An efficient and convergent synthesis of the potent and selective H3 antagonist ABT-239

An efficient and convergent process for the preparation of a potent and selective H₃ receptor antagonist, ABT-239, 1A was accomplished with an overall yield of 64%. The key step in the synthesis is a Sonogashira coupling/cyclization reaction of 1-but-3-ynyl-2-(R)-methylpyrrolidine (9) with 4′-hydroxy-3′-iodo-biphenyl-4-carbonitrile (3). Additionally, the key amine component 2-(R)-methylpyrrolidine (7) was effectively synthesized from the readily available Boc-l-prolinol with a simple catalytical hydrogenolysis as the key step. This column chromatography-free process is highlighted by several simple work-up and purification procedures and is amendable to the large-scale preparation of 1A.     

Dimolybdenum complexes containing anions of N,N′-bis(pyrimidine-2-yl)formamidine and N-(2-pyrimidinyl)formamide

The reactions of Mo₂(O₂CCH₃)₄ with different equivalents of N,N′-bis(pyrimidine-2-yl)formamidine (HL1) and N-(2-pyrimidinyl)formamide (HL2) afforded dimolybdenum complexes of the types Mo₂(O₂CCH₃)(L1)₂(L2) (1) trans-Mo₂(L1)₂(L2)₂ (2) cis-Mo₂(L1)₂(L2)₂ (3) and Mo₂(L2)₄ (4). Their UV–Vis and NMR spectra have been recorded and their structures determined by X-ray crystallography. Complexes 2 and 3 establish the first pair of trans and cis forms of dimolybdenum complexes containing formamidinate ligands. The L1 ligands in 1–3 are bridged to the metal centers through two central amine nitrogen atoms, while the L2 ligands in 1–4 are bridged to the metal centers via one pyrimidyl nitrogen atom and the amine nitrogen atom. The Mo–Mo distances of complexes 1 [2.0951(17) Å], 2 [2.103(1) Å] and 3 [2.1017(3) Å], which contain both Mo?N and Mo?O axial interactions, are slightly longer than those of complex 4 [2.0826(12)–2.0866(10) Å] which has only Mo?O interactions.     

Nickel(II) and zinc(II) complexes of N-substituted di(2-picolyl)amine derivatives: Synthetic and structural studies

The interaction of di(2-picolyl)amine (1) and its secondary N-substituted derivatives, N-(4-pyridylmethyl)-di(2-picolyl)amine (2), N-(4-carboxymethyl-benzyl)-di(2-picolyl)amine (3), N-(4-carboxybenzyl)-di(2-picolyl)amine (4), N-(1-naphthylmethyl)-di(2-picolyl)amine (5), N-(9-anthracenylmethyl)-di(2-picolyl)amine (6), 1,4-bis[di(2-picolyl)aminomethyl]benzene (7), 1,3-bis[di(2-picolyl)aminomethyl]benzene (8) and 2,4,6-tris[di(2-picolyl)amino]triazine (9) with Ni(II) and/or Zn(II) nitrate has resulted in the isolation of [Ni(1)(NO₃)₂], [Ni(2)(NO₃)₂], [Ni(3)(NO₃)₂], [Ni(4)(NO₃)₂]·CH₃CN, [Ni(5)(NO₃)₂], [Ni(6)(NO₃)₂], [Ni₂(7)(NO₃)₄], [Ni₂(8)(NO₃)₄], [Ni₃(9)(NO₃)₆]·3H₂O, [Zn(3)(NO₃)₂]·0.5CH₃OH, [Zn(5)(NO₃)₂], [Zn(6)(NO₃)₂], [Zn(8)(NO₃)₂] and [Zn₂(9)(NO₃)₄]·0.5H₂O. X-ray structures of [Ni(4)(NO₃)₂]·CH₃CN, [Ni(6)(NO₃)₂] and [Zn(5)(NO₃)₂] have been obtained. Both nickel complexes exhibit related distorted octahedral coordination geometries in which 4 and 6 are tridentate and bound meridionally via their respective N₃-donor sets, with the remaining coordination positions in each complex occupied by a monodentate and a bidentate nitrato ligand. For [Ni(4)(NO₃)₂]·CH₃CN, intramolecular hydrogen bond interactions are present between the carboxylic OH group on one complex and the oxygen of a monodentate nitrate on an adjacent complex such that the complexes are linked in chains which are in turn crosslinked by intermolecular offset π-π stacking between pyridyl rings in adjacent chains. In the case of [Ni(6)(NO₃)₂], two weak CH?O hydrogen bonds are present between the axial methylene hydrogen atoms on one complex and the oxygen of a monodentate nitrate ligand on a second unit such that four hydrogen bonds link pairs of complexes; in addition, an extensive series of π-π stacking interactions link individual complex units throughout the crystal lattice. The X-ray structure of [Zn(5)(NO₃)₂] shows that the metal centre once again has a distorted six-coordinated geometry, with the N₃-donor set of N-(1-naphthylmethyl)-di(2-picolyl)amine (5) coordinating in a meridional fashion and the remaining coordination positions occupied by a monodentate and a bidentate nitrato ligand. The crystal lattice is stabilized by weak intermolecular interactions between oxygens on the bound nitrato ligands and aromatic CH hydrogens on adjacent complexes; intermolecular π-π stacking between aromatic rings is also present.     

