N-heterocyclic carbene catalyzed reactions of α-bromo-α,β- unsaturated aldehydes/α,β-dibromoaldehydes with 1,3-dinucleophilic reagents

Article abstract of DOI:10.1002/chem.201103358

Carbenes ring true: N-Heterocyclic carbene (NHC) catalyzed reactions of α-bromo-α,β-unsaturated aldehydes/α,β- dibromoaldehydes with 1,3-dinucleophilic reagents, such as 1,3-dicarbonyl compounds, β-enamino ketones, and β-enamino esters through umpolung processes gave functionalized 3,4-dihydropyranones and 3,4-dihydropyridinones (see scheme). The availability of the starting materials, lack of external oxidant, and usefulness of the products make this strategy attractive.

Full text of DOI:10.1002/chem.201103358

DOI: 10.1002/chem.201103358
N-Heterocyclic Carbene Catalyzed Reactions of a-Bromo-a,b-unsaturated
Aldehydes/a,b-Dibromoaldehydes with 1,3-Dinucleophilic Reagents
Changsheng Yao,*[a] Donglin Wang,[b] Jun Lu,[b] Tuanjie Li,[b] Weihui Jiao,[b] and
Chenxia Yu[b]
Over the past few years, N-heterocyclic carbene (NHC)-
catalyzed umpolung reactions have drawn considerable at-
tention from organic chemists due to their wide variety of
applications in organic synthesis.[1] The classical umpolung
reactions of aldehydes catalyzed by NHCs are the benzoi-
n[1a,c,2] and Stetter reactions.[1a,c,3] Recent reports have re-
vealed that NHCs could catalyze various redox-type trans-
formations of functionalized aldehydes bearing reducible
Firstly, a-bromocinnamic aldehyde (5a) and acetylacetone
(2a) were used as model substrates to investigate the car-
bene catalyst precursors 8A–8E (Table 1). Of these precata-
lysts, 8A, 8D, and 8E were the less reactive compounds for
functionalities.[1a,c,4] The Michael reaction is a prominent
[5]
way to construct C C bonds. Acylazolium ions A,[6] for
ꢀ
use as Michael acceptors to conduct 1,4-addition reactions
(or 1,2-addition reactions followed by Claisen rearrange-
ments), can be obtained through oxidation or from a,b-un-
saturated acid fluorides (Scheme 1).[6a,7] The NHC-catalyzed
reactions of alkynyl aldehydes through intermediates of
type A have also been documented (Scheme 2).[8] Since
redox reactions catalyzed by NHCs provide an unconven-
tional route to designed target molecules, more and more
effort has recently been devoted to this area. Asymmetric
NHCs have also been successfully applied to the redox reac-
tion of 2-enal through acylazolium ion A as the Michael ac-
ceptor to conduct 1,4-addition reactions.[9,10] Inspired by this,
we envisioned that Breslow intermediates B, generated by
the reaction of 2-bromo-2-enal and an NHC, would readily
give intermediates A through a3!d3 umpolung and debro-
mination. This compound should then react with dinucleo-
philes without the need for external oxidants (Scheme 3).
Herein, we report our preliminary results on the NHC-cata-
lyzed reaction of 2-bromo-2-enal with dinucleophiles, such
as 1,3-dicarbonyl compounds (b-keto enols), b-enamino ke-
tones, and b-enamino esters (Scheme 4).
Scheme 1. The generation of acylazolium ions by oxidation or from a,b-
unsaturated acid fluorides (TMS=trimethylsilyl).
Scheme 2. The generation of acylazolium ions from alkynyl aldehydes.
[a] Prof. Dr. C. Yao
School of Chemistry and Engineering
Key Laboratory of Biotechnology for Medicinal Plants
Xuzhou Normal University, Xuzhou, Jiangsu 221116 (P.R. China)
Fax : (+86)516-83500365
E-mail: csyao@xznu.edu.cn
[b] D. Wang, J. Lu, Prof. Dr. T. Li, W. Jiao, Prof. C. Yu
School of Chemistry and Engineering
Jiangsu Key Laboratory of Green Synthetic Chemistry for
Functional Materials, Xuzhou Normal University
Xuzhou Jiangsu 221116 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103358.
Scheme 3. An envisioned pathway for generating acylazolium ions from
2-bromo-2-enal.
1914
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Chem. Eur. J. 2012, 18, 1914 – 1917

