A dramatic effect of the reaction conditions on the course of a palladium-catalyzed cyclization of an alkene bearing a vinyl bromide and a nucleophile: A new route to the trans-hydrindane system

Article abstract of DOI:10.1055/s-1998-1829

Upon treatment with catalytic Pd(dppe) in the presence of KH, the malonate derivative 3 underwent a Wacker-type cyclization leading exclusively to compound 4 having the trans-hydrindane system. However, the course of the cyclization is dramatically dependent on the reaction conditions, mainly on the nature of the base. In the presence of a carbonate, a quaternary ammonium salt and the catalytic system (Pd(OAc)₂ + PPh₃) the cyclization of the same substrate 3 led only to compounds resulting from an initial Heck reaction of the vinyl bromide on the neighbouring olefin.

Full text of DOI:10.1055/s-1998-1829

September 1998
SYNLETT
995
A Dramatic Effect of the Reaction Conditions on the Course of a Palladium-Catalyzed
Cyclization of an Alkene Bearing a Vinyl Bromide and a Nucleophile: A New Route to the
trans-Hydrindane System
Isabelle Coudanne, Jaume Castro 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 3 May 1998
Abstract: Upon treatment with catalytic Pd(dppe) in the presence of
KH, the malonate derivative 3 underwent a Wacker-type cyclization
leading exclusively to compound 4 having the trans-hydrindane system.
However, the course of the cyclization is dramatically dependent on the
reaction conditions, mainly on the nature of the base. In the presence of
a carbonate, a quaternary ammonium salt and the catalytic system
(
Pd(OAc) + PPh ) the cyclization of the same substrate 3 led only to
2 3
compounds resulting from an initial Heck reaction of the vinyl bromide
on the neighbouring olefin.
Scheme 2
The hydrindane framework is found in many biologically active natural
products and therefore numerous strategies for the construction of this
skeleton have been reported.
1
2
In light of the excellent stereocontrol inherent in the cyclization of the
malonate derivative 1 using the “Wacker-type” reaction developed in our
group, it was of interest to determine whether a trans-hydrindane system
might be prepared from 3 in a stereocontrolled fashion using this
methodology (Scheme 1).
Scheme 3
Scheme 1
vinyl bromide 9. Mesylation of this alcohol followed by reaction with
the sodium enolate of dimethyl malonate gave the vinyl bromide 3.
9
3
However, in earlier papers, we reported that this palladium-catalyzed
cascade cyclization could compete with the classical intramolecular
Heck reaction by slightly changing the nature of the nucleophile. 4
With cyclization precursor 3 in hand, we first focused our attention on
the construction of the hydrindane system.
Therefore, taking advantage of our previous experience, the same
reaction conditions1 as used for 1 (1.1 equivalent of KH, 5 mol%
Therefore, we reasoned that, from the same substrate 3, it would also be
possible to obtain another bicyclic compound by favoring the competing
Heck reaction. Indeed we hoped that, since 5-exo cyclizations are
usually preferred to 6-endo in intramolecular Heck reactions,5 the
palladium mediated addition of the vinyl bromide to the double bond via
an exo mode would first occur followed by a palladium migration to
form a π-allylpalladium intermediate. An intramolecular displacement
of palladium by the carbon nucleophile would lead to bicyclic
compound 5 (Scheme 2).
Pd(dppe), THF, 55°C) were applied to substrate 3. These conditions
provided the bicyclic compound 4 as a single isomer and no traces of
any other product could be detected by GC or NMR.
