Cyclic tertiary amines

The oxidation of amines by mercuric acetate is an old reaction (54) which up until recent years was employed primarily to modify alkaloid structures (55). A systemic study of the oxidizing action of mercuric acetate by Leonard and co-workers led to the development of a general method for the synthesis of enamines from cyclic tertiary amines. An observation made after a large number of compounds were oxidized, but which is worth noting at the onset, is that a tertiary hydrogen alpha to the nitrogen atom is removed preferentially to a secondary a-hydrogen. 

Lewis acidcomplexes of saturated cyclic tertiary amines andrelated compounds 97CRV721. 

Besides aromatic tertiary amines, the aliphatic cyclic tertiary amines such as N-methyl(or ethyl) morpholine can also be used in coupling with BPO to enhance the Rp of MMA polymerization [20], Since the... 

The spin adducts of free radicals and MNP or DMPO were observed by means of an ESR spectrometer. The data of hyperfine splitting constants were compiled in Tables 9 and 10 [40-42,44,45]. ESR studies on the initial free radicals revealed that the monoalkylamino radical RHN-, dialkylamino radical R2N-, and aminomethyl radical -CH2N< or aminoethylidene radical >N( CHCH3) were obtained from the corresponding primary, secondary, and cyclic tertiary amine. In case of a tertiary diamine such as TMEDA, formation of... 

In a similar reaction, tertiary amines are converted to amides " and cyclic tertiary amines (e.g., 30) can be converted to lactams by oxidation with Hg —EDTA complex in basic solution. 

Expansion of aminocyclopropanols Oxidation of cyclic tertiary amines... 

Irradiation at 77 K in trichlorofluoromethane of cyclic tertiary amines also affords radical cations that can be trapped indefinitely. In these systems there apparently is no reaction between the radical cations and free amine. The EPR spectra of the radical cations were recorded. The cations produced under these conditions can be trapped indefinitely and do not undergo proton loss to give the corresponding carbon-centred radical. Several systems (20-24) were examined in this way and all were found to be stable. In the bis amine (22, n = 1) evidence was obtained from the EPR study that there was weak N-N interaction4. The influence of silicon in 25 was also examined16. 

Dunsmore, C.J., Carr, R., Fleming, T. and Turner, N.J., A chemo-enzymatic route to enantio-merically pure cyclic tertiary amines. J. Am. Chem. Soc., 2006, 128, 2224. 

Nicotine has two nitrogen atoms, one as a cyclic tertiary amine and one in a pyridine ring. The basicities are easily distinguished, in that a pyridine system is much less basic than a simple amine. This is essentially a hybridization effect, the nitrogen lone pair in pyridine being held in an sp orbital. This means the lone pair electrons are held closer to the nitrogen, and are consequently less available for protonation than in an sp -hybridized aliphatic amine. Hence, as mentioned above, pyridine has p Ta approximately 5. It follows that pA"a 8.1 is more appropriate for the pyrrolidine nitrogen. 

Quinine has two potentially basic centres, a cyclic tertiary amine at a ring junction, and one in a quinoline ring system. pAfa 8.5 is reasonably basic, and this is most likely from the aliphatic tertiary amine. We need to convince ourselves that the quinoline nitrogen is less basic. This is true. As far as reactivity is concerned, a quinoline ring system behaves as two separate parts, either pyridine or benzene, depending upon the reagent. Thus, quinoline has pATa very similar to that of pyridine, i.e. around 5. 

Oxidation of cyclic secondary amines such as pyrrolidine (351) and piperidine (353) with iodosobenzene in water leads to lactams 352 and 354, respectively (88TL6913, 88TL6917) (Scheme 90). Similar oxidation of 2-piperidinecarboxylic acid and 2-pyrrolidinecarboxylic acid is accompanied by decarboxylation. Cyclic tertiary amines 355, 357, and 359 (Eq. 48) are likewise oxidized to the corresponding lactams. Other examples include phencyclidine (360) to A-(l-phenylcyclohexyl)piperidone (361), N-(cyanocyclohexyl)piperidine (362) to A-(l-cyanocyclohexyl)piperidone (363) (Scheme 91), and 1,2,3,4-tetrahydroisoquinoline to 1,2,3,4-tetrahy-droisoquinolinone (Eq. 49). 

In 1955, Leonard described a general method for the oxidation of cyclic tertiary amines to give enamines. Quinolizidine was dehydrogenated using mercuric acetate in 5 % aqueous acetic acid by heating on the steam bath for hr to give 92% mercurous acetate and 60% dehydroquinolizidine. 

An important breakthrough was made very recently in this area. A chemoenzymatic method developed by Turner has allowed the cyclic deracemization of tertiary amines [80]. Enantiopure tertiary amines cannot be obtained via DKR. One of the variants obtained by directed evolution of the monoamine oxidase from Aspergillus niger showed high activity and enantioselectivity toward cyclic tertiary amines (Scheme 5.40). 

