A new approach to isoindoloisoquinolinones. A simple synthesis of nuevamine

Article abstract of DOI:10.1016/j.tet.2004.05.033

A convenient and versatile short step synthesis of isoindoloisoquinolinones, illustrated by the total synthesis of the alkaloid nuevamine 1a, is described. The tetracyclic lactam compounds were obtained by a tactical combination of the Parham procedure for the elaboration of the isoindolinone template and an aryne-mediated cyclization giving rise to the nitrogen containing six-membered heteroring unit.

Full text of DOI:10.1016/j.tet.2004.05.033

Tetrahedron 60 (2004) 6169–6176
A new approach to isoindoloisoquinolinones.
A simple synthesis of nuevamine
*
Anne Moreau, Axel Couture, Eric Deniau, Pierre Grandclaudon and Stephane Lebrun
´
´ ˆ
Laboratoire de Chimie Organique Physique, UMR 8009 “Chimie Organique et Macromoleculaire”, Batiment C3(2),
´
´
Universite des Sciences et Technologie de Lille, F-59655 Villeneuve d’Ascq Cedex, France
Received 8 March 2004; revised 14 May 2004; accepted 14 May 2004
Available online 10 June 2004
Abstract—A convenient and versatile short step synthesis of isoindoloisoquinolinones, illustrated by the total synthesis of the alkaloid
nuevamine 1a, is described. The tetracyclic lactam compounds were obtained by a tactical combination of the Parham procedure for the
elaboration of the isoindolinone template and an aryne-mediated cyclization giving rise to the nitrogen containing six-membered heteroring
unit.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Members of the plant family Berberidaceae are known to
produce an array of unusual isoquinoline alkaloids. Their
study is facilitated by the fact that relatively large amounts
of these plants can be collected. This therefore makes
conceivable the study of minor alkaloids present, that is,
those available only in small amounts, which often afford an
insight into the catabolic pathways for the principal
alkaloids. This is notably the case of isoindolo[1,2-a]-
isoquinolinones 1, a class of tetracyclic lactams which are
interesting due to the real and potential biological activities
of many of their derivatives.1 The eminent example
nuevamine 1a has been isolated from Berberis darwinii
Hook, gathered in southern Chile, in the vicinity of Cuidad
Osorno.2 This alkaloid occupies a special place since it was
the first recognized isoindoloisoquinolinone reported from
natural sources. Initially, its structure was erroneously
assigned but later revision led unambiguously to structure
1a.3 Two main general approaches to the synthesis of
isoindolo[1,2-a]isoquinolinones have been reported so far.
Scheme 1.
this synthetic approach has been confined to the develop-
ment of new precursors of the acyliminium species.
They differ in the type of the annulation process and in the
heteroring unit embedded in the alkaloid skeleton, formed in
the last step. Thus, creation of ring A has been generally
achieved by intramolecular cyclization of N-acyliminium
Thus, intramolecular amidoarylation as the key ring-
forming step has been ensured from a-hydroxy (X¼OH)4
and a-alkoxy (X¼OMe)5 lactamic precursors by treatment
with a wide variety of Lewis acid catalysts such as scandium
and copper triflates,5c,d SnCl4,5e TMSOTf,5c BF3·OEt2,5e,f
ions derived from a-substituted isoindolinone derivatives 2
(Retrosynthetic Scheme 1, path A) and a closer analysis of
TiCl4,5b and trifluoroacetic acid.4,5a An original structural
the literature reveals that improvement and modification of
modification recently developed by Katritzky led to the
generation of the N-acyliminium cation by loss of a
benzotriazolyl anion upon treatment of 2 (X¼benzo-
triazolyl) with TiCl4.6 An alternative synthetic tactic has
Keywords: Alkaloids; Parham procedure; Arynes; Isoindolinones.
*
been also proposed by Sotomayor in which the intermediate
N-acyliminium species was generated from a preformed
Corresponding author. Tel.: þ33-3-20-43-44-32; fax: þ33-3-20-33-63-
09; e-mail address: axel.couture@univ-lille1.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.033

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A. Moreau et al. / Tetrahedron 60 (2004) 6169–6176
annulated model 1 (R¼OH).7 This skilful approach allowed
intermolecular a-amidoalkylation, giving access to a wide
variety of C-12b substituted nuevamine-type alkaloids.
However, probably due to difficulties associated with the
elaboration of the starting compounds and particularly the
absolute necessity of having an unsymmetrically disubsti-
tuted isoindolinone parent compound available, most of
these syntheses have only been claimed to give access to the
nuevamine skeleton. Isoindoloisoquinolinones have been
also accessed by ring B formation performed by intramo-
lecular Heck cyclization of aromatic enamides 3 (Scheme 1,
path B). In this annulation process the 6-endo-trig cycliza-
tion often competes with the 5-exo-trig cyclization but this
problem has been circumvented by the addition of a hydride
source which favors the regio-controlled formation of the
five-membered ring product.8 Unfortunately, all models
elaborated by this technique are inevitably alkylated at the
C-12b position and this precludes the synthesis of
unsubstituted models such as the alkaloid nuevamine.
