Gold-catalyzed intermolecular reactions of propiolic acids with alkenes: [4 + 2] Annulation and enyne cross metathesis

Article abstract of DOI:10.1021/ja210792e

A gold-catalyzed intermolecular reaction of propiolic acids with alkenes led to a [4 + 2] annulation or enyne cross metathesis. The [4 + 2] annulation proceeds with net cis-addition with respect to alkenes and provides an expedient route to α,β-unsaturate

Full text of DOI:10.1021/ja210792e

Communication
pubs.acs.org/JACS
Gold-Catalyzed Intermolecular Reactions of Propiolic Acids with
Alkenes: [4 + 2] Annulation and Enyne Cross Metathesis
Hyun-Suk Yeom,† Jaeyoung Koo,† Hyun-Sub Park,† Yi Wang,‡ Yong Liang,‡ Zhi-Xiang Yu,*,‡
and Seunghoon Shin*,†
†Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea
‡Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering,
College of Chemistry, Peking University, Beijing 100871, China
S
* Supporting Information
Scheme 1. Propiolic Acid as a Functional Equivalent of 1,4-
C,O-Dipole or Biscarbene
ABSTRACT: A gold-catalyzed intermolecular reaction of
propiolic acids with alkenes led to a [4 + 2] annulation or
enyne cross metathesis. The [4 + 2] annulation proceeds
with net cis-addition with respect to alkenes and provides
an expedient route to α,β-unsaturated δ-lactones, for which
preliminary asymmetric reactions were also demonstrated.
For 1,2-disubstituted alkenes, unprecedented enyne cross
metathesis occurred to give 1,3-dienes in a completely
stereospecific fashion. DFT calculations and experiments
indicated that the cyclobutene derivatives are not viable
intermediates and that the steric interactions during
concerted σ-bond rearrangements are responsible for the
observed unique stereospecificity.
We commenced our study using propiolic acid (4a) and
styrene derivatives as substrates. After extensive optimization,10
we found that treating styrene 3a with 4a in the presence of a
catalytic amount of Au(L1)Cl and AgSbF6 (5 mol % each) in
chloroform (L1 = tBu2P(o-biphenyl), JohnPhos) provided a
lactone 1a in a good isolated yield (75%, eq 1). However, under
lectrophilic metal-catalyzed cyclization of 1,n-enynes has
E
attracted considerable attention.1 Despite its apparent
merits in greatly expanding the scope of potential applications,2
the intermolecular version of this process has been reported
only scarcely, especially with gold catalysts.3 The slow
intermolecular reaction causes problems resulting from
competing olefin isomerization and/or polymerization. Also,
in the absence of a tether, it is difficult to control regio- and
stereoselectivity.
To address this challenge, we projected using electronically
polarized alkynes as reaction partners to facilitate the
intermolecular reaction with selectivity control. While donor-
substituted alkynes, such as ynol ethers4 and ynamides,5 have
led to various novel reactions, acceptor-substituted alkynes have
been far less studied.6 Based on the precedents in the
electrophilic metal-catalyzed intramolecular reactions of 1,n-
enynes,7 we envisioned that a propiolic acid, when catalyzed by
a gold complex, would function as an equivalent of a 1,4-C,O-
dipole or a vicinal dicarbene in the intermolecular reaction with
alkenes (Scheme 1). The activation of an acetylene portion of a
propiolic acid would generate a functional equivalent of a 1,4-
C,O-dipole for [4 + 2] annulation with alkenes to provide α,β-
unsaturated δ-lactones 1 that form the core of diverse
biologically active natural products and pharmaceutical
agents.8,9 On the other hand, a vicinal dicarbene synthon
could be exploited in the enyne cross metathesis that is
unprecedented in the electrophilic metal-catalyzed intermolec-
ular reactions. Herein, we report the discovery of these two new
processes.
otherwise identical conditions, p-MeO-styrene 3b failed to
provide the desired product 1b and inspection of the crude
NMR as well as GC-MS indicated a significant amount of
polymers/oligomers formed from 3b. Reversing the stoichiom-
etry or slow addition of 3b or propiolic acid did not improve
the yield.
