Unveiling the reactivity of propargylic hydroperoxides under gold catalysis

Article abstract of DOI:10.1021/ja3108966

Controlled gold-catalyzed reactions of primary and secondary propargylic hydroperoxides with a variety of nucleophiles including alcohols, phenols, 2-hydroxynaphthalene-1,4-dione, and indoles allow the direct and efficient synthesis of β-functionalized ke

Full text of DOI:10.1021/ja3108966

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Article
Unveiling the Reactivity of Propargylic Hydroperoxides under Gold Catalysis
Benito Alcaide, Pedro Almendros, M. Teresa Quirós, Ramón
Lopez, Maria Isabel Menendez, and Aleksandra Sochacka-#wik#a
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja3108966 • Publication Date (Web): 11 Dec 2012
Downloaded from http://pubs.acs.org on December 15, 2012
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Unveiling the Reactivity of Propargylic
Hydroperoxides under Gold Catalysis
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a
Benito Alcaide, Pedro Almendros, b M. Teresa Quirós,a Ramón López,c María I. Menéndezc and
*
*
Aleksandra SochackaꢀĆwikłaa,b
aGrupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad
Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040-Madrid,
Spain
bInstituto de Química Orgánica General, IQOG, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
c Departamento de Química Física y Analítica, Universidad de Oviedo, Julián Clavería 8, 33006
Oviedo, Asturias, Spain
Eꢀmail: alcaideb@quim.ucm.es; Palmendros@iqog.csic.es
Abstract: Controlled goldꢀcatalyzed reactions of primary and secondary propargylic
hydroperoxides with a variety of nucleophiles including alcohols, phenols, 2ꢀhydroxynaphthaleneꢀ
1,4ꢀdione, and indoles allow the direct and efficient synthesis of βꢀfunctionalized ketones. Besides,
the utility of some of the resulting products for the selective preparation of fused polycycles has
been demonstrated. In addition, density functional theory (DFT) calculations and 18Oꢀlabeling
experiments were performed to obtain an insight into various aspects of the controlled reactivity of
propargylic hydroperoxides with external nucleophiles under gold catalysis.
INTRODUCTION
The last decade has witnessed dramatic growth in the number of reactions catalyzed by gold
complexes because of their powerful soft Lewis acidic nature.1 In particular, activation of alkynes
toward attacks by oxygen nucleophiles such as carbonyls, carboxylic acids, and alcohols, is an
important C–O bondꢀforming reaction.2 Although many efforts have been made in these fields and
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despite that alkylhydroperoxides are important reactants in several processes,3 metalꢀcatalyzed
reactions of alkynes bearing a hydroperoxide moiety have remained unexplored. It should be
mentioned that recently, even the formation of hydroperoxides by a oneꢀpot sequence of goldꢀ
catalyzed isomerization/autoxidation has been described, these peroxides survived the presence of
the gold catalysts.4 Encouraged by our recent results in catalytic processes,5 we decide to analyze
the possibility of performing metalꢀcatalyzed reactions to unravel the reactivity of propargylic
hydroperoxides. Moreover, the mechanism of the reactions has additionally been investigated by a
theoretical study.
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RESULTS AND DISCUSSION
Propargylic hydroperoxides 1a–h required for our study were easily prepared from the
corresponding propargylic bromides in oneꢀpot procedure (see Supporting Information for details).
