Reaction of Bicyclo[3.2.1]octenols with Thionyl Chloride. Preliminary paper

The allylic 1-methyl-3-bromobicyclo[3.2.1]octenyl exo-2 and exo-4 alcohols were treated with thionyl chloride in ether or pentane solution at 0°. In each case, a 50/50 mixture of exo allylic chlorides was obtained. No evidence for a predominant S_N l′ reaction was detected; reported cases of such S_N l′ processes using these conditions should therefore be treated with reserve.     

New synthesis of isoxazolidines

A new synthesis of 5-substituted isoxazolidines was developed by direct isoxazolidine ring formation of allylic hydroxylamines under acidic conditions. The cyclization process is an electrophilic S_N1 type reaction. The formed carbocation intermediate is stabilized by electron rich groups (i.e., phenyl). A moiety that mediates oxonium ion formation (i.e., para-methoxy) accelerates the rate of product formation.     

Convenient Synthesis of Some Novel Pyridazinone‐Bearing Triazole Moieties

The chemoselective reactions of 2‐(5‐mercapto‐4‐phenyl‐4H‐[1,2,4]triazol‐3‐ylmethyl)‐6‐p‐tolyl‐4,5‐dihydro‐2H‐pyridazin‐3‐one ( 3 ) with different electrophiles were evaluated. Triazole 3 reacted with alkyl halides in the presence of triethylamine in alcohol to give the corresponding S‐substituted derivatives. On the basis of S‐chemoselective reactions of triazole 3 , a series of amino acid 10a – d and dipeptide derivatives 12a – d were prepared via azide coupling of the corresponding hydrazides 9 and 15 with amino acid ester hydrochlorides, respectively. N‐Substituted triazoles 6a – c or 7a – d attached to pyridazin‐3‐one moiety were successfully formed by the reaction of 3 with activated acrylic acid derivatives or with amines. Antibacterial activities of the synthesized derivatives were investigated through correlation with Escherichia coli FabH inhibitory activities using molecular modeling docking software. The antimicrobial activity of synthesized compounds was evaluated, showing best inhibition zone for N‐substituted carboxylic acid 5a and N‐substituted nitrile 5c parallel to the molecular modeling studies.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.     

A kinetic study of the high temperature rearrangement of 4‐ethyl‐3,5‐diphenyl‐4H‐1,2,4‐triazole

The kinetics of the thermal rearrangement 4‐ethyl‐3,5‐diphenyl‐4H‐1,2,4‐triazoles, 1 , to the corresponding 1‐ethyl‐3,5‐diphenyl‐1‐alkyl‐1H‐1,2,4‐triazoles, 2 , was studied in 15‐Crown‐5 and octadecane at 330 °C. The reaction was very slow in octadecane but proceed well in 15‐Crown‐5. The reaction order for the reaction was not constant but changed from an initial second order rate law towards a first order rate law as the reaction progressed. This was confirmed by the concentration dependent reaction order, n_c, which was larger than the time dependent rate law, n_t. The rationale for the observation was, that at high substrate concentrations the reaction order was second order while at lower concentrations a competing solvent assisted reaction plays an increasing important role. The data were in agreement with a mechanism in which the neutral 4‐alkyl‐triazoles in an intermolecular nucleophilic displacement reaction form a triazolium triazolate, which in a subsequent nucleophilic reaction gives the observed product.     

Nickel-catalyzed allyl-transfer reactions

The reaction of allylic compounds in the presence of some nickel catalysts has been studied. 2,7-Octadienyl isopropyl ether is converted into 2-methylenevinylcyclopentane in moderate yield by NiX₂(n-Bu₃P)₂-t-BuOK (1:2) (where X is Cl, Br, or NO₃) in ethanol. In amines the hydroxyl or ether group of allyl compound is smoothly substituted with the amino group; corresponding allyl substituted amines are formed in high yields. Allyl alcohol is selectively converted to diallyl ether in the presence of Ni(Acac)₂-n-Bu₃P-NaBH₄ (1:3:1) at 40°C. At higher temperature isomerization of allyl alcohol into propionaldehyde is predominate. These reactions are considered to proceed through π-allyl intermediates.     

