MUTULE ILGA (LV)
SUNA EDGARS (LV)
| DE10142262A1 | 2003-03-20 |
HONGBO LI ET AL: "A Highly Efficient, Practical, and General Route for the Synthesis of (R 3 P) 2 Pd(0): Structural Evidence on the Reduction Mechanism of Pd(II) to Pd(0)", ORGANIC LETTERS, vol. 12, no. 15, 2 July 2010 (2010-07-02), pages 3332 - 3335, XP055103553, ISSN: 1523-7060, DOI: 10.1021/ol101106z
IVORY D. HILLS ET AL: "Elucidating Reactivity Differences in Palladium-Catalyzed Coupling Processes: The Chemistry of Palladium Hydrides", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 126, no. 41, 28 September 2004 (2004-09-28), pages 13178 - 13179, XP055103554, ISSN: 0002-7863, DOI: 10.1021/ja0471424
FU, G. C., ACC. CHEM. RES., vol. 41, 2008, pages 1555
ADAMO, C. ET AL., J. AM. CHEM. SOC., vol. 128, 2008, pages 6829
AMATORE, C. ET AL., ORGANOMETALLICS, vol. 14, 1995, pages 1818
AMATORE, C. ET AL., ORGANOMETALLICS, vol. 12, 1993, pages 3168
FRASER, A. W. ET AL., ORGANOMETALLICS, vol. 31, 2012, pages 2470
FAIRLAMB, I. J. S., ORG. BIOMOL. CHEM., vol. 6, 2008, pages 3645
ZALESSKIY, S. S.; ANANIKOV, V. P., ORGANOMETALLICS, vol. 31, 2012, pages 2302
COLACOT, T. J.; SHEA, H. A., ORG. LETT., vol. 6, 2004, pages 3731
SIMMONS, E. M.; HARTWIG, J. F., J. AM. CHEM. SOC., vol. 132, 2010, pages 17092
GURAM, A. S. ET AL., ORG. LETT., vol. 8, 2006, pages 1787
HE, A.; FALCK, J. R., J. AM. CHEM. SOC., vol. 132, 2010, pages 2524
BOLLIGER, J. L.; FRECH, C. M., CHEM.-EUR. J., vol. 16, 2010, pages 4075
BURNS, M. J. ET AL., ORG. LETT., vol. 9, 2007, pages 5397
BUTTERS, M. ET AL., ANGEW. CHEM. INT.ED., vol. 49, 2010, pages 5156
COLACOT, T. J. ET AL., ORG. LETT., vol. 12, 2010, pages 3332
HILLS, I. D.; FU, G. C., J. AM. CHEM. SOC., vol. 126, 2004, pages 13178
GOEL, A. B.; GOEL, S., INORG. CHIM. ACTA, vol. 45, 1980, pages L85 - L86
| We claim: 1 . Use of hydridopalladium(ll) halides of general formula LnPd(H)Hal as catalysts for the C-C bond forming cross-coupling reaction between optionally substituted aryl- and heteroaryl boron derivatives and optionally substituted aryl- and heteroaryl halides in the presence of a base and a solvent, wherein: Hal is CI, Br or I, L is a phosphine ligand, n is 1 , when phosphine L is a bidentate phosphine, or n is 2, when phosphine L is a monophosphine. 2. The use according to claim 1 , wherein ligand L is selected from the group of electron-rich phosphines, comprising phenyl-di-terf-butylphosphine, di-terf-butyl-neopentylphosphine, 1 ,2,3,4, 5-pentaphenyl-1 '- (di-te/t-butylphosphino)ferrocene, triphenylphosphine, tricyclohexyl phosphine, tri(terf-butyl)phosphine, 1 -adamantyl-di-te/t-butylphosphine, benzyldi-1 - adamantylphosphine, butyldi-1 -adamantylphosphine, cyclohexyldi-terf- butylphosphine, 2-di-terf-butylphosphino-1 ,1 '-binaphtyl, 2-(di-terf- butylphosphino)biphenyl, 2-di-terf-butylphosphino-2'-(/V,/V- dimethylamino)biphenyl, 2-di-ie/t-butylphosphino-2',4',6'-th-/'-propyl-1 ,1 '- biphenyl, 2-(dicyclohexylphosphino) biphenyl, 2-(dicyclohexylphosphino)-2',6'- dimethoxy-1 ,1 '-biphenyl, 1 ,2-bis(di-terf-butylphosphinomethyl)benzene, 1 ,3-bis(di-te/t-butylphosphinomethyl)propane, 1 -(2-methoxyphenyl)-2-(di- cyclohexylphosphino)pyrrole, A/-phenyl-2-(dicyclohexylphosphino)indol, A/-phenyl-2-(di-cyclohexylphosphino)pyrrole and 1 -(2,4,6-trimethylphenyl)-2- (dicyclohexylphosphino)imidazole. 3. The use according to claim 1 , wherein aryl- and heteroaryl boron derivatives are selected from the group, comprising aryl- and heteroaryl boronic acids, pinacolyl boronates, catechol boronates, neopentylglycolato boronates, hexyleneglycolato boronates and trifluoroborates. 4. The use according to claim 1 , wherein said base is inorganic base, selected from the group comprising hydroxides, alkoxides, carbonates, phosphates or acetates and mixtures or combinations thereof. 5. The use according to claim 1 , wherein said solvent is selected from the group comprising protic solvents, aprotic solvents and combinations thereof. |