To explore the reactivity of alkynes 1 towards metal catalysis we selected hydroperoxide 1a as a
model substrate. PdCl2, AuCl3, AuCl, and PtCl2, either failed to catalyze the reaction or gave a
complex reaction mixture. Gratifyingly, after considerable experimentation, it was found that using
a catalyst system consisting of [Au(OTf)PPh3] (2.5 mol%), generated in situ from AuClPPh3 and
AgOTf,6 and pꢀtoluenesulfonic acid (PTSA) (10 mol%) in the presence of ethanol (200 mol%) in
dichloromethane, the reaction proceeded cleanly and afforded βꢀalkoxy ketone 2a in 46% yield
(Scheme 1). On the basis of the structure of 2a, we believed that ambient H2O in the reaction
system was involved in this Au(I)ꢀcatalyzed reaction. The addition of 2.0 equivalent of H2O raised
the yield of 2a up to 66% (Scheme 1). In order to show the beneficial use of water, we performed
the goldꢀcatalyzed reaction of hydroperoxide 1a with ethanol under otherwise identical conditions
but working under anhydrous conditions and replacing PTSA H2O by methanesulfonic acid. The
dramatic decrease of yield in the formation of βꢀalkoxy ketone 2a, did clearly establish the essential
role of water for this transformation. Change on the nature of the counterion has little effect in the
reaction, because alternate counterions (AgSbF
6
, AgBF ) showed a minimal effect to improve the
4
yield of the product. Using [AuClIPr] or Ph3PAuNTf2 as the gold catalysts did not improve the
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reaction outcome. The comparative studies of βꢀalkoxy ketone formation without addition of
PTSA demonstrated that the presence of the Brønsted acid gives higher yields, acting the acid
additive as a beneficial collaborator.7 Optimization of solvent revealed that chlorinated solvents
were superior to acetonitrile or aromatic solvents. No advantage accrues from changing the
dichloromethane for ethanol as solvent. Under the optimized reaction conditions, we investigated
the generality of the goldꢀcatalyzed transformation of differently substituted propargylic
hydroperoxides 1b–g. As shown in Scheme 1, the above process in a oneꢀpot operation from
readily available alkynyl hydroperoxides and alcohols (methanol, ethanol, ethylene glycol) serves
as a general approach to βꢀalkoxy ketones 2b–l.8 Interestingly, secondary alkynyl hydroperoxide 1f
also undergoes this interesting transformation to give in an efficient manner βꢀalkoxy ketones 2k
and 2l. The selective transformation of diols bearing similar hydroxyl groups is one of the
significant challenges in organic synthesis.9 Interestingly, the mildness of the method allows the
control of both the mono and the double reaction of bis(hydroperoxide) 1g (Scheme 1).
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Scheme 1. Controlled gold-catalyzed reaction of propargylic hydroperoxides with alcohols.
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2.5 mol% [AuClPPh3], 2.5 mol% AgOTf
O OH
10 mol% PTSA, 200 mol% R3OH
R1
OR3
R1
O
R2
200 mol% H2O
R2
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CH2Cl2, RT, 20h
1
2
3
1a
2a
R = Et (66%)
R = Ph, R = H
1a R1 = Ph, R2 = H
1b R1 = 4-BrC6H4, R2 = H
2b R3 = Me (59%)
2c R3 = Et (73%)
1
2
3
1b
2d
R = 4-BrC6H4, R = H
R = Me (75%)
1c R1 = 4-MeOC6H4, R2 = H
1c R1 = 4-MeOC6H4, R2 = H
2e R3 = Et (67%)
2f R3 = Me (80%)
1
2
3
1c
2g
R = 4-MeOC6H4, R = H
R = (CH2)2OH (72%)
1d R1 = 2-Thiophenyl, R2 = H
1d R1 = 2-Thiophenyl, R2 = H
2h R3 = Et (62%)
2i R3 = Me (72%)
1
2
3
1e
2j
R = CH2OBn, R = H
R = Et (57%)
1f R1 = Ph, R2 = Me
1f R1 = Ph, R2 = Me
2k R3 = Et (70%)
2l R3 = Me (75%)
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
EtO
10 mol% PTSA
200 mol% EtOH
200 mol% H2O, CH2Cl2, RT, 20h
HO O
O OH
O
O OH
1g
2m
(50%)
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
400 mol% EtOH
200 mol% H2O, CH2Cl2, RT, 40h
OEt
EtO
O
O
2n
(47%)
When we investigated the reactivity of propargylic hydroperoxides 1 with phenols at room
temperature the starting materials were recovered. Only after heating at reflux temperature, the
goldꢀcatalyzed reactions evolved. Surprisingly, the use of substituted phenols including catechol
did not result in the formation of the corresponding phenoxy ketones; arylketones 3a–h were
obtained instead as the result of a hydroarylation reaction (Scheme 2).10 1,4ꢀType FriedelꢀCrafts
reactions of phenols remain underdeveloped owing to problems rooted in reaction selectivities
(chemoꢀ and regioꢀ) and reactivities.11 Fortunately, compounds 3 were exclusively isolated as the
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paraꢀsubstituted phenol regioisomers. Besides, the gold(I)ꢀcatalyzed selective monoarylation of
bis(hydroperoxide) 1g as well as the double hydroarylation reaction were successfully developed
(Scheme 2).
