Subject Diels-Alder transform

Estrone (54, Chart 6) contains a full retron for the o-quinonemethide-Diels-Alder transform which can be directly applied to give 55. This situation, in which the Diels-Alder transform is used early in the retrosynthetic analysis, contrasts with the case of ibogamine (above), or, for example, gibberellic acid (section 6.4), and a Diels-Alder pathway is relatively easy to find and to evaluate. As indicated in Chart 6, retrosynthetic conversion of estrone to 55 produces an intermediate which is subject to further rapid simplification. This general synthetic approach has successfully been applied to estrone and various analogs. ... 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Inter- and intramolecular hetero-Diels-Alder cycloaddition reactions in a series of functionalized 2-(lH)-pyrazinones have been studied in detail by the groups of Van der Eycken and Kappe (Scheme 6.95) [195-197]. In the intramolecular series, cycloaddition of alkenyl-tethered 2-(lH)-pyrazinones required 1-2 days under conventional thermal conditions involving chlorobenzene as solvent under reflux conditions (132 °C). Switching to 1,2-dichloroethane doped with the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) and sealed-vessel microwave technology, the same transformations were completed within 8-18 min at a reaction temperature of 190 °C (Scheme 6.95 a) [195]. Without isolating the primary imidoyl chloride cycloadducts, rapid hydrolysis was achieved by the addition of small amounts of water and subjecting the reaction mixture to further microwave irradia-... 

We also discovered the ability of 2-azadienes of this sort to cycloadd to unactivated carbon—carbon double and triple bonds in an intramolecular fashion (89CC267) (Scheme 50) such a process appears to be one of the first examples of intramolecular [4 + 2] cycloadditions of simple 2-azadienes. Azadiene 216 was made from O-allyl salicylaldehyde 215 (R = allyl) and heated at 120°C in toluene to furnish the trans-fused tricyclic adduct 217 in excellent yield further dehydrogenation of 217 with DDQ afforded 5H-[ 1 ]-benzopyran[4,3-6]pyridine 218. On the other hand, when 0-(2-butynyl) salicylaldehyde 215 (R = 2-butynyl) was transformed into azadiene 219 and subjected to heating in a sealed tube at 150°C, pyridine 222 was isolated in very high yield. Its formation can be rationalized to occur via the expected Diels-Alder intermediate 220 thus, [1,5]-H shift in 220 would give rise to tautomer 221, which would suffer electro-cyclic ring-opening and aromatization to pyridine derivative 222. 

A highly exo-selective asymmetric hetero Diels-Alder reaction was the key step in D.A. Evans total synthesis of (-)-epibatidine. The bicyclic cycloadduct was then subjected to a fluoride-promoted fragmentation that afforded a (f-keto ester, which was isolated exclusively as its enol tautomer. The removal of the ethoxycarbonyl functionality was achieved using the Krapcho decarboxylation. Interestingly, the presence of a metal salt was not necessary in this transformation. Simply heating the substrate in wet DMSO gave rise to the decarboxylated product in quantitative yield. 

Jig (19) Octalin kebil (163) is converted to kete dithioacetal (164) by die cleavage of ketal function and cmdensation with caibon disulfide and methyl iodide. Subjection of (164) t the action of dimethylsulfonium methylide and acid hydrolysis leads to the formation of unsaturated lactone (165).Its fiiian silyl ether derivative is caused to undergo Diels-Alder reaction with methyl acrylate to obtain salicyclic ester (166) which is converted by standard organic reactions to abietane ether (167). It is converted to allylic alcohol (168) by epoxidation and elimination. Alcohol (169) obtained fiom (168) yields orthoamiite which undergoes transformation to amide (170). Its conversion to the previously reported intermediate has been achieved by epoxidation, elimination and hydrolysis. 

A route from furan-vinylene carbonate Diels-Alder adduct to inositols has been reinvestigated. Endo and exo isomers of oxabicyclo-[2,2,l]-hept-5-ene-2,3-diol carbonate (7) were separated and subjected to epoxidation or c -hydroxy-lation. Successive alkaline and acidic hydrolysis of epoxide 497, obtained from the endo adduct, produced a mixture of alio and myo inositols. cis-Hydroxylation of the endo adduct gave 1,4-anhydro-a//o-inositol 498, which afforded neo-inositol upon acidic hydrolysis. An analogous transformation of the exo adduct... 

The same research group reported on synthesis of [2]rotaxane employing Diels-Alder reaction of terminal alkyne with 1,2,4,5-tetrazine to provide stopper units (Scheme 8.2) [11]. Synthetic concept is identical as in the previous example. Two components in acetonitrile after evaporation gave pseudorotaxane 9, which was subjected to ball milling with ym-tetrazine 10. After 9h, [2]rotaxane 11 was obtained in high yield. Silica gel was added to facilitate transformation in solid state. Under mechanochemical solvent-free conditions, small, but sufficiently bulky pyridazine rings were used for stoppering the pseudorotaxanes. 

The oxidation of ort/to-alkylphenols 49 with iodine(V) derivatives of type 42 containing chiral oxazoline moieties led to asymmetric [4+2] Diels-Alder dimerizations. The <9ri/io-alkylphenols 49 were transformed into ort/io-quinol dimers 50 with significant levels of asymmetric induction (up to 77% ee) (Scheme 21) [71], Similar substrates 51 were subjected to hydroxylative phenol dearomatization to give ort/io-quinol products 53 (Scheme 22) [72], The protocol was devised making use of the chiral iodoarene 52 in combination with mCPBA however, an... 

The TST strategy has been the subject of diverse applications. For example, the Shea research group employed the concept of type II intramolecular Diels-Alder chemistry in conjunction with a temporary silicon tether and a chiral 1,2-diol auxiliary to effect diastereomeric transformation of 28 to compounds 29 and 30 in a 1 6 ratio (eq 8). ... 

---