Compound IIIa Research Articles

Reactions of polyhalopyridines. 9. Perfluoroalkylation of 2,3,5,6-tetrafluoro-4-mercaptopyridine with compounds of xenon containing fluorine

We showed recently that the decomposition of xenon bisperfluoroalkanecarboxylates in the presence of thiols may lead to the perfluoroalkylation of the latter [2]. This method of perfluoroalkylation is preferable for thiols with electronaccepting substituents stable in the presence of such strong oxidizing agents as compounds of xenon (II) and sensitive to the action of nucleophilic reagents. In the present report we give results of an investigation of the perfluoroalkylation of 2,3,5,6-tetra-fluoro-4-mercaptopyridine (1) using compounds of xenon containing fluorine. New derivatives of tetrafluoropyridine, viz., 2,3,5,6-tetrafluoro-4perfluoroalkylthiopyridines (IIIa-c), were obtained in 25-50% yield on carrying out the thermolytic conversion of the xenon bisperfluoroalkanecarboxylates (IIa-c) in the presence of compound (I). The xenon derivatives (IIa-c) were synthesized by the action of xenon difluoride with perfluoroalkanecarboxylic acids either previously (method A) or in situ (method B) [2]. Method A is preferred for perfluoromethylation [compound (IIia)]. Method B provides higher yields for compounds (IIIb, c).

Oxidation and halogenation of methyl 4,5,6,7-tetrafluoro-benzo[ b]thiophen-2-carboxylate

4,5,6,7-Tetrafluorobenzo[ b]thiophen-2-carboxylic acid ( IA) was prepared by a modified literature procedure in two steps from pentafluorobenzaldehyde and rhodanine. Its methyl ester ( IB) was synthesised via the acid chloride ( IC) by reaction with methanol. Oxidation of IB with either CF 3CO 2H/H 2O 2 or meta-chloroperbenzoic acid gave methyl 2,3-dihydro-2,3-epoxy-4,5,6,7-tetrafluorobenzo[ b]thiophen-1,1-dioxide-2-carboxylate ( II). Methyl 2,3-dichloro- 2,3-dihydro-4,5,6,7-tetrafluorobenzo[ b]thiophen-2-carboxylate ( IIIA) was prepared by reaction of IB either with chlorine, or with sulphuryl chloride and azobisisobutyronitrile. Chloromethyl 4,5,6,7-tetrafluorobenzo[ b]thiophen-2-carboxylate ( V) was also produced with the latter reagents. Compound IIIA underwent thermal dehydrochlorination to give methyl 3-chloro-4,5,6,7-tetrafluorobenzo[ b]thiophen- 2-carboxylate ( IVA), behaviour also observed during analyses involving gas chromatography. Treatment of IB with iodine pentafluoride in CF 2ClCFCl 2 and CF 3Cl gave, as shown by GLC, one major and several minor compounds. Analyses by coupled GLC-MS and GLC-IR methods indicated that the major product was IVA. Two of the minor products appeared to be methyl 3-iodo- ( IVB) and methyl 3-fluoro-4,5,6,7-tetrafluoro- benzo[ b]thiophen-2-carboxylate ( IVC). It is not known if these were produced during analysis or in the IF 5 reaction.

A novel constrained reduced-amide inhibitor of HIV-1 protease derived from the sequential incorporation of gamma-turn mimetics into a model substrate.

C7 mimetics, designed to lock three amino acid residues of a peptide chain into a gamma-turn conformation, were introduced sequentially between the P3 to P2' positions of a model HIV-1 protease substrate I (resulting in compounds II-IV) to probe its conformational requirements in binding to HIV-1 protease. Of these, compound IIIa with the C7 mimetic replacing Asn-Tyr-Pro, corresponding to the P2 through P1' positions of substrate, was found to be an inhibitor with a Ki of 147 microM. Reduction of the amide bond in the C7 mimetic of IIIa resulted in a novel constrained reduced-amide mimetic VIa with a Ki of 430 nM. This corresponds to over a 300-fold improvement in inhibitory activity over the original C7 mimetic. The inhibitory activity of mimetic VIa was in addition found to be 44-fold better than a similar linear reduced-amide containing inhibitor V. The synthesis of these mimetics are described.

