Metal-Free Synthesis of Carbamoylated Chroman-4-Ones via Cascade Radical Annulation of 2-(Allyloxy)arylaldehydes with Oxamic Acids

An efficient and straightforward approach for the synthesis of carbamoylated chroman-4-ones has been well-developed. The reaction is triggered through the generation of carbamoyl radicals from oxamic acids under metal-free conditions, which subsequently undergoes decarboxylative radical cascade cyclization on 2-(allyloxy)arylaldehydes to afford various amide-containing chroman-4-one scaffolds with high functional group tolerance and a broad substrate scope.

For this reason, and because of the demand for practical and environmentally friendly approaches to various functionalized chroman-4-ones, we herein disclose a (NH4)2S2O8-mediated protocol for selective intermolecular radical decarboxylative cyclization of 2-(allyloxy)arylaldehydes with oxamic acids to access diverse carbamoylated chroman-4-one derivatives under metal-free conditions (Scheme 1d).
On the other hand, amides are extremely important because of the ubiquitous existence of amide motifs in many pharmaceuticals, agrochemicals, natural products, and functional materials [32][33][34][35]. During the past few decades, various efficient synthetic methods have been widely explored for the construction of amide units [34,[36][37][38]. Traditionally, synthesis of amides relies on the condensation reactions of carboxylic acids, acyl chlorides or anhydrides with various amines [39,40]. These approaches need the pre-installation of a carboxyl group in the substrate. Doubtlessly, the direct introduction of a carbamoyl group to organic molecules represents a more efficient strategy. In this study, we speculate whether carbamoyl radicals could participate in the cascade annulation process with o-(allyloxy)arylaldehydes to construct amide-containing chroman-4-ones. To the best of our knowledge, the carbamoyl-radical-triggered cascade radical cyclization of 2-(allyloxy)arylaldehydes toward amide-functionalized chroman-4-ones has never been reported.
For this reason, and because of the demand for practical and environmentally friendly approaches to various functionalized chroman-4-ones, we herein disclose a (NH 4 ) 2 S 2 O 8mediated protocol for selective intermolecular radical decarboxylative cyclization of 2-(allyloxy)arylaldehydes with oxamic acids to access diverse carbamoylated chroman-4-one derivatives under metal-free conditions (Scheme 1d).

