Unexpected isolation, and structural characterization, of a β-hydrogen-containing σ-alkylpalladium halide complex in the course of anintramolecular Heck reaction. Synthesis of polycyclic isoquinoline derivatives

Article abstract of DOI:10.1039/b211856b

The isolation of a stable β-hydrogen-containing R-PdL_n-X complex (R = alkyl; X = halide) issued from a Heck reaction is reported together with some aspects of its reactivity.

Full text of DOI:10.1039/b211856b

Unexpected isolation, and structural characterization, of a
b-hydrogen-containing s-alkylpalladium halide complex in the course of
an intramolecular Heck reaction. Synthesis of polycyclic isoquinoline
derivatives†
Blandine Clique, Charles-Henry Fabritius, Cédric Couturier, Nuno Monteiro* and Geneviève Balme*
Laboratoire de Chimie Organique 1, CNRS UMR 5622, Université Claude Bernard, Lyon I, CPE. 43, Bd du
11 Novembre 1918, 69622 Villeurbanne, France. E-mail: balme@univ-lyon1.fr
Received (in Cambridge, UK) 28th November 2002, Accepted 6th December 2002
First published as an Advance Article on the web 19th December 2002
The isolation of a stable b-hydrogen-containing R-PdLn-X
complex (R = alkyl; X = halide) issued from a Heck
reaction is reported together with some aspects of its
reactivity.
methylene malonate (1b) which, in case of success, would open
access to interesting steroid-like polycycles. When subjected to
identical reaction conditions, 1b proved less reactive than its
homologue 1a thus allowing for unidentified side reactions to
take place. Clean conversion was nevertheless achieved in 81%
yield by simply increasing the quantities of both base (20 mol%)
and copper complex (15 mol%). With pyrrolidines 3a,b in hand,
we then turned our attention to the Pd-catalyzed annelation
reaction. After examining several catalyst systems we found
that PdCl2(PPh3)2 (20 mol%), in the presence of an excess of
PPh3 (120 mol%), effectively induced the cyclization of 3a to
furnish the targeted pyrrolo[2,1,c]pyrrolidine 4a in 81%
isolated yield. However, when applying the same conditions to
3b, we observed that most starting material remained unreacted
even after prolonged reaction times. After workup and chroma-
tography on silica gel, we were nevertheless able to isolate small
quantities of a new compound. Early NMR (1H, 13C, HMBC,
and COSY) experiments indicated that a tetracyclic fragment
had been obtained. However, to our surprise, it soon appeared
that we had in fact intercepted the palladium-containing
intermediate 5 (Scheme 1).
Transition metal-catalyzed carbocyclizations of unsaturated
compounds constitute powerful tools to build up complex
polycyclic structures in a minimum number of steps.1 Intra-
molecular versions of the Pd-catalyzed arylation of alkenes are
among the highest performing transformations available in this
field as they may be involved in cascade processes or be
integrated in sequential reactions.2 In recent papers we have
demonstrated the synthetic utility of a new Pd-(or Cu)-promoted
anionic [3 + 2] cycloaddition reaction involving propargylic
amines and electron-deficient olefins, which gives direct access
to five-membered heterocycles containing useful functionalities
for further synthetic transformations.3 By building on our
expertise in this area, we recently explored the feasibility of
combining this type of cycloaddition with a subsequent
intramolecular Heck reaction as it should enable the develop-
ment of versatile routes toward polycyclic isoquinoline deriva-
tives and particularly the pyrrolo[2,1,a]isoquinolines (4). These
structures are of interest as components of plant alkaloids4 and
biologically active compounds.5 The strategy relies on the
assembly of a N-propargyl allylic amine 2 and a arylidene
malonate 1 via one carbon–nitrogen and two carbon–carbon
linkages (Fig. 1).
We report herein our preliminary results toward this goal
which will emphasize the unexpected and unprecedented
isolation and characterization of a stable amine-stabilized s-
alkylpalladium halide bearing b-hydrogens in the course of a
Heck reaction .
For preliminary studies, we chose dimethyl 2-iodobenzyli-
dene malonate (1a), which is readily available by Knoevenagel
condensation, as a substrate, and carried out the Cu-catalyzed
cycloaddition reaction with N-allylpropargylamine (2a) under
the conditions previously reported (10 mol% n-BuLi, 3 mol%
CuI(PPh3)3, THF, rt).3 The desired 4-exo-methylene pyrrolidine
3a was indeed obtained in good yield (79%). In parallel, we also
examined the reaction of dimethyl 1-iodonaphthalen-2-yl-
Indeed, 1H NMR showed the presence of 15 hydrogen atoms
around d 7.0 ppm which suggested that one molecule of PPh3
had been incorporated into the product. This was confirmed by
31P{1H}NMR analysis which showed one singlet at d 39.3 ppm.
13C{1H}NMR showed a doublet at d 50.6 ppm (JC,P 2 Hz)
which was in agreement with the expected value for a carbon
linked to the metal in sp3-hybridized alkylpalladium com-
plexes.6,7 Further evidence was provided by low resolution
mass spectrometry (positive ion) which gave M+ = 732.3
corresponding to the cationic phosphine-coordinated species
[(C22H22NO4)Pd(PPh3)]+ and exhibiting isotopic patterns indic-
ative of the presence of the metal. We then repeated the reaction
in the presence of 100 mol% PdCl2(PPh3)2 and were pleased to
obtain after 3 h palladium complex 5 in 62% isolated yield.
Remarkably, despite the presence of a hydrogen atom b to the
metal, the complex showed unexpected stability towards
thermal decomposition (205–210 °C), and proved stable to air
and moisture, withstanding shelf storage without noticeable
decomposition. While a few stable alkyl-PdLn-X complexes (X
= halide) which could suffer b-H-elimination have been
isolated in the course of Wacker-type reactions,6,8 to the best of
our knowledge, such an event is unprecedented in the field of
Heck reactions.9 Fortunately, the alleged molecular structure of
5 was unambiguously confirmed by X-ray diffraction analysis.
Fig. 1
†
Electronic supplementary information (ESI) available: Experimental
information for compounds 1–7. Crystal data for 5. Fig. SI 1 (possible
conformations for the Heck insertion step). See http://www.rsc.org/
suppdata/cc/b2/b211856b
Scheme 1 Reagents and conditions: (i) 20 mol% PdCl2(PPh3)2; 120 mol%
PPh3; K2CO3, DMF, 90 °C, 20 h.
272
CHEM. COMMUN., 2003, 272–273
This journal is © The Royal Society of Chemistry 2003

