Enantioselective [4+2] cycloaddition of ketenes and 1-azadienes catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1039/c0cc04839a

Optically active highly functionalized 3,4-dihydropyridin-2-ones were synthesized by N-heterocyclic carbene-catalyzed [4+2] enantioselective cycloaddition of ketenes and 1-azadienes.

Full text of DOI:10.1039/c0cc04839a

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COMMUNICATION
Enantioselective [4+2] cycloaddition of ketenes and 1-azadienes
catalyzed by N-heterocyclic carbenesw
Teng-Yue Jian, Pan-Lin Shao and Song Ye*
Received 7th November 2010, Accepted 29th November 2010
DOI: 10.1039/c0cc04839a
Optically active highly functionalized 3,4-dihydropyridin-2-ones
were synthesized by N-heterocyclic carbene-catalyzed [4+2]
enantioselective cycloaddition of ketenes and 1-azadienes.
dihydropyridinone 3aa in 67% yield with 4 : 1 diastereoselectivity
and 71% ee (Scheme 1). It is interesting that the diastereo-
selectivity was improved dramatically (trans : cis > 20 : 1)
albeit with some loss of enantioselectivity when DME was
used as the solvent. The better solubility of Cs2CO3 in DME
may facilitate the epimerization of the cis-3aa to trans-3aa.
Thus, DME was added after the completion of the reaction
in toluene, giving the cycloadduct 3aa as nearly pure trans-
isomer without erosion of enantioselectivity.
The hetero-Diels–Alder (HDA) reaction is one of the most
powerful methods for the construction of six-membered hetero-
cycles, which are widely presented in many natural and unnatural
bioactive compounds.1 In 1989, Boger et al. successfully
employed N-sulfonyl 1-azadienes for the HDA reaction with
vinyl ethers.2 Several decades later, the HDA reaction of
1-azadienes has been developed as an efficient approach to a
wide variety of N-heterocycles.3 However, the catalytic enantio-
selective HDA reactions of 1-azadienes are very limited so far.
In 2006, Bode et al. reported an enantioselective HDA
reaction of 1-azadienes, in which the enolates, generated
in situ from enals and the nucleophilic catalyst of
N-heterocyclic carbenes, acted as the dienophile for the DA
A series of NHC precursors were then tested for the model
reaction (Table 1). The NHC precursors 4a–f, derived from
L-pyroglutamic acid,9,14 were first tested. The NHCs 4a0 and
4b0 with either TBS or TMS group gave similar results (entries
1 and 2). NHC 4c0 with N-4-methoxylphenyl group gave the
best yield and selectivity, while NHC 4d0 with N-2-isopropyl-
phenyl group is inferior to NHC 4c0 (entries 4 and 5). The
NHCs 4e0 and 4f0 with a free hydroxy group showed decreased
or reversed enantioselectivity (entries 6 and 7).9c The Rovis’
tetracyclic NHCs 5a0 and 5b0 derived from aminoindanol
and You’s bis-NHC 60 also worked in the reaction
(entries 8–10).15,16
reaction.4 In 2007 Arraya
´
s and Carretero et al. developed the
enantioselective HDA reaction of 1-azadienes with vinyl ethers
catalyzed by a nickel complex with chiral ligand.5 In 2008,
Chen et al. successfully applied the aminocatalysis to the HDA
reactions of 1-azadienes with aldehydes.6
It is surprising that better yields and enantioselectivities
were observed when excess Cs2CO3 was used, which may be
due to the facilitation of the formation of the NHCs (entries 11
and 12). Further optimization of solvents showed that benzene
is the best choice, in which high yield and 91% ee were
achieved (entries 13–18).
During the past decades, N-heterocyclic carbenes (NHCs)
were found to be efficient catalysts for a wide variety of
reactions.7,8 In 2008, We and Smith et al. independently
reported a series of NHC-catalyzed cycloaddition of ketenes,
involving the enolates generated by the addition of NHC to
ketenes.9,10 Latterly, we reported an NHC-catalyzed enantio-
selective [4+2] cycloaddition of ketenes and oxodienes.11 We
conjecture that the enolate generated in situ from the ketene
may be able to react with 1-azadienes in a inverse-electron-
demand DA mode to afford 3,4-dihydropyridin-2-ones.12,13
Initially, we found that NHC 4a0, generated freshly from its
precursor 4a in the presence of Cs2CO3, could catalyze
the cycloaddition reaction of phenyl ethyl ketene 1a and
1-azadiene 2a in toluene to give the corresponding
A variety of ketenes were then tested for the NHC-catalyzed
reaction with 1-azadiene 2a (Table 2). Aryl(alkyl)ketenes
1b–1e with either electron-withdrawing group (Ar1 = 4-ClC6H4,
4-BrC6H4) or electron-donating group (Ar1 = 4-MeC6H4,
4-MeOC6H4) worked well to give the cycloadducts 3 in good
Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190,
China. E-mail: songye@iccas.ac.cn; Fax: (+86)10 6255 4449;
Tel: (+86)10 6264 1156
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterizations. CCDC 799082. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc04839a
Scheme 1
c
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Chem. Commun., 2011, 47, 2381–2383 2381

