1-Methylgalanthamine derivatives

Article abstract of DOI:10.1007/s00706-004-0220-8

The syntheses of pharmaceutically interesting galanthamine analogues bearing a methyl group at the Cl position are described. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-004-0220-8

Monatshefte f€ur Chemie 135, 1275–1287 (2004)
DOI 10.1007/s00706-004-0220-8
1-Methylgalanthamine Derivatives#
Margit Hemetsberger1, Matthias Treu1, Ulrich Jordis1,
¨
Kurt Mereiter , Christian Hametner , and Johannes Frohlich
2
1
1;ꢀ
1
Institute of Applied Synthetic Chemistry, Vienna University of Technology,
A-1060 Vienna, Austria
2
Institute of Chemical Technologies and Analytics, Vienna University
of Technology, A-1060 Vienna, Austria
Received April 22, 2004; accepted May 5, 2004
Published online July 23, 2004 # Springer-Verlag 2004
Summary. The syntheses of pharmaceutically interesting galanthamine analogues bearing a methyl
group at the C1 position are described.
Keywords. Acetylcholine esterase inhibitor; Drug research; Galanthamine analogue; Tandem cycli-
zation; Total synthesis.
Introduction
(ꢁ)-Galanthamine, which has been introduced into the European market and
approved by the FDA for the treatment of Alzheimer’s disease, is a reversible,
competitive cholinesterase inhibitor that also allosterically modulates nicotinic
acetylcholine receptors [1–3]. For SAR studies 1-methylgalanthamine derivatives
were prepared.
Results and Discussion
1-Methylgalanthamine (6) was prepared in a sequence analogous to the industrial
synthesis of (ꢁ)-galanthamine [4, 5] starting from 5-hydroxy-4-methoxy-2-methyl-
benzaldehyde [6]. Reductive amination with tyramine gave rise to the phenethyl-
benzylamine 1 in 96% yield. N-Formylation using methyl formate=formic acid in
dioxane led to 2 in 83% yield. Tandem cyclization by phenol oxidation yielded the
1-methylnarwedine derivative 3 in 55%. Ketal formation using propylene glycol
gave rise to the protected species 4 with a yield of 73%. By reduction of the amide
moiety and subsequent cleavage of the protecting group under acidic conditions
ꢀ
Corresponding author. E-mail: johannes.froehlich@tuwien.ac.at
Dedicated to Professor Peter Stanetty on the occasion of his 60th birthday
#

1276
M. Hemetsberger et al.
Fig. 1. Molecular structures of 5 (left) and (ꢁ)-6 ꢂ HBr (right) in crystalline state (20% ellipsoids)
1-methylnarwedine (5) was synthesized in 93% yield. An X-ray crystallographic
study of racemic 5 (Fig. 1, for further details see experimental section) showed it to
crystallize in the non-chiral centrosymmetric, monoclinic space group P21=n. This
made a crystallization-induced asymmetric transformation [7] to enantiopure 5
impossible that works so well with narwedine. In this case crystallization of the
compound in the chiral space group P212121 combined with chiral seeding and
continuous re-equilibration of its enantiomers in solution via a base-catalyzed
retro-Michael addition opened an elegant and efficient access to either (ꢁ) or
(þ)-narwedine starting with racemic educt [4, 5]. Attempts to resolve the racemate
5 employing tartaric acid derivatives failed. Final stereoselective reduction of
ketone 5 using L-Selectride+ gave 1-methylgalanthamine (6) in 70% yield. For
analytical purposes and for X-ray analysis the free base was converted into the
crystalline HBr-salt by treatment with concentrated HBr (Scheme 1). Interestingly,
Scheme 1

1-Methylgalanthamine Derivatives
1277
Fig. 2. Comparison of the two isomorphic structures of (ꢁ)-6 ꢂ HBr (left) and (ꢁ)-galanthamine
hydrobromide [8] (right) viewed down the a-axis of their orthorhombic unit cells (space group
3
˚
˚
P212121; left: a ¼ 7.499, b ¼ 14.395, c ¼ 15.937 A, V ¼ 1720 A ; right: a ¼ 7.371, b ¼ 14.327,
3
˚
˚
c ¼ 15.932 A, V ¼ 1682 A )
this salt (6 ꢂ HBr) crystallizes spontaneously in the chiral space group P212121 and
is, moreover, isostructural with (ꢁ)-galanthamine hydrobromide [8] (Figs. 1 and 2,
see also experimental section). This crystallographic property of 6 ꢂ HBr would in
principle permit the separation of the enantiomers by crystallization techniques [7],
but was not tested due to lacking sufficiently large amounts of the compound.
As a key intermediate for the synthesis of the 6-epi-derivatives, epi-1-
methylgalanthamine (8) was prepared by stereoselective reduction of 5 using
Scheme 2

1278
M. Hemetsberger et al.
Scheme 3
Scheme 4
L-Selectride+ in the presence of CeCl3 ꢂ7H2O in 67% yield. N-Demethylation
employing bis(1,1-dimethylethyl)azodicarboxylate yielded the secondary amine
10 in 53%. L-Selectride+ reduction of the keto group of 3 with concomitant loss
of the N-formyl group gave rise to the isomeric 7 in 96% yield. Conversion of 7
into 10 via the intermediate acetate 9 was disfavored due to low yields for both
steps (see Scheme 2). N-Alkylation of 7 and 10 led to derivatives of 1-methyl-
galanthamine (11a–11d) and epi-1-methylgalanthamine (12) (see Scheme 3).
Quarternary ammonium salts 13a–13d and 14a–14f were prepared by treat-
ment of 6 and 8 with various alkyl halides (see Scheme 4).
Experimental
Melting points were measured on a Kofler micro hot stage. 1H and 13C NMR-spectra were recorded on
a Bruker AC-200 or a Bruker Avance 400 FT-NMR spectrometer in CDCl3 or DMSO-d6 using TMS as
internal standard. Thin layer chromatography (TLC) was performed on precoated plates (Merck TLC
aluminum sheets silica 60 F254) with detection by UV light or with phosphomolybdic acid in aqueous

