Allyl complexes for use in coupling reactions

Abstract

A complex of formula (1), ##STR00001##
wherein, M is palladium or nickel, R.sub.1 and R.sub.2 are independently organic groups having 1-20 carbon atoms, or R.sub.1 and R.sub.2 are linked to form a ring structure with the phosphorus atom, R.sub.3 is selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl, R.sub.4 is an organic group having 1-20 carbon atoms, n is 0, 1, 2, 3, 4 or 5, X is an anionic ligand. A process for the preparation of the complex, and its use in carbon-carbon or carbon-nitrogen coupling reactions is also provided.

Claims

1. A complex of formula (1): ##STR00168## wherein: M is palladium or nickel; R.sub.1 and R.sub.2 are, independently, C.sub.1-C.sub.20 straight-chain alkyl, C.sub.1-C.sub.20 branched-chain alkyl, C.sub.3-C.sub.15 cycloalkyl, C.sub.5-C.sub.20 aryl, or C.sub.3-C.sub.20 heteroaryl; R.sub.3 is: (a) dimethylaminophenyl; or (b) a substituted metallocenyl of formula (2): ##STR00169## wherein: R.sub.10 is C.sub.1-C.sub.20 alkyl, C.sub.6-C.sub.20 aryl, (C.sub.1-C.sub.20 alkyl)HN, (C.sub.1-C.sub.20 dialkyl)N, (C.sub.1-C.sub.20 dialkyl)amino-C.sub.1-C.sub.20-alkyl or C.sub.1-C.sub.20 alkoxy-C.sub.1-C.sub.20-alkyl; R.sub.11 is C.sub.1-C.sub.20 alkyl or C.sub.6-C.sub.20 aryl; p is 0, 1, 2, 3 or 4, wherein when p is 2, 3 or 4, each R.sub.10 is the same or different; q is 2, 3, 4 or 5, wherein each R.sub.11 is the same or different, R.sub.4 is C.sub.1-C.sub.20 straight-chain alkyl, C.sub.1-C.sub.20 branched-chain alkyl, C.sub.3-C.sub.15 cycloalkyl, C.sub.6-C.sub.20 aryl, or C.sub.5-C.sub.20 heteroaryl, n is 0, 1, 2, 3, 4 or 5; and X is a halo group, each alkyl, alkoxy, heteroalkyl, aryl or heteroaryl is optionally substituted with one or more halo, C(halo).sub.3, R.sup.a, O, S, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, NR.sup.a, NOR.sup.a, CN, SCN, NCS, NO.sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(S)R.sup.a, C(S)OR.sup.a, S(O).sub.2OH, S(O).sub.2R.sup.a, S(O).sub.2NR.sup.aR.sup.b, OS(O)R.sup.a, or C(O)NR.sup.aR.sup.b, wherein: R.sup.a and R.sup.b are, independently, H, C.sub.1-20 alkyl, C.sub.6-20 aryl, C.sub.6-20 aryl-(C.sub.1-20alkyl), or C.sub.1-20 heteroalkyl, C.sub.6-20 heteroaryl, or together with the atom to which they are attached form a C.sub.3-15 heterocycloalkyl; and the heteroatoms in the heteroaryl, heteroalkyl or heterocycloalkyl are sulfur, oxygen, or nitrogen.

2. The complex according to claim 1, wherein M is palladium.

3. The complex according to claim 1, wherein R.sub.3 is dimethylaminophenyl.

4. The complex according to claim 1, wherein R.sub.3 is of formula (3): ##STR00170## wherein: R.sub.11 is C.sub.1-20 alkyl or aryl; and q is 2, 3, 4 or 5.

5. The complex according to claim 1, wherein: R.sub.11 is phenyl, naphthyl, methoxyphenyl, halophenyl, methylphenyl, or F.sub.3C-phenyl; and q is 4 or 5.

6. The complex according to claim 1, wherein: R.sub.11 is phenyl, methoxyphenyl, methylphenyl, or F.sub.3C-phenyl; and q is 4 or 5.

7. The complex according to claim 1, wherein R.sub.3 is of formula (4): ##STR00171##

8. The complex according to claim 1, that is: ##STR00172##

9. A method for preparing a complex of formula (1), ##STR00173## comprising the step of reacting a complex of formula (5) with PR.sub.1R.sub.2R.sub.3, ##STR00174## wherein: M is palladium or nickel; R.sub.1 and R.sub.2 are, independently, C.sub.1-C.sub.20 straight-chain alkyl, C.sub.1-C.sub.20 branched-chain alkyl, C.sub.3-C.sub.15 cycloalkyl, C.sub.5-C.sub.20 aryl, or C.sub.3-C.sub.20 heteroaryl; R.sub.3 is: (a) dimethylaminophenyl; or (b) a substituted metallocenyl of formula (2): ##STR00175## wherein: R.sub.10 is C.sub.1-C.sub.20 alkyl, C.sub.6-C.sub.20 aryl, (C.sub.1-C.sub.20 alkyl)HN, (C.sub.1-C.sub.20 dialkyl)N, (C.sub.1-C.sub.20 dialkyl)amino-C.sub.1-C.sub.20-alkyl or C.sub.1-C.sub.20 alkoxy-C.sub.1-C.sub.20-alkyl; R.sub.11 is C.sub.1-C.sub.20 alkyl or C.sub.6-C.sub.20 aryl; p is 0, 1, 2, 3 or 4, wherein when p is 2, 3 or 4, each R.sub.10 is the same or different; q is 2, 3, 4 or 5, wherein each R.sub.11 is the same or different; R.sub.4 is C.sub.1-C.sub.20 straight-chain alkyl, C.sub.1-C.sub.20 branched-chain alkyl, C.sub.3-C.sub.15 cycloalkyl, C.sub.6-C.sub.20 aryl, or C.sub.5-C.sub.20 heteroaryl; n is 0, 1, 2, 3, 4 or 5; X is a halo group; each alkyl, alkoxy, heteroalkyl, aryl or heteroaryl is optionally substituted with one or more halo, C(halo).sub.3, R.sup.a, O, S, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, NR.sup.a, NOR.sup.a, CN, SCN, NCS, NO.sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(S)R.sup.a, C(S)OR.sup.a, S(O).sub.2OH, S(O).sub.2R.sup.a, S(O).sub.2NR.sup.aR.sup.b, OS(O)R.sup.a, or C(O)NR.sup.aR.sup.b, wherein: R.sup.a and R.sup.b are, independently, H, C.sub.1-20 alkyl, C.sub.6-20 aryl, C.sub.6-20 aryl-(C.sub.1-20alkyl), or C.sub.1-20 heteroalkyl, C.sub.6-20 heteroaryl, or together with the atom to which they are attached form a C.sub.3-15 heterocycloalkyl; and the heteroatoms in the heteroaryl, heteroalkyl or heterocycloalkyl are sulfur, oxygen or nitrogen.

10. The complex according to claim 1, wherein: (a) both R.sub.1 and R.sub.2 are tert-butyl; (b) R.sub.4 is phenyl or methyl and n is 1 or 2; (c) n is 0; (d) X is chlorine; (e) two or more of (a), (b), and (d); or (f) two or more of (a), (c), and (d).

Description

(1) The invention will now be described by way of example only and with reference to the following drawings in which:

(2) FIG. 1 is an X-ray crystal structure of Pd(-cinnamyl)QPhosCl.

