Recent Advances in Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
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This review is an endeavor to highlight the progress in the inverse-electron-demand hetero-Diels–Alder reactions of 1-oxa-1,3-butadienes in recent years. The huge number of examples of 1-oxadienes cycloadditions found in the literature clearly demonstrates the incessant importance of this transformation in pyran ring synthesis. This type of reaction is today one of the most important methods for the synthesis of dihydropyrans which are the key building blocks in structuring of carbohydrate and other natural products. Two different modes, inter- and intramolecular, of inverse-electron-demand hetero-Diels–Alder reactions of 1-oxadienes are discussed. The domino Knoevenagel hetero-Diels–Alder reactions are also described. In recent years the use of chiral Lewis acids, chiral organocatalysts, new optically active heterodienes or dienophiles have provided enormous progress in asymmetric synthesis. Solvent-free and aqueous hetero-Diels–Alder reactions of 1-oxabutadienes were also investigated. The reactivity of reactants, selectivity of cycloadditions, and chemical stability in aqueous solutions and under physiological conditions were taken into account to show the potential application of the described reactions in bioorthogonal chemistry. New bioorthogonal ligation by click inverse-electron-demand hetero-Diels–Alder cycloaddition of in situ-generated 1-oxa-1,3-butadienes and vinyl ethers was developed. It seems that some of the hetero-Diels–Alder reactions described in this review can be applied in bioorthogonal chemistry because they are selective, non-toxic, and can function in biological conditions taking into account pH, an aqueous environment, and temperature.
KeywordsHetero-Diels–Alder reactions 1-Oxa-1,3-butadienes Dihydropyrans Domino Knoevenagel hetero-Diels–Alder reactions Bioorthogonal cycloaddition
- (S,S)- t-Bu-box
Ethylene diammonium diacetate
Modularly designed organocatalyst
Tetrabutylammonium hydrogen sulfate
Cycloaddition reactions provide quick and economic methods for the construction of monocyclic, polycyclic and heterocyclic systems. The use of hetero-substituted diene and dienophiles is important for the application of Diels–Alder cycloadditions towards natural and biologically active product synthesis. Dihydro- and tetrahydropyran derivatives are prevalent structural subunits in a variety of natural compounds, including carbohydrates, pheromones, alkaloids, iridoids and polyether antibiotics [1, 2, 3, 4, 5, 6, 7, 8]. The abundance of carbohydrates in living cells is a reason for the development of new synthetic procedures for the preparation of natural and unnatural sugars. There are two synthetic routes leading to dihydropyran derivatives via [4 + 2] cycloadditions. The first one is the [4 + 2] cycloaddition of the carbonyl group of aldehydes or ketones, acting as heterodienophiles, with electron-rich 1,3-butadienes [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]. The second route is the hetero-Diels–Alder (HDA) reactions of electron-deficient α,β-unsaturated carbonyl compounds, representing an 1-oxa-1,3-butadiene system, with electron-rich alkenes. Excellent diastereoselectivity is a characteristic feature of heterocycloaddition of many substituted α,β-unsaturated carbonyl compounds. The HDA reactions of oxabutadienes also show a high regioselectivity. These reactions have been classified as cycloadditions with inverse-electron-demand . The reviews on this topic have already been published but they cover the literature until only 1997 [1, 2, 3, 4, 5, 6, 7, 8, 24]. The most comprehensive one was written by Tietze and Kettschau in Topics in Current Chemistry in 1997 . The presented review is an endeavor to highlight the progress in the HDA reactions with inverse-electron-demand of 1-oxa-1,3-butadienes after the year 2000.
