Palladium-mediated intramolecular C-N bond formation involving allyl substituted pyridines. Application to a novel strategy for the synthesis of the skeleton of berberinium derivatives

Article abstract of DOI:10.1016/j.jorganchem.2003.06.001

The insertion of allenes in the Pd-C σ bond of cyclopalladated pyridine derivatives afforded (η³-allyl) Pd complexes. The ideally located imine unit reacted selectively with the allyl functionality to yield a series of new cationic heterocycles. The process opened the route to a novel strategy for the synthesis of berberiniums, a class of molecules of pharmacological interest.

Full text of DOI:10.1016/j.jorganchem.2003.06.001

Journal of Organometallic Chemistry 687 (2003) 313ꢀ321
/
www.elsevier.com/locate/jorganchem
Palladium-mediated intramolecular Cꢀ
/
N bond formation involving
allyl substituted pyridines. Application to a novel strategy for the
synthesis of the skeleton of berberinium derivatives
Jaganaiden Chengebroyen, Myriam Linke, Mike Robitzer, Claude Sirlin *,
Michel Pfeffer *
Laboratoire de Syntheses Me´tallo-Induites, UMR 7513, Universite´ Louis Pasteur, 4 rue Blaise Pascal, 67000 Strasbourg, France
Received 27 May 2003; received in revised form 30 June 2003; accepted 30 June 2003
This paper is dedicated to our friend Jean-Pierre Geneˆt on the occasion of his 60th birthday
Abstract
The insertion of allenes in the Pdꢀ
/
C s bond of cyclopalladated pyridine derivatives afforded (h3-allyl) Pd complexes. The ideally
located imine unit reacted selectively with the allyl functionality to yield a series of new cationic heterocycles. The process opened the
route to a novel strategy for the synthesis of berberiniums, a class of molecules of pharmacological interest.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Palladium-mediated synthesis; CꢀN bond formation; Allenes; Cyclopalladated complexes; Heterocyles; Berberiniums
/
1. Introduction
Whilst trying to perform a similar reaction with
pyridines (Eq. (2)) ortho-substituted by an allyl func-
tionality to afford quinolizinium compounds, we found
that the reaction indeed took place, but with rather poor
Palladium has long been known as the most powerful
tool for the formation of Cꢀ
/
C or Cꢀ
/
Y bonds (Yꢁ
/
heteroatom) [1]. However, as far as Yꢁ/N was con-
yields (B10%) [8].
/
cerned, this property has been mainly limited to those
cases where the N atom was that of primary or
secondary amines [2]. Only very few examples of either
tertiary amines or secondary imines used in CꢀN bond
/
synthesis have yet been reported. Our laboratory has
been involved in such a project (Eq. (1)) as we found
ð2Þ
that intramolecular Cꢀ
/
N bonds could be obtained with
We thus decided to investigate whether more reliable
routes would be achievable for the solution of this latter
problem. As it appeared that the low yield of the
heterocyclic compounds was mainly due to the forma-
tion of ortho-substituted pyridine complexes of palla-
dium(II), we thought that we should rather look for
p-allyl-Pd complexes bearing a pyridine ring whose N
atom might be less prone to coordinate to the metal
centre. A solution to this would be to place the pyridine
unit at the central carbon of the allylic group rather than
at one terminal carbon as we had in the previous studies.
It is well known that the insertion of allenes into the
allyl substituted tertiary amines [3ꢀ
/
7].
ð1Þ
* Corresponding authors. Tel.:
90241526.
E-mail
pfeffer@chimie.u-strasbg.fr (M. Pfeffer).
ꢂ
/
33-3-90241622; fax:
ꢂ/
33-3-
addresses:
sirlin@chimie.u-strasbg.fr
(C.
Sirlin),
0022-328X/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2003.06.001

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J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ321
/
Pdꢀ
C s bonds affords h3-allyl-palladium complexes in
/
which the central carbon atom of the allylic group is
substituted by the unit s bonded to Pd in the starting
material. We thus reasoned that cyclopalladated imines
should be the ideal starting materials to afford, through
reaction with allenes, such p-allyl moieties from which
the imine unit would be ideally located to perform an
intramolecular allylic substitution. We have already
described the success of this simple strategy in pre-
liminary forms [9,10]. In this paper we thus describe
further studies connected to this reaction together with
its application to the synthesis of the skeleton of
berberinium derivatives.
ð3Þ
In CH2Cl2, complexes 4a and 5a were reacted with the
appropriate allenes to yield the organic molecules 4c and
5c (Eq. (4) and Eq. (5), respectively).
ð4Þ
Regardless whether these organopalladium intermedi-
ates were isolated or not, the reaction proceeds through
2. Results and discussion
the initial formation of a h3-allylꢀ
/
palladium complex.
This intermediate results from the insertion of the allene
into the PdꢀC bond of the starting cyclopalladated
complex. A carbonꢀcarbon bond is formed between the
/
2.1. Syntheses
/
previously metallated carbon and the central electro-
philic carbon of the allene molecule. At this stage of the
reaction, two types of nucleophilic attack of the
A series of symmetric or unsymmetric allenes 1ꢀ
[11ꢀ15] have been reacted with a selection of cyclopal-
ladated compounds 4aꢀ7a [16ꢀ19] having a pyridine
unit coordinated to the palladium atom (Chart 1 and 2).
Whereas 4a and 5a led directly to the organic products
4c and 5c respectively, in a few cases stable, isolable
organometallic compounds were obtained as for, e.g. the
/
3
/
/
/
intramolecular nitrogen on the metalꢀallyl complexe
/
are possible (Eq. (5)). Thus, a mixture of two regioi-
somers may be obtained.
reaction of 1ꢀ
(Scheme 1)
Combustion analysis and 1H-NMR spectrometry
established that these products were h3-allylꢀ
palladium
/
3 with 6a and the reaction of 1 with 7a
/
complexes (see for example the chem. shifts of the
terminal allylic protons, exp. section). They are inter-
mediates in the normal course of the reaction. In
consequence we reacted them further in methanol in
the presence of three to four equivalents of triphenyl-
phosphane to afford the cationic heterocyclic com-
pounds 6e, 6f, 6g and 7c.