Field of the invention
The present invention relates to chemistry, and particularly to the use of well-defined hydridopalladium(ll) halides of a general formula L n Pd(H)(X) as catalysts for Suzuki-Miyaura cross-coupling reaction. This invention is particularly relevant for, but not limited to, the industrial-scale Suzuki-Miyaura cross-coupling reaction.
Background of the invention
Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction has found broad application in chemical and pharmaceutical industry as an efficient tool for the construction of new C-C bonds. Commonly used catalysts for the cross-coupling are preformed L n Pd(0) complexes containing triaryl- and trialkylphosphines as ligands. Among them, triarylphosphines (L=PPh 3 or P(o- tolyl)3) have been traditionally used owing to relatively low cost and sufficient stability. However, triarylphosphines are efficient as ligands only for the cross- coupling of relatively active halides such as iodides and bromides. The use of challenging substrates such as sterically hindered coupling partners as well as less reactive but more widely available chlorides often requires the use of electron-rich trialkylphosphines as ligands for Pd(0) (Fu, G. C. Acc. Chem. Res. 2008, 41, 1555).
The preformed catalytically active L 2 Pd(0) complexes possessing electron-rich trialkylphosphines typically are highly air sensitive. Dioxygen easily adds to Pd(0) center, forming palladium (II) peroxo species, which catalyzes homocoupling side-reactions (Adamo, C. et al J. Am. Chem. Soc. 2008, 128, 6829). Because handling of L 2 Pd(0) complexes requires especial precautions, they are relatively rarely utilized as catalysts in large-scale industrial cross-coupling processes. To overcome the catalyst's instability issue, the L 2 Pd(0) complexes are generated in situ from triaryl- and trialkylphosphines and a suitable Pd source such as Pd(OAc) 2 (Amatore, C. et al Organometallics 1995, 14, 1818) or PdCI 2 , Pd(dba) 2 (Amatore, C. et al Organometallics 1993, 12, 3168), Pd 2 (dba) 3 and Pd(n 3 -1 -PhC 3 H 4 )(n 5 -C 5 H5) (Fraser, A. W. et al Organometallics 2012, 31, 2470). This approach, however, is compromised by poor stability of trialkylphosphines, which typically are highly air-sensitive and often pyrophoric. Besides, in situ generation of the L 2 Pd(0) catalyst from Pd(dba) x (x=1 .5 or 2) and phosphines can bring about reproducibility problems associated with difficulty in controlling the proper ratio of phosphine ligands to Pd. Furthermore, it has also been demonstrated that the dba ligand remains ligated to L 2 Pd(0) complex forming a tri -coord in ate L 2 Pd(dba) species (Fairlamb, I. J. S. Org. Biomol. Chem. 2008, 6, 3645) which are less efficient as catalysts in the cross-coupling reaction (Amatore, C. et al Organometallics 1993, 12, 3168). Finally, various batches of commercially available Pd 2 (dba)3 may contain different amounts of Pd nanoparticles (up to 40%) (Zalesskiy, S. S.; Ananikov, V. P. Organometallics 2012, 31, 2302) which renders difficult a reproducibility of the Suzuki-Miyaura cross-coupling.