The reactivity of α,β-unsaturated carbonyl compounds in HDA reactions is low and the reactions must be conducted at high temperature [25, 26, 27] or under high pressure [28, 29, 30]. The use of enol ethers as dienophiles with electron-donating groups improves the cycloadditions but high temperature is needed and diastereoselectivity of these reactions is still low. Aza-substituted dienophiles have been used more rarely than their oxygenated counterparts in the HDA reactions of 1-oxa-1,3-butadienes. Enamines can participate in these reactions, providing entry to highly complex molecules [31, 32, 33]. The reactivity of 1-oxa-1,3-butadiene can be enhanced by introducing electron-withdrawing substituents [34, 35, 36, 37, 38, 39]. Presence of an electron-withdrawing group in the 1-oxadiene system lowers the lowest energy unoccupied molecular orbital (LUMO) energy level which then can more easily overlap with the highest energy unoccupied molecular orbital (HOMO) orbital of the dienophile. Tietze et al. calculated the influence of various substituents on the energy of LUMO orbitals in 4-N-acetylamino-1-oxa-1,3-butadienes using semiempirical methods . It was found that the energy depends on the type and position of a substituent in the 1-oxadiene system. The cyano and trifluoromethyl groups in the 3 position were found to have the highest influence on reactivity of 1-oxa-1,3-butadienes in cycloadditions with enol ethers. In addition to the effect of the substituents in the heterodiene, Lewis acid catalysts, such as ZnCl2, TiCl4, SnCl4, EtAlCl2, Me2AlCl, LiClO4, Mg(ClO4)2, Eu(fod)3, Yb(fod)3, accelerate the HDA reactions [41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53]. The choice of the Lewis acid also has influence on the stereoselectivity of cycloadditions because this catalyst is involved in an endo or an exo-transition structure and steric interactions are important for stereochemistry.
Tietze et al. extensively described the domino Knoevenagel hetero-Diels–Alder reactions of unsaturated aromatic and aliphatic aldehydes with different 1,3-dicarbonyl compounds for the synthesis of heterocycles with a pyran ring [54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68]. In the intramolecular mode, the 1-oxa-1,3-butadienes are prepared in situ by a Knoevenagel condensation of aldehydes bearing the dienophile moiety. This method has a broad scope since a multitude of different aldehydes and 1,3-dicarbonyl compounds can be used.
Different examples of inter- and intramolecular HDA reactions of 1-oxa-1,3-butadienes described in literature after the year 2000 are discussed below. The usefulness of HDA reactions of oxadienes is connected with the number of bonds which are formed in one sequence and with the fact that complex molecules can be obtained by this method. Thus, the HDA reactions of α,β-unsaturated carbonyl compounds are atom economic and they allow for regio-, diastereo- and enantioselective synthesis of multifunctional pyran derivatives from relatively simple compounds. Therefore, these cycloadditions can be potentially applied in bioorthogonal chemistry.
2 Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
2.1 Intermolecular Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
2.1.1 Non-catalytic Intermolecular Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
Enaminocarbaldehyde 1 was found to be less reactive than propenenitriles 5 since reactions of 5 with enol ethers 2 occurred at room temperature whereas reactions with 1 required heating in boiling toluene.
Tetrasubstituted dihydropyrans 16 were prepared in quantitative yields. All the products 16 were the diastereomeric mixtures.
N-Vinyl-2-oxazolidinone 26 can act as a valuable dienophile in inverse-electron-demand heterocycloaddition. This compound was found to be less reactive than enol ethers because similar reactions of dienes 25 and 29 with enol ethers occurred at room temperature [71, 82] whereas reactions with 26 required heating in boiling toluene.
2.1.2 Three-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
The amino aldehydes 32 were treated with the 1,3-dicarbonyl components 34 and benzoyl enol ethers 33 in toluene in the presence of catalytic amounts of EDDA and trimethyl orthoformate as dehydrating agent in an ultrasonic bath. The domino reaction sequence of Knoevenagel, HDA reaction, and hydrogenation allows rapid access to a number of N-heterocycles of different ring sizes and with different substituents in a betaine 37.
Radi et al. described a protocol for the multicomponent microwave-assisted organocatalytic domino Knoevenagel HDA reaction for the synthesis of substituted 2,3-dihydropyran[2,3-c]pyrazoles . The reported procedure can be used for the fast generation of pyran[2,3-c]pyrazoles with potential anti-tuberculosis activity.
2.1.3 Catalytic Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes with Achiral Lewis Acids
A complete reversal of facial differentiation was achieved by using a different Lewis acid, leading to the stereoselective formation of either endo-α 79 or endo-β 80 adducts. The endo-α adduct 79 was obtained with using Eu(fod)3 as the catalyst and endo-β adducts 80 was the main product if the promoter was SnCl4 (Scheme 13) [88, 89].
