A radical cyclization approach to isoindolobenzazepines. Synthesis of lennoxamine

Article abstract of DOI:10.1021/jo952113k

The alkaloid lennoxamine (1) was synthesized by transannular cyclization of a 10-membered lactam obtained by intramolecular addition of an aryl radical to a (trimethylsilyl)acetylene. The isoindolo[1,2-b][3]benzazepine skeleton present in lennoxamine was also obtained by means of regioselective 7-endo-trig radical cyclization of methylenephthalimidines.

Full text of DOI:10.1021/jo952113k

2780
J . Org. Chem. 1996, 61, 2780-2782
A Ra d ica l Cycliza tion Ap p r oa ch to Isoin d oloben za zep in es.
Syn th esis of Len n oxa m in e†
Gema Rodr´ıguez, M. Magdalena Cid, Carlos Saa´, Luis Castedo,* and Domingo Dom´ınguez*
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de Santiago y Seccio´n de
Alcaloides del C. S. I. C. 15706 Santiago, Spain
Received November 29, 1995X
The alkaloid lennoxamine (1) was synthesized by transannular cyclization of a 10-membered lactam
obtained by intramolecular addition of an aryl radical to a (trimethylsilyl)acetylene. The isoindolo-
[1,2-b][3]benzazepine skeleton present in lennoxamine was also obtained by means of regioselective
7-endo-trig radical cyclization of methylenephthalimidines.
Sch em e 1
In tr od u ction
Isoindolobenzazepine alkaloids, exemplified by lennox-
amine (1, see Scheme 1), are a class of alkaloids belonging
to the aporhoedane series isolated from Chilean Berberi-
daceae.1 Although biogenetically related to protober-
berines,2,3 and usually classified as isoquinoline alkaloids,
they are distinguished by the presence of an isoindolo-
[1,2-b][3]benzazepine system. This system has been the
objective of several synthetic approaches based on bio-
mimetic pathways,4 electrophilic alkylation,5 photochem-
istry of enamides,6 or vinyl azide chemistry.7 More
recently, the five-membered ring has also been formed
by a combination of intramolecular aromatic substitution
and radical cyclization.8 We now report the total syn-
thesis of lennoxamine (1) by two new approaches in which
radical cyclizations are used either to prepare the mac-
rocyclic lactam intermediate 2a (route a) or as the final
step in the construction of the azepine nucleus from the
methylenephthalimidine 3 (route b).
Sch em e 2a
Resu lts a n d Discu ssion
We recently showed that the unsubstituted 10-mem-
bered lactam 2b, obtained by radical macrocyclization,
could be regioespecifically converted by transannular
cyclization into products with either the isoindolobenza-
zepine or the protoberberine skeletons.9 We therefore
pursued this strategy to obtain the alkaloid lennoxamine
(1). The precursor to the required 10-membered lactam
2a is the trimethylsilyl derivative 4, which was prepared
from piperonal (5) and 2,3-dimethoxybenzoic acid (6) as
shown in Scheme 2.
a
Reagents: (i) CH3NO2, NaOAc, CH3NH‚HCl, rt, 94%; (ii) Zn-
Hg, CH3OH, HCl, 85%; (iii) Br2, AcOH, rt, 78%; (iv) (a) Tl(O-
COCF3)3, CF3COOH; (b) NaI, 94%, (v) SOCl2; (vi) Et3N, THF, 83%;
(vii) (trimethylsilyl)acetylene, PdCl2(PPh3)2, CuI, Et3N, 89%.
2,3-Dimethoxybenzoic acid (6) was iodinated10 (94% yield)
and subsequently converted into the acid chloride 8. The
amide 9 was readily obtained in 83% yield by condensa-
tion of 7 and 8 in THF at room temperature in the
presence of triethylamine. Finally, treatment of the
dihalogenated amide 9 with (trimethylsilyl)acetylene (1.1
equiv) in the presence of CuI (0.05 equiv) and PdCl2-
(PPh3)2 (0.05 equiv)11 in triethylamine at room temper-
ature under argon gave the bromo amide 4 chemoselec-
tively in 89% yield (Scheme 2).
The radical reaction was performed by slow (5 h)
dropwise addition of a benzene solution of tributyltin
hydride (2 equiv) and AIBN (20% by weight) to a
refluxing benzene solution (5 mM) of the bromo amide 4
under argon. This gave a 74% yield of the desired
macrocycle 2a , derived by endo cyclization resulting from
intramolecular attack by the aryl radical on the terminal
end of the triple bond (Scheme 3). A single geometric
Piperonal (5) was converted in three steps into the
corresponding bromophenethylamine 7 (62% overall yield).
