Michael addition of N-unprotected 2-oxindoles to nitrostyrene catalyzed by bifunctional tertiary amines: Crucial role of dispersion interactions

Article abstract of DOI:10.1002/cctc.201301052

Bifunctional thiourea- or sulfonamide-derived tertiary amines catalyze the enantioselective nitro-Michael addition of N-unprotected 3-substituted 2-oxindoles to nitrostyrene in up to 99 % yields, 94:6 er, and 87:13 dr. Overcoming the necessity to introduc

Full text of DOI:10.1002/cctc.201301052

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DOI: 10.1002/cctc.201301052
Michael Addition of N-Unprotected 2-Oxindoles to
Nitrostyrene Catalyzed by Bifunctional Tertiary Amines:
Crucial Role of Dispersion Interactions
Christoph Reiter,[a] Sꢀnia Lꢁpez-Molina,[a] Bernhard Schmid,[b] Christian Neiss,[b]
Andreas Gçrling,*[b] and Svetlana B. Tsogoeva*[a]
Bifunctional thiourea- or sulfonamide-derived tertiary amines
catalyze the enantioselective nitro-Michael addition of N-un-
protected 3-substituted 2-oxindoles to nitrostyrene in up to
99% yields, 94:6 er, and 87:13 dr. Overcoming the necessity to
introduce and remove activating or protecting groups at the
nitrogen moiety leads to a reduction of energy use, costs, and
waste. Transition-state geometries for the formation of all pos-
sible stereoisomers in the nitro-Michael addition of N-unpro-
tected 3-substituted 2-oxindole to nitrostyrene catalyzed by
Takemoto’s tertiary amine–thiourea are calculated. It is shown
that the relative positions and binding patterns of the reac-
tants and the catalyst molecule are largely determined by van
der Waals interactions.
Introduction
Compounds with an N-unsubstituted oxindole core that pos-
sess a tertiary and/or a quaternary stereo center at the C3 posi-
tion are ubiquitous in natural products, drugs, and pharmaco-
logically active compounds. Therefore, N-unsubstituted oxin-
doles are a highly attractive group of substances, the biologi-
cal properties of which mostly depend on their functional
groups at the C3 position (Figure 1). 7-(O-b-Glucosyloxy)oxin-
dole-3-acetic acid (GOA, 1), for example, has shown to be
a potent antioxidant occurring in super-sweet corn powder.[1]
In nature, several examples of spirooxindoles such as coerules-
cine (2) and horsfiline (3), having analgesic effects, can be
found.[2] Convolutamydine A (4) has been demonstrated to be
an effective compound against leukemia HL-60 cells.[3] Cynthi-
chlorine (5) is an antibacterial, antifungal, and cytotoxic agent
from the tunicate Cynthia savignyi.[4]
These versatile properties justify the great efforts put in the
catalytic asymmetric synthesis of 3,3-disubstituted oxindoles.
In the last years, a couple of different organocatalyzed asym-
metric reactions have been used[5] for transformations of the
Figure 1. Biologically active N-unsubstituted oxindoles in nature. GOA=7-
(O-b-Glucosyloxy)oxindole-3-acetic acid.
