Nickel catalyst, process for preparation and use thereof

Abstract

The present invention disclosed to a novel nickel catalyst of formula (I) process for preparation of the same and use of nickel catalyst of formula (I) for CH bond alkylation, and benzylation of heteroarenes.

Claims

1. A nickel catalyst of formula (I): ##STR00006## wherein: R and R.sup.1 are the same and are selected from the group consisting of alkyl, aryl, benzyl, heteroaryl; and X is selected from the group consisting of hydrogen, halogen, OC(O)CH.sub.3, OC(O).sup.tBu, OC(O)Ph, OC(O)admantyl, OSO.sub.2CF.sub.3, BF.sub.4, and SbF.sub.6.

2. The nickel catalyst of claim 1, wherein said nickel catalyst of formula (I) is selected from the group consisting of: a nickel catalyst of formula (I), wherein R and R.sup.1 are ethyl and X is chloro; and a nickel catalyst of formula (I), wherein R and R.sup.1 are ethyl and X is OC(O)CH.sub.3.

3. A process for the preparation of the nickel catalyst of formula (I) of claim 1, the process comprising: (a) refluxing a reaction mixture of 2-bromo-N-(quinolin-8-yl) acetamide and an amino compound in a solvent for from 20 hours to 24 hours at a temperature from 60 C. to 80 C., to afford a ligand having formula (IA): ##STR00007## where R and R.sup.1 are the same as in the nickel catalyst of formula (I); and (b) adding triethylamine to a mixture of the ligand afforded in (a), a nickel compound, and a solvent, followed by refluxing the resulting reaction mixture for 3 hours to 12 hours at a temperature from 60 C. to 70 C., to afford the nickel catalyst of formula (I).

4. The process of claim 3, wherein said amino compound is selected from diisopropyl amine, diethylamine, and dimethyl amine; and wherein said nickel compound is selected from (DME)NiCl.sub.2, (THF)NiBr.sub.2, and Ni(OAc).sub.2, where DME is dimethoxyethane, THF is tetrahydrofuran, and OAc is acetate.

5. The process of claim 3, wherein said solvent in (a) and (b) is selected from acetone or tetrahydrofuran (THF).

6. A process for the alkylation or benzylation of a heteroarene using a nickel catalyst according to claim 1, the process comprising: stirring a reaction mixture of (a)-(e): (a) the heteroarene, (b) an organic halide compound or a benzyl compound, (c) the nickel catalyst of formula (I), (d) a base, and (e) a solvent, at a temperature from 120 C. to 160 C. for a period of 6 hours to 36 hours, to afford either: an alkylated heteroarene compound when (b) is the organic halide compound; or a benzylated heteroarene compound when (b) is the benzyl compound, wherein: the heteroarene has formula (3): ##STR00008## where: R.sup.2 is 2-pyridine, 2-pyrimidine, 2,4-pyrazine, or 2-oxazole; and each R.sup.3 is hydrogen, alkyl, alkoxy, substituted alkoxy, phenoxy, halogen, or trifluoromethyl; the organic halide compound has formula XR.sup.4, where X is chlorine, bromine, or iodine and R.sup.4 is alkyl, whereby the alkylated heteroarene compound has formula (II): ##STR00009## where R.sup.2 and each R.sup.3 are the same as in formula (3), and where R.sup.4 is the same as in the organic halide compound; and the benzyl compound has formula (6): ##STR00010## where R.sup.4 is hydrogen, methyl, or alkoxy, whereby the benzylated heteroarene compound has formula (III): ##STR00011## where R.sup.2 and R.sup.3 are the same as in formula (3) and R.sup.4 is the same as in formula (6).

7. The process of claim 6, wherein said heteroarene is selected from the group consisting of 1-(pyridine-2-yl)-1H-indole, 5-methyl-1-(pyridine-2-yl)-1H-indole, 5-methoxy-1-(pyridine-2-yl)-1H-indole, 5-fluoro-1-(pyridin-2-yl)-1H-indole, 5-bromo-1-(pyridine-2-yl)-1H-indole, 1-(pyridin-2-yl)-1H-indole-5-carbonitrile, 3-methyl-1-(pyridine-2-yl)-1H-indole, 1-(pyrimidin-2-yl)-1H-indole, and 5-methoxy-1-(pyrimidin-2-yl)-1H-indole.

8. The process of claim 6, wherein said organic halide compound is selected from the group consisting of 1-iodobutane, 1-iodopentane, 1-bromohexane, 1-bromodecane, 1-iodododecane, 1-bromotridecane, 1-bromotetradecane, 1-bromohexadecane, 1-bromooctadecane, 1-bromo-2-methylpropane, 1-bromo-3-methylbutane, (bromomethyl)cyclohexane, (2-bromoethyl)cyclohexane, 1-bromo-2,2-dimethylpropane, (3-bromopropyl)benzene, 1-(3-bromopropyl)-4-methoxybenzene, 1-chloro-4-iodobutane, 5-bromopent-1-ene, 9-(4-iodobutyl)-8a,9a-dihydro-9H-carbazole, 2-iodopropane, (1-bromoethyl)benzene, (bromoethylene)dibenzene, 2-iodobutane, bromocyclopropane, iodocyclopentane, bromocyclohexane, bromocycloheptane, and 6-bromo-1-hexene.

9. The process of claim 6, wherein said benzyl compound is selected from the group consisting of toluene, p-xylene, m-xylene, 1-methoxy-4-methylbenzene, 1-fluoro-4-methylbenzene, 1-chloro-4-methylbenzene, 1-bromo-4-methylbenzene, ortho-xylene, 1-fluoro-2-methylbenzene, 1-chloro-2-methylbenzene, 1-bromo-2-methylbenzene, 1-methyl-2-(trifluoromethyl)benzene, mesitylene, 2,4-difluoro-1-methylbenzene, 1-methylnaphthalene, and 1-(p-tolyl)-1H-indoletoluene.

