A practical and highly efficient synthesis of lennoxamine and related isoindolobenzazepines

Article abstract of DOI:10.1016/j.tet.2004.03.049

Lennoxamine and related isoindolobenzazepines were prepared in high yield by intramolecular condensation of aldehyde isoindolones under basic conditions followed by catalytic hydrogenation of the resulting dehydroisoindolobenzazepines.

Full text of DOI:10.1016/j.tet.2004.03.049

Tetrahedron 60 (2004) 4169–4172
A practical and highly efficient synthesis of lennoxamine and
related isoindolobenzazepines
Poolsak Sahakitpichana and Somsak Ruchirawata,b,c
,
*
aLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
bDepartment of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
cChulabhorn Research Centre, Institute of Science and Technology for Research and Development, Mahidol University, Salaya Campus,
Bangkok, Thailand
Received 12 January 2004; revised 27 February 2004; accepted 18 March 2004
Abstract—Lennoxamine and related isoindolobenzazepines were prepared in high yield by intramolecular condensation of aldehyde
isoindolones under basic conditions followed by catalytic hydrogenation of the resulting dehydroisoindolobenzazepines.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
isoindolone and the benzazepine skeleton was the focus of
the fourth approach.6c,8 The fifth approach utilized the
rearrangement of various isoquinoline derivatives as a
means to synthesize the isoindoloisoquinolines.9a–e
Lennoxamine (1a), an isoindolobenzazepine, was isolated
from the Chilean plant Berberis darwinii.1 Even though no
important pharmacological activity of lennoxamine has
been reported as normally found in the benzazepine
derivatives,2a–e its unique structural features have captured
the interest of many synthetic groups over the past 20 years.
2. Results and discussion
In our previous synthetic routes (Scheme 1), the aldehyde
isoindolone 3a was the common unisolated intermediate
which further cyclized smoothly to the dehydrolennoxamine
The previous syntheses of lennoxamine and other isoindo-
lobenzazepine derivatives could be classified into various
approaches depending on the order of bond formation as
shown in Figure 1.
Figure 1.
The first approach involved prior construction of the
benzazepine skeleton followed by isoindolone ring for-
maton via bond A3a,b or bond F.4 The second approach
concentrated on first the isoindolone ring formation which
could then be manipulated to form the benzazepine ring via
formation of bond B5a–c or bond C.6a–c Bond D formation
of various phthalimide derivatives7a–d has been exploited in
the third approach. The simultaneous formation of the
Keywords: Lennoxamine; Isoindolobenzazepine alkaloids.
*
Corresponding author. Address: Laboratory of Medicinal Chemistry,
Chulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok
10210, Thailand. Tel.: þ66-2-5740601; fax: þ66-2-5742027;
e-mail address: somsak@tubtim.cri.or.th
Scheme 1. Synthetic route.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.049

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P. Sahakitpichan, S. Ruchirawat / Tetrahedron 60 (2004) 4169–4172
2a in high yield. The former pathway provided the desired
isoindolone via hydroxide addition to the iminium salt to
give the carbinolamine derivative which was opened to give
the amide anion followed by intramolecular alkylation. The
above pathway worked well only when the sixth position of
the isoquinoline derivative was substituted with a methoxy
group. The methoxy group apparently facilitated the
breaking of the carbon–nitrogen bond to give the aldehyde
and amide anion. Alternatively, in the other pathway, the
methoxy group ortho to the carboethoxy group is required
for the success of the synthesis. The methoxy group
presumably activates the leaving group ability of the
ester.10 In this paper, we report a highly efficient, direct
synthesis of aldehyde isoindolone which could be success-
fully cyclized to the isoindolobenzazepine derivatives
irrespective of the oxygenation pattern on the aromatic ring.
The aldehyde isoindolone 3 could be synthesized by
formylation of the isoindolone precursor 4 which could
conceivably be prepared by alkylation–acylation of the
arylethylamine derivatives with ethyl 2-chloromethyl-
benzoates 6.
To test the above idea, homoveratrylamine 5 was heated at
reflux with ethyl 2-chloromethylbenzoate 6 in acetonitrile in
the presence of triethylamine to give the expected
isoindolone 4c in 74% yield. Similarly, the other two
isoindolones, 4a, 4b were obtained in 81 and 76% yields
respectively from the reaction of the appropriate aryl-
ethylamines and ethyl 2,3-dimethoxy-6-chloromethyl-
benzoate.11
Formylation of the resulting isoindolones were carried out
conveniently using dichloromethyl methyl ether and
titanium tetrachloride in dichloromethane12a–c to give the
aldehyde isoindolones, 3a, 3b, 3c in excellent yields
The aldehyde isoindolone was synthesized by the route
suggested by retrosynthetic analysis as shown in Scheme 2.
The derived aldehyde isoindolones were cyclized smoothly
in refluxing methanolic KOH to give the required
dehydroisoindolobenzazepines, 2a, 2b, and 2c, in excellent
yields.
Lennoxamine, 1a as well as other isoindolobenzazepines,
1b, 1c, could be readily obtained by catalytic hydrogenation
of the dehydro intermediates 2a, 2b, and 2c in 76, 80 and
90% yields, respectively (Scheme 3).
3. Conclusion
We have successfully developed a practical and highly
efficient synthetic route for lennoxamine and other related
isoindolobenzazepines. The route involved condensing of
aldehyde isoindolones under basic conditions followed by
catalytic hydrogenation of the resulting dehydroisoindolo-
benzazepines. The key aldehyde isoindolones were derived
in two steps from alkylation–acylation of arylethylamines
with ethyl 2-chloromethylbenzoate derivatives and insertion
Scheme 2. Retrosynthetic analysis.
Scheme 3. Preparation of lennoxamine and its derivatives.

