English

• 1.   Introduction

  In contrast to the classical polar reaction pathway (two electron pathway), radicals can serve as both nucleophile and electrophile, and radical mediated transformations have higher functional group compatibility.^[1] Thereby, the merger of radical and transition metal catalysis is an attractive strategy in organic synthesis.^[2] Owing to the diverse readily available oxidation states (Ni⁰, Ni^Ⅰ, Ni^Ⅱ, Ni^Ⅲ, and Ni^Ⅳ) and less prone to β-H elimination, ^[3] Ni-catalyzed cross-couplings via alkyl radical has been developed as a powerful tool to forge carbon-carbon (C—C) and carbon-heteroatom (C—Y) bonds, including asymmetric variants.^[4]

  Alkyl halides, sulfones, and redox-active esters are widely used as alkyl radical precursors for Ni-catalyzed cross-coupling.^[5~7] Alternatively, cycloketone oximes are attractive alkyl radical precursors, wherein the N—O bond of oximes can be activated upon single-electron-transfer (SET) to generate alkyl radicals via C—C bond cleavage from resulting iminyl radicals.^[8] For instance, Zard and co-workers^[9] reported a ring opening of iminyl radicals when sulphenylimines was irradiated by UV or initiated by organotin reagent in 1991. Subsequently, they disclosed that oxime esters could also be activated to generate iminyl radicals by iron and nickel powder.^[10] Since then, much efforts have been devoted to develop new transformations based on cycloketone oxime esters, wherein various valuable alkyl nitriles can be obtained, avoiding the use of extremely toxic NaCN or KCN.^[11~15] Alkyl nitriles not only widely exist in natural products, pharmaceuticals and agrochemicals, but are also versatile intermediate in organic synthesis and can be easily converted to amides, ketones, imidazoles, and oxazoles.^[16]

  Recently, Selander and co-workers^[17] reported a nickel catalyzed Suzuki coupling, wherein only three examples were shown (left, Scheme 1a). However, the reaction requires super stoichiometric amount (10 equiv.) of Et₃N as the base under elevated temperature (90 ℃). Later, Wang and Ding^[18] reported a Ni-catalyzed cross-coupling of cycloketone oxime esters with aromatic acid chlorides using metal Mn as the reductant (right, Scheme 1a). As part of our continuing interest in Ni-catalyzed reactions and radical chemistry, ^[19] we wondered whether alkyl radicals generated from oxime esters by Ni catalysis could be captured by aryl nickel species and thus providing an efficient and mild protocol to prepare alkyl nitriles (Scheme 1b).^[20] Herein, we report a Ni-catalyzed Negishi coupling of cyclobutanone oxime esters with aryl zinc reagents, in which Ni catalysis servers as dual roles for iminyl radical generation and cross-coupling of an alkyl radical with an aryl zinc reagent (Scheme 1c). The protocol provides an efficient method for the syntheses of various aliphatic nitriles in good yield, avoiding the use of poisonous cyanide. The broad substrate scope and good functional group compatibility make this method attractive for the synthesis of valuable nitriles. Preliminary mechanistic studies indicate that a radical pathway is involved in the product formation.

  Scheme 1

  

  Scheme 1.  Nickel-catalyzed transformations of oxime esters

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  2.   Results and discussion

  To test our hypothesis, cyclobutanone oxime ester 1a was initially selected as the substrate. However, no desired product was observed (Table 1, Entry 1). To our delight, changing acetate 1a to benzoate 1a' afforded 3a in 46% yield (Entry 2). Replacement of 1a' with p-trifluoromethyl-benzoate 1a'' further improved the yield to 96% (Entry 3), indicating a significant electronic effect of the acyl group on the reaction. Other metal catalyst such as Co(acac)₂ was not effective for the reaction (Entry 4). While with FeCl₃ as catalyst, it afforded only 19% yield of 3a (Entry 5). The inferior yield of FeCl₃ was attributed to the formation of the halogenation side product. A brief ligand screening revealed obvious ligand effects, and 4, 4'-di-tert-butyl-2, 2'-bipyridine (L5) was found to be optimal (Entries 6~12). Notably, solvents were also critical, reaction carried out in tetrahydrofuran (THF) furnished product 3a in 53% yield, which was much lower than that of in N, N'-dimethyl-formamide (DMF) (Entry 13). Switching catalyst from NiBr₂(glyme) to NiCl₂(glyme) and reducing the catalyst loading to 5 mol% slightly decreased the yield (Entries 14, 15). Further reducing the catalyst loading to 1 mol% decreased the yield to 73% (Entry 16). The amount of 2a was also investigated, increasing the amount of 2a did not improve the yield, decreasing it led to the low yield.

  Table 1

  

  Table 1.  Optimization of reaction conditions^a

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  Entry	Oxime ester	Catalyst	Ligand	Yieldb/%
  1	1a	NiBr2(glyme)	L5	Trace
  2	1a'	NiBr2(glyme)	L5	46
  3	1a''	NiBr2(glyme)	L5	96
  4	1a''	Co(acac)2	L5	Trace
  5	1a''	FeCl3	L5	19
  6	1a''	NiBr2(glyme)	L1	66
  7	1a''	NiBr2(glyme)	L2	93
  8	1a''	NiBr2(glyme)	L3	71
  9	1a''	NiBr2(glyme)	L4	82
  10	1a''	NiBr2(glyme)	L6	44
  11	1a''	NiBr2(glyme)	L7	79
  12	1a''	NiBr2(glyme)	L8	93
  13c	1a''	NiBr2(glyme)	L5	53
  14d	1a''	NiBr2(glyme)	L5	86
  15e	1a''	NiCl2(glyme)	L5	91
  16f	1a''	NiCl2(glyme)	L5	73
  a Reaction conditions: 10 mol% NiBr2(glyme), 10 mol% L5, 1a (0.2 mmol, 1.0 equiv.), 2a (0.2 mmol, 1.0 equiv.) in DMF (0.2 mL), r.t., 12 h. b Yield determined by HNMR using 1, 4-dimethoxybenzene as internal standard. c THF as solvent. d 5 mol% NiBr2(glyme) was used. e 5 mol% NiCl2(glyme) was used. f 1 mol% NiCl2(glyme) was used.

  With the optimized conditions in hand, we further investigated the substrate scope of oxime esters (Table 2). A variety of 3-substituted cyclobutanone oxime esters react smoothly to afford the corresponding alkyl nitriles in good yields (3a~3n). Substrates bearing functional groups including fluoro, chloro, bromo, and CF₃ groups were well-tolerated under the standard reaction conditions. For 2-substituted oxime esters, C—C bond cleavage selectively occurs on the more substituted side, affording a thermodynamically favorable secondary radical intermediate. The corresponding product was obtained in 64%~94% yield (3o~3q). The oxime ester derived from benzocyclobutenone was also efficient substrate and product 3r was obtained in 91% yield. Notably, alkenyl groups were also compatible, 3s and 3t were obtained in 90% and 81% yields, respectively. This result indicated that the capture of alkyl radicals by aryl nickel species was much faster than the intermolecular addition of radicals to alkenes. Substrates bearing 5- and 6-membered rings gave products 3u and 3v in trans-configuration.

  Table 2

  

  Table 2.  Substrate scope of oxime esters

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  Next, we turned our attention to examine the scope of organozinc reagents (Table 3). Under the standard conditions, organozinc reagents bearing chloro, bromo and iodo substituent gave the desired products in moderate to good yields (4b~4d). Organozinc reagents with electron withdrawing group such as CF₃ and OCF₃ groups were well-tolerated (4e, 4f, 4q). Ortho-substituted zinc reagents successfully afforded 4g and 4r in 94% and 85% yields, respectively. It was noteworthy that sulfur and nitrogen containing organozinc reagents reacted smoothly with 1a'' to afford the corresponding products in 66%~85% yields (4j, 4k, 4r~4t). However, alkenyl zinc or alkynyl zinc reagents delivered no cross-coupling products. But 23% yield of 4u was obtained when 3-phenyl propyl zinc reagent was used.