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Scheme 2. Controlled gold-catalyzed reaction of propargylic hydroperoxides with phenols.
2.5 mol% [AuClPPh3]
OH
2.5 mol% AgOTf
OH
R1
O OH
10 mol% PTSA
R3
R1
+
R2
R3
R2
H2O (2 equiv)
O
CH2Cl2, reflux, 6–14h
2 equiv
1
2
3
1a
3a
R = Ph, R = H
R = H (71%)
1a R1 = Ph, R2 = H
3b R3 = OH (75%)
1
2
3
1b
3c
R = 4-BrC6H4, R = H
R = H (59%)
1
2
3
1b
3d
R = 4-BrC6H4, R = H
1d R1 = 2-Thiophenyl, R2 = H
R = Br (73%)
3e R3 = H (52%)
1
2
3
1d
3f
R = 2-Thiophenyl, R = H
R = OH (34%)
1
2
3
1h
3g
R = 2-BrC6H4, R = H
1f R1 = Ph, R2 = Me
R = H (56%)
3h R3 = H (44%)
HO
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
Br
2-bromophenol (2 equiv)
HO O
O OH
1g
H2O (2 equiv)
CH2Cl2, reflux, 7h
O
O OH
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
3i
(52%)
2-bromophenol (4 equiv)
H2O (2 equiv), CH2Cl2, reflux, 15h
HO
OH
Br
Br
O
O
3j
(48%)
To investigate the scope of external carbon nucleophiles, we focused on two different
nuclei, 4 and 5, which are envisioned to deliver quinone and indole12 derivatives bearing a skeleton
of potential biological interest. It turned out that indole and 5ꢀbromoꢀ1Hꢀindole are suitable
external nucleophiles for the reaction with primary and secondary propargylic hydroperoxides 1.
Worthy of note, despite that C–C bond formation through C–H functionalization of quinones
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remains a challenge due to their unique electronic properties and their ability to coordinate with
metals,13 our conditions were also effective for the direct C–coupling of hydroperoxides 1 with the
electronꢀdeficient cyclic olefin 2ꢀhydroxynaphthaleneꢀ1,4ꢀdione. Both types of substrates either
indole or naphthoquinone provided in a totally selective fashion the desired 3ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ1ꢀ
arylpropanꢀ1ꢀones 6a–d and 2ꢀhydroxyꢀ3ꢀ(3ꢀoxoꢀ3ꢀarylpropyl)naphthaleneꢀ1,4ꢀdiones 7a–d in
synthetically useful yields (Scheme 3).
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Scheme 3. Controlled gold-catalyzed reaction of propargylic hydroperoxides with indole and
quinone derivatives.
R3
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
R3
O
R2
O OH
R2
10 mol% PTSA
R1
R1
+
N
H2O (2 equiv)
CH2Cl2, reflux, 9–18h
H
NH
2 equiv
1c R1 = 4-MeOC6H4, R2 = H
1c R1 = 4-MeOC6H4, R2 = H
1h R1 = 2-BrC6H4, R2 = H
1f R1 = Ph, R2 = Me
6a (49%)
4a R3 = H
4b R3 = Br
4b R3 = Br
4b R3 = Br
6b (49%)
6c (45%)
6d (47%)
O
R2
O
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
O
OH
R1
O OH
R1
+
HO
R2
H2O (2 equiv)
CH2Cl2, reflux, 5–10h
O
5
O
1a R1 = Ph, R2 = H
7a (65%)
7b (50%)
7c (53%)
7d (50%)
2 equiv
1b R1 = 4-BrC6H4, R2 = H
1c R1 = 4-MeOC6H4, R2 = H
1f R1 = Ph, R2 = Me
To capitalize on the above findings for the preparation of different products, a route for a
polycyclic core which appears in several products of biological interest was envisioned. Indoleꢀ
fused sevenꢀmembered benzocycles are essential components of alkaloids such as ambiguine,
caulersin, silicone, oxophenylarcyriaflavin, paullones, and arcyriacyanin A, which show a wide
array of biological properties.14 On the other hand, bis(benzo)ꢀfused sevenꢀmembered carbocycles
can be found in cytotoxic colchinols and allocolchicinoids.15 Thus, the concise methods for the
construction of these polycyclic skeletons are highly attractive. To achieve the desired conversion
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to the natural product frameworks from our products, we performed the direct synthesis of tricycle
8 and tetracycle 9 from βꢀfunctionalized ketones 3g and 6c, respectively (Scheme 4). Upon
treatments of 3g and 6c under palladiumꢀcatalyzed conditions, the corresponding polycyclic
compounds 8 and 9 were obtained in fair yields (Scheme 4).
