The development of a mild and general method for the alkylation of amides with relatively unreactive alkyl halides (i.e., poor substrates for S N 2 reactions) is an ongoing challenge in organic synthesis. We describe herein a versatile transition-metal-catalyzed approach: in particular, a photoinduced, copper-catalyzed monoalkylation of primary amides. A broad array of alkyl and aryl amides (as well as a lactam and a 2-oxazolidinone) couple with unactivated secondary (and hindered primary) alkyl bromides and iodides using a single set of comparatively simple and mild conditions: inexpensive CuI as the catalyst, no separate added ligand, and C−N bond formation at room temperature. The method is compatible with a variety of functional groups, such as an olefin, a carbamate, a thiophene, and a pyridine, and it has been applied to the synthesis of an opioid receptor antagonist. A range of mechanistic observations, including reactivity and stereochemical studies, are consistent with a coupling pathway that includes photoexcitation of a copper−amidate complex, followed by electron transfer to form an alkyl radical.

N‐alkylations of carbazoles with a variety of secondary and hindered primary alkyl iodides can be achieved by using a simple precatalyst (CuI) under mild conditions (0 °C) in the presence of a Brønsted base; at higher temperature (30 °C), secondary alkyl bromides also serve as suitable coupling partners. A Li[Cu(carbazolide)2] complex has been crystallographically characterized, and it may serve as an intermediate in the catalytic cycle.

II. Photoinduced, Copper-Catalyzed N-Arylations (Tables 1-5) General Procedure. The nitrogen heterocycle (1.00 mmol), LiOt-Bu (112 mg, 1.40 mmol), and CuI (19.0 mg, 0.10 mmol) were added to an oven-dried 10-mL quartz test tube that contained a stir bar. The test tube was fitted with a rubber septum, the joint was wrapped with electrical tape, and the test tube was evacuated and backfilled with nitrogen (three cycles). Then, CH 3 CN (4.0 mL) and the aryl iodide (1.40 mmol; if the aryl iodide is a solid, then it was added immediately after the addition of CuI) were added in turn via syringe. The test tube was detached from the nitrogen manifold, and the puncture holes in the septum were covered with vacuum grease. The resulting mixture was stirred for 5 min, and then the test tube was transferred to a Luzchem LZC-4V photoreactor, where it was irradiated at 254 nm for 24 h (adequate stirring is important). Next, the mixture was passed through a long plug of silica gel (monitored by TLC), the solvent was removed, and the residue was purified by column chromatography. Notes: (a) A Honeywell ultraviolet air treatment system (model #RUVLAMP1), available for ~$110 from retail outlets such as Amazon or The Home Depot, furnishes a comparable result: indole and iodobenzene couple in 63% yield (calibrated GC analysis) after 48 h. (b) Use of a borosilicate, rather than a quartz, test tube leads to a low yield of the C-N coupling product. N 1-Phenyl-1H-indole (Table 1, entry 1) [16096-33-6]. The title compound was synthesized according to the General Procedure from indole (117 mg, 1.00 mmol), LiOt-Bu (112 mg, 1.40 mmol), CuI (19.0 mg, 0.10 mmol), and iodobenzene (286 mg, 1.40 mmol). The reaction mixture was filtered through a plug of silica gel (10% EtOAc/hexanes) and purified by column chromatography (hexanes). Pale-yellow oil. First run: 142 mg (73% yield). Second run: 148 mg (77% yield). N Me 1-(p-Tolyl)-1H-indole (Table 1, entry 2) [167283-32-1]. The title compound was synthesized according to the General Procedure from indole (117 mg, 1.00 mmol), LiOt-Bu (112 mg, 1.40 mmol), CuI (19.0 mg, 0.10 mmol), and 4-iodotoluene (305 mg, 1.40 mmol). The reaction mixture was filtered through a plug of silica gel (10% EtOAc/hexanes) and purified by column chromatography on silica gel (hexanes→1% Et 2 O/hexanes). Colorless oil. First run: 140 mg (68%). Second run: 143 mg (69%).

We have exploited a typically undesired elementary step in cross-coupling reactions, β-hydride elimination, to accomplish palladium-catalyzed dehydrohalogenations of alkyl bromides to form terminal olefins. We have applied this method, which proceeds in excellent yield at room temperature in the presence of a variety of functional groups, to a formal total synthesis of (R)-mevalonolactone. Our mechanistic studies establish that the rate-determining step can vary with the structure of the alkyl bromide, and, most significantly, that L2PdHBr (L=phosphine), an often-invoked intermediate in palladium-catalyzed processes such as the Heck reaction, is not an intermediate in the active catalytic cycle.