N-Heterocyclic Carbene-Catalyzed Umpolung of Alkynyl 1,2-Diketones

Article abstract of DOI:10.1002/adsc.201700700

The umpolung of alkynyl 1,2-diketones via N-heterocyclic carbene (NHC) catalysis was achieved for the first time, allowing the rapid access to a large variety of synthetically and pharmaceutically important α-pyrones under very mild conditions. A completely new NHC-catalyzed umpolung pattern involving an O-acylated allenolate as the key intermediate was proposed. Moreover, an unprecedented reaction pathway, featured by a series of group migrations and new bond formation, was postulated to demonstrate the formation of the products. (Figure presented.).

Full text of DOI:10.1002/adsc.201700700

Title: N-Heterocyclic Carbene-Catalyzed Umpolung of Alkynyl 1,2-
Diketones
Authors: Xinqiang Fang, Xiangwen Kong, Guoxiang Zhang, Shuang
Yang, and Xiaozhi Liu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700700
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Advanced Synthesis & Catalysis
10.1002/adsc.201700700
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
N-Heterocyclic Carbene-Catalyzed Umpolung of Alkynyl 1,2-
Diketones
c
a
b
c
b
Xiangwen Kong, Guoxiang Zhang, Shuang Yang, Xiaozhi Liu, and Xinqiang Fang *
a
College of Chemistry, Fuzhou University, Fuzhou, 350116, China.
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
b
Academy of Sciences, Fuzhou, 350100, China. Email: xqfang@fjirsm.ac.cn
Liaoning University, Shenyang, 110036, China.
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The umpolung of alkynyl 1,2-diketones via N- indole synthesis through the umpolung of aldimines.[9]
heterocyclic carbene (NHC) catalysis was achieved for the Despite all these tremendous advances, we believe
first time, allowing rapid access to a large variety of that the capability of NHC catalysis in enabling the
synthetically and pharmaceutically important α-pyrones umpolung of electron-deficent species remains to be
under very mild conditions. A completely new NHC- further exploited. For instance, alkynyl 1,2-diketones,
catalyzed umpolung pattern involving an O-acylated
allenolate as the key intermediate was proposed. Moreover,
an unprecedented reaction pathway, featured by a series of
group migrations and new bond formation, was postulated
to demonstrate the formation of the products.
with an alkyne moiety connected to two adjacent
carbonyl groups, and featured by a series of
nucleophilic additions, condensations, and Diels-
[10]
Alder reactions, have never been able to achieve
polarity reversal (Scheme 1a-d). The challenges arise
from the multiple reactive positions within this type
of substrates, and realizing the catalyst regeneration.
Keywords: alkynyl 1,2-diketone; N-heterocyclic carbene;
umpolung; O-acylated allenolate; migration
The strategy of umpolung has attracted long-
standing and intense research interest owing to its
[1]
unique and irreplaceable roles in organic synthesis.
In this context, N-heterocyclic carbene (NHC)
catalysis has been one of the most versatile and
powerful approaches to achieve the umpolung of
molecules. Various polarity reversal modes and the
corresponding NHC-bound intermediates have laid
the foundation of the modern NHC organocatalysis
chemistry.[ Although for long time the NHC-
mediated umpolung refers to the polarity reversal of
2]
[
3]
aldehydes via Breslow intermediate,
Glorius and Bode independently reported the a ‒d
umpolung of enals through homoenolate intermediate,
in 2004,
3
3
[4]
and thus opened up the new age of NHC catalysis.
Similar reactivity was observed when alkynals were
used in NHC-catalyzed reactions (via allenolate
intermediate).[ Furthermore, Fu, Matsuoka, Glorius,
and Lupton have developed the umpolung of Michael
5]
[6]
acceptors via deoxy-Breslow intermediates. In 2013,
NHC-catalyzed reaction of cinnamils leading to
Scheme 1. Reactivities of alkynyl diketones.
2
,3,8-triaryl vinyl fulvenes was reported by the Nair
group, and the mechanism features an initial [3,3]-
[7]
rearrangement pathway. In 2014, the Takaki group
disclosed the NHC-catalyzed polarity reversal of
benzils leading to the acylation of enones through O-
Herein we report for the first time the umpolung of
alkynyl diketones via NHC catalysis, which can
rapidly afford
a
large variety of densely
[8]
acylated Breslow intermediate. Very recently, Biju
and Suresh demonstrated respectively the elegant
functionalized α-pyrones under very mild conditions
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700700
(
Scheme 1e). Mechanistically, in sharp contrast to the
Noteworthy is that α-pyrone units are ubiquitous in
a large number of natural products and many
approved drugs, and also useful synthons in organic
[6]
prior reports of the umpolung of Michael acceptors,
a completely new umpolung pattern initiated by the
selective nucleophilic addition of carbene catalyst to
the α-carbonyl group of the substrate was postulated.
