Reaction Suzuki

Suzuki reaction concerns the coupling of aryl or vinyl boronic acid with aryl or vinyl halide. Nitrile-functionalized pyridium ILs [C3CNPy][PF,5], [C3CNPy][BF4,  

The nitrile group in ILs can coordinate to the Pd NP surface and thus stabilize the Pd NPs and prevent its leaching. 

Carbene, for example 11, PdCl2 weakly active ptecatalyst 

Dominant V active species that enter catalytic cycle 

Alternatively a Mannich-like pathway may be followed (see Mannich reaction), where ammonia reacts with the aldehyde 1 to give an intermediate imininm species, that adds hydrogen cyanide to give the a-amino nitrile 2. The actnal mechanistic pathway followed depends on substrate structure and reaction conditions. 

The scope of the reaction depends on the availability of the starting aldehyde (or ketone). A drawback is the toxicity of the hydrogen cyanide used as reactant. A variant of the Strecker synthesis is the Bucherer-Bergs reaction it gives better yields, and proceeds via formation of an intermediate hydantoin 5  

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N—CH2—COOH and the corresponding amino acid from symmetrical ketones R—CO—R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well.  

Wieland, R. Muller, E. Niemann, L. Birkhofer, A. Schoberl, A. Wagner, H. Soil, Methoden Org. Chem. (Houben-Weyl), 1959, Vol. Xl/2, p. 305-306. 

-J-Altenbach In J. Mulzer, H.-J. Altenbach, M. Braun, K. Rrohn, H.-U. Reissig, Organic Synthesis Highlights, VCH, Weinheim, 1991, p. 300-305. 

A variant of the Strecker synthesis is the Bucherer-Bergs reaction it gives better yields, and proceeds via formation of an intermediate hydantoin 5  

The use of palladium catalyst in Suzuki reaction has been to be particular appealing for the formation of aromatic carbon- arbon bonds [63,64]. 

NiCl2(PCy3)2 associated with PCyj promotes the selective cross-coupling of aryl-tosylates with arylboronic acids under relatively mild conditions, and a variety of function groups are tolerated in both arenes [70]. It is particularly noteworthy that no reducing agent such as Zn is required in this reaction. More recently, room-temperature nickel-catalyzed Suzuki coupling reactions of arenesulfonates with arylboronic acids have been disclosed [71]. 

The Ni(0) catalyst, generated in situ from the reduction of NiCl2(PPh3)2) with BuLi, has been shown to be active for the Suzuki couplings of aryl chloride with boronic adds [72]. 

Nickel-catalyzed readion of 1,3-disubstituted allylic carbonates and lithium aryl- and alkenylborates provided a regio- and stereoselective route under mild conditions for the synthesis of the corresponding substitution products [75]. 

A catalytic system consisted of Ni(COD)2) and 1,3-bismesitylimidazole carbene ligand in the presence of CsF has been shown to catalyze Suzuki reaction of aryl trimethylammonium ion. Substituents such as ether, ester or fluoride on either eledrophiles or nudeophiles are stable under these conditions [76,77]. 

In addition to the well-known organic-phase transformations, the Suzuki reaction also offers methods for the crosscoupling of aryl halides with hydrophilic functional groups. These reactions therefore, require polar solvents such as water. El-Sayed s group prepared 3.6 0.73 nm PVP-stabilized palladium nanoparticles and showed them to act as efficient catalysts for the Suzuki crosscouplings as colloids 

El-Sayed s group also investigated the effect of three different stabilizers on the catalytic activity and stability of the Pd nanoparticles when catalyzing a Suzuki reaction in the aqueous phase [17]. Results showed that the Pd nanoparticles, when stabihzed by PVP, block copolymer and G3 dendrimer, were aU efficient catalysts. However, in the case of dendrimers, the strong encapsulation of Pd particles within the dendrimers resulted in a loss of catalytic activity. 

In another study, Gallon et al. used polyaniline (PANI) nanofiber-supported palladium nanoparticles as catalysts for the coupling of aryl chlorides with phenyl boronic acid in water [98]. Typically, the aryl chlorides were ineffective in most Suzuki coupling reactions but, by subshtuhng the aryl halide appropriately, it could be shown that Pd nanoparticles were capable of carrying out the transforma-hon in the aqueous phase. 