2.1.4 Enantioselective Approach: Catalytic Enantioselective Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes with Chiral Lewis Acids
A dramatic improvement was observed in reactions carried out under solvent-free conditions and excess ethyl vinyl ether 100. Usage of solvents generally resulted in significantly lower enantioselectivity in the cycloaddition. As the steric bulk of the alkyl group of dienophile was increased, the selectivity and reactivity decreased. The optimal dienophile was ethyl vinyl ether. In the solid state, catalyst 101 exists as a dimeric structure, bridged through a single water molecule and bearing one terminal water ligand on each chromium center. Opening of a coordination site by dissociation of the terminal water molecule for complexation of the aldehyde substrate explains the important role of molecular sieves in these reactions [95, 96].
2.1.5 Enantioselective Approach: Catalytic Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes with Chiral Organocatalysts
In most of the cycloadditions of 107 and 108, good yields and high regio- and stereoselectivities were obtained. High stereoselectivities were observed by employing a bifunctional squaramide-containing aminocatalyst 109. The authors postulated that dienamine intermediate is formed by condensation of aminocatalyst 109 with the α,β-unsaturated aldehyde 108, and the next heterodiene 107 in s-trans conformation is recognized by the catalyst. Two cycloreactants 107 and 108 are activated through H-bond interactions and are positioned to facilitate the cycloaddition step.
The high yield and enantioselectivity of the reactions was restored (up to 95 % yield and 95 % ee). The ester alkyl group of β,γ-unsaturated α-ketoesters 111 has almost no influence on either the reactivity or enantioselectivity. Similarly, the substituent on the phenyl ring of the enones 111 has minimal effects on the reactivity and the asymmetric induction of these reactions. β,γ-Unsaturated α-ketophosphonates 111 may also be applied in these reactions if a higher loading of the precatalyst modules (10 mol%) is used. The authors proposed a plausible transition state on the basis of the product 116 stereochemistry and the MDO structure . They showed that the aldehyde 112 reacts with the OHIC moiety of the MDO to form an (E)-enamine. Next, the thiourea moiety of the MDO forms hydrogen bonds with the enone 111 and directs to enamine from the front. The attack of the enone 111 onto the Re face of the enamine in an endo transition state leads to the formation of the observed (4S, 5R)-product 116.
2.1.6 Enantioselective Approach: Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes with Chiral Auxiliaries
Two molecules of α,β-unsaturated ketone 118 undergo the HDA reaction affording the 10 carbon sugar 119. Reduction and catalytic hydrogenation of cycloadduct 119 gave stereoselectively a single product 121 in an excellent yield.
Both reactions 136 with 135 and 137 with 135 provided respectively pyrans 138 and 139 in 58 and 54 % yields, as single isomers, after heating in a sealed tube at 85 °C for 48 h in acetonitrile as the solvent (Scheme 25).
2.2 Intramolecular Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
2.2.1 Two-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes with an Intramolecular Cycloaddition
Knoevenagel condensations of 1-(phenylsulfenyl)-, 1-(phenylsulfinyl)-, and 1-(phenylsulfonyl)-2-propanones 140 with 2-alkenyloxy aromatic aldehydes 141 yielded the corresponding condensation products 142 which in turn underwent intramolecular HDA reactions during heating in boiling toluene or xylene (Scheme 26). Cis-fused 2H-pyran derivatives 143 were the major products. An increase of the reactivity and a decrease of the diastereoselectivity of the HDA reactions were observed in order: PhS derivative, PhSO2 derivative and compounds containing PhSO group [108, 109].
Chemoselectivity was achieved with the reduction in reaction time because the cycloadducts 147 and 148 formed in the ratios ranging from 79:21–95:5 when the reactions were carried out under microwave irradiation for 10–150 s. Reactions of unsymmetrical 1,3-diones 144 with citronellal were also described .
The authors made the experiment to show that obtaining macrocycle 151 involves the formation of intermediate 155. Dimerization of hydroxyamide 152 by olefin cross metathesis with Grubbs second generation catalyst gave the bis-amide 153 (Scheme 28). Protection of the two hydroxyl groups in 153 as the bis-silyl ether 154 and then the reaction with 2-propenylmagnesium bromide resulted in formation of the macrocycle 156. Deprotection of the silyl ethers in 156 furnished the macrocycle 151 in 85 % yield. These studies represent the first example of a tandem olefin cross metathesis HDA reaction sequence.
