Catalytic enantioselective reductive domino alkyl arylation of acrylates via nickel/photoredox catalysis

Nonsteroidal anti-inflammatory drug derivatives (NSAIDs) are an important class of medications. Here we show a visible-light-promoted photoredox/nickel catalyzed approach to construct enantioenriched NSAIDs via a three-component alkyl arylation of acrylates. This reductive cross-electrophile coupling avoids preformed organometallic reagents and replaces stoichiometric metal reductants by an organic reductant (Hantzsch ester). A broad range of functional groups are well-tolerated under mild conditions with high enantioselectivities (up to 93% ee) and good yields (up to 90%). A study of the reaction mechanism, as well as literature precedence, enabled a working reaction mechanism to be presented. Key steps include a reduction of the alkyl bromide to the radical, Giese addition of the alkyl radical to the acrylate and capture of the α-carbonyl radical by the enantioenriched nickel catalyst. Reductive elimination from the proposed Ni(III) intermediate generates the product and forms Ni(I).

Alkylation Reactions with Alkylsulfonium Salts

Application of alkylsulfonium salts as alkyl transfer reagents in organic synthesis has reemerged over the past years. Numerous heteroatom- and carbon-centered nucleophiles, alkenes, arenes, alkynes, organometallic reagents, and others were readily alkylated by alkylsulfonium salts under mild conditions. The reactions feature convenience, high efficiency, readily accessible and structurally diversified alkylation reagents, good functional group tolerance, and a wide range of substrate types, allowing for facile synthesis of various useful organic molecules from the commercially available building blocks. This review summarizes the alkylation reactions using either isolated or in situ formed alkylsulfonium salts via nucleophilic substitution, transition-metal-catalyzed reactions, and photoredox processes.

Direct C-H-Sulfonylation of 6-Membered Nitrogen-Heteroaromatics

Heterocyclic sulfones and sulfonamides represent important structural motives in medicinal chemistry and drug development. Therefore, efficient and reliable methods for their construction from simple building blocks are in high demand. Herein we report a novel approach for the direct C-H-sulfonylation of N heteroaromatics via N-activation with triflic anhydride (Tf2O), base-mediated addition of a sulfinate salt and subsequent rearomatization through trifluoromethanesulfinate elimination. This operationally simple one-pot protocol enables direct access to various sulfonylated 6-ring N-heterocycles. It is applicable to the late-stage functionalization of complex, drug-like molecules. The direct incorporation of sulfur dioxide with organometallic reagents as well as the utilization of a rongalite-based sulfonylation reagent provide opportunities for a highly modular synthesis of N-heterocyclic sulfones and sulfonamides from three different building blocks.

Direct alkylation of N,N-dialkyl benzamides with methyl sulfides under transition metal-free conditions

Amides are a fundamental and widespread functional group, and are usually considered as poor electrophiles owing to resonance stabilization of the amide bond. Various approaches have been developed to address challenges in amide transformations. Nonetheless, most methods use activated amides, organometallic reagents or transition metal catalysts. Here, we report the direct alkylation of N,N-dialkyl benzamides with methyl sulfides promoted by the readily available base LDA (lithium diisopropylamide). This approach successfully achieves an efficient and selective synthesis of α-sulfenylated ketones without using transition-metal catalysts or organometallic reagents. Preliminary mechanism studies reveal that the deprotonative aroylation of methyl sulfides is promoted by the directed ortho-lithiation of the tertiary benzamide with LDA.

A Perspective of Diverse Synthetic Approaches and Biological Applications of Vitamin K

Vitamin-K is a demanding multi-functional health product in the market and belongs to a class of isoprenoid molecules that comprises methylnaphthoquinone (MK) unit attached to an isoprene side chain. They are fat soluble and differ in the extent of side chain & obtained in the nature as vitamin K1 (phylloquinone), menaquinone/vitamin K2, and other lipoquinones. Owing to their owned polyprenyl side chain, they are hydrophobic/lipophilic in nature. Generally, the synthesis of vitamin K and its variants suffers with isomerization (for example 11 isomers were identified for cis/trans MK-7). Naturally, in bio-systems vitamin K produces through shikimic acid pathway and terpene biosynthetic pathway for the synthesis of menaquinone part & prenyl side chain parts respectively. Menadione or its auxiliaries are commonly being used as substrates to the synthesis of vitamin K variants through the involvement of condensation reactions, Friedel-Craft alkylation’s, Claisen rearrangement, Diels-Alder reactions and others. Importantly, organometallic reagents, such as Grignard, Gilman, organotelluride and other reagents could be the promising and consistent choice of substrate to the synthesis of various vitamin K’s. Vitamin K is well known for blood coagulation. As an antihaemorrhagic vitamin, it’s also being the current interest for the treatment of bone and vascular diseases. In addition, vitamin k is indispensable for the activation of vitamin K dependent (VKD) proteins and that are present almost in all tissues and responsible for hemostasis, bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction. This chapter summarizes various synthetic approaches of vitamin K & derivatives and their biological functions.

Fritsch–Buttenberg–Wiechell rearrangement of magnesium alkylidene carbenoids leading to the formation of alkynes

A series of 1-heteroatom-substituted vinyl p-tolyl sulfoxides were prepared and treated with organometallic reagents to evaluate which combination of sulfoxides and organometallic reagents yielded alkynes the most efficiently. The use of 1-chlorovinyl p-tolyl sulfoxide and isopropylmagnesium chloride was optimal for this purpose. A variety of 1-chlorovinyl p-tolyl sulfoxides were prepared from carbonyl compounds and chloromethyl p-tolyl sulfoxide and were converted into alkynes via the sulfoxide/magnesium exchange reaction and subsequent Fritsch–Buttenberg–Wiechell (FBW) rearrangement of the resulting magnesium alkylidene carbenoids. The mechanism of the FBW rearrangement of magnesium alkylidene carbenoids was studied by using 13C-labeled sulfoxides and by using DFT calculations.