ð5Þ
The cationic heterocycles we obtained arose indeed
selectively from these two types of reactions. In the case
of the benzoquinoleine and phenylpyridine ligands, six-
membered rings 4c and 5c, bearing a 3-ethylidene
substituent were formed. Starting with the benzylpyr-
idine ligand, we obtained the seven-membered rings 6e,
6f and 6g, bearing various substituted 3-ethylidene units.
The five-membered heterocycle 7c resulted from the
attack of the nitrogen of an aminopyridine ligand. Such
heterocyclic structures are without precedent in the
literature.
Chart 1.
2.2. Regioselectivity
We have been able to select the best conditions under
which it was possible to observe the formation of the
two possible regioisomers. Instantaneous formation of
1
the h3-allylꢀ
/
palladium 5b was observed by H-NMR
spectrometry after mixing the cyclopalladated phenyl-
pyridine 5a and butadiene 1 in CH2Cl2. The limiting step
Chart 2.

J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ
/321
315
Scheme 1.
of the process was the disappearance of the complex 5b.
The formation of the 3-ethylideneꢀquinolizinium 5c and
of its regioisomer 5d were also followed versus time (see
/
Fig. 1).
As the hypothesis of a first order disappearance of the
metalꢀallyl complex 5b was unsatisfactory (see Fig. 2),
/
we tested a second order reaction. With this latter
hypothesis, a good linear correlation between 1/5b and
time was obtained, leading to the rate constant k1ꢁ
/
1809
/
10 mMꢃ1 sꢃ1 (see Fig. 3).
Thus, it seems that some kind of association should
occur between two molecules of 5b prior to the
depalladation reaction. Ryabov et al. [20] has shown
that the reactions of organopalladium dimers with
nucleophiles such as pyridine, alkynes or alkenes are in
each case first-order in the palladium dimers and in the
nucleophiles. As in our case the only nucleophile present
in the reaction mixture is the pyridine fragment of the
molecule 5b we suggest that one pyridine nitrogen atom
of one molecule of 5b interacts with the palladium center
of another molecule of 5b akin to the intermediates
postulated by Ryabov (Scheme 2).
Fig. 1. Kinetics of the Eq. (5) in CH2Cl2.
Concerning the isomeric heterocycles, they were
formed in a constant ratio 5c/5dꢁ
/
3.090.1. This result
/
Fig. 2. Log evolution of the concentration of 5b in Eq. (5).
implies that the process is under kinetic control, the two
regioisomers being formed through two parallel path-
ways. The rate constants ratio k2/k3 equals the products
ratio (see experimental part). It was thus possible to
Scheme 2.
Fig. 3. Reciprocal evolution of the concentration of 5b in Eq. (5).

316
J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ321
/
simulate the kinetics of the disappearance of the
intermediate 5b and the formation of the products 5c
and 5d. The obtained curves fit nicely with the experi-
mental data as shown by their R2 values that are close to
1.
The previous reaction, when performed in MeOH, led
only to the formation of the regioisomer 5c, which is the
less congested isomer (and thus the most stable one) as
shown in Scheme 3.
However, if the previous kinetic results are of general
scope, a kinetic point of view has to be considered.
Compounds 4c and 5c result from the attack of the
pyridine ligand on the more substituted, i.e. the more
electrophilic, extremity of the allyl unit. On the other
hand (compounds 6e, 6f, 6g and 7c), the same attack will
lead to a crowded transition state and therefore attack
of the less substituted carbon is that time preferred.
As depicted in Scheme 4, compound 11a was synthe-
sised in 78% yield by refluxing the organopalladium
complex 10a in PhCl, according to published procedure.
[30] Only one regioisomer was obtained. [31] Since the
formation of cycle B is the most critical one of this new
process, we decided to perform it with the properly
substituted substrates 8b and 9b. The insertion com-
pound 10b, obtained in CH2Cl2, was not further
purified. It was directly refluxed in PhCl in the presence
of catalytic amounts of pyridine to yield the 3-phenyli-
soquinoline derivative 11b as the main product. Its
isolation was, however, more tedious than 11a as it
required two successive chromatographies (overall yield
20%). Compared to a recent synthesis of cycle B in the
berberines series, this yield is low. However our synth-
esis is convergent and might be useful for labscale
syntheses [32]. It originates from a peculiar process of
amino-dealkylation and aromatisation of the insertion
intermediate 10b.
2.3. Palladium-mediated synthesis of berberiniums
Berberines are tetracyclic alkaloids [21]. This class of
molecules present the peculiarity of containing a pyri-
dine cycle whose nitrogen atom is shared between two
rings, as it is the case in the above described compounds.
Many berberines display interesting biological and/or
pharmacological activities, like anti-inflammatory
[22,23], antibacterial [24], immunostimulant [25], anti-
oxidant [26]. Since Haworth and coworkers first synth-
esis [27], synthetic strategies have been developed using a
Mannich reaction [28] or a photochemical process [29].
The reaction of the isoquinoline 11a in acetic acid
with palladium acetate afforded 12a in 97% yield. A
subsequent metathesis with lithium chloride led to the
quantitative formation of 12b. The insertion of buta-
diene 1 into the Pdꢀ
C bond of the latter yielded the h3-
/
Application of the insertion of an allene into the Pdꢀ
/
allylpalladium derivative 12c as a stable solid (92%). The
tetracyclic compound 13a was obtained from 12c
through thermal demetallation at 80 8C in PhCl. Finally
the 6-ethoxycarbonyl-3-isopropylidene-dibenzo(d,h)
quinolizinium was isolated from 13a as its PF6 salt 13b
C bond of a cyclopalladated pyridine derivative opens
the possibility to plan a new synthesis. Cycle C might be
obtained by this new reaction. On the other hand, the
starting isoquinoline might result from the insertion of
an internal alkyne in the PdꢀC bond of a cyclometal-
/
in 87% yield.
lated benzylamine, a reaction previously studied in our
laboratory [30].
