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Redox-enabled cooperative catalysis by activating secondary alcohols using low-valent Zn complexes†

Arup Samanta, Amit Chaubey, Debjyoti Pal, Krishna Majhi and Dipankar Srimani*
Department of Chemistry, Indian Institute of Technology-Guwahati, Kamrup, Assam 781039, India. E-mail: dsrimani@iitg.ac.in

First published on 26th August 2024

The direct alkylation with alcohol using the BH pathway via metal-hydride species⁵ formation is well known in the literature, but dehydrogenation⁶ via a radical mechanism remaining back seated may be due to some challenges associated with the increased reactivity of in situ formed α-oxy carbon-centered radical species towards pinacol-type reaction. Chemists have been inspired by enzymatic reactions⁷ to imitate this system for efficient chemical conversions by installing a redox-active element into organic ligand scaffolds. In catalysis, where key stages are primarily controlled by ligand-dominated redox processes, the capacity of particular ligands to store and deliver proton-coupled electrons has created new opportunities.⁸ This opens up a new prospect to activate Zn metal with d¹⁰ metal species, which is highly significant due to their less toxicity and economical nature compared to other transition metal surrogates.⁹ The coordinated redox-active scaffold(s) and Zn-metal participate synergistically in the electron transfer process, and under controlled conditions, these chelated ligands generate stable radicals, which activates the catalytic process. Recently, non-innocent Zn-complexes have been utilized to activate primary alcohols for de(hydrogenative) processes.¹⁰ Very recently, we demonstrated β-alkylation of secondary alcohols with primary alcohols using Zn-complexes.^10c However, Zn catalysed chemoselective BH-alkylation of ketones using a diverse range of challenging secondary alcohols is limited.

The Donohoe group,¹¹ in their pioneering work, employed penta-substituted phenyl (Ph*) methyl ketones for the BH-alkylation of ketones. One of the key benefits is that after alkylation, the Ph* group can be released by retro Friedel–Crafts acylation to aid new routes for diverse useful compounds. Encouraged by the utility of the process and engrossed by the non-toxic and cost-effective nature of 3d-transition metals, other groups studied their ability for this process.¹² Despite the potential of these processes, it would be important to create non-precious, and environment-friendly zinc-complexes for the BH-alkylation of such ketones with secondary alcohols, which, to the best of our knowledge, have not yet been developed.

Herein, we developed various well-defined Zn-complexes (Fig. 1) for the alkylation of ketones with a diverse range of secondary alcohols to produce β-disubstituted ketones. Several post-synthetic modifications of the products were also performed. Mechanistic studies indicate that the reaction proceeds via a radical mechanism and redox-noninnocent behaviour of the hydrazone ligands.

	Fig. 1 Prepared Zn-complexes. SC-XRD structures of Zn-5 and Zn-6. Ellipsoids plotted at 50% probability and hydrogen atoms are omitted for clarity except NH.

At the outset, a series of hydrazone-based ligands were synthesized and complexation was done using a ZnBr₂ metal precursor. Complexes were well characterized using NMR, SC-XRD and HRMS. Furthermore, their catalytic activity was checked towards the activation of secondary alcohols. Our assessment started with choosing the reaction between 2,3,4,5,6-pentamethylacetophenone (1a) and 1-phenylethanol (2a) as an example (Table 1). The reaction of 1a with 2a, using 5 mol% of Zn-2 catalyst and 2 equiv. of KO^tBu loading yielded the desired product 3aa in 31% yield (see ESI†). With further increase of alcohol loading from 1.2 equiv. to 2.0 equiv. and catalyst loading from 5 mol% to 7.5 mol% and lowering of KO^tBu from 2.0 equiv. to 1.0 equiv., the yield was drastically improved from 31% to 76% (see ESI†). The product yield increases to 94% when the reaction time is further extended from 24 to 36 hours, maintaining other conditions the same (Table 1, entry 1). The relative effectiveness of catalyst Zn-1 to Zn-6 was also checked. Catalysts Zn-1, Zn-3 and Zn-6 give comparative yield, whereas Zn-4 and ZnBr₂ failed to give the desired product and Zn-5 led to the formation of a lower yield of the product (Table 1, entries 2 and 3). During the course of base optimization, KO^tBu was found as elite rather than NaO^tBu, NaOH, KOH, Na₂CO₃ and Cs₂CO₃ (Table 1, entry 4).

