Exploiting 3-Oxidopyraziniums toward Diazabicyclo[3.2.1]octanes and Their Conversion into Diazabicyclo[2.2.2]octanes and Tricyclic Lactone-Lactams.

3-Oxidopyraziniums are azomethine ylides derived from 2(1H)-pyrazinones that can undergo 1,3-dipolar cycloadditions with acrylate and acrylic acid derivatives. The cycloaddition of 1-(4-methoxybenzyl)-5,6-dimethyl-3-oxidopyrazinium with methyl and tert-butyl acrylate and with methyl crotonate afforded a 3,8-diazabicyclo[3.2.1]octane in 51-73% yield together with traces of the 2,5-diazabicyclo[2.2.2]octane. In contrast, cycloaddition of this 3-oxidopyrazinium with methyl 2-phenyl acrylate provided the [2.2.2] product in 40% yield. Herein, we show that the 2,5-diazabicyclo[2.2.2]octanes were formed from the [3.2.1] compounds via a Wagner-Meerwein rearrangement. Remarkably, when acrylic acid and 2-phenylacrylic acid were employed as dipolarophiles, novel tricyclic fused lactone-lactam systems were obtained in 71% and 50% yields, respectively. The formation of these tricyclic compounds can be rationalized via the mechanism described above followed by lactonization of the 2,5-diazabicyclo[2.2.2]octane.

2(1H)-Pyrazinones from acyclic building blocks: methods of synthesis and further derivatizations.

Pyrazinones (2(1H)-pyrazinones) are found as components of a range of natural substances and are involved in the preparation of a great number of bioactive molecules. Synthesis of such compounds, and analogues, requires knowledge of the heterocyclic properties of pyrazinones and, in particular, methods for their ring construction. This review deals with the strategies that have been developed for the synthesis of pyrazinones from acyclic precursors, especially α-amino acid-derived units, from the first examples in 1905 up to the most recent in 2021.

A DFT study of the [3 + 2] versus [4 + 2] cycloaddition reactions of 1,5,6-trimethylpyrazinium-3-olate with methyl methacrylate.

The reaction between 1,5,6-trimethylpyrazinium-3-olate and methyl methacrylate (MMA) yielding a lactone-lactam has been studied using the DFT method at the B3LYP/6-31G(d) level. It is concluded that formation of the lactone-lactam is a domino process involving three consecutive reactions: (i) a 1,3-dipolar cycloaddition (13DC) reaction between the pyrazinium-3-olate and MMA yielding a [3 + 2] cycloadduct (CA); (ii) a skeletal rearrangement, which converts the [3 + 2] CA into a formal [4 + 2] CA, possessing a diazabicyclo[2.2.2]octane structure; and finally, (iii) an S(N)2 reaction, promoted by halide anion, with concomitant nucleophilic attack of the created carboxylate anion on an iminium carbon with formation of the lactone ring present in the lactone-lactam. Analysis of the four competitive channels associated with the 13DC reaction indicates that this cycloaddition takes place with complete endo stereoselectivity and 6 regioselectivity, yielding [3 + 2] CA. The subsequent skeletal rearrangement also takes place in an elementary step via a non-concerted mechanism. Electron localization function bonding analysis makes it possible to establish that the bicyclo[2.2.2]octane skeleton present in the lactone-lactam complex structure is not attained via a Diels-Alder reaction between pyrazinium-3-olate and MMA.

Three anilides of 2,2'-thiodibenzoic acid.

The structures of N,N'-bis(2-methylphenyl)-2,2'-thiodibenzamide, C(28)H(24)N(2)O(2)S, (Ia), N,N'-bis(2-ethylphenyl)-2,2'-thiodibenzamide, C(30)H(28)N(2)O(2)S, (Ib), and N,N'-bis(2-bromophenyl)-2,2'-thiodibenzamide, C(26)H(18)Br(2)N(2)O(2)S, (Ic), are compared with each other. For the 19 atoms of the consistent thiodibenzamide core, the r.m.s. deviations of the molecules in pairs are 0.29, 0.90 and 0.80 Å for (Ia)/(Ib), (Ia)/(Ic) and (Ib)/(Ic), respectively. The conformations of the central parts of molecules (Ia) and (Ib) are similar due to an intramolecular N-H···O hydrogen-bonding interaction. The molecules of (Ia) are further linked into infinite chains along the c axis by intermolecular N-H···O interactions, whereas the molecules of (Ib) are linked into chains along b by an intermolecular N-H···π contact. The conformation of (Ic) is quite different from those of (Ia) and (Ib), since there is no intramolecular N-H···O hydrogen bond, but instead there is a possible intramolecular N-H···Br hydrogen bond. The molecules are linked into chains along c by intermolecular N-H···O hydrogen bonds.

