Review
Development of Transition-Metal-Catalyzed Dearomatization Reactions
2023 Volume 71 Issue 8 Pages 624-632
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2023 Volume 71 Issue 8 Pages 624-632
To develop dearomatization reactions based on a nucleophilic activation of phenols, naphthols, and indoles, ipso-Friedel–Crafts-type C-alkylation must be selectively promoted over competitive O- or N-alkylation reactions. Resolving this chemoselectivity issue is essential for developing this class dearomatization reaction. We found that various dearomatization reactions could be developed using appropriately designed aromatic substrates with an electrophilic moiety for intramolecular reactions. This review describes the transition-metal-catalyzed dearomatization reactions developed by our group. π-Allylpalladium species, η3-propargylpalladium species, alkynes activated by Au(I) species, and silver carbene species could be applied as electrophiles in our reaction system, which provided access to a wide variety of dearomatized products from planar aromatic compounds in a highly chemoselective manner.
Dearomatization reactions have attracted considerable attention in the field of synthetic organic chemistry. These reactions can provide access to three-dimensional molecules from planar aromatic compounds; therefore, they are useful in various chemical science studies such as natural product synthesis and medicinal chemistry. Among the numerous methods for the dearomatization of arenes,1–4) the oxidative dearomatization of phenols using hypervalent iodine reagents, pioneered by Kita and colleagues, is recognized as one of the most representative methods in organic synthesis.5,6) In this process, the phenol moiety is electrophilically activated by hypervalent iodine, and the subsequent nucleophilic attack on the aromatic ring affords cyclohexadienone derivatives (Chart 1). Cyclohexadienone derivatives can be also synthesized by a dearomative ipso-Friedel–Crafts-type addition of phenol to the electrophilic species. However, this process is atypical because of the intrinsic nucleophilicity of the phenoxide oxygen under basic conditions. To develop dearomatization reactions based on a nucleophilic activation of phenols, ipso-Friedel–Crafts-type C-alkylation must be selectively promoted over competitive O-alkylation reactions. To resolve this chemoselectivity issue, we focused on synthesizing spirocyclohexadienones via the base-promoted intramolecular ipso-Friedel–Crafts-type addition of phenols to alkyl halides or their equivalents (equiv.) utilized in natural product syntheses.7–10) These examples led us to hypothesize that various dearomatization reactions could be developed using appropriately designed phenolic substrates with an electrophilic moiety for intramolecular reactions (Chart 2). In this review, transition-metal-catalyzed dearomatization reactions developed by our group based on this reaction design are presented.
Phenols are generally utilized as oxygen nucleophiles in transition-metal-catalyzed allylic substitutions. The preferential promotion of Friedel–Crafts-type C-allylation reactions over O-alkylation reactions has been considered difficult in this type of transformation. However, the Pd-catalyzed intramolecular allylic substitution of meta-substituted phenol derivative 1 occurred on the aromatic ring to give the corresponding C-allylated products 2 and 3 in good yields (Chart 3). This surprising result led us to hypothesize that the intramolecular Friedel–Crafts-type addition of phenol to the π-allylpalladium unit occurs at the ipso-position if para-substituted phenol derivatives such as 4 are used as substrates, thus providing a new access to spirocyclohexadienone derivative 5.