Results and Discussion
Initially, 2-(allyloxy)benzaldehyde (1a) and 2-oxo-2-(phenylamino)acetic acid (2a) were used as the model substrates to optimize the reaction conditions (Table 1). When the reaction was preceded using (NH 4 ) 2 S 2 O 8 as the oxidant and DMSO as the solvent, at 70 • C under a N 2 atmosphere for 12 h, the desired product 3aa was obtained at a 78% isolated yield (Entry 1). Some other common solvents including CH 3 CN, DMF, DCE, THF, acetone, and H 2 O were also investigated. To our surprise, only DMSO was effective for the current reaction and the desired product 3aa was not detected with other examined solvents (Entries 2-7). Furthermore, various oxidants for this transformation were tested. (NH 4 ) 2 S 2 O 8 was found to be the best oxidant, whereas other oxidants, such as Na 2 S 2 O 8 , K 2 S 2 O 8 , TBHP, PhI(OAc) 2 , and Selectfluor did not generate the target product (Entry 1 vs. . Specially, in contrast to (NH 4 ) 2 S 2 O 8, Na 2 S 2 O 8 and K 2 S 2 O 8 showed no activities in the current reaction; the solubility of these oxidants in DMSO may explain why (NH 4 ) 2 S 2 O 8 is efficient for the current reaction compared to Na 2 S 2 O 8 and K 2 S 2 O 8 . We found that (NH 4 ) 2 S 2 O 8 was completely soluble in DMSO in our reaction system, while Na 2 S 2 O 8 and K 2 S 2 O 8 were only slightly soluble in DMSO. By decreasing the reaction temperature from 70 • C to 60 • C, a slight improved yield of 3aa was achieved (Entry 13 vs. Entry 1), while further reducing the temperature to 50 • C or increasing to 80 • C resulted in lower yields (Entries 14-15 vs. Entry 13). In addition, reducing the amount of (NH 4 ) 2 S 2 O 8 or 2a was not beneficial for the reaction and produced a lower yield (Entries [16][17]. When the reaction was carried out in an open air, a 68% yield for 3aa was obtained, indicating that a N 2 atmosphere is crucial for improving the yield (Entry 18 vs. Entry 13). Additionally, in the absence of the oxidant, no reaction occurred, suggesting that an oxidant is essential for the current reaction (Entry 19). Initially, 2-(allyloxy)benzaldehyde (1a) and 2-oxo-2-(phenylamino)acetic acid (2a) were used as the model substrates to optimize the reaction conditions (Table 1). When the reaction was preceded using (NH4)2S2O8 as the oxidant and DMSO as the solvent, at 70 °C under a N2 atmosphere for 12 h, the desired product 3aa was obtained at a 78% isolated yield (Entry 1). Some other common solvents including CH3CN, DMF, DCE, THF, acetone, and H2O were also investigated. To our surprise, only DMSO was effective for the current reaction and the desired product 3aa was not detected with other examined solvents (Entries 2-7). Furthermore, various oxidants for this transformation were tested. (NH4)2S2O8 was found to be the best oxidant, whereas other oxidants, such as Na2S2O8, K2S2O8, TBHP, PhI(OAc)2, and Selectfluor did not generate the target product (Entry 1 vs. . Specially, in contrast to (NH4)2S2O8, Na2S2O8 and K2S2O8 showed no activities in the current reaction; the solubility of these oxidants in DMSO may explain why (NH4)2S2O8 is efficient for the current reaction compared to Na2S2O8 and K2S2O8. We found that (NH4)2S2O8 was completely soluble in DMSO in our reaction system, while Na2S2O8 and K2S2O8 were only slightly soluble in DMSO. By decreasing the reaction temperature from 70 °C to 60 °C, a slight improved yield of 3aa was achieved (Entry 13 vs. Entry 1), while further reducing the temperature to 50 °C or increasing to 80 °C resulted in lower yields (Entries 14-15 vs. Entry 13). In addition, reducing the amount of (NH4)2S2O8 or 2a was not beneficial for the reaction and produced a lower yield (Entries [16][17]. When the reaction was carried out in an open air, a 68% yield for 3aa was obtained, indicating that a N2 atmosphere is crucial for improving the yield (Entry 18 vs. Entry 13). Additionally, in the absence of the oxidant, no reaction occurred, suggesting that an oxidant is essential for the current reaction (Entry 19). With the optimal reaction conditions established (Table 1, entry 13), we first explored the generality of the reaction by employing various 2-(allyloxy)arylaldehydes with 2-oxo-2-((phenylamino)acetic acid (2a). As depicted in Scheme 2, 2-(allyloxy)benzaldehydes bearing either electron-donating groups (Me, t-Bu and OMe) or electron-withdrawing groups (F, Cl, Br, CO 2 Me) all proceeded smoothly, affording the desired products at moderate to good yields (3aa-3na) (Supplementary Materials). Furthermore, the naphthalene-derived substrate could also undergo transformation to obtain 3oa at a moderate yield. To our delight, substrate 1p bearing a methyl group close to C=C bond and 2-allylbenzaldehyde 1q also reacted well, providing product 3pa and 3qa at 68% and 53% yields, respectively. However, N-allyl-N-(2-formylphenyl)acetamide failed to generate the expected product (3ra). We next investigated the scope of this decarboxylative radical cyclization by varying oxamic acids with