Amines eight-membered ring

Preparation of nefopam starts with the acylation of aminobenzhydrol 1 (obtainable by reduction of the corresponding benzoylbenzamide) with chloroacetyl chloride treatment of the chloroamide (2) with potassium tertiary butoxide results in internal alkylation to give the eight-membered ring (3). Reduction of the lactam function with lithium aluminum hydride gives the amine and, thus, nefopam (4). ... 

A-allylamine 23 (obtained by standard transformations of 6-iodogluco-side 22) underwent cyclization into the monocycle 24. However, when the amine was in situ protected as a Boc derivative it could be subjected to the RCM process. The products were further converted into the bicyclic aza sugar 26.19 A similar approach to eight-membered ring aza sugars was recently reported (Fig. 9).20... 

Fig. 1 Geometry of approach of the amine nitrogen to the carbonyl carbon in the eight-membered ring of clivorine [partial structure, left drawn using the published coordinates (Birnbaum, 1972)]. The full formula is also shown. Note the out-of-plane displacement of the carbonyl carbon towards the nitrogen atom.

Based on previous success in the Pauson-Khand reaction [43], Evans demonstrated a sequential approach to the synthesis of eight-membered rings, which involved a rhodium-catalyzed aUyhc amination reaction followed by carbocyclization, to effect a three-component couphng (Scheme 12.11). To date, this transformation is only the second example of a sequential rhodium-catalyzed reaction in which only temperature is used to modulate catalytic activity. 

It has been reported that amines (32JCSH42) or imines (53JCS143), when reacted with formaldehyde and hydrogen sulfide, give rise to N-substituted 1,3-thiazetidines. However, in at least one case the structure was established to be an eight-membered ring dimer, which calls into question the structure of these compounds. 

Unlike carbocyclic and oxygen-containing heterocyclic systems, catalytic enantioselective synthesis of eight-membered ring amines proceeds efficiently and with excellent enantioselectivity. These catalytic ARCM reactions can be carried out in the absence of solvent as well. Representative data regarding cat-... 

Preparation of five to eight-membered rings A number of common ring amines and ethers have been prepared [25]. The five-membered amine is obtained from the diallylamine 74 [26,27]. (+)-Citronelene (75), 0.75M in toluene, was converted to 3-methylcyclopentene quantitatively in 30 min with retention of stereochemistry using... 

In conclusion, six-, seven- or as here eight-membered rings as well as macrocycles can be synthesized. Stereogenic centers are not touched and the process is compatible with many other functional groups like esters, amines, alcohols and epoxides. 

A modified Ugi reaction was used in the synthesis of lactams of type 191 (Scheme 80 <1997T5591>). The acid and carbonyl functionalities required for the Ugi reaction are tethered with the appropriate spacing to afford the eight-membered ring in good yields, and the other two components - the amine and the nitrile - are introduced stepwise. Methanol plays a crucial catalytic role in the reaction as it adds to the acyl center and facilitates the lactam formation. 

Benzodiazocine 264 was prepared through a 4-component Ugi reaction including a primary amine tethered to a BOC-protected internal amino nucleophile, followed by a postcondensation base-catalyzed cyclization. Thus, 2 equiv of aldehyde 262 were employed to promote Schiff base formation and a one-pot, double scavenging protocol with immobilized tosylhydrazine and di-isopropylethylamine removed both the excess aldehyde and any unreacted acid 261. The intermediate 263 was then subjected to treatment with TFA, followed by proton scavenging with resin bound morpholine, to promote cyclization to afford the eight-membered ring (Scheme 47) <2001TL4963>. 

A closely related synthesis of symmetrically substituted bispidinones 19a-w is provided by the Mannich reaction with acetone derivatives 319, paraformaldehyde, and the acetate salts of various amines. Such a reaction is formally a C2N + C2N + 2C synthesis but is reported here because of its relationship to the above bispidinone synthesis. In this case the intermediate piperidinone cannot be isolated but once formed, it reacted with the primary amine and formaldehyde to give the eight-membered ring <1995T2055, 19970M1167>. Similarly, the diamine 320 reacted with dibenzyl ketone and formaldehyde to give the macrocycle 321 in 48% yield <1995T4819>. 

Reduction of this intermediate by hydrogen transfer from 1,4-cyclohexa-diene in the presence of platinum leads to loss of the carbobenzoxy group and formation of the transient primary amine 119. The terminal primary amino group in that product then participates in a second addition-elimination sequence to form an eight-membered ring (120). Treatment of this intermediate with trimethylsilyl bromide then cleaves the ethyl ethers on phosphorus to give the free phosphonic acid and thus perzinfotel (121). ... 

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