A new approach to isoindolobenzazepines. A simple synthesis of lennoxamine

Article abstract of DOI:10.1016/S0040-4020(00)00067-3

A convenient and versatile short-step synthesis of isoindolobenzazepines, illustrated by a total synthesis of the alkaloid lennoxamine 1, is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00067-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1491–1499
A New Approach to Isoindolobenzazepines.
A Simple Synthesis of Lennoxamine
*
Axel Couture, Eric Deniau, Pierre Grandclaudon and Christophe Hoarau
´
Laboratoire de Chimie Organique Physique, UPRES A 8009, Universite des Sciences et Technologies de Lille,
F-59655 Villeneuve d’Ascq Cedex, France
Received 3 November 1999; accepted 25 January 2000
Abstract—A convenient and versatile short-step synthesis of isoindolobenzazepines, illustrated by a total synthesis of the alkaloid
lennoxamine 1, is described. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
besides by oxygenated substituents render these molecules
attractive and synthetically challenging targets. The ring
system which is accessible in vivo and in vitro by oxidation
of berbine alkaloids1,8,9 has been the objective of several
synthetic approaches which involve (i) the cyclization of
2-arylbenzazepine derivatives ortho-substituted with
carboxylate groups10,11 (ii) the ring-expansion of isoindolo-
isoquinoline derivatives obtained by cyclization of acyli-
minium precursors12 (iii) the Pummerer rearrangement of
3-phenylsulfanylisoindolinones followed by intramolecular
electrophilic aromatic substitution and desulfuration13 and
(iv) the photochemically induced cyclization of aromatic
enamides.14 They are also accessible through biomimetic
pathways,15 by means of a regioselective 7-endo-trig radical
cyclization of methylenephthalimidines16 and by cyclization
under harsh conditions of a chlorovinyl ether derived
from 3-arylmethylphthalimidines.17 All these synthetic
approaches invariably involve either the formation of the
isoindolinone template or of the azepine ring system
found in the alkaloid framework for the final step. The
Isoindolobenzazepine alkaloids, exemplified by lennoxa-
mine 1 (Fig. 1), are a new class of alkaloids belonging to
the aporhoedane series which have been extracted from
Chilean Berberidaceae.1 They are biogenetically related
to protoberberines and usually ranked as isoquinoline
alkaloids but their main structural feature is the presence
of the distinctive isoindolo[1,2-b][3]benzazepine unit
embedded in their skeleton.
Despite the fact that their structures incorporate the 3H-3-
benzazepine moiety which possesses important biological
activities2 and equally an isoindolinone ring system which is
interesting due to the real and potential biological properties
of many of its derivatives,3–7 these alkaloids appear to be
devoid of any useful pharmacology. However, their archi-
tecturally sophisticated structures which include five- and
seven-membered rings fused with environmentally different
aromatic moieties contiguously and differently substituted
sole exception concerns
a synthetic route recently
developed by C. Saa et al. who incidentally observed the
simultaneous formation of the five and seven-membered
rings by fluoride-induced transannular macrocyclization of
silylated 10-membered-ring-stilbene lactams.18
Results and Discussion
We now report an alternative, more efficient and tactically
new approach to isoindolobenzazepines, illustrated by the
total synthesis of the alkaloid lennoxamine 1, which has
been isolated as a racemate from the Chilean barberries
Berberis darwinii Hook.19 Our strategy, which is depicted
in retrosynthetic Scheme 1, is based on the use of 3-aryl-
methylenelactams 4–6 as key intermediates (see Table 1).
Figure 1.
Keywords: alkaloids; benzazepines; carbanions; cyclisation.
* Corresponding author. Fax: ϩ33-3-20-33-63-09;
e-mail: axel.couture@univ-lille1.fr
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00067-3

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A. Couture et al. / Tetrahedron 56 (2000) 1491–1499
Scheme 1.
These lactams were obtained by Horner reaction between
a suitably substituted benzaldehyde 10–12 and the
phosphorylated isoindolinones possessing an acetaldehyde
dimethylacetal appendage 7–9. Two reduction steps
supporting a cyclization process performed on the aryl-
methyleneisoindolinones 4–6 then should complete the
synthesis of the target isoindolobenzazepines 1–3.
Exposure of the phosphorylated bromobenzamide deriva-
tives 18 and 19 to potassium bis(trimethylsilyl)azide
(KHMDS, 2 equiv.) at Ϫ78ЊC in THF induced the regio-
selective formation of the phosphoryl stabilized a-amino-
carbanion and the concomitant formation of the aryne unit.
Addition of the carbon nucleophile across the aryne moiety
caused an intramolecular arylation reaction and after usual
work-up the phosphorylated isoindolinones 8 and 9 were
obtained with excellent yields (Scheme 4).
The first facet of this synthesis, the assembly of the
phosphorylated isoindolinone unit equipped with the acetal
functionality, was accomplished by taking advantage of a
newly developed aryne-mediated cyclization method-
ology applied to halogeno-N-(phosphinylmethyl)benzamide
derivatives.20–22 The required parent phosphorylated
carboxamides 17–19 were easily and efficiently synthesized
by coupling the N-[(diphenylphosphinyl)methyl]-N-(2-yl-
acetaldehyde dimethylacetal) 16 with the acid chlorides
13–15 (Scheme 2).
