Hetero Diels-Alder reactions stepwise

The spiro dimer of a-tocopherol (9, see also Fig. 6.4) is formed as mixture of two diastereomers by dimerization of the o-QM 3 in a hetero-Diels-Alder reaction with inverse electron demand. Both isomers are linked by a fluxion process (Fig. 6.22), which was proven by NMR spectroscopy.53 The detailed mechanism of the interconversion, which is catalyzed by acids, was proposed to be either stepwise or concerted.53-55... 

Such a conclusion is, nevertheless, connected with the synchronous character of the mechanism. If a stepwise process is involved (nonsimultaneous formation of the two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels-Alder reactions, a specific microwave effect could intervene, because charges are developed in the transition state. This could certainly be so for several cycloadditions [47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has... 

An intramolecular hetero-Diels-Alder reaction has been used to prepare octahydro-14//-benzo[g]quinolino[2,3- 7]-quinolidines (Scheme 38) <1998BML2881>. The same researchers have published a major study on the mechanism of this hetero-Diels-Alder reaction and have shown that under Lewis acid-catalyzed conditions it proceeds via a stepwise mechanism <1996T955>. 

Silyloxy-2-aldehydes can undergo hetero-Diels-Alder reaction with aldehydes to give useful heterocycles.350 A model reaction, H2C=C(OSiH3)-N=CH2 with formaldehyde, has been explored theoretically. Lewis acids such as boron trifluoride catalyse the reaction by coordinating to the aldehyde oxygen, making the aldehyde more electrophilic. Concerted and stepwise mechanisms for this process are considered. 

Tab. 5.3. process. Comparison of the domino- -Knoevenagel-hetero- Diels-Alder reaction with the stepwise ... 

Although the reactions of carbonyl compounds with dienes follow a stepwise addition, the overall stereochemical outcome mimics that of the Diels-Alder reaction.1 2 5 242-244 The products of the hetero Diels-Alder reaction have been used as substrates for a wide variety of transformations and natural products syntheses.242,245-258 Many hetero Diels-Alder reactions use chiral auxiliaries or catalysts that have been successful for the Diels-Alder reaction. 

For hetero Diels-Alder reactions it has been shown by calculations that the transition structures are usually less symmetric than for the all-carbon Diels-Alder reactions also a change from a concerted non-synchronous to a stepwise mechanism depending on the substituents at the reacting species and the reaction conditions can occur. 

Blechert et al. have opened a very elegant alternative to the classical hetero Diels-Alder methodology by generating the cationic radical 3-31 - which might be conceived as 1-aza-1,3-butadiene - from the 2-vinyl indole 3-30 by means of a single electron transfer process. In the presence of the tetrahydropyridine derivative 3-32 the radicalic intermediate was transformed into the tetracyclic compound 3-33 which contains the complete skeleton of the alkaloid gonio-mitine [250, 251]. The authors have postulated a stepwise mechanism for this [4+2] process, therefore it should be understood as a formal hetero Diels-Alder reaction (Fig. 3-11). 

Diels-Alder reactions of heterodienophiles have been known for decades, but only recently has this methodology become widely accepted by the synthetic community. There is enormous diversity in the structural types of compounds which can act as heterodienophiles, and a wide array of heterocyclic adducts can be prepared via these [4 + 2] cycloadditions. It seems clear that hetero Diels-Alder reactions span a range of mechanism from concerted to stepwise ionic processes. In many instances, mechanistic information is totally lacking. The discussion below therefore classifies heterodienophiles by structural rather than mechanistic class. Only the major types of synthetically useful heterodienophiles have been included. Moreover, the significant regio- and stereo-chemical features of the reactions have been exemplified as much as possible using recently reported cases. Other more comprehensive and more specialized reviews should be consulted for older material and more obscure hetero Diels-Alder cycloadditions. 

Sakai, S. Theoretical analysis of concerted and stepwise mechanisms of the hetero-Diels-Alder reaction of butadiene with formaldehyde and thioformaldehyde. THEOCHEM 200Z, 630, 177-185. 

Stereochemical and theoretical aspects of hetero Diels-Alder reactions have been intensively studied and recently reviewed. A clear definition for the endo- and exo-orientation regarding intermolecular all-carbon and hetero Diels-Alder reactions was recently suggested by Tietze in a review covering the literature of the last decade. The reaction mechanisms of several hetero Diels-Alder reactions have been investigated and calculated and concerted processes as well as stepwise reaction pathways have been proposed depending on the compounds employed and the reaction conditions. 

