[(NHC)AuI]-catalyzed formation of conjugated enones and enals: An experimental and computational study

Article abstract of DOI:10.1002/chem.200700134

The [(NHC)Au^I]-catalyzed (NHC = N-heterocyclic carbene) formation of α,β-unsaturated carbonyl compounds (enones and enals) from propargylic acetates is described. The reactions occur at 60°C in 8 h in the presence of an equimolar mixture of [(NHC)AuCl] and AgSbF₆ and produce conjugated enones and enals in high yields. Optimization studies revealed that the reaction is sensitive to the solvent, the NHC, and, to a lesser extent, to the silver salt employed, leading to the use of [(ItBu)AuCl]/ AgSbF₆ in THF as an efficient catalytic system. This transformation proved to have a broad scope, enabling the stereoselective formation of (E)-enones and -enals with great structural diversity. The effect of substitution at the propargylic and acetylenic positions has been investigated, as well as the effect of aryl substitution on the formation of cinnamyl ketones. The presence or absence of water in the reaction mixture was found to be crucial. From the same phenylpropargyl acetates, anhydrous conditions led to the formation of indene compounds via a tandem [3,3] sigmatropic rearrangement/intramolecular hydroarylation process, whereas simply adding water to the reaction mixture produced enone derivatives cleanly. Several mechanistic hypotheses, including the hydrolysis of an allenol ester intermediate and S_N2′ addition of water, were examined to gain an insight into this transformation. Mechanistic investigations and computational studies support [(NHC)AuOH], produced in situ from [(NHC)AuSbF₆] and H ₂O, instead of cationic [(NHC)AuSbF₆] as the catalytically active species. Based on DFT calculations performed at the B3LYP level of theory, a full catalytic cycle featuring an unprecedented transfer of the OH moiety bound to the gold center to the C≡C bond leading to the formation of a gold-allenolate is proposed.

Full text of DOI:10.1002/chem.200700134

FULL PAPER
DOI: 10.1002/chem.200700134
ACHTREUNG
Nicolas Marion,[a] Peter Carlqvist,[a] Ronan Gealageas,[a, d] Pierre de FrØmont,[b]
[a]
Feliu Maseras,*[a, c] andSteven P. Nolan*
Abstract: The [(NHC)AuI]-catalyzed
(NHC = N-heterocyclic carbene) for-
mation of a,b-unsaturated carbonyl
compounds (enones and enals) from
propargylic acetates is described. The
reactions occur at 608C in 8 h in the
presence of an equimolar mixture of
ty. The effect of substitution at the
propargylic and acetylenic positions
has been investigated, as well as the
effect of aryl substitution on the forma-
tion of cinnamyl ketones. The presence
or absence of water in the reaction
mixture was found to be crucial. From
the same phenylpropargyl acetates, an-
hydrous conditions led to the forma-
enone derivatives cleanly. Several
mechanistic hypotheses, including the
hydrolysis of an allenol ester inter-
mediate and SN2’ addition of water,
were examined to gain an insight into
this transformation. Mechanistic inves-
tigations and computational studies
support [(NHC)AuOH], produced in
situ from [(NHC)AuSbF6] and H2O, in-
stead of cationic [(NHC)AuSbF6] as
the catalytically active species. Based
on DFT calculations performed at the
B3LYP level of theory, a full catalytic
cycle featuring an unprecedented trans-
fer of the OH moiety bound to the
[(NHC)AuCl] and AgSbF and pro-
6
duce conjugated enones and enals in
high yields. Optimization studies re-
vealed that the reaction is sensitive to
the solvent, the NHC, and, to a lesser
extent, to the silver salt employed,
leading to the use of [(ItBu)AuCl]/
AgSbF6 in THF as an efficient catalytic
system. This transformation proved to
have a broad scope, enabling the ste-
reoselective formation of (E)-enones
and -enals with great structural diversi-
tion of indene compounds via
tandem [3,3] sigmatropic rearrange-
ment/intramolecular hydroarylation
a
process, whereas simply adding water
to the reaction mixture produced
ꢀ
gold center to the C C bond leading to
Keywords: carbenes
·
density
the formation of a gold–allenolate is
proposed.
functional calculations · enones ·
gold · potential energy surface
Introduction
Conjugated enones arguably represent one of the most
useful building blocks in organic synthesis;[1] two of their
main uses are as reactants in 1,4 addition and Diels–Alder
reactions.[2,3] a,b-Unsaturated ketones and aldehydes are
usually obtained by aldol- or Knoevenagel-type condensa-
tion reactions[4] and by the Horner–Wadsworth–Emmons re-
action.[5,6] These methods generally require strong basic
media and therefore functional group compatibility and se-
lectivity issues can be problematic. Other methods that
afford enones include the use of widely available propargyl-
ic alcohols.[7] The Meyer–Schuster rearrangement[8] of prop-
argylic alcohols, involving a formal 1,3-shift of the hydroxy
moiety, and the Rupe rearrangement,[9] proceeding via a 1,3-
enyne, produce isomeric a,b-unsaturated carbonyl com-
pounds (Scheme 1). Despite some reports on the utilization
of the Meyer–Schuster reaction under mild conditions,[10,11]
these isomerization reactions have not been widely used or
[a] N. Marion, Dr. P. Carlqvist, R. Gealageas, Prof. Dr. F. Maseras, Prof.
Dr. S. P. Nolan
Institute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16, 43007 Tarragona (Spain)
Fax : (+34)977-920-224
E-mail: fmaseras@iciq.es
snolan@iciq.es
[b] P. de FrØmont
Department of Chemistry, University of New Orleans
2000 Lakeshore drive, New Orleans, LA70148 (USA)
[c] Prof. Dr. F. Maseras
Unitat de Química Física, Edifici Cn
Universitat Autònoma de Barcelona, 08193 Bellaterra (Spain)
[d] R. Gealageas
Visiting student from the UniversitØ d’OrlØans (France)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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6437

À
been reported for the mild and efficient formation of C C,
À
À
À
C N, C O, and C S bonds by both inter- and intramolecu-
lar reactions. As a testimony to the high potential of this
chemistry, and despite being in its infancy, total syntheses of
complex natural products featuring gold-catalyzed transfor-
mations as the key step have already been reported.[15]
Capitalizing on early work conducted with PtCl2,[16] it has
been found that propargylic acetates have played a special
role in the field of gold-catalyzed activation of alkynes be-
cause of the ability of the ester function to migrate.[17] Thus,
upon coordination of the gold center to the alkyne moiety,
the acetate undergoes 1,2- or 1,3-migration leading, respec-
tively, to a gold carbene or to an allene poised for subse-
quent reaction.[18,19] We investigated these two types of acti-
vation and took advantage of the 1,2- and 1,3-migration to
form [n.1.0]bicyclic compounds and indenes, respective-
ly.[20,21] Of note, although additional types of rearrangement
of the acetate moiety have been proposed,[22] the propensity
of an acetate to behave as a leaving group has never been
observed in the context of gold catalysis.
Scheme 1. Meyer–Schuster and Rupe rearrangements of propargylic alco-
hols.
developed. Several reports on the use of transition metals to
ꢀ
activate the C C bond for Meyer–Schuster rearrangement
have appeared, but their use has had only limited success in
terms of scope and reaction conditions.[12]
ꢀ
The activation of C C bonds towards cyclization or func-
tionalization with AuI or AuIII salts is attracting huge inter-
est.[13] Beyond the widespread interest in the cycloisomeriza-
tion of polyunsaturated systems,[14] numerous processes have
Herein, we report the formation of a,b-unsaturated ke-
tones and aldehydes from propargylic acetates promoted by
[(NHC)AuCl] catalysts in conjunction with a silver salt
(NHC=N-heterocyclic carbene). The transformation, which
can be viewed as a formal SN2’ process, occurs under ex-
tremely mild conditions and does not require the addition of
base or acid. Furthermore, computational studies were per-
formed in order to gain an insight into the mechanistic as-
pects of this transformation and led to the proposal of
[(NHC)AuOH] as the active species in this catalytic system.
Abstract in Catalan: Es descriu la reacció de formació de
compostos de carbonil a,b-insaturats (enones i enals) a partir
d’acetats propargílics catalitzada per [(NHC)AuI] (NHC=
carb› N-heterocíclic). Les reaccions tenen lloc a 608C en 8 h
en pres›ncia d’una mescla equimolar de [(NHC)AuCl] i
AgSbF6 i produeix rendiments alts d’enones i enals conjugats.