† Dedicated to Prof. Antonio Gonza´lez Gonza´lez in celebration of his
half-century of contribution to natural product chemistry.
X Abstract published in Advance ACS Abstracts, March 15, 1996.
(1) Valencia, E.; Weiss, I.; Firdous, S.; Freyer, A.; Shamma, M.;
Urzu´a, A.; Fajardo, V. Tetrahedron 1984, 40, 3957.
(2) Moniot, J . L.; Hindenlang, D. M.; Shamma, M. J . Org. Chem.
1979, 44, 4347.
(3) Dorn, C. R.; Koszyk, F. J .; Lenz, G. R. J . Org. Chem. 1984, 49,
2642.
(4) Kessar, S. V.; Singh, T.; Vohra, R. Indian J . Chem. 1991, 30B,
299.
(5) Napolitano, E.; Spinelli, G.; Fiaschi, R.; Marsili, A. J . Chem. Soc.
Perkin Trans. 1 1986, 785.
(6) Bernhard, H. O.; Snieckus, V. Tetrahedron Lett. 1971, 4867.
(7) Moody, C. J .; Warrellow, G. J .; Tetrahedron Lett. 1987, 28, 6089.
(8) (a) Yasuda, S.; Sugimoto, Y.; Mukai, C.; Hanaoka, M. Heterocycles
1990, 30, 335. (b) Ishibashi, H., Kawanami, H., Iriyama, H., Ikeda,
M. Tetrahedron Lett. 1995, 36, 6733.
(10) Dyke, S. F.; Tiley, E. P.; Tetrahedron 1975, 31, 561.
(11) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627.
(9) Lamas, C.; Saa´, C.; Castedo, L.; Dom´ınguez, D. Tetrahedron Lett.
1992, 33, 5653.
0022-3263/96/1961-2780$12.00/0 © 1996 American Chemical Society

Radical Cyclization Approach to Isoindolobenzazepines
J . Org. Chem., Vol. 61, No. 8, 1996 2781
Sch em e 3
We therefore proceeded to apply this strategy to the
synthesis of lennoxamine (1). The methylenephthalimi-
dine 3 was readily obtained by desilylation and further
cyclization of 4 under basic conditions (95% yield)16 and
was then subjected to radical cyclization under the same
conditions as for 11, giving a 61% yield of lennoxamine
(1).
To sum up, we obtained good yields of the isoindolo-
[1,2-b][3]benzazepine skeleton by both radical macrocy-
clization (route a) and aryl-radical cyclization of an
enamide double bond (route b). Both cyclizations were
regioselective, giving 10-endo-dig or 7-endo-trig adducts,
respectively. In the former case, the resulting macrocycle
was finally transformed into lennoxamine by transan-
nular cyclization. We are currently exploring the utility
of these reactions for the synthesis of other natural
products.
Sch em e 4
Exp er im en ta l Section
Gen er a l. All reactions were carried out under argon.
Solvents were dried by distillation from a drying agent: THF
and benzene from Na/benzophenone, Et3N from CaH2. Slow
additions were carried out using a syringe pump (Harvard 11).
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3.
N-[2-(6-Br om o-1,3-b en zod ioxol-5-yl)et h yl]-2-iod o-5,6-
d im eth oxyben za m id e (9). To a cold, stirred solution of 717
(1 g, 4.09 mmol) and triethylamine (1.2 mL, 8.6 mmol) in THF
(5 mL) under argon was added dropwise (via a cannula) a
solution of 8 (1.5 g, 4.6 mmol) in 5 mL of THF. Once addition
was finished, stirring was continued for 12 h at room temper-
ature. The residue obtained by removal of volatiles under
reduced pressure was dissolved in CH2Cl2, and this solution
was washed with 5% HCl, dried over Na2SO4 and evaporated
to dryness to yield 1.81 g of 9 (83%), which was crystallized
as fine crystals of mp 155-157 °C (MeOH). IR (KBr) ν 3260,
isomer of unknown stereochemistry was obtained, which
contrasts with the E/Z-mixture observed when the cor-
responding desilylated acetylene9 was subjected to the
same cyclization conditions.
