Condensed Isoquinolines. 12. Synthesis of Novel Heterocyclic Systems Containing a Partially Hydrogenated Spiro[isoquinoline-4,4'-(2H)-pyran] Fragment

By condensation of 4-(2-bromomethyl)-3,4,5,6-tetrahydro-2H-pyran-4-carbonitrile with anthranilic acid, its derivatives substituted in the benzene ring (esters, nitrile), and with esters of 2-aminothiophene-3-carboxylic acids and 3-amino-5-bromobenzofuran-2-carboxylic acid there have been synthesized novel derivatives which include spiro-linked tetrahydropyran and 5,10-dihydro-3H-pyrimido[1,2-b]isoquinoline fragments. The pyrimidine ring of the latter was annelated by a substituted benzene, thiophene, or 5-bromobenzofuran ring.     

Synthesis of functionalised cephalosporins : Diphenylmethyl(1S,6R,7S)-3-bromomethyl-7-formamido-7-methoxyceph-3-em-4-carboxylate-1-oxide: a useful intermediate in the preparation of 7α-methoxycephalosporins

The N-formamido cephalosporins 4a and4b undergo direct methoxylation at the Pα-position to give the 7α-methoxy derivatives 5a and 5b. These were converted to other 7β-acylamido compounds by the sequence : oxidation, deformylation, acylation and reduction. The 3-bromomethyl derivatives 2b,6b and 8b proved amenable to nucleophilic substitution with 5-mercapto-1-methyltetrazole.     

Synthesis of some bifunctional derivatives of 8-methylquinoline-5-carboxylic acid

Derivatives of 8-methylquinoline-5-carboxylic acid were synthesized. Alcoholysis of 8-methyl-5-cyanoquinoline gave methyl and ethyl 8-methylquinoline-5-carboxylates, which were converted to the corresponding 8-bromomethyl derivatives. The latter were used for the introduction of a methylamino group and the synthesis of N-acyl derivatives. The hydrazide, amide, and anilide of 8-methylquinoline-5-carboxylic acid were obtained as model compounds.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 785–788, June, 1982.     

Pyrimidine derivatives. VI. Synthesis of mono-, di-, tri-, and tetrabromo-substituted pyrimidine derivatives

The following bromo-2,4(1H,3H)-pyrimidinediones possessing a bromo substituent at the 5-position and side chains at the 1- and 6-positions were prepared. The three types of mono-bromo derivatives are: 1-(bromoalkyl)-3,6-dimethyl- 3a-d , 5-bromo-3,6-dimethyl-1-(hydroxyalkyl)- 4a-d , and 1-(acetoxyalkyl)-5-bromo-3,6-dimethyl-2,4(1H,3H)-pyrimidinediones 11a-d . The three types of dibromo derivatives are: 5-bromo-1-(bromoalkyl)-3,6-dimethyl- Sa-d , 1-(acetoxyalkyl)-5-bromo-6-bromomethyl- 8a, 8c , and 8d , and 5-bromo-6-bromomethyl 1-(hydroxyalkyl)-2,4(1H,3H)-pyrimidinediones 9a, 9c , and 9d . Likewise one group of tribromo and one group of tetrabromo derivatives are: 5-bromo-1-(bromoalkyl)-6-bromomethyl -7a-d and 5-bromo-1-(bromoalkyl)-6-dibromomethyl-2,4(1H,3H)-pyrimidinediones 6a-d .     

Transformations of 5-methyl-6-carbethoxy-3,4-dihydrothieno-[2,3-d]pyrimidine for synthesis of 4-methoxy-, 4-alkylamino-, and other derivatives of thieno[2,3-d]pyrimidine

4-Chloro derivatives of thieno[2,3-d]pyrimidine are formed by the action of phosphorus oxychloride on 5-methyl- and 5-methyl-6-carbethoxythieno[2,3-d]pyrimidin-4-ones. Action of nucleophilic reagents (methanol, sodium methylate, primary and secondary amines) on these chloro derivatives gave 4-methoxy-, 4-alkylamino-, and 4-dialkylamino substituted thieno[2,3-d]pyrimidines. It was found that 4-methoxy derivatives of thieno[2,3-d]pyrimidines undergo a thermal rearrangement into 3-methyl-substituted thieno[2,3-d]pyrimid-4-ones. In the bromination of 5-methyl-4-chloro- and 5-methyl-4-methoxy-substituted thieno[2,3-d]pyrimidines by N-bromosuccinimide, 5-bromomethyl derivatives of thieno[2,3-d]pyrimidine are formed, from which, by the action of primary and secondary amines, 5-aminomethyl-substituted thieno[2,3-d]pyrimidines were obtained. A synthesis of 1,2,3,4-tetrahydro-1,3-diazepino[4a,10-d,e] thieno[2,3-d]pyrimidines was also carried out.Deceased.Translated from Khimiya Geterotsilicheskikh Soedinenii, No. 7, pp. 925–928, July, 1985.     

