Gold(I)-Catalyzed Ring Expansion of Alkynylcyclopropyl Allyl Ethers to Construct Tetrasubstituted Methylenecyclobutanones: A Mechanistic Investigation about the Character of Catalytic Amount of Water

Article abstract of DOI:10.1002/adsc.201900053

A gold(I)-catalyzed ring expansion of alkynylcyclopropyl allyl ethers to produce tetrasubstituted methylenecyclobutanones in moderate to good yields has been disclosed in this paper. This reaction proceeded through an intramolecular [3,3]-sigmatropic rearrangement followed by [1,2]-allyl shift pathway in the presence of catalytic amount of water upon gold(I) catalysis. The intriguing reaction mechanism has been proposed on the basis of deuterium and ¹⁸O-labeling experiments, Mass spectroscopic analysis, ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopic tracking and density functional theory (DFT) calculations. The further transformation of these methylenecyclobutanones into polycyclic skeleton has been realized by a practical three-step synthetic procedure. Several other transformations have been also indicated. (Figure presented.).

Full text of DOI:10.1002/adsc.201900053

Title: Gold(I)-Catalyzed Ring Expansion of Alkynylcyclopropyl Allyl
Ethers to Construct Tetrasubstituted Methylenecyclobutanones:
A Mechanistic Investigation about the Character of Catalytic
Amount of Water
Authors: Min Shi, Wenqing Zang, Lei Wang, Yin Wei, and Yinlong Guo
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900053
Link to VoR: http://dx.doi.org/10.1002/adsc.201900053

10.1002/adsc.201900053
Advanced Synthesis & Catalysis
Full paper
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Gold(I)-Catalyzed Ring Expansion of Alkynylcyclopropyl Allyl Ethers
to Construct Tetrasubstituted Methylenecyclobutanones:
A
Mechanistic Investigation about the Character of Catalytic Amount of
Water
Wenqing Zang,a Lei Wang,a Yin Wei,a,* Min Shi,a,* Yinlong Guoa,*
a State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese
Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
Fax: (+86)-21-6416-6128; e-mail: weiyin@sioc.ac.cn, mshi@sioc.ac.cn, ylguo@mail.sioc.ac.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
groups reported an intramolecular ring expansion of
Abstract:
A
gold(I)-catalyzed
ring
expansion
of
alkynylcyclopropanols to deliver methylenecyclobutanones in
high yields in the presence of gold or ruthenium catalysts,
respectively (Scheme 1a).[8b, e] Later in 2012, Fensterbank and co-
workers discovered a gold-catalyzed cycloisomerization of O-
tethered 1,6-enynes to produce natural-product-like macrocycles
(Scheme 1b).[11] During our ongoing investigations on the
chemical transformation of strained small rings,[12] we envisioned
that introducing a highly strained cyclopropane ring into enyne’s
backbone might lead to an interesting ring expansion consequence
to give functionalized four-membered-ring scaffolds. Inspired by
this working hypothesis, various enynes bearing cyclopropane
moiety were synthesized and we found that some of them
exhibited unique chemical reactivities. Herein, we wish to
disclose that a cyclopropane-tethered enyne could be rapidly
transformed to the scarcely tetrasubstituted vinylcyclobutanone in
assistance with catalytic amount of water upon gold catalysis
(Scheme 1c). Furthermore, the obtained vinylcyclobutanone could
be further transformed to [4.7.3] polycyclic compound by several
steps. The framework of these polycyclic compounds is similar to
those of natural products, such as Dilospirane B which possesses
potential antibiotic activity, and Koraiol and (-)-Neomeranol B as
well (Figure 1),[13] indicating the potential application of this
methodology (Scheme 1c).
alkynylcyclopropyl allyl ethers to produce tetrasubstituted
methylenecyclobutanones in moderate to good yields has been
disclosed in this paper. This reaction proceeded through an
intramolecular [3,3]-sigmatropic rearrangement followed by
[1,2]-allyl shift pathway in the presence of catalytic amount of
water upon gold(I) catalysis. The intriguing reaction mechanism
has been proposed on the basis of deuterium and 18O-labeling
experiments, Mass spectroscopic analysis, 1H and 13C nuclear
magnetic resonance (NMR) spectroscopic tracking and density
functional theory (DFT) calculations. The further transformation
of these methylenecyclobutanones into polycyclic skeleton has
been realized by a practical three-step synthetic procedure.
