Radical-Induced Cascade Annulation/Hydrocarbonylation for Construction of 2-Aryl-4H-chromen-4-ones

A robust metal- and solvent-free cascade radical-induced C-N cleavage/intramolecular 6-endo-dig annulation/hydrocarbonylation for the synthesis of the valuable 2-aryl-4H-chromen-4-ones is described. This practical synthesis strategy utilizes propargylamines and air as the oxygen source and green carbonylation reagent, in which propargylamines are activated by the inexpensive and available dimethyl 2,2′-azobis(2-methylpropionate) (AIBME) and (PhSe)2 as the radical initiators. This simple and green protocol features wide substrate adaptability, good functional group tolerance, and amenability to scaling up and derivatizations.


Results and Discussion
We commenced with an investigation of propargylamine 1aa as a model substrate with air as the oxygen and carbonyl source to identify the reaction conditions (Table 1). The initial test of 1aa in the presence of diphenyl diselenide and dimethyl 2,2 -azobis (2-methylpropionate) (AIBME) in 1,2-dichloroethane (DCE) under an air atmosphere gave the desired product 2aa in a 63% isolated yield (entry 1). The influence of the solvents in this model reaction was then examined, and inferior results were obtained (entries 2-6). The following screening of the amount of diphenyl diselenide and AIBME (entries [7][8][9][10][11][12] showed that the 0.5 equiv. of diphenyl diselenide and 3.0 equiv. of AIBME was the best choice (entry 8). Changing the radical initiator from AIBME to AIBN (azodiisobutyronitrile) decreased the yield to 37% (entry 13). Interestingly, the yield of 2aa increased to 85% and 78% when the reaction was performed under solvent-free and blue LED light conditions, respectively (entries 14,15). Furthermore, the effect of the reaction temperature and time was investigated, and the results revealed that these attempts did not show any improvement in the obtainable yield (entries [16][17][18][19]. After extensive experimentation, we selected the conditions used in entry 14 as the optimal ones for the further investigations.