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Scheme 4. Palladium-catalyzed cyclization of β-aryl ketones.
H
O
NH2
N
O
HO
O
NH
NH
Br
MeO
MeO
MeO
OMe
colchinol
OH
OH
N
N
HO
H
H
natural product from
arcyriacyanin A
kenpaullone
Cinnamomum subavenium
3 mol% Pd2(dba)2
4.5 mol% BINAP
O
Br
O
OH
K2CO3 (1.5 equiv)
1,4-dioxane, 120oC
sealed tube, 48h
OH
3g
8 (71%)
3 mol% Pd2(dba)2
4.5 mol% BINAP
K2CO3 (1.5 equiv)
Br
O
O
Br
1,4-dioxane, 120oC
sealed tube, 40h
N
H
NH
Br
6c
9
(69%)
The reaction of propargylhydroperoxides to yield βꢀfuntionalized ketones may be catalyzed
by the Au(I) salt. The catalytic reaction is likely divided into five parts.16 Firstly, coordination of
the carbon–carbon triple bond of propargylic hydroperoxides 1 to the Au(I) salt gives goldꢀπꢀ
alkynyl complex 1-Au. Species 1-Au evolves through a 1,3ꢀhydroperoxide transposition to
intermediate 10. Regioselective nucleophilic addition of water to the disubstituted allene double
bond in goldꢀallenyl complex 10 to give intermediate 11, followed by loss of hydrogen peroxide
provides the α,βꢀunsaturated ketonic gold complex 12. Next, 1,4ꢀaddition of the corresponding
external nucleophile to the species 12,17 would form the gold intermediate 13. Demetalation linked
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to proton transfer provides final products 2, 3, 6, or 7 and regenerates the gold catalyst, closing the
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catalytic cycle (Scheme 5).
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Scheme 5. Mechanistic explanation for the gold-catalyzed controlled preparation of β-functionalized
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ketones.
R1
Nu
O OH
O
R1
1
2 3 6 7
, , ,
AuPPh3
–H
+H
O OH
O
R1
Ph3PAu
HNu
R1
AuPPh3
1-Au
13
1,3-hydroperoxide
transposition
NuH
HO O
•
O
R1 AuPPh3
R1
10
Ph3PAu
H2O
12
AuPPh3
–H2O2
HO O
HO R1
11
To shed light on the active participation of the propargylic hydroperoxide moiety in the
transformation, some control and 18Oꢀlabeling experiments were carried out. Insight into the direct
participation of the hydroperoxide group in the goldꢀcatalyzed process was obtained by running
control experiments with a propargylic alcohol and its acetate.18 Thus, both the reaction of 3ꢀ
phenylpropꢀ2ꢀynꢀ1ꢀol 14 as well as the reaction of its acetate 15 with phenol were run under the
optimum reaction conditions (Scheme 6). Notably, the βꢀfunctionalized ketone formation event was
cut down because compound 3a was formed from 14 and 15 in only 7% and 10% yields,
respectively, under otherwise identical conditions. NMR and mass spectrometric analyses of the
product of reaction of propargylic hydroperoxide 1a with ethanol in presence of H218O with isotope
abundance of 97% (Scheme 6), showed that the βꢀfunctionalized ketone was 18Oꢀlabelled (48%),
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revealing that the carbonylic oxygen was not coming from the hydroperoxide moiety. When H218O
was added to the goldꢀcatalyzed reaction between propargylic hydroperoxide 1b and phenol,
product 18Oꢀ3c with 52% 18O content was formed in 55% yield, further indicating that external H2O
is involved in this reaction (Scheme 6). A similar trend was observed for compounds 18Oꢀ3k and
18Oꢀ6e, but the efficiency of the labeling process was lower (Scheme 6). 18O‐Labelled isomers in
Scheme 6 contain, as much, a 50% of 18O‐isotope abundance which may be not consistent with a
solely water assisted mechanism; meaning that a competitive pathway implying hydroperoxide 16O
during the formation of intermediates 12 is involved. However, taking into account the almost
absence of product 2a by performing the experiment under anhydrous conditions, we are confident
that the carbonylic oxygen in products 2, 3, 6, and 7 was not coming from the hydroperoxide
moiety. The explanation for the partial (<50%) 18O‐labelling in ketones 3 and 6 using H218O, may
arise from the presence of ambient H216O in the open air reaction system. Thus, when we
performed the goldꢀcatalyzed reaction of hydroperoxide 1a with methanol under Schlenk
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18
conditions but using PTSA H2O in presence of H218O (97% of 18O), product Oꢀ2b with 80% 18O
content was formed (Scheme 6, bottom equation).
