Benzylic Deprotonation Research Articles

Chiral Bis(binaphthyl) Cyclopentadienyl Ligands for Rhodium-Catalyzed Desymmetrization of Diarylmethanes via Selective Arene Coordination.

Owing to substantial advances in the past several decades, transition-metal-catalyzed asymmetric reactions have garnered considerable attention as pivotal methods for constructing chiral molecules from abundant, readily available achiral counterparts. These advances are largely attributed to the development of chiral ligands that control stereochemistry through steric repulsion and other noncovalent interactions between the ligands and functional groups or prochiral centers on the substrates. However, stereocontrol weakens dramatically with increasing distance between the reaction site and the functional group or prochiral center. Herein, we report a symphonic strategy for remote stereocontrol of Rh(III)-catalyzed asymmetric benzylic C-H bond addition reactions of diarylmethanes in which the two aryl motifs differ at the meta and/or para position. Specifically, catalysts bearing a new type of chiral cyclopentadienyl (Cp) ligand differentiate between the two aromatic rings of the diarylmethane by arene-selective η6 coordination, setting up an opportunity for ligand-controlled stereoselective benzylic deprotonation and subsequent stereoselective addition to the 1,1-bis(arylsulfonyl)ethylene.

Rhodium-catalyzed addition reactions of benzylic C–H bonds to cyclic N-sulfonyl ketimines via π-coordination

Mannich-type reactions are a widely used method for the synthesis of amines due to the readily availability of nucleophiles and electrophiles. However, the inclusion of alkylarenes instead of active carbon pronucleophiles such as aldehydes and ketones in these addition reactions has been a challenge due to the inherent difficulty of benzylic deprotonation. In this study, we present a novel approach for the construction of N-sulfonyl amines via rhodium-catalyzed addition of unbiased benzylic CH bonds to cyclic N-sulfonyl ketamines through π-coordination. This strategy enables the synthesis of a diverse range of N-sulfonyl amines, and subsequent diversification of the addition products showcases the synthetic potential of this protocol.

Catalytic Dehydrogenative (3 + 2) Cycloaddition of Alkylbenzenes via π-Coordination

Given the wide availability and low cost of alkylbenzenes, direct C-H functionalization of these aromatic hydrocarbons to afford structurally complex building blocks has long been of interest in organic synthesis. Herein we describe a method for rhodium-catalyzed dehydrogenative (3 + 2) cycloaddition reactions of alkylbenzenes with 1,1-bis(phenylsulfonyl)ethylene. The π-coordination with a rhodium catalyst facilitates the benzylic deprotonation, allowing for the subsequent (3 + 2) cycloaddition in which the metal-complexed carbanion serves as a unique all-carbon 1,3-dipole equivalent. We demonstrated the generality of this catalytic method by carrying out reactions of a large array of alkylbenzenes to generate dihydroindene derivatives bearing two synthetically versatile sulfonyl groups. Quantum-chemical calculations revealed details of the reaction process.

Copper-Catalyzed Decarboxylative Elimination of Carboxylic Acids to Styrenes.

A copper-catalyzed decarboxylative elimination reaction of (hetero)aromatic propionic acids to vinyl (hetero)arenes has been developed. This method furnishes alkenes from carboxylic acids without the need for stochiometric Pb or Ag additives or expensive or specialized photocatalysts. A series of mechanistic experiments indicate that the reaction proceeds via benzylic deprotonation and subsequent radical decarboxylation; a pathway that is distinct from the single-electron-transfer mechanisms implicated in related decarboxylative elimination reactions.

Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe3)2/Cs+ System.

Chemoselective deprotonative functionalization of benzylic C-H bonds is challenging, because the arene ring contains multiple aromatic C(sp2)-H bonds, which can be competitively deprotonated and lead to selectivity issues. Recently it was found that bimetallic [MN(SiMe3)2 M = Li, Na]/Cs+ combinations exhibit excellent benzylic selectivity. Herein, is reported the first deprotonative addition of toluenes to Weinreb amides mediated by LiN(SiMe3)2/CsF for the synthesis of a diverse array of 2-arylacetophenones. Surprisingly, simple methyl benzoates also react with toluenes under similar conditions to form 2-arylacetophenones without double addition to give tertiary alcohol products. This finding greatly increases the practicality and impact of this chemistry. Some challenging substrates with respect to benzylic deprotonations, such as fluoro and methoxy substituted toluenes, are selectively transformed to 2-aryl acetophenones. The value of benzylic deprotonation of 3-fluorotoluene is demonstrated by the synthesis of a key intermediate in the preparation of Polmacoxib.