1-Methylgalanthamine Derivatives
1279
EtOH by heating. All reactions were magnetically stirred under Ar. All liquid reagents were freshly
distilled prior to use. Elemental analyses were found to agree favorably with the calculated values.
5-[N-[2-(4-Hydroxyphenyl)ethyl]aminomethyl]-2-methoxy-4-methylphenol
(1, C17H21NO3)
2-Methyl-4-methoxy-5-hydroxybenzaldehyde (27.8 g, 168mmol) and 23.0g of tyramine (168 mmol)
were refluxed in 300 cm3 of dry EtOH for 8.5 h. The mixture was cooled to 0ꢃC, and 5.20 g of NaBH4
(134 mmol) in 20 cm3 of H2O were added and stirred for 30 min. Then the mixture was poured into
4.5 dm3 of ice=H2O, and the precipitate was collected by filtration and dried at 50ꢃC=50mbar. Yield
43.3g of colorless solid (96%); mp 122–124ꢃC (H2O); TLC: CHCl3:MeOH:conc. NH4OH ¼ 89:10:1,
Rf ¼ 0.2; 1H NMR (200MHz, DMSO-d6): ꢀ ¼ 6.90 (m, 2H), 6.67 (s, 1H), 6.62 (m, 2H), 6.55 (s, 1H),
3.72 (s, 3H), 3.51 (s, 2H), 2.73 (t, J ¼ 6.5 Hz, 2H), 2.60 (t, J ¼ 6.5Hz, 2H), 2.10 (s, 3H) ppm; 13C NMR
(50 MHz, DMSO-d6): ꢀ ¼ 155.4 (s), 145.8 (s), 143.9 (s), 130.9 (s), 130.4 (s), 129.3 (d), 126.0 (s), 116.2
(d), 115.0 (d), 114.3 (d), 55.7 (q), 51.1 (t), 50.3 (t), 35.0 (t), 17.9 (q) ppm.
N-[(5-Hydroxy-4-methoxy-2-methylphenyl)methyl]-N-[2-(4-hydroxyphenyl)ethyl]-
formamide (2, C18H21NO4)
1 (55.0 g, 191 mmol) and 23.5cm3 of methyl formiate (383mmol) were refluxed in 400 cm3 of dioxane=
11cm3 of DMF=1.5 cm3 of formic acid for 7 h. Then the mixture was concentrated in vacuo. The residue
was dissolved in 55 cm3 of MeOH, and 2.7dm3 of ice=H2O were added under vigorous stirring. The
precipitate was collected by filtration and dried at 50ꢃC=50mbar. Yield 49.8 g of colorless crystals
1
(83%); mp 170–171ꢃC (H2O); TLC: CHCl3:MeOH:conc. NH4OH¼ 89:10:1, Rf ¼ 0.35; H NMR
(200 MHz, DMSO-d6): ꢀ ¼ 9.20 (s, 1H), 8.74 (d, J ¼ 15.3Hz, 1H), 8.19 (s, 0.5H), 7.88 (s, 0.5H),
7.00–6.87 (m, 2H), 6.74 (s, 1H), 6.72–6.56 (m, 2H), 6.59 (s, 1H), 4.31 (s, 1H), 4.23 (s, 1H), 3.73 (s,
3H), 3.21 (dd, J ¼ 15.3, 7.6 Hz, 2H), 2.60 (t, J ¼ 7.6 Hz, 2H), 2.12 (s, 3H) ppm; 13C NMR (50 MHz,
DMSO-d6): ꢀ ¼ 162.7 and 162.3 (2d), 155.7 (s), 146.7 and 146.5 (2s), 144.4 and 144.2 (2s), 129.7 and
129.4 (2d), 128.9 and 128.4 (2s), 126.5 (s), 126.4 and 126.3 (2s), 116.3 and 115.9 (2d), 115.1 (d), 114.6
and 114.4 (2d), 55.6 (q), 48.0 and 47.4 (2t), 43.3 and 41.6 (2t), 33.2 and 31.9 (2t), 18.1 and 18.0 (2q) ppm.
ꢀ
6H-benzofuro[3a,3,2-ef][2]benzazepine-11-carboxaldehyde (3, C18H19NO4)
[(ꢄ)-(4aꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-6-oxo-
To a vigorously stirred mixture of 47.0 g of K2CO3 (338mmol), 47.0g of K3[Fe(CN)6] (142 mmol),
1.6 dm3 of toluene, and 470 cm3 of H2O 11.4g of 2 (69.8 mmol) were added at 80ꢃC and it was stirred
for 1 h at this temperature. Then 40g of diatomaceous earth were added and it was stirred for additional
10min. The mixture was filtered, and the solid was triturated with 100 cm3 of water and 3ꢅ200 cm3
of hot toluene. The aqueous layer was extracted with 200 cm3 of toluene and the combined organic
layer was washed with 2 ꢅ 500 cm3 of 1 N HCl, 2 ꢅ 500 cm3 of H2O, and 500 cm3 of brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with 2 ꢅ 10 cm3 of i-Pr2O.
Yield 6.17g of light yellow crystals (55%); mp 215ꢃC (decomp) (i-Pr2O); TLC: CHCl3:MeOH:conc.
NH4OH ¼ 89:10:1, Rf ¼ 0.5 and 0.4; 1H NMR (mixture of 2 rotamers, 200 MHz, DMSO-d6):
ꢀ ¼ 8.18 (s, 0.2H), 8.10 (s, 0.8H), 7.25 (dd, J ¼ 10.4, 1.9Hz, 0.8H), 7.15 (dd, J ¼ 10.4, 1.9 Hz,
0.2H), 6.73 (s, 0.2H), 6.69 (s, 0.8H), 5.95 (d, J ¼ 10.3Hz, 0.8H), 5.93 (d, J ¼ 10.3Hz, 0.2H), 5.14
(d, J ¼ 15.4Hz, 0.8H), 4.83 (d, J ¼ 15.4 Hz, 0.2H), 4.67 (bs, 1H), 4.51 (d, J ¼ 15.4 Hz, 0.2H), 4.07 (d,
J ¼ 15.4Hz, 0.8H), 3.97 (bs, 1H), 3.78–3.60 (m, 4H) 3.07 (dd, J ¼ 17.4, 3.4Hz, 1H), 2.78 (dd,
J ¼ 17.4, 1.9Hz, 1H), 2.33 (s, 3H), 2.30 (s, 0.8H), 2.22 (s, 0.2H), 1.86 (dt, J ¼ 13.5, 3.7 Hz, 1H)
ppm; 13C NMR (mixture of 2 rotamers, 50 MHz, DMSO-d6): ꢀ ¼ 194.9 (s), 162.8 and 162.1 (2d), 145.2
and 144.8 (2d), 145.5 and 145.3 (2s), 142.9 and 142.8 (2s), 130.6 and 130.3 (2s), 128.2 (s), 127.5 and

