Search

By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.

Under catalyst-free reaction conditions, solvent-mediated addition of thiol 2 to β-nitrostyrene 1 proceeded with regioselective control to afford either adduct 3 or vinyl sulfide 4 in good to excellent yield. Thermodynamic and autocatalytic reaction mechanisms were proposed to rationalize the products thus formed.

Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.

A mild and efficient process for the 1,4-addition of thiols and benzeneselenols to various α,β-unsaturated ketones using a catalytic amount of CAN with excellent product yields is described. This inexpensive, nontoxic, and readily available catalytic ceric(IV) ammonium nitrate system efficiently catalyzes conjugate addition reactions between thiol derivatives and various α,β-unsaturated ketones under solvent-free conditions. A plausible mechanism for the role of CAN, both as a promoter in free radical chain addition reactions as well as a catalyst for the conjugate addition process is proposed.

The 1,4-addition of various thiols to α,β-unsaturated ketones was completed rapidly in the presence of a catalytic amount (2–3 mol %) of anhydrous iron(III) chloride under solvent free conditions and an air atmosphere. Anhydrous iron(III) chloride is more active than that of other ferric salts. With more reactive and/or less steric reagents ( 1a – c and/or 2a – 2c ), expeditious conditions (short reaction times at room temperature) could be employed. With less reactive and/or steric reagents ( 1d – g and/or 2d – e ), a slight increase in reaction time was required, but high yields were obtained. The FeCl 3 catalyst causes preferential interactions with α,β-unsaturated ketones present in the reaction.

We have described herein molecular iodine catalyzed Michael addition of thiol to α,β-unsaturated carboxylic acids. This environmentally benign catalytic system (iodine) used under mild and solvent-free conditions to achieve the corresponding adducts in excellent yield.

A simple and efficient method for the Michael reaction between various mercaptans and α,β-unsaturated ketones using a catalytic amount of iodine (5 mol %) to generate the 1,4-adduct has been reported. The significant features of the iodine catalyzed Michael addition are (a) operational simplicity, (b) inexpensive reagents, (c) high yields of products, (d) the use of relatively low or nontoxic reagents and (e) solvent-free conditions.

Reactions of (E)-beta-nitrostyrenes 1 and triethylborane 2 or tricyclohexylborane 4 in THF solution at room temperature in the presence of oxygen in the air as radical initiator generate high yields of trans-alkenes (E)-3 or (E)-5. Medium to high yields of different (E)-alkenes (E)-5, 7, 10, 12, and 14 also can be prepared when 1 reacts with different radicals, prepared from secondary alkyl iodides 6 and 8 or tertiary alkyl iodides 9, 11, and 13, in the presence of 2 and air as radical initiator. The generation of the only product (E)-alkenes can be explained by the generation of the benzylic radical A and/or B as the intermediate only and the mechanism is similar to Scheme 1. Both (E)- and (Z)-16a-c are generated when (E)- and (Z)-15a-c are used to react with adamantyl radical under similar conditions. Only (Z)-16d was observed when either (E)- or (Z)-15d was used to react with adamantyl radical. The generation of the (E)- and/or (Z)-alkenes can be explained by the free rotation of the A and/or B to generate A' and/or B' and vice versa, and the mechanism is proposed to be a free-radical reaction via NO2/alkyl substitution and is shown as Scheme 2.

β-Nitrostyrenes 1 react with triethylaluminium or diethylaluminium chloride in diethyl ether solution and under nitrogen or argon to generate the alkenes 2 and the hydroximoyl chlorides 3 after work-up with ice-cold, conc. hydrochloric acid. The formation of the alkenes 2 is proposed to be a free-radical reaction via NO2/alkyl substitution since the yields of the alkenes 2 are increased in the presence of benzoyl peroxide (Bz2O2) and decreased in the presence of galvinoxyl. Only the alkenes 2 are produced with a high stereoselectivity for the E isomers when β-nitrostyrenes react with triethylaluminium in the presence of one to two equivalents of Bz2O2 as free-radical initiator. The mechanism of the generation of the hydroximoyl chlorides 3 is proposed to proceed through a 1,4-addition pathway to produce nitronates A, then the protonated nitronates B or the nitroso cations C are trapped by chloride ion to form the final products. The yields of compounds 3 are also improved by the presence of Lewis acids such as MgCl2. Medium to high yields of the hydroximoyl chlorides 3 and traces or low yields of the alkenes 2 are generated when triethylaluminium or diethylaluminium chloride react with β-nitrostyrenes in the presence of three equivalents of MgCl2 under argon.

