The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 18. A short synthesis of swietenidin A

N-Methylisatoic anhydrides react with the lithium enolate of ethyl methoxyacetate at low temperatures to produce intermediates which, when cyclized, afford 4-hydroxy-3-methoxy-2(1H)-quinolinones. By this route, 3-methoxy-N-methylisatoic anhydride ( 8 ) can be converted to the alkaloid swietenidin A (2) in 71% yield.     

Ring closure reaction of 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride. Synthesis of pyrimido[5,4-c] [1,5]benzoxazepin-5(11H)ones

Syntheses of 11-acety1-2-phenylpyrimido[5,4-c][1,5]benzoxazepin-5(11H)one ( 16a ) and analogs ( 16b,c, 22 ) were described. The reaction of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 7 ) with 2-aminophenol afforded 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester ( 8a ). The latter was also prepared by catalytic reduction of 4-(2-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 9 ), which was obtained from 7 and 2-nitrophenol. Involvement of 4-(2-aminophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 12a ) in this reduction as an intermediate was demonstrated by an independent synthesis of 12a and its subsequent rearrangement to 8a. Hydrolysis of 8a or 12a gave 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid ( 15a ). Reaction of 15a with acetic anhydride afforded 16a , the first member of a novel ring system, the pyrimido[5,4- c ][1,5]-benzoxazepin. Additional examples ( 16b,c ) were prepared similarly. The corresponding 11-ethyl derivative ( 22 ) was prepared in similar fashion, starting with 7 and 2-ethylaminophenol. A possible reaction mechanism for the formation of 16a-c from 15a-c and acetic anhydride was discussed.     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 12. Synthesis of araliopsine and isoplatydesmine

N-Methylisatoic anhydride reacts with the lithium enolate derived from 3,3-dimethyloxiranepropanoic acid ethyl ester (7) to initially produce the acyclic β-ketoester 8 . Under neutral conditions, 8 spontaneously cyclizes to the alkaloid araliopsine ( 1a ). In the presence of acid, 8 cyclizes to a mixture of 1a and its leanear isomer isoplatydesmine (2a).     

Die Struktur des Bisindolalkaloides Amatain ( = Grandifolin,Subsessilin)

The structure of the bisindole alkaloid amataine (= grandifoline, subsessiline) Amataine ( 1 ) was isolated from the roots of Hedranthera barteri (HOOK . F .) PICHON (Apocynaceae). In comparison to the alkaloid vobtusine ( 5 ), which was isolated from the same plant, 1 contains two hydrogen atoms less. By reduction of 1 with H₂/PtO₂ or with NaBH₄ dihydromataine ( = isovobtusine, 13 ) was formed which is isomeric to 5 . Acid catalysed water addition to 1 afforded hydratoamataine ( 15 ), which was reduced to 5 with NaBH₄. Thermolysis of 15 gave 1 . The difference between the two isomeric bases 5 and 13 has to be attributed to a different configuration at the spirocenter C(7). In contrast to 5 amataine ( 1 ) contains an ether bridge instead of a hydroxy group; this bridge is located between C (2′) and C (8).     

Indolalkaloids of Pleiocarpa talbotii Wernham. 145. Alkaloids

Besides talbotine ( 1 ) three new indole alkaloids, talpinine ( 2 ), talcarpine ( 3 ) and 16-epi-affinine ( 4 ) were isolated from the stem bark of Pleiocarpa talbotii Wernham. The structure of 2 was deduced by chemical degradation and by analyses of the spectra of the alkaloid and its derivatives. One of these derivatives is identical with talcarpine ( 3 ). The structures 2 and 3 are similar to that of macroline ( 14 ), a splitting product of the bisindole alkaloid villalstonine from Alstonia species. 16-epi-Affinine ( 4 ) was chemically correlated with the known alkaloid vobasine ( 19 ). Talpinine ( 2 ) and 16-epi-affinine ( 4 ) were also isolated from the root bark of Pleiocarpa talbotii.     

Palladium‐Catalyzed 2‐Phenylethenylation of Codeine: 8‐[(1E)‐2‐Phenylethenyl]codeinone Dimethyl Ketal as the Unexpected ‘Masked’ Diene for the Preparation of 19‐Substituted Diels–Alder Adducts of Thebaine

In a search for starting materials for the preparation of 7,8‐fused morphine alkaloid derivatives, 8‐[(1E‐2‐phenylethenyl]codeinone dimethyl ketal ( 4 ) and 8‐[(1E‐2‐phenylethenyl]codeine ( 5 ) were prepared. These dienes were used as substrates in the Diels–Alder reactions. Compound 5 formed the ‘normal’ adduct 12 with N‐phenylmaleimide, while compound 4 behaved in reactions with dienophiles as the ‘masked’ diene 11 , a 8‐[(1E)‐2‐phenylethenyl]‐substituted thebaine, yielding the corresponding 19‐substituted 6,14‐endo‐etheno‐6,7,8,14‐tetrahydrothebaines. Specifically, reaction of 4 with methyl vinyl ketone gave rise to 19‐[(1E)‐phenylethenyl]thevinone ( 14 ) whose structure was elucidated by an X‐ray diffraction analysis. The thebaine derivative 11 was also prepared from 4 .     

