Palladium-catalyzed [3 + 2] intramolecular cycloaddition of alk-5-enylidenecyclopropanes

Article abstract of DOI:10.1021/ja054487t

Readily accessible alk-5-enylidenecyclopropanes undergo [3 + 2] intramolecular cycloaddition reactions upon treatment with appropriate palladium complexes. The method allows the rapid and efficient assembly of a variety of bicyclo[3.3.0]octane systems wit

Full text of DOI:10.1021/ja054487t

Published on Web 12/20/2005
Palladium-Catalyzed [3 + 2] Intramolecular Cycloaddition of
Alk-5-enylidenecyclopropanes
Moise´s Gul´ıas, Rebeca Garc´ıa, Alejandro Delgado, Luis Castedo, and Jose´ L. Mascaren˜as*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, UniVersidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Received July 7, 2005; E-mail: qojoselm@usc.es
Table 1. Palladium-Catalyzed Cycloadditiona
Small, strained cyclic systems that are capable of undergoing
metal-triggered ring-opening processes are attractive fragments for
use in metal-catalyzed cycloadditions. In particular, alkylidene-
cyclopropanes (ACPs) have been shown to participate as three-
carbon components in several intermolecular palladium- or nickel-
catalyzed [3 + 2] cycloadditions to unsaturated bonds.1 We recently
demonstrated that alk-5-ynylidenecyclopropanes undergo a mild
intramolecular [3 + 2] cycloaddition under palladium catalysis to
give interesting bicyclo[3.3.0]octenes.2 A challenging and mecha-
nistically interesting extension of this research concerns the
feasibility of using alkenes as two-carbon components in the
cycloaddition, a process that could generate bicyclic systems
containing up to three stereogenic centers (Scheme 1). To the best
of our knowledge, this type of annulation has not been previously
examinedsexcept for an isolated study published in 1989, which
described how the cycloaddition can be achieved with peculiar
cyclooctanic substrates bearing exocyclopropylidene and methylene
units at relative positions 1 and 5, but fails with more common
precursors, such as (E)-ethyl-7-cyclopropylidene-5,5-dimethylhept-
2-enoate.3 Studies by Motherwell and by Lautens indicate that
isomeric methylenecyclopropane precursors of type 2 undergo the
cycloaddition, although its success is restricted to activated alkenes
(conjugated to EWG groups) and is fairly dependent on the substrate
structure and reaction conditions.4
entry
1
R
R
′
L
product
yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(Z)-1a
(Z)-1a
(Z)-1b
1cc
CO2Et (E)
CO2Et (E)
CO2Et (E)
CO2Et (E)
CO2Et (Z)
CO2Et (Z)
COMe (Z)
CN
H
H
H
H
H
H
H
H
H
P(OiPr)3 4a
PPh3 4a
P(OPh)3 4a
8b
4a
P(OiPr)3 4a
74%
30%
25%
82%
72%
8b
6a+7ad 87% (5.3:1)
P(OiPr)3 4b
P(OiPr)3 1c
78%
1cc
(Z)-1d
1e
CN
8b
4c+6c
96% (3.5:1)
83% (5:1)
CO2Et (Z) Me P(OiPr)3 4d+6d
H
H
Ph
H
H
H
H
H
H
P(OiPr)3
e
1e
8b
8b
8b
8b
4e+7e
4f
5e
5g
83% (1:1.6)
70%
82%
(E)-1f
3e
(E)-3gf CH3
57%
a Reactions were carried out in refluxing dioxane (50 mM), using
Pd2(dba)3 (6%) and L (20%). b Tris(2,4-di-tert-butylphenyl)phosphite (8).
c Substrate prepared as a ∼3.5:1 mixture of E:Z stereoisomers. d These
compounds can be readily separated by chromatography. e This reaction
leads to cycloisomerization products, but cycloadducts were not observed.
f This substrate contains a small amount (<10%) of the Z-isomer.
Scheme 1
di-tert-butylphenyl)phosphite (8) being particularly efficient and
with PPh3 or P(OPh)3 significantly less productive.
Herein we demonstrate that alk-5-enylidenecyclopropanes of type
1, which can be readily assembled from allylcyclopropyltosylate,5
do undergo a mild and stereoselective [3 + 2] intramolecular cyclo-
addition upon treatment with appropriate palladium catalysts. We
also present a putative mechanistic scenario formulated on the basis
of preliminary theoretical studies carried out on a model system.
