Preparation of Cyclic Amines

As cyclic amines are at the heart of medicinal chemistry, there is always interest in new methods for their preparation. Marco Ciufolini of the Universite Claude Bernard in Lyon reports (Organic. Lett. 5 4943, 2003) the preparation of a series of dihydro indole derivatives, exemplified here by 3, 6, and 9, by free radical cyclization of an N-O precursor. The N-O precursor can be prepared from the corresponding bromide, as illustrated by the conversion of 1 to 2 and of 4 to 5. Alternatively, a radical precursor such as 8 can be piepaicd separately. The generated radical is then trapped by 7 to make a new radical, that cyclizes to 9. 

Heteroaromatics such as 10 are inexpensive compared to enantiomerically-pure cyclic amines such as 11. Yong-Gui Zhou of the Dalian Instilute of Chemical Physics reports (J. Am. Chem. Soc. 125 10536, 2003) the development of a chiral Ir catalyst that effects hydrogenation 

The Fischer indole synthesis has been a workhorse of medicinal chemistry. What has been needed is a procedure of comparable ease and efficiency for converting a ketone or aldehyde such as 12 to the corresponding pyridine, such as 13. Antonio Arcadi of the University of Milan has now developed (J. Org. Chem. 68 6959, 2003) just such a procedure, based on a gold-catalyzed condensation with propargylamine. The gold catalyst is commercially available. The regioselectivity of this procedure is noteworthy. 

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Table 14.3. Preparation of cyclic amines from alkenyl thioacetals. ...

The synthetic method may be seen to be complementary to direct nucleophilic displacement. Whereas amines often react relatively sluggishly in metal-mediated nucleophilic displacements, they usually undergo facile reaction with carbonyls to form imines. The reduction of the imines (free or co-ordinated) may then be achieved by reduction with Na[BH4] or (less conveniently) by direct hydrogenation. This provides a very convenient method for the preparation of cyclic amines (Fig. 6-14). 

In the preparation of cyclic amines, especially large-membered and strained ones, the use of cesium salts of tosylamides exhibits enhanced reactivity (Scheme 13). The solvent also plays an important role. Macrocyclization can also be successfully carried out under high pressure conditions. ... 

The Cope eUmination is reversible and the intramolecular reverse Cope elimination, involving the addition of a tethered hydroxylamine to an alkene, has found recent application for the stereocontrolled preparation of cyclic amines."... 

This reaction has general application in the preparation of cyclic amines, including aziridines and azetidines. 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Detailed information on the copolymerization of cyclic trifluoropropylmethyl-siloxane trimer and octamethylcyclotetrasiloxane is also very limited in the open literature26 27 . Recently, preparation of various amine terminated (dimethyl-tri-fluoropropyl,methyl)siloxane oligomers with varying molecular weights and backbone compositions has been reported 69115 ll7). Table 11 shows various properties of the oligomers produced as a function of composition. These types of modification play very important roles in determining the solubility characteristics and hence the compatibility of resultant polysiloxanes with other conventional organic monomers... 

Nitrones have been generally prepared by the condensation of /V-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of /V,/V-disubstituted hydroxylamines, / -alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H202 in the presence of catalytic amounts of Na2W04 this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64... 

It seems reasonable that polyester cyclics could be prepared by an extension of the /wendo-high-dilution [17] chemistry used for the preparation of cyclic carbonate oligomers [18, 19] however, such proved not to be the case. Brunelle et al. showed that the reaction of terephthaloyl chloride (TPC) with diols such as 1,4-butanediol did not occur quickly enough to prevent concentration of acid chlorides from building up during condensation [14]. Even slow addition of equimolar amounts of TPC and butanediol to an amine base (triethylamine, pyridine or dimethylaminopyridine) under anhydrous conditions did not form cyclic oligomers. (The products were identified by comparison to authentic materials isolated from commercial PBT by the method of Wick and Zeitler [9].)... 

This work has since been extended to cyclobutyl isoxazolidine adducts (e.g., 86) from the cycloaddition of 87 to methylenecyclopropane (88) (Scheme 1.18) (124— 127). Thermolysis afforded a mixture of products, of which the bicyclic azepinone (89) predominated. Spirocyclic adducts were also prepared from an intramolecular reaction in the synthesis of cyclic amines (Scheme 1.72, Section 1.11.3). 

Unsymmetrical secondary and tertiary amines. Unsymmetrical amines are obtained in 50-95% yield by reaction of an alcohol and amine in the presence of this ruthenium catalyst. The intramolecular version of this reaction provides an efficient synthesis of cyclic amines either from oc,a>-amino alcohols and an alcohol or from a,tu-diols and an amine. The cyclization is useful for preparation of tetrahydroiso-quinolines.3... 

Potassium phthalimide is a "NH2-synthon which allows the preparation of primary amines by reaction with alkyl halides. After alkylation, the phthalimid is not nucleophile and does not react anymore. Product is cleaved by reaction with base or hydrazine, which leads to a stable cyclic product. 

