Next Article in Journal
Development of Resorbable Phosphate-Based Glass Microspheres as MRI Contrast Media Agents
Previous Article in Journal
The Importance of Biotinylation for the Suitability of Cationic and Neutral Fourth-Generation Polyamidoamine Dendrimers as Targeted Drug Carriers in the Therapy of Glioma and Liver Cancer
Previous Article in Special Issue
Transition-Metal-Catalyzed Directed C–H Bond Functionalization with Iodonium Ylides: A Review of the Last 5 Years
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 29
Issue 18
10.3390/molecules29184295
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Nickel-Catalyzed Three-Component 1,2-Carboacylation of Alkenes

by
Shengzhou Jin
3,
Lanfen Wang
1,
Yinggang Jia
1,
Wenbo Ma
2,* and
Dingyi Wang
1,*
1
College of Sciences, Northeastern University, Shenyang 110004, China
2
Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, National Base for International Science and Technology Cooperation of Chengdu University, Chengdu University, Chengdu 610106, China
3
Hubei Key Laboratory of Pollutant Analysis & Reuse Technology, College of Chemistry and Chemical Engineering, Hubei Normal University, Huangshi 435002, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(18), 4295; https://doi.org/10.3390/molecules29184295
Submission received: 13 August 2024 / Revised: 5 September 2024 / Accepted: 6 September 2024 / Published: 10 September 2024
(This article belongs to the Special Issue Recent Advances in Transition Metal Catalysis)
Browse Figures
Versions Notes

Abstract

:
Ketones, prevalent in many biologically significant molecules, require the development of novel methods to synthesize these structures, which is a critical endeavor in organic synthesis. Transition metal catalysis has proven to be an effective method for synthesizing ketones. However, the scope of these substrates remains relatively limited, particularly due to their incompatibility with sensitive functional groups. Herein, we report a Ni-catalyzed three-component 1,2-carboacylation of alkenes, which activates secondary/tertiary alkyl bromides. This method offers significant advantages: simplicity of operation, ready availability of substrates, and broad substrate applicability. A series of experimental studies have helped clarify the key mechanistic pathways involved in this cascade reaction.

1. Introduction

Ketones find widespread applications in pharmaceuticals, pesticides, and natural products [1,2,3,4]. Additionally, carbonyl compounds, a crucial class of organic synthesis intermediates, can undergo various transformations, including Wittig and reductive amination reactions [5,6,7]. Over the past few decades, the traditional industrial methods for the preparation of ketones have mainly involved catalytic oxidation in the presence of oxygen. However, these methods depend heavily on costly metal catalysts, stoichiometric oxidants, and high temperatures, which lead to poor functional group compatibility, substantial costs, and safety concerns, especially in large-scale production. Consequently, the development of efficient methods for synthesizing carbonyl compounds has become a critical area of research. In 2002, Miura and co-workers described a Rh-catalyzed coupling of sodium tetraphenylborate with acid anhydrides, both with and without norbornene, yielding aryl or alkyl ketones with moderate to good yields (Scheme 1a) [8]. This pioneering work demonstrated that transition-metal-catalyzed 1,2-dicarbofunctionalization via one-pot reactions is an effective method for rapidly synthesizing complex ketones by continuously introducing two functional groups into alkenes. Inspired by this work, various other transition-metal-catalyzed three-component carbonylation reactions have been documented [9,10,11,12,13,14,15,16,17,18]. Given this context and the demands of industrial production, it is imperative to develop simpler, more sustainable, and practical methods for alkene carboacylation.
Among the 3d transition metals, nickel has garnered significant attention from organic chemists due to its abundance in the Earth’s crust, non-toxic properties, and affordability [19,20,21,22,23,24,25,26,27]. Furthermore, owing to its small atomic radius, high nucleophilicity, and multiple oxidation states, nickel exhibits exceptional reactivity and selectivity in catalytic reactions [28,29,30,31,32,33,34,35]. Therefore, nickel-catalyzed carboacylation of alkenes offers unparalleled advantages over traditional synthetic methods [36,37,38,39,40,41,42,43,44,45,46,47]. In 2017, Nevado et al. first reported a nickel-catalyzed reductive three-component difunctionalization of alkenes utilizing both aryl/alkyl(pseudo)halides [41]. Subsequently, a selective intermolecular three-component alkene carboacylation was developed using Ni/photoredox dual catalysis [37]. Despite previous successes, there were notable limitations: (1) the need for costly photocatalysts; (2) the restriction of radical receptors to activated alkenes; (3) the preparation of acyl reagents via multi-step synthesis (Scheme 1b). To address these challenges, we developed a nickel-catalyzed three-component 1,2-carboacylation of alkenes that produces a variety of ketones with quaternary carbon centers. We utilized cost-effective and readily available bromo-alkanes and acyl chlorides as acylation reagents and radical precursors, respectively. This method boasts mild reaction conditions, simple operation, excellent regioselectivity and chemoselectivity, and robust functional group tolerance (Scheme 1c). Although Wangn [21] and Chu [26] also reported the 1,2-carboacylation of alkenes, their method, however, was limited to primary fluoroalkanes or tertiary bromoalkanes, whereas our reaction system is compatible with secondary haloalkanes.

2. Results

Motivated by this objective, we began exploring the multicomponent cascade reaction using commercially available tert-butyl bromides 1a, methylacrylate 2a, and 4-methylbenzoyl chloride 3a as coupling agents (Table 1). We were pleased to achieve the first successful alkene difunctionalization using 10 mol% NiBr2•DME as the catalyst, 12 mol% 4,4-di-tert-butyl bipyridine (dtbbpy) L1 as the ligand, tetrabutylammonium bromide (TBAB) as the additive, and zinc powder as the reductant in 3.0 mL of MeCN, with a 78% yield of the target product (entry 1). Systematic evaluation of additional pyridine-type ligands (L2–L6), which possess varying electronic effects, failed to enhance the yield of this transformation beyond that achieved with dtbbpy (entries 2–6). Our findings also showed that changing solvents significantly reduced the yield of the desired products (entries 7 and 8). The carbonyl compound was produced in low yield using 3.0 equivalents of manganese powder instead of zinc powder (entry 9). Finally, control experiments confirmed that this addition process was dependent on the presence of the nickel catalyst, ligand, and TBAB (entries 10–12).
With the optimized conditions established, we evaluated the robustness of the nickel-catalyzed domino addition reaction (Scheme 2). We initially investigated the substitution patterns of aryl chlorides, discovering that various substituents at different positions on the aryl ring resulted in variable conversions. Aryl chlorides substituted with groups at the para- and meta-positions, including methyl, tert-butyl, methoxy, trifluoromethyl, fluorine, and chlorine, yielded products with modest to good yields (4–14). Notably, various acyl chlorides with heteroaromatic rings, including benzofurans and furans, were also well tolerated (15 and 16).
Acrylic esters bearing alkyl, alkoxy, benzyl, or trifluoroethyl groups at the ester O atom yielded additional products in 42–83% yields (17–22). Moreover, this transformation also accommodated the more challenging alkyl chloride substituents in acrylic esters. Additionally, electron-deficient substituted styrenes, such as 4-ethenylbenzoic acid methyl ester, reacted to produce the target products (26) in modest yields. We think it may have a certain relationship with the steric hindrance of the substrate, and some other possible side reactions will also affect the yield.
Subsequently, the substrate scope with substituted alkyl bromides was explored (Scheme 3). Tertiary alkyl bromides, featuring groups like methyl, methoxy, benzyl, halogen, trifluoromethyl, cyano, thiophene, and furan, were feasible and generated products 27–39 in good yields with excellent site selectivity. Additionally, secondary alkyl bromides, such as 2-bromopropanes, cyclopentyl bromide, cyclohexyl bromides, and 2-bromobicyclo [2.2.1]heptane, were likewise amenable (40–43).

