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DOI: 10.1039/D5QO00972C (Research Article) Org. Chem. Front., 2025, Advance Article

Substrate-controlled regioselective dibenzylation of enaminones

Xiuju Wang*a, Jin Zhanga, Xingyu Zhaoa, Yiran Wanga, Jinwen Simaa, Zihan Wanga, Xue Jiaa, Siyu Songb and Fuchao Yu*b
aDepartment of Chemistry, North Henan Medical University, Xinxiang, 453003, P. R. of China. E-mail: wangxiuju0205@163.com
bFaculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650504, P. R. China. E-mail: yufuchao05@126.com; yufc@kust.edu.cn

Received 1st July 2025 , Accepted 26th July 2025

First published on 29th July 2025

Abstract

A substrate-controlled α,α-dibenzylation and O-benzylation-α-benzylation reaction of enaminones with benzyl bromides is described. This divergent strategy provides efficient access to a new class of structurally diverse α,α-dibenzylated products and O-benzylated-α-benzylated products, through adjusting the alkyl or aryl substituent at the β-position of the enaminone. This protocol represents the first example of transition-metal-free-catalyzed and regioselective dibenzylation reactions of alkenes. This approach is notable for its mild and operationally simple conditions, good functional group tolerance, gram-scale reaction and late-stage derivatization.

Introduction

The difunctionalization of alkenes represents an ideal and powerful tool to increase molecular and functional complexity in one step from readily available chemicals.1 Compared to the difunctionalization of alkenes that involves the introduction of two different functional groups,2 the introduction of the same two functional groups in the difunctionalization of alkenes is difficult to achieve and challenging,3 as the addition to the C[double bond, length as m-dash]C bond involves competing reactions at two reactive sites. Among the methods for difunctionalization of alkenes, the dibenzylation reaction has received much less attention, and only four strategies to achieve the α,β-dibenzylation of alkenes have been reported recently.4 In 2023, Feng and coworkers realized an Ni(II)-catalyzed α,β-dibenzylation of α-CF3 styrenes with benzyl bromides (Scheme 1a).4a More recently, an Fe(0)-mediated α,β-dibenzylation of styrenes with benzyl bromides was reported by Giri and coworkers (Scheme 1b).4b In 2018, Cheng and coworkers developed the visible-light-promoted Ir(III)-catalyzed α,β-dibenzylation of styrenes using benzylated Hantzsch esters as benzylating reagents (Scheme 1c).4c In 2024, Murakami advanced the field with the visible-light-promoted decarboxylation α,β-dibenzylation of alkenes catalyzed by 4CzIPN, employing hypervalent iodine as a benzylating reagent (Scheme 1d).4d However, these methods start from terminal olefins and are limited to the α,β-dibenzylation reaction, providing α,β-dibenzylated products. To the best of our knowledge, no examples of other types of dibenzylation reactions of alkenes have been described.
image file: d5qo00972c-s1.tif
Scheme 1 Synthetic strategy for the dibenzylation of alkenes.

The dibenzyl group is a common unit in the fields of synthetic chemistry and drug development, which can be found in bioactive natural products and pharmaceutical molecules (Fig. 1).5 Therefore, the development of efficient and novel dibenzylation reactions of alkenes for the construction of dibenzylated molecules is highly desirable. Additionally, enaminones are versatile building blocks that have been widely used in functionalization and annulation reactions in organic synthesis.6 With our continued interest in enaminone chemistry,7 herein, we report a novel substrate-controlled regioselective dibenzylation reaction of enaminones with benzyl bromides for the efficient and practical synthesis of dibenzylated products at room temperature (Scheme 1e). This dibenzylation reaction of alkenes features the sequential introduction of two dibenzyl groups to form α,α-dibenzylated products and O-benzylated-α-benzylated products, by adjusting the alkyl or aryl substituent at the β-position of the enaminones.


image file: d5qo00972c-f1.tif
Fig. 1 Representative bioactive compounds bearing dibenzylated fragments.

Results and discussion

Initially, we examined the reaction conditions, employing enaminone 1a with 3.0 equiv. of benzyl bromide 2a as model substrates to test the α,α-dibenzylation reaction (Table 1). To our delight, the desired α,α-dibenzylated product 3a was successfully obtained with a 56% yield, when the reaction was conducted in the presence of NaH (3.0 equiv.) in DMF at room temperature (entry 1). First, a series of bases was evaluated (entries 2–8). Among the bases tested, MeOLi proved to be the most effective, affording product 3a in 87% yield. In addition, acceptable yields were obtained in the presence of other organic bases, such as t-BuONa, t-BuOK or t-BuOLi. However, the α,α-dibenzylated product 3a could not be obtained when LiOH, DBU or DABCO were used. Next, the effect of the solvent was investigated, and DMF was still the optimal solvent, but other solvents, including DMSO, DCM, MeCN, THF, and toluene, all inhibited the reaction (entries 9–13). The yield was not improved by further decreasing or increasing the reaction temperature, or reducing or prolonging the reaction time (entries 14–17). When the loading of benzyl bromide 2a or MeOLi was decreased to 2.0 equiv., the yield of 3a also decreased to 56% and 58% (entries 18 and 19). Finally, the optimal conditions were identified as 3.0 equiv. of MeOLi in DMF at room temperature for 2.0 h.
Table 1 Optimization of reaction conditionsa