On the other hand, tert-butyl propiolate 4b was probed as a
surrogate of propiolic acid 4a to prevent possible acid-catalyzed
side reactions of sensitive alkenes.11 Treatment of 4b in the
absence of an olefin with [Au(L1)]SbF6 (5 mol %, generated in
situ) in a closed vessel gave 1c in a surprisingly high 74%
isolated yield (eq 2). Apparently, isobutene 3c formed in situ
Received: November 16, 2011
Published: November 29, 2011
© 2011 American Chemical Society
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Communication
a
from a tert-butyl cation that was generated upon coordination
of 4b to the cationic [Au(L1)]+ complex and 3c proved to be an
excellent nucleophilic olefin partner.
Table 1. [4 + 2] Annulations with Alkenes
Encouraged by these initial results, we next examined the
scope of this [4 + 2] annulation employing various alkenes (5
equiv) with 4a or 4b (1 equiv). As expected, 1,1-disubstituted
alkenes 3d−g were found to be good substrates for the [4 + 2]
annulation (entries 1−5). In the case of 3f, the desired lactone
1f was accompanied by the unexpected formation of 1k,
indicating isomerization of 3f to 3k, most probably caused by
the acid 4a. As expected, the formation of 1k could be
suppressed by using 4b (entries 3−4). By incorporation of a
silyl group that stabilizes the β-carbocation, even the
monosubstituted alkene 3h reacted with similar efficiency
(entry 6). On the other hand, reactions of cyclic 1,2-
disubstituted alkenes 3i were sluggish, thereby requiring longer
times for completion (entry 7). The reaction scope was further
extended to trisubstituted alkenes without difficulty (entries 9−
10). Importantly, the stereochemistry of major products in 1i
and 1j indicated that the formation of C−O and C−C bonds
occurred at the same face of the olefin.12 To our delight, the
current reaction could also be effected with 1,3-dienes and
allenes as the reaction partners (entries 11−13). Notably, a
natural product, goniothalamin (1n), could be synthesized in a
single operation, with O-attack occurring at the more cation-
stabilized site (i.e., cinnamyl cation) from diene 3n (entry 12).
While the reactions with cyclopentene 3i gave only [4 + 2]
adducts in moderate yield, the larger homologous cycloalkenes
3p−q gave unexpected enyne metathesis products 2pa−qa in
good isolated yields, respectively (entries 1−2, Table 2).
Examination of reaction parameters (ligand, counteranion, and
solvents) revealed that the optimal conditions for this
metathesis pathway are essentially identical to those for [4 +
2] annulation.10 Remarkably, while [4 + 2] annulation required
an excess amount of either alkenes or alkynes for efficient
cyclization, metathesis proceeds with as little as 1.5 equiv of
alkenes with essentially identical yields.
Surprisingly, the enyne metathesis turned out to be highly
stereospecific; for example cis-3r gave E,E-2ra, while trans-3r
gave E,Z-2ra, exclusively (entries 3−4). This enyne metathesis
also accommodates ethyl (4c) and allyl propiolate (4d) as well
as sulfonyl acetylene (4e) (entries 5−9), and the stereo-
specificity remained identical. The reaction with unsymmetrical
3s showed that there is only mediocre regioselectivity in this
metathesis (entry 10). The reactions with E/Z mixtures of
olefins revealed that Z-olefin reacted significantly faster than E-
olefin (entries 10−11): while the reaction with 3s (Z/E =
3.8:1) gave 14:1 (E,E/E,Z) of 2sc (and 2sc’), that with 3t (E/Z
= 4.8:1) gave only a 1.5:1 (E,Z/E,E-2tc) ratio. The reaction of
3u with 4a gave only [4 + 2] adduct 1u, further indicating that
the cation-stabilizing substituent (cyclopropyl) favored the [4 +
2] reaction manifold (eq 3).10
a
The reactions were conducted at rt in the presence of Au(L1)Cl (5
b
mol %) and AgSbF6 (5 mol %) in CHCl3. Isolated yield after
chromatography. 4a (1 equiv) and alkenes 3 (5 equiv). 4b (1 equiv)
c
d
e
and alkenes 3 (5 equiv) in an open vessel. 10 equiv of 3h were used.
f
The stereochemistry of the major isomer was determined by NOE
g
experiments. Allene 3o (1 equiv) and 4a (5 equiv).
from the cyclopropyl group and the substituent(s) of the
cyclopropane ring is oriented away from the carboxylic acid.