The viability of the reaction was first tested on substrate 1a,6
which bears a conjugated ester group at the trans-terminal position
of the alkene. When a solution of (E)-1a with 6 mol % of Pd2(dba)3
and 20% of P(OiPr)3 was heated in refluxing dioxane for 6 h, the
desired [3 + 2] cycloadduct (4a) was obtained in 74% yield. The
stereochemistry of the adduct was assigned on the basis of NOE
experiments as well as by analysis of NMR spectra (including
NOEs) of the product resulting from acid-induced isomerization7
and of the ketone resulting from ozonolysis of the exomethylene
moiety (see the Supporting Information). The formation of the cis-
fused stereoisomer is consistent with the results observed in previous
related cycloadditions of Pd-trimethylenemethane (Pd-TMM)
species generated from bifunctional conjuctive reagents.7,8 The
cycloaddition can be achieved using other ligands, with tris(2,4-
Remarkably, when the cis-alkene (Z)-1a was subjected to the
reaction conditions, we obtained the same diastereoisomeric product
as formed from the trans isomer.9 When the reaction was run to
partial conversion, the recovered starting material maintained the
original alkene stereochemistry. This provides firm evidence that
isomer 6a does not epimerize to 4a under the reaction conditions,
meaning that the stereochemistry of the product must be a reflection
of the reaction mechanism. The epimeric product 6a was surpris-
ingly obtained as the major product when the reaction of (Z)-1a
was carried out in the presence of the bulky phosphite 8 rather
than P(OiPr)3 (entry 6, Table 1).
The behavior of ketone 1b is similar to that of the ester. However,
nitrile 1c is reluctant to react under standard conditions,10 but does
react if 8 is used as ligand (entry 9). The cycloaddition is also
feasible with substrate 1d, in which the alkene bears a â-methyl
substituent, leading to a relevant bicyclic skeleton with a quaternary
methyl group at the fusion position.
Not unexpectedly, substrate 1e, in which the alkene is not
activated, failed to undergo the cycloaddition under standard
9
384
J. AM. CHEM. SOC. 2006, 128, 384-385
10.1021/ja054487t CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Tandem Coupling Cycloaddition
13), the zwitterionic path can be discarded, and the reaction must
proceed either via path 1 or 2 (see theoretical data in the Supporting
Information).
In conclusion, we have described the first examples of a metal-
catalyzed intramolecular cycloaddition of alk-5-enylidenecyclo-
propanes. Theoretical evidence has unveiled new, previously un-
suspected mechanistic pathways based on a metalla-ene rearrange-
ment or a stepwise process involving a zwitterionic intermediate.
The reaction is highly diastereoselective andsgiven the ease of
assembling the required precursorssoffers a particularly rapid and
practical entry to bicyclo[3.3.0]octane systems containing three
stereocenters.
a Conditions: (a) Na+CH(CO2Et)2-, Pd2dba3, P(OiPr)3, dioxane, rt to
reflux.
Scheme 3. Plausible Cycloaddition Mechanisms and Calculated
Structures of D and TS2
Acknowledgment. This work was supported by the Spanish
MEC and the ERDF (SAF2004-01044). We acknowledge Johnson
Matthey for the generous loan of the palladium source. R.G. thanks
the Spanish M.E.C., and M.G. and A.D. thank the Xunta de Galicia
for predoctoral fellowships. We are also grateful to the CESGA
for computation time, as well as to Dr. D. Ca´rdenas for his
invaluable help with the calculations.
Supporting Information Available: Experimental and computa-
tional details, including characterization data for new compounds, and
reaction coordinates for paths 1, 2, and 3, as well as Cartesian
coordinates of calculated structures. This material is available free of
charge via the Internet http://pubs.acs.org.
References
(1) For reviews, see: (a) Binger, P.; Bu¨ch, H. M. Top. Curr. Chem. 1987,
135, 77. (b) Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1-217. (c)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49-87. (d)
Nakamura, E.; Yamamoto, Y. AdV. Synth. Catal. 2002, 344, 111-129.
(e) Brandi, A.; Cachi, S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003,
103, 1213-1269.
conditions (Pd/P(OiPr)3), but it does react in the presence of the
bulky phosphite 8 (entry 12), as does the phenyl-substituted alkene
1f (entry 13). Substrate 3e, which bears a nitrogen atom instead of
the geminal diester in the tether, cyclizes to give 5e as the only
product (entry 14). Quite remarkably, the cycloaddition also occurs
with the methyl-substituted derivative 3g (entry 15), although this
reaction produces dienyl cycloisomerization side products (∼25%
yield). It is noteworthy that using as ligand the bulky phosphite 8
the cycloaddition of all substrates can be carried out with similar
efficiency using only 2-3% of the Pd source.