Fe or FeNO Catalysis? A Quantum Chemical Investigation of the [Fe(CO)3(NO)]−‐Catalyzed Cloke–Wilson Rearrangement

A quantum chemical investigation of the Bu₄N[Fe(CO)₃(NO)]‐catalyzed Cloke–Wilson rearrangement of vinyl cyclopropanes is reported. It was found that allylic C?C bond activation can proceed through a S_N2′ or S_N2‐type mechanism. The application of the recently reported intrinsic bond orbital (IBO) method for all structures indicated that one Fe?N π bond is directly involved. Further analysis showed that during the reaction oxidation occurs at the NO ligand exclusively.     

Synthesis of Novel Polymers with a Chiral 1,2-Diamine Moiety by Polycondensation and their Application to Catalyst for Asymmetric Hydrogenation of Aromatic Ketones

Summary: Novel polymers with chiral 1,2-diamine moiety were successfully synthesized by polycondensation of N-Boc protected enantiopure 1,2-diamine bearing two phenol groups ( S , S )-4 , bisphenol derivatives, and dibromides, followed by deprotection of N-Boc moiety. Hydrogenation of acetophenone was performed with use of polymeric catalyst system prepared from the polymer-supported chiral 1,2-diamine and RuCl₂/(S)-BINAP. The reaction proceeded smoothly even in 2-propanol to give 1-phenylethanol in quantitative yield with high level of enantioselectivity. Furthermore, various other aromatic ketones could be asymmetrically hydrogenated by the polymeric catalyst system.     

Catalytic enantioselective carboncarbon bond formation by addition of dialkylzinc reagents to cyclic 1,3-diene monoepoxides

Chiral copper complexes of 2,2′-binaphthyl-based phosphorus amidites are shown to be highly effective catalysts for the conjugate addition of dialkylzinc reagents to vinyloxiranes. The corresponding allylic alcohol reaction products (S_N2′-pathway) were obtained with moderate to high regioselectivity. Both direct- (S_N2-pathway) and conjugate-opening addition (S_N2′-pathway) seem to proceed with complete anti stereoselectivity. The enantioselectivity of these addition reactions according to a kinetic resolution protocol turned out to be high (>90% ee) with 1,3-cyclohexadiene and 1,3-cycloheptadiene monoepoxides.     

Some Aspects of the Chemistry of Nitro Compounds

The present brief account relates our discovery of new reactions revolving around the chemistry of the NO₂ group. It covers the condensation of MeNO₂ with hindered ketones, and the synthesis of pyrroles, triazoles, and enamides. It also describes new transformations of allylic nitro compounds, such as their conversion to allylic sulfones and unsaturated lactones, their sigmatropic rearrangement into allylic nitrites and thence into allylic alcohols, as well as their use in a short synthesis of nitroestrone derivatives. This is followed by an unusual reduction method furnishing unsubstituted amines (RR′C?NH) under conditions where these hydrolytically labile species can be captured inter‐ or intramolecularly. Finally, a mechanistic study of a strange alkyne‐forming reaction, first reported by Abidi and later shown by Corey and co‐workers to proceed through allylic nitro intermediates, ultimately led to a practical and powerful synthesis of alkynes starting from β‐keto esters.     

α-Methylidene- and α-Alkylidene-β-lactams from Nonproteinogenic Amino Acids

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2 , which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (S_N2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4 (S_N2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the S_N2 reaction occurring in MeCN and the S_N2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8 , containing an exocyciic alkylidene and methylidene group at C(3), respectively.     

Regio- and stereoselective reactions between cyclic Baylis-Hillman type adducts and N-nucleophiles and P-nucleophile

New important organic compounds multifunctionalized cyclic 6-membered and 7-membered allylic amines, azide and phosphonates have been obtained via regio- and diastereoselective reactions of cyclic Baylis-Hillman type adducts 1 with N-nucleophiles and P-nucleophile. We have found that the reactions proceed by S_N2 or S_N2′ processes exclusively, or by both processes simultaneously. The S_N2′ process occurs with anti stereochemistry.     