10. The process of claim 6, wherein said base is selected from lithium bis(trimethylsilyl)amide, lithium tert-butoxide, or mixture thereof; and wherein said solvent is selected from toluene, chlorobenzene, or mixture thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

(2) In the view of above, the present invention provides a novel nickel catalyst of formula (I), process for preparation of the same and use of these nickel catalyst of formula (I) for CH bond alkylation and, benzylation of heteroarenes.

(3) In an embodiment, the present invention provides novel nickel catalyst of formula (I);

(4) ##STR00002##

(5) Wherein;

(6) R and R.sup.1 are the same and are selected from the group consisting of alkyl, aryl, benzyl, heteroaryl, (CH.sub.2).sub.2O(CH.sub.2).sub.2, (CH.sub.2).sub.2N(Me)(CH.sub.2).sub.2, (CH.sub.2).sub.4, (CH.sub.2).sub.5, etc. X is selected from the group consisting of hydrogen, halogen, OC(O)CH.sub.3, OC(O).sup.tBu, OC(O)Ph, OC(O)admantyl, OSO.sub.2CF.sub.3, BF.sub.4, SbF.sub.6, etc.

(7) In preferred embodiment, said nickel catalyst of formula (I) is selected from (.sup.R2NNN.sup.8-Quin)-H, [2-(diethylamino)-N-(quinolin-8-yl)acetamide] (.sup.Et2NNN.sup.8-Quin)NiCl [2-(diethylamine)-N-(quinolin-8-yl)acetamide](NiCl), (.sup.Et2NNN.sup.8-Quin)Ni(OAc) [2-(diethylamino)-N-(quinolin-8-yl)acetamide].

(8) In another embodiment, the present invention provides a process for the preparation of nickel catalyst of formula (I), wherein said process comprising the steps of: a) Refluxing the reaction mixture of 2-bromo-N-(quinolin-8-yl) acetamide and amino compound in solvent for the period ranging from 20 to 24 hrs at temperature ranging from 60 to 80 C. afford (.sup.R2NNN.sup.8-Quin)-H Ligands; b) Adding triethylamine to the mixture of compound of step (a), nickel compound and solvent followed by refluxing the reaction mixture for the period in the range of 3 to 12 hrs at a temperature ranging from 60 to 70 C. to afford compound of formula (I).

(9) In preferred embodiment, said amino compound is selected from diisopropyl amine, diethylamine, dimethyl amine, morpholine, N-methyl piperazine, cyclopentyl amine, cyclohexyl amine.

(10) In another preferred embodiment, said nickel compound is selected from (DME)NiCl.sub.2, (THF)NiBr.sub.2, Ni(OAc).sub.2.

(11) In yet another preferred embodiment said solvent in step (a) and (b) is selected from Acetone or Tetrahydrofuran (THF).

(12) In yet another embodiment, the present invention provides a process for the alkylation or benzylation of heteroarene in presence of novel catalyst of formula (I), comprising stirring the reaction mixture of heteroarene, organic halide compound or benzyl compound, catalyst of formula (I), base and solvent at temperature ranging from 120 to 160 C. for the period ranging from 6 to 36 hrs to afford desired compound of formula (II).

(13) In preferred embodiment, said heteroarene is selected from 1-(pyridine-2-yl)-1H-indole, 5-methyl-1-(pyridine-2-yl)-1H-indole, 5-methoxy-1-(pyridine-2-yl)-1H-indole, 5-fluoro-1-(pyridin-2-yl)-1H-indole, 5-bromo-1-(pyridine-2-yl)-1H-indole, 1-(pyridin-2-yl)-1H-indole-5-carbonitrile, 3-methyl-1-(pyridine-2-yl)-1H-indole, 1-(pyrimidin-2-yl)-1H-indole, 5-methoxy-1-(pyrimidin-2-yl)-1H-indole.

(14) In another preferred embodiment, said organic halide compound is selected from 1-iodobutane, 1-iodopentane, 1-bromohexane, 1-bromodecane, 1-iodododecane, 1-bromotridecane, 1-bromotetradecane, 1-bromohexadecane, 1-bromooctadecane, 1-bromo-2-methylpropane, 1-bromo-3-methylbutane, (bromomethyl)cyclohexane, (2-bromoethyl)cyclohexane, 1-bromo-2,2-dimethylpropane, (3-bromopropyl)benzene, 1-(3 -bromopropyl)-4-methoxybenzene, 1-chloro-4-iodobutane, 5-bromopent-1-ene, 9-(4-iodobutyl)-8a,9a-dihydro-9H-carbazole, 2-iodopropane, (1-bromoethyl)benzene, (bromoethylene)dibenzene, 2-iodobutane, bromocyclopropane, iodocyclopentane, bromocyclohexane, bromocycloheptane, 6-bromo-1-hexene.

(15) In yet another preferred embodiment, said base is selected from Lithium bis(trimethylsilyl)amide [LiHMDS], Lithium tert-butoxide (LiOtBu) or mixture thereof.

(16) In still another preferred embodiment, said benzyl compound is selected from toluene, p-xylene, m-xylene, 1-methoxy-4-methylbenzene, 1-fluoro-4-methylbenzene, 1-chloro-4-methylbenzene, 1-bromo-4-methylbenzene, ortho-xylene, 1-fluoro-2-methylbenzene, 1-chloro-2-methylbenzene, 1-bromo-2-methylbenzene, 1-methyl-2-(trifluoromethyl)benzene, mesitylene, 2,4-difluoro-1-methylbenzene, 1-methylnaphthalene, 1-(p-tolyl)-1H-indoletoluene.

(17) In yet still another preferred embodiment, said solvent is selected from toluene, chlorobenzene or mixture thereof.

(18) The process for the alkylation of heteroarenes is as shown in scheme 1:

(19) ##STR00003##

(20) Wherein,

(21) X is halogen selected from chlorine, bromine, iodine.

(22) R.sup.2 is selected from 2-pyridine, 2-pyrimidine, 2,4-pyrazine, etc.

