1- Bromo-2- acetylenes

A coupling procedure particularly suited to the synthesis of unsymmetrical diacetylenes involves the reaction of a terminal acetylene with a 1-bromo-acetylene in the presence of a catalyst consisting of a solution of copper(i) chloride in a primary amine to which small quantities of hydroxylamine hydrochloride is added (the Cadiot-Chodkiewicz coupling). 

It was soon realized that the far more readily available 1-chloro and bromo acetylenes w 16) could be used too and in fact phenylchloroacetylene gives with lithium dimethylamide in ether, 87 % of the corresponding ynamine 6). Similarly, N-lithium pyrroline affords 67% of the corresponding ynamine17. ... 

Corey-Fuchs reaction has also been employed to make pharmaceutically interesting compounds. The treatment of bromo-acetylene 20 with /-BuLi and the quench of resulting lithium alkylanide with phenyl isocyanate produced amide 21. After SEM removal, NMDA receptor antagonist 22 for stoke therapy was obtained. ... 

Tertiary acetylenic halides give unsatisfactory results owing to further isomerization of the allenic halide into a conjugated diene system under the influence of the copper salt. Bromo- and iodoallenes with the structures R R2C=C=CH-X can also be synthesized by an aqueous procedure, consisting of reaction between... 

In the receiver was collected almost pure 3-bromo-3-methyl-l-butyne, n 1.466B, in 50iS yield. The residue consisted of the HBr adduct of the acetylenic bromide. 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

The photolysis of chlorodiazirine was investigated in several cases. From chloromethyl-diazirine (232) vinyl chloride was formed as the stable primary product of stabilization of chloromethylcarbene, with acetylene and hydrogen chloride as secondary products. Some 1,1-dichloroethane was assumed to have been formed through a linear diazo compound by reaction with HCl. Added HBr yielded 1-bromo-l-chloroethane (76MI5Q800). 

Dehydrochlorination of bis(tnfluoromethylthio)acetyl chloride with calcium oxide gives bis(trifluoromethylthio)ketene [5] (equation 6) Elimination of hydrogen chloride or hydrogen bromide by means of tetrabutylammonium or potassium fluoride from vinylic chlorides or bromides leads to acetylenes or allenes [6 (equation 7) Addition of dicyclohexyl-18-crown-6 ether raises the yields of potassium fluoride-promoted elimination of hydrogen bromide from (Z)-P-bromo-p-ni-trostyrene in acetonitrile from 0 to 53-71 % In dimethyl formamide, yields increase from 28-35% to 58-68%... 

Examples of dehydrobromination leading to bromoethynylpyrazoles as illustrated by Scheme 36 are described in a patent (99USP5925769). Treatment of 1,1-dibromooleflns with tetrabutylammonium fluoride in THE at room temperature for about 24 h under N2 gives the l-bromo-2-(pyrazol-3-yl)acetylenes where R, R, R, and R" are independently selected from H and alkyl, alkoxy. 

The reactivity of arylhalides in the acetylenic condensation sharply decreases in the series Ar—I, Ar—Br, Ar—Cl. The rate of reaction of phenylacetylene with iodo derivatives is 800 times higher than that of the reaction with bromo derivatives and is 10 higher than that of the reaction with corresponding chlorides (75JOM253). Taking into account the very low activity of halogenopyrazoles (66AHC347), the catalytic variant of acetylenic condensation mainly involves the most active iodo derivatives. 

Solution The desired product can be synthesized in four steps from acetylene and 1-bromo-propane. 

Silver fluoborate, reaction with ethyl bromide in ether, 46, 114 Silver nitrate, complexing with phenyl-acetylene, 46, 40 Silver oxide, 46, 83 Silver thiocyanate, 45, 71 Sodium amide, in alkylation of ethyl phenylacetate w ith (2-bromo-ethyl)benzene, 47, 72 in condensation of 2,4-pentanedione and 1 bromobutane to give 2,4-nonanedione, 47, 92 Sodium 2 ammobenzenesulfinate, from reduction of 2 mtrobenzenesul-finic acid, 47, 5... 

A striking result of this reinvestigation (128, 129) is the observation that the ratio of the product ketone to the acetylene formed from a-bromo-p-aminostyrene is a function of the pH (Table Vll) but that the rate at which they are formed is not. As the pH increases from 3.9 to 13.1, the relative yield of acetylene increases from 16% to 85%. Therefore, the acetylene formation by elimination of a proton from the vinyl cation (path b in route D in Scheme XI) is more susceptible to an increase in base strength than is ketone formation via the enol (path a). This observation is a rare case of pH control over product composition in a 1-El reaction. 

