Gold-catalyzed cycloisomerization of 1,5-allenynes via dual activation of an ene reaction

Article abstract of DOI:10.1021/ja711058f

Tris(thphenylphosphinegold) oxonium tetrafluoroborate, [(Ph ₃PAu)₃O]BF₄, catalyzes the rearrangement of 1,5-allenynes to produce cross-conjugated trienes. Experimental and computational evidence shows that the ene reaction proceeds through a unique nucleophilic addition of an allene double bond to a cationic phosphinegold(I)-complexed phosphinegold(I) acetylide, followed by a 1,5-hydrogen shift.

Full text of DOI:10.1021/ja711058f

Published on Web 03/08/2008
Gold-Catalyzed Cycloisomerization of 1,5-Allenynes via Dual
Activation of an Ene Reaction
Paul Ha-Yeon Cheong,† Philip Morganelli,‡ Michael R. Luzung,‡ K. N. Houk,*,† and
F. Dean Toste*,‡
Department of Chemistry, UniVersity of California, Berkeley, California 94720, and Department
of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received December 12, 2007; E-mail: houk@chem.ucla.edu; fdtoste@berkeley.edu
Abstract: Tris(triphenylphosphinegold) oxonium tetrafluoroborate, [(Ph3PAu)3O]BF4, catalyzes the rear-
rangement of 1,5-allenynes to produce cross-conjugated trienes. Experimental and computational evidence
shows that the ene reaction proceeds through a unique nucleophilic addition of an allene double bond to
a cationic phosphinegold(I)-complexed phosphinegold(I) acetylide, followed by a 1,5-hydrogen shift.
Introduction
Substrate Scope. Reaction of 1,5-allenyne 2a under typical
Transition metal-catalyzed allenyne cycloisomerization reac-
tions provide an atom-economical entry into polyunsaturated
carbo- and heterocycles.1-3 These reactions involving Rh, Pd,
or Pt are generally postulated to proceed via metallacyclopentene
intermediates, inherently involving an increase in the formal
oxidation state of the metal.1,4 On the other hand, gold(I)-
catalyzed enyne5 and some related 1,6-allenyne cycloisomer-
ization reactions6 are proposed to proceed without a change in
the formal oxidation state of the catalyst.7 We report a combined
experimental and computational investigation of gold(I) catalysis
of an allenyne cyclization that proceeds via a unique mechanism
involving cationic phosphinegold(I) activation of an in situ
generated phosphinegold(I) acetylide.2,8-10
conditions for the cycloisomerization of 1,5-enynes [1 mol %
Ph3PAuCl, 1 mol % AgSbF6, CH2Cl2, room temperature (rt)]5c
resulted in rapid formation of a complex mixture. Switching
the catalyst to the less reactive tris(phosphinegold)oxonium
complex [(Ph3PAu)3O]BF4 1 furnished triene 3a in 31% yield.
The yield was further improved to 88% when the reaction was
conducted at 60 °C in chloroform (Table 1, entry 1). Under
these optimal conditions, a variety of 1,5-allenynes participate
in the gold-catalyzed cycloisomerization. Substitutions on the
tether (entries 1-6) and on the allene moiety (entries 7 and 8)
are well tolerated.11 Both diastereomers of bicyclo[4.3.0]nonanes
5a,b could be prepared with complete retention of stereochem-
istry. In addition to cyclopentenes, cyclohexene 11 was produced
from the gold-catalyzed cycloisomerization of 1,6-allenyne 10,
albeit with diminished yield (entry 9). Of mechanistic impor-
tance, nonterminal alkyne substrates were inert under these
conditions.12,13
† University of California, Los Angeles.
‡ University of California, Berkeley.
(1) Allenyne cycloisomerizations proceeding through metallacyclopentene
intermediates: For Rh, (a) Brummond, K. M.; Chen, H.; Sill, P.; You, L.
