Gold-catalyzed, intramolecular, oxygen-transfer reactions of 2-alkynyl-1,5-diketones or 2-alkynyl-5-ketoesters: Scope, expansion, and mechanistic investigations on a new [4+2] cycloaddition

Article abstract of DOI:10.1002/chem.201101448

The gold-catalyzed intramolecular oxygen-transfer reactions of 2-alkynyl-1,5-diketones or 2-alkynyl-5-ketoesters-obtained from tetra-n-butylammonium fluoride mediated Michael addition of activated allenes to electron-deficient olefins-furnished cyclopente

Full text of DOI:10.1002/chem.201101448

DOI: 10.1002/chem.201101448
Gold-Catalyzed, Intramolecular, Oxygen-Transfer Reactions of 2-Alkynyl-
1,5-diketones or 2-Alkynyl-5-ketoesters: Scope, Expansion, and Mechanistic
Investigations on a New [4+2] Cycloaddition
Le-Ping Liu,*[a] Deepika Malhotra,[a] Zhuang Jin,[a] Robert S. Paton,[b]
K. N. Houk,*[b] and Gerald B. Hammond*[a]
Abstract: The gold-catalyzed intramo-
lecular oxygen-transfer reactions of 2-
alkynyl-1,5-diketones or 2-alkynyl-5-
ketoesters—obtained from tetra-n-bu-
tylammonium fluoride mediated Mi-
chael addition of activated allenes to
corresponding products were obtained
in very good yields. Mechanistic inves-
tigations on the cycloisomerization
were carried out by means of both 18O
isotopic experiments and quantum
chemical calculations. The results from
both, the designed isotopic experiments
and theoretical calculations, satisfacto-
rily supported the novel proposed in-
tramolecular [4+2] cycloaddition of a
gold-containing furanium intermediate
to a carbonyl group, instead of the pre-
vious well-accepted [2+2] pathway.
electron-deficient
olefins—furnished
Keywords: cycloaddition
·
gold
·
cyclopentenyl ketones under very mild
conditions. These reactions proceeded
much easier and faster than similar re-
actions reported in literature, and the
homogeneous catalysis
· oxygen
transfer · quantum chemical calcu-
lations
Introduction
Brønsted acid catalyzed intermolecular or intramolecular
alkyne–carbonyl metathesis reactions have been extensively
developed (Scheme 1, top).[4] Notably, by using tethered al-
kynylketones as the substrates, Yamamoto and co-workers
reported gold- or TfOH-catalyzed oxygen-transfer reactions
to give highly substituted cyclic enones as the products
(Scheme 1, bottom).[5]
The construction of a,b-unsaturated enones or similar com-
pounds has been at the forefront of synthetic organic
chemistry since its inception, not only because these com-
pounds are important building blocks in organic synthesis,
but also because the conjugated enone substructure itself is
a significant motif in natural products or biologically active
compounds.[1] Aldol condensations and Wittig-type reactions
have been utilized to construct this moiety for decades.[2]
Recently though, an oxygen transfer from a carbonyl group
to a carbon–carbon triple bond, also known as alkyne–car-
bonyl metathesis, has attracted the interest of synthetic
chemists, because this methodology could be an efficient
and atom-economic alternative to the Wittig reaction by
forming the new carbon–carbon double bond and carbonyl
group simultaneously.[3] In this regard, many Lewis or
Scheme 1. Lewis or Brønsted acid and gold catalyzed intermolecular or
intramolecular alkyne–carbonyl metathesis.
[a] Dr. L.-P. Liu, D. Malhotra, Z. Jin, Prof. Dr. G. B. Hammond
Department of Chemistry, University of Louisville
2320 South Brook Street, Louisville, KY 40292 (USA)
Fax : (+1)502-852-3899
Few years ago, we became interested in investigating the
reactivity of alkynylenolates and other extended enolates,[6]
and found that 2-alkynyl-1,5-dicarbonyl derivatives could be
conveniently obtained from the tetra-n-butylammonium flu-
oridemediated Michael addition of activated allenes to elec-
tron-deficient olefins (Scheme 2).[7] Considering the exis-
tence of two carbonyls and a carbon–carbon triple bond in
1, we envisioned that an oxonium intermediate could arise
from one of the carbonyls and the triple bond, and engender
E-mail: leping.liu@louisville.edu
gb.hammond@louisville.edu
[b] Dr. R. S. Paton, Prof. Dr. K. N. Houk
Department of Chemistry and Biochemistry
University of California, Los Angeles
607 Charles E. YoungDrive East
Los Angeles, CA 90095 (USA)
E-mail: houk@chem.ucla.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101448.