We then examined the reaction using allyl carbonate derivative 4a as a model substrate. As a result of optimization of transition metal catalyst, ligand, and solvent, desired spirocyclohexadienone derivative 4a was obtained in 94% yield when the reaction was performed using 5 mol % of Pd(dba)2 and 12 mol % of PPh3 in CH2Cl2 at room temperature (Chart 4). Notably, the cyclic trimer 6 was formed in 1% yield via an intermolecular O-alkylation reaction, indicating that the intramolecular Friedel–Crafts-type C-allylation proceeded in a highly chemoselective manner. Substrate scope studies revealed that the developed reaction system is widely applicable to the synthesis of spiro[4,5]cyclohexadienones 5a–5h. When meta-substituted phenol derivatives were used, the corresponding spirocyclic products were obtained with good-to-high diastereoselectivities.11)
In contrast to the spirocyclization shown in Chart 4, when compound 7 with a CH2 unit-longer tether compared to that of 4a was used, spiro[5,5]cyclohexadienone derivative 8 was obtained in only 5% yield, while the conventional O-alkylation reaction predominantly occurred to give cyclic dimer 9 in 16% yield along with the formation of other oligomeric species (Chart 5). This result indicated that the reactivity of this spirocyclization process was significantly affected by the tether length between the phenol and π-allylpalladium unit. To determine a plausible reason for this remarkable difference in reactivity, we performed density functional theory (DFT) calculations for the spirocyclization processes.12) Computational studies indicated that allylic alkylation involving the backside nucleophilic attack of an aromatic ring on π-allylpalladium complexes is the reasonable reaction pathway for the five-membered ring formation, and the marked difference in the reactivity for the six-membered ring formation originated from the structural distortion of the tethering unit of the substrate.
This dearomatization process can be extended to an asymmetric synthesis by replacing PPh3 with a chiral ligand.11,13) The screening of various chiral ligands using 4i as a substrate revealed that the ANDEN-phenyl Trost ligand was suitable for this reaction, and the corresponding product 5i was obtained in 80% yield (diastereomeric ratio (dr) = 9.2 : 1) with a high enantiomeric excess (89% ee) (Chart 6). Immediately after our report, You and colleagues reported the same asymmetric dearomatization reaction using chiral Ir catalysts; this catalytic reaction system can be applied to the intramolecular asymmetric dearomatization of phenols with a broader substrate generality.14)
Pd(II) species generated by the oxidative addition of the Pd(0) catalyst to aryl halides react with allenes to give the corresponding π-allylpalladium species via Heck insertion. If this reactivity is applied to the aforementioned dearomative spirocyclization, spirocyclohexadienone derivatives with a 1-arylvinyl group can be obtained via a Pd-catalyzed cascade reaction. In practice, when allene-tethered phenol derivative 9 and iodobenzene were heated in N,N-dimethylformamide (DMF) in the presence of 5 mol% of Pd(dba)2, 12 mol % of PPh3, and 1 equiv. of K2CO3, the designed cascade reaction proceeded efficiently via π-allylpalladium intermediate 10. The subsequent ipso-Friedel–Crafts-type allylic alkylation afforded the desired spirocyclohexadienone derivative 11 in 94% yield15) (Chart 7).
Reaction of Pd(0) catalyst with propargyl carbonates provides an equilibrium mixture of allenylpalladium complexes and η3-propargylpalladium complexes. We envisioned that if these species are utilized as the electrophiles for the intramolecular ipso-Friedel–Crafts-type addition of phenols, a novel synthetic method to produce functionalized spirocyclohexadienone derivatives can be developed. We first examined the reaction using propargyl carbonate derivative 12a as a model substrate in the presence of 5 mol % of Pd(dba)2 and 12 mol% of PPh3 (Chart 8). When the reaction was conducted in a single-solvent system, the reactivity was low, and allene-type product 15a was obtained as the major product via the corresponding allenylpalladium species 13a. Conversely, when the reaction was performed in a mixed-solvent system with methanol, the reactivity increased, and diene-type product 16a was obtained as the major product via the corresponding η3-propargylpalladium species 14a. Further investigations of the reaction temperature and reaction time suggested the