image file: d5qo00972c-u1.tif
Entry Base (eq.) Solvent T (°C) Time (h) Yieldb (%)
a Reaction conditions: 1a (0.5 mmol), 2a (3.0 equiv.), base (1.5 mmol) in 2 mL of solvent.b Isolated yields.c [thin space (1/6-em)]2a (2.0 equiv.).
1 NaH (3.0) DMF r.t. 2.0 56
2 t-BuONa (3.0) DMF r.t. 2.0 71
3 t-BuOK (3.0) DMF r.t. 2.0 62
4 t-BuOLi (3.0) DMF r.t. 2.0 80
5 MeOLi (3.0) DMF r.t. 2.0 87
6 LiOH (3.0) DMF r.t. 2.0 n.d
7 DBU (3.0) DMF r.t. 2.0 n.d
8 DABCO (3.0) DMF r.t. 2.0 n.d
9 MeOLi (3.0) DMSO r.t. 2.0 n.d
10 MeOLi (3.0) DCM r.t. 2.0 n.d
11 MeOLi (3.0) MeCN r.t. 2.0 n.d
12 MeOLi (3.0) THF r.t. 2.0 n.d
13 MeOLi (3.0) Toluene r.t. 2.0 n.d
14 MeOLi (3.0) DMF 0 2.0 60
15 MeOLi (3.0) DMF 50 2.0 30
16 MeOLi (3.0) DMF r.t. 1.0 65
17 MeOLi (3.0) DMF r.t. 3.0 82
18c MeOLi (3.0) DMF r.t. 2.0 56
19 MeOLi (2.0) DMF r.t. 2.0 58

With the optimized reaction conditions in hand, we then investigated the scope of the α,α-dibenzylation reaction when the substituent (R2) of the enaminone at the β-position was an alkyl group (Table 2). Initially, a diverse array of N-aryl enaminones was subjected to the α,α-dibenzylation reaction. Diversified monosubstituted enaminones with electron-donating (OMe, Me, Et, t-Bu) or electron-withdrawing (F, Cl, Br, I, CF3) functional groups at the para-, ortho-, or meta-positions on the N-aromatic ring were suitable for the α,α-dibenzylation reaction, and the corresponding α,α-dibenzylated products 3a–3l were isolated in 65%–87% yields. A large conjugated system for the N-aryl group, such as 1-naphthyl, was also proven to have no effect on reactivity and afforded the corresponding products 3m in 72% yield. The carbonyl fragments of enaminones with aryl or alkyl groups were also smoothly converted to the desirable products 3n–3o in 66%–75% yields. When the methyl at the β-position of the enaminone was replaced by other alkyl groups, such as Et or Bn, the corresponding products 3p and 3q were obtained in 35% and 76% yields, respectively. When the carbonyl fragment and the group at the β-position of the enaminone were identical alkyl groups (Me, Et) that could also be compatible for this transformation, the corresponding products 3r–3s were delivered in 69%–80% yields. Moreover, the scope of benzyl bromides was also investigated. Benzyl bromides bearing electron-donating (Me), electron-withdrawing (F, Cl, Br, CF3), 2-naphthyl, or 2-thienylmethyl groups at the para-, ortho-, or meta-positions of the aromatic ring were all subjected to this transformation, affording the target α,α-dibenzylated products 3t–3f′ in 62%–83% yields. In addition, the molecule structure of 3b was further confirmed by X-ray crystallographic analysis (CCDC 2444967).

Table 2 Scope of the α,α-dibenzylation reactiona,b
a Reaction conditions: 1 (0.5 mmol), 2 (3.0 equiv.), MeOLi (3.0 equiv.) in 2.0 mL of DMF at r.t. for 2.0 h.b Isolated yields.
image file: d5qo00972c-u2.tif

Subsequently, when the R2 of the enaminone was an aryl group, the scope of the dibenzylation reaction was also investigated (Table 3). Interestingly, due to the conjugation effect of the aryl group (R2), the α,α-dibenzylation reaction could not be achieved in this transformation, but a new O-benzylation-α-benzylation reaction was developed to assemble the O-benzylated-α-benzylated products 4. For enaminone derivatives, irrespective of whether electron-withdrawing (Me, OMe, Et), or electron-donating (F, Cl, Br, I, CF3, 4-Ph) substituents were present at the ortho-, meta-, or para-positions of the N-phenyl moiety or N-(2-thienylmethyl) moiety, the corresponding products 4a–4i were obtained in moderate yields. In addition, the corresponding products 4j–4n could be obtained in 61%–72% yields when the R1 and R2 groups of the enaminone were the same aryl groups bearing electron-donating (Me), electron-withdrawing (F, Cl, Br, CF3), or fused aryl (2-naphthyl) substituents. In terms of benzyl bromides, the aryl group also worked well, achieving the corresponding O-benzylated-α-benzylated products 4o–4v in moderate to acceptable yields. The main reason for the relatively low yield in Table 3 was that it was difficult to separate and purify the byproducts and products, and significant product loss occurred during the post-treatment process. Furthermore, the O-benzylated-α-benzylated product structure of 4c was also identified using X-ray crystallography (CCDC 2444851).

