophosphate–Pd system225 and also with tetrakis(triphenylphosphine)palladium (Scheme 57).226 This method also furnishes 4,5,6,7-tetrahydroindoles and pyrroles. A related electrolytic cyclization of o-nitrophenethylamines gives N-aminoalkylindoles.227 6.2 Knölker indole-carbazole synthesis Over the past several years Knölker and co-workers have parlayed the oxidative cyclization of tricarbonyliron–cyclo￾hexadiene complexes into a remarkably versatile synthesis of Scheme 56 Scheme 57