Results and Discussion
We commenced with an investigation of propargylamine 1aa as a model substrate with air as the oxygen and carbonyl source to identify the reaction conditions (Table 1). The initial test of 1aa in the presence of diphenyl diselenide and dimethyl 2,2′-azobis(2methylpropionate) (AIBME) in 1,2-dichloroethane (DCE) under an air atmosphere gave the desired product 2aa in a 63% isolated yield (entry 1). The influence of the solvents in this model reaction was then examined, and inferior results were obtained (entries 2-6). The following screening of the amount of diphenyl diselenide and AIBME (entries [7][8][9][10][11][12] showed that the 0.5 equiv. of diphenyl diselenide and 3.0 equiv. of AIBME was the best choice (entry 8). Changing the radical initiator from AIBME to AIBN (azodiisobutyronitrile) decreased the yield to 37% (entry 13). Interestingly, the yield of 2aa increased to 85% and 78% when the reaction was performed under solvent-free and blue LED light conditions, respectively (entries 14,15). Furthermore, the effect of the reaction temperature and time was investigated, and the results revealed that these attempts did not show any improvement in the obtainable yield (entries [16][17][18][19]. After extensive experimentation, we selected the conditions used in entry 14 as the optimal ones for the further investigations. acetone instead of DCE 0 7 0.2 equiv. of (PhSe)2 was used 55 8 0.5 equiv. of (PhSe)2 was used 71 9 1.5 equiv. of (PhSe)2 was used 59 10 2.0 equiv. of (PhSe)2 was used 64 11 c 2.0 equiv. of AIBME was used 44  With the optimized conditions in hand, the influence of the substituents at the phenolic or alkynyl arene rings was first evaluated (Scheme 2). Generally, electron-donating (e.g., −Me, −OMe) and electron-withdrawing R groups (e.g., −F, −Cl, −Br) were well tolerated, giving the desired products 2ba-2fa in 63-72% yields. Substrates with multiple halo acetone instead of DCE 0 7 0.2 equiv. of (PhSe) 2 was used 55 8 0.5 equiv. of (PhSe) 2 was used 71 9 1.5 equiv. of (PhSe) 2 was used 59 10 2.0 equiv. of (PhSe) 2  With the optimized conditions in hand, the influence of the substituents at the phenolic or alkynyl arene rings was first evaluated (Scheme 2). Generally, electron-donating (e.g., -Me, -OMe) and electron-withdrawing R groups (e.g., -F, -Cl, -Br) were well tolerated, giving the desired products 2ba-2fa in 63-72% yields. Substrates with multiple halo substituents and a bulky tert-butyl group at the orthoand para-phenolic position were compatible under this reaction system with slightly lower yields (products 2ga, 2ha, and 2ia). Moreover, substituents at the meta-phenolic position were well tolerated, affording the desired products 2ja and 2ka in 45% and 67% yields, respectively. Subsequently, the scope and generality of the substituents on the alkynyl arene rings were explored. Substituents with electron-donating groups (-OMe, -Me) and electron-withdrawing groups (-F, -Cl, -Br) at the 2-, 3-, and 4-positions of the benzene rings were well tolerated, affording the corresponding products 2ab-2ai in 60-83% yields. In particular, trifluoromethyl as a strong electron-withdrawing substituent afforded the desired product 2aj in a 59% yield. Moreover, reactions with alkenyl-, thienyl-, and pyrenyl-containing substrates proceeded smoothly as well, giving the products 2ka, 2la, and 2ma in 65%, 69%, and 73% yields, respectively. It is notable that the halo moiety, e.g., -F, -Cl, and -Br, located at either the phenolic or alkynyl arene rings, remained intact (products 2da-2ha, 2ja-2ka, 2ad-2ah). These results exhibit an excellent opportunity for further arene functionalization by transition-metal-catalyzed cross-couplings.
Molecules 2022, 27, x FOR PEER REVIEW 4 of compatible under this reaction system with slightly lower yields (products 2ga, 2ha, an 2ia). Moreover, substituents at the meta-phenolic position were well tolerated, affordin the desired products 2ja and 2ka in 45% and 67% yields, respectively. Subsequently, th scope and generality of the substituents on the alkynyl arene rings were explored. Su stituents with electron-donating groups (−OMe, −Me) and electron-withdrawing grou (−F, −Cl, −Br) at the 2-, 3-, and 4-positions of the benzene rings were well tolerated, affor ing the corresponding products 2ab-2ai in 60-83% yields. In particular, trifluorometh as a strong electron-withdrawing substituent afforded the desired product 2aj in a 59 yield. Moreover, reactions with alkenyl-, thienyl-, and pyrenyl-containing substrates pr ceeded smoothly as well, giving the products 2ka, 2la, and 2ma in 65%, 69%, and 73 yields, respectively. It is notable that the halo moiety, e.g., -F, -Cl, and -Br, located at eith the phenolic or alkynyl arene rings, remained intact (products 2da-2ha, 2ja-2ka, 2ad 2ah). These results exhibit an excellent opportunity for further arene functionalization b transition-metal-catalyzed cross-couplings. Furthermore, we investigated various propargylamines bearing with different su stituents on both the phenolic and alkynyl arene rings to showcase the prospective utili of this protocol (Scheme 3). Substituents with electron-rich (e.g., -Me, -Et, -OMe) grou and electron-deficient (e.g., -F, -Cl, -Br) groups at the phenolic and alkynyl arene rin were well-tolerated. The corresponding products 2bb-2en were obtained in good-to-e cellent yields (62-91%). Moreover, the extended π structure did not show an influenc and the desired product 2bo was successfully obtained in a 78% yield. In addition, th structure of compound 2bo was unambiguously characterized via single crystal X-ra crystallographic analysis (details appear in Supplementary Materials). Furthermore, we investigated various propargylamines bearing with different substituents on both the phenolic and alkynyl arene rings to showcase the prospective utility of this protocol (Scheme 3). Substituents with electron-rich (e.g., -Me, -Et, -OMe) groups and electron-deficient (e.g., -F, -Cl, -Br) groups at the phenolic and alkynyl arene rings were well-tolerated. The corresponding products 2bb-2en were obtained in good-to-excellent yields (62-91%). Moreover, the extended π structure did not show an influence, and the desired product 2bo was successfully obtained in a 78% yield. In addition, the structure of compound 2bo was unambiguously characterized via single crystal X-ray crystallographic analysis (details appear in Supplementary Materials). To further prove the robustness and the general utility of this protocol, we carried out the reaction of propargylamine 1aa on the gram scale under the standard condition When the reaction was amplified to a large scale (scaled up to 50 times), the protoco worked well, and the corresponding product 2aa was isolated in a 75% yield (Scheme 4a) which showed promise for this synthetic strategy as a useful tool in practical syntheti terms. Taking advantage of the flavones, we then explored their reactivity in further syn thetic transformations. Rhodium-catalyzed oxidative C-H functionalization at the C-5 po sition of chromones successfully realized the formation of alkenyl flavones 4aa, 4ab, and 4af in 80%, 75%, and 71% yields, respectively (Scheme 4b). To further prove the robustness and the general utility of this protocol, we carried out the reaction of propargylamine 1aa on the gram scale under the standard condition. When the reaction was amplified to a large scale (scaled up to 50 times), the protocol worked well, and the corresponding product 2aa was isolated in a 75% yield (Scheme 4a), which showed promise for this synthetic strategy as a useful tool in practical synthetic terms. Taking advantage of the flavones, we then explored their reactivity in further synthetic transformations. Rhodium-catalyzed oxidative C-H functionalization at the C-5 position of chromones successfully realized the formation of alkenyl flavones 4aa, 4ab, and 4af in 80%, 75%, and 71% yields, respectively (Scheme 4b). Insights into this cascade reaction were gained by performing control experim clarify the reaction mechanism. To find the source of oxygen, the reaction with pro amine 1aa was initially carried out in the presence of an oxygen and nitrogen atmo In both cases, the desired product 2aa was isolated in 85% and 0% yields, resp clearly indicating an oxygen supply from molecular oxygen of air (Scheme 5a). M the desired product 2aa was not obtained when the reaction was carried out usin hydroxyphenyl alkynone 5 instead of ortho-hydroxyphenyl propargylamine 1 un standard conditions (Scheme 5b). The reaction of 2′-hydroxychalcone 6 was furthe ined under the standard conditions, providing the desired product 2aa in an 8 (Scheme 5c). Moreover, the addition of radical scavengers, namely (2,2,6,6-tetram piperidinyl)oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT), under th ard conditions significantly inhibited the reaction. The radical-trapping products were detected by GC-MS, implying that the reaction proceeds via the radical p (Scheme 5d,e). Furthermore, the control experiments showed that AIBME and were both necessary for this transformation (Scheme 5f).