Here the use of isotopic labels has been used with mechanistic purposes to confirm and
indeed quantify the transfer of molecular components between species. Besides, the preparation of
18Oꢀlabeled compounds may be of pharmaceutical interest because the use of labeled compounds
becomes increasingly interesting for the development of new drugs;19 for example, labeled
derivatives are necessary for metabolite studies as well as for production of novel radiotracers
intended for complex imaging studies in humans. Obviously, our goldꢀcatalyzed reaction is suited
for the synthesis of 18Oꢀlabeled βꢀfunctionalized ketones.
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Scheme 6. Control and 18O-labeling experiments.
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OH
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
unreacted 14 (71%)
Ph
+
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phenol (2 equiv)
200 mol% H2O
OH
Ph
14
O
CH2Cl2, reflux, 20h
3a
(7%)
PTSA = 4-MeC6H4SO3H H2O
OH
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
15
(58%)
Ph
+ unreacted
OAc
phenol (2 equiv)
200 mol% H2O
Ph
15
O
CH2Cl2, reflux, 20h
3a
(10%)
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
OMe
MeO
MeO
10 mol% PTSA
18O (16O 52%)
O OH
200 mol% MeOH
200 mol% H218O, CH2Cl2, RT, 14h
1c
18
2f
O- (53%)
OH
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
Br
Br
18O (16O 48%)
phenol (2 equiv)
200 mol% H218O
CH2Cl2, reflux, 27h
O OH
1b
18O-3c (55%)
OH
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
MeO
MeO
18O (16O 85%)
phenol (2 equiv)
O OH
200 mol% H218O
CH2Cl2, reflux, 54h
1c
18O-3k (44%)
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
10 mol% PTSA
18O (16O 61%)
Br
indole (2 equiv)
200 mol% H218O
O OH
NH
Br
1b
18O-6e (47%)
CH2Cl2, reflux, 54h
2.5 mol% [AuClPPh3]
2.5 mol% AgOTf
OMe
10 mol% PTSA, 200 mol% MeOH
Schlenk conditions
200 mol% H218O, CH2Cl2, RT, 18h
18O (16O 20%)
O OH
1a
18O-2b (63%)
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We also decided to isolate the intermediate α,βꢀunsaturated ketones and to submit these
carbonyl compounds to the reaction conditions to demonstrate their intermediacy in this novel
reaction. Decomplexed α,βꢀunsaturated ketones 12a, 12b, and 12e were isolated when the reactions
of their corresponding hydroperoxides 1a, 1b, and 1e were quenched after 3 h with hydrochloric
acid (1 M). These observations were informative but insufficient. Consequently, the decomplexed
unsaturated ketones 12a and 12b were allowed to react with phenol under goldꢀcatalyzed
conditions. The reactions did form 3ꢀ(4ꢀhydroxyphenyl)ꢀpropanꢀ1ꢀones 3a and 3c in reasonable
yields (Scheme 7); thus accounting for the intermediacy of unsaturated ketones 12.
10
11
12
13
14
15
16
17
18
19
20
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22
23
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Scheme 7. Gold-catalyzed reaction of intermediate α,β-unsaturated ketones with phenol.
