Fluoride ion-induced cyclization of o-[bis(trimethylsilyl)methyl]-N-acylbenzamide derivatives. New efficient synthesis of 2,3-differentially substituted 1(2H)-isoquinolones

Article abstract of DOI:10.1039/a605077h

A wide variety of 2-alkyl-3-alkyl, -3-aryl and -3-heteroaryl-1(2H)-isoquinolones have been obtained by fluoride ion-induced intramolecular alkenation of o-[bis(trimethylsilyl)methyl]-N-acylbenzamide derivatives.

Full text of DOI:10.1039/a605077h

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Fluoride ion-induced cyclization of o-[bis(trimethylsilyl)methyl]-N-
acylbenzamide derivatives. New efficient synthesis of 2,3-differentially
substituted 1(2H)-isoquinolones
Axel Couture,* Hélène Cornet, Eric Deniau, Pierre Grandclaudon and
Stéphane Lebrun
Laboratoire de Chimie Organique Physique, URA CNRS 351, Université des Sciences et
Technologies de Lille I, 59655 Villeneuve d’Ascq Cédex, France
A wide variety of 2-alkyl-3-alkyl, -3-aryl and -3-heteroaryl-1(2H )-isoquinolones have been obtained by
fluoride ion-induced intramolecular alkenation of o-[bis(trimethylsilyl)methyl]-N-acylbenzamide
derivatives.
either 3-alkyl or -aryl derivatives equally well, relies upon the
Introduction
reaction of dilithiated N,2-dimethylbenzamides with alkyl and
It is well known that the 1(2H )-isoquinolone skeleton constitutes
the framework of a wide array of plant alkaloids and drugs and
that many naturally occurring or synthetic compounds based
on the 1(2H )-isoquinolone structure exhibit great diversity in
their biological activities.1 Accordingly, synthesis of this hetero-
bicyclic system has developed remarkably in recent years, and
this is obviously linked to the synthetic potential of compounds
comprising the 1-oxodihydroisoquinoline unit. Indeed, such
compounds may be regarded as synthetic precursors of di-
hydro- and tetrahydro-isoquinoline derivatives and the import-
ance of isoquinoline derivatives, many of which are pharmaco-
logically active, as intermediates in the synthesis of natural
products and in medicinal chemistry is particularly well
documented.2
arylcarboxylic acid derivatives.15
O
O
R1
R1
R2
N
R2
N
O
CH3
α
1
2
R1 = alkyl, R2 = alkyl, aryl, heteroaryl
O
R1
N
R2
R2 = o-DMG, Hal, CF3
O
As part of our continuing work in this field we embarked
some time ago on a programme aimed at developing new
approaches to the 1(2H )-isoquinolone skeleton allowing
incorporation of different substitution patterns at the 3- and 4-
position of this heterocyclic nucleus.3 Examination of literature
data revealed the lack of general methods for the construction
of 3-substituted-1(2H )-isoquinolones 1 and demonstrated that
existing synthetic strategies are strongly influenced by the
nature of the substituents linked to the six-membered hetero-
cyclic moiety. Thus the main synthetic routes to 2-alkyl-3-aryl-
CH3
α
3
A few years ago we proposed a new methodology for the
construction of this fused heterocyclic framework which hinges
upon the lithiated base-induced annulation of a variety of N-
acyl-o-toluamide derivatives 2.16 In this new cyclization process
the N-acylbenzamide moiety plays a dual role. Indeed, it facili-
tates deprotonation of the adjacent benzylic α-position, an
unprecedented phenomenon, and consequently enriches the
repertoire of carboxylic acid derivatives promoting lateral lithi-
ation reactions.17 Furthermore, it is a partner in the annu-
lation process since the resulting benzylic carbanion undergoes
cyclization by intramolecular attack on the sufficiently electro-
philic terminal N-acyl function.18 This new concept has been
successfully applied to the synthesis of 3-styryl-1(2H )-isoquino-
lones 1 (R2 = styryl) from appropriately designed N-acyl-o-
toluamides 2 (R2 = styryl). However, attempts to extend the
scope of these reactions to include the preparation of 3-alkyl
and 3-heteroaryl derivatives 1 (R2 = alkyl or heteroaryl respect-
ively) were unrewarding, probably due to the presence of eno-
lizable groups bearing the imidoyl moiety or to sites that can be
easily deprotonated on the heterocyclic nucleus. On the other
hand, even though the potential of this process has been demon-
strated for the elaboration of models incorporating aromatic
hydrocarbon entities, it was anticipated that problems could
also arise with compounds 3 possessing on the pendant aryl
unit either ortho-directing metallation groups (o-DMG)19 at C-
3 or substituents at C-4 which are known to play strong meta-
acidifying effects, such as halogen or trifluoromethyl groups.20
For these compounds 3 indeed lithiated base-induced deproto-
nation may be directed to the ortho-position in preference to the
1(2H )-isoquinolones
1
(R2 = aryl) involve the mercury-
mediated cyclization of N-alkylimines derived from stilbene-
carbaldehydes,4 the reaction of 2Ј-carboxy-2-hydroxydeoxy-
benzoin with primary amines,5 the treatment of homo-
phthalic anhydride with imidoyl chlorides6 or the cyclo-
addition of benzyne to 5-phenylpyrroline-2,3-dione.7 They are
also accessible by different photochemical processes which
include the electrocyclization of aromatic enamides,3a the
photochemically induced arylation of chloroisoquinolones8
and the SR N
1 reaction of o-halogenobenzamides with
ketone enolates.9 They may also be derived from the oxidation
of the corresponding 3,4-dihydroisoquinolones,10 1,2-dihydro-
isoquinolines11 or the quaternary salts of quinoline deriv-
atives.10,11a However none of these methods permits the
introduction of a great diversity of aromatic and even less
of heteroaromatic units onto the six-membered heterocyclic
moiety. On the other hand, 2,3-dialkyl-1(2H )-isoquinolones 1
(R2 = alkyl) are only accessible by a few special methods such as
ortho-thallation and subsequent palladium-promoted olefin-
ation of benzamide derivatives,12 palladium-induced cycliza-
tion of 2-alkyl-N-alkylbenzamides13 or substitution of the oxy-
gen atom of isocoumarins by primary amines.14 Finally, the
most attractive route so far reported, which enables access to
J. Chem. Soc., Perkin Trans. 1, 1997
469

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benzylic α-position due to the cooperative effect of the 1,3-
interrelated o-DMG in promoting metallation at their common
ortho ‘in-between’ site and to additional inductive factors,
respectively. With the aim of delineating the scope of our previ-
ously reported procedure we first examined the base-induced
cyclization of the potentially problematic N-acyl-o-toluamides
2a–d.
R3
R4
CH3
N
O
O
CH3
R6
i
N
OH
R5
R5
o
O
CH
R3 R4
2a–d R3 = R4 = H
9a,c R3 = H, R4 = SiMe3
R6
12a–d R3 = R4 = H
13a,c R3 = H, R4 = SiMe3
Results and discussion
Compounds 2a–d were easily obtained by deprotonation with
butyllithium of N,2-dimethylbenzamide 4 and subsequent
treatment with the appropriate acyl chlorides 10a–d (Scheme 1).
