Synthesis of New 2-[(Substituted-pyrazolin-1-yl)carbonyl]-thieno[2,3-b]pyridine Derivatives

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate chalcones 2a-2d in the presence of acid catalyst produced the corresponding 3-amino-2-[(3,5-disubstituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d . 3-Amino-2-[(3-substituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 7a, 7b were also obtained by the cyclization reaction of carbohydrazide 1 with Mannich base derivatives 6a, 6b under basic condition.     

2‐(2‐Naphthyloxy)acetate derivatives. I. A new class of antiamnesic agents

The title compounds 1‐(2‐naphthyloxymethylcarbonyl)piperidine, C₁₇H₁₉NO₂, (I), and 3‐methyl‐1‐(2‐naphthyl­oxy­methyl­carbonyl)­piperidine, C₁₈H₂₁NO₂, (II), are potential antiamnesics. In (II), the methyl‐substituted piperidine ring is disordered over two conformations. The piperidine ring has a chair conformation in both compounds. In (I), the mol­ecules are linked by weak intermolecular C—H⃛O interactions to give networks represented by C(4), C(6) and (18) graph‐set motifs, while in (II), weak intermolecular C—H⃛O interactions generate (5), C(4) and C(7) graph‐set motifs. The dihedral angle between the naphthalene moiety and the piperidine ring is 33.83 (7)° in (I), while it is 31.78 (11) and 19.38 (19)° for the major and minor conformations, respectively, in (II).     

New Results in the Synthesis of Styrylazulene Derivatives: Application of the ‘Anil synthesis’ to the preparation of azulenes substituted with styryl groups at the seven-membered ring

The synthesis of 4,6,8-trimethyl-1-[(E)-4-R-styryl]azulenes 5 (R=H, MeO, Cl) has been performed by Wittig reaction of 4,6,8-trimethylazulene-1-carbaldehyde ( 1 ) and the corresponding 4-(R-benzyl)(triphenyl)phosphonium chlorides 4 in the presence of EtONa/EtOH in boiling toluene (see Table 1). In the same way, guaiazulene-3-carbaldehyde ( 2 ) as well as dihydrolactaroviolin ( 3 ) yielded with 4a the corresponding styrylazulenes 6 and 7 , respectively (see Table 1). It has been found that 1 and 4b yield, in competition to the Wittig reaction, alkylation products, namely 8 and 9 , respectively (cf. Scheme 1). The reaction of 4,6,8-trimethylazulene ( 10 ) with 4b in toluene showed that azulenes can, indeed, be easily alkylated with the phosphonium salt 4b . 4,6,8-Trimethylazulene-2-carbaldehyde ( 12 ) has been synthesized from the corresponding carboxylate 15 by a reduction (LiAlH₄) and dehydrogenation (MnO₂) sequence (see Scheme 2). The Swern oxidation of the intermediate 2-(hydroxymethyl)azulene 16 yielded only 1,3-dichloroazulene derivatives (cf. Scheme 2). The Wittig reaction of 12 with 4a and 4b in the presence of EtONa/EtOH in toluene yielded the expected 2-styryl derivatives 19a and 19b , respectively (see Scheme 3). Again, the yield of 19b was reduced by a competing alkylation reaction of 19b with 4b which led to the formation of the 1-benzylated product 20 (see Scheme 3). The ‘anil synthesis’ of guaiazulene ( 21 ) and the 4-R-benzanils 22 (R=H, MeO, Cl, Me₂N) proceeded smoothyl under standard conditions (powered KOH in DMF) to yield the corresponding 4-[(E)-styryl]azulene derivatives 23 (see Table 4). In minor amounts, bis(azulen-4-yl) compounds of type 24 and 25 were also formed (see Table 4). The ‘anil reaction’ of 21 and 4-NO₂C₆H₄CH=NC₆H₅ ( 22e ) in DMF yielded no corresponding styrylazulene derivative 23e . Instead, (E)-1,2-bis(7-isopropyl-1-methylazulen-4-yl)ethene ( 27 ) was formed (see Scheme 4). The reaction of 4,6,8-trimethylazulene ( 10 ) and benzanil ( 22a ) in the presence of KOH in DMF yielded the benzanil adducts 28 to 31 (cf. Scheme 5). Their direct base-catalyzed transformation into the corresponding styryl-substituted azulenes could not be realized (cf. Scheme 6). However, the transformation succeeded smoothly with KOH in boiling EtOH after N-methylation (cf. Scheme 6).     