J. Am. Chem. Soc. 2002, 124, 15186. (b) Shibata, T.; Takesue, Y.;
Kadowaki, S.; Takagi, K. Synlett 2003, 268. (c) Mukai, C.; Inagaki, F.;
Yoshida, T.; Kitagaki, S. Tetrahedron Lett. 2004, 45, 4117. For Ti, (d)
Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc. 1997, 119,
11295. For Pt, (e) Cadran, N.; Cariou, K.; Herve, G.; Aubert, C.;
Fensterbank, L.; Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc. 2004,
126, 3408. (f) Matsuda, T.; Kadowski, S.; Goyam, T.; Murakami, M. Synlett
2006, 575. For Mo, (g) Shen, Q.; Hammond, G. B. J. Am. Chem. Soc.
2002, 124, 6534.
(6) (a) Lemie`re, G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; de Kozak, A.;
Aubert, C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006,
45, 7596. (b) The allyl cation intermediate was trapped by the use of
deuterated methanol. (c) Protodemetallations are known to occur stereo-
selectively. In the case of 1,6-allenyne rearrangements, the same anti
incorporation of deuterium was observed.
(2) Alternative mechanisms for allenyne cycloisomerization: For Co, (a)
Lierena, D.; Aubert, C.; Malacria, M. Tetrahedron Lett. 1996, 37, 7027.
For Ga, (b) Lee, S. I.; Sim, S. H.; Kim, S. M.; Kim, K.; Chung, Y. K. J.
Org. Chem. 2006, 71, 7120. For Mo-catalyzed allenyne metathesis, (c)
Murakami, M.; Kadowski, S.; Matsuda, T. Org. Lett. 2005, 7, 3953.
(3) Thermal reactions of allenynes: (a) Ohno, H.; Mizutani, T.; Kadoh, Y.;
Miyamura, K.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 5113. (b) Oh,
C. H.; Gupta, A. K.; Park, D. I.; Kim, N. Chem. Commun. 2005, 5670.
(4) DFT-based theoretical study of the Pt(II)-catalyzed cycloisomerization of
allenynes: Soriano, E.; Marco-Contelles, J. Chem - Eur. J. 2005, 11, 521.
(5) Cycloisomerization of 1,5- and 1,6-enynes involving nucleophilic addition
of olefins to gold(I)-acetylene complexes: (a) Nieto-Oberhuber, C.;
Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A.
M. Angew. Chem., Int. Ed. 2004, 43, 2402. (b) Mamane, V.; Gress, T.;
Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (c) Luzung,
M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858.
(d) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J. Am. Chem. Soc.
2005, 127, 6178. (e) Gagosz, F. Org. Lett. 2005, 7, 4129. (e) Sun, J.; Conley,
M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2006, 128, 9705. (f)
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 2006, 45, 2901. (g) Park, S.;
Lee, D. J. Am. Chem. Soc. 2006, 128, 10664. (h) Horino, Y.; Luzung, M.
R.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 11364. For reviews: (i)
Nieto-Oberhuber, C.; Lo´pez, A.; Jime´nez-Nu´n˜ez, E.; Echavarren, A. M.
Chem. Eur. J. 2006, 12, 5916. (j) Ma, S.; Yu, S.; Gu, Z. Angew. Chem.,
Int. Ed. 2006, 45, 200.
(7) Recent reviews of gold-catalyzed reactions: (a) Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem. Commun. 2007, 333. (b) Gorin, D. J.; Toste, F.
D. Nature 2007, 446, 395. (c) Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 2. (d) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180.
(8) Gupta, A. K.; Rhim, C. Y.; Oh, C. H.; Mane, R. S.; Han, S.-H. Green
Chem. 2006, 8, 25.
(9) Dipolar cycloadditions catalyzed by a two copper mechanism have been
reported recently: Ahlquist, M.; Fokin, V. V. Organometallics 2007,
26, 4389.
(10) A related allenyne rearrangement has been reported: Zriba, R.; Gandon,
V.; Aubert, C.; Fensterbank, L.; Malacria, M. Chem.sEur. J. 2008, 14,
1482.
