Synthesis of 3-(arylmethylene)isoindolin-1-ones from ynamides by Heck-Suzuki-Miyaura domino reactions. Application to the synthesis of lennoxamine

Article abstract of DOI:10.1016/j.tet.2005.11.089

Substituted 3-(arylmethylene)isoindolin-1-ones can be efficiently synthesized from various ynamides and boronic acids by palladium-catalyzed Heck-Suzuki-Miyaura domino reactions. This methodology has been applied to the total synthesis of lennoxamine and a concise route to this isoindolobenzazepine alkaloid was achieved in eight steps from 2,3-dimethoxybenzoic acid via a key intermediate ynamide.

Full text of DOI:10.1016/j.tet.2005.11.089

Tetrahedron 62 (2006) 3882–3895
Synthesis of 3-(arylmethylene)isoindolin-1-ones from
ynamides by Heck–Suzuki–Miyaura domino reactions.
Application to the synthesis of lennoxamine
*
ˆ
Sylvain Couty, Benoıt Liegault, Christophe Meyer and Janine Cossy
*
´
Laboratoire de Chimie Organique, associe au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 14 November 2005; accepted 26 November 2005
Available online 28 February 2006
Abstract—Substituted 3-(arylmethylene)isoindolin-1-ones can be efficiently synthesized from various ynamides and boronic acids by
palladium-catalyzed Heck–Suzuki–Miyaura domino reactions. This methodology has been applied to the total synthesis of lennoxamine and
a concise route to this isoindolobenzazepine alkaloid was achieved in eight steps from 2,3-dimethoxybenzoic acid via a key intermediate
ynamide.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Isoindolin-1-ones of type A are also found as the structural
feature of biologically active compounds such as AKS186
that displays vasorelaxant properties3 or compound 1 whose
hydrochloride was claimed to exhibit local anesthetic
activity superior to that of procaine4 (Fig. 1).
Substituted 3-methyleneisoindolin-1-ones of type A, and in
particular those in which R3 is an aromatic substituent (R3Z
Ar), are encountered in a number of naturally occurring
products such as enterocarpam II, a member of the
aristolactam alkaloids family1 or the secophthalide–iso-
quinoline ene-lactam fumaridine2 (Fig. 1).
The synthesis of isoindolin-1-ones of type A has elicited
considerable synthetic interest as several representative
general strategies have been developed (Scheme 1). In the
earliest routes [routes (a), Scheme 1], phthalimides of type
B were often considered as starting materials and were
converted to isoindolin-1-ones of type A by Wittig reaction
with stabilized phosphoranes5 or addition of organometallic
reagents followed by dehydration of the resulting
3-hydroxyphthalimidines.3,6 However, this approach can
lead to a mixture of regioisomers in the case of an
unsymmetrical substrate.3,6 Furthermore, the synthesis of
3-(arylmethylene)-isoindolin-1-ones of type A where R3Z
Ar by the latter route requires the use of benzylic Grignard
reagents as nucleophiles whose preparation is not always
trivial. More recently, an interesting alternative benzylation
procedure of phthalimides of type B, based on the photo-
decarboxylation of arylacetates, has been developed.7
Phthalides of type C (or the corresponding open-chain
keto-benzoic acids) are also useful precursors since they can
be readily converted to compounds of type A by treatment
with primary amines, followed by dehydration [route (b),
Scheme 1].8 Another general route towards substituted
3-methyleneisoindolin-1-ones of type A relies on an
ortholithiation–anionic cyclization sequence initiated by
treatment of N-acyl-2-bromobenzamides of type D with
Figure 1. Naturally occurring and/or biologically active substituted
3-methyleneisoindolin-1-ones.
Keywords: Suzuki–Miyaura reactions; Ynamides; Isoindolinones;
Lennoxomine.
Corresponding authors. Tel.: C33 1 40 79 44 29; fax: C33 1 40 79 46 60;
e-mail addresses: christophe.meyer@espci.fr; janine.cossy@espci.fr
*
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.089

S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
3883
Scheme 1. Representative synthetic strategies towards substituted 3-methyleneisoindolin-1-ones of type A.
n-butyllithium, followed by dehydration of the resulting
3-hydroxyphthalimidines [route (c), Scheme 1].9 Efficient
syntheses of isoindolin-1-ones of type A have also been
achieved by cyclization of 2-alkynylbenzamides of type E
induced by treatment with a base or a palladium(II) catalyst
[route (d), Scheme 1].10,11 Interestingly, the disubstituted
alkynes of type E are readily available by Sonogashira
cross-coupling reactions involving 2-halobenzamides as
substrates and, in some cases, both transformations leading
to isoindolin-1-ones of type A have been carried out in a
one-pot sequence.10c A palladium(0)-catalyzed three-com-
ponent reaction involving 2-bromoacetophenone 2 and a
variety of primary amines under carbon monoxide pressure
can also be used to synthesize 3-methyleneisoindolin-1-
ones of type A (R3ZH) [route (e), Scheme 1].12 A related
process has been described from 2-bromoaryl ketones
wherein a titanium–isocyanate complex was used as the
nitrogen donor.13 Alternative palladium(0)-catalyzed pro-
cesses towards compounds of type A exploit the synthetic
potential of intramolecular Heck reactions of enamide
derivatives of type F [route (f), Scheme 1].14 Finally, the
Horner condensation of 3-(diphenylphosphinoyl)isoindolin-
1-ones of type G with a variety of aldehydes constitutes a
particularly interesting entry to isoindolin-1-ones of type A
that has culminated with several applications to natural
products synthesis [route (g), Scheme 1].15 Besides these
main representative strategies, other reactions leading to
isoindolin-1-ones of type A have also been reported.16
We became interested in the development of an alternative
synthetic strategy towards a variety of (E)-3-(arylmethyl-
ene)isoindolin-1-ones of type A that proceeds from
ynamides of type H and arylboronic acids and relies on
Pd(0)-catalyzed Heck–Suzuki–Miyaura domino reactions
(Scheme 2).
Scheme 2. Synthesis of 3-(arylmethylene)isoindolin-1-ones of type A by
Heck–Suzuki–Miyaura domino reactions from ynamides of type H.
When we began our investigations on this project,
hydrostannation30 and an heteroannulation strategy towards
2-aminoindoles, based on the nucleophilic addition of
amines to the triple bond of ynamides activated by an
intramolecular arylpalladium(II) complex,31 were the only
reported examples of palladium-catalyzed processes invol-
ving ynamides as substrates. Herein, we report a full
account of our work on the synthesis of 3-(arylmethylene)-
isoindoloin-1-ones by Heck–Suzuki–Miyaura domino
reactions involving ynamides,32 as well as its application
to the total synthesis of the natural product lennoxamine.
2. Results and discussion
In recent years, the synthetic application of ynamides has
expanded enormously.17 Indeed, these stable electron-
deficient variants of ynamines can participate in several
transformations usually carried out with alkynes such as
thermal, metal- or Lewis acid-catalyzed cycloadditions,18–21
platinum(II)-catalyzed cycloisomerization,22 ring-closing
metathesis,23 titanium(II)-mediated coupling reactions,24
carbocupration,25 hydroboration26 and hydrohalogenation27
followed by cross-coupling reactions, as well as sigmatropic
rearrangements.28 Some radical cyclization cascades invol-
ving ynamides as substrates have also been reported as a
route to various nitrogen heterocycles, including substituted
isoindolin-1-ones of type A.29
In order to investigate the feasibility of the Pd(0)-catalyzed
Heck–Suzuki–Miyaura domino reactions as a route to
isoindolinones of type A, several ynamides of type H
were prepared from 2-iodobenzoic acid 3. This carboxylic
acid was coupled with benzylamine, 2-bromobenzylamine
and allylamine N-ethyl-N0-(3-dimethylaminopropyl)carbo-
diimide hydrochloride (EDCI), cat. DMAP, CH2Cl2 or
CH2Cl2/THF, rt] to afford the corresponding 2-iodobenza-
mides 4a (60%), 4b (81%) and 4c (73%), respectively. After
formation of the potassium amides (KHMDS, toluene, 0 8C
to rt) and addition of the alkynyliodonium salt 5,33 the
trimethylsilyl-substituted ynamides 6a (48%), 6b (72%) and
6c (63%) were obtained in acceptable yields.18a Subsequent

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S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
7b did not alter the course of the reaction, and the carbon–
bromine bond in the final product 13 was also unaffected
(Scheme 5).
Scheme 5. Reductive Heck reaction applied to ynamides of type H.
Having demonstrated that ynamides were viable substrates
in carbopalladation processes, the Suzuki–Miyaura coup-
ling reactions36 of the intermediate s-vinylpalladium
complexes of type I could be next examined, with the
goal of achieving both processes in a domino fashion from
the starting ynamides (Table 1). When ynamide 7a was
treated with benzeneboronic acid in the presence of aqueous
sodium hydroxide as the base and a catalytic amount of
Pd(PPh3)4 (5 mol%) in refluxing 1,2-dimethoxyethane
(DME), the corresponding 3-benzylideneisoindolin-1-one
15 was obtained in acceptable yield (48%) as a single
geometric isomer. Additional experiments revealed that
THF was also a suitable solvent for this reaction and other
palladium catalysts were then screened. Thus, the use of
Pd(dba)2 led to a slightly increased yield of 15 (59%) but the
optimal result (70% yield) was obtained when a combi-
nation of Pd(OAc)2 (5 mol%) and PPh3 (10 mol%) was used
to catalyze the reaction. Interestingly, the heterogeneous
catalyst Pd/C was also effective and led to the isoindolinone
15 albeit in slightly diminished yield (56%) (Table 1).
Scheme 3. Preparation of ynamides 7a–7c.
desilylation by using tetra(n-butyl)ammonium fluoride
(TBAF) in THF finally provided the ynamides 7a (96%),
7b (79%) and 7c (85%), respectively (Scheme 3).
A structurally related ynamide possessing a pyridine ring
was also prepared from 2-bromo-3-methylpyridine 8. This
latter compound was oxidized with potassium permanga-
nate to generate 2-bromonicotinic acid 934 (55%) which was
coupled with allylamine (EDCI, cat. DMAP, CH2Cl2, rt) to
afford the corresponding amide 10 (52%). After deprotona-
tion with KHMDS and condensation with trimethylsilyl-
iodonium salt 5,33 the resulting ynamide 11 (58%) was
desilylated (TBAF, THF, 0 8C) to deliver the terminal
ynamide 12 (88%) (Scheme 4).
The Pd(0)-catalyzed Heck–Suzuki–Miyaura domino
reactions were applied to ynamide 7b in the presence of
benzeneboronic acid and ynamide 7c in the presence of
2-methoxybenzeneboronic acid, under optimized conditions
[Pd(OAc)2 (5 mol%), PPh3 (10 mol%), aqueous NaOH,
THF, reflux]. The resulting 3-(arylmethylene)-isoindolin-1-
ones 16 (51%) and 17 (67%) were obtained in moderate to
good yields, as single geometric isomers. Subjecting the
ynamide 12, containing a pyridine ring, to the Heck–
Suzuki–Miyaura domino reactions with benzeneboronic
acid and 3,4-dichlorobenzeneboronic acid, under the
previously optimized conditions, afforded the pyrrolopyr-
idinones 18 (52%) and 19 (68%), respectively. It is worth
mentioning that the use of the heterogeneous catalyst Pd/C
was unsatisfactory in the case of ynamide 12, presumably
due to poisoning of the catalyst by the nitrogen atom of the
pyridine ring (Table 1).
Scheme 4. Synthesis of ynamide 12 containing a pyridine ring.
Since the planned strategy towards 3-(arylmethylene)-
isoindolin-1-ones of type A from ynamides of type H
involved two different Pd(0)-catalyzed steps, it was of
interest to initially examine the feasibility of the Heck
reaction.35 Thus, ynamides 7b and 7c (Scheme 3) were
treated with a catalytic amount of Pd(OAc)2 (5 mol%) and
PPh3 (10 mol%) in DMF at 80 8C and the reaction was
carried out in the presence of ammonium formate
(1.5 equiv) as the reducing agent, in order to regenerate
the Pd(0) catalyst from the intermediate s-vinylpalladium
complexes of type I.35 Under these conditions, the desired
3-methyleneisoindolin-1-ones 13 and 1412 were generated
and isolated in 56% and 62% yield, respectively. It is
noteworthy that the presence of an arylbromide in substrate
Apparently, in the case of ynamides 7a–c and 12, the
Heck–Suzuki–Miyaura domino reactions afforded the
corresponding 3-(arylmethylene)isoindolin-1-ones 15, 16 and
17 or the pyrrolopyridinones 18 and 19 as single
geometric isomers. The (E)-configuration of the known
isoindolin-1-one 15 was readily assigned by NMR and
comparison with the literature data.8a,10c In order to
unambiguously assign the configuration of the isoindoli-
nones 16 and 17 as well as that of the pyrrolopyridinone 19,
authentic samples of their corresponding geometric isomers