Fluorinated N-[2-(haloalkyl)phenyl]imidoyl chloride, a key intermediate for the synthesis of 2-fluoroalkyl substituted indole derivatives via Grignard cyclization process

Fluorinated N-[2-(haloalkyl)phenyl]imidoyl chloride, which was readily available from the corresponding anilines by using Uneyama's one-pot synthesis of fluorinated imidoyl chloride, was found to be a key intermediate for the facile synthesis of 2-fluoroalkyl substituted indole derivatives via the Grignard cyclization process. The bromination of 3-methyl group of 3-methyl-2-trifluoromethyl indole with NBS/CCl₄ led to the formation of 3-bromomethyl substituted indole which can be further utilized to synthesize some new and biologically interested indole derivatives.     

3, 3-不对称二取代甲基氧杂丁环的合成

以2,2-二(溴甲基)-1,3-丙二醇(1)为原料合成了3-溴甲基-3-羟甲基氧杂丁环(2)、3-乙氧甲基-3-羟甲基氧杂丁环(3)、3-叠氮甲基-3-羟甲基氧杂丁环(4)、3-叠氮甲基-3-硝酸酯甲基氧杂丁环(5)、3-溴甲基-3-硝酸酯甲基氧杂丁环(6)及3-乙氧基甲基-3-硝酸酯甲基氧杂丁环(7)共六种3,3-不对称二取代甲基氧杂丁环化合物,其中6和7的合成未见文献报道。也提出了合成5的改进路线。     

Synthesis of fused 1,2,4-triazines as potential antimicrobial and antitumor agents

5-Benzylidene-3-(p-chlorophenyl)-2-aminothiocarbonyl-1,2,4-triazine (2) was prepared via condensation of oxazolinone (1) with thiosemicarbazide. Fused 1,2,4-triazine derivatives (3, 4 and 9) were synthesized from the reaction of compound 2 with ω-bromomethyl aryl ketones, ethyl chloroacetate, and acetic anhydride. Treatment of 4 with acetic anhydride and aromatic aldehydes yielded the corresponding acetyl, diacetyl derivatives (6 and 7) and 7-benzylidene-5-(p-chlorophenyl)-4-thioxo-3-arylidene-1,2,4-triazino [2,1-a]-1,2,4-triazine-1,8-diones (8). The electron impact mass spectra of both the above series of compounds have also been recorded and their fragmentation pattern is discussed. All synthesized fused 1,2,4-triazine derivatives were primary in vitro screened for their antimicrobial and antitumor activity.

     

Reaction of 2,4-Difunctional Esters of 5-tert-Butylfuran-3-carboxylic Acid with Nucleophilic Reagents

Ethyl 5-tert-butyl-4-(chloromethyl)-2-methylfuran-3-carboxylate was brominated with N-bromo-succinimide to obtain the corresponding 2-bromomethyl derivative. The latter is selectively phosphorylatedwith trimethyl, triethyl phosphites by the bromomethyl group. The resulting [4-(chloromethyl)furyl]methyl-phosphonates in the presence of secondary amines and sodium butanethiolate behave as alkylating agents,while sodium phenolate causes their decomposition. 4-Acetoxymethyl- and 4-phenoxymethyl derivatives of the starting product are also selectively brominated with N-bromosuccinimide by the 2-methyl group. The first of the 2-(bromomethyl)furans formed is smoothly phosphorylated with trimethyl phosphite, while the second one under the action of triethyl phosphite gives a mixture of phosphorylation and debromination products. In all the cases, an additional electron-acceptor group in position 4 of alkyl 2-(bromomethyl)-5-tert-butylfuran-3-carboxylate considerably accelerates the Arbuzov reaction.     

