Enol ethers cycloaddition reactions

Inspired by the previous results, Leighton et al. reported the enantioselective [3 + 2] acylhydrazone-enol ether cycloaddition reaction by employing the same pseudoephedrine-based chiral silane. The pyrazohdine product was obtained in 61% yield with 6 1 dr and 77% ee in 24 h. The use of tert-butyl vinyl ether led to an improvement in both diastereoselectivity and enantioselectivity as shown in Scheme 34 [108]. 

Greene and co-workers used a dichloroketene/enol ether cycloaddition and a Beckmann ring expansion as key reactions en route to (+)-preussin [76]. 

Nowadays, it is an accepted mechanistic model [5, 6] that the photolysis step (which proceeds under thermo-reversible CO insertion) leads to species best described as chromium ketene complexes of type 7 (Scheme 2). Indeed, these intermediates exhibit a ketene-like reactivity they undergo [2 + 2] cycloaddition reactions with olefins, imines and enol ethers, whereas reaction with nucleophiles leads to carboxylic acid derivatives. 

Most examples of the Bradsher cycloaddition reaction have utilized fused polycyclic aromatics as the cationic aza-diene fragment. Falck and co-workers have reported that one can carry out this reaction using monocyclic quaternary aza-aromatics. The application of this methodology was illustrated using the A -(2,4-dinitrophenyl) salt of A, A -diethylnicotin-amide 3 and ethyl nicotinate 4 in conjunction with enol ethers. The reaction proceeded at room temperature to generate adducts 5. This was the result of the exo-addition at the C2-C5 positions of the pyridyl ring. The resultant iminium ion was then trapped by the methanolic solvent. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

A chiral titanium(IV) complex has also been used by Wada et al. for the intermole-cular cycloaddition of ( )-2-oxo-l-phenylsulfonyl-3-alkenes 45 with enol ethers 46 using the TADDOL-TiX2 (X=C1, Br) complexes 48 as catalysts in an enantioselective reaction giving the dihydropyrans 47 as shown in Scheme 4.32 [47]. The reaction depends on the anion of the catalyst and the best yield and enantioselectivity were found for the TADDOL-TiBr2 up to 97% ee of the dihydropyrans 47 was obtained. 

The chiral BOX-copper(ll) complexes, (S)-21a and (l )-21b (X=OTf, SbFg), were found by Evans et al. to catalyze the enantioselective cycloaddition reactions of the a,/ -unsaturated acyl phosphonates 49 with ethyl vinyl ether 46a and the cyclic enol ethers 50 giving the cycloaddition products 51 and 52, respectively, in very high yields and ee as outlined in Scheme 4.33 [38b]. It is notable that the acyclic and cyclic enol ethers react highly stereoselectively and that the same enantiomer is formed using (S)-21a and (J )-21b as the catalyst. It is, furthermore, of practical importance that the cycloaddition reaction can proceed in the presence of only 0.2 mol% (J )-21a (X=SbF6) with minimal reduction in the yield of the cycloaddition product and no loss of enantioselectivity (93% ee). 

More recently, further developments have shown that the reaction outlined in Scheme 4.33 can also proceed for other alkenes, such as silyl-enol ethers of acetophenone [48 b], which gives the endo diastereomer in up to 99% ee. It was also shown that / -ethyl-/ -methyl-substituted acyl phosphonate also can undergo a dia-stereo- and enantioselective cycloaddition reaction with ethyl vinyl ether catalyzed by the chiral Ph-BOX-copper(ll) catalyst. The preparative use of the cycloaddition reaction was demonstrated by performing reactions on the gram scale and showing that no special measures are required for the reaction and that the dihydro-pyrans can be obtained in high yield and with very high diastereo- and enantioselective excess. 

Two different alkenes can be brought to reaction to give a [2 -I- 2] cycloaddition product. If one of the reactants is an o, /3-unsaturated ketone 11, this will be easier to bring to an excited state than an ordinary alkene or an enol ether e.g. 12. Consequently the excited carbonyl compound reacts with the ground state enol ether. By a competing reaction pathway, the Patemo-Buchi reaction of the 0, /3-unsaturated ketone may lead to formation of an oxetane, which however shall not be taken into account here ... 