R5
R6
a
b
c
OCH2O
Cl
H
H
H
Cl
CF3
O
CH3
d
N
i, ii
H
Scheme 2 Reagents and conditions: i, LDA, THF, Ϫ30 ЊC, 30 min
CH
R4
4 R3 = R4 = H
5 R3 = H, R4 = SiMe3
6 R3 = R4 = SiMe3
R3
δC 90.1. The structure of compound 12a was further con-
firmed by the independent and unambiguous synthesis depicted
in Scheme 3. Thus the piperonylic carboxamide 14 was treated
O
CH3
R2
N
O
CH
R4
2 R3 = R4 = H
O
O
CH3
H
R3
CH3
N
N
i
12a
H
8 R3 = R4 = SiMe3
9 R3 = H, R4 = SiMe3
O
i, iii
O
O
CH3
14
N
O
N
OCH3
O
CH3
Cl
7
15
R2COCl
10
CH(SiMe3)2
Scheme 3 Reagents and conditions: i, BuLi (2 mol equiv.), THF, 0 ЊC;
then N-methoxy-N-methyl-o-toluamide 15, THF, room temp., 1 h
11
2, 8, 9 R2
8
g
R2
with butyllithium (2 mol equiv.) and efficiently converted into
the bis-(N- and C-ortho)-lithiated derivative (confirmed by D2O
quench).21c Subsequent treatment of the lithiated species with
N-methoxy-N-methyl-o-toluamide 15 (Weinreb amide)22
afforded the cyclocondensed product 12a quantitatively.
Although disappointing from a synthetic point of view‡ these
reactions deserve some comment. Compounds 2a–d, on treat-
ment with LDA, give products resulting from exclusive ortho-
deprotonation and subsequent intramolecular attack of the
aryllithium species on the terminal acyl moiety. Now, in com-
petitive processes involving ortho versus adjacent benzylic-
directed lithiation of N,N-disubstituted-2-alkylbenzamides,
ortho-lithiation is favoured over α-lithiation only with sterically
hindered 2-alkyl groups23 (i.e. isopropyl) and with models
where steric congestion renders the α-proton inaccessible.24
The exclusive deprotonation of the ortho site in the eastern part
of the models 2a–d rather than lateral α-lithiation promoted by
the N-acylcarboxamide group of the opposite part clearly indi-
cates the predominant influence of the cooperative effects in
1,3-related o-DMG and 1,4-DMG-halogen or CF3 combin-
ations in compounds 2a,b and 2c,d, respectively, even though
methylenedioxy and chlorine groups only rank modestly in the
hierarchy of o-DMGs.19a Another noteworthy feature is that the
annulation is performed by making use of LDA as the base.
Lithium dialkylamides25 are generally of insufficient kinetic
basicity for ortho-directed metallation reactions. However,
recent reports that aromatic and heteroaromatic systems can
be deprotonated with these bases, provided that the (hetero)aryl
lithiated species can be trapped in situ,26 afford justification for
a
3,4-(OCH2O)C6H3
m-(Me2NSO2)C6H4
b
m-ClC6H4
h
N
O
c
p-ClC6H4
d
p-CF3C6H4
i
2-furyl
e
f
Ph
j
cyclohexyl
Pri
3,4-(MeO)2C6H3
k
Scheme 1 Reagents and conditions: i, BuLi, THF, 0 ЊC; ii, R2COCl
10a–g, 10i–k, THF, Ϫ78 ЊC to room temp.; iii, o-[bis(trimethyl-
silyl)methyl]benzoyl chloride 11, THF, Ϫ78 ЊC to room temp.
Exposure of the diacylamines 2a–d to lithium diisopropylamide
(LDA) in tetrahydrofuran (THF) at Ϫ78 ЊC led to the rapid
disappearance of the parent compounds and to the exclusive
and efficient formation of the phthalimidine derivatives with an
aminal function 12a–d (Scheme 2). The structures of com-
pounds 12a–d were mainly determined from IR spectra which
exhibit stretching bands at 3245 and 1673 cmϪ1 characteristic of
the aminal and carbonyl lactam functions. The 1H NMR spec-
tra further indicate the survival of the two methyl groups† at δ
2.52 (NCH3) and 1.62 (ArCH3) and the presence of a hydroxy
function at δ 4.80 (deuterium exchanged). 13C NMR distortion-
less enhancement by polarization transfer (DEPT) experiments
confirm the presence of the aminal quaternary carbon centre at
‡ N-Benzyl-substituted hydroxylactams have been used as precursors of
tetracyclic indanones,21a of spiroindane21b and o-aroylbenzoic acid
derivatives,21c and of 3,4-diarylisoquinoline derivatives.21d
† Values given for compound 12a.
470
J. Chem. Soc., Perkin Trans. 1, 1997

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Table
isoquinolones
1
Hydroxyphthalimidines and 2,3-disubstituted-1(2H )-
the formation of the diversely substituted phthalimidine
derivatives 12. Owing to the competition between ortho- and α-
deprotonation, which sets a limit to the applicability of the
method for the elaboration of varied 2,3-disubstituted-1(2H )-
isoquinolinones 1, alteration of the strategy was inevitable.
Owing to the erratic nature of the metallation process it was
imperative to develop a methodology which forces metallation
to occur at the alternative benzylic site and which tolerates a
wide array of substitution patterns tethering the N-acyl moiety.
The Peterson reaction has proved to be one of the best meth-
odologies for carbonyl olefination.27 It conceptually involves
the reaction between a carbonyl component and an α-silyl car-
banion followed by elimination of the resulting β-hydroxy-
silane. This olefination procedure is particularly useful in the
synthesis of functionalized and strained alkenes28 and its appli-
cation to heterocyclic synthesis has been reviewed.27a The pres-
ent work originated with the following premises: (i) α,α-disilyl-o-
toluamide should be easily derived by metallation of compound
4,17,29 thus permitting the incorporation of a silyl functionality
into the parent diacylamines 2, (ii) the formation of α-silyl car-
banions may be promoted by fluoride ion attack on organo-
silicon compounds bearing two trialkylsilyl units on the same
carbon atom.30 This carbodesilylation is an effective way for the
transfer of α-silyl carbanions to electrophilic centres, especially
carbonyl functions.31 The final inspiration of this work came
from the possibility that this new C᎐C double-bond-forming
process could be applied intramolecularly to systems incorpor-
ating base-sensitive electrophilic centres.31 With these ideas in
mind we undertook a study of the fluoride ion-promoted reac-
tion of a large and significant variety of N-acyl-N-methyl-α,α-
bis(trimethylsilyl)-o-toluamides 8a–k bearing a pendant alkyl
or (hetero)aromatic unit, 8j,k and 8e,i, respectively, and also
aromatic ring systems carrying in addition diverse functional
groups which disfavour the α-lateral lithiation approach (8a–d
and 8f–h). In the list of functionalities likely to promote
undesirable ortho-metallation and yet liable to confer interest-
ing properties in many aspects to the targeted annulated
products the moderate methylenedioxy, dimethoxy and strong
dialkylsulfonamido and oxazolino ortho-directing groups19b
occupy a place of choice. Indeed the presence of dimethoxy-
and methylenedioxy-aryl units connected to the 3-position of
the isocarbostyril framework is observed in a wide range of
alkaloids, namely in the benzo[c]phenanthridinone series.32
Several patents emphasizing the pharmaceutical properties of
isoquinolones bearing sulfinyl and sulfonyl substituents have
been registered.33 Finally, the oxazoline nucleus may serve as a
versatile handle for further synthetic manipulation since it
can be converted into a wide variety of functional groups
including acids, amides, nitriles, alcohols and aldehydes.34
Initially the requisite disilylated toluamide 6 was prepared in
high yield from the o-toluamide 4 either via the monosilylated
derivative 535 or directly in a one-pot procedure (Scheme 4).
Deprotonation of the NH carboxamide function of product 6
with butyllithium followed by addition of the appropriate acid
chlorides 10a–g, 10i–k proceeded uneventfully and this proto-
col delivered the different N-acyl-o-toluamide derivatives 8a–k
incorporating the disilyl functionality (Scheme 1). Owing to
unpredictable difficulties associated with the synthesis of the
benzoic acid chloride bearing the oxazoline moiety, compound
10h, an alternative method was developed for the elaboration of
compound 8h. Thus the disilyl functionality was inserted via o-
[bis(trimethylsilyl)methyl]benzoyl chloride 1136 (Scheme 1)
which was treated with the anion of the secondary amide 7
obtained by the three-step sequence outlined in Scheme 5.