The structure of 4 was established by NMR experiments10 in
deuterobenzene at 300 MHz and confirmed by an X-ray crystallographic
analysis.11
In agreement with the results obtained in the palladium-promoted
cyclization of compound 1, the annelation of the vinyl bromide 3 was
highly diastereoselective and afforded only the trans-hydrindane 4 in
The requisite vinyl bromide 3 was prepared from pent-4-yn-1-ol as
illustrated in Scheme 3. Oxidation under Swern conditions followed by
6
in situ Wittig condensation afforded the ester 6 which was reduced with
7
0% yield (Scheme 5).
diisobutylaluminium hydride to provide the allyl alcohol 7. Then the
7
ester obtained by thermal Claisen-Johnson rearrangement was reduced
Having established that the efficient synthesis of the trans-hydrindane
skeleton could be effected under these conditions, we next turned our
attention to the synthesis of the biquinane 5 by favoring the Heck
reaction. We considered altering the reaction conditions for the
cyclization of compound 3 in order to determine whether the
with lithium aluminium hydride. The resulting alcohol 8 was then
acylated with acetic anhydride in the presence of triethylamine.
Bromoboration of the carbon-carbon triple bond of this acetate with
8
commercial B-Br-9-BBN followed by protonolysis with acetic acid and
4
subsequent treatment with potassium carbonate in methanol gave the
intramolecular version of Weinreb’s three component reaction would

9
96
LETTERS
SYNLETT
work on this compound. Then, using the reaction conditions developed
4
b
by that group (5% Pd(OAc) , 10% P(o-tol) , 1.5 equiv. NaH, 2 equiv
2
3
n-Bu Cl in DMF at 50°C) the attempted cyclization of substrate 3
4
failed; the NMR and GC/MS spectra of the crude reaction product
revealed the presence of a major product identified as 4 along with three
minor untractable products. In order to enhance the formation of
compounds resulting from the Heck reaction i.e. to favour the alkene
insertion of the organopalladium halide over the nucleophilic attack of
the malonate, the substrate 3 was subjected to reaction conditions
1
2
13
developed by Jeffery and slightly modified by Larock in which
weaker bases than sodium hydride are used. So, by only changing the
nature of the base (KHCO3 instead of NaH) the cyclization of the
1
4
Scheme 5
dimethyl malonate derivative 3 gave a 50/20/30 mixture of bicyclic
compounds 5 and 10 along with the diene 11 in 78 % combined yield. In
this case, compound 4 was not formed (Scheme 4). Our efforts to
exclusively obtain compound 5, resulting from the Heck reaction were
only partially successful due to two competitive reactions. Indeed, the
formation of the bridged compound resulted from an initial 6-endo ring
closure followed by a palladium migration to form a π-allylpalladium
intermediate whereas that of the diene was due to the slow nucleophilic
attack of the π-allyl intermediate leading to a competing β-hydride
elimination.
nucleophilic attack of the malonate. Then, a reductive elimination of the
palladacycloheptane derivative lead to the cyclic product 418 (Scheme
1
9
6). An alternative pathway has been considered by some authors. They
suggested that it might be a two-step reaction with insertion of the
alkene (Heck reaction) giving an alkylpalladium derivative which would
then be attacked by the malonate without undergoing elimination of β-
hydrogen. According to this mechanism, the cyclization of compound 3
would lead to another bicyclic compound 12. Thus, the alternative
hypothesis on the reaction path can undoubtedly be excluded.
Scheme 4
Numerous attempts were realized in order to improve the
chemoselectivity in favor of product 5 and to prevent or reduce the
formation of diene 11. Along this line, different bases (K CO , KHCO ,
2
3
3
Na CO , NaHCO ), solvents (THF, DMSO, NMP, DMF, CH CN),
2
3
3
3
palladium catalysts (Pd(OAc) , Pd(dba) , Pd(PPh ) ) with or without
2
2
3 4
added phosphine ligand (PPh , P(o-tol) ) in the presence or absence of
quaternary ammonium salts were screened. Best results were obtained
3
3
Scheme 6
by using 5% Pd(OAc) as the palladium source with 10% PPh as ligand
2
3
in the presence of
2
equiv. of
a
quaternary ammonium salt
In addition to its synthetic interest, this study has then clarified the
mechanism of the biscyclization reaction in ruling out this alternative
mechanism.
