Catalyst-controlled Regioselectivity Research Articles

A Chiral Titanocene Complex as Regiodivergent Photoredox Catalyst: Synthetic Scope and Mechanism of Catalyst Generation.

We describe a combined synthetic, spectroscopic, and computational study of a chiral titanocene complex as a regiodivergent photoredox catalyst (PRC). With Kagan's complex catCl2 either monoprotected 1,3-diols or 1,4-diols can be obtained in high selectivity from a common epoxide substrate in a regiodivergent epoxide opening depending on which enantiomer of the catalyst is employed. Due to the catalyst-controlled regioselectivity of ring opening and the broader substrate scope, the PRC with catCl2 is also a highly attractive branching point for diversity-oriented synthesis. The photochemical processes of cat(NCS)2, a suitable model for catCl2, were probed by time-correlated single-photon counting. The photoexcited complex displays a thermally activated delayed fluorescence as a result of a singlet-triplet equilibration, S1 ⇄ T1, via intersystem crossing and recrossing. Its triplet state is quenched by electron transfer to the T1 state. Computational and cyclic voltammetry studies highlight the importance of our sulfonamide additive. By bonding to sulfonamide additives, chloride abstraction from [catCl2]- is facilitated, and catalyst deactivation by coordination of the sulfonamide group is circumvented.

Catalyst-Controlled Regioselectivity in Pd-Catalyzed Aerobic Oxidative Arylation of Indoles.

Pd-catalyzed C-H arylation of heteorarenes is an important and widely studied synthetic transformation; however, the regioselectivity is often substrate-controlled. Here, we report catalyst-controlled regioselectivity in the Pd-catalyzed oxidative coupling of N-(phenylsulfonyl)indoles and aryl boronic acids using O2 as the oxidant. Both C2- and C3-arylated indoles are obtained in good yield with >10:1 selectivity. A switch from C2 to C3 regioselectivity is achieved by including 4,5-diazafluoren-9-one or 2,2'-bipyrimidine as an ancillary ligand to a "ligand-free" Pd(OTs)2 catalyst system. Density functional theory calculations indicate that the switch in selectivity arises from a change in the mechanism, from a C2-selective oxidative-Heck pathway to a C3-selective C-H activation/reductive elimination pathway.

Understanding Catalyst Structure–Selectivity Relationships in Pd-Catalyzed Enantioselective Methoxycarbonylation of Styrene

Catalyst-controlled regioselectivity in palladium-catalyzed carbonylation of alkenes has been a long-standing goal of homogeneous catalysis. In general, monophosphines do favor branched regioselect...

Nucleophilic Transformations of Lewis Acid-Activated Disubstituted Epoxides with Catalyst-Controlled Regioselectivity.

Due to their inherent ring strain and electrophilicity, epoxides are highly attractive building blocks for fundamental organic reactions. However, controlling the regioselectivity of disubstituted epoxide transformations is often particularly challenging. Most Lewis acid-mediated processes take advantage of intrinsic steric or electronic substrate bias to influence the site of nucleophilic attack. Therefore, the scope of many of these systems is frequently quite limited. Recent efforts to generate catalysts that can overcome substrate bias have expanded the synthetic utility of these well-known reactions. In this Perspective, we highlight various regioselective transformations of disubstituted epoxides, emphasizing those that have inspired the production of challenging, catalyst-controlled processes.

Catalyst-Controlled Regioselective Nitrosocarbonyl Aldol Reaction of Deconjugated Butenolides.

An unprecedented regiodivergent nitrosocarbonyl aldol reaction of γ-substituted deconjugated butenolides is described. While Lewis base catalyst quinidine leveraged O-selective nitrosocarbonyl aldol reaction exclusively at the γ-position of deconjugated butenolides to produce γ-aminoxylation products, Lewis acid catalyst Cu(OTf)2 steered the competitive N-selective nitrosocarbonyl aldol reaction at the β-position, resulting in heterodifunctionalized butenolides. Both processes were amenable to a broad range of substrates and scalable, while the latter one represents a rare example of one-pot hetero-β,γ-difunctionalization of butenolide scaffolds.

