Asymmetric Dearomative (3+2)-Cycloaddition Involving Nitro-Substituted Benzoheteroarenes under H-Bonding Catalysis

In our studies, the organocatalytic 1,3-dipolar cycloaddition between 2-nitrobenzofurans or 2-nitrobenzothiophene and N-2,2,2-trifluoroethyl-substituted isatin imines has been developed. The reaction has been realized by employing bifunctional organocatalysis, with the use of squaramide derivative being crucial for the stereochemical efficiency of the process. The usefulness of the cycloadducts obtained has been confirmed in selected transformations, including aromative and non-aromative removal of the nitro group.

In continuation of our efforts on the development of asymmetric dearomative transformations [50][51][52][53][54][55], we became interested in CADA reactions involving electrondeficient heteroaromatic systems. Herein, we report the organocatalytic dearomative 1,3dipolar cycloaddition between nitro-substituted benzoheteroarenes with azomethine ylides, as realized under bifunctional catalysis, yielding optically active pyrrolidine-fused spirocyclic dihydrobenzofuran and dihydrobenzothiophene derivatives bearing four contiguous stereocenters. In the context of our studies, it should be noted that a complementary approach involving bifunctional phase-transfer catalysis (PTC) was recently developed by Ren and Wang et al. [56].

Optimization Studies
Optimization studies were performed using 2-nitrobenzofuran 1a and N-2,2,2trifluoroethyl-substituted isatin imine 2a as model reactants. Initially, quinine 4a was employed as a catalyst and the reaction was run in CDCl3 for the ease of data processing ( Table 1, entry 1). Pleasingly, the formation of desired 1,3-dipolar cycloadduct 3a was observed; however, low yield and diastereoselectivity were observed. Furthermore, chiral UPC 2 analysis of isolated product 3a showed that the reaction proceeded without induction of asymmetry. Therefore, various Brønsted base-type catalysts were evaluated to improve effectiveness and stereoselectivity of the process. Interestingly, the use of In continuation of our efforts on the development of asymmetric dearomative transformations [50][51][52][53][54][55], we became interested in CADA reactions involving electron-deficient heteroaromatic systems. Herein, we report the organocatalytic dearomative 1,3-dipolar cycloaddition between nitro-substituted benzoheteroarenes with azomethine ylides, as realized under bifunctional catalysis, yielding optically active pyrrolidine-fused spirocyclic dihydrobenzofuran and dihydrobenzothiophene derivatives bearing four contiguous stereocenters. In the context of our studies, it should be noted that a complementary approach involving bifunctional phase-transfer catalysis (PTC) was recently developed by Ren and Wang et al. [56].

Optimization Studies
Optimization studies were performed using 2-nitrobenzofuran 1a and N-2,2,2trifluoroethyl-substituted isatin imine 2a as model reactants. Initially, quinine 4a was employed as a catalyst and the reaction was run in CDCl 3 for the ease of data processing (Table 1, entry 1). Pleasingly, the formation of desired 1,3-dipolar cycloadduct 3a was observed; however, low yield and diastereoselectivity were observed. Furthermore, chiral UPC 2 analysis of isolated product 3a showed that the reaction proceeded without induction of asymmetry. Therefore, various Brønsted base-type catalysts were evaluated to improve effectiveness and stereoselectivity of the process. Interestingly, the use of commercially available dimeric catalysts 4b or 4c provided a significant increase in conversion and diastereoselectivity (  [4][5][6][7][8]. Performed experiments revealed that squaramide-based catalysts 4e-h derived from quinine were appropriate for the developed cycloaddition (Table 1, entries 5-8). Finally, catalyst 4h was selected for further studies, as its utilization ensured the formation of 3a with good yield and excellent diastereo-and enantioselectivity ( Table 1,  entry 8). Subsequently, screening of solvents was initiated (Table 1, entries 9-15). Unfortunately, the decrease in reactivity caused by poor substrate solubility or diminished imine 2a stability was observed. Decrease in concentration of the reaction mixture did not bring improvement in terms of yield or stereoselectivity of the transformation, but a longer reaction time was required (Table 1, entry 16). However, imine 2a degradation was observed as the consequence of prolonged reaction time. This problem was eventually solved by the use of 1.5-fold excess of 2a. This change resulted in almost full conversion of 2-nitrobenzofurane 1a, and 3a was obtained with excellent yield and stereoselectivity ( Table 1, entry 17). In the hope of improving enantioselectivity, the reaction was performed at lower temperature but, disappointingly, without any enhancement of cycloadduct 3a enantiomeric ratio (Table 1, entry 18). Moreover, 20 mol% loading of the catalyst turned out to be crucial for completion of the reaction, as its lowering led to an inhibition of the process ( Table 1, entry 19). Finally, it was found that the reaction proceeded with comparable results in freshly distilled chloroform (Table 1, entry 20). It is worth noting that the presented reaction was readily scalable to one-mmol scale, affording product 3a with a good outcome ( Table 1, entry 21).

