Intramolecular Substitution Reaction Research Articles

Total synthesis of the lycopodium alkaloid (+)-serratezomine A.

The first total synthesis of (+)-serratezomine A is described. Key aspects of the synthesis include (a) the first deployment of free-radical-mediated vinyl amination (an intramolecular alkyne aminostannation) in a complex target synthesis, (b) the use of a beta-stannyl enamine as the lynchpin for convergent assembly of the natural product backbone, (c) the use of an oxidative allylation promoted by cerium(IV) (CAN) to establish the all-carbon quaternary chiral center with the proper configuration, and (d) an intramolecular substitution reaction to form the sensitive bridging lactone. Overall, 15 steps (longest linear sequence) are required to prepare the natural product from a commercially available aldehyde, and assembly of the contiguous array of six stereocenters is accomplished with high stereocontrol.

Synthesis of a Novel trans-3’,4’-BNA Monomer Bearing a 4,8-Dioxa-5-azabicyclo[5.3.0]decane Skeleton

A novel trans-3',4'-BNA monomer, in which sugar conformation was restricted to S-type by a trans-fused 3-oxa-4-azapentylene bridge between C3' and C4' position, was designed and synthesized. The trans-fused 7-membered cyclic structure within a 4,8-dioxa-5-azabicyclo|5.3.0]decane skeleton was prepared by means of intramolecular substitution reaction using potassium carbonate as a base. We found that all of protecting groups (benzyl, benzyloxymethyl, and benzyloxycarbonyl group) were able to be removed smoothly by DDQ oxidation followed by boron trichloride treatment without cleavage of N-O linkage to afford the desired trans-3',4'-BNA monomer.

Substituted 1H-Pyrazoles and Isoxazoles from Cyclopropyl Oximes

Reported here is a synthesis of substituted 1H-pyrazoles and isoxazoles from the oximes of 1-acyl and 1-carbamyl cyclopropanes under mild reaction conditions. The synthesis of the pyrazoles was achieved under Vilsmeier conditions (DMF/POCl3) via ring opening and chloro­vinylation followed by intramolecular cyclization. When DMF was replaced with CH2Cl2, the same substrates afforded isoxazoles via ring opening followed by an intramolecular vinylic substitution reaction. In some cases, the yields for 1H-pyrazoles were very low and the reactions furnished inseparable and uncharacterizable mixtures.

Enzyme‐Triggered and Self‐Cleaving Fragrant Alcohol Precursors

The high volatility and water solubility of many natural perfumery alcohols leads to their rapid loss in fabric-care and personal-care applications. A dramatically enhanced substantivity is achieved by the use of fragrance precursors as controlled-release systems. In the first part of this article, we present multi-odorant precursors, in which the enzymatic cleavage of esters or carbonates of fragrant alcohols triggers subsequent steps leading to the release of fragrant ketones, lactones, and additional fragrant alcohols. In the second part, a study on oligocarbonates of fragrant alcohols is presented. Therein, the outstanding enzyme-independent performance of gluconolactone oligocarbonate 27 for the long-lasting release of (Z)-hex-3-en-1-ol is highlighted. We show that these polyfunctional compounds undergo complex rearrangements and intramolecular substitution reactions which lead to the observed release kinetics.

Theoretical investigation of the decomposition mechanisms of N-(2-chloroethyl)-N-nitrosourea

The initial reaction mechanisms of N-(2- chloroethyl)-N-nitrosourea (CENU) decomposition have been investigated at the MP2/6-311+G(d,p) level. The mechanistic processes considered were the hydrogen shifting from the nitrogen to the oxygen of the nitroso group, the oxygen of the nitroso and the carbonyl groups nucleophilic displacing the chlorine. The computational results showed that the energy barrier of retro-ene reaction was lower in the gas phase than that of substitution reactions. In the solvent, however, the energy values of each barrier in these three processes approach each other. It is concluded that the CENU decomposition in solvent can proceed via retro-ene reaction and intramolecular substitution reactions.