analysis, Dr D. Bouchu for mass spectrometric analyses, and Dr
C. Copéret for his interest in this work.
Notes and references
1 L. F. Tietze, Chem. Rev., 1996, 96, 115; L. F. Tietze and F. Haunert, in:
Stimulating Concepts in Chemistry, eds. M. Shibasaki, J. F. Stoddart and
F. Vögtle, Wiley-VCH, Weinheim, 2000, pp. 39–64.
2 S. Bräse and A. de Meijere, in: Metal-catalyzed Cross-coupling
Reactions, eds. F. Diederich, P. J. Stang, Wiley-VCH, Weinheim, 1998,
pp. 99–166; I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000,
100, 3009.
3 N. Clique, S. Vassiliou, N. Monteiro and G. Balme, Eur. J. Org. Chem.,
2002, 1493; N. Monteiro and G. Balme, J. Org. Chem., 2000, 65,
3223.
Fig. 2 ORTEP view of complex 5. Hydrogen atoms are omitted for clarity.
Selected bond lengths (Å): Pd–C(110) 2.061, Pd–N 2.187, Pd–P 2.236, Pd–I
2.721.
4 V. Boekelheide, Alkaloids, 1960, 7, 201; R. K. Hill, Alkaloids, 1967, 9,
483; K. W. Bentley, Nat. Prod. Rep., 2001, 18, 148 and previous annual
reports.
An ORTEP representation of the structure is shown in Fig.
2.10
5 B. E. Maryanoff, J. L. Vaught, R. P. Shank, D. F. McComsey, M. J.
Costanzo and S. O. Nortey, J. Med. Chem., 1990, 33, 2793; Y. S. Lee,
D. W. Kang, S. J. Lee and H. Park, J. Org. Chem., 1995, 60, 7149; S. M.
Allin, S. L. James, W. P. Martin, T. A. D. Smith and M. R. J. Elsegood,
J. Chem. Soc., Perkin Trans. 1, 2001, 3029.
The structure shows a phosphine-coordinated s-alkyl palla-
dium iodo complex stabilized through chelation by the nitrogen
atom contained in the carbon ligand backbone. The clear
interaction between the metal and the nitrogen atom is reflected
in the palladium–nitrogen distance of 2.187 Å which can be
regarded as a dative bonding. The metal is thus conformation-
ally locked in a five-membered metallacycle and cannot easily
adopt the cisoid conformation needed toward the b-hydrogen
which may account for the stability of the complex. However, at
this time, the question why switching from the phenyl to the
naphthyl nucleus influenced the stability of the intermediates so
dramatically remains unanswered. Other factors of steric and/or
stereoelectronic nature must be providing further stabilization
to the naphthyl-containing alkylpalladium complex 5. In-
vestigations in this direction are currently underway.8
Inhibition of competitive b-hydride eliminations of alkyl-Pd-
X intermediates remains a great challenge in the development of
palladium-catalyzed coupling processes. Recent successes in
this area have mentioned a beneficial stabilization of the
intermediate complexes through coordination of the metal with
an adjacent heteroatom.11 The availability of complex 5
therefore offers a remarkable opportunity to investigate its
reactivity against carbon-carbon bond forming reactions that
would elaborate this intermediate further and preserve the new
stereogenic center. To this end, preliminary experiments have
been directed toward the synthesis of carbonylated compounds.
Gratifyingly, 5 inserted carbon monoxide efficiently. Carbony-
lative esterification yielded isoquinoline ester 612 in 68%
isolated yield. Surprisingly, however, reaction of 5 with an
excess of acetyl chloride furnished the hydrogenolyzed com-
pound 712 in almost quantitative yield in place of the expected
acetylated compound.13,14 Under identical conditions benzoyl
chloride did not produce any carbonylated compound either
