Synthesis and cytotoxic activity of gamma-aryl substituted alpha-alkylidene-gamma-lactones and alpha-alkylidene-gamma-lactams

A series of 5-aryl-3-alkylidenedihydrofuran-2(3H)-ones 6a–g″ and 11a,b as well as 5-aryl-3-methylidenepyrrolidin-2-ones 10a–c and 12 were synthesized starting from 4-aryl-2-diethoxyphosphoryl-4-oxobutanoates 3a–g. Reaction sequence includes reduction or reductive amination of the carbonyl group, lactonization or lactamization step and finally the Horner–Wadsworth–Emmons olefination of aldehydes using thus obtained 5-aryl-3-diethoxyphosphoryl-3,4-dihydrofuran-2(5H)-ones 5a–g″ or 5-aryl-3-diethoxyphosphorylpyrrolidin-2-ones 9a–c. Furanones 6 and 11, as well as pyrrolidinones 10 and 12, were evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines HL-60 and NALM-6. Several of the obtained furanones proved to be very potent against all three cell lines with IC₅₀ values lower than 6 μM. Structure–activity relationships of these compounds, as well as 5-alkyl or 5-arylmethyl-3-methylidenedihydrofuran-2(3H)-ones 13a–e, previously obtained in our laboratory, are discussed.     

Furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives as potential inhibitors of inflammatory factors in sepsis

Synthesis and anti-inflammatory effects of certain furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives 12–18 were studied. These compounds were synthesized from naphtho[1,2-b]furan-4,5-dione (10) which in turn was prepared from the known 2-hydoxy-1,4-naphthoquinone (7) in a one pot reaction. Furo[3′,2′:3,4]naphtho[1,2-d]imidazole (12) was inactive (IC₅₀ value of >30 μM) while its 5-phenyl derivative 13, with an IC₅₀ value of 16.3 and 11.4 μM against lysozyme and β-glucuronidase release, respectively, was comparable to the positive trifluoperazine. The same potency was observed for 5-furan derivative 16 with an IC₅₀ value of 19.5 and 11.3 μM against lysozyme and β-glucuronidase release, respectively. An electron-withdrawing NO₂ substituted on 5-phenyl or 5-furanyl group led to the devoid of activity as in the cases of 14 and 17. Among them, compound 15 exhibited significant inhibitory effects, with an IC₅₀ value of 7.4 and 5.0 μM against lysozyme and β-glucuronidase release, respectively.For the LPS-induced NO production, the phenyl derivatives 12–15 were inactive while the nitrofuran counterparts 17 and 18 suppress LPS-induced NO production significantly, with an IC₅₀ value of 1.5 and 1.3 μM, respectively, which are more active than that of the positive 1400 W. Compounds 16–18 were capable of inhibiting LPS-induced iNOS protein expression at a dose-dependent manner in which compound 18, with an IC₅₀ of 0.52 μM in the inhibition of iNOS expression, is approximately fivefold more potent than that of the positive 1400 W. In the CLP rat animal model, compound 18 was found to be more active than the positive hydrocortisone in the inhibition of the iNOS mRNA expression in rat lung tissue. The sepsis-induced PGE2 production in rat serum decreased 150% by the pretreatment of 18 in a dose of 10 mg/kg.     

Gas chromatographic–mass spectrometric determination of α-ketoisocaproic acid and [H7]α-ketoisocaproic acid in plasma after derivatization with N-phenyl-1,2-phenylenediamine

A method for determination of α-ketoisocaproic acid (KIC) and [4,5,5,5,6,6,6-²H₇]α-ketoisocaproic acid ([²H₇]KIC) in rat plasma was developed using gas chromatography–mass spectrometry-selected ion monitoring (GC–MS-SIM). [5,5,5-²H₃]α-Ketoisocaproic acid ([²H₃]KIC) was used as an analytical internal standard to account for losses associated with the extraction, derivatization and chromatography. The keto acids were extracted by cation-exchange chromatography using BondElut SCX cartridge and derivatized with N-phenyl-1,2-phenylenediamine to form N-phenylquinoxalinone derivatives. Quantitation was performed by SIM of the respective molecular ions at m/z 278, 281 and 285 for the derivatives of KIC, [²H₃]KIC and [²H₇]KIC on the electron impact method. The limit of detection was found to be 70 fmol per injection (S/N=3) and the limit of quantitation for [²H₇]KIC was around 50 nM in rat plasma. Endogenous KIC concentrations in 50 μl of rat plasma were measured with relative intra- and inter-day precision of 4.0% and 3.3%, respectively. The intra- and inter-day precision for [²H₇]KIC spiked to rat plasma in the range of 0.1 to 10 μM gave good reproducibility with relative standard deviation (RSD) of 6.5% and 5.4%, respectively. The intra- and inter-day relative errors (RE) for [²H₇]KIC were less than 6.4% and 3.8%, respectively. The method was applied to determine the plasma concentration of [²H₇]KIC after an intravenous administration of [²H₇]KIC in rat.     

