A new route to 1,3-bis-exocyclic dienes using a palladium-mediated cyclization/coupling reaction of conjugated enynes with organic halides and triflates

Article abstract of DOI:10.1055/s-2002-33542

The palladium catalyzed tandem cyclization/coupling reaction of conjugated enynes having a stabilizing carbon nucleophile with unsaturated halides or triflate afforded stereodefined functionalized 1,3-bis-exocyclic dienes. Moderate yields were obtained wi

Full text of DOI:10.1055/s-2002-33542

LETTER
1439
A New Route to 1,3-bis-Exocyclic Dienes Using a Palladium-mediated
Cyclization/Coupling Reaction of Conjugated Enynes with Organic Halides
and Triflates
A
N
ewRoute to
h
1,3-bis-Exo
i
cyclic
D
ienes usin
r
ga Palla
r
dium-m
y
ediatedCyclizationLomberget, Didier Bouyssi, Geneviève Balme*
Laboratoire de Chimie Organique 1, associé au CNRS, Université Claude Bernard Lyon 1, CPE, 43 Bd du 11 Novembre 1918,
69622 Villeurbanne, France
Fax +33(4)72431214; E-mail: balme@univ-lyon1.fr
Received 25 April 2002
R1
Abstract: The palladium catalyzed tandem cyclization/coupling re-
action of conjugated enynes having a stabilizing carbon nucleophile
with unsaturated halides or triflate afforded stereodefined function-
n
R1
R2
n
R2
alized 1,3-bis-exocyclic dienes. Moderate yields were obtained with
substrates of type 1. However, higher homologs of type 2 led to the
formation of functionalized 1,3-bis-exocyclic dienes and
hexatrienes in good yields. An initial study on the sequential cy-
clization/coupling reaction/electrocyclization in a one-pot proce-
dure leading to cyclohexadienes is also presented.
R
∆
Z
Z'
n
Z
Z'
R
n
R3
R4
n
R3
R4
Z
Z'
∆
Key words: palladium, cyclizations, enynes, dienes, electrocy-
clization
1a,b : n = 1
2a,b : n = 2
Z, Z' = electron-
withdrawing groups
Z
Z
Z'
Z'
Over the last decade, transition-metal catalyzed cycliza-
tion reactions have attracted considerable attention as new
powerful methods for the construction of a wide range of
complex systems.1 Following this trend, our group has re-
cently developed a new palladium-mediated cyclization
of unsaturated substrates bearing a nucleophilic substitu-
ent, and various types of hetero and carbocylic com-
pounds were then obtained with high regio- and
stereoselectivities.2 In line with this continuing interest,
we first planned to extend this strategy to the formation of
stereodefined functionalized 1,3 bis-exocyclic dienes by
cyclization of enynes 1 (Scheme 1). Such products would
be useful synthons for the formation of more complex ring
systems since their dienic system offers opportunities for
subsequent electrocyclization or Diels–Alder reactions.3
Scheme 1
Br
OH
c, d
a, b
Z
+
OH
Si
Z'
1a Z = CN, Z' = CO2Me
1b Z, Z' = CO2Me
Scheme 2 a) Pd(PPh3)4 0.01 equiv, CuI 0.015 equiv, Et3N, THF,
83%. b) K2CO3 0.15 equiv, MeOH, 81%. c) Imidazole, PPh3, I2, Et2O/
CH3CN, 78%. d) Methyl cyanoacetate or dimethylmalonate, NaH,
THF/DMF, 1a 62% and 1b 74%
The preformed enolate (1a and 1.2 equiv of KH) and 0.2
equivalents of 18-crown-6 were stirred in THF at 30 °C in
presence of 1.5 equivalents of iodobenzene and 5 mol% of
Pd(dppe).5 The reaction required 6 hours to reach comple-
tion and gave rise to the formation of two cyclized com-
pounds: the expected product 3a and the dienic substrate
4a which results from a decarboxylative reaction of 3a in
40% combined yields (26% and 14% isolated yield, re-
spectively, after chromatography; Table 1, entry 1). The
use of PdCl2(PPh3)2 reduced in situ by n-BuLi as catalyst6
in place of Pd(dppe) improved the results since the two
cyclized products 3a and 4a were obtained in a reasonable
combined isolated yield of 58% (Table 1, entry 2). The
use of t-BuOK instead of KH did not improve the yield.
