Biphenyl-2-carboxamides

A mixture of polyphosphoric acid and nitromethane converts fluorenone into phenanthridone at 250°. The reaction probably proceeds via the oxime, which can be isolated when the reaction is carried out at 190°.107 The same conversion can be achieved, though in lower yield, by the action of sodamide on fluorenone in liquid ammonia or (-butylamine. In this reaction biphenyl-2-carboxamide (isolated in 5% yield) is probably a precursor of phenanthridone, since the conversion of the amide to the latter in 40% yield has been demonstrated in a second experiment. The major product of the reaction with fluorenone in liquid ammonia is, not surprisingly, fluorenimine.108... 

Although oral conivaptan, [l,l -biphenyl]-2-carboxamide, A-[4-[(4,5-dihydro-2-methylimi-dazo[4,5-d][l]benzazepm-6(lH)-yl)carbonyl] phenyl] monohydrochloride, was efficacious, drug development has been discontinued because of significant inhibition of CYP3A4. 

Two relevant examples for categories A and D are presented (Schemes 26.9 and 26.10). Reaction of A,A-diethyl 2-biphenyl carboxamide 39 with i-BuLi/TMEDA (1.1 equiv) at-78°C followed by the addition of an electrophile affords C3-substituted derivatives 40 (DoM process, CIPE mechanism). In contrast, cyclization to give fluorenone 45 occurs with EDA at 0°C-rt (84%, DreM process) [ 1 34]. When an excess of LDA (4 equiv) and TMSCl (4 equiv) are premixed in THE at -78°C prior to addition of A,A-diethyl 2-biphenyl carboxamide 39 (ISQ conditions), the 3-trimethylsilyl derivative 42 is formed exclusively (65%). 

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... 

Fluorenone derived linker 17 prepared in two steps was coupled to aminomethyl-PS via DIPCDI [21]. Due to the presence of an electron-withdrawing carboxamide group, the release of carboxylic acids from this support requires strong acids, such as trifluoromethanesulfonic acid (TFMSA) (Scheme 1). Insertion of an oxygen adjacent to the biphenyl rings to the fluorenone scaffold provides xanthene 18 handle [22]. The oxygen is strategically located to decrease the acid concentration required... 

Naphthalenes biphenyls.3 The reaction of 1,3-diphenylacetone (1) with DMF dimethyl acetal at 110° affords the bisenamine 2 when conducted at 180° the reaction results in a naphthalene derivative (3) (equation I). This synthesis of naphthalenes is general and yields are usually 50-90%. The same reaction when applied to 4 results in a 4-methoxybiphenyl derivative (5) (equation II). When the carbonyl group in 1 is labeled with 13C, it can be identified as the carboxyl group in the carboxamide 3. Thus an extensive rearrangement is involved. 

Mutlib, A. et al., Formation of unusual glutamate conjugates of l-[3-(aminomethyl) phenyl]-/V-[3-fluoro-2 -(methylsulfonyl)-[l,l -biphenyl]-4-yl]-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (DPC 423) and its analogs the role of gamma-glutamyltrans-peptidase in the biotransformation of benzylamines, Drug Metab. Dispos., 29 (10), 1296, 2001. 

Upon heating in Dowtherm [a mixture of biphenyl (26.5%) and diphenyl ether (73.5%)], some 4-(acylamino)pyrimidine-5-carboxamides 3 furnish 2-substituted pyrimido[4,5-cf]pyrimidin-4-ols 4.118... 

Widenhoefer and Han have reported an effective protocol for the intramolecular hydroamination of unactivated C=C bonds with carbamates [52]. As an example of this protocol, treatment of the N-y-alkenyl carbamate 76 with a catalytic 1 1 mixture of [P(f-Bu)2(o-biphenyl)]AuCl and AgOTf (5 mol%) in dioxane at 60 C for 22 h formed pyrrolidine 77 in 91% isolated yield as a 3.6 1 mixture of diastereomers (Eq. (11.43)). The protocol tolerated substitution at the internal olefinic carbon atom and along the alkyl backbone and the method was applied to the synthesis of both heterobicyclic compounds and piperidine derivatives. This protocol was subsequently expanded to include the intramolecular hydroamination of N-alkenyl carboxamides including 2-allyl aniline derivatives (Eq. (11.44)) [53]. 

C-H-Oleflnation. Pd(II)-mediated aromatic C(sp2)-H olefi-nation occurs via a tandem reaction with tosylamide as directing group and bond formation partner (eq 12). The reaction tolerates different substituents at the phenyl ring such as methyl, methoxy, bromine, fluorine, trifluoromethyl and biphenyl with yields from 64% to 87%. Further, instead of CO Bu aliphatic esters as well as carbonyl, carboxamide, halogens, and aryl substitutents are suitable substrates. ... 

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