Catalytically active Pd(0) species for the Suzuki-Miyaura cross-coupling reactions can also be generated in situ from Pd(ll) halides L 2 PdCI 2 , where L=Cy 3 P (Colacot, T. J.; Shea, H. A. Org. Lett. 2004, 6, 3731 . Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 17092), 4-Me 2 N-C 6 H 4 P(f-Bu) 2 (Guram, A. S. et al Org. Lett. 2006, 8, 1787. He, A.; Falck, J. R. J. Am. Chem. Soc. 2010, 132, 2524) and (CioH 5 N)P(C 6 Hii) 2 (Bolliger, J. L; Freeh, C. M. Chem.-Eur. J. 2010, 16, 4075), as well as from (PPh 3 ) 2 Pd(A/-Succ)Br (Burns, M. J. Et al Org. Lett. 2007, 9, 5397). These well-defined Pd(ll) complexes feature pre-installed phosphine ligands in a 2:1 phosphine to Pd ratio. They are moisture and air-stable and therefore can be conveniently handled. However, in situ transformation of Pd(ll) halides L 2 PdCI 2 to catalytically active L 2 Pd(0) species may involve generation of homocoupling side-product, which complicates isolation of the desired product, especially if relatively high catalyst loading is employed (Butters, M. et al. Angew. Chem. Int.Ed. 2010, 49, 5156).
Thus, the development of air and moisture stable, well-defined palladium catalyst precursors for the Suzuki-Miyaura cross-coupling in industrial scale is highly desirable. Description of the invention
In the first aspect, the present invention features the use of well-defined hydridopalladiunn(ll) halides of a general formula L n Pd(H)(X) 1 as catalysts for Suzuki-Miyaura cross-coupling reaction. Considerable air- and moisture stability of the hydridopalladium(ll) halides 1 makes them superior the known L n Pd(0) complexes. This invention is particularly relevant for, but not limited to, the industrial-scale Suzuki-Miyaura cross-coupling reaction.
In the presence of a suitable base, hydridopalladium(ll) halides
L n Pd(H)(X) 1 undergo facile base-mediated reductive elimination of H-X to form L„Pd(0) species (Colacot, T. J.ef a/ Org. Lett. 2010, 12, 3332. Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178. ). Because the Suzuki- Miyaura cross-coupling reaction requires the presence of stoichiometric amounts of base, hydridopalladium(ll) halides 1 are convenient precursors to catalytically active Pd(0) species (eq 1 ).
H \ / PR, 3 base
.Pd (R 3 P) 2 Pd (1 )
R 3 P X
1
Hydridopalladium(ll) halides L n Pd(H)(X) 1 could be readily obtained from inexpensive precursors, preferably Pd(olefin)(X) 2 in a β-hydride elimination reaction, in the presence of suitable phosphine ligand (eq 2) (Goel, A. B.; Goel, S. Inorg. Chim. Acta 1980, 45, L85-L86. Colacot, T. J.ef al Org. Lett. 2010, 12, 3332).
In another aspect, the present invention broadly relates to the use of well-defined hydridopalladium(ll) halides L n Pd(H)(X) 1 as catalysts for Suzuki- Miyaura cross-coupling reaction between aryl- and heteroaryl halides and aryl and heteroaryl boron derivatives.
Electron-rich bulky tricyclohexylphospine and tert- butyldicyclohexylphosphine are the most suitable phosphine ligands as they afford the best results in the Suzuki-Miyaura cross-coupling reaction. Other bulky phosphines such as, but not limited to, benzyl-di-1 -adamantylphosphine and (4-(/V,/V-dimethylamino)phenyl)di-terf-butyl phosphine, and mixtures or combinations thereof can be used.
