BtH
 Ph- O aq. HCHO Ph O

 H2N NHR R = C6H4Me-p Bt CH2NH NHC6H4Me-p
 3.10a-c 3.13
 BtH (CH20), AIC13
 (CH20)n


 Bt, ` N
 N /N R 3

 3.14a-c 3.15a-c

 a, R = p-MeC6H4; b, R = c-C6H11; c, R = PhCH2

Scheme 3-3. Synthesis of tetrahydroimidazo[1,5-b]isoquinolin- 1 (5H)-ones

3.2.4 Syntheses of Chiral 3-Substituted-2,3,10,1 Oa-tetrahvdroimidazo[1,5-b]isoquinolin-
1(5H)-ones 3.18a-c. (c.f. Scheme 3-4)

 We further investigated the modification of 2,3,10,10a-tetrahydroimidazo[1,5-

b]isoquinolin-1(5H)-ones 3.15 at 3-position. In agreement with the previous reactions of

a-amino-amides and aldehydes, [85T611] [75JHC995] we obtained 3.16b,c exclusively

as the trans-isomers; however, trans-3.16a was isolated in 38% yield together with the

corresponding cis-3.16'a in 31% isolated yield. The absolute configurations of trans-

3.16a-c and cis-3.16'a were determined by NOE experiments. For example, a strong

positive NOE effect between H(2) (5.81 ppm, s) and H(5) (4.00 ppm, t) in 16'a confirms

its cis-configuration. For trans-16a-c, no positive NOE effect was observed between

H(2) and H(5); however, small but distinct NOE effects between H(2) and PhCH2 at the

5-position proved their trans-configurations.

 Reaction of 3.16a-c with benzotriazole and aqueous formaldehyde readily gave Bt

intermediates 3.17a-c, which were directly treated with AlC13 to furnish enantiopure

trans-3-substituted-2,3,10,10a-tetrahydroimidazo[ 1,5-b]isoquinolin- (5H)-ones 3.18a-c.