Cyclopropylamines, formation

Cyclopropylamine Formation. The cyclopropylation of a variety of amines is easily accomplished by reductive amination with 1-ethoxy-1-trimethylsilyloxycyclopropane (eq 23). This mild and general one-pot cyclopropylation method is useful in medicinal and synthetic organic chemistry to enhance the biological activity of compounds bearing amine functions. ... 

Next analyzed was the behavior of the third quadrant amines, propylamine (PrAM) and cyclopropylamine (CprAM). Surprisingly, PrAM not only did not favor the formation of DHQ, but also decreased the conversion rate of Q in comparison to data observed in the absence of amine, suggesting an effective... 

Lactam ring formation is observed in the rhodium-catalyzed ring-opening carbonylation of cyclopropylamine 20 to N-cyclopropylpyrrolidone 21 (Scheme 8) [14]. (Scheme 8)... 

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 formation of the same cyclopropylamine from 2-methyl-l,3-pentadiene as from 4-methyl-l,3-pentadiene (entries 2 and 3 in Table 11.11) can most probably be attributed to initial isomerization of the former to the latter under the conditions employed. The fact that the conjugated 6-methyl-l,3,5-heptatriene yields only the 2,3-dialkenylcyclopro-... 

In the hydroxycyclopropanation of alkenes, esters may be more reactive than N,N-dialkylcarboxamides, as is illustrated by the exclusive formation of the disubstituted cyclopropanol 75 from the succinic acid monoester monoamide 73 (Scheme 11.21) [91]. However, the reactivities of both ester- as well as amide-carbonyl groups can be significantly influenced by the steric bulk around them [81,91]. Thus, in intermolecular competitions for reaction with the titanacydopropane intermediate derived from an alkylmagnesium halide and titanium tetraisopropoxide or methyltitanium triisoprop-oxide, between N,N-dibenzylformamide (48) and tert-butyl acetate (76) as well as between N,N-dibenzylacetamide (78) and tert-butyl acetate (76), the amide won in both cases and only the corresponding cyclopropylamines 77 and 79, respectively, were obtained (Scheme 11.21) [62,119]. 

Inhibition mechanisms by A/-cyclopropyl MPTP analogues are also discussed in terms of two catalytic pathways, one of which is based on an initial SET step from the nitrogen lone pair, as proposed by Silverman, and the second is based on an initial a-carbon hydrogen atom transfer (HAT) step, as proposed by Edmondson, leading to a radical and dihydropyridinium product formation. The observation that MAO B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET-generated aminyl radical cations [122], Further studies will be necessary to clarify all the facets of the mechanism of inhibition of MAO by cyclopropylamines. 

Cyclopropylamines and cyclopropanols can be prepared from alkyknagnesium ha-lides. The reaction is catalyzed by titanium alcoholates and its mechanism includes the formation of a dialkoxytitanacyclopropane 270, which reacts with a carbonyl compound or nitrile (Scheme 22). The use of chiral titanium alcoholates allows the reaction to be performed with up to 78% ee (equation 171) . 

A very useful class of chiral auxiliaries has been developed for alkenes substituted with a heteroatom. These auxiliaries, attached to the heteroatom, allow for the preparation of enantiomerically enriched cyclopropanols, cyclopropylamines and cyclopropylboronic acids. Tai and coworkers have developed a method to efficiently generate substituted cyclopropanol derivatives using the cyclopropanation of a chiral enol ether (equation 78) . The reaction proceeds with very high diastereocontrol with five- to eight-membered ring sizes as well as with acyclic enol ethers. The potential problem with the latter is the control of the double bond geometry upon enol ether formation. A detailed mechanistic study involving two zinc centers in the transition structure has been reported. ... 

The next section makes use of the much more recent observation19 that there is a nearly constant difference of the enthalpies of formation of corresponding vinyl and phenyl derivatives. If vinyl relates to cyclopropyl, and vinyl also relates to phenyl, then how do corresponding cyclopropyl and phenyl derivatives relate Conceptually, vinylcyclopropane (10), also identified as 1, X = Cypr and 2, X = Vi) and styrene (11, X = Vi, also identified as 1, X = Ph) are thus relatable. Likewise, relatable are cyclopropylamine (2, X = NH2) and aniline (11, X = NH2)18. This thermochemical comparison of benzene and cyclopropane derivatives is not merely a check of two purported identities in terms of a third, arithmetically derivable, identity. Benzene is the archetypical 7i-delocalized aromatic species from which understanding of this widespread phenomenon evolves. Cyclopropane is the paradigm of cr-aromatic species from which understanding of this more exotic phenomenon evolves20. Benzene and cyclopropane are thus naturally paired as conceptual models for delocalization and aromaticity. Section III discusses these and related issues. 

