Synthesis of functionalized γ-lactones via a three-component cascade reaction catalyzed by consecutive N-heterocyclic carbene systems

Article abstract of DOI:10.1039/c5ra01254f

Two consecutive N-heterocyclic carbene (NHC) catalytic systems were combined in a one-pot cascade reaction for the assembly of aromatic aldehydes and 2-haloenals into a structurally complex γ-lactone backbone. To our knowledge, this is the first report of NHC-catalyzed [3 + 2] annulation of α,β-unsaturated acylazoliums with 1,2-bisnucleophiles.

Full text of DOI:10.1039/c5ra01254f

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Synthesis of functionalized g-lactones via a three-
component cascade reaction catalyzed by
consecutive N-heterocyclic carbene systems†
Cite this: RSC Adv., 2015, 5, 26972
a
b
a
b
ab
a
Received 21st January 2015
Accepted 6th March 2015
*
*
and Wei Huang
Qian Zhao,‡ Bo Han,‡ Biao Wang, Hai-Jun Leng, Cheng Peng
DOI: 10.1039/c5ra01254f
www.rsc.org/advances
Two consecutive N-heterocyclic carbene (NHC) catalytic systems unsaturated variants.1 Despite these advances, few studies have
were combined in a one-pot cascade reaction for the assembly of explored the combination of two NHC-mediated activation
aromatic aldehydes and 2-haloenals into a structurally complex modes in one multicomponent cascade reaction in a way that
g-lactone backbone. To our knowledge, this is the first report of NHC- takes advantage of the inherent basicity and compatibility of
catalyzed [3 + 2] annulation of a,b-unsaturated acylazoliums with both catalysts.
1,2-bisnucleophiles.
An efficient NHC-catalyzed activation mode that recently
received immense attention is the generation of a,b-unsatu-
rated acylazolium, which may be achieved from a,b-unsatu-
rated acyl uorides, enol esters, enals (under oxidative
conditions), ynals, or 2-haloenals.6–14 This reactive interme-
diate may serve as an analogue of 1,3-biselectrophiles and form
the basis for novel domino reactions. In fact, the groups of
Lupton,6 Bode,7 Studer,8 Biju,9 You,10 Ye,11 Yao,12 Chi13 and
Xiao14 have independently described NHC-catalyzed [3 + 3]
annulation of a,b-unsaturated acylazoliums with 1,3-bisnu-
cleophiles, leading to the formation of dihydropyranone or
dihydropyridinone derivatives (Scheme 1, eqn (a)). To the best
of our knowledge, the analogous [3 + 2] cycloaddition with 1,2-
bisnucleophiles to synthesize ve-membered heterocycles has
not been reported (Scheme 1, eqn (b)).
N-Heterocyclic carbene (NHC) catalysis, an elegant organo-
catalytic method for forming new bonds, is used broadly in
organic synthesis.1 A number of NHC catalytic multicomponent
cascade reactions have been developed, but most rely on a
single catalyst, to perform continuous operations.2
Combining two catalytic bond-forming tactics into a single
cascade reaction can offer unique synthetic opportunities, as it
can allow unprecedented transformations that would be
impossible in the presence of either catalyst on its own. NHC
catalysis has been successfully integrated with transition metal
catalysis,3 Lewis acid catalysis4 or aminocatalysis.5 These
combinations have opened up synthetic possibilities, but they
are severely limited by self-quenching between NHCs and
transition metals/Lewis acids and by mutual interference
between NHCs and the acidic additive in aminocatalytic
systems. Over the past decade, NHC-mediated HOMO/LUMO
activation of carbonyl compounds at the ipso-, a-, b- or g-posi-
tion has become well established; these carbonyl compounds
include aldehydes, ketones and esters, as well as their a,b
As part of our ongoing investigations aimed at assembling
multiple substrates into synthetically important cyclic mole-
cules,15 we envisaged a two-step organocatalytic relay cascade,
beginning with NHC-catalyzed benzoin condensation,16 as a
way to synthesize functionalized g-lactones (Scheme 2).
Condensation of aldehyde 1 generates an a-hydroxyketone
aMinistry of Education Key Laboratory of Standardization of Chinese Medicine, School
of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137,
P. R. China. E-mail: huangwei@cdutcm.edu.cn; Fax: +86 28 61800234
bState Key Laboratory Breeding Base of Systematic Research, Development and
Utilization of Chinese Medicine Resources, Chengdu University of Traditional
Chinese Medicine, Chengdu 611137, P. R. China. E-mail: pengcheng@cdutcm.edu.
cn; Fax: +86 28 61800231
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for new compounds. CCDC 958885. For ESI and
crystallographic data in CIF or other electronic formats see: DOI:
10.1039/c5ra01254f
Scheme
a,b-unsaturated acylazoliums.