(3) FIG. 2 is an X-ray crystal structure of Pd(-crotyl)QPhosCl

(4) FIG. 3 is an X-ray crystal structure of Pd(-allyl)QPhosCl.

EXAMPLES

(5) All solvents and reagents were purchased from commercial sources and used as received. All catalysts, ligands or precious metal precursors were obtained from Johnson Matthey Catalysis or Alfa Aesar. Flash chromatography was performed on a Flashmaster Personal (Biotage) using prepacked ISOLUTE silica gel cartridges. .sup.1H and .sup.13C NMR spectra were recorded on a Bruker 400 MHz spectrometer at ambient temperature in CDCl.sub.3 or C.sub.6D.sub.6 (Sigma Aldrich). All reactions were carried out in individual Schlenk tubes under a nitrogen atmosphere. The purity of the isolated products was >95% as determined by .sup.1H NMR, GC/MS or elemental analysis.

Example 1

(6) General Procedure for the Preparation of [Pd(Optionally Substituted (R.sub.4).sub.n-allyl)(X)].sub.2 Complexes:

(7) Distilled H.sub.2O in a three-necked roundbottom flask was purged with nitrogen for 30 minutes. PdCl.sub.2 and KCl were subsequently added to the flask and the solution was stirred at room temperature for 1 h. Then, optionally substituted (R.sub.4).sub.n-allyl chloride was added and the resulting reaction mixture stirred at room temperature overnight (18-20 hrs). The reaction was extracted with chloroform, and the aqueous layer washed with chloroform three times. The organic layers were combined, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was recrystallised from chloroform and methyl tert-butyl ether, and the resulting solid was isolated by filtration and dried in vacuo.

[Pd(-cinnamyl)Cl]2

(8) ##STR00015##

(9) PdCl.sub.2 (590 mg, 3.33 mmol); KCl (473 mg, 6.67 mmol); cinnamyl chloride (1.39 mL, 9.99 mmol); H.sub.2O (83 mL). The dimer was obtained as a yellow solid (494 mg, 58%).

[Pd(-1-crotyl)Cl]2

(10) ##STR00016##

(11) PdCl.sub.2 (590 mg, 3.33 mmol); KCl (473 mg, 6.67 mmol); crotyl chloride (0.97 mL, 9.99 mmol); H.sub.2O (83 mL). The dimer was obtained as a yellow solid (636 mg, 97%).

[Pd(-prenyl)Cl]2

(12) ##STR00017##

(13) PdCl.sub.2 (590 mg, 3.33 mmol); KCl (473 mg, 6.67 mmol); 1-chloride-3-methyl-2-butene (1.13 mL, 9.99 mmol); H.sub.2O (83 mL). The dimer was obtained as a yellow solid (606 mg, 87%).

[Pd(-prenyl)Cl]2

(14) ##STR00018##

(15) PdCl.sub.2 (590 mg, 3.33 mmol); KCl (473 mg, 6.67 mmol); 3-chloride-2-methyl-1-propene (0.98 mL, 9.99 mmol); H.sub.2O (83 mL). The dimer was obtained as a yellow solid (269 mg, 41%).

(16) General Procedure for the Preparation of Pd(-Optionally) Substituted R.sub.4).sub.n-alkyl)(PR.sub.1R.sub.2R.sub.3)(X) Complexes:

(17) The [Pd(-optionally substituted (R.sub.4).sub.n-allyl)Cl].sub.2 and the PR.sub.1R.sub.2R.sub.3 ligand were put in a Schlenk flask. The flask was evacuated and backfilled with nitrogen three times, then the solvent was added. The reaction mixture was stirred at room temperature for the indicated time and then the solvent was removed in vacuo. The resulting solid was triturated with anhydrous hexane and the solid isolated by filtration and dried in vacuo to give the desired palladium complex. The structures of the various complexes prepared in this manner may be represented as follows:

(18) ##STR00019##

Pd(-cinnamyl)(QPhos)Cl

(19) ##STR00020##

(20) [Pd(-cinnamyl)Cl].sub.2 (74 mg, 0.14 mmol); QPhos (223 mg, 0.31 mmol); THF (2.8 mL); 18 hrs. Product obtained as a pink solid (233 mg, 86%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.48-7.46 (m, 2H, CH2=CHCHC.sub.6H.sub.5), 7.37-7.35 (m, 3H, CH2=CHCHC.sub.6H.sub.5), 7.14-7.03 (m, 25H, HAr), 5.68-5.60 (m, 1H, CH.sub.2CHCHC.sub.6H.sub.5), 5.20 (dd, J 13.2, 9.6, 1H, CH.sub.2CHCHC.sub.6H.sub.5), 5.08 (br s, 1H, Cp-H), 4.84-4.81 (m, 1H, Cp-H), 4.53 (app. s, 2H, Cp-H), 4.02 (br s, 1H, CH.sub.2CHCHC.sub.6H.sub.5), 2.79 (br s, 1H, CH.sub.2CHCHC.sub.6H.sub.5), 1.27-1.07 (m, 18H, PC(CH.sub.3).sub.3); .sup.13C (CDCl.sub.3, 100 MHz): 136.4, 135.1, 132.6, 128.6, 128.3, 127.4, 126.5, 107.3, 87.7, 68.0, 53.9, 30.7; .sup.31P NMR (CDCl.sub.3, 162 MHz): 67.4. Elemental analysis, found: C, 70.39; H, 5.93; Cl, 3.52; P, 3.18; (theoretical C, 70.60; H, 5.82; Cl, 3.66; P, 3.19).

(21) Single crystals of Pd(cinnamyl)QPhosCl were obtained by slow diffusion of 40-60 petroleum ether into a CH.sub.2Cl.sub.2 solution, respectively, at 18 C. (see FIG. 1).

Pd(-crotyl)(QPhos)Cl

(22) ##STR00021##

(23) [Pd(-crotyl)Cl].sub.2 (200 mg, 0.51 mmol); QPhos (798 mg, 1.12 mmol); THF (10 mL); 18 hrs. The complex was obtained as a pink solid (891 mg, 96%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.15-7.03 (m, 25H, HAr), 5.34 (br s, 1H, Cp-H), 5.09-5.00 (m, 2H, CH.sub.2CHCHCH.sub.3, Cp-H), 4.54-4.53 (m, 2H, Cp-H), 4.49-4.39 (m, 1H, CH.sub.2CHCHCH.sub.3), 3.77 (d, J 6.4, 1H, CH.sub.2CHCHCH.sub.3), 2.54 (d, J 11.6, 1H, CH.sub.2CHCHCH.sub.3), 1.74 (dd, J 8.4, 6.8, 3H, CH.sub.2CHCHCH.sub.3), 1.17 (t, J 13.2, 18H, PC(CH.sub.3).sub.3); .sup.13C (CDCl.sub.3, 100 MHz): 135.2, 132.6, 127.3, 126.5, 113.2, 103.0, 102.7, 87.7, 80.8, 80.1, 52.2, 37.8, 30.6; .sup.31P NMR (CDCl.sub.3, 162 MHz): 65.{tilde over (0)}. Elemental analysis, found: C, 68.90; H, 6.16; Cl, 3.77; P, 3.40; (theoretical: C, 68.81; H, 6.00; Cl, 3.91; P, 3.41).

(24) Single crystals of Pd(-crotyl)QPhosCl were obtained by slow diffusion of 40-60 petroleum ether into an EtOAc solution at 18 C. (see FIG. 2).

