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A Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides for Sp3-Sp2 Bond Formation

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In 2012, a nickel-catalyzed reductive alkylation method of aryl bromides and chlorides was reported. Under the optimized conditions, a variety of aryl and vinyl bromides as well as active aryl chloride can be reductively coupled with alkyl bromides in high yields. The protocols were highly functional-group tolerant and the reactions were not air or moisture sensitive. The reaction showed different chemoselectivity than conventional cross-coupling reactions. Substrates bearing both anelectrophilic and nucleophilic carbon resulted in selective coupling at the electrophilic carbon (R-X) and no reaction occurred at the nucleophilic carbon (R-[M]).

The 2010 Nobel Prize in Chemistry was awarded for the Pd-catalyzed cross-coupling, and in the past decade the progress in cross-coupling has not only had a significant impact on academic research but has also influenced the industrial synthetic application. The transition-metal-catalyzed union of nucleophilic organo-boronic acids with electrophilic organic halides has become the dominant approach to carbon-carbon (C-C) bond formation. These conventional cross-coupling reactions catalytically join nucleophilic carbon (R-[M]) with electrophilic carbon(R-X). But direct coupling of two electrophilic carbons has been much less investigated before 2012. Also, there are many known limitation for the conventional cross-coupling reaction. For example, the most widely used nucleophilic carbon reagents, organoboron compounds, have limited commercial availability, and some are unstable. As a result, organoboron (as well as others: RMgX, RZnX, RSnR′3, RSiR′3) reagents are frequently synthesized when needed. Many organometallic reagents or the intermediates used in their synthesis require special care to exclude oxygen and moisture. Similarly, the reactivity of the reagents (RMgX and RZnX) or basic reagents required to facilitate transmetalation (RB(OR′)2, RSnR′3, and RSiR′3) can place limitations on the use of functional groups that are electrophilic or that have acidic protons.

Conventional transition-metal-catalyzed C-C bond formation (Cδ– + Cδ+) compared to direct reductive C-C bond formation (Cδ+ + Cδ+)..webp

Conventional transition-metal-catalyzed C-C bond formation (Cδ– + Cδ+) compared to direct reductive C-C bond formation (Cδ+ + Cδ+).

The authors previously reported that iodoarenes can be coupled with unactivated iodoalkanes and bromoalkanes to formSp3-Sp2 bond in high yield, but the use of bromoarenes resulted in lower yield and selectivity for product. Two years later, they report here a new catalyst system that for the first time enables the coupling of activated and unactivated bromoarenes, vinyl bromides, and activated chloroarenes with bromoalkanes in good yield and selectivity. They also highlight several key differences in functional-group compatibility between conventional and reductive cross-coupling reactions.

Table 1. Reaction Optimization.webp

Table 1. Reaction Optimization

They first (in Table 1) the optimized the coupling conditions. The major challenges they met werethe development of atrulycross-selective process and minimization of following three side reaction: dimerization, β-hydride elimination and hydrodehalogenation. Three important changes led to generally high yields:(1) the addition of catalytic amounts of sodium iodide; (2) changing the reducing agent from Mn0 to Zn0; and (3) changing the ligands used. The addition of substoichiometric amounts of sodium iodideto the reaction reduced the amount of dimeric byproduct 8. Changing the reducing agent from Mn0 to Zn0 further decreased dimerization of the aryl halide (8) and suppressed dimerization of the alkyl halide (9) and the best yields are obtained by using only bipyridine ligands. According to their results, a reaction run without nickel did not consume starting materials, suggesting that direct insertion of zinc into the organic bromides is not likely. While the beneficial effect of sodium iodide was obvious the improvement due to pyridine is less clear. The addition of pyridine does not dramatically affect the yield, but omission of pyridine has led to slow and/or partial conversion of starting materials. Lastly, they showed the use of catalytic amounts of chlorotrimethylsilane and 1,2-dibromoethane to activate the reducing agent resulted in reaction times as short as 3.5 h with no change in selectivity. The omission of zinc resulted in no reaction. Possible mechanisms were showed below in Scheme 1.