Lowering the reaction temperature from 140 °C to 120 °C, the product yield was decreased (Table 1, entry 5). A control experiment without catalyst or base led to a trace amount of yield (Table 1, entry 6). With the optimized conditions in hand, we planned to span the substrate scope in two divisions – (i) using aromatic secondary alcohols and (ii) cyclic or acyclic aliphatic secondary alcohols having different substitution patterns (Scheme 1). Reaction with 1-phenylethanol and 1-aryl ethanol containing electron-donating substituents at the para position of the phenyl ring gave good to excellent product yields 76–94% (3aa–3ae). Substituents like fluoro, chloro and bromo groups on the aromatic ring are also successfully converted to the corresponding products with higher yields (3af–3ah) compared to the previously reported methods.^12a,b These halide groups can be further functionalized with the help of cross-coupling reactions. Unfortunately, challenging functional groups did not deliver the desired products (3ai–3al), whereas the dehydration product of secondary alcohol was observed (see ESI†). Polycyclic aromatic hydrocarbons (PAHs), such as α-methyl-2-naphthalenemethanol, substituted indanol and α-tetralol were also compatible with the reaction conditions (3am–3ap & 3av). Alkylation of fluorenol is troublesome due to the retro-aldol product, but delightfully under these optimized conditions 3aq was obtained in 65% yield. Heterocycles pyridine, thiophene, biomass-derived furan and piperonyl motifs reacted smoothly to deliver good yields of products (3ar–3au).

	Scheme 1 Substrate scope. a,bConditions: 1 (0.5 mmol), 2 (1.0 mmol), Zn-2 cat. (7.5 mol%), KOtBu (0.5 mmol.), toluene (2 mL), under argon, 140 °C, isolated yield; c2 (1.5 mmol); dtemperature: 120 °C; e2 (1 mL).

Next, we explored the scope of cyclic and acyclic aliphatic secondary alcohols. Under the standard reaction conditions, cyclohexanol gave a moderate yield (62%) of 3ba (see ESI,† 6.b). Nevertheless, using three equivalents of alcohol resulted in an excellent yield (96%) of the coupled product. Secondary alcohols having 3-membered to 8-membered carbocycles were tested, which gave good to excellent yields of the desired alkylated ketones (3ba–3bi). Even cyclododecanol was found to be compatible with our protocol and furnished a good yield of the corresponding product (3bj). However, cyclobutanol failed to give the desired product (3be). We noticed that the size and position of the substituents on the cyclohexane ring gave a diastereoselective product with good yield (3bl–3bn). The reaction of 4-phenyl-2-butanol with pentamethyl aryl ketone gave excellent yield of product (3bp). The reactivities of 1-mesitylethan-1-one and α-tetralone were checked towards this reaction, and in both cases we observed good to excellent product yields (3bb–3bd). Next, we were interested to investigate the suitability of acyclic secondary alcohols. Long chain acyclic aliphatic alcohols such as 2-decanol and 2-octanol delivered good/excellent yields of the product (3bq–3br). Even short chain acyclic alcohols such as 2-butanol, 4-methyl-2-pentanol, 3-pentanol and isopropanol produce fair yields of the corresponding products (3bs–3bv). Then, we executed the chemo-selective alkylation reaction where an internal triple bond (3aw) and terminal double bond (3ax & 3az) remained untouched after the end of the catalytic cycle. Cyclic and acyclic monoterpenoid menthol and citronellol successfully delivered the desired products with 62% and 57% yield (3ay & 3az). The most challenging steroid molecule cholesterol (3bw) was chemo-selectively alkylated under the reaction medium. To check the synthetic utility of our developed protocol, gram scale synthesis was done.

Next, we were interested to remove the Ph* group using the Br₂-assisted retro Friedel–Crafts acylation pathway to convert Ph* alkylated products into different types of alkylated esters, amides, etc. (Scheme 2). The strategy involves in situ formation of acid bromide, followed by the addition of nucleophiles to produce a variety of compounds (4a–4c). L-Phenylalanine methyl ester was utilized to obtain 4d having both ester and amide groups in 66% yield. Br₂ assisted removal of the Ph*group and subsequent reduction with LAH results in the corresponding alcohol (4e). Furthermore, the Ph* is replaced by a 4-OMePh group by reacting 3ba with anisole in the presence of TfOH. Here, anisole acts as a nucleophile to give 4f.

