What’s with aminoquinoline directing groups all of a sudden?

Seriously, did someone start giving 8-aminoquinoline away for free?


I started noticing a particular trend in the ASAPs of some of the organic journals I follow, all involving various uses of the aminoquinoline amide as a directing group. The number of papers to come out in the past month or so is absolutely staggering, and why not–the results are some really cool reactions! The one that first caught my attention was actually published back-to-back by both Silas Cook1 (Indiana) and Nakamura2 (U. Tokyo):

 aminoquinoline 1

As far as alkylation reactions go, this one hits a lot of the points on the “want” list—highly selective, uses a non-precious metal, doesn’t require ludicrous temperatures, and is done very, very quickly. But again, two groups simultaneously discovered nearly identical reactions—something must have been going on to make this happen, especially since these directed reactions have continued to inspire new variants even in the month following their publication. Assuming that these folks took longer than a week or two to put together their reactions, all of these groups must have been working on this at the same time! What started this trend? 

Well, there has definitely been plenty of literature on the use of aminoquinoline directing groups. In recent years, it has been used to direct copper-catalyzed alkynylation,3 etherification,4 fluorination,5 arylation,6 and sulfenylation7; iron-catalyzed alkylation,1,2,8 allylation,9 and amination10; nickel-catalyzed alkylation11; and a whole slew of palladium-catalyzed functionalization reactions12-17. This, of course, only covers the aryl amides in the literature, and all of them are perfectly ortho-selective.

 aminoquinoline 2

Daugulis and coworkers first showed this directing effect in 2005,12 where the appropriate size of the N^N chelate was demonstrated with picolinamides and aminoquinoline amides. It turns out that a two sp2 carbon bridge is a sweet spot for these complexes, especially for Pd(II), which is stabilized by the anionic amide ligand.

 aminoquinoline 3

It’s worth noting that in the large majority of these cases, the reactions in hand are reactions that don’t rely on the quinoline to work; instead, they merely take advantage of the arrangement of the substrate being bound in a bidentate fashion to lower the barrier to activating the ortho proton specifically. Some of these reactions proceed through single electron mechanisms, others via two-electron processes, but in all cases the ortho proton stares the metal in the face and is activated preferentially over the others simply as a result of proximity. More than that, however, it also appears to cut down on bimetallic processes—because the ligand is the substrate (or the other way around, depending on your perspective), each reactive metal center is always entropically poised to engage in the monometallic mechanism, which may otherwise may not be true, particularly of iron chemistry, where homodimerization is a common side reaction.

In fact, it might be just this last point that inspired the most recent deluge of chemistry on the subject. It’s worth noting that nearly every aminoquinoline-directed reaction published this summer featured iron catalysis, and I doubt that’s a coincidence. Earlier this year, Chatani and co-workers published a paper that described an unusually strong electronic effect in the ruthenium-catalyzed arylation of these compounds18 (see the paper for some beautiful Hammett studies). Between the entropic sequestration of the substrate coupled with enhanced substituent effects, it makes perfect sense to use these substrates to “tame” iron catalysts, which are notorious for having non-selective or off-target reactivity, especially in alkylation reactions. Indeed, despite being pigeon-holed into benzoic acid derivatives, these are by far some of the most selective iron-mediated alkylations in the literature, and I fully expect this principle to be expanded upon in great detail in future applications of first-row metals in catalysis.

Is there anything else that is particularly cool here, though? I think so—it turns out that these aminoquinoline amides are remarkable in field strength and coordination environment to the iron-containing active site of nitrile hydratase, and some of the better models for it actually use ligands that have exactly this motif.19 Especially with respect to Chatani’s electronic effects, I wonder if the electronic parameters of these reactions and their selectivity toward small molecule substrates have any implications for the mechanism of the metalloenzyme or related biomolecules. That would certainly be a different take on things, with catalysis informing biochemistry, rather than the reverse!