Estudis d’optimització van mostrar que la reacció era sensible
al solvent, el NHC, i, en menor grau, a la natura de la sal de
plata emprada; això va portar a escollir [(ItBu)AuCl]/
AgSbF6 en THF com a sistema catalític eficient. La transfor-
mació va mostrar posseir un ampli espectre, i es va aconse-
guir la formació estereoselectiva d’(E)-enones i -enals amb
gran diversitat estructural. La influ›ncia de la substitució en
les posicions propargílica i acetil›nica va ser investigada, així
com la substitució d’aril per donar lloc a la formació de cina-
milcetones. La pres›ncia o abs›ncia d’aigua en el medi de
reacció es va mostrar com a crucial. A partir dels mateixos
fenilpropargilacetats, condicions anhidres van portar a la for-
mació de compostos ind›nics mitjanÅant una reacció tàndem
de reorganització sigmatròpica [3,3] i hidroarilació intramo-
lecular, mentre que l’addició d’aigua a la reacció portava de
manera neta a derivats del tipus enona. Diverses hipòtesis
mecanístiques, entre elles la hidròlisi d’un intermedi del tipus
al.lenol ester i l’addició SN2’ d’aigua, han estat examinades
per millorar la comprensió del procØs. Les dades mecanísti-
ques i els estudis computacionals suggereixen que l’esp›cie
catalítica activa Øs [(NHC)AuOH], produït in situ a partir de
Results andDiscussion
Investigation of by-product formation: In the context of
gold-catalyzed alkyne activation, we recently reported an
unprecedented type of 1,5-enyne cycloisomerization cata-
lyzed by cationic [(NHC)AuX] complexes (X=BF4, PF6, or
SbF6).[20] Further investigation of the activity of NHC-con-
taining gold complexes allowed us to observe the tandem
[3,3] rearrangement/intramolecular hydroarylation of phe-
nylpropargyl acetates 1 leading to indenes 2 [Eq. (1)].[21]
[(NHC)AuSbF6]
i
H2O,
i
no el complex catiònic
[(NHC)AuSbF6]. A partir d’estudis DFT realitzats al nivell
B3LYP, es proposa un cicle catalític complet, que inclou un
nou tipus d’etapa consistent en la transfer›ncia d’un grup OH
In the course of these studies, we observed, in the 1H
NMR spectrum of the crude product, the formation of a
very minor amount (ca. 5%) of an unidentified by-product.
More disturbing, these observations were found to be irre-
ꢀ
des de l’or cap a l’enllaÅ C C per produir un complex or-
al.lenolat.
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Gold-Catalyzed Formation of Conjugated Enones and Enals
FULL PAPER
producible. We then carried out a scale-up experiment
(10 mmol) to isolate and fully characterize this by-product.
After purification, the H NMR spectrum of the by-product
exhibited two doublets at d=7.55 and 6.75 ppm (J=
16.2 Hz), characteristic of two vinylidene protons of a disub-
stituted olefin placed in an E arrangement. In addition, a
signal typical of a carbonylic carbon atom (d=200.9 ppm)
was observed in its 13C NMR spectrum and permitted un-
equivocal characterization of a,b-unsaturated ketone 3a
[Eq. (2)].
water, respectively. The presence of water dramatically
changed the outcome of the reaction, affording selectively
either the indene or the enone (Scheme 3). The use of anhy-
drous DCM rendered the formation of 2a almost quantita-
tive and simply adding water to the reaction mixture pro-
duced 3a cleanly as the (E)-olefin, albeit in poor yield (the
starting propargylic acetate accounting for the remaining
mass balance).
1
Optimization studies: After control experiments with only
[(IPr)AuCl] and with no metal
catalyst, which led to the recov-
ery of the starting propargylic
acetate 1a, AgBF4 alone was
found, as expected, to produce
the
[3,3]-rearranged
allene
4a.[21] We then attempted com-
plete conversion of the precur-
To rationalize the formation of conjugated enone 3, we
envisaged the two mechanisms depicted in Scheme 2. The
first mechanism relies on the gold-catalyzed formation of
sors into enone products. Reaction at room temperature,
even with a prolonged reaction time, led to only partial con-
version (Table 1, entry 2). On the other hand, increasing the
temperature permitted total
conversion of 1a, but yielded
allene 4a as a by-product along
with substantial amounts of oli-
gomerized products (Table 1,
entry 3).
We then screened
number of solvents (Table 1,
entries 4–12). 1,2-Dichloro-
a large
ethane and 1,4-dioxane proved
no better than DCM and were
not very selective (Table 1, en-
tries 4 and 12), whereas using
acetone resulted in the forma-
Scheme 2. Mechanisms envisioned for the formation of 3.
allene 4, which was shown to be a plausible intermediate en
route to indenes 2,[21] followed by further hydrolysis under
ꢀ
the reaction conditions. Alternatively, the C C bond could
be activated by a cationic gold species allowing nucleophilic
attack of water on I. Rather than a classical hydration prod-
uct,[23] the presence of a leaving group at the propargylic po-
sition would allow for the formation of allenol II, which fur-
ther tautomerizes to the conjugated enone 3. At this point
in our studies, it was unclear whether the departure of the
AcOÀ fragment would be assisted by the gold species, never-
theless, the overall process could be considered as an SN2’
reaction. More importantly, regardless of the adopted mech-
anism, the presence of water appeared mandatory for pro-
duction of the enone compound. We then thought that anhy-
drous conditions should inhibit the formation of 3 and yield
only indene 2. Conversely, addition of water should promote
the formation of the enone.
Scheme 3. Critical role of water in the reaction of phenylpropargyl ace-
tate 1.
tion of a complex mixture of products (Table 1, entry 7).
THF provided by far the best results, allowing conversion of
1a into 3a almost quantitatively (Table 1, entry 8). As water
seemed to act as a reagent in this reaction, its concomitant
use as solvent was attractive, notably for environmental rea-
To validate our hypothesis, we carried out two experi-
ments under identical conditions, one with anhydrous di-
chloromethane (DCM) and one with DCM saturated with
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6439

F. Maseras, S. P. Nolan et al.
Table 1. Optimization of solvents in the formation of 3a.[a]
whereas the use of unencumbered ITM resulted in the for-
mation of substantial amounts of oligomerized products
(Table 2, entry 4). Finally, silver salts AgBF4, AgPF6, and
AgSbF6 were screened and showed similar behavior
(Table 2, entries 3, 5, and 6).
Entry Solvent
T [8C]
t
Yield [%][b]
2a
3a
4a
Reaction scope: Next, we investigated the scope of this AuI-
catalyzed reaction. We first examined the effect of substitu-
tion on the phenyl ring (Table 3). Overall, the reaction was
1
2
DCM
DCM
DCM
DCE
DMF
pentane
acetone
THF
25
25
45
80
90
40
50
65
90
90
40
5 min
24 h
24 h
2 h
24 h
24 h
–
–
–
8
–
17
58
72
64
–
–
12
4
3[c]
4[c]
5
Table 3. Gold-catalyzed formation of cinnamyl ketones.[a]
3
–
6
7
8
9
no reaction
4 h unidentified mixture of products
4 h
24 h
24 h
24 h
4 h
–
–
90
–
–
10
toluene
H2O
Et2O
10
no reaction
no reaction
56
Entry Propargyl acetate
1
1
Enone
3
Yield [%][b]
98
11
12[c]
1,4-dioxane 90
–
–
1a
3a
[a] Reaction conditions: alkyne 1a (0.5 mmol), [(IPr)AuCl]/AgBF
(2 mol%), solvent (5 mL), H2O (0.5 mL). [b] As determined by H NMR
4
1
spectroscopy. [c] Substantial amounts of oligomerized by-products were
formed.
2
3
4
1b
1c
1d
3b
3c
3d
97
98
91
sons.[24] Unfortunately, as with DMF, pentane, Et2O, and, to
a lesser extent, toluene, precursor 1a was recovered unreact-
ed after 24 h (Table 1, entries 5, 6, and 9–11) under these
conditions. We attribute these last observations to the insol-
ubility of the gold species in these solvents. On the other
hand, THF seems to possess the right combination of misci-
bility with water and solubility of the [(NHC)AuCl] complex
to allow for complete conversion.
Next, we optimized the ligand on the gold center
(Table 2). Steric hindrance of the ligand appeared to be cru-
cial for the selectivity of the reaction. The more sterically
encumbered the ligand, the more selective the formation of
a,b-unsaturated ketone 3a (Table 2, entries 1–4) proved to
be. Hence, the extremely bulky ItBu, compared with IPr
and IMes,[25] yielded enone 3a cleanly (Table 2, entry 3),
5
6
1e
1 f
3e
3 f
89
88
[a] Reaction conditions: alkyne
(2 mol%), THF (10 mL), H2O (1 mL). [b] Yield of isolated product, aver-
age of two runs.
