Gold-catalyzed [4C+3C] intramolecular cycloaddition of allenedienes: Synthetic potential and mechanistic implications

Article abstract of DOI:10.1002/chem.200900164

An experiment was conducted to discover that Au complex generated in situ from [(IPr)AuCl] and AgSbF₆ catalyzes the [4C+3C] intramolecular cycloaddition of a variety of allenedienes at room temperature. Allenediene was treated with 10 mol% of A

Full text of DOI:10.1002/chem.200900164

DOI: 10.1002/chem.200900164
Gold-Catalyzed [4C+3C] Intramolecular Cycloaddition of Allenedienes:
Synthetic Potential and Mechanistic Implications
Beatriz Trillo,[a] Fernando Lꢀpez,*[a, b] Sergi Montserrat,[c] Gregori Ujaque,*[c]
Luis Castedo,[a] Agustꢁ Lledꢀs,[c] and Jose L. MascareÇas*[a]
Dedicated to Professor Josep Font on the occasion of his 70th birthday
Transition-metal-catalyzed cycloadditions are among the
most powerful methods for rapidly assembling polycyclic
products from simple acyclic precursors.[1] We recently re-
portantly, provided impetus for further investigation of a
gold-catalyzed process. This research led to the discovery
that the cationic gold complex generated in situ from
[(IPr)AuCl][4] and AgSbF6 promotes a particularly efficient
reaction, which can be now carried out at room temperature.
The mildness of the new conditions allowed the intramolec-
ular [4C+3C] cycloaddition of allenes with several dienes,
and even with furans, dienes that gave very poor results
under the PtCl2-promoted conditions.[2]
ported
a Pt-catalyzed [4C+3C] cycloaddition between
dienes and tethered allenes, a transformation that provides a
short and stereoselective route to synthetically useful
bicycloACHTUNGTRENNUNG[5.3.0]decane skeletons. The reaction proceeds with
10 mol% of PtCl2, but typically requires heating at elevated
temperatures (1108C) for efficient conversions.[2]
The well known ability of gold salts to promote reactions
of allenes via electrophilic activation pathways,[3] suggested
that gold complexes might also catalyze the aforementioned
annulations. However, preliminary assays with substrates
containing terminally monosubstituted allenes led to disap-
pointing results.[2] We therefore decided to carry out a com-
putational study to establish a reliable mechanism and gain
insights into potential differences in the performance of
platinum and gold catalysts.
As previously stated, the mechanistic assumption underly-
ing the Pt-catalyzed [4C+3C] cycloadditions consists of an
initial allene activation to generate a metal–allyl cation in-
termediate, which could participate in a [4p+2p] cycloaddi-
tion with the diene to provide the cycloheptene skeleton.[2]
A subsequent 1,2-hydride shift on the resulting carbene
should yield the final adduct and regenerate the catalyst.
This outcome and other alternatives were explored by
means of DFT calculations,[5] using the dimethylallene 1aꢂ
as model substrate, and PtCl2, AuCl, or AuCl3 as catalysts.
The results with PtCl2 are consistent with the originally pro-
posed mechanism (Figure 1). The initial step (selected as
energy reference) involves coordination of the allene to the
metal center. This species (2) evolves easily to the metal–
allyl cation intermediate 3 (energy barrier of 8.0 kcalmolÀ1).
The cycloaddition step conveys a low barrier (1.1 kcalmolÀ1)
and gives rise to the expected carbene 4, the most stable in-
termediate within the overall catalytic cycle. The transition
state for the cycloaddition (ts2) is consistent with a synchro-
nous and concerted process, involving an exo-like (extended)
approach of the allyl–metal cation to the diene.[6,7] Efforts to
identify alternative stepwise pathways for the cycloaddition
were unsuccessful. The last step, consisting of a 1,2-H-shift
Herein we present the results of such a study that support
the originally hypothesized mechanism with PtCl2 and, im-
[a] B. Trillo, Dr. F. Lꢀpez, Prof. Dr. L. Castedo,
Prof. Dr. J. L. MascareÇas
Departamento de Quꢁmica Orgꢂnica
Universidad de Santiago de Compostela
Facultad de Quꢁmica, 15782, Santiago de Compostela (Spain)
Fax : (+34)981-595012
E-mail: joseluis.mascarenas@usc.es
[b] Dr. F. Lꢀpez
Instituto de Quꢁmica Orgꢂnica General (CSIC)
Juan de la Cierva, 3, 28006, Madrid (Spain)
E-mail: fernando.lopez@iqog.csic.es
[c] S. Montserrat, Dr. G. Ujaque, Prof. Dr. A. Lledꢀs
Departament de Quꢁmica, Universitat Autꢃnoma de Barcelona
08193 Bellaterra, Barcelona (Spain)
À
with simultaneous coordination of the newly formed C C
double bond to the metal, features the highest relative
energy barrier of the profile (25.6 kcalmolÀ1, ts3), and might
thus be rate-determining.
