Galanthamine analogs: 6H-benzofuro[3a,3,2,-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine

Article abstract of DOI:10.1016/j.tet.2005.05.055

The known cholinesterase inhibitory capability of the Amarylidaceae alkaloid galanthamine prompted preparation of analogs in which the position of the nitrogen within the azepine ring is altered. The analogs 6H-benzofuro[3a,3,2-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3] benzazepine were prepared in 19 and 2.5%, respectively, following Kametani and Shimizu approaches, respectively. The aniline derivative 6H-benzofuro[3a,3,2-e, f][1]benzazepine failed to undergo most of the reactions typical for galanthamine. Thus, it neither oxidized to the analogous narwedine, nor epimerized to the analogous epigalanthamine, nor reduced to the lycoramine analog, under the conditions used for galanthamine.

Full text of DOI:10.1016/j.tet.2005.05.055

Tetrahedron 61 (2005) 7144–7152
Galanthamine analogs: 6H-benzofuro[3a,3,2,-e,f][1]benzazepine
and 6H-benzofuro[3a,3,2-e,f][3]benzazepine
*
Anita H. Lewin, Jerzy Szewczyk, Joseph W. Wilson and F. Ivy Carroll
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, North Carolina 27709-2194, USA
Received 27 August 2004; revised 4 May 2005; accepted 16 May 2005
Available online 13 June 2005
Abstract—The known cholinesterase inhibitory capability of the Amarylidaceae alkaloid galanthamine prompted preparation of analogs
in which the position of the nitrogen within the azepine ring is altered. The analogs 6H-benzofuro[3a,3,2-e,f][1]benzazepine and
6H-benzofuro[3a,3,2-e,f][3]benzazepine were prepared in 19 and 2.5%, respectively, following Kametani and Shimizu approaches,
respectively. The aniline derivative 6H-benzofuro[3a,3,2-e,f][1]benzazepine failed to undergo most of the reactions typical for galanthamine.
Thus, it neither oxidized to the analogous narwedine, nor epimerized to the analogous epigalanthamine, nor reduced to the lycoramine
analog, under the conditions used for galanthamine.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The Amarylidaceae alkaloid galanthamine (1), available in
the form of its hydrobromide salt as the drug Nivalin, has
been identified as a cholinesterase inhibitor. It is widely
used in Europe, especially in neuromuscular diseases such
as myasthenia gravis,4 as well as in antagonism of skeletal
neuromuscular blockade (e.g., by curare),2 drug-induced
respiratory depression (e.g., by narcotics)3 and central anti-
cholinergic effect induced by scopolamine.15 The positive
results obtained by the use of Nivalin to treat patients
suffering from Alzheimer’s dementia5 have prompted the
2. Results
suggestion that galanthamine (1) and/or its congeners may
be active in the treatment of this disorder. As part of a
Our preparation of the [1]benzazepine 2 followed the classic
program directed towards the preparation of analogs of 1
Kametani synthesis of galanthamine,6 utilizing the oxi-
the synthesis of compounds in which the position of the
dative cyclization of the bromo-protected bisphenol 13
azepine nitrogen is altered was targeted. Thus, the
(Scheme 1). The acid chloride 8 and the aniline 12, both
syntheses of the [1]benzazepine analog 2 and of the
required for preparation of the precursor to 13, were
[3]benzazepine analog 3 were undertaken. The recent
publication9 of the synthesis of 3 prompts us to report our
results for 2 and 3.
prepared as follows. Starting from commercially available
p-hydroxyphenylpropionic acid (4) the benzyl protected
analog (7) was prepared by esterification of 4 with
methanolic hydrochloric acid to give the methyl ester 5
(in 95% yield) followed by benzylation to give 6 (in 92%
yield) and saponification (90% yield). Treatment of 7 with
thionyl chloride afforded the required acid chloride 8 in
quantitative yield. Synthesis of the aniline 12 was
accomplished by formylation of commercially available
3-hydroxy-4-methoxyaniline (9) with ethyl formate (85%
Keywords: Galanthamine; 6H-Benzofuro[3a,3,2-e,f][1]benzazepine; 6H-
yield) to give the formanilide 10 and O-protection by
Benzofuro[3a,3,2-e,f][3]; Kametani synthesis; Shimizu synthesis.
benzylation with benzyl bromide to afford 11 in 85% yield.
Bromination of 11 with N-bromoacetamide in chloroform
*
Corresponding author. Tel.: C1 919 541 6691; fax: C1 919 541 8868;
e-mail: ahl@rti.org
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.055

A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
7145
Scheme 1.
and reduction with diborane provided the required
N-methyl-5-benzyloxy-2-bromo-4-methoxyaniline (12).
Coupling of the acid chloride 8 with the aniline 12, followed
by debenzylation with hydrobromic acid, gave the bisphenol
13 required for cyclization in 81% yield. Oxidative
cyclization by potassium ferricyanide gave the narwedine-
type bromoamide 14 in 50% yield. Reduction of 14 with
lithium aluminum hydride effected both reduction of the
keto and amide groups to give the galanthamine analog 2 in
59% yield; it was accompanied by the epimeric alcohol 15
(7% yield). The overall yield from commercially available
starting materials was 18.9%.