Investigations in the imidazole series

The reaction of 2-aminobenzothiazole and its 6-substituted derivatives with-bromomethyl alkyl (aryl, heteryl) ketones was investigated in detail. Under mild conditions, 3-acylmethyl-2-iminobenzothiazolines were isolated. Their structures were established, and their properties and the conditions for cyclization to imidazo[2,1-b]benzothiazole derivatives were studied.See [1] for communication LXXVII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1271–1274, September, 1972.     

Stereoselective Synthesis of Some Dialkyl (E)-2-Bromomethylene Glutarates

Reaction of 2-bromo-2-bromomethyl glutaric acid esters with tetraalkylammonium fluoride in HMPA, conveniently provides the corresponding dialkyl (E)-2-bromomethylene derivatives in good yields.     

Irreversible enzyme inhibitors. LXXXIX. candidate active-site-directed irreversible inhibitors of dihydrofolic reductase. X. derivatives of 2-amino-5-benzamidopropyl-4-pyrimidinol

Since 2-amino-5-benzamidopropyl-6-methyl-4-pyrimidinol (VII) was a reasonably good reversible inhibitor of dihydrofolic reductase, the benzamido group was substituted with p-bromomethyl (XVIIa), m-bromomethyl (XVIIIa), and p-bromoacetyl (XIXa) groups; these compounds, and the corresponding 6-phenylpyrimidines, were synthesized from the proper 2-amino-5-aminopropyl-4-pyrimidinol (V) by devising methods that were compatible with the high reactivity of the halogen. Compounds XVII-XIX showed in-activation of dihydrofolic reductase; the fact that p-nitrobenzyl bromide inactivated the enzyme as rapidly as XVII and XVIII and phenacyl bromide inactivated the enzyme as rapidly as XIX indicated that these inactivations proceeded by a random bimolecular mechanism and not the desired active-site-directed mechanism.     

Bromination of 1,3,5-trimethyl-4-chloropyrazole

The bromination of 1,3,5-trimethyl-4-chloropyrazole with N-bromosuccinimide (NBS) in the presence of benzoyl peroxide leads to 5-bromomethyl-1,3-dimethyl-4-chloropyrazole, whereas 3,5-bis(bromomethyl)-1-methyl-4-chloropyrazole predominates in the case of a twofold excess of NBS. Products of subsequent substitution in the 3- and 5-bromomethyl groups of the 3,5-bis(bromomethyl) compound in a ratio of 31 were detected in small amounts; this is evidently associated with the syn orientation of the bromine atom in the 5-bromomethyl group, which hinders attack by the bromine radical.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 40–42, January, 1988.     

Synthesis of Terpyridine Derivatives Containing β—Cyclodextrin

A novel β-cyclodextrin-based terpyridine derivatives has been prepared by the coupling of 4‘‘‘‘‘‘‘‘-(4“-bromomethyl phenyl)-2,2‘‘‘‘‘‘‘‘:6‘‘‘‘‘‘‘‘,2“-terpyridine with mono-6-hydroxy permethylated β-cyclodextrin.The cyclodextrin dimmer appending a 4‘‘‘‘‘‘‘‘-phenyl-2,2‘‘‘‘‘‘‘‘:6‘‘‘‘‘‘‘‘,2“-terpyridine spacer on the primary faces was synthesized by reaction of 4‘‘‘‘‘‘‘‘-phenyl-2,2‘‘‘‘‘‘‘‘:6‘‘‘‘‘‘‘‘,2“-terpyridine-6,6‘‘‘‘‘‘‘‘-dicarbonitrile with an excess of 6-deoxy-6-O-tosyl-β-cyclodextrin.     

Reaction of Some Dibromomethyl-Substituted Cyclohexadienones with Molecular Bromine

4-Dibromomethyl-4-methyl-2,5-cyclohexadienone and its 2- and 3-methyl-substituted derivatives react with an equimolar amount of molecular bromine in carbon tetrachloride, yielding vinyl bromination products at the -position with respect to the carbonyl group. The reaction of 4-dibromomethyl-3,4-dimethyl-2,5-cyclohexadienone with a large excess of bromine, apart from the vinyl bromination product, gives the corresponding 3-bromomethyl and 3-dibromomethyl derivatives. 4-Dibromomethyl-2,4-dimethyl-2,5-cyclohexadienone takes up bromine molecule at the C ² ÍC ³ double bond.     