Copper-induced N-N bond cleavage results in an octanuclear expanded-core grid-like complex.

Reaction of copper(I) acetate and 4-amino-3,5-di(2-pyridyl)-1,2,4-triazole (adpt) in methanol under ambient conditions yields octanuclear [Cu(II)(8)(dpt)(4)(OH)(4)(OAc)(8)]; OAc = acetate anion, and dpt(-) = anion of deaminated adpt, 3,5-di(2-pyridyl)-1,2,4-triazolate. However, reaction of copper(ii) acetate with dptH gives tetranuclear [Cu(II)(4)(dpt)(2)(OH)(OMe)(OAc)(4)].

2-[(Z)-4,7-Dichloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-yl-idene]-3-oxopropane-nitrile.

In the title compound, C(13)H(10)Cl(2)N(2)O, the ring N atom and its three attached atoms are essentially coplanar with angles adding to 359.8°, indicating conjugation with the 2-formyl-acrylonitrile subunit. The aldehyde group is oriented to place the carbonyl O atom 2.02 (3) Šfrom the N-H hydrogen atom. Intra-molecular N-H⋯O and C-H⋯Cl inter-actions occur. The geometry of the exocyclic double bond is Z. In the crystal, weak C-H⋯N hydrogen bonds link the mol-ecules into chains along [1[Formula: see text]0].

2-(4-Chloro-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-yl-idene)-2-cyano-acetamide.

Reaction of 2-(4-chloro-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-yl-idene)propane-dial with hydroxyl-amine gives the title compound, C(14)H(14)ClN(3)O, in which the ring N atom is essentially planar [sum of angles around the ring N atom = 361°], indicating conjugation with the 2-cyano-acryl-amide unit. The orientation of the acetamide group arises from intra-molecular hydrogen bonding between the indole N-H and carbonyl groups. In the crystal, inversion-related acetamide groups form N-H⋯O hydrogen-bonded dimers in graph-set R(2) (2)(8) motifs, whilst dimers are also formed by pairs of amine-nitrile N-H⋯N hydrogen bonds in R(2) (2)(12) motifs. These inter-actions together generate ribbons that propagate along the b-axis direction.

N'-[1-(2,4-Dioxo-3,4-dihydro-2H-1-benzopyran-3-yl-idene)eth-yl]thiophene-2-carbo-hydrazide.

The title compound, C(16)H(12)N(2)O(4)S, was obtained by the condensation of 3-acetyl-4-hy-droxy-coumarin with thien-2-ylcarbonyl hydrazide. The pyran ring adopts a 2,4-dione tautomeric form. The benzopyran ring system is almost coplanar with the thio-phene ring [dihedral angle 0.9 (2)°]. The exocyclic C=C double bond has an E geometry. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond. In the crystal, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into chains along the a axis.

1-[(E)-4-(5-Bromo-1H-indol-3-yl)-1-methyl-2,5,6,7-tetra-hydro-1H-azepin-2-yl-idene]propan-2-one.

In the title compound, C(18)H(19)BrN(2)O, the seven-membered azepine ring adopts a twist-boat conformation: the bond angles about the azepine N atom are indicative of sp(2) hybridization. The dihedral angle between the plane of the carbon-carbon double bond of the enone unit and the mean plane of the indole ring is 27.8 (1)°. In the crystal, an N-H⋯O hydrogen bond links the mol-ecules into chains along the b axis.

N,N'-Bis(3-phenyl-prop-2-en-1-yl-idene)-2,2'-disulfanediyldianiline.

In the title compound, C(30)H(24)N(2)S(2), the two phenyl rings attached to the S atoms are oriented nearly perpendicularly, making a dihedral angle of 86.14 (8)°. Each of the two ArCH=CHCH=N units is almost planar, having maximum deviations from the least-squares planes of 0.125 and 0.149 Å, and rotated around the C-N bonds relative to the adjacent phenyl ring by 110.26 and 30.30°.

3-(1-Methyl-pyrrolidin-2-yl-idene)-3H-indole sesquihydrate.

The asymmetric unit of the title compound, C(13)H(14)N(2)·1.5H(2)O, contains two similar mol-ecules of 3-(1-methyl-pyrrolidin-2-yl-idene)-3H-indole, (I), and three water mol-ecules. (I) is the product of reacting indole with 1-methyl-pyrrolidin-2-one in the presence of phospho-rus oxychloride. Both organic molecules are almost completely planar; the maximum distances above and below the least-squares plane through all the atoms of mol-ecule 1 are 0.050 (8) and -0.045 (8) Å, respectively, and the deviations for mol-ecule 2 are 0.096 (8) and -0.059 (8) Å, respectively. In the crystal, the two crystallographically different mol-ecules alternate in π-stacked columns [centroid-centroid distances = 3.729 (5) and 3.858 (5) Å], which are linked by O-H⋯N hydrogen bonds to a network of hydrogen-bonded water mol-ecules. O-H⋯O inter-actions are also present.

