Diels-Alder reactions cascade

Very recently, Ma has reported a rhodium-catalyzed route to 18,19-norsteroid skeletons from bis-allenes, involving a cyclometallation-carbometallation-reductive elimination-Diels-Alder reaction cascade process.410... 

In K.C. Nicolaou s biomimetic synthesis of 1-O-methylforbesione, the construction of the 4-oxatricyclo[4.3.1.0]decan-2-one framework was achieved by using a double Claisen rearrangement that was followed by an intramolecular Diels-Alder reactionJ This one-pot biomimetic double Claisen rearrangement/intramolecular Diels-Alder reaction cascade afforded the natural product in 63% yield. 

Kobayashi, M., Suda, T., Noguchi, K., Tanaka, K. (2011). Enantioselective construction of bridged multicyclic skeletons intermolecular [2+2+2] cycloaddition/intramolecular Diels-Alder reaction cascade. Angewandte Chemie, International Edition, 50,1664-1667. 

In this year, White et al. [113] reported highly effective synthesis of tricyclic lactone structure, which is a common structure of class I galbulimima alkaloids, through tandem allylic C-H activative alkylation/Diels-Alder reaction cascade of a-allylated y-butenolide 167 (Scheme 67). In the presence of Pd(II) bis(sulfoxide) complex, the reaction of 167 with active methane compoxmd 168 initially gave triene 169. Under the present conditions, 169 smoothly cyclized to give tricyclic lactone 170 as a mixture of endo/exo adducts in 75% yield. 

An interesting transannular Diels-Alder/retro-Diels-Alder reaction cascade was employed in a formal total synthesis of ( )-strychnine by Bodwell and Li (Scheme 20.5). ° The reaction cascade involved a transannular inverse-electron-demand Diels-Alder (lEDDA) reaction of cyclophane 12 to form 13, which spontaneously expelled a molecule of nitrogen by the retro-Diels-Alder reaction to give 14 in quantitative yield. This led to a formal total synthesis of strychnine after 14 was converted into a common... 

SCHEME 20.5. The transannular Diels-Alder/retro-Diels-Alder reaction cascade in the synthesis of ( )-strychnine. 

The Boekelheide reaction has found utility in other synthetic methodology. An approach to 2,3-pyridynes made use of this chemistry in the preparation of the key intermediate 30. Treatment of 28 with acetic anhydride produced the desired pyridone 29. Lithiation was followed by trapping with trimethylsilyl chloride and exposure to triflic anhydride gave the pyridyne precursor 30. Fluoride initiated the cascade of reactions that resulted in the formation of 2,3-pyridyne 31 that could be trapped with appropriate dienes in Diels-Alder reactions. 

To rapidly construct complex structures, a recent synthetic strategy uses the Diels-Alder cycloaddition in sequence with another Diels-Alder reaction or with other reactions without isolating the intermediates (domino, tandem, cascade, consecutive, etc., reactions) [4-6]. Scheme 1.2 illustrates some examples. 

A domino Diels-Alder reaction (the term was chosen from the well-known game) is a one-pot process involving two or more Diels-Alder reactions carried out under the same reaction conditions without adding additional reagents or catalyst such that the second, third, etc., cycloaddition is the consequence of the functionality generated in the previous reaction. A historical example is illustrated in Equation 1.28 [60]. This type of transformation is sometimes named tandem or cascade, but these terms seem less appropriate for describing a time-resolved transformation. 

A tandem Diels-Alder reaction (the term refers to two operating units that are distinct but working at the same time) would indicate a process involving two distinct Diels-Alder reactions working at the same time (Equation 1.29) [6], and a cascade Diels-Alder reaction would refer to a transformation involving at least two Diels-Alder reactions occurring in sequence, without any reference to the fact that the subsequent reaction is the consequence of the functionality generated in the previous reaction (Equation 1.30) [61]. 

Treatment of bicyclic lactones 66, derived from Diels-Alder reaction of 3-carboxy-2-pyrone under standard radical conditions using (TMSlsSiH, leads to bridged lactones 67, which can smoothly be converted to bicyclo[3.3.0]-lactones 68 (Scheme 10). For X = CHaOMe, this cascade of rearrangements took place in a 78% overall yield, providing 68 in diastereomerically pure form. Three additional steps provided a novel route toward Corey s lactone 69. 

In contrast to the failure of Diels-Alder reactions, dipolar cycloadditions of indoles are much more successful, and the Boger group has reported a fascinating [4+2]/l,3-dipolar cycloaddition cascade involving indole as the dipolarophile in their impressive synthesis of vindoline (Scheme 4.8) [26]. After the initial... 

