Acid/Base-Steered Cascade Cyclization: An Efficient One-Pot Access to Diverse Isobenzofuranone and Isoindolobenzoxazinone Derivatives

We herein report the acid/base-steered two distinct reaction pathways of 2-acylbenzoic acids with isatoic anhydrides. In the presence of Na2CO3, the cascade process consists of the cyclization of 2-acetylbenzoic acid and nucleophilic ring-opening reaction of isatoic anhydride to furnish isobenzofuranone derivatives with high efficiency. However, p-toluenesulfonic acid can promote the product isobenzofuranones to undergo sequential intramolecular rearrangment, nucleophilic addition and cyclization reaction to produce diverse isoindolobenzoxazinones in good yields. The synthetic utility of this method was further demonstrated by the gram-scale preparation of the desired products and the facile transformations of the resulting products.


Introduction
Polyheterocyclic scaffolds, as a kind of recognized privileged structure, are widely found in numerous natural products and biologically active compounds. Because of their restricted conformational flexibilities, polyheterocyclic molecules often exhibit the powerful ability to bind to diverse receptors through a variety of non-covalent interactions [1], which allows them to show significant biological activities and play very important roles in chemical biology and drug discovery [2][3][4][5][6]. Among various rigid polyheterocycles, isobenzofuranone and isoindolobenzoxazinone are two prominent substructures because of their broad existence in pharmaceuticals, agrochemicals and biologically active natural products [7], and display a wide range of biological and pharmaceutical properties, which include antibacterial [8,9], antimalarial [10][11][12], anticancer [13,14], anticonvulsant [15,16], and antiulcerogenic activities [17]. For instance, Butylphthalide is a commercial drug for the treatment of acute ischemic stroke (Figure 1), which can increase ischaemic perfusion and reduce the death of nerve cells [18]. Moreover, Penicidone A is the first group of isobenzofuranone analogues isolated from the culture of Penicillium sp. and exhibit moderate cytotoxicity against many cancer cell lines [19]. Terresoxazine, a natural product possessing pyrrolobenzoxazine core structure, was isolated from the plant Tribulus terrestris, used for a long time in the treatment of a number of diseases in Chinese folk medicine [20]. In addition, these dominant skeletons are also employed as multifunctional ingredients in the total synthesis of natural products and organic materials, and undergo all kinds of chemical transformations [21][22][23][24]. As a result of these practical applications, construction of these polyheterocyclic scaffolds has drawn considerable attention from both academic and industrial organizations. Recently, Mal and co-workers have reviewed the strategies for the synthesis of isobenzofuranones including the lactonization of 2-(hydroxymethyl)-benzoic acids or their analogues that is the most easily conceivable access to phthalides, the reduction of phthalic anhydrides, the oxidation of phthalans and other reactions [25]. On the other hand, the most widely-used and straightforward approaches to isoindolobenzoxazinone derivatives are the Brønsted or Lewis acid-catalyzed cascade cyclization of 2-formylbenzoic acid with anthranilamides [26][27] or anthranilic acid [28][29][30]. Moreover, SanMartin, Zhao et al. also demonstrated that such similar polyheterocyclic scaffold can be constructed through transition metal-catalyzed cascade reactions between alkyne-containing carboxylic acids and anthranilic acids, anthranilamides or functionalized amines [31][32][33][34][35]. Despite tremendous achievements, it is still challenging and highly desirable to develop new, efficient, environmentally benign and cost-effective approaches to diverse polyheterocyclic compounds.