Dicyclopropylidene derivative 9, in which the alkene is activated
by strain, undergoes an efficient cycloaddition even in the presence
of the standard ligand (P(OiPr)3) to produce a mixture of cis- and
trans-fused cycloadducts (10:11, approximately 1:0.8). Interestingly,
the cycloaddition of 9 can be combined with its assembly, meaning
that the whole process (coupling and cycloaddition) can be achieved
from diethyl malonate in a straightforward, one-step procedure (79%
yield, Scheme 2).
(2) Delgado, A.; Rodr´ıguez, J. R.; Castedo, L.; Mascaren˜as, J. L. J. Am. Chem.
Soc. 2003, 125, 9282-9283.
(3) (a) Yamago, S.; Nakamura, E. J. Chem. Soc., Chem. Commun. 1988,
1112-1113. (b) Yamago, S.; Nakamura, E. Tetrahedron 1989, 45, 3081-
3088.
(4) (a) Lewis, R. T.; Motherwell, W. B.; Shipman, M.; Slawin, A. M. Z.;
Williams, D. J. Tetrahedron 1995, 51, 3289-3302. (b) Corlay, H.;
Motherwell, W. B.; Pennel, A. M. K.; Shipman, M.; Slawin, A. M. Z.;
Williams, D. J. Tetrahedron 1996, 52, 4883-4902. (c) Lautens, M.; Ren,
Y. J. Am. Chem. Soc. 1996, 118, 10668-10669.
(5) (a) Stolle, A.; Ollivier, J.; Piras, P. P.; Salau¨n, J.; de Meijere, A. J. Am.
Chem. Soc. 1992, 114, 4051-4067. (b) Delogu, G.; Salau¨n, J.; de Candia,
C.; Fabri, D.; Piras, P. P.; Ollivier, J. Synthesis 2002, 2271-2279 and
references therein.
(6) The synthesis of substrates 1, described in the Supporting Information,
was accomplished by Pd-catalyzed alkylation of allylcyclopropyltosylate
with the sodium salt of diethyl malonate, followed by alkylation with
appropriate allylic bromides.
(7) (a) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1982, 104, 3733-
3734. (b) Trost, B. M.; Greese, T. A.; Chan, D. M. T. J. Am. Chem. Soc.
1991, 113, 7350-7362.
(8) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1-20. (b) For a
discussion of the mechanism of these cycloadditions, see: Singleton, D.
A.; Schulmeier, B. E. J. Am. Chem. Soc. 1999, 121, 9313-9317.
(9) Partial loss of stereospecificity has previously been observed in cyclo-
additions between activated cis-alkenes and Pd-TMM species generated
from bifunctional reagents: Trost, B. M.; Chan, D. M. T. J. Am. Chem.
Soc. 1983, 105, 2315-2325. See also ref 4b.
(10) The lack of reactivity seems to be associated with the substrate structure
rather than to the presence of a CN group because the cycloaddition of
1a is inhibited by the presence of 1 equiv of 1c but not by the addition of
excess of valeronitrile.
(11) The calculations were carried out with the Gaussian 98 set of programs
using the B3LYP hybrid functional to perform vibrational analysis,
characterize stationary points, and determine zero-point energies (ZPE).
Whereas the transition state corresponding to the carbometalation step in
path 1 for model system 12 is 28.7 kcal/mol above palladacyclobutane
A, TS2 for the E-alkene is only 16.4 kcal/mol higher in energy than A.
On the other hand, the activation energy required to convert A (with a
Z-alkene geometry) into D through TS3 is 14.5 kcal/mol. Further
computational details are described in the Supporting Information, and
full details will be reported in due course.
The cycloaddition mechanism may involve initial insertion of
the metal at the distal position of the cyclopropane to give
palladacyclobutane A, followed by isomerization to B through a
TMM-like transition state and carbometalation to C. Reductive
elimination of C provides the final adduct (path 1, Scheme 3).
However, preliminary DFT calculations on the model system 12,
using PH3 as the ligand (L), suggest alternative and even less costly
pathways that consist of either a concerted pallada-ene reaction from
A to C (path 2) or a stepwise process involving the zwitterionic
intermediate D (path 3).11 This latter pathway, which recalls that
proposed for the cycloadditions of TMM-Pd species derived from
bifunctional reagents,8 is particularly relevant in terms of explaining
the lack of stereospecificity observed in the cycloaddition of (Z)-
1a (entry 5, Table 1). In the case of unsubstituted alkenes (model
JA054487T
9
J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006 385