Gold-Catalyzed Oxidative Cyclization/Aldol Addition of Homopropargyl Alcohols with Isatins

Article abstract of DOI:10.1021/acs.orglett.8b03502

A novel gold-catalyzed oxidative cyclization/aldol addition of homopropargyl alcohols with isatins has been developed that provides an effective access to the 3-hydroxyoxindoles in high yields under mild reaction conditions with high diastereoselectivities. In comparison with disclosed transformations of alkyne oxidations via an α-oxo gold carbene route, this is the first example of an aldol-type interception of an ylide (or its enolate form) intermediate with alkyne as a safe and readily available nondiazo carbene precursor.

Full text of DOI:10.1021/acs.orglett.8b03502

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed Oxidative Cyclization/Aldol Addition of
Homopropargyl Alcohols with Isatins
Ju Cai,†,‡,§ Xin Wang,†,§ Yu Qian,† 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 oxidative cyclization/aldol addition of
homopropargyl alcohols with isatins has been developed that provides an
effective access to the 3-hydroxyoxindoles in high yields under mild reaction
conditions with high diastereoselectivities. In comparison with disclosed
transformations of alkyne oxidations via an α-oxo gold carbene route, this is the
first example of an aldol-type interception of an ylide (or its enolate form)
intermediate with alkyne as a safe and readily available nondiazo carbene
precursor.
n recent decades, the α-oxo gold carbene species, which is
carbene forms the gold enolates after addition with the
Igenerated from gold-catalyzed alkyne oxidantion, has shown corresponding nucleophiles, followed by protodeauration.
broad applications in synthetic organic chemistry for the C−C
and C−X bond formations.1 For example, these reactive gold
carbene intermediates could react with a variety of nucleophilic
reagents to form the X−H (X = C, N, and O) insertion
products2−5 and others (Scheme 1a).6 In 2010, Zhang’s group
reported the first access to α-oxo gold carbene via
intermolecular oxidation to the terminal alkyne and then an
O−H insertion (Scheme 1b).5 In these studies, the gold
Inspired by these advances and as a continuation of our
interest in multicomponent reactions (MCRs) via the
electrophilic trapping the in situ generated ylide intermedi-
ates,7 for example, Aldol-type interception of in situ generated
oxonium ylide intermediates with carbonyl compounds
(Scheme 1c).8 We envisioned that electrophilic interception
of this ylide or its enolate form might be enabled in the
presence of reactive electrophilic reagents, such as isatin,
instead of direct proton shift.9 Herein, we report a successful
implementation of interception the in situ generated oxonium
ylide intermediate via aldol-type addition with carbonyl
reagents. Notably, this is the first example that the catalytic
alkyne oxidation via an α-oxo gold carbene route was
introduced as a safe and readily available nondiazo carbene
approach in an aldol-type trapping process (Scheme 1d).10 In
addition, these 3-hydroxyoxindoles are privileged heterocyclic
motifs that existed in a variety of natural products11 and
biological active molecules.12 Thus, the development of
efficient approaches to the direct construction of polyfunc-
tional oxindole skeletons with readily available materials under
mild conditions is of continuing interest in organic synthesis.13
To validate our hypothesis, the readily accessible homo-
propargylic alcohol 1a and isatin 2a were used as the model
substrates (Table 1). To our delight, the expected trapping
product 3a was obtained in 58% yield (entry 1) in the presence
of gold catalyst with O1 as the oxidant (1.2 equiv) and TFA as
additive (2.0 equiv). MsOH was less effective as an acidic
additive, and the yield dropped to 46% (entry 2). The
investigation of the pyridine-derived oxidants revealed that the
less steric hindered oxidant O1 was best (entries 3−5). Further
Scheme 1. Catalytic Interception of Metal Carbene
Intermediates
Received: November 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Condition Optimization
Scheme 2. Substrate Scope
b
entry
1
2
3
4
5
6
7
8
9
cat (mol %)
oxidant
yields (%)
JohnphosAu(MeCN)SbF6 (5.0)
JohnphosAu(MeCN)SbF6 (5.0)
JohnphosAu(MeCN)SbF6 (5.0)
JohnphosAu(MeCN)SbF6 (5.0)
JohnphosAu(MeCN)SbF6 (5.0)
PPh3AuNTf2 (5.0)
JohnphosAuCl (5.0)/AgNTf2 (5.0)
PPh3AuCl (5.0)/AgSbF6 (5.0)
BrettPhosAuNTf2 (5.0)
O1
O1
O2
O3
O4
O1
O1
O1
O1
58
46
<5
c
d
d
<5
32
65
48
d
<5
75
a
Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), and oxidant
(1.2 equiv) in 4.0 mL of DCE with corresponding catalyst at room
b
temperature under argon atmosphere for 6 h. Isolated yields of 3a.