1
(1 mmol), [(ItBu)AuCl]/AgSbF
6
not affected by aromatic substitution and cinnamyl ketones
possessing neutral, electron-withdrawing, and electron-do-
nating groups were produced in excellent yields (Table 3,
entries 1–5). In the case of electron-rich arenes, the forma-
tion of addition products, either on the alkene or the ketone
moiety, as described by Hashmi and Dyker and their co-
workers, was not observed.[26] This is probably due to the ox-
idation state of the gold atom (AuI); since this type of reac-
tivity has only been described with AuIII species. In addition,
this highlights the chemoselectivity of the present catalytic
system and its robustness towards disproportionation under
the reaction conditions. Of note, although conjugated
enones were produced from 1a in 4 h, with 1b–e extended
reaction times were required. The tertiary acetate 1 f reacted
similarly, yielding trisubstituted olefin 3 f in good yield
(Table 3, entry 6). It is noteworthy that the procedure is ex-
tremely simple to perform and does not require any precau-
tions as the gold complex is air- and moisture-stable.
Table 2. Optimization of ligands and silver salts in the formation of 3a.
Entry
L
AgX
Yield [%][b]
2a
3a
4a
1
2
3
IPr
AgBF4
AgBF4
AgBF4
AgBF4
AgPF6
AgSbF6
–
–
–
6
–
–
90
87
98
63
95
96
–
6
–
4
–
–
IMes
ItBu
ITM
ItBu
ItBu
4[c]
5
6
[a] Reaction conditions: alkyne 1a (0.5 mmol), [(L)AuCl]/AgX
(2 mol%), THF (5 mL), H2O (0.5 mL). [b] As determined by 1H NMR
spectroscopy. [c] Substantial amounts of oligomerized by-products were
formed.
Next, we turned our attention to the effect of acetylenic
substitution. The results are presented in Table 4. Atermi-
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Gold-Catalyzed Formation of Conjugated Enones and Enals
FULL PAPER
Table 4. Effect of acetylenic substitution on the gold-catalyzed reactio-
n.[a]
Table 5. Gold-catalyzed formation of cinnamaldehydes.[a]
Entry Propargyl acetate
1
1
Enal
3
Yield [%][b]
90
Entry Propargyl acetate
1
1
Enone/enal
3
Yield [%][b]
98
1g
3g
1a
3a
2
3
1k
1l
3k
3l
83
96
2
3
1g
1h
3g
3h
90
92
[a] Reaction conditions: alkyne
(2 mol%), THF (10 mL), H2O (1 mL). [b] Yield of isolated product, aver-
age of two runs.
1
(1 mmol), [(ItBu)AuCl]/AgSbF
6
4[c]
1i
1j
3i
3j
nr
nr
5[c]
acetates (Table 6). When subjected to gold catalysis, benzyl-
propargyl acetate 1m afforded butyl ketone 3m in good
yield (Table 6, entry 1), expanding the scope of this enone
synthesis to systems that are not fully conjugated. Even
without the driving force of full conjugation, the scope of
the reaction proved remarkably broad. a,b-Unsaturated al-
dehydes can be produced (Table 6, entry 2) in excellent
yield, as can phenyl (Table 6, entry 3) or divinyl ketones
(Table 6, entry 5).
[a] Reaction conditions: alkyne
(2 mol%), THF (10 mL), H2O (1 mL). [b] Yield of isolated product, aver-
age of two runs. nr=no reaction [c] [(ItBu)AuCl]/AgSbF (10 mol%),
24 h.
1
(1 mmol), [(ItBu)AuCl]/AgSbF
6
6
nal alkyne was tested as it would afford an a,b-unsaturated
aldehyde, which is an extremely valuable building block.
Cinnamaldehyde 3g was produced in excellent yield
(Table 4, entry 2). Similarly, trans-chalcone 3h was obtained,
showing the compatibility of the reaction with phenylacety-
lenes (Table 4, entry 3). We examined the possibility of ob-
taining acylsilanes by subjecting precursor 1i to gold cataly-
sis. The TMS-containing alkyne did not react even with a
high catalyst loading (10 mol%), at an elevated tempera-
ture, and/or after a prolonged reaction time (entry 4). The
lack of reactivity of silylated alkynes, notably towards cycloi-
somerization, has already been reported.[27] Interestingly, the
presence of a tert-butyl group at the acetylenic position re-
sulted in a similar lack of reactivity (Table 4, entry 5). We
therefore believe that more than the electronic effect of the
TMS group, it is its bulky character that inhibits its reactivi-
ty.
Table 6. Gold-catalyzed formation of unactivated enones.[a]
Entry Propargyl acetate
1
1
Enone/enal
3
Yield [%][b]
87
1m
3m
2
1n
3n
94
82 (E:Z,
12:1)
3
4
5
1o
1p
1q
3o
3p
3q
Because of the high potential of enals as electrophiles in
organic synthesis, we decided to subject more terminal al-
kynes to our catalytic system. As shown in Table 5, the reac-
tion is tolerant to aryl substitution (Table 5, entries 1 and 2).
Furthermore, a tertiary acetate was converted into a trisub-
stituted enal (Table 5, entry 3).
94
89
All the substrates examined up to this point possessed an
aryl moiety at the propargylic position, therefore yielding
enones or enals that have a fully conjugated p system from
the carbonyl through to the aryl. We envisaged that this full
conjugation could be a major driving force for the formation
of the enones. To address this possibility and to further
expand the scope of the reaction, we tested alkyl and benzyl
90 (E:Z,
1.2:1)
6
1r
3r
[a] Reaction conditions: alkyne
1
(1 mmol), [(ItBu)AuCl]/AgSbF
6
(2 mol%), THF (10 mL), H2O (1 mL). [b] Yield of isolated product, aver-
age of two runs.
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F. Maseras, S. P. Nolan et al.
Totally unactivated propargyl acetate 1p afforded dialkyl
enone 3p in excellent yield (Table 6, entry 4), highlighting
the efficiency of this synthetic method. In addition, trisubsti-
tuted enone 3r was produced in a good overall yield, but, as
expected, with poor E:Z selectivity as ethyl and butyl
groups have only slight structural differences.
column chromatography and were found to be >95% pure
by 1H NMR spectroscopy. It should be noted that under
these conditions, the NHC-containing gold catalytic system
proved remarkably robust.[30]
Mechanistic studies
Gold-catalyzed transformations usually have extremely
short reaction times (e.g., minute time frame), even those
performed at room temperature. Apossible drawback of the
catalytic system presented herein is the lengthy reaction
time (i.e., 8 h) required for the synthesis of enones or enals.
As we wished this protocol to be as user friendly as possible
to synthetic chemists, we investigated the use of microwave
heating to shorten the reaction time.
Microwave-assisted organic and organometallic syntheses
have recently witnessed a remarkable explosion in interest,
notably because of their ability to shorten reaction times
considerably.[28] After tests to optimize reaction condi-
tions,[29] enone 1a was produced in high yield under micro-
wave heating after only 12 minutes at 808C in THF
(Table 7, entry 1). We screened more substrates and were
able to obtain a,b-unsaturated ketones and aldehydes, even
with strongly unactivated dialkyl substrates (entry 7), in ex-
cellent yields and in remarkably shortened reaction times
(Table 7). Most of the conjugated compounds produced by
microwave heating did not require further purification by
Allenes as intermediates? In view of the striking effect of
water on the outcome of the reaction, as depicted in
Scheme 3, we investigated the possible mechanisms for this
transformation. The first pathway we envisaged involves a
[3,3] sigmatropic rearrangement of the propargylic acetate
to allene 4 (see Scheme 2) followed by hydrolysis of the
ester group to yield allenol II, the tautomer of enone 3.[31]
To address this possibility, we synthesized and isolated
allene 4a by silver-catalyzed [3,3] sigmatropic rearrange-
ment of propargylic acetate 1a[32] and subjected it to the cat-
alytic conditions for enone formation. Strikingly, even after
a prolonged reaction time, both under conventional and mi-
crowave-assisted heating, the formation of enone 3a was not
observed (Scheme 4), ruling out a possible hydrolysis path-
way under these reaction conditions.
Table 7. Microwave-assisted gold-catalyzed formation of conjugated
enones and enals.[a]
Scheme 4. Formation of allene 4a and its subjection to gold catalysis.