2.2.2 Catalytic Intramolecular HDA Reaction of 1-Oxa-1,3-Butadienes and Alkynes
Furopyranopyrans 178, 180, 182 and 184 were prepared in 75–90 % yields. The authors assumed that these cycloadditions proceed in a concerted way via an endo-E-syn transition state . Acyclic 1,3-diketones such as acetyl acetone and ethyl acetoacetate can’t be used in the reaction.
The major advantage of this reaction is the fact that pentacyclic indole derivatives 188 can be isolated by filtration from the reaction mixture. This method also has advantages such as the use of commercially available, non-toxic and inexpensive ZnO as catalyst, low loading of catalyst, and high yields of products.
The solutions of aldehyde 190 and appropriate 1,3-dicarbonyl compound 189, ZrO2 and base in ionic liquid or organic solvent were stirred for 5–40 min at room temperature and desired products were obtained in 80–95 % yields. The best results were obtained for 5-nitro-O-propargylated salicylaldehyde and 1-butyl-3-methylimidazolium nitrate [bmim][NO3] as the reaction medium. Balalaie et al. also used ionic liquid [bmim][NO3] in the presence of 30 mol% CuI in the domino Knoevenagel HDA reactions of O-propargylated salicylaldehydes with some active methylene compounds .
2.2.3 Two-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes with Intramolecular Cycloaddition in Water or Solvent-Free
Aldehydes 193 underwent the Knoevenagel condensation with 4-hydroxy-dithiocoumarin 194 in water at reflux to give the intermediates 195 in which two different heterodiene fragments were presented. The thiocarbonyl group of the thioester 195 reacted as heterodiene. The cycloadducts were obtained as a mixture of cis- and trans-isomers. The authors observed the influence of the substituent R 2 on reaction diastereoselectivity. The trans-isomer 196 was the main product for some reactions whereas for others, the products 197 were formed with the predominance of the cis-isomers (Scheme 35).
To introduce the dienophile in compound 201, the reactions of 2-chloro-3-formylquinolines 199 with alcohol 200 in presence of aqueous sodium hydroxide under phase transfer catalytic conditions were used. Domino Knoevenagel HDA reactions of 201 and active methylene compound 202, 204 and 206 in presence of piperidine at room temperature in water gave the cis fused penta or hexacyclic pyrano[2,3-b]quinoline derivative 203, 205 or 207 with high yield (70–80 %) and diastereoselectivity (>99 %). The products were isolated by filtration in the pure form from aqueous medium.
3 Application of Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes in Bioorthogonal Chemistry
It seems that some of the HDA reactions described in Chapter 2 can be used in bioorthogonal chemistry in the future because they are selective, non-toxic, and can function in biological conditions taking into account pH, an aqueous environment, and temperature.
This review article is an effort to summarize recent developments in inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes. Some of the papers related to the inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes found in the literature clearly demonstrate the importance of this transformation which opened up efficient and creative routes to different natural products containing six-membered oxygen ring systems. This type of cycloaddition is today one of the most important methods for the synthesis of dihydropyrans which are the key building blocks in carbohydrate derivative synthesis. Especially, the domino Knoevenagel HDA reactions have been frequently applied for the synthesis of natural products. The main advantage of the inverse-electron-demand HDA reaction of oxabutadienes is formation of dihydropyran derivatives with up to three stereogenic centers in one step from simple achiral precursors. This transformation characterizes the huge diversity, excellent efficiency, high regioselectivity, diastereoselectivity, and enantioselectivity observed in many cases. In recent years, the use of chiral Lewis acids, chiral organocatalysts, new heterodienes, or new dienophiles have given enormous progress. Recently, HDA reactions of 1-oxabutadienes conducted without a solvent or in water were developed and the results suggested that the presented green methods may displace other methods that use various organic solvents and that are performed at high temperature. Application of inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes in bioorthogonal chemistry is still challenging because there is only one example of this bioorthogonal cycloaddition in the literature. The author of this review sincerely hopes that this article will stimulate future research in bioorthogonal inverse-electron-demand cycloaddition of 1-oxa-1,3-butadienes and will encourage scientists to design novel bioorthogonal ligations.
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