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regenerate the indole ring. Harran and coworkers reported a PIDA mediated intramolecular oxidative marcocyclization between an

Figure 8 regenerate the indole ring. Harran and coworkers reported a PIDA mediated intramolecular oxidative marcocyclization between an

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transformations, such as alkylation and cyanation will be described (section 4). umpolung with hypervalent iodine reagents and reported nucleophilic partners.
transformations, such as alkylation and cyanation will be described (section 4). umpolung with hypervalent iodine reagents and reported nucleophilic partners.
Scheme 2. Halogenation of indoles involving betaine intermediate 2 yased on electrophilic chlorination would lead to the formation of products such as 4 as major outcome
Scheme 2. Halogenation of indoles involving betaine intermediate 2 yased on electrophilic chlorination would lead to the formation of products such as 4 as major outcome
2.2. FUNCTIONALIZATION WITH OXYGEN NUCLEOPHILES
2.2. FUNCTIONALIZATION WITH OXYGEN NUCLEOPHILES
was directly used for indigo synthesis by oxidation, no yield was reported for its formation. In 1980, Awang and Vincent introduced alkoxy groups on the C3 position of 2,3-disubstituted indoles 11,
was directly used for indigo synthesis by oxidation, no yield was reported for its formation. In 1980, Awang and Vincent introduced alkoxy groups on the C3 position of 2,3-disubstituted indoles 11,
Scheme 5. Introduction of alkoxy groups at the C3 position of indole derivatives using PIDA Ciufolini and co-workers observed that the reaction of dimethyl indole 15 with PIDA in CF3CH20H
Scheme 5. Introduction of alkoxy groups at the C3 position of indole derivatives using PIDA Ciufolini and co-workers observed that the reaction of dimethyl indole 15 with PIDA in CF3CH20H
In contrast, the 2-methylindole derivatives 20 gave quinonimine monoketals 24 a,b in a 1: 1.2 ratio via
In contrast, the 2-methylindole derivatives 20 gave quinonimine monoketals 24 a,b in a 1: 1.2 ratio via
Scheme 7. Formation of quinonimine monoketals 24 in 30% isolated yield.
Scheme 7. Formation of quinonimine monoketals 24 in 30% isolated yield.
of material for completion of the synthesis.'** driven to completion, tetrahydro-B-carboline 31 was successively recycled to provide sufficient quantity 2.3. FUNCTIONALIZATION WITH NITROGEN NUCLEOPHILES
of material for completion of the synthesis.'** driven to completion, tetrahydro-B-carboline 31 was successively recycled to provide sufficient quantity 2.3. FUNCTIONALIZATION WITH NITROGEN NUCLEOPHILES
ye achieved with recyclable hypervalent iodine reagent 36 with slightly lower yields (52-78%).!*°
ye achieved with recyclable hypervalent iodine reagent 36 with slightly lower yields (52-78%).!*°
Scheme 14. C3 Amination of electron-rich heterocycles via hypervalent iodine intermediates amine derivatives 55-59 in 57-78% yields.
Scheme 14. C3 Amination of electron-rich heterocycles via hypervalent iodine intermediates amine derivatives 55-59 in 57-78% yields.
“SCN nucleophile and thiocyanate 69 was obtained in 84% yield. Very few examples were reported in literature regarding sulfur-based nucleophilic functionalization of electron rich heterocycles with hypervalent iodine reagents. The PIFA mediated SET oxidative thiocyanation of 3-hexylthiophene (7) was reported by Kita (Scheme 18).* TMSCN was used as source of “ON fiYRT ..... .1. . ..1.°1.. ... 4 210° . 2... .. i. SOK 2... .1.4.2.°...]°.. QANS ..' .1]
“SCN nucleophile and thiocyanate 69 was obtained in 84% yield. Very few examples were reported in literature regarding sulfur-based nucleophilic functionalization of electron rich heterocycles with hypervalent iodine reagents. The PIFA mediated SET oxidative thiocyanation of 3-hexylthiophene (7) was reported by Kita (Scheme 18).* TMSCN was used as source of “ON fiYRT ..... .1. . ..1.°1.. ... 4 210° . 2... .. i. SOK 2... .1.4.2.°...]°.. QANS ..' .1]
derivatives 72 were obtained in 50-75% yields. Scheme 19. PIDA mediated thiolation of porphyrins fields. In case of bromo substituted porphyrins the corresponding demetalated di-thiolated porphyrin formation of the oxidative coupling product. Demetalated starting porphyrin 71 was recovered in 15-40%
derivatives 72 were obtained in 50-75% yields. Scheme 19. PIDA mediated thiolation of porphyrins fields. In case of bromo substituted porphyrins the corresponding demetalated di-thiolated porphyrin formation of the oxidative coupling product. Demetalated starting porphyrin 71 was recovered in 15-40%
or this approach is the formation of oligomers by reaction of the starting heteroarene with the forme 3. UMPOLUNG (HETERO-)ARYLATION OF ELECTRON RICH HETEROCYCLES 3.1 REACTION INVOLVING A SET MECHANISM 3. UMPOLUNG (HETERO-)ARYLATION OF ELECTRON RICH HETEROCYCLE:! The work of the Kita group on this type of biheteroaryl synthesis is summarized in Table 1. Compounds
or this approach is the formation of oligomers by reaction of the starting heteroarene with the forme 3. UMPOLUNG (HETERO-)ARYLATION OF ELECTRON RICH HETEROCYCLES 3.1 REACTION INVOLVING A SET MECHANISM 3. UMPOLUNG (HETERO-)ARYLATION OF ELECTRON RICH HETEROCYCLE:! The work of the Kita group on this type of biheteroaryl synthesis is summarized in Table 1. Compounds
Table 1. Summary of SET oxidative couplings of electron rich heterocycles and pyrroles to give EDOT-pyrroles 81 in 33-85% yields.”