1280
M. Hemetsberger et al.
127.0 (2s), 126.4 and 126.2 (2d), 114.5 and 114.2 (2d), 87.0 and 86.8 (2d), 55.6 (q), 49.2 and 49.0 (2s),
47.4 and 45.6 (2t), 41.8 and 40.1 (2t), 37.7 (t), 37.5 (t) 37.4 (t), 34.1 (t), 19.2 and 18.9 (2q) ppm.
ꢀ
[(ꢄ)-(4aꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,40-dimethylspiro[6H-
benzofuro[3a,3,2-ef][2]benzazepine-6,20-[1,3]-dioxolane]-11-carboxaldehyde
(4, C21H25NO5)
Compound 3 (6.17 g, 19.7mmol), 11.1 cm3 of propylene glycol (149mmol), and 375 mg of p-TsOH
(1.97 mmol) were refluxed in 40 cm3 of dry toluene for 13h using a Dean-Stark-apparatus. The toluene
layer was separated, and the remaining glycol was extracted with 7 ꢅ 5 cm3 of toluene. The combined
organic layer was washed with 2 ꢅ 50cm3 of 8% AcOH, 2 ꢅ 50 cm3 of satd. NaHCO3 solution and
50cm3 of brine, dried (Na2SO4), filtered, and concentrated in vacuo. Yield 5.34 g of off-white foam
(73%); TLC: CHCl3:MeOH¼ 90:10, Rf ¼ 0.7; 1H NMR (mixture of diastereomers and rotamers,
200 MHz, CDCl3): ꢀ ¼ 8.14–8.01 (m, 1H), 7.30–7.09 (m, 2H), 6.51 (s, 1H), 6.22–5.97 (m, 1H),
5.85–5.61 (m, 1H), 5.38 and 4.77 (d, J ¼ 15.7Hz, 1H), 4.49 (bs, 1H), 4.37–4.01 (m, 2H), 3.93–
3.74 (m, 5H), 3.71–3.10 (m, 1H), 2.79–2.58 (m, 1H), 2.41 (s, 2H), 2.32 (d, J ¼ 10.2Hz, 3H), 2.25–
1.74 (m, 3H) ppm; 13C NMR (mixture of diastereomers and rotamers, 50MHz, CDCl3): ꢀ ¼ 162.5 (d),
161.7 (d), 143.7 (s), 143.6 (s), 143.3 (d), 142.7 (d), 129.9 (s), 129.6 (s), 127.8 (d), 127.6 (d), 126.0 (s),
125.7 (s), 114.6 (d), 114.4 (d), 87.5 (d), 87.4 (d), 68.2 (d), 68.0 (t), 56.1 (q), 56.0 (q), 49.2 (s), 49.0 (s),
48.7 (t), 46.7 (t), 43.2 (t), 41.2 (t), 38.7 (t), 37.2 (t), 37.1 (t), 34.8 (t), 19.7 (q), 19.4 (q), 18.9 (q) ppm.
ꢀ
6H-benzofuro[3a,3,2-ef][2]benzazepine-6-one (5, C18H21NO3)
[(ꢄ)-(4aꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11-dimethyl-
To 5.34 g of 4 (14.4 mmol) in 20cm3 of dry THF 25.2cm3 of a LiAlH4 solution (1M in THF,
25.2mmol) were added at ambient temperature and stirred for 15 min. 10cm3 of toluene, 1.5cm3 of
H2O, and 1.5 cm3 of 15% aqueous NaOH were subsequently added and stirred for 15min. 1.5 g of
diatomaceous earth were added, then the mixture was stirred under reflux for 1 h and filtered. The
remainder was triturated with 3 ꢅ 10cm3 of hot toluene:THF ¼ 1:1, the combined organic layer was
concentrated in vacuo, dissolved in 25cm3 of 4 N HCl, stirred for 25min at 60ꢃC and washed with
2 ꢅ 5 cm3 of EtOAc (discard). The pH of the aqueous solution was adjusted to >8.5 using conc.
NH4OH and the mixture was extracted with 5 ꢅ 15cm3 of CHCl3. The combined organic layer was
washed with 50cm3 of brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
recrystallized from 15 cm3 of i-Pr2O:EtOAc¼ 9:1. Yield 4.01g of yellow crystals (93%); mp 121–
1
122ꢃC (i-Pr2O=EtOAc); TLC: CHCl3:MeOH¼ 95:5, Rf ¼ 0.4; H NMR (200MHz, CDCl3): ꢀ ¼ 7.01
(dd, J ¼ 10.4, 1.6 Hz, 1H), 6.56 (s, 1H), 5.99 (d, J ¼ 10.4 Hz, 1H), 4.68–4.62 (m, 1H), 3.97 (d,
J ¼ 15.7Hz, 1H), 3.80 (s, 3H), 3.79 (d, J ¼ 15.7 Hz, 1H), 3.22–2.95 (m, 3H), 2.71 (dd, J ¼ 17.8,
3.7 Hz, 1H), 2.44 (s, 3H), 2.23 (s, 3H), 2.20–2.01 (m, 1H), 1.87 (dt, J ¼ 13.8, 3.4 Hz, 1H) ppm; 13C
NMR (50 MHz, CDCl3): ꢀ ¼ 194.4 (s), 145.2 (s), 142.9 (s), 131.0 (s), 128.9 (s), 126.8 (2dþ s), 114.3
(d), 87.7 (d), 55.9 (q), 55.8 (t), 54.1 (t), 48.9 (s), 43.5 (q), 37.1 (t), 33.4 (t), 19.4 (q) ppm.
ꢀ
6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (6, C18H23NO3)
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11-dimethyl-
To a suspension of 170 mg of 5 (0.57 mmol) in 5 cm3 of dry THF 0.70cm3 of an L-Selectride solution
(1M in THF, 0.70 mmol) were added at ꢁ25ꢃC and stirred for 30 min at ꢁ15ꢃC. The mixture was
allowed to warm up to ambient temperature, then 0.25 cm3 of H2O and 1 cm3 of conc. NH4OH were
added and it was stirred for 10 min. Additional 2 cm3 of conc. NH4OH were added, and the aqueous
solution was extracted with 3 ꢅ 10 cm3 of CH2Cl2. The combined organic layer was washed with
2 ꢅ 10cm3 of H2O and 10cm3 of brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue

1-Methylgalanthamine Derivatives
1281
was purified by MPLC (10 g SiO2, CHCl3:MeOH ¼ 90:10) and triturated with 2 ꢅ 2 cm3 of Et2O. Yield
120 mg of colorless foam (70%); TLC: CHCl3:MeOH ¼ 95:5, Rf ¼ 0.4; 1H NMR (200 MHz, CDCl3):
ꢀ ¼ 6.54 (s, 1H), 6.10 (dd, J ¼ 10.2, 1.2 Hz, 1H), 5.98 (dd, J ¼ 10.2, 4.7 Hz, 1H), 4.56 (bs, 1H), 4.12 (bs,
1H), 3.99 (d, J ¼ 15.6Hz, 1H), 3.82 (s, 3H), 3.81 (d, J ¼ 15.6Hz, 1H), 3.20 (ddd, J ¼ 14.2, 12.1, 2.1Hz,
1H), 2.96 (dt, J ¼ 14.2, 3.4Hz, 1H), 2.65 (ddd, J ¼ 15.7, 3.2, 1.5 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 1.99
(ddd, J ¼ 15.5, 5.0, 2.5 Hz, 2H), 1.60 (ddd, J ¼ 13.7, 4.0, 2.4 Hz, 1H) ppm; 13C NMR (50 MHz, CDCl3):
ꢀ ¼ 144.0 (s), 143.0 (s), 133.4 (s), 128.9 (s), 127.4 (2d), 127.0 (s), 126.6 (s), 113.6 (d), 88.3 (d), 61.9 (d),
55.7 (q), 55.4 (t), 53.8 (t), 48.2 (s), 42.7 (q), 33.8 (t), 29.8 (t), 19.4 (q) ppm.
Conversion into the HBr salt: The above reaction solution was quenched with 3 cm3 of EtOH and
stirred for 30 min. Then the pH of the solution was adjusted to ꢆ1 using conc. HBr, and the mixture
was stirred for 12 h. The precipitate was collected by filtration and triturated with EtOH. Colorless
crystals; mp 246–250ꢃC (EtOH).
ꢀ
6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (7, C17H21NO3)
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-
To a suspension of 500 mg of 3 (1.60 mmol) in 12cm3 of dry THF 6.0 cm3 of an L-Selectride solution
(1M in THF, 6.0 mmol) were added at 0ꢃC and stirred for 1 h. Then 0.25cm3 of H2O and 1 cm3 of
conc. NH4OH were added and stirred for 10 min. The mixture was concentrated to a volume of 5 cm3,
additional 10 cm3 of conc. NH4OH were added, and the aqueous solution was extracted with 3ꢅ 15cm3
of CH2Cl2. The combined organic layer was washed with 2 ꢅ 10cm3 of 2 N NH4OH, 2 ꢅ 10cm3 of
H2O, and 10 cm3 of brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified
by MPLC (20 g SiO2, CHCl3:MeOH:conc. NH4OH¼ 89:10:1). Yield 440mg of colorless foam (96%);
TLC: CHCl3:MeOH:conc. NH4OH¼ 89:10:1, Rf ¼ 0.4; 1H NMR (200MHz, CDCl3): ꢀ ¼ 6.51 (s, 1H),
6.06 (d, J ¼ 10.2Hz, 1H) , 5.97 (dd, J ¼ 10.2, 4.5Hz, 1H), 4.57 (bs, 1H), 4.27 (d, J ¼ 16.0Hz, 1H),
4.11 (t, J ¼ 4.4 Hz, 1H), 3.80 (s, 3H), 3.77 (d, J ¼ 16.0Hz, 1H), 3.40–3.10 (m, 2H), 2.65 (dd, J ¼ 15.6,
3.2 Hz, 1H), 2.23 (s, 3H), 1.99 (ddd, J ¼ 15.6, 4.9, 2.3 Hz, 1H), 1.89–1.63 (m, 2H) ppm; 13C NMR
(50 MHz, CDCl3): ꢀ ¼ 144.4 (s), 142.9 (s), 133.4 (s), 130.5 (s), 127.8 (s), 127.5 (d), 127.1 (d), 113.5
(d), 88.1 (d), 61.4 (d), 55.8 (q), 49.0 (s), 48.9 (t), 46.9 (t), 39.7 (t), 29.8 (t), 19.4 (q) ppm.
ꢀ
6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (8, C18H23NO3)
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11-dimethyl-
Compound 5 (2.0g, 6.68 mmol) was dissolved in 150 cm3 of boiling MeOH, then 2.50 g of
CeCl3 ꢂ 7H2O (6.68 mmol) were added at 0ꢃC and stirred for 1 h. 0.50g of NaBH4 (13.4 mmol) were
added and stirred at 0–5ꢃC for 2 h. 5 cm3 of 2 N HCl were added, the mixture was concentrated in
vacuo to a volume of 10 cm3, and the residue was diluted with 150 cm3 of H2O. The pH of the solution
was adjusted to >8.5 using conc. NH4OH, and the mixture was extracted with 5 ꢅ 30cm3 of EtOAc.
The combined organic layer was washed with 100cm3 of brine, dried (Na2SO4), filtered, and con-
centrated in vacuo. The residue was purified by MPLC (100g SiO2, CHCl3:MeOH:conc.
NH4OH ¼ 89.5:10:0.5). Yield 1.34 g of colorless oil (67%); TLC: CHCl3:MeOH ¼ 90:10, Rf ¼ 0.2;
1H NMR (200MHz, CDCl3): ꢀ ¼ 6.51 (s, 1H), 6.10 (d, J ¼ 10.2Hz, 1H), 5.79 (d, J ¼ 10.2Hz, 1H),
4.69–4.56 (m, 1H), 4.55 (bs, 1H), 3.96 (d, J ¼ 15.3Hz, 1H), 3.82 (s, 3H), 3.79 (d, J ¼ 15.3Hz, 1H),
3.21 (td, J ¼ 13.1, 1.7 Hz, 1H), 2.97 (dt, J ¼ 14.1, 3.3 Hz, 1H), 2.75 (dddd, J ¼ 14.1, 5.3, 4.0, 1.2Hz,
1H), 2.38 (s, 3H), 2.23 (s, 3H), 2.10 (dd, J ¼ 13.1, 3.2 Hz, 1H), 2.03 (bs, 1H), 1.69 (ddd, J ¼ 13.6, 10.7,
2.6 Hz, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢀ ¼ 145.0 (s), 142.9 (s), 133.5 (s), 131.7 (d), 128.5 (s),
126.7 (d), 126.6 (s), 113.5 (d), 88.3 (d), 63.1 (d), 55.8 (q), 55.2 (t), 54.1 (t), 48.3 (s), 42.6 (q), 34.6 (t),
32.4 (t), 19.5 (q) ppm.
Conversion into the HBr salt: The free base was dissolved in EtOH, treated with conc. HBr, and
stored at ꢁ20ꢃC for 24 h. The precipitate was collected by filtration and triturated with cold EtOH.
Colorless crystals; mp 254–255ꢃC (EtOH).

