Organocatalytic asymmetric conjugate addition of 3-monosubstituted oxindoles to (E)-1,4-diaryl-2-buten-1,4-diones: A strategy for the indirect enantioselective furanylation and pyrrolylation of 3-alkyloxindoles

Article abstract of DOI:10.1002/chem.201103293

An asymmetric conjugate addition of 3-monosubstituted oxindoles to a range of (E)-1,4-diaryl-2-buten-1,4-diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3'-disubstituted oxindoles that contain a 1,4-dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high-to-excellent yields (up to 98 %), with excellent diastereomeric and moderate-to-high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4-dicarbonyl moiety in the resultant Michael adducts under different Paal-Knorr conditions results in two new kinds of 3,3'-disubstituted oxindoles-3-furanyl- and 3-pyrrolyl-3-alkyl-oxindoles-in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two-step strategy of sequential conjugate addition/Paal-Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3-alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3'-disubstituted oxindole derivatives. Copyright

Full text of DOI:10.1002/chem.201103293

FULL PAPER
DOI: 10.1002/chem.201103293
Organocatalytic Asymmetric Conjugate Addition of 3-Monosubstituted
Oxindoles to (E)-1,4-Diaryl-2-buten-1,4-diones: A Strategy for the Indirect
Enantioselective Furanylation and Pyrrolylation of 3-Alkyloxindoles
Yu-Hua Liao,[a, d] Xiong-Li Liu,[a, d] Zhi-Jun Wu,[b] Xi-Lin Du,[c] Xiao-Mei Zhang,[a] and
Wei-Cheng Yuan*[a]
Abstract: An asymmetric conjugate ad-
dition of 3-monosubstituted oxindoles
to a range of (E)-1,4-diaryl-2-buten-
1,4-diones, catalyzed by commercially
available cinchonine, is described. This
organocatalytic asymmetric reaction af-
fords a broad range of 3,3’-disubstitut-
ed oxindoles that contain a 1,4-dicar-
bonyl moiety and vicinal quaternary
and tertiary stereogenic centers in
high-to-excellent yields (up to 98%),
with excellent diastereomeric and mod-
erate-to-high enantiomeric ratios (up
to 99:1 and 95:5, respectively). Subse-
quently, cyclization of the 1,4-dicarbon-
yl moiety in the resultant Michael ad-
ducts under different Paal–Knorr con-
ditions results in two new kinds of 3,3’-
disubstituted oxindoles—3-furanyl- and
3-pyrrolyl-3-alkyl-oxindoles—in
high
yields and good enantioselectivities.
Notably, the studies presented here suf-
ficiently confirm that this two-step
strategy of sequential conjugate addi-
tion/Paal–Knorr cyclization is not only
an attractive method for the indirect
enantioselective heteroarylation of 3-
alkyloxindoles, but also opens up new
avenues toward asymmetric synthesis
of structurally diverse 3,3’-disubstituted
oxindole derivatives.
Keywords: butendiones · conjugate
addition · organocatalysis · oxin-
doles · Paal–Knorr cyclization
Introduction
among the various established strategies for preparation of
optically active 3,3’-disubstituted oxindoles, the direct asym-
metric functionalization (alkylation,[3] hydroxylation,[4] ami-
nation,[5] amino-oxygenation[6a] or hydroxyamination,[6b]
chlorination,[7] arylation,[8] fluorination,[9] aldol reaction,[10]
Mannich reaction,[11] and Michael addition reaction)[12] of 3-
monosubstituted oxindoles with various electrophiles should
be the most straightforward approach (Scheme 1). Indeed,
The efficient and highly stereoselective construction of com-
plex heterocycles is an ongoing challenge for synthetic
chemistry. In particular, oxindoles with a chiral tetrasubsti-
tuted carbon atom at the C3 position have emerged as at-
tractive synthetic targets because of their “privileged struc-
ture” status in synthetic and medicinal chemistry.[1] Accord-
ingly, considerable effort has been devoted to the construc-
tion of diverse 3,3’-disubstituted oxindole cores.[2] However,
[a] Y.-H. Liao, X.-L. Liu, Prof. Dr. X.-M. Zhang, Prof. Dr. W.-C. Yuan
National Engineering Research Center of Chiral Drugs
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
Scheme 1. Direct asymmetric functionalization of 3-monosubstituted ox-
indoles with electrophiles.
