L-oxa-1,3 butadienes

Novel complex heterocycles such as 2-148 can easily be obtained using the hetero Diels-Alder reaction of enol ethers like 2-147 and 2-146 as l-oxa-1,3-butadiene (Fig. 2-40) [149]. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cycloaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the l-oxa-1,3-butadiene moiety in 2-816. The formed spirocyclic ketones 2-818/2-819 can be used in natural products synthesis and in medicinal chemistry [410]. They have also been used in the preparation of exotic amino acids these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Table 3 Representative Lewis Acid Catalyzed and Pressure-promoted [4 + 2] Cycloaddition Reactions of l-Oxa-1,3-butadienes... 

Tab. 8.7. Kinetic data of the hetero-Diels-Alder reaction of l-oxa-1,3-butadienes (60a-d) and 61a in dichloromethane.

The first example of a true positive high pressure effect on the enantioselectivity was found for the intramolecular hetero-Diels-Alder reaction of the l-oxa-1,3-butadiene (173) in the presence of the Narasaka catalyst (164) to give the two enantiomeric bridged cycloadducts 174 and 175 (Scheme 8.44) [80]. At atmospheric pressure the two enantiomers were formed with 4.5 % ee, whereas at 500 MPa an increase to 20.4 % ee was observed which corresponds to a AAV = —(1.7 + 0.2) cm mol . In addition, the yield was improved from 50 to 89 %. It was assumed that under high pressure complexes of different stoichiometry may be formed which are more favorable towards a facial selective addition. However, a clear interpretation of the results cannot be given at this point. 

These thoughts do not only count for the 1-oxa-1,3-butadiene, but also for the dienophile. Thus, in an intermolecular cycloaddition with a benzylidenepyrazo-lone, ethyl vinyl ether reacts about 50 times faster than (Z)-l,2-dimethoxyethe-ne and 1,1-diethoxyethene about 2000 times faster than 1,1,2,2-tetramethoxy-ethene, 3000 times faster than ( )-l,2-diethoxyethene, and 5000 times faster than (Z)-diethoxyethene [119]. 

Also ynamines can be used in the hetero Diels-Alder reaction of 1-oxa-1,3-butadiene. Novel examples are described by Dell et al. [138] using e.g. the 2-ben-zylidene-indane-l,3-dione 2-117 and 2-118 to give 2-119 (Fig. 2-32). However, the yields are only modest. 

Since the disclosures that the thermal dimerizations of acrolein and methyl vinyl ketone provide the 3,4-dihydro-2//-pyrans (1, 2) derived from 4ir and 2Tt participation of the a,3-unsaturated carbonyl compound in a Diels-Alder reaction, an extensive series of related observations have been detailed. This work has been the subject of several comprehensive reviews - - including the Desimoni and Tacco-ni extensive tabular compilation of work through 1974. Consequently, the prior reviews should be consulted for thorough treatments of the mechanism, scope, and applications of the [4 + 2] cycloaddition reactions of a,3-unsaturated carbonyl compounds. The [4 + 2] cycloaddition reactions of 1-oxa-1,3-butadienes with their 4-it participation in the Diels-Alder reaction exhibit predictable regioselectivity with the preferential or exclusive formation of 2-substituted 3,4-dihydro-2W-pyrans (equation 1). The exceptions to the predicted regioselectivity that have been observed involve the poorly matched [4 + 2] cycloaddition reaction of an electron-deficient l-oxa-l,3-butadiene with an electron-deficient dienophile, e.g. methyl crotonate or methacrolein. - Rigorous or simplified theoretical treatments of the [4 + 2] cycloaddition reaction of 1-oxa-1,3-butadienes predict the preferential formation of 2-substituted 3,4-dihy-dro-2f/-pyrans and accommodate the preferred endo approach of the reactants in which the carbon-carbon bond formation is more advanced than carbon-oxygen bond formation, i.e. a concerted but nonsynchronous [4 + 2] cycloaddition reaction. ... 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation l)i, 60 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and selected simple alkene and alkyne dienophiles, - although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. - The most extensively studied reaction in the series is the [4 + 2] cycloaddition reaction of a,3-unsaturated ketones with enol ethers and E)esimoni,... 

