1, l- carbonyldiimidazole

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

Treatment of a chiral amine with phosgene is the cheapest way to prepare symmetrical ureas [29]. Nevertheless, due to the toxicity and reactivity of that reagent, it can advantageously be replaced by triphosgene [30] or l,l -carbonyldiimidazole [31-34] or other derivatives such as l,l -carbonyldi-2(lH)-pyridinone [35]. This procedure can be extended to thiophosgene (Scheme 1) and its thio-analogues, such as l,l -thiocarbonyldi-2(lH)-pyridinone to produce thioureas [36] chiral diamines can thus be transformed into the corresponding monoureas or monothioureas. 

A-(l//-5-Tetrazolyl)-10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxamide was prepared on treatment of the 3-carboxylic acid with l,l -carbonyldiimidazole in dimethyl-formamide at ambient temperature under nitrogen, then with 5-amino-lH-tetrazole at 100°C for 1 h (85EUP143001). Treatment of lO-(acylamido)-... 

M -Carbonylbis(3-methyiimidazoliuni) triflate (1, m.p. 78-80°). The reagent is prepared by reaction of l,l -carbonyldiimidazole with methyl triflate in CH3N02 at... 

To a 5 L 3-neck round bottom flask with stir bar was added the crude N-(3-amino)-propyl)valine methyl ester (150 g, 0.8 mol) and dichloromethane (3.2 L). Carbonyldiimidazole (232 g, 1.44 mol) was added slowly in portions over 25 min. The solution was allowed to stir at ambient temperature for 40 hours. Water (200 mL) was added over 1 h with stirring until no more gas evolution occurred. A solution of 35% HCI was slowly added to the stirring solution until the solution became acidic. The solution was then partitioned and was washed with water. The organic layer was dried over sodium sulfate and was concentrated to yield 126 g (74%) of 2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid methyl ester as a colorless solid. 

In a closed system equipped with an oil bubbler, 30 ml of tetrahydrofuran were added to a mixture of 4-amino-5-chloro-2-methoxybenzoic acid, 2.02 g (0.010 mole) and l,l -carbonyldiimidazole, 1.62 g (0.010 mole) with stirring. When evolution of carbon dioxide ceased, nitrogen was bubbled through the reaction mixture for 1 hr. A solution of 3-aminoquinuclidine, 1.26 g (0.010 mole) in 10 ml tetrahydrofuran was added dropwise to the stirred reaction mixture and stirring at room temperature continued for 3 hrs. TLC analysis (3% cone, ammonium hydroxide solution in methanol) showed some product formation. The mixture was heated at reflux temperature for 18 hours and then concentraded to an oil. TLC analysis showed the presence of the product, imidazole and 3-aminoquinuclidine. The oil was dissolved in methylene chloride (75 ml) and washed twice with 50 ml portions of aqueous sodium bicarbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated to yield 2.0 g (67%) of a glassy amorphous solid, the free base of the title compound. 

To a solution of 7.5 g thereof, in 300 ml of tetrahydrofuran is added 5 g of l,l -carbonyldiimidazole and the resultant mixture stirred at room temperature for 1 hour. To this mixture is added 5 g of l,3-dihydro-l-(4-piperidyl)-2H-benzimidazol-2-one, and the reaction is heated at reflux temperature for 48 hours. After cooling to room temperature, the reaction mixture is poured into 150 ml of ice-water and extracted into 150 ml of methylene chloride. The organic extracts are washed successively with 150 ml of sodium carbonate solution, 150 ml of water and 150 ml of dilute hydrochloric acid, then dried over magnesium sulfate, filtered, and the solvent is evaporated under reduced pressure to yield l,3-dihydro-l- l-[(4-methyl-4H,6H-pyrrolo[l,2-a][4,l]benzoxazepin-4-yl)carbonyl]-4-piperidinyl -2H-benzimidazol-2-one, m.p. 208°-210°C. 

SCHEME 14.1 Synthesis of lipids I and II by VanNieuwenhze et al. Bn, benzyl CDI, l,l -carbonyldiimidazole DBU, l,8-diazabicyclo[5.4.0]undec-7-ene DIPEA, diisopropylethyl-amine EDC, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide NHS, A-hydroxysuccinimide Pyr, pyridine TFA, trifluoroacetyl Troc, 2,2,2-trichloroethoxycarbonyl. 

T-Carbonyldiimidazole (0.900mmol) was added to the Step 9 product (0.451 mmol) dissolved in 7 ml THF and stirred for 3 hours. The mixture was cooled to 0°C, then treated with methanesulfonamide (0.90 mmol) followed by l,8-diazabicyclo[5.4.0]undec-7-ene (0.903 mmol), and stirred 4 hours at ambient temperature. The reaction mixture was diluted with EtOAc, washed once with 1M HC1, twice with water, once with brine, then dried, and concentrated. The residue was reconcentrated from CH2C12 and the product isolated in 98% yield as a white solid. 

When intermediate 81 is formed from indole 80 and l,l -carbonyldiimidazole (GDI) using DMAP to promote indole nitrogen acylation in acetonitrile at reflux, it is reasonably stable, observed by TLC, but not isolated. Treatment of intermediate 81 in situ with amines, alcohols, or thiols afforded the desired derivatives 82. During the reaction of indoles with GDI, some carbonyl diindole 83 was formed. In many cases this material could be isolated and characterized. In an alternative approach, alcohols reacted with GDI stoichiometrically to form an unstable intermediate carbamate species 84, which could in turn be reacted with indoles to form the desired indole-1-carboxylates 82. This new methodology for the formation of compound 82 proved to be useful in one of the approaches for the synthesis of novel Serotonergics. 

Among the most useful of these azolides is l,l -carbonyldiimidazole (253). This compound is extremely reactive towards nucleophilic reagents because the carbonyl group is subject to electron withdrawal from both sides. Also, although it is very rapidly hydrolyzed by water at room temperature with vigorous carbon dioxide evolution, tihe compound is crystalline, and much more easily handled than phosgene which has similar reactivity. In the formation of 1-acylimidazoles compound (253) reacts in equimolar proportions with a carboxylic acid in an inert solvent to give practically quantitative yields. This reaction comprises a two-step mechanism (Scheme 145) in which the carboxylic acid reacts initially... 

Oxo-1 -methyl-3,4,5,6-tetrahydro-1H-1,2,4-thiadiazine-5-carboxylate 1 -oxide (364) was obtained in 87% yield from (S)-methylcysteine sulfoximine (363) with l,l -carbonyldiimidazole in the presence of DBU in dimethyl sulfoxide (84JMC228). 

Ried et ah551 recently found a generally applicable aldehyde synthesis in the hydrogenolytic fission of l-acyl-3,5-dimethylpyrazole by lithium aluminum hydride, a reaction that takes place with very good yields in ether at 0-20°. An appreciably better method still is to use the same hydride in ether or tetrahydrofuran to reduce the corresponding 1-acylimidazoles, which are readily obtained from the free acids and l,l -carbonyldiimidazole with 0.25 mole of hydride per mole of acylimidazole the reduction is complete in 30-60 min at —20°,552 and it is an advantage of the method that it can be carried out entirely in one vessel without isolation of the acylimidazole intermediate. 

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