[a] C. Reiter,+ S. Lꢀpez-Molina,+ Prof. Dr. S. B. Tsogoeva
Chair of Organic Chemistry I
oxindole core, including Michael additions,[6,7] Henry reac-
tions,[8] aldol reactions,[9] Mannich reactions,[10] alkylations,[11]
cycloadditions,[12] and domino reactions.[11a,13]
Friedrich-Alexander University of Erlangen-Nuremberg
Henkestrasse 42, 91054 Erlangen (Germany)
Fax: (+49)9131-85-22865
Among these reactions, the Michael addition of oxindoles to
nitro olefins is a useful tool because its products can be con-
verted to alkaloids or derivatives thereof. To efficiently perform
this type of Michael reaction, efforts have been made to devel-
op cinchona-alkaloid-derived bifunctional catalysts.[14] Besides
the regularly used bifunctional thiourea catalysts, a recent ap-
proach is to catalyze the conjugate additions with N-sulfona-
mides.[15] These catalysts containing an acidic hydrogen have
been shown to be effective and useful cinchona-alkaloid bi-
functional catalysts and have demonstrated their ability of
E-mail: svetlana.tsogoeva@fau.de
[b] B. Schmid, Dr. C. Neiss, Prof. Dr. A. Gçrling
Chair of Theoretical Chemistry and Interdisciplinary Center
for Molecular Materials (ICMM)
Friedrich-Alexander University of Erlangen-Nuremberg
Egerlandstraße 3, 91058 Erlangen (Germany)
Fax: (+49)9131-85-27736
E-mail: andreas.goerling@fau.de
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201301052.
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single-hydrogen-bonding interactions in asymmetric organo-
catalysis.
Table 1. Screening of solvents for the Michael addition using Takemoto’s
catalyst 8.[a]
The first step in the course of this Michael reaction is depro-
tonation at the C3 position of 2-oxindole. As the pKa value is
comparatively high,[16] the deprotonation is a challenging step.
By introduction of an electron-withdrawing group at the nitro-
gen moiety of 3-substituted oxindoles, the pKa value can be
lowered and thereby the deprotonation step facilitated.[6f]
Therefore, several reactions have been published applying 3-
substituted oxindoles that are protected or substituted at the
nitrogen atom,[6] and only limited examples are known based
on 2-oxindoles with a free NH group.[7] As the introduction and
removal of activating groups imply an extra cost of time,
chemicals, waste, and energy through the additional steps, it is
desirable to develop reactions with N-unprotected/N-unsubsti-
tuted oxindoles. Following our previous work on the 1,4-conju-
gate addition of N-unprotected 2-oxindoles to a,b-unsaturated
ketones[17] and applying our expertise in the research fields of
the catalytic construction of quaternary carbon centers[18] and
different 1,4-conjugate additions,[19] we decided to study the
nitro-Michael addition of different N-unprotected 3-substituted
2-oxindoles to nitrostyrene.
Entry
Solvent
t [h]
Yield [%][b]
dr (syn/anti)[c,d]
ee [%][c,d]
1
2
3
4
5
6
7
toluene
CH2Cl2
CH3CN
DMF
THF
EtOAc
Et2O
45
46
46
46
48
48
48
64
60
86
73
99
93
96
64:36
66:34
80:20
74:26
80:20
78:22
70:27
67
69
73
53
65
60
61
[a] The reactions were performed on a 0.20 mmol scale of rac-3-methyl-2-
oxindole 6 using nitrostyrene (1.0 equiv.) 7 and catalyst 8 (30 mol%) in
solvent (1.0 mL). [b] Yields of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] The relative and absolute config-
uration of the product was established by comparison with literature
data (see Supporting Information).
Applying to our reaction conditions, ether solvents such as
THF and Et2O (entries 5 and 7), as well as EtOAc (entry 6) led to
the highest yields of Michael product 9a (up to 99% yield).
Notably, the reaction in DMF as a solvent also performed well
with a yield of 73% (entry 4). In CH3CN the Michael addition
proceeded smoothly regarding the yield (86%) and additional-
ly delivered the best results in terms of diastereomeric ratio
(syn/anti 80:20) and enantioselectivity (73% ee, entry 3).
