A Mild, Palladium-Catalyzed Method for the Dehydrohalogenation of Alkyl Bromides: Synthetic and Mechanistic Studies

We have exploited a typically undesired elementary step in cross-coupling reactions, β-hydride elimination, to accomplish palladium-catalyzed dehydrohalogenations of alkyl bromides to form terminal olefins. We have applied this method, which proceeds in excellent yield at room temperature in the presence of a variety of functional groups, to a formal total synthesis of (R)-mevalonolactone. Our mechanistic studies have established that the rate-determining step can vary with the structure of the alkyl bromide and, most significantly, that L_2PdHBr (L = phosphine), an intermediate that is often invoked in palladium-catalyzed processes such as the Heck reaction, is not an intermediate in the active catalytic cycle

Photoinduced, Copper-Catalyzed Alkylation of Amides with Unactivated Secondary Alkyl Halides at Room Temperature

The development of a mild and general method for the alkylation of amides with relatively unreactive alkyl halides (i.e., poor substrates for S_N2 reactions) is an ongoing challenge in organic synthesis. We describe herein a versatile transition-metal-catalyzed approach: in particular, a photoinduced, copper-catalyzed monoalkylation of primary amides. A broad array of alkyl and aryl amides (as well as a lactam and a 2-oxazolidinone) couple with unactivated secondary (and hindered primary) alkyl bromides and iodides using a single set of comparatively simple and mild conditions: inexpensive CuI as the catalyst, no separate added ligand, and C–N bond formation at room temperature. The method is compatible with a variety of functional groups, such as an olefin, a carbamate, a thiophene, and a pyridine, and it has been applied to the synthesis of an opioid receptor antagonist. A range of mechanistic observations, including reactivity and stereochemical studies, are consistent with a coupling pathway that includes photoexcitation of a copper–amidate complex, followed by electron transfer to form an alkyl radical

Transition-Metal-Catalyzed Alkylations of Amines with Alkyl Halides: Photoinduced, Copper-Catalyzed Couplings of Carbazoles

N-alkylations of carbazoles with a variety of secondary and hindered primary alkyl iodides can be achieved by using a simple precatalyst (CuI) under mild conditions (0 °C) in the presence of a Brønsted base; at higher temperature (30 °C), secondary alkyl bromides also serve as suitable coupling partners. A Li[Cu(carbazolide)_2] complex has been crystallographically characterized, and it may serve as an intermediate in the catalytic cycle

A Versatile Approach to Ullmann C−N Couplings at Room Temperature: New Families of Nucleophiles and Electrophiles for Photoinduced, Copper-Catalyzed Processes

The use of light to facilitate copper-catalyzed cross-couplings of nitrogen nucleophiles can enable C−N bond formation to occur under unusually mild conditions. In this study, we substantially expand the scope of such processes, establishing that this approach is not limited to reactions of carbazoles with iodobenzene and alkyl halides. Specifically, we demonstrate for the first time that other nitrogen nucleophiles (e.g., common pharmacophores such as indoles, benzimidazoles, and imidazoles) as well as other electrophiles (e.g., hindered/deactivated/heterocyclic aryl iodides, an aryl bromide, an activated aryl chloride, alkenyl halides, and an alkynyl bromide) serve as suitable partners. Photoinduced C−N bond formation can be achieved at room temperature using a common procedure with an inexpensive catalyst (CuI) that does not require a ligand coadditive and is tolerant of moisture and a variety of functional groups

Phosphine-Scavenging Cationic Gold(I) Complexes: Alternative Applications of Gold Cocatalysis in Fundamental Palladium-Catalyzed Cross-Couplings

We have demonstrated that air-stable cationic gold(I) cocatalysts have the capacity to enhance the efficiency of palladium-catalyzed cross-couplings. Specifically, we determined that a 1:1 [Pd{P(t-Bu)3}2]/[Au{P(t-Bu)3}(NTf2)] system provides superior reactivity relative to [Pd{P(t-Bu)3}2], across Suzuki-Miyaura, Stille, and Mizoroki-Heck reactions performed under mild conditions. Our results are consistent with cationic gold(I) species serving primarily as phosphine scavengers in this chemistry, as recently predicted by density functional theory (DFT)

