carboxylation of heteroarenes with ambient CO 2 †

Strategies for the fixation of carbon dioxide (CO2) as an easily accessible, inexpensive, naturally abundant, and renewable C1 source towards valuable commodity chemicals have attracted major topical interest. While significant progress has been witnessed in the chemical use of CO2 during the recent decade, the vast majority of these procedures require pre-functionalized substrates, such as aryl halides or aryl boronic acids. The synthesis of the prerequisite preoxidized arenes calls for a number of reaction steps, which contradicts the principles of green chemistry. In contrast, the direct functionalization of otherwise inert C–H bonds represents a considerably more atomand step-economical strategy, with important advances in direct carboxylations accomplished by Iwasawa, Nolan, Hou, Hu, Klankermayer/Leitner, and Beller, among others. Within our program on catalytic C–H activation, we became attracted by devising reaction conditions for sustainable C–H carboxylation with ambient CO2 under mild conditions. 31 As a result of our efforts, we have developed a highly effective protocol for step-economical C–H carboxylations of heteroarenes with ambient CO2 under transition metal-free reaction conditions, on which we now wish to report herein. In contrast to previously reported methods, our C–H carboxylation protocol is operative in the absence of transition metals at relatively low temperatures of only 80–100 °C. Results and discussion


Introduction
Strategies for the fixation of carbon dioxide (CO 2 ) as an easily accessible, inexpensive, naturally abundant, and renewable C1 source towards valuable commodity chemicals 1,2 have attracted major topical interest. 3While significant progress has been witnessed in the chemical use of CO 2 during the recent decade, [4][5][6][7][8][9][10][11][12][13][14] the vast majority of these procedures require pre-functionalized substrates, such as aryl halides or aryl boronic acids. 1 The synthesis of the prerequisite preoxidized arenes calls for a number of reaction steps, which contradicts the principles of green chemistry. 15In contrast, the direct functionalization of otherwise inert C-H bonds represents a considerably more atom-and step-economical strategy, 16 with important advances in direct carboxylations 17,18 accomplished by Iwasawa, [19][20][21] Nolan, 22,23 Hou, 24 Hu, 25 Klankermayer/Leitner, 11 and Beller, 26,27 among others. 28Within our program on catalytic C-H activation, 29,30 we became attracted by devising reaction conditions for sustainable C-H carboxylation with ambient CO 2 under mild conditions. 31As a result of our efforts, we have developed a highly effective protocol for step-economical C-H carboxylations of heteroarenes with ambient CO 2 under transition metal-free reaction conditions, on which we now 31 wish to report herein.In contrast to previously reported methods, [22][23][24] our C-H carboxylation protocol is operative in the absence of transition metals at relatively low temperatures of only 80-100 °C.

Results and discussion
At the outset of our studies, we chose reaction conditions similar to the ones previously described for the carboxylations of organoboronic esters with CO 2 (Table 1). 32Thus, when reacting benzo[d]oxazole (1a) in the presence of 10 mol% of the well-defined N-heterocyclic carbene copper(I) complex [Cu(IPr)Cl] in DMF at 80 °C under an atmosphere of CO 2 , 82% isolated yield of methylbenzo[d]oxazole-2-carboxylate (3a) were obtained upon treatment with methyl iodide (2a) (Table 1, entry 1).In order to establish a more economical and userfriendly method, the reaction was conducted with simple CuCl as the catalyst under ligand-free reaction conditions, which provided product 3a in a comparable yield (entry 2).Interestingly, when conducting a test reaction in the absence of a transition metal catalyst solely with the base KOt-Bu 33 in DMF at 100 °C, 34 the desired product 3a was isolated in 80% yield (entry 3).‡ An elevated reaction temperature of 125 °C failed to afford an improvement (entry 4), whilst a reaction conducted at 80 °C proceeded efficiently (entries 4 and 5), clearly highlighting the beneficial features of KOt-Bu as compared to Cs 2 CO 3 that required 125 °C (vide infra). 25Polar solvents other than DMF, such as NMP, 1,4-dioxane, THF and DMSO, provided less satisfactory results (entries 7-10), did apolar toluene (entry 11).However, the encouraging result obtained with NMP as the solvent (entry 7) indicates the potential of our strategy for the use of greener solvents, such as 1-butylpyrrolidinone or Cyrene. 35On the contrary, the C-H functionalization performed in DMA furnished carboxylic acid ester 3a with a high efficacy (entry 12).Interestingly, bases other than KOt-Bu, including Cs 2 CO 3 or Rb 2 CO 3 , proved to be considerably less effective under otherwise identical reaction conditions (entries 13 and 14), illustrating the unique power of KOt-Bu as the base, particularly at a reaction temperature of 80 °C (entry 15 versus 5).
With the optimized reaction conditions in hand, the scope of the C-H carboxylation was explored next (Scheme 1). 36series of representative heteroarenes 1 was successfully converted into the desired carboxylic acid esters 3 under transition metal-free reaction conditions with atmospheric CO 2 .
Various alkyl carboxylates 3 were obtained upon subsequent esterification with different alkyl iodides 2 under rather mild reaction conditions.Methyl-as well as chlorosubstituted benzo[d]oxazoles 1b and 1c were site-selectively functionalized, affording the 2-substituted carboxylic acid esters 3b-d in high yields after treatment with the corresponding alkyl iodide 2. Notably, the use of Cs 2 CO 3 as the base under otherwise identical reaction conditions resulted in an inferior yield of only 48% for product 3b.Likewise, it is noteworthy that chloro-substituted azole 1c provided the corresponding product 3d in an excellent yield of 91%, whereas Cs 2 CO 3 delivered only 55% of the desired ester 3d.As showcased in a representative set of C-H functionalizations, our sustainable approach was not restricted to the use of methyl iodide as the electrophile, but also allowed esterification with a variety of alkyl iodides 2.Moreover, our protocol set the stage for the C-H carboxylation of benzothiazole in a step-economical fashion.Indeed, the corresponding methyl ester 3f and hexyl ester 3g were isolated in 66% and 62% yield, respectively.
Furthermore, oxazoles 4 served as viable substrates for the C-H carboxylation, delivering the corresponding carboxylic acid derivatives 5a-d in a step-and atom-economical manner (Scheme 2). 37Intriguingly, valuable chlorine substituents on the heteroarenes were well tolerated under the optimized reaction conditions, which should prove instrumental for further late-stage diversification by inter alia cross-coupling technology.
Finally, we were pleased to observe that 1,3,4-oxadiazoles 6 proved to be viable substrates for the C-H carboxylation under an ambient CO 2 atmosphere as well, providing the desired carboxylic acid esters 7a-c with high levels of selectivity control (Scheme 3).
Based on the literature precedents, 25,38 we propose the reaction to proceed by initial reversible C-H cleavage (Scheme 4), along with subsequent C-C formation by the action of ambient CO 2 .
Scheme 1 C-H carboxylation with ambient CO 2 .a Cs 2 CO 3 as the base.
Scheme 2 C-H carboxylation of oxazoles 4. a GC-conversion.In summary, we have reported on the use of CO 2 as an easily accessible, inexpensive, and renewable C1 source for green C-H carboxylations under transition metal-free reaction conditions.Hence, KOt-Bu enabled efficient C-H functionalizations on heteroarenes with an ample substrate scope under mild 39 reaction conditions, namely at a rather low reaction temperature and ambient pressure of CO 2 .