3. Discussion

To gain mechanistic insights into this addition reaction, we conducted a series of experimental studies. Adding 3.0 equivalents of TEMPO significantly inhibited these transformations and prevented the detection of the corresponding products. Consequently, we detected the TEMPO-trapped species 44 using HR-MS (Scheme 4a). Moreover, we did not observe the corresponding product when using the pre-isolated Ni(II) complex 45 as a substrate in reactions with tert-butyl bromides 1a and methylacrylate 2a (Scheme 4b). This finding suggests that oxidative addition occurs subsequent to the alkyl capture by the nickel (II) complex 45. However, when the reaction was conducted using 10 mol% of 45 as a catalyst, we achieved a 55% yield of the additional product 7 (Scheme 4c).
Based on our investigation and previous findings [36,37,38,39,40,41,42,43,44,45,46,47,48], we propose a plausible mechanism for this alkene addition (Scheme 5). Initially, the alkyl bromide is converted to an alkyl radical by a low-valent nickel species. Subsequently, intermediate A reacts with alkene 2, forming secondary alkyl radical B, which is captured by nickel(0) species C to form the alkyl-Ni(I) intermediate D. Intermediate D undergoes a concerted oxidative addition with acyl chloride 3, producing Ni(III) species E, which then undergoes reductive elimination to yield the target carbonyl product and reform the Ni(I) species F. The latter is then reduced by zinc powder to regenerate the Ni(0) species C.

4. Materials and Methods

Molecules 29 04295 i002
The mixture of 1 (1.0 mmol), 2 (0.2 mmol), 3 (0.6 mmol), NiBr2•DME (10 mol%), dtbbpy (10 mol%), TBAB (2.0 equiv.), and Zn (2.0 equiv.) was protected with N2 in anhydrous MeCN (3 mL). Then, the mixture was stirred at room temperature for 12 h. Removal of the solvent under reduced pressure afforded a residue that was purified by chromatography on silica gel to afford the products 4–43. The general experimental details and NMR spectra of the compounds can be found in the Supplementary Materials.

5. Conclusions

In conclusion, our study reports on a nickel-catalyzed three-component alkenes carboacylation via the activation of alkyl bromides. This electrocatalytic platform facilitates the efficient synthesis of valuable ketones from cost-effective commercial materials, achieving excellent regioselectivity. Several mechanistic studies elucidated the key reaction pathways involved in the cascade process. We contend that this strategy offers a versatile platform for synthesizing value-added ketones in an environmentally friendly and sustainable manner.