1 Annulation based on NHC-catalyzed generation of
‡ These authors contributed equally to this work.
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Table 1 Optimization of reaction conditionsa
Scheme 2 Combination of two NHC catalytic cycles to construct
g-lactone bearing a quaternary carbon center.
intermediate 2, which then serves as the 1,2-bisnucleophile in
the second NHC catalytic cycle. Subsequent [3 + 2] cyclization
between the NHC-generated a,b-unsaturated acylazolium with
a-hydroxyketone affords the desired g-lactone 4. This approach,
if successful, would provide an alternative method for preparing
pharmacologically interesting g-lactones or dihydrofur-
anones,17 and it would broaden the applications of sequential
dual catalysis.18
At the very rst beginning, we wondered whether
NHC-catalyzed [3 + 2] annulation of a,b-unsaturated acylazo-
liums with 1,2-bisnucleophiles could work. So we investigated
the reaction of benzoin 2a and a-bromo cinnamaldehyde 3a in
the presence of NHC precursor with cesium carbonate. Fortu-
nately, we were able to isolate the desired 4a product in
moderate yield (Scheme 3). Since NHCs are known to catalyze
benzoin condensation, we also wondered whether benzoin 2a
could be generated in situ. If successful, two sequential NHC
catalytic systems could be combined.
To probe the feasibility of the proposed two-step cascade
process, the preliminary experiment was carried out with pre-
catalyst Ia and benzaldehyde 1a to afford benzoin 2a in situ,
aer which precatalyst IIa and a-bromocinnamic aldehyde 3a
were added in the reaction mixture. To our delight, by per-
forming the reaction in dichloromethane with Cs2CO3, we were
able to isolate the desired product with good diaster-
eoselectivity, albeit in moderate yield (Table 1, entry 1).
Screening various catalyst combinations (entries 1–5) showed Id
and IIa to be the most promising catalyst pair for the reaction
(entry 4). Different bases led to different yields, with DBU giving
the best results (entries 6–10). Replacing dichloromethane with
other solvents did not improve yield or diastereoselectivity
(entries 10–13). We wondered whether one NHC catalyst could
be used in both catalytic cycles. Performing the cascade reaction
in the absence of precatalyst Id furnished only a trace amount of
the desired product (entry 14), as did the reaction with only
precatalyst Id (entry 15). At the same time, a-hydroxyketone 2a
Entry
Cat. I
Cat. II
Base
Solvent
Yieldb (%)
drc
1
2
3
4
5
6
7
8
Ia
Ib
Ic
IIa
IIa
IIa
IIa
IIb
IIa
IIa
IIa
IIa
IIa
IIa
IIa
IIa
IIa
Id
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
tBuOK
TEA
DABCO
DBU
DBU
DBU
DBU
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
MeCN
41
37
49
59
52
59
54
39
46
64
48
59
34
<10
<10
85 : 15
80 : 20
85 : 15
88 : 12
88 : 12
86 : 14
78 : 22
85 : 15
82 : 18
90 : 10
85 : 15
86 : 14
80 : 20
n.d.
Id
Id
Id
Id
Id
Id
Id
Id
Id
Id
IIa
Id
9
10
11
12
13
14
15
THF
CH2Cl2
CH2Cl2
DBU
DBU
n.d.
a
Unless otherwise noted, reactions were performed with precatalyst I
(0.1 mmol), base (0.3 mmol) and 1a (1.6 mmol) in solvent (2 mL) at
50 ꢀC for a specied reaction time until the sufficient benzoin 2a was
generated (monitored by TLC), aer which precatalyst II (0.1 mmol)
b
and 3a (0.4 mmol) were added. Isolated yield of pure diastereomer
c
4a. Based on 1H NMR analysis of the crude reaction mixture. Mes ¼
2,4,6-(CH3)3C6H2; Ar ¼ 2,6-(CH3CHCH3)2C6H3.
was detected by 1H NMR and HRMS of the crude reaction
mixture (entry 15). These results suggest that different NHC
catalysts are required in the two catalytic systems.
With the optimal reaction conditions in hand, we explored
the substrate scope of the procedure (Table 2). Annulation of
a-bromo cinnamaldehyde 3a proceeded smoothly with a variety
of aldehydes 1 to give moderate to high yield with good dia-
stereoselectivity (entries 1–10). Most substituted aromatic
aldehydes 1 bearing electron-withdrawing groups led to higher
yield than those possessing electron-donating groups, and dr
values for products varied in the trend ortho > meta and para.