Application of the Gould-Jacobs reaction to 4-amino-2,1,3-benzoselenadiazole

An effective method for the synthesis of 4-amino-2,1,3-benzoselenadiazole (4) has been described. Reduction of readily available 4-nitrobenzothiadiazole 6 with SnCl₂·2H₂O afforded 1,2,3-triaminobenzene dihydrochloride 2. The latter upon treatment with aqueous SeO₂ solution provided desired amine 4. Nucleophilic vinylic substitution of activated enol ethers 7 with amine 4 led to (benzoselenadiazol-4-ylamino)methylene derivatives 8. Thermal cyclization of derivatives 8a-c, e, f under Gould-Jacobs reaction conditions gave angularly annelated 7-(non)substituted selenadiazolo[3,4-h]quinolones 9. Acid hydrolysis of etyl ester 9c afforded corresponding acid 10. All prepared selenadiazoloquinolones were tested for antimicrobial activity.     

Synthesis of tridentate 2,6-bis(imino)pyridyl aminechlorohydro ruthenium(II) complexes: The convenient use of amine hydrochlorides to generate metal-hydride

The reaction of low-valent ruthenium complexes with 2,6-bis(imino)pyridine ligand, [η²-N₃]Ru(η⁶-Ar) (1) or {[N₃]Ru}₂(μ-N₂) (2) with amine hydrochlorides generates six-coordinate chlorohydro ruthenium (II) complexes with amine ligands, [N₃]Ru(H)(Cl)(amine) (4). Either complex 1 or 2 activates amine hydrochlorides 3, and the amines coordinate to the ruthenium center to give complex 4. This is a convenient and useful synthetic approach to form ruthenium complexes with amine and hydride ligands using amine hydrochloride.     

Synthesis, properties and complexation of (pS)-1-isocyano-2-methylferrocene, the first planar-chiral isocyanide ligand

Reaction of enantiomerically pure, planar-chiral (_pS)-1-bromo-2-methylferrocene (1) with phthalimide in the presence of Cu₂O produces (_pS)-1-phthalimido-2-methylferrocene (2), quantitative reduction of which with hydrazine hydrate affords (_pS)-1-amino-2-methylferrocene (3) with >99% ee. Formylation of amine 3 followed by dehydration of the resulting (_pS)-1-formamido-2-methylferrocene (4) provides (_pS)-1-isocyano-2-methylferrocene (5), the first example of a planar-chiral isocyanide ligand, in a good yield. Isocyanide 5 reacts with PdI₂ to give the crystallographically characterized chiral complex trans-[PdI₂{(_pS)-1-isocyano-2-methylferrocene}₂] (6). The redox behavior of 4, 5, and 6, accessed by cyclic voltammetry, is discussed.     

