HDA cycloaddition reaction

Besides nucleophile-induced transformations the Hetero Diels-Alder (HDA) cycloaddition reactions are also very suitable ways to perform the pyrimidine-to-pyridine ring transformations. They can occur either by a reaction of an electron-poor pyrimidine system with an electron-rich dienophile (inverse HDA reactions) or by reacting an electron-enriched pyrimidine with an electron-poor dienophile (normal HDA reactions) (see Section II.B). 

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). 

Asymmetric Hetero-Diels-Alder Reactions. By using stoichiometric amounts of the bis(oxazoline)-copper(II) triflate system as catalyst, asymmetric hetero-Diels-Alder (HDA) cycloaddition reactions were performed with cyclic and acyclic 1,3-dienes. The reported enantioselectivity (70-98% ee) and... 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

The use of the zinc complex of the BINOL ligand 946 in the hDA reaction between Danishefsky s diene 947 and aldehydes proceeds in excellent yield and enantioselectivity to afford dihydropyran-4-ones 948 (Equation 370, Table 45) <2002OL4349>. An asymmetric diethyl zinc addition can occur in tandem with the cycloaddition reaction between Danishefsky s diene 947 and isophthalaldehyde using a related catalyst 949 (Equation 371) <20030L1091, 2005T9465>. 

The HDA reaction allows for rapid access to chiral six-membered heterocyclic structures that serve as valuable intermediates in organic synthesis. The first highly enantioselective HDA reaction promoted by a chiral hydrogen bond donor was reported from the Rawal laboratory. While investigating the cycloaddition reactions of amino-siloxy diene 115, it was observed that this diene was exceptionally reactive to heterodienophiles, and underwent HDA reactions with various aldehydes at room temperature, even in the absence of any added catalyst (Scheme 6.14). Subsequent treatment of the intermediate cycloadducts (116) with acetyl chloride afforded the corresponding dihydro-4-pyrones (117) in good overall yields [101]. Further studies of this reaction revealed a pronounced solvent effect,... 

Diels-Alder (HDA, reaction VII) and [2 + 2] cycloadditions (reactions VII and VIII) were kinetically examined at various pressures (Scheme 10.3, Table 10.2)... 

In this article, we focus the discussion on our investigations on [27t + 2n + 2ti] (homo Diels-Alder, HDA) and [2 i + 2 t] cycloaddition reactions of norbomadiene that were carried out during the past seven years. 

Similar studies of the regioselectivity in the HDA reaction between 2-substituted norbomadienes and unactivated terminal acetylenes catalyzed by a cobalt catalyst were also undertaken. Unfortunately, 2-sub-stituted norbomadienes are much less reactive with unactivated acetylenes in the cobalt-catalyzed HDA reaction than with electron-deficient olefins in the Ni-catalyzed HDA cycloadditions. When an electron-withdrawing group (Y = COOMe) or an electron-donating group (Y = OMe) is attached to the 2-position of the NBD, no desired [2 + 2 + 2] cycloadduct is observed with 1-hexyne, even in refluxing toluene for three days under the usual cobalt-catalyzed conditions (Scheme 12). Instead, some NBD dimers and acetylene trimers are detected. With a... 

Figure 1.15 Modern variants of the Diels-Alder cycloaddition reaction (a) Inverse-electron-demand Diels-Alder (lEDA) reaction between tetrazine and norbornene/ and (b) hetero Diels-Alder (HDA) reaction between thiocarbonyl and cyclopentadiene. ...

Some other highly efficient cycloaddition reactions have been used for polymer end-group modification and polymer-polymer conjugation. These include an additive-free version of the hetero Diels-Alder (HDA) reaction or the nitrile-imine-mediated tetrazole-ene cycloaddition (NITEC), the latter only requiring photoirradiation. Both techniques meet the criteria to be considered bioorthogonal reactions and can be performed under mild reaction conditions. As such, these reactions should also be applicable for the preparation of bioconjugates. 