The most frequently encountered, and most useful, cycloaddition reactions of silyl enol ethers are Diels-Alder reactions involving silyloxybutadicncs (Chapter 18). Danishefsky (30) has reviewed his pioneering work in this area, and has extended his studies to include heterodienophiles, particularly aldehydes. Lewis acid catalysis is required in such cases, and substantial asymmetric induction can be achieved using either a chiral lanthanide catalyst or an a-chiral aldehyde. 

The insertion of alkynes into a chromium-carbon double bond is not restricted to Fischer alkenylcarbene complexes. Numerous transformations of this kind have been performed with simple alkylcarbene complexes, from which unstable a,/J-unsaturated carbene complexes were formed in situ, and in turn underwent further reactions in several different ways. For example, reaction of the 1-me-thoxyethylidene complex 6a with the conjugated enyne-ketimines and -ketones 131 afforded pyrrole [92] and furan 134 derivatives [93], respectively. The alkyne-inserted intermediate 132 apparently undergoes 671-electrocyclization and reductive elimination to afford enol ether 133, which yields the cycloaddition product 134 via a subsequent hydrolysis (Scheme 28). This transformation also demonstrates that Fischer carbene complexes are highly selective in their reactivity toward alkynes in the presence of other multiple bonds (Table 6). 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

Cyclopropyl ketones 95 also react with enol ether 100 in presence of 5 mol% of [Au(NTf2)(lPr)] in a [4+2] cycloaddition reaction to afford the bicycle[3.2.0] heptane skeleton 101 (Scheme 5.26) [26]. 

Scheme 5.26 [4+2] cycloaddition reaction catalysed by golden-NHC complex between cyclopropyl ketones and enol ether... 

The stereochemistry of these reactions depends on the lifetime of the dipolar intermediate, which, in turn, is influenced by the polarity of the solvent. In the reactions of enol ethers with tetracyanoethylene, the stereochemistry of the enol ether is retained in nonpolar solvents. In polar solvents, cycloaddition is nonstereospecific, as a result of a longer lifetime for the zwitterionic intermediate.177... 

Lewis acid catalysis has been used to promote stepwise [2 + 2] cycloaddition of silyl enol ethers and unsaturated esters.178 The best catalyst is (C2H5)2A1C1 and polyfluoroalkyl esters give the highest stereoselectivity. The reactions give the more stable trans products. 

The low yields, which are observed among styrenyl adducts, reflect a combination of the poor reactivity of the styrene at the low temperature of the reaction. For example, the combination of t-butyl Grignard with the 2,4-bis-OBoc-benzyl alcohol 15 affords the corresponding benzopyran 50 in only 50% yield even when carried out in the presence of 5-10 equivalents of the styrene (method H, Fig. 4.27).27 Yields for substituted benzopyran styrene adducts are still lower (method G, Fig. 4.27). For example, addition of methyl lithium to 2,4-bis-OBoc-benzylaldehyde 5 followed by the addition of the dienophile and magnesium bromide affords benzopyran 51 in a paltry 27% yield. Method F is entirely ineffective in these cases, because the methyl Grignard reagent competes with the enol ether and with styrene 1,4-addition of methyl supercedes cycloaddition. 

As expected, other enol ethers work well in these procedures. For example, Jones and Selenski find that implementation of method F, which occurs by addition of MeMgBr to benzaldehyde 5 in the presence of dihydropyran (DHP) at 78 °C affords a 66% yield of the corresponding tricyclic ketal 59 with better than 50 1 endo diastereoselectivity (Fig. 4.31).27 On the contrary, Lindsey reports use of method H with the benzyl alcohol 35 and diethylketene acetal. The cycloaddition reaction occurs almost instantaneously upon deprotonation of the benzyl alcohol 35 by f-butyl-magnesium bromide in the presence of the ketene acetal and yields the corresponding benzopyran ortho ester 60 in a 67% yield.29... 

Jason Green has successfully applied the Selenski method to the synthesis of (+ )-bromoheliane (79, Fig. 4.38).34 In this example, two equivalents of the chiral enol ether are added to the benzaldehyde 77 in diethyl ether (0.1 M) and cooled to —78 °C. Methyl Grignard is then added. The cycloaddition occurs while the reaction warms to room temperature. The benzopyran adduct 78 forms in 80% yield with 50 1 diaster-eoselectivity. DFT calculations and experiments suggest that the diastereoselectivity depends on the magnitude of the HOMO-LUMO band gap. In this instance, the LUMO of the supposed o-QM intermediate is computed to be —2.6 eV, whereas the HOMO of the enol ether is —5.9 eV. A 50 1 selectivity is recorded for resulting 3.3 eV gap. For reactions of 2,5-bis-OBoc-4-methyl-benzaldehyde, where the HOMO-LUMO gap is larger (3.6 eV), a 20 1 ratio of diastereomers is observed. 

