First total synthesis of cichorine and zinnimidine

Article abstract of DOI:10.1039/b504602e

The first total synthesis of the phytotoxins cichorine and zinnimidine is described. The synthetic tactics involve the sequential connection of the dense and diverse functionalities on the aromatic nucleus followed by a Parham cyclization process, giving rise to the lactam unit embedded in the title compound framework. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504602e

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A R T I C L E
First total synthesis of cichorine and zinnimidine
Anne Moreau, Axel Couture,* Eric Deniau, Pierre Grandclaudon and Ste´phane Lebrun
UMR 8009 “Chimie Organique et Macromole´culaire”, Laboratoire de Chimie Organique
Physique, Baˆtiment C3(2), Universite´ des Sciences et Technologies de Lille, 59655, Villeneuve
d’Ascq Ce´dex, France. E-mail: axel.couture@univ-lille1.fr; Fax: +33(0)3 20 33 63 09;
Tel: +33(0)3 20 43 44 32
Received 4th April 2005, Accepted 28th April 2005
First published as an Advance Article on the web 13th May 2005
The first total synthesis of the phytotoxins cichorine and zinnimidine is described. The synthetic tactics involve
the sequential connection of the dense and diverse functionalities on the aromatic nucleus followed by a Parham
cyclization process, giving rise to the lactam unit embedded in the title compound framework.
diverse and dense functionalities within the compact molecular
framework of alkaloids such as cichorine (1) and zinnimidine (2).
Introduction
Cichorine (1) and zinnimidine (2) are eminent representatives
of phytotoxins, which have been isolated from the stationary
liquid cultures of a variety of phytopathogenic fungi from the
genus Alternaria.1 Recent interest stimulated in the scientific
community for this class of isoindol-1-ones stems mainly from
their implication in diseases of commercially important plants,
namely through necrosis of the tips and margins of infected
specimens.1 Cichorine (1), which has been also isolated as
a minor component from the culture filtrate of Aspergillus
silvaticus, was found to be highly active on knapweed, corn
oats and soyabeans.2,3 Zinnimidine (2) has been produced by
the fungus Alternaria porri (Ellis) Ciferi, the casual fungus of
the black spot disease in stone-leeks and onions.4 Finally, the
fungal metabolites 1 and 2 have been isolated from Alternaria
cichorii, which causes foliar blight of Russian knapweed, an
important pest weed.2 As far as we are aware, no total synthesis
of these two phytotoxins have appeared in the literature. This
is undoubtedly due to the difficulties associated with the con-
struction of the compact isoindolinone framework, densely and
diversely functionalized on the basic aromatic nucleus. Due to
the diverse biological activities of many of their derivatives,5 the
chemistry of isoindolinones has been the focus of new synthetic
methodologies during the last few years and organic chemists
have at their disposal a great number of synthetic methods for
the preparation of these bicyclic lactams. The main general
synthetic approaches involve: (i) the free radical bromination
of 2-methylbenzoyl ester derivatives and subsequent treatment
with an appropriate primary amine;6 (ii) the condensation of a
primary amine with the corresponding phthalides;7 (iii) the de-
phosphorylation of the corresponding 3-phosphorylated parent
models;8 (iv) the reduction of phthalimides via their aminals or
thioaminals;9 and, finally, (v) the reaction of o-phthalaldehyde
with a primary amine.10 All these methods are simple and
proceed in good yields. Unfortunately, their applicability is
generally unsatisfactory mainly because of restrictions in the
choice of substituents, namely in their nature, number and their
position on the aromatic nucleus. Thus, the first method does
not tolerate the presence in the parent models of substituents
sensitive to the bromination step (e.g. an additional methyl
group). Issues raised by elaboration of diversely substituted
isoindolinones by applying the second and third methods may
not be simply addressed from their corresponding oxo analogues
or their phosphorylated derivatives. Finally, the last synthetic
methods genuinely lack selectivity and hence have been confined
to the synthesis of bare or symmetrically substituted models.