S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
Table 1. Heck–Suzuki–Miyaura domino reactions involving ynamides
3885
Ynamides
Reagents: boronic acid,
Pd catalyst (5 mol%), base, solvent
Product (yield)
PhB(OH)2
Pd(PPh3)4, aqueous NaOH, DME
Pd(dba)2, aqueous NaOH, THF
Pd(OAc)2C2PPh3, aqueous NaOH, THF
Pd (10%)/C, aqueous NaOH, THF
15 (48%)
15 (59%)
15 (70%)
15 (56%)
7a
PhB(OH)2
7b
Pd(OAc)2C2PPh3, aqueous NaOH, THF
16 (51%)
7c
Pd(OAc)2C2PPh3, aqueous NaOH, THF
17 (67%)
PhB(OH)2
12
12
Pd(OAc)2C2PPh3, aqueous NaOH, THF
Pd (10%)/C, aqueous NaOH, THF
18 (52%)
18 (0%)
Pd(OAc)2C2PPh3, aqueous NaOH, THF
19 (68%)
having a trisubstituted double bond of (Z) configuration
were prepared by a different route.10c According to this
latter strategy, the N-(2-bromobenzyl)-2-iodobenzamide 4b
was subjected to a Sonogashira coupling reaction with
phenylacetylene in the presence of a catalytic amount of
PdCl2(PPh3)2 (3.5 mol%), CuI (8 mol%) and Et3N (4 equiv)
in DMF at 80 8C. After work-up, the resulting 2-alkynyl-
benzamide was not purified but directly cyclized under
alkaline conditions (NaOEt, EtOH, reflux), the latter
reaction having been demonstrated to involve an anti-
addition across the carbon–carbon triple bond.10 Under
these conditions, the amide 4b led to a 70/30 mixture of the
known (Z)-3-benzylideneisoindolin-1-one 208a,10c and the
desired (Z)-3-(2-bromobenzylidene)isoindolin-1-one 21.
Substantial reduction of the carbon–bromine bond of the
2-bromobenzyl nitrogen substituent also took place as a
side-reaction during the Sonogashira coupling reaction. It is
noteworthy that such a side-reaction was not observed when
ynamide 7b was converted to the 3-(arylmethylene)isoi-
ndolin-1-one 16 by Heck–Suzuki–Miyaura domino
reactions. Similarly, the N-allyl-2-iodobenzamide 4c and
the N-allyl-2-bromonicotinamide 10 were coupled with (2-
methoxyphenyl)acetylene and with phenylacetylene,
respectively. The resulting intermediate disubstituted alkynes
underwent subsequent ring-closure by treatment with sodium
ethoxide in refluxing ethanol, to afford the (2-methoxybenzyl-
idene)isoindolin-1-one 22 (76%) and the pyrrolopyridinone
23 (58%) with high (Z) stereoselectivity ((Z):(E)R95:5)
(Scheme 6). Comparison of the spectral data of compounds
20–23 with those of isoindolin-1-ones 15–17 and the
pyrrolopyridinone 18 confirmed that the latter products were
obtained as single geometric isomers of (E) configuration. The
configuration of the other 3-(arylmethylene)isoindolinones
described in this study was attributed on the basis of these
results. The observed stereochemical outcome was in
agreement with the fact that carbopalladation of alkynes
involves a syn-addition process and cross-coupling reactions
of s-vinylpalladium complexes are known to generally
proceed with retention of the olefinic configuration.35 Some
exceptions to both trends have been reported but they appear
limited to particular classes of substrates.37,38
As the Suzuki–Miyaura cross-coupling reactions require the
presence of a base,36 and because alkynylsilanes are known
to be deprotected under these conditions, it was envisaged to
carry out
a one-pot sequence starting from the

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S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
Figure 2. Structure of lennoxamine.
this natural product have been reported relying on the
construction of ring B or/and ring C as the key steps.15b,41
As previous syntheses of lennoxamine indicate that the
seven-membered ring can arise from the cyclization of an
isoindolinone of type J under acidic conditions followed by
catalytic hydrogenation,15b,41o it was envisaged to apply the
Heck–Suzuki–Miyaura reactions to an ynamide of type K.
The latter compound should be prepared from
2,3-dimethoxybenzoic acid 25 (Scheme 8).
Scheme 6. Preparation of the (Z)-3-benzylideneisoindolin-1-ones 20–22
and the (Z)-pyrrolopyridinone 23.
trimethylsilylynamide 6a. Indeed, treatment of 6a with
aqueous NaOH in THF at reflux generated the terminal
ynamide 7a in situ that underwent the subsequent Heck–
Suzuki–Miyaura domino reactions by addition of benzene-
boronic acid or 3,4-dichlorobenzeneboronic acid and the
palladium catalyst. Under these conditions, the 3-(aryl-
methylene)isoindolinones 15 and 24 were obtained in 65%
and 45% overall yield, respectively (Scheme 7).
Scheme 8. Retrosynthetic analysis of lennoxamine.
The synthesis of lennoxamine (Scheme 9) started with the
bromination of 2,3-dimethoxybenzoic acid 25 with 1,3-
dibromo-5,5-dimethylhydantoin 26 (aqueous NaOH, rt)
which led to 2,3-dimethoxy-6-bromobenzoic acid 27 in
quantitative yield.42 Initial attempts to couple the carboxylic
acid 27 with aminoacetaldehyde dimethyl acetal 28 (EDCI,
cat. DMAP, CH2Cl2, rt) provided the corresponding
secondary amide 29 in low yield (35%). Therefore, the
carboxylic acid 27 was converted to the corresponding acyl
chloride (SOCl2, reflux) and the latter was coupled with
aminoacetaldehyde dimethyl acetal 28 (Et3N, cat. DMAP,
CH2Cl2, rt) to afford the secondary amide 29 (67% overall
yield, one-pot process). After formation of the potassium
amide (KHMDS, toluene, 0 8C to rt) and condensation with
the alkynyliodonium salt 5, the ynamide 30 was obtained in
relatively modest yield (47%).43 The trimethylsilyl group
was then removed by treatment of 30 with TBAF in THF to
afford the terminal ynamide 31 (90%). The next key stage of
our synthetic strategy was to construct ring B and hence
elaborate the isoindolinone core of lennoxamine by the
palladium-catalyzed Heck–Suzuki–Miyaura domino
reactions.
Scheme 7. One-pot desilylation and Heck–Suzuki–Miyaura reactions from
ynamide 6a.
Having demonstrated that ynamides could efficiently
participate in palladium(0)-catalyzed Heck–Suzuki–
Miyaura reactions, it was envisaged to highlight the interest
of this methodology by an application to the synthesis of the
natural product lennoxamine.
3. Synthesis of lennoxamine
Polycyclic nitrogen containing heterocycles are encoun-
tered in naturally occurring alkaloids and numerous
physiologically active drugs.39 Lennoxamine, an isoindolo-
benzazepine alkaloid belonging to the aporhoedane series,
was extracted from the Chilean plant Berberis darwinii.
This natural product exists as a racemate (Fig. 2).40
The terminal ynamide 31 was treated with a catalytic
amount of Pd(OAc)2 (5 mol%), PPh3 (10 mol%) and a base
(aqueous NaOH) in the presence of the commercially
available boronic acid 32 that incorporates both the D and E
rings of the natural product (THF, reflux). Under these
Although this compound has no important biological
activity, its unique structural feature, five- and seven-
membered rings fused with an aromatic moiety, has elicited
considerable synthetic interest and several total syntheses of

S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
3887
Scheme 9. Synthesis of lennoxamine.
conditions, the Heck–Suzuki–Miyaura domino reactions
proceeded smoothly and the resulting 3-(arylmethylene)-
isoindolin-1-one 33 was isolated in 77% yield but as a
mixture of two geometric isomers [(E):(Z)Z85:15]
(Scheme 9). The (E) configuration of the major isomer
was readily assigned by comparison with the spectroscopic
data reported for this compound.15b
1 atm H2, AcOH, rt) to afford lennoxamine in 65% yield
(Scheme 9). The spectroscopic and analytical data of this
compound were in perfect agreement with those reported in
the literature.41
4. Conclusion
This latter result was in sharp contrast with our initial
observation that 3-(arylmethylene)isoindolin-1-ones of type
A were obtained with high (E) stereoselectivity by Heck–
Suzuki–Miyaura domino reactions from ynamides of type
H. Although we cannot rule out that an isomerization may
have occurred during the palladium-catalyzed domino
reactions,37 the particular structure of the 3-(arylmethylene)
isoindolin-1-one 33, which bears a rather electron-rich
enamide moiety, may explain a possible isomerization
subsequent to its formation. The latter could take place
through a reversible protonation of the double bond or a
hydration–dehydration pathway.6–8,15e A photochemical
process could also not be excluded due to the light
sensitivity of compound 33.
We have reported an efficient and stereoselective access to
(E)-3-(arylmethylene)isoindolin-1-ones by using Pd(0)-
catalyzed Heck–Suzuki–Miyaura domino reactions invol-
ving ynamides and arylboronic acids. The interest of this
methodology, which further expands the synthetic utility of
ynamides, has been highlighted by its application to the
preparation of the natural product lennoxamine. A concise
route to this isoindolobenzazepine alkaloid was achieved
from 2,3-dimethoxybenzoic acid (eight steps, 7% overall
yield) via an intermediate ynamide from which the
isoindolone core of the natural product was elaborated by
Heck–Suzuki–Miyaura domino reactions.
5. Experimental
However, this lack of stereoselectivity in the synthesis of
compound 33 had no consequence for the total synthesis of
lennoxamine since the mixture of geometric isomers was
subsequently hydrogenated (cat. Pd (10%)/C, 1 atm H2,
MeOH, rt) to afford the 3-(arylmethyl)isoindolin-1-one 34
in 60% yield. Completion of the total synthesis was
achieved from compound 34, as previously reported,15b by
treatment under acidic conditions (H2SO4 in AcOH, rt) that
served to elaborate the seven-membered ring (ring C) and
generate dehydrolennoxamine 35 (60%). This latter
compound was finally hydrogenated (cat. Pd (10%)/C,
5.1. General procedures
Infrared (IR) spectra were recorded on a Perkin-Elmer 298
or a Bruker Tensor 27 (IR-FT), wavenumbers are indicated
1
in cmK1. H NMR spectra were recorded on a Bruker AC
300 at 300 MHz in CDCl3 (unless otherwise specified) and
data are reported as follows: chemical shift in parts per
million from tetramethylsilane as an internal standard,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet or overlap of non-equivalent resonances),