C chemical shifts and carbonyl stretching frequencies as structural probes for ferrocenyl ketones

¹³C chemical shifts (δ(CO)) have been measured for a series of aromatic ferrocenyl ketones (FcCOC₆H₄X) and some sterically hindered analogues (FcCOR, R = mesityl, anthracyl, t-Bu, adamantyl). The shifts correlated quite well with those of the corresponding benzophenones. From the carbonyl carbon shifts (δ(CO)), estimates were made of the interplanar angle between the carbonyl sp² and the phenyl ring planes. Substituent effects of the Cp ring carbons are discussed. The solution (CCl₄) infrared spectra of the derivatives were obtained and the carbonyl stretching frequency (ν(CO)) was found to correlate roughly with δ(CO). Estimates were also made of the interplanar angle between the cyclopentadienyl ring plane and the carbonyl plane, for sterically hindered ketones using δ(CO) values.     

Synthesis and characterization of substituted (benzo[b]thiophen‐2‐yl)‐4‐methyl‐4,5‐dihydro‐1H‐imidazol‐5‐ones

Reactions of 3‐chlorobenzo[b]thiophene‐2‐carbonyl chloride with 2‐alkyl‐2‐aminopropanamides have been used to prepare a series of carboxamides 1a‐d (yields 61‐85%). The products were submitted to base‐catalysed ring closure reactions to give the corresponding 4,5‐dihydro‐1H‐imidazol‐5‐ones 2a‐d (yields 69‐97%). By N‐methylation and N‐benzylation were prepared the corresponding 1‐alkyl derivatives 3a (91%) and 3b (85%). These two alkyl derivatives were studied from the standpoint of potential replacement of 3‐chlorine substituent by piperidine via the Buchwald‐Hartwig reaction. It was found that the reaction gives besides except required products of C‐N coupling 5a (14%) and 5b (12%) also products of reductive dechlorination 4a (max. 57%) and 4b (max. 56%). The reductive dechlorination product 4a is formed exclusively (42%) if butyl‐di‐(1‐adamantyl)phosphine (BDAP) is used.     

Synthesis of piperidine analogs of 1-(3-chlorophenyl)piperazine,a well known serotonin ligand

Synthesis of arylpiperideines 3a-3d and arylpiperidines 4a-4d as analogs of a well known serotonin ligand 1-(3-chlorophenyl)piperazine is reported. Starting aryllithium derivatives were treated with 1-methyl-piperdin-4-one to provide the corresponding hydroxy derivatives 6a and 6b. N-Methylpiperideine derivatives 3a and 3c were obtained by their dehydration while the corresponding N-unsubstituted compounds 3b and 3d were prepared indirectly by a three-step procedure. Hydrogenation of piperideine 3a provided the corresponding piperidine derivative 4a which after demethylation yielded 4b. Similar 4-pyridyl derivatives 4c and 4d were prepared by a similar strategy via the corresponding methoxy derivatives.     

Effect of Through‐Bond Interaction on Conformation and Structure in Rod‐Shaped Donor–Acceptor Systems. Part 2.