Interestingly, when the reaction was performed with 1-cy-
However, a potential problem was anticipated in the cy-
clization of enynes of type 1. We assumed that the strain
generated by the presence of the alkene moiety would ren-
der the 5-exo cyclization too slow allowing for competi-
tive reactions. In order to investigate the feasibility of the
5-exo ring closure, functionalized enynes 1a,b were syn-
thesized. These substrates were easily prepared from tri-
methylsilyl acetylene and the known 3-bromo-3-buten-1-
ol4 using standard procedures (Scheme 2).
The ring closure sequence of the less sterically demanding
nucleophile 1a with iodobenzene was first examined us-
ing the optimum reaction conditions that recently gave
good results in related cyclization-coupling reactions.2a
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1439,1442,ftx,en;G11202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1440
T. Lomberget et al.
LETTER
Table 1 Access to 1,3-bis-Exocyclic Cyclopentadienes
Entry
Starting Enyne
Halide or Triflate
PhI
Reaction Time (h)a
4
Products (isolated yields)
1
2
1a
+
Ph
Z = CN,
Z = CO2Me
Ph
NC
CO2Me
CN
3a (26%)b
4a (14%)b
(39%)
(19%)
3
4
1a
3
3
TfO
NC
CO2Me
5ac (49%)
+
Ph
1b
PhI
Ph
MeO2C
Z = Z = CO2Me
CO2Me
CO2Me
3b (30%)
4b (traces)
a All reactions were performed at 30 °C in THF with 1.2 equiv of KH and 1.5 equiv of halide or triflate, using 5 mol% of PdCl2(PPh3)2 reduced
by n-BuLi.
b 5 mol% Pd(dppe) as catalyst.
c No decarboxylation product was detected.
clohexenyl triflate in place of iodobenzene, the stereode- The cyclization precursors 2a and 2b were obtained in
fined product 5a was isolated in 49% yield (Table 1, entry two steps from the known10 4-methylene-hex-5-yn-1-ol
3). No traces of the corresponding decarboxylated product by reaction of the corresponding iodide with the sodium
were observed. This tandem reaction seems to be sensitive salts of methyl cyanoacetate or dimethylmalonate.
to the nature of the electrophilic partner. To explain this
Treatment of 2b with t-BuOK in presence of iodobenzene
difference of behavior, we suggest that potassium iodide
using the above procedure resulted in the formation of the
liberated during the cyclization reaction involving iodo-
desired cyclic compound 6b and the expected linear cou-
pling product 10b in approximately 5/1 ratio and 76%
combined yield. By changing the base from t-BuOK to
benzene would be able to affect a demethoxycarbonyla-
tion of the resulting sterically hindered substrate 3a.7
When the bulkier nucleophile 1b was subjected to the cy- KH, an improvement in the yield of the target compound
clization/coupling reaction with iodobenzene according to was observed since only a minimal amount of the compet-
the protocol developed for homologue 1a, the desired cy- ing product was formed (6b/10b = 19/1) (Scheme 3).
clized product 3b was isolated in moderate yield (30%) However, material losses due to the difficulty to separate
along with traces of the monoester 4b (Table 1, entry 4). this by-product during purification resulted in moderate
This result showed that the yield of this tandem reaction is yields (61%) of the pure dienic substrate 6b (Table 2, en-
strongly influenced by the nature of the nucleophilic part try 1).
of the starting material. The low yield observed with the
Best results have been obtained with aryl iodide bearing
bulky nucleophile is presumably due to steric interaction
electron-donating substituents in the aromatic ring. For in-
of the two adjacent methylene groups and the geminal
stance, 7b was obtained in 83% isolated yield (Table 2,
dimethylesters in the rigid coplanar system 3b.
entry 2).11
With these results in mind, we reasoned that the exocy-
clization reaction might be favored by using substrates
with one carbon more in the side chain. However, while
base, 18-C-6
Ph
+
the methodology for the preparation of cyclopentane de-
rivatives has been well developed,8 the construction of cy-
clohexane homologs proved to be more difficult. Several
preliminary attempts9 to obtain six-membered rings from
alkynes were unsuccessful due to the strong tendency to
give a direct coupling reaction of the alkyne with the aryl
halide (Sonogashira coupling reaction).