Several other transformations have been also indicated.
Keywords: gold-catalyzed; alkynylcyclopropyl allyl ethers;
methylenecyclobutanones; water
Introduction
Methylenecyclobutanones are ubiquitous functional building
blocks that can be further transformed to various ring skeletons in
organic synthesis.[1] However, the synthetic methods for the
preparation of these compounds are underdeveloped along with
limited substrate scope due to the existence of the strained four-
membered-ring moiety.[2] Moreover, the present synthetic
approaches are basically under very special or harsh reaction
conditions to realize these four-membered carbocycles.[3] On the
other hand, the cyclopropane could be easily prepared by many
known synthetic methods, such as Simmons-Smith reaction,[4]
Kulinkovich reaction or de Meijere-Kulinkovich reaction,[5] and
others.[6] It is conceivable that a strain-driven ring expansion
strategy[7] might be an alternatively efficient approach for
construction of diversified cyclobutanone derivatives.[8]
During the last decade, gold catalysis has attracted
considerable attention in organic synthesis due to its unique
performance as Lewis acid catalyst, π–activator or carbenoid
intermediate.[9] Particularly, the gold catalyst as the most soft
Lewis acid performed very well in ring expansion reactions under
mild conditions as compared with the other transition metal
catalysts.[10] For example, in 2005 and 2008, Toste’s and Trost’s
1
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10.1002/adsc.201900053
Advanced Synthesis & Catalysis
Scheme 1. Gold-catalyzed ring expansion reactions to construct
methylenecyclobutanone derivatives
1
PPh3AuCl
AgNTf2
DCM
12
complex
/
2
3
4
5
6
7
8
9
JohnPhosAuCl
IPrAuCl
AgNTf2
AgNTf2
AgOTf
AgSbF6
AgBF4
NaBArF
/
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
12
60
12
12
12
12
12
12
complex
60
/
12
16
18
17
16
13
15
IPrAuCl
48
IPrAuCl
65
IPrAuCl
66
IPrAuCl
63
Figure 1. Structure of several polycyclic natural compounds
IPrAuNTf2
66
c
IPrAuNTf2
/
76
Results and Discussions
The examination of the reaction conditions was conducted by
applying 1a as a model substrate, and the results are summarized
in Table 1. First, using AgNTf2 as the silver salt, we examined the
gold catalysts with different phosphine ligands such as PPh3AuCl
(10 mol %) and JohnPhosAuCl (10 mol %) in DCM, but we
found that the reaction only afforded a complex mixture (Table 1,
entries 1 and 2). However, when IPrAuCl (10 mol %), a NHC
ligated (N-heterocyclic carbene-type ligand) gold complex, was
used as the catalyst, the desired product 2a was given in 60%
yield within 60 h (Table 1, entry 3). Subsequently, the use of
other silver salts or NaBArF as the additives was examined in
order to accelerate the reaction rate. We found that adding AgOTf,
AgSbF6, AgBF4 or NaBArF as the additive into this gold-
catalyzed reaction system indeed could accelerate the reaction
proceeding, giving 2a in slightly improved yields within 12 h
(Table 1, entries 4-7). However, their NMR spectra and TLC
plates indicated that besides products 2a and 3a, the final reaction
mixtures always contain some other impurities, perhaps due to the
excessive activity of silver salt. Using prepared IPrAuNTf2 as the
catalyst delivered the desired product 2a in 66% yield within 12 h,
suggesting that the reaction could proceed more smoothly in the
absence of silver salt (Table 1, entry 8). To our surprise, the yield
of 2a experienced an enhancement to 76% when we cut down the
amount of gold catalyst to 5 mol % presumably due to that the use
of less amount of gold catalyst could suppress the partial
decomposition of the formed products 2a and 3a, leading to a
cleaner reaction system (Table 1, entry 9). In addition, we
discovered that the reaction rate was further accelerated when the
wet solvent was employed. Enlightened by this phenomenon and
our previous work, we assumed that extra H2O might be able to
facilitate this gold-catalyzed reaction.[14] Subsequently, 1.0 equiv
of water was added and we found the reaction was indeed
accelerated although 2a was obtained in 62% yield within 6 hours
(Table 1, entry 10). Then the solvent effect was investigated
thoroughly with addition of 1.0 equiv of water, revealing that 1,2-
dichloroethane (1,2-DCE) was the best one, affording 2a in 66%
yield within 6 hours (Table 1, entries 11-14). However, the fall in
yield of 2a indicated that redundantly external water might hedge
the water effect in this reaction. Thus, we reduced the amount of
H2O to 0.5 equiv and found that the yield of 2a was improved to
80% yield (78% isolated yield) within 6 h as the optimized result
(Table 1, entry 15). The control experiment indicated that no
reaction occurred in the absence of gold catalyst (Table 1, entry
16). It should be also mentioned that 3a was detected as a by-
product during these screening processes.
