[3,3]-sigmatropic rearrangement versus carbene formation in gold-catalyzed transformations of alkynyl aryl sulfoxides: Mechanistic studies and expanded reaction scope

Article abstract of DOI:10.1021/ja401343p

Gold-catalyzed intramolecular oxidation of terminal alkynes with an arenesulfinyl group as the tethered oxidant is a reaction of high impact in gold chemistry, as it introduced to the field the highly valued concept of gold carbene generation via alkyne o

Full text of DOI:10.1021/ja401343p

Article
pubs.acs.org/JACS
[3,3]-Sigmatropic Rearrangement versus Carbene Formation
in Gold-Catalyzed Transformations of Alkynyl Aryl Sulfoxides:
Mechanistic Studies and Expanded Reaction Scope
Biao Lu,†,# Yuxue Li,*,‡ Youliang Wang,† Donald H. Aue,† Yingdong Luo,† and Liming Zhang*,†
†Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93117, United States
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Ling Ling Road 345,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Gold-catalyzed intramolecular oxidation of
terminal alkynes with an arenesulfinyl group as the tethered
oxidant is a reaction of high impact in gold chemistry, as it
introduced to the field the highly valued concept of gold
carbene generation via alkyne oxidation. The proposed inter-
mediacy of α-oxo gold carbenes in these reactions, however,
has never been substantiated. Detailed experimental studies
suggest that the involvement of such reactive intermediates in
the formation of dihydrobenzothiepinones is highly unlikely.
Instead, a [3,3]-sigmatropic rearrangement of the initial cycliza-
tion intermediate offers a reaction path that can readily explain the high reaction efficiency and the lack of sulfonium formation.
With internal alkyne substrates, however, the generation of a gold carbene species becomes competitive with the [3,3]-sigmatropic
rearrangement. This reactive intermediate, nevertheless, does not proceed to afford the Friedel−Crafts-type cyclization product.
Extensive density functional theory studies support the mechanistic conclusion that the cyclized product is formed via an
intramolecular [3,3]-sigmatropic rearrangement instead of the previously proposed Friedel−Crafts-type cyclization. With the new
mechanistic insight, the product scope of this versatile formation of mid-sized sulfur-containing cycloalkenones has been expanded
readily to various dihydrobenzothiocinones, a tetrahydrobenzocyclononenone, and even those without the entanglement of a fused
benzene ring. Besides gold, Hg(OTf)2 can be an effective catalyst, thereby offering a cheap alternative for this intramolecular redox
reaction.
Scheme 1. Gold-Catalyzed Oxidation of Alkynes Using
Oxygen-Delivering Oxidants
INTRODUCTION
■
Homogeneous gold catalysis1 is a rather recent phenomenon
but has generated tremendous interest and excitement in the
synthetic community. Its explosive growth owes much to various
aspects of novel and unprecedented reactivities of gold com-
plexes and to synergistic efforts from many research groups
around the world.
One particularly rewarding, and still evolving, area in gold
catalysis is the oxidation of alkynes using oxygen-delivering
nucleophilic oxidants.2 These oxidants are composed of two
parts: a negatively charged, thus nucleophilic, oxygen and a
positively charged, thus potent, leaving group (nucleofuge).
The gold catalysis follows the sequence outlined in Scheme 1:
first, the nucleophilic oxygen from the oxidant would attack
a gold-activated C−C triple bond in an anti addition; the
alkenylgold intermediate thus formed (i.e., A) would then
undergo γ-elimination, expelling the nucleofugal part of the
oxidant and generating an α-oxo gold carbene intermediate
(i.e., B). Since B could formally be formed through selective
oxidation of the carbene center of an α-carbene gold carbene C,
the overall transformation in Scheme 1 makes stable and benign
alkynes in the presence of a gold complex equivalent to the
imaginary species C, offering a formal access to the reactivities
of this provocative structure and foretelling the synthetic
potential of this strategy.
