N-heterocyclic carbene-catalyzed reaction of alkynyl aldehydes with 1,3-keto esters or 1,3-diketones

Article abstract of DOI:10.1002/adsc.201000240

The N-heterocyclic carbene-catalyzed reaction of alkynyl aldehydes with 1,3-keto esters or 1,3-diketones has been studied. This protocol offers an entirely new, mild and atom-economical access to highly functionalized 3,4-dihydropyranones.

Full text of DOI:10.1002/adsc.201000240

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DOI: 10.1002/adsc.201000240
N-Heterocyclic Carbene-Catalyzed Reaction of Alkynyl
Aldehydes with 1,3-Keto Esters or 1,3-Diketones
Zhi-Qiang Zhua and Ji-Chang Xiaoa,*
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86) 21-6416-128; e-mail: jchxiao@mail.sioc.ac.cn
Received: March 27, 2010; Revised: June 27, 2010; Published online: September 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000240.
Abstract: The N-heterocyclic carbene-catalyzed re-
action of alkynyl aldehydes with 1,3-keto esters or
1,3-diketones has been studied. This protocol offers
an entirely new, mild and atom-economical access
to highly functionalized 3,4-dihydropyranones.
Our explorations commenced with the reaction of
3-phenylpropiolaldehyde with ethyl 3-oxobutanoate
in the presence of carbene precursors A–E (Table 1).
The thiazolium salt A proved unsuitable for this reac-
tion (entry 1), making the reaction system very com-
plicated. To our delight, with imidazolium salt B1
(IMes·HCl) and t-BuOK in THF, 3,4-dihydropyra-
none[10] 3a was isolated in 65% yield (entry 2), and its
structure was confirmed by spectroscopic and X-ray
analysis (Figure 1).[11] A similar result was obtained in
the case of NHC precursor B2 (entry 3). In compari-
son, imidazolinium salts C1 and C2 as well as triazoli-
Keywords: aldehydes; dihydropyranones; N-hetero-
cyclic carbenes; organocatalysis; umpolung
N-Heterocyclic carbene (NHC)-catalyzed umpolung um salts D and E are less active for this reaction (en-
reactions have attracted considerable attention due to tries 4–7). Further investigation on catalyst loading,
their wide applications in organic synthesis.[1] The base and solvent (entries 8–15) revealed the optimal
Breslow intermediates[2] generated from aldehydes in reaction conditions: 10 mol% of B1 and 10 mol% of
situ can react with a variety of electrophiles, such as t-BuOK in THF at ambient temperature for 2 h
aldehydes,[3] ketones,[4] imines,[5] diazenes,[6] activated (entry 8).
and even unactivated C=C double bonds.[7] Among
After the optimal conditions had been established,
the numerous aldehydes, much attention has been the generality of the reaction was explored (Table 2).
paid to a,b-unsaturated aldehydes especially the a,b- It was demonstrated that the reaction is able to ac-
unsaturated enals over the past few years. However, commodate a variety of substituted alkynyl aldehydes.
there were extremely few reports on the reaction in- The electronic nature of the substituents on the aro-
volving a,b-unsaturated ynals, namely alkynyl alde- matic ring of the aldehydes has limited influence on
hydes,[8] which also possess a rich reactivity pattern.[9] the reaction (entries 1–7). Moreover, the reaction pro-
Recently, Zeitler has achieved for the first time an ceeded smoothly in the case of 3-cyclohexenylpropio-
NHC-catalyzed redox esterification of alkynyl alde- laldehyde, an aliphatic-substituted alkynyl aldehyde,
hydes. It was proposed that, similar to cinnamalde- which also indicated that the existence of a conjugat-
hyde and its derivatives, protonation of the Breslow ed double bond has no effect on the reaction
intermediates generated from alkynyl aldehydes (entry 8). The reaction works equally well for other
would also give activated carboxylates, which subse- 1,3-keto esters like methyl 3-oxobutanoate and ethyl
quently regenerate the NHC catalyst upon acylation 3-oxopentanoate (entries 9 and 10). As for 1,3-dike-
of oxygen nucleophiles.[8a]
tones, the corresponding 3,4-dihydropyranones 3k and
À
