Anionic Diels–Alder Chemistry of Cyclic Sodium Dien-1-olates Delivering Highly Stereoselective and Functionalized Polycyclic Adducts

Anionic Diels–Alder chemistry of electron-deficient cross-conjugated vinylogous alkenones, providing highly stable sodium dienolate ion pairs as electron-rich dienes in the presence of a weak sodium base in THF, has been newly developed, leading to a single Diels–Alder adduct, in racemic form, in moderate to high yields (up to 97%, 37 examples).

D iels−Alder cycloaddition reactions remain and continue to be of extreme utility in synthetic organic chemistry particularly in terms of their extraordinary capacity to construct, in one step, fused polycyclic skeletons in a highly regio-and stereoselective manner. 1 As shown in Figure 1, 2-cyclohexenone (I) and its α-activated analogue (II) have been well studied in their Diels−Alder chemistry as dienophiles, and several vital conclusions can be derived: (1) Diels−Alder cycloaddition of 2cycloalkenone (I) is a rather poor process; (2) employing Lewis acid as catalyst and/or introducing an additional electronwithdrawing group at its α to ketone position can significantly enhance the dienophilicity of the carbon−carbon double bond; (3) introducing a second double bond into the ring can enhance the secondary effect; (4) C-4 substituent can control the facial selectivity by steric hindrance. 2,3 In our long-lasting interest in Diels−Alder chemistry of 2cycloalkenones, β-substituted α-activated 2-cyclohexenones (III) are further designed to evaluate whether they are as synthetically useful as their enone counterparts (II). Unfortunately, they have experimentally proved to be rather poor dienophiles for Diels−Alder reactions, most likely because of steric hindrance imposed on the β substituent as indicated by many historic cases bearing a similar structure. 4 Instead, they are found to be desirable donors for Michael-type [4 + 2] anionic annulation when EWG is an ester group 5 and excellent dienes for unexpected anionic Diels−Alder reactions when EWG is an aldehyde group (the present work, Figure 2d).
Regularly, dienes in Diels−Alder chemistry are referred to as 1,3-butadienes, usually installed with an electron-rich functional group(s) as represented by various classical reagents ( Figure  2a). 6 Though some Nazarov reagents, as typified by 1 in Figure  2b, could undergo a base-catalyzed Diels−Alder reaction with a conjugated olefin, mechanistically many turned out to proceed with a tandem double-Michael addition rather than a concerted cycloaddition. 7 Several dienolate salts of 2 (Figure 2c), generated in situ through transmetalation, also have been reported to undergo Diels−Alder reactions effectively, but they must be prepared and operated at low temperature (−78 to −20°C ) because of thermal instability. 8 Herein, we wish to report that a novel series of dienolate salts (Figure 2d), derived in situ from the cross-conjugated vinylogous alkenones 3 with base, are found to be highly thermally stable, allowing reaction with a broad diversity of dienophiles to afford a variety of highly oxygenated Diels−Alder adducts in moderate to high yields. Details of these studies are presented in the following.
According to Scheme 1, using 1,3-dioxin 4 as starting material, 9 cyclohexenone 7 was readily prepared as a model compound via a three-step synthetic sequence, involving repeated α-methylation, Stork−Danheiser methylation, 10 and Dess−Martin oxidation, 11 in an overall yield of ca. 60%. Not unexpectedly, different from α-activated 2-cyclohexenones (II) serving as versatile dienophiles, α-aldehyde 7 with a β substituent is a rather poor dienophile for Diels−Alder reactions under either thermal or Lewis acid-catalyzed conditions. Instead, its γ protons can be easily deprotonated and isomerized to form 1,3-dien-1-olates to serve as an electron-rich diene.
