Cross-couplings reactions

Depending on the conditions, the ligand, the metal, the organic groups, and the main group metal the reaction can be very selective and fast. Numerous variations have been published. Not many kinetic studies have been carried out, or at least they have not been published. It is conceivable that all three reactions can be rate determining  

Suppose that the oxidative addition is the slowest reaction in the system. One can then minimise the occurrence of the un-catalysed reactions between the aryl halide and the Grignard reagent by keeping the concentration of the Grignard reagent very low. 

A very pure product is required. The palladium content may not exceed 10 ppm and the impurities should be below 0.1 %. Classical syntheses as the Ullmann reaction cannot be applied because they give a lot of by-products. 

Two steps are critical the cross-coupling itself, and making the Grignard of 4-bromoanisole. Zambon has spent 10 man-year on the optimisation of the cross-coupling reaction In the following we summarise the results. 

The Grignard is made from 4-bromoanisole, Mg (3 % excess), I2 catalyst, in tetrahydrofuran (3 M), at 70 °C. The major problem is the formation of the homo coupled product during the Grignard synthesis. Up to 6% of 4,4 -dimethoxybiphenyl may be formed. The amount depends on the type of 

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Transition Metal Catralyzed Cross-Coupling Reactions... 

One of the newer and more fmitful developments in this area is asymmetric hydroboration giving chiral organoboranes, which can be transformed into chiral carbon compounds of high optical purity. Other new directions focus on catalytic hydroboration, asymmetric aHylboration, cross-coupling reactions, and appHcations in biomedical research. This article gives an account of the most important aspects of the hydroboration reaction and transformations of its products. For more detail, monographs and reviews are available (1—13). 

Moderate yields of acids and ketones can be obtained by paHadium-cataly2ed carbonylation of boronic acids and by carbonylation cross-coupling reactions (272,320,321). In an alternative procedure for the carbonylation reaction, potassium trialkylborohydride ia the presence of a catalytic amount of the free borane is utilized (322). FiaaHy, various tertiary alcohols including hindered and polycycHc stmctures become readily available by oxidation of the organoborane iatermediate produced after migration of three alkyl groups (312,313,323). 

Alkyl- and aryl-pyridazines can be prepared by cross-coupling reactions between chloropyridazines and Grignard reagents in the presence of nickel-phosphine complexes as catalysts. Dichloro[l,2-bis(diphenylphosphino)propane]nickel is used for alkylation and dichloro[l,2-bis(diphenylphosphino)ethane]nickel for arylation (78CPB2550). 3-Alkynyl-pyridazines and their A-oxides are prepared from 3-chloropyridazines and their A-oxides and alkynes using a Pd(PPh3)Cl2-Cu complex and triethylamine (78H(9)1397). 

Cross-coupling reactions of aromatic or vinylic halides and olefins catalyzed by palladium. 

The preparation of perfluoroalkylzinc compounds has been achieved earlier 111 ethereal solvents [26] However, solvent effects play a significant role in the course of this reaction When a mixture of acetic anhydride and methylene chloride is used, coupled and cross-coupled products can be formed [27, 28] (equations 19 and 20) However, the cross-coupling reaction often gives mixtures, a fact that seriously restricts the synthetic applicability of this reaction [27, 28, 29]... 

These zinc reagents are useful precursors for stereocontrolled palladium-catalyzed cross-coupling reactions, as illustrated in equations 73-80 [100, 101, 102, 103, 104, 105, 106, 107, 108] This methodology has been used to prepare new fluorinated analogues of codlemone [I09. ... 

Trifluoromethylalion of aryl iodides was carried out by the fluoride ion in duced cross-coupling reaction of aromatic iodides with tnfluoromethyltnalkyl-silanes in the presence ofcopper(I) salts [219 (equation 147) Some pentafluoro- ethyl derivative was also formed This methodology was extended to pentafluoroethyl-and heptafluoropropyltriethylsilanes [2/9]... 