	Scheme 2 Post synthetic modifications.

Several control and kinetic experiments were conducted to comprehend the mechanism (Scheme 3). Due to steric crowding around the double bond, the reaction of pentamethyl substituted ketone (1a) with bulky borneol (2x) and 2-adamantanol (2y) stops at the enone-stage, which indicates the involvement of an enone intermediate. The subsequent reaction of cyclohexanone with a substituted ketone in the presence and absence of a catalyst indicates that, even if the base is capable of carrying out the condensation step, the catalyst accelerates this process (see ESI,†). Treatment of deuterated secondary alcohol with 1a gave 65% product yield. From ¹H NMR analysis, it was found that 85% D incorporation happened at the β-position of the carbonyl group and 11% D incorporation at the α-position of the carbonyl group. This experiment indicated the involvement of BH catalysis. Of note, when cyclobutanol (2e) is treated with 1a, the ring opening alkylated product was found, which suggests the involvement of a radical pathway in the catalytic cycle, which was further confirmed via free radical scavenger studies (BHT and TEMPO) and HRMS analysis revealed the existence of a TEMPO incorporated ketyl adduct. The formation of intermediate I via NH proton abstraction was confirmed by NMR analysis. Then, the addition of KO^tBu results in the formation of paramagnetically active catalytic intermediate II via a 1e⁻ reduction process. The direct addition of KO^tBu in Zn-2 in THF gave an X-band EPR signal with g = 2.020. Furthermore, a kinetic study was performed for the entire reaction. In the beginning, there is a greater rate of reactant consumption and product (3ba) formation. The pace of the reaction slows down after six hours, and by thirty hours, pentamethyl ketone is almost completely consumed. The remaining time is then needed to convert the enone to the product 3ba via a borrowing hydrogen step. Then, we checked the rate law with respect to both the starting materials. This followed first order kinetics for both of them (Scheme 4).

	Scheme 3 Control experiments.

	Scheme 4 (a) Overall time profile of the reaction progress, and (b) and (c) plots for the initial rate determination with respect to 1a & 2b.

Next, we proposed the catalytic cycle based on literature reports and our previous studies.^10c Treatment of the Zn-2 catalyst with KOH results in a dehydrobromination reaction, leading to the formation of compound I. Addition of KO^tBu can directly convert pre-catalyst Zn-2 to catalytically active species II. The catalytic cycles started with the activation of the secondary alcohol by II to form III via a proton transfer pathway. Then the coordinated alcohol forms the ketyl radical via a HAT process to the ligand arm, which facilitates the outer sphere generated enone binding to generate V. Then, an intramolecular electron transfer process liberates the ketone molecule with the simultaneous formation of VI. Next, HAT followed by PCET releases this enol product with the regeneration of active catalyst II. The enol further tautomerizes to deliver the desired alkylated ketone (Scheme 5).

	Scheme 5 (a) Mechanistic investigation and (b) catalytic cycle.

In conclusion, redox active Zn(II)-complexes were developed for an efficient α-alkylation of ketones with secondary alcohols. This protocol disclosed good functional group tolerance and chemo-selectivity for distally unsaturated compounds with good to excellent yields. Gram scale synthesis and post synthetic modification of the products also elevated the utility of this protocol. In different control experiments, organometallic and kinetic studies were executed to comprehend the catalyst role and reaction route. KO^tBu plays a crucial role in generating the active catalyst by dehydrobromination and single electron transfer to the pre-catalyst. The use of nontoxic, inexpensive and biocompatible Zn(II) for BH-mediated synthesis of β-disubstituted carbonyl compounds makes this protocol sustainable.

The work is financially supported by SERB (CRG/2021/000402). The authors thank the Department of Chemistry, IIT Guwahati (COE-FAST:5-5/2014-TS VII and FIST:SR/FST/CS-II/2017/23C), Central Instrumentation Facility for the use of NMR and HRMS facilities. The authors acknowledge PMRF, UGC, and IIT-Guwahati for their support.

Data Availability

Conflicts of interest

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