Asymmetric synthesis of dihydrofurans via organocatalytic domino michael-alkylation reaction

Article abstract of DOI:10.1002/adsc.201401198

The chiral N,N-dioxide C-PrPr₂ has been developed as an efficient organocatalyst to catalyze the asymmetric domino Michael-alkylation reaction between cyclohexane-1,3-dione derivatives and bromonitrostyrenes. For dimedone, the corresponding bicyclic 2,3-dihydrofurans with two stereocenters were obtained in up to 99 % yield with 95:5 d.r. and 96 % ee. For prochiral 5-monosubstituted cyclohexane-1,3-diones, the desymmetrization reaction provided the bicyclic 2,3-dihydrofurans with three stereocenters in up to 90 % yield with 82:18 d.r. and 94 % ee.

Full text of DOI:10.1002/adsc.201401198

UPDATES
DOI: 10.1002/adsc.201401198
Asymmetric Synthesis of Dihydrofurans via Organocatalytic
Domino Michael–Alkylation Reaction
Juhua Feng,a Lili Lin,a Kunru Yu,a Xiaohua Liu,a and Xiaoming Fenga,b,*
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, People’s Republic of China
Fax : (+86) 28 85418249; phone: (+86) 28 85418249; e-mail: xmfeng@scu.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, People’s Republic of China
b
Received: December 31, 2014; Revised: February 1, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201401198.
Abstract: The chiral N,N’-dioxide C-PrPr2 has been
developed as an efficient organocatalyst to catalyze
the asymmetric domino Michael–alkylation reaction
between cyclohexane-1,3-dione derivatives and bro-
monitrostyrenes. For dimedone, the corresponding
bicyclic 2,3-dihydrofurans with two stereocenters
were obtained in up to 99% yield with 95:5 d.r. and
96% ee. For prochiral 5-monosubstituted cyclohex-
ane-1,3-diones, the desymmetrization reaction pro-
vided the bicyclic 2,3-dihydrofurans with three ste-
reocenters in up to 90% yield with 82:18 d.r. and
94% ee.
Figure 1. Selected examples of natural products.
HeLa cells (Figure 1).[13] In 2010, Xieꢁs and Ruepingꢁs
groups reported the chiral thiourea-catalyzed domino
Michael alkylation reaction of dimedone with bromo-
nitrostyrenes for the synthesis of bicyclic 2,3-dihydro-
furans.[14] Considering the important biological activi-
ty of bicyclic 2,3-dihydrofurans, developing new cata-
lysts and further improving the enantioselectivity of
the domino Michael–alkylation reaction are desirable.
Chiral N,N’-dioxides,[15] developed by our group,
were found to be efficient bifunctional organocata-
Keywords: asymmetric catalysis; chiral N,N’-diox-
ide; desymmetrization; dihydrofuran; domino Mi-
chael–alkylation reaction; organocatalysis
The enantiomerically enriched dihydrofuran deriva- lysts, which could activate the reactants with the N-
tives[1] have been found in a variety of natural prod- oxide moiety and the amide N H moiety simultane-
À
ucts and biologically active molecules.[2] And they are ously.[16] So, we envisioned that the N-oxide moiety of
also useful intermediates for the synthesis of valuable N,N’-dioxide could activate the enolate form of the
tetrahydrofurans.[3] As a consequence, a great efforts diketone and the N H moiety could activate the bro-
À
have been devoted to developing efficient methods monitrostyrene by hydrogen bonding, and thus the
for the synthesis of chiral dihydrofurans,[4] such as domino Michael–alkylation reaction of diketones with
ring enlargement,[5] cyclization[6] and “interrupted” bromonitrostyrenes was promoted (Scheme 1).