Making C C bonds is a fundamental method in 3l were obtained in good yields (entries 11 and 12).
synthetic organic chemistry that is often used to con- The structure of 3l was determined by NOE experi-
struct complicated molecules. The development of ef- ments (see Supporting Information). It is worth
À
ficient methods for C C bond formation prompted us noting that the reaction of the unsymmetrical 1,3-di-
to investigate the NHC-catalyzed reaction of alkynyl ketone 1-phenylbutane-1,3-dione was highly selective,
aldehydes with carbon nucleophiles.
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Zhi-Qiang Zhu and Ji-Chang Xiao
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Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst (mol%) Solvent
Base
Yield[b] [%]
–
Figure 1. Single crystal X-ray structure of 3a.
1
2
3
4
5
6
7
8
A (20)
B1 (20)
B2 (20)
C1 (20)
C2 (20)
D (20)
E (20)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
t-BuOK
t-BuOK 65
t-BuOK 63
t-BuOK 45
t-BuOK 48
t-BuOK 14
t-BuOK 15
t-BuOK 72
t-BuOK 38
t-BuOK 69
Table 2. Substrate scope.[a]
B1 (10)
B1 (5)
9
10
11
12
13
14
15
B1 (15)
B1 (10)
B1 (10)
B1 (10)
B1 (10)
B1 (10)
Entry
R
R1, R2
Product Yield[b] [%]
NaH
DBU
Et3N
57
32
42
1
2
3
4
5
6
7
8
Ph
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
3a
3b
3c
3d
3e
3f
3g
3h
72
54
69
58
41
56
71
75
74
70
65
66
4-MeO-C6H4
4-Me-C6H4
4-F-C6H4
4-Br-C6H4
1-naphthyl
2-thienyl
Toluene t-BuOK 31
Dioxane t-BuOK 57
[a]
Performed on a 0.5 mmol scale at 0.25M with 1 equiv. of
3-phenylpropiolaldehyde, 1.2 equiv. of ethyl 3-oxobuta-
noate, the indicated amounts of catalyst, and equal
amounts (to catalyst) of base at room temperature for
2 h.
1-cyclohexenyl Me, OEt
9
Ph
Ph
Ph
Ph
Me, OMe 3i
[b]
10
11
12
Et, OEt
Me, Me
Me, Ph
3j
3k
3l
Isolated yield after chromatography.
[a]
giving the corresponding 3,4-dihydropyranone 3l as
the only product (Figure 2).
Performed on a 0.5 mmol scale at 0.25M with 1 equiv. of
alkynyl aldehyde, 1.2 equiv. of 1,3-keto ester or 1,3-dike-
tone, 10 mol% B1, and 10 mol% t-BuOK in THF at
room temperature for 2 h.
Lupton and co-workers have recently reported a
conjugate addition reaction involving enolate anions
and a,b-unsaturated acyl azoliums.[10d] Inspired by
this, we postulated that the above reaction may pro-
ceed along the following lines. As might be expected,
the NHC reacted with the alkynyl aldehyde to furnish
the Breslow intermediate I. The subsequent protona-
tion of II with the more acidic (compared with alco-
hol) H-donor, 1,3-keto ester or 1,3-diketone, afforded
the enolate anion III and activated carboxylate IV,
which subsequently underwent conjugate addition, H-
migration and acylation to deliver the product 3,4-di-
[b]
Isolated yield after chromatography.
hydropyranone
(Scheme 1).
3
and regenerated the NHC
Figure 2. Proof of the structure by NOE experiments.
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Adv. Synth. Catal. 2010, 352, 2455 – 2458

N-Heterocyclic Carbene-Catalyzed Reaction of Alkynyl Aldehydes with 1,3-Keto Esters
Acknowledgements
We thank the Chinese Academy of Sciences (Hundreds of
Talents Program) and the National Natural Science Founda-
tion (20772147, 20972179) for financial support.
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Scheme 1. Proposed reaction mechanism.
In conclusion, an NHC-catalyzed reaction of alkyn-
yl aldehydes with 1,3-keto esters or 1,3-diketones was
disclosed, which might become an efficient method
for the direct synthesis of highly functionalized 3,4-di-
hydropyranones from simple substrates. The ready
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of Alkynyl Aldehydes and 1,3-Keto Esters or 1,3-
Diketones
Into an oven-dried 10-mL vial were weighed catalyst B1
(17 mg, 0.05 mmol) and t-BuOK (6 mg, 0.05 mmol). THF
(1 mL) was added to the mixture. The resulting mixture was
stirred at room temperature under N2 for 10 min followed
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a solution of alkynyl aldehyde
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