N-heterocyclic carbene-catalyzed enantioselective annulation of bromoenal and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1002/adsc.201100622

Highly enantioselective [3+3]-annulation reactions of bromoenals and 1,3-dicarbonyl compounds are reported. In addition, both enantiomers of the resultant dihydropyranone could be easily obtained by choosing N-heterocyclic carbenes (NHCs) with the same stereocenter but different substituents under the optimized reaction conditions. Copyright

Full text of DOI:10.1002/adsc.201100622

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DOI: 10.1002/adsc.201100622
N-Heterocyclic Carbene-Catalyzed Enantioselective Annulation
of Bromoenal and 1,3-Dicarbonyl Compounds
Fang-Gang Sun,a Li-Hui Sun,a and Song Yea,*
a
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, Peopleꢀs Republic of China
Fax : +86-10-6255-4449; e-mail: songye@iccas.ac.cn
Received: July 5, 2011; Revised: August 4, 2011; Published online: November 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100622.
Abstract: Highly enantioselective [3+3]annulation
reactions of bromoenals and 1,3-dicarbonyl com-
pounds are reported. In addition, both enantiomers
of the resultant dihydropyranone could be easily
obtained by choosing N-heterocyclic carbenes
(NHCs) with the same stereocenter but different
substituents under the optimized reaction condi-
tions.
Keywords: annulation reactions; asymmetric cataly-
sis; bromoenals; dihydropyranones; N-heterocyclic
carbenes
Scheme 1. NHC-catalyzed generation of homoenolate from
enals [reaction (a)], and a,b-unsaturated acylazolium from
enals with leaving group [reaction (b)].
The N-heterocyclic carbene (NHC) catalysis can be ported from a,b-unsaturated acyl fluorides by Lupton
traced back to 1943 when Ugai et al. reported the et al.,[10] from ynals by Bode et al. and Xiao et al.[11]
thiazolium salt-catalyzed benzoin reaction of alde- and from enals with an oxidant by Studer et al.[12] In
hydes, and 1958 when Breslow proposed the mecha- this communication, we wish to report the generation
nism with in situ generated carbene as the active cata- of a,b-unsaturated acylazolium from bromoenal and
lyst.[1,2] In 2002, Bode et al. and Glorius et al. inde- the enantioselective reaction with 1,3-dicarbonyl com-
pendently reported the pioneering NHC-catalyzed re- pounds. During the preparation of this manuscript,
action of enals, involving the homoenolate intermedi- You et al. and Xiao et al. reported the enantioselec-
ate (I) which may work as an analogue of a 1,3-dipole tive reaction of a,b-unsaturated acylazolium generat-
[Scheme 1, reaction (a)].[3] After that, the extended ed in situ from enals and ynals, respectively.[13]
umpolung reactions of a-functionalized aldehydes cat-
Firstly, the reaction of 2-bromocinnamaldehyde
alyzed by NHC have received great attention and (1a) and acetoacetone (2a) catalyzed by achiral NHCs
made tremendous progress. Beside enals,[4] many was investigated (Table 1). We are pleased to find
functionalized aldehydes, including ynals,[5] a-chloro- that the corresponding annulation product 3aa could
ACHTUNGTRENNUNG
aldehydes,[6] aryloxyacetaldehydes,[7] a-ring alde- be obtained in 80% yield in the presence of 10 mol%
hydes,[8] and b-haloenals,[9] have been explored for triazolium salt A and 1.2 equivalents of DIPEA
NHC-catalyzed extended umpolung reaction. (entry 1). The reaction also worked well using
We envision that a,b-unsaturated acylazolium inter- DABCO, Cs2CO3, or K2CO3 as the base (entries 2–4).
mediate (II) could be generated when enals with a Solvent screening revealed THF to be the best choice
leaving group were used, thus reversing the reactivity (entries 4–7). Imidazolium salt B led to better yields
of the 1,3-dipole of homoenolate (I) to a 1,3-biselec- than thiazolium salt C (entry 8 vs. 9).
trophile (II) [Scheme 1, reaction (b)]. Interestingly,
After establishing the feasibility of the reaction cat-
the generation of 1,3-biselectrophile (II) has been re- alyzed by achiral NHCs, the enantioselective reaction
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N-Heterocyclic Carbene-Catalyzed Enantioselective Annulation of Bromoenal and 1,3-Dicarbonyl Compounds
Table 1. Reaction catalyzed by achiral NHCs.
weak base (DBACO and DMAP), a non-nucelophilic
but strong base (DIPEA and K2CO3) resulted in low
enantioselectivities (entries 2, 4–6). The reaction also
worked in toluene or dichloromethane, albeit with de-
creased selectivity (entries 7 and 8). Lowering the
temperature to 08C benefits the enantioselectivity
(À92% ee) (entry 2 vs. 9)
With two optimized reaction conditions A (Cat.