This will lead to an unprecedented synthesis of
berberines as it will be performed via two successive
CꢀH bond activation reactions which are mediated by
/
stoichiometric amounts of palladium(II) complexes.
Scheme 3.
Scheme 4.

J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ
/321
317
3. Conclusion
Built-in allylꢀ
vatives have been reacted intramolecularly to yield a
new series of cationic heterocyclic compounds. The
reaction was regioselective with the respect to the
structure of the starting material. Kinetic studies fa-
voured kinetic over thermodynamic control of the
course of the reaction. The process has been successfully
applied to a novel synthesis of berberiniums.
Chloro-3-methyl-1-butyne (40.5 g; 0.4 mol) was placed
in the dropping funnel, 3 ml added to the zincꢀbutanol
/
/
palladium complexes of pyridine deri-
slurry and the mixture heated cautiously, with stirring,
until the reaction started. Slow addition of the remain-
ing propargyl chloride followed, controlled by the
distilling rate of the allene (distilling temperature
between 38 and 42 8C). The collected material was
redistilled, giving a colourless liquid of b.p. 38ꢀ41 8C
/
(19.5 g; 71% yield). Lit. [13]: 39.5ꢀ
/
41 8C. [1]H-NMR
3.1, CH2); 1.70 (t, 6H,
5
(CDCl3): 4.53 (septet, 2H, Jꢁ
/
5Jꢁ
/3.1, 2 CH3).
4. Experimental
4.2. 3-Methoxy-1,2-propadiene 2
Solvents (dichloromethane, methanol, diethyl ether
1
and hexane) were dried and distilled under argon. H-
Potassium t-butoxide (0.25 g, 2.5 mmol) was added to
molecular sieve dried methyl propargyl ether (7 g, 0.1
mol). The mixture was heated to reflux for 3 h and then
(300.13 or 200.13 MHz) and 13C- (75.47 or 50.32 MHz)
NMR spectra were recorded on AC 300 or AC 200
Bruker instruments. Chemical shifts are expressed in
¨
distilled under reduced pressure at r.t. to a dry-iceꢀ
acetone cooled trap. Redistillation afforded a colourless
liquid of b.p. 50ꢀ2 8C (6.4 g, 91% yield). Lit. [14]: 50ꢀ
/
ppm relative to TMS, the coupling constants in Hz.
Abbreviations: Ar aromatic, br broad, quat. quaternary,
Py pyridine. The number of H atoms at the carbon
atoms was determined through DEPT experiments. The
amounts of residual solvents have been measured by 1H-
/
/
1
4
2 8C. H-NMR (CDCl3): 6.74 (t, 1H, Jꢁ6, CH); 5.45
/
4
(d, 2H, Jꢁ6, CH2); 3.39 (s, 3H, OCH3).
/
NMR. IR spectra were recorded on an IRFT Bruker.
¨
The positions of the absorption bands are given in
cmꢃ1. Combustion analyses were performed by the
Service central de microanalyses du CNRS, Universite´
Louis Pasteur, Strasbourg. The mass spectra were
carried out by the Laboratoire de spectroscopie de
masse de l’Universite´ Louis Pasteur, Strasbourg.
4.3. 1,2-Heptadiene 3
The compound was prepared as described previously
[15].
The cyclopalladated compounds: bis [(2-pyri-
dyl(h)naphtyl (kN, kC1)] di(m-chloro) dipalladium 4a,
16 bis [2-(2-pyridyl)phenyl (kN, kC1)] di(m-chloro)
dipalladium 5a [17], bis [2-(2-pyridyl)methylphenyl
(kN, kC1)] di(m-chloro) dipalladium 6a [18] and bis [2-
pyridyl-2-aminophenyl (kN, kC1)] di(m-chloro) dipalla-
dium 7a [19] were prepared according to published
methods.
4.1. 3-Methyl-1,2-butadiene 1
Calcium chloride (93 g; 0.83 mol) was added in
portions to a cold (0ꢀ5 8C) stirred mixture of concen-
/
trated hydrochloric acid (400 ml), 2-methyl-3-butyn-2-ol
(70 g; 0.83 mol) and hydroquinone (0.75g). After
addition, the cooling bath was removed and the stirring
continued for 1 h. The top layer was separated, dried
over sodium carbonate, and distilled under reduced
pressure. All the material that distilled up to 40 8C under
110 mmHg was collected and distilled again. 3-Chloro-
3-methyl-1-butyne was thus collected as a colourless
4.4. Synthesis of the heterocyclic compounds 4c(PF6),
5c(PF6), 4c(Cl), 4c(PF6)
liquid (b.p. 74ꢀ
/
6 8C) (45.5 g; 53% yield). Lit. [11]: 75ꢀ
/
(a) A mixture of the cyclopalladated complex 4a (320
mg, 0.5 mmol) and 2.5 equivalents of propadiene 1 (85
mg, 1.25 mmol) in 20 ml of dichloromethane was stirred
for 1 h at r.t. A black heterogenous solution was
observed. The black metallic palladium was removed
by a filtration over a Celite pad. The yellow filtrate left
was concentrated. On addition of hexane, a yellow
precipitate was formed. After drying the latter under
vacuum, the cationic heterocycle was obtained as a
yellow powder. The product was fully characterized as
its hexafluorophosphate salt, which was obtained by
treating a water solution with one equivalent of KPF6.
6 8C. 1H-NMR (CDCl3): 2.48 (s, 1H, CH); 1.82 (s, 6H, 2
CH3).
For the next step, the described procedure [12] was
improved in the following way. Metallic zinc powder (52
g; 0.79 mol) was washed with aqueous 3% hydrochloric
acid solution (4ꢄ
solution (2ꢄ60 ml), ethanol (2ꢄ
(2ꢄ60 ml). The thus treated zinc was rinsed with 110 ml
/40 ml), aqueous 2% copper sulfate
/
/60 ml), and n-butanol
/
n-butanol in a two-neck round-bottom flask provided
with a dropping funnel, a magnetic stirrer bar and a
distillation head with Vigreux column (30 cm). 3-

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J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ321
/
4.4.1. 2,2-Dimethyl-3-ethylidene-
anthra(d,e,f)quinolizinium 4c(PF6)
Yield 75%. Anal. Calc. for C18H16F6NP: C, 55.24; H,
4.5. Isolation of the (h3-allyl) Pd complexes 6b,c,d and
7b
1
4.09; N, 3.58. Found: C, 55.59; H, 3.80; N, 3.43%. H-
To a suspension of starting cylopalladated complex 6a
(1 mmol) in CH2Cl2 (20 ml) was added dropwise a
solution of 2.5 equivalents of allene in CH2Cl2 (10 ml).
