Selective Removal of Aminoquinoline Auxiliary by IBX Oxidation | The

Jun 6, 2019 - The ee value of 2 was slightly eroded (96% ee). IBX generated via in situ oxidation of 5 with Oxone was likely responsible for the cleav...
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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

Selective Removal of Aminoquinoline Auxiliary by IBX Oxidation Zhiguo Zhang,*,† Xiang Li,† Mengmeng Song,† Yameng Wan,† Dan Zheng,† Guisheng Zhang,*,† and Gong Chen*,‡ †

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Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China ‡ State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China S Supporting Information *

ABSTRACT: 8-Aminoquinoline (AQ) is a widely used bidentate auxiliary in metal-catalyzed directed C−H functionalization reactions. Herein, we report an efficient and chemoselective method to convert various N-quinolyl carboxamides to primary amides with the treatment of a stoichiometric amount of 2-iodoxybenzoic acid oxidant or the combination of a catalytic amount of 2-iodobenzoic acid and Oxone co-oxidant in mixed solvents of H2O and HFIP. Its unique compatibility with the Phth-protected α-amino acid (αAA) substrates enhances the overall synthetic utility of the AQ-directed palladium-catalyzed C−H functionalization strategy for synthesis of complex αAAs.

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INTRODUCTION 8-Aminoquinoline (AQ) has been widely used as a bidentate auxiliary in various metal-catalyzed C−H functionalization reactions.1 A number of protocols, including hydrolysis or alcoholysis of amide under acidic or basic conditions,2 Boc activation/LiOH cleavage,3 ozonolysis/cleavage of imide;4 oxidative cleavage of 5-methoxy-8-aminoquinoline (MQ),5 and Ni-catalyzed alcoholysis,6 have been reported for the removal of the AQ group, forming free carboxylic acid or primary amide (Scheme 1). Despite these advances, important practical issues such as chemoselectivity, functional group tolerance, and racemization of chiral Cα remain to be improved. Methods suitable for complex substrates such as peptides bearing different amide groups are still greatly desired to achieve broader application of AQ-directed C−H functionalization chemistry. Herein, we report an efficient and chemoselective method to convert various N-quinolyl carboxamides to primary amides with the treatment of stoichiometric 2-iodoxybenzoic acid (IBX) oxidant or the combination of catalytic 2-iodobenzoic acid (2-IBA) and Oxone co-oxidant in a mixed solvent of H2O and HFIP.7 Its unique compatibility with the Phth-protected α-amino acid (αAA) substrates greatly enhances the overall synthetic utility of AQ-directed palladium-catalyzed C−H functionalization strategy for synthesis of complex αAAs.

Scheme 1. Removal of Amide-Linked AQ Group

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RESULTS AND DISCUSSION Recently, we demonstrated that reactions of N-aryl carboxamides featuring relatively electron-rich arenes with IBX in hexafluoro-2-propanol (HFIP) and water at room temperature undergo C(aryl)−N cleavage to give primary amides in good yield and selectivity.8 Notably, the mechanism of the C(aryl)− © XXXX American Chemical Society

Special Issue: C-H Bond Functionalization Received: May 22, 2019 Published: June 6, 2019 A

DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 1. Reaction Optimization of Phth-Ala-AQ 1a

Unless otherwise indicated, reactions were conducted with 0.3 mmol of 1 in 2 mL of solvent at 60 °C, isolated yield. bIsolated yield of 2 on a 3 mmol scale. c59% yield of 3 based on 1H NMR of crude reaction mixture after workup. dNo 3 was formed; about 12% of 4 was isolated. eComplex reaction mixture was obtained.

a

As shown in Table 1, we were pleased to find that reaction of Ala substrate 1 with 2 equiv of IBX in mixed solvents of HFIP and H2O (1:1) at 60 °C for 1.5 h gave primary amide product 2 in excellent isolated yield (89%) and with excellent maintenance of chirality at Cα (>99% ee) (entry 1). Quinoline-7,8-dione 3 and 2-IBA 5 were identified as the byproducts. Lower loading of IBX gave a lower conversion of starting material (entries 2 and 3). Dess−Martin periodinane (DMP, I(V)) gave a slightly lower yield than IBX (entry 4). Use of hydroxy benziodoxolone (BI−OH, I(III)) oxidant only

N cleavage reaction was not well understood.9 Encouraged by that discovery, we wondered whether a similar operation can be used to remove the AQ auxiliary attached to N-Phthprotected αAA substrates. Previous work from others and our lab have shown that palladium-catalyzed AQ-directed side chain C−H functionalization offered a powerful strategy to construct various complex αAA from simple αAA precursors.2b,10 However, facile removal of the AQ group of the complex αAA products remains challenging especially for the sterically encumbered β-disubstituted compounds. B

DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 2. Scope of AQ-Coupled αAAs

gave a trace amount of 2 (entry 5).11 Phenyliodonium diacetate (PIDA, I(III)) or iodosobenzene (PhIO, I(III)) gave 2 in low yield (entries 6 and 7). Interestingly, quinoline5,8-dione 4 was isolated as the only quinolone byproduct when the organoiodine(III) reagents were used. Use of ceric ammonium nitrate (CAN) gave a complex mixture (entry 8).5 The mixed solvents of HFIP and H2O in 1:1 ratio is critical to obtain a high yield of 2 (entries 1 vs 9 and 10). No reaction took place in the absence of H2O (entry 11). Other organic solvents including 2,2,2-trifluoroethanol (TFE), DMSO, THF, and DMF gave much inferior results (entries 12−16). Reaction at 40 °C for 24 h gave a slightly lower yield of 2 (entry 17). A gram-scale reaction 1 (3 mmol scale) gave 2 in 75% isolated yield in 2 h (entry 1). As shown in entry 18, we were pleased to find that the combination of catalytic amount of 5 (0.3 equiv) and Oxone co-oxidant (3 equiv) successfully gave product 2 in good yield (83%) in HFIP/H2O (1:1). The ee value of 2 was slightly eroded (96% ee). IBX generated via in situ oxidation of 5 with Oxone was likely responsible for the cleavage of AQ.12 As shown in Scheme 2, the scope of AQ-coupled Phthprotected αAA substrates was next evaluated under the optimized conditions A with IBX or conditions B with 2IBA/Oxone. Many of the corresponding AQ-coupled αAAs were prepared from simple αAA precursors via Pd-catalyzed AQ-directed C−H functionalization including alkylation (6− 8),10b,g,h arylation (13, 14, 17, and 18),10f,13 alkenylation (10),10d alkynylation (11),10e acetoxylation (15),14 and silylation (16).10a−h,15 The cleavage reactions of the AQcoupled secondary amides generally worked well to give the primary amide products in excellent yield. Functional groups such as ester (8), BocNH (9), olefin (10), and alkyne (11) were well tolerated. In contrast, cleavage of AQ group from tertiary amide 12, prepared via Pd-catalyzed AQ-directed intramolecular C−H amidation of a valine precursor,5a failed to proceed with starting material largely recovered. As exemplified by 13 and 14, reaction of αAA bearing plain or alkyl-substituted aryl side chains proceeded cleanly to give the amide products with little byproducts. β-Substituted Phe substrates (15, 16) also worked well. In comparison, reaction of αAA bearing electron-rich alkoxy-substituted aryl groups gave the desired products (e.g., 17 and 18) in moderate yield, along with a small amount of spirodienone byproduct 19. 19 is likely formed via an IBX-mediated spirocyclization of primary amide intermediates.16 Notably, reaction of Trp substrate 20 gave spiro-fused morpholine 21 in good yield and excellent diastereoslectivity.17 The structure of 21 was confirmed by Xray crystallography. As exemplified by 8, 10, 11, 13, and 15, cleavage of AQ with 2-IBA/Oxone under conditions B gave comparable results with conditions A. Reactions of other AQ-coupled substrates were next evaluated (Scheme 3). Reaction of Cbz and Fmoc protected Ala substrates gave the corresponding amide products 22 and 23 in a slightly lower yields (50% and 37%), along with small amounts of unidentified byproducts. Reaction of Boc protected Ala gave a complex mixture (24). In contrast, Fmoc-protected dipeptide substrates with C-linked AQ group reacted cleanly to give the desired primary amide products (25−27), suggesting the terminal carbamate and internal secondary and tertiary amide functional groups do not interfere with the IBXmediated removal of AQ. The reaction of a tripeptide substrate proceeded with a lower conversion but gave the desired product (28) in high selectivity. Reaction of AQ-coupled 3-

a

Isolated yield on 0.3 mmol scale. b93% of starting material was recovered.

phenylpropanamide gave product 29 in excellent yield. Nquinolyl aryl carboxamides also worked well (30 and 31). Notably, the normal N-aryl carboxamide linkage of 32 was untouched possibly due to the deactivation by electronwithdraw carboxamide group on the aniline moiety. As shown in eqs 1 and 2, the resulting primary amide derivatives of αAA can be readily converted to the free

carboxylic acids with the treatment of tert-butyl nitrite (TBN) in AcOH at 75 °C.18 The Phth-protected Phe 33 was obtained in excellent yields and chiral integrity. The β-OAc group of 34 was untouched. C

DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

pyridine N of AQ probably promotes the amide tautomerization of I under slightly acidic conditions in FHIP, leading to the high reactivity of the relatively electron deficient AQ group. Intramolecular nucleophilic attack of the oxo group on the iodine center of II onto the ortho-position of AQ group triggers the dearomatization of aniline moiety and the cleavage of the O−I bond of II to form III.17,19 Deprotonation and cleavage of exocyclic O−I bond of III gives o-iminoquinone species IV and 2-iodobenzoic acid 5. Hydrolysis of IV gives the primary amides V and quinoline-7,8-dione 3.20 The diastereoselective formation of morpholine 21 is consistent with an intramolecular [4 + 2] cycloaddition of o-iminoquinone intermediate 37 with the side chain indole (Scheme 4B).17 In comparison, the removal of AQ group with the treatment of PIDA could be explained by the intermolecular nucleophilic attack of H2O to the C5 carbon of iodoimidate intermediate VI.21 Hydrolysis of p-iminoquinone VII give the primary amide products and quinoline-5,8-dione 4 (Scheme 4C).22