A Mild, Palladium-Catalyzed Method for the Dehydrohalogenation of Alkyl Bromides: Synthetic and Mechanistic Studies

We have exploited a typically undesired elementary step in cross-coupling reactions, β-hydride elimination, to accomplish palladium-catalyzed dehydrohalogenations of alkyl bromides to form terminal olefins. We have applied this method, which proceeds in excellent yield at room temperature in the presence of a variety of functional groups, to a formal total synthesis of (R)-mevalonolactone. Our mechanistic studies have established that the rate-determining step can vary with the structure of the alkyl bromide and, most significantly, that L2PdHBr (L = phosphine), an intermediate that is often invoked in palladium-catalyzed processes such as the Heck reaction, is not an intermediate in the active catalytic cycle.National Institutes of Health (U.S.) (Grant R01- GM62871)National Institute of General Medical Sciences (U.S.) (Grant R01- GM62871)Merck & Co., Inc. (American Australian Association Merck Company Foundation Fellowship)American Australian Association (Merck Company Foundation Fellowship)Massachusetts Institute of Technology. Undergraduate Research Opportunities Program (Paul E. Gray (1954) Endowed Fund)Massachusetts Institute of Technology (John Reed Fund

Applications of visible light photoredox catalysis to the synthesis of natural products and related compounds

The total synthesis of natural products and their derivatives continues to inspire organic chemists to identify and test new synthetic strategies and develop and explore novel methodology.</p

Preparation of thermoresponsive hydrogels : Via polymerizable deep eutectic monomer solvents

We report the preparation of thermoresponsive poly(N-isopropylacrylamide) (polyNIPAM) hydrogels via the free radical polymerization of deep eutectic monomer solvents (DEMs) for the first time, where NIPAM serves as a polymerizable hydrogen bond donor. DEMs were prepared by a simple heating and stirring protocol using NIPAM and either choline chloride (ChCl) or acetylcholine chloride (AcChCl) (as hydrogen bond acceptor) in various ratios to yield low-melting point liquids (as low as 15 °C). 1D and 2D NMR spectroscopy supported the association of the NIPAM and choline salts present within the DEM structure, in addition to the low self-diffusion coefficients of the species present compared to when dissolved in water. Thermogravimetric analysis demonstrated an enhanced thermal stability of the DEMs compared to NIPAM. Hydrogels prepared by free-radical polymerization of the prepared DEMs in the presence of N,N′-methylenebisacrylamide (BIS) as crosslinker showed a significant increase in reaction rate compared to the equivalent reaction in water, which was attributed in part to the high viscosity of the DEMs. These gels exhibited thermoresponsive swelling behaviour when immersed in water. Specifically, gels prepared via DEMs featured reduced swelling capacity and increased mechanical strength relative to those prepared by aqueous polymerization, attributed to a significant increase in cross-linking density. This journal is </p

Non-Classical Anionic Naked <i>N</i>-Heterocyclic Carbenes: Fundamental Properties and Emerging Applications in Synthesis and Catalysis

Ongoing research exploring the chemistry of N-heterocyclic carbenes (NHCs) has led to the development and discovery of new NHC subclasses that deviate beyond Arduengo&#8217;s prototypical N,N&#8242;-disubstituted imidazol-2-ylidene-based structures. These systems continue to enable and extend the fundamental role of NHC ligands in synthesis and catalysis. In this regard, the advent of protic NHCs has garnered particular interest. This derives in part from their applications to the selective preparation of unique molecular scaffolds and their unprecedented bifunctional reactivity, which can be exploited in transition metal-catalyzed processes. In comparison, the synthetic applications of closely related anionic naked NHCs remain rather underexplored. With this in mind, this review highlights the interesting fundamental properties of non-classical anionic naked NHCs, and focuses on their emerging applications in synthesis and catalysis