(11) A preference for formation of Z-9a can be rationalized by conformational
analysis of the proton transfer step. A conformation leading to an E-olefin,
placing ethyl planar with phenyl group, introduces a significant strain. The
final product distribution of 7:1, corresponding to an energy difference of
1.2 kcal/mol, is an acceptable value for A(1,2)-strain.
(12) Both alkyl- (2e) and aryl- (2f) substituted alkynes failed to react under the
reported reactions conditions. See Experimental Section for details.
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J. AM. CHEM. SOC. 2008, 130, 4517-4526
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A R T I C L E S
Cheong et al.
Table 1. Scope of Gold(I)-Catalyzed Allenyne Cycloisomerization
a Isolated yields after flash column chromatography. For reaction times, see Supporting Information. b Reaction was run in CH2Cl2 at 40 °C. c Regio- and
1
stereoselectivities measured by H NMR.
Deuterium Labeling Experiments. Deuterium labeling
experiments reveal that the hydrogen transfer is stereoselec-
tive; the allenic hydrogen is always incorporated syn to the
newly formed C-C bond (eq 1). A double-labeled crossover
hydrogen transfer (eq 2). The proton at the alkyne terminus,
however, does exchange (eq 3). In deuterated methanol, nearly
complete anti incorporation of deuterium is observed in the
product (eq 4).
experiment showed no exchange of the deuterium label,
suggesting the reaction proceeds through an intramolecular
(13) In contrast, triphenylphosphine hexafluoroantimonate catalyzed the cyclo-
isomerization of 1,6-allenynes containing phenyl-substituted alkynes via a
tandem 5-endo-dig/Nazarov cyclization mechanism: Lin, G.-Y.; Yang, C.-
Y.; Liu, R. S. J. Org. Chem. 2007, 72, 6753. Related 6-endo-dig cyclization
of allenynes: Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc.
2006, 128, 7436.
Kinetic Isotope Effect. Two kinetic isotope experiments were
performed (eqs 5 and 6). The kCD /kCH isotope effect (1.89 (
0.02) and the kH/kD isotope effect (1.84 ( 0.15) were essentially
3
3
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Gold-Catalyzed Cycloisomerization of 1,5-Allenynes
A R T I C L E S
Scheme 1. Potential Intermediates Involved in the Trimer (1)-Catalyzed Allenyne Cycloisomerization
identical, suggesting that the formal 1,5-sigmatropic shift is
responsible for the measured isotope effects. Additionally, these
measured kinetic isotope effects are much smaller than the
typical values of 3-5 for 1,5-sigmatropic shifts.14-16
A mechanism involving double activation by phosphinegold-
(I) is plausible. This is supported by three experimental
observations: (i) inertness of nonterminal alkyne substrates
under reaction conditions,12 (ii) deuterium exchange at the
terminal alkyne position (eq 4), and (iii) observation of the
transient formation of phosphinegold acetylide 2a′ from 2a under
the reaction conditions.18 We believe this reaction to undergo
catalysis via species I.19
Computational Method. The geometry optimizations and
thermodynamic corrections were performed with hybrid
density functional theory (B3LYP) with the 6-31+G* and
LANL2DZ+ECP basis sets. Solvation corrections for chloro-
form were computed by the PCM method with single points at
the HF level with 6-31+G(d,p) and LANL2DZ basis sets. All
calculations were performed with the Gaussian series of
programs.20
The computationally investigated reaction was the conversion
of unsubstituted substrate 2b to triene product 3b. Phosphine
was used as a model for the triphenylphosphine. Species
involving the triphenylphosphine were also optimized to com-
pare experimental and computed kinetic isotope effects (KIEs).
Computed KIEs between transition structures involving simple
phosphines and triphenyl phosphines were indistinguishable in
all computed cases.
Proposed Mechanisms. Numerous mechanistic possibilities
exist for catalysis of this formal ene reaction (top, Scheme 1).
In fact, no less than nine possibilities emerged during our
investigation.
The mechanism through B involves an oxidative cyclization
of the allenyne to form gold(III)-metallacycle, followed by
â-hydride elimination and reductive elimination. Mechanisms
involving A and C are ene reactions of phosphinegold vinylidene
and phosphinegold acetylide, respectively. Mechanisms through
D and E are ene reactions catalyzed by the coordination of a
phosphinegold to either the acetylene or allene17 in the substrate.