Feist-Bꢀnary reaction.[7] Since the pioneering work of
Herein, we report our efforts in developing a chiral
Dauzonne and coworkers,[8] the domino Michael–al- N,N’-dioxide organocatalyst to catalyze the highly ef-
kylation reaction[9] between easily available dinucleo- ficient domino Michael–alkylation reaction of cyclo-
philes and (2-halo-2-nitroethenyl)benzenes has hexane-1,3-dione derivatives with bromonitrostyrenes
become a particularly attractive method.[10] Especially, for the synthesis of various polysubstituted bicyclic di-
the reaction of cyclohexane-1,3-dione derivatives with hydrofurans. Furthermore, a remarkable desymmetri-
bromonitrostyrenes can efficiently construct bicyclic zation of 5-monosubstituted cyclohexane-1,3-diones
2,3-dihydrofurans. The annulated structure of these was observed, which makes it possible to obtain bicy-
compounds is widely found in pharmaceuticals.[11] For clic dihydrofurans with three stereocenters.
example, phyllaemblic acid methyl ester exhibits sig-
Initially, the domino Michael–alkylation reaction
nificant anti-CVB3 activity[12] and maoecrystal V pres- between (Z)-bromonitrostyrene[17] 1a and dimedone 2
ents potent and selective inhibitory activity against was used as the model reaction to identify the optimal
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C-PiPr2 and l-ramipril acid derived C-RaPr2 gave
66% ee and only 17% ee, respectively (Table 1, en-
tries 3–4). The preliminary results showed that chiral
N,N’-dioxides catalyzed the reaction in very low activ-
ity if there was not any additive. Considering the gen-
eration of hydrogen bromide in the reaction, we de-
cided to add different base additives to the catalytic
system.[18] As expected, most of the base additives
could improve the reactivity. The addition of Et3N im-
proved dramatically the yield to 94% with a decreas-
ing ee value (53% ee, Table 1, entry 5). When pyri-
dine was used, the reaction proceeded with higher
enantioselectivity (85% ee), but delivered the desired
product in only 28% isolated yield (Table 1, entry 6).
Further investigation of the base additives indicated
that K2HPO4·3H2O could be a promising additive.
Adding 1.0 equiv of K2HPO4·3H2O to the catalyst
system, the yield was improved to 52% while the
enantioselectivity of the reaction was improved to
91% ee (Table 1, entry 7). In order to further improve
the yield, extensive investigation of other reaction
Scheme 1. The synthesis of bicyclic dihydrofurans.
Figure 2. Chiral N,N’-dioxides employed for the domino Mi-
chael–alkylation reaction.
reaction conditions. A series of chiral N,N’-dioxides conditions was carried out. It was found that mixed
(Figure 2) were tested under air. The catalyst C-PrPr2 solvent showed positive effect: 84% yield could be
derived from (S)-proline, which contained bulkier iso- obtained by using toluene/ethyl acetate as solvent
propyl groups at the ortho positions of aniline groups, with no loss in enantioselectivity (Table 1, entry 8).
delivered a better ee value than catalyst C-PrPh Better results (88% yield and 92% ee) were obtained
(80% ee vs 14% ee, Table 1, entry 2 vs 1). When with toluene/THF (Table 1, entry 9). By increasing
other chiral backbone moieties of N,N’-dioxide cata- the amount of K2HPO4·3H2O to 1.2 equiv, the yield
lysts were investigated, the (S)-pipecoic acid derived was further improved to 94% with 92% ee main-
Table 1. Optimization of the reaction conditions.
Entry[a]
Catalyst
Solvent
Additive
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
C-PrPh
C-PrPr2
C-PiPr2
C-RaPr2
C-PrPr2
C-PrPr2
C-PrPr2
C-PrPr2
C-PrPr2
C-PrPr2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene/ethyl acetate
toluene/THF
toluene/THF
no
no
no
no
10
22
14
22
94
28
52
84
88
94
14
80
66
–17
53
85
91
91
92
92
Et3N
pyridine
[K2HPO4]
[K2HPO4]
[K2HPO4]
[K2HPO4]
8[d]
9[e]
10[e,f]
[a]
Unless otherwise noted, the reaction was carried out with 1a (0.12 mmol), 2 (0.10 mmol), catalyst (10 mol%) and addi-
tive (1.0 equiv) in solvent (1.0 mL) at À508C for 72 h under air.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
1
Determined by chiral HPLC analysis. The d.r. was determined by H NMR spectra.