Compounds 8a–k were subsequently subjected to a fluoride
ion source to induce benzylic carbodesilylation. Exploration
of a variety of reagents, methods and conditions including CsF
in dimethylformamide (DMF),38 tris(diethylamino)sulfonium
fluoride (TASF) in DMF,39 KF-crown ether in THF or
CH3CN 40 led to the use of ‘anhydrous’ tetrabutylammonium
N-acyl-o-toluamide Method a
Product (% yield)b
2a
2b
2c
2d
8a
8b
8c
8d
8e
A
A
A
A
B
B
B
B
B
C
D
E
B
B
B
B
B
B
A
A
12a (91)
12b (88)
12c (87)
12d (78)
1a (76)
1b (75)
1c (75)
1d (72)
1e (84)
1e (56) + 2e (14)
1e (61) + 2e (16)
1e (64) + 2e (15)
1f (75)
1g (66)
1h (28)
1i (59)
1j (48)
1k (42)
13a (88)
13c (79)
8f
8g
8h
8i
8j
8k
9a
9c
a
Method: (A) LDA, THF, Ϫ30 ЊC; (B) Bu4NF, THF, room temp., 5
min. Traces (yield < 5%) of desilylated N-acyl-o-toluamides were
detected in the crude reaction product; (C) CsF, DMF, room temp., 0.5
h; (D) TASF, DMF, room temp., 1 h; (E) KF–crown ether, THF, 5 h.
b Yields were evaluated before recrystallization.
O
CH3
N
i, ii
H
CH2SiMe3
O
CH3
5
N
H
i
CH3
O
CH3
H
4
N
iii, ii
SiMe3
CH
SiMe3
6
Scheme 4 Reagents and conditions: i, BuLi (2 mol equiv.), THF,
Ϫ78 ЊC; then Me3SiCl (2 mol equiv.); ii, H3O+; iii, BuLi (2 mol equiv.),
THF, Ϫ78 ЊC; then Me3SiCl (2 mol equiv.), Ϫ78 ЊC; then BuLi (1 mol
equiv.), Me3SiCl (1 mol equiv.), Ϫ78 ЊC
Br
Br
CHO
iii, iv
i
ii
7
ref. 37
CO2H
O
N
O
N
16
17
Scheme 5 Reagents and conditions: i. SOCl2, 2-amino-2-methyl-
propan-1-ol; then SOCl2; ii, BuLi, THF, Ϫ100 ЊC; then DMF, THF; iii,
NBS, AIBN, CCl4, reflux; iv, CH3NH2, 0 ЊC
fluoride (TBAF) in THF 41 as the initiator. As reported in Table
1 the reaction proceeded smoothly at room temperature, giving
the expected cyclization products 1a–k with moderate to high
yields. This anionic carboannulation provides rapid assemblage
of the 3-substituted isoquinolone framework. Since it proceeds
under mild and almost neutral conditions via metal-free car-
banionic species the reaction can be applied to compounds
possessing acid- or base-sensitive functionalities such as oxa-
zolino, heteroaromatic and alkyl groups.
J. Chem. Soc., Perkin Trans. 1, 1997
471

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From a mechanistic point of view we can assume that the
annulation is initiated by fluoride ion to generate the α-silyl
carbanion 18 which then reacts with the terminal carbonyl
moiety to give the corresponding β-silylethoxide 19. Further
elimination of trimethylsilylalkoxide gives rise to the desired 2-
methyl-3-alkyl, -3-aryl and -3-heteroaryl-1(2H )-isoquinolones
1a–k (Scheme 6). Particularly noteworthy is the fact that
glassware equipped with rubber septa; transfer of reagents was
performed by syringe or cannula techniques. Commercial butyl-
lithium in hexanes (1.6 mol dmϪ3) was titrated just before use.44
Extracts were dried over MgSO4.
Compound 5 was prepared following the reported experi-
mental procedure.35
2-[Bis(trimethylsilyl)methyl]-N-methylbenzamide 6
A solution of butyllithium (20 mmol) was added slowly to a
solution of N,2-dimethylbenzamide 4 (1.49 g, 10 mmol) in
anhydrous THF (40 cm3) under a stream of Ar at Ϫ78 ЊC. The
mixture was stirred for 0.5 h at this temperature after which a
solution of Me3SiCl (2.22 g, 20 mmol) in THF (20 cm3) was
slowly transferred by way of a cannula. The mixture was stirred
at Ϫ78 ЊC for 1 h. Butyllithium (10 mmol) was then added drop-
wise by way of a syringe to the mixture at Ϫ78 ЊC and the
mixture was stirred at this temperature for an additional 0.5 h.
Further solution of Me3SiCl (1.11 g, 10 mmol) in THF (10
cm3) was subsequently added, and the mixture was slowly
warmed to room temperature and finally hydrolysed with dil.
HCl (10%; 30 cm3). The aqueous layer was extracted twice with
CH2Cl2 (2 × 30 cm3) and ethyl acetate (20 cm3). The combined
organic extracts were washed with brine, then dried. Removal
of the solvents afforded a solid, which was finally purified by
recrystallization from hexane–toluene to give title compound 6
(2.6 g, 89%), mp 158–159 ЊC (Found: C, 61.1; H, 9.5; N, 5.0;
Si, 19.4. C15H27NOSi2 requires C, 61.4; H, 9.3; N, 4.8; Si,
19.1%); δH 0.01 (18 H, s), 2.41 (1 H, s), 2.94 (3 H, d, J 4.9), 5.69
(1 H, br s), 7.02 (2 H, m) and 7.24 (2 H, m); δC 171.3 (CO),
142.6, 135.8, 129.3, 129.2, 127.0, 123.0, 26.6, 24.1 and 0.3; m/z
293 (M+, 14%), 278 (88), 206 (50) and 73 (100); νmax/cmϪ1 3292
(NH) and 1631 (CO).
O
CH3
O
R2
N
CH3
R2
N
i
O
SiMe3
SiMe3
1a–k
8a–k
ii
O
CH3
O
R2
N
CH3
R2
N
O
–
O–
SiMe3
SiMe3
19
18
Scheme 6 Reagents and conditions: i, Bu4NF, THF, room temp., 5 min;
ii, FϪ
attempts to generate the α-silylbenzylic carbanionic species 18 by
metallation 42 of monosilylated N-acylamines 9, readily access-
ible (Scheme 1) from N-methyl-α-trimethylsilyl-o-toluamide 5,
proved unfruitful. Indeed despite the enhanced acidity of the
α-hydrogen of organosilanes relative to hydrogens of the cor-
responding hydrocarbons,43 the silyl functionality is not
affected by basic treatment of these compounds, as exemplified
by the exclusive and efficient formation of the hydroxy-
phthalimidines 13a,c (Scheme 2) upon treatment of mono-
silylated N-acylamides 9a,c with LDA.
The reaction reported here represents therefore a tactically
and conceptually new approach to the construction of the iso-
carbostyril framework with different substitution patterns at
the 3-position of the heterocyclic nucleus. Since this process is
carried out under essentially neutral conditions it complements
the existent methodology based on the metallation approach
and consequently is valuable for the preparation of substituted
systems that cannot tolerate strongly basic conditions. These
TBAF-induced desilylative cyclizations, which allow the sur-
vival of organic functions, represent a new development of the
modified Peterson reaction and undoubtedly deserve further
attention. The efficiency and the versatility of this intra-
molecular process invite futher use of this tactic for the con-
struction of other heterocyclic frameworks.
