Decorated oxazolines are important structural motifs of various bioactive compounds of relevance to crop protection and medicinal chemistry (Figure 4).[106] Moreover, oxazolines are easily accessible and can be transformed into a variety of valuable functional groups,[128] which renders them key intermediates in organic synthesis and useful ligands in metal catalysis.[126] Consequently, the development of flexible methods that provide general access to substituted oxazolines are highly desirable.
Figure 4. Selected bioactive 2-aryl oxazolines.
In recent years, transition metal-catalyzed C−H functionalization has made important progress for the atom- and step-economic diversification of oxazolines.[20e, 25] However, catalytic C−H amidations on aryl oxazolines are as of yet restricted to the use of precious rhodium and iridium catalysts, as developed by Chang, among others.[107] As a result, in this chapter we started to explore the possibility for cobalt(III)-catalyzed C−H amidations of oxazolines by employing dioxazolones[129] as user-friendly amidating reagent.
3.5.1 Optimization Studies
At the outset of our studies, we explored the feasibility of the envisioned cobalt-catalyzed C−H amidation of aryl oxazoline 130i with dioxazolone 132a (Table 6). Preliminary solvent optimization showed that aprotic solvents enabled the desired C−H amidation, with DCE being optimal (entries 1−3). Then a variety of additives, including mono protected Amino acid (MPAA), were tested. NaOAc proved to be the most effective (entries 3−10). These observations demonstrated the importance of carboxylate assistance in the
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C−H functionalization regime (entries 3−10). Different cobalt(III) complexes were explored thereafter. While CpCo(CO)I2 and CoCl2 proved to be completely unreactive, [Cp*CoI2]2 and[Cp*Co(MeCN)3](SbF6)2 showed similar reactivity with Cp*Co(CO)I2, albeit with inferior yields (entries 10−14). A control experiment revealed that there was no reaction in the absence of cobalt catalyst (entry 16). The beneficial effect of the carboxylate additive was further verified by the result of entry 15.
Table 6. Oxazolinyl-assisted C−H amidation.a
58 3.5.2 Scope of the Oxazolinyl-Assisted C−H Amidation
Scheme 75. Scope of the oxazolinyl-assisted C−H amidation.
With the optimized conditions identified, we tested the cobalt(III) catalyst in the C−H amidation of various aryl oxazolines 130 (Scheme 75). Thus, a remarkable functional group tolerance that included chloro-, bromo-, cyano-, ester- and trifluromethyl-substituents was observed, which highlighted the excellent chemo-selectivity of this cobalt(III) catalysis (130m-v). For the meta-substituted arenes 130v-w featuring two inequivalent ortho C−H bonds an excellent positional selectivity was observed, which was fully controlled by oxazolinyl assistance and secondary steric interactions. Thereafter, we tested substrates bearing substituents on the oxazoline ring. Thus, oxazolines 130 derived from different β-amino alcohols gave the desired products
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133xa−133za with synthetically meaningful yields. Interestingly, the six-membered ring 1,3-oxazine 130aa also smoothly delivered the corresponding product. The efficiency of the protocol was further demonstrated by the gram-scale synthesis of amide 133ia in comparable yield.
Scheme 76. Cobalt(III)-catalyzed C−H amidation of indoles and pyrroles.
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To our delight, apart from oxazolines and oxazines 130, indoles 102 bearing removable pyridyl and pyrimidyl directing group also proved to be viable substrates for the Cp*Co(CO)I2-catalyzed C−H amidation (Scheme 76). Again, the excellent chemoselectivity of the cobalt(III) catalyst was demostrated by a remarkable tolerance of valuable electrophilic functional groups, such as fluoro, chloro, bromo, iodo, ester or thiophene substituents (154ca−154ga). Meanwhile, aryl, heteroaryl, and alkyl amide moieties could be introduced in a step-economical manner by this user-friendly protocol (154bb−154bf). The robustness of the Cp*Co(CO)I2 -catalyzed C−H amidation was illustrated by the gram-scale synthesis of amidated indole 154ba at low catalyst loading of only 1.0 mol %. The catalytic system was not only applicable to indole substrates but also enabled the cobalt-catalyzed C−H nitrogenation of pyrroles (155aa), pyrozoles (156aa-156ba), phenyl pyridines and phenyl pyrimidines (157aa-157ca) as well (Scheme 77).
Scheme 77. Cobalt(III)-catalyzed C−H amidation of other substrates.
3.5.3 Mechanistic Studies
Attracted by the robustness of the cobalt(III)-catalyzed C−H amidation, we conducted mechanistic studies to elucidate its mode of action. Only a minor loss in catalytic activity was observed when typical radical scavengers were introduced into the catalytic system. These findings do not provide support for a radical-based mechanism (Scheme 78a). Furthermore, a mercury-test experiment confirmed the cobalt catalysis to be homogeneous in nature (Scheme 78b).
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Scheme 78. Radical scavenger experiments and mercury test.
In the absence of the dioxazolinone 132a, reactions performed in the presence of an isotopically labelled cosolvent revealed a considerable H/D scrambling (Scheme 79a). However, no H/D exchange was observed in the presence of dioxazolinones 132a (Scheme 79b). The kinetic isotope effect (KIE) was determined to be kH/kD ≈ 2.3 by independent experiments. This result indicated that the C−H cobaltation step might be kinetically relevant.
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Scheme 79. H/D exchange and KIE studies.
Intermolecular competition experiments between differently substituted substrates revealed electron-rich arenes 130m and electron-rich dioxazolones 132b to be converted preferentially (Scheme 80). These results could be rationalized in terms of the key C−H activation step occurring by a base-assisted, intermolecular electrophilic substitution-type (BIES) C−H activation.
Scheme 80. Competition experiments.
63 3.5.4 Product Diversivications
The synthetic utility of the cobalt(III)-catalyzed C−H amidation was illustrated by the postsynthetic diversification of the obtained amides 133 (Scheme 81). Thus, the liberation of the free primary amine was easily accomplished within 30 min by microwave irradiation, and then following a modified procedure, a novel quinazolinone 159 could be prepared in a step-economical manner. Moreover, adopting Yu’s protocol
[130]
our catalytic product could easily underwent C−H oxygenation process via copper catalysis.
Scheme 81. Diversification of 2-amidoaryloxazolines 133.
Based on our mechanistic studies and previous reports,[131] we propose a plausible catalytic cycle as follow (Scheme 82): First, a kinetically relevant, acetate-assisted C−H cobaltation occurres to form the metallacycle 160. Subsequent coordination of the dioxazolones 132 forms the intermediate 161, which then undergoes CO2
extrusion. Finally, proto-decobaltation by the originally formed AcOH regenerates the catalyst cobalt-(III) carboxylate and yields the desired product 133.
Scheme 82. Proposed catalytic cycle.
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