D1, K2CO3,) and conditions B (Cat. D2, DABCO) for
(À)-3 and (+)-3, respectively, in hand, the reaction
scope was briefly investigated (Table 3). Reactions of
the bromoenal with a para-chlorophenyl group (1b)
gave the desired dihydropyranones (À) and (+)-3ba,
respectively, in good yield with high enantioselectivity
(entry 2). The bromoenal with a strong electron-with-
drawing group (1c, R1 =4-NO2C6H4) gave (À)-3ca in
74% yield with 84% ee (conditions A), and (+)-3ca in
82% yield with 87% ee (conditions B) (entry 3). The
bromoenal with a strong electron-donating group (1d,
R1 =4-MeOC6H4) resulted in decreased yield and
enantioselectivity of (À)-3da under conditions A,
while high eanantioselectivity was kept to give
(+)-3da in 76% yield with 92% ee under conditions B
(entry 4). Bromoenals with meta- or ortho- substituted
Entry
Catalyst
Base
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
A
B
DIPEA
DABCO
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
THF
THF
Et2O
toluene
DCM
THF
THF
80
74
79
85
17
52
48
98
49
C
[a]
Isolated yield.
was then investigated (Table 2). A series of chiral aryl groups (R1 =3-Cl-, 2-Cl-, 2-NO2-C6H4) all worked
NHC precursors D, easily prepared from l-pyrogluta- well under conditions A and B to give (À)-3 and
mic acid, was screened. After some optimization, we (+)-3, respectively, in good yield with high enantiose-
are pleased to find that the reaction with 10 mol% of lectivity (entries 5–7). It is noteworthy that bromoenal
pre-NHC D1 gave the desired adduct (À)-3aa in 72% 1h with an alkyl chain (R1 =n-Pr) also gave the de-
yield with 93% ee (entry 1). It is interesting that the sired annulation product with good enantioselectivity
enantioselectivity could be reversed when the proper [72% ee for (À)-3ha, 93% ee for (+)-3ha] albeit with
NHCs and conditions are employed (entry 2). Experi- quite low yields under our current conditions
ments revealed that both the structure of the NHCs (entry 8).
and the property of the base play roles in the reversal
Several 1,3-dicarbonyl compounds were also tested
of the selectivity. NHCs with a free hydroxy group for the reaction (entires 9–12). Alkyl acetoacetates
showed reversed but varied selectivity (entries 2 and (2b and 2c) gave comparable results as acetoacetone
3). In contrast with the nucleophilic but relatively (entries 9 and 10). The reaction of butyryl acetate
Table 2. Reaction of 1a and 2a catalyzed by chiral NHCs.
Entry
Catalyst
Base
Solvent
T [oC]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
D1
D2
D3
D2
D2
D2
D2
D2
D2
K2CO3
toluene
THF
THF
THF
THF
À20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
72
93
44
81
45
93
52
61
82
93
DABCO
DABCO
DMAP
DIPEA
K2CO3
DABCO
DABCO
DABCO
À89
À45
À88
4
THF
35
toluene
CH2Cl2
THF
À35
À74
À92
[a]
Isolated yield.
Determined by chiral HPLC.
[b]
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Table 3. Enantioselective synthesis of (+)- and (À)-3 catalyzed by NHC D1 or D2.
