Alkyl derivatives heterocyclic synthesis, intramolecular

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

Torok and co-workers312 have reported the one-pot synthesis of /V-arylsulfonyl heterocycles through the reaction of primary aromatic sulfonamides with 2,5-dimethoxytetrahydrofuran. When triflic acid is used in catalytic amount, IV-arylsulfonylpyrroles are formed (Scheme 5.34). Equimolar amount of triflic acid results in the formation of N- ary I s u I fo n y I i n do I e s, whereas /V-arylsu Ifonylcar-bazoles are isolated in excess acid (Scheme 5.34). In the reaction sequence 1,4-butanedial formed in situ from 2,5-dimethoxytetrahydrofurane reacts with the sulfonamide to give the pyrrole derivative (Paal-Knorr synthesis). Subsequently, one of the formyl groups of 1,4-butanal alkylates the pyrrole ring followed by a second, intramolecular alkylation (cyclialkylation) step. 

In some cases, further functionalization of the preformed phostones allows their more complex derivatives to be obtained. For example, a-alkylation of six-membered 2-oxo-1,2-oxaphosphinanes 62 opens the way to 3-hydroxymethyl-substituted heterocycle 104 as a mixture of cis- and trans-isomers. It is interesting to note that isomeric compounds possess different stability the ds-isomer was isolated in an individual state while the trans isomer easily underwent intramolecular rearrangement to yield the compound 105 bearing the exocyclic phosphoryl moiety (Scheme 59) [134, 135], Furthermore, synthesis of bicyclic compounds 65 (ds-isomers) is based on alkylation of monocyclic phostone by protected 3-bromopropane-l-ol followed by intramolecular transesterification (Scheme 60) [54],... 

Intramolecular photoelimination of HCl from A -chloroacetamide derivatives is also a useful and versatile approach to the synthesis of aza-heterocycles. The N-alkyl-jV-chloroacetyl derivatives (202), for example, undergo photocyclization to the l,2,3,4-tetrahydroisoquinolin-3-ones (203), and the conversion of the N-chloroacetamide (204) into the lactam (205) is the key step in a synthesis of 20-de-ethylcatharanthine. Intermolecular photoeliminations of HX of potential... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Examples 136 and 137 used Boc-protected sulfonamides to prepare alkylated sulfonamides. The chiral cyclopentene derivative 138 was prepared using a nitrosulfonamide activated amine equivalent. In an intramolecular cyclisation approach, Bell et al. prepared a series of 1-heterocyclic-3-aminopyrrolidines. The Mitsunobu reagents PBU3 and DBAD were premixed prior to addition to the homoserine amide to provide, for example, compound 139. This approach is similar to an already reported synthesis of 7V-arylpiperazinones by Weissmann et al. 

Our strategy for the synthesis of (+)-dactylolide (2.217) is outlined in Scheme 2.69. We envisioned that the 20-membered macrolactone in 2.332 could be constructed by intramolecular iV-heterocyclic carbene (NHC)-catalyzed oxidative macrolactonization of co-hydroxy aldehyde 2.333. Intramolecular NHC-catalyzed oxidative esterification reactions have been recognized as an attractive tool and rapidly growing area in the synthetic community. Indeed, several examples of these reactions have recently been reported [208-216], which clearly provide a new opportunity for the development of catalytic acyl transfer agents in macrolactonization reactions of co-hydroxy aldehydes in the presence of oxidants. The substrate for the macrolactonization reaction would be derived firom the cyanohydrin alkylation of 2,6-dr-tetrahydropyran enal 2.335 with dienyl chloride 2.334. 2,6 -di-tetrahydropyran enal would in turn be constructed by employing the 1,6-oxa conjugate addition reaction of co-hydroxy 2,4-dienal 2.336. Despite the... 

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