  Table 3

  

  Table 3.  Substrate scope of organozinc reagents

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  To gain insights into the reaction mechanism, control experiments was performed. When oxime ester 1x reacted with 2a under standard condition, 29% of 3x was isolated. Theoretically, the direct capture of ring opening radical intermediate Int Ⅰ by aryl nickel species could form 3y. Int Ⅰ could produce Int Ⅱ through an intramolecular cyclization, and trapping Int Ⅱ by aryl nickel could deliver 3z. However, 3y and 3z were not detected and 3x was isolated instead. We speculated that Int Ⅲ was formed from Int Ⅱ via a fast 1.5-hydrogen atom transfer process. The more stable radical in the α-position of cyano group then reacted with aryl nickel to produce 3x (Scheme 2a). Moreover, stoichiometric amount of TEMPO was added to the reaction system of 1a and 2a, formation of the desired product 3a was inhibited and radical trapping product 5 was isolated in 16% yield (Scheme 2b). Stoichiometric experiment was also carried out with an in-situ formed nickel complex. And the corresponding product 4v was isolated in 60% yield (Scheme 2c).

  Scheme 2

  

  Scheme 2.  Mechanistic experiments

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  Based on these aforementioned results and related literature, ^[21] a possible mechanism is proposed in Scheme 3. First, oxime ester is activated by nickel catalyst Ⅰ via SET and furnishing iminyl radical Ⅴ which is further converted to radical Ⅵ by fragmentation. Aryl nickel species Ⅲ is formed by transmetalation of aryl zinc reagents to a Ni(Ⅱ) intermediate Ⅱ. Then the radical Ⅵ is trapped by aryl nickel species Ⅲ, affording a trivalent nickel intermediate Ⅳ. Subsequent reductive elimination gives the desired product 3 and regenerates the catalyst.

  Scheme 3

  

  Scheme 3.  Proposed reaction mechanism

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  3.   Conclusions

  Overall, we have developed a nickel catalyzed crosscoupling of cyclobutanone oxime esters with organozinc reagents. The mild reaction conditions, wide substrate scope and excellent functional group compatibility made this protocol an efficient method to prepare a wide variety of alkyl nitriles. Preliminary mechanistic experiments suggest that the reaction proceeds through a radical intermediate.

  4.   Experimental section

  4.1   Instruments and reagents

  Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers and used without further purification. ¹H NMR and ¹³C NMR spectra were recorded at 400 MHz NMR spectrometer using CDCl₃ as solvent and TMS as an internal standard.

  4.2   Preparation of compound 1

  Cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime (1a): According to the literature, ^[22a] 1a was prepared from the commercially available cyclobutanone as a white solid (73% yield). The data is consistent with the literature report.

  3-Benzylcyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1b): According to the literature, ^[22a] 1b was prepared from the commercially available allylbenzene as a white solid (64% yield). The data is consistent with the literature report.

  3-Methyl-3-phenylcyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1c): According to the literature, ^[22b] 1c was prepared from the commercially available prop-1-en-2-ylbenzene as a yellow solid (81% yield). The data is consistent with the literature report.

  3-Phenylcyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1d): According to the literature, ^[22b] 1d was prepared from the commercially available styrene as a white solid (86% yield). The data is consistent with the literature report.

  3-(4-Fluorophenyl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1e): According to the literature, ^[22a] 1e was prepared from the commercially available 1-fluoro-4-vinylbenzene as a white solid (77% yield). m.p. 111.3~114.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (d, J＝8.1 Hz, 2H), 7.74 (d, J＝8.2 Hz, 2H), 7.26 (m, 2H), 7.06 (m, 2H), 3.77~3.53 (m, 3H), 3.23 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 166.44, 162.80, 160.55 (d, J＝246 Hz), 138.53 (d, J＝3 Hz), 134.65 (q, J＝33 Hz), 132.20, 130.06, 127.86 (d, J＝8 Hz), 125.59 (q, J＝4 Hz), 124.89 (q, J＝271 Hz), 115.55 (q, J＝21 Hz), 39.73, 39.71, 31.92; ¹⁹F NMR (376 MHz, CDCl₃) δ: －63.18, －115.53; IR (neat) v: 1739, 1687, 1323, 1262, 1221, 1125, 1076, 825, 528 cm^－1. HRMS (ESI) cacld for C₁₈H₁₃F₄NO₂Na [M+Na]⁺ 374.0775, found 374.0783

  3-(2-Fluorophenyl)cyclobutan-1-one O-(4-(trifluoromethyl) benzoyl) oxime (1f): According to the literature, ^[22b] 1f was prepared from the commercially available 1-fluoro-2-vinylbenzene as a white solid (69% yield). m.p. 70.6~71.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.16 (d, J＝8.2 Hz, 2H), 7.72 (d, J＝8.2 Hz, 2H), 7.24 (m, 2H), 7.14 (td, J＝7.5, 1.3 Hz, 1H), 7.09~7.02 (m, 1H), 3.86 (p, J＝8.4 Hz, 1H), 3.69~3.53 (m, 2H), 3.40~3.25 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 166.71, 162.78, 161.21 (d, J＝244 Hz), 134.73 (q, J＝33 Hz), 132.25, 130.06, 129.19 (d, J＝14 Hz), 128.74 (d, J＝8 Hz), 127.62 (d, J＝4 Hz), 125.57 (q, J＝4 Hz), 124.30 (d, J＝4 Hz), 123.61 (q, J＝273 Hz), 115.60 (d, J＝22 Hz), 38.51 (d, J＝2 Hz), 38.32 (d, J＝2 Hz), 27.44 (d, J＝2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －63.19, －116.78; IR (neat) v: 1739, 1492, 1323, 1262, 1164, 1075, 872, 753 cm^－1. HRMS (ESI) cacld for C₁₈H₁₃F₄NO₂Na [M+Na]⁺ 374.0775, found 374.0769

  3-(3-Bromophenyl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1g): According to the literature, ^[22b] 1g was prepared from the commercially available 1-bro-mo-3-vinylbenzene as a white solid (83% yield). m.p. 67.3~72.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.18~8.13 (d, J＝8.1 Hz, 2H), 7.72 (d, J＝8.1 Hz, 2H), 7.43~7.37 (m, 2H), 7.26~7.18 (m, 2H), 3.75~3.53 (m, 3H), 3.30~3.17 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 166.03, 162.73, 145.10, 134.65 (q, J＝33 Hz), 132.16, 130.39, 130.16, 130.06, 129.62, 125.59 (q, J＝3 Hz), 124.98, 122.91, 122.18, 39.37, 32.17; ¹⁹F NMR (376 MHz, CDCl₃) δ: －63.18; IR (neat) v: 1740, 1408, 1321, 1256, 1126, 1067, 844, 767, 687 cm^－1. HRMS (ESI) cacld for C₁₈H₁₃-BrF₃NO₂Na [M+Na]⁺ 433.9974, found 433.9984

  3-(4-Chlorophenyl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1h): According to the literature, ^[22b] 1h was prepared from the commercially available 1-chloro-4-vinylbenzene as a white solid (88% yield). m.p. 137.2~140.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.19 (d, J＝8.0 Hz, 2H), 7.76 (d, J＝8.0 Hz, 2H), 7.35 (d, J＝1.7 Hz, 2H), 7.30~7.23 (d, J＝1.7 Hz, 2H), 3.79~3.58 (m, 4H), 3.25 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 166.23, 162.77, 141.28, 134.67 (q, J＝33 Hz), 132.83, 132.17, 130.07, 128.94, 127.75, 125.60 (q, J＝3 Hz), 123.60 (q, J＝274 Hz), 39.57, 39.55, 32.03; ¹⁹F NMR (377 MHz, CDCl₃) δ: －63.15; IR (neat) v: 1738, 1687, 1323, 1261, 1181, 1124, 1074, 1011, 867, 818, 698 cm^－1. HRMS (ESI) cacld for C₁₈H₁₃ClF₃NO₂Na [M+Na]⁺ 390.0479, found 390.0483

  3-(4-(Trifluoromethyl)phenyl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1i): According to the literature, ^[22b] 1i was prepared from the commercially available 1-(trifluoromethyl)-4-vinylbenzene as a white solid (80% yield). m.p. 156.3~158.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.15 (d, J＝8.1 Hz, 2H), 7.72 (d, J＝8.2 Hz, 2H), 7.61 (d, J＝8.0 Hz, 2H), 7.39 (d, J＝8.0 Hz, 2H), 3.78 (p, J＝7.9 Hz, 1H), 3.72~3.57 (m, 2H), 3.34~3.18 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 165.84, 162.73, 146.77, 135.02 (q, J＝33 Hz), 132.12, 130.06, 129.26 (q, J＝33 Hz), 126.78, 125.82 (q, J＝3 Hz), 125.60 (q, J＝3 Hz), 124.87 (q, J＝53 Hz), 122.16 (q, J＝54 Hz), 39.40, 32.35; ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.52, －63.21; IR (neat) v: 2935, 1738, 1511, 1323, 1244, 1159, 1109, 1064, 827, 584 cm^－1. HRMS (ESI) cacld for C₁₉H₁₃F₆N-O₂Na [M+Na]⁺ 424.0743, found 424.0748

  3-(4-(Tert-butyl)phenyl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1j): According to the literature, ^[22c] 1j was prepared from the commercially available 1-(tert-butyl)-4-vinylbenzene as a white solid (89% yield). The data is consistent with the literature report.

