Oxoarylation of ynamides with N-aryl hydroxamic acids

Article abstract of DOI:10.1016/j.cclet.2021.02.054

Ynamides are electron-rich alkynes with unique reactivities and act as flexible building blocks in organic synthesis. Therefore, the investigation for transformation of ynamides with exceptional selectivity and efficiency is attractive and interesting. He

Full text of DOI:10.1016/j.cclet.2021.02.054

G Model
CCLET-6183; No. of Pages 5
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Oxoarylation of ynamides with N-aryl hydroxamic acids
b
Changwei Chenb, Hongyu Zhanga, Gang Xua, , Sunliang Cui
*
a
College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Ynamides are electron-rich alkynes with unique reactivities and act as flexible building blocks in organic
synthesis. Therefore, the investigation for transformation of ynamides with exceptional selectivity and
efficiency is attractive and interesting. Herein, we report an oxoarylation of ynamides with N-aryl
hydroxamic acids. In the presence of catalytic Cu(OTf)2, both the terminal and internal ynamides could
undergo an addition/[3,3] sigmatropic rearrangement cascade with N-aryl hydroxamic acids to achieve
oxoarylation, along with providing selective entry to (ortho-amino)arylacetamides and oxindoles.
Moreover, deuterium-labelling reaction and gram-scale reaction were conducted to probe the
mechanism and showcase the scalability.
Received 30 November 2020
Received in revised form 19 February 2021
Accepted 22 February 2021
Available online xxx
Keywords:
Ynamide
Hydroxamic acid
Oxoarylation
Oxindole
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Rearrangement
Ynamide is a type of N-substituted electron rich alkynes which
exhibits unique chemical properties and serves as flexible
synthons in organic synthesis [1]. Therefore, the development of
divergent transformations for ynamides has gained considerable
attention [2]. In typical, their oxofunctionalization was widely
investigated since this process could deliver privileged function-
alized amides. For example, Liu and Ye reported that the
oxofunctionalization of ynamides could be achieved upon transi-
tion-metal-catalysis with pyridine-N-oxide [3]. Meanwhile, the
addition reaction of ynamides with carboxylic acids could trigger
oxofunctionalization [4]. This has been successfully applied in
racemization-free ligation of amides, peptides and macrocyclic
esters by Zhao and coworkers [5]. Besides, an oxoallylation of
ynamide with allyl alcohol has been nicely established by Ye, and
this process could produce privileged medium-sized lactams in an
efficient manner [6]. Liu reported a PtCl2-catalyzed oxoarylation of
terminal ynamides with nitrones [7], while the internal ynamides
could not achieve oxoarylation in this process [8]. Therefore, the
investigation of oxoarylation for both terminal and internal
ynamides toward privileged molecules construction remains
challenging and important.
rearrangement of hydroxamic acid, and this process involved an
addition reaction between hydroxamic acid and the in situ
generated electrophilic enolonium-like intermediate [13]. More-
over, they also tested the addition reaction of hydroxamic acid with
oxazolidinone-derived ynamide to give an oxoarylation product in
30% yield upon treatment with triflimide. This indicated that the
oxoarylation of ynamides with hydroxamic acids would be
promising. In continuation of our interests in ynamides [14], we
hypothesized that the utilization of transition-metal-catalyst
might promote their oxoarylation process in an efficient manner.
Herein, we would like to report a Cu(OTf)2-catalyzed oxoarylation
of ynamides with hydroxamic acids for facile and selective entry to
(ortho-aminoaryl) amides and oxindoles.
We commenced our study by investigating N-sulfonyl ynamide
1a and N-benzoyl-N-phenylhydroxylamine 2a. Initially, we con-
ducted the reaction in DCE at 45 ꢀC without any catalyst and there
was no new product detected (Table 1, entry 1). When AuCl(PPh3)/
AgNTf2 was used as catalyst (5 mol%), and gratifyingly, a new
product 3a was observed and isolated in 75% yield (entry 2). The
standard analysis including 1H NMR, 13C NMR and HRMS showed
that 3a was an (ortho-aminoaryl)amide compound. This indicated
an oxoarylation occurrence. Variations of the catalysts to IPrAuCl/
AgNTf2 and XPhosAuCl/AgNTf2 would decrease the yield to 49%
and 52% respectively (entries 3–4). The next survey of catalysts
showed that Cu(OTf)2 could deliver 3a in a comparable 75% yield
(entry 5), while the use of AgOTf and Sc(OTf)3 would lead to lower
yields (entries 6 and 7). To our surprise, the utilization of Zn(OTf)2
would only give trace product (entry 8). When PtCl2 was used, the
hydrolyzation rather than oxoarylation was observed (entry 9). On
the other hand, either increasing the temperature to 60 ꢀC with Cu
N-Aryl hydroxamic acids exist extensively in naturally occur-
ring secondary metabolites and these compounds exhibit weak
acidities [9]. They are known to be used as metal-chelating agents
in biological investigation and directing group in metal-catalyzed
tansformation [10–12]. In typical, Maulide reported a sigmatropic
* Corresponding author.
E-mail address: xugang_1030@zju.edu.cn (G. Xu).
https://doi.org/10.1016/j.cclet.2021.02.054
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: C. Chen, H. Zhang, G. Xu et al., Oxoarylation of ynamides with N-aryl hydroxamic acids, Chin. Chem. Lett., https://doi.
org/10.1016/j.cclet.2021.02.054

