Construction of Bisbenzopyrone via N-Heterocyclic Carbene Catalyzed Intramolecular Hydroacylation-Stetter Reaction Cascade

Article abstract of DOI:10.1021/acs.orglett.8b00882

An efficient synthesis of bisbenzopyrones by a N-heterocyclic carbene (NHC)-catalyzed intramolecular hydroacylationaStetter reaction cascade has been developed. A series of symmetrical and unsymmetrical bisbenzopyrones were obtained with good to excellent

Full text of DOI:10.1021/acs.orglett.8b00882

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of Bisbenzopyrone via N‑Heterocyclic Carbene
Catalyzed Intramolecular Hydroacylation−Stetter Reaction Cascade
Ming Zhao,† Jia-Lin Liu,† Hang-Fan Liu, Jie Chen,* and Ling Zhou*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710127, P. R. China
S
* Supporting Information
ABSTRACT: An efficient synthesis of bisbenzopyrones by a
N-heterocyclic carbene (NHC)-catalyzed intramolecular hy-
droacylation−Stetter reaction cascade has been developed. A
series of symmetrical and unsymmetrical bisbenzopyrones
were obtained with good to excellent yields. Bisbenzopyran-4-
ol was synthesized efficiently.
Scheme 1. Construction of Bisbenzopyrone Skeleton
isbenzopyrone and bisbenzopyran are important scaffolds
Bin natural products such as chamaejasmine and bisbenzo-
pyran-4-ol (Figure 1).1 These molecules display a wide range of
biological and medicinal activities in plant growth, develop-
ment, self-defense, and the treatment of wounds, burns, asthma,
and ulcers.2 Many remarkable endeavors have been made to
synthesize these natural products. The key step is how to
construct the bisbenzopyrone or bisbenzopyran core. Only a
few examples utilizing Ullmann-type coupling/reduction or
radical dimerization have been reported, although a long
reaction route or low yield was encountered (Scheme 1, eqs 1,
2).3 Therefore, the development of direct and efficient
synthetic methods to synthesize these molecules using simple
starting materials is highly desirable.
In recent decades, the NHC-catalyzed reaction has emerged
as a powerful strategy to assemble relatively complex
molecules.4 Among them, NHC-catalyzed intramolecular
Stetter reactions of aldehydes with various Michael acceptors
have been extensively studied.5 Remarkable advances have been
recorded in the NHC-catalyzed hydroacylation of unactivated
alkenes.6 Meanwhile, the NHC-catalyzed hydroacylation of
alkynes has also been developed.7 Recently, we have developed
several unconventional NHC-catalyzed reactions.8 To continue
our research interest in the development and application of
NHC-catalyzed reactions, herein, we report the first NHC-
catalyzed intramolecular hydroacylation−Stetter reaction cas-
cade,9 which leads to the formation of bisbenzopyrones
efficiently.
Inspired by NHC-catalyzed addition reactions, it was
anticipated that bisbenzopyrone skeletons could be generated
via the NHC-catalyzed intramolecular hydroacylation−Stetter
reaction cascade of the corresponding alkynl bisbenzaldehydes,
which could be prepared easily from commercially available 1,4-
dibromobut-2-yne and 2-hydroxybenzaldehydes (Scheme 1, eq
3). Furthermore, unsymmetric bisbenzopyrones will be
obtained conveniently starting from different hydroxy-
Figure 1. Selected bisbenzopyrone and bisbenzopyran natural
products.