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Table 1 Screening of NHCs and optimization of reaction conditions
The scope of 1-azadienes was also briefly explored (Table 3).
Both azadienes with an electron-withdrawing group
(2b, Ar2 = 4-ClC6H4) and with an electron-donating group
(2c, Ar2 = 4-MeOC6H4) reacted smoothly (entries 1 and 2).
Azadiene 2d with b-naphthyl group and azadiene 2e with
2-furyl group also worked well (entries 3 and 4). N-Phenyl-
sulfonyl azadiene 2f showed similar reactivity with N-tosylate
azadiene 2a (entry 5). It is interesting that when the
ethoxycarbonyl group moved from 4- to 3-position in the
1-azadienes, the tetracyclic NHC 5b0 catalyzed reaction of
3-ethoxycarbonyl-1-azadienes (2g and 2h) gave the cyclo-
adducts in good yields but with very low enantioselectivities,
while the corresponding reaction catalyzed by bicyclic NHC
Entry 4–6 (mol%) Cs2CO3 (mol%) Solvent Yielda (%) eeb,c (%)
1
2
3
4
5
6
8
9
10
11
12
13
14
15
16
17
18
4a (20)
4b (20)
4c (20)
4d (20)
4e (20)
4f (20)
5a (20)
5b (20)
6 (20)
4a (20)
5a (20)
5a (20)
5a (20)
5a (20)
5a (20)
5a (20)
5a (20)
20
20
20
20
20
20
20
20
20
40
40
40
40
40
40
40
40
Toluene 68
Toluene 69
Toluene 71
Toluene 59
Toluene 30
Toluene 37
Toluene 15
Toluene 38
Toluene 47
Toluene 72
Toluene 73
71
72
74
60
Table 3 Variation of 1-azadienes
Entry
2
3
Yielda (%) ee (%)b
37
ꢀ67
ꢀ60
ꢀ45
57
1
81
87
88
86
75
ꢀ86
ꢀ72
ꢀ46
—
ꢀ66
ꢀ72
ꢀ91
THF
DME
Et2O
DCM
47
37
Trace
61
2
Xylene 55
Benzene 87
a
Isolated yield of the pure trans-isomer, and trans : cis > 20 : 1 for all
c
b
the entries. Determined by chiral HPLC. The minus ee value
indicates a reversed enantioselectivity. DME = 1,2-dimethoxylethane.
3
4
82
88
91
83
Table 2 Variation of ketenes
Entry
1 (Ar1, R1)
3
Yielda (%)
ee (%)b
1
2
3
4
5
6
7
8
9
1a Ph, Et
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
87
88
87
84
87
78
Trace
87
81
91
91
92
90
83
93
/
5
6
81
87
1b 4-ClC6H4, Et
1c 4-BrC6H4, Et
1d 4-MeC6H4, Et
1e 4-MeOC6H4, Et
1f 3-ClC6H4, Et
1g 2-ClC6H4, Et
1h Ph, n-Pr
71 (72)c
61 (58)c
7(ꢀ68)c
3(ꢀ52)c
87
93
1i Ph, n-Bu
a
b
Isolated yield of pure trans-isomer. Determined by chiral HPLC.
7
yields with high enantioselectivities (entries 2–5). Ketene 1f
with 3-chlorophenyl also worked well, while ketene 1g with
2-chlorophenyl failed (entries 6 and 7). The reaction of ketenes
with other alkyl groups (R = n-Pr, n-Bu) afforded the
cycloadducts in high yields with high enantioselectivities
(entries 8 and 9).
a
b
Isolated yields of pure trans-isomer. Determined by chiral HPLC.
The result of reactions catalyzed by NHC 4b0 is shown in
parenthesis.
c
c
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2382 Chem. Commun., 2011, 47, 2381–2383

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Fig. 1 X-Ray crystal structure of dihydropyridinone 3ad.
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Fig. 2 Possible catalytic cycle.
4b0 afforded much better enantioselectivities for these two
3-substituted-1-azadienes (entries 6 and 7).
The structure of dihydropyridinone 3ad was unambiguously
established by X-ray crystallographic analysis (Fig. 1) (ESIw).
One possible catalytic cycle of the NHC-catalyzed cyclo-
addition of ketenes and 1-azadienes is shown in Fig. 2. The
nucleophilic addition of NHC to ketenes gives enolate A,
which reacts with 1-azadienes 2 in an inverse-electron-demand
Diels–Alder reaction mode to afford the adduct B. The
fragmentation of adduct B gives the final dihydropyridinone
3 and regenerates the NHC catalyst.
Org. Biomol. Chem., 2008, 6, 1108; (b) C. Concellon, N. Duguet
´
In conclusion, the enantioselective synthesis of highly
substituted 3,4-dihydropyridin-2-ones was realized by the
chiral N-heterocyclic carbene-catalyzed cycloaddition of
ketenes and 1-azadienes. To the best of our knowledge, this
is the first example of the catalytic enantioselective [4+2]
cycloaddition reaction of ketenes and 1-azadienes. The highly
functionalized 3,4-dihydropyridin-2-ones may find potential
usage in organic synthesis.
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Financial support from National Natural Science
Foundation of China (No. 20872143, 20932008), the Ministry
of Science and Technology of China (2009ZX-5909501-018),
and the Chinese Academy of Sciences is gratefully
acknowledged.
Notes and references
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2381–2383 2383