4,4-Dimethyl-2-[3-(N-methylcarbamoyl)phenyl]-4,5-dihydro-
oxazole 7
Compound 7 was prepared according to the following proce-
dure. 3-Bromobenzoic acid was initially converted into 2-(3-
bromophenyl)-4,4-dimethyl-4,5-dihydrooxazole 16 by adapting
a previously reported general procedure.45 To a solution of
compound 16 (1 g, 3.9 mmol) in anhydrous THF (30 cm3)
cooled at Ϫ100 ЊC was added a solution of butyllithium (4.3
mmol). The mixture was stirred at Ϫ100 ЊC for 15 min and
then was treated with a solution of DMF (1.45 g, 20 mmol)
in THF (3 cm3). The mixture was warmed to room temper-
ature, water (50 cm3) was added and the aqueous layer was
extracted with diethyl ether (2 × 30 cm3). The organic layer
was washed successively with water and brine and finally
dried over MgSO4. After removal of the solvent the product
17 was purified by flash chromatography using ethyl acetate–
hexane (1:1) as eluent and finally was recrystallized from
hexane–toluene (0.52 g, 65%). Compound 7 was obtained
from aldehyde 17 by applying a recently described pro-
cedure37 for the conversion of an aromatic aldehyde into the
corresponding carboxamide.
2-(3-Bromophenyl)-4,4-dimethyl-4,5-dihydrooxazole 16. Pale
yellow crystals, mp 43–44 ЊC (Found: C, 52.2; H, 4.6; N, 5.3.
C11H12BrNO requires C, 52.0; H, 4.75; N, 5.5%); δH 1.26 (6 H,
s), 3.92 (2 H, s), 7.14 (1 H, m), 7.46 (1 H, d, J 7.6), 7.74 (1 H, d,
J 7.6) and 8.01 (1 H, s).
2-(3-Formylphenyl)-4,4-dimethyl-4,5-dihydrooxazole 17. Crys-
tals, mp 81–82 ЊC (Found: C, 70.7; H, 6.7; N, 7.2. C12H13NO2
requires C, 70.9; H, 6.45; N, 6.9%); δH 1.24 (6 H, s), 4.08 (2 H, s),
7.49 (1 H, t, J 7.7), 7.81 (1 H, dt, J 1.4 and 7.6), 8.08 (1 H, dt, J
1.4 and 7.6), 8.35 (1 H, t, J 1.4) and 9.98 (1 H, s).
Experimental
Mp determinations were carried out on
Thermopan apparatus and are uncorrected. IR absorption
spectra were run on a Perkin-Elmer 881 spectrometer. H and
a
Reichert-
1
13C NMR spectra were recorded at 300 MHz and 75 MHz,
respectively, on a Bruker AM 300 spectrometer, as solutions in
deuteriochloroform. Chemical shifts are referenced to tetra-
methylsilane and J-values are given in Hz and rounded to the
nearest 0.1 Hz. Mass spectral analyses were performed on a
Ribermag 10-10 mass spectrometer. Elemental analyses were
determined by the CNRS microanalysis centre. For flash
chromatography, Merck silica gel 60 (230–400 mesh ASTM)
was used. THF was freshly distilled over LiAlH4, and diisopro-
pylamine over CaH2. Dry glassware for moisture-sensitive reac-
tions was obtained by oven-drying and assembly under Ar. An
inert atmosphere was obtained with a stream of dry Ar and
4,4-Dimethyl-2-[3-(methylcarbamoyl)phenyl]-4,5-dihydro-
oxazole 7. Fawn crystals, mp 106–107 ЊC (Found: C, 66.9; H,
7.0; N, 12.4. C13H16N2O2 requires C, 67.2; H, 6.9; N, 12.1%); δH
1.15 (6 H, s), 2.78 (3 H, d, J 4.9), 3.88 (2 H, s), 7.21 (1 H, t, J
7.7), 7.54 (1 H, d, J 4.9), 7.78 (2 H, dt, 2.1 and 7.7) and 8.16 (1
H, t, J 2.1).
472
J. Chem. Soc., Perkin Trans. 1, 1997

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General procedure for the synthesis of the N-acyl-o-toluamide
derivatives 2a–d, 8a–k and 9a,c
12.7%); 0.04 (18 H, s), 2.37 (1 H, s), 3.25 (3 H, s), 7.08–7.32 (3
H, m), 7.37 (2 H, d, J 8.3), 7.43–7.51 (1 H, m) and 7.62 (2 H, d,
J 8.3); δC 174.4 (CO), 172.1 (CO), 145.8, 138.0, 134.0, 132.4,
131.1, 130.9, 130.4, 129.2, 128.9, 123.4, 35.3, 24.6 and 0.7; m/z
(M+, 3%), 342 (45), 320 (68), 152 (65), 139 (37) and 73 (100);
νmax/cmϪ1 1680 (CO).
2-[Bis(trimethylsilyl)methyl]-N-methyl-N-[p-(trifluoro-
methyl)benzoyl]benzamide 8d. Yellow oil (Found: C, 59.0; H,
6.5; N, 3.3; Si, 12.2. C23H30F3NO2Si2 requires C, 59.3; H, 6.5; N,
3.0; Si, 12.1%); δH 0.00 (18 H, s), 2.36 (1 H, s), 3.27 (3 H, s) and
7.09–7.57 (4 H, m), 7.65 (2 H, d, J 8.0) and 7.76 (2 H, d, J 8.0);
δC 173.8 (CO), 172.4 (CO), 145.5, 135.8 (CF3, d, J 295), 132.2,
131.7, 130.5, 129.9, 129.6, 128.4, 128.0, 125.0, 122.9, 34.7, 24.2
and Ϫ0.1; m/z 465 (M+, 4%), 376 (59), 320 (52), 186 (94), 173
(44), 145 (49) and 73 (100); νmax/cmϪ1 1685 (CO).
N-Benzoyl-2-[bis(trimethylsilyl)methyl]-N-methylbenzamide
8e. Crystals, mp 73–74 ЊC (Found: C, 66.2; H, 8.0; N, 3.3; Si,
14.3. C22H31NO2Si2 requires C, 66.4; H, 7.9; N, 3.5; Si, 14.1%);
δH 0.03 (18 H, s), 2.37 (1 H, s), 3.26 (3 H, s) 7.06–7.13 (2 H, m),
7.30–7.49 (5 H, m) and 7.66–7.70 (2 H, m); δC 174.2 (CO), 174.0
(CO), 145.3, 135.2, 131.8, 130.4, 130.0, 128.8, 128.4, 123.1,
35.1, 24.3 and 0.5; m/z 397 (M+, 9%), 118 (100), 105 (91) and 73
(71); νmax/cmϪ1 1689 and 1670 (CO).
2-[Bis(trimethylsilyl)methyl]-N-(3,4-dimethoxybenzoyl)-N-
methylbenzamide 8f. Crystals, mp 102–103 ЊC (Found: C,
62.8; H, 7.9; N, 2.9; Si, 12.5. C24H35NO4Si2 requires C, 63.0; H,
7.7; N, 3.1; Si, 12.3%); δH 0.02 (18 H, s), 2.42 (1 H, s), 3.26 (3 H,
s), 3.84 (3 H, s), 3.89 (3 H, s), 6.82 (1 H, d, J 8.3), 6.97–7.06 (1
H, m), 7.09 (1 H, d, J 8.0), 7.19–7.37 (3 H, m) and 7.43 (1 H, d,
J 8.0); δC 174.3 (CO), 173.6 (CO), 152.4, 145.3, 142.5, 130.3,
130.0, 129.1, 128.6, 127.0, 122.9, 122.7, 111.9, 110.2, 56.0, 55.9,
35.3, 24.2 and 0.8; m/z 457 (M+, 1%), 292 (27), 278 (100) and 73
(95); νmax/cmϪ1 1675 (CO).
