Ethyl hetero-Diels-Alder reaction

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). 

A similar use of maleimide was seen in Yu s hetero-Diels-Alder reactions. The Ar-ethyl pyrazole reacted under aqueous conditions at room temperature, with air oxidation to furnish the fully aromatized product <2001TL8931>. Other 1,3-substituted pyrazoles required heating in acetic acid at 50°C for 24h, with product yields of 42-67%. 

Li et al.39 reported the hetero Diels-Alder reaction of alkyl-3-(t-butyldimethylsilyl) oxy-1,3-butadiene 95 with ethyl glyoxylate 96 in the presence of a salen-Co(II) catalyst 94 (2 mol%). Product 97 was obtained in 75% isolated yield with an endo. exo ratio >99 1. The enantiomeric excess of the endo-iorm was up to 52% (Scheme 5-30). 

Figure 26. Proposed stereochemical model for the hetero-Diels-Alder reaction of ethyl vinyl ether and acylphosphonate catalyzed by 55c-Cu(II) complex.

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

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). ... 

In hetero-Diels-Alder reactions, the effect of ligand structure and acidity on the catalytic activity of lanthanide catalysts has been reviewed.191 The effect of different C(2)-symmetric bisoxazolines on the zinc(II)-catalysed hetero-Diels-Alder reaction of ethyl glyoxylate with conjugated 1,3-dienes has been investigated.192 The hetero-Diels-Alder reaction 4-dimethylamino-2-phenyl-l-thiabuta-1,3 -diene with methyl acrylate and /V-cnoyloxazolidinone produces cw-3,4-disubstituted 3,4-dihydro-2//-... 

The hetero-Diels-Alder reaction between sulfinyl diene 152a and ethyl gly-oxalate [149] has also been reported. (Scheme 89). In the presence of LiCl04,the endo adducts 185 are predominant, but under Eu(fod)3 or ZnCl2 catalysis the exo adducts 186 are the major ones. The endo/exo selectivity is rather moderate, and the 7r-facial selectivity is low in all cases. 

The enamine (287 R3 = Bn, R1 + R2 = (CH2)20(CH2)2) reacts with ethyl benzoylacetate affording heterocycle (99) (87JHC111). Enamines (287 R3 = Me, R1, R2 = various groups) react with the ester (288) giving products (289) in moderate yield and related enamines behave similarly in this hetero-Diels-Alder reaction <85AP(318)648>. 

Wyler et al. [146a-c] have focused on the hetero Diels-Alder reaction of a,/)-unsaturated-acyl cyanides such as 2-140 with ethyl vinyl ether, N-methylated uracil and l-bromo-2-ethoxyethenes 2-141. In the latter case the dihydropyran... 

The advanced state of the art in carbohydrate synthesis basing on hetero Diels-Alder reactions of 1-oxa-l,3-butadienes has opened an access to enan-tiopure sugar derivatives. Thus, our group found the cycloaddition of the chiral heterodiene 7-1 and the electron-rich alkene 7-2 under the influence of Me2AlCl to give the dihydropyran 7-3 in excellent endo selectivity (endo/exo >50 1) and as well excellent induced diastereoselectivity (54 1) [478]. A short sequence involving one simple recrystallisation then led to the ethyl-/)-D-mannopyrano-side 7-4 in enantiomerically pure form (Fig. 7-1). 

Tietze and Schuffenhauer explored the intermolecular hetero Diels-Alder reaction of ethyl vinyl ether and sulfinimine 204 and found that at high pressures (11 kbar) and long reaction times (48 h at room temperature), tetrahydropyridines 205 and 206 were obtained in 96% yield and in a ratio of 1.7 1.107 The exo-adducts were not observed. Phenyl vinyl sulfide reacts similarly, but simple alkenes failed. Theoretical calculations and the experimental results suggest that while the cycloaddition is concerted, it is highly asynchronous. 

For the enantioselective hetero Diels-Alder reaction, very similar bis(oxazoline) complexes proved to be highly efficient [28]. The conversion of several unsaturated keto-esters 59 with ethyl-vinyl ether 60 gave cycloaddition products 61 in 97-99% ee. 

The hetero-Diels-Alder reaction is amongst the most efficient processes for the synthesis of six-membered heterocyclic ring systems. Solvent-free conditions have been used to improve reactions of heterodienophiles and heterodynes with low reactivities. Cado et al. (1997) have described the hetero-Diels-Alder reaction of ethyl lH-perimidine-2-acetate as heterocyclic ketene aminal with ethyl propiolate nnder solvent-free conditions with focused microwave irradiation. The new fused perimi-dines (23) were obtained in good yields (67-98%). 

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... 

The product formed in this hetero-Diels-Alder reaction of ethyl glyoxylate with a cyclic diene catalyzed by (.S, iS )-t-Bu-box in combination with a copper(II) salt was used in the simple synthetic approach to enantiopure synthons for a class of natural products. Saponification of the bicyclic adduct followed by acidification with aqueous HCl provides the enantiopure (>99% ee) rearrangement product (eq 8). ... 

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. 

In the course of a formal total synthesis of 3-deoxy-D-maimo-2-octulosonic acid (KDO), a chiral (salen)Co(II) complex was used to catalyze a highly double-stereoselective hetero-Diels-Alder reaction between an electron-rich chiral diene and ethyl glyoxylate (Sch. 56) [201]. This reaction was subsequently extended to achiral dienes [202]. 

Iron(III) 2-ethylhexanoate is a catalyst for the stereoselective hetero-Diels-Alder reaction of ethyl ( )-4-oxobutenoate with alkyl vinyl ethers to give ci5 -2-alkoxy-3,4-dihydro-2//-pyran-4-carboxylic acid ethyl esters with a high diastereoselectivity (Sch. 57) [203],... 

Zamojski, A. De novo synthesis of enantiopure carbohydrates preparation of ethyl (i-D- and 3-L-mannopyranosides by an asymmetrically induced hetero Diels-Alder reaction. Chemtracts Org. Chem. 1995, 8, 69-72. 

The enantioselective hetero-Diels-Alder reactions of a,p-unsaturated acylphosphonates with enol ethers catalyzed by Cu(II)bzT(oxazoline) complexes have been investigated in depth. It was found that Cu(II)bA(oxazoline) complexes activate a,p-unsaturated acylphosphonates to the extent that they undergo facile cycloaddition reactions at low temperature with electron-rich alkenes. For example, dimethyl ( )-l-oxo-2-butenylphosphonate reacts with ethyl vinyl ether in the presence of Cu[(S,5)-t-Bu-box] (OTf)2 complex (10 mol% catalyst) to generate the cycloadduct in 89% yield (Scheme 7.86) with exceptional stereoselectivity (endo/exo = 99/1, 99% ee). Cyclic enol ethers also undergo stereoselective reactions with dimethyl ( )-l-oxo-2-butenylphosphonate. It specifically reacts with 2,3-dihydrofuran in the presence of Cu[(5,5)-t-Bu-box] (OTf)2 to deliver the bicyclic enolphosphonate. Of particular merit is the fact that a large variety of p.y-unsaturated acylphosphonates may be tolerated with no loss in selectivity for the derived cycloadducts. ... 

Evans et al. reported that in the presence of Cz-symmetric bis(oxazoline)—Cu(II) complex 438 the inverse electron demand hetero-Diels—Alder reaction of the a,/Tunsaturated carbonyl compounds 436 with ethyl vinyl ether gave the chiral dihydropyrans 437 in high diastereo- and enantioselectivities (Scheme 139).199c... 

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