Table 3 Scope of the O-benzylation-α-benzylation reactiona,b
a Reaction conditions: 1 (0.5 mmol), 2 (3.0 equiv.), MeOLi (3.0 equiv.) in 2.0 mL of DMF at r.t. for 2.0 h.b Isolated yields.
image file: d5qo00972c-u3.tif

To evaluate the potential synthetic utility of this protocol, a gram-scale reaction and its derivatization reaction were performed (Scheme 2). 1.56 g of the α,α-dibenzylated product 3a was obtained using 5.0 mmol of enaminone 1a in 75% yield (Scheme 2a). In addition, hydrogenated product 5 was afforded in 85% yield by a reduction reaction in the presence of LiAlH4 (Scheme 2b).


image file: d5qo00972c-s2.tif
Scheme 2 Synthetic applications.

A plausible mechanism for this regioselective dibenzylation reaction is proposed in Scheme 3a. First, enaminone 1 forms imine intermediate A through imine–enamine tautomerization,8 further generating carbanion intermediate B in the presence of MeOLi. Then, intermediate B reacts with the benzylic cation, which is formed in situ from benzyl bromide 2a promoted by MeOLi, to generate α-benzylated intermediate C. Subsequently, the α-position of intermediate C continues to remove a proton in the presence of MeOLi, and forms enol intermediate D. When the R substituent of the enaminone at the β-position is Me with small steric hindrance, the α-position of enol intermediate D with another molecule of benzyl bromide 2a finally enables the formation of α,α-dibenzylated product 3a (path a). When the R substituent of the enaminone at the β-position is Ph with large steric hindrance, the O-position of enol intermediate E reacts with another molecule of benzyl bromide 2a by a further nucleophilic substitution process, affording O-benzylated-α-benzylated product 4a (path b). In order to further explore the main reasons linking the substituent of enaminones at the β-position and the selectivity of dibenzylization, we evaluated the relative nucleophilicities of intermediates E and F at the C and O sites using DFT methods (Scheme 3b). The result showed that the nucleophilicity of both intermediates at the C site was higher than that at the O site, and the electron effect of methyl and phenyl at the β-position was not the main reason for the selective dibenzylization. Next, when a dipicolinoylmethane-derived enaminone was used, O-benzylated-α-benzylated product 4w could not be obtained, but α,α-dibenzylated product 3g′ was obtained in 31% yield (Scheme 3c). This might be due to the formation of a stable complex intermediate between the “N” atom on the pyridine and the “O” atom of enol with Li+, which greatly reduced the nucleophilicity of the enol oxygen anion, thus forcing the α-carbon of the enaminone to undergo a nucleophilic reaction with benzyl bromide. These results showed that the selectivity of dibenzylization was mainly affected by the steric hindrance of the substituent of the enaminone at the β-position.


image file: d5qo00972c-s3.tif
Scheme 3 (a) Proposed mechanism. (b) The relative nucleophilicities of intermediates from DFT calculations. (Dual descriptors: green and blue correspond to parts of the spin density that are positive and negative, respectively.) (c) Control experiment.

Conclusions

In summary, a substrate-controlled regioselective dibenzylation reaction of enaminones with benzyl bromides has been developed for the first time. Compared with previous α,β-dibenzylation reactions of terminal olefins leading to α,β-dibenzylated products, this transition-metal-free-catalyzed methodology enables the divergent synthesis of structurally diverse α,α-dibenzylated products and O-benzylated-α-benzylated products with excellent functional group tolerance in moderate to high yields at room temperature. By adjusting the inductive effect of the alkyl or aryl substituent at the β-position of the enaminone, two dibenzyl groups are introduced into the carbonyl oxygen and α-position of the enaminone, respectively.

Author contributions

J. Zhang, X. Zhao, Y. Wang, S, Sima, Z. Wang, and X. Jia performed the experiments. X. Wang and S. Song analyzed the data. X. Wang and F. Yu designed and directed the project, and wrote the paper with feedback from F. Yu.

Conflicts of interest

There are no conflicts to declare.

Data availability

All experimental procedures, characterisation data, mechanistic investigations, and NMR spectra. See DOI: https://doi.org/10.1039/d5qo00972c.

Crystallographic data for compounds 3b and 4c have been deposited with the Cambridge Crystallographic Data Centre (CCDC) under accession numbers CCDC 2444967 and 2444851, respectively.9a,b

Acknowledgements

We are a Key Discipline of Henan Province (Teaching and Re-search [2023] No. 414), the Natural Science Foundation of Yunnan Province (202501AT070311), the Natural Science Project of Sanquan College of Xinxiang Medical University (xjky2021001), and the Yunnan Revitalization Talent Support Program “Young Talent” Project.

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