English

• 1.   Introduction

  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

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  1.   Result and discussion

  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 isatins^{a, 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 isatins^a

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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

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  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

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  (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

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  2.   Conclusion

  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.

  3.   Experimental section

  3.1   General considerations

  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]}

  3.2   General procedure for Cu-catalyzed decarbonylation cyclization for the synthesis of isatins

  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, J＝1.2, 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, J＝8.0 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

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

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  Figure 1  Reaction profile using 1a as the model substrate

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  Scheme 3  Postulated mechanism for the formation of isatins

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  Table 1.  Optimization of reaction conditions for the synthesis of isatins^{a, 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 isatins^a

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