Copper-Catalyzed Aerobic Oxidation Strategy: A Concise Route to Isatin

Muhammad Siddique Ahmad Yamin Zhu Yunlong Guo Saisai Zhang Zengming Shen

Citation:  Ahmad Muhammad Siddique, Zhu Yamin, Guo Yunlong, Zhang Saisai, Shen Zengming. Copper-Catalyzed Aerobic Oxidation Strategy: A Concise Route to Isatin[J]. Chinese Journal of Organic Chemistry, 2019, 39(11): 3244-3249. doi: 10.6023/cjoc201903024 shu

铜催化的有氧氧化合成靛红类衍生物的方法

    通讯作者: 沈增明, shenzengming@sjtu.edu.cn
  • 基金项目:

    国家自然科学基金(No.21672144)资助项目

    国家自然科学基金 21672144

摘要: 研究了铜催化的脱羰环化生成靛红的方法,使用氧气作为最终的氧化剂.这个互补的C(sp3)—H官能团化方法为合成靛红提供了一种新方案.Cu/O2/Co体系显示出良好的反应性和兼容性,富电子和缺电子的官能团都可以很好地兼容.并基于机理研究和以前的文献报道,提出了一个可能的假设机理.

English

  • Isatins and their derivatives are a group of important structural units which have been found in many bioactive molecules.[1] Isatins are also powerful building blocks for the construction of heterocyclic systems and spirocyclic compounds.[2] Therefore, many methods have been developed for the synthesis of isatins. Traditionally, the synthesis of isatins was achieved through the methods developed by Sandmeyer, [3] Stolle, [4] and Martinet.[5] However, these methods suffer from harsh conditions, poor yields and limited substrate choices. In view of this, new synthetic methods to overcome these drawbacks are still highly required. Inspiringly, some efficient methods have been found, such as aryne-based methods, [6] transition-metal catalyzed oxidation, [7] oxidative cleavage of carbon-carbon triple bond, [8] sulfur ylide-mediated carbonyl homologation, [9] iodine-mediated oxidation, [10] and C—H amination (Scheme 1).[11] Although these methods showed some improvements, there are still many problems like the requirement of heavy metal catalysts and excess amount of bases or strong oxidants and relatively low yields of products. Thus, the development of a concise and environmentally benign process to access isatins remains highly desirable. In 2010, Li and co-workers[7c] reported a significant and elegant example concerning copper-catalyzed preparation of isatins through intramolecular aromatic C—H and aldehyde C—H dual activation to construct C—C bonds (Scheme 1). After that, Cheng and co-workers[7g] documented that 2-aminoacetophenones can undergo intramolecular cyclization to form isatins in the presence of a catalytic amount of copper salt under a balloon of O2 (Scheme 1). Inspired by these works, we envisioned a complementary way of C(sp3)—H bond functionalization catalyzed by copper to form β-ketoamide core structure. Herein, a copper-catalyzed decarbonylation cyclization to form isatins using oxygen as terminal oxidant is reported.

