Among direct C–H functionalizations direct alkylations and arylations catalyzed by efficient, versatile and inexpensive iron complexes remain underexploited. However, a few examples of iron-catalyzed C‒H functionalizations have been reported thus far.[151, 152] Pioneering work on iron-catalyzed arylations of arenes of the type 92 with a nitrogen-containing directing group have been accomplished by Nakamura et al. (Scheme 45).[152]
Scheme 45: Iron-catalyzed phenylation of benzo[h]quinolone (92).
The scope of this reaction was successfully probed by Nakamura and coworkers employing alkenes and arenes bearing a number of directing groups (Scheme 46).[153] Later, this reaction could be improved by the in situ formation of the Grignard reagent.[154] In general, these arylations were not limited to the reaction profile described for iron-catalyzed cross-coupling reactions.[155]
Scheme 46: Different directing groups employed in iron-catalyzed arylations according to Nakamura et al.
An additional contribution to iron-catalyzed C‒C bond transformations was made by DeBoef and coworkers who presented the arylation of heteroarenes 94 through directed C‒H bond activation (Scheme 47).[156] The use of DMPU or KF as additives minimized the homo-coupling of the Grignard reagents.[136, 139]
Scheme 47: Pyridine arylation by DeBoef et al.
In contrast to C(sp2)‒H bond functionalizations, the chemoselective direct alkylation and arylation of unactivated C(sp3)–H bonds remains challenging. Albeit, benzylic C(sp3)‒H bonds in α-position to a heteroatom undergo such transformations easily. The introduction of bidentate directing groups set the stage for new strategies of C(sp3)‒H functionalizations (vide supra).[157, 158]
Thus, employment of 8-aminoquinoline 70 or picolinamide 96 as bidentate directing groups (Figure 7) allowed for the first time palladium-catalyzed arylations and alkylations of C(sp3)‒H in a highly site-selective fashion, as reported by Daugulis and coworkers.[117, 119]
Figure 7: N-containing bidentate directing groups for C(sp3)‒H and C(sp2)‒H bond functionalizations.
Recently, a few publications on the direct C(sp3)‒H functionalization involving transition metals, like palladium,[159] nickel[160, 161] and others[162] were released. Chatani and coworkers explored the influence of the substitution pattern on diversely substituted benzamides.[163]
The aromatic amide 97 (Figure 7) was used as an effective directing group for the synthesis of phthalimides using Ru3(CO)12 as the catalyst. Moreover, the contribution by B.-F. Shi et al.
was succeeded through the 2-(pyridine-2-yl)isopropylamine 72 as new directing group by palladium catalysis.[120] In 2014, Ackermann et al. reported on a triazole-assisted ruthenium-catalyzed arylation of aromatic amides 98 (Figure 7).[164] Additionally, ruthenium-catalyzed alkylations of C(sp2)–H and C(sp3)–H bonds could be achieved via additions of C–H bonds onto alkenes by the groups of Chatani[165] and Ackermann,[166, 167] through chelation assistance. Further substantial contributions by Nakamura[168-170] and coworkers established iron-catalyzed direct functionalizations. for the direct ortho-allylation of N-(quinolin-8yl)carboxamide derivatives 99 with allylic ether 100 (Scheme 48).[169]
Scheme 48: Iron-catalyzed ortho-allylation of carboxamide 101.
Through continuous work on exploring the bidentate directing group, alkylations of aromatic and olefinic carboxamides 102 with alkyl tosylates 103, mesylates and halides were accomplished (Scheme 49a).[171] The effect of the ligand and the directing group is crucial for the iron-catalyzed reaction. The employment of diphosphine ligands, such as dppen and dppbz, possessing a rigid π-bridge were successful, while using dppe, monophosphines or bipyridyl ligands was ineffective (Scheme 49b). Recently, Cook et al. reported on an iron-catalyzed arylation and alkylation reaction by directly using aryl and alkyl chlorides as an
unified strategy for the direct functionalization of aromatic and heteroaromatic benzamides.[172]
Scheme 49: Iron-catalyzed directed alkylation and the applied ligands.
As the C(sp3)–H bond functionalization is of special importance in direct iron-catalyzed functionalizations, Nakamura presented an arylation of ß-methyl group in 2,2-disubstituted propionamides 105 (Scheme 50).[168] The structure of the directing group, the ligand and the substrate were very important for the success of the reaction. The torsion angle between the ß-H atom and the amide moiety in the substrate is crucial for the effective formation of a chelated intermediate with the iron catalyst. Furthermore, the higher reactivity of the methyl group over a benzylic group excluded a radical pathway and thereby implied an organoiron species as the key intermediate.
Scheme 50: Iron-catalyzed arylation of the ß-methyl group of 2,2-disubstituted propionamides 105.
2 Objectives
In recent years, the research group of Ackermann developed versatile, useful protocols for oxidative ruthenium-catalyzed annulations for the synthesis of heteroarenes.[41, 173] Satoh and Miura reported on analogous rhodium-catalyzed reactions for C–H/O–H bond functionalization.[56] However, ruthenium-catalyzed annulation reactions with benzoic acids 4 for the synthesis of isocoumarins 12 were thus far unprecedented. Therefore, the development of such an alkyne annulations as well as investigations on the substrate scope and detailed mechanistic studies were highly attractive objectives (Scheme 51).
Scheme 51: Ruthenium(II)-catalyzed oxidative alkyne annulation of 4 via C–H/O–H functionalization.
Furthermore, the developed catalytic system with the rather inexpensive ruthenium(II) complexes should be applicable for oxidative olefinations of benzoates 6. The use of substrates with such a weakly coordinating group as an ester would give a facile access to styrene derivatives 7 (Scheme 52).
Scheme 52: Ruthenium(II)-catalyzed oxidative alkenylation of benzoates 6.
The introduction of bidentate directing groups enabled new strategies of C‒H functionalizations.[158, 165, 174]
The work of Daugulis[117, 119]
and further contribution by Nakamura[168, 169]
provided new C(sp2)–H and C(sp3)–H disconnection reactions. Further contributions to ruthenium- and nickel-catalyzed C(sp3)–H bond arylation and alkylation reactions were provided by Chatani,[161] Ackermann[178] and Ge.[160] To meet the requirements for this challenge, new concepts in bidentate directing groups have to be developed. A novel family of directing groups was developed by the group of Ackermann and applied for ruthenium-catalyzed C(sp2)–H arylations of aromatic amides (Scheme 53).[164]
Scheme 53: Triazole-assisted ruthenium-catalyzed C(sp2)–H arylations of aromatic amides.
However, the corresponding iron-catalyzed arylation of unactivated C(sp3)–H bonds remains a challenging transformation. Hence, the major focus in this work was set on the use of the bidentate triazolyldimethylmethyl (TAM) directing group (110) for the C(sp3)–H arylation (Scheme 54).
Scheme 54: Triazole-assisted iron-catalyzed C(sp3)–H arylation of aromatic amides.
Known methylation methods (DoM) or inefficient palladium-mediated methylation protocols have limited functional group tolerance or high waste production. Therefore, the development of new methylation methods using the less expensive iron catalyst is in high demand. Exploiting the novel bidentate TAM directing group, we became interested in the direct methylation reaction of unactivated arenes 112 (Scheme 55).
Scheme 55: Triazole-assisted iron-catalyzed methylation.