Pd(-prenyl)(QPhos)Cl

(25) ##STR00022##

(26) [Pd(-prenyl)Cl].sub.2 (200 mg, 0.48 mmol); QPhos (751 mg, 1.06 mmol); THF (10 mL); 18 hrs. Product obtained as a pink solid (867 mg, 98%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.19-7.04 (m, 25H.sup., C6H5), 5.44 (br s, 1H, Cp-H), 4.94-4.81 (m, 2H, CH.sub.2CH(CH.sub.3).sub.2, Cp-H), 4.51 (s, 2H, Cp-H), 3.52 (d, J 6.8, 1H CH.sub.2CH(CH.sub.3).sub.2), 2.71 (d, J 12.0, CH.sub.2CH(CH.sub.3).sub.2), 1.80 (d, J 8.4, 3H, CH.sub.2CH(CH.sub.3).sub.2), 1.62 (t, J 7.2, 3H, CH.sub.2CH(CH.sub.3).sub.2), 1.24 (d, J 14.4, 9H, PC(CH.sub.3).sub.3), 1.15 (d, J 14.4, 9H, PC(CH.sub.3).sub.3); .sup.13C (CDCl.sub.3, 100 MHz): 135.2, 132.6, 127.3, 126.5, 121.2, 106.8, 87.7, 80.3, 47.4, 37.8, 30.9, 30.6; .sup.31P NMR (CDCl.sub.3, 162 MHz): 68.3. Elemental analysis, found: C, 68.81; H, 6.44; Cl, 4.57; P, 3.25; (theoretical C, 69.06; H, 6.12; Cl, 3.85; P, 3.36).

Pd(-2-crotyl)(QPhos)Cl

(27) ##STR00023##

(28) [Pd(-2-crotyl)Cl].sub.2 (200 mg, 0.51 mmol); QPhos (798 mg, 1.12 mmol); THF (5 mL); 18 hrs. The complex was obtained as a pink solid (788 mg, 85%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.19-6.98 (m, 25H, HAr), 5.27 (br s, 1H, Cp-H), 4.93 (br s, 1H, Cp-H), 4.65 (dd, J 6.4, 2.8, 1H, CH.sub.2C(CH.sub.3)CH.sub.2), 4.55 (br s, 2H, Cp-H), 3.84 (d, J 2.8, 1H, CH.sub.2C(CH.sub.3)CH.sub.2), 3.77 (d, J 8.4, 1H, CH.sub.2C(CH.sub.3)CH.sub.2), 2.68 (s, 1H, CH.sub.2C(CH.sub.3)CH.sub.2), 1.94 (s, 3H, CH.sub.2C(CH.sub.3)CH.sub.2), 1.18 (d, J 14.0, 9H, PC(CH.sub.3).sub.3), 1.13 (d, J 14.0, 9H, PC(CH.sub.3).sub.3); .sup.13C (CDCl.sub.3, 100 MHz): 134.5, 131.9, 128.6, 126.7, 126.6, 125.9, 87.1, 79.4, 57.2, 30.0, 29.9, 29.6, 29.5, 21.8; .sup.31P NMR (CDCl.sub.3, 162 MHz): 62.0. Elemental analysis, found: C, 69.59; H, 6.23; Cl, 3.41; P, 3.42; (theoretical C, 68.81; H, 6.00; Cl, 3.91; P, 3.41).

Pd(-allyl)QPhosCl

(29) ##STR00024##

(30) [Pd(-allyl)Cl].sub.2 (2.0 mmol); QPhos (4.4 mmol); THF (45 mL); 18 hrs. The product was obtained as a pink solid (3.2 g, 90%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.17-7.01 (m, 25H.sup., C.sub.6H.sub.5), 5.46-5.36 (m, 1H, CH.sub.2CHCH.sub.2), 5.33 (br s, 1H, FeH), 5.08 (br s, 1H, FeH), 4.83 (t, J 6.8, 1H, CH.sub.2CHCH.sub.2), 4.56 (br s, 1H, FeH), 4.54 (br s, 1H, FeH), 4.04 (d, J 4.8, 1H, CH.sub.2CHCH.sub.2), 3.87 (dd, J 13.6, 8.4, CH.sub.2CHCH.sub.2), 2.78 (d, J 12.4, 2H, CH.sub.2CHCH.sub.2), 1.17 (d, J 14.0, PC(CH.sub.3).sub.3); .sup.13C (CDCl.sub.3, 100 MHz): 135.2, 132.7, 132.5, 132.1, 127.3, 126.5, 114.2, 87.8, 83.5, 79.7, 67.1, 57.5, 37.8, 30.5; .sup.31P NMR (CDCl.sub.3, 162 MHz): 61.8. Elemental analysis, found: C, 68.40; H, 6.00; Cl, 3.83; P, 3.42; (theoretical C, 68.54; H, 5.87; Cl, 3.97; P, 3.47).

(31) Single crystals of Pd(-allyl)QPhosCl were obtained by slow diffusion of diethyl ether into a CH.sub.2Cl.sub.2 solution (see FIG. 3).

(32) The X-ray structures of Pd(-allyl)QPhosCl and Pd(-crotyl)QPhosCl (see FIG. 2) are different in terms of the opposite orientation of the halide, presumably due to the steric effect of the Me group on the 3-position of the allyl in Pd(-crotyl)QPhosCl.

Pd(-allyl)(Amphos)Cl

(33) ##STR00025##

(34) [Pd(-allyl)Cl].sub.2 (311 mg, 0.85 mmol); Amphos (496 mg, 1.87 mmol); THF (17 mL); 18 hrs. Product obtained as a yellow solid (727 mg, 96%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.50 (app. t, J 8.8, 2H, HAr), 6.65 (d, J 8.0, 2H, HAr), 5.50 (heptet, J 7.2, 1H, CH.sub.2CHCH.sub.2), 4.63 (dt, J 6.8, 2.0, 1H, CH.sub.2CHCH.sub.2), 3.69 (dd, J 13.2, 9.2, 1H, CH.sub.2CHCH.sub.2), 3.39 (d, J 6.0, 1H, CH.sub.2CHCH.sub.2), 3.01 (s, 6H, N(CH.sub.3).sub.2), 2.68 (d, J 12.0, 1H CH.sub.2CHCH.sub.2), 1.47 (d, J 14.0, 9H, PC(CH.sub.3).sub.3), 1.39 (d, J 14.0, 9H, PC(CH.sub.3).sub.3); .sup.13C (CDCl.sub.3, 100 MHz): 150.9, 136.7, 136.6, 116.9, 116.6, 115.2, 110.4, 110.3, 80.7, 80.4, 58.8, 39.9, 36.0, 30.6, 29.9; .sup.31P NMR (CDCl.sub.3, 162 MHz): 61.9. Elemental analysis, found: C, 51.44; H, 7.51; Cl, 7.54; P, 6.94; (theoretical C, 50.90; H, 7.42; Cl, 7.91; P, 6.91).