The obtained results indicate that there is no requirement
for protection of nitrogen atom of 2-oxindole to achieve the
results comparable or even better than reported for N-protect-
ed substrates.[6d]
We supplemented our experimental efforts by density func-
tional calculations to analyze the origin of stereoselectivity and
the role of van der Waals interactions in the selected nitro-Mi-
chael addition reaction using Takemoto’s organocatalyst.[20]
Results and Discussion
To explain the observed enantio- and diastereoselectivity,
and to get information that can be transferred to larger bifunc-
tional catalytic systems, we decided to conduct a computation-
al investigation of this nitro-Michael reaction employing densi-
ty functional calculations. As it is well-known that standard
density functionals are not able to describe dispersion interac-
tions properly, special corrections for van der Waals interaction-
s[29a] were included if not stated otherwise. The inclusion of
these corrections has been shown to improve both geometries
and energies especially for organic molecules (similar to those
investigated in the present study).[29]
Nitro-Michael reaction catalyzed by Takemoto’s catalyst
To the best of our knowledge, no examples of using Takemo-
to’s catalyst to the nitro-Michael addition of N-unprotected
rac-3-methylindolin-2-one 6 to nitrostyrene have been report-
ed yet, whereas one example of the addition of N-phenyl sub-
stituted rac-3-methylindolin-2-one to nitrostyrene at 48C to
give the adduct with 93% yield, 3:1 dr and 69% ee is
known.[6d] Thus, we decided to investigate first the reaction be-
tween N-unprotected oxindole 6 and nitrostyrene 7 catalyzed
by Takemoto’s catalyst 8 as a test reaction (Scheme 1). Our ini-
tial experiments were performed at room temperature and by
using toluene or dichloromethane as a solvent (Table 1, en-
tries 1 and 2). The results obtained in these first experiments
are summarized in Table 1.
Theoretical studies: DFT calculations
As the catalyst molecule influences the stereoselectivity of the
reaction, both the oxindole 6
and the nitrostyrene 7 molecules
must bind to it during the rele-
vant transition states. By careful-
ly testing different binding
modes and protonation states of
the oxindole 6, it turned out
that the first step of the reaction
must be a deprotonation of the
oxindole 6 by the basic amino
group of catalyst 8, yielding four
educt complexes corresponding
Scheme 1. Nitro-Michael addition of rac-3-methyl-2-oxindole 6 to nitrostyrene 7 using Takemoto’s catalyst 8.
to the four possible stereoiso-
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11 kJmolꢀ1), and SS (+18 kJmolꢀ1) isomers. Inspection of the
geometries reveals that the destabilization of the SR and SS
educt complexes stems from an unfavorable interaction be-
tween the oxindole 6 methyl group with the aryl ring of the
catalyst 8. The slight destabilization of the RS with respect to
the RR isomer cannot be easily rationalized. It originates
mostly from a higher zero-point vibrational energy. Without
taking vibrational and thermal effects into account, the RR and
Table 2. Calculated free energies [kJmolꢀ1] for the educt complexes and
reaction steps of the Michael addition of oxindole 6 to nitrostyrene 7
catalyzed by Takemoto’s catalyst 8.[a]
¼
Stereoisomer
Grel(E)
DG (E!TS)
DG(E!IM)
DG(IM!P)
RS
RR
SR
SS
5
0
11
18
10
28
36
19
ꢀ21
ꢀ26
ꢀ12
ꢀ30
ꢀ42
ꢀ17
ꢀ20
ꢀ14
RS educt complexes have the same energy within 1 kJmolꢀ1 [21]
.
[a] E=Educt, TS=transition state, IM=intermediate, P=product.