Computational study of catalyst-controlled regiodivergent pathways in hydroboration of 1,3-dienes: mechanism and origin of regioselectivity

DFT calculations were performed to elucidate the origins of catalyst-controlled regioselectivity in the hydroboration of 2-substituted 1,3-dienes.

Nucleophilic ring opening of trans-2,3-disubstituted epoxides to β-amino alcohols with catalyst-controlled regioselectivity

We report the nucleophilic ring opening of unsymmetrical trans-epoxides to β-amino alcohols with catalyst-controlled regioselectivity. This cationic aluminum salen catalyst, which contains bulky mesityl groups in the ortho-position of the phenoxide and a 2,2'-diamino-1,1'-binaphthalene backbone, transforms a variety of epoxides with high regioselectivity using nitrogen-containing nucleophiles. Unlike most reports, in which regioselectivity is substrate controlled, the regioselectivity in this system is catalyst controlled and allows selective nucleophilic ring opening of unbiased trans-epoxides.

Catalyst-controlled regioselectivity in phosphine catalysis: the synthesis of spirocyclic benzofuranones via regiodivergent [3+ 2] annulations of aurones and an allenoate.

Catalyst-controlled regiodivergent [3 + 2] annulations of aurones and allenoates have been developed. When a dipeptide phosphine catalyst with an l-d- configuration was employed, α-selective [3 + 2] annulation products could be obtained with good regioselectivities and enantioselectivities. With the employment of l-l- dipeptide phosphines, γ-selective annulation products could be selectively obtained with excellent enantioselectivities. By simply tuning the catalyst configurations, a wide range of α-selective or γ-selective spirocyclic benzofuranones with either aryl or alkyl substitutions could be readily prepared. DFT calculations suggest that the conformation of the dipeptide phosphines influences the hydrogen bonding interactions or the distortion energy, resulting in delicate energy differentiation in the transition states, and accounting for the observed regioselectivity.

Regioselective aerobic oxidative Heck reactions with electronically unbiased alkenes: efficient access to α-alkyl vinylarenes.

Branched-selective oxidative Heck coupling reactions have been developed between arylboronic acids and electronically unbiased terminal alkenes. The reactions exhibit high catalyst-controlled regioselectivity favoring the less common branched isomer. The reactions employ a catalyst composed of Pd(TFA)2/dmphen (TFA = trifluoroacetate, dmphen = 2,9-dimethyl-1,10-phenanthroline) and proceed efficiently at 45-60 °C under 1 atm of O2 without requiring other additives. A broad array of functional groups, including aryl halide, allyl silane and carboxylic acids are tolerated.

Enzyme-controlled nitrogen-atom transfer enables regiodivergent C-H amination.

We recently demonstrated that variants of cytochrome P450BM3 (CYP102A1) catalyze the insertion of nitrogen species into benzylic C–H bonds to form new C–N bonds. An outstanding challenge in the field of C–H amination is catalyst-controlled regioselectivity. Here, we report two engineered variants of P450BM3 that provide divergent regioselectivity for C–H amination—one favoring amination of benzylic C–H bonds and the other favoring homo-benzylic C–H bonds. The two variants provide nearly identical kinetic isotope effect values (2.8–3.0), suggesting that C–H abstraction is rate-limiting. The 2.66-Å crystal structure of the most active enzyme suggests that the engineered active site can preorganize the substrate for reactivity. We hypothesize that the enzyme controls regioselectivity through localization of a single C–H bond close to the iron nitrenoid.

ChemInform Abstract: Catalyst‐Controlled Regioselective Reactions of Carbohydrate Derivatives

AbstractReview: ca. 100 refs.

