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Enantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel-type alkenylation followed by a 1,2-elimination reaction. The process involves use of α-lithio vinyl bromide or vinyl carbamate species, for which application to Zweifel-type reactions has not previously been explored. The resulting functionalized 1,1-disubstituted alkenes undergo facile base-mediated elimination to generate terminal alkyne products in high yield and excellent levels of enantiospecificity over a wide range of pinacolboronic ester substrates. Furthermore, along with terminal alkynes, internal and silyl-protected alkynes can be formed by simply introducing a suitable carbon- or silicon-based electrophile after the base-mediated 1,2-elimination reaction.

We have developed an efficient method for the synthesis of trisubstituted (E)-vinyl bromides by a Friedel–Crafts-type addition of alkynes to oxocarbenium ions formed in situ from acetals. The success of this reaction relies on the identification of magnesium bromide etherate as both a Lewis-acid promoter and a source of bromide. This reaction employs simple inexpensive starting materials and proceeds under mild conditions to allow the preparation of a range of vinyl bromide products in high yields and high E/Z selectivities. Furthermore, the vinyl bromides also contain an allylic ether functional group. Both the vinyl bromide and allylic ether groups are effective handles for the elaboration of these useful synthetic intermediates.

The reaction of various vinyl bromide substrates with copper complex (II) affords the desired thioethers with good to excellent yields.

(R)-α-Aminoadipic acid is a readily available enantiomerically pure starting material for the synthesis of (R)-pipecolic acid and its derivatives. Sonogashira or Suzuki cross-coupling reactions of an N-formyl pipecolate-derived vinyl bromide furnish 6-alkynyl or aryl derivatives. Reduction with sodium cyanoborohydride and subsequent N-deformylation provide 6-alkynyl substituted (R)-pipecolic acid derivatives, valuable building blocks for amino acid and peptide chemistry.

An atom-economic, practical and cost-effective protocol for synthesis of chiral amino acid anilides via ligand-free copper-catalyzed selective CN cross coupling of chiral amino acid amides and aryl halides, hetereoaryl halides and a vinyl bromide has been developed. No racemization occurred during the CN coupling. A plausible mechanism is proposed.

The present regioselectivity is opposite to that traditionally observed for Heck reactions between a vinyl bromide and an alkene.

The coupling of aryl bromides with vinyl bromides in a flow microreactor is best performed via Br/Li exchange of the aryl bromide with BuLi, followed by the Pd(OAc)2-catalyzed Murahashi coupling of the lithiated arene with the vinyl bromide.

Two syntheses of versatile intermediate azepinones 2 and 3 are described. A 6-step intramolecular Dieckmann cyclization and decarboxylation led to the intermediate 3 while an alternate 4-step synthesis of 2 was developed and used for scale-up. The highlight of the second synthesis is the one-step per-bromination/elimination protocol from readily available azepinone 13a to provide a versatile scaffold in vinyl bromide 5, which enables SAR around the aryl moiety. An example of the elaboration of the intermediate 2 toward a heteroaryl azepinone is also described.

Direct oxidation of enolizable ketones to α-hydroxy derivatives, vicinal dicarbonyls or tricarbonyl compounds has been achieved by a catalytic amount of 2-alkylidene-4-oxothiazolidine vinyl bromide in DMSO as a solvent. The yields range from moderate to good.