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

When the cyclic acetylene 260 is generated from a suitable precursor, it undergoes an isomerization reaction spontaneously generating naphthalene (263) and benzo-fulvene (264) as the finally isolable products. Very likely the process begins with a retro-Diels-Alder reaction to the [3]cumulene 261, which in a cascade reaction via the semicydic allene 262 rearranges to 263 and 264 [111]. 

Recently, further examples for dehydro Diels-Alder reactions were published, which are believed to proceed via intermediates of the type 205. To explain the formation of products besides those of the type 206, the authors [132] proposed a remarkable reaction cascade and supported it by quantum-chemical calculations. Accordingly, an isonaphthalene of the type 205 undergoes an electrocyclic ring expansion to give a l,2-dehydro[10]annulene derivative, in which a configurational isomerization occurs followed by an electrocyclic ring closure, yielding a further isonaphthalene of the type 205, and aromatization. 

The domino cycloaddition-iV-acyliminium ion cyclization cascade has been extensively reviewed. Tandem reactions combining Diels-Alder reactions and sigma-tropic rearrangement reactions in organic synthesis have been extensively reviewed. The tandem Diels-Alder reaction between acetylenedicarboxaldehyde and N,N -dipyrrolylmethane has been extensively studied at the RHT/3-21G and RHF/6-31G levels.The molecular mechanism of the domino Diels-Alder reaction between hexafluorobut-2-yne and A,A -dipyrrolylmethane has been studied using density functional theory. 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

Grigg and Xu have developed a variety of so-called queuing cascades involving allenes. The intra-intermolecular carbopalladation sequence of the <9-iodo-A-methyl-A -(methylallyl)aniline 142 and 1,1-dimethylallene 143 with subsequent / -dehydropalladation leads to the 1,3-dienyl-substituted indole derivative 144, which is immediately trapped by an added dienophile (e.g., A-methylmaleimide) in a Diels-Alder reaction to yield 145 (Scheme 37)7 ... 

A strained azo-bridged tricyclic system (1) undergoes a selective retro inverse electron-demand Diels-Alder reaction on heating, leading through a cascade of tautomeric and sigmatropic shifts to the pyridazine derivative (2) (Scheme 2).16 The proposed mechanism was supported by quantum chemical calculations and experimental evidence. 

When the carbopalladation of the bicyclopropylidene is performed in the presence of methyl acrylate, the reaction takes a different course (Scheme 8.34) [79]. The 1,3-diene intermediate 75 reacts in situ with the dienophile to give the spiro[2.5]octane derivative 76. An extension of this cascade Heck-Diels-Alder reaction involving l,3-dicyclopropyl-l,2-propadiene as the alkene partner, an alkenyl or aryl halide and a dienophile has been reported [80]. 

Alcaide et al. have used their methanesulfonate route to fused /3-lactams in a cascade sequence of reactions, including an intramolecular Diels-Alder reaction to obtain tetracyclic compounds (Scheme 17) <2003JOC3106>. 

Ru-catalysed enyne metathesis offers a short approach to chiral derivatives of 3-vinyl-5,6-dihydro-2//-pyrans. Some epimerisation can occur at the pyranyl C atom at elevated temperatures (Scheme 3) <02T5627>. The bispropargyloxynorbomene derivative 6 undergoes a cascade of metathesis reactions in the presence of alkenes and Grubbs catalyst incorporating an enyne-RCM that leads to fused cyclic dienes. A dienophile can be added to the reaction mixture, resulting in Diels-Alder reactions and the formation of functionalised polycyclic products <02TL1561>. 

These examples demonstrate that a selective Heck-Diels-Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28-30]. At 60 °C the cycloaddition was sufficiently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels-Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CC Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2OH) or allyl acetate 27 (R = CH2OAc) and dimethyl fumarate (28). 

The same authors also presented a completely selective three-component cascade reaction but of a slightly different type. By reacting 26 with a vinyl-stannane 27 (R = SnBus) in the presence of methyl acrylate or diethyl maleate, a sequential Stille-type [31] cross-coupling-Diels-Alder reaction took place, which only gave the desired products [30]. Since the Stille coupling proceeds without a base present, the dienophile does not participate in a Heck reaction, but only in a [4 + 2] cycloaddition with the initially formed electron-rich diene. 

Scheme 6 A cascade reaction consisting of a Heck coupling and a transmissive Diels-Alder reaction [37,38]...

Chung has used a combined PK/Diels-Alder cascade reaction to synthesize [5.5.5.6] fenestranes and triquinanes. The first products (181) were obtained in high yield from diendiynes 180 upon reaction with dicobalt octacarbonyl (5%) under 30 atm of CO at 130 °C. The authors think it is more probable that the Diels-Alder reaction occurs after the PKR instead that the diene reacts first with the closer triple bond to form a 1,4-cyclohexadiene that would undergo the PKR (Scheme 53) [ 170]. 

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