Received: March 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Symmetric Substituted Aromatic
Aldehydes
a
temp
time
(h)
yield
b
entry NHC
base
solvent
THF
(°C)
(%)
1
3
4
5
6
6
6
6
6
6
6
6
6
6
6
6
6
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
tBuOK
DBU
iPr2NEt
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
70
70
70
70
70
70
70
70
80
80
80
80
80
90
80
80
5
5
5
5
5
5
5
5
2
2
2
2
2
2
2
2
0
2
THF
0
3
THF
0
4
THF
51
0
5
THF
6
THF
0
7
THF
16
0
8
THF
9
THF
66
0
10
11
12
13
14
15
16
toluene
CH3CN
DMF
21
trace
82
81
82
46
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
c
d
a
Reactions were carried out with 1 (0.10 mmol), 6 (0.02 mmol), and
K2CO3 (0.04 mmol) in 1,4-dioxane (1.0 mL) under N2 at 80 °C for 2
h. Yields of isolated products are reported. The dr value was
determined by 1H NMR or HPLC analysis; the major isomer is shown.
a
Reactions were carried out with 1a (0.10 mmol), NHC·HX (0.02
b
mmol), and base (0.04 mmol) in solvent (1.0 mL) under N2. Isolated
yield. 1.0 equiv of K2CO3 was used. 6 (0.01 mmol), K2CO3 (0.02
mmol).
c
d
b
c
Reaction time is 4.0 h. 0.04 mmol 6 was used.
benzaldehydes (R1 ≠ R2), which are difficult to obtain from
those dimerization strategies.
(Scheme 2). In general, a variety of symmetrical bisbenzopyr-
ones were successfully prepared via this cascade reaction.
Substrates with a methy or methoxyl substituent at the 3-
position of the phenyl ring resulted in the desired
bisbenzopyrones with high yields (2b, 2c). However, the
methoxyl substituted substrate at the 4-position resulted in a
lower yield (2d). The negative effects of the electron-donating
substitution at the para position on the yield may be attributed
to the low reactivity of the aldehyde with the NHC catalyst.
Substitutions of the phenyl ring at the 5-position worked well
(2e−2h); both electron-withdrawing and -donating substitu-
ents gave the corresponding products in good to excellent
yields. Moreover, the di-tert-butyl substituted substrate and the
1-naphthaldehyde substrate were also well tolerated (2i, 2j).
Satisfactorily, the reaction was readily scalable without losing
any efficiency (Scheme 2, 2a). The structure of syn-2a (major
isomer) was confirmed by X-ray analysis.10
Then, we turned our attention to the construction of
unsymmetrical bisbenzopyrones. As shown in Scheme 3,
installing various unsymmetrial substituents on the phenyl
ring had little influence on the reaction outcomes, and the
corresponding products were also formed in good to excellent
yields. Monomethoxyl substituted substrate 1k returned the
desired unsymmetrical bisbenzopyrone product 2k with 87%
yield. Substrates with different substituents at the 5-position of
To test this hypothesis, 2,2′-(but-2-yne-1,4-diylbis(oxy))-
dibenzaldehyde (1a) was prepared as the model substrate. As
shown in Table 1, a screening of different NHC catalysts (3−6)
was first carried out (entries 1−4). To our delight, the desired
cascade reaction product bisbenzopyrone 2a was obtained in
51% yield as a diastereomeric mixture (syn/anti = 2:1) when
catalyst 6 was used in the presence of 40 mol % K2CO3 in THF
at 70 °C for 5 h (entry 4). The diastereomeric ratio (dr) was
1
determined by H NMR and HPLC using a chiral column, in
which three peaks were detected as a mixture of racemate and
meso isomers.10 Next, other bases such as Cs2CO3, BuOK,
t
i
DBU, and Pr2NEt were evaluated (entries 5−8); K2CO3 was
the optimal base for this cascade reaction. Increasing the
reaction temperature returned a measurable increase in yield
(entry 9). Then, various solvents were screened, and 1,4-
dioxane gave the best results (entry 13). Additionally, further
increasing the reaction temperature or the loading of K2CO3
had no obvious influence on the reaction (entries 14 and 15).