Scheme 3. Scope of Other AQ-Coupled Substrates

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CONCLUSIONS In summary, we have developed an efficient and selective method to remove the amide-linked 8-aminoquinoline auxiliary with IBX oxidant under mild conditions. We also demonstrated a more economical protocol using a catalytic amount of 2-iodobenzoic acid and Oxone co-oxidant. The reactions worked well with a variety of Phth-protected α-amino acid substrates bearing both β-mono- and disubstituted side chains. The reactions showed remarkable chemoselectivity of the C-terminal N-quinolyl carboxamide without effecting the internal alkyl amide and common carbamate protecting groups in peptides. Mechanistic studies indicated an o-iminoquinone intermediate was generated via the intramolecular nucleophilic attack of the oxo group of iodoimidate onto the ortho-position of AQ group. The resulting primary amides can be cleanly converted to free carboxylic acids with the treatment of TBN in AcOH. Overall, this method complements the AQ-directed palladium-catalyzed C−H functionalization strategy for synthesis of complex αAAs from simple precursors and would likely find broad application in other AQ-directed reactions.

a

Isolated yield on 0.3 mmol scale. bComplex mixture. cThe yield was based on the conversion of SM; 36% of SM was recovered.

As outlined in Scheme 4A, the IBX-mediated removal of AQ group likely starts with the substitution reaction of amide O atom of I with the iodo center of IBX to form iodoimidate II.19 The facile intramolecular proton transfer from NH to the Scheme 4. Mechanistic Considerations

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EXPERIMENTAL SECTION

General Remarks. All reagents were purchased from commercial sources and used without further treatment, unless otherwise indicated. Other materials were prepared according to the literature.10a−h,13−15,20 Petroleum ether (PE) used here refers to the 60−90 °C boiling point fraction of petroleum. Ethyl acetate is abbreviated as EA. 1H and 13C{1H} NMR spectra were recorded on a Bruker Avance/600 (1H: 600 MHz, 13C{1H}: 150 MHz at 25 °C) or Bruker Avance/400 (1H: 400 MHz, 13C{1H}: 100 MHz at 25 °C) with tetramethylsilane as the internal standard. Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, and m = multiplet), and coupling constants in Hertz (Hz). All highresolution mass spectra (HRMS) were measured on a mass spectrometer by using electrospray ionization orthogonal acceleration time-of-flight (ESI-OA-TOF), and the purity of all samples used for HRMS (>95%) was confirmed by 1 H and 13 C{ 1 H} NMR spectroscopic analysis. Melting points were measured on a melting point apparatus equipped with a thermometer and were uncorrected. All reactions were monitored by thin-layer chromatography (TLC) with GF254 silica gel coated plates, and in general, the reaction was assumed to have completed 20 min after the starting material 1 was completely consumed. Flash chromatography was carried out on SiO2 (silica gel 200−300 mesh). D

DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

1.14 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 168.4, 134.5, 131.4, 123.7, 62.9, 27.6, 19.8, 19.5; HRMS (ESI) m/z calcd for C13H14N2NaO3 ([M + Na]+) 269.0897, found 269.0890. (S)-2-(1,3-Dioxoisoindolin-2-yl)pentanamide (7). The product was isolated by flash chromatography (eluent: EA/PE = 1/2) as a white solid (66 mg, 90%): mp 160−162 °C; 1H NMR (600 MHz, CDCl3) δ 7.88−7.83 (m, 2H), 7.74 (m, 2H), 6.27 (s, 1H), 5.92 (s, 1H), 4.80 (dd, J = 10.8, 4.8 Hz, 1H), 2.33−2.27 (m, 1H), 2.08−2.03 (m, 1H), 1.33−1.27 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.6, 168.4, 134.4, 131.6, 123.6, 54.3, 30.8, 19.6, 13.4; HRMS (ESI) m/z calcd for C13H14N2NaO3 ([M + Na]+) 269.0897, found 269.0898. Methyl (S)-5-Amino-4-(1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (8). The product was isolated by flash chromatography (eluent: EA/PE = 2/1) as a white solid (74 mg, 85%); mp 144−147 °C; 1H NMR (600 MHz, CDCl3) δ 7.85−7.83 (m, 2H), 7.76−7.72 (m, 2H), 6.38 (s, 1H), 5.99 (s, 1H), 4.82 (dd, J = 9.6, 6.0 Hz, 1H), 3.59 (s, 3H), 2.56−2.48 (m, 2H), 2.40−2.30 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 172.9, 170.6, 168.0, 134.5, 131.6, 123.7, 53.2, 51.9, 30.9, 24.2; HRMS (ESI) m/z calcd for C14H14N2NaO5 ([M + Na]+) 313.0795, found 313.0798. tert-Butyl (S)-(6-Amino-5-(1,3-dioxoisoindolin-2-yl)-6-oxohexyl)carbamate (9). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (90 mg, 80%): mp 119−121 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 5.4, 3.0 Hz, 2H), 7.75 (dd, J = 5.4, 3.0 Hz, 2H), 6.34 (s, 1H), 5.69 (s, 1H), 4.79 (dd, J = 10.6, 5.4 Hz, 1H), 4.55 (s, 1H), 3.20−3.01 (m, 2H), 2.39−2.27 (m, 1H), 2.23−2.12 (m, 1H), 1.58−1.46 (m, 2H), 1.39 (s, 9H), 1.35− 1.27 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 168.1, 156.1, 134.4, 131.6, 123.7, 54.4, 39.8, 29.3, 28.4, 23.5; HRMS (ESI) m/z calcd for C19H25N3NaO5 ([M + Na]+) 398.1686, found 398.1682. Methyl (S)-6-amino-5-(1,3-dioxoisoindolin-2-yl)-6-oxohex-2enoate (10). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (77 mg, 86%): mp 156−159 °C; 1H NMR (400 MHz, CDCl3) δ 7.89−7.81 (m, 2H), 7.80−7.72 (m, 2H), 6.83−6.75 (m, 1H), 6.25 (s, 1H), 5.96 (s, 1H), 5.90−5.82 (m, 1H), 4.92 (dd, J = 10.4, 5.2 Hz, 1H), 3.62 (s, 3H), 3.24−3.03 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.1, 167.7, 166.2, 143.2, 134.6, 131.4, 124.6, 123.8, 52.6, 51.6, 31.5; HRMS (ESI) m/z calcd for C15H14N2NaO5 ([M + Na]+) 325.0795, found 325.0786. (S)-2-(1,3-Dioxoisoindolin-2-yl)-5-(triisopropylsilyl)pent-4-ynamide (11). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (112 mg, 94%): mp 193−194 °C; 1H NMR (600 MHz, CDCl3) δ 7.86 (dd, J = 5.4, 3.0 Hz, 2H), 7.74 (dd, J = 5.4, 3.0 Hz, 2H), 6.34 (s, 1H), 5.76 (s, 1H), 5.00 (dd, J = 9.6, 6.6 Hz, 1H), 3.29−3.14 (m, 2H), 0.89−0.82 (m, 21H); 13 C{1H} NMR (150 MHz, CDCl3) δ 169.7, 167.7, 134.4, 131.7, 123.7, 103.0, 84.4, 52.5, 20.8, 18.4, 11.0; HRMS (ESI) m/z calcd for C22H30N2NaO3Si ([M + Na]+) 421.1918, found 421.1916. 2-((3S)-4-Methyl-2-oxo-1-(quinolin-8-yl)pyrrolidin-3-yl)isoindoline-1,3-dione (12). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (93% of starting material was recovered): mp 73−75 °C; 1H NMR (400 MHz, CDCl3) δ 8.93 (dd, J = 4.0, 1.6 Hz, 1H), 8.18 (dd, J = 8.4, 1.6 Hz, 1H), 7.90 (m, 3H), 7.79 (dd, J = 8.4, 1.2 Hz, 1H), 7.74 (dd, J = 5.4, 3.0 Hz, 3H), 7.59 (t, J = 7.8, 1H), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H), 4.27 (t, J = 9.6 Hz, 1H), 4.01 (dd, J = 9.6, 8.4 Hz, 1H), 3.25−3.13 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 167.8, 150.0, 144.0, 136.2, 135.9, 134.1, 132.1, 129.4, 128.5, 127.5, 126.4, 123.5, 121.4, 57.8, 55.4, 33.6, 16.3; HRMS (ESI) m/z calcd for C22H18N3O3 ([M + H]+) 372.1343, found 372.1345. (S)-2-(1,3-Dioxoisoindolin-2-yl)-3-phenylpropanamide (13). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (62 mg, 70%): mp 220−222 °C; 1H NMR (600 MHz, CDCl3) δ 7.78 (dd, J = 5.1, 2.7 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.23−7.10 (m, 5H), 6.14 (s, 1H), 5.61 (s, 1H), 5.12 (t, J = 8.4 Hz, 1H), 3.55 (d, J = 7.8 Hz, 2H); 13C{1H} NMR (150 MHz,

