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Article

Rh(III)-Catalyzed Annulation of Boc-Protected Benzamides with Diazo Compounds: Approach to Isocoumarins

by
Guangyu Dong
1,2,3,
Chunpu Li
1 and
Hong Liu
1,2,3,*
1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
2
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
3
School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210,China
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(5), 937; https://doi.org/10.3390/molecules24050937
Submission received: 2 February 2019 / Revised: 20 February 2019 / Accepted: 22 February 2019 / Published: 7 March 2019
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Abstract

:
A mild rhodium-catalyzed annulation of Boc-protected benzamides with diazo compounds via C−C/C−O bond formation has been explored. In the presence of [Cp*RhCl2]2, AgSbF6 and Cs2CO3, Boc-protected benzamides can be effectively annulated to yield isocoumarins in 0.5–2 h.

Graphical Abstract

1. Introduction

Isocoumarins are valuable structural subunits because of their wide presence in numerous natural and synthetic compounds that exhibit potent biological activities (Figure 1) [1,2,3,4]. Some approaches to synthesize isocoumarins have been developed. Of the reported methods, the transition metal mediated coupling reaction facilitated by preactived C-X or C-M reagents has been recognized as a way to furnish the isocoumarin ring [5,6,7,8,9]. Additionally, oxidative annulations of the carboxylic acid with alkynes could also be viewed as an alternate strategy [10,11,12,13,14,15,16]. No doubt these methods are useful and practical, but the application of these reactions is somehow limited due to its requirements of a stoichiometric amount of oxidants and unkind temperatures. Consequently, it is highly desirable to develop more efficient methodologies for the synthesis of isocoumarins.
Rhodium-catalyzed C-H activation/cyclization has recently been pursued for constructing diverse heterocyclic systems [17,18,19,20]. Within rhodium catalysis, amide has attracted attention because of their particularly stable functionality. In this context, diazo compounds, as versatile partners of amides for C-H activation or cyclization, are widely applied in the organic process [21,22,23,24,25,26,27]. Prior contributions in this area include Rh(III)-catalyzed cyclization of benzamides and diazo compounds to construct isoindolinones via C-C/C-N bond formation reported by groups of Rovis, Yu and Cramer [28,29,30]. Besides, Rh(III) or Ir(III) catalysts were found to be effective for the synthsis of isoquinolinones, which is followed by the C-H coupling of N-methoxybenzamides with diazo compounds [31,32]. Despite significant progress, most of the reported studies are limited to bear N-heterocycles along with the formation of a C-C/C-N bond. In sharp contrast, few examples of Rh(III)-catalyzed C-C/C-O bond formation related to C-H cyclization of aromatics with diazo compounds are developed. Notably, C-C/C-O bond formation via Rh(III)-catalyzed C-H activation/cyclization of aromatics with diazo compounds has been achieved in 2015(Scheme 1, eqn (1)) [33]. In 2016, Rh(III)-catalyzed C-H annulation of N-tosylacrylamides and diazo compounds via C-C or C-N cleavages has been reported (Scheme 1, eqn (2)) [34]. Recently, A simple Rh(III)-catalyzed C-H activation that uses cyclic 2-diazo-1,3-diketones as starting materials has been developed (Scheme 1, eqn (3)) [35]. Though these methods are of high synthetic value, restricted substrate scope and high temperature or long reaction time may preclude their widespread application. Thus, it is necessary to develop more methods to construct a C-C/C-O bond by C-H annulation. Given that the directing group (DG) is pivotal in the construction of various heterocycles, we thus focus on finding DGs which could offer a tool to form diverse molecules in the means of breaking the C-N bond. In response to this unmet need, we show herein that N-tert-butoxycarbonyl (N-Boc) benzamides together with diazo compounds, allows delivery of corresponding isocoumarins under Rh(III) catalysis via C-C/C-O bond formation (Scheme 1, (4)). In this protocol, the Boc-protected benzamides could serve as good substrates and the reaction proceeds with concomitant removal of NHBoc auxiliary to afford the corresponding isocoumarins with high efficacy in short time (0.5–2 h). In this work, the tert-butyl formylcarbamate group formally served as an oxidizing DG using the C-N bond as an internal oxidant. Meanwhile, tert-butyl formylcarbamate group is an important structural motif of many biologically active compounds. Our work may provide a method to enable the late-stage diversification of functional molecules with tert-butyl formylcarbamate groups.

2. Results and Discussion

2.1. Optimization of Reaction Conditions for Synthesis of Ethyl 3-Methyl-1-oxo-1H-Isochromene-4-Carboxylate 3aa

We initiated our investigation by evaluating the feasibility of the combination of N-Boc benzamides 1a or other N-substituted benzamides 1a1–1a5 and ethyl diazoacetoacetate 2a. As shown in Table 1, amide derivatives 1a1–1a5 failed to undergo the annulation (Table 1, entries 1–5), while N-Boc benzamides could be utilized. Therefore N-Boc benzamides 1a was opted to be used for optimization with ethyl diazoacetoacetate 2a. We hypothesize that the electron-withdrawing capability of the Boc group makes the C-N bond easy to break. Several additives were further screened (Table 1, entries 7–10). When Ag2O and AgOAc were added to the reaction, no evidence of 3aa was observed, while 3aa was obtained in 33% yield with AgSbF6. We then turned our attention to screen solvents and acetonitrile was found to give the higher yield (47%; Table 1, entry 11). However, the explored efficiency was deficient, so the kind of bases was further explored (Table 1, entries 13–15). To our delight, we found that Cs2CO3 accompanied by AgSbF6 could obtain the highest yield (80%; Table 1, entry 14). Based on this model, we then explored catalyst species Co, Ru, Ir (Table 1, entries 16–18). [Cp*RhCl2]2 was chosen to be employed as catalysts for this annulation according to the obtained yields listed on Table 1. Interestingly, product 3aa was obtained in a slightly lower yield when the reaction was carried out under N2 atmosphere (Table 1, entry 19). Next, an attempt to lower the reaction temperature to 25 °C resulted in a decreased yield (Table 1, entry 20). Notably, there was no obvious change in yield, whether the reaction dealt with higher temperature or longer reaction time (Table 1, entries 21 and 23). Hence the optimized conditions of Rh(III)-Catalyzed annulation of Boc-protected benzamides with diazo compounds were as follows: 5 mmol% [Cp*RhCl2]2 as catalyst, 2.0 equiv Cs2CO3 and 15 mmol% AgSbF6 as the additives. The reaction performed best at 60 °C for 0.5 h under air with acetonitrile as the solvent.