Catalyst-Controlled Regioselective Reactions of Carbohydrate Derivatives

The efficient synthesis of oligosaccharides requires methods for regioselective manipulation of hydroxyl groups in monosaccharide derivatives. Catalysis represents a potentially general solution to this problem, and over the past decade, the development of catalyst-controlled methods for regioselective functionalization of carbohydrates has intensified. This Short Review highlights the range of catalysts and catalytic mechanisms that may be exploited to alter the reactivity of hydroxyl groups in carbohydrate substrates. 1 Introduction 2 Intrinsic Trends in the Reactivity of Carbohydrate Hydroxyl Groups 2.1 Steric Control 2.2 Electronic Control 3 Enzyme Catalysis 4 Phase-Transfer Catalysis 5 Lewis Base Catalysis 5.1 Peptide-Based Catalysts 5.2 Modified DMAP Catalysts 5.3 Chiral Amines 6 Lewis Acid Catalysis 6.1 Tin(IV) Reagents 6.2 Transition-Metal Reagents 6.3 Lanthanum(III) Reagents 6.4 Multistep One-Pot Methods 6.5 Organoboron Reagents 7 Conclusions and Outlook

Catalyst-controlled regioselectivity in the synthesis of branched conjugated dienes via aerobic oxidative Heck reactions.

Pd-catalyzed aerobic oxidative coupling of vinylboronic acids and electronically unbiased alkyl olefins provides regioselective access to 1,3-disubstituted conjugated dienes. Catalyst-controlled regioselectivity is achieved by using 2,9-dimethylphenanthroline as a ligand. The observed regioselectivity is opposite to that observed from a traditional (nonoxidative) Heck reaction between a vinyl bromide and an alkene. DFT computational studies reveal that steric effects of the 2,9-dimethylphenanthroline ligand promote C-C bond formation at the internal position of the alkene.

Regioselective Diversification of a Cardiac Glycoside, Lanatoside C, by Organocatalysis

Acylation of lanatoside C in the presence of organocatalyst 5 gave the C(4'''')-O-acylate in up to 90% regioselectivity (catalyst-controlled regioselectivity). Various functionalized acyl groups can be introduced at the C(4'''')-OH by a mixed anhydride method in the presence of 5 or the related organocatalyst. On the other hand, DMAP-catalyzed acylation of lanatoside C gave the C(3'''')-O-acylate in up to 97% regioselectivity (substrate-controlled regioselectivity). Thus, diverse regioselective introduction of acyl groups among eight free hydroxy groups of lanatoside C was achieved.

A general strategy for regiocontrol in nickel-catalyzed reductive couplings of aldehydes and alkynes.

A strategy for catalyst-controlled regioselectivity in aldehyde-alkyne reductive couplings has been developed. This strategy is the first where either regiochemical outcome may be selected for a broad range of couplings, without relying on substrate biases or directing effects. The complementary use of small cyclopropenylidene carbene ligands or highly hindered N-heterocyclic carbene ligands allows the regiochemical reversal with unbiased internal alkynes, aromatic internal alkynes, conjugated enynes, or terminal alkynes.

Catalyst-Controlled Regioselective Suzuki Couplings at Both Positions of Dihaloimidazoles, Dihalooxazoles, and Dihalothiazoles

Various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki coupling. By changing the palladium catalyst employed, the selectivity can be switched for some dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond. These conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of diarylazoles in a modular fashion.

Brønsted Base-Modulated Regioselectivity in the Aerobic Oxidative Amination of Styrene Catalyzed by Palladium

Palladium(II)-catalyzed aerobic oxidative amination of styrene with oxazolidinone proceeds with catalyst-controlled regioselectivity: (CH3CN)2PdCl2 (1) and (Et3N)2PdCl2 (2) catalyze formation of the anti-Markovnikov and Markovnikov enecarbamate products, 3 and 4, respectively. Kinetic studies and deuterium kinetic isotope effects demonstrate that these two reactions possess different rate-limiting steps, and the data indicate that the product regiochemistry arises from the presence or absence of an effective Brønsted base in the reaction. In the presence of a Brønsted base such as triethylamine or acetate, the kinetically preferred Markovnikov aminopalladation adduct of styrene is trapped via rapid deprotonation of a zwitterionic intermediate and leads to formation of 4. In the absence of an effective Brønsted base, however, slow deprotonation of this adduct enables aminopalladation to be reversible, and product formation proceeds through the thermodynamically preferred anti-Markovnikov aminopalladation adduct to yield 3.