English

• 1.   Introduction

  1, 2, 3, 4-Tetrahydroisoquinoline (THIQ) analogues are of particular interest in synthetic chemistry, as they are commonly used as key intermediates or precursors for the synthesis of various bioactive molecules and natural products.^[1] Cross-dehydrogenative coupling (CDC) reaction has been an attractive strategy for constructing C—C bonds by activation of C—H bonds adjacent to the N-atoms in tertiary amines, because it can provide an atom economical and environmentally benign synthetic alternative for the synthesis of THIQs, which avoids prefunctionalization of the coupling partners.^[2] Since the pioneering work reported by Li’s groups, ^{[2b, 3]} and others, ^[4] various catalytic systems based on metal salts or complexes of Cu, ^[5] Fe, ^[6] Ru, ^[7] Au, ^[8] Rh, ^[9] Co, ^[10] and metal-free systems, ^[11] have been developed along with oxidants, such as H₂O₂, O₂, TBHP (tert-butyl hydroperoxide), DTBT (ditert- butyl peroxide). However, peroxides are corrosive and unstable at room temperature, which make them less suitable for large scale industrial reactions. Besides this, the excess use of hazardous or toxic oxidants in the reaction processes is considered non-benign according to green metrics. Therefore, the developments of CDC reactions that make use of cheap and abundant oxidants, such as air/oxygen, which generate water as the sole byproduct, are highly desirable.

  Over the past few years, nickel has emerged as a good choice to replace precious transition metals for the development of C—H bond functionalization. Some nickel-catalyzed CDC reactions have also been reported. Zhou, et al.^[12] reported the asymmetric synthesis of 2-substi- tuted-tetrahydroisoquinolin-1-yl glycines from THIQs via CDC reaction under the catalysis of chiral nickel(Ⅱ) glycinate using o-chloranil as the oxidant. Kumar et al.^[13] developed an efficient synthetic strategy to α-C—H phenolated tertiary amines via CDC reaction of arylboronic acids with tertiary amines over NiCl₂ with TBHP. Cai’s group has developed nickel-catalyzed CDC reaction of α-C(sp³)—H bonds in N-methylamides with C(sp³)—H bonds from cyclic alkanes and C2-indoles versus C3-in- doles with 1, 4-dioxane in the presence of DTBT.^[14] The same group has also found that Ni(Ⅱ) could accelerate the regioselective C—H acylation of chelating arenes in the presence of Ag₂CO₃ additive.^[15] A method to directly transform both aromatic and aliphatic aldehydes into either esters or amides has been successfully developed by Whittaker et al.^[16] using [Ni(cod)₂] as catalyst. Wang et al.^[15] reported a Ni-catalyzed oxidative C—H/C—H CDC reaction by employing thiophenes and aliphatic (aromatic) amides that contain an 8-aminoquinoline as a removable directing group using a silver oxidant. Recently, a photoinduced dehydrogenative coupling reaction between benzylic and aldehydic C—H bonds in the presence of iridium and nickel catalysts is reported by Murakami et al.^[18] Verheyen et al.^[19] developed an intermolecular coupling of primary alcohols and organotriflates to ketones by the action of Ni(0) catalyst under mild conditions. It can be concluded that only a few reports are known in the literature wherein nickel metal is used for CDC reactions, and all the catalytic systems require the aid of peroxides or additives.

  Henceforth, we report a facile and operationally convenient protocol for the oxidative coupling of N-aryl tetrahydroisoquinolines with various pro-nucleophiles over nickel using molecular oxygen as the sole oxidant under mild conditions.

  2.   Results and discussion

  We started the investigation by choosing the cross-cou- pling between N-phenyltetrahydroisoquinoline (1a) and nitromethane (2a) as a model reaction (Table 1). Various nickel salts, including NiCl₂, Ni(AcO)₂, Ni(NO₃)₂ and Ni(Ⅱ) acetylacetonate, were firstly screened. It can be observed that although most of the selected nickel salts could provide excellent conversion of the substrate without any additive using 100 kPa of O₂ as the oxidant, the selectivity of the CDC product was not satisfactory (Entries 1~4). Among these nickel salts, NiCl₂ was proven to be a good catalyst and the desired product (3aa) was afforded in 90% conversion with 83% selectivity (Entry 1). Therefore, NiCl₂ was selected as the catalyst for the further optimization of the reaction conditions.