Hot Water‐Promoted SN1 Solvolysis Reactions of Allylic and Benzylic Alcohols

During the studies of hydrolysis of epoxides in water, we found that the hydrolysis of (?)‐α‐pinene oxide at 20 °C gave enantiomerically pure trans‐(?)‐sobrerol, whereas the same reaction in water heated at reflux unexpectedly gave a racemic mixture of trans‐ and cis‐sobrerol (trans/cis=6:4). We have examined this remarkable difference in detail and found that hot water, whose behavior is quite different compared with room‐ or high‐temperature water, could promote S_N1 solvolysis reactions of allylic alcohols and thus caused the racemization of trans‐(?)‐sobrerol. The effect of reaction temperature, the addition of organic co‐solvent, and the concentration of the solute on the rate of the racemization of trans‐(?)‐sobrerol were further examined to understand the role that hot water played in the reaction. It was proposed that the catalytic effects of hot water are owing to its mild acidic characteristic, thermal activation, high ionizing power, and better solubility of organic reactant. Further investigation showed that the racemization of other chiral allylic/benzylic alcohols could efficiently proceed in hot water.     

Iodine-Mediated One-Pot Synthesis of 1,4,5-Substituted Pyrazoles from MBH Acetates via Allyl Hydrazone Intermediate

Herein, we report the regioselective one-pot synthesis of 1,4,5-trisubstituted pyrazoles by reacting Morita-Baylis-Hillman (MBH) acetates derived from aryl aldehydes with alkyl or aryl hydrazines in the presence of iodine under aerobic conditions. The reaction proceeds through sequential S_N2′ nucleophilic substitution of substituted hydrazine onto the MBH acetate, I₂-catalyzed oxidation of the allylic hydrazine to allylic hydrazone, heating-induced intramolecular aza-Michael reaction and cyclization, and oxidative aromatization. The key intermediate, the s-trans allyl hydrazones were isolated in good yields by performing the reactions at room temperature. However, the allyl hydrazones prepared from the MBH acetates of aliphatic aldehydes did not furnish the pyrazole owing to the absence of an activated methylene group in the substrate. The synthetic applications of the pyrazoles in Ugi reactions, decarboxylative halogenation, Pd-catalyzed benzoylation of the N-aryl ring, and metal-free tetrazole synthesis has been demonstrated.     

Enantioselective Allylic Substitution Catalyzed by Chiral [Bis(dihydrooxazole)]palladium Complexes: Catalyst structure and possible mechanism of enantioselection

Allylpalladium complexes with chiral bis(dihydrooxazole) ligands were studied as catalysts for the enantioselective allylic substitution reaction of rac-1,3-diphenylprop-2-enyl acetate (rac- 5 ) with the anion of dimethyl malonate (Scheme 1). Using enantiomerically pure (S,E)-1-(4-tolyl)-3-phenylprop-2-enyl acatete ((S)- 25 ) as substrate, the reaction was shown to proceed by a clean ‘syn’ displacement of acetate by dimethyl malonate (Scheme 6). The [Pd¹¹(η³-allyl)] complex 18 and the analogous [Pd(η³-1,3-diphenylallyl)] complex 20 , both containing the same bis(dihydrooxazole) ligand, were characterized by X-ray structure analysis and by NMR spectroscopy in solution. The structural data reveal that steric interactions of the allyl system with the chiral ligand result in selective electronic activation of one of the allylic termini. The higher reactivity of one allylic terminus toward nucleophilic attack is reflected in a significantly longer Pd? C bond and a shift of the corresponding ¹³C-NMR resonance to higher frequency.     

Cu‐Catalyzed Aerobic Oxidative Cyclizations of 3‐N‐Hydroxyamino‐1,2‐propadienes with Alcohols,Thiols, and Amines To Form α‐O‐, S‐, and N‐Substituted 4‐Methylquinoline Derivatives

A one‐pot, two‐step synthesis of α‐O‐, S‐, and N‐substituted 4‐methylquinoline derivatives through Cu‐catalyzed aerobic oxidations of N‐hydroxyaminoallenes with alcohols, thiols, and amines is described. This reaction sequence involves an initial oxidation of N‐hydroxyaminoallenes with NuH (Nu=OH, OR, NHR, and SR) to form 3‐substituted 2‐en‐1‐ones, followed by Brønsted acid catalyzed intramolecular cyclizations of the resulting products. Our mechanistic analysis suggests that the reactions proceed through a radical‐type mechanism rather than a typical nitrone‐intermediate route. The utility of this new Cu‐catalyzed reaction is shown by its applicability to the synthesis of several 2‐amino‐4‐methylquinoline derivatives, which are known to be key precursors to several bioactive molecules.     