2.2. Substrate Scope for the Boc-Protected Benzamides

With the optimized conditions in hand, we embarked on the investigation of the substrate scope of Boc-protected benzamides to test the generality of this C-H activation/annulation reaction (Table 2). It was found that a variety of amides could successfully cyclize to give the desired products in moderate to good yields. Electron-donating groups such as methyl, tert-butyl and methoxy group at the para-position of the benzene ring gave 3ba, 3ea and 3fa in 87%, 79% and 81% yields, respectively. In contrast, electron-withdrawing groups such as CF3 and nitro group afforded 3ka and 3la in 22% and trace yields. Halogen substituents (F, Cl, Br and I) provided 3ga–3ja in 48–72% yields, indicating that the products of this reaction were compatible in transition-metal-catalyzed coupling reactions. In particular, we were pleased to obtain the single crystal X-ray of 3ga (see Supporting Information (SI), CCDC: 1891024). Presumably owing to the steric effect, meta-phenzyl-substituted benzamide provided 3pa in 60% yield, while para- and ortho-phenzyl-substituted benzamides provided 3ba and 3ra in 87% and 65% yields. Notably, 1-naphthamide gave the desired product 3ua in 51% yield. In regard to the heteroaromatic amides such as thiophene, delivered the desired products 3va in 68% yields.

2.3. Substrate Scope for the Diazo Compounds

After the examination of benzamides, diazo coupling partners were also investigated, and the results are described in Table 3. When the R2 with phenyl groups were used, the 3ab−3ae were given in 51−79% yields. R2 with a cyclopropyl and a cyclohexyl group gave 3af and 3ag in moderate yield. When R2 with branched alkyl groups such as an isopropyl and an ethyl group were used, the 3ai and 3aj were given in 45% and 61% yields. When R3 with a methyl, a tert-butyl, an n-propyl or a benzyl group was used, the 3ak–3ao were given in 25–70% yields.

2.4. Gram-Scale Preparation and Derivatization of the Annulation Product

In addition, 60% yield was obtained for the gram-scale synthesis of 3aa, thus offering a practical access to highly functionalized isocoumarins (Scheme 2a). The applications of the isocoumarins have been demonstrated in several derivatization reactions. Formation of the desired 4 was achieved by reaction with ammonium acetate. In order to be more similar to the structures of Figure 1, removal of carboxylic esters at 4-position has been carried out to give 5 in 75% yield.

2.5. Mechanism

To obtain a more mechanistic insight, further experiments were carried out (Scheme 3). When p-methoxy-Boc-benzamide 1f was run in competition with the p-trifluoromethyl-Boc-benzamide 1k, the reaction favors the electron-donating substituent of the benzamide, suggesting that electrophilic-type benzamide were inherently less reactive (Scheme 3a). To gain further insights, the kinetic-isotope effect (KIE) was studied in parallel and competition experiments (Scheme 3b,c). Experiments with the same amounts of 1a and deuterium-labeled benzamide 1a–d5 were conducted, and a kH/kD value of 1.44 was obtained (Scheme 3b). Furthermore, separate reactions of 1a or 1a–d5 together with 2a gave the corresponding products 3aa and 3aa–d4, respectively, displaying the similar KIE value of 1.24 (Scheme 3c). These results suggested that C−H cleavage is likely involved in the rate-limiting step. Moreover, when 1a was treated with diethyl 2-diazomalonate, corresponding products was not observed under the standard reaction conditions, indicating that the final lactonization of ketone is significant in the transformation (Scheme 3d).
Based on the preliminary mechanistic experiments and literature precedents, a plausible mechanistic pathway is proposed in Scheme 4. Firstly, the catalytically active Rhodium species A is formed from [Cp*RhCl2]2, then the C-H metalation takes place to afford five-membered cyclometalated Rhodium species B via a Rh(III)-catalyzed C(sp2)-H bond cleavage. After insertion of the diazo compounds, Rh(III)-carbene species C can be formed with extrusion of N2. Subsequently, the species C undergoes a migratory insertion of carbene into the Rh-C bond, provided six-membered species D. Then, complex D could undergo protonation to give intermediate E, which can tautomerize to intermediate F. Finally, lactonization of intermediate F could afford the desired isocoumarin product 3 and the active catalyst A.

3. Materials and Methods

3.1. Chemistry

Reagents and Solvents: Rh catalysts and additives were commercially available. PE refers to petroleum ether (b.p. 60–90 °C), EA refers to ethyl acetate. Acetonitrile was used to the HPLC grade. All commercially available reagents and reactants were used without purification unless otherwise noted.
Chromatography: Flash column chromatography was carried out using commercially available 200–300 mesh under pressure unless otherwise indicated. Gradient flash chromatography was conducted eluting with PE/EA, they are listed as volume/volume ratios.
Data Collection: Nuclear magnetic resonance (NMR) spectra were run on 500 MHz instrument. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Data are reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz) and integration. Low- and high-resolution mass spectra (LRMS and HRMS) were measured on spectrometer.

3.2. Experimental Part Method

3.2.1. General Procedure for the Synthesis of Isocoumarins and α-Pyrones

To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol, 15 mol%) in acetonitrile (2 mL) was added tert-butyl benzoylcarbamate 1 (0.1 mmol), diazo compounds 2 (0.12 mmol), Cs2CO3(65 mg, 0.2 mmol, 2 equiv). The reaction mixture was stirred at 60 °C for 0.5–2 h and the progress was monitored using TLC detection. After completion of present reaction, the solvent was evaporated under reduced pressure and the residue passed through flash column chromatography on silica gel to afford the desired products 3.

3.2.2. Procedure for the Synthesis of Diazo Substrates

Diazo substrates were synthesized from the corresponding ketonic esters or 1,3 di-ketones as shown in Scheme S1. 2a–2o was synthesized according to the literatures [36].
To a solution of ketonic ester or 1,3-di-ketone (5 mmol) in CH3CN, 6 mmol TsN3 was added. Then the reaction mixture was cooled to 0 °C and a solution of DBU (6 mmol) in 10 mL CH3CN was added dropwise. Next, the reaction temperature was raised to room temperature. After stirring for 3 h, the residue was extracted with EA for 3 times. The combined organic layers were washed with water and brine sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (PE: EA = 100:1) to afford the corresponding product in 50–90% yields.