6. Characterization Data of Products

  • Methyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (4). This compound was prepared according to the general procedures, 40.9 mg, 78% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 4.40 (t, J = 6.0 Hz, 1H), 3.67 (s, 3H), 2.42 (s, 3H), 2.03 (d, J = 6.0 Hz, 2H), 0.90 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.1, 171.1, 144.4, 133.5, 129.5, 128.9, 52.5, 50.5, 42.0, 30.9, 29.4, 21.7. HR-MS (ESI) C16H23O3 [M + H]+: 263.1642, found: 263.1644.
  • Methyl-4,4-dimethyl-2-(2-methylbenzoyl)pentanoate (5). This compound was prepared according to the general procedures, 33.5 mg, 64% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.29–7.25 (m, 2H), 4.28 (dd, J = 7.0, 5.0 Hz, 1H), 3.68 (s, 3H), 2.47 (s, 3H), 2.04–1.91 (m, 2H), 0.89 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 198.9, 171.2, 139.1, 136.8, 132.1, 131.6, 128.3, 125.7, 53.4, 52.4, 41.7, 30.8, 29.2, 21.1. HR-MS (ESI) C16H23O3 [M + H]+: 263.1642, found: 263.1642.
  • Methyl-4,4-dimethyl-2-(3-methylbenzoyl)pentanoate (6). This compound was prepared according to the general procedures, 43 mg, 82% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 7.2 Hz, 2H), 7.41–7.35 (m, 2H), 4.41 (t, J = 6.0 Hz, 1H), 3.68 (s, 3H), 2.42 (s, 3H), 2.03 (d, J = 6.0 Hz, 2H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.7, 171.1, 138.7, 136.0, 134.3, 129.2, 128.6, 125.9, 52.6, 50.7, 42.0, 30.9, 29.4, 21.4. HR-MS (ESI) C16H23O3 [M + H]+: 263.1642, found: 263.1644.
  • Methyl-2-benzoyl-4,4-dimethylpentanoate (7). This compound was prepared according to the general procedures, 37.2 mg, 75% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.04–7.97 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.52–7.45 (m, 2H), 4.42 (t, J = 6.0 Hz, 1H), 3.68 (s, 3H), 2.04 (d, J = 6.0 Hz, 2H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.5, 171.0, 136.0, 133.5, 128.8, 128.7, 52.6, 50.7, 42.0, 30.9, 29.4. HR-MS (ESI) C15H21O3 [M + H]+: 249.1485, found: 249.1486.
  • Methyl-2-(2-naphthoyl)-4,4-dimethylpentanoate (8). This compound was prepared according to the general procedures, 43 mg, 72% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 11.3, 8.4 Hz, 2H), 7.64–7.56 (m, 2H), 4.58 (t, J = 6.0 Hz, 1H), 3.69 (s, 3H), 2.10 (d, J = 5.9 Hz, 2H), 0.94 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.4, 171.1, 135.7, 133.4, 132.5, 130.6, 129.8, 128.8, 128.7, 127.8, 126.9, 124.3, 52.6, 50.8, 42.1, 31.0, 29.4. HR-MS (ESI) C19H23O3 [M + H]+: 299.1642, found: 299.1645.
  • Methyl-2-(4-(tert-butyl)benzoyl)-4,4-dimethylpentanoate (9). This compound was prepared according to the general procedures, 48.7 mg, 80% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.42 (t, J = 6.0 Hz, 1H), 3.68 (s, 3H), 2.04 (d, J = 6.0 Hz, 2H), 1.35 (s, 9H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.0, 171.1, 157.3, 133.4, 128.7, 125.8, 52.5, 50.5, 42.0, 35.2, 31.1, 30.9, 29.4. HR-MS (ESI) C19H29O3 [M + H]+: 305.2111, found: 305.2112.
  • Methyl-2-(4-methoxybenzoyl)-4,4-dimethylpentanoate (10). This compound was prepared according to the general procedures, 39.5 mg, 71% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.38 (t, J = 6.0 Hz, 1H), 3.88 (s, 3H), 3.67 (s, 3H), 2.06–1.99 (m, 2H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 193.9, 171.2, 163.8, 131.1, 129.0, 114.0, 55.5, 52.5, 50.4, 42.0, 30.9, 29.4. HR-MS (ESI) C16H23O4 [M + H]+: 279.1591, found: 279.1590.
  • Methyl-2-(3-methoxybenzoyl)-4,4-dimethylpentanoate (11). This compound was prepared according to the general procedures, 33.4 mg, 60% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 7.7 Hz, 1H), 7.54–7.51 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.13 (dd, J = 8.2, 2.1 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 3.86 (s, 3H), 3.68 (s, 3H), 2.03 (d, J = 6.0 Hz, 2H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.3, 171.0, 160.0, 137.4, 129.7, 121.2, 120.1, 113.0, 55.5, 52.6, 50.8, 42.0, 30.9, 29.4. HR-MS (ESI) C16H23O4 [M + H]+: 279.1591, found: 279.1591.
  • Methyl-4,4-dimethyl-2-(4-(trifluoromethyl)benzoyl)pentanoate (12). This compound was prepared according to the general procedures, 39.2 mg, 62% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 4.39 (t, J = 6.0 Hz, 1H), 3.69 (s, 3H), 2.05 (d, J = 6.0 Hz, 2H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 194.6, 170.5, 138.8, 135.1, 129.1, 127.5, 125.9 (q, J = 4.0 HZ), 52.8, 51.0, 41.8, 30.9, 29.3. 19F NMR (376 MHz, Chloroform-d) δ -63.20. HR-MS (ESI) C16H20F3O3 [M + H]+: 317.1359, found: 317.1363.
  • Methyl-2-(4-fluorobenzoyl)-4,4-dimethylpentanoate (13). This compound was prepared according to the general procedures, 41.0 mg, 77% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.07-8.03 (m, 2H), 7.20–7.11 (m, 2H), 4.38 (t, J = 6.0 Hz, 1H), 3.68 (s, 3H), 2.04 (d, J = 6.0 Hz, 2H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 193.8, 170.8, 165.9 (d, J = 255.7 Hz), 132.4 (d, J = 2.9 Hz), 131.4 (d, J = 9.4 Hz), 128.7 (d, J = 4.9 Hz), 115.9 (d, J = 21.9 Hz), 52.6, 50.7, 41.9, 30.8, 29.3. 19F NMR (376 MHz, Chloroform-d) δ -104.4. HR-MS (ESI) C15H20FO3 [M + H]+: 267.1391, found: 267.1392.
  • Methyl-2-(4-chlorobenzoyl)-4,4-dimethylpentanoate (14). This compound was prepared according to the general procedures, 40.7 mg, 72% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.98–7.93 (m, 2H), 7.49–7.44 (m, 2H), 4.36 (t, J = 6.0 Hz, 1H), 3.68 (s, 3H), 2.03 (d, J = 6.0 Hz, 2H), 0.90 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 194.3, 170.7, 140.0, 134.3, 130.1, 129.1, 52.7, 50.7, 41.9, 30.8, 29.3. HR-MS (ESI) C15H20ClO3 [M + H]+: 283.1095, found: 283.1099.
  • Methyl-2-(benzofuran-5-carbonyl)-4,4-dimethylpentanoate (15). This compound was prepared according to the general procedures, 42.1 mg, 73% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 1.5 Hz, 1H), 8.02 (dd, J = 8.7, 1.7 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.90–6.88 (m, 1H), 4.51 (t, J = 6.0 Hz, 1H), 3.69 (s, 3H), 2.08 (dd, J = 6.0, 2.6 Hz, 2H), 0.92 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 194.9, 171.2, 157.7, 146.6, 131.6, 127.7, 125.5, 123.1, 111.8, 107.4, 52.6, 50.8, 42.2, 30.9, 29.4. HR-MS (ESI) C17H21O4 [M + H]+: 289.1434, found: 289.1440.
  • Methyl-2-(furan-2-carbonyl)-4,4-dimethylpentanoate (16). This compound was prepared according to the general procedures, 36.2 mg, 76% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.64–7.62 (m, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.57 (dd, J = 3.6, 1.6 Hz, 1H), 4.22 (s, 1H), 3.69 (s, 3H), 2.02 (d, J = 6.0 Hz, 2H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 184.3, 170.7, 151.8, 147.0, 118.5, 112.6, 52.6, 50.9, 41.5, 30.8, 29.3. HR-MS (ESI) C12H17O4 [M + H]+: 225.1121, found: 225.1127.
  • Ethyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (17). This compound was prepared according to the general procedures, 42.6 mg, 77% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.86–7.81 (m, 2H), 7.20 (d, J = 7.8 Hz, 2H), 4.29 (t, J = 6.0 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.94 (d, J = 5.9 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H), 0.84 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 194.1, 169.6, 143.2, 132.6, 128.4, 127.9, 60.3, 49.8, 40.9, 29.9, 28.4, 20.6, 12.9. HR-MS (ESI) C17H25O3 [M + H]+: 277.1798, found: 277.1800.
  • Tert-butyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (18). This compound was prepared according to the general procedures, 50.5 mg, 83% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 8.2 Hz, 2H), 7.30–7.23 (m, 2H), 4.23 (t, J = 5.9 Hz, 1H), 2.42 (s, 3H), 1.98 (dd, J = 5.9, 1.2 Hz, 2H), 1.35 (s, 9H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.6, 169.8, 144.0, 133.9, 129.3, 128.9, 81.5, 52.0, 41.6, 30.8, 29.5, 27.7, 21.6. HR-MS (ESI) C19H29O3 [M + H]+: 305.2111, found: 305.2115.
  • Isobutyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (19). This compound was prepared according to the general procedures, 48.1 mg, 79% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 6.9 Hz, 2H), 4.39 (t, J = 6.0 Hz, 1H), 3.84 (d, J = 6.6 Hz, 2H), 2.42 (s, 3H), 2.10–1.99 (m, 2H), 1.85 (dt, J = 13.4, 6.7 Hz, 1H), 0.91 (s, 9H), 0.82 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 195.1, 170.7, 144.2, 133.7, 129.4, 128.9, 71.5, 50.7, 41.8, 30.8, 29.4, 27.6, 21.6, 18.9. HR-MS (ESI) C19H29O3 [M + H]+: 305.2111, found: 305.2114.
  • Cyclohexyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (20). This compound was prepared according to the general procedures, 48.9 mg, 74% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 4.9 Hz, 2H), 4.76 (td, J = 8.5, 3.9 Hz, 1H), 4.32 (t, J = 5.9 Hz, 1H), 2.42 (s, 3H), 2.01 (d, J = 6.0 Hz, 2H), 1.77–1.57 (m, 5H), 1.39–1.22 (m, 5H), 0.91 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.2, 170.1, 144.1, 133.7, 129.3, 128.9, 73.5, 51.2, 41.7, 31.2, 31.1, 30.9, 29.4, 25.3, 23.4, 23.4, 21.7. HR-MS (ESI) C21H31O3 [M + H]+: 331.2268, found: 331.2270.
  • Phenyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (21). This compound was prepared according to the general procedures, 40.5 mg, 63% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 8.1 Hz, 2H), 7.34-7.29 (m, 4H), 7.18 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.1 Hz, 2H), 4.59 (dd, J = 7.2, 4.7 Hz, 1H), 2.42 (s, 3H), 2.19 (dd, J = 14.4, 7.3 Hz, 1H), 2.05 (dd, J = 14.4, 4.6 Hz, 1H), 1.00 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 194.9, 169.4, 150.7, 144.6, 133.3, 129.6, 129.4, 129.0, 126.0, 121.3, 51.0, 41.9, 31.1, 29.5, 21.7. HR-MS (ESI) C21H25O3 [M + H]+: 325.1798, found: 325.1800.
  • Benzyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (22). This compound was prepared according to the general procedures, 48.7 mg, 72% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 8.2 Hz, 2H), 7.29–7.19 (m, 7H), 5.14–5.07 (m, 2H), 4.41 (t, J = 6.0 Hz, 1H), 2.41 (s, 3H), 2.04 (d, J = 6.0 Hz, 2H), 0.89 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.0, 170.5, 144.3, 135.5, 133.5, 129.4, 128.9, 128.5, 128.2, 128.1, 67.1, 50.8, 41.9, 30.9, 29.4, 21.7. HR-MS (ESI) C22H27O3 [M + H]+: 339.1955, found: 339.1961.
  • 2-Methoxyethyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (23). This compound was prepared according to the general procedures, 35.5 mg, 58% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.0 Hz, 2H), 7.29–7.26 (m, 2H), 4.43-4.40 (m, 1H), 4.30–4.19 (m, 2H), 3.55–3.47 (m, 2H), 3.28 (s, 3H), 2.42 (s, 3H), 2.07–1.96 (m, 2H), 0.92 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 195.0, 170.6, 144.3, 133.5, 129.4, 128.9, 70.2, 64.3, 58.8, 50.7, 41.9, 30.9, 29.4, 21.7. HR-MS (ESI) C18H27O4 [M + H]+: 307.1904, found: 307.1905.
  • 2,2,2-Trifluoroethyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (24). This compound was prepared according to the general procedures, 35.0 mg, 53% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.93–7.88 (m, 2H), 7.28 (d, J = 7.7 Hz, 2H), 4.53 (dd, J = 7.0, 4.5 Hz, 1H), 2.51–2.44 (m, 2H), 2.42 (s, 3H), 2.20–2.15 (m, 1H), 1.84 (dd, J = 14.1, 4.5 Hz, 1H), 0.87 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 206.8, 196.1, 144.5, 134.0, 129.5, 128.9, 59.6, 41.8, 33.8, 31.1, 29.5, 21.6, 7.8. HR-MS (ESI) C17H22F3O3 [M + H]+: 331.1516, found: 331.1520.
  • 2-Chloroethyl-4,4-dimethyl-2-(4-methylbenzoyl)pentanoate (25). This compound was prepared according to the general procedures, 26.1 mg, 42% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 4.43 (dd, J = 6.7, 5.3 Hz, 1H), 4.33 (4.37-4.28, m, 2H), 3.65–3.56 (m, 2H), 2.42 (s, 3H), 2.08–1.98 (m, 2H), 0.92 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 194.8, 170.3, 144.5, 133.3, 129.5, 128.9, 64.7, 50.5, 41.9, 41.2, 30.9, 29.4, 21.7. HR-MS (ESI) C17H24ClO3 [M + H]+: 311.1408, found: 311.1410.
  • Methyl-4-(4,4-dimethyl-1-oxo-1-(p-tolyl)pentan-2-yl)benzoate (26). This compound was prepared according to the general procedures, 27.1 mg, 40% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.95–7.88 (m, 4H), 7.39 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 4.78-4.75 (m, 1H), 3.91-3.87 (m, 4H), 2.63-2.58 (m, 1H), 2.37 (s, 3H), 0.88 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 199.0, 166.9, 146.5, 143.9, 134.2, 130.2, 129.4, 129.3, 128.7, 128.2, 52.1, 49.5, 47.4, 31.3, 29.8, 21.6. HR-MS (ESI) C22H27O3 [M + H]+: 339.1955, found: 339.1955.
  • Methyl-6-(benzyloxy)-4,4-dimethyl-2-(4-methylbenzoyl)hexanoate (27). This compound was prepared according to the general procedures, 47.4 mg, 62% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.99–7.85 (m, 2H), 7.39–7.19 (m, 7H), 4.45 (d, J = 3.3 Hz, 2H), 3.73–3.48 (m, 5H), 2.41 (d, J = 2.9 Hz, 3H), 2.12–2.00 (m, 2H), 1.72 (s, 1H), 1.61-1.58 (m, 2H), 0.89 (d, J = 4.6 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.9, 171.0, 144.4, 138.5, 133.5, 129.5, 128.9, 128.3, 127.6, 127.5, 73.0, 67.1, 52.6, 50.0, 41.1, 40.5, 32.7, 27.4, 27.3, 21.7. HR-MS (ESI) C24H31O4 [M + H]+: 383.2217, found: 383.2222.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl benzoate (28). This compound was prepared according to the general procedures, 62.6 mg, 79% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.03–7.98 (m, 2H), 7.95–7.90 (m, 2H), 7.57–7.51 (m, 1H), 7.43-7.40 (m, 2H), 7.29–7.25 (m, 2H), 4.46 (t, J = 6.0 Hz, 1H), 4.41-4.38 (m, 2H), 3.66 (s, 3H), 2.41 (s, 3H), 2.21–2.09 (m, 2H), 1.73 (t, J = 7.0 Hz, 2H), 0.97 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 170.9, 166.6, 144.5, 133.4, 132.9, 130.3, 129.5, 128.9, 128.3, 62.0, 52.6, 49.9, 40.5, 40.2, 32.8, 27.1, 27.0, 21.7. HR-MS (ESI) C24H29O5 [M + H]+: 397.2010, found: 397.2011.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 2-naphthoate (29). This compound was prepared according to the general procedures, 63.4 mg, 71% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.94 (dd, J = 8.6, 1.7 Hz, 1H), 7.85 (dd, J = 10.4, 8.5 Hz, 3H), 7.78 (dd, J = 8.3, 3.6 Hz, 2H), 7.52–7.44 (m, 2H), 7.17 (d, J = 7.8 Hz, 2H), 4.41–4.33 (m, 3H), 3.58 (s, 3H), 2.31 (s, 3H), 2.17–2.05 (m, 2H), 1.71 (t, J = 7.2 Hz, 2H), 0.92 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 171.0, 166.7, 144.5, 135.5, 133.5, 132.5, 131.0, 129.5, 129.4, 128.9, 128.2, 128.1, 127.7, 127.6, 126.6, 125.2, 62.1, 52.6, 50.0, 40.5, 40.3, 32.9, 27.1, 27.0, 21.7. HR-MS (ESI) C28H31O5 [M + H]+: 447.2166, found: 447.2175.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 4-methylbenzoate (30). This compound was prepared according to the general procedures, 67.3 mg, 82% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.93-7.88 (m, 4H), 7.27 (d, J = 7.1 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 4.45 (t, J = 6.0 Hz, 1H), 4.38-4.32 (m, 2H), 3.66 (s, 3H), 2.40 (d, J = 5.7 Hz, 6H), 2.20–2.08 (m, 2H), 1.72 (t, J = 7.2 Hz, 2H), 0.97 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 170.9, 166.6, 144.5, 143.5, 133.5, 129.5, 129.5, 129.0, 128.9, 127.6, 61.7, 52.6, 50.0, 40.6, 40.2, 32.8, 27.1, 27.0, 21.7, 21.6. HR-MS (ESI) C25H31O5 [M + H]+: 411.2166, found: 411.2171.