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FULL PAPER
Thus, we were interested in studying the scope of the gold-
catalyzed, intramolecular, oxygen-transfer reaction and de-
veloping a fast and efficient synthetic method to construct
this important substructure. Various substrates were subject-
ed to this reaction; the results are summarized in Table 1.
It was found that the reactions of 2-alkynyl-1,5-diketones
with either aromatic or aliphatic groups substituted at the
R1 position proceeded smoothly, and the corresponding
products 2a–2i were isolated in excellent yields (Table 1, en-
tries 1–9). The variation on R4 from methyl to ethyl and
phenyl did not have a deleterious effect on the reaction, and
the corresponding products 2j–2m were obtained in very
good yields (Table 1, entries 10–13). Also, replacing the
phenyl at R3 position with a methyl group did not dimin-
ished the efficiency of the reaction (Table 1, entry 14). To
our surprise though, when the phenyl at R3 position was re-
placed by an ethoxy group, that is, when 2-alkynyl-5-ketoest-
ers were used, the reaction still proceeded as smoothly and
efficiently as before, although longer reaction times were
needed. The only exception occurred with 1u, from which
2u was isolated in only 50%, along with unidentified prod-
ucts (Table 1, entries 15–22). For the 2-alkynyl-5-ketoester
substrate 1w bearing an aliphatic group at R1 position, the
Scheme 2. Synthesis of 2-alkynyl-1,5-diketones and the gold-catalyzed
oxygen-transfer reaction thereof.
novel transformations. The chemistry of the oxonium ions
formed from alkynylic aldehydes or ketones by mediation of
transition metals, Lewis acids, Brønsted acids, or even elec-
trophiles such as iodine, has attracted a lot of attention, be-
cause these intermediates could undergo both inter- and in-
tramolecular cycloadditions to carbon–carbon multiple
bonds to give myriad products of synthetic importance.[8–16]
Because of our continuous interest in gold catalysis,[17,18] we
subjected compound 1a to gold catalysis and found that the
reaction, using AuCl as the catalyst, cleanly furnished cyclo-
pentenyl ketone 2a—an intramolecular-oxygen-transferred
product—in excellent yields after only 5 min at room tem-
perature.[19] Herein, we wish to report a comprehensive
study of gold-catalyzed oxygen-transfer reactions of 2-alkyn-
yl-1,5-diketones or 2-alkynyl-5-ketoesters, especially a de-
tailed mechanistic investigation on the newly proposed in-
tramolecular [4+2] cycloaddition mechanism by means of
isotopic experiments and quantum chemical calculations.
Table 1. Gold-catalyzed, intramolecular, oxygen-transfer reactions of 2-
alkynyl-1,5-diketones or 2-alkynyl-5-ketoesters.[a]
Entry
R1
R2
R3
R4
2, Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24[c]
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1n
1m
1o
1p
1q
1r
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
Ph
Ph
Me
Me
Me
Me
Ph
2a, 98
2b, 99
2c, 92
2d, 99
2e, 96
2 f, 95
2g, 91
2h, 94
2i, 99
2j, 98
2k, 93
2l, 91
2m, 99
2n, 92
2o, 88
2p, 92
2q, 90
2r, 91
2s, 92
2t, 92
2u, 50
2v, 90
NR
4-MeOC6H4
4-ClC6H4
nC6H13
iPr
tBu
Me
Bn
CypCH2
Ph
Results and Discussion
Highly substituted five-membered rings bearing a quaterna-
ry carbon tethered to a carbonyl group, are often found in
natural products or biologically active compounds. Selected
examples include Xestenone,[20] Chloriolin-A,[21] Spergulage-
nin-A[22] and Saussureal.[23] Methods for the construction of
these highly substituted carbocycles are rare in literature.