  3-Methyl-3-(3-(trifluoromethyl)phenyl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1k): According to the literature, ^[22b] 1k was prepared from the commercially available 1-(prop-1-en-2-yl)-4-(trifluoromethyl)benzene as a white solid (78% yield). m.p. 87.5~89.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.21 (d, J＝8.0 Hz, 2H), 7.77 (d, J＝8.0 Hz, 2H), 7.59~7.46 (m, 4H), 3.52 (m, 2H), 3.41~3.25 (m, 2H), 1.65 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 165.03, 162.72, 148.73, 134.68 (q, J＝33 Hz), 132.15, 130.94 (q, J＝32 Hz), 130.08, 129.31, 128.62, 125.62 (q, J＝4 Hz), 125.15 (q, J＝50 Hz), 123.47 (q, J＝3 Hz), 122.44 (q, J＝50 Hz), 121.89 (q, J＝3 Hz), 44.71, 44.67, 44.67, 38.11, 30.74; ¹⁹F NMR (377 MHz, CDCl₃) δ: －62.55, －63.14; IR (neat) v: 1743, 1325, 1264, 1127, 1064, 862, 696 cm^－1. HRMS (ESI) cacld for C₂₀H₁₅F₆-NO₂Na [M+Na]⁺ 438.0899, found 438.0888

  3-(Naphthalen-2-yl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1l): According to the literature, ^[22d] 1l was prepared from the commercially available 2-vinylnaphthalene as a white solid (75% yield). The data is consistent with the literature report.

  3-Propylcyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1m): According to the literature, ^[22b] 1m was prepared from the commercially available cyclobutanone as an oil (68% yield), m.p. 42.8~44.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.16 (d, J＝8.1 Hz, 2H), 7.72 (d, J＝8.2 Hz, 2H), 3.23 (m, 2H), 2.76~2.64 (m, 2H), 2.45 (p, J＝7.4 Hz, 1H), 1.56 (qd, J＝7.2, 3.3 Hz, 3H), 1.34 (h, J＝7.3 Hz, 2H), 0.94 (t, J＝7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 168.40, 162.89, 134.82 (q, J＝32 Hz), 132.41, 130.02, 125.48 (q, J＝3 Hz), 122.21 (q, J＝271 Hz), 38.24, 37.46, 28.14, 20.51, 13.90; ¹⁹F NMR (376 MHz, CDCl₃) δ: －63.17; IR (neat) v: 1740, 1323, 1261, 1160, 1113, 1065, 1013, 891, 837, 740, 698 cm^－1. HRMS (ESI) cacld for C₁₅H₁₆F₃NONa [M+Na]⁺ 322.1025, found 322.1024

  Spiro[3.11]pentadecan-2-one O-(4-(trifluoromethyl)benzoyl) oxime (1n): According to the literature, ^[22b] 1n was prepared from the commercially available cyclobutanone as a white solid (75% yield). m.p. 125.4~132.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.18 (d, J＝8.1 Hz, 2H), 7.75 (d, J＝8.1 Hz, 2H), 2.81 (m, 4H), 1.61 (m, 4H), 1.38 (s, 18H); ¹³C NMR (101 MHz, CDCl₃) δ: 167.78, 162.90, 134.50 (q, J＝33 Hz), 132.45, 130.02, 125.50 (q, J＝3 Hz), 123.50 (q, J＝274 Hz), 42.49, 36.71, 33.41, 26.26, 25.93, 22.44, 22.18, 19.44; ¹⁹F NMR (377 MHz, CDCl₃) δ: －63.13; IR (neat) v: 2932, 1744, 1322, 1252, 1127, 1078, 1013, 882, 696 cm^－1. HRMS (ESI) cacld for C₂₃H₃₀F₃NO₂ [M+Na]⁺ 432.2121, found 432.2130

  (Z)-2-Benzylcyclobutan-1-one O-(4-(trifluoromethyl)-benzoyl) oxime (1o): According to the literature, ^[22e] 1o was prepared from the commercially available cyclobutanone as a yellow oil (54% yield), The spectrum was a mixture of cis and trans isomers. The data is consistent with the literature report.

  3-Phenethylcyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1p): According to the literature, ^[22b] 1p was prepared from the commercially available cyclobutanone as a yellow oil (83% yield). ¹H NMR (400 MHz, CDCl₃) δ: 8.08 (d, J＝8.1 Hz, 2H), 7.65 (d, J＝8.2 Hz, 2H), 7.22 (dd, J＝8.1, 6.7 Hz, 2H), 7.17~7.08 (m, 3H), 3.25~3.10 (m, 2H), 2.72~2.59 (m, 2H), 2.60~2.53 (m, 2H), 2.38 (tt, J＝9.5, 7.0 Hz, 1H), 1.88~1.77 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 167.95, 162.85, 141.24, 134.51 (q, J＝33 Hz), 132.39, 130.03, 128.52, 128.36, 126.11, 125.53 (q, J＝4 Hz), 123.59 (q, J＝274 Hz), 37.70, 37.39, 37.34, 33.67, 27.85; ¹⁹F NMR (377 MHz, CDCl₃) δ: －63.12; IR (neat) v: 1743, 1323, 1258, 1166, 1125, 1067, 1014, 859, 767, 697 cm^－1. HRMS (ESI) cacld for C₂₀H₁₈F₃-NO₂Na [M+Na]⁺ 384.1182, found 384.1183

  (Z)-2-Pentylcyclobutan-1-one O-(4-(trifluoromethyl)-benzoyl) oxime (1q): According to the literature, ^[22b] 1q was prepared from the commercially available cyclobutanone as a yellow oil (43% yield). The spectrum was a mixture of cis and trans isomers. ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (d, J＝8.0 Hz, 2H), 7.74 (d, J＝8.4 Hz, 2H), 3.47~2.96 (m, 2H), 2.57~2.20 (m, 2H), 1.94~1.58 (m, 3H), 1.49~1.25 (m, 6H), 0.91 (t, J＝6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 173.55, 162.90, 134.57 (q, J＝33 Hz), 132.56, 129.97, 125.49 (q, J＝3 Hz), 123.57 (q, J＝273 Hz), 45.77, 32.28, 31.59, 29.09, 26.51, 22.49, 20.95, 14.02; ¹⁹F NMR (377 MHz, CDCl₃) δ: －63.15; IR (neat) v: 2931, 1746, 1323, 1258, 1166, 1127, 1066, 1014, 860, 769, 699 cm^－1. HRMS (ESI) cacld for C₁₇H₂₀F₃-NO₂Na [M+Na]⁺ 350.1338, found 350.1334.

  (E)-Bicyclo[4.2.0]octa-1(6), 2, 4-trien-7-one O-(4-(trifluoromethyl)benzoyl) oxime (1r): According to the literature, ^22b 1r was prepared from the commercially available cyclobutanone as a white solid (85% yield). The spectrum was a mixture of cis and trans isomers. the data is consistent with the literature report.