existence of a conversion pathway from 15a to 16a. Finally, compound 16a was obtained as a single product (100% NMR yield) in 95% isolated yield when the reaction was performed in (CH2Cl)2–MeOH (4 : 1) at 60 °C. The developed reaction conditions could be applied to various substrates. As shown in Chart 9, spiro[5,5]cyclohexadienones with a diene motif such as 16b–16g were obtained in excellent yields. In addition, this reaction mode is applicable to the dearomative intramolecular spirocyclization of indoles. When tryptamine derivatives with a propargyl carbonate unit 17a–17c were treated under the optimized conditions, the corresponding aza-spiroindolenine derivatives 18a–18c were obtained in good yields.16)
The observed thermodynamic-control-like reaction profile was attributed to the unexpected reactivity of 15a (Chart 10). When 15a was treated under optimized reaction conditions, compound 16a was obtained in 96% yield. A time-course experiment also revealed that 15a was preferentially formed from 12a in the initial stage of the reaction, after which 15a gradually transformed into 16a. Furthermore, when compound 15a was reacted with 5 mol % of Pd(dba)2 and 12 mol % of PPh3 in MeOH under a CO atmosphere, allene-conjugated methyl ester derivative 19a and spirocyclohexadienone derivative 20a were produced in 14 and 72% yields, respectively, indicating the regeneration of Pd(II) intermediates 13a and 14a from allenyl spirocyclohexadienone 15a. These results suggest that the oxidative addition of 15a to the Pd(0) catalyst is important for explaining the observed characteristic reaction profile (Chart 11). After the formation of 15a, rearomatization-assisted oxidative addition to the Pd(0) catalyst cleaved the C(sp3)–C(sp2) bond and generated an equilibrium mixture of Pd(II) intermediates 21a, 14a, and 13a. The intramolecular ipso-Friedel–Crafts-type addition of phenol to the η3-propargylpalladium unit in 14a resulted in the formation of π-allylpalladium intermediate 22a. Finally, β-hydride elimination occurred to afford the diene-type adduct 16a.
Electron-rich arenes are effective nucleophiles for Au-catalyzed intramolecular hydrofunctionalization of alkynes. This type of reaction produces fused polycyclic aromatic compounds via intramolecular Friedel–Crafts-type addition to π–Lewis acid-activated alkynes. We hypothesized that if para-substituted phenol derivatives with an alkyne unit could be utilized for this type of gold catalysis, a novel method for synthesizing functionalized spirocyclohexadienones with an exocyclic olefin could be developed. Thus, we examined the reaction using phenol derivative with a terminal alkyne 23a as a model substrate. As a result of the optimization of the catalyst and additives, spirocyclic compound 24a was obtained in 98% yield when the reaction was performed using 5 mol % of IPrAuNTf2 (IPr: 1,3-bis(2,6-diisopropyl-phenyl)imidazol-2-ylidene), 1 equiv. of methanesulfonic acid (MsOH), and 1 equiv. of 2,6-di-tert-butylpyridine in (CH2Cl)2 at 60 °C (Chart 12). When the amount of MsOH exceeded that of 2,6-di-tert-butylpyridine, the dienone-phenol rearrangement proceeded sequentially to afford compound 25a. An equivalent amount of the additives was essential for controlling the product formation. As shown in Chart 13, spiro[4,5]cyclohexadienones with a exo-olefine motif such as 24b–24h were obtained in good-to-excellent yields. However, when substrate 26 with a CH2 unit-longer tether compared to that of 23a was used, the postulated spiro[5.5]cyclohexadienone derivative was not obtained, suggesting the importance of tether length between the phenol parts. In addition, no reaction occurred when the internal alkyne-type compound 27 was used as the substrate.17)
Since the initial report in 2010, we have developed phenol dearomatization reactions using π-allylpalladium species, η3-propargylpalladium species, and alkynes activated by Au(I) species as electrophiles for the intramolecular ipso-Friedel–Crafts-type addition of phenols. Among other organometallic species, metal carbenes are candidates as electrophiles in our reaction system. However, representative metal carbenes, such as rhodium and copper carbenes, are highly reactive species; therefore, controlling chemoselectivity is essential for developing carbene-mediated dearomatization reactions. For example, when metal carbene species 28 is used as a substrate, C–H insertion and Büchner ring expansion reactions can be regarded as side reactions (Chart 14).