1.0 equiv
H2O
c
10
11
12
13
14
15
16
IPrAuNTf2
DCM
1,2-DCE
1,2-DCE
THF
6
62
66
13
15
1.0 equiv
H2O
c
IPrAuNTf2
6
1.0 equiv
H2O
c
IPrAuNTf2
12
12
12
6
trace
trace
/
1.0 equiv
H2O
c
IPrAuNTf2
complex
trace
1.0 equiv
H2O
c
IPrAuNTf2
toluene
1,2-DCE
1,2-DCE
trace
14
0.5 equiv
H2O
c
IPrAuNTf2
80 (78)
AgNTf2,
0.5 equiv
/
12
N.A.
trace
aThe reaction scale is 0.1 mmol of 1a in anhydrous solvent (0.1 M) at
room temperature. bYield was determined by 1H-NMR yield using 1-
bromo-4-methoxybenzene as an internal standard. c5 mol % of gold
catalyst was used.
Having established the optimal reaction conditions, we
decided to investigate the substrate scope and the results are
summarized in Scheme 2. We firstly examined the reaction
outcomes by using 1 with different electron-donating group
(EDG) substituted aromatic rings as substrates. As can be seen
from Scheme 2, for substrates 1b-1k, most of the reactions
proceeded smoothly in 1,2-DCE, furnishing the corresponding
products 2b-2k in 44-85% yields. Especially, the substrates
bearing Et (1e), nPr (1f) or OMe (1i) group afforded the
desired products in good yields, ranging from 82% to 85%.
However, changing the phenyl group to 2-naphthyl group, the
desired product 2l was obtained in 37%. When the phenyl
group in substrates 1 was substituted by electron-withdrawing
group (EWG) (1m to 1o), the desired products 2m-2o were
given in relatively lower yields, perhaps due to the electronic
effect. The reaction also performed very well when vinyl
group was installed on the phenyl moiety, giving the
corresponding product 2p with the yield of 62%.
Heteroaromatic group was also tolerated, furnishing the
desired product 2q in 75% yield. Substrate 1r bearing an
aliphatic alkyl group is also compatible, giving the desired
product 2r in 53% yield after prolonging the reaction time. In
addition, this reaction also tolerated a wide variety of allyl
derivatives, giving the desired products 2s-2v with the yields
ranging from 28% to 79%. The structure of 2j has been
unequivocally confirmed by X-ray diffraction. The
corresponding ORTEP drawing is shown in Scheme 2.
Table 1. Optimization of the reaction conditions for the
transformation of 1a to 2a
yield/%b
[Ag]
time
(h)
entry
Au cat
solvent
or additive
3a
2a
2
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10.1002/adsc.201900053
Advanced Synthesis & Catalysis
Moreover, adding D2O and H218O into the reaction mixture
respectively, to our surprise, 3a as a by-product was successfully
labeled by both deuterium and 18O atoms, but 2a was formed
without incorporation of deuterium and 18O atoms (Schemes 3b
and 3c). This intriguing result motivated us to do further
1
investigation on H2O effect in this reaction. On the basis of H-
NMR spectroscopic tracking experiment, the formation of allyl
alcohol was identified in nearly 8% yield under the standard
conditions along with the formation of 3a. Furthermore, the 13C-
NMR spectroscopic tracking experiment disclosed a signal at δ =
98.3 ppm, indicating the formation of ketal intermediate or its
analogues (see Supporting Information for the details). We also
found that this signal stayed throughout the reaction even after the
reaction completed, suggesting that this species is quite stable and
less reactive. Although we failed to isolate this species, the
SAESI-MS analysis of the reaction mixture showed a possibly
corresponding potassium ion peak (m/z = 839.33) (Schemes 3b,
3c). On the basis of these results, the existence of a hemiacetal
species could be identified, which could be considered as a resting
state in the catalytic cycle due to its relatively low reactivity.