  (Z)-2-(But-3-en-1-yl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1s): According to the literature, ^[22b] 1s was prepared from the commercially available cyclobutanone as a mixture of trans and cis isomers, yellow oil (39% yield). ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (d, J＝8.1 Hz, 2H), 7.74 (d, J＝8.2 Hz, 2H), 5.83 (ddt, J＝16.9, 10.2, 6.6 Hz, 1H), 5.15~4.97 (m, 2H), 3.54~3.39 (m, 1H), 3.21~2.95 (m, 2H), 2.37~2.11 (m, 3H), 2.00 (ddt, J＝13.4, 8.5, 6.6 Hz, 1H), 1.83~1.73 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 173.29, 162.88, 137.59, 134.47, 132.51, 130.41, 129.98, 125.51, 115.32, 45.14, 31.41, 30.99, 29.12, 20.94; ¹⁹F NMR (377 MHz, CDCl₃) δ: －63.15; IR (neat) v: 1745, 1323, 1258, 1166, 1126, 1066, 1014, 859, 768, 698 cm^－1. HRMS (ESI) cacld for C₁₆H₁₆-F₃NO₂Na [M+Na]⁺ 334.1025, found 334.1029

  (Z)-2-Allylcyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1t): According to the literature, ^[22b] 1t was prepared from the commercially available cyclobutanone as a white solid (43% yield). The data is consistent with the literature report.

  (E)-2, 2a, 7, 7a-Tetrahydro-1H-cyclobuta[a]inden-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1u): According to the literature, ^[22b] 1u was prepared from the commercially available cyclobutanone as a white solid (71% yield), The spectrum was a mixture of cis and trans isomers. m.p. 114.2~123.7 ℃; ¹H NMR (400 MHz, CDCl₃) (major) δ: 8.10 (d, J＝8.1 Hz, 2H), 7.69 (d, J＝8.2 Hz, 2H), 7.33~7.17 (m, 4H), 4.25~4.13 (m, 1H), 4.05 (ddd, J＝13.1, 8.4, 4.0 Hz, 1H), 3.66~3.27 (m, 3H), 3.12~2.88 (m, 1H); ¹H NMR (400 MHz, CDCl₃) (minor) δ: 8.21 (d, J＝8.1 Hz, 2H), 7.78 (d, J＝8.2 Hz, 2H), 7.33~7.17 (m, 4H), 4.25~4.13 (m, 1H), 4.05 (ddd, J＝13.1, 8.4, 4.0 Hz, 1H), 3.66~3.27 (m, 3H), 3.12~2.88 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ: 172.59, 162.68, 144.02, 143.13, 142.37, 134.53 (q, J＝33 Hz), 132.26, 130.00, 127.71, 127.49, 125.53 (q, J＝4 Hz), 125.38, 124.97, 47.91, 40.45, 40.15, 36.96. ¹⁹F NMR (376 MHz, CDCl₃) δ: －63.19; IR (neat) v: 1744, 1323, 1246, 1131, 1063, 1011, 838, 768, 681 cm^－1. HRMS (ESI) cacld for C₁₉H₁₄F₃NO₂Na [M+Na]⁺ 368.0869, found 368.0863

  (E)-Bicyclo[3.2.0]hept-2-en-6-one O-(4-(trifluoromethyl)benzoyl) oxime (1v): According to the literature, ^[22b] 1v was prepared from the commercially available cyclobutanone as a yellow oil (67% yield), The spectrum was a mixture of cis and trans isomers. ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (d, J＝8.1 Hz, 2H), 7.71 (d, J＝8.2 Hz, 2H), 5.88~5.77 (m, 2H), 3.95 (m, 1H), 3.52~3.39 (m, 1H), 3.28 (m, 1H), 2.94~2.63 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 173.80, 162.78, 134.47 (q, J＝33 Hz), 132.57, 132.04, 129.99, 125.48 (q, J＝3 Hz), 123.58 (q, J＝274 Hz), 46.90, 40.83, 38.98, 37.66; ¹⁹F NMR (376 MHz, CDCl₃) δ: －63.22; IR (neat) v: 1742, 1322, 1256, 1164, 1126, 1063, 976, 843, 768, 699 cm^－1. HRMS (ESI) cacld for C₁₅H₁₂F₃NONa [M+Na]⁺ 318.0712, found 318.0706

  (Z)-2-Methylcyclobutan-1-one O-(4-(trifluoromethyl)-benzoyl) oxime (1w): According to the literature, ^[22b] 1w was prepared from the commercially available cyclobutanone as a yellow oil (53% yield). The data is consistent with the literature report.

  (Z)-2-(Pent-4-en-1-yl)cyclobutan-1-one O-(4-(trifluoromethyl)benzoyl) oxime (1x): According to the literature, ^[22b] 1x was prepared from the commercially available cyclobutanone as an yellow oil (44% yield), ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (d, J＝8.1 Hz, 1H), 7.74 (d, J＝8.2 Hz, 1H), 5.82 (ddt, J＝16.9, 10.2, 6.7 Hz, 1H), 5.08~4.95 (m, 1H), 3.43 (ddtd, J＝9.4, 6.2, 4.3, 3.6, 2.2 Hz, 1H), 3.19~2.93 (m, 1H), 2.28 (dtd, J＝11.2, 9.6, 5.9 Hz, 1H), 2.11 (qd, J＝6.8, 1.5 Hz, 1H), 1.96~1.64 (m, 2H), 1.60~1.48 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 173.32, 162.87, 138.33, 134.43 (q, J＝33 Hz), 132.52, 129.97, 125.49 (q, J＝3 Hz), 123.41 (q, J＝274 Hz), 114.87, 45.59, 33.48, 31.74, 29.11, 26.10, 20.91; ¹⁹F NMR (376 MHz, CDCl₃) δ: －63.18; IR (neat) v: 1743, 1324, 1258, 1153, 1065, 983, 768, 687 cm^－1. HRMS (EI) cacld for C₁₇H₁₈F₃-NO₂Na [M+Na]⁺ 348.1182, found 348.1177.

  4.3   General procedure for compounds 3 and 4

  To a 4 mL screwed-capped vial was added oxime ester 1 (0.2 mmol), NiCl₂ glyme (2 mg, 0.01 mmol), ligand (3 mg, 0.01 mmol), DMF (0.2 mL) in Glove box. The resulting mixture was stirred for 15 min at room temperature. To the solution was added organo-zinc reagent (0.8 mL, 0.25 mol·L^－1, 0.2 mmol). The vial was removed from Glove box and stirred at room temperature for 12 h. After this time, the reaction mixture was quenched with saturated ammonia chloride (1 mol·L^－1), and diluted with ethyl acetate. The organic layer was separated and dried over anhydrous Na₂SO₄, filtered and removed under vacuum. The corresponding product 3 or 4 was obtained by flash chromatography.

  4-(4-Methoxyphenyl)butanenitrile (3a): Colorless oil, 29.8 mg, 85% yield. The data is consistent with the literature report.^[22f]

  3-Benzyl-4-(4-methoxyphenyl)butanenitrile (3b): Colorless oil, 33.1 mg, 62% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.36~7.29 (m, 2H), 7.28~7.23 (m, 1H), 7.23~7.18 (m, 2H), 7.12 (d, J＝8.5 Hz, 2H), 6.89~6.84 (m, 2H), 3.80 (s, 3H), 2.84 (ddd, J＝19.0, 13.9, 5.7 Hz, 2H), 2.66 (td, J＝13.3, 8.8 Hz, 2H), 2.26~2.18 (m, 1H), 2.15 (d, J＝4.9 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.37, 138.89, 130.74, 130.00, 129.04, 128.74, 126.67, 118.43, 114.11, 55.30, 39.70, 38.87, 20.26; IR (neat) v: 2925, 1780, 1511, 1452, 1245, 1178, 1033, 741, 701 cm^－1. HRMS (ESI) cacld for C₁₈H₁₉NONa [M+Na]⁺ 288.1359, found 288.1353.

  4-(4-Methoxyphenyl)-3-methyl-3-phenylbutanenitrile (3c): Colorless oil, 42.9 mg, 81% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.37 (m, 2H), 7.34~7.22 (m, 3H), 6.73 (m, 4H), 3.77 (s, 3H), 3.02 (s, 2H), 2.68 (s, 2H), 1.54 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.40, 143.98, 131.24, 128.56, 128.52, 126.96, 126.08, 118.51, 113.34, 55.18, 47.31, 41.31, 29.38, 25.52; IR (neat) v: 3031, 2242, 1721, 1609, 1510, 1245, 1178, 1030, 836, 812, 755, 698 cm^－1. HRMS (ESI) cacld for C₁₈H₁₉NONa [M+Na]⁺ 288.1365, found 288.1359.