Table 1. Summary of SET oxidative couplings of electron rich heterocycles and pyrroles to give EDOT-pyrroles 81 in 33-85% yields.”
and TMSCI. The PIFA mediated SET-oxidative coupling was also used for porphyrins by Zheng and coworkers ADS PAs) MIA OL THUAIUAUVE LOUDER Was dlsY UstU LULL VPULPHYIMIS UY AMIS alu CUWUTREIDS (Scheme 22).*4* A single bond linked diporphyrines 86 was obtained in 86-93% yields when compounds 85 was treated with 0.5 equivalent of PIFA (Scheme 22A). With an excess of PIFA (2.5 equiv.) fused diporphyrin derivates 87 were obtained in 83-90% yields. This reaction occurred only for Zn(II) porphyrins 85. When other metals were used, e.g Cu(II), Ni(II) or Pd(II), then only single linked diporphyrins were observed even on treatment with 2.5 equiv. of PIFA. The same group also extended this methodology to the synthesis of a directly linked (single linked) zinc chlorin dimer (Scheme 22B).”4° In this reaction, PIFA is more efficient and faster than PIDA. The reaction shows high regioselectivity at the 20-position near the hydrogenated pyrrole ring producing selective dichlorin 89 in 74% yield and aww dada at the wewcen Saw etaw nesld ke eerxdalad (Scheme 22).*4* A single bond linked diporphyrines 86 was obtained in 86-93% yields when compounds
and TMSCI. The PIFA mediated SET-oxidative coupling was also used for porphyrins by Zheng and coworkers ADS PAs) MIA OL THUAIUAUVE LOUDER Was dlsY UstU LULL VPULPHYIMIS UY AMIS alu CUWUTREIDS (Scheme 22).*4* A single bond linked diporphyrines 86 was obtained in 86-93% yields when compounds 85 was treated with 0.5 equivalent of PIFA (Scheme 22A). With an excess of PIFA (2.5 equiv.) fused diporphyrin derivates 87 were obtained in 83-90% yields. This reaction occurred only for Zn(II) porphyrins 85. When other metals were used, e.g Cu(II), Ni(II) or Pd(II), then only single linked diporphyrins were observed even on treatment with 2.5 equiv. of PIFA. The same group also extended this methodology to the synthesis of a directly linked (single linked) zinc chlorin dimer (Scheme 22B).”4° In this reaction, PIFA is more efficient and faster than PIDA. The reaction shows high regioselectivity at the 20-position near the hydrogenated pyrrole ring producing selective dichlorin 89 in 74% yield and aww dada at the wewcen Saw etaw nesld ke eerxdalad (Scheme 22).*4* A single bond linked diporphyrines 86 was obtained in 86-93% yields when compounds
Scheme 22. Oxidative coupling of porphyrins and chlorins The PIFA-mediated homodimerisation of pyrroles was also used by Panda and coworkers in the synthesi: of B-octa-substituted porphycenes (Scheme 23A).”° The bispyrroles 91 were subjected to formylation followed by McMurry coupling to afford the porphycenes skeleton 93. For the synthesis o: B-octamethoxyporphycenes, a one pot dimerization-formylation protocol was developed as the dime: underwent decomposition during purification. The desired product 92 was obtained in 39% yield. Ar alternative approach for the synthesis of porphycenes was reported by Ono and co-workers.”° In this approach the McMurry coupled product 95, obtained from formylated pyrrole 94, was reacted with PIFA
Scheme 22. Oxidative coupling of porphyrins and chlorins The PIFA-mediated homodimerisation of pyrroles was also used by Panda and coworkers in the synthesi: of B-octa-substituted porphycenes (Scheme 23A).”° The bispyrroles 91 were subjected to formylation followed by McMurry coupling to afford the porphycenes skeleton 93. For the synthesis o: B-octamethoxyporphycenes, a one pot dimerization-formylation protocol was developed as the dime: underwent decomposition during purification. The desired product 92 was obtained in 39% yield. Ar alternative approach for the synthesis of porphycenes was reported by Ono and co-workers.”° In this approach the McMurry coupled product 95, obtained from formylated pyrrole 94, was reacted with PIFA
Scheme 23. Synthesis of porphycenes derivatives via PIFA mediated oxidative coupling
Scheme 23. Synthesis of porphycenes derivatives via PIFA mediated oxidative coupling
Scheme 24. Arylation of N-acetylindoles 97 using PIFA (HETERO-)ARYLATED-HYPERVALENT IODINE REAGENTS One of the major drawback of SET based approaches is the difficulty to prevent homo-dimerization when
Scheme 24. Arylation of N-acetylindoles 97 using PIFA (HETERO-)ARYLATED-HYPERVALENT IODINE REAGENTS One of the major drawback of SET based approaches is the difficulty to prevent homo-dimerization when
108 was also reported in 41% yield, although the mechanism is less clear in this case (Scheme 11C).”°
