Synthesis of α-keto imides through copper-catalyzed oxidation of: N -sulfonyl ynamides

Article abstract of DOI:10.1039/c7ob02728a

A novel copper-catalyzed N-oxide oxidation of N-sulfonyl ynamides is disclosed. This non-noble metal-catalyzed protocol enables facile and efficient access to valuable α-keto imides in generally good to excellent yields. Other notable features of this method include widespread availability of the substrates, compatibility with broad functional groups, a simple procedure, mild conditions, and in particular, no need to exclude moisture or air ("open flask").

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Synthesis of ɑ-Keto Imides through Copper-
Catalyzed Oxidation of N-Sulfonyl Ynamides
Xin Liu,a,‡ Zhi-Xin Zhang,a‡ Bo Zhou,a Ze-Shu Wang,a Ren-Hua Zheng,*b and Long-Wu
NCite this: DOI: 10.1039/x0xx00000x
Ye*a,c
A novel copper-catalyzed N-oxide oxidation of N-sulfonyl ynamides is disclosed. This non-
noble metal-catalyzed protocol enables facile and efficient access to valuable ɑ-keto imides in
generally good to excellent yields. Other notable features of this method include widespread
availability of the substrates, compatibility with broad functional groups, a simple procedure,
mild conditions, and in particular, no need to exclude moisture or air (“open flask”).
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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1,2-Dicarbonyl compounds are privileged structural motifs in highly site-selective synthesis of various isoquinolones and β-
various bioactive natural products1 as well as versatile building carbolines through a facile oxidative C-H functionalization.11
blocks2 in a wide range of organic reactions. In the past decades, On the basis of this work, we further developed the non-noble
various methods have been developed for the synthesis of 1,2- metal-catalyzed
oxidative
azidation,
thiocyanation,
dicarbonyls and their analogues from the readily available halogenation and formal X–H bond insertion, thus delivering
alkynes, and they can be typically divided into the metal- diverse valuable α-functionalized amides from readily and
catalyzed systems such as Pd/Cu/DMSO oxidation and available ynamides.12 Importantly, these non-noble metal-
RuCl3·3H2O/NaOCl oxidation,3a-3g and metal-free systems such catalyzed oxidative reactions were proposed to proceed through
as NIS/DMSO oxidation and I2/H2O oxidation.3h-3j In particular, a Lewis acid-catalyzed SN2’ pathway based on both control
Al-Rashid and Hsung reported an elegant protocol for the experiments and theoretical calculations, which is distinctively
preparation of ɑ-keto imides via a RuO2/NaIO4 mediated different from the related oxidative gold catalysis where the
oxidation and a DMDO oxidation reaction of ynamides metal carbene intermediate is presumably proposed.
(Scheme 1a).4 Despite these significant achievements, these
methodologies still suffer from drawbacks such as limited
substrate scope, low chemoselectivity and high toxicity.
Consequently, the development of novel and general methods
for their efficient and practical synthesis is highly desirable.
Recently, gold-catalyzed intermolecular N-oxide oxidation of
alkynes, presumably involving an α-oxo gold carbenoid
intermediate,5 has attracted much attention, as this approach can
make alkynes as equivalents of hazardous, not easily accessible
and potentially explosive ɑ-diazo ketones for carbene
generation.6 As a result, a range of new reactions have been
discovered based on this strategy in the past decade, providing
an efficient way for C–C and C–heteroatom bond formation.7 In
this regard, Li and co-workers disclosed a gold-catalyzed
intermolecular oxidation reaction of alkynes by employing
sulfoxides as oxidants, thus affording various 1,2-dicarbonyl
compounds (Scheme 1b).8 In our recent study on ynamide
chemistry,9,10 we realized the first non-noble metal-catalyzed
Scheme 1 Synthesis of 1,2-dicarbonyls through the oxidation of alkynes.
intermolecular alkyne N-oxide oxidation reaction, allowing the
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Inspired by these results, we envisioned that the synthesis of
13). Of note, no desired product 2a was formed without the
ɑ-keto imides might be accessed by a non-noble metal- use of copper catalyst (>95% of 1a remained unreacted).
catalyzed intermolecular double oxidation of ynamides by N-
Table 2 Reaction scope for the formation of ɑ-keto imides 2a
oxides. Herein, we report a novel copper-catalyzed such an
ynamide oxidation, leading to the efficient and practical
formation of various functionalized ɑ-keto imides in generally
good to excellent yields under mild conditions (Scheme 1c).
Thus, this protocol provides a very efficient and practical
alternative route to synthetically useful ɑ-keto imides.
At the outset, N-sulfonyl ynamide 1a was used as model
substrate to demonstrate our designed oxidation reaction, as
