Syntheses of N-heterocyclic carbenes and intermediates therefor

Abstract

A method of preparing a 2,6 disubstituted anilines includes, reacting a 2-amino isophthalic acid diester with sufficient Grignard reagent R.sub.2CH.sub.2MgX to form the corresponding diol product, dehydrating the diol product to the corresponding dialkene; and hydrogenating the diol product to form the corresponding aniline. The 2,6 disubstituted anilines can be used to produce N-Heterocyclic Carbenes (NHCs). The NHCs can find application in various fields such as organic synthesis, catalysis and macromolecular chemistry. Palladium catalysts containing the NHCs are also described.

Claims

1. An imidazolium salt of structure III; ##STR00075## wherein X.sup. is a halogen anion, each R.sup.2 is the same and is n-propyl; and wherein the groups Z.sub.1 and Z.sub.3 are H and the group Z.sub.2 is selected from methyl, methoxy and NMe.sub.2.

2. The imidazolium salt of claim 1, wherein the groups Z.sub.1 and Z.sub.3 are H and the group Z.sub.2 is methyl or methoxy.

3. A metal complex comprising an N-heterocyclic carbene prepared from an imidazolium salt of structure XX; ##STR00076## wherein X.sup. is a halogen anion, each R.sup.2 is the same and selected from ethyl and n-propyl; and Z.sub.1, Z.sub.2, and Z.sub.3 is a substituent independently selected from the group consisting of H, I, CF.sub.3, OR.sup.5, R.sup.6 and NR.sup.7.sub.2; wherein each group R.sup.5,R.sup.6 or R.sup.7 is independently selected from the group consisting of: alkyl that may be unsaturated, substituted alkyl that may be unsaturated, aryl, substituted aryl, aralkyl and substituted aralkyl; or from an imidazolium salt of structure XVII or XXa: ##STR00077## wherein X.sup. is an anion, the groups R.sup.2 are the same and selected from H, methyl, ethyl, n-propyl and ##STR00078## wherein either R.sup.3 is H and R.sup.4 is alkyl that may be substituted, or each of R.sup.3, R.sup.4 are an independently selected alkyl that may be substituted; and Z.sub.1, Z.sub.2, Z.sub.3 are independently selected from the group consisting of: H, I, CF.sub.3, OR.sup.5, R.sup.6 and NR.sup.7.sub.2; wherein each group R.sup.5, R.sup.6 or R.sup.7 is independently selected from the group consisting of: alkyl that may be unsaturated, substituted alkyl that may be unsaturated, aryl, substituted aryl, aralkyl and substituted aralkyl.

4. A method of preparing an N-heterocyclic carbene, the method comprising: reacting an aniline of general formula I: ##STR00079## wherein each group R.sup.2 is n-propyl; and wherein the groups Z.sub.1, Z.sub.2 and Z.sub.3 are H; with glyoxal to form a diimine of general formula II; ##STR00080## cyclizing the diimine of structure II with paraformaldehyde to form an imidazolium salt of structure Ill; ##STR00081## wherein X.sup. is an anion; and reacting the imidazolium salt of structure Ill with a base to form the N-heterocyclic carbene.

Description

DESCRIPTION OF SOME PREFERRED EMBODIMENTS AND EXPERIMENTAL RESULTS

(1) All reagents, reactants and solvents were used as purchased. Anhydrous tetrahydrofuran was collected from a solvent purification system. Flash column chromatography was performed on silica gel 60 pore diameter and 40-63 m particles size. .sup.1H and .sup.13C Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker-400 MHz or 300 MHz spectrometer at ambient temperature in CDCl3 without TMSCl as internal standard. NMR peaks were assigned by using COSY and HSQC experiments. Elemental analyses were performed at London Metropolitan University 166-220 Holloway Road, London, N7 8DB. High resolution mass spectrometry was performed by the EPSRC National Mass Spectrometry Service Centre (NMSSC), Grove Building Extn., Swansea University, Singleton Park, Swansea, SA2 8PP, UK.

(2) 2-Nitroisophthalic acid XIII. KMnO.sub.4 (643 g, 4.07 mol, 4.0 eq) was added to solution of NaOH (135 g, 3.38 mol, 3.3 eq) in tap water (4080 mL) at room temperature. 2-Nitro-m-xylene XII (153 g, 1.01 mol, 1.0 eq) was added and the resulting solution was allowed to stir vigorously under strong reflux. The purple colour slowly disappeared as the KMnO.sub.4 was reduced and the reaction was continued overnight (12 h). The suspension was cooled to room temperature before being filtered through a sintered funnel. The resulting yellow filtrate was carefully acidified below pH 2 with concentrated sulphuric acid (98%, 200 mL). The white solid formed was collected by filtration and washed with dichloromethane to recover the pure unreacted starting material (31.9 g) after evaporation. The crude white cake was washed with ethyl acetate and filtered. The insoluble white solid was discarded and the resulting filtrate was dried over anhydrous magnesium sulphate. Evaporation of the solvents in vaccuo provided the pure diacid XIII as a white powder (112 g, 52%) and was taken on crude to the next step. (CAS 21161-11-5)

(3) Dimethyl 2-Nitroisophthalate XIV (where R.sup.1 is methyl). The diacid XIII (136 g, 0.64 mol, 1.0 eq) was diluted in regular methanol (1200 mL) and the resulting solution was carefully treated with concentrated sulphuric acid (98%, 122 mL, 2.24 mol, 3.5 eq). The mixture was allowed to stir overnight under strong reflux and stirring. A large quantity of white solid formed and the condenser was removed to allow half of the methanol to evaporate. The suspension was cooled down to room temperature and was diluted with water (1200 mL) to precipitate more solid. The solid was isolated by filtration and washed with water (1200 mL) before being dissolved in dichloromethane. The solution was dried over anhydrous magnesium sulphate and the solvents were evaporated to give the pure diester 3 (130 g, 84%) as a white powder. (CAS 57052-99-0)

(4) Dimethyl 2-aminoisophtalate X (where R.sup.1 is methyl). A stream of hydrogen was bubbled through a solution of nitroarene XIV (130 g, 544 mmol, 1.0 eq) and Pd/C (10%, dry, 7.95 g, 6.31 mmol, 1.2 mol %) in regular ethyl acetate (1450 mL) at room temperature. Completion was obtained within 20 h as indicated by TLC analysis. However the reaction time greatly varied depending on the scale and conditions used. The mixture was filtered through a sintered funnel and Pd/C was recovered and successfully reused in other hydrogenations. In the case where wet Pd/C was used, the filtrate was first dried over anhydrous sodium sulphate. The solvents were removed under vacuum to give the desired aniline X (where R.sup.1 is methyl) (113 g, 99%) in excellent purity and as a smelly off-white powder. (CAS 57053-02-3)

(5) General Procedure for Grignard Reaction: A solution of alkylmagnesium bromide was prepared under strictly anhydrous conditions from commercially available magnesium and alkylbromide as followed. A suspension of fresh magnesium (9 eq) in anhydrous THF was treated with the slow addition of a premade solution of alkylbromide (8 eq) in anhydrous THF over 1 h in maintaining the temperature below 40 C. After 2 h at room temperature, the suspension was cooled down to 0 C. and a solution of diester (1 eq) in THF was cannulated at 0 C. The reaction was allowed to warm up to room temperature and was stirred until completion as indicated by TLC analysis (<1 h). The reaction was then cooled down to 0 C and carefully quenched with sat. NH.sub.4Cl solution and diluted in Et.sub.2O. The organic layer was washed with sat. NH.sub.4Cl solution then dried over anhydrous magnesium sulphate and concentrated under vacuum. The resulting crude oil was generally obtained in excellent purity and no further purification was required.

(6) 2,6-Di(3-hydroxypentan-3-yl)aniline XIa (R.sup.2=Me).

(7) A solution of ethylmagnesium bromide was prepared under strictly anhydrous conditions from commercially available magnesium and ethylbromide. A suspension of fresh magnesium (105 g, 4.33 mol, 9.0 eq) in anhydrous THF (1700 mL) was treated with the slow addition of a premade solution of ethylbromide (285 mL, 3.82 mol, 8.0 eq) in anhydrous THF (1700 mL) over 1 h in maintaining the temperature below 40 C. After 2 h at room temperature, the suspension was cooled down to 0 C., causing the formation of a precipitate, and the diester X (where R.sup.1 is methyl) (100 g, 0.48 mol, 1.0 eq) was carefully added portionwise over 5 min at 0 C. The reaction was allowed to warm up to room temperature and was stirred until completion as indicated by TLC analysis (<1 h). The reaction was then cooled down to 0 C. and carefully quenched with sat. NH.sub.4Cl solution (500 mL). The mixture was diluted in Et.sub.2O (1700 mL) and washed with sat. NH.sub.4Cl solution (2500 mL). The organic layer was then dried over anhydrous magnesium sulphate and concentrated under vacuum. The resulting crude oil was then filtered thru a pad of silica and flushed with Et.sub.2O to get a more accurate yield. Evaporation of the solvent provided the crude diol XIa (116 g, 91%) as a yellow/greenish oil in excellent purity. No further purification was required for the next steps.

