All-carbon N-heterocyclic Carbene-catalyzed (3+2) Annulation using Donor-Acceptor Cyclopropanes

Donor-acceptor cyclopropanes are known to serve as dipole precursors capable of engaging in (3+2) annulations with electron-deficient π-systems. In 2013, the reaction of donor-acceptor cyclopropanes with α,β-unsaturated acyl fluorides in an all-carbon (3+2) annulation was discovered. The reaction proceeds in good yields using the IMes NHC to provide diastereomerically pure β-lactone-fused cyclopentanes bearing four contiguous stereocentres. Subsequent studies demonstrated that N-t-butyl substituted homochiral morpholinone NHCs allowed the reaction to be achieved in up to 98 % ee. In this account, a background to this reaction is introduced, along with a complete account of the strengths, limitations and challenges encountered while developing this chemistry.     

Lewis Acid‐Catalyzed [3+4] Annulation of 2‐(Heteroaryl)‐ cyclopropane‐1,1‐dicarboxylates with Cyclopentadiene

A novel Lewis acid‐catalyzed [3+4] annulation of 2‐(heteroaryl)cyclopropane‐1,1‐dicarboxylates with cyclopentadiene is reported. This reaction proceeds via an electrophilic attack of the Lewis acid‐activated donor‐acceptor cyclopropane onto cyclopentadiene followed by Friedel–Crafts intramolecular alkylation of the heteroarene substituent. This is the first general example of reactions of donor‐acceptor cyclopropanes wherein the donor substituent serves as a nucleophile. The described annulation represents a convenient approach to bicyclo[3.2.1]octa‐2,6‐dienes with heteroarenes annulated to C(2)‐C(3) bond. Its efficiency was demonstrated for a series of furyl, thienyl, pyrrolyl, benzofuryl, benzothienyl, and indolyl substituted cyclopropanes. Additionally, in the case of 2‐(5‐methyl‐2‐furyl)cyclopropane‐1,1‐diester we observed the predominant formation of product of the [3+4] annulation or the tetracyclic 5,8‐methanocyclopenta[a]azulene derivative, depending on the reaction conditions.     

Reactivity of Donor-Acceptor Cyclopropanes with Saturated and Unsaturated Heterocyclic Compounds

Strain in the ring engenders versatile reactivity that can be utilized for the synthesis of complex molecules by the assimilation of suitable substituents. In this context, vicinal donor-acceptor cyclopropanes (DACs) serve as three-carbon synthetic equivalents in organic synthesis from the last few decades. Owing to their zwitterionic nature, they have been frequently utilized in [3+n]-annulation reactions with different dipolarophiles like aldehydes, imines, oximes, epoxides, aziridines, etc. This review highlights developed synthetic tools for annulation reactions of vicinal donor-acceptor cyclopropanes with saturated and unsaturated heterocyclic compounds.     

Efficient approaches to the stereoselective synthesis of cyclopropyl alcohols

Cyclopropanes occur in a diverse array of natural products, including pheromones, steroids, terpenes, fatty acid metabolites, and amino acids, and compounds that contain cyclopropanes exhibit interesting and important pharmacological properties. These valuable synthetic intermediates can be functionalized, or their rings can be opened, and the synthetic utility and unique biological activity of cyclopropanes have inspired many investigations into their preparation. One of the most powerful methods to generate cyclopropanes is the Simmons-Smith cyclopropanation. Since the original studies in the late 1950s reported that IZnCH(2)I could transform alkenes into cyclopropanes, researchers have introduced various modifications of the original procedure. Significantly, Furukawa demonstrated that diethylzinc and CH(2)I(2) react to generate carbenoids, and Shi described more reactive zinc carbenoids that contain electron-withdrawing groups on zinc (XZnCHI(2)). Despite these advances, the development of catalytic asymmetric Simmons-Smith reactions remains challenging. Although researchers have achieved catalytic asymmetric cyclopropanation of allylic alcohols, these reactions have had limited success. One attractive approach to the synthesis of cyclopropanes involves tandem reactions, where researchers carry out sequential synthetic transformations without the isolation or purification of intermediates. Such a synthetic strategy minimizes difficulties in the handling and purification of reactive intermediates and maximizes yields and the generation of molecular complexity. This Account summarizes our recent effort in the one-pot enantio- and diastereoselective synthesis of cyclopropyl alcohols. In one approach, an asymmetric alkyl addition to α,β-unsaturated aldehydes or asymmetric vinylation of aliphatic or aromatic aldehydes generates allylic zinc alkoxide intermediates. Directed diastereoselective cyclopropanation of the resulting alkoxide intermediates using in situ generated zinc carbenoids provides cyclopropyl or halocyclopropyl alcohols with high enantio-, diastereo-, and chemoselectivity. Other strategies employ bimetallic reagents such as 1-alkenyl-1,1-heterobimetallics or CH(2)(ZnI)(2) and provide access to di- and trisubstituted cyclopropyl alcohols. These methods enable facile access to skeletally diverse chiral cyclopropyl alcohols in high yields and stereoselectivities without the isolation or purification of the intermediates.     

