Pyridine. Suzuki reactions

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... 

Pyridine-containing tricyclic compounds have been produced via a sequence consisting of a Suzuki reaction and a subsequent annulation. Gronowitz et al. coupled 2-formylthienyl-3-boronic acid with 3-amino-4-iodopyridine. The resulting adduct spontaneously condensed to yield thieno[2,3-c]-l,7-naphthyridine 59 [47]. They also synthesized thieno[3,4-c]-l,5-naphthyridine-9-oxide (60) in a similar fashion [48]. Neither the amino nor the N-oxide functional group was detrimental to the Suzuki reactions. 

In a sequence analogous to the Suzuki reaction and annulation described in section 4.2.4, pyridine-containing tricyclic compounds have also been prepared via the Stille reaction and a ... 

Chloro-P-carboline (25) has served as a common intermediate in palladium-catalyzed cross-coupling reactions, offering easy access to several pyridine alkaloids. In Bracher s total synthesis of perlolyrine (27), a P-carboline alkaloid, the Suzuki reaction of 25 with 5-formylfuranyl-2-boronic acid (26) formed the C-C bond between the pyridine and the furan rings <92LA1315>. Reduction of the resulting Suzuki adduct with NaBIL subsequently... 

In a sequence analogous to the Suzuki reaction and annulation described in section 4.2.4, pyridine-containing tricyclic compounds have also been prepared via the Stille reaction and a subsequent annulation [80, 81]. For instance, benzo[c]-2,7-naphthyridine 94 was assembled from the adduct of 3-formyl-4-(trimethylstannyl)pyridine (93) and 2-bromo-4-methoxyacetanilide. The reaction was facilitated by addition of CuO as the co-catalyst. 

Isomeric thienonaphthyridines were synthesized using the Suzuki reaction. For example, 2-formyl-3-thiopheneboronic acid (200) with aminopyridines 201 and 202 produced thieno[2,3-c][l,7]naphthyridine (203) and thieno[2,3-c][l,8]naphthyridine (204) (1994JHC11). This method was also used to synthesize (1993H245) isomeric A-oxides 205 and 206 from pyridine A-oxides 207 and 208, respectively. 

The tricyclic skeleton of thieno[3,2-c][l,5]naphthyridine 9-7V-oxidc (263) was constructed (1993H245) in two ways by condensation of aldehyde 256 with pyridine /V-oxide 207 or (in lower yield) by the modified Suzuki reaction of the latter with 3-formylthiophene-2-boronic acid (264). 

While oxidation of the benzenediboronic acids with alkaline hydrogen peroxide affords the corresponding 1,3- and 1,4-dihydroxybenzenes (70-72%), the pyridinediboronic acids lead via a double Pd(0) catalyzed Suzuki reaction with 4-iodoanisole to 2,5- and 2,6-Z /s-(4-methoxyphenyl)pyridines (Sch. 36) [107]. 

More recently, Chiu and coworkers have developed a Ni complex containing a tetradentate pyridine/NHC ligand (complex 18, Eq. 22) which catalyzes the Suzuki reaction at catalyst loadings between 1 and 3 mol% [56]. Aryl iodides, bromides, and chlorides with both electron-rich and -poor aryl rings were compatible. However, electronically poor or electronically neutral aryl bromides performed much better than did electron-rich aryl bromides. It was also found that the use of 2 equivalents of PPh3 was crucial to achieving high yields with aryl chlorides. 

N-Arylation of phenylpyrrolylmethanone 199 to afford A -aryl derivative 200 was performed in Suzuki reaction conditions using phenylboronic acid, Cu(ii) acetate, and pyridine (Scheme 43) <2005JME5140>. The best yields were obtained in the presence of A -methylpyrrolidone (NMP) by microwave-assisted heating (60 W, 120 °C, 3 x 50 s). Reduction of methanone 200 with LiAlH4 gave methanols 201, which were then treated with GDI to afford imidazoles 202, potent anti-Candida agents. 