Attempts to prepare the [3]benzazepine 3 following an
analogous route (Scheme 2) or following our improved
protocol for the preparation of galanthamine12 (Scheme 3)
were unsuccessful. Thus, treatment of either bisphenol 16 or
bisphenol 17 with potassium ferricyanide led to rapid
consumption of the starting material and formation of
multiple products; none was formed in quantities justifying

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A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
Scheme 2.
isolation and identification. Use of the dibrominated
bisphenol intermediate in our modified13 Shimizu syn-
thesis10 (Scheme 4) afforded the product 3 in 11% yield. The
oxidative cyclization precursor 25 was obtained by
formylation (46% yield) of the product obtained from
reductive amination of 3-bromo-4-hydroxybenzaldehyde
(24)7 (prepared in 83% yield by bromination of commer-
cially available 4-hydroxybenzaldehyde 23) with 2-bromo-
5-hydroxy-4-methoxyphenethylamine (22). The latter1 was
prepared by bromination of commercially available
3-hydroxy-4-methoxyphenylacetic acid (18) to afford the
known11 2-bromo-5-hydroxy-4-methoxphenylacetic acid 19
(96% yield), followed by esterification and in situ conver-
sion to the amide 21 (82% yield) and borane reduction (93%
yield). The overall yield of 3 from commercially available
starting materials was only 2.5%.
3. Discussion
We had previously determined that the yield in the oxidative
cyclization step in the synthesis of galanthamine could be
substantially improved by enhancing both the chloroform
solubility and the steric hindrance to chelation of the

A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
7147
Scheme 3.
oxidative cyclization substrate.13 A further example of the
important role of molecular distribution properties is
provided by comparison of our results to those of Poschalko
et al.9 Thus, while we were unable to isolate any meaningful
amounts of cyclized product by attempted oxidation of the
precursor 17 in chloroform, the cyclization product was
obtained in 19–25% yield when the reaction was carried out
in toluene.9 Moreover, whereas the galanthamine precursor,
1,7-dibromo-N-formyl-N-nornarwedine had been obtained
in 38–43% yield from the dibromo bisphenol,13 the
analogous 10-aza-compound 26, the precursor of the
[3]benzazepine analog 3, was obtained in only 11%. Thus,
although the oxidative cyclization process has been
successfully applied to the synthesis of carbocyclic
galanthamine analogs,14 the results of our preparation of 2
and 3 confirm that this cyclization is highly sensitive to
molecular features.
analog 32 could not be carried out under the conditions used
to convert galanthamine (1) to lycoramine due to the
insolubility of 2 in ethanol. Attempted hydrogenation of
the hydrochloride salt of 2 in ethanol produced
6-desoxylycoramine (33), presumably by catalytic hydro-
genation of the diene 31 formed by the reaction of 2 with
hydrochloric acid (Scheme 5). The lycoramine analog 32
was successfully prepared by hydrogenation of 2 in
tetrahydrofuran; 33 was a byproduct (Scheme 6).
4. Conclusion
Oxidative cyclization has been utilized to prepare the [1]-
and [3]benzazepine analogs of galanthamine, 2 and 3,
respectively. Despite the general structural similarity of 2, 3,
and galanthamine (1), these compounds differ greatly in the
reaction yields associated with the oxidative cyclization
reaction as well as in their chemical reactivity.
Altering the position of the nitrogen atom has striking
effects on reactivity. Specifically, attempts to oxidize 2 to
the narwedine analog 29 using manganese dioxide produced
only minute amounts of 29 (Scheme 5), although treatment
of galanthamine (1) afforded narwedine in 87% yield under
the same conditions (unpublished results). Similarly,
attempted epimerization of 2 to 30 (Scheme 5), under
conditions that had been used successfully to convert
galanthamine (1) to epigalanthamine failed; 1H NMR (data
not shown) suggested that the reaction product was the
diene 31 (Scheme 5). The instability of this material
precluded characterization. Preparation of the lycoramine
5. Experimental
5.1. General
Melting points were determined on a Koffler hot stage.
Proton magnetic resonance spectra were obtained on either a
Bruker WM250 or a Varian EM390 spectrometer. Chemical
shifts are relative to internal tetramethylsilane. Mass
Spectra were recorded on an Applied Biosystems, Sciex

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A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
Scheme 4.
API single quadrupole mass spectrometer using atmos-
pheric pressure chemical ionization.
methyl ester (5) (36 g, 0.2 mol) in DMF (distilled, 275 mL)
was added K2CO3 (165 g) followed by benzyl chloride
(26 mL). After stirring for 18 h at 120 8C, this mixture was
poured into ice-water (1500 mL) and concentrated HCl was
added to pH 1. The solid product was removed by filtration
and dried under vacuum to give 49.7 g (92% yield) of white
5.1.1. 3-(4-Hydroxyphenyl)propionic acid methyl ester
(5). After 3 h at ambient temperature a solution of 3-(4-
hydroxyphenyl)propionic acid (4) (50 g, 0.3 mol) in 5%
methanolic HCl (500 mL) was evaporated, and the residue
was dissolved in EtOAc (300 mL). The solution was washed
with saturated aqueous NaHCO3, dried over MgSO4 and
1
crystals: H NMR (250 MHz, CDCl3) d (ppm): 2.56–2.83
(AA0BB0, JABZ7.5 Hz, JAB Z7.5, 4 Hz, CH2CH2), 3.62 (s,
0
3, COOCH3), 4.98 (s, 2, OCH2), 6.86, 7.07 (AA0BB0, JAB
Z
1
0
8.5 Hz, JAB Z2.5, 4 Hz, ArH), 7.2–7.43 (m, 5, Ph). Anal.
Calcd for C17H18O3: C, 75.56; H, 6.67. Found: C, 75.50; H,
6.74.