Mechanisms F-I are transformations analogous to B-E
involving a phosphinegold acetylide.
All relative energies presented in this paper are free energies
in kilocalories per mole, with respect to separated substrate and
tris(phosphinegold)oxonium catalyst complex.
Possible Substrate-Gold Complexes. The tris[phosphine-
gold(I)]oxonium catalyst 1 can transfer a phosphinegold cation
(14) Houk, K. N.; Li, Y.; Evanseck, J. D. Angew. Chem., Int. Ed. 2003, 31,
682.
(18) The 1H NMR spectrum of acetylide 2a′ was compared to the spec-
trum obtained from a reaction in progress of 2a with stoichiometric
quantities of trimer 1. A transient peak at 5.05 ppm observed in the
latter spectrum is a match with the C5 proton of the acetylide spectrum at
5.07 ppm.
(15) Examples: Doering, W. von E.; Zhao, X. J. Am. Chem. Soc. 2006, 126,
9080 and references therein.
(16) A kCD /kCH isotope effect of 1.43 was measured in the related Schmittel-
3
3
ene cyclization of enyne-allenes: Bekele, T.; Christian, C. F.; Lipton, M.
A.; Singleton, D. A. J. Am. Chem. Soc. 2005, 127, 9216.
(17) Coordination of cationic triphenylphosphinegold(I) to the internal olefin
of the allene does not lead to viable catalysis and therefore was excluded
from analyses.
(19) A related dual-activation mechanism has recently been proposed for the
copper-catalyzed azide-alkyne cycloaddition: Ahlquist, M.; Fokin, V. V.
Organometallics 2007, 26, 4389.
(20) Frisch, M. J.; et al. Gaussian 03, Revision C.02; Gaussian, Inc.: Pittsburgh,
PA, 2004.
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Cheong et al.
Scheme 2. Possible Substrate-Gold Complexes
to the alkyne, a process with an unfavorable enthalpy and
entropy (∆G ) 37.4 and ∆Gsolv ) 21.8 kcal/mol, E), although
this is likely to be much more favorable with sterically hindered
phosphines. The formation of phosphinegold acetylide is very
favorable, and subsequent transfer of a second phosphinegold
cation is also favorable (Scheme 2).
without added catalyst failed to furnish the desired products
(eq 8).
Uncatalyzed Reaction: Ene Reaction of 1,5-Allenyne. The
parent uncatalyzed ene reaction involves a concerted C-C bond
formation and asynchronous hydrogen transfer (Figure 1). The
free energy barrier of this process (∆Gq ) 33.0 and ∆Gsolv
)
q
32.3 kcal/mol, TS-15) is typical for pericyclic reactions.17 The
reaction exergonicity is computed to be large (∆Grxn ) ∼-38
kcal/mol, 16).
Mechanism via A: Ene Reaction of Phosphinegold Acetyl-
ide. The ene reaction of phosphinegold acetylide, A, was
postulated by analogy to copper-catalyzed pericyclic
reactions.22 The coordination of copper(I) to a terminal alkyne
reportedly lowers the pKa of the proton by ∼8 pKa units,
allowing for facile formation of copper acetylides.22 A similar
pathway is proposed for the formation of phosphinegold
acetylide (see Scheme 2).