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S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
integration. 13C NMR spectra were recorded on a Bruker
AC 300 at 75 MHz in CDCl3 and data are reported as
follows: chemical shift in parts per million from tetra-
methylsilane with the solvent as an internal indicator
(CDCl3 d 77.0 ppm), multiplicity with respect to proton
(deduced from DEPT experiments, s, quaternary C; d, CH; t,
CH2; q, CH3). Mass spectra with electronic impact (MS-EI)
were recorded from a Hewlett-Packard tandem 5890A GC
(12 m capillary column)—5971 MS (70 eV). Mass spectra
with chemical ionization (CIC) and high-resolution mass
spectra (HRMS) were performed by the Centre de Spectro-
142.7 (s), 139.2 (d), 137.4 (s), 132.4 (d), 130.9 (d), 129.0
(d), 128.9 (d), 128.2 (d), 128.0 (d), 127.7 (d), 122.3 (s), 93.5
(s), 43.0 (t); MS-EI m/z (relative intensity) 337 (MC
H–BrC, 15), 336 (MKBrC, 100), 231 (27), 203 (13), 107
(14), 76 (12). Anal. Calcd for C14H11BrINO: C, 40.42; H,
2.66; N, 3.37. Found: C, 40.12; H, 2.66; N, 2.90.
5.2.3. N-Allyl-2-iodobenzamide (4c). This compound was
synthesized from allylamine (1.7 mL, 22 mmol), 2-iodo-
benzoic acid (5.00 g, 20.2 mmol) in the presence of EDCI
(4.90 g, 25.4 mmol) and DMAP (493 mg, 4.03 mmol) in
CH2Cl2/THF (80 mL/110 mL), as described for the pre-
paration of 4a from benzylamine. After purification by flash
chromatography (petroleum ether/EtOAc: 60:40), 4.22 g
(73%) of 4c were obtained as a white powder; mp 106 8C;
IR 3410, 3350, 1645, 1580, 1510, 1300, 1260, 1010, 990,
´
chimie Organique de l’Ecole Normale Superieure Ulm
(Paris). Elemental analyses were performed by the Centre
´
´
Regional de Microanalyses (Universite Pierre et Marie
Curie, Paris VI). THF and diethyl ether were distilled from
sodium/benzophenone. CH2Cl2, CH3CN, toluene, Et3N,
DMF were distilled from CaH2. Other reagents were
obtained from commercial suppliers and used as received.
TLC was performed on Merck 60F254 silica gel plates
visualized either with a UV lamp (254 nm), or by using
solutions of p-anisaldehyde/H2SO4/AcOH in EtOH or
KMnO4/K2CO3 in water followed by heating. Flash
chromatography was performed with SDS 60 silica gel
(230–400 mesh).
1
730 cmK1; H NMR d 7.83 (d, JZ7.7 Hz, 1H), 7.36–7.32
(m, 2H), 7.07 (m, 1H), 6.16 (br s, 1H, NH), 5.93 (ddt, JZ
17.3, 10.3, 5.9 Hz, 1H), 5.29 (dq, JZ17.3, 1.5 Hz, 1H), 5.17
(dq, JZ10.3, 1.5 Hz, 1H), 4.02 (dt, JZ5.9, 1.5 Hz, 2H); 13C
NMR d 169.0 (s), 142.0 (s), 139.7 (d), 133.5 (d), 131.0 (d),
128.1 (d), 128.0 (d), 116.8 (t), 92.3 (s), 42.3 (t); MS-EI m/z
(relative intensity) 287 (MC, 10), 272 (3), 232 (8), 231
(100), 203 (21), 160 (11), 105 (4), 77 (6), 76 (17).
5.2. Preparation of ynamides of type H
5.2.4. N-Benzyl-2-iodo-N-trimethylsilylethynyl-benz-
amide (6a). To a solution of 4a (2.84 g, 8.43 mmol) in
toluene (100 mL) at 0 8C was added KHMDS (15.3 mL,
15% in toluene, 10.1 mmol, 1.2 equiv). After 2 h at 0 8C, the
iodonium salt 5 (4.55 g, 10.1 mmol, 1.2 equiv) was added.
After 24 h at rt, the reaction mixture was filtered through
Celite (toluene/ether: 80:20). The filtrate was evaporated
under reduced pressure and the crude material was purified
by flash chromatography (petroleum ether/EtOAc gradient:
90:10–60:40) to afford 1.75 g (48%) of 6a as a white
powder; mp 57 8C; IR 2180, 1680, 1580, 1430, 1370, 1290,
5.2.1. N-Benzyl-2-iodobenzamide (4a). To a solution of
2-iodobenzoic acid 3 (5.00 g, 20.2 mmol) in a mixture of
CH2Cl2 (200 mL) and THF (50 mL) at 0 8C were
successively added DMAP (493 mg, 4.03 mmol,
0.2 equiv), benzylamine (2.4 mL, 22 mmol, 1.1 equiv) and
EDCI (5.40 g, 28.2 mmol, 1.4 equiv) portionwise. After
12 h, the reaction mixture was hydrolyzed with water and
extracted with CH2Cl2. The combined organic extracts were
successively washed with a 1 M aqueous solution of
hydrochloric acid, a saturated aqueous solution of
NaHCO3, brine, dried over MgSO4, filtered and concen-
trated under reduced pressure. The crude material was
purified by recrystallization from absolute EtOH to afford
4.08 g (60%) of 4a as a white powder; mp 126 8C; IR 3420,
1
1250, 820, 760, 745 cmK1; H NMR d 7.79 (dd, JZ7.7,
0.7 Hz, 1H), 7.50–7.45 (m, 2H), 7.40–7.31 (m, 4H), 7.28
(dd, JZ7.7, 1.8 Hz, 1H), 7.08 (apparent td, JZ7.7, 1.8 Hz,
1H), 4.82 (s, 2H), K0.11 (s, 9H); 13C NMR d 171.1 (s),
141.3 (s), 138.7 (d), 135.2 (s), 130.6 (d), 129.2 (d, 2C),
128.4 (d, 2C), 128.1 (d), 127.8 (d), 127.6 (d), 96.3 (s), 92.1
(s), 76.1 (s), 51.6 (t), K0.43 (q, 3C); MS-EI m/z (relative
intensity) 433 (MC, 8), 418 (MKMeC, 5), 306 (4), 232 (7),
231 (55), 203 (15), 92 (8), 91 (100), 76 (7).
1660, 1585, 1510, 1300, 1015, 750 cmK1; H NMR d 7.78
1
(d, JZ7.7 Hz, 1H), 7.35–7.25 (m, 7H), 7.04 (m, 1H), 6.43
(br s, 1H, NH), 4.53 (d, JZ5.5 Hz, 2H); 13C NMR d 169.1
(s), 141.9 (s), 139.7 (d), 137.5 (s), 131.0 (d), 128.6 (d, 2C),
128.1 (d), 128.0 (d, 3C), 127.5 (d), 92.4 (s), 44.0 (t); MS-EI
m/z (relative intensity) 337 (MC, 92), 336 (19), 231 (100),
210 (45), 203 (32), 192 (13), 132 (15), 105 (22), 104 (16), 91
(31), 77 (19), 76 (25).
5.2.5.
N-(2-Bromobenzyl)-2-iodo-N-trimethylsilyl-
ethynylbenzamide (6b). This compound was prepared
from 4b (1.50 g, 3.60 mmol), KHMDS (14.4 mL, 0.5 M in
toluene, 7.20 mmol, 2 equiv) and iodonium salt 5 (3.25 g,
7.20 mmol, 2 equiv) in toluene (85 mL), as described for the
preparation of 6a from 4a. The crude material was purified
by flash chromatography (petroleum ether/EtOAc: 95:5) to
afford 1.32 g (72%) of 6b as a yellow solid; mp 140 8C; IR
2180, 1685, 1585, 1570, 1370, 1295, 1250, 1025, 985, 850,
5.2.2. N-(2-Bromobenzyl)-2-iodobenzamide (4b). This
compound was synthesized from 2-bromobenzylamine
(2.1 g, 11 mmol), 2-iodobenzoic acid (2.5 g, 10 mmol) in
the presence of EDCI (2.3 g, 12 mmol) and DMAP (244 mg,
2 mmol) in CH2Cl2 (100 mL), as described for the
preparation of 4a from benzylamine. After purification by
flash chromatography (petroleum ether/EtOAc: 80:20),
3.36 g (81%) of 4b were obtained as white solid; mp
154 8C; IR 3277, 1644, 1585, 1540, 1305, 1242, 1027, 1013,
986, 743, 719, 684, 666 cmK1; 1H NMR (DMSO-d6) d 8.98
(t, JZ5.9 Hz, 1H, NH), 7.91 (d, JZ7.7 Hz, 1H), 7.64 (dd,
JZ7.7, 1.1 Hz, 1H), 7.56–7.38 (m, 4H), 7.27–7.16 (m, 2H),
4.47 (d, JZ5.9 Hz, 2H); 13C NMR (DMSO-d6) d 169.1 (s),
1
750, 700 cmK1; H NMR d 7.83 (d, JZ8.1 Hz, 1H), 7.60
(dd, JZ7.7, 1.1 Hz, 1H), 7.55 (dd, JZ7.7, 1.5 Hz, 1H),
7.40–7.32 (m, 3H), 7.20 (apparent td, JZ7.7, 1.5 Hz, 1H),
7.12 (m, 1H), 5.00 (s, 2H), 0.13 (s, 9H); 13C NMR d 171.1
(s), 141.1 (s), 138.8 (d), 134.3 (s), 132.8 (d), 130.8 (d), 130.5
(d), 129.5 (d), 127.9 (d), 127.6 (d), 127.4 (d), 124.1 (s), 95.6
(s), 92.2 (s), 76.5 (s), 51.2 (t), K0.44 (q, 3C); MS-EI m/z
(relative intensity) 513 (M[81Br]C, 4), 511 (M[79Br]C, 4),

