Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Metal‑, Photocatalyst‑, and Light-Free, Late-Stage C−H Alkylation of Heteroarenes and 1,4-Quinones Using Carboxylic Acids Daniel R. Sutherland, Marcos Veguillas, Conor L. Oates, and Ai-Lan Lee* Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, U.K.
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ABSTRACT: Contrary to the accepted convention, this work shows that Minisci-type C−H alkylation does not require any metal, photocatalyst, light, or prefunctionalization of the readily available and inexpensive carboxylic acids to proceed well under mild conditions. These mild conditions can be utilized for late-stage alkylations of complex molecules, including pharmaceutical compounds and light-sensitive compounds which degrade under photocatalytic conditions. to render the Minisci-type reactions4 milder, more substrate scope tolerant, and thereby more suitable for late-stage functionalizations of N-heteroarenes. The predominant approach is to replace the carboxylic acid alkylating agent with a different radical source, such as alkyl halides, boronic acid and derivatives, sulfonates, activated esters, and peroxides, in conjunction with metal or photoredox catalysis (Scheme 1A).5,6 Alternatively, cross-dehydrogenative coupling with alkanes can be achieved using bis[(trifluoroacetoxy)iodo]benzene and sodium azide, although this approach is mainly for simple alkanes.7 Recently, Molander has elegantly demonstrated that the use of 1,4-dihydropyridines 3, made in one step from aldehydes, even allows for mild conditions without the need for metal or photocatalysts8 (Scheme 1B). Nevertheless, the ability to use carboxylic acids directly without prefunctionalization is extremely appealing as they are inexpensive, abundant, stable, nontoxic, and readily available, derived directly from natural resources, and release only traceless CO2.9 However, approaches utilizing carboxylic acids so far require the use of either a transition metal reagent3,5e or more recently photocatalysis10 or light.11 The ability to combine the benefits of using readily available carboxylic acids, without the need for metal, photocatalysts, or light, would be a significant advance in the field, not only from a cost, availability, nontoxicity, and byproduct perspective but also for the ability to functionalize light-sensitive substrates which degrade under photocatalytic conditions. We herein present the first C−H alkylation protocol for heterocycles and quinones using carboxylic acids under metal-, photocatalyst-, and light-free conditions and showcase its application in late-
N-Heteroarenes and quinones are important and ubiquitous motifs present in pharmaceuticals, natural products, and ligand scaffolds.1 Rapid, mild, and selective direct C−H functionalization of these motifs is therefore one of the most sought after strategies for late-stage modification of pharmaceuticals.2 The classical Minisci reaction, silver-mediated alkylation of Nheterocycles using carboxylic acids, is a good starting point, but harsh reaction conditions limit its scope (Scheme 1A).3 Within this context, several elegant approaches have recently emerged Scheme 1. Approaches to C−H Alkylation of NHeteroarenes
Received: September 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02988 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters stage functionalizations of medicinally relevant compounds, as well as light-sensitive substrates. Due to our interest in direct C−H functionalization of 1,4quinones,12 our original aim at the start of this project was to develop a mild, silver-free method for C−H alkylation of 1,4quinones13 using readily available and inexpensive alkylcarboxylic acids 4. So far, these mild alkylations have been developed for N-heteroarenes10,11 but not 1,4-quinones. To this end, we initiated our studies by investigating the alkylation of naphthoquinone 5 under Glorius’ mild photoredox-catalyzed conditions for alkylating N-heterocycles10a (Table 1, Entry 1).
Scheme 2. Heteroarene Scope
Table 1. Selected Optimization
entry
LED
temp (°C)
time (h)
oxidant
5 (%)a
6 (%)a
b ,c
blue blue blue green green green green green green green green green dark
rt 30 30 30 30 30 30 30 30 30 30 40 40
16 16 16 72 40 40 40 40 40 40 40 16 16
(NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 Na2S2O8 K2S2O8 t-Bu2O2 DDQ (NH4)2S2O8 (NH4)2S2O8
7 22 28 87 26 21 30 80 86 85 83