(23) R.sup.3 is selected from hydrogen, alkyl, alkoxy, substituted alkoxy, phenoxy, halogens, trifluoromethyl, etc.

(24) R.sup.4 is selected from octyl, butyl, decyl, dodecyl, tetradecyl and others alkyl group

(25) The process for the benzylation of heteroarenes is as shown in scheme 2:

(26) ##STR00004##

(27) Wherein,

(28) R.sup.2 is selected from 2-pyridine, 2-pyrimidine, 2,4-pyrazine, 2-oxazole, etc.

(29) R.sup.3 is selected from hydrogen, alkyl, alkoxy, substituted alkoxy, phenoxy, halogens, trifluoromethyl, etc.

(30) R.sup.4 is selected from hydrogen, methyl, alkoxy, etc.

(31) The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

EXAMPLES

Example 1: Synthesis of 2-Bromo-N-(Quinolin-8-yl)Acetamide

(32) To a solution of 8-aminoquinoline (1.0 g, 6.94 mmol) in CH.sub.2C.sub.12 (40 mL), Et.sub.3N (1.02 mL, 7.32 mmol) was added at 0 C. and stirred for 20 min. To the resulted reaction mixture, bromo acetyl chloride (1.20 g, 7.64 mmol) was added dropwise via a syringe. The reaction mixture was then allowed to warm to room temperature and continued stirring for 24 h. At ambient temperature, the reaction mixture was quenched with water (20 mL) and extracted with CH.sub.2Cl.sub.2 (15 mL3). The combined organic phase was washed with H.sub.2O (15 mL3) and dried over Na.sub.2SO.sub.4. After filtration and evaporation of the solvents in vacuo, the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc: 5/1) yielded the desired product as light yellow solid. Yield: 1.30 g (71%). .sup.1H-NMR (400 MHz, CDCl.sub.3): =10.89 (br s, 1H, NH), 8.85 (dd, J=4.2, 1.5 Hz, 1H, ArH), 8.74 (dd, J=6.1, 2.9 Hz, 1H, ArH), 8.17 (dd, J=8.3, 1.5 Hz, 1H, ArH), 7.57-7.54 (m, 2H, ArH), 7.47 (dd, J=8.3, 4.2 Hz, 1H, ArH), 4.32 (s, 2H, CH.sub.2). .sup.13C-NMR (100 MHz, CDCl.sub.3): =164.6 (CO), 148.8 (CH), 138.8 (C.sub.q), 136.6 (CH), 133.7 (C.sub.q), 128.1 (C.sub.q), 127.4 (CH), 122.7 (CH), 121.9 (CH), 116.9 (CH), 43.5 (CH.sub.2). HRMS (ESI): m/z Calcd for C.sub.11H.sub.9BrN.sub.2O+H.sup.+ [M+H].sup.+ 264.9971 and 266.9953; Found 264.9966 and 266.9945.

Example 2: General Procedure for the Synthesis of (.SUP.R2.NNN.SUP.8-Quin.)-H Ligands

(33) ##STR00005##

(34) A mixture of 2-bromo-N-(quinolin-8-yl)acetamide (1.0 g, 3.77 mmol) and Et.sub.2NH (0.83 g, 11.35 mmol) in acetone (30 mL) was refluxed for 24 h. The reaction mixture was then cooled to room temperature and quenched with distilled H.sub.2O (20 mL). The crude aminated product was extracted with EtOAc (15 mL3), and the combined organic extract was washed with H.sub.2O (15 mL3) and dried over Na.sub.2SO.sub.4. After filtration and evaporation of the volatiles in vacuo, the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc/Et.sub.3N: 5/1/0.5) yielded the desired product (.sup.Et2NNN.sup.8-Quin)-H.

(35) (.sup.Et2NNN.sup.8-Quin)-H: Yield: 0.95 g, 98%. .sup.1H-NMR (200 MHz, CDCl.sub.3): =11.56 (br s, 1H, NH), 8.85-8.79 (m, 2H, ArH), 8.12 (dd, J=8.3, 1.6 Hz, 1H, ArH), 7.57-7.46 (m, 2H, ArH), 7.41 (dd, J=8.3, 4.2 Hz, 1H, ArH), 3.29 (s, 2H, CH2), 2.70 (q, J=7.2 Hz, 4H, CH.sub.2), 1.16 (t, J=7.2 Hz, 6H, CH.sub.3). .sup.13C-NMR (100 MHz, CDCl.sub.3): =171.3 (CO), 148.6 (CH), 139.3 (C.sub.q), 136.2 (CH), 134.7 (C.sub.q), 128.2 (C.sub.q), 127.4 (CH), 121.7 (CH), 121.6 (CH), 116.6 (CH), 59.2 (CH.sub.2), 48.9 (2C, CH.sub.2), 12.7 (2C, CH.sub.3). (.sup.MorphNNN.sup.8-Quin)-H: Yield: 92%. .sup.1H-NMR (400 MHz, CDCl.sub.3): =11.45 (br s, 1H, NH), 8.85 (dd, J=4.2, 1.6 Hz, 1H, ArH), 8.76 (dd, J=6.9, 1.8 Hz, 1H, ArH), 8.14 (dd, J=8.3, 1.6 Hz, 1H, ArH), 7.55-7.48 (m, 2H, ArH), 7.44 (dd, J=8.3, 4.3 Hz, 1H, ArH), 3.89 (t, J=4.5 Hz, 4H, CH.sub.2), 3.27 (s, 2H, CH.sub.2), 2.68 (t, J=4.5 Hz, 4H, CH.sub.2). .sup.13C-NMR (100 MHz, CDCl.sub.3): =168.9 (CO), 148.7 (CH), 139.1 (C.sub.q), 136.3 (CH), 134.4 (C.sub.q), 128.2 (C.sub.q), 127.4 (CH), 121.9 (CH), 121.7 (CH), 116.7 (CH), 67.4 (2C, CH.sub.2), 62.9 (CH.sub.2), 53.9 (2C, CH.sub.2).

