高价碘直接氧化α氨基酸

moleculesLetterA Novel Synthesis of 4-Acetoxyl 5(4H )-Oxazolones by Direct α-Oxidation of N -Benzoyl Amino-Acid Using Hypervalent IodineGang Wen, Wen-Xuan Zhang * and Song Wu *State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; wengang@ * Correspondences: wxzhang@ (W.-X.Z); ws@ (S.W.); Tel.: +86-010-8316-3542 (S.W.) Received: 17 June 2017; Accepted: 29 June 2017; Published: 3 July 2017Abstract: We have developed a new method to prepare 4-acetoxy substituted 5(4H)-oxazolones by direct oxidation of N-benzoyl amino-acids using hypervalent iodine. The method is efficient, economical and easy to perform for the synthesis of quaternary substituted amino acid derivatives. We used online FTIR monitoring techniques to analyze the reaction, and gave a plausible reaction mechanism. Keywords: oxidation; hypervalent iodine; 4-acetoxyl 5(4H)-oxazolones; N-benzoyl amino-acid; online FTIR1. Introduction 2-Substituted amino acids and their derivatives are known as structural elements with important physiology [1–3]. As an important synthetic intermediate of 2-substituted amino acids, 2-acetoxy-2-amino acids have attracted tremendous interest in organic synthesis [4]. However, to date, chemists have only reported a few methods to synthesize these amino acids, such as oxidating the protected cystinylserine with Pb(OAc)4 to the 2-acetoxy compound [5–7], using 2-benzamidotrifluorolactic acid as starting materials to yield 4-acetoxy-4-trifluoromethyl-2-phenyloxazol-5(4H)-one [8], treating oxazolone with mercuric acetate to form the diacetyl compound [9], transforming 2-acylaminoacrylate with N-chlorosuccinimide/HCl/LiOAc in acetic acid to the 2-acetoxy-2-amine acid derivatives [2], converting β-lactams with ruthenium trichloride in the presence of acetaldehyde and acetic acid with molecular oxygen into the corresponding 4-acyloxy β-lactams [10], and using anodic oxidation of 2-ethoxycarbonyl-2-acetamidoacetic acid derivatives, followed by saponification of the one ester groups to 2-alkoxy-2-amino acids and 2-acetoxy-2-amino acids [11]. There are some problems in these methods: 1. It is difficult to prepare the raw materials; 2. The use of metal reagents is expensive and not environmentally-friendly. Metal-free reagents such as hypervalent iodine compounds have received much attention for low toxicity, mild reaction condition, easy handling and special reactivity compared with heavy metal reagents in organic synthesis reactions. Furthermore, hypervalent iodine reagents have been widely used in various oxidations, such as oxidative dearomatized reactions [12,13], oxidative coupling reactions [14,15], oxidative halogenation reactions [16–18], oxidative cyclization reactions [19], oxidative addition [20,21], oxidative amination reaction [22], and so on. Boto synthesized 2-acetoxy glycine through an unstable α-iodoglycine intermediate, which was then substituted by acetate ions from the reagent PhI(OAc)2 (Scheme 1a) [23]. Recently, Xu’s group developed a cobalt-catalyzed decarboxylative C−O bond-forming reaction using hypervalent iodine as oxidizing agent (Scheme 1a). However, these methods involve deiodination or decarboxylativeMolecules 2017, 22, 1102; doi:10.3390/molecules22071102 /journal/moleculesMolecules 2017, 22, 1102 Molecules 2017, 22, 11022 of 6 2 of 7Molecules 2017, 22can , 1102 of 6 process, which only give tertiary substituted carbon atoms. Herein, we wish to report a2direct oxidation of α -C–H bond of N -benzoyl amino-acid using hypervalent iodine (Scheme 1b). With this process, which can only give tertiary substituted carbon atoms. Herein, we wish to report