Scheme 1. Possible Mechanisms for the DirectCross-Coupling of Aryl Halides with Alkyl Halides.webp

Scheme 1. Possible Mechanisms for the DirectCross-Coupling of Aryl Halides with Alkyl Halides

Next, a wide range of functionalized substrates were tested with their optimized conditions. While initial optimization was conducted with 10 mol % catalyst, the catalyst loading could generally be lowered to 5 or 7 mol % (Scheme 2). These lower catalyst loadings represent progress for reductive cross-coupling, which has previously been reported with 10-20 mol % catalyst. Even with these lower catalyst loadings, the electron-rich aryl bromides 4-bromoanisole and 4-bromo-N,N-dimethylaniline were coupled successfully for the first time, affording alkylated arene products in high yield.

640 (5).webp

Scheme 2. Substrate Scope of Aryl and Alkyl Bromides for the Nickel-Catalyzed Reductive Cross-Coupling

Aryl chlorides are often more readily available than aryl bromides, and usually at lower cost, but their first-generation catalyst failed with chloroarenes. A slight modification of the conditions used for the coupling of electron-rich aryl bromides proved to be general for the coupling of electron poor aryl chlorides with alkyl bromides (Scheme 3). Omission of sodium iodide, higher reaction temperature and a slight excess of alkyl bromide combined to provide generally high yields of alkylated arene products. In general, there was less biaryl formation and hydro-dehalogenation of the chloroarenes compared to reductive couplings with bromoarenes.

Scheme 3. Substrate Scope of Aryl Chlorides for the Nickel-Catalyzed Reductive Cross-Coupling,.webp

Scheme 3. Substrate Scope of Aryl Chlorides for the Nickel-Catalyzed Reductive Cross-Coupling,

Furthermore, a variety of functional groups that are sensitive or reactive under the conditions employed for conventional cross-coupling reactions were tested under these reductive conditions (Scheme 4). In addition to substrates with acidic or electro-philic functional groups, several bifunctional substrates bearing both an electrophilic carbon (C-Br) and a nucleophilic carbon (C-B, C-Si, C-Sn) were tested in order to probe the selectivity of these conditions for the coupling of two electrophiles versus the coupling of an electrophile with a nucleophile. Several functional groups bearing acidic protons were also examined because organozinc and organomagnesium reagents react rapidly with such protons, requiring workarounds such as prior or in situ deprotonation,34 protection, 35 or syringe-pump addition (RZnX·LiCl only).

Scheme 4. Substrates That Demonstrate the Complementarity of Direct Reductive Cross-Coupling to Conventional Cross-Coupling,.webp

Scheme 4. Substrates That Demonstrate the Complementarity of Direct Reductive Cross-Coupling to Conventional Cross-Coupling,

In conclusion, transition metal-catalyzed systems offer a straightforward route for the formation of carbon-carbon bonds. Suzuki-Miyaura, Heck, and Negishi cross coupling are all classical methods for introducing molecular complexity and for simplifying the synthesis of desired targets.The authors presented here a new catalyst system that enables the coupling of aryl bromides, vinyl bromides, and activated aryl chlorides with alkyl bromides in high yield and selectivity. The work built upon their results with aryl iodides that have been previously reported. In addition to a large improvement of substrate scope, they demonstrated compatibility with a variety of functional groups, and demonstrated the chemoselective coupling of two electrophilic organic halides over the coupling of a nucleophilic carbon with anorganic halide. This work gave the different mechanisms and reaction conditions and the direct reductive approach offered the opportunity for synthetic orthogonality to conventional approaches. All these discoveries have enhanced considerably the power of synthetic organic chemists to assemble complex molecular frameworks.

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[1] Daniel A Everson, et al.Replacing conventional carbon nucleophiles with electrophiles: nickel-catalyzed reductive alkylation of aryl bromides and chlorides. J Am Chem Soc. 2012 Apr 11;134(14):6146-59. doi: 10.1021/ja301769r. Epub 2012 Mar 30.
[2] Soumik Biswas, et al.Mechanism and selectivity in nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides. J Am Chem Soc. 2013 Oct 30;135(43):16192-7. doi: 10.1021/ja407589e. Epub 2013 Oct 21.

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