    Scheme 1

    Scheme 1.  Synthetic approaches for isatins

    To optimize reaction conditions, N-(2-acetylphenyl)-N-methylformamide (1a) derived from readily available 1-(2-aminophenyl)ethanone was chosen as a model substrate. Pleasingly, by using catalytic amounts of CuCl2 in the presence of THF and oxygen at 100 ℃, the conversion of 1a into the desired N-methyl isatine 2a was smoothly performed (34% yield of 2a, Table 1, Entry 1). Next, a series of other copper catalysts was screened, such as CuCl, CuBr, CuI, CuSCN, CuCN, Cu2O and Cu(OAc)2. The results exhibited that activity of these copper salts is inferiors to CuCl2 or even ineffective (Table 1, Entries 2~8). Using CuCl2 as the catalyst, a variety of Lewis acids were examined. A significant Lewis acid effect was observed. CoCl2 was the most effective Lewis acid for promoting formation of α-ketoamide structure, affording 2a in 62% isolated yield (Table 1, Entry 16). ZnCl2 and CoSO4 slightly increased yield to 40% and 45%, respectively (Table 1, Entries 9 and 15). Other Lewis acids, such as AlCl3, BF3·Et2O, FeCl3, PdCl2, Cu(ClO4)2·6H2O, Yb(OTf)3, Ni(OAc)2·4H2O, Co(NO3)2·6H2O and Cu(OAc)2·4H2O suppressed reaction and even shut down the process (Table 1, Entries 10~14 and 17~20). Interestingly, when 1 equiv. of protonic acid, PhCOOH, combined with CoCl2 (1 equiv.) was added into the reaction, the yield of 2a was increased to 69% (Table 1, Entry 24). To our surprise, when the loading of CoCl2 and PhCOOH was decreased to 20 mol% catalytic amount, the efficiency of reaction was further improved and 78% yield of 2a was obtained (Table 1, Entry 25). Notably, control experiment showed that CoCl2 could not promote this transformation in the absence of CuCl2 (Entry 26). Consequently, the optimal conditions involved the use of CuCl2 (20 mol%), CoCl2 (20 mol%), PhCOOH (20 mol%) in O2 and THF at 100 ℃.

    Table 1

    Table 1.  Optimization of reaction conditions for the synthesis of isatinsa, b
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    Entry Cat. Additive Time/h Yieldb/%
    1 CuCl2 None 49 34
    2 CuCl None 110 23
    3 CuBr None 110 17
    4 CuI None 82 N.R.
    5 CuSCN None 82 N.R.
    6 CuCN None 82 N.R.
    7 Cu2O None 110 Trace
    8 Cu(OAc)2 None 66 N.R.
    9 CuCl2 ZnCl2 (1 equiv.) 49 40
    10 CuCl2 AlCl3 (1 equiv.) 49 N.R.
    11 CuCl2 BF3·Et2O (1 equiv.) 67 N.R.
    12 CuCl2 FeCl3 (1 equiv.) 67 N.R.
    13 CuCl2 PdCl2 (1 equiv.) 67 N.R.
    14 CuCl2 Cu(ClO4)·6H2O (1 equiv.) 67 N.R.
    15 CuI CoSO4 (1 equiv.) 59 45
    16 CuSCN CoCl2 (1 equiv.) 59 62
    17 CuCN Yb(OTf)3 (1 equiv.) 48 N.R.
    18 Cu2O Ni(OAc)2·4H2O (1 equiv.) 65 16
    19 Cu(OAc)2 Co(NO3)2·6H2O (1 equiv.) 65 Trace
    20 CuCl2 Cu(OAc)2·4H2O (1 equiv.) 65 N.R.
    21 CuCl2 LiCl (1 equiv.) 49 N.R.
    22 CuCl2 CaCl2 (1 equiv.) 49 23
    23 CuCl2 CoCl2 (1 equiv.)+
    PivOH (1 equiv.)
    58 47
    24 CuCl2 CoCl2 (1 equiv.)+
    PhCOOH (1 equiv.)
    57 69
    25 CuCl2 CoCl2 (20 mol%)+
    PhCOOH (20 mol%)
    84 78
    26 None CoCl2 (1 equiv.)+
    PhCOOH (20 mol%)
    77 N.R.
    a Conditions: 1a (50 mg, 0.28 mmol), CuCl2 (20 mol%), additive (1 equiv.), THF (1.2 mL), O2, 100 ℃. b Isolated yield.