Intramolecular Gold-Catalyzed Oxidation of Alkynes
by Tethered Sulfoxides. The application of this concept was
first realized using tethered sulfoxides as the oxygen-delivering
oxidant by Toste3 and us4 independently at around the same
time, and dihydrobenzothiepinones (e.g., 2) were formed in
typically excellent yields (Scheme 2). Along the same line as in
Received: April 28, 2012
© XXXX American Chemical Society
A
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state E, underwent a [2,3]-sigmatropic rearrangement to render
the final sulfur heterocycle. The fact that this mechanistic
rationale is seemingly the only viable one for this transforma-
tion strongly suggests that α-oxo gold carbenes of type B are
accessible via the strategy outlined in Scheme 1, but argues
strongly that the sulfonium intermediate E should be formed in
Scheme 2. This begs the question of why E, presumably much
more stable than the gold carbene, does not impede the
observed cyclization.
Scheme 2. Sulfoxides as Intramolecular Oxidants in Gold
Catalysis3,4
Many researchers including us have subsequently applied this
intramolecular strategy to other oxygen-delivering oxidants
including nitrone,6 N-oxides,7 epoxide,8 and nitro9 successfully,
under the assumption10 that α-oxo gold carbenes were generated.
Intermolecular Gold-Catalyzed Alkyne Oxidation Using
Sulfoxides as Oxidants. With all these successes with intra-
molecular oxidations, intermolecular alkyne oxidation using
sulfoxides was studied by Ujaque and Asensio.11 However, in
their elegant work, the experimental results do not support the
formation of an α-oxo gold carbene intermediate of type B.
Instead, a [3,3]-sigmatropic rearrangement is invoked to explain
the reaction outcomes, which is further corroborated by
computational studies (Scheme 5). This study prompted us to
Scheme 1, a common mechanism via an α-oxo gold carbene
intermediate (e.g., D) was proposed.3,4 In addition, we hypo-
thesized the sulfonium ion E as a resting state of the gold
carbene, although it might instead act to trap the gold carbene
irreversibly. Particularly noteworthy in these reactions are the
mild nature of sulfoxides as oxidants and the extremely high
efficiencies in the formation of the seven-membered thiepinone
ring. In an attempt to further explore its synthetic utility, we
coupled the alkyne oxidation with a subsequent pinacol rearrange-
ment upon modifying the phenyl group to hinder the
benzothiepinone formation (Scheme 3), and β-diketones were
Scheme 5. Gold-Catalyzed Alkyne Oxidation by an External
Sulfoxide
Scheme 3. Sequential Oxidation/Pinacol-Type
Rearrangement
contemplate an alternative 3,3-rearrangement mechanism for
the original intramolecular chemistry (see Scheme 2).3,4
Later, Liu1k reported a gold-catalyzed intermolecular oxidative
ring expansion using Ph2SO as the external oxidant. In the
proposed mechanism (Scheme 6), no α-oxo gold carbene is
isolated in fair to good yields. The reaction results were con-
sistent with the formation of a gold carbene intermediate F.
Later, Davies5 employed a similar strategy to access such a
gold carbene (Scheme 4), which is subsequently trapped by the
tethered nascent sulfide to form a sulfur ylide G. This inter-
mediate, similar in nature to our previously proposed resting
Scheme 6. Gold-Catalyzed Alkyne Oxidation by an External
Sulfoxide
Scheme 4. Tandem Gold-Catalyzed Intramolecular Alkyne
Oxidation and 2,3-Sigmatropic Rearrangement via the
Intermediacy of a Sulfur Ylide
involved, and the reaction proceeds via a concerted ring
expansion and ejection of nucleofugal Ph2S.
All these studies using sulfoxides as oxidants seemingly
suggest that the reaction pathways depend simply on whether
the oxidant is tethered or not, that is, [3,3]-rearrangement or
concerted elimination when intermolecular and gold carbene
B
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formation when intramolecular. This, however, need not be the
case. Due to the tremendous synthetic potential of α-oxo gold
carbenes, coupled with the surprisingly efficient formation of
seven-membered thiepinone 2 and the absence of reaction
inhibition due to the likely formation of sulfonium E, we
embarked on mechanistic studies of the dihydrobenzo-
thiepinone formation both experimentally and theoretically.
Herein we disclose our findings and the extension of this
chemistry to the formation of even larger S-heterocycles and to
nonaromatic substrates.
expected thiepinone 1. Instead, α-chloroketone 19 was formed
in <10% yields in some cases (e.g., Scheme 8), which was the
result of chloride abstraction5a,19 from the reaction solvent,
dichloroethane. This is consistent with the intermediacy of the
highly electrophilic α-oxo gold carbene D. In addition, the
rearranged enone 20 was formed during isolation, which can be
explained via a cyclization and elimination process. As a control
experiment, no sulfoxide was observed after stirring a mixture of
sulfide 17 and the oxidant, 8-isopropylquinoline N-oxides 18, in
DCE for 20 h.