Synthesis of the alkaloid thalactamine and a new synthesis for the alkaloid N-methyl-6,7-dimethoxy-1(2H)isoquinolone

The alkaloid thalactamine (N-methyl-5,6,7-trimethoxy-1(2H)isoquinolone) was synthesised in two steps from 4,5,6-trimethoxyhomophthalic acid (1a). Heating la with DMF/POCI₃ at 100° furnished thalactamine-4-earhoxylic acid which was easily decarboxylated to give the alkaloid thalactamine. By the same two steps, the alkaloid N-methyl-6,7-dimethoxy-1(2H)-isoquinolone is obtained from 4,5-dimethoxyhomophthalic acid. Synthesis for la from 2-bromogallic acid trimethyl ether was modified to give excellent yield. 5,6,7-Trimethoxy and 6,7-dimethoxyisocoumarin-4-carboxylic acid esters were synthesised from the homophthalic acids 1a and b by interacting them with DMF/phosphoryl chloride at 0°, to give corresponding 4-(N,N-dimethylaminoformylidene)isochroman-1,3-dione derivatives Vla and b and treating their alcoholic solutions with dry hydrogen chloride gas. The isocoumarins were converted into N-methyl-1(2H)isoquinolonesby treating them with aqueous methylamine. The isochromandione Vla slowly changed into 3-chloro-4-formyl-5,6,7-trimethoxyisocoumarin during the working up of the reaction.     

The hydrated and anhydrous gold(III) tetrachloride salts of l‐ecgonine,an important forensic toxicology marker for cocaine

The structure of the hydrated gold(III) tetrachloride salt of l ‐ecgonine {hydronium tetrakis[(1R,2R,3S,5S,8S)‐3‐hydroxy‐8‐methyl‐8‐azoniabicyclo[3.2.1]octane‐2‐carboxylate pentakis[tetrachloridoaurate(III)] hexahydrate}, (C₉H₁₆NO₃)₄(H₃O)[AuCl₄]₅·6H₂O, demonstrates an unprecedented stoichiometric relationship between the cations and anions in the unit cell. The previous tropane alkaloid structures, including the related hydrochloride salts, all have a cation–anion ratio of 1:1, as does the anhydrous salt described here, namely (1R,2R,3S,5S,8S)‐3‐hydroxy‐8‐methyl‐8‐azoniabicyclo[3.2.1]octane‐2‐carboxylate tetrachloridoaurate(III), (C₉H₁₆NO₃)[AuCl₄]. The hydrated salt, however, consists of four monopositive N‐protonated units of the alkaloid and five [AuCl₄]⁻ counter‐ions, plus seven solvent water molecules. The H atom required for change balance has been assigned to a water molecule. In addition, the hydrate has a novel arrangement, with all seven of the water molecules and all of the O atoms in the cations participating in an alternating arrangement of interleaved sheets of the anionic species. Both the hydrate and the anhydrous salt of the same toxicologically important marker for cocaine show that the cation and anion are in close proximity to each other, as was found in the gold(III) tetrachloride salt of l ‐cocaine.     

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 ).     

Aromatization of 1-Benzyltetrahydroisoquinolines: Racemization of (−)-(S)-(N-nor)-Reticuline

Aromatization in the series of optically active 1-benzyltetrahydroisoquinolines has been accomplished with (—)-(S)?(N-nor)-reticuline ( 1b ) and analogs. Direct catalytic or chemical reduction of the isoquinoline 4 obtained could not be achieved in a practical way but 4 was converted into 1 in three steps ( 4 → 8 → 9 → 1 ), in 55% overall yield. Partial O-methylation of the isoquinoline 4 gave the isoquinoline alkaloid palaudine ( 5 ), before papaverine ( 6 ) was formed.     