    With the optimized reaction conditions in hand, the generality and limitations of this Cu-catalyzed decarbonylation cyclization for forming isatins were explored (Table 2). A series of electron-donating and electron-withdrawing substitutents on the aromatic ring was examined. It was found that these substrates could be successfully converted to the corresponding isatins in moderate to good yields. Isatin derivatives 2f and 2g containing Br and F atoms were smoothly obtained in 71% and 56% yields, respectively, which had potential application for further functionalization into some bioactive compounds (Table 2). It is worth noting that electron-withdrawing CF3 and COOMe substitutents at the meta position on the aromatic rings were tolerated well to furnish the products 2h and 2i in moderate yields. To the best of our knowledge, the previous approach reported by Cheng et al.[7g] could not synthesize these isatins. Accordingly, a complementary access to isatin derivatives with electron-withdrawing groups was offered. In addition to examining the substituents on the aromatic ring, the substrates with different size chain on nitrogen atom were also investigated. As expected, substrates with Et, Bn, n-Bu on nitrogen efficiently underwent the Cu-catalyzed annulation to give the corresponding isatins in 54%~69% yields (Table 2). To our surprise, N-(2-acetylphenyl)formamide without methyl group on the nitrogen also worked well under the standard conditions and provided the desired product 2m in 48% yield (Table 2).

    Table 2

    Table 2.  Scope of substrates for the synthesis of isatinsa
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    Substrates 1p and 1q were also subjected to the standard conditions. Substrate 1p did not work. Substrate 1q could give the desired product 2a in 33% yield after 131 h. These substrates did not show good reactivity (Scheme 2).

    Scheme 2

    Scheme 2.  Reaction of compounds 1p and 1q in standard conditions

    To gain insight into the reaction mechanism, some mechanistic studies were conducted. Compound ln bearing 13C isotope on aldehyde group was prepared, and 1n was subjected to the standard conditions (Eq. 1). It was found that the carbon of amide in 2a came from methyl group, not aldehyde. In addition, it was found that the substrate 1o without aldehyde on nitrogen was performed sluggishly under Cu catalytic conditions to furnish the corresponding product 2a with low 29% yield (Eq. 2). It was worth noting that an intermediate was discovered during the course of reaction, which was determined as a dichloronated compound 3a by the analysis of 1H/13C NMR and HRMS. To our surprise, compound 3a smoothly converted into the deserted product 2a under the standard conditions (75% yield, Eq. 3), which revealed that compound 3a was a key intermediate in this reaction. Consequently, the reaction profile using 1a as the model substrate was obtained. It was found that the desired product 2a was produced with the formation of intermediate 3a (Figure 1). It further supported dichloronated compound 3a as a key intermediate in this reaction. When a radical trapping agent such as 2, 2, 6, 6-tetramethyl-1-piperidinyloxy free radical (TEMPO) (20 mol%) was added into the reaction, no reaction occurred (Eq. 4). However, although the mechanism for the present catalytic reaction is not clear, a radical process for this reaction can be possible.

    Figure 1

    Figure 1.  Reaction profile using 1a as the model substrate

    (1)

    (2)

    (3)

    (4)

    On the base of the above mechanistic studies and previous reports, [7] a tentative reaction mechanism was proposed (Scheme 3). First, substrate reacts with CuCl2 under the acidic conditions to undergo the halogenation of ketone, forming a dichloronated intermediate A, [12] followed by decarbonyaltion in Cu/Co system to give a secondary amine radical intermediate C.[7i, 7j] The secondary amine radical attacks one of C—Cl bonds to yield compound D which undergo substitution reaction with H2O to provide the cyclic α-keto alcohol E. Finally, intermediate E is oxidized by Cu(Ⅱ)/O2 to form isatin 2.

    Scheme 3

    Scheme 3.  Postulated mechanism for the formation of isatins

    In summary, a copper-catalyzed decarbonylation cyclization to form isatins using oxygen as a terminal oxidant was developed. This complementary way offers a new protocol for the synthesis of isatins through C(sp3)—H bond functionalization in Cu/O2/Co system. This system shows good reactivity and compatibility. Both electron-rich and electron-deficient functional groups can be tolerated. Further exploration of the generality and application of this approach is ongoing in our laboratory.

