Enantioselective N -heterocyclic carbene-catalyzed Michael addition to α,β-unsaturated aldehydes by redox oxidation

Article abstract of DOI:10.1021/ol201595f

Enantioselective N-heterocyclic carbene-catalyzed Michael addition reactions to α,β-unsaturated aldehydes by redox oxidation were realized. With 10 mol % of camphor-derived triazolium salt D, 15 mol % of DBU, 5 mol % of NaBF₄, and 100 mol % of

Full text of DOI:10.1021/ol201595f

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4080–4083
Enantioselective N-Heterocyclic
Carbene-Catalyzed Michael Addition
to R,β-Unsaturated Aldehydes by
Redox Oxidation
Zi-Qiang Rong, Min-Qiang Jia, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received June 14, 2011
ABSTRACT
Enantioselective N-heterocyclic carbene-catalyzed Michael addition reactions to R,β-unsaturated aldehydes by redox oxidation were realized.
With 10 mol % of camphor-derived triazolium salt D, 15 mol % of DBU, 5 mol % of NaBF4, and 100 mol % of quinone oxidant, the reactions of various
dicarbonyl compounds with R,β-unsaturated aldehydes led to 3,4-dihydro-R-pyrones in good yields and excellent ee’s.
N-Heterocyclic carbenes (NHCs) have received enor-
mous attention and experienced very rapid development in
the past two decades.1 The inversion of the normal reac-
tivity (umpolung) of aldehydes catalyzed by NHCs has
become an intense area recently, providing an unconven-
tional access to designed target molecules.2 The asym-
metric reactions catalyzed by chiral NHCs have also
witnessed significant progress over the past decade.1,3 In
addition to umpolung reactions of aryl aldehydes such
as the benzoin reaction4 and Stetter reaction,5 NHCs
were also found to catalyze various redox type transfor-
mations of functionalized aldehydes containing reducible
functionalities.6 More recently, the elegant work by Studer
and co-workers showed that the Breslow intermediate can
be readily oxidized with an external organic oxidant to
acylazolium ions,7,8 which can undergo O-acylation
(amidation) with various oxygen (nitrogen) nucleophiles
to afford esters (amides) or the Michael addition reaction
(2) For recent examples: (a) Ye, W.; Cai, G.; Zhuang, Z.; Jia, X.;
Zhai, H. Org. Lett. 2005, 7, 3769. (b) Liu, Y.-K.; Li, R.; Yue, L.; Li, B.-J.;
Chen, Y.-C.; Wu, Y.; Ding, L.-S. Org. Lett. 2006, 8, 1521. (c) He, J.;
Zheng, J.; Liu, J.; She, X.; Pan, X. Org. Lett. 2006, 8, 4637. (d) Li, G.-Q.;
Dai, L.-X.; You, S.-L. Chem. Commun. 2007, 852. (e) Wong, F. T.; Patra,
P. K.; Seayad, J.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10, 2333. (f)
Phillips, E. M.; Wadamoto, M.; Roth, H. S.; Ott, A. W.; Scheidt, K. A.
Org. Lett. 2009, 11, 105. (g) Li, Y.; Shi, F.-Q.; He, Q.-L.; You, S.-L. Org.
Lett. 2009, 11, 3182. (h) Yadav, L. D. S.; Rai, V. K.; Singh, S.; Singh, P.
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Tetrahedron Lett. 2010, 51, 3571. (j) Nair, V.; Varghese, V.; Paul, R. R.;
Jose, A.; Sinu, C. R.; Menon, R. S. Org. Lett. 2010, 12, 2653. (k) Gu, L.;
Zhang, Y. J. Am. Chem. Soc. 2010, 132, 914. (l) Biju, A. T.; Glorius, F.
Angew. Chem., Int. Ed. 2010, 49, 9761. (m) Padmanaban, M; Biju, A. T.;
Glorius, F. Org. Lett. 2011, 13, 98. (n) Wu, K.-J.; Li, G.-Q.; Li, Y.; Dai,
L.-X.; You, S.-L. Chem. Commun. 2011, 493. (o) Vedachalam, S.; Wong,
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259.
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37, 534. (b) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326. (c)
Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. (d) Zeitler, K.
ꢀ
Angew. Chem., Int. Ed. 2005, 44, 7506. (e) Marion, N.; Dıez-Gonzalez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (f) Enders, D.;
Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (g) Nair, V.;
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r
10.1021/ol201595f
Published on Web 07/06/2011
2011 American Chemical Society