Horner reaction between the metallated isoindolinone 8 and
9 and the suitably substituted aromatic carboxaldehydes 11
and 12 proceeded uneventfully to afford fairly good yields
of the 3-arylmethyleneisoindolinones 5 and 6 (Scheme 5) in
both E- and Z-forms but with the E-form predominant by a
large margin as unambiguously assigned from their 1H
NMR spectra with the help of NOE experiments.† For the
reduction of the exocyclic carbon–carbon double bond of
enamides 5 and 6 a rarely employed method making use of
Pd on C and ammonium formate23,24 was tested and, to our
delight, this protocol delivered straightforwardly and
quantitatively the 3-arylmethylisoindolinones 23 and 24,
candidates for the final cyclization step (Scheme 5). Thus
treatment of compounds 23 and 24 with acetic acid in the
presence of sulfuric acid gave cyclization of the opened
models and formation of the endocyclic aromatic enamides
26 and 27 with very satisfactory yields (Scheme 5). The
ultimate reduction of the N–CvC unit of the annulated
compounds 26 and 27 was performed by repeating the
previously mentioned procedure and this protocol afforded
the desired isoindolobenzazepines 2 and 3 in excellent
yields (Scheme 5).
This synthetic route necessitated the preliminary elabora-
tion of the polyfunctional secondary amine 16. We found
that this amine could be readily prepared via the two step
sequence depicted in Scheme 3 involving the treatment with
diphenylphosphine oxide of the appropriate hexahydro-
triazine 21, product of the Mannich reaction of amino-
acetaldehyde dimethylacetal 20.
Table 1. Compounds prepared and/or used
Compound
R1
R2
R3 R4
R5
R6
1, 4, 22, 25 OMe OMe
H
H
H
H
–O–CH2–O
OMe
2, 5, 23, 26
3, 6, 24, 27
7, 13, 17
8, 14, 18
9, 15, 19
10
H
H
H
OMe
OMe
–
–
–
–O–CH2–O
OMe OMe
–
–
–
H
H
OMe OMe
H
H
–
–
–
H
H
–
H
–O–CH2–O
–
–
–
–
–
–
–O–CH2–O
OMe
†
The structure and the E/Z ratio were established by NOE difference
11
–
OMe
OMe
experiments. For E-isomers, the N-methylene H2 (d 4.01 ppm) showed a
strong NOE to vinylic H (d 6.68 ppm, 20%) [values given for 5(E)].
12
–
OMe OMe

A. Couture et al. / Tetrahedron 56 (2000) 1491–1499
1493
Scheme 2.
Scheme 3.
Scheme 4.
Scheme 5.

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A. Couture et al. / Tetrahedron 56 (2000) 1491–1499
Scheme 6.
Scheme 7.

A. Couture et al. / Tetrahedron 56 (2000) 1491–1499
1495
Encouraged by the success of the aryne-mediated cycliza-
Experimental
tion of phosphorylated o-bromobenzamides associated with
four appealing, convenient and efficient steps of procedural
simplicity, we then proceeded to apply this method to the
synthesis of isoindolobenzazepine alkaloid lennoxamine 1.
The required parent ortho-bromobenzamide derivative 17
was conveniently prepared as depicted in Scheme 2.
However, to our surprise, the basic treatment of 17 did not
give rise to the expected dimethoxyisoindolinone 7 but
instead to the bromomethoxy analogue 28, product
arising from the intramolecular nucleophilic aromatic
substitution by the preliminarily generated a-amino-
carbanion (Scheme 6).
General
Methanol and ethanol were distilled from magnesium
turnings. Tetrahydrofuran (THF) and ether (Et2O) were
pre-dried with anhydrous Na2SO4 and distilled over sodium
benzophenone ketyl under Ar before use. CH2Cl2, NEt3 and
toluene were distilled from CaH2. Dry glassware was
obtained by oven-drying and assembly under dry Ar. The
glassware was equipped with rubber septa and reagent
transfer was performed by syringe techniques. For flash
chromatography, Merck silica gel 60 (230–400 mesh
ASTM) was used. The melting points were measured on a
Reichert–Thermopan apparatus and are not corrected.
Unless otherwise stated, proton, carbon and phosphorus
NMR spectra were recorded with CDCl3 as solvent at 300,
75 and 121 MHz respectively on a Bruker AM 300
spectrometer. Microanalyses were performed by the
CNRS microanalysis centre.
Assuming that this failure could be attributable to the diffi-
culties associated with the formation of the aryne moiety in
compounds such as 17 we then anticipated that the replace-
ment of the bromine by a fluorine atom could circumvent
this problem by facilitating the ortho-metallation process
required for the generation of the aryne functionality.25 It
is indeed well established that the rates of initial proton
removal assisted by halogen atoms rank as FϾClϾBrϾI.25
We thus set out to prepare the ortho-fluorobenzamide
derivative 30. The synthesis started with the preparation
of the ortho-fluorobenzoic acid 29 which was easily
prepared by regioselective metallation at the ‘in between’
position of 4-fluoroveratrole26 and subsequent trapping of
the transient lithiated species with carbon dioxide (Scheme
7). This protocol delivered exclusively the ortho-fluoro-
benzoic acid 29 albeit in moderate yield (63%). Conversion
into the corresponding acid chloride and subsequent reac-
tion with the phosphorylated amine 16 afforded the desired
ortho-fluorobenzamide derivative 30 almost quantitatively
(Scheme 7).