Entry Propargyl acetate
1[c]
1
Enone/enal
3
Yield [%][b]
Additional information supporting the non-involvement
of allenes as intermediates in the formation of enones was
provided by the experiments shown in Scheme 5. In an at-
tempt to evaluate the effect of a hypothetical leaving group
at the propargylic position and to gather further information
related to the reaction mechanism, we synthesized ana-
logues of acetate 1a and tested them for the production of
enone 3a. Alcohol 5 did not react under our catalytic condi-
tions and was almost fully recovered (89%). This seems to
exclude a Meyer–Schuster-like pathway in which a formal
rearrangement of the propargylic alcohol assisted by gold
would have been involved.[8] Interestingly, precursor 6, the
methyl ether analogue of 1a, afforded enone 3a in moder-
ate yield.[33] We believe that this last result strongly supports
the nonparticipation of allene 4a as a possible intermediate
1a
3a 98
3c 99
3d 90
3g 98
3m 93
2[c]
1c
3
1d
1g
1m
4[c]
5
6[c]
1n
1p
3n 93
3p 95
7[c]
[a] Reaction conditions: alkyne
1
(1 mmol), [(ItBu)AuCl]/AgSbF
6
(2 mol%), THF (10 mL), H2O (1 mL). [b] Yield of isolated product, aver-
age of two runs. [c] No purification by silica gel column chromatography
was needed.
Scheme 5. Effect of O-substitution on the formation of 3a.
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Gold-Catalyzed Formation of Conjugated Enones and Enals
FULL PAPER
because of the inability of methoxy groups to undergo [3,3]
rearrangements.[34]
sidered. However, it was found to have an energy
200 kcalmolÀ1 greater than that of I. We strongly believe
that such a large energy gap prohibits the formation of IV,
therefore rendering the bottom pathway highly unlikely,
even in the condensed phase.
An SN2’-like mechanism? An “intuitive” mechanism we
could propose for the transformation of propargyl acetate 1
to enone 3 is depicted in Scheme 6.
An alternative SN2’ mechanism:
The mechanistic proposals in
Scheme 6 are based on the as-
sumption that the role of the
gold catalyst is to activate the
alkyne. This is exemplified by
the initial formation of species
I. The unexpected failure of our
calculations to support this
mechanism prompted us to ex-
amine the possibility that the
cationic gold species activates a
water molecule or another co-
ordinating species in solution.
From an experimental point of
view, the former possibility is
Scheme 6. “Intuitive” mechanism for the formation of 3 from 1.
not infeasible, as the experi-
ments reported above showed
that in the absence of water a
Three possible SN2’-like mechanisms were considered:
1) Aconcerted mechanism with assistance of cationic gold,
in accordance with most proposals on gold homogeneous
catalysis, to render the alkyne more prone to nucleophilic
attack (middle pathway); 2) a stepwise mechanism involving
the addition of water and the formation of a vinylgold spe-
cies III followed by expulsion of acetic acid (top path);
3) another stepwise mechanism proceeding by the release of
AcOÀ and subsequent addition of water (bottom path). We
evaluated the possibility of these SN2’ mechanisms with the
help of computational chemistry. DFT calculations at the
B3LYP level of theory were carried out on a model system
in which the leaving group was formate, the propargylic and
alkyne substituents were methyl groups, and the NHC was
represented by IDM (N,N’-dimethylimidazol-2-ylidene). All
the energetic data discussed are enthalpies calculated at
298.15 K and 1 atm (DHG,298.15).
different chemical transformation takes place (see above).
The energies of the different gold species that may be
formed in the reaction mixture from the cationic
[(NHC)AuSbF6] complex are reported in Scheme 7. Cationic
complexes of the type [(NHC)AuX], where X is a noncoor-
dinating ligand, are known to exist experimentally and have
been characterized:[35] the energies are given relative to
[(NHC)AuSbF6] (C1). Two groups of ligands have been ana-
À
lyzed: neutral (1, H2O, THF) and anionic (SbF6 , OHÀ).
Unexpectedly, these calculations failed to support the
mechanisms proposed in Scheme 6. Following the middle
path, the nucleophilic addition of water onto a complex in
which the cationic gold species is bound to the alkyne, we
were not able to locate a transition state leading to allenol
II. Our trial optimizations all reverted to the reactants.
When optimizing the vinylgold intermediate III proposed in
the top path, it was found to be unstable, reverting to I and
water. We consider these results conclusive because neither
of the paths relating to species II or III involves charge sep-
aration, which, therefore, makes them very unlikely to be af-
fected by solvation effects. Finally, the lower path, with ace-
tate as the leaving group leading to complete charge separa-
tion and intermediate IV, is difficult to analyze by gas phase
calculations and would require solvation effects to be con-
Scheme 7. Relative binding energies of ligands to gold species present in
the reaction mixture (energies in kcalmolÀ1).
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6443

F. Maseras, S. P. Nolan et al.
Comparison between the different groups is hampered by
the lack of solvation effects, but analysis of the trends within
each group is informative. Regarding the neutral species, of
the three possible complexes that can form between 1 and a
cationic NHC–gold species, the most stable one involves the
coordination of gold to the carbonyl oxygen atom and not
to the triple bond as expected. Moreover, the calculations
indicate that the THF–gold complex is more stable than the
corresponding complexes with the propargylic formate.
The very stable complex formed by the association of a
hydroxide anion and the cationic gold center caught our at-
tention.[36,37] The [(NHC)AuOH] species C2 could be the
active form of the catalyst in solution. We decided to ana-
lyze the possible formation of this complex from the initial
species C1. Direct reaction of C1 with water can indeed pro-
duce C2, but the reaction is endothermic by 48.9 kcalmolÀ1
because the other product, HSbF6, is a high-energy com-
pound with strong acidity. In the presence of water, HSbF6
would be strongly solvated. We found in fact that its associa-
tion with four water molecules leads to a reasonable net-
work of hydrogen bonds, with abstraction of the proton
from the antimonate and a species better described as
À
+
SbF6À···H7O3
. Formation of [(NHC)AuOH] (C2) and
+
SbF6 ···H7O3 from [(NHC)AuSbF6] and four water mole-
cules is exothermic by 21.1 kcalmolÀ1, thus favorable. C2 is
therefore likely to be present under the reaction conditions.
On the other hand, the protonated water cluster is unlikely
to play any role in the subsequent reaction as it is not acidic
enough to transfer its proton to the weak basic centers in
the reaction medium. In contrast, the hydroxy complex C2
is a viable catalyst.[38]
Scheme 8. Influence of water on the reactivity.
could not be overruled and accordingly two control reac-
tions were performed. Alkyne 1a, when heated at 608C for
16 h in THF and water in the presence of up to 20 mol% of
HPF6, was mainly recovered (80%) along with degradation
products (15%) and traces of 3a (<5%). When HBF4 was
employed under the same conditions, only a small amount
of degradation (5%) was observed along with unreacted
alkyne 1a. It seems reasonable then to exclude the possibili-
ty of strong Brønsted acids acting as catalysts in this trans-
formation.
To verify the suggested mechanism, all the stationary
points in the catalytic cycle were calculated and are present-
ed in the potential energy profile (Figure 1). The optimized
geometries of some key structures (I1, TS1, and I2) are
shown in Figure 2. Unless stated otherwise, all the energies
discussed are given relative to the free reactant R1 and the
gold complex C2.
In the first step of the reaction a complex (I1) between
C2 and R1 is formed with an energy of À4.8 kcalmolÀ1. The
complex rearranges to transition state TS1, in which the
proton of the hydroxy group of C2 has been transferred to
the inner oxygen atom of R1. The oxygen atom of C2 binds
in a concerted process to the most electron-deficient carbon
atom of the triple bond in R1, “delivering” the oxygen atom
to the alkyne.[39] Formic acid is formed and acts as a leaving
group. Apossible alternative transition state involves the
transfer of the proton to the carbonyl oxygen atom. Howev-
er, this TS was found to have a higher energy than TS1. The
transition state has an energy of 20.6 kcalmolÀ1 and the for-
In addition, the fact that from the exact same propargylic
acetate, two very different compounds are produced in the
presence or absence of water can be attributed to two dis-
tinct catalytic species. It should also be noted that not only
the nature of the products but the reaction conditions are
dramatically altered for the transformation to proceed.
Thus, extended reaction time and heating are required for
the formation of enones, whereas indenes are produced at
room temperature in minutes, as shown in Scheme 8. From
observations, the presence of water slows down the reaction
significantly and leads to a new type of product. This means
that water does not only allow the formation of enones, but
inhibits the pathway leading to indenes. We therefore be-
lieve that these observations, together with the results of our
computational studies, strongly support two distinct catalytic
species for the formation of indenes and enones,
[(NHC)AuX] (X is
a
non-coordinating ligand) and
[(NHC)AuOH], respectively.
Following the general SN2’ scheme presented earlier, but
with complex C2 as the active species, we propose the cata-
lytic cycle presented in Scheme 9. In contrast to our first
suggestion, in which the gold center was thought to activate
À
the carbon carbon triple bond of 1, the gold instead acti-
vates water by forming the hydroxide complex C2 and re-
leases a solvated cluster of HSbF6. At this point in our
study, the possibility of a Brønsted acid catalyzed reaction
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Gold-Catalyzed Formation of Conjugated Enones and Enals
FULL PAPER
step of the gold-catalyzed reac-
tion, from I1 to TS1, is 25.4 kcal
molÀ1.