Pd(-crotyl)(Amphos)Cl

(35) ##STR00026##

(36) [Pd(crotyl)Cl].sub.2 (132 mg, 0.34 mmol); P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4) (180 mg, 0.68 mmol); THF (3.7 mL); 90 min. Product obtained as a yellow solid (263 mg, 85%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.52 (t, J 8.8, 2H), 6.65 (d, J 8.0, 2H), 5.25-5.17 (m, 1H), 4.40-4.29 (m, 1H), 3.21-3.19 (m, 1H), 3.00 (s, 3H), 2.47 (d, J 11.6, 1H), 1.77 (dd, J 8.4, 6.4, 3H), 1.44 (d, J 13.6, 9H), 1.38 (d, J 13.6, 9H); .sup.13C (CDCl.sub.3, 100 MHz): 150.9, 149.6, 136.9, 136.7, 117.1, 116.8, 114.1, 110.3, 99.8, 99.6, 53.5, 40.0, 35.8, 30.6, 29.9, 17.4; .sup.31P NMR (CDCl.sub.3, 162 MHz): 65.5; Elemental analysis, found: C, 51.93; H, 7.54; N, 2.84; P, 6.58; (theoretical C, 51.96; H, 7.63; N, 3.03; P, 6.70).

Pd(-allyl)(Pt-Bu2Ph)Cl

(37) ##STR00027##

(38) [Pd(-allyl)Cl].sub.2 (100 mg, 0.27 mmol); Pt-Bu.sub.2Ph.HBF.sub.4 (169 mg, 0.55 mmol); toluene (1.5 mL), 18 hrs. The product was obtained as a yellow solid (217 mg, 98%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.90-7.68 (m, 5H, HAr), 5.51-5.42 (m, 1H, CH.sub.2CHCH.sub.2), 4.12 (d, J 6.4, 2H, CH.sub.2CHCH.sub.2), 3.05 (d, J 12.0, 2H, CH.sub.2CHCH.sub.2), 1.55 (d, J 16.8, PPh(CH.sub.3).sub.2); .sup.13C (CDCl.sub.3, 100 MHz): 135.0, 130.5, 127.4, 116.0, 115.3, 111.2, 63.0, 34.4, 28.0; .sup.31P NMR (CDCl.sub.3, 162 MHz): 44.4.

Example 2

(39) General Procedure for the Buchwald-Hartwig Coupling Reaction:

(40) A Schlenk flask was charged with the catalyst, NaOtBu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the amine in toluene was added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for the indicated time, then the mixture was absorbed onto silica gel and purified by flash column chromatography (EtOAc/40-60 petroleum ether eluent).

(41) The relative activities of Pd(-allyl)QPhosCl and Pd(-crotyl)QPhosCl were explored in a model CN coupling reaction of 4-bromoanisole with N-methylaniline at room temperature (see Tables 1 and 2).

(42) TABLE-US-00001 TABLE 1 Optimization and Activities of Pd(-allyl)QPhosCl and Pd(-crotyl)QPhosCl..sup.a toluene time catalyst (mL) T ( C.) (hrs) conversion.sup.b (%) Pd(-allyl)QphosCl (1.0 mol %) 4.0 25 6 97 Pd(-crotyl)QPhosCl (1.0 mol %) 4.0 25 3 100 Pd(-allyl)QPhosCl (0.5 mol %) 4.0 25 23 54 Pd(-crotyl)QPhosCl (0.5 mol %) 4.0 25 5 100 Pd(-allyl)QPhosCl (0.5 mol %) 2.0 25 7 93 Pd(-crotyl)QPhosCl (0.5 mol %) 2.0 25 1 100 .sup.a4-bromoanisole (1.6 mmol), N-methylaniline (2.0 mmol), NaOt-Bu (2.4 mmol) .sup.bGC/MS conversion.

(43) Pd(allyl)QPhosCl on comparison with Pd(-1-crotyl)QPhosCl at a lower concentration (0.5 mol %) gave 54% conversion after 23 hours vs 100% at 5 hours of reaction time. However, by keeping the catalyst loadings of Pd(allyl)QPhosCL at 0.5 mol % while increasing the concentration from 0.4 to 0.8M, 93% conversion was observed within 7 hours. The catalyst Pd(-1-crotyl)QPhosCl gave 100% conversion to the product after 1 hour, demonstrating its superiority.

(44) TABLE-US-00002 TABLE 2 Comparison of the Relative Activities of Pd(-allyl)QPhosCl and Pd(- crotyl)QPhosCl..sup.a time ArX amine T ( C.) catalyst (hrs) conversion.sup.b (%) 0 50 50 Pd(-allyl)QPhosCl Pd(-crotyl)OPhosCl 6.5 2 97 100 100 100 Pd(-allyl)QPhosCl Pd(-crotyl)OPhosCl 0.6 0.6 99 99 .sup.aaryl halide (1.6 mmol), amine (2.0 mmol), NaOt-Bu (2.4 mmol), tolune (2.0 mL) .sup.bGC/MS conversion.

Example 3

(45) General Procedure for the Buchwald-Hartwig Coupling Reaction:

(46) A Schlenk flask was charged with the catalyst, NaOtBu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the amine in toluene was added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for the indicated time, then the mixture was absorbed onto silica gel and purified by flash column chromatography (EtOAc/40-60 petroleum ether eluent).

(47) TABLE-US-00003 TABLE 3 Reaction of 4-bromoanisole and N-methylaniline with various complexes catalyst (mol %) T ( C.) time (hrs) Conversion.sup.a (%) Pd(allyl)QPhosCl (1.0) 25 6 97 (96) Pd(allyl)P.sup.tBu.sub.2PhCl (1.0) 25 22 8 (8) Pd(allyl)AmPhosCl (1.0) 25 22 18 Pd(1-crotyl)AmPhosCl (1.0) 25 22 95 Pd(prenyl)QPhosCl (1.0) 25 6 100 (99) Pd(prenyl)QPhosCl (0.5) 25 22 100 Pd(cinnamyl)QPhosCl (1.0) 25 22 81 (66) Pd(1-crotyl)QPhosCl (1.0) 25 3 100 (99) Pd(1-crotyl)QPhosCl (0.5) 25 18 99 Pd(1-crotyl)QPhosCl (0.1) 25 18 95 Pd(2-crotyl)QPhosCl (1.0) 25 18 62 .sup.aGC/MS conversion. Isolated yield in parentheses

(48) In order to get an idea of the relative activities of the present catalysts, a CN coupling reaction of 4-bromoanisole with N-methylaniline at room temperature was carried out. At 1 mol % palladium loading, the Q-Phos based catalysts Pd(-allyl)QPhosCl, Pd(-1-crotyl)QPhosCl and Pd(-prenyl)QPhosCl all provided the product with conversions greater than 90% within 3-18 hours. The Pd(crotyl)QPhosCl complex gave the desired product in the highest conversion even at 0.1 mol % palladium loading, while Pd(-prenyl)QPhosCl gave the second highest activity. Pd(-1-crotyl)AmphosCl resulted in 95% conversion to the product with 22 hours of reaction time.

Example 4

(49) Comparison of In Situ and Commercially Available Catalysts in CN Coupling

(50) A comparison of in situ and commercially available catalysts and catalytic systems in a CN coupling reaction was carried out. In this reaction, N-methylaniline was coupled with 4-bromoanisole to give N-(4-bromophenyl)-N-methyl-phenylamine under the conditions set out in Table 4.