Synthesis of the phosphorylated amine 16
Triazine 21. A suspension of paraformaldehyde (4.3 g) in a
solution of aminoacetaldehyde dimethylacetal 20 (15 g,
14.2 mmol) in CH2Cl2 (150 mL) was stirred at room
temperature for 2 h. After filtration, evaporation of the
solvent left a colourless oil (15.9 g, 95%) corresponding
to the triazine 21 which was used in the next step without
1
further purification; H NMR d 2.57 (d, Jˆ5.2 Hz, 6H,
NCH2), 3.28 (s, 18H, OCH3), 3.44 (br. s, 6H, NCH2N),
4.36 (t, Jˆ5.2 Hz, 3H, CHOMe2); 13C NMR d CH 103.8,
CH 2 54.3, 75.0, CH 3 53.5.
Phosphorylated amine 16. A solution of triazine 21
(12.45 g, 35.5 mmol) and diphenylphosphine oxide27
(21.5 g, 106.4 mmol) was refluxed in toluene (300 ml) for
1 h under Ar. After evaporation of the solvent under vacuum
the crude product was chromatographed on SiO2 column
using acetone/hexane (80:20) as eluent and the phosphoryl-
ated amine 16 was finally purified by recrystallization from
Gratifyingly our expectations were successfully fulfilled
because, when the phosphorylated ortho-fluorobenzamide
30 was treated with KHMDS, regioselective cyclization
took place to give the desired dimethoxyisoindolinone 7
exclusively and in excellent yield (90%, Scheme 7). Horner
reaction between the phosphorylated isoindolinone 7 and
piperonal afforded, after reduction of the arylmethylene
derivative 4, the 3-arylmethylisoindolinone 22 (Scheme
7). This compound was in turn subjected to the cyclization
conditions described above and the resulting endocyclic
enamide 25 was finally transformed into the target natural
product lennoxamine 1 in a 66% yield (over the last five
steps).
1
hexane/toluene: 28.5 g (84%); mp 69–70ЊC; H NMR d
2.01 (br. s, 1H, NH), 2.75 (d, Jˆ5.4 Hz, 2H, NCH2), 3.25
(s, 6H, OCH3), 3.48 (d, Jˆ7.5 Hz, 2H, NCH2P), 4.35 (t,
Jˆ5.4 Hz, 1H, CHOMe2), 7.32–7.48 (m, 6H, Harom),
7.70–7.77 (m, 4H, Harom); 13C NMR d C 131.7 (d,
JCPˆ84 Hz), CH 103.6, 128.6 (d, JCPˆ12 Hz), 131.1 (d,
JCPˆ9 Hz), 131.9 (d, JCPˆ2 Hz), CH2 49.4, 52.4, CH
3
53.9; 31P NMR d 29.2. Anal. Calcd for C17H22NO3P: C,
69.94; H, 6.94; N, 4.39. Found: C, 70.18; H, 6.73; N, 4.55.
Conclusion
Synthesis of the ortho-fluorobenzoic acid 29
In conclusion the 3-arylmethyleneisoindolinone synthesis,
consecutive reduction and sequential cyclization and reduc-
tion reactions reported here, proceeds in high yields and
affords efficient access to isoindolobenzazepine ring
systems. The total synthesis of alkaloid lennoxamine
emphasizes the synthetic potential of these exocyclic
aromatic enamides and we believe that this work demon-
strates a general new methodology for the preparation of
other naturally occurring isoindolobenzazepine alkaloids
as well as their biogenetically related congeners.
Metallation of 4-fluoroveratrole (1.56 g, 10 mmol) was
performed according to an already reported procedure26 by
making use of n-BuLi (1.6 M in hexanes, 7.8 ml,
12.5 mmol) in THF (40 ml) at Ϫ78ЊC. Dry ice was poured
into reaction mixture which was warmed to room tempera-
ture for 3 h. Water (40 ml) and Et2O (30 ml) were added.
The aqueous layer was acidified with aq HCl and the crude
product was extracted with Et2O (3×20 ml). Drying over
Na2SO4 and concentration in vacuo left 29 as a white
solid which was recrystallized from EtOH/H2O: 1.26 g

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A. Couture et al. / Tetrahedron 56 (2000) 1491–1499