2.5 mol% [AuClPPh3]
OH
2.5 mol% AgOTf
O
OH
R1
10 mol% PTSA
R1
+
200 mol% H2O
CH2Cl2, reflux
O
2 equiv
12a R1 = Ph
3a (52%)
3c
1
12b
R = 4-BrC6H4
(45%)
Theoretical calculations on the gold(I)ꢀcatalyzed controlled preparation of 2b from 1a in
Scheme 1, support the mechanistic proposal shown in Scheme 5. The computational study indicates
that the starting hydroperoxide transforms into the corresponding ketone through five consecutive
stages, whose electronic energy in the gas phase and Gibbs energy in CH2Cl2 solution profiles are
collected in Figures 1 and 2. Unless otherwise stated we shall discuss in the text relative Gibbs
energies in solution. The first stage corresponds to the separation of the Au(PH3)+ moiety from the
triflate anion and the bonding of this cation to the C2 atom of the propargylic hydroperoxide (see
Figures 1 and 1S),20 with a Gibbs energy barrier of 9.3 kcal/mol. Isolated reactants and
intermediate 1-Au could easily reach the chemical equilibrium but, actually, it is shifted to product
side due to the further evolution of 1-Au. Experiments show that the replacement of AgOTf by
AgSF6 or AgBF4 hardly affects the product yield. Besides, we have checked that triflate anion does
not directly participate in any of the remaining reaction steps, so we eliminated it from our reactant
systems (see Computational Details).21
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The second reaction stage involves the 1,3ꢀtransposition of the hydroperoxide group. It
takes place with the direct assistance of a water molecule from the reaction medium (see Figures 1
and 2S). The work of Hashmi et al on the hydration of alkynes catalyzed by gold(I) already pointed
out the relevant role played by several environmental water molecules to reduce the involved
barriers.22 Intermediate 1-Au undergoes a four step transformation: an intramolecular cyclization
(TS2 ꢀ I2), a 1,3ꢀH transfer from O2 to C2 (TS3 ꢀ I3), a new 1,3ꢀH transfer from C2 to O1 (TS4
ꢀ I4), and, eventually, the opening of the cycle (TS5 ꢀ 10). The most stable structure along this
piece of the reaction mechanism is the endoperoxide I3, which lies 21.0 kcal/mol below reactants
energy. At the end of the 1,2ꢀdioxole ring opening, the allene 10 is formed, being the rateꢀlimiting
step for the OOH transposition the endoperoxide ring opening.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Electronic energy in the gas phase (dashed line) and Gibbs energy in CH2Cl2 solution
(continuous line) profiles obtained for the first and second stages of the gold-catalyzed reaction of
the alkynic hydroperoxide 1a at the M06/6-31++G(d,p) (LANL2DZ + f for Au) theory level. All the
energies are referred to the reactants: alkynic hydroperoxide (1a) + [Au(OTf)PH3].
TS5
TS2
TS1
15.7
11.4
9.3
TS3
4.8
TS4
2.1
2.1
0.7
0.3
ꢀ4.1
0.0
ꢀ3.6
ꢀ6.9
TS1
ꢀ3.9
ꢀ3.5
1a
+
ꢀ6.1
ꢀ7.5
TS5
1-Au
TS2
TS4
[Au(OTf)PH3]
ꢀ10.8
ꢀ10.1
ꢀ10.0
ꢀ10.6
I4
1-Au-H2O
I2
TS3
ꢀ21.0
ꢀ24.6
10
1a
I4
1-Au-H2O
I2
ꢀ41.3
I3
[Au(OTf)PH3]
10
I3
Reaction coordinate
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In the third reaction stage, a water molecule is added to the C2–C3 double bond of allene
10. Knowing the relevant role played by environmental water22 we included a chain of three water
molecules, one extreme donating an OH group to C3 and the other a H atom to C2; both moieties
are added on perpendicular faces. The relative Gibbs energy barrier for the OH donation is
significantly larger (TS6, 13.1 kcal/mol above reactants) than that for the H donation (TS7, 0.3
kcal/mol under reactants), which ends up in the stable intermediate 11, able to rotate around the
single C2–C3 bond.
10
11
12
13
14
15
16
17
18
19
20
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22
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The fourth reaction stage is the concerted elimination of H2O2 from C3 in 11, thus yielding
the α,βꢀunsaturated carbonyl intermediate 12. A water molecule acts as a bifunctional catalyst,
extracting the H atom from the OH group at C3 and donating one of its H atoms to the leaving
OOH fragment.24 Molecular description of the third and fourth reaction stages corroborates isotopic
labeling experiments.