Studies on antiulcer drugs. IV. Synthesis and antiulcer activities of imidazo[1,2-a]pyridinylethylbenzothiazoles and -benzimidazoles.

A series of 6-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]benzothiazoles (II) and benzimidazole analogues (III) was synthesized and tested for histamine H2-receptor antagonist, gastric antisecretory and anti-stress ulcer activity. A benzimidazole derivative (IIIa) exhibited strong antisecretory activity, whereas the corresponding benzothiazole derivative (IIb) lacked this potency in in vivo test. In contrast to compound IIIa, however, compound IIb demonstrated good inhibition against stress induced ulcer. The structure-activity relationships of these compounds are discussed.

Isolation and characterization of eight lipid A precursors from a 3-deoxy-D-manno-octylosonic acid-deficient mutant of Salmonella typhimurium.

Temperature-sensitive mutants of Salmonella typhimurium that are defective in the biosynthesis of 3-deoxy-D-manno-octulosonate are known to accumulate disaccharide precursor(s) of lipid A at 42 degrees C (Rick, P. D., Fung, L. W.-M., Ho, C., and Osborn, M. J. (1977) J. Biol. Chem. 252, 4904-4912). We have devised new methods for purifying this material by chromatography on DEAE-cellulose and silicic acid columns and have fractionated it into eight related anionic components that fall into four sets, as judged by their charge. Substances IA and IB have an apparent net charge of -1, IIA and IIB of -2, IIIA and IIIB of -3, and IVA and IVB of -4. Negative ion fast atom bombardment mass spectrometry reveals that the simplest component is IVA [( M - H]- at m/z 1404). Compound IVA is also the most abundant, representing 30-50% of the accumulated lipids after 3 h at 42 degrees C. Structural studies of IVA, including NMR spectroscopy described in the accompanying paper, reveal that it consists of O-(2-amino-2-deoxy-beta-D-glucopyranosyl)-(1----6)-2-amino-2-deoxy-alpha - D-glucose, acylated at positions 2, 3, 2', and 3' with beta-hydroxymyristoyl moieties and bearing phosphate groups at positions 1 and 4'. Compound IIIA ([M - H]- at m/z 1527) contains an additional phosphoethanolamine residue, while IIA ([M - H]- m/z 1535) bears an aminodeoxypentose substituent, presumably 4-amino-4-deoxy-L-arabinose. Compound IA ([M - H]- at m/z 1658) bears both a phosphoethanolamine and an aminodeoxypentose. The compounds of the less abundant B series are further derivatized with an ester-linked palmitoyl moiety. Our results demonstrate that these precursors are far more heterogeneous than previously suspected.

Synthesis and reactions of β-substituted derivatives of furan

The 1,4-cycloaddition reaction of 4-phenyl-1,3-oxazole to 2-propinyl benzoate and dimethyl butinedioate afforded the respective 3-furylmethyl benzoate (I) and 3,4-bis(methoxycarbonyl)furan (II). These compounds served for the synthesis of 3-chloromethylfuran and 3,4-bis(chloromethyl)furan, which afforded via Wittig reaction 3-(β-arylvinyl)furans III (aryl = 5-nitro-2-furyl (IIIa), 5-nitro-2-thienyl (IIIb), 1-methyl-4-nitro-2-pyrrolyl (IIIc), and 4-nitrophenyl (IIIe)) and 3,4-bis(β-arylvinyl)furans IV (aryl = 5-nitrofuryl (IVa), 5-nitro-2-thienyl (IVc), and 4-nitrophenyl (IVd)). According to spectral evidence (1H NMR, IR, UV spectra), compound IIIa and IIIb originated as E isomers, whilst the remaining products are a mixture of E and Z isomers; some couples were succeded to separate.

Photochemical exchange reactions of thymine, uracil and their nucleosides with selected amino acids.

