Lele
Wang‡
a,
Huabin
Han‡
a,
Lijie
Gu
a,
Wenjing
Zhang
*b,
Junwei
Zhao
*a and
Qilin
Wang
*a
aCollege of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, China. E-mail: zhaojunwei@henu.edu.cn; wangqilin@henu.edu.cn
bGreen Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou 450001, China. E-mail: zhangwj@zzu.edu.cn
First published on 9th November 2021
Simultaneous deconstructive ring-opening and skeletal reconstruction of an inert, aromatic pyridinium ring is of great importance in synthetic communities. However, research in this area is still in its infancy. Here, a skeletal re-modeling strategy was developed to transform chalcone-based pyridinium salts into structurally intriguing polycyclic isoindolines through a dearomative ring-opening/ring-closing sequence. Two distinct driving forces for the deconstruction of the pyridinium core were involved in these transformations. One was the unprecedented harnessing of the instability of in situ generated cyclic β-aminoketones, and the other was the instability of the resultant N,N-ketals. The desired isoindoline polycycles could undergo the Wittig reaction with various phosphorus ylides to achieve structural diversity and complexity. Notably, by tuning the Wittig conditions by addition of one equivalent of base, an additional bridged ring was introduced. A plausible mechanism was proposed on the basis of control experiments and theoretical calculations.
Stemming from the pioneering work of Zincke and König,5 dearomative ring-opening of pyidinium salts has received increasing attention (Scheme 1A). This strategy is very reliable for the construction of structurally interesting 5-amino-2,4-pentadienals, a new class of D–π–A dienes, using secondary amines as nucleophiles. The pentadienals can undergo further cyclization to generate valuable molecules with increasing complexity and diversity.6 Although valuable progress has been made, there are still some challenges to be overcome, including the following: (1) the driving force for the deconstruction needs to be further explored. Currently, methods for the ring-opening of pyridinium salts are dominated by N,O- or N,N-ketal formation via nucleophilic attack by an amine or hydroxyl group followed by heterolytic C–N bond cleavage by taking advantage of the instability of the in situ generated aminals. (2) The reactions are often associated with low regio- and stereo-selectivity issues.7 When unsymmetrical pyridiniums are employed as substrates, their C2-, C4- and C6-positions are all potential electrophilic sites and it is quite difficult to identify subtle differences in reactivity. In addition, both Z- and E-isomers of the resulting diene intermediates are generated concomitantly. (3) The reactivity of the activating groups is underutilized. After the reaction reaches completion, the pre-installed activating groups are released without participating in the subsequent reaction. Rational reaction design to allow for the utilization of the activation group would be of great value to increase structural complexity. (4) The reactivity of the resultant 5-amino-2,4-pentadienals has not been fully exploited. Structurally, they possess a D–π–A conjugated system. In addition to their identity as electron-deficient all-carbon dienes that can participate in inverse-electron-demand [4+2] cycloadditions,6c–f they could also serve as azadienes to undergo normal [4+2] cycloaddition with electron-deficient dienophiles because of their structural characteristics with “push–pull” electrons. However, research in this area is lacking.
On the basis of fully understanding the above challenges, we envisioned that if a reactive group with appropriate reactivity was attached on the activating group, we would solve the activating-group utilization and product-diversity problems. Once the D–π–A diene intermediate was obtained after the dearomative ring-opening of the pyridinium core, it could be intercepted by the reactive sites on the activating group. This would achieve skeletal re-modeling of the pyridinium salts to assembly novel and complex molecules (Scheme 1B). The key to the success of this strategy is the identification of a suitable reactive group. The electronic characteristics of the dienes provide an important clue that incorporating a Michael acceptor on the activating group could meet the need for subsequent reconstruction. Based on this analysis, our previously designed chalcone-based pyridinium salts came into our sight.8 If successful, this skeletal re-modeling strategy would enable scaffold hopping from one planar and aromatic pyridinium ring to another three-dimensional azaheteropolycycle without the need for costly reagents and harsh conditions.
