The N-9, C-1 dianion of tetrahydro-β-carbolines. Regioselective alkylation leading to indole alkaloid systems

By treatment of β-carboline formamidine (1) with potassium hydride followed by an alkyl lithium reagent, both the pyrrole proton (N-9) and the proton at C-1 are removed. The resulting dianion (3) alkylates cleanly at C-1 and ultimately at N-9 or N-2.     

Anthracene derivatives of benzo[f]quinoline. Synthesis,spectra, and luminescence

By condensation of 9-[N-(2-naphthyl)formimidoyl]anthracene with methyl ketones under conditions of acid catalysis, 1-R-3-(9-anthryl)benzo[f]quinolines have been obtained. The byproducts of the reaction have been identified: 1-R-3-(9-anthyl)-2-propen-1-ones and N-[1-(p-aminophenyl)-3-(9-anthryl)-2-propen-1-ylidene]-2-naphthylamines. The spectral and luminenscence properties of these compounds have been examined critically.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1536–1541, November, 1985.     

A convenient synthesis of 2′-deoxy-6-thioguanosine,ara-guanine,ara-6-thioguanine and certain related purine nucleosides by the stereospecific sodium salt glycosylation procedure

A simple and high-yield synthesis of biologically significant 2′-deoxy-6-thioguanosine ( 11 ), ara-6-thioguanine ( 16 ) and araG ( 17 ) has been accomplished employing the Stereospecific sodium salt glycosylation method. Glycosylation of the sodium salt of 6-chloro- and 2-amino-6-chloropurine ( 1 and 2 , respectively) with 1-chloro-2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranose ( 3 ) gave the corresponding N-9 substituted nucleosides as major products with the β-anomeric configuration ( 4 and 5 , respectively) along with a minor amount of the N-7 positional isomers ( 6 and 7 ). Treatment of 4 with hydrogen sulfide in methanol containing sodium methoxide gave 2′-deoxy-6-thioinosine ( 10 ) in 93% yield. Similarly, 5 was transformed into 2′-deoxy-6-thioguanosine (β-TGdR, 11 ) in 71 % yield. Reaction of the sodium salt of 2 with 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose ( 8 ) gave N-7 and N-9 glycosylated products 13 and 9 , respectively. Debenzylation of 9 with boron trichloride at ?78° gave the versatile intermediate 2-amino-6-chloro-9-β-D-arabinofuranosyl-purine ( 14 ) in 62% yield. Direct treatment of 14 with sodium hydrosulfide furnished ara-6-thioguanine ( 16 ). Alkaline hydrolysis of 14 readily gave 9-β-D-arabinofuranosylguanine (araG, 17 ), which on subsequent phosphorylation with phosphorus oxychloride in trimethyl phosphate afforded araG 5′-monophosphate ( 18 ).     

Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione, the B,C,D ring core of the shermilamine alkaloids

Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione (4), from N-(4-bromo-2,5-dimethoxyphenyl)acetamide (23) is described. Oxidative cyclisation of 2,2'-disulfanediylbis[N-(2,5-dimethoxyphenyl)acetamide] (19) to 5,8-dimethoxy-2H-1,4-benzothiazin-3(4H)-one (7b) is also reported.     

Novel approach to aminocarboranes by mild amidation of selected iodo-carboranes

A mild protocol for the palladium-catalyzed Buchwald-Hartwig amidation of icosahedral carboranes is described. Employing 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (1) as a ligand and K(3)PO(4) as a base, benzamide, trifluoroacetamide, acetamide, and formamide were coupled to a series of mono- and di-iodo carboranes furnishing the respective carborane derivatives in good to excellent yields. Subsequent base-mediated saponification of the trifluoroacetamide derivatives was shown to provide the free aminocarboranes. The structures of N-(1,7-dicarba-closo-dodecaboran-9-yl)benzamide (8a), N-(1,7-dicarba-closo-dodecaboran-9-yl)trifluoroacetamide (8b), N-(1,12-dicarba-closo-dodecaboran-2-yl)benzamide (10a), N-(1,2-dicarba-closo-dodecaboran-9-yl)benzamide (12a), N-(1,2-dicarba-closo-dodecaboran-9-yl)acetamide (12c), N-(1,2-dicarba-closo-dodecaboran-9-yl)formamide (12d), N-(1,2-dicarba-closo-dodecaboran-3-yl)benzamide (13a), N,N'-(1,7-dicarba-closo-dodecaboran-9,10-diyl)dibenzamide (15a), and N,N'-(1,7-dicarba-closo-dodecaboran-9,10-diyl)bis(trifluoroacetamide) (15b) have been established through X-ray single-crystal diffraction studies.     

