Diastereo- and enantioselective michael addition of 3-substituted oxindoles to trifluoromethyl-substituted nitro olefins catalyzed by a cinchona-alkaloid-derived squaramide

Article abstract of DOI:10.1002/ejoc.201301457

Highly efficient diastereo- and enantioselective Michael addition reactions between 3-substituted oxindoles and trifluoromethylated nitro olefins catalyzed by a quinine-derived squaramide have been investigated. The corresponding adducts, each bearing a chiral tertiary carbon center attached to a trifluoromethyl group and adjacent to a quaternary stereocenter at the C3 position of the oxindole, were obtained in good to excellent yields (up to 99 %) and with high diastereoselectivities (up to >20:1 dr) and excellent enantioselectivities (up to 99 % ee). We have developed highly effective diastereo- and enantioselective Michael additions of 3-substituted oxindoles to trifluoromethylated nitro olefins catalyzed by a quinine-derived squaramide catalyst. The corresponding adducts are obtained in good to excellent yields (up to 99 %) along with high diastereoselectivities (up to >20:1 dr) and excellent enantioselectivities (up to 99 % ee). Copyright

Full text of DOI:10.1002/ejoc.201301457

FULL PAPER
DOI: 10.1002/ejoc.201301457
Diastereo- and Enantioselective Michael Addition of 3-Substituted Oxindoles
to Trifluoromethyl-Substituted Nitro Olefins Catalyzed by a Cinchona-
Alkaloid-Derived Squaramide
Mei-Xin Zhao,*[a] Fei-Hu Ji,[a] Xiao-Li Zhao,[b] Ze-Zheng Han,[a] and Min Shi*[a,c]
Keywords: Organocatalysis / Michael addition / Heterocycles / Alkaloids / Fluorine
Highly efficient diastereo- and enantioselective Michael ad- to a trifluoromethyl group and adjacent to a quaternary
dition reactions between 3-substituted oxindoles and tri-
fluoromethylated nitro olefins catalyzed by a quinine-derived
squaramide have been investigated. The corresponding ad-
ducts, each bearing a chiral tertiary carbon center attached
stereocenter at the C3 position of the oxindole, were ob-
tained in good to excellent yields (up to 99%) and with high
diastereoselectivities (up to Ͼ20:1 dr) and excellent enantio-
selectivities (up to 99% ee).
adducts can readily be converted into alkaloids or their de-
rivatives.[6] Barbas III[6a] and Shibasaki[6b] independently
pioneered highly enantioselective conjugate additions of N-
Boc-protected 3-alkyl(aryl)oxindoles to nitro olefins
(Scheme 1) catalyzed either by chiral thioureas or by chiral
homodinuclear MnIII2-Schiff base complexes, and addition
of this type has since then been fully investigated by Maruo-
ka,[6c] Cheng,[6d] Yuan,[6e] Zhou,[6f] Enders,[6g] Du,[6h] and
their co-workers with use of chiral quaternary ammonium
salts, alkyl-substituted bifunctional thioureas, chiral
Ni(OAc)2-diamine complexes, cinchonidine-derived phos-
phoramides, chiral secondary amines, or bifunctional terti-
ary amine-squaramides as catalysts, respectively. However,
to the best of our knowledge, most of these protocols were
limited to nitrostyrene derivatives.[7]
Introduction
Trifluoromethylated compounds have played a unique
and significant role in agricultural and medicinal chemistry
due to the fact that the introduction of a trifluoromethyl
moiety into an organic structure can greatly modify that
system’s physicochemical features and consequently its bio-
logical properties.[1] Broad research efforts have thus been
focused on developing general methods for the synthesis of
compounds of this kind, and especially on the enantioselec-
tive construction of stereogenic centers bearing CF3
groups.[2] To date, two complementary strategies for the for-
mation of CF3-substituted stereogenic centers involve:
(i) direct asymmetric trifluoromethylation with the aid of
nucleophilic, electrophilic, or radical reagents, or (ii) asym-
metric reactions of prochiral trifluoromethylated sub-
strates.[3]
Recently, oxindoles containing quaternary chiral centers
at their 3-positions have emerged as attractive synthetic tar-
gets, because this structural motif is widely present in nu-
merous biologically and pharmaceutically active natural
products and molecules.[4] Among various excellent ap-
proaches for the asymmetric synthesis of 3,3-disubstituted
oxindole derivatives,[5] Michael additions of oxindoles to ni-
tro olefins are of particular interest because the Michael
[a] Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 Mei Long Road, Shanghai, 200237, P. R. China
E-mail: mxzhao@ecust.edu.cn
Scheme 1. Enantioselective Michael addition of oxindoles to nitro
olefins.
Mshi@mail.sioc.ac.cn
http://hyxy.ecust.edu.cn/new/index.php
As part of our ongoing interest in the asymmetric syn-
thesis of chiral 3,3-disubstituted oxindoles, we have pre-
viously developed cinchona-alkaloid-catalyzed enantio-
selective chlorination of 3-aryl-N-Boc-oxindoles with N-
chlorosuccinimide (NCS)[8a] and Michael additions between
3-aryl-N-Boc-oxindoles and phenyl vinyl sulfone[8b] or vinyl
[b] Department of Chemistry, East China Normal University,
3663 N. Zhongshan Road, Shanghai, 200062, P. R. China
[c] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301457.
644
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 644–653

Selective Michael Additions to Fluorinated Nitro Olefins
bisphosphonates.[8c] Considering that the incorporation of Table 1. Catalyst screening for enantioselective Michael addition of
oxindole 2a to nitro olefin 3[a]
.
tertiary trifluoromethyl stereocenters into heterocycles
could provide new drug candidates with unusual biological
activities,[9] and that trifluoromethylated nitro olefin have
been utilized as valuable and unique acceptors in many
asymmetric conjugate additions,[10] we envisioned that cin-
chona alkaloid catalysts might facilitate Michael additions
between 3-aryl-N-Boc-oxindoles and trifluoromethylated
nitro olefins to afford the desired adducts, each bearing a
chiral tertiary carbon center attached to a trifluoromethyl
group and adjacent to a quaternary stereocenter at the C3
position of the oxindole, which are of potential biological
activity and synthetic potential in organic synthesis
(Scheme 1). To the best of our knowledge, there are no ex-
amples of organocatalytic asymmetric Michael addition of
oxindoles to trifluoromethylated nitro olefins. Here we wish
to report our studies on this subject.
Entry
Catalyst 1
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
73
84
70
85
85
73
89
96
87
85
64
71
89
5.8:1
16:1
8.5:1
4
71
77
93
94
86
98.3
97
97.7
97
[e]
[e]
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
[e]
[e]
1g
1h
1i
9
10
11
12
13
1j
[e]
1k
1l
89
89
91
[e]
[e]
1m
Results and Discussion
[a] Unless noted otherwise, all reactions were carried out with ox-
indole 2a (0.10 mmol), nitro olefin 3a (0.15 mmol), and catalyst 1
(10 mol-%) in CH2Cl2 (1.0 mL) at 10 °C for 3 h. [b] Yield of iso-
lated product. [c] The dr of the purified product was determined by
1H NMR spectroscopy. [d] The ee was determined by HPLC on a
chiral stationary phase. [e] The opposite enantiomer was obtained.
Initial studies were carried out by using the reaction be-
tween 3-phenyl-N-Boc oxindole 2a (Table 1) and (E)-3,3,3-
trifluoro-1-nitroprop-1-ene (3) in CH2Cl2 at 10 °C as model
reaction in the presence of a variety of cinchona-alkaloid-
derived organocatalysts (Figure 1) to determine the optimal
conditions; the results of these experiments are summarized
in Table 1. With naturally available quinine (1a, Figure 1)
as catalyst the reaction took place smoothly and the desired
product 4a was obtained in good yield but with low stereo-
selectivity (Table 1, Entry 1). The cinchona-alkaloid-de-
rived bifunctional amine-thiourea catalysts 1b and 1c
showed only moderate catalytic activity in this reaction, af-
fording 4a in good yields with moderate diastereo- and
enantioselectivities (Table 1, Entries 2 and 3).
Chiral squaramides have become increasingly utilized as
a new class of hydrogen-bonding donor organocatalysts in
many asymmetric Michael addition reactions,[11] so squar-
amide catalysts 1d–f, based on a chiral cyclohexane-1,2-di-
amine skeleton, were synthesized and evaluated. To our de-
light, dimethyl- and pyrrolidine-substituted squaramide cat-
alysts 1d and 1e gave much better results, affording the de-
sired product 4a in good yields and with good stereoselecti-
vites (Ͼ20:1 dr, 93–94% ee, Table 1, Entries 4–6). Further
evaluation of cinchona-alkaloid-derived squaramide cata-
lysts 1g–m (Table 1, Entries 7–13) revealed that quinine-de-
rived squaramide 1g was the best catalyst for this reaction,
furnishing 4a in 89% yield and with Ͼ20:1 dr and 98.3% ee
(Table 1, Entry 7). Replacing the bis(trifluoromethyl)phenyl
group on the squaramide moiety of 1g with 4-trifluoro-
methylphenyl and 4-fluorophenyl groups gave the desired
product 4a with relatively lower enantioselectivities, prob-
ably due to the weak acidity of the squaramide ArN–H
groups in 1h and 1i (Table 1, Entries 7–9).