Chengdu 610041 (P.R. China)
E-mail: yuanwc@cioc.ac.cn
[b] Dr. Z.-J. Wu
each of these methods can lead to a different class of 3,3’-
disubstituted oxindoles that may show promise as biological-
ly active compounds or serve as extremely versatile building
blocks for synthetically useful transformations. Asymmetric
Michael addition[13] is one of the most powerful strategies
used to obtain chiral compounds in organic synthesis and
the 3-monosubstituted oxindoles have emerged as valuable
synthons for the synthesis of natural products and biologi-
cally active compounds.[2] As a result, the synthetic and me-
dicinal chemistry communities have paid much attention to
the reaction between 3-monosubstituted oxindole donor
substrates and various Michael acceptors. However, the Mi-
Chengdu Institute of Biology
Chinese Academy of Sciences
Chengdu 610041 (P.R. China)
[c] Prof. X.-L. Du
Department of General Surgery
TangDu Hospital
The Fourth Military Medical University
Xi’an 710038 (P.R. China)
[d] Y.-H. Liao, X.-L. Liu
Graduate School of Chinese Academy of Sciences
Beijing 100049 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103293.
Chem. Eur. J. 2012, 00, 0 – 0
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chael acceptors have generally been limited to nitro-ole-
fins,[12c–e,14] enals,[12a,f] enones,[7,11c,12b,15] vinyl sulfones,[12b,16]
vinyl selenones,[17] 2-chloroacrylonitrile,[18] maleimides,[19]
and ethyl 2-phthalimidoacrylate.[20] To the best of our knowl-
edge, there is no current precedent for the catalytic asym-
metric conjugate addition of 3-monosubstituted oxindoles to
(E)-1,4-diaryl-2-buten-1,4-diones (Scheme 2).[21]
Scheme 2. Asymmetric conjugate addition of 3-monosubstituted oxin-
doles to (E)-1,4-diaryl-2-buten-1,4-diones.
Scheme 3. 3-Monosubstituted oxindoles as starting materials for the con-
struction of 3-aryl-3-alkyl-oxindole scaffolds.
In accordance with our recent research into the develop-
ment of new methods for the catalytic asymmetric construc-
tion of structurally diverse 3,3’-disubstituted oxindo-
les,[14c,19,22] we devised a research program to investigate the
asymmetric conjugate addition of 3-monosubstituted oxin-
doles to (E)-1,4-diaryl-2-buten-1,4-diones (Scheme 2). This
reaction possesses some significant merits: 1) delivery of
a new series of chiral 3,3’-disubstituted oxindoles that con-
tain a 1,4-dicarbonyl moiety, 2) creation of two sterically
hindered contiguous quaternary and tertiary stereogenic
centers in one step, and, more importantly, 3) the 1,4-dicar-
bonyl moieties in the resultant adducts may be further trans-
formed into a heteroaryl unit by Paal–Knorr cyclization, to
deliver a series of 3,3’-disubstituted oxindoles that bear
a substituted heteroaryl group.[23] The 3-aryl-3-alkyl-oxin-
dole structural motif is a prominent feature in a number of
biologically active natural products and pharmaceutically
important molecules.[24] Either installing an aryl group on
a to 3-alkyloxindole, or installing an alkyl group onto a 3-ar-
yloxindole is the most straightforward approach to the 3-
aryl-3-alkyl-oxindole scaffold. However, to the best of our
knowledge, the most commonly used method in this re-
search field is alkylation of 3-aryloxindoles, which utilizes
the high nucleophilicity of the oxindole C3 position
(Scheme 3a).[2] In contrast, only a single report describes the
asymmetric arylation of 3-alkyloxindoles (Scheme 3b).[8] Ac-
cordingly, more efficient and general methods for the enan-
tioselective arylation of 3-alkyloxindoles are anticipated. We
envisioned that a sequential asymmetric conjugate addition
of 3-monosubstituted oxindoles to (E)-1,4-diaryl-2-buten-
1,4-diones and subsequent Paal–Knorr cyclization of the 1,4-
dicarbonyl moiety contained in the adducts might provide
an alternative approach to optically active 3-aryl-3-alkyl-ox-
indoles (Scheme 3c). Certainly, if successful, this process
would present another method for the arylation of 3-alky-
loxindoles further to Buchwaldꢁs report.[8]
1,4-diaryl-2-buten-1,4-diones with commercially available
cinchonine as a catalyst. A range of 3,3’-disubstituted oxin-
doles that bore a 1,4-dicarbonyl moiety were afforded in
high yields (up to 98%) with good-to-excellent diastereose-
lectivities (diastereomeric ratio (d.r.) up to 99:1) and moder-
ate-to-high enantioselectivities (enantiomeric ratio (e.r.) up
to 95:5). In addition, two sterically hindered contiguous qua-
ternary and tertiary stereogenic centers were created in one
reaction step (Scheme 3c). Moreover, we have investigated
the cyclization of the related 1,4-dicarbonyl moiety con-
tained in the resultant adducts under different Paal–Knorr
conditions and achieved the synthesis of 3-furanyl or 3-pyr-
rolyl chiral 3,3’-disubstituted oxindoles with good results
(Scheme 3c). Herein, we report our results on this subject.