Some more confidential methods based upon the phosphoric
acid cyclization of b-phenylethylaminophthalide9 or by a
combination of the Pictet–Spengler reaction with Pd-
catalyzed carbonylation applied to (2-iodobenzylidene)-
phenethylamine derivatives10 have been also used occasion-
ally for the assemblage of the isoindoloisoquinolinone
framework. Consequently, the elegant synthetic approach
reported by Castedo et al.3 which allowed the unambiguous
assignment of the structure of the alkaloid nuevamine can
arguably be deemed to be the sole total synthesis to date of
this natural product.
2. Results and discussion
In continuation of our investigation into the synthesis of
alkaloids with an isoindolinone ring system as the main
structural subunit11 we herein wish to disclose an alterna-
tive, efficient and tactically new approach to isoindoloiso-
quinolinones illustrated by the total synthesis of the alkaloid
nuevamine isolated as a racemate from Chilean barberries.
Our strategy, which is depicted in retrosynthetic Scheme 2,
is based on the use of 2-arylethylisoindolinones 4 as key
Scheme 2.
Scheme 3.

A. Moreau et al. / Tetrahedron 60 (2004) 6169–6176
6171
intermediates. These lactams were obtained by Parham-type
cyclization induced by aromatic lithiation of the halogeno-
diarylalkylamine 5 with a carbamate function acting as the
internal electrophile.12 Aryne-mediated cyclization induced
by basic treatment of the primarily annulated compounds 4
then should complete the synthesis of the target isoindolo-
isoquinolinones 1. A contentious issue in the elaboration of
the starting compounds was judging the proper choice for
the halogen atoms X1, X2 connected to the environmentally
different aromatic units of 5. Critical to the success of the
strategy was the incorporation of a halogen atom X1 liable
to cause the aromatic metallation–cyclization sequence
leading to 4 by a metal–halogen exchange, while sparing
the second halogen atom X2. In contrast X2 should allow
and, if feasible, facilitate the mandatory aryne formation for
the ultimate annulation step. Since it has been clearly
established that metal–halogen exchange occurs preferen-
tially with aryl bromides and iodides, whereas arylfluorides
and chlorides do not normally react with organolithium
compounds but undergo instead ortho-metallation and aryne
formation afterwards13 we embarked on the synthesis of the
diversely halogenated carbamates 5a–d (Scheme 3).
13 a THF solution of the appropriate arylbromide was
treated with 1.1 equiv. of t-BuLi at 2100 8C in THF. The
intramolecular ring closure was instantaneous as demon-
strated by the isolation solely of the annulated compounds
4a–d upon aqueous work-up (Table 1).
The concept of the subsequent generation of the six-
membered heteroring unit embedded in the isoindolo-
isoquinolinone skeleton originated from the following
premises: (i) isoindolinones have been easily metalated at
the benzylic position of the lactam unit thus allowing the
connection of a range of electrophiles at the 3-position of
the heteroring system;14 (ii) arylfluorides are good candi-
dates for the generation of arynes13,15a and the anion–aryne
cyclization processes, particularly those involving nitrogen-
bearing nucleophiles and carbanions, occupy a place of
choice in the arsenal of alkaloid synthesis tactics.15b
Compounds 4b–d were then treated with KHMDS [potas-
sium bis(trimethylsilyl)amide] (2.2 equiv.) in the presence
of 18-crown-6 at 278 8C in THF and gratifyingly classical
work-up delivered single compounds which were unam-
biguously identified as the annulated isoindolinones 1b–d.
Performing this reaction sequence with the appropriate open
model 4a led straightforwardly to the target natural product
nuevamine 1a with a very satisfactory yield (38% over last
three steps).
The first facet of the synthesis was the elaboration of the
halogenated diarylalkylamines 6a–d. These compounds
were readily obtained by a reductive amination process
involving the bromobenzaldehyde derivatives 7a–d and the
appropriate fluorinated arylethylamines 8, 9. Initially, the
aromatic fluorinated amine 8 was obtained by the three step
sequence depicted in Scheme 4 which involves the double
reduction of the nitrostyrene derivative 12 deriving from the
fluorocarboxaldehyde derivative 11.
It is worth noting that reactions must be preferably carried
out after careful degassing of the solution since quite
significant amounts of products which were hydroxylated at
C-12b, as exemplified by the formation of 14d, were
obtained in reactions performed in non-deoxygenated
solutions (Scheme 5). The formation of this a-hydroxy-
lactam may tentatively be explained by capture of the
carbanionic species 15 by oxygen. Intermediate 15 would be
formed by a prototropy of 16, attributable to a greater
stabilization of the bibenzylic carbanionic species which
can further adopt the o-quinodimethane structure 17. The
fact that acidic work-up with D3Oþ led to the exclusive
incorporation of deuterium on the bibenzylic C-12b position
as exemplified by the formation of 1a(D) corroborates this
hypothesis. However, this reaction was not really detri-
mental to the elaboration of the desired compounds 1a–d
since the hemiaminal compounds (e.g., 14d) can be almost
quantitatively converted into the dehydroxylated models
(e.g., 1d)7 and can also serve for the introduction of
substituents at C-12b.7
Scheme 4.
The compound 11 was readily accessible by linking the
vicinal hydrophenolic functions of the parent compound 10
(Scheme 4).