    All experiments were carried out under an oxygen atmosphere unless otherwise noted. Reactions were monitored using thin-layer chromatography (TLC). 1H NMR and 13C NMR spectra were obtained at 400 and 100 MHz, respectively on a Mercury Plus-400. NMR spectra were run in a solution of deuterated chloroform (CDCl3). High-resolution mass spectra (HRMS) were recorded using electrospray ionization (ESI) with a Q-TOF MS Spectrometer. The substrates were prepared according to the reported literatures.[13, 14]

    An oven-dried Schlenk tube equipped with a magnetic stir bar was evacuated and backfilled with oxygen three times. Under oxygen, substrates 1 (0.3 mmol), CuCl2 (20 mol%, 0.06 mmol, 8.1 mg), CoCl2 (20 mol%, 0.06 mmol, 7.8 mg), PhCOOH (20 mol%, 0.06 mmol, 7.3 mg) and tetrahydrofuran (THF) (1.2 mL) were added into the tube. Then the reaction was stirred at 100 ℃ for specific time. THF was removed under reduced pressure. Then, the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the corresponding isatin products. All of products are known compounds.[14~18]

    1-Methylindoline-2, 3-dione (2a):[15] 78% yield. 1H NMR (400 MHz, CDCl3) δ: 3.26 (s, 3H), 6.91 (d, J=8.0 Hz, 1H), 7.16 (td, J=1.2, 7.6 Hz, 1H), 7.62~7.59 (m, 2H); HRMS (ESI) calcd for C9H8NO2 162.0555, found 162.0544.

    1, 6-Dimethylindoline-2, 3-dione (2b):[15] 62% yield. 1H NMR (400 MHz, CDCl3) δ: 2.45 (s, 3H), 3.23 (s, 3H), 6.69 (s, 1H), 6.93 (d, J=7.6 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H); HRMS (ESI) calcd for C10H10NO2 176.0712, found 176.0704.

    6-Methoxy-1-methylindoline-2, 3-dione (2c):[16] 44% yield. 1H NMR (400 MHz, CDCl3) δ: 3.22 (s, 3H), 3.93 (s, 3H), 6.37 (d, J=2.4 Hz, 1H), 6.57 (dd, J=8.4, 2.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H); HRMS (ESI) calcd for C10H10NO3 192.0661, found 192.0647.

    1, 5-Dimethylindoline-2, 3-dione (2d):[15] 61% yield; 1H NMR (400 MHz, CDCl3) δ: 2.33 (s, 3H), 3.22 (s, 3H), 6.80 (d, J=7.6 Hz, 1H), 7.41~7.38 (m, 2H); HRMS (ESI) calcd for C10H10NO2 176.0712, found 176.0700.

    5-Methoxy-1-methylindoline-2, 3-dione (2e):[15] 65% yield; 1H NMR (400 MHz, CDCl3) δ: 3.24 (s, 3H), 3.82 (s, 3H), 6.84 (d, J=8.4 Hz, 1H), 7.19~7.15 (m, 2H); HRMS (ESI) calcd for C10H10NO3 192.0661, found 192.0651.

    5-Bromo-1-methylindoline-2, 3-dione(2f):[15] 71% yield; 1H NMR (400 MHz, CDCl3) δ: 3.25 (s, 3H), 6.82 (dd, J=7.2, 1.6 Hz, 1H), 7.71 (s, 1H), 7.74 (dd, J=7.6, 2.0 Hz, 1H); HRMS (ESI) calcd for C9H7NO3Br 239.9660, found 239.9640.

    5-Fluoro-1-methylindoline-2, 3-dione (2g):[15] Orange solid, 56% yield. m.p. 150.4~151.3 ℃(lit. 150.7~152.5 ℃); 1H NMR (400 MHz, CDCl3) δ: 3.26 (s, 3H), 6.88~6.85 (m, 1H), 7.36~7.31 (m, 2H); HRMS (ESI) calcd for C9H7NO3F 180.0461, found 180.0454.