As a continuation of our research into the dearomatization of six-membered oxonium and pyridinium salts to construct various novel and complex molecules,9 herein, we wish to disclose a skeletal re-modeling strategy for pyridinium salts to assemble polycyclic isoindolines and their bridged derivatives. Our skeletal re-modeling strategy has two distinct driving forces (Scheme 1C). When active methylene compounds such as 1,3-diketone are used as nucleophiles, the cyclic architecture of the pyridine ring was broken by harnessing the instability of the β-aminoketone. When secondary amines were used as nucleophiles, the driving force for deconstruction was the instability of the in situ generated N,N-ketals. This strategy would enable the synthesis of isoindoline-fused polycyclic systems, which are the core structures of many biologically active natural products and medicinally relevant molecules (Scheme 1D).10 Although great advancement has been made toward their synthesis, current methods often need tedious procedures and custom reagents.11
Entry | Base | Solvent | Time | Yieldb (%) |
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a Reactions performed at 60 °C on a 0.15 mmol scale using 1.5 equivalents of 1 in the presence of 2.0 equivalents of base in 1.0 mL of solvent. b Yields determined by 1H NMR analysis of the crude mixture using 1,3,5-trimethoxybenzene as the internal standard. c Isolated yield obtained by silica gel column chromatography. d At 50 °C. e At 30 °C. TMG = 1,1,3,3-tetramethyl guanidine. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. n.r. = no reaction. | ||||
1 | TMG | CH3CN | 5 min | 84 |
2 | DBU | CH3CN | 1 h | 63 |
3 | NEt3 | CH3CN | 24 h | n.r. |
4 | Cs2CO3 | CH3CN | 1 h | 78 |
5 | TMG | CHCl3 | 5 min | 57 |
6 | TMG | DMF | 5 min | 93 |
7 | TMG | Acetone | 5 min | 95 (90)c |
8d | TMG | Acetone | 5 min | 87 |
9e | TMG | Acetone | 5 min | 77 |
With the optimized conditions established, the substrate scope of this dearomative ring-opening/reconstruction sequential synthetic strategy was explored. A wide range of pyridinium salts bearing substituents with different electronic characters and varied positions were all compatible (Table 2), which allowed for the synthesis of polycyclic isoindolines 3–17 in 50–98% yields. Notably, the nitro group on the pyridine ring was not indispensable, and replacement of it with benzoyl or cyano groups produced 18 in 36% yield and 19 in 89% yields, respectively. Next, the generality of 1,3-dicarbonyl compounds was investigated. More steric 1,3-diketones, such as heptane-3,5-dione, 1,3-diphenylpropane-1,3-dione, and even unsymmetrical 1-cyclopropylbutane-1,3-dione and 1-phenylbutane-1,3-dione were all suitable reaction partners. These compounds generated the desired products 20–23 in 27–82% yields. Remarkably, when 1,3-diphenylpropane-1,3-dione was used, the CC double bond migrated. In view of the significance and synthetic challenges of quaternary carbon centers,12 the applicability of our strategy in the construction of isoindoline polycycles with a tetrasubstituted quaternary carbon center was examined. The more hindered pyridinium salts 1r and 1s could also participate in this dearomative ring-opening/reconstruction cascade reaction successfully to deliver 24 in 80% yield and 25 in 32% yield as sole diastereomers with tetrasubstituted quaternary carbon centers.
a Reactions performed on a 0.15 mmol scale using 1.5 equivalents of 1 with 2.0 equivalents of TMG in 1.0 mL of acetone at 60 °C. Yields refer to the isolated products after column chromatography. |
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Encouraged by the success of this synthetic strategy, a series of 3-alkenyl oxindile-based pyridinium salts (1t-ac, for details, see Section S2†) were prepared and evaluated in the cascade reaction using a similar process to construct polycyclic isoindoline spirooxindoles. As anticipated, the dearomative ring-opening/reconstruction cascade reaction between 1t and 2 took place successfully under slightly modified conditions (0.10 mmol of 1t and 1.2 equivalents of 2 at 35 °C), and produced polycyclic isoindoline spirooxindole 26 in 88% yield (Table 3). It should be noted that this reaction could also be scaled up without compromising the efficiency (2.5 mmol and 89% yield). Next, the substrate scope was evaluated. Generally, a wide range of 3-alkenyl oxindole-based pyridinium salts were tolerable in these transformations. Regardless of their substitution patterns and electronic nature, all reactions proceeded smoothly to produce 27–35 in 37–82% yields. In addition to acetylacetone, 1-cyclopropylbutane-1,3-dione was also an appropriate reaction partner to give 36 in 50% yield.