Based on this background, examinations were initiated using substrate 29a as the substrate (Chart 15). When Rh or Cu catalysts, the most common catalysts for carbene-mediated reactions, were used, Büchner ring expansion product 31a and C–H insertion adducts 32a and 33a were obtained preferentially, while the dearomatized product 30a was formed in a very low yield. In contrast, a dramatic reversal of chemoselectivity was observed when the Au(I) complex with a bulky phosphite ligand was used, which was previously utilized by the Liu and Zhang group,18) as well as the Lan and Shi group,19) to study the chemoselective C–H insertion of phenol. This trend was also observed for the Ag(I) catalysts. Finally, compound 30a was obtained in 51% yield and 62% ee when using the chiral silver complex, (S)-TRIPAg.
Silver carbenes are relatively rare in organic synthesis compared to other common metal carbenes, such as rhodium or copper carbenes. Several studies have reported the unique reactivity of silver carbenes in organic synthesis.20–26) However, very limited success has been reported for silver-carbene-mediated asymmetric reactions.27–29) This led us to conduct further experiments using chiral silver phosphate as a catalyst. The effect of solvent was examined in the presence of the (S)-TRIPAg catalyst, and polar solvents were found to be suitable for this reaction. Compound 30a was obtained in 61% yield and 90% ee when 2-butanone was used as the solvent. The additive effect was also examined, and the addition of 1 equiv. of benzoic acid increased the yield to 89% without decreasing the enantiomeric excess (Chart 16). Using the optimized conditions, we next examined the substrate scope of the reaction. In addition to meta-substituted phenols, ortho-substituted phenols were found to be suitable substrates for this reaction, and products 30b–30f were obtained in good yields with excellent enantioselectivities (up to 98% ee). Potentially reactive terminal alkenes were also tolerated in this reaction, and the corresponding products 30g and 30 h were obtained in good yields with excellent enantioselectivities. Furthermore, the six-membered ring formation proceeded to give the corresponding 6–6 membered ring-fused product 30i with excellent enantioselectivity. The naphthol derivative was also applicable to this reaction, and 30j was obtained with high enantioselectivity.30)
To elucidate the origin of the metal-dependent chemoselectivity, we performed the lowest unoccupied molecular orbital (LUMO) map analysis based on DFT calculations at the M06 level with the 6-311G* basis set (LANL2TZ(f) basis set for Rh and Ag) (Chart 17). The LUMO map shows that silver carbene has a higher electrophilicity (deeper blue) than rhodium carbene. In addition, the Ag−carbene bond order is 0.29 lower than that of the Rh−carbene bond, indicating weak back-donation from the silver metal to the vacant carbene π-orbital. Thus, the longer distance makes the silver carbene carbon more carbocationic, facilitating electrophilic addition to phenol. We also measured asymmetric amplification under the optimized reaction conditions, and no non-linear effect was observed. In addition, kinetic experiments were performed, and the reaction rate exhibited a first-order dependency on the (S)-TRIPAg catalyst under optimized reaction conditions. These findings suggested that a single catalyst is involved in the enantio- and rate-determining step. Furthermore, comparative experiments with phenol derivatives 29 and their corresponding anisole derivatives under the optimized conditions revealed the importance of phenol in this dearomative spirocyclization. These data indicated that the interaction between the phenol and the catalyst via hydrogen bonding interaction plays a key role in this asymmetric catalysis.
Interestingly, a negative non-linear effect was observed when the reactions were performed in the absence of benzoic acid. Furthermore, the reaction rate exhibited a half-order dependency on the (S)-TRIPAg catalyst in the absence of benzoic acid. Other mechanistic studies using NMR experiments and DFT calculations revealed that in addition to its role as a proton source for the silver enolate intermediate, benzoic acid plays a role in generating catalytically active monomeric (S)-TRIPAg species from the catalytically inactive dimeric species [(S)-TRIPAg]2, which is the resting state of this reaction process31) (Chart 18).