Typical Experimental Procedure. Removal of AQ under Conditions A on a 0.3 mol Scale. To a round-bottom flask (25 mL) were added (S)-2-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl) propanamide 1 (104 mg, 0.3 mmol) and IBX (168 mg, 0.6 mmol). The mixture in 2 mL of mixed solvent (VHFIP/VH2O = 1:1) was stirred at 60 °C in oil bath under air atmosphere for 1.5 h (monitored by TLC). The reaction was quenched by the addition of NaHCO3 (aq 10 mL); the resulting mixture was extracted with dichloromethane (3 × 5 mL). The organic solvent was concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography using ethyl acetate (EA) and petroleum ether (PE) as eluent to give primary amide product 2 as a white solid (58 mg, 89%). Removal of AQ under Conditions B on a 0.3 mol Scale. To a round-bottom flask (25 mL) were added (S)-2-(1,3-dioxoisoindolin2-yl)-N-(quinolin-8-yl)propanamide 1 (104 mg, 0.3 mmol), 2-IBA (22 mg, 0.09 mmol), and Oxone (553 mg, 0.9 mmol). The mixture in 2 mL of mixed solvent (VHFIP/VH2O = 1:1) was stirred at 70 °C for 5 h. The reaction was quenched by the addition of NaHCO3 (aq 10 mL); the resulting mixture was extracted with dichloromethane (3 × 5 mL). The organic solvent was concentrated in vacuo; the resulting residue was purified by silica gel flash column chromatography using EA and PE as eluent to give primary amide product 2 as a white solid (54 mg, 83%). Conversion of Primary Amide to Carboxylic Acid. To a stirred solution of primary amide 13 (88 mg, 0.3 mmol) in acetic acid (2 mL) was slowly added tert-butyl nitrite (178 μL, 1.5 mmol). The reaction mixture was stirred at 75 °C under air atmosphere for 3 h while the progress was monitored by TLC. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography using EA and PE as eluent to give the free carboxylic acid product 33 as a white solid (83 mg, 94%).18 Removal of AQ under Conditions A on a 3 mol Scale. To a round-bottom flask (50 mL) were added (S)-2-(1,3-dioxoisoindolin2-yl)-N-(quinolin-8-yl)propanamide 1 (1.04 g, 3 mmol) and IBX (1.68 g, 6 mmol). The mixture in 10 mL of mixed solvents (VHFIP/ VH2O = 1:1) was stirred at 60 °C in oil bath under air atmosphere for 2 h. The reaction was quenched by the addition of NaHCO3 (aq 20 mL); the resulting mixture was extracted with dichloromethane (3 × 10 mL). Then the organic solvent was concentrated in vacuo. The residue was purified by flash column chromatography with EA and PE as eluent to give primary amide 2 as a white solid (490 mg, 75%). (S)-2-(1,3-Dioxoisoindolin-2-yl)propanamide (2). The product was isolated by flash chromatography (eluent: EA/PE = 1/2) as a white solid (58 mg, 89%): mp 208−211 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 5.2, 3.2 Hz, 2H), 7.75 (dd, J = 5.6, 3.2 Hz, 2H), 6.02 (s, 1H), 5.65 (s, 1H), 4.95 (q, J = 7.4 Hz, 1H), 1.72 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.4, 167.8, 134.4, 131.8, 123.6, 49.2, 15.4; HRMS (ESI) m/z calcd for C11H10N2NaO3 ([M + Na]+) 241.0584, found 241.0584. Quinoline-7,8-dione (3). The product was isolated by flash chromatography (eluent: EA) as a white solid (13 mg, 27%): mp 160−162 °C; 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J = 4.8, 1.6 Hz, 1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (dd, J = 7.6, 4.4 Hz, 1H), 7.48 (d, J = 10.0 Hz, 1H), 6.58 (d, J = 10.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.7, 178.3, 151.6, 147.4, 142.8, 137.0, 132.1, 129.3, 128.7; HRMS (ESI) m/z calcd for C9H6NO2 ([M + H]+) 160.0393, found 160.0373. Quinoline-5,8-dione (4). The product was isolated by flash chromatography (eluent: EA) as a white solid (6 mg, 12%): mp 128−129 °C; 1H NMR (400 MHz, CDCl3) δ 9.07 (dd, J = 4.8, 2.0 Hz, 1H), 8.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (dd, J = 8.0, 4.4 Hz, 1H), 7.17 (d, J = 10.8 Hz, 1H), 7.07 (d, J = 10.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.5, 183.2, 154.8, 147.4, 139.1, 138.0, 134.6, 129.1, 127.9; HRMS (ESI) m/z calcd for C9H5NaNO2 ([M + Na]+) 182.0212, found 182.0211. (S)-2-(1,3-Dioxoisoindolin-2-yl)-3-methylbutanamide (6). The product was isolated by flash chromatography (eluent: EA/PE = 1/ 2) as a white solid (56 mg, 76%): mp 176−178 °C; 1H NMR (600 MHz, CDCl3) δ 7.89−7.86 (m, 2H), 7.79−7.75 (m, 2H), 6.95 (s, 1H), 6.03 (s, 1H), 4.40 (d, J = 11.4 Hz, 1H), 2.89−2.81 (m, 1H), E

DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry CDCl3) δ 170.6, 167.9, 136.5, 134.4, 131.4, 128.9, 128.7, 127.1, 123.6, 55.6, 34.9; HRMS (ESI) m/z calcd for C17H14N2NaO3 ([M + Na]+) 317.0897, found 317.0890. (S)-2-(1,3-Dioxoisoindolin-2-yl)-3-(p-tolyl)propanamide (14). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (76 mg, 85%): mp 235−236 °C; 1H NMR (400 MHz, CDCl3) δ 7.82−7.75 (m, 2H), 7.68−7.71 (m, 2H), 7.05− 7.06 (m, 2H), 7.00−6.98 (m, 2H), 6.13 (s, 1H), 5.67 (s, 1H), 5.12− 5.07 (m, 1H), 3.51 (dd, J = 8.4, 2.4 Hz, 2H), 2.22 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 167.9, 136.7, 134.4, 133.4, 131.5, 129.4, 128.7, 123.6, 55.7, 34.5, 21.0; HRMS (ESI) m/z calcd for C18H16N2NaO3 ([M + Na]+) 331.1053, found 331.1021. (1S,2S)-3-Amino-2-(1,3-dioxoisoindolin-2-yl)-3-oxo-1-phenylpropyl Acetate (15). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (92 mg, 87%): mp 128−130 °C; 1H NMR (600 MHz, CDCl3) δ 7.73−7.71 (m, 2H), 7.67−7.64 (m, 2H), 7.35 (d, J = 7.3 Hz, 2H), 7.21−7.14 (m, 3H), 6.75 (d, J = 10.4 Hz, 1H), 6.62 (s, 1H), 5.78 (s, 1H), 5.26 (d, J = 10.4 Hz, 1H), 2.11 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.4, 168.5, 167.3, 135.8, 134.4, 131.1, 129.1, 128.5, 127.5, 123.6, 72.6, 56.9, 21.1; HRMS (ESI) m/z calcd for C19H16N2NaO5 ([M + Na]+) 375.0951, found 375.0948. (2R,3S)-2-(1,3-Dioxoisoindolin-2-yl)-3-phenyl-3-(trimethylsilyl)propanamide (16). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (80 mg, 73%): mp 209−210 °C; 1H NMR (400 MHz, CDCl3) δ 7.67−7.58 (m, 4H), 7.20 (s, 1H), 7.06 (t, J = 7.4 Hz, 2H), 6.96−6.89 (m, 3H), 5.60 (s, 1H), 5.33 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 13.6 Hz, 1H), 0.06 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 173.5, 170.6, 141.4, 136.2, 133.1, 130.3, 127.6, 125.4, 60.5, 39.1, 0.0; HRMS (ESI) m/z calcd for C20H22N2NaO3Si ([M + Na]+) 389.1292, found 389.1290. (S)-3-(4-(Benzyloxy)phenyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (17).21 The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (58 mg, 48%): mp 150−151 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (m, 2H), 7.71 (m 2H), 7.39−7.28 (m, 5H), 7.09 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.12 (s, 1H), 5.47 (s, 1H), 5.09 (t, J = 8.4 Hz, 1H), 4.95 (s, 2H), 3.50 (d, J = 8.4 Hz, 2H); HRMS (ESI) m/z calcd for C24H20N2NaO4 ([M + Na]+) 423.1315, found 423.1316. (S)-2-(1,3-Dioxoisoindolin-2-yl)-3-(4-methoxyphenyl)propanamide (18). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (49 mg, 50%): mp 185−187 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.15 (s, 1H), 5.63 (s, 1H), 5.08 (t, J = 8.6 Hz, 1H), 3.70 (s, 3H), 3.49 (d, J = 8.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 168.0, 158.5, 134.3, 131.4, 129.9, 128.4, 123.6, 114.1, 55.7, 55.2, 34.0; HRMS (ESI) m/z calcd for C18H16N2NaO4 ([M + Na]+) 347.1002, found 347.1000. (S)-3-(1,3-Dioxoisoindolin-2-yl)-1-azaspiro[4.5]deca-6,9-diene2,8-dione (19). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (18 mg, 20%): mp 150−151 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 5.4, 3.0 Hz, 2H), 7.77 (dd, J = 5.6, 2.8 Hz, 2H), 7.11 (dd, J = 10.0, 3.2 Hz, 1H), 6.95 (dd, J = 10.0, 3.2 Hz, 1H), 6.37−6.23 (m, 3H), 5.18 (t, J = 10.0 Hz, 1H), 2.75 (dd, J = 13.4, 10.2 Hz, 1H), 2.59 (dd, J = 13.4, 9.8 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ 184.2, 171.5, 167.3, 149.2, 148.3, 134.6, 131.7, 129.6, 128.7, 123.8, 54.5, 48.1, 35.7; HRMS (ESI) m/z calcd for C17H12N2NaO4 ([M + Na]+) 331.0689, found 331.0685. 2-((7aS,12bS,14S)-15-Oxo-8-tosyl-7a,8,14,15-tetrahydro-13Hindolo[3′,2′:5,6]pyrrolo[1′,2′:4,5][1,4]oxazino[2,3-h]quinolin-14-yl)isoindoline-1,3-dione (21). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (139 mg, 74%): mp 219−221 °C; 1H NMR (600 MHz, CDCl3) δ 8.97 (d, J = 3.6 Hz, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.93−7.90 (m, 2H), 7.92 (s, 1H), 7.78−7.76 (m, 2H), 7.68 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 6.6 Hz, 3H), 7.25−7.23 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 9.0 Hz, 1H), 6.43 (d, J = 11.4 Hz, 1H), 5.35 (t, J = 10.2 Hz, 1H), 2.85−2.75 (m, 2H), 2.45