(Scheme 2).
6 R. A. Holton and J. R. Zoeller, J. Am. Chem. Soc., 1985, 107, 2124.
1
7 The presence of single sets of signals in the crude H and 13C NMR
spectra indicated that the palladium-containing compound was obtained
as a single diastereomer. The stereochemistry of the newly created
stereogenic center as depicted in Scheme 1 could be predicted by the
reported preference for intramolecular Heck insertions to occur via
eclipsed orientations of the metal–carbon s and the alkene p bond (Fig.
SI 1†). See M. M. Abelman, L. E. Overman and V. D. Tran, J. Am.
Chem. Soc., 1990, 112, 6959.
8 For interesting discussions on the factors governing the thermal stability
of alkylpalladium complexes bearing b-hydrogens see: L. Zhang and K.
Zetterberg, Organometallics, 1991, 10, 3806 and references therein.
9 Another stable b-hydrogen-containing s-alkylpalladium complex is-
sued from an intramolecular Heck reaction has been reported recently:
M. Oestreich, P. R. Dennison, J. J. Kodanko and L. E. Overman, Angew.
Chem., Int. Ed., 2001, 40, 1439. This complex of a different nature
resulted of the intramolecular trapping of an intermediate cationic
species [alkyl-PdLn]+OTf2 by an internal nitrogen atom to form a stable
alkyl-PdLn-N palladacycle. It should be noted that in our case triflate
derivatives (i.e. 3a with X = OTf) proved essentially unreactive.
10 The crystal data have been deposited in the Cambridge Crystallographic
Data Center as CCDC 1267/701 (see http://www.rsc.org/suppdata/cc/
b2/b211856b/ for crystallographic files in CIF or other electronic
format). C. Bavoux, C.-H. Fabritius, B. Clique, N. Monteiro and G.
Balme, Z. Kristallogr., 2001, 216, 633–634.
11 For recent reports: C. Copéret and E.-I. Negishi, Org. Lett., 1999, 1, 165;
C.-W. Lee, K. S. Oh, K. S. Kim and K. H. Ahn, Org. Lett., 2000, 2, 1213.
See also V. K. Aggarwal, P. W. Davies and W. O. Moss, Chem.
Commun., 2002, 972.
12 Compounds 6 and 7 have both been obtained as approximatively 1.5+1
mixtures of isomers as indicated by their 1H and 13C NMR spectra. We
believe that these are conformational isomers having restricted
pyramidal nitrogen inversion and further experiments will be carried out
to confirm this hypothesis.
13 R. A. Holton and K. J. Natalie Jr., Tetrahedron Lett., 1981, 22, 267.
14 We may suggest that the putative acyl palladium complex 8 undergoes
b-hydrogen elimination of the acyl ligand with elimination of ketene
faster than reductive elimination of the ketone. The resulting palladium
hydride 9 would then undergo reductive elimination to give 7.
Scheme 2
Other coupling reactions involving unsaturated reagents (i.e.
Suzuki, Stille couplings) are also currently being investigated.
The ultimate goal would be to devise catalytic pathways
combining the carbocyclization process with a suitable termi-
nating coupling reaction. The results of these studies will be
reported in due course.
A similar hypothesis has been considered in reactions of acyl chlorides
with ruthenium complexes leading to stable metal hydrides. S. I.
Hommeltoft and M. C. Baird, J. Am. Chem. Soc., 1985, 107, 2548.
Further work will be needed so as to understand this behavior more
fully.
We acknowledge the financial assistance by the E.U. TMR
program. We thank Dr C. Bavoux for the X-ray crystallographic
CHEM. COMMUN., 2003, 272–273
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