Organic & Biomolecular Chemistry (v.17, #41)

Front cover (9073-9074).

Contents list (9075-9080).

Recent trends and applications of the Cadiot–Chodkiewicz reaction by Sankaran Radhika; Nissy Ann Harry; Mohan Neetha; Gopinathan Anilkumar (9081-9094).
The Cadiot–Chodkiewicz reaction offers an elegant strategy for the formation of 1,3-diynes via Cu-catalyzed cross-coupling of alkynyl halides with terminal alkynes in the presence of an amine. Since both unsymmetrical and symmetrical diacetylenes are of considerable interest due to their pharmaceutical, biological and synthetic applications, novel developments in the field of the Cadiot–Chodkiewicz reaction are of great importance. C(sp)–C(sp) coupling plays a central role in the total synthesis of many natural products and polyynes. This review is devoted to the new protocols and applications of the Cadiot–Chodkiewicz cross-coupling reaction that have been developed recently (2015–2019).

The Stille coupling between organostannanes and organohalides is an effective catalytic method for organic synthesis. Despite the ample amount of published results in this area, finding the optimal conditions for this transformation is often not straightforward. It was observed that this reaction could be accelerated with improved efficiency by the addition of a Cu(i) salt and fluoride. This review summarises the application of this simple protocol in the synthesis of natural products, their analogues and other biologically active molecules, from 2004 to 2018.

An easily accessible isospiropyran switch by Taylor A. Neal; Jennifer F. Neal; Allyson B. Eippert; Curtis Moore; Heather C. Allen; Jovica D. Badjić (9124-9128).
In the presence of SiCl4, three molecules of 5′-bromo-2′-hydroxyacetophenone underwent an unexpected tandem aldol condensation to give a novel isospiropyran switch (69%), with X-ray crystallography confirming its structure. The strong Brønsted acid CH3SO3H turned the colorless isospiropyran into its protonated and open form possessing red color. This process was reversed using the Et3N base, with the acid/base toggling repeatable for at least six times (UV-Vis). When printed on a silica plate, however, the isospiropyran formed a blue-colored product due to, as posited, its stabilization by hydrogen bonding (HB) to silica. An exposure to HB-competing ethyl acetate temporarily “erased” the print only to be brought back by subjecting the plate to a higher temperature for evaporating the solvent. The isospiropyran described here is an easily accessible, chromic, modular and switchable compound that one can incorporate into dynamic materials or use for building chemosensors, molecular machines and organic electronic devices.

A synthesis method of doubly linked flavan dimers is reported via the acid-promoted annulation reaction using nascent catechins, (+)-catechin or (−)-epicatechin, as a dianionic partner and an ethylenedioxy-bridged flavan as a dicationic partner. Procyanidins A1 and A2 were synthesized. On the high regioselectivity of the annulation reactions, model experiments and computational studies were carried out.

Vinyl cations exhibit remarkable reactivity towards arene C–H functionalizations. This computational study revealed the key mechanistic details of intramolecular C–H vinylation through a vinyl cation intermediate. Based on the reaction mechanism, the effects of substitution, ring strain and tether length on the reactivity of the vinyl cation were elucidated.

An efficient and convenient synthesis of diversely substituted naphtho[1′,2′:4,5]imidazo[1,2-a]-pyridine derivatives from the cascade reactions of 2-arylimidazo[1,2-a]pyridines with a-diazo carbonyl compounds via Rh(iii)-catalyzed regioselective C(sp2)–H alkylation followed by intramolecular annulation is presented. Interestingly, when simple 2-arylimidazo[1,2-a]pyridines were used as the substrates, 5,6-disubstituted naphtho[1′,2′:4,5]imidazo[1,2-a]pyridines were efficiently obtained, whereas using 2-arylimidazo[1,2-a]pyridine-3-carbaldehydes as the substrates afforded naphtho[1′,2′:4,5]imidazo[1,2-a]-pyridine-5-carboxylates as the dominating products. Compared with literature methods for the synthesis of naphtho[1′,2′:4,5]imidazo[1,2-a]pyridine derivatives, the protocol presented herein has advantages such as easily obtainable substrates, simple operational procedure, high efficiency and excellent regio- and chemoselectivity.