2-[Bis(trimethylsilyl)methyl]-N-[3-(dimethylsulfamoyl)benzoyl]-
N-methylbenzamide 8g. Crystals, mp 110–111 ЊC (Found:
C, 56.9; H, 6.9; N, 5.7; Si, 11.05. C24H36N2O4SSi2 requires C,
57.1; H, 7.2; N, 5.55; Si, 11.1%); δH 0.11 (18 H, s), 2.22 (1 H, s),
2.54 (6 H, s), 3.24 (3 H, s), 7.13 (1 H, d, J 7.8), 7.15 (1 H, t, J 7.4),
7.37 (1 H, t, J 7.8), 7.57 (1, H, d, J 7.8), 7.62 (1 H, t, J 7.8),
7.86 (1 H, d, J 7.8) and 7.92–7.96 (2 H, m); δC 174.3 (CO),
171.6 (CO), 146.4, 135.2, 134.3, 132.2, 131.4, 131.1, 130.3,
130.1, 129.4, 128.3, 126.7, 123.4, 37.9, 35.2, 24.4 and 0.4; m/z
504 (M+, 5%), 212 (73), 278 (91) and 73 (100); νmax/cmϪ1 1678
(CO).
2-[Bis(trimethylsilyl)methyl]-N-[3-(4,4-dimethyl-4,5-dihydro-
oxazol-2-yl)benzoyl]-N-methylbenzamide 8h. From com-
pounds 7 and 11,36 a yellow oil (Found: C, 65.3; H, 8.0; N, 5.85;
Si, 11.5. C27H38N2O3Si2 requires C, 65.5; H, 7.8; N, 5.7; Si,
11.35%); δH 0.01 (18 H, s), 1.34 (6 H, s), 2.33 (1 H, s), 3.24 (3 H,
s), 4.07 (2 H, s), 7.02–7.48 (5 H, m), 7.71 (1 H, d, J 7.6), 8.0 (1
H, d, J 7.6) and 8.20 (1 H, s); δC 173.7 (CO), 172.8 (CO), 160.8,
144.8, 135.3, 132.2, 131.0, 130.3, 130.0, 129.6, 128.3, 128.0,
127.8, 122.7, 78.9, 67.4, 34.7, 28.0, 24.0 and 0.0; m/z 494 (M+,
11%), 405 (38), 320 (100), 215 (74) and 73 (91); νmax/cmϪ1 1690
and 1650 (CO).
2-[Bis(trimethylsilyl)methyl]-N-(2-furoyl)-N-methylbenzamide
8i. Crystals, mp 51–52 ЊC (Found: C, 62.05; H, 7.4; N, 3.8; Si,
14.2. C20H29NO3Si2 requires C, 62.0; H, 7.55; N, 3.6; Si, 14.5%);
δH 0.03 (18 H, s), 2.35 (1 H, s), 3.25 (3 H, s), 6.49 (1 H, dd, J 1.7
and 3.6), 7.05–7.11 (2 H, m), 7.18 (1 H, dd, J 0.7 and 3.6) and
7.26–7.47 (3 H, m); δC 173.7 (CO), 162.6 (CO), 147.6, 144.9,
144.2, 132.7, 130.0, 129.5, 122.8, 117.9, 111.9, 33.7, 24.0 and
0.2; m/z 387 (M+, 2%), 108 (100) and 73 (81); νmax/cmϪ1 1677
(CO).
2-[Bis(trimethylsilyl)methyl]-N-(cyclohexylcarbonyl)-N-
methylbenzamide 8j. Crystals, mp 44–45 ЊC (Found: C, 65.7;
H, 9.4; N, 3.2; Si, 13.7. C22H37NO2Si2 requires C, 65.4; H, 9.25;
N, 3.5; Si, 13.9%); δH 0.04 (18 H, s), 1.23–1.94 (11 H, m), 2.10 (1
H, s), 3.00 (3 H, s) and 7.04–7.33 (4 H, m); δC 180.6 (CO), 173.7
(CO), 144.4, 134.4, 130.0, 129.7, 127.9, 123.2, 44.8, 34.7, 29.8,
The N-lithiated derivatives of the secondary toluamides 4, 5, 6,
7 were prepared by the dropwise addition of butyllithium (21
mmol) to a stirred solution of amide 4, 5, 6 or 7 (20 mmol) in
anhydrous THF (50 cm3) cooled at 0 ЊC. The appearance of a
red-wine colour corresponding to the formation of the benzylic
carbanion indicated the NH deprotonation end-point. The mix-
ture was cooled to Ϫ78 ЊC and a solution of the appropriate
carboxylic acid chloride 10a–d, 10a–g,i–k and 10a, 10c and 11
respectively (20 mmol) in THF (10 cm3) was added dropwise
with the internal temperature maintained at below Ϫ50 ЊC. The
cooling bath was removed and the mixture was warmed to
room temperature and stirred for 1 h. Aq. NaHCO3 was added
and the organic layer was separated. The aqueous solution was
extracted with ethyl acetate (2 × 50 cm3) and the combined
organic layers were washed successively with water and brine
and finally dried over MgSO4. Evaporation of the solvent fur-
nished an oily product, which was purified by flash column
chromatography using ethyl acetate–hexane (2:3) as eluent.
N,2-Dimethyl-N-(3,4-methylenedioxybenzoyl)benzamide
2a. Crystals, mp 78–79 ЊC (lit.,3c 79 ЊC); δH 2.34 (3 H, s), 3.46 (3
H, s), 5.91 (2 H, s), 6.62 (1 H, d, J 8.3), 6.87 (1 H, s) and 6.97–
7.46 (5 H, m); δC 173.5 (CO), 173.4 (CO), 150.4, 147.4, 147.3,
136.4, 136.1, 130.6, 130.2, 127.2, 125.0, 123.6, 108.2, 107.2,
101.4 (OCH2O), 33.2 and 19.3; m/z 297 (M+, 24%), 149 (83) and
119 (100); νmax/cmϪ1 1695 and 1652 (CO).
N-(m-Chlorobenzoyl-N,2-dimethylbenzamide 2b. Crystals,
mp 75–76 ЊC (Found: C, 67.0; H, 5.1; N, 5.0. C16H14ClNO2
requires C, 66.8; H, 4.9; N, 4.9%); δH 2.26 (3 H, s), 3.44 (3 H, s),
6.89 (1 H, d, J 7.4), 6.96 (1 H, d, J 7.4), 7.03–7.18 (5 H, m) and
7.26 (1 H, s); δC 173.6 (CO), 173.1 (CO), 138.5, 137.1, 135.9,
133.9, 131.3, 131.0, 130.8, 129.6, 129.4, 127.8, 125.9, 125.4, 33.3
and 19.6; m/z 289 (M+, 2%), 287 (M+, 5) and 119 (100); νmax
/
cmϪ1 1694 and 1653 (CO).
N-(p-Chlorobenzoyl)-N,2-dimethylbenzamide 2c. Crystals,
mp 74–75 ЊC (lit.,3c 75 ЊC); δH 2.20 (3 H, s), 3.36 (3 H, s), 6.87–
6.96 (2 H, m), 7.00–7.07 (4 H, m) and 7.22 (2 H, d, J 8.4); δC
173.9 (CO), 173.7 (CO), 138.0, 137.1, 136.2, 135.3, 131.3, 131.0,
129.5, 128.5, 128.0, 125.7, 33.6 and 19.8; m/z 289 (M+, 1%), 287
(M+, 3), 141 (5), 139 (13) and 119 (100); νmax/cmϪ1 1696 and
1668 (CO).
N,2-Dimethyl-N-[p-(trifluoromethyl)benzoyl]benzamide 2d.
Crystals, mp 61–62 ЊC (Found: C, 63.4; H, 4.3; N, 4.1.