3. Conclusion
Treatment of amines 6a–d with methyl chloroformate
delivered the carbamates 5a–d in excellent yields (73–
91%). To ensure the formation of the lithiated intermediate
In summary, we have identified a novel and flexible
synthetic approach to isoindoloisoquinolinones. In only
two key synthetic steps from easily accessible precursors
we have prepared the isoindolinone template by reliance
on the Parham procedure and the creation of the isoquino-
line ring system by an aryne-mediated cyclization
process. The total synthesis of the alkaloid nuevamine
emphasizes the versatility and regiospecificity of this
new conceptual approach and we believe that this work
demonstrates a general new methodology for the prepa-
ration of similar structurally modified isoindoloisoquino-
linone alkaloids.
Table 1. Yields for compounds 6a–d, 5a–d and 4a–d produced via
Scheme 3
6 (%)
5 (%)
4 (%)
a
b
c
94
86
97
95
78
91
76
73
68
72
64
62
d

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A. Moreau et al. / Tetrahedron 60 (2004) 6169–6176
Scheme 5.
4. Experimental
mmol) and cesium carbonate (6.57 g, 20.2 mmol) in
anhydrous DMF (20 mL) and the resulting mixture was
heated at 110 8C for 3 h. After cooling to room temperature
the mixture was filtered through a pad of Celitew which was
subsequently washed with EtOAc (50 mL). Water (50 mL)
was added, the organic layer was separated and the aqueous
layer was extracted with EtOAc (3£50 mL). The organic
layers were combined, washed with water, brine and dried
(MgSO4). Evaporation of the solvent left a residue, which
was purified by flash column chromatography with hexanes/
AcOEt (50:50) as eluent. Yield 1.60 g (71%); mp 72–73 8C;
1H NMR (d) 6.05 (s, 2H, OCH2O), 6.61 (d, JHF¼9.8 Hz, 1H,
aromatic H), 7.19 (d, JHF¼5.4 Hz, 1H, aromatic H), 10.15
(s, 1H, CHO); 13C NMR (d) 97.9 (d, JCF¼29 Hz), 102.9,
4.1. General
Tetrahydrofuran (THF) was pre-dried with anhydrous
Na2SO4 and distilled over sodium benzophenone ketyl
under Ar before use. DMF, 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 chroma-
tography, Merck silica gel 60 (40–63 m; 230–400
mesh ASTM) was used. The melting points were obtained
on a Reichert–Thermopan apparatus and are not
corrected. NMR spectra: Bruker AM 300 (300 and
104.9 (d, JCF¼3 Hz), 117.9 (d, JCF¼8 Hz), 144.8 (d, JCF
¼
75 MHz, for H and 13C respectively). For H, 13C NMR,
CDCl3 was used as solvent, TMS as internal standard.
Microanalyses were performed by the CNRS microanalysis
center.
1 Hz), 154.0 (d, JCF¼15 Hz), 162.5 (d, JCF¼252 Hz), 185.4
(d, JCF¼8 Hz). Anal. Calcd for C8H5O3F (168.1): C, 57.15;
H, 3.00%. Found: C, 57.35; H, 2.94%.
1
1
4.2.2. 5-Fluoro-6-(2-nitrovinyl)-benzo[1,3]dioxole (12).
A solution of 6-fluorobenzo[1,3]dioxole-5-carbaldehyde
(1.45 g, 8.6 mmol), AcONH4 (0.15 g, mmol) in nitro-
methane (CH3NO2, 6.5 mL) was refluxed for 5 h. After
cooling, the yellow precipitate was filtered and washed with
MeOH (20 mL) to afford yellow crystals. Yield 1.12 g,
(67%); mp 143–144 8C; 1H NMR (d) 6.07 (s, 2H, OCH2O),
6.68 (d, JHF¼9.8 Hz, 1H, aromatic H), 6.87 (d, JHF¼5.9 Hz,
1H, aromatic H), 7.55 (d, J¼13.7 Hz, 1H, CHv), 8.03 (d,
J¼13.7 Hz, 1H, CHv); 13C NMR (d) 98.7 (d, JCF¼30 Hz),
102.9, 106.8 (d, JCF¼4 Hz), 110.6 (d, JCF¼13 Hz), 132.2
The bromobenzaldehyde derivatives 7a16,17 and 7c18,19
were synthesized according to literature methods.
4.2. Synthesis of 2-(6-fluorobenzo[1,3]dioxol-5-yl)-
ethylamine (8)
2-Fluoro-4,5-dihydroxybenzaldehyde 10 was obtained from
4-fluoroveratrole by sequential formylation20 and demethyl-
ation.21
4.2.1. 6-Fluorobenzo[1,3]dioxole-5-carbaldehyde (6-
fluoropiperonal, 11). Bromochloromethane (2.61 g,
20.2 mmol) was added, under Ar, to a stirred suspension
of 2-fluoro-4,5-dihydroxybenzaldehyde 10 (2.10 g, 13.4
(d, JCF¼3 Hz), 137.0 (d, JCF¼9 Hz), 144.9, 152.1 (d, JCF¼
15 Hz), 158.5 (d, JCF¼250 Hz). Anal. Calcd for C9H6FNO4
(211.1): C, 51.20; H, 2.86; N, 6.63%. Found: C, 51.02; H,
3.01; N, 6.55%.

A. Moreau et al. / Tetrahedron 60 (2004) 6169–6176
6173
4.2.3. 2-(6-Fluorobenzo[1,3]dioxol-5-yl)ethylamine (8).
