Identification of some isomeric 3,5-unsymmetrically substituted 1-aroyl-pyrazole derivatives by NMR spectroscopy

The ¹H and ¹³C nmr chemical shifts are used for the structural assignment of isomeric 1-aroyl-4,5-dihydro-5-hydroxy-4,4-dimethyl-1H-pyrazoles 1 unsymmetrically substituted with phenyl or methyl in the 3,5-positions of the pyrazole ring. The ¹H nmr spectra of 1-aroyl- or 1-acetyl-4-methyl-1H-pyrazoles 2 are useful in structure elucidation of unsymmetrically 3- or 5-methyl substituted derivatives.     

The synthesis of novel polycyclic heterocyclic ring system via photocyclization. 18. Benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c]quinoline and benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c] [1,2,4]triazolo[4,3-a]quinoline

The synthesis of two previously unknown polycyclic ring systems, benzo[h]naphtho[1′2′:4,5]-thieno[2,3-c]quinoline ( 1 ) and benzo[h]naphtho[1′,2′:4,5]thieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline ( 2 ), was achieved via oxidative photocyclization of 1-chloro-N-(1-naphthyl)naphtho[2,1-b]thiophene-2-carboxamide ( 5 ). The total assignment of their ¹H and ¹³C nmr spectra was determined by the concerted use of two-dimensional nmr methods.     

The Synthesis of Novel Polycyclic Heterocyclic Ring Systems via Photocyclization. 12. Benzo[h]naphtho-[2′,1′:4,5]thieno[2,3-c]quinoline and benzo[f]-naphtho[2′,1′:4,5]thieno[2,3-c]quinoline

The synthesis of two previously unknown heterocyclic ring systems, namely benzo[h]naphtho[2′,1′:4,5]thi-eno[2,3-c]quinoline (1) and benzo[f]naphtho[2′,1:4,5]thieno[2,3-c]quinoline (2) was accomplished via photocyclization of the appropriate amides followed by chlorination and catalytic dechlorination. The total assignment of ¹H and ¹³C nmr spectra of 2 was determined utilizing two-dimensional nmr methods, providing unequivocal structural proof of the two novel polycyclic ring systems.     

Synthesis of some 2,4-disubstituted tetrahydropyrimido[4,5-b]quinolines as potential antitumor agents

Cyclocondensations of two 2,4-disubstituted 6-aminopyrimidines with 2-chloro-1-cyclohexenecarboxaldehyde afforded in each case a new regiospecific synthesis of tricyclic, linear disubstituted 6,7,8,9-tetrahydro-pyrimido[4,5-b]quinolines 2 and 3 in excellent yields. The linear structures and hence the regiospecificity of the synthesis were established using ¹H nmr and ¹³C nmr. The growth of leukemia L1210 cells in culture was inhibited 50% by 2 at 30 × 10^?6M and 48% by 3 at 100 × 10^?6M.     

Synthesis and 13C-NMR study of pyrazolo[4,5-c] and pyrazolo[4,3-c benzazepines. III

The synthesis of pyrazolo[4,5-c][1]benzazepin-10-ones 10 and 13 and pyrazolo[4,3-c][1]benzazepin-10-ones 11 and 12 is reported. The structure of compounds 10-13 and that of their parent compounds 2-5 ensues from a ¹³C nmr study.     

The synthesis of 3-deazapyrimidine nucleosides related to uridine and cytidine and their derivatives

Condensation of 2,4-bis(trimethylsilyloxy)pyridine ( 1 ) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2 ) gave 4-hydroxy-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 3 ). Deblocking of 3 gave 4-hydroxy-1-β-D-ribofuranosyl-2-pyridone (3′-deazauridine) ( 4 ). Treatment of 4 with acetone and acid gave 2′,3′-O-isopropylidene-3-deazauridine ( 6 ). Reaction of 4 with diphenylcarbonate gave 2-hydroxy-1-β-D-arabinofuranosyl-4-pyridone-O₂←2′-cyclonucleoside ( 7 ) which established the point of gylcosidation and configuration of 4 . Base-catalyzed hydrolysis of 7 gave 4-hydroxy-1-β-D-arabinofuranosyl-2-pyridone (3-deazauracil arabinoside) ( 12 ). Fusion of 1 with 3,5-di-O-p-toluyl-2-deoxy-D-erythro-pentofuranosyl chloride ( 5 ) gave the blocked anomeric deoxynucleosides 8 and 10 which were saponified to give 4-hydroxy-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazauridine) ( 11 ) and its α anomer ( 9 ). Condensation of 4-acetamido-2-methoxypridine ( 13 ) with 2 gave 4-acetamido-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 14 ) which was treated with alcoholic ammonia to yield 4-acetamido-1-β-D-ribofuranosyl-2-pyridone ( 15 ) or with methanolic sodium methoxide to yield 4-amino-1-β-D-ribofuranosyl-2-pyridone (3-deazacytidine) ( 16 ). Condensation of 13 and 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride ( 17 ) gave the blocked nucleoside 22 which was treated with base and then hydrogenolyzed to give 4-amino-1-β-D-arabinofuranosyl-2-pyridone (3-deazacytosine arabinoside) ( 23 ). Fusion of 13 with 5 gave the blocked anomeric deoxynucleosides 18 and 20 which were deblocked with methanolic sodium methoxide to yield 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazacytidine) ( 21 ) and its a anomer 19 . The 2′-deoxy-erythro-pentofuranosides of both 3-deazauracil and 3-deazacytosine failed to obey Hudson's isorotation rule but did follow the “quartet”-“triplet” anomeric proton splitting pattern in the ¹H nmr spectra.     