(51) TABLE-US-00004 TABLE 4 Reaction of 4-bromoanisole and N-methylaniline substrates.sup.a catalyst (mol %) T ( C.) time (hrs) Conversion.sup.b (%) Pd(-1-crotyl)QPhosCl (1.0) Pd(-1-crotyl)QPhosCl (0.5) Pd(-1-crotyl)QPhosCl (0.1) Pd(-allyl)QPhosCl (1.0) Pd.sub.2(dba).sub.3 (0.25) QPhos (0.5) 25 25 25 25 25 3 18 18 6 21 3 100.sup. 99.sup.c 95.sup. 97.sup. 53.sup. Pd-113 (0.25).sup.d 25 23 80.sup. Pd-116 (0.5).sup.e 25 21 55.sup. Nolan's cat. (0.5) 25 0.sup. Pd(OAc).sub.2 (0.5) 25 21 0.sup. XPhos (0.5) .sup.f Pd(OAc).sub.2 (0.5) 25 23 0.sup. QPhos (0.5) .sup.aamine (1.0 mmol), aryl halide (0.8 mmol), NaOtBu (1.2 mmol), toluene (2.0 mL) .sup.bGC/MS conversions .sup.cAverage of three reactions .sup.dPd-113 = [Pd(u-Br) .sup.t-Bu.sub.3P).sub.2] .sup.ePd-116 = .sup.tBu.sub.3P-Pd-P.sup.tBu.sub.3 .sup.f XPhos = 2,46-triisopropylbiphenyl-2-dichlorohexylphosphine Nolan's Catalyst

(52) The Pd(1-crotyl)QPhos complex showed a superior activity to the other catalytic systems with a 99% conversion at 0.5 mol % catalyst loading and a 95% conversion at 0.1 mol % loading. The Pd(allyl)QPhosCl complex also provided the desired product with a good conversion.

(53) Pd-113 showed good activity, however, the conversion in this case was lower than that of Pd(1-crotyl)QPhos and Pd(allyl)QPhosCl. In addition, Pd-113 is air- and moisture sensitive and has to be stored under a nitrogen atmosphere.

Example 5

(54) Substrate Scope of CN Coupling

(55) General Procedure for the Buchwald-Hartwig Coupling Reaction

(56) A Schlenk flask was charged with the catalyst, NaOt-Bu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the amine in toluene was added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature and time (see Tables in communication). The crude mixture was absorbed onto silica gel (Merck Silica Gel 60 (0.040-0.063 mm)) and purified by flash column chromatography (MTBE/40-60 petroleum ether eluent).

(57) TABLE-US-00005 TABLE 5 CN Bond Formation Mediated by 0.5 mol % Pd(crotyl)QPhosCl.sup.a time ArX amine X T C. (h) product (%) 0 Br 110 20 65.sup.b Br Cl 25 100 1.5 0.5 96.sup.c 95 Br Cl 50 100 16 2.5 98 96 NHPh.sub.2 Br Cl 25 100 3 3 84.sup.d 68.sup.d 0 Br 50 2 91 Br Cl I 25 100 25 1 1 16 93 98 95.sup.e Br 50 3 88 0 Br 25 1 97 Br Cl 50 100 2.5 21 96 87.sup.f Br Cl 50 100 22 2.5 91 83 Cl 80 3 0 91.sup.c Br 80 4 93.sup.c Br Cl 100 100 1 1 83.sup.g 92.sup.h Br 100 2 91.sup.g .sup.aaryl halide (1.6 mmol), amine (2.0 mmol), NaOtBu (2.4 mmol), toluene (2.0 mL) .sup.bUsing 2 mol % Pd(crotyl)QPhosCl .sup.cUsing 1 mol % Pd(crotyl)QPhosCl .sup.dNMR yield of isolated mixture of excess diphenylamine and desired product .sup.gUnoptimized reaction time .sup.fGC/MS conversion .sup.gUsing 0.05 mol % Pd(-crotyl)QPhosCl .sup.hUsing 0.1 mol % Pd(-crotyl)QPhosCl.

(58) Pd(-crotyl)QPhosCl has been evaluated in several substrates for CN coupling using a range of aryl halides with both primary and secondary amines (Table 5). The inventors have also demonstrated a number of examples of a chemoselective amination reaction of an aryl bromide in the presence of a chloride functionality. This was achieved by virtue of the fact that the aryl bromides required lower reaction temperatures than the aryl chlorides. In addition, Pd(-crotyl)QPhosCl effected the amination of an aryl iodide, a substrate which has been considered to be a problematic coupling partner in Pd catalysed CN bond formation processes.

(59) The order of reactivity in aminations mediated by Pd(-crotyl)QPhosCl appears to be the reverse to that observed in conventional Pd mediated coupling reactions. In this respect, electronrich aryl halides are aminated in higher yields at shorter reaction times than the electron-deficient electrophiles. Noteworthy is the amination of a very electron-rich tris-methoxybromobenzene in 65% yield.

(60) As can be seen from Table 6, heterocyclic halides have also been successfully coupled.

(61) TABLE-US-00006 TABLE 6 CN Bond Formation using Heterocyclic Halides Mediated by 2 mol % Pd(crotyl)QPhosCl.sup.a 0 ArX amine X T C. time (h) product yield(%) Br Cl 100 100 3.5 3.5 94 86 Br Cl 100 100 2 2.5 79 88 Br 50 3h 83 0 Br Br Cl 100 25 100 3 18 3 90 76.sup.b 57 Br 25 20 44 .sup.aaryl halide (1.6 mmol), amine (2.0 mmol), NaOtBu (2.4 mmol), toluene (2.0 mL) .sup.bIsolated yield using 1 mol % Pd(crotyl)QPhosCl. Unreacted aryl bromide could be detected by TLC before purification, indicating an incomplete reaction.

(62) Pyridine-, pyrimidine- and thiophene halides gave CN coupled products in good yields at 100 C. The reaction using 3-bromothiophene has been demonstrated at room temperature.

(63) Experimental Data for the Products Detailed in Tables 5 and 6

2-CO2Me-3,4,5-trimethoxy-diphenylamine

(64) ##STR00096##

(65) Methyl anthranilate (390 L, 3.0 mmol); 5-bromo-1,2,3-trimethoxybenzene (594 mg, 2.3 mmol); NaOtBu (345 mg, 3.6 mmol); Pd(-crotyl)QPhosCl (43.5 mg, 0.06 mmol, 2.0 mol %); toluene (5.0 mL). The general procedure afforded the title compound as an off-white solid (462 mg, 65%); .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.39 (br s, 1H), 7.96 (dd, J 4.4, 1.6, 1H), 7.33 (dd, J 6.8, 1.6, 1H), 7.21 (d, J 8.4, 1H), 6.73 (dd, J 8.0, 0.8, 1H), 6.49 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.83 (s, 6H); .sup.13C (CDCl.sub.3, 100 MHz): 169.0, 153.8, 148.4, 136.6, 134.6, 134.2, 131.6, 116.9, 114.1, 111.6, 100.7, 61.0, 56.1, 51.8; Elemental analysis, found: C, 64.30; H, 6.06; N, 4.41; (theoretical: C, 64.34; H, 6.03; N, 4.41).

N-(2,6-diisopropylphenyl)-N-(p-methoxy)amine

(66) ##STR00097##

(67) 4-bromoanisole (200 L, 1.6 mmol) or 4-chloroanisole (196 L, 1.6 mmol); 2,6-diisopropylaniline (377 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (X=Br; 14.4 mg, 0.016 mmol, 1.0 mol %) or Pd(-crotyl)QPhosCl (X=Cl; 7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 96% yield (434 mg; X=Br) and 95% yield (429 mg; X=Cl); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.29-7.19 (m, 3H), 6.73 (d, J 6.8, 2H), 6.44 (d, J 6.8, 2H), 4.95 (br s, 1H), 3.73 (s, 3H), 3.19 (heptet, J 6.8, 2H), 1.14 (d, J 7.2, 12H); .sup.13C (CDCl.sub.3, 100 MHz): 152.2, 147.1, 142.2, 136.0, 126.7, 123.8, 115.0, 114.2, 55.7, 28.0, 23.8; Elemental analysis, found: C, 80.95; H, 9.05; N, 5.03; (theoretical: C, 80.52; H, 8.89; N, 4.94).