Results and Discussion
Reaction optimization: Initially, the conjugate addition of
oxindoles 1a–e to (E)-1,4-diphenyl-2-buten-1,4-dione (2a)
were carried out in CH2Cl2 at room temperature to examine
compatibility with the substituent at the C3 position and the
N-protecting group of the oxindoles (Scheme 4). With Take-
motoꢁs thiourea catalyst 3a as the promoter, both 3-benzy-
loxindole 1a and 3-phenyloxindole 1b reacted well to afford
the adducts 4a and 4b, respectively, in similar yield, but 1a
gave better enantioselectivity than 1b, although with a slight-
ly inferior diastereoselectivity. Significantly, the reaction ac-
tivity was very sensitive to the N-protecting group. Very
poor reactivity was observed with N-acetyloxindole 1c and
there was almost no reaction with either NH oxindole 1d or
N-methyloxindole 1e as the substrate. Based on these re-
sults, we chose to use N-Boc-3-benzyl oxindole (1a) for fur-
ther optimization of the reaction conditions.
Additionally, because asymmetric organocatalysis is ma-
turing into a powerful tool in organic synthesis,[25] we have
recently investigated the diastereo- and enantioselective
conjugate addition of 3-monosubstituted oxindoles to (E)-
Subsequent studies were focused on the optimization of
various chiral organocatalysts 3a–q (Scheme 5) for the con-
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Addition of Monosubstituted Oxindoles to Diarylbutendiones
FULL PAPER
Table 1. Screening of various chiral organocatalysts for the reaction of
1a with 2a.[a]
Entry
3
Yield [%][b]
d.r.[c]
e.r. [%][d]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
93
86
93
80
56
71
73
89
89
69
86
96
95
89
89
71
98
76:24
77:23
75:25
95:5
92:8
96:4
87:13 (À)
74:26 (À)
84:16 (À)
60:40 (À)
73:27 (À)
66:34 (À)
81:19 (À)
67:33 (À)
65:35 (À)
63:37 (À)
55:45 (À)
87:13 (À)
60:40 (À)
85:15 (+)
62:38 (+)
63:37 (À)
75:25 (À)
95:5
84:16
82:18
82:18
79:21
90:10
81:19
85:15
70:30
91:9
9
10
11
12
13
14
15
16
17
Scheme 4. Screening of the substituents at the C3 position and the N-pro-
tecting groups of oxindoles 1. The reaction was performed with
1 (0.12 mmol), 2a (0.1 mmol) and 3a (5 mol%) in CH2Cl2 (1.0 mL) at
RT for 6 h. The isolated yields are reported; d.r. values were determined
by 1H NMR spectroscopy; e.r. values were determined by chiral HPLC
analysis for the major diastereomer; nd=not determined. Boc=tert-bu-
toxycarbonyl; Bn=benzyl; Ac=acetyl.
93:7
[a] The reaction was performed with 1a (0.12 mmol), 2a (0.1 mmol), and
3 (5 mol%) in CH2Cl2 (1.0 mL) at RT for 6 h. [b] Isolated product yield.
[c] Determined by 1H NMR spectroscopy. [d] Determined by chiral
HPLC analysis for the major diastereomer (the major isomer is indicated
in parentheses).
jugate addition of 2a to 1a (Table 1). To our delight, the
model reaction generally exhibited high efficiency in the
presence of organocatalysts 3a–q at room temperature in
CH2Cl2. We found that the reactions with chiral bifunctional
thiourea tertiary amines 3a–k as catalysts (Table 1, en-
tries 1–11) could deliver the corresponding adduct 4a in up
to 93% yield (Table 1, entries 1 and 3) with a d.r. of up to
96:4 (Table 1, entry 6) and an e.r. of up to 87:13 (Table 1,
entry 1) for the major diastereomer. We also investigated or-
ganocatalysts 3l–q, the Cinchona alkaloids and their deriva-
tives, with the same model reaction (Table 1, entries 12–17).
It was found that reaction with 3q as the catalyst proceeded
smoothly and afforded the product in 98% yield with a 93:7
d.r. but only a 75:25 e.r. (Table 1, entry 17). In addition,
commercially available cinchonine 3l promoted the reaction
to give 4a in 96% yield with a 90:10 d.r. and up to an 87:13
e.r. (Table 1, entry 12). Therefore, we selected 3l as the opti-
mal catalyst for further optimization of the reaction condi-
tions.