Entry
1
2
Conditions A
Conditions B
(À)-3
Yield [%][a] ee [%][b] (+)-3
Yield [%][a] ee [%][b]
1
2
1a
1b
2a (À)-3aa 72
2a (À)-3ba 96
93
92
(+)-3aa 82
92
93
(+)-3ba 87
(+)-3ca 82
3
1c
2a (À)-3ca 74
84
87
4
5
6
1d
1e
1f
2a (À)-3da 57
2a (À)-3ea 94
2a (À)-3 fa 88
78
91
95
(+)-3da 76
(+)-3ea 88
(+)-3fa 95
92
90
83
7
8
1g
1h
2a (À)-3ga 81
2a (À)-3ha 37[c]
94
72
(+)-3ga 82
87
93
(+)-3ha 25[c]
9
1a
1a
1a
1a
2b (À)-3ab 82
2c (À)-3ac 78
2d (À)-3ad 63
2e (À)-3ae 83
89
93
93
92
(+)-3ab 90
(+)-3ac 90
(+)-3ad 81
(+)-3ae 59[d]
88
10
11
90
72
12
47[d]
[a]
Isolated yield.
Determined by chiral HPLC.
Most bromoenal 1h was recovered.
Reaction carried out at room temperature.
[b]
[c]
[d]
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N-Heterocyclic Carbene-Catalyzed Enantioselective Annulation of Bromoenal and 1,3-Dicarbonyl Compounds
(2d) afforded (À)-3ad in 63% yield with 93% ee
under conditions A, and (+)-3ad in 81% yield with
decreased selectitivity (72% ee) (entry 11). The reac-
tion of benzoyl acetate (2e) worked well under the
catalyst D1 (conditions A) to give (À)-3ad, but re-
quired room temperature to give (+)-3ae in moderate
yield with moderate enantioselectivity under catalyst
D2 (conditions B) (entry 12).
Figure 2. Possible transition states.
The possible catalytic cycle is depicted in Figure 1.
The addition of NHC to bromoaldehyde gives Bre-
slow intermediate A, which is tautomerized to bromo-
In conclusion, a highly enantioselective [3+3]annu-
lation reaction of bromoenals and 1,3-dicarbonyl com-
pounds has been reported. The a,b-unsaturated acyl-
AHCTUNGTREGUNaNN zolium salt is believed to be the key intermediate
generated from the addition of an N-heterocyclic car-
bene to bromoenals. In addition, both enantiomers of
the resultant dihydropyranone could be easily ob-
tained by choosing NHCs with same stereocenter but
different substituents under optimized reaction condi-
tion.
Experimental Section
Typical Procedure
An oven-dried 50-mL Schlenk tube equipped with a stir bar
was charged with triazolium salt [conditions A: D1 (7.6 mg,
0.0284 mmol); condition B: D2 (18.6 mg, 0.0284 mmol)] and
2-bromocinnamaldehyde (60 mg, 0.284 mmol). The tube was
closed with a septum, evacuated, and back-filled with nitro-
gen. To this mixture was added solvent [conditions A: tolu-
ene (0.56 mL); conditions B: THF (2.8 mL)] and acetoace-
tone (56.9 mg, 0.569 mmol), then the mixture was cooled to
the given temperature (conditions A: À208C; conditions B:
08C). The base [conditions A: K2CO3 (47.1 mg,
0.341 mmol); conditions B: DABCO (41.6 mg, 0.341 mmol)]
was added to the tube. The mixture was further stirred over-
night, then diluted with ethyl acetate and passed through a
short silica pad. The solvent was removed under reduced
pressure and the residue was purified by chromatography on
silica gel (ethyl acetate/petroleum ether) to give the desired
product (À)-3 (conditions A) or (+)-3 (conditions B).
Figure 1. Possible catalytic cycle.
ketone B. The leaving of the bromide generates key
intermediate C,[15] which is a potential 1,3-biselectro-
phile. The Michael addition of 1,3-carbonyl com-
pounds gives adduct D, followed by ring-closure to
furnish the annulation product and regenerate the
NHC.
Based on the stereochemical outcome and the cru-
cial effect of the hydroxy group of the catalyst, two
possible favored transition states A and B are pro-
posed for the reaction catalyzed by NHC D1 and D2,
respectively (Figure 2). In TS A, the enolate attacks
Acknowledgements
Financial supports from National Natural Science Founda-
tion of China (20872143, 20932008), the Ministry of Science
and Technology of China (2011CB808600) and the Chinese
from the less hindered face of the unsaturated acyla- Academy of Sciences are greatly acknowledged.
zolium generated from NHC D1. In TS B, there is a
H-bonding between NHC D2 and enolate, which thus
reverses the selectivity. Strong bases, such as K2CO3
and DIPEA, may deprotonate the free hydroxy group
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