  4-(4-Methoxyphenyl)-3-phenylbutanenitrile (3d): Colorless oil, 25.1 mg, 50% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.32 (dd, J＝8.1, 6.5 Hz, 2H), 7.29~7.23 (m, 1H), 7.21 (dd, J＝7.1, 1.8 Hz, 2H), 7.03~6.97 (m, 2H), 6.82~6.76 (m, 2H), 3.76 (s, 3H), 3.17 (p, J＝6.9 Hz, 1H), 2.99 (dd, J＝7.6, 2.4 Hz, 2H), 2.63~2.46 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.34, 141.37, 130.33, 130.01, 128.79, 127.46, 127.25, 118.51, 113.94, 55.21, 43.99, 40.33, 23.47; IR (neat) v: 3004, 2242, 1720, 1610, 1511, 1244, 1176, 1032, 816, 699 cm^－1. HRMS (EI) cacld for C₁₇H₁₇NO [M]⁺ 251.1310, found 251.1305.

  3-(4-Fluorophenyl)-4-(4-methoxyphenyl)butanenitrile (3e): Colorless oil, 45.7 mg, 85% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.20~7.13 (m, 1H), 7.05~6.94 (m, 2H), 6.83~6.76 (m, 2H), 3.76 (s, 3H), 3.17 (qd, J＝7.4, 5.7 Hz, 1H), 2.96 (d, J＝7.5 Hz, 2H), 2.61~2.46 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 163.23, 160.78, 158.40, 137.03, 130.04, 129.98, 128.80 (d, J＝129 Hz), 118.32, 115.67 (d, J＝21 Hz), 113.98, 55.21, 43.33, 40.46, 23.66; ¹⁹F NMR (376 MHz, CDCl₃) δ: －114.99; IR (neat) v: 2915, 1606, 1508, 1242, 1177, 1031, 830, 535 cm^－1. HRMS (EI) cacld for C₁₇H₁₆FNO [M]⁺ 269.1216, found 269.1210.

  3-(2-Fluorophenyl)-4-(4-methoxyphenyl)butanenitrile (3f): Colorless oil, 31.2 mg, 58% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.22~7.13 (m, 2H), 7.05 (m, 1H), 7.02~6.94 (m, 3H), 6.76~6.70 (m, 2H), 3.70 (s, 3H), 3.44 (dt, J＝8.3, 6.7 Hz, 1H), 3.01~2.89 (m, 2H), 2.56 (d, J＝6.5 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 160.66 (d, J＝246 Hz), 158.45, 130.10, 130.00, 129.03 (d, J＝8 Hz), 128.65 (d, J＝4 Hz), 127.99 (d, J＝14 Hz), 124.49 (d, J＝3 Hz), 118.32, 115.78 (d, J＝22 Hz), 114.03, 55.26, 38.83, 37.66, 22.09; ¹⁹F NMR (376 MHz, CDCl₃) δ: －118.03; IR (neat) v: 2933, 1722, 1611, 1511, 1490, 1245, 1033, 821 cm^－1. HRMS (EI) cacld for C₁₇H₁₆FNO [M]⁺ 269.1216, found 269.1212.

  3-(3-Bromophenyl)-4-(4-methoxyphenyl)butanenitrile (3g): Colorless oil, 49.7 mg, 75% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.39 (dt, J＝7.8, 1.5 Hz, 1H), 7.35 (s, 1H), 7.27~7.09 (m, 2H), 7.03~6.95 (m, 2H), 6.83~6.74 (m, 2H), 3.77 (s, 3H), 3.14 (p, J＝7.0 Hz, 1H), 3.02~2.87 (m, 2H), 2.61~2.43 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.48, 143.64, 130.67, 130.38, 130.35, 129.98, 129.75, 126.02, 122.83, 118.10, 114.06, 55.24, 43.73, 40.21, 23.30; IR (neat) v: 2933, 1611, 1511, 1490, 1245, 1033, 821, 756 cm^－1. HRMS (EI) cacld for C₁₇H₁₆BrNO [M]⁺ 329.0415, found 329.0410.

  3-(4-Chlorophenyl)-4-(4-methoxyphenyl)butanenitrile (3h): Yellow solid, 41.4 mg, 73% yield. m.p. 56.2~58.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.25~7.19 (m, 2H), 7.09~7.03 (m, 2H), 6.94~6.87 (m, 2H), 6.75~6.70 (m, 2H), 3.69 (s, 3H), 3.09 (m, 1H), 2.89 (d, J＝7.5 Hz, 1H), 2.55~2.39 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.46, 139.79, 133.28, 130.03, 129.91, 129.00, 128.70, 118.30, 114.05, 55.27, 43.50, 40.32, 23.52; IR (neat) v: 2930, 1610, 1511, 1244, 1177, 1032, 784, 694 cm^－1. HRMS (EI) cacld for C₁₇H₁₆ClNO [M]⁺ 285.0920, found 285.0915.

  4-(4-Methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)butanenitrile (3i): Colorless oil, 41.1 mg, 64% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (d, J＝8.1 Hz, 2H), 7.32 (d, J＝8.1 Hz, 2H), 7.04~6.94 (m, 2H), 6.80 (d, J＝8.6 Hz, 2H), 3.76 (s, 3H), 3.24 (td, J＝7.5, 5.8 Hz, 1H), 3.00 (d, J＝7.5 Hz, 2H), 2.65~2.51 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.51, 145.26, 129.96, 129.58, 127.72, 125.81 (q, J＝3 Hz), 123.98 (q, J＝273 Hz), 118.01, 115.38 (q, J＝123 Hz), 114.08, 55.22, 43.86, 40.15, 23.26; ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.52; IR (neat) v: 2935, 1613, 1511, 1323, 1245, 1162, 1109, 1067, 833 cm^－1. HRMS (EI) cacld for C₁₈H₁₆F₃NO [M]⁺ 319.1184, found 319.1179.

  3-(4-(tert-Butyl)phenyl)-4-(4-methoxyphenyl)butanenit-rile (3j): Yellow solid, 48.8 mg, 79% yield. m.p. 102.7~104.9 ℃, ¹H NMR (400 MHz, CDCl₃) δ: 7.28 (d, J＝8.4 Hz, 2H), 7.10 (d, J＝8.4 Hz, 2H), 6.97 (d, J＝8.6 Hz, 2H), 6.74 (d, J＝8.6 Hz, 2H), 3.70 (s, 3H), 3.13~3.02 (m, 1H), 2.92 (qd, J＝13.8, 7.5 Hz, 2H), 2.52–2.37 (m, 2H), 1.24 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.38, 150.34, 138.49, 130.64, 130.06, 126.89, 125.72, 118.73, 114.00, 55.28, 43.45, 40.23, 34.52, 31.37, 23.44; IR (neat) v: 2917, 1661, 1508, 1235, 1175, 1089, 1028, 827, 572 cm^－1. HRMS (EI) cacld for C₂₁H₂₅NO [M]⁺: 307.1936, found 307.1931.

  4-(4-Methoxyphenyl)-3-methyl-3-(3-(trifluoromethyl)-phenyl) butanenitrile (3k): Yellow oil, 48.1 mg, 72% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.55 (d, J＝7.6 Hz, 1H), 7.51~7.38 (m, 3H), 6.75~6.67 (m, 4H), 3.76 (d, J＝0.9 Hz, 3H), 2.99 (m, 2H), 2.75~2.61 (m, 2H), 1.56 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.61, 145.04, 131.20, 130.65, 129.54 (q, J＝1 Hz), 129.03, 127.78, 125.41, 123.90 (q, J＝4 Hz), 122.94 (q, J＝4 Hz), 117.94, 113.52, 55.19, 47.29, 41.54, 29.26, 25.34; ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.53; IR (neat) v: 2933, 1683, 1511, 1321, 1248, 1162, 1119, 1069, 1033, 802, 701 cm^－1. HRMS (EI) cacld for C₁₉H₁₈F₃NO [M]⁺ 333.1340, found 333.1335.