The reaction mixture was stirred for 2 h at r.t.: a clear
yellow solution containing a light black palladium
deposit was obtained. After filtration over Celite, the
yellow filtrate was concentrated (ca. 5 ml) and hexane
added to precipitate a pale yellow solid corresponding to
the (h3-allyl) Pd complex, 6b.
3
NMR (acetone-d6): 9.90 (1H, d, Jꢁ
/
6.3, Hoꢀ
/
Py); 9.35
8.30
7.8, Ar); 6.14 (2H, s, Ä
CH2); 2.16 (6H, s, 2 CH3). MS (EI) Calc. for C18H16N:
m/zꢁ
246. Found: [Mꢂ] 246.
3
(1H, d, Jꢁ
(3H, m, Ar); 8.15 (1H, t, Jꢁ
/
8.1, Ar); 8.46ꢀ
/
8.41 (2H, m, Ar); 8.38ꢀ
/
3
/
/
/
(b) Compound 5c was prepared via a similar proce-
dure to that described for 4c, starting from 5a and using
methanol instead of dichloromethane. The PF6 salt was
obtained directly by treating the methanol filtrate with
one equivalent of KPF6.
6b: obtained from 1. 87% yield. Anal. Calc. for
C17H18ClNPd: C, 54.81; H, 5.08; N, 3.60. Found: C,
55.18; H, 5.14; N, 3.40%.1H-NMR (CDCl3ꢂ
/
Py-d5):
Py); 7.92 (1H, d, 3Jꢁ
6.7,
8.4, 4Jꢁ
1.5, Ar); 7.27ꢀ7.19 (3H,
8.48 (1H, d, 3Jꢁ
/
4.6, Hoꢀ
/
/
Ar); 7.51 (1H, td, 3Jꢁ
/
/
/
4.4.2. 2,2-Dimethyl-3-ethylidene-benzo(d)quinolizinium
5c(PF6)
Yield 51%. Anal. Calc. for C16H16F6NP: C, 52.32; H,
3
3
m, Ar); 7.06 (1H, t, Jꢁ
/
5.2, Ar); 6.93 (1H, d, Jꢁ
/7.7,
2
Ar); 4.25 and 4.12 (2H, 2d, Jꢁ/15.6, CH2); 3.46 and
3.42 (2H, 2 br s, allylic H); 1.34 and 1.04 (6H, 2 s,
C(CH3)2).
1
4.36; N, 3.82. Found: C, 52.63; H, 4.26; N, 3.70%. H-
NMR (CD3OD): 9.23 (1H, d, 3Jꢁ
/
5.7, HoꢀPy); 8.66
/
6c (syn isomer): obtained from 2; 86% yield. Anal.
Calc. for C16H16ClNOPd: C, 52.30; H, 4.86; N, 3.49.
3
4
3
(1H, dd, Jꢁ
4Jꢁ
1.3, Ar); 8.25 (1H, t, Jꢁ
3Jꢁ6.7, 4Jꢁ
1.6, Ar), 7.84ꢀ
s, ÄCH2); 1.91 (6H, s, CH3). MS (EI) Calc. for C16H16N:
m/zꢁ
222. Found: [Mꢂ] 222.
/
8.3, Jꢁ
/
1.5, Ar); 8.57 (1H, td, Jꢁ
/7.9,
3
Found: C, 52.67; H, 4.88; N, 3.31%. 1H-NMR (CDCl3ꢂ
/
/
/
7.3, Ar); 7.99 (1H, td,
Py-d5): 8.52 (1H, d, 3Jꢁ
/
4.5, Hoꢀ
/
Py); 8.02 (1H, dd, 3Jꢁ
/
/
/
/
7.66 (3H, m, Ar); 5.80 (2H,
4
3
4
/
6.5, Jꢁ
7.34ꢀ7.26 (3H, m, Ar); 7.10 (1H, t, Jꢁ
(1H, d, 3Jꢁ
4.33 (2H, 2d, Jꢁ
/
2.2, Ar); 7.53 (1H, td, Jꢁ
/
7.6, Jꢁ
/1.7, Ar);
3
/
/
/
6.1, Ar); 6.99
(c) The cyclopalladated complex 4a (0.8 mmol) and
2.5 equivalents of propadiene 1 (134 mg, 2 mmol) in 20
ml of dichloromethane were stirred overnight at RT. A
black heterogenous solution was obtained. The black
metallic palladium so formed was filtered. The yellow
filtrate left was concentrated and redissolved in water.
After filtration over paper, water was evaporated and
the residue dried under vacuum. The cationic hetero-
/
7.8, Ar); 5.79 (1H, br s, CHOCH3); 4.39 and
2
/16.4, CH2); 3.46 (3H, br s, OCH3);
3.31 and 2.70 (2H, 2 s, allylic H).
6d: obtained from 3; 83% yield; 3:1 mixture of syn and
1
anti isomers as measured by H-NMR. Anal. Calc. for
C19H22ClNPd: C, 56.16; H, 5.42; N, 3.45. Found: C,
1
55.99; H, 5.39; N, 3.37%. H-NMR (CDCl3ꢂ
/
Py-d5): Z
3.0, Hoꢀ
7.8, Ar);
4.50 (1H, br t, CH); 3.83 and 3.63 (2H, 2 br s, allylic H);
isomer (characteristic signals) 8.53 (1H, d, 3Jꢁ
/
/
3
cycle as
a
chloride salt was recrystallized from
diethyl ether.