(36) (.sup.PiperNNN.sup.8-Quin)-H: .sup.1H-NMR (400 MHz, CDCl.sub.3): =11.43 (br s, 1H, NH), 8.85 (dd, J=4.3, 1.8 Hz, 1H, ArH), 8.76 (dd, J=6.1, 2.8 Hz, 1H, ArH), 8.15 (dd, J=8.3, 1.8 Hz, 1H, ArH), 7.55-7.49 (m, 2H, ArH), 7.44 (dd, J=8.3, 4.3 Hz, 1H, ArH), 3.29 (s, 2H, CH.sub.2), 2.73 (br s, 4H, CH.sub.2), 2.64 (br s, 4H, CH.sub.2), 2.38 (s, 3H, CH.sub.3). .sup.13C-NMR (100 MHz, CDCl.sub.3): =169.3 (CO), 148.6 (CH), 139.2 (C.sub.q), 136.3 (CH), 134.5 (C.sub.q), 128.2 (C.sub.q), 127.5 (CH), 121.8 (CH), 121.7 (CH), 116.7 (CH), 62.5 (CH.sub.2), 55.5 (2C, CH.sub.2), 53.5 (2C, CH.sub.2), 46.2 (CH.sub.3).

Example 3: Synthesis of (.SUP.Et2.NNN.SUP.8-Quin.)NiCl

(37) To a schlenk flask equipped with magnetic stir bar was introduced (.sup.Et2NNN.sup.8-Quin)NH (0.3 g, 1.166 mmol) and (DME)NiCl.sub.2 (0.27 g, 1.229 mmol), and THF (20 mL) was added into it. Then, the Et.sub.3N (0.16 mL, 1.148 mmol) was added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to ambient temperature and all the volatiles were evaporated under vacuum. The resultant residue was washed with n-hexane (10 mL3) and the product was extracted with toluene (10 mL2). The toluene extract was concentrated and n-hexane was added to precipitate the pure product of (.sup.Et2NNN.sup.8-Quin)NiCl complex. Yield: 0.375 g, 92%. .sup.1H-NMR (400 MHz, CDCl.sub.3): =8.59 (d, J=7.9 Hz, 1H, ArH), 8.54 (dd, J=5.2, 0.9 Hz, 1H, ArH), 8.17 (dd, J=8.2, 1.2 Hz, 1H, ArH), 7.43 (vt, J=7.9 Hz, 1H, ArH), 7.29-7.25 (m, 2H, ArH), 3.20 (s, 2H, CH.sub.2), 3.15 (app sextet, J=4.9 Hz, 2H, CH.sub.2), 2.38 (t, J=7.0 Hz, 6H, CH.sub.3), 2.06 (app sextet, J=5.5 Hz, 2H, CH.sub.2). .sup.13C-NMR (100 MHz, CDCl.sub.3): =176.3 (CO), 151.4 (CH), 145.9 (C.sub.q), 143.7 (C.sub.q), 138.8 (CH), 129.4 (CH), 128.7 (C.sub.q), 121.2 (CH), 119.6 (CH), 119.3 (CH), 63.5 (CH.sub.2), 57.8 (2C, CH.sub.2), 13.7 (2C, CH.sub.3).

Example 4: Synthesis of (.SUP.Et2.NNN.SUP.8-Quin.)Ni(OAc)

(38) This complex was synthesized following the procedure similar to the synthesis of (.sup.Et2NNN.sup.8-Quin)NiCl, using (.sup.Et2NNN.sup.8-Quin)NH (0.3 g, 1.166 mmol), Ni(OAc).sub.2 (0.216 g, 1.222 mmol) and Et.sub.3N (0.16 mL, 1.148 mmol).

(39) .sup.1H-NMR (400 MHz, CDCl.sub.3): =8.46 (d, J=7.5 Hz, 1H, ArH), 8.19 (d, J=7.8 Hz, 1H, ArH), 7.55 (d, J=4.5 Hz, 1H, ArH), 7.42 (vt, J=7.9 Hz, 1H, ArH), 7.32-7.22 (m, 2H, ArH), 3.22 (s, 2H, CH.sub.2), 2.86 (app sextet, J=5.1 Hz, 2H, CH.sub.2), 2.34 (t, J=6.7 Hz, 6H, CH.sub.3), 2.21 (app sextet, J=6.1 Hz, 2H, CH.sub.2), 1.98 (s, 3H, CH.sub.3). .sup.13C-NMR (100 MHz, CDCl.sub.3): =178.6 (CO), 175.2 (CO), 148.7 (CH), 145.6 (C.sub.q), 143.4 (C.sub.q), 138.7 (CH), 129.4 (CH), 128.8 (C.sub.q), 121.4 (CH), 119.7 (CH), 119.0 (CH), 62.6 (CH.sub.2), 56.1 (2C, CH.sub.2), 24.5 (COCH.sub.3), 13.1 (2C, CH.sub.3).

Example 5: Representative Procedure for the Alkylation of Indoles:

(40) a) Synthesis of 2-Octyl-1-(Pyridine-2-yl)-1H-Indole:

