Synthesis of 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitriles and -6-carboxylic acid esters

Dieckmann ring closure reactions of 4-[(2-cyanoethyl)substituted amino]-2-phenyl-5-pyrimidinecarboxylates (Ha-f) afforded several 5,6,7,8-tetrahydro-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitriles (IIIa-f). The open-chain intermediates (IIa-f) were prepared by dechloroamination of 5-carbethoxy-4-chloro-2-phenylpyrimidine (1a) with several 3-substituted amino- propionitriles. Alkylation of the sodium salt of 5,6,7,8-tetrahydro-8-methyl-5-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6- carbonitrile (IIIa) with methyl iodide in DMF resulted in methylation at C-6 to afford IV. Tosylation of IIIa in pyridine gave the corresponding tosyl ester (V) of the enolic form. Oxidative dehydrogenation at the 6,7-position resulted when IIIa reacted with thionyl chloride, affording 5,8-dihydro-8-methyl-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitrile (VII). Dechloroamination of la or 5-carbethoxy-4-chloro-2-methylthiopyrimidine (Ib) with ethyl 3-ethylaminopropionate followed by Dieckmann cyclization of the resulting open-chain intermediates gave the corresponding ethyl 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates IX'a and IX'b, respectively. These exist predominately in the enol form and undergo alkylation and oxidation reactions similar to IIIa.     

Synthesis of unsymmetrical 2,4-dialkylpyrazolo[1,5-a]-1,3,5-triazines

The reaction of 3-aminopyrazole with imidate esters such as ethyl acetimidate, gave N-(pyrazol-3-yl)acetamidine (1) rather than the isomeric 2-acetamidoyl-3-aminopyrazole. Ring closure of 1 with orthoesters such as ethyl propionimidate, afforded unsymmetrically substituted 2.4-dialkylpyrazolo[1,5-a]-1,3,5-triazines such as 4-ethyl-2-methylpyrazolo[1,5-a]-1,3,5-triazine (3). The structure of 1 was confirmed by several alternate syntheses. The unique feature of this two-step synthetic approach to the synthesis of pyrazolo[1,5-a]-1,3,5-triazines is that it is a convenient method of preparing fused triazines based on available pyrazoles rather than the less accessible dialkyltriazines.     

The solid solutions Na3(1−x)Alx2xPO4: room temperature powder neutron diffraction studies of the two compositions x=0.025 and x=0.2

The crystal structures of the high-temperature modifications of sodium and silver orthophosphates have been determined using powder neutron diffraction (PND) data. II-Na₃PO₄ adopts the space group Fm3m with at 400°C. The PO³⁻₄ group is centered around the origin, but it shows high orientational disorder. The sodium ions occupy the and sites. II-Ag₃PO₄, at 650°C, is similar with . The structure of I-Ag₃PO₄ at room temperature

Full-size image (<1K)

has been re-examined by single-crystal X-ray diffraction. The derived model, with R=0.019 for 116 independent reflections, is in agreement with the latest work reported in the literature. The structure of I-Ag₃PO₄ at 375°C, as determined by PND, has , and displays no gross modifications from that observed at 25°C, although the anisotropic nature of the silver sites is markedly more pronounced at this higher temperature. The cation mobility is discussed in relation to the high-temperatures structures.     

cis‐(6RS,13RS)‐3,3,10,10‐Tetra­methyl‐6,13‐diphenyl‐1,8‐dioxa‐4,11‐diaza­cyclo­tetra­decane‐2,5,9,12‐tetra­one and two of its precursors