Ph
4-MeOC6H4
4-ClC6H4
Ph
Ph
Me
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Ph
4-MeOC6H4
4-ClC6H4
Ph
4-MeOC6H4
4-ClC6H4
Ph
Ph
nC6H13
nC6H13
1s
1t
1u
1v
1w
1w
Ph
Ph
Me
Ph
Me
Me
Bn
Me
Me
complex
[a] General reaction conditions: 2-alkynyl-1,5-diketone or 2-alkynyl-5-ke-
toester 1 (0.3 mmol), CH2Cl2 (2.0 mL); for alkynyldiketones, reaction
time=5 min; for alkynylketoesters, reaction time=30 min; Cyp=cyclo-
pentanyl; NR=no reaction. [b] Isolated yields. [c] Reaction was conduct-
ed in toluene at 808C.
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G. B. Hammond, K. N. Houk, L.-P. Liu et al.
reaction did not take place (Table 1, entry 23). The tradi-
tional mechanism of the oxygen-transfer reaction invoked a
[2+2] pathway (Scheme 3, top) for the inter-/intramolecular
alkyne–carbonyl metathesis.[4,5] However, the fact that the
oxygen-transfer reaction of 2-alkynyl-1,5-diketones or 2-al-
kynyl-5-ketoesters could be completed in minutes at room
temperature, and with higher yields than previously report-
ed oxygen transfer, prompted us to propose an alternative
[4+2] mechanism (Scheme 3, bottom). We envisioned that
five-membered ring furanium C[24] would be much easier to
form than the seven-membered ring oxonium A, this is fol-
lowed by a [4+2] cycloaddition of the furanium intermedi-
ate to the other carbonyl group to form the intermediate D
that finally yields the product after several electron transfer
steps.
Scheme 4. Synthesis of substrate 1b-18O and its 13C NMR spectrum.
To elucidate which pathway—the well-accepted [2+2]
mechanism or our newly proposed [4+2] pathway—was re-
sponsible for the gold-catalyzed, intramolecular, oxygen
transfer of 2-alkynyl-1,5-diketones and 2-alkynyl-5-ketoest-
ers, we designed an isotopic labeling experiment
(Scheme 3). We speculated that if an 18O atom could be in-
corporated into one of the carbonyls of the substrates, then
the 13C NMR of the reaction product could be used to
locate the 18O atom,[25] and provide clues as to the more fa-
vorable mechanistic pathway. Hence, using alkynyldiketone
1b-18O (R1 =p-methoxyphenyl, R2 =phenyl) and alkynylke-
toester 1o-18O (R1 =phenyl, R2 =ethoxy) as the model sub-
strates, if the reactions followed a [2+2] route then the 18O
would end up on the left carbonyl group in 2a-18O
(Scheme 3, top), whereas it would be incorporated on the
benzoyl group or ester group in 2b-18O if the reaction fol-
lowed a [4+2] pathway (Scheme 3, bottom).
methyl carbonyl group, as indicated by 13C NMR spectrosco-
py. A 0.05 ppm (5 Hz) upfield chemical shift[25] was found on
carbon 1 in the substrate, whereas no chemical shift change
occurred on carbon 2. With substrate 1b-18O in hand, we
carried out the gold-catalyzed oxygen-transfer reaction and
the product 2b-18O was obtained in quantitative yield, with-
out any 18O loss as determined by its ESI mass spectrum. It
was found that only the C4 atom in the product 2b-18O ex-
hibited the 0.05 ppm (5 Hz) upfield chemical shift in its
13C NMR spectrum (Scheme 5).
By utilizing the same methodology, substrate 1o-18O was
also synthesized from the 18O exchange of compound 1o
with H218O under acidic conditions. Again, the 18O exchange
happened only at the methyl carbonyl group, as indicated by
13C NMR spectroscopy. A 0.05 ppm (5 Hz) upfield chemical
shift was found only on C1 (Scheme 6). Substrate 1o-18O
was subjected to the gold-catalyzed oxygen-transfer reaction
under the same conditions, and the corresponding product
2o-18O was isolated in good yield. By running its 13C NMR
spectroscopy, it was found that only the C4 atom at the
ester group in the product 2o-18O showed the 0.037 ppm
(3.7 Hz) upfield chemical shift (Scheme 7). The absence of
any detectable 18O incorporation at the C3 atom in both
Substrate 1b-18O was synthesized from the 18O exchange
of compound 1b with H218O under acidic conditions
(Scheme 4).[26] The 18O exchange occurred only on the
Scheme 5. 18O isotopic experiment of alkynyldiketone and its 13C NMR
spectrum.