Having prepared the macrolactam 2a , we next inves-
tigated how to achieve transannular cyclization through
nucleophilic attack by the nitrogen atom. We found that
under basic conditions (0.2 equiv of potassium tert-
butoxide in THF under argon at room temperature),
addition at the â-position of the vinylsilane occurred to
give 10. Desilylation by addition of tetrabutylammonium
fluoride (1.1 equiv in THF) to the crude reaction mixture
at room temperature12 led to the isoindolobenzazepine
lennoxamine (1) in 60% yield (over two steps). The
spectroscopic data of synthetic 1 agree with those re-
ported for the natural alkaloid.13
Our second approach to lennoxamine is based on our
previous results concerning the efficient synthesis of
benz[d]indeno[1,2-b]azepines by intramolecular addition
of an aryl radical to an enamide double bond.14 We were
intrigued by the possibility of generating the 3-benza-
zepine unit of lennoxamine by a related cyclization in the
methylenephthalimidine 3 (Scheme 1). This type of
precursor has previously been used by Snieckus,6 who
reported its photochemical transformation into isoin-
dolobenzazepines, albeit in poor yields (20%).
3080, 2940, 1640, 1480 cm-1 1H NMR δ 7.46 (d, J ) 8.7 Hz,
.
1H), 6.99 (s, 1H), 6.89 (s, 1H), 6.66 (d, J ) 8.7 Hz, 1H), 5.94
(s, 2H), 5.78 (m, NH), 3.84 (s, 6H), 3.69 (m, 2H), 3.01 (t, J )
7 Hz, 2H). 13C NMR δ 167.3, 153.1, 147.5, 147.2, 146.6, 137.8,
134.6 (CH), 131.1, 114.9 (CH), 114.6, 112.8 (CH), 110.7 (CH),
101.6 (CH2), 81.1, 62.0 (CH3), 55.9 (CH3), 39.6 (CH2), 35.6
(CH2). MS m/z (relative intensity) 454 (M+ - Br, 19), 291
(100), 228 (90), 226 (90). Anal. Calcd for C18H17NO5BrI, C
40.47, H 3.2, N 2.62. Found: C 40.14, H 3.12, N 2.84.
N-[2-(6-Bromo-1,3-benzodioxol-5-yl)ethyl]-5,6-dimethoxy-2--
[(tr im eth ylsilyl)eth yn yl]ben za m id e (4). Compound 9 (0.2
g, 0.37 mmol), PdCl2(PPh3)2 (13 mg, 0.02 mmol), CuI (4 mg,
0.02 mmol), and (trimethylsilyl)acetylene (160 µL, 1.11 mmol)
were placed in a flask containing 5.5 mL of degassed Et3N,
and this reaction mixture was stirred under argon for 6 h at
room temperature. The resulting suspension was vacuum
filtered through a pad of Celite. The filtrate was concentrated
and dissolved in CH2Cl2. The resulting solution was washed
with 5% HCl, dried over Na2SO4, and chromatographed on
silica gel. Benzamide 4 (0.17 g, 89%) was obtained as colorless
crystals of mp 133-135 °C (MeOH). IR (KBr) ν 3260, 2960,
2940, 2160, 1680, 1485, 855, 850 cm-1 1H NMR δ 7.22 (d, J
.
As a preliminary, we investigated the behavior of the
dimethoxy derivative 11 (see Scheme 4), which was
prepared by heating 6-bromohomoveratrylamine with
2-acetylbenzoic acid at 140 °C for 1 h (94% yield).15 When
11 (0.05 M in benzene) was subjected to the radical
conditions, regioselective 7-endo-trig cyclization gave the
desired 3-benzazepine 12 in 81% yield (Scheme 4).
) 8.5 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.84 (d, J ) 8.5 Hz,
1H), 5.94 (s, 2H), 5.88 (m, NH), 3.87 (s, 3H), 3.85 (s, 3H), 3.65
(m, 2H), 2.99 (t, J ) 7.1 Hz, 2H), 0.2 (s, 9H). 13C NMR δ 166.1,
153.4, 147.5, 147.2, 145.8, 135.1, 131.2, 129.3 (CH), 114.5,
113.3, 112.7 (2 x CH), 110.7 (CH), 102.1, 101.6 (CH2), 96.4,
61.9 (CH3), 55.8 (CH3), 39.6 (CH2), 35.8 (CH2), -0.15 (CH3).