(benzyltriethylammonium chloride or TEBA) and 2 equiv. of carbonate
bases (K CO or KHCO ) in DMF at 60°C. These conditions gave an
2
3
3
inseparable 70/15/15 mixture of the three compounds 5, 10 and 11 in
5% combined yield. Fortunately, as intermolecular Diels-Alder
8
15
References and Notes
reactions of bis-exocyclic 1,3-dienes are well known the treatment of
the mixture with dimethyl acetylenedicarboxylate (DMAD) in toluene
allowed to separate 11 from the two bicyclic products. This produced16
a 4:1 mixture of the fused and the bridged bicyclic compounds 5 and 10
in a combined yield of 55 %.
(1) (a) Nara, S.; Toshima, H.; Ichihara, A. Tetrahedron Lett. 1996, 37,
6745. (b) Tamao, K.; Nagata, Y. Ito; Maeda, K.; Shiro, M. Synlett
1994, 257. (c) Satoh, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J.
Org. Chem. 1991, 56, 2278 and references cited therein. (d)
Shibasaki, M.; Boden, J.D.; Kojima, A. Tetrahedron 1997, 53,
7
371.
In conclusion, we have shown that the palladium tandem catalyzed
biscyclization (Wacker-type reaction) can be performed on the dimethyl
malonate derivative 3 providing a new route to the trans-hydrindane
system. By changing the reaction conditions, it was possible, from the
same substrate 3 to obtain selectively compounds resulting from an
initial Heck reaction.
Moreover, we observed that there is often a misunderstanding17
concerning the mechanism of the new reaction that we have been
developing in our group. As far as we are concerned, we explained the
result of the cyclization by an activation of the olefinic double bond by
complexation of the electrophilic palladium species which initiates the
(
2) Coudame, I.; Balme, G. Synlett 1998, 998.
(3) (a) Vittoz, P.; Bouyssi, D.; Traversa, C.; Goré, J.; Balme, G.
Tetrahedron Lett. 1994, 35, 1871. (b) Bouyssi, D.; Coudanne, I.;
Uriot, H.; Goré, J.; Balme, G. Tetrahedron Lett. 1994, 35, 1871.
(
4) Interestingly, recent studies by Weinreb’s group have shown that a
novel variation of the Heck reaction can be applied on substrates
which contain a vinyl halide, an olefin and a nucleophile leading
to various carbo- and heterobicyclic compounds. Nevertheless, it
is important to note that the Weinreb’s three component reactions
were never applied to substrates which could be involved in the

September 1998
SYNLETT
997
Wacker-type reaction: (a) Nylund, C.S.; Klopp, J.M.; Weinreb,
(12) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287. (b)
Jeffery, T. Synthesis 1987, 70.
S.M. Tetrahedron Lett. 1994, 35, 4287. (b) Nylund, C.S.; Smith,
D.T.; Klopp, J.M.; Weinreb, S.M. Tetrahedron 1995, 51, 9301.
(13) Larock, R.C.; Baker, B.E. Tetrahedron Lett. 1988, 29, 905.
(
5) (a) Shi, L.; Narula, C.K.; Mak, K.T.; Kao, L.; Xu, Y.; Heck, R.F. J.
Org. Chem. 1983, 48, 3894. (b) Grigg, R.; Stevenson, P.;
Worakun, T.J. Tetrahedron 1988, 44, 2033. (c) Meyer, F. E.; Ang,
K.H.; Steinig, A.G.; de Meijere, A. Synlett 1994, 191. (d)
Henniges, H.; Meyer, F.E.; Schick, U.; Funke, F.; Parsons, P.J.; de
Meijere, A. Tetrahedron 1996, 52, 11503.
(
14) The structure assigned to each compound was in full accord with
its spectral (1H and 13C NMR, IR, MS) characteristics. All yields
are based on isolated material except where inseparable isomers
were formed for which ratios were determined by GC and 1
H
NMR spectroscopy.