3.2.3. Procedure for the Synthesis of Benzoylcarbamate Derivatives [37]

To a solution of benzamide (4.1 mmol) in dichloromethane (10.0 mL) was slowly added oxalyl chloride (630 mg, 0.43 mL 4.94 mmol) at 0 °C. The reaction mixture was warmed to 50 °C and stirred for 1 h. After cooling to 0 °C, a solution of the corresponding alcohol in dichloromethane was added, which was stirred at that temperature for 2 h. The reaction mixture was quenched by the addition of sat. aq. NaHCO3 and then extracted with dichloromethane. The combined organic layer was washed with brine and dried over Na2SO4. The volatiles were evaporated and the resulting crude product was purified by silica gel chromatography (eluent: dichloromethane to dichloromethane/ethyl acetate = 9/1) to give white powder. 1a, 1b and 1f were synthesized according to the literatures [37,38,39].
tert-Butyl (4-ethylbenzoyl)carbamate (1c). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.47 (s, 9H), 1.19 (t, J = 7.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.7, 150.4, 148.6, 130.9, 128.4, 127.6, 80.6, 28.0, 27.7, 15.1. HRMS (ESI) calcd for [C14H19NO3+Na] 272.1365, found 272.1253.
tert-Butyl (4-isopropylbenzoyl)carbamate (1d). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 2.95 (dt, J = 13.8, 6.9 Hz, 1H), 1.47 (s, 9H), 1.22 (s, 3H), 1.21 (s, 3H). 13C NMR (126 MHz, DMSO) δ 165.7, 153.1, 150.4, 131.1, 128.4, 126.2, 80.6, 33.3, 27.7, 23.5. HRMS (ESI) calcd for [C15H21NO3+Na] 286.1521, found 286.1417.
tert-Butyl (4-(tert-butyl)benzoyl)carbamate (1e). White solid. 1H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 1.47 (s, 9H), 1.30 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.7, 155.3, 150.4, 130.7, 128.2, 125.1, 80.6, 34.7, 30.8, 27.7. HRMS (ESI) calcd for [C18H23NO3-H]− 276.1678, found 276.1603.
tert-Butyl (4-fluorobenzoyl)carbamate (1h). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.92 (dd, J = 8.9, 5.5 Hz, 2H), 7.31 (t, J = 8.8 Hz, 2H), 1.48 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.9, 165.4, 163.9, 150.8, 131.6 (d, J = 9.3 Hz), 130.5 (d, J = 2.6 Hz), 115.8, 115.6, 81.2, 28.2. HRMS (ESI) calcd for [C12H14FNO3+Na] 262.0958, found 262.0848.
tert-Butyl (4-chlorobenzoyl)carbamate (1g). White solid. 1H NMR (500 MHz, CD3OD) δ 10.76 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 1.47 (s, 8H). 13C NMR (126 MHz, DMSO-d6) δ 165.4, 150.61, 137.5, 132.6, 130.5, 128.6, 81.1, 28.0. HRMS (ESI) calcd for [C12H14ClNO3+Na] 278.0662, found 278.0561.
tert-Butyl (4-bromobenzoyl)carbamate (1i). White solid. 1H NMR (400 MHz, CD3OD) δ 10.76 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.2, 150.2, 132.7, 131.2, 130.3, 126.1, 80.8, 27.7. HRMS (ESI) calcd for [C12H14BrNO3+Na] 278.0662, found 278.0561.
tert-Butyl (4-iodobenzoyl)carbamate (1j). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.89–7.84 (m, 2H), 7.64–7.59 (m, 2H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.5, 150.3, 137.1, 132.9, 130.1, 100.4, 80.8, 27.7. HRMS (ESI) calcd for [C12H14INO3+Na] 370.0018, found 369.9917.
tert-Butyl (4-(trifluoromethyl)benzoyl)carbamate (1k). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.3, 150.2, 137.5, 129.1, 125.2 (d, J = 3.6 Hz), 122.7, 81.0, 27.7. HRMS (ESI) calcd for [C13H14F3NO3+Na] 312.0926, found 312.0814.
tert-Butyl (4-nitrobenzoyl)carbamate (1l). White solid. 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.32 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.5, 150.5, 149.8, 139.7, 130.1, 123.7, 81.6, 28.1. HRMS (ESI) calcd for [C12H11N2O5+Na] 289.0903, found 289.0801.
tert-Butyl (4-(benzyloxy)benzoyl)carbamate (1m). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 5.19 (s, 2H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.1, 161.6, 150.5, 136.5, 130.40, 128.4, 127.9, 127.7, 125.7, 114.3, 80.5, 69.4, 27.7. HRMS (ESI) calcd for [C19H21NO4+Na] 350.1471, found 350.1353.
tert-Butyl (4-(dimethylamino)benzoyl)carbamate (1n). White solid. 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.1 Hz, 2H), 3.03 (s, 6H), 1.51 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.5, 164.1, 160.4, 153.6, 130.6, 128.9, 116.1, 110.7, 83.3, 27.5. HRMS (ESI) calcd for [C14H20N2O3+Na] 287.1474, found 287.1353.
tert-Butyl [1,1′-biphenyl]-4-carbonylcarbamate (1o). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.76 (dd, J = 25.2, 7.9 Hz, 4H), 7.50 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 1.49 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 166.2, 150.9, 144.3, 139.4, 132.8, 129.5, 128.8, 127.4, 126.9, 81.2, 28.3. HRMS (ESI) calcd for [C18H19NO3+Na] 320.1365, found 320.1262.
tert-Butyl (3-methylbenzoyl)carbamate (1p). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.71–7.60 (m, 2H), 7.37 (dt, J = 15.0, 7.4 Hz, 2H), 2.36 (s, 3H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 166.1, 150.4, 137.6, 133.5, 132.9, 128.7, 128.2, 125.4, 80.7, 27.8, 20.80. HRMS (ESI) calcd for [C13H17NO3-H]− 234.1208, found 234.1132.
tert-Butyl (3-chlorobenzoyl)carbamate (1q). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.89 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 164.74, 150.16, 135.54, 133.04, 132.06, 130.24, 127.96, 126.94, 80.92, 27.71. HRMS (ESI) calcd for [C12H14ClNO3-H]− 254.0662, found 254.0587.
tert-Butyl (2-methylbenzoyl)carbamate (1r). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.38–7.30 (m, 2H), 7.27–7.19 (m, 2H), 2.30 (s, 3H), 1.39 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 169.6, 150.8, 136.4, 135.5, 130.8, 130.4, 127.6, 125.9, 81.16, 28.1, 19.6. HRMS (ESI) calcd for [C13H17NO3-H]− 234.1208, found 234.1131.
tert-Butyl (2-chlorobenzoyl)carbamate (1s). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.50–7.42 (m, 3H), 7.41–7.36 (m, 1H), 1.35 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 167.1, 150.1, 136.3, 131.02, 129.2, 128.4, 127.1, 81.2, 27.5. HRMS (ESI) calcd for [C12H14ClNO3-H]− 254.0662, found 254.0583.
tert-Butyl (3,4-dimethylbenzoyl)carbamate (1t). White solid. 1H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.59 (d, J = 1.1 Hz, 1H), 7.51 (dd, J = 7.9, 1.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 2.30 (s, 6H), 1.53 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 165.3, 149.8, 142.4, 137.5, 130.9, 130.1, 128.9, 124.9, 82.7, 28.2, 20.1, 19.9. HRMS (ESI) calcd for [C14H19NO3-H]− 248.1365, found 248.1287.
tert-Butyl 2-naphthoylcarbamate (1u). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.55 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.91 (dd, J = 8.6, 1.8 Hz, 1H), 7.73–7.60 (m, 2H), 1.53 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 165.8, 150.1, 134.3, 131.5, 130.4, 128.8, 127.9, 127.6, 127.3, 126.5, 124.2, 80.4. HRMS (ESI) calcd for [C16H17NO3 + Na] 294.1208, found 294.1104.
tert-Butyl thiophene-2-carbonylcarbamate (1v). White solid. 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.06 (d, J = 3.5 Hz, 1H), 7.92 (d, J = 4.7 Hz, 1H), 7.23–7.09 (m, 1H), 1.48 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 159.8, 150.0, 138.6, 133.8, 131.0, 128.3, 80.9, 27.8. HRMS (ESI) calcd for [C10H13NO3S-H]− 226.0616, found 226.0539.
1a1–1a5 were synthesized according to the literatures [40,41,42,43].

