Hetero-Diels-Alder reaction Subject

The hetero-Diels-Alder reaction of activated butadienes with carbonyl compounds is a convenient method for the preparation of precursors of sugars. Up to three chiral centers are created simultaneously. The high-pressure [4 + 2]cycloaddition of l-methoxybuta-1,3-diene 32 to N-mono- and N,N-diprotected alaninals was investigated [42-45]. The Eu(fod)3-mediated reaction of 32 with alaninal 25 gave a mixture of four diastereoisomers, which was then subjected to acidic isomerization, leading to the thermodynamically more stable pair of adducts syn-33 and anti-34, with predominance of the latter isomer (Scheme 12). The N-monoprotected alaninals reacted with a moderate ryn-diastereoselectivity. This method was used in the synthesis of purpurosamines (see Sec. DI.C). 

Very few mechanistic studies have appeared on this subject and Houk group has studied the hetero-Diels-Alder reaction between thioformaldehyde and butadiene475, using ab initio calculations, to show that the reaction is concerted and nearly synchronous. In the case of unsymmetrical dienes, several rules are known to establish the regiochemistry of the cycloadducts1 471. 

Enaminothiones react smoothly with heterodienophiles such as azo esters as well [419]. Very recently, thioacetylindoles which also may be conceived as ena-minothioketones have been subjected to hetero Diels-Alder reactions with numerous electron-deficient dienophiles [420]. 

The enantioselective total synthesis of (-)-epibatidine was accomplished in the laboratory of D.A. Evans." The key steps in the synthetic sequence included a hetero Diels-Alder reaction and a modified Hofmann rearrangement. The primary carboxamide was subjected to lead tetraacetate in fert-butyl alcohol that brought about the rearrangement and gave the corresponding A/-Boc protected primary amine in good yield. A few more steps from this intermediate led to the completion of the total synthesis. 

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. 

The research team of J.E. Baldwin developed the first synthetic sequence for the preparation of N(5)-ergolines. The key step was a hetero-Diels-Alder reaction of a substituted phenyl butadiene to form the piperidine ring. The phenyl butadiene substrate was prepared via the Meerwein aryiation of 1,4-butadiene and a diazonium salt derived from 2,6-dinitrotoluene. The initially formed chlorinated product was subjected to dehydrochlorination using DBU as the base. 

The total synthesis of the antitumor antibiotic FR901464 was accomplished by E.N. Jacobsen et al. The preparation of the central six-membered fragment was achieved via a highly enantioseiective hetero Diels-Alder reaction between a diene and an aldehyde. The resulting silyl end ether was subjected to a modified Rubottom oxidation condition (buffer and nonpolar solvent) with mCPBA to afford the desired a-hydroxy ketone with compiete diastereoseiectivity. 

The heating behavior of ionic liquids combined with organic solvents under microwave irradiation has also been the subject of a recent paper by Ondruschka and coworkers [84]. Kappe et al. have used microwaves for inter and intramolecular hetero Diels-Alder reactions of 2(ll-f)-pyrazinones using dichloroethane as a solvent with small amounts of ionic liquid as heating aids (Scheme 7.26) [85], The conventional reaction can take up to 2 days to reach completion. With the micro-wave heating the reaction time could be reduced to 50 min in the absence of the ionic liquid and only 18 min in its presence. Product yields were reported to be similar to those obtained by use of conventional heating. Interestingly, when the... 

Interestingly, when the same indole-3-carboxaldehyde derivative 65 is subjected to Diels-Alder reactions with Danishefsky s diene (52), either under thermal or hyperbaric activation, it is the aldehyde and not the indole carbon-carbon double bond that serves as the dienophilic component (Scheme 19) [34]. The hetero-Diels-Alder reaction with the carboxaldehyde proceeded at quantitative conversion (82% yield) under thermal conditions (12 equiv Danishefsky s diene, 170°C, 24 h) and provided the cycloadduct 69 in quantitative yield under hyperbaric conditions (12 equiv Danishefsky s diene, 45°C, 96 h, 12 kbar). 

In addition to metal-based catalysts, organocatalysts are also selective promoters of asymmetric Diels-Alder reactions. Several groups reported the use of cinchona alkaloid catalysts in standard Diels-Alder reactions. Deng combined 2-pyrones with a,P unsaturated ketones, while Bernard and Ricci focused on the reactions of vinylindoles with quinones and maleimides. Lectka reported enantioselective inverse electron demand hetero Diels-Alder reactions of ketene enolates and o-benzoquininone diimides catalyzed by a combination of benzoylquinidine and zinc triflate. For example, subjecting diimide 51 to the standard reaction conditions yields cycloadduct 52 as a single stereoisomer, which can be easily converted to... 

Recently pyrimidine substituted alkynes 476 were subjected to intramolecular inverse-electron-demand hetero-Diels-Alder reaction with extrusion of HCN affording fused fluorinated pyridines 478. The reaction proceeds at high temperatures in sealed tubes for small amount of the starting materials [256] or as scalable flow process [257] (Scheme 89)... 

The enormous synthetic potential of the Diels-Alder reaction for the construction of a wide array of substituted cyclohexenes is mirrored in the versatility of the hetero-Diels-Alder reaction for the formation of 6-membered heterocycles. The mechanistic possibilities of the hetero-Diels-Alder reaction span the range from concerted to stepwise ionic processes, which is likely a function of the particular catalysts and reaction conditions employed. Although the hetero-Diels-Alder cycloaddition reaction was historically slower than its all-carbon counterpart in gaining widespread recognition, its utilization has been the subject of intense investigations in more recent years [13, 36, 37]. 

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-... 

Tetrahydroalstonine 7-7, a heteroyohimboid alkaloid, has been synthesised in enantiopure form by Martin et al. by means of an oxa Diels-Alder reaction as key step. The trienic precursor 7-5 underwent a thermal intramolecular cycloaddition to form a 5 1 mixture of 7-6 and its 15/J-epimer. The main cycloadduct was then subjected to a straightforward sequence to yield the natural product 7-7 (Fig. 7-2) [483-485]. In earlier work, Ogasawara et al. have employed a con-ceptionally different domino Knoevenagel-hetero Diels-Alder approach to this alkaloid and other natural products [486-488]. 

For previous recent reviews of this subject see (a) S. M. Weinreb and R. R. Staib, Tetrahedron, 1982, 38, 3087 (b) D. L. Roger and S. M. Weinreb, Hetero Diels-Alder Methodology in Organic Synthesis , Academic Press, Orlando, 1987 (c) T. Kametani and S. Hibino, Adv. Heterocycl. Chem., 1987, 42, 245 (d) J. Hamer (ed.), 1,4-Cycloaddition Reactions, the Diels-Alder Reaction in Heterocyclic Synthesis , Academic Press, New York, 1967. 

T. Kametani and S. Hibino have contributed an account of the synthesis of natural products by hetero Diels-Alder cycloaddition reactions, a subject to which they have contributed extensively. 

The catalytic cycle of this NHC-catalyzed reaction originates by the addition of the NHC to the vinylketene 39, which in turn was created from the acyl chloride 43 in basic media, to afford the diene A as an intermediate (Scheme 17). The diene A and ketone 47 are subjected to hetero—Diels—Alder (HDA) cycloaddition reaction or undergoes a stepwise vinylogous aldol reaction with intramolecular cyclization to afford the zwitterionic B. The breakdown of zwitterionic B gives the dihydropyra-none 48 and recreates the NHC catalyst (Scheme 17) (2011MI1943). 

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