A solution of the nitro derivative 12 (2.00 g, 10.3 mmol)
in dry THF (15 mL) was added dropwise, under Ar, to an ice
cooled suspension of lithium aluminum hydride (LiAlH4,
3.89 g, 102.6 mmol) in dry THF (50 mL). The mixture was
stirred at 0 8C for 2 h and then refluxed overnight. The
suspension was cooled to 0 8C and the excess of LiAlH4 was
quenched with 6 M aqueous sodium hydroxide (50 mL).
The precipitate was filtered off and extracted with boiling
THF for 1 h, then filtered and washed with Et2O (50 mL).
The combined organic layers were washed with brine and
dried (Na2SO4). After evaporation of the solvent the residue
was purified by flash column chromatography with AcOEt/
3H, aromatic H), 7.15–7.29 (m, 3H, aromatic H), 7.37 (d,
J¼7.6 Hz, 1H, aromatic H), 7.53 (d, J¼7.8 Hz, 1H,
aromatic H); 13C NMR (d) 29.8 (d, JCF¼2 Hz), 49.1 (d,
JCF¼1 Hz), 53.5, 115.3 (d, JCF¼22 Hz), 124.0 (d, JCF
4 Hz), 124.0, 126.9 (d, JCF¼16 Hz), 127.4, 127.9 (d, JCF
¼
¼
8 Hz), 128.5, 130.2, 131.0 (d, JCF¼5 Hz), 132.8, 139.3,
161.3 (d, JCF¼243 Hz). Anal. Calcd for C15H15BrFN
(308.2): C, 58.46; H, 4.91; N, 4.54%. Found: C, 58.21; H,
5.14; N, 4.41%.
4.3.3. (5-Benzyloxy-2-bromo-4-methoxybenzyl)-[2-(2-
fluorophenyl)ethyl]amine (6c). Yield 4.31 g (97%); oil;
1H NMR (d) 1.56 (br s, 1H, NH), 2.81 (s, 4H, 2£CH2), 3.76
(s, 2H, CH2), 3.85 (s, 3H, CH3), 5.10 (s, 2H, CH2), 6.93 (s,
1H, aromatic H), 6.98–7.07 (m, 3H, aromatic H), 7.16–7.21
(m, 2H, aromatic H), 7.25–7.36 (m, 3H, aromatic H), 7.42
1
Et3N (90:10) as eluent. Yield 0.96 g (51%); oil; H NMR
(dH) 1.76 (br s, 2H, NH2), 2.73 (t, J¼7.1 Hz, 2H, CH2), 3.23
(t, J¼7.1 Hz, 2H, CH2), 5.79 (s, 2H, OCH2O), 6.43 (d,
JHF¼8.8 Hz, 1H, aromatic H), 6.54 (d, JHF¼5.6 Hz, 1H,
(d, J¼7.1 Hz, 2H, aromatic H); 13C NMR (d) 29.7 (d, JCF
¼
aromatic H); 13C NMR (dC) 29.2, 51.9, 97.7 (d, JCF
¼
2 Hz), 48.8, 53.0, 56.3, 71.1, 114.2, 115.3 (d, JCF¼22 Hz),
115.6, 116.1, 124.0 (d, JCF¼4 Hz), 126.9 (d, JCF¼16 Hz),
31 Hz), 101.5, 109.6 (d, JCF¼6 Hz), 119.0 (d, JCF¼14 Hz),
143.3 (d, JCF¼2 Hz), 146.2 (d, JCF¼14 Hz), 155.6 (d,
JCF¼237 Hz). Anal. Calcd for C9H10FNO2 (183.2): C,
59.01; H, 5.50; N, 7.65%. Found: C, 59.23; H, 5.40; N,
7.77%.
127.4, 127.9 (d, JCF¼8 Hz), 128.0, 128.6, 130.9 (d, JCF
¼
5 Hz), 131.3, 136.8, 147.4, 149.2, 161.3 (d, JCF¼243 Hz).
Anal. Calcd for C23H23BrFNO2 (444.35): C, 62.17; H, 5.22;
N, 3.15%. Found: C, 62.23; H, 5.30; N, 3.29%.
4.3. General procedure for the synthesis of the amines
6a–d
4.3.4. (6-Bromobenzo[1,3]dioxol-5-ylmethyl)-[2-(2-fluoro-
phenyl)ethyl]amine (6d). Yield 3.34 g (95%); oil; 1H NMR
(d) 1.54 (br s, 1H, NH), 2.86 (s, 4H, 2£CH2), 3.77 (s, 2H,
CH2), 5.94 (s, 2H, CH2), 6.86 (s, 1H, aromatic H), 6.96 (s,
1H, aromatic H), 7.02–7.08 (m, 2H, aromatic H), 7.14–7.25
(m, 2H, aromatic H); 13C NMR (dC) 29.8 (d, JCF¼2 Hz),
48.9 (d, JCF¼1 Hz), 53.4, 101.6, 110.0, 112.7, 114.0,
115.3 (d, JCF¼22 Hz), 124.0 (d, JCF¼4 Hz), 126.8 (d,
JCF¼16 Hz), 127.9 (d, JC–F¼8 Hz), 131.0 (d, JCF¼5 Hz),
132.5, 147.3, 147.4, 161.3 (d, JCF¼243 Hz). Anal. Calcd for
C16H15BrFNO2 (352.2): C, 54.56; H, 4.29; N, 3.98%.
Found: C, 54.23; H, 4.51; N, 4.19%.