Synthesis of novel pyrazole carboxamide derivatives and discovery of modulators for apoptosis or autophagy in A549 lung cancer cells

A series of novel 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxamide derivatives 3a–l, were synthesized by the reaction of 3-aryl-1-arylmethyl-1H-pyrazole-5-carbonyl chloride with substituted amine in excellent yields. The compounds 3e–h could suppress A549 lung cancer cell growth. More interestingly, compounds 3e and 3f might inhibit the A549 cell growth by inducing apoptosis; whereas compounds 3g and 3h with fluorine group might inhibit the A549 cell growth by inducing autophagy.     

A study of the reactivity and structure of cyclic α,β-unsaturated Fischer-type carbene complexes

Cycloaddition reactions with α,β-unsaturated carbene complexes of the Fischer-type bearing the carbene carbon atom and the double bond incorporated in the same ring are described. Pentacarbonyl(2H-benzopyran-2- ylidene)chromium(0) complexes (2a-c) and pentacarbonyl(4-methoxy-3,3-dimethyl-2-oxacyclopentylidene)- chromium(0) (3) show a rather low reactivity towards 1,3-dipoles and 1,3-dienes. The reactions with diazomethane are regioselective but not chemoselective; compounds 2 and 3 show two sites of attack: the α,β carbon-carbon and the carbon-metal double bond. The crystal and molecular structures of 2a and 3 have been elucidated by single crystal X-ray analysis. Crystals of 2a are monoclinic, space group P2₁/c, a=7.614(3), b=14.033(3), c=12.766(3) Å, β=95.24°, V=1358.3(7) Å Z=4; crystals of 3 are triclinic, space group P , a=6.553(1), b=9.408(1), c=10.620(1) Å α=92.70(1), β=92.30(1), γ=92.12(1)°, V=653.0(1), ų, Z=2. Final agreement indices for 2a and 3 are R=0.034 and 0.033, respectively. Vibrational properties of the Cr(CO)₅ moiety were interpreted by FT-IR and FT-Raman spectroscopy. Electronic spectra and π electron distribution were interpreted by resonance Raman spectroscopy.     

Synthesis, structural characterization and in vitro cytotoxicity and anti-bacterial activity of some copper(I) complexes with N,N′-disubstituted thioureas

A series of copper(I) complexes of N,N′-disubstituted thioureas, [C₆H₅CONHCSNHR]Cu(I)Cl where R = C₆H₅ (1a), 2-ClC₆H₄ (2a), 3-ClC₆H₄ (3a), 4-ClC₆H₄ (4a), 2,3-Cl₂C₆H₃ (5a), 2,4-Cl₂C₆H₃ (6a), 2,5-Cl₂C₆H₃ (7a), 2,6-Cl₂C₆H₃ (8a), 3,4-Cl₂C₆H₃ (9a) and 3,5-Cl₂C₆H₃ (10a) have been synthesized. These complexes (1a–10a) have been characterized by elemental analyses, IR, ¹H and ¹³C NMR spectroscopy, cyclic voltammetry and single crystal XRD for 1a and 8a, and for ligand 7. The X-ray crystal structures reveal that the complexes 1a and 8a are mononuclear in the solid state in which the copper atoms adopt a distorted tetrahedral geometry. In both the cases, the neutral N,N′-disubstituted thiourea ligands have been coordinated to the Cu(I) through the sulphur atom in a terminal mode. The complexes have been screened for their in vitro cytotoxic activity in human cell lines carcinomas A498 (Renal), EVSA-T (Breast), H226 (Lung), IGROV (Ovarian), M19 (Melanoma-Skin), MCF-7 (Breast) and WIDR (Colon). They show a moderate cytotoxicity against these seven human cancer cell lines comparable to that of the less active standard chemotherapeutic drugs used for comparison. They were also screened for their anti-bacterial activity and were found less active than the standard drug Imipenem.     