  表 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Catalyst	T/℃	Solvent	Base	Conv. (Sel.)b /%
  1	NiCl2	80	1, 4-Dioxane	—	90 (83)
  2	Ni(AcO)2	80	1, 4-Dioxane	—	95 (47)
  3	Ni(NO3)2	80	1, 4-Dioxane	—	92 (22)
  4	N(Ⅱ) acetyl-acetonate	80	1, 4-Dioxane	—	97 (53)
  6	NiCl2	80	Acetonitrile	—	53 (82)
  7	NiCl2	80	DCE	—	47 (65)
  8	NiCl2	80	Toluene	—	87 (56)
  9	NiCl2	80	Methanol	—	66 (57)
  10	NiCl2	80	H2O	—	78 (41)
  11	NiCl2	80	DMF	—	60 (69)
  12	NiCl2	60	1, 4-Dioxane	—	65 (87)
  13	NiCl2	100	1, 4-Dioxane	—	＞99 (57)
  14c	NiCl2	80	1, 4-Dioxane	—	88 (78)
  15d	NiCl2	80	1, 4-Dioxane	—	92 (85)
  16	NiCl2	80	1, 4-Dioxane	Na2CO3	79 (78)
  17	NiCl2	80	1, 4-Dioxane	NaHCO3	＞99 (92)
  18	NiCl2	80	1, 4-Dioxane	K2CO3	89 (72)
  a Reaction conditions: 1a (0.5 mmol), 6 equiv. of 2a, NiCl2 (5%), solvent (2 mL), base (20%), 18 h, O2 atmosphere (101 kPa). b Based on the 1H NMR analysis. c 3 equiv. of 2a.d 8 equiv. of 2a.

  Various solvents were then evaluated in the cross-coup- ling reaction. It is notable that acetonitrile could give good selectivity to the desired product, but the conversion was not satisfactory (Entry 6). The results showed that the highest conversion of 1a could be observed under the solvent of dioxane with the highest selectivity. Although a comparable conversion could be obtained in the case of toluene, the selectivity was low (Entry 8). The main byproduct was the over-oxidation product of 2-phenyl-3, 4- dihydroisoquinolin-1(2H)-one (4), as been found in some other catalytic systems.^{[5a, 10, 20]} The low selectivity might be due to the fact that the rate of over-oxidative amide formation was higher than that of enamine nucleophilic attack under toluene. For the reaction temperature, decreasing the temperature to 60 ℃ led to a significantly reduced 65% conversion of 1a with a slightly improved selectivity of 3aa (Entry 12). However, a quite low selectivity of 3aa was observed under an increased temperature of 100 ℃ (Entry 13), which should be due to the overoxidation of the substrate. Decreasing the ratio of 2a/1a to 3 resulted in reduction of conversion and selectivity, whilst further increasing the value to 8 only gave slightly improved yield of 3aa (Etnries 14, 15). Finally, some base additives, including Na₂CO₃, NaHCO₃ and K₂CO₃, were tested. NaHCO₃ could improve the CDC reaction to some extend, and the substrate could fully converted with an exellent selectivity of 92% under the selected condtions (Entry 17). Summary, an convenient and efficient catalytic system based on nickel has been developed for the CDC reaction between N-phenyltetrahydroisoquinoline and nitromethane, and excellent conversion and selectivity could be obtained under mild reaction conditions.

  With the optimized reaction conditions in hand, the scope of this protocol was investigated in the CDC reaction under analogous reaction conditions (Table 2). A variety of N-phenyltetrahydroquinolin derivatives with different substituents were subjected to the Ni-catalyzed aerobic cross-coupling reaction. It can be observed that electron-donating groups on the para-site of the aromatic rings could accelerate the reaction, and good to excellent yields of the cross-coupling product were obtained (Entries 2~4), comparable with the reported Fe-based catalytic systems.^[6a] Delightedly, N-(4-Methoxylphenyl)-1, 2, 3, 4-tetra- hydroisoquinoline gave 90% isolated yield of the corresponding CDC product (3ca). The longer reaction time required for 3da might be due to the influence of the bulky tert-butyl group, and the low yield was probably due to the overoxidation of the substrate. The reactivity reduced with longer reaction time and lower yields when methyl or methoxyl group locates on the ortho- or meta-site (Entries 5~8), which further verifies the steric effect. On the other hand, the substrates with electron-withdrawing groups locating on the aromatic rings suppressed the CDC reactivity, and significantly longer reaction times were required (Entries 9~12), indicating the existence of electronic effect. For these substrates, moderate to good yields to the products could be obtained under the selected conditions.

  表 2

  

  Table 2.  Reaction scope for the Ni-catalyzed aerobic CDC reaction^a

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  Entry	1	2	3	Time/h	Yieldb/%
  1		CH3NO2 (2a)		18	81
  2		2a		18	83
  3		2a		18	90
  4		2a		24	58
  5		2a		24	75
  6		2a		36	65
  7		2a		24	81
  8		2a		18	37
  9		2a		24	74
  10		2a		24	71
  11		2a		24	62
  12		2a		28	63
  13		2a		20	50
  14	1a			24	79
  15	1a			24	73
  16	1a			36	25
  17	1a			24	53
  18	1a			24	68
  a Reaction conditions: 1 (0.5 mmol), 2 (3 mmol), NiCl2 (5%), NaHCO3 (20%), dioxane (2 mL), 80 ℃, O2 atmosphere (101 kPa). b Isolated yield.

  Subsequently, some other nucleophiles with C_sp3—H have been tested. The results in Table 2 indicate that the current catalytic system tolerates various nitroalkanes (3ab and 3ac), and good yields could be obtained. It behaves slightly higher performance than the Fe and Cu systems.^{[3a, 6a]} The reactivity discernibly decreased as the carbon atoms increase, which was probably due to the steric effect (Entries 14, 15). For the carbonyl compounds with α-C—H, 4-methyl-2-pentanone gave only 25% yield (Entry 16), whilst increased yield was obtained for acetophenone (Entry 17), which might be due to steric hindrance.^[11b] Trimethylsilyl cyanide was also investigated in the catalytic system, and 68% yield was obtained (Entry 18).