This reaction mode could be applied to the asymmetric intramolecular dearomative spirocyclization of indoles. The reaction conditions were optimized using an indole derivative with a diazo amide moiety and para-methoxybenzyl (PMB) group 34a. Tetrahydrofuran (THF) was found to be a suitable solvent for this reaction, and the amount of benzoic acid could be reduced to catalytic levels without decreasing the enantioselectivity. Using 5 mol % of (S)-TRIPAg catalyst (=2.5 mol % of [(S)-TRIPAg]2 catalyst), the corresponding product 35a was obtained in 84% yield and 90% ee. The substrate scope of this reaction was evaluated under the optimized conditions. As shown in Chart 19, the corresponding aza-spiroindolenine derivatives were obtained in good yields with good-to-high enantioselectivities. In particular, when the substrate with a cyclohexyl group on the 2-position of indole was used, the product 35i was obtained in 87% yield and 98% ee.32)
Intramolecular dearomatization of 2-naphthol allows the rapid construction of fused ring systems containing spirocyclic structures. The reaction pattern of the previously reported dearomative spirocyclization of β-naphthol is limited to the reaction occurring at the C1 position of β-naphthol because of the inherently high reactivity of this position. However, theoretical analysis of the potential charges and molecular orbitals of 2-naphthol suggested that the C6 position also possesses sufficient nucleophilicity towards electrophilic species. This prompted us to examine the reaction scheme shown in Chart 20. The reaction design was based on the reaction of β-naphthol derivative 36 with a metal carbene, followed by the capture of the dearomatized intermediates with triethylsilane as a hydride nucleophile to afford spirocyclic compound 37. The reaction was performed using 36 in the presence of 10 mol % of AgNTf2, 1 equiv. of benzoic acid, and 3 equiv. of triethylsilane in CH2Cl2 at 0 °C and the corresponding product 37 was obtained in 80% yield. In contrast, compounds 38 and 39 were formed when the reaction was performed in the presence of the Rh and Cu catalysts, and no reaction occurred when the Au catalyst was used. Interesting chemoselectivity was also observed in this reaction.
Furthermore, the dearomatization reaction of 36 with indole as the nucleophile under the developed silver catalysis conditions, followed by one-pot 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation, which gave compound 40 in 97% yield (Chart 21). In the 1H-NMR spectra, rotamers of 40 were detected (dr = 86 : 14) because one of the created σ-bond axes was partially fixed owing to steric repulsion between the indole unit and the spirocyclic moiety. Compound 40 possesses an axis that is rotatable by F anions, allowing it to function as a F-anion-selective chemosensor.33)
During the mechanistic analysis of the Ag-catalyzed asymmetric intramolecular dearomatization of phenols, we obtained the result shown in Chart 22, where compound 41 with a dimethylphenylmethyl group on the nitrogen was treated with the (S)-TRIPAg catalyst, forming compound 42 in 31% yield via the Büchner reaction, along with the formation of chiral spirocyclohexadienone derivative 43 (55% yield, 96% ee). These data suggested that silver carbenes can react with non-activated aromatic rings to produce ring expanded products. Dearomatization reaction of non-activated arenes using metal carbene species is challenging in organic synthesis. Although some examples have been reported, successful examples are limited,34) particularly in asymmetric catalysis.35–37) This prompted us to examine the Ag-catalyzed asymmetric dearomatization of non-activated arenes.