Role of Benzylic Deprotonation in Nickel-Catalyzed Benzylic Dehydrogenation

AbstractAlkylarenes are readily functionalized via the corresponding benzylic anions. Benzylic anions have been used for a range of catalytic reactions, including Ni-catalyzed dehydrogenation. Interestingly, the employment of Zn(TMP)2 for slow and incomplete deprotonation of the benzylic position was observed. This manuscript describes a preliminary investigation into the deprotonation of heteroarenes and its relationship to Ni-catalyzed benzylic dehydrogenation.

Straightforward Access to Anthrone Functionalized Benzylic Amines via Organocatalytic 1,2-Addition of Anthrones to Imines at Ambient Temperature

Activation of anthrone via benzylic deprotonation in the presence of triethylamine paves the way for the 1,2-addition reaction with imines to provide the desired functionalized anthrones in good to excellent yields under mild and operationally simple reaction conditions with a broad range of substrate scopes without using any external additives or toxic stoichiometric reagents.

Electrochemical Synthesis of Fused Indole Alkaloids By Controlling Radical Cation Reactivities

Pyrrolophenanthridone alkaloids are isolated from Amaryllidaceae and it has fused N-benzoyl indole as core structure. Many researchers targeted this simple alkaloids to demonstrate various synthetic method1), such as palladium- or hypervalent iodine-mediated intramolecular cross-coupling, tetrazine-promoted inverse electron-demand Diels-Alder reaction. All examples required DDQ oxidation to convert indoline to indole.We established metal- and oxidant-free electrochemical intramolecular C(sp2)-H cross-coupling and indole synthesis reaction. These reactions were initiated by same anodic oxidation for electron-rich indoline ring, but different electron-transfer pathway was occurred in both cyclization and indole forming reaction. Moreover, non-coordinative medium has crucial role to control reactivity of radical cation. Increasing electrophilicity of radical cation is key strategy to accomplish intramolecular cross-coupling. MeNO2-LiClO4 and HFIP (1,1,1,3,3,3,-hexafluoro-2-propanol), which known as suitable medium for radical cation-mediated reaction2), had not worked well for this reaction. However, MeNO2-HFIP (9:1) mixed solvent strongly enhanced the reactivity of radical cations. This phenomenon was occurred by synergetic stabilization effect of MeNO2 and HFIP3). The low donor number of MeNO2 and anion trapping ability of HFIP made non-coordinative environment and resulting electrophilic radical cation was maintained in this medium. Dehydrogenative indole forming reaction was accomplished in Lewis-basic condition (MeCN-Bu4NClO4), and collidine additive enhanced benzylic deprotonation from radical cation.Finally, we applied both reactions for the synthesis of seven naturally occurred pyrrolophenanthridone alkaloids4). References (1) (a) Black, DC.; Keller, PA.; Kumar, N. Tetrahedron Lett. 1989, 30, 5807-5808; (b) Ganton, MD.; Kerr, MA. Org. Lett. 2005, 21, 4777-4779; (c) Boger, DL.; Wolkenberg, SE. J. Org. Chem. 2000, 65, 9120-9124.(2) (a) Okada, Y.; Chiba, K. Chem. Rev. 2018, 118, 4592-4630; (b) Kirste, A.; Nieger, M.; Malkowsky, IM.; Stecker, F.; Fisher, A.; Waldvogel, SR. Chem. Eur. J. 2009, 15, 2273-2277.(3) (a) Shida, N.; Imada, Y.; Nagahara, S.; Okada, Y.; Chiba, K. Commun. Chem. 2019, 2, 24; (b) Shida, N.; Imada, Y.; Okada, Y.; Chiba, K. Eur. J. Org. Chem. 2020, 2020, 570-574.(4) Okamoto, K.; Chiba, K. Org. Lett. 2020, accepted (DOI: 10.1021/acs.orglett.0c01082). Figure 1

An Expedient Synthesis of 2-Aryl-1,4-benzoxazin-3-ones via Tandem Anionic Cyclisation/Alkylation Reactions of N-Boc-O-benzyl-2-aminophenols

A one-pot, tandem anionic cyclization/alkylation reaction of <i>N</i>-Boc-<i>O</i>-benzylated-2-aminophenols to give 2-aryl-1,4-benzoxazin-3-ones is described. The Boc protecting group plays a crucial role in the process, as the <i>tert</i>-butoxide liberated in the cyclisation step facilitates the benzylic deprotonation necessary for the subsequent alkylation. The reaction gives expedient access to a range of substitution patterns in 1,4-benzoxazin-3-ones of potential biological relevance.