S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
3889
498 (6), 496 (6), 432 (7), 232 (10), 231 (100), 203 (30), 172
(7), 171 (88), 170 (8), 169 (91), 90 (13), 89 (9), 76 (15).
5.2.9. N-Allyl-N-ethynyl-2-iodobenzamide (7c). This
compound was synthesized from ynamide 6c (1.50 g,
3.90 mmol) by treatment with TBAF (5.1 mL, 1 M in
THF, 5.1 mmol, 1.3 equiv) in THF (50 mL), as described
for the preparation of 7a from 6a. The crude material was
purified by flash chromatography (petroleum ether/EtOAc:
70:30) to afford 1.03 g (85%) of 7c as a white powder; mp
55–57 8C; IR 3300, 2140, 1580, 1360, 1290, 1255, 1015,
5.2.6. N-Allyl-2-iodo-N-trimethylsilylethynyl-benzamide
(6c). This compound was prepared from 4c (2.50 g,
8.71 mmol), KHMDS (30.7 mL, 0.5 M in toluene,
15.3 mmol, 1.8 equiv) and iodonium salt 5 (7.53 g,
16.7 mmol, 1.9 equiv) in toluene (200 mL), as described
for the preparation of 6a from 4a. The crude material was
purified by flash chromatography (petroleum ether/EtOAc:
95:5–90:10) to afford 2.10 g (63%) of 6c as a white waxy
solid; mp !45 8C; IR 2180, 1665, 1585, 1360, 1290, 1250,
1
935, 770, 740 cmK1; H NMR d 7.83 (dd, JZ8.0, 0.7 Hz,
1H), 7.42–7.30 (m, 2H), 7.11 (apparent td, JZ7.7, 1.8 Hz,
1H), 5.99 (ddt, JZ16.6, 10.3, 6.3 Hz, 1H), 5.43 (dq, JZ
16.6, 1.5 Hz, 1H), 5.34 (dq, JZ10.3, 1.5 Hz, 1H), 4.31 (dt,
apparent br d, JZ6.3, 1.5 Hz, 2H), 2.64 (s, 1H); 13C NMR d
170.8 (s), 140.9 (s), 138.9 (d), 130.9 (d), 130.6 (d), 127.7
(d), 127.5 (d), 119.4 (t), 92.0 (s), 76.6 (s), 61.3 (d), 50.4 (t);
MS-EI m/z (relative intensity) 311 (MC, 4), 271 (15), 232
(8), 231 (100), 203 (33), 182 (5), 76 (24). Anal. Calcd for
C12H10INO: C, 46.33; H, 3.24; N, 4.50. Found: C, 46.68; H,
3.47; N, 4.29.
1
840, 760, 740 cmK1; H NMR d 7.81 (dd, JZ8.1, 0.9 Hz,
1H), 7.41–7.27 (m, 2H), 7.10 (ddd, JZ8.1, 7.4, 0.9 Hz, 1H),
5.98 (ddt, JZ16.5, 10.3, 6.2 Hz, 1H), 5.41 (dq, JZ16.5,
1.5 Hz, 1H), 5.32 (dq, JZ10.3, 1.5 Hz, 1H), 4.27 (dt, JZ
6.2, 1.5 Hz, 2H), K0.07 (s, 9H); 13C NMR d 171.1 (s),
141.4 (s), 138.7 (d), 130.8 (d), 130.6 (d), 127.6 (d, 2C),
119.3 (t), 96.0 (s), 92.1 (s), 75.6 (s), 50.1 (t), K0.29 (q, 3C);
MS-EI m/z (relative intensity) 383 (MC, 9), 368 (MKMeC,
17), 294 (6), 256 (13), 231 (100), 203 (28), 180 (6), 76 (17).
Anal. Calcd for C15H18INOSi: C, 47.00; H, 4.73; N, 3.65.
Found: C, 47.11; H, 4.74; N, 3.63.
5.2.10. N-Allyl-2-bromonicotinamide (10). This com-
pound was synthesized from 2-bromonicotinic acid 934
(2.0 g, 9.9 mmol) and allylamine (0.93 mL, 12.4 mmol,
1.25 equiv) in the presence of EDCI (2.3 g, 12 mmol,
1.2 equiv) and DMAP (0.12 g, 0.99 mmol, 0.1 equiv) in
CH2Cl2 (200 mL) as described for the preparation of 4a
from benzylamine and 2-iodobenzoic acid. After purifi-
cation by flash chromatography (diethyl ether), 1.25 g
(52%) of 10 were obtained as a white solid; mp 97–98 8C;
5.2.7. N-Benzyl-N-ethynyl-2-iodobenzamide (7a). To a
solution of 6a (70 mg, 0.16 mmol) in THF (5 mL) at 0 8C
was added tetra(n-butyl)ammonium fluoride (TBAF)
(0.21 mL, 1 M in THF, 0.21 mmol, 1.3 equiv). After
10 min at 0 8C, the reaction mixture was hydrolyzed with
a saturated aqueous solution of NH4Cl and extracted with
ether. The combined extracts were washed with brine, dried
over MgSO4, filtered and concentrated under reduced
pressure. The crude material was purified by flash
chromatography (petroleum ether/EtOAc: 90:10) to afford
56 mg (96%) of 7a as a pale yellow solid; mp 100–102 8C;
IR 3290, 2140, 1680, 1580, 1355, 1320, 1285, 1250, 1140,
1
IR 1660, 1580, 1395, 1300, 1055, 990, 930, 820 mK1; H
NMR d 8.31 (dd, JZ4.8, 1.8 Hz, 1H), 7.75 (dd, JZ7.7,
1.8 Hz, 1H), 7.27 (dd, JZ7.7, 4.8 Hz, 1H), 6.79 (br s, 1H,
NH), 5.86 (ddt, JZ17.3, 10.3, 5.9 Hz, 1H), 5.25 (dq, JZ
17.3, 1.5 Hz, 1H), 5.14 (dq, JZ10.3, 1.5 Hz, 1H), 3.99 (ddt,
apparent tt, JZ5.9, 1.5 Hz, 2H); 13C NMR d 165.6 (s), 150.7
(d), 138.3 (s), 138.0 (d), 134.7 (s), 133.0 (d), 122.6 (d),
116.9 (t), 42.4 (t); MS-EI m/z (relative intensity) 242
(M[81Br]C, 5), 240 (M[79Br]C, 5), 227 (20), 225 (20), 186
(97), 184 (100), 161 (23), 158 (30), 156 (31), 76 (17), 56 (6),
51 (7).
1
760, 730, 710, 695 cmK1; H NMR d 7.81 (dd, JZ8.1,
0.7 Hz, 1H), 7.52–7.46 (m, 2H), 7.42–7.28 (m, 5H), 7.10
(ddd, JZ8.1, 7.4, 1.8 Hz, 1H), 4.87 (s, 2H), 2.60 (s, 1H); 13C
NMR d 170.9 (s), 138.9 (s), 135.0 (s), 130.8 (d), 128.9 (d,
2C), 128.4 (d, 2C), 128.4 (s), 128.1 (d), 127.8 (d, 2C), 91.9
(s), 76.6 (s), 61.7 (d), 51.7 (t); MS-EI m/z (relative intensity)
361 (MC, 2), 232 (7), 231 (43), 203 (16), 91 (100), 76 (12).
5.2.11. N-Allyl-2-bromo-N-trimethylsilylethynyl-nicotin-
amide (11). This compound was synthesized from 10
(800 mg, 3.32 mmol), KHMDS (10.6 mL, 0.5 M in toluene,
5.3 mmol, 1.6 equiv) and iodonium salt 5 (2.39 g, 5.30 mmol,
1.6 equiv) in toluene (50 mL), as described for the preparation
of 6a from 4a. After purification by flash chromatography
(petroleum ether/EtOAc: 90:10), 643 mg (58%) of 11 were
obtained as a yellow oil; IR 2180, 1685, 1645, 1575, 1555,
1390, 1365, 1295, 1250, 1205, 1165, 1120, 1055, 990, 920,
840, 760, 705, 640 cmK1; 1H NMR d 8.42 (dd, JZ4.8, 1.9 Hz,
1H), 7.64 (dd, JZ7.7, 1.9 Hz, 1H), 7.32 (dd, JZ7.7, 4.8 Hz,
1H), 5.93 (ddt, JZ17.2, 10.3, 6.2 Hz, 1H), 5.40 (dq, JZ17.2,
1.1 Hz, 1H), 5.32 (dq, JZ10.3, 1.1 Hz, 1H), 4.27 (dt, JZ6.2,
1.1 Hz, 2H), K0.06 (s, 9H); 13C NMR d 168.0 (s), 150.5 (d),
138.5 (s), 136.5 (d), 134.5 (s), 130.3 (d), 122.1 (d), 119.6 (t),
95.4 (s), 76.3 (s), 50.2 (t), K0.35 (q, 3C); MS-EI m/z (relative
intensity) 338 (M[81Br]C, 15), 336 (M[79Br]C, 15), 323 (58),
321 (57), 257 (56), 249 (14), 247 (14), 186 (97), 185 (14), 184
(100), 180 (14), 158 (48), 156 (49), 139 (20), 137 (20), 84(14),
76(19), 73(18). Anal. Calcd for C14H17BrN2OSi: C, 49.85; H,
5.08; N, 8.31. Found: C, 49.89; H, 5.27; N, 8.27.
5.2.8. N-(2-Bromobenzyl)-N-ethynyl-2-iodobenzamide
(7b). This compound was synthesized from ynamide 6b
(600 mg, 1.17 mmol) by treatment with TBAF (1.53 mL,
1 M in THF, 1.53 mmol, 1.3 equiv) in THF (15 mL), as
described for the preparation of 7a from 6a. The crude
material was purified by flash chromatography (petroleum
ether/EtOAc: 90:10) to afford 408 mg (79%) of 7b as an
orange solid; mp 105–106 8C; IR 3300, 2150, 1690, 1585,
1350, 1295, 1030, 980, 770, 750 cmK1; 1H NMR d 7.86 (br
d, JZ8.1 Hz, 1H), 7.62 (br d, JZ8.1 Hz, 1H), 7.56 (dd, JZ
7.7, 1.5 Hz, 1H), 7.43–7.35 (m, 3H), 7.23 (dd, JZ7.7,
1.5 Hz, 1H), 7.15 (m, 1H), 5.04 (s, 2H), 2.55 (s, 1H); 13C
NMR d 171.0 (s), 140.8 (s), 139.2 (d), 134.2 (s), 133.0 (d),
131.2 (d), 130.3 (d), 129.6 (d), 127.9 (d), 127.8 (d), 127.5
(d), 124.0 (s), 92.2 (s), 76.5 (s), 62.2 (d), 51.4 (t); MS-EI m/z
(relative intensity) 271 (MCH–CH2(C6H4Br)C, 100), 243
(5), 242 (5), 215 (3), 116 (32), 89 (36), 88 (13), 63 (7), 62
(8). Anal. Calcd for C16H11BrINO: C, 43.67; H, 2.52; N,
3.18. Found: C, 43.89; H, 2.65; N, 3.06.