The uncatalyzed reaction: To
compare the energetics and to
learn more about the catalytic
function of the gold complex,
the corresponding uncatalyzed
reaction was investigated, that
is, the addition of water to R1.
The reaction mechanism for
the uncatalyzed reaction is pre-
sented in Scheme 10 and its
energy profile in Figure 3. In
the first step a reaction complex
is formed with water bound to
the reactant, forming complex
I3, exothermic by 9.6 kcalmolÀ1.
Allenol P1 is formed via transi-
tion state TS3, with a proton
from H2O being transferred to
the carbonyl oxygen of R1 to
form formic acid which departs
concomitantly to the formation
À
of the C O bond. This is in
sharp contrast to the gold-cata-
lyzed reaction in which the
proton from C2 is transferred
to the inner oxygen atom of R1
and not to the carbonyl oxygen.
An alternative transition state
for the uncatalyzed reaction,
corresponding to TS1, was opti-
mized, however, this six-mem-
bered structure was found to
have a higher energy than TS3
(3.4 kcalmolÀ1 above TS3).
Scheme 9. Proposed reaction mechanism for the gold-catalyzed production of a,b-unsaturated carbonyl com-
pounds based on calculations.
TS3 has an energy of
26.6 kcalmolÀ1 relative to R1+
H2O. The barrier computed for
the rate-limiting step of the un-
catalyzed reaction, from I3 to
TS3, is 36.2 kcalmolÀ1. This bar-
rier is 10.8 kcalmolÀ1 higher
than that for the gold-catalyzed
reaction. The catalytic effect is
thus properly reproduced.
Figure 1. Computed potential energy profile for the gold-catalyzed formation of enones.
Finally, we noticed that in the
key rate-determining step of the
mation of gold allenolate I2 is exothermic by 7.4 kcalmolÀ1.
To complete the catalytic cycle, water adds to I2, proceeding
through a cyclic six-membered ring TS (TS2), to give the
enone and regenerating catalyst C2. The barrier for this step
is only 1.4 kcalmolÀ1 relative to I2 and the overall process is
exothermic by nearly 40 kcalmolÀ1 relative to the free reac-
tants. The energy barrier computed for the rate-determining
catalyzed reaction, from I1 to TS1, the sum of Mulliken
charges in the [(NHC)Au] fragment changes from +0.432 to
+0.542 atomic units, a change of 0.090 atomic units. On the
other hand, in the uncatalyzed reaction, the Mulliken charge
on the proton occupying the equivalent position changes by
only 0.045 atomic units (from +0.470 to +0.515 atomic
units) in the equivalent step, that is, going from I3 to TS3.
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6445

F. Maseras, S. P. Nolan et al.
Therefore, the advantage of replacing a proton by a gold
species lies probably in the better ability of the latter to sta-
bilize the positive charge that develops at this position
during the reaction cycle.
Conclusion
In summary, we have described a novel type of AuI-cata-
lyzed transformation that enables the formation of a,b-unsa-
turated carbonyl compounds from easily accessible propar-
gylic acetates. The use of [(NHC)AuCl] complexes in con-
junction with a silver salt has allowed the efficient and ste-
reoselective formation of a wide array of conjugated (E)-
enones and -enals in high yields. Water has been found to
play a crucial role in the outcome of the reaction, which has
also been investigated by computational methods. These
studies have led to the proposal of an unprecedented type
of reactivity in the field of gold catalysis and strongly sup-
port [(NHC)AuOH] as the active catalyst. Based on calcula-
tions of a full catalytic cycle, this gold species is proposed to
deliver its hydroxy moiety to the alkyne to form a gold–alle-
nolate intermediate that is hydrolyzed by water to produce
the enone and regenerate [(NHC)AuOH]. Additional re-
search to experimentally verify this unprecedented reactivity
of gold(I) complexes is being devised. Further investigations
on this novel type of reactivity are ongoing in our laborato-
ries.
Figure 2. Geometries of stationary points in the gold-catalyzed reaction.
Experimental Section
General information: All reagents were used as purchased. Reactions
were carried out under anhydrous nitrogen unless otherwise indicated.
Dry tetrahydrofuran (THF) and dry dichloromethane (DCM) were puri-
fied by passing through a purification column from Innovative Technolo-
gy Inc. (SPS-400-6). Silver salts were stored in a desiccator wrapped in
aluminium foil. [(NHC)AuCl] complexes were synthesized according to
literature procedures.[35b] The microwave-assisted reactions were carried
out using a Biotage Initiator 2.0. Thin-layer chromatography (TLC) of re-
action mixtures was performed on EMD Chemicals silica gel 60 F254
plates and visualized using UV light at 254 nm. Flash chromatography
was performed on silica gel 60 (230–400 mesh, Silicycle). 1H and 13C
NMR spectra were recorded with a Varian-300, Varian-400, Bruker-300
or Bruker-500 spectrometer at ambient temperature in CDCl3 containing
tetramethylsilane. Chemical shifts are given in ppm and are referenced to
the peak of tetramethylsilane (0.0 ppm). Some 1H and 13C NMR signals
were assigned by COSY and/or HMBC experiments. Elemental analyses
were performed at Robertson Microlit Laboratories, Inc., Madison, NJ
(USA).
Scheme 10. Plausible mechanism for the uncatalyzed production of a,b-
unsaturated carbonyl compounds.
Synthesis of propargylic acetates 1: Compounds 1a–1e,[21] 1h,[40] 1i,[41]
and 1p[42] have already been reported and fully characterized.
General procedures
Alkynylation: In an oven-dried round-bottom flask, the alkyne (13 mmol,
1.3 equiv) and 1.6m nBuLi (12 mmol, 1.2 equiv) were added to THF
(20 mL) and stirred for 20 min under nitrogen at À788C. The aldehyde
or the ketone (10 mmol, 1 equiv) was added and the reaction mixture
stirred for 20 min. The mixture was then allowed to warm up to room
temperature, quenched with a saturated aqueous NH4Cl solution, and ex-
tracted with diethyl ether. The combined organic layers were washed
with brine, dried with magnesium sulfate, filtered, and evaporated to give
Figure 3. Computed potential energy profile for the uncatalyzed forma-
tion of enones.
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Gold-Catalyzed Formation of Conjugated Enones and Enals
FULL PAPER
the crude propargylic alcohol which was engaged in the next step without
further purification.
1,1-Diphenylprop-2-ynyl acetate (1l): The corresponding alcohol was pur-
chased and acylated as described above to yield, after flash chromatogra-
phy on silica gel (pentane/Et2O, 98:2), 1.80 g (72%) of the title com-
pound. 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.47–7.43 (m, 2H;
Acylation: The propargylic alcohol (10 mmol, 1 equiv), 1,2-dichloro-
ethane (DCE) (30 mL), 4-dimethylaminopyridine (DMAP) (0.360 g,
3.0 mmol, 0.3 equiv), Et3N (5.6 mL, 40 mmol, 4 equiv), and Ac2O
(1.8 mL, 20 mmol, 2 equiv) were added in turn to a round-bottom flask
equipped with a condenser. The reaction mixture was heated overnight
at 808C, quenched with a saturated aqueous NH4Cl solution, and extract-
ed with diethyl ether. The combined organic layers were washed with
brine, dried with magnesium sulfate, filtered, and evaporated to give a
crude product that was purified by flash chromatography on silica gel.
HAr), 7.23–7.17 (m, 8H; HAr), 2.72 (s, 1H; CH), 2.04 ppm (s, 3H; OAc);
ꢀ
13C NMR (75 MHz, CDCl3, 258C, TMS): d=170.1 (C; C=O), 146.4 (C;
CAr), 129.6 (CH; CAr), 128.4 (CH; CAr), 126.9 (CH; CAr), 86.4 (C; C
ꢀ
ꢀ
CH), 84.2 (C; C-OAc), 75.2 (CH; C CH), 21.2 ppm (CH3; OAc); ele-
mental analysis calcd (%) for C16H20O2 (250.29): C 81.58, H 5.64; found:
C 81.36, H 5.77.