outlined in Table 1. Different N-oxides were first screened
(Table 1, entries 1-4), and it was found that 8-methylquinoline
N-oxide 3d gave the best result (Table 1, entry 4). We then
turned to investigate the effect of different metal catalysts
(Table 1, entries 5-8). To our delight, the reaction occurred
efficiently to produce the corresponding ɑ-keto imide 2a in 76%
and 81% yield by using Cu(OTf)2 and Cu(CH3CN)4PF6 as
catalysts, respectively (Table 1, entries 7-8). Somewhat
surprisingly, Brønsted acids such as HNTf2 and MsOH could
also catalyze this reaction albeit in relatively low efficiency
(Table 1, entries 9-10).13 In addition, solvents were found to
affect the reaction yield dramatically. The use of toluene as
solvent only gave 32% yield (Table 1, entry 11) while 87%
yield could be achieved by employing DCE as solvent (Table 1,
entry 12). Further investigation revealed that the reaction also
proceeded at lower temperature, but resulting in a slightly
decreased yield and a much longer reaction time (Table 1, entry
Table 1 Optimization of reaction conditionsa
a Reactions run in vials; [1] = 0.05 M; isolated yields are reported.
With the optimal reaction conditions in hand (Table 1, entry
12), the scope of the reaction was then examined. As
summarized in Table 2, the reaction proceeded smoothly with
different R1-substituted ynamides 1a
corresponding ɑ-keto imides 2a
excellent yields (Table 2, entries 1-5). Then, the reaction scope
was explored by using different aryl-substituted ynamides 1f 1j
(R2 = aryl), and the desired products 2f
2j were formed in 79-
-
1e to generate the
-
2e in generally good to
-
-
87% yields (Table 2, entries 6-10). In addition, styryl-
substituted ynamide 1k also underwent smooth oxidation,
producing the corresponding 2k in 80% yield (Table 2, entry
11). Finally, it was found that other sulfonyl-protected
ynamides (Ms, Bs and Ns) and even oxazolidinone-type
ynamide were also suitable substrates for this reaction to
deliver the desired ɑ-keto imides 2l-2o in generally good to
excellent yields (Table 2, entries 12-15). Thus, this copper-
catalyzed oxidation reaction provides an efficient and practical
a Reactions run in vials; [1a] = 0.05 M. b Estimated by 1H NMR using diethyl
phthalate as an internal reference.
2 | J. Name., 2016, 00, 1-3
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route for the preparation of synthetically useful ɑ-keto imides non-noble metal-promoted oxidative catalysis is ongoing in our
from readily available N-sulfonyl ynamides.
laboratory.
These ɑ-keto imides are potentially useful in organic synthesis2
and will constitute valuable precursors for the construction of
important ɑ-hydroxyl imide derivatives.14 For example, ɑ-keto imide
2a could undergo facile reduction by NaBH4 to produce the
corresponding ɑ-hydroxyl imide 4a in 55% yield while the addition
of allylic Grignard reagent to 2a led to the efficient formation of the
desired quaternary carbon-containing ɑ-hydroxyl imide 5a in 79%
yield (Scheme 2).
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21572186 and
21622204), the Natural Science Foundation of Fujian Province
for Distinguished Young Scholars (2015J06003), the President
Research Funds from Xiamen University (20720150045), and
NFFTBS (No. J1310024).
‡ These authors contributed equally to this work.
Notes and references
aCollaborative Innovation Center of Chemistry for Energy Material, State
Key Laboratory of Physical Chemistry of Solid Surfaces and Key
Laboratory for Chemical Biology of Fujian Province, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China
E-mail: longwuye@xmu.edu.cn
bSchool of Pharmaceutical and Chemical Engineering, Taizhou
Scheme 2 Synthetic applications.
University, Taizhou 318000, China
On the basis of these experimental observations and our previous
work,11,12 a plausible mechanism to rationalize this copper-promoted
oxidative catalysis is proposed, as outlined in Scheme 3. Taking N-
sulfonyl ynamide 1a for example, the quinoline N-oxide 3d first
attacked the Cu-activated ynamide to generate vinyl copper
intermediate A, which was further attacked by the same oxidant via
an SN2’ pathway delivering intermediate B.8,15 Finally, Cu-assisted
quinoline release ought to produce the product 2a and regenerate the
catalyst.
cState Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China
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oxidation reaction of N-sulfonyl ynamides for the preparation of
various functionalized ɑ-keto imides, providing a very efficient and
practical alternative route to synthetically useful ɑ-keto imides.
Other notable features of this method include widespread availability
of the substrates, compatibility with broad functional groups, a
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A novel copperꢀcatalyzed Nꢀoxide oxidation of Nꢀsulfonyl ynamides has been
developed, allowing the facile synthesis of various ɑꢀketo imides in generally
moderate to good yields.