Gold(I)-Catalyzed and H2O-Mediated Carbene Cascade Reaction of Propargyl Diazoacetates: Furan Synthesis and Mechanistic Insights

Article abstract of DOI:10.1021/acs.orglett.8b02251

A novel gold-catalyzed water-mediated carbene cascade reaction of propargyl diazoacetates has been developed. Mechanistic investigation indicates that this reaction is initiated by gold-catalyzed gold-carbene formation followed by an unprecedented 6-endo-

Full text of DOI:10.1021/acs.orglett.8b02251

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold(I)-Catalyzed and H2O‑Mediated Carbene Cascade Reaction of
Propargyl Diazoacetates: Furan Synthesis and Mechanistic Insights
Ming Bao,†,‡ Yu Qian,† Han Su,‡ Bing Wu,‡ Lihua Qiu,‡ Wenhao Hu,*,† and Xinfang Xu*,†,‡
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
‡Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: A novel gold-catalyzed water-mediated carbene cascade
reaction of propargyl diazoacetates has been developed. Mechanistic
investigation indicates that this reaction is initiated by gold-catalyzed
gold−carbene formation followed by an unprecedented 6-endo-dig
carbocyclization with tethered alkyne through an oxonium ylide
intermediate, terminated by a β-H elimination/protodeauration process
to give the aromatized furan products in good to high yields with broad
substrate generality. Notably, the proposed gold−carbene intermediates
are verified by interception experiments.
Scheme 1. Catalytic Reaction of Diazo with Alkyne
ransition-metal-catalyzed carbene reactions of diazo
Tcompounds represent a powerful tool in modern organic
synthesis, allowing for the rapid assembly of valuable complex
molecules which cannot be readily synthesized by other
methods.1 A variety of metal catalysts have been reported to
mediate these transformations effectively, including rhodium,2
copper,3 palladium,4 gold,5 silver,6 and others.7 In particular,
different metal−carbenes often exhibit distinct reactivity and
selectivity, and the selection of metal catalysts is vital to the
chemoselectivity in the carbene reactions.8 For example,
divergent outcomes have been disclosed in the catalytic reaction
of diazoesters with propargylic alcohols,9,10 although these
transformations go through a common intermediate oxonium
ylide A (Scheme 1a). Davies has reported that α-hydroxy allene
was formed with excellent enantioselectivity through [2,3]-
sigmatropic rearrangement (Scheme 1a, path a).9 A stepwise
formal [4 + 1] cycloaddition was then observed through a gold-
catalyzed 5-endo-dig cyclization of in situ generated α-hydroxy
allene (path b).10a Meanwhile, Hu developed a Pd-catalyzed
direct [4 + 1] cycloaddition of diazoesters with propargylic
alcohols to produce 2,5-dihydrofurans via corresponding
oxonium ylide A (path c).10b Recently, Toste has disclosed a
gold-catalyzed oxidative rearrangement of alkyne-tethered
diazoketones via a gold-catalyzed 5-exo-dig carbocyclization.11
Instead of using a diazo compound, Hashmi12a and Tang12b
reported a catalytic oxidative 5-exo-dig cyclization of diynes in
the presence of gold and rhodium catalysts, respectively. On the
other hand, Zhang reported a gold-promoted 5-endo-dig
carbocyclization of alkyne-tethered diazoacetates through a
zwitterionic intermediate (Scheme 1b).13 Inspired by these
advances, and in continuation of our interest in carbene/alkyne
metathesis (CAM) transformations,14−16 we envisioned that the
CAM process might be facilitated by the gold catalyst due to its
soft Lewis acidity, which can activate the alkyne and bring this
part close to the gold−carbene center for the metathesis process
to occur preferentially. Herein, we report our recent results on
this direction, a novel gold-catalyzed carbene cascade reaction of
propargyl diazoacetates, which provides general access for the
synthesis of multisubstituted furans in good to high yields with
broad substrate generality under mild reaction conditions. In
addition, the key step in this cascade transformation involving an
unprecedented gold-catalyzed 6-endo-dig diazo-yne cyclization
Received: July 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02251
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Organic Letters
Letter
a,b
(Scheme 1c) and the proposed gold−carbene intermediates are
verified by interception experiments.
Scheme 2. Substrate Scope
Initially, the propargyl diazoacetate 1a, which was readily
prepared with phenylacetic acid and propiolic alcohol via
esterification followed by a diazo-transfer reaction,17 was used as
the model substrate (Table 1). To our delight, the furan product
a
Table 1. Condition Optimization
b
entry
cat.