Ringschlussreaktionen mit 2-(β-Styryl)benzylaminen 5-Phenyl-1H-2-benzazepine. 23. Mitteilung über siebengliedrige Heterocyclen

Cyclization reactions with 2-(β-styryl)benzylamines 5-Phenyl-1H-2-benzazepines Cyclization of the urea derivative 3 with POCl₃ to give 2-(4-methyl-1-piperazinyl)-4-phenylquinoline ( 4 ) was carried out in analogy to the quinoline synthesis of Foulds & Robinson. This reaction was used for the preparation of 2-benzazepines. The trisubstituted ureas 6 and 8 , derived from the 2-(β-styryl)-benzylamines 5 , were cyclized with POCl₃ to yield the 3-amino-5-phenyl-1H-2-benzazepines 7 and 9 , respectively. Similarly, cyclization of the corresponding acetyl-derivatives 10 gave the 3-methyl-5-phenyl-1H-2-benzazepines 12 . On the other hand, the disubstituted urea 15 , cyclized under the same conditions to the 1-methyl-1-phenylisoindoline derivative 16 , and 2-(β-styryl)benzylamine ( 5a ) on treatment with phosgene gave the isoindoline 17 in an analogous manner.     

A New Alkaloid from the Roots of Aconitum carmichaeli Debx.

A new diterpene alkaloid, 12‐epi‐15‐O‐acetyl‐17‐benzoyl‐16‐hydroxy‐16,17‐dihydronapelline ( 1 ), along with nine known diterpene alkaloids including yunaconitine ( 2 ), neoline ( 3 ), mesaconitine ( 4 ), beiwutine ( 5 ), chasmanine ( 6 ), songorine ( 7 ), 12‐epi‐napelline ( 8 ), foresticine ( 9 ), and 15α‐hydroxyneoline ( 10 ) were isolated from the roots of Aconitum carmichaeli Debx. The structure of compound 1 was elucidated by comprehensive spectroscopic analysis.     

Aldehyde Intermediates in the Synthesis of Tacamine-Type Indole Alkaloids: Preparation of (±)-apotacamine

The synthesis of aldehyde intermediates suitable for the preparation of indole alkaloids of the tacamine ( 1 ) type is described. The four possible aldehydes 4–7 were prepared from methyl 5-ethylnicotinate ( 8 ) in a few simple steps using a base-catalyzed epimerization as the final step (Schemes 1 and 2). The key aldehyde 4 , which is an analogue of the important vincamine intermediate 3 (‘Oppolzer's aldehyde’), was finally converted into the indole alkaloid (±)-apotacamine ( 21 ).     

Alkaloids of Siberia and Altai flora: XVIII. Alkyl 2-acetylamino-5-[2-(pyridin-3-yl)vinyl]benzoates in the synthesis of indolizines containing an anthranilic acid ester moiety

Methyl 2-acetylamino-5-[2-(6-methylpyridin-3-yl)vinyl]benzoate reacted with phenacyl bromide to produce quaternary 1-(2-aryl-2-oxoethyl)-2-methyl-5-(4-acetylamino-3-methoxycarbonyl)pyridinium bromides. 1,3-Dipolar cycloaddition of the latter to methyl propynoate and dimethyl but-2-ynedioate gave the corresponding indolizine derivatives containing an anthranilic acid ester moiety. Reactions of acetylenes with N-phenacylpyridinium salts obtained from a diterpene alkaloid derivative, 2-(pyridin-3-yl)vinyl-substituted lappaconitine afforded analogous compounds in which the indolizine fragment is conjugated to the aromatic ring of the alkaloid. 1,3-Dipolar cycloaddition of 1-(2-aryl-2-oxoethyl)-2-methyl-5-(4-acetylamino-3-methoxycarbonyl) pyridinium bromides with methyl propynoate was regioselective.     

Total Synthesis of Racemic and Optically Active Compounds Related to Physostigmine and Ring-C Heteroanalogues from 3-[2′-(dimethylamino)ethyl]2,3-dihydro-5-methoxy-1,3-dimethyl-1H-indo l-2-ol

Oxindole 11 , obtained on 3-[2′-(dimethylamino)ethyl]alkylation of oxindole 12 , yielded, on stereoselective reduction with sodium dihydridobis(2-methoxyethoxy)aluminate, aminoalcohol 8 (Scheme 2). The quaternary methiodide 10 , obtained from 8 with MeI, gave, in nucleophilic displacements concurring with a Hofmann elimination, (±)-esermethole 6 , (±)-5-O-methylphysovenol ( 14 ), (±)-5-O-methyl-1-thiaphysovenol ( 15 ), and (±)-1-benzyl-1-demethylesermethole ( 16 ). Syntheses of (±)-1-benzyl-1-demethylphenserine ( 18 ), (±)-1-demethylphenserine ( 19 ), and (±)-phenserine ( 4 ) from 6 and 16 are described. Optically active 8a and 8b , obtained by chemical resolution, similarly gave the enantiomers 6a and 14a–16a of the (3aS)-series (prepared earlier from physostigmine ( 1a )) and their (3R)-enantiomers. The anticholinesterase activity of (±)- 4 , (±)- 18 , and (±)- 19 was compared with that of their optically active enantiomers.     