Quinidine- and cinchonine-derived squaramides 1k–m
also promoted this reaction, but gave 4a with opposite ab-
solute configuration and with much lower ee values than
those achieved with the corresponding quinine- and cin- Figure 1. Catalyst screening.
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645

M.-X. Zhao, F.-H. Ji, X.-L. Zhao, Z.-Z. Han, M. Shi
FULL PAPER
chonidine-derived catalysts 1g–j (Table 1, Entries 11–13 vs. 2 were varied (Table 3). For N-Boc-3-phenyloxindoles, sub-
7–10). stituents in either the 5- or the 6-positions were well toler-
Solvent effects were then extensively studied. It was ated and the corresponding adducts were obtained in good
found that variations in diastereoselectivity and yield were yields (80–94%) together with excellent stereoselectivities
slight, but significant variations in enantioselectivity were (Ͼ20:1 dr, 95–98% ee, Table 3, Entries 1–7). Substrates pos-
observed. Despite similar yields and dr values for these scre- sessing electron-donating groups gave the adducts in higher
ened solvents, very high ee values were obtained in chlorin- yields but with slightly lower enantioselectivities than those
ated solvents (Table 2, Entries 1–3) and in toluene (Table 2, of the corresponding substrates without substituents or
Entry 4), together with good ee values in THF (Table 2, En- with electron-withdrawing substituents (Table 3, Entries 4
try 5) and in CH3CN (Table 2, Entry 6). Dichloromethane and 5 vs. 1–3).
was found to be the optimal solvent for this reaction in
Table 3. Substrate scope of oxindoles 2 for enantioselective Michael
addition to nitro olefin 3.[a]
terms of reactivity and stereoselectivity, affording 4a in up
to 89% yield and with Ͼ20:1 dr and 98.3% ee (Table 2, En-
try 1).
Table 2. Optimization of reaction conditions for the enantioselec-
tive Michael addition of oxindole 2a to nitro olefin 3 catalyzed by
1g[a]
.
Entry Solvent
T [°C]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
CH2Cl2
CHCl3
DCE
toluene
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
10
10
10
10
10
10
10
20
0
89
88
90
89
87
87
85
73
83
85
91
91
90
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
98.3
97.8
97.0
97.6
87.8
88.0
98.1
97.1
97.4
97.9
97.8
97.9
98.1
Entry 2 [X, R]
4
Yield [%][b] dr[c]
ee [%][d]
7[e]
8[f]
9[e]
10[e]
1
2
3
4
5
6
7
8
2a [H, Ph]
2b [5-Cl, Ph]
2c [5-Br, Ph]
2d [5-Me, Ph]
2e [5-OMe, Ph]
2f [6-Cl, Ph]
2g [6-Br, Ph]
2h [H, p-FC6H4]
2i [H, pTol]
2j [5-F, pTol]
2k [5-Me, pTol]
2l [5-OMe, pTol]
2m [H, m-FC6H4]
2n [H, mTol]
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
90
90
80
94
93
84
85
80
88
95
96
99
93
96
84
61
trace
93
80
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
n.d
98
98
95
97
97
96
95
97
96
92
96
97
97
98
97
99
n.d
69
71
11[e,g] CH2Cl2
12[e,g,h] CH2Cl2
13[e,g,i] CH2Cl2
10
10
10
[a] Unless noted otherwise, all reactions were carried out with ox-
indole 2a (0.10 mmol), nitro olefin 3 (0.15 mmol), and cat. 1g
(10 mol-%) in solvent (1.0 mL) for 3 h. [b] Yield of isolated prod-
uct. [c] The dr of the purified product was determined by 1H NMR
spectroscopy. [d] The ee was determined by HPLC on a chiral sta-
tionary phase. [e] 5 mol-% of cat. 1g. [f] 3 mol-% of cat. 1g.
[g] 2.0 mL of CH2Cl2 were used. [h] 30 mg of 3 Å MS were added.
[i] 30 mg of 4 Å MS were added.
9
10
11
12
13
14
15
16[e]
17[f]
18[e]
19[e]
2o [H, m-MeOC6H4] 4o
2p [H, 2-naphthyl]
2q [5-F, oTol]
2r [H, Me]
4p
4q
4r
4s
Further examination of catalyst loading revealed that re-
ducing the equivalent of cat. 1g from 10 mol-% to 5 mol-%
still afforded 4a with comparable results (Table 2, Entries 7–
8). Changes in the reaction temperature were unproductive;
similar yields and slightly lower enantioselectivities were
obtained with elevated or reduced reaction temperatures
(Table 2, Entries 9–10). Changing the concentration of 2a
from 0.1 to 0.05 m was able to improve the yield slightly,
but with similar enantioselectivity (Table 2, Entries 11 vs.
7). Furthermore, the reaction produced 4a with a slight im-
provement in enantioselectivity and without detriment to
12:1
Ͼ20:1
2s [H, Bn]
[a] Unless noted otherwise, all reactions were carried out with ox-
indoles 2 (0.20 mmol), nitro olefin 3 (0.30 mmol), catalyst 1g
(5 mol-%), and 4 Å MS (30 mg) in CH2Cl2 (4.0 mL) at 10 °C for
3 h. [b] Yield of isolated product. [c] The dr of the purified product
was determined by 1H NMR spectroscopy. [d] The ee was deter-
mined by HPLC on a chiral stationary phase. [e] For 24 h. [f] For
48 h.
Further investigation of the substituent at C-3 revealed
the yield when 4 Å molecular sieves were used (Table 1, En- that the presence of para-substituted aryl groups led to
tries 12–13). smooth reactions, giving the desired adducts in good yields
Optimal reaction conditions have thus been identified as and with high stereoselectivities (Table 3, Entries 8–12). In
the use of 1.0 equiv. of 2a and 1.5 equiv. of 3 in dichloro- the cases of oxindoles 2m–o, substituted at C-3 with meta-
methane (0.05 m for 2a) at 10 °C in the presence of 5 mol- substituted aryl groups, the corresponding products 4m–o
% catalyst 1g and 4 Å molecular sieves.
were obtained in high yields together with excellent stereo-
With the optimized reaction conditions to hand, the sub- selectivities (Table 3, Entries 13–15). Substrate 2p, bearing
strate scope of this reaction was then examined by carrying a sterically bulky 2-naphthyl group at the oxindole C-3 po-
out a range of reactions in which both X and R in oxindoles sition, also gave the corresponding product 4p in moderate
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Selective Michael Additions to Fluorinated Nitro Olefins
yield and with excellent dr and ee values on prolongation Table 4. Substrate scope of oxindoles 5 for the enantioselective
Michael addition to nitro olefin 3.[a]
of the reaction time to 24 h (Table 3, Entry 16). With 3-
(o-tolyl)-substituted oxindole 2q, however, the reaction was
sluggish and only a trace of desired product 4q was afforded
even after prolongation of the reaction time to 48 h, pre-
sumably due to steric hindrance (Table 3, Entry 17). No-
tably, 3-alkyloxindoles 2r and 2s are not suitable substrates
for this Michael addition, affording the corresponding ad-
ducts 4r and 4s in good yields but with only moderate
enantioselectivities (Table 3, Entries 18 and 19).
The effect of N-protecting group on this Michael ad-
dition was also investigated, by subjection of several 3-
phenyloxindoles with different N-protecting groups to the
optimized reaction conditions (Table 4). With N-unprotec-
Entry 2, 5 [R]
4, 6 t [h] Yield [%][b]
dr[c]
ee [%][d]
ted oxindole 5a, N-methyl-substituted oxindole 5b, and N-
benzyl-substituted oxindole 5c as the corresponding sub-
strates the reactions were more sluggish than in the case of
N-Boc-substituted oxindole 2a, affording the corresponding
adducts 6a–c in moderate yields (27–66%) but with moder-
ate to good diastereoselectivies (6:1–16:1 dr) and good to
excellent enantioselectivities (83–98% ee) on prolongation
of the reaction time to up to 6 days (Table 4, Entries 2–4 vs.
1). N-Acetyl-protected oxindole 5d gave the corresponding
product 6d in good yield along with high dr and ee values
with a reaction time prolonged to 3 days (Table 4, Entry 5).
N-Methoxycarbonyl- and N-Cbz-protected oxindoles 5e
and 5f, however, gave high yields along with high stereose-
lectivities (Ͼ20:1 dr, 96–98% ee), thus indicating that the
presence of a N-carbonate protecting group is crucial for
satisfactory reactivity and good stereochemical outcome
(Table 4, Entries 6 and 7).
