Propargylic cyclization

SCHEME 8 Furocoumarin formation through a propargylation/cyclization sequence. 

TRANSITION METAL-CATALYSED CYCLIZATION OF A/-ALLYL-AND /V-PROPARGYL ANILINES... 

The indole skeleton can also be constructed by Pd-mediated cyclization of A -propargyl-n-haloanilines. The vinylpalladium intermediates formed in the cyclization are sufficiently stable to permit further rcaction[4,5]. For example. 

Reaction of the chloro-substituted propargyl acetate 132 with aniline gave the pyrrolidine derivative 133 that was cyclized through treatment with... 

A small library of highly functionalized pyrrolines 95 was synthesized by reaction of allylic and propargylic isocyanides 94 with thiols followed by radical cyclization (Scheme 33). The radical reaction was carried out using a radical initiator (AIBN) under flash heating microwave irradiation [67]. 

The (TMS)3Si radical addition to terminal alkenes or alkynes, followed by radical cyclization to oxime ethers, were also studied (Reaction 50). The radical reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized pyrrolidines via a carbon-carbon bond-forming process. Yields of 79 and 63% are obtained for oxime ethers connected with an olefin or propargyl group, respectively. 

Reaction (62) reports the cyclization of a thermally instable propargyl bromide cobalt complex mediated by Ph2SiH2 at room temperature and Et3B/02 as the... 

In another route employing alkynes, it was found that heating propargyl azadienes 7 in toluene at 25-60 °C produces pyrrolic imines 8 which hydrolyze upon work-up to afford 3-acylpyrroles 9 <96JOC2185>. This exo-dig cyclization occurs with complete chemoselectivity wherein the more substituted nitrogen is involved in the cyclization. 

The acyclic oligoynes 23-26 can be cyclized under Friedel-Crafts conditions, i. e. by treatment with AICI3 in CS2, which presumably proceeds via the intermediate tertiary propargylic 27 and )3-silyl-substituted vinylic carbocations of type 28 (Scheme 5). 

Friedel-Crafts reaction remains unexplored, possibly due to the difficulty of the cycloalkyne formation. A mild, versatile, and efficient method for the one-step synthesis of substituted dihydro- and tetrahydroisoquinolines has been developed by the FeCl3-6H20-catalyzed intramolecular allenylation/cyclization reaction of benzylamino-substituted propargylic alcohols, representing the first example of the intramolecular Friedel-Crafts reaction of propargylic alcohols (Scheme 8) [24, 25]. FeCls, InCls, and Yb(OTf)3 also exhibit good catalytic activity for the reaction. 

Alternatively, two propargyl radicals ( CH2-C=CH) can combine and undergo H-atom transfers, followed by cyclization, to yield benzene. 

Cyclization to six-membered rings (Eq. 15) provided modest diastereoselectivity and required the use of bulkier PhMeSiH2 to prevent olefin hy-drosilylation. Propargyl and homopropargyl amines 94 afforded a variety of heterocycles (Scheme 21), if the catalyst was added slowly over the reaction course to diminish side reactions resulting from metal coordination to the basic amine [56]. The reaction procedure was extended to the diastereoselect-ive bicyclization of dienyne substrate 95, giving 96 as product in a cascade fashion (Eq. 16) [57]. 

Owing to flexibility in the substrate, the TycATE was also used to synthesize a variety of novel cyclic structures. Inclusion of a propargylated amino acid into the linear substrate allowed the synthesis of over 247 macrocyclic glycopeptides, where azido-sugars were coupled onto the cyclized alkyne via copper-catalyzed 1,3-dipolar cycloaddition [44] (Figure 13.12). 

The key feature of the first total synthesis of (+)-homopumiliotoxin 223G 418 was a Lewis acid-induced, chelation-controlled propargylation of the trifluoroacetate salt of (. )-2-acetyl pi peri dine 415, derived from iV-Cbz-L-pipecolinic acid. Alkyne 416 thus formed was transformed after several steps into 417, which was cyclized by activation of the primary hydroxyl with the carbon tetrabromide-triphenylphosphine system to give the natural product (Scheme 98) <1998TL2149>. 

Some examples of the lateral cyclization of suitable O-allyl and O-propargyl derivatives were discussed in CHEC-11(1996) <1996CHEC-II(8)747>. Thermal reaction of silyl diazoacetate 303 in xylene provides unspecific decomposition and a minor amount (about 2%) of a colorless solid can be precipitated with ether. The X-ray diffraction analysis identified the structure 305, which is a product of the lateral criss-cross cycloaddition of primarily formed azine 304 (Scheme 43) <2000T4139>. 

Intramolecular inverse electron-demand Diels-Alder reaction of iV-propargyl-2-(pyrimidin-2-yl)pyrrolidine provides an alternative route to pyridopyrrolizines. For example, heating of 130 to 170 °C in nitrobenzene affords the cyclized product with the loss of HCN <1992JOC3000> (Equation 9). The above reference includes molecular orbital (MO) calculations on relative reactivities in this series. 

Diterpenoids related to lambertianic acid were prepared by intramolecular cyclization of either an alkene or an alkyne with a furan ring <2005RJ01145>. On heating amine 101 with allyl bromide, the intermediate ammonium ion 102 was formed which then underwent [4+2] cycloadditions in situ to give the spiroazonium bromides 103 and 104 (Scheme 13). These isomers arose from either endo- or co-transition states. The analogous reaction was also carried out with the same amine 101 and propargyl bromide. The products 105 and 106 contain an additional double bond and were isolated in 58% yield. The product ratios of 103 104 and 105 106 were not presented. 

Ni(cyclam)]2+ was shown to be an efficient electrocatalyst for the intramolecular cyclization-carboxylation of allyl or propargyl-2-haloaryl ethers,200 and for the synthesis of cyclic carbonates from epoxides and carbon dioxide.201... 

Aryl furans were prepared in moderate yields by Rh-catalyzed regioselective hydroformylation of substituted propargylic alcohols followed by cyclization, and an example is shown below <06ASC545>. 

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