7-Chloro-2-[1-(4-methoxy-phen-yl)pyrazol-4-yl]-3,3-dimethyl-3H-indole.

In the title compound, C(20)H(18)ClN(3)O, the dihedral angle between the pyrazole and the 3H-indole components is only 13.28 (6)°, indicating that there is conjugation between the two heterocyclic subunits. The N-methoxy-phenyl unit makes a dihedral angle of 25.10 (7)° with the pyrazole ring.

N,N'-(2,2'-Dithiodi-o-phenyl-ene)bis-(furan-2-carboxamide).

The reaction of 2,2'-dithio-bis(benzenamine) with furan-2-carbonyl chloride produced the bis-amide title compound, C(22)H(16)N(2)O(4)S(2), which, in the crystal, formed a helix; the structure consists of two planar furanoylbenzenamines related by an improper rotation of 96.3° about the S-S bond. The N-furanoylbenzenamine units are planar (maximum deviations = 0.316 and 0.132 Å). Each electron-deficient acyl-furan stacks (centroid-centroid separations of the two pairs of π-π stacked aromatic rings are 3.918 and 3.953 Å) with the electron-rich benzenamine of the other N-furan-oyl-benzenamine unit, leading to a spiral structure. The conformation is stabilized by two bifurcated intramolecular N-H⋯(O,S) interactions.

4-(Pyrrol-1-yl)-1,2,4-triazole.

The asymmetric unit of the title compound, C(6)H(6)N(4), comprises one and a half molecules with a C(2) axis through the second molecule. Each molecule consists of two planar five-membered rings connected by a triazole-pyrrole N-N bond with the triazole ring close to being at right angles to the pyrrole ring. The molecules are linked by C-H...N hydrogen bonds and weaker offset face-to-face pi-pi interactions.

The role of tetrahydrobiopterin in catalysis by nitric oxide synthase.

Electronic structure calculations show that the cofactor H4B can be a key factor in a proton transfer relay in nitric oxide synthase, and that 4-amino-H4B cannot fulfill this role.

Promotion of oxygen atom transfer in Mo and W enzymes by bicyclic forms of the pterin cofactor.

Density functional theory calculations suggest that bicyclic structures of the "molybdopterin" in DMSO reductases may have an important catalytic role in oxygen atom transfer reactions.

Total syntheses of variolin B and deoxyvariolin B.

Two alternative synthetic routes have been developed for the preparation of variolin B and deoxyvariolin B. The strategy is based on the preparation of the core tricyclic ring common to all variolins, pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine, followed by a palladium-catalyzed cross-coupling reaction to give the tetracyclic system.

Synthesis of 1,3-dithiol-2-ones as proligands related to molybdopterin.

The reaction of suitably disubstituted alkynes with diisopropyl xanthogen disulfide gives differentially substituted 4,5-disubstituted-1,3-dithiol-2-ones as proligands for metal complexes related to the molybdenum cofactor.

Synthesis of Pyrrolo[4,3,2-de]quinolines from 6,7-Dimethoxy-4-methylquinoline. Formal Total Syntheses of Damirones A and B, Batzelline C, Isobatzelline C, Discorhabdin C, and Makaluvamines A-D.

2-Amino-4-nitrophenol and 2-methoxy-5-nitroaniline were converted into the 5-nitroquinolines 6b and 6d, respectively, and then the latter into nitro-acetal 6f. 6,7-Dimethoxy-4-methylquinoline (6g) was nitrated at C-5 and then the methyl substituent converted into aldehyde 6j and then protected giving acetal 6l. Various means, notably a large excess of NiCl(2)/NaBH(4), were used to reduce both nitro group and pyridine ring, forming 1,2,3,4-tetrahydroquinolines such as 7b, 7c, 7d, which under acidic conditions closed to give 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolines 9a, 9d, 9c, respectively. In some cases it was unnecessary to protect the aldehyde function, for example quinolinium salt 12c gave 9j and nitro-aldehyde 6j gave 9e (after BOC protection) directly by reaction with NiCl(2)/NaBH(4). Substitution of the indole and aniline nitrogens in the 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolines was based on a combination of protection, selective deprotection, and the exploitation of the greater acidity of the indole N-hydrogen. 8-Chlorination of 6h and then conversions, as above, gave chloro-diamine-acetal 7e which on acid treatment produced iminoquinone 11b; formylation of the nitrogens in 7e and then acidic treatment allowed formation of the chlorine-substituted 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline 9m which was then converted into 9p. De-O-methylation and then oxidation of 9b and 9c gave o-quinones 10b and 10a, respectively.