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S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
5.2.12. N-Allyl-2-bromo-N-ethynylnicotinamide (12).
This compound was synthesized from 11 (500 mg,
1.48 mmol) by treatment with TBAF (1.4 mL, 1 M in
THF, 1.4 mmol, 1.25 equiv) in THF (18 mL). After
purification by flash chromatography (petroleum ether/
EtOAc: 80:20), 345 mg (88%) of 12 were obtained as a
yellow oil; IR 3305, 2150, 1685, 1580, 1560, 1395, 1365,
1290, 1055, 810, 760, 750 cmK1; 1H NMR (CDCl3) d 8.44
(dd, JZ4.8, 2.0 Hz, 1H), 7.67 (dd, JZ7.7, 2.0 Hz, 1H), 7.34
(dd, JZ7.7, 4.8 Hz, 1H), 5.95 (ddt, JZ17.3, 10.3, 5.9 Hz,
1H), 5.42 (dq, JZ17.3, 1.5 Hz, 1H), 5.35 (dq, JZ10.3,
1.5 Hz, 1H), 4.31 (dt, JZ5.9, 1.5 Hz, 2H), 2.68 (s, 1H); 13C
NMR (CDCl3) d 167.7 (s), 150.8 (d), 138.3 (s), 136.5 (d),
134.0 (s), 130.1 (d), 122.2 (d), 119.8 (t), 76.1 (s), 61.7 (d),
50.4 (t); MS-EI m/z (relative intensity) 266 (M[81Br]C, 29),
264 (M[79Br]C, 29), 199 (33), 197 (34), 186 (96), 184 (100),
158 (62), 156 (65), 77 (20), 76 (49), 50 (20). HRMS (CIC,
CH4) calcd for C11H10ON729Br (MCHC): 264.9976. Found:
264.9974.
1H), 4.43 (dt, JZ5.1, 1.6 Hz, 2H); 13C NMR d 166.7 (s),
141.5 (s), 136.2 (s), 132.2 (d), 131.8 (d), 129.3 (d), 129.1 (s),
123.1 (d), 119.7 (d), 116.6 (t), 89.3 (t), 41.6 (t); MS-EI m/z
(relative intensity) 186 (MCHC, 13), 185 (MC, 100), 184
(67), 170 (35), 156 (33), 130 (13), 129 (16), 115 (14), 103
(14), 102 (14), 77 (13), 76 (13).
5.4. Palladium-catalyzed Heck–Suzuki–Miyaura domino
reactions involving ynamides
5.4.1. 2-Benzyl-3-(E)-benzylidene-2,3-dihydro-1H-iso-
indol-1-one (15) (representative procedure). To a solution
of ynamide 7a (40 mg, 0.11 mmol) in THF (5 mL) were
added a 1 M aqueous solution of NaOH (0.17 mL,
0.17 mmol, 1.5 equiv) and benzeneboronic acid (16 mg,
0.14 mmol, 1.2 equiv). To the resulting degassed mixture
[argon bubbling, 10 min] were added PPh3 (3.0 mg,
0.011 mmol, 0.1 equiv) and Pd(OAc)2 (1.3 mg,
0.0055 mmol, 0.05 equiv). After 1.5 h at reflux, the reaction
mixture was cooled to rt, hydrolyzed with a saturated
aqueous solution of NH4Cl and extracted with ether. The
combined organic extracts were washed with brine, dried
over MgSO4, filtered and concentrated under reduced
pressure. The crude material was purified by flash
chromatography (petroleum ether/EtOAc: 75:25) to
afford 25 mg (70%) of 15 as a yellow oil; IR 3020, 1695,
1635, 1405, 1335, 1175, 1150, 1115, 970, 820, 765, 735,
5.3. Reductive Heck reaction of ynamides
5.3.1. 2-(2-Bromobenzyl)-3-methylene-2,3-dihydro-1H-
isoindol-1-one (13) (representative procedure). To a
solution of ynamide 7b (80 mg, 0.18 mmol) in DMF
(8 mL) were successively added ammonium formate
(17 mg, 0.27 mmol, 1.5 equiv), Pd(OAc)2 (2 mg,
0.009 mmol, 0.05 equiv) and PPh3 (4.8 mg, 0.018 mmol,
0.1 equiv). After 1 h at 80 8C, the reaction mixture was
cooled to rt, diluted with water and extracted with ether. The
combined organic extracts were washed with brine, dried
over MgSO4, filtered and concentrated under reduced
pressure. The crude material was purified by flash
chromatography (petroleum ether/EtOAc: 95:5) to afford
34 mg (56%) of 13 as a pale yellow solid; mp 110 8C; IR
1705, 1640, 1395, 1025, 980, 845, 770, 755 cmK1; 1H NMR
d 7.92 (apparent br d, JZ7.5 Hz, 1H), 7.72 (apparent dt, JZ
7.5, 1.1 Hz, 1H), 7.63 (apparent td, JZ7.5, 1.1 Hz, 1H),
7.61–7.53 (m, 2H), 7.24–7.09 (m, 2H), 6.98 (apparent br d,
JZ7.5 Hz, 1H), 5.18 (d, JZ2.6 Hz, 1H), 5.18 (br s, 2H),
4.74 (d, JZ2.6 Hz, 1H); 13C NMR d 167.2 (s), 141.3 (s),
136.4 (s), 135.4 (s), 132.8 (d), 132.3 (d), 129.6 (d), 129.1 (s),
128.8 (d), 127.7 (d, 2C), 123.5 (d), 122.4 (s), 120.0 (d), 90.2
(t), 43.2 (t); MS (CIC, CH4) m/z (relative intensity) 316
(M[81Br]CHC, 100), 314 (M[79Br]CHC, 100), 234 (17).
HRMS (CIC, CH4) calcd for C16H13ON79Br (MCHC):
314.0181. Found: 314.0178.
1
695 cmK1; H NMR d 7.91–7.21 (m, 14H), 6.46 (s, 1H),
5.13 (s, 2H); 13C NMR d 166.7 (s), 136.7 (s), 135.9 (s),
135.0 (s), 134.9 (s), 131.6 (d), 130.1 (s), 129.4 (d, 2C), 129.2
(d), 128.7 (d, 2C), 128.5 (d, 2C), 127.7 (d), 127.3 (d), 126.9
(d, 2C), 123.4 (d), 123.1 (d), 111.5 (d), 43.1 (t); MS-EI m/z
(relative intensity) 312 (MCHC, 23), 311 (MC, 100), 310
(MKHC, 31), 282 (10), 234 (15), 232 (27), 220 (22), 167
(17), 165 (16), 91 (72), 65 (9).
5.4.2. 2-(2-Bromobenzyl)-3-(E)-benzylidene-2,3-dihydro-
1H-isoindol-1-one (16). This compound was synthesized
from ynamide 7b (61 mg, 0.14 mmol) and benzeneboronic
acid (20 mg, 0.16 mmol, 1.2 equiv) in the presence of
Pd(OAc)2 (1.5 mg, 0.007 mmol, 0.05 equiv), PPh3 (3.6 mg,
0.014 mmol, 0.1 equiv) and a 1 M aqueous solution of
NaOH (0.20 mL, 1 M, 0.20 mmol, 1.5 equiv) in THF
(6 mL), according to the representative procedure (2 h at
reflux). After purification by flash chromatography
(pentane/EtOAc gradient: 95:5–80:20), 27 mg (51%) of 16
were obtained as a yellow solid; mp 178 8C; IR 1700, 1635,
1440, 1410, 1270, 1220, 1175, 1025, 970, 860, 830, 770,
1
755, 730 cmK1; H NMR d 7.94 (dt, JZ7.3, 1.1 Hz, 1H),
5.3.2. 2-Allyl-3-methylene-2,3-dihydro-1H-isoindol-1-
one (14).12 This compound was synthesized from ynamide
7c (70 mg, 0.22 mmol) in the presence of ammonium
formate (21 mg, 0.34 mmol, 1.5 equiv), Pd(OAc)2 (2.5 mg,
0.011 mmol, 0.05 equiv) and PPh3 (5.9 mg, 0.022 mmol,
0.10 equiv) in DMF (9 mL), according to the representative
procedure (2 h at 80 8C). After purification by flash
chromatography (petroleum ether/EtOAc: 90:10), 21 mg
(62%) of 14 were obtained as an orange oil; IR 1710, 1640,
7.61 (dd, JZ7.7, 1.1 Hz, 1H), 7.49 (m, 1H), 7.45–7.32 (m,
7H), 7.25 (ddd, apparent td, JZ7.3, 1.1 Hz, 1H), 7.15 (ddd,
apparent td, JZ7.3, 1.8 Hz, 1H), 7.06 (dd, JZ7.7, 1.5 Hz,
1H), 6.37 (s, 1H), 5.21 (s, 2H); 13C NMR d 166.7 (s), 135.6
(s), 135.3 (s), 135.0 (s), 134.8 (s), 132.7 (d), 131.7 (d), 130.0
(s), 129.3 (d, 2C), 129.2 (d), 128.7 (d), 128.5 (d, 2C), 127.7
(d), 127.6 (d), 127.5 (d), 123.4 (d), 123.1 (d), 122.2 (s),
111.7 (d), 43.3 (t).
1
1390, 1340, 1095, 925, 840, 770, 730, 715, 700 cmK1; H
NMR d 7.85 (ddd, apparent dt, JZ7.7, 1.1 Hz, 1H), 7.69
(ddd, apparent dt, JZ7.7, 1.1 Hz, 1H), 7.59 (ddd, apparent
td, JZ7.7, 1.1 Hz, 1H), 7.50 (ddd, apparent td, JZ7.7,
1.1 Hz, 1H), 5.87 (ddt, JZ16.9, 10.3, 5.1 Hz, 1H), 5.22–
5.13 (m, 2H), 5.20 (d, JZ2.2 Hz, 1H), 4.87 (d, JZ2.2 Hz,
5.4.3. 2-Allyl-3-(E)-(2-methoxybenzylidene)-2,3-dihydro-
1H-isoindol-1-one (17). This compound was syn-
thesized from ynamide 7c (116 mg, 0.372 mmol) and
2-methoxybenzeneboronic acid (85 mg, 0.56 mmol,
1.5 equiv) in the presence of Pd(OAc)2 (4.2 mg,

