Copper-Catalyzed Trifunctionalization of Alkynes: Rapid Formation of Oxindoles Bearing Geminal Diboronates

Article abstract of DOI:10.1002/chem.201804480

A copper-catalyzed trifunctionalization of alkynes that provides rapid access to oxindoles bearing a geminal diboronate side chain, highlighted by the simultaneous formation of one C?C bond and two C?B bonds, is reported. This new reaction features simple

Full text of DOI:10.1002/chem.201804480

A Journal of
Accepted Article
Title: Copper-Catalyzed Trifunctionalization of Alkynes: Rapid
Assembly of Oxindoles Bearing Geminal Diboron
Authors: Tao He, Bin Li, Li-Chuan Liu, Jing Wang, Wenpeng Ma,
Guang-Yu Li, Qing-Wei Zhang, and Wei He
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To be cited as: Chem. Eur. J. 10.1002/chem.201804480
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Copper-Catalyzed Trifunctionalization of Alkynes: Rapid
Assembly of Oxindoles Bearing Geminal Diboron
Tao He[a], Bin Li[a], Li-Chuan Liu[a], Jing Wang[a], Wen-Peng Ma[a], Guang-Yu Li[c], Qing-Wei Zhang*[b]
and Wei He*[a]
Dedication ((optional))
Abstract: We report a copper catalyzed trifunctionalization of alkynes
that provides rapid entry to oxindoles bearing geminal
controlled manner would ultimately install the 3-geminal
bis(boronates) functionality[14] (Scheme 1c). Given the versatile
reactivity of the C-B bonds,[15] the obtained products will be
amenable to late stage derivatizations in lead optimization efforts,
which will also serve as a useful starting point for the syntheses
of other bioactive oxindoles as they are privileged scaffolds in
numerous marketed drugs and investigational compounds.[16]
a
bis(boronates) side chain, highlighted by the simultaneous formation
of one C-C bond and two C-B bonds. This new reaction features
simple reaction conditions (ligand free catalysis), a general substrate
scope, as well as excellent chemoselectivity. Mechanistic study
revealed a reaction sequence in the order of borylation/intramolecular
cross coupling/hydroboration, which has been rarely documented.
Since the ground-breaking discovery of Suzuki and Miyaura[1] in
1993, transition metal catalyzed addition of stable diboron
reagents (e.g. bis(pinacolato)diboron,B2Pin2) to alkynes[2] has
emerged as a powerful means to prepare pivotal organoboron
building blocks.[3] In the past two decades, the field has witnessed
significant progresses with regard to catalyst systems and
reaction complexity. In terms of catalysts, the current toolbox has
expanded to homogeneous metal complex (Pt,[1,4] Ir,[5] and Cu[6]),
heterogeneous
metal
composites
(Pt
nanoparticles,[7]
nanoporous Au,[8] and Au nanoparticles[9]) as well as
organocatalysts.[10] In terms of reaction complexity, the focus has
moved beyond the relatively simple cis-diborylation (forming two
C-B bonds), which now encompasses the simultaneous formation
of a C-B bond and another C-X bond. The latter design was
accomplished by intercepting the reactive M-C(sp2) intermediate
with an electrophile or a cross coupling partner (Scheme 1a).
Along this line, Cu catalyzed carboborylation[11] and
borylstannylation[12] have met with encouraging successes. On an
important note, with no exception these reactions afforded
substituted alkenes as the desired products.
We took great inspiration from the remarkable work of Hall[6b]
and Brown[11d] (Scheme 1b), when pursuing a drug lead that
features an oxindole[13] bearing a functionalized side chain on the
3 position. We envisioned that the Cu catalyzed intermolecular
cross coupling invented by Brown would lead to the ring formation.
A subsequent addition resembling the Hall’s report in a stereo-
Scheme 1. Overall reaction design.
Herein we disclose a simple, ligand free Cu(I) catalyzed
trifunctionalization of 2-ynamide that provides rapid entry to
oxindoles bearing a geminal bis(boronates) moiety on the side
chain. It is worthy to mention that the reported examples[17] of
alkyne trifunctionalization are still limited and our products are of
the highest molecule complexity to date.