Isatoic anhydride is a cheap and commercially available compound that is a raw material for the synthesis of pharmaceuticals, agrochemicals and dyes, as well as an intermediate in the production of herbicide, Bentazone. The chemistry of isatoic anhydride and its reaction with amines has been investigated in detail [36][37][38][39]. We found that isatoic anhydride undergoes ring opening upon heating with various amines to produce 2-amino-N-alkylbenzamides, which can react with aldehydes [40][41][42] or orthoesters [43][44][45][46] and 2formylbenzoic acid [47][48][49] to produce quinazolinones and isoindoloquinazolinones, respectively (Scheme 1a,b). Continuing with our research efforts to develop novel efficient and eco-friendly accesses to the construction of polyheterocyclic skeletons from easily available starting materials [50][51][52][53][54][55][56], we undertook the current study with the aim to construct polyheterocyclic compounds. We envisioned that the multi-component reaction of 2-acetylbenzoic acid, amines and isatoic anhydride would yield functionalized isoindoloquinazolinones (Scheme 1c). Unfortunately, the experiment did not proceed as assumed and did not yield the desired product, but provided the 3-substituted isobenzofuranones. Reported herein is our systematic study on the cascade reaction of 2-acetylbenzoic acid and isatoic anhydride with the discovery of the base/acid-steered divergent reaction pathways leading selectively to diverse isoindolobenzoxazinone and isobenzofuranone derivatives, respectively (Scheme 1d). As a result of these practical applications, construction of these polyheterocyclic scaffolds has drawn considerable attention from both academic and industrial organizations. Recently, Mal and co-workers have reviewed the strategies for the synthesis of isobenzofuranones including the lactonization of 2-(hydroxymethyl)-benzoic acids or their analogues that is the most easily conceivable access to phthalides, the reduction of phthalic anhydrides, the oxidation of phthalans and other reactions [25]. On the other hand, the most widely-used and straightforward approaches to isoindolobenzoxazinone derivatives are the Brønsted or Lewis acid-catalyzed cascade cyclization of 2-formylbenzoic acid with anthranilamides [26,27] or anthranilic acid [28][29][30]. Moreover, SanMartin, Zhao et al. also demonstrated that such similar polyheterocyclic scaffold can be constructed through transition metal-catalyzed cascade reactions between alkyne-containing carboxylic acids and anthranilic acids, anthranilamides or functionalized amines [31][32][33][34][35]. Despite tremendous achievements, it is still challenging and highly desirable to develop new, efficient, environmentally benign and cost-effective approaches to diverse polyheterocyclic compounds.
Isatoic anhydride is a cheap and commercially available compound that is a raw material for the synthesis of pharmaceuticals, agrochemicals and dyes, as well as an intermediate in the production of herbicide, Bentazone. The chemistry of isatoic anhydride and its reaction with amines has been investigated in detail [36][37][38][39]. We found that isatoic anhydride undergoes ring opening upon heating with various amines to produce 2-amino-N-alkylbenzamides, which can react with aldehydes [40][41][42] or orthoesters [43][44][45][46] and 2-formylbenzoic acid [47][48][49] to produce quinazolinones and isoindoloquinazolinones, respectively (Scheme 1a,b). Continuing with our research efforts to develop novel efficient and eco-friendly accesses to the construction of polyheterocyclic skeletons from easily available starting materials [50][51][52][53][54][55][56], we undertook the current study with the aim to construct polyheterocyclic compounds. We envisioned that the multi-component reaction of 2-acetylbenzoic acid, amines and isatoic anhydride would yield functionalized isoindoloquinazolinones (Scheme 1c). Unfortunately, the experiment did not proceed as assumed and did not yield the desired product, but provided the 3-substituted isobenzofuranones. Reported herein is our systematic study on the cascade reaction of 2-acetylbenzoic acid and isatoic anhydride with the discovery of the base/acid-steered divergent reaction pathways leading selectively to diverse isoindolobenzoxazinone and isobenzofuranone derivatives, respectively (Scheme 1d).

Results and Discussion
At the outset of this study, we attempted the multi-component reaction of 2acetylbenzoic acid (1a), benzylamine and isatoic anhydride (2a), and envisioned that isatoic anhydride (2a) undergoes ring opening reaction with benzylamine to produce 2amino-N-benzylbenzamide, which then reacts with 2-acetylbenzoic acid (1a) to form isoindoloquinazolinones. Surprisingly, instead of the expected product, 1-methyl-3-oxo-1,3dihydroisobenzofuran-1-yl 2-aminobenzoate (4aa) was isolated as major product in 90% yield (entry 1, Table 1). It's structure was confirmed unambiguously through the NMR spectra and X-ray single crystal diffraction (see the Supplementary Materials). The result indicates that benzylamine is not involved in the designed reaction and the 3-substituted isobenzofuranone 4aa is generated most probably from sequential cyclization of 2acetylbenzoic acid (1a) and nucleophilic ring-opening reaction of isatoic anhydride (2a) attacked by the product of previous step. We speculate that this is attributed to the lower reactivity of 2-acetylbenzoic acid with 2-amino-N-benzylbenzamide than 2-formylbenzoic acid and the incidental cyclization of 2-acetylbenzoic acid under basic conditions [57,58]. Then the experiment was performed in the absence of benzylamine and generated product 4aa in comparable yield, which confirmed our hypothesis (entry 2, Table 1).