́
Perez, Nolan, and Echavarren recently reported in several
interesting studies20 that gold catalysts could decompose
α-diazoesters to access reactivities of gold carbenes such as
C−H insertion and cyclopropanation. However, one experiment
in our recent work10 led to our tentative conclusion that α-oxo
gold carbenes might not be generated upon gold-catalyzed
decomposition of α-diazoketones due to competing facile Wolff
rearrangement. To exhaust all possible approaches to generating
D, we nevertheless prepared α-diazoketone 21 and treated it
RESULTS AND DISCUSSION
■
Mechanistic Studies of the Benzothiepinone Forma-
tion. In our continued effort to implement the general strategy
shown in Scheme 1, we have recently reported the first case of
successful generation of α-oxo gold carbenes using an external
oxidant.12 This strategy was later expanded by us to (1) an
efficient synthesis of oxetan-3-ones from propargyl alcohols
(Scheme 7),13 (2) a regioselective synthesis of α,β-unsaturated
21
with Ph3PAuNTf2 (5 mol %). No thiepinone 2 was detected
and neither were the ketone products 19 and 20. Instead, the
carboxylic acid 22 was formed via apparent sequential Wolff re-
arrangement22 and hydration in a 71% isolated yield (Scheme 9).
Scheme 7. Generation of α-Oxo Gold Carbenes via
Intermolecular Alkyne Oxidation and Its Application in
Oxetan-3-one Formation
Scheme 9. Attempt To Generate Gold Carbene D via
Dediazotization
ketones from internal alkynes,14 (3) a rapid [2 + 2 + 1] approach
to 2,5-disubstituted oxazoles,15 (4) a stereoselective synthesis of
azetidin-3-ones from propargylic amides,16 and (5) a rapid access
to chroman-3-ones.17 The suitable oxidants were not sulfoxides
but pyridine N-oxides and quinoline N-oxides, and the forma-
tion of gold carbene intermediates (e.g., H) is strongly implicated
in the formation of oxetan-3-ones (Scheme 7)13 and the
azetidine-3-ones.16 To our delight, this strategy has also been
adopted by other researchers in the development of versatile
synthetic methods.18
This easy access to α-oxo gold carbenes from alkynes using
external pyridine/quinoline N-oxides provided us a valuable
opportunity to probe the mechanism of the dihydrobenzo-
thiepinone formation. Hence, a variety of oxidants and gold
catalysts were examined with alkynyl sulfide 17 as the substrate,
but most of the reactions were messy, and none gave the
This result is consistent with our previous observation10 and
likewise suggests that the gold carbenoid I instead of the gold
carbene D is most likely the reactive intermediate generated.
It is worthwhile to point out that the mechanism of the Wolff
rearrangement catalyzed by metal complexes including preferred
silver salts has not been clearly elucidated.
These results raise serious doubts about the nature of the
gold intermediate en route to the thiepinone 2. If one of the
reaction intermediates were indeed the gold carbene D, it might
then be expected to abstract chloride, as in Scheme 8, and/or be
trapped as the sulfonium species E. An alternative mechanism,
in line with the intermolecular studies,11 would be a [3,3]-
rearrangement for the key C−C bond forming step (Scheme 10).
This would also readily explain the facile formation of seven-
membered thiepinones and the absence of catalyst trapping by E.
Scheme 8. Access to Gold Carbene D via Intermolecular Oxidation
C
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As the gold carbene J was most likely the formed intermediate en
route to 26, this result suggests that the apparent carbene 1,2-C−H
insertion handily outcompetes cyclization, which in turn corroborates
that 25 was formed via a [3,3]-rearrangement.
Scheme 10. Alternative Mechanism for Benzothiepinone
Formation
Formation of Benzene-Fused Larger S-Heterocycles.
With a better understanding of the reaction mechanism, we
reasoned that benzene-fused larger S-heterocycles could be
readily accessible via metal-catalyzed cycloisomerizations,
provided that the initial sulfoxide cyclization could be realized
(Scheme 12).