The crystal structures of seven N‐aryltropan‐3‐one (=8‐aryl‐8‐azabicyclo[3.2.1]octan‐3‐one) derivatives 1T1, 2T1, 2T2, 3T2, 5T2, 2T3 , and 3T3 are presented (Fig. 2 and Tables 1–5) and discussed together with the derivatives 1T2 and 4T2 published previously. The piperidine ring adopts a chair conformation. In all structures, the aryl group is in the axial position, with the plane through the aryl C‐atoms nearly perpendicular to the mirror plane of the piperidine ring. The through‐bond interaction between the piperidine ring N‐atom (one‐electron donor) and the substituted exocyclic C?C bond (acceptor) not only elongates the central C? C bonds of the piperidine ring but also increases the pyrimidalization at C(4) of the piperidine ring. Flattening of the C(2)–C(6) part of the piperidine ring decreases the through‐bond interaction.     

Synthesis of certain alkenyl purines and purine analogs

Synthesis of alkenyl derivatives of certain purines and purine analogs is described. Direct alkylation of the sodium salt of 6-chloropurine (1) either with 1-bromo-2-pentene or 4-bromo-2-methyl-2-butene in N,N-dimethylformamide furnished N-7, 4a and N-9, 3a , 3b alkenyl derivatives. Similar alkylation of 2-amino-6-chloropurine (2) provided the corresponding N-7, 4c-4e and N-9, 3c-3e alkenyl derivatives. Acid hydrolysis of these chloro derivatives 3a-3e, 4a,c-e furnished the corresponding alkenyl hypoxan-thines 6a, 6b and 7a or alkenyl guanines 6c-6e and 7c-7e. Treatment of 3a-3d with thiourea in absolute ethanol provided the corresponding 6-thio derivatives 5a-5d. Alkylation of the sodium salt of either purine-6-carboxamide (8) or 1,2,4-triazole-3-carboxamide (10) gave mainly one isomer 9a, 9b and 11a, 11b. The direct alkylation of pyrrolo[2,3-d]pyrimidin-4(3H)-one (12) gave N-3 alkenyl derivatives 13a, 13b , and the N-7 alkenyl derivatives 16a, 16b have been prepared starting from the 4-chloro derivative 14 . Synthesis of 2-amino-7-(2-penten-1-yl)pyrrolo[2,3-d]pyrimidin-4(3H)-one (19a) has been accomplished starting from 2-amino-4-methoxypyrrolo[2,3-d]pyrimidine (17) . These alkenyl derivatives were found to be devoid of anti-HCMV activity in vitro.     

Aktivierte Chinone: Substitution von Azulenen,Benzofuran und Indolen durch 2-Methoxycarbonyl-1,4-benzochinon. Regiospezifische Synthesen von Polymethoxy-fluorenonen und eine neue Synthese des 2,6-Dihydro-naphtho[1,2,3-cd]indol-6-on-Systems

Activated quinones: substitution reactions by methoxy-carbonyl-1,4-benzoquinone of azulenes, benzofuran and indoles; regiospecific syntheses of polymethoxy-fluorenones; a new synthesis of the 2,6-dihydro-naphtho[1,2,3-cd]indol-6-one system. We present new electrophilic substitution reactions of azulenes and 5-membered heterocyclics by methoxy-carbonyl-1,4-benzoquinone. Hydroquinones 3a and 5 are prepared from azulene, and 3b from guaiazulene (see Scheme 1). Benzofuran undergoes α- and β-substitution (hydroquinones 9 10 ) (see Scheme 2). Only β-substitution is observed with indole (hydroquinone 20 ) (see Scheme 4). After methylation, saponification and intramolecular acylation of the substituted indoles 22c, 22d , derivatives of 2,6-dihydro-naphtho[1,2,3-cd]indol-6-one have been obtained. Spectral data prove the presence of the methylidenequinone tautomer. By protonation or alkylation at the carbonyl group of 23 , the violet, highly delocalized 16π-electron systems 25 are generated. Analogously, polymethoxy-fluorenones have been prepared from methoxylated diphenylquinones 15 (see Scheme 3). They also are transformed by protonation and alkylation to the highly coloured and delocalized 12 π-electron systems 18 . By contrast, anthracene is not substituted by methoxycarbonyl-1,4-benzoquinone, but undergoes cycloaddition to the triptycene derivative 1 (see Scheme 1). A summary is presented of previously described reactions of activated quinones.     