Scope Studies
With the optimized reaction conditions in hand, the scope of the reaction was evaluated. In the first step, structurally diversified dipole precursors 2a-k were tested in an organocatalytic process (Scheme 2). Imines 2a-c with different protecting groups at the nitrogen atom were well tolerated in the developed (3+2)-cycloaddition, providing products 3a-c in good yields and with excellent stereocontrol. Moreover, non-protected isatin-derived imine 2d worked well, giving access to 3d with similar results. It is worth noting that the developed reaction was unbiased towards the electronic properties of substituents in dipole precursors 2, as products with both electron-donating (2e,f) and electron-withdrawing groups (2g-j) were efficiently obtained in a highly stereoselective manner. Moreover, imine 2k with a double substitution pattern gave access to product 3k as a single diastereoisomer, in high yield but with diminished enantiocontrol.
In the next step, the scope of dipolarophiles 1 was examined (Scheme 3). 2-Nitrobenzofuranes 1b-f substituted in the 5-position with groups of different electron properties reacted smoothly in the developed cycloaddition, providing products 3l-p in high yields and with excellent stereoselection. Notably, the bulky tert-butyl group in 1d and the strongly electron-withdrawing nitro substituent in 1f were well tolerated, as demonstrated in the synthesis of 3n and 3p, where the desired reaction proceeded without any loss in enantioselectivity. Notably, cycloadduct 3q with the benzofuran ring functionalized in the 6-position was efficiently obtained following the developed method. Moreover, the substrate scope was further expanded by the use of 2-nitrobenzothiophene 1h. Surprisingly, the developed cycloaddition provided 3r in high yield but with poor enantiocontrol under standard conditions. Thankfully, short re-optimization studies revealed that thiourea catalyst 4d significantly enhanced the stereocontrol affording 3r with good enantioselectivity. products 3a-c in good yields and with excellent stereocontrol. Moreover, non-protected isatin-derived imine 2d worked well, giving access to 3d with similar results. It is worth noting that the developed reaction was unbiased towards the electronic properties of substituents in dipole precursors 2, as products with both electron-donating (2e,f) and electron-withdrawing groups (2g-j) were efficiently obtained in a highly stereoselective manner. Moreover, imine 2k with a double substitution pattern gave access to product 3k as a single diastereoisomer, in high yield but with diminished enantiocontrol. Scheme 2. Asymmetric dearomative (3+2)-cycloaddition between nitro-substituted benzoheteroarenes 1 and N-2,2,2-trifluoroethyl-substituted isatin imines 2-scope studies. In the next step, the scope of dipolarophiles 1 was examined (Scheme 3). 2-Nitrobenzofuranes 1b-f substituted in the 5-position with groups of different electron properties reacted smoothly in the developed cycloaddition, providing products 3l-p in high yields and with excellent stereoselection. Notably, the bulky tert-butyl group in 1d and the strongly electron-withdrawing nitro substituent in 1f were well tolerated, as demonstrated in the synthesis of 3n and 3p, where the desired reaction proceeded without any loss in enantioselectivity. Notably, cycloadduct 3q with the benzofuran ring functionalized in the 6-position was efficiently obtained following the developed method. Moreover, the substrate scope was further expanded by the use of 2-nitrobenzothiophene 1h. Surprisingly, the developed cycloaddition provided 3r in high yield but with poor enantiocontrol under standard conditions. Thankfully, short re-optimization studies revealed that thiourea catalyst 4d significantly enhanced the stereocontrol affording 3r with good enantioselectivity.

Synthetic Utility of Products 3
With the scope studies accomplished, the usefulness of obtained products 3 was demonstrated in selected transformations (Scheme 4). Base-promoted nitro group removal gave access to spirocyclic compound 5 with aromatic benzofuran moiety. Furthermore, the reductive denitration of the starting material 3a was easily performed by utilization of tributyltin hydride and AIBN, providing dihydrobenzofuran 6 in high yield. Notably, the stereochemical composition of the starting material 3a was fully preserved in both cases, as products 5 and 6 were obtained as single diastereoisomers.

Synthetic Utility of Products 3
With the scope studies accomplished, the usefulness of obtained products 3 was demonstrated in selected transformations (Scheme 4). Base-promoted nitro group removal gave access to spirocyclic compound 5 with aromatic benzofuran moiety. Furthermore, the reductive denitration of the starting material 3a was easily performed by utilization of tributyltin hydride and AIBN, providing dihydrobenzofuran 6 in high yield. Notably, the stereochemical composition of the starting material 3a was fully preserved in both cases, as products 5 and 6 were obtained as single diastereoisomers.
With the scope studies accomplished, the usefulness of obtained products 3 was demonstrated in selected transformations (Scheme 4). Base-promoted nitro group removal gave access to spirocyclic compound 5 with aromatic benzofuran moiety. Furthermore, the reductive denitration of the starting material 3a was easily performed by utilization of tributyltin hydride and AIBN, providing dihydrobenzofuran 6 in high yield. Notably, the stereochemical composition of the starting material 3a was fully preserved in both cases, as products 5 and 6 were obtained as single diastereoisomers. Scheme 4. Asymmetric dearomative (3+2)-cycloaddition between nitro-substituted benzoheteroarenes 1 and N-2,2,2-trifluoroethyl-substituted isatin imines 2-transformations.