Consequently, all these strategies will be inevitably plagued
with difficulties associated with the exquisite arrangement of
Results and discussion
In the course of our ongoing project dealing with the syn-
thesis and subsequent biological evaluation of a variety of
isoindolinone-centered natural products11 we herein wish to dis-
close an efficient synthetic approach to isoindolinones illustrated
by the first total synthesis of the exemplary representatives of
the Alternaria species, i.e. cichorine (1) and zinnimidine (2). Our
strategy is based upon the exploitation of the Parham cyclization
process for the creation of the five-membered lactam unit em-
bedded in the isoindolinone framework. The protocol developed
by Parham hinges upon aromatic lithiation, usually carried out
by lithium–halogen exchange and subsequent reaction with an
internal electrophile.12 This technique occupies a place of choice
in the arsenal of synthetic tactics for the assembling of carbo-
and heterocyclic systems, but applications for the elaboration of
five-membered lactams are quite scarce and have been confined
thus far to the construction of dibenzoindolones,13 chromeno-14
and arylmethylene isoindolinones.15
We then anticipated that zinnimidine (2) would be obtained by
prenylation of cichorine (1) (Scheme 1) and we conjectured that
this fused alkaloid would be conceivably assembled by a Parham
type cyclization of the pentasubstituted aromatic carbamate 3,
incorporating differentiated protecting groups on the sensitive
hydroxy phenolic and N-acyl functionalities.
Scheme 1 Retrosynthetic analysis and disconnections for the synthesis
of the parent compound 3.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 0 5 – 2 3 0 9
2 3 0 5
©

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A contentious issue in the elaboration of this rather congested
compound was the initial judgement of the proper strategy for
the tailored incorporation of the diverse aromatic substituents
and, above all, of the appropriate functionalities liable to secure
the creation of the lactam unit. Retrosynthetic analysis led to
the disconnections indicated on Scheme 1.
It was assumed that the installation of the carbamate function,
acting as the internal electrophile, would be achieved by
acylation of the corresponding protected amine, produced by
a reductive amination process involving the appropriate amine
and the suitably substituted carboxaldehyde. The bromine atom
would be regioselectively connected to the benzene nucleus by
an electrophilic process exploiting the presence of the vicinal
carboxaldehyde function.
The first facet of the synthesis was then the elaboration
of the requisite tetrasubstituted benzaldehyde derivative 6.
This compound was readily synthesized by the three step se-
quence depicted in Scheme 2. Formylation of 2-methylresorcinol
with POCl3–DMF proceeded regioselectively to afford the
benzaldehyde derivative 4 in an excellent yield. Sequential
O-alkylations of this biphenolic compound were performed
in basic medium but under differentiated conditions. Thus,
alkylation with isopropyl iodide16 was achieved in the polar
aprotic solvent acetone, which diminishes hydrogen bonding
interactions between the vicinal carboxaldehyde and phenol
functions in 4, thus favouring alkylation of the remote hydroxy
phenolic group. O-Methylation of the resulting monophenolic
derivative 5 was readily achieved under standard conditions
to deliver the required contiguously and diversely substituted
benzaldehyde 6, albeit in moderate yield (47% over two steps).
We next planned to install the bromine atom at the mandatory
vicinal position of the carboxaldehyde function. Due to the
erratic nature of aromatic bromination processes, a metallation–
electrophilic bromination process was more appealing. Critical
to the success of this strategy was then the ability to identify a
masked carboxaldehyde synthon that was capable not only of
retaining the formyl functionality, but also of directing subse-
quent lithiation to the ortho ring position. After considerable
experimentation with various temperatures, ethereal solvents,
bases and brominating agents, we found that adding 2 eq. of tert-
butyllithium in pentane to 1 eq. of imidazolidine 717 in Et2O at
−30 ◦C and then quenching with 1,2-dibromotetrachloroethane
led to bromination exclusively adjacent to the imidazolidine
group. Regeneration of the formyl functionality provided a
62% yield of the desired 6-bromo-4-isopropoxy-2-methoxy-
3-methylbenzaldehyde (8). The subsequent synthesis of the
secondary amine 9, incorporating the nitrogen protecting group
PMB (para-methoxybenzyl), was achieved by a reductive amina-
tion process and the dibenzylamine 9 was delivered with a fairly
good yield. Finally, treatment of 9 with methyl chloroformate
provided almost quantitatively the carbamate 3 (82% over two
steps), a candidate for the planned Parham cyclization process.