    1-Methyl-6-(trifluoromethyl)indoline-2, 3-dione (2h):[17] 45% yield. 1H NMR (400 MHz, CDCl3) δ: 3.32 (s, 3H), 7.11 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 26.4, 106.9 (d, J=3.5 Hz, 1C), 119.4, 120.8 (d, J=3.7 Hz, 1C), 124.1, 125.5, 139.2 (d, J=33.3 Hz, 1C), 151.5, 157.4, 182.4; HRMS (ESI) calcd for C10H7NO2F3 230.0429, found 230.0425.

    1-Methyl-2, 3-dioxoindoline-6-carboxylate (2i):[18] 50% yield. 1H NMR (400 MHz, CDCl3) δ: 3.32 (s, 3H), 3.98 (s, 3H), 7.54 (d, J=1.2 Hz, 1H), 7.68 (dd, J=8.0, 0.8 Hz, 1H), 7.84 (dd, J=7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 26.4, 52.9, 110.6, 120.0, 125.2, 138.5, 151.1, 157.6, 165.2, 183.1; HRMS (ESI) calcd for C11H10NO4 220.0610, found 220.0604.

    1-Ethylindoline-2, 3-dione (2j):[19] 69% yield. 1H NMR (400 MHz, CDCl3) δ: 1.34 (t, J=7.2 Hz, 1H), 3.82 (q, J=7.2 Hz, 2H), 6.92 (d, J=7.6 Hz, 1H), 7.13 (td, J=0.8, 7.2 Hz, 1H), 7.62~7.57 (m, 2H); HRMS (ESI) calcd for C10H10NO2 176.0712, found 176.0700.

    1-Butylindoline-2, 3-dione (2k):[20] 54% yield. 1H NMR (400 MHz, CDCl3) δ: 0.99 (t, J=7.2 Hz, 3H), 1.46~1.37 (m, 2H), 1.72~1.65 (m, 2H), 3.74 (t, J=7.2 Hz, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.13 (dt, J=7.6, 0.8Hz, 1H), 7.61~7.56 (m, 2H); HRMS (ESI) calcd for C12H14NO2 204.1025, found 204.1011.

    1-Benzylindoline-2, 3-dione (2l):[15] 62% yield. 1H NMR (400 MHz, CDCl3) δ: 4.93 (s, 2H), 6.78 (d, J=8.0 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.37~7.30 (m, 5H), 7.50 (dt, J=7.6, 0.8 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H); HRMS (ESI) calcd for C15H12NO2 238.0868, found 238.0858.

    Indoline-2, 3-dione (2m):[15] 48% yield; 1H NMR (400 MHz, CDCl3) δ: 6.93 (d, J=8.0 Hz, 1H), 7.15 (td, J=0.8, 7.6 Hz, 1H), 7.59 (td, J=1.2, 7.6 Hz, 1H), 7.63(d, J=7.6 Hz, 1H), 8.09 (br s, 1H); HRMS (ESI) calcd for C8H6NO2 148.0399, found 148.0386.

    N-(2-Acetylphenyl)-N-methylformamide-13C (1n): Major:Minor=3:1; 1H NMR (400 MHz, CDCl3) δ: Major: 2.51 (s, 3H), 3.26 (s, 3H), 7.25 (dd, J=1.2, 7.2 Hz, 1H), 7.43 (td, J=1.2, 7.6 Hz, 1H), 7.57 (td, J=1.6, 7.6 Hz, 1H), 7.70 (dd, J=7.6, 1.6 Hz, 1H), 8.38 (s, 1H); Minor: 2.56 (s, 3H), 3.37 (s, 3H), 7.24 (d, J=7.2 Hz, 1H), 7.38 (td, J1.2, 7.6 Hz, 1H) 7.53 (td, J=1.6, 7.6 Hz, 1H), 7.65 (dd, J=1.2, 7.6 Hz, 1H), 8.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 29.5, 33.8, 128.0, 129.8, 132.7, 136.4, 162.6, 199.6; HRMS (ESI) calcd for C10H12NO2 178.0902, found178.0891.