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Table 1
Reaction conditions.a
Entry
Catalyst
Solvent
Temp. (oC)
Yield (%)b
1
–
DCE
DCE
45
45
–
2c
AuCl(PPh3)/
AgNTf2
IPrAuCl/AgNTf2
XPhosAuCl/
AgNTf2
75
3c
4c
DCE
DCE
45
45
49
52
5
6
7
8
Cu(OTf)2
AgOTf
Sc(OTf)3
Zn(OTf)2
PtCl2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
Toluene
CH3CN
45
45
45
45
45
60
45
45
45
45
75
61
50
trace
–
9
10
11
12
13
14
65
56
trace
trace
trace
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 4 Å MS (50 mg), catalyst (20 mol%), solvent (2 mL), argon, 2 h.
Yield refers to isolated product.
5 mol% catalyst was used.
b
c
(OTf)2 catalyst or changing the solvent to DCM at 45 ꢀC would
decrease the yield (entries 10 and 11). Moreover, the survey of
solvents showed that THF, toluene and CH3CN would shut down
the reactivity to deliver trace product (entries 12–14).
With the optimized reaction condition in hand, we next tested
the substrate scope (Scheme 1). As shown in Scheme 1, the N-
protecting groups of hydroxamic acids varied from benzoyl to Cbz,
ester and Boc, and these hydroxamic acids could serve as
oxoarylation source for ynamide 1a to give the products in good
yields (3b-3d). Meanwhile, many functional groups substituted on
the aromatic ring of N-aryl hydroxamic acids were tested. For
example, the para-substituted N-aryl hydroxamic acids could well
engage in this cascade process to deliver the corresponding (ortho-
aminoaryl)amides in good yields (3e-3j). The functionalities
including methyl, hydroxymethyl, methoxy, N-Boc amine, ester,
ketone, were well tolerated in this process and also offered ample
opportunities for further derivatization. Moreover, the structure of
3e was confirmed by X-ray analysis (CCDC: 2021769). On the other
hand, the halogen substitutions like fluoro, chloro, bromo, and CF3,
were compatible in this reaction (3k-3n). The heterocyclic
substitutions like furan and thiophene could also perform well
in this process (3o-3p). Meanwhile, the ortho-substituted N-aryl
hydroxamic acids were employed in this oxoarylation to furnish
the products smoothly (3q-3r). When the N-(naphthalen-1-yl)
hydroxamic acid 1s was used, the regioselective (naphthalen-1-
amino-2-yl)amide 3s could be formed exclusively. When the meta-
substituted N-aryl hydroxamic acid 2t was subjected, the process
would deliver a mixture of oxoarylation products 3t and 3u (total
60% yield). The ratio of 3t and 3u was 3:2, probably because the
process would favor the less steric transition state and the
corresponding product 3t was the major isomer.
Meanwhile, the generality of ynamides were also explored. As
shown in Scheme 2, the terminal ynamides with N-substitutions
like isobutyl, furan-2-methyl, (S)-1-phenylethyl, could well engage
in this process (4a-4c). And the functionalities like hydroxy, prenyl,
cyclohexenyl, were tolerated (4d-4f) and also offer considerable
potential for late-stage transformation. On the other hand, the
sulfonyl substitutions were investigated while thiophene, phenyl
Scheme 1. Substrate scope of hydroxamic acid. Reaction conditions: 1a (0.2 mmol),
2 (0.3 mmol), 4 Å MS (50 mg), Cu(OTf)2 (20 mol%), DCE (2 mL), 45 ꢀC, argon, 2 h.
Yields refer to isolated products.
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Scheme 3. Scope of oxoarylation/lactamization. Reaction conditions: 1 (0.2 mmol),
2 (0.3 mmol), 4 Å MS (50 mg), Cu(OTf)2 (20 mol%), DCE (2 mL), 45 ꢀC, argon, 2 h, then
K2CO3 (0.4 mmol), 45 ꢀC, 2 h. Yields refer to isolated products.
Moreover, this process could also produce the 7-substituted and
naphthalene-containing oxindoles in moderate yields (5q-5s),
which were difficult to be synthesized in conventional methods.
Meanwhile, when the internal ynamides were used, this process
could deliver the corresponding oxindole products (5t-5y) rapidly.
Considering the wealth of oxindoles in medicinal chemistry