  It can be concluded from the above results that N- phenyl-1, 2, 3, 4-tetrahydroisoquinoline and its derivatives and some nucleophiles with C_sp3—H were compatible in the Ni-catalyzed aerobic CDC reaction. They could uniformly provide the corresponding products in good to excellent isolated yields in appropriate reaction times.

  Some controlled experiments have also been performed to validate the reaction mechanism, and the results are summarized in Table 3. Only 43% selectivity could be observed with a lower conversion without catalyst. It implies the catalytic function of Ni salt for the CDC reaction (Entry 2). Under nitrogen atmosphere, only trace of the substrate could be transformed (Entry 3), suggesting that molecular oxygen was crucial in the reaction. Additionally, when air was applied instead of O₂, significantly reduced reactivity and only a 49% selectivity of 3aa were observed (Entry 4), further verifying the above deduction. These results also suggest that the reaction is predominantly driven by oxygen, thus confirming an oxidative CDC pathway. Introduction of 2 equiv. of 2, 6-di-tert-butyl-4- methylphenol (BHT) or 2, 2, 6, 6-tetramethylpiperidine-1- oxyl (TEMPO) as a radical scavenger into the reaction led to quite lower conversion of the substrate (Entries 5~6), although a similar selectivity was observed in the case of TEMPO. These results imply that a radical pathway is probable involved in the nickel-catalyzed aerobic CDC reaction of N-aryl tetrahydroisoquinolines.

  表 3

  

  Table 3.  Results of some controlled experiments^a

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  Entry	Catalyst	Reaction condition	Conv.b/%	Sel.b/%
  1	NiCl2/NaHCO3	O2	＞99	92
  2	—	O2	78	43
  3	NiCl2/NaHCO3	N2	Trace	—
  4	NiCl2/NaHCO3	Air	74	49
  5	NiCl2/NaHCO3	O2/BHTc	Trace	—
  6	NiCl2/NaHCO3	O2/TEMPOc	45	93
  a Reaction conditions: 1, 2, 3, 4-tetrahydroquinoline (0.5 mmol), nitromethane (3 mmol), NiCl2 (5%), NaHCO3 (20%), dioxane (2 mL), 18 h, 80 ℃, O2 atmosphere (101 kPa). b Based on the 1H NMR analysis. c 2 equiv. of substrate.

  To demonstrate the possibility of the formation of iminium intermediate, which has been proposed as the key intermediate in the CDC reactions, ^{[3, 4, 6]} the reaction was performed without nucleophile, and the filtrate was analysed by MS with ESI ion source. The iminum could be obviously observed at 208.13 apart from the substrate peak (210.19). The MS2 spectra of the peak of 208.13 further verified the formation of iminium ion. Both of the conversion and selectivity decreased without catalyst, suggesting that NiCl₂ might accelerate not only the transform of the substrate, but also the nucleophilic attack of the formed iminum. On the basis of the obtained and reported results, ^{[3, 4, 6, 10, 14]} a plausible mechanism is described in Scheme 1. We believe that the intermediate ammoniumyl radical cation (Ⅰ) may firstly formed through a single-electron transfer (SET), which then transforms to iminium ion intermediate (Ⅱ) via loss of an H atom (or a combination of electron and H⁺). Subsequently, the intermediate reacts nucleophilic species to furnish the desired coupled product 3aa with the catalysis by NiCl₂ (Scheme 1).

  图式 1

  

  Scheme 1.  A possible reaction path for the Ni-catalyzed aerobic CDC reaction of N-phenyltetrahydroisoquinolines with nitromethane

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  3.   Conclusions

  In summary, a convenient catalytic system based on nickel salt for the aerobic CDC reaction has been developed.^[21] Various substrates could be tolerated by the present protocol, and it provides an alternative method to achieve CDC reaction for the a-functionalization of N-aryl tetrahydroisoquinolines. Further studies on the application of the protocol to other substrates and nucleophiles are under way in our laboratory.

  4.   Experimental section

  4.1   General information

  All the chemicals were purchased from Energy or Aladdin. Unless otherwise specified, reagents and solvents were used as received. Substituted N-phenyl-1, 2, 3, 4-tetrohydro- quinolines were prepared from the corresponding tetrahydroisoquinolines and aryl halides according to the reported method.^[21] Reactions were monitored by thin layer chromatography (TLC) using silica gel F254 plates. The conversion of the substrate and the selectivity of coupling products were obtained on the basis of ¹H NMR analysis (1, 4-dinitrobenzene was used as the internal standard reference). Products were purified using flash chromatography over 300~400 mesh silica gel under a positive pressure of air. NMR spectra were recorded at 25 ℃ on an Bruker AVANCE Ⅲ 400-NMR spectrometer at 400 MHz for ¹H NMR and 100 MHz for ¹³C NMR using CDCl₃ as solvent with TMS as the internal standard. High- resolution mass spectra (HRMS) were obtained using a Agilent 6546 Q-TOF spectrometer (ESI).