  4-(4-Methoxyphenyl)-3-(naphthalen-2-yl)butanenitrile(3l): Yellow solid, 52.4 mg, 87% yield. m.p. 143.1~144.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (td, J＝9.7, 9.1, 4.4 Hz, 3H), 7.58 (d, J＝1.8 Hz, 1H), 7.45~7.34 (m, 2H), 7.28 (dd, J＝8.5, 1.9 Hz, 1H), 6.99~6.93 (m, 2H), 6.76~6.66 (m, 2H), 3.69 (s, 3H), 3.29 (p, J＝7.0 Hz, 1H), 3.10~2.96 (m, 2H), 2.66~2.51 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.39, 138.78, 133.43, 132.75, 130.30, 130.08, 128.66, 127.88, 127.69, 126.33, 126.20, 126.00, 125.23, 118.57, 114.01, 55.25, 44.18, 40.36, 23.57; IR (neat) v: 2925, 1610, 1510, 1243, 1176, 1032, 817, 747, 477 cm^－1. HRMS (EI) cacld for C₂₁H₁₉NO [M]⁺ 301.1467, found 301.1461.

  3-(4-Methoxybenzyl)hexanenitrile (3m): Yellow oil, 36.1 mg, 83% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.07–6.97 (m, 2H), 6.82~6.75 (m, 2H), 3.72 (s, 3H), 2.69 (dd, J＝13.9, 5.6 Hz, 1H), 2.44 (dd, J＝13.9, 9.0 Hz, 1H), 2.24~2.05 (m, 2H), 1.96–1.73 (m, 1H), 1.43~1.23 (m, 4H), 0.87 (t, J＝7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.25, 131.02, 130.00, 118.71, 114.01, 55.28, 38.90, 37.18, 35.53, 20.91, 19.98, 14.04; IR (neat) v: 2923, 1610, 1512, 1453, 1322, 1245, 1033, 745, 699 cm^－1. HRMS (EI) cacld for C₁₄H₁₉NO [M]⁺ 217.1467, found 217.1460.

  2-(1-(4-Methoxybenzyl)cyclododecyl)acetonitrile (3n): White solid, 45.6 mg, 70% yield. m.p. 85.7~87.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.20~7.14 (m, 2H), 6.88~6.82 (m, 2H), 3.80 (s, 3H), 2.63 (s, 2H), 2.00 (s, 2H), 1.37 (m, 22H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.30, 131.29, 128.95, 118.94, 113.69, 55.22, 41.86, 39.97, 32.08, 26.66, 26.02, 25.57, 22.80, 22.25, 19.14; IR (neat) v: 2933, 1608, 1467, 1246, 1181, 1031, 841, 585 cm^－1. HRMS (ESI) cacld for C₂₂H₃₃NONa [M+Na]⁺ 350.2460, found 350.2454.

  4-(4-Methoxyphenyl)-5-phenylpentanenitrile (3o): Yellow oil, 50.3 mg, 95% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.29~7.13 (m, 3H), 7.09~7.01 (m, 4H), 6.90~6.80 (m, 2H), 3.80 (s, 3H), 3.01~2.78 (m, 3H), 2.27~2.10 (m, 1H), 2.09~1.94 (m, 2H), 1.91~1.77 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.49, 139.55, 134.14, 129.08, 128.53, 128.31, 126.20, 119.59, 114.15, 55.24, 45.99, 43.56, 31.05, 15.38; IR (neat) v: 2930, 1610, 1511, 1422, 1246, 1177, 1031, 830, 699 cm^－1. HRMS (EI) cacld for C₁₈H₁₉NO [M]⁺ 265.1467, found 265.1461.

  3-(4-Methoxybenzyl)-5-phenylpentanenitrile (3p): Yellow oil, 35.8 mg, 64% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.38~7.30 (m, 2H), 7.27~7.17 (m, 3H), 7.14~7.07 (m, 2H), 6.87 (dd, J＝8.3, 1.6 Hz, 2H), 3.82 (s, 3H), 2.87 (m, 1H), 2.73 (m, 2H), 2.59 (m, 1H), 2.40~2.20 (m, 2H), 1.99 (m, 1H), 1.92~1.77 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.33, 141.17, 130.69, 130.01, 128.58, 128.34, 126.17, 118.49, 114.07, 55.30, 38.72, 36.72, 34.92, 33.02, 21.00; IR (neat) v: 2923, 1610, 1510, 1453, 1244, 1177, 1032, 835, 699 cm^－1. HRMS (ESI) cacld for C₁₉H₂₁NONa [M+Na]⁺ 302.1515, found 302.1513.

  4-(4-Methoxyphenyl)nonanenitrile (3q): Colorless oil, 36.2 mg, 74% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.06 (d, J＝8.5 Hz, 2H), 6.86 (d, J＝8.5 Hz, 2H), 3.79 (s, 3H), 2.59 (m, 1H), 2.23~2.09 (m, 2H), 2.09~1.93 (m, 1H), 1.84~1.71 (m, 2H), 1.65~1.49 (m, 6H), 1.31~1.08 (m, 3H), 0.87–0.78 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.31, 134.99, 128.41, 119.82, 114.08, 55.22, 44.05, 36.62, 32.41, 31.75, 27.09, 22.50, 15.38, 14.03; IR (neat) v: 2926, 1610, 1511, 1459, 1245, 1177, 1034, 829 cm^－1. HRMS (ESI) cacld for C₁₆H₂₃NONa [M+Na]⁺ 268.1672, found 268.1271.

  2-(4-Methoxybenzyl)benzonitrile (3r): Colorless oil, 40.5 mg, 91% yield. The data is consistent with the literature.^[22g]

  4-(4-Methoxyphenyl)oct-7-enenitrile (3s). Colorless oil, 41.2 mg, 90% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.11~7.04 (m, 2H), 6.90~6.84 (m, 2H), 5.74 (ddt, J＝18.1, 9.4, 6.6 Hz, 1H), 5.00~4.87 (m, 2H), 3.80 (s, 3H), 2.70~2.51 (m, 1H), 2.25~2.10 (m, 1H), 2.09~1.97 (m, 2H), 1.91 (m, 2H), 1.78 (m, 1H), 1.74~1.62 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.44, 138.11, 134.37, 128.51, 119.71, 114.92, 114.17, 55.24, 43.38, 35.72, 32.36, 31.48, 15.37; IR (neat) v: 2928, 1639, 1511, 1245, 1177, 1034, 911, 829 cm^－1. HRMS (EI) cacld for C₁₅H₁₉NO [M]⁺ 229.1467, found 229.1461.

  (E)-4-(4-Methoxyphenyl)oct-6-enenitrile (3t): Colorless oil, 35.8 mg, 64% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.14~6.98 (m, 2H), 6.88~6.79 (m, 2H), 5.64 (ddt, J＝17.2, 10.2, 7.0 Hz, 1H), 5.07~4.89 (m, 2H), 3.78 (s, 3H), 2.69 (m, 1H), 2.35 (m, 2H), 2.25~2.14 (m, 1H), 2.11~1.96 (m, 2H), 1.87~1.68 (m, 1H): ¹³C NMR (101 MHz, CDCl₃) δ: 158.44, 135.97, 134.28, 128.43, 119.62, 116.72, 114.13, 113.70, 55.22, 43.76, 41.04, 31.40, 15.27; IR (neat) v: 2930, 1610, 1511, 1443, 1245, 1177, 1033, 915, 830 cm^－1. HRMS (ESI) cacld for C₁₄H₁₇NONa [M+Na]⁺ 238.1202, found 238.1206.

  2-(2-(4-Methoxyphenyl)-2, 3-dihydro-1H-inden-1-yl)acetonitrile (3u): Colorless oil, 48.2 mg, 92% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.44~7.36 (m, 1H), 7.31 (m, 5H), 7.01~6.83 (m, 2H), 3.85 (s, 3H), 3.52 (m, 1H), 3.44~3.28 (m, 2H), 3.14 (m, 1H), 2.82 (ddd, J＝17.0, 5.0, 1.4 Hz, 1H), 2.63 (ddd, J＝17.0, 6.5, 1.3 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.75, 142.39, 142.11, 134.12, 128.53, 128.00, 127.19, 124.72, 123.25, 118.48, 114.25, 55.36, 51.77, 48.99, 40.19, 20.49; IR (neat) v: 2934, 1609, 1510, 1466, 1248, 1180, 1029. 829, 776 cm^－1. HRMS (ESI) cacld for C₁₈H₁₇NONa [M+Na]⁺ 286.1202, found 286.1203.