The title macrocycle, C₂₆H₃₀N₂O₆, (VI), was obtained by `direct amide cyclization' from the linear precursor 3‐hydr­oxy‐N‐[1‐methyl‐1‐(N‐methyl‐N‐phenyl­carbamoyl)ethyl]‐2‐phenylpropanamide, the N‐methyl­anilide of rac‐2‐methyl‐2‐[(3‐hydroxy‐2‐phenyl­propanoyl)­amino]­propanoic acid, C₁₃H₁₇NO₄, (IV). The reaction proceeds via the inter­mediate rac‐2‐(2‐hydroxy‐1‐phenyl­ethyl)‐4,4‐dimethyl‐1,3‐oxazol‐5(4H)‐one, C₁₃H₁₅NO₃, (V), which was synthesized independently and whose structure was also established. Unlike all previously described analogues, the title macrocycle has the cis‐diphenyl configuration. The 14‐membered ring has a distorted rect­angular diamond‐based [3434] configuration and inter­molecular N—H⋯O hydrogen bonds link the mol­ecules into a three‐dimensional framework. The propanoic acid precursor forms a complex series of inter­molecular hydrogen bonds, each of which involves pairwise association of mol­ecules and which together result in the formation of extended two‐dimensional sheets. The oxazole inter­mediate forms centrosymmetric hydrogen‐bonded dimers in the solid state.     

Rapid transacylations of activated ester substrates bound to the primary side β-cyclodextrin-cyclen conjugate and its M2+ complexes

The ability of cyclodextrins to effect rapid transacylations of bound substrates has been well studied. One important difference between cyclodextrin and enzyme-mediated transacylation is the pH required. Because the pK _a of a cyclodextrin secondary-side hydroxyl group is about 12, transacylations are accelerated in the presence of cyclodextrin under basic conditions (pH > 10.5). In 1988, our group reported the synthesis of cyclodextrin with attached cyclen-Co(III) complexes; significant acceleration in the reaction withp-nitrophenyl acetate was observed only with the primary side derivative. Of course, metalloenzymes utilize M²⁺ and not M³⁺ catalytic centers; in addition, large rate accelerations in the transacylations of both activated and unactivated substrates have been observed previously in systems utilizing M²⁺ ions (e.g., Zn, Cu, Ni) as well as M³⁺ ions (e.g. Co, Ir, Cr). In this paper, we describe the ability of CD-cyclen-M²⁺ conjugates to transacylate activated esters, amides, and phosphates. In addition, the ability of the apoenzyme mimic to effect transacylations was examined.     

Synthesis of a Derivative of the Peptaibol‐Antibiotic Trichovirin I 1B by Means of the ‘Azirine/Oxazolone Method’

According to the earlier published synthesis of the C‐terminal nonapeptide of Trichovirin I 1B, Z‐Ser(^tBu)‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 5 ), the complete tetradecapeptide Z‐Aib‐Asn(Trt)‐Leu‐Aib‐Pro‐Ser(^tBu)‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 11b ), a protected Trichovirin I 1B, has now been prepared by means of the ‘azirine/oxazolone method’. With the exception of the N‐terminal Aib(1), all Aib residues were introduced by the coupling of the corresponding amino or peptide acids with 2,2‐dimethyl‐2H‐azirine‐3‐(N‐methyl‐N‐phenylamine) ( 1a ) and methyl N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)‐L ‐prolinate ( 3a ) as the Aib and Aib‐Pro synthons, respectively. Single crystals of two segments, i.e., the N‐terminal hexapeptide Z‐Aib‐Asn(Trt)‐Leu‐Aib‐Pro‐Ser(^tBu)‐OMe ( 23 ) and the C‐terminal octapeptide Z‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 17 ), were obtained and their structures have been established by X‐ray crystallography. Following the same strategy, the C‐terminal nonapeptide of Trichovirin I 4A, Z‐Ala‐Val‐Aib‐Pro‐Aib‐Leu‐Aib‐Pro‐Leuol ( 26 ), was also synthesized and characterized by X‐ray crystallography.     

Enhancement of combinatorial chemistry by microwave-assisted organic synthesis

It was in the 1980 s that the first papers in which the use of either combinatorial methods or microwave heating in organic chemistry were published. Unlike combinatorial chemistry, which quite readily became an accepted method, particularly in the pharmaceutical industry, it is only now that microwave heating is truly gaining acceptance. Our aim in this review is to attempt to rationalize this slow acceptance and to show the benefits to be gained by employing microwave heating in tandem with combinatorial chemistry. We will also give a number of examples of successful applications.     

