Cyclopropylamines synthesis

More detailed isotopic labeling studies have also been performed. Hydroxycyclopropanation of trans-f.3-deutero-styrene 273 under Kulinkovich conditions furnishes m-2-phcny 1-1 -cyclopropanol, 274, indicating retention of configuration at the carbon bound to titanium and is consistent with frontside attack of the Ti-C bond on a titanium-bound carbonyl.220 For the related de Meijere cyclopropylamine synthesis, the opposite outcome has been observed where a 3 1 mixture of A, Wdimethyl-W(/ra t-3-deutero-/ra j-2-phenylcyclopropyl)amine 278 and -dim ethyl-. V-((7.i-dcutcro-t7r-2-phony Icyclopropy I )amine 277 is produced. These products require inversion of configuration at the carbon bound to titanium and are consistent with a W-shaped transition structure for ring closure (Scheme 46). 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

The synthesis of compound 27 was initiated with the treatment of ke-toester 29, reported by Yoshida et al. [25], with ethyl orthoformate in acetic acid, followed by reaction with (l.R,2S)-2-fluoro-1-cyclopropylamine p-toluenesulfonic acid salt in the presence of triethylamine to yield an enam-inoketoester intermediate, cyclization of which under NaH in dioxane yields the 5-nitroquinolone derivative (30). Reduction of the nitro group of compound 30 followed by acid hydrolysis provides compound 27 via the amino-quinolone derivative (31), according to Scheme 7. 

Cyclophanes, 24 37-38 Cyclopropanes, 13 654 26 654 Cyclopropenyl acids, 5 28 Cyclopropylamine (CPA) in nevirapine synthesis, 15 741-742 physical properties of, 2 498t Cyclopropyl bromide, physical properties of, 4 350t... 

This modification of the Curtius reaction has been used extensively in many laboratories and has been found to be generally applicable. Some examples from the literature include the stereoselective synthesis of a wide variety of cyclopropylamine derivatives from the corresponding acids,11-13 the stereoselective preparation of some substituted norbornylamines from easily isomerized acids,14 the preparation of some 1-aminocyelobutancearboxylic acids from the corresponding acid esters,18 the preparation of a substituted cyclobutanone from... 

In a recent paper, cyanobenziodoxole 38 was applied to the synthesis of N-cyanomethyl-AT-cyclopropylamine, which is an important metabolite of the cyclopropylamine derived drugs [37]. 

The reaction of an epoxide containing molecule with a nucleophile is typically an excellent manner in which to open the epoxide ring. A recent synthesis of carbocyclic nucleoside analogues provides an excellent example of reaction conditions that epoxides can sometimes withstand <07T5050>. Treatment of epoxide 18 with chloropurine under Mitsunobu conditions provides a good yield of epoxy purine derivative 19. This derivative was then converted to adenine derivative 20 by ester hydrolysis and subsequent chloride displacement with cyclopropylamine. 

The Kulinkovich reaction has been widely developed, offering important synthetic potential. Thus, the intramolecular and enantioselective variants have been reported. More recently, similar Ti-mediated reactions were reported which allow the synthesis of tertiary and primary cyclopropylamines from N,N-dialkylamides [5,6] and nitriles [7], respectively. 

The monoamine oxidase inhibitors epitomize cyclical fashions in drug use and the impact of adverse effects. They were the first psychotropic drugs for which a clear biochemical action was defined. Early excitement was quickly tempered by reports of liver toxicity with the hydrazine derivatives, leading to synthesis of the cyclopropylamine drug, tranylcypromine, which in turn elicited the food and drug interactions that led to an overall decline in popularity. 

Cyclopropylamines and their substituted derivatives are important building blocks in a large number of biologically active compounds. The synthesis of potentially biologically active A/,A/-dimethyl bicyclic cyclopropylamines from N-allylamino acid dimethylamides by the intramolecular variant of the Kulinkovich reaction was accomplished by M.M. Joullie and co-workers. 

Chaplinski, V., de Meijere, A. Cyclopropyl building blocks for organic synthesis. 33. A versatile new preparation of cyclopropylamines from acid dialkylamides. Angew. Chem., Int. Ed. Engl. 1996, 35, 413-414. 

Cao, B., Xiao, D., Joullie, M. M. Synthesis of Bicyclic Cyclopropylamines by Intramolecular Cyclopropanation of N-Allylamino Acid Dimethylamides. Org. Lett. 1999, 1, 1799-1801. 

Cyclopropane derivatives. The intramolecular Kulinkovich reaction of 2-substituted 5-hexenoyl bomanesultams is a useful method for the synthesis of chiral endo-2-substituted bicyclo[3.1.0]hexan-l-ols. Extension of the reaction scope to amides results in the formation of cyclopropylamines and cyclopropylstannanes. ... 

The use of 2-(trimethylsilyl)ethanol allows the very mild and selective conversion of the initially formed urethanes into the cyclopropylamines with tetrabutylammonium fluoride, e.g. the synthesis of 2,2-dimethyl-3-(2-methylprop-l -enyl)cyclopropylamine (13) from /ra i-chrysanthemic acid (11). ... 

The synthesis of cyclopropylamines is also conveniently realized through the Hofmann rearrangement of carboxylic amides. Hofmann degradation of cyclopropanecarboxamide gives access to the parent cyclopropylamine (17) in an excellent yield of 82%. ... 

Synthesis of a-Methylated Carbonyl Compounds from Cyclopropanols, Cyclopropylamines... 

Erhardt, P. W., Gorczynski, R. J., Anderson, W.G. (1979). Conformational analogus of dopamine—Synthesis and pharmacological activity of (E)-and (Z)-2-(3,4-dihydroxyphenyl)-cyclopropylamine hydrochlorides. Journal of Medicinal Chemistry, 22, 907—911. 

Insertion into C—H bonds is also a reaction type common to nitrene chemistry. This is observed in the formation of the cyclopropylamine 615 from reaction with 1-ethoxy-l-trimethylsilyloxycyclopropane. Details have been reported of the use that can be made of the addition of the same nitrene to the chiral silyloxyalkene 616. This leads to an asymmetric synthesis of the amine 6YT. Insertion of a nitrene into C—H bonds is also reported for the photodecomposition of/7-trimethylsilylbenzoyl azide in hydrocarbons Reports have been made concerning the non-specificity of this particular nitrene. Apprently, some control can be exercised on its reactivity by using a micellar system. Under conditions of this type, using N, A-dimethyloctylammonium propionate as the micellar material, only the formamidine 618 is obtained ... 

This procedure has been applied to the synthesis of Af-cyanomethyl-lV-cyclopropylamine, which is a possible metabolite of cyclopropylamine-derived drugs [1042]. 

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