P. Sahakitpichan, S. Ruchirawat / Tetrahedron 60 (2004) 4169–4172
4171
of the C-1 aldehyde onto the aromatic ring using
dichloromethyl methyl ether and TiCl4.
131.11, 131.28, 132.8, 141.1, 147.6, 148.9, 168.4. EIMS
297(Mþ, 13), 165(12), 164(100), 146(42), 91(15). Anal.
Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.59; H, 6.28; N, 4.76.
4. Experimental
4.1. General
4.3. General procedure for the synthesis of aldehyde
isoindolones
1H and 13C NMR spectra were recorded in CDCl3 at 400 and
100 MHz respectively using TMS as an internal standard.
Mass spectra were determined at an ionizing voltage of
70 eV. Column chromatographic purifications were carried
out using silica gel (70–230 mesh).
A solution of isoindolones (2.18 mmol) in 25 mL of dry
CH2Cl2 was cooled in an ice bath, and 0.3 mL of
dichloromethyl methyl ether was added. While the solution
was stirred and cooled, 1.2 mL (10.91 mmol) of TiCl4 was
added. After the addition was complete, the mixture was
stirred for 5 min in an ice bath and for 3 h at room
temperature. The reaction mixture was then poured into a
flask containing crushed ice and was shaken thoroughly.
The organic layer was separated, and the aqueous solution
was extracted with CH2Cl2. The combined organic solution
was washed with water and dried over anhydrous Na2SO4.
After evaporation of the solvent, the white solid so obtained
was further purified by column chromatography using 2%
MeOH/CH2Cl2 as eluting solvent to give the aldehyde
isoindolones as white solid.
4.2. General procedure for the synthesis of isoindolones
A solution of arylethylamine derivatives (1 mmol), ethyl
2-chloromethylbenzoates (1 mmol) and triethylamine
(1.2 mmol) in CH3CN (5 mL) was heated under reflux for
3 h under nitrogen atmosphere. CH3CN was removed
and the crude product was extracted with CH2Cl2 and
washed with water. The organic extracts were dried over
anhydrous Na2SO4 and evaporated to dryness to give the
crude amide as yellow solid, the product was further
purified by column chromatography using 2% MeOH/CH2-
Cl2 as eluting solvent to give the isoindolones as pale yellow
solid.
4.3.1. 2-(2-Formyl-4,5-methylenedioxyphenethyl)-6,7-
dimethoxyphthalimidine (3a). White crystals (97%), mp
(EtOH) 175.5–176.5 8C; IR (nujol) 1670 (broad),
1
1748 cm21; H NMR d 3.32 (t, 2H, J¼7.0 Hz), 3.74 (t,
2H, J¼7.0 Hz), 3.89 (s, 3H), 4.08 (s, 3H), 4.28 (s, 2H), 6.05
(s, 2H), 6.82 (s, 1H), 7.06, 7.09 (AB, 1H each, J¼8.0 Hz),
7.27 (s, 1H), 10.09 (s, 1H). 13C NMR d 31.4, 44.4, 49.6,
56.7, 62.5, 102.0, 111.1, 111.3, 116.4, 117.7, 124.9, 128.4,
134.5, 138.5, 147.1, 152.25, 152.29, 166.8, 190.1. EIMS
369 (Mþ, 27), 206(100), 194(8), 162(9), 148(9). Anal. Calcd
for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C, 65.11;
H, 5.14; N, 3.79.
4.2.1. 2-(3,4-Methylenedioxyphenethyl)-6,7-dimethoxy-
phthalimidine (4a). Pale yellow crystals (81%), mp
1
(EtOAc) 99–100 8C; IR (nujol) 1678 cm21; H NMR d
2.88 (t, 2H, J¼7.5 Hz), 3.75 (t, 2H, J¼7.5 Hz), 3.88 (s, 3H),
