Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins

[3 + 2] Cycloaddition reactions of heteroaromatic N-ylides with electron-deficient olefins have been developed. The heteroaromatic N-ylides, in situ generated from N-phenacylbenzothiazolium bromides, can smoothly react with maleimides under very mild conditions, affording fused polycyclic octahydropyrrolo[3,4-c]pyrroles in good-to-excellent isolated yields. This reaction concept could also be extended to 3-trifluoroethylidene oxindoles and benzylidenemalononitriles as electron-deficient olefins for accessing highly functionalized polyheterocyclic compounds. A gram-scale experiment was also carried out to verify the practicability of the methodology.


Introduction
Polyheterocyclic skeletons are frequently found as the common backbone in a variety of natural alkaloids and synthetic organic molecules with remarkable biological activities [1][2][3][4]. As shown in Figure 1, the oxo-evodiamine analogue (I), YM-201627 (II), and camptothecin (III) have been verified to be tumor inhibitors. Spirocyclic furan analog (IV) has been identified as a potent inhibitor of bacterial phenylalanyl-tRNA synthetase. Spirotryprostatin A (V) has been isolated as a novel cell cycle inhibitor in mammals. Therefore, the construction of highly functionalized polyheterocyclic compounds continues to be an important area of research in modern organic synthetic chemistry. A large number of efficient synthetic tactics have been developed for the synthesis of various functionalized polyheterocycles [5][6][7][8][9][10]. Among the various reported methods, [3 + 2] cycloaddition has become one of the most powerful and straightforward synthetic approaches that can be used to construct polycyclic compounds [11][12][13][14][15][16].

R PEER REVIEW
3 of 20 Scheme 1. Profile of [3 + 2] cycloaddition of nitrogen-ylides in situ generated from imines or heteroarenium salts and the strategy for the diverse synthesis of structurally diverse fused polyheterocyclic compounds in this study.