To ensure the formation of the lithiated intermediate 10,
a THF solution of the arylbromide 3 was exposed to tert-
butyllithium at −100 ◦C (Scheme 3). The ring-closure was
instantaneous as demonstrated by the isolation solely of the
annulated compound 11 upon immediate aqueous work-up.
Subsequent benzylic lactam deprotection was obtained by treat-
ment of 11 with TFA in the presence of the carbocation scavenger
anisole, to provide the monoprotected isoindolinone 12. Finally,
treatment of 12 with boron chloride (BCl3) in dichloromethane
under mild conditions triggered off the cleavage of the phenolic
isopropyl protecting group16 and this simple operation delivered
the target natural product cichorine (1). This compound can
be regarded as an immediate precursor of zinnimidine (2),
which was easily obtained by prenylation of the 6-OH group
(Scheme 3). By the reaction sequence depicted in Scheme 2 and
Scheme 3 the phytotoxins 1 and 2 were obtained respectively in
4.8% (over 10 steps for 1) and 3.3% yield (over 11 steps for 2),
starting from 2-methylresorcinol. The constitution of the target,
final compounds 1 and 2 was secured by matching their 1H and
13C NMR, IR and mass spectra with those published for the
products extracted from vegetal sources.2–4
Scheme 2 Reagents and conditions: (i) POCl3, DMF, 20 ◦C 12 h;
(ii) iPrI, K2CO3, acetone, reflux, 12 h; (iii) MeI, K2CO3, DMF, 40 ◦C,
12 h; (iv) N,Nꢀ-dimethylethylenediamine, toluene, reflux, 3 h; (v) tBuLi,
Et2O, Ar, −30 ◦C, then 20 ◦C, 6 h, then −30 ◦C, (BrCl2C)2, then 20 ◦C,
12 h, then HCl 10%, 20 ◦C, 30 min; (vi) p-CH3OC6H4CH2NH2, toluene,
reflux, 3 h, then NaBH4, MeOH, 20 ◦C, 2 h; (vii) ClCOOMe, NEt3,
CH2Cl2, 0 ◦C, then 20 ◦C, 3 h.
Scheme 3 Reagents and conditions: (i) tBuLi, THF, −100 ◦C, Ar,
30 min; (ii) TFA, anisole, reflux, 48 h; (iii) BCl3, CH2Cl2, −78 ◦C, 2 h;
(iv) 1-bromo-3-methylbut-2-ene, K2CO3, acetone, reflux, 12 h.
2 3 0 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 0 5 – 2 3 0 9

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2-(4-Isopropoxy-2-methoxy-3-methylphenyl)-1,3-
dimethylimidazolidine 7
Conclusions
A simple and efficient first total synthesis of the naturally
occurring isoindolinones cichorine (1) and zinnimidine (2) from
Alternaria species has been disclosed. The synthetic approach
clearly emphasizes the prominent place of the Parham cy-
clization process in the arsenal of the synthetic tactics for the
assembling of heterocyclic systems, namely alkaloids.
A solution of the benzaldehyde 6 (2.39 g, 11.5 mmol) and N,Nꢀ-
dimethylethylenediamine (1.06 g, 12.0 mmol) in toluene (75 mL)
was refluxed in a Dean–Stark apparatus for 3 h. The solvent
was removed under a reduced pressure to leave an oily residue,
which was purified by distillation under a reduced pressure (102–
103 ◦C; 10−2 mm Hg) to give the imidazolidine 7 (2.11 g, 66%)
as a yellow oil (found: C, 68.8; H, 9.6; N, 10.0%. C16H26N2O2
requires C, 69.0; H, 9.4; N, 10.1%); IR mmax (film)/cm−1 2760
(NCH3); 1H NMR dH (300 MHz; CDCl3; Me4Si): 1.31 (6 H, d,
J1,3 6.1, 2 × CHCH3), 2.13 (3 H, s, ArCH3), 2.18 (6 H, s, 2 ×
NCH3), 2.52–2.58 (2 H, m, NCH2), 3.33–3.38 (2 H, m, NCH2),
3.69 (3 H, s, OCH3), 4.51 (1 H, heptuplet, J1,3 6.1, CHMe2), 6.69
(1 H, d, J1,3 8.5, Har), 7.40 (1 H, d, J1,3 8.5, Har); 13C NMR dC
(75 MHz; CDCl3; Me4Si) 9.4 (CH3), 22.3 (2 × CH3), 39.7 (2 ×
NCH3), 53.3 (2 × NCH2), 61.3 (OCH3), 70.2 (ArOCH), 84.4
(NCHN), 109.7 (CHar), 119.5 (Car), 123.8 (Car), 126.8 (CHar),
156.8 (Car), 159.3 (Car).