The isomerization of propargylic alcohols to α,βꢀunsaturated carbonyl compounds is known
as Meyer–Schuster rearrangement, and it has been widely used recently to perform organic
synthesis with atom economy.25 Several reaction mechanisms have been proposed depending on
the catalyst used, which vary from acid catalysts to transition metals such as Ru, Re, Au and Ag,
including oxoꢀmetal catalysts.25 The mechanism here outlined from isolated reactants 1 to
intermediates 12 resembles a Meyer–Schuster rearrangement, but notably, the presence and
geometry characteristics of the OOH functional group allow a new mechanism to happen, which
cannot apply to porpargylic alcohols.
Finally, the fifth reaction stage corresponds to the addition of an alcohol molecule to the
C1–C2 bond of intermediate 12, where we considered methanol as a model alcohol. Similarly to
water, the addition of methanol happens in two steps; one for the bonding of the RO moiety (TS9
ꢀ13), with practically no energy barrier relative to the preceding intermediate, and the last one for
the addition of the H atom (TS10 ꢀ 2b).
Figure 2. Electronic energy in the gas phase (dashed line) and Gibbs energy in CH2Cl2 solution
(continuous line) profiles obtained for the third, fourth, and fifth stages of the gold-catalyzed
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reaction of the alkynic hydroperoxide 1a at the M06/6-31++G(d,p) (LANL2DZ + f for Au) theory level.
All the energies are referred to the reactants: alkynic hydroperoxide (1a) + [Au(OTf)PH3].
5
6
7
8
9
10
11
12
13
14
15
16
17
18
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22
23
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45
46
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TS6
TS8
TS7
TS10
13.1
0.7
0.3
0.0
ꢀ0.3
ꢀ3.2
ꢀ9.2
ꢀ11.0
TS9
TS10
TS8
ꢀ15.2
ꢀ20.2
ꢀ22.3
ꢀ19.8
ꢀ22.5
ꢀ23.2
ꢀ24.6
TS6
ꢀ26.5
10
TS7
ꢀ30.1
11
ꢀ32.7
I5
ꢀ34.3
ꢀ35.5
ꢀ34.3
12
TS9
ꢀ41.7
ꢀ43.6
ꢀ43.4
13
11-isom
2b
I5
12
2b
13
11-isom
Reaction coordinate
Conclusions
In conclusion, selective goldꢀcatalyzed reactions of primary and secondary propargylic
hydroperoxides with alcohols or carbon nucleophiles allow the direct and efficient synthesis of βꢀ
functionalized ketones. The scope of these protocols has been investigated and the utility of the
resulting products for the selective preparation of fused polycycles has been demonstrated. In
addition, density functional theory (DFT) calculations and 18Oꢀlabeling experiments were
performed to obtain an insight into various aspects of the controlled reactivity of propargylic
hydroperoxides with external nucleophiles under gold catalysis. At present time, the application of
this methodology into the selective preparation of different types of heterocyclic compounds is
ongoing in our group.
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Acknowledgment. Support for this work by the DGIꢀMICINN (Projects CTQ2007ꢀ63266,
CTQ2009ꢀ09318, and CTQ2010ꢀ18231), and Comunidad Autónoma de Madrid (Project
S2009/PPQꢀ1752) are gratefully acknowledged. M. T. Q. thanks MEC for a predoctoral grant. A. S.
thanks UE for a fellowship.
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Supporting Information Available: Experimental procedures, characterization data of new
compounds, copies of NMR spectra, and computational details. This material is available free of
charge via the Internet at http://pubs.acs.org.
References and Notes
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(d) Das, A.; Sohel, S. M. A.; Liu, R.ꢀS. Org. Biomol. Chem. 2010, 8, 960. (e) Yamamoto, Y.;
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(c) Silva, E. M. P.; Pye, R. J.; Brown, G. D.; Harwood, L. M. Eur. J. Org. Chem. 2012, 1209.