Although diazo substrates are versatile as precursors for metal carbenes, the use of diazo substrates involves technical drawbacks. The first is the stability problem and potentially explosive properties of diazo compounds. Second, additional steps are required to install the diazo moiety. Therefore, to develop a new Ag-catalyzed dearomatization reaction, we aimed to avoid the use of diazo compounds. For this purpose, the generation of metal carbenes form alkynes and amine oxides, particularly Au catalysts with pyridine oxide systems, is recognized as the most representative strategy for realizing diazo-free systems.38) Thus, we first investigated whether this process can be applied to the generation of silver carbene. The reaction conditions were optimized using ynamide 44a as the substrate. Compound 44a was treated with 5 mol % of (S)-TRIPAg catalyst and 2 equiv. of 8-methylquinoline N-oxide in chlorobenzene. The desired product 45a was obtained in 84% yield and 88% ee, accompanied by the formation of dicarbonyl compound 46a in 13% yield. Further optimization revealed that the yield and enantiomeric excess increased when the reaction was performed in the presence of MS3A, and 45a was obtained in 91 and 94% ee (Chart 23). The substrate scope was examined under optimized conditions. Substrates with various substituents on the aromatic ring in the benzyl unit, as well as the alkyne terminal unit, were applicable to this ring expansion process, and the corresponding products 45b–45j were obtained in high enantiomeric excess. Regarding the substituent on the alkyne terminus, the aliphatic-type substrate gave less satisfactory results than the aromatic-type substrates (Chart 24).
The reaction products, cycloheptatriene derivatives, were obtained from the corresponding divinyl cyclopropane intermediates (norcaradienes) via equilibrium. If the diene intermediate can be utilized as a reactive substrate for sequential [4 + 2] cycloadditions, highly functionalized molecules can be directly accessed from the linear ynamides. Thus, we attempted the reactions shown in Chart 25. After completing the asymmetric ring-expansion reaction of 44a, dienophile 48 was added to the reaction. [4 + 2] Cycloaddition proceeded with cyclopropane derivative 47a generated in small amounts in the reaction mixture via equilibrium, affording pentacyclic product 49a in high yield and high stereoselectivity.
The transition-state model of the enantioinduction step was analyzed by using this simplified chiral ligand system (Chart 26). Computational analyses were performed at the RM06/cc-pVTZ/LanL2TZ(f)(Ag) level in PhCl solvent//RB3LYP/LanL2DZ(Ag)/6-31G* level of theory. In both transition-state models, TS major and TS minor, providing the (R)- and (S)-products, respectively, a C–H···O nonclassical hydrogen bonding interaction is operative between the chiral counteranion and C–H bonds at the ortho-position of the arenes. Although the key bond lengths and bond angles were relatively close, TS minor exhibited steric and electronic repulsion between the sulfonamide functionality and the aryl group on the catalyst. Simultaneously, an attractive interaction was observed between the aryl group on the ligand and the silver center (2.55 and 2.93 Å, TS major and TS minor, respectively). The relative energy difference was ΔΔG‡=−2.27 kcal/mol, corresponding to a 98 : 2 ratio. These models explain the origin of the observed enantioselectivity.39)
Over the past 15 years, we have conducted continuous research on the development of dearomatization reactions. Our works on transition-metal-catalyzed dearomatization reactions is reviewed from the first report in 2010 on the Pd-catalyzed intramolecular ipso-Friedel–Crafts-type allylic alkylation of phenols to the development of Ag-catalyzed asymmetric ring expansion reactions reported in 2021. In addition to the studies presented in this review, organocatalytic dearomatization reactions using Brønsted acid/thiourea catalyst40–42) and borane catalyst systems43) have been successfully developed by our group (see cited references). Dearomatization has become one of the most attractive and competitive research topics in synthetic organic chemistry. We aim to continue disseminating the cutting-edge research in this field.
I would like to thank Professor Yasumasa Hamada, who was my mentor until March 2015, for his guidance in carrying out the research described herein. Dr. Shingo Harada is the main contributor regarding the development of dearomatization reactions using silver catalysis. I would also like to thank co-workers on the projects described herein for their continuous efforts, whose names are acknowledged on the publications from our group cited in the reference section.
The author declares no conflict of interest.
This review of the author’s work was written by the author upon receiving the 2022 Pharmaceutical Society of Japan Award for Divisional Scientific Promotion.