Experimental
General methods
Mps were determined on a Reichert–Thermopan apparatus
and are uncorrected. Infrared spectra were recorded on a FT-
IR Bruker Vector 22 spectrometer. H and 13C NMR spectra
1
were recorded on a Bruker AM 300 spectrometer. Coupling
constants (J) are given in Hz and rounded to the nearest 0.1 Hz.
Elemental analyses were determined by the CNRS microanalysis
centre. The silica gel used for flash column chromatography was
Merck Kieselgel of 0.040–0.063 mm particle size. Dry glassware
was obtained by oven-drying and assembly under Ar. Ar was
used as the inert atmosphere and was passed through a drying
tube to remove moisture. The glassware was equipped with
rubber septa and reagent transfer was performed by syringe
techniques. Tetrahydrofuran (THF) and diethylether (Et2O)
were distilled from sodium benzophenone ketyl immediately
before use. Methanol (MeOH) was distilled from magnesium
turnings and dichloromethane (CH2Cl2) from CaH2, before
6-Bromo-4-isopropoxy-2-methoxy-3-methylbenzaldehyde 8
tBuLi (1.7 M in pentane, 10.0 mL, 17.0 mmol) was added
dropwise at −30 ◦C under Ar to a solution of the imidazolidine
7 (2.35 g, 8.4 mmol) in dry Et2O (30 mL). The solution was
allowed to warm to rt, stirred at this temperature for 6 h, then re-
cooled to −30 ◦C. A solution of 1,2-dibromotetrachloroethane
(5.50 g, 16.9 mmol) in Et2O (10 mL) was added dropwise at
−30 ◦C, the mixture was then allowed to warm to rt and stirring
at rt was maintained for 12 h. The solution was poured onto a
10% HCl aqueous solution (50 mL), the mixture was stirred for
30 min and extracted with Et2O (4 × 25 mL). The combined
extracts were washed with water and brine, dried (Na2SO4) and
evaporated under a reduced pressure to leave an oily residue,
which was purified by column chromatography on silica using
Et2O–hexanes (50 : 50) as eluent to give the aldehyde 8 (1.49 g,
62%) as a yellow oil (found: C, 50.4; H, 5.4%. C12H15BrO3
requires C, 50.2; H, 5.3%); IR mmax (film)/cm−1 1685 (CHO);
1H NMR dH (300 MHz; CDCl3; Me4Si): 1.35 (6 H, d, J1,3 6.1,
2 × CHCH3), 2.05 (3 H, s, ArCH3), 3.79 (3 H, s, OCH3), 4.59
(1 H, heptuplet, J1,3 6.1, CHMe2), 6.80 (1 H, s, Har), 10.23
(1 H, s, CHO); 13C NMR dC (75 MHz; CDCl3; Me4Si) 8.6 (CH3),
22.0 (2 × CH3), 62.4 (OCH3), 71.1 (ArOCH), 114.0 (CHar),
120.3 (Car), 121.5 (Car), 124.0 (Car), 161.4 (Car), 162.2 (Car), 189.7
(CHO).
˚
storage on 4 A molecular sieves.
Starting material
The aldehyde 4 was prepared according to a standard
procedure.18
2-Hydroxy-4-isopropoxy-3-methylbenzaldehyde 5
A stirred solution of the benzaldehyde derivative 4 (4.50 g,
29.6 mmol) and isopropyl iodide (5.35 g, 31.5 mmol) in acetone
(100 mL) was refluxed with K2CO3 (4.30 g, 31.2 mmol) for 12 h.
