Chemoselective Additions of Chloromethyllithium Carbenoid to Cyclic Enones: A Direct Access to Chloromethyl Allylic Alcohols

Chloromethyllithium carbenoid has been chemoselectively added to cyclic enones (5‐, 6‐ and 7‐membered systems, including two natural products) to provide chloromethyl allylic alcohols. Under the optimized reaction conditions neither concomitant (n+1) homologation nor conjugate addition or Simmons–Smith‐like cyclopropanation takes place. The presence of LiBr is estimated to play a dual role, namely as a carbenoid stabilizer and mild Lewis acid activator of the CO group. Notably, the mesomeric effect caused by β‐heteroatom‐containing substituents promotes the attack of the reagent at the most activated position.

     

Chemoselective Ruthenium‐Catalyzed Reduction of Acid Chlorides to Aldehydes with Dimethylphenylsilane

A variety of aromatic and alkyl acid chlorides can be selectively converted into aldehydes using dimethylphenyl silane (HSiMe₂Ph) as the reducing reagent in the presence of the cationic ruthenium catalyst {Cp[(i‐Pr)₃P]Ru(NCMe)₂}⁺ [PF₆]⁻. The reactions proceed under very mild conditions and are tolerant to many functional groups.     

Highly Efficient and Chemoselective Ruthenium‐Catalyzed Hydrosilylation of Aldehydes

The highly chemoselective hydrosilylation of aldehydes was achieved using a ruthenium catalyst activated by a household fluorescent light (30 W) at or below room temperature. The hydrosilylation was almost exclusive to aldehydes over ketones and olefins.     

Organocatalytic Enantioselective Decarboxylative Addition of Malonic Acids Half Thioesters to Isatins

The organocatalytic enantioselective decarboxylative addition of malonic acids half thioesters to isatins using a squaramide catalyst afforded the products with high enantioselectivity. These products are key intermediates in the synthesis of 3‐substituted 3‐hydroxy‐2‐oxindole derivatives. The first enantioselective synthesis of (−)‐flustraminol B has been accomplished.     

Synthesis of Glutamic Acid and Highly Functionalized Pyrrolidine Derivatives by Utilizing Tunable Calcium Catalysts for Chemoselective Asymmetric 1,4‐Addition and [3+2] Cycloaddition Reactions

A current trend in organic chemistry is the development of highly efficient, environmentally friendly and inexpensive catalysts for asymmetric transformations. Alkaline earth metals, due to their specific chemical properties and abundance in nature, provide promising and challenging catalysts in organic synthesis. This article describes the utilization of alkaline earth metals in the development of an effective catalytic system based on calcium salts in combination with Box‐type ligands. We disclose asymmetric 1,4‐addition and [3+2] cycloaddition reactions using simple catalytic systems consisting of calcium chloride dihydrate, chiral ligands and tetramethylguanidine. Various Box ligands were synthesized and the most effective proved to be that bearing an indane chiral backbone and a cyano group. Depending on the structure of both glycine Schiff bases and α,β‐unsaturated compounds, the corresponding Michael adducts or pyrrolidine derivatives were obtained in moderate to high yields with high enantioselectivities. Modification of the catalytic system by using more Lewis acidic calcium salts such as calcium triflate and neutral Pybox‐type ligands allows a tuning of the chemoselectivity and leads to suppression of the [3+2] cycloadition reactions. Various β‐substituted acrylates provided 1,4‐addition adducts exclusively in high yields with moderate to high diastereo‐ and enantioselectivities. This methodology has broadened a synthetic route to β‐branched glutamic acid derivatives and established calcium salts as useful and attractive catalysts for asymmetric catalysis.     

Bismuth Triflate‐Catalyzed Addition of Allylsilanes to N‐Alkoxycarbonylamino Sulfones: Convenient Access to 3‐Cbz‐Protected Cyclohexenylamines

Bismuth triflate was found to be an efficient catalyst in the Sakurai reaction of allyltrimethylsilanes with N‐alkoxycarbonylamino sulfones. The reaction proceeded smoothly with a low catalyst loading of Bi(OTf)₃⋅4 H₂O (2–5 mol%) to afford the corresponding protected homoallylic amines in very good yields (up to 96%). A sequential allylation reaction followed by ring‐closing metathesis delivers 6–8 membered 3‐Cbz‐protected cycloalkenylamines.     