Carbazole substituted N-acylated linear polyethylenimines (PEI). synthesis and characterization of poly[N-(9-carbazolyl)acetylethylenimine] and poly[N-(2-(9-carbazolyl))propanoylethylenimine]

The synthesis of carbazola substituted N-acylated polyethylenimines, namely, poly[N-(9-carbazolyl)acetylethylenimine] 20 and poly[N-(2-(9-carbazolyl))propanoylethylenimine] 21 by a grafting reaction onto PEI and isomerization polymerization of the carbazole substituted 2-oxazolines is reported. A complete acylation of amino groups in PEI by the 9-carbazolylacetyl groups was achieved by the p-nitrophenyl active ester method but PEI was only partially N-acylated by the 2-(9-carbazolyl)propanoyl groups under similar reaction conditions. The carbazole substituted 2-oxazolines, namely, 2-(9-carbazolyl)methyl-2-oxazoline 18 and (R,S)-2-[1-(9-carbazolyl)]ethyl-2-oxazoline 19 , were prepared by a base induced cyclization of ß-chloroamides. The ring-opening isomerization polymerization of 18 and 19 in the molten state with a cationic initiator (dimethyl sulfate, methyl triflate, or ethylene glycol ditosylate) gave 20 and 21. Gel permeation chromatography of 20 and 21 obtained with different monomerto-initiator ratios gave evidence of a chain transfer reaction with the monomer. The polymers were characterized by elemental analyses, IR, and ¹H-NMR spectroscopy.     

Theoretical studies of spin state‐specific [2 + 2] and [5 + 2] photocycloaddition reactions of n‐(1‐penten‐5‐yl)maleimide

N‐alkenyl maleimides are found to exhibit spin state‐specific chemoselectivities for [2 + 2] and [5 + 2] photocycloadditions; but, reaction mechanism is still unclear. In this work, we have used high‐level electronic structure methods (DFT, CASSCF, and CASPT2) to explore [2 + 2] and [5 + 2] photocycloaddition reaction paths of an N‐alkenyl maleimide in the S₁ and T₁ states as well as relevant photophysical processes. It is found that in the S₁ state [5 + 2] photocycloaddition reaction is barrierless and thus overwhelmingly dominant; [2 + 2] photocycloaddition reaction is unimportant because of its large barrier. On the contrary, in the T₁ state [2 + 2] photocycloaddition reaction is much more favorable than [5 + 2] photocyclo‐addition reaction. Mechanistically, both S₁ [5 + 2] and T₁ [2 + 2] photocycloaddition reactions occur in a stepwise, nonadiabatic means. In the S₁ [5 + 2] reaction, the secondary C atom of the ethenyl moiety first attacks the N atom of the maleimide moiety forming an S₁ intermediate, which then decays to the S₀ state as a result of an S₁ → S₀ internal conversion. In the T₁ [2 + 2] reaction, the terminal C atom of the ethenyl moiety first attacks the C atom of the maleimide moiety, followed by a T₁ → S₀ intersystem crossing process to the S₀ state. In the S₀ state, the second C C bond is formed. Our present computational results not only rationalize available experiments but also provide new mechanistic insights. © 2017 Wiley Periodicals, Inc.     

Synthesis of Branched Alkylboronates by Copper‐Catalyzed Allylic Substitution Reactions of Allylic Chlorides with 1,1‐Diborylalkanes

Reported herein is a copper‐catalyzed S_N2′‐selective allylic substitution reaction using readily accessible allylic chlorides and 1,1‐diborylalkanes, a reaction which proceeds with chemoselective C?B bond activation of the 1,1‐diborylalkanes. In the presence of a catalytic amount of [Cu(IMes)Cl] [IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene] and LiOtBu as a base, a range of primary and secondary allylic chlorides undergo the S_N2′‐selective allylic substitution reaction to produce branched alkylboronates. The synthetic utilities of the obtained alkylboronates are also presented.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).