evaporated, giving a yellow oil (51.3 g, 95% yield): H
NMR (250 MHz, CDCl3) d (ppm): 2.55, 2.74 (AA0BB0,
0
JABZJAB Z4 Hz, CH2CH2), 3.60 (s, 3, COOCH3), 6.67,
7.00 (AA0BB0, JABZ7.2 Hz, JAB Z2.8, 4 Hz, ArH), 9.18 (s,
1, OH). Anal. Calcd for C10H12O3: C, 66.67; H, 6.67.
Found: C, 66.55; H, 6.75.
0
5.1.3. 3-(4-Benzyloxyphenyl)propionic acid (7). To a
suspension of 3-(4-benzyloxyphenyl)propionic acid methyl
ester (6) (54 g, 0.2 mol) in MeOH (500 mL) was added
0.4 N KOH (1 L), and the mixture was stirred at 60 8C until
TLC showed the saponification to be complete. The volatile
5.1.2. 3-(4-Benzyloxyphenyl)propionic acid methyl ester
(6). To a solution of 3-(4-hydroxyphenyl)propionic acid

A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
7149
5.1.5. 3-Benzloxy-4-methoxyformanilide (11). To a
mixture of 3-hydroxy-4-methoxyformanilide (10) (16.7 g,
0.1 mmol) and K2CO3 (75 g) in DMF (100 mL) was added
benzyl chloride (12 mL, 0.107 mol), and the mixture was
stirred for 8 h at 120 8C. After cooling to room temperature,
the reaction mixture was poured into ice-water, the pH was
adjusted to 1 with concentrated HCl and the resultant solid
was collected by filtration. After drying the brown powder
1
weighed 21 g (82% yield): H NMR (250 MHz, CDCl3)
exhibits the presence of two amide rotamers d (ppm): 3.81,
3.84 (2s, 3, OCH3), 5.06, 5.10 (2s, 2, OCH2), 6.50–6.70 (m,
3, ArH), 7.20–7.38 (m, 5, Ph), 7.40, 8.17 (br s, d, JZ0.5,
1 Hz, NH), 8.35, 8.43 (2d, JZ10, 2, 1 Hz, CHO). Anal.
Calcd for C15H15NO3: C, 70.04: H, 5.84; N, 5.45. Found: C,
70.12; H, 5.88; N, 5.40.
5.1.6. N-Methyl-2-bromo-5-benzyloxy-4-methoxyaniline
(12). To a solution of 3-benzyloxy-4-methoxyformanilide
(11) (25.7 g, 0.1 mol) in dry THF (600 mL) at 0 8C was
added N-bromoacetamide (15.2 g, 0.11 mol) in several
portions. After stirring overnight, the solvent was evapo-
rated, and the residue was dissolved in CHCl3 (500 mL).
This solution was washed twice with H2O (100 mL), dried
over MgSO4, and evaporated. Chromatography on SiO2 (2%
MeOH in CHCl3) afforded 29 g (86%) of the intermediate
bromo formamide as an off-white powder: 1H NMR
(90 MHz, CDCl3) d (ppm): 3.80 (s, 3, OCH3), 5.08 (s, 2,
OCH2), 6.95 (s, 1, H-3), 7.20–7.45 (m, 6, Ph and NH), 8.07
(s, 1, H-6), 8.35 (d, JZ2, 1 Hz CHO).
Scheme 5.
solvent (MeOH) was evaporated, the pH brought to 1 with
concentrated HCl, and the solution extracted with EtOAc
(2!400 mL). The combined extract was dried over MgSO4
and evaporated. The residue was triturated with hexane to
give 46 g (90% yield) of white crystals, mp 122–123 8C: 1H
NMR (250 MHz, CDCl3) d (ppm): 2.60, 2.86 (AA0BB0,
A solution of the above product (16.8 g, 0.05 mol) in THF
(100 mL) was cooled to 0 8C, and 1 M BH3$THF (100 mL,
0.1 mol) was added. After refluxing for 30 min, the reaction
mixture was cooled to 0 8C, and the excess BH3 was
decomposed by the addition of H2O followed by 10%
NaOH. Stirring was continued for 30 min, EtOAC (200 mL)
was added, and the layers were separated. The organic layer
was evaporated, and the aqueous layer was washed with
EtOAc (200 mL). The combined organic phase was dried
and evaporated to give 12 as an off-white semisolid, after
0
JABZJAB Z7.5, 4 Hz, CH2CH2), 4.99 (s, 2, OCH2), 6.86,
6.90 (AA0BB0, JABZ8.5 Hz, JAB Z2.5, 4 Hz, ArH), 7.2–
7.4 (m, 5, Ph), 11.4 (br s, 1, COOH). Anal. Calcd for
C16H16O3: C, 75.00; H, 6.25. Found: C, 75.04; H, 6.30.