Scheme 12. Synthesis of Benzene-Fused Larger
S-Heterocycles
The revised mechanism suggests that other metals could
catalyze this cycloisomerization as long as they could promote
the initial 5-exo-dig cyclization. Indeed, Hg(OTf)2 promotes
this reaction, albeit in a much lower efficiency (eq 1).
In our early work,23 the cycloisomerization of sulfoxide
29a was examined only with dichloro(2-picolinato)gold(III)
(Table 1, entry 1) under the assumption that the formation
Table 1. Catalyst Screening for the Formation of 30a
In the case of the sulfoxide 23 containing an internal alkyne
(Scheme 11), Hg(OTf)2 catalyzed the cycloisomerization with
a much higher over all efficiency. Besides the formation of the
methylated thiepinone 24 as the minor product, the formation of
the major product, the thiochroman 25, could also be explained
by a [3,3]-rearrangement, which is preceded by a likely favored
6-endo-dig cyclization. When Ph3PAuNTf2 was used as the catalyst, a
small amount of the enone 26 was detected, indicative of competing
formation of carbene intermediate J. The thiochroman 25 could be
also formed from J via a Friedel−Crafts-type cyclization; however,
this alternative was not supported by an intermolecular study.
As shown in eq 2, following the intermolecular oxidation protocol14
a
entry
catalyst
time
12 h
yield (%)
b
1
2
3
4
5
dichloro(2-picolinato)gold(III)
Ph3PAuNTf2
52
4 h
97
c
IPrAuNTf2
4 h
74
(4-CF3Ph)3PAuNTf2
Hg(OTf)2
4 h
82
d
40 min
75
a
b
NMR yield using diethyl phthalate as reference. Data from our
previous paper;4 the reaction was run at 50 °C. 20% of 29a left.
c
d
Methyl ketone (20%) was formed due to alkyne hydration.
of a thiocine ring via gold carbene cyclization would be too
challenging. Indeed, the reaction yield was modest. However, a
quick screening of gold catalysts revealed that the common
gold catalyst, Ph3PAuNTf2,21 was highly effective, and dihydro-
benzothiocinone 30a was formed in 97% yield (entry 2),
we previously developed, the enone 26 was formed as the major
regioisomer in a good yield; notably, neither 24 nor 25 was detected.
Scheme 11. Gold-Catalyzed Oxidation of Internal Alkyne by a Tethered Sulfoxide
D
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consistent with the [3,3]-rearrangement mechanism. Other
gold catalysts were capable of catalyzing this reaction, as well,
albeit with lower efficiencies (entries 3 and 4). Hg(OTf)2 again
was effective, although a competing hydration was observed,
and the reaction was much faster than in the cases of gold
catalysis (entry 5).
To probe the reaction scope, the benzene ring of 29a was
substituted with groups of varying electronic natures at either
the ortho or the para position. All the cases studied (Table 2,
attachment strongly influenced the reaction outcomes for both
Au and Hg but with opposite trends: with a 5-methyl group,
IPrAuNTf2 was the better catalyst; with a n-butyl group at the
3-position, Hg(OTf)2 was better. cis-Fusion of the pentyne
chain with a cyclohexane ring at the 4,5-positions caused no
problem for the chemistry (entry 9), but a 3,4-fusion with a
benzene ring only permitted the Hg catalysis in a moderate yield
(entry 10). The sulfoxide 29m containing an electron-deficient
C−C triple bond was allowed (entry 11), and in this case,
IPrAuNTf2 was better.
a
When sulfoxide 31 containing an ethyl group at the alkyne
terminus was treated with Ph3PAuNTf2, both the cyclized
product 32 and the enone 33 derived from an initial 6-exo-dig
cyclization were formed (eq 3); in addition, the enone 34
Table 2. Scope Studies of Benzothiocinone Formation
formed from an initial 7-endo-dig cyclization was detected as
trace material. Somewhat to our surprise, Hg(OTf)2 promoted
the formation of 32 rapidly and efficiently, with only a trace
amount of 33 formed. The Hg counterpart24 of α-oxo gold
carbene B may be difficult to form. These results point to
divergent mechanisms, similar to those shown in Scheme 11,
where 32 is formed via a [3,3]-rearrangement of the initial
6-exo-dig cyclization intermediate, and 33 is formed via an
α-oxo gold carbene intermediate. Indeed, no cyclized product
was observed when the sulfide 34 was subjected to inter-
molecular oxidation by 8-methylquinoline N-oxide, confirming
that the thiocinone 32 was not formed via a gold carbene
intermediate (eq 4). Notably, when IPrAuNTf2 was used as the
catalyst, 33 was formed at the expense of 32 (see Eq 3), which
nevertheless is consistent with the fact that IPr is a much better
σ-donor than Ph3P and hence can facilitate the formation of
electrophilic gold carbene intermediates, thereby favoring the
enone formation.