A solution of the [2-(2-fluorophenyl)ethyl]amine derivative
8 or 9 (10 mmol) and the appropriate bromobenzaldehyde
derivative 7a–d (10 mmol) in toluene (40 mL) was refluxed
for 3 h in a Dean–Stark apparatus. After removal of toluene
in vacuo the N-benzylidene-[2-(2-fluorophenyl)ethyl]-
amine derivative was used directly in the next step without
further purification. NaBH4 (20 mmol, 0.76 g) was added
portionwise to a solution of the previously obtained Schiff
base in MeOH (50 mL) at room temperature. The mixture
was stirred at room temperature for 1 h and the solvent was
removed under vacuo. The crude mixture was dissolved in
dichloromethane (50 mL), washed with saturated aqueous
NH4Cl solution (30 mL) and then brine (30 mL). The
organic solution was dried (Na2SO4), filtered and concen-
trated in vacuo. The crude oily amines 6a–d were purified
by flash column chromatography with AcOEt/hexanes/NEt3
(80:10:10) as eluent.
4.4. General procedure for the synthesis of the carbamic
acid methyl esters 5a–d
Methyl chloroformate (0.99 g, 10.5 mmol) was added
dropwise at 0 8C to a stirred solution of the secondary
amine 6a–d (7.0 mmol) and NEt3 (1.42 g, 14.0 mmol) in
CH2Cl2 (40 mL). The mixture was allowed to warm to room
temperature and then stirred for an additional 3 h. The
mixture was washed with water (30 mL) and brine (30 mL).
The organic layer was dried (MgSO4) and concentrated in
vacuo to left an oily residue which was purified by flash
column chromatography with AcOEt/hexanes (40:60) as
eluent.
4.3.1. (6-Bromo-2,3-dimethoxybenzyl)-[2-(6-fluoro-
benzo[1,3]dioxol-5-yl)ethyl]amine (6a). Yield 3.78 g,
1
(94%), oil; H NMR (d) 1.70 (br s, 1H, NH), 2.68–2.77
(m, 4H, 2£CH2), 3.79 (s, 6H, 2£CH3), 3.92 (s, 2H, CH2),
5.86 (s, 2H, OCH2O), 6.50 (d, JHF¼9.0 Hz, 1H, aromatic
H), 6.60 (d, JHF¼6.1 Hz, 1H, aromatic H), 6.67 (d, J¼
8.8 Hz, 1H, aromatic H), 7.19 (d, J¼8.8 Hz, 1H, aromatic
H); 13C NMR (d) 29.4 (d, JCF¼2 Hz), 47.6, 48.7, 55.8, 61.1,
97.8 (d, JCF¼31 Hz), 101.5, 112.5 (d, JCF¼6 Hz), 112.5,
4.4.1. (6-Bromo-2,3-dimethoxybenzyl)-[2-(6-fluorobenzo-
[1,3]dioxol-5-yl)ethyl]carbamic acid methyl ester (5a).
Yield 2.57 g (78%); oil; 1H NMR (d, mixture of two
rotational isomers 2:3) 2.52–2.64 (m, 2H, CH2), 3.12–3.23
(m, 2H, CH2), 3.74 (s, 3H, CH3), 3.76 (s, 6H, 2£CH3), 4.61
and 4.68 (2£s, together 2H, CH2), 5.81 (s, 2H, OCH2O),
6.41 (d, JHF¼8.6 Hz, 1H, aromatic H), 6.59 (d, JHF¼7.3 Hz,
1H, aromatic H), 6.70 (d, J¼8.8 Hz, 1H, aromatic H), 7.18
(d, J¼8.8 Hz, 1H, aromatic H); 13C NMR (d, mixture of two
rotational isomers) 28.0 (d, JCF¼2 Hz), 45.0, 45.4, 52.5,
115.4, 118.7 (d, JCF¼19 Hz), 127.8, 133.6, 143.4 (d, JCF
¼
2 Hz), 146.2 (d, JCF¼14 Hz), 148.6, 152.2, 155.6 (d,
JCF¼236 Hz). Anal. Calcd for C18H19BrFNO4 (412.3): C,
52.44; H, 4.65; N, 3.40%. Found: C, 52.56; H, 4.78; N,
3.17%.
4.3.2. (2-Bromobenzyl)-[2-(2-fluorophenyl)ethyl]amine
1
(6b). Yield 2.65 g (86%); oil; H NMR (d) 1.57 (br s, 1H,
NH), 2.91 (s, 4H, 2£CH2), 3.90 (s, 2H, CH2), 6.99–7.13 (m,
55.9, 60.8, 97.6 (d, JCF¼30 Hz), 101.5, 109.4 (d, JCF¼
5 Hz), 113.4, 115.8, 117.6 (d, JCF¼15 Hz), 127.9, 130.1,

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A. Moreau et al. / Tetrahedron 60 (2004) 6169–6176
143.3 (d, JCF¼2 Hz), 146.3 (d, JCF¼14 Hz), 149.5, 152.3,
155.6 (d, JCF¼237 Hz), 156.6. Anal. Calcd for C20H21-
BrFNO6 (470.3): C, 51.08; H, 4.50; N, 2.98%. Found: C,
51.27; H, 4.32; N, 2.84%.
