A series of hexa(heteroaryl)benzenes were synthesized by the Ru(II)–carboxylate-catalyzed multiple C–H activation of benzenes carrying pyridyl, pyrimidyl, or pyrazolyl directing groups using ...N-heteroaryl bromides as coupling partners. The reactions proceeded with high selectivity under microwave irradiation in water. Iterative penta-arylation could be implemented via activation of C–H bonds of generated intermediates by cascade chelation assistance of in situ installed pyridyl groups. This strategy provides multidentate ligands for selective complexation of transition metals and potential building of photoredox systems.
Self-assembly of AgOTf and AgF with the hexatopic ligands hexakis(pyridin-2-yl)benzene (2) and 2,4,6-tris(pyridin-2-yl)-1,3,5-tris(quinolin-2-yl)benzene (3) affords the discrete sandwich-shaped ...complexes Ag4F(2)2(OTf)3, Ag4F(3)2(OTf)3, and Ag5F(2)2(OTf)4. The solid-state structures of the complexes were characterized by single-crystal X-ray diffraction analysis, which revealed that the fluoride anion is coordinated in the center of the Ag4-square or Ag5-pentagon units which are positioned between two molecules of the hexakis(azaheteroaryl)benzene. The generation of complexes is dictated by a unique cooperation of ligand coordination, argentophilicity, and fluoride anion inclusion. All three complexes adopt highly symmetrical structures in solution, as evidenced by appearance of one set of proton resonances for the two ligands arranged face to face.
Ru(II)/carboxylate/PPh3 catalyst system enabled the preparation of highly conjugated pyrazine derivatives in water under microwave irradiation. Both nitrogen atoms efficiently dictated cleavage of ...the ortho-C–H bonds in both benzene rings of 2,3-diphenylpyrazine substrates through chelation assistance. In conformationally more flexible diphenyldihydropyrazine 1, the arylation of four ortho-C–H bonds was possible, while in the aromatic analog 2, the triarylation was the limit.
Despite the fact that it was put on the market more than 60 years ago, hydrochlorothiazide (HCT) is still one of the most important antihypertensive drugs. Due to its chemical structure, which ...contains the secondary aryl-alkyl-amino moiety, it is vulnerable to the formation of N-nitrosamine drug substance-related impurity (NDSRI) N-nitroso-hydrochlorothiazide (NO-HCT). In our study, we reveal that NO-HCT degrades rapidly at pH values 6 to 8. The main degradation products identified are formaldehyde, thiatriazine, and aminobenzenesulfonic acid derivative. Interestingly, degradation of NO-HCT at pH values from 5 to 1 is significantly slower and provides a different impurity profile when compared to the profile generated between pH 6 and 8. Specifically, between pH 1 and 5, HCT is observed as one of the key degradation products of NO-HCT in addition to formaldehyde and aminobenzenesulfonic acid. Moreover, at pH 1, the aminobenzenesulfonic acid derivative is transformed to the corresponding diazonium salt in approximately 3% yield with the nitrosyl cation, which is released during the decomposition of NO-HCT to HCT. This diazonium is highly unstable above pH 5. To verify that degradation of NO-HCT does not produce the corresponding diazonium salt that could be formed via metabolic activation of NO-HCT, this diazonium salt and its hydrolytic and reduction degradation products were synthesized and used as standards for the identification of species formed during the degradation of NO-HCT. This enabled us to confirm that the corresponding aryl diazonium salt, which would be obtained from metabolic activation of NO-HCT, is not observed in the NO-HCT degradation pathway. Our study also demonstrates that this diazonium salt is stable only in the presence of a large excess of strong mineral acid under anhydrous conditions. In the presence of water, it is instantaneously converted to an aminobenzenesulfonic acid derivative. These findings suggest that the NO-HCT should not be considered as a typical compound belonging to the cohort of the concern.
The synthesis of 7-substituted pyrazolo1,5-apyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo1,5-apyrimidine-3-carboxylate (5) was prepared in three steps from methyl ...5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl3 gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a–h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo1,5-apyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a–f furnished the 1-alkyl derivatives 17a–f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a–d and 16m,n, selectively.
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Efficient diarylation of ortho‐C−H bonds of 2‐arylpyrimidines was achieved by Ru(II)−carboxylate‐catalyzed reaction with aryl bromides in water, whereas meta‐substituted phenylpyrimidines selectively ...led to monoarylation. The reaction is strongly accelerated under microwave irradiation, and is compatible with various functional groups on both coupling partners. As established from Hammett plots, electron‐withdrawing groups on the pyrimidine substrates facilitate the arylation, while both, electron‐withdrawing and electron‐donating groups on the aryl bromides lead to a faster reaction. The C−H functionalization of 2‐arylpyrimidines with heteroaryl halides provides potential multidentate ligands.
Enjoy the waves: Ru(II)‐catalyzed C−H bond cleavage of 2‐arlylpyrimidines is achieved by microwave irradiation in water as a green solvent.
Cyclizations of Cbz-protected
-didehydro-
-arylalanine esters
with excess hydrazine hydrate afforded mixtures of the expected 3-pyrazolidinones
and the unexpected 1-amino-5-benzylidenehydantoins
and
...-Cbz-
-arylalanine hydrazides
. Presumably, the pyrazolidinones
and hydantoins
are formed as primary products
competitive 1,2- and 1,4-addition of hydrazine hydrate followed by cyclization, whereas
-arylalanine hydrazides
are formed as secondary products
reductive cleavage of the C(5)–N(1) bond in pyrazolidinones
. The overall selectivity depends on the reaction time and on the
-substituent in the starting dehydroalanine ester
Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ7-hexahydropyrazolo1,5-apyridin-8-ium-1-ide, were prepared in seven steps from the respective commercially available δ-keto acids. The ...addition of Grignard reagents followed by N-alkylation at position 1 afforded the 1,7,7-trisubstituted hexahydropyrazolo1,5-apyridin-2(1H)-ones, whereas 1,3-dipolar cycloadditions of these dipoles to typical acetylenic and olefinic dipolarophiles gave 4a-substituted 2a,2a1-diazacyclopentacdindene derivatives as the first representatives of a novel heterocyclic system. Regio- and stereoselectivity as well as the mechanism of these 3 + 2-cycloadditions were evaluated using computational and experimental methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism via the energetically favorable syn/endo-transition states.
Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ
-hexahydropyrazolo1,5-apyridin-8-ium-1-ide, were prepared in seven steps from the respective commercially available δ-keto acids. The ...addition of Grignard reagents followed by N-alkylation at position 1 afforded the 1,7,7-trisubstituted hexahydropyrazolo1,5-apyridin-2(1H)-ones, whereas 1,3-dipolar cycloadditions of these dipoles to typical acetylenic and olefinic dipolarophiles gave 4a-substituted 2a,2a
-diazacyclopentacdindene derivatives as the first representatives of a novel heterocyclic system. Regio- and stereoselectivity as well as the mechanism of these 3 + 2-cycloadditions were evaluated using computational and experimental methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism via the energetically favorable syn/endo-transition states.
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