N-Heterocyclic carbene-catalyzed cascade epoxide-opening and lactonization reaction for the synthesis of dihydropyrone derivatives

Article abstract of DOI:10.1039/c1ob05854a

N-Heterocyclic carbene was employed as an efficient organic catalyst to catalyze a cascade epoxide-opening and lactonization reaction. This organocatalytic process could transform various readily accessible γ-epoxy-α,β-enals into dihydropyrone derivatives in good to excellent yields.

Full text of DOI:10.1039/c1ob05854a

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N-Heterocyclic carbene-catalyzed cascade epoxide-opening and lactonization
reaction for the synthesis of dihydropyrone derivatives†
Jing Qi,a Xingang Xie,a Jinmei He,a Ling Zhang,a Donghui Maa and Xuegong She*a,b
Received 30th May 2011, Accepted 24th June 2011
DOI: 10.1039/c1ob05854a
N-Heterocyclic carbene was employed as an efficient or-
ganic catalyst to catalyze a cascade epoxide-opening and
lactonization reaction. This organocatalytic process could
transform various readily accessible c-epoxy-a,b-enals into
dihydropyrone derivatives in good to excellent yields.
dropyrone derivatives (Scheme 1). Successful implementation of
this idea would constitute a novel route to synthetic dihydropy-
rone derivatives and also broaden the scope of application of
NHCs.
N-Heterocyclic carbenes (NHCs) as organocatalysts have at-
tracted a great deal of attention in the past decades, as they provide
a broad range of useful synthetic transformations.1 Among the
reactions found to be promoted by this family of catalysts,
the benzoin-type condensation,2 the Stetter-type reaction,3 the
intra/intermolecular redox reaction,4 and the generation of
homoenolate species followed by a C–C bond formation were
involved.5 Remarkably, the Bode group and the Rovis group
respectively reported that a-reducible aldehydes led to a novel
reaction pathway under NHC catalysis in the presence of alcohols
as nucleophiles.6 Upon formation of the acyl anion equivalent,
redox reaction occurs, with addition of an alcohol resulting in
the desired esters. However, the NHC-catalyzed redox reaction of
g-reducible-a,b-enals have received extremely rare consideration.
To the best of our knowledge, there has been only one report
on the application of NHCs to this type of organocatalytic
transformations.4i Herein, we report the first example of an
NHC-catalyzed intramolecular redox reaction of g-epoxy-a,b-
enals to afford dihydropyrones via a cascade epoxide-opening and
lactonization pathway.
Although dihydropyrone subunits are widely recognized in a
large class of bioactive natural products, the typical strategies
applied for constructing this type of molecules usually require
the utilization of either expensive or toxic metals and lacked step
economy.7 To overcome such limitations, we decided to develop
a facile synthesis of dihyropyrones during our work. Inspired
by the elegant work from Bode and Rovis, we reasoned that
g-epoxy-a,b-enals in the presence of an NHC catalyst would,
in principle, undergo an epoxide-opening reaction followed by
intramolecular esterification resulting in the formation of dihy-
Scheme 1 NHC-catalyzed epoxide-opening and lactonization reaction.
Our initial efforts were focused on the systematic evaluation
of various catalysts and optimization of reaction conditions.