A new strategy for the synthesis of 1,4-benzodiazepine derivatives based on the tandem N-alkylation-ring opening-cyclization reactions of methyl 1-arylaziridine-2-carboxylates with N-[2-bromomethyl(phenyl)]trifluoroacetamides

A new method for the synthesis of novel 1,4-benzodiazepine derivatives has been established from a one-pot reaction of methyl 1-arylaziridine-2-carboxylates with N-[2-bromomethyl(aryl)]trifluoroacetamides. The reaction proceeds through the N-benzylation and highly regioselective ring-opening reaction of aziridine by bromide anion followed by Et3N-mediated intramolecular nucleophilic displacement of the bromide by the amide nitrogen. The easy availability of starting materials, simple and convenient synthetic procedure, and formation of functionalized 1,4-benzodiazepine scaffold ready for further chemical manipulations render this strategy useful in synthetic and medicinal chemistry.     

2-,3-和4-溴甲基吡啶的水解反应的动力学研究

用HPLC测定了2-、3-和4-溴甲基吡啶在60℃、离子强度μ为0.15、pH 0.9～9.9的缓冲溶液中水解成相应的羟甲基吡啶的反应速度.通过数学处理,求得溴甲基吡啶的一级和二级反应速度常数以及溴甲基吡啶共轭酸的一级反应速度常数.水解反应的可能机理是S_N1和S_N2.     

Through-space electronic interactions of [2.2]metacyclophane benzyl cations

The hydrolysis of 8-bromomethyl[2.2]metacyclophanes 3 to the corresponding 8-hydroxymethyl derivatives 4 was carried out in 83% aqueous dioxane solution at 25°C. Substituent effect through space on the rate of the hydrolysis of bromomethyl groups attached on the opposite aromatic ring was first found in this investigation. Interestingly, the introduction of the substituents at the internal position 16 tends to enhance the hydrolysis reaction rate 10–100 times. It was found also that the stabilization by both the direct through-space cation-π-interaction and the interaction through the intra-annular 8,16-position are possible in the [2.2]metacyclophane 8-benzyl cations. The good correlation with log(K/K_H) and σ_p ⁺ was observed for the hydrolysis of internally unsubstituted 5-bromomethyl[2.2]MCPs 7, in which the direct through-space cation-π-interactions are not possible. TiCl₄ and Nafion-H, a perfluorinated resinsulfonic acid, catalysed Friedel-Crafts benzylation of benzene and substituted benzenes with 8-bromomethyl- and 8-hydroxymethyl[2.2]metacyclophanes to afford 8-benzyl[2.2]metacyclophanes is described. A high substrate and positional selectivity were observed in the present benzylation reaction quite different from those obtained from the benzyl bromide and benzyl alcohol. The benzyl cation intermediate stabilized by the through-space electronic interaction among the opposite benzene ring was first demonstrated in the benzylation of [2.2]metacyclophane systems. The mild and selective transannular reaction attributable to the highly strained character of [2.2]metacyclophane skeleton and the increased stabilization of the 5-benzyl cation intermediate arising from the electronic interactions among the opposite benzene ring through the intra-annular 8,16-positions was also observed.     

Access to the spiro hydrindandione ring system of Fredericamycin A through spiroalkylation and oxidation.

Indene could be spiro alkylated with bis-1,2-bromomethyl benzene derivatives. Further functionalization of the benzylic positions led to the dihydroxy dibenzospiro 4,4 nonane dione ring system of Fredericamycin A.     

A route to a wide range of cyclopentanecarboxylic acids via 4-substituted camphors

4-Carboxycamphor, easily obtainable starting from camphor, is used as a versatile precursor in high-yielding syntheses of a wide range of cyclopentanecarboxylic acids using just a few steps. Regioselective bromination of 4-carboxy- and 4-methoxycarbonyl-3-bromocamphors leads to 10-bromomethyl derivatives in good yields. Grob-type fragmentation reactions proceed smoothly for 10-bromocamphor-4-carboxylic acid, 10-bromocamphorquinone-4-carboxylic acid and 3,4-dibromocamphor with the formation of unsaturated cyclopentanecarboxylic acids. Detailed studies of bromination and rearrangement reactions of brominated camphor-4-carboxylic acid and its derivatives, reported herein, highlight the unique chemistry of substituted camphor and offer easy access to a wide range of 2,2-dimethyl-3-methylenecyclopentanecarboxylic acid derivatives.