Py); 7.32ꢀ
/
7.24 (4H, m, Ar); 6.94 (1H, d, Jꢁ
/
chloroformꢀ
/
4c(Cl): 32% yield. Anal. Calc. for C18H16ClN×
/
2H2O:
E isomer (characteristic signals) 7.18ꢀ
/
7.08 (4H, m, Ar);
7.9, Ar); 3.96 (1H, br t, CH); 3.44 and
3
C, 68.02; H, 5.07; N, 4.40. Found: C, 67.49; H, 5.33; N,
7.00 (1H, d, Jꢁ
/
1
3
4.10%. H-NMR (CD3OD): 9.76 (1H, d, Jꢁ
Py); 9.22 (1H, dd, 3Jꢁ8.1, 4Jꢁ
0.9, Ar); 8.33ꢀ8.18 (5H,
m, Ar); 8.10 (1H, t, 3Jꢁ
7.9, Ar); 6.08 and 6.08 (2H, 2s,
CH2); 2.06 (6H, s, 2 CH3). 13C-NMR (CD3OD): 141.6;
/
6.3, Hoꢀ
/
3.06 (2H, 2 br s, allylic H).
/
/
/
7b: obtained from 1 as a beige solid with a 78% yield.
Anal. Calc. for C16H17ClN2Pd: C, 51.66; H, 4.86; N,
7.16. Found: C, 51.71; H, 4.89; N, 6.72%. 1H-NMR
/
Ä
/
135.8; 134.0; 131.4; 129.6; 118.3 (Cquat.); 145.6; 141.3;
132.5; 130.9; 129.0; 125.2; 124.8; 123.9 (CHaromatic);
(CDCl3ꢂ
HoꢀPy); 7.63ꢀ
Ar); 7.09 (1H, br t, Ar); 6.83ꢀ
3.62 (2H, 2 broad s, allylic H); 1.40 and 1.21 (6H, 2 br s,
C(CH3)2).
/
Py-d5): 8.15 (1H, br s, NH); 7.91 (1H, br s,
3
/
/
7.40 (2H, m, Ar); 7.31 (1H, d, Jꢁ
/6.4,
117.3 (Ä
1626 (CÄ
5c(Cl): 50% yield. Anal. Calc. for C16H16ClNꢂ
C, 69.68; H, 6.58; N, 5.08. Found: C, 69.15; H, 6.15; N,
/CH2); 70.6 (NC); 26.3 (CH3). IR (KBr pellet):
/6.62 (2H, m, Ar); 3.66 and
/
C).
/H2O:
1
3
4.6. Depalladation reaction of the (h3-allyl) Pd
complexes, synthesis of the heterocyclic compounds:
7c(PF6), 6e(Cl), 6f(PF6), 6g(PF6) and 7c(PF6)
4.89%. H-NMR (CDCl3): 10.40 (1H, d, Jꢁ
/
6.5, Hoꢀ
8.49 (3H, 2m, Ar); 8.07 (1H, d, Jꢁ7.3, Ar);
CH2);
/
3
Py); 8.53ꢀ
/
/
7.73ꢀ
/
7.65 (3H, m, Ar), 5.82 and 5.81 (2H, 2s, Ä
/
2.07 (6H, s, 2 CH3). 13C-NMR (D2O): 151.0; 143.8;
136.5; 127.0 (Cquat.); 147.6; 142.3; 136.7; 132.7; 128.9;
(a) Under an argon atmosphere, triphenylphosphane
(0.63 g, 2.4 mmol) was added to a solution of 7b (0.26 g,
0.34 mmol) in 25 ml of methanol. After stirring for 10
128.7; 128.0 (CHaromatic); 119.4 (Ä
/
CH2); 71.4 (NC); 28.1
(CH3). IR (KBr pellet): 1619 (CÄ
/C).

J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ
/321
319
min, the fine yellow precipitate formed was removed by
a filtration over Celite. The orange yellow filtrate was
evaporated to dryness. The residue was extracted with 5
ml of dichloromethane. Precipitation using hexane
afforded derivative 7c as a pale yellow solid. The PF6
salt was obtained by reacting a water solution of 7c with
KPF6.
5.84 (2H, s, NCH2); 5.02 (2H, s, CH2); 3.90 (3H, s,
OCH3).
4.6.4. 5-Hexylidene-dibenzo(a,d)azepizinium 6g(PF6)
Yield 26%; 8:1 mixture of E and Z isomers as
1
measured by H-NMR. H-NMR (acetone-d6): Z iso-
1
mer (characteristic signals): 6.31 (1H, br t, CH); 5.88
(2H, br s, NCH2); 2.41ꢀ
/
2.24 (2H, m, a CH2); 0.79 (3H,
4.6.1. 2-H-3-Isopropylidene-1-(2-pyridyl)indolinium
7c(PF6)
Yield 63%. Anal. Calc. for C16H17F6N2P: C, 50.26; H,
t, d CH3); E isomer (characteristic signals): 9.25 (1H, d,
3Jꢁ
8.32 (1H, d, Jꢁ
1.4, Ar); 6.37 (1H, t, 4Jꢁ
NCH2); 4.94 (2H, br s, CH2); 2.60ꢀ
/
6.1, Hoꢀ
/
Py); 8.64 (1H, td, Jꢁ
/
7.9, Jꢁ1.4, Ar);
/
3
4
3
3
4
/
7.9, Ar); 8.12 (1H, td, Jꢁ
7.4, CH); 6.08 (2H, br s,
2.53 (2H, m,
/
6.6, Jꢁ
/
1
4.45; N, 7.33. Found: C, 50.36; H, 4.55; N, 7.26%. H-
/
NMR (acetone-d6): 10.23 (1H, br s, NH); 8.50 (1H, d,
/
3
3Jꢁ
3Jꢁ
6.8, 4Jꢁ
/
6.5, Hoꢀ
/
Py); 8.15ꢀ
/
8.10 (1H, m, Ar); 7.56 (1H, d,
3
a?CH2); 0.97 (3H, t, Jꢁ7.2, d CH3).