(8) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.84 (12H, app t, J=7.4 Hz, 4CH.sub.3), 1.92 (4H, m, 4CH), 2.05 (4H, m, 4CH), 4.26 (2H, vbs, NH.sub.2), 6.57 (1H, t, J=7.7 Hz, H.sup.p-Ar), 6.92 (2H, d, J=7.7 Hz, H.sup.m-Ar).

(9) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 8.3 (4CH.sub.3), 30.8 (4CH.sub.2), 79.9 (2C.sub.IVOH), 115.4 (CH.sup.p-Ar), 126.8 (2CH.sup.m-Ar), 128.2 (2CHO-Ar), 146.7 (C.sub.IV.sup.ArNH.sub.2).

(10) HRMS (NSI+): found m/z [M+H]+ 266.2115, calcd for C.sub.16H.sub.28NO.sub.2266.2115.

(11) 2,6-Di(4-hydroxyheptan-4-yl)aniline XIb (R.sup.2=Et). A suspension of fresh magnesium (20.9 g, 0.86 mol, 8.6 eq) in anhydrous THF (300 mL) was treated with the slow addition of a premade solution of n-propylbromide (69.5 mL, 0.77 mol, 7.7 eq) in anhydrous THF (300 mL) over 20 min in maintaining the temperature below 40 C. After 1.5 h at room temperature, the suspension was cooled down to 0 C., causing the formation of a precipitate, and a premade solution of diester X (where R.sup.1 is methyl) (20.0 g, 0.10 mol, 1.0 eq) in dry THF (300 mL) was cannulated at 0 C. The reaction was allowed to warm up to room temperature and was stirred for 2 h. The reaction was then cooled down to 0 C. and carefully quenched with sat. NH.sub.4Cl solution (300 mL). The mixture was diluted in Et.sub.2O (400 mL) and washed with sat. NH.sub.4Cl solution (2200 mL). The organic layer was then dried over anhydrous magnesium sulphate and concentrated under vacuum. The resulting brown crude solid (30.9 g) (Pure by .sup.1H NMR) was then further purified by successive recrystallisation from pentane to give the pure diol XIb (26.6 g, 86%) as a white crystalline solid.

(12) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.90 (12H, app t, J=7.3 Hz, 4CH.sub.3), 1.08-1.23 (4H, m, 4CH), 1.26-1.41 (4H, m, 4CH), 1.78-1.88 (4H, td, J=12.5, 4.5 Hz, 4CH), 1.95-2.05 (4H, td, J=12.5, 4.5 Hz, 4CH), 4.24 (3H, vbs, NH.sub.2+2OH), 6.54 (1H, t, J=7.7 Hz, H.sup.p-Ar), 6.89 (2H, d, J=7.7 Hz, H.sup.m-Ar).

(13) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 14.5 (4CH.sub.3), 17.2 (4CH.sub.2), 41.2 (4CH.sub.2), 79.4 (2C.sub.IvOH), 115.1 (CH.sup.p-Ar), 126.5 (2CH.sup.m-Ar), 128.7 (2CH.sup.o-Ar), 146.7 (C.sub.IV.sup.ArNH.sub.2).

(14) HRMS (NSI+): found m/z [M+H]+ 322.2745, calcd for C.sub.20H.sub.36O.sub.2N 322.2741.

(15) 2,6-Di(5-hydroxynonan-5-yl)aniline XIc (R.sup.2=n-Pr). A solution of n-butylmagnesium bromide was prepared under strictly anhydrous conditions from commercially available magnesium and n-butylbromide as followed. A suspension of fresh magnesium (16.0 g, 0.66 mol, 9.4 eq) in anhydrous THF (200 mL) was treated with the slow addition of a premade solution of n-butylbromide (58.0 mL, 0.54 mol, 7.7 eq) in anhydrous THF (200 mL) over 1 h in maintaining the temperature below 40 C. After 2 h at room temperature, the suspension was cooled down to 0 C., causing the formation of a precipitate, and a solution of diester X (where R.sup.1 is methyl) (14.0 g, 0.07 mol, 1.0 eq) in dry THF (200 mL) was cannulated at 0 C. The reaction was allowed to warm up to room temperature and was stirred until completion as indicated by TLC analysis (<1 h). The reaction was then cooled down to 0 C. and carefully quenched with sat. NH.sub.4Cl solution (200 mL). The mixture was diluted in Et.sub.2O (250 mL) and washed with sat. NH.sub.4Cl solution (2150 mL). The organic layer was then dried over anhydrous magnesium sulphate and concentrated under vacuum. The resulting brownish crude solid (pure by .sup.1H NMR) was then recrystallized from hot pentane to give the pure diol XIc (24.4 g, 97%) as an off-white crystalline solid.

(16) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.88 (12H, app t, J=7.2 Hz, 4CH.sub.3), 1.14 (4H, m, 4CH), 1.32 (12H, m, 12CH), 1.87 (4H, m, 4CH), 2.03 (4H, m, 4CH), 2.24 (2H, partially hidden vbs, 2OH), 5.98 (2H, vbs, NH.sub.2), 6.56 (1H, t, J=7.9 Hz, H.sup.p-Ar), 6.91 (2H, d, J=7.9 Hz, H.sup.m-Ar).

(17) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 14.0 (4CH.sub.3), 23.1 (4CH.sub.2), 26.1 (4CH.sub.2), 38.1 (4CH.sub.2), 79.3 (2C.sub.IvOH), 115.0 (CH.sup.p-Ar), 126.5 (2CH.sup.m-Ar), 128.4 (2CH.sup.o-Ar), 146.7 (C.sub.IV.sup.ArNH.sub.2).

(18) HRMS (NSI+): found m/z [M+H]+ 378.3369, calcd for C.sub.24H.sub.44NO.sub.2 378.3367.

(19) General Procedure for Diol Dehydration and Dialkene Hydrogenation: A solution of diol (1.0 eq) in regular THF was treated with the careful addition of conc. sulphuric acid (98%, 10 eq) and stirred at 100 C. in an open vessel. After 1-2 h at 100 C. most of the THF evaporated and completion was observed by TLC analysis of a worked up crude sample. The reaction was cooled down to room temperature and was carefully poured into a separating funnel containing a saturated aqueous solution of sodium hydroxide. The basic mixture was then extracted with diethyl ether and the combined extracts were dried over anhydrous magnesium sulphate. Filtration followed by concentration of the organic extracts under vacuum gave the crude dialkene as a brownish viscous oil. The crude dialkene was obtained in excellent purity as a variable mixture of (E)- and (Z)-double bond isomers and was used without any further purification in the next step.

(20) Pd/C (10 mol %) was added to a solution of crude dialkene (1.0 eq) in regular ethanol. The reaction was then purged under vacuum then nitrogen and was finally placed under positive pressure of hydrogen. The mixture was allowed to reflux until completion as indicated by .sup.1H NMR. The reaction time required to reach completion varied (6 to 48 h) depending on the substrate, the scale and the conditions used. The mixture was filtered through a sintered funnel and the recovered Pd/C was efficiently reused for larger scale reactions. The yellow filtrate was concentrated under vacuum to afford the desired aniline as a light yellow to brown oil. Excellent purity was obtained and the crude oil was generally used without any further purification. However filtration through a pad of silica and flushing with pentane/Et.sub.2O can be used to get rid of coloured impurities and traces of Pd/C.

(21) 2,6-Di(pentan-3-yl)aniline Ia (R.sup.2=Me). A solution of diol (2.72 g, 10.2 mmol, 1.0 eq) in regular THF (100 mL) was treated with the careful addition of conc. sulphuric acid (98%, 5.50 mL, 101 mmol, 9.9 eq) and stirred at 100 C. in an open vessel. After 2 h at 100 C most of the THF evaporated and completion was observed by TLC analysis of a worked up crude sample. The reaction was cooled down to room temperature and was carefully poured into a separating funnel containing a saturated aqueous solution of sodium hydroxide (12 mL). The basic mixture was then extracted with diethyl ether (3100 mL) and the combined extracts were dried over anhydrous magnesium sulphate. Filtration followed by concentration of the organic extracts under vacuum gave the crude dialkene (2.31 g, 98%) as a brownish viscous oil in excellent purity.

(22) Pd/C (10%, 59.6% wet, 1.84 g, 1.03 mmol, 10 mol %) was added to a solution of crude dialkene (2.31 g, 10.2 mmol, 1.0 eq) in regular ethanol (50 mL). The mixture was allowed to reflux under a positive pressure of hydrogen until completion (48 h) and was filtered through a sintered funnel. The yellow filtrate was concentrated under vacuum to afford the desired aniline Ia (2.00 g, 84% over 2 steps) as a light yellow to brown oil in excellent purity. (KS19) On larger scale (>80 g) the aniline was purified by distillation under reduced pressure as described in the literature. Distillation afforded the pure aniline Ia as a slightly yellowish oil (7 mbar, bp 140 C.). However slight decomposition was observed during distillation and prolonged storage at room temperature. The data obtained are in full agreement with those from the literature.