    N-(2-(2, 2-Dichloroacetyl)phenyl)-N-methylformamide (3a): Major:Minor=3:1; 1H NMR (400 MHz, CDCl3) δ: Major: 3.25 (s, 3H), 6.48 (s, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 8.19 (s, 1H); Minor: 3.39 (s, 3H), 6.51 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.44 (t, J8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 8.18 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: Major: 34.6, 69.3, 128.7, 129.5, 130.4, 132.1, 134.5, 141.8, 162.8, 188.1; Minor: 38.0, 69.0, 127.9, 128.1, 129.3, 132.7, 134.0, 139.1, 163.1, 188.3; HRMS (ESI) calcd for C10H9Cl2NO2Na (M+Na+) 267.9908, found 267.9903.

    Supporting Information   1H NMR spectra of all products and data of intermediate 3a. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.


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  • Scheme 1  Synthetic approaches for isatins

    Scheme 2  Reaction of compounds 1p and 1q in standard conditions

    Figure 1  Reaction profile using 1a as the model substrate

    Scheme 3  Postulated mechanism for the formation of isatins

    Table 1.  Optimization of reaction conditions for the synthesis of isatinsa, b

    Entry Cat. Additive Time/h Yieldb/%
    1 CuCl2 None 49 34
    2 CuCl None 110 23
    3 CuBr None 110 17
    4 CuI None 82 N.R.
    5 CuSCN None 82 N.R.
    6 CuCN None 82 N.R.
    7 Cu2O None 110 Trace
    8 Cu(OAc)2 None 66 N.R.
    9 CuCl2 ZnCl2 (1 equiv.) 49 40
    10 CuCl2 AlCl3 (1 equiv.) 49 N.R.
    11 CuCl2 BF3·Et2O (1 equiv.) 67 N.R.
    12 CuCl2 FeCl3 (1 equiv.) 67 N.R.
    13 CuCl2 PdCl2 (1 equiv.) 67 N.R.
    14 CuCl2 Cu(ClO4)·6H2O (1 equiv.) 67 N.R.
    15 CuI CoSO4 (1 equiv.) 59 45
    16 CuSCN CoCl2 (1 equiv.) 59 62
    17 CuCN Yb(OTf)3 (1 equiv.) 48 N.R.
    18 Cu2O Ni(OAc)2·4H2O (1 equiv.) 65 16
    19 Cu(OAc)2 Co(NO3)2·6H2O (1 equiv.) 65 Trace
    20 CuCl2 Cu(OAc)2·4H2O (1 equiv.) 65 N.R.
    21 CuCl2 LiCl (1 equiv.) 49 N.R.
    22 CuCl2 CaCl2 (1 equiv.) 49 23
    23 CuCl2 CoCl2 (1 equiv.)+
    PivOH (1 equiv.)
    58 47
    24 CuCl2 CoCl2 (1 equiv.)+
    PhCOOH (1 equiv.)
    57 69
    25 CuCl2 CoCl2 (20 mol%)+
    PhCOOH (20 mol%)
    84 78
    26 None CoCl2 (1 equiv.)+
    PhCOOH (20 mol%)
    77 N.R.
    a Conditions: 1a (50 mg, 0.28 mmol), CuCl2 (20 mol%), additive (1 equiv.), THF (1.2 mL), O2, 100 ℃. b Isolated yield.
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    Table 2.  Scope of substrates for the synthesis of isatinsa

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  • 发布日期:  2019-11-25
  • 收稿日期:  2019-03-14
  • 修回日期:  2019-05-28
  • 网络出版日期:  2019-11-12
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