After cooling and filtration on celite, the solvent was removed
under a reduced pressure to leave an oily residue, which was
purified by flash column chromatography on silica using Et2O–
hexanes (50 : 50) as eluent to give the benzaldehyde 5 (4.70 g,
82%) as a colourless oil (found: C, 67.8; H, 7.4%. C11H14O3
requires C, 68.0; H, 7.3%); IR mmax (film)/cm−1 3390 (OH), 1640
1
(CHO); H NMR dH (300 MHz; CDCl3; Me4Si): 1.36 (6 H, d,
J
J
1,3 5.9, 2 × CHCH3), 2.07 (3 H, s, ArCH3), 4.66 (1 H, heptuplet,
1,3 5.9, CHMe2), 6.52 (1 H, d, J1,3 8.8, Har), 7.31 (1 H, d, J1,3 8.8,
N-(6-Bromo-4-isopropoxy-2-methoxy-3-methyl)-N-(4-
methoxybenzyl)amine 9
Har), 9.68 (1 H, s, CHO); 13C NMR dC (75 MHz; CDCl3; Me4Si)
7.5 (CH3), 22.2 (2 × CH3), 70.7 (ArOCH), 104.7 (CHar), 114.1
(Car), 114.9 (Car), 133.0 (CHar), 161.4 (Car), 163.1(Car), 194.5
(CHO).
A solution of the aldehyde 8 (1.15 g, 4.0 mmol) and para-
methoxybenzylamine (0.55 g, 4.0 mmol) in toluene (50 mL) was
refluxed in a Dean–Stark apparatus for 3 h. The solvent was
evaporated under a reduced pressure and the crude imine was
used without further purification. The imine was dissolved in
MeOH (50 mL) and treated with sodium borohydride (0.30 g,
8.0 mmol). After stirring for 2 h, NH4Cl (1 g) was added and
stirring was maintained for 30 min. The solvent was evaporated
under a reduced pressure and the residue was dissolved in
CH2Cl2 (50 mL). The solution was washed with water and brine,
then concentrated under a vacuum. Purification by column
chromatography on silica using ethyl acetate–hexanes (90 : 10) as
eluent afforded the amine 9 (1.39 g, 85%) as a yellow oil (found:
C, 59.1; H, 6.35; N, 3.7%. C20H26BrNO3 requires C, 58.8; H, 6.4;
N, 3.4%); IR mmax (film)/cm−1 3335 (NH); 1H NMR dH (300 MHz;
CDCl3; Me4Si): 1.32 (6 H, d, J1,3 6.1, 2 × CHCH3), 2.08
(3 H, s, ArCH3), 3.71 (3 H, s, OCH3), 3.74 (2 H, s, NCH2), 3.79
(3 H, s, OCH3), 3.85 (2 H, s, NCH2), 4.46 (1 H, heptuplet, J1,3 6.1,
CHMe2), 6.84 (1 H, s, Har), 6.85 (2 H, d, J1,3 8.5, Har), 7.27 (2 H,
d, J1,3 8.5, Har); 13C NMR dC (75 MHz; CDCl3; Me4Si) 9.5 (CH3),
22.1 (2 × CH3), 47.5 (NCH2), 55.3 (OCH3), 58.2 (NCH2), 61.4
4-Isopropoxy-2-methoxy-3-methylbenzaldehyde 6
A solution of the benzaldehyde 5 (2.40 g, 12.4 mmol) and methyl
iodide (2.0 g, 14.0 mmol) in D◦MF (50 mL) was stirred with
K2CO3 (8.55 g, 62 mmol) at 40 C for 12 h. After cooling and
filtration on celite, the solvent was removed under a reduced
pressure to leave a solid residue, which was purified by flash
column chromatography on silica using Et2O–hexanes (50 : 50)
as eluent to give the benzaldehyde 6 (1.47 g, 57%) as a white
solid; mp 44–45 ◦C (found: C, 69.3; H, 7.6%. C12H16O3 requires
C, 69.2; H, 7.75%); IR mmax (KBr)/cm−1 1679 (CHO); 1H NMR
dH (300 MHz; CDCl3; Me4Si): 1.35 (6 H, d, J1,3 5.9, 2 × CHCH3),
2.13 (3 H, s, ArCH3), 3.84 (3 H, s, OCH3), 4.64 (1 H, m, CHMe2),
6.71 (1 H, d, J1,3 8.8, Har), 7.70 (1 H, d, J1,3 8.8, Har), 10.20
(1 H, s, CHO); 13C NMR dC (75 MHz; CDCl3; Me4Si) 8.7 (CH3),
22.1 (CH3), 22.15 (CH3), 63.1 (OCH3), 70.6 (ArOCH), 108.4
(CHar), 120.8 (Car), 122.3 (Car), 127.7 (CHar), 162.7 (Car), 162.9
(Car), 189.1 (CHO).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 0 5 – 2 3 0 9
2 3 0 7

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(OCH3), 70.8 (ArOCH), 113.5 (CHar), 113.6 (2 × CHar), 120.8
(Car), 121.8 (Car), 125.4 (Car), 129.4 (2 × CHar), 132.7 (Car), 156.6
(Car), 158.5 (Car), 158.6 (Car).