Toluene/ethyl acetate=4:1.
Toluene/THF=4:1.
1.2 equiv of additive was used. [K2HPO4]=K2HPO4·3H2O
2
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Table 2. Substrate scope for the asymmetric domino Michael–alkylation reaction between various (Z)-bromonitrostyrenes
1 and dimedone 2.
Entry[a]
R1
Product
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
Ph
2-MeC6H4
2-FC6H4
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
94
72
95
76
79
88
85
95
96
96
76
87
99
98
98
97
92 (2S,3S)
94 (2S,3S)
95 (2S,3R)
90 (2S,3R)
91 (2S,3R)
87 (2S,3S)
87 (2S,3S)
85 (2S,3S)
86 (2S,3S)
86 (2S,3S)
91 (2S,3S)
94 (2S,3S)
92 (2S,3S)
94 (2S,3S)
94 (2S,3S)
93 (2S,3R)
2-ClC6H4
2-BrC6H4
3-MeOC6H4
3-MeC6H4
3-FC6H4
3-ClC6H4
3-BrC6H4
4-MeOC6H4
4-MeC6H4
4-FC6H4
9
10
11
12
13
14
15
16
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
17
18
19
3q
3r
3s
3t
84
98
88
83
94
96
87 (2S,3R)
82 (2S,3S)
20
[a]
Unless otherwise noted, the reaction was carried out with 1 (0.12 mmol), 2 (0.10 mmol), C-PrPr2 (10 mol%) and
K2HPO4·3H2O (1.2 equiv) in solvent (1.0 mL, toluene/THF=4:1) at À508C for 72 h under air.
Isolated yield.
[b]
[c]
1
Determined by chiral HPLC analysis. The d.r. was determined by H NMR spectra.
tained (Table 1, entry 10). Thus, the optimal reaction (85–87% ee, Table 2, entries 6–10). The reaction of
conditions were as follows: catalyst C-PrPr2 ring-fused substrate 1r performed well, giving the cor-
(10 mol%), K2HPO4·3H2O (1.2 equiv), bromonitros- responding product 3r in 98% yield with 96% ee
tyrene (1, 0.12 mmol) and diketone (2, 0.10 mmol) in (Table 2, entry 18). Notably, the heteroaryl-containing
toluene/THF (1.0 mL, v:v=4:1) at À508C.
substrates 1s and 1t were also well tolerated in this
Under the optimized reaction conditions, a range of reaction, providing 3s in 88% yield with 87% ee and
(Z)-bromonitrostyrenes 1 were examined, and the re- 3t in 83% yield with 82% ee (Table 2, entries 19–20).
sults were summarized in Table 2.[19] The substrates The absolute configuration of 3o[20] was assigned un-
with electron-donating or electron-withdrawing ambiguously by X-ray crystallography to be (2S,3S)
groups at the ortho or para position of the aromatic (Scheme 3), while the absolute configurations of 3a,
ring were suitable for the reaction, and delivered the 3b, 3 f–3n and 3t were assigned to be (2S,3S), and the
corresponding products in high to excellent yields absolute configuration of 3c–3e, 3p and 3s were as-
with excellent enantioselectivities (72–99% yields, signed to be (2S,3R) by comparing their circular-di-
90–95% ee, Table 2, entries 1–5, and 11–17). For the chroism spectra with that of 3o (see the Supporting
substrates with a substituent in the meta position, Information). In addition, cyclohexane-1,3-dione and
slightly decreased enantioselectivities were obtained acyclic 1,3-dicarbonyl compounds were also examined
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Scheme 2. The desymmetrization of 5-monosubstituted cyclohexane-1,3-diones.
as dinucleophiles. When cyclohexane-1,3-dione was selectivities (87–94% ee) were obtained (Scheme 2).
used, the corresponding product was obtained in 61% It is worth mentioning that this is the first time that
yield with 63% ee under the same reaction conditions. the desymmetrization of prochiral 5-monosubstituted
For acyclic 1,3-dicarbonyl compounds, such as ethyl cyclohexane-1,3-diones 4 using the Michael–alkylation
acetylacetate, methyl acetoacetate and acetylacetone, reaction of bromonitrostyrenes was achieved.
unfortunately, only trace amounts of products were
obtained.