N-(4-methoxyphenyl)morpholine

(68) ##STR00098##

(69) 4-bromoanisole (200 L, 1.6 mmol) or 4-chloroanisole (196 L, 1.6 mmol); morpholine (175 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 98% yield (302 mg; X=Br) and 96% yield (297 mg; X=Cl).

N-(4-methoxyphenyl)diphenylamine

(70) ##STR00099##

(71) 4-bromoanisole (200 L, 1.6 mmol) or 4-chloroanisole (196 L, 1.6 mmol); diphenylaniline (338 mg, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 84% yield (370 mg; X=Br) and 68% yield (298 mg; X=Cl).

4-Methoxydiphenylamine

(72) ##STR00100##

(73) 4-bromoanisole (200 L, 1.6 mmol); aniline (182 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 91% yield (288 mg).

N-(4-methoxyphenyl)-N-methylaniline

(74) ##STR00101##

(75) 4-bromoanisole (200 L, 1.6 mmol), 4-chloroanisole (196 L, 1.6 mmol) or 4-iodoanisole (374 mg, 1.6 mmol); N-methylaniline (217 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 93% yield (315 mg; X=Br), 98% yield (335 mg; X=Cl) and 95% yield (325 mg; X=I).

4-chloro-2-methyldiphenyl-methylamine

(76) ##STR00102##

(77) 2-bromo-5-chlorotoluene (213 L, 1.6 mmol); N-methylaniline (217 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 88% yield (324 mg); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.27 (d, J 2.0, 1H), 7.21-7.16 (m, 3H), 7.07 (d, J 8.4, 1H), 6.73 (t, J 7.2, 1H), 6.53 (d, J 8.0, 2H), 3.19 (s, 3H), 2.11 (s, 3H); .sup.13C (CDCl.sub.3, 100 MHz) 146.5, 143.1, 136.4, 129.1, 128.9, 127.2, 126.7, 125.3, 114.9, 110.7, 36.8, 15.5; Elemental analysis, found: C, 72.31; H, 6.13; N, 6.05; (theoretical: C, 72.57; H, 6.09; N, 6.04).

3-chloro-4-methyldiphenyl-methylamine

(78) ##STR00103##

(79) 4-bromo-2-chlorotoluene (217 L, 1.6 mmol); N-methylaniline (217 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 97% yield (358 mg); .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.30-7.26 (m, 2H), 7.08 (d, J 8.4, 1H), 7.02-6.96 (m, 4H), 6.79 (dd, J 8.4, 2.4, 1H), 3.27 (s, 3H), 2.30 (s, 3H); .sup.13C (CDCl.sub.3, 100 MHz): 148.7, 148.1, 134.7, 131.2, 129.4, 128.2, 121.9, 121.0, 120.3, 118.5, 40.4, 19.2; Elemental analysis, found: C, 72.01; H, 6.04; N, 5.98; (theoretical: C, 72.57; H, 6.09; N, 6.04).

N-(2,6-diisopropylphenyl)-N-(o-tolyl)amine

(80) ##STR00104##

(81) 2-bromotoluene (274 mg, 1.6 mmol) or 2-chlorotoluene (168 L, 1.6 mmol); 2,6-diisopropylaniline (377 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 96% yield (410 mg; X=Br) and 87% conversion (X=Cl).

2-Methyldiphenylamine

(82) ##STR00105##

(83) 2-bromotoluene (274 mg, 1.6 mmol) or 2-chlorotoluene (168 L, 1.6 mmol); aniline (182 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (7.2 mg, 0.008 mmol, 0.5 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 91% yield (267 mg; X=Br) and 83% yield (242 mg; X=Cl).

3-Methoxydiphenylamine

(84) ##STR00106##

(85) 3-chloroanisole (196 L, 1.6 mmol); aniline (182 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (14.4 mg, 0.016 mmol, 1.0 mol %); toluene (2.0 mL). The general procedure afforded the title compound as a white solid in 91% yield (290 mg).

4-Cyanodiphenylamine

(86) ##STR00107##

(87) 4-bromobenzonitrile (292 mg, 1.6 mmol); aniline (182 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (14.4 mg, 0.016 mmol, 1.0 mol %); toluene (2.0 mL). The general procedure afforded the title compound as an off-white solid (288 mg, 93%).

2-aniline-pyridine

(88) ##STR00108##

(89) 2-bromopyridine (153 L, 1.6 mmol) or 2-chloropyridine (151 L, 1.6 mmol); aniline (182 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (28.8 mg, 0.032 mmol, 2.0 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 94% yield (257 mg; X=Br) and 86% yield (235 mg; X=Cl): .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.20 (d, J 4.0, 1H), 7.50-7.46 (m, 1H), 7.33 (d, J 4.0, 4H), 7.08-7.02 (m, 2H), 6.89 (d, J 8.4, 1H), 6.74-6.71 (m, 1H); .sup.13C (CDCl.sub.3, 100 MHz): 156.1, 148.4, 140.6, 137.7, 132.5, 129.3, 122.8, 120.7, 120.4, 115.0, 108.2; Elemental analysis, found: C, 77.11; H, 5.99; N, 16.20; (theoretical: C, 77.62; H, 5.92; N, 16.46).

3-aniline-pyridine

(90) ##STR00109##

(91) 3-bromopyridine (154 L, 1.6 mmol) or 3-chloropyridine (152 L, 1.6 mmol); aniline (182 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (28.8 mg, 0.032 mmol, 2.0 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 79% yield (215 mg; X=Br) and 88% yield (239 mg; X=Cl): .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.38 (d, J 2.0, 1H), 8.15 (d, J 4.0, 1H), 7.42 (d, J 7.2, 1H), 7.30 (t, J 7.6, 2H), 7.16 (dd, J 8.0, 4.4, 1H), 7.08 (d, J 8.0, 2H), 6.99 (t, J 7.2, 1H), 6.01 (br s, 1H); .sup.13C (CDCl.sub.3, 100 MHz): 142.0, 141.8, 140.1, 139.9, 129.6, 123.8, 123.4, 122.0, 118.3; Elemental analysis, found: C, 77.19; H, 6.02; N, 15.96; (theoretical: C, 77.62; H, 5.92; N, 16.46).

2-N-Methylaniline-pyrimidine

(92) ##STR00110##

(93) 2-bromopyrimidine (127 mg, 0.8 mmol); N-methylaniline (109 L, 1.0 mmol); NaOtBu (115 mg, 1.2 mmol); Pd(-crotyl)QPhosCl (14.4 mg, 0.016 mmol, 2.0 mol %); toluene (1.0 mL). The general procedure afforded the title compound in 83% yield (123 mg): .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.34 (d, J 4.4, 2H), 7.42 (t, J 8.0, 2H), 7.32 (d, J 7.6, 2H), 7.24-7.22 (m, 1H), 6.57 (t, J 4.8, 1H), 3.53 (s, 3H); .sup.13C (CDCl.sub.3, 100 MHz): 162.0, 157.7, 145.5, 129.2, 126.6, 125.9, 110.8, 38.7; Elemental analysis, found: C, 71.33; H, 6.08; N, 22.51; (theoretical: C, 71.33; H, 5.99; N, 22.69).