Overall cis-addition of propiolic acid with respect to the
prochiral face of olefins strongly suggests that the cyclopropane
ring opening to form the homoallyl cation A′ immediately
precedes the cyclization,10,12 so that the subsequent C−O bond
formation occurs faster than C−C rotation of homoallyl
carbocation A′, except when the cation is sufficiently stabilized
(i.e., allylic cation as in the reaction with 3o). To support the
intermediacy of A/A′, we prepared N,N-diallylpropiolamide 5
to trap this intermediate (eq 4). As expected, we obtained 6 in
36% yield, lending further support for the intermediacy of A/
A′.13
From the reaction profile in Tables 1 and 2, the following
mechanistic model was deduced (Scheme 2). Both [4 + 2]
annulation and enyne metathesis seem to proceed via initial
formation of a cyclopropyl carbenoid intermediate A/A′, where
the Au-moiety with a bulky JohnPhos ligand is positioned away
According to the model in Scheme 2, it is challenging to
differentiate prochiral faces of an olefin with a chiral ligand
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Journal of the American Chemical Society
Communication
dichloroethane solvent. Although the observed enantioselectiv-
ity is not sufficiently high at the present stage, this preliminary
result represents the first example of an asymmetric intermolecular
reaction between alkenes and alkynes via direct activation of alkynes
by gold complexes, to the best of knowledge.14
Table 2. Enyne Cross Metathesis with Alkenes
For the enyne cross metathesis, we first considered a
possibility that a common intermediate A-trans undergoes σ-
bond rearrangements to form B-trans, followed by Au(I)-
catalyzed ring opening of cyclobutenes (Scheme 3). Thermal
electrocyclic ring opening of 3,4-trans-dialkyl cyclobutenes
Scheme 3. Possible Intermediacy of Cyclobutene: Disproved
takes place through outward conrotatory motion of alkyl
substituents due to the torquoelectronic effect,15 while the
current Au(I)-catalyzed enyne metathesis proceeds through a
disfavored inward conrotation. Independently prepared trans-
7,16 in the presence or absence of a Au(I)-catalyst, reacted only
at elevated temperatures and gave Z,E-2rc exclusively (out-
ward), contrary to the current results (entry 9, Table 2),
suggesting a different reaction pathway could happen in the
present system.
a
Isolated yield after chromatography; a single diastereomer unless
b
otherwise noted. The stereochemistry was determined by NOE
c
d
experiments after reduction of the acid. The reactions at 60 °C. The
To understand how this unique stereoselectivity occurs, we
conducted DFT calculations to study the reaction pathway
leading to the enyne metathesis product from E-alkene.10 Our
computational studies suggested that once cyclopropyl Au-
carbenoid A-trans is generated, it will not give intermediate B-
trans. Instead, the most favored pathway starts from the
transformation of A-trans to C-t via the σ-bond rearrangement
transition state TS1-t, in which C2−C3 (bond t) and C3−C4
σ-bonds are breaking and the C1−C3 σ-bond is forming
(Figure 1).10 Then C-t undergoes reorganization of the
coordination of Au, giving complex E,Z-D. This pathway
requires an overall activation free energy of 8.0 kcal/mol in
CHCl3. However, another σ-bond rearrangement transition
state TS1-c with the cleavage of σ-bond c leading to Z,E-D is
5.7 kcal/mol higher than TS1-t (13.7 versus 8.0 kcal/mol,
Figure 1). This suggests that the E,Z-diene will be generated
exclusively, which is in good agreement with the experiment
(Table 2, entry 4). Analyzing the structures of TS1-t and TS1-
c,10 we found that the cleavage of σ-bond c in A-trans will
result in obvious steric repulsion between the migrating methyl
group and the carboxylic acid in TS1-c (Figure 1). Therefore,
the stereoselectivity of the gold-catalyzed enyne metathesis is
mainly controlled by the steric effect. Other computational
support for this pathway rather than the involvement of Au(I)-
cyclobutene complex B-trans is that B-trans favors giving Z,E-
D but not the experimentally observed E,Z-D, agreeing with the
torquoselectivity (Figure 1).15a
E,E/E,Z ratios of 2sc (R1 = Bn, R2 = nBu) and 2sc′ (R1 = nBu, R2 =
e
f
Bn) were both 14:1. Regioselectivity (rs). 3 equiv of 3s or 3t.