(41) To a flame-dried screw-capped tube equipped with a magnetic stir bar were introduced 1-pyridine-2-yl-1H-indole (0.58 g, 0.3 mmol), 1-iodooctane (0.144 g, 0.6 mmol), (.sup.Et2NNN.sup.8-Quin)Ni(OAc) (0.0056 g, 0.015 mmol, 5.0 mol %), LiHMDS (0.010 g, 0.06 mmol, 20 mol %) and LiOtBu (0.048 g, 0.60 mmol), and toluene (0.15 mL) was added into it. The resultant reaction mixture was stirred at 150 C. in a preheated oil bath for 16 h. At ambient temperature, H.sub.2O (5 mL) was added and the reaction mixture was extracted with CH.sub.2Cl.sub.2 (20 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4 and the solvent was evaporated in vacuo. The remaining residue was purified using column chromatography on neutral alumina (n-hexaneEtOAc 50/1) to yield desired compound (0.075 g, 82%) as an oily liquid. .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.68 (d, J=5.0 Hz, 1H, ArH), 7.88 (td, J=7.6, 1.8 Hz, 1H, ArH), 7.60-7.58 (m, 1H, ArH), 7.44 (d, J=8.0 Hz, 1H, ArH), 7.35-7.31 (m, 2H, ArH), 7.16-7.12 (m, 2H, ArH), 6.47 (s, 1H, ArH), 2.85 (t, J=7.6 Hz, 2H, CH.sub.2), 1.61-1.55 (m, 2H, CH.sub.2), 1.31-1.24 (m, 10H, CH.sub.2), 0.89 (t, J=6.9 Hz, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): =151.8 (C.sub.q), 149.8 (CH), 141.9 (C.sub.q), 138.4 (CH), 137.4 (C.sub.q), 128.8 (C.sub.q), 122.1 (CH), 121.7 (CH), 121.3 (CH), 120.7 (CH), 120.0 (CH), 110.2 (CH), 102.2 (CH), 32.0 (CH.sub.2), 29.5 (2C, CH.sub.2), 29.3 (CH.sub.2), 28.7 (CH.sub.2), 27.6 (CH.sub.2), 22.8 (CH.sub.2), 14.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.21H.sub.26N.sub.2+H.sup.+ [M+H].sup.+ 307.2169; Found 307.2172.

(42) b) 2-Octadecyl-1-(Pyridin-2-yl)-1H-Indole (5aj):

(43) The representative procedure was followed, using substrate 3a (0.058 g, 0.3 mmol), 1-bromooctadecane (4j; 0.20 g, 0.6 mmol) and KI (0.1 g, 0.6 mmol), and the reaction mixture was stirred for 20 h. Purification by column chromatography on neutral alumina (Pet ether/EtOAc/Et3N: 50/1/0.5) yielded 5aj (0.075 g, 56%) as a light yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): 45=8.68 (dd, J=5.0, 1.8 Hz, 1H, ArH), 7.92-7.87 (m, 1H, ArH), 7.61-7.57 (m, 1H, ArH), 7.44 (d, J=8.2 Hz, 1H, ArH), 7.35-7.32 (m, 2H, ArH), 7.15-7.12 (m, 2H, ArH), 6.46 (s, 1H, ArH), 2.85 (t, J=7.3 Hz, 2H, CH.sub.2), 1.60-1.58 (m, 2H, CH.sub.2), 1.36-1.24 (m, 30H, CH.sub.2), 0.91 (t, J=6.4 Hz, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (100 MHz, CDCl.sub.3): =151.8 (C.sub.q), 149.8 (CH), 142.0 (C.sub.q), 138.4 (CH), 137.4 (C.sub.q), 128.8 (C.sub.q), 122.2 (CH), 121.7 (CH), 121.3 (CH), 120.7 (CH), 120.0 (CH), 110.2 (CH), 102.2 (CH), 32.1 (CH.sub.2), 29.9 (8C, CH.sub.2), 29.8 (CH.sub.2), 29.7 (CH.sub.2), 29.6 (2C, CH.sub.2), 29.5 (CH.sub.2), 28.8 (CH.sub.2), 27.6 (CH.sub.2), 22.9 (CH.sub.2), 14.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.31H.sub.46N.sub.2+H.sup.+ [M+H].sup.+ 447.3734; Found 447.3730.

(44) c) 2-Dodecyl-5-Methyl-1-(Pyridin-2-yl)-1H-Indole (5bf):

(45) The representative procedure was followed using, 5-methyl-1-(pyridine-2-yl)-1H-indole (3b; 0.062 g, 0.3 mmol) and iodide 4f (0.178 g, 0.6 mmol), and the reaction mixture was stirred for 16 h. Purification by column chromatography on neutral alumina (Pet ether/EtOAc/Et3N: 20/1/0.5) yielded 5bf (0.105 g, 93%) a light yellow liquid. .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.67 (dd, J=5.0, 1.5 Hz, 1H, ArH), 7.87 (td, J=7.6, 1.9 Hz, 1H, ArH), 7.42 (d, J=8.0 Hz, 1H, ArH), 7.37 (s, 1H, ArH), 7.31-29 (m, 1H, ArH), 7.24 (d, J=8.4 Hz, 1H, ArH), 6.96 (dd, J=8.3, 1.1 Hz, 1H, ArH), 6.38 (s, 1H, ArH), 2.84 (t, J=7.6 Hz, 2H, CH.sub.2), 2.45 (s, 3H, CH.sub.3), 1.59-1.53 (m, 2H, CH.sub.2), 1.34-1.23 (m, 18H, CH.sub.2), 0.91 (t, J=6.9 Hz, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): 152.0 (C.sub.q), 149.7 (CH), 142.0 (C.sub.q), 138.3 (CH), 135.8 (C.sub.q), 129.9 (C.sub.q), 129.1 (C.sub.q), 123.1 (CH), 121.9 (CH), 121.1 (CH), 119.8 (CH), 109.9 (CH), 101.9 (CH), 32.1 (CH.sub.2), 29.8 (CH.sub.2), 29.8 (CH.sub.2), 29.8 (CH.sub.2), 29.7 (CH.sub.2), 29.5 (2C, CH.sub.2), 29.5 (CH.sub.2), 28.8 (CH.sub.2), 27.7 (CH.sub.2), 22.9 (CH.sub.2), 21.5 (CH.sub.3), 14.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.26H.sub.36N.sub.2+H.sup.+ [M+H].sup.+ 377.2946; Found 377.2951.