A Convenient Approach to Heterocyclic Building Blocks: Synthesis of Novel Ring Systems Containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one Moiety

Starting from commercially available educts, a straightforward synthetic route to new heterocyclic building blocks is exemplified with the one- or two-step synthesis of tri-, tetra-, or pentacyclic ring systems. Representatives of the following novel ring systems are prepared from 3-methyl-1-phenyl-2-pyrazolin-5-one and the corresponding o-halo-arenecarbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane: pyrimidino[4',5':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3',2':5,6]pyrano[2,3c]pyrazol- 4-(1H)-one, thieno[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3'',2'':4',5']thieno[2',3':5,6]-pyrano[2,3-c]pyrazol-4(1H)-one, [1,3]dioxolo[5',6'][1]benzothieno[2',3':5,6]pyrano-[2,3-c]- pyrazol-4(1H)-one, pyridazino[4',3':5,6]pyrano[2,3-c]pyrazol-4(1H)-one and pyrazolo-[4'',3'':5',6']pyrido[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one. While the latter two ring systems are directly obtained due to a spontaneous intramolecular substitution reaction, in the other reactions uncyclised 4-aroylpyrazol-5-ols are produced, which are cyclised into the target heterocycles in a subsequent synthetic step (i.e. treatment with NaH in DMF). Detailed NMR spectroscopic investigations ((1)H-, (13)C-, (15)N-) with the obtained compounds were undertaken to unambiguously prove the new structures.

Intramolecular Benzylic Cyclization with Nitrenium Ions Generated from N-Acylaminophthalimides Using Phenyliodine(III) Bis(trifluoroacetate): Formation of Phenyl Substituted Lactams

N-Phthalimido-N-acylnitrenium ions generated from N-acylaminophthalimides using phenyliodine(III) bis(trifluoroacetate) in polyfluoro alcohols do not undergo intramolecular aromatic substitution reactions. Instead, intramolecular cyclization to the benzylic position occurs to afford lactams having a phenyl group substituted at the α-position to the ring nitrogen. These reactions proceed in moderate to good yields.

Preparation of Zinc–Homoenolate from α-Sulfonyloxy Ketone and Bis(iodozincio)methane

Abstract Treatment of α-sulfonyloxy ketone with bis(iodozincio)methane gives a zinc cyclopropoxide which is formed via a nucleophilic addition of the reagent to carbonyl group followed by an intramolecular substitution reaction.

Reaction of bis(bis(trimethylsilyl)amido)mercury(II) with 3,3′-disubstituted binaphthols: Cyclization via an intramolecular electrophilic aromatic substitution reaction

Reaction of the mercury(II) amide Hg[N(SiMe 3) 3] 2 with 3,3′-disubstituted binaphthols (HO) 2C 20H 10(R) 2-3,3′ (R = SiMe 3, SiMe 2Ph, SiMePh 2, SiPh 3) in a 2:1 stoichiometric ratio furnishes four hexacyclic 1,7-disilylsubstituted derivatives of peri-xanthenoxanthene (PXX). Reaction of these two reagents in a 1:1 ratio results in a mixture of the hexacyclic products as well as the related pentacyclic species which contain one hydroxyl group and only one C–O–C ring fusion. The structures of three of the hexacyclic products (R = SiMe 3, SiMe 2Ph, SiMePh 2) and one of the pentacyclic products (R = SiMe 3) have been obtained. The reaction of Hg[N(SiMe 3) 3] 2 with the 3,3′-disubstituted binaphthols proceeds via an intramolecular electrophilic aromatic substitution reaction and several intermediates in this process have been detected using NMR ( 1H and 199Hg) spectroscopy.

Intramolecular Electrophilic Aromatic Substitution of α‐Alkylcinnamaldehydes Affording 1‐Alkoxy‐2‐alkylindenes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Intramolecular electrophilic aromatic substitution of α-alkylcinnamaldehydes affording 1-alkoxy-2-alkylindenes

Abstract Treatment of α-alkylcinnamaldehydes with orthoesters, alcohols, or thiols in the presence of BF 3 ·OEt 2 induces an intramolecular electrophilic aromatic substitution reaction to afford 1-alkoxy-2-alkylindenes. The reaction mechanisms of the indene formation have been elucidated on the basis of the reaction behaviors of β-deuterated α-methylcinnamaldehyde and the NMR studies of the reaction mixture. The transformation process involves successive reactions, i.e., alkoxylation of the carbonyl carbon of α-alkylcinnamaldehydes to form acetals, elimination of alkoxide from the acetals to give alkoxycarbenium ion and γ-alkoxyallyl cation, and intramolecular electrophilic arylation to afford the indene ring structure.

