F. D. King / Tetrahedron 63 (2007) 2053–2056
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3.1.1. Synthesis of N-(4,4-diethoxybutyl)-2-(3,4-dimeth-
oxyphenyl)acetamide (4). Method (A). DCC (7.3 g,
0.035 mol) was added in one portion to a stirred solution
of (3,4-dimethoxyphenyl)acetic acid (6.9 g, 0.035 mol) and
HOSu (4.2 g, 0.036 mol) in EtOAc (250 mL), at ambient
temperatures under argon. After stirring for 3 h, a solution
of 4-aminobutyraldehyde diethylacetal (ex. Aldrich, 90%
pure) (6 mL, 0.035 mol) in EtOAc (25 mL) was added in
one portion. The reaction mixture was stirred over night.
Et2O (200 mL) was then added and the precipitated DCU
collected by filtration, and washed with Et2O (100 mL).
The combined filtrates were washed with 2 M NaOH
(50 mL), H2O (50 mL) and brine (50 mL), and then dried
(MgSO4), filtered and concentrated by rotary evaporation.
On further drying on a high vacuum line, the oil solidified.
The solid was triturated, initially with Et2O (50 mL), and
subsequently hexane (150 mL) was added in portion. The
white solid was collected, washed with hexane (100 mL)
and dried to give 4 as a white crystalline solid (8.5 g,
(400 MHz, CDCl3): d 1.7–2.2 (m, 4H), 3.59 (s, 2H), 3.87
(br s, 6H), 4.12 (br s, 1H), 5.66 (br s, 1H), 6.77–6.90 (m,
3H), 9.74 (br s, 0.1H). 13C NMR+DEPT (75 MHz, CDCl3)
d¼23.23 (CH2), 32.04 (CH2), 41.63 (CH2), 46.67 (CH2),
55.87 (CH3), 55.90 (CH3), 81.90 (CH), 111.24 (CH),
112.16 (CH), 121.14 (CH), 126.55 (C), 148.04 (C), 149.07
(C), 171.70 (C). The crude 3b (6.7 g) was dissolved in
CH2Cl2 (150 mL) and stirred at ambient temperatures with
˚
EtOH (4 mL), 3 A molecular sieves (25 g) and TFA
(0.5 mL) for 3.5 h. Et3N (1 mL) was added and the reaction
mixture filtered through a pad of Kieselghur, washing the
collected solids with CH2Cl2 (2ꢃ100 mL). The combined
organics were washed with H2O (50 mL) and brine
(50 mL), and dried (MgSO4). Concentration of the filtered
organics under reduced pressure gave 3a as a colourless
oil (6.9 g,w100%). 1H NMR (400 MHz, CDCl3): d 1.16 (t,
J¼7.2 Hz, 1.5H), 1.27 (t, J¼7.2 Hz, 1.5H), 1.64–2.21 (m,
4H), 3.31–3.72 (m, 6H), 3.86 (s, 6H), 5.10 (d, J¼4.8 Hz,
0.5H), 5.55 (d, J¼4.8 Hz, 0.5H), 6.77–6.88 (m, 3H). 13C
NMR+DEPT (75 MHz, CDCl3) d¼15.37 (CH3), 15.44
(CH3), 21.06 (CH2), 23.08 (CH2), 31.55 (CH2), 31.88
(CH2), 40.70 (CH2), 41.76 (CH2), 45.86 (CH2), 46.31
(CH2), 55.85 (CH3), 55.91 (CH3), 62.08 (CH2), 64.46
(CH2), 85.94 (CH), 87.51 (CH), 111.18 (CH), 111.23
(CH), 112.19 (CH), 112.33 (CH), 121.15 (CH), 121.30
(CH), 127.04 (C), 127.66 (C), 147.92 (C), 148.97 (C),
149.03 (C), 171.02 (C), 171.32 (C). HRMS: calcd for
C16H23NO4Na [M+Na]+ 316.1525, found 316.1530.
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72%); mp 56–57 ꢁC. H NMR (400 MHz, CDCl3): d 1.17
(t, J¼7.2 Hz, 6H), 1.49–1.60 (m, 4H), 3.23 (m, 2H), 3.40–
3.48 (m, 2H), 3.51 (s, 2H), 3.55–3.63 (m, 2H), 3.88 (s,
6H), 4.43 (t, J¼5.2 Hz, 1H), 5.53 (br s, 1H), 6.77 (s, 1H),
6.78 (d, J¼8.4 Hz, 1H), 6.84 (d, J¼8.4 Hz, 1H). 13C
NMR+DEPT (75 MHz, CDCl3) d¼12.27 (CH3), 24.51
(CH2), 30.79 (CH2), 39.25 (CH2), 43.37 (CH2), 55.86
(CH2), 61.09 (CH3), 61.26 (CH3), 102.49 (CH), 111.50
(CH), 112.42 (CH), 121.56 (C), 127.46 (C), 148.26 (C),
149.23 (C), 171.31 (C). HRMS: calcd for C18H29NO5Na
[M+Na]+ 362.1943, found 362.1949. The mother liquors
from the crystallisation contained 4 (w2 g), which could be
used for the subsequent hydrolysis reaction.