ChemInform Abstract: Gold‐Catalyzed Intramolecular Cyclization of Alkynones with Pyridine Anhydrobases.

AbstractAcylation of alkynone substrates followed by benzylic deprotonation produces anhydrobase intermediates which undergo endo‐dig cyclization to afford pyridyl substituted γ‐ and δ‐lactams.

Synthesis, separation, and structural analysis of planar chiral carboxy-substituted [2.2]metacyclophanes

A two-step synthesis of carboxy-functionalized planar chiral [2.2]metacyclophanes from m-xylenes is described. Both transformative steps utilize LiNK metalation conditions (BuLi, KOt-Bu, TMP(H)) for m-xylene benzylic deprotonation with subsequent in situ oxidative C–C coupling. Inclusion of the carboxy substituents at either C4, or C4 and C14, renders the [2.2]metacyclophanes planar chiral and the structural analysis of both substitution patterns has been achieved with X-ray crystallography and NMR spectroscopy. The C4 mono- and C4/14 di-substituted carboxylic acid methyl ester racemates were readily separated by analytical and preparative chiral HPLC and their inversion barriers measured in heptanes at 373 K at 125.3 kJ/mol and 130.9 kJ/mol, respectively. The facile synthesis, separation, and high inversion barriers of planar chiral [2.2]metacyclophanes present an opportunity for their investigation as chiral catalysts and ligands, which to date has yet to be explored.

Substituent effect on benzylic lithiation of sulfides. Synthesis of diboronic acids derived from aryl–alkyl sulfides

The relative benzylic deprotonation rate constants of aryl–benzyl sulfides have been measured and the obtained values were compared with the substituent constants using the Hammett equation and with deprotonation Gibbs energies calculated on B3LYP/aug-cc-pVDZ level. The deprotonation rate depends on the stabilization of the negative charge, which is spread over the benzene ring. The series of brominated alkyl–aryl sulfides was di-lithiated by Br/Li exchange using t-BuLi and the obtained organolithium compounds were converted into the respective diboronic acids. Lithiation of aryl–benzyl sulfides containing a bromine atom in the para or ortho positions occurs selectively, however for the meta derivative, the process is plagued by competitive benzylic deprotonation. This fact can be rationalized on the basis of the obtained relative deprotonation rate constants. The X-ray analysis of bis-(2-dihydroxyborylphenylthio)methane revealed the existence of three different structural motifs, which stabilize the structure by hydrogen bonding formation.

On the control of secondary carbanion structure utilising ligand effects during directed metallation

N,N-Diisopropyl-2-propylbenzamide 6-H undergoes lateral deprotonation by t-BuLi in the presence of the Lewis base PMDTA (N,N,N′,N″,N″-pentamethyldiethylenetriamine) to give a benzyllithium 6-Lil·PMDTA that incorporates a trigonal planar secondary carbanion. In the solid state, the amide directing group and the PMDTA additive work together to abstract the metal ion from the deprotonated α-C of the propyl group (4.107(4) Å). A short distance of 1.376(3) Å is observed between the deprotonated carbon centre and a planar aromatic system that shows a pattern of bond lengths which contrasts with that reported for related tertiary carbanion systems. Analogous benzylic deprotonation is seen if 6-H is treated with t-BuLi in the presence of diglyme to give 6-Lil·DGME. X-ray crystallography now shows that the metal ion more closely approaches the tertiary carbanion (2.418(6) Å) but that the planarity of the deprotonated carbon centre and the bonding pattern in the organic anion seen in the PMDTA complex are retained. DFT analysis corroborates both the short distance between aromatic ring and carbanion centre and the unperturbed nature of aromaticity in 6-Lil·L (L = Lewis base). The observation of two structure-types for the carbanion in solution is explained theoretically and by NMR spectroscopy in terms of cis and trans isomerism imparted by partial double bond character in the arene–(α-C) bond.