o-(allyloxy)aryl-aldehydes (1a), as shown in Scheme 3. N-aryl oxamic acids with electron-donating and electron-withdrawing groups all provided the desired products at 63-83% yields. Some important functional groups, such as alkyl (3ab), alkoxyl (3ac), halide (3ad-3af and 3ah), and CF3 (3ag) groups at different benzene rings positions were well-compatible. Furthermore, N-alkyl oxamic acids were also suitable substrates. Various alkyl groups, including benzyl (3ai), cyclohexyl (3aj), cyclopentyl acids with electron-donating and electron-withdrawing groups all provided the desired products at 63-83% yields. Some important functional groups, such as alkyl (3ab), alkoxyl (3ac), halide (3ad-3af and 3ah), and CF 3 (3ag) groups at different benzene rings positions were well-compatible. Furthermore, N-alkyl oxamic acids were also suitable substrates. Various alkyl groups, including benzyl (3ai), cyclohexyl (3aj), cyclopentyl (3ak), butyl (3al), and adamantly (3an), smoothly proceeded to provide the desired products at good yields. However, using 2o and 2p as substrates, no desired products (3ao and 3ap) were detected and most of substrate 1a was recycled. GC-Ms showed that 2o and 2p were almost converted to the corresponding N,N-dibutylformamide and N-ethyl-N-phenylformamide via the release of CO 2 . In addition, we also tried using 2-oxo-2-phenylacetic, pivalic, and 2,2-difluoro-2-phenylacetic acids as substrates instead of oxamic acid 2, but no desired decarboxylative cyclization products were obtained. (3ao and 3ap) were detected and most of substrate 1a was recycled. GC-Ms showed that 2o and 2p were almost converted to the corresponding N,N-dibutylformamide and N-ethyl-N-phenylformamide via the release of CO2. In addition, we also tried using 2-oxo-2-phenylacetic, pivalic, and 2,2-difluoro-2-phenylacetic acids as substrates instead of oxamic acid 2, but no desired decarboxylative cyclization products were obtained. To demonstrate the scalability of this protocol, a gram-scale reaction was conducted by using substrate 1a (5 mmol, 0.81 g) with 2a under the standard reaction conditions (Scheme 4). As anticipated, the desired product 3aa was obtained at a 77% isolated yield, which suggests that the present reaction is a practical method for the synthesis of various carbamoylated chroman-4-ones. (Scheme 4). As anticipated, the desired product 3aa was obtained at a 77% isolated yield, which suggests that the present reaction is a practical method for the synthesis of various carbamoylated chroman-4-ones. To better understand the cascade annulation process, several control experiments were carried out (Scheme 5). When the reaction was performed in the presence of 2 equiv. of radical scavengers (TEMPO or BHT) under the standard reaction conditions, the desired product 3aa was not observed (Scheme 5a), suggesting that a free-radical pathway might be involved in the current transformation. In addition, in conducting the reaction between 1a and 2o in the presence of 2 equiv. of TEMPO, TEMPO-adduct 4o was detected by GC-MS analysis (Scheme 5b), which implied that carbamoyl radicals generated during the reaction. Furthermore, radical adducts I and II were not detected upon adding 3 equiv. of TEMPO in the absence of 2a under the standard conditions (Scheme 5c), indicating that a radical-radical coupling process could be ruled out.  To better understand the cascade annulation process, several control experiments were carried out (Scheme 5). When the reaction was performed in the presence of 2 equiv. of radical scavengers (TEMPO or BHT) under the standard reaction conditions, the desired product 3aa was not observed (Scheme 5a), suggesting that a free-radical pathway might be involved in the current transformation. In addition, in conducting the reaction between 1a and 2o in the presence of 2 equiv. of TEMPO, TEMPO-adduct 4o was detected by GC-MS analysis (Scheme 5b), which implied that carbamoyl radicals generated during the reaction. Furthermore, radical adducts I and II were not detected upon adding 3 equiv. of TEMPO in the absence of 2a under the standard conditions (Scheme 5c), indicating that a radical-radical coupling process could be ruled out. To better understand the cascade annulation process, several control experiments were carried out (Scheme 5). When the reaction was performed in the presence of 2 equiv. of radical scavengers (TEMPO or BHT) under the standard reaction conditions, the desired product 3aa was not observed (Scheme 5a), suggesting that a free-radical pathway might be involved in the current transformation. In addition, in conducting the reaction between 1a and 2o in the presence of 2 equiv. of TEMPO, TEMPO-adduct 4o was detected by GC-MS analysis (Scheme 5b), which implied that carbamoyl radicals generated during the reaction. Furthermore, radical adducts I and II were not detected upon adding 3 equiv. of TEMPO in the absence of 2a under the standard conditions (Scheme 5c), indicating that a radical-radical coupling process could be ruled out.