  4.2   General procedure for the aerobic oxidative cou- pling reaction

  Taking the cross-coupling reaction of N-phenyltetrahy- droisoquinoline (1a) with nitromethane (2a) as an example. N-Phenyltetrahydroisoquinoline (0.50 mmol), nitromethane (3 mmol), NiCl₂ (3.3 mg, 5%), NaHCO₃ (8.4 mg, 20%) and dioxane (2 mL) were mixed in a carousel reaction tube. The reaction mixture was stirred at 80 ℃ under oxygen atmosphere, the reaction was sampled periodically and monitored by TLC (petroleum ether/ethyl acetate, V:V＝10:1). The reaction mixture was then cooled to room temperature and purified using flash chromatography (petroleum ether/ethyl acetate, V:V＝10:1) to give dimethyl 1-nitromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquino- line (3aa) with 81% yield. Yellow solid, m.p. 90.0~91.5 ℃ (lit.^[5e] 89.0~90.0 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.35~7.24 (m, 5H), 7.18 (s, 1H), 7.03 (d, J＝8.2 Hz, 2H), 6.91 (d, J＝7.3 Hz, 1H), 5.60 (s, 1H), 4.91 (dd, J＝11.8, 7.9 Hz, 1H), 4.60 (dd, J＝11.8, 6.6 Hz, 1H), 3.73~3.63 (m, 2H), 3.16~3.09 (m, 1H), 2.83 (d, J＝16.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 148.7, 135.5, 133.1, 129.7, 128.4, 127.2, 126.9, 119.6, 115.3, 79.0, 58.4, 42.3, 26.7. HRMS (ESI⁺) calcd for C₁₆H₁₇N₂O₂[M+H]⁺ 269.1285, found 269.1281.

  Dimethyl 1-nitromethyl-2-(p-tolyl)-1, 2, 3, 4-tetrahydro- isoquinoline (3ba):^[7b] Yellow oil. ¹H NMR (300 MHz, CDCl₃) δ: 7.22~7.03 (m, 5H), 6.76 (ddd, J＝30.8, 18.6, 7.9 Hz, 3H), 5.51 (d, J＝7.3 Hz, 1H), 4.84 (dd, J＝11.8, 7.8 Hz, 1H), 4.53 (dd, J＝11.8, 6.7 Hz, 1H), 3.59 (dd, J＝8.6, 4.8 Hz, 2H), 3.06 (ddd, J＝14.3, 8.1, 6.1 Hz, 1H), 2.74 (ddd, J＝16.0, 10.4, 4.7 Hz, 1H), 2.28 (d, J＝20.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 148.7, 139.5, 135.6, 133.3, 129.6, 129.4, 128.4, 127.3, 126.9, 120.6, 116.2, 112.5, 79.1, 58.5, 42.4, 26.8, 22.2. HRMS (ESI⁺) calcd for C₁₇H₁₉N₂O₂[M+H]⁺ 283.1441, found 283.1438.

  Dimethyl 2-(4-methoxyphenyl)-1-nitromethyl-1, 2, 3, 4- tetrahydroisoquinoline (3ca):^{[6a, 7b]} Yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.30~7.21 (m, 4H), 7.16 (d, J＝7.5 Hz, 1H), 6.63 (d, J＝8.3 Hz, 1H), 6.58 (s, 1H), 6.45 (d, J＝8.1 Hz, 1H), 5.58 (t, J＝7.3 Hz, 1H), 4.90 (dd, J＝11.8, 7.6 Hz, 1H), 4.59 (dd, J＝11.8, 6.8 Hz, 1H), 3.84 (s, 3H), 3.70~3.62 (m, 2H), 3.17~3.10 (m, 1H), 2.83 (dt, J＝16.3, 5.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 161.1, 150.0, 135.5, 133.1, 130.5, 129.4, 128.4, 127.2, 126.9, 107.8, 104.3, 101.7, 79.0, 58.5, 55.4, 42.4, 26.8. HRMS (ESI⁺) calcd for C₁₇H₁₉N₂O₃[M+H]⁺ 299.1390, found 299.1388.

  Dimethyl 2-(4-(tert-butyl)phenyl)-1-nitromethyl-1, 2, 3, 4-tetrahydroisoquinoline (3da):^[6a] Yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.35~7.21 (m, 5H), 7.16 (d, J＝7.5 Hz, 1H), 7.08 (s, 1H), 6.93 (d, J＝7.7 Hz, 1H), 6.83 (dd, J＝8.2, 2.2 Hz, 1H), 5.59 (t, J＝7.1 Hz, 1H), 4.91 (dd, J＝11.7, 7.6 Hz, 1H), 4.59 (dd, J＝11.8, 6.7 Hz, 1H), 3.72~3.63 (m, 2H), 3.17~3.10 (m, 1H), 2.84 (dt, J＝16.1, 4.9 Hz, 1H), 1.35 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 152.9, 148.5, 135.6, 133.5, 129.4, 129.3, 128.4, 127.3, 126.9, 117.0, 112.7, 112.4, 79.2, 58.9, 42.3, 35.2, 31.6, 27.0. HRMS (ESI⁺) calcd for C₂₀H₂₅N₂O₂[M+H]⁺325.1911, found 325.1905.