(23) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.88 (12H, 2t, J=27.5 Hz, 4CH.sub.3), 1.65 (4H, m, 2CH.sub.2), 1.75 (4H, m, 2CH.sub.2), 2.53 (2H, m, 2CH), 3.62 (23H, vbs, NH.sub.2), 6.82 (1H, t, J=7.4 Hz, H.sup.p-Ar), 6.95 (2H, d, J=7.4 Hz, H.sup.m-Ar).

(24) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 12.0 (4CH.sub.3), 28.0 (4CH.sub.2), 42.3 (2CH), 118.4 (CH.sup.p-Ar), 123.8 (2CH.sup.m-Ar), 129.9 (2C.sub.IV.sup.o-Ar), 142.5 (2NC.sub.IV.sup.Ar).

(25) 2,6-Di(heptan-4-yl)aniline Ib (R.sup.2=Et). A solution of diol (25.9 g, 80.6 mmol, 1.0 eq) in regular THF (200 mL) was treated with the careful addition of conc. sulphuric acid (98%, 43.0 mL, 790 mmol, 9.8 eq) and stirred at 100 C. in an open vessel. After 2 h at 100 C. most of the THF evaporated and completion was observed by TLC analysis of a worked up crude sample. The reaction was cooled down to room temperature and was carefully poured into a separating funnel containing a saturated aqueous solution of sodium hydroxide (90 mL). The basic mixture was then extracted with diethyl ether (3500 mL) and the combined extracts were dried over anhydrous magnesium sulphate. Filtration followed by concentration of the organic extracts under vacuum gave the crude dialkene (22.7 g, 99%) as a viscous light yellow oil in excellent purity.

(26) Pd/C (10%, recycled, 30.0 g, 28.2 mmol, 35 mol %) was added to a solution of crude dialkene (22.7 g, 80.6 mmol, 1.0 eq) in regular ethanol (600 mL). The mixture was allowed to reflux under a positive pressure of hydrogen until completion (3.5 h) and was filtered through a sintered funnel. The yellow filtrate was concentrated under vacuum to afford the desired aniline Ib (21.1 g, 91% over 2 steps) as a light yellow oil in excellent purity.

(27) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.87 (12H, app t, J=7.3 Hz, 4CH.sub.3), 1.21-1.31 (8H, m, 4CH.sub.2), 1.52-1.68 (8H, m, 4CH.sub.2), 2.66 (2H, m, 2CH), 3.66 (2H, vbs, NH.sub.2), 6.77 (1H, t, J=7.5 Hz, H.sup.p-Ar), 6.92 (2H, d, J=7.5 Hz, H.sup.m-Ar).

(28) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3, SEM233) 14.5 (4CH.sub.3), 17.2 (4CH.sub.2), 41.2 (4CH.sub.2), 79.4 (2C.sub.IVOH), 115.1 (CH.sup.p-Ar), 126.5 (2CH.sup.m-Ar), 128.7 (2CH.sup.o-Ar), 146.7 (C.sub.IV.sup.ArNH.sub.2).

(29) HRMS (NSI+): found m/z [M+H]+ 290.2847, calcd for C.sub.20H.sub.36N 290.2842.

(30) 2,6-Di(nonan-5-yl)aniline Ic (R.sup.2=n-Pr). A solution of diol (10.1 g, 26.7 mmol, 1.0 eq) in regular THF (230 mL) was treated with the careful addition of conc. sulphuric acid (98%, 14.3 mL, 263 mmol, 9.9 eq) and stirred at 100 C. in an open vessel. After 1 h at 100 C. most of the THF evaporated and completion was observed by TLC analysis of a worked up crude sample. The reaction was cooled down to room temperature and was carefully poured into a separating funnel containing a saturated aqueous solution of sodium hydroxide (42 mL). The basic mixture was then extracted with diethyl ether (3250 mL) and the combined extracts were dried over anhydrous magnesium sulphate. Filtration followed by concentration of the organic extracts under vacuum gave the crude dialkene (10.2 g) as a yellowish clear viscous oil in excellent purity.

(31) Pd/C (10% dry, 3.21 g, 3.02 mmol, 11 mol %) was added to a solution of crude dialkene (10.2 g, 26.7 mmol, 1.0 eq) in regular ethanol (150 mL). The mixture was allowed to reflux under a positive pressure of hydrogen until completion (19 h) and was filtered through a sintered funnel. The yellow filtrate was concentrated under vacuum to afford the desired aniline Ic (8.05 g, 87% over 2 steps) as a clear yellow to orange oil in excellent purity.

(32) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.88 (12H, app t, J=7.0 Hz, 4CH.sub.3), 1.28 (16H, m, 8CH.sub.2), 1.65 (8H, m, 4CH.sub.2), 2.65 (2H, m or bs, 2CH), 3.65 (2H, bs, NH.sub.2), 6.80 (1H, m, H.sup.p-Ar), 6.95 (2H, d, J=7.2 Hz, H.sup.m-Ar).

(33) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 14.0 (4CH.sub.3), 23.0 (4CH.sub.2), 29.8 (4CH.sub.2), 35.7 (4CH.sub.2), 39.0 (2CH), 118.4 (CH.sup.p-Ar), 123.7 (2CH.sup.m-Ar), 130.6 (2CH.sup.o-Ar), 142.1 (C.sub.IV.sup.ArNH.sub.2).

(34) HRMS (NSI+): found m/z [M+H]+ 346.3474, calcd for C.sub.24H.sub.44N 378.346.3468.

(35) General Procedure for Diimine Preparation: A stirred solution of aniline (2.0 eq) in regular methanol was treated with glyoxal (40% in H.sub.2O, 1.2 eq) followed by catalytic amount of formic acid (0.3 eq) at room temperature. The desired diimine started to precipitate from the reaction media and stirring was continued until completion as indicated by .sup.1H NMR analysis. The pure diimine was successfully obtained by either recrystallization of the crude from methanol or ethanol or by filtration through a pad of silica.

(36) The spontaneous crystallisation of the diimine at the end of the reaction can be increased by ceasing the stirring after 15 min, and leaving the reaction mixture overnight or placing the reaction mixture in the freezer. The reaction can also be done in ethanol but spontaneous crystallisation of the diimine at the end of the reaction was not as efficient as in methanol. Residual diimine obtained by concentration of the filtrate can also be purified successfully by filtration through silica gel and flushing (eluting) with pentane.

(37) N,N-Bis[2,6-di(pentan-3-yl)phenyl]diazabutadiene IIa (R.sup.2=Me). A stirred solution of IPent aniline (la)(18.3 g, 78.6 mmol, 2.0 eq) in regular methanol (230 mL) was treated with glyoxal (40% in H.sub.2O, 5.40 mL, 49.1 mmol, 1.3 eq) followed by catalytic amount of formic acid (460 L, 12.2 mmol, 0.3 eq) at room temperature. The desired diimine started to precipitate from the reaction media and stirring was continued until completion (3 h). The solid was isolated by filtration and the filtrate was concentrated under vacuum. The resulting brownish solid was recrystallized from methanol. Both solids were combined and dried under high vacuum to afford the pure desired diimine IIa as a bright and shiny yellow crystalline powder (16.0 g, 83%).

(38) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.82 (24H, t, J=7.3 Hz, 8CH.sub.3), 1.59 (8H, m, 4CH.sub.2), 1.68 (8H, m, 4CH.sub.2), 2.52 (4H, m, 4CH), 7.08-7.10 (4H, m, 4H.sup.m-Ar), 7.14-7.18 (2H, m, 2H.sup.p-Ar), 8.04 (2H, s, 2HCN).

(39) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 12.2 (8CH.sub.3), 28.9 (8CH.sub.2), 42.5 (4CH), 123.9 (4CH.sup.m-Ar), 124.8 (2CH.sup.p-Ar), 133.8 (4C.sub.IV.sup.o-Ar), 150.9 (2NC.sub.IV.sup.Ar), 163.9 (2HCN).

(40) HRMS (NSI+): found m/z [M+H]+ 489.4199, calcd for C.sub.34H.sub.53N2489.4203.

(41) N,N-Bis [2,6-di(heptan-4-yl)phenyl]diazabutadiene IIb (R.sup.2=Et). A stirred solution of IHept aniline (Ib)(20.6 g, 71.2 mmol, 2.0 eq) in regular methanol (210 mL) was treated with glyoxal (40% in H.sub.2O, 4.88 mL, 44.4 mmol, 1.2 eq) followed by catalytic amount of formic acid (420 L, mmol, 0.3 eq) at room temperature. The desired diimine started to precipitate from the reaction media and stirring was continued until completion (5 h). The solid was isolated by filtration and the filtrate was concentrated under vacuum. The resulting brownish solid was filtered through a plug of silica and flushed with pentane. After concentration, both solids were combined and dried under high vacuum to afford the pure desired diimine IIb as a bright and shiny yellow crystalline powder (19.1 g, 89%).