AbstractThe photoinduced exchange reactions of thymine with lysine at basic pH, using 254 nm light, have been studied. Three products have been isolated, namely, 6‐amino‐2‐(1‐thyminyl)hexanoic acid (Ia), 2‐amino‐6‐(1‐thyminyl)hexanoic acid (IIa) and 1‐amino‐5‐(1‐thyminyl)pentane (IIIa). Compound IIIa was shown to be a secondary product, produced by photochemical decarboxylation of Ia. Photochemical reaction of thymine with glycine and alanine at basic pH led, respectively, to formation of 2‐(1‐thyminyl)acetic acid (Ic) and 2‐(1‐thyminyl)propionic acid (Id). Compounds Ic and Id underwent photolysis to produce the decarboxylated secondary products 1‐methylthymine and 1‐ethylthymine, respectively. Thymidine reacts photochemically with glycine and alanine to produce the same products.Irradiation of DNA in the presence of lysine at basic pH led to the formation of the same products formed in the thymine‐lysine system, namely Ia, IIa and IIIa.Uracil was found to undergo analogous photochemical exchange reactions with lysine to form 6‐amino‐2‐(1‐uracilyl) hexanoic acid (Ib), and 2‐amino‐6‐(1‐uracilyl)hexanoic acid (IIb). Compound Ib was found to undergo photodecarboxylation to form 1‐amino‐5‐(1‐uracilyl)pentane (IIIb), analogous to the secondary photoreaction of Ia. Photoreaction of uracil with 1,5‐diaminopentane (cadaverine) likewise led to formation of IIIb.

ChemInform Abstract: PYROLYSIS OF BENZYL 2-OXAZOLECARBAMATES AND BENZYL 4-ALKYLALLOPHANATES

Die Pyrolyse des Benzylcarbamats (I) führt zum dimeren Isocyanat (II).

Reactivity of cyclopalladated compounds: VIII. Synthesis of cyclometallated compounds with an oxygen as the donor atom. Crystal and molecular structure of (8-methylquinoline- C,N)-(1-methoxynaphthalene-8- C,O)palladium(II)

Treatment of 1-methoxynaphthalene (MXNH) with n-butyllithium in a diethyl ether/n-hexane solution gives 1-methoxynaphthalene-8-lithium (MXNLi) in 30% yield as an insoluble material. This compound reacts with PdCl 2(SEt 2) 2 to give bis(1-methoxynaphthalene-8- C,O)palladium(II) (I)_and with PtCl 2(SEt 2) 2 to give cis- and trans-(1-methoxynaphthalene-8- C,O)(1-methoxynaphthalene-8- C)(diethylsulfide)platinum(II) (II), which are non-rigid molecules in solution. With the cyclopalladated dimers [{ Pd(CN )Cl 2} 2], MXNLi gives the palladobicyclic compounds: ( N∩C)P d(C∩O ) (III). An X-ray diffraction study of compound IIIa where N∩N = 8-methylquinoline- C,N reveals the planarity of the molecule, shows that it has a cis configuration with respect to the PdC bonds, and confirms that the oxygen atom of MXN is bonded to palladium: PdO 2.236(4) Å. The geometry of IIIa is maintained in solution, whereas the corresponding compounds IIIb and IIIc in which N∩C is benzo[ h]quinoline-9- C,N and N,N-dimethyl-1-naphthylamine-8- C,N, respectively, appear to be mixtures of cis and trans isomers in solution. With PMe 2Ph I and II give trans-Pd(MXN) 2(PMe 2Ph) 2 and cis-Pt(MNX) 2(PMe 2Ph) 2, respectively, in which the methoxynaphthalene is bound to the metals via the 8-carbon of the naphthalene ring. Only one phosphine ligand adds to compounds IIIb and IIIc with displacement of the O → Pd bond. One carbon monoxide ligand can be added to the platinum compound II to give Pt(MXN) 2(SEt 2)CO which in solution exists as two isomers in equilibrium.