We turned our attention to the further optimization of the
3l catalyzed reaction to improve the conjugate addition re-
action efficiency (Table 2). A solvent screen revealed that
the product 4a could be obtained from the reaction cata-
lyzed by 3l (5 mol%) in high yields after 6 h in all cases, but
variation of the solvent did have an effect on the stereose-
lectivity (Table 2, entries 1–13). Very poor asymmetric in-
duction was obtained when the reaction was conducted in
DMF (Table 2. entry 1). Good diastereoselectivity (d.r.=
92:8) but low enantioselectivity (e.r.=57:43) was observed
with CH3CN as the solvent (Table 2, entry 2). Among sever-
al other solvents surveyed (Table 2, entries 3–13), the best
results could be achieved in trichloroethane (yield=95%,
d.r.=95:5, e.r.=88:12; Table 2, entry 13). When the reaction
temperature was lowered from room temperature to À308C
there was an improvement of diastereoselectivity (d.r.=
Scheme 5. The chiral organocatalysts evaluated in this study.
Chem. Eur. J. 2012, 00, 0 – 0
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W.-C. Yuan et al.
Table 2. Further screening of various reaction conditions.[a]
6). In addition, the reaction with 2e, which bears an elec-
tron-donating group on each phenyl ring, also proceeded
well and furnished the desired product 4i in 95% yield, 97:3
d.r. and 91:9 e.r. (Table 3, entry 4). The reaction also took
place with the heteroaromatic substituent thiophene on the
dienone (2h) to give 4l in good yield and diastereoselectiv-
ity, but moderate enantioselectivity (Table 3, entry 7). The
bulkier naphthyl group could be present (2i) without imped-
ing the course of the reaction and 4m was obtained with ac-
ceptable results (Table 3, entry 8).
Entry Solvent
x [mol%] T [oC] Yield [%][b] d.r.[c] e.r. [%][d]
1
2
3
4
5
6
7
8
DMF
5
5
5
5
5
5
5
5
5
5
5
5
5
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
À30
À30
À30
À30
84
89
93
88
90
93
89
93
96
89
93
95
95
92
92
94
94
51:49 52:48
92:8 57:43
91:9 80:20
91:9 69:31
96:4 67:33
90:10 86:14
92:8 83:17
92:8 85:15
90:10 87:13
90:10 80:20
91:9 86:14
93:7 83:17
95:5 88:12
99:1 89:11[e]
99:1 92:8[e]
98:2 93:7[e]
98:2 94:6[e,f]
CH3CN
EtOAc
THF
Et2O
PhOMe
On the other hand, we prepared a library of 3-benzyl ox-
indoles 1 that bore different substituents and employed
them in the reaction with 2a under the standard conditions
(Table 3, entries 9–17). Gratifyingly, these cinchonine-cata-
lyzed conjugate addition reactions proceeded well to pro-
vide Michael adducts 4n–v in very high yields, with excellent
d.r. and good e.r. values. These results revealed that the re-
activity and the selectivity of these asymmetric Michael ad-
dition reactions were not sensitive to the electronic and
steric properties of the substituents incorporated into the
benzene ring of the oxindole C3-benzyl group (Table 3, en-
tries 9–15). The bulkier oxindole 1m could also be smoothly
converted into 4u with very good results (Table 3, entry 16).
Meanwhile, installation of a thienylmethyl group at the ox-
indole C3 position allowed the conjugate addition between
1n and 2a to proceed smoothly to give 4v (Table 3,
entry 17). We also found that electron-donating and elec-
tron-withdrawing substituents could be tolerated on the ox-
indole aromatic ring (Table 3, entries 18 and 19). Notably,
an aliphatic group (a methyl group in 1q) at the C3 position
of the oxindole was tolerated and the desired product 4y
was obtained with good selectivity (d.r.=93:7 and e.r.=
88:12), albeit in only 37% yield (Table 3, entry 20). Similar-
ly, substrate 1r could smoothly deliver the expected adduct
4z with acceptable results (Table 3, entry 21). Reaction with
ester-substituted oxindole 1s was also successful and afford-
ed 4a’ with pleasing results (Table 3, entry 22). Unfortunate-
ly, the reaction with (E)-hex-3-ene-2,5-dione (2j) as the ac-
ceptor did not proceed (Table 3, entry 23). However, it was
gratifying to find that (E)-ethyl-4-oxo-4-phenylbut-2-enoate
(2k) was able to give 4c’ in a reasonable yield with moder-
ate d.r. and e.r. values under the optimized reaction condi-
tions (Table 3, entry 24).
A
toluene
CH2Cl2
CHCl3
ClCH2CH2Cl
Cl2CHCHCl2
Cl3CCH3
Cl3CCH3
Cl3CCH3
Cl3CCH3
Cl3CCH3
9
10
11
12
13
14
15
16
17
5
10
20
20
[a] Unless specified, the reaction was performed with 1a (0.12 mmol), 2a
(0.1 mmol), and 3l (5 mol%) in specified solvent (1.0 mL) for 6 h.