Scheme 1. Oxidative NHC Catalysis to 3,4-Dihydro-R-pyrones
by Studer et al.
Figure 1. Several readily available chiral NHC precursors.
(3) as the oxidant, 10 mol % of triazolium salt (AÀE), and
15 mol % of DBU in THF, the desired oxidative annula-
tion reaction generally proceeded to afford dihydropyra-
none 6a. The results are summarized in Table 1. The
D-camphor-derived NHCs13 all led to the formation of 6a
with soft carbon nucleophiles (Scheme 1). Starting with the
dicarbonyl compounds, the substituted dihydropyranones
were obtained smoothly. Given the fact that 3,4-dihydro-
R-pyrones are useful intermediates for the synthesis of
γ-lactones, substituted benzenoids, pyridones, etc.,9 and
their enantioselective synthesis is still limited,10 we decided
to contribute a catalytically asymmetric synthesis of 3,4-
dihydro-R-pyrones by a chiral NHC-catalyzed redox-type
Michael addition reaction to R,β-unsaturated aldehydes.11,12
To our knowledge, there is no catalytic asymmetric report on
this mechanistically interesting reaction. Herein, we report
our preliminary results from the study of this subject.
Our studies began with an initial examination of several
readily available chiral NHCs (Figure 1) developed in our
laboratory, for the redox-type Michael addition reactions
reported by Sarkar and Studer.7a Cinnamaldehyde (4a)
and 1,3-diphenylpropane-1,3-dione(5a) wereusedasmod-
el substrates. To our great delight, with 1 equiv of quinone
(6) Selected examples: (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem.
Soc. 2004, 126, 8126. (b) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T.
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Org. Lett., Vol. 13, No. 15, 2011
4081