0
5.1.4. 3-Hydroxy-4-methoxyformanilide (10). To a sus-
pension of 3-hydroxy-4-methoxyaniline (9) (20.85 g,
0.15 mol) in HCOOEt (500 mL) was added HCOOH (3
drops). The reaction mixture was refluxed for 48 h at which
time TLC indicated all the starting material had been
consumed. The solvent was evaporated, and the residue was
dissolved in warm Me2CO and passed through a 5!5.5 cm
charcoal column (Norit). Evaporation of the solvent yielded
21.3 g of gray crystals (85%): 1H NMR (250 MHz, CDCl3/
DMSO-d6) exhibits the presence of two amide rotamers d
(ppm): 3.75 (s, 3, OCH3), 6.61, 7.00 (2dd, JZ8.5, 2.5, 1 Hz,
H-6), 6.70, 7.25 (2d, JZ2.5, 1 Hz, H-2), 6.85 (d, JZ8.5,
1 Hz, H-5), 8.22, 8.62 (2d, JZ2, 10, 1 Hz, CHO), 9.13 (br s,
1, OH), 9.89, 9.98 (2s, 1, NH). Anal. Calcd for C8H9NO3: C,
57.48; H, 5.39; N, 8.38. Found: C, 57.57; H, 5.44; N, 8.36.
1
drying under high vacuum (14.6 g, 91% yield): H NMR
(90 MHz, CDCl3) d (ppm): 2.65 (s, 3, NCH3), 3.68 (s, 3,
OCH3), 3.65–3.95 (br s, 1, NH), 5.03 (s, 2, OCH2), 6.20 (s,
1, H-6), 6.97 (br s, 1H-3), 7.12–1.40 (m, 5, Ph). Anal. Calcd
for C15H16BrNO2: C, 55.92; H, 5.01; N, 4.35. Found: C,
55.94; H, 5.02; N, 4.27.
5.1.7. N-Methyl-3-(4-hydroxphenyl)propion-(2-bromo-
5-hydroxy-4-methoxy)anilide (13). A solution of 3-(4-
benzyloxyphenyl)propionic acid (7) (25.6 g, 0.1 mol) in
SOCl2 (75 mL) was refluxed for 2 h. The excess SOCl2 was
removed at reduced pressure; the residue was dissolved in
Scheme 6.

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A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
CHCl3 (pentene stabilized) and the solvent evaporated.
After drying under high vacuum for 2 h, 27.5 g (100% yield)
of the product 8 was obtained. A portion (14 g, 0.051 mol)
was dissolved in CHCl3 (150 mL) (pentene stabilized) and
the solution was added to a solution of N-methyl-2-bromo-
5-benzyloxy-4-methoxyaniline (12) (16.1 g, 0.05 mol) in
CHCl3 (pentene stabilized, 200 mL), followed by Et3N
(56 g) in CHCl3 (50 mL). After stirring for 1 h, TLC showed
the starting material to be consumed. The reaction mixture
was then washed with 1% HCl, followed by H2O, dried and
evaporated to give a brown oil (23.8 g, 85% yi0eld): 1H NMR
(250 MHz, CDCl3) d (ppm): 2.05–2.30 (AA , 2, CH2CO),
2.65–2.87 (BB0, 2, CH2CH2CO), 3.10 (s, 3, NCH3), 3.80 (s,
3, OCH3), 4.95 and 5.00 (2s, 4, CH2O), 6.55 (s, 1H-3), 6.80–
7.10 (AA0BB0, 4, ArH), 7.25 (s, H-6), 7.20–2.50 (m, 10, Ph).
sequential addition of H2O and 15% NaOH. The solids were
removed by filtration and washed with EtOAc (200 mL).