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(6) AgOTf alone does not catalyze the reaction, thus indicating that a gold complex is the active
catalyst. AgOTf cannot be considered a coꢀcatalyst because its action is generally assumed to
be restricted to form cationic gold species by anion exchange. See: (a) Duschek, A.; Kirsch,
S. F. Angew. Chem. Int. Ed. 2008, 47, 5703. (b) Gaillard, S.; Bosson, J.; Ramón, R. S.; Nun,
P.; Slawin, A. M. Z.; Nolan, S. P. Chem. Eur. J. 2010, 16, 13729. However, despite proving
that the silver activators themselves are unreactive, there are examples of gold(I)ꢀcatalyzed
reactions where Ag(I) salts effected either activity or selectivity: (c) Tarselli, M. A.;
Chianese, A. R.; Lee, S. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2007, 46, 6670. (d) Wang,
D. ; Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli, S. K.; Akhmedov, N. G.; Zhang, H.; Liu,
X.; Petersen, J. L.; Shi, X. J. Am. Chem. Soc. 2012, 134, 9012.
(7) For a review on gold and protons, see: (a) Hashmi, A. S. K. Catal. Today 2007, 122, 211. For
a selected report, see: (b) Hashmi, A. S. K.; Schwarz, L.; Rubenbauer, P.; Blanco, M. C. Adv.
Synth. Catal. 2006, 348, 705.
(8) Protected βꢀhydroxy carbonyl compounds related to 2 are of significant importance since this
structural motif is present in a variety of natural products and also because they are versatile
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building blocks. See: (a) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570. (b)
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and Natural Phenols, Elsevier, Amsterdam, 1996.
(11) With regards to selectivity, a major challenge is to obtain monoꢀalkylated adducts without
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6470.
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(17) This step is supported by literature precedents, because goldꢀcatalyzed reactions of α,βꢀ
unsaturated carbonyl compounds with arenes in principle are known, see: (a) Hashmi, A. S.
K.; Schwarz, L.; Choi, J. H.; Frost, T. M. Angew. Chem. Int. Ed. 2000, 39, 2285. (b) Dyker,
G.; Muth, E.; Hashmi, A.S.K.; Ding, L. Adv. Synth. Catal. 2003, 345, 1247. (c) Alfonsi, M.;
Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265.
(18) For the goldꢀcatalyzed nucleophilic substitution of propargylic alcohols with various Cꢀ, and
Oꢀnucleophiles, see: Georgy, M.; Boucard, V.; Campagne, J.ꢀM. J. Am. Chem. Soc. 2005,
127, 14180.
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(20) Pernpointner, M.; Hashmi, A. S. K. J. Chem. Theory Comput. 2009, 5, 2717.
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(21) The computational investigation was carried out with the simplified species AuPH3 and
methanol, which were chosen to mimic the Au(OTf)PPh3 catalyst and the alcohols
experimentally used, respectively. These simplifications not only minimize the computational
time but also make possible computations involving the catalyst linked to the alkynic reagents
without any significant changes in the obtained theoretical results. In particular, two recent
theoretical studies on both the addition of water and methanol to propyne22 as well as the
hydroamination of 3ꢀmethylꢀ1,3ꢀpentadiene23 catalyzed by a gold(I)ꢀphosphine complex have
+
proved the adequacy of using the AuPH3 catalyst. For computational details see the
Supporting Information.
(22) Krauter, C. M.; Hashmi, A. S. K.; Pernpointner, M. ChemCatChem 2010, 2, 1226.
(23) Kovács, G.; Ujaque, G.; Lledós, A. J. Am. Chem. Soc. 2008, 130, 853.
(24) We did try to analyze the evolved H2O2 by mass spectrometry, but our spectrometer did not
allow us to do it. However, the presence of H2O2 can be easily detected using a simple redox
reaction with iodide. After total consumption of the starting propargylic hydroperoxide, a
brown color (molecular iodine) developed within seconds after the addition of aqueous
potassium iodide to the crude reaction mixture.
(25) (a) Ramón, R. S.; Pottier, C.; GómezꢀSuárez, A.; Nolan, S. P. Adv. Synth. Catal. 2011, 353,
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Marion, N.; Carlqvist, P.; Gealageas, R.; deFrémont, P.; Maseras, F.; Nolan, S.P. Chem. Eur.
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Table of Contents (TOC)
Br
R1
Nu
R1
O
H2O2
AgNO3
H2O NuH
AuPPh3
O OH
HO O
R1
•
R1 AuPPh3
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