/
/
8.9, Ar); 7.37ꢀ
/
7.35 (3H, m, Ar); 7.28 (1H, td, Jꢁ
/
/
1.2, Ar); 7.24ꢀ
/7.18 (1H, m, Ar); 5.39 (2H, br s,
4.7. bis[(2-Dimethylaminomethyl-3,4-
dimethoxy)phenyl(kN, kC1)]di(m-iodo)dipalladium 8b
NCH2); 2.14 and 1.99 (6H, 2s, C(CH3)2). 13C-NMR
(acetone-d6): 151.1; 143.1; 141.2; 141.0; 137.0; 132.0;
130.6; 128.7; 126.4; 124.0; 120.9; 119.2; 116.5 (Arꢂ
olefinic); 60.4 (NCH2); 22.5 and 20.5 (C(CH3)2).
/
This compound was obtained by metathesis, per-
formed on the chloro analog [33] in acetone and
presence of excess of sodium iodide (i.e. four equivalents
of NaI per Pd atom). Anal. Calc. for C22H32I2N2O4Pd2:
C, 30.90; H, 3.77; N, 3.28. Found: C, 30.10; H, 3.62; N,
4.6.2. 5-Isopropylidene-dibenzo(a,d)azepizinium 6e(Cl)
Yield 53%. Anal. Calc. for C17H18ClNꢂ
/
1/10 CH2Cl2:
C, 72.80; H, 6.40; N, 4.90. Found: C, 73.14; H, 6.17; N,
3.04%. 1H-NMR (CDCl3ꢂ
/
Py-d5): 6.42 (1H, d, 3Jꢁ
/8.3,
1
3
4.92%. H-NMR (CDCl3): 10.18 (1H, d, Jꢁ
Py); 8.30 (1H, t, 3Jꢁ7.6, Ar); 7.94 (1H, d, 3Jꢁ
6.6, Ar); 7.30ꢀ7.18 (4H, m, Ar); 6.14
/
5.7, Hoꢀ
/
H6); 5.38 (1H, d, 3Jꢁ
and 3.75 (6H, 2s, OCH3); 3.10 (6H, s, NCH3).
/8.3, H5); 4.11 (2H, s, NCH2); 3.79
/
/7.4, Ar);
3
7.88 (1H, t, Jꢁ
/
/
(2H, s, NCH2); 4.55 (2H, s, CH2); 2.13 and 1.82 (6H, 2s,
C(CH3)2). 13C-NMR (CD2Cl2): 157.5; 147.3; 146.4;
4.7.1. Ethyl 3,4-methylendioxyphenylpropiolate 9b
1,1-Dibromo-2-(3,4-methylendioxyphenyl)ethane (4.5
g, 14.7 mmol), prepared with a 88% yield according to
Corey [34], was treated with 3.5 equivalents of methyl-
138.5; 137.0; 133.5; 131.5; 129.0ꢀ
(Arꢂolefinic); 62.6 (NCH2); 40.5 (CH2); 23.4 and 21.1
(C(CH3)2). MS (EI) Calc. for C17H18N: m/zꢁ236.
Found: [Mꢂ] 236.
/
128.3; 126.9; 124.5;
/
/
lithium in THF at ꢃ
returned to RT, became red. This latter was cooled to
78 8C and 2.2 equivalents of ethyl chloroformate
/
78 8C. The yellow solution, when
(b) 6f(PF6) was obtained from compound 6c. The
reaction and primary separation were performed as for
7c. An oily residue was obtained which was extracted in
water. The cationic heterocycle was precipitated by
addition of one equivalent of potassium hexafluoropho-
sphate. After a filtration, the white solid was extracted
with 2 ml of acetone. The solvent was evaporated to
dryness. The pale yellow residue left was then washed
with ether and dried in vacuo.
ꢃ
/
added to it. The following day, the solution was
quenched at 0 8C by addition of aqueous sodium
bicarbonate. After diethyl ether extraction, the crude
product was chromatographied over SiO2 (eluent Hexꢀ
Et2O 20%) to give 1.6 g substance 9b (yield 50%).
M.p. (Hex): 86; lit. 83.5ꢀ84.4 [35,36]; Anal. Calc. for
C12H10O4: C, 66.05; H, 4.62. Found: C, 65.95; H, 4.56%.
1H-NMR (CDCl3): 7.18 (1H, dd, 3Jꢁ8.0, 4Jꢁ
1.6, H5);
7.03 (1H, d, 4Jꢁ1.6, H2); 6.82 (1H, d, 3Jꢁ
7.7, H6); 5.04
(2H, s, OCH2O); 4.31 (2H, q, 3Jꢁ
7.1, OCH2); 1.37 (3H,
t, 3Jꢁ7.1, CH3). 13C-NMR (CDCl3): 154.2 (CO); 150.0
/
/
/
/
/
/
4.6.3. 5-Methoxyethylidene-dibenzo(a,d)azepizinium
6f(PF6)
Yield 42%; 3:1 mixture of E and Z isomers as
/
/
and 147.6 (C1, C3, C4); 128.8; 112.5 and 108.7 (C2, C5,
C6); 101.8 (OCH2O); 86.5 and 79.7 (C1’, C2’); 62.0
(OCH2) and 14.1 (CH3).
1
measured by H-NMR. Anal. Calc. for C16H16F6NOP:
C, 50.13; H, 4.18; N, 3.66. Found: C, 50.26; H, 4.01; N,
1
3.52%. H-NMR (acetone-d6): Z isomer (characteristic
signals) 9.17 (1H, d, 3Jꢁ
8.8, Ar); 7.12 (1H, s, CHOCH3); 5.96 (2H, s, NCH2);
/
6.2, Hoꢀ
/
Py); 7.53 (1H, d, 3Jꢁ
/
4.7.2. 7,8-dimethoxy-4-ethoxycarbonyl-3-(3,4-
methylendioxyphenyl) isoquinoline 11b
4.96 (2H, s, CH2); 3.96 (3H, s, OCH3); E isomer
3
Compound 8b (500 mg, 0.58 mmol) was dissolved in
50 ml of dichloromethane. Propiolate 9b (250 mg, 1.15
mmol) in 150 ml of CH2Cl2 was added dropwise to the
previous solution under vigorous stirring. Stirring was
continued until next day and the solvent evaporated.