(
15) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
(6) Ireland, R.E.; Norbeck, D.W. J. Org. Chem. 1985, 50, 2198.
Wiley: New York, 1990.
(
7) Ziegler, F.E. Chem. Rev. 1988, 88, 1423.
(
16) Optimized experimental procedure for the Heck reaction
(preparation of compound 5 and 10): on the one hand, the
malonate derivative 3 (200 mg, 0.6 mmol), was stirred at room
temperature for 10 min with K CO (120 mg, 1.2 mmol, 2 equiv).
(
(
(
8) Hara, S.; Dojo, H.; Takinani, S.; Suzuki, A. Tetrahedron Lett.
1983, 24, 731.
9) The product ratio was determined by integration of the vinyl
2
3
1
On the other hand, a mixture of Pd(OAc) (6.7 mg, 0.03 mmol, 5
2
proton peaks in the H NMR spectrum.
mol %) and PPh (15.7 mg, 0.06 mol, 10 mol %) in 5 ml of DMF
3
10) Experimental procedure for the « Wacker-type reaction »
was stirred under a nitrogen atmosphere at 60°C until a
homogeneous solution was obtained. Then the addition of this
Pd(0) solution was made at room temperature via a cannula on the
malonate anion prepared above followed by the addition of TEBA
(
preparation of compound 4): on the one hand, a suspension of
0% KH in mineral oil (122 mg, 1.3 mmol) was washed with
5
pentane (2 x 20 ml) and then suspended in anhydrous THF (5 ml).
The malonate derivative 3 (300 mg, 0.9 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
(
273 mg, 1.2 mmol, 2.0 equiv). The mixture was heated for 12 h at
5°C. After completion of the reaction (GC), the reaction mixture
was quenched with water and extracted with ether. The combined
5
in THF (3ml) by reaction of Pd(OAc) (10.1 mg, 0.045 mmol, 5
2
organic layers were dried over MgSO . The solvent was
4
mol%) and dppe (18 mg, 0.045 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
evaporated and the residue was purified by flash chromatography
with petroleum ether/ Et O 90/10 to give 5, 10 and 11 in a ratio of
2
7
5/15/15 (130 mg, 85%). This mixture of three compounds was
placed in 3 ml of toluene and 20 mg (0.14 mmol) of dimethyl
acetylenedicarboxylate was added. The solution was heated at
reflux for 3 h. Removal of the solvent under reduced pressure and
by flash chromatography with petroleum ether/ Et O 85/15 to
2
flash chromatography of the residue with petroleum ether/Et O
2
afford 4 as a colorless solid (160 mg, 70%).
9
0/10 gave an inseparable mixture of fused and bridged bicyclic
Compound 4: 1H -NMR (300 MHz, C D , δ ppm) (assignment
6
6
compounds 5 and 10 in a ratio of 4:1 (combined 85 mg, 55%). A
facilitated by selective irradiations) 4.72 (2H, m); 3.40 (3H, s); 3.30
3H, s); 2.96 (1H, dd, J=12.35, 2.3 Hz); 2.72 (1H, dt, J=14.0, 8.80
further careful flash chromatography allowed isolation of small
(
amounts of each compound:
Hz); 2.18 (1H, dq, J=13.60, 2.05 Hz); 2.14 (1H, td, J=11.95, 2.32
Hz); 2.03 (1H, ddd, J=13.3, 10.6, 2.3 Hz); 1.89 (1H, t, J=12.8 Hz);
1
Compound 5: H NMR (300 MHz, CDCl , δ ppm) 4.9 (1H, m);
3
,
4
.8 (1H, m); 4.7 (1H, m); 3.70 (3H, s); 2.7 (1H, quint, J=5 Hz),
1
.8-1.7 (1H, m); 1.7-1.6 (3H, m); 1.5-1.0 (2H, m). 13C NMR (50
2
13
.5-2.3 (2H, m); 2.3-1.9 (3H, m); 1.8-1.5 (3H, m); 1.39 (3H, s).