Solution structure investigations of olefin Pd(II) and Pt(II) complex ion pairs bearing α-diimine ligands by F, H-HOESY NMR

Complexes [M(η¹,η²-C₈H₁₂OMe)((2,6-(R)₂---C₆H₃)N=C(R′)---C(R′)=N((2,6-(R)₂---C₆H₃))]PF₆ (where M=Pd, R=H and R′₂=Me₂ (1), M=Pd, R=Me and R′₂=Me₂ (2), M=Pd, R=Et and R′₂=Me₂ (3), M=Pd, R=iPr and R′₂=Me₂ (4), M=Pd, R=iPr and R′₂=An (5), M=Pt, R=iPr and R′₂=An (6)) were synthesized by the reaction of [M(η¹,η²-C₈H₁₂OMe)Cl]₂ with the appropriate α-diimine ligand in the presence of NH₄PF₆. Their ion pair structure in solution was investigated by detecting dipolar interactions between protons belonging to the cation and fluorine nuclei of the anion (interionic contacts) in the ¹⁹F, ¹H-HOESY NMR spectra. In complexes 1–4, the anion in solution is located close to the peripheral protons of the α-diimine ligand and it interacts with the R′ protons and with the R protons that point toward the R′ groups. The steric protection of apical position exerted by the R substituents is clearly illustrated by the absence of interionic contacts between any protons of the cycloctenylmethoxy-moiety and the anion for R≥Me in 1–4. In complexes 5 and 6 the interactions between the anion and the peripheral N,N protons also predominate but other anion–cation orientations are significantly present and, consequently, the interionic structure is less specific.     

Design and synthesis of novel substituted quinazoline derivatives as antileishmanial agents

4-(Substituted-benzylidine)-2-substituted-5,6-dihydrobenzo[h]quinazoline (5a–p) and 4-(substituted-benzylidine)-2-substituted-3, 4, 5, 6-tetrahydrobenzo[h]quinazoline (6a–p) have been synthesized from 2-(substituted-benzylidine)tetralone-1(3a–d) and several substituted guanidine sulfates(4a–d).These compounds were tested for their in vitro antileishmanial activity. The compounds 6i, 6f, 6g show promising antileishmanial activity against Leishmania donovani.     

β3-Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropionic acid

In a search for novel analogues of β₃-adrenoceptor (AR) agonists relaxing the bladder for treatment of urinary dysfunction, 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropionic acids (1a–e), into which a fibrate-like structure had been incorporated, were synthesised. Compound 1a was found to be a selective β₃-AR agonist in functional assays using the ferret detrusor (β₃-AR), rat uterus (β₂-AR), and rat atrium (β₁-AR); β₃: EC₅₀=7.8 nM, β₂: IC₅₀=7,300 nM, β₁: EC₂₀=23,000 nM. The introduction of a chlorine atom or methyl substituent at the ortho-position on the phenyl ring of 1a further improved β₃-AR selectivity. In an in vivo study, 1a lowered intrabladder pressure (ED₅₀=31 μg/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that 1a and its analogues (1b–e), possess β₃-AR agonistic activity in the absence of undesirable β₁- or β₂-AR mediated actions, and may be useful for clinical treatment and pharmacological studies.     

Tryptamine-based human β3-adrenergic receptor agonists. Part 2: SAR of the methylene derivatives

A series of tryptamine derivatives with modified sulfonamide were designed, synthesized, and evaluated for their ability to stimulate cAMP accumulation in CHO cells expressing the cloned human β₃-adrenergic receptor (AR). For this series of compounds, our objective was to symmetrize the α-position of the tryptamine moiety maintaining its activity and reducing the cost of production. Compound 11h, having m-aminobenzene, exhibited excellent agonistic activity for β₃-AR with excellent subtype selectivity.     