E-mail: gregori@klingon.uab.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900164.
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Chem. Eur. J. 2009, 15, 3336 – 3339

COMMUNICATION
Scheme 2. Gold-catalyzed [4C+3C] cycloaddition of allenediene 1a.
complex A promoted the formation of 90% of the cycload-
duct 6a after just 40 min at 08C, most of the starting allene-
diene (1a) remained intact after several hours of treatment
with 10 mol% of PtCl2 or AuCl at that temperature.[7]
In agreement with this higher activity, the calculated
DFT-energy profile for
a
model (NHC)Au+ catalyst
(Figure 2) showed a particularly favorable energetic scenario,
Figure 1. DFT energy profiles (electronic energies) for the cycloaddition
of 1a’, and structures of the transition states (ts1–3) found with PtCl2.
In consonance with this mechanism, treatment of enan-
tioenriched substrate 1b (44% ee, Scheme 1),[8] with
10 mol% of PtCl2 at 1108C provided the major cycloadduct
Figure 2. DFT energy profile for the cycloaddition of 1aꢂ with NHCAu+,
and structures of the relevant transition states (ts1–3).
Scheme 1. Stereochemical mechanistic probe.
7b in racemic form. When the same reaction was carried
out for 2 h at room temperature (temperature at which the
cycloaddition does not occur), 1b was recovered after 2 h,
as a racemate (ee <6%). The loss of chiral information is
consistent with a fast and reversible metal–allyl cation for-
mation.
exhibiting a significantly lower energy barrier for the 1,2-H
shift step (8.6 kcalmolÀ1). Curiously, this step appears to re-
quire a small conformational change on the seven-mem-
bered ring prior to the H-shift (from 4 to 4’).[7] The energy
values and optimized geometries for the most relevant tran-
sition-state structures are depicted in Figure 2.
The excellent reactivity profile of complex A led us to
test its performance with other allenedienes. The results are
summarized in Table 1. Importantly, in contrast to the reac-
tion with PtCl2, which required heating for efficient conver-
sions, the cycloaddition of the phenyl-substituted allene 1b
took place smoothly, at room temperature, to give the cyclo-
adducts 6b and 7b in 85% yield after 3 h (Table 1, entry 1).
Use of other gold complexes such as AuCl, AuCl3, or
[PPh3AuCl]/AgSbF6, led to less than 40% of conversion,
even after 24 h at room temperature.
As can be deduced from the diagrams in Figure 1, the re-
action profile for the process promoted by AuCl or AuCl3 is
qualitatively similar to that obtained for PtCl2, but signifi-
cantly less demanding in terms of electronic energy barriers.
Consequently, dimethylallenyl precursors analogous to 1aꢂ
might experience the cycloaddition under mild conditions
upon treatment with such gold salts. Indeed, when allene-
diene 1a was treated with 10 mol% of AuCl3 or AuCl, the
desired [4C+3C] cycloadduct 6a was obtained in good yield
(Scheme 2). Remarkably, screening of other Au catalysts re-
vealed that this cycloaddition was particularly rapid and effi-
cient with the AuI complex [[(IPr)AuCl]/AgSbF6] (A),[4]
which features a s-donating N-heterocyclic carbene (IPr)
ligand. Accordingly, NMR monitoring of the cycloaddition
of 1a using 10 mol% of several catalysts revealed that while
Gratifyingly, complex A also catalyzes the cycloaddition
of furan–allene derivatives 1c–e (Table 1, entries 2–5), sub-
strates that performed very poorly under standard Pt-cata-
lyzed conditions as well as with other gold catalysts. Indeed,
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J. L. MascareÇas, F. Lꢀpez, G. Ujaque et al.