We commenced our study using 2-ynamide 1a and
Bis(pinacolato)diboron (B2pin2) (2.1 equiv.) as the model
substrates, with CuCl (20 mol%) as the catalyst and NaOtBu (2.1
[a]
[b]
[c]
T. He, B. Li, L.-C. Liu, J. Wang, W.-P. Ma, Prof. Dr. W. He
MOE Key Laboratory of Bioorganic Phosphorus Chemistry &
Chemical Biology and School of Pharmaceutical Sciences
Tsinghua University, Beijing, P. R. China, 100084
E-mail: whe@tsinghua.edu.cn
Prof. Dr. Q.-W. Zhang
Department of Chemistry
University of Science and Technology of China, Hefei, China,
230026
E-mail: qingweiz@ustc.edu.cn
1
equiv.) as the base. The reactions were monitored by H NMR
using 1-(4-nitrophenyl)ethanone as the internal standard. The
initial trial gave the desired product 2a at room temperature, albeit
in a 33% yield (entry 1, Table 1). Other reaction parameters were
then extensively screened to identify the optimized condition. First,
various CuI catalysts were screened (entries 2-7), which showed
distinct impacts on the reaction yields. For example, CuI has the
best performance compared with CuCl and CuBr (entry 3 vs
entries 1 and 2). Moderate yields were observed with CuOAc
(entry 4), CuOTf (entry 5) and CuTC (entry 6). Cu2O was not a
competent catalyst (entry 7) and no product was observed in the
G.-Y. Li
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Ling Ling Road, Shanghai, 200032, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201804480
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absence of a copper catalyst (entry 8). Gratifyingly, decreasing
the catalyst loading to 5 mol% did not compromise the reaction,
as a comparable yield (75%) was obtained (entry 9 vs entry 3).
The choice of the base was important (entries 9-14): NaOtBu was
the best while other bases such as NaOEt, LiOtBu, DMAP, Et3N
and KOH gave diminished yields (entry 9 vs 10-14). No desired
product was observed in the absence of a base (entry 15). A lower
yield was observed when only 1.0 equiv. of NaOtBu was used
(entry 16). Increasing the reaction temperature to 60 oC or 80 oC
also resulted in diminished yield (entries 17 and 18). Other
solvents, such as THF, DCE or DMF, gave unsatisfactory yields
(entries 19-21).
opportunity to further elaborate the aryl ring by either SNAr
reactions or cross-coupling reactions, as long as the desired
halogen atom is properly installed beforehand. However, for
reasons that we have yet to understand, the substrate containing
ortho-bromine to amide (1n) gave a complex mixture that defied
silica gel purification and the NMR yield was low (14%).
Table 2. Substrate scope of aryls.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry
1
Cat.[mol%]
CuCl [20]
CuBr [20]
CuI [20]
CuOAc [20]
CuOTf [20]
CuTC[c] [20]
Cu2O [20]
none
Base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
T[oC]
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
60
Yield[%][b]
33
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOEt
LiOtBu
KOH
2
51
3
74
4
68
5
45
6
45
7
<5
8
0
9
CuI [5]
75
10
11
12
13
14
15
16[d]
17
18
19
20
21
CuI [5]
35
CuI [5]
37
CuI [5]
15
[a] Reaction conditions: 2-ynamide 1 (0.10 mmol), B2pin2 (0.21 mmol, 2.1
equiv.), NaOtBu (0.21 mmol, 2.1 equiv) and CuI (5 mol%, 1.0 mg) under Ar in
toluene (2.0 mL) at room temperature. [b] Yield of the isolated product after silica
gel column chromatography. [c] On 8.26 mmol scale. [d] At 60 oC. [e] NMR yield
using 4-nitroacetophenone as the internal standard.