H2O (equiv)
yield (%) of 2a/3a/4a/5a
c
1
PPh3AuCl
0
2
PPh3AuNTf2
AuCl3
JohnphosAuSbF6
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
0
0
0
0
5.0
5.0
57/12/<5/−
d
3
d
4
e
−/<5/<5/−
−/<5/<5/−
83/8/<5/<5
81/6/8/<5
5
6
7
f
a
Unless indicated otherwise, the reaction of 1a (55.2 mg, 0.2 mmol)
was carried out at 30 °C in the presence of catalyst (2.0 mol %) in
DCE (2.0 mL) with indicated equivalents of water for 8 h under
b
c
argon atmosphere. Isolated yields. No reaction occurred, and most
d
of the material 1a was recovered. All of the starting material was
decomposed into a complex mixture. 100 mg of 4 Å MS was added,
and the cross-coupling product of 1a was obtained. The reaction was
e
f
carried out under open air.
2a was obtained in moderate yield combined with 3a in 12%
yield when the reaction was catalyzed by PPh3AuNTf2 (entry 2).
It should be noted that only the cross-coupling product of diazo
compound was generated when 4 Å MS was used as additive
(entry 5), which indicates that water might be involved in the
formation of furan product 2a. NMR Analysis was conducted of
the cationic gold catalyst in the presence of water, and no
detectable variation was observed (see Figure S9 for details).
After further optimizing the conditions by conducting the
reaction in the presence of H2O (5 equiv), the yield was
improved significantly (83% yield, entry 6).18 The other
transition-metal catalysts, which have been reported to activate
the diazo compound, were screened under these conditions,
such as silver, rhodium, copper, and palladium salts (see Table
S1).17 Unfortunately, products 3−5 were isolated as the major
products.17 Notably, comparably high yield was obtained when
the reaction was carried out under open air (entry 7). The
structure of 2a was inferred from X-ray diffraction analysis of its
bromo analogue 2d, and the generated 2-benzoylfuran motif is a
core structure in many bioactive molecules,20 such as the anti-
inflammatory drug furprofen.20a
With the optimal reaction conditions established, the
substrate scope with respect to the diazo compounds was
investigated (Scheme 2). On the pendant alkyne, both electron-
neutral and electron-rich aryl groups were all tolerated and gave
the corresponding products in 67−87% yields (2a−j).
Pleasingly, the sterically encumbered substrates had little impact
on the efficiency of this transformation, and comparably high
yields were obtained with both ortho- and meta-substituted diazo
compounds (2i,j). In the case of alkyne with o-azido and o-
alkenyl groups, the corresponding furan products 2k and 2l were
also generated in 85% and 65% yields, respectively. The 1-
a
Reactions were carried out on a 0.2 mmol scale with PPh3AuNTf2
(3.0 mg, 2.0 mol %) in DCE (2.0 mL) at 30 °C under open air for 8
h. The reaction was carried out on a 5.0 mmol scale.
b
thienyl and 1-naphthyl group substituted diazo compounds also
underwent the reaction smoothly, leading to the furan products
in high yields (2m and 2n). The effect of the aryl group adjacent
to the diazo group was then evaluated; both electron-donating
and electron-withdrawing group substituted aryl diazo com-
pounds smoothly transformed to the corresponding products
with fairly good yields (2o−v). Notably, the alkyl and terminal
alkynes were well tolerated, and the desired products were
isolated in high yields (2w−y). When the methylene part was
exchanged with a cyclic species, the corresponding fused-cyclic
products 2z and 2A were obtained in 83% and 42% yields.
Moreover, with methyl- or phenyl-substituted methine as the
linkage, substrates 1B and 1C performed well under these
conditions to offer the H-migration products 2B and 2C20e in
81% and 78% yields, respectively. In addition, this reaction could
be performed on a gram scale with slightly lower yields (2t, 78%
yield, Scheme 2, note b).