MS m/z (relative intensity) 505 (M+, 3), 424 (6), 278 (45), 261
(100), 228 (28), 226 (28). Anal. Calcd for C23H26NO5BrSi, C
54.76, H 5.19, N 2.78. Found: C 54.51, H 5.18, N 2.84.
7,8-Dih ydr o-13-(tr im eth ylsilyl)diben z[c,g]azecin -5(6H)-
on e (2a ). To a solution of 4 (0.1 g, 0.2 mmol) in 40 mL of dry
(12) Mills, R. J .; Taylor, N. J .; Snieckus, V. J . Org. Chem. 1989, 54,
4372.
(13) Valencia, E.; Freyer, A. J .; Shamma, M.; Fajardo, V. Tetrahe-
dron Lett. 1984, 25, 599.
(14) Fidalgo, J .; Castedo, L.; Domı´nguez, D. Tetrahedron Lett. 1993,
34, 7317.
(15) Gabriel, S.; Giebe, G. Chem. Ber. 1896, 29, 2518.
(16) Padwa, A.; Krumpe, K. E.; Weingarten, M. D. J . Org. Chem.
1995, 60, 5595.
(17) Harley-Mason, J . J . Chem. Soc. 1953, 200.

2782 J . Org. Chem., Vol. 61, No. 8, 1996
Rodr´ıguez et al.
degassed benzene, refluxing under argon, a solution of n-Bu3-
SnH (0.11 mL, 2 equiv) and AIBN (20 mg, 20% by weight) in
10 mL of benzene was added via a syringe pump over 5 h.
Once addition had finished, refluxing was kept up for a further
4 h. The benzene was evaporated under vacuum, and the
resulting residue was dissolved in CH3CN. This solution was
washed with hexane, dried over Na2SO4, concentrated, and
chromatographed on silica gel using 1:2 EtOAc/hexane as
eluent. Macrolactam 2a (64 mg, 74%) was obtained as
colorless crystals of mp 187-189 °C (MeOH). IR (KBr) ν 3380,
1H), 7.57 (dt, J ) 7.4, J ) 1 Hz, 1H), 7.49 (dt, J ) 7.5, J ) 1
Hz, 1H), 7.00 (s, 1H), 6.68 (s, 1H), 5.16 (d, J ) 2.4 Hz, 1H),
4.98 (d, J ) 2.4 Hz, 1H), 3.99 (t, J ) 7.4 Hz, 2H), 3.85 (s, 3H),
3.68 (s, 3H), 3.04 (t, J ) 7.4 Hz, 2H). 13C NMR δ 167.5, 148.9,
148.8, 142.0, 136.7, 132.3 (CH), 130.1, 129.9 (CH), 129.6, 123.4
(CH), 120.3 (CH), 115.7 (CH), 114.5, 113.9 (CH), 89.6 (CH2),
56.5 (CH3), 56.4 (CH3), 39.7 (CH2), 34.9 (CH2). MS m/z
(relative intensity) 308 (M+ - Br, 100), 244 (28), 242 (28), 158
(40). Anal. Calcd for C19H18NO3Br, C 58.76, H 4.64, N 3.61.
Found: C 59.10, H 4.63, N 3.61.
2940, 1695, 1505, 1480, 845 cm-1
.
1H NMR δ 6.93 (s, 2H),
7,8,13,13a -Tetr a h yd r o-10,11-d im eth oxy-5H-isoin d olo-
[1,2-b][3]ben za zep in -5-on e (12). To a solution of 11 (0.29
g, 0.75 mmol) and AIBN (58 mg, 20% by weight) in 80 mL of
dry degassed benzene, refluxing under argon, was added n-Bu3-
SnH (0.42 mL, 1.56 mmol) dropwise over 6 min. Once addition
had finished, refluxing was kept up for a further 6 h. The
benzene was evaporated under reduced pressure, and the
resulting residue was taken up in CH3CN. This solution was
washed with hexane, dried over Na2SO4, concentrated, and
chromatographed on silica gel using 1:1 EtOAc/hexane as
eluent. Benzazepine 12 (0.19 g, 81%) was obtained as colorless
crystals of mp 179 °C (EtOAc). IR (KBr) v 3455, 1684, 1518,
6.85 (s, 1H), 6.67 (s, 1H), 6.58 (s, 1H), 5.93 (m, 2H), 5.50 (m,
NH), 4.14 (m, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.30 (m, 1H), 2.98
(m, 1H), 2.34 (m, 1H), -0.10 (s, 9H). 13C NMR δ 167.9, 152.2,
149.9, 147.3, 145.7, 145.5, 145.1 (CH), 139.8, 132.7, 132.6,
130.7, 122.3 (CH), 113.3 (CH), 110.9 (CH), 107.2 (CH), 100.8
(CH2), 61.9 (CH3), 55.9 (CH3), 43.7 (CH2), 31.2 (CH2), -0.7
(CH3). MS m/z (relative intensity) 425 (M+, 19), 382 (23), 352
(100), 351 (23), 337 (29), 336 (35), 73 (23). Anal. Calcd for
C23H27NO5Si, C 64.92, H 6.39, N 3.29. Found: C 64.93, H 6.56,
N 3.46.