Enantioselektive Verseifung der Diacetate von 2-Nitro-1,3-diolen mit Schweineleber-Esterase und Herstellung enantiomerenreiner Derivate von 2-Nitro-allylalkoholen (chirale Verknüpfungsreagenzien)

Enantioselective Saponification of Diacetates of 2-Nitro-1,3-propanediols by Pig-Liver Esterase and Preparation of Enantiomerically Pure Derivatives of 2-Nitro-allylic Alcohols (Chiral Multiple-Coupling Reagents) The reproducible enantioselective saponification of open-chain and cyclic diacetates of meso-2-nitro-1,3-propanediols (see 4b – 13b ) with pig-liver esterase (PLE) gives monoacetates (see 4c – l3c ) of > 95% enantiomeric excess. The Re enantiotopic acetate group appears to be saponified preferentially, as proved by the X-ray crystal structure analysis of three camphanoates 4d , 6d , and 7d . Elimination of H₂O or AcOH from the hydroxy acetates thus available gives derivatives of nitro-allylic alcohols (see 20 – 24 , 27 , and 29 ) which are subjected to diastereoselective Michael additions or S_N2′ substitutions.     

Synthesis of pyridazino[4,5-b]indole derivatives from 2-(3-carboxy-1-methylindole)acetic acid anhydride

2-(3-Carboxy-1-methylindole)acetic acid anhydride ( 1 ) reacts with aryldiazonium salts to give 85–95% of the corresponding α-hydrazono anhydrides 2 . Treating 2 with boiling hydrazine hydrate in xylene, the respective 2-aryl-4-carbohydrazido-5-methyl-1-oxo-1,2-dihydro-5H/-pyridazino[4,5-b]indoles 3 were obtained (47–67%), and these compounds characterized as the respective benzylidene derivatives 4 . Compounds 2 react with amines (aniline, morpholine, piperidine) to give the respective 2-(3-carboxy-1-methylindole)aceta-mide 5 or the respective 2-aryl-4-carboxamido-5-methyl-5H-pyridazino[4,5-b]indole 6 , the product obtained depending on the structure of the aryl substituent. Boiling 2b (aryl = 4-chlorophenyl) with 5% sodium hydroxide gave (80%) 2-(3-carboxy-1-methylindole)acetic acid ( 7 ). Hydrolysis of 2b gave a mixture of 7 and 2-(3-carboxy-1-methylindolyl)-2-(4-chlorophenylhydrazono)acetic acid ( 8 ).     

Synthesis of pyrido[2,3-d]pyrimidines from aminopyrimidinecarbaldehydes

2-Methoxy-4-amino-5-pyrimidinecarbaldehyde ( 2a ) as well as its 6-methyl 2b and 6-phenyl derivatives 2c were prepared by reduction of the corresponding aminopyrimidinecarbonitriles 1 . Catalytic hydrogenation of 1a, 1b gives 5-hydroxymethylpyrimidines 3a, 3b ; under the same conditions 1c afforded 5-aminomethylpyrimidine 4 . Condensation of 2 with carbonitriles, ketones and polyfunctional carbonyl compounds bearing the -CH₂CO- moiety afforded the pyrido[2,3-d]pyrimidines and pyrimido-[4,5-b]quinoline derivatives.     

Reaction of piperidine and morpholine with 2H-pyran-2-ones, 2H-thiopyran-2-ones, 2H-pyran-2-thiones,and 2H-thiopyran-2-thiones. A novel route to thiophene derivatives

The reaction of piperidine or morpholine with 2H-pyran-2-ones was found to give open chain δ-oxoamides, while with 2H-thiopyran-2-ones, thiophene derivatives were formed. For 2H-pyran-2-thiones, either open chain δ-oxothioamides or thiophene derivatives were obtained. From the ¹ H nmr data of the pyran derivatives, the effect of the replacement of ring and carbonyl oxygens with sulphur on the chemical shift of the H-3 proton could be studied.     