Pd(0) PhI
THF, 30 °C
Ph
Z
Z
Z
Z
Z
Z
2b
6b
10b
Z = CO2Me
tBuOK
KH
6b / 10b : 5 / 1
6b / 10b : 19 / 1
76%
78%
Scheme 3
Synlett 2002, No. 9, 1439–1442 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Route to 1,3-bis-Exocyclic Dienes Using a Palladium-mediated Cyclization
1441
Table 2 Extension to Six-membered Rings
Entry
1
Starting Enyne
Halide or Triflate
PhI
Product
Reaction Time (h)a Yield (%)
CO2Me
CO2Me
7
61b
Ph
MeO2C
CO2Me
2b
2b
6b
OMe
OMe
OMe
OMe
OMe
2
4
3
83
77
I
OMe
MeO2C
CO2Me
7b
CN
PhI
3
4
Ph
CO2Me
NC
CO2Me
2a
2a
6a
5
7
77
TfO
NC
CO2Me
8a
Ph
Ph
5
2a
71c
Br
NC
CO2Me
9a
a All reactions were performed at 30 °C in THF with 1.2 equiv of KH and 1.5 equiv of halide or triflate, using 5 mol% of PdCl2(PPh3)2 reduced
by n-BuLi.
b Yield after purification by flash chromatography and further crystallization in CH2Cl2/MeOH 1/1 (elimination of 5% of coupling product 10b).
c 2 Equiv of commercial -bromostyrene were used (mixture of 85% trans and 15% cis isomers). Only the trans isomer was incorporated.
These last conditions, applied to the cyanoester 2a, result- analysis (Table 2, entry 5). As an example, the electrocy-
ed in the exclusive formation of 6a in high yield (no cou- clic ring closure of 9a was performed in refluxing toluene,
1
pling product was detected by H and 13C NMR in the leading to an inseparable diastereomeric mixture (85/15)
crude reaction mixture).12 This result shows again the in- of the expected functionalized cyclohexadienes 11 in 90%
fluence that the steric demand of the nucleophilic part has isolated yield. The one-pot transformation avoiding the
on the selectivity of the reaction (Table 2, entry 3).
isolation of the intermediate was also envisaged. To do
this, the sequential cyclization/coupling reaction/electro-
cyclization was carried out in refluxing toluene leading to
11 in 60% isolated yield (Scheme 4).
An interesting application of this methodology would be
the efficient synthesis of conjugated trienes through a cy-
clization/coupling reaction involving vinyl substrates in
place of aryl iodides. Indeed, such systems are able to un-
dergo an electrocyclic rearrangement to form cyclohexa-
dienes.13 To this end, we examined the tandem reaction of
2a with 1-cyclohexenyltriflate under the optimum condi-
tions (THF, 30 °C, 5 h). The reaction resulted in the exclu-
sive formation of the expected product in good yields
(Table 2, entry 4). This cyclization/coupling reaction was
further applied with success to commercial -bromosty-
rene (mixture of 85% trans and 15% cis isomers) to afford
hexatriene 9a as a single geometric isomer. Only the trans
isomer was incorporated14 and the E stereochemistry of
H
Ph
Pd(0), KH 1.2 equiv, toluene, reflux, 5h
2a
β-bromostyrene 2 equiv
60%
Pd(0),
NC
CO2Me
KH 1.2 equiv
THF, 30 °C, 7h
β-bromostyrene
2 equiv
toluene
reflux, 5 h
11
Ph
90%
71%
NC
CO2Me
9a
1
the styrene fragment was assigned by H NMR spectra
Scheme 4
Synlett 2002, No. 9, 1439–1442 ISSN 0936-5214 © Thieme Stuttgart · New York