(63%); mp 148–149ЊC; 1H NMR d 3.77 (s, 3H, OCH3), 3.80
(s, 3H, OCH3), 6.99 (t, Jˆ9.0 Hz, 1H, Harom), 7.12 (dd,
Jˆ9.0, 5.5 Hz, 1H, Harom), 10.53 (br. s, 1H, COOH); 13C
NMR d C 124.8 (d, JCFˆ21 Hz), 150.8 (d, JCFˆ6.5 Hz),
154.2 (d, JCFˆ2.5 Hz), 156.9 (d, JCFˆ240 Hz), 169.5
(CO), CH 115.7 (d, JCFˆ22 Hz), 119.4 (d, JCFˆ10 Hz),
Phosphorylated amide 30. (94%); mp 116–117ЊC; 1H
NMR d 3.20 (s, 3H, OCH3), 3.23 (s, 3H, OCH3), 3.52 (s,
3H, OCH3), 3.66 (d, Jˆ5.5 Hz, 2H, NCH2), 3.77 (s, 3H,
OCH3), 4.40 (t, Jˆ5.5 Hz, 1H, CHOMe2), 4.80 (d,
Jˆ5.7 Hz, 2H, NCH2P), 6.69 (t, Jˆ8.5 Hz, 1H, Harom),
6.78 (dd, Jˆ9.1, 5.2 Hz, 1H, Harom), 7.41–7.56 (m, 6H,
Harom), 7.83–7.99 (m, 4H, Harom); 13C NMR d C 119.3 (d,
JCFˆ21 Hz), 131.3 (d, JCPˆ98 Hz), 131.4 (d, JCPˆ99 Hz),
145.6 (d, JCFˆ6.5 Hz), 149.1 (d, JCFˆ3 Hz), 152.0 (d,
JCFˆ243 Hz), 164.5 (CO), CH 103.3, 110.4 (d,
JCFˆ22 Hz), 113.5 (d, JCFˆ9 Hz), 128.5 (d, JCPˆ12 Hz),
128.6 (d, JCPˆ12 Hz), 131.2 (d, JCPˆ10 Hz), 131.3 (d,
CH 61.4, 66.3. Anal. Calcd for C9H9FO4: C, 54.00; H,
3
4.53. Found: C, 53.84; H, 4.59.
Phosphorylated amides 17–19, 30
The phosphorylated amides 17–19, 30 were synthesized
according to an already reported procedure.21
JCPˆ10 Hz), 132.1, CH 44.6 (d, JCPˆ76 Hz), 50.1, CH
3
53.8, 54.1, 56.3, 61.2; 321P NMR d 30.0. Anal. Calcd for
C26H29FNO6P: C, 62.27; H, 5.83; N, 2.79. Found: C,
62.18; H, 6.03; N, 2.55.
1
Phosphorylated amide 17. (86%); mp 84–85ЊC; H NMR
d 3.16 (s, 3H, OCH3), 3.23 (s, 3H, OCH3), 3.50 (dd, Jˆ15.2,
6.0 Hz, 1H, NCH2), 3.51 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
3.77 (dd, Jˆ15.2, 5.2 Hz, 1H, NCH2), 4.42 (dd, Jˆ6.0,
5.2 Hz, 1H, CHOMe2), 4.68 (dd, Jˆ15.5, 6.1 Hz, 1H,
NCH2P), 4.94 (dd, Jˆ15.5, 5.0 Hz, 1H, NCH2P), 6.70 (d,
Jˆ8.8 Hz, 1H, Harom), 7.09 (d, Jˆ8.8 Hz, 1H, Harom), 7.39–
7.50 (m, 6H, Harom), 7.86–7.97 (m, 4H, Harom); 13C NMR d
C 109.1, 131.3 (d, JCPˆ98 Hz), 132.5, 146.0, 152.1, 166.7
(CO), CH 103.3, 114.4, 128.2, 128.6, 128.8 (d, JCPˆ12 Hz),
131.2 (d, JCPˆ10 Hz), 131.6 (d, JCPˆ10 Hz), 132.0, 132.1,
CH 2 44.2 (d, JCPˆ76 Hz), 49.9, CH 3 53.5, 53.9, 56.0, 61.3;
31P NMR d 30.1. Anal. Calcd for C26H29BrNO6P: C, 55.53;
H, 5.20; N, 2.49. Found: C, 55.58; H, 5.05; N, 2.45.
Phosphorylated isoindolinones 7–9, 28
The phosphorylated isoindolinones 7–9, 28 were synthe-
sized according to an already reported procedure.20
Phosphorylated isoindolinone 7. (90%); mp 142–143ЊC;
1H NMR d 3.27 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.34
(dd, Jˆ14.3, 6.9 Hz, 1H, NCH2), 3.79 (s, 3H, OCH3), 3.80
(s, 3H, OCH3), 3.98 (dd, Jˆ14.3, 3.7 Hz, 1H, NCH2), 4.52
(dd, Jˆ6.9, 3.7 Hz, 1H, CHOMe2), 5.67 (d, Jˆ8.7 Hz, 1H,
NCHP), 6.68 (dd, Jˆ8.4, 1.4 Hz, 1H, Harom), 6.89 (d,
Jˆ8.4 Hz, 1H, Harom), 7.32–7.68 (m, 10H, Harom); 13C
NMR d C 124.4 (d, JCPˆ2.5 Hz), 128.0 (d, JCPˆ102 Hz),
128.3 (d, JCPˆ98 Hz), 132.2, 147.1, 152.6, 167.0 (CO), CH
60.6 (d, JCPˆ73 Hz), 102.3, 116.1, 119.4, 128.5 (d,
JCPˆ11.5 Hz), 128.7 (d, JCPˆ12 Hz), 131.8 (d, JCPˆ9 Hz),
132.1 (d, JCPˆ9 Hz), 132.7 (d, JCPˆ2 Hz), 132.8 (d,
JCPˆ2 Hz), CH 42.8, CH , 53.4, 54.9, 56.6, 62.5; 31P
Phosphorylated amide 18. (92%); mp 143–144ЊC; 1H
NMR (mixture of two rotational isomers, 80:20): d (major
rotational isomer) 3.20 (s, 3H, OCH3), 3.26 (s, 3H, OCH3),
3.54 (dd, Jˆ15.0, 6.2 Hz, 1H, NCH2), 3.72 (dd, Jˆ15.0,
4.5 Hz, 1H, NCH2), 4.45 (dd, Jˆ6.2, 4.5 Hz, 1H,
CHOMe2), 4.78 (d, Jˆ5.2 Hz, 2H, NCH2P), 6.73 (dd,
Jˆ7.5, 1.8 Hz, 1H, Harom), 7.08–7.22 (m, 2H, Harom),
7.32–7.56 (m, 7H, Harom), 7.85–7.93 (m, 4H, Harom); 13C
NMR (mixture of two rotational isomers) d (major rota-
tional isomer) C 119.2, 131.3 (d, JCPˆ69 Hz), 136.9,
169.4 (CO), CH 103.0, 127.2, 128.5 (d, JCPˆ9.5 Hz),
128.6, 128.8 (d, JCPˆ11 Hz), 130.4, 131.2 (d, JCPˆ10 Hz),
2
3
NMR d 31.5. Anal. Calcd for C26H28NO6P: C, 64.86; H,
5.86; N, 2.91. Found: C, 64.78; H, 6.00; N, 2.85.