In order to further improve the productivity of 4aa, we investigated the effect of the amount of Na2CO3 and a variety of bases on the cascade reaction. The results show that the dosage and type of base have no significant influence and all tested bases could promote the reaction well affording the target product with excellent yield (Table 1, entries 3-6). Interestingly, when this reaction was carried out under acidic conditions, no product 4aa was obtained (Table 1, entries 7-10), but 6a-methyl-5H-benzo [4,5][1,3]oxazino[2,3a]isoindole-5,11(6aH)-dione (3aa) was produced in 45% yield in the presence of anhydrous p-toluenesulfonic acid (entry 7, Table 1). Compound 3aa might be formed by the cascade

Results and Discussion
At the outset of this study, we attempted the multi-component reaction of 2-acetylbenzoic acid (1a), benzylamine and isatoic anhydride (2a), and envisioned that isatoic anhydride (2a) undergoes ring opening reaction with benzylamine to produce 2-amino-N-benzylbenzamide, which then reacts with 2-acetylbenzoic acid (1a) to form isoindoloquinazolinones. Surprisingly, instead of the expected product, 1-methyl-3-oxo-1,3-dihydroisobenzofuran-1-yl 2-aminobenzoate (4aa) was isolated as major product in 90% yield (entry 1, Table 1). It's structure was confirmed unambiguously through the NMR spectra and X-ray single crystal diffraction (see the Supplementary Materials). The result indicates that benzylamine is not involved in the designed reaction and the 3-substituted isobenzofuranone 4aa is generated most probably from sequential cyclization of 2-acetylbenzoic acid (1a) and nucleophilic ring-opening reaction of isatoic anhydride (2a) attacked by the product of previous step. We speculate that this is attributed to the lower reactivity of 2-acetylbenzoic acid with 2-amino-N-benzylbenzamide than 2-formylbenzoic acid and the incidental cyclization of 2-acetylbenzoic acid under basic conditions [57,58]. Then the experiment was performed in the absence of benzylamine and generated product 4aa in comparable yield, which confirmed our hypothesis (entry 2, Table 1). In order to further improve the productivity of 4aa, we investigated the effect of the amount of Na 2 CO 3 and a variety of bases on the cascade reaction. The results show that the dosage and type of base have no significant influence and all tested bases could promote the reaction well affording the target product with excellent yield (Table 1, entries 3-6). Interestingly, when this reaction was carried out under acidic conditions, no product 4aa was obtained (Table 1, entries 7-10), but 6a-methyl-5H-benzo [4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)-dione (3aa) was produced in 45% yield in the presence of anhydrous p-toluenesulfonic acid (entry 7, Table 1). Compound 3aa might be formed by the cascade reaction of 2a with 2-aminobenzoic acid that might derive from isatoic anhydride hydrolysis or thermal decomposition [59]. Subsequently, the amount of p-toluenesulfonic acid was scrutinized and the productivity of this cascade cyclization was increased slightly when 0.8 equivalent of p-toluenesulfonic acid was used (entry 12, Table 1). It is noteworthy that the reaction temperature played a vital role in the cascade process. Increasing reaction temperature can improve the efficiency of the reaction, and the chemical yield of 3aa was drastically improved to 87% when the reaction was executed at 140 • C (entry 17, Table 1). Moreover, the influence of the ratio of reagents was also investigated, and the result show that reducing the amount of isatoic anhydride 2a would decrease the yield of product, but increasing the amount had no obvious effect (Table 1, entries [19][20]. Briefly, the most efficient synthesis of 3-substituted isobenzofuranone 4aa and isoindolobenzoxazinone 3aa was to conduct the cascade reaction of 2-acetylbenzoic acid (1a) with isatoic anhydride (2a) in the presence of Na 2 CO 3 (20 mol%) or anhydrous p-toluenesulfonic acid (80 mol%) in toluene at 110 • C or 140 • C, respectively (Table 1, entry 2 and 17).