(42) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.88 (24H, app t, J=7.4 Hz, 8CH.sub.3), 1.24 (16H, m, 8CH.sub.2), 1.59 (16H, m, 8CH.sub.2), 2.74 (4H, m, 4CH), 7.12-7.19 (6H, m, H.sup.Ar), 8.05 (2H, s, 2CHN).

(43) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 14.3 (4CH.sub.3), 20.8 (4CH.sub.2), 38.4 (4CH), 39.1 (4CH.sub.2), 123.8 (CH.sup.p-Ar), 124.8 (2CH.sup.m-Ar), 134.3 (2CH.sup.o-Ar), 150.6 (C.sub.IV.sup.ArNH.sub.2), 163.8 (CHN).

(44) HRMS (APCI+): found m/z [M+H]+ 601.5453, calcd for C.sub.42H.sub.69N.sub.2 601.5455.

(45) N,N-Bis [2,6-di(nonan-5-yl)phenyl]diazabutadiene IIc (R.sup.2=n-Pr). A stirred solution of INon aniline (Ic) (1.43 g, 4.14 mmol, 2.0 eq) in regular methanol (12 mL) was treated with glyoxal (40% in H.sub.2O, 284 L, 2.48 mmol, 1.2 eq) followed by catalytic amount of formic acid (24 L, mmol, 0.3 eq) at room temperature. The desired diimine started to precipitate from the reaction media and stirring was continued until completion (4 h). The methanol was evaporated under vacuum and the residue was diluted in pentane (12 mL) then dried over anhydrous sodium sulfate. The filtrate was passed through a short pad of silica and flushed with pentane. The pentane was evaporated under vacuum and the remaining yellow solid was recrystallized from ethanol. The pure desired diimine IIc was obtained as a bright and shiny yellow crystalline powder (1.02 g, 69%).

(46) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.85 (24H, app t, J=7.2 Hz, 4CH.sub.3), 1.13-1.33 (32H, m, 16CH.sub.2), 1.53-1.66 (16H, m, 8CH.sub.2), 2.68 (4H, m, 4CH), 7.11 (4H, d, J=6.8 Hz, H.sup.m-Ar), 7.16 (2H, t, J=6.8 Hz, H.sup.m-Ar), 8.00 (2H, s, 2CHN).

(47) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 14.0 (8CH.sub.3), 22.9 (8CH.sub.2), 29.9 (8CH.sub.2), 36.6 (8CH.sub.2), 38.9 (4CH), 123.8 (2CH.sup.p-Ar), 124.8 (4CH.sup.m-Ar), 134.4 (4CH.sup.o-Ar), 150.7 (2C.sub.IV.sup.ArNH.sub.2), 163.6 (2CHN).

(48) HRMS (APCI+): found m/z [M+H]+ 713.6711, calcd for C.sub.50H.sub.85N.sub.2 713.6707.

(49) General Procedure for Imidazolium Chloride Preparation: A solution of diimine (1.0 eq) in regular THF was treated with anhydrous zinc chloride (1.0 eq) at 70 C. and stirred for 5 min. para-formaldehyde (1.1 eq) was subsequently added followed by the dropwise addition of anhydrous HCl (4.0 M in dioxane, 1.5 eq). The reaction was stirred for 3 h at 70 C. and concentrated down under vacuum. The residue was dissolved in ethyl acetate and was washed with water and brine. The combined aqueous phases were extracted with ethyl acetate and the organic phases were combined and dried over anhydrous magnesium sulphate. The solvent was partially evaporated under vacuum until the formation of a solid and the resulting suspension was diluted with pentane and placed in the freezer for 20 min. The solid was isolated by filtration and washed with pentane to afford the pure desired imidazolium chloride as an off-white crystalline powder.

(50) In general it was found that crystallization of the crude imidazolinium salts is improved by work up procedures such as that described above, including extraction into ethyl acetate and/or brine washes after reaction.

(51) 1,3-Bis[2,6-di(pentan-3-yl)phenyl]imidazolium chloride IIIa (R.sup.2=Me, IPent.HCl). A solution of IPent diimine IIa (3.00 g, 6.14 mmol, 1.0 eq) in regular tetrahydrofuran (240 mL) was treated with anhydrous zinc chloride (837 mg, 6.14 mmol, 1.0 eq) at 70 C. and stirred for 5 min. p-formaldehyde (193 mg, 6.43 mmol, 1.1 eq) was subsequently added followed by the dropwise addition of anhydrous HCl (4.0 M in dioxane, 2.3 mL, 9.1 mmol, 1.5 eq). The reaction was stirred for 3 h at 70 C. and concentrated down under vacuum. The residue was dissolved in ethyl acetate (200 mL) and was washed with water (3200 mL) and brine (200 mL). The combined aqueous phases were extracted with ethyl acetate (200 mL) and the organic phases were combined and dried over anhydrous magnesium sulphate. The solvent was partially evaporated under vacuum until the apparition of a solid and the resulting suspension was diluted with pentane and placed in the freezer for 20 min. The solid was isolated by filtration and washed with pentane to afford the pure desired imidazolium chloride IIIa as an off-white crystalline powder (2.36 g, 71%).

(52) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.78 (12H, t, J=7.4 Hz, 4CH.sub.3), 0.86 (12H, t, J=7.4 Hz, 4CH.sub.3), 1.68 (16H, m, 8CH.sub.2), 1.96 (4H, m, 4CH), 7.29 (4H, d, J=7.9 Hz, 4H.sup.m-Ar), 7.61 (2H, t, J=7.9 Hz, 2H.sup.p-Ar), 8.32 (2H, app d, J=1.7 Hz, 2HCN), 8.87 (1H, bs, NCHN).

(53) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 11.9 (4CH.sub.3), 12.1 (4CH.sub.3), 28.0 (4CH.sub.2), 28.7 (4CH.sub.2), 43.1 (4CH), 125.0 (4CH.sup.m-Ar), 127.5 (2HCN), 131.8 (2CH.sup.p-Ar), 132.1 (4C.sub.IV.sup.o-Ar) or 135.9 (NCHN), 142.0 (2NC.sub.IV.sup.Ar).

(54) Anal. Calcd for C.sub.35H.sub.53ClN.sub.2: C, 78.24; H, 9.94; N, 5.21. Found: C, 78.13; H, 10.03; N, 5.19.

(55) 1,3-Bis [2,6-di(heptan-4-yl)phenyl]imidazolium chloride IIIb (R.sup.2=Et, IHept.HCl). A solution of diimine (19.1 g, 31.8 mmol, 1.0 eq) in regular tetrahydrofuran (1500 mL) was treated with anhydrous zinc chloride (4.33 g, 31.8 mmol, 1.0 eq) at 70 C. and stirred for 5 min. p-formaldehyde (1.00 g, 33.4 mmol, 1.1 eq) was subsequently added followed by the dropwise addition of anhydrous HCl (4.0 M in dioxane, 11.8 mL, 47.72 mmol, 1.5 eq). The reaction was stirred for 3 h at 70 C. and concentrated down under vacuum. The residue was dissolved in ethyl acetate (1000 mL) and was washed with water (2750 mL) and brine (750 mL). The combined aqueous phases were extracted with ethyl acetate (200 mL) and the organic phases were combined and dried over anhydrous magnesium sulphate. The solvent was partially evaporated under vacuum until the formation of a solid and the resulting suspension was diluted with pentane and placed in the freezer for 20 min. The solid was isolated by filtration and washed with pentane to afford the pure desired imidazolium chloride IIIb as a white crystalline powder (9.72 g, 47%).

(56) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.84 (12H, t, J=7.2 Hz, 4CH.sub.3), 0.87 (12H, t, J=7.2 Hz, 4CH.sub.3), 0.97-1.14 (12H, m, 4CH+4 CH.sub.2), 1.27 (4H, m, 4CH), 1.49-1.69 (16H, m, 4CH.sub.2+4CH.sub.2), 2.05 (4H, sharp m, 4 CH+impurity), 7.29 (4H, d, J=7.8 Hz, H.sup.m-Ar), 7.60 (2H, t, J=7.8 Hz, H.sup.p-Ar), 8.20 (1H, s, NCHN), 8.41 (2H, s, 2CHN).

(57) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 13.8 (4CH.sub.3), 14.1 (4CH.sub.3), 20.6 (4CH.sub.2), 21.0 (4CH.sub.2), 37.9 (4CH), 39.1 (4CH.sub.2), 40.3 (4CH), 125.0 (CH.sup.m-Ar), 127.7 (2HCN), 131.4 (2C.sub.IV.sup.Ar), 132.0 (2CH.sup.p-Ar), 134.9 (NCHN), 142.5 (NC.sub.IV.sup.Ar).