Scheme 3. 18O isotopic labeling experiment for mechanistic studies.
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Oxygen-Transfer Reactions
FULL PAPER
formed on these optimized structures with a larger (triple-z)
6-311+GACTHNUTRGNEUG(N d,p) basis set on C, H, O and Cl. Where it was
computationally tractable, we also performed optimizations
at the “double-hybrid” density functional level of theory
with the B2PLYP functional.[32] This method replaces a frac-
tion of the semilocal correlation energy by a nonlocal corre-
lation energy expression that employs the Kohn–Sham orbi-
tals in second order perturbation theory and delivers im-
proved energetics over hybrid density functionals such as
B3LYP. Geometries and energetics obtained at this level
and from single-point energy calculations at the SCS-MP2
level[33] were also compared with the B3LYP and M06-2X
results, to verify that the hybrid-GGA functionals gave ge-
AHCTUNGTREGoNNNU metries and energetics agreed with these more demanding
methods. Transition structures were confirmed by the pres-
ence of an imaginary harmonic vibrational frequency corre-
sponding to a displacement along the proposed reaction co-
ordinate. NBO version 3.1 was used for the calculation of
Wiberg bond order (BO) from the natural bond orbitals.[34]
Competing [2+2] and [4+2] reaction coordinates were
computed for a model substrate for which R1, R2, R3, and
R4 are all methyl groups, allowing us to compare the perfor-
mance of DFT at the hybrid-GGA level with more demand-
ing B2PLYP and SCS-MP2 calculations. Experimentally, we
demonstrated that similar substrates (Table 1, entry 7: R1,
R2, R4 =Me/R3 =Ph and entry 14: R2, R3, R4 =Me/R1 =Ph)
rearranged in 91–92% yield. We begin with a discussion of
our newly proposed [4+2] pathway, for which the computed
B2PLYP reaction coordinate is shown in Figure 1. The rate-
limiting step in the rearrangement is the intramolecular nu-
cleophilic addition to the Au-coordinated alkyne—the acti-
vation barrier for this step is computed to be a modest
8.8 kcalmolÀ1, forming five-membered ring oxonium inter-
mediate B (via 5-endo-dig TS-1). Once this cyclization has
occurred to form C the remaining transformations that lead
to the rearranged product are all computed to be relatively
facile. The transition state TS-2, formally a [4+2] cycloaddi-
Scheme 6. Synthesis of substrate 1o-18O and its 13C NMR spectrum.
Scheme 7. 18O isotopic experiment of alkynylketoester and its 13C NMR
spectrum.
products (2b-18O and 2o-18O) demonstrates that the [2+2]
pathway is disfavored, and instead it is the newly proposed
[4+2] pathway that accounts for the mechanism of the
gold-catalyzed, intramolecular, oxygen transfer of 2-alkynyl-
1,5-diketones and 2-alkynyl-5-ketoesters.
À
À
tion, involving the formation of two new C C and C O s-
bonds lies only 4.4 kcalmolÀ1 above the starting complex 1.
The barriers for TS-3, the opening of acetal intermediate C,
and TS-4, the opening of oxonium D, are very small indeed.
At room temperature this process would be expected to
occur readily, consistent with the 5 min reaction times ob-
served experimentally.