Haemoglobin adducts of aromatic amines: diamines and polyaromatic amines

Aromatic amines and nitroarenes are important antioxidants and intermediates in the synthesis of dyes, pesticides and plastics. In the present paper we introduce methods for the synthesis of deuterated standards: 3-[²H₈]aminofluoranthene, 3,3′-dimethyl-[²H₄]benzidine, [²H₄]benzidine, N′-acetyl-[²H₄]benzidine, 2,4-[²H₆]toluenediamine, 2,6-[²H₆]toluenediamine. These standards have been used for the quantification of haemoglobin adducts of diamines and polyaromatic amines. Haemoglobin was hydrolysed in 0.1 M sodium hydroxide and the hydrolysate extracted with dichloromethane. The extracts were derivatised with heptafluorobutyric anhydride and analysed by GC–MS with negative chemical ionisation. In one run up to 15 aromatic amines can be determined: 6-aminochrysene, 3-aminofluoranthene, 2-aminofluorene, 1-aminopyrene, benzidine, 3,3′-dichlorobenzidine, 3,3′-dimethoxybenzidine, 3,3′-dimethylbenzidine, 3,3′-methylenedianiline, 4,4′-methylenedianiline, N′-acetyl-benzidine, N′-acetyl-4,4′-methylenedianiline, 4,4′-methylene bis(2-chloroaniline), 2,4-toluenediamine and 2,6-toluenediamine.     

Effect of torpor on the water economy of an arid-zone marsupial,the stripe-faced dunnart (<Emphasis Type="Italic">Sminthopsis macroura</Emphasis>)

Metabolic rate and evaporative water loss (EWL) were measured for a small, arid-zone marsupial, the stripe-faced dunnart (Sminthopsis macroura), when normothermic and torpid. Metabolic rate increased linearly with decreasing ambient temperature (T_a) for normothermic dunnarts, and calculated metabolic water production (MWP) ranged from 0.85±0.05 (T_a=30°C) to 3.13±0.22 mg H₂O g^–1 h^–1 (T_a=11°C). Torpor at T_a=11 and 16°C reduced MWP to 24–36% of normothermic values. EWL increased with decreasing T_a, and ranged from 1.81±0.37 (T_a=30°C) to 5.26±0.86 mg H₂O g^–1 h^–1 (T_a=11°C). Torpor significantly reduced absolute EWL to 23.5–42.3% of normothermic values, resulting in absolute water savings of 50–55 mg H₂O h^–1. The relative water economy (EWL/MWP) of the dunnarts was unfavourable, remaining >1 at all T_a investigated, and did not improve with torpor. Thus torpor in stripe-faced dunnarts results in absolute, but not relative, water savings.     

The synthesis of polyoxygenated, enantiomerically pure cyclopentane derivatives on route to neplanocin A stereoisomers via alkylidenecarbene species prepared from sugar templates

Our new method for the generation of alkylidenecarbenes, based on the reaction of trimethylsilylazide/Bu₂SnO with α-cyanomesylates, has been applied to the synthesis of enantiomerically pure polyhydroxylated cyclopentane derivatives from conveniently functionalized sugar intermediates prepared from d-mannose. The stereoselectivity of the 1,5 C–H insertion reaction leading to the major trans-isomers (8a,b) has been assigned by ¹H RMN spectroscopic data, and correctly rationalized by a computational analysis at DFT level. Compounds 8a and 8b have been designed as suitable intermediates for the synthesis of neplanocin A enantiomer.     

Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis,characterization and evaluation of anticancer and antimicrobial activities

A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones (8a–t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-2(1H)-thiones (4a–f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with various indole-3-carbaldehydes (7a–d) under conventional method. All the synthesized compounds were characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities. Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and comparable antifungal activities against all the tested microorganisms.     

Discovery,structure–activity relationship studies,and anti-nociceptive effects of 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one as novel opioid receptor agonists

The μ-opioid receptor (MOR) is the major opioid receptor targeted by most analgesics in clinical use. However, the use of all known MOR agonists is associated with severe adverse effects. We reported that the 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-ones are novel opioid receptor agonists. Subsequent structural modification resulted in the potent MOR/KOR (κ-opioid receptor) agonists 19, 20, and 21. Testing the analgesic effect of these in WT B6 mice (tail-flick test) gave ED₅₀ values of 8.4, 10.9, and 26.6 mg/kg, respectively. The 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one core could be addressed in 1 or 2 synthetic steps with moderate to high percent of yield. In the adenylyl cyclase assay, compound 19 displayed a MOR/KOR agonist profile, with IC₅₀ values of 0.73 and 0.41 μM, respectively. Current results suggest that compound 19 is a promising lead to go further development and in vitro/in vivo adverse effects studies.     