1
2
3
4
5
6
7
2a [Boc]
5a [H]
5b [Me]
5c [Bn]
5d [Ac]
5e [CO2Me]
5f [Cbz]
4a
6a 120
6b 144
6c
6d
6e
6f
3
90
66
27
37
86
98
99
Ͼ20:1
8:1
6:1
98
83
90
98
97
98
96
24
72
3
16:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
3
[a] Unless noted otherwise, all reactions were carried out with ox-
indoles 2 or 5 (0.20 mmol), isocyanoacetate 3a (0.30 mmol), cata-
lyst 1g (5 mol-%), and 4 Å MS (30 mg) in CH2Cl2 (4.0 mL) at
10 °C. [b] Yield of isolated product. [c] The dr of the purified prod-
uct was determined by 1H NMR spectroscopy. [d] The ee was deter-
mined by HPLC on a chiral stationary phase.
The absolute and relative configurations of the major
diastereomers of adducts 4 were unambiguously assigned
by X-ray crystallographic analysis of the optically pure
compound 4f,[12] which was obtained by recrystallization
from chloroform (Table 3, Entry 8). The configuration of
the stereogenic center of the major diastereomer of product
4f at the C3 position was determined to be R and that at
the remaining stereocenter also as R (Figure 2). The config-
urations of other adducts 4 and 6 were then assigned by
analogy.
On the basis of the above results and commonly accepted
mechanism, a plausible transition-state model as shown in
Scheme 2 is proposed. The nitro group of olefin 3 is H-
bonded to the squaramide motif, whereas oxindole is de-
protonated by the quinuclidine nitrogen of catalyst 1g, re-
sulting in a single H-bonding interaction between the OH
group of the enolized oxindole and the tertiary amine. Ad-
ditionally, a weak H-bonding interaction might concur-
rently be produced between the carbonyl group of Boc and
the enolized oxindole, which enables the enolized oxindole
to attack much more easily the nitroolfin from the Re-face,
leading to formation of the two newly generated stereocen-
ters with (3R,2ЈR) configuration.
Figure 2. ORTEP drawing of 4f.
To illustrate the synthetic utility of the Michael addition
products 4, we next explored their transformations into
some trifluoromethylated natural product analogues, which
might possess important biological activity and are hence Scheme 2. Proposed transition state model.
Eur. J. Org. Chem. 2014, 644–653
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647

M.-X. Zhao, F.-H. Ji, X.-L. Zhao, Z.-Z. Han, M. Shi
FULL PAPER
5,[15] nitro olefin 3,[16] and catalysts 1[17] were prepared by literature
methods. Racemic Michael addition products for chiral HPLC
analysis were prepared from the corresponding oxindoles 2 or 5
(0.20 mmol) and olefin 3 (0.30 mmol) in the presence of DABCO
(0.2 mmol) in CH2Cl2 (2.0 mL) at room temperature.
valuable for drug discovery. Raney nickel reduction of ad-
duct 4a followed by methyl carbamate formation, for exam-
ple, provided compound 7.[6a] Moreover, trifluoromethyl-
substituted 2,3,3a,8-tetrahydropyrrolo[2,3-b]indole deriva-
tive 8, with a core structure similar to those of many impor-
tant natural products,[13] can easily be obtained by Raney
General Procedure for Enantioselective Michael Addition of Ox-
nickel reduction of adduct 4a followed by removal of the indoles 2 or 5 to Nitro Olefin 3 with Catalysis by 1g: A solution of
nitro olefin 3 (0.3 mmol), cat. 1g (0.01 mmol), and 4 Å molecular
sieves (30 mg) in CH2Cl2 (4.0 mL) was stirred at 10 °C for 15 min,
followed by addition of the oxindole 2 or 5 (0.2 mmol). The re-
sulting mixture was stirred at 10 °C for 3–144 h until the reaction
was complete (monitoring by TLC). After concentration, the resi-
due was directly subjected to flash column chromatography on sil-
ica gel (petroleum ether/ethyl acetate 25:1 as eluent) to furnish the
corresponding adduct 4 or 6.
Boc protecting group with trifluoroacetic acid in CH2Cl2
and reductive cyclization in good yield and without any ef-
fect on the enantioselectivity (Scheme 3).[6c]
tert-Butyl (R)-2-Oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-nitroprop-
an-2-yl]indoline-1-carboxylate (4a): Yield 81.0 mg (90%). White so-
lid, m.p. 125.7–127.5 °C. [α]2D5 = +166.3 (c = 3.40, CH2Cl2); 98% ee
(Chiralpak AS-H; hexane/propan-2-ol 98:2; 0.8 mLmin–1; 254 nm;
tminor = 12.99 min, tmajor = 15.85 min); Ͼ20:1 dr. 1H NMR
(400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 1 H, ArH), 7.50 (td,
J = 8.0, 1.2 Hz, 1 H, ArH), 7.36 (s, 5 H, ArH), 7.32 (td, J = 7.6,
0.8 Hz, 1 H, ArH), 7.14 (d, J = 7.6 Hz, 1 H, ArH), 4.87–4.79 (m,
2 H, CH2), 4.52–4.47 (m, 1 H, CH), 1.60 (s, 9 H, 3ϫCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.4, 148.7, 139.9, 135.0, 130.1,
129.6, 129.3, 127.4, 125.7, 125.1 (d, J = 280.9 Hz), 124.5, 124.4,
116.2, 85.1, 71.2, 55.1, 48.6 (q, J = 25.8 Hz), 27.9 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.7 (d, J = 6.8 Hz, 3 F) ppm. IR (film):
Scheme 3. Synthetic transformations of adduct 4a.
Conclusions
ν = 1794, 1768, 1737, 1566, 1373, 1343, 1296, 1249, 1148 cm–1.
We have developed efficient diastereo- and enantioselec-
tive Michael additions of 3-substituted oxindoles to a tri-
fluoromethyl-substituted nitro olefin catalyzed by a quin-
ine-derived bifunctional squaramide catalyst. A wide vari-
ety of substituted oxindoles, with different electronic and
steric properties, were tolerated in these catalytic enantiose-
lective Michael additions, which afforded the corresponding
adducts in high yields (up to 99%) along with good to ex-
cellent diastereo- and enantioselectivities (up to Ͼ20:1 dr,
up to 99% ee). Furthermore, the adducts can readily be
transformed into trifluoromethylated natural product ana-
logues for medicinal research. Investigations directed
towards fully understanding the reaction mechanism and
developing more effective addition reactions between ox-
indoles and other electrophiles are continuing.
˜
HRMS (ESI-TOF): calcd. for C22H21F3N2NaO5 [M + Na]+
473.1300; found 473.1305.
tert-Butyl
(R)-5-Chloro-2-oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4b): Yield 87.0 mg (90%).
White solid, m.p. 143.2–145.0 °C. [α]2D5 = +241.6 (c = 3.40,
CH2Cl2); 98% ee (Chiralcel OD-H; hexane/propan-2-ol 98:2;
0.5 mLmin–1; 254 nm; tmajor = 12.00 min, tminor = 25.94 min);
1
Ͼ20:1 dr. H NMR (CDCl3, 400 MHz): δ = 8.01 (d, J = 9.2 Hz, 1
H, ArH), 7.48 (dd, J = 9.2, 2.4 Hz, 1 H, ArH), 7.41–7.33 (m, 5 H,
ArH), 7.12 (d, J = 2.4 Hz, 1 H, ArH), 4.86–4.79 (m, 2 H, CH2),
4.46 (dd, J = 12.0, 6.8 Hz, 1 H, CH), 1.59 (s, 9 H, 3ϫCH3) ppm.
13C NMR (CDCl3, 100 MHz): δ = 172.7, 148.5, 138.6, 134.3, 130.2,
130.1, 129.8, 129.6, 127.2, 126.2, 125.7, 125.0 (d, J = 280.8 Hz),
117.5, 85.5, 70.9, 55.2, 48.4 (d, J = 26.0 Hz), 27.9 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.7 (d, J = 6.8 Hz, 3 F) ppm. IR (film):
ν = 1796, 1771, 1738, 1568, 1475, 1373, 1331, 1296, 1249, 1149,
˜
761 cm–1. HRMS (ESI-TOF): calcd. for C22H20ClF3N2NaO5 [M +
Na]+ 507.0911; found 507.0912.
Experimental Section
General: NMR spectra were recorded with a Bruker AVANCE
400 MHz spectrometer in CDCl3 with tetramethylsilane (TMS) as
the internal standard; J values are given in Hz. IR spectra were
recorded with a Bruker tensor 27 infrared spectrometer. Chiral
HPLC was performed with a Shimadzu SPD-10A series instrument
and chiral columns. MS (EI) and HRMS (ESI or EI) were recorded
with a Waters LCT Premier XE spectrometer or a Finnigan MA+
spectrometer. Optical rotations were determined with a PolAAr
3005 high-accuracy polarimeter; [α]D values are given in units of
10–1 degcm2 g–1. Flash column chromatography was performed
with silica gel (300–400 mesh). Melting points were measured with
a digital apparatus. Unless otherwise noted, all commercially ob-
tained reagents were used without further purification. All reac-
tions were carried out under air in closed systems. Oxindoles 2[14]or
tert-Butyl
(R)-5-Bromo-2-oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4c): Yield 85.5 mg (80%).