The enol triflate derived from a 1-(4-alkoxyphenyl)-2-phenyl-1-butanone is unstable, fragmenting to a vinyl cation that can be trapped by bromide ion. The E isomer of the vinyl bromide which is formed in preference (20:1) gave, upon palladium-catalyzed coupling with phenylzinc chloride, an immediate precursor of (Z)-tamoxifen. Similarly, coupling with other aryl metal reagents led to the first stereoselective synthesis of the potent antiestrogen metabolite (Z)-4-hydroxytamoxifen and to (E)-4-bromotamoxifen. The alkoxy substituent assisted fragmentation of the enol triflate, but as a 1-phenyl group was sufficient to allow stereoselective vinyl bromide formation, the methodology could have generality in the stereoselective synthesis of tetrasubstituted olefins that are styrene derivatives

N-Alkylation of iodo lactams with reactive alkyl halides, or of the derived selenide lactams with less reactive alkyl halides, leads to substrates for free radical initiated cyclization to pyrrolizidinones and indolizidinones, e. g. 2 → 3. The first examples of iodide / vinyl bromide, selenide / aldehyde, and selenide / vinyl chloride radical cyclizations are described.

2-Trimethylsilylethyl-1,3-butadiene, readily prepared by the cross-coupling reaction of the Grignard reagent of 3-bromo-3-butenyltrimethylsilane with vinyl bromide catalyzed by a nickel-phosphine complex, works as a synthetic equivalent to 3-methylene-1,4-pentadiene (parent [3]dendralene) by the consecutive Diels-Alder reactions.

Vibrational relaxation of the ν2 and 2ν2 CC stretch vibrational states in the ground electronic state of acetylene has been investigated using infrared kinetic spectroscopy. Excited vibrational states of acetylene are produced by 193 nm ArF excimer laser photolysis of vinyl bromide in a room‐temperature helium buffer gas. Vibrational state populations are probed by direct absorption with the continuous single‐frequency output of a color center laser operating in the 3 μm region. The vibrational transitions observed were the ν2+ν3−ν2 and the 2ν2+ν3−2ν2 combination bands. Rate constants for He vibrational relaxation are 1.5(3)×10−14 and 2.1(7)×10−14 cm3 molecule−1 s−1 for ν2 and 2ν2, respectively.

Several methods for converting vinyl bromides and vinyl dibromides to oxazoles are described. Cyclization of vinyl bromide 6 with cesium carbonate in dioxane forms oxazole 7 while 6 is converted to the corresponding bromooxazole 12 by treatment with CuBr 2 /DBU.

A new access to 11β-(alkynyl)estranes I is described. The synthesis of key intermediate 11β-ethynylestr-4-ene-3,17-dione 8 can be achieved by stereoselective thermodynamically controlled formation of 11β-aldehyde 1 , its conversion to vinyl bromide 7 by Wittig reaction and subsequent dehydrobromination. Broad variation of the acetylenic 11β-substitution is possible by nucleophilic substitution as well as transition metal mediated coupling reactions.

An efficient asymmetric synthesis of the A-ring of 1α,25-dihydroxyvitamin D 3 from α-bromoacrolein is described. The key steps of the synthesis are the Evans type syn -selective asymmetric aldol reaction of bromoacrolein with the boron enolate of 3-chloroacetyl-4(S)-isopropyl oxazolidinone and ring closure by Heck type reaction of a vinyl bromide onto an α,β-unsaturated ester in the exo-mode. This paper is warmly dedicated to Professor Sir Derek H.R. Barton, FRS, inventor of chemical reactions, scholar, teacher and mentor par excellence, on the happy occasion of his seventy-fifth birthday.

Synthesis of a novel aza- C -disaccharide is described using a Suzuki coupling of the alkyl boron reagent 8 and vinyl bromide 7 as the key step.

An intramolecular 2-azaallyl anion cycloaddition with a diene produced the 2,3,4,6,7,7a-hexahydroindole 33 with complete control of relative stereochemistry, thus providing the first example of the use of such a cycloaddition in an approach to a relatively complex target molecule. The 2-azaallyl anion was generated by tin-lithium exchange of the (2-azaallyl)stannane 32. The stannane was prepared by a convergent route using a Stille coupling of the vinyl bromide 14 with the vinylstannane 28, providing the diene 29. An unexpected isomerization occurred in the Stille coupling. Transformation of the cycloadduct 33 to the allylic methyl ethers 36 and 37 produced potential precursors of 6a-epiprecriwelline (4) and 6a-epipretazettine (3), respectively. The inability to carry out an oxidative desilylation thwarted the completion of the syntheses of these alkaloids

Two CC bonds are readily formed by nucleophilic addition of stabilized carbanions to the π-allylpalladium intermediate regioselectively produced by the Heck reaction of a vinyl bromide and an unactivated olefin. An intramolecular version of this condensation gives functionalized carbobicyclic compounds as products.