Although in the most embodiments aryl- and heteroaryl chlorides are the preferred halogenated aryls for the Suzuki-Miyaura cross-coupling using the hydridopalladium(ll) halides 1 , aryl- and heteroaryl halides such as bromides and iodides can be used as well .
In the most embodiments aryl- and heteroaryl boronic acids are employed in the Suzuki-Miyaura cross-coupling, catalyzed by the hydridopalladium(ll) halides 1 . However, aryl- and heteroaryl pinacolyl boronates could also be used.
Any inorganic base compatible with the solvent are suitable for the
Suzuki-Miyaura cross-coupling, which is catalyzed by hydridopalladium(ll) halides 1 . The most preferred bases include, but are not limited to, CsF and K 3 PO 4 . Other carbonates, phosphates, acetates or fluorides such as CsOAc,
KOAc, NaOAc, K2CO3, Na2CO3, CS2CO3, KF and mixture or combinations thereof are suitable as base.
In one embodiment, the present invention demonstrates the use of hydridopalladium(ll) halides 1 a-d in the Suzuki-Miyaura reaction between sterically hindered electron-rich aryl chlorides and ο/ΐ/70-substituted aryl boronic acids (Table 1 ). The efficiency of hydridopalladium(ll) halides 1 a-b as catalysts in the Suzuki-Miyaura cross-coupling reactions was compared to the corresponding Pd(ll) halides L 2 PdCl2 and L n Pd(0) complexes, which both contain the same ligands L. The general reaction conditions are: aryl chloride (0.3 mmol, 1 .0 equiv), aryl boronic acid (0.33 mmol, 1 .1 equiv.), CsF (0.9 mmol, 3.0 equiv.), hydridopalladium(ll) halide 1 a-d (0.0015 mmol, 5mol%), dioxane (3 ml_), 100 °C. Table 1 . Suzuki-Miyaura cross-coupling with different catalysts 1 a-d, 2a-b, 3a-b.
Pd catalyst 1-3
(5 mol%)
Ar 1 — CI + Ar 2 — B(OH),
' 2 — CsF—— *" Ar 1 Ar 2
(3 eq)
dioxane (100 °C)
1 a (Cy 3 P) 2 Pd(H)CI 2a: (Cy 3 P) 2 Pd
1 b (Cy 2 Pf-Bu) 2 Pd(H)CI 2b: (Cy 2 Pf-Bu) 2 Pd
1 c: (Cy 3 P) 2 Pd(H)Br 3a: (Cy 3 P) 2 PdCI 2
1 d (Cy 2 Pf-Bu) 2 Pd(H)Br 3b: (Cy 2 Pf-Bu) 2 PdCI 2
In general, hydridopalladium(ll) halide catalysts 1 a-d and the corresponding L n Pd(0) complexes 2a, b provided comparable yields of the Suzuki-Miyaura cross-coupling products. Importantly, different Pd(ll) complex L 2 PdCl 2 3a was inferior as catalyst in terms of yields. Furthermore, in one example (entry 5, Table 1 ) catalyst 3a was totally inefficient.
In another embodiment, the present invention includes the use of hydridopalladium(ll) halide 1 a as catalyst for the Suzuki-Miyaura reaction between sterically hindered electron-rich aryl chlorides and ο/ΐ/70-substituted aryl pinacolyl boronates.
1 a: (Cy 3 P) 2 Pd(H)CI Yield using catalyst 1 a: 85% 2a: (Cy 3 P) 2 Pd Yield using catalyst 2a: 74%
In another embodiment, the present invention includes the use of hydridopalladium(ll) halide 1 a as catalyst for the Suzuki-Miyaura reaction between sterically hindered electron-rich aryl and heteroaryl chlorides and pyridine-3-boronic acid. The efficiency of hydridopalladium(ll) halides 1 a-b as catalysts in the Suzuki-Miyaura cross-coupling reactions was compared to the corresponding (CysP^PdC^ complex 3a and (Cy3P)2Pd complex 2a, which both contain the same ligands L. The general reaction conditions are: aryl or heteroaryl chloride (0.3 mmol, 1.0 equiv), pyridyl-3-boronic acid (0.33 mmol, 1.1 equiv), K 3 PO 4 (0.51 mmol, 1.7 equiv), Pd catalyst (0.0015 mmol, 5 mol%), 2:1 dioxane-water (1.5 ml_), 100 °C.