CuI [5]
DMAP
trace
trace
0
CuI [5]
Et3N
CuI [5]
none
CuI [5]
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
25
CuI [5]
49
Table 3. Substrate scope of alkynes and protecting groups on N-atom.[a,b]
CuI [5]
80
53
CuI [5]
RT
RT
RT
45
CuI [5]
DCE
12
CuI [5]
DMF
<5
[a] Reaction conditions: 2-ynamide 1a (0.10 mmol), B2pin2 (0.21 mmol, 2.1
equiv.), base (0.21 mmol, 2.1 equiv.) and catalyst under argon in the indicated
solvent (2.0 mL). [b] NMR yields using 1-(4-nitrophenyl)ethanone (0.10 mmol)
as the internal standard. [c] TC = thiophene-2-carboxylate. [d] 1.0 equiv. base
was used.
We then demonstrated the substrate scope under the optimized
conditions (Table 2). Different substitutions on the aryl group (R1)
were first tested. With 2-ynamide 1a, the desired product 2a was
isolated in a 72% yield for a 0.1 mmol scale reaction. The reaction
is amenable to scale up, as the 8.26 mmol reaction (80 fold scale
up) gave a 68% yield. Substrates bearing electron-donating
methyl (2b), methoxyl (2c), piperonyl (2d) groups reacted
smoothly, furnishing the desired product in 68%, 77% and 83%
yield, respectively. Substrates with electron-withdrawing groups
gave higher yields, as seen in the cases of CF3 (2e) and CO2Et
(2f). However, substrate 1g containing a nitro group suffered from
a low 26% yield (2g). Aryl halides ranging from fluoride (2h),
chloride (2i), bromide (2j, 2l and 2m) to iodide (2n) are compatible
with the reaction. It is remarkable that in the reaction of diiodide
1k, only the ortho-iodine participated the arylation reaction while
the other one remained intact. The excellent chemoselectivity
among these halides (1h, 1i, 1j, 1l, 1m and 1n) provide ample
[a] Reaction conditions: 2-ynamide 1 (0.10 mmol), B2pin2 (0.21 mmol, 2.1 equiv),
NaOtBu (0.21 mmol, 2.1 equiv) and CuI (5 mol%, 1.0 mg) under argon in toluene
(2.0 mL) at room temperature. [b] Yield of the isolated product after silica gel
column chromatography. [c] At 60 oC.
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The substituents on the alkyne (R) as well as the protecting
groups (R‘) on the N-atom were then examined (Table 3).
Substrates containing n-butyl (1o), ethylphenyl (1p) and
cyclopropyl (1q) groups are compatible with the reaction, resulting
in moderate to good yields. Increasing the steric hindrance of the
R2 groups decreased the reactivity of the substrates, such that a
high reaction temperature was demanded and the reaction yields
dropped. For examples, substrate 1r containing a tert-butyl group
gave a 31% yield. Interestingly, the even bulkier trimethylsilyl
substrate 1s gave a higher yield of 50%. We want to point out that
the C-Si bond in product 2s would allow functionalization
orthogonal to that of the C-B bonds. Electron-donating protecting
groups such as allyl (1t, 1u) and alkyl (1v) were compatible with
the reaction, giving satisfactory yields. The structure of the
compound 2v were unequivocally determined by single crystal X-
ray crystallography,[18] which indicates the benzylic hydrogen is
trans to the terminal methyl group. Besides, the distance between
the carbonyl oxygen and the B was measured to be 2.858 Å in the
X-ray structure, which is shorter than the Bondi’s van der Waals
radii sum (3.65 Å) of B and O.[19] This indicates that a nonbonding
interaction existed between the B and O atoms in the product.
force for this fast addition, as the similar addition to acyclic
enons[14] were reported to be slow. In other words, the successful
geminal bisborylation could not be assumed despite the traits
reported by Hoveyda[20] and Yun.[14]
Scheme 3. Mechanism exploration. [a] NMR yields using 1-(4-
nitrophenyl)ethanone as internal standard. [b] See supporting information for
the preparation and identification of 3a and 4a.
A possible catalytic cycle was proposed as shown in Scheme 4
using 1a as the example. The reaction begins with the addition of
Cu-BPin species[21] to 2-ynamide 1a, forming the Cu-C(sp2)
species I. As a side reaction, intermediate I could be protonated
by a proton source in the reaction mixture to give acyclic
byproduct 3a. A second borylation of 3a followed by protonation
Scheme 2. Illustration for interaction between O and B.