(58) Anal. Calcd for C.sub.43H.sub.69ClN.sub.2: C, 79.52; H, 10.71; N, 4.31. Found: C, 79.39; H, 10.72; N, 4.35.

(59) 1,3-Bis [2,6-di(nonan-5-yl)phenyl]imidazolium chloride IIIc (R.sup.2=n-Pr, INon.HCl). A solution of diimine IIc (685 mg, 0.96 mmol, 1.0 eq) in regular tetrahydrofuran (35 mL) was treated with anhydrous zinc chloride (131 mg, 0.96 mmol, 1.0 eq) at 70 C. and stirred for 5 min. p-formaldehyde (30.0 mg, 1.00 mmol, 1.0 eq) was subsequently added followed by the dropwise addition of anhydrous HCl (4.0 M in dioxane, 355 L, 1.42 mmol, 1.5 eq). The reaction was stirred for 3 h at 70 C. and concentrated down under vacuum. The residue was dissolved in ethyl acetate (30 mL) and was washed with water (320 mL) and brine (20 mL). The combined aqueous phases were extracted with ethyl acetate (10 mL) and the organic phases were combined and dried over anhydrous magnesium sulphate. The solvent was completely evaporated under vacuum and the resulting solid was washed with pentane to afford the pure desired imidazolium chloride IIIc as a white crystalline powder (262 mg, 36%).

(60) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.81 (12H, t, J=7.2 Hz, 4CH.sub.3), 0.88 (12H, t, J=7.2 Hz, 4CH.sub.3), 0.96-1.10 (12H, m, 4CH+4 CH.sub.2), 1.18-1.34 (20H, m, 8CH.sub.2+4CH), 1.51-1.77 (16H, m, 4CH.sub.2+4CH.sub.2), 2.06 (4H, m, 4 CH), 7.32 (4H, d, J=7.8 Hz, H.sup.m-Ar), 7.63 (2H, t, J=7.8 Hz, H.sup.p-Ar), 8.23 (1H, s, NCHN), 8.48 (2H, s, 2CHN).

(61) .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) 13.8 (4CH.sub.3), 13.9 (4CH.sub.3), 22.6 (4CH.sub.2), 22.9 (8CH.sub.2), 30.0 (4CH.sub.2), 30.1 (4CH.sub.2), 35.5 (4CH.sub.2), 36.8 (4CH.sub.2), 40.6 (4CH), 125.3 (CH.sup.m-Ar), 128.0 (2HCN), 131.7 (2C.sub.IV.sup.Ar), 132.3 (2CH.sup.p-Ar), 135.0 (NCHN), 142.8 (NC.sub.IV.sup.Ar).

(62) Anal. Calcd for C.sub.51H.sub.85ClN.sub.2: C, 80.42; H, 11.25; N, 3.68. Found: C, 80.25; H, 11.12; N, 3.77.

(63) Procedure for the Preparation of Imidazolium Chlorides with para-Methoxy Substituents p-Iodo anilines

(64) ##STR00034##

(65) A solution of the aniline in regular cyclohexane was treated with a saturated aqueous solution of Na.sub.2CO.sub.3 followed by solid iodine at room temperature. The reaction was stirred overnight at room temperature (14 h). The crude solution was diluted in Et.sub.2O and washed with a saturated aqueous solution of Na.sub.2S.sub.2O.sub.3. The organic layer was then dried over anhydrous sodium sulphate and concentrated under vacuum. The resulting residue was generally obtained in excellent purity and was either used without further purification or filtered through silica and flushed with 1% Et.sub.2O in pentane.

(66) Procedure for p-Iododiimine Preparation

(67) ##STR00035##

(68) A solution of p-iodo-aniline (2.0 eq) in MeOH was treated with formic acid (1 drop) followed by the dropwise addition of glyoxal (40% in H.sub.2O, 1.2 eq) at 70 C. The solution was stirred at this temperature for 3 h and the methanol was evaporated under vacuum and replaced by Et.sub.2O.

(69) Reaction overnight at room temperature may also be used to affect the transformation. The solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuuo. The residue was purified by flash column chromatography (silica gel, 1-5% Et.sub.2O in pentane) to yield the pure desired diimine as a bright yellow solid. Purification by flash column chromatography was preferred on small scale synthesis to obtain accurate yields. However on larger scale, the pure desired diimines usually precipitated out of the methanolic solution and can be easily isolated by filtration.

(70) Procedure for p-Methoxydiimine Preparation

(71) ##STR00036##

(72) A sealed tube was loaded with regular methanol, CuI (0.5 eq), phenanthroline (0.8 eq) and Cs.sub.2CO.sub.3 (4.3 eq) at room temperature. To this brown mixture was added the starting diiodo diimine (1.0 eq) and the reaction was stirred overnight at for example 110 C. The reaction was allowed to cool down to room temperature and was filtered through cotton wool. The remaining solid was washed with diethyl ether and the filtrate was transferred into a separating funnel. The organic layer was washed with 10% NH.sub.4OH then brine and was then dried over anhydrous sodium sulphate. Concentration in vacuuo afforded the crude dimethoxy diimine. Although excellent purity was generally obtained (.sup.1H NMR), filtration through silica was preferred to remove colouring agents and traces of copper. The silica was flushed with pentane and the filtrate was evaporated to yield the pure desired diimine.

(73) Anhydrous conditions are not required. Preliminary results show that completion is actually reached within a few hours. Conditions were not optimised and quantities of reagents may be significantly reduced.

(74) Where the diimine has groups R.sup.2H (isopropyl substituents at the 2 and 6 positions) the expected p-methoxydiimine was not formed but instead the corresponding p-methoxyaniline (below) was produced (73% yield, overnight in a sealed tube reaction at 120 C). The diimine bridge is cleaved in this example. Bulkier R.sup.2 groups such as methyl, ethyl and n-propyl produced high yields 100% to 94%) of the methoxydiimines, with little free aniline (3%) indicating a steric effect.

(75) The diisopropyl aniline produced can be readily converted to the corresponding diimine by reacting again with formic acid and glyoxal (40% in H.sub.2O) in methanol as shown below.

(76) ##STR00037##

(77) More generally if the p-methoxy anilines are desired the diimine bridge of the p-methoxy diimines can be readily cleaved as shown below. For example reaction with acid such as hydrochloric acid in aqueous solvent (e.g. water/THF) at moderate temperature (e.g. room temperature to 100 C). Reaction may be complete in as little as 20 to 30 minutes. Thus the diimine function can serve as a protecting group when anilines of the invention are desired products.

(78) ##STR00038##

(79) Procedure for p-Methoxyimidazolium Chloride Preparation

(80) ##STR00039##

(81) A solution of p-methoxydiimine (1.0 eq) in regular tetrahydrofuran was treated with anhydrous zinc chloride (1.0 eq) at 70 C. and stirred for 5 min. p-formaldehyde (1.1 eq) was subsequently added followed by the dropwise addition of anhydrous HCl (4.0 M in dioxane, 1.5 eq). The reaction was stirred for at 70 C. and concentrated under vacuum. The residue was dissolved in ethyl acetate and was washed with water and brine. The combined aqueous phases were extracted with ethyl acetate and the organic phases were combined and dried over anhydrous magnesium sulphate. The solvent was evaporated under vacuum and the resulting brown solid was triturated with pentane to yield the pure desired imidazolium chloride as the remaining solid.

(82) The above procedure was used to prepare the imidazolium salts: IPrOMe.HCl IPent-OMe.HCl, IHept-OMe.HCl and INon-OMe.HCl. (The structures III(OMe) above where groups R.sup.2 are respectively H, Me, Et, and n-Pr.) These imidazolium salts were used to prepare NHC containing palladium complexes as described below.

(83) Procedure for the Preparation of SIPrOMe.HCl

(84) ##STR00040##

(85) AThe diimine precursor N,N-Bis(4-methoxy-2,6-diisopropylphenyl)1,4-diazabutadiene (A) was made by following a variation of the General Procedure for Diimine Preparation discussed above. A solution of 4-methoxy-2,6-diisopropylaniline (15.2 g, 73.4 mmol, 2.0 eq) in MeOH (300 mL) was treated with formic acid (2 drops) followed by the dropwise addition of glyoxal (40% in H2O, 6.43 mL, 74.4 mmol, 1.0 eq) at rt. The solution was stirred at this temperature for 2 h and the methanol was evaporated under vacuum and replaced by pentane (300 mL). The solution was dried over anhydrous sodium sulfate, filtered and partially concentrated in vacuuo. Although good purity was obtained, the residual oil was preferably purified by flash column chromatography (silica gel, 10% Et2O in pentane to yield the pure desired diimine A as an orange solid (11.5 g, 72%). 1H NMR (400 MHz, CDCl3) 0.81 (24H, d, J=6.9 Hz, 8CH3), 3.04 (4H, m, 4CH), 3.87 (OCH3), 6.79 (4H, s, 4H.sup.m-Ar), 8.14 (2H, s, 2HCN). 13C NMR (100 MHz, CDCl3) 23.3 (8CH3), 28.1 (4CH), 55.1 (2OCH3), 108.6 (4CHm-Ar), 138.6 (4CIVo-Ar), 141.6 (2NCIVAr), 157.2 (2OCIVAr), 163.5 (2HCN). HRMS (NSI+): found m/z [M+H]+ 437.3158, calcd for C28H41O2N2 437.3163.

