Synthesis of 1,4-disilacyclohexa-2,5-dienes

Title compounds of the type 2,3,5,6-tetraphenyl-1,4-di-X-1,4-di-Y-1,4-disilacyclohexa-2,5-diene wherein X=Y=NMe₂ (4); X=NMe₂, Y=Cl (cis, trans-5); X=NMe₂, Y=Me [(trans)-6] and X=t-Bu, Y=Cl (trans-8) were synthesized from Si₂(NMe₂)₅Cl, sym-Si₂(NMe₂)₄Cl₂, sym-Si₂(NMe₂)₄Me₂, and sym-Si₂Cl₄(t-Bu)₂, respectively, in the presence of diphenylacetylene at 200 °C. Similarly the analogous title compound from the combination of 1-phenyl-1-propyne and Si₂(NMe₂)₅Cl [X=Y=NMe₂ (cis and trans-7) was synthesized. In all cases where cis/trans diastereomers could arise from two different silicon substituents (5, 6, 8) the trans isomer was the sole or dominant product. Evidence for the intermediacy of the silylene Si(NMe₂)₂ in these reactions was gained from a trapping experiment. Compound 4 upon treatment with SiCl₄, SiBr₄ or PI₃ provided the corresponding 1,1,4,4-tetrahalo derivatives 9a-c, respectively. Treatment of 4 with MeOH or PhOH gave the 1,1,4,4-tetramethoxy and tetraphenoxy analogues 9d and 9e, respectively. The tetrachloro derivative 9a upon LAH reduction led to the corresponding tetrahydro compound 10, while the reaction of 9a with H₂O gave the tetrahydroxy derivative 11. Allowing (trans)-6 to react with SiCl₄ provided a ca. 1:1 cis/trans ratio of the derivative 12 in which X=Cl, Y=Me, and possible pathways that rationalize this loss of stereochemistry are proposed. Synthesis of trans-13 in which X=t-Bu, Y=H was achieved by LAH reduction of 8. All of the title compounds except 8 experience free phenyl rotation at room temperature. At −30 °C this rotation in 8 is essentially halted. The molecular structures of 4, 8, 9c, 9e, 10 and 13 were determined by X-ray crystallography.     

Revision of the stereochemistry of the reductive Heck cyclisation of 1-(2-iodobenzoyl)-4-substituted-1.4-dihydro-pyridine-3-carbaldehyde aminals

The stereochemistry of reductive and non reductive Heck cyclisations of 4-substituted-1.4-dihydropyridines is reexamined. The both reactions occur mainly via an anti (from the C₄ substituent) 5-exo process without any epimerisation of the C₄-H.     

Cover Picture: Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates (Chem. Eur. J. 13/2009)

In Buddhist imagery the gestures of the hand are very significant, which reflects the themes of asymmetry and chirality (derived from the word “hand”) found in the Full Paper by K. A. Jørgensen et al. on page 3093 ff. The professor is shown as a Buddha‐like image and is gesturing down with one hand and making the Buddhist gesture for “method and wisdom” with the other. Dice tumbling from his hand represent the organocatalytic Michael–Knoevenagel condensation domino reaction discussed in the paper, with the front die representing the cyclohexenone center of the molecule being formed. The two students standing by are making Buddhist gestures for “accomplishment” and “meditation”. Artwork by cartoonist Jorge Cham, http://www.phdcomics.com.

     

Cover Picture: Total Synthesis and Absolute Configuration of the Bisanthraquinone Antibiotic BE‐43472B (Angew. Chem. Int. Ed. 19/2009)

A cascade sequence featuring a Diels–Alder reaction, a lactolization, and an S_N(Ar)‐type substitution forms the core of the bisanthraquinone antibiotic BE‐43472B in its first total synthesis, which K. C. Nicolaou et al. describe in their Communication on page 3444 ff. The background of the cover picture is a photograph of Ecteinascidia turbinata (courtesy of John Easley Photography), the marine source of the streptomyces strain producing this antibiotic.