108 was also reported in 41% yield, although the mechanism is less clear in this case (Scheme 11C).”°
Scheme 26. Arylation of nitrogen heterocycles via iodonium salts reagents to form stable iodonium(III) salts I (Scheme 26A).~*
Scheme 26. Arylation of nitrogen heterocycles via iodonium salts reagents to form stable iodonium(III) salts I (Scheme 26A).~*
Scheme 27. PIDA mediated homocoupling of imidazole-derived heterocycles (115 &117) Finally, a more general cross coupling of indoles with electron-rich arenes/heteroarenes was reported by
Scheme 27. PIDA mediated homocoupling of imidazole-derived heterocycles (115 &117) Finally, a more general cross coupling of indoles with electron-rich arenes/heteroarenes was reported by
Scheme 29. Transition-metal catalyzed C-H functionalizations with Indole- and Pyrrole-BX reagents 4, MISCELLANEOUS
Scheme 29. Transition-metal catalyzed C-H functionalizations with Indole- and Pyrrole-BX reagents 4, MISCELLANEOUS
products 134 in 60-71% yields (Scheme 30). In 2016, an intermolecular asymmetric cascade dearomatization reaction of indole acetamides 135 with In 2016, an intermolecular asymmetric cascade dearomatization reaction of indole acetamides 155 witt 3-indolylphenyliodonium salts 136 was developed by You and co-workers (Scheme 31).°° The combination of chiral (4R,5R)-bis-oxazoline ligand 137 (11 mol%) and [Cu(MeCN)4]PFs (10 mol%. provided a straightforward access to 3-(3a-indolyl)hexahydropyrroloindolines 138 bearing an all-carbor
products 134 in 60-71% yields (Scheme 30). In 2016, an intermolecular asymmetric cascade dearomatization reaction of indole acetamides 135 with In 2016, an intermolecular asymmetric cascade dearomatization reaction of indole acetamides 155 witt 3-indolylphenyliodonium salts 136 was developed by You and co-workers (Scheme 31).°° The combination of chiral (4R,5R)-bis-oxazoline ligand 137 (11 mol%) and [Cu(MeCN)4]PFs (10 mol%. provided a straightforward access to 3-(3a-indolyl)hexahydropyrroloindolines 138 bearing an all-carbor
Finally, a PIFA mediated SET oxidative cyanation of electron-rich heterocycles has been reported by Kita The presence of some donating groups, e.g., OMe, on the thiophene ring was tolerated, but no reaction
Finally, a PIFA mediated SET oxidative cyanation of electron-rich heterocycles has been reported by Kita The presence of some donating groups, e.g., OMe, on the thiophene ring was tolerated, but no reaction
Scheme 32. Cyanation of electron-rich heterocycles using PIFA and TMSCN
Scheme 32. Cyanation of electron-rich heterocycles using PIFA and TMSCN
Table 2. Summary of the transformations described in this review
Table 2. Summary of the transformations described in this review
vite its success, the umpolung approach has been so far mostly limited to the reaction with heteroato: eophiles and (hetero)arenes and the regioselectivity is dictated by the electron density on the reactio 1er. Only two examples of the formation of C(SP”)-C(SP?) bonds have been reported and majc rts are still needed in this area. Combining hypervalent iodine-based activation with transition met lysis has been also rarely exploited. Although this approach has the disadvantage to lose tt tal-free" aspect, it has the potential for accessing a much broader range of transformations, not limite 1e innate reactivity of the nucleophilic partners. The time is now ripe for a new generation « archers to build upon the impressive pioneering work of the Kita group to develop new useft hetic methods for heterocycle functionalization based on hypervalent iodine chemistry.
vite its success, the umpolung approach has been so far mostly limited to the reaction with heteroato: eophiles and (hetero)arenes and the regioselectivity is dictated by the electron density on the reactio 1er. Only two examples of the formation of C(SP”)-C(SP?) bonds have been reported and majc rts are still needed in this area. Combining hypervalent iodine-based activation with transition met lysis has been also rarely exploited. Although this approach has the disadvantage to lose tt tal-free" aspect, it has the potential for accessing a much broader range of transformations, not limite 1e innate reactivity of the nucleophilic partners. The time is now ripe for a new generation « archers to build upon the impressive pioneering work of the Kita group to develop new useft hetic methods for heterocycle functionalization based on hypervalent iodine chemistry.
Related topics:
ChemistryOrganic ChemistryIodine Compounds
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