Similarly, the noncomplementary C-2 - or C-4 addition of an electron-withdrawing substituent to the 1-oxa-1,3-butadiene serves to lower substantially the 1-oxa-1,3-butadiene lumo> accelerates its 4 ir participation in a LUMOdiene-controlled [4 + 2] cycloaddition reaction, maintains the endb-derived diastereoselectivity through the maintenance (C-4) or enforcement (C-2) of a large LUMO C-2 coefficient, and does not alter the observed [4 + 2] cycloaddition regioselectivity, although such substitution may decrease the magnitude of the difference between the O-l/C-4 LUMO coefficients (Table 5). 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

Boger, D L, Robarge, K D, A divergent de novo synthesis of carbohydrates based on an accelerated inverse electron demand Diels-Alder reaction of 1-oxa-1,3-butadienes, J. Org. Chem., 53, 5793-5796, 1988. 

The domino Knoevenagel condensation hetero-Diels-Alder reaction was used for the enantioselective total synthesis of the active anti-influenza A virus indole alkaloid hirsutine and related compounds by L.F. Tietze and co-workers. The Knoevenagel condensation was carried out between an enantiopure aldehyde and Meldrum s acid in the presence of ethyienediamine diacetate. The resulting highly reactive 1-oxa-1,3-butadiene underwent a hetero-Diels-Alder reaction with 4-methoxybenzyi butenyl ether ElZ = 1 1) in situ. The product exhibited a 1,3-asymmetric induction greater than 20 1. 

Tietze, L. F., Kettschau, G., Gewert, J. A., Schuffenhauer, A. Hetero-Diels-Alder reactions of 1-oxa-1,3-butadienes. Curr. Org. Chem. 1998, 2,19-62. 

Other studies devoted to mononuclear iron complexes include evidence for a photoinduced haptotropic shift of the coordinated pyrrolyl ligand in (C5H5)(C4H4N)Fe(CO)2. The photochemistry was studied in low-temperature matrices and in room-temperature solution. The preparation and properties of carbonyliron complexes of l-aza-4-oxa-1,3-butadiene have also been described. ... 

Scheme 6.71 Generation of l-oxa-3,4-cyclohexadiene (333) from 6,6-dichloro-3-oxabicyclo[3.1. OJhexane (332) by n-butyllithium and interception of333 by n-butyllithium, styrene, 1,3-butadiene, isopreneand 2,3-dimethyl-l,3-butadiene.

Scheme 6.7S Prod ucts of the cycloadditions of 1 -oxa-2,3-cyclohexadiene (351), liberated from exo-6-bromo-endo-6-fluoro-2-oxabicyclo[3.1.0]-hexane (354), to styrenes, 1,3-butadiene, isoprene, 2,3-dimethyl-l, 3-butadiene,...

Scheme 6.76 Generation of l-oxa-2,3-cyclohexadiene (351) from 5-bromo-3,4-dihydro-2H-pyran (376) and trapping products of351 obtained from furan, 2,3-dimethyl-1,3-butadiene, 1,1-diphenyl-ethylene, ( )-l-phenylpropene, ( )-2-butene, (Z)-2-butene and tert-butyl alcohol , according to Schlosserand co-workers.

The intermediate 79 obtained by the Knoevenagel condensation of 80 and 81 contains a 1-oxa-l,3-butadiene as well as a normal 1,3-butadiene moiety thus both a hetero-Diels-Alder and a normal Diels-Alder reaction is possible. The dom-... 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

A wide range of hetero 2-aza-1,3-butadienes have been shown to participate as 4rr components of Diels-Alder reactions (Figure 4). Perhaps the most widely recognized class of hetero 2-aza-1,3-butadienes is the A -acylimines (l-oxa-3-aza-l,3-butadiene) ° and comprehensive reviews of their 4tt participation in LUMOdiene-controlled Diels-Alder reactions are available. The recent disclosure of the 4ir participation of A -acylimines in intramolecular [4 + 2] cycloaddition reactions (equation 11), and the use of optically active A -acylimines in productive LUMOdiene-controlled [4 + 2] cycloaddition reactions, illustrate applications of the systems that have not been explored fully (equation 12). ... 

Trifluoromethyl-l-oxa-2-aza-l,3-butadienes can be prepared in situ by 1,4-HBr elimination from the corresponding a-bromo oxime on treatment with base, and provide an interesting and versatile four-skeleton-atom building block [262] (equation 57). 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

---