α-(4-Tolyl)dopamine, derivatives and analogues; Synthesis and pharmacological screening

The ketone XIII, obtained by Friedel-Crafts reaction of toluene with homoveratroyl chloride, was converted by the Leuckart reaction to the formamido derivative IXb which was used as the starting product for the synthesis of amines IIIb-Vb. Reduction of the ketone XIII gave the alcohol XVI which was treated with hydrogen chloride and afforded the chloro compound XVII. Its substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)piperazine and 1-phenylpiperazine resulted in the piperazines VIb-VIIIb. Acylations of the amine IIIb with acetic anhydride and homoveratroyl chloride gave the amides Xb and XIb which, together with the formamide IXb, were subjected to the Bischler-Napieralski reaction. 3,4-Dihydroisoquinolines XXII-XXIV were obtained and reduced to the 1,2,3,4-tetrahydroisoquinolines XXVb-XXVIIb. Treatment of XXVIIb with formaldehyde afforded the berbine derivative XXVIII. Demethylation of the amine IIIb with hydrobromic acid resulted in the title compound IIIa. Similar demethylations of the dimethoxyamines IVb-VIIIb, XXVb and XXVIb led to the dihydroxyamines IVa-VIIIa, XXVa and XXVIa which are dopamine derivatives. Reaction of Va with benzoyl chloride gave the dibenzoate XXX. The CNS activities of the compounds prepared are of a low degree. Several of them (IIIa-VIa, IIIb-Vb, XXVb) show in higher doses signs of central stimulant action but only for compound IVa an antireserpine effect was proven. The expected anticataleptic activity was found only in a low degree with compound VIIIa; on the contrary, compounds IIIa and XXVa are procataleptogenic. Some compounds (IIIa, IXb, XXVIa, XXVIII) potentiated thiopental. In single cases local anaesthetic, spasmolytic, hypotensive, hypertensive, hypoglycaemic, diuretic and antiarrhythmic effects were observed.

Pyrolysis of benzyl 2-oxazolecarbamates and benzyl 4-alkylallophanates.

The pyrolysis of benzyl 2-oxazolecarbamates (I) and benzyl 4-alkylallophanates (II) was investigated. Heating of benzyl 5-phenyl-2-oxazolecarbamate (Ia) at 230°C gave benzyl alcohol and 2-phenyl-6-(5-phenyl-2-oxazolyl)-5H-oxazolo [3, 2-α] [1, 3, 5] triazine-5, 7-(6H)-dione (IIIa). Compound IIIa was also obtained by heating the azide prepared from 5-phenyl-2-oxazolecarbohydrazide (IVa). In the same way, 2-methyl-6-(5-methyl-2-oxazolyl)-5H-oxazolo [3, 2-α] [1, 3, 5] triazine-5, 7 (6H)-dione (IIIb) and 2-phenyl-6-(5-phenyl-2-thiazolyl)-5H-thiazolo [3, 2-α] [1, 3, 5] triazine-5, 7 (6H)-dione (IIIc) were obtained from the corresponding hydrazides (IVb and IVc). Next, heating of benzyl 4-(2-phenylethyl)-allophanate (IIa) at 230°C gave cyanuric acid (VII), benzyl (2-phenylethyl) carbamate (VIII) and 1, 3-bis (2-phenylethyl)-1, 3, 5-triazine-2, 4, 6 (1H, 3H, 5H)-trione (IX).

Preparation of conjugates of uridine with proteins by the imido ester condensation method

Reaction of 5'-O-p-toluenesulfonyl-2',3'-O-isopropylideneuridine (I) with sodium 4-cyanophenoxide afforded 2',3'-O-isopropylidene-5'-O-(4-cyanophenyl)uridine (II) which was converted by acid hydrolysis into 5'-O-(4-cyanophenyl)uridine (IIIa). Acid-catalyzed addition of ethanol to compound IIIa gave the imido ester hydrochloride IIIb which on reaction with ammonia or ethylamine was transformed into the amidine derivatives IIIc and IIId. Compound IIIb reacted with human serum albumine or bovine gamma-globuline at pH 9.2 to give protein conjugates with uridine, bound covalently by an amidine bond (IIIe,f).