Moreover, an unprecedented reaction pathway,
featured by
rearrangements), were proposed to demonstrate the
formation of the products.
As outlined in Table 1, our study commenced by
selecting 1a as the model substrate for the
optimization of reaction conditions. To our delight,
[11]
synthesis.
However, approaches to afford
polysubstituted α-pyrones under mild conditions are
[12]
still challenging and highly desirable.
In this
a
series group migrations (or
regard, we evaluated the generality of this protocol
and substrates bearing diaryl substituents were tested
1
first (Table 2). When the alkynyl substituent Ar was
set as phenyl group, we were delighted to find that
2
the reaction can tolerate different Ar groups as either
electron- rich or electron-poor phenyl rings (Table 2,
2
when 1a was treated with imidazolium A and K
in THF, α-pyrone 2a was obtained in 87% yield
Table 1, entry 1). The base of DBU resulted in
slightly decreased yield (Table 1, entry 2), but almost
quantitative yield of 2a was obtained when Cs CO
was tested (Table 1, entry 3). The evaluation of other
solvents such as toluene and CH Cl did not show
2
CO
3
2b‒f). Then we set the Ar as phenyl group, and
observed that a wide array of substrates with different
1
(
Ar
groups proceeded well to afford the
corresponding
pyrones
(Table
2,
2g‒p).
2
3
Furthermore,the synchronous alteration of both the
1
2
Ar and Ar groups as differently substituted phenyl
rings showed little impact on the results (Table 2, 2r‒
u). Gram-scale reaction using 1a was also tested and
proved successful (Table 2, 2a). In addition, the
structure of 2p was confirmed via single crystal X-
2
2
better results (Table 1, entries 4 and 5). However, we
were pleased to find that the 10 mol% of the catalyst
loading had no influence on the outcome (Table 1,
entry 6). Furthermore, catalysts B, C, and D proved
inert to this transformation (Table 1, entry 7), and
very low yields were observed when E, F, and G
were used (Table 1, entries 8‒10). For comparison,
no any reaction occurred in the absence of catalyst
[13]
ray analysis.
Table 2. Substrate scope of diaryl alkynyl diketonesa)
(
Table 1, entry 11).
Table 1. Optimization of the reaction conditions[a]
Entry Catalyst
Base
CO
DBU
Solvent Yield [%][b]
1
2
3
4
5
6
7
8
9
1
1
A
A
A
A
A
A
K
2
3
THF
THF
THF
87
82
99
Cs
Cs
Cs
Cs
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
toluene 71
CH
2
Cl
2
93
99
0
12
32
12
0
[
c]
THF
THF
THF
THF
THF
THF
[
[
a]
b]
B, C, or D Cs
E
F
G
Reaction conditions: 1 (0.2 mmol), A (0.02 mmol),
Cs
Cs
Cs
Cs
Cs CO (0.02 mmol), THF (2 mL), rt, under argon
2
3
protection, 4‒6 h. All isolated yields were based on
substrate 1.
1a (1 gram) was used.
0
1
none
[
a]
Reaction conditions: 1a (0.2 mmol), NHC (0.04 mmol),
base (0.04 mmol), solvent (2 mL), rt, argon protection,
‒6 h.
Isolated yields based on 1a.
NHC (10 mol%) and base (10 mol%) were used.
4
Then, we wondered whether substrates with vinyl
[
[
b]
c]
or alkyl substituents can be tolerated. To our delight,
substrate containing a styryl group worked well under
the optimal conditions (Table 3, 4a). Then we found
that the introduction of a methyl or an ethyl group
into the ketone moiety showed little impact on the
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700700
reaction, with the corresponding pyrones isolated in
6
5‒66% yields (Table 3, 4b and 4c). Moreover,
replacement of the phenyl group at the alkyne unit
with aliphatic groups such as n-hexyl delivered
product 4d in 60% yield. Finally, the substrate with
both aliphatic substituents was tested, and it also
proved to be compatible. (Table 3, 4e).
Table 3. Substrate scope of alkynyl diketones with vinyl or
alkyl substituents
Scheme 3. Product derivatizations.
[
a]
On the basis of the prior reports[5,7,8] and our
experimental results, we proposed a catalytic cycle to
illustrate the formation of α-pyrones. As shown in
Scheme 4, nucleophilic attack of α-carbonyl group of
1
a by carbene catalyst leads to intermediate I, and O-
acylated allenolate equivalent II is formed after the
first acyl transfer. Then the nucleophilic addition of
II/III to the second molecule of 1a affords IV, and V
is furnished via the second acyl transfer. An unusual
acyloxy migration happens between V and VI, and
finally a lactonization process releases 2a. In this
cycle, totally four bonds, i.e., one C‒C bond and
three C‒O bonds, are formed.