(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.2, 167.3, 151.4, 150.1, 144.9, 143.8, 140.2, 136.5, 135.6, 134.5, 131.7, 130.7, 130.5, 129.9, 127.9, 127.6, 125.2, 124.9, 124.6, 123.8, 120.3, 120.2, 117.8, 113.3, 95.6, 67.5, 48.9, 36.0, 21.7; HRMS (ESI) m/z calcd for C35H25N4O6S ([M + H]+) 629.1489, found 629.1480. Benzyl (S)-(1-Amino-1-oxopropan-2-yl)carbamate (22). The product was isolated by flash chromatography (eluent: EA/PE = 1/ 2) as a red solid (33 mg, 50%): mp 157−158 °C; 1H NMR (400 MHz, CDCl3) δ 7.40−7.30 (m, 5H), 6.09 (s, 1H), 5.53 (s, 1H), 5.36 (s, 1H), 5.11 (s, 2H), 4.32−4.21 (m, 1H), 1.40 (d, J = 7.2 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 143.8, 141.3, 127.8, 127.1, 125.1, 120.0, 66.9, 47.2, 28.4; HRMS (ESI) m/z calcd for C11H14N2NaO3 ([M + Na]+) 245.0897, found 245.0896. (9H-Fluoren-9-yl)methyl (S)-(1-Amino-1-oxopropan-2-yl)carbamate (23).22 The product was isolated by flash chromatography (eluent: EA/PE = 1/5) as a white solid (34 mg, 37%): mp 187−189 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 6.05 (s, 1H), 5.66−5.52 (m, 1H), 5.42 (s, 1H), 4.52−4.38 (m, 2H), 4.35−4.15 (m, 2H), 1.40 (d, J = 5.6 Hz, 3H); HRMS (ESI) m/z calcd for C18H18N2NaO3 ([M + Na]+) 333.1210, found 333.1203. (9H-Fluoren-9-yl)methyl (S)-2-((S)-2-Carbamoylpyrrolidine-1carbonyl)pyrrolidine-1-carboxylate (25). The product was isolated by flash chromatography (eluent: EA/PE = 1/3) as a white solid (101 mg, 78%): mp 157−159 °C; 1H NMR (400 MHz, DMSO) δ 7.91− 7.88 (m, 2H), 7.68−7.54 (m, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.36− 7.30 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 6.83 (s, 1H), 4.47−4.14 (m, 5H), 3.64−3.06 (m, 5H), 2.19−2.12 (m, 1H), 2.03−1.88 (m, 4H), 1.81−1.73 (m, 2H); 13C{1H} NMR (150 MHz, DMSO) δ 174.0, 173.9, 170.4, 170.3, 154.3, 154.2, 144.5, 144.4, 144.3, 141.2, 141.2, 128.2, 128.1, 127.6, 127.5, 125.6, 125.4, 125.3, 120.6, 120.5, 66.9, 66.6, 59.9, 59.0, 58.4, 57.8, 48.7, 29.9, 29.5, 29.1, 24.9, 24.2, 23.0; HRMS (ESI) m/z calcd for C25H27N3NaO4 ([M + Na]+) 456.1894, found 456.1890. (9H-Fluoren-9-yl)methyl (2-((2-Amino-2-oxoethyl)amino)-2oxoethyl)carbamate (26). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (90 mg, 85%): mp 193−195 °C; 1H NMR (600 MHz, DMSO) δ 8.04 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.57 (s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.24 (s, 1H), 7.07 (s, 1H), 4.29 (d, J = 6.6 Hz, 2H), 4.24 (d, J = 6.6 Hz, 1H), 3.64 (t, J = 6.6 Hz, 4H); 13C{1H} NMR (150 MHz, DMSO) δ 171.3, 169.7, 157.0, 144.3, 141.2, 128.1, 127.6, 125.7, 120.6, 66.2, 47.1, 44.0, 42.3; HRMS (ESI) m/z calcd for C19H19N3NaO4 ([M + Na]+) 376.1268, found 376.1265. (9H-Fluoren-9-yl)methyl (2-((2-Amino-2-oxoethyl)(propionyloxy)amino)-2-oxoethyl)carbamate (27). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (110 mg, 86%): mp 163−165 °C; 1H NMR (600 MHz, DMSO) δ 7.90 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 5.7 Hz, 1H), 7.49 (s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.08 (s, 1H), 4.32−4.28 (m, 4H), 4.22−4.18 (m, 4H), 1.26−1.21 (m, 4H); 13C{1H} NMR (150 MHz, DMSO) δ 172.5, 169.4, 157.0, 154.0, 144.3, 141.2, 128.1, 127.6, 125.7, 120.6, 66.2, 63.4, 47.1, 46.7, 46.3, 14.4; HRMS (ESI) m/z calcd for C22H23N3NaO6 ([M + Na]+) 448.1479, found 448.1473. N-((S)-1-(((R)-1-(((S)-1-Amino-6-(1,3-dioxoisoindolin-2-yl)-1-oxohexan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-6-(1,3-dioxoisoindolin-2-yl)-1-oxohexan-2-yl)palmitamide (28). The product was isolated by flash chromatography (eluent: EA/PE = 10/1) as a white solid (230 mg, 88%): mp 210−211 °C; 1H NMR (400 MHz, CDCl3) δ 7.87−7.79 (m, 4H), 7.73 (d, J = 2.0 Hz, 4H), 6.77 (d, J = 10.0 Hz, 1H), 6.62 (d, J = 9.2 Hz, 1H), 6.55 (s, 1H), 6.39−6.22 (m, 3H), 5.45 (s, 2H), 4.34−4.22 (m, 3H), 3.72−3.64 (m, 4H), 2.36− 2.20 (m, 7H), 2.04−1.61 (m, 12H), 1.38 (s, 8H), 0.95−0.86 (m, 20H); 13C{1H} NMR (150 MHz, MeOD) δ 171.6, 168.5, 134.0, 132.0, 122.7, 67.5, 60.1, 56.9, 37.1, 35.3, 31.7, 29.8, 29.4, 29.1, 29.1, 29.0, 28.9, 27.8, 25.6, 25.1, 22.9, 22.3, 19.5, 18.5, 17.0, 16.5, 13.1; HRMS (ESI) m/z calcd for C49H70N6NaO8 ([M + Na]+) 893.5147, found 893.5144. F

DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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3-Phenylpropanamide (29). The product was isolated by flash chromatography (eluent: EA/PE = 4/1) as a white solid (40 mg, 90%): mp 119−121 °C; 1H NMR (400 MHz, CDCl3) δ 7.26−7.32 (m, 2H), 7.20 (d, J = 6.8 Hz, 3H), 5.74 (s, 1H), 5.44 (s, 1H), 2.97 (t, J = 7.8 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.7, 140.7, 128.6, 128.3, 126.3, 37.5, 31.4; HRMS (ESI) m/z calcd for C9H11NNaO ([M + Na]+) 172.0733, found 172.0733. Benzamide (30). The product was isolated by flash chromatography (eluent: EA/PE = 1/2) as a white solid (35 mg, 95%): mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.84−7.79 (m, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 6.23 (s, 2H); 13 C{1H} NMR (150 MHz, CDCl3) δ 169.7, 133.4, 132.0, 128.6, 127.4; HRMS (ESI) m/z calcd for C7H8NO ([M + H]+) 122.0600, found 122.0604. [1,1′-Biphenyl]-2-carboxamide (31). The product was isolated by flash chromatography (eluent: EA/PE = 1/4) as a white solid (55 mg, 93%): mp 158−160 °C; 1H NMR (600 MHz, CDCl3) δ 7.77 (dd, J = 7.5, 0.9 Hz, 1H), 7.50 (td, J = 7.2, 1.2 Hz, 1H), 7.45−7.41 (m, 5H), 7.41−7.38 (m, 1H), 7.36 (dd, J = 7.5, 0.9 Hz, 1H), 5.76 (s, 1H), 5.28 (s, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.4, 140.2, 139.9, 134.4, 130.6, 130.4, 129.1, 128.8, 128.7, 128.0, 127.6; HRMS (ESI) m/z calcd for C13H11NNaO ([M + Na]+) 220.0733, found 220.0731. N-(2-Carbamoylphenyl)-4-methylbenzamide (32).23 The product was isolated by flash chromatography (eluent: EA/PE = 1/2) as a white solid (71 mg, 93%): mp 183−186 °C; 1H NMR (600 MHz, MeOD) δ 8.70 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 7.9, 1.2 Hz, 1H), 7.58−7.53 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 2.43 (s, 3H); HRMS (ESI) m/z calcd for C15H14N2NaO2 ([M + Na]+) 277.0947, found 277.0942. (S)-2-(1,3-Dioxoisoindolin-2-yl)-3-phenylpropanoic acid (33). The product was isolated by flash chromatography (eluent: EA/PE = 2/1) as a white solid (82 mg, 94%): mp 181−185 °C; 1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 7.79−7.77 (m, 2H), 7.69−7.66 (m, 2H), 7.19−7.13 (m, 5H), 5.23 (t, J = 8.2 Hz, 1H), 3.60 (d, J = 8.4 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 174.8, 167.4, 136.4, 134.2, 131.5, 128.8, 128.6, 127.0, 123.6, 53.1, 34.4; HRMS (ESI) m/z calcd for C17H13NNaO4 ([M + Na]+) 318.0737, found 318.0735. (2S,3S)-3-Acetoxy-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic Acid (34). The product was isolated by flash chromatography (eluent: EA/PE = 2/1) as a white solid (98 mg, 93%): mp 141−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.72−7.71 (m, 2H), 7.66−7.64 (m, 2H), 7.32 (d, J = 4.4 Hz, 2H), 7.19−7.14 (m, 3H), 6.69−6.67 (m, 1H), 5.34−5.33 (m, 1H), 2.11 (s, 3H); 13C{1H} NMR (150 MHz, MeOD) δ 170.4, 167.4, 137.6, 133.9, 131.5, 127.9, 127.6, 127.3, 122.6, 74.1, 55.9, 19.9; HRMS (ESI) m/z calcd for C19H15NNaO6 ([M + Na]+) 376.0792, found 376.0790.

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ACKNOWLEDGMENTS We thank Prof. Bingfeng Shi at Zhejiang University and Prof. Jie Wu at Fudan University for providing selected starting materials for testing this AQ cleavage method. We thank the NSFC (U1604285, 21772032, and 21702051), PCSIRT (IRT1061), the 111 Project (D17007), Henan Provincial Natural Science Foundation (162300410180), Science & Technology Innovation Talents in Universities of Henan Province (17HASTIT002), and Program for Innovative Research Team of Science and Technology in the University of Henan Province (18IRTSTHN004).

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01362. HPLC data; 1H and 13C NMR spectra of all new compounds (PDF) X-ray crystallographic data for compound 21 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Zhiguo Zhang: 0000-0001-6920-0471 Guisheng Zhang: 0000-0001-9880-950X Gong Chen: 0000-0002-5067-9889 Notes

The authors declare no competing financial interest. G

DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

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DOI: 10.1021/acs.joc.9b01362 J. Org. Chem. XXXX, XXX, XXX−XXX