Synthesis of (2,4,6-cycloheptatrien-1-ylidene)methyl triphenylphosphonium tetrafluoroborate: a strongly stabilized ylide ?

The synthesis of (cycloheptatrienylmethyl)triphenylphosphonium tetrafluoroborates is reported. Hydride abstraction to the corresponding tropylium salt followed by proton abstraction afforded the title compound IIIa which shows little, if any, ylidic character.

Participation of 19-substituents in electrophilic additions. influence of 3β-substitution on hypobromous acid addition to 5,6-unsaturated steroids

Reactions of 19-hydroxy-, methoxy- and acetoxy-5-cholestenes Ia, IIa, IIIa were studied and compared with those previously obtained with analogous 3β-acetoxy-19-substituted 5-cholestenes Ib, IIb, IIIc. A marked difference was found in 19-acetoxy derivatives where the 3-unsubstituted compound IIIa yields exclusively the bromohydrin XVIa as a product of 6(O)π,n participation while the 3β-acetoxy derivative IIIb gives, apart from the analogous bromohydrin XVIb, also products of competing reactions: The epoxide XIIb and the bromohydrin XIIIb.

2',3'=Carbonates in the synthesis of uridine 5'-deoxy and 2',5'-dideoxy derivatives.

Detritylation of 2',3'-O-carbonyl-5'-O-trityluridine (Ia) with ethereal hydrogen chloride affords 2',3'-O-carbonyluridine (Ib; 83%) which is converted by mesylation to the 5'-mesylcarbonate Ic (75%). Reaction of compound, Ic with tetrabutylammonium bromide in DMF affords the 5'-bromo carbonate Id (77%) which is reduced with tributyltin hydride to the 5'-deoxyuridine 2',3'-cyclic carbonate Ie (70%). When heated with imidazole, compound Ie affords the 2,2'-anhydro derivative IIa (76%) which is converted to the 2'-chloro derivative IIIa (88%) on heating with HC1/DMF. The tributyltin hydride reduction of compound IIIa gives 2',5'-dideoxyuridine (IIIb; 68%). When heated with NaHCO3 in DMF, the 5'-bromo carbonate Id affords the anhydro bromo derivative IIb (50%) which is converted to the 2',5'-dichloro derivative IIIc (86%) on heating with HC1/DMF. The tributyltin hydride reduction of compound IIIc affords the 2',5'-dideoxy derivative IIIb (59%). Alkaline hydrolysis of the 2,2'-anhydro derivative IIa affords the arabinosyl derivative IVa which is converted to the diacetyl derivative IVb (34%) by acetylation. When refluxed in water, the 2',3'-cyclic carbonates Ib, Id, and Ie are hydrolysed to the parent nucleosides, namely, uridine (Va; 81%), 5'-bromo-5'-deoxyuridine (Vb; 78%), and 5'-deoxyuridine (Vc; 83%). Hydrolysis of carbonates Ib and Ie is accompanied by the formation of the 2,2'-anhydro derivatives IIc (10%) and IIa (5%) as by-products.

An INDO study of the isomerization of aziridinone

AbstractThe only pathway postulated in the literature for the isomerization of aziridinone (Ia) to iminooxirane (IIIa) involves a planar, open‐chain, dipolar intermediate (IIa); however, INDO calculations suggest a possible alternative pathway in which an in‐plane bending of the oxygen atom towards the alkyl carbon atom occurs rather than a stretching of the alkyl‐nitrogen bond. INDO calculations also suggest that the unknown compound IIIa has the same degree of stability as Ia.

New Compounds: Oxazolidines and Derived Amino Alcohols

Oxazolidines II and V were prepared from 1-methyl-4-piperidone (I) and from 2-naphthalenecarboxaldehyde or p-chloro-benzaldehyde (IV) and appropriate secondary 2-aminoethanols. Platinum-catalyzed hydrogenation of II and II V gave amino alcohols III and VI, respectively. These oxazolidines and the corresponding amino alcohols showed no carcinolytic activity in experimental tests. Compound IIIa had marginal antimalarial activity in the mouse, P. berghei screen.