0 8C over a period of 30 min followed by addition of
saturated aqueous NH4Cl (5 mL). The mixture was diluted
with water (30 mL), extracted with Et2O (2£25 mL) and the
combined organic layers were dried (Na2SO4). Evaporation
of solvent in vacuo left a solid residue which was purified by
flash column chromatography with AcOEt/hexanes (60:40)
as eluent. Isoindolinones 4a–d were finally purified by
recrystallization from hexane–toluene.
4.4.2. (2-Bromobenzyl)-[2-(2-fluorophenyl)ethyl]carba-
1
mic acid methyl ester (5b). Yield 2.33 g (91%); oil; H
NMR (d) (d, mixture of two rotational isomers 4:5) 2.86–
2.94 (m, 2H, CH2), 3.44–3.50 (m, 2H, CH2), 3.68 (s, 3H,
CH3), 4.46 and 4.57 (2£s, together 2H, CH2), 6.96–7.25 (m,
7H, aromatic H), 7.51 (d, J¼7.8 Hz, 1H, aromatic H); 13C
NMR (dC), (d, mixture of two rotational isomers A and B)
27.7 (A), 28.3 (B), 46.9 (B), 47.9 (A), 50.6 (B), 50.9 (A),
52.8, 115.3 (d, JCF¼22 Hz), 122.9 (A), 123.4 (B), 124.1 (d,
JCF¼4 Hz), 125.7 (d, JC–F¼16 Hz), 127.6 (B), 127.9 (A),
128.3 (d, JCF¼8 Hz), 128.8 (two peaks overlapping), 129.1,
131.2 (d, JCF¼5 Hz), 132.8, 136.8, 156.8 (A), 157.2 (B),
161.3 (d, JCF¼244 Hz). Anal. Calcd for C17H17BrFNO2
(366.2): C, 55.75; H, 4.68; N, 3.82%. Found: C, 55.65; H,
4.49; N, 4.13%.
4.5.1. 2-[2-(6-Fluorobenzo[1,3]dioxol-5-yl)ethyl]-4,5-di-
methoxy-2,3-dihydro-isoindol-1-one (4a). Yield 942 mg
(68%); mp 161–162 8C; 1H NMR (d) 2.89 (t, J¼6.8 Hz, 2H,
CH2), 3.76 (t, J¼6.8 Hz, 2H, CH2), 3.90 (s, 3H, CH3), 3.92
(s, 3H, CH3), 4.30 (s, 2H, CH2), 5.91 (s, 2H, OCH2O), 6.55
(d, JHF¼9.0 Hz, 1H, aromatic H), 6.65 (d, JHF¼6.4 Hz, 1H,
aromatic H), 6.99 (d, J¼8.3 Hz, 1H, aromatic H), 7.52 (d,
J¼8.3 Hz, 1H, aromatic H); 13C NMR (d) 28.0, 42.9, 48.1,
56.2, 60.3, 97.9 (d, JCF¼31 Hz), 101.7, 109.3 (d, JCF
¼
5 Hz), 112.7, 117.2 (d, JCF¼18 Hz), 119.5, 126.3, 133.2,
143.4, 143.7, 146.7 (d, JCF¼14 Hz), 154.6, 155.7 (d, JCF
¼
236 Hz), 168.1. Anal. Calcd for C19H18FNO5 (359.4): C,
63.51; H, 5.05; N, 3.90%. Found: C, 63.44; H, 4.84; N, 4.17%.
4.4.3. (5-Benzyloxy-2-bromo-4-methoxybenzyl)-[2-(2-
fluorophenyl)ethyl]carbamic acid methyl ester (5c).
Yield 2.67 g (76%); mp 54–55 8C (from hexane–toluene);
1H NMR (d, mixture of two rotational isomers 4:5) 2.70–
2.85 (m, 2H, CH2), 3.22–3.34 (m, 2H, CH2), 3.66 (s, 3H,
CH3), 3.85 (s, 3H, CH3), 4.33 and 4.46 (2£s, together 2H,
CH2), 5.10 (s, 2H, OCH2O), 6.62 and 6.84 (2£s, together
1H, s, aromatic H), 6.96–7.25 (m, 6H, aromatic H), 7.29–
7.37 (m, 4H, aromatic H); 13C NMR (dC, mixture of two
rotational isomers) 29.7, 46.4, 49.8, 52.7, 56.3, 71.1, 113.9,
115.2 (d, JCF¼22 Hz), 115.8, 116.1, 124.0 (d, JCF¼4 Hz),
125.8 (d, JCF¼16 Hz), 127.4, 127.9, 128.2 (d, JCF¼8 Hz),
128.6, 128.9, 131.2 (d, JCF¼5 Hz), 136.6, 147.6, 149.5,
157.2, 161.3 (d, JCF¼244 Hz). Anal. Calcd for C25H25-
BrFNO4 (502.4): C, 59.77; H, 5.02; N, 2.79%. Found: C,
59.92; H, 5.11; N, 3.02%.