3.2.4. Characterization of the Products

Ethyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3aa). Colorless oil. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (dd, J = 7.9, 0.8 Hz, 1H), 7.93–7.81 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.9, 161.3, 157.8, 135.2, 134.8, 129.8, 128.3, 124.2, 119.7, 110.4, 61.8, 19.4, 14.3. HRMS (ESI) calcd for [C13H12O4 + H]+ 233.0736, found 233.0808.
Ethyl 3,6-dimethyl-1-oxo-1H-isochromene-4-carboxylate (3ba). White solid. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 2.41 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.9, 161.3, 157.5, 146.3, 134.7, 129.7, 129.5, 124.1, 117.1, 110.2, 61.7, 22.3, 19.3, 14.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892, found 247.0960.
Ethyl 6-ethyl-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ca). White solid. 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.75 (q, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.1, 161.4, 157.7, 152.5, 134.9, 129.9, 128.4, 123.1, 117.4, 110.4, 61.7, 29.6, 19.4, 15.1, 14.4. HRMS (ESI) calcd for [C15H16O4 + H]+ 261.1049, found 261.1125.
Ethyl 6-isopropyl-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3da). White solid. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.01 (dt, J = 13.8, 6.9 Hz, 1H), 2.44 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.29 (s, 3H), 1.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.12, 161.37, 157.74, 156.99, 134.93, 129.96, 127.08, 121.84, 117.55, 110.48, 34.91, 23.66, 19.39, 14.39. HRMS (ESI) calcd for [C16H18O4 + H]+ 275.1205, found 275.1284.
Ethyl 6-(tert-butyl)-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ea). White solid. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 166.2, 161.3, 159.2, 157.8, 134.6, 129.5, 126.1, 120.6, 117.1, 110.6, 61.6, 35.7, 31.1, 19.4, 14.4. HRMS (ESI) calcd for [C17H20O4 + H]+ 289.1362, found 289.1437.
Ethyl 6-methoxy-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3fa). White solid. 1H NMR (500 MHz, D2O) δ 8.18 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.8, 2.4 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 2.44 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, D2O) δ 166.0, 165.0, 161.0, 158.9, 137.0, 132.0, 116.3, 112.6, 110.0, 107.0, 61.7, 55.73, 19.7, 14.4. HRMS (ESI) calcd for [C14H14O5 + H]+ 263.0841, found 263.0911.
Ethyl 6-chloro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ga). White solid. 1H NMR (500 MHz, CDCl3) δ 8.22 (dd, J = 8.5, 0.4 Hz, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.48 (dd, J = 8.5, 1.2 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 164.6, 159.7, 159.0, 141.4, 135.4, 130.6, 128.0, 123.5, 117.1, 108.6, 61.2, 19.0, 13.6. HRMS (ESI) calcd for [C13H11ClO4 + H]+ 267.0346, found 267.0415.
Ethyl 6-fluoro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ha). White solid. 1H NMR (500 MHz, CDCl3) δ 8.29 (dd, J = 8.4, 6.2 Hz, 1H), 7.54 (d, J = 10.5 Hz, 1H), 7.23–7.13 (m, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 168.0, 166.2, 165.5, 160.3, 160.1, 137.5, 133.1, 116.4, 116.0, 110.8, 109.6 (d, J = 2.6 Hz), 61.9, 19.8, 14.4. HRMS (ESI) calcd for [C13H11FNO3 - H]− 249.0641, found 249.0562.
Ethyl 6-bromo-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ia). White solid. 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.1, 160.3, 159.5, 135.9, 131.5, 131.0, 130.8, 127.1, 118.0, 109.0, 61.7, 19.5, 14.1. HRMS (ESI) calcd for [C13H12BrO4 + H]+ 310.9841, found 310.9917.
Ethyl 6-iodo-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ja). White solid. 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.93 (dd, J = 8.3, 2.0 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 4.48–4.41 (m, 2H), 2.46 (s, 3H), 1.43 (dd, J = 7.4, 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.3, 160.8, 159.5, 137.4, 135.8, 133.4, 130.8, 118.7, 109.0, 104.1, 62.0, 19.7, 14.3. HRMS (ESI) calcd for [C13H12IO4 + H]+ 358.9702, found 358.9773.
Ethyl 3-methyl-1-oxo-6-(trifluoromethyl)-1H-isochromene-4-carboxylate (3ka). White solid. 1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.2, 160.3, 160.1, 136.7, 136.4, 135.3, 130.7, 124.5 (d, J = 3.3 Hz), 122.2–121.4 (m), 109.7, 62.1, 19.8, 14.3. HRMS (ESI) calcd for [C14H11F3O4 + H]+ 301.0609, found 301.0676.
Ethyl 3-methyl-6-nitro-1-oxo-1H-isochromene-4-carboxylate (3la). White solid. HRMS (ESI) calcd for [C13H11NO6 - H]− 276.0586, found 276.0518.
Ethyl 6-(benzyloxy)-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ma). White solid. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz, 1H), 7.49–7.39 (m, 4H), 7.36 (dd, J = 16.5, 4.7 Hz, 2H), 7.12 (dd, J = 8.8, 2.4 Hz, 1H), 5.18 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.2, 164.4, 161.2, 159.1, 137.3, 136.1, 132.3, 129.1, 128.7, 127.9, 117.1, 113.1, 110.3, 108.3, 70.7, 61.9, 19.9, 14.6. HRMS (ESI) calcd for [C20H18IO5 + H]+ 339.1154, found 339.1230.