MHz, CDCl ) 173, 172.2, 147.8, 109.4, 61.7, 52.8, 52.4, 52.1,
3
C NMR (50 MHz, CDCl ) 171.8, 171.0, 158.3, 107.9, 69.3,
3
4
2.7, 37.2, 34.2, 33.1, 32.3, 30.9. MS, m/z (relative intensity): 220
23), 192 (43), 160 (31), 145 (27), 133 (46), 120 (100), 106 (96),
1 (49), 77 (27), 59 (36), 41 (29), 39 (20).
11) Bond distances (Å) and bond angles (°) of compound 4: O1-C11
.201(3), C1-C10 1.573(4), C4-C6 1.510(5), O2-C11 1.319(4),
C1-C11 1.519(4), C6-C7 1.540(4), O2-C12 1.454(4), C1-C13
.507(4), C7-C8 1.517(4), O3-C13 1.197(3), C2-C3 1.518(3), C8-
5
7.7, 52.2, 51.8, 51.6, 35.5, 35.4, 31, 29.7, 23.5. MS, m/z (relative
(
intensity): 192 (32), 145 (48), 133 (25), 120 (100), 113 (51), 108
9
(
22), 91 (24), 77 (24), 59 (18), 41 (13).
1
(
Compound 10 : H NMR (300 MHz, CDCl , δ ppm) 4.8 (1H, m);
3
1
4.7 (1H, m); 3.75 (3H, s); 3.64 (3H, s); 3.2 (1H, m); 2.63-1.5
(11H, dd, J=14.34, 6.25 Hz); 2.54 (1H, dd, J=14.05, 10.05 Hz);
1
3
1
C NMR (50 MHz, CDCl ) 171.7, 171.2, 148.2, 111.2, 58.6,
3
C9 1.550(4), O4-C13 1.316(3), C2-C8 1.530(4), C9-C10 1.535(5),
O4-C14 1.456(4), C3-C4 1.514(4), C1-C2 1.563(4), C4-C5
52.6, 52.4, 43, 32.6, 31, 30.8, 28.6, 26.5. MS, m/z (relative
+
intensity): M 252 (7), 220 (7), 192 (53), 160 (16), 145 (16), 132
1
1
1
1
1
1
1
1
1
1
.314(4), C11-O2-C12 115.7(3), C3-C2-C8 111.4(2), C8-C9-C10
03.0(3), C13-O4-C14 116.4(2), C2-C3-C4 108.3(2), C1-C10-C9
07.0(2), C2-C1-C10 103.1(2), C3-C4-C5 122.9(3), O1-C11-O2.
24.0(3), C2-C1-C11 109.6(2), C3-C4-C6 115.2(2), O1-C11-C1
24.6(3), C2-C1-C13 112.1(2), C5-C4-C6 121.9(3), O2-C11-C1
11.3(2), C10-C1-C11 111.0(2), C4-C6-C7 111.2(3), O3-C13-O4
23.0(3), C10-C1-C13 110.3(2), C6-C7-C8 109.0(3), O3-C13-C1
25.4(3), C11-C1-C13 110.5(2), C2-C8-C7 110.6(2), O4-C13-C1
11.5(2), C1-C2-C3 119.4(2), C2-C8-C9 101.1(2), C1-C2-C8
04.1(2), C7-C8-C9 116.1(3).
(36), 120 (100), 106 (36), 91 (41), 77 (30), 59 (31), 41 (23).
(
17) See for example: Boden C.; Pattenden, G. Contemporary Organic
Synthesis 1996, 3, 19.
(
18) Balme, G.; Bouyssi, D.; Goré, J.; Faure, R.; Van Hemelryck, B.
Tetrahedron 1992, 48, 3891.
(19) (a) Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis, John Wiley & Sons, Chichester: 1995; p. 156;
(b) Negishi, E.I.; Copéret, C.; Ma, S.; Liou, S.Y.; Liu, F. Chem.
Rev. 1996, 96, 365.