Chiral aminophosphines 4, 5 and 8 were synthesized from 1 in 34%, 57% and 42% overall yield, respectively. The new ligands were investigated with respect to their efficiency in the allylic alkylation of 1,3-diphenyl-1-acetoxy-2-propene with sodium malonate, the cross-coupling reaction of phenethylmagnesium chloride with vinyl bromide, and asymmetric hydrogenations of unsatured mono- and dicarbonic acids. The highest asymmetric inductions were observed with 4 (dimethyl 1,3-diphenyl-allyl-propandioate, 96% e.e.) and 5 (N-acetylphenylalanine, 77% e.e.; methylsuccinic acid, 56% e.e., 3-phenyl-1-butene 47% e.e.).

Carbon nucleophiles are alkylated with π-allylpalladium complexes formed by the palladium-catalyzed Heck reaction of a vinyl bromide and an olefin. This methodology achieves the consecutive formation of two carbon-carbon bonds in one simple operation and can be applied both inter- and intramolecularly. The rapid construction of functionalized carbobicyclic compounds is effected by the intramolecular version of this condensation.

The photochemical reaction between optically active ene carbamates and chromium alkoxycarbene complexes containing unsaturated aliphatic side chains was further developed. Although remote olefinic groups, including conjugated dienes, were tolerated, a homoallylic side chain underwent intramolecular reaction to give a strained cyclobutanone. (+)-Cerulenin was synthesized utilizing the photochemical reaction of an alkynylcarbene complex with an optically active ene carbamate and the bis(π-crotyl)nickel halide alkylation of a vinyl bromide as key steps.

Three azaphospha ligands with a chiral dinaphthoazepine subunit were prepared and used in asymmetric carbon-carbon bond forming reactions. The nickel catalyzedGrignard cross coupling reaction of 1-phenylethyl magnesium chloride and vinyl bromide afforded the product in up to 47% ee. The palladium catalyzed allylic substitution of 1,3-substituted propenylacetates with dimethyl malonate and the coupling of allylacetate with methyl N-(diphenylmethylene)-glycinate resulted in asymmetric inductions of up to 97% ee and 51% ee, respectively.

The kinetics of bromination of 1,1-diphenylethylene (1a), 4-trifluoromethyl-1,1-diphenylethylene (1b), and 1-(3-trifluoromethylphenyl)-1-(4-trifluoromethylphenyl)ethylene (1c) and of their 2,2-dideuterio derivatives have been investigated in 1,2-dichloroethane. The rate law was always second-order in Br2 and first-order in olefin, with the following k3: 1a (L = H), 1.7 (0.1) × 107; 1b (L = H), 8.0 (0.1) × 104; 1c (L = H), 52 (2) dm6 mol-2 s-1. Olefin 1a (L = H) gave dibromide 4a and vinyl bromide 3a in a ratio changing from 99∶1 at 10-2 mol dm-3 to 5∶95 at 10-4 mol dm-3 Br2 and olefin. The k3 was independent of the reagent concentrations and of the extent of proton loss from the intermediate, showing that the last step was not rate limiting and the formation of the intermediate was completely rate determining. In the whole investigated concentration range, only dibromides 4b and 4c were instead obtained from 1b and 1c, respectively. A negligible KIE, 0.97 (0.01) was found for 1a, whether the dibromide or the vinyl bromide was the main product, while significant inverse KIEs were obtained for 1b, 0.75 (0.05), for 1c, 0.70 (0.05), on deuteriation of the methylene group, and for cis-1,2-diphenylethylene, 2. The kinetic and product distribution data are discussed in terms of nature of the intermediates, depending on substituent effect and reagent concentration.

