Diyne, skipped

This is a rare case all the substrates have a skipped diyne structure, automatically raising the question of which triple bond will isomerize. In the case of the phenyl-substituted 48 it is the terminal alkyne, delivering the larger conjugated system in 49 [86] (Scheme 1.20). 

Treatment of "skipped" enynes H CCH2CH=CHR with alkali amides presumably will lead to extensive isomerization into C>CCH=CHCH2R. With alkyllithium bases inverse addition has to be applied to avoid dimetallation. This isomerization reaction is likely to be even more serious in the case of the diynes HC=CCH2OCR, since the CH2-protons have kinetic acidities comparable with that of the ethynyl proton. 

Interaction between "skipped" enynes or diynes (RCH CHCT OCH or ROC--CH2C3CH) and alkali amides will lead to partial or complete isomerization (into RCH2CH=CHChCM or RCH=C=CHC=CM). Alkali amides in ammonia are unsuitable reagents if the compounds RSCT C IH and PhCH2C=CH are to be terminally mctallated (isomerization to RSCH=C=CH2 and PhCH OCHj). 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

The synthetic route described here has been used for various skipped diynes and related 1,3-diynes, among which are precursors or analogs of naturally occurring polyynes.2 The cuprous chloride-promoted coupling reaction in tetrahydro-furan provides the best and often the sole route to the 1,4-diynes.2 From these it is simple to proceed to the 1,3-diyne, possibly with a stop on the way at the isomeric allene.2-6 Because all of these compounds appear to be sensitive, e.g., to heat and oxygen, the relatively mild conditions of their syntheses are noteworthy. 

The present route to conjugated diynes is the method of choice if the corresponding skipped diyne or allene is available.2-6 With naturally occurring polyynes this is often the case. Depending on the 1,4-diyne, the base-catalyzed isomerization may be successfully stopped (by acidification) to yield the intermediate allenylacetylene. Since the isolation of the allene may or may not be desired, it seems prudent to monitor the progress of isomerization of new 1,4-diynes, e.g., by n.m.r., and establish the approximate lifetimes of transient species. In this way some allenes as well as conjugated diynes may be obtained.6... 

A large number of skipped systems, 1,4-enynes and 1,4-diynes, have been prepared by the reaction of alkynylmagnesium halides with allyl and propargyl halides, as illustrated in equations (139)-(144). Several of these products have served in the preparation of annulenes. These reactions are carried out in THF solution close to reflux temperature and in the presence of CuCl as catalyst. 

Coupling of terminal acetylenes [top of 1, 169, after the formulation]. Miller173 has described a procedure for the cuprous chloride-catalyzed coupling of an alkynyl Grignard reagent (1) with propargyl bromide to produce a skipped 1,4-diyne (2) and its isomerization under mild conditions to a conjugated 1,3-diyne (3). 

Diynes. A synthesis of the skipped diynes from 1-alkynes and propargyhc mesylates involves prior conversion of the former compounds into aluminum derivatives. 

Skipped diynes and triynes. A new route to skipped diyncs involves coupling of rropargylic halides or tosylates with 1-alkyncs catalyzed by Cul, NaCOj, and Bu4NCI n DMF or CH3CN. This reaction can be extended to skipped triynes (equation II). 

This method has been used for the synthesis of a series of skipped cyclic ene- and diene-diynes [5]. Remarkably high yields are obtained in some cases even for strained compounds, e.g., 4,9-diisopropylidene-l,6-cyclodecadiyne (6) can be obtained in yield by this simple cyclization reaction. The power of this method is further demonstrated by the remarkable synthesis of a tetrasilacyclohexyne (9) by Barton et al. [Eq. (1)] [6]. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

Wendebom et al. developed the novel synthesis of skipped diynes by performing the reaction of propargylic electrophiles and dimethylalkynylaluminum reagents (Scheme 18) [31, 32]. 

Kessabi J, Beaudegnies R, Jung PM, Martin B, Montel F, Wendebom S (2006) Copper-free synthesis of skipped diynes via cross-coupling reactions of alkynylalanes with propargylic electrophiles. Org Lett 8 5629-5632... 

In their efforts to prepare a [D4]-labeled p4t-neuroprostane, the Galano group carried out partial reduction of the skipped diyne substrate in order to access the Z,Z,Z-triene moiety of the final product (Fig. 12) [34]. While Lindlar s catalyst provided a mixture of mono-reduction of the less hindered alkyne (with the ethyl substituent), the desired triene as well as over-reduced diene product, P-2 nickel yielded a much cleaner conversion to the desired product with 98% purity. The product was then transformed into the target molecule by a sequence of TBAF deprotection of the TBS ether and saponification. 

---