Reversed steric order of reactivity for tert-butyl and adamantyl-3-cyanomethylene-1,2,4-triazines

Reactions of 2-(6-tert-butyl-5-oxo-4,5-dihydro-1,2,4-triazin-3(2H)-ylidene)-3-oxo-3-R-propanenitriles (R = t-Bu, Ad-1) with tert-butyl bromoacetate gave the corresponding N(2), C(5)O bis-alkylation products. Treatment of the latter with t-BuLi, in the case of R = t-Bu, led to intramolecular condensation at the exocyclic nitrile group. However, in the case of R = Ad-1, the condensation with the sterically more hindered carbonyl group was observed to give diastereomerically pure 8-cyanopyrrolo[1,2-b][1,2,4]triazine-6-carboxylate derivatives. The structures of the isolated products were confirmed by spectral methods and X-ray single-crystal diffraction.     

Photolyse von 3-Methyl-2, 1-benzisoxazol (3-Methylanthranil) und 2-Azido-acetophenon in Gegenwart von Schwefelsäure und Benzolderivaten

Photolysis of 3-Methyl-2, 1-benzisoxazole (3-Methylanthranil) and 2-Azido-acetophenone in the Presence of Sulfuric Acid and Benzene Derivatives Irradiation of 3-methylanthranil ( 1 ) in acetonitrile in the presence of sulfuric acid and benzene, toluene, p-xylene, mesitylene or anisole with a mercury high-pressure lamp through a pyrex filter yields beside varying amounts of 2-amino-acetophenone ( 3 ) and 2-amino-5-hydroxy- ( 4a ) and 2-amino-3-hydroxy-acetophenone ( 4b ) the corresponding diphenylamine derivatives 5 (see Table 1). In the case of toluene and anisole mixtures of the corresponding ortho- and para-substituted isomers ( 5b, 5d or 5g, 5i respectively), but no meta-substituted isomers ( 5c or 5h ) are obtained. In addition to these products, the irradiation of 1 in the presence of anisole yields also 2-amino-5-(4′-methoxyphenyl)-acetophenone ( 7 ), 2-amino-3-(4′-methoxyphenyl)-acetophenone ( 8 ) and 2-methoxy-9-methyl-acridine ( 6 ; see Scheme 1). The latter product is also formed thermally by acid catalysis from the diphenylamine derivative 5i . Irradiation of 2-azido-acetophenone ( 2 ) in acetonitrile solution in the presence of sulfuric acid and benzene leads to the formation of 1, 3, 4a, 4b, 5a and 9 (see Table 2). Compounds 3, 4a, 4b and 5a are also obtained after acid catalyzed decomposition of 2 in the presence of benzene. Thus, it is concluded that irradiation of 1 or 2 in the presence of sulfuric acid yields 2-acetyl-phenylnitrenium ions 10 in the singlet ground state which will undergo electrophilic substitution of the aromatic compounds, perhaps via the π-complex 11 (see Scheme 2).     

Pyrimidine derivatives. IX . Synthesis of bromosubstituted 5-nitro-2,4(1H,3H)-pyrimidinedione derivatives

The following 5-nitro-2,4(1H,3H)-pyrimidinediones possessing bromo substituted side chains at the 1- and 6-positions were prepared by bromination of 3,6-dimethyl-1-(ω-hydroxyalkyl)-5-nitro-2,4(1H,3H)-pyrimidinediones 4a and 4b and its nitrates 2a and 2b . The three of mono-bromo derivatives are: 1-(ω-acetoxyalkyl and ω-hydroxyalkyl)-6-bromomethyl-3-methyl. 6a, 6b, 7a and 7b and 1-(ω-bromoalkyl)-3,6-dimethyl-2,4(1H,3H)- pyrimidinediones 8a and 8b . The one type dibromo derivatives are: 1-(ω-bromoalkyl)-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinediones 5a and 5b .     