Alongside our experimental studies, we turned to quan-
tum chemical calculations to seek further verification that
the proposed [4+2] mechanism is the preferred pathway
and to understand the origins of this selectivity. We also
sought to clarify the mechanism of the competing [2+2]
pathway, which has previously been invoked on a number of
occasions to rationalize carbonyl–alkyne metathesis reac-
tions. All calculations were performed with Gaussian 09.[27]
Stationary points were fully optimized with the B3LYP[28]
(hybrid GGA) and M06-2X[29] (hybrid meta-GGA) density
functionals, using a fine grid for numerical integration. Both
functionals have been utilized extensively in computational
studies of AuI catalysis,[30] although the M06-2X functional
may be expected to describe nonbonding interactions with
greater accuracy. For optimizations we used a combination
of the Pople 6-31G(d) basis set for C, H, O and Cl and the
LANL2DZ (Hay–Wadt) basis including an effective core
potential for Au.[31] Single-point calculations were per-
B2PYLP optimized transition structures (TSs) along the
[4+2] pathway are also shown in Figure 1. Rate-limiting
TS-1 involves a 5-endo-dig cyclization, which is allowed ac-
cording to Baldwinꢁs rules. Bond formation in TS-2 can be
À
seen to be highly asynchronous, with the forming C O bond
À
at 1.66 ꢂ (Wiberg BO 0.60) and the C C bond at 2.67 ꢂ
(Wiberg BO 0.12); however, this process is concerted as no
intermediate exists between B and C. All of the computa-
tional levels examined suggest the rate-limiting step in the
[4+2] pathway is carbonyl-oxygen addition to the Au-coor-
dinated alkyne, giving energetic profiles similar to those
shown in Figure 1 and optimizations with either B2PLYP,
B3LYP or M06-2X density functionals result in similar ge-
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G. B. Hammond, K. N. Houk, L.-P. Liu et al.
Figure 1. Top: B2PLYP/6-311+GACTHNUTRGNEUGN(d,p)//B2PLYP/6-31G(d) (using LANL2DZ ECP on Au) relative energy profile computed for both [2+2] and [4+2]
pathways for a model substrate. R1, R2, R3, R4 =Me, Au=AuCl. Bottom: B2PLYP/6-311+G
model sytem. Energies relative to reactant 1(Au). Bond forming/breaking distances in ꢂ.
ACHTUNGTREN(NUGN d,p)/B2PLYP/6-31G(d) computed stationary points for the
A
though our proposed mechanism is still computed to be
viable at room temperature. The transition structures for the
rearrangement of the ketoester substrate are shown below
in Figure 2.
computed for experimental substrate 1a to compare with
our results for the model system used. These calculations
were in good accordance with those shown in Figure 1,
again with the 5-endo addition as the rate-limiting step. Full
details of all additional calculations are presented in the
Supporting Information.
Experimentally we observed that alkynylketoesters under-
went Au-catalyzed rearrangement more slowly than the al-
kynyldiketones. The computed [4+2] pathway for the rear-
rangement of a model alkynylketoester suggested that the
overall energy change of reaction (À31.7 kcalmolÀ1) is very
close to that of the alkynyldiketone (À31.1 kcalmolÀ1).
However, the energetic barrier for 5-endo cyclization (i.e.,
TS-1’) is 13.4 kcalmolÀ1 (c.f., a value of 8.8 kcalmolÀ1 for
the diketone) suggests the initial alkyne addition is more
difficult for the ester substrate. Interestingly the relative
energy of TS-2’ at 19.2 kcalmolÀ1 means that the [4+2] ad-
dition step is now more difficult than the cyclization step for
the alkynylketoester. These values are consistent with the
observations of the ester substrates reacting more slowly, al-
Figure 2. B2PLYP/6-311+GACTHNUGRTNEUNG(d,p)/B2PLYP/6-31G(d) computed stationary
points for the ketoester substrate. Energies relative to reactant 1. Bond
breaking distance in ꢂ.