Starting from these educt complexes, we located four transi-
tion states for the CꢀC coupling step corresponding to the
four possible product configurations RS, SR (both syn), and SS,
RR (both anti). We found that the activation barriers (with re-
spect to the corresponding educt complexes) for the CꢀC
bond formation are clearly different in energy for the four ste-
reoisomers: 10 kJmolꢀ1 (RS), 19 kJmolꢀ1 (SS), 28 kJmolꢀ1 (RR),
and 36 kJmolꢀ1 (SR), respectively, see Table 2. Thus, the lowest
activation barrier corresponds to the RS isomer, which is the
predominant product in experiment. The relative stabilities of
the transition states can be explained by some specific interac-
tions within the activated complexes. As already pointed out
for the educt complexes, the SS and SR configurations are de-
stabilized by steric hindrance, because the orientation of the
methyl group of oxindole 6 points towards the aryl ring of the
catalyst. An additional unfavorable interaction emerges in the
transition state for the RR and SR stereoisomers: as in these
structures the aryl group of the nitrostyrene molecule 7 points
towards the CF3-substituted phenyl group of the catalyst, re-
pulsion between these two groups prevents an optimal orien-
tation of the reactants 6 and 7 with respect to each other
during the CꢀC bond forming step. Thus, the transition state
leading to the RS isomer exhibits the least steric hindrance.
mers (Table 2, Figure 2). As educt complexes, we define mini-
mum structures in which the reactants are already oriented in
such a way that the CꢀC bond formation is feasible, that is, we
only consider “reactive” coordinations. By performing molecu-
lar dynamics simulations, we found in some cases other mini-
mum geometries that are lower in energy but cannot directly
lead to the observed reaction.
The four educt complexes differ in the relative orientation of
the catalyst 8, the oxindole 6, and the nitrostyrene 7 mole-
cules. In all cases, the nitrostyrene molecule 7 undergoes hy-
drogen bonding with the catalyst 8 via one oxygen atom of
the nitro group interacting with the two hydrogen atoms of
the thiourea moiety (Figure 2), which is consistent with previ-
ous calculations by Yalalov et al. for the bifunctional primary
amine–thiourea-catalyzed nitro-Michael addition reaction.[19f]
The enolate of oxindole 6 forms a hydrogen bond with the
protonated amino group of the catalyst 8. The educt com-
plexes are clearly different in energy (see Table 2): the complex
yielding the RR stereoisomer was predicted to be most stable,
followed by the corresponding RS (+5 kJmolꢀ1), SR (+
Figure 2. Schematic representations of educt, intermediate, and product complexes of the Michael addition of oxindole 6 to nitrostyrene 7 catalyzed by
Takemoto’s catalyst 8. As an example, the formation of the RS isomer 9a is considered. Relative orientations and some specific interactions between the mole-
cules are indicated; the new CꢀC bond is colored in red.
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The completed CꢀC bond formation leads to an intermedi-
ate complex, and subsequent proton transfer (which we
assume to be fast) yields the final product complex, see
Figure 2. We found that both the intermediate and product
complexes are more stable than the educt complexes, indicat-
ing a clear thermodynamic driving force for the reaction
(Table 2). Moreover, the product complex of the RS stereoiso-
mer is by far the most stable one.
Notably, the proper inclusion of van der Waals interactions
was found to be crucial in this study: optimizations of the rele-
vant complexes without van der Waals corrections to the DFT
functional lead to by far less compact structures because of
the missing dispersion interactions between the aryl rings
(compare, e.g., the structures of
Figure 3. Optimized structures of the educt complex for the formation of
the RS stereoisomer 9a obtained with (left) and without (right) adopting
van der Waals corrections to the density functional.
the RS educt complex in
Figure 3 obtained with and with-
out taking into account van der
Waals interactions, respectively).
As a result, the stereoselectiv-
ity determining interactions are
largely lost, and the correspond-
ing activation barriers for the Cꢀ
C bond forming step agree for
all isomers within 10 kJmolꢀ1
.
that is, the observed selectivities
cannot be (even qualitatively)
understood using
a level of
theory that does not take into
account van der Waals interac-
tions.
Moreover, if van der Waals in-
teractions between the aryl rings
are neglected, the optimal “reac-
tive” coordination of nitrostyrene
to the catalyst occurs via both
oxygen atoms (and not only one
oxygen atom) of the nitro
group. Such structures were ob-
tained in earlier calculations by
Pꢃpai and co-workers[22a] as well
as Liu and co-workers[22b] for the
interaction of Takemoto’s cata-
lyst with nitro compounds. Both
investigations adopted a stan-
dard density functional without
explicitly correcting the missing
Figure 4. Catalysts used for the Michael addition of rac-3-methyl-2-oxindole 6 to nitrostyrene 7.