Scheme 4. Synthetic applications.
Insights into this cascade reaction were gained by performing control experiments to clarify the reaction mechanism. To find the source of oxygen, the reaction with propargylamine 1aa was initially carried out in the presence of an oxygen and nitrogen atmosphere. In both cases, the desired product 2aa was isolated in 85% and 0% yields, respectively, clearly indicating an oxygen supply from molecular oxygen of air (Scheme 5a). Moreover, the desired product 2aa was not obtained when the reaction was carried out using ortho-hydroxyphenyl alkynone 5 instead of ortho-hydroxyphenyl propargylamine 1 under the standard conditions (Scheme 5b). The reaction of 2 -hydroxychalcone 6 was further examined under the standard conditions, providing the desired product 2aa in an 8% yield (Scheme 5c). Moreover, the addition of radical scavengers, namely (2,2,6,6-tetramethyl-1piperidinyl)oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT), under the standard conditions significantly inhibited the reaction. The radical-trapping products 7 and 8 were detected by GC-MS, implying that the reaction proceeds via the radical pathway (Scheme 5d,e). Furthermore, the control experiments showed that AIBME and (PhSe) 2 were both necessary for this transformation (Scheme 5f).
Based on the literature reports [65][66][67] and the results of the above control experiments, a plausible mechanism is proposed (Scheme 6). Initially, AIBME releases nitrogen under thermal conditions to form the free radical A, which attacks (PhSe) 2 to generate the phenylselenyl radical (PhSe·) and compound B (detected by CC-Ms) via radical transfer. Phenylselenyl radical then reacts with propargylamine 1aa to form the radical intermediate Based on the literature reports [65][66][67] and the results of the above control exp ments, a plausible mechanism is proposed (Scheme 6). Initially, AIBME releases nitro under thermal conditions to form the free radical A, which attacks (PhSe)2 to generate phenylselenyl radical (PhSe•) and compound B (detected by CC-Ms) via radical tran Phenylselenyl radical then reacts with propargylamine 1aa to form the radical interm ate

Materials and Methods
The detailed procedures for the synthesis and characterization of the produ given in Appendix A.