4.5.2. 2-[2-(2-Fluorophenyl)ethyl]-2,3-dihydro-isoindol-
1-one (4b). Yield 707 mg (72%); mp 116–118 8C; 1H
NMR (d) 3.02 (t, J¼7.3 Hz, 2H, CH2), 3.86 (d, J¼7.3 Hz,
2H, CH2), 4.25 (s, 2H, CH2), 6.98–7.05 (m, 2H, aromatic
H), 7.15–7.25 (m, 2H, aromatic H), 7.36–7.52 (m, 3H,
aromatic H), 7.82 (d, J¼7.3 Hz, 1H, aromatic H); 13C NMR
(d) 28.3 (d, JCF¼2 Hz), 42.73 (d, JCF¼1 Hz), 50.5, 115.3
(d, JCF¼22 Hz), 122.6 123.6, 124.3 (d, JCF¼4 Hz), 125.6
(d, JCF¼16 Hz), 128.0, 128.4 (d, JCF¼8 Hz), 131.1 (d, JCF
¼
5 Hz), 131.2, 132.8, 141.2, 161.3 (d, JCF¼244 Hz), 168.5.
Anal. Calcd for C16H14FNO (255.3): C, 75.28; H, 5.53; N,
5.49%. Found: C, 75.48; H, 5.79; N, 5.27%.
4.5.3. 5-Benzyloxy-2-[2-(2-fluorophenyl)ethyl]-6-meth-
oxy-2,3-dihydro-isoindol-1-one (4c). Yield 966 mg
1
4.4.4. (6-Bromobenzo[1,3]dioxol-5-ylmethyl)-[2-(2-fluoro-
phenyl)ethyl]carbamic acid methyl ester (5d). Yield
(64%); mp 123–124 8C; H NMR (d) 2.97 (t, J¼7.1 Hz,
2H, CH2), 3.80 (t, J¼7.1 Hz, 2H, CH2), 3.89 (s, 3H, CH3),
4.08 (s, 2H, CH2), 5.15 (s, 2H, OCH2O), 6.84 (s, 1H,
aromatic H), 6.95–7.03 (m, 2H, aromatic H), 7.13–7.22 (m,
2H, aromatic H), 7.28–7.37 (m, 6H, aromatic H); 13C NMR
(d) 28.3 (d, JCF¼2 Hz), 42.7, 50.0, 56.2, 71.1, 105.7, 107.3,
115.3 (d, JCF¼22 Hz), 124.2 (d, JCF¼4 Hz), 125.5, 125.7 (d,
JCF¼16 Hz), 127.2, 1281, 128.3 (d, JCF¼8 Hz), 128.7,
131.0 (d, JCF¼5 Hz), 134.4, 136.4, 150.2, 151.5, 161.2 (d,
JCF¼243 Hz), 168.7. Anal. Calcd for C24H22FNO3 (377.4):
C, 73.64; H, 5.66; N, 3.58%. Found: C, 73.51; H, 5.75; N,
3.84%.
1
2.09 g (73%); mp 76–78 8C (from hexane–toluene); H
NMR (dH, mixture of two rotational isomers 2:3) 2.80–2.89
(m, 2H, CH2), 3.36–3.44 (m, 2H, CH2), 3.64 (s, 3H, CH3),
4.34 and 4.44 (2£s, together 2H, CH2), 5.91 (s, 2H,
OCH2O), 6.60 and 6.75 (2£s, together 1H, aromatic H),
6.93 (s, 1H, aromatic H), 6.96–7.09 (m, 2H, aromatic H),
7.18–7.25 (m, 2H, aromatic H); 13C NMR (dC, mixture of
two rotational isomers A and B) 27.6 (A), 28.2 (B), 46.7 (B),
47.6 (A), 50.2 (B), 50.5 (A), 52.8, 101.8, 108.1 (A), 109.0
(B), 112.5 (B), 112.7 (A), 113.3 (A), 113.6 (B), 115.2 (d,
JCF¼22 Hz), 124.1 (d, JCF¼4 Hz), 125.7 (d, JCF¼16 Hz),
128.2 (d, JCF¼8 Hz), 130.0 (A), 130.1 (B), 131.2 (d, JCF
¼
4.5.4. 6-[2-(2-Fluorophenyl)ethyl]-6,7-dihydro-[1,3]di-
oxolo[4,5-f]-isoindol-5-one (4d). Yield 716 mg (62%);
mp 104–105 8C; 1H NMR (d) 3.00 (t, J¼7.1 Hz, 2H,
CH2), 3.81 (t, J¼7.1 Hz, 2H, CH2), 4.12 (s, 2H, CH2), 6.02
(s, 2H, OCH2O), 6.77 (s, 1H, aromatic H), 6.98–7.05 (m,
2H, aromatic H), 7.16–7.26 (m, 3H, aromatic H); 13C NMR
(d) 28.4 (d, JCF¼2 Hz), 42.8, 50.2, 101.8, 103.0, 103.4,
5 Hz), 147.7, 156.6 (A), 157.2 (B), 161.3 (d, JCF¼244 Hz).
Anal. Calcd for C18H17BrFNO4 (410.2): C, 52.70; H, 4.18;
N, 3.41%. Found: C, 52.61; H, 4.04; N, 3.31%.
4.5. General procedure for the synthesis of the
isoindolinones 4a–d
115.3 (d, JCF¼2 Hz), 124.3 (d, JCF¼4 Hz), 125.7 (d, JCF
¼
A solution of t-BuLi (2.5 mL, 1.7 M in pentane, 4.25 mmol)
was added dropwise by syringe at 2100 8C under Ar to a
solution of carbamate 5a–d (3.86 mmol) in dry THF
(50 mL). The reaction mixture was allowed to warm to
16 Hz), 126.7, 128.4 (d, JCF¼8 Hz), 131.1 (d, JCF¼5 Hz),
136.5, 148.2, 151.1, 161.3 (d, JCF¼243 Hz), 168.1. Anal.