In the course of their work on suitable materials for use as blood substitutes the group at the University of Padua have studied the electrochemical fluorination of cyclic tertiary amines [80]. The ECF of NW-diethylcyclohexylamine and N-ethyldicyclohexylamine gave the corresponding perfluoroamines together with several other compounds arising from incomplete fluorination and fragmentation reactions. 

Ethers in which at least one group is primary alkyl can be oxidized to the corresponding carboxylic esters in high yields with ruthenium tetroxide.297 Cyclic ethers give lactones. The reaction, a special case of 9-16, has also been accomplished with CrO, in sulfuric acid.39" with benzyltriethylammonium permanganate,299 and with trichloroisocyanuric acid in the presence of an excess of water.300 In a similar reaction, cyclic tertiary amines (e.g., 28) can... 

Data for the reactions of several cyclic tertiary amines with phenyl, 4-nitro-phenyl and 2,4-dinitrophenyl acetates, at 25°C and ionic strength 1.0, appear in Table 40, and as a Bronsted plot in Fig. 20. The usual irregularities of such plots for nucleophilic attack are evident. Linear relationships between log k and pKa are generally found for groups of compounds of closely similar structure, as for the substituted pyridines in Fig. 20. The data for the two tricyclic amines fall on separate curves, and the points for imidazole clearly fall on neither of the first two sets of lines. The separate lines for the reactions of particular classes of nucleophile are approximately parallel, as is usually found. 

PET activations of cyclic tertiary amines utilizing 1,4-dicyanonaphtha-lene (DCN) as electron acceptor have been studied by Pandey et al. [37]. The iminium cationic intermediates are generated via a electron-proton-electron (E-P-E) transfer sequence in a highly regiospecific fashion and as an example, tetrahydro-l,3-oxazines (26) were synthesized from substrates 25 with high control of regio- and stereoselectivity (Sch. 16). 

Answer Xl-g is an aliphatic cyclic tertiary amine (a-pyrro-lidino-m-nitroethy (benzene). 

In the series of N—CH3 cyclic tertiary amines the relative order of barrier heights as a function of ring size is ... 

Cyclic tertiary amines, such as A -methylpyrrolidine, react with (l//,3//)-quinazoline-2,4-dione (18) in the presence of POCI3 to give 2-(/V-methyl-4-chlorobutylamino)-4-chloroquinazoline (19) in 67% yield (82CPB347I, 82H7, 82HI5, 82H1879). 

Cyclic amines are oxidized to lactams using a mixture of RuCls and NaI04. Lactams are also formed using KMn04 with benzyltriethylammonium chloride. Tertiary amines are converted to amides and cyclic tertiary amines can be converted to lactams by oxidation with Hg -EDTA complex in basic solution. Lactams, which need not be A-substituted, can be converted to cyclic imides by oxidation with a hydroperoxide or peroxyacid and an Mn(II) or Mn(III) salt. Lactams are oxidized to cyclic imides with oxygen and Co(OAc)2 in the presence A-hydroxysuccinimide. ... 

Tertiary amines are also substrates for the cyanation reaction [220,223,238-241], with substitution taking place at the carbon atom a to the nitrogen atom. In this case substitution often occurs preferentially at a primary carbon atom in mixed amines, such as A -ethyl-A -methylaniline [Eq. (65)]. This is not so for cyclic tertiary amines [Eq. (66)] [238]. 

The Skraup synthesis can be used with a number of substituted arylamines. p-Toluidine forms 6-methylquinoline and o-toluidine 8-methylquinoline. Both quinoline and pyridine are cyclic tertiary amines and react with acid to form salts (pyridinium and quino-linium salts) and with alkyl halides to form quaternary salts. 

Lactams are formed by bromination (bromine, iV-bromosuccinimide) of cyclic tertiary amines, resulting in an intermediate iminium salt that can be isolated. Oxidation by met oxides, autoxidation, photochemical oxidation and electrooxidation are alternatives with limited scope. 

To date no reports of the Polonovski reaction of N-oxides of four- or seven- and higher-membered cyclic tertiary amines have appeared. Aziridine N-oxides can be prepared by ozonolysis of N-r-butylazi-ridine however, these compounds are unstable above 0 C. At higher temperatures compound (33) undergoes first-order decomposition to ethylene and 2-methyl-2-nitrosopropane (equation 11). 

Dehydrogenation of tertiary amines. Leonard found that cyclic tertiary amines can be oxidized to enamines with 4 mole equivalents of mercuric acetate in 5% aqueous acetic acid at steam-bath temperature. When quinolizidine was treated in... 

There is speculation that long-term exposure to cyclic tertiary amines such as cocaine, phencyclidine, and phenothiazines may result in biochemical lesions through the formation of reactive metabolites. This premise is supported by the induction of a parkinsonian state by MPTP. Although the initial product of microsomal oxidation is an electrophilic endocyclic iminium intermediate which is thought to be the reactive species primarily responsible for neurotoxicity, there is now evidence that the iminium is in equilibrium with the endocyclic enamine and that the latter is transformed to reactive species. The presence of iminium- detoxifying enzymes in cytosolic and microsomal fractions suggests that rapid inactivation of the iminium... 

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