The introduction of an atom other than carbon to either dienes or dienophiles will result in the hetero-Diels-Alder reaction. Owing to the nature (steric effect, electronic effect, etc.) of substituents on dienes and dienophiles, the Diels-Alder reaction might occur through a synchronous concerted, an asynchronous concerted, or a stepwise reaction mechanism. The stepwise and asynchronous concerted Diels-Alder reactions proceed via diradical intermediates, whereas the synchronous concerted mechanisms does not. It should be pointed out that most of the Diels-Alder reactions are concerted as a result, both the rate constants and the stereoselectivities of Diels-Alder reaction are only moderately sensitive to the changes in the nature of organic sol vents. However, it has been clearly shown that the applications of water to the reaction system can greatly accelerate such reactions. Other modifications on this reactions include the application of high pressure, Lewis acid, and ultrasound radiation.More information about this reaction can be easily attained from reviews and relevant books. 

A formal [4h-2] cycloaddition between arylidenoxin-doles and ethyl allenoate afforded dihydropyran-fused indoles, as shown by Wang and colleagues (Scheme 10, equation 1) [67]. Density functional theory (DFT) implicates a stepwise mechanism. A not-unrelated synthesis of indole-annulated dihydropyrano[3,4-c]chromenes via a hetero-Diels-Alder reaction was discovered by Jha and colleagues (equation 2) [68]. The requisite precursors 26... 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

The mechanism of tetrahydroquinoline formation by the Povarov reaction has been debated. A stepwise mechanism involves ionic intermediate 13, followed by an intramolecular electrophilic substitution. A concerted hetero Diels-Alder reaction was proposed where a concerted asynchronous transition state 14 was suggested. 

This is generally a concerted synchronous process with both new bonds forming simultaneously. Combinations of some highly polar substrates undergo concerted asynchronous reactions in which the two new o bonds are formed at different rates. In some rare cases, the reaction proceeds in a stepwise fashion with the absence of expected stereoselectivity. Orfanopoulos reported an example of a stepwise hetero Diels-Alder reaction in 2009. ... 

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]. 

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). 

Reactions with conjugated enynes as dienes in Diels-Alder reactions yield cyclohexadiene or benzene products on reaction with alkene or alkyne dienophiles, respectively. These reactions proceed via a stepwise mechanism to avoid formation of a cyclic allene and are referred to as dehydro-Diels-Alder reactions. In 2008, Barluenga and Aguilar demonstrated that gold catalysts promote intermolecular hetero-dehydro-Diels-Alder reactions between dienynes and nitriles. Dienyne 99 combines with phenyinitrile (100) to afford substituted pyridine 101. ... 

The theoretical principles of cycloaddition reactions are well understood and there have been many computational studies (see Pericyclic Reactions The Diels-Alder Reaction). Often the hetero-cycloaddition reaction shows similar characteristics to the carbocyclic analog, but a number of special features have been noted. In heterocyclic chemistry the cycloaddition reactions are often dipolar computational studies show that a concerted mechanism is followed in the gas phase. However, a number of studies have noted that these dipolar cycloaddition reactions become stepwise when solvent effects are included (via the reaction field method), with a consequent loss of stereospecificity." Other characteristics of hetero-cycloaddition reactions which have been studied include the endo/exo selectivity" and the regiose-lectivity (for example, [2-1-2] vs. [2-1-4])." High levels of electron correlation are generally required in order to establish these selectivities. 

Af-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4+2] cycloaddition with alkenes and alkynes.15 The reaction has been utilized as a useftil method for the construction of heterocycles and acyclic amino alcohols. The reaction can be explained in terms of an inverse electron demand Diels-Alder type process that involves an electron-deficient hetero-diene with an electron-rich dienophile. Af-Acyliminium ions generated by the cation pool method were also found to undergo [4+2] cycloaddition reaction to give adduct 7 as shown in Scheme 7.16 The reaction with an aliphatic olefin seems to proceed by a concerted mechanism, whereas the reaction with styrene derivatives seems to proceed by a stepwise mechanism. In the latter case, significant amounts of polymeric products were obtained as byproducts. The formation of polymeric byproducts can be suppressed by micromixing. 

There are two different modes of cyclizations in hetero [4+2] cycloadditions involving Danishefsky s diene 1) concerted (pericyclic) and 2) stepwise. When carbonyl compounds are reacted with Danishefsky s diene, the stepwise pathway is often referred to as the Mukaiyama aldol reaction pathway. The concerted process is called the Diels-Alder pathway. The mode of cyclization in the case of Lewis acid catalyzed reactions depends on the Lewis acid itself and whether it is present in stoichiometric or catalytic amounts. The Mukaiyama aldol pathway has been... 

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