Scheme 2. Nitro-Michael addition of rac-3-methylindolin-2-one 6 to nitrostyrene 7 using organocatalysts 10–13.
van der Waals interactions. However, these structures turned
out to be less favorable in our calculations if van der Waals in-
teractions are taken into account.
would perform as well as or even better than catalyst 8 in the
same nitro-Michael addition.
The alternative catalysts 10–13 promoted, however, a less
stereoselective nitro-Michael transformation to afford the op-
posite enantiomer (S,R-configured product) (Scheme 2). The re-
sults of the catalyst screening are shown in Table 3.
Nitro-Michael reaction catalyzed by cinchona-alkaloid-
derived bifunctional catalysts
The tertiary amine thiourea catalyst 11 gave product 9b
with the highest yield of 94% (entry 2, Table 3). Therefore, this
catalyst was chosen for the solvent screening (Table 4). If THF
and an aqueous buffer solution were used as solvents for the
nitro-Michael addition, the yields were very low and also the
As cinchona-alkaloid-derived bifunctional catalysts are sterically
more demanding than Takemoto’s catalyst 8, we were interest-
ed in exploring whether organocatalysts 10–13 (Figure 4)
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Table 3. Screening of organocatalysts 10–13 for the nitro-Michael addi-
tion of oxindole 6 to nitrostyrene 7 in toluene.[a]
Table 5. Screening of solvents for the nitro-Michael addition of oxindole
6 to nitrostyrene 7 using tosylate catalysts 14 and 15.[a]
Entry
t [h]
Cat. [mol%]
Yield [%][b]
dr (syn/anti)[c,d]
ee [%][c,d]
Entry t [h] Solvent
Cat. Yield [%][b] dr (syn/anti)[c] ee [%][c]
1[e]
2
3
4[f]
44
48
46
48
10 (12)
11 (10)
12 (10)
13 (10)
87
94
87
86
75:25
68:32
68:32
62:38
62
64
67
52
1
2
3
4
5[d]
6[e]
7
8[g]
9[h]
10
11
12[i]
13
14[e]
15[d]
16
17[d]
18[e]
24
48
48
48
48
48
48
48
48
48
48
48
48
48
48
47
46
46
toluene
toluene
CH2Cl2
HFB
HFB
HFB
Buffer[f]
HFB/toluene 14
HFB/toluene 14
THF
14
14
14
14
14
14
14
79
74
56
49
77
87
27
67
62
80
n.r.
61
54
84
62
49
69
65
71:29
80:20
67:33
82:18
77:23
76:24
58:42
78:22
82:18
79:21
n.d.
70:30
79:21
77:23
64:36
80:20
80:20
78:22
82
82
84
87
81
80
29
88
86
83
n.d.
77
87
84
81
83
84
81
[a] The reactions were performed on a 0.14 mmol scale of rac-3-methyl-2-
oxindole 6 using nitrostyrene 7 (1.2 equiv.) in solvent (0.68 mL). [b] Yields
of isolated product. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] The relative and absolute configuration of the product were es-
tablished by comparison with literature data (see Supporting Informa-
tion). [e] This reaction was performed in CH3CN and with 1 equiv. of nitro-
styrene 7. [f] T=508C.