Even a nine-membered S-heterocycle could be readily
prepared via this cycloisomerization approach (eq 5). Hg(OTf)2
a
b
[29] = 0.05 M. Isolated yield reported. Unreacted substrate.
entries 1−6) worked smoothly and efficiently with Hg(OTf)2
as the catalyst. IPrAuNTf2 was found to be the best gold catalyst
in most cases but was generally less efficient than Hg(OTf)2.
Moreover, Au catalysis was much slower than that by Hg(OTf)2
in these cases. Aliphatic substitutions at the pentyne chain were
allowed (entries 7−9). Interestingly, the positions of their
E
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turned out to be the catalyst of choice, and various gold
complexes did not promote this reaction.
40. To our delight, it underwent a similar cyclization and [3,3]-
rearrangement process albeit with decreased efficiency in the case
of either a Au catalyst or Hg(OTf)2, affording the product 41
with the double bond migrated (eq 7).
With the aromatic ring merely providing a C−C double bond
in the [3,3]-rearrangement, we reason that a simple C−C double
bond would play a similar, if not a better, role. Indeed, when
enone sulfoxide 38 was treated with IPrAuNTf2, cyclohexenone-
fused dihydrothiocinone 39 was formed in 75% yield. A lower
yield was observed with Hg(OTf)2 as the catalyst (eq 6).
In addition, the enone could be reduced into the allylic alcohol
COMPUTATIONAL STUDIES
To provide theoretical support for the [3,3]-sigmatropic rearrangement
mechanism, density functional theory (DFT)25 studies have been
■
a
Scheme 13. Calculated Reaction Pathways for Substrate 31
a
(A) (Path-a) 7-endo-dig and (Path-b) 6-exo-dig cyclization of the reactant complex R. (B) Gold carbene intermediate pathway (Path-b1) and the
[3,3]-sigmatropic rearrangement pathway (Path-b2) of the alkenylgold intermediate INT2. The selected bond lengths are in angstroms, and the
relative free energies in dichloromethane (ΔG°sol) are in kcal/mol. Calculated at the PBE1PBE/6-31+G**/SDD level.
F
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Figure 1. Main optimized structures on the reaction pathways shown in Scheme 13. The selected bond lengths are in angstroms, and the relative free
energies in dichloromethane (ΔG°sol) are in kcal/mol. Calculated at the PBE1PBE/6-31+G**/SDD level.
Figure 2. Optimized singlet states of α-oxo gold carbene structures with terminal ethyl (INT3-singlet) and H group (INT3-H-singlet). The selected
bond lengths are in angstroms, angles are in degrees. Calculated in dichloromethane at the PBE1PBE/6-31+G**/SDD level.
performed with the GAUSSIAN09 program26 using the PBE1PBE27
method. For C, H, O, N, P, and S, the 6-31+G** basis set was
used, and for Au and Hg, the SDD basis set with an effective core
potential (ECP)28 was used. Geometry optimization was performed in
G
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Figure 3. Selected molecular orbitals and the depiction of the orbital interactions in the singlet state α-oxo gold carbene INT3-H-singlet.
a
Scheme 14. Calculated Reaction Pathways of the Substrate 29a
a
The selected bond lengths are in angstroms, and the relative free energies in dichloromethane (ΔG°sol) are in kcal/mol. Calculated at the PBE1PBE/
6-31+G**/SDD level.
dichloromethane using the SMD29 method. Harmonic vibration
frequency calculations were carried out, and the optimized structures
are all shown to be either minima (with no imaginary frequency) or
transition states (with one imaginary frequency). Reactions with three
different substrates were calculated. First, the reaction shown in eq 3 was
explored by using the simplified H3P as the metal ligand. The likely
competing occurrence of the gold carbene pathway and the [3,3]-
sigmatropic rearrangement pathway in this reaction makes it an excellent
case for theoretical studies. Then, the sulfoxide 29a, which differs from
31 by having a terminal alkyne, was examined using the experimentally
employed catalyst IPrAu+. Finally, the reaction of the homopropargyl
sulfoxide 1 (Scheme 2), reported by both Toste3 and us4 in the pioneer
studies of gold carbene chemistry, was studied. All the calculations
support the experimental conclusion that the cyclized products are
formed via the [3,3]-sigmatropic rearrangement pathway, where no gold
carbene intermediate is involved.