In principle, a cycloaddition product obtained from reacting the 1,3-dien-1-olate of 7 with an electron-deficient olefin 8 can be explained by either a sequential double-Michael addition or a Diels−Alder concerted cycloaddition. Preliminary results of this study are listed in Table 1 and discussed below. As seen in entries 1−3, all tested reactions using a strong, medium or weak lithium base in a less polar solvent THF turned out to be fruitless at either ambient or elevated temperature. To further activate the lithium−enolate ion pair, solvation of lithium cation by HMPA in THF (V/V = 1/4) was then examined; 12 however, reactions resulted in a complex unidentified mixture as observed on TLC (entry 4). Interestingly, when lithium carbonate was applied in the more polar solvent DMF at higher temperature (entry 5, 100°C), products 9 and 10 were obtained in 70% and 15%, respectively, of which the relative configuration is unambiguously determined by a single-crystal X-ray analysis. 13 Encouraged by these results, attention was then paid to using other alkali-metal carbonates. When reactions were tested with sodium base, such as Na 2 CO 3 and NaHCO 3 , they all proceeded efficiently in THF to afford a single diastereomer 9 in high yields (entries 6 and 7). More importantly, when the reaction was performed in refluxing THF, the reaction rate could be significantly accelerated and completed in ca. 30 min (entry 8), affording product 9 in quantitative yield (97%). Thus, the reaction system (Na 2 CO 3 (1.2 equiv)/THF/66°C) is tentatively considered to be optimal for this newly developed [4 + 2] annulation process. When the quantity of Na 2 CO 3 was further reduced to a catalytic amount (20 mol %; entry 9), product 9 was also produced in high yield (88%), but reaction time should be prolonged overnight (20 h), indicating that the annulation process can proceed with a cost-effective catalytic cycle. Also noticed is that as reactions are carried out using Na 2 CO 3 as base at room temperature (entries 7, 10, and 11), rate acceleration is reflected by the increase of solvent polarity (THF, 16 h; CH 3 CN, 12 h; DMF, 1 h). Interestingly, the formation of 10 is also significantly increased when more polar solvents (CH 3 CN, 6%; DMF, 30%) are employed, which is totally not detected in a less polar solvent (THF, 0%) by the crude 1 H NMR spectrum.
Similarly, when Cs 2 CO 3 is used as base at room temperature, product 10 is formed increasingly with the increase of solvent polarity, culminating in a maximal yield of 65% in DMF (entries 13−16). As well, reaction rates are dramatically enhanced and completed within 5−30 min whether in less or more polar solvents. The size of the cation counterion appears to affect both product distribution and reaction rate, as seen in entries 7, 12, and 14. The Hunig base, trimethylamine, is apparently too weak to deprotonate γ acidic protons in CH 2 Cl 2 . As a result, no reaction occurred, and reactants 7 and 8 were recovered intact (entry 17). However, when an extra Lewis acid was added (entry  Organic Letters pubs.acs.org/OrgLett Letter 18), the reaction was triggered and proceeded smoothly to afford 9 in 81% along with a trace of 10, as detected by the crude 1 H NMR. In sharp contrast, when a strong base DBU was used, a high selectivity for product 10 over 9 was observed, particularly in a more polar solvent DMF (entry 19 vs 20). According to Table 1, not only was the trans isomerism of dienophile 8 constantly preserved in products, but also no Michael-addition intermediates were detected in all cases examined. 14 To elucidate these outcomes, a plausible mechanism is proposed as follows. Obtaining merely a pair of products 9 and 10 is actually hard to be justified by simply applying an exo or endo addition rule to a single dienolate (Z)-7a or (E)-7a because they are basically in equilibrium (Figure 3). Instead, they are thought to be formed by a concerted addition of dienophile 8 to both dienolates following the endo approach A and B, respectively. Because product distribution and reaction rate are highly dependent on the base and solvent used, conformers (Z)-7a and (E)-7a are assumed to be interconvertible with a small energy barrier.
In addition, (Z)-7a is assigned to have a lower ground-state energy than (E)-7a because of forming the more stable sixmembered ring ion pairs. The reaction-energy profile is conceptually drawn in Figure S1 to interpret their relative relationships along the reaction course. Lithium cation (Li + ), because of its exceptional oxophilicity, 15 might reduce electron density on the oxy anion significantly and thus stop enriching dienolates in sufficient electron density from activating the cycloaddition process (entries 1−4). However, this high degree of cation coordination appears to be loosened/disrupted under harsh reaction conditions in a polar solvent (entry 5). Analogous to the anionic oxy-Cope rearrangement, 16 we believe the negative charge on the oxygen of dienolates should play a crucial role to promote the observed Diels−Alder chemistry. Sodium carbonate in a noncoordinating solvent like THF allows Na + to form a stable chelated bridge with two oxygen atoms of the (Z)dienolate, leading to product 9 exclusively in high yields. However, the well-coordinating solvent DMF can solvate Na + such that Na + is free and two partially negative charged oxygen atoms tend to be as far apart as possible, as in (E)-dienolate. Collectively, it is concluded that anionic Diels−Alder reactions proceed primarily through the endo approach A in a less polar solvent with a small countercation Li + or Na + but shift significantly toward the endo approach B in a more polar solvent with a bulky countercation K + or Cs + . The reactivity trend of base and solvent is found to be in descending order of cation size and polarity, namely, Cs + > K + > Na + > Li + and DMF > CH 3 CN > THF > CH 2 Cl 2 . Thus, a maximum synergistic effect on reaction rate (ca. 5 min) was observed when the reaction was carried out in combination with Cs 2 CO 3 and DMF (entry 16).