4.08 (s, 3H), 4.13 (s, 3H), 5.91 (s, 2H), 6.67 (dd, 1H, J¼8.0,
1.6 Hz), 6.71 (d, 1H, J¼8.0 Hz), 6.73 (d, 1H, J¼1.6 Hz),
7.02, 7.06 (AB, 1H each, J¼8.0 Hz). 13C NMR d 34.4, 44.3,
49.6, 56.7, 62.5, 100.8, 108.3, 109.0, 116.3, 117.6, 121.5,
125.0, 132.6, 134.5, 146.1, 147.1, 147.7, 152.2, 166.6.
EIMS 341(Mþ, 23), 206(96), 194(67), 193(16), 162(13),
149(16), 148(100), 135(13). Anal. Calcd for C19H19NO5: C,
66.85; H, 5.61; N, 4.10. Found: C, 66.90; H, 5.80; N, 3.92.
4.3.2. 2-(2-Formyl-4,5-dimethoxyphenylethyl)-6,7-
dimethoxyphthalimidine (3b). White crystals (96%), mp
(EtOH) 157–158 8C; IR (nujol) 1675 (broad), 1748 cm21
;
1H NMR d 3.37 (t, 2H, J¼7.0 Hz), 3.78 (t, 2H, J¼7.0 Hz),
3.87 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.09 (s, 3H), 4.22 (s,
2H), 6.81 (s, 1H), 7.04, 7.08 (AB, 1H each, J¼8.0 Hz), 7.33
(s, 1H), 10.15 (s, 1H). 13C NMR d 30.7, 44.2, 49.7, 56.0,
56.2, 56.8, 62.5, 113.6, 114.0, 116.3, 117.7, 124.9, 126.8,
134.5, 136.2, 147.1, 147.8, 152.2, 153.6, 166.8, 190.5.
EIMS 385(Mþ, 31), 207(13), 206(100), 193(14), 192(19),
164(31). Anal. Calcd for C21H23NO6: C, 65.44; H, 6.02; N,
3.63. Found: C, 65.31; H, 6.05; N, 3.80.
4.2.2. 2-(3,4-Dimethoxyphenethyl)-6,7-dimethoxy-
phthalimidine (4b). Pale yellow crystals (76%), mp
1
(EtOAc) 120–120.5 8C; IR (nujol) 1670 cm21; H NMR d
2.94 (t, 2H, J¼7.5 Hz), 3.80 (t, 2H, J¼7.5 Hz), 3.81 (s, 3H),
3.86 (s, 3H), 3.89 (s, 3H), 4.10 (s, 3H), 4.11 (s, 2H), 6.77 (d,
1H, J¼8.5 Hz), 6.80 (dd, 1H, J¼8.0, 0.4 Hz), 7.01, 7.07
(AB, 1H each, J¼8.0 Hz). 13C NMR d 34.1, 44.2, 49.7,
55.72, 55.74, 55.81, 62.5, 111.3, 111.8, 116.3, 117.6, 120.5,
125.1, 131.4, 134.5, 147.1, 147.6, 148.9, 152.21, 166.6.
EIMS 357(Mþ, 13), 206(34), 165(14), 164(100). Anal.
Calcd for C20H23NO5: C, 67.21; H, 6.49; N, 3.92. Found: C,
66.83; H, 6.60; N, 3.82.
4.3.3. 2-(2-Formyl-4,5-dimethoxyphenylethyl)phthali-
midine (3c). White crystals (93%), mp (EtOAc–hexane)
144–145 8C, lit.9a 148–150 8C; IR (nujol) 1680 (broad),
1748 cm21; 1H NMR d 3.39 (t, 2H, J¼7.0 Hz), 3.84 (s, 3H),
3.85 (t, 2H, J¼7.0 Hz), 3.94 (s, 3H), 4.32 (s, 2H), 6.80 (s,
1H), 7.32 (s, 1H), 7.41 (d, 1H, J¼7.0 Hz), 7.46 (t, 1H,
J¼7.0 Hz), 7.52 (td, 1H, J¼7.0, 1.0 Hz), 7.85 (d, 1H,
J¼7.0 Hz), 10.14 (s, 1H). 13C NMR d 30.9, 44.1, 50.6, 56.0,
56.2, 113.7, 114.3, 122.7, 123.5, 126.8, 128.0, 131.3, 132.7,
136.1, 141.2, 147.8, 153.7, 168.5, 190.7. EIMS 325(Mþ,
10), 192(38), 191(48), 146(80), 105(100), 77(55), 51(20).
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31.
Found: C, 69.81; H, 6.11; N, 4.31.
4.2.3. 2-(3,4-Dimethoxyphenylethyl)phthalimidine (4c).
Pale yellow crystals (74%), mp (EtOAc–Hexane) 98–
;
99 8C; IR (nujol) 1670 cm21 1H NMR d 2.95 (t, 2H,
J¼7.0 Hz), 3.78 (s, 3H), 3.85 (s, 3H), 3.86 (t, 2H,
J¼7.0 Hz), 4.19 (s, 2H), 6.74 (s, 1H), 6.77 (d, 1H,
J¼8.0 Hz), 6.78 (d, 1H, J¼8.0 Hz), 7.37 (d, 1H,
J¼7.0 Hz), 7.45 (t, 1H, J¼7.0 Hz), 7.51 (td, 1H, J¼7.0,
1.0 Hz), 7.85 (d, 1H, J¼7.0 Hz). 13C NMR d 34.3, 44.2,
50.7, 55.74, 55.82, 111.3, 111.8, 120.5, 122.6, 123.5, 127.9,