[b] Isolated product yield. [c] Determined by 1H NMR spectroscopy.
[d] Determined by chiral HPLC analysis for the major diastereomer (the
major isomer is indicated in parentheses). [e] Run for 36 h. [f] c=
0.2 molLÀ1
.
99:1) and a similar enantioselectivity without sacrifice to the
yield, although an extended reaction time was required
(Table 2, entry 14 versus 13). Next, a survey of the catalyst
loading revealed that the enantioselectivity improved slight-
ly with an increase of catalyst loading (Table 2, entries 15
and 16). Finally, up to a 98:2 d.r. and a 94:6 e.r. could be
reached at higher concentration (Table 2, entry 17). To sum-
marize, the optimized reaction conditions for the asymmet-
ric conjugate addition of 3-monosubstituted oxindoles 1 to
(E)-1,4-diaryl-2-buten-1,4-diones 2 were: 1a (0.24 mmol), 2a
(0.2 mmol), and 3l (20 mol%) at À308C in trichloroethane
(1.0 mL).
Substrate scope of the asymmetric conjugate addition of ox-
indoles 1 to dienones 2: With the optimized reaction condi-
tions in hand, we next examined a variety of 3-substituted
oxindoles (1a and 1 f–s) and (E)-1,4-diaryl-2-buten-1,4-
diones (2a–j) to establish the general utility of this asym-
metric transformation (Table 3). First, we focused our stud-
ies on addition of 1a to 2b–i to investigate the scope and
limitations of the electrophile. As shown in Table 3, the re-
action tolerated different electron-withdrawing groups on
the aryl moieties of 2; compounds 4 f–h were obtained in
high yields, with high d.r. and good e.r. values (Table 3, en-
tries 1–3). We also found that electrophilic substrates 2c, 2 f,
and 2g, which contain the same electron-withdrawing group
but in different positions on the phenyl ring, smoothly deliv-
ered the corresponding adducts 4g, 4j, and 4k in high yield
and with good d.r. and e.r. values (Table 3, entries 2, 5, and
Determination of the absolute configuration of the product
and proposed working model for the reaction: To determine
the absolute and relative configuration of the asymmetric
conjugate addition products, single crystals suitable for X-
ray crystallographic analysis were fortunately obtained from
enantiopure 4k, which bears a chlorine atom.[26] As shown
in Figure 1, 4k contains a (C7R, C21S) configuration. The
configuration of the other adducts in this work were tenta-
tively assigned by analogy.
Based on the experimental results discussed above and
the observed absolute configuration of 4k, a possible work-
ing model to account for the stereoselectivity of the reaction
is shown in Scheme 6. One double hydrogen-bonding inter-
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Addition of Monosubstituted Oxindoles to Diarylbutendiones
FULL PAPER
Table 3. Asymmetric conjugate addition of 3-monosubstituted oxindoles 1 to (E)-1,4-diaryl-2-buten-1,4-diones 2.[a]
Entry
1
2
4
Yield [%][b]
d.r.[c]
e.r.[d]
À
1
2
3
4
5
6
7
8
Ar=p-F Ph (2b)
4 f
4g
4h
4i
4j
4k
4l
96
93
88
95
88
92
93
61
95:5
97:3
92:8
97:3
95:5
97:3
93:7
91:9
90:10
94:6
89:11
91:9
87:13
87:13[e]
78:22[f]
76:24[f]
À
Ar=p-Cl Ph (2c)
À
Ar=p-Br Ph (2d)
À
Ar=m-MeO Ph (2e)
AHCTUNGTERG(NNUN 1a)
À
Ar=m-Cl Ph (2 f)
À
Ar=o-Cl Ph (2g)
Ar=2-thienyl (2h)
Ar=2-naphthyl (2i)
4m
À
9
Ar=p-MeO Ph (1 f)
(2a)
4n
94
98:2
92:8
À
10
11
12
13
14
15
16
17
Ar=p-F Ph (1g)
4o
4p
4q
4r
4s
4t
95
95
93
88
90
96
95
95
98:2
97:3
98:2
96:4
96:4
98:2
98:2
98:2
93:7
87:13
93:7
84:16
90:10
92:8
À
Ar=m-Me Ph (1h)
À
Ar=m-F Ph (1i)
À
Ar=o-MeO Ph (1j)
À
Ar=o-F Ph (1k)
À
Ar=3,4-(MeO)2 Ph (1l)
Ar=1-naphthyl (1m)
Ar=2-thienyl (1n)
4u
4v
93:7
95:5
18
19
20
21
G
4w
4x
4y
4z
82
93
37
70
96:4
98:2
93:7
98:2
89:11
94:6
88:12[f]
89:11[f]
22
23
G
4a’
4b’
97
93:7
–
92:8
–
G
NR[f,g]
24
4c’
81
75:25
87:13
[a] Unless specified, the reaction was performed with 1 (0.24 mmol), 2 (0.2 mmol), and 3l (20 mol%) in trichloroethane (1.0 mL) at À308C for 36 h.