Finally, the use of deuterated 1a-D (D content = 93%) produced
2a-D in 54% yield along with 92% D content under the standard
conditions, indicating a [3,3]-sigmatropic rearrangement process
in the catalytic cycle (Scheme 3d).
aGeneral condition: 1 (0.2 mmol), IPrAuNTf2 (0.01 mmol), H2O (0.1
b
mmol) in 1,2-DCE (0.1 M), at room temperature, 6 h. All yields are the
isolated yields. cThe reaction time was 24 h.
Scheme 2. Substrate scope of alkynylcyclopropyl allyl ethers 1.a,b
To clarify the reaction mechanism, several mechanistic
investigations have been carried out as shown in Scheme 3. We
firstly added 3Å molecular sieves into the reaction system to
remove the ambient water from the reaction mixture and found
that the reaction proceeding became sluggish, affording 2a in 32%
yield and 34% of 1a was recovered (Scheme 3a). To figure out
the exact role of water in this reaction, further analysis of this
reaction with different amount of water was conducted, and the
results illustrated that the H2O participated in the catalytic process
and accelerated the reaction proceeding, although variation on the
concentration of extra water exhibited little correlation with the
reaction velocity, which is nearly constant at the initial stage
(Figure 2).
Scheme 3. Mechanistic control experiments
We also embarked on a DFT study to gain insight into the
reaction mechanism. All calculations have been performed at
CPCM/M06/6-311+G(d,p)/SDD//B3LYP/6-31G(d)/SDD
level
with Gaussian 09 program.[15] The solvation Gibbs free energy
profile in 1,2-DCE for the suggested reaction pathway is shown in
Figure 3 (the ∆G298 (kcal/mol), see Supporting Information for the
details). We investigated the reaction pathway starting from gold
complex A shown in Figure 3. First, the cyclopropane moiety of
the gold complex A undergoes a ring expansion process to give
intermediate B via transition state TS1 with an energy barrier of
20.8 kcal/mol. Then, the intermediate B could be resonanced to a
gold carbenoid intermediate C. In addition, intermediate C will
produce intermediate D through transition state TS2 peaked at
22.8 kcal/mol, followed by the participation of ambient H2O to
afford intermediate E. Then, the intermediate E passes through
transition state TS3 with an energy barrier of 22.1 kcal/mol to
furnish a key intermediate F. The intermediate F is hard to be
located without extra water, and a possibly ion-dipole interaction
between carbenium ion and H2O (Distance between carbon and
oxygen atom is 1.61Å) is shown in the 3D-geometric model of
intermediate F. At last, the intermediate F undergoes the
elimination of gold catalyst to give the final product, H2O and
AuL+ through transition state TS4 with 17.7 kcal/mol energy
barrier. Moreover, the total ∆G298 in 1, 2-DCE of this reaction is -
30.8 kcal/mol overall, indicating that this reaction is
Figure 2. Analysis of the reaction rate with different amount
of H2O
3
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10.1002/adsc.201900053
Advanced Synthesis & Catalysis
thermodynamically favorable and has a significant driving force
to be transformed from the starting materials to the product.
Figure 3. DFT calculation on reaction pathway (a relative Gibbs energy values in 1,2-dichloroethane solution are given in kcal/mol and
selected bond distances in Å).
As the last part of this scenario, further derivatizations of the
obtained vinylcyclobutanone were performed. Ketone 2a can be
transformed into polycyclic compound 5a through a three-step
synthetic sequence. As shown in Scheme 5a, addition of ethynyl
Grignard reagent to 2a, followed by esterification with Ac2O,
afforded the corresponding alkynylcyclobutyl acetate 4a in 65%
On the basis of these mechanistic studies and our previous
work, a plausible mechanism is outlined in Scheme 4. As for
substrate 1a, the coordination with the employed gold catalyst
gives intermediate A, followed by a ring expansion to furnish
intermediate B. Then, the intermediate B can be transformed to its
resonance form as the carbenoid intermediate C, which triggers a
[3,3]-sigmatropic rearrangement to deliver the corresponding
intermediate D. Subsequently, extra amount of water participates
in the catalytic cycle, affording the hydrated intermediate E,
which is supported by DFT calculation as shown in Figure 3. A
[1,2]-allyl shift process[16] takes place to give intermediate F, in
which the carbenium ion must be stabilized by H2O. Finally, the
regeneration of gold catalyst produces the desired product 2a
along with the release of water. During this catalytic cycle, the
existence of a resting state B’ (shown as an 18O species), which
has been proven by the mechanistic experiments, also contributes
to the formation of side product 3a through a deallyl alcohol step
and a protodeauration process.