A variety of three-membered carbocycles including cyclopropylcarbonyl and -sulfonyl derivatives, cyclopropylcarbonitriles and -methanols, nitrocyclopropanes, cyclo-propanols and cyclopropylamines have been prepared via the 1,3-elimination of HX. Some representative cyclopropyl derivatives recently prepared by this method are shown in Scheme 116-18 and in equations 8-26. Conversion of chelated homoserine, 5,to chelated 2-amino-4-bromobutyrate and treatment with aqueous base directly affords chelated 1-aminocyclopropane-l-carboxylate (equation 8)19. The 1,3-elimination in 6 interestingly leads to the preferential formation of the cis isomer, from which 7, a key structural element of synthetic pyrethroid insecticides, is obtained (equation 9)20. A sulfur substituent can serve both as an activating group and as a leaving group in this type of reaction and, thus, 1,3-bis(phenylthio)propane affords cyclopropyl phenyl sulfide upon treatment with butyl-... 

Recently, the arylation of several specific primary amines have been studied because of the potential biological relevance of the products or products further downstream in a synthetic sequence. For example, cyclopropylamine was shown to be a viable substrate for the coupling under standard conditions [203]. Reactions of 7-azabicyclo[2.2.1]heptane have also been conducted [204] under relatively standard conditions, but with bis(imidazol-2-ylidene) as ligand. Complexes of this ligand and DPPF showed similar catalytic activities, which proved to be superior to those of most bis(phosphine)s. ortfio-Halo anilines were also studied, in this case to provide access to carbolines after use of the halogen as a means of effecting cycliza-tions by an electrophilic or reductive C-C bond formation with the other N-aryl group [205]. 

Formation of cyclopropylamines and cyclopropanols from alkylmagnesium halides and esters, amides, or nitriles, catalyzed by titanium alcoholates, was discovered by Kulinkovich in 1989. The reaction mechanism includes the formation of dialkoxytitanacyclopropanes, which reacts with a carbonyl compound or a nitrile (Scheme 109). 

Warming solutions of both allylamine and cyclopropylamine in CF2C1CC12F to 110 K led in both cases to a change in the ESR spectrum and to the formation of an 80 G doublet. This doublet is attributed to the CH3CH2CH=N radical, formed by ion-molecule reactions in the matrix. 

This loses one of the carboxylates on heating in the presence of toluene-sulfonic acid to afford the (B-ketoester (82). Reaction of this intermediate with ethylorthoformate then adds a carbon atom to the activated methylene. Heating that compound with cyclopropylamine in effect exchanges the ethoxy group with the amine to afford enamine (84). Treatment 84 with sodium fluoride leads to displacement of one of the ring fluoro groups by the basic nitrogen on the side chain. This step concludes the formation... 

Identification of 74 on incubation of MAO with 69 confirmed the initial formation of the 1-phenylcyclobutylaminium radical. That a variety of cyclopropylamines and cyclobutylamines inactivate MAO and result in ring-opened adducts is consistent with the intermediacy of the aminyl radicals. These results strongly suggest that the MAO-catalyzed oxidation of amines involves one-electron transfer as the first step. 

Cyclopropylamine (77) could be oxidized to nitrosocyclopropane (432) by oxygen difluoride or m-chloroperbenzoic acid (equation 106). Azo compounds 433 and 435 were obtained by oxidation of 434 by IF5 (equation 107) or condensation of 77 with a nitroso compound (equation 106). Interconversions of an aminocyclopropane into an isocyano or azido cyclopropane are described, for example, in Refs 105,479-481,515,516 and Refs 89, 461, 517, respectively. For formation of an N-cyclopropyl iminiophos-phorane see Ref. 518. Nitrosation of iV-cyclopropylurea derivatives was usually performed... 

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. ... 

Electron-rich aryl groups in 16 a (R = NHAr) can be used as intramolecular nucleophiles to produce tricyclic cyclopropylamines, e.g. formation of 21 from 20. ... 

N-N bond formation also occurs when cyclopropylamines are converted to the corresponding cyclopropyl azides by treatment with methyllithium or methylmagnesium bromide ° followed by tosyl azide. The yield can be as high as 50%, but is usually significantly lower ° when methylmagnesium bromide is used. 

Cyclopropylamines react with aldehydes to yield the corresponding imines in fair yield.Cyclopropane-1,2-diamine reacted with two equivalents of benzaldehyde to give corresponding diimine 1 in 58% yield. Imine formation is also involved as the key step in multistep reactions leading to a variety of complex compounds. For example, 4-[2,2-bis(benzyloxymethyl)cyclopropylamino]-6-chloro-5-formamidopyrimidine (2) reacted with triethyl orthoformate in the presence of hydrochloric acid to give purine derivative 3 in 58% yield. An analogous reaction took place when 1-azido-l-vinylcyclopropane was treated successively with triphenylphosphane and benzaldehyde to give iV-benzylidene-l-vinyl-cyclopropylamine in almost quantitative yield. 

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