Len n oxa m in e (1). A suspension of 2a (0.2 g, 0.5 mmol)
and potassium tert-butoxide (11.5 mg, 0.1 mmol) in 4 mL of
dry THF was stirred under argon for 1 h, concentrated under
vacuum, and dissolved in CH2Cl2. This solution was washed
with NH4Cl and brine, dried over Na2SO4, and finally concen-
trated at reduced pressure to give crude 10. IR ν 2954, 2857,
1293 cm-1 1H NMR δ 7.87 (d, J ) 7.5 Hz, 1H), 7.59-7.46 (m,
.
3H), 6.83 (s, 1H), 6.74 (s, 1H), 4.82-4.76 (m, 1H), 4.43 (d, J )
9.8 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.19 (dd, J ) 14.7, 1.6
Hz, 1H), 3.05-2.81 (m, 4H). 13C NMR δ 167.5, 148.0, 147.6,
145.3, 134.1, 132.4, 131.9 (CH), 130.1, 128.8 (CH), 124.2 (CH),
122.5 (CH), 114.1 (CH), 113.9 (CH), 61.8 (CH), 56.5 (CH3), 56.4
(CH3), 42.6 (CH2), 41.9 (CH2), 36.3 (CH2). MS m/z (relative
intensity) 309 (M+, 100), 294 (43), 177 (73). Anal. Calcd for
C19H19NO3, C 73.79, H 6.15, N 4.53. Found: C 73.86, H 6.33,
N 4.58.
1684, 1491, 1429, 1267, 1040, 844 cm-1 1H NMR δ 7.16 (d, J
.
) 8.2 Hz, 1H), 7.12 (d, J ) 8.2 Hz, 1H), 6.65 (s, 2H), 5.95 (m,
2H), 4.64 (m, 2H), 4.09 (s, 3H), 3.91 (s, 3H), 2.98-2.77 (m, 4H),
-0,32 (s, 9H). 13C NMR δ 165.8, 152.8, 147.4, 146.1, 145.5,
137.9, 135.8, 133.1, 125.0, 117.8 (CH), 115.9 (CH), 111.1 (CH),
110.6 (CH), 101.0 (CH2), 62.7 (CH3), 62.5 (CH3), 56.7 (CH), 44.0
(CH), 41.1 CH2), 35.8 (CH2), 0.8 (CH3). MS m/z (relative
intensity) 425 (M+, 67), 424 (100), 410 (30), 394 (18), 352 (13),
336 (12), 264 (27), 149 (11), 76 (56).
N-[2-(6-Br om o-1,3-ben zod ioxol-5-yl)eth yl]-2,3-d ih yd r o-
6,7-d im eth oxy-3-m eth ylen e-1H-isoin d ol-1-on e (3). Potas-
sium carbonate (90 mg, 0.65 mmol) was added to a stirred
solution of 4 (91 mg, 0.18 mmol) in methanol (2 mL), and the
reaction mixture was kept at room temperature for 30 min.
The solid was filtered off, the solvent was removed from the
filtrate under reduced pressure, and the resulting residue was
chromatographed on silica gel using 1:3 EtOAc/hexane as
eluent. Phthalimidine 3 was obtained (74 mg, 95%) as
colorless crystals of mp 149 °C (EtOAc). IR (KBr) ν 3459, 1714,
Tetrabutylammonium fluoride (0.22 g, 0.84 mmol) (1 M
solution in THF, from Acros Chimica) was added to a solution
of this crude product in 3 mL of THF, and this mixture was
stirred at room temperature for 15 min, concentrated, and
dissolved in CH2Cl2. This solution was washed, dried over Na2-
SO4, concentrated under vacuum, and finally chromatographed
on silica gel using 1:2 EtOAc/hexane as eluent. Lennoxamine
(1) (0.1 g, 60%) was obtained as colorless crystals of mp 223-
225 °C (lit.13 225 °C) (MeOH). IR (KBr) ν 2950, 1685, 1430,
1510, 1220 cm-1
.