3.1.3. 8,9-Bis(methyloxy)-2,3,6,10b-tetrahydropyr-
rolo[2,1-a]isoquinolin-5(1H)-one (2). Method (A). AlCl3
(3.5 g, 0.026 mol) was added to a stirred solution of 3a
(5.0 g, 0.017 mol) in dry CH2Cl2 (100 mL) at ambient
temperatures under argon. After 2 h, ice (50 g) was added
and the reaction stirred for a further 15 min. The organic
layer was separated and the aqueous layer extracted
with CH2Cl2 (50 mL). The combined organics were dried
(MgSO4), filtered and concentrated in vacuo. Trituration
with Et2O (50 mL) gave 2 (3.8 g, 90%); mp 164–165 ꢁC
Method (B). A solution of (3,4-dimethoxyphenyl)acetyl
chloride (ex. Aldrich) (10 g, 0.047 mol) in anhydrous
CH2Cl2 (20 mL) was added, dropwise, over 20 min to stirred
solution of 4-aminobutyraldehyde diethylacetal (7.8 mL,
0.045 mol) and Et3N (6.5 mL, 0.047 mol) in anhydrous
CH2Cl2 (200 mL) at 0 ꢁC. The reaction mixture was stirred
and allowed to warm to ambient temperatures over 2 h.
The CH2Cl2 was removed by rotary evaporation and re-
placed with Et2O (300 mL). After washing with H2O
(2ꢃ50 mL) and brine (50 mL), the separated organic layer
was dried (MgSO4), filtered and concentrated by rotary
evaporation. The resultant oil was re-dissolved in Et2O
(200 mL) and hexane added until the mixture was slightly
cloudy. A seed crystal from Method (A) was added to initiate
crystallisation. Additional hexane was added to approxi-
mately 1:1 Et2O/hexane and the solid collected, washed
with hexane (2ꢃ100 mL) and dried to give 4 (12.2 g, 80%)
as a beige-coloured solid.
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(lit.8 163–165 ꢁC). H NMR (400 MHz, CDCl3): d 1.83–
1.93 (m, 1H), 1.96–2.09 (m 1H), 2.12–2.19 (m, 1H), 2.58–
2.64 (m, 1H), 3.46–3.71 (m, 4H), 3.88 (s, 3H), 3.89 (s,
3H), 4.57–4.62 (m, 1H), 6.67 (s, 1H), 6.68 (s, 1H). 13C
NMR+DEPT (75 MHz, CDCl3) d¼23.09 (CH2), 31.81
(CH2), 38.14 (CH2), 44.72 (CH2), 56.06 (CH3), 56.19
(CH3), 59.56 (CH), 107.69 (CH), 111.27 (CH), 124.93 (C),
127.99 (C), 147.88 (C), 148.56 (C), 167.60 (C). HRMS:
calcd for C14H17NO3 [MH]+ 248.1287, found 248.1291.
Method (B). The method was identical to Method (A) except
that 4 (1.0 g, 0.003 mol) was used to give 2 (0.65 g, 87%),
identical to that obtained from Method (A).
3.1.2. 1-{[3,4-Bis(methyloxy)phenyl]acetyl}-2-(ethyloxy)-
pyrrolidine (3a). A solution of 4 (8.4 g, 0.025 mol), dis-
solved in EtOAc (20 mL) and Et2O (100 mL) was stirred
vigorously at ambient temperatures with aqueous 2 M HCl
(50 mL) for 1 h. Hexane (100 mL) was then added and the
aqueous layer separated. The organics were washed with
H2O (2ꢃ50 mL) and the combined aqueous extracts basified
with solid K2CO3. The product (3b) was extracted into
CH2Cl2 (3ꢃ100 mL), dried (MgSO4) and concentrated
under reduced pressure to give 3b as an oil in equilibrium
withw10% of the amidoaldehyde (6.7 g,w100%). 1H NMR
3.1.4. 8,9-Bis(methyloxy)-1,2,3,5,6,10b-hexahydropyr-
rolo[2,1-a]isoquinoline [( )-crispine A] (1). Concd
H2SO4 (0.13 mL, 0.0025 mol) was added, dropwise over
5 min, to a stirred solution of LAH (5 mL of a 1 M solution,
0.005 mol) at 0 ꢁC under argon. After stirring at 0 ꢁC for
15 min, 2 (0.33 g, 0.0013 mol) was added in one portion
and the reaction stirred at room temperature for 14 h. The re-
action mixture was then cooled to 0 ꢁC and 2 N NaOH
(0.6 mL) was then carefully added and the reaction mixture
stirred for 15 min. The solid was collected and washed with