This implies that the substitution pattern on the phenyl rings
affects the reaction to some extent. Heteroaryl aldehydes
participated efficiently, giving even higher yields than aryl
aldehydes but with slightly lower dr values (entries 9 and 10).
We also evaluated the use of aliphatic aldehydes (such as
octanal and 3-phenylpropanal) in the optimal reaction condi-
tions, but no [3 + 2] annulation products were obtained.19 To
extend the scope of the reaction further, we explored other
Scheme
3 NHC-catalyzed [3 + 2] annulation of benzoin and
2-bromoenal.
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Table 2 Scope of the cascade reactiona
Entry R1
R2
Product Yieldb (%) drc
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
64
65
68
65
70
65
70
54
72
71
60
61
66
57
61
68
63
54
50
35
90 : 10
95 : 5
88 : 15
92 : 8
85 : 15
87 : 13
92 : 8
86 : 14
80 : 20
75 : 25
92 : 8
86 : 14
85 : 15
90 : 10
85 : 15
82 : 18
84 : 16
80 : 20
87 : 13
80 : 20
2-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
4-FC6H4
2,4-Cl2C6H3 Ph
4-i-PrC6H4
2-Furyl
2-Thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
Scheme 5 Two possible pathways for [3 + 2] annulation mediated by
a,b-unsaturated acylazolium.
10
11
12
13
14
15
16
17
18
19
20
2-ClC6H4
4-ClC6H4
4-BrC6H4
2-FC6H4
3-FC6H4
4-FC6H4
4-NO2C6H4
4-MeC6H4
of the other dihydrofuranones were tentatively assigned by
analogy.
We also performed experiments on the asymmetric version
of this [3 + 2] annulation (Scheme 4). We envisioned that
treatment of benzoin 2a and 2-bromoenal 3a in the presence of
chiral triazolium salts IIc and IId, which has proven effective in
many asymmetric [3 + 3] cycloadditions involving activation of
a,b-unsaturated acylazolium, might furnish the desired chiral
product. Unfortunately, numerous attempts were unsuccessful,
with only the a,b-unsaturated ester product 5a obtained in
nearly quantitative yield. This linear product presumably
formed via direct intermolecular O-acylation of the benzoin to
the chiral a,b-unsaturated acylazolium intermediate (Scheme
4). Notably, the nal product 5a was a racemic mixture, sug-
gesting no kinetic or dynamic kinetic resolution during the
conversion.
Based on these results, we were puzzled by what the reaction
mechanism might be. We reasoned that the g-butyrolactone
might form either by tandem 1,4-addition followed by intra-
molecular acylation (Scheme 5, path A) or by tandem intermo-
lecular acylation followed by 2,3-wittig rearrangement-acylation
(Scheme 4, path B). Importantly, the product 5a (generated in
Scheme 4) did not undergo cyclization under various alkaline
conditions,21 suggesting that pathway A is more reasonable to
describe this a,b-unsaturated acylazolium-mediated [3 + 2]
annulation.
2-OCH3C6H4 4s
2-Furyl 4t
Ph
a
b
See entry 13 and footnote a in Table 1. Isolated yield of pure
diastereomer 4. Based on 1H NMR analysis of the crude reaction
mixture.
c
2-bromoenals 3. The position and electronic properties of
substituents on the aromatic ring of aryl-substituted 2-bro-
moenals did not signicantly affect reaction efficiency (entries
11–19). The transformation was rather sluggish in the case of
2-bromo-3-furanylacrylaldehyde, and the corresponding
g-butyrolactone was afforded in only 35% yield aer prolonged
reaction time (entry 20). The relative conguration of 4a was
determined by X-ray crystallographic analysis.20 Congurations
Conclusions
In summary, we have developed a exible and simple organo-
catalytic cascade reaction involving two sequential NHC cata-
lytic cycles, and we have used it to assemble a functionalized
g-lactone (or dihydrofuranone) scaffold bearing a quaternary
carbon center. Starting from aromatic aldehydes and 2-hal-
oenals, we obtained the desired products in moderate to good
yield with high diastereoselectivity. The present work is the rst
Scheme 4 Studies on the enantioselectivity of the annulation process. report of NHC-catalyzed [3 + 2] annulation of a,b-unsaturated
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acylazoliums with 1,2-bisnucleophiles. Studies are under way in
our laboratory to clarify the detailed reaction mechanism and
explore whether this method can be applied to asymmetric
domino reactions.
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Acknowledgements
We are grateful for nancial support from the National Natural
Science Foundation of China (21302016 and 81303208), the
Science
& Technology Department of Sichuan Province
(2014JQ0020) and the Foundation for the Author of National
Excellent Doctoral Dissertation of PR China.
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