An operationally simple and high-yielding procedure has been developed for the conversion of primary amides to the corresponding nitriles, using ethyl dichlorophosphate/DBU as the mild dehydrating agent.

The β-nitrostyrenes 1 or 2 react with Grignard or organolithium reagents in ether or THF solution to generate by 1,4-addition the intermediate nitronates A . When A is treated with dilute hydrochloric acid, high yields of the nitroalkanes 3 (and oximes 4 ) or 5 are obtained. Hydroximoyl halides 6, 8 or nitrile oxides 7 can be isolated when the intermediate A is slowly added to the ice cold concentrated hydrohalic acid. The same products 6 and/or 7 are observed if the nitronates, generated from the substrate 1a , are added to 85% aqueous H 2 SO 4 but only the hydrolyzed carboxylic acids 9 are generated when the β-nitrostyrenes 2 are reacted with Grignard reagents and worked up under the same condition. The nitrile oxides 7 can undergo 1,3-dipolar cycloaddition with alkenes or alkynes to generate 2-isoxazolines or isoxazoles. A one-pot synthesis of the [n,3,0] bicyclic (n = 3 or 4) compounds 23–27 by intramolecular nitrile oxide-olefin cycloadditions is reported.

The N-N ligands of PhHC(3,5-Me 2 Pz) 2 , H 2 C(3,5-Me 2 ;4-BzPz) 2 , H 2 C(3- t BuPz) 2 and H 2 C(3(5)-PhPz) 2 wsere prepared readily from PhHCCl 2 or CH 2 Cl 2 by the same procedure as for H 2 C(3,5-Me 2 Pz) 2 (Pz = pyrazol-1-yl). Subsequent reactions with either [Mo(pip) 2 (CO) 4 ] (pip = piperidine) or [Mo(CO) 6 ], however, gave only [MoPhHC(3,5-Me 2 Pz) 2 (CO) 4 ] ( 1 ), [MoH 2 C(3-PhPz)(5-PhPz)(CO) 4 ] ( 2 ) and [MoH 2 C(3,5-Me 2 ;4-BzPz) 2 (CO) 4 ] ( 3 ). The structural characteristics of 1–3 , [WH 2 C(3,4,5-Me 3 Pz) 2 (CO) 4 ], [WH 2 C(3,5-Me 2 Pz) 2 (CO) 4 ] and [MoH 2 C(3,5-Me 2 Pz) 2 (CO) 4 ], reported previously, suggest firstly that the presence of a bulky substituent such as a phenyl or tert-butyl group at the pyrazolyl skeleton may afford strong nonbonded interaction in [MO(N-N)(CO) 4 ] and inhibit the formation of the stable complexes, [MoH 2 C(3- t BuPz) 2 (CO) 4 ] or [Mo(H 2 C(3-PhPz) 2 (CO) 4 ] and secondly, that the phenyl substituent at the carbon end of the six-membered boat metallacyle, formed by the N-N ligand and the central metal atom, is cis to the most distorted carbonyl in 1 . This explains the facile formation of the η 2 -arene compound, [MoPhHC(3,5-Me 2 Pz) 2 (CO) 3 ] as well as the regiospecific formation of [MoPhHC(3,5-Me 2 Pz) 2 (CO) 2 (η 3 -allyl)(Br)]. 1 , monoclinic, P 2 1 / n , a = 9.718(2), b = 14.198(4), c = 16.076(4) A, β = 96.62(2), Z = 4, R = 0.034, R w = 0.037, based on 2538 reflections with I ⪢ 3σ( I ); 2 , monoclinic, P 2 1 / n , a = 18.093(12), b = 13.138(4), c = 18.745(6) A, β = 98.79(6), Z = 8, R = 0.040, R w = 0.031, based on 4465 reflections with I ⪢ 2σ( I ); and 3 , orthorhombic, Pbca , a = 12.2387(18), b = 22.525(4), c = 20.028(5) A, Z = 8, R = 0.035, R w = 0.032, based on 2095 reflections with I ⪢ 2σ( I ).