Conclusions
In summary, we established a novel and straightforward metal-and solvent-fr cade reaction of propargylamines with air for the construction of 2-aryl-4H-chrom ones with substantial substitution diversity in generally good yields. This cascade p presumably involves a sequence of radical-induced C-N cleavage, followed by Cpling, intramolecular 6-endo-dig annulation, thermal hemolytic cleavage, and ox hydrocarbonylation. The preliminary mechanistic studies suggest that this reaction ably proceeds via a radical pathway. The practical protocol employs air as an o source and represents a simple, economically acceptable, and eco-friendly route t the straightforward construction of a 2-aryl-4H-chromen-4-one skeleton. In additi current strategy can be scaled-up to a gram-scale reaction and the synthetic utility transformation was also accomplished.

Materials and Methods
The detailed procedures for the synthesis and characterization of the products are given in Appendix A.

Conclusions
In summary, we established a novel and straightforward metal-and solvent-free cascade reaction of propargylamines with air for the construction of 2-aryl-4H-chromen-4-ones with substantial substitution diversity in generally good yields. This cascade process presumably involves a sequence of radical-induced C-N cleavage, followed by C-O coupling, intramolecular 6-endo-dig annulation, thermal hemolytic cleavage, and oxidative hydrocarbonylation. The preliminary mechanistic studies suggest that this reaction probably proceeds via a radical pathway. The practical protocol employs air as an oxygen source and represents a simple, economically acceptable, and eco-friendly route toward the straightforward construction of a 2-aryl-4H-chromen-4-one skeleton. In addition, the current strategy can be scaled-up to a gram-scale reaction and the synthetic utility of this transformation was also accomplished.  Institutional Review Board Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available in this article, Characterization data for product 3 and 4, including 1 H-and 13 C-NMR spectroscopies, are available online. CCDC 2195370 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting. The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336033.

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.

Appendix A Experimental Section
Unless otherwise noted, all reagents were purchased from commercial suppliers and used without purification. All cascade reactions were performed in a resealable screwcapped Schlenk flask (approximately a 15 mL volume) in the presence of a Teflon-coated magnetic stirrer bar (4 mm× 10 mm). Reactions were monitored using thin-layer chromatography (TLC) on commercial silica gel plates (GF 254). Visualization of the developed plates was performed under UV lights (GF 254 nm). Flash column chromatography was performed on silica gel (200-300 mesh). 1 H NMR spectra were recorded on a 400 MHz spectrometer and 13 C NMR spectra were recorded on a 100 MHz spectrometer. Chemical shifts were expressed in parts per million (δ) and the signals were reported as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), and m (multiplet), and coupling constants (J) were given in Hz. Chemical shifts as internal standard were referenced to CDCl 3 (δ = 7.26 for 1 H and δ = 77.16 for 13 C NMR) as internal standard. HRMS analysis with a quadrupole time-of-flight mass spectrometer yielded ion mass/charge (m/z) ratios in atomic mass units. The melting points were measured using an SGWX-4 melting point apparatus and were not corrected. The X-ray source used for the single-crystal X-ray diffraction analysis of compound 3na was Mo Kα (λ = 0.71073 Å), and the thermal ellipsoid was drawn at the 30% probability level.
General procedure for the synthesis of 2-aryl-4H-chromen-4-ones 2. A mixture of propargylamines 1 (0.2 mmol), diphenyl diselenide (0.1 mmol), and dimethyl 2,2 -azobis (2-methylpropionate) (0.6 mmol) were added to a resealable screw-capped Schlenk tube. The resulting mixture was stirred in an oil bath preheated to 80 • C under an open air atmosphere for 10 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled to room temperature, extracted with CH 2 Cl 2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na 2 SO 4 , filtered, and then evaporated under a vacuum. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether (1:5, v/v) as the elution solvent to give the desired products 2.