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Oxygen-Transfer Reactions
FULL PAPER
We considered a number of alternative mechanisms that
could constitute a competing [2+2] pathway so that we
could safely discount these possibilities. These alternatives
are discussed below. We have found that all of these mecha-
nisms are disfavored relative to the [4+2] presented above,
consistent with our 18O-labeled experiments. These comput-
ed [2+2] pathways, however, may well be important in Au-
catalyzed transformations in which there is no possibility of
a [4+2] pathway occuring. The Au- or Ag-catalyzed formal
[2+2] addition of a carbonyl to an alkyne has been pro-
posed to occur in a number of ways. Intra- and intermolecu-
lar reactions of aldeyhydes with alkynes catalyzed by AgI
have been proposed by Krische to procede via an oxetene
(or oxete) intermediate.[4c] Yamamoto has instead proposed
that an Au-coordinated intermediate is more likely based on
the formation of a g,d-enone byproduct in the carbocycliza-
tion of alkynyl ketones.[5] DFT calculations suggest that in-
tramolecular reactions of 1,n-enynes catalyzed by AuI pro-
ceed via the formation of a cyclopropanyl Au–carbene com-
plex, which then undergoes a 1,2-alkyl shift, fragmentation
and elimination of Au.[35] We investigated the viability of
each of these pathways computationally.
Figure 3. Proposed mechanism and B2PLYP/6-311+GACTHUNRTGNEUNG(d,p)/B2PLYP/6-
31G(d) computed stationary points for the oxetene pathway. Energies
relative to reactant 1. Bond breaking distance in ꢂ.
First of all we considered the viability of the [2+2] oxe-
tene mechanism, in which a four-membered ring is formed
from addition of the carbonyl across the alkyne and is fol-
lowed by an electrocylic ring-opening to give the enone
product. The computed structure of the oxetene intermedi-
ate and of the ring-opening TS are shown below in Figure 3.
In accordance with Bredtꢁs rule oxetene E is highly strained
due to the presence of a bridgehead C=C bond, lying
12.5 kcalmolÀ1 above the starting material. Therefore any
TS or intermediate lying between 1 and E is necessarily
higher in energy than TS-1 and so disfavored kinetically.
Ring-opening of E is possible in the absence of a coordinat-
ing metal (e.g. Au/Ag), via the 4p-electrocyclic TS-5, al-
though this transformation would not be expected to occur
readily at room temperature with a relative free energy of
14.0 kcalmolÀ1. Therefore this pathway is disfavored relative
to the [4+2] pathway.
We next considered the possibility of nucleophilic attack
of the Au-coordinated alkyne from the carbonyl in a 7-
endo-dig fashion, followed by a 4p electrocyclic ring closure
which leads to the formation of a Au-coordinated bicyclic G,
the ring-opening of which leads to the Au-coordinated
enone product (Figure 4). This mechanism represents an
Au-catalyzed form of the mechanism shown in Figure 3. The
initial attack of the Au-coordinated alkyne is disfavored rel-
Figure 4. Proposed mechanism and B2PLYP/6-311+GACHTUNTRGNEU(GN d,p)/B2PLYP/6-31G(d) computed stationary points for the 7-endo-dig pathway. Energies relative
to reactant 1. Bond breaking distance in ꢂ.
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G. B. Hammond, K. N. Houk, L.-P. Liu et al.
ative to the 5-endo dig attack in the preferred [4+2] mecha-
nism. Furthermore, as a consequence of the anti-addition of
the carbonyl and Au across the alkyne (syn-addition is im-
possible in this intramolecular case) and of the conrotatory
fashion of the electrocyclic ring-closing, the ring junction of
G is necessarily trans-fused. This creates a significant degree
of strain, such that ring-closing TS-7 lies 67.9 kcalmolÀ1
above the starting material and the relative energy of G is
22.4 kcalmolÀ1. The final ring-opening step to form the
enone product via TS-8 lies uphill at 33.1 kcalmolÀ1. Clearly
this mechanism is highly unfavorable.