Other applications might involve the synthesis of substituted alkylarenes useful as liquid crystalline materials. Liquid crystalline materials often contain bi-aryls or cyclohexylaryls and these can also made via one of the coupling reactions discussed above. 

1 Trost, B. M. Verhoeven, T. R. Eds. Wilkinson, Able, Stone, Comprehensive Organometallic Chemistry, 1982, Vol. 8, 799. Tsuji, J. Takahashi, H. Morikawa, M. Tetrahedron Letters, 1965,4387. 

26 Giordano, C. Peniscola Meeting Cataluna Network on Homogeneous Catalysis, 1995. Giordano, C. Coppi, L. Minisci, F. (Zambon Group S.p.A.), Eur. Pat. Appl. 1992, EP 494419, Chem. Abstr. 1992,117,633603. 

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Vinylation can also be done by Pd-catalysed cross-coupling in which one component is used as a halide or triflate and the other as a stannane (Stille reaction) or boronic acid (Suzuki reaction). Entry 9, Table 11.3, is an example of the use of a vinylstannane with a haloindole. lndole-3-boronic acids, which can be prepared by mcrcuration/boration, undergo coupling with vinyl triflates (Entry 10). 

Bromoquinolines behave in the Suzuki reaction similarly to simple carbocyclic aryl bromides and the reaction is straightforward. Examples include 3-(3-pyridyl)quinoline (72) from 3-bromoquinoline (70) and 3-pyridylboronic acid (71) (91JOC6787) and 3-phenyl-quinoline 75 from substituted 3,7-dibromoquinoline 73 and (2-pivaloylaminophenyl)boronic acid 74 (95SC4011). Notice that the combination of potassium carbonate and ethanol resulted in debromination at the C(7) position (but the... 

Palladium-catalyzed carbon-carbon bond forming reactions like the Suzuki reac-tion as well as the Heck reaction and the Stille reaction, have in recent years gained increased importance in synthetic organic chemistry. In case of the Suzuki reaction, an organoboron compound—usually a boronic acid—is reacted with an aryl (or alkenyl, or alkynyl) halide in the presence of a palladium catalyst. 

The mechanism " of the Suzuki reaction is closely related to that of the Stille coupling reaction, and is also best described by a catalytic cycle ... 

Many types of functional groups are tolerated in a Suzuki reaction, and the yields are often good to very good. The presence of a base, e.g. sodium hydroxide or sodium/potassium carbonate, is essential for this reaction. The base is likely to be involved in more than one step of the catalytic cycle, at least in the transmetal-lation step. Proper choice of the base is important in order to obtain good results." In contrast to the Heck reaction and the Stille reaction, the Suzuki reaction does not work under neutral conditions. 

This method has been applied to a large-scale preparation of 6-bromoindole, which reacts with various arylboronic acids via the Suzuki reaction to afford 6-aryhndoles fEq. 10.50. 6-Bromo-5-methoxyindole for use in the synthesis of marine bromoindole " and 5-amino-7-ethoxycarbonyhndole for use in synthesis of l//-pyrrolo[3,2-g quina2ohne ring system fEq. 10.51 " have been prepared from the appropriate o-nitrotoluene. 

The utility of the Suzuki reaction in the challenging arena of natural product total synthesis has been explored. The constitution of bombykol (106) (see Scheme 26), a well-known pheromone, lends itself to a Suzuki coupling. Indeed, in a short stereospecific synthesis of 106, Suginome et al. demonstrated that ( )-vinylboronic acid ( )-104 can be smoothly cross-coupled with (Z)-l-pentenyl bromide [(Z)-105] 44 the configurations of both coupling partners are preserved in the C-C bond forming process. 

Figure 5.21 (a) Monomers and (b) polymers syntheses by Suzuki reaction. 

The Suzuki reaction was also used to prepare the polyketone since this particular reaction tolerates the subsequent step (Scheme 6.19).135 Palladium-catalyzed cross-coupling of aromatic diacid chlorides and bis(trimethylstannane) monomers was utilized to prepare poly(arylene ether ketone)s.136... 

Bromo-6,7-dichloro-2-quinoxalinamine (60, R = Br) gave 6,7-dichloro-3-phenyl-2-quinoxalinamine (60, R = Ph) by the Suzuki reaction [PhB(OH)a,... 