1442
T. Lomberget et al.
LETTER
(7) The demethoxycarbonylation of malonate ester using
In conclusion, we have demonstrated a convenient meth-
od for the preparation of stereodefined functionalized 1,3-
bis exocyclic dienes and conjugated trienes, each of which
offers synthetically useful possibilities in subsequent
transformations. As an example, a combination of this
tandem cyclization/coupling reaction with a 6- electro-
cyclization in a one-pot procedure yielding a bicyclic sys-
tem was performed. The synthetic scope of these tandem
reactions is currently investigated.
Krapcho’s conditions generally needs prolonged heating in
polar solvent. The strain generated by the two contiguous
exocyclic double bonds and the malonate could explain this
rather mild conditions.
(8) Bouyssi, D.; Balme, G.; Fournet, G.; Monteiro, N.; Goré, J.
Tetrahedron Lett. 1991, 32, 1641.
(9) (a) Fournet, G.; Balme, G.; Goré, J. Tetrahedron 1991, 47,
6293. (b) Coudanne, I. PhD Dissertation; Université Claude
Bernard: Lyon, 1997.
(10) Klusener, P. A. A.; Kulik, W.; Brandsma, L. J. Org. Chem.
1987, 52, 5261.
(11) Only traces of the corresponding coupling product were
observed which were easily removed by flash
Acknowledgement
T. L. wishes to thank the Ministère de l’Education Nationale, de la
Recherche et de la Technologie for a fellowship.
chromatography.
(12) Experimental Procedure for the Synthesis of 6a:
Potassium hydride (35% in mineral oil) was washed with
anhyd THF, dried and stored under nitrogen prior to use.
To a suspension of KH (48 mg, 1.2 mmol) in 3 mL of anhyd
THF was added 18-C-6 (53 mg, 0.2 mmol), enyne 2a (191
mg, 1 mmol) in 4 mL of THF, and iodobenzene (170 L, 1.5
mmol). This mixture was stirred at r.t. for 15 min. In a
separate flask, n-BuLi (2 M in hexanes) was added dropwise
at r.t. to a suspension of PdCl2(PPh3)2 (35 mg, 0.05 mmol) in
3 mL of THF until the mixture becomes dark green. After
heating at reflux for 5 min and cooling, the mixture turned to
a dark red homogeneous solution and was added at r.t. via a
cannula to the cyanoester anion prepared above. The
resulting mixture was then stirred at 30 °C for 3 h (monitored
by TLC until completion). The solution was then filtered
through a short pad of silica gel (eluting with diethyl ether)
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography with
petroleum ether/Et2O 80/20 to afford 6a as a pale yellow
References
(1) (a) Tsuji, J. Palladium Reagents and Catalysts, Innovations
in Organic Chemistry; Wiley: Chichester, 1995. (b)
Tetrahedron Symposium-in-Print, 1996, 52, 35 (c) Metal-
catalysed Cross-coupling Reactions; Diederich, F.; Stang, P.
J., Eds.; Wiley-VCH: Weinheim, 1998, 99. (d) Takacs, J.
M.; Weidner, J. J.; Newsome, P. W.; Takacs, B. E.;
Chidambaram, R.; Shoemaker, R. J. Org. Chem. 1995, 60,
5261; and references cited therein.
(2) (a) Balme, G.; Bouyssi, D. Tetrahedron 1994, 50, 403.
(b) Coudanne, I.; Balme, G. Synlett 1998, 998. (c) Bruyère,
D.; Gaignard, G.; Bouyssi, D.; Balme, G.; Lancelin, J. M.
Tetrahedron Lett. 1997, 38, 827. (d) Garçon, S.; Vassiliou,
S.; Cavicchioli, M.; Hartmann, B.; Monteiro, N.; Balme, G.
J. Org. Chem. 2001, 66, 4069; and references cited therein.
(e) Balme, G.; Bouyssi, D.; Monteiro, N. In Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i., Ed.; Wiley Interscience: New York, 2002,
2245.
