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Rh(III)-catalyzed Distal Alkylation Of Quinoline: Application In Total Synthesis

One of the common goals of all organic chemists is to utilize easily available feedstock for the synthesis of valuable targeted molecules. In this direction, activation of ubiquitous C-H bonds offers various advantages over traditional coupling reactions, the selective functionalization of inert C-H bonds is always challenging due to their abundance and large bond dissociation energies.1

Although, great progress has been made in last two decades in the field of proximal C-H activation by employing various directing group with or without transition metal catalysis, selective activation of C-H bonds beyond proximity still in its early stage of development.

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Catalytic method for alkylation of heterocyclic compounds with abundantly available olefins is considered as an ideal approach. Considering the importance of quinoline moiety in medicinal and material chemistry, the synthesis and functionalization of these scaffolds attracted pronounced attention. Recently, chemists have focused mainly on proximal bond formation approaches and very few devoted efforts for distal functionalization.1

To develop leading advancements in quinoline chemistry, Dr. Upendra Sharma Group (CSIR-IHBT, Palampur, India) has focused to provide approaches for proximal as well as distal C-H bond functionalization via metal free2,3,4 or metal catalyzed5,6 processes. Moreover, few successful attempts have been made and more are being explored. A huge literature has been found for C2 bond formation along with few reports on functionalization of C8 bond1.

In recent studies, Dr. Sharma’s group has tried to overcome the existing difficulties and enhance the step economy by releasing the directing group in one step along with enhanced selectivity which always remains desirable.5,6 Current research work opened the way for C-8 alkylation of quinoline by employing N-oxide as a traceless directing group.6 The main challenge for the successful realization of this approach is β–hydride elimination which can lead to an olefinated product instead of desired alkylated one.

The reaction pathway was elucidated by detail mechanistic studies. The rhodacycle has been synthesized, isolated and finally characterized with the help of spectroscopic and XRD studies for the first time. The synthesized rhodacycle was used as a catalyst to explain its role as an intermediate in the pathway. The kinetic isotopic effect (KIE) study revealed the fate of C-H bond cleavage. DMF has been employed as solvent media as well as proton source in the reduction of olefin.

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C-8 olefinated quinoline was identified as the reaction intermediate, which gets reduced to the desired C-8 alkylated product in the presence of Rh(I) species (produced from Rh(III) during the reaction) and formic acid. Formic acid is produced from DMF in the presence of AgBF4. This finding has been utilized for the synthesis of EP4 agonist used for the treatment of wounds and skin repair. This method is more efficient as compared to earlier known methodology regarding decreasing the complexity and making it more economical. Total 37 C-8 alkylated quinolines have been synthesized. Most importantly the developed catalytic method is also applicable for unreactive aphetic olefins.  This work is recently published in Advanced Synthesis & Catalysis.6

In continuation of this work, Dr. Sharma’s group is further trying to develop new methodologies for C-X bond formation at the C8 position under milder reaction conditions. Detail mechanistic understanding of developed catalytic protocols with the help of experimental as well as DFT study will be the focus.

References

  1. R. Sharma, K. Thakur, R. Kumar, I. Kumar, U. Sharma, Catal. Rev. 2015, 57, 345.
  2. R. Kumar, I. Kumar, R. Sharma, U. Sharma, Org. Biomol. Chem. 2016, 14, 2613.
  3. R. Kumar, R. Kumar, A. K. Dhiman, U. Sharma, Asian J. Org. Chem. 2017, 6, 1043.
  4. A. K. Dhiman, R. Kumar, R. Kumar, U. Sharma, J. Org. Chem., 2017, DOI: 10.1021/acs.joc.7b02149.
  5. R. Sharma, R. Kumar, I. Kumar, U. Sharma, Eur. J. Org. Chem. 2015, 7519.
  6. R. Sharma, I. Kumar, R. Kumar, U. Sharma, Adv. Synth Catal. 2017, 359, 3022.

This study, Rhodium-Catalyzed Remote C-8 Alkylation of Quinolines with Activated and Unactivated Olefins: Mechanistic Study and Total Synthesis of EP4 Agonist was recently published in the journal Advanced Synthesis & Catalysis.

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