The combined organic phase was dried with MgSO4 and
evaporated. The product mixture was separated by column
chromatography eluting with 0.4% EtOH in CHCl3
affording 1.7 g (59%) of the 4a,6b isomer 2 and 0.2 g
1
(7%) of the 4a,6a isomer 15: H NMR for 2 (250 MHz,
CDCl3) d (ppm): 1.41, 1.71 (AB, 2, H-9), 1.88, 2.15 (AB, 2,
H-10), 2.04, 2.68 (AB, JZ15.6, 2 Hz, H-5), 2.35 (d, JZ
11.4, 1 Hz, OH), 2.78, 3.30 (AB, 2, H-11), 2.86 (s, 3,
NCH3), 3.80 (s, 3, OCH3), 4.11 (m, JZ11.4, 1 Hz, H-6),
4.58 (m, 1, H-4), 5.90 (dd, JZ10.3, 4.8, 0.9, 1 Hz, H-7),
6.00 (dd, JZ10.3, 0.9, 1 Hz, H-8), 6.28 (d, JZ8.75, 1 Hz,
H-1), 6.69 (d, JZ8.75, 1 Hz, H-2): 1H NMR for 15
(250 MHz, CDCl3) d (ppm): 1.49, 1.87 (AB, 2, H-9), 1.72,
2.75 (AB, 2, H-5), 1.82, 2.07 (AB, 2, H-10), 2.11 (br s, 1,
OH), 2.75, 3.24 (AB, 2, H-11), 2.81 (s, 3, NCH3), 3.78 (s, 3,
OCH3), 4.55 (m, 1, H-4), 4.59 (m, 1, H-6), 5.68 (d, JZ10.3,
1 Hz, H-7), 6.01 (d, JZ10.3, 1 Hz, H-8), 6.22 (d, JZ8.7,
1 Hz, H-1), 6.64 (d, JZ8.7, 1 Hz, H-2).
To a solution of this oil (14 g, 0.025 mol) in EtOH (75 mL)
was added 48% HBr (150 mL) and the mixture was stirred
for 2 h at 60 8C. The reaction mixture was treated with
charcoal and allowed to come to room temperature. The
residue obtained after filtration through a pad of Celite and
evaporation of the solvent was dissolved in EtOAc
(200 mL), and the solution was washed with H2O, dried
over MgSO4 and evaporated. The product (7.7 g, 81% yield)
was obtained as an off-white semicrystalline solid after
purification by column chromatography using SiO2 and 2%
MeOH in CHCl3 on the eluent: 1H NMR (250 MHz, CDCl3)
d (ppm): 2.27, 2.83 (AA0BB0, JABZ8.5, 4 Hz, CH2CH2),
3.13 (s, 3, NCH3), 3.89 (s, 3, OCH3), 5.60–6.50 (br s, 2, OH),
5.1.10. (4aa,6b)-4a,5,9,10,11,12-Hexahydro-3-methoxy-
12-methyl-6H-benzofuro[3a,3,2-e,f][1]benzazepin-6-ol
(2) hydrochloride. The free base 2 (1.7 g, 0.006 mol) was
dissolved in EtOH, and ethanolic HCl was added. The
solvent was evaporated, and the product was recrystallized
from EtOH/Et2O to give 1.7 g (89%) of the hydrochloride
salt, mp 181.5–182.0 8C. Anal. Calcd for C11H22C1NO3$1/
4H2O: C, 62.20; H, 6.87; N, 4.27. Found: C, 62.23; H, 6.93;
N, 4.26.
6.28 (s, 1H-3), 6.70, 6.88 (AA0BB0, JABZ9 Hz, JAB Z2,
0
4 Hz, ArH), 7.03 (s, 1, H-6). Anal. Calcd for C17H18BrNO4:
C, 53.68; H, 4.74; N, 3.68. Found: C, 53.78; H, 4.82; N,
3.62.
5.1.11. 2-Bromo-5-hydroxy-4-methoxyphenylacetic acid
(19).11 To a solution of 3-hydroxy-4-methoxyphenylacetic
acid (18) (70 g, 0.386 mol) in HOAc (1000 mL) was added
a solution of Br2 (67.74 g, 0.424 mol) in HOAc (100 mL) at
room temperature. The mixture was stirred overnight and
the solvent evaporated. The residue was dissolved in toluene
and the solvent evaporated. The residue was treated with
toluene (800 mL), the mixture heated for 15 min, cooled to
room temperature and the product filtered, to afford 97 g
(96%) of semicrystalline solid: 1H NMR (90 MHz, DMSO-
d6) d (ppm): 3.48 (s, 2, CH2), 3.69 (s, 3, OCH3), 6.70 (s, 1,
Ar), 6.97 (s, 1, Ar). m/z Calcd for C9H9BrO4: 259.9685 and
261.9664. Found: 259.9691 and 261.9674.
5.1.8. (4aa)-4a,5,9,10,11,12-Hexahydro-1-bromo-3-
methoxy-12-methyl-11-oxobenzofuro[3a,3,2-e,f][1]ben-
zazepin-6-one (14). To a well-stirred mixture of CHCl3
(3000 mL), aqueous 5% NaHCO3 (500 mL) and K3Fe(CN)6
(57 g, 0.173 mol) at 60 8C was added N-[3-(4-hydroxy-
phenyl)propionyl]-N-methyl-2-bromo-5-hydroxy-4-meth-
oxyaniline (13) (11 g, 0.029 mol) in one portion. After
stirring at 60 8C for 1.5 h the layers were separated, the
CHCl3 evaporated and the residue filtered through a 5 cm
column of SiO2 in EtOH stabilized CHCl3. Evaporation of
the solvent afforded 5.5 g (50%) of the product 14 (TLC
pure) as a pink foam: 1H NMR (250 MHz, CDCl3) d (ppm):
2.03–3.15 (m, 6H, CH2CH2 and CH2C]O), 3.36 (s, 3,
NCH3), 3.88 (s, 3, OCH3) 4.84 (m, 1, H-4), 6.00 (d, JZ9,
1 Hz, H-8), 6.36 (dd, JZ9, 2, 1 Hz, H-7), 7.08 (s, 1, H-2).
Anal. Calcd for C17H16BrNO4: C, 53.97; H, 4.23; N, 3.70.
Found: C, 54.03; H, 4.30; N, 3.62.
5.1.12. 2-Bromo-5-hydroxy-4-methoxyphenylacetamide
(21). Dry HCl was passed through a solution of 2-bromo-
5-hydroxy-4-methoxphenylacetice acid (19) (97 g,
0.371 mol) in MeOH (1000 mL) at 0 8C for 30 min. The
mixture was left overnight, then the solvent was evaporated,
and the residue (20) was dissolved in EtOAc. The solution
was washed twice with water, aqueous NaHCO3 and brine,
dried with MgSO4 and the solvent was evaporated. The ester
was dissolved in MeOH (800 mL) and NH3 was bubbled
through for 8 h at 0 8C. The reaction mixture was left in the
dark for 10 days. The volatiles were removed under reduced
pressure and the residue was suspended in MeOH (150 mL)
and filtered, affording 79 g (82%) of amide 21, mp 185–187:
1H NMR (90 MHz, DMSO-d6) d (ppm): 3.25 (s, 2, CH2);
3.75 (s, 3, OCH3); 6.50–7.40 (m, 4, NH2, Ar); 8.82 (s, 1,
OH). m/z Calcd for C9H10BrNO2: 258.9844 and 260.9824.