In 1980 Sonogashira reported a convenient synthesis of ethynylarenes - the Pd-catalyzed cross-coupfing of bromo- or iodoarenes with trimethylsilylacetylene followed by protiodesilylation in basic solution [15]. Prior to this discovery, formation of terminal acetylenes required manipulation of a preformed, two-carbon side chain via methods that include halogenation/dehydrohalogenation of vinyl- and acetylarenes, dehalogenation of /1,/1-dihaloalkenes, and the Vils-meier procedure [ 14]. With the ready availability of trialkylsilylacetylenes, the two-step Sonogashira sequence has become the cornerstone reaction for the construction of virtually all ethynylated arenes used in PAM and PDM synthesis (vide infra). 

Terminal acetylenes such as phenylacetylene are transformed by Znl2, CuCl, CuBr, or CuCN and BTSP 1949 into 1-iodo- 1976, 1-chloro- 1978, 1-bromo- 1979, or l-cyano-4-phenylaIkynes 1980 and to the diacetylene 1977 [156] (Scheme 12.44). 

Synthesis of Functionalized Enynes by Palladium/Copper-catalyzed Coupling Reactions of Acetylenes with (Z)-2,3-Dibromopropenoic Acid Ethyl Ester (Z)-2-Bromo-5-(trimethylsilyl)-2-penten-4-ynoic Acid Ethyl Ester. 

The reaction of 3-bromo-5-(methylthio)-2-methylselenophene (61) with ethyllithium and ethyl bromide (Eq. 18) gives mixed thioselenoacetals of an acetylenic ketene (62) in high yield.80 Similarly, isomeric 3-bromo-5-methyl-2-(methylthio)selenophene (63) is also easily cleaved to give 2-ethylseleno-5-methylthio-2-hepten-4-yne (64) (Eq. 17). Such compounds are difficult to obtain by other methods. 

Alkynyl-substituted sydnones 106 are prepared from the new trimethylsilylethynyl derivative 105. 4-Cuprio-3-phenylsydnone 104 <1996CHEC-II(4)165> reacts with l-bromo-2-trimethylsilyl acetylene to give product 105,... 

In 1987, Yamanaka s group described a Pd-catalyzed reaction of halothiazoles with terminal acetylenes [51]. While the yield for the Sonogashira reaction of 2-bromo-4-phenylthiazole (89) with phenylacetylene to afford 90 was moderate (36% after desilylation), the coupling of 4-bromothiazole and 5-bromo-4-methylthiazole with phenylacetylene gave the desired internal acetylenes 91 and 92 in 71% and 65% yield, respectively. 

In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [22a]. Submission of 4-bromo- and 5-bromo-4-methyloxazoles to the Sonogashira reaction conditions with phenylacetylene led to the expected internal acetylenes. 

The transition metal-catalyzed domino reactions will undoubtedly have a splendid future which is underlined by the increasing number of publications in this area Steglich et al. presented an approach to arcyriacyanin A via a domino Heck reaction between a bromo(indolyl)maleiimide and 4-bromoindole.1811 The synthesis of 33 -bifurans by Ling et al. was achieved using a novel palladium-catalyzed domino dimerization and subsequent cyclization of acetylenic ketones.1821 Other applications of a combination of Heck reactions for domino processes are the syntheses of aza-heterocydes developed by our group.1831... 

The elimination of HBr from ds-yS-bromo-p-nitrostyrene [155] producing the acetylene [156], has been studied by Naso and Ronzini (1974) using KF as the base (25). Their results (Table 43) show that the rate enhancement due to the... 

SYNTHESIS OF FUNCTIONALIZED ENYNES BY PALLADIUM/COPPER-CATALYZED COUPLING REACTIONS OF ACETYLENES WITH (Z)-2,3-DIBROMOPROPENOIC ACID ETHYL ESTER (Z)-2-BROMO-5-(TRIMETHYLSILYL)-2-PENTEN-4-YNOIC... 

S)-(-)-CITRONELLOL from geraniol. An asymmetrically catalyzed Diels-Alder reaction is used to prepare (1 R)-1,3,4-TRIMETHYL-3-C YCLOHEXENE-1 -CARBOXALDEHYDE with an (acyloxy)borane complex derived from L-(+)-tartaric acid as the catalyst. A high-yield procedure for the rearrangement of epoxides to carbonyl compounds catalyzed by METHYLALUMINUM BIS(4-BROMO-2,6-DI-tert-BUTYLPHENOXIDE) is demonstrated with a preparation of DIPHENYL-ACETALDEHYDE from stilbene oxide. A palladium/copper catalyst system is used to prepare (Z)-2-BROMO-5-(TRIMETHYLSILYL)-2-PENTEN-4-YNOIC ACID ETHYL ESTER. The coupling of vinyl and aryl halides with acetylenes is a powerful carbon-carbon bond-forming reaction, particularly valuable for the construction of such enyne systems. 

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