Au(I)-Catalyzed Annulation of Propargyl Amine with Aldehydes: One-Pot Cascade Synthesis of 2,5-Dimethylpyrazines

3-Substituted 2,5-dimethylpyrazines were synthesized in high yields via a one-pot cascade annulation of easily available propargyl amine with aldehydes catalyzed by Au(PPh₂Cy)Cl.     

3,5-二甲基苯酚合成工艺改进

以乙酰乙酸乙酯和乙醛为起始原料，以碳酸钠作为碱，经过Robinson环合反应得到4-乙氧羰基-3,5-二甲基-2-环己烯-1-酮，收率为95 %。对碳酸钠体系催化的Robinson环合反应进行应用拓广，在该体系催化下，脂肪醛和芳香醛底物均可顺利转化为相应二取代环己烯酮产物。环合产物4-乙氧羰基-3,5-二甲基-2-环己烯-1-酮经皂化脱羧过程可定量转化为关键中间体3,5-二甲基-2-环己烯酮，收率为99 %。将3,5-二甲基-2-环己烯酮直接脱氢芳构化，得到了目标产物3,5-二甲基苯酚。采用1HNMR和13CNMR对产物及中间体结构进行了表征。本文建立的工艺条件下，3,5-二甲基苯酚的总收率为66 %。该工艺也应用于3-甲基-5-丙基苯酚的合成，具有一定的普适性。     

Synthesis of 2,5-diaroyl-3-arylthiophenes: novel tandem reactions mediated 3+2-self annulation of bis(aroylmethyl) sulfides

A series of 2,5-diaroyl-3-arylthiophenes were obtained from the 3+2-self annulation of bis(aroylmethyl) sulfides in the presence of sodium hydroxide. This transformation occurs presumably via a tandem intermolecular condensation - ring closing intramolecular displacement-aromatization via air oxidation and elimination sequence.     

Asymmetric Ring-Opening Reactions of Donor-Acceptor Cyclopropanes and Cyclobutanes

Donor-acceptor (DA) cyclopropanes are particularly useful synthetic building blocks, which have been widely applied in the total synthesis of natural products and important chiral molecules in organic synthesis. The asymmetric ring-opening reactions of racemic DA cyclopropanes and cyclobutanes, for example, aryl-substituted 1,1-cyclopropane diesters and aryl-substituted 1,1-cyclobutane diesters, with nucleophiles provides versatile access to optically active γ- and δ-functionalized carbon skeletons, as well as the kinetic resolution of racemic DA cyclopropanes, which are useful chiral skeletons in organic synthesis. Recently, we have developed a series of highly enantioselective ring-opening and annulation reactions of DA cyclopropanes and cyclobutanes with various nucleophiles, such as amines, alcohols, nitrones, azomethine imines, enol silyl ethers, and indoles, by employing nickel and copper catalysts with TOX and SaBOX as ligands. The reactions worked smoothly with excellent diastereoselectivities and enantioselectivities (up to >99/1 dr and up to 99 % ee) over broad substrate scopes.     