a direct process, which can only give tertiary substituted carbon atoms. Herein, we wish to report a direct method, a of new synthesis substituted 5(using 4H)-oxazolones was carried out. There are three oxidation α-C–H bondof of 4-acetoxy N-benzoyl amino-acid hypervalent iodine (Scheme 1b). With this oxidation of α-C–H bond of N-benzoyl amino-acid using hypervalent iodine (Scheme 1b). With this advantages in our method: 1. Only hypervalent iodine oxidizing agent was used, which was cheap method, a new synthesis of 4-acetoxy H)-oxazolones )-oxazoloneswas was carried out. There are three method, a new synthesis of 4-acetoxysubstituted substituted 5(4 5(4H carried out. There are three and easy to get; 2. Our method can directly oxidize the αoxidizing -C–H bond of amino acid derivatives, which advantages in our method: 1. Only hypervalent iodine agent was used, which was cheap advantages in our method: 1. Only hypervalent iodine oxidizing agent was used, which was cheap doeseasy nottoinvolve deiodination or decarboxylative process; 3. With this method, quaternary and get; 2.2. Our method the α α -C–Hbond bond of amino acid derivatives, which and easy to get; Our methodcan candirectly directly oxidize oxidize the -C–H of amino acid derivatives, which substituted amino acid derivatives could be prepared. does notnot involve deiodination or decarboxylative process; 3. With3. this method, substituted does involve deiodination or decarboxylative process; With this quaternary method, quaternaryamino acid derivatives could be prepared. substituted amino acid derivatives could be prepared.Scheme 1. Hypervalent iodine-mediated oxidation of 2-amino acids. Scheme 1.1. Hypervalent oxidationof of2-amino 2-amino acids. Scheme Hypervalent iodine-mediated iodine-mediated oxidation acids.2. Results 2. Results 2. Results Reaction of N-benzoyl isoleucine (1a) with 1.0 equiv PhI(OCOCF3)2 in acetic anhydride and Reaction -benzoylisoleucine isoleucine (( 1a with 1.0 1.0 equiv equiv PhI(OCOCF PhI(OCOCF3) in acetic anhydride and Reaction ofof NN -benzoyl 1a )) with in acetic anhydride and 32)2 toluene (v/ v = 4:1) atat 60 °C for 1.5 h gave 4-acetoxy substituted5( 5( 4H )-oxazolone (1b ) as oxidative ◦ toluene ( v / v = 4:1) 60 °C for 1.5 h gave 4-acetoxy substituted 4H )-oxazolone ( 1b ) as oxidative toluene (v/v = 4:1) at 60 C for 1.5 h gave 4-acetoxy substituted 5(4H)-oxazolone (1b) as oxidative 3)2 give much better product in 40% yield (dr = 1:1,Table 1). We found that 1.5 1.5 equiv equivof of PhI(OCOCF 3)2 give much better product 40% yield (dr 1:1,Table1). 1).We Wefound found that that product in in 40% yield (dr == 1:1,Table 1.5 equiv of PhI(OCOCF PhI(OCOCF 3 )2 give much better yield, but the increase of PhI(OCOCF 3)2 to 3.0 equivalent afford lower yield (entry 2–3). Replacement yield, but the increase PhI(OCOCF 3)2 to 3.0 equivalent afford lower yield (entry 2–3). Replacement yield, but the increase of of PhI(OCOCF 3 )2 to 3.0 equivalent afford lower yield (entry 2–3). Replacement of of of PhI(OCOCF 3 ) 2 with PhI(OAc) 2 or PhI(OPiv) to the the reducing reducingof ofthe the yield, and the latter gave PhI(OCOCF 3)2 with PhI(OAc)2 or PhI(OPiv)2 2 led led to yield, and the latter gave PhI(OCOCF 3 )2 with PhI(OAc)2 or PhI(OPiv)2 led to the reducing of the yield, and the latter gave only only 19% yield (entry 5–6). In the absence of PhI(OCOCF 3 ) 2 , only oxazolones ( 1c ) was afforded, which only 19% yield (entry 5–6). In the absence of PhI(OCOCF3)2, only oxazolones (1c) was afforded, which 19% yield (entry 5–6). In the absence of PhI(OCOCF3 )2 , only oxazolones (1c) was afforded, which