Mechanism via B or F: Metallacycles. Despite extensive
computational searching, no metallacycle intermediates similar
to B or F could be found. Any attempts to locate these
metallacycle intermediates computationally lead to substrate
phosphinegold complexes with a preferential monoligation to
either the alkyne or the allene (17 and 18, Figure 3). Indeed,
this is not surprising, considering that, relative to other late
transition metals, oxidative additions involving cationic phos-
phinegold(I) complexes are known to be difficult.24
A mechanism involving a metallacycle intermediate neces-
sitates a â-hydride elimination step to generate product (Scheme
3). Such a reaction should be very sensitive to the electronic
bias of the hydrogen being transferred. An experimental
intramolecular Hammett study was designed to probe the nature
of the hydrogen transfer. Cyclization of unsymmetric substrate
19 yielded a regioisomeric product distribution of 1.3:1.0,
Computationally, the ene reaction via A is found to be
extremely similar to the uncatalyzed reaction; it features
concerted C-C bond formation and highly asynchronous
hydrogen transfer (A-TS-1 in Figure 2). The computed free
q
energy barrier (∆Gq ) 35.2 and ∆Gsolv ) 34.0 kcal/mol) is
approximately equal to that of the uncatalyzed process
(∆Gsolvq ) 32.3 kcal/mol, TS-15 in Figure 1). These computed
barriers suggest that this mechanism is unlikely. Moreover, the
computed KIEs for this process (1.25 and 1.32, respectively)
did not match the experimentally observed KIEs of ∼1.85 (eqs
5 and 6).
While the deuterium exchange experiments are consistent with
in situ generation of phosphinegold acetylide (eq 3), independent
evidence for acetylide participation in the catalytic cycle was
sought. To this end, phosphinegold acetylide 2a′ was prepared
by formation of the lithium acetylide of substrate 2a and
subsequent transmetallation with triphenylphosphinegold(I)
chloride (eq 7).23 However, as predicted from computations,
the exposure of the acetylide 2a′ to reaction conditions
(21) Figures prepared with CYLview: Legault, C. Y. CYLView, version 1.0b;
UCLA: Los Angeles, CA, 2007.
(22) Computational study of copper-catalyzed pericyclic reactions has
been reported: Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005,
127, 210.
(23) Schuster, O.; Liau, R.-Y.; Schier, A.; Schmidbaur, H. Inorg. Chim. Acta
2005, 358, 1429.
(24) Oxidative addition of phosphinegold(I)halide complexes to elemental
halogens: Schneider, D.; Schier, A.; Schmidbaur, H. Dalton Trans. 2004,
1995 and references therein.
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Gold-Catalyzed Cycloisomerization of 1,5-Allenynes
A R T I C L E S
Figure 1. Uncatalyzed reaction: computed reactant, transition structure, and product.21
Figure 2. Computed reactant, transition structure, and product corresponding to the ene reaction of a gold acetylide A.21
Figure 3. Computed intermediates, 17 and 18, resulting from computational efforts to locate metallacycle intermediates B and F, respectively.21
slightly favoring transfer of the hydrogen benzylic to the
p-trifluoromethyl group (eq 9). This near-equal distribution of
isomers is suggestive of electronic neutrality in the hydrogen
transfer transition state and is inconsistent with a mechanism
involving â-hydride elimination. Finally, the measured KIEs
of ∼1.85 (eq 5 and 6) are inconsistent with transition metal-
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A R T I C L E S
Cheong et al.
Figure 4. Computed vinylidene intermediate C and the intermediate I arising from computational efforts to locate the gold acetylide vinylidene intermediate
G.21
Figure 5. Computed intermediates and transition structures corresponding to the ene reaction of Au(I) phosphine allene coordination complex D.21
Scheme 3. Hypothetical Au(III) Metallacycle Mechanism
catalyzed reactions that are proposed to proceed via metallacycle
intermediates.25,26
Mechanism via D or H: Catalysis by Phosphinegold
Coordination to the Allene π-Bond. The computed structures
corresponding to the transformations arising from phosphinegold
coordination to the allene of the substrate (D, Scheme 1) are
shown in Figure 5.17 This coordination mode leads to concerted
C-C bond formation and asynchronous hydrogen transfer,
similar to the uncatalyzed process. The free energy of activation
Mechanism via C or G: Gold Vinylidenes. The gold
vinylidene intermediate C was found to be extremely unstable
(∆G ) 52.9 and ∆Gsolv ) 36.7 kcal/mol, Figure 4). Since
this intermediate is higher in energy than the transition structure
of the uncatalyzed reaction (Figure 1),
a mechanism
for this process is prohibitively high (∆Gq ) 63.7 and ∆Gsolv
q
involving C is not operative. The gold vinylidene of the gold
acetylide G is not a minimum, and calculations lead to
spontaneously rearrangement to a structure corresponding to
intermediate I.