White solid, m.p. 134.0–135.1 °C. [α]2D5 = +260.7 (c = 4.20,
CH2Cl2); 95% ee (Chiralcel OD-H; hexane/propan-2-ol 90:10;
0.7 mLmin–1; 230 nm; tmajor = 6.86 min, tminor = 12.90 min);
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.8 Hz, 1
H, ArH), 7.63 (dd, J = 8.8, 2.0 Hz, 1 H, ArH), 7.40–7.38 (m, 3 H,
ArH), 7.35–7.33 (m, 2 H, ArH), 7.25 (d, J = 1.6 Hz, 1 H, ArH),
4.86–4.79 (m, 2 H, CH2), 4.46 (dd, J = 12.4, 6.8 Hz, 1 H, CH),
1.58 (s, 9 H, 3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
172.6, 148.5, 139.1, 134.4, 133.2, 129.8, 129.6, 128.5, 127.2, 126.6,
125.0 (d, J = 280.7 Hz), 117.9, 117.4, 85.5, 71.0, 55.1, 48.4 (d, J =
26.0 Hz), 27.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –65.7 (d, J
= 7.1 Hz, 3 F) ppm. IR (film): ν = 1796, 1771, 1738, 1567, 1474,
˜
648
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 644–653

Selective Michael Additions to Fluorinated Nitro Olefins
1373, 1331, 1296, 1249, 1149, 823 cm–1. HRMS (ESI-TOF): calcd.
for C22H20BrF3N2NaO5 [M + Na]+ 551.0405; found 551.0411.
85.7, 71.0, 55.0, 48.4 (q, J = 26.0 Hz), 27.9 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.7 (d, J = 6.8 Hz, 3 F) ppm. IR (film):
ν = 1797, 1774, 1738, 1567, 1477, 1373, 1337, 1294, 1281, 1244,
˜
tert-Butyl (R)-5-Methyl-2-oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4d): Yield 87.1 mg (94%).
White solid, m.p. 154.8–156.3 °C. [α]2D5 = +162.8 (c = 4.30,
CH2Cl2); 97% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2;
1148, 841, 759 cm–1. HRMS (ESI-TOF): calcd. for
C22H20BrF3N2NaO5 [M + Na]+ 551.0405; found 551.0400.
tert-Butyl (R)-3-(4-Fluorophenyl)-2-oxo-3-[(2ЈR)-1,1,1-trifluoro-3-
0.5 mLmin–1; 254 nm; tmajor = 13.50 min, tminor = 15.95 min); nitropropan-2-yl]indoline-1-carboxylate (4h): Yield 75.0 mg (80%).
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.4 Hz, 1
H, ArH), 7.36 (s, 5 H, ArH), 7.30 (d, J = 8.4 Hz, 1 H, ArH), 6.93
(s, 1 H, ArH), 4.89–4.79 (m, 2 H, CH2), 4.49 (d, J = 13.6 Hz, 1 H,
White solid, m.p. 117.9–119.7 °C. [α]2D5 = +170.2 (c = 3.70,
CH2Cl2); 97% ee (Chiralpak AS-H; hexane/propan-2-ol 98:2;
0.7 mLmin–1; 254 nm; tminor = 13.39 min, tmajor = 16.03, min);
1
CH), 2.44 (s, 3 H, CH3), 1.59 (s, 9 H, 3ϫCH3) ppm. 13C NMR Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.0 Hz, 1
(100 MHz, CDCl3): δ = 173.5, 148.7, 137.6, 135.2, 134.2, 130.6, H, ArH), 7.50 (td, J = 8.4, 0.8 Hz, 1 H, ArH), 7.36 (dd, J = 8.4,
129.5, 129.2, 127.4, 126.5 (d, J = 280.8 Hz), 126.1, 124.4, 115.9,
84.9, 71.2, 55.2, 48.4 (q, J = 26.1 Hz), 27.9, 21.1 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.7 (d, J = 7.5 Hz, 3 F) ppm. IR (film):
5.2 Hz, 2 H, ArH), 7.31 (dd, J = 7.6, 0.8 Hz, 1 H, ArH), 7.14 (d,
J = 7.2 Hz, 1 H, ArH), 7.05 (t, J = 8.4 Hz, 2 H, ArH), 4.84 (dd, J
= 14.4, 8.8 Hz, 1 H, CH), 4.75 (quint-d, J = 8.8, 1.6 Hz, 1 H, CH),
4.74 (d, J = 14.4 Hz, 1 H, CH), 1.60 (s, 9 H, 3ϫCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 173.3, 163.0 (d, J = 249.4 Hz), 148.6,
139.9, 130.7 (d, J = 3.0 Hz), 130.3, 129.5 (d, J = 8.2 Hz), 125.6,
125.0 (d, J = 280.8 Hz), 124.6, 124.2, 116.6 (d, J = 21.5 Hz), 116.3,
85.3, 71.1, 54.6, 48.6 (q, J = 25.9 Hz), 27.9 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.9 (d, J = 7.5 Hz, 3 F), –111.6 ppm. IR
ν = 1792, 1765, 1737, 1566, 1491, 1373, 1334, 1310, 1246, 1151,
˜
821 cm–1. HRMS (ESI-TOF): calcd. for C23H23F3N2NaO5 [M +
Na]+ 487.1457; found 487.1457.
tert-Butyl (R)-5-Methoxy-2-oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4e): Yield 88.7 mg (93%).
White solid, m.p. 136.5–137.1 °C. [α]2D5 = +295.9 (c = 4.00,
CH2Cl2); 97% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2;
0.5 mLmin–1; 254 nm; tmajor = 16.45 min, tminor = 35.87 min);
(film): ν = 1793, 1767, 1738, 1566, 1509, 1372, 1341, 1296, 1239,
˜
1148, 835, 761 cm–1. HRMS (ESI-TOF): calcd. for
C22H20F4N2NaO5 [M + Na]+ 491.1206; found 491.1205.
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 9.2 Hz, 1
H, ArH), 7.37 (br. s, 5 H, ArH), 7.01 (dd, J = 9.2, 2.4 Hz, 1 H,
ArH), 6.67 (d, J = 1.2 Hz, 1 H, ArH), 4.86–4.79 (m, 2 H, CH2),
tert-Butyl
(R)-2-Oxo-3-(p-tolyl)-3-[(2ЈR)-1,1,1-trifluoro-3-nitro-
propan-2-yl]indoline-1-carboxylate (4i): Yield 81.5 mg (88%). White
4.51–4.46 (m, 1 H, CH), 3.86 (s, 3 H, OCH3), 1.58 (s, 9 H, solid, m.p. 109.5–110.6 °C. [α]2D5 = +144.3 (c = 4.00, CH2Cl2);
3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.3, 156.6,
148.8, 135.0, 133.3, 129.6, 129.2, 127.4, 125.7, 125.1 (d, J =
281.1 Hz), 117.0, 113.9, 112.7, 84.8, 71.1, 55.7, 55.4, 48.4 (q, J =
25.9 Hz), 27.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –65.7 (d, J
96% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2; 0.5 mLmin–1;
254 nm; tmajor = 13.02 min, tminor = 14.88 min); Ͼ20:1 dr. 1H NMR
(400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 1 H, ArH), 7.49 (td,
J = 8.4, 1.2 Hz, 1 H, ArH), 7.31 (dd, J = 7.2, 0.4 Hz, 1 H, ArH),
7.24 (d, J = 8.4 Hz, 2 H, ArH), 7.16 (d, J = 8.0 Hz, 2 H, ArH),
7.14 (d, J = 8.0 Hz, 1 H, ArH), 4.87–4.77 (m, 2 H, CH2), 4.52 (d,
= 7.1 Hz, 3 F) ppm. IR (film): ν = 1794, 1765, 1736, 1568, 1490,
˜
1373, 1296, 1279, 1248, 1151, 846, 818, 735 cm–1. HRMS (ESI-
TOF): calcd. for C23H23F3N2NaO6 [M + Na]+ 503.1406; found J = 13.2 Hz, 1 H, CH), 2.31 (s, 3 H, CH3), 1.59 (s, 9 H,
503.1407.
3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.5, 148.7,
139.9, 139.4, 132.0, 130.3, 130.0, 127.2, 125.7, 125.1 (d, J =
280.9 Hz), 124.5, 124.4, 116.1, 85.0, 71.2, 54.8, 48.5 (q, J =
25.8 Hz), 27.9, 20.8 ppm. 19F NMR (376 MHz, CDCl3): δ = –65.7
tert-Butyl
(R)-6-Chloro-2-oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4f): Yield 80.3 mg (84%).
White solid, m.p. 129.0–130.0 °C. [α]2D5 = +134.7 (c = 3.00,
CH2Cl2); 96% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2;
0.5 mLmin–1; 254 nm; tmajor = 11.90 min, tminor = 14.01 min);
(d, J = 7.1 Hz, 3 F) ppm. IR (film): ν = 1794, 1767, 1737, 1566,
˜
1466, 1372, 1342, 1296, 1248, 1149, 760 cm–1. HRMS (ESI-TOF):
calcd. for C23H23F3N2NaO5 [M + Na]+ 487.1457; found 487.1444.