Phosphorylated isoindolinone 8. (88%); mp 175–176ЊC;
1H NMR d 3.26 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.46
(dd, Jˆ14.4, 6.6 Hz, 1H, NCH2), 4.04 (dd, Jˆ14.4, 4.0 Hz,
1H, NCH2), 4.54 (dd, Jˆ6.6, 4.0 Hz, 1H, CHOMe2), 5.77 (d,
Jˆ10.3 Hz, 1H, NCHP), 6.92 (t, Jˆ6.5 Hz, 1H, Harom),
7.28–7.64 (m, 13H, Harom); 13C NMR d C 127.6 (d,
JCPˆ98 Hz), 128.6 (d, JCPˆ98 Hz), 132.3 (d, JCPˆ3 Hz),
139.2, 168.9 (CO), CH 61.8 (d, JCPˆ72 Hz), 102.1, 123.8,
124.1, 128.6, 128.65 (d, JCPˆ12 Hz), 128.7 (d, JCPˆ12 Hz),
131.3, 131.6 (d, JCPˆ9 Hz), 132.1 (d, JCPˆ9 Hz), 132.8
(d, JCPˆ2.5 Hz), 132.9 (d, JCPˆ2.5 Hz), CH 42.7, CH
131.4 (d, JCPˆ10 Hz), 132.2, 132.3, 132.9, CH 44.4 (d,
2
JCPˆ76 Hz), 50.3, CH 3 54.0, 54.4; 31P NMR d (major rota-
tional isomer) 30.6. Anal. Calcd for C24H25BrNO4P: C,
57.38; H, 5.02; N, 2.79. Found: C, 57.20; H, 4.83; N, 2.61.
Phosphorylated amide 19. (88%); mp 103–104ЊC; 1H
NMR (mixture of two rotational isomers, 80:20): d (major
rotational isomer) 3.22 (s, 3H, OCH3), 3.28 (s, 3H, OCH3),
3.56 (dd, Jˆ15.0, 6.4 Hz, 1H, NCH2), 3.69 (dd, Jˆ15.0,
4.4 Hz, 1H, NCH2), 4.48 (dd, Jˆ6.4, 4.4 Hz, 1H,
CHOMe2), 4.72 (dd, Jˆ6.1, 5.5 Hz, 2H, NCH2P), 5.89 (d,
Jˆ3.2 Hz, 2H, OCH2O), 6.09 (s, 1H, Harom), 6.83 (s, 1H,
Harom), 7.37–7.50 (m, 6H, Harom), 7.82–7.97 (m, 4H, Harom);
13C NMR (mixture of two rotational isomers) d (major rota-
tional isomer) C 110.3, 129.7, 131.0 (d, JCPˆ98 Hz), 131.3
(d, JCPˆ98 Hz), 147.2, 148.9, 169.2 (CO), CH 102.9, 108.1,
112.9, 128.6 (d, JCPˆ11.5 Hz), 128.8 (d, JCPˆ10.5 Hz),
131.2 (d, JCPˆ10 Hz), 131.4 (d, JCPˆ10 Hz), 132.2, 132.3,
2
3
53.1, 54.7; 31P NMR d 31.2. Anal. Calcd for C24H24NO4P:
C, 68.40; H, 5.74; N, 3.32. Found: C, 68.62; H, 5.88; N,
3.50.
Phosphorylated isoindolinone 9. (81%); mp 186–187ЊC;
1H NMR d 3.25 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.22
(dd, Jˆ14.4, 6.5 Hz, 1H, NCH2), 3.97 (dd, Jˆ14.4, 4.0 Hz,
1H, NCH2), 4.49 (dd, Jˆ6.5, 4.0 Hz, 1H, CHOMe2), 5.65 (d,
Jˆ10.2 Hz, 1H, NCHP), 5.98 (dd, Jˆ9.1, 1.2 Hz, 2H,
OCH2O), 6.48 (t, Jˆ0.7 Hz, 1H, Harom), 7.01 (s, 1H,
Harom), 7.38–7.63 (m, 10H, Harom); 13C NMR d C 129.0,
134.9 (d, JCPˆ3 Hz), 148.7, 151.1, 168.7 (CO), CH 61.4
(d, JCPˆ72 Hz), 102.2, 103.2, 104.4, 128.7 (d,
JCPˆ12 Hz), 128.75 (d, JCPˆ11.5 Hz), 131.6 (d,
CH 2 44.4 (d, JCPˆ76 Hz), 50.4, 102.1, CH 3 54.1, 54.6; 31
P
NMR (major rotational isomer) d 30.8. Anal. Calcd for
C25H25BrNO6P: C, 54.96; H, 4.61; N, 2.56. Found: C,
55.18; H, 4.53; N, 2.75.