) 50.1 kcal/ mol, D-TS-1), due to the development of an
unstabilized vinyl cation in the transition state. In fact, the
computed barrier is much greater (∆Gsolvq > 50 kcal/mol) than
that of the uncatalyzed reaction (∆Gsolvq ) 32.3 kcal/mol, TS-
15 in Figure 1).
(25) [Rh(CO)2Cl]2 also catalyzes the same reaction, but the measured kCD /kCH
3
3
isotope effect (1.19 ( 0.05) is much lower.
(26) Examples of kH/kD isotope effect on â-hydrogen elimination: (a) Ozawa,
F.; Ito, T.; Yamamoto, A. J. Am. Chem. Soc. 1980, 120, 6457. (b) Evans,
J.; Schwarts, J.; Urquhart, P. W. J. Organomet. Chem. 1974, 81, C37.
The analogous computed structures corresponding to mech-
anism via H (Figure 6), which involves phosphinegold coor-
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Gold-Catalyzed Cycloisomerization of 1,5-Allenynes
A R T I C L E S
Figure 6. Computed intermediates and transition structures corresponding to the ene reaction of phosphinegold coordination to the allene of a gold
acetylide, H.21
dination to the allene of a phosphinegold acetylide, closely
resemble those involving D (Figure 5); it also features concerted
C-C bond formation and asynchronous hydrogen transfer (H-
TS-1). However, this process is much more facile because it
does not incur the energetic penalty of transferring a single
phosphinegold cation (D versus H, Scheme 1). This mechanism
is still unlikely to occur because the free energy of activation
The greater stability of the alkyne coordination pathway (E
in Scheme 1) as compared to the allene coordination (D in
Scheme 1 and D-TS-1 in Figure 5) stems primarily from the
stabilization of the developing allylic substituted cation versus
a vinyl cation.
A mechanism involving intermediate E appears viable,
although still relatively slow. We believe it does not actually
occur for several reasons: (i) This mechanism fails to account
for the inertness of nonterminal alkyne substrates.12 (ii) Forma-
tion of the C-C bond is predicted to result in formation of a
relatively stable vinyl gold intermediate (E-2-anti) that should
be observable. Despite extensive trials to trap this intermediate
via addition of methanol to the reaction mixture, products
corresponding to this intermediate could not be isolated.6b (iii)
Computed KIEs for this mechanism (1.02 and 4.04 for eqs 5
and 6, respectively) did not fit the experimentally observed KIEs
of ∼1.85.
q
(∆Gsolv ) 31.4 kcal/mol, H-TS-1) is very similar to that of
q
the uncatalyzed process (∆Gsolv ) 32.3 kcal/mol, TS-15 in
Figure 1).
Mechanism via E or I: Catalysis by Phosphinegold
Coordination to the Alkyne π-Bond. The cyclization involving
phosphinegold alkyne complex E occurs via a stepwise process.
C-C bond formation (E-TS-1-syn and E-TS-1-anti) following
phosphinegold coordination leads to a relatively stable vinyl
cation intermediate in which the gold is either syn or anti to
the forming C-C bond (E-2-syn and E-2-anti, respectively).
The subsequent hydrogen transfer (E-TS-3-syn and E-TS-3-
anti) from an adjacent allenyl methyl group to the nascent
allylgold furnishes the product phosphinegold complex E-4.27
The anti coordination mode is favored over the syn for the
C-C bond formation by ∼7 kcal/mol. Steric repulsions will
cause the anti isomer to be even more strongly favored with
larger alkylphosphine ligands. While subsequent hydrogen
transfer is more favored for the syn than the anti isomer,
isomerization of the vinyl gold intermediate E-2 from the anti
arrangement to the syn is extremely difficult (∆Gq ) 44.4 kcal/
mol). The anti C-C bond formation (E-TS-1-anti) and subse-
quent hydrogen transfer process (E-TS-3-anti) exhibit free
energy barriers of ∼28 kcal/mol. It is interesting to note that
most of the barrier for C-C bond formation arises from the
energetic penalty of transferring a single phosphinegold cation
(E versus I, Scheme 1): E-TS-1-anti is essentially barrierless
from E.