  Dimethyl 1-nitromethyl-2-methyl-1, 2, 3, 4-tetrahydroiso- quinoline (3ea):^[22] Yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.30~7.19 (m, 5H), 6.82 (d, J＝8.2 Hz, 2H), 6.71 (d, J＝7.4 Hz, 1H), 5.58 (t, J＝7.2 Hz, 1H), 4.90 (dd, J＝11.8, 7.8 Hz, 1H), 4.59 (dd, J＝11.7, 6.7 Hz, 1H), 3.72~3.60 (m, 2H), 3.19~3.08 (m, 1H), 2.82 (dt, J＝16.3, 4.9 Hz, 1H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 148.7, 139.5, 135.6, 133.3, 129.6, 129.4, 128.3, 127.3, 126.9, 120.6, 116.2, 112.5, 79.1, 58.4, 42.4, 26.8, 22.1. HRMS (ESI⁺) calcd for C₁₇H₁₉N₂O₂[M+H]⁺283.1441, found 283.1435.

  Dimethyl 1-nitromethyl-2-(o-tolyl)-1, 2, 3, 4-tetrahydro- isoquinoline (3fa):^[22] Yellow oil. ¹H NMR (300 MHz, CDCl₃) δ: 7.23~7.09 (m, 5H), 6.78~6.76 (m, 2H), 6.69~6.63 (m, 1H), 5.52 (t, J＝7.2 Hz, 1H), 4.83 (dd, J＝11.8, 7.8 Hz, 1H), 4.53 (dd, J＝11.8, 6.7 Hz, 1H), 3.67~3.52 (m, 2H), 3.11~3.00 (m, 1H), 2.76 (dt, J＝16.3, 4.9 Hz, 1H), 2.31 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 148.7, 139.5, 135.6, 133.2, 129.6, 129.4, 128.3, 127.2, 126.9, 120.5, 116.1, 112.4, 79.0, 58.4, 42.3, 26.7, 22.1. HRMS (ESI⁺) calcd for C₁₇H₁₉N₂O₂ [M+H]⁺ 283.1441, found 283.1438.

  Dimethyl 2-(2-methoxyphenyl)-1-nitromethyl-1, 2, 3, 4- tetrahydroisoquinoline (3ga):^{[5e, 6a]} Yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.30~7.20 (m, 4H), 7.15 (d, J＝7.5 Hz, 1H), 6.62 (d, J＝8.3 Hz, 1H), 6.56 (s, 1H), 6.44 (d, J＝8.2 Hz, 1H), 5.57 (t, J＝7.3 Hz, 1H), 4.90 (dd, J＝11.8, 7.6 Hz, 1H), 4.58 (dd, J＝11.8, 6.8 Hz, 1H), 3.83 (s, 3H), 3.70~3.59 (m, 2H), 3.16~3.08 (m, 1H), 2.83 (dt, J＝16.2, 5.1 Hz, 1H); ¹³C NMR (125MHz, CDCl₃) δ: 160.9, 149.8, 135.2, 132.9, 130.3, 129.2, 127.0, 126.7, 107.6, 104.1, 101.5, 78.8, 58.3, 55.2, 42.2, 26.6. HRMS (ESI⁺) calcd for C₁₇H₁₉N₂O₃ [M+H]⁺ 299.1390, found 299.1389.

  Dimethyl 2-(2, 5-dimethylphenyl)-1-nitromethyl-1, 2, 3, 4- tetrahydroisoquinoline (3ha): Yellow solid, m.p. 133.8~135.7 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.29~7.16 (m, 4H), 7.05 (d, J＝7.6 Hz, 1H), 6.81 (dd, J＝7.6, 0.7 Hz, 1H), 6.53 (s, 1H), 5.14 (dd, J＝10.1, 4.6 Hz, 1H), 4.78 (dd, J＝11.9, 10.2 Hz, 1H), 4.57 (dd, J＝12.0, 4.6 Hz, 1H), 3.46 (ddd, J＝13.9, 11.8, 3.7 Hz, 1H), 3.25~3.15 (m, 1H), 2.85 (ddd, J＝17.1, 11.7, 5.5 Hz, 1H), 2.59~2.50 (m, 1H), 2.21 (s, 3H), 2.15 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 149.2, 136.6, 136.2, 133.5, 131.3, 131.1, 130.0, 127.8, 126.9, 126.8, 125.3, 123.6, 79.7, 59.8, 43.7, 25.1, 21.4, 17.6. HRMS (ESI⁺) calcd for C₁₈H₂₁N₂O₂[M+H]⁺297.1598, found 297.1587.