(3) For some examples using organometallic compounds see:
(a) Nugent, W. A.; Thorn, D. L.; Harlow, R. L. J. Am. Chem.
Soc. 1987, 109, 2788. (b) Bailey, W. F.; Wachter-Jurcsak,
N. M.; Pineau, M. R.; Ovaska, T. V.; Warren, R. R.; Lewis,
C. E. J. Org. Chem. 1996, 61, 8216. (c) Trost, B. M.; Shi, Y.
J. Am. Chem. Soc. 1993, 115, 12491. (d) Trost, B. M.;
Romero, D. L.; Rise, F. J. Am. Chem. Soc. 1994, 116, 4268.
(e) Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988,
44, 2033. (f) Le Paih, J.; Rodríguez, D. C.; Dérien, S.;
Dixneuf, P. H. Synlett 2000, 95.
(4) (a) Cousseau, J. Synthesis 1980, 805. (b) Barton, T. J.; Lin,
J.; Ijadi-Maghsoodi, S.; Power, M. D.; Zhang, X.; Ma, Z.;
Shimizu, H.; Gordon, M. S. J. Am. Chem. Soc. 1995, 117,
11695.
(5) The palladium-diphenylphosphinoethane was preformed by
heating Pd(OAc)2 (5 mol%) and dppe (5 mol%) in the
presence of 1-heptene (10 mol%, THF, 50 °C) until a
homogeneous dark red solution was obtained.
(6) The palladium(0) catalyst generated in situ by reduction of
PdCl2(PPh3)2 with n-BuLi has been found particularly
effective in related carbopalladation reactions: (a) See
ref.2d (b) Bottex, M.; Cavicchioli, M.; Hartmann, B.;
Monteiro, N.; Balme, G. J. Org. Chem. 2001, 175.
solid (206 mg, 77%). 1H NMR (CDCl3, 300 MHz, ppm):
=
1.94 (2 H, m), 2.17 (1 H, dt, J = 14.0, 6.5 Hz), 2.43 (2 H, t,
J = 6.5 Hz), 2.60 (1 H, dt, J = 14.0, 5.5 Hz), 3.85 (3 H, s),
4.81 (1 H, d, J = 1.1 Hz), 5.02 (1 H, d, J = 1.5 Hz), 6.63 (1
H, s), 7.18–7.30 (3 H, m), 7.34 (2 H, m). 13C NMR (CDCl3,
50 MHz, ppm): = 23.46, 35.36, 35.44, 53.19, 53.66,
117.35, 117.94, 127.44, 128.04, 128.07, 128.95, 135.73,
135.76, 141.05, 167.13. Anal. Calcd for C17H17NO2: C,
76.38; H, 6.41; N, 5.24. Found: C, 76.43; H, 6.50; N, 5.19.
The E-configuration of this isomer was deduced from
differential NOE experiments in the 1H NMR.
(13) For related examples of palladium catalyzed reaction
combined with 6- electrocyclization processes see: (a) See
ref.2c (b) Gilchrist, T. L.; Summersell, R. J. Tetrahedron
Lett. 1987, 28, 1469. (c) Gilchrist, T. L.; Healy, M. A. M. J.
Chem. Soc., Perkin Trans. 1 1992, 749. (d) Trost, B. M.;
Pfrengle, W.; Urabe, H.; Dumas, J. J. Am. Chem. Soc. 1992,
114, 1923. (e) Grigg, R.; Savic, V. Tetrahedron Lett. 1996,
36, 6565. (f) von Zezschwitz, P.; Petry, F.; de Meijere, A.
Chem.–Eur. J. 2001, 7, 4035.
(14) Similar results were recently reported for palladium
catalyzed tandem cyclization/coupling reactions involving
commercial -bromostyrene: (a) See ref.6 (b) Arcadi, A.;
Cacchi, S.; Cassetta, A.; Fabrizi, G.; Parisi, L. M. Synlett
2001, 1605.
Synlett 2002, No. 9, 1439–1442 ISSN 0936-5214 © Thieme Stuttgart · New York