HDA 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 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. 

A numher of azabenzisochromanquinone antibiotics have been synthesised by the HDA reaction between isochromanquinones and 1-aza-1,3-dienes <96LA1385>. 

Complete diastereoselection is observed in the HDA reaction of Danishefsky s diene with o-substituted benzaldehyde chromium tricarbonyl complexes. Decomplexation is facile and good yields of 2-aryl-2,3-dihydropyran-4-ones result <96SL258>. Cis-2,3-disubstituted pyranones are accessible from the Lewis-acid catalysed HDA reaction between (triisopropylsilyloxy) dienes and aldehydes and dehydrogenation of the resulting dihydropyrans <96JOC7600>. 

The first examples of intramolecular diene transmissive HDA reactions have been reported. Thus, the divinyl thioketones, derived from the ketones by treatment with Lawesson s reagent, spontaneously cyclise to the thiopyran derivative (27) and react further as shown <96CC811>. 

Similarly, the macrocyclic a,p-unsaturated thioketone (28) undergoes a stereoselective transannular HDA reaction < 96SL72>. 

Alder (hDA) reaction <00CEJ3755> and the electrochemical oxidation of m-hydroxyalkyl tetrahydropyrans offers a different approach to spiroketals <00TL4383>. The synthesis and stereochemistry of insect derived spiroacetals has been reviewed <00S1956>. 

Further examples of the use of the hDA reaction in dihydropyran synthesis include the formation of the fused pyrans 18 from vinylallenes 17 and aldehydes (Scheme 8) <00TL6781> and a trans-fused dihydropyran containing a phosphonate group 19 . A total synthesis of the 11-oxa steroid system is based on an intramolecular Diels-Alder reaction involving an orthoquinodimethane derived from a benzocyclobutene (Scheme 9) <00TL1767>. 

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 enantioselective hetero-Diels-Alder (HDA) reaction of carbonyl compounds with 1,3-dienes represents an elegant access to optically active six-membered oxo-heterocycles. Since the pioneering work of Rawal et al. in 2003 [55], the enantioselective HDA reaction catalyzed by diols (such as TADDOLs) has become a flourishing field of research [56]. 

Scheme 9 Enantioselective hetero-Diels-Alder (HDA) reaction of Danishefsky s diene with benzaldehyde...

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]. 

The energy of the localized transition state for the ortho route (uncatalyzed reaction) is 14kcal/mol higher than that of the meta channel. Therefore, the ortho channel can be excluded. Unlike the uncatalyzed transformation, the TADDOL-catalyzed HDA reaction exhibited a clear energetic preference for the endo- over the exo-approach. Thus, only endo transition states were considered. The number of possible reaction paths/transition states is thus reduced from eight to two, namely endo-approach with re- or si-face attack of the model diene to the activated benzaldehyde. 

Ding extended the scope of TADDOL catalyzed HDA reactions to the use of Brassard s diene with a variety of aromatic aldehydes (Scheme 5.54) [104]. Starting... 

Tetraacetylethene yields dihydropyrans in hDA reactions with ethyl vinyl ether and cyclopentadiene, but 1,2-dimethylenecyclohexane affords both the hDA and normal Diels-Alder adducts, the latter presumably arising via ring opening of the former adduct to a zwitterionic intermediate (Scheme 2) <99EJ03343>. 

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>. 

Thiabutadienes undergo highly enantioselective hDA reactions in the presence of homochiral bis(oxazoline) and bis(imine) complexes with Cu and Ni (Scheme 37) <99CC1001>. Homochiral camphor-based thiabutadienes show good exo selectivity and give rise to bomene ring-fused dihydrothiopyrans (Scheme 38) <99TL8383>. 

Synthesis of a key 3,4-dihydropyran 196 during synthetic studies towards reveromycin B is achieved using an asymmetric hDA reaction. No chiral Lewis acid catalysts or auxiliaries are necessary as the stereochemistry at the spirocentre is controlled by the anomeric effect (Equation 93) <1997JOCl 196>. 

An hDA reaction of carbonyl compounds with dienes provides a powerful tool for the synthesis of 3,6-dihydropyrans (Equation 121), and has been discussed in detail in the preceding volumes <1984CHEC, 1996CHEC-II>. As with the synthesis of 3,4-dihydropyrans via the hDA reaction, the reviews mentioned previously are also relevant here C2000AGE3558, 2004EJ02093>. 

Vinyl allenes 267 undergo Lewis-acid-promoted intermolecular hDA reactions with simple aldehydes to afford syn-2,6-disubstituted 3,6-dihydropyrans 268 (Equation 125) <2000TL6781>. An intramolecular variant of this reaction has also been reported <2003TL8471>. 

Vinylcyclopropane 514 undergoes a rhodium catalyzed [5+2] cycloadditon reaction with 6-ethynyl-3,4-dihydropyran to furnish intermediate diene 515 that then undergoes an hDA reaction with dienophiles to afford complex pentacyclic chromans 516, 517 (Scheme 113) <2001AGE3895>. 

Resin-supported benzocyclobutenol 597 provides a solid phase source of of/fo-quinoncdimethidc 598, which undergoes hDA reactions with aldehydes to afford 1,3-disubstituted isochromans 599, treatment of which with a Lewis acid liberates isochromans 600 with excellent 1,3-anti selectivity (Scheme 128, Table 28) <1998SL1381>. 

The //////-substituted benzocyclobutenes 601 undergo bond reorganization under mild conditions to form ortho-quinone dimethide intermediates 602, which function as dienes in an hDA reaction with aldehydes to afford all syn-substituted isochromans 603 in excellent yield (Scheme 129) <2000AGE1937>. 

The (2pyrrolidine derivative 843 can catalyze a hetero Diels-Alder (hDA) reaction between aldehydes and enones 844 to form dihydropyranols 845, PCC oxidation of which affords tf //-3,4-dihydropyran-2-ones 846 in good yield and enantioselectivity (Scheme 238) <2003AGE1498>. 

An hDA reaction of the thermally generated (trialkylsilyl)vinylketene 888 with diethyl ketomalonate furnishes the 5,6-dihydropyran-2-one 889 in excellent yield. Protodesilylation of the cycloadduct 889 is achieved in quantitative yield upon its exposure to methanesulfonic acid (Scheme 244). A photochemical Wolff rearrangement of the silyl diazo compound 890 can also be used to generate an intermediate diene for reaction with diethyl ketomalonate to afford the 5,6-dihydropyran-2-ones 891 (Equation 358) <19990L641>. 

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>. 

An hDA reaction between Danishefsky s diene and nitrosubstituted aromatic aldehydes is catalyzed by dirhodium(n) complexes in up to 95% ee <2001JA5366, 2003JM093>. Similar dirhodium(n) complexes are also reported to be effective catalysts for this reaction <2004SL2425, 2004AGE2665, 2005JOC5291>. 

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>. 

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