2-(N-Methyl-N-phenylamino)thiophene

(94) ##STR00111##

(95) 3-bromothiophene (150 L, 1.6 mmol) or 3-chlorothiophene (149 L, 1.6 mmol); N-methylaniline (217 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (28.8 mg, 0.032 mmol, 2.0 mol %); toluene (2.0 mL). The general procedure afforded the title compound in 90% yield (272 mg; X=Br) and 57% yield (172 mg; X=Cl): .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.27-7.20 (m, 3H); 7.01 (d, J 7.6, 2H), 6.91 (t, J 7.6, 1H), 6.87 (dd, J 5.2, 1.6, 1H), 6.57 (dd, J 3.2, 1.2, 1H), 3.29 (s, 3H); .sup.13C (CDCl.sub.3, 100 MHz) 149.3, 148.4, 129.1, 124.9, 123.3, 120.7, 118.8, 107.8, 41.0; Elemental analysis, found: C, 70.13; H, 5.84; N, 7.32; (theoretical: C, 69.80; H, 5.86; N, 7.40).

2-Chloro-5-N-methylaniline-thiophene

(96) ##STR00112##

(97) 2-bromo-5-chlorothiophene (175 L, 1.6 mmol); N-methylaniline (217 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (28.8 mg, 0.032 mmol, 2.0 mol %); toluene (2.0 mL); 25 C.; 20 hrs. The general procedure afforded the title compound as an off-white oil in 44% yield (155 mg): .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.26-7.23 (m, 2H), 6.94-6.88 (m, 3H), 6.70 (d, J 4.0, 1H), 6.44 (d, J 4.0, 1H), 3.28 (s, 3H); .sup.13C (CDCl.sub.3, 100 MHz): 151.3, 148.8, 129.1, 124.6, 123.3, 120.3, 119.1, 116.1, 41.8; Elemental analysis, found: C, 59.28; H, 4.54; N, 6.29; (theoretical: C, 59.05; H, 4.51; N, 6.26).

4-methyldiphenyl-methylamine

(98) ##STR00113##

(99) 4-bromotoluene (274 mg, 1.6 mmol); N-methylaniline (217 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (0.7 mg, 0.0008, 0.05 mol %); toluene (0.5 mL). The general procedure afforded the title compound in 83% yield (261 mg): .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.24-7.20 (m, 2H), 7.11 (d, J 8.4, 2H), 7.01-6.97 (m, 2H), 6.91 (app. d, J 7.6, 2H), 6.86 (app. t, J 7.6, 1H), 3.28 (s, 3H), 2.31 (s, 3H); .sup.13C (CDCl.sub.3, 100 MHz): 149.4, 146.6, 132.1, 130.0, 129.1, 122.6, 119.8, 118.2, 40.4, 20.8; Elemental analysis, found: C, 85.25; H, 7.75; N, 7.29; (theoretical: C, 85.24; H, 7.66; N, 7.10).

N-4-toluene-2,6-diisopropylaniline

(100) ##STR00114##

(101) 4-bromotoluene (274 mg, 1.6 mmol); 2,6-diisopropylaniline (377 L, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(-crotyl)QPhosCl (0.7 mg, 0.0008, 0.05 mol %); toluene (0.5 mL). The general procedure afforded the title compound in 91% yield (387 mg): .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.30-7.25 (m, 1H), 7.22-7.19 (m, 2H), 6.94 (d, J 8.0, 2H), 6.39 (d, J 8.4, 2H), 5.02 (br s, 1H), 3.19 (heptet, J 6.8, 2H), 2.23 (s, 3H), 1.13 (d, J 6.8, 12H); .sup.13C (CDCl.sub.3, 100 MHz): 147.4, 145.9, 135.6, 129.8, 127.0, 126.9, 123.9, 113.1, 28.2, 23.9, 20.5; Elemental analysis, found: C, 85.22; H, 9.45; N, 5.29; (theoretical: C, 85.34; H, 9.42; N, 5.24).

Example 6

(102) N-Arylations at Low Catalyst Loadings of Pd(-crotyl)QPhosCl

(103) The arylation of amines at lower catalyst loadings were evaluated (Table 7) and, in this respect, reactions carried out with 0.05 or 0.1 mol % loading were successfully achieved.

(104) TABLE-US-00007 TABLE 7 N-Arylations at Low Catalyst Loadings of Pd(-crotyl)QPhosCl..sup.a catalyst loading yield ArX amine X (mol %) product (%) Br Cl 0.05, 1 h 0.10, 1 h 83 92 0 Cl Cl 0.05, 16 hrs 0.1, 2 hrs 90.sup.b 95 Br 0.05, 2 hrs 91 .sup.aaryl halide (1.6 mmol), amine (2.0 mmol), NaOtBu (2.4 mmol), toluene (0.5 mL) .sup.bGC/MS conversion.

(105) See Example 5 for the experimental data for the products listed in Table 7

Example 7

(106) Synthesis of the Toddaliopsin Framework

(107) The synthesis of the toddaliopsin framework was realised by implementing a Pd(-1-crotyl)QPhosCl catalysed aryl amination step incorporating a very electronrich aryl bromide. As can be seen, the CN coupling reaction proceeded smoothly to provide the required product in 65% yield.

(108) ##STR00125##

Example 8

(109) General Procedure for the -Arylation Reaction of Aldehydes:

(110) A Schlenk flask was charged with the catalyst, Cs.sub.2CO.sub.3 and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the aldehyde in solvent were added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for the indicated time, then the mixture was absorbed onto silica gel and purified by flash column chromatography (EtOAc/40-60 petroleum ether eluent).

(111) ##STR00126##

Example 9

(112) General Procedure for the -Arylation of Ketones:

(113) A Schlenk flask was charged with the catalyst, NaOtBu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, the aryl halide (if liquid), followed by ketone and solvent were added via syringe. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for 18 hours, then the mixture was absorbed onto silica gel and purified by flash column chromatography (MTBE/40-60 petroleum ether eluent).

(114) TABLE-US-00008 TABLE 8 -arylation of ketones catalyst (mol %) solvent T ( C.) time (hrs) Conversion.sup.a (%) Pd(allyl)QPhosCl (1.0) THF 60 17 76 Pd(1-crotyl)QPhosCl (1.0) THF 60 17 99.sup.b (85) Pd(1-crotyl)QPhosCl (0.25) THF 60 17 (90) Pd(dba).sub.2/QPhos (0.25) (Comparative) THF 60 17 (80) Pd(OAc).sub.2/QPhos (0.25) (Comparative) THF 60 17 (85) Pd-118 (0.25) (Comparative).sup.c THF 60 17 (64) .sup.aConversion using GC/MS. Isolated yield in parenthesis .sup.bAll starting material consumed .sup.cPd-118 = dichloro[1,1-bis(di-tert-butylphosphino)]ferrocene palladium (II)

(115) It can be seen from the results in the above table that the Pd(-1-crotyl)QPhosCl precatalyst provided the best results in the -arylation reaction. Moreover, in comparison with in situ generated QPhos based catalysts, the preformed complexes exhibited comparable or superior activities.