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 1.6 Hz, 1
H, ArH), 7.38–7.33 (m, 5 H, ArH), 7.32 (dd, J = 8.0, 1.6 Hz, 1 H,
ArH), 7.07 (d, J = 8.0 Hz, 1 H, ArH), 4.81–4.78 (m, 2 H, CH2),
tert-Butyl (R)-5-Fluoro-2-oxo-3-(p-tolyl)-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4j): Yield 79.6 mg (95%).
4.48–4.42 (m, 1 H, CH), 1.59 (s, 9 H, 3ϫCH3) ppm. 13C NMR White solid, m.p. 157.9–158.5 °C. [α]2D5 = +78.6 (c = 4.50, CH2Cl2);
(100 MHz, CDCl3): δ = 173.0, 148.5, 140.9, 136.1, 134.5, 129.7, 92% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2; 0.5 mLmin–1;
129.5, 127.3, 126.5, 125.1 (d, J = 281.0 Hz), 124.6, 122.8, 117.0,
85.7, 71.0, 54.9, 48.5 (q, J = 26.0 Hz), 27.9 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.7 (d, J = 6.4 Hz, 3 F) ppm. IR (film):
1
254 nm; tmajor = 11.60 min, tminor = 17.32 min); 20:1 dr. H NMR
(400 MHz, CDCl3): δ = 8.05 (dd, J = 8.8, 4.8 Hz, 1 H, ArH), 7.23–
7.17 (m, 5 H, ArH), 6.85 (dd, J = 7.6, 2.4 Hz, 1 H, ArH), 4.84–
4.77 (m, 2 H, CH2), 4.51–4.46 (m, 1 H, CH), 2.32 (s, 3 H, CH3),
1.59 (s, 9 H, 3ϫCH3) ppm. 13C NMR (CDCl3, 100 MHz): δ =
173.1, 159.5 (d, J = 243.9 Hz), 148.7, 139.7, 136.0, 131.4, 130.5,
127.1, 126.3 (d, J = 7.6 Hz), 125.1 (d, J = 281.2 Hz), 117.6 (d, J =
8.0 Hz), 116.8 (d, J = 22.4 Hz), 113.1 (d, J = 24.3 Hz), 85.3, 71.0,
55.1, 48.4 (q, J = 26.2 Hz), 27.9, 20.9 ppm. 19F NMR (376 MHz,
CDCl3): δ = –65.8 (d, J = 6.4 Hz, 3 F), –116.7 (m) ppm. IR (film):
ν = 1797, 1773, 1738, 1568, 1373, 1338, 1295, 1243, 1147, 841,
˜
770 cm–1. HRMS (ESI-TOF): calcd. for C22H20ClF3N2NaO5 [M +
Na]+ 507.0911; found 507.0901.
tert-Butyl
(R)-6-Bromo-2-oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4g): Yield 89.3 mg (85%).
White solid, m.p. 123.7–125.1 °C. [α]2D5 = +154.8 (c = 1.00,
CH2Cl2); 95% ee (Chiralpak AD-H; hexane/propan-2-ol 98:2;
ν = 1792, 1772, 1734, 1566, 1458, 1376, 1245, 1148, 1126, 821,
˜
0.8 mLmin–1; 254 nm; tminor
= 8.01 min, tmajor = 9.01 min);
720 cm–1. HRMS (ESI-TOF): calcd. for C23H22F4N2NaO5 [M +
Na]+ 505.1363; found 505.1365.
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 1.6 Hz, 1
H, ArH), 7.47 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 7.38–7.33 (m, 5 H,
ArH), 7.01 (d, J = 8.4 Hz, 1 H, ArH), 4.82–4.78 (m, 2 H, CH2),
tert-Butyl (R)-5-Methyl-2-oxo-3-(p-tolyl)-3-[(2ЈR)-1,1,1-trifluoro-3-
4.47–4.43 (m, 1 H, CH), 1.60 (s, 9 H, 3ϫCH3) ppm. 13C NMR nitropropan-2-yl]indoline-1-carboxylate (4k): Yield 91.0 mg (96%).
(100 MHz, CDCl3): δ = 172.8, 148.5, 141.0, 134.4, 129.8, 129.5, White solid, m.p. 130.2–131.3 °C. [α]2D5 = +118.3 (c = 4.00,
127.6, 127.3, 126.8, 125.0 (d, J = 281.2 Hz), 124.0, 123.3, 119.8,
CH2Cl2); 96% ee (Chiralpak IC-H; hexane/propan-2-ol 99:1;
649
Eur. J. Org. Chem. 2014, 644–653
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

M.-X. Zhao, F.-H. Ji, X.-L. Zhao, Z.-Z. Han, M. Shi
FULL PAPER
0.7 mLmin–1; 254 nm; tmajor = 12.85 min, tminor = 15.00 min); 1.60 (s, 9 H, 3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
1
Ͼ20:1 dr. H NMR (CDCl3, 400 MHz): δ = 7.90 (d, J = 8.4 Hz, 1
173.4, 148.8, 139.9, 139.5, 135.0, 130.07, 130.02, 129.4, 128.0,
H, ArH), 7.28 (dd, J = 8.0, 0.8 Hz, 1 H, ArH), 7.23 (d, J = 8.0 Hz, 125.7, 125.1 (d, J = 280.8 Hz), 124.53, 124.48, 124.4, 116.2, 85.1,
2 H, ArH), 7.16 (d, J = 8.4 Hz, 2 H, ArH), 6.91 (s, 1 H, ArH),
4.85 (dd, J = 14.0, 9.2 Hz, 1 H, CH), 4.78 (quint., J = 8.0 Hz, 1
71.3, 55.1, 48.5 (q, J = 25.9 Hz), 27.9, 21.5 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.7 (d, J = 6.8 Hz, 3 F) ppm. IR (film):
H, CH), 4.51 (d, J = 14.4 Hz, 1 H, CH), 2.44 (s, 3 H, CH3), 2.31 ν = 1794, 1767, 1737, 1566, 1482, 1466, 1372, 1342, 1295, 1174,
˜
(s, 3 H, CH3), 1.59 (s, 9 H, 3ϫCH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 173.6, 148.8, 139.3, 137.6, 134.2, 132.2, 130.6, 130.3,
127.3, 126.1, 125.2 (d, J = 279.7 Hz), 124.6, 115.9, 84.8, 71.3, 55.0,
48.4 (q, J = 25.9 Hz), 27.9, 21.2, 20.9 ppm. 19F NMR (376 MHz,
1148, 1128, 742 cm–1. HRMS (ESI-TOF): calcd. for
C23H23F3N2NaO5 [M + Na]+ 487.1457; found 487.1458.
tert-Butyl (R)-3-(3-Methoxyphenyl)-2-oxo-3-[(2ЈR)-1,1,1-trifluoro-
3-nitropropan-2-yl]indoline-1-carboxylate (4o): Yield 80.2 mg
(84%). White solid, m.p. 146.0–147.7 °C. [α]2D5 = +150.7 (c = 4.00,
CH2Cl2); 97% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2;
0.5 mLmin–1; 254 nm; tmajor = 15.30 min, tminor = 17.87 min);
CDCl ): δ = –65.7 (d, J = 7.1 Hz, 3 F) ppm. IR (film): ν = 1791,
˜
3
1765, 1737, 1566, 1491, 1373, 1335, 1311, 1246, 1151, 1123, 821,
739 cm–1. HRMS (ESI-TOF): calcd. for C24H25F3KN2O5 [M +
K]+ 517.1353; found 517.1302.
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.4 Hz, 1
H, ArH), 7.51 (t, J = 7.6 Hz, 1 H, ArH), 7.33 (t, J = 7.6 Hz, 1 H,
ArH), 7.28 (t, J = 8.0 Hz, 1 H, ArH), 7.15 (d, J = 7.6 Hz, 1 H,
ArH), 6.95 (s, 1 H, ArH), 6.90 (d, J = 8.4 Hz, 2 H, ArH), 4.90–
4.79 (m, 2 H, CH2), 4.54 (d, J = 12.8 Hz, 1 H, CH), 3.79 (s, 3 H,
OCH3), 1.62 (s, 9 H, 3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 173.3, 160.3, 148.7, 139.9, 136.5, 130.5, 130.1, 125.7, 125.1 (d,
J = 280.8 Hz), 124.5, 120.9, 119.6, 116.2, 114.8, 113.2, 85.1, 71.2,
55.2, 55.1, 48.5 (q, J = 25.9 Hz), 27.9 ppm. 19F NMR (376 MHz,
tert-Butyl (R)-5-Methoxy-2-oxo-3-(p-tolyl)-3-[(2ЈR)-1,1,1-trifluoro-
3-nitropropan-2-yl]indoline-1-carboxylate (4l): Yield 98.0 mg (99%).