To further verify the reaction mechanism, some control experiments were carried out. Isatoic anhydride (2a) was decomposed into 2-aminobenzoic acid 8 in 62% yield under standard conditions, which could not react with 2-acetylbenzoic acid (1a) to deliver the desired product 3aa (Scheme 2, (1) and (2)). The result indicated that 2-aminobenzoic acid was not the intermediate of this process, which is inconsistent with our hypothesis above. In addition, to check the effect of water present in the solvent, the reaction was performed with one equivalent H 2 O under standard conditions or using dried toluene treated with sodium as the solvent (Scheme 2, (3) and (4)). Additional water would decrease the yield, while the yield of this reaction performed in dried toluene was improved slightly. Unexpectedly, the model reaction can take place without Na 2 CO 3 to afford the target product 4aa in 46% yield, but the corresponding product 3aa was not obtained in the absence of anhydrous p-TSA (Scheme 2, (5) and (6)). Furthermore, compound 4aa could be converted into compound 3aa in high efficiency when it was heated at 140 • C in toluene with 0.8 equivalent of anhydrous p-toluenesulfonic acid (Scheme 2, (7)).
With both optimized conditions in hand, the reaction scope for the synthesis of isoindolobenzoxazinone derivatives was firstly surveyed.
A number of substituted 2-acylbenzoic acids and isatoic anhydrides underwent smoothly the cascade reaction under standard conditions to give functionalized isoindolobenzoxazinones (Scheme 3). When the R 2 group in 2-acylbenzoic acid was evaluated, the desired products 3aa-3ea were obtained in moderate to good yields, but the R 2 group has significant effect on the cascade process. The results indicate that the larger the bulk of R 2 group, the lower the yield of product, which may be caused by steric hindrance. Introduction of substituents like halogen or methyl on the benzene ring of 2-acetylbenzoic acid has no obvious effect on the reaction and the corresponding products 3fa-3ka can be produced in 61-75% yield. Moreover, the position and type of substituent on the isatoic anhydride were also inspected and electron-rich substituent exhibited a beneficial effect as the yield of product increased with the increase of electron-donating power of the substituent on phenyl ring. The variation in the chloro substitution pattern had a distinct effect on the outcomes of the reaction. The yields are similar when the chlorine atom is at 5-, 6-and 7-position of isatoic anhydride, but had a drastic decrease using 8-chloro-2H-benzo [d][1,3]oxazine-2,4(1H)-dione as the substrate, most likely due to the steric hindrance of chlorine atom.
Subsequently, we scrutinized the scope of base-catalyzed cascade reaction of 2-acylbenzoic acids with isatoic anhydrides as depicted in Scheme 4. A variety of substituted 2-acylbenzoic acids reacted efficiently with isatoic anhydride under the catalysis of Na 2 CO 3 (0.2 equv) to produce diverse isobenzofuranones in high efficiency. For instance, benzoic acids with different acyl group at ortho-position 1a-1e successfully achieved the cascade process to provide the desired products 4aa-4ea in similar yield, which did not show the steric effect as evident as the acid-catalyzed reaction. However, in comparison to the previous reaction, the synthesis of isobenzofuranone derivatives from 2-acylbenzoic acids that contain halogen or methyl on the benzene ring appeared more efficient and the corresponding products 4fa-4ka were synthesized in the yields from 72% to 94%. In addition, various substituted isatoic anhydrides were also transformed into isobenzofuranones in moderate to good yield. On the contrary, electron-rich substituent exhibited a detrimental effect as the yield of product decreased with the increase of electron-donating power of the substituent on phenyl ring. For example, the yield of fluorine-substituted product 4af was 80%, compared with 44% for methoxy-substituted 4ai. Moreover, the variation of the position of the chlorine atom on the phenyl ring had a marginal effect on the cascade reaction. Furthermore, N-methyl-isatoic anhydride was also found to be suitable substrate, which undergo the cascade reaction with 2-acetylbenzoic acid to give the corresponding product 4aj in 59% yield. obtained in the absence of anhydrous p-TSA (Scheme 2, Equations (5) and (6)). Furthermore, compound 4aa could be converted into compound 3aa in high efficiency when it was heated at 140 °C in toluene with 0.8 equivalent of anhydrous p-toluenesulfonic acid (Scheme 2, Equation (7)). To display the potential applications of this method, the gram-scale cascade reaction was performed. For example, when 2-acetylbenzoic acid (1a, 5.0 mmol) was employed in the gram-scale reaction under two different optimal conditions, the acid-promoted reaction afforded 1.06 g of the isoindolobenzoxazinone derivative 3aa in 80% yield and the base-catalyzed reaction produced 1.20 g of the isobenzofuranone derivative 4aa in 85% yield (Scheme 5). This result indicated that the base/acid-steered cascade reaction can be effectively scaled up with slightly lower efficiency.