Configurationally and conformationally homogeneous cyclicN-aryl sulfimides. II.13C-and1H NMR spectra

The configuration and (in case of mobile ring systems) the preferred conformation in a series of thiane- and ofcis-andtrans-1-thiadecalin-1-N-4-chlorophenyl imides were assigned by means of¹³C- and¹H nmr spectroscopy.¹H nmr criteria known to be valid for determination of the stereochemistry of cyclic sulfoxides may be applied (with limitations) to cyclicN-aryl sulfimides, if both isomers (S–N bond equatorial and axial, respectively) are known. The assignments are easier, and unambiguous for single isomers, by comparison of¹³C nmr chemical shifts of ring carbon atoms of sulfimides and sulfides. The influence of equatorially and axially oriented sulfimide groups on the chemical shifts of neighbouring protons, and on the carbon atoms of the heterocyclic rings are discussed in detail.

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Konfigurativ und konformationell einheitliche cyclische N-Aryl-sulfimide. II.¹³C- und¹H-NMR-Spektroskopie

Zusammenfassung Die Konfiguration und (bei beweglichen Ringsystemen) die bevorzugte Konformation einer Reihe von Thian- und voncis- undtrans-1-Thiadekalin-1-N-4-chlorophenylimiden wurde durch¹³C- und¹H-NMR-Spektroskopie bestimmt. Bekannte¹H-NMR-Kriterien zur Festlegung der Stereochemie cyclischer Sulfoxide sind (mit Einschränkungen) auch bei cyclischenN-Arylsulfimiden anwendbar, wenn beide Isomere (S–N-Bindung äquatorial bzw. axial) bekannt sind. Leichter, und auch bei Vorliegen von nur einem Isomeren eindeutig, gelingt die Zuordnung durch Vergleich der¹³C-NMR-Verschiebungen der Ringkohlenstoffatome von Sulfimiden und Sulfiden. Die Einflüsse äquatorial oder axial orientierter Sulfimidgruppen auf die chemischen Verschiebungen benachbarter Wasserstoffe und der Kohlenstoffe des Heterorings werden diskutiert.

     

Synthesis of the (Z) and (E) isomers of 1,2-diaryl-3-methyl-4,5-dioxo-3-pyrrolidinecarboxylic acid esters. Structural assignment by nmr and mass spectroscopy

Reaction of N-benzylideneaniline, 1a , with 3-methyl-2-oxobutanedioic acid diethyl ester, 2a , produced isomeric 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic acid ethyl esters, 3a and 3b . The higher melting isomer, 3a , was shown to have the (Z) configuration by nmr spectroscopy. The (Z) and (E) isomers of 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic acid methyl esters, 3c and 3d , were prepared from 1a and 3-methyl-2-oxobutanedioic acid dimethyl ester, 2b . The higher melting isomer, 3c , was shown to have the (Z) configuration. Similarly, N-benzylidene-p-toluidine, 1b , reacted with 2a to form (Z) and (E) isomers of 3-methyl-4,5-dioxo-1-(4-methylphenyl)-2-phenyl-3-pyrrolidinecarboxlic acid ethyl esters, 3e and 3f . Assignment of the ¹³C carbonyl carbon nmr chemical shift was made by preparing 2-methyl-3-oxobutanedioic-1-¹³C acid diethyl ester, 4 , and from it the corresponding (Z) and (E) isomers of 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic ¹³C acid ester, 5a and 5b . The mass spectra of the (Z) isomers exhibit prominent ions corresponding to the masses of the Schiff bases used to make them, and ions corresponding to the loss of ArNCOCO from the parent ion. The (E) isomers 3b, 3d and 5b exhibit a prominent ion of mass 264; 3f gives mass 278, corresponding to the loss of the carboalkoxy group.     