White solid, m.p. 148.3–150.1 °C. [α]2D5 = +171.0 (c = 4.80,
CH2Cl2); 97% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2;
0.5 mLmin–1; 254 nm; tmajor = 16.55 min, tminor = 34.53 min);
1
Ͼ20:1 dr. H NMR (CDCl3, 400 MHz): δ = 7.96 (d, J = 9.2 Hz, 1
H, ArH), 7.25 (d, J = 8.8 Hz, 2 H, ArH), 7.17 (d, J = 8.0 Hz, 2 H,
ArH), 7.01 (dd, J = 9.2, 2.4 Hz, 1 H, ArH), 6.67 (d, J = 2.4 Hz, 1
H, ArH), 4.84 (dd, J = 13.6, 8.8 Hz, 1 H, CH), 4.79 (quint., J =
8.8 Hz, 1 H, CH), 4.50 (d, J = 13.2 Hz, 1 H, CH), 3.86 (s, 3 H,
OCH3), 2.31 (s, 3 H, CH3), 1.59 (s, 9 H, 3ϫCH3) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 173.5, 156.5, 148.8, 139.4, 133.2, 131.9,
130.2, 127.2, 125.9, 125.1 (d, J = 280.9 Hz), 117.0, 113.8, 112.7,
84.7, 71.2, 55.7, 55.1, 48.3 (q, J = 26.0 Hz), 27.9, 20.8 ppm. 19F
NMR (376 MHz, CDCl3): δ = –65.7 (d, J = 7.5 Hz, 3 F) ppm. IR
CDCl ): δ = –65.8 (d, J = 7.1 Hz, 3 F) ppm. IR (film): ν = 1794,
˜
3
1767, 1737, 1566, 1466, 1372, 1341, 1294, 1249, 1147, 840, 773,
759 cm–1. HRMS (ESI-TOF): calcd. for C23H23F3KN2O6 [M +
K]+ 519.1145; found 519.1133.
tert-Butyl (R)-3-(Naphthalen-2-yl)-2-oxo-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4p): Yield 70.0 mg (61%).
White solid, m.p. 150.7–152.0 °C. [α]2D5 = +117.7 (c = 3.50,
CH2Cl2); 99% ee (Chiralpak AS-H; hexane/propan-2-ol 98:2;
0.5 mLmin–1; 254 nm; tminor = 20.39 min, tmajor = 24.15 min);
(film): ν = 1791, 1765, 1735, 1567, 1509, 1350, 1298, 1248, 1152,
˜
816, 739 cm–1. HRMS (ESI-TOF): calcd. for C24H25F3N2NaO6 [M
+ Na]+ 517.1562; found 517.1535.
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.4 Hz, 1
H, ArH), 7.92 (d, J = 9.2 Hz, 1 H, ArH), 7.83 (d, J = 8.0 Hz, 1 H,
ArH), 7.76 (d, J = 8.8 Hz, 1 H, ArH), 7.70 (d, J = 8.0 Hz, 1 H,
ArH), 7.49–7.46 (m, 4 H, ArH), 7.39 (t, J = 7.6 Hz, 1 H, ArH),
7.23 (d, J = 7.6 Hz, 1 H, ArH), 4.98 (quint., J = 8.0 Hz, 1 H, CH),
4.88 (dd, J = 14.8, 9.2 Hz, 1 H, CH), 4.51 (d, J = 14.8 Hz, 1 H,
CH), 1.60 (s, 9 H, 3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 173.3, 148.7, 140.0, 133.1, 132.8, 132.3, 130.2, 130.0, 128.3, 127.7,
127.5, 127.4, 126.9, 125.8, 125.2 (d, J = 280.8 Hz), 124.6, 124.4,
123.7, 116.3, 85.1, 71.2, 55.3, 48.4 (q, J = 25.9 Hz), 27.9 ppm. 19F
NMR (376 MHz, CDCl3): δ = –65.6 (d, J = 7.1 Hz, 3 F) ppm. IR
tert-Butyl (R)-3-(3-Fluorophenyl)-2-oxo-3-[(2ЈR)-1,1,1-trifluoro-3-
nitropropan-2-yl]indoline-1-carboxylate (4m): Yield 86.4 mg (93%).
White solid, m.p. 135.7–137.5 °C. [α]2D5 = +174.4 (c = 4.20,
CH2Cl2); 97% ee (Chiralpak IC-H; hexane/propan-2-ol 98:2;
0.5 mLmin–1; 254 nm; tmajor = 13.11 min, tminor = 16.40 min);
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 1
H, ArH), 7.51 (td, J = 8.8, 1.2 Hz, 1 H, ArH), 7.40–7.31 (m, 2 H,
ArH), 7.26 (d, J = 8.0 Hz, 1 H, ArH), 7.14 (d, J = 7.2 Hz, 1 H,
ArH), 7.06 (tdd, J = 8.0, 2.4, 0.8 Hz, 1 H, ArH), 7.03–6.98 (m, 1
H, ArH), 4.85 (dd, J = 14.4, 8.8 Hz, 1 H, CH), 4.75 (qd, J = 7.6,
1.6 Hz, 1 H, CH), 4.47 (d, J = 14.8 Hz, 1 H, CH), 1.60 (s, 9 H,
3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9, 163.1 (d,
J = 247.5 Hz), 148.6, 139.9, 137.5 (d, J = 6.9 Hz), 131.3 (d, J =
8.4 Hz), 130.4, 125.6, 125.0 (d, J = 281.1 Hz), 124.7, 123.9, 123.2
(d, J = 2.7 Hz), 116.6, 116.4, 115.0 (d, J = 24.3 Hz), 85.3, 71.1, 54.9,
48.6 (q, J = 26.1 Hz), 27.9 ppm. 19F NMR (376 MHz, CDCl3): δ
(film): ν = 1793, 1766, 1737, 1565, 1482, 1466, 1372, 1339, 1293,
˜
1246, 1148, 759 cm–1. HRMS (ESI-TOF): calcd. for
C26H23F3N2NaO5 [M + Na]+ 523.1457; found 523.1428.
tert-Butyl (S)-3-Methyl-2-oxo-3-[(2ЈR)-1,1,1-trifluoro-3-nitroprop-
an-2-yl]indoline-1-carboxylate (4r): Yield 71.6 mg (93%). White so-
lid, m.p. 121.3–123.1 °C. [α]2D5 = +3.2 (c = 3.50, CH2Cl2); 69% ee
(Chiralpak AD-H; hexane/propan-2-ol 98:2; 0.7 mLmin–1; 254 nm;
= –65.8 (d, J = 7.1 Hz, 3 F), –109.6 (m) ppm. IR (film): ν = 1793,
˜
= 12.36 min, tmajor =
14.34 min); 12:1 dr. 1H NMR
1768, 1738, 1484, 1467, 1373, 1340, 1294, 1247, 1146, 841,
760 cm–1. HRMS (ESI-TOF): calcd. for C22H20F4KN2O5 [M +
K]+ 507.0945; found 507.0930.
tminor
(400 MHz, CDCl3): δ = 7.91 (d, J = 8.4 Hz, 1 H, ArH), 7.40–7.35
(m, 1 H, ArH), 7.23–7.17 (m, 2 H, ArH), 4.92 (dd, J = 14.8, 4.0 Hz,
1 H, CH), 4.80 (dd, J = 14.8, 2.8 Hz, 1 H, CH), 4.03–3.99 (m, 1
H, CH), 1.64 (s, 9 H, 3ϫCH3), 1.50 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 175.6, 148.7, 138.7, 129.5, 127.9, 125.0 (d,
J = 280.8 Hz), 124.8, 123.1, 115.7, 85.1, 70.5, 47.9 (q, J = 26.3 Hz),
47.0, 27.9, 23.2 ppm. 19F NMR (376 MHz, CDCl3): δ = –65.7 (d,
tert-Butyl
(R)-2-Oxo-3-(m-tolyl)-3-[(2ЈR)-1,1,1-trifluoro-3-nitro-
propan-2-yl]indoline-1-carboxylate (4n): Yield 89.1 mg (96%).
White solid, m.p. 132.5–134.1 °C. [α]2D5 = +121.6 (c = 4.40,
CH2Cl2); 98% ee (Chiralcel OD-H; hexane/propan-2-ol 99:1;
0.5 mLmin–1; 254 nm; tmajor = 15.28 min, tminor = 29.03 min);
J = 8.3 Hz, 3 F) ppm. IR (film): ν = 1759, 1720, 1567, 1466, 1373,
˜
1
Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.0 Hz, 1
1274, 1240, 1185, 1130, 763 cm–1. HRMS (ESI-TOF): calcd. for
C17H19F3KN2O5 [M + K]+ 427.0883; found 427.0883.