Calcd for C17H14FNO3 (299.3): C, 68.22; H, 4.71; N,
4.68%. Found: C, 68.03; H, 4.94; N, 4.65%.

A. Moreau et al. / Tetrahedron 60 (2004) 6169–6176
6175
4.6. General procedure for the generation of isoquinoline
skeleton of the compounds 1a–d by intramolecular ring
closure
73.11; H, 4.69; N, 5.01%. Found: C, 73.08; H, 4.80; N,
4.87%.
4.6.5. 13b-Hydroxy-5,6,8,13b-tetrahydro[1,3]dioxolo
[40,50:5,6]isoindolo[1,2-a]isoquinolin-8-one (14d). Yield
190 mg (62%); mp 189–190 8C; H NMR (dH, DMSO d6)
A solution of isoindolinone 4a–d (1.04 mmol) and 18-
crown-6 (600 mg, 2.28 mmol) in dry THF (50 mL) was
carefully degassed by three freeze–thaw cycles and stirred
at 278 8C under dry deoxygenated Ar. Then a solution of
KHMDS (4.6 mL, 0.5 M in toluene, 2.28 mmol) was added
dropwise. The mixture was stirred for 15 min at 278 8C and
then allowed to warm to room temperature within 2 h.
Aqueous NH4Cl solution (10%, 5 mL) was added and after
dilution with water (30 mL) the mixture was extracted with
Et2O (2£25 mL). The combined organic layers were dried
(Na2SO4) and the solvents were evaporated in vacuo to left
1a–d as solids which were purified by flash column
chromatography with Et2O as eluent.
1
2.77–2.83 (m, 2H, CH2), 3.36 (dt, Jgem¼12.7 Hz, J¼8.1 Hz,
1H, CH2), 4.12–4.19 (m, 1H, CH2), 6.10 (s, 1H, OCH2O),
6.16 (s, 1H, OCH2O), 6.95 (br s, 1H, OH), 7.05 (s, 1H,
aromatic H), 7.11–7.27 (m, 3H, aromatic H), 7.73 (s, 1H,
aromatic H), 8.00 (d, J¼7.8 Hz, 1H, aromatic H); 13C NMR
(dC, DMSO d6) 28.8, 34.6, 85.1, 101.9, 102.2, 104.5, 124.3,
126.4, 127.7, 128.1, 128.9, 134.2, 137.6, 144.4, 148.5,
151.4, 165.9. Anal. Calcd for C17H13NO4 (295.3): C, 69.15,
4.44; N, 4.74%. Found: C, 69.22; H, 4.25; N, 4.89%.
Acknowledgements
4.6.1. 5,12b-Dihydro-6H-11,12-dimethoxy-1,3-dioxolo-
[4,5-g]isoindolo[1,2a]isoquinolin-8-one (Nuevamine,
1a). Yield 250 mg (71%); mp 210–211 8C (lit.2 212 8C);
1H NMR (d) 2.85 (dt, Jgem¼15.4 Hz, J¼6.1 Hz, 1H, CH2),
3.00 (dt, Jgem¼15.4 Hz, J¼6.1 Hz, 1H, CH2), 3.57 (dt,
Jgem¼12.5 Hz, J¼6.1 Hz, 1H, CH2), 3.96 (s, 3H, CH3), 3.98
(s, 3H, CH3), 3.94–4.02 (m, 1H, CH2), 5.61 (s, 1H, NCH),
5.87 (d, Jgem¼17.9 Hz, 1H, OCH2O), 5.88 (d, Jgem¼17.9
Hz, 1H, OCH2O), 6.65 (s, 1H, aromatic H), 7.05 (d,
J¼8.3 Hz, 1H, aromatic H), 7.28 (s, 1H, aromatic H), 7.57
(d, J¼8.3 Hz, 1H, aromatic H); 13C NMR (d) 28.9, 38.9,
56.3, 58.5, 60.5, 101.0, 107.5, 108.4, 113.3, 119.8, 126.4,
128.2, 128.8, 136.0, 144.4, 146.5, 146.8, 155.6, 167.9.
This research was supported by the Centre National de la
Recherche Scientifique and MENESR (grant to A. M.).
Also we acknowledge helpful discussions and advice from
Dr. T. G. C. Bird (Astra-Zeneca Pharma).
References and notes
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Kampe, W.; Seidel, H.; Leser, U.; Leinert, H. J. Med. Chem.
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1
mp 147–149 8C; H NMR (d) 2.78 (ddd, Jgem¼15.6 Hz,
J¼4.6, 4.9 Hz, 1H, CH2), 2.94 (ddd, Jgem¼15.7 Hz, J¼6.4,
9.0 Hz, 1H, CH2), 3.36–3.48 (m, 1H, CH2), 3.87 (s, 3H,
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(69%); mp 170–172 8C; 1H NMR (d) 2.82 (ddd, Jgem¼15.7
Hz, J¼4.5, 4.9 Hz, 1H, CH2), 3.01 (ddd, Jgem¼15.7 Hz,
J¼5.7, 9.3 Hz, 1H, CH2), 3.41 (ddd, Jgem¼12.9 Hz, J¼4.5,
9.3 Hz, 1H, CH2), 4.35 (ddd, Jgem¼12.9 Hz, J¼4.9, 5.7 Hz,
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