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

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.


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 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].
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 Nheterocycles 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.

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 1a 1 -1a 5 and ethyl diazoacetoacetate 2a. As shown in Table 1, amide derivatives 1a 1 -1a 5 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 Ag 2 O and AgOAc were added to the reaction, no evidence of 3aa was observed, while 3aa was obtained in 33% yield with AgSbF 6 . 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 (

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 (

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 CF 3 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 paraand 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.

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.

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.

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.

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.

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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 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.

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 R 2 with phenyl groups were used, the 3ab−3ae were given in 51−79% yields. R 2 with a cyclopropyl and a cyclohexyl group gave 3af and 3ag in moderate yield. When R 2 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 R 3 with a methyl, a tert-butyl, an n-propyl or a benzyl group was used, the 3ak-3ao were given in 25-70% yields.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Mechanism
To obtain a more mechanistic insight, further experiments were carried out (Scheme 3). When pmethoxy-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 electrophilictype benzamide were inherently less reactive (Scheme 3a). To gain further insights, the kineticisotope effect (KIE) was studied in parallel and competition experiments (Scheme 3b and 3c). 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).

Scheme 2.
Gram-scale reaction (a) and derivatization (b) of the annulation product.

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-d 5 were conducted, and a k H /k D value of 1.44 was obtained (Scheme 3b). Furthermore, separate reactions of 1a or 1a-d 5 together with 2a gave the corresponding products 3aa and 3aa-d 4 , 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*RhCl 2 ] 2 , then the C-H metalation takes place to afford five-membered cyclometalated Rhodium species B via a Rh(III)-catalyzed C(sp 2 )-H bond cleavage. After insertion of the diazo compounds, Rh(III)-carbene species C can be formed with extrusion of N 2 . Subsequently, the species C undergoes a migratory insertion of carbene into the Rh-C bond, provided six-membered species D.

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.

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 CH 3 CN, 6 mmol TsN 3 was added. Then the reaction mixture was cooled to 0 • C and a solution of DBU (6 mmol) in 10 mL CH 3 CN 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 Na 2 SO 4 , 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.

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. NaHCO 3 and then extracted with dichloromethane. The combined organic layer was washed with brine and dried over Na 2 SO 4 . 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]. DMSO-d 6 ) δ 10.65 (s, 1H), 1.47 (s, 10H). 13 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF 6 (5 mg, 0.015 mmol, 15 mol%) in acetonitrile (2 mL) was added 1a (22.1 mg, 0.6 mmol), 1a-d 5 (22.6 mg, 0.1mmol) and ethyl 2-diazo-3-oxobutanoate 2a (18.7 mg, 0.12 mmol), Cs 2 CO 3 (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-d 4 with 17.0 mg (74% yield).

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.