  Dimethyl 2-(4-fluorophenyl)-1-nitromethyl-1, 2, 3, 4-te- trahydroisoquinoline (3ia):^{[6a, 23]} Yellow oil. ¹H NMR (300 MHz, CDCl₃) δ: 7.25~7.10 (m, 4H), 6.95~6.84 (m, 4H), 5.41 (dd, J＝8.6, 5.9 Hz, 1H), 4.79 (dd, J＝12.0, 8.7 Hz, 1H), 4.53 (dd, J＝12.0, 5.8 Hz, 1H), 3.56 (dd, J＝9.2, 4.3 Hz, 2H), 3.05~2.93 (m, 1H), 2.68 (dt, J＝16.6, 4.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.8, 155.7, 145.5 (d, J_{C, F}＝2.3 Hz), 135.4, 132.7, 129.6, 128.3, 127.1 (d, J_{C, F}＝16.6 Hz), 126.9, 118.1, 118.0 (d, J_{C, F}＝7.6 Hz), 116.2, 115.9 (d, J_{C, F}＝22.1 Hz), 79.0, 58.9, 42.9, 25.9. HRMS (ESI⁺) calcd for C₁₆H₁₆FN₂O₂ [M+H]⁺ 287.1190, found 287.1179.

  Dimethyl 2-(4-chlorophenyl)-1-nitromethyl-1, 2, 3, 4-te- trahydroisoquinoline (3ja):^[23] Yellow solid, m.p. 97.8~99.0 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.30~7.13 (m, 6H), 6.94~6.85 (m, 2H), 5.53~5.43 (m, 1H), 4.84 (dd, J＝11.9, 8.2 Hz, 1H), 4.56 (dd, J＝11.9, 6.3 Hz, 1H), 3.66~3.54 (m, 2H), 3.11~3.00 (m, 1H), 2.77 (dt, J＝16.4, 4.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.4, 135.3, 132.7, 129.6, 128.5, 127.2, 127.1, 124.6, 78.9, 58.5, 42.4, 26.4. HRMS (ESI⁺) calcd for C₁₆H₁₆ClN₂O₂ [M+H]⁺ 303.0895, found 303.0893.

  Dimethyl 2-(4-bromophenyl)-1-nitromethyl-1, 2, 3, 4-te- trahydroisoquinoline (3ka):^[6a] Yellow oil. ¹H NMR (300 MHz, CDCl₃) δ: 7.33~7.08 (m, 6H), 6.82 (d, J＝9.1 Hz, 2H), 5.46 (t, J＝7.2 Hz, 1H), 4.80 (dd, J＝11.8, 8.2 Hz, 1H), 4.53 (dd, J＝10.4, 6.4 Hz, 1H), 3.59~3.54 (m, 2H), 3.08~2.98 (m, 1H), 2.79~2.70 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.8, 135.3, 132.5, 129.6, 128.6, 127.2, 127.1, 117.0, 111.8, 78.9, 58.4, 42.4, 26.5. HRMS (ESI⁺) calcd for C₁₆H₁₆Br- N₂O₂ [M+H]⁺ 347.0390, found 347.0378.

  Dimethyl 2-(3-fluorophenyl)-1-nitromethyl-1, 2, 3, 4-te- trahydroisoquinoline (3la):^[24]:Yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.32~7.22 (m, 4H), 7.17 (d, J＝7.5 Hz, 1H), 6.78 (dd, J＝8.4, 1.9 Hz, 1H), 6.69 (d, J＝12.4 Hz, 1H), 6.57 (dd, J＝8.2, 1.7 Hz, 1H), 5.56 (t, J＝7.2 Hz, 1H), 4.89 (dd, J＝11.9, 7.7 Hz, 1H), 4.60 (dd, J＝11.9, 6.7 Hz, 1H), 3.65 (t, J＝6.1 Hz, 2H), 3.16~3.09 (m, 1H), 2.86 (dt, J＝16.3, 5.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 165.3, 163.3 (d, J_{C, F}＝241.9 Hz), 150.3 (d, J_{C, F}＝10.0 Hz), 150.2, 135.3, 132.8, 130.9, 130.8(d, J_{C, F}＝10.1 Hz), 129.4, 128.6, 127.3, 127.1 (d, J_{C, F}＝13.2 Hz), 110.2 (d, J_{C, F}＝2.0 Hz), 106.0, 105.8 (d, J_{C, F}＝21.3 Hz), 102.1, 101.9 (d, J_{C, F}＝25.7 Hz), 78.8, 58.3, 42.3, 26.7. HRMS (ESI⁺) calcd for C₁₆H₁₆FN₂O₂ [M+H]⁺ 287.1190, found 287.1179.

  Dimethyl 6, 7-dimethoxy-1-nitromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (3ma):^[6a] Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.25 (t, J＝8.0 Hz, 2H), 6.96 (d, J＝8.1 Hz, 2H), 6.84 (t, J＝7.3 Hz, 1H), 6.62 (d, J＝12.1 Hz, 2H), 5.46 (t, J＝7.2 Hz, 1H), 4.84 (dd, J＝11.8, 8.1 Hz, 1H), 4.56 (dd, J＝11.8, 6.3 Hz, 1H), 3.84 (d, J＝2.4 Hz, 6H), 3.70~3.54 (m, 2H), 3.04~2.92 (m, 1H), 2.66 (dt, J＝16.2, 4.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 148.9, 148.8, 147.9, 129.6, 127.6, 124.7, 119.7, 115.7, 111.9, 109.8, 78.9, 58.1, 56.2, 56.1, 42.1, 25.9. HRMS (ESI⁺) calcd for C₁₈H₂₁N₂O₄ [M+H]⁺329.1496, found 329.1489.