[b] Isolated product yield. [c] Determined by 1H NMR spectroscopy. [d] Determined by chiral HPLC analysis for the major diastereomer (the major
isomer is indicated in parentheses). [e] Single crystals suitable for X-ray crystallographic analysis were obtained, see ref. [26]. [f] Run at RT for 24 h.
[g] NR=no reaction.
action might be formed between the protonated tertiary
amine group of the catalyst and the two carbonyl units of
the protected oxindole. Meanwhile, another hydrogen-bond-
ing interaction would be generated between the C9 hydroxyl
group of the catalyst and one carbonyl group of 2g. Conse-
quently, the nucleophilic oxindole 1a and the electrophilic
dienone 2g are simultaneously activated by bifunctional or-
ganocatalyst 3l through multiple hydrogen-bonding interac-
tions. Here, there are two possible transition states, A and
B. Of them, transition state A is formed predominately;
transition state B is disfavored, likely due to the unfavorable
hydrogen-bonding interaction between the C9 hydroxyl
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W.-C. Yuan et al.
3-furanyl-3-alkyl-oxindoles 5a–s with good e.r. values (up to
94:6) and yields from 88–95% (Scheme 7).[27] Electron-do-
nating (5g) and electron-withdrawing groups (5b–f) on the
aryl ring of the 1,4-dicarbonyl moiety were compatible with
the Paal–Knorr furanylation conditions. Similarly, a variety
of functional groups on the benzyl moiety (5i–n) and the ox-
indole aromatic ring (5p–q) were also tolerated. Additional-
ly, reversal of the steric properties of the substituents on the
1,4-dicarbonyl and C3-benzyl moieties (5h versus 5o)
showed almost no influence on the cyclization. Replacement
of the benzyl group with a methyl (5r) or n-butyl group (5s)
at the C3 position had no effect on the reaction. The Mi-
chael adduct 4a’ also could be smoothly transformed to give
product 5t (Scheme 7). Notably, in all cases, the N-Boc
group of compounds 4 was cleanly removed during the
Paal–Knorr furanylation reaction and, thus, afforded a class
of unprotected 3-furanyl-3-alkyl-oxindoles 5 that are diffi-
cult to access by other methods.
Figure 1. X-ray structure of 4k.
Cyclization of the 1,4-dicarbonyl moiety of Michael adducts
4 for the synthesis of 3-pyrrolyl-3-alkyl-oxindoles 6: Inspired
by the success of the Paal–Knorr furanylation described
above, we attempted to convert the diverse 1,4-dicarbonyl
moieties of the Michael adducts 4 into pyrrolyl rings. As
shown in Scheme 8, various Michael adducts 4 were subject-
ed to Paal–Knorr pyrrolylation conditions with ammonium
acetate (10 equiv) in acetic acid at 1008C for 3.5 h.[27] Similar
to the preceding Paal–Knorr furanylation studies, the 1,4-di-
carbonyl group cyclized smoothly to give the pyrrole ring.
As a result, an array of 3-pyrrolyl-3-alkyl-oxindoles 6a–
s with various steric and electronic parameters were con-
structed in high yields (up to 94%) with moderate-to-good
e.r. values that ranged from 75:25 to 94:6 (Scheme 8). Inter-
estingly, the N-Boc group of compounds 4 was also depro-
tected under these Paal–Knorr pyrrolylation conditions.
Overall, two kinds of unprotected chiral 3,3’-disubstituted
oxindole derivative, namely, 3-furanyl-3-alkyl-oxindoles 5
and 3-furanyl-3-alkyl-oxindoles 6, were obtained smoothly
under different Paal–Knorr conditions by the indirect strat-
egies described above.
Scheme 6. Proposed working model for the asymmetric conjugate addi-
tion of 3-monosubstituted oxindoles to (E)-1,4-diaryl-2-buten-1,4-diones.
group of the catalyst and one carbonyl group of the dienone.
In light of the X-ray crystallographic analysis of product 4k,
it is likely deduced that the Si face of dienone 2g was pref-
erentially attacked by the Re face of the enolate of 1a to
afford the Michael adduct 4k with a (C7R,C21S) configura-
tion.