S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
3891
0.018 mmol, 0.05 equiv), PPh3 (10 mg, 0.037 mmol,
0.1 equiv) and a 1 M aqueous solution of NaOH (0.56 mL,
0.56 mmol, 1.5 equiv) in THF (10 mL), according to the
representative procedure (0.75 h at reflux). After purifi-
cation by flash chromatography (petroleum ether/EtOAc
gradient: 90:10–70:30), 73 mg (67%) of 16 were obtained as
a light brown solid; mp 110 8C; IR 1690, 1645, 1600, 1250,
133.9 (s), 132.5 (d), 132.0 (d), 131.9 (s), 131.8 (s), 131.3 (d),
130.2 (d), 129.7 (d), 124.1 (s), 124.0 (d), 117.3 (t), 112.6 (d),
41.8 (t); MS-EI m/z (relative intensity) 334 (M[37Cl2]C, 12),
333 (M[37Cl2]KHC, 20), 332 (M[35Cl37Cl]C, 67), 331
(M[35Cl37Cl]KHC, 67), 330 (M[35Cl2]C, 100), 329
(M[35Cl2]KHC, 78), 315 (13), 303 (23), 301 (33), 295
(18), 267 (16), 256 (22), 254 (68), 191 (22), 185 (57), 171
(35). HRMS (CIC, CH4) calcd for C17H13ON235Cl2 (MC
HC): 331.0405. Found: 331.0407.
1
1025, 760, 750 cmK1; H NMR d 7.85 (br d, JZ7.2 Hz,
1H), 7.49–7.26 (m, 5H), 7.02–6.95 (m, 2H), 6.49 (s, 1H),
5.94 (ddt, JZ17.0, 10.2, 5.3 Hz, 1H), 5.25 (dq, JZ17.0,
1.5 Hz, 1H), 5.23 (dq, JZ10.2, 1.5 Hz, 1H), 4.57 (dt, JZ
5.3, 1.5 Hz, 2H), 3.83 (s, 3H); 13C NMR d 166.3 (s), 157.6
(s), 135.5 (s), 135.3 (s), 132.6 (d), 131.4 (d), 131.2 (d), 130.2
(s), 129.6 (d), 129.0 (d), 123.9 (s), 123.1 (d), 123.0 (d),
120.4 (d), 116.9 (t), 110.8 (d), 107.9 (d), 55.6 (q), 41.9 (t);
MS-EI m/z (relative intensity) 292 (MCHC, 21), 291 (MC,
100), 290 (MKHC, 23), 276 (13), 262 (17), 260 (18), 232
(18), 219 (32), 206 (14), 190 (14), 185 (31), 184 (43), 182
(18), 170 (39), 165 (19).
5.5. Attribution of the configuration of the isoindolin-1-
ones 15–17 and the pyrrolopyridinone 18. Synthesis
of the geometric isomers of (Z) configuration
5.5.1. 2-(2-Bromobenzyl)-3-(Z)-benzylidene-2,3-dihydro-
1H-isoindol-1-one (21). To a solution of 4b (416 mg,
1.00 mmol) in DMF (5 mL) were successively added
PdCl2(PPh3)2 (25 mg, 0.035 mmol, 0.035 equiv), CuI
(15 mg, 0.080 mmol, 0.08 equiv) and Et3N (0.56 mL,
4.02 mmol, 4 equiv). After 1 h at rt, phenylacetylene
(0.13 mL, 1.2 mmol, 1.2 equiv) was added and the resulting
mixture was heated at 80 8C. After 1 h, the reaction mixture
was hydrolyzed with a saturated aqueous solution of NH4Cl
and extracted with EtOAc. The combined extracts were
washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material
was added to a solution of sodium ethoxide in absolute
ethanol [prepared by adding Na (70 mg, 3.0 mmol, 3 equiv)
in EtOH (20 mL)]. After 2 h at reflux, the reaction was
quenched by addition of a saturated aqueous solution of
NH4Cl and the resulting mixture was evaporated under
reduced pressure. The residue was portioned between
EtOAc and water and the organic layer was separated,
dried over MgSO4, filtered and concentrated under reduced
pressure. Purification of the crude material by flash
chromatography (petroleum ether/EtOAc: 90:10) afforded
275 mg (70%) of an inseparable mixture of the known (Z)-
3-benzylideneisoindolin-1-one 208a,10c and 21 (70/30 ratio).
An analytically pure sample of 21 was obtained after
separation by preparative TLC (toluene/etherZ96:4) for
individual characterization; IR 1705, 1645, 340, 1110, 1025,
980, 955 cmK1; 1H NMR d 7.94 (br d, JZ7.0 Hz, 1H), 7.80
(br d, JZ7.5 Hz, 1H), 7.67 (td, JZ7.5, 1.1 Hz, 1H), 7.56
(td, JZ7.5, 1.1 Hz, 1H), 7.35–6.99 (m, 6H), 6.90 (m, 2H),
6.80 (s, 1H), 6.73 (br d, JZ8.3 Hz, 1H), 4.81 (s, 2H); 13C
NMR d 168.6 (s), 138.2 (s), 135.7 (s), 134.3 (s), 133.7 (s),
132.35 (d), 132.3 (d), 129.2 (d), 128.7 (d), 128.1 (d, 2C),
128.0 (s), 127.9 (d, 2C), 127.5 (d), 127.1 (d), 126.5 (d),
123.6 (d), 122.2 (s), 119.6 (d), 107.8 (d), 45.8 (t); MS-EI m/z
(relative intensity) 391 (M[81Br]C, 5), 389 (M[79Br]C, 5),
311 (MCH–BrC, 25), 310 (MKBrC, 100), 232 (11), 170
(8), 168 (8), 165 (11), 90 (7), 89 (6).
5.4.4. 6-Allyl-7-(E)-benzylidene-6,7-dihydropyrrolo-
[3,4-b]pyridin-5-one (18). This compound was synthesized
from ynamide 12 (154 mg, 0.58 mmol) and benzeneboronic
acid (84.5 mg, 0.68 mmol, 1.2 equiv) in the presence of
Pd(OAc)2 (6.4 mg, 0.028 mmol, 0.05 equiv), PPh3 (15 mg,
0.058 mmol, 0.1 equiv) and a 1 M aqueous solution of
NaOH (0.85 mL, 0.85 mmol, 1.5 equiv) in THF (25 mL),
according to the representative procedure (5 h at reflux).
After purification by flash chromatography (petroleum
ether/EtOAc: 80:20), 78.5 mg (52%) of 18 were obtained
as a brown oil; IR 3060, 1695, 1640, 1605, 1575,
1395, 1340, 1280, 1265, 1170, 1100, 920, 795, 770, 735,
1
695 cmK1; H NMR d 8.77 (dd, JZ4.8, 1.8 Hz, 1H), 8.18
(dd, JZ7.7, 1.8 Hz, 1H), 8.04–7.99 (m, 2H), 7.45–7.32 (m,
4H), 6.57 (s, 1H), 5.95 (ddt, JZ17.2, 10.3, 5.1 Hz, 1H),
5.30–5.21 (m, 2H), 4.62 (dt, JZ5.1, 1.5 Hz, 2H); 13C NMR
(CDCl3) d 164.0 (s), 154.8 (s), 152.7 (d), 134.0 (s), 133.8 (s),
132.3 (d), 131.1 (d), 130.9 (d, 2C), 128.3 (d), 127.9 (d, 2C),
124.1 (s), 123.5 (d), 117.2 (t), 115.7 (d), 41.8 (t); MS-EI m/z
(relative intensity) 262 (MC, 67), 261 (MKHC, 100), 233
(18), 221 (15), 220 (15), 192 (16), 185 (11), 166 (12), 139
(5), 89 (5), 77 (6). HRMS (CIC, CH4) calcd for C17H15ON2
(MCHC): 263.1184. Found: 263.1179.
5.4.5.
6-Allyl-7-(E)-(3,4-dichlorobenzylidene)-6,7-
dihydropyrrolo[3,4-b]pyridin-5-one (19). This compound
was synthesized from ynamide 12 (204 mg, 0.754 mmol)
and 3,4-dichlorobenzeneboronic acid (173 mg, 0.905 mmol,
1.2 equiv) in the presence of Pd(OAc)2 (8.5 mg, 0.38 mmol,
0.05 equiv), PPh3 (20 mg, 0.076 mmol, 0.1 equiv) and a
1 M aqueous solution of NaOH (1.1 mL, 1.1 mmol,
1.5 equiv) in THF (30 mL), according to the representative
procedure (1.5 h at reflux). After purification by flash
chromatography (petroleum ether/EtOAc: 80:20), 170 mg
(68%) of 16 were obtained as a yellow solid; mp 127 8C; IR
1700, 1640, 1610, 1580, 1475, 1400, 1340, 1030, 925, 880,
5.5.2. 2-Allyl-3-(Z)-(2-methoxybenzylidene)-2,3-dihydro-
1H-isoindol-1-one (22). This compound was synthesized
from 4c (287 mg, 1.00 mmol) by a Sonogashira coupling
with 2-methoxyphenylacetylene44 (158 mg, 1.2 mmol,
1.2 equiv) in the presence of PdCl2(PPh3)2 (25 mg,
0.035 mmol, 0.035 equiv), CuI (15 mg, 0.080 mmol,
0.08 equiv) and Et3N (0.56 mL, 4.0 mmol, 4 equiv) in
DMF (5 mL) (1.5 h at 80 8C). The resulting crude
disubstituted alkyne was cyclized by treatment with a
solution of EtONa in EtOH [Na (70 mg) in EtOH (20 mL),
1
795, 695, 640 cmK1; H NMR d 8.78 (dd, JZ4.8, 1.8 Hz,
1H), 8.21 (br d, JZ2.2 Hz, 1H), 8.18 (dd, JZ7.7, 1.8 Hz,
1H), 7.82 (m, 1H), 7.45 (br d, JZ8.1 Hz, 1H), 7.43 (dd, JZ
7.7, 4.8 Hz, 1H), 6.40 (s, 1H), 5.92 (ddt, JZ17.3, 10.4,
5.1 Hz, 1H), 5.28 (apparent br d, JZ10.4 Hz, 1H), 5.24
(apparent br d, JZ17.3 Hz, 1H), 4.59 (dt, JZ5.1, 1.8 Hz,
2H); 13C NMR d 164.0 (s), 154.5 (s), 152.8 (d), 135.4 (s),