With the proof of concept established, the substrate scope of this skeletal re-editing strategy was explored (Table 4). Initially, the effects of Ar groups neighboring the carbonyl group with different substitution patterns were evaluated. Broadly, a variety of pyridinium salts were applicable in these transformations, successfully producing 39–46 in satisfactory yields. The reactions were apparently sensitive to the substituent positions. Compared with meta- or para-Br substituted substrates, the ortho-Br substituted substrate gave a much lower yield (see 39vs.41 and 44). The electronic characteristics also affected the reaction outcomes. The Ar groups with electron-withdrawing groups performed much better than those with electron-donating groups (39–41 and 43–44vs.42 and 45–46). The Ar groups were not crucial, and they could be replaced by methyl, for which an additional aldol reaction took place with the formation of 47 in 10% yield. The introduction of a halogen on the phenyl group adjacent to the pyridine ring was also compatible, delivering 48–51 in acceptable yields. The substituents on the pyridine ring were not limited to nitro groups, and cyano, benzoyl and ester groups were also tolerable (CN, 52; Bz, 53; and CO2Et, 54). Next, the scope of phosphorus ylides was evaluated. Except for ester-derived ylides, acetophenone-derived ylide could also participate in this cascade process successfully, enabling the formation of 54 in excellent yield with complete diastereocontrol. Encouragingly, yildes containing natural products and drug molecules were also applicable in this reaction and produced 56–60 in 60–82% yields.
Inspired by the success of the above two-pot reactions, the reduction of this cascade process to a one-pot reaction was investigated. When the reaction of pyridinium salt 1, piperidine and Wittig reagent was performed in water at 100 °C, an unexpected bridged isoindoline polycycle 61 was obtained in 25% yield with complete diastereocontrol and no traces amount of 38 (Scheme 3). This transformation might proceed through an additional piperidine-promoted Michael addition, as evidenced by the fact that 38 could be smoothly transformed into 61 in the presence of one equivalent of TMG in 61% yield with >20:1 d.r. (Table S4,† entry 1). As shown in Scheme 3, this reaction was presumably initiated by the deprotonation of the benzylic proton of 38 with the help of a base to generate nucleophilic reactive sites, followed by an intramolecular Michael addition with α,β-unsaturated ester. Further investigations revealed that water was beneficial to the first ring-opening/reconstruction but detrimental to the subsequent Wittig/cyclization reaction (Table S3†). Solvent mixtures also failed to improve the synthetic efficiency (Table S2,† entry 3). Therefore, this reaction was conducted in a two-step fashion. After some experimentation, the optimum conditions were established (Table S4,† entry 1).
Next, the generality and robustness of this approach were investigated (Table 5). Broadly, this transformation could tolerate a plethora of pyridinium salts with different electronic and steric effects, affording 62–69 in 35–59% yields (for step B). Notably, although the products contained four stereocenters and a challenging rigid bridged ring, only one diastereomer was obtained in all cases. In addition, isoindoline polycycle-based aldehyde 37 could undergo an intramolecular Aldol reaction with the help of TMG, which successfully produced 70 and its diastereomer 70′ in 83% yield with 2:1 d.r.
a Reaction conditions: Step A: pyridinium salts (0.2 mmol), piperidine (2.5 equivalents), H2O (1.0 mL), and 80 °C. Step B: ylides (1.5 equivalents based on the products of step A), TMG (1.0 equivalent), toluene (1.0 mL), and 110 °C. The d.r. value was determined by 1H NMR. b The yields of step A. c The yields of step B. |
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The structures and relative configurations of 3, 21, 25, 26, 47, 48, 52, 61, 70, 72 and 74 were unequivocally determined by X-ray single crystal diffraction.13 The relative configurations of other products were determined by analogy.