Although the acetylide 2a′ was bench-top-stable in both
solution and solid state, addition of trimer 1 afforded triene 3a
(eq 10). Use of PPh3AuOTf also proved successful when applied
toward the preformed acetylide 2a′. Even simple Lewis acids
such as ZnCl2 or Brønsted acid elicited product formation.28
As previously stated, the use of PPh3AuCl/AgOTf leads to
the formation of a complex mixture. In light of this, the
cyclization of 2a′ by Brønsted acid catalysis shown in eq 10 is
curious because this should amount to an equivalent process.
However, complex 1 contains a basic oxo ligand that promotes
deprotonation to form the gold acetylide (Scheme 2). Addition-
ally, in the absence of formation of the phosphinegold acetylide,
(27) Formation of a bicyclo[3.1.0]hexane intermediate has been proposed in
previously reported gold-catalyzed cycloisomerization reactions of 1,5-
enynes.5c The analogous intermediate is not accessible in the current reaction
as it would require the formation of a strained bicyclo[3.1.0]hex-1-ene
species, in violation of Bredt’s rule.
(28) Reaction of analogous silver acetylides with various Lewis acids yielded
no observable triene product.
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A R T I C L E S
Cheong et al.
Figure 7. Computed intermediates and transition structures corresponding to the ene reaction of Au(I) phosphine alkyne coordination complex E.21
the phosphinegold cation may lead to an unselective reaction,
perhaps due to pathways involving activation of the allene.29,30
It is conceivable that phosphinegold could also catalyze the
degradation of the allene in phosphinegold acetylide intermediate
D, but we observe selective formation of the desired triene
products. Additionally, while there is little difference in the
preference for phosphinegold to coordinate to an alkyne or
allene,30 there is a strong preference (∼22 kcal/mol) for
coordination to an acetylide over an allene.31
The computed transformations following phosphinegold
coordination to the alkyne of a phosphinegold acetylide (I,
Scheme 1) are shown in Figure 8. This process is stepwise,
similar to mechanism via D (Figure 7). C-C bond formation
(I-TS-1) has a reasonable free energy barrier (∼21 kcal/mol),
leading to a gem-diauraalkene intermediate (I-2). The free
energy barrier for the subsequent 1,5-sigmatropic hydrogen
transfer (I-TS-3) is slightly lower (∼20 kcal/mol). The reaction
is exergonic by -45.5 kcal/mol.
The structure of intermediate I-4 requires some elaboration.
The computed structure of this intermediate features a three-
centered two-electron bond (Figure 9). The structure is best
regarded as a vinyl anion coordinated by two phosphinegold
cations.
The experimentally observed diastereoselective incorporation
of hydrogen (eq 1) and anti incorporation of solvent deuterium
(eq 4) are explained by the following: (i) the 1,5-sigmatropic
(29) Examples of cycloisomerizations enallenes involving activation of allenes
by cationic phosphine gold complexes: (a) Zhang, L. J. Am. Chem. Soc.
2005, 127, 16804. (b) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128,
12614. (c) Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912.
(d) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398. (e) Luzung,
M. R.; Mauleo´n, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402. (f)
Lemie´re, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.-L.;
Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207. (g) Tarselli, M.
A.; Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew. Chem., Int. Ed. 2007,
46, 6670.
(30) There is a slight preference for the phosphinegold to coordinate to the allene
over the alkyne.