To gain insight into the reaction mechanism, a series of
control experiments were carried out. First, compounds 4a and
5a were isolated, and each was subjected to the standard reaction
conditions. However, the furan product 2a was not detected,
which excluded the process of formation 2a through 4a or 5a.9,17
B
DOI: 10.1021/acs.orglett.8b02251
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Letter
No reaction occurred with corresponding substrate without the
diazo group under the standard conditions,17 which indicates
that the reaction might initiate with the diazo group. Moreover,
corresponding carbonylation and cyclopropanation products 4a
and 7 were isolated in high yields when the reactions were
carried out under standard conditions in the presence of
diphenyl sulfoxide and styrene, respectively (eq 1), which
elimination/protodeauration process to give the aromatized
furan product 2a.22 An alternative reaction order, β-H
elimination/protodeauration to form F followed by ring
expansion and release of a molecule of H2O, may also contribute
to the formation of final furan product 2. Direct 1,2-shift of E
may also possible led to the formation of 2, especially in the cases
for the formation of 2z and 2A (path c). The carbonylation
byproduct 4a and O−H insertion byproduct 5a are generated
from intermediates A and B, respectively. The formation of 3a
might go through a 1,2-acyl migration to form gold carbene H
via G23 followed by a coupling reaction with the diazo part to
form the 5-membered framework (path d).24
To verify the existence of the second gold carbenoid
intermediate (either D or E in Scheme 3), interception
experiments of materials with tethered carbene-philic species
were carried out. Although only furan product 2E was observed
in high yield with material 1E (eq 3), the Friedel−Crafts-type
indicate that the reaction was initiated via the formation of gold
carbene A (Scheme 3). Then isotope-labeled experiments were
Scheme 3. Proposed Reaction Mechanism
reaction product 9, which might be generated via trapping of the
corresponding gold carbenoid species E or another potential
electrophilic intermediate (Scheme 3), was isolated and
characterized from substrate 1F under the standard conditions
(eq 4).
To demonstrate the synthetic utility of the current method,
further transformations with these furan products were
conducted (Scheme 4). [4 + 2]-Cycloaddition of 2a with
Scheme 4. Derivatization of 2
carried out under the standard conditions. The deuterated
product 2a was observed (eq 2, 42% D, see Figure S3 for
details),17 which suggests that a hydrogen elimination/
protodeauration should be involved in this cascade process. In
addition, the corresponding 2a-O18 product was formed when
the reaction was performed in the presence of 5.0 equiv of
H2O18 (eq 2, 75% O,18 see Figure S6 for details).17 These results
indicate that water must be involved in this cascade reaction, and
the oxygen atom on the carbonyl group of the furan product
comes from water. On the basis of the above results and previous
reports,11,21 a possible mechanism is described in Scheme 3.
Initially, gold-catalyzed dinitrogen expulsion of diazoacetate 1
forms the gold carbene A, followed by 6-endo-dig carbocycliza-
tion with tethered alkyne through an oxonium ylide B, or via the
corresponding enol form species B′, to give intermediate C. Ring
contraction with simultaneous H-shift of C delivers the second
carbene intermediate D, which converts to another carbene
intermediate E through a pinacol rearrangement with the
assistance of intramolecular H-bond activation and releasing a
molecular of H2O. Finally, the reaction is terminated by a β-H
diethyl acetylenedicarboxylate occurred smoothly to form 10 in
75% yield. The furan product could be converted to 2-bromo
derivative 11 in 88% yield when treated with bromine, which
could be used for further modifications via coupling reactions.17
Notably, the quinoline product 12 was obtained in 83% yield via
an intramolecular catalytic reductive cyclization. In addition, the
8-membered heterocyclic product 13 could be generated in 51%
yield from 2k catalyzed by Rh2(pfb)4. These postsynthetic
modifications of these generated 2-carboxyl furan products
enhanced the potential value of this process.
In summary, we have developed a novel gold(I)-catalyzed
carbene cascade reaction of propargyl diazoacetates that
C
DOI: 10.1021/acs.orglett.8b02251
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02251.
■
S
Experimental procedure and spectroscopic data for all
compounds and crystallographic data for 2d (PDF)
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CCDC 1827998 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
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AUTHOR INFORMATION
Corresponding Authors
■
́
́
*E-mail: huwh9@mail.sysu.edu.cn.
*E-mail: xinfangxu@suda.edu.cn.
ORCID
́
́
̀
Wenhao Hu: 0000-0002-1461-3671
Xinfang Xu: 0000-0002-8706-5151
Notes
The authors declare no competing financial interest.
(17) See the Supporting Information for details.
(18) Li, L.; Shu, C.; Zhou, B.; Yu, Y.; Xiao, X.; Ye, L. Chem. Sci. 2014,
5, 4057.
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ACKNOWLEDGMENTS
■
Support for this research from the National Natural Science
Foundation of China (21602148 and 21332003) and the
Program for Guangdong Introducing Innovative and Entrepre-
neurial Teams (No. 2016ZT06Y337) is greatly acknowledged.
We thank Prof. L. Zhang from UCSB for the suggestions
regarding the mechanism.
H.; Muller, K. J. Med. Chem. 2012, 55, 7273. (c) Jana, R.; Paul, S.;
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