(characteristic signals): 9.25 (1H, d, Jꢁ
/
6.1, Hoꢀ
/
Py);
7.7, Ar); 8.23
8.66 (1H, t, 3Jꢁ
/
7.8, Ar); 8.31 (1H, d, 3Jꢁ
/
3
4
3
(1H, dd, Jꢁ
/
7.9, Jꢁ
/
1.4, Ar); 8.16 (1H, t, Jꢁ
/
7.4,
3
Ar); 7.40 (1H, d, Jꢁ
/6.3, Ar); 7.06 (1H, s, CHOCH3);

320
J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ321
/
Chlorobenzene (50 ml) and five drops of pyridine were
then added and the mixture refluxed for 4 h. After
evaporation of the volatiles, the crude product was first
(CDCl3): 9.26 (1H, s, Hoꢀ
Ar); 8.12 (1H, d, 3Jꢁ8.0, Ar); 7.80 (1H, t, 3Jꢁ
7.5, Ar); 7.55ꢀ7.35 (3H, m, Ar); 4.16
7.1, OCH2); 3.74 and 3.40 (2H, 2s, allylic
CH2); 1.21 (3H, t, 3Jꢁ
7.1, CH3); 1.08 and 1.02 (6H, 2s,
C(CH3)2).
/
Py); 8.23 (1H, d, 3Jꢁ
7.6, Ar);
/
7.3,
/
/
3
7.68 (1H, t, Jꢁ
/
/
3
filtered over SiO2 with a CH2Cl2ꢀ
then flash chromatographed over Al2O3 with a CH2Cl2ꢀ
MeOH 0.5ꢀ5%) gradient to yield 88 mg (20%) of the
isoquinoline derivative 11b.
M.p. (AcOEtꢀHex): 195; Anal; Calc. for C21H19NO6:
/
MeOH 5ꢀ/10% eluent,
(2H, q, Jꢁ
/
/
/
/
/
4.7.5. 6-Ethoxycarbonyl-3-isopropylidene-
C, 66.14; H, 5.02; N, 3.67. Found: C, 65.10; H, 4.75; N,
1
3.51%. H-NMR (CDCl3, 300 MHz): 9.52 (1H, s, H1);
dibenzo(d,h)quinolizinium hexafluorophosphate 13b
The allylpalladium compound 12c (0.21g, 0.22 mmol)
in 15 ml of PhCl was heated at 80 8C for 16 h, this
leading to the formation of palladium black. After
filtration over Celite and evaporation of the solvent,
an orange residue of 13a was obtained. Treatment with
one equivalent in MeOH led to a beige solid (13b: 0.19g,
87% yield).
3
3
7.31 (1H, d, Jꢁ
/
8.3, H6); 6.92 (1H, d, Jꢁ8.3, H5’);
/
3
4
4
6.86 (1H, dd, Jꢁ
/
6.1, Jꢁ
/
1.7, H6’); 6.85 (1H, d, Jꢁ
8.1, H5); 6.08 (2H, s,
7.1, OCH2); 3.93 and 3.78
7.1, CH3).
/
1.7, H2’); 6.53 (1H, d, 3Jꢁ
/
3
OCH2O); 4.15 (2H, q, Jꢁ
/
(6H, 2s, OCH3); 2.00 (H2O); 1.07 (3H, t, 3Jꢁ
/
13C-NMR (CDCl3, 50 MHz): 169.3 (CO); 166.0 (C3);
151.4, 149.2, 148.1, 136.3, 128.1, 126.2, 124.9, 121.2 (C4,
C7, C8, C10, C1’, C3’, C4’); 146.9, 124.2, 119.5, 110.2,
108.7, 100.4 (C1, C5, C6, C2’, C5’, C6’); 101.9 (OCH2O);
61.7 (OCH2); 56.0 and 44.2 (OCH3); 13.9 (CH3). MS
1H-NMR (CD3OD): 10.09 (1H, s, Hoꢀ
Py); 8.50 (1H,
/
3
d, Jꢁ
m, Ar); 7.90 (1H, d, Jꢁ
Ar); 7.57ꢀ
(2H, q, 3Jꢁ
C(CH3)2); 1.27 (3H, t, Jꢁ
for C23H22NO2: m/zꢁ
344. Found: [Mꢂ] 344; [Mꢂ ꢃ
1]; [Mꢂ ꢃ
2].
/
8.4, Ar); 8.32ꢀ
/
8.23 (2H, m, Ar); 8.11ꢀ
/
8.05 (1H,
3
/
7.7, Ar); 7.73ꢀ/7.66 (2H, m,
/7.52 (1H, m, Ar); 5.48 (2H, br s, NCH2); 4.52
(EI) Calc. for C21H19NO6: m/zꢁ
/
381.4. Found: [Mꢂ]
/7.1, OCH2); 2.15 and 2.14 (6H, 2s,
381.2; [Mꢂ ꢃ29]; [Mꢂ ꢃ
/
/71].
3
/7.1, CH3). MS (EI) Calc.
/
/
4.7.3. Cyclopalladated phenylisoquinoline 12a
/
To a solution of 3-phenylisoquinoline 11a prepared
by published procedure [30] (1.2 g, 4.5 mmol) in 40 ml of
acetic acid, was added one equivalent of palladium
acetate (1.02 g). The mixture was stirred for 1 day at r.t.
leading to an orange solution and a greenish solid. The
solid was filtered and washed with water, methanol and
ether. After drying, the solid was obtained as a yellow
powder (1.95 g, 97% yield).