The synthesis of (1→6), (1→4), and (1→1) linked aza-C-disaccharides, a novel class of glycomimetic compounds, is described. The polyhydroxylated piperidine ring was synthesized using vinyl bromide 11 as a common intermediate which was synthesized de novo from bromobenzene utilizing the microbial oxidation metabolite bromodiol 10. A Suzuki coupling of 11 with an alkylboron reagent derived from olefinated carbohydrate precursors via hydroboration was used to form the C-glycosidic bond. Ozonolysis and selective reduction of the resultant carbonyl functions served to produce the azasugar ring. Fully deprotected aza-C-disaccharides were obtained upon acidic deprotection. Biological screening of the title compounds against several common glycosidase enzymes as well as in vitro anti-HIV assays are reported.

Methodology for the construction of diverse α-1- C -substituted-deoxymannojirimycin analogues is reported. The pseudoanomeric carbon-carbon bond was formed using a Suzuki cross-coupling between vinyl bromide 5 , derived biocatalytically from bromobenzene, and an aryl, alkyl, or carbohydrate boron coupling partner. Ozonolysis and stereoselective reduction followed by an intramolecular nucleophilic ring closing served to form the polyhydroxylated piperidine ring. © 1997 Elsevier Science Ltd.

The synthesis of 11 β-1-C-aryl-deoxymannojirimycin analogues using a versatile de novo strategy is described. The origins of this report are derived from several recent developments in the area of C1-substituted glycomimetic polyhydroxylated piperidines. This study is designed as a structure−activity comparison to explore the effects of aryl substitution on the ability of the title compounds to inhibit glycosidase enzymes. The polyhydroxylated piperidine ring was constructed using vinyl bromide 10, which was synthesized in six steps from the bromobenzene microbial oxidation metabolite bromo diol 9. A palladium-catalyzed Suzuki cross-coupling of vinyl bromide 10 and the corresponding arylboronic acid served as the key pseudoanomeric carbon−carbon bond-forming step. Ozonolysis and selective reduction of the resultant carbonyl functions followed by reductive amination served to produce the azasugar ring. The complete NMR analysis of the resultant piperidine ring stereochemistry is also discussed. Fully depro...

Synthesis of two retinoids in which the 9,13-dicis double bonds were locked in cycloalkene or thiophene was described. The key step was carbonylation of vinyl bromide 9 and 16 with carbon monoxide in the presence of Pd(PPh 3 ) 4 . © 1997 Elsevier Science Ltd.

Stille coupling of 1,1-bis(tri-n-butylstannyl)ethenes proceeds in a stereoselective manner to afford the E-vinylstannanes. Repetition of this sequence affords a new route to tri-substituted alkenes. Intramolecular Stille coupling of a suitable vinyl bromide affords a pyranyl-derived vinylstannane. In certain cases, with bulky electrophiles, butyl migration rather than that of the sp2 - hybridised centre is observed. A working model is put forward in order to rationalise these results.

The addition of 0.1 M quaternary ammonium bromide to a solution of 20% trifluoroacetic acid in methylene chloride causes a large rate increase in the reaction of non-conjugated alkynes. The initial vinyl bromide product reacts further to provide a mixture of isomeric vinyl bromides and dibromides. At high salt concentrations however, the secondary reactions are prevented and only the initial vinyl bromide is found. In contrast to the corresponding addition to alkenes, the predominant mechanism is proposed to involve a one-step, concerted, nucleophilic attack by halide ion upon an acid–alkyne π-complex which produces the vinyl halide directly. A minor path involving syn addition is also seen. At all salt concentrations, allenes produce significant amounts of rearrangement products suggesting the significant involvement of a cationic mechanism.