Conclusion
Cyclization of the 1,4-dicarbonyl moiety of Michael adducts
4 for the synthesis of 3-furanyl-3-alkyl-oxindoles 5: The 3-
aryl-3-alkyl-oxindole structural motif is the ubiquitous core
of some bioactive natural products and pharmaceutically
active compounds.[24] With the successful construction of
a wide range of 3,3’-disubstituted oxindoles substituted at
the C3 position with a 1,4-dicarbonyl moiety realized, we
decided to further transform these resultant Michael adducts
4 into 3-tetrasubstituted oxindoles which possess a heteroaryl
group at the C3 position by treatment with different Paal–
Knorr conditions.[23] First, we tried to convert the 1,4-dicar-
bonyl moiety into furanyl ring. To our delight, treatment of
the Michael adducts 4 with TsOH (2 equiv) in toluene at
808C for 12 h, resulted in the formation of a wide scope of
We have developed an efficient method for the catalytic
asymmetric conjugate addition reaction of 3-monosubstitut-
ed oxindoles 1 to various (E)-1,4-diaryl-2-buten-1,4-diones 2
with cinchonine (3l) as a catalyst. This new organocatalytic
reaction proceeds with excellent diastereo- and moderate-
to-high enantioselectivity to deliver a broad range of 3,3’-
disubstituted oxindole derivatives 4 in high-to-excellent
yields. The resultant 3-tetrasubstituted oxindole adducts 4
are characterized by the presence of a 1,4-dicarbonyl moiety
and two adjacent quaternary and tertiary stereocenters that
are difficult to access by other methods. A plausible working
model that involves concerted activation has been proposed.
Furthermore, the cyclization of the 1,4-dicarbonyl moiety
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Addition of Monosubstituted Oxindoles to Diarylbutendiones
FULL PAPER
method for the indirect enan-
tioselective heteroarylation of
3-alkyl-oxindole derivatives, but
also provides a new route to-
wards the synthesis of structur-
ally diverse 3,3’-disubstituted
oxindole derivatives.
Experimental Section
General: 1H and 13C NMR spectra
were recorded on a Bruker 300 MHz
spectrometer in CDCl3 or [D6]DMSO
with tetramethylsilane (TMS) as an in-
ternal standard. Optical rotations were
measured on a PerkinElmer 241 polar-
imeter. Melting points were recorded
on a Bꢂchi melting point B-545 appa-
ratus. HPLC was performed with a Shi-
madzu instrument. 1,1,1-Trichloro-
ethane was distilled over CaH2 prior
to use; toluene was distilled from
sodium benzophenone. Unless noted,
commercial reagents were used with-
out further purification. All reactions
were conducted in
a closed system
under an atmosphere of air and were
monitored by TLC, except when
noted. 3-Monosubstituted oxindoles
1[28] and (E)-1,4-diaryl-2-buten-1,4-
diones 2[29] were prepared by literature
procedures.
General procedure for cinchonine-cat-
alyzed asymmetric conjugate addition
of oxindoles 1 to dienones 2 (4a): A
solution of 1a (0.24 mmol), 2a
(0.2 mmol),
and
cinchonine
3l
(0.04 mmol) in 1,1,1-trichloroethane
(1 mL) was stirred for 36 h at À308C.
The reaction mixture was directly sub-
jected to flash column chromatogra-
phy on silica gel (petroleum ether/
ethyl acetate) to furnish 4a as a white
solid (94%, d.r.=98:2, e.r.=94:6).
HPLC (performed after the N-Boc
group was deprotected by treatment
with CF3COOH in CH2Cl2 at RT,
Chiralcel AD-H column, iPrOH/
hexane 50:50, flow rate=1.0 mLminÀ1
UV detection at l=254 nm): tR(major)
,
=
Scheme 7. Transformation of Michael adducts 4 (0.2 mmol) to 3-furanyl-3-alkyl-oxindole derivatives 5. The
yield given is the isolated yield and e.r. values were determined by chiral HPLC analysis.
84.80 min,
tR(minor) =17.30 min; m.p.
84.6–87.38C; [a]2D0 =À2.4 (c=1.37 in
contained in the Michael adducts 4 under different Paal–
Knorr conditions results in unprotected 3-furanyl- or 3-pyr-
rolyl-3-alkyl-oxindoles (5 and 6, respectively). These two
classes of chiral 3-heteroaryl-3-alkyl-oxindoles have been
obtained smoothly, with wide substrate scope, in high yields,
and with good enantioselectivities. In addition, the reactivity
and selectivity of the Paal–Knorr furanylation and pyrrolyla-
tion reactions are not sensitive towards the steric and elec-
tronic variation of the Michael adducts. Notably, the realiza-
tion of this two-step strategy of sequential conjugate addi-
tion/Paal–Knorr cyclization not only furnishes an efficient
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.56 (s, 9H), 2.86 (d, J=
12.6 Hz, 1H), 3.14 (d, J=12.6 Hz, 1H), 3.46 (dd, J=7.5, 18.6 Hz, 1H),
3.85 (dd, J=4.5, 18.6 Hz, 1H), 5.18 (dd, J=4.5, 7.5 Hz, 1H), 6.63 (d, J=
7.5 Hz, 2H), 6.92–7.01 (m, 3H), 7.06–7.15 (m, 2H), 7.41–7.54 (m, 8H),
7.93 (d, J=7.5 Hz, 2H), 8.11 ppm (d, J=12.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=27.9, 38.1, 43.9, 46.7, 54.6, 83.8, 114.6, 123.9, 124.0,
126.7, 127.4, 128.2, 128.3, 128.4, 128.6, 128.7, 129.7, 133.2, 133.5, 133.9,
135.9, 137.4, 139.9, 148.5, 177.2, 197.6, 200.7 ppm; IR (KBr): n˜ =1757,
1730, 1677, 1597, 1482, 1294, 1150, 750, 698 cmÀ1; HRMS (ESI): m/z
calcd for C36H33NNaO5: 582.2251 [M+Na]+; found: 582.2244.
