Nitrogen heterocycles, unsaturated, synthesis

As an extension of this chemistry, 7V-sulfinyl aziridine 188, prepared from (/ )-187, was utilized in the asymmetric synthesis of protein kinase C inhibitor D-e/yf/iro-sphingosine 189" and in the first enantioselective synthesis of the marine cytotoxic antibiotic (/ )-(-)-dysidazirine (190).100 This latter result constitutes the first general method for preparing nonracemic 2//-azirines, the smallest of the unsaturated nitrogen heterocycles.100,101... 

G. A. Lee, Simplified synthesis of unsaturated nitrogen-heterocycles using nitrile betaines, Synthesis (1982) 508-509. 

The generation of the carbcxi-carbon double bond of unsaturated nitrogen heterocycles by the rDA reaction of cycloadducts that act as protected ethylenes has been accomplished. Azetines have been prepared by this method. Another example is the synthesis of l-methyl-3-pyrroline (201). By protecting the ethylene of N-methylmaleimide (199) with furan and then reducing with lithium aluminum hydride, adduct (200) was obtained (equation 86). Pyrolysis of adduct (200) at 250-300 C gave l-methyl-3-pyrroline (201) in 60% isolated yield. The ethylene moiety of N-substituted maleimides can also be generated via rDA reactions. Examples include the generation of N-phenylmaleimide (equation 87) and of N-acetoxymaleimide (equation 88). ... 

Nitrogen Heterocycles.- Reactions of iminophosphoranes have been used to prepare a wide range of heterocycles. Examples of compounds prepared by intramolecular aza-Wittig reactions include 3,4-dihydroquinazolines (191) and quinazolines (192), quinazoline derivatives (e.g. 193),pyrrolo( 1,2-a)quinoxalines (194), indolo[3,2-clquinolines (195), and indolo[l,2-c]quinazolines (196),"8 imidazolinones (197),"9 quinazolinones (198),"9, 120 pyrido[2,3-d]pyrimidine derivatives (199), 21 and 4,5-dihydropyrazolo(3,4-d]pyrimidine derivatives (200). 22 Tributyl(cyclohepta-1,3,5-trienylimino)phosphorane (201), prepared by thermal isomerization of the 2,4,6-derivative, reacts with a,p-unsaturated ketones to give 9H-cyclohepta[b]pyridine derivatives (202). 23 a synthesis of (2,4)pyridinophanes (204) by the reaction of N-vinyliminophosphoranes (203) with a,P-unsaturated ketones has been reported. 24... 

R = Ph, R = Et) and arylaldehydes ArCHO has been reported to yield azadienes with general formula ArC=N-C(R)=CHC02R. These azadienes appear to be very useful as starting materials for the preparation of nitrogen heterocycles. An easy one-pot synthesis of dihydropyrimidines from NH=C(Ph)N=PPh3 and a,(3-unsaturated aldehydes has been described. The reaction is supposed to proceed via an aza-Wittig mechanism followed by ring closure. ... 

This type of transformation has been employed for the synthesis of several different nitrogen heterocycles [98], and an analogous reaction of unsaturated A-chloroamines that generates pyrrolidine products has also been described [99]. 

Catalytic hydrogenation of unsaturated nitrogen heterocycles plays an important role in the synthesis of nitrogen-containing natural products such as alkaloids and amino acids. 

Six-membered nitrogen heterocycles are found in a wide variety of naturally occurring alkaloids, and are often incorporated into the design of biologically active pharmaceutical products. Of the many ways to construct these heterocycles, the aza-annulation of enamine substrates with a,(J-unsaturated carboxylic acid derivatives has been a versatile and efficient method for the formation of dihydropyridone and pyridone products. The synthetic utility of this approach has led to incorporation of aza-annulation methodology as a key step in the synthesis of a number of interesting heterocyclic molecules. 

The 4-unsaturated-5-oxazolones provide convenient starting materials for the synthesis of other nitrogen-containing heterocyclic systems. The preparation of tetrazoles and isoquinolines is discussed in Sections II,B, 1 and II,B,2,b. 