A. Couture et al. / Tetrahedron 56 (2000) 1491–1499
1497
JCPˆ9 Hz), 132.0 (d, JCPˆ9 Hz), 132.8 (d, JCPˆ2 Hz),
31P NMR d 30.6. Anal. Calcd for C25H24NO6P: C, 64.51;
General procedure for the synthesis of the 3-aryl-
methylisoindolinones 22–24
132.9 (d, JCPˆ2 Hz), CH 42.9, 102.0, CH 53.2, 54.8;
2
3
H, 5.20; N, 3.01. Found: C, 64.39; H, 5.02; N, 3.15.
A solution of compounds 4–6 (2 mmol) in methanol (30 ml)
was stirred with activated Pd/C (10%, 20 mg) and a solution
of HCOONH4 (640 mg, 10 mmol) in distilled water (5 ml)
was slowly added. The solution mixture was refluxed for
15 min, filtered through celite᭨ and water was added.
Extraction with CH2Cl2 (3×20 ml), drying with MgSO4
and concentration in vacuo left a solid which was recrystal-
lized from hexane/toluene.
Phosphorylated isoindolinone 28. (83%); mp 75–76ЊC; 1H
NMR d 3.13 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.30 (s, 3H,
OCH3), 3.50 (dd, Jˆ14.5, 6.6 Hz, 1H, NCH2), 4.00 (dd,
Jˆ14.5, 3.5 Hz, 1H, NCH2), 4.46 (dd, Jˆ6.6, 3.5 Hz, 1H,
CHOMe2), 5.73 (d, Jˆ5.6 Hz, 1H, NCHP), 6.61 (d,
Jˆ8.6 Hz, 1H, Harom), 7.31–7.35 (m, 4H, Harom), 7.38–
7.61 (m, 5H, Harom), 7.73–7.80 (m, 2H, Harom); 13C NMR
d C 109.0, 128.1 (d, JCPˆ98 Hz), 130.6 (d, JCPˆ2 Hz),
130.9, 131.5 (d, JCPˆ96 Hz), 153.4, 166.6 (CO), CH 60.8
(d, JCPˆ68 Hz), 102.4, 114.0, 128.2 (d, JCPˆ12 Hz), 128.4
(d, JCPˆ12 Hz), 131.5 (d, JCPˆ9.5 Hz), 131.6 (d,
JCPˆ10 Hz), 132.3 (d, JCPˆ2 Hz), 132.4 (d, JCPˆ2 Hz),
134.7, CH 43.2, CH 53.7, 54.5, 54.8; 31P NMR d 30.1.
3-Arylmethylisoindolinone 22. 814 mg (98%); mp 126–
1
127ЊC (lit.17 126–127ЊC); H NMR d 2.65 (dd, Jˆ13.8,
8.0 Hz, 1H, ArCH2), 3.18 (dd, Jˆ14.1, 6.6 Hz, 1H,
NCH2), 3.31 (dd, Jˆ13.8, 3.8 Hz, 1H, ArCH2), 3.39 (s,
3H, OCH3), 3.44 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.99
(s, 3H, OCH3), 4.17 (dd, Jˆ14.4, 3.6 Hz, 1H, NCH2), 4.53
(dd, Jˆ6.6, 3.6 Hz, 1H, CHOMe2), 4.79 (dd, Jˆ8.0, 3.8 Hz,
1H, ArCHN), 5.90 (d, Jˆ1.4 Hz, 2H, OCH2O), 6.38–6.45
(m, 2H, Harom), 6.62 (d, Jˆ8.3 Hz, 1H, Harom), 6.69 (d,
Jˆ7.8 Hz, 1H, Harom), 6.96 (d, Jˆ8.3 Hz, 1H, Harom); 13C
NMR d C 124.1, 129.6, 138.9, 146.4, 147.0, 147.5, 152.2,
166.7 (CO), CH 60.2, 103.4, 108.1, 109.7, 116.0, 117.9,
122.7, CH 2 37.8, 42.2, 100.9, CH 3 54.7, 55.3, 56.7, 62.4.
2
3
Anal. Calcd for C25H25BrNO5P: C, 56.62; H, 4.75; N, 2.64.
Found: C, 56.78; H, 4.85; N, 2.59.