The 1′,1‴-diacetyl and 1′-acetyl-1‴-(1-naphthylimino-ethyl)substituted biferrocenes, CH3COFcFcCOCH3 (1) and CH3COFcFcC(CH3)Nnp (2), where Fc = C5H4FeC5H4 and np = 1-naphthyl, and the corresponding monocations as salts with I3−, I5−, FeCl4− and CuI2− have been prepared. The crystal structures of 1 and 2 have been determined. The temperature-dependent Mossbauer spectra of the biferrocenium salts with the exception of the I3− salt from 2 revealed them all to be of the mixed-valence type. The interaction between counter anions and the biferrocenium cations is discussed.

Reaction of [MO(pip) 2 (CO) 4 ] (pip=piperidine) with (S, S) − in acetonitrile gives readily [Moη 2 -(S, S)(CO) 4 ] − , isolated as [PPN][Mo(η 2 -(S, S))(CO) 4 ] (PPN + = bis(triphenylphosphine)iminium; (S, S) − = pyrrolidine- ( 1 ) or piperidine-1-carbodithioato ( 2 )). The two compounds have been characterized by elemental analysis, IR, nuclear magnetic resonance and X-ray crystallography. 1 : monoclinic, P 2 1 / n ; a = 16.207(5), b = 12.804(3) A, c = 20.398(4) A; β = 91.02(2)°; V = 4232(2) A 3 , Z = 4; R = 0.034, R w = 0.037 based on 4989 reflections with I > 3.0σ( I ). 2 : monoclinic, P 2 1 / n ; a = 14.148(4) A, b = 13.646(5) A, c = 22.535(8) A; β = 95.92(3)°; V = 4327(3) A 3 , Z = 4; R = 0.054, R w = 0.041 based on 2048 reflections with I > 2.0σ( I ). No appreciably modified ligand structure is found in response to the different p K a of the amine used to form the specific (S, S) − in the compounds. This feature is rationalized by the electron-withdrawing effect of the metal carbonyl fragment, leading to the observed similarity in both the CO stretching and the MoCO distances.

Compounds [M(H2CAz2)(CO)4] (M  Cr, Mo, or W), were obtained readily and similarly by refluxing the equivalent amounts of N,N′-di(azol-1-yl)methanes, H2CAz2 (Az = pyrazol-1-yl (Pz), 3,5-dimethylpyrazol-1-yl (Pz′) or 3,4,5-trimethylpyrazol-1-yl (Pz″) with [M(CO)6] (M  Cr, Mo, or W) in a mixed solvent system of 1,2-dimethoxyethane and tetrahydrofuran. Under phase transfer catalysis conditions this gives rise to the new nitrogen-bidentate ligand, H2CPz2″, by reaction of HPz″ with methylene chloride. IR absorption bands in the carbonyl region indicate that no regular trends can be found for different substituents on the pyrazolyl ring. This irregularity is attributed to flexibility of the boat conformation formed from the metal centre and the ligand, which is supported by comparative structure details of [Mo(H2CPz2′)(CO)4], reported previously, [W(H2CPz2″)(CO)4] (6) and [W(H2CPz2′)(CO)4] (7): 6, triclinic, P1, a = 8.403(3), b = 9.589(3), c = 13.310(3) A, α = 94.476(22), β = 102.837(21), γ = 110.355 (25)°, Z = 2, R = 0.024, Rw = 0.023, based on 3070 with I > 2σ (I). 7, monoclinic, P21/c, a = 9.178(3), b = 15.885(9), c = 12.394(10) A, β = 108.64(9)°, Z = 4, R = 0.030, Rw = 0.030, based on 2625 reflections with I > 2.5σ(I).