Molecules 2023, 28, x FOR PEER REVIEW 9 of 19 the gram-scale reaction under two different optimal conditions, the acid-promoted reaction afforded 1.06 g of the isoindolobenzoxazinone derivative 3aa in 80% yield and the base-catalyzed reaction produced 1.20 g of the isobenzofuranone derivative 4aa in 85% yield (Scheme 5). This result indicated that the base/acid-steered cascade reaction can be effectively scaled up with slightly lower efficiency. To further demonstrate the utility of the synthetic protocol, some chemical transformations of products were attempted. In the presence of Pd(PPh3)4 and tripotassium phosphate, product 3af underwent the Suzuki-Miyaura coupling reaction with phenylboronic acid in mixed solvent and compound 5 was obtained in 78% yield (Scheme 6, Equation (1)). Moreover, product 4aa was treated with an equivalent benzylamine in the hope of producing isoindolinone 7, but which yielded enamide 6 in 73% yield instead. (Scheme 6, Equation (2)). These resulting compounds are useful in organic synthesis, which can be further converted into the variant of bioactive molecules or natural products through many other reactions. To further demonstrate the utility of the synthetic protocol, some chemical transformations of products were attempted. In the presence of Pd(PPh 3 ) 4 and tripotassium phosphate, product 3af underwent the Suzuki-Miyaura coupling reaction with phenylboronic acid in mixed solvent and compound 5 was obtained in 78% yield (Scheme 6, (1)). Moreover, product 4aa was treated with an equivalent benzylamine in the hope of producing isoindolinone 7, but which yielded enamide 6 in 73% yield instead. (Scheme 6, (2)). These resulting compounds are useful in organic synthesis, which can be further converted into the variant of bioactive molecules or natural products through many other reactions. the gram-scale reaction under two different optimal conditions, the acid-promoted reaction afforded 1.06 g of the isoindolobenzoxazinone derivative 3aa in 80% yield and the base-catalyzed reaction produced 1.20 g of the isobenzofuranone derivative 4aa in 85% yield (Scheme 5). This result indicated that the base/acid-steered cascade reaction can be effectively scaled up with slightly lower efficiency. To further demonstrate the utility of the synthetic protocol, some chemical transformations of products were attempted. In the presence of Pd(PPh3)4 and tripotassium phosphate, product 3af underwent the Suzuki-Miyaura coupling reaction with phenylboronic acid in mixed solvent and compound 5 was obtained in 78% yield (Scheme 6, Equation (1)). Moreover, product 4aa was treated with an equivalent benzylamine in the hope of producing isoindolinone 7, but which yielded enamide 6 in 73% yield instead. (Scheme 6, Equation (2)). These resulting compounds are useful in organic synthesis, which can be further converted into the variant of bioactive molecules or natural products through many other reactions. Based on the above experimental results and previous literatures, the plausible mechanism was proposed in Scheme 7. In the presence of base, 2-acetylbenzoic acid (1a) turns into the intermediate B, followed by the nucleophilic attack on the isatoic anhydride (2a) to form product 4aa and release carbon dioxide. Compound A and 2-acetylbenzoic acid (1a) are a pair of ring-chain tautomers that exist in an equilibrium in solution, and the former can also react with isatoic anhydride (2a) to provide compound 4aa. That is why the reaction could take place in the absence of Na 2 CO 3 . p-Toluenesulfonic acid not only catalyzed the equilibrium reaction, but also promoted the product 4aa to continue the subsequent reaction. In the presence of acid, compound 4aa undergo an intramolecular rearrangement to generate the intermediate C, followed by the consecutive nucleophilic addition and dehydration reaction to produce the N-acyliminium intermediate D. Subsequently, the N-acyliminium was trapped by carboxyl group within the molecule to afford the final product 3aa with elimination of a proton. Based on the above experimental results and previous literatures, the plausible mechanism was proposed in Scheme 7. In the presence of base, 2-acetylbenzoic acid (1a) turns into the intermediate B, followed by the nucleophilic attack on the isatoic anhydride (2a) to form product 4aa and release carbon dioxide. Compound A and 2-acetylbenzoic acid (1a) are a pair of ring-chain tautomers that exist in an equilibrium in solution, and the former can also react with isatoic anhydride (2a) to provide compound 4aa. That is why the reaction could take place in the absence of Na2CO3. p-Toluenesulfonic acid not only catalyzed