H, ArH), 7.49 (t, J = 8.0 Hz, 1 H, ArH), 7.31 (t, J = 7.6 Hz, 1 H,
ArH), 7.22 (d, J = 7.6 Hz, 1 H, ArH), 7.20 (s, 1 H, ArH), 7.14 (t,
J = 8.0 Hz, 2 H, ArH), 7.10 (d, J = 7.6 Hz, 1 H, ArH), 4.87–4.79
(S)-tert-Butyl 3-Benzyl-2-oxo-3-[(2ЈR)-1,1,1-trifluoro-3-nitropropan-
(m, 2 H, CH2), 4.50 (d, J = 12.8 Hz, 1 H, CH), 2.31 (s, 3 H, CH3), 2-yl]indoline-1-carboxylate (4s): Yield 74.2 mg (80%). White solid,
650
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 644–653

Selective Michael Additions to Fluorinated Nitro Olefins
m.p. 118.3–119.7 °C. [α]2D5 = –1.9 (c = 3.40, CH2Cl2); 71% ee (Chi-
ralpak AD-H; hexane/propan-2-ol 98:2; 0.5 mLmin–1; 254 nm;
tminor = 26.62 min, tmajor = 29.50 min); Ͼ20:1 dr. 1H NMR
(400 MHz, CDCl3): δ = 7.55 (d, J = 8.0 Hz, 1 H, ArH), 7.35 (d, J
= 7.6 Hz, 1 H, ArH), 7.29 (td, J = 7.6, 1.2 Hz, 1 H, ArH), 7.24 (t,
J = 7.2 Hz, 1 H, ArH), 7.07 (t, J = 7.6 Hz, 1 H, ArH), 6.98 (t, J
= 7.6 Hz, 2 H, ArH), 6.63 (d, J = 7.6 Hz, 2 H, ArH), 5.05 (dd, J
= 14.8, 4.4 Hz, 1 H, CH), 4.92 (dd, J = 14.8, 6.4 Hz, 1 H, CH),
4.31–4.26 (m, 1 H, CH), 3.21 (d, J = 12.0 Hz, 1 H, CH), 3.08 (d,
J = 12.0 Hz, 1 H, CH), 1.50 (s, 9 H, 3ϫCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.3, 147.9, 139.8, 131.8, 129.8, 129.6,
127.7, 127.4, 125.3, 125.0 (d, J = 280.8 Hz), 124.5, 123.4, 115.4,
84.4, 70.7, 53.2, 47.8 (q, J = 26.2 Hz), 42.7, 27.8 ppm. 19F NMR
(376 MHz, CDCl3): δ = –65.1 (d, J = 9.0 Hz, 3 F) ppm. IR (film):
1189, 1173, 1119, 806 cm–1. HRMS (ESI-TOF): calcd. for
C24H19F3N2NaO3 [M + Na]+ 463.1245; found 463.1248.
(R)-1-Acetyl-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-nitropropan-2-yl]-
indolin-2-one (6d): Yield 70.0 mg (86%). White solid, m.p. 120.1–
121.3 °C. [α]2D5 = +166.4 (c = 3.50, CH2Cl2); 97% ee (Chi-
ralpak AD-H; hexane/propan-2-ol 98:2; 0.7 mL min–1; 254 nm;
tminor = 15.61 min, tmajor = 29.25 min); Ͼ20:1 dr. 1H NMR
(400 MHz, CDCl3): δ = 8.40 (d, J = 8.0 Hz, 1 H, ArH), 7.52 (td,
J = 7.6, 1.2 Hz, 1 H, ArH), 7.39–7.34 (m, 6 H, ArH), 7.16 (d, J =
7.2 Hz, 1 H, ArH), 4.90–4.81 (m, 2 H, CH2), 4.52 (d, J = 12.4 Hz,
1 H, CH), 2.60 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 176.0, 170.6, 140.2, 134.9, 130.3, 129.7, 129.5, 127.3, 125.5,
125.3, 125.1 (d, J = 280.9 Hz), 124.6, 117.6, 71.1, 55.3, 48.4 (q, J
= 26.0 Hz), 26.5 ppm. 19F NMR (376 MHz, CDCl3): δ = –65.8 (d,
ν = 1789, 1768, 1738, 1566, 1468, 1372, 1339, 1291, 1248, 1149,
˜
J = 7.1 Hz, 3 F) ppm. IR (film): ν = 1760, 1721, 1570, 1374, 1293,
˜
1094, 772 cm–1. HRMS (ESI-TOF): calcd. for C23H23F3KN2O5 [M
+ K]+ 503.1196; found 503.1209.
1 1 8 7 , 1 1 3 2 , 7 8 3 c m – 1 . H RM S ( ES I- TO F) : c al cd . for
C19H15F3N2NaO4 [M + Na]+ 415.0882; found 415.0886.
(R)-3-Phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-nitropropan-2-yl]indolin-2-
one (6a): Yield 46.3 mg (66%). White solid, m.p. 210.3–212.2 °C.
[α]2D5 = +130.2 (c = 2.30, CH2Cl2); 83% ee (Chiralpak AD-H; hex-
ane/propan-2-ol 95:5; 0.7 mLmin–1; 254 nm; tminor = 29.73 min,
Methyl (R)-2-Oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-nitropropan-2-
yl]indoline-1-carboxylate (6e): Yield 80.5 mg (98%). White solid,
m.p. 117.4–119.0 °C. [α]2D5 = +163.8 (c = 4.00, CH2Cl2); 98% ee
(Chiralpak AS-H; hexane/propan-2-ol 95:5; 0.7 mLmin–1; 254 nm;
tminor = 28.18 min, tmajor = 55.76 min); Ͼ20:1 dr. 1H NMR
(400 MHz, CDCl3): δ = 8.11 (d, J = 8.4 Hz, 1 H, ArH), 7.53 (td,
J = 8.4, 1.2 Hz, 1 H, ArH), 7.38–7.34 (m, 6 H, ArH), 7.17 (d, J =
7.2 Hz, 1 H, ArH), 4.89–4.80 (m, 2 H, CH2), 4.50 (d, J = 12.8 Hz,
1 H, CH), 3.96 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 173.4, 151.0, 139.4, 134.7, 130.3, 129.7, 129.5, 127.3, 125.8,
125.1 (d, J = 280.8 Hz), 124.9, 124.4, 116.3, 71.1, 55.2, 54.2, 48.4
(q, J = 26.0 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –65.7 (d,
1
tmajor = 39.02 min); 8:1 dr. H NMR (400 MHz, CDCl3): δ = 8.82
(s, 1 H, NH), 7.43–7.39 (m, 3 H, ArH), 7.38–7.35 (m, 3 H, ArH),
7.22–7.14 (m, 2 H, ArH), 7.07 (d, J = 7.6 Hz, 1 H, ArH), 4.85 (dd,
J = 14.4, 9.2 Hz, 1 H, CH), 4.74 (qd, J = 8.0, 2.0 Hz, 1 H, CH),
4.50 (d, J = 14.0 Hz, 1 H, CH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 177.5, 141.0, 135.2, 129.9, 129.5, 129.1, 127.3, 126.2, 126.0,
125.2 (d, J = 280.9 Hz), 122.8, 111.4, 71.4, 55.2 (d, J = 1.3 Hz),
48.1 (q, J = 26.2 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –66.0
(d, J = 7.1 Hz, 3 F) ppm. IR (film): ν = 1794, 1767, 1737, 1566,
˜
J = 7.1 Hz, 3 F) ppm. IR (film): ν = 1799, 1769, 1744, 1566, 1483,
˜
1466, 1372, 1341, 1294, 1249, 1147, 840, 773, 759 cm–1. HRMS
(ESI-TOF): calcd. for C17H12F3N2O3 [M – H]+ 349.0800; found
349.0796.
1467, 1439, 1378, 1346, 1297, 1242, 1178, 1129, 762 cm–1. HRMS
(ESI-TOF): calcd. for C19H15F3N2NaO5 [M + Na]+ 431.0831;
found 431.0836.
(R)-1-Methyl-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-nitropropan-2-yl]-
indolin-2-one (6b): Yield 20.0 mg (27%). White solid, m.p. 112.3–
114.1 °C. [α]2D5 = +209.0 (c = 1.0, CH2Cl2); 90% ee (Chiralpak AS-
Benzyl (R)-2-Oxo-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-nitropropan-2-
yl]indoline-1-carboxylate (6f): Yield 96.0 mg (99%). White solid,
m.p. 100.9–102.3 °C. [α]2D5 = +107.7 (c = 4.90, CH2Cl2); 96% ee
(Chiralpak IC-H; hexane/propan-2-ol 98:2; 0.5 mLmin–1; 254 nm;
tmajor = 24.19 min, tminor = 28.24 min); Ͼ20:1 dr. 1H NMR
(400 MHz, CDCl3): δ = 8.11 (d, J = 8.4 Hz, 1 H, ArH), 7.53 (d, J
= 7.6 Hz, 1 H), 7.50–7.47 (m, 2 H, ArH), 7.41–7.34 (m, 9 H, ArH),
7.17 (d, J = 7.6 Hz, 1 H, CH), 5.41 (dd, J = 28.4, 12.4 Hz, 2 H,
H; hexane/propan-2-ol 95:5; 0.7 mL min–1; 254 nm; tminor
=
22.80 min, tmajor = 33.39 min); 6:1 dr. 1H NMR (400 MHz, CDCl3):
δ = 7.49–7.43 (m, 3 H, ArH), 7.40–7.34 (m, 3 H, ArH), 7.24–7.17
(m, 2 H, ArH), 6.98 (d, J = 7.6 Hz, 1 H, ArH), 4.84 (dd, J = 14.4,
8.8 Hz, 1 H, CH), 4.75 (qd, J = 7.6, 1.6 Hz, 1 H, CH), 4.50 (d, J =
14.0 Hz, 1 H, CH), 3.19 (s, 3 H, NCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 175.1, 143.9, 135.3, 129.9, 129.5, 129.1, 127.3, 126.1,
125.6, 125.2 (d, J = 280.8 Hz), 122.7, 109.5, 71.5, 54.6, 48.3 (q, J
= 26.0 Hz), 26.9 ppm. 19F NMR (376 MHz, CDCl3 ): δ =
OCH2), 4.89–4.83 (m, 2 H, CH), 4.55–4.50 (m, 1 H, CH) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 173.2, 150.3, 139.4, 134.7, 134.5,
130.2, 129.6, 129.4, 128.6, 128.5, 128.0, 127.4, 125.8, 125.1 (d, J =
280.9 Hz), 124.8, 124.4, 116.3, 71.1, 69.0, 55.2, 48.5 (q, J =
25.9 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –65.6 (d, J =
–66.1 ppm. IR (film): ν = 1719, 1613, 1564, 1495, 1472, 1374, 1351,
˜
1281, 1246, 1173, 1126, 802, 762 cm–1. MS (EI): m/z (%) = 364
[M]+ (48), 223 (14), 222 (100), 148 (93), 207 (8), 194 (6). HRMS
(EI): calcd. for C18H15F3N2O3 [M]+ 364.1035; found 364.1036.