Me4Si) 9.6 (CH3), 21.9 (2 × CH3), 43.3 (NCH2), 58.9 (OCH3),
70.2 (ArOCH), 101.5 (CHar), 121.6 (Car), 124.7 (Car), 132.2 (Car),
153.5 (Car), 156.5 (Car), 169.8 (CO).
N-(6-Bromo-4-isopropoxy-2-methoxy-3-methyl)-N-(4-
methoxybenzyl)carbamic acid methyl ester 3
6-Hydroxy-4-methoxy-5-methyl-2,3-dihydro-1H-isoindol-1-one
(cichorine) 1
Methyl chloroformate (0.56 g, 5.88 mmol) was added dropwise
to a stirred solution of the amine 9 (1.60 g, 3.92 mmol) and
triethylamine (0.79 g, 7.85 mmol) in CH2Cl2 (50 mL). After
stirring for 3 h, the mixture was washed with water then brine
and dried (Na2SO4). The solvent was evaporated under a reduced
pressure to leave a residue, which was purified by column
chromatography on silica using ethyl acetate–hexanes (30 : 70)
as eluent to give the carbamate 3 (1.75 g, 96%) as a yellow
oil (found: C, 56.4; H, 6.33; N, 2.9%. C22H28BrNO5 requires
A solution of BCl3 (1 M in CH2Cl2, 1.06 mL, 1.06 mmol) was
added dropwise with stirring to a solution of the isoindolinone
12 (0.20 g, 0.85 mmol) in CH2Cl2 (15 mL) maintained at −78 ◦C
under Ar. The mixture was stirred at −78 ◦C for 2 h, then MeOH
(3 × 5 mL) was added. The solvent was evaporated under a
reduced pressure and the solid residue was dissolved in Et2O
(25 mL). The solution was washed with brine (20 mL), dried
(MgSO4) and evaporated under a reduced pressure to leave a
solid residue, which was purified by column chromatography on
silica using ethyl acetate–hexanes (50 : 50) as eluent to give the
cichorine 1 (0.13 g, 78%) as white crystals, mp 215–216 ◦C (from
EtOH) (lit.,19 217 ◦C); 13C NMR dC (75 MHz; DMSO-d6; Me4Si)
9.4 (CH3), 43.2 (NCH2), 58.9 (OCH3), 103.0 (CHar), 119.1 (Car),
123.1 (Car), 132.0 (Car), 153.6 (Car), 156.5 (Car), 169.9 (CO).
C, 56.7; H, 6.05; N, 3.0%); IR mmax (film)/cm−1 1725 (C O);
=
1H NMR dH (300 MHz; CDCl3; Me4Si): 1.31 (6 H, d, J1,3 5.9,
2 × CHCH3), 2.04 (3 H, s, ArCH3), 3.61 (3 H, s, OCH3), 3.75
(3 H, s, OCH3), 3.78 (3 H, s, OCH3), 4.22 (2 H, br. s, NCH2), 4.44
(1 H, heptuplet, J1,3 5.9, CHMe2), 4.71 (2 H, br. s, NCH2), 6.74
(2 H, d, J1,3 8.5, Har), 6.77 (1 H, s, Har), 7.06 (2 H, br. s, Har); 13
C
NMR dC (75 MHz; CDCl3; Me4Si) 9.5 (CH3), 22.1 (2 × CH3),
45.1 (NCH2), 52.7 (OCH3), 55.2 (OCH3), 60.2 (NCH2), 60.9
(OCH3), 70.7 (ArOCH), 113.5 (CHar), 113.4 (2 × CHar), 120.7
(Car), 121.4 (Car), 122.4 (Car), 128.3 (2 × CHar), 130.4 (Car), 157.1
(Car), 158.4 (Car), 159.5 (2 × Car).