Synthesis of substituted dihydrobenzo[f]pyrimido[4,5-b]-quinolines as tetracyclic 5-deaza nonclassical folates

Cyclocondensation of 2,4,6-triaminopyrimidine ( 10 ) with chlorovinyl aldehyde 7 afforded the linear regioisomer 9,1 1-diamino-5,6-dihydrobenzo[f]pyrimido[4,5-c]quinoline ( 1 ) while the cyclocondensation of 2,6-diamino-4-hydroxypyrimidine ( 11 ) or 6-amino-2,4-dihydroxypyrimidine ( 12 ) with chlorovinyl aldehyde 7 was regiospecific affording the linear regioisomers 9-amino-11-oxo-5,6-dihydrobenzo[f]pyrimido[4,5-c]quinoline ( 2 ) and 9,11-dioxo-5,6-dihydrobenzo[f]pyrimido[4,5-c]quinoline ( 3 ) respectively. The linear structures of these compounds were established by ¹H nmr and ¹³C nmr spectral data.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 10. Synthesis and structure determination of naphtho[1′,2′:4,5]thieno[3,2-a]-4,7-phenanthroline

Naphtho[1′,2′:4,5]thieno[3,2-a]-4,7-phenanthroline, a novel hexacyclic ring system has been synthesized in four steps. The ¹H and ¹³C nmr assignments have been made using two-dimensional nmr techniques. The tertiary helical structure was determined by X-ray crystallographic analysis.     

17O NMR spectroscopy: Intramolecular hydrogen bonding in hydroxypyridine carboxy esters

Natural abundance ¹⁷O nmr chemical shift data for 8 aryl esters and 10 pyridine carboxy esters, including 6 ortho-hydroxy esters, recorded in acetomitrile at 75° are reported. The carbonyl group ¹⁷O nmr chemical shift data for methyl 2-, 3- and 4-pyridinecarboxylate are correlated with σ⁺ constants. The hydrogen bonding component (Δδ_HB) to the ester carbonyl ¹⁷O nmr chemical shift for the intramolecular hydrogen bonded ortho-hydroxy systems are 9.8 ppm, 13.6 ppm and 4.3 ppm for benzoates, 2-pyridinecarboxylates and 4-pyridinecarboxylates, respectively. The relationships of the ester Δδ_HB values to other hydrogen bond acceptor Δδ_HB values are discussed.     

Synthesis and structure of novel 1,2-dihydro-phthalazine containing betaines

1,2-Dihydro-2-(4,5-dihydroimidazol-2yl)phthalazin-1-ol 1 reacts exothermically with dialkyl acetylenedicarboxylates to give 3-[2-(4,5-dihydro-1H-imidazol-3-iurn-2-yl)-1,2-dihydro-1-phthalazin]-1,4-dialkoxy-1,4-dioxo-2-buten-2-olates 7 and 8 . Enolic ester compounds underwent further transesterification reactions with formation of the betaines 9 and 10 . The unequivocal structural assignement of these compounds was achieved by spectroscopic ¹H and ¹³C nmr methods as well as X-ray analysis of 7 .     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 4 . Benzo[f]thieno[2′,3′:4,5]thieno[2,3-c]quinoline and Benzo[h]thieno[2′,3′:4,5]thieno[2,3-c]quinoline and the total assignment of their 1H- and 13C-NMR spectra

The synthesis of two novel polycyclic heterocyclic ring systems via photocyclization are reported. These are benzo[f]thieno[2′,3′:4,5]thieno[2,3-c]quinoline and benzo[A]thieno-[2′,3′:4,5]thieno[2,3-c]quinoline. The total assignment of their ¹H- and ¹³C-nmr spectra was determined by utilizing two-dimensional nmr spectroscopic methods.     

13C NMR spectra of 1-(α-aroyloxyarylideneamino)-1,2,3-triazoles. Identification of 4,5-unsymmetrically substituted derivatives

The ¹³C nmr spectra of the title compounds are reported. Chemical shifts of C-4 and C-5 carbons of the triazole ring are used for structural assignment of the 4,5-unsymmetrically substituted 1-(α-aroyloxyarylideneamino)-v-triazoles (triazolylisoimides). A complete assignment of the shifts of the α-aroyloxyarylideneamino group is given. Some J_C-H values are also reported.     