Example 10

(116) Substrate Scope for the -Arylation of Ketones

(117) It was demonstrated that the mono-arylation of propiophenone proceeded smoothly using a range of electronrich and -neutral aryl halides and the Pd(-1-crotyl)QPhosCl catalyst. Substituents were tolerated in the ortho- and meta- as well as the para-position of the aryl moiety.

(118) TABLE-US-00009 TABLE 9 Substrate scope for the -arylation of ketones 0 X = Br 90% yield.sup.b 76% yield.sup.a 63% yield.sup.a (0.25 mol %, 60 C.) (0.25 mol %, 60 C.) (0.25 mol %, 60 C.) X = Cl 82% yield 61% yield.sup.a 65% yield.sup.a (1.0 mol %, 100 C.) (0.25 mol %, 100 C.) (1.0 mol %, 100 C.) X = Br 88% yield.sup.a 99% yield.sup.a (0.25 mol %, 60 C.) (1.0 mol %, 60 C.) .sup.aProduct co-running with propiophenone. Yield given is NMR yield from isolated mixture of product and propiophenone .sup.bAverage yield from 3 reactions

Example 11

(119) -Arylation of 1-Tetralone

(120) General Procedure

(121) A Schlenk flask was charged with Pd(X)LCl (0.05 mol %, 0.001 mmol) and NaOt-Bu (365 mg, 3.8 mmol). The flask was evacuated and backfilled with nitrogen three times, then dioxane (2.0 ml), 4-chloroanisole (245 L, 2.0 mmol) and -tetralone (266 L, 2.0 mmol) were added. The reaction mixture was stirred for 16 hours, then an aliquot was removed for analysis by GC/MS.

(122) The activities of the -allyl catalysts bearing the QPhos and P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4) ligands were evaluated in the -arylation of cyclic ketone 1-tetralone. Pd(allyl)QPhosCl provided the product in 80% conversion after 3 hours reaction time, whereas Pd(allyl)P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)Cl gave 96% conversion after the same time (Table 10, entries 1 and 2). The product was isolated in 91% yield after an overnight reaction using catalyst loading as low as 0.05 mol % of Pd(allyl)P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)Cl (entry 3).

(123) TABLE-US-00010 TABLE 10 -Arylation of 1-Tetralone Using 0.05 mol % Pd Loading..sup.a entry catalyst time (hours) conversion (%).sup.b 1 Pd(allyl)QPhosCl 3 80 2 Pd(allyl)P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)Cl 3 96 3 Pd(allyl)P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)Cl 22 100(91) .sup.a4-chloroanisole (2.0 mmol), 1-tetralone (2.0 mmol), NaOtBu (3.8 mmol), dioxane (2.0 mL). .sup.bGC/MS conversion. Average of two runs. Isolated yield in parenthesis.

Example 12

(124) Suzuki Coupling Reactions

(125) General Procedure for the Suzuki Reaction:

(126) A Schlenk flask was charged with the catalyst, KOtBu (1.2 eq), boronic acid (1.1 eq) and aryl halide (1.0 eq), if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, the aryl halide (if liquid) and solvent were added via syringe. The resulting reaction mixture was stirred under nitrogen at the indicated temperature, then the crude reaction mixture was analysed by GC/MS.

(127) TABLE-US-00011 TABLE 11 Suzuki coupling reactions X solvent C (M) loading (mol %) time (h) T ( C.) conversion (%).sup.a Br toluene:H.sub.2O (4:1) 0.8 0.01 20 100 100 Br toluene:H.sub.2O (4:1) 0.8 1.0 1 25 100 Cl toluene 0.27 1.0 20 80 68 .sup.aconversion into product, taking into account deboronated product formed.

(128) The high activity of Pd(crotyl)Q-PhosCl was subsequently demonstrated in the sterically challenging Suzuki reaction of bromomesitylene and 1-naphthalene boronic acid. This coupling could be carried out at ambient temperature with 100% GC conversion and 86% isolated yield within 45 minutes of the reaction time.

(129) ##STR00136##

Example 13

(130) Aryl Chlorides in Suzuki Coupling

(131) Extending the scope of the substrates to aryl chlorides, the coupling product of 4-chloroanisole with 4-tert-butylbenzene boronic acid gave 90% conversion (Table 12, entry 1) using the same reaction conditions as for the aryl bromides, but at 80 C. The present inventors also decided to investigate the base effect and the use of heterocyclic chlorides employing the -allyl catalysts in comparison with the use of PdCl.sub.2(P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)).sub.2 as reported by Guram (Guram et al, Org. Lett., 2006, 8, 1787). Substituting K.sub.2CO.sub.3 for KOt-Bu in the case of 4-chloroanisole provided the coupling product in relatively low conversions, using both Pd(crotyl)QPhosCl and Pd(allyl)P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)Cl (entries 2 and 3). However, employing 2-chlorothiophene in the Suzuki reaction, it was found that the yield of the product was comparable to the Guram conditions for PdCl.sub.2(P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)).sub.2 and the new Pd(allyl) P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)Cl (entries 4-5, 6-7, 8-9), demonstrating that a Pd:L ratio of 1:1 was sufficient for an efficient reaction. Using the reaction conditions developed for the aryl bromides, 2-chlorothiophene was coupled with 4-tert-butyl-benzene boronic acid to obtain 52% yield, with Pd(crotyl)QPhosCl catalyst (entry 10). The same reaction gave a lower yield (33%) under the Guram conditions (entry 11). For chloropyridine substrate, Pd(-allyl)AmphosCl gave 73% yield (entry 13).

(132) The described investigation of aryl chlorides in Suzuki coupling illustrates the importance of a careful choice of the catalyst and the reaction conditions to get the optimized yields.

(133) TABLE-US-00012 TABLE 12 Aryl Chlorides in Suzuki Coupling..sup.a yield Entry catalyst conditions RB(OH).sub.2 ArCl (%).sup.a 1 1 mol % Pd(1-crotyl) QPhosCl A 0 90.sup.b 2 1 mol % Pd(1-crotyl) QPhosCl B 38.sup.b 3 1 mol % Pd(allyl) AmphosCl B 29.sup.b 4 5.sup.c 1 mol % Pd(allyl) AmphosCl 1 mol % Pd-132 B 64 68 6 7.sup.c 1 mol % Pd(allyl) AmphosCl 1 mol % Pd-132 B 0 70 84 8 9.sup.c 0.01 mol % Pd(allyl) AmphosCl 0.01 mol % Pd-132 B 85 79 10 1 mol % Pd(1-crotyl) QPhosCl A 52 11 1 mol % Pd(1-crotyl) QPhosCl B 0 33 12 1 mol % Pd(1-crotyl) AmphosCl B 29 13 1 mol % Pd(allyl) AmphosCl B 73 .sup.aConditions A: aryl chloride (1.6 mmol), boronic acid (1.76 mmol), KOtBu (1.92 mmol), toluene (1.8 mL), water (0.2 mL), 80 C. Conditions B: aryl chloride (1.0 mmol), boronic acid (1.2 mmol), K.sub.2CO.sub.3 (2.0 mmol), toluene (5.0 mL), water (0.5 mL), 100 C. Isolated yield. .sup.bGC/MS conversion. .sup.cPd-132; PdCl.sub.2[P(t-Bu).sub.2(p-NMe.sub.2C.sub.6H.sub.4)].sub.2.

(134) In the Suzuki coupling reactions, the present inventors have been the first to demonstrate that K.sub.2CO.sub.3 can be used as the base in conjunction with -allyl precatalysts.