(46) d) 5-Methoxy-2-Octyl-1-(Pyridin-2-yl)-1H-Indole (5ca):

(47) The representative procedure was followed, using 5-methoxy-1-(pyridine-2-yl)-1H-indole (3c; 0.067 g, 0.3 mmol) and iodide 4a (0.144 g, 0.6 mmol), and the reaction mixture was stirred for 16 h. Purification by column chromatography on neutral alumina (Pet ether/EtOAc/Et3N: 10/1/0.5) yielded 5ca (0.053 g, 53%) as a light yellow liquid. .sup.1H-NMR (400 MHz, CDCl.sub.3): =8.63 (dd, J=4.4, 1.0 Hz, 1H, ArH), 7.85 (td, J=7.8, 1.8 Hz, 1H, ArH), 7.38 (d, J=8.3 Hz, 1H, ArH), 7.29-26 (m, 1H, ArH), 7.22 (d, J=8.8 Hz, 1H, ArH), 7.04 (d, J=2.5 Hz, 1H, ArH), 6.76 (dd, J=8.8, 2.5 Hz, 1H, ArH), 6.36 (s, 1H, ArH), 3.84 (s, 3H, CH.sub.3), 2.81 (t, J=7.3 Hz, 2H, CH.sub.2), 1.58-1.50 (m, 2H, CH.sub.2), 1.31-1.21 (m, 10H, CH.sub.2), 0.86 (t, J=6.6 Hz, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (100 MHz, CDCl.sub.3): 154.9 (C.sub.q), 151.9 (C.sub.q), 149.7 (CH), 142.6 (C.sub.q), 138.4 (CH), 132.6 (C.sub.q), 129.4 (C.sub.q), 121.9 (CH), 121.0 (CH), 111.2 (CH), 111.0 (CH), 102.3 (CH), 102.1 (CH), 56.0 (CH.sub.3), 32.0 (CH.sub.2), 29.5 (2C, CH.sub.2), 29.3 (CH.sub.2), 28.8 (CH.sub.2), 27.7 (CH.sub.2), 22.8 (CH.sub.2), 14.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.22H.sub.28N.sub.2O+H.sup.+ [M+H].sup.+ 337.2274; Found 337.2273. The .sup.1H and .sup.13C spectra are consistent with those reported in the literature..sup.4

(48) e) 2-Octyl-1-(Pyridin-2-yl)-1H-Indole-5-Carbonitrile (5fa):

(49) The representative procedure was followed using, 1-(pyridin-2-yl)-1H-indole-5-carbonitrile (3f; 0.066 g, 0.3 mmol) and iodide 4a (0.144 g, 0.6 mmol), and the reaction mixture was stirred for 16 h. Purification by column chromatography on neutral alumina (Pet ether/EtOAc/Et3N: 20/1/0.5) yielded 5fa (0.038 g, 38%) a light yellow liquid. .sup.1H-NMR (400 MHz, CDCl.sub.3): =8.69 (dd, J=4.4, 1.0 Hz, 1H, ArH), 7.95 (td, J=7.8, 2.0 Hz, 1H, ArH), 7.90 (s, 1H, ArH), 7.43-7.39 (m, 2H, ArH), 7.36-7.29 (m, 2H, ArH), 6.50 (s, 1H, ArH), 2.78 (t, J=7.3 Hz, 2H, CH.sub.2), 1.56 (pent, J=7.3 Hz, 2H, CH.sub.2), 1.30-1.22 (m, 10H, CH.sub.2), 0.86 (t, J=6.9 Hz, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (100 MHz, CDCl.sub.3): 150.7 (CN), 150.2 (CH), 144.6 (C.sub.q), 139.1 (C.sub.q), 138.8 (CH), 128.6 (C.sub.q), 125.3 (CH), 124.9 (CH), 123.2 (CH), 121.6 (CH), 120.9 (C.sub.q), 111.1 (CH), 103.7 (C.sub.q), 102.4 (CH), 32.0 (CH.sub.2), 29.4 (2C, CH.sub.2), 29.3 (CH.sub.2), 28.5 (CH.sub.2), 27.5 (CH.sub.2), 22.8 (CH.sub.2), 14.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.22H.sub.25N.sub.3+H.sup.+ [M+H].sup.+ 332.2121; Found 332.2119.

(50) f) 2-Dodecyl-1-(Pyridin-2-yl)-1H-Indole-5-Carbonitrile (5ff):

(51) The representative procedure was followed using, substrate 3f (0.066 g, 0.3 mmol) and iodide 4f (0.178 g, 0.6 mmol), and the reaction mixture was stirred for 16 h. Purification by column chromatography on neutral alumina (Pet ether/EtOAc/Et3N: 20/1/0.5) yielded 5ff (0.052 g, 45%) a light yellow liquid. .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.69 (d, J=4.2 Hz, 1H, ArH), 7.94 (td, J=7.6, 1.5 Hz, 1H, ArH), 7.89 (s, 1H, ArH), 7.42-7.38 (m, 2H, ArH), 7.34-7.29 (m, 2H, ArH), 6.49 (s, 1H, ArH), 2.78 (t, J=7.6 Hz, 2H, CH.sub.2), 1.56 (pent, J=7.4 Hz, 2H, CH.sub.2), 1.34-1.22 (m, 18H, CH.sub.2), 0.88 (t, J=6.9 Hz, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): 150.7 (CN), 150.1 (CH), 144.6 (C.sub.q), 139.1 (C.sub.q), 138.8 (CH), 128.6 (C.sub.q), 125.2 (CH), 124.8 (CH), 123.2 (CH), 121.5 (CH), 120.9 (C.sub.q), 111.1 (CH), 103.7 (C.sub.q), 102.3 (CH), 32.1 (CH.sub.2), 29.8 (CH.sub.2), 29.8 (CH.sub.2), 29.7 (CH.sub.2), 29.6 (CH.sub.2), 29.5 (CH.sub.2), 29.4 (CH.sub.2), 29.4 (CH.sub.2), 28.5 (CH.sub.2), 27.5 (CH.sub.2), 22.8 (CH.sub.2), 14.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.26H.sub.33N.sub.3+H.sup.+ [M+H].sup.+ 388.2747; Found 388.2744.

