Directed palladium-catalyzed cascade cyclization as an approach to trans- and cis-hexahydro-1H-benz[f]indenes

Article abstract of DOI:10.1055/s-1998-1828

The hydrogenation of the acetylenic substrate 6 followed by a palladium-catalyzed cascade bis-cyclization process led to a trans-hexahydro-1H-benz[f]indene. By changing the order of the two preceding steps, only the cis-hexahydro-1H-benz[f]indene structur

Full text of DOI:10.1055/s-1998-1828

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Directed Palladium-Catalyzed Cascade Cyclization as an Approach to trans- and cis-
Hexahydro-1H-benz[f]indenes
Isabelle Coudanne and Geneviève Balme*
Laboratoire de chimie organique I, associé au CNRS, Université Claude Bernard, CPE, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
Fax: Int.33.4.72.43.12.14. E-mail: balme@univ-lyon1.fr
Received 5 May 1998
Abstract: The hydrogenation of the acetylenic substrate 6 followed by a
palladium-catalyzed cascade bis-cyclization process led to a trans-
hexahydro-1H-benz[f]indene. By changing the order of the two
preceding steps, only the cis-hexahydro-1H-benz[f]indene structure was
obtained.
Scheme 3
Over the last decade, cascade palladium-catalyzed cyclizations have
emerged as an efficient new synthetic route for the single-step
elaboration of complex polycyclic systems with high levels of regio- and
stereocontrol.1 Current efforts in our group are focusing on the synthetic
potential of a new palladium-mediated cyclization of unsaturated
substrates bearing a nucleophilic substituent (Scheme 1).2
state C could be envisaged. However, we assumed that the transition
state B is the less favorable since the benzylic substituent occupies a
pseudo-axial orientation.
This reaction proceeds in a completely stereoselective trans manner
since it involves an attack by the carbon nucleophile onto the
unsaturation electrophilically activated by the σ-aryl- or the σ-vinyl-
palladium species. Finally, a reductive elimination from the resulting σ-
bonded palladium species 1 leads to the reaction product 2.
Scheme 4
The stereochemical outcome of the reaction was then dependent on
whether the reaction would proceed via the chairlike transition state A
or the boatlike transition state C.
Scheme 1
Substrate 3 was subjected to our cyclization reaction conditions.3 The
preformed potassium enolate (3 + 1.1 equivalent of KH or t-BuOK) was
heated in THF in the presence of 5% Pd(dppe),6 the progress of the
reaction being monitored by GC. This resulted in the rapid formation (2
hours at 55°C) of a sole crystalline product isolated in 70% yield to
which we assigned the structure trans-4 based on spectral data,
particularly the NMR absorptions.7 Indeed, 2D homo- and heteronuclear
Through recent studies on these cyclizations catalyzed by transition-
metal complexes we have developed efficient stategies for the
construction of tricyclic structures.3
We now describe that this palladium-catalyzed cascade bis-cyclization
process provides a fast and stereoselective access to hexahydro-1H-
4
benz[f]indene structure 4 from the easily available (2-bromobenzyl)-4-
experiments in [D ]benzene allowed for identification of most of the
pentenylmalonate derivative 3 (Scheme 2 ).
6
hydrogens and carbons, in particular the C-9a proton resonance appears
at δ 2.43 ppm and has the expected coupling pattern (ddd, J = 12.4, 11.8
and 4.7 Hz) that would arise for two large couplings Jax-ax (J9a-9ax, J9a-3a
and one small Jax-eq (J9a-9eq) of a trans- hexahydro-1H-benz[f]indene.
)
Such stereocontrol could be explained by considering the two transition
states A and C and assuming as the most favorable situation the benzylic
substituent and the double bond in a pseudoequatorial orientation
(minimum 1,3-allylic strain)8 (Scheme 5).
Scheme 2
The preparation of the malonate derivative 3 was accomplished as
outlined in Scheme 3. The synthesis begins with the easily available
acetylenic alcohol 5.5 Mesylation of this alcohol followed by reaction
with the sodium salt of methyl malonate afforded the acetylenic
substrate 6. Transformation of 6 into the ethylenic homologue 3 was
achieved by selective hydrogenation of the triple bond using Lindlar's
catalyst (Pd/BaSO4, 1 equivalent of quinoline in EtOH)
Concerning the palladium-catalyzed cyclization of the ethylenic
substrate 3, the key question encountered in evaluating this plan was the
stereochemistry of the final product. As illustrated in Scheme 4, in this
palladium-catalyzed cascade cyclization, two distinct conformationally
isomeric chairlike transition states A and B and one boatlike transition
Scheme 5
Following the success of this stereocontrolled synthesis of trans-
hexahydro-1H-benz[f]indene we turned our attention to its isomer, the