(86) B N,N-Bis-(4-methoxy-2,6-diisopropylphenylamino)ethane (B). A solution of diimine A (11.5 g, 26.3 mmol, 1.0 equiv) in anhydrous THF (200 mL) was cooled to 20 C. and treated with LiAIH4 (2.4 M in THF, 44.0 mL, 106 mmol, 4.0 equiv). Upon addition of LiAIH4, the yellow solution rapidly turned very dark purple and important bubbling was observed. After 15 min at 20 C., the colour of the reaction changed back to clear orange and the reaction was allowed to stir for 45 min at room temperature. The reaction was then cooled to 0 C., diluted with diethyl ether (200 mL), and carefully quenched with water (5.0 mL). After stirring for 10 min, a 15% aqueous solution of NaOH (5.0 mL) was added, followed by water (12 mL). The suspension was allowed to warm to room temperature and was stirred for 15 min before anhydrous magnesium sulfate was added until a fine solid was obtained. The solids were discarded by filtration and the filtrate was concentrated in vaccuo affording a clear orange and very viscous oil (11.80 g) in excellent purity. However, the oil was preferably purified by flash column chromatography (silica, 10-20% diethyl ether in pentane) to provide the pure desired diamine 25 as an orange viscous oil (11.35 g, 98%). 1H NMR (400 MHz, CDCl3) 1.26 (24H, d, J=6.9 Hz, 4CH3), 3.08 (6H, vbs, 2CH2+2NH), 3.40 (4H, m, 4CH), 3.82 (6H, m, 2OCH3), 6.68 (4H, s, 4Hm-Ar). 13C NMR (100 MHz, CDCl3) 24.2 (8CH3), 27.9 (4CH), 52.6 (2CH2), 55.2 (2OCH3), 108.9 (4CH.sup.m-Ar), 136.4 (2OCIVp-Ar), 144.6 (4CIVo-Ar), 156.2 (2NCIVAr). HRMS (NSI+): found m/z [M+H]+ 441.3470, calcd for C28H45O2N2 441.3476.

(87) C1,3-Bis-(4-methoxy-2,4-diisopropylphenyl)imidazolinium chloride (SIPrOMe.HCl).

(88) A solution of diamine B (7.35 g, 16.7 mmol, 1.0 equiv) in triethyl orthoformate (60 mL) was heated to 120 C. and treated with the rapid addition of HCl (4.0 M in dioxane, 5.0 mL, 1.2 equiv). Upon addition of the HCl, the clear solution immediately turned into a white suspension and the stirring was continued for 10 min at 120 C. The reaction was cooled to room temperature and was diluted with pentane (60 mL). The white solid was isolated by filtration and washed with pentane (360 mL). After drying under high vacuum, the desired imidazolinium chloride C was obtained as a bright white powder (7.80 g, 96%). 1H NMR (400 MHz, CDCl3) 1.14 (12H, d, J=6.9 Hz, 4CH3), 1.25 (12H, d, J=6.9 Hz, 4CH3), 2.84 (4H, m, 4CH), 3.74 (6H, m, 2OCH3), 4.58 (4H, s, 2NCH2), 6.62 (4H, s, 4H.sup.m-Ar), 8.64 (1H, s, NCHN). 13C NMR (100 MHz, CDCl3) 23.3 (4CH3), 25.1 (4CH3), 29.1 (4CH), 55.2 (2OCH3), 109.8 (4CHm-Ar), 121.9 (2CHp-Ar), 147.4 (4CIVo-Ar), 159.4 (NCHN), 161.1 (2NCIVAr). Anal. Calcd for C29H43ClN2O2: C, 71.51; H, 8.90; N, 5.75. Found: C, 71.40; H, 9.01; N, 5.85.

(89) Procedure for the Preparation of Palladium Complexes

(90) Synthesis of [Pd(IPent)(acac)Cl]

(91) In a Schlenk flask equipped with a magnetic stirring bar were added IPent.HCl (IIIa) (215 mg, 0.4 mmole) and Pd(acac).sub.2 (91 mg, 0.4 mmole) in dry 1,4-dioxane (6 mL) under an atmosphere of nitrogen. The reaction mixture was heated under reflux for 24 h. After this time, the dioxane was evaporated and the crude product dissolved in pentane.

(92) The solution was filtered on a pad of silica covered with Celite and the product eluted with pentane. After evaporation of the solvent and drying under high vacuum, the desired complex was obtained as a yellow powder (183 mg, 82%). 1H NMR (300 MHz, CDCl3): =7.39 (t, J=8 Hz, 2H), 7.20 (d, J=8 Hz, 4H), 7.04 (s, 2H), 5.00 (s, 1H), 2.71 (m, 4H), 2.15 (m, 4H), 1.73 (s, 3H), 1.53 (s, 3H), 1.80-1.38 (m, 12H), 0.96 (t, J=7.3 Hz, 12H), 0.74 (t, J=7.4, 12H). Anal. Calcd for C40H59ClN2O2Pd: C, 64.77; H, 8.02; N, 3.78. Found: C, 64.86, H, 8.15, N, 3.82.

(93) Procedure for the Synthesis of [Pd(IHept)(Acac)Cl]

(94) In a Schlenk flask equipped with a magnetic stirring bar were added IHept.HCl (IIIb)(260 mg, 0.4 mmole) and Pd(acac)2 (91 mg, 0.30 mmole) in dry 1,4-dioxane (6 mL) under an atmosphere of nitrogen. The reaction mixture was heated under reflux during 24 h. After this time, the dioxane was evaporated and the crude product dissolved in Et.sub.2O.

(95) The solution was filtered on a pad of silica covered with Celite and the product eluted with Et20. After evaporation of the solvent and drying under high vacuum, the desired complex was obtained as a yellow powder (219 mg, 87%).

(96) 1H NMR (300 MHz, CDCl.sub.3): =7.36 (t, J=7.8 Hz, 2H), 7.21 (d, 7.8 Hz, 4H), 7.02 (s, 2H), 4.98 (s, 1H), 2.82 (m, 4H), 2.17 (m, 4H), 1.77 (s, 3H), 1.40 (s, 3H), 1.73-1.25 (m, 20H), 1.15-1.08 (m, 8H), 0.80 (t, J=7.1 Hz, 24H). 13C NMR (CDCl.sub.3, 75 MHz): 186.36, 184.05, 154.47, 144.77, 136.98, 129.32 125.25, 99.94, 67.51, 39.99, 39.94, 39.74, 39.06, 26.86, 25.99, 21.95, 21.73, 21.22, 15.14. Anal. Calcd for C48H75ClN2O2Pd: C, 67.51; H, 8.85; N, 3.28. Found: C, 67.39; H, 8.77; N, 3.39.

(97) Procedure for the Synthesis of [Pd(INon)(Acac)Cl]

(98) A similar procedure was employed to those discussed above for the IHept and IPent complexes.

(99) Anal. Calcd for C56H91ClN2O2Pd: C, 69.61; H, 9.49; N, 2.90. Found: C, 69.67; H, 9.62; N, 3.01.

(100) Procedure for the Synthesis of [Pd(IPent-OMe)(Acac)Cl]

(101) In a Schlenk flask equipped with a magnetic stirring bar were added IPentOMe.HCl (223 mg, 0.37 mmole) and Pd(acac)2 (85 mg, 0.28 mmole) in dry 1,4-dioxane (6 mL) under an atmosphere of nitrogen.

(102) The reaction mixture was heated under reflux for 24 h. After this time, the dioxane was evaporated and the crude product dissolved in pentane. The solution was filtered on a pad of silica covered with Celite and the product eluted with pentane. After evaporation of the solvent and drying under high vacuum, the desired complex was obtained as a yellow powder (152 mg, 68%). Higher yield can be obtained on heating the reaction mixture for longer e.g. 82% after using a heating time of 40 h.

(103) 1H NMR (300 MHz, CDCl3): =7.01 (s, 2H), 6.73 (s, 4H), 5.04 (s, 1H), 3.86 (s, 6H), 2.66 (m, 4H), 2.11 (m, 4H), 1.78 (s, 3H), 1.61 (s, 3H), 1.75-1.40 (m, 12H), 0.97 (t, J=7.3 Hz, 12H), 0.75 (t, J=7.4 Hz, 12H). 13C NMR (CDCl3, 75 MHz): 186.57, 184.07, 159.89, 155.21, 145.94, 130.63, 125.68, 110.79, 100.17, 55.67, 41.93, 28.93, 27.85, 27.13, 26.42, 12.81, 11.93. Anal. Calcd for C42H63ClN2O4Pd: C, 62.91; H, 7.92; N, 3.49. Found: C, 62.84; H, 8.03; N, 3.53.