Ethyl 6-(dimethylamino)-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3na). White solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 9.9 Hz, 2H), 4.42 (q, J = 6.8 Hz, 2H), 3.08 (s, 6H), 2.39 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.5, 161.6, 158.1, 154.5, 136.3, 131.5, 112.7, 110.2, 107.5, 103.9, 61.4, 40.2, 19.5, 14.4. HRMS (ESI) calcd for [C15H17NO4 + H]+ 276.1158, found 276.1230.
Ethyl 3-methyl-1-oxo-6-phenyl-1H-isochromene-4-carboxylate (3oa). White solid. 1H NMR (500 MHz, CDCl3) δ 8.37–8.31 (m, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 8.2, 1.7 Hz, 1H), 7.64 (dd, J = 7.9, 0.9 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.0, 161.3, 158.3, 148.0, 139.7, 135.2, 130.4, 129.2, 128.8, 127.6, 127.3, 122.6, 118.3, 110.4, 61.8, 19.5, 14.4. HRMS (ESI) calcd for [C19H16O4 + H]+ 309.1049, found 309.1120.
Ethyl 3,7-dimethyl-1-oxo-1H-isochromene-4-carboxylate (3pa). White solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 8.3, 1.5 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 2.43 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.0, 161.5, 157.0, 138.5, 136.4, 132.2, 129.4, 124.1, 119.5, 110.2, 61.7, 21.2, 19.3, 14.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892, found 247.0961.
Ethyl 7-chloro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3qa). White solid. 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.4, 160.0, 158.5, 135.3, 134.1, 133.1, 129.0, 126.0, 120.8, 109.6, 61.8, 19.4, 14.2. HRMS (ESI) calcd for [C13H11ClO4 + H]+ 267.0346, found 267.0422.
Ethyl 3,5-dimethyl-1-oxo-1H-isochromene-4-carboxylate (3ra). White solid. 1H NMR (500 MHz, CDCl3) δ 7.59–7.53 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.80 (s, 3H), 2.38 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.4, 160.6, 156.6, 143.81, 136.2, 134.3, 131.2, 121.9, 118.1, 110.9, 61.7, 23.6, 19.0, 14.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892, found 247.0960.
Ethyl 8-chloro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3sa). White solid. 1H NMR (500 MHz, CDCl3) δ 7.63–7.56 (m, 2H), 7.53 (d, J = 7.6 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.8, 158.0, 157.7, 137.7, 137.3, 134.8, 131.2, 122.9, 116.8, 110.3, 62.0, 19.2, 14.3. HRMS (ESI) calcd for [C13H11ClO4 + H]+ 267.0346, found 267.0425.
Ethyl 3,6,7-trimethyl-1-oxo-1H-isochromene-4-carboxylate (3ta). White solid. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.51 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.0, 161.4, 156.8, 145.4, 137.6, 132.6, 129.8, 124.6, 117.3, 110.0, 61.5, 20.7, 19.6, 19.2, 14.2. HRMS (ESI) calcd for [C15H16O4 + H]+ 261.1049, found 261.1116.
Ethyl 3-methyl-1-oxo-1H-benzo[g]isochromene-4-carboxylate (3ua). White solid. 1H NMR (500 MHz, CDCl3) δ 8.97–8.93 (m, 1H), 8.26–8.21 (m, 1H), 8.07–8.02 (m, 1H), 7.98–7.92 (m, 1H), 7.71–7.62 (m, 1H), 7.62–7.55 (m, 1H), 4.58–4.50 (m, 2H), 2.52–2.49 (m, 3H), 1.53–1.47 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 166.3, 161.6, 156.1, 136.6, 132.2, 132.1, 129.8, 129.7, 129.6, 129.2, 128.5, 127.2, 123.1, 110.3, 61.8, 19.4, 14.4. HRMS (ESI) calcd for [C17H14O4 + H]+ 283.0892, found 283.0966.
Ethyl 5-methyl-7-oxo-7H-thieno [2,3-c]pyran-4-carboxylate (3vq). White solid. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.0, 164.5, 157.2, 145.4, 136.7, 126.3, 122.4, 108.3, 61.7, 20.2, 14.4. HRMS (ESI) calcd for [C11H10O4S + H]+ 283.0300, found 239.0371.
Ethyl 1-oxo-3-phenyl-1H-isochromene-4-carboxylate (3ab). White solid. 1H NMR (500 MHz, CDCl3) δ 8.37 (dd, J = 8.0, 0.8 Hz, 1H), 7.82–7.77 (m, 1H), 7.75 (dd, J = 8.1, 0.7 Hz, 1H), 7.65 (dd, J = 8.0, 1.6 Hz, 2H), 7.61–7.55 (m, 1H), 7.50–7.43 (m, 3H), 4.20 (q, J = 7.2 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.3, 161.1, 155.4, 135.3, 134.7, 132.6, 130.5, 129.9, 128.8, 128.5, 128.1, 124.1, 119.8, 110.9, 61.9, 13.5. HRMS (ESI) calcd for [C18H14O4 + H]+ 295.0892, found 295.0961.
Ethyl 3-(4-methoxyphenyl)-1-oxo-1H-isochromene-4-carboxylate (3ac). white solid.1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.6, 161.4, 161.2, 155.1, 135.2, 134.9, 129.8, 128.4, 124.8, 123.9, 119.5, 113.9, 109.9, 61.9, 55.4, 13.7. HRMS (ESI) calcd for [C19H16O5 + H]+ 325.0998, found 325.1069.
Ethyl 3-(4-chlorophenyl)-1-oxo-1H-isochromene-4-carboxylate (3ad). White solid. 1H NMR (500 MHz, CDCl3) δ 8.36 (dd, J = 7.9, 0.9 Hz, 1H), 7.82–7.77 (m, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.62–7.56 (m, 3H), 7.47–7.41 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.0, 160.8, 153.9, 136.7, 135.3, 134.4, 130.9, 129.9, 129.4, 129.0, 128.7, 124.1, 119.7, 111.2, 62.0, 13.6. HRMS (ESI) calcd for [C18H13ClO4 + H]+ 329.0502, found 329.0575.
Ethyl 3-(naphthalen-2-yl)-1-oxo-1H-isochromene-4-carboxylate (3ae). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.39 (dd, J = 7.9, 0.7 Hz, 1H), 8.20 (s, 1H), 7.95–7.86 (m, 3H), 7.84–7.75 (m, 2H), 7.71 (dd, J = 8.6, 1.7 Hz, 1H), 7.63–7.51 (m, 3H), 4.21 (q, J = 7.1 Hz, 2H), 0.99 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.5, 161.2, 155.3, 135.4, 134.9, 134.1, 132.8, 129.9, 128.9, 128.7, 128.3, 127.8, 127.0, 124.8, 124.3, 119.9, 111.3, 62.1, 13.7. HRMS (ESI) calcd for [C22H16O4 + H]+ 345.1049, found 345.1111.