Results and Discussion
Initially, optimization of the reaction conditions was conducted by choosing benzothiazolium salt 1a and N-phenylmaleimide 2a as the model substrates (Table 1). Several inorganic bases were first tested in DCM at room temperature, and the use of Na 2 CO 3 gave product 3aa in a relatively high yield (entry 3 vs. entries 1, 2, and 4). Interestingly, triethylamine furnished trace product (entry 5). Upon further solvent examination (entries 6-9), the toluene was found to be an appropriate medium to yield the corresponding cycloaddition product with a 99% yield (entry 6). As a result, the best reaction condition consisted of a 1.5 equivalent of Na 2 CO 3 and toluene as the solvent at room temperature.
To verify the scalability of the developed [3 + 2] cycloaddition, the optimal reaction conditions were applied to other benzothiazolium salts (Scheme 2). The electronic nature and size of the substituents on benzoyl group showed little influence on the reactivity of the reaction, and the desired products 3ba-3ha could be isolated in good to excellent yields (52-99%). Benzothiazolium salts 1i and 1j with two substituents on the benzene ring delivered good yields for 3ia (79%) and 3ja (73%). As for the introduction of naphthyl to benzothiazolium salt, the reaction also proceeded smoothly to provide the corresponding octahydropyrrolo [3,4-c]pyrrole 3ka with a 96% yield. A smooth conversion of the substrate 1l-bearing chlorine substituent on benzothiazole was observed in the reaction with 2a to give product 3la in a 92% yield.
Following this, the reaction scope with respect to maleimides 2 was investigated (Scheme 3). The electronic properties of the substituent on the para-position of the phenyl ring had almost no effect on the developed transformation, leading to products 3ab-3ad in excellent isolated yields (89-91%). Similarly, meta-substituted maleimides 2e-2g were well tolerated in [3 + 2] cycloaddition and smoothly switched into octahydropyrrolo [3,4-c]pyrroles 3ae-3ag with 88-94% yields. The reaction involving maleimide 2h also performed very well, and a good yield was produced. Moreover, N-alkyl substituted maleimides 2i and 2j were compatible with the current system, resulting in 93% and 99% yields, respectively. use of Na2CO3 gave product 3aa in a relatively high yield (entry 3 vs. entries 1, 2, and 4). Interestingly, triethylamine furnished trace product (entry 5). Upon further solvent examination (entries 6-9), the toluene was found to be an appropriate medium to yield the corresponding cycloaddition product with a 99% yield (entry 6). As a result, the best reaction condition consisted of a 1.5 equivalent of Na2CO3 and toluene as the solvent at room temperature. To verify the scalability of the developed [3 + 2] cycloaddition, the optimal reaction conditions were applied to other benzothiazolium salts (Scheme 2). The electronic nature and size of the substituents on benzoyl group showed little influence on the reactivity of the reaction, and the desired products 3ba-3ha could be isolated in good to excellent yields (52-99%). Benzothiazolium salts 1i and 1j with two substituents on the benzene ring delivered good yields for 3ia (79%) and 3ja (73%). As for the introduction of naphthyl to benzothiazolium salt, the reaction also proceeded smoothly to provide the corresponding octahydropyrrolo [3,4-c]pyrrole 3ka with a 96% yield. A smooth conversion of the substrate 1l-bearing chlorine substituent on benzothiazole was observed in the reaction with 2a to give product 3la in a 92% yield. ring had almost no effect on the developed transformation, leading to products 3ab-3ad in excellent isolated yields (89-91%). Similarly, meta-substituted maleimides 2e-2g were well tolerated in [3 + 2] cycloaddition and smoothly switched into octahydropyrrolo [3,4c]pyrroles 3ae-3ag with 88-94% yields. The reaction involving maleimide 2h also performed very well, and a good yield was produced. Moreover, N-alkyl substituted maleimides 2i and 2j were compatible with the current system, resulting in 93% and 99% yields, respectively. The synthetic practicability of the developed [3 + 2] cycloaddition was demonstrated by the scale-up experiment of benzothiazolium salt 1a and N-phenylmaleimide 2a under the standard conditions, and the product octahydropyrrolo [3,4-c]pyrrole 3aa was isolated with a 85% yield (Scheme 4). In addition, the structure of 3aa was unambiguously determined using single crystal X-ray diffraction analysis (Scheme 4, CCDC 2193494 (3aa) contains the supplementary crystallographic data for this paper. For details, see the Supporting Information). The synthetic practicability of the developed [3 + 2] cycloaddition was demonstrated by the scale-up experiment of benzothiazolium salt 1a and N-phenylmaleimide 2a under the standard conditions, and the product octahydropyrrolo [3,4-c]pyrrole 3aa was isolated with a 85% yield (Scheme 4). In addition, the structure of 3aa was unambiguously determined using single crystal X-ray diffraction analysis (Scheme 4, CCDC 2193494 (3aa) contains the supplementary crystallographic data for this paper. For details, see the Supporting Information).
in excellent isolated yields (89-91%). Similarly, meta-substituted maleimides 2e-2g were well tolerated in [3 + 2] cycloaddition and smoothly switched into octahydropyrrolo [3,4c]pyrroles 3ae-3ag with 88-94% yields. The reaction involving maleimide 2h also performed very well, and a good yield was produced. Moreover, N-alkyl substituted maleimides 2i and 2j were compatible with the current system, resulting in 93% and 99% yields, respectively. The synthetic practicability of the developed [3 + 2] cycloaddition was demonstrated by the scale-up experiment of benzothiazolium salt 1a and N-phenylmaleimide 2a under the standard conditions, and the product octahydropyrrolo [3,4-c]pyrrole 3aa was isolated with a 85% yield (Scheme 4). In addition, the structure of 3aa was unambiguously determined using single crystal X-ray diffraction analysis (Scheme 4, CCDC 2193494 (3aa) contains the supplementary crystallographic data for this paper. For details, see the Supporting Information). Owing to the unique properties of the trifluoromethyl unit in promoting the metabolic stability and bioavailability of many bioactive compounds [62,63], several CF 3 -containing heterocyclic compounds, in particular of trifluoromethyl-substituted pyrrolidines, have been synthesized with [3 + 2] cycloaddition reaction in the past few years [64][65][66][67][68]. To expand the application of benzothiazolium salts in constructing spiro-pyrrolidines, the [3 + 2] cycloaddition between benzothiazolium salts and 3-trifluoroethylidene oxindoles was conducted. After a careful screening of bases and solvents (For the detail of the procedure, see Supporting Information), the reaction of benzothiazolium salt 1a with 3-trifluoroethylidene oxindole 4a proceeded smoothly to produce the CF 3 -containing  [2,1-b]thiazole 5aa with a 95% isolated yield (Scheme 5). On this basis, other 3-trifluoroethylidene oxindoles 4b-4h were evaluated under the optimal reaction conditions, these substrates could be smoothly converted into the corresponding cycloadducts 5ab-5ah in good yields (70-90%). Moreover, 3-trifluoroethylidene benzofuranone was also compatible with the developed system to give product 5ai with a 85% yield.
have been synthesized with [3 + 2] cycloaddition reaction in the past few years [64-68 expand the application of benzothiazolium salts in constructing spiro-pyrrolidines, t + 2] cycloaddition between benzothiazolium salts and 3-trifluoroethylidene oxindoles conducted. After a careful screening of bases and solvents (For the detail of the proced see Supporting Information), the reaction of benzothiazolium salt 1a with 3-trifluoroe idene oxindole 4a proceeded smoothly to produce the CF3-containing tetrahy benzo[d]pyrrolo [2,1-b]thiazole 5aa with a 95% isolated yield (Scheme 5). On this b other 3-trifluoroethylidene oxindoles 4b-4h were evaluated under the optimal reac conditions, these substrates could be smoothly converted into the corresponding cycl ducts 5ab-5ah in good yields (70-90%). Moreover, 3-trifluoroethylidene benzofuran was also compatible with the developed system to give product 5ai with a 85% yield Encouraged by the above success, we questioned whether the application of be thiazolium salt can be further expanded. Subsequently, many benzylidenemalononit 6 were surveyed via reaction with 1a. The reaction optimization study demonstrated triethylamine (TEA) was the best base for promoting the transformation (For the deta the procedure, see Supporting Information). The reaction between 1a and 6a could fur the desired product 7aa in 95% yield (Scheme 6). Further studies indicated that Encouraged by the above success, we questioned whether the application of benzothiazolium salt can be further expanded. Subsequently, many benzylidenemalononitriles 6 were surveyed via reaction with 1a. The reaction optimization study demonstrated that triethylamine (TEA) was the best base for promoting the transformation (For the detail of the procedure, see Supporting Information). The reaction between 1a and 6a could furnish the desired product 7aa in 95% yield (Scheme 6). Further studies indicated that the substituents on the aryl ring (Ar) of benzylidenemalononitriles have a limited effect on the reactivity of the reaction. The benzylidenemalononitriles 6b-6f were compatible with the reaction condition to give the corresponding products 7ab-7af in 87-97% yields. substituents on the aryl ring (Ar) of benzylidenemalononitriles have a limited effect on the reactivity of the reaction. The benzylidenemalononitriles 6b-6f were compatible with the reaction condition to give the corresponding products 7ab-7af in 87-97% yields.