No carrier added synthesis of O-(2'-[18F]fluoroethyl)-L-tyrosine via a novel type of chiral enantiomerically pure precursor, NiII complex of a (S)-tyrosine Schiff base

O-(2′-[¹⁸F]fluoroethyl)-l-tyrosine ([¹⁸F]FET) has gained much attention as a promising amino acid radiotracer for tumor imaging with positron emission tomography (PET) due to favorable imaging characteristics and relatively long half-life of ¹⁸F (110 min) allowing remote-site application. Here we present a novel type of chiral enantiomerically pure labeling precursor for [¹⁸F]FET, based on NiII complex of a Schiff’s base of (S)-[N-2-(N′-benzylprolyl)amino]benzophenone (BPB) with alkylated (S)-tyrosine, Ni-(S)-BPB-(S)-Tyr-OCH2CH2X (X = OTs (3a), OMs (3b) and OTf (3c)). A series of compounds 3a–c was synthesized in three steps from commercially available reagents. Non-radioactive FET as a reference was prepared from 3a in a form of (S)-isomer and (R,S) racemic mixture. Radiosynthesis comprised two steps: (1) n.c.a. nucleophilic fluorination of 3a–c (4.5–5.0 mg) in the presence of either Kryptofix 2.2.2.or tetrabutylammonium carbonate (TBAC) in MeCN at 80 °C for 5 min, followed by (2) removal of protective groups by treating with 0.5 M HCl (120 °C, 5 min). The major advantages of this procedure are retention of enantiomeric purity during the ¹⁸F-introduction step and easy simultaneous deprotection of amino and carboxy moieties in 3a–c. Radiochemically pure [¹⁸F]FET was isolated by semi-preparative HPLC (C18 μ-Bondapak, Waters) eluent aq 0.01 M CH₃COONH₄, pH 4/C₂H₅OH 90/10 (v/v). Overall synthesis time operated by Anatech RB 86 laboratory robot was 55 min. In a series of compounds 3a–c, tosyl derivative 3a provided highest radiochemical yield (40–45%, corrected for radioactive decay). Enantiomeric purity was 94–95% and 96–97%, correspondingly, for Kryptofix and TBAC assisted fluorinations. The suggested procedure involved minimal number of synthesis steps and suits perfectly for automation in the modern synthesis modules for PET radiopharmaceuticals. Preliminary biodistribution study in experimental model of turpentine-induced aseptic abscess and Glioma35 rat’s tumor (homografts) in Wistar rats has demonstrated the enhanced uptake of radiotracer in the tumor area with minimal accumulation in the inflamed tissues.     

Synthesis of bent titanocene metalloligands with the (diphenylphosphino)tetramethylcyclopentadienyl moiety. X-ray structure of [(η-C5Me4 2)2TiCl2]Mo(CO)4

The reactions of lithium(diphenylphosphino)tetramethylcyclopentadienide with CpTiCl₃ and secondly with TiCl₃ followed by CCl₄ oxidation lead to the formation of two titanocene phosphines: (η⁵-C₅H₅)[η⁵-C₅Me₄P(C₆H₅)₂]TiCl₂ (2) and [η⁵-C₅Me₄P(C₆H₅)₂]₂TiCl₂ (3), respectively. The metalloligand 3 reacts readily with Mo(CO)₄cod, Mo(CO)₅THF and Mo(CO)₆ to give in each case [(η⁵-C₅Me₄ o(CO)₄ (6) as a sole product. The structure of 6 has been determined by X-ray diffraction. Crystal data: P , a = 11.716(1), b = 11.753(2), c = 16.110(2) Å, α = 99.06(1), β = 92.61(1), γ = 104.20(1)°, Z = 2. The molybdenum-titanium distance of 5.194(1) Å rules out any metal-metal interaction. The chlorine substitution reactions by CO in 2 and 3 and by thiolate group (pH₃C-C₆H₄-S) in 16 are reported.     