1-Phenyloct-3-yn-2-yl acetate (1m): The above general procedure yield-
Alternatively, the propargylic alcohols could be acylated under micro-
wave-heating conditions as follows. The propargylic alcohol (10 mmol,
1 equiv), DMAP (0.360 g, 3.0 mmol, 0.3 equiv), Et3N (5.6 mL, 40 mmol,
4 equiv), and Ac2O (1.8 mL, 20 mmol, 2 equiv) were added in turn to a
vial designed for use in a microwave. The reaction mixture was heated
under microwave heating at 1008C for 12 min. The reaction was then
quenched with a saturated aqueous NH4Cl solution and extracted with
diethyl ether. The combined organic layers were washed with brine, dried
with magnesium sulfate, filtered, and evaporated to give a crude product
that was purified by flash chromatography on silica gel when necessary.
ed, after flash chromatography on silica gel (pentane/Et2O, 98:2), 2.12 g
1
(87% over two steps) of the title compound. H NMR (300 MHz, CDCl3,
258C, TMS): d=7.34–7.22 (m, 5H; HAr), 5.56 (tt, J=6.8, 2.0 Hz, 1H;
CH-OAc), 3.05 (m, 2H; CAr-CH2), 2.19 (dt, J=6.9, 2.0 Hz, 2H; C-CH2),
ꢀ
2.05 (s, 3H; OAc), 1.51–1.41 (m, 2H; CH2), 1.40–1.29 (m, 2H; CH2),
0.90 ppm (t, J=7.2 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=170.1 (C; C=O), 136.4 (C; CAr), 129.9 (CH; CAr), 128.4 (CH;
CAr), 127.0 (CH; CAr), 87.4 (C; C), 77.2 (C; C), 65.2 (CH; CH-OAc),
ꢀ
ꢀ
41.7 (CH2; CAr-CH2), 30.6 (CH2; C-CH2), 22.0 (CH2), 21.2 (CH3; OAc),
ꢀ
18.5 (CH2), 13.8 ppm (CH3); elemental analysis calcd (%) for C16H20O2
(244.33): C 78.65, H 8.25; found: C 78.86, H 8.07.
Desilylation: Compounds 1g, 1k, 1l, and 1n were obtained by desilyla-
tion of the alkyne. The silylated alkyne (10 mmol, 1 equiv) was diluted
with DMSO (17 mL). KF (480 mg, 8.3 mmol, 1.5 equiv) and a few drops
of water were added. After 45 min the reaction mixture was quenched
with water and extracted with diethyl ether. The combined organic layers
were washed with brine, dried with MgSO4, and evaporated to give a
crude product purified by flash chromatography on silica gel.
1-Phenylbut-3-yn-2-yl acetate (1n): The above general procedure yielded,
after flash chromatography on silica gel (pentane/Et2O, 98:2), 1.51 g
(80% over three steps) of the title compound. 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=7.30–7.23 (m, 5H; HAr), 5.53 (td, J=6.8, 2.2 Hz,
ꢀ
1H; CH-OAc), 3.07–3.04 (m, 2H; CH2), 2.44 (d, J=2.2 Hz, 1H; CH),
2.00 ppm (s, 3H; OAc); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
169.7 (C; C=O), 135.7 (C; CAr), 129.7 (CH; CAr), 128.4 (CH; CAr), 127.1
1,1-Diphenylhept-2-ynyl acetate (1 f): The above general procedure yield-
(CH; CAr), 80.8 (C; C CH), 74.5 (CH; C CH), 64.3 (CH; CH-OAc),
41.0 (CH2), 20.8 ppm (CH3; OAc); elemental analysis calcd (%) for
C12H12O2 (188.22): C 78.01, H 5.87; found: C 77.89, H 5.68.
ed, after flash chromatography on silica gel (pentane/Et2O, 98:2), 2.21 g
ꢀ
ꢀ
1
(83% over two steps) of the title compound. H NMR (300 MHz, CDCl3,
258C, TMS): d=7.37–7.34 (m, 2H; HAr), 7.23–7.20 (m, 8H; HAr), 2.16
ꢀ
(dt, J=6.9, 2.0 Hz, 2H; C-CH2), 2.03 (s, 3H; OAc), 1.48–1.42 (m, 2H;
1-Phenylhex-1-yn-3-yl acetate (1o): The above general procedure yield-
CH2), 1.40–1.34 (m, 2H; CH2), 0.89 ppm (t, J=7.2 Hz, 3H; CH3); 13C
NMR (75 MHz, CDCl3, 258C, TMS): d=170.1 (C; C=O), 140.2 (C; CAr),
ed, after flash chromatography on silica gel (pentane/Et2O, 95:5), 1.67 g
1
(77% over two steps) of the title compound. H NMR (300 MHz, CDCl3,
129.8 (CH; CAr), 127.9 (CH; CAr), 127.5 (CH; CAr), 87.2 (C; C CH), 82.7
ꢀ
258C, TMS): d=7.45–7.42 (m, 2H; HAr), 7.30–7.27 (m, 3H; HAr), 5.61 (t,
J=6.7 Hz, 1H; CH-OAc), 2.09 (s, 3H; OAc), 1.87–1.79 (m, 2H; CH2-
ꢀ
(C; C-OAc), 78.2 (CH; C CH), 31.6 (CH2), 22.3 (CH2), 21.0 (CH3;
OAc), 18.7 (CH2), 13.1 ppm (CH3); elemental analysis calcd (%) for
C21H22O2 (306.40): C 82.32, H 7.24; found: C 82.04, H 7.27.
CH(OAc)), 1.59–1.47 (m, 2H; CH2-CH3), 0.98 ppm (t, J=7.4 Hz, 3H;
R
CH2-CH3); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=170.0 (C; C=O),
1-Phenylprop-2-ynyl acetate[43]
(1g): The above general procedure yield-
A
131.9 (CH; CAr), 128.6 (CH; CAr), 128.3 (CH; CAr), 122.4 (C; CAr), 86.7
ed, after flash chromatography on silica gel (pentane/Et2O, 98:2), 1.11 g
(64% over three steps) of the title compound. 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.52–7.49 (m, 2H; HAr), 7.33–7.30 (m, 3H; HAr),
ꢀ
ꢀ
(C; C), 85.2 (C; C), 64.4 (CH; CH-OAc), 37.0 (CH2; CH2-CH(OAc)),
A
21.1 (CH3; OAc), 18.5 (CH2; CH2-CH3), 13.7 ppm (CH3; CH2-CH3); ele-
mental analysis calcd (%) for C14H16O2 (216.28): C 77.75, H 7.46; found:
C 77.89, H 7.38.
ꢀ
6.45 (d, J=2.0 Hz, 1H; CH-OAc), 2.66 (d, J=2.0 Hz, 1H; CH),
1.99 ppm (s, 3H; OAc); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
169.3 (C; C=O), 136.5 (C; CAr), 128.9 (CH; CAr), 128.6 (CH; CAr), 127.6
1-Cyclohexenylhex-1-yn-3-yl acetate (1q): The above general procedure
yielded, after flash chromatography on silica gel (pentane/Et2O, 98:2),
1.89 g (86% over two steps) of the title compound. 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=6.13–6.11 (m, 1H; =CH), 5.50 (t, J=6.6 Hz, 1H;
CH-OAc), 2.10–2.07 (m, 7H; OAc, =C-CH2), 1.78–1.70 (m, 2H; CH2-
(CH; CAr), 80.2 (C; C CH), 75.5 (CH; C CH), 65.1 (CH; CH-OAc),
20.7 ppm (CH3; OAc).
ꢀ
ꢀ
4,4-Dimethyl-1-phenylpent-2-ynyl acetate (1j): The above general proce-
dure yielded, after filtration through a plug of Celite, 1.72 g (75% over
two steps) of the title compound. 1H NMR (400 MHz, CDCl3, 258C,
TMS): d=7.53–7.51 (m, 2H; HAr), 7.39–7.33 (m, 3H; HAr), 6.49 (s, 1H;
CH-OAc), 2.08 (s, 3H; OAc), 1.25 ppm (s, 9H; tBu); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=170.1 (C; C=O), 138.1 (C; CAr), 128.9
CH
(OAc)), 1.66–1.53 (m, 4H; CH2cyclohexene), 1.50–1.40 (m, 2H; CH2-
N
CH3), 0.95 ppm (t, J=7.4 Hz, 3H; CH2-CH3); 13C NMR (75 MHz,
CDCl3, 258C, TMS): d=169.6 (C; C=O), 135.9 (CH; =CH), 120.0 (C; C=
ꢀ
ꢀ
CH), 87.1 (C; C), 83.9 (C; C), 64.6 (CH; CH-OAc), 37.2 (CH2; CH2-
(CH; CAr), 128.7 (CH; CAr), 128.0 (CH; CAr), 96.5 (C; C C-tBu), 75.4 (C;
CH(OAc)), 29.1 (CH2; =C-CH2), 25.7 (CH2; =CH-CH2), 23.3
A
ꢀ
(CH2cyclohexene), 21.5 (CH2cyclohexene), 21.2 (CH3; OAc), 18.5 (CH2; CH2-
CH3), 13.7 ppm (CH3; CH2-CH3); elemental analysis calcd (%) for
C14H20O2 (220.31): C 76.33, H 9.15; found: C 76.35, H 9.28.