NMR experiments on the reactions of halophosphates esters with pyridine showed that equilibria involving the formation of pyridinium salts in these reactions are almost entirely shifted to the left for chloro- and bromo-phosphates and to the right for the corresponding iodophosphates. This explains dramatic differences in chemical reactivity between these compounds. Substituted medium-sized and large N-heterocycles (117) have been prepared via an extension of the Suzuki reaction involving the palladium-catalysed coupling of vinyl-phosphates (118) with aryl or heteroaryl boronic acids (Scheme 27). ... 

Salen ligands have found utility in a number of synthetically useful reactions. Pyridine modified salicylaldehydes 212 have been prepared by the hydrolysis of 211, the product of a Suzuki reaction of 209 with 210 [75]... 

Figure 4.8 graphically illustrates the result of a simple keyword search of SciFinder using the name reactions and pyridine. The pubhcation frequency shows the dramatic increase in use of these cross-coupling reactions over the past 10 years. In particular, the Sonogashira and the Suzuki reactions have experienced a geometric increase in use. 

Bromoquinolines behave in the Suzuki reaction similarly to simple carbocyclic aryl bromides and the reaction is straightforward. Examples include 3-(3-pyridyl)-quinoline 80 from 3-bromoquinoline 58 and 3-pyridylboronic acid 79 [36] and 3-phenyl-quinoline 83 from substituted 3,7-dibromoquinoline 81 and (2-pivaloylaniinophenyl)boronic acid 82 [37]. Notice that the combination of potassium carbonate and ethanol resulted in debromination at the C(7) position (but the combination of sodium carbonate and methanol left the C(7) bromide intact). It was speculated that the debromination arose from a second palladium insertion, followed by hydrolysis of the intermediate. Further manipulations of biaryl 83 delivered an interesting ll//-indolo[3,2-c]quinoline 84. The result is particularly intriguing since the cyclization of the azide is regioselective which is not usually the case in the pyridine series [38]. 

Femtodez and co-workers have also reported Suzuki reactions of resin bound pyridine. However in this case, the pyridine is immobilized via an amide bond of a nicotinic ester <05TL581>. Similarly, Schell et al. utilize resin bound nicotinic carboximidamides as a key intermediate in the synthesis of pyrido[2,3- flpyrimidin-4-ones <05JCO96>. 

Castanet and his team demonstrated a palladium-catalyzed carbonylative Suzuki reaction of pyridine halides in 2001. Under their conditions, pyridine halides reacted with aryl boronic acids to 2-pyridyl ketones in good yields (81-95 % Scheme 4.8). The proper choice of solvent, catalyst precursor, and CO pressure enabled the selective transformation of mono- and dihalopyridines. Later on, they... 

Suzuki reactions were carried out at C-8 in the pyridine ring of pyr-ido[3, 2 4,5]thieno[3,2-(/]pyrimidin-4-amines (Scheme 40) (13TL1160). This work provides access to a number of arylated pyrido[3, 2 4,5]... 

However, compound 22 showed poor oral bioavailability (f =3%). Our efforts to identify compounds with good oral bioavailability by systematically varying the substitution pattern on the pyridine ring led to the discovery of Cg-aryl derivatives that, in general, had excellent potency and oral bioavailability. The synthesis of Cg-aryl derivatives was carried out by Suzuki reaction of the corresponding triflate or bromide (Figiu-e 19.7). From this subseries, compound 24 was identified as the first recommended development candidate that met all the development criteria [7]. 

An efficient microwave-assisted Suzuki reaction using a new pyridine-pyrazole/ Pd (II) species as catalyst in aqueous media was reported by Shen et al. (2013). 

Later, fireflv oxyluciferin was successfully synthesi2ed (403. 408) and has been isolated and identified in firefly lanterns (luciola cruaciata) after the lanterns were treated with pyridine and acetic anhydride to prevent decomposition (409). In 1972, Suzuki and Goto firmly established that oxyluciferin is involved in the bioluminescence of firefly lanterns and in the chemiluminescence of firefly luciferin (403. 410).. A. mechanism involving a four-membered ring cyclic peroxide has been proposed for the reaction (406. 411). However, it was not confirmed by 0 -labelinE experiments (412). 

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