Nucleoside 5′- C-phosphonates: reactivity of the α-hydroxyphosphonate moiety

We found that various dialkyl phosphites, dialkyl trimethylsilyl phosphites, and tris-trimethylsilyl phosphite reacted smoothly with nucleoside 5′-aldehydes to afford epimeric nucleoside 5′- C-phosphonates in high yields. A number of these compounds in both the 2′-deoxyribo and ribo series were prepared. In the case of 2′-deoxythymidine-5′-aldehyde, a thorough study was made on the influence of the 3′-hydroxyl protecting group, type of phosphite, base, and solvent, on the yield and epimeric ratio of the resulting 5′-hydroxyphosphonates. Partial stereoselectivity in favour of either R or S epimers was observed. An attempt to transform the α-hydroxyl of the phosphonate moiety into a halo or azido moiety was not successful. Only intramolecular substitution reaction of the mesyloxy group for an alkoxy residue of the 2-hydroxyethyl ester took place in a low yield.

Fluorescent Sensors for Organophosphorus Nerve Agent Mimics

We present a small molecule sensor that provides an optical response to the presence of an organophosphorus (OP)-containing nerve agent mimic. The design contains three key features: a primary alcohol, a tertiary amine in close proximity to the alcohol, and a fluorescent group used as the optical readout. In the sensor's rest state, the lone pair of electrons of the basic amine quenches the fluorescence of the nearby fluorophore through photoinduced electron transfer (PET). Exposure to an OP nerve agent mimic triggers phosphorylation of the primary alcohol followed rapidly by an intramolecular substitution reaction as the amine displaces the created phosphate. The quaternized ammonium salt produced by this cyclization reaction no longer possesses a lone pair of electrons, and a fluorescence readout is observed as the nonradiative PET quenching pathway of the fluorophore is shut down.

Solid phase synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins

A solid phase strategy has been developed for the synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins. The key transformation is an intramolecular ipso substitution reaction which forms the coumarin heterocycle and culminates with cleavage of product from the polymer support. The pyridine moiety at C3 can be further modified with Suzuki coupling. A sample library with two diversity elements has been synthesized to demonstrate this ipso substation-based cyclo-elimination strategy.

Theoretical Study on the Lithium−Halogen Exchange Reaction of 1,1-Dihaloalkenes with Methyllithium and the Nucleophilic Substitution Reaction of the Resulting α-Halo Alkenyllithiums

Transition structures for the lithium-bromine exchange reaction of 1,1-dibromoalkenes with methyllithium have been located by both the B3LYP and the MP2 levels of theory with the 6-31+G basis set. The reaction with methyllithium dimer gave similar results with lower activation energies. These calculations predict both the kinetic and the thermodynamic stereoselectivity correctly. That is, the sterically more constrained bromine atom of 1,1-dibromoalkenes was predominantly reacted with alkyllithium (dimer) in the kinetic condition. The intramolecular substitution reaction of 4,4-dibromo-3-methyl-3-pentenol in the presence of methyllithium has been investigated. After deprotonation of the alcohol and the lithium-bromine exchange reaction, the intramolecular substitution reaction occurs to give dihydrofuran in a concerted manner. The intermolecular substitution of alpha-chloro alkenyllithium with methyllithium was also studied for comparison. The formation of the indene derivative from 3-(o-bromophenyl)-1,1-dibromo-1-propene in the presence of methyllithium occurs in a similar manner. The lithium-bromine exchange reaction of bromobenzene with methyllithium occurs in an S(N)2 mechanism and the solvent plays an important role.