  2-(2-(4-Methoxyphenyl)cyclopent-3-en-1-yl)acetonitrile (3v): Colorless oil, 39.8 mg, 94% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.23~7.03 (m, 2H), 6.89~6.77 (m, 2H), 5.99~5.84 (m, 1H), 5.72 (m, 1H), 3.78 (s, 3H), 3.01 (m, 2H), 2.95~2.79 (m, 1H), 2.58~2.40 (m, 2H), 2.39 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 158.38, 136.17, 132.71, 130.58, 128.14, 118.58, 114.09, 55.28, 50.87, 49.41, 41.84, 22.22; IR (neat) v: 2963, 1611, 1512, 1441, 1245, 1024, 824, 725 cm^－1. HRMS (ESI) cacld for C₁₄H₁₅NONa [M+Na]⁺ 236.1046, found 236.1045.

  4-(4-Methoxyphenyl)pentanenitrile (3w): Colorless oil, 33.7 mg, 89% yield. The data is consistent with the literature.^[22h]

  2-(4-Methoxyphenyl)-3-(2-methylcyclopentyl)propane-nitrile (3x): Colorless oil, 14.1 mg, 29% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.28~7.23 (m, 2H), 6.92 (m, 2H), 3.84 (s, 3H), 3.75~3.67 (m, 1H), 2.17~1.99 (m, 2H), 1.97~1.51 (m, 6H), 1.42~1.23 (m, 2H), 0.83 (dd, J＝7.0, 1.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.26, 128.39, 128.34, 121.72, 114.44, 55.37, 40.76, 37.81, 36.15, 35.66, 33.45, 29.29, 22.54, 15.00; IR (neat) v: 2934, 1609, 1511, 1229, 1032, 842, 729 cm^－1. HRMS (EI) cacld for C₁₆H₂₁NO [M]⁺: 243.1618, found 243.1616

  4-Phenylbutanenitrile (4a): Colorless oil, 24.3 mg, 84% yield. The data is consistent with the literature.^[22f]

  4-(4-Chlorophenyl)butanenitrile (4b): Colorless oil, 31.5 mg, 88% yield. The data is consistent with the literature.^[22h]

  4-(4-Bromophenyl)butanenitrile (4c): Colorless oil, 36.4 mg, 82% yield. The data is consistent with the literature.^[22h]

  4-(4-Iodophenyl)butanenitrile (4d): White solid, 33.6 mg, 62% yield. m.p. 80.5~82.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71~7.61 (m, 2H), 7.03~6.90 (m, 2H), 2.75 (t, J＝7.5 Hz, 2H), 2.34 (t, J＝7.0 Hz, 2H), 1.98 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 139.35, 137.76, 130.55, 119.31, 91.71, 33.88, 26.70, 16.41; IR (neat) v: 2930, 2244, 1483, 1399, 1059, 1005, 824, 786, 501 cm^－1. HRMS (EI) cacld for C₁₀H₁₀IN [M]⁺ 270.9858, found 270.9852.

  4-(4-(Trifluoromethyl)phenyl)butanenitrile (4e): Colorless oil, 30.7 mg, 72% yield. The data is consistent with the literature.^[22h]

  4-(4-(Trifluoromethoxy)phenyl)butanenitrile (4f): Colorless oil, 38.6 mg, 84% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.20 (d, J＝8.6 Hz, 2H), 7.14 (d, J＝8.4 Hz, 2H), 2.78 (t, J＝7.5 Hz, 2H), 2.32 (t, J＝7.0 Hz, 2H), 1.96 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 147.86, 138.45, 129.74, 121.27, 120.45 (q, J＝258 Hz), 119.28, 33.65, 26.80, 16.41; ¹⁹F NMR (376 MHz, CDCl₃) δ: －57.98; IR (neat) v: 2933, 1509, 1253, 1218, 1155 cm^－1. HRMS (EI) cacld for C₁₁H₁₀F₃NO [M]⁺ 229.0714, found 229.0709.

  4-([1, 1'-Biphenyl]-2-yl)butanenitrile (4g): Yellow solid, 41.5 mg, 94% yield. m.p. 182.6~185.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.48~7.22 (m, 9H), 2.82–2.75 (t, J＝7.2 Hz, 2H), 2.17 (t, J＝7.2 Hz, 2H), 1.81~1.71 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 142.05, 141.35, 137.29, 130.41, 129.39, 129.05, 128.34, 127.70, 127.15, 126.53, 119.49, 31.97, 26.51, 16.63; IR (neat) v: 2933, 2244, 1478, 1435, 1008, 749, 702 cm^－1. HRMS (EI) cacld for C₁₆H₁₅N [M]⁺ 221.1204, found 221.1199.

  4-([1, 1'-Biphenyl]-3-yl)butanenitrile (4h): Yellow solid, 39.2 mg, 89% yield. m.p. 187.8~190.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.60–7.55 (m, 2H), 7.49–7.31 (m, 6H), 7.16 (m, 1H), 2.83 (t, J＝7.4 Hz, 2H), 2.33 (t, J＝7.1 Hz, 2H), 2.01 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 141.72, 141.00, 140.29, 129.17, 128.86, 127.46, 127.42, 127.37, 127.21, 125.46, 119.57, 34.51, 27.00, 16.50; IR (neat) v: 2926, 2244, 1599, 1501, 1478, 1453, 754, 698 cm^－1. HRMS (EI) cacld for C₁₆H₁₅N [M]⁺ 221.1204, found 221.1199

  4-(4-(tert-Butyl)phenyl)butanenitrile (4i): Colorless oil, 34.4 mg, 86% yield. The data is consistent with the literature.^[22h]

  4-(4-(Methylthio)phenyl)butanenitrile (4j): Colorless oil, 28.6 mg, 75% yield. The data is consistent with the literature.^[22i]

  4-(4-(Dimethylamino)phenyl)butanenitrile (4k): Yellow solid, 24.9 mg, 66% yield. m.p. 68.4~70.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.11~7.05 (m, 2H), 6.78~6.68 (m, 2H), 2.95 (s, 6H), 2.71 (t, J＝7.3 Hz, 2H), 2.33 (t, J＝7.1 Hz, 2H), 1.96 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 149.43, 129.14, 127.57, 119.82, 112.99, 40.80, 33.37, 27.24, 16.31; IR (neat) v: 2925, 1614, 1523, 1445, 1349 cm^－1. HRMS (EI) cacld for C₁₂H₁₆N₂ [M]⁺ 188.1314, found 188.1308.

  4-(4-Cyclopropylphenyl)butanenitrile (4l): Colorless oil, 31.4 mg, 84% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.10 (m, 2H), 7.07~7.02 (m, 2H), 2.76 (t, J＝7.4 Hz, 2H), 2.33 (t, J＝7.1 Hz, 2H), 1.98 (p, J＝7.2 Hz, 2H), 1.90 (tt, J＝8.4, 5.1 Hz, 1H), 1.01~0.93 (m, 2H), 0.70 (dt, J＝6.6, 4.6 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 142.25, 136.67, 128.42, 125.94, 119.65, 33.92, 27.01, 16.38, 15.05, 9.22; IR (neat) v: 3006, 2928, 2244, 1516, 1457, 1424, 1047, 1018, 898, 810 cm^－1. HRMS (EI) cacld for C₁₃H₁₅N [M]⁺ 185.1204, found 185.1199.

