Experimental and computational evidence for gold vinylidenes: Generation from terminal alkynes via a bifurcation pathway and facile C-H insertions

Article abstract of DOI:10.1021/ja2091992

Facile cycloisomerization of (2-ethynylphenyl)alkynes is proposed to be promoted synergistically by two molecules of BrettPhosAuNTf₂, affording tricyclic indenes in mostly good yields. A gold vinylidene is most likely generated as one of the reaction intermediates on the basis of both mechanistic studies and theoretical calculations. Different from the well-known Rh, Ru, and W counterparts, this novel gold species is highly reactive and undergoes facile intramolecular C(sp³)-H insertions as well as O-H and N-H insertions. The formation step for the gold vinylidene is predicted theoretically to be complex with a bifurcated reaction pathway. A pyridine N-oxide acts as a weak base to facilitate the formation of an alkynylgold intermediate, and the bulky BrettPhos ligand in the gold catalyst likely plays a role in sterically steering the reaction toward formation of the gold vinylidene.

Full text of DOI:10.1021/ja2091992

Communication
pubs.acs.org/JACS
Experimental and Computational Evidence for Gold Vinylidenes:
Generation from Terminal Alkynes via a Bifurcation Pathway and
Facile C−H Insertions
Longwu Ye,† Yanzhao Wang, Donald H. Aue,* and Liming Zhang*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
gold catalysts and pyridine/quinoline N-oxides. While complex
ABSTRACT: Facile cycloisomerization of (2-ethynyl-
phenyl)alkynes is proposed to be promoted synergistically
by two molecules of BrettPhosAuNTf2, affording tricyclic
indenes in mostly good yields. A gold vinylidene is most
likely generated as one of the reaction intermediates on the
basis of both mechanistic studies and theoretical
calculations. Different from the well-known Rh, Ru, and
W counterparts, this novel gold species is highly reactive
and undergoes facile intramolecular C(sp3)−H insertions
as well as O−H and N−H insertions. The formation step
for the gold vinylidene is predicted theoretically to be
complex with a bifurcated reaction pathway. A pyridine
N-oxide acts as a weak base to facilitate the formation of an
alkynylgold intermediate, and the bulky BrettPhos ligand
in the gold catalyst likely plays a role in sterically steering
the reaction toward formation of the gold vinylidene.
mixtures often resulted, a clean transformation was noticed when
BrettPhosAuNTf27a,8 (5 mol %) and 2,6-dibromopyridine N-oxide
(5, 1.1 equiv) were used. To our surprise, the oxidant 5 was not
consumed at all, and the major product (92% NMR yield) was a
hydrocarbon whose structure was assigned as 1,2-dihydrocyclopenta-
[a]indene 2a (Table 1, entry 1).9 Notably, this reaction involved
Table 1. Optimization of Reaction Conditionsa
As a result of intense efforts by many research groups in the
past decade, various initially novel aspects of homogeneous
gold catalysis1 have now been well-accepted and increasingly
applied in synthesis of complex structures.2 Further develop-
ment of gold chemistry likely hinges on the discovery of novel
gold intermediates and the application of their new reactivities.
Vinylidene complexes3 of various metals such as Ru, Rh, and
W are versatile intermediates that promote the formation of
various carbon−heteroatom and carbon−carbon bonds in a
range of powerful catalytic reactions. Little is known, however,
about gold vinylidenes. Several studies have invoked their
intermediacy,4 but later calculations have suggested alternative
pathways.5 The only exception is the formation of gold β-
halovinylidene intermediates via AuCl-promoted [1,2]-halo
migration of terminally halogenated alkynes (i.e., haloalkynes),4d
which was later supported by density functional theory (DFT)
calculations.6 For synthetic usefulness, terminal alkynes are ideal,
simple starting materials to access metal vinylidenes. To date,
no proven case of gold vinylidene formation from terminal
alkynes has been reported. Herein we report a gold-catalyzed
cycloisomerization of (2-ethynylphenyl)alkynes, where a gold
vinylidene is the most likely intermediate on the basis of both
mechanistic studies and theoretical calculations; importantly,
this novel gold intermediate, in contrast to its Ru, Rh, and W
counterparts, which often can be isolated,3 is highly reactive and
undergoes facile C(sp3)−H insertions to form tricyclic indenes.