Bismuth(III) bis(trifluoromethanesulfonyl)amide

Bismuth(III) bis(trifluoromethanesulfonyl)amide (Bi(NTf₂)₃, 3) has been prepared from the reaction of protiodemetallation of tri-p-tolylbismuth by a stoichiometric amount of bis(trifluoromethanesulfonyl)amine (1). The intermediates BiPh_3−n(NTf₂)_n (n=2 (4), 1 (5)) resulting from the reaction of 1 with triphenylbismuth have also been isolated. The amide 3 was able to catalyze the benzoylation and the benzenesulfonylation of toluene.     

Synthesis of aromatic tetracyclic tin compounds by template and transmetallation reactions: Alkyl vs aryl migration from tin to nitrogen

The syntheses of [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]diphenyltin (1) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]dichloro-phenyl-stannate (2) by template reactions using 3,5-di-tert-butylcatechol, aqueous ammonia and SnPh₂Cl₂ are reported. We also report the syntheses of compounds 2, [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]trichloro-stannate (4), [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)methylamine]chloro-methyltin (5), and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)-n-butylamine]n-butyl-chlorotin (6) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]n-butyl-dichloro-stannate (7), performed by transmetallation reactions of the octahedral zinc coordination compound Zn[3,5-di-tert-butyl-1,2-quinone-(3,5-di-tert-butyl-2-hydroxy-1-phenyl)imine]₂ (3) with SnPhCl₃ or SnPh₂Cl₂, SnCl₄, SnMe₂Cl₂, Sn(nBu)₂Cl₂ and Sn(nBu)Cl₃, respectively. The X-ray diffraction structures of compounds 1, 2, 4 and 6 are reported. The transmetallation reactions with Sn(alkyl)₂Cl₂ afforded pentacoordinated tin compounds, where an alkyl group migrated from tin to nitrogen, while similar reactions with Sn-Ph compounds did not present any phenyl group migration.     

Regio- and stereoselective synthesis of spiro-pyrrolidine/pyrrolizidine/thiazolidine-grafted macrocycles through intramolecular 1,3-dipolar cycloaddition reaction

Regioselective synthesis of spiropyrrolidine-grafted 11-membered macrocycle was accomplished through an intramolecular [3+2] cycloaddition of azomethine ylides. The key precursor alkenyl diketone (4a–b) was obtained from simple starting materials. The dipole generated from isatin tethered to O-alkyl enone (4a–b) was reacted intramolecularly to yield the spiropyrrolidine-grafted macrocycles (6a–b). The structures of the cycloadducts were assigned by 2D NMR and confirmed by single crystal analysis.     

Synthetic access to optically active isoflavans by using allylic substitution

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.     

Structural characterization and catalytic activities of copper complexes with pyridine-amine-phosphine-oxide ligand

A new tetradentate containing pyridine, amine and phosphine oxide donor systems (1) was synthesized by the condensation of o-diphenylphosphinoaniline with 2-pyridinecarbaldehyde. Reaction of 1 with equal molar amount of CuCl₂ and Cu(ClO₄)₂ provided the formation of [CuCl₂(1)] (4) and [[Cu(1)(H₂O)](ClO₄)₂] (5), respectively. The ligand 1 behaves as a tridentate in 4, while as a tetradentate in 5. Both complexes were characterized by EPR, UV-Vis spectroscopy and X-ray diffraction. Both copper(II) complexes are in a square-pyramidal geometry. Single crystal structure of the copper complex reveals that the copper center is surrounded by three nitrogen donors and two chloride for 4; three nitrogen donors, water and oxygen donor from the moiety of phosphine oxide for 5. Complexation of 1 with CuCl in dichloromethane resulted in the formation of the corresponding copper(I) species, which catalyzed the oxidation of benzylic alcohols under aerobic conditions.     