1H NMR δ 7.35 (d, J ) 8.2 Hz, 1H), 7.13 (d,
J ) 8.2 Hz, 1H); 7.01 (s, 1H), 6.78 (s, 1H), 5.91 (s, 2H), 5.08 (s,
1H), 4.83 (s, 1H), 4.10 (s, 3H), 3.91 (s, 3H), 3.89 (m, 2H), 3.00
(t, J ) 7.7 Hz, 2H). 13C NMR δ 166.1, 154.0, 147.9, 147.7,
141.5, 131.4, 130.6, 123.6, 116.7 (CH); 115.6 (CH), 114.9, 113.1
(CH), 111.0 (CH), 102.1 (CH2), 87.1 (CH2), 62.9 (CH3), 57.1
(CH3), 39.8 (CH2), 35.2 (CH2). MS m/z (relative intensity) 352
(M+ - Br, 100), 218 (62). Anal. Calcd for C20H18BrNO5, C
55.55, H 4.17, N 3.24. Found: C 55.27, H 4.32, N 3.17.
1290, 1270, 1040 cm-1 1H NMR δ 7.17 (d, J ) 8.2 Hz, 1H),
.
7.12 (d, J ) 8.2 Hz, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 5.95 (d, J
) 1.4 Hz, 1H), 5.94 (d, J ) 1.4 Hz, 1H), 4.73 (m, 1H) 4.29 (dd,
J 13a,13R ) 1.3, J 13a,13â ) 10.6 Hz, H13a), 4.09 (s, 3H), 3.91 (s,
3H), 3.09 (dd, J 13a,13R ) 1.3, J 13R,13â ) 14.6 Hz, H13R), 2.81 (dd,
J 13a,13â ) 10.6, J 13R,13â ) 14.6 Hz, H13â), 2.99-2.77 (m, 3H). 13
C
NMR δ 165.2, 152.7, 147.4, 146.4, 146.2, 138.3, 134.9, 131.0,
124.2, 117.1 (CH), 116.4 (CH), 110.4 (2 × CH), 101.1 (CH2),
62.5 (CH3), 60.1 (CH), 56.8 (CH3), 42.7 (CH2), 41.1 (CH2), 35.9
(CH2). MS m/z (relative intesity) 353 (M+, 100), 352, 23), 338
(67), 335 (43), 162 (76), 161 (90), 131 (73). Anal. Calcd for
C20H19NO5, C 67.98, H 5.42, N 3.96. Found: C 68.18; H 5.17,
N 3.88.
Len n oxa m in e (from 3). To a solution of 3 (31 mg, 0.07
mmol) and AIBN (7 mg, 20% by weight) in dry degassed
benzene (12 mL), refluxing under argon, was added n-Bu3SnH
(50 µL, 0.14 mmol) over 2 min. Once addition had finished
refluxing was kept up for 5 h. After the usual workup, the
residue was chromatographed on silica gel using 1:1 EtOAc/
hexane, which gave lennoxamine (15mg, 61%).
N-[2-(2-Br om o-4,5-dim eth oxyph en yl)eth yl]-2,3-dih ydr o-
3-m eth ylen e-1H-isoin d ol-1-on e (11). A mixture of 6-bro-
mohomoveratrylamine (0.97 g, 3.74 mmol) and 2-acetylbenzoic
acid (0.66 g, 4.02 mmol) was heated at 140 °C for 1 h. Once
the mixture had cooled to room temperature, EtOAc (2 mL)
was added and the mixture was then left at 0 °C overnight,
affording a crystalline solid (1.36 g, 94%) which was identified
as 11. Mp 123 °C (EtOAc). IR (KBr) ν 3416, 1720, 1507, 1216
Ack n ow led gm en t. We are grateful to the CICYT
and the Xunta de Galicia for financial support under
projects SAF93-0607 and XUGA 26202A92, respec-
tively. G. Rodr´ıguez and M. M. Cid thanks the Xunta
de Galicia and CICYT, respectively, for fellowships.
cm-1
.
1H NMR δ 7.82 (d, J ) 7.4 Hz, 1H), 7.67 (d, J ) 7.5 Hz,
J O952113K