Chalcone dibromides are advantageous intermediates for the preparation of various nitrogen-containing heterocycles (refs. 1-4). In the case of exocyclic a,P-unsaturated ketones, however, only few examples are known concerning the utilization of their dibromides for such purposes (ref. 5). Our aim was, therefore, the synthesis of the dibromides of various exocyclic a,P-unsaturated ketones (ref. 6) and to study their chemical transformations. In our present paper the reaction of such dibromides with azide nucleophile is reported. 

Going one step beyond, the reaction of these n-donor-substituted Group 6 allenylidenes with bifunctional N,N- or W, 5-dinucleophiles opened up a fruitful route for the synthesis of an extensive family of N- or 5-heterocyclic carbenes. Thus, treatment of complex [Cr =C=C=C(NMe2)Ph (CO)5] with benzamidine, guanidine or thioacetamide has been reported to yield the a,(3-unsaturated carbenes 54 (Scheme 16) [62], arising from nitrogen attack at Cy, subsequent HNMe2... 

The synthesis of oxygen- and nitrogen-containing heterocyclic compounds by anionic cyclization of unsaturated organolithium compounds has been reviewed recently. " Broka and Shen reported the first intramolecular reaction of an unstabilized a-amino-organolithium compound using reductive lithiation of an A,5-acetal derived from a homoaUylic secondary amine (Scheme 21). Just one example was reported treatment with lithium naphthalenide gave the pyrrolidine product, predominantly as the cis isomer. 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

Cycloaddition Reactions. Isocyanates undergo cycloadditions across the carbon—nitrogen double bond with a variety of unsaturated substrates. Addition across the C=0 bond is less common. The propensity of isocyanates to undergo cydization reactions has been widely explored for the synthesis of heterocyclic systems. Substrates with C=0, C=N, C=S, and C=C bonds have been found to yield either 2 + 2, 2 + 2 + 2, or 2 + 4 cycloadducts or a variety of secondary reaction products (2). 

The main aim of this monograph is a comprehensive review and organization of the known literature data devoted to the reactions of o,/3-unsaturated ketones, their synthetic equivalents and their precursors utilized in the synthesis of nitrogen-containing heterocycles. The book is separated into four chapters and an Addendum, and contains nearly 900 literature references. Each chapter describes the synthesis and chemical and other interesting properties and features of certain classes of heterocyclic compounds. 

Tandem radical additions have also been utilized for the synthesis of nitrogen containing heterocycles. These reactions have the same requirements as those discussed for the oxygen heterocycles. The reductive addition of phenylsulfanyl radicals to the unsaturated amide 153 has been investigated [95JCS(P1)19], The nucleophilic radical adds selectively to the enamide followed by 5-exo-cyclization to give 154 in excellent yield with high trans selectivity. 

Examples of nitrogen-containing heterocycle syntheses based on condensation reactions continue to be forthcoming. Examples include a tandem oxidation-annulation of propargyl alcohols in a one-pot synthesis of pyridines (Equation 148) <2003SL1443>, trifluoromethyl-substituted pyridines (Scheme 94) <2003S1531>, and standard malononitrile additions to a,/3-unsaturated ketones <1995JCM392>. 

Many of the chiral selenium electrophiles have also been employed in cyclization reactions. Various internal nucleophiles can be used and access to different heterocycles is possible. Not only oxygen nucleophiles can be used for the synthesis of heterocyclic compounds, but also nitrogen nucleophiles are widely employed and even carbon nucleophiles can be used for the synthesis of carbacycles with new stereogenic centers. Oxygen nucleophiles have been widely used and some selected examples of selenolactonizations of unsaturated acids 50 and 52 and seleno-etherifications of unsaturated alcohols 54 and 56 are shown in Scheme 10. 

The carbon-carbon unsaturated substrates have now expanded from aminoalkenes to aminoalkynes, aminoallenes, and aminodienes, and the hydroamination/cyclization reactions of these substrates have produced functionalized nitrogen-containing heterocycles. It is worth noting that the aminoallene hydroamination/cyclization reactions are highly diastereoselective, and can provide concise routes to the synthesis of some natural products (Figure 8.38) [126]. 

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