Reaction Pathways of the Sulfoxide 31. As shown in
Scheme 13, the complex of 31 and H3PAu+, R, may undergo
7-endo-dig (TS-7-endo-dig, ΔGs°ol = 12.9 kcal/mol) or 6-exo-dig-anti
(TS-6-exo-dig, ΔG°sol = 12.1 kcal/mol) cyclization to afford the
intermediates INT1 or INT2, respectively. The 6-exo-dig cyclization
(Path b) is slightly more favorable (with full models, the energy dif-
ference increases to 1.3 kcal/mol),30 qualitatively consistent with the
experimental observations that the products resulting from the 6-exo-dig
cyclization (i.e., 32 and 33, eq 3) were dominant. Another reactant
complex R′, in which the gold coordinates with the sulfoxide oxygen,
H
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Figure 4. Main optimized structures on the reaction pathways shown in Scheme 14. The selected bond lengths are in angstroms, and the relative free
energies in dichloromethane (ΔG°sol) are in kcal/mol. Calculated at the PBE1PBE/6-31+G**/SDD level.
is 1.0 kcal/mol less stable than R, and its syn addition to the tethered
alkyne (TS-6-exo-dig-syn) has an energy barrier of 19.4 kcal/mol, much
higher than that of TS-6-exo-dig-anti (Figure 1).10
The angle O−C2−C1 is 109.4°, smaller than the other two angles
O−C2−C4 (126.7°) and C1−C2−C4 (123.8°), showing that the
carbonyl oxygen atom becomes closer to C1. The calculated Wiberg
bond index33 of O−C1 is 0.2112, indicating that, to some extent, the
lone pair of the carbonyl oxygen atom fills the empty p orbital on C1,
stabilizing the carbocation. These features are much more pronounced
in INT3-H-singlet: the angle O−C2−C1 decreases dramatically to
84.8°, and the O−C1 distance decreases to 1.803 Å, and the calculated
Wiberg bond index of O−C1 increases to 0.6154. Without the
electron-donating ethyl group, the carbonyl oxygen atom has a very
strong interaction with C1. The structure of the α-oxo gold carbene
intermediate may be rationalized by the resonance structures shown in
Figure 3. The interaction between the lone pair of the carbonyl oxygen
atom and the empty p orbital of the carbocation is supported by the
There are two likely pathways for the alkenylgold intermediate
INT2 to proceed. One is Path-b1, where it undergoes S−O bond
breaking (TS-OS) to afford the α-oxo gold carbene intermediate, of
which the singlet state is the ground state (INT3-singlet).30 The
C−Au bond length in INT2 is 2.059 Å, which is decreased to 2.010 Å
in INT3-singlet, indicating a significant interaction between the
carbocation and the Au atom, which can be ascribed to the π-donation
of the 5d electrons of the Au atom.31 The NBO32 charge on Au is
increased from +0.220 in INT2 to +0.371 in INT3-singlet.
As shown in Figure 2, interestingly, in INT3-singlet, the carbonyl
group (C2−O) is nearly perpendicular to the C3−C1−Au plane.
I
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a
Scheme 15. Calculated Reaction Pathways for Substrate 1
a
The selected bond lengths are in angstroms, and the relative free energies in dichloromethane (ΔG°sol) are in kcal/mol. Calculated at the PBE1PBE/
6-31+G**/SDD level.
molecular orbital analysis. In the α-oxo gold carbene, in addition to
the π-donation of the 5d electrons of the Au atom, the lone pair of
the carbonyl oxygen atom is also involved in the stabilization of the
carbocation.