Absolute Configuration Assignment and Mechanistic Considerations
The absolute configuration of product 3a was assigned by X-ray analysis (Scheme 5, top) [57]. The stereochemistry of products 3b-r was determined by analogy. The absolute stereochemistry allowed us to propose a plausible stereochemical model of the cycloaddition (Scheme 5, bottom). The reaction is initiated by two independent processes. The substrate 1 is activated and oriented by the hydrogen bonds of squaramide moiety of the catalyst 4h. Simultaneously, the quinuclidine moiety of the alkaloid catalyst deprotonates the N-2,2,2-trifluoroethyl-substituted isatin imine 2, leading to the formation of azomethine ylide 7. According to the proposed dual-activation model (3+2)-cycloaddition between 1 and 7 takes place providing 3 in a stereoselective manner.

Absolute Configuration Assignment and Mechanistic Considerations
The absolute configuration of product 3a was assigned by X-ray analysis (Scheme 5, top) [57]. The stereochemistry of products 3b-r was determined by analogy. The absolute stereochemistry allowed us to propose a plausible stereochemical model of the cycloaddition (Scheme 5, bottom). The reaction is initiated by two independent processes. The substrate 1 is activated and oriented by the hydrogen bonds of squaramide moiety of the catalyst 4h. Simultaneously, the quinuclidine moiety of the alkaloid catalyst deprotonates the N-2,2,2-trifluoroethyl-substituted isatin imine 2, leading to the formation of azomethine ylide 7. According to the proposed dual-activation model (3+2)cycloaddition between 1 and 7 takes place providing 3 in a stereoselective manner.

General
NMR spectra were acquired on a Bruker Ultra Shield 700 instrument, running at 700 MHz for 1 H and 176 MHz for 13 C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl3: 7.26 ppm for 1 H NMR, 77.16 ppm for 13 C NMR). Mass spectra were recorded on a Bruker Maxis Impact spectrometer using electrospray

General
NMR spectra were acquired on a Bruker Ultra Shield 700 instrument, running at 700 MHz for 1 H and 176 MHz for 13 C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl 3 : 7.26 ppm for 1 H NMR, 77.16 ppm for 13 C NMR). Mass spectra were recorded on a Bruker Maxis Impact spectrometer using electrospray (ES+) ionization referenced to the mass of the charged species. Optical rotations were measured on a PerkinElmer 241 polarimeter and [α] D values are given in deg·cm·g −1 ·dm −1 ; concentration c is listed in g·(100 mL) −1 . Analytical thin layer chromatography (TLC) was performed using pre-coated aluminum-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation or Hanessian's stain. The enantiomeric ratio (er) of the products was determined by chiral stationary phase UPC 2 (Daicel Chiralpak IA column). Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. For flash chromatography (FC), silica gel (60, 35-70 µm, Merck KGaA, Darmstadt, Germany), 2-Nitrobenzofurans 1, 2-nitro-benzo[b]thiophene 1r, and imines 2 were obtained using literature procedures [58][59][60].

General Procedure for the Enantioselective Synthesis of 3
In an ordinary 4 mL glass vial equipped with a Teflon-coated magnetic stirring bar and screw cap, nitro-substituted benzoheteroarene 1 (1.0 equiv., 0.05 mmol), catalyst 4h (0.2 equiv., 0.01 mmol, 6.3 mg), and the corresponding imine 2 (1.5 equiv., 0.075 mmol) were dissolved in freshly distilled CHCl 3 (0.1 mL). The reaction mixture was stirred for the indicated time at ambient temperature. After full conversion of the starting material 1 (as confirmed by 1 H NMR of a crude reaction mixture), the reaction mixture was directly subjected to flash chromatography on silica gel to obtain pure products 3. The standard samples of products 3 for chiral UPC 2 separation studies were prepared using equimolar mixture of quinine and quinidine as catalyst (See Supplementary Materials).

Conclusions
In conclusion, asymmetric dearomative (3+2)-cycloaddition between nitro-substituted benzoheteroarenes 1 and N-2,2,2-trifluoroethyl-substituted isatin imines 2 was developed. A squaramide-based cinchona alkaloid derivative efficiently promoted the reaction, ensuring high stereoselectivity of the process. Substrate specificity of the catalysts with regard to heteroaromatic framework was observed. Enantiomerically enriched products underwent chemoselective transformations that involved removal of the nitro group proceeding either with the concomitant aromatization of the heteroarene framework or in a non-aromative manner.
Supplementary Materials: The following are available online. Characterization data for obtained products, X-ray data for product 3a, copies of 1 H and 13 C NMR spectra, UPC 2 plots for the cycloaddition products 3.