Found: 258.9840 and 260.9827.
5.1.9. (4aa,6b)-4a,5,9,10,11,12-Hexahydro-3-methoxy-
12-methyl-6H-benzofuro-[3a,3,2-e,f][1]benzazepin-6-ol
(2) and (4aa,6a)-4a,5,9,10,11,12-hexahydro-3-methoxy-
12-methyl-6H-benzofuro[3a,3,2-e,f][1]benzazepin-6-ol
(15). A solution of (4a)-4a,5,9,19,11,12-hexahydro-1-
bromo-3-methoxy-12-methyl-11-oxobenzofuro[3a,3,2-e,f]-
[1]benzazepin-6-one (14) (3.8 g, 0.01 mol) in THF
(100 mL) was added dropwise to a suspension of LiAlH4
(5 g, 0.47 mol) in THF (100 mL). The reaction mixture was
refluxed for 36 h and stirred at room temperature for an
additional 48 h. The excess LiAlH4 was decomposed by the

A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
7151
5.1.13. 2-Bromo-5-hydroxy-4-methoxyphenethylamine
(22).1 To the amide 21 (64 g, 0.246 mol) in a 2 L round-
bottom flask was added slowly 1 N BH3/THF (800 mL,
0.266 mol). The reaction mixture was refluxed for 5 h,
cooled to 0 8C and concentrated methanolic HCl was added
(500 mL). After stirring overnight, the solvent was
evaporated, the residue redissolved in MeOH and the
solvent evaporated again. This operation was repeated three
times. The residue was dissolved in MeOH (500 mL) and
the pH was brought to 8 by addition of MeONa in MeOH.
The precipitated salt was removed by filtration and the
solvent was evaporated at reduced pressure to afford 56 g
formamide 25 (10 g, 0.022 mol) in one portion. After
stirring at 60 8C for 2 h, the reaction mixture was cooled and
the CHCl3 layer was separated. The aqueous layer was
washed with CHCl3 (1000 mL). The combined organic
phase was evaporated and the product was separated on
100 g of SiO2 using 1% MeOH in CHCl3 as eluant. After
solvent removal under reduced pressure, 1.1 g (11% yield)
1
of HPLC-pure product was obtained as a yellow foam: H
NMR (90 MHz, CDCl3) showed two rotamers d (ppm):
2.62–3.56 (m, 6, 3!CH2); 3.75 (s, 3, OCH3); 3.80–4.12 (m,
1, H-12a); 4.58–4.82 (m, 1, H-4a); 4.45 and 4.48 (two-d, JZ
17, 1 Hz, H-12b); 6.75–6.90 (m, 1, H-8); 6.95 (s, 1, H-2);
8.01 and 8.05 (two-s, 1, CHO). MS (APCI-ESI) calcd for
C17H15Br2NO4: 455/457/459. MCK1. Found: 456/458/
460; MKK1. Found: 454/456/458. High resolution mass
spectra could not be obtained for this material.
1
(93%) of 22 as a light brown wax: H NMR (90 MHz,
DMSO-d6) d (ppm): 2.84 (s, 4, CH2CH2); 3.72 (s, 3, OCH3);
6.78 (s, 1, Ar); 7.02 (s, 1, Ar).
5.1.14. 3-Bromo-4-hydroxybenzaldehyde (24). To a
solution of 4-hydroxybenzaldehyde (23) (50 g, 0.409 mol)
in a mixture of CHCl3 (500 mL) and MeOH (50 mL) was
added a solution of Br2 (71 g, 23 mL, 0.45 mol) in CHCl3
(100 mL) dropwise at room temperature. The mixture was
stirred for 2 h and washed with water to neutral pH. The
organic phase was dried with MgSO4 and the solvent was
evaporated. Recrystallization from CHCl3 afforded 68.4 g
(83%) of 24, mp 118–120 8C (lit.8 124 8C).
5.1.17. (rac)-(4aa)-4a,5,9,10,11,12-Hexahydro-1-bromo-
3-methoxy-10-formyl-6H-benzofuro[3a,3,2-e,f][3]benza-
zepin-6-one (27). To a solution of dibromoenone 26
(0.89 g, 0.002 mol) in EtOH (50 mL) was added 2.6 g of
activated zinc powder. The mixture was refluxed until
HPLC (2% MeOH in CHCl3) showed completion of the
reaction (overnight). The solution was filtered hot and the
zinc was washed thoroughly with hot EtOH. The alcohol
was evaporated and the residue was separated on a SiO2
column (1% MeOH in CHCl3) providing 0.65 g (88%) of
the product 27 as a white foam: 1H NMR (90 MHz, CDCl3)