Table 2.
Pd catalyst
dioxane-water 2:1
100 °C
3
6 70 92 38
H
4 CI
1
6 91 94 61
H
In general, hydridopalladiunn(ll) halide 1 a and the corresponding (Cy3P) 2 Pd complex 2a provided comparable yields of the Suzuki-Miyaura cross-coupling products, whereas Pd(ll) complex (Cy3P) 2 PdCl 2 3a was inferior as catalyst in terms of yields.
The invention is illustrated with the following non-limiting examples. All solvents and reagents were purchased from commercial sources (e.g. Alfa Aesar, Sigma Aldrich) and used as received. All ligands or precious metal precursors were obtained from Strem Chemicals. All reactions were performed under inert atmosphere. All air and moisture sensitive reagents were handled in the glove box. Palladium hydrides L 2 Pd(H)(X) were synthesized according to literature procedure (Colacot, T. J.ef al Org. Lett. 2010, 12, 3332) from corresponding Pd(COD)X 2 complexes and phosphine ligands L. Solvents for the Suzuki-Miyaura reaction was degassed by freeze- thaw method prior to use.
1 H, 13 C, and 31 P-NMR spectra were recorded on a Varian Mercury-400 spectrometer. All 1 H NMR experiments are reported in δ units, parts per million (ppm) downfield from tetramethylsilane (internal standard) and were measured relative to the signals for residual chloroform (7.26 ppm). The yields in Tables 1 -2 refer to isolated yields (average of two runs) of compounds estimated to be >95% pure as determined by 1 H NMR. Conversion of starting compound is monitored by GC analysis that were performed on Agilent 7890A with MS detector Agilent 5975C, column HP-5MS, 30m x 0,25mm x 0,25μηη. Temperature gradient: 50°C (1 min), 50-80°C (5°C/min), 80-250°C (15°C/min), 250°C (10 min).
Example 1 . Preparation of Pd(PCy 3 ) 2 (H)CI (1 a)
A suspension of Pd(COD)Cl 2 (100 mg, 0.35 mmol) in anhydrous toluene (1 mL) was cooled to 0 °C. A solution of NaOMe (prepared by dissolving NaOH (17 mg, 0.42 mmol) in 0.3 mL of anhydrous MeOH) was added via cannula, and stirring at 0 °C was continued for 20 min. The resulting pale-yellow suspension was added to a cold (0 °C) solution of PCy3 (196.3 mg, 0.70 mmol) in anhydrous toluene (2.2 mL). After stirring at 0 °C for 2.5 h, a colorless suspension was formed, which dissolved upon addition of cold (0 °C) MeOH (15 mL). The clear solution was kept in freezer (-18 °C) for 72 hours whereupon precipitate was formed . Filtration and drying in vacuo afforded 1 a as colorless crystals, 108 mg (44% yield).
1 H NMR (400 MHz, CDCI 3 ) δ 2.08 (tt, 6H, J=12.2, 2.8 Hz), 2.02-1 .94 (m, 12H), 1 .85-1 .63 (m, 18H), 1 .54-1 .43 (m, 1 2H), 1 .35-1 .13 (m, 18H), -15.10 (t, 1 H, J=6.4 Hz).
13 C-NMR (100 MHz, CDCI 3 ) δ 34.1 (t, J C _ P =9.9 Hz), 30.4, 27.4 (t, J c- P=5.4 Hz).
31 P-NMR (400 MHz, CDCI 3 ) δ 40.64.
Anal . Calcd for C 3 6H 6 7CI P 2 Pd: C 61 .44, H, 9.60. Found C 61 .59, H 9.88
Example 2. Preparation of Pd(PCy 3 ) 2 (H)Br (1 b)
A suspension of Pd(COD)Br 2 (200 mg, 0.53 mmol) in anhydrous toluene (1 mL) was cooled to 0 °C. A solution of NaOMe (prepared by dissolving NaOH (25.6 mg, 0.64 mmol) in 0.5 mL of anhydrous MeOH) was added via cannula, and stirring at 0 °C was continued for 20 min. The resulting pale-yellow suspension was added to a cold (0 °C) solution of PCy 3 (329.5 mg, 1 .18 mmol) in anhydrous toluene (2.5 mL). After stirring at 0 °C for 2.5 h, a colorless suspension was formed, which dissolved upon addition of cold (0 °C) MeOH (25 mL). The clear solution was kept in freezer (-18 °C) for 24 hours whereupon precipitate was formed . Filtration and drying in vacuo afforded 1 b as colorless crystals, 346 mg (87% yield).