Directed regiospecificity of 1,3-dipolar cycloaddition of 2-diazopropane to 4- and 5-substituted pyridazin-3(2H)-ones

6-Methoxy-2-methylpyridazin-3(2H)-one ( 1 ) gave with 2-diazopropane ( 8 ) a mixture of 3H-pyrazolo[3,4-d]-pyridazin-4(5H)-one derivative 12 , as the main product, and -7(6H)-one derivative 10 , as the minor product. On the other hand, 4-substituted pyridazin-3(2H)-ones 2, 3 , and 4 gave 3H-pyrazolo[3,4-d]pyridazin-7(6H)-one 10 , exclusively, while 5-substituted pyridazin-3(2H)-ones 5, 6 , and 7 produced only the isomeric 3H-pyrazolo[3,4-H]pyridazin-4(5H)-one 12 . The 5-phenylsulfonyl derivative 13 gave with 8 by elimination of a molecule of nitrogen, followed by rearrangement, 1,2-diazepine derivative 15 and with an excess of 8 3H-pyrazolo[3,4-d][1,2]diazepine derivative 16. 1 ,2-Dimethylpyridazine-3,6-(1H,2H)-dione and its derivatives 18 and 19 produced 3H-pyrazolo[3,4-d]pyridazine-4,7(5H,6H)-dione derivative 23 , while from 17 and 1-diazoindane ( 24 ) the spiro compound 27 was obtained. The 1,2-dihydro and 3a,7a-dihydro intermediates 21 and 25 were isolated.     

On the formation and reactivity of N(2),N(2′)-tetrasubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles

By the reaction of weak bases with N(2)-disubstituted 2-amino-4-thiazoliniminium chlorides 3, easily available by the reaction of thioureas 1 with α-chloroacetonitrile 2, N(2),N(2′)-persubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles 8 are formed. These new bis-thiazoles react, as exemplified with the dimorpholino derivative 8a, with different electrophilic reagent, such as phenyl isothiocyanate 9, 4-nitro-phenyldiazonium salt 11, or 4-dialkylaminobenzaldehydes 13 at their 5H-substituted thiazole moieties to give the corresponding thioanilides 10, azo compounds 12, and methine dyes 14, respectively. With sodium nitrite and the Vilsmeier reagent the thiazole 8a is transformed, via unstable intermediates, into the tricyclic 2,7-dimorpholinothiazolo[4,5-c]thiazolo[4,5-e]pyridazine 16 and 2,7-dimorpholinothiazolo[4,5-b]thiazolo[4,5-d]pyridine 19, respectively.     

Novel Synthesis of 1-(1,2,3,5,6,7-Hexahydro- s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]urea,an Anti-inflammatory Agent

Abstract

A novel synthesis of the anti-inflammatory agent 1-(1,2,3,5,6,7- hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl] urea 1 is described. Sulfonamide 5 was prepared starting from ethyl 3-furoate 2. Key steps were a one-pot sulfonylation with chlorosulfonic acid in methylene chloride followed by pyridinium salt formation and reaction with phosphorus pentachloride to provide ethyl 2-(chlorosulfonyl)-4-furoate 7. This sulfonyl chloride was treated with ammonium bicarbonate to form sulfonamide 8, followed by treatment with excess methyl magnesium chloride to provide 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide 5. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 16 was prepared from indan in five steps. The formation of the desired sulfonyl urea was carried out both with the isolated isocyanate 16 and via an in situ method.     

2H-3,1-benzoxazine-2,4-(1H)-dione (isatoic anhydride). 15. Reactions with lactone enolates

The reaction of N-methylisatoic anhydride, 1 , with the lithium enolates derived from various butyrolactones or δ-valerolactone produces stable anthranoyl lactone derivatives 4 . Heating these products in toluene results in a cyclization to afford 4-hydroxy-3-(2-hydroxyalkyl)-1-methyl-2(1H)-quinolinones, 8 and 14 , in good yields.     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 9. Synthesis of 2-arylquinoline alkaloids

A one-step synthesis of N-methyl-2-aryl-4-quinolone alkaloids is described. These compounds are readily prepared from the reaction of an N-methylisatoic anhydride with the lithium enolate of an acetophenone. By this method, the reaction of N-methylisatoic anhydride ( 5 ) or 5-methoxy-N-methylisatoic anhydride ( 7 ) with acetophenone produces the alkaloids N-methyl-2-phenyl-4-quinolone ( 1 ) and eduline ( 2 ) in 81% and 70% yield, respectively. An analogous reaction of 5 with 3,4-methylenedioxyacetophenone gives graveoline ( 3 ) in 63% yield whereas 7 and α-methoxyacetophenone affords japonine ( 4 ) in 61% yield.