On treatment with tributyltin hydride, the vinyl bromide 11 and the vinyl iodide 26 cyclize to give mixtures of the (E)- and (Z)-4-(alkoxycarbonylmethylene)tetrahydropyrans 12/13 and 27/28 in which the (E)-isomers 12 and 27 are the major components accounting for 80% of the products. Addition of triphenyltin hydride to the alkyne 34 similarly initiates cyclization giving a mixture of products 35–37, the composition of the mixture depending upon the concentration of the tin hydride. These results are consistent with faster cyclization of the (Z)-vinyl radical with kinetic formation of five-membered ring containing products which are either trapped by hydrogen transfer from the tin hydride or which rearrange to form a 4-methylenetetrahydropyran. This chemistry was applied to prepare the cis-2,6-disubstituted 4-(methoxycarbonylmethylene)tetrahydropyran 50 which may be useful for the introduction of the C(10)–C(16) fragment into the bryostatins. Cyclization of the p-methoxybenzyl protected vinyl iodide 58 is less stereoselective, perhaps because of intramolecular hydrogen transfer from the p-methoxybenzyl group.

Substoichiometric quantities of copper or zinc species dramatically improve both conversion rate and efficiency of Pd(0)-catalyzed cyanation reactions. The optimum reaction conditions involve the use of a nitrile solvent, NaCN, and a catalyst system employing the combination of cuprous iodide with tetrakis(triphenylphosphine)palladium(0), [Pd(PPh3)4]. Beneficial effects were observed for the conversion of aryl halides, aryl triflates, and a vinyl bromide to the corresponding nitriles. The process was demonstrated on preparative scale with a broad range of aromatic and heteroaromatic substrates containing diverse functionality. A dual catalytic cycle is proposed to explain the profound influences of the cocatalyst system.

Very long chain fatty acids are isolated from many different natural sources. However their unsaturated and particularly their diunsaturated derivatives with a Δ n,n+4 pattern are almost exclusively encountered in marine organisms, until we found some derivatives in the botanical family of the Annonaceae. In this letter we present a very efficient synthesis of this family of products based on the new transition metal-catalyzed coupling reaction between an organomagnesium reagent and a functionalized vinyl bromide.

We have developed a highly convergent synthesis of the manumycin-type m-C7N-antibiotic nisamycin that is applicable to other members of this family of antibiotics. The synthesis features a three-step sequence to the epoxyquinol core that serves as a scaffold for the attachment of the polyene side chains. The eastern polyene side chain was constructed via a novel organozirconocene-mediated synthesis. Zirconocene methodology was also applied to the synthesis of the polyene side chains of asukamycin. The southern side chain of nisamycin was introduced via a Stille reaction that employed a vinyl bromo ketone, derived from an acid-sensitive bromo ketal. Pd-mediated coupling of the vinyl bromide with a stannyl TIPS ester gave TIPS-protected nisamycin that was readily converted to the natural product.

The palladium catalyzed tandem cyclization–cross-coupling reaction of indolylborate (2) with vinyl bromide (9) was developed for the preparation of pyrido[4,3-b]carbazole as a key reaction. The cross-coupling reaction of 2a provided hexatriene (10), and then cyclization of 10 to pyrido[4,3-b]carbazole (12) was effected with irradiation or Lewis acid. Using indolylborate (2c) for the cross-coupling reaction, a novel construction of ellipticine was attained through similar reaction sequences.

The syntheses of a range of 5′-deoxy-5′-methylidene phosphonate-containing thymidine dimers have been achieved using a palladium-catalysed cross coupling reaction as a key step. The optimised reaction conditions comprising of palladium acetate, 1,1′-bis(diphenylphosphino)ferrocene and propylene oxide in THF were found to couple a range of H-phosphonates and vinyl bromide 3 in fair to excellent yield.