  4-(Naphthalen-2-yl)butanenitrile (4m): Colorless oil, 35.3 mg, 90% yield. The data is consistent with the literature.^[22h]

  4-(2-Fluoro-[1, 1'-biphenyl]-4-yl)butanenitrile (4n): White solid, 41.2 mg, 86% yield. m.p. 175.4~177.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (dt, J＝8.1, 1.5 Hz, 2H), 7.51~7.38 (m, 2H), 7.08 (dd, J＝7.8, 1.7 Hz, 2H), 7.03 (dd, J＝11.4, 1.7 Hz, 1H), 2.85 (t, J＝7.5 Hz, 2H), 2.40 (t, J＝7.1 Hz, 2H), 2.05 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.85 (d, J＝247 Hz), 141.30 (d, J＝4 Hz), 135.55, 130.95 (d, J＝4 Hz), 128.97 (d, J＝4 Hz), 128.52, 127.69, 127.24 (d, J＝13 Hz), 124.54 (d, J＝3 Hz), 119.38, 115.55 (q, J＝23 Hz), 33.85, 26.64, 16.47; ¹⁹F NMR (400 MHz, CDCl₃) δ: －117.88; IR (neat) v: 2933, 2246, 1624, 1483, 1416, 1126, 765, 697 cm^－1. HRMS (EI) cacld for C₁₆H₁₄FN [M]⁺ 239.1110, found 239.1105

  4-(3a, 7a-Dihydrobenzo[d][1, 3]dioxol-5-yl)butanenitrile (4o): Colorless oil, 28.5 mg, 75% yield. The data is consistent with the literature.^[22j]

  4-(2, 3-Dihydrobenzo[b][1, 4]dioxin-6-yl)butanenitrile (4p): Colorless oil, 35.4 mg, 87% yield. ¹H NMR (400 MHz, CDCl₃) δ: 6.78 (d, J＝8.1 Hz, 1H), 6.68~6.60 (m, 2H), 4.23 (s, 4H), 2.65 (t, J＝7.3 Hz, 2H), 2.29 (t, J＝7.1 Hz, 2H), 1.91 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 143.49, 142.14, 132.93, 121.38, 119.61, 117.34, 117.05, 64.39, 64.31, 33.61, 26.98, 16.29; IR (neat) v: 2932, 2245, 1588, 1505, 1284, 1204, 884, 812 cm^－1. HRMS (EI) cacld for C₁₂H₁₃NO₂ [M]⁺ 203.0946, found 203.0941.

  4-(3, 5-Bis(trifluoromethyl)phenyl)butanenitrile (4q): Colorless oil, 40.4 mg, 72% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (s, 1H), 7.68 (s, 2H), 3.00~2.92 (t, J＝6.9, 2H), 2.44 (t, J＝6.9, 2H), 2.07 (p, J＝7.0 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 142.25, 131.85 (q, J＝33 Hz), 128.60, 123.38 (q, J＝274 Hz), 120.77 (p, J＝4 Hz), 118.81, 34.15, 26.57, 16.69; ¹⁹F NMR (377 MHz, CDCl₃) δ: －62.89; IR (neat) v: 2935, 1381, 1275, 1167, 1121, 895, 681 cm^－1. HRMS (EI) cacld for C₁₂H₉F₆N [M]⁺ 281.0639, found 281.0634.

  4-(Dibenzo[b, d]thiophen-4-yl)butanenitrile (4r): Yellow solid, 42.8 mg, 85% yield. m.p. 232.5~235.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.18~8.09 (m, 1H), 8.04 (dd, J＝7.9, 1.2 Hz, 1H), 7.90~7.82 (m, 1H), 7.50~7.38 (m, 3H), 7.31~7.22 (m, 1H), 3.05 (t, J＝7.4 Hz, 2H), 2.37 (t, J＝7.1 Hz, 2H), 2.17 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 139.01, 138.86, 136.04, 135.98, 133.94, 126.92, 126.53, 125.02, 124.59, 122.87, 121.84, 120.09, 119.48, 33.71, 24.74, 16.71; IR (neat) v: 2933, 2244, 1441, 1400, 797, 748 cm^－1. HRMS (EI) cacld for C₁₆H₁₃NS [M]⁺ 251.0769, found 251.0763.

  4-(4-Morpholinophenyl)butanenitrile (4s): Yellow solid, 36.5 mg, 79% yield. m.p. 123.4~125.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.10 (d, J＝8.5 Hz, 2H), 6.87 (d, J＝8.5 Hz, 2H), 3.89~3.83 (m, 4H), 3.16~3.10 (m, 4H), 2.70 (t, J＝7.3 Hz, 2H), 2.30 (t, J＝7.1 Hz, 2H), 1.94 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 149.91, 131.13, 129.22, 119.68, 115.98, 66.93, 49.49, 33.42, 27.04, 16.30; IR (neat) v: 2930, 2856, 1453, 746, 898 cm^－1. HRMS (EI) cacld for C₁₄H₁₈N₂O [M]⁺ 230.1419, found 230.1414.

  4-(5-Methylthiophen-3-yl)butanenitrile (4t): Colorless oil, 23.0 mg, 69% yield. ¹H NMR (400 MHz, CDCl₃) δ: 6.71 (s, 1H), 6.57 (s, 1H), 2.69 (t, J＝7.3 Hz, 2H), 2.44 (s, 3H), 2.31 (t, J＝7.1 Hz, 2H), 1.93 (p, J＝7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 140.52, 139.78, 126.06, 119.57, 118.89, 29.01, 26.05, 16.40, 15.34; IR (neat) v: 2934, 2244, 1441, 1400, 1054, 1020, 748 cm^－1. HRMS (EI) cacld for C₉H₁₁NS [M]⁺ 165.0612, found 165.0607

  7-Phenylheptanenitrile (4u): Colorless oil, 10.0 mg, 23% yield. The data is consistent with the literature.^[22f]

  4-((2, 2, 6, 6-Tetramethylpiperidin-1-yl)oxy)butanenitrile (5): Yellow oil, 7.0 mg, 16% yield. The data is consistent with the literature report.^[22c]

  4.4   Preparation of compound 4v

  To a 4 mL screwed-capped vial were added bromide 2v (34 mg, 0.2 mmol), Ni(cod)₂ (55 mg, 0.2 mmol), dtbbpy (54 mg, 0.2 mmol) and THF (0.4 mL) in Glove box. The resulting mixture was stirred for 2 h at room temperature to prepare nickel complex solution. To another 4 mL screwed-capped vial were added oxime ester 1a (52 mg, 0.2 mmol) and DMF (0.2 mL) in Glove box. Then the aforementioned in-situ formed nickel complex solution was added. The vial was removed from Glove box and stirred at room temperature for 12 h. After this time, the reaction mixture was quenched with saturated ammonia chloride (1 mol·L^－1), and diluted with ethyl acetate. The organic layer was separated and dried over anhydrous Na₂SO₄, filtered and removed under vacuum. The corresponding product 4-(o-tolyl)butanenitrile (4v) was obtained as a colorless oil by flash chromatography with 60% yield (19.2 mg). The data is consistent with the literature.^[22h]

  Supporting Information The optimization details, experimental procedures for the preparation of oxime esters and spectra of reported compounds is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
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• 

  Scheme 1  Nickel-catalyzed transformations of oxime esters

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  Scheme 2  Mechanistic experiments

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  Scheme 3  Proposed reaction mechanism

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  Table 1.  Optimization of reaction conditions^a

  Entry	Oxime ester	Catalyst	Ligand	Yieldb/%
  1	1a	NiBr2(glyme)	L5	Trace
  2	1a'	NiBr2(glyme)	L5	46
  3	1a''	NiBr2(glyme)	L5	96
  4	1a''	Co(acac)2	L5	Trace
  5	1a''	FeCl3	L5	19
  6	1a''	NiBr2(glyme)	L1	66
  7	1a''	NiBr2(glyme)	L2	93
  8	1a''	NiBr2(glyme)	L3	71
  9	1a''	NiBr2(glyme)	L4	82
  10	1a''	NiBr2(glyme)	L6	44
  11	1a''	NiBr2(glyme)	L7	79
  12	1a''	NiBr2(glyme)	L8	93
  13c	1a''	NiBr2(glyme)	L5	53
  14d	1a''	NiBr2(glyme)	L5	86
  15e	1a''	NiCl2(glyme)	L5	91
  16f	1a''	NiCl2(glyme)	L5	73
  a Reaction conditions: 10 mol% NiBr2(glyme), 10 mol% L5, 1a (0.2 mmol, 1.0 equiv.), 2a (0.2 mmol, 1.0 equiv.) in DMF (0.2 mL), r.t., 12 h. b Yield determined by HNMR using 1, 4-dimethoxybenzene as internal standard. c THF as solvent. d 5 mol% NiBr2(glyme) was used. e 5 mol% NiCl2(glyme) was used. f 1 mol% NiCl2(glyme) was used.

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  Table 2.  Substrate scope of oxime esters

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  Table 3.  Substrate scope of organozinc reagents

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•