Hetero-Diels-Alder reaction 1.3- cyclohexadiene

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

The scope of this methodology was extended to the enantioselective hetero-Diels-Alder reaction between 1,3-cyclohexadiene and ethylglyoxylate,... 

It has been shown that complete selectivity for the hetero-Diels-Alder cycloadduct 109 (100% endo, 60% ee) can be achieved in the hetero-Diels-Alder reaction of 1,3-cyclohexadiene 108 and ethyl glyoxylate 99 using ent-6 and copper(II) triflate derived catalyst complex. Another interesting reaction introduced by Jprgensen and co-workers was the reaction between 1,3-cyclohexadiene 108 and diethyl ketomalonate 110 to form cycloadduct 111 in 76% yield with an ee of 84% (Fig. 9.35b, p. 558). ... 

Furthermore, azo dienophiles have been employed in diene-transmissive hetero Diels-Alder reactions of cross-conjugated trienes which allow the straightforward construction of polycyclic compounds [297]. Theoretical interest has been directed to the hetero Diels-Alder reaction of diethyl azo di-carboxylate with 1,3-cyclohexadiene whose concerted course was demonstrated by means of a high pressure study [298]. 

Hetero-Diels-Alder Reactions of Aldehydes. Cyclic conjugated dienes, such as 1,3-cyclohexadiene, are excellent substrates for the hetero-Diels-Alder reaction with ethyl glyoxylate catalyzed by Cu[(5, 5 )-t-Bu-box] (OTf)2 (eq 7). The rate of this reaction is dependent on the counterion and the solvent. To obtain... 

Hetero-Diels-Alder Reactions of Ketones. Ketonic substrates such as ethyl pyruvate (eq 9, R =Me, R = OEt) do not react with simple dienes such as cyclopentadiene or 1,3-cyclohexadiene in the presence of (5, 5)-/-Bu-box and a metal salt as catalyst. However, using activated dienes such as /ranf-l-methoxy-3-[(trimethylsilyl)oxyl]-l,3-butadiene (Danishefsky s diene), a hetero-Diels-Alder reaction with ethyl pyruvate and similar substrates catalyzed by 10 mol% of Cu[(5, 5)-/-Bu-box] (OTf)2 takes place in good yields and enantioselec-tivities (eq 9). Surprisingly, it was even possible to reduce the catalyst loading to only 0.5 mol % without affecting the yield of the product, and in some cases the enantiomeric excess was even improved. 

A number of diverse stmctural types of cyclic imino dienophiles have been used in cycloadditions. For instance, dehydrohydantoins are useful partners in hetero Diels-Alder reactions. Two methods have been developed for in situ generation of these species. In one tqjproach, methoxyhydantoins such as (24) (equation S) are heated or are treated with acid to promote elimination of methanol, affording dienophile (25).22- This intermediate can be trapped regio- and stereo-selectively with 1,3-dienes. For example, with 1,3-cyclohexadiene only endo adduct (26) is formed. There is no ambiguity in this case concerning the dienophile configuration, and thus product (26) clearly derives from an endo transition state. 

Further examples of hetero-Diels-Alder reactions of carbohydrate-derived chloronitroso compounds have been reported. When the chloronitroso compound 214, made from D-xylose, reacted with cycloheptadiene in the presence of some water, the cycloadduct 215, which could be used in a synthesis of (-)-physoperuvine, was obtained in a96% ee, together with the sugar ketone which can be recycled to 214. The pseudoenantiomeric species 216, from L-sorbose, gave the dihydrooxazine 217 on reaction with cyclohexadiene, again in high e.e. The chloronitroso compound 218, easily accessible from D-ribose, underwent... 

Mikami carried out the asymmetric hetero Diels-Alder reaction of ethyl glyoxy-late (27) with 1,3-cyclohexadiene and obtained the cycloadduct 33 with 94% ee in 62% yield [10],... 

A hetero-Diels-Alder reaction between the imine (115) and the cyclohexadiene (116) produces the aza-bicyclo-octane (117), which after Baeyer-Villiger ring expansion followed by reduction, gave the triol (1l8), an advanced intermediate with all three chiral centres in their correct relative stereochemistry, for the synthe-... 

The second example of enantiodiveregent hetero-Diels-Alder reaction is shown in Scheme 6.28. Thus, racemic cyclohexadiene 132 was reacted with 2-nitrosopyridine 133 in the presence of a copper(I) source and the chiral phosphine ligand 134 to afford regioisomeric hetero-Diels-Alder products 135 (48% and 97% ee) and 136 (52% and 92% ee) [49b]. The Cu(I) complex of 134 functions as a chiral Lewis acid that catalyses the 2-1-4 cycloaddition. 

Hetero Diels-Alder reactions involving chloronitroso sugars have been described by Vasella (42). A single cycloadduct was obtained in the reaction of 67 with cyclohexadiene. Compound 67 was obtained from D-mannose. The carbohydrate moiety was cleaved from the cycloadduct by in situ methanolysis to give 68. 

Atroposelective cycloaddition reactions of A-2-(r-butylphenyl)- and A-2,5-(di-r-butylphenyl)-maleimide show good to excellent stereoselectivities and the high rotation barriers prevent cycloadducts from interconverting. The stereospeciflc hetero-Diels-Alder reaction of o-quinone methides (80) with o-quinones (79) in MeOH at room temperature produce the 4a,8-di(hydroxymethyl)chromane derivatives (81) and (82) in high yields (Scheme 29). The intramolecular inverse-electron-demand Diels-Alder reaction of o-quinone methides (84) derived from 2-(l-hydroxy-5-alkenyl)phenol derivatives (83) produces l,2,3,3a,4,9b-hexahydrocyclopenta[c][l]benzopyrans (85) under mild acidic conditions (Scheme 30). The Diels-Alder reactions between dimethyl-cyclohexadiene derivatives and di-(-)-menthyl acetylenedicarboxylate exhibit modest diastereoselectivity. ... 