General procedure for the synthesis of 3-furanyl-3-alkyl-oxindoles (5a):
A solution of 4a (0.2 mmol) and TsOH (0.4 mmol) in toluene (5 mL)
was heated at 808C for 12 h. After cooling to RT, the reaction mixture
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W.-C. Yuan et al.
698 cmÀ1; HRMS (ESI): m/z calcd for
C31H23NNaO2: 464.1621 [M+Na]+;
found: 464.1632.
General procedure for the synthesis of
3-pyrrolyl-3-alkyl-oxindoles (6a):
A
mixture of 4a (0.2 mmol) and
NH4OAc (2 mmol) in AcOH (2 mL)
was heated at 1008C for 3.5 h. After
cooling to RT, the reaction mixture
was diluted with CH2Cl2 and washed
with H2O. The aqueous phase was ex-
tracted with CH2Cl2, dried over anhy-
drous Na2SO4, then the combined or-
ganic phase was concentrated in vacuo
and purified by flash chromatography
(petroleum ether/ethyl acetate) on
silica gel to afford 6a as a white solid
(90%; e.r.=94:6). HPLC (Chiralcel
AD-H column, iPrOH/hexane 30:70,
flow rate=1.0 mLminÀ1, UV detection
at l=254 nm):
tR(major) =43.76 min,
tR(minor) =10.70 min; m.p. 80.1–82.68C;
[a]2D0 =+26.7 (c=3.12 in CHCl3);
1H NMR (300 MHz, CDCl3): d=3.50
(d, J=12.6 Hz, 1H), 3.74=(d, J=
12.6 Hz, 1H), 6.36 (d, J=7.8 Hz, 1H),
6.81–6.87 (m, 4H), 6.90–7.04 (m, 6H),
7.09–7.12 (m, 5H), 7.15–7.20 (m, 1H),
7.35–7.38 (m, 2H), 7.52 (d, J=7.8 Hz,
2H), 8.38 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=44.0, 54.2, 106.5,
109.2, 120.7, 121.7, 123.6, 124.7, 126.0,
126.3, 127.2, 127.3, 127.4, 128.7, 129.4,
129.9, 130.5, 130.8, 132.2, 133.3, 135.3,
140.5, 180.8 ppm; IR (KBr): n˜ =1707,
1619, 1584, 1490, 1471, 1219, 699 cmÀ1
;
HRMS
(ESI):
m/z
calcd
for
C31H24N2NaO: 463.1781 [M+Na]+;
found: 463.1784.
Acknowledgements
This work was supported by the Na-
tional Natural Science Foundation of
China (No. 20802074) and the Nation-
al Basic Research Program of China
(973 Program) (2010CB833300).
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Addition of Monosubstituted Oxindoles to Diarylbutendiones
FULL PAPER
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Received: October 19, 2011
Revised: February 2, 2011
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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W.-C. Yuan et al.
Asymmetric Catalysis
Y.-H. Liao, X.-L. Liu, Z.-J. Wu,
X.-L. Du, X.-M. Zhang,
W.-C. Yuan* ................... &&&& — &&&&
Organocatalytic Asymmetric Conju-
gate Addition of 3-Monosubstituted
Oxindoles to (E)-1,4-Diaryl-2-buten-
1,4-diones: A Strategy for the Indirect
Enantioselective Furanylation and
Pyrrolylation of 3-Alkyloxindoles
Itꢀs a cinch! An efficient cinchonine-
catalyzed asymmetric conjugate addi-
tion of 3-monosubstituted oxindoles to
(E)-1,4-diaryl-2-buten-1,4-diones
Cyclization of the 1,4-dicarbonyl
moiety in the Michael adducts gener-
ates 3-furanyl- or 3-pyrrolyl-3-alkyl-
oxindoles under different Paal–Knorr
conditions (see scheme).
results in 3,3’-disubstituted oxindoles.
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!