4.8. Kinetic study of the reaction of 1 with the palladium
complex 5a
The cyclopalladated complex 5a (119 mg, 0.2 mmol)
was dissolved in 15 ml of dichloromethane. At time tꢁ
/
0, 2.5 equivalents of propadiene 1 (34 mg, 0.5 mmol)
were added. The yellow solution turned immediatly
black. The kinetics was followed by sampling at regular
1H-NMR (CDCl3ꢂ
/
Py-d5): 9.37 (1H, s, Hoꢀ
/
Py); 7;99
7.61
1.1, Ar); 7.05
3
(1H, d, Jꢁ
/
8.2, Ar); 7.83ꢀ7.78 (2H, m, Ar); 7.67ꢀ
(1H, m, Ar); 7.35 (1H, dd, Jꢁ
/
/
time until 360 min. A last sample was made at tꢁ1140
/
3
4
/
7.9, Jꢁ
/
min. The samples of 1 ml were obtained under a
nitrogen flux with a syringe. They were then filtered
over a celite pad in test tubes. Then the samples were
evaporated under vacuum and stored in the freezer. To
3
4
3
4
(1H, Jꢁ
1.2, Ar); 6.27 (1H, d, 3Jꢁ
OCH2); 2.02 (3H, s, OAc); 1.43 (3H, t, Jꢁ
/
7.6, Jꢁ
/
1.1, Ar); 6.89 (1H, td, Jꢁ
/
7.5, Jꢁ
/
/
7.7, Ar); 4.60 (2H, q, 3Jꢁ
/7.1,
3
/
7.1, CH3).
1
A mixture of 12a (0.73g, 0.83 mmol) and four
equivalents of lithium chloride (0.14 g) in 30 ml of
acetone was stirred at r.t. overnight, yielding a red
solution and a yellow precipitate. After filtration,
washing with diethylether and drying, a fine beige solid
was obtained (12b: 0.68 g, 98% yield).
be analysed by H-NMR, the samples were dissolved in
0.4 ml of CDCl3 just before recording the different
spectra.
1H-NMR: h3-allyl complex 5b: 8.65 (1H, br s, Hoꢀ
/
Py); 8.13 (2H, br d, Ar); 7.35 (1H, br d, Ar); 7.25ꢀ7.00
/
(4H, m, Ar); 3.91 and 3.66 (2H, 2 br s, H allylic); 1.04
and 0.73 (6H, 2 br s, C(CH3)2).
4.7.4. h3-Allylpalladium complexe 12c
5d (opposite regioisomer of 5c): 10.45 (1H, d, 3Jꢁ
/
6.1,
7.8,
H0ꢀ
/
Py); 8.43 (1H, t, 3Jꢁ
/
7.3, Ar); 8.29 (1H, d, 3Jꢁ
7.5, Ar); 7.65ꢀ
/
A solution of propadiene 1 (0.14 g, 2.1 mmol) in 2 ml
of CH2Cl2 was added at r.t. to a suspension of the
cyclopalladate compound 12b (0.68 g, 0.82 mmol) in 20
ml CH2Cl2. After 15 min, a yellow solution was
obtained. It was stirred during 2 h. After filtration
over Celite and concentration of the filtrate, a yellow
solid was obtained by addition of hexane (12c: 0.73g,
92% yield).
3
Ar); 7.95 (1H, d, Jꢁ
/
/7.45 (3H, m, Ar);
5.78 (2H, s, NCH2); 2.26 and 2.04 (6H, 2s, C(CH3)2).
[5b]ꢁA; [5c]ꢁB; [5d]ꢁC:
Ln A and 1=A were quoted versustime:
The second curve was straight with a slope k1ꢁ
/
1809
/
10 mMꢃ1 sꢃ1 and a correlation coefficient 0.998: the
kinetic is second-order. The products ratio B/C was
Anal. Calc. for C23H22ClNO2Pd: C, 56.79; H, 4.53; N
2.88. Found: C, 56.70; H, 4.43; N 2.76%.1H-NMR
constant (3.090.1) with time: 5c and 5c? are formed
/

J. Chengebroyen et al. / Journal of Organometallic Chemistry 687 (2003) 313ꢀ
/321
321
[14] S. Hoff, L. Brandsma, J.F. Arens, Rec. Trav. Chim. Pays-Bas 87
(1968) 91624.
with parallel rates (rate constants k2 and k3, respec-
tively). In consequence the expression of the different
[15] D.J. Pasto, S.H. Chou, A. Waterhouse, R.H. Shults, G.F.
Hennion, J. Org. Chem. 43 (1978) 1385.
rates are the following: ꢃ
k2A2; 1/2 dC/dtꢁk3A2; leading to the integrate forms:
AꢁA0/(1ꢂk1A0t);
Cꢁ(2A0k3/k1)[1ꢃ
sꢃ1; k3ꢁ 2 mMꢃ1 sꢃ1
229
/
dA/dtꢁ
/
k1A2; 1/2 dB/dtꢁ
/
/
[16] G.E. Hartwell, R.V. Lawrence, M.J. Smas, J. Chem. Soc. Chem.
Commun. (1970) 912.
/
/
Bꢁ
/
(2A0k2/k1)[1ꢃ
/
1/(1ꢂ
/
k1A0t)];
/
/
1/(1ꢂk1A0t)]; k2ꢁ
/
/
689
/6
mMꢃ1
[17] A. Kasahara, Bull. Chem. Soc. Jpn 41 (1968) 1272.
[18] K. Hiraki, Y. Fuchita, K. Takechi, Inorg. Chem. 20 (1981) 4316.
[19] F. Maassarani, M. Pfeffer, J. Spencer, E. Wehman, J. Organomet.
Chem. 466 (1994) 265.
/
/
.
[20] (a) A.D. Ryabov, L.G. Kuz’mina, V.A. Polyakov, G.M. Kazan-
kov, E.S. Ryabova, M. Pfeffer, R. van Eldik, J. Chem. Soc.
Dalton Trans. (1995) 999.;
Acknowledgements
(b) A.D. Ryabov, I.K. Sakodinskaya, A.K. Yatsimirsky, J. Chem.
Soc. Perkin Trans. (1983) 1511.;
We thank the ministe`re de l’enseignement supe´rieur et
de la recherche (fellowships to M.R. & J.C.) and the
CNRS for support of this work.
(c) A.D. Ryabov, R. van Eldik, G. Le Borgne, M. Pfeffer,
Organometallics 12 (1993) 1386.
[21] S.W. Pelletier, Chemistry of the Alkaloids, van Nostrand Rein-
hold Company (Ed.), New York, 1970.
[22] N. Ivanovska, S. Philipov, Int. J. Immunopharmacol. 18 (1997)
553.
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