Scheme 2. Proposed Reaction Pathway for the Formation of
α,β-Unsaturated δ-Lactones
oriented away from the cyclopropyl ring in A. With (R)-DM-
SEGPHOS (L2) as a chiral ligand and 4b as an alkyne
component, we found that trisubstituted olefin 3k gave a much
higher enantioselectivity than styrene 3a, presumably because
of a maximized steric interaction of the olefin substituent (R3 =
Me vs H) with the carboxylic ester (or acid) moiety (eq 5). The
% ee was further increased to 65% ee in slower reacting 1,2-
In conclusion, we report herein two new reactions of
acceptor-substituted alkynes with alkenes catalyzed by a Au(I)-
complex. The newly discovered [4 + 2] annulation allows an
expedient access to α,β-unsaturated δ-lactones with a diverse
array of olefin substrates, the efficiency of which is epitomized
by a one-step synthesis of goniothalamin (1n). We have also
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T. Angew. Chem., Int. Ed. 2011, 50, 5090. (c) Li, C.-W.; Pati, K.; Lin,
G.-Y.; Sohel, S. M. A.; Hung, H.-H.; Liu, R.-S. Angew. Chem., Int. Ed.
2010, 49, 9891. (d) Davies, P. W.; Cremonesi, A.; Martin, N. Chem.
Commun. 2011, 47, 379. (e) Davies, P. W.; Cremonesi, A.;
Dumitrescu, L. Angew. Chem., Int. Ed. 2011, 50, 8931. (f) Dateer, R.
B.; Shaibu, B. S.; Liu, R.-S.; Angew. Chem., Int. Ed. 2011, 50, DOI:
10.1002/anie.201105921.
(6) For intermolecular reactions of propiolates, see: (a) Shi, Z.; He,
C. J. Org. Chem. 2004, 69, 3669. (b) Haro, T.; Nevado, C. J. Am. Chem.
Soc. 2010, 132, 1512. (c) Luo, T.; Dai, M.; Zhang, S.-L.; Schreiber, S.
L. Org. Lett. 2011, 13, 2834.
(7) For selected examples of electrophilic metal catalyzed processes,
see: (a) Trost, B. M.; Ganoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636.
(b) Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am. Chem. Soc.
1994, 116, 6049. (c) Furstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J.
̈
Am. Chem. Soc. 1998, 120, 8305. (d) Chatani, N.; Inoue, H.; Kotsuma,
T.; Murai, S. J. Am. Chem. Soc. 2002, 124, 10294. (e) Men
́
dez, M.;
Munoz, M. P.; Echavarren, A. M. J. Am. Chem. Soc. 2000, 122, 11549.
̃
(f) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.;
Cardenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
́
̃
̃
2402.
(8) Buck, S. B.; Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C.-
M.; Hwang, I.; Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.;
Boger, D. L. J. Am. Chem. Soc. 2003, 125, 15694.
Figure 1. DFT-calculated free energy surfaces for enyne metathesis
and cyclobutene ring-opening pathways.10
(9) Standard synthetic routes typically involve multistep sequences:
(a) BouzBouz, S.; Cossy, J. Org. Lett. 2003, 5, 1995. (b) Terada, M.;
Mikami, K.; Nakai, T. Tetrahedron Lett. 1991, 32, 935.
(10) See the Supporting Information for details. Control experiments
employing TfOH (20%) or BF3·OEt2 (1 equiv) in the reaction of 4a
with styrene gave no [4 + 2] adduct 1a. The reaction of 4a with cis-
cyclooctene 3q under TfOH (20%) gave a hydroesterification product
instead of the metathesis product 2qa (see Tables S6 and S7). In
addition, there was no contamination by [4 + 2] vs metathesis
products for all substrates listed in Tables 1 and 2.
discovered a stereospecific enyne cross metathesis leading to
stereodefined 1,3-dienes. Considering unmet challenges in the
Grubbs catalyst based enyne cross metathesis (e.g., limited
scope and geometry control), the current process holds great
potential as an atom-economical C−C bond formation.2
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) For trapping cationic intermediates generated from Au-catalyzed
reactions by acid (or tert-butyl esters/carbonates), see: (a) Kang, J.-E.;
Lee, E.-S.; Park, S.-I.; Shin, S. Tetrahedron Lett. 2005, 46, 7431.