1282
M. Hemetsberger et al.
ꢀ
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-
methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (10, C17H21NO3)
ꢀ
Method A. Step 1: Preparation of [(ꢄ)-(4aꢁ,6ꢁ,8aR )]-6-Acetyloxy-4a,5,9,10,11,12-hexahydro-
3-methoxy-1-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine (9, C19H23NO4)
To 100 mg of 7 (0.35 mmol) in 12 cm3 of dry toluene a mixture of 0.50 cm3 of N,N-dimethylfor-
mamide-bis(2,2-dimethylpropyl)acetal (1.74 mmol) and 0.10cm3 of AcOH (1.74 mmol) in 2 cm3 of dry
toluene was added at 80ꢃC over a period of 1 h. The mixture was stirred at 80ꢃC for 22 h, cooled to
ambient temperature, and extracted with 2ꢅ 5 cm3 of H2O and 5 ꢅ 10cm3 of 2 N HCl. The pH of the
combined aqueous layer was adjusted to >8.5 using conc. NH4OH, and the mixture was extracted
with 5 ꢅ 10 cm3 of EtOAc. The combined organic layer was washed with 100 cm3 of brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was purified by MPLC (5g SiO2,
1
CHCl3:MeOH ¼ 95:5). Yield 45mg of colorless oil (39%); TLC: CHCl3:MeOH ¼ 95:5, Rf ¼ 0.2; H
NMR (200MHz, CDCl3): ꢀ ¼ 6.50 (s, 1H), 6.14 (d, J ¼ 10.2Hz, 1H), 5.72 (d, J ¼ 10.2Hz, 1H), 5.67–
5.58 (m, 1H), 4.57 (bs, 1H), 4.24 (d, J ¼ 16.0 Hz, 1H), 3.83 (s, 3H), 3.75 (d, J ¼ 16.0Hz, 1H), 3.40–
3.09 (m, 2H), 2.90–2.70 (m, 1H), 2.23 (s, 3H), 2.07 (s, 3H), 2.01–1.73 (m, 3H) ppm; 13C NMR
(50 MHz, CDCl3): ꢀ ¼ 170.2 (s), 145.3 (s), 142.8 (s), 133.0 (s), 130.5 (s), 128.4 (d), 127.2 (d), 127.0
(s), 113.5 (d), 87.3 (d), 66.4 (d), 55.8 (q), 48.8 (s þ t), 47.1 (t), 40.4 (t), 28.2 (t), 21.1 (q), 19.4 (q) ppm.
Step 2: Saponification. 17 mg of 9 (0.05 mmol), 17mg of K2CO3 (0.12 mmol) and 0.1cm3 of 2 N
KOH were stirred in 0.5 cm3 of MeOH at ambient temperature. When complete conversion was
detected by TLC, 1 cm3 of H2O was added, the mixture was concentrated in vacuo to a volume of
1 cm3, and diluted with 4 cm3 of 2 N HCl. The aqueous layer was washed with 3 ꢅ 5 cm3 of EtOAc
(discard), the pH was adjusted to >8.5 using conc. NH4OH, and the mixture was extracted with
5 ꢅ 5 cm3 of EtOAc. The combined organic layer was washed with 10cm3 of brine, dried (Na2SO4),
filtered, and concentrated in vacuo. Yield 10 mg of colorless foam (67%).
Method B. A solution of 0.80g of 8 (2.65 mmol) and 1.50g of bis(1,1-dimethylethyl)azodicarbox-
ylate (6.63 mmol) in 80 cm3 of dry THF was stirred for 24h at ambient temperature. The mixture was
concentrated in vacuo, and the residue was dissolved in 20cm3 of 20% TFA in CH2Cl2, stirred for
30min, and cooled to 0ꢃC. The pH was adjusted to >8.5 using conc. NH4OH, and the mixture was
extracted with 5 ꢅ 5 cm3 of CH2Cl2. The combined organic layer was washed with 10cm3 of brine,
dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by MPLC (30 g SiO2,
CHCl3:MeOH ¼ 90:10). Yield 400 mg of colorless oil (53%); CHCl3:MeOH ¼ 95:5, Rf ¼ 0.1; 1H NMR
(200 MHz, CDCl3): ꢀ ¼ 6.50 (s, 1H), 6.08 (d, J ¼ 10.3Hz, 1H), 5.80 (d, J ¼ 10.3Hz, 1H), 4.70–4.62
(m, 1H), 4.57 (bs, 1H), 4.26 (d, J ¼ 15.7Hz, 1H), 3.83 (s, 3H), 3.75 (d, J ¼ 15.7Hz, 1H), 3.35–3.20 (m,
1H), 2.85–2.70 (m, 1H), 2.50–2.29 (m, 2H), 2.23 (s, 3H), 2.00–1.64 (m, 2H) ppm; 13C NMR (50 MHz,
CDCl3): ꢀ ¼ 145.4 (s), 142.9 (s), 133.5 (s), 131.6 (d), 130.7 (s), 127.2 (d), 126.8 (s), 113.3 (d), 88.2 (d),
63.1 (d), 55.9 (q), 48.9 (t), 48.8 (s), 47.2 (t), 32.2 (t), 28.2 (t), 19.5 (q) ppm.
General Procedure for the Preparation of N-Substituted Compounds 11a–11d
200 mg of 7 (0.70 mmol), 195 mg of K2CO3 (1.40 mmol), and 115 mg of NaI (0.77 mmol) were freshly
ground and stirred under reflux with 1.2 equiv of alkylating agent in 5 cm3=100 mg of dry acetone. The
conversion was monitored by TLC. Then the mixture was concentrated in vacuo, and the residue was
dissolved in 2 N HCl and washed with 2 ꢅ 25cm3 of EtOAc (discard). The pH of the aqueous solution
was adjusted to >8.5 using conc. NH4OH, and the mixture was extracted with 5 ꢅ 25cm3 of EtOAc.
The combined organic layer was washed with 50 cm3 of brine, dried (Na2SO4), filtered, and concen-
trated in vacuo. The residue was purified by MPLC (SiO2, CHCl3:MeOH:conc. NH4OH ¼ 89:10:1).
ꢀ
(2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (11a, C20H25NO3)
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-
Reagent 0.07 cm3 of 1-bromo-2-propene (0.84 mmol); reaction time 10h. Yield 50mg of colorless
1
foam (22%); TLC: CHCl3:MeOH:conc. NH4OH¼ 89:10:1, Rf ¼ 0.2; H NMR (200MHz, CDCl3):