(52) g) 1-(Pyrimidin-2-yl)-2-Tetradecyl-1H-Indole (5hh):

(53) The representative procedure was followed, using 1-(pyrimidin-2-yl)-1H-indole (3h; 0.039 g, 0.2 mmol), bromide 4h (0.111 g, 0.4 mmol) and KI (0.067 g, 0.4 mmol), and the reaction mixture was stirred for 24 h. Purification by column chromatography on neutral alumina (Pet ether/EtOAc/Et3N: 50/1/0.5) yielded 5hh (0.044 g, 56%) as a light yellow liquid. .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.80 (d, J=5.0 Hz, 2H, ArH), 8.21 (d, J=8.0 Hz, 1H, ArH), 7.53 (d, J=7.2 Hz, 1H, ArH), 7.22-7.14 (m, 3H, ArH), 6.47 (s, 1H, ArH), 3.15 (t, J=7.8 Hz, 2H, CH.sub.2), 1.61 (pent, J=7.6 Hz, 2H, CH.sub.2), 1.39-1.33 (m, 2H, CH.sub.2), 1.31-1.22 (m, 20H, CH.sub.2), 0.88 (t, J=6.9 Hz, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): 158.5 (C.sub.q), 158.3 (2C, CH), 142.6 (C.sub.q), 137.1 (C.sub.q), 129.6 (C.sub.q), 122.5 (CH), 121.9 (CH), 119.8 (CH), 117.2 (CH), 113.7 (CH), 105.6 (CH), 32.1 (CH.sub.2), 29.9 (3C, CH.sub.2), 29.8 (2C, CH.sub.2), 29.8 (CH.sub.2), 29.7 (2C, CH.sub.2), 29.6 (CH.sub.2), 29.5 (CH.sub.2), 29.2 (CH.sub.2), 22.9 (CH.sub.2), 14.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.26H.sub.37N.sub.3+H.sup.+ [M+H].sup.+ 392.3060; Found 392.3053.

(54) h) 2-Benzyl-1-(Pyridin-2-yl)-1H-Indole:

(55) .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.66 (dd, J=3.8, 0.8 Hz, 1H, ArH), 7.77 (td, J=8.0, 1.7 Hz, 1H, ArH), 7.62-7.56 (m, 1H, ArH), 7.36-7.31 (m, 1H, ArH), 7.29-7.26 (m, 2H, ArH), 7.20-7.13 (m, 5H, ArH), 7.06 (d, J=6.9 Hz, 2H, ArH), 6.40 (s, 1H, ArH), 4.28 (s, 2H, CH2). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): =151.5 (C.sub.q), 149.7 (CH), 140.3 (C.sub.q), 138.9 (C.sub.q), 138.3 (CH), 137.6 (C.sub.q), 129.0 (2C, CH), 128.6 (C.sub.q), 128.3 (2C, CH), 126.3 (CH), 122.2 (CH), 122.0 (CH), 121.3 (CH), 120.8 (CH), 120.3 (CH), 110.2 (CH), 104.3 (CH), 34.2 (CH2). HRMS (ESI): m/z Calcd for C.sub.20H.sub.16N.sub.2+H.sup.+ [M+H].sup.+ 285.1386; Found 285.1386.

Example 6: Representative Procedure for Benzylation of Indoles

(56) a) Synthesis of 2-Benzyl-1-(Pyridin-2-yl)-1H-Indole (7aa):

(57) Procedure A: To a flame dried screw-cap tube (5 mL) equipped with magnetic stir bar was introduced 1-pyridine-2-yl-1H-indole (3a; 0.058 g, 0.3 mmol), 2-iodobutane (0.083 g, 0.45 mmol), cat 1a (0.0056 g, 0.015 mmol, 5.0 mol %), LiHMDS (0.010 g, 0.06 mmol, 20 mol %), LiO.sup.tBu (0.048 g, 0.6 mmol) and toluene (6a; 0.96 mL, 9.0 mmol) inside the glove-box. The resultant reaction mixture was stirred at 150 C. in a preheated oil bath for 20 h. At ambient temperature, the reaction mixture was quenched with distilled H.sub.2O (10 mL) and then neutralized with 2N HCl (0.5 mL). The crude product was then extracted with CH.sub.2Cl.sub.2 (20 mL3). The combined organic extract was dried over Na.sub.2SO.sub.4 and the volatiles were evaporated in vacuo. The remaining residue was purified by column chromatography on neutral alumina (petroleum ether/EtOAc/Et.sub.3N: 20/1/0.5) to yield 7aa (0.060 g, 70%) as a light yellow liquid.

(58) Procedure B: This procedure was similar to procedure A, except the solvent chlorobenzene (0.304 mL, 3.0 mmol, 10 equiv) was added in addition to toluene (0.96 mL, 9.0 mmol, 30 equiv). The yield of the product 7aa obtained by this procedure was 82% (0.070 g).

(59) 2-Benzyl-1-(pyridin-2-yl)-1H-indole (7aa): .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.66 (dd, J=3.8, 0.8 Hz, 1H, ArH), 7.77 (td, J=8.0, 1.7 Hz, 1H, ArH), 7.62-7.56 (m, 1H, ArH), 7.36-7.31 (m, 1H, ArH), 7.29-7.26 (m, 2H, ArH), 7.20-7.13 (m, 5H, ArH), 7.06 (d, J=6.9 Hz, 2H, ArH), 6.40 (s, 1H, ArH), 4.28 (s, 2H, CH.sub.2). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): =151.5 (C.sub.q), 149.7 (CH), 140.3 (C.sub.q), 138.9 (C.sub.q), 138.3 (CH), 137.6 (C.sub.q), 129.0 (2C, CH), 128.6 (C.sub.q), 128.3 (2C, CH), 126.3 (CH), 122.2 (CH), 122.0 (CH), 121.3 (CH), 120.8 (CH), 120.3 (CH), 110.2 (CH), 104.3 (CH), 34.2 (CH.sub.2). HRMS (ESI): m/z Calcd for C.sub.20H.sub.16N.sub.2+H.sup.+ [M+H].sup.+ 285.1386; Found 285.1386.