can can give desired product with addition additionof ofPhI(OCOCF PhI(OCOCF 2 (see can give desired product1b 1b by by the the oxidative oxidative annulation annulation with 3)2 3) (see give desired product 1b by the oxidative annulation with addition of PhI(OCOCF3 )2 (see supporting 2 2 gave product without without desired desiredproduct. product. The supporting gave only only coupling coupling product The supportingInformation). Information). AgF AgF Information). AgF2 gave only coupling product without desired product. The temperature also has temperature also has great influence reaction,which whichgave gave lower yields at 30 °C and temperature also has great influenceon onthis this oxidation oxidation reaction, lower yields at 30 °C and great influence on this oxidation reaction, which gave lower yields at 30 ◦ C and 90 ◦ C (entry 7–8). (entry 7–8). Further assessmentof ofthe the solvent solvent effect toluene was the best solvent 90 90 °C°C (entry 7–8). Further assessment effect indicated indicatedthat that toluene was the best solvent Further assessment of the solvent effect indicated that toluene was the best solvent for this reaction, this reaction, providinghigher higher yield yield than than other commonly such asas ACN, DCE, forfor this reaction, providing commonly used usedsolvents solvents such ACN, DCE, providing higher yield than other commonly used solvents such as ACN, DCE, Acetone and THF Acetone and THF (entry 10–13). Acetone and THF (entry 10–13). (entry 10–13).Table Direct -oxidationof ofN N-benzoyl -benzoyl amino-acid iodine. Table 1.1. Direct αα -oxidation amino-acidusing usinghypervalent hypervalent iodine. Table 1. Direct α-oxidation of N-benzoyl amino-acid using hypervalent iodine.Entry EntryEntry 1 11 2 2 2 3 3 43 4 54 5 65 6 7 67 7Oxidant(equiv) (equiv) Oxidant Oxidant (equiv) PhI(OCOCF3)2 (1) PhI(OCOCF3 ) 2 (1) (1) PhI(OCOCF 3)2 PhI(OCOCF3 )2 (1.5) PhI(OCOCF ) (1.5) 3 2 PhI(OCOCF 3)2 (1.5) PhI(OCOCF 3)2 (3) PhI(OCOCF 3 )2 (3) PhI(OCOCF 3 ) 2 (3) PhI(OCOCF 3) (0) PhI(OCOCF 3) 22 (0) PhI(OCOCF 3 ) 2 (0) PhI(OAc) (1.5) 22 (1.5) PhI(OAc) PhI(OPiv) (1.5) 22 PhI(OAc) 2 (1.5) PhI(OPiv) (1.5) AgF2 (1.5) PhI(OPiv) 2 (1.5) AgF2 (1.5) AgF2 (1.5)Temp Temp (°C) (◦ C) Temp (°C) 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60a Solvent Solvent Yield (%) Yield (%) a Solvent Yield (%) a toluene 40 toluene toluene 40b) 40 b toluene 68 (63 toluene 68 (63 ) toluene 68 (63 b) toluene 50 toluene 50 toluene 50 no toluene no toluene toluene no 42 toluene toluene 42 toluene toluene 42 19 toluene 19 toluene toluene 19 no toluene notoluenenoMolecules 2017, 22, 11023 of 7Molecules 2017 ,22 22 ,1102 1102 Molecules Molecules 2017 , 22 ,22 1102 Molecules 2017 , Molecules 2017 ,,2017 22 ,, 1102 Molecules 2017 22 1102 , ,1102 Molecules 2017 , 22 1102 Molecules 2017 , 22 , 1102 Molecules 2017 , 22 1102 Molecules 2017 , 22 ,, ,1102Table 1. Cont.of 3 of of 66 3 of 6 3 of 6 3 of 666 3 of 63 3 of 33 of 6 3 of 613 based onPhI(OCOCF 60 THF no a Yields were 3 )2 (1.5) 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid aaYields Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid a were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid Yields were based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid a Yieldsbwere b based on 1H NMR analysis of reaction mixture after 1.5 h using (2 E )-2-Butenedioic acid as standard; b Isolated bb b b as standard; Isolated yields. b b as standard; yields. as standard; Isolated yields. b as standard; Isolated yields. b as standard; Isolated yields. b as standard; standard; Isolated yields. Isolated yields. as as