General Information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored with TLC. The NMR spectra were recorded with a Bruker Avance NEO 400 or 300. 1 H NMR and 13 C NMR spectra were recorded in CDCl3 or DMSO-d6. 1 H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13 C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 at 77.16 ppm, DMSO-d6 at 39.52 ppm). Melting points products were recorded on a Büchi Melting Point B-545. The HRMS was recorded with an Agilent 6545 LC/Q-TOF mass spectrometer.

General Experimental Procedures for the Synthesis of Compounds 3 (Schemes 2 and 3)
In an ordinary vial charged with a magnetic stirring bar, N-phenacylbenzothiazolium bromides 1 (0.15 mmol, 1.5 equiv), maleimides 2 (0.1 mmol, 1.0 equiv), Na2CO3 (0.15 mmol, 1.5 equiv), and toluene (1.0 mL) were successively added. Then, the mixture was stirred at room temperature for the indicated time. Products 3 were isolated using flash chromatography on silica gel.

General Information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored with TLC. The NMR spectra were recorded with a Bruker Avance NEO 400 or 300. 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 or DMSO-d 6 . 1 H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl 3 at 7.26 ppm, DMSO-d 6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13 C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl 3 at 77.16 ppm, DMSO-d 6 at 39.52 ppm). Melting points products were recorded on a Büchi Melting Point B-545. The HRMS was recorded with an Agilent 6545 LC/Q-TOF mass spectrometer.