Lowering the catalyst loading to 10 mol % resulted in a lower
yield (entry 16). Unfortunately, attempts to optimize the
stereoselectivity were met with limited success.10
With the optimized reaction conditions in hand, we
examined this synthetic method with a range of substrates
with different substitution patterns of the aromatic ring
B
DOI: 10.1021/acs.orglett.8b00882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of Unsymmetric Substituted Aromatic
Aldehydes
Scheme 4. Proposed Catalytic Cycle
a
Scheme 5. Synthesis of Bisbenzopyran-4-ol
a
Reactions were performed with compound 1 (0.10 mmol), 6 (0.02
one 2a and release of the NHC catalyst to complete the
catalytic cycle. The stereochemistry could arise from an
intramolecular proton transfer event from the enolate
intermediate E, in which the NHC moiety is too far away to
control the stereoselectivity.
mmol), and K2CO3 (0.04 mmol) at 80 °C in 1,4-dioxane (1.0 mL)
under N2 for 2 h. Yields of isolated products are reported. The dr value
1
was determined by H NMR or HPLC analysis; the major isomer is
shown.
In summary, we have developed an efficient strategy for the
synthesis of bisbenzopyrones by an NHC-catalyzed intra-
molecular hydroacylation−Stetter reaction cascade. This
reaction involves the construction of two benzopyrones
through two carbon−carbon bond formations. A variety of
symmetrical and unsymmetrical bisbenzopyrones were ob-
tained with good to excellent yields, and the obtained
bisbenzopyrone 2g could be transformed into the natural
product bisbenzopyran-4-ol by simple reduction (Scheme 5).
Further investigations on the mechanism and other NHC-
catalyzed cascade reactions are underway in our laboratory.
one phenyl ring all worked well in this cascade reaction (2l−
2n). Substrates with a methoxyl substituent at the 3-position of
one phenyl ring, and monosubstituted, disubstituted at the
other phenyl ring or naphthyl ring, were well tolerated; the
desired unsymmetrical bisbenzopyrone products were obtained
with excellent results (2o−r). Substrates bearing substituents at
the 5- and 5′-position of the phenyl rings were also converted
to the products in good yields (2t, 2u).
A plausible catalytic cycle is depicted in Scheme 4. The
catalytic cycle starts with the addition of the NHC catalyst to
aldehyde 1a to generate Breslow intermediate A.11 The
nucleophilic Breslow intermediate A subsequently participates
in an intramolecular hydroacylation of unactivated alkyne to
give intermediate B, which affords the α,β-unsaturated ketone
C and liberation of the NHC catalyst. The configuration of C
remains unclear, and an attempt to trap C failed due to the next
Stetter reaction, which may be faster than the first step. Then,
the nucleophilic Breslow intermediate is formed again through
the addition of the NHC catalyst to C, which undergoes an
intramolecular Stetter reaction to give the desired bisbenzopyr-
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.8b00882.
Experimental procedures, characterization data for all
1
new compounds, and copies of H, 13C NMR spectra
(PDF)
C
DOI: 10.1021/acs.orglett.8b00882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015,
115, 9307. (s) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015,
44, 5040. (t) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016,
55, 14912. (u) Zhang, C.; Hooper, J. F.; Lupton, D. W. ACS Catal.
2017, 7, 2583. (v) Zhao, M.; Zhang, Y.-T.; Chen, J.; Zhou, L. Asian J.
Org. Chem. 2018, 7, 54.
CCDC 1830600 contains 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.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chmchenj@nwu.edu.cn.
*E-mail: zhoul@nwu.edu.cn.
ORCID
Ling Zhou: 0000-0002-6805-2961
Author Contributions
†M.Z. and J.-L.L. contributed equally.
Notes
The authors declare no competing financial interest.
Z.; Yang, S.; Fang, X. Chem. Commun. 2016, 52, 6459. (q) Rafin
́
ski, Z.;
ACKNOWLEDGMENTS
■
Kozakiewicz, A.; Rafinska, K. ACS Catal. 2014, 4, 1404.
́
We thank the National Natural Science Foundation of China
(NSFC-21672170), the Key Science and Technology Innova-
tion Team of Shaanxi Province (2017KCT-37), and the
Northwest University (YZZ17109) for financial support.
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Org. Lett. XXXX, XXX, XXX−XXX