(60) b) 2-(4-Methylbenzyl)-1-(Pyridin-2-yl)-1H-Indole (7ab):

(61) The representative procedure A was followed, using substrate 3a (0.058 g, 0.3 mmol) and p-xylene (6b; 1.1 mL, 9.0 mmol). Purification by column chromatography on neutral alumina (petroleum ether/EtOAc/Et.sub.3N: 30/1/0.5) yielded 7ab (0.074 g, 83%) as a light yellow liquid. .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.68 (d, J=4.2 Hz, 1H, ArH), 7.78 (td, J=8.0, 1.3 Hz, 1H, ArH), 7.60 (dd, J=5.7, 3.1 Hz, 1H, ArH), 7.37-7.35 (m, 1H, ArH), 7.32-7.28 (m, 2H, ArH), 7.19-7.16 (m, 2H, ArH), 7.03 (d, J=8.0 Hz, 2H, ArH), 6.99 (d, J=7.9 Hz, 2H, ArH), 6.40 (s, 1H, ArH), 4.25 (s, 2H, CH.sub.2), 2.32 (s, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): =151.5 (C.sub.q), 149.6 (CH), 140.6 (C.sub.q), 138.3 (CH), 137.6 (C.sub.q), 135.8 (C.sub.q), 135.7 (C.sub.q), 129.0 (2C, CH), 128.9 (2C, CH), 128.6 (C.sub.q), 122.1 (CH), 121.9 (CH), 121.3 (CH), 120.8 (CH), 120.3 (CH), 110.2 (CH), 104.1 (CH), 33.7 (CH.sub.2), 21.1 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.21H.sub.18N.sub.2+H.sup.+ [M+H].sup.+ 299.1543; Found 299.1542.

(62) c) 2-(4-Methoxybenzyl)-1-(Pyridin-2-yl)-1H-Indole (7ac):

(63) The representative procedure B was followed, using substrate 3a (0.058 g, 0.3 mmol) and 1-methoxy-4-methylbenzene (6c; 1.13 mL, 9.0 mmol). Purification by column chromatography on neutral alumina (petroleum ether/EtOAc/Et.sub.3N: 10/1/0.5) yielded 7ac (0.062 g, 66%) as a light yellow liquid. .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.65 (dd, J=4.6, 0.8 Hz, 1H, ArH), 7.77 (td, J=7.6, 1.9 Hz, 1H, ArH), 7.57 (dd, J=5.7, 3.1 Hz, 1H, ArH), 7.32 (dd, J=5.7, 3.1 Hz, 1H, ArH), 7.29-7.25 (m, 2H, ArH), 7.15-7.12 (m, 2H, ArH), 6.97 (d, J=8.8 Hz, 2H, ArH), 6.73 (d, J=8.8 Hz, 2H, ArH), 6.37 (s, 1H, ArH), 4.19 (s, 2H, CH.sub.2), 3.75 (s, 3H, CH.sub.3). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): =158.1 (C.sub.q), 151.5 (C.sub.q), 149.6 (CH), 140.8 (C.sub.q), 138.3 (CH), 137.6 (C.sub.q), 130.9 (C.sub.q), 130.0 (2C, CH), 128.6 (C.sub.q), 122.2 (CH), 122.0 (CH), 121.4 (CH), 120.8 (CH), 120.3 (CH), 113.8 (2C, CH), 110.2 (CH), 104.1 (CH), 55.4 (CH.sub.2), 33.3 (CH.sub.3). HRMS (ESI): m/z Calcd for C.sub.21H.sub.18N.sub.2O+H.sup.+ [M+H].sup.+ 315.1492; Found 315.1489.

(64) d) 2-(4-Fluorobenzyl)-1-(Pyridin-2-yl)-1H-Indole (7ad):

(65) The representative procedure A was followed, using substrate 2a (0.058 g, 0.3 mmol) and 1-fluoro-4-methylbenzene (6d; 0.99 mL, 9.0 mmol). Purification by column chromatography on neutral alumina (petroleum ether/EtOAc/Et.sub.3N: 20/1/0.5) yielded 7ad (0.069 g, 76%) as a light yellow liquid. .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.64 (dd, J=5.7, 1.9 Hz, 1H, ArH), 7.77 (td, J=7.6, 1.9 Hz, 1H, ArH), 7.59 (dd, J=5.7, 3.1 Hz, 1H, ArH), 7.33-7.30 (m, 1H, ArH), 7.28-7.26 (m, 2H, ArH), 7.17-7.14 (m, 2H, ArH), 7.00-6.97 (m, 2H, ArH), 6.89-6.80 (m, 2H, ArH), 6.39 (s, 1H, ArH), 4.24 (s, 2H, CH.sub.2). .sup.13C{.sup.1H}-NMR (125 MHz, CDCl.sub.3): =161.5 (d, .sup.1J.sub.C-F=244.1 Hz, C.sub.q), 151.4 (C.sub.q), 149.7 (CH), 140.2 (C.sub.q), 138.4 (CH), 137.6 (C.sub.q), 134.6 (d, .sup.4J.sub.C-F=2.9 Hz, C.sub.q), 130.4 (d, .sup.3J.sub.C-F=7.6 Hz, 2C, CH), 128.5 (C.sub.q), 122.2 (CH), 122.2 (CH), 121.3 (CH), 120.9 (CH), 120.4 (CH), 115.1 (d, .sup.2J.sub.C-F=21.0 Hz, 2C, CH), 110.2 (CH), 104.3 (CH), 33.4 (CH.sub.2). .sup.19F-NMR (377 MHz, CDCl.sub.3): =117.0 (s). HRMS (ESI): m/z Calcd for C.sub.20H.sub.15FN.sub.2+H.sup.+ [M+H].sup.+ 303.1292; Found 303.1293.

Advantages of Invention

(66) 1. Novel and inexpensive nickel catalysts of formula (I) is provided.

(67) 2. Novel compounds of formula (II) provided.

(68) 3. The Novel and inexpensive nickel catalysts effectively used to performs the alkylation and benzylation indoles, pyrazoles, imidazoles, etc.