As we were preparing this paper, DFT studies35 of the gold-catalyzed
rearrangements of alkynyl aryl sulfoxides appeared. Notably, only the
reaction pathways involving the generation of gold carbene intermediates
and their subsequent Friedel−Crafts cyclizations, identical to the original
proposed mechanisms by Toste3 and us,4 were calculated. The [3,3]-
sigmatropic rearrangement pathway and the gold carbene pathways
involving the 1,2-hydride migration and the formation of sulfonium
species were not considered. Although the Friedel−Crafts cyclizations by
gold carbene moieties have calculated energy barriers ranging from 6.0 to
22.8 kcal/mol, they are, as we have shown both experimentally and by
calculation, not likely to be the processes leading to the cyclized product.
Reaction Pathways of Sulfoxide 29a. Based on the systematic
theoretical studies with the sulfoxide 31, similar reaction pathways
were also obtained with the sulfoxide 29a, which instead is a terminal
alkyne. To reflect the fact that IPrAuNTf2 was also an effective catalyst
(Table 1), the calculation used the full model of IPr as the metal
ligand36 (Scheme 14 and Figure 4).
As shown in Scheme 14, the 6-exo-dig cyclization (IPr-TS-6-exo-dig)
is much favorable than 7-endo-dig cyclization (IPr-TS-7-endo-dig)
by 5.8 kcal/mol, which is consistent with the experimental
observations that only the product resulting from the 6-exo-dig cycliza-
tion (i.e., 30a) was observed. In the competing product-forming steps
from IPr-INT2, the barrier of [3,3]-sigmatropic rearrangement
(IPr-TS-33, ΔG°sol = 4.9 kcal/mol) is lower than that of O−S bond
breaking (IPr-TS-OS, ΔG°sol = 6.0 kcal/mol), which is consistent with
the formation of 30a experimentally. The α-oxo gold carbene
intermediate IPr-INT3-singlet has structural features similar to that
of INT3-H-singlet (Figure 2).
For the gold carbene intermediate INT3-singlet, the 1,2-H shift
(TS-HT) is very easy, with only a small energy barrier of 2.3 kcal/mol
to form the enone product 33. In contrast, the energy barrier for the
Friedel−Crafts-type electrophilic aromatic substitution reaction via
TS-CC is much higher (12.6 kcal/mol). The trapping of the gold
carbene by the tethered sulfide to form of the sulfonium ion K has
a barrier of intermediate energy of 8.6 kcal/mol. These results indicate
that the benzothiocinone 32 cannot be obtained from the gold carbene
intermediates since the Friedel−Crafts pathway leading to its forma-
tion is much less favorable than the 1,2-H shift. The 1,2-H shift, hence,
is the predominant route for the decomposition of the gold carbene
intermediate, consistent with the experimental observation (eq 3).
Even for substrates where the 1,2-H shift pathway is not available,
the formation of sulfoniums of type E (see Scheme 2) could be sub-
stantially favored over the Friedel−Crafts-type cyclization.
Alternatively, after a conformational conversion (TS-INT2-conf),
INT2′ may undergo a [3,3]-sigmatropic rearrangement (TS-33) to
afford INT4, which will lead to the benzothiocinone product 32 after
1,2-H shift.30 The lengths of the breaking O−S bond and the forming
C−C bond are 2.023 and 3.261 Å, respectively, comparable to that of
the former theoretical study (2.565 and 3.251 Å).11
The barriers of the competing product-forming steps from INT2
are close to each other for Path-b1 (TS-OS, ΔG°sol = 6.7 kcal/mol) and
Path-b2 (TS-33, ΔG°sol = 7.0 kcal/mol), which is consistent with the
formation of both 32 and 33 experimentally. With full models, the
energy diffence between TS-OS and TS-33 is 0.2 kcal/mol.30
When using Hg(OTf)2 as the catalyst, Hg cannot stabilize the
carbocation like Au does due to a much weaker relativistic effect,34
thus the energy of the S−O bond breaking transition state will increase
relative to that of the [3,3]-sigmatropic rearrangement. The calcula-
tions show that Hg-TS-33 is much more favorable than Hg-TS-OS,30
thus the cyclic product 32 was obtained predominantly.