standard; Isolated yields. asstandard; standard; Isolated yields. as Isolated yields. ba aa a a aa a8PhI(OCOCF PhI(OCOCF (1.5) PhI(OCOCF 3 ) 2 (1.5) PhI(OCOCF 33 ) 22(1.5) PhI(OCOCF 2 (1.5) 3 2 3 2 3) 2) 8Entry PhI(OCOCF 32 ) 2 (1.5) PhI(OCOCF 3 ) (1.5) 8 888 3)3 2) (1.5) 88 PhI(OCOCF 3 2 (1.5) Oxidant (equiv) 9PhI(OCOCF PhI(OCOCF (1.5) 3 2 9 PhI(OCOCF ) 22 (1.5) PhI(OCOCF 3 2 (1.5) PhI(OCOCF 3 ) (1.5) PhI(OCOCF 3 ) 2 PhI(OCOCF 33 )3 2) (1.5) 999 3) 2) (1.5) 32 2(1.5) 3 99 PhI(OCOCF ) (1.5) 9 9 PhI(OCOCF )2 (1.5) 3 2 8 PhI(OCOCF ) (1.5) 3 2 10 PhI(OCOCF 3 ) 2 (1.5) 3 2 10 PhI(OCOCF 3 ) 2 (1.5) 10 PhI(OCOCF 3 ) 2 (1.5) 10 PhI(OCOCF 3 ) 2 (1.5) 10 PhI(OCOCF 3 ) 2 (1.5) 3)2 2 (1.5) 32 10 10 3)2 3 (1.5) PhI(OCOCF ) 10 10 PhI(OCOCF )2(1.5) (1.5) PhI(OCOCF 3 9 PhI(OCOCF PhI(OCOCF 3 )2 (1.5) 11 PhI(OCOCF ) (1.5) 11 PhI(OCOCF 3 ) 2 (1.5) 11 PhI(OCOCF 33 ) 22(1.5) 11 PhI(OCOCF 2 (1.5) 3 2 3 2 3) 2) 11 11 PhI(OCOCF 32 ) 2 (1.5) 11 PhI(OCOCF 3 ) (1.5) 11 PhI(OCOCF 3)3 2) (1.5) 10 PhI(OCOCF (1.5) PhI(OCOCF 3 2 (1.5) 3 2 12 PhI(OCOCF 3 ) 2 (1.5) 3 2 12 PhI(OCOCF 3 ) 2 (1.5) 12 PhI(OCOCF 3 ) 2 (1.5) 12 PhI(OCOCF 3 ) 2 (1.5) 12 PhI(OCOCF 3 ) 2 (1.5) 11 PhI(OCOCF ) 12 PhI(OCOCF 3 ) 2 (1.5) 12 PhI(OCOCF 3 ) 2 (1.5) 3 2 3 3 )2 12 PhI(OCOCF 12 PhI(OCOCF ) (1.5) (1.5) 3 2 2 (1.5) 12 PhI(OCOCF ) 2(1.5) (1.5) 13 PhI(OCOCF 3 (1.5) 3 2 3 13 PhI(OCOCF 3 ) 13 PhI(OCOCF 3 ) 2 (1.5) 13 PhI(OCOCF 3 ) 2 (1.5) 3 2 3)2 222 32 PhI(OCOCF ) 1313 3)2 3 (1.5) 13 13 PhI(OCOCF PhI(OCOCF )2(1.5) (1.5) PhI(OCOCF 3 (1.5)30 ◦toluene toluene 38 38 30 toluene 30 toluene 38 30 toluene 3838 30 toluene 38 38 30 30 30 toluene Temp ( C)toluene Solvent 38 Yield (%) a 90 toluene 43 90 toluene 43 90 toluene 43 90 toluene 43 90 toluene 43 90 toluene 43 90 toluene 43 90 toluene 43 90 toluene 43 30 toluene 60 ACN 50 38 60 ACN 50 60 ACN 50 60 ACN 50 60 ACN 50 60 ACN 50 60 ACN 50 60 60 ACN 50 50 ACN 90 toluene 43 60 DCE 43 50 60 DCE 43 60 DCE 43 60 DCE 43 60 60 DCE 43 43 60 DCE 43 60 60 DCE ACN 43 DCE 60 Acetone 8 43 60 Acetone 8 60 Acetone 60 Acetone 60 Acetone 60 Acetone DCE 888 Acetone 60 60 Acetone 88 60 60 Acetone 8 8 60 Acetone 8 60 THF no 60 THF no 60 THF no 60 THF no THF 6060 THF nono 60 60 THF nono THFIsolated yields.With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino With the optional conditions in hand, we then examined the substrate scope of Nbenzoyl amino acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid ( – gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid ( 2a – 10a gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid (2a –– 10a ) gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid ( – 10a ) gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid ( 2a 10a ) gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid ( 2a – 10a ))) gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid (2a 10a )2a gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid (– 2a – 10a ) gave acid substrates (Table 2). Both  -alkyl and benzyl substituted N -benzoyl amino-acid (2a 2a – 10a )10a gave acid substrates (Table 2). Both α -alkyl and benzyl substituted N-benzoyl amino-acid ( 2a –10a ) gave desired 4-acetoxyl 5( 4H )-oxazolones ( 2b – 10b ) in moderated yields with some coupling products in desired 4-acetoxyl 5( 4H )-oxazolones ( 2b – 10b ) in moderated yields with some coupling products in desired 4-acetoxyl 5( 4H )-oxazolones ( 2b – 10b ) in moderated yields with some coupling products in desired 4-acetoxyl 5( 4H )-oxazolones ( 2b – 10b ) in moderated yields with some coupling products in desired 4-acetoxyl 5( 4H )-oxazolones ( 2b – 10b ) in moderated yields with some coupling products in