(b) Kang, J.-E.; Shin, S. Synlett 2006, 717. (c) Lim, C.; Kang, J.-E.; Lee,
AUTHOR INFORMATION
Corresponding Author
sshin@hanyang.ac.kr; yuzx@pku.edu.cn
■
E. S.; Shin, S. Org. Lett. 2007, 9, 3539. (d) Furstner, A.; Morency, L.
̈
Angew. Chem., Int. Ed. 2008, 47, 5030. (e) Crone, B.; Kirsch, S. F.;
Umland, K.-D. Angew. Chem., Int. Ed. 2010, 49, 4661.
(12) In contrast, in gold-catalyzed domino cyclizations of 1,n-enynes
followed by trapping with external nucleophiles, C−C and C−Nu
bonds typically form with net anti-addition with respect to an alkene:
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF-2009-0080741 and NRF-2011-0023686).
H.S.Y. thanks the BK21 program for financial support and
the Seoul Science Foundation for a fellowship. Z.X.Y. thanks
NSFC (20825205) for financial support.
Pradal, A.; Chao, C.-M.; Vitale, M. R.; Toullec, P. Y.; Genet
́
, J.-P.
Tetrahedron 2011, 67, 4371.
(13) Kim, S. M.; Park, J. H.; Choi, S. Y.; Chung, Y. K. Angew. Chem.,
Int. Ed. 2007, 46, 6172.
(14) Asymmetric intermolecular reaction of propargylic esters with
alkenes: (a) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J.
Am. Chem. Soc. 2005, 127, 18002. Asymmetric desymmetrization:
(b) Hashmi, A. S. K.; Hamzic, M.; Rominger, F.; Bats, J. W. Chem.
Eur. J. 2009, 15, 13318. For a review on asymmetric gold catalysis,
see: (c) Pradal, A.; Toullec, P. Y.; Michelet, V. Synthesis 2011, 1501.
(15) (a) Dolbier, W. R.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc.
Chem. Res. 1996, 29, 471. (b) Um, J. M.; Xu, H.; Houk, K. N.; Tang,
W. J. Am. Chem. Soc. 2009, 131, 6664. (c) Liang, Y.; Jiao, L.; Zhang, S.;
Yu, Z.-X.; Xu, J. J. Am. Chem. Soc. 2009, 131, 1542. For thermal
electrocyclic opening of related cyclobutenes, see: (d) Snider, B. B.;
Rodini, D. J.; Conn, R. S. E.; Sealfon, S. J. Am. Chem. Soc. 1979, 101,
5283.
REFERENCES
■
(1) (a) Jimen
́
ez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108,
́
̃
3326. (b) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008,
108, 3351. (c) Michelet, V.; Toullec, P. Y.; Genet
Int. Ed. 2008, 47, 4268. (d) Furstner, A. Chem. Soc. Rev. 2009, 38,
́
, J.-P. Angew. Chem.,
̈
3208. (e) Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371.
(2) For Ru-catalyzed enyne cross metathesis, see: (a) Giessert, A. J.;
Diver, S. T. Chem. Rev. 2004, 104, 1317. (b) Kim, M.; Park, S.;
Maifeld, S. V.; Lee, D. J. Am. Chem. Soc. 2004, 126, 10242. (c) Kim,
M.; Lee, D. Org. Lett. 2005, 7, 1865.
(3) For cyclobutene formation, see: (a) Lopez-Carrilo, V.;
́
Echavarren, A. M. J. Am. Chem. Soc. 2010, 132, 9292. For the first
Au-catalyzed intermolecular reaction, see: (b) Hashmi, A. S. K.;
Blanco, M. C.; Kurpejovic,
(16) Xu, H.; Zhang, W.; Shu, D.; Werness, J. B.; Tang, W. Angew.
Chem., Int. Ed. 2008, 47, 8933.
́
E.; Frey, W.; Bats, J. W. Adv. Synth. Catal.
2006, 348, 709.
(4) (a) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 11806.
(b) Hashmi, A. S. K.; Rudolph, M.; Bats, J. W.; Frey, W.; Rominger, F.;
Oeser, T. Chem.Eur. J. 2008, 14, 6672.
(5) (a) Li, C.; Zhang, L. Org. Lett. 2011, 13, 1738. (b) Kramer, S.;
Odabachian, Y.; Overgaard, J.; Rottlander, M.; Gagosz, F.; Skrydstrup,
̈
211
dx.doi.org/10.1021/ja210792e | J. Am. Chem.Soc. 2012, 134, 208−211