Mononuclear Schiff base boron halides: synthesis, characterization, and dealkylation of trimethyl phosphate

A series of mononuclear boron halides of the type LBX(2) [LH = N-phenyl-3,5-di-tert-butylsalicylaldimine, X = Cl (2), Br (3)] and LBX [LH2 = N-(2-hydroxyphenyl)-3,5-di-tert-butylsalicylaldimine, X = Cl (7), Br (8); LH2 = N-(2-hydroxyethyl)-3,5-di-tert-butylsalicylaldimine, X = Cl (9), Br (10); and LH2 = N-(3-hydroxypropyl)-3,5-di-tert-butylsalicylaldimine, X = Cl (11), Br (12)] were synthesized from their borate precursors LB(OMe)2 (1) (LH = N-phenyl-3,5-di-tert-butylsalicylaldimine) and LB(OMe) [LH2 = N-(2-hydroxyphenyl)-3,5-di-tert-butylsalicylaldimine (4), N-(2-hydroxyethyl)-3,5-di-tert-butylsalicylaldimine (5), N-(3-hydroxypropyl)-3,5-di-tert-butylsalicylaldimine (6)]. The boron halide compounds were air and moisture sensitive, and upon hydrolysis, compound 7 resulted in the oxo-bridged compound 13 that contained two seven-membered boron heterocycles. The boron halide compounds dealkylated trimethyl phosphate in stoichiometric reactions to produce methyl halide and unidentified phosphate materials. Compounds 8 and 12 were found to be the most effective dealkylating agents. On reaction with tert-butyl diphenyl phosphinate, compound 8 produced a unique boron phosphinate compound LB(O)OPPh2 (14) containing a terminal phosphinate group. Compounds 1-14 were characterized by 1H, 13C, 11B, 31P NMR, IR, MS, EA, and MP. Compounds 5, 6, and 11-14 also were characterized by single-crystal X-ray diffraction.     

Synthesis of seco-chlorinated derivatives of phenanthroindolizidine precursors via Friedel-Crafts reaction

In the course of synthesizing 3-demethyltylophorine (1) by Lewis acid catalyzed intramolecular Friedel-Crafts reaction starting from N-(3-hydroxy-2,6,7-trimethoxy-phenanthr-9-ylmethyl)-2-chloromethylpyrrolidine, two chlorinated phenanthrene derivatives N-(4,10-dichloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (4) and N-(4-chloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (5) were obtained. The structures of these compounds were determined by spectroscopic analysis.     

Photochemical reactivity of 9-vinyladenine with diethyl fumarate

The photochemical reaction between 9-vinyladenine ( 2 ) and diethyl fumarate ( 4 ) gave an unusual photoadduct, epimers 4 and 5 , probably derived from attack of the vinyl group on N-3 and reaction of diethyl fumarate on N-9 and N-6.     

Über N-(α-Aminoacyl)-sulfonamide, 2. Mitt.

Zusammenfassung Es wird über die Synthese von N-(-Aminoacyl)-p-toluolsulfonamiden und N-(-Aminoacyl)-methansulfonamiden berichtet, deren Acylreste sich vonl-Tyrosin,d,l--Methyl-tyrosin undd,l-3,4-Dihydroxy-phenylalanin ableiten.

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The synthesis of N-(-aminoacyl)-p-toluenesulfonamides and N-(-aminoacyl)-methanesulfonamides containing the acyl groups ofl-tyrosine,d,l--methyltyrosine andd,l-3,4-dihydroxy-phenylalanine is described.

     

1H, 13C and 15N NMR observations on the protonation of 1- and 3-deazapurine

Using ¹H, ¹³C and ¹⁵N NMR it has been concluded that 3-deazarpurine protonates exclusively at N-1 with a pK of about 5.6. The base exhibits rapid tautomerism with proportions of 70:30, with the N–7-H tautomer in the majority. The salt exists predominantly as the N-7-H tautomer. 1-Deazapurine protonates essentially in a 1:1 ratio at N-3 and at the imidazole ring, with a pK of about 3.1. This base also exhibits rapid tautomerism with proportions of 30:70, this time with the N-9-H in the majority. The salt also exists in a tautomcric mixture with approximately equal proportions. One form has N-3 and N-9 bearing hydrogens and the other has N-7 and N-9 bearing hydrogens.     