Synthesis and electronic characterization of bipyridine dithiolate rhodium(III) complexes

Five new mixed diimine 1,1'-dithiolate or dithiocarbamate ligand complexes of the form [Rh(bpy)2(SS)][PF6]n, where bpy = 2,2'-bipyridine and SS = various substituted dialkyldithiocarbamates or 1,1'-dithiolates, were synthesized from cis-[Rh(bpy)2(OTf)2][OTf]. The triflate ligands are easily displaced by other ligands and allow these syntheses to proceed in high yields (80-90% overall) under relatively mild reaction conditions and to give high purity products. Electrochemistry shows irreversible two-electron reduction of Rh(III) to Rh(I) and a concomitant loss of one bipyridine ligand; this is followed by reversible one-electron reduction of the remaining 2,2'-bipyridine ligand. The electronic characterizations of these complexes are consistent with significant delocalization of the sulfur electron density onto the empty metal d orbitals. The 1,1'-dithiolate ligands induce larger red shifts in the absorption and emission spectra than the dithiocarbamates as the 1,1'-dithiolates have a more extensive conjugation system.     

Metal-oxygen-metal arrays in lamellar hybrid materials: cobalt and manganese 4-cyclohexene-1,2-dicarboxylates

We have obtained three layered hybrid materials from the hydrothermal reaction of 4-cyclohexene-1,2-dicarboxylic acid with Co and Mn salts: Co(C(8)H(8)O(4))[1], Mn(H(2)O)(C(8)H(8)O(4))[2], and Mn(4)(H(2)O)(C(8)H(8)O(4))(4).0.3(H(2)O)[3]. The structures for all materials were solved by single-crystal XRD ([1]P1, a=4.805(2) A, b=6.650(3) A, c=12.960(6) A, alpha=98.285(7) degrees, beta=98.986(7) degrees, gamma=95.689(7) degrees, V= 401.6(3) A(3), R(1)= 0.0438; [2] P2(1)/c, a=11.151(2) A, b=11.330(2) A, c=7.6560(15) A, beta=108.813(3) degrees , V=915.6(3) A(3), R(1)=0.0412; [3] P1, a= 11.412(3) A, b=12.136(4) A, c=13.809(4) A, alpha=104.703(6) degrees, beta=103.207(6) degrees, gamma=92.468(5) degrees, V=1790.6(9) A(3), R(1)=0.1056). While all three structures are two-dimensional overall, the metal-oxygen-metal dimensionality within the layers varies from isolated metal atoms in the case of [1] to 1D ribbons of vertex sharing MnO(6) octahedra [2] and 2D arrays of edge- and vertex-sharing polyhedra in [3].     

The behaviour of micro-bitumen drops in aqueous clay environments

This study summarises the rheological behaviour of emulsion bitumen drops in the presence of aqueous solutions of de-ionised or process water (DIW or PW) containing montmorillonite clays (M) and/or calcium ions (Ca++). The presence of calcium ions and montmorillonite clays resulted in the plastic behaviour of bitumen drops. In a DIW+M+Ca++ system, increasing temperature and calcium ion concentration resulted in an increase in the number and degree of plastic bitumen drops. In the presence of considerable amounts of Ca++ ions and/or at higher experimental temperature, bitumen drops in a PW+M system exhibited no significant overall plasticity of their surfaces. Both calcium and sodium ions contained in process water compete with each other to occupy the montmorillonite clay surface. At the pH value of process water (pH congruent with8), increasing the temperature did not change the value of bitumen droplet zeta potential. Stability of bitumen-in-water emulsions at 22 degrees C showed that bitumen droplets coalesced upon contact in the DIW+M system. The addition of calcium ions (Ca++) led to the inhibition of coagulation and coalescence of bitumen droplets, which may indicate the formation of CaM aggregates at the bitumen-water interface.