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cis-hexahydro-1H-benz[f]indene 4. We reasoned that it would be
possible to achieve its synthesis just by changing the order of the two
preceding steps, that is to say first, carbopalladation of the acetylenic
substrate 6 and secondly, hydrogenation of the expected unsaturated
cyclized product 7. Indeed, we hoped that this reduction would be
highly stereoselective, because examination of molecular models
indicated that 7 possesses marked facial differentiation and that
hydrogenation of the double bond would then occur preferentially on
the more convex face of the molecule (Scheme 6).
J.; Balme, G. Tetrahedron Lett. 1996, 37, 1429. d) Cavicchioli,
M.; Decortiat, S.; Bouyssi, D.; Goré, J.; Balme, G. Tetrahedron
1996, 52, 11463. e) Bruyère, D.; Gaignard, G.; Bouyssi, D.;
Balme, G.; Lancelin, J.M. Tetrahedron Lett. 1997, 38, 827.
(4) For a recent synthesis of trans-hexahydro-1H-benz[f]indene via a
radical cyclization see: (a) Pal, S.; Mukherjee, M.; Podder, D.;
Mukherjee, A.K.; Ghatak, U.R. J. Chem. Soc., Chem. Commun.
1991, 1591. (b) Pal, S.; Mukhopadhyaya, K.; Ghatak, U.R. J. Org.
Chem. 1994, 59, 2687.
(5) The acetylenic alcohol 5 was previously prepared by our group,
see ref. 3d.
(6) The palladium-diphenylphosphinoethane was preformed by
heating Pd(OAc) (5 mol%) and dppe (5 mol %) in the presence of
2
1-heptene (10 mol%, NMP, 50°C) until a homogeneous dark red
solution was obtained.
(7) Experimental procedure for the preparation of compound trans-4:
on the one hand, tBuOK (20 mg, 0.23 mmol) was suspended in
anhydrous THF (0.5 ml). The malonate derivative 3 (80 mg, 0.215
mmol) was added and the resultant mixture was stirred at room
temperature for 15 min. On the other hand, the palladium(0)
complex was preformed at 50°C in THF (1 ml) by reaction of
Scheme 6
Initial attempts to perform the cyclization of 6 using the conditions
described above for 3 → trans-4 gave poor results: the desired tricyclic
compound 7 was formed in low yields essentially due to a low
conversion and degradation of the starting material. Changing the
solvent to 1-methyl-2-pyrrolidinone9 allowed the isolation of 7 in 55%
yield as the sole product. As anticipated, catalytic hydrogenation of 7
over Pd/C at atmospheric pressure occurred with complete selectivity
from the least hindered face to afford cis-4 in essentially quantitative
yield.10 An unequivocal answer to the stereochemistry of the
hydrogenation product was based upon direct comparisons (GC11 and
1H, 13C spectra) with the diastereomer trans-4 obtained above. In
Pd(OAc) (2.41 mg, 0.01 mmol, 5 mol%) and dppe (4.28 mg, 0.01
2
mmol, 5 mol%). Then the addition of this Pd(0) solution was
made at room temperature via a cannula on the malonate anion
prepared above and the reaction mixture was heated at 55°C and
stirred at this temperature for 2 hours. The solution was then
filtered through a short pad of silica gel and the solvent removed
under reduced pressure. The residue was purified by flash
chromatography with petroleum ether/Et O 80/20 to afford trans-
2
1
particular, the small H NMR coupling constant (J = 5.9 Hz) observed
4 as a colorless solid (45 mg, 70%).
1
between C-9a and C-3a protons confirmed the expected cis ring
junction. On the other hand, C-3a and C-9a 13C resonances in cis-4 (δ:
37.8, 43.6) are more shielded than those of trans-4 (δ: 39.9, 48.6) which
is in accord with the fact that the 13C NMR shift values for a cis ring
junction are smaller than those for a trans junction.12
H NMR data (assignment facilitated by selective irradiations)
(300 MHz, C D δ ppm) trans-4: 7.1-6.9 (4H, m, ArH); 3.41 (3H,
6
6,
s, CH ); 3.27 (3H, s, CH ); 3.40-3.27 (1H, m, C(9eq)-H); 2.8-2.6
3
3
(2H, m, C(4eq)-H, C(2eq)-H), 2.43 (1H, ddd, J =11.8, 12.4, 4.7
Hz, C(9a)-H); 2.27 (1H, dd, J =15.8, 11.2 Hz, C(4ax)-H); 2.11
(1H, ddd, J =14, 10.8, 3 Hz, C(2ax)-H); 2.1-1.85 (2H, m, C(3a),
(3eq)-H); 1.1-1.0 (1H, m, C-3ax-H).
In conclusion, we have developed a practical and efficient strategy for
the synthesis of either cis- or trans-hexahydro-1H-benz[f]indene.
Further studies along this line and extensions are currently in progress.
(8) Hoffmann, R.W. Chem. Rev. 1989, 89, 875.
(9) The beneficial effect in the use of 1-methyl-2-pyrrolidinone in our
palladium-catalyzed cyclization has already been observed:
Bouyssi, D.; Coudanne, I.; Uriot, H.; Goré, J.; Balme, G.
Tetrahedron Lett. 1995, 36, 8019 and ref. 2b and 3e.
Acknowledgments: We wish to thank Bernard Fenet for measurements
of NMR spectra. We acknowledge the Ministère de la Recherche et de
l’Enseignement Supérieur for a Fellowship (I.C.).
(10) Experimental procedure for the preparation of compound cis-4:
on the one hand, a suspension of 50% KH in mineral oil (100 mg,
0.75 mmol) was washed with pentane (2 x 10 ml) and then
suspended in anhydrous NMP (2.5 ml). The malonate derivative 6
(250 mg, 0.68 mmol),was added and the resultant mixture was
stirred at room temperature for 15 min. On the other hand, the
palladium(0) complex was preformed at 50°C in NMP (2.5 ml) by
References and Notes
(1) For leading references see : a) Cascade reactions, Tetrahedron
Symposia-in-print 1996, 52. b) Negishi, E.I. Pure Appl. Chem.
1992, 64, 323. c) Overman, L.E.; Abelman, M.M.; Kucera, D.J.;
Tran, V.D.; Ricca, D.J. Pure Appl. Chem. 1992, 64, 1813. d) Hok,
T.L. Tandem Organic Reactions, Wiley Interscience, New York:
1992. e) Tietze, L.F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. f) de Meijere, A.; Meyer, F.E. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2379.
reaction of Pd(OAc) (7.64 mg, 0.03 mmol, 5 mol%) and dppe
2
(13.6 mg, 0.03 mmol, 5 mol%). Then the addition of this Pd(0)
solution was made at room temperature via a cannula on the
malonate anion prepared above and the reaction mixture was
heated at 55°C and stirred at this temperature for 2 hours. The
solution was then filtered through a short pad of silica gel and the
solvent removed under reduced pressure. The residue was purified
(2) a) Fournet, G.; Balme, G.; Goré, J. Tetrahedron 1991, 47, 6293. b)
Balme, G.; Bouyssi, D.; Faure, R.; Goré, J.; Van Hemelryck, B.
Tetrahedron 1992, 48, 3881. c) Bouyssi, D.; Balme, G.; Fournet,
G.; Monteiro, N.; Goré, J. Tetrahedron Lett. 1991, 32, 1641.
by flash chromatography with petroleum ether/Et O 80/20 to
2
afford 7 as a colorless solid (107 mg, 55%).
(3) a) Vittoz, P.; Bouyssi, D.; Traversa, C.; Goré, J.; Balme, G.
Tetrahedron Lett. 1994, 35, 1871. b) Balme, G.; Bouyssi, D.
Tetrahedron 1994, 50 , 403. c) Cavicchioli, M.; Bouyssi, D.; Goré,
A round-bottom flask containing a mixture of 7 (52 mg, 0.18
mmol) and 10% Pd/C (40 mg, 0.018 mmol) in ethanol was
degassed and then pressurised with hydrogene (1 atm). After