(104) Procedure for the Synthesis of [Pd(IHept-OMe)(Acac)Cl]

(105) In a Schlenk flask equipped with a magnetic stirring bar were added IHeptOMe.HCl (193 mg, 0.27 mmole) and Pd(acac)2 (62 mg, 0.2 mmole) in dry 1,4-dioxane (5 mL) under an atmosphere of nitrogen.

(106) The reaction mixture was heated under reflux for 24 h. After this time, the dioxane was evaporated and the crude product dissolved in pentane. The solution was filtered on a pad of silica covered with Celite and the product eluted with pentane. After evaporation of the solvent and drying under high vacuum, the desired complex was obtained as a yellow powder (150 mg, 82%). A higher yield (87%) was obtained after using a heating time of 40 h. 1H NMR (300 MHz, CDCl3): =6.96 (s, 2H), 6.70 (s, 4H), 4.99 (s, 1H), 3.84 (s, 3H), 2.76 (m, 4H), 2.10 (m, 4H), 1.76 (s, 3H), 1.46 (s, 3H), 1.68-1.04 (m, 20H), 0.79 (t, J=7.1 Hz, 24H). 13C NMR (CDCl3, 75 MHz): 186.36, 184.02, 178.93, 159.89, 154.88, 146.33, 130.42, 125.44, 110.49, 99.97, 55.68, 40.05, 28.92, 26.89, 26.13, 21.67, 21.17, 15.15. Anal. Calcd for C50H79ClN2O4Pd: C, 65.70; H, 8.71; Cl, N, 3.06. Found: C, 65.64; H, 8.80; N, 3.15.

(107) Procedure for the Synthesis of [Pd(INon-OMe)(Acac)Cl]

(108) In a Schlenk flask equipped with a magnetic stirring bar were added INonOMe.HCl (221 mg, 0.27 mmole) and Pd(acac)2 (62 mg, 0.2 mmole) in dry 1,4-dioxane (5 mL) under an atmosphere of nitrogen. The reaction mixture was heated under reflux for 24 h. After this time, the dioxane was evaporated and the crude product dissolved in pentane.

(109) The solution was filtered on a pad of silica covered with Celite and the product was eluted with pentane. After evaporation of the solvent and drying under high vacuum, the desired complex was obtained as a yellow powder (160 mg, 78%).

(110) 13C NMR (CDCl3, 75 MHz): 186.36, 183.83, 159.88, 154.87, 146.39, 130.45, 125.36, 110.47, 100.11, 59.69, 40.10, 37.45, 36.42, 30.88, 30.22, 27.02, 26.24, 23.94, 23.70, 14.59, 14.48. Anal. Calcd for C58H95ClN2O4Pd: C, 67.88; H, 9.33; N, 2.73. Found: C, 67.72; H, 9.46; N, 2.88.

Exemplary Reactions of [Pd(IPent-OMe)(acac)Cl], [Pd(IHept-OMe)(acac)Cl] and [Pd(INon-OMe)(acac)Cl]

Example 1 Amination with 4-fluoroanisole

(111) TABLE-US-00001 Entry Catalyst. Solvent Base Conv..sup.b 1 [Pd(IPent-OMe)(acac)Cl] Toluene KO.sup.tBu 91 2 [Pd(IPent-OMe)(acac)Cl] Toluene KO.sup.tAm 100 3 [Pd(IPent-OMe)(acac)Cl] Toluene LiHMDS 85 4 [Pd(IPent-OMe)(acac)Cl] 1,4-dioxane KO.sup.tBu 48 5 [Pd(IPent-OMe)(acac)Cl] 1,4-dioxane KO.sup.tAm 35 6 [Pd(IPent-OMe)(acac)Cl] 1,4-dioxane LiHMDS 18 7 [Pd(IPent-OMe)(acac)Cl] DME KO.sup.tBu 40 8 [Pd(IPent-OMe)(acac)Cl] DME KO.sup.tAm 37 9 [Pd(IPent-OMe)(acac)Cl] DME LiHMDS 21 10 [Pd(IPent-OMe)(acac)Cl] DMF KO.sup.tAm 23 11 [Pd(IHept-OMe)(acac)Cl] Toluene KO.sup.tAm 100 12 [Pd(INon-OMe)(acac)Cl] Toluene KO.sup.tAm 100 Reagents and conditions: 4-chloroanisole (0.5 mmol), 4-fluoroaniline (0.55 mmol), base (0.55 mmol), solvent (1.0 mL), catalyst (0.25 mol %). .sup.bConversion to coupling product based on starting aryl chloride by GC, average of three runs. DME; dimethoxyethane.

(112) As can be seen from the above table more polar solvents such as DME tended to give poorer results whilst the combination of toluene as solvent and KO.sup.tAm as base can give 100% conversion.

Example 2

(113) Amination with 4-fluoroaniline (entry 1, table below) and 3-trifluoromethylaniline (entry 2) at reduced catalyst loading.

(114) 4-Chloroanisole was reacted with the aniline using palladium catalysts with ITent or ITent-OMe as NHC ligands.

(115) The results show that in each case the catalyst with the ITent-OMe ligand produced higher yields than the corresponding catalyst without the OMe ligand. As the gain in activity is general with all of the ITent-OMe series, these results indicate the positive effect of the methoxy group. As the methoxy substituent resides away from the coordination sphere of the metal, the stronger -donor properties of ITent-OMe ligand compared with ITent ligands could explain the difference in the catalytic activity observed. This extra -donation may offer a greater stabilization of the Pd.sup.0NHC complex. [Pd(IHept-OMe)(acac)Cl] combines the presence of the methoxy group and the optimal length of alkyl chain for CN bond formation in these experiments.

(116) TABLE-US-00002 Entry Product NHC ligand GC conversions (%).sup.d 1.sup.b IPent IPent-OMe IHept IHept-OMe INon INon-OMe 58 70 82 98 76 86 2.sup.c IPent IPent-OMe IHept IHept-OMe INon INon-OMe 41 53 68 85 64 76 .sup.aReagents and conditions: ArCl (0.5 mmol), ArNH.sub.2 (0.55 mmol), KO.sup.tAm (0.55 mmol), toluene (1.0 mL). .sup.b0.05 mol % Pd catalyst, 80 C., 3 h; .sup.c0.1 mol % Pd catalyst, 110 C., 6 h. .sup.dConversion to coupling product based on starting aryl chloride by GC, average of three runs.

Example 3 Scope of the Buchwald-Hartwig Arylamination with [Pd(IHept-OMe)(acac)Cl]

(117) TABLE-US-00003 Catalyst Entry ArCl Product (%) Yield 1 0.05 95 2 0.05 91 3 0 0.05 96 4 0.1 92 5 0.1 87 6 0.1 79 7 0.1 74 8 0 0.2 91 9 0.2 88 10 0.2 90 11 0.2 83 aReagents and conditions: ArCl (0.5 mmol), ArNH.sub.2 (0.55 mmol), KO.sup.tAm (0.55 mmol), [Pd(IHept- OMe)(acac)Cl] (x mol %), toluene (1.0 mL), 80 C., 3h. .sup.bIsolated yields after chromatography on silica gel, average of two runs. .sup.c110 C., 6h.

(118) The system, shown in the table above, displays excellent catalytic activity for the coupling of various substrates. Good yields are obtained with electron-poor anilines and electron-rich aryl chlorides, which are challenging coupling partners (entries 1-4 and 8-10). The system appears unaffected by the presence of substituents in the ortho-position of the aryl chlorides: couplings of 2-chloroanisole and 4-chloroanisole with 4-fluoroaniline gave very similar results (Entries 1 and 3). Similar results are observed for the coupling of 2-chloroanisole or 4-chloroanisole with 3-trifluoromethylaniline (Entries 8 and 9). Moreover, very good yields were obtained with sterically hindered substrates (Entries 4, 6 and 11). The increased conformational flexibility of IHept-OMe may allow it to better accommodate sterically hindered substrates in the coordination sphere of the metal center. Finally, various anilines were successfully coupled with deactivated 1,3-dimethoxychlorobenzene (entries 5, 6 and 9) and, for the first time, with very deactivated 1,3,5-trimethoxychlorobenzene at low catalyst loading (entry 10), attesting to the high reactivity of [Pd(IHept-OMe)(acac)Cl].

Example 4

(119) The efficiency of catalyst, [Pd(IHept-OMe)(acac)Cl] with more nucleophilic amines was also tested.