[15,16], this method provides a direct approach to these molecules
in an efficient way.
In order to probe the mechanism, a deuterium-labelling
reaction was conducted (Scheme 4). The [D]-1a was prepared
and subject to reaction with 2a, and [D]-3a was obtained in 73%
yield and deuterium is incorporated in the α-position of amide.
Additionally, the [D]-2a was prepared and subject to an
Scheme 2. Substrate scope of ynamides. Reaction conditions: 1 (0.2 mmol), 2a
(0.3 mmol), 4 Å MS (50 mg), Cu(OTf)2 (20 mol%), DCE (2 mL), 45 ꢀC, argon, 2 h. Yields
refer to isolated products.
and 4-nitrophenyl were found compatible (4g-4i). Furthermore,
the internal ynamides were next subject to this oxoarylation
process. As shown in Scheme 2, the substitutions like butyl,
cyclopropyl, phenylethyl, allyl, hydroxy, ester, were well applicable
to yield the functionalized products smoothly (4j-4o). The aryl
substituted ynamides diverged from the reactivity pattern and
were observed with hydrolyzation products. Therefore, this
process represents a general oxoarylation for both terminal and
internal ynamides, and provides a distinct approach to (ortho-
aminoaryl) amides.
Considering that the moiety of N-tosyl of amides 3 and 4 could
act as leaving group in intramolecular cyclization, we envisioned
that treatment of 3 and 4 with base might enable a lactamization.
Upon completion of the Cu(OTf)2-catalyzed oxoarylation of
ynamide 1a and hydroxamic acid 2a, we treated the reaction
solution with K2CO3 at 45 ꢀC. To our delight, we indeed found the
consumption of (ortho-aminoaryl) amides and a new product 5a
was isolated in 72% yield. The standard analysis showed that 5a
was an oxindole compound. We next investigated the scope of this
oxoarylation/lactamization process in a one-pot manner. As shown
in Scheme 3, a variety of ynamides and hydroxamic acids were
subject to this reaction. Besides benzoyl groups, differential
protecting groups of hydroxamic acids including Cbz, ester and
Boc, were all amenable to this process to deliver the N-protected
oxindoles in good yields (5b-5d). The structure of 5c was
confirmed by X-ray analysis (CCDC: 2021773). The para-substitu-
tions of hydroxamic acids with methyl, hydroxymethyl, methoxy,
amino, ester, ketone, fluoro, chloro, bromo, trifluoromethyl, furan,
thiophene, were well tolerated in this one-pot process (5e-5p).
Scheme 4. Isotope labelling experiments.
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deliver intermdiate B. The following rapid [3,3] sigmatropic
rearrangement would deliver (ortho-aminoaryl) amide (3 and 4)
to constitute the oxoarylation of ynamides. Upon treatment with
K2CO3, the (ortho-aminoaryl) amide (3 or 4) would undergo a
lactamization to deliver the cyclized oxindoles 5. Therefore, the
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acids has been successfully developed. Both the terminal and
internal ynamides could undergo addition/[3,3] sigmatropic
rearrangement with hydroxamic acids to constitute an oxoaryla-
tion process. This method would produce (ortho-aminoaryl)
amides and oxindoles with mild reaction condition, broad
substrate scope and high efficiency.
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Declaration of competing interest
(b) C. Rouanet-Mehouas, B. Czarny, F. Beau, et al., J. Med. Chem. 60 (2017) 403–
414.
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The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
(b) J. Wen, A. Wu, P. Chen, et al., Tetrahedron Lett. 56 (2015) 5282–5286.
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Acknowledgments
We are grateful for the financial support by the National Natural
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Appendix A. Supplementary data
10938–10941.
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4568;
Supplementarymaterialrelatedto thisarticlecanbefound, inthe
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