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 3-methylbenzoate (31). This compound was prepared according to the general procedures, 63.2 mg, 77% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.95–7.90 (m, 2H), 7.84–7.77 (m, 2H), 7.37–7.26 (m, 4H), 4.47–4.32 (m, 3H), 3.66 (s, 3H), 2.40 (d, J = 7.6 Hz, 6H), 2.21–2.11 (m, 2H), 1.73 (t, J = 7.3 Hz, 2H), 0.97 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 170.9, 166.8, 144.5, 138.1, 133.6, 133.4, 130.2, 130.1, 129.5, 128.9, 128.2, 126.7, 61.9, 52.6, 50.0, 40.5, 40.2, 32.8, 27.1, 27.0, 21.7, 21.3. HR-MS (ESI) C25H31O5 [M + H]+: 411.2166, found: 411.2171.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 2-methylbenzoate (32). This compound was prepared according to the general procedures, 62.4 mg, 76% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.32–7.28 (m, 1H), 7.21–7.18 (m, 2H), 7.15 (d, J = 7.5 Hz, 2H), 4.38 (t, J = 6.0 Hz, 1H), 4.31–4.21 (m, 2H), 3.58 (s, 3H), 2.50 (s, 3H), 2.34 (s, 3H), 2.12–2.01 (m, 2H), 1.67–1.62 (m, 2H), 0.89 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 170.9, 167.6, 144.5, 140.1, 133.5, 131.9, 131.7, 130.5, 129.5, 128.9, 125.7, 61.7, 52.6, 49.9, 40.5, 40.2, 32.8, 27.1, 27.0, 21.7, 21.7. HR-MS (ESI) C25H31O5 [M + H]+: 411.2166, found: 411.2171.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 4-methoxybenzoate (33). This compound was prepared according to the general procedures, 75.0 mg, 64% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.99–7.90 (m, 4H), 7.27 (d, J = 6.8 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 4.45 (t, J = 6.0 Hz, 1H), 4.39-4.29 (m, 2H), 3.85 (s, 3H), 3.66 (s, 3H), 2.41 (s, 3H), 2.20–2.08 (m, 2H), 1.71 (t, J = 7.2 Hz, 2H), 0.96 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 170.9, 166.3, 163.3, 144.5, 133.5, 131.5, 129.5, 128.9, 122.8, 113.6, 61.6, 55.4, 52.6, 50.0, 40.6, 40.2, 32.8, 27.1, 27.0, 21.7. HR-MS (ESI) C25H31O6 [M + H]+: 427.2115, found: 427.2120.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 4-(trifluoromethyl)benzoate (34). This compound was prepared according to the general procedures, 70.6 mg, 76% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.29–7.26 (m, 2H), 4.47–4.37 (m, 3H), 3.67 (s, 3H), 2.41 (s, 3H), 2.22–2.10 (m, 2H), 1.74 (t, J = 7.2 Hz, 2H), 0.98 (d, J = 2.1 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.5, 170.9, 165.3, 144.6, 134.5, 134.2, 133.5, 133.4, 129.9, 129.5, 128.9, 128.1, 125.4, 125.4, 125.3, 62.5, 52.7, 50.0, 40.4, 40.2, 32.8, 27.1, 27.0, 21.6. 19F NMR (376 MHz, Chloroform-d) δ −63.11. HR-MS (ESI) C25H28F3O5 [M + H]+: 465.1883, found: 465.1889.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 4-cyanobenzoate (35). This compound was prepared according to the general procedures, 53.1 mg, 63% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 4.39–4.30 (m, 3H), 3.59 (s, 3H), 2.34 (s, 3H), 2.15–2.00 (m, 2H), 1.69–1.64 (m, 2H), 0.90 (d, J = 4.3 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.5, 170.9, 164.9, 144.6, 134.1, 133.4, 132.2, 130.0, 129.5, 128.9, 118.0, 116.3, 62.8, 52.7, 49.9, 40.3, 40.2, 32.8, 27.1, 27.0, 21.7. HR-MS (ESI) C25H28NO5 [M + H]+: 422.1962, found: 422.1966.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 4-fluorobenzoate (36). This compound was prepared according to the general procedures, 58.9 mg, 71% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 8.04–7.99 (m, 2H), 7.95–7.89 (m, 2H), 7.28 (d, J = 7.5 Hz, 2H), 7.09 (t, J = 8.6 Hz, 2H), 4.47–4.32 (m, 3H), 3.67 (s, 3H), 2.42 (s, 3H), 2.21-2.01 (m, 2H), 1.72 (t, J = 7.2 Hz, 2H), 0.97 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.6, 170.9, 167.0, 165.6, 164.4, 144.5, 133.4, 132.1, 132.0, 129.5, 128.9, 126.6, 126.5, 115.6, 115.3, 62.1, 52.6, 50.0, 40.5, 40.2, 32.8, 27.1, 27.0, 21.7. HR-MS (ESI) C24H28FO5 [M + H]+: 415.1915, found:415.1918.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl 4-chlorobenzoate (37). This compound was prepared according to the general procedures, 56.0 mg, 65% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.94–7.91 (m, 4H), 7.38 (d, J = 8.6 Hz, 2H), 7.29–7.26 (m, 2H), 4.47–4.34 (m, 3H), 3.66 (s, 3H), 2.41 (s, 3H), 2.21–2.09 (m, 2H), 1.73 (d, J = 7.0 Hz, 2H), 0.97 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.6, 170.9, 165.7, 144.5, 139.3, 133.4, 130.9, 129.5, 128.9, 128.8, 128.7, 62.2, 52.6, 50.0, 40.4, 40.2, 32.8, 27.1, 27.0, 21.7. HR-MS (ESI) C24H28ClO5 [M + H]+: 431.1620, found: 431.1627.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl thiophene-2-carboxylate (38). This compound was prepared according to the general procedures, 46.7 mg, 58% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.1 Hz, 2H), 7.76 (dd, J = 3.8, 1.2 Hz, 1H), 7.53 (dd, J = 5.0, 1.2 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.08 (dd, J = 5.0, 3.8 Hz, 1H), 4.44 (t, J = 6.0 Hz, 1H), 4.39-4.31 (m, 2H), 3.67 (s, 3H), 2.41 (s, 3H), 2.19–2.09 (m, 2H), 1.70 (t, J = 7.2 Hz, 2H), 0.96 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 170.9, 162.2, 144.5, 133.9, 133.5, 133.3, 132.3, 129.5, 128.9, 127.7, 62.1, 52.6, 49.9, 40.5, 40.1, 32.8, 27.1, 27.0, 21.7. HR-MS (ESI) C22H27SO5 [M + H]+: 403.1574, found: 403.1575.
  • 6-methoxy-3,3-dimethyl-5-(4-methylbenzoyl)-6-oxohexyl furan-2-carboxylate (39). This compound was prepared according to the general procedures, 43.3 mg, 56% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.93–7.90 (m, 2H), 7.53-7.47(m, 1H), 7.29–7.26 (m, 2H), 7.21-7.17 (m, 1H), 7.15–7.06 (m, 1H), 4.48–4.33 (m, 3H), 3.66 (s, 3H), 2.41 (s, 3H), 2.22–2.07 (m, 2H), 1.73 (t, J = 7.1 Hz, 2H), 0.96 (d, J = 1.9 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.7, 170.9, 144.5, 134.4, 134.3, 133.4, 132.0, 129.5, 128.9, 123.9, 123.9, 117.1, 116.8, 62.3, 52.6, 49.9, 40.5, 40.0, 32.8, 27.1, 27.0, 21.7. HR-MS (ESI) C22H27O6 [M + H]+: 387.1802, found: 387.1810.
  • Methyl-4-methyl-2-(4-methylbenzoyl)pentanoate (40). This compound was prepared according to the general procedures, 31.8 mg, 64% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 4.43–4.39 (m, 1H), 3.68 (s, 3H), 2.42 (s, 3H), 1.99–1.82 (m, 2H), 1.67-1.56 (m, 1H), 0.96–0.91 (m, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.9, 170.8, 144.5, 133.7, 129.5, 128.7, 52.4, 52.1, 37.9, 26.4, 22.6, 22.3, 21.7. HR-MS (ESI) C15H21O3 [M + H]+: 249.1485, found: 249.1485.
  • Methyl 2-(cyclopentylmethyl)-3-oxo-3-(p-tolyl)propanoate (41). This compound was prepared according to the general procedures, 36.7 mg, 67% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 7.6 Hz, 2H), 4.44–4.40 (m, 1H), 3.69 (s, 3H), 2.43 (s, 3H), 2.00–1.82 (m, 2H), 1.67-1.56 (m, 1H), 0.95-0.91 (m, 6H). 13C NMR (101 MHz, Chloroform-d) δ 195.0, 170.7, 144.5, 132.7, 129.5, 127.7, 52.3, 52.2, 37.8, 26.4, 22.5, 22.3, 21.6. HR-MS (ESI) C17H23O3 [M + H]+: 275.1642, found: 275.1645.
  • Methyl 2-(cyclohexylmethyl)-3-oxo-3-(p-tolyl)propanoate (42). This compound was prepared according to the general procedures, 41.4 mg, 72% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 4.44–4.39 (m, 1H), 3.67 (s, 3H), 2.43 (s, 3H), 2.00–1.82 (m, 2H), 1.68-1.57 (m, 1H), 0.97–0.92 (m, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.9, 170.8, 144.5, 134.1, 129.5, 128.7, 52.4, 52.1, 37.9, 26.4, 22.6, 22.3, 21.7. HR-MS (ESI) C18H25O3 [M + H]+: 289.1789, found: 289.1792.
  • Methyl 2-(bicyclo[2.2.1]heptan-2-ylmethyl)-3-oxo-3-(p-tolyl)propanoate (43). This compound was prepared according to the general procedures, 36.6 mg, 61% yield as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 87.9 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 4.43-4.39 (m, 1H), 3.69 (s, 3H), 2.42 (s, 3H), 1.97–1.82 (m, 2H), 1.67–1.57 (m, 1H), 0.96–0.92 (m, 6H). 13C NMR (101 MHz, Chloroform-d) δ 194.9, 170.7, 144.6, 133.8, 129.6, 128.8, 52.4, 52.1, 38.0, 26.4, 22.6, 22.4, 21.7. HR-MS (ESI) C19H25O3 [M + H]+: 301.1798, found: 301.1781.