C17H14F3NO2 requires C, 63.5; H, 4.4; N, 4.4%); δH 2.26 (3 H, s),
3.47 (3 H, s), 6.86–7.18 (4 H, m) and 7.43 (4 H, s); δC 173.7
(CO), 173.2 (CO), 140.1, 137.0, 135.8, 131.1, 130.0, 128.7
(CF3, d, J 240), 128.0, 125.6, 125.0, 33.4 and 19.6; m/z 321 (M+,
36%), 173 (14), 119 (100) and 91 (97); νmax/cmϪ1 1653 (CO).
2-[Bis(trimethylsilyl)methyl]-N-methyl-N-(3,4-methylene-
dioxybenzoyl)benzamide 8a. Crystals, mp 143–144 ЊC (Found:
C, 62.7; H, 6.9; N, 3.1; Si, 12.5. C23H31NO4Si2 requires C, 62.5;
H, 7.1; N, 3.2; Si, 12.7%); δH 0.03 (18 H, s), 2.36 (1 H, s), 3.24 (3
H, s), 6.02 (2 H, s), 6.81 (1 H, d, J 8.1), 7.05–7.12 (2 H, m), 7.17
(1 H, d, J 1.7), 7.29 (2 H, dd, J 1.7 and 8.1) and 7.39–7.42 (1 H,
m); δC 174.2 (CO), 173.3 (CO), 151.0, 147.8, 145.2, 132.8,
130.3, 130.0, 128.9, 128.5, 124.3, 123.0, 109.1, 108.1, 101.8
(OCH2O), 35.3, 24.3 and 0.5; m/z 441 (M+, 1%), 292 (34), 278
(100) and 73 (91); νmax/cmϪ1 1697 and 1654 (CO).
2-[Bis(trimethylsilyl)methyl]-N-(m-chlorobenzoyl)-N-methyl-
benzamide 8b. Crystals, mp 63–64 ЊC (Found: C, 61.3; H, 6.8;
N, 3.0; Si, 13.3. C22H30ClNO2Si2 requires C, 61.1; H, 7.0; N,
3.2; Si, 13.0%); δH 0.04 (18 H, s), 2.35 (1 H, s), 3.25 (3 H, s),
7.14 (2 H, d, J 7.6), 7.34 (2 H, d, J 7.6), 7.40–7.54 (3 H, m) and
7.66 (1 H, s); δC 174.3 (CO), 172.8 (CO), 145.7, 137.4, 134.7,
132.4, 131.7, 130.9, 130.3, 129.8, 128.8, 128.6, 126.2, 122.1,
35.3, 24.7 and 0.6; m/z 431 (M+, 3%), 342 (47), 320 (41), 152
(59), 139 (41) and 73 (100); νmax/cmϪ1 1676 (CO).
2-[Bis(trimethylsilyl)methyl]-N-(p-chlorobenzoyl)-N-methyl-
benzamide 8c. Yellow oil (Found: C, 61.4; H, 7.2; N, 3.5; Si,
J. Chem. Soc., Perkin Trans. 1, 1997
473

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25.9, 25.6, 24.7 and 0.5; m/z 403 (M+, 1%), 320 (100) and 73
(93); νmax/cmϪ1 1688 (CO).
5.0. C16H14ClNO2 requires C, 66.9; H, 4.9; N, 4.9%); δH 1.47 (3
H, s), 2.54 (3 H, s), 47.0 (1 H, s), 7.01 (1 H, d, J 7.2), 7.24–7.42
(4 H, m), 7.48 (1 H, d, J 7.2) and 8.28 (1 H, d, J 7.6); δC 166.8
(CO), 143.6, 134.5, 133.9, 133.5, 133.3, 131.8, 130.9, 129.7,
129.6, 129.0, 126.1, 121.6, 90.0 (C-3), 23.9 and 19.4; m/z 289
2-[Bis(trimethylsilyl)methyl]-N-methyl-N-(2-methylpro-
panoyl)benzamide 8k. Yellow oil (Found: C, 62.8; H, 9.0; N, 3.7;
Si, 15.6. C19H33NO2Si2 requires C, 62.7; H, 9.2; N, 3.85; Si,
15.4%); δH 0.03 (18 H, s), 1.16 (6 H, d, J 6.7), 2.13 (1 H, s), 3.03
(3 H, s), 3.46 (1 H, sept, J 6.7) and 7.03–7.30 (4 H, m); δC 182.0
(CO), 173.9 (CO), 143.9, 133.9, 130.2, 129.3, 127.5, 124.3, 35.2,
34.7, 24.6, 19.7 and 0.4; m/z 363 (M+, 5%), 320 (88), 278 (63)
and 73 (100); νmax/cmϪ1 1689 and 1656 (CO).
N-Methyl-N-(3,4-methylenedioxybenzoyl)-2-[(trimethylsilyl)-
methyl]benzamide 9a. Yellow oil (Found: C, 64.8; H, 6.0; N, 3.7;
Si, 7.8. C20H23NO4Si requires C, 65.0; H, 6.3; N, 3.8; Si, 7.6%);
δH 0.18 (9 H, s), 2.09 (2 H, s), 3.48 (3 H, s), 6.04 (2 H, s), 6.57
(1 H, d, J 8.1), 6.77–6.96 (2 H, m), 7.03–7.13 (2 H, m), 7.43 (1
H, t, J 1.6) and 7.61 (1 H, dd, J 1.6 and 8.2); δC 175.0 (CO),
174.1 (CO), 151.3, 148.3, 141.8, 135.2, 131.1, 130.3, 129.1,
126.0, 124.6, 124.4, 109.1, 108.1, 102.4 (OCH2O), 33.9, 24.6
and Ϫ1.3; m/z 369 (M+, 3%), 220 (55), 149 (85) and 73 (100);
νmax/cmϪ1 1709 and 1654 (CO).
N-(p-Chlorobenzoyl)-N-methyl-2-[(trimethylsilyl)methyl]-
benzamide 9c. Mp 64–65 ЊC (Found: C, 63.7; H, 5.9; N, 4.2; Si,
7.6. C19H22ClNO2Si requires C, 63.5; H, 6.2; N, 3.9; Si, 7.8%);
δH 0.04 ( 9 H, s), 2.09 (2 H, s), 3.48 (3 H, s), 6.83 (1 H, d, J 7.6),
6.94 (1 H, d, J 7.6) and 7.08–7.32 (6 H, m); δC 173.9 (CO), 173.8
(CO), 141.3, 137.4, 135.2, 134.0, 130.7, 129.7, 129.2, 128.7,
128.2, 123.8, 33.6, 24.5 and 0.4; m/z 361 (M+, 8%), 360 (11), 359
(M+, 21), 152 (61), 139 (98), 119 (63), 118 (56) and 73 (100);
νmax/cmϪ1 1697 and 1649 (CO).
(M+, 6%), 287 (M+, 17), 221 (100), 198 (22) and 196 (65); νmax
/
cmϪ1 3250 (OH) and 1688 (CO).
5-Chloro-3-hydroxy-2-methyl-3-(2-methylphenyl)-1-isoindo-
lone 12c. Crystals, mp 199–200 ЊC (Found: C, 66.7; H, 4.7; N,
5.2%); 1.52 (3 H, s), 2.61 (3 H, s), 4.40 (1 H, s), 7.03 (1 H, d, J
7.6), 7.18–7.47 (5 H, m) and 8.23 (1 H, d, J 7.6); δC 166.7 (CO),
149.2, 138.7, 134.8, 134.0, 132.0, 129.5, 128.8, 128.0, 126.1,
123.8, 123.0, 89.6 (C-3), 23.6 and 19.0; m/z 289 (M+, 7%), 287
(M+, 20), 287 (20), 119 (100) and 91 (63); νmax/cmϪ1 3275 (OH)
and 1665 (CO).