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stirring at 20°C for 3 h, the mixture was filtered through Celite.
The filtrate residue was concentred to dryness to give pure cis-4
(52 mg, quant.).
C NMR data (CDCl ) of the non CH benzylic carbons and of
3
CH carbons for compounds:
trans-4: 48.6 (CH), 39.9 (CH), 36.5 (CH ), 33.3 (CH ), 32.3
(CH ), 30.7 (CH ).
2 2
2
2
2
1
H NMR data (assignment facilitated by selective irradiations)
(500 MHz, C D δ ppm) cis-4: 7.1-6.9 (4H, m, ArH ); 3.45 (3H,
cis-4: 43.6 (CH), 37.8 (CH), 34.7 (CH ), 33.0 (CH ), 30.9 (CH ),
2 2 2
6
6,
s, CH ); 3.43 (3H, s, CH ); 3.39-3.33 (1H, ddd, J = 9.9, 6.2, 5.9
30.3 (CH ).
2
3
3
Hz, C(9a)-H); 2.79 (1H, dd, J =14.04, 6.2 Hz, C(9eq)-H); 2.6 (1H,
dd, J =14.34, 6.25 Hz, C(4eq)-H); 2.54 (1H, dd, J = 14.05, 10.05
Hz, C(9ax)-H); 2.57-2.54 (1H, m, C(2)-H); 2.49-2.46 (1H, m,
C(3a)-H); 2.29 (1H, dd, J = 14.2, 9.6 Hz, C(4ax)-H); 2.15-2.1
(1H, m, C(2)-H); 1.81-1.73 (1H, m, C(3)-H); 1.56-1.51 (1H, m,
C(3)-H).
(11) Cis-4 is homogeneous by GC while a coinjection of trans-4 with a
sample of cis-4 shows two distinct peaks.
(12) Metzger, P.; Casadevall, E.; Pouet, M. J. Org. Magn. Reson. 1982,
91, 229.