The simple readily prepared aldehyde 1a was selected as the
model substrate while DBU (1,8-diazabicyclo[5,4,0]undec-7-ene)
was used as the base, then a number of different catalysts were
screened, and the results are summarized in Table 1. Among
the tested catalysts, the commonly used catalysts A–D did not
provide any reactivity (entry 1). The thiazolium salt E reported
by Glorius group was found to be efficient for this reaction.8 As
we observed, the results were extremely dependant on the base
and solvent. When the reaction was performed in DCM with 0.3
equiv of thiazolium salt E and 0.3 equiv of DBU as the base
under reflux, 3a was generated in low yield as the desired product
(entry 2). It was worth noting that when 0.3 equiv of K2CO3 was
used as the base, a mixture of 2a and 3a was observed in a ratio
of 1 : 2 (entry 3). We envisaged that the use of a stronger base
would facilitate the subsequent C C bond migration to give the
more thermodynamically stable 2a as the major product. To our
great delight, utilization of 0.3 equiv of tBuOK afforded 2a as the
major product along with a small amount of 3a in 89% overall
yield (entry 5). No improvement was observed for the reaction in
acetonitrile, toluene or 1,2-dichloroethane (entry 6–8). However,
aState Key Laboratory of Applied Organic Chemistry, Department of
Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
t
when the reaction was carried out with 0.6 equiv of BuOK, the
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou
730000, People’s Republic of China. E-mail: shexg@lzu.edu.cn; Fax: +86-
931-8912582; Tel: +86-931-8912276
yield dropped sharply (entry 9). Thiazolium salt F also worked well
for this reaction (entry 10). Interestingly, when the reaction was
performed in the presence of 5 equiv MeOH as the nucleophile,
we did not detect the formation of the non-cyclized product and
the yield was decreased (entry 11). Thus, the optimized conditions
† Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/c1ob05854a
5948 | Org. Biomol. Chem., 2011, 9, 5948–5950
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Table 1 Optimization of reaction conditionsa
Table 2 Reaction scopea
entry R1, R2,
R3, R4, R5 product yield (%) ratio (2 : 3)
1
2
3
4
5
6
7
8
1a C6H5, H
H, H, H
H, H, H
H, H, H
H, H, H
2a, 3a
2b, 3b
2c, 3c
2d, 3d
2e, 4e
2f, 3f
2g, 3g
2h, 3h
2i, 3i
2j, 3j
2k
89
91
95
58
68
68
80
98
50
70
45
82
98
—
56
—
42
—
3 : 1
3 : 1
2 : 1
3 : 1
4 : 1
2 : 1
1.5 : 1
3 : 1
2 : 1
3 : 1
—
1b p-Cl-C6H5, H
1c p-Br-C6H5, H
1d p-Me-C6H5, H
1e p-NO2-C6H5, H H, H, H
1f o-Me-C6H5, H
1g m-Cl-C6H5, H
1h o-Br-C6H5, H
H, H, H
H, H, H
H, H, H
entry
NHCb
solvent
basec
productsd
yielde
9
1i 3,4-Me-C6H5, H H, H, H
1
2
3
4
5
6
7
8
A–D
E
DCM
DCM
DCM
DCM
DBU
DBU
—
3a
0
33
22
0
89
58
40
48
< 10
63
35
10
11
12
13
14
15
16
17
18
1j 1-Naphth, H
1k C6H5, Me
H, H, H
H, H, H
E
K2CO3
Cs2CO3
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
2a : 3a = 1 : 2
—
2a:3a = 3 : 1
2a
2a : 3a = 8 : 1
2a : 3a = 1 : 1
N.D.h
1l p-NO2-C6H5, Me H, H, H
2l
—
—
E
1m C6H5, C6H5
1n BnCH2, H
H, H, H
H, H, H
2m
E
DCM
N.R.b
2o
E
CH3CN
Toluene
DCE
1o phenylethynyl, H H, H, H
—
—
—
—
E
1p C6H5, H
1q C6H5, H
1r m-Cl-C6H5, H
Me, H, H N.R.b
H, C6H5, H 4q
E
9f
10
11g
E
DCM
DCM
DCM/MeOH
H, H, Me N.R.b
F
2a : 3a = 3 : 1
2a
E
a All reactions were performed on a 0.5 mmol scale at 0.02 M. b No
reaction.
a All reactions were performed on a 0.5 mmol scale at 0.02 M under reflux
for 24 h. b 30 mmol% catalyst was used. c 30 mmol% base was used unless
otherwise noted. d The ratios were determined by 1H NMR. e Isolated
t
overall yields. f 60 mol% BuOK was used. g 5 equiv MeOH was used.