In order to evaluate the performance of these dithioesters in HDA cycloadditions, poly (ethylene glycol) monomethyl ether (PEG) was equipped with an open-chain diene and, in another example, with a cyclopentadienyl endgroup in order for the HDA adducts to be clearly characterized by electrospray mass spectrometry (ESI-MS). The reaction schematic is presented in Figure 2.5a. 

In the case where the open-chain diene functional PEG was utilized, 24 h were required to attain completion in a catalyst-free, ambient-temperature reaction. However, use of the more-reactive Cp-functional PEG resulted in complete conversion (under identical reaction conditions) in less than 1 h. Despite this high performance, the HDA adduct partially degrades to form the structures depicted in Figure 2.5b. The degree of degradation can be qualitatively discerned from the ESI-MS spectra presented in Figure 2.5c. It must be noted that residual precursor material observed in the spectra (species 1) is attributed to the occurrence of a retro-HDA cycloaddition under the conditions of measurement. 

Recently, Hoye and coworkers [257, 258] reported a new fluorenone synthesis by a novel hexadehydro-Diels-Alder (HDA) reaction (Scheme 6.109). In the HDA reaction, a 1,3-diyne 418 is engaged in a [4+2] cycloisomerization with a diynophile to produce the highly reactive benzyne intermediate 419. When trapping reagents are absent, the generated benzyne 419 undergoes a cycloaddition reaction with benzene as the solvent to form adduct 420. 

To rationalize the enantioselectivity of the TADDOL-catalyzed HDA reaction between Danishefsky s diene and benzaldehyde, eight possible diastereomeric transition states of different regio- and stereochemistry should in principle be considered for comprehensive analysis. The cycloaddition between the model diene and benzaldehyde can take place along two regio-isomeric meta (C1-06, C4-C5 bond formation) and ortho (C1-C5, C4-06 bond formation) reaction channels. For both of these pathways, an exo- and an endo-approach can be formulated (Scheme 11) [64]. 

There are a number of examples of the synthesis of chromans using o-quinone methides as the heterodiene in a hDA reaction. Both pyrano[3 -c]-benzopyrans and cyclopenta[c][l]benzopyrans result from an intramolecular cycloaddition of a substituted o-quinonemethide generated under mild conditions. In the former case, salicylaldehyde and an unsaturated alcohol yield the rra/is-fused tetrahydropyranobenzopyran (Scheme 10) <99JOC9507>. However, the latter synthesis (Scheme 11) is less selective <99BCJ73>. 

The use of hDA methodology as a means of constructing the dihydropyran-4-one ring system continues to attract much interest. A review concerning the enantioselective hDA reaction covers the synthesis of dihydropyran-4-ones using this cycloaddition approach <2000AGE3558>. 

In an extension of the above hDA reaction, the cycloaddition of the thiabutadiene with maleic anhydride gives a 2-amido-277-thiopyran by way of elimination and addition of Me2NH to the anhydride unit (Equation 128) <2001M947>. 

Taddols can also catalyze the HDA reactions of other electron-rich dienes, as demonstrated by Ding and co-workers, who showed that taddol 119 catalyzed the cycloaddition of Brassard s diene with various aromatic aldehydes to give... 

Phosphonoacrolein, (Et0)2P(0)C(CH0)=CH2, takes part in hDA reactions with alkenes and cyclic conjugated dienes, to give phosphono-substituted 3,4-dihydro-2W-pyrans and their annulated derivatives. The reaction with alkynes gives the 1 1 adduct, a 4//-pyran, initially but this undergoes a second cycloaddition leading to a tetrahydropyrano[3,2-6]pyran 3... 

An enantioselective aryloxylation of aldehydes is based on their prior conversion to an enamine through reaction with a chiral secondary amine catalyst. A subsequent inverse HDA reaction with o-quinones leads to 3-alkyl-2-hydroxy-l,4-benzodioxins with ee ca. 80% (Scheme 47). Manipulation allows the synthesis of (S)-2-alkyl-2,3-dihydro-l,4-benzodioxins <07TL1605>. In like manner, racemic nitidanin, which possesses antimalarial properties, has been synthesised through a regioselective cycloaddition of an o-quinone with a protected 3-arylpropen-l-ol <07TL771>. 

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