desired 4-acetoxyl 5(4H )-oxazolones (2b –2b 10b )– in moderated yields with some coupling products in in desired 4-acetoxyl 5( 4H )-oxazolones (2b – 10b ) )in yields with some coupling products desired 4-acetoxyl 5( 4H )-oxazolones ( 10b in moderated yields with some coupling products in in desired 4-acetoxyl 5( 4H )-oxazolones (– 2b 10b )moderated in moderated yields with some coupling products desired 4-acetoxyl 5(4 H )-oxazolones ( 2b – 10b ) in moderated yields with some coupling products 0–20% yields (except for 1a , see supporting information). Beside coupling products,  -alkyl 0–20% yields (except for 1a , see supporting information). Beside coupling products,  -alkyl 0–20% yields (except for 1a , supporting see supporting information). Beside coupling products,  -alkylin 0–20% yields (except for 1a , see information). Beside coupling products, -alkyl 0–20% yields (except for 1a ,1a see supporting information). Beside coupling products,  -alkyl 0–20% yields (except for 1a , see see supporting information). Beside coupling products,  -alkyl 0–20% yields (except for 1a , information). Beside coupling products,  -alkyl 0–20% yields (except for ,supporting see supporting information). Beside coupling products,  -alkyl 0–20% yields (except for 1a , see supporting information). Beside coupling products, α -alkyl substrates substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide inabout about 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in about 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in about 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in about 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in about 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in about 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in about 20% substrates 3a and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide in about 20% 3awhile and 5a also gave rearrangement product N -(1-oxo-alkyl)-benzamide inproducts about 20% yields, while yields, while substituted Nbenzoyl amino-acids ( 6a – 10a ) gave some elimination products in about yields, while substituted Nbenzoyl amino-acids ( 6a – 10a ) gave some elimination products in about yields, while substituted Nbenzoyl amino-acids ( 6a – 10a ) gave some elimination in about yields, substituted Nbenzoyl amino-acids ( 6a – 10a ) gave some elimination products in about yields, while substituted benzoyl amino-acids (– 6a – 10a ) some elimination products yields, while substituted N-Nbenzoyl amino-acids (6a 10a )– gave elimination products in in about yields, while substituted Nbenzoyl amino-acids (6a 10a )gave gave some elimination products inabout about yields, while substituted N-benzoyl amino-acids (– 6a 10a ) some gave some elimination products in about substituted Nbenzoyl amino-acids (6aIn –10a ) gave some elimination products in groups about 10–30% yields 10–30% yields (see supporting Information). In these conditions, ether and ester groups were very 10–30% yields (see supporting Information). In these conditions, ether and ester groups were very 10–30% yields (see supporting Information). In these conditions, ether and ester groups were very 10–30% yields (see supporting Information). these conditions, ether and ester groups were very 10–30% yields (see supporting Information). In these conditions, ether and ester were very 10–30% yields (see supporting Information). In these conditions, ether and ester groups were very 10–30% yields (see supporting Information). these conditions, ether and ester groups were very 10–30% yields (see supporting Information). In In these conditions, ether and ester groups were very (see supporting Information). In these conditions, ether and ester groups were very tolerant, as shown tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. tolerant, as shown in entry 8–9. in entry 8–9.Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of Nbenzoyl amino-acids. Table 2. Substrate scope of N-benzoyl amino-acids.Products Products Products Products Products Products Products Products Products Products Products Products Products Products Products Products Products Entry Substrates Entry Substrates Substrates Products Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Substrates Entry Entry Substrates Products (Isolated Yield) Entry Substrates Products (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) (Isolated Yield) 1 1 1 1 11 11 1 1 6 6 6 6 6 66 6 6 6 2b (53%) 2b (53%) 2b (53%) 2b (53%) 2b (53%) 2b (53%) 2b (53%) 2b (53%) 2b (53%) 7 7 7 7 7 77 7 7 7 3b (47%) 3b (47%) 3b (47%) 3b (47%) 3b (47%) 3b (47%) 3b (47%) 3b (47%) 3b (47%) 8 8 8 8 8 88 8 8 8 4b (53%) 4b (53%) 4b (53%) 4b (53%) 4b (53%) 4b (53%) 4b (53%) 4b (53%) 4b (53%)9 9 9 9 99 99 9 92a 2a 2a 2a 2a 2a2a 2a 2a7a 7a 7a 7a 7a 7a 7a 7a7b (47%) 7b (47%) 7b (47%) 7b (47%) 7b (47%) 7b (47%) 7b (47%) 7b (47%) 7b (47%)2 2 2 2 22 22 2 23a 3a 3a 3a 3a3a 3a 3a 3a8a 8a 8a 8a 8a 8a 8a 8a8b (45%) 8b (45%) 8b (45%) 8b (45%) 8b (45%) 8b (45%) 8b (45%) 8b (45%) 8b (45%)3 3 3 3 33 33 3 34a 4a 4a 4a 4a4a 4a 4a 4a9a 9a 9a 9a 9a 9a 9a 9a 9a9b (51%) 9b (51%) 9b (51%) 9b (51%) 9b (51%) 9b (51%) 9b (51%) 9b (51%) 9b (51%)4 4 4 4 44 44 4 45a 5a 5a 5a 5a5a 5a 5a 5aNH NH NH NH NH NH NH NH NH NH NH NH NH NH O O O OO O O OH O OO OH OOH OH O O O O OH O O O OH O OH O O O OH O OH O OH O OH OH O OH5b (47%) 5b (47%) 5b (47%) 5b (47%) 5b (47%) 5b (47%) 5b (47%) 5b (47%) 5b (47%)10a 10a 10a 10a 10a 10a 10a 10a 10a10b (45%) 10b (45%) 10b (45%) 10b (45%) 10b (45%) 10b (45%) 10b (45%) 10b (45%) 10b (45%) 10b (45%)5 5 5 5 55 55 5 56a 6a 6a 6a 6a6a 6a 6a 6a6b (60%) 6b (60%) 6b (60%) 6b (60%) 6b (60%) 6b (60%) 6b (60%) 6b (60%) 6b (60%)3. Discussion 3. Discussion 3. Discussion 3. Discussion 3. Discussion 3. Discussion 3. Discussion 3. Discussion 3. Discussion In order tostudy study the reaction kinetics, we used online FTIR techniques (fourier-transform In order the reaction kinetics, we online FTIR (fourier-transform infrared In order to study the reaction kinetics, we used online FTIR techniques (fourier-transform In order to study the reaction kinetics, we used online FTIR techniques (fourier-transform In order to study the reaction kinetics, we used online FTIR techniques (fourier-transform In order to study the reaction kinetics, we used online FTIR techniques (fourier-transform In order to study the reaction kinetics, we used online FTIR techniques (fourier-transform In order to study the reaction kinetics, we used online FTIR techniques (fourier-transform In order to study the reaction kinetics, we used online FTIR techniques (fourier-transform In order to the reaction kinetics, we used online FTIR techniques (fourier-transform infrared spectra, React IR 15) to monitor the reaction [24–26]. At first, we collected the FTIR data of infrared spectra, React IR 15) to monitor the reaction [24–26]. At first, we collected the FTIR data of spectra, React IR 15) to monitor the [24–26]. At first, we collected FTIR data ofof raw infrared spectra, React IR 15) tomonitor monitor the reaction [24–26]. At first, we collected the FTIR data of infrared spectra, React IR 15) to monitor reaction [24–26]. At first, we collected the FTIR data of infrared spectra, React IR 15) to monitor the reaction [24–26]. At