     

cis- and trans-N-(Benzylsulfinyl)hexahydrobenzoxazolidin-2-ones as novel chiral sulfinyl transfer reagents

The synthesis of N-benzylsulfinyl derivatives 5a–d from both pairs of enantiomeric hexahydrobenzoxazolidin-2-ones 4a–d is reported. The use of 5a–d as effective chiral sulfinylating reagents in the preparation of enantiopure sulfoxides (e.e.>98%) is also reported.     

Synthesis of Some Pyridothienopyrazolopyrimidopyrimidine and Mercaptomethylpyrazolopyrimidine Derivatives

Mercaptomethylpyrazolopyrimidine (2) was synthesized and reacted with ethyl chloroacetate to afford ethyl pyrazolpyrimidinylmethylmercapto acetate ( 3) , which in turn was converted into the corresponding carbohydrazide 4 . Carbohydrazide 4 reacts with a variety of reagents to give different pyrazolopyrimidines ( 5–12 ). Chloromethyl-pyrazolopyrimidine (1) reacts with chloropyridine to give compound 13 , which was subjected in a series of reactions to give new compounds 14–20 .     

Facile Synthesis and Crystal Structure of a Novel Cyanopyridine

The title compound 2-amino-4-(4-hydroxy-3,5-dimethoxyphenyl)-5-methyl-6-phenyl nicotinonitrile,C 21 H 19 N 3 O 3,was synthesized via four-component reactions between propio-phenone,malononitrile,syringaldehyde and ammonium acetate in ethanol under reflux without catalyst and characterized by IR,1 H NMR,13 C NMR,MS,EA and single-crystal X-ray diffraction.Single-crystal X-ray diffraction analysis shows that the compound is of monoclinic system,space group P2 1 /n with a=8.4600(17),b=17.139(3),c=13.408(3),β=107.06(3)°,V=1858.6(6)3,Z=4,M r=361.39,F(000)=760,μ(MoKα)=0.088 mm-1,D c=1.292 g/cm 3,λ=0.71073,the final R=0.0751 and wR=0.0938 for 3333 observed reflections with I > 2σ(I).The crystal packing of the title compound is stabilized by intermolecular hydrogen bonds.     

Functionalized Templates for the Convergent Assembly of Polyethers: Synthesis of the HIJK Rings of Gymnocin A

Extension ladder : The successful application of epoxide‐opening strategies towards the synthesis of ladder‐type polyethers is contingent upon further elaboration of the product. By employing two different functionalized templates, a fragment of gymnocin A that bears four sites for subsequent fragment coupling has been prepared (see scheme; Bn=benzyl).

     

Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates

Versatile dominoes : A novel, organocatalytic, Michael–Knoevenagel condensation domino reaction of ethyl 4‐diethoxyphosphoryl‐3‐oxobutanoate with various aryl‐ and aliphatic‐substituted α,β‐unsaturated aldehydes catalyzed by a chiral diarylprolinol ether has been successfully performed. The reaction proceeds in a highly enantio‐ and diastereoselective manner giving access to optically active 6‐substituted‐3‐diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates (see scheme).

     

Microwave activated solvent-free cascade reactions yielding highly functionalised 1,3-thiazines

One-pot cascade reactions of N-acylglycines, acetic anhydride, anhydrous sodium acetate, aromatic aldehydes, and ammonium N-aryldithiocarbamates expeditiously and diastereoselectively yield 5-acylamino-3,6-diarylperhydro-2-thioxo-1,3-thiazin-4-ones (5a-j) in solvent-free conditions under microwave irradiation.     