Palladium‐Catalyzed Selective Aryl Ring C–H Activation of N‐Acyl‐2‐aminobiaryls: Efficient Access to Multiaryl‐Substituted Naphthalenes

Palladium‐catalyzed cycloaromatization of N‐acyl‐2‐aminobiaryls, through a sequence of ortho C−H bond activation/alkyne insertion/meta C−H bond activation/alkyne insertion, was developed. An efficient synthesis of multiaryl‐substituted naphthalenes, N‐[2‐(5,6,7,8‐tetraarylnaphthalen‐1‐yl)aryl]acetamides, was demonstrated using molecular oxygen as the sole oxidant. Furthermore, through Buchwald's synthetic protocol, two compounds were converted into corresponding fluorescent carbazoles in 30–40% yield by intramolecular C−N bond formation.

     

Chemoselective Synthesis of N‐Substituted α‐Amino‐α′‐chloro Ketones via Chloromethylation of Glycine‐Derived Weinreb Amides

Functionalized α‐arylamino‐α′‐chloro ketones are obtained in high yield via a straightforward homologation reaction of Weinreb amides derived from N‐arylglycines using in situ generated chloromethyllithium. The use of the Weinreb amides is essential and allows the chemoselective homologation of N‐aryl‐N‐substituted glycine analogues, a transformation which is not possible using similar glycine esters. The procedure is promising for the large‐scale preparation of α‐amino‐α′‐chloropropanones, which are valuable precursors for a variety of bioactive compounds.     

Spiro‐Pyrrolidine‐Catalyzed Asymmetric Conjugate Addition of Hydroxylamine to Enals and 2,4‐Dienals

A spiro‐pyrrolidine‐catalyzed tandem aza‐1,4‐addition/hemi‐acetalization reaction was developed with excellent enantioselectivity (12 examples of ≥99% ee), and several substrates proceeded with higher ee (up to 10% increase) compared with the literature data. Particularly, an interesting and unusual aza‐1,6‐/oxa‐1,4‐addition for some substrates was also observed.

     

Novel Palladium‐on‐Carbon/Diphenyl Sulfide Complex for Chemoselective Hydrogenation: Preparation,Characterization, and Application

A diphenyl sulfide immobilized on palladium‐on‐carbon system, Pd/C[Ph₂S], was developed to achieve the highly chemoselective hydrogenation of alkenes, acetylenes, azides, and nitro groups in the presence of aromatic ketones, halides, benzyl esters, and N‐Cbz protective groups. Instrumental analyses of the heterogeneous catalyst demonstrated that diphenyl sulfide was embedded on Pd/C via coordination of its sulfur atom to palladium metal or physical interaction with graphite layers of the activated carbon. The catalyst could be recovered and reused at least five times without any significant loss of the reactivity.     

Organocatalysis in Natural Product Synthesis: A Simple One‐Pot Approach to Optically Active β‐Diols

Optically active β‐diols have been prepared using an organocatalytic one‐pot approach from α,β‐unsaturated aldehydes using (E)‐benzaldehyde oxime as nucleophile in an oxa‐Michael reaction with subsequent in situ reduction or Grignard addition. With this protocol at hand, two biologically active compounds, an insect sex pheromone and a glycerol kinase substrate have been synthesized.     

Direct Organocatalytic Asymmetric Mannich Addition of 3‐Substituted‐2H‐1,4‐Benzoxazines: Access to Tetrasubstituted Carbon Stereocenters

3‐Substituted‐2H‐1,4‐benzoxazines undergo a highly enantioselective direct Mannich reaction with acetone in the presence of an L ‐proline catalyst at room temperature. The corresponding N‐heterocycles with α‐tetrasubstituted carbon stereocenters were obtained in good yields (48–92%) and excellent enantioselectivity (up to >99% ee). Furthermore, a novel modification involving the diastereoselective reduction of the Mannich adduct was carried out leading to the formation of a 1,3‐amino alcohol with a chiral tetrasubstituted carbon stereocenter in high yield.