3-Arylmethyleneisoindolinones 4–6
The 3-arylmethyleneisoindolinones 4–6 were synthesized
according to an already reported procedure.28
3-Arylmethylisoindolinone 23. 728 mg (98%); mp 107–
1
3-Arylmethyleneisoindolinone 4. (92%), (E)- and (Z)-
isomers (ratio 85:15 from H NMR spectrum). (E)-isomer:
108ЊC; H NMR d 2.75 (dd, Jˆ13.8, 8.0 Hz, 1H, ArCH2),
1
3.26 (dd, Jˆ14.4, 6.6 Hz, 1H, NCH2), 3.37–3.47 (m, 7H,
2×OCH3ϩArCH2), 3.67 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),
4.26 (dd, Jˆ14.4, 3.6 Hz, 1H, NCH2), 4.55 (dd, Jˆ6.6,
3.6 Hz, 1H, CHOMe2), 4.79 (dd, Jˆ8.0, 3.8 Hz, 1H,
ArCHN), 6.38 (d, Jˆ1.6 Hz, 1H, Harom), 6.59 (dd, Jˆ8.1,
1.6 Hz, 1H, Harom), 6.72 (d, Jˆ8.1 Hz, 1H, Harom), 6.96–7.04
(m, 1H, Harom), 7.34–7.48 (m, 2H, Harom), 7.71–7.78 (m, 1H,
Harom); 13C NMR d C 128.2, 132.0, 145.6, 147.9, 148.5,
168.5 (CO), CH 61.2, 103.5, 111.0, 112.5, 121.6, 123.0,
123.6, 128.0, 130.9, CH2 37.1, 42.0, CH3 54.7, 55.3, 55.7,
55.8. Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77.
Found: C, 68.08; H, 6.91; N, 3.87.
mp 154–155ЊC (lit.17 152–154ЊC); 1H NMR d 3.38 (s, 6H,
OCH3), 3.79 (s, 3H, OCH3), 3.90 (d, Jˆ5.4 Hz, 2H, NCH2),
4.01 (s, 3H, OCH3), 4.63 (t, Jˆ5.4 Hz, 1H, CHOMe2), 5.95
(d, Jˆ0.8 Hz, 2H, OCH2O), 6.43 (s, 1H, CHv), 6.74–6.85
(m, 4H, Harom), 7.06 (dd, Jˆ9.1, 0.6 Hz, 1H, Harom); 13C
NMR d C 122.2, 128.8, 129.1, 135.7, 146.5, 147.0, 147.8,
153.3, 164.8 (CO), CH 102.3, 108.5, 108.7, 109.7, 114.9,
118.9, 123.1, CH 2 41.8, 101.2, CH 3 54.4, 56.4, 62.3.
3-Arylmethyleneisoindolinone 5. (95%). (E)- and (Z)-
1
isomers (ratio 80:20 from H NMR spectrum). (E)-isomer:
1
mp 95–96ЊC; H NMR d 3.43 (s, 6H, OCH3), 3.84 (s, 3H,
OCH3), 3.93 (s, 3H, OCH3), 4.01 (d, Jˆ5.4 Hz, 2H, NCH2),
4.71 (t, Jˆ5.4 Hz, 1H, CHOMe2), 6.68 (s, 1H, CHv), 6.91
(d, Jˆ8.2 Hz, 1H, Harom), 6.93 (d, Jˆ1.7 Hz, 1H, Harom),
6.98–7.01 (m, 1H, Harom), 7.32 (dd, Jˆ7.0, 1.2 Hz, 1H,
Harom), 7.37–7.42 (m, 2H, Harom), 7.81–7.85 (m, 1H,
Harom); 13C NMR d C 127.6, 129.9, 135.2, 136.1, 148.8,
148.9, 166.7 (CO), CH 102.2, 111.2, 112.6, 122.1, 123.2,
129.0, 131.5, CH 41.9, CH 54.4, 55.9. Anal. Calcd for
3-Arylmethylisoindolinone 24. 864 mg (97%); mp 137–
1
138ЊC; H NMR d 2.61 (dd, Jˆ13.8, 8.2 Hz, 1H, ArCH2),
3.18 (dd, Jˆ14.5, 6.4 Hz, 1H, NCH2), 3.31 (dd, Jˆ13.8,
4.1 Hz, 1H, ArCH2), 3.37 (s, 3H, OCH3), 3.41 (s, 3H,
OCH3), 3.72 (s, 6H, OCH3), 3.77 (s, 3H, OCH3), 4.18 (dd,
Jˆ14.5, 3.5 Hz, 1H, NCH2), 4.48 (dd, Jˆ6.4, 3.5 Hz, 1H,
CHOMe2), 4.82 (dd, Jˆ8.2, 4.1 Hz, 1H, ArCHN), 5.95 (dd,
Jˆ3.8, 0.9 Hz, 2H, OCH2O), 6.22 (s, 2H, Harom), 6.38 (s, 2H,
Harom), 7.12 (s, 1H, Harom); 13C NMR d C 125.9, 131.6,
137.0, 141.1, 148.1, 150.9, 153.0, 168.1 (CO), CH 60.9,
103.2, 103.4, 103.5, 106.6, 128.3, CH2 38.0, 42.0, 101.8,
CH3 54.7, 55.3, 56.0, 60.8. Anal. Calcd for C23H27NO8: C,
62.01; H, 6.11; N, 3.14. Found: C, 62.17; H, 6.01; N, 3.27.
2
3
C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.19; H,
6.34; N, 3.66.