Protecting‐Group‐Free Total Synthesis of Isoquinoline Alkaloids by Nickel‐Catalyzed Annulation of o‐Halobenzaldimine with an Alkyne as the Key Step

An efficient short total synthesis of benzo[c]phenanthridine alkaloids including oxyavicine, oxynitidine, and oxysanguinarine is described. Thus, N‐methyl‐o‐bromobenzaldimines 1 b – d undergo regioselective cyclization with 4‐(benzo[d][1,3]dioxol‐5‐yl)but‐3‐yn‐1‐ol ( 2 b ) in the presence of [Ni(cod)₂] (cod=1,5‐cyclooctadiene). In situ oxidation of the resultant isoquinolinium salts gives isoquinolinone derivatives 5 b – d with benzo[d][1,3]dioxol‐5‐yl substitution at the C₃ atom and a (CH₂)₂OH group at the C₄ atom. Later, oxidation of the alcohol group in 5 b – d to the aldehyde moiety followed by acid‐catalyzed cyclization and dehydration completes the total syntheses to give oxyavicine, oxynitidine, and oxysanguinarine in 67, 65, and 60 % yields, respectively. The synthesis requires four steps from o‐bromobenzaldehyde derivatives. Transformations of these alkaloids to the other alkaloids in this family are also discussed herein.     

A three-component reaction for diversity-oriented synthesis of polysubstituted piperidines: solution and solid-phase optimization of the first tandem aza[4+2]/allylboration

This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted alpha-hydroxyalkyl piperidines in a highly diastereocontrolled fashion from maleimides, 4-boronohydrazonodienes, and aldehydes. The aldehyde component does not interfere with the first aza[4+2] step, and it was found that this tandem reaction provides better yields of piperidine products 5 when carried out in one-pot. The required 4-borono-hydrazonodienes 1 are synthesized efficiently from the condensation of 3-boronoacrolein pinacol ester (4) with hydrazines. Overall, the three-component process using N-substituted maleimides as dienophiles produces four stereogenic centers and is quite general. It tolerates the use of a wide variety of aldehydes and hydrazine precursors with different electronic and steric characteristics. By allowing such a wide substrate scope and up to four elements of diversity, this reaction process is particularly well adapted towards applications in diversity-oriented synthesis of polysubstituted piperidine derivatives. The suitability of the aza[4+2]/allylboration reaction for use in solid-phase chemistry was also demonstrated using a N-arylmaleidobenzoic acid functionalized resin. This novel multicomponent reaction thus offers a high level of stereocontrol and versatility in the preparation of densely functionalized nitrogen heterocycles.     

Palladium-catalyzed enantioselective domino heck-cyanation sequence: development and application to the total synthesis of esermethole and physostigmine

An efficient synthesis of functionalized 3-alkyl-3-cyanomethyl-2-oxindole 1 by a palladium-catalyzed domino Heck-cyanation reaction has been developed. Reaction of ortho-iodoanilide 5 with potassium ferro(II)cyanide, K(4)[Fe(CN)(6)], dissolved in DMF in the presence of palladium acetate and sodium carbonate afforded oxindole 1 in good to excellent yields. An enantioselective domino Heck-cyanation process has been developed for the first time using (S)-DIFLUORPHOS as a chiral supporting ligand, and an enantioselectivity of up to 79 % ee in the enantiomerically enriched oxindole was obtained under optimized conditions. A concise total synthesis of esermethole and physostigmine, powerful inhibitors of acetyl- and butyryl-cholinesterase, is documented.     

Highly Efficient Access to Bi‐ and Tricyclic Ketals through Gold‐Catalyzed Tandem Reactions of 4‐Acyl‐1,6‐diynes

Single step : Fused bicyclic and bridged tricyclic ketals were synthesized in a single step from the reactions of easily available 4‐acyl‐1,6‐diynes with H₂O and alkanols (see scheme). The highly efficient AuCl₃‐catalyzed multicomponent domino reactions, involving five C ? O bond formations, can proceed in a highly regio‐ and diastereoselective manner at room temperature under air and lead to structures of high molecular complexity from simple starting materials in an atom economic way.

     

Recent Trends in the Chemistry of 4-Amino-1,2,4-triazole-3-thiones

The synthesis and reactions of substituted 4-amino-1,2,4-triazole-5-thione derivatives as well as their biological activity are reviewed.     