c
d
MsOH (2.0 equiv) was used asthe additive instead of TFA. The
material 1a was decomposed to a complex mixture.
optimization of the conditions by screening the gold catalysts
−
−
indicates that switching the counterion from NTf2 to SbF6
resulted in lower yields (entries 6−8), and the best results were
obtained when the reaction was catalyzed by BrettPhosAuNTf2
(entry 9, 75% yield). No reaction took place with other tested
metal catalysts, including rhodium, palladium, and copper
complex (see Table S1). Notably, only one diastereoisomer
was observed in this reaction, and the structure as well as the
stereochemistry of 3a was confirmed by X-ray diffraction
analysis.
Under the optimal reaction conditions, we examined the
reaction generality with various homopropargylic alcohols 1
and electrophiles 2. As shown in Scheme 2, the reaction
showed broad functional group compatibility with high
diastereoselectivity (>95:5 dr). The electronic property and
position of substituent groups on the aryl ring of isatins had
little influence on the reactivity, yielding the products 3a−n in
64%−86% yields. It was also possible to employ a variety of N-
substituted isatins in this transformation, including Ac, p-
methoxybenzyl (PMB), propargyl, and allyl groups, which were
all tolerated to this transformation, delivering the addition
products in high yields (3o−r). Moreover, the scope of these
carbonyl compounds was expanded to 1,2-indanedione and
phenanthrene-9,10-dione and gave the corresponding products
3s and 3t in 62% and 73% yields, respectively. Then the
reaction was further applied to a series of substituted
homopropargylic alcohol derivates; these afforded the desired
products 3u−3B in high yields. However, (2-ethynylphenyl)-
methanol and pent-4-yn-1-ol did not give the desired product
under the current conditions. The structure as well as the
stereochemistry of 3v was confirmed by X-ray diffraction
analysis. It is worth noting that high yield was maintained even
when the reaction was carried out on a gram scale (3a, 65%
yield, Scheme 2, footnote b).
a
Reaction conditions: 1 (0.24 mmol), 2 (0.2 mmol), oxidant O1 (45
mg, 0.24 mmol), TFA (29.7 μL, 0.4 mmol), and BrettPhosAuNTf2
(11.0 mg, 5.0 mol %) in DCE (4.0 mL) at room temperature under
b
argon atmosphere for 6 h. The reaction was carried out on a 5.0
mmol scale with 2.5 mol % of gold catalyst.
The synthetic transformations of product 3a were illustrated
in Scheme 3. The reduction product 4 was obtained in 89%
yield by using NaBH4 as the reducing agent in methanol. The
stereochemistry of this product was determined by NOE
analysis (see the SI for details). The treatment of 3a with
oxidant m-CPBA gave the lactone product 5 in 92% yield with
high diastereoselectivity (>95:5). These postsynthetic mod-
ifications of these generated 3-hydroxyindolin-2-one products
enhanced the potential value of this process.