The traditional synthesis of cyclic sulfimidates from /3-aminoalcohols and SOCl2 in the presence of amine as a base has been developed further to the preparation of the enantiopure monocyclic as well fused sulfimidates (Schemes 26 and 27). 1,2,3-Oxathiazolidine mono-.Y-oxides are readily oxidized to corresponding sulfamidates by RuCR and NalCb, and the synthesis of sulfamidates can be performed in a one-pot procedure from -aminoalcohols without isolation of intermediate sulfimidates (Equation 37). The reaction of sulfamate esters 145 with PhI(OAc)2 and various catalysts proved to be a reliable method for the enantioselective preparation of cyclic sulfamidates 146 (Equation 35). 

The initial catalyst systems described above were effective with aryl bromides and a relatively narrow array of amines, although these procedures found utility in the preparation of diaminofluorenes [22], poly(aryleneamines) [23], certain iV-aryl-aza-crown ethers [24], N -arylpiperazines [25], and diaminobenzenes [26] (Fig. 1). These original methods often proved reasonably effective in the coupling of cyclic amines. Presumably, cyclic amines are less challenging substrates for the palladium-catalyzed coupling because the cyclic palladium (II) amide intermediates are less prone to /1-H elimination compared to their acyclic counterparts. 

Lithium aluminum hydride reduction in equally effective with both acyclic aitd i ctic amides, i r lactams. The reduction of a lactam is a good method for preparing a cyclic amine. 

Iminium salts bearing a labile trimethylsilyl group can be generated in situ and undergo nucleophilic addition (see Sections 1.12.4.2 and 1.12.7.3). Bis(trimethylsilyl)methoxymethylamine (75), for example, has been used as a formaldehyde equivalent for the preparation of primary amines. Cyclic imines, such as 3,4-dihydroquinolines, react with trimethylsilyl triflate (TMS-OTf) to provide reactive labile iminium salts (55), which condense with picoline anions. The addition of nonstabilized Grignard and organolithium reagents to acyclic aromatic ketimines and aldimines, however, is often not facilitated by the presence of TMS-OTf ... 

Carboxylic acid azides give rise to three different reactions under different conditions. Azide coupling (equation 9) was the earliest method in peptide synthesis and is still one of the most important in fragment condensation and preparation of cyclic peptides due to its almost complete lack of racemization. At elevated temperatures a frequent side reaction is the Curtius rearrangement. Trapping of the intermediate isocyanate with amines (equation 10) gives urea derivatives and with carboxylic acids rearranged amides are obtained (equation 11). ... 

The nitrogen atoms of cyclic amines are readily substituted by reaction with nucleophiles (usually alkyl halides in base), or with Michael acceptors (usually acrylic compounds). A variety of TV-substituted cyclams, e.g., (54), (57), and homologues, has been prepared by reducing substituted dioxo cyclams (53) and (56). TV-Functionalization can be introduced for precursors before cyclization, e.g., (20), (24), (52), and (55), and the azacyclam macrocycles (74)-(79). 

Still another intramolecular cyclization system is the coumarin-based prodrug system 134 that can be used for bioreversible derivatization of amine and alcohol drugs and the preparation of cyclic peptide prodrugs (Scheme 23).76,77 This system takes advantage of the known facile lactonization of coumarinic acid and its... 

The monomers that have been explored most extensively are propylene carbonate methacrylate (PCMA) and propylene carbonate acrylate (PCA). These monomers are readily copolymerized with other commonly used unsaturated monomers to yield polymers with cyclic carbonate functionality. There are a few patents discussing the formation of coatings by the amine cross linking of these cyclocarbonate functional polymers. However, they do not appear commercially available. Thus, their use in the preparation of cyclic carbonate functional polymers has been limited. 

The above mentioned methods for preparation of cyclic bis-amides were patterned after peptide chemistry reactions where amide bonds dominate. Also in peptide chemistry, DCC, and DCC plus 1-hydroxybenzotriazole (HOBT) have been used in amide formation reactions. Using this procedure, 16-membered peraza-crowns have been prepared in 50-55% yields for the cyclization step (Vellacio et al., 1977). The carboxyl group can also condense with secondary amines in DMF in the presence of 1.1 mol of DCC and 1.2 mol of HOBT per mole of the dicarboxylic acid (Krakowiak et al., 1989). 

Several substituted cyclic sulfites have been prepared by the reaction of glycidol with a suitable sec-amine to furnish an amino diol, which is then treated with thionyl chloride in the presence of a base such as pyridine or triethylamine. This strategy of preparation of cyclic sulfites is of commercial importance because amine-substituted cyclic sulfites have been used as intermediates in the pharmaceutical industry (82JAP(K)82/02246 84JAP(K)59/07186 85MIP2 86JAP(K)61/227578). 

A wide variety of perfluorinated cyclic materials has been prepared and a large body of experimental material on the synthesis and chemistry of perfluorinated nonaromatic heterocyclic was accumulated. Despite the fact that the saturated perfluorinated heterocycles are expected to be chemically inert, this group of materials actually have an interesting and unusual chemistry, which can be exemplified by reductive defluorination of cyclic perfluorinated N—F amines under the action of mild reducing agents or cleavage of cyclic amines under the action of strong acids. 

DIBAL can also be used for the reductive cleavage of cyclic aminals and amidines (eq 19). Oximes can be reduced to amines. Due to the Lewis acidity of DIBAL, however, rearranged products are obtained (eq 20). This chemistry was used to prepare the alkaloid pumiliotoxin C via the Beckmann rearrange-ment/alkylation sequence shown in eq 21. ... 

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