Asymmetric tandem Michael-aldol reactions between 3-cinnamoyloxazolidine-2-thiones and aldehydes

Reactions between chiral 3-cinnamoyl-4-methyl-5-phenyl-1,3-oxazolidine-2-thiones and aromatic aldehydes in the presence of BF3Et2O diastereoselectively produced tricyclic compounds incorporating a bridgehead carbon bound to four heteroatoms in high yields. Four stereocenters were induced during the reaction. The tricyclic products were transformed into propane-1,3-diols bearing three consecutive stereocenters by acid hydrolysis, S-methylation, and reductive removal of the chiral auxiliary.     

Ring‐Opening Reactions of 3‐Aryl‐1‐benzylaziridine‐2‐carboxylates and Application to the Asymmetric Synthesis of an Amphetamine‐Type Compound

Nucleophilic ring‐opening reactions of 3‐aryl‐1‐benzylaziridine‐2‐carboxylates were examined by using O‐nucleophiles and aromatic C‐nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3) was observed with O‐nucleophiles as a major reaction path in the ring‐opening reactions of aziridines carrying an electron‐poor aromatic moiety, whereas mixtures containing preferentially the syn‐diastereoisomer were generally obtained when electron‐rich aziridines were used (Tables 1–3). In the reactions of electron‐rich aziridines with C‐nucleophiles, S_N2 reactions yielding anti‐type products were observed (Table 4). Reductive ring‐opening reaction by catalytic hydrogenation of (+)‐trans‐(2S,3R)‐3‐(1,3‐benzodioxol‐5‐yl)aziridine‐2‐carboxylate (+)‐trans‐ 3c afforded the corresponding α‐amino acid derivative, which was smoothly transformed into (+)‐tert‐butyl [(1R)‐2‐(1,3‐benzodioxol‐5‐yl)‐1‐methylethyl]carbamate((+)‐ 14 ) with high retention of optical purity (Scheme 6).     

Enantioselective Total Syntheses of Lyconadins A–E through a Palladium‐Catalyzed Heck‐Type Reaction

A novel palladium‐catalyzed Heck‐type reaction of thiocarbamates has been designed to construct bridged seven‐membered‐ring systems that are otherwise challenging to prepare. Taking advantage of this newly developed method, enantioselective syntheses of lyconadins A–E ( 1 – 5 ), lycopecurine ( 6 ), and dehydrolycopecurine ( 7 ) have been realized in a divergent fashion. Our synthetic strategy also features an intramolecular cyclization of a N‐chloroamine to forge the C6?N bond, a transannular Mannich‐type reaction of a cyclic nitrone to stitch the C4 and C13 together, and a cyclocondensation to deliver the (dihydro‐)pyridone motif.     

Stereoselective Synthesis of Enantiomerically Pure Nupharamine Alkaloids from Castoreum

An animalic note : The first total synthesis of the all‐cis nupharamine 2 , an alkaloid from beaver castoreum, is based on the stereoselective domino Mannich–Michael reaction of N‐galactosylfurylaldimine to give 1 (Piv=pivaloyl), subsequent conjugate cuprate addition, and stereoselective protonation of the enolate. These reactions are all controlled by the carbohydrate. Protonation of the enolate after cleavage of the auxiliary leads to epimer 3 .

     

A new green approach for the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-one derivatives using task specific acidic ionic liquid[NMP]H_2PO_4

12-Aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-one derivatives were synthesized by a convenient and environmentally benign procedure involving multicomponent condensation reactions of substituted aromatic aldehydes with 2,7-dihydroxynaphthalene/2-naphthols/2,6-dihydroxynaphthlene and cyclic 1,3-dicarbonyl compounds in task specific acidic ionic liquid[NMP]H_2PO_4 at 80 ℃.This protocol has proved to be efficient in terms of good yields,operational simplicity,easy workup,recyclability of reaction medium/catalyst,and short reaction time.