β,β-Difluoro analogs of α-oxo-β-phenylpropionic acid and phenylalanine

A simple three-step procedure converted the readily accessible (2-bromo-1,1-difluoroethyl)arenes (2) into α-aryl-α,α-difluoroacetaldehydes (1). Subsequent hydrocyanation, hydrolysis, oxidation and again hydrolysis afforded β-aryl-β,β-difluoro-α-oxopropionic acids (3). Reductive amination transformed the oxoacids 3 into a separable mixture of α-hydroxyacids 11 and racemic β,β-difluoro-β-phenylalanine derivatives (4). Enantiomerically pure β,β-difluorophenylalanine (l-4a) was obtained when α,α-difluoro-α-phenylacet-aldehyde (1a) was condensed with homochiral 1-phenylethylamine, hydrogen cyanide added to the resulting imine, the diastereomeric mixture thus produced hydrolyzed to the carboxamides (15) which were found to be separable by fractional crystallization or chromatography. The pK_a values of the β-aryl-β,β-difluoroalanines (4) were measured and biological profile of the latter probed. 3-(4-Chlorophenyl)-3,3-difluoro-2-oxopropionic acid (4c) proved to be a potent (K_i 27 μM) and selective inhibitor of arogenate dehydratase, a key enzyme catalyzing the last step of the phenylalanine biosynthesis.     

Tris(4-hydroxy-3,5-diisopropylbenzyl)amine as a new bridging ligand for novel trinuclear titanium complexes

Tris(4-hydroxy-3,5-diisopropylbenzyl)amine (LH₃) was synthesized by the reaction of 2,6-diisopropylphenol and hexamethylenetetramine in the presence of p-toluenesulfonic acid or paraformaldehyde. Its solid state structure was determined by single crystal X-ray diffraction. Its fully deprotonated specie, (4-O-3,5-i-Pr₂PhCH₂)₃N (L), was used to form novel trinuclear half-sandwich titanocene complexes, namely [(η⁵-C₅Me₅)TiCl₂]₃L (1) and [(η⁵-C₅Me₅)Ti(OMe)₂]₃L (2), which were then tested for the syndiospecific polymerization of styrene in the presence of methylaluminoxane (MAO) cocatalyst. Their catalytic properties were directly compared with those of trichloro(pentamethylcyclopentadienyl)titanium(IV) (3) and dichloro(2,6-diisopropylphenolato)(pentamethylcyclopentadienyl)titanium(IV) (4). 1/MAO and 2/MAO systems showed higher activities towards styrene polymerization than the mononuclear catalytic systems 3/MAO and 4/MAO, giving syndiotactic polystyrene of high molecular weight.     

A facile stereoselective synthesis of 1,3-dienyl sulfones via Stille coupling reactions of (E)-α-stannylvinyl sulfones with alkenyl iodides

Palladium-catalyzed hydrostannylation of acetylenic sulfones 1 in benzene at room temperature gives stereoselectively (E)-α-stannylvinyl sulfones 2 in good yields. (E)-α-Stannylvinyl sulfones 2 are new difunctional group reagents which undergo Stille coupling reactions with alkenyl iodides 3 to afford stereoselectively 1,3-dienyl sulfones 4 in high yields.     

Synthesis of sulfur-substituted quinolizidines and pyrido[1,2-a]azepines by ring-closing metathesis

Sulfur-substituted quinolizidines and pyrido[1,2-a]azepines (7) can be prepared by ring-closing metathesis (RCM) of 4-(phenylthio)-1,2,5,6-tetrahydropyridin-2-ones (6) bearing terminal alkenyl groups at both N-1 and C-6 positions, which are obtained from 3-(phenylthio)-3-sulfolene (1) in four steps. Some synthetic transformations of 2-(phenylthio)-1,6,9,9a-tetrahydroquinolizin-4-one (7a) and 2-(phenylthio)-1,6,9,10,10a-pentahydropyrido[1,2-a]azepin-4-one (7d) are also reported.     

o-(Trialkylstannyl)anilines and their utility in Migita-Kosugi-Stille cross-coupling: direct introduction of the 2-aminophenyl substituent

We have developed shelf- and air-stable ortho-stannylated aniline reagents that can directly be coupled with alkenyl and aryl halides via Migita-Kosugi-Stille cross-coupling. We report (i) the efficient preparation of o-(tributylstannyl)aniline (2a) and o-(trimethylstannyl)aniline (2b), (ii) the comparison of the reactivities of 2a and 2b with those of related organostannanes in cross-coupling reaction with an alkenyl halide, and (iii) the cross-coupling of 2a and 2b with a series of arylhalides and triflate.     