Preparation and antiviral properties of new acyclic, achiral nucleoside analogues: 1- or 9-[3-hydroxy-2-(hydroxymethyl)prop-1-enyl]nucleobases and 1- or 9-[2,3-dihydroxy-2-(hydroxymethyl)propyl]nucleobases

Acyclic, achiral nucleoside derivatives 1b-e of adenine, cytosine, 5-methylcytosine, and guanine, containing a 3-hydroxy-2-(hydroxymethyl)prop-1-enyl group on N-1 or N-9, have been prepared analogously to the previously described thymine derivative 1a. In contrast to the adenine and guanine derivatives, the cytosine derivative 9 was unstable, and was obtained in a low yield due to side reactions. These include cleavage of the propenyl group from the base, and the formation of a bicyclic compound. The thymine derivative, although stable under neutral conditions, likewise underwent a reversible cyclization reaction (Michael addition) in the presence of acids or bases. The 5-methylcytosine derivative was stable under neutral and basic conditions. Four other nucleoside derivatives 26a-d containing a 2,3-dihydroxy-2-(hydroxymethyl)propyl group on N-1 or N-9, three of which are new, have likewise been prepared. All compounds were evaluated as antiviral agents against HIV-1 and HSV-1 but were devoid of antiviral activity.     

Reactions of 1, 5-diketones

N-R-9-R′-Decahydroacridines, which are formed as a result of the reaction of alicyclic 1,5-diketones with primary aliphatic amines, split out a substituent from the nitrogen atom and a hydrogen atom from the 9 position to give 9-R′-sym-octahydroacridines. On the basis of the IR spectra, it was concluded that the N-(Β-hydroxyethyl)-9-R′-decahydroacridines cyclize.     

N-Alkylation of 2,6-Dichloropurine Hydrochloride with a Variety of Alcohols over Alumina Catalyst

2,6-Dichloropurine hydrochloride reacts with various types of alcohols using different alumina catalysts and converts into its N-9-alkyl-2-chloro-6-hydroxy-9H-purine products to an extent of 49–74%. The product selectivity depends on the stability of carbocation generated from the alcohol. More stable carbocation formulates both N-7 and N-9-alkyl-2,6-dichloropurine products, whereas the less stable carbocation results in exclusively N-9-alkyl-2-chloro-6-hydroxy-9H-purine. The catalytic activity of alumina prepared using the sol-gel method has larger Brunauer, Emmett, and Teller (BET) surface area and hence shows significantly greater catalytic activity than the commercially available alumina samples.     

N-(17-Acyloxy-acyl)-glutamines: novel surfactants from oral secretions of lepidopteran larvae

N-(17-Acyloxy-acyl)-glutamine conjugates such as N-(17-linolenoyloxy-linolenoyl)-glutamine (6), N-(17-linolenoyloxy-linoleoyl)-glutamine (7), N-(17-linoleoyloxy-linolenoyl)-glutamine (8), and N-(17-linoleoyloxy-linoleoyl)-glutamine (9) were identified as novel surfactants in the oral secretion of several lepidopteran larvae (S. exigua, S. littoralis, S. frugiperda, and H. virescens) by LC-MS/MS and chemical degradation. Authentic reference compounds were synthesized via a dissymmetric bis-Wittig approach and confirmed the assigned structures.     

Study of the factors that control the ratio of the products between 5-fluorouracil, uracil, and tetrahydrobenzoxazepine O,O-acetals bearing electron-withdrawing groups on the nitrogen atom

(RS)-1-(2-Nitrobenzenesulfonyl)- and (RS)-1-(4-nitrobenzenesulfonyl)-3-methoxy-1,2,3,5-tetrahydro-4,1-benzoxazepines are better substrates than 1-acyl-3-methoxy-1,2,3,5-tetrahydro-4,1-benzoxazepine derivatives for the Lewis acid mediated condensation reaction with pyrimidine bases to give O,N-acetals. Acetonitrile, stannic chloride, 50 degrees C, and a reaction time higher than 48 h are the optimum conditions for such condensation reactions. Under these conditions, 5-fluorouracil preferably links to the aminalic carbon through its N-1" position, while the attachment of the uracil fragment is through N-3" or N-1" of the cyclic or acyclic products, respectively. The causes that influence the course of the reactions are analyzed and discussed. Examination of the (1)H NMR spectra revealed the presence of a single form for the secondary amine 11 and of two conformers for the tertiary sulfonamides 7a,b, 9a,b, and 10b and for the amides 7d and 13, with the following distribution: 7a, 59/41; 7b, 53/47; 9a, 52/48; 9b, 59/41; 10b, 56/44; 7d, 50/50; 13, 80/20. On increasing the temperature, the (1)H NMR spectrum (DMSO-d(6)) of 7b showed coalescence at 110 degrees C. The torsional barrier determined [DeltaG(c)++ value of 19.0 +/- 0.2 kcal.mol(-1) (79.1 +/- 1.0 kJ.mol(-1))] proved to be the highest ever observed for sulfonamide moieties.     