COMMUNICATION
Table 2. Substrate scope.
Entry
R1
R2
R3
R4
Product
Yield
[%][a]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Ph
Me
3a
3b
3c
3d
3e
3 f
3g
3h
3i
94
92
93
90
93
91
88
84
88
90
83
76
OEt
OMe
Ph
Scheme 4. The reactions presented in this work.
Table 1. Optimization of the reaction conditions.[a]
Ph
Ph
OEt
OEt
OMe
Me
Me
Me
3-Br-4-MeOPh
3-Br-4-MeOPh
2-NO2Ph
4-MeOPh
Me
Me
Me
Me
Me
Me
Me
10
11
12
3j
3k
3l
Me
Me
[a] Isolated yield.
(2d) was employed, product 3d was obtained regiospecifi-
cally. The reaction also worked well for 1,3-keto esters, such
as methyl 3-oxobutanoate (2c).
Entry
Precatalyst
([mol%])
Solvent
Base
([mol%])
T
[8C]
t
Yield
[%][b]
G
G
[h]
Furthermore, the results also indicated that both electron-
donating (such as the methoxyl group, Table 2, entry 10) and
electron-withdrawing groups (such as the nitro group,
Table 2, entry 9) on compounds 5 were well tolerated in this
protocol. More importantly, an a-bromo-b-disubstituted 2-
enal could also participate in the reaction and gave the de-
sired product 3l efficiently, which highlights the fact that
our strategy can be used to construct quaternary carbon cen-
ters (Table 2, entry 12).
To further explore the versatility of this protocol, other di-
nucleophiles, such as a b-enamino ketone and a b-enamino
ester were used instead of the 1,3-dicarbonyl compounds.
These reactions provided the desired dihydropyridine deriv-
atives smoothly at 708C (Scheme 5).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
8A (20)
8B (20)
8C (20)
8D (20)
8E (20)
8B (20)
8B (20)
8B (20)
8B (20)
8B (20)
8B (5)
8B (10)
8B (15)
8B (10)
8B (10)
8B (10)
8B (10)
8B (10)
8B (10)
THF
THF
THF
THF
tBuOK (150)
tBuOK (150)
tBuOK (150)
tBuOK (150)
tBuOK (150)
tBuOK (150)
tBuOK (150)
tBuOK (150)
DBU (150)
Cs2CO3 (150)
Cs2CO3 (150)
Cs2CO3 (150)
Cs2CO3 (150)
Cs2CO3 (110)
Cs2CO3 (120)
Cs2CO3 (130)
Cs2CO3 (120)
Cs2CO3 (120)
Cs2CO3 (120)
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
15
20
30
10
3
3
10
10
3
3
3
3.5
2.5
3.5
2.5
2.5
2.5
2.5
2.5
4.5
3.5
2.5
n.r.
72
68
n.r.
n.r.
26
18
83
72
90
80
94
92
91
94
94
86
88
90
THF
CH2Cl2
CHCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Inspired by reports concerning the reaction of a-chloroal-
dehydes and a-dichloroaldehydes catalyzed by NHCs, we
utilized a,b-dibromoaldehydes in place of the 2-bromo-2-
[a] Mes=2,4,6-(CH3)3C6H2; Ar’=2,6-(CH3CHCH3)2C6H3; Bn=benzyl;
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene. [b] Isolated yield; n.r.=no re-
action.
ACHTUNGTRENNUNG
this reaction. With precatalyst 8B (20 mol%) and tBuOK
(150 mol%) in THF, product 3a was formed in a slightly
higher yield than with 8C. Thus, in the presence of 8B
(20 mol%), solvent and base screening was performed and
showed that toluene and Cs2CO3 were preferable. The sub-
sequent optimization study showed that the reaction pro-
ceeded better at 258C in the presence of 10 mol% 8B and
120 mol% Cs2CO3.
To expand the scope of this NHC-catalyzed addition reac-
tion, various dinucleophiles were tested (Table 2). The re-
sults revealed that symmetrical 1,3-diketones bearing ali-
phatic and aromatic substituents gave the desired products
3a and 3e in good yields. If an asymmetrical 1,3-diketone
Scheme 5. The use of b-enamino ketones and b-enamino esters as the di-
nucleophiles.
Chem. Eur. J. 2012, 18, 1914 – 1917
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1915