1 H NMR (400 MHz, CDCI 3 ) δ 2.08 (tt, 6H, J=12.2, 2.8 Hz), 2.02-1 .93 (m, 12H), 1 .82-1 .65 (m, 18H), 1 .55-1 .40 (m, 1 2H), 1 .34-1 .1 1 (m, 18H), -14.0 (t, 1 H, J=6.4 Hz).
13 C-NMR (100 MHz, CDCI 3 ) δ 34.7 (t, J c-P =10.2 Hz), 30.4, 27.4 (t,
31 P-NMR (400 MHz, CDCI 3 ) δ 40.56.
Anal . Calcd for C 36 H6 7 BrP 2 Pd: C 57.79, H, 9.03. Found C 58.10, H 8.86 Example 3. Preparation of Pd(PCy 2 t-Bu) 2 (H)CI (1 c)
A suspension of Pd(COD)Cl2 (150 mg, 0.53 mmol) in anhydrous toluene (2 mL) was cooled to 0 °C. A solution of NaOMe (prepared by dissolving NaOH (25 mg, 0.64 mmol) in 1 .0 mL of anhydrous MeOH) was added via cannula, and stirring at 0 °C was continued for 20 min. The resulting pale-yellow suspension was added to a cold (0 °C) solution of PCy 2 f-Bu (295 mg, 1 .16 mmol) in anhydrous toluene (3 mL). After stirring at 0 °C for 2.5 h, a colorless suspension was formed, which dissolved upon addition of cold (0 °C) MeOH (20 mL). The clear solution was kept in freezer (- 18 °C) whereupon precipitate was formed. Filtration and drying in vacuo afforded 1 c as colorless crystals, 60 mg (9% yield).
1 H-NMR (400 MHz, CDCI 3 ) δ 3.47 (s, 1 H), 2.25-2.15 (m, 8H), 2.02- 1 .96 (m, 4H), 1 .84-1 .47 (m, 20H), 1 .42-1 .10 (m, 29H), -15.43 (t, 1 H, J=5.8 Hz).
13 C-NMR (100 MHz, CDCI 3 ) δ 34.7 (t, J c-P =8.2 Hz), 33.6 (t, J c-P =9.0 Hz), 31 .7, 30.8, 29.3, 27.6 (t, J c-P =6.0 Hz), 27.3 (t, J c-P =4.5 Hz), 26.5.
3 1 P-NMR (400 MHz, C 6 D 6 ) δ 55.50. Example 4. Preparation of Pd(PCy 2 t-Bu) 2 (H)Br (1 d)
A suspension of Pd(COD)Br 2 (100 mg, 0.27 mmol) in anhydrous toluene (1 mL) was cooled to 0 °C. A solution of NaOMe (prepared by dissolving NaOH (13.0 mg, 0.32 mmol) in 0.5 mL of anhydrous MeOH) was added via cannula, and stirring at 0 °C was continued for 20 min. The resulting pale-yellow suspension was added to a cold (0 °C) solution of PCy 2 f-Bu (149 mg, 0.59 mmol) in anhydrous toluene (1 .1 mL). After stirring at 0 °C for 2.5 h, a colorless suspension was formed, which dissolved upon addition of cold (0 °C) MeOH (10 mL). The clear solution was kept in freezer (-18 °C) for 15 min whereupon precipitate was formed. Filtration and drying in vacuo afforded 1 d as colorless crystals, 160 mg (86% yield).