Enantio‐ and Diastereoselective Synthesis of Highly Substituted Acylcyclopropanes from Homoaldol Products by Stereospecific Homoallylic Cyclization

AbstractHighly enantioenriched 4‐hydroxy‐1‐alkenyl N,N‐diisopropylcarbamates, easily available by asymmetric homoaldol reaction, cyclize by treatment with sodium hydride to form (1r,2t,3t)‐configured 1‐acylcyclopropanes with high diastereoselectivity. The decisive steps are the migration of the N,N‐diisopropylcarbamoyl group onto the alkoxide oxygen atom, followed by an intramolecular homoallylic substitution reaction of the intermediate γ‐carbamoyloxy enolate with inversion of the configuration at the γ‐C atom. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Synthesis of Methyl (E)‐2‐Nitromethylcinnamates Derived from Baylis—Hillman Acetates and Conversion into Several Coumarin Derivatives.

Fast and easy access to methyl (E)-2-nitromethylcinnamates, from the corresponding Baylis-Hillman acetates with NaNO 2 in DMF is described. Several ortho-chloro-2-nitromethylcinnamates undergo intramolecular aromatic substitution reaction followed by rearrangement to yield coumarin derivatives.

Electrophilic‐Induced Cyclization Reaction of Hexahydroindolinone Derivatives and Its Application Toward the Synthesis of (.+‐.)‐Erysotramidine.

A convenient synthesis of variously substituted octahydroindolo[7a,1a]-isoquinolinones has been achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups. The formation of a single lactam diastereomer is the result of the stereoelectronic preference for axial attack by the aromatic ring onto the initially formed N-acyliminium ion from the least hindered side. Additional experiments showed that a variety of hexahydroindolinones containing tethered pi-bonds undergo a related acid-induced cyclization reaction. Treatment of the 3-methylbut-3-enyl-substituted hexahydroindolinone with acid furnished a 3:1 mixture of isomeric octahydropyrido[2,1-i]indolinones in near-quantitative yield. Interestingly, cyclization of the closely related 1-(3-methoxybut-3-enyl)-substituted hexahydroindolin-one afforded a pyrrolo[3,2,1-ij]quinolinone as the exclusive product. With this system, initial protonation takes place on the more nucleophilic enol ether pi-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido pi-bond to give the observed product. The electrophilic promoted cyclizations were extended to include the related hexahydro[1]pyrindinone and 1H-quinolinone systems. An NBS-promoted intramolecular electrophilic aromatic substitution reaction of 1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tetrahydroindolinone was used to assemble the tetracyclic core of the erythrinone skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps.

Improved Catalytic Properties of Halohydrin Dehalogenase by Modification of the Halide-Binding Site

Halohydrin dehalogenase (HheC) from Agrobacterium radiobacter AD1 catalyzes the dehalogenation of vicinal haloalcohols by an intramolecular substitution reaction, resulting in the formation of the corresponding epoxide, a halide ion, and a proton. Halide release is rate-limiting during the catalytic cycle of the conversion of (R)-p-nitro-2-bromo-1-phenylethanol by the enzyme. The recent elucidation of the X-ray structure of HheC showed that hydrogen bonds between the OH group of Tyr187 and between the Odelta1 atom of Asn176 and Nepsilon1 atom of Trp249 could play a role in stabilizing the conformation of the halide-binding site. The possibility that these hydrogen bonds are important for halide binding and release was studied using site-directed mutagenesis. Steady-state kinetic studies revealed that mutant Y187F, which has lost both hydrogen bonds, has a higher catalytic activity (k(cat)) with two of the three tested substrates compared to the wild-type enzyme. Mutant W249F also shows an enhanced k(cat) value with these two substrates, as well as a remarkable increase in enantiopreference for (R)-p-nitro-2-bromo-1-phenylethanol. In case of a mutation at position 176 (N176A and N176D), a 1000-fold lower catalytic efficiency (k(cat)/K(m)) was obtained, which is mainly due to an increase of the K(m) value of the enzyme. Pre-steady-state kinetic studies showed that a burst of product formation precedes the steady state, indicating that halide release is still rate-limiting for mutants Y187F and W249F. Stopped-flow fluorescence experiments revealed that the rate of halide release is 5.6-fold higher for the Y187F mutant than for the wild-type enzyme and even higher for the W249F enzyme. Taken together, these results show that the disruption of two hydrogen bonds around the halide-binding site increases the rate of halide release and can enhance the overall catalytic activity of HheC.

A Novel Simple Pyrolytic Approach Towards Anhydronucleosides.

AbstractFor Abstract see ChemInform Abstract in Full Text.