showed two rotamers d (ppm): 2.55–3.08 (m, 5); 3.10–3.98
(m, 2); 3.70 (s, 3, OCH3); 4.45–4.84 (m, 2, H-4a, H-9); 5.92
and 6.02 (two-d, JZ10, 1 Hz, H-7); 6.46 and 6.50 (two-d-d,
JZ10, 1.8, 1 Hz, H-8); 6.90 (s, 1, Ar); 8.00 and 8.18 (two-s,
1, CHO). m/z Calcd for C17H16BrNO4: 377.0263 and
379.0242. Found: 377.0263 and 379.0226.
5.1.15. N-(2-Bromo-5-hydroxy-4-methoxyphenethyl)-N-
(3-bromo-4-hydroxybenzyl)formamide (25). A mixture
of the aldehyde 24 (45.7 g, 0.227 mol) and the crude amine
22 (56 g, 0.227 mol) in anhydrous MeOH (1600 mL) and
˚
molecular sieves 4 A (230 g) was stirred overnight at room
temperature. After the sieves were removed by filtration and
the mixture diluted to 3200 mL with MeOH, NaBH4 (19 g,
0.5 mol) was added in six equal portions at 0 8C. After
stirring for 3 h at room temperature, the reaction mixture
was treated with 15% HCl/MeOH to pH 1, and the mixture
was left overnight at room temperature. The solvent was
then removed under reduced pressure, the residue redis-
solved in MeOH, and the NaCl removed by filtration. This
procedure was repeated three times. The residue was then
dissolved in MeOH (700 mL) and methanolic MeONa was
added until the pH was 8. The precipitated NaCl was filtered
off, and the solvent was evaporated. The residue was
suspended in HCOOEt (1000 mL) with NEt3 (10 mL), and
the mixture was refluxed until TLC (CHCl3/MeOH/NH4OH
aqueous, 90:10:1) showed complete consumption of starting
material (3 days). The solvent was removed under reduced
pressure. The crude material was purified on a SiO2 (1000 g)
column (2% MeOH in CHCl3) providing 48 g (46%) of the
5.1.18. (rac)-(4aa,6b)-4a,5,9,10,11,12-Hexahydro-1-
bromo-3-methoxy-10-methyl-6H-benzofuro[3a,3,2-e,f]
[3]-benzazepin-6-ol (28). A solution of (rac)-(4aa)-
4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-10-formyl-
6H-benzofuro[3a,3,2-e,f][3]benzazepin-6-one (27) (3.67 g,
0.0097 mol) in dry THF (150 mL) at K78 8C was stirred
under dry argon for 20 min, and 1 M L-Selectride (19.5 mL,
0.0195 mol) was added dropwise. After stirring at K78 8C
for 2 h, the mixture was allowed to warm up to 0 8C, and
1 M LiAlH4/THF (19.5 mL, 0.0195 mol) was added
dropwise. Stirring was continued overnight. Excess redu-
cing agent was decomposed by sequential addition of H2O
(2.65 mL) and 10% NaOH (8 mL). The inorganic salts were
removed by filtration, and the solution was dried with
MgSO4. Column chromatography on SiO2 (2% MeOH in
1
formamide 25 as a semicrystalline light yellow solid: H
1
NMR (90 MHz, DMSO-d6) shows two rotamers d (ppm):
2.50–2.95 (m, 2, ArCH2); 3.22–3.55 (m, 2, ArCH2CH2N);
3.82 (s, 3, OCH3); 4.18 and 4.45 (two-s, 2, ArCH2N); 6.55–
7.33 (m, 5, Ar); 8.00 and 8.28 (two-s, 1, CHO). m/z Calcd
for C17H17Br2NO4: 456.9524, 458.9504, and 460.9486.
Found: 456.9523, 458.9519, and 460.9482.
CHCl3) provided 2.55 g (72%) of 28 as a white foam: H
NMR (90 MHz, CDCl3) d (ppm): 1.62–1.90 (m, 2), 2.01–
2.25 (m, 3), 2.30 (s, 3, NCH3), 2.35–2.75 (m, 2), 2.80–3.22
(m, 2), 3.70 (s, 3, OCH3), 3.99–4.11 (m, 1, H-6), 4.51 (m, 1,
H-4), 5.86–6.02 (m, 2, H-7, H-8), 6.79 (s, 1, H-2). m/z Calcd
for C17H20BrNO3: 365.0627 and 367.0606. Found:
365.0630 and 367.0619.
5.1.16.