During our continuing study of gold-catalyzed intermolecular
alkyne oxidation,7 we subjected diyne 1a to various combinations of
a
Reaction run in vials using regular DCE as the solvent; [1a] = 0.1 M.
b
Measured by 1H NMR analysis using diethyl phthalate as the internal
c
d
standard. 90% isolated yield. Reaction temperature: 60 °C.
an apparent C(sp3)−H insertion leading to a tricyclic structural
motif found in natural products such as pallidol10 and
sporolides11 and patented compounds of medical interest.12
A
minor product, also involving C−H insertion, was assigned as the
six-membered structural isomer 3a.
Received: August 11, 2011
Published: December 14, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
We were rather curious about the role of 5 and first probed the
impact of its quantity on the reaction outcome. As shown in
Table 1, entries 1−4, the reaction became slower and less efficient
as the amount of the N-oxide was decreased. Lutidine N-oxide
(6) also worked well as an additive, though the reactions were a
bit slower (entries 5−7). We suspected that the N-oxides might
simply function as bases. Indeed, 2,6-dibromopyridine offered a
small improvement to the reaction (entry 8 vs 4), whereas
lutidine was deleterious (entry 9), perhaps because of its strong
basicity (conjugate acid pKa = 6.77). Sodium toluenesulfinate,
with moderate basicity (conjugate acid pKa = 1.9913), led to an
acceptable reaction rate and 79% yield (entry 10). Subsequent
catalyst screening (entries 11−14) revealed that bulky BrettPhos
was uniquely effective as the Au(I) ligand, rendering both a high
yield and excellent chemoselectivity (i.e., 2a vs 3a). Contrary to
BrettPhosAuNTf2, PtCl2 promoted selective formation of 4
(entry 15), consistent with Liu’s previously published results.14
The reaction scope for this rapid construction of 1,2-dihydro-
cyclopenta[a]indenes was then studied. As shown in Table 2,
zthe aliphatic substituent on the internal alkyne tolerated a
range of functional groups, including phenyl (entries 1 and 2),
isolated in addition to 2n. X-ray diffraction studies of product 2c
confirmed our structural assignments.
To probe the reaction mechanism, we performed deuterium-
labeling studies. The results shown in eq 1 indicated that the
hydrogen isotope at C-8 of 2a came mostly from the added
H2O or D2O and little from the alkyne terminus in the
substrate. Labeling the aliphatic side chain with deuteriums
(eq 2) allowed the origin of the C-3 H/D in the products to be
firmly established, consistent with the formation of the C-2 and
C-3 bond via an intramolecular carbene C−H insertion.
Table 2. Reaction Scope and X-ray Crystal Structure of 2ca,b
Equation 1 further suggested that the C-8 hydrogen in 2a
might be installed via protodeauration and that the alkyne
terminal hydrogen in 1a might become labile in the course of
the reaction. Using phenylacetylene as the model alkyne, we
indeed observed facile exchange of its alkyne terminal hydrogen
with added D2O (10 equiv) in CDCl3 in the presence of
BrettPhosAuNTf2 and N-oxide 6 (50% conversion in 5 min);
an alkynylgold species is the most likely intermediate.15
Importantly, without 6, the exchange was much slower (50%
conversion after 1.5 h). This result suggests that 5 or 6 acts
as a base to facilitate the removal of the alkyne terminal
hydrogen to form alkynylgold 1a-Au (see eq 3). Fortunately,
this intermediate could be prepared in its pure form. When we
treated 1a-Au with 5 mol % BrettPhosAuNTf2, the reaction
proceeded to completion in 5 min, and 8-aurated-1,2-
dihydrocyclopenta[a]indene 2a-Au was formed in a quantita-
tive yield (eq 3). To confirm the uniquely effective nature
of BrettPhosAuNTf2, Ph3PAuNTf2 was used as the catalyst
instead, and the reaction was much slower and less efficient (eq 3)
The use of Ph3P in place of BrettPhos in 1a-Au with either
BrettPhosAuNTf2 or Ph3PAuNTf2 as the catalyst led to even
slower reactions and little desired products.16
a
b
Reactions were run in vials; isolated yields are reported. The yields
of the six-membered ring isomer 3 were <5%.
A mechanism consistent with the above results is proposed
in Scheme 1. First, the N-oxide acts as a base to abstract the
proton from the terminal alkyne, which is activated by
BrettPhosAu+. This affords the alkynylgold complex 1-Au.
The reverse process (i.e., protodeauration) may occur, but the
presence of a base should help shift the equilibrium toward
1-Au. A strong base such as lutidine, however, would bind to
the gold catalyst and therefore hinder the overall reaction.