7. Mechanistic Investigations

Molecules 29 04295 i003
A dry 10 mL vial equipped with a Teflon-coated magnetic stir bar was charged with benzoyl chlorides (0.60 mmol, 3.0 equiv.), 2-bromo-2-methylpropanes (1.0 mmol, 5 equiv.), methyl acrylate (0.20 mmol, 1.0 equiv.), TBAB (2.0 equiv.), NiBr2•DME (10 mol%), dtbbpy (10 mol%), Zn (0.4 mmol, 2.0 equiv.), and TEMPO (0.6 mmol, 3.0 equiv.) were dissolved in MeCN (3.0 mL). The reaction mixture was stirred under N2 for 12 h. After the reaction was completed, the reaction mixture was analyzed by HRMS.
Molecules 29 04295 i004
Molecules 29 04295 i005
A dry 10 mL vial equipped with a Teflon-coated magnetic stir bar was charged with 2-bromo-2-methylpropanes (1.0 mmol, 5 equiv.), methyl acrylate (0.20 mmol, 1.0 equiv.), TBAB (2.0 equiv.), complex 45 (10 mol%), and Zn (0.4 mmol, 2.0 equiv.) were dissolved in MeCN (3.0 mL). The reaction mixture was stirred under N2 for 12 h. After the reaction was completed, the reaction mixture was analyzed by gas chromatography to obtain the yield of 7 using dodecane as an internal standard.
Molecules 29 04295 i006
A dry 10 mL vial equipped with a Teflon-coated magnetic stir bar was charged with benzoyl chlorides (0.60 mmol, 3.0 equiv.), 2-bromo-2-methylpropanes (1.0 mmol, 5 equiv.), methyl acrylate (0.20 mmol, 1.0 equiv.), TBAB (2.0 equiv.), complex 45 (10 mol%), and Zn (0.4 mmol, 2.0 equiv.) were dissolved in MeCN (3.0 mL). The reaction mixture was stirred under N2 for 12 h. After the reaction was completed, the reaction mixture was analyzed by gas chromatography to obtain the yield of 7 using dodecane as an internal standard.

Supplementary Materials

The general experimental details, optimization of the reaction condition and NMR spectra can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29184295/s1.

Author Contributions

D.W., W.M. and Y.J. conceived and designed the study and wrote the paper. S.J. and L.W. performed the experiments. All authors have read and agreed to the published version of the manuscript.

Funding

This research was Supported by National Base for International Science and Technology Cooperation of Chengdu University (grant number: ISTC202301) and the National Natural Science Foundation of China (grant number: 22301032).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.