On the basis of the experimental results, a tentative reaction pathway was proposed as shown in Scheme 6. Generally, two successive processes of deconstructive ring-opening and reconstruction were involved in these transformations. The reactions began with dearomative addition by nucleophiles such as acetylacetone and piperidine to generate intermediate Int-A, which was not stable and was prone to undergo ring-opening to form the reactive D–π–A intermediate. In this process, two distinct driving forces for the deconstruction of the pyridine core were utilized. When acetylacetone was used as the nucleophile, the driving force was the instability of the cyclic β-aminoketones. When piperidine was used as the nucleophile, the driving force was the instability of the in situ generated N,N-ketals. Followed by intramolecular [4+2] cycloaddition, the desired isoindoline polycycles were afforded. When piperidine was used as the nucleophile, an additional hydrolysis from Int-B occurred to produce 37. By reacting with phosphorus ylide, 37 was smoothly converted into 38 bearing an α,β-unsaturated ester group. With the help of TMG, an intramolecular Michael addition of 38 occurred to deliver the desired bridged isoindoline polycycle 61. This product could also be obtained from 37 in a one-pot fashion.
A mechanistic study using density functional theory (DFT)14 provided further verification. When acetylacetone was used as the nucleophile, it could be activated through deprotonation by a reaction with TMG, which produced the carbon anion R2 (Fig. 1). The combination with pyridinium R1 at the C(6)-position was slightly endothermic by 1.1 kcal mol−1. After neutral compound Int1 was activated by proton transfer to the TMG base, it underwent successive ring opening, [4+2] cycloaddition, and protonation. The energy barrier for the ring opening via transition state TS2 was 17.3 kcal mol−1, and the generated D–π–A intermediate Int3 was 11.0 kcal mol−1 higher in energy than cyclic compound Int2. The direct [4+2] cycloaddition from Int3via transition state TS3 would result in an energy barrier of 24.7 kcal mol−1. This could be attributed mainly to the instability of the cis configuration of Int3 and TS3. The conformation transformation from cis-Int3 to trans-Int4 led to an exothermic release of 7.8 kcal mol−1. The following [4+2] cycloaddition occurred through a stepwise mechanism because the energy barrier of the concerted reaction viaTS4 was 2.4 kcal mol−1 higher than that of the nucleophilic addition viaTS5. The protonated TMG played an important role in stabilizing the enolate anion in intermediate Int5. The energy barriers for the two steps of cycloaddition were 15.2 kcal mol−1 and 6.3 kcal mol−1, respectively, and the resultant isoindoline polycycle compound Int6 was 30.9 kcal mol−1 lower in energy than TS5, indicating an irreversible process. Finally, the protonation of the terminal enolate anion by proton transfer from protonated TMG gave the stable neutral product 3 with an energy barrier of 1.9 kcal mol−1 and exothermic release of 10.1 kcal mol−1.
The reaction with acetylacetone anion R2 added to the C(2)-position of pyridinium R1 was also investigated in detail. The computational results indicated that the energy barrier of the initial deprotonation activation was 9.6 kcal mol−1 higher than that of the corresponding reaction at the C(6)-position. In the following step, the barrier for either the ring opening or the Michael addition was more than 4.5 kcal mol−1 higher than that of the stepwise [4+2] cycloaddition as illustrated above. Therefore, the regioselectivity was at the C(6)-position rather than the C(2)-position (for more details, see Fig. S5†).
Footnotes |
† Electronic supplementary information (ESI) available: Experimental procedures; characterization data of all the new products; detailed mechanistic studies; copies of 1H NMR and 13C NMR. CCDC 2071226 (3), 2071227 (21), 2071228 (25), 2071230 (26), 2116271 (47), 2086413 (48), 2086415 (52), 2086416 (61), 2086417 (70), 2071232 (72), 2071233 (74) and 2086418 (82). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc05741c |
‡ These authors contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2021 |