Reactions of 3-heterospiro[5.5]undecan-9-ones

3-Heterospiro[5.5]undecan-9-ones (B) were available by catalytic hydrogenation of 3-heterospiro[5.5]undec-7-en-9-ones (A).

a: H2, Pd/C, EtOAc; yield: 80 - 90%

I. Preparation of various heterocycles starting from 3-heterospiro[5.5]undecan-9-ones

3-Heterospiro[5.5]undecan-9-ones (B) were used as starting compounds in the syntheses of target systems as depicted in the scheme below.

X = N-CH3: a: CN-CH2-COOEt, S, Et2NH/EtOH; yield: 66%; b: 2-Pyrrolidinone, POCl3/(CH2Cl)2; yield: 57%; c: CH2(CN)2, S, no base/EtOH; yield: 40%; e: PhNHNH2/AcOH; yield: 38%
X = S: a: CN-CH2-COOEt, S, Et2NH/EtOH; yield: 43%
X = O: a: CN-CH2-COOEt, S, Et2NH/EtOH; yield: 50%; b: 2-Pyrrolidinone, POCl3/(CH2Cl)2; yield: 39%; c: CH2(CN)2, S, Et2NH/EtOH; yield: 64%; d: CHO-NH2, HCOOH/DMF; yield: 67%; e: PhNHNH2/AcOH; yield: 43%

II. Preparation of 3-hetero-9-azaspiro[5.6]dodecan-10-ones via Schmidt rearrangement

Via Schmidt rearrangement 3-hetero-9-azaspiro[5.6]dodecan-10-ones (F) were prepared using hydroxylamine-O-sulfonic acid in formic acid solution [6]. These compounds represent precursors to the spiroazepine parent system (H) which was successfully accomplished using lithiumaluminiumhydride in THF-solution with yields ranging from 65% to 71% for X = N-CH3, S, O.

X = S,O: a: H2N-O-SO3H/HCOOH; yield: 30 - 60%

The Schmidt rearrangement worked well for 3-thia- and 3-oxaspiro[5.5]undecan-9-one, whereas for 3-methyl-3-azaspiro[5.5]undecan-9-one (15) the classical Beckmann conditions were applied.

a: H2NOH.HCl, NaOAc/H2O; yield: 67%; b: TosCl/pyridine; yield: 12%

In the case of the Boc-3-azaspiro[5.5]undecan-9-one (18) the protecting group was lost under acidic conditions, but could be attached again.

a: H2N-O-SO3H/HCOOH; b: di-tert-butyl dicarbonate, 1 M NaOH/THF