3892
S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
2 h at reflux]. The crude material was purified by flash
chromatography (petroleum ether/EtOAc: 90:10) to afford
222 mg (76%) of 22 as a waxy orange solid; IR 1707, 1656,
1595, 1578, 1487, 1460, 1328, 1248, 1216, 1103, 1017, 954,
d 166.7 (s), 137.1 (s), 136.5 (s), 135.2 (s), 134.7 (s), 132.8
(s), 132.0 (d), 131.8 (s), 131.3 (d), 130.6 (d), 130.2 (s), 129.8
(d), 129.0 (d), 128.8 (d), 128.2 (d), 127.5 (d), 126.9 (d, 2C),
123.7 (d), 123.0 (d), 108.4 (d), 43.3 (t); MS-EI m/z (relative
intensity) 384 (M[37Cl2]CHC, 1), 383 (M[37Cl2]C, 6), 382
(M[37Cl35Cl]CHC, 9), 381 (M[37Cl35Cl]C, 32), 380
(M[35Cl35Cl]CHC, 19), 379 (M[35Cl2]C, 48), 378 (12),
300 (7), 253 (8), 235 (10), 207 (14), 190 (7), 92 (8), 91
(100), 65 (10). HRMS (CIC, CH4) calcd for C22H16ON35Cl2
(MCHC): 380.0609. Found: 380.0605.
1
910, 748, 698 cmK1; H NMR d 7.85 (d, JZ7.5 Hz, 1H),
7.78 (d, JZ7.5 Hz, 1H), 7.58 (apparent td, JZ7.5, 1.1 Hz,
1H), 7.47 (apparent td, JZ7.5, 1.1 Hz, 1H), 7.32 (apparent
br td, JZ8.1, 1.5 Hz, 1H), 7.25 (br d, JZ7.5 Hz, 1H), 6.96
(dd, apparent t, JZ7.5 Hz, 1H), 6.89 (br d, JZ8.1 Hz, 1H),
6.70 (s, 1H), 5.44 (ddt, JZ17.1, 10.3, 5.4 Hz, 1H), 4.85 (dq,
JZ10.3, 1.5 Hz, 1H), 4.54 (dq, JZ17.1, 1.5 Hz, 1H), 4.31
(dt, JZ5.4, 1.5 Hz, 2H), 3.83 (s, 3H); 13C NMR d 168.6 (s),
157.6 (s), 138.5 (s), 134.8 (s), 132.6 (s), 131.9 (d), 131.6 (d),
129.3 (d), 128.8 (d), 128.2 (s), 123.7 (s), 123.2 (d), 119.9
(d), 119.6 (d), 116.1 (t), 110.4 (d), 103.6 (d), 55.4 (q), 43.7
(t); MS-EI m/z (relative intensity) 291 (MC, 100), 290 (MK
HC, 24), 276 (MKMeC, 11), 262 (17), 260 (MKOMeC,
18), 232 (18), 219 (21), 206 (15), 185 (30), 184 (42), 182
(15), 185 (30), 184 (42), 182 (15), 170 (37), 165 (21), 152
(10), 102 (9).
5.7. Synthesis of lennoxamine
5.7.1. 6-Bromo-2,3-dimethoxybenzoic acid (27).42 To a
solution of 2,3-dimethoxybenzoic acid (2.50 g, 13.7 mmol)
in a 0.7 M aqueous solution of NaOH (21 mL) at 0 8C, was
added 1,3-dibromo-5,5-dimethylhydantoin (2.16 g,
7.55 mmol, 0.55 equiv). After 6 h at rt, the reaction was
quenched by addition of solid sodium sulfite until the yellow
color disappeared. The reaction mixture was diluted with
ether and acidified to pHZ2 by addition of a 1 M aqueous
solution of hydrochloric acid. After extraction with ether,
the combined extracts were washed with water, dried over
MgSO4, filtered and concentrated under reduced pressure.
The resulting viscous oil was dried under reduced pressure
to afford 3.58 g (100%) of 27 as a white solid, which was
directly engaged in the next step without further purifi-
cation; mp 110–112 8C; IR 3220 (br), 1734, 1575, 1470,
1416, 1294, 1236, 1177, 1161, 1043, 988, 814, 790, 702,
5.5.3. 6-Allyl-7-(Z)-benzylidene-6,7-dihydropyrrolo-
[3,4-b]pyridin-5-one (23). This compound was synthesized
according to the experimental procedure described for the
preparation of 22 from amide 4c, by a Sonogashira coupling
between amide 10 (114 mg, 0.473 mmol) and phenylacety-
lene (0.063 mL, 0.57 mmol, 1.2 equiv) in the presence of
PdCl2(PPh3)2 (12 mg, 0.016 mmol, 0.035 equiv), CuI
(7.2 mg, 0.038 mmol, 0.08 equiv) and Et3N (0.26 mL,
1.9 mmol, 4 equiv) in DMF (2.5 mL) (2 h at 80 8C). The
resulting crude disubstituted alkyne was cyclized by
treatment with a solution of EtONa in EtOH (2 h at reflux)
and after purification of the crude material by flash
chromatography (petroleum ether/EtOAc gradient: 80:20–
70:30), 68 mg (58%) of 23 were obtained as a viscous oil;
1
634 cmK1; H NMR d 9.53 (br s, 1H), 7.27 (d, JZ8.9 Hz,
1H), 6.86 (d, JZ8.9 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H); 13C
NMR d 170.8 (s), 152.1 (s), 147.0 (s), 130.4 (s), 128.2 (d),
114.9 (d), 108.6 (s), 61.9 (q), 56.1 (q).
5.7.2. 6-Bromo-N-(2,2-dimethoxyethyl)-2,3-dimethoxy-
benzamide (29). To the carboxylic acid 27 (2.86 g,
10.9 mmol) was added thionyl chloride (6 mL) and the
resulting mixture was heated at reflux. After 3 h, the
reaction mixture was cooled to rt and excess SOCl2 was
distilled off under reduced pressure (15 mmHg). The residue
was dissolved in CH2Cl2 (30 mL) and a solution of
aminoacetaldehyde dimethyl acetal 28 (1.80 mL,
16.5 mmol, 1.5 equiv), Et3N (2.30 mL, 16.5 mmol,
1.5 equiv), and DMAP (67 mg, 0.55 mmol, 0.05 equiv) in
CH2Cl2 (30 mL) was added at 0 8C. After 5 h at rt, the
reaction mixture was hydrolyzed with a 0.5 M aqueous
solution of hydrochloric acid and extracted with ether. The
combined extracts were washed with a saturated aqueous
solution of NaHCO3, brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material
was purified by flash chromatography (petroleum ether/
EtOAc gradient: 60:40–50:50) to afford 2.57 g (67%) of 29
as a pale yellow solid; mp 90 8C; IR 3420, 3330, 1665, 1570,
1515, 1470, 1410, 1295, 1265, 1080, 1005, 915, 855,
805 cmK1; 1H NMR d 7.20 (d, JZ8.8 Hz, 1H), 6.77 (d, JZ
8.8 Hz, 1H), 6.04 (br t, JZ5.5 Hz, 1H, NH), 4.50 (t, JZ
5.5 Hz, 1H), 3.83 (s, 3H) 3.82 (s, 3H) 3.56 (t, JZ5.5 Hz,
2H), 3.39 (s, 6H); 13C NMR d 165.5 (s), 152.0 (s), 146.7 (s),
133.7 (s), 127.9 (d), 114.0 (d), 109.4 (s), 102.4 (d), 61.8 (q),
55.9 (q), 54.2 (q), 54.1 (q), 41.2 (t); MS (CIC, CH4) m/z
(relative intensity) 348 (M[81Br]CHC, 95), 346 (M[79Br]C
HC, 95), 319 (M[81Br]KMeOC, 35), 318 (M[81Br]K
MeOHC, 100), 317 (M[79Br]KMeOC, 35), 316
1
IR 1700, 1655, 1600, 1585, 1170, 780 cmK1; H NMR d
8.80 (dd, JZ4.9, 1.5 Hz, 1H), 8.15 (dd, JZ7.9, 1.5 Hz, 1H),
7.45–7.29 (m, 7H), 5.48 (ddt, JZ17.3, 10.5, 5.3 Hz, 1H),
4.93 (dq, JZ10.5, 1.5 Hz, 1H), 4.63 (dq, JZ17.3, 1.5 Hz,
1H), 4.35 (dt, JZ5.3, 1.5 Hz, 2H); 13C NMR d 166.3 (s),
156.6 (s), 153.3 (d), 134.4 (s), 133.6 (s), 132.2 (d), 131.3 (d),
129.6 (d, 2C), 128.0 (d, 2C), 127.9 (d), 123.7 (d), 121.8 (s),
116.6 (t), 109.4 (d), 43.6 (t); MS-EI m/z (relative intensity)
262 (MC, 67), 261 (100), 233 (17), 221 (17), 220 (13), 192
(15), 185 (10), 166 (10), 139 (5), 89 (5), 77 (6).
5.6. One-pot desilylation–Heck–Suzuki–Miyaura domino
reactions from trimethylsilylynamides. 2-Benzyl-3-(E)-(3,
4-dichlorobenzylidene)-2,3-dihydro-1H-isoindol-1-one (24)
To a solution of 7a (300 mg, 0.692 mmol) in THF (30 mL)
was added a 1 M aqueous solution of NaOH (1.7 mL,
1.7 mmol, 2.5 equiv). After 0.5 h at reflux, the resulting
mixture was cooled to rt and benzeneboronic acid (158 mg,
0.828 mmol, 1.2 equiv), Pd(OAc)2 (7.8 mg, 0.035 mmol,
0.05 equiv), PPh3 (18.5 mg, 0.069 mmol, 0.1 equiv) were
successively added. After 1.5 h at reflux, the reaction
mixture was worked-up as usual. Purification by flash
chromatography (petroleum ether/EtOAc: 90:10) gave
119 mg (45%) of 24 as an orange solid; mp 136 8C; IR
1
1700, 1635, 1470, 1410, 1340, 1315, 770, 695 cmK1; H
NMR (CDCl3) d 7.92 (d, JZ7.0 Hz, 1H), 7.80–7.05
(m, 11H), 6.27 (s, 1H), 5.10 (s, 2H); 13C NMR (CDCl3)

