Ring closing allylation

When the R group in the Baylis-Hillman products is not H, a problem might arise in the allylic ring-closing etherification (direct vs allylic attack of the phenolate), leading to mixtures of regio-isomers. Therefore, in an initial study we used parent acid 88 to avoid these problems (Scheme 15). 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

One contributing factor, which seems to have been largely ignored, is that the ring closed radical (in many cases a primary alkyl radical) is likely to be much more reactive towards double bonds than the allyl radical propagating species. This species will also have a different propensity for degradative chain transfer (a particular problem with allylamines and related monomers - see 6.2.6.4) and other processes which complicate polymerizations of the monoencs. 

A nice application of this reaction for the synthesis of cyclic a-sulfanylphos-phonates 63 has been reported [42]. It involves a Rh(II)-catalyzed [2,3]-sigmatropic rearrangement and a ring-closing metathesis of the resulting a-(S-allyl) y,d-unsaturated phosphonates 62 (Scheme 16). However, the last step occurs with a low yield (19%) when R = H. 

The role of complexes 23-28 as catalyst precursors in the ring closing metathesis reactions was investigated. Three different diene substrates diethyldiallyl-malonate (29), diallyltosylamine (30). and dielhyldi(2-methylallyl)malonate (31) were added to the NMR tubes containing a solution of 5 mol% of catalyst precursor in an appropriate deuterated solvent. The NMR tubes were then kept at the temperatures reported in Table X. Product formation and diene disappearance were monitored by integrating the allylic methylene peaks in the H NMR spectra and the results are presented in Table X and the catalytic transformations are depicted in Scheme 3. 

The synthesis and olefin metathesis activity in protic solvents of a phosphine-free ruthenium alkylidene bound to a hydrophilic solid support have been reported. This heterogeneous catalyst promotes relatively efficient ring-closing and cross-metathesis reactions in both methanol and water.200 The catalyst-catalyzed cross-metathesis of allyl alcohol in D20 gave 80% HOCH2CH=CHCH2OH. 

The ruthenium-catalyzed isomerization of aryl allyl ethers or amines followed by ring-closing metathesis with ruthenium catalyst 1 furnishes fused benzo-heterocycles in good yield (Scheme 40).66 67... 

High oxidation state alkylidene complexes in which a heteroatom is bound to the alkylidene carbon atom are extremely rare [41]. Since the approach shown in Eq. 43 failed, the related approach shown in Eq. 44 was taken to prepare the medium-sized ring subunits [222]. The latter product was formed in good yield when n=2, R H, R2=Et, but only poor yield when n=2, R =Et, R2=H, possibly due to unfavorable interactions between the ethyl substituent and transannular groups in the transition state for cyclization of the allyl ether [222]. Ruthenium catalysts either failed or gave low yields, presumably because of the steric hindrance associated with ring-closing dienes of this type. 

It is interesting to note that the two reactions involving allyl acetate and the unprotected alcohol, but-3-en-l-ol, failed when the molybdenum catalyst was used. The failure of the Schrock catalyst to tolerate unprotected alcohols has also been observed in ring-closing metathesis [40], where a tertiary alcohol has proved to be the only success [41]. 

Dihydropyrroles and y-Lactams via Allylic Substitution and Ring-Closing Metathesis... 

Scheme 9.28 2,5-Disubstituted 2,5-dihydropyrroles via allylic substitution in combination with ring-closing metathesis.

Scheme 9.29 Preparation of a, 3-unsaturated y-lactams via allylic amlnatlon/ring-closing metathesis.

Figu re 9.5 Formulas of compounds prepared via combination of an allylic substitution and ring-closing metathesis. 

Evans and Kennedy later combined the regioselective rhodium-catalyzed allylic alkylation, using a-substituted malonates, with ring-closing metathesis for the construction of five-, six-, and seven-membered carbocycles (Scheme 10.2) [13]. The combination of these methodologies allowed for the rapid and flexible assembly of carbocycles possessing vicinal ternary-quaternary or quaternary-quaternary stereogenic centers. 

Scheme 10.2 The allylic alkylation/ring-closing metathesis approach to vicinally substituted carbocycles.

Interestingly, treatment of the allylic carbonate 23, which had proven problematic in the previous study, under analogous reaction conditions with the copper enolate derived from 24 furnished the a,/9-disubstituted ketone. Subsequent ring-closing metathesis furnished the 1,2-cyclohexenes 25a/25b in 75% overall yield favoring the trans-dia-stereomer 25a (2° 1°=30 1, ds=10 l) [14]. Overall, this reaction provides an alternative approach to an exo-selective Diels-Alder cycloaddition, and indicates that a-substituted enolates are even more tolerant nucleophiles than the unsubstituted derivatives. 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

Bicyclic systems 146 have been further elaborated into other natural productlike structures by acid-promoted rearrangement, which affords fused tricyclic systems [125], or by ring-opening/ring-closing metathesis processes [123, 126], after installing allyl groups into the structure. 

Bicyclic dienic products recently synthesized by this method (Scheme 36) are lactams 144a and b (07T8267) and enamine ester 145 (09CEJ4565). The precursor of the latter substance originates from a four-component synthesis followed by y-allylation. The alternative y-propargylation and subsequent ring-closing enyne metathesis performed under an ethene atmosphere lead to the 8-vinyl derivative of product 145. 

Tricyclic amine 259 forms by allylation and ring-closing metathesis from optically enriched precursor 258 that itself is the product of asymmetric RCM (03OL4899). 

Scheme 5 Allylation of Alloc-derived sulfones and ring-closing metathesis of an Alloc-protected homoallylic amine...

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