Ethyl 3-cyclopropyl-1-oxo-1H-isochromene-4-carboxylate (3af). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.25 (ddd, J = 8.0, 1.4, 0.7 Hz, 2H), 7.76–7.65 (m, 4H), 7.47 (ddd, J = 8.4, 6.8, 1.6 Hz, 2H), 4.49 (q, J = 7.2 Hz, 4H), 2.31 (tt, J = 8.3, 5.0 Hz, 2H), 1.45 (t, J = 7.1 Hz, 6H), 1.33–1.22 (m, 5H), 1.09–0.97 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 166.2, 160.8, 160.3, 135.1, 129.7, 127.6, 123.6, 119.1, 109.4, 61.7, 14.3, 12.5, 8.5. HRMS (ESI) calcd for [C15H14O4 + H]+ 259.0892, found 259.0957.
Ethyl 3-cyclohexyl-1-oxo-1H-isochromene-4-carboxylate (3ag). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.34–8.28 (m, 1H), 7.77–7.72 (m, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 11.2, 4.0 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.79 (tt, J = 11.8, 3.2 Hz, 1H), 1.87 (d, J = 10.2 Hz, 4H), 1.84–1.71 (m, 3H), 1.45 (t, J = 7.1 Hz, 3H), 1.32 (dd, J = 15.5, 5.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.4, 163.1, 161.8, 135.3, 135.1, 130.0, 128.4, 124.2, 120.0, 109.6, 62.1, 42.1, 30.3, 26.3, 25.8, 14.6. HRMS (ESI) calcd for [C18H20O4 + H]+ 301.1362, found 301.1433.
7,8,9,10-tetrahydrocyclohepta[c]isochromene-5,11-dione (3ah). White solid. 1H NMR (500 MHz, CD3OD) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.53 (d, J = 6.5 Hz, 1H), 2.96 (s, 2H), 2.81 (d, J = 3.1 Hz, 2H), 1.94 (d, J = 2.5 Hz, 4H). 13C NMR (126 MHz, CD3OD) δ 204.4, 165.5, 162.6, 136.2, 135.9, 130.2, 129.2, 125.7, 120.8, 117.3, 43.7, 33.1, 24.2, 23.4. HRMS (ESI) calcd for [C14H12O3 + H]+ 227.0786, found 227.0708.
Ethyl 3-isopropyl-1-oxo-1H-isochromene-4-carboxylate (3ai). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.28 (dd, J = 7.9, 1.0 Hz, 1H), 7.74–7.69 (m, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.52–7.47 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 3.13 (dt, J = 13.7, 6.8 Hz, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.32 (s, 3H), 1.31 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.1, 163.2, 161.5, 135.1, 134.8, 129.8, 128.3, 124.0, 119.8, 109.2, 61.9, 31.7, 20.2, 14.3. HRMS (ESI) calcd for [C15H16O4 + H]+ 261.1049, found 261.1123.
Ethyl 3-ethyl-1-oxo-1H-isochromene-4-carboxylate (3aj). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.8 Hz, 1H), 7.76–7.68 (m, 2H), 7.53–7.48 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.71 (q, J = 7.5 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.9, 161.6, 135.1, 134.8, 129.8, 128.3, 124.2, 119.7, 109.8, 61.8, 26.4, 14.3, 12.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892, found 247.0964.
tert-Butyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ak). White solid. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 1H), 7.81–7.69 (m, 2H), 7.52 (t, J = 7.2 Hz, 1H), 2.45 (s, 3H), 1.65 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 165.1, 161.5, 156.3, 135.1, 135.0, 129.8, 128.1, 123.9, 119.7, 111.8, 83.2, 28.3, 19.1. HRMS (ESI) calcd for [C15H16O4 + H]+ 261.1049, found 261.1114.
Benzyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3al). White solid. 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz, 1H), 7.70 (ddd, J = 11.6, 9.6, 4.7 Hz, 2H), 7.52–7.43 (m, 3H), 7.43–7.34 (m, 3H), 5.42 (s, 2H), 2.40 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.7, 161.1, 158.0, 135.1, 134.6, 129.7, 128.9, 128.6, 128.2, 124.1, 119.5, 109.99, 67.6, 19.4. HRMS (ESI) calcd for [C18H14O4 + H]+ 295.0892, found 295.0962.
Allyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3am). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.27 (dd, J = 27.2, 8.0 Hz, 1H), 7.80–7.70 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 6.05 (ddt, J = 16.5, 10.4, 6.0 Hz, 1H), 5.45 (dd, J = 17.2, 1.3 Hz, 1H), 5.35 (dd, J = 10.4, 0.9 Hz, 1H), 4.88 (d, J = 6.0 Hz, 2H), 2.46 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.6, 161.2, 158.1, 135.2, 134.6, 131.3, 129.7, 128.3, 124.2, 119.8, 119.5, 110.0, 66.4, 19.4. HRMS (ESI) calcd for [C14H12O4 + H]+ 245.0736, found 245.0811.
Methyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3an). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.31–8.25 (m, 1H), 7.73 (qd, J = 8.4, 4.0 Hz, 2H), 3.97 (s, 3H), 2.45 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.3, 161.1, 158.1, 135.1, 134.5, 129.7, 128.2, 124.2, 119.5, 110.0, 52.4, 19.4. HRMS (ESI) calcd for [C12H10O4 + H]+ 219.0579, found 219.0648.
Propyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ao). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.31–8.26 (m, 1H), 7.74 (qd, J = 8.3, 4.0 Hz, 2H), 7.51 (ddd, J = 8.2, 6.7, 1.8 Hz, 1H), 4.35 (t, J = 6.7 Hz, 2H), 2.46 (s, 3H), 1.87–[44]1.75 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 166.1, 161.4, 157.8, 135.2, 134.8, 129.8, 128.3, 124.3, 119.7, 110.5, 67.5, 22.1, 19.5, 10.7. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892, found 247.0964.