Table 1. Screening of the Chiral NHC Catalysts and the
Additivesa
Table 2. Optimization of the Reaction Conditionsa
time
(h)
yield
ee
additive
(mol %)
time
(h)
yield
(%)b
ee
entry
cat.
(%)c
entry
base
DBU
solvent
(%)
(%)
1
THF
27
40
40
40
40
40
27
27
27
27
27
15
24
24
24
80
66
70
93
81
81
44
44
11
20
NR
85
73
67
83
94
92
91
86
91
95
91
92
90
88
NR
90
93
93
92
1
A
B
C
D
E
A
B
C
D
E
D
D
D
D
D
À
24
12
2.5
24
27
24
12
2.5
27
27
27
27
27
27
27
59
80
85
61
<5
77
73
86
80
38
64
63
72
62
37
45
62
52
16
62
37
55
6
2
DBU
toluene
xylene
CH2Cl2
CHCl3
Et2O
THF
2
À
3
DBU
3
À
4
DBU
4
À
5
DBU
5
À
6
DBU
6
NaBF4 (5)
NaBF4 (5)
NaBF4 (5)
NaBF4 (5)
NaBF4 (5)
LiBF4 (5)
KBF4 (5)
NaBF4 (10)
NaBF4 (20)
NaBF4 (50)
7
DIEA
Et3N
KHMDS
dabco
no base
DBU
7
8
THF
8
9
THF
9
94
60
85
15
90
90
89
10
11
12b
13c
14d
15e
THF
10
11
12
13
14
15
THF
THF
DBU
THF
DBU
THF
DBU
THF
a Reaction conditions: 4a (0.1 mmol), 5a (0.3 mmol), 3 (0.1 mmol),
10 mol % of D, 5 mol % of NaBF4, and 15 mol % of DBU in solvent
(1.0 mL) at 25 °C, unless noted otherwise. b At 40 °C. c 4a/5a: 1/2. d 4a/5a:
1/1.2. e 4a/5a: 2/1.
a Reaction conditions: 4a (0.1 mmol), 5a (0.3 mmol), 3 (0.1 mmol),
10 mol % of cat., and 15 mol % of DBU in THF (1.0 mL) at 25 °C.
b Isolated yield. c Determined by HPLC.
in moderate to good yields except catalyst E, which gave
onlya trace amountof the product. Toour great surprise, a
serendipitous testing of NaBF4 as the additive provided
very exciting results. With 5 mol % of NaBF4, the catalyst
generated from triazolium salt D, bearing a C6F5 group,
gave dihydropyranone 6a in a significantly improved en-
antioselectivity (94% ee) (entry 9, Table 1). By variation of
the counter cations, we found that addition of the initially
usedNaBF4 led to thebest results and the use ofLiBF4 also
enhanced the enantioselectivity significantly (entries 9, 11,
and 12, Table 1). The loading of NaBF4 was then exam-
ined, and the yields of 6a decreased along with the in-
creased amount of NaBF4 while excellent enantioselec-
tivity was maintained in all cases (entries 13À15, Table 1).
The effects of the additives in this reaction have not been
fully understood.14 In our opinion, it is likely that the
interaction between NaBF4 and the C6F5 group of triazo-
lium saltD impacted the transition state of the reactionand
led to the high enantioselectivity.
In the presence of 10 mol % of triazolium salt D and
5 mol % of NaBF4, different reaction parameters were
further examined. The results are summarized in Table 2.
All the tested solvents including toluene, xylene, CH2Cl2,
CHCl3, andetherwerewelltolerated(entries2À6,Table2).
A slightly higher ee (95%) was obtained in ether, but the
reaction was relatively slower. Several other organic bases
(DIEA, Et3N, and dabco) and KHMDS afforded the
desired product 6a in reduced yield but with excellent ee’s
(entries 7À10, Table 2). The reaction did not occur in the
absence of the base (entry 11, Table 2). The reaction at
40 °C did not show any beneficial effect on either the
reaction rate or the enantioselectivity of the reaction
(entry 12, Table 2). Varying the ratios between the two
substrates led to excellent enantioselectivities, but the
yields were slightly decreased when 2 or 1.2 equiv of 5a
were used (entries 13À14, Table 2). When 2 equiv of 4a
and 1 equiv of 5a were used, the yield of 6a was not
affected but the enantioselectivity was slightly decreased
(entry 15, Table 2).
(13) (a) Li, Y.; Feng, Z.; You, S.-L. Chem. Commun. 2008, 2263. (b)
Li, Y.; Wang, X.-Q.; Zheng, C.; You, S.-L. Chem. Commun. 2009, 5823.
(c) Rong, Z.-Q.; Li, Y.; Yang, G.-Q.; You, S.-L. Synlett 2011, 1033.
(14) For book and review: (a) Tchoubar, B.; Loupy, A. Salt Effects in
Organic and Organometallic Chemistry; VCH: New York, 1992; pp
€
1À322. (b) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int.
Ed. 1999, 38, 1570. For selected examples of salt effects: (c) Krasovskiy,
A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333. (d) Krasovskiy,
A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 6040. (e) Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. J. Am.
Chem. Soc. 2007, 129, 5376. (f) Ochiai, H.; Jang, M.; Hirano, K.;
Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 2681. (g) Hatano, M.;
Ito, O.; Suzuki, S.; Ishihara, K. Chem. Commun. 2010, 46, 2674. (h)
Hatano, M.; Ito, O.; Suzuki, S.; Ishihara, K. J. Org. Chem. 2010, 75,
5008. (i) Hevia, E.; Mulvey, R. E. Angew. Chem., Int. Ed. 2011, 50, DOI:
10.1002/anie.201102054.
In the presence of 10 mol % of D, 15 mol % of DBU,
5 mol % of NaBF4, and 100 mol % of quinone 3 in THF at
25 °C, the reactions of various dicarbonyl compounds with
R,β-unsaturated aldehydes were tested to investigate the
generality of the reaction. The results are summarized in
4082
Org. Lett., Vol. 13, No. 15, 2011

