Hetero-Diels-Alder reaction intramolecular, forming

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

This observation has been used in a key step during a total synthesis of the alkaloid ( )-dihydrocanni-vonine (77) outlined in Scheme 9.30 The final product is formed by intramolecular hetero-Diels-Alder reaction of the intermediate (76), which is not isolated. 

An intramolecular hetero-Diels-Alder reaction has been used to produce the cyclopentaquinoline core of a series of alkaloids <20030L2509>. They form in high diastereoselectivity, generating up to four contiguous stereogenic atoms (Equation 134). 

A high asymmetric induction in intramolecular hetero Diels-Alder reactions was found using chiral 1-oxa-1,3-butadienes with a stereogenic center in the tether [54]. Such compounds can easily be obtained by a Knoevenagel condensation of a 1,3-dicarbonyl compound such as iV,N-dimethylbarbituric acid with a chiral aldehyde bearing a dienophile moiety [169 a] (Scheme 2-3). With the stereogenic center in a-position relative to the oxadiene or dienophile moiety an excellent induced diastereoselectivity is obtained for the nearly exclusively formed trans-cycloadduct (simple diastereoselectivity = 97.9 2.1 and 98.3 1.7,... 

Such syntheses take advantage of transannular intramolecular hetero Diels-Alder reactions [426], another impressive example is the diene transmissive hetero Diels-Alder reaction of the thioketone 5-14. The diene 5-15 formed by this cycloaddition underwent a second Diels-Alder reaction with N-phenyl-maleimide to yield the fused polycycle 5-16 as single diastereomer (Fig. 5-5) [427]. 

Snider et al. have synthesised the antiinsectan ( )-leporin [496] 7-26 using the domino-Knoevenagel-hetero Diels-Alder sequence. The intermediate 1-oxa-1,3-butadiene 7-25 was formed in situ by condensation of the pyridone 7-23 and the dienal 7-24. Subsequently, a hetero Diels-Alder reaction occurred accompanied by minor side reactions. Thus, the desired cycloadduct 7-27 was formed only in moderate yield as 5 1 mixture with its trans-fused diastereomer (Fig. 7-6). Functionalisation of the nitrogen atom yielded the natural product. A similar reaction sequence occurred in the synthesis of the structurally related free radical scavenger ( )-pyridoxatin, however, in this approach the hetero Diels-Alder reaction represented only a side reaction competing with the desired intramolecular ene reaction [497]. 

Apart form the aforementioned highly enantioselective hetero-Diels-Alder reactions, that proceed with very low catalyst loadings, the catalytically accessible enolates have also been used for related intramolecular Michael reactions (Philips et al. 2007) and for the desym-metrization of 1,3-diketones yielding cyclopentenes via an intramolecular aldol reaction (Wadamoto et al. 2007). The formation of cyclopentenes, however, presents a special case, so—depending on the stereochemical nature of the enone substrates (s-cis or s-trans) and the stereochemistry of the final products—two different mechanisms are discussed in the literature. Whereas /ran.v-cycl open (cries are proposed to be available upon conjugate addition of a homoenolate to chalcones,... 

One sure way to make the hetero Diels-Alder reaction go well and with regio-and stereoselectivity is to make it intramolecular.14 The highly reactive diene 90 is formed by elimination with fluoride ion from 89. The cycloaddition is rapid because it restores aromaticity. The regiose-lectivity is as expected from HOMO of dienophile plus LUMO of diene but is probably controlled by the tether.15 The stereochemistry certainly is the azadiene is attached to the bottom face of the five-membered ring and is delivered to the bottom face of the dienophile to give the all-trans aza-oestrone 91. 

A remarkable observation is the cyclization of biscarbamate (194) to y-lactone (195) mediated by methanesulfonic acid (equation 133). No trace of the expected 8-lactone is formed, presumably because of the unfavorable ester geometry in the transition state required for six-membered ring formation. Such problems with 8-lactone formation have been observed also in Diels-Alder chemistry. A nice example related to A-acyliminium chemistry is the thermal hetero Diels-Alder reaction of acylimine precursor (196) to bicyclic -y-lactone (197) in good yield. The corresponding intramolecular cycloaddition of (198) fails. Finally, Lewis acid mediated cyclization of allylsilane (199) is unsuccessful, although lactonization of (200) proceeds very well (equation 135, cf. equation 119). ... 

A common problem in Diels-Alder reactions is the regioselectivity. It is usually controlled by the coefficients of the interacting orbitals in the transition structures and can be improved in many cases by using Lewis acids. However, the application of high pressure also has a great influence as shown for the intramolecular hetero-Diels-Alder reaction of the benzylidenebarbituric acid derivative 48 (Scheme 8.13). In this transformation the ortho-adduct 49 and the meta-adduct 50 are formed. 

Pressure effects on the diastereoselectivity can also be observed for intramolecular cycloadditions such as the hetero-Diels-Alder reaction of 90, even though the AAV are smaller compared to intermolecular reactions (Scheme 8.23). The kinetics were again measured by on-line FT-IR spectroscopy and the stereoselectivity by HPLC. At atmospheric pressure in toluene under reflux the reaction of 90 led to a 5.2 1 ratio of the diastereomeric cycloadducts 91 and 92 in 93 % yield. Increasing pressure favors the formation of the cis-adduct 91, which is probably formed via an endo-E-syn transition structure. Interestingly, in the ground state of 90 the Z-configuration is more stable and it is therefore assumed that isomerization of the Z- to the B-double bond occurs prior to the cycloaddition [51]. From the slope of the plot of ln(91/92) versus pressure, AAV is calculated to be -(1.6 + 0.2) cm mol with the individual values for AV = -(19.4 + 0.2) and AV = —(17.9 0.6) cm mol at 343 K. Although the AV values are relatively low in comparison with data reported for other intramolecular Diels-Alder reactions e.g. 