The Suzuki reaction has been successfully used to introduce new C - C bonds into 2-pyridones [75,83,84]. The use of microwave irradiation in transition-metal-catalyzed transformations is reported to decrease reaction times [52]. Still, there is, to our knowledge, only one example where a microwave-assisted Suzuki reaction has been performed on a quinolin-2(lH)-one or any other 2-pyridone containing heterocycle. Glasnov et al. described a Suzuki reaction of 4-chloro-quinolin-2(lff)-one with phenylboronic acid in presence of a palladium-catalyst under microwave irradiation (Scheme 13) [53]. After screening different conditions to improve the conversion and isolated yield of the desired aryl substituted quinolin-2( lff)-one 47, they found that a combination of palladium acetate and triphenylphosphine as catalyst (0.5 mol %), a 3 1 mixture of 1,2-dimethoxyethane (DME) and water as solvent, triethyl-amine as base, and irradiation for 30 min at 150 °C gave the best result. Crucial for the reaction was the temperature and the amount of water in the... 

The first microwave-assisted Suzuki reactions involving heteroaromatic skeletons were reported in 1996 [35]. Hallberg et al. Hnked the substrates 4-iodo and 4-bromobenzoic acid to a TentaGel-Rink resin (Scheme 16). Suzuki reactions on these soUd-phase-Unked substrates were easily performed in less than 4 min using a constant microwave irradiation power (45 W) (no temperature control Standard acidic cleavage with TEA yielded the corresponding biaryls with an excellent yield. 

Other types of HIV-1 protease inhibitors have also been prepared using microwave-promoted Suzuki reaction [37]. The symmetric cyclic sulfamide (3K,4S,5S,6it)-3,6-bis(phenoxymethyl)-2,7-bis[4-(2-thienyl)benzyl]-l,2,7-thi-adiazepane-4,5-diol 1,1-dioxide, for instance, was synthesized via cross-couphng of (3aS,4R,8it,8aS) - 5,7 - bis(4 - bromobenzyl) - 2,2 - dimethyl - 4,8 - bis-(phenoxymethyl) hexahydro [1,3] dioxolo [4,5 - d] [ 1,2,7 ] - thiadiazepine 6,6 - dioxide with 2-thienylboronic acid for 3 min at 45 W (Scheme 19). 

Solvent-free microwave-assisted Suzuki reaction on AI2O3 as soHd support using KF as base has also been described in the hterature by Villemin [38] (Scheme 20). Ligand-free Pd(OAc)2 was used as a precatalyst. In a reaction... 

Heteroarylphenylalanines could be smoothly obtained via microwave-promoted Suzuki reaction of heteroaryl halides with 2-amino-3-[4-(dihy-droxyboryl)phenyl]propanoic acid (Scheme 28) [46]. Interestingly, the free amino acid could be used without any protection of the amine and carboxylic acid fimctionahty. When 4-(dihydroxyboryl)-L-phenylalanine was used as organometallic partner no racemization was observed. The carboxylate anion and free amino group seem to shield the a-C - H from deprotonation and thus hmit racemization. 

Heteroarylboronic esters, useful as organometalUc partners in Suzuki reactions, have also been prepared under microwave irradiation by Fiirst-... 

AT-acetyltryptamines could be obtained via microwave-assisted transition-metal-catalyzed reactions on resin bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide. While acceptable reaction conditions for the application of microwave irradiation have been identified for Stille heteroaryla-tion reactions, the related Suzuki protocol on the same substrate gave poor results, since at a constant power of 60 W, no full conversion (50-60%) of resin-bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide could be obtained even when two consecutive cross-coupling reaction cycles (involving complete removal of reagents and by-products by washing off the resin) were used (Scheme 36). Also under conventional heating at 110 °C, and otherwise identical conditions, the Suzuki reactions proved to be difficult since two cross-coupling reaction cycles of 24 h had to be used to achieve full conversion. 

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

Organ et al. from York University demonstrated that a diarylated IH-pyrazole-based library, based on the structure of the potent COX II inhibitor Celecoxib [4-(3-trifluoromethyl-5-(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide], could be rapidly prepared using MAOS [59]. Microwave-accelerated Suzuki reaction on 4-(5-iodo-3-methyl-lH-pyrazol-l-yl)-benzenesulfonamide using heterogeneous Pd/C was the principal diversification step investigated (Scheme 41). The interest of the team in microwave... 

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