N-(acridin-9-yl)arenesulfonamides: Synthesis,quantum chemical studies and crystal structure analysis to establish the tautomeric preferences

The potentiality of the N-(acridin-9-yl)arenesulfonamide moiety as a hybrid pharmacophore due to the distinct pharmacological activities of acridines and aryl/heteroaryl sulfonamides prompts to synthesise N-(acridin-9-yl)arenesulfonamides and study their structural properties. Various N-(acridin-9-yl)arene/heteroarenesulfonamides were obtained through the development of a new methodology adopting the Pd₂(dba)₃-catalyzed CN bond formation strategy for the reaction of 9-chloloroacridine with arene/heteroarenesulfonamides. The 1H and ¹³C NMR spectra suggest these N-(acridin-9-yl)arene/heteroarenesulfonamides to exist solely as the sulfonimide tautomer rather than anticipated sulfonamide form and was confirmed by the single crystal XRD analysis of one of the newly synthesized compounds. The quantum chemical studies rationalized this tautomeric preference revealing that the sulfonimide tautomers are more stable than the sulfonamide tautomers by ?0.67 to ?5.12?kcal/mol in the gas phase. In the solid state, the sulfonimide tautomer is stabilized by intermolecular hydrogen bond between NH?OS and π? π stacking between the acridine rings.     

Synthesis of enantiopure 7-[3-azidopyl]indolizidin-2-one amino acid. A constrained mimic of the peptide backbone geometry and heteroatomic side-chain functionality of the ala-lys dipeptide

Enantiopure N-(BOC)amino-7-[3-azidopropyl]indolizidin-2-one acid 1 has been synthesized by displacement of the methanesulfonate of its 7-hydroxypropyl counterpart 11 with sodium azide and subsequent ester hydrolysis. N-(BOC)Amino-7-[3-hydroxypropyl]indolizidin-2-one ester 11 was obtained from a sequence commencing with the alkylation of (2S,8S)-di-tert-butyl 5-oxo-2,8-di-[N-(PhF)amino]azelate 5 (PhF = 9-(9-phenylfluorenyl)). Stereoselective allylation of 5, regioselective olefin hydroboration, selective primary alcohol protection as a silyl ether, and oxidation of the secondary alcohol gave (2S,4R,8S)-di-tert-butyl 4-[3-tert-butyldimethylsiloxypropyl]-5-oxo-2,8-di-[N-(PhF)amino]azelate 9 as a pure diastereomer in 33% overall yield. Linear ketone 9 was then converted into the indolizidinone heterocycle by a route featuring reductive amination, lactam cyclization, and isolation by way of a silyl ether which provided the (6S,7R)-isomer of 11.     

Conformationally constrained dipeptide surrogates with aromatic side-chains: synthesis of 4-aryl indolizidin-9-one amino acids by conjugate addition to a common alpha,omega-diaminoazelate enone intermediate

Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.     

Regiodependent luminescence quenching of biotinylated N-sulfonyl-acridinium-9-carboxamides by avidin

[reaction: see text] Biotin was conjugated to chemiluminescent N-sulfonylacridinium-9-carboxamides at the N-10 or 9-position carboxamide. Upon binding to avidin, the light output of the N-10 derivative (8) was quenched up to 92% upon triggering with basic peroxide, while the 9-position carboxamide conjugate (9) was quenched only 33%. The utility of this effect was demonstrated in a model homogeneous chemiluminescence assay.     

The aminomethylation of adenine,cytosine and guanine

Aminomethylated derivatives of adenine, cytosine and guanine have been isolated and characterized for the first time. These results are important because of the potential for similar adducts being formed transiently between nucleosides and nucleotides, and endogenous aldehydes and amines in vivo, and of the potential use of similar adducts for drug delivery. Mono-alkylated products obtained were from the reaction of adenine with one equivalent of aminomethylating agent derived from amines exhibiting lower basicity (e.g., morpholine and N-methylpiperazine); bis-alkylated products were obtained with agents derived from more basic amines regardless of the stoichiometry. On the other hand, only bis-alkylated products were obtained from the reaction of cytosine or guanine with the aminomethylating agent regardless of the basicity of the secondary amine used or the stoichiometry of the reaction. The mono-alkylated adenine products were alkylated on N-9 while the bis-alkylated cytosine products were alkylated on N-9 and N⁴ and the bis-alkylated adenine products were alkylated on N-9 and N⁶. The adenine and cytosine aminomethyl adducts hydrolyzed rapidly in dilute aqueous solution.