Cyclic secondary amines

An enamine is easily prepared by reaction of the corresponding aldehyde or ketone 4 and a secondary amine 5. A cyclic secondary amine like pyrrolidine, piperidine or morpholine is most often used. A general procedure has been reported by Mannich and Davidseti in 1936 ... 

A mixture of 2-butoxy-37/-azepine (16.52 g, 0.2 mol) and the cyclic secondary amine (0.4 mol) was heated under reflux for 6 h. The excess amine was removed under reduced pressure and the residue distilled under high vacuum through a Vigreux column. 

A convenient way of obtaining secondary amines without contamination by primary or tertiary amines involves treatment of alkyl halides with the sodium or calcium salt of cyanamide NH2—CN to give disubstituted cyanamides, which are then hydrolyzed and decarboxylated to secondary amines. Good yields are obtained when the reaction is carried out under phase-transfer conditions. The R group may be primary, secondary, allylic, or benzylic. 1, co-Dihalides give cyclic secondary amines. 

Chlorofluorans react with a wide variety of primary amines such as alkylamines, cycloalkylamines, aralkylamines, and arylamines, as well as cyclic secondary amines such as piperidine, morpholine, etc., to prepare 3 -aminofluorans. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

The [l,3]oxazino[2,3- ]quinazolin-6-one 305 reacted with cyclic secondary amines (e.g., as in Equation 33) to afford the quinazolin-2,4-diones 306 <2002EPP1178048>. 

With the exception of intramolecular amination reactions, all of the early aryl halide aminations were catalyzed by palladium complexes containing the sterically hindered P(o-tol)3. In papers published back-to-back in 1996, amination chemistry catalyzed by palladium complexes of DPPF and BINAP was reported.36,37 These catalysts allowed for the coupling of aryl bromides and iodides with primary alkyl amines, cyclic secondary amines, and anilines. 

HNRR,= primary amine, cyclic secondary amine, HNMeBn, HNMePh... 

It was shown that microwave irradiation accelerated the 1,4 Michael addition of primary and cyclic secondary amines to acrylic esters, leading to several /j-amino acid derivatives in good yields within short reaction times [78] (Eq. 25). 

Thiadiazole 57 reacts with cyclic secondary amines such as piperidine, piperazine, and morpholine to afford the substituted derivatives 64 in 80-85% yield (Equation 13) <2005EJM1346>. Under similar conditions, thiadiazole 57 reacts with hydrazine hydrate to give the thiadiazolhydrazine 65 in 97% yield <2004BML5967>. 

TABLE 6. /In ionization potentials (eV) of cyclic secondary amines... 

Comparison of IP( n) values of cyclic secondary amines (Table 6) with those of the respective 1-methyl derivatives (Table 7) reveals that the effect of the additional methyl group decreases from 0.6 eV in aziridine to 0.1 eV in hexahydroazepine (hexa-methyleneimine). 

Carr, R., Alexeeva, M., Dawson, M.J., Gotor-Fernandez, V., Humphrey, C.E., Turner, N.J., Directed evolution of an amine oxidase for the preparative deracemisation of cyclic secondary amines. ChemBioChem, 2005, 6, 631. 

Microwave irradiation has been reported to accelerate the Michael addition of primary and cyclic secondary amines to esters of a ,/i-unsaturated Q -unsubstituted carboxylic acids to produce /3-amino acids. ... 

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 order to extend the approach to include deracemization of chiral secondary amines, this group carried out directed evolution on the monoamine oxidase (MAO) enzyme MAO-N (Scheme 2.32). A new variant was identified with improved catalytic properties towards a cyclic secondary amine 64, the substrate used in the evolution experiments. This new variant had a single point mutation, lle246Met, and was found to have improved catalytic properties towards a number of other cyclic secondary amines. The new variant was used in the deracemization of rac-64 yielding (R)-64 in high yield and enantiomeric excess [34]. 

Cyclic secondary amines with pyrrolo[2,l-c][l, 4]-benzodiazepine rings were oxidised with TPAP/NMO/PMS/CH3CN to the corresponding imines. Thns (llaS)-1,2,3,10,ll,lla-hexahydro-5H-pyrrolo[2,l-c][l, 4]-benzodiazepine-5-one gave (llaS)-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l, 4]benzo-diazepine-5-one [23]. 

The reaction works well when R and are alkyl or benzyl, or when NR R is a cyclic secondary amine. ° It also works with benzil and its para-substituted derivatives and with guanidine and its mono-substituted derivatives, giving high yields of products 35 having Ar = phenyl para-substituted with H, Cl, Me, and MeO, and R = R = R = H,... 