The first example of a true positive high pressure effect on the enantioselectivity was found for the intramolecular hetero-Diels-Alder reaction of the l-oxa-1,3-butadiene (173) in the presence of the Narasaka catalyst (164) to give the two enantiomeric bridged cycloadducts 174 and 175 (Scheme 8.44) [80]. At atmospheric pressure the two enantiomers were formed with 4.5 % ee, whereas at 500 MPa an increase to 20.4 % ee was observed which corresponds to a AAV = —(1.7 + 0.2) cm mol . In addition, the yield was improved from 50 to 89 %. It was assumed that under high pressure complexes of different stoichiometry may be formed which are more favorable towards a facial selective addition. However, a clear interpretation of the results cannot be given at this point. 

A domino reaction involving two consecutive oxidations followed by a hetero Diels-Alder reaction led to the formation of bicyclic dihydropyran 14 in 74% yield (Scheme 9.3). In this process, developed by Koo et al. [5] using Mn(OAc)3 and Cu(OAc)2, the P-ketoester 11 having a geranyl group at the a-position is converted into the a-ketoester 12, which undergoes further oxidation to form the tertiary alcohol 13 and is followed by an intramolecular hetero Diels-Alder reaction to provide the desired bicyclic trans-fused dihydro cyclopenta[c]pyran 14. In 2012,... 

The domino reaction started with an intramolecular hetero-Diels-Alder reaction of 215 to give 218, which was followed by elimination of molecular nitrogen to form the 1,3-dipole 219. The final step in the sequence was an intramolecular [3 + 2]-cycloaddition to provide rac-216 in 71% yield as a single diastereomer. Compound... 

A new efficient and stereoselective synthesis of furo[2, 3 5,6]pyrano[4,3-i)]quinoline derivatives and has been achieved by intramolecular hetero Diels-Alder reactions of aldimines generated in situ from aromatic amines and the O-allyl derivative of the chiral sugar derived aldehyde in acetonitrile in the presence of a catalytic amount (10 mol%) of BiCl3. The products are formed with extremely high (>95%) trans-selectivity in good to excellent yields (Equation 20) [38a]. The authors have also carried out the diastereoselective synthesis of new hexahydropyrazolo[4, 3 5,6]thiopyrano[4,3-t>] in the similar conditions [38b]. 

Tietze also reported an increase in the enantioselectivity of a cycloaddition reaction which was carried out in the presence of a chiral Lewis acid under high pressure. The intramolecular hetero Diels-Alder reaction (HIMDA) [68] of the benzyli-dine compound 186 proceeds by a mcte-addition to give two enantiomeric bridged cycloadducts 187 and 188 (Scheme 45). At ambient pressure (dichloromethane, RT, 31 h), in the presence of the chiral titanium Lewis acid catalyst, product 187 was formed preferentially (with 4.5% ee). In addition to die increase in chemical yield obtained at normal pressure (from 50%), enantioselectivity of the cycloaddition at 5 kbar was increased to (20.4% ee), in favor of the (-) enantiomer 188. 

The enantioselective intramolecular formal 2+4-cycloaddition of acrylates and a, -unsaturated imines (99) catalysed by chiral phosphines (100), derived from amino acids, produced A-heterocycles (101) (Scheme 31). Chiral dirhodium(II) carboxamidates (102) catalysed the hetero-Diels-Alder reactions between 2-aza-3-silyloxy-l,3-butadienes and aldehydes to yield all cw-substituted l,3-oxazinan-4-ones in high yields and high enantioselectivity (98% ee)P The nickel-catalysed 4 + 2-cycloaddition of a, -unsaturated oximes with alkynes yielded 2,3,4,6-tetrasubstituted pyridine derivatives. The reaction of isoquinoline, an activated alkyne, and 4-oxo-4//-l-benzopyran-3-carboxaldehyde (103), in ionic solvents, produced 9a//,15//-benzo[a][l]benzopyrano[2,3-/t]quinolizine derivatives (105) via the zwitterion (104) selectively and in good yields (Scheme 32).The Diels-Alder cycloaddition of ethyl 3-(tetrazol-5-yl)-l,2-diaza-l,3-butadiene-l-carboxylates with -rich heterocycles, nucleophilic olefins, and cumulenes formed 3-tetrazolyl-l,4,5,6-tetrahydropyridazines regioselectively. The silver-catalysed formal inverse-electron-demand Diels-Alder... 

Lactone 5 can be obtained in both enantiomeric forms or as a racemate according to the described procedure. The reaction sequence includes the in situ formation of an alkylidene-1,3-dicarbonyl system 7 which can act as a heterodiene in an intramolecular hetero-Diels-Alder addition. A small amount of the ene product 4 with de > 98% is formed at room temperature as well. The remarkable selectivity in formation of diastereomer 3 is explained by an energetically more favorable exo transition state 8 with a pseudo-chair arrangement having the methyl group quasi-equatorial. Polycyclic cis-fused compounds can also be synthesized by the procedure above,9 and a related sequence to the cannabinoid skeleton has been described using appropriate 1,3-dicarbonyl reactants.10... 

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]. 

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