(31)
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4524 J. AM. CHEM. SOC. VOL. 130, NO. 13, 2008

Gold-Catalyzed Cycloisomerization of 1,5-Allenynes
A R T I C L E S
Figure 8. Computed intermediates and transition structures corresponding to the ene reaction of phosphinegold cation coordination to the alkyne of a
phosphinegold acetylide, I.21
Scheme 4. Mechanism Involving I (Scheme 1)
Figure 9. Side view of intermediate I-4.21
cations from I-4 to form species I and the release of product is
exergonic by 10 kcal/mol. Efforts to trap the gem-diauraalkene
shift (I-TS-3) is stereospecific; (ii) subsequent isomerizations
around the double bond of intermediate I-4 are hindered by the
steric bulk of the gold phosphines; and (iii) protodemetallations
are known to occur stereospecifically.6c Additionally, the
computed KIE values of mechanism I are 1.8 and 2.0,
respectively, for eqs 5 and 6, which are in excellent agree-
ment with experimentally observed KIE of ∼1.85 for both
cases.32
The steady-state catalytic cycle of this reaction is summarized
in Scheme 4. The coordination of a phosphinegold cation to
the in situ generated phosphinegold acetylide lowers the alkyne
lowest unoccupied molecular orbital (LUMO) toward 5-endo-
dig cyclization, generating a gem-diauraalkene and tertiary
allylic carbocation. A subsequent 1,5-hydrogen shift followed
by protodemetallation and transfers of phosphinegold to another
substrate closes the catalytic cycle (Scheme 4).
I-2 have failed, presumably because the subsequent hydrogen
transfer is extremely fast (∆Gsolv ) 12.6 kcal/mol) from this
q
intermediate. The most difficult barrier of the catalytic cycle
shown in Figure 10 is C-C bond formation step (I-TS-1) with
an activation free energy of 21.6 kcal/mol. Unfortunately, the
overall free energy barrier for the catalytic cycle cannot be
computed because the transition structures of the phosphinegold
acetylide formation could not be located in the gas phase and
the actual barrier heights are dependent on the unknown
instantaneous concentrations of every species in the reaction
mixture. Regardless, the observation that the deuterium labels
at the alkyne terminus tend to wash out in the product, while
the starting material showed no comparable decrease, suggests
that formation of the phosphinegold acetylide is an irreversible
process and possibly rate-limiting (eq 11).
The free energy profile for the steady-state catalytic process
via I is shown in Figure 10. The transfer of two phosphinegold
(32) This was the only case presented in this paper where the KIE was computed
by use of a simple phosphine.
9
J. AM. CHEM. SOC. VOL. 130, NO. 13, 2008 4525

A R T I C L E S
Cheong et al.
Figure 10. Free energy progress profile for two cycles in the mechanism via alkyne coordination to phosphinegold acetylide (I, Scheme 1). Free energies
were computed by use of gas-phase standard state; dashed lines signify transfer of phosphinegold cations from products to reactants.
Acknowledgment. F.D.T., P.M., and M.R.L. gratefully
acknowledge the University of California, Berkeley, NIHGMS
(R01 GM073932), Merck Research Laboratories, Bristol-Myers
Squibb, Amgen Inc., and Novartis for financial support. P.H.-
Y.C. and K.N.H. gratefully acknowledge the University of
California, Los Angeles, NIHGMS (GM 36700), and NSF
(CHE-0548209), for financial support. The computational study
was facilitated through the Partnerships for Advanced Compu-
tational Infrastructure (PACI) through the support of the National
Science Foundation. Computations were performed on the
National Science Foundation Terascale Computing System at
the SGI Altix Cobalt and the California Nano Systems Institute
cluster. P.H.-Y.C. is grateful to Claude Y. Legault for helpful
discussions.
Conclusions
Supporting Information Available: Experimental procedures
In summary, we have presented a Au(I)-catalyzed rearrange-
and compound characterization data; Cartesian coordinates,
ment of allenynes to cross-conjugated trienes. Combined
energies, and thermodynamic corrections for all reported
experimental and computational evidence reveal that a mech-
structures; complete ref 20. This material is available free of
anism involving nucleophilic addition of an allene double bond
charge via the Internet at http://pubs.acs.org.
to a phosphinegold-complexed phosphinegold acetylide is more
likely than oxidative cyclization or simple nucleophilic addition
to phosphinegold-complexed substrate.
JA711058F
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4526 J. AM. CHEM. SOC. VOL. 130, NO. 13, 2008