Phosphonium ylides are being reported here as a catalyst for the formation of thiazolidines and 1,3-thiazinanes from β-ketothioamides (which act as a three atom N, C, and S synthon) with dihaloalkanes via [3 + 2] and [3 + 3] annulations under metal-free conditions. An N,C,S-centred chemoselective dihaloalkane-controlled cascade process has been identified for the preparation of cyclic N,S-heterocycles (thiazolidines and 1,3-thiazinanes) from identical β-ketothioamides. The reaction proceeds via consecutive sulfur and nitrogen nucleophilic attack of the thioamide on dihaloalkanes enabling the formation of S–C and N–C bonds. The ring size of the skeletally distinct N,S-heterocycles has been efficiently tuned by switching the use of 1,2- and 1,3-dihaloalkanes as α,β- and α,γ-dielectrophiles. It is noteworthy that the products possess Z-stereochemistry with regard to the exocyclic CC double bond at the 2-position of the ring, revealing exclusive diastereoselectivity. Since phosphorus ylides have found limited use as catalysts, control experiments revealed their behaviour as a catalyst, which not only increase the catalyst tool box, but also would contribute to the field of ylide chemistry.

A three-component approach to isoxazolines and isoxazoles under metal-free conditions by Dahan Wang; Feng Zhang; Fuhong Xiao; Guo-Jun Deng (9163-9168).
A 1,3-dipolar cycloaddition of 2-methylquinoline, tert-butyl nitrite (TBN) and alkynes or alkenes for the synthesis of biheteroaryls containing both isoxazoline/isoxazole and quinoline motifs has been developed. In this protocol, TBN serves as a convenient N–O source to convert 2-methylquinoline into intermediate nitrile oxides in situ.

The Mukaiyama type aldol reaction for the synthesis of trans-2,6-disubstituted tetrahydropyrans: synthesis of diospongin A and B by Yada Bharath; Utkal Mani Choudhury; N. Sadhana; Debendra K. Mohapatra (9169-9181).
An efficient synthesis protocol for the preparation of trans-2,6-disubstituted tetrahydropyrans by the reaction of 1-phenyl-1-triemthylsiloxyethylene with six membered cyclic hemiacetals in the presence of iodine is developed. This reaction proceeds smoothly under mild conditions employing a catalytic amount of molecular iodine. The feature of this novel conversion includes milder reaction conditions, broader substrate scope, functional group tolerance and good diastereoselectivity. The efficiency and practicality of the current method were successfully displayed in the total synthesis of diospongin A and B in good yields.

A mild and efficient route to prepare nitriles from aldehydes by combining photoredox catalysis with oxoammonium cations is reported. The reaction is performed using ammonium carbamate as the nitrogen source. The practicality of the method is increased by the extension of the dual catalytic system to one-pot two-step conversion of alcohols to nitriles.

Facile synthesis of N-1,2,4-oxadiazole substituted sulfoximines from N-cyano sulfoximines by Chenna Reddy M. L.; Fazlur Rahman Nawaz Khan; Vadivelu Saravanan (9187-9199).
A divergent approach has been successfully developed for the synthesis of N-1,2,4-oxadiazole substituted sulfoximines starting from N-cyano sulfoximines. This method has a wide degree of substrate scope that includes aryl, heteroaryl, alkyl, fluoroalkyl and saturated heterocyclic compounds. Excellent functional group tolerability was also observed. Extension of this methodology to nucleosides, amino acids and dipeptides was found to be successful. A gram scale reaction was also established. The major part of this method is metal free and the utility of environmentally friendly solvents such as 2-methyl THF and ionic liquids is an added advantage.

A highly efficient domino aza-MIRC (Michael Induced Ring Closure) reaction between barbiturate-derived alkenes and N-alkoxy α-haloamides has been achieved in moderate to excellent yields. This reaction proceeds smoothly under mild conditions via a domino aza-Michael addition/intramolecular SN2 sequence, providing a practical tool in the synthesis of bioactive molecules spirobarbiturate-3-pyrrolidinones.

Palladium-catalyzed direct C2-arylation of azoles with aromatic triazenes by Can Liu; Zhiming Wang; Lei Wang; Pinhua Li; Yicheng Zhang (9209-9216).
A highly efficient palladium-catalyzed arylation of azoles at the C2-position using 1-aryltriazenes as aryl reagents was developed. Azoles including oxazoles, thiazoles, imidazoles, 1,3,4-oxadiazoles, and oxazolines could react with 1-aryltriazenes smoothly to generate the corresponding products in good to excellent yields, and various substitution patterns were tolerated toward the reaction.

Enantio- and diastereoselective synthesis of spiropyrazolones via an organocatalytic [1 + 2 + 3] multicomponent reaction by Yan-Ling Ji; He-Ping Li; Yue-Yan Ai; Guo Li; Xiang-Hong He; Wei Huang; Rui-Zhen Huang; Bo Han (9217-9225).
An asymmetric catalytic multicomponent reaction of malononitrile, benzaldehyde, and α-arylidene pyrazolinones to produce spiropyrazolones has been reported. The [1 + 2 + 3] multicomponent reaction was catalyzed by chiral cinchona alkaloids to provide spiropyrazolones in high yields, with excellent enantioselectivities and good diastereoselectivities. We also performed control experiments and proposed a plausible catalytic cycle based on the observed experimental results to explain the reaction process and stereoselectivity of the asymmetric multicomponent reaction.