6.8 Hz, 3 F) ppm. IR (film): ν = 1798, 1772, 1742, 1568, 1449, 1436,
˜
1380, 1296, 1228, 1181, 736 cm–1. HRMS (ESI-TOF): calcd. for
C25H19F3N2NaO5 [M + Na]+ 507.1144; found 507.1137.
(R)-1-Benzyl-3-phenyl-3-[(2ЈR)-1,1,1-trifluoro-3-nitropropan-2-yl]-
indolin-2-one (6c): Yield 32.2 mg (37%). White solid, m.p. 135.1–
137.2 °C. [α]2D5 = +332.6 (c = 1.50, CH2Cl2); 98% ee (Chiralpak AS-
Synthetic Transformation of Adducts 4a: Adduct 4a (40.0 mg,
0.08 mmol) was added to a suspension of Raney Ni (15 mg) in
MeOH (1.0 mL). The flask was evacuated and refilled with H2
three times. The reaction mixture was stirred at room temperature
under H2 (balloon) for 2 h and was then filtered through celite and
washed with methanol several times. The filtrate was concentrated
and dissolved in THF (1.5 mL). Hünig base (20 uL, 0.12 mmol)
H; hexane/propan-2-ol 98:2; 0.7 mL min–1; 254 nm; tminor
=
33.10 min, tmajor = 37.97 min); 16:1 dr. 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.36 (m, 2 H, ArH), 7.32–7.23 (m, 4 H, ArH),
7.20–7.15 (m, 3 H, ArH), 7.11–7.07 (m, 4 H, ArH), 6.79 (d, J =
8.0 Hz, 1 H, ArH), 4.84–4.75 (m, 4 H, 2 CH2), 4.46 (d, J = 13.2 Hz, and chloromethyl formate (0.1 mL, 1.3 mmol) were added slowly
1 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.2, 143.0, to this solution. The reaction mixture was then allowed to warm
135.6, 135.0, 129.8, 129.5, 129.1, 128.7, 127.7, 127.2, 127.1, 126.0,
to room temperature and stirred overnight. After dilution with
125.7, 125.2 (d, J = 280.9 Hz), 122.7, 110.6, 71.5, 54.7, 48.0 (q, J CH2Cl2, then reaction was quenched with saturated aqueous
= 26.0 Hz), 44.4 ppm. 19F NMR (376 MHz, CDCl3): δ = –65.8 (d,
J = 7.1 Hz, 3 F) ppm. IR (film): ν = 1714, 1611, 1563, 1467, 1377,
Na2CO3 solution. The aqueous layer was separated and extracted
with CH2Cl2 (3ϫ 5 mL). The combined organic layers were dried
˜
Eur. J. Org. Chem. 2014, 644–653
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
651

M.-X. Zhao, F.-H. Ji, X.-L. Zhao, Z.-Z. Han, M. Shi
FULL PAPER
with Na2SO4, filtered, and concentrated. The residue was then
purified by silica gel flash column chromatography with petroleum
ether/ethyl acetate (6:1 v/v) as eluent to afford 7 as a white solid
(27 mg, 70% over two steps), m.p. 153.0–153.7 °C. [α]2D5 = +283.8
(c = 0.8, CH2Cl2); 97% ee (Chiralpak IC-H; hexane/propan-2-ol
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90:10; 0.7 mL min–1; 254 nm; tmajor = 33.25 min, tminor
=
1
42.07 min); Ͼ20:1 dr. H NMR (400 MHz, CDCl3): δ = 7.98 (d, J
= 8.0 Hz, 1 H, ArH), 7.45 (td, J = 8.4, 1.2 Hz, 1 H, ArH), 7.37–
7.27 (m, 7 H, ArH), 4.85–4.84 (m, 1 H, NH), 3.94–3.92 (m, 1 H,
CH), 3.63 (s, 3 H, OCH3), 3.62–3.57 (m, 2 H, CH2), 1.58 (s, 9 H,
3 ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.6, 156.4,
148.9, 140.0, 135.5, 129.5, 128.9, 128.6, 127.6, 126.6, 126.4 (d, J =
281.2 Hz), 125.5, 124.1, 115.8, 84.7, 55.3, 52.3, 50.3 (q, J =
23.4 Hz), 37.7, 27.9 ppm. 19F NMR (376 MHz, CDCl3): δ =
[2]
–62.9 ppm. IR (film): ν = 1792, 1730, 1289, 1160, 1120, 1024,
˜
775 cm–1. MS (EI): m/z (%)=478 [M]+ (1), 346 (29), 208 (100), 180
(20), 165 (7). HRMS (EI): calcd. for C24H25F3N2O5 [M]+ 478.1716;
found 478.1720.
(3R,3aR)-3a-Phenyl-3-(trifluoromethyl)-2,3,3a,8-tetrahydropyrrolo-
[2,3-b]indole (8): Adduct 4a (90.0 mg, 0.2 mmol) was added to a
suspension of Raney Ni (30 mg) in MeOH (2.0 mL). The flask was
evacuated and refilled with H2 three times. The reaction mixture
was stirred at room temperature under H2 (balloon) for 2 h and
was then filtered through celite and washed with methanol several
times. The filtrate was concentrated and dissolved in CH2Cl2
(1 mL). TFA (228 mg, 2.0 mmol, 10 equiv.) was added to this solu-
tion, and the mixture was stirred at room temperature for 0.5 h.
Concentrated and dried under vacuum for 1 h, the resulted residue
was added to a suspension of LiAlH4 (72 mg, 2.0 mmol, 10 equiv.)
in THF (1.5 mL). The mixture was then heated at 75 °C for 2 h.
After having cooled to room temperature, the reaction mixture was
quenched with ethyl acetate (4.0 mL) and H2O (0.5 mL) and con-
centrated and the residue was purified by silica gel flash column
chromatography with petroleum ether/ethyl acetate (2:1 v/v) as elu-
ent to afford 8 as a white solid (36.0 mg, 60% overall yield for three
steps), m.p. 173.7–174.9 °C. [α]2D5 = –105.2 (c = 1.40, CH2Cl2);
97% ee (Chiralpak AS-H; hexane/propan-2-ol 90:10; 0.7 mLmin–1;
254 nm; tmajor = 15.37 min, tminor = 12.67 min); Ͼ20:1 dr. 1H NMR
(400 MHz, CDCl3): δ = 7.67 (d, J = 7.6 Hz, 1 H, ArH), 7.40 (d, J
= 7.6 Hz, 2 H, ArH), 7.31 (t, J = 7.6 Hz, 3 H, ArH), 7.25 (s, 1 H,
NH), 7.19 (t, J = 7.6 Hz, 1 H, ArH), 7.00 (t, J = 7.6 Hz, 1 H,
ArH), 6.79 (d, J = 7.6 Hz, 1 H, ArH), 4.15–4.11 (m, 1 H, CH),
4.05–3.99 (m, 1 H, CH), 3.36–3.30 (m, 1 H, CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 180.4, 148.7, 132.6, 132.0, 129.0, 128.5,
127.82, 127.80, 125.3 (d, J = 276.4 Hz), 125.2, 121.4, 111.7, 63.0,
57.3, 53.8 (q, J = 27.8 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ
[3]
[4]
[5]
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˜
HRMS (ESI-TOF): calcd. for C17H14F3N2 [M + H]+ 303.1109;
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and X-ray crystal data for product 4f.
Acknowledgments
The authors are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant numbers
20772030, 21072056, 21272067), the Fundamental Research Funds
for the Central Universities, the Scientific Research Foundation for
the Returned Overseas Chinese Scholars, and the State Education
Ministry, P. R. China.
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Received: September 25, 2013
Published Online: November 15, 2013
Eur. J. Org. Chem. 2014, 644–653
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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