Reactions of 1 with epoxides involve some cycloaddition products, and thus will be treated here. Such reactions are quite complicated and have been studied in some depth.84,92 With cyclohexene oxide, 1 yields the disilaoxirane 48, cyclohexene, and the silyl enol ether 56 (Eq. 29). With ( )- and (Z)-stilbene oxides (Eq. 30) the products include 48, ( > and (Z)-stilbenes, the E- and Z-isomers of silyl enol ether 57, and only one (trans) stereoisomer of the five-membered ring compound 58. The products have been rationalized in terms of the mechanism detailed in Scheme 14, involving a ring-opened zwitterionic intermediate, allowing for carbon-carbon bond rotation and the observed stereochemistry. 

The reactions of benzyne with enol-ethers and enol-acetates have been much studied very recently 115-118). We were not surprised therefore to isolate a product derived from the attack of tetrafluorobenzyne on the bis-enol-ether (75). This product is derived from a (2 + 2) n cycloaddition and the available evidence suggests that this product has the structure (78). 

In a recent publication, Perumal and coworkers [441] described the condensation of an aldehyde 2-863 with an aniline 2-864 to give an imine which is trapped by a dienophile. However, when using this approach an intermolecular cycloaddition takes place as the reaction is performed as a three-component process using enol ethers or cyclopentadiene as dienophiles (Scheme 2.192). When using enol ether 2-... 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

Diels-Alder cycloaddition of 5-bromo-2-pyrone with the electron-rich tert-butyldi-methylsilyl (TBS) enol ether of acetaldehyde, using superheated dichloromethane as solvent, has been investigated by Joullie and coworkers (Scheme 6.90) [188]. While the reaction in a sealed tube at 95 °C required 5 days to reach completion, the anticipated oxabicyclo[2.2.2]octenone core was obtained within 6 h by microwave irradiation at 100 °C. The endo adduct was obtained as the main product. Similar results and selectivities were also obtained with a more elaborate bis-olefin, although the desired product was obtained in diminished yield. Related cydoaddition reactions involving 2-pyrones have been discussed in Section 2.5.3 (see Scheme 2.4) [189]. 

Alkenes are scavengers that are able to differentiate between carbenes (cycloaddition) and carbocations (electrophilic addition). The reactions of phenyl-carbene (117) with equimolar mixtures of methanol and alkenes afforded phenylcyclopropanes (120) and benzyl methyl ether (121) as the major products (Scheme 24).51 Electrophilic addition of the benzyl cation (118) to alkenes, leading to 122 and 123 by way of 119, was a minor route (ca. 6%). Isobutene and enol ethers gave similar results. The overall contribution of 118 must be more than 6% as (part of) the ether 121 also originates from 118. Alcohols and enol ethers react with diarylcarbenium ions at about the same rates (ca. 109 M-1 s-1), somewhat faster than alkenes (ca. 108 M-1 s-1).52 By extrapolation, diffusion-controlled rates and indiscriminate reactions are expected for the free (solvated) benzyl cation (118). In support of this notion, the product distributions in Scheme 24 only respond slightly to the nature of the n bond (alkene vs. enol ether). The formation of free benzyl cations from phenylcarbene and methanol is thus estimated to be in the range of 10-15%. However, the major route to the benzyl ether 121, whether by ion-pair collapse or by way of an ylide, cannot be identified. 

In another conceptually novel [5 + 2]-process, Tanino and co-workers synthesized cycloheptene derivatives by stereoselective [5 + 2]-cycloadditions involving hexacarbonyldicobalt-acetylene complexes as the five-carbon component and enol ethers as the two-carbon component (Schemes 22 and 23).60 61 The role of the dicobalthexacarbonyl complex is to facilitate formation and reaction of the propargyl cation putatively involved as an intermediate in this reaction. The dicobalthexacarbonyl moiety can be removed using various conditions (Scheme 24) to provide alkane 60, alkene 62, and anhydride 63. 

---