ꢀ
C C-tBu), 66.1 (CH; CH-OAc), 31.0 (CH3; tBu), 27.7 (C; tBu), 21.5 ppm
(CH3; OAc); HRMS: m/z: calcd for C21H22O2Na [M+Na]+: 253.1204;
found: 253.1206.
3-Ethyl-1-phenylhept-1-yn-3-yl acetate (1r): The above general proce-
dure yielded, after flash chromatography on silica gel (pentane/Et2O,
99:1), 1.73 g (67% over two steps) of the title compound. 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.46–7.41 (m, 2H; HAr), 7.31–7.26 (m,
1-(4-Methoxyphenyl)prop-2-ynyl acetate (1k): The above general proce-
dure yielded, after filtration through a plug of silica, 1.59 g (78% over
three steps) of the title compound. 1H NMR (500 MHz, CDCl3, 258C,
TMS): d=7.46 (d, J=8.7 Hz, 2H; HAr), 6.90 (d, J=8.7 Hz, 2H; HAr),
3H; HAr), 2.20–1.90 (m, 7H; OAc+CH2-CH
(OAc)), 1.53–1.30 (m, 4H;
G
ꢀ
6.40 (s, 1H; CH-OAc), 3.80 (s, 3H; OMe), 2.65 (d, J=2.3 Hz, 1H; CH),
2.08 ppm (s, 3H; OAc); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
CH2), 1.04 (t, J=7.4 Hz, 3H; CH2-CH3), 0.94 ppm (t, J=7.2 Hz, 3H;
CH2-CH3); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=169.5 (C; C=O),
132.0 (CH; CAr), 128.4 (CH; CAr), 128.3 (CH; CAr), 123.0 (C; CAr), 89.0
169.9 (C; C=O), 160.4 (C; CAr-OMe), 129.5 (CH; CAr), 128.9 (C; CAr-CH-
(OAc)), 114.2 (CH; CAr), 80.7 (C; C CH), 75.3 (CH; C CH), 65.2 (CH;
ꢀ
ꢀ
ꢀ
ꢀ
(C; C), 85.9 (C; C), 80.1 (C; C-OAc), 37.8 (CH2), 31.5 (CH2), 26.5
(CH2), 22.9 (CH2), 22.2 (CH3; OAc), 14.3 (CH3), 8.7 ppm (CH3); elemen-
for C12H12O3Na [M+Na]+: 227.0684; found: 227.0686.
Chem. Eur. J. 2007, 13, 6437 – 6451
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6447

F. Maseras, S. P. Nolan et al.
tal analysis calcd (%) for C17H22O2 (258.36): C 79.03, H 8.58; found: C
79.28, H 8.47.
14.1 ppm (CH3; CH3); elemental analysis calcd (%) for C14H18O2
(218.29): C 77.03, H 8.31; found: C 77.12, H 8.61.
N
3
:
1,1-Diphenylhept-1-en-3-one (3 f): The above general procedure using
conventional heating yielded, after flash chromatography on silica gel
(pentane/Et2O, 95:5), 233 mg (88%) of the title compound. 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.41–7.36 (m, 3H; HAr), 7.35–7.28 (m,
5H; HAr), 7.22–7.18 (m, 2H; HAr), 6.58 (s, 1H; =CH), 2.23 (t, J=7.3 Hz,
2H; CH2-C=O), 1.52–1.43 (m, 2H; CH2CH2CH3), 1.24–1.12 (m, 2H;
CH2CH3), 0.80 ppm (t, J=7.3 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=202.8 (C; C=O), 153.3 (C; Ph2C=CH), 141.2 (C; CAr),
139.3 (C; CAr), 129.7 (CH; CAr), 129.5 (CH; CAr), 128.7 (CH; CAr), 128.6
(CH; CAr), 128.5 (CH; CAr), 126.9 (CH; =CH), 43.1 (CH2; CH2-C=O),
26.6 (CH2), 22.5 (CH2), 14.0 ppm (CH3); elemental analysis calcd (%) for
C19H20O (264.36): C 86.32, H 7.63; found: C 86.15, H 7.51.
(E)-1-Phenyloct-2-en-4-one (3m): The above general procedure using
conventional heating yielded, after flash chromatography on silica gel
(pentane/Et2O, 98:2), 176 mg (87%) of the title compound. The above
general procedure using microwave heating yielded, after flash chroma-
tography on silica gel (pentane/Et2O, 98:2), 188 mg (93%) of the title
compound. 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.35–7.29 (m,
2H; HAr), 7.27–7.21 (m, 1H; HAr), 7.19–7.16 (m, 2H; HAr), 6.38 (dt, J=
15.8, 6.8 Hz, 1H; CH2-CH=), 6.09 (dt, J=15.8, 1.6 Hz, 1H; =CH-C=O),
5.52 (dd, J=6.8, 1.6 Hz, 2H; CH2-CH=), 2.53 (t, J=7.3 Hz, 2H; CH2-C=
O), 1.63–1.53 (m, 2H; CH2CH2CH3), 1.38–1.26 (m, 2H; CH2CH3),
0.90 ppm (t, J=7.3 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=200.9 (C; C=O), 145.2 (CH; CH2-CH=), 137.9 (C; CAr), 131.3
(CH; =CH-C=O), 129.0 (CH; CAr), 128.9 (CH; CAr), 126.9 (CH; CAr),
40.0 (CH2; CH2-CH=), 38.9 (CH2; CH2-C=O), 26.4 (CH2), 22.6 (CH2),
14.1 ppm (CH3); elemental analysis calcd (%) for C14H18O (202.29): C
83.12, H 8.97; found: C 83.05, H 8.98.
(E)-4-Phenylbut-2-enal (3n): The above general procedure using conven-
tional heating yielded, after flash chromatography on silica gel (pentane/
Et2O, 98:2), 137 mg (94%) of the title compound. The above general pro-
cedure using microwave heating yielded, after filtration through a plug of
-
1
Celite, 135 mg (93%) of the title compound. H NMR (300 MHz, CDCl3,
258C, TMS): d=9.53 (d, J=7.9 Hz, 1H; CHO), 7.33–7.23 (m, 3H; HAr),
7.19–7.17 (m, 2H; HAr), 6.95 (dt, J=15.5, 6.7 Hz, 1H; CH2-CH=), 6.09
(ddt, J=15.5, 7.9, 1.5 Hz, 1H; =CH-C=O), 3.64 ppm (d, J=6.7 Hz, 2H;
CH2-CH=); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=193.9 (C; C=O),
156.6 (CH; CH2-CH=), 137.2 (C; CAr), 133.6 (CH; =CH-C=O), 129.0
(CH; CAr), 128.9 (CH; CAr), 127.1 (CH; CAr), 39.1 ppm (CH2); elemental
analysis calcd (%) for C10H10O (146.19): C 82.16, H 6.89; found: C 82.28,
H 7.07.
(E)-1-Phenylhex-2-en-1-one (3o): The above general procedure yielded,
after flash chromatography on silica gel (pentane/Et2O, 98:2), 143 mg
(82%) of the title compound. The product was collected in two fractions.
The first one (110 mg) contained only the E olefin, while the second one
(33 mg) contained a mixture (E:Z, 2:1) of the two isomers of the title
compound.[47] 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.95–7.91 (m,
2H; HAr), 7.55 (tt, J=7.2, 1.4 Hz, 1H; HAr), 7.49–7.43 (m, 2H; HAr), 7.07
(dt, J=15.4, 6.9 Hz, 1H; CH2-CH=), 6.88 (dt, J=15.4, 1.3 Hz, 1H; =CH-
C=O), 2.34–2.26 (m, 2H; CH2-CH=), 1.62–1.47 (m, 2H; CH2CH3),
0.98 ppm (t, J=7.4 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=191.1 (C; C=O), 150.1 (CH; CH2-CH=), 138.2 (C; CAr), 132.8
(CH; CAr), 128.70 (CH; CAr), 128.68 (CH; CAr), 126.2 (CH; =CH-C=O),
35.0 (CH2; CH2-CH=), 21.6 (CH2; CH2CH3), 13.9 ppm (CH3); elemental
analysis calcd (%) for C12H14O (174.24): C 82.72, H 8.10; found: C 82.78,
H 8.07.