3.2.5. Derivatization Experiments

Ethyl 3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (4) [45]. A mixture of the product 3aa (323 mg) and ammonium acetate (250 mg) in 0.5 mL of acetic acid is stirred at 80 °C overnight, and then cooled and poured into water. The solid is collected by filtration, washed with water and dried to yield the title compound [44]. White solid. 1H NMR (400 MHz, CDCl3) δ 11.74 (s, 1H), 8.42 (dd, J = 8.0, 1.0 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.74–7.65 (m, 1H), 7.48 (t, J = 7.2 Hz, 1H), 4.46 (d, J = 7.1 Hz, 2H), 2.59 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). 13C NMR (126MHz, CDCl3) δ 167.2, 141.2, 135.9, 133.4, 127.4, 126.5, 124.5, 109.5, 61.4, 19.1, 14.5. HRMS (ESI) calcd for [C13H13NO3 + H]+ 232.0895, found 232.0970.
3-methyl-1H-isochromen-1-one (5) [46]. To a 100 mL rd-bottom flask was charged with conc. HCl (3.51 mL, 96 mmol) and heated to 110 °C. 3aa (232 mg, 1 mmol) was then added portionwise and the mixture was allowed to stir at reflux for 22 h. The resulting white solid and yellow solution was cooled to room temperature and the solid was collected by vacuum filtration. The solid was further dried using a mechanical vacuum pump (10−3 torr), and then heated over a hot water bath at 50–60 °C for 1 h to give isocoumarin 5 as an off-white solid (120 mg, 75%) [47]. White solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 1H), 7.61 (td, J = 7.7, 1.3 Hz, 1H), 7.42–7.33 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.19 (s, 1H), 2.21 (d, J = 0.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 163.1, 154.7, 137.8, 134.8, 129.6, 127.6, 124.9, 120.0, 103.6, 19.7. HRMS (ESI) calcd for [C10H8O2 + H]+ 161.0524, found 161.0593.

3.2.6. Compete Experiments and Mechanistic Studies

1a–d5. Benzoic acid-d5 (10 mmol) in SOCl2 (10 mL) was refluxed at 85 °C. After 30 min, the mixture turned clear. The reaction was stopped, and the reaction solution was concentrated to give the acyl chloride. A solution of acyl chloride prepared above in anhydrous dichloromethane (10 mL) was injected dropwise to an aqueous ammonia solution (con. 20 mL) in an ice bath. After stirring for 30 min, the precipitate was collected by suction filtration, washed with water and n-hexane, and dried under reduced pressure at 50 °C. Recrystallization from ethyl acetate afforded the compounds benzamide following general Procedure for the synthesis of benzoylcarbamate derivatives. 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 1.47 (s, 10H). 13C NMR (126 MHz, DMSO-d6) δ 166.47, 150.87, 133.82, 132.31, 128.35, 81.17, 28.20. HRMS (ESI) calcd for [C12H10D5NO3 + Na]+ 249.1366, found 249.1256.
Scheme 3b: To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol, 15 mol%) in acetonitrile (2 mL) was added 1a (22.1 mg, 0.6 mmol), 1a-d5(22.6 mg, 0.1mmol) and ethyl 2-diazo-3-oxobutanoate 2a (18.7 mg, 0.12 mmol), Cs2CO3(65 mg, 0.2 mmol, 2 equiv). The reaction mixture was stirred at 60 °C for 1 min and the progress was monitored using TLC detection. After completion of the present reaction, the solvent was evaporated under reduced pressure and the residue passed through flash column chromatography on silica gel to afford the mixture of products 3a and 3a–d4 with 17.0 mg (74% yield).
Scheme 3c: To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol, 15 mol%) in acetonitrile (2 mL) was added 1a (22.1 mg, 0.6 mmol) or 1a–d5 (22.6 mg, 0.1mmol) and ethyl 2-diazo-3-oxobutanoate 2a (18.7 mg, 0.12 mmol), Cs2CO3(65 mg, 0.2 mmol, 2 equiv). The reaction mixture was stirred at 60 °C for 1 min and the progress was monitored using TLC detection. After completion of the present reaction, the solvent was evaporated under reduced pressure and the residue passed through flash column chromatography on silica gel to afford the mixture of products 3aa (17.0 mg, 74%) or 3aa–d4 (14.1 mg, 59.7%).
Scheme 3d: To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol, 15 mol%) in acetonitrile (2 mL) was added 1a (22 mg, 0.1 mmol) and diethyl 2-diazomalonate (22 mg, 0.12 mmol), Cs2CO3 (65 mg, 0.2 mmol, 2 equiv). The reaction mixture was stirred at 80 °C and the progress was monitored using TLC detection.

4. Conclusions

In conclusion, we have successfully developed a Rhodium-catalyzed C-H activation/annulation of diazo compounds with Boc-protected benzamidesubstrates for efficient synthesis of isocoumarins. The tert-butyl formylcarbamate group formally served as an oxidizing DG using the C-N bond as an internal oxidant. In this strategy, the novel Boc-amide groups as removable directing groups enable the benzamides to construct C-C/C-O bonds to provide isocoumarins. Moreover, this reaction features broad substrate scopes and good tolerance. We believe the mild procedure will be of importance to medicinal chemists.

Supplementary Materials

The following are available online. 1. X-ray single crystal structure of compound 3ga; 2. 1H and 13C NMR Spectra of benzamides; 3. 1H and 13C NMR Spectra of Products; 4. 1H Spectra of Compete experiments; 5. MS Spectra of benzamides; 6. MS Spectra of Products.

Author Contributions

Experiments and investigation, G.D.; formal analysis and data curation, G.D. and C.L.; writing—original draft preparation, G.D.; writing—review and editing, C.L. and H.L.

