Cyclic aminals synthesis

Figure 1.35 Cyclic amine synthesis by transfer hydrogenation.

This chapter is about the advantage that cyclisations have over intermolecular reactions and therefore about the simplicity of heterocyclic synthesis. We need to look first at some details. It is not true that all cyclisations are favourable. A general cyclic amine synthesis shows that there is a large difference in the rates of formation of rings of different sizes.1 Five-membered rings... 

Miscellaneous Reactions. - p-Toluenesulfonaraide undergoes Mitsunobu-type reactions in the presence of alcohols and cyanomethylenetriphenyl-phos-phorane (56) to give predominantly mono-N-alkylation products. This reaction has also been applied to the synthesis of cyclic ethers from diols and cyclic amines from amino alcohols and to carbon-carbon bond formation. Examples of cyclic amine synthesis include that of (+)-a-skytanthine (57). A comparative study of the reactions of active methine compounds (58) as nucleophiles using... 

Each of the unsaturated cyclic amines shown below has been synthesized by reaction of an amino-substituted allylic silane under iminium ion cyclization conditions (CH2=0, TFA). By retrosynthetic analysis, identify the appropriate precursor for each cyclization. Suggest a method of synthesis of each of the required amines. 

Allylation of imines using this type of reagent has been extensively studied, and this transformation has become important for the synthesis of acyclic and cyclic amine derivatives. 

Analogously to the carbocycle and oxycycle synthesis, cyclic amines can be obtained by the hydrosilylation of a suitable enyne, such as 46 (Reaction 7.54), which gave the six-membered ring via a 6-endo cyclization of the vinyl radical onto the C=N bond [63]. In another example, the isothiocyanide functionality of compounds 47 or 48 reacts with silane under radical conditions... 

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). 

S. Ohki, Yuki Gosei Kagaku Shi 30, 1-18 (1972) . .Synthesis and Reactions of Five-Membered Cyclic Amines". 

Ammonium ylides undergo [l,2]-shift in a manner similar to oxonium and sulfonium ylides. A preferentially migrating group is usually a benzyl group. A sequence of intramolecular formation of ammonium ylide and subsequent rearrangement was extensively explored by West and co-workers in the synthesis of cyclic amines. ... 

Another field where ATH catalysts have made an industrial impact is in the area of chiral amine synthesis by stereocontrolled reduction of imines. First demonstrated by Uematsu et the reduction of cyclic imines to yield chiral amines... 

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... 

Iron complexes can also catalyze allylic amination [31,32]. Enders et al. have demonstrated the nucleophilic addition of various acyclic and cyclic amines to the optically active l-methoxycarbonyl-3-methyl-(T)3-allyl)-tetracarbonyliron cation 49 formed in high yield from reaction of 48 with iron carbonyls. Oxidative removal of the tetracarbonyliron group by reaction with CAN gives 50 with high optical purity and retention of the stereochemistry (Eq. (12)) [31]. The reaction proceeds well for the different amines, and has been used for the synthesis of a compound showing cytotoxic activity against diverse cell lines [31b]. 

The formylation of phenols with the electron-rich olefin to give imidazolidin-2-yl-phenols is very selective and avoids mixtures of o- and p-isomers which are frequently obtained by methods commonly employed for the synthesis of phenolaldehydes. Para substitution of the cyclic aminal group in the phenol is preferred. If the p-position is blocked or sterically hindered, the reaction proceeds via the ortho- aminals to salicylaldehydes. Incorporation of more than one aldehyde group in the benzene nucleus is often achieved with hydroxy- and aminophenols. 

This chapter does not cover cyclic amides and peptides, since their number would enormously expand this text. They are reviewed only if they serve as reaction intermediates during synthesis of cyclic amines. In addition, metal ions complexation will be presented in required minimum, for example, if it serves for template formation during ring synthesis or as a main topic in some application. In this chapter, most of the sections deal with the literature data for all cycle types, except Section 14.11.6, which focuses mainly on chemistry of cyclen and cyclam and their analogs and derivatives. In Section 14.11.8, we give only a brief overview of the utilizations and provide a reader with reviews where more detailed information may be found. 

Method of choice for synthesis of 1,5,9-triazacyclododecane 7 and some of its C-substituted derivatives is a ring closure on a guanidine derivative (Scheme 7). The method mostly gives reasonable yields and cyclic aminal can serve as a protective group. 

In 1999, Wolfe and Buchwald reported the synthesis of hindered, electron-rich phosphine 6 and its use in the amine arylation reaction. Use of this new ligand resulted in a catalyst capable of effecting the room temperature reaction between cyclic amines and aryl bromides [42a, 44,48,49]. The catalyst derived from Pd2(dba)3 and 6 couples 3,5-dimethybromobenzene with morpholine in 80% yield while stirring for 20 hours at room temperature, Eq. (18). This new highly active catalyst efficiently arylates a variety of amines with aryl bromides as well as chlorides at room temperature. 

Sulfenocycloamination. Treatment of an w-alkenylamine hydrochloride with C H SCI gives a mixture of two adducts that undergoes ring closure via an episulfonium ion to a single cyclic amine on treatment with base (K,CO,)- The reaction is useful for synthesis of pyrrolidines and piperidines (equation I) and pyrrolizidines (equation 11). 

Synthesis of cyclic amines containing alkyne groups. 

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