Another BrettPhosAu+ can then activate the other C−C triple
chloro (entry 3), protected amino (entry 4), and protected
hydroxyl (entries 5 and 6). Moreover, cycloalkyl groups such as
cyclopentyl (entry 7) and cyclohexyl (entry 8) were allowed,
leading to tetracyclic products. Substitutions on the benzene
ring (entries 9−11) at different positions were readily allowed.
In addition to efficient insertion into methylene C−H bonds,
the insertion into a methine C−H bond proceeded equally well
(entry 12). Insertion into a methyl C−H bond was less efficient
(entry 13), and a small amount of 2-ethyl-1H-indene (7) was
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single-point calculations at the M06/aug-cc-pVTZ/aug-cc-pVTZ-
PP(Au)(SMD) level. This reaction step forms the novel gold
Scheme 1. Proposed Reaction Mechanism
vinylidene intermediate B, with a predicted ΔGC°HCl of 6.9 kcal/
3
mol from A. The calculated bond lengths and charges clearly
support the vinylidene character of B.16 This intermediate is highly
reactive and can rapidly undergo an intramolecular C−H insertion
reaction with a calculated free energy barrier of 9.2 kcal/mol
for primary C−H bonds to form the tricyclic intermediate D.
The corresponding energy barrier for insertion into the secondary
C−H bonds of a pendent n-propyl group was calculated to be
4.9 kcal/mol.16 The observed product is formed from D following
sequential decomplexation and protodeauration steps.
The theoretical energy surface for the critical 5-endo-dig
cyclization step to give B shows a most interesting situation in
which the alternative 6-endo-dig cyclization to form C actually
forms from the same transition state, TS1. This constitutes
a bifurcated reaction pathway with a ridge−valley inflection
point on a relatively flat energy surface, as shown in Figure 1.
A second transition state structure, TS1a, that is 0.89 kcal/mol
lower in electronic energy than the first, was found for
bond of 1-Au via the intermediacy of 1-Au2, which undergoes a
5-endo-dig cyclization that we believe leads to gold vinylidene
intermediate I.17 This novel species is apparently highly reactive
and may undergo facile C−H insertion18 leading to 2-Au,
which is followed by protodeauration to form the observed
product. The formation of the six-membered structural isomer
(e.g., 3a, Table 1) could be readily explained by a competing
1,6-C−H insertion by the gold vinylidene. A likely competing
6-endo-dig cyclization by 1-Au2 could lead to intermediate II,
which is somewhat analogous to that leading to 4 with platinum
catalysis;14 however, no naphthalenic products were observed.
The preference for the 5-endo-dig cyclization over the
6-endo-dig cyclization might be attributed on one hand to
the bulky BrettPhosAu moiety at the alkyne end, as its bulk19
might help steer the approach of the other C−C triple bond to
the less hindered distal alkyne end, and on the other hand to
back-bonding of the Au center to the adjacent carbocation in
the form of a gold vinylidene (i.e., I).
Figure 1. Energy diagram showing a bifurcation at a ridge−valley
inflection, calculated at the M06/aug-cc-pVTZ-PP(SMD)//M06/-
6-31+G(d,p)/LANL2DZ(Au) level. Relative electronic energies are
given in parentheses and relative free energies in chloroform in brackets,
all in kcal/mol at 298 K. For pictures of typical 3D surfaces, see ref 20.
DFT calculations of the reaction energy surface of a
model reaction (Scheme 2) at the M06/6-31+G(d,p)/
LANL2DZ(Au)(SMD) in CHCl3 level have shown that this
is a reasonable mechanism, supporting the hypothesis that a
gold vinylidene intermediate would be stable enough to form yet
interconversion of the five- and six-membered ring inter-
mediates B and C. In situations of this sort, the choice between
B and C is made on the basis of dynamical factors along the
ridge (between TS1 and TS1a) separating the valleys for B and
C, and the product ratios must be predicted by dynamical
effects in trajectory calculations rather than classical transition
state theory.20,21 Preliminary atom-centered density matrix
propagation (ADMP) molecular dynamics calculations for a
simplified model reaction with PH3 ligands, a methyl substituent,
and no benzo fusion gave reaction trajectories starting from the
first transition state and going to both the five- and six-
membered ring products within 150−300 fs with no
intermediate formation. The trajectories predicted that the five-
membered ring product should prevail, as observed, but not
overwhelmingly. It was expected that the stronger selectivity
toward the 5-endo-dig cyclization observed experimentally might
be attributed to the steric bulk of one of the BrettPhos ligands.