yield under mild conditions. Next,
a gold-catalyzed 1,2-
rearrangement gave gold carbenoid intermediate, which
a
underwent a carbene insertion process to afford 5a bearing a
polycyclic skeleton in 78% yield within 10 minutes (see
Supporting Information for the condition screening).[17] The
substrate scope has been examined and the results are shown in
Scheme 5. All of the reactions proceeded smoothly, affording the
desired products 5b-5g in moderate to good yields. These
synthesized polycyclic products have the similar framework as
those of natural products shown in Figure 1. The structure of 5a
has been further confirmed by X-ray diffraction (Scheme 5a).
More details about the corresponding ORTEP drawing and the
CIF data are summarized in the Supporting Information. In
addition, treating 2a with vinylmagnesium bromide afforded 6a in
76% yield, which could be further transformed to synthetically
important benzocyclobutene 7a in 31% yield through a subsequent
RCM reaction procedure along with a dehydration pathway
(Scheme 5b). Meanwhile, 2a could be easily converted to 8a in
51% yield through a Pd/C-catalyzed hydrogenation at room
temperature (Scheme 5b).
Scheme 4. A plausible reaction mechanism
.
4
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10.1002/adsc.201900053
Advanced Synthesis & Catalysis
reduced pressure and the residue was purified by silica gel flash
column chromatography with petroleum ether-EtOAc (100:1) as
an eluent to afford the desired product (E)-2-(1-phenylbut-3-en-1-
ylidene)cyclobutan-1-one (2a).
Supporting Information Available
Detailed descriptions of experimental procedures and their
spectroscopic data as well as the crystal structures are presented in
the Supporting Information. CCDC 1843477 (2j) and CCDC
1851584 (5a) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Center
via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We are grateful for financial support from the National Basic
Research Program of China [(973)-2015CB856603], the
Strategic Priority Research Program of the Chinese Academy of
Sciences (Grant No. XDB20000000) and sioczz201808, and the
National Natural Science Foundation of China (Nos. 20472096,
21372241, 21572052, 20672127, 21421091, 21372250, 21121062,
21302203, 20732008, 21772037, 21772226 and 21861132014).
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Scheme 5. Further transformations of the synthesized
tetrasubstituted methylenecyclobutanones
Conclusion
In summary, we have disclosed the first example of gold(I)-
catalyzed ring expansion of alkynylcyclopropyl allyl ethers to
construct tetrasubstituted methylenecyclobutanones in moderate
to good yields under mild conditions. This reaction proceeded
through
a gold(I)-catalyzed intramolecular [3,3]-sigmatropic
rearrangement followed by [1,2]-allyl shift process in the
presence of catalytic amount of water. The intriguing reaction
mechanism has been verified on the basis of a series of
mechanistic studies and DFT calculation, demonstrating the
intriguing character of catalytic amount of water in this gold-
catalyzed transformation. These methylenecyclobutanones could
be transformed to natural-product-like polycyclic skeletons
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through
a practical three-step synthetic protocol. Further
investigations on expanding the scope and applications of this
method are undergoing in our laboratory.
Experimental Section
General procedure for the synthesis of tetrasubstituted
methylenecyclobutanones
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argon atmosphere, and then ((1-
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5
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10.1002/adsc.201900053
Advanced Synthesis & Catalysis
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10.1002/adsc.201900053
Advanced Synthesis & Catalysis
Full paper
Gold(I)-Catalyzed
Ring
Expansion
of
Alkynylcyclopropyl Allyl Ethers to Construct
Tetrasubstituted Methylenecyclobutanones:
A
Mechanistic Investigation about the Character of
Catalytic Amount of Water
Adv. Synth. Catal. Year, Volume, Page – Page
Wenqing Zang, Lei Wang, Yin Wei,* Min Shi,*
Yinlong Guo*
7
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