Here we report the design, single crystal conformations, impact of the substituents and structural differences of two structurally important motifs, β-sheets and β-double helices. Though β-sheets are common structural motifs in protein structures, β-double helices are not common in proteins and peptides. We found that both β-sheet mimetics and β-double helices can be constructed from the homooligomers of α,β-unsaturated γ-amino acids. Results suggested that introducing gem-dialkyl substitutions at the γ-carbon of the homooligomer of α,β-unsaturated γ-amino acids resulted in the β-double helix conformation, while the same oligomer with monosubstitution at the γ-carbon displayed a β-sheet structure.

The mechanism and structure–activity relationship of amide bond formation by silane derivatives: a computational study by Ben Hu; Yuan-Ye Jiang; Peng Liu; Rui-Xue Zhang; Qi Zhang; Tian-Tian Liu; Siwei Bi (9232-9242).
The condensation of carboxylic acids and amines mediated by silane derivatives provided a straightforward and sustainable method for amide bond formation with minimal waste. However, the detailed mechanism and structure–activity relationship of substrates, the topics that are of interest for both academic and industrial applications, were not clear. Herein, a systematic computational study was conducted to solve the two questions. We found that the two previously proposed mechanisms involving intramolecular acyl transfer or silanolate were less likely because the associated silanone intermediate and zwitterion adducts were too unstable with higher overall energy barriers. By comparison, the mechanism involving deprotonation of carboxylic acids, addition of carboxylates on silane reagents, dihydrogen formation to afford an acyloxysilane intermediate, carboxylic-acid-assisted addition of amines, and concerted proton transfer/amide formation, was found to be more favorable with overall energy barriers varying between 24 and 28 kcal mol−1 for the different calculated cases. Meanwhile, the dihydrogen formation and amide formation processes are both potential rate-determining steps. Energy composition, atomic charge, and distortion–interaction analyses indicated that the steric effect of silane reagents was more important than the electronic effect, making less bulky silane reagents more reactive. On the other hand, the dihydrogen formation process was mainly controlled by the electronic effect of the substituents of carboxylic acids and amines while the amide formation process was mainly influenced by their steric effect. As a result, less bulky, less acidic alkyl carboxylic acids are more reactive than unsaturated carboxylic acids, and less bulky, medium basic primary alkyl amines are more reactive than secondary alkyl amines and primary aryl amines. The related results provided deeper mechanistic insights into the amide bond formation mediated by silane derivatives and can act as a reference for further experimental design.

Understanding the effects of solvate ionic liquids as solvents on substitution processes by Karin S. Schaffarczyk McHale; Michaela J. Wong; Alicia K. Evans; Alyssa Gilbert; Ronald S. Haines; Jason B. Harper (9243-9250).
The effects of solvate ionic liquids as solvents have been considered for two substitution processes where the solvent effects of typical ionic liquids have been extensively investigated previously; the bimolecular nucleophilic substitution (SN2) reaction between pyridine and benzyl bromide and the nucleophilic aromatic substitution (SNAr) reaction between ethanol and 1-fluoro-2,4-dinitrobenzene. It was found that use of solvate ionic liquids gave rise to similar trends in the activation parameters for both substitution processes as typical ionic liquids, implying the microscopic interactions responsible for the effects were the same. However, different effects on the rate constants compared to typical ionic liquids were observed due to the changes in the balance of enthalpic and entropic contributions to the observed rate constants. From these data it is clear that the reaction outcome for both of these substitution reactions fall within the ‘predictive framework’ established in previous studies with a cautionary tale or two of their own to add to the general knowledge of ionic liquid solvent effects for these processes, particularly with respect to potential reactivity of the solvate ionic liquids themselves.

Thiophenol detection using an AIE fluorescent probe through self-assembly with TPE-based glycoclusters by Lei Dong; Guo-Rong Chen; Xiao-Peng He; Sébastien Vidal (9251-9256).
We describe a novel green-emitting tetraphenylethylene-dicyanomethylene-4H-pyran (TPE-DCM) based fluorescent probe (TD-1). Conjugating TPE and DCM moieties allowed TD-1 to display high selectivity for thiophenol with excellent AIE properties in aqueous solution. Nevertheless, the poor water solubility of the hydrophobic structure resulted in a weak and unstable emission intensity. The non-covalent self-assembly of TD-1 with a TPE glycocluster (TPE2S) led to a largely improved water solubility producing a reliable and stable sensing system. The corresponding glyco-probe could sensitively detect exogenous thiophenol concentrations in PBS buffer or environmental water samples.

Back cover (9257-9258).