Mg(II)-Catalyzed [4+2] Annulation for the Synthesis of 2-Arylquinoline Motifs: Applications and DFT Studies

Mg-catalyzed [4+2] cycloaddition reactions between 2-aminobenzaldehydes and ynones offered an array of 2-arylquinoline motifs merged with a CF₃-acyl group. Furthermore, with Mg-catalyzed [4+2] annulation as the key step, DDD107498, DDD102542, and Hit analogues were assembled. Finally, a computational study of the reaction mechanism was conducted.     

TiO_2负载磷钨酸催化合成1,4-丁二醇双琥珀酸十八醇双酯磺酸钠

采用1,4-丁二醇、马来酸酐、十八醇为主要原料,合成出一种双子表面活性剂1,4-丁二醇双琥珀酸十八醇双酯磺酸钠.此化合物的合成由两步酯化以及一步磺化反应组成,双酯化反应采用TiO_2负载磷钨酸(PW_)12)/TiO_2)为催化剂.通过正交实验确定了1,4-丁二醇双马来酸十八醇双酯合成的优化反应条件为:n(1,4-丁二醇双马来酸单酯)∶n(十八醇)=1.00∶2.20,催化剂用量ω(PW_(12)/TiO_2)=1.5%,反应温度150 ℃,反应8 h,酯化率达到95.8%,产率为82.4%.通过正交实验确定了磺化反应的优化条件为:双酯与NaHSO_3物质的量比1.00∶3.00;反应4 h;反应温度90 ℃;催化剂(CTAB)用量1.5%,磺化率达到92.7%,产率为74.9%.     

The Annulation of Nitrones and Donor-Acceptor Cyclopropanes: A Personal Account of our Adventures to Date

This review is an account of our work in the development of the annulation reaction between nitrones and donor-acceptor cyclopropanes. Methods development, mechanistic studies, and applications to total synthesis are discussed.     

N‐Heterocyclic Carbene‐Catalyzed Enantioselective Annulation of Bromoenal and 1,3‐Dicarbonyl Compounds

Highly enantioselective [3+3] annulation reactions of bromoenals and 1,3‐dicarbonyl compounds are reported. In addition, both enantiomers of the resultant dihydropyranone could be easily obtained by choosing N‐heterocyclic carbenes (NHCs) with the same stereocenter but different substituents under the optimized reaction conditions.     

The Development of the Asymmetric Nozaki–Hiyama–Kishi Reaction

This review collates the literature to date on the development of the Nozaki–Hiyama–Kishi (NHK) reaction into an important chromium‐mediated, carbon‐carbon bond forming process. The initial research employed stoichiometric quantities of chromium and this was exploited in the key steps of a range of total syntheses. Thereafter, the NHK reaction was further developed with the discovery of the catalytic variant. The focus of recent investigations is on the application of this reaction in asymmetric synthesis. The asymmetric NHK typically employed a range of salen‐ and oxazoline‐derived chiral ligands and tethered bis(8‐quinolinato)‐chromium complexes. To date, good to high enantioselectivities have been obtained in a variety of NHK‐type processes, including allylation, crotylation, methallylation, allenylation, propargylation and vinylation of a range of aldehydes, with limited examples employing ketones as substrates. Selected examples of the asymmetric NHK in total synthesis will also be described.     

Oxime‐Derived Palladium Complexes as Very Efficient Catalysts for the Heck–Mizoroki Reaction

Oxime‐derived, chloro‐bridged palladacycles 16 are efficient complexes for the Heck vinylation of aryl halides. The isolated catalysts are thermally stable, not sensitive to air or moisture and easily accessible from inexpensive starting materials. The reaction can be performed under aerobic conditions, with aryl iodides, bromides and chlorides with acrylic esters and olefins displaying turnover numbers (TON) of up to 10¹⁰ for phenyl iodide and turnover frequencies (TOF) of 1.4×10⁸ h⁻¹. Deactivated aryl bromides undergo the Heck reaction with styrene with TON and TOF values up to 97,000 and 6063 h⁻¹, respectively. Even aryl chlorides undergo the coupling reaction with olefins with TON up to 920. Complexes 16 catalyze the synthesis of 2,3‐disubstituted indenones and indoles in good yields via annulation reaction of internal alkynes with o‐bromo‐ or o‐chlorobenzaldehyde and o‐iodoaniline, respectively.     