Table 1. Au ([(IPr)AuCl]/AgSbF6)-catalyzed [4C+3C] cycloaddition of 1.[a]
product must arise from
a
competitive Au-catalyzed
Entry
Allenediene, 1
Cycloadducts (6, 7)
6:7
(ratio)[b]
Yield
ACHTUNGTRENNUNG
(time)[c]
G
[4C+2C] annulation process,
as the reaction doesn’t proceed
under thermal activation.[11] In
this particular case we found
that the [4C+3C] cycloadduct
7i can be more efficiently ob-
tained by using either AuCl
(74% yield, 2 h) or AuCl3
(70% yield, 2 h) (Table 1, en-
tries 10 and 11).[12]
Finally, as an additional ex-
perimental mechanistic proof,
precursor 1b was treated with
[(IPr)AuCl]/AgNTf2 (10 mol%)
in the presence of diphenyl
sulfoxide (4 equiv), conditions
previously used for oxidative
trapping of gold carbenes.[13] In
addition to observing the for-
mation of traces of 6b and 7b
and recovering unreacted 1b,
we could isolate the ketone 9b
(25% yield, Scheme 3). This
result is consistent with the
participation of carbene spe-
1
1b
6b:7b (1:2)
85 (3)
2
3
4
5
1c, R=Me
1d, R=Ph
1e, R=tBu
1e
6c:7c (1:3)
82 (1)
7d
7e
7e
50 (12)
57 (20)
85 (3)[d]
6
7
8
1 f, R1 =Me[e]
1g, R2 =Me[e]
1h, R3 =Me[e]
6 f
6g
6h
93 (2)
84 (2)
77 (2)
9
1i
1i
1i
7i:8i (3:1)
7i
7i
66 (3)
74 (2)
70 (2)
10[f]
11[g]
[a] Conditions: [(IPr)AuCl] (10%) and AgSbF6 (10%) in CH2Cl2 (0.15m) at room temperature (20–258C)
unless otherwise noted. X=C(CO2Et)2, Y=C(CO2Me)2, and Z=NTs. [b] Determined by NMR spectroscopy.
[c] Yield of isolated product (%) after the reaction time (hours). [d] Reaction at 858C in 1,2-dichloroethane.
[e] Unspecified substituents are H. [f] Carried out with AuCl (10 mol%) at room temperature. [g] Carried out
with AuCl3 (10 mol%) at room temperature.
G
ACHTUNGTRENNUNG
whereas AuCl, AuCl3, [Ph3PAuCl]/AgSbF6, chloro[(1,1’-bi-
phenyl-2-yl)di-tert-butylphosphine]gold(I)/AgSbF6 or (di-
cies of type 4 in the catalytic cycle, and confirms the poten-
tial of the method to directly obtain stereochemically rich
oxygenated bycyclic products.
chloropyridine-2-carboxylato)goldACTHNUTRGNEUNG
(III),[9] led to low conver-
sions and/or formation of several unidentified side products,
the reaction of 1c with A (10 mol%) provided the cycload-
ducts 6c and 7c in 82% combined isolated yield, in less
than 1 h at room temperature (Table 1, entry 2).
The reaction also proceeds with furan derivatives 1d and
1e, providing the expected cycloadducts with complete se-
lectivity (Table 1, entries 3–5). As expected, sterically hin-
dered substrate 1e (Table 1, entry 5, R=tBu) resulted in a
slower reaction, but full conversion could be achieved after
3 h at 858C, providing the cycloadduct 7e with complete se-
lectivity and excellent yield. The above-mentioned results
(Table 1, entries 1–5) clearly indicate that the use of com-
plex A is critical for the success in cycloadditions involving
terminally monosubstituted allenes such as 1b–e. Notewor-
thy, the well known synthetic potential of oxabridged sys-
tems similar to those present in products 7c–e, bodes well
for the potential applicability of the method in the prepara-
tion of target-relevant bicarbocyclic systems.[10]
As can be seen in Table 1, the presence of substituents at
the diene unit was well tolerated (1 f–h, Table 1, entries 6–
8), and the corresponding [4C+3C] cycloadducts were ob-
tained in good yields (77–93%), and with complete stereo-
control. Surprisingly, the reaction of cyclopentylallene deriv-
ative 1i in the presence of catalyst A, in addition to provid-
ing the expected tricycle 7i that results from a 1,2 alkyl shift
in the intermediate carbene species, led also to a minor cy-
cloadduct identified as the bicycle 8i (Table 1, entry 9). This
Scheme 3. Oxygen atom transfer from the sulfoxide to the carbene
gold(I) species.
In summary, we have discovered that the Au complex
generated in situ from [(IPr)AuCl] and AgSbF6 catalyzes
the [4C+3C] intramolecular cycloaddition of a variety of al-
lenedienes at room temperature. The new conditions repre-
sent a significant step forward in terms of the scope and ver-
satility with respect to the previous PtCl2-catalyzed process,
and opens the door for the development of asymmetric ver-
sions. According to DFT calculations, the cycloaddition
must involve the formation of a metal–allyl cation inter-
mediate and its subsequent concerted cycloaddition with a
1,3-diene. These studies point to a 1,2-hydride shift on the
generated carbene intermediate as the rate-limiting step of
the process. The mechanistic insights derived from the de-
scribed theoretical and experimental studies, in addition to
providing a detailed account of the transformation, might
help to explain and design other gold-mediated processes.