Reduction in post-prandial hyperglycemic excursion through alpha-glucosidase inhibition by beta-acetamido carbonyl compounds

A series of β-acetamido carbonyl compounds (S₁–S₇) were prepared using Dakin-West reaction from different substituted aldehyde and acetophenone in the presence of lanthanum triflate as a solid catalyst. All the compounds were tested for their α-glucosidase inhibitory potential against rat intestinal α-glucosidase. The most potent rat intestinal α-glucosidase inhibitors S₅ and S₇ were tested for their antihyperglycemic activity following carbohydrate tolerance test. Both the compounds displayed antihyperglycemic activity equivalent to the standard drug acarbose.     

Synthesis and evaluation of indolinyl- and indolylphenylacetylenes as PET imaging agents for beta-amyloid plaques

Two new phenylacetylene derivatives, 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)indoline 8 and 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)-1H-indole 14, targeting β-amyloid (Aβ) plaques have been prepared. In vitro binding carried out in tissue homogenates prepared from postmortem AD brains with [¹²⁵I]IMPY (6-iodo-2-(4′-dimethylamino-)phenyl-imidazo[1,2-a]pyridine) as the radioligand indicated good binding affinities (K_i = 4.0 and 1.5 nM for 8 and 14, respectively). Brain penetration of the corresponding radiofluorinated ligands, evaluated in the normal mice, showed good initial brain penetration (4.50 and 2.43% ID/g (injected dose/gram) for [¹⁸F]8 and [¹⁸F]14 at 2 min after injection) with moderate to low washout rates from the brain (1.71% ID/g at 2 h and 2.10% ID/g at 3 h, respectively). Autoradiography and homogenate binding studies demonstrated the high specific binding of [¹⁸F]14 to the Aβ plaques; however, [¹⁸F]8 showed low specific binding. These preliminary results identified that indolylphenylacetylene, 14, may be a good lead for further structural modification to develop a useful Aβ plaque imaging agent.     

Synthesis of 5,6-dihydro-4H-1,3-oxazines from neutral and cationic platinum(II) nitrile complexes. X-ray structure of trans-[Pt(CF3){ H2CH2}(PPh3)2]BF4

The 1,3-oxazine complexes cis- and trans-[PtCl₂{ C(R)OCH₂CH₂C}H₂₂] (cis: R=CH₃ (1a), CH₂CH₃ (2a), (CH3)₃C (3a), C₆H₅ (4a); trans:R =CH₃ (1b), C₆H₅ (4b)) were obtained in 51-71% yield by reaction in THF at 0 °C of the corresponding nitrile complexes cis- and trans-[PtCl2(NCR)₂] with 2 equiv. of ⁻OCH₂CH₂CH₂Cl, generated by deprotonation of 3-chloro-1-propanol with n-BuLi. The cationic nitrile complexes trans-[Pt(CF₃)(NCR)(PPh₃)₂]BF₄ (R=CH3, C₆H₅) react with 1 equiv, of ⁻ OCH2CH2CH2Cl to give a mixture of products, including the corresponding oxazine derivatives trans-[Pt(CF₃){ CH₂}(PPh₃)₂]BF₄ (5 and 6), the chloro complex _trans- [Pt(CF₃)Cl(PPh₃)₂] and free oxazine H2. For short reaction times (c. 5–15 min) the oxazine complexes 5 and 6 could be isolated in modest yield (37–49%) from the reaction mixtures and they could be separated from the corresponding chloro complex (yield 40%) by taking advantage of the higher solubility of the latter derivative in benzene. For longer reaction times (> 2 h), trans-[Pt(CF₃)Cl(PPh₃)₂] was the only isolated product. Complex 6 was crystallographically characterized and it was found to contain also crystals of trans- [PtCl{ H₂}(PPh₃)₂]BF₄, which prevented a more detailed analysis of the bond lengths and angles within the metal coordination sphere. The 1,3-oxazine ring, which shows an overall planar arrangement, is characterized by high thermal values of the carbon atoms of the methylene groups indicative of disordering in this part of the molecule in agreement with fast dynamic ring processes suggested on the basis of ¹H NMR spectra. It crystallizes in the trigonal space group P , with a=22.590(4), b=15.970(3) Å, γ=120°, V=7058(1) ų and Z=6. The structure was refined to R=0.059 for 3903 unique observed (I3σ(I)) reflections. A mechanism is proposed for the conversion of nitrile ligands to oxazines in Pt(II) complexes.