first, we collected the FTIR data of infrared spectra, React IR 15) to monitor the reaction [24–26]. At first, we collected the FTIR data of infrared spectra, React IR 15) to monitor the reaction [24–26]. At first, we collected the FTIR data of infrared spectra, React IR 15) to the reaction [24–26]. At first, we collected the FTIR data raw material 1a the intermediate 1c , PhI(OCOCF ) acetic acid, trifluoroacetic acid and product 1b 3 2 material 1a , the intermediate 1c , ,,PhI(OCOCF acid, trifluoroacetic acid and product 1b raw material 1a ,, the intermediate 1c PhI(OCOCF 3 ) 2 ,, acetic acid, trifluoroacetic acid and product 1b raw material 1a , the 1c , PhI(OCOCF 3 ) 2 , acetic acid, trifluoroacetic acid and product 1b raw material 1a ,,the the intermediate 1c ,,PhI(OCOCF PhI(OCOCF 3 ) 2 acid, trifluoroacetic acid and product 1b raw material 1a , intermediate , 3 ) 2 acid, trifluoroacetic acid and product 1b raw material 1a ,intermediate the intermediate 1c PhI(OCOCF 3acetic )3 2 ,,2 acetic acid, trifluoroacetic acid and product 3 2 raw material 1a , the intermediate 1c ,1c PhI(OCOCF 3) 2 ,3 acetic acid, trifluoroacetic acid and product 1b 3 2, 2 raw material 1a , the intermediate 1c , PhI(OCOCF ) , acetic acid, trifluoroacetic acid and product 1b raw material 1a the intermediate 1c PhI(OCOCF ), ,acetic acetic acid, trifluoroacetic acid and product 1b 1b 3 2 in the solvent (anhydrous toluene: acetic anhydride = 4:1) respectively. To prove the formation of in the solvent (anhydrous toluene: acetic anhydride = 4:1) respectively. To prove the formation of in the solvent (anhydrous toluene: acetic anhydride = 4:1) respectively. To prove the formation of in the solvent (anhydrous toluene: acetic anhydride = 4:1) respectively. To prove the formation of solvent (anhydrous toluene: acetic anhydride ==4:1) respectively. prove the formation in in the solvent (anhydrous toluene: acetic anhydride = 4:1) respectively. ToTo prove the formation of of inthe the solvent (anhydrous toluene: acetic anhydride 4:1) respectively. To prove the formation of of in the solvent (anhydrous toluene: acetic anhydride = 4:1) respectively. To prove the formation intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 3 ) 2 in the reaction system intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 3 ) 2 in reaction system intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 3 ) 2the in the reaction system intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 2 in the reaction system 3 2 3 2 intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 3 ) 2 in the reaction system intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 32 ) 2in in the reaction system intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 3 ) the reaction system intermediate 1c before the oxidative annulation, we added the PhI(OCOCF 3)3 2) in the reaction system 3 2 10 min after raw material 1a and acetic anhydride were heated at °C .experiments, In the experiments, ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 °C .the In the experiments, ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 °C .60 In the experiments, ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 In experiments, ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 °C . experiments, ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 °C .the In the experiments, ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 °C .°C In the ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 °C .. In the experiments, ReactIR 10 min after raw material 1a and acetic anhydride were heated at 60 °C .In In the experiments, ReactIR。