Furopyridines. X. Synthesis of tricyclic heterocycles,furo[2,3-b:4,5-c']-, furo[3,2-b:4,5-c']-, furo[2,3-c:4,5-c']- and furo[3,2-c:4,5-c']dipyridine

This paper describes the synthesis of four tricyclic heterocycles, furo[2,3–6:4,5-c']- ( 5a ), furo[3,2-b:4,5-c']- ( 5b ), furo[2,3-c:4,5-c']- ( 5c ) and furo[3,2-c:4,5-c']dipyridine ( 5d ). Starting with 2-formylfuropyridines ( 1a-d ), β-(2-furopyridyl)acrylic acids 2a-d were obtained by condensing with malonic acid. The acrylic acids were converted to the acid azides by reaction with ethyl chloroformate and the subsequent reaction with sodium azide. Heating of the acid azides at 230–240° with diphenylmethane and tributylamine gave tricyclic pyridinones 3a-d , which were converted to the respective chloro derivatives 4a-d by reaction with phosphorus oxychloride. Reduction of the chloro compounds over palladium-charcoal yielded compounds 5a-d respectively. All the compounds 2 to 5 were characterized by elemental analysis and spectral data. The H and ¹³C nmr and electronic spectral features of the furodipyridines were discussed comparing with those of the parent furopyridines.     

Nitrogen Bridgehead Compounds. Part 79. Synthesis and structure elucidation of benzimidazolo[2,1-f][1,6]naphthyridine aza-derivatives

6-Substituted 1,6-naphthyridine-5(6H)-ones were prepared from diethyl 2-[2-(dimethylamino)vinyl]-6-methylpyridine-3,5-dicarboxylate 1 [2] by ring closure with aromatic and heteroaromatic diamines (o-phenylenediamine, 2,3-diaminopyridine, 3,4-diaminopyridine and 4,5-diaminopyrimidine, respectively). 1,6-Naphthyridine-5(6H)-ones were cyclised in phosphoryl chloride to yield nitrogen bridgehead tetracycles 6-9 . The structure of the products was established by nOe difference spectroscopy. A complete ¹H and ¹³C nmr assignment was achieved by different 2D carbon-proton correlation measurements.     

Stereospecific synthesis of new 5-substituted 6-methyl-4,5-dihydro-2H-pyridazin-3-ones. X-ray assignment study

Reaction of hydrazine hydrate with 4,5-dihydro-3H-4-acetyl furan-2-ones I led to ring opening and rearrangement into 6-methyl-4,5-dihydro-2H-pyridazin-3-ones II ( 1–20 ), the structure of which was determined by spectroscopic methods (ir, ¹H and ¹³C nmr). An X-ray crystal structure study of compound 2 supports the assignment of configuration erythro (5RS, 7SR) for pyridazinones II. Stereochemical courses of this new synthetic route are discussed.     

Assignments of the 1H and 13C NMR spectra of pseudo-symmetric heterocyles using the HMQC-TOCSY experiment to differentiate overlapping spin systems

The ¹H nmr spectra of phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline, benzo[f]phenanthro-[9′,10′:4,5]thieno[2,3-c]quinoline and benzo[h]phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline are highly congested. For each compound, all protons abide in an aromatic environment complicated by pseudo-symmetric regions which result in multiple overlap of the different spin systems these molecules contain. We illustrate here the utility of the HMQC-TOCSY experiment to identify spin systems when the proton spectrum is highly congested. To complete the assignment of the ¹H and ¹³C nmr spectra of each compound the HMBC experiment is used to assign the quaternary carbons.     

Synthesis of two novel ring systems via photocyclization: Thieno[2′,3′:4,5]thieno[2,3-c][1,10]phenanthroline and thieno[3′,2′:4,5]thieno[2,3-c][1,10]phenanthroline

The synthesis of thieno[2′,3′:4,5]thieno[2,3-c][1,10]phenanthroline ( 5 ) and thieno[3′,2′:4,5]thieno-[2,3-c][1,10]phenanthroline ( 10 ) are described. Each compound was obtained in four steps from known starting materials. The basic skeleton of the molecule and of the phenanthroline ring were formed via photocyclization. The total assignment of ¹H-nmr spectra was accomplished with the aid of two-dimensional nmr methods.     

Synthesis and NMR studies of some imidazo[4,5-d]pyridazine nucleosides

Unlike imidazo[4,5-d]pyridazin-4(5H)-one ( 1a ), which undergoes ribosylation at N-6 in the Vorbruggen procedure for nucleoside synthesis, the 5-benzyloxymethyl derivative 12 undergoes ribosylation at N-1 and N-3 to give a separable mixture of 14 and 15 . Removal of the N-5 blocking groups from 14 and 15 by treatment with boron trichloride at −78° affords the intermediates 16 and 17 , which were debenzoylated to give the 4-oxo nucleosides 5 and 6 . Thiation of 16 and 17 , followed by S-methylation and ammonolysis leads to the 4-amino nucleosides 2 and 3 . The glycosylation sites of these nucleosides were assigned by using a combination of ¹H and ¹³C nmr data, especially measurements of the spin-lattice relaxation times (T₁) of the base protons. Using these techniques, it is shown that a nucleoside previously reported to be 3 is in fact the N-6 isomer.