C. Yao et al.
enal in this reaction.[11] The results show that 2-bromo-2-
enals generated in situ by the reaction of a,b-dibromoalde-
hydes and Cs2CO3 efficiently give the final products 3
(Table 3, for details, see the Supporting Information).
through 1,4-addition and intramolecular acylation to deliver
the final dihydropyranone product and regenerate the NHC
catalyst.[6a,7a] However, the 1,2-addition of A and the dinu-
cleophile, followed by a Claisen rearrangement and intramo-
lecular acylation, could also liberate the NHC catalyst and
give the ultimate product.[7b,8b] A detailed mechanistic study
is currently underway in our laboratory.
Table 3. The N-heterocyclic carbene catalyzed reaction of a,b-dibromoal-
dehyde with 1,3-dinucleophiles.
In summary, we have discovered an NHC-catalyzed reac-
tion of 2-bromo-2-enal/a,b-dibromoaldehyde with 1,3-dinu-
cleophilic reagents, such as 1,3-dicarbonyl compounds (b-
keto enols), b-enamino ketones, and b-enamino esters, to
form highly functionalized 3,4-dihydropyranones or 3,4-di-
Entry
Ar
R3
R4
Product
Yield
[%][a]
hydropyridin-2ACTHNUTRGNEUNG(1H)-ones from simple substrates. The ready
availability of the starting materials, avoidance of external
oxidants and the usefulness of the products all make this
strategy quite attractive. More importantly, these studies not
only provide a new method of forming two kinds of highly
functionalized six-membered heterocyclic compound, but
also expand on the applications of NHC-catalyzed reactions.
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
Me
3a
3b
3c
3d
3e
3 f
3g
3h
3i
92
72
81
87
80
79
74
78
83
OEt
OMe
Ph
Ph
Ph
OEt
OEt
OMe
Me
3-Br-4-MeOPh
3-Br-4-MeOPh
2-NO2Ph
Me
Me
Me
Experimental Section
[a] Isolated yield.
Typical procedure for the NHC-catalyzed reaction of 2-bromo-2-enal/
a,b-dibromoaldehyde with 1,3-dinucleophilic reagents: Catalyst 8B
(34 mg) and Cs2CO3 (391 mg or 716 mg for reactions with a,b-dibromoal-
dehydes) were weighed into an oven-dried vial (25 mL) and toluene
(5 mL) was added to the reaction mixture. The resulting mixture was
stirred at room temperature for 5 min. A solution of 2-bromo-2-enal (or
a,b-dibromoaldehyde; 1.0 mmol) and the 1,3-dinucleophilic reagent
(1.0 mmol) in toluene (5 mL) was then added. The mixture was stirred at
room temperature (or, for the b-enamino ketone and b-enamino ester re-
agents as the dinucleophile, at 708C)
The postulated catalytic cycle for this annulation reaction
is shown in Scheme 6. Breslow intermediate B, generated by
the reaction of a-bromocinnamic aldehyde with the NHC, is
transformed into acylazolium ion A through a3!d3 umpo-
lung and debromination. This is followed by reaction of the
dinucleophile, such as a 1,3-dicarbonyl compound, with A
until completion (monitored by TLC).
After removal of the solvent under re-
duced pressure, the crude product was
purified by column chromatography
(silica gel, mixtures of ethyl acetate/
petroleum ether, 1:5 v/v).
Acknowledgements
We are grateful for financial support
from a project funded by the Priority
Academic Program Development of
Jiangsu Higher Education Institutions,
the Major Basic Research Project of
the Natural Science Foundation of the
Jiangsu Higher Education Institutions
(09KJA430003), and the Natural Sci-
ence Foundation of Xuzhou City
(XM09B016).
Keywords: carbenes
·
heterocycles N-heterocyclic
·
carbenes · redox chemistry ·
Scheme 6. A proposed mechanism for these reactions.
umpolung
1916
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N-Heterocyclic Carbene Catalyzed Reactions
COMMUNICATION
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Received: October 25, 2011
Published online: January 19, 2012
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1917