The bulky BrettPhos ligand on the gold vinylidene moiety in B is
held a CC bond length further away from the ring and
pendant ethyl group than in C. This steric preference for B with
a BrettPhos ligand was confirmed with calculations on structures
optimized at the B3LYP/6-31G(d)/LANL2DZ(Au) level that
showed a steric shift in the free energy differences toward the five-
membered ring intermediate of 5.1 kcal/mol.16 The calculation was
performed on a model with the full BrettPhos structure for the
relavent ligand and PMe3 for the other ligand. The conformation
Scheme 2. Free Energy Diagram for the Reaction in
Chloroform at 298 K Calculated at the M06/aug-cc-pVTZ-
PP(SMD)//M06/6-31+G(d,p)/LANL2DZ(Au) Level (All
Values in kcal/mol Relative to 1n)
reactive enough to carry out the required C−H insertion reaction
readily. The energetics for the expected proton abstraction by
pyridine N-oxides is favorable (uphill by only 2.2 kcal/mol in
chloroform16), and the 5-endo-dig ring closure was found to occur
with a free energy barrier in chloroform of only 14.7 kcal/mol in
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Journal of the American Chemical Society
Communication
2010, 16, 8238. (c) Trost, B. M.; McClory, A. Chem.Asian J. 2008,
3, 164. (d) Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2006, 45,
chosen for the BrettPhos ligand was the same as that found in the
crystal structure of BrettPhosAuNTf2.7a Interestingly, such
bifurcation pathways are still very rare in organometallic chemistry
but have recently been seen for gold-catalyzed reactions.22
The gold vinylidene intermediate of type I was also found to
insert readily into O−H (eq 4) and N−H bonds (eq 5), leading
to highly efficient formation of useful tricyclic furan and pyrrole
structures, respectively. Interestingly, when there was a
2176. (e) Varela, J. A.; Saa,
́
C. Chem.Eur. J. 2006, 12, 6450.
(f) McDonald, F. E. Chem.Eur. J. 1999, 5, 3103. (g) Bruneau, C.;
Dixneuf, P. H. Acc. Chem. Res. 1999, 32, 311. (h) Bruce, M. I. Chem.
Rev. 1991, 91, 197.
(4) (a) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Tetrahedron
2008, 64, 6876. (b) Lavallo, V.; Frey, G. D.; Kousar, S.; Donnadieu, B.;
Bertrand, G. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 13569. (c) Seregin,
I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050. (d) Mamane,
V.; Hannen, P.; Furstner, A. Chem.Eur. J. 2004, 10, 4556.
̈
(5) (a) Xia, Y.; Dudnik, A. S.; Li, Y.; Gevorgyan, V. Org. Lett. 2010,
̂
12, 5538. (b) Rabaa, H.; Engels, B.; Hupp, T.; Hashmi, A. S. K. Int. J.
Quantum Chem. 2007, 107, 359.
(6) Soriano, E.; Marco-Contelles, J. Organometallics 2006, 25, 4542.
(7) (a) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50,
3236. (b) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 8482.
(c) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550.
(d) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
3258. (e) Lu, B.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070.
(8) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(9) (a) Lian, J. J.; Chen, P. C.; Lin, Y. P.; Ting, H. C.; Liu, R. S.
J. Am. Chem. Soc. 2006, 128, 11372. (b) Lin, G. Y.; Yang, C. Y.; Liu,
R. S. J. Org. Chem. 2007, 72, 6753.
competition between O−H and C−H bonds (i.e., in the case
of 1p in eq 4), the gold vinylidene preferred the O−H bond,
and no C−H insertion product was found.
In summary, we have reported a gold-catalyzed cyclo-
isomerization of benzene-1,2-dialkynes in which two molecules
of BrettPhosAuNTf2 are proposed to work synergistically and a
gold vinylidene is the most likely intermediate on the basis of
both mechanistic studies and theoretical calculations.
(10) Bavaresco, L.; Vezzulli, S. Rec. Prog. Med. Plants 2006, 11, 389.
(11) Buchanan, G. O.; Williams, P. G.; Feling, R. H.; Kauffman, C.
A.; Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731.
(12) (a) Jakubowski, J. A.; Utterback, B. G.; Mais, D. E.; Hardinger,
S. A.; Braish, T. F.; Nevill, C. R.; Fuchs, P. L. Prostaglandins 1994, 47,
189. (b) Tomyama, T.; Ikegami, S.; Hashimoto, S.; Imamaki, T. Jpn.