To gain insight into the reaction mechanism, a control
experiment of substrate 1a in the absence of isatin 2a was
carried out under the standard conditions. The oxidation/O−
H insertion product 6 was obtained in 42% NMR yield
B
DOI: 10.1021/acs.orglett.8b03502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Derivatization of 3a
Scheme 5. Proposed Reaction Mechanism
combined with other unidentified byproduct(s) (Scheme 4a;
see Figure S1 for details), which is consistent with reported
Scheme 4. Control Experiments
(or its enolate form C′) with the carbonyl group of isatin 2 in
the aldol-type addition step (D).10
In summary, we have developed an unprecedented gold-
catalyzed oxidative cyclization/Aldol addition of homopro-
pargyl alcohols and isatins that provides an efficient approach
to the direct construction oxindole derivatives with two vicinal
stereocenters in high yields with high diastereoselectivities.
The salient features of this reaction include readily available
materials, mild reaction conditions, and good functional group
tolerance. In addition, this is the first example of aldol-type
interception of an ylide (or its enolate form) intermediate with
homopropargyl alcohol as carbene precursor. Further novel
applications in this content with alkyne as a safe and readily
available nondiazo carbene precursor can be expected in the
near future.
results.5 To rule out the possibility that product 3a resulted
from a stepwise reaction of an intramolecular O−H insertion
and then an aldol-type addition, an additional control
experiment of premade O−H insertion product 6 with isatin
2a was conducted under standard conditions with/without
additional 5-bromo-2-methylpyridine (1.2 equiv) as an
additive. No 3a was observed, and most of the reactants
remained intact (Scheme 4b; see Figure S2 for details). These
results suggested a concerted reaction pathway, which is in
agreement with previous studies in ylide intermediate trapping
processes with electrophilic carbonyl compounds.8 In addition,
the enantioenriched 1e (66% ee) was subjected to the reaction
conditions, furnishing 3x in 63% yield with full chirality
transfer (66% ee).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03502.
Experimental procedure and spectroscopic data for all
compounds and crystallographic data for 3a and 3v
(PDF)
Accession Codes
CCDC 1868090 and 1876615 contain 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 CB2 1EZ, UK; fax: +44 1223 336033.
On the basis of the above results and reported literature,7−10
a rationalized mechanism is proposed in Scheme 5. The
reaction is initiated via the formation of a π-complex A with
the gold catalyst and homopropargyl alcohol 1a. Then α-oxo
gold carbene intermediate B is generated in the presence of
pyridine N-oxides, followed by a 5-endo-dig cyclization to
deliver the gold oxonium ylide C (or its enolate form C′).
Finally, interception of this reactive intermediate with
electrophilic carbonyl reagent through possible hydrogen
bonding gives the aldol addition product 3 and regenerates
the gold catalyst. The observed exceptionally high stereo-
selectivity of this reaction may attributed to the existing of
potential hydrogen bonding between the ylide intermediate C
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
C
DOI: 10.1021/acs.orglett.8b03502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Dong, K.-Y.; Qiu, L.-H.; Wu, B.; Hu, W.-H.; Xu, X.-F. Angew. Chem.,
Int. Ed. 2018, 57, 17200.
(11) (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748. (b) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.;
Author Contributions
§J.C. and X.W. contributed equally to this work.
Notes
Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat.
̈
The authors declare no competing financial interest.
Chem. 2010, 2, 735. (c) Albrecht, B. K.; Williams, R. M. Org. Lett.
2003, 5, 197. (d) Bergonzini, G.; Melchiorre, P. Angew. Chem., Int. Ed.
2012, 51, 971.
ACKNOWLEDGMENTS
■
Support for this research from the National Natural Science
Foundation of China (21602148 and 21332003) and the
Program for Guangdong Introducing Innovative and En-
trepreneurial Teams (No. 2016ZT06Y337) are greatly
acknowledged.
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DOI: 10.1021/acs.orglett.8b03502
Org. Lett. XXXX, XXX, XXX−XXX