Weak coordination as a powerful means for developing broadly useful C-H functionalization reactions

Abstract

Reactions that convert carbon-hydrogen (C-H) bonds into carbon-carbon (C-C) or carbon-heteroatom (C-Y) bonds are attractive tools for organic chemists, potentially expediting the synthesis of target molecules through new disconnections in retrosynthetic analysis. Despite extensive inorganic and organometallic study of the insertion of homogeneous metal species into unactivated C-H bonds, practical applications of this technology in organic chemistry are still rare. Only in the past decade have metal-catalyzed C-H functionalization reactions become more widely utilized in organic synthesis. Research in the area of homogeneous transition metal-catalyzed C-H functionalization can be broadly grouped into two subfields. They reflect different approaches and goals and thus have different challenges and opportunities. One approach involves reactions of completely unfunctionalized aromatic and aliphatic hydrocarbons, which we refer to as "first functionalization". Here the substrates are nonpolar and hydrophobic and thus interact very weakly with polar metal species. To overcome this weak affinity and drive metal-mediated C-H cleavage, chemists often use hydrocarbon substrates in large excess (for example, as solvent). Because highly reactive metal species are needed in first functionalization, controlling the chemoselectivity to avoid overfunctionalization is often difficult. Additionally, because both substrates and products are comparatively low-value chemicals, developing cost-effective catalysts with exceptionally high turnover numbers that are competitive with alternatives (including heterogeneous catalysts) is challenging. Although an exciting field, first functionalization is beyond the scope of this Account. The second subfield of C-H functionalization involves substrates containing one or more pre-existing functional groups, termed "further functionalization". One advantage of this approach is that the existing functional group (or groups) can be used to chelate the metal catalyst and position it for selective C-H cleavage. Precoordination can overcome the paraffin nature of C-H bonds by increasing the effective concentration of the substrate so that it need not be used as solvent. From a synthetic perspective, it is desirable to use a functional group that is an intrinsic part of the substrate so that extra steps for installation and removal of an external directing group can be avoided. In this way, dramatic increases in molecular complexity can be accomplished in a single stroke through stereo- and site-selective introduction of a new functional group. Although reactivity is a major challenge (as with first functionalization), the philosophy in further functionalization differs; the major challenge is developing reactions that work with predictable selectivity in intricately functionalized contexts on commonly occurring structural motifs. In this Account, we focus on an emergent theme within the further functionalization literature: the use of commonly occurring functional groups to direct C-H cleavage through weak coordination. We discuss our motivation for studying Pd-catalyzed C-H functionalization assisted by weakly coordinating functional groups and chronicle our endeavors to bring reactions of this type to fruition. Through this approach, we have developed reactions with a diverse range of substrates and coupling partners, with the broad scope likely stemming from the high reactivity of the cyclopalladated intermediates, which are held together through weak interactions.

Figure 1

Early examples of well defined metallacycles using strong directing groups.^-

Figure 2

Palladacycles using representative traditional directing groups.

Figure 3

Palladacycles resulting from C(sp³)–H cleavage.^,

Figure 4

Versatile auxiliaries for organic synthesis.

Figure 5

Representative weakly coordinating substrates.

Figure 6

(a) Lithiation through the CIPE and (b) a hypothetical example of Pd(II)-mediated C–H cleavage through weak coordination.

Figure 7

κ² coordination structures.

Figure 8

Possible pre-transition state coordination structures with electron-deficient N-substituted amide directing groups.

Scheme 1

Comparison of “first functionalization” and “further functionalization”.

Scheme 2

C–H cleavage promoted by a proximal directing group (DG).

Scheme 3

Ru(0)-catalyzed C–H functionalization of arylketones.

Scheme 4

Versatile reactivity of [Pd(II)–aryl] and [Pd(II)–alkyl] intermediates.

Scheme 5

Different catalytic manifolds in Pd-catalyzed C–H functionalization.

Scheme 6

C–H olefination of benzene along a Pd(II)/Pd(0) catalytic cycle.

Scheme 7

Pd(II)-catalyzed ortho-C–H functionalization of substrates bearing directing groups.^,

Scheme 8

ortho-C–H functionalization via Pd(II)/Pd(IV) or Pd(II)₂/Pd(III)₂ catalysis.^-

Scheme 9

Pd(II)-catalyzed C–H/R–BX₂ cross-coupling with oxazoline substrates.

Scheme 10

Classical substrate-directable reaction in organic synthesis.^-

Scheme 11

New retrosynthetic disconnections for heterocyclic ring formation.

Scheme 12

A new retrosynthetic disconnection for β-functionalization.

Scheme 13

Hypothetical synthetic route to chiral building blocks containing all-carbon quaternary stereocenters from pivalic acid using sequential C(sp³)–H functionalization.

Scheme 14

Precise geometrically positioning of the target methyl group triggers a room temperature C–H cleavage event from square-planar pretransition state coordination structure 99.

Scheme 15

Boc-directed C(sp³)–H acetoxylation of α-methyl groups.

Scheme 16

Possible carboxylate binding modes.

Scheme 17

Dramatic countercation effect in the ortho-C–H iodination of benzoic acids.

Scheme 18

Evidence for proposed coordination structures in counteraction-promoted C–H cleavage by Pd(II).

Scheme 19

C–H/R–BX₂ cross-coupling of carboxylic acid substrates.

Scheme 20

C–H/R–BX₂ cross-coupling of carboxylic acid substrates.

Scheme 21

Weakly coordinating acidic N-aryl amide auxiliaries.

Scheme 22

Applications of remote, weakly coordinating directing groups.

Scheme 23

Diverse reactivity in C–H functionalization using weakly coordinating substrates.

Scheme 24

Divergent C–H functionalization of drug candidates.

Scheme 25

Enantioselective C–H activation.^,

Scheme 26

Ligand-accelerated Pd(II)-catalyzed C–H olefination.