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

Heterocycles in metal-catalyzed cross-coupling reactions 98MI32. 

Catalytic cross-coupling reactions in synthesis of bihetarenes and arylhetarenes 98T263. 

F. Diederich and P. J. Stang (eds.), Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1998. 

They have also developed a route to 2-allenylindole derivatives (98T13929). When prop-2-ynyl carbonates (76) are reacted with 73 in the presence of palladium catalyst, a cross-coupling reaction occurs to give 77a (46%) and 77b (45%). Under a pressurized carbon monoxide atmosphere (10 atm), the palladium-catalyzed reaction of 73 with 78 provides 79a (60%) and 79b (60%) (2000H2201). In a similar reaction, when the substrate is changed to aryl halides (80), 2-aryl-1-methoxyindoles such as 81a (70%) and 81b (60%) are prepared (97H2309). 

Despite being activated by the nitrogen atom, 2-chloroquinoline (25) is still a poor substrate for the Stille cross-coupling reactions, though yields are usually improved under Negishi conditions. For instance, the coupling of... 

In one case, an unpurified sample of pyrrolyl-bisboronic ester 78, synthesized using conditions described by Masuda and coworkers (2000JOC164), was readily engaged in a Suzuki cross-coupling reaction (95JOC7508) with 5-bromoquinoline 77, giving the desilylated product 79 in 29% overall yield (2002JCS(Pl) 1320). 

Heck reaction, palladium-catalyzed cross-coupling reactions between organohalides or triflates with olefins (72JOC2320), can take place inter- or intra-molecularly. It is a powerful carbon-carbon bond forming reaction for the preparation of alkenyl- and aryl-substituted alkenes in which only a catalytic amount of a palladium(O) complex is required. 

In summary, palladium-mediated reactions, especially cross-coupling reactions have found many applications in quinoline synthesis. It is noteworthy that due to the a and S activation for the C(2) and C(4) positions, even 2-chloro- and 4-chloro-quinolines are viable substrates for palladium-catalyzed reactions under standard conditions. With the advent of the palladium chemistry and more commercially available organometallic substrates, more palladium-mediated quinoline syntheses are to be added to the repertoire of quinoline chemistry. 

Cross-coupling reactions between alkenylzirconocenes sucli as 133 and aryl or alkenyl iodides ocrur read dy in tlie presence of CuCl and PdiPPb ), producing tetrasLibstituted olelins sucli as 134 in good yields Sclieme 2.65) [141, 142]. 

Scheme 5.2-18 Pd-catalyzed Suzuki cross-coupling reaction in a [BMIM][BF4] ionic liquid.

Knochel et al. described Pd-catalyzed Negishi cross-coupling reactions between zinc organometallics and aryl iodides in [BMMlM][Bp4]. Scheme 5.2-20 illustrates the reaction for the formation of a 3-substituted cyclohexenone from 3-iodo-2-cyclo-hexen-l-one [82]. 

One of the first examples was the above mentioned work from Yoshino et al. [7] concerning the synthesis of poly(9,9-dialkylfluorene)s via oxidative coupling of fluorene derivatives. Poly(9,9-dialkylfluorene) derivatives have been also synthesized via Ni- and Pd-catalyzed aryl-aryl homo- and cross-coupling reactions of sui-... 

Z)-3-(Tributylstannyl)allylamine participates in a palladium-catalyzed cross-coupling reaction with 2-bromobenzaldehyde (73, R = H) to give 3//-2-benzazepine (75, R = H). A similar reaction with the corresponding acetophenone 73 (R = Me) produces 1 -methyl-3//-2-benzazepine (75 R = Me), whereas with ethyl 2-bromobenzoate (73, R = OMe), 3//-2-benzazepin-(12/7)-one (74) is formed.237... 

TABLE 3. Cross-coupling reaction of vinyl sulfones with Grignard reagents12 ... 

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