Cyclopropyl amines

Sheremetev and co-workers employed diazo compounds of type 60, prepared from the corresponding amines in moderate yields as alternative excellent precursors for the preparation of side-chain-functionalized derivatives (Scheme 29). Several furazans bearing reactive groups or cyclopropyl or five-membered heterocyclic substituents have been prepared by standard procedures (99MI6). 

A number of miscellaneous reactions involving diazonium ions and possible vinyl cations have been reported. Treatment of amine 138 with sodium nitrite in 20% aqueous acetic acid is reported to give methyl cyclopropyl ketone as one of four products (116). The reaction has been postulated to involve a vinyl cation, presumably by the following sequence of reactions (116) ... 

Aziridinocyclopropanes 163 derived from 2-phenylsulfonyl-l,3-dienes undergo BF3-induced rearrangement to bicyclic amines 165, which feature the skeleton of the tropane alkaloids. The reaction proceeds via cyclopropyl carbinyl cation 164, an intermediate also invoked in the analogous epoxide rearrangements. Trapping by fluoride ion is a competing pathway <96TL3371>. 

C. Reactions not involving P=0 or P=S Groups.—Enamine phosphine oxides (45) have been prepared by the addition of amines to 1-alkynyl-phosphine oxides, and the reactions of their anions with various electrophiles have been reported. - With ketones a Wittig-type reaction leads to the formation of a/3-unsaturated ketones, in 53—70% yield, while with epoxides cyclopropyl ketimines are formed. A Diels-Alder reaction of l-phenyl-A -phospholen-l-oxide (46) with 1,4-diacetoxybutadiene has been used in the preparation of l-phenyl-benzo[/>]phosphole (47), as... 

Cyclopropyl imines can be used as five-atom components in intermolecular [5 + 2]-cycloaddition reactions with dimethylacetylene dicarboxylate (DMAD) (Scheme 14).45 In this hetero-[5 + 2]-cycloaddition reaction, dihydroaze-pines are constructed from simple, readily available starting materials. The cyclopropyl imines can be preformed or made in situ by the condensation of cyclopropyl carboxaldehydes and amines. Although, thus far, DMAD is the only... 

FIGURE 8.23 One electron oxidation of a cyclopropyl amine leading to ring opening and the formation of a carbon-centered free radical and an iminium ion. 

A general method for the generation of aminyl radicals is by treatment of sulphenamides 340, prepared from secondary amines and A-benzenesulphenylphthalimide, with tributyltin hydride in the presence of AIBN (2,2/-azobisisobutyronitrile). The cyclopropyl derivative... 

Moriwaki et al. studied the photochemical behavior of various substituted homonaphthoquinones under PET conditions using amine and arene compounds as electron donors. Thereby, the main reaction path found was the opening of the cyclopropyl system, following dimerization [18]. 

Likewise, inactivation of MAO by N-cyclopropyl-AT-(arylakyl)amines 13a, b has been shown to involve the iminium ions 14 a, b which could accumulate to form the flavin adducts 15a,b Eq. (6) [15]. 

Surprisingly though, the rather weakly nucleophilic (diphenylmethylene) amine (DPMA-H) and its cyclopropyl analog (cyclopropylphenylmethylene) amine (CPMA-H) 93 [8, 9, 10 c, 21b, 22b, 58-601 which can also serve as ammonia equivalents, add to 1-R and 2-R cleanly and in most cases quantitatively in a 1,4-fashion (Scheme 29). 

The A-Boc group also activates secondary acyclic amines toward deprotonation, and unsymmetrical amines may be deprotonated regioselectively in some instances. For example, selective deprotonation of a methyl proton over a methylene can be expected, as shown by the example in Scheme 30a. Similarly, regioselective removal of a cyclopropyl proton occurs in preference to a methylene, as shown in Scheme 30b. 

Miiller has used cyclopropyl clock experiments to test for the possible intermediacy of radical species prior to C-N bond formation (Scheme 17.7). The diphenylcyclopro-pane derivative 3, which fragments at a rate of 2x10 ° s , affords nosylated amine 4 no product from ring opening is observed. Such a result mitigates the viability of a productive stepwise oxidation process, though it is important to note that sulfonamide 4 is formed in only 5% yield. 

The synthesis of the moxifloxacin core (de Souza, 2006 Martel et al., 1997 Seidel et al., 2000) proceeds from a Grohe-Heitzer sequence as described earlier in the chapter. Unlike the traditional Grohe-Heitzer sequence, however, the opening step involved the reaction between acid chloride 101 with the mono potassium salt of malonic acid monoethyl ester (102) in the presence of triethylamine to deliver ketoester 103 (Scheme 4.18). Treatment of 103 with ethyl orthoformate furnished acrylate 104, which reacted with cyclopropyl amine to afford 105. Cyclization of 105 in the presence of sodium fluoride in DMF gave the moxifloxicin core 106. 

Effects of fluorine substitution on inhibition of SSAO by cyclopropyl amines 683... 

In the 1970s, Fuller examined the effects of jS,/f-difluoro substitution on the biological properties of a series of arylethylamines. Among the compounds prepared were p,p-difluoroamphetamine (19), )S,)S-difluoro phenethylamine (20), and A/-cyclopropyl-4-chloro-jS,jS-difluorophenylethylamine (21). A drop in amine pKg of about 2.5 pH units resulted from the fluorine substitution. Included in biological studies were effects on activities toward MAO. In vitro )S,)S-difluoroamphetamine was a less active inhibitor of MAO than amphetamine and )S,)S-difluorophenylethylamine was a poorer substrate for deamination than phenylethylamine. A/-Cyclopropyl-4-chlorophenylethylamine is an irreversible inhibitor of MAO. There was little difference in vivo in MAO inhibition in various tissues of the rat [72]. 

As discussed above, many cyclopropylamines are good inhibitors of MAOs. In addition, as discussed in Section 3.2, fluorine substitution had substantial effects on the inhibition of MAOs by such analogues as allylamines. We undertook a broadly based study of the effects of fluorine substituted on the cyclopropyl ring of cyclopropyl amines on potency and selectivity of amine oxidase inhibition. In addition to effects on amine pKg and lipophilicity, we expected additional consequences resulting from altered geometry and ring strain due to the presence of fluorine. 

Propargylic, cyclopropyl, and fluoroallyl amines are powerful and irreversible mechanism-based inhibitors of MAOs. Oxidation by the enzyme affords a very active entity onto which a nucleophile of the enzyme, or of the cofactor, can be added (Figure 7.53). 

A detailed study of the inhibition of MAOs by fluorophenyl cyclopropyl amines shows that the presence of fluorine has very important effects on this inhibition. While some of the regioisomers are inhibitors of the CAO (copper-containing amine oxidase), some other ones, such as 2-fluoro-l-arylcylopro-pyl amines, are excellent selective and irreversible inhibitors of MAO A. In this latter case, the nonfluorinated parent compound is a poor inhibitor of MAO B (Figure 7.55). ° " ... 

Figure 7.55 Inhibition of the monoamine oxidases CAO, MAO A, and MAO B by fluorophenyl cyclopropyl amines. " ...

The electrophilic reaction of magnesium cyclopropylidene (113) with Ai-lithioaryl-amines was reported (equation 31) . Thus, electrophilic reaction of magnesium cyclopropylidene (113) derived from 112 with iV-lithio iV-methyl p-anisidine resulted in the formation of a-amino-substituted cyclopropylmagnesium (119) in good yield. Methanol-ysis of the reaction mixture with CH3OD gave a-deuteriated Af-cyclopropyl-Af-methyl-p-anisidine (120) in 82% yield with 98% D-content. 

---