A number of experiments were carried out to probe the reaction
mechanism (Scheme 3, also see the supporting information).
When water was deliberately added to the reaction, the acyclic
products 3a and 4a were isolated in a combined 68% yield. When
tBuOD was used to quench the reaction, besides the desired
product 2a-d (89% deuterium incorporation), a small amount of
both 3a-d and 4a-d (4a-d1 and/or 4a-d2) were observed (Scheme
3a). The formation of the acyclic product 3 and 4, as well as the
would afford byproduct 4a. Alternatively,
a
productive
intramolecular oxidative insertion of intermediate I would form the
putative Cu(III) intermediate II. Reductive elimination would form
the C-C bond, [11d] affording the 3-ylidene 2-oxindole 5a. This C-C
bond formation step is likely the rate limiting step. A consequential
borylcupration of C=C bond would proceed rapidly to form the
second C-B bond in the form of sodium enolates, which upon
workup would give the final product 2a.
deuterium incorporation at the
substantiated the existence of
α
a
position of the amide
Cu-C intermediate. The
protonation/deuteration of such a Cu-C intermediate (leading to
product 3 and 4) is a pathway competing with the C-C bond
formation pathway (leading to product 2). The remaining question
is whether the C-C bond formation is by virtue of a Cu-C(sp2)
intermediate (the precursor to product 3) or a Cu-C(sp3)
intermediate (the precursor to product 4). To distinguish these two
possible scenarios, we prepared 3a using an independent method
(see supporting information) and subjected it to the reaction
conditions (Scheme 3b). Compound 4a was observed in a 50%
NMR yield while 2a was not detected, therefore ruling out the
second scenario. This is consistent with the report of Brown[11d]
and confirms our initial reaction design. If such a mechanism is
operative, compound 5a might be detected in the reaction mixture,
especially when the second equiv. of B2pin2 is deprived. To this
end, we performed the reaction with 1.0 equiv. of B2pin2 and
NaOtBu under otherwise identical conditions (Scheme 3c).
However, the product 2a was observed in a 29% yield while 5a
was not observed. These observations indicated that the addition
of Cu-Bpin to 5a is much faster than the formation of 5a. We
believe that relief of the ring strain in 5a serves as a major driving
Scheme 4. Proposed catalytic cycle.
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[13]
C. Liu, Q. Zhang, H. B. Li, S. X. Guo, B. Xiao, W. Deng, L. Liu, W. He,
In summary, we have developed a ligand free, copper catalyzed
trifunctionalization of alkynes, with the simultaneous construction
of one C-C bond and two C-B bonds. The reaction shows a wide
substrate scope, good efficiency and excellent chemoselectivity.
The reaction products feature a unique oxindole skeleton bearing
a geminal diboron functionality, which could be easily elaborated
into interesting drug-like lead compounds. Efforts to trap the Cu-
C(sp2) in an enantioselective manner are undergoing in our labs.
Chem. Eur. J. 2016, 22, 6208-6212.
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ethyl 2-butynoate, see: H. Y. Jung, X. Feng, H. Kim, J. Yun, Tetrahedron
2012, 68, 3444-3449.
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Acknowledgements
We gratefully acknowldege financial support form the National
Key R&D Program of China (No. 2017YFA0505200) and NSFC
(21625104, 21521091).
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Keywords: trifunctionalization • oxindole • alkyne • bis-borylation
• copper
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Entry for the Table of Contents (Please choose one layout)
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Tao He, Bin Li, Li-Chuan Liu, Jing
Wang, Wen-Peng Ma, Guang-Yu Li,
Qing-Wei Zhang* and Wei He*
Page No. – Page No.
Copper-Catalyzed Trifunctionalization
of Alkynes: Rapid Assembly of
Oxindoles Bearing Geminal Diboron
A ligand free Cu(I) catalyzed trifunctionalization of 2-ynamide is developed, which
provides rapid entry to oxindoles bearing a geminal bis(boronates) substitution on
the side chain. The new reaction features simple reaction conditions, a general
substrate scope and excellent chemoselectivity.
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