Based on previous experimental and computational stud-
ies of Au-catalyzed rearrangements of enynes,[36] in which
the formation of cyclopropyl Au–carbenes have been in-
voked, we also considered the possibility of the [2+2]
mechanism proceeding via an epoxy Au–carbene as shown
in Figure 5. In this mechanism we envisaged that an initial
6-exo cylization via TS-9 to form H could then form epoxide
I. Fragmentation of this epoxide could then lead to the
formal [2+2] addition bicyclic J that upon ring-opening
forms the enone product. Compared to the 5-endo cycliza-
tion TS-1 the cyclization via 6-exoTS-9 is disfavored, again
highlighting the preference for the [4+2] mechanism. We
were unable to locate a TS corresponding to the formation
of an epoxy Au–carbene at the B2PLYP level of theory, I
lies uphill at 23.0 kcalmolÀ1 suggesting that this process
would be difficult at room temperature. Rearrangement to
J, however, does result in the formation of a much more
stable 5,4-bicycle at À4.0 kcalmolÀ1—being cis-fused this is
much more stable than the corresponding trans-fused bicy-
clic G found in Figure 4. The final ring-opening step is rela-
tively facile via TS-11. We have therefore considered three
distinct mechanisms which could account for a [2+2] path-
way; however, all three are clearly disfavored relative to the
computed [4+2] mechanism, in support of our experimental
observations. Of the [2+2] pathways considered, none is
predicted to occur readily at room temperature and a 4p-
electrocylization step (TS-7) can be effectively discounted
due to the large energetic barrier. The [4+2] pathway is fa-
vored in large part due to the initial selectivity for alkyne
addition via a five-membered TS. To understand why 5-
endo-dig attack is so dramatically preferred over 6-exo-dig
or 7-endo-dig we computed the activation barrier for some
model intra- and intermolecular additions of a carbonyl to
an Au-coordinated alkyne (Figure 6). Notably, the intermo-
lecular addition of acetone to AuCl-coordinated butyne
Figure 6. B2PLYP/6-311+GACTHNUGRTNEUNG(d,p)/B2PLYP/6-31G(d) (hydrogen-deleted)
transition structures for intramolecular and intermolecular cyclization of
a ketone onto a Au-coordinated alkyne. Bond lengths in ꢂ with associat-
ed Wiberg bond indices italicized. Activation energies relative to Au-co-
ordinated alkyne in kcalmolÀ1
.
Figure 5. Proposed mechanism and B2PLYP/6-311+G
reactant 1. Bond breaking distance in ꢂ.
ACHTUNGTRENN(UNG d,p)/B2PLYP/6-31G(d) computed stationary points for the 6-exo-dig pathway. Energies relative to
10696
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10690 – 10699

Oxygen-Transfer Reactions
FULL PAPER
occurs with an energy barrier of 19.3 kcalmolÀ1, and the bar-
riers of model 6-exo (20.4 kcalmolÀ1) and 7-endo (19.9 kcal
molÀ1) intramolecular reactions are very close to this value.
In stark contrast the 5-exo mode of attack takes place with a
much lower barrier of 9.5 kcalmolÀ1. From this we can con-
clude that the preference for 5-exo cyclization comes about
as TS-1 (Eact 8.8 kcalmolÀ1) is remarkably stable rather than
any inherent instability of competing pathways proceeding
via 6-exo or 7-endo transition states. Acceleration of this
ring-closing due to the presence of a quaternary center
(Thorpe–Ingold effect) in the five-membered ring is only
marginal, since replacing this carbon with methylene raises
the barrier by just 0.7 kcalmolÀ1. It seems that 5-exo attack
benefits from an almost planar dihedral angle (0.88) be-
tween the alkyne and attacking carbonyl not present in
other modes of attack owing to the constraints of the six-
membered (188) or seven-membered ring (528), and also in
the intermolecular reaction (768) due to steric demands
absent in TS-1. Bond lengths and Wiberg bond indices show
the 5-exo TS to be earlier, which is a consequence of the in-
creased stability of the cyclized 5-exo product.
Acknowledgements
We are grateful to the National Science Foundation for financial support
(CHE-0809683 and CHE-1111316) and the Royal Commission for 1851
(R.S.P.). Professor K. N. Houk is grateful to the National Science Foun-
dation (CHE-0548209) for financial support. We acknowledge the sup-
port provided by the CREAM Mass Spectrometry Facility (University of
Louisville) funded by NSF/EPSCoR grant #EPS-0447479. We also thank
Prof. Dr. Eugene Mueller for generously donating us the H218O.
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In conclusion, we have developed a synthetic methodology
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General procedure for gold-catalyzed oxygen transfer of 2-alkynyl-1,5-di-
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1H NMR (CDCl3, 500 MHz): d=1.58 (s, 3H), 1.70 (s, 3H), 2.14–2.18 (m,
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Published online: August 9, 2011
Chem. Eur. J. 2011, 17, 10690 – 10699
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10699