Under the same conditions, the trioxo analogue 114 gave the chloro derivative 115, which upon boiling in anhydrous xylene with a series of cyclic secondary amines gave the amines 116 <1998FA475>. 

The corresponding reaction of 23 with dimethylamine and with cyclic secondary amines (piperidine and morpholine) is less facile and gives the thermodynamically more favored C-3 addition product (Equation 13) <1999RCB1150>. Using ethylenediamine, the cyclization product 29 is obtained in 80% yield (Scheme 12), although with 1,3-propane-diamine, 1,4-butanediamine, and 1,2-cyclohexanediamine the yields are reduced (70%, 25%, and 1%, respectively), consistent with the importance of entropy as a driving force for the second (intramolecular) amination. 

The formation of -butyldiazoate by reaction of [Fe(CN)5(NO)]2 with lithium -butyl amide contrasts with the formation of dibutylamine as the main product in the reaction of the same complex with -butylamine (85). This can be explained if the diazoic/diazoate equilibrium shown in Fig. 18 is shifted to the left far enough to form of a diazenido by loss of hydroxide. Attack of -butylamine on the a-carbon of the diazenido species, produces dibutylamine. DFT computed results suggest that the stabilization by complexation of the intermediate diazonium ion (see Fig. 18) is large for the iron-pentacyano complex, in agreement with the fact that no rearrangement products were observed in the reaction of this species with -butylamine (86). The reaction has been proposed as a good route for the preparation of symmetrical, unsymmetrical, and cyclic secondary amines (85). 

Cyclic secondary amines have been added to the C-2—C-3 bond of benzo[6]thiophene and 3-methylbenzo[6]thiophene in the presence of an alkali metal salt of the amine (Scheme 39) (78JOC4379). Aromatization of the adducts with stoichiometric amounts of sulfur leads to the corresponding 2-aminobenzo[6]thiophenes. 

Dimethyl-3,4-dinitrothiophene undergoes a different type of reaction with cyclic secondary amines. The product from the reaction with morpholine, obtained in nearly quantitative yield, has been identified as 2,5-dimethyl-rrans-2,3-dimorpholino-4-nitro-2,3-dihydrothiophene. Most notable in this reaction is the high stereospecificity. The reaction probably proceeds through initial reversible addition of a molecule of morpholine to the 2,3-double bond (Scheme 139) <80JCS(P2)1764). 

The ruthenium carbonyl complexes [Ru(CO)2(OCOCH3)] n, Ru3(CO)12, and a new one, tentatively formulated [HRu-(CO)s ] n, homogeneously catalyze the carbonylation of cyclic secondary amines under mild conditions (1 atm, 75°C) to give exclusively the N-formyl products. The acetate polymer dissolves in amines to give [Ru(CO)2(OCOCH3)(amine)]2 dimers. Kinetic studies on piperidine carbonylation catalyzed by the acetate polymer (in neat amine) and the iiydride polymer (in toluene-amine solutions) indicate that a monomeric tricarbonyl species is involved in the mechanism in each case. 

Kinetic studies on catalytic amine carbonylation reactions are scarce, although Brackman (13) has reported kinetics on a copper(I)-copper(II) catalyzed production of ureas from cyclic secondary amines using carbon monoxide-oxygen mixtures at ambient conditions. Saegusa and coworkers (14) used cuprous salts and other group IB and IIB metal compounds to car bony late piperidine to N-formylpiperidine under more severe conditions. We have published (15) a brief report involving some of the studies described in this paper. 

The unsubstituted, saturated aza macrocycles, the family of cyclic secondary amines, [ ]aneNm, are generally prepared by the method shown in Scheme 1. Some other types of aza macrocycle, particularly cyclic amides7 and macrocycles with N=CRCR=CRNH functions (see below), are also prepared conventionally. The preformed ligands are then reacted with the desired metal ion under appropriate conditions. 

Careful inspection of the reported photocatalytic reactions may demonstrate that reaction products can not be classified, in many cases, into the two above categories, oxidation and reduction of starting materials. For example, photoirradiation onto an aqueous suspension of platinum-loaded Ti02 converts primary alkylamines into secondary amines and ammonia, both of which are not redox products.34) ln.a similar manner, cyclic secondary amines, e.g., piperidine, are produced from a,co-diamines.34) Along this line, trials of synthesis of cyclic imino acids such as proline or pipecolinic acid (PCA) from a-amino acids, ornithine or lysine (Lys), have beer. successfuL35) Since optically pure L-isomer of a-amino acids are available in low cost, their conversion into optically active products is one of the most important and practical chemical routes for the synthesis of chiral compounds. It should be noted that l- and racemic PCA s are obtained from L-Lys by Ti02 and CdS photocatalyst, respectively. This will be discussed later in relation to the reaction mechanism. 

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