To show the synthetic potential of the catalytic
system, a gram-scale synthesis of the dihydrofuran 3o
Inspired by the results obtained in the reaction of was carried out. By treatment of 4.0 mmol of 1o
dimedone 2, prochiral 5-monosubstituted cyclohex- under the optimized condition, the desired dihydro-
ane-1,3-diones 4 were next investigated. The desym- furan 3o was obtained in 97% yield (1.42 g) with 95:5
metrization reaction could afford bicyclic 2,3-dihydro- d.r. and 93% ee (Scheme 3).
furans with three stereocenters. When phenyl-, 4-fluo-
In summary, we have developed an efficient chiral
rophenyl-, as well as furyl-substituted cyclohexane- N,N’-dioxide organocatalyst system for the catalytic
1,3-diones 4 were examined, the reactions proceeded asymmetric domino Michael–alkylation reactions be-
well, delivering the dihydrofurans 5a–5c in 72–90% tween dimedone and 5-monosubstituted cyclohexane-
yields with 78:22–80:20 d.r. and 82–86% ee. Subse- 1,3-diones with bromonitrostyrenes. A wide variety of
quently, a broad spectrum of (Z)-bromonitrostyrenes bicyclic 2,3-dihydrofurans with two or three chiral ste-
1 was probed. Regardless of the electronic properties reogenic centers were obtained in up to 99% yields
or steric hindrance of the substituents on the aromatic and 95:5 d.r. with 96% ee. Among them, the desym-
ring of the bromonitrostyrenes, moderate to good metrization of 5-monosubstituted cyclohexane-1,3-
yields (63–81% yields) and good to excellent enantio- diones using the Michael–alkylation reaction of bro-
4
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Scheme 3. Gram-scaled version of the reaction and the X-ray crystallographic structure of 3o.
monitrostyrenes was studied for the first time. Further
investigations on the application of chiral N,N’-diox-
ides as organocatalyst to other reactions are in prog-
ress.
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Experimental Section
In a test tube, (Z)-bromonitrostyrene 1 (0.12 mmol), dime-
done
2
or 5-monosubstituted cyclohexane-1,3-dione
4
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(0.10 mmol),
catalyst C-PrPr2 (0.01 mmol), and
K2HPO4·3H2O (0.12 mmol) were dissolved in 1.0 mL of sol-
vent (toluene/THF=4:1) at À508C under air. The mixture
was stirred for 72 h. Then the crude product was purified di-
rectly by column chromatography on silica gel (petroleum
ether/ethyl acetate=10:1 to 5:1) to afford the corresponding
products.
Acknowledgements
We appreciate the National Natural Science Foundation of
China (Nos. 21290182 and 21172151) and the Ministry of
Education (NCET-11–0345) for financial support.
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[18] Other base additives were also examined; see the Sup-
porting Information for details.
[19] The bromonitrostyrene with an alkyl group was also
examined. When R1 was cyclohexyl, isobutyl or tert-
butyl groups, no reaction were detected. When R1 was
isopentyl group, the corresponding product was ob-
tained in 61% yield, and 55% ee.
[20] CCDC-1032711 (3o) contains the supplementary crys-
tallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
6
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UPDATES
Asymmetric Synthesis of Dihydrofurans via Organocatalytic
Domino Michael–Alkylation Reaction
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Adv. Synth. Catal. 2015, 357, 1 – 7
Juhua Feng, Lili Lin, Kunru Yu, Xiaohua Liu,
Xiaoming Feng*
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