[
a]
Reaction conditions: 3 (0.2 mmol), A (0.02 mmol),
Cs CO (0.02 mmol), THF (2 mL), rt, under argon
2
3
protection, 4‒6 h. All isolated yields were based on 3.
Cross-annulations were also investigated. When 1c
and 1d (1:1) coexisted in the same reaction system,
d was selectively activated (Scheme 2, eq 1). Then,
1
using 3:1 ratio of 1c and 1d, two separable cross-
annulation products 2dc and 2cd were obtained in 32%
[14]
and 15% yield, respectively (Scheme 2, eq 2).
Scheme 4. Postulated reaction mechanism.
In conclusion, we have achieved the umpolung of
alkynyl 1,2-diketones for the first time, and its
synthetic application has been demonstrated by
accessing a diverse set of synthetically and
biologically valuable α-pyrones in a concise and
efficient fashion. The powerfulness of NHC
organocatalysis in facilitating complicated cascade
transformations was also clearly demonstrated.
Mechanistically, in contrast to the prior reports using
Michael acceptors, an umpolung pattern initiated by
the nucleophilic addition of carbene catalyst to the α-
carbonyl group of the substrate was postulated.
Furthermore, different to the conventional reactivity
of allenolate, an unprecedented reaction pathway,
which is featured by a series of group shifts and new
C‒C/C‒O bond formation, was postulated to
demonstrate the formation of the products. Further
investigations on the trap of the O-acylated allenolate
intermediate with electrophilic species and
Scheme 2. Cross-annulation reactions.
The synthetic utility of this method was
preliminarily demonstrated in Scheme 3. Several
synthetically valuable molecules can be obtained via
the further transformations of the α-pyrones obtained
in this work. For instance, pyridinone 5a was
[15]
produced from the reaction of 2a and benzylamine,
and the Diels-Alder reaction of 2a with dimethyl
acetylenedicarboxylate afforded fully-substituted
benzene 5b.[
16]
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700700
intramolecular annulations via this intermediate are
ongoing in our group.
Yetra, A. Patra, A. T. Biju, Synthesis 2015, 47, 1357; e)
R. S. Menon, A. T. Biju, V. Nair, Beilstein J. Org.
Chem. 2016, 12, 444.
[
4] a) C. Burstein, F. Glorius, Angew. Chem. Int. Ed. 2004,
43, 6205; b) S. S. Sohn, E. L. Rosen, J. W. Bode, J. Am.
Chem. Soc. 2004, 126, 14370.
Experimental Section
Under argon atmosphere, to a 10 mL Schlenk tube was
[5] For selected reports on the formation of NHC-
allenolate intermediates from alkynals, see: a) J. Qi, X.
Xie, R. Han, D. Ma, J. Yang, X. She, Chem. Eur. J.
2013, 19, 4146; b) R. Han, J. Qi, J. Gu, D. Ma, X. Xie,
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A. Wespe, T. J. Poore, S. A. Snyder, Angew. Chem. Int.
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2 3
taken unsaturated 1a (46.85 mg, 0.2 mmol), Cs CO (6.5
mg, 10 mol%), catalyst A (6.8 mg, 10 mol%), and stirring
bar. The flask was then evacuated and refilled with dry
argon. To this mixture 2 mL of THF was added and the
reaction was stirred at room temperature for 4‒6 h. The
progress of the reaction was monitored by TLC analysis.
After completion of the reaction, solvent was evaporated
and the crude products were purified by column
chromatography on silica gel with petroleum ether-ethyl
acetate mixture (4:1 v/v) as eluent to afford the product 2a.
[
6] a) C. Fischer, S. W. Smith, D. A. Powell, G. C. Fu, J.
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Angew. Chem. Int. Ed. 2016, 55, 3135.
Acknowledgements
This work was supported by the strategic priority research
program of the Chinese Academy of Sciences (XDB20000000),
NSFC (21402199 and 21502192), and the Chinese Recruitment
Program of Global Experts. We also thank Professor Daqiang
Yuan in FJIRSM for the help of X-ray crystallographic analysis.
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Advanced Synthesis & Catalysis
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COMMUNICATION
N-Heterocyclic Carbene-Catalyzed Umpolung of
Alkynyl 1,2-Diketones
Adv. Synth. Catal. Year, Volume, Page – Page
c
a
b
Xiangwen Kong, Guoxiang Zhang, Shuang Yang,
c
b
Xiaozhi Liu, and Xinqiang Fang *
6
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