Acknowledgments

Generous support from the National Natural Science Foundation of China, the National Base for International Science and Technology Cooperation of Chengdu University, and Northeastern University is greatly appreciated.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Kurth, M.C.; Adler, C.H.; St. Hilaire, M.; Singer, C.; Waters, C.; Le Witt, P.; Chernik, D.A.; Dorflinger, E.E.; Yoo, K. Tolcapone Improves Motor Function and Reduces Levodopa Requirement in Patients with Parkinson’s Disease Experiencing Motor Fluctuations: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. Neurology 1997, 48, 81–87. [Google Scholar] [CrossRef] [PubMed]
  2. Walter, M.W. Structure-based design of agrochemicals. Nat. Prod. Rep. 2002, 19, 278–291. [Google Scholar] [CrossRef]
  3. Koh, K.K.; Han, S.H.; Quon, M.J.; Yeal Ahn, J.; Shin, E.K. Beneficial Effects of Fenofibrate to Improve Endothelial Dysfunction and Raise Adiponectin Levels in Patients With Primary Hypertriglyceridemia. Diabetes Care 2005, 28, 1419–1424. [Google Scholar] [CrossRef] [PubMed]
  4. Rong, Z.-Q.; Lim, H.N.; Dong, G. Intramolecular Acetyl Transfer to Olefins by Catalytic C-C Bond Activation of Unstrained Ketones. Angew. Chem. Int. Ed. 2018, 57, 475–479. [Google Scholar] [CrossRef] [PubMed]
  5. Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Iron-Catalyzed Oxidative 1,2-Carboacylation of Activated Alkenes with Alcohols: A Tandem Route to 3-(2-Oxoethyl)-indolin-2-ones. Eur. J. Org. Chem. 2014, 2014, 3395–3401. [Google Scholar] [CrossRef]
  6. Walker, J.A., Jr.; Vickerman, K.L.; Humke, J.N.; Stanley, L.M. Ni-Catalyzed Alkene Carboacylation via Amide C-N Bond Activation. J. Am. Chem. Soc. 2017, 139, 10228–10231. [Google Scholar] [CrossRef]
  7. Deng, L.; Fu, Y.; Lee, S.Y.; Wang, C.; Liu, P.; Dong, G. Kinetic Resolution via Rh-Catalyzed C-C Activation of Cyclobutanones at Room Temperature. J. Am. Chem. Soc. 2019, 141, 16260–16265. [Google Scholar] [CrossRef]
  8. Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. Rhodium Catalyzed Coupling of Sodium Tetraphenylborate with Acid Anhydrides in the Presence or Absence of Norbornene. J. Organomet. Chem. 2002, 648, 297–301. [Google Scholar] [CrossRef]
  9. Giri, R.; KC, S. Strategies toward Dicarbofunctionalization of Unactivated Olefins by Combined Heck Carbometalation and Cross-Coupling. J. Org. Chem. 2018, 83, 3013–3022. [Google Scholar] [CrossRef]
  10. Mizutani, K.; Shinokubo, H.; Oshima, K. Cobalt-Catalyzed Three-Component Coupling Reaction of Alkyl Halides, 1,3-Dienes, and Trimethylsilylmethylmagnesium Chloride. Org. Lett. 2003, 5, 3959–3961. [Google Scholar] [CrossRef]
  11. Terao, J.; Kato, Y.; Kambe, N. Titanocene-Catalyzed Regioselective Alkylation of Styrenes with Grignard Reagents Using β-Bromoethyl Ethers, Thioethers, or Amines. Chem.—Asian J. 2008, 3, 1472–1478. [Google Scholar] [CrossRef] [PubMed]
  12. Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G. Asymmetric Cu-Catalyzed Intermolecular Trifluoromethylarylation of Styrenes: Enantioselective Arylation of Benzylic Radicals. J. Am. Chem. Soc. 2017, 139, 2904–2907. [Google Scholar] [CrossRef] [PubMed]
  13. Lin, J.-S.; Li, T.-T.; Liu, J.-R.; Jiao, G.-Y.; Gu, Q.-S.; Cheng, J.-T.; Guo, Y.-L.; Hong, X.; Liu, X.-Y. Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric Three-Component Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2019, 141, 1074–1083. [Google Scholar] [CrossRef] [PubMed]
  14. Klauck, F.J.R.; Yoon, H.; James, M.J.; Lautens, M.; Glorius, F. Visible-Light-MediatedDeaminative Three-Component Dicarbofunctionalization of Styrenes with Benzylic Radicals. ACS Catal. 2019, 9, 236–241. [Google Scholar] [CrossRef]
  15. Mega, R.S.; Duong, V.K.; Noble, A.; Aggarwal, V.K. Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis. Angew. Chem. Int. Ed. 2020, 59, 4375. [Google Scholar] [CrossRef]
  16. Lei, G.; Zhang, H.; Chen, B.; Xu, M.; Zhang, G. Copper-Catalyzed Enantioselective Arylalkynylation of Alkenes. Chem. Sci. 2020, 11, 1623–1628. [Google Scholar] [CrossRef]
  17. Sun, S.-Z.; Duan, Y.; Mega, R.S.; Somerville, R.J.; Martin, R. Site-Selective 1,2-Dicarbofunctionalization of Vinyl Boronates through Dual Catalysis. Angew. Chem. Int. Ed. 2020, 59, 4370–4374. [Google Scholar] [CrossRef]
  18. Yang, T.; Chen, X.; Rao, W.; Koh, M.J. Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds. Chem 2020, 6, 738–751. [Google Scholar] [CrossRef]
  19. Zheng, Y.-L.; Newman, S.G. Nickel-Catalyzed Domino Heck-Type Reactions Using Methyl Esters as Cross-Coupling Electrophiles. Angew. Chem. Int. Ed. 2019, 58, 18159–18164. [Google Scholar] [CrossRef]
  20. Xu, S.; Wang, K.; Kong, W. Ni-Catalyzed Reductive Arylacylation of Alkenes toward Carbonyl-Containing Oxindoles. Org. Lett. 2019, 21, 7498–7503. [Google Scholar] [CrossRef]
  21. Wang, L.; Wang, C. Nickel-Catalyzed Three-Component Reductive Alkylacylation of Electron-Deficient Activated Alkenes. Org. Lett. 2020, 22, 8829–8835. [Google Scholar] [CrossRef] [PubMed]
  22. Kadam, A.A.; Metz, T.L.; Qian, Y.; Stanley, L.M. Ni-Catalyzed Three-Component Alkene Carboacylation Initiated by Amide C-N Bond Activation. ACS Catal. 2019, 9, 5651–5656. [Google Scholar] [CrossRef]
  23. Ping, Y.; Kong, W. Ni-Catalyzed Reductive Difunctionalization of Alkenes. Synthesis 2020, 52, 979–992. [Google Scholar] [CrossRef]
  24. Luo, Y.-C.; Xu, C.; Zhang, X. Nickel-Catalyzed Dicarbofunctionalization of Alkenes. Chin. J. Chem. 2020, 38, 1371–1394. [Google Scholar] [CrossRef]
  25. Derosa, J.; Apolinar, O.; Kang, T.; Tran, V.T.; Engle, K.M. Recent Developments in NickelCatalyzed Intermolecular Dicarbofunctionalization of Alkenes. Chem. Sci. 2020, 11, 4287–4296. [Google Scholar] [CrossRef]
  26. Zhao, X.; Tu, H.-Y.; Guo, L.; Zhu, S.; Qing, F.-L.; Chu, L. Intermolecular selective carboacylation of alkenes via nickel-catalyzed reductive radical relay. Nat. Commun. 2018, 9, 3488. [Google Scholar] [CrossRef]
  27. Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X. Tandem Difluoroalkylation-Arylation of Enamides Catalyzed by Nickel. Angew. Chem. Int. Ed. 2016, 55, 12270–12274. [Google Scholar] [CrossRef]
  28. Shrestha, B.; Basnet, P.; Dhungana, R.K.; KC, S.; Thapa, S.; Sears, J.M.; Giri, R. Ni-Catalyzed Regioselective 1,2-Dicarbofunctionalization of Olefins by Intercepting Heck Intermediates as Imine-Stabilized Transient Metallacycles. J. Am. Chem. Soc. 2017, 139, 10653–10656. [Google Scholar] [CrossRef]
  29. Derosa, J.; Tran, V.T.; Boulous, M.N.; Chen, J.S.; Engle, K.M. Nickel-Catalyzed β, γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling. J. Am. Chem. Soc. 2017, 139, 10657–10660. [Google Scholar] [CrossRef]
  30. Basnet, P.; Dhungana, R.K.; Thapa, S.; Shrestha, B.; KC, S.; Sears, J.M.; Giri, R. Ni-Catalyzed Regioselective β, δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones. J. Am. Chem. Soc. 2018, 140, 7782–7786. [Google Scholar] [CrossRef]