Table 3. When pentane-2,4-dione was used, the correspond-
ing product 6b was obtained in 78% yield and 93% ee
(entry 2, Table 3). However, symmetrical 1,3-diketones
with strong electron-withdrawing or bulky groups led to
low reactivity (entries 3À4, Table 3). Moreover, β-keto
esters were also demonstrated as suitable nucleophiles for
NHC-catalyzed oxidative 1,4-additions, providing the de-
sired 3,4-dihydro-R-pyrones in moderate yields with excel-
lent ee’s (entries 5À7, Table 3). The use of ethyl 3-oxo-3-
phenylpropanoate provided high enantioselectivity albeit
low yield (entry 8, Table 3). Various R,β-unsaturated
aldehydes were then evaluated as suitable electrophiles
with 1,3-diphenylpropane-1,3-dione (5a) (entries 9À17,
Table 3). Both electron-donating and -withdrawing sub-
stituents were accommodated on the aromatic ring, with
moderate to good yields and excellent levels of enantios-
electivity obtained (entries 9À16, Table 3). Unfortunately,
the use of crotonaldehyde under the optimal reaction
conditions gave the desired product 6o in 61% ee and
10% yield (entry 17, Table 3). To determine the absolute
configuration of the product, the crystal structure of
enantiopure 6g was obtained, and a single crystal X-ray
analysis determined its configuration as S.15
Table 3. NHC-Catalyzed Redox-Type Michael Addition of
Dicarbonyl Compounds to R,β-Unsaturated Aldehydesa
time yield ee
product (h) (%)b (%)c
entry
R1
R2
R3
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph Ph
Me Me
CF3 CF3
t-Bu t-Bu
6a
6b
À
27
30
80
78
94
93
NR NR NR
À
trace trace trace
Me OMe
Me OEt
Me OCH2
6c
6d
6e
42
28
30
58
70
50
89
91
91
CHdCH2
8
9
Ph
Ph OEt
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph
6f
20
1
17
95
70
90
77
69
89
79
45
10
94
96
94
96
93
94
93
92
89
61
2-BrC6H4
6g
6h
6i
10 4-BrC6H4
11 2-ClC6H4
12 3-ClC6H4
13 4-ClC6H4
43
1
To shed light on the reaction mechanism, compound 7
was synthesized and subjected to the reaction conditions
(eq 1). The fact that no desired product was observed in the
reaction likely excludes enol ester (7) as the competent
intermediate. However, either Michael addition of enolate
to NHC-mediated R,β-unsaturated acceptor7a or the
Claisen rearrangement11b pathway cannot be excluded
for this asymmetric process.
6j
27
43
24
6k
6l
14 4-CO2MeC6H4 Ph Ph
15 2-CH3C6H4
16 4-OMeC6H4
17 Me
Ph Ph
Ph Ph
Ph Ph
6m 19
6n
6o
60
70
a Reaction conditions: 4 (0.2 mmol), 5 (0.6 mmol), 3 (0.2 mmol),
10 mol % of D, 5 mol % of NaBF4, and 15 mol % of DBU in THF
(2.0 mL) at rt, unless noted otherwise. b Isolated yield. c Determined by
HPLC.
yields with excellent ee’s. The mild reaction conditions
and ready accessibility of both the starting materials
and catalysts make the current methodology particu-
larly attractive in organic synthesis.
In summary, we have developed an enantioselective
N-heterocyclic carbene-catalyzed Michael addition re-
action to R,β-unsaturated aldehydes using redox oxi-
dation. The camphor-derived triazolium salt together
with a catalytic amount of NaBF4 was found to be
highly efficient for this reaction providing enantioen-
riched substituted 3,4-dihydro-R-pyrones in good
Acknowledgment. We thank the National Natural
Science Foundation of China (20732006, 20821002,
20972177, 21025209) and National Basic Research
Program of China (973 Program 2009CB825300) for
generous financial support.
Supporting Information Available. Experimental pro-
cedures and characterization of the products. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(15) CCDC 827900 contains the supplementary crystallographic
data for (S)-6g. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Org. Lett., Vol. 13, No. 15, 2011
4083