the equilibrium reaction, but also promoted the product 4aa to continue the subsequent reaction. In the presence of acid, compound 4aa undergo an intramolecular rearrangement to generate the intermediate C, followed by the consecutive nucleophilic addition and dehydration reaction to produce the N-acyliminium intermediate D. Subsequently, the N-acyliminium was trapped by carboxyl group within the molecule to afford the final product 3aa with elimination of a proton. In summary, we have provided practical methods for selective synthesis of both isoindolobenzoxazinone and isobenzofuranone derivatives from the cascade reaction of 2acylbenzoic acids with isatoic anhydrides simply using different catalysts. This one-pot synthetic strategy evaded the use of metal catalyst and occurred efficiently with good tolerance of functional groups. The cascade reaction is very promising because that could construct diverse polyheterocyclic skeletons in gram-scale, which are widely found in natural and pharmaceutical compounds. Moreover, the resulting products can undergo a variety of chemical transformations to turn into various synthetic analogues. At present, the biological applications of these compounds and other new reactions of 2-acylbenzoic acids are in progress in our laboratory, and the results will be reported in due course.

General Information
All chemicals were commercially available for direct use unless otherwise stated. Dried toluene was treated with sodium according to standard procedures prior to use. Flash column chromatography was performed on silica gel (100-200). Reactions were monitored using pre-coated, glass-backed silica gel plates and visualized by means of UV Scheme 7. The proposed reaction mechanism.
In summary, we have provided practical methods for selective synthesis of both isoindolobenzoxazinone and isobenzofuranone derivatives from the cascade reaction of 2-acylbenzoic acids with isatoic anhydrides simply using different catalysts. This one-pot synthetic strategy evaded the use of metal catalyst and occurred efficiently with good tolerance of functional groups. The cascade reaction is very promising because that could construct diverse polyheterocyclic skeletons in gram-scale, which are widely found in natural and pharmaceutical compounds. Moreover, the resulting products can undergo a variety of chemical transformations to turn into various synthetic analogues. At present, the biological applications of these compounds and other new reactions of 2-acylbenzoic acids are in progress in our laboratory, and the results will be reported in due course.

General Information
All chemicals were commercially available for direct use unless otherwise stated. Dried toluene was treated with sodium according to standard procedures prior to use. Flash column chromatography was performed on silica gel (100-200). Reactions were monitored using pre-coated, glass-backed silica gel plates and visualized by means of UV irradiation (254 nm) or KmnO 4 . The 1 H NMR and 13 C NMR spectra were recorded on a Bruker AV500 spectrometer at ambient temperature. Chemical shifts are reported in ppm with either tetramethylsilane or the residual solvent resonance used as an internal standard. High-resolution mass spectra (HRMS) were measured on a quadrupole time-of-flight mass spectrometer (Q-TOF-MS) using electrospray ionization (ESI) as an ionization method. Crystallographic data were collected on a Rigaku XtaLAB Synergy (Cu) X-ray single crystal diffractometer. All yields reported are isolated yields.

General Procedure for the Synthesis of Isoindolobenzoxazinones 3
In a 10 mL reaction tube, substituted 2-acylbenzoic acid 1 (1.0 mmol), substituted isatoic anhydrides 2 (1.20 mmol), TsOH (137.8 mg, 0.80 mmol) and toluene (5.0 mL) were mixed. Then, the reaction tube was capped with a septum and allowed to stir at 140 • C in a pre-heated oil bath for 12 h. After being cooled to room temperature, the solvent was evaporated in vacuo and the residue was purified by column chromatography eluted with a mixture of petroleum ether and ethyl acetate (2:1) to give the pure target product.

The Procedure for the Reaction of 4aa with Benzylamine
To a solution of 4aa (85 mg, 0.30 mmol, 1.0 equiv) in 3 mL DCM, benzylamine (36 mg, 0.33 mmol, 1.1 equiv) was added. Then, the contents were stirred at room temperature for 24 h. Upon completion of the reaction, it was quenched with 5 mL water and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was dried over Na 2 SO 4 and the organic layer was collected and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography using ethyl acetate/hexane (1:3) as the eluent to obtain 6.