  Dimethyl 1, 2, 3, 4-tetrahydro-1-(1-nitroethyl)-2-phenyl- isoquinoline (3ab):^{[5e, 6a]} Yellow oil. The ratio of isolated diastereoisomers is 2. The major isomer: ¹H NMR (400 MHz, CDCl₃) δ: 5.29~5.18 (m, 1H), 3.65~3.48 (m, 2H), 1.54 (d, J＝6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 149.1, 129.6, 129.4, 128.6, 128.5, 127.5, 126.4, 119.6, 115.7, 85.7, 63.0, 42.9, 26.7, 16.7; the miner isomer: ¹H NMR (400 MHz, CDCl₃) δ: 5.10~4.99 (m, 1H), 3.88~3.79 (m, 2H), 1.70 (d, J＝6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 149.4, 129.7, 128.99, 128.6, 128.5, 127.5, 126.9, 119.0, 114.7, 89.2, 61.4, 43.8, 27.0, 17.7; Other overlapped peaks: ¹H NMR (400 MHz, CDCl₃) δ: 7.31~7.07 (m), 7.02~6.97 (m), 6.85~6.79 (m), 5.27~5.22 (m), 3.17~3.00 (m), 2.95~2.82 (m). HRMS (ESI⁺) calcd for C₁₇H₁₉N₂O₂ [M+H]⁺ 283.1441, found 283.1435.

  Dimethyl 1, 2, 3, 4-tetrahydro-1-(1-nitropropyl)-2-phenyl- isoquinoline (3ac):^[3f] Yellow oil. The ratio of isolated diastereoisomers is 1.2. The major isomer: ¹H NMR (400 MHz, CDCl₃) δ: 5.13 (d, J＝9.6 Hz, 1H), 4.90~4.82 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 149.1, 135.6, 132.6, 129.5, 129.3, 128.8, 128.3, 126.0, 119.4, 115.9, 93.1, 62.2, 42.3, 25.7, 24.7, 10.8; the miner isomer: ¹H NMR (400 MHz, CDCl₃) δ: 5.24 (d, J＝9.3 Hz, 1H), 4.71~4.63 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 149.0, 134.8, 134.0, 129.4, 128.7, 128.3, 127.3, 126.7, 118.6, 114.1, 96.2, 60.8, 43.6, 26.9, 25.1, 10.8; Other overlapped peaks: ¹H NMR (400MHz, CDCl₃)δ: 7.29~7.12 (m), 7.00~6.91 (m), 6.83~6.75 (m), 3.88~3.78 (m), 3.69~3.45 (m), 3.10~2.99 (m), 2.93~2.80 (m), 2.28~2.01 (m), 1.88~1.75 (m), 0.95~0.89 (m). HRMS (ESI⁺) calcd for C₁₈H₂₁N₂O₂[M+H]⁺ 297.1598, found 297.1597.

  Dimethyl 4-methyl-1-(2-phenyl-1, 2, 3, 4-tetrahydroiso- quinolin-1-yl)pentan-2-one (3ad):^[11b] Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.27~7.15 (m, 6H), 6.94 (d, J＝8.3 Hz, 2H), 6.77 (t, J＝7.2 Hz, 2H), 5.43 (t, J＝6.3 Hz, 2H), 3.66~3.51 (m, 2H), 3.05~2.98 (m, 2H), 2.85~2.72 (m, 2H), 2.25~2.09 (m, 2H), 1.28~1.24 (m, 1H), 0.84 (dd, J＝6.3, 1.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 209.5, 149.1, 138.7, 134.7, 129.6, 128.9, 127.2, 127.0, 126.5, 118.3, 114.8, 54.9, 53.3, 50.0, 42.3, 27.6, 24.6, 22.8, 22.8. HRMS (ESI⁺) calcd for C₂₁H₂₆NO [M+H]⁺ 308.2009, found 308.1997.

  Dimethyl 1-phenyl-2-(2-phenyl-1, 2, 3, 4-tetrahydroiso- quinolin-1-yl)ethan-1-one (3ae):^{[11b, 25]} Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.86~7.82 (m, 2H), 7.53~7.47 (m, 1H), 7.41~7.36 (m, 2H), 7.25~7.20 (m, 3H), 7.15~7.07 (m, 3H), 6.96 (d, J＝8.0 Hz, 3H), 6.76~6.71 (m, 1H), 5.68~5.64 (m, 1H), 3.69~3.53 (m, 3H), 3.42~3.34 (m, 1H), 3.15~3.05 (m, 1H), 2.95~2.86 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 198.9, 149.0, 138.8, 137.4, 134.7, 133.3, 129.6, 128.8, 128.3, 127.4, 127.1, 126.5, 118.1, 114.5, 55.2, 45.6, 42.4, 27.8. HRMS (ESI⁺) calcd for C₂₃H₂₂NO [M+H]⁺ 328.1696, found 328.1693.

