Rhodium-Catalyzed Alkylation of Aromatic Ketones with Allylic Alcohols and α , β -Unsaturated Ketones

: The direct transition-metal-catalyzed addition of C–H bonds to unsaturated C=X (X=C, O, and N) bonds via C–H bond activation has been recognized as a powerful tool for the construction of C–C bonds (in terms of atom and step economy). Herein, the direct rhodium-catalyzed C–H bond addition of aromatic ketones to allylic alcohols and α , β -unsaturated ketones that affords β -aryl carbonyl compounds is described, in which a ketone carbonyl acts as a weakly coordinating directing group. It was found that the type of alkyl in aromatic ketones is crucial for the success of the reaction. This transformation provides a convenient and efﬁcient methodology for the synthesis of 2-alkyl aromatic ketones in moderate-to-excellent yields.


Introduction
The direct addition of C-H bonds to unsaturated C=X (X=C, O, and N) bonds catalyzed by transition-metal-catalyzed reactions has been recognized as a powerful strategy for the construction of C-C bonds in terms of atom and step economy [1][2][3].Over the past two decades, remarkable achievements regarding the addition of metal-catalyzed C-H bonds to unsaturated bonds have been achieved [4,5].As for unsaturated compounds, α,β-unsaturated ketones and allylic alcohols represent two important coupling partners to C-H reagents for C-C bond formation.In the cases of α,β-unsaturated ketones, the useful synthetic carbonyl group makes such an addition reaction more powerful in the construction of drug-related complex molecules [6].Allylic alcohols have the advantages of commercial availability, low cost, and easy preparation.The tandem reactions of C-H bond addition to allylic alcohol, β-hydride elimination, and keto-enol tautomerism generate β-aryl carbonyl compounds [7][8][9], which is identical with the direct addition of C-H bonds to α,β-unsaturated ketones.Therefore, allylic alcohols have been used as substitutes for α,β-unsaturated ketones in some cases.In order to enhance the site selectivity of C-H bond functionalization, directing groups are often employed.Among the direct directing-group-assisted addition of C-H bonds to allylic alcohols and α,β-unsaturated ketones, nitrogen-based functional groups, such as quinoline N-oxide [10], pyrazolone [11], N-heterocycle [12][13][14], amide [15][16][17][18][19], pyridine [20][21][22][23][24][25], and imide [26,27], were usually utilized to promote the activation of C-H bonds owing to their good coordination ability with transition metals (Scheme 1a).In addition, Jayarajan and Maiti et al. achieved meta-C-H alkylation with allylic alcohols and long-linker-bearing pyrimidine [28][29][30].
Ketone moieties are widely found in many functional materials and bioactive molecules.They are often employed as versatile synthetic intermediates due to the fact that they can be readily converted into diverse functional groups.However, due to the weakly coordinating ability of ketone carbonyl, the application of ketone as a directing group is much rarer [31,32].Although direct ketone-assisted additions of C-H bonds to simple alkenes [33], maleimide [34,35], and trimethoxy(vinyl)silane [36,37] have been illuminated by Martinez, Prabhu, and Murai, et al., as of now, the direct transitional-metal-catalyzed C-H bond additions of aromatic ketones to allylic alcohols and α,β-unsaturated ketones that afford β-aryl carbonyl compounds, which are important synthetic precursors in synthetic organic chemistry [38], have seldom been demonstrated.Only heteroaromatic ketones containing indole were successfully explored by Yu and Punniyamurthy et al. to instigate a reaction with allylic alcohols [39,40], restricting the application of aromatic ring moiety.As a continuation from our study on the direct addition of C-H bonds to unsaturated double bonds [41,42], we herein present the direct rhodium-promoted C-H bond alkylation of aromatic ketones with allylic alcohols and α,β-unsaturated ketones (Scheme 1b), generating the corresponding β-aryl carbonyl compounds.
Catalysts 2023, 13, x FOR PEER REVIEW 2 of 12 they can be readily converted into diverse functional groups.However, due to the weakly coordinating ability of ketone carbonyl, the application of ketone as a directing group is much rarer [31,32].Although direct ketone-assisted additions of C-H bonds to simple alkenes [33], maleimide [34,35], and trimethoxy(vinyl)silane [36,37] have been illuminated by Martinez, Prabhu, and Murai, et al., as of now, the direct transitional-metal-catalyzed C-H bond additions of aromatic ketones to allylic alcohols and α,β-unsaturated ketones that afford β-aryl carbonyl compounds, which are important synthetic precursors in synthetic organic chemistry [38], have seldom been demonstrated.Only heteroaromatic ketones containing indole were successfully explored by Yu and Punniyamurthy et al. to instigate a reaction with allylic alcohols [39,40], restricting the application of aromatic ring moiety.As a continuation from our study on the direct addition of C-H bonds to unsaturated double bonds [41,42], we herein present the direct rhodium-promoted C-H bond alkylation of aromatic ketones with allylic alcohols and α,β-unsaturated ketones (Scheme 1b), generating the corresponding β-aryl carbonyl compounds.