Synthesis of glutamic acid and glutamine peptides possessing a trifluoromethyl ketone group as SARS-CoV 3CL protease inhibitors

Trifluoromethyl-β-amino alcohol 11 [(4S)-tert-butyl 4-amino-6,6,6-trifluoro-5-hydroxyhexanoate] was synthesized in five steps starting from Cbz-l-Glu-OH 5 where the key step involved the introduction of the trifluoromethyl (CF₃) group to oxazolidinone 7, resulting in the formation of silyl ether 8 [(4S,5S)-benzyl 4-(2-(tert-butoxycarbonyl)ethyl)-5-(trifluoromethyl)-5-(trimethylsilyloxy)oxazolidine-3-carboxylate]. Compound 11 was then converted into four tri- and tetra-glutamic acid and glutamine peptides (1-4) possessing a CF₃-ketone group that exhibited inhibitory activity against severe acute respiratory syndrome coronavirus protease (SARS-CoV 3CL^pro).     

Synthesis, coordination studies and redox properties of a novel ditertiary phosphine bearing two ferrocenyl groups

The new ferrocenyl substituted ditertiary phosphine {FcCH₂N(CH₂PPh₂)CH₂}₂ [Fc = (η⁵-C₅H₄)Fe(η⁵-C₅H₅)] (1) was prepared, in 72% yield, by Mannich based condensation of the known bis secondary amine {FcCH₂N(H)CH₂}₂ with 2 equiv. of Ph₂PCH₂OH in CH₃OH. Phosphine 1 readily coordinates to various transition-metal centres including Mo⁰, Ru^II, Rh^I, Pd^II, Pt^II and Au^I to afford the heterometallic complexes {RuCl₂(p-cym)}₂(1) (2), (AuCl)₂(1) (3), cis-PtCl₂(1) (4), cis-PdCl₂(1) (5), cis-Mo(CO)₄(1) (6), trans,trans-{Pd(CH₃)Cl(1)}₂ (7) and trans,trans-{Rh(CO)Cl(1)}₂ (8). In complexes 2, 3, 7 and 8 ligand 1 displays a P,P′-bridging mode whilst for 4-6 a P,P′-chelating mode is observed. All new compounds have been fully characterised by spectroscopic and analytical methods. Furthermore the structures of 1, 2 · 2CH₂Cl₂, 3 · CH₂Cl₂, 4 · CH₂Cl₂, 6 · 0.5CHCl₃ and 8 have been elucidated by single crystal X-ray crystallography. Electrochemical measurements have been undertaken, and their redox chemistry discussed, on both noncomplexed ligand 1 and representative compounds containing this new ditertiary phosphine.     

Unexpected Schiff-base complex formation from the oxidation reaction of a nickel(II) complex with the meso-HMPAO ligand by molecular oxygen

The synthesis and characterization of the amine–oxime complex [Ni(meso-HMPAO)–H] · ClO₄ (1) and its oxidized Schiff-base product [Ni(meso-HMPAO)-5H] · ClO₄ (2), where HMPAO is hexamethyl propylene amine oxime, are presented. Complex 2 results from the oxidation of 1 by molecular oxygen in basic aqueous solution. The structural change of the amine complex 1 to the Schiff-base complex 2 was investigated by the means of NMR spectroscopy and X-ray crystallography.     

Palladium complexes of N-aryl-2-pyridylamines

Palladium complexes of N-phenyl-2-pyridylamine (4) and dipyridylamine substrates (7, 11) have been studied. Due to the coordination ability of the pyridine-nitrogen atoms, the pyridyl substrates, 4, 7, 11 were subjected to Pd(OAc)₂ complexations and a number of N-aryl-2-pyridylamine Pd complexes (13-17) were isolated and characterised, in particular by NMR and ESI-MS. A new method for the preparation of the acetato-bridged six-membered ring palladacycle complex (13) of 4 is reported. The dipyridyl amines 7, 11 formed cis/trans bis-dentate acetato-bridged dimeric Pd₂Lig₂(OAc)₂ (14a,b/16a,b) and Pd₃Lig₂(OAc)₄ complexes (15a,b/17a,b). The N-aryl-2-pyridylamine substrates (4, 7, 11) were prepared by oxidative nucleophilic substitution, by 1,3-cycloaddition reaction or by Buchwald amination.