Alkyl halides as both hydride and alkyl sources in catalytic regioselective reductive olefin hydroalkylation

Abstract

Among the plethora of catalytic methods developed for hydrocarbofunctionalization of olefins to date, reactions that regioselectively install a functionalized alkyl unit at the 2-position of a terminal unactivated C=C bond to afford branched products are scarce. Here, we show that a Ni-based catalyst in conjunction with a stoichiometric reducing agent promote Markovnikov-selective hydroalkylation of unactivated alkenes tethered to a recyclable 8-aminoquinaldine directing auxiliary. These mild reductive processes employ readily available primary and secondary haloalkanes as both the hydride and alkyl donor. Reactions of alkenyl amides with ≥ five-carbon chain length regioselectively afforded β-alkylated products through remote hydroalkylation, underscoring the fidelity of the catalytic process and the directing group's capability in stabilizing five-membered nickelacycle intermediates. The operationally simple protocol exhibits exceptional functional group tolerance and is amenable to the synthesis of bioactive molecules as well as regioconvergent transformations.

Fig. 1. The significance of developing branched- and β-selective hydroalkylation of unactivated alkenes.

a Reported methods that involve anti-Markovnikov-selective hydroalkylation of aliphatic olefins. b Reported methods that involve Markovnikov-selective hydroalkylation of aliphatic olefins. c An attractive catalytic approach for Markovnikov- and β-selective olefin hydroalkylation takes advantage of haloalkanes to transfer the hydride and alkyl motif under mild reductive conditions without additional hydrosilane, acidic or basic additives. d The resulting hydroalkylation products are versatile building blocks that may be used to access biologically active molecules. R, functional group; Phth, phthaloyl; pyr., pyridinium; cat., catalyst.

Fig. 2. The challenges involved in developing site-selective reductive hydroalkylation reactions.

As shown in the Ni catalytic cycle, the key to efficient transformation of 4 to 5 requires faster conversion of intermediate ii to iv in order to suppress adventitious formation of the undesired dialkylation adduct 6. Under the reductive conditions, both the hydrogen and alkyl unit are derived from the haloalkane reagent. R, G, functional group; X, halide; L, ligand; cat., catalyst.

Fig. 3. The range of products accessible by reductive olefin hydroalkylation.

The protocol is compatible with both primary and secondary alkyl halides bearing Brønsted/Lewis acidic and basic functionalities, including those derived from complex bioactive molecules. Both mono- and 1,2-disubstituted alkenyl amides are tolerated in the catalytic system. For 9w, the reaction was conducted with neopentyl bromide (3 equiv.) and isopropyl bromide (1.2 equiv.) using NiI₂ as the catalyst. For 9ac and 9af, reactions were conducted using iodides (X = I). For 9ad, 9ae, and 9ag, reactions were conducted using bromides (X = Br). For 9j, ~20% of an inseparable hydrodeiodination side product was detected. For 9m, ~3% of an inseparable self-coupling side product of iodide substrate was detected. 9g, 9i, 9u, 9ab, and 9af were obtained as 88:12, 93:7, 92:8, 90:10, and 91:9 regioisomeric mixtures, respectively. 9l and 9z were obtained as 5:1 and 1:1 diastereomeric mixtures, respectively. Regioisomeric and diastereomeric ratios were determined by ¹H NMR analysis. Yields are for isolated and purified products. R, functional group; X, halide; NMP, N-methyl-2-pyrrolidone; Boc, tert-butoxycarbonyl.

Fig. 4. Application to synthesis of biologically active molecules and remote hydroalkylation.

a The products resulting from reductive hydroalkylation can be conveniently transformed to a variety of medicinal compounds of interest. b Alkenyl amides bearing ≥ five-carbon chain length undergo remote hydroalkylation through in situ isomerization of alkylnickel intermediates, providing reliable access to β-alkylated molecules. Regioisomeric olefin mixtures can be regioconvergently converted to a single value-added product. Regioisomeric ratios were determined by ¹H NMR analysis. Yields are for isolated and purified products. 9ah was obtained as a 96:4 regioisomeric mixture. For 18a, 18d, 18e, and 18g, reactions were conducted using iodides (X = I). For 18b, 18c, and 18f, reactions were conducted using bromides (X = Br). For 18g, 5 equiv. of 1-iodobutane was used. R, functional group; X, halide; NMP, N-methyl-2-pyrrolidone; DMA, N,N-dimethylacetamide; NHPI, N-hydroxyphthalimide; DIC, N,N′-diisopropylcarbodiimide; DMAP, 4-dimethylaminopyridine; dtbbpy, 4,4′-di-tert-butyl-2,2′-bipyridine; Boc, tert-butoxycarbonyl; Phth, phthaloyl; Cp, cyclopentadienyl; RT, room temperature.

Fig. 5. Mechanistic studies.

a Control experiment ruling out the intermediacy of 7a′. b Deuterium labeling experiment. c Radical clock experiment. d Complete stereochemical erosion with an enantioenriched alkyl halide. Diastereomeric ratios were determined by ¹H NMR analysis. Enantiomeric ratios were determined by chiral HPLC analysis. Yields are for isolated and purified products. NMP, N-methyl-2-pyrrolidone; RT, room temperature.