Funding

We gratefully acknowledge financial support from the National Natural Science Foundation of China (81620108027, 21632008, and 21672231), the Major Project of Chinese National Programs for Fundamental Research and Development (2015CB910304).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Not available.
Molecules 24 00937 g001 550
Figure 1. Bioactive isocoumarins derivatives.
Figure 1. Bioactive isocoumarins derivatives.
Molecules 24 00937 g001
Molecules 24 00937 sch001 550
Scheme 1. Rh(III)-catalyzed C-H activation of benzamides derivatives: (1) N-alkyl-substituted benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (2) Acylsulfonamide-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (3) Primary benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (4) N-Boc benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation.
Scheme 1. Rh(III)-catalyzed C-H activation of benzamides derivatives: (1) N-alkyl-substituted benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (2) Acylsulfonamide-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (3) Primary benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (4) N-Boc benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation.
Molecules 24 00937 sch001
Molecules 24 00937 sch002 550
Scheme 2. Gram-scale reaction (a) and derivatization (b) of the annulation product.
Scheme 2. Gram-scale reaction (a) and derivatization (b) of the annulation product.
Molecules 24 00937 sch002
Molecules 24 00937 sch003 550
Scheme 3. Mechanistic Studies: (a) Intermoleculalr competition:benzamides; (b) Competition experiment; (c) Parallel experiment; (d) Verify the role of the final lactonization of ketone experiment.
Scheme 3. Mechanistic Studies: (a) Intermoleculalr competition:benzamides; (b) Competition experiment; (c) Parallel experiment; (d) Verify the role of the final lactonization of ketone experiment.
Molecules 24 00937 sch003
Molecules 24 00937 sch004 550
Scheme 4. Plausible reaction mechanism.
Scheme 4. Plausible reaction mechanism.
Molecules 24 00937 sch004
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 24 00937 i001
EntryR1R2BaseAddtiveSolvent3aa Yield (%)
1HAcetylNaOAc-DCEnr
2MeBocNaOAc-DCEnr
3BocBocNaOAc-DCEnr
4HCO2MeNaOAc-DCEnr
5HCO2iprNaOAc-DCEtrace
6HBocNaOAc-DCE19
7HBocNaOAcAg2ODCEnr
8HBocNaOAcAgOAcDCEnr
9HBocNaOAcCu(OAc)2DCE23
10HBocNaOAcAgSbF6DCE33
11HBocNaOAcAgSbF6CH3CN47
12HBocNaOAcAgSbF6MeOHtrace
13HBocNa2CO3AgSbF6CH3CN67
14HBocCs2CO3AgSbF6CH3CN80
15HBocNa2OpivAgSbF6CH3CN30
16 bHBocNaOAc-DCEnr
17 cHBocNaOAc-DCE14
18 dHBocNaOAc-DCE16
19 eHBocCs2CO3AgSbF6CH3CN78
20 fHBocCs2CO3AgSbF6CH3CN54
21 gHBocCs2CO3AgSbF6CH3CN79
22 hHBocCs2CO3AgSbF6CH3CN65
23 iHBocCs2CO3AgSbF6CH3CN78
a Unless otherwise specified, all the reactions were carried out with 0.1 mmol of 1a, 1a1–1a5 and 0.12 mmol of 2a, 5 mol% of Rh-cat, 2.0 equiv Cs2CO3 and 15 mol% AgSbF6 under air atmosphere at 60 °C for 0.5 h. All listed yields are isolated ones. b Cp*Co(CO)I2 instead of [Cp*RhCl2]2. c [(p-cymene)RuCl2]2 instead of [Cp*RhCl2]2. d [Cp*IrCl2]2 instead of [Cp*RhCl2]2. e The reaction was carried out under N2 atmosphere. f The reaction was carried out at room temperature for 1 h under air. g The reaction was carried out at 80 °C for 0.5 h under air. h The reaction was carried out at 60 °C for 5 min under air. i The reaction was carried out at 60 °C for 6 h under air.
Table
Table 2. Scope of Boc-protected benzamides derivatives a.
Table 2. Scope of Boc-protected benzamides derivatives a.
Molecules 24 00937 i002
Molecules 24 00937 i003 Molecules 24 00937 i004 Molecules 24 00937 i005 Molecules 24 00937 i006
3aa, 80%3bab, 87%3ca, 68%3da, 61%
Molecules 24 00937 i007 Molecules 24 00937 i008 Molecules 24 00937 i009 Molecules 24 00937 i010
3ea, 79%3fab, 81%3ga, 72%3ga
Molecules 24 00937 i011 Molecules 24 00937 i012 Molecules 24 00937 i013 Molecules 24 00937 i014
3ha, 48%3ia, 61%3ja, 51%3kac, 22%
Molecules 24 00937 i015 Molecules 24 00937 i016 Molecules 24 00937 i017 Molecules 24 00937 i018
3la, trace3ma, 69%3na, 75%3oa, 61%
Molecules 24 00937 i019 Molecules 24 00937 i020 Molecules 24 00937 i021 Molecules 24 00937 i022
3pa, 60%3qa, 48%3ra, 65%3sa, 53%
Molecules 24 00937 i023 Molecules 24 00937 i024 Molecules 24 00937 i025
3ta, 82%3ua, 51%3va, 68%
a Unless otherwise specified, 0.1 mmol of 1, 0.12 mmol of 2a, 5 mol% of Rh-cat, 2.0 equiv Cs2CO3 and 15 mol% AgSbF6 under air atmosphere at 60 °C for 0.5 h. All listed yields are isolated ones. b The reaction was performed at 60 °C for 2 h. c The reaction was performed at 80 °C for 2 h.
Table
Table 3. Scope of Diazo Compounds a.
Table 3. Scope of Diazo Compounds a.
Molecules 24 00937 i026
Molecules 24 00937 i027 Molecules 24 00937 i028 Molecules 24 00937 i029 Molecules 24 00937 i030
3ab, 79%3acb, 69%3adb, 61%3aeb, 51%
Molecules 24 00937 i031 Molecules 24 00937 i032 Molecules 24 00937 i033 Molecules 24 00937 i034
3af, 68%3ag, 61%3ah, 77%3ai, 45%
Molecules 24 00937 i035 Molecules 24 00937 i036 Molecules 24 00937 i037 Molecules 24 00937 i038
3aj, 61%3ak, 53%3al, 50%3amc, 25%
Molecules 24 00937 i039 Molecules 24 00937 i040
3an, 70%3ao, 63%
a Unless otherwise specified, 0.1 mmol of 1, 0.12 mmol of 2a, 5 mol% of Rh-cat, 2.0 equiv Cs2CO3 and 15 mol% AgSbF6 under air atmosphere at 60 °C for 0.5 h. All listed yields are isolated ones. b The reaction was performed at 60 °C for 2 h. c The reaction was performed at 80 °C for 2 h.

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Dong, G.; Li, C.; Liu, H. Rh(III)-Catalyzed Annulation of Boc-Protected Benzamides with Diazo Compounds: Approach to Isocoumarins. Molecules 2019, 24, 937. https://doi.org/10.3390/molecules24050937

AMA Style

Dong G, Li C, Liu H. Rh(III)-Catalyzed Annulation of Boc-Protected Benzamides with Diazo Compounds: Approach to Isocoumarins. Molecules. 2019; 24(5):937. https://doi.org/10.3390/molecules24050937

Chicago/Turabian Style

Dong, Guangyu, Chunpu Li, and Hong Liu. 2019. "Rh(III)-Catalyzed Annulation of Boc-Protected Benzamides with Diazo Compounds: Approach to Isocoumarins" Molecules 24, no. 5: 937. https://doi.org/10.3390/molecules24050937

APA Style

Dong, G., Li, C., & Liu, H. (2019). Rh(III)-Catalyzed Annulation of Boc-Protected Benzamides with Diazo Compounds: Approach to Isocoumarins. Molecules, 24(5), 937. https://doi.org/10.3390/molecules24050937

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