1-Methylgalanthamine Derivatives
1283
ꢀ ¼ 6.52 (s, 1H), 6.12 (d, J ¼ 10.3Hz, 1H), 6.03–5.78 (m, 2H), 5.18 (bs, 1H), 5.11 (d, J ¼ 4.5 Hz, 1H),
4.57 (bs, 1H), 4.12 (bs, 1H), 4.09 (d, J ¼ 15.0Hz, 1H), 3.81 (s, 3H), 3.78 (d, J ¼ 15.0Hz, 1H), 3.32–
3.02 (m, 4H), 2.72–2.58 (m, 1H), 2.21 (s, 3H), 2.07–1.89 (m, 2H), 1.57 (ddd, J ¼ 13.7, 3.4, 2.7 Hz, 1H)
ppm; 13C NMR (50 MHz, CDCl3): ꢀ ¼ 144.0 (s), 143.0 (s), 136.0 (d), 133.6 (s), 129.1 (s), 127.4 (d),
127.2 (d), 126.9 (s), 117.5 (t), 113.7 (d), 88.4 (d), 62.0 (d), 57.2 (t), 55.8 (q), 52.9 (t), 52.0 (t), 48.4 (s),
33.9 (t), 29.8 (t), 19.4 (q) ppm.
ꢀ
(phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (11b, C24H27NO3)
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-
Reagent 0.1 cm3 of benzyl bromide (0.84 mmol); reaction time 24 h. Yield 140mg of colorless foam
(53%); TLC: CHCl3:MeOH:conc. NH4OH¼ 89:10:1; Rf ¼ 0.4; 1H NMR (200MHz, CDCl3): ꢀ ¼ 7.30
(m, 5H), 6.50 (s, 1H), 6.16 (d, J ¼ 10.2Hz, 1H), 5.99 (dd, J ¼ 10.2, 4.9Hz, 1H), 4.61 (bs, 1H), 4.13
(bs, 1H), 4.00 (d, J ¼ 15.7Hz, 1H), 3.82 (s, 3H), 3.81 (d, J ¼ 15.7Hz, 1H), 3.69 (s, 2H), 3.34 (ddd,
J ¼ 14.1, 12.4, 1.8 Hz, 1H), 3.13 (td, J ¼ 14.1, 3.5Hz, 1H), 2.74–2.37 (m, 2H), 2.19–1.93 (m, 2H),
1.90 (s, 3H), 1.57 (dt, J ¼ 13.7, 3.0 Hz, 1H) ppm; 13C NMR (50 MHz, CDCl3): ꢀ ¼ 143.9 (s), 143.0
(s), 138.9 (s), 133.6 (s), 129.2 (s), 128.7 (d), 128.2 (d), 127.4 (d), 127.3 (d), 127.2 (s), 126.9 (d),
113.7 (d), 88.4 (d), 62.0 (d), 57.4 (t), 55.8 (q), 52.4 (t), 52.2 (t), 48.5 (s), 33.7 (t), 29.8 (t), 19.1 (q)
ppm.
ꢀ
[2-(4-morpholinyl)ethyl]-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (11c, C23H32N2O4)
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-
Reagent 155 mg of 4-(2-chloroethyl)morpholine ꢂ HCl (0.84 mmol); reaction time 24h. Yield 210 mg
of colorless foam (75%); TLC: CHCl3:MeOH:conc. NH4OH ¼ 89:10:1, Rf ¼ 0.5; 1H NMR (200 MHz,
CDCl3): ꢀ ¼ 6.52 (s, 1H), 6.10 (d, J ¼ 10.3Hz, 1H), 5.97 (dd, J ¼ 10.3, 4.8 Hz, 1H), 4.55 (bs, 1H), 4.13
(bs, 1H), 4.12 (d, J ¼ 15.9 Hz, 1H), 3.88 (d, J ¼ 15.9 Hz, 1H), 3.81 (s, 3H), 3.75–3.65 (m, 4H), 3.30
(ddd, J ¼ 14.3, 12.4, 2.0 Hz, 1H), 3.10 (dt, J ¼ 14.3, 3.3 Hz, 1H), 2.76–2.58 (m, 4H), 2.55–2.41 (m,
5H), 2.25 (s, 3H), 2.08–1.90 (m, 2H), 1.55 (dd, J ¼ 13.7, 2.8Hz, 1H) ppm; 13C NMR (50 MHz,
CDCl3): ꢀ ¼ 144.1 (s), 143.0 (s), 133.5 (s), 128.9 (s), 127.4 (d), 127.1 (d), 126.9 (s), 113.7 (d), 88.4
(d), 66.7 (2t), 66.6 (t), 61.9 (d), 57.1 (t), 55.8 (q), 54.0 (2t), 53.4 (t), 52.0 (t), 48.4 (s), 33.4 (t), 29.8 (t),
19.4 (q) ppm.
ꢀ
piperidinyl)propyl]-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (11d, C25H36N2O3)
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-[3-(1-
Reagent 166 mg of 1-(3-chloropropyl)piperidineꢂ HCl (0.84 mmol); reaction time 24h. Yield 180 mg
of colorless foam (63%); TLC: CHCl3:MeOH:conc. NH4OH ¼ 89:10:1, Rf ¼ 0.3; 1H NMR (200 MHz,
CDCl3): ꢀ ¼ 6.52 (s, 1H), 6.10 (d, J ¼ 10.4Hz, 1H), 5.96 (dd, J ¼ 10.4, 4.7 Hz, 1H), 4.55 (bs, 1H), 4.12
(bs, 1H), 4.08 (d, J ¼ 15.7 Hz, 1H), 3.83 (d, J ¼ 15.7Hz, 1H), 3.81 (s, 3H), 3.24 (ddd, J ¼ 14.2, 12.2,
2.0 Hz, 1H), 3.07 (dt, J ¼ 14.2, 3.5 Hz, 1H), 2.71–2.13 (m, 10H), 2.24 (s, 3H), 2.07–1.88 (m, 2H),
1.77–1.35 (m, 9H) ppm; 13C NMR (50 MHz, CDCl3): ꢀ ¼ 144.0 (s), 142.9 (s), 133.5 (s), 128.9 (s),
127.3 (2d), 127.2 (s), 113.7 (d), 88.4 (d), 62.0 (d), 57.2 (t), 55.8 (q), 54.5 (3t), 53.3 (t), 51.4 (t), 48.5 (s),
33.4 (t), 29.8 (t), 25.7 (2t), 25.0 (t), 24.2 (t), 19.5 (q) ppm.
ꢀ
piperidinyl)propyl)-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol (12, C25H36N2O3)
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-[3-(1-
This compound was prepared following the general procedure given for the synthesis of compounds
11a–11d. Reagents100 mgof10(0.35 mmol), 83mgof1-(3-chloropropyl)piperidineꢂ HCl(0.42 mmol);
reaction time 28h. Yield 60 mg of colorless oil (42%); TLC: CHCl3:MeOH ¼ 90:10, Rf ¼ 0.1;

1284
M. Hemetsberger et al.
1H NMR (200MHz, CDCl3): ꢀ ¼ 6.50 (s, 1H), 6.10 (d, J ¼ 10.2Hz, 1H), 5.78 (dd, J ¼ 10.2, 1H),
4.70–4.57 (m, 1H), 4.54 (bs, 1H), 4.05 (d, J ¼ 15.2Hz, 1H), 3.82 (d, J ¼ 15.2Hz, 1H), 3.82 (s, 3H),
3.25 (ddd, J ¼ 13.5, 12.8, 1.6 Hz, 1H), 3.09 (dt, J ¼ 13.5, 2.5Hz, 1H), 2.75 (dt, J ¼ 13.7, 4.1Hz, 1H),
2.56–2.27 (m, 8H), 2.23 (s, 3H), 2.08 (td, J ¼ 13.1, 4.0, 2H), 1.81–1.38 (m, 9H) ppm; 13C NMR
(50 MHz, CDCl3): ꢀ ¼ 144.9 (s), 142.7 (s), 133.4 (s), 131.3 (s), 128.3 (2d), 127.0 (s), 113.3 (d), 88.1
(d), 63.0 (d), 57.2 (t), 55.7 (q), 54.4 (3t), 53.1 (t), 51.6 (t), 48.4 (s), 33.1 (t), 29.5 (t), 25.6 (2t), 24.8 (t),
24.1 (t), 19.5 (q) ppm.
General Procedure for the Preparation of Quarternary Ammonium Salts 13a–14f
The tertiary amine was dissolved in a minimum amount of dry DMF, then the alkylating agent was
added and stirred at elevated temperature. The conversion was monitored via TLC. The mixture was
slowly poured into Et2O, the precipitate was collected by filtration and washed with Et2O. The crude
product was dissolved in EtOH and precipitated using EtOAc.
ꢀ
1,11-dimethyl-11-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-
chloride (13a, C22H30ClNO3)
Amine 280 mg of 6 (0.94 mmol); reagent 0.30 cm3 of 1-chloro-2-methylprop-2-ene (3.08 mmol);
reaction conditions 2 h, 70ꢃC. Yield 270 mg of colorless crystals (73%); mp 239–241ꢃC; 13C NMR
(50 MHz, DMSO-d6): ꢀ ¼ 144.6 (s), 134.2 (s), 133.5 (s), 131.1 (s), 130.9 (d), 127.5 (t), 124.9 (d), 115.9
(s), 114.4 (d), 86.3 (d), 73.0 (t), 60.8 (t), 59.4 (d), 55.5 (q), 46.3 (s), 43.0 (q), 31.1 (t), 23.8 (q), 18.9 (q)
ppm.
ꢀ
1,11-dimethyl-11-(2-propinyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium bromide
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-
(13b, C21H26BrNO3)
Amine 350 mg of 6 (1.16 mmol); reagent 0.13cm3 of 3-bromo-1-propine (1.16 mmol); reaction con-
ditions 19 h, 60ꢃC. Yield 300 mg of colorless crystals (62%); mp 216–218ꢃC; 13C NMR (50 MHz,
DMSO-d6): ꢀ ¼ 144.8 (s), 144.7 (s), 133.4 (s), 131.0 (s), 125.2 (d), 115.3 (s), 114.5 (d), 86.2 (d), 83.7
(d), 72.6 (t), 60.6 (t), 59.7 (d), 55.6 (q), 46.2 (s), 43.0 (q), 31.0 (t), 18.8 (q) ppm.
ꢀ
dimethyl-11-(phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium bromide
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-
(13c, C25H30BrNO3)
Amine 240 mg of 6 (0.80 mmol); reagent 0.25cm3 of benzyl bromide (1.00 mmol); reaction conditions
10min, 60ꢃC. Yield 262 mg of colorless crystals (69%); mp 246–248ꢃC; 13C NMR (50 MHz, DMSO-
d6): ꢀ ¼ 144.7 (s), 133.4 (d), 130.7 (s), 130.4 (d), 129.0 (d), 128.1 (s), 114.5 (d), 86.3 (d), 59.7 (t), 59.5
(d), 55.6 (q), 46.2 (s), 18.6 (q) ppm.
ꢀ
trimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium iodide (13d, C19H26INO3)
[(ꢄ)-(4aꢁ,6ꢂ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11,11-
Amine 140 mg of 6 (0.46 mmol); reagent 200 mg of methyl iodide (1.40 mmol); reaction conditions
1.5 h, 40ꢃC. Yield 146 mg of colorless crystals (71%); mp 278–280ꢃC; 13C NMR (50 MHz, DMSO-d6):
ꢀ ¼ 144.6 (s), 144.1 (s), 132.8 (s), 131.6 (s), 114.2 (d), 86.3 (d), 62.6 (t), 59.5 (d), 55.4 (q), 45.9 (s),
31.0 (t), 18.4 (q) ppm.