=
-
(E)-Dec-6-en-5-one[48]
(3p): The above general procedure using conven-
T
tional heating yielded, after flash chromatography on silica gel (pentane/
Et2O, 99:1), 145 mg (94%) of the title compound. The above general pro-
cedure using microwave heating yielded, after filtration through a plug of
-
1
Celite, 147 mg (95%) of the title compound. H NMR (300 MHz, CDCl3,
258C, TMS): d=6.83 (dt, J=15.9, 6.9 Hz, 1H; CH2-CH=), 6.10 (dt, J=
15.9, 1.5 Hz, 1H; =CH-C=O), 2.54 (t, J=7.3 Hz, 2H; CH2-C=O), 2.23–
2.16 (m, 2H; CH2-CH=), 1.64–1.44 (m, 4H; CH2), 1.40–1.28 (m, 2H;
CH2), 0.97–0.89 ppm (m, 6H; CH3); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=201.2 (C; C=O), 147.3 (CH; CH2-CH=), 130.7 (CH; =CH-C=
6448
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Chem. Eur. J. 2007, 13, 6437 – 6451

Gold-Catalyzed Formation of Conjugated Enones and Enals
FULL PAPER
O), 40.0 (CH2; CH2-C=O), 34.6 (CH2; CH2-CH=), 26.6 (CH2), 22.6
(CH2), 21.6 (CH2), 14.1 (CH3), 14.1 ppm (CH3).
Notz, F. Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004, 37, 580–
591.
[4] For reviews, see: a) G. Jones, Org. React. 1967, 15, 204–599;
b) M. B. Smith, J. March, Advanced Chemistry: Reactions, Mecha-
nisms, and Structure, 5th ed., Wiley, New York, 2001, pp. 1218–1231.
[5] a) W. S. Wadsworth, Jr., Org. React. 1977, 25, 73–253; b) W. J. Stec,
Acc. Chem. Res. 1983, 16, 411–417.
[6] For an extensive list of preparative methods for enones and enals,
see: M. B. Smith, J. March, Advanced Chemistry: Reactions, Mecha-
nisms, and Structure, 5th ed., Wiley, New York, 2001, p. 1691.
[7] S. Swaminathan, K. V. Narayanan, Chem. Rev. 1971, 71, 429–438.
[8] a) K. H. Meyer, K. Schuster, Chem. Ber. 1922, 55, 819–823; b) E. T.
Clapperton, W. S. MacGregor, J. Am. Chem. Soc. 1950, 72, 2501–
2502; c) G. F. Hennion, B. R. Fleck, J. Am. Chem. Soc. 1955, 77,
3253–3258; d) M. Edens, D. Boerner, C. R. Chase, D. Nass, M. D.
Schiavelli, J. Org. Chem. 1977, 42, 3403–3408; e) J. Andres, R. Car-
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f) M. Yoshimatsu, M. Naito, M. Kawahigashi, H. Shimizu, T. Katao-
ka, J. Org. Chem. 1995, 60, 4798–4802.
[9] a) H. Rupe, E. Kambli, Helv. Chim. Acta 1926, 9, 672; b) G. F.
Hennion, R. B. Davis, D. E. Maloney, J. Am. Chem. Soc. 1949, 71,
2813–2814; c) E. E. Smissman, R. H. Johnsen, A. W. Carlson, B. F.
Aycock, J. Am. Chem. Soc. 1956, 78, 3395–3400.
[10] For examples of the Meyer–Schuster reaction under mild conditions,
see: a) K. Narasaka, H. Kusama, Y. Hayashi, Tetrahedron 1992, 48,
2059–2068; b) C. Y. Lorber, J. A. Osborn, Tetrahedron Lett. 1996,
37, 853–856; c) D. Crich, S. Natarajan, J. Z. Crich, Tetrahedron 1997,
53, 7139–7158; d) C. Sun, X. Lin, S. M. Weinreb, J. Org. Chem.
2006, 71, 3159–3166.
[11] Two reports on the Meyer–Schuster rearrangement as a competing
reaction have recently appeared: a) M. R. Luzung, F. D. Toste, J.
Am. Chem. Soc. 2003, 125, 15760–15761; b) B. M. Trost, C. K.
Chung, J. Am. Chem. Soc. 2006, 128, 10358–10359.
[12] For Ag-promoted Meyer–Schuster rearrangement, see: a) Y. Shige-
masa, H. Oikawa, S.-i. Ohrai, H. Sashiwa, H. Saimoto, Bull. Chem.
Soc. Jpn. 1992, 65, 2594–2598; for Au, see: b) M. Georgy, V. Bou-
card, J.-M. Campagne, J. Am. Chem. Soc. 2005, 127, 14180–14181;
c) D. A. Engel, G. B. Dudley, Org. Lett. 2006, 8, 4027–4029; for Re,
see: d) K. Narasaka, H. Kusama, Y. Hayashi, Chem. Lett. 1991,
1413–1416.
(E)-1-Cyclohexenylhex-2-en-1-one (1q): The above general procedure
using conventional heating yielded, after flash chromatography on silica
gel (pentane/Et2O, 99:1), 159 mg (89%) of the title compound. 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=6.87 (dt, J=15.6, 7.0 Hz, 1H; CH2-
CH=CH), 6.64–6.60 (m, 1H; CH2-CH=C), 6.48 (dt, J=15.6, 1.3 Hz, 1H;
=CH-C=O), 1.98–1.86 (m, 6H; CH2-C=), 1.68–1.61 (m, 4H; CH2), 1.52–
1.45 (m, 2H; CH2), 0.95 ppm (t, J=7.4 Hz, 3H; CH3); 13C NMR
(75 MHz, CDCl3, 258C, TMS): d=190.3 (C; C=O), 155.1 (CH; CH2-CH=
CH), 146.2 (CH; CH2-CH=C), 137.8 (C; CH=C), 127.7 (CH; =CH-C=O),
35.0 (CH2; CH2-CH=CH), 26.6 (CH2), 25.8 (CH2), 24.0 (CH2), 23.7
(CH2), 23.2 (CH2), 13.7 ppm (CH3); elemental analysis calcd (%) for
C12H18O (178.27): C 80.85, H 10.18; found: C 80.69, H 10.26.
3-Ethyl-1-phenylhept-2-en-1-one (3r): The above general procedure
yielded, after flash chromatography on silica gel (pentane/Et2O, 98:2),
195 mg (90%) of the title compound. 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.81–7.75 (m, 3H; HAr), 7.48–7.43 (m, 2H; HAr), 6.70 (brs, 1H;
=CH), 2.03–1.92 (m, 4H; CH2-CH=), 1.33–1.27 (m, 4H; CH2), 1.01 (t,
J=7.3 Hz, 3H; CH2-CH3), 0.91 ppm (t, J=7.4 Hz, 3H; CH2-CH3). 13C
NMR (75 MHz, CDCl3, 258C, TMS): d=191.0 (C; C=O), 163.1 (C; C=
CH), 139.2 (C; CAr), 138.7 (C; CAr), 134.8 (CH; CAr), 134.7 (CH; CAr),
129.8 (CH; CAr), 128.7 (CH; CAr), 128.6 (CH; CAr), 118.2 (CH; C=CH),
33.0 (CH2), 32.8 (CH2), 31.6 (CH2), 21.9 (CH2), 21.7 (CH2), 21.6 (CH2),
21.2 (CH2), 13.9 (CH3), 9.3 (CH3), 9.1 ppm (CH3); elemental analysis
calcd (%) for C15H20O (216.32): C 83.28, H 9.32; found: C 83.40, H 9.07.
Computational methods: In the computational model, the acetate of re-
actant 1 was represented by a formate. Amethyl group was used as the
alkyne substituent. The NHC ligand was represented by IDM (N,N’-di-
methylimidazol-2-ylidene). The stationary points for the uncatalyzed and
the gold-catalyzed reactions were fully optimized by DFT at the
B3LYP[49, 50] level of theory. The gold atom was described by using the
LANL2DZ basis set;[51] this basis set includes the Los Alamos effective
core potential for the inner electrons and a double-z basis set for the
outer electrons. To improve the basis set applied to the gold atom, an f
polarization shell was added (exponent 1.050).[52] The 6-31+G(d) basis
set[53] was used for all remaining atoms. All stationary points were charac-
terized by frequency calculations and transition states were identified by
using a single negative eigenvalue in the Hessian matrix. All calculations
were performed using the Gaussian03 suite of programs.[54]
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Acknowledgements
The ICIQ Foundation is gratefully acknowledged for the financial the
support of this work. Eli Lilly and Co. and Umicore AG are gratefully
acknowledged for their gifts of materials. P.C. and F.M. thank the Spanish
MEC (projects CTQ 2005-09000-C01/BQU and Consolider Ingenio 2010
CSD2006-003) and the Catalan DURSI (project 2005SGR00715) for fi-
nancial support. S.P.N. is an ICREAResearch Professor. N.M. acknowl-
edges Lilly Spain for a Student Award. We thank Prof. M. Murakami
(Kyoto University) for helpful discussions.
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membered oxonium species, resulting from the attack of the acetate
ꢀ
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6450
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Chem. Eur. J. 2007, 13, 6437 – 6451

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Chem. Eur. J. 2007, 13, 6437 – 6451
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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