Scheme 5.
Control experiments (a) Radical inhibition experiment using TEMPO or BHT as radical inhibitor; (b) Radical capture experiment between 1a and 2o using TEMPO as a radical scavenger; (c) Reaction between 1a and TEMPO under standard conditions. On the basis of the above control experiment and the recent literature [41][42][43][44][45][46][47][48][49][50], a plausible reaction pathway for this carbamoylation reaction is proposed. As shown in Scheme 6, initially, the radical anion SO4 −• generates via the decomposition of (NH4)2S2O8 in DMSO. The resulting sulfate radical anion SO4 −• performs hydrogen atom transfer (HAT) with 2-oxo-2-(phenylamino)acetic acid (2a) to form the carbamoyl radical A alongside emission of CO2. The radical A attacks the carbon-carbon double bond of 1a to form radical intermediate B. Then, the radical intermediate B cyclizes to afford an oxygen radical C, which undergoes a 1,2-hydrogen atom transfer (HAT) process to deliver the benzyl radical D. Finally, the further oxidation of intermediate D results in the corresponding carbocation E with the remaining sulfate radical anion SO4 −• , followed by deprotonation to generate the target product 3aa.

General Information
Unless otherwise specified, all reagents and solvents were obtained from commercial suppliers and used without further purification. All reagents were weighed and handled in air at room temperature. 1 H-NMR spectra were recorded at 400 MHz and 13 C-NMR spectra were recorded at 100 MHz by using a German Bruker Avance 400 spectrometer. Chemical shifts were calibrated using residual undeuterated solvent as an internal reference ( 1 H-NMR: CDCl3 7.26 ppm, 13 C-NMR: CDCl3 77.0 ppm). The following abbreviations were used to describe peak splitting patterns when appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Mass spectra were performed on a spectrometer operating on ESI-TOF.

General Procedure for the Preparation of Carbamoylated Chroman-4-Ones
To a solution of 2-(allyloxy)arylaldehyde 1 (0.3 mmol) and oxamic acid 2 (0.9 mmol) in DMSO (2 mL), (NH4)2S2O8 (1.2 mmol) was added. The reaction mixture was stirred at 60 °C under N2 atmosphere conditions. The progress of the reaction was monitored by TLC. The reaction typically finished within 12 h. After completion, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL × 3); the solvent was then removed under vacuum. The residue was purified by flash column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to generate the desired products 3.

General Information
Unless otherwise specified, all reagents and solvents were obtained from commercial suppliers and used without further purification. All reagents were weighed and handled in air at room temperature. 1 H-NMR spectra were recorded at 400 MHz and 13 C-NMR spectra were recorded at 100 MHz by using a German Bruker Avance 400 spectrometer. Chemical shifts were calibrated using residual undeuterated solvent as an internal reference ( 1 H-NMR: CDCl 3 7.26 ppm, 13 C-NMR: CDCl 3 77.0 ppm). The following abbreviations were used to describe peak splitting patterns when appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Mass spectra were performed on a spectrometer operating on ESI-TOF.

General Procedure for the Preparation of Carbamoylated Chroman-4-Ones
To a solution of 2-(allyloxy)arylaldehyde 1 (0.3 mmol) and oxamic acid 2 (0.9 mmol) in DMSO (2 mL), (NH 4 ) 2 S 2 O 8 (1.2 mmol) was added. The reaction mixture was stirred at 60 • C under N 2 atmosphere conditions. The progress of the reaction was monitored by TLC. The reaction typically finished within 12 h. After completion, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL × 3); the solvent was then removed under vacuum. The residue was purified by flash column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to generate the desired products 3.

Conclusions
In summary, we developed a convenient and straightforward decarboxylative radical cascade cyclization of 2-(allyloxy)arylaldehydes and oxamic acids, leading to biological carbamoylated chroman-4-one scaffolds. The present reaction has the advantages of a readily available substrate, metal-free conditions, operational simplicity, a broad substrate scope, and favorable functional group compatibility, thus providing an attractive and practical approach for the synthesis of amide-functionalized chroman-4-ones.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules27207049/s1, Copies of the 1 H-NMR and 13 C-NMR for compounds 3aa-3qa and 3ab-3an can be found in Supplementary Materials.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.