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Stereoselective Synthesis of N-Acylaminohydroperoxides and -peroxides

Haiko Blumenthal, Oxana Sieck, Jrgen Liebscher*


Department of Chemistry, Humboldt-University Berlin Brook-Taylor-Strae 2, 12489 Berlin (alcyon@snafu.de)

N-Acyliminium salts are known as very reactive intermediates with various synthetic applications[1]. In case of addition reactions of soft nucleophiles to the CN double bond a new stereogenic centre is generated. In the classical Reissert reaction achiral 1-carbonitrilesubstituted N-acylisoquinolines are synthesised from isoquinoline via N-acyliminium salts[2], the potential of asymmetric synthesis has not been used so far.
Cl i-Pr + Cl N O
1 2

i-Pr N OOH O
5

i-Pr N OOH O
6

Further on it was possible to synthesise the hydroperoxides 6, 8 and 10 starting from 3,4-dihydroisoquinolines and 3,4-dihydro-carbolines. For this substances a diastereomeric ratio of only 60:40 was found. In comparison to the unsaturated system 5 and 9 the two additional hydrogen atoms strongly affect the facial selectivity of 6 and 8 (10) as shown in scheme 3.
H H H * N OMenthyl N H * N OOH O
10

H OMenthyl

CH3 3 Cl -3 C 3
o

i-Pr N
3 O

Br i-Pr N OOH O O O O N OOH


8

OOH O i-Pr O O Cl N O OMenthyl


5

Nu :

CN R-MgX R-SnBu3 HOO

Nu -3 C 3
o

H H H N

H OMenthyl

Cl

N H
13

i-Pr N Nu
4

O O N OOH
9

O O

i-Pr O O N H HOO
10

i-Pr N O O
3

Scheme 1: Synthetic pathway

Recently we found that a new stereogenic centre can be created using chiral acyl groups like (-)-(1R)- menthyl chloroformate (Scheme 1). In the case of cyanide as nucleophile the reaction is highly diastereoselective[3]. Remarkably, it was also possible to use H2O2 (eth.) as nucleophile in this reaction to form the isoquinolinehydroperoxides 5 in good yield (up to 76%) with a diastereomeric ratio of > 95 : 5 (NMR). We used different isoquinolines as precusors to investigate this new stereoselective route to hydroperoxides . The 4-bromo substituted hydroperoxide 7 turned out to be more stable than the unsubstituted product 5. Methoxygroups are also tolerated, but the formation of the corresponding hydroperoxide 9 seems to be reversible because the starting isoquinoline 1 was formed during aqueous work up.

Scheme 3: Discussion of the stereoselectivity To create peroxides instead of hydroperoxides we used tertbutylhydroperoxide and tetralinehydroperoxide. We obtained the desired products, the diastereomeric ratio for compound 11 was 70 : 30 but could not be determined for 12, because of superimposition of signals in NMR spectra. In summary we found a new asymmetric route to isoquinolinehydroperoxides and peroxides via a Reissert type reaction.
11 12

i-Pr N O O O O O O N O O

i-Pr

References: [1] W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56, 3817 3856 [2] A. Reissert, Chem. Ber. 1905, 38, 3415 3435 [3] O. Sieck, Dissertation HU-Berlin, 2004; O. Sieck, S. Schaller, S. Grimme, J. Liebscher, Synlett 2003, 3, 337-340

Scheme 2: Products of asymmetric (hydro-) peroxidation