(rac)-(4aa)-4a,5,9,10,11,12-Hexahydro-1,7-
dibromo-3-methoxy-10-formyl-6H-benzofuran[3a,3,2-
e,f][3]benzazepin-6-one (26). To a well stirred biphase of
CHCl3 (3500 mL) and a solution of K3Fe(CN)6 (27.3 g,
0.083 mol) and NaHCO3 (14 g, 0.17 mol) in H2O (27.5 mL)
at 60 8C in a 5 L Morton flask under N2 was added
5.1.19. (rac)-(4aa,6b)4a,5,9,10,11,12-Hexahydro-3-
methoxy-10-methyl-6H-benzofuro[3a,3,2-e,f][3]-benza-
zepin-6-ol (3). A solution of (rac)-(4aa,6b)-4a,5,9,10,
11,12-Hexahydro-1-bromo-3-methoxy-10-methyl-6H-ben-
zofuro[3a,3,2-e,f][3]benzazepin-6-ol 28 (2.55 g, 0.007 mol)

7152
A. H. Lewin et al. / Tetrahedron 61 (2005) 7144–7152
in dry THF (150 mL) was added to a suspension of 4 g
(0.073 mol) of LiAlH4 (4 g, 0.073 mol) at 0 8C, and the
mixture was refluxed for 72 h. After cooling to 0 8C, the
excess LiAlH4 was decomposed by sequential addition of
H2O (4 mL) and 10% NaOH (12 mL). The inorganic salts
were removed by filtration, the filtrate dried over MgSO4,
and the solvent evaporated. Column chromatography on
SiO2 (3% MeOH in CHCl3) provided 1.98 g of 3. The amine
was converted to a p-toluenesulfonic acid salt, which was
collected by filtration and recrystallized from EtOH/ether
providing 2.8 g (96%) of 3$TsOH, mp 206 8C (dec); IR
(KBr): 3300, 3010, 1510, 1450, 1235, 1145, 1050, 790,
690 cmK1: 1H NMR (250 MHz, DMSO-d6) d (ppm): 2.04–
2.29 (m, 1), 2.29 (s, 3, NCH3), 2.80–2.97 (m, 3), 3.21–3.71
(m, 5), 3.73 (s, 3, OCH3), 4.07–4.15 (m, 1, H-6), 4.52–4.58
(m, 1, H-4), 5.87–5.98 (m, 2, H-7, H-8), 6.67 (d, JZ8.2,
1 Hz, H-2), 6.90 (d, JZ8.2, 1 Hz, H-1), 7.12 (d, JZ8.0,
2 Hz, H-3, H-5), 7.48 (d, JZ8.0, 2 Hz, H-2, H-6), 9.66 (br s,
1, N]H). Anal. Calcd for C24H29NO6S: C, 62.73; H, 6.36;
N, 3.05. Found: C, 62.85; H, 6.39, N, 3.03.
1% HCl in EtOH gave the hydrochloride salt. Crystal-
lization from EtOH/Et2O gave 1.2 g (81%) of the pure salt,
mp 235 8C (dec): 1H NMR (250 MHz, D2O) d (ppm): 1.60–
2.63 (m), 3.27 (2, 3, NCH3), 3.55 (t, 1, H-11a), 3.74–3.82
(m, 1, H-11e), 3.89 (s, 3, OCH3), 4.17 (br s, 1, H-4), 4.33 (br
s, 1, H-6), 4.80 (s, 1.5, NH–HOD), 7.01 (AB, 2, ArH). Anal.
Calcd for C17H24ClNO3: C, 62.67; H, 7.37; N, 4.50; Cl,
10.91. Found: C, 62.76; H, 7.46; N, 4.27; Cl, 10.85.
Acknowledgements
Supported in part by the US Army medical research and
Development Command under contracts DAMD17-85-C-
5221 and DAMD17-88-C-8114. The authors gratefully
acknowledge the help of Mr. C. McElhinney, Jr. in
obtaining the HRMS data.
5.1.20. (4aa)-4a,5,7,8,9,10,11,12-Octahydro-3-methoxy-
12-methyl-6H-benzofuro-[3a,3,2-e,f][1]benzazepine (33)
hydrochloride. To a solution of (4aa,6)-4a,5,9,10,11,12-
hexahydro-3-methoxy-12-methyl-6H-benzofuro[3a,3,2-
e,f][1]benzazepin-6-ol (2) (1.1 g, 3.5 mmol) in 1% ethanolic
HCl (50 mL) was added Pd/C (200 mg) and the mixture was
hydrogenated for 2 h at 40 psi. The catalyst was removed by
filtration, and the product was crystallized from EtOH/Et2O
to afford 1.1 g (92%) of the hydrochloride salt of the
References and notes
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Chem. Soc. (C) 1966, 1052–1057.
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1
product, mp 205–2208 (dec): H NMR (250 MHz, D2O) d
(ppm): 1.17–1.82 (m, 7), 2.00–2.62 (m, 5), 3.23 (s, 3,
NCH3), 3.53 (t, 1, H-11a), 3.69–3.89 (m, 1, H-11e), 3.89 (s,
3, OCH3), 4.22 (br s, 1, H-4), 4.82 (s, 4, NHCHOD), 7.01
(AB, 2, ArH). Anal. Calcd for C17H23NO2$HCl: C, 65.91;
H, 7.75; N, 4.52; Cl, 11.47. Found: C, 65.70; H, 7.86; N,
4.48; Cl, 11.48.
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5.1.21. (4aa,6b)-4a,5,7,8,9,10,11,12-Octahydro-3-meth-
oxy-6H-benzofuro[3a,3,2-e,f][1]benzazepin-6-ol (32)
hydrochloride. To a solution of (4aa,6b)-4a,5,9,10,11,12-
hexahydro-3-methoxy-12-methyl-6H-benzofuran[3a,3,2-
e,f][1]benzazepin-6-ol (2) (2.87 g, 0.01 mol) in THF
(150 mL) was added 10% Pd/C (400 mg), and the mixture
was shaken under 40 psi of H2 for 7 h. The catalyst was
removed by filtration, the solvent evaporated, and the
residue purified by chromatography using 0.2–0.5% EtOH
in CHCl3 to afford 1.39 (46%) of 32. The desoxy compound
33 was isolated in 26% as a byproduct. Treatment of 32 with
11. Szantzy, C.; Dornyie, G.; Blasko, G.; Barczai-Beke, M.;
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J. Heterocycl. Chem. 1995, 32, 195.
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15. Winslow, J. T.; Camacho, F. Psychopharmacology (Berl)
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