1-Methylgalanthamine Derivatives
1285
ꢀ
dimethyl-11-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-
chloride (14a, C22H30ClNO3)
Amine 150 mg of 8 (0.50 mmol); reagent 45 mg of 1-chloro-2-methylprop-2-ene (1.50 mmol); reaction
conditions 10 min, 70ꢃC. Yield 160 mg of colorless crystals (82%); mp 162–164ꢃC; 13C NMR (50 MHz,
DMSO-d6): ꢀ ¼ 144.7 (s), 134.2 (s), 134.1 (s), 131.1 (d), 127.5 (t), 114.4 (d), 87.3 (d), 73.0 (t),
60.7 (d), 59.4 (t), 55.6 (q), 46.3 (s), 23.8 (q), 18.9 (q) ppm.
ꢀ
dimethyl-11-(2-propinyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium bromide
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-
(14b, C21H26BrNO3)
Amine 150 mg of 8 (0.50 mmol); reagent 180mg of 3-brom-1-propine (1.50 mmol); reaction condi-
tions 2.5 h, 70ꢃC. Yield 167 mg of colorless crystals (82%); mp 158–162ꢃC; 13C NMR (50 MHz,
DMSO-d6): ꢀ ¼ 144.8 (s), 133.9 (s), 131.2 (s), 114.5 (d), 87.2 (d), 83.7 (d), 72.6 (d), 55.6 (q), 46.3 (s),
31.9 (t), 18.8 (q) ppm.
ꢀ
(phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium bromide (14c, C25H30BrNO3)
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-
Amine 153 mg of 8 (0.51 mmol); reagent 92 mg of benzyl bromide (0.51 mmol); reaction conditions
3 h, 70ꢃC. Yield 150 mg of colorless crystals (63%); mp 169–175ꢃC; 13C NMR (50 MHz, DMSO-d6):
ꢀ ¼ 144.6 (s), 134.1 (s), 133.4 (d), 131.0 (s), 130.4 (d), 128.9 (d), 128.1 (s), 114.4 (d), 87.2 (d), 61.8 (d),
59.4 (t), 55.6 (q), 46.3 (s), 31.5 (t), 18.6 (q) ppm.
ꢀ
trimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium iodide (14d, C19H26INO3)
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11,11-
Amine 210 mg of 8 (0.70 mmol); reagent 290 mg of methyl iodide (2.10 mmol); reaction conditions
2 h, 40ꢃC. Yield 240 mg of colorless crystals (77%); mp 280ꢃC (decomp); 13C NMR (50 MHz, DMSO-
d6): ꢀ ¼ 144.7 (s), 133.6 (s), 131.1 (s), 114.4 (d), 87.1 (d), 62.2 (t), 60.7 (q), 55.5 (q), 48.4 (d), 46.2 (s),
31.5 (t), 18.9 (q) ppm.
ꢀ
11-(2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium bromide (14e, C21H28BrNO3)
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-
Amine 150 mg of 8 (0.50 mmol); reagent 0.13 cm3 of 3-bromo-1-propene (1.50 mmol); reaction con-
ditions 2 h, 60ꢃC. Yield 150 mg of colorless crystals (64%); mp 140–145ꢃC; 13C NMR (50 MHz,
DMSO-d6): ꢀ ¼ 144.7 (s), 134.5 (d), 134.0 (s), 131.1 (s), 128.3 (s), 126.1 (d), 115. 3 (d), 114.4 (d), 87.2
(d), 60.7 (d), 59.8 (t), 55.6 (q), 46.3 (s), 31.5 (t), 18.8 (q) ppm.
ꢀ
11-(4-(trifluoromethyl)phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium bromide
[(ꢄ)-(4aꢁ,6ꢁ,8aR )]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-
(14f, C26H29BrF3NO3)
Amine 150 mg of 8 (0.50 mmol); reagent 357 mg of 4-(trifluoromethyl)benzylbromide (1.50 mmol);
reaction conditions 1 h, 70ꢃC. Yield 140 mg of colorless crystals (53%); mp 178–182ꢃC; 13C NMR
(50 MHz, DMSO-d6): ꢀ ¼ 144.8 (s), 134.4 (d þ d), 134.2 (d), 132.6 (s), 131.2 (s), 130.9 (s), 130.3 (s),
126.6 (d), 125.8 (s), 121.2 (d), 114.5 (d), 87.3 (d), 60.8 (d), 55.6 (q), 46.3 (s), 34.3 (t), 18.7 (q)
ppm.