  Dimethyl 2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline-1-car- bonitrile (3af): Yellow solid, m.p. 93.5~96 ℃ (lit.^[26] 94~96 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.43~7.28 (m, 6H), 7.14 (d, J＝7.9 Hz, 2H), 7.07 (t, J＝7.3 Hz, 1H), 5.56 (s, 1H), 3.82 (dd, J＝12.1, 2.5 Hz, 1H), 3.53 (td, J＝12.2, 3.6 Hz, 1H), 3.20 (ddd, J＝16.5, 10.7, 6.0 Hz, 1H), 3.01 (d, J＝16.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 148.5, 134.8, 129.8, 129.5, 128.9, 127.2, 127.0, 122.0, 118.0, 117.7, 53.3, 44.3, 28.7. HRMS (ESI⁺) calcd for C₁₆H₁₄N₂ [M+H]⁺ 235.1230, found 235.1226.

  Dimethyl 2-phenyl-3, 4-dihydroisoquinolin-1(2H)-one (4): Purified by column chromatography with eluting (petroleum ether/ethyl acetate, V:V＝15/1). Yellow solid, m.p. 78~90 ℃ (lit.^[26] 76~78 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (dd, J＝7.6, 1.1 Hz, 1H), 7.50~7.36 (m, 6H), 7.28~7.23 (m, 3H), 4.01 (t, J＝6.5 Hz, 1H), 3.17 (t, J＝6.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 164.2, 143.1, 138.3, 132.1, 129.7, 129.0, 128.8, 127.2, 127.0, 126.3, 125.3, 49.4, 28.7. HRMS (ESI⁺) calcd for C₁₅H₁₄NO [M+H]⁺ 224.1070, found 224.1066.

  Supporting Information ESI-MS spectra of imine intermediate and copies of ¹H NMR and ¹³C NMR spectra of compounds 3 and 4. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
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• 

  Scheme 1  A possible reaction path for the Ni-catalyzed aerobic CDC reaction of N-phenyltetrahydroisoquinolines with nitromethane

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of the reaction conditions^a

  Entry	Catalyst	T/℃	Solvent	Base	Conv. (Sel.)b /%
  1	NiCl2	80	1, 4-Dioxane	—	90 (83)
  2	Ni(AcO)2	80	1, 4-Dioxane	—	95 (47)
  3	Ni(NO3)2	80	1, 4-Dioxane	—	92 (22)
  4	N(Ⅱ) acetyl-acetonate	80	1, 4-Dioxane	—	97 (53)
  6	NiCl2	80	Acetonitrile	—	53 (82)
  7	NiCl2	80	DCE	—	47 (65)
  8	NiCl2	80	Toluene	—	87 (56)
  9	NiCl2	80	Methanol	—	66 (57)
  10	NiCl2	80	H2O	—	78 (41)
  11	NiCl2	80	DMF	—	60 (69)
  12	NiCl2	60	1, 4-Dioxane	—	65 (87)
  13	NiCl2	100	1, 4-Dioxane	—	＞99 (57)
  14c	NiCl2	80	1, 4-Dioxane	—	88 (78)
  15d	NiCl2	80	1, 4-Dioxane	—	92 (85)
  16	NiCl2	80	1, 4-Dioxane	Na2CO3	79 (78)
  17	NiCl2	80	1, 4-Dioxane	NaHCO3	＞99 (92)
  18	NiCl2	80	1, 4-Dioxane	K2CO3	89 (72)
  a Reaction conditions: 1a (0.5 mmol), 6 equiv. of 2a, NiCl2 (5%), solvent (2 mL), base (20%), 18 h, O2 atmosphere (101 kPa). b Based on the 1H NMR analysis. c 3 equiv. of 2a.d 8 equiv. of 2a.

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  Table 2.  Reaction scope for the Ni-catalyzed aerobic CDC reaction^a

  Entry	1	2	3	Time/h	Yieldb/%
  1		CH3NO2 (2a)		18	81
  2		2a		18	83
  3		2a		18	90
  4		2a		24	58
  5		2a		24	75
  6		2a		36	65
  7		2a		24	81
  8		2a		18	37
  9		2a		24	74
  10		2a		24	71
  11		2a		24	62
  12		2a		28	63
  13		2a		20	50
  14	1a			24	79
  15	1a			24	73
  16	1a			36	25
  17	1a			24	53
  18	1a			24	68
  a Reaction conditions: 1 (0.5 mmol), 2 (3 mmol), NiCl2 (5%), NaHCO3 (20%), dioxane (2 mL), 80 ℃, O2 atmosphere (101 kPa). b Isolated yield.

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  Table 3.  Results of some controlled experiments^a

  Entry	Catalyst	Reaction condition	Conv.b/%	Sel.b/%
  1	NiCl2/NaHCO3	O2	＞99	92
  2	—	O2	78	43
  3	NiCl2/NaHCO3	N2	Trace	—
  4	NiCl2/NaHCO3	Air	74	49
  5	NiCl2/NaHCO3	O2/BHTc	Trace	—
  6	NiCl2/NaHCO3	O2/TEMPOc	45	93
  a Reaction conditions: 1, 2, 3, 4-tetrahydroquinoline (0.5 mmol), nitromethane (3 mmol), NiCl2 (5%), NaHCO3 (20%), dioxane (2 mL), 18 h, 80 ℃, O2 atmosphere (101 kPa). b Based on the 1H NMR analysis. c 2 equiv. of substrate.

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