Ylide-initiated michael addition-cyclization reactions beyond cyclopropanes

[Reaction: see text]. Ylides are nucleophiles that bear a unique leaving group, L n M, and can attack aldehydes, ketones, imines, and electron-deficient alkenes. Over the course of the reaction, they react with CX (X = C, N, O, etc.) double bonds to form betaine or oxetane intermediates, which further eliminate the heteroatom-containing group in one of two ways to give the corresponding olefination or cyclization product. Since the discovery of the Wittig reaction, ylide olefination has developed as one of the most useful approaches in constructing carbon-carbon double bonds. These reactions provide unambiguous positioning of the C-C double bond and good stereoselectivity. Researchers have also widely used ylides for the synthesis of small ring compounds such as epoxides, cyclopropanes, and aziridines. However, the use of ylides to prepare larger cyclic structures was very limited. This Account outlines our recent work on ylide-initiated Michael addition/cyclization reactions. By altering the heteroatoms and the ligands of the ylides, we have modulated the reactivity of ylides. These modified ylides provide easy access to diverse cyclic compounds with the ability to control regioselectivity, chemoselectivity, diastereoselectivity, and enantioselectivity. Reactions using these ylides produce the structural components of many biologically active compounds and valuable intermediates in organic synthesis. Allylic telluronium and sulfonium ylides can react with alpha,beta-unsaturated esters, ketones, amides, and nitriles to afford multisubstituted vinylcyclopropanes with high selectivities. Telluronium allylides react with aromatic N-phenyl aldimines to give trans-vinylaziridines and with chiral N- tert-butylsulfinylimines to afford the optically active cis-2-substituted vinylaziridines, both with high diastereoselectivities. We also used sulfonium and telluronium allylides to prepare vinylepoxides. In addition, ylides are good reagents for the synthesis of five-membered heterocyclic compounds. By treatment of stable camphor-derived sulfur ylides with alpha-ylidene-beta-diketones, we obtained multisubstituted dihydrofurans with high diastereo- and enantioselectivities. Ammonium salts derived from cinchonidine and cinchonine react smoothly with 3-aryl and 3-heteroaryl-2-nitro acrylates, affording both enantiomers of isoxazoline N-oxides with up to 99% ee. Ylides can initiate tandem cyclizations for the synthesis of chromenes, bicyclic compounds, and cyclohexadiene epoxides. Varying the choice of base allows access to 2 H-chromenes and 4 H-chromenes from 3-(2-(bromomethyl)phenoxy)acrylates via a tandem ylide Michael addition/elimination/substitution reaction. Phosphines can catalyze an intramolecular ylide [3 + 2] annulation constructing bicyclo[ n.3.0] ring systems with three contiguous stereogenic centers. The reaction of crotonate-derived sulfur ylides with alpha,beta-unsaturated ketones affords cyclohexadiene epoxides with excellent diastereoselectivities (>99/1) in good to high yields. Using a camphor-derived sulfonium salt, we have produced asymmetric cyclohexadiene epoxides with high ee's. Overall, these results illustrate the versatility and tunability of ylides for the preparation of cyclic systems containing more than three atoms.     

SiO_2负载磷钨酸催化合成1,4-丁二醇双琥珀酸十八醇双酯磺酸钠

采用1,4-丁二醇、马来酸酐、十八醇为主要原料,合成出一种双子表面活性剂1,4-丁二醇双琥珀酸十八醇双酯磺酸钠。此化合物的合成由两步酯化以及一步磺化反应组成,双酯化反应采用SiO2负载磷钨酸(PW12/SiO2)为催化剂。通过正交实验确定了1,4-丁二醇双马来酸十八醇双酯合成的优化反应条件为:n(1,4-丁二醇双马来酸单酯):n(十八醇)=1.00:2.20,催化剂用量1.5%,反应温度150℃,反应8h,酯化率达到97.2%,产率为84.9%。磺化反应的条件为:n(1,4-丁二醇双马来酸双酯):n(NaHSO3)=1.00:3.00;反应4h;反应温度90℃;催化剂(CTAB)用量1.5%,磺化率达到92.7%,产率为74.9%。在25℃水溶液中测得该表面活性剂的表面张力γcmc为41.9mN/m,CMC为7.2×10-5mol/L。表明该表面活性剂具有很低的临界胶束浓度。     