Kokai Tokkyo Koho JP 07076550 A 19950320, 1995. (c) Ratilainen,
J.; Huhtala, P.; Karjalainen, A.; Karjalainen, A.; Haapalinna, A.;
Virtanen, R.; Lehtimaeki, J. PCT Int. Appl., WO2001085698 A1
20011115, 2001
ASSOCIATED CONTENT
* Supporting Information
■
S
(13) Burkhard, R. K.; Sellers, D. E.; DeCou, F.; Lambert, J. L. J. Org.
Chem. 1959, 24, 767.
(14) Taduri, B. P.; Ran, Y.-F.; Huang, C.-W.; Liu, R.-S. Org. Lett.
2006, 8, 883.
Experimental procedures, compound characterization data, and
computational details. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Cheong, P. H. Y.; Morganelli, P.; Luzung, M. R.; Houk, K. N.;
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 4517.
(16) For details, see the Supporting Information (SI).
(17) Chen, K.-H.; Feng, Y. J.; Ma, H.-W.; Lin, Y.-C.; Liu, Y.-H.; Kuo,
T.-S. Organometallics 2010, 29, 6829.
(18) (a) Bhunia, S.; Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16488.
(b) Horino, Y.; Yamamoto, T.; Ueda, K.; Kuroda, S.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 2809. (c) Lemiere, G.; Gandon, V.;
Cariou, K.; Hours, A.; Fukuyama, T.; Dhimane, A. L.; Fensterbank, L.;
Malacria, M. J. Am. Chem. Soc. 2009, 131, 2993.
AUTHOR INFORMATION
Corresponding Author
aue@chem.ucsb.edu; zhang@chem.ucsb.edu
■
Present Addresses
†College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen 361005, P. R. China.
ACKNOWLEDGMENTS
■
We are grateful for the generous financial support by NIH (R01
GM084254), the National Center for Supercomputing Applica-
tions, NSF (CHE100123) utilizing the NCSA Ember system, and
UCSB and the kind donation of BrettPhos by Sigma-Aldrich.
(19) Benitez, D.; Tkatchouk, E.; Gonzalez, A. Z.; Goddard, W. A. III;
Toste, F. D. Org. Lett. 2009, 11, 4798.
̈
̧elebi-Olcu̧ m, N.;
̈
(20) Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.; C
Houk, K. N. Angew. Chem., Int. Ed. 2008, 47, 7592.
(21) While Scheme 2 suggests the possibility that B and C might
equilibrate through TS1a, this equilibration was calculated to be
somewhat slower than the competing C−H insertion reaction for a
secondary C−H bond. The possible fate of any C formed in the
reaction was predicted computationally. It was found to undergo an
exothermic gold migration and C−H insertion with a barrier as low as
that for B and to be faster than equilibration of B and C. This insertion
product would lead to 2,3-cyclopentano-fused naphthalenes rather
than the 1,2-fusion seen in 4 from Pt. See the SI for details.
REFERENCES
(1) For selected reviews, see: (a) Corma, A.; Leyva-Per
■
́
ez, A.;
Sabater, M. J. Chem. Rev. 2011, 111, 1657. (b) Wang, S.; Zhang, G.;
Zhang, L. Synlett 2010, 692. (c) Abu Sohel, S. M.; Liu, R.-S. Chem. Soc.
Rev. 2009, 38, 2269. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008,
108, 3395. (e) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239.
(f) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351.
(g) Arcadi, A. Chem. Rev. 2008, 108, 3266. (h) Hashmi, A. S. K. Chem.
Rev. 2007, 107, 3180. (i) Furstner, A.; Davis, P. W. Angew. Chem., Int.
Ed. 2007, 46, 3410.
(2) (a) Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37,
(22) (a) Noey, E. L.; Wang, X.; Houk, K. N. J. Org. Chem. 2011, 76,
̈
́
3477. (b) Garayalde, D.; Gomez-Bengoa, E.; Huang, X.; Goeke, A.;
Nevado, C. J. Am. Chem. Soc. 2010, 132, 4720. (c) Wang, Z. J.; Benitez,
D.; Tkatchouk, E.; Goddard, W. A. III; Toste, F. D. J. Am. Chem. Soc.
2010, 132, 13064.
1766. (b) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208.
̈
(3) (a) Metal Vinylidenes and Allenylidenes in Catalysis: From Reactivity
to Applications in Synthesis; Bruneau, C., Dixneuf, P. H., Eds.; Wiley-
VCH: Weinheim, Germany, 2008. (b) Lynam, J. M. Chem.Eur. J.
34
dx.doi.org/10.1021/ja2091992 | J. Am. Chem.Soc. 2012, 134, 31−34