Entry
Additive Solvent Yield (%) b 3a 3a After the optimal reaction conditions were established, the scope of this addition reaction was explored.Firstly, the adaptability of substituted 2,2-dimethyl-1-phenylpropan-1one was examined.2,2-Dimethyl-1-phenylpropan-1-one-bearing electron-donating groups at paraand meta-positions smoothly reacted with 2a to give 3a-3e (Figure 1, 39-74% yields).2,2-Dimethyl-1-phenylpropan-1-one-bearing electron-withdrawing groups (e.g., -CF 3 , -Cl, etc.) could not deliver the addition products, which may be attributable to the decreased electron density on the benzene ring, and is unfavorable for the attack of electrophilic rhodium.Unsubstituted secondary alkyl ketones also successfully participated in this transformation, delivering products 3f and 3g in moderated yields (Figure 1, 40-51% yields).This protocol was compatible with different 3,4-dihydronaphthalen-1(2H)-ones, such as 3,4-dihydronaphthalen-1(2H)-one, 6-methoxy-3,4-dihydronaphthalen-1(2H)-one, and 4-methyl-3,4-dihydronaphthalen-1(2H)-one, producing good targeted products (3h-3j, 54-60% yields).The reaction of 2,2-dimethyl-1-phenylpropan-1-one and but-3-en-2-ol furnished 3k in a 57% yield.To our excitement, heteroaromatic tert alkyl ketone, i.e., 2,2dimethyl-1-(thiophen-2-yl)propan-1-one, worked well with allylic alcohol bearing different carbon chains, and successfully converted to moderate-to-excellent product yields (Figure 1, 3l-3p, 38-80% yields).However, aryl primary alkyl ketones, such as acetophenone and propiophenone, did not yield any desired products (Figure 1, 3q and 3r).This may be because the electron-donating ability of tertiary or secondary alkyl groups is stronger than that of primary alkyl groups, which is beneficial for the attack of electrophilic rhodium.Inspired by the reaction results of ketones and allylic alcohol, we envisioned that by replacing allylic alcohols with α,β-unsaturated ketones, the alkylation reactions may take place under simpler reaction conditions without the oxidant.After screening several parameters, such as catalysts, additives, solvents, etc., we were pleased to find that the addition reaction between 2,2-dimethyl-1-phenylpropan-1-one and pent-1-en-3-one proceeded well when 3 mol% of [Cp*RhCl2]2 was employed in combination with NaOAc (0.25 equiv.) in HFIP at 120 °C for 16 h, furnishing the targeted product 3a in an excellently isolated yield of 87% (Figure 2, 3a).Subsequently, the scope of this reaction was studied with pent-1-en-3-one by varying different aromatic ketones.Similar to the reaction using allylic alcohol as a coupling partner, aryl tert-alkyl ketones, aryl secondary alkyl ketones, and 3,4-dihydronaphthalen-1(2H)-one were all found to provide targeted products in moderate-to-excellent isolated yields (Figure 2; 3b-3j and 3s-3u, 48-80%).But-3-en-2-one and oct-1-en-3-one also furnished the corresponding products 3k and 3v in excellent yields (Figure 2; 86% and 90%, respectively).2,2-Dimethyl-1-(thiophen-2-yl)propan-1-one reacted smoothly with pent-1-en-3-one to give 3l in a 73% yield.Inspired by the reaction results of ketones and allylic alcohol, we envisioned that by replacing allylic alcohols with α,β-unsaturated ketones, the alkylation reactions may take place under simpler reaction conditions without the oxidant.After screening several parameters, such as catalysts, additives, solvents, etc., we were pleased to find that the addition reaction between 2,2-dimethyl-1-phenylpropan-1-one and pent-1-en-3-one proceeded well when 3 mol% of [Cp*RhCl 2 ] 2 was employed in combination with NaOAc (0.25 equiv.) in HFIP at 120 • C for 16 h, furnishing the targeted product 3a in an excellently isolated yield of 87% (Figure 2, 3a).Subsequently, the scope of this reaction was studied with pent-1-en-3-one by varying different aromatic ketones.Similar to the reaction using allylic alcohol as a coupling partner, aryl tert-alkyl ketones, aryl secondary alkyl ketones, and 3,4-dihydronaphthalen-1(2H)-one were all found to provide targeted products in moderate-to-excellent isolated yields (Figure 2; 3b-3j and 3s-3u, 48-80%).But-3-en-2-one and oct-1-en-3-one also furnished the corresponding products 3k and 3v in excellent yields (Figure 2; 86% and 90%, respectively).2,2-Dimethyl-1-(thiophen-2-yl)propan-1-one reacted smoothly with pent-1-en-3-one to give 3l in a 73% yield.In order to explicate the mechanistic insights of this transformation, several experiments were conducted.A 40% H/D exchange was observed when 2,2-dimethyl-1-phenylpropan-1-one was treated in the presence of D2O under standard conditions (Scheme 3a; see Supporting Information for details).This result suggests that the cyclorhodation process via the C-H bond cleavage should be reversible.The kinetic isotope effect (KIE) was determined via parallel experiments, and a kH/kD ratio was found to be 5.23 (Scheme 3b; see Supporting Information for details), which indicates that the C-H bond cleavage might be related to the rate-determining step.In order to explicate the mechanistic insights of this transformation, several experiments were conducted.A 40% H/D exchange was observed when 2,2-dimethyl-1-phenylpropan-1-one was treated in the presence of D 2 O under standard conditions (Scheme 3a; see Supplementary Materials for details).This result suggests that the cyclorhodation process via the C-H bond cleavage should be reversible.The kinetic isotope effect (KIE) was determined via parallel experiments, and a k H /k D ratio was found to be 5.23 (Scheme 3b; see Supplementary Materials for details), which indicates that the C-H bond cleavage might be related to the rate-determining step.In order to explicate the mechanistic insights of this transformation, several experiments were conducted.A 40% H/D exchange was observed when 2,2-dimethyl-1-phenylpropan-1-one was treated in the presence of D2O under standard conditions (Scheme 3a; see Supporting Information for details).This result suggests that the cyclorhodation process via the C-H bond cleavage should be reversible.The kinetic isotope effect (KIE) was determined via parallel experiments, and a kH/kD ratio was found to be 5.23 (Scheme 3b; see Supporting Information for details), which indicates that the C-H bond cleavage might be related to the rate-determining step.