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Chem. Eur. J. 2009, 15, 3336 – 3339

Gold-Catalyzed [4C+3C] Intramolecular Cycloaddition of Allenedienes
COMMUNICATION
Angew. Chem. 2008, 120, 7644–7648; Angew. Chem. Int. Ed. 2008,
47, 7534–7538; for a review on allene reactivity, see: h) S. Ma, Al-
drichim. Acta 2007, 40, 91–102; Other references with Pt: i) R.
Zriba, V. Gandon, C. Aubert, L. Fensterbank, M. Malacria, Chem.
Eur. J. 2008, 14, 1482–1491, and references therein; j) G. Zhang,
V. J. Catalano, L. Zhang, J. Am. Chem. Soc. 2007, 129, 11358–11359.
[4] a) P. De Frꢇmont, N. M. Scott, E. D. Stevens, S. P. Nolan, Organome-
tallics 2005, 24, 2411–2418; b) N. Marion, S. P. Nolan, Chem. Soc.
Rev. 2008, 37, 1776–1782. IPr denotes 1,3-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidine.
[5] Calculations were performed with Gaussian 03 using the B3LYP
functional. Metal centers were described by the lanl2dz pseudopo-
tential and their associated basis set, and the main-group elements
by the 6-31Gd basis set. See Supporting Information for details.
[6] This type of exo-like (extended) transition state also explains the ob-
served stereseoselectivity (see reference [2]).
Experimental Section
General procedure for performing the [4C + 3C] cycloaddition with
complex A (exemplified for the cycloaddition of 1c): A solution of com-
pound 1c (50 mg, 0.16 mmol) in CH2Cl2 (0.4 mL) was added to a suspen-
sion of [(IPr)AuCl] (10.1 mg, 0.016 mmol) and AgSbF6 (5.6 mg,
0.016 mmol) in CH2Cl2 (0.4 mL) in a dried Schlenk tube under argon.
The mixture was stirred at room temperature for 1 h and then filtered
through a short pad of florisil by eluting with Et2O. The filtrate was con-
centrated and purified by flash chromatography (1–4% Et2O/hexanes) to
afford a mixture of cycloadducts 6c and 7c (41 mg; 82%, 6c:7c=1:3).[7]
Acknowledgements
[7] See the Supporting Information for details.
This work was supported by the Spanish MEC [SAF2007–61015,
CTQ2008–06866-CO2–01, and Consolider-Ingenio 2010 (CSD2007–
00006)], Xunta de Galicia (GRC2006/132 and PGIDIT06P-
XIB209126PR), and Generalitat de Catalunya (2005SGR00715). B.T.,
S.M., and F.L. thank the Spanish MICINN for each FPU fellowship and
a Ramon y Cajal contract, respectively. We thank Johnson–Matthey for a
gift of metals. We thank Isaac Alonso for carrying out some supporting
experiments.
[8] Enantioenriched 1b was prepared following the procedure described
in: M. Ogasawara, H. Ikeda, T. Nagano, T. Hayashi, J. Am. Chem.
Soc. 2001, 123, 2089–2090.
[9] For leading references on other uses of these gold complexes, see:
a) C. Nieto-Oberhuber, S. Lꢀpez, A. M. Echavarren, J. Am. Chem.
Soc. 2005, 127, 6178–6179, and references therein; b) A. S. K.
Hashmi, J. P. Weyrauch, M. Rudolph, E. Kurpejovic, Angew. Chem.
2004, 116, 6707–6709; Angew. Chem. Int. Ed. 2004, 43, 6545–6547;
See also references [3a–f].
[10] For an illustration of the potential of these oxabicyclic systems in
synthesis, see: I. V. Hartung, H. M. R. Hoffmann, Angew. Chem.
2004, 116, 1968–1984; Angew. Chem. Int. Ed. 2004, 43, 1934–1949.
[11] Further details on this new [4C+2C] Au-catalyzed cycloaddition, as
well as the possibility for promoting it in a chemoselective manner
are being experimentally and theoretically investigated and will be
reported in due course. CCDC-711014 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[12] The fact that the cycloaddition of terminally disubstituted allene 1i
proceeds efficiently with AuCl and AuCl3 is in agreement with the
results obtained with 1a (see Scheme 2).
[13] C. A. Witham, P. Mauleꢀn, N. D. Shapiro, B. D. Sherry, F. D. Toste,
J. Am. Chem. Soc. 2007, 129, 5838–5839.
Keywords: allenes · carbocycles · cycloaddition · density
functional calculations · gold · homogeneous catalysis
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Received: January 20, 2009
Published online: February 19, 2009
Chem. Eur. J. 2009, 15, 3336 – 3339
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www.chemeurj.org
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