Recent studies on phosphorus-bridging carbonyl derivatives: organophosphorus analogs of aldehydes and ketones

Reactions of disodium tetracarbonylferrate, Na₂Fe(CO)₄, with sterically hindered dialkylaminodichlorophosphines, R₂NPCl₂ (R₂N=diisopropylamino, dicyclohexylamino, and 2,2, 6, 6-tetramethylpiperidino) in diethyl ether lead to the air-stable phosphorus-bridging carbonyl derivatives (R₂NP)₂COFe₂(CO)₆ as the major products. The phosphorus-bridging carbonyl group in (i-Pr₂NP)₂COFe₂(CO)₆ has been found to undergo the following types of reactions: 1)Reduction, 2)Acylation, 3)Extrusion of the carbonyl group. The mechanisms of the reactions have been considered.This work was presented at the Workshop «The Modern Problems of Heteroorganic Chemistry» held on the ship «Nikolai Bauman» during the period May 8–13, 1993.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1858–1867, November, 1993.     

Cyanoacetamide in heterocyclic chemistry: Synthesis,antitumor and antioxidant activities of some new benzothiophenes

Cyanoacylation of 2‐amino‐tetrahydrobenzothiophene‐3‐carboxylate ethyl ester with 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile afforded cyanoacetamide 2 . The later was utilized as key intermediate for the synthesis of 3‐substituted 2‐iminocoumarins 3 , 4 , 5 , 6 and acrylamides 7a , b via Knoevenagel condensation with 2‐hydroxy‐1‐naphthaldehyde; 2‐hydroxybenzaldehyde; 1‐nitrosonaphthalen‐2‐ol; 7‐hydroxy‐5‐methoxy‐2‐methyl‐4‐oxo‐4H‐chromene‐6‐carbaldehyde; 4‐dimethylamino‐benzaldehyde; and 4‐piperidin‐1‐yl‐benzaldehyde in EtOH/piperidine. The derivatives 7a , b did not afford the pyrazoles 8a , b upon treating with phenyl hydrazine. Furthermore, coupling of 2 with 4‐amino‐1,5‐dimethyl‐2‐phenyl‐1H‐pyrazol‐3(2H)‐one and 4,6‐dimethyl‐1H‐pyrrolo[2,3‐b]pyridin‐3‐amine afforded the hydrazone derivatives 9 and 10 , respectively. The later derivative 10 was cyclized in acetic acid to afford the pyridopyrazolotriazine 11 . Finally, 2 was treated with dimethylformamide‐dimethylacetal (DMF‐DMA) to afford the dimethylaminoacrylamide 12 which underwent transamination with 4,6‐dimethyl‐1H‐pyrrolo[2,3‐b]pyridin‐3‐amine to afford the pyrazole 13 . Cyclization of compound 13 in acetic acid or pyridine was unsuccessful. The antitumor and antioxidant activities of the synthesized products were evaluated; several were found to exhibit promising antioxidant activities. J. Heterocyclic Chem., (2011).     

Synthesis and reaction of methylbenzo[a]quinolizinium salts

All isomers of (monomethyl)benzo[a]quinolizinium salts including five new monomethyl derivatives were prepared by photocyclization, sulfur extrusion, or cyclodehydration reaction, and their aldol-type condensation was examined. The 2- and 4-methyl derivatives 3b and 3c reacted with p-methoxybenzaldehyde in the presence of piperidine to yield trans-(p-methoxystyryl)benzo[a]quinolizinium salts 11 . The other methyl derivatives did not react with the aldehyde. The methyl group was reactive at the 2- and 4-positions, located para and ortho to the azonia ring nitrogen, respectively; however, it was unreactive at the 6-position located at another ortho position.