General Remarks
The NMR spectra were recorded on a Bruker 400 MHz NMR or Bruker 600 MHz NMR, Karlsruhe, Germany.The 1 H NMR and 13 C NMR chemical shifts were determined using tetramethylsilane as an internal reference.The high-resolution mass spectra (HRMS) were obtained with a Bruker Compass Maxis instrument (ESI), Karlsruhe, Germany.All the commercial reagents were directly used without purification.The solvents used in this study were all analytical reagents.

General Remarks
The NMR spectra were recorded on a Bruker 400 MHz NMR or Bruker 600 MHz NMR, Karlsruhe, Germany.The 1 H NMR and 13 C NMR chemical shifts were determined using tetramethylsilane as an internal reference.The high-resolution mass spectra (HRMS) were obtained with a Bruker Compass Maxis instrument (ESI), Karlsruhe, Germany.All the commercial reagents were directly used without purification.The solvents used in this study were all analytical reagents.

General Process for Instigating the Reactions between Aromatic Ketones and Allylic Alcohols
The [RhCp*Cl 2 ] 2 (Rh*, 4.9 mg, 4 mol %, 0.008 mmol), Cu(OAc) 2 •H 2 O (59.9 mg, 1.5 equiv., 0.3 mmol), KOAc (29.4 mg, 1.5 equiv., 0.3 mmol), TFE (0.6 mL), aromatic ketones (0.2 mmol), and allylic alcohols (0.4 mmol) were added to the microwave vial.Then, TFE (0.6 mL) was added to microwave the vial under an Ar atmosphere.The reaction mixture was heated at 120 • C (oil bath temperature) for 24 h.The mixture was diluted with EtOAc (5 mL), and the solid in the mixture was removed by filtration.The obtained liquid was concentrated, and the residue was purified via thin-layer preparation chromatography to provide the corresponding product.

Conclusions
In summary, we unprecedentedly developed a reaction centered around the rhodiumcatalyzed conjugate addition of aromatic ketones with allylic alcohols/α,β-unsaturated ketones using weakly coordinating ketone carbonyl as a directing group.From commercially available substrates, the approach allows for the facile access of 2-alkyl aromatic ketones, which cannot be obtained by the traditional Friedel-Crafts alkylation reaction.No significant decrease in isolated yields was observed in the scale-up experiments.Further efforts to investigate the practicality of this method are ongoing in our laboratory.

Scheme 1 .
Scheme 1. Alkylation reactions assisted by different directing groups reported in previous work(a) and developed in this work(b).

Figure 1 .
Figure 1.Substrate scope for the alkylation of aromatic ketones using allylic alcohols.

Figure 1 .
Figure 1.Substrate scope for the alkylation of aromatic ketones using allylic alcohols.

Table 1 .
Selected results for optimizing reaction conditions a .