A review containing 123 references on recent mechanistic and theoretical studies of hetero-Diels-Alder reactions has been presented. The hetero-Diels-Alder reactions of homochiral 1,2-diazabuta-1,3-dienes with diethyl azodicarboxylate are accelerated by microwave irradiation to produce the corresponding functionalized 1,2,3,6-tetrahydro-l,2,3,4-tetrazines. " The transition structures for hetero-Diels-Alder reactions involving the heteroatoms O, S, and N in dienes and also in dienophiles were determined at the MP2 and the hybrid DPT levels of theory. The activation volume of the Diels-Alder reaction between dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate and hex-l-ene indicates the conservation of all four nitrogen atoms in the transition state. " 4-n-Propyl-l,2,4-triazoline-3,5-dione reacts with cyclopentadienes, cyclohexadienes, and cycloheptadienes to yield 4 + 2-cycloadducts. ... 

The preparation of a conduramine derivative 90 by hetero-Diels-Alder reaction of a chloronitroso sugar derivatives with cyclohexadienes has been reported. (See Vol. 25, p. 210, ref. 73 for similar work). 

The initial work on the asymmetric [4-1-2] cycloaddition reactions of A -sulfinyl compounds and dienes was performed with chiral titanium catalysts, but low ee s were observed <2002TA2407, 2001TA2937, 2000TL3743>. A great improvement in the enantioselectivity for the reaction of AT-sulfinyl dienophiles 249 or 250 and acyclic diene 251 or 1,3-cyclohexadiene 252 was observed in the processes involving catalysis with Cu(ll) and Zn(ii) complexes of Evans bis(oxazolidinone) (BOX) ligands 253 and 254 <2004JOC7198> (Scheme 34). While the preparation of enantio-merically enriched hetero-Diels-Alder adduct 255 requires a stoichometric amount of chiral Lewis acid complex, a catalytic asymmetric synthesis of 44 is achieved upon the addition of TMSOTf. 

Most importantly, the scope of the Diels-Alder reaction is very high - not only allowing the synthesis of cyclohexenes and 1,4-cyclohexadienes using 1,3-butadienes and alkenes and alkynes, respectively, but also giving access to a multitude of different heterocycles by exchanging the atoms a-d in the butadiene as well as the atoms e and f in the alkene by hetero atoms such as oxygen, nitrogen and sulfur. However, also dienes and dienophiles with several other atoms as phosphorous, boron, silicone, and selenium have been described. Thus, many different heterodienes and heterodienophiles have been developed over the years (Tables 1-1 and 1-2). 

BicycUc N-allyl anilines 40, and armulated quinoHnes 41, could be prepared by means of hetero Diels-Alder cycloadditions of cyclopentadiene 39 (n= 1) and cyclohexadiene 39 (n= 2), respectively, and imine 38 [9ej. The reaction of cyclopentadiene 39 (reaction as dienophile) in the presence of strong Lewis acids such as BE3 and SOj directly resulted the formation of the quinoline derivative 41 (n=l, P benzoyl) with 87-88% even at ambient temperature. The use of weaker Lewis acids (CuCl) and low temperatures (-20 °C) enabled to isolate some unstable bicycle 40 (8%, R= NO2), which could be completely converted into the quinoline 41 upon heating or after treatment with a stronger Lewis acid. In the case of the conversion of cyclohexadiene 39 (n=2), the acceptor substituted anilines 38 (R = NOj, Cl) predominantly reacted as dienophiles to give the bicycles 40 with... 

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 cycloaddition reaction of substituted dialkyl a-keto-P,y-unsaturated phospho-nates with cyclopentadiene, cyclohexadiene, dihydrofuran, and dihydropyran was reported. The authors surveyed a series of Lewis acids, Sc(OTf)3, Yb(OTf)3, BiCl3, TiCU, and SnCU to assess their influence on the ratio of the hetero Diels-Alder product (3) and the Diels-Alder cycloadduct (4). BiCl3 was found to be not efficient concerning the selectivity between these two competitive reactions (Equation 22) [40a]. 

Theoretical studies have been carried out on the conrotatory and disrotatory reaction pathways of hexa-l,3,5-triene to cyclohexadiene, and the effect of solvent and salt effects on the rates of the electrocyclic ring closure of (IZ, 3Z, 5 )-l,2,6-triphenylhexa-l,3,5-triene has been determined. An ab initio study of the electro-cyclization of (Z)-hexa-l,3,5-triene and its hetero-substituted analogues has been undertaken.The involvement of a lone pair on the nitrogen or oxygen atom appears to facilitate the interaction between the terminal atoms that bond to each other to close the ring. It has been reported that the intramoiecular aza-Diels-Alder reaction of an a./S-unsaturated hydrazones to a quinone, as in (197), is followed by an unprecedented rearrangement in which the aminoaryi moiety formally undergoes a 1,2-shift to yield benzo- or pyrido-[fc]acridine-6,11-dienes (198). 

Diels-Alder reactivity of 4-aza-6-nitrobenzofuroxan 235 has been studied via reactions with cyclopentadiene, cyclohexadiene, and 2,3-dimethylbutadiene this has led to three types of Diels-Alder adducts, namely the normal Diels-Alder adducts 234, 236, a Diels-Alder hetero-adduct 238, and the di-adducts 237, 239 arising from a minor dinitroso tautomer of compound 235 (Scheme 59) <1999CC1009, 2000JOC7391>. 

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