In view of these interesting results, we further investigated the
scope of the reaction by using phenyl or methyl substituents at
the a, b or g positions of the aldehyde. To our disappointment,
the a-substituted 1r and g-substituted 1p did not work in this
transformation. Importantly, the reaction of the b-disubstituted
aldehyde 1q provided the elimination product 4q as the only
product in moderate yield. (entry 17).
h Not determined.
were established to be as follows: thiazolium salt E as the pre-
t
catalyst, BuOK as the base, DCM as the solvent and stirring
under reflux for 24 h.
Under the optimized reaction conditions, various aldehydes
were tested to investigate the scope of the reaction (Table 2). For
the R1 group, various phenyl groups bearing different electron-
donating and -withdrawing groups at o, m, p-positions all un-
derwent the proposed tandem epoxide-opening and lactonization
sequence smoothly to afford the corresponding dihydropyrones in
moderate to excellent yields (entry 1–10).
A preliminary study on the transformation of 3,6-dihydro-2H-
pyran-2-one to 5,6-dihydro-2H-pyran-2-one was also performed.9
For instance, upon treatment with 1.2 equiv of tBuOK under reflux
for 1 h, 3h was easily covered to 2h in quantitative yield (Scheme 2).
When the substrate 1e was used, 2e was generated in 54% yield
along with 4e as minor product and the reason is still unclear
(entry 5). A significant exception was noted, when methyl or
phenyl substituents were included at the R2 position under the
standard reaction conditions, the dihydropyrones 2k, 2l and 2m
were generated as the only products in moderate to good yields
(entry 11–13). The probable reason is that the substrates 1k–1m
suffer from an increased 1,3-strain over 1a–1j, therefore they are
more likely to transform to the thermodynamically stable products
under the same reaction conditions. Unfortunately, reaction of
the alkyl-substituted substrate 1n failed to produce any products
under the standard conditions (entry 14). It should be noted
that phenylethynyl substituted aldehyde 1o could also be used in
this reaction although the yield was slightly decreased (entry15).
Scheme 2 Conversion 3,6-dihydro-2H-pyran-2-one to 5,6-dihydro-2H-
pyran-2-one.
The postulated catalytic cycle for this NHC-catalyzed re-
action is shown in Scheme 3. In the first step, the
N-heterocyclic carbene, generated by base induced deprotonation
of the corresponding thiazolium salt, adds to the aldehyde 1
to afford the “Breslow intermediate” I.10 Then, the extended
homoenolate II equivalent undergoes the epoxide-opening path-
way and subsequently generates the intermediate III.11 In the
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Scheme 3 Proposed mechanism of the reaction.
epoxide-opening step, a Z-carboxylate is formed probably due
to the electronic interaction. Finally an intramolecular attack
of the alkoxide moiety provides the product 3 while the NHC
catalyst releases back to the catalytic cycle. Then the product 3
subsequently isomerizes to the thermodynamically more stable
product 2 under the alkaline conditions.
In summary, we have developed a highly efficient N-heterocyclic
carbene catalyzed cascade epoxide-opening and lactonization
reaction, which is a more direct and efficient way to construct
the skeleton of dihydropyrones. A variety of readily accessible
substrates underwent the reaction in good to excellent yield. We
postulated a mechanism for this reaction forming dihydropyrones,
which proceeds via the NHC-catalyzed tandem epoxide-opening
and lactonization reaction. Further investigations into the precise
mechanism of this reaction as well as the use of chiral carbenes
as organocatalysts in other asymmetric reaction are currently
underway in our laboratory.
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We are grateful for the generous financial support by the MOST
(2010CB833200), the NSFC (20872054, 20732002, 21072086) and
program 111.
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5950 | Org. Biomol. Chem., 2011, 9, 5948–5950
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