3-Hydroxy-2-methyl-3-(2-methylphenyl)-5-trifluoromethyl-1-
isoindolone 12d. Crystals, mp 146–147 ЊC (Found: C, 63.8; H,
4.3; N, 4.5. C17H14F3NO2 requires C, 63.55; H, 4.4; N, 5.35%);
δH 1.48 (3 H, s), 2.65 (3 H, s), 4.84 (1 H, s), 7.03 (1 H, d, J 6.5),
7.25–7.60 (5 H, m) and 8.26 (1 H, d, J 6.5); δC 168.7 (CO),
148.3, 134.8, 134.4, 133.9, 130.6 (CF3, d, J 263), 129.4, 128.5,
126.7, 126.6, 123.3, 119.9, 90.1 (C-3), 24.1 and 19.8; m/z 321
(M+, 54%), 176 (25), 118 (100) and 90 (35); νmax/cmϪ1 3215 (OH)
and 1667 (CO).
3-Hydroxy-2-methyl-4,5-methylenedioxy-3-{2-[(trimethyl-
silyl)methyl]phenyl}-1-isoindolone 13a. Crystals, mp 175–
176 ЊC (Found: C, 65.2; H, 6.2; N, 4.0; Si, 7.7. C20H23NO4Si
requires C, 65.0; H, 6.3; N, 3.8; Si, 7.6%); δH , two rotamers A
and B (2:1), Ϫ0.35 (9 H, s, A), 0.07 (9 H, s, B), 1.47 and 1.65 (2
H, 2 d, J 15.5, A), 2.31 and 3.27 (2 H, 2 d, J 11.5, B), 2.53 (3 H, s,
A), 2.68 (3 H, s, B), 4.50 (1 H, s, A), 4.61 (1 H, s, B), 5.60 and
6.03 (2 H + 2 H, m, A + B), 6.63–7.25 (5 H + 6 H, m, A + B)
and 8.23 (1 H, br s, A); δC, two rotamers, 166.3 (2 CO), 152.6,
148.8, 147.5, 142.3, 140.5, 139.8, 135.6, 133.8, 129.5, 128.4,
128.1, 126.0, 125.8, 124.7, 124.2, 116.3, 115.9, 108.9, 102.2,
101.9, 91.2 (C-3), 89.7 (C-3), 25.8, 24.3, 24.1, 20.7 and 0.4; m/z
369 (M+, 37%), 354 (24), 311 (61) and 73 (100); νmax/cmϪ1 3268
(OH) and 1678 (CO).
5-Chloro-3-hydroxy-2-methyl-3-{2-[(trimethylsilyl)methyl]-
phenyl}-1-isoindolone 13c. Crystals, mp 163–164 ЊC (Found: C,
63.3; H, 6.4; N, 3.8; Si, 8.1. C19H22ClNO2Si requires C, 63.5; H,
6.2; N, 3.9; Si, 7.8%); δH , two rotamers A and B (1:1), Ϫ0.37 (9
H, s, A), 0.11 (9 H, s, B), 1.31 and 1.49 (2 H, 2 d, J 14.6, A), 2.44
and 3.29 (2 H, 2 d, J 12.2, B), 2.57 (3 H, s, A), 2.75 (3 H, s, B),
5.05 (1 H, s, A), 5.16 (1 H, s, B), 6.54 (1 H, d, J 8.0, A), 6.85–
7.48 (5 H + 7 H, m, A + B) and 8.24 (1 H, m, A); δC, two
rotamers, 167.1 (2 CO), 151.8, 151.0, 141.2, 139.2, 138.8, 138.7,
132.7, 132.3, 132.1, 130.5, 129.6, 129.4, 129.1, 128.8, 128.2,
127.6, 126.5, 124.6, 124.3, 124.2, 123.8, 123.2, 93.9 (C-3), 89.9
(C-3), 26.6, 24.5, 24.3, 20.8 and Ϫ1.0; m/z 359 (M+, 8%), 358
(11), 357 (5), 344 (21), 234 (25) and 73 (100); νmax/cmϪ1 3215
(OH) and 1669 (CO).
General procedure for the synthesis of the hydroxyphthalimidine
derivatives 12a–d and 13a,c
To a solution of diisopropylamine (0.47 cm3, 3.36 mmol) in
THF (10 cm3) at Ϫ78 ЊC and under Ar was added butyllithium
(3.36 mmol). After being stirred for 0.5 h at Ϫ78 ЊC the solution
was warmed to Ϫ30 ЊC and a solution of the N-acyl-o-
toluamide 2a–d and 9a,c (3.36 mmol) in THF (10 cm3) was added
dropwise during 5 min, then the reaction mixture was allowed
to come to room temperature over a period of 1 h. After this,
several drops of dil. HCl (10%), water (10 cm3) and diethyl ether
(2 × 30 cm3) were added. The organic layer was separated,
rinsed with brine, dried (MgSO4) and concentrated to dryness.
The crude product was finally purified by flash chromatography
using ethyl acetate–hexane (1:1) as eluent and finally was
recrystallized from ethanol.
Alternative procedure for the synthesis of compound 12a
Compound 12a was also prepared in the following manner. To
a solution of N-methyl-3,4-methylenedioxybenzamide 14 (0.90
g, 5.5 mmol) in THF (20 cm3) was added butyllithium (11
mmol) under Ar at 0 ЊC. The mixture was maintained at this
temperature for 0.5 h after which a solution of N-methoxy-N-
methyl-o-toluamide 15 (0.98 g, 5.5 mmol), readily obtained
from the corresponding acid chloride,22 in THF (5 cm3) was
added dropwise during 5 min. The mixture was stirred for an
additional 1 h and the usual work-up afforded a crude product
which was purified by flash column chromatography using ethyl
acetate–hexane (7:3) as eluent and recrystallized from ethanol.
3-Hydroxy-2-methyl-4,5-methylenedioxy-3-(2-methylphenyl)-
1-isoindolone 12a. Crystals, mp 157–158 ЊC (Found: C, 68.7;
H, 5.3; N, 4.8. C17H15NO4 requires C, 68.7; H, 5.1; N, 4.7%); δH
1.62 (3 H, br s), 2.52 (3 H, s), 4.80 (1 H, s), 5.90 (1 H, d, J 1.0),
6.00 (1 H, d, J 1.0), 6.81 (1 H, d, J 7.9), 7.05 (1 H, m), 7.17 (1 H,
d, J 7.9), 7.25–7.35 (2 H, m) and 8.22 (1 H, m); δC 167.7 (CO),
152.5, 141.7, 134.6, 132.4, 129.2, 128.7, 126.6, 126.4, 118.0,
109.3, 102.9 (OCH2O), 90.1 (C-3), 24.1 and 19.9; m/z 297 (M+,
23%), 280 (27) and 206 (100); νmax/cmϪ1 3245 (OH) and 1673
(CO).
General procedure for the synthesis of the 2,3-disubstituted
1(2H)-isoquinolones 1a–k
Commercial TBAFؒ3H2O (500 mg) was placed in a 25 cm3 two-
necked, round-bottom flask equipped with a rubber septum.
The mixture was heated and stirred under reduced pressure
(0.05 mmHg) at 45 ЊC for 48 h and during that time the sample
liquefied. The product was maintained under vacuum and
anhydrous THF (5 cm3) was added by way of a syringe, fol-
lowed by the slow addition of a solution of the appropriate
disilyl derivatives 8a–k (1.57 mmol) in THF (10 cm3). The mix-
ture was then stirred for 5 min. Dil. HCl (10%; 20 cm3) was
added and the mixture was extracted with ethyl acetate (2 × 20
cm3). The organic layer was washed with water, rinsed with
brine and dried (MgSO4). The crude reaction mixture was puri-
fied by flash column chromatography using ethyl acetate–
hexane (3:2) as eluent to give the cyclized products 1a–k which
were finally recrystallized from hexane–toluene.