The preference to the [3,3]-sigmatropic rearrangement pathway by
the sulfoxide 29a, in relation to the case of 31, can be qualitatively
rationalized: when the electron-donating ethyl group of 31 is changed
to the hydrogen in 29a, the stabilization of the corresponding
transition state TS-OS by the ethyl group is lost, whereas during the
[3,3]-sigmatropic rearrangement the steric congestion caused by the
ethyl group in TS-33 is relieved, and the electrophilicity of the carbon
center ipso to AuL in IPr-TS-33 should increase. All the factors should
J
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Figure 5. Main optimized structures on the reaction pathways shown in Scheme 15. The selected bond lengths are in angstroms, and the relative free
energies in dichloromethane (ΔG°sol) are in kcal/mol. Calculated at the PBE1PBE/6-31+G**/SDD level.
synergistically promote the benzothiocinone formation relative to the
gold carbene pathway.
Reaction Pathways of Sulfoxide 1. As discussed in the
Introduction, the gold-catalyzed transformation of 1 is a pioneer
of benzothiepinone via Friedel−Crafts-type cyclizations of
α-oxo gold carbene intermediates is disproved experimentally
by generating these reactive species via intermolecular oxidation
and by extensive DFT studies, which reveal a high energy barrier
reaction in gold carbene chemistry. While the experimental studies
for such cyclizations relative to a 1,2-H shift or an intramolecular
trapping by the tethered nascent sulfide. Instead, a [3,3]-
sigmatropic rearrangement of the initial cyclization intermediate
offers a reaction path that is consistent with both experimental
results and the theoretical data. With internal alkyne substrates,
however, the intermediacy of a gold carbene species becomes
possible. This reactive intermediate, nevertheless, does not proceed
to afford the Friedel−Crafts-type cyclization product. Instead, a
facile 1,2-H shift leads to exclusive formation of an enone product.
The [3,3]-sigmatropic rearrangement can still compete with gold
carbene formation, yielding mid-sized sulfur-containing cyclo-
alkenone products. With this new mechanistic insight, the product
scope of this versatile formation of mid-sized sulfur-containing
cycloalkenones has been expanded to various dihydrobenzo-
thiocinones and even a tetrahydrobenzocyclononenone. Besides
suggest strongly that gold carbene intermediates are not involved in
the formation of benzothiepinones, DFT calculations of the reac-
tion would provide further support for the conclusion. As shown in
Scheme 15 and Figure 5, the calculated reaction pathways using IMe as
the metal ligand are similar to that of 29a. The 5-exo-dig cyclization
(IMe-TS-5-exo-dig) is favorable than 6-endo-dig cyclization (IMe-TS-
6-endo-dig) by 6.2 kcal/mol, and the barrier of [3,3]-sigmatropic
rearrangement (IMe-TS-33, ΔG°sol = 3.2 kcal/mol) is more favorable
than that of O−S bond breaking (IMe-TS-OS, ΔG°sol = 4.6 kcal/mol).
CONCLUSION
■
Through a combination of experiments and density functional
theory studies, we have addressed lingering questions on the
mechanism of gold-catalyzed intramolecular oxidation of
terminal alkynes with an arenesulfinyl group as the tethered
oxidant. The previous proposed mechanism for the formation
K
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ASSOCIATED CONTENT
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2012, 134, 1078−1084.
■
S
* Supporting Information
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Lledos, A.; Medio-Simon, M.; Ujaque, G.; Asensio, G. Org. Lett. 2009,
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Experimental procedures, compound characterization and
spectra, all the structures in the calculated pathways, the
relaxed potential energy surface (PES) scan, and the calculated
total energies and geometrical coordinates. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
14072.
Corresponding Author
zhang@chem.ucsb.edu; liyuxue@sioc.ac.cn
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Present Addresses
#Shanghai Hengrui Pharmaceuticals Co. Ltd, Shanghai, 200245,
P. R. China
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
B.L., Y.L., and L.Z. thank NSF (CAREER CHE-0969157) and
NIGMS (R01 GM084254) for generous financial support. L.Z.
thanks PIRE-ECCI for supporting the collaboration between him
and Y.L. Y.L. thanks the National Natural Science Foundation of
China (Grant Nos. 21172248, 21121062). D.A. acknowledges
support from the Center for Scientific Computing at the CNSI
and MRL (NSF MRSEC DMR-1121053 and NSF CNS-
0960316) and the National Center for Supercomputing
Applications (NSF TG-CHE100123) utilizing the NCSA Gordon
and Blacklight systems.
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