Diynes reaction with amines

The reaction of diyne 2.59 with but-2-yn-l,4-diol 2.60b or with but-2-yn-l-ol 2.60c gave axially chiral diol 2.61b and monool 2.61c (Scheme 2.21). The reaction proceeded effectively even at room temperature in 1,2-dimethoxyethane [61, 62]. Monoalkynes including a nitrogen atom 2.60d,e also react well in the coupling reaction with diyne to form axially chiral amines and amino alcohols 61d,e with excellent diastereoselectiv-ity and enantioselectivity (Scheme 2.22) [61, 62],... 

A 3 2 mixture of cis-trans isomers is obtained from the addition of secondary amines to butadiyne in dioxane . The ratio remains constant during the course of the reaction signifying that the isomers are formed in this ratio. This, coupled with the second-order kinetics observed and large negative values for the activation entropy (AS — 50 e.u.), led to the postulation of a mechanism involving ratedetermining attack by the amine on the diyne, followed by stereochemical equilibration of the dipolar ion and proton transfer, as illustrated in Scheme 7. 

The [2 -I- 2 -I- 2] cycloaddition reaction was used successMly in the synthesis of the sesquiterpene alkaloid illudinine (Scheme 2.6) [5], The terminal diyne 27 bearing a gm-dimethyl group in the backbone successfully undergoes a nickel-catalyzed cycloaddition reaction with protected homopropargyl amine 28 to afford cycloadduct 29. This intermediate (29) was converted successfully to the natural product illudinine 30 in five simple steps. 

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

Recently, Marino et al. reported a Cadiot-Chodkiewicz cross-coupling reaction of bulky trialkylsilyl-protected alkynes with 1-bromoalkynes in aqueous amine to form a variety of unsymmetrical diynes in good yields (75 95%) (Eq. 4.23).44... 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Various acetylenes having functional groups such as halide, alcohol, ether, amine, alkene and nitrile, are tolerated in the reaction. An asymmetric (2+2+2) cydoaddition of a,03-diynes with alkyne was achieved by a [IrCl(cod)]2 catalyst combined with a chiral phosphine ligand such as MeDUPHOS and EtDUPHOS, and gave axially chiral aromatic compounds [20]. 

There have also been several reports of the cyclization of diynes with amines under the influence of copper(I) chloride (equation 73) (65CB98, 70KGS125, 72TL3487). This is a potentially useful reaction for symmetrically substituted pyrroles, since symmetrical diynes can be obtained by oxidative coupling of alkynes. 

Whereas Glaser-type oxidative coupling opens efficient synthetic pathways toward symmetrical diynes, its performance in heterocoupling is poor. The latter may be accomplished by Cadiot-Chodkiewicz coupling of terminal alkynes with 1-haloalkynes (usually 1-bromoalkynes). The reaction is conducted in the presence of an amine and catalytic amounts of a copper(I) salt. Because, in contrast with the Glaser-type reactions described above, it follows a nonoxidative reaction mechanism, oxygen is not necessary - but needs often not to be excluded (Scheme 4) [9]. 

More often such bromo- and iodoalkynes are employed with another synthetic goal in mind, namely, in the Cadiot-Chodkiewicz reaction for the formation of symmetric or asymmetric 1,3-diynes by reaction of the haloalkyne with a terminal alkyne (Figure 13.25). Additional reagents essential for the success of this reaction are one equivalent or more of an amine and a substoichiometric amount of Cul. As with the Cacchi and Stephens-Castro coupling reactions of Section 13.3.4, a Cu-acetylide is the reactive species in the Cadiot-Chodkiewicz coupling. It is formed in step 1 of the mechanism illustrated in Figure 13.25. 

Addition of amines to carbonyl-activated diynes occurs with great ease, and often the initial adducts react further to give cyclic products. Syn addition occurs in the reaction of piperidine with l-phenyl-2,4-pentadiyne-l-one (151) in either ethanol or ether as solvent giving 152... 

The rearrangement that occurs when thioethers of type 347 are heated in the presence of secondary amines provides an interesting analogy to 1,5-diynes . The products are 349, 350 and 351, and it is postulated that these arise by the reaction of the amine with the thioketene 348, which, in turn, is formed by a [3, 3] sigmatropic rearrangement of 347... 

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. 

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. 

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