Lactams and oxazolidinones containing a 3-butynyl side chain at the four- and the three-position, respectively, have been prepared by reductive alkylation of cyclic imides or by SN2′-substitution of bromopropadiene with highly functionalized enantiopure organozinc reagents. Treatment of these compounds with aryl halides and one vinyl bromide using Pd(PPh3)4 as a catalyst gives rise to a coupling-cyclization reaction, yielding bicyclic enamides in which the aryl or vinyl moiety is incorporated. Remarkably, these groups are transferred stereoselectively cis with respect to the nitrogen nucleophile onto the triple bond. Structural proof for this unusual stereochemical outcome has been obtained by crystal structure analysis and NOE-difference spectroscopy of the cyclized products.

New β-aminoalkylphosphines with a stereogenic nitrogen center have been synthesized from quincorine and quincoridine. Nickel catalysts were studied for their enantioselectivity in the asymmetric Kumada–Corriu reaction. The (2 S ,4 S ,5 R )-2-diphenylphosphinomethyl-5-ethyl-quinuclidine–nickel complex led to e.e. of 85% for the cross-coupling of 1-phenylethylmagnesium chloride with vinyl bromide.

The total synthesis of the new cytotoxic marine macrolide (+)-dactylolide (1) has been achieved in nine steps from known vinyl bromide (−)-AB. In addition, (+)-zampanolide (2) has been converted to...

The Garner aldehyde-derived methylene alkene 5 and the corresponding benzyloxycarbonyl compound 25 undergo hydroboration with 9-BBN-H followed by palladium-catalyzed Suzuki coupling reactions with aryl and vinyl halides. After one-pot hydrolysis−oxidation, a range of known and novel nonproteinogenic amino acids were isolated as their N-protected derivatives. These novel organoborane homoalanine anion equivalents are generated and transformed under mild conditions and with wide functional group tolerance: electron-rich and -poor aromatic iodides and bromides (and a vinyl bromide) all undergo efficient Suzuki coupling. The extension of this methodology to prepare meso-DAP, R,R-DAP, and R,R-DAS is also described.

Synthesis of α- and β-(aminomethyl)vinylphosphonates was achieved from vinyl bromide via a cross-coupling reaction with triethyl phosphite and by cross-metathesis of allyl bromide and vinylphosphonate, respectively. The 1,3-dipolar cycloaddition of these vinylphosphonates with a dipole in the presence of trifluoroacetic acid afforded selectively the β-aminopyrrolidinephosphonates. Syntheses of cis- and trans-γ-aminopyrrolidinephosphonates are also described.

The Suzuki–Miyaura cross-coupling reaction of a hydroxylated vinyl bromide obtained by a chemoenzymatic approach with a diverse range of potassium organotrifluoroborates has been accomplished catalyzed by Pd(PPh3)4 in satisfactory yields. A variety of functional groups are tolerated in the nucleophilic partner.

New isoxazolidines were synthesized in good to excellent yields by 1,3-dipolar cycloaddition of N-vinylamide dipolarophiles and nitrones. Strikingly, solvent-free conditions gave high conversion and yields, shortened reaction time, and minimized degradation products. N-Vinyloxazolidin-2-one and its analogues used in these cycloaddition reactions were conveniently prepared in excellent yields by a modified version of Buchwald's one-step copper-catalyzed vinylation using vinyl bromide. From the adducts, a two-step access to various unsymmetric aspartate derivatives was also described.

The first asymmetric synthesis of the trans-3,4-dimethyl-4-arylpiperidine opioid antagonist scaffold is reported. C-3 stereochemistry was established via CBS reduction and stereoselective anti-SN2‘ cuprate displacement of the derived allylic phosphonate. The resultant vinyl bromide was then elaborated to the target compound by Suzuki coupling and trans-selective 4-methylation. Extension of this methodology should allow general enantioselective access to highly substituted piperidine ring systems.