Lewis acid MgBr 2 (entry 18) appears to be an effective catalyst to intensify the formation of (Z)-7a isomer through bidentate chelation, leading to product 9 predominantly. When DBU was applied (entry 20), the reaction rate was dramatically enhanced, suggesting that the conjugate acid DBUH + could behave like a bulky cation Cs + (entry 16) to shift the equilibrium to isomer (E)-7a. The standard protocol depicted in entry 8 is then employed to explore the scope and limitation of the methodology. Results are listed in Table 2, wherein Diels−Alder adducts highlighted in blue are dienolate parts generated in situ from the corresponding α-aldehyde cycloalkenones, including 5−8 membered ring, verbenones, cumarins, and cinnamates, and those parts in green belong to structurally different dienophiles, individually comprising a cyclic maleimide, cumarin, p-quinone, Figure 3. A proposed endo approach for Diels−Alder products 9 and/or 10. Table 2. Diels−Alder Adducts Derived from Aldehydedienolates a Reaction was carried out in a sealed tube. b A mixture of (E)-and (Z)-cinnamate ester was used. c Product 31a (8%) and 35a (10%) was individually isolated. d The relative configuration was determined by an X-ray analysis.
Organic Letters pubs.acs.org/OrgLett Letter acylic α-substituted acrolein, fumarate, or isobutylidene malonate unit. Expected products were commonly obtained in moderate to excellent yields as a single diastereomer, indicating that the methodology is synthetically practicable. More importantly, many are structurally unambiguously identified by X-ray analysis, lending substantial evidence to Diels−Alder chemistry claimed for this novel [4 + 2] annulation. For example, products 15 (89%) and 25 (90%), 13 formed exclusively in high yields as a single stereoisomer, are considered to be typically governed by the ortho and endo addition rule with complete face selectivity via effectively shielding the gemdimethyl side of verbenone. Product 30 (84%), 13 containing four contiguous stereogenic centers precisely predicted by the ortho and endo rule, also provides strong support for a concerted Diels−Alder approach. Encouragingly, when starting αaldehyde β-methyl alkenones allow both γ and γ′ sites to undergo deprotonation, the desired aldehyde-dienolate products are still constantly formed in good to excellent yields (77− 96%) as seen in 12−14, 17, 18, 23, 26, 27, 29−33, and 35−37, with the exception of 18 (53%) in a moderate yield, presumably because of the obstruction of the transannular strain in medium rings. Nevertheless, when products 31 (85%) and 35 (79%) were isolated, the corresponding ketone-dienolate adducts 31a and 35a (see the Supporting Information) were also individually identified in 8% and 10% yield, indicating that cisoid dienolates through enolization of γ′ protons could also be formed and captured by certain active dienophiles such as N-phenylmaleic imide. A single diastereomer 21 (84%) obtained exclusively also supports that a concerted approach should be adopted as both cisoid and transoid dienolates were generated during the reaction. Indeed, the highly conserved configuration of the dienophile during the transformation into the corresponding product is hard to explain if a two-step Michael−Aldol addition is thought to be a preferred pathway.
To further confirm whether ketone-dienolate D−A adducts are synthetically useful and general, a series of α-aldehyde cycloalkenones, containing only γ′ protons, or α-ester cycloalkenones, containing γ and/or γ′ protons, were designed in order to generate merely the ketone-type cisoid dienolate. Results are listed in Table 3. As predicted by a concerted endoaddition approach, all products 38−46 were obtained with high regio-and stereoselectivity in good to high yields (71∼95%). 17 Products 38−41, produced at higher temperature (100°C) than their α-aldehyde counterparts 42−46 (66°C), are somewhat contradictory because dienolates containing a weaker electronwithdrawing ester group should be more reactive in terms of inductive effects. These reverse outcomes might result from the steric hindrance caused by the ester group during cycloaddition.
In conclusion, unprecedented anionic Diels−Alder chemistry of highly electron-deficient cross-conjugated vinylogous systems has been newly developed, in which the cyclic sodium dienolate ion pairs, generated in situ in the presence of a weak sodium base in THF, are highly thermally stable and operationally simple to play the role of electron-rich dienes during reactions. Products thus obtained contain multiple contiguous chiral centers, whose stereochemical arrangements could be accurately predicted by the ortho and endo rule, thus strongly supporting a concerted [4 + 2] cycloaddition rather than a consecutive Michael−Aldol type annulation.