4-Methoxy-5-methyl-6-(3-methylbut-2-enyloxy)-2,3-dihydro-
1H-isoindol-1-one (zinnimidine) 2
A stirred solution of cichorine 1 (100 mg, 0.52 mmol) and
1-bromo-2-methylbut-2-ene (93 mg, 0.62 mmol) in acetone
(15 mL) was refluxed with K2CO3 (0.11 g, 0.80 mmol) for
12 h. The mixture was filtered on celite, concentrated under
a vacuum, then the solid residue was dissolved in Et2O (15 mL).
The cooled solution was washed with water, 10% NaOH solution
(2 × 15 mL), brine and dried (Na2SO4). The organic layer was
evaporated under a reduced pressure to afford the zinnimidine
2 (93 mg, 68%), which was purifie◦d by recrystalliza◦tion from
EtOH. White crystals, mp 136–138 C (lit.,4 136–138 C).
6-Isopropoxy-4-methoxy-2-(4-methoxybenzyl)-5-methyl-2,3-
dihydro-1H-isoindol-1-one 11
tBuLi (1.7 M in pentane, 2.2 mL, 3.68 mmol) was added
dropwise at −100 ◦C under Ar to a solution of the carbamate 3
(1.56 g, 3.35 mmol) in THF (40 mL). The solution was stirred
at −100 ◦C for 30 min, then aqueous saturated NH4Cl solution
was added (5 mL). The cooled mixture was extracted with Et2O
(2 × 25 mL). The combined extracts were dried (Na2SO4) and
evaporated under a reduced pressure to leave a solid, which
was purified by column chromatography on silica using ethyl
acetate–hexanes (50 : 50) as eluent to give the isoindolinone
11 (0.68 g, 55%) as white crystals, mp 74–75 ◦C (found: C,
Acknowledgements
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 G. Cooke
(Heriot–Watt University, Edinburgh).
70.7; H, 7.0; N, 3.85%. C21H25NO4 requires C, 71.0; H, 7.1; N,
1
3.9%); IR mmax (KBr)/cm−1 1675 (C O); H NMR dH (300 MHz;
=
CDCl3; Me4Si): 1.35 (6 H, d, J1,3 6.1, 2 × CHCH3), 2.14 (3 H, s,
ArCH3), 3.78 (6 H, s, 2 × OCH3), 4.25 (2 H, s, NCH2), 4.61
(1 H, heptuplet, J1,3 6.1, CHMe2), 4.71 (2 H, s, NCH2), 6.85
(2 H, d, J1,3 8.5, Har), 7.11 (1 H, s, Har), 7.22 (2 H, d, J1,3 8.5,
Har); 13C NMR dC (75 MHz; CDCl3; Me4Si) 9.7 (CH3), 22.1 (2 ×
CH3), 45.8 (NCH2), 47.5 (NCH2), 55.3 (OCH3), 59.7 (OCH3),
70.7 (ArOCH), 102.7 (CHar), 114.1 (2 × CHar), 123.2 (Car), 123.8
(Car), 129.2 (Car), 129.4 (2 × CHar), 131.4 (Car), 156.3 (Car), 157.6
(Car), 159.1 (Car), 168.5 (CO).
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one 12
A solution of the isoindolinone 11 (0.53 g, 1.5 mmol) and
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1
=
(C O); H NMR dH (300 MHz; CDCl3; Me4Si): 1.30 (6 H, d,
J
1,3 6.1, 2 × CHCH3), 2.09 (3 H, s, ArCH3), 3.89 (3 H, s, OCH3),
4.49 (2 H, s, NCH2), 4.66 (1 H, heptuplet, J1,3 6.1, CHMe2), 6.94
(1 H, s, Har), 8.56 (1 H, br s, NH); 13C NMR dC (75 MHz; CDCl3;
2 3 0 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 0 5 – 2 3 0 9

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