  1. Fruchey, E. R., Monks, B. M. & Cook, S. P. A Unified Strategy for Iron-Catalyzed ortho-Alkylation of Carboxamides. J. Am. Chem. Soc. (2014). doi:10.1021/ja506823u
  2. Ilies, L., Matsubara, T., Ichikawa, S., Asako, S. & Nakamura, E. Iron-Catalyzed Directed Alkylation of Aromatic and Olefinic Carboxamides with Primary and Secondary Alkyl Tosylates, Mesylates, and Halides. J. Am. Chem. Soc. (2014). doi:10.1021/ja5066015
  3. Dong, J., Wang, F. & You, J. Copper-mediated tandem oxidative C(sp2)-H/C(sp)-H alkynylation and annulation of arenes with terminal alkynes. Org. Lett. 16, 2884–2887 (2014).
  4. Roane, J. & Daugulis, O. Copper-catalyzed etherification of arene C-H bonds. Org. Lett. 15, 5842–5845 (2013).
  5. Truong, T., Klimovica, K. & Daugulis, O. Copper-catalyzed, directing group-assisted fluorination of arene and heteroarene C-H bonds. J. Am. Chem. Soc. 135, 9342–9345 (2013).
  6. Nishino, M., Hirano, K., Satoh, T. & Miura, M. Copper-mediated C-H/C-H biaryl coupling of benzoic acid derivatives and 1,3-azoles. Angew. Chem. Int. Ed. Engl. 52, 4457–4461 (2013).
  7. Tran, L. D., Popov, I. & Daugulis, O. Copper-promoted sulfenylation of sp2 C-H bonds. J. Am. Chem. Soc. 134, 18237–18240 (2012).
  8. Monks, B. M., Fruchey, E. R. & Cook, S. P. Iron-Catalyzed C(sp(2) )-H Alkylation of Carboxamides with Primary Electrophiles. Angew. Chem. Int. Ed. Engl. (2014). doi:10.1002/anie.201406594
  9. Asako, S., Ilies, L. & Nakamura, E. Iron-catalyzed ortho-allylation of aromatic carboxamides with allyl ethers. J. Am. Chem. Soc. 135, 17755–17757 (2013).
  10. Matsubara, T., Asako, S., Ilies, L. & Nakamura, E. Synthesis of anthranilic acid derivatives through iron-catalyzed ortho amination of aromatic carboxamides with N-chloroamines. J. Am. Chem. Soc. 136, 646–649 (2014).
  11. Aihara, Y. & Chatani, N. Nickel-catalyzed direct alkylation of C-H bonds in benzamides and acrylamides with functionalized alkyl halides via bidentate-chelation assistance. J. Am. Chem. Soc. 135, 5308–5311 (2013).
  12. Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of sp3 C-H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127, 13154–13155 (2005).
  13. Gou, F.-R. et al. Palladium-catalyzed aryl C-H bonds activation/acetoxylation utilizing a bidentate system. Org. Lett. 11, 5726–5729 (2009).
  14. Shabashov, D. & Daugulis, O. Auxiliary-assisted palladium-catalyzed arylation and alkylation of sp2 and sp3 carbon-hydrogen bonds. J. Am. Chem. Soc. 132, 3965–3972 (2010).
  15. Ano, Y., Tobisu, M. & Chatani, N. Palladium-catalyzed direct ortho-alkynylation of aromatic carboxylic acid derivatives. Org. Lett. 14, 354–357 (2012).
  16. Nadres, E. T., Santos, G. I. F., Shabashov, D. & Daugulis, O. Scope and limitations of auxiliary-assisted, palladium-catalyzed arylation and alkylation of sp2 and sp3 C-H bonds. J. Org. Chem. 78, 9689–9714 (2013).
  17. Kanyiva, K. S., Kuninobu, Y. & Kanai, M. Palladium-catalyzed direct C-H silylation and germanylation of benzamides and carboxamides. Org. Lett. 16, 1968–1971 (2014).
  18. Aihara, Y. & Chatani, N. Ruthenium-catalyzed direct arylation of C–H bonds in aromatic amides containing a bidentate directing group: significant electronic effects on arylation. Chemical Science 4, 664–670 (2013).
  19. Harrop, T. C., Olmstead, M. M. & Mascharak, P. K. Modeling the active site of nitrile hydratase: synthetic strategies to ensure simultaneous coordination of carboxamido-N and thiolato-S to Fe(III) centers. Inorg. Chem. 44, 9527–9533 (2005).

EDIT: Yet another one, a day later in JOC: http://pubs.acs.org/doi/abs/10.1021/jo501691f


2 comments on “What’s with aminoquinoline directing groups all of a sudden?

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