4-Chloro-3-hydroxy-2-methyl-3-(2-methylphenyl)-1-isoindol-
one 12b. Crystals, mp 190–191 ЊC (Found: C, 67.1; H, 4.8; N,
474
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
2-Methyl-3-(3,4-methylenedioxyphenyl)-1(2H)-isoquino-
lone 1a. Crystals, mp 114–115 ЊC (lit.,3c 115 ЊC); δH 3.45 (3 H,
s), 6.06 (2 H, s), 6.45 (1 H, s), 6.84–6.89 (3 H, m), 7.44–7.49 (2
H, m), 7.59–7.65 (1 H, m) and 8.45 (1 H, d, J 7.5); δC 163.4
(CO), 148.2, 147.7, 143.5, 136.3, 132.2, 129.9, 127.8, 126.5,
125.7, 124.9, 122.7, 109.3, 108.4, 107.5, 101.5 (OCH2O) and
3-Cyclohexyl-2-methyl-1(2H)-isoquinolone 1j. Crystals, mp
86–87 ЊC (Found: C, 79.8; H, 8.1; N, 6.05. C16H19NO requires
C, 79.6; H, 7.9; N, 5.8%); δH 1.24–1.45 (5 H, m), 1.78–2.00 (5
H, m), 2.59–2.65 (1 H, m), 3.64 (3 H, s), 6.34 (1 H, s), 7.36–7.44
(2 H, m), 7.57 (1 H, d, J 7.0) and 8.36 (1 H, d, J 8.0); δC 163.7
(CO), 148.3, 136.6, 132.0, 127.8, 125.8, 125.4, 124.2, 102.5,
40.5, 33.1, 30.3, 26.7 and 26.1; m/z 241 (M+, 100%); νmax/cmϪ1
1648 and 1617 (CO).
34.0; m/z 279 (M+, 100%), 278 (94), 248 (20) and 220 (21); νmax
/
cmϪ1 1653 and 1616 (CO).
3-(m-Chlorophenyl)-2-methyl-1-(2H)-isoquinolone 1b. Crys-
tals, mp 119–120 ЊC (Found: C, 71.05; H, 4.7; N, 5.1.
C16H12ClNO requires C, 71.2; H, 4.5; N, 5.2%); δH 3.38 (3 H, s),
6.45 (1 H, s), 7.28–7.69 (7 H, m) and 8.46 (1 H, d, J 7.9); δC
163.4 (CO), 142.6, 138.0, 136.2, 134.9, 132.5, 130.1, 129.3,
129.1, 128.1, 127.2, 127.1, 126.1, 125.3, 108.0 and 34.3; m/z 271
(M+, 26%), 270 (43), 269 (M+, 78) and 268 (100); νmax/cmϪ1 1644
and 1618 (CO).
3-Isopropyl-2-methyl-1(2H )-isoquinolone 1k. Crystals, mp
83–84 ЊC (lit.,3c 84 ЊC); δH 1.31 (6 H, d, J 6.6), 3.08 (1 H, sept, J
6.6), 3.65 (3 H, s), 6.40 (1 H, s), 7.37 (1 H, t, J 7.9), 7.43 (1 H, d,
J 7.9), 7.58 (1 H, t, J 7.9) and 8.39 (1 H, d, J 7.9); δC 163.2 (CO),
149.1, 136.2, 131.6, 127.3, 125.5, 125.1, 123.8, 101.3, 29.9, 29.6
and 21.9; m/z 201 (M+, 74%) and 186 (100); νmax/cmϪ1 1645 and
1616 (CO).
3-(p-Chlorophenyl)-2-methyl-1(2H )-isoquinolone 1c. Crys-
tals, mp 142–143 ЊC (lit.,3c 142 ЊC); δH 3.42 (3 H, s), 6.44 (1 H,
s), 7.28–7.57 (7 H, m) and 8.46 (1 H, d, J 7.7); δC 163.3 (CO),
142.6, 136.1, 135.1, 134.6, 132.4, 130.1, 127.9, 128.9, 126.9,
125.9, 125.0, 107.5 and 34.1; m/z 271 (M+, 28%) and 269 (100);
νmax/cmϪ1 1645 and 1616 (CO).
2-Methyl-3-[p-(trifluoromethyl)phenyl]-1(2H)-isoquinolone1d.
Crystals, mp 154–155 ЊC (Found: C, 67.0; H, 4.3; N, 4.5.
C17H12F3NO requires C, 67.3; H, 4.0; N, 4.6%); δH 3.43 (3 H, s),
6.47 (1 H, s), 7.49–7.79 (7 H, m) and 8.47 (1 H, d, J 8.6); δC
163.2 (CO), 142.4, 139.7, 136.1, 134.8, 132.5, 129.5 (CF3, d, J
290), 129.3, 127.9, 127.1, 125.8, 125.7, 125.2, 108.0 and 34.1;
m/z 303 (M+, 80%), 302 (100) and 284 (19); νmax/cmϪ1 1643 and
1621 (CO).
2-Methyl-3-phenyl-1(2H )-isoquinolone 1e. Crystals, mp 62–
63 ЊC (lit.,46 59–60 ЊC or lit.,6b 68.5–70.5 ЊC); δH 3.42 (3 H, s),
6.45 (1 H, s), 7.26–7.61 (8 H, m) and 8.45 (1 H, d, J 7.5); δC
164.1 (CO), 143.9, 136.4, 136.2, 132.2, 128.9, 128.8, 128.6,
127.9, 126.6, 125.8, 124.9, 107.5 and 34.1; m/z 235 (M+, 88%)
and 234 (100); νmax/cmϪ1 1651 and 1617 (CO).
Acknowledgements
We are grateful to the Centre National de la Recherche Scienti-
fique and the Ministère de l’Enseignement Supérieur et de la
Recherche for financial support (grant to S. L.). We would like
also to thank G. Bird (Zeneca Pharma, Reims) for help with the
manuscript.
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3-(3,4-Dimethoxyphenyl)-2-methyl-1(2H)-isoquinolone
1f.
Crystals, mp 172–173 ЊC (Found: C, 73.4; H, 6.0; N, 4.6.
C18H17NO3 requires C, 73.2; H, 5.8; N, 4.7%); δH 3.43 (3 H, s),
3.90 (3 H, s), 3.94 (3 H, s), 6.46 (1 H, s), 6.88–6.96 (3 H, m),
7.44–7.49 (2 H, m), 7.59–7.66 (1 H, m) and 8.43 (1 H, d, J 7.8);
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126.6, 125.8, 124.9, 121.6, 112.2, 111.3, 107.5, 56.1 and 34.2;
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3-[(Dimethylsulfamoyl)phenyl]-2-methyl-1(2H)-isoquinolone
1g. Crystals, mp 182–183 ЊC (Found: C, 62.9; H, 5.5; N, 8.15.
C18H18N2O3S requires C, 63.1; H, 5.3; N, 8.2%); δH 2.77 (6 H,
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127.8, 127.2, 126.2, 126.0, 108.3, 37.9 and 34.2; m/z 342 (M+,
100%); νmax/cmϪ1 1644 and 1618 (CO).
3-[3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl]-2-methyl-
1(2H)-isoquinolone 1h. Crystals, mp 101–102 ЊC (Found: C,
76.2; H, 6.4; N, 8.2. C21H20N2O2 requires C, 75.9; H, 6.1; N,
8.4%); δH 1.26 (6 H, s), 3.38 (3 H, s), 4.02 (2 H, s), 6.41 (1 H, s),
7.23–7.51 (5 H, m), 7.62–7.73 (2 H, m) and 8.41 (1 H, d, J 7.9);
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129.8, 129.3, 129.0, 128.5, 123.6, 107.6, 79.1, 68.1, 34.5 and
28.1; m/z 332 (M+, 100%) and 331 (76); νmax/cmϪ1 1646 and 1620
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Paper 6/05077H
Received 22nd July 1996
Accepted 18th September 1996
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476
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