Innate and guided C-H functionalization logic

Abstract

The combustion of organic matter is perhaps the oldest and most common chemical transformation utilized by mankind. The generation of a C-O bond at the expense of a C-H bond during this process may be considered the most basic form of C-H functionalization. This illustrates the extreme generality of the term "C-H functionalization", because it can describe the conversion of literally any C-H bond into a C-X bond (X being anything except H). Therefore, it may be of use to distinguish between what, in our view, are two distinct categories of C-H functionalization logic: "guided" and "innate". Guided C-H functionalizations, as the name implies, are guided by external reagents or directing groups (covalently or fleetingly bound) to install new functional groups at the expense of specifically targeted C-H bonds. Conversely, innate C-H functionalizations may be broadly defined as reactions that exchange C-H bonds for new functional groups based solely on natural reactivity patterns in the absence of other directing forces. Two substrates that illustrate this distinction are dihydrojunenol and isonicotinic acid. The C-H functionalization processes of hydroxylation or arylation, respectively, can take place at multiple locations on each molecule. Innate functionalizations lead to substitution patterns that are dictated by the inherent bias (steric or electronic) of the substrate undergoing C-H cleavage, whereas guided functionalizations lead to substitution patterns that are controlled by external directing forces such as metal complexation or steric bias of the reagent. Although the distinction between guided and innate C-H functionalizations may not always be clear in cases that do not fit neatly into a single category, it is a useful convention to consider when analyzing reactivity patterns and strategies for synthesis. We must emphasize that although a completely rigorous distinction between guided and innate C-H functionalization may not be practical, we have nonetheless found it to be a useful tool at the planning stage of synthesis. In this Account, we trace our own studies in the area of C-H functionalization in synthesis through the lens of "guided" and "innate" descriptors. We show how harnessing innate reactivity can be beneficial for achieving unique bond constructions between heterocycles and carbonyl compounds, enabling rapid and scalable total syntheses. Guided and innate functionalizations were used synergistically to create an entire family of terpenes in a controlled fashion. We continue with a discussion of the synthesis of complex alkaloids with high nitrogen content, which required the invention of a uniquely chemoselective innate C-H functionalization protocol. These findings led us to develop a series of innate C-H functionalization reactions for forging C-C bonds of interest to the largest body of practicing organic chemists: medicinal chemists. Strategic use of C-H functionalization logic can have a dramatically positive effect on the efficiency of synthesis, whether guided or innate.

Scheme 1

Guided and innate C–H functionalization. Bonds formed by guided transformations are indicated in red, and those formed by innate transformations are indicated in blue throughout this account.

Scheme 2

A) A family of marine natural products (9–15) that could all be retrosynthetically traced back to a common indole–carvone intermediate (16); B) Innate indole–enolate coupling yielding the common indole–carvone intermediate 16.^,

Scheme 3

Innate C–H coupling between indoles and enolates (% yields are shown in parenthesis).

Scheme 4

Innate C–H coupling between pyrroles and enolates (% yields are shown in parenthesis).^,

Scheme 5

Innate C–H coupling of 2-carboxymethyl-3-oxindoles and indoles (% yields are shown in parenthesis).

Scheme 6

Guided and innate^,, C–H indole functionalization.

Scheme 7

Innate C–H coupling between oxazolidinones and ketones (% yields are shown in parenthesis).^,

Scheme 8

Innate C–H coupling between oxindoles and ketones (% yields are shown in parenthesis).^,

Scheme 9

Innate C–H coupling between oxazolidinones and esters.

Scheme 10

A) Synthesis of bursehernin (42) via innate C–H enolate coupling;^, B) Structures of avrainvillamide (44), stephacidin A (43) and B (45); C) Innate C–H enolate coupling in the synthesis of 44, 43 and 45.

Scheme 11

Guided and innate C–H enolate coupling.

Scheme 12

A) Hofmann–Loeffler–Freytag reaction; B) Guided C–H oxidation to form 1,3-diols.

Scheme 13

Guided C–H 1,3-diol formation from various alcohols (% yields are shown in parenthesis; ^ayields based on recovered starting material).

Scheme 14

A) Cyclase phase synthesis resulting in the formation of sesquiterpene dihydrojunenol (64);^, B) Synthesis of eudesmane natural products (65–68) from dihydrojunenol (64) by innate and guided C–H oxidation.

Scheme 15

Guided and innate C–H oxidation.^,

Scheme 16

Synthesis of palau’amine (77), massadine (78), axinellamine A (82) and B (83) (% yields are shown in parenthesis).

Scheme 17

Proposed mechanism of the innate C–H arylation.

Scheme 18

Innate C–H arylation of 4-t-butylpyridine (% yields are shown in parenthesis).

Scheme 19

Innate C–H arylation of various N-containing heterocycles (% yields are shown in parenthesis).

Scheme 20

Guided and innate C–H arylation.⁼

Scheme 21

Innate C–H arylation of quinones (% yields are shown in parenthesis).

Scheme 22

Innate C–H arylation of benzoquinone with various arylboronic acids (% yields are shown in parenthesis).

Scheme 23

Innate trifluoromethylation of N-heterocycles (% yields are shown in parenthesis).

Scheme 24

Guided and innate^,, C–H trifluoromethylation.

Scheme 25

Complementary reactivity of electron-deficient CF₃ and electron-rich arene radicals (% yields are shown in parenthesis).^,

Scheme 26

Increased efficiency in synthetic routes when applying innate and/or guided C–H functionalization logic, in the context of: A) intermediate 118 in the synthesis of hapalindoles;^, B) natural products isorengyol (59α) and rengyol (59β);^, c) trifluoromethylated derivative of varenicline (112).