Ligand Effects in the Formation of Tertiary Carbanions from Substituted Tertiary Aromatic Amides

Reaction of 2-isopropyl-(N,N-diisopropyl)-benzamide 5 with tBuLi in ether results in ortho deprotonation and the formation of a hemisolvate based on a tetranuclear dimer of (5-Li(o))(2)⋅Et(2)O. The solid-state structure exhibits a dimer core in which the amide oxygen atoms fail to stabilize the metal ions but are instead available for interaction with two metalated monomers that reside peripheral to the core. Reaction of 5 with tBuLi in the presence of the tridentate Lewis base PMDTA (N,N,N',N'',N''-pentamethyldiethylenetriamine) takes a different course. In spite of the tertiary aliphatic group at the 2-position in 5, X-ray crystallography revealed that a remarkable benzylic (lateral) deprotonation had occurred, giving the tertiary benzyllithium 5-Li(l)⋅PMDTA. The solid-state structure reveals that amide coordination and solvation by PMDTA combine to distance the Li(+) ion from the deprotonated α-C of the 2-iPr group (3.859(4) Å), thus giving an essentially flat tertiary carbanion and a highly distorted aromatic system. DFT analysis suggests that the metal ion resides closer to the carbanion center in solution. In line with this, the same (benzylic) deprotonation is noted if the reaction is attempted in the presence of tridentate diglyme, with X-ray crystallography revealing that the metal is now closer to the tertiary carbanion (2.497(4) Å). Electrophilic quenches of lithiated 5 have allowed, for the first time, the formation of quaternary benzylic substituents by lateral lithiation.

Application of Chromium-Arene Complexes in the Organic Synthesis. Efficient Synthesis of Stilbene Phytoalexins

Planar chiral η6-arene-Cr(CO)3 complexes represent highly valuable building blocks for the diastereo- and enantioselective synthesis. Their employment as synthons offer new and unique opportunities for the stereoselective multistep synthesis of complex natural products. The strategy of novel efficient synthesis of stilbene phytoalexins was based on arene chromium chemistry and the chemical and stereochemical effects of the metal unit on the reactivity of complexed arene ligand and stereochemical features of such compounds. Two variants for the construction of the trans-stilbene and diarylethanol framework via facilitated benzylic deprotonation of an η6-benzene-Cr(CO)3 complex and subsequent coupling with para-anisaldehyde in an aldol-type or a Wittig–Horner reaction were suggested.

Atroposelectivity of Reactions of Benzylic Metalated Thiobenzamides and Thionaphthamides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Atroposelectivity of Reactions of Benzylic Metalated Thiobenzamides and Thionaphthamides

AbstractN,N‐Dialkyl‐2‐methylbenzenecarbothioamides and naphthalenecarbothioamides were prepared by thionation of amides with Lawesson’s reagent under unusual conditions. Their axial chirality was evidenced. Benzylic deprotonation of thioamides bearing N,N‐diisopropyl groups with sec‐butyllithium was selective. The resulting anions were reacted with prochiral electrophiles (aromatic aldehydes, an unsaturated aldehyde or ketone, and an imine) to afford diastereomeric adducts (up to 88:12 dr). This is the first report on atroposelective C−C bond formation in the benzylic position of thioamides. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2003)

η6‐Arene‐tricarbonylchromium Complexes in the Syntheses of trans‐Resveratrol and Pinostilbene.

AbstractFor Abstract see ChemInform Abstract in Full Text.

η 6-Arene–tricarbonylchromium complexes in the syntheses of trans-resveratrol and pinostilbene

New syntheses of trans-resveratrol (trans-3,5,4'-trihydroxystilbene) and pinostilbene (trans-3,4'-dihydroxy-5-methoxystilbene) via nucleophilic demethylation of trimethoxystilbene were performed, whereby trans-3,5,4'-trimethoxystilbene was obtained through facilitated benzylic deprotonation of an η6-benzene-Cr(CO)3 derivative and subsequent coupling with para-anisaldehyde in an aldol-type or Wittig–Horner reaction.

Selective ortho and benzylic functionalization of secondary and tertiary p-tolylsulfonamides. Ipso-bromo desilylation and Suzuki cross-coupling reactions.

Kinetic vs thermodynamic deprotonation studies on secondary and tertiary sulfonamides 1 and 2 using n-BuLi have been carried out. While both 1 and 2 show kinetic ortho-metalation, thermodynamic conditions lead to ortho and benzylic deprotonation, respectively (Figures 1 and 2). Metalation of 1 using the n-BuLi/KOtBu superbase led to regioselective benzylic metalation (Figure 4); LDA deprotonation was also briefly explored. Application of the developed conditions allows the synthesis of diverse sulfonamide products 5a-e, 6a-e, 7a,b, and 8a-e. Ipso-bromo desilylation reactions afford sulfonamides 9a,b while Suzuki cross-coupling reactions furnish biaryl sulfonamides 11a-c.