     

Substitution‐ and Elimination‐Free Phosphorylation of Functionalized Alcohols Catalyzed by Oxidomolybdenum Tetrachloride

Among 14 oxidometallic species examined for catalytic phosphorylation of the tested alcohols, oxidomolybdenum tetrachloride (MoOCl₄) was found to be the most efficient with a negligible background reaction mediated by triethylamine (Et₃N). The new catalytic protocol can be applied to the chemoselective phosphorylations of primary, secondary and tertiary alcohols as well as the substitution‐free phosphorylations of allylic, propargylic, and benzylic alcohols. Functionalized alcohols bearing acetonide, tetrahydropyranyl ether, tert‐butyldimethylsilyl ether, or ester group are also amenable to the new catalytic protocol. The most difficult scenarios involve substitution‐free phosphorylations of 1‐phenylethanol and 1‐(2‐naphthyl)ethanol which can be effected in 95 and 90% yields, respectively. ESI‐MS, IR, ¹H, and ³¹P NMR spectroscopic analyses of the reaction progress suggest the intermediacy of an alkoxyoxidomolybdenum trichloride‐triethylamine adduct such as [(RO)Mo(O)Cl₃‐Et₃N] to be responsible for the catalytic turnover.     

A Chiral Functionalized Salt‐Catalyzed Asymmetric Michael Addition of Ketones to Nitroolefins

The chiral functionalized salt catalysis, which differs from the known enzyme‐ and transition metal‐based methods, has been successfully developed to carry out the Michael addition of ketones to nitroolefins. Chiral anion salt (type I ), chiral cation salt (type II ), or chiral anion‐chiral cation salt (type III ) could be expected to be remarkably effective catalysts and afford the corresponding chemically and optically pure Michael addition adducts. A primary amine group activating the ketone during salt catalysis was their obvious and common property. Based on preliminary experimental investigations and previous reports on primary amine catalysis, a reaction pathway via imine, enamine, iminium ion to imine was proposed.     

A Simple and Efficient Access to New Functionalized 4‐Phenacylideneflavenes#

An innovative and efficient approach towards diversity‐oriented synthesis of 4‐phenacylideneflavenes has been developed from substituted salicylaldehydes and acetophenones using iodine under solvent‐free conditions. Both symmetrical and unsymmetrical functionalized 4‐phenacylideneflavenes were synthesized in good to excellent yields and their mechanism of formation is discussed.     

Chemoselective Immobilization of Proteins by Microcontact Printing and Bio‐orthogonal Click Reactions

Herein, a combination of microcontact printing of functionalized alkanethiols and site‐specific modification of proteins is utilized to chemoselectively immobilize proteins onto gold surfaces, either by oxime‐ or copper‐catalyzed alkyne–azide click chemistry. Two molecules capable of click reactions were synthesized, an aminooxy‐functionalized alkanethiol and an azide‐functionalized alkanethiol, and self‐assembled monolayer (SAM) formation on gold was confirmed by IR spectroscopy. The alkanethiols were then individually patterned onto gold surfaces by microcontact printing. Site‐specifically modified proteins—horse heart myoglobin (HHMb) containing an N‐terminal α‐oxoamide and a red fluorescent protein (mCherry‐CVIA) with a C‐terminal alkyne—were immobilized by incubation onto respective stamped functionalized alkanethiol patterns. Pattern formation was confirmed by fluorescence microscopy.     

Cobalt‐Catalyzed Cross‐Coupling Reaction between Functionalized Primary and Secondary Alkyl Halides and Aliphatic Grignard Reagents

The coupling of primary and secondary unactivated alkyl bromides with alkyl‐Grignard reagents was performed in good yields under mild conditions by using a new catalytic system: consisting of cobalt chloride and tetramethylethylenediamine (CoCl₂⋅2 LiI, 4 TMEDA). The reaction is very chemoselective since ketone, ester and nitrile functions are tolerated.     

Insights into the Cerium Chloride‐Catalyzed Grignard Addition to Esters

Addition of methylmagnesium chloride to ester 1 in the presence of cerium chloride gave significantly better yields of the tertiary alcohol 2 than the reaction performed in the absence of cerium chloride. The beneficial effect of added cerium chloride is postulated to be due to suppression of the enolization of the ketone intermediate. The use of properly “activated” anhydrous cerium chloride which is proposed to generate a less basic, more nucleophilic species to overcome this undesired reaction was found to be critical. The activated cerium chloride was identified as the known seven‐coordinate THF solvate, [CeCl(μ‐Cl)₂(THF)₂]_n. Inactive crystal forms were also identified and the key parameters for formation of the active form were delineated.