1286
M. Hemetsberger et al.
X-Ray Structure Determinations of 5 and 6 ꢂ HBr
Crystal data of 5: C18H21NO3, Mr ¼ 299.36, colorless block of 0.80ꢅ 0.52 ꢅ 0.22mm from
˚
˚
CHCl3=MeOH, monoclinic, space group P21=n (no. 14), a ¼ 11.591(2) A, b ¼ 9.925(2) A, c ¼
3
3
ꢃ
˚
˚
˚
13.267(3) A, ꢂ ¼ 92.11(1) , V ¼ 1525.2(5) A , Z ¼ 4, Dx ¼ 1.304Mg=m , ꢃ(Mo-Kꢁ) ¼ 0.71073A,
m ¼ 0.088 mmꢁ1, T ¼ 300(2) K. X-Ray data collection with a Bruker SMART CCD area detector
diffractometer and graphite monochromatized Mo-Kꢁ radiation. 19740 reflections with ꢄ<27.5ꢃ were
measured, corrected for absorption, and merged to 3470 unique reflections, Rint ¼ 0.027. Structure
solved with direct methods, structure refinement on F2 using program SHELXL97. All non-hydrogen
atoms were refined anisotropically. Hydrogen atoms had isotropic temperature factors and rided on the
atoms to which they were bonded. The final refinement varied 204 parameters and converged at
2
2
2
1=2
2
2
R1 ¼ SjjFoj ꢁ jFcjj=SjFoj ¼ 0:052, wR2 ¼ ½SðwðFo ꢁ Fc Þ Þ=SðwðFo Þ Þꢇ ¼ 0:121, and S ¼
1.04 for the 3470 unique reflections; R1 ¼ 0.040 for the 2767 observed data [I>2ꢅ(I)].
The molecular structure of 5 in crystalline state is shown in Fig. 1. The compound differs from
racemic narwedine mainly in two respects. It does not crystallize spontaneously in a chiral space group
(P212121 in case of narwedine [12]), and the methoxy group adopts an unusual orientation being
approximately syn-oriented to O1 (torsion angle C2–C3–O2–C16 ¼ 36.4ꢃ, Fig. 1).
Crystal data of 6 ꢂ HBr: C18H24BrNO3, Mr ¼ 382.29, colorless prism of 0.26 ꢅ 0.10ꢅ 0.06 mm
˚
˚
from 96% ethanol, orthorhombic, space group P212121 (no. 19), a ¼ 7.499(2) A, b ¼ 14.395(4) A, c ¼
3
3
ꢁ1
˚
˚
˚
15.937(4) A, V ¼ 1720.4(8) A , Z ¼ 4, Dx ¼ 1.476Mg=m , ꢃ(Mo-Kꢁ) ¼ 0.71073 A, ꢆ ¼ 2.404mm
,
T ¼ 300(2) K. X-Ray data collection with a Bruker SMART CCD area detector diffractometer and
graphite monochromatized Mo-Kꢁ radiation. 14235 reflections with ꢄ<25.0ꢃ were measured,
corrected for LP and absorption, and merged to 3021 unique reflections, Rint ¼ 0.056 [9]. Structure
solved with direct methods, structure refinement on F2 using program SHELXL97 [10]. All non-
hydrogen atoms were refined anisotropically. Hydrogen atoms had isotropic temperature factors, the OH
and NH hydrogen atoms were refined without restraints, all other hydrogen atoms rided on the atoms
to which they were bonded. The absolute structure was determined via a highly significant Flack
parameter of ꢁ0.014(12) and showed that the molecules of 6 in the investigated crystal corresponded
to (ꢁ)-galanthamine [8] in configuration. The final refinement varied 220 parameters and converged
2
2
2
1=2
2
2
at R1 ¼ SjjFoj ꢁ jFcjj=SjFoj ¼ 0:061, wR2 ¼ ½SðwðFo ꢁ Fc Þ Þ=SðwðFo Þ Þꢇ ¼ 0:074, and S ¼
1.03 for the 3021 unique reflections; R1 ¼ 0.037 for the 2351 observed data [I>2ꢅ(I)] [11].
The asymmetric unit of 6 ꢂ HBr is shown in Fig. 1. The compound turned out to be practically
isostructural with (ꢁ)-galanthamine hydrobromide [8] (Fig. 2). Corresponding atom positions of the
˚
two structures differ on the average only by 0.30A and the differences can be attributed to the extra
space requirement of the additional CH3 group in 6 ꢂ HBr.
References
[1] Raskind MA, Peskind ER, Wessel T, Yuan W, Allen FH, Aronson SM, Baumel B, Eisner L,
Brenner R, Cheren S, Verma S, Daniel DG, DePriest M, Ferguson JM, England D, Farmer MV,
Frey J, Flitman SS, Harrell LE, Holub R, Jacobson A, Olivera GF, Ownby RL, Jenkyn LR,
Landbloom R, Leibowitz MT, Zolnouni PP, Lyketosos C, Mintzer JE, Nakra R, Pahl JJ, Potkin
SG, Richardson BC, Richter RW, Rymer MM, Saur DP, Daffner KR, Scinto L, Stoukides J,
Targum SD, Thein SG, Thien SG, Tomlinson JR (2000) Neurology 54: 2261
[2] Moghul S, Wilkinson D (2001) Expert Review of Neurotherapeutics 1: 61
[3] Bores GM, Kosley RW (1996) Drugs Future 21: 621
[4] Kueenburg B, Czollner L, Froehlich J, Jordis U (1999) Org Process Res Dev 3: 425
[5] Czollner L, Treu M, Froehlich J, Kueenburg B, Jordis U (2001) Arkivoc 2001 (i): 191
[6] Scarpati ML, Bianco A, Mascitelli L, Passacantilli P (1990) Synth Commun 20: 2565
[7] Jacques J, Collet A, Wilen SH (1994) Enantiomers, Racemates, and Resolutions. Krieger
Publishing, Malabar, FL

1-Methylgalanthamine Derivatives
1287
[8] Peeters OM, Baton NM, De Ranter CJ (1997) Acta Crystallogr Sect C 53: 1284
[9] Bruker AXS: Programs SMART, v 5.054; SAINT, v 6.2.9; SADABS v 2.03; XPREP, v 5.1;
SHELXTL, v 5.1. Bruker AXS Inc, Madison, WI, USA, 2001
[10] Sheldrick GM (1997) SHELX97. Program system for crystal structure determination. University
€
of Gottingen, Germany
[11] CCDC 185482 and 185483 contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk=conts=retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ 44 1223 336033; e-mail: deposit@
ccdc.cam.ac.uk)
[12] Unpublished crystallographic data of (ꢁ)-narwedine: C17H19NO3, Mr ¼ 285.33, ortho-
˚
˚
˚
rhombic, space group P212121 (no. 19), a ¼ 9.659(2) A, b ¼ 10.184(2) A, c ¼ 15.061(3) A, V ¼
3
3
1481.5(5) A , Z ¼ 4, Dx ¼ 1.279 Mg=m , ꢃ(Mo-Kꢁ) ¼ 0.71073 A, ꢆ ¼ 0.088 mmꢁ1, T ¼ 297(2)
˚
˚
K, R1 ¼ 0.0524, wR2 ¼ 0.1054 (all 4291 data)