Total Synthesis of Capsaicin Analogues from Lignin‐Derived Compounds by Combined Heterogeneous Metal,Organocatalytic and Enzymatic Cascades in One Pot

The total synthesis of capsaicin analogues was performed in one pot, starting from compounds that can be derived from lignin. Heterogeneous palladium nanoparticles were used to oxidise alcohols to aldehydes, which were further converted to amines by an enzyme cascade system, including an amine transaminase. It was shown that the palladium catalyst and the enzyme cascade system could be successfully combined in the same pot for conversion of alcohols to amines without any purification of intermediates. The intermediate vanillylamine, prepared with the enzyme cascade system, could be further converted to capsaicin analogues without any purification using either fatty acids and a lipase, or Schotten–Baumann conditions, in the same pot. An aldol compound (a simple lignin model) could also be used as starting material for the synthesis of capsaicin analogues. Using L ‐alanine as organocatalyst, vanillin could be obtained by a retro‐aldol reaction. This could be combined with the enzyme cascade system to convert the aldol compound to vanillylamine in a one‐step one‐pot reaction.

     

Preparation and some Reactions of 4-Phenyl-6-(2-thienyl)-2(1H)-pyridone Derivatives

Michael condensation of benzal-α-acetothienone 1 with ethyl cyanoacetate, cyanoacetamide and acetoacetamide led to the 2(1H)-pyridone derivatives 2 and 3 . Compound 2 was condensed with aldehydes, and compound 3 with ethyl acetate, to yield the chalcone analogues 4 and the diketone 7 , respectively. By action of phenylhydrazine and hydroxylamine on 4 and 7 , the corresponding pyrazole and isoxazole derivatives 5 , 6 and 9 were obtained. Reaction of urea and thiourea with 1 gave the dihydropyrimidine derivatives 10 and 11 , respectively.     

Synthetic Applications of Carbohydrate-derived Donor-Acceptor Cyclopropanes

In this account, we elaborate our group's contribution towards understanding the chemistry of carbohydrate-derived donor-acceptor (DA) cyclopropanes. Our work was mainly focused on the ring opening of these versatile chiral synthons under the influence of Lewis acid promoters like electrophilic halogen species, TMSOTf, BF₃.OEt₂, etc. We studied various modes of ring opening on these DA cyclopropanes, envisaging the access to intriguing molecular architectures. These modes of reaction of the DA cyclopropanes can be controlled by strategically introducing an electron-withdrawing group (EWG) onto the cyclopropane ring, which could direct the ring cleavage by polarizing the cyclopropane C−C bond. Our studies also revealed that the ring opening is sluggish in the absence of an EWG. Using this concept, we demonstrated the synthesis of various biologically interesting molecular skeletons, viz., glycoamino acids (GAA), GAA nucleotides, α-levoglucosan amino acid, and septano-oligosaccharides, with high selectivity. We also applied our understanding to the first stereoselective synthesis of (S)-(−)-longianone and confirmed its absolute configuration. Apart from the inherently activated DA cyclopropanes, we introduced the in situ generation of DA cyclopropanes, starting from vinylcyclopropanes (VCPs). The ring-opening and ring-expansion chemistry of these easily accessible synthons was studied. The chemistry developed for carbohydrate-fused cyclopropanes was also applied for carbohydrate-derived spiro-cyclopropanes. The Lewis-acid-mediated ring opening of spiro-DA-cyclopropanes enabled easy access to fused furopyrans and spirolactones.     

Mannich reaction catalyzed by a novel catalyst under solvent-free conditions

An acidic catalyst [Py][CF₃COO] (pyridinium trifluoroacetate) was synthesized and used in the Mannich reaction of various kinds of aromatic aldehydes, aromatic ketones and aromatic amines. β-Amino carbonyl compounds were obtained in reasonable yields when the Mannich reaction was carried out at room temperature under solvent-free conditions. The products could be separated from the catalyst simply via washing with water and after removing water, the catalyst could be recycled and reused for up to four times without noticeably decreasing in catalytic activity.