1-Bromoalkynes synthesis

The two reactions described above can be applied for the synthesis of symmetrical -acetylenes only. Unsymmetrical bis-acetylenes can be prepared by using the Cadiot-Chodkiew icz reaction For that method a terminal alkyne 1 is reacted with a bromoalkyne 8 in the presence of a copper catalyst, to yield an unsymmetrical coupling product 9 ... 

Bromoalkynes also couple with vinylstannanes readily to result in enynes. Synthesis of protected enynals via cross-coupling of vinylstannanes with 1-bromoalkynes in the presence of a catalytic amount of Pd(II) has been reported (equation 143)252. Hiyama and coworkers extended the Stille methodology for sequential three-component coupling of trimethylstannyl(trimethylsilyl)acetylene with a vinyl iodide in the first step and cross-coupling of the intermediate trimethylsilylethyne with another alkenyl iodide in the presence of tris(diethylamino)sulphonium trimethyldifluorosilicate in the second step to generate a dienyne (equation 144)253. Both steps occur under palladium catalysis, in one-pot, to result in stereodefined l,5-dien-3-ynes. 

Tlie cross-coupling of a terminal alkyne 9 with a 1 -bromoalkync 8 in the presence of an aliphatic amine and a catalytic amount of a Cu(I) salt affords unsymmetrically substituted diynes [10, Eq.(5)]. This useful reaction, discovered by Cadiot and Chodkiewicz [8], can be employed advantageously for the synthesis of several polyunsaturated systems. Generally the bromoalkyne is introduced dropwise to a mixture of the alkyne, ethylamine, and MeOH or EtOH in the presence of a catalytic amount of CuCl, and a small amount of NH OH-HCl. The reducing agent, NHjOH-HCl, is used to reduce the copper(TI) ion. The alkynylcopper(I) is assumed to be the reactive intermediate. The formation of the symmetrical diyne can be suppressed by maintaining the concentration of the bromoalkyne. This side reaction is particularly significant in the case of less acidic alkynes such as alkylalkynes [9J. 

Michel, P., Gennet, D., Rassat, A. A one-pot procedure for the synthesis of alkynes and bromoalkynes from aldehydes. Tetrahedron Lett. 1999,40, 8575-8578. 

The heterocoupling of a terminal alkyne with a 1-bromoalkyne in the presence of an aliphatic amine and a catalytic amount of a copper(I) salt affords unsymmetrically substituted diynes (2 equation 5). This useful reaction, discovered by Chodkiewicz and Cadiot, can be employed advantageously for the synthesis of several polyunsaturated systems. 

A useful and convenient synthesis of l-trimethylsilyl-l,3-diynes (7) by the reaction of copperd) alkynides (5) with bromoalkynes (6) has been reported by Zweifel and coworkers (Scheme 2). 

Alkenylstannanes. Hydrostannylation of 1-bromoalkynes by employing BUjSnH, (dba)jPd2, and PhjP provides ( )-alkenylstannanes. It is convenient to effect a Stille coupling immediately because the proper Pd catalyst is already present. From 1 -alkynes and 1-bromoalkenes the synthesis of 1,3-dienes requires only catalytic amounts of the tin reagent. 

Homoconjugated or skipped trienes are vital components of natural products such as fatty acids, leucotrienes and insect pheromones. Pohnert and Boland have reported a detailed discussion of the synthesis of these molecules using a one-pot Wittig approach which employs bis(ylides) (77), (78) and (79) as key building blocks.New one-pot Wittig procedures have also been developed for the synthesis of alkynes and bromoalkynes (Scheme 13) and iodoalkynes (Scheme 14). The latter process utilises diiodomethyltriphenyl-phosphorane (80), which is generated in situ from triphenylphosphine, iodoform and potassium butoxide. 

The decisive step in the stereoselective synthesis of ( )-l-bromo-and (Z)-l-iodo-l-alkenes, which were required for the preparation of various pheromones, consists in the hydroboration of different 1-bromo- and 1-iodoacetylenes [107-109] conjugated alkenynes could be readily prepared by metal-catalyzed cross-coupling of 1-alkenylboranes with 1-bromoalkynes [110]. 

Synthesis of 1-BromoaIkynes. The dehydrobromination of 1,1-dibromoalkenes leading to 1-bromoalkynes was usually performed with NaHMDS (eq 17). In comparison, stronger bases such as butyllithium led to the corresponding acetylide anion via... 

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

At that time, we strived for the first total synthesis of a polyunsaturated natural product named xerulinic acid (22 Scheme 4). We envisaged using the hexatriene-l,6-distannane trans,trans,trans-lS (Fig. 5) as a Cg linchpin for joining the Z-configured y-(hromomethylidene)butenolide 20 and the polyunsaturated bromoalkyne 23 by sequential Stille couplings. 

The triethylsilyl group has found extensive use in poly-yne synthesis. Thus the bromoalkyne (14) is coupled to phenylacetylene (Cadiot-Chodkiewicz... 

Miyaura, N. Yamada, K. Suginome, H. Suzuki, A. (1985) Novel and convenient method for the stereo and regiospecific synthesis of conjugated alkadienes and alkenynes via the palladium catalyzed cross-coupling reaction of 1-alkenylboranes with bromoalkenes and bromoalkynes, J. Am. Chem. Soc., 107,972-80. 

For the synthesis of nonsymmetrically substituted 1,3-butadiynes the Cadiot-Chodkiewicz coupling is usually apphed [30, 31]. In this protocol a terminal alkyne is reacted with a terminal bromoalkyne derivative in the presence of a Cu(i) salt and an amine. As examples we show in Scheme 7.3 the synthesis of the l-azacydotetradeca-3,5,10,12-tetrayne derivatives 10(3)a to 10(3)f [32], 1-isopropyl-l-azacydopentadeca-3,5,ll,13-tetrayne (10(4)(c)) [33] and 1-isopropyl-l-azacydo-hexadeca-3,5,12,14-tetrayne (10(S)(c)) [33]. 

One of the classic routes to the synthesis of alkynyl aryl sulfides involved the treatment of bromoalkynes with sodium thiophenolate and related compounds [1(X)]. Using this approach, moderate to good yields of the alkynyl aryl sulfides were obtained under very mild conditions. Following this work, a considerable amount of effort has been focused on... 

SCHEME 7.153 Hunsdiecker synthesis of bromoalkynes using TBAFTFA/NBS [246]. 

SCHEME 7.154 Triethylamine-promoted Hunsdiecker synthesis of bromoalkynes [172],... 

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