S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
3893
(M[79Br]KMeOHC, 100). HRMS (CIC, CH4) calcd for
C13H19O5N81Br (MCHC): 348.0447. Found: 348.0440.
Pd(OAc)2 (17 mg, 0.075 mmol, 0.05 equiv) and PPh3
(40 mg, 0.15 mmol, 0.1 equiv). After 2 h at reflux, the
reaction mixture was hydrolyzed with a saturated aqueous
solution of NH4Cl and extracted with EtOAc. The combined
extracts were washed with brine, dried over MgSO4, filtered
and concentrated under reduced pressure. The crude
material was purified by flash chromatography (petroleum
ether/EtOAc: 60:40) to afford 480 mg (77%) of 3315b as a
yellow oil and as a 85/15 mixture of (E)/(Z) geometric
isomers; IR 1690, 1640, 1500, 1430, 1330, 1270, 1235,
1120, 1095, 1035, 935, 825, 740 cmK1; 1H NMR (only the
signals corresponding to the (E) major isomer could all be
attributed unambiguously) d 7.09 (d, JZ8.5 Hz, 1H), 6.90–
6.75 (m, 4H), 6.48 (s, 1H), 6.00 (s, 2H) 4.67 (t, JZ5.1 Hz,
1H) 4.06 (s, 3H), 3.94 (d, JZ5.1 Hz, 2H), 3.84 (s, 3H), 3.43
(s, 6H); 13C NMR (only the signals corresponding to the
major (E) isomer could all be attributed unambiguously) d
164.7 (s), 153.2 (s), 147.7 (s), 146.9 (s), 146.4 (s), 135.5 (s),
129.0 (s), 128.7 (s), 123.0 (d), 122.0 (s), 118.8 (d), 115.8
(d) 109.6 (d), 108.7 (d), 108.4 (d), 102.2 (d), 101.1 (t), 62.2
(q), 56.4 (q), 54.4 (q, 2C), 41.7 (t); MS-EI m/z (relative
intensity) 414 (MCHC, 3), 413 (MC, 42), 398 (3), 381 (8),
350 (6), 338 (14), 325 (11), 308 (9), 294 (7), 280 (8), 264
(6), 207 (20), 75 (100).
5.7.3. 6-Bromo-N-(2,2-dimethoxyethyl)-2,3-dimethoxy-
N-trimethylsilylethynylbenzamide (30). To a solution of
amide 29 (1.00 g, 2.87 mmol) in toluene (50 mL) at 0 8C,
was added KHMDS (11.5 mL, 0.5 M in toluene, 5.74 mmol,
2 equiv). After 2 h at 0 8C, the iodonium salt 5 (2.59 g,
5.74 mmol, 2 equiv) was added to the reaction mixture.
After 48 h at rt, the reaction mixture was filtered through
Celite (toluene/diethyl ether: 80:20) and the filtrate was
evaporated under reduced pressure. The crude material was
purified by flash chromatography (petroleum ether/EtOAc
gradient: 90:10–80:20) to afford 596 mg (47%) of 30 as a
yellow oil; IR 2180, 1690, 1585, 1575, 1470, 1410, 1355,
1315, 1295, 1250, 1180, 1125, 1090, 1060, 1005, 845, 760,
720, 705, 670, 665, 655, 620 cmK1; 1H NMR d 7.21 (d, JZ
8.8 Hz, 1H), 6.83 (d, JZ8.8 Hz, 1H), 4.78 (apparent t, JZ
5.9 Hz, 1H), 3.89 (s, 3H) 3.85 (s, 3H), 3.84 (dd, ABX syst.,
JZ13.6, 5.9 Hz, 1H), 3.75 (dd, ABX syst., JZ13.6, 5.9 Hz,
1H), 3.43 (s, 6H), K0.08 (s, 9H); 13C NMR d 168.2 (s),
151.9 (s), 146.8 (s), 132.4 (s), 127.4 (d), 114.6 (d), 109.3 (s),
100.8 (d), 96.2 (s), 74.4 (s), 61.4 (q), 56.2 (q), 53.6 (q), 53.5
(q), 48.0 (t), K0.30 (q, 3C); MS (CIC, CH4) m/z (relative
intensity) 446 (M[81Br]CHC, 45), 444 (M[79Br]CHC, 44),
414 (60), 412 (58), 351 (25), 350 (100), 334 (25), 260 (20).
HRMS calcd for C18H27O5NSi81Br (MCHC): 446.0824.
Found: 446.0823.
5.7.6. (1-Benzo[1,3]dioxol-5-yl)methyl-2-(2,2-dimethox-
yethyl)-6,7-dimethoxy-2,3-dihydroisoindol-1-one (34).
A mixture of 33 (231 mg, 0.559 mmol) and Pd (10%)/C
(30 mg, 0.028 mmol, 0.05 equiv) inMeOH (8 mL) was stirred
under an atmospheric pressure of hydrogen. After 4 h, the
reaction mixture was filtered through Celite (MeOH) and the
filtrate was evaporated under reduced pressure. The crude
material was purified by flash chromatography (petroleum
ether/EtOAc: 60:40) to afford 187 mg (80%) of 3415b as a
whitesolid;mp125–126 8C;IR1682, 1490, 1440, 1404, 1266,
1245, 1192, 1122, 1094, 1036, 981, 927, 811, 782, 730, 662,
609 cmK1; 1H NMR d 6.97 (d, JZ8.4 Hz, 1H), 6.65 (d, JZ
8.4 Hz, 1H), 6.62 (dd, JZ8.1, 0.7 Hz, 1H), 6.47–6.41 (m, 2H),
5.90(d, JZ1.4 Hz, 1H), 5.89(d, JZ1.4 Hz, 1H), 4.80(dd, JZ
8.1, 3.7 Hz, 1H), 4.54 (dd, JZ6.6, 3.6 Hz, 1H), 4.18 (dd, JZ
14.3, 3.6 Hz, 1H), 4.00 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H), 3.39
(s, 3H), 3.31 (dd, JZ13.8, 3.8 Hz, 1H), 3.19 (dd, JZ14.3,
6.6 Hz, 1H), 2.65 (dd, JZ13.8, 8.0 Hz, 1H); 13C NMR d 166.7
(s), 152.3(s), 147.5(s), 147.0(s), 146.4 (s), 138.9(s), 129.6(s),
124.1 (s), 122.7 (d), 118.0 (d), 116.0 (d), 109.7 (d), 108.1 (d),
103.4 (d), 100.9 (t), 62.4 (q), 60.2 (d), 56.7 (q), 55.4 (q), 54.7
(q), 42.2 (t), 37.8 (t); MS-EI m/z (relative intensity) 414 (MK
HC, 0.1), 384 (5), 281 (16), 280 (100), 249 (12), 248 (79), 206
(6), 205 (4), 190 (5), 176 (4), 162 (4), 135 (9), 77 (6), 75 (12).
5.7.4. 6-Bromo-N-ethynyl-N-(2,2-dimethoxyethyl)-2,3-
dimethoxybenzamide (31). To a solution of 30 (500 mg,
1.12 mmol) in THF (15 mL) at 0 8C, was added TBAF
(1.5 mL, 1 M in THF, 1.5 mmol, 1.3 equiv). After 10 min,
the reaction mixture was hydrolyzed with a saturated
aqueous solution of NH4Cl and extracted with EtOAc.
The combined extracts were washed with brine, dried over
MgSO4, filtered and concentrated under reduced pressure.
The crude material was purified by flash chromatography
(petroleum ether/EtOAc: 70:30) to afford 376 mg (90%) of
31 as a pale yellow solid; mp 100–101 8C; IR 3300, 2150,
1690, 1475, 1415, 1355, 1295, 1270, 1090, 1050, 1000, 805,
670, 640 cmK1; 1H NMR d 7.23 (d, JZ8.5 Hz, 1H), 6.83 (d,
JZ8.5 Hz, 1H), 4.79 (t, JZ5.7 Hz, 1H), 3.89 (s, 3H) 3.85 (s,
3H), 3.85 (dd, ABX syst., JZ13.9, 5.7 Hz, 1H), 3.81 (dd,
ABX syst., JZ13.9, 5.7 Hz, 1H), 3.44 (s, 6H), 2.63 (s, 1H);
13C NMR d 167.8 (s), 151.7 (s), 146.6 (s), 131.8 (s), 127.4
(d), 114.5 (d), 108.9 (s), 100.7 (d), 77.1 [(NC^C), the
signal corresponding to the other ynamide carbon could not
be unambiguously assigned presumably due to overlap],
61.4 (q), 55.9 (q), 53.8 (q), 53.7 (q), 48.5 (t); MS-EI m/z
(relative intensity) 374 (M[81Br]CHC, 0.4), 373
(M[81Br]C, 3), 372 (M[79Br]CHC, 0.5), 371 (M[79Br]C,
3), 342 (6), 340 (6), 245 (77), 243 (79), 232 (8), 230 (6), 228
(10), 202 (11), 201 (5), 200 (12), 199 (5), 157 (5), 97 (6), 75
(100). HRMS calcd for C15H18NO759Br (MCHC):
372.0447. Found: 372.0448.
5.7.7. Dehydrolennoxamine (35).15b To a solution of 34
(115 mg, 0.277 mmol) in AcOH (3 mL) was slowly added
H2SO4 (0.12 mL, 2.4 mmol, 8.5 equiv). After 3 h at rt, the
reaction mixture was neutralized by dropwise addition of
28% aqueous NH4OH at 0 8C. The resulting mixture was
diluted with water and extracted with CH2Cl2. The
combined extracts were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material
was purified by flash chromatography (petroleum ether/
EtOAc: 60:40) to afford 58 mg (60%) of 35 as a yellow
solid; mp 224–225 8C; IR 1689, 1650, 1491, 1450, 1357,
5.7.5. 3-[(E)-(1-Benzo[1,3]dioxol-5-yl)methylidene]-2-
(2,2-dimethoxyethyl)-6,7-dimethoxy-2,3-dihydro-1H-
isoindol-1-one (33). To a solution of ynamide 31 (561 mg,
1.51 mmol) in THF (60 mL) were successively added the
arylboronic acid 32 (300 mg, 1.81 mmol, 1.2 equiv), a 1 M
aqueous solution of NaOH (2.3 mL, 2.3 mmol, 1.5 equiv),
1266, 1237, 1216, 1032, 928, 854, 828, 814, 792, 769 cmK1
1H NMR d 7.18 (s, 2H), 7.10 (d, JZ10.5 Hz, 1H), 6.70
;

3894
S. Couty et al. / Tetrahedron 62 (2006) 3882–3895
Sect. B 1978, 16, 301–304. (f) Marsili, A.; Scartoni, V. Gazz.
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Zhang, Y. Tetrahedron Lett. 2001, 42, 8507–8510. (i) Ha,
D.-C.; Yun, C.-S.; Yu, E. Tetrahedron Lett. 1996, 37,
2577–2580.
(apparent s, 2H), 5.96 (apparent br s, 2H), 5.66 (d, JZ
10.5 Hz, 1H), 4.68 (d, JZ9.4 Hz, 1H), 4.10 (s, 3H), 3.92 (s,
3H), 3.34 (d, JZ15.7 Hz, 1H), 3.00 (dd, JZ15.1, 9.4 Hz,
1H); 13C NMR d 163.6 (s), 152.8 (s), 147.6 (s), 146.7 (s),
146.4 (s), 137.4 (s), 130.0 (s), 129.2 (s), 123.0 (s), 120.0 (d),
117.4 (d), 117.2 (d), 110.5 (d), 110.0 (d), 109.2 (d), 101.2
(t), 62.5 (q), 59.7 (d), 56.8 (q), 42.2 (t); MS-EI m/z (relative
intensity) 352 (MCHC, 20), 351 (MC, 100), 350 (MKHC,
9), 336 (8), 322 (8), 207 (11), 160 (48), 130 (18), 102 (14).
¨
7. (a) Griesbeck, A. G.; Kramer, W.; Oelgemoller, M. Synlett
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Neudorfl, J. M.; Gorner, H. Synlett 2004, 2347–2350.
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5.7.8. Lennoxamine.15b,41 A mixture of 35 (58 mg,
0.16 mmol) and Pd (10%)/C (17.5 mg, 0.016 mmol,
0.05 equiv) in AcOH (15 mL) was stirred under an atmos-
pheric pressure of hydrogen. After 14 h at rt, the reaction
mixture was filtered through Celite (AcOH) and the filtrate
was evaporated under reduced pressure. The crude material
waspurifiedbyflashchomatography(petroleumether/EtOAc:
50:50) to afford 37 mg (65%) of lennoxamine as a white solid;
mp226–228 8C;IR1679, 1483, 1424, 1263, 1196, 1172, 1035,
934, 834 cmK1; 1H NMR d 7.16 (d, JZ8.3 Hz, 1H), 7.11 (d,
JZ8.3 Hz, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 5.94 (d, JZ1.5 Hz,
1H), 5.93(d, JZ1.5 Hz, 1H), 4.78–4.67 (m, 1H), 4.28(dd, JZ
10.5, 1.5 Hz, 1H), 4.09 (s, 3H), 3.90 (s, 3H), 3.09 (dd, JZ14.7,
1.9 Hz, 1H), 2.93–2.75 (m, 4H); 13C NMR d 165.2 (s), 152.6
(s), 147.3(s), 146.4(s), 146.1(s), 138.2 (s), 134.8(s), 131.0(s),
124.2 (s), 117.0 (d), 116.2 (d), 110.4 (d), 110.3 (d), 101.1 (t),
62.5 (q), 60.2 (d), 56.7 (q), 42.7 (t), 41.1 (t), 35.9 (t); MS (CIC,
CH4) m/z (relative intensity) 354 (MCHC, 100), 353 (8), 318
(10), 316 (10). HRMS calcd for C20H20NO5 (MCHC):
354.1341. Found: 354.1337.
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Acknowledgements
11. Electrophilic cyclizations of 2-alkynylbenzamides have also
been reported, see: (a) Kundu, N. G.; Khan, M. W.
Tetrahedron Lett. 1997, 38, 6937–6940. (b) Kundu, N. G.;
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We thank Johnson and Johnson for financial support (Focus
´
Giving Award to J.C.) and Dr. Axel Couture (Universite des
Sciences et Technologies de Lille) for providing us with a
detailed experimental procedure for the cyclization of
compound 34.
12. Cho, C. S.; Shim, H. S.; Choi, H.-J.; Kim, T.-J.; Shim, S. C.
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