The melt reaction between 1-H-1,2,4-triazole (HTz) and NaBPh4 affords Na(PhBTz3) while a similar process between HTz and KBH4 gives K(HBTz3). The uninegative L anion (L  PhBTz3 or HBTz3) reacts with [Mo(CO)6] to give [MoL(CO)3]-. Upon addition of electrophiles, [MoL(CO)2(η3-allyl)], [MoL (CO)2(NO)], [MoL(CO)3Br], and [MoL(CO)3I] are obtained. Two structures have been characterized by X-ray crystallography: [NEt4][Mo(HBPz3)(CO)3], orthorhombic, Pbca, a = 15.832(3), b = 15.799(4), c = 19.388(5) A, Z = 8, R = 0.043, Rw = 0.031 based on 2591 reflections with I > 3.0σ(I; [N(PPh3)2][Mo(HBTz 3)(CO)3], orthorhombic, Pbca, a = 17.815(3), b = 32.017(2), c = 15.331(3) A, Z = 8, R = 0.044, Rw = 0.061 based on 5743 reflections with I > 2.0σ(I). Although comparison of the averaged ν(CO) values reveals the increasing order of the electron donativity as HBBz3− < HBTz3−, PhBTz3− < HBPz′3−, < HBPzp3−, < HBPz′3−, neither structural features nor reactivit ies show an appreciable substituent effect (i.e. HBTz3− vs. HBPz3− and HBTz3− vs. PhBTz3−). Neither is the 5-methyl-group effect for nickel pseudohalides suggested by Trofimenko et al. supported strongly by the solid-state structures of [MoL′(CO)3]− (L′ = HBPz3−, HBPz′3−, or HBPz3−; Pz′ =3,5-dimethylpyrazol-1-yl; Pz = 3-methylpyrazol-1-yl).

The coordination chemistry of a tripodal phosphine thioether, 2,2-bis(diphenylphosphinomethyl)-1-phenylthiopropane (P 2 S), towards Fe II , Ni II , Pd II , Pt II , Co II , Rh I was investigated. The ligand reacts with CpFe(CO) 2 I, NiCl 2 , PdCl 2 (CH 3 CN) 2 , K 2 PtCl 4 , CoCl 2 ,[(NBD)RhCl] 2 and (NBD) 2 RhBF 4 [NBD = 2,5-norbornadiene] to give the respective complexes. The tripodal ligand behaves as tridentate in [( P,P′,S -P 2 S)FeCp]PF 6 and [( P,P′,S -P 2 S)Rh(NBD)]BF 4 , but as bidentate in the other complexes. Crystal structures of [ P,P′,S -(P 2 S)FeCp]PF 6 ( 2a ) and [ P,P′,S -(P 2 S)]NiI 2 ( 5 ) have been determined.

β-Nitrostyrenes 1 react with trialkylboranes under a nitrogen atmosphere to generate high yields of alkenes 2. The mechanism is proposed to be a free-radical reaction via NO2/alkyl substitution since the reaction is stimulated by the presence of a trace of oxygen in the nitrogen or tert-butyl peroxide or by photolysis and is retarded or inhibited by the addition of galvinoxyl to the solution.

Under catalyst-free reaction conditions, solvent-mediated addition of thiol 2 to β-nitrostyrene 1 proceeded with regioselective control to afford either adduct 3 or vinyl sulfide 4 in good to excellent yield. Thermodynamic and autocatalytic reaction mechanisms were proposed to rationalize the products thus formed.

Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.

Iodine mediates the hydroarylation of styrenes with arenes and heteroarenes to afford 1,1-diarylalkanes in good to high yields. Details regarding the substrate scope and selectivity of this hydroarylation reaction are discussed.