Alkynes, halo coupling

Haloboration of terminal alkynes yielded stereodefined (Z)-2-halo-l-alkenylboron compounds e.g., 114, 115 that allowed further functionalization of the resulting C-Br or G-B bond. 2,2-Disubstituted-l-alkenylboronic esters were stereoselectively obtained when the haloboration was followed by cross-coupling with 1-alkynylzinc chlorides (Equation (18)).192 The iodoboration-conjugate addition sequence gave alkenyl iodides that were used as intermediate for the total synthesis of deoxyepothilone derivatives (Equation (19)).193-195... 

Enynes can also be synthesized in excellent yields with high regio- and stereoselectivity by transition metal catalyzed cross-coupling reaction. Thus, ( >l-alkenyl-disiamylboranes react with 1-halo-1-alkynes in the presence of catalytic amount of tetrakis(tripheny]phosphine)palladium to afford conjugated trans enynes (Eq. 100)145). 

The chemistry of haloalkynes with low-valent metal complexes has been reviewed.142 Two competing reactions of anionic metal carbonyls [M(CO) ] with halo-alkynes are (i) abstraction of X+ to give MX(CO) and (ii) nucleophilic displacement of X- to give M(C=CX)(CO) and M(CO) 2(ji-C=C). A recent study of reactions of haloalkynes with [M(CO)3Cp ]- (M = Cr, Mo, W Cp = Cp, Cp )] has clarified the reaction conditions, which are determined by the nucleophilicity of the anionic metal carbonyl and the electron-withdrawing power of any substituent on the C=C triple bond. Cross-coupling of the anion with a chloroalkyne is catalyzed by palladium.143... 

Tin-functionalized 1-phosphanorbornadienes can be prepared from tin-substituted alkynes using this type of methodology. Subsequent tin-halogen exchange affords the corresponding halo derivatives, which may be further elaborated using palladium-catalyzed reactions such as Stille coupling, for example (see Section 3.15.12.1.2). 

A couple of years ago we have disclosed a new mode of alkyne activation towards isomerization as a detouring outcome of the Sonogashira coupling. As a result of coupling electron deficient (hetero)aryl halides (or a,p-unsaturated p-halo carbonyl compounds) 11 and aryl propargyl alcohols 12 a new access to 1,3-di (hetero)aryl propenones 13, i.e., chalcones, was established (Scheme 9) [77, 78]. The scope for electron deficient (hetero)aromatic halides 11 is fairly broad and even organometallic complexes like 13c can be synthesized by this sequence. 

Cross-coupling of 1-alkenylboron compounds with 1-halo-1-alkynes leads to conjugated enynes, which can serve as precursors for conjugated dienes. ... 

Unsymmetrically substituted 1,3-diynes can be obtained via the Cadiot-Chodkiewicz copper(I)-catalyzed coupling of 1-alkynes with 1-halo-l-alkynes in the presence of hydroxylamine hydrochloride and an amine. ... 

COUPLING OF ORGANOMETALLIC ALKYNIDES WITH 1-HALO ALKYNES... 

The Pd-catalyzed coupling of 2-halo-, and 2,6-dihaloquinoxalines (217) with propargyl alcohol was reported [110]. This process worked well for the simple alkyl-, and a range of aryl-alkynes, resulting in the corresponding 2-substituted quinoxalines. 

Palladium(0)-catalysed coupling of an orf/to-halophenolic ether (thioether) with a terminal alkyne (or with an alkynylboronic ester ) and ring closure promoted with an electrophile - iodine has been most often used - is an excellent method to make both benzothiophenes °° ° and benzofurans. ortfto-AIkynyl-phenols can be comparably closed with palladium catalysis in the presence of copper(II) halides to give the corresponding 3-halo-benzofurans, ° and ortfto-alkynyl pyridin-2- and -3-yl acetates likewise ring close with iodine, generating furopyridines. ... 

Several syntheses of dihydropyran-2-ones use smaller ring systems as precursors. A direct conversion of cyclopropylidene acetates into 4-halo-5,6-dihydropyran-2-ones occurs on treatment with Cu(II) halides. The products undergo a Pd-catalysed cross coupling with terminal alkynes <04JOC839>. 

All other cross-couplings involving terminal alkynes and halo amides have involved ring closure on nitrogen. Thus, o-halobenzamides react with simple terminal alkynes in the presence of a Pd/Cu catalyst to afford either (Z)-3-aryl(alkyl)idene isoindolin-l-ones or the corresponding 2-(l-alkynyl)benza-mides, which are readily cyclized by NaOEt/EtOH or Pd(OAc)2 catalyst to give isoindolin-l-ones (Eq. 11) [35,36]. When acetylenic aryl carbinols are employed as the alkynes, 3-(acylmethyl)isoindolin-l-ones are obtained instead (Eq.l2) [37]. 

The palladium-catalyzed annulation of alkynes by a couple of other halo-amine/amide systems has been reported to provide a useful route to nitrogen heterocycles. For example, 8-dimethylamino-l-iodonaphthalene reacts with internal alkynes in the presence of a cyclopalladation catalyst to afford N-methylbenzo[d,c]quinolines (Eq.48) [110]. 

The first report of a Sonogashira coupling reaction of an oxazole was by Yamanaka in 1987. Oxazoles substituted with bromine at the 4- or 5-positions were coupled with phenylacetylene yielded the alkyne in 83% and 89% yield, respectively. The Sonogashira reaction with 2-halooxazoles was not attempted however, 2-halothiazoles and 2-halo-A -methylimidazoles were subjected to Sonogashira conditions. Yields in both cases were low and not synthetically useful. 

Several coupling reactions of 2-substituted cycloalkenyhnetal reagents have been re-ported. " " For example, cyclobutenylmetals, generated in situ via carbometallation of 4-halo-1-metaUo-l-alkynes, are reacted with iodobenzene to give 1,2-disubstituted cyclobutenes, as shown in Scheme 35. 

The a-substituted alkenylmetals used in Pd-catalyzed cross-coupling have been mainly those containing Mg, Zn, B, and Sn, as shown in Table 12 as well as Schemes 54-57. Of these, a-substituted alkenylmetals containing Mg and Zn can readily be prepared by direct oxidative metaUation of 2-halo-l-alkenes that are easily accessible by Markovnikov addition of HX to 1-alkynes (Scheme 54). a-Substituted alkenyltin compounds have been prepared and used in the construction of bicyclic diene systems via intramolecular Stille coupling, as shown in Scheme 55. ... 

Compared with chiral nonracemic a-amino carbonyl compounds - which are not suitable substrates for MBH reaction, mainly due to their racemization under normal conditions after prolonged exposure times to catalyst or due to poor diastereoselectivity " a-keto lactams, enantiopure 3-oxo-azetidin-2-ones 168, readily react with various activated vinyl systems promoted by DABCO to afford the corresponding optically pure MBH adducts 169 without detectable epimerization (Scheme 1.69). " However, the Lewis acid-mediated reaction of electron-deficient alkynes with azetidine-2,3-diones 168 as an entry to p-halo MBH adduets was not very sueeessful the coupling product 170 was achieved with concomitant acetonide cleavage as a single ( )-isomer in low yield, in the presence of trimethylsilyl iodide under BF3 OEt2-induced catalysis (Scheme 1.69). 

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