  31. KC, S.; Dhungana, R.K.; Shrestha, B.; Thapa, S.; Khanal, N.; Basnet, P.; Lebrun, R.W.; Giri, R. Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)-C(sp3)/C(sp3)-C(sp2) Bond Formation and Mechanistic Studies. J. Am. Chem. Soc. 2018, 140, 9801–9805. [Google Scholar] [CrossRef] [PubMed]
  32. Gao, P.; Chen, L.-A.; Brown, M.K. Nickel-Catalyzed Stereoselective Diarylation of Alkenylarenes. J. Am. Chem. Soc. 2018, 140, 10653–10657. [Google Scholar] [CrossRef] [PubMed]
  33. Fu, L.; Zhou, S.; Wan, X.; Chen, P.; Liu, G. Enantioselective Trifluoromethylalkynylation of Alkenes via CopperCatalyzed Radical Relay. J. Am. Chem. Soc. 2018, 140, 10965–10969. [Google Scholar] [CrossRef] [PubMed]
  34. Luridiana, A.; Mazzarella, D.; Capaldo, L.; Rincón, J.A.; García-Losada, P.; Mateos, C.; Frederick, M.O.; Nuño, M.; Buma, W.J.; Noël, T. The Merger of Benzophenone HAT Photocatalysis and Silyl RadicalInduced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins. ACS Catal. 2022, 12, 11216–11225. [Google Scholar] [CrossRef]
  35. Derosa, J.; Kleinmans, R.; Tran, V.T.; Karunananda, M.K.; Wisniewski, S.R.; Eastgate, M.D.; Engle, K.M. Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides. J. Am. Chem. Soc. 2018, 140, 17878–17883. [Google Scholar] [CrossRef]
  36. Li, W.; Boon, J.K.; Zhao, Y. Nickel-Catalyzed Difunctionalization of Allyl moieties using Organoboronic Acids and Halides with Divergent Regioselectivities. Chem. Sci. 2018, 9, 600–607. [Google Scholar] [CrossRef]
  37. GarcíaDomínguez, A.; Mondal, R.; Nevado, C. Dual Photoredox/NickelCatalyzed Three-Component Carbofunctionalization of Alkenes. Angew. Chem. Int. Ed. 2019, 58, 12286–12290. [Google Scholar] [CrossRef]
  38. Campbell, M.W.; Compton, J.-S.; Kelly, C.B.; Molander, G.A. Three-Component Olefin Dicarbofunctionalization Enabled by Nickel/Photoredox Dual Catalysis. J. Am. Chem. Soc. 2019, 141, 20069–20078. [Google Scholar] [CrossRef]
  39. Kc, S.; Dhungana, R.K.; Khanal, N.; Giri, R. Nickel Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives. Angew. Chem. Int. Ed. 2020, 59, 8047–8051. [Google Scholar] [CrossRef]
  40. Xu, C.; Cheng, R.; Luo, Y.-C.; Wang, M.-K.; Zhang, X. trans-Selective Aryldifluoroalkylation of Endocyclic Enecarbamates and Enamides via Nickel Catalysis. Angew. Chem. Int. Ed. 2020, 59, 18741–18747. [Google Scholar] [CrossRef]
  41. García-Domínguez, A.; Li, Z.; Nevado, C. Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2017, 139, 6835–6838. [Google Scholar] [CrossRef]
  42. Shu, W.; García-Domínguez, A.; Quiros, M.T.; Mondal, R.; Cárdenas, D.J.; Nevado, C. Ni-Catalyzed Reductive Dicarbofunctionalization of Nonactivated Alkenes: Scope and Mechanistic Insights. J. Am. Chem. Soc. 2019, 141, 13812–13821. [Google Scholar] [CrossRef] [PubMed]
  43. Guo, L.; Tu, H.-Y.; Zhu, S.; Chu, L. Selective, Intermolecular Alkylarylation of Alkenes via Photoredox/Nickel Dual Catalysis. Org. Lett. 2019, 21, 4771–4776. [Google Scholar] [CrossRef] [PubMed]
  44. Tu, H.-Y.; Wang, F.; Huo, L.-P.; Li, Y.; Zhu, S.; Zhao, X.; Li, H.; Qing, F.-L.; Chu, L. Enantioselective Three-Component Fluoroalkylarylation of Unactivated Olefins through Nickel-Catalyzed Cross-Electrophile Coupling. J. Am. Chem. Soc. 2020, 142, 9604–9611. [Google Scholar] [CrossRef] [PubMed]
  45. Wei, X.; Shu, W.; García-Domínguez, A.; Merino, E.; Nevado, C. Asymmetric Ni-Catalyzed Radical Relayed Reductive Coupling. J. Am. Chem. Soc. 2020, 142, 13515–13522. [Google Scholar] [CrossRef] [PubMed]
  46. Wang, X.-X.; Lu, X.; He, S.-J.; Fu, Y. Nickel-Catalyzed Three-Component Olefin Reductive Dicarbofunctionalization to Access Alkylborates. Chem. Sci. 2020, 11, 7950–7956. [Google Scholar] [CrossRef]
  47. Wang, Z.K.; Wang, Y.P.; Rao, Z.W.; Liu, C.-Y.; Pan, X.-H.; Guo, L. General Method for Selective Three-Component Carboacylation of Alkenes via Visible-Light Dual Photoredox/Nickel Catalysis. Org. Lett. 2023, 25, 1673–1677. [Google Scholar] [CrossRef]
  48. Fan, H.; Wang, B.; Wu, T.; Kang, Q.; Wang, H.; Sun, J.; Wei, X. Ball-milling-enabled nickel-catalyzed radical relayed reductive cross-coupling. Cell Rep. Phys. Sci. 2024, 5, 101831. [Google Scholar] [CrossRef]
Molecules 29 04295 sch001
Scheme 1. Transition-metal-catalyzed three-component 1,2-carboacylation of alkenes.
Scheme 1. Transition-metal-catalyzed three-component 1,2-carboacylation of alkenes.
Molecules 29 04295 sch001
Molecules 29 04295 sch002
Scheme 2. Scope of acyl chlorides and alkenes. Reaction conditions: 1 (1.0 mmol), 2 (0.2 mmol), 3 (0.6 mmol), NiBr2•DME (10 mol%), dtbbpy (10 mol%), TBAB (2.0 equiv.), Zn (2.0 equiv.), MeCN (3.0 mL), 12 h, rt, nitrogen, with isolated yields.
Scheme 2. Scope of acyl chlorides and alkenes. Reaction conditions: 1 (1.0 mmol), 2 (0.2 mmol), 3 (0.6 mmol), NiBr2•DME (10 mol%), dtbbpy (10 mol%), TBAB (2.0 equiv.), Zn (2.0 equiv.), MeCN (3.0 mL), 12 h, rt, nitrogen, with isolated yields.
Molecules 29 04295 sch002
Molecules 29 04295 sch003
Scheme 3. Scope of alkyl bromides. Reaction conditions: 1 (1.0 mmol), 2 (0.2 mmol), 3 (0.6 mmol), NiBr2•DME (10 mol%), dtbbpy (10 mol%), TBAB (2.0 equiv.), Zn (2.0 equiv.), MeCN (3.0 mL), 12 h, rt, nitrogen, with isolated yields.
Scheme 3. Scope of alkyl bromides. Reaction conditions: 1 (1.0 mmol), 2 (0.2 mmol), 3 (0.6 mmol), NiBr2•DME (10 mol%), dtbbpy (10 mol%), TBAB (2.0 equiv.), Zn (2.0 equiv.), MeCN (3.0 mL), 12 h, rt, nitrogen, with isolated yields.
Molecules 29 04295 sch003
Molecules 29 04295 sch004
Scheme 4. Mechanistic studies.
Scheme 4. Mechanistic studies.
Molecules 29 04295 sch004
Molecules 29 04295 sch005
Scheme 5. Possible reaction mechanism.
Scheme 5. Possible reaction mechanism.
Molecules 29 04295 sch005
Table 1. Optimization of reaction conditions [a].
Table 1. Optimization of reaction conditions [a].
Molecules 29 04295 i001
EntryVariation from “Standard Conditions”4 [%] [b]
1none78 [c]
2L2 as ligand47
3L3 as ligand12
4L4 as ligand55
5L5 as ligand10
6L6 as ligand0
7THF as solventtrace
8DMA as solvent24
9Mn powder as a reducing agent32
10w/o NiBr2•DME0
11w/o TBAB12
12w/o ligand0
[a] Reaction conditions: 1a (1.0 mmol), 2a (0.2 mmol), 3a (0.6 mmol), NiBr2•DME (10 mol%), L (10 mol%), TBAB (2.0 equiv.), Zn (2.0 equiv.), MeCN (3.0 mL), 12 h, rt, nitrogen. [b] GC yields using dodecane as an internal standard. [c] Isolated yields.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Jin, S.; Wang, L.; Jia, Y.; Ma, W.; Wang, D. Nickel-Catalyzed Three-Component 1,2-Carboacylation of Alkenes. Molecules 2024, 29, 4295. https://doi.org/10.3390/molecules29184295

AMA Style

Jin S, Wang L, Jia Y, Ma W, Wang D. Nickel-Catalyzed Three-Component 1,2-Carboacylation of Alkenes. Molecules. 2024; 29(18):4295. https://doi.org/10.3390/molecules29184295

Chicago/Turabian Style

Jin, Shengzhou, Lanfen Wang, Yinggang Jia, Wenbo Ma, and Dingyi Wang. 2024. "Nickel-Catalyzed Three-Component 1,2-Carboacylation of Alkenes" Molecules 29, no. 18: 4295. https://doi.org/10.3390/molecules29184295

APA Style

Jin, S., Wang, L., Jia, Y., Ma, W., & Wang, D. (2024). Nickel-Catalyzed Three-Component 1,2-Carboacylation of Alkenes. Molecules, 29(18), 4295. https://doi.org/10.3390/molecules29184295

Article Metrics

Back to TopTop