(120) Non-activated aryl chlorides were successfully coupled with N-methylaniline at low catalyst loadings (as low as 50 ppm of [Pd(IHept-OMe)(acac)Cl]); remarkable catalyst productivityturnover number [TON] up to 18,000 or more, was observed (Entries 2 and 3 in the table below). These results are comparable with results obtained with the most efficient Pd/phosphine systems for similar substrates.

(121) TABLE-US-00004 [Pd(IHept-OMe)(acac)Cl] Yield Entry Product (ppm) (%).sup.b TON 1 0 (control) 0 2 0 50 91 18200 3 50 93 18600 4 100 84 8400 5 200 83 4150 .sup.aReagents and conditions: ArCl (0.5 mmol), ArNH.sub.2 (0.55 mmol), KO.sup.tAm (0.55 mmol), [Pd(IHept-OMe)(acac)Cl] (x ppm), toluene (1.0 mL), 110 C. .sup.bIsolated yields after chromatography on silica gel, average of two runs.

(122) Preparation of [Pd(NHC)(cinnamyl(Cl]:

(123) General Procedure

(124) In a glovebox (under a nitrogen atmosphere), in a round bottom flask equipped with a magnetic stirring bar were added the NHC.HCl imidazolium salt precursor (2.2 eq) and KO.sup.tBu (2.4 eq) in THF. In these examples IPent.HCl, IHept.HCl and INon.HCl were employed.

(125) The reaction mixture was stirred at room temperature for 3 h and then [Pd(cinnamyl)(-Cl)].sub.2 (1 eq) was added. The reaction mixture was then stirred overnight at room temperature.

(126) After this time, outside the glovebox, the THF was evaporated and the crude product was dissolved in DCM, filtered on a pad of celite and eluted with DCM. After evaporation of the solvent, the complex was dissolved in pentane and passed through a frit (sintered glass filter). The pentane was evaporated and after drying under high vacuum, the pure complex was obtained.

(127) ##STR00074##

(128) [Pd(IPent)(cinnamyl)Cl]: The general procedure starting from 0.425 mmol of [Pd(cinnamyl)(p-Cl)].sub.2 yielded the complex as a yellow powder (600 mg, 93%).

(129) The pentane was evaporated rapidly using a Schlenk line, yielding the complex as a foam which was crumbled to a powder.

(130) .sup.1H NMR (400 MHz, C.sub.6D.sub.6): 7.31-7.26 (m, 2H, H.sub.Ar), 7.19 (t, J=7.7 Hz, 2H, H.sub.Ar), 7.04 (d, J=7.7 Hz, 4H, H.sub.Ar), 7.04-6.93 (m, 3H, H.sub.Ar), 6.63 (S, 2H, H.sub.lm), 5.23 (dt, J=12.8 Hz; J=9.3 Hz, 1H, H.sub.cin), 4.54 (d, J=12.8 Hz, 1H, H.sub.cin), 2.89-2.50 (m, br, 5H, CH+H.sub.cin), 2.23-2.06 (m, br, 4H, CH.sub.2), 1.82-1.36 (m, br, 13H, CH.sub.2+H.sub.cin), 1.23-1.03 (m, br, 12H, CH.sub.3), 0.76 (t, J=7.4 Hz, 12H, CH.sub.3). .sup.13C NMR (100 MHz, CD.sub.2Cl.sub.2): 182.1 (NCN), 144.5 (br, C.sub.Ar), 138.4 (C.sub.Ar), 138.2 (C.sub.Ar), 129.1 (CH.sub.Ar), 128.5 (CH.sub.Ar), 127.6 (CH.sub.Ar), 126.9 (CH.sub.Ar), 125.3 (br, CH.sub.Ar), 124.9 (CH.sub.lm), 108.5 (C.sub.cin), 90.5 (C.sub.cin), 46.5 (C.sub.cin), 42.1 (CH), 28.3 (CH.sub.2), 27.9 (CH.sub.2), 13.1 (CH.sub.3), 11.5 (br, CH.sub.3). Anal. Calcd. for C.sub.44H.sub.61ClN.sub.2Pd: C, 69.55; H, 8.09; N, 3.69. Found: C, 69.52; H, 8.03; N, 3.75.

(131) [Pd(IHept)(cinnamyl(Cl]: The general procedure starting from 0.35 mmol of [Pd(cinnamyl)(p-Cl)].sub.2 yielded the complex as an orange powder (605 mg, 99%).

(132) The pentane was evaporated rapidly using a Schlenk line, yielding the complex as a foam which was crumbled to a powder.

(133) .sup.1H NMR (400 MHz, C.sub.6D.sub.6): 7.38-7.34 (m, 2H, H.sub.Ar), 7.23 (t, J=7.9 Hz, 2H, H.sub.Ar), 7.10 (d, J=7.9 Hz, 4H, H.sub.Ar), 7.05-7.00 (m, 2H, H.sub.Ar), 6.98-6.94 (m, 1H, H.sub.Ar), 6.83 (S, 2H, H.sub.lm), 5.26 (dt, J=12.9 Hz; J=9.2 Hz, 1H, H.sub.cin), 4.64 (d, J=12.9 Hz, 1H, H.sub.cin), 2.93-2.66 (m, br, 5H, CH+H.sub.cin), 2.18-2.05 (m, 4H, CH.sub.2), 1.78-1.34 (m, 21H, CH.sub.2+H.sub.cin), 1.25-1.11 (m, 8H, CH.sub.2), 1.11-0.94 (m, 12H, CH.sub.3), 0.82 (t, J=7.2 Hz, 12H, CH.sub.3). .sup.13C NMR (100 MHz, CD.sub.2Cl.sub.2): 181.8 (NCN), 145.1 (br, C.sub.Ar), 138.5 (C.sub.Ar), 137.8 (C.sub.Ar), 129.2 (CH.sub.Ar), 128.5 (CH.sub.Ar), 127.7 (CH.sub.Ar), 126.9 (CH.sub.Ar), 125.2 (br, CH.sub.Ar), 124.9 (CH.sub.lm), 108.5 (C.sub.cin), 91.1 (C.sub.cin), 46.0 (C.sub.cin), 39.7 (CH), 39.5 (CH.sub.2), 38.4 (CH.sub.2), 22.0 (CH.sub.2), 20.9 (CH.sub.2), 14.9 (CH.sub.3), 14.8 (CH.sub.3). Anal. Calcd. for C.sub.52H.sub.77ClN.sub.2Pd: C, 71.62; H, 8.90; N, 3.21. Found: C, 71.75; H, 8.84; N, 3.18.

(134) [Pd(INon)(cinnamyl(Cl]: The general procedure starting from 0.113 mmol of [Pd(cinnamyl)(p-Cl)].sub.2 yielded the complex as a yellow/green powder (200 mg, 90%).

(135) After evaporation of the pentane, the complex remained an oil. It solidified slowly after a few weeks storage inside a glovebox (under an N.sub.2 atmosphere).

(136) .sup.1H NMR (400 MHz, C.sub.6D.sub.6): 7.40-7.36 (m, 2H, H.sub.Ar), 7.25 (t, J=7.7 Hz, 2H, H.sub.Ar), 7.13 (d, J=7.7 Hz, 4H, H.sub.Ar), 7.06-7.01 (m, 2H, H.sub.Ar), 7.00 (s, 2H, H.sub.lm), 6.98-6.94 (m, 1H, H.sub.Ar), 5.28 (dt, J=12.9 Hz; J=9.3 Hz, 1H, H.sub.cin), 4.68 (d, J=12.9 Hz, 1H, H.sub.cin), 2.99-2.71 (m, br, 5H, CH+H.sub.cin), 2.24-2.10 (m, br, 4H, CH.sub.2), 1.89-1.34 (m, 29H, CH.sub.2+H.sub.cin), 1.28-1.15 (m, 16H, CH.sub.2), 1.09-0.97 (m, 12H, CH.sub.3), 0.89-0.82 (m, 12H, CH.sub.3). .sup.13C NMR (100 MHz, CD.sub.2Cl.sub.2): 181.9 (NCN), 145.2 (br, C.sub.Ar), 138.6 (C.sub.Ar), 137.7 (C.sub.Ar), 129.2 (CH.sub.Ar), 128.5 (CH.sub.Ar), 127.7 (CH.sub.Ar), 126.9 (CH.sub.Ar), 125.2 (br, CH.sub.Ar), 124.9 (CH.sub.lm), 108.7 (C.sub.cin), 91.0 (C.sub.cin), 46.0 (C.sub.cin), 39.8 (CH), 36.9 (CH.sub.2), 35.9 (CH.sub.2), 31.3 (br, CH.sub.2), 29.9 (br, CH.sub.2), 23.9 (CH.sub.2), 23.7 (CH.sub.2), 14.5 (CH.sub.3), 14.2 (CH.sub.3). Anal. Calcd. for C.sub.60H.sub.93ClN.sub.2Pd: C, 73.22; H, 9.52; N, 2.85. Found: C, 73.40; H, 9.69; N, 2.84.

REFERENCES

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