1 H-NMR (400 MHz, CDCI 3 ) δ 3.47 (s, 1 H), 2.28-2.16 (m, 8H), 2.03- 1 .95 (m, 4H), 1 .83-1 .48 (m, 20H), 1 .41 -1 .13 (m, 29H), -14.24 (t, 1 H, J=7.4). 13 C-NMR (1 00 MHz, CDCI 3 ) δ 34.7 (t, J C-P =8.3 Hz), 33.5 (t, J c-P = 9.2 Hz), 31 .7 (t, JC-P=2.3 Hz), 30.7 (t, J C-P =2.9 Hz), 29.1 , 27.3 (t, J C-P =6.3 Hz), 27.1 (t, JC-P=4.8 Hz), 26.3.
31 P-NMR (400 MHz, CDCI 3 ) δ 53.71 .
Anal. Calcd for C 3 2H63BrP 2 Pd: C 55.21 , H, 9.12. Found C 55.01 , H 9.43
Example 5. (PCy 3 ) 2 Pd(H)(CI) as catalyst in the synthesis of 2,4,6,2'- tetramethyl-biphenyl in Suzuki-Miyaura reaction.
An oven dried reaction flask with screw cap containing a magnetic stir bar was placed in a„glove box" and charged with 2-fluorophenylboronic acid (46 mg, 0.33 mmol, 1 .1 eq), (PCy 3 ) 2 Pd(H)(CI) catalyst (10.5 mg, 0.015 mmol, 0.05 eq), and CsF (137 mg, 0.9 mmol, 3eq; CsF is highly moisture sensitive). Flask was closed with septa, removed from„glove box" and dry degassed 1 ,4-dioxane (3 ml_) and 2-chloromesitylene (44 μΙ_, 0.3 mmol, 1 eq) were added by syringe. Septum was replaced with screw cap and reaction mixture was heated in oil bath at 100 °C for 16 h. The mixture was then diluted with EtOAc (5 ml_) and filtered trough a Celite pad (20x20mm), which was washed with EtOAc (3x5ml). Filtrate was dried over Na 2 SO 4 and filtered through a plug of silica (20x20mm). The silica plug was washed with EtOAc (3x5ml), evaporated and dried in vacuo, yielding the product as colorless oil: run 1 :58 mg (90%), run 2: 59 mg (92%).
1H NMR (400 MHz, CDCIs) 5 7.37 - 7.30 (m, 1 H), 7.22 - 7.10 (m, 3H),
6.96 (s, 2H), 2.34 (s, 3H), 2.03 (s, 6H).
Example 6. (PCy 3 ) 2 Pd(H)(CI) as catalyst in the synthesis of 3-(2,4,6-trimethyl- phenyl)-pyridine in Suzuki-Miyaura reaction.
100°C, 6h
3-Pyridineboronic acid (43 mg, 0.35 mnnol, 1 .1 eq) and
(PCy 3 ) 2 Pd(H)(CI) (1 1 .3 mg, 0.016 mmol, 0.05 eq) were added to a reaction flask equipped with a stir bar. The flask was closed with septa and flushed with argon. 1 ,4-Dioxane (2 mL), 2-chloromesitylene (48 μί, 0.32 mmol, 1 eq) and aqueous K 3 PO 4 (0.54M, 1 mL, 1 .7 eq) were added by syringe. Septum was replaced by a screw cap and the flask was heated in an oil bath at 100 °C for 6 h. The mixture was then diluted with EtOAc (5 mL) and filtered trough a Celite pad (20x20mm). The Celite pad was washed with EtOAc (3x5mL). Filtrate was dried over Na2SO 4 and filtered through a plug of silica (20x20mm). The silica plug was washed with EtOAc (3x5mL), concentrated and dried in vacuo. The residue is colorless oil which crystallized upon standing: run 1 :57 mg (91 %), run 2: 58 mg (92%), run 3:59 mg (94 %).
H NMR (400 MHz, CDCI 3 ) δ 8.60 (dd, J = 4.8, 1 .7 Hz, 1 H), 8.44 - 8.43
(m, 1 H), 7.50 (dt, J = 7.7, 1 .9 Hz, 1 H), 7.36 (dd, J = 7.7, 4.9 Hz, 1 H), 6.97 (s 2H), 2.34 (s, 3H), 2.01 (s, 6H).