Magic Methyl Effect: Transition Metal Catalyzed

The insertion of a methyl group, the smallest alkyl group, into a C-H bond has been shown to enhance such pharmacological charactistics as bioavailability and potency.¹ Traditionally, incorporation of a methyl group into a bioactive compound has required lengthy de novo synthesis. Consequently, synthetic reactions that allow late-stage installation of methyl groups into advanced intermediates are of great potential value in the pharmaceutical industry. In the past two decades interest in directed C−H activation followed by the methylation led to the development of strategies which use precious metals catalysts forarenes ortho-functionalizations.^{2, 3}

Currently, only a few reactions exist which enable such transformations to be achieved in a single step,^{1, 4} highlighting the difficulty in converting a C-H bond to C-Me bond. Most of these methods require heavy loadings of precious metal catalysts to obtain the desired methylated product (Scheme 1).⁴ Moreover, some of them use hazardous and toxic methylating reagents¹ with strongly basic reaction media what results in a limited scope^1,4 and the uncontrolled formation of both mono- and dimethylated products.² This reflects the need for new methylation methods which will overcome mentioned limitations.

Scheme 1. Ortho-methylation with precious metal

To address the toxicity and expense of the precious metal catalysis, first row metal-catalyzed C−H functionalization has recently been recognized as a straightforward and a powerful tool for the formation of C_sp²– C_sp³ bonds in modern organic synthesis. In addition first row transition metals introduce interesting mechanistic possibilities for ortho-methylation; they are readily available and relatively low toxicity.^{1, 4}

Recently Lu and co-workers reported the cobalt (II)-catalyzed direct C-H methylation of unactivated (hetero)arenes using dicumyl peroxide (DCP) as the methyl source, base and most importantly as an oxidant. Cobalt mediated C-H functionalization is a maturing field; however, there exist only two examples of its application to methylation of aromatics, using N-methyl-1-naphthamide and benzo[h]quinolone substrates respectively. The reaction proved to be mild, functional group tolerant and uses a less toxic methylating reagent. The paper reports effective access to a range of ortho-methylated (hetero)aromatic carboxamides (Scheme 2).⁵

Scheme 2. Ortho-methylation with cobalt catalysts

Chatani and co-workers reported the use of aryltrimethylammonium bromide and iodide as new methylating reagents in conjunction with nickel-catalyzed C-H bond activation (Scheme 3). Changing from a palladium⁶ catalyst to nickel makes the ammonium salt act as a methyl source rather than aryl source for a range of 8-aminoquinoline aryl amides. Unfortunately harsh conditions make it difficult to control the selectivity between mono- and dimethylation at the ortho positions in some cases.⁷

Scheme 3. Ortho-methylation with nickel catalyst using aryltrimethylammonium iodide as methylating reagent

Nakamura and co-workers have reported two separate iron-catalyzed conditions seemingly solving a lot of issues associated with the previous examples. The direct C-H methylation reaction with a picolinoyl or 8-aminoquinolyl directing groups, an iron/diphospine catalyst, and inexpensive 2,3-dichlorobutane as an oxidant furnished an efficient, robust reaction (Scheme 4).⁸ Unfortunately the method relies upon superstoichiometric methyl equivalents in the form of the pyrophoric trimethylaluminum.

Scheme 4. Ortho-methylation with iron catalyst using trimethylaluminum as methyl source

Nakamura and co-workers further optimized the iron-catalyzed C-H methylation reaction by screening ligands.⁹ The tridentate phosphine ligand NMe₂-TP in combination with Fe(acac)₃ catalyzed the ortho C-H methylation of simple aromatic carbonyl compounds without requiring additional directing groups. This reaction showed wide substrate generality, functional group tolerance, and resistance to catalytic poisons taking advantage of functional groups inherent to the advanced intermediates (Scheme 4).⁹

This seminar will discuss the scope and limitations of these recently published methods, and assess the progress towards developing general solutions to the challenge of late-stage methyl incorporation.

References:

1. Schönherr H., Cernak T. Angew. Chem. Int. Ed. 2013, 52, 12256
2. Lyons T. W., Sanford M. S. Chem. Rev. 2010, 110, 1147
3. Snieckus V. Chem. Rev. 1990, 90, 879
4. Yan G., Borah A. J., Wang L. and Yanga M. Adv. Synth. Catal. 2015, 357, 1333
5. Li Q., Li Y., Hu W., Hu R., Li G. and Lu H. Chem. Eur. J. 2016, 22, 12286
6. Zhu F., Tao J.-L., Wang Z.-X. Org. Lett. 2015, 17, 4926
7. Uemura T., Yamaguchi M., and Chatani N. Angew. Chem. Int. Ed. 2016, 128, 3214
8. Shang R., Ilies L, and Nakamura E. J. Am. Chem. Soc. 2015, 137, 7660
9. Shang R., Ilies L. and Nakamura E. J. Am. Chem. Soc. 2016, 138, 10132