3-Arylmethyleneisoindolinone 6. (89%). (E)- and (Z)-
1
isomers (ratio 95:5 from H NMR spectrum). (E)-isomer:
mp 165–166ЊC; 1H NMR d 3.02 (s, 6H, OCH3), 3.55 (s, 6H,
OCH3), 3.77 (s, 3H, OCH3), 3.95 (d, Jˆ5.4 Hz, 2H, NCH2),
4.68 (t, Jˆ5.4 Hz, 1H, CHOMe2), 5.99 (s, 2H, OCH2O),
6.56 (s, 1H, CHv), 6.60 (s, 2H, Harom), 6.80 (s, 1H,
Harom), 7.18 (s, 1H, Harom); 13C NMR d C 125.0, 130.5,
130.6, 136.3, 137.7, 149.1, 151.1, 153.4, 166.3 (CO), CH
102.1, 102.8, 103.6, 106.5, 110.3, CH 41.9, 102.0, CH
General procedure for the synthesis of the cyclo-
condensed products 25–27
Sulfuric acid (95–98%, 10 ml) was added dropwise to a
solution of acetals 22–24 (0.5 mmol) in acetic acid (glacial,
6 ml). The mixture was stirred at room temperature for
0.5 h. Neutralisation was performed by slow addition of
aqueous ammonia (30%). Extraction with CH2Cl2
2
3
54.4, 56.2, 61.1. Anal. Calcd for C23H25NO8: C, 62.30; H,
5.28; N, 3.16. Found: C, 62.48; H, 5.34; N, 3.14.

1498
A. Couture et al. / Tetrahedron 56 (2000) 1491–1499
(2×30 ml), drying with Na2SO4 and concentration in
vacuo left a yellow solid which was finally purified by
recrystallization from Et2O/methanol.
1H, CH2), 2.83 (dd, Jˆ13.5, 11.5 Hz, 1H, CH2), 2.91 (dd,
Jˆ14.6, 10.7 Hz, 1H, CH2), 3.10 (dd, Jˆ14.6, 1.5 Hz, 1H,
CH2), 3.44 (dd, Jˆ15.0, 5.6 Hz, 1H, CH2), 3.82 (s, 3H,
OCH3), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.30 (dd,
Jˆ10.7, 1.5 Hz, 1H, CH), 4.74 (ddd, Jˆ13.5, 5.6, 2.0 Hz,
1H, CH2), 6.05 (s, 2H, OCH2O), 6.61 (s, 1H, Harom), 6.94 (s,
1H, Harom), 7.23 (s, 1H, Harom); 13C NMR d C 126.0, 127.5,
133.6, 140.2, 148.4, 151.2, 151.5, 166.6 (CO), CH 56.1,
102.4, 103.5, 109.5, CH2 26.2, 41.4, 43.0, 101.9, CH3
60.7, 60.9, 61.4. Anal. Calcd for C21H19NO6: C, 66.14; H,
5.02; N, 3.67. Found: C, 65.89; H, 5.23; N, 3.49.
Dihydroisoindolobenzazepine-8-one 25. 148 mg (84%);
1
mp 227–228ЊC (lit.17 226–228ЊC); H NMR d 2.98 (dd,
Jˆ15.4, 9.5 Hz, 1H, ArCH2), 3.32 (d, Jˆ15.4 Hz, 1H,
ArCH2), 3.91 (s, 3H, OCH3), 4.09 (s, 3H, OCH3), 4.66 (d,
Jˆ9.5 Hz, 1H, ArCHN), 5.65 (d, Jˆ10.4 Hz, 1H, CHv),
5.95 (d, Jˆ1.4 Hz, 2H, OCH2O), 6.69 (s, 2H, Harom), 7.08 (d,
Jˆ10.4 Hz, 1H, CHv), 7.17 (s, 2H, Harom); 13C NMR d C
122.9, 129.2, 130.0, 137.4, 146.4, 146.7, 147.5, 152.8, 163.6
(CO), CH 68.0, 109.2, 110.0, 110.5, 117.1, 117.4, 120.0, CH
Lennoxamine 1. (98%); the analytical and spectral data of
synthetic 1 matched those reported for the natural product.1
42.2, 101.2, CH 3 56.8, 59.7.
2
Dihydroisoindolobenzazepine-5-one 26. 125 mg (86%);
1
mp 182–183ЊC; H NMR d 3.03 (dd, Jˆ15.4, 9.8 Hz, 1H,
Acknowledgements
ArCH2), 3.42 (dd, Jˆ15.4 Hz, 1H, ArCH2), 3.87 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 4.78 (d, Jˆ9.8 Hz, 1H,
ArCHN), 5.71 (d, Jˆ10.3 Hz, 1H, CHv), 6.71 (s, 1H,
Harom), 6.72 (s, 1H, Harom), 7.11 (d, Jˆ10.3 Hz, 1H,
CHv), 7.48 (dt, Jˆ6.9, 1.0 Hz, 1H, Harom), 7.56–7.65 (m,
2H, Harom), 7.85 (d, Jˆ7.5 Hz, 1H, Harom); 13C NMR d C
127.8, 128.5, 130.8, 144.2, 147.6, 147.7, 165.5 (CO), CH
60.6, 109.6, 113.2, 114.0, 120.0, 122.2, 124.0, 128.8, 132.7,
CH2 41.5, CH3 56.0, 56.1. Anal. Calcd for C19H17NO3: C,
74.25; H, 5.58; N, 4.56. Found: C, 74.14; H, 5.67; N, 4.41.
We thank Dr T. G. C. Bird (Zeneca Pharma) for helpful
comments on the manuscript. This research was supported
by the Centre National de la Recherche Scientifique and
MENESR (grant to C. H.).
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(dd, Jˆ14.7, 1.5 Hz, 1H, CH2), 3.88 (s, 3H, OCH3), 3.91
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