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4.4. General procedure for the synthesis of dehydro-
isoindolobenzazepine derivatives
the facilities in the Department of Chemistry, Mahidol
University, provided by the Postgraduate Education and
Research Program in Chemistry (PERCH).
Aldehyde (1 mmol) was dissolved in a solution of KOH
(500 mg) in MeOH (25 mL) and the mixture was heated at
reflux for 1 h. MeOH was removed by evaporation and
water was added. The aqueous mixture was extracted with
CH2Cl2 and dried. The organic extracts were evaporated to
dryness under reduced pressure. The crude product was
recrystallized from MeOH to give the required
dehydroisoindolobenzazepines.
References and notes
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4.4.1. 3,4-Dimethoxy-7,8-dihydro-10,11-methylene-
dioxy-5H-isoindolo[1,2-b][3]benzazepine-5-one
(2a).
Yellow crystals (84%), mp (MeOH) 208–209 8C, lit.6b
209–211 8C, lit.9e 213–214 8C. The spectroscopic data of
compounds 2a, 2b, and 2c are the same as those previously
published.9c
4.4.2. 3,4-Dimethoxy-7,8-dihydro-10,11-dimethoxy-5H-
Yellow
¨
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crystals (87%), mp (MeOH) 185–189 8C, lit.9c 185–189 8C.
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4.4.3. 7,8-Dihydro-10,11-dimethoxy-5H-isoindolo[1,2-
b][3]benzazepine-5-one (2c). Yellow crystals (94%), mp
(MeOH) 192–194 8C, lit.6a 195–196 8C, lit.9a 190–192 8C.
4.5. General procedure for the synthesis of
isoindolobenzazepine derivatives
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4867–4870. (b) Ishibashi, H.; Kawanami, H.; Iriyama, H.;
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To a stirred solution of dehydroisoindolobenzazepines
(250 mg) in EtOAc (15 mL), 10% Pd on carbon (51 mg)
was slowly added. The mixture was hydrogenated (1 atm,
balloon) and when the reaction was complete (TLC showed
the absence of the highly fluorescent spot of the starting
material), catalyst residue was removed by filtration,
washed with EtOAc, and evaporated to dryness to give the
required isoindolobenzazepines.
4.5.1. 3,4-Dimethoxy-13,13a-tetrahydro-10,11-methyl-
enedioxy-5H-isoindolo[1,2-b][3]benzazepine-5-one (1a).
White crystals (76%), mp (MeOH) 226–227 8C, lit.1
225 8C, lit.3a 228–229 8C. lit.9e 235–235.5 8C.
9. (a) Ruchirawat, S.; Lertwanawatana, W.; Thianpatanagul, S.;
Cashaw, J. L.; Davis, V. E. Tetrahedron Lett. 1984, 25,
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4.5.2. 3,4-Dimethoxy-13,13a-tetrahydro-10,11-
dimethoxy-5H-isoindolo[1,2-b][3]benzazepine-5-one
(1b). White crystals (80%), mp (MeOH) 213–214 8C, lit.9c
213–214 8C.
4.5.3. 7,8,13,13a-Tetrahydro-10,11-dimethoxy-5H-iso-
indolo[1,2-b][3]benzazepine-5-one (1c). White crystals
(90%), mp (EtOAc) 178–179 8C, lit.5c 178–179 8C, lit.6c
179 8C.
10. Ruchirawat, S.; Lertwanawatana, W.; Thianpatanagul, S.;
Sahakitpichan, P. Unpublished result.
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Acknowledgements
We are grateful to the Thailand Research Fund (TRF) for
the generous support of our research program and the award
of Senior Research Scholar to S.R. We also acknowledge