14
14
14
15
15
15
15
15
15
HFP
HFB/THF
toluene
toluene
CH2Cl2
HFB
HFB
HFB
Table 4. Screening of solvents for the nitro-Michael addition of oxindole
6 to nitrostyrene 7 using selected thiourea catalyst 11.[a]
[a] The reactions were performed on a 0.14 mmol scale of rac-3-methyl-2-
oxindole 6 using nitrostyrene 7 (1.2 equiv.) and catalyst (10 mol%) in sol-
vent (0.35–1.3 mL). [b] Yields of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] In this reaction 20 mol% catalyst
was used. [e] T=508C. [f] A phosphate buffer (Na2HPO4·2H2O and
NaH2PO4·2H2O) at pH 7.0 was used. [g] HFB/toluene (6:1). [h] HFB/toluene
(1:1). [i] HFB/THF (1:3).
Entry
t [h]
Solvent
Cat.
Yield [%][b]
dr (syn/anti)[c]
ee [%][c]
1
2
3[d]
4[e]
5
48
48
48
48
48
48
toluene
CH2Cl2
CH3CN
HFB
THF
Buffer[f]
11
11
11
11
11
11
94
99
99
42
37
12
68:32
71:29
76:24
73:27
75:25
54:46
64
68
66
72
50
39
6
[a] The reactions were performed on a 0.14 mmol scale of rac-3-methyl-2-
oxindole 6 using nitrostyrene 7 (1.2 equiv.) and catalyst (10 mol%) in sol-
vent (0.5–0.7 mL). [b] Yields of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] 1 equiv. of nitrostyrene 7 was
used. [e] 1.2 mL solvent was used. [f] A phosphate buffer (Na2HPO4·2H2O
and NaH2PO4·2H2O) at pH 7.0 was used.
lysts (Table 5). If polar solvents like an aqueous buffer system
(entry 7, catalyst 14) or HFP (hexafluoropropanol-2, entry 11,
catalyst 14) were used for the Michael addition, low yields and
low enantioselectivities (in aqueous buffer), or no reaction (in
HFP) were observed, respectively. Applying dichloromethane
(entries 3 and 15) as the solvent for the catalysis, the yields
were only moderate (56% with catalyst 14 and 62% with cata-
lyst 15), but the enantioselectivities were promising (84% and
81%, respectively). Changing the solvent to toluene (entries 1,
2, 13, and 14) improved the yield up to 84% (entry 14, catalyst
15) and the enantioselectivity up to 87% (entry 13, catalyst
15). The best results in toluene regarding both aspects (84%
yield and 84% ee) were obtained if the reaction mixture was
heated to 508C for 48 h (entry 14, catalyst 15). Additionally, we
applied HFB as the solvent for the nitro-Michael addition and
already in our first approach we were able to obtain an ee
value of 87% (entry 4, catalyst 14). To further improve the ob-
tained yield of the adduct 9b (entry 4), we conducted the reac-
tion also at 508C and thereby increased the yield to 87%
(entry 6, catalyst 14). Inspired by the results observed in the
solvents toluene and HFB, we next used a mixture of these sol-
vents (HFB/toluene 6:1 and HFB/toluene 1:1) expecting to im-
prove the results further (entries 8 and 9, catalyst 14). In both
cases, the enantioselectivities were very good (88% and 86%,
respectively), but yields decreased to 67% and 62%,
respectively.
enantioselectivities were moderate: 50% and 39%, respectively
(entries 5 and 6).
Application of dichloromethane (entry 2) and CH3CN
(entry 3) led to high yields (99%), as well as enantioselectivities
over 65%. If hexafluorobenzene (HFB) was used as a solvent
for the reaction, the yield decreased to 42% but an enantiose-
lectivity of 72% could be achieved (entry 4).
We next examined two cinchona-based organocatalysts 14
and 15 with a sulfonamide instead of a thiourea moiety
(Figure 5). A solvent screening was performed for both cata-
The improved reaction outcome achieved with catalysts 14
and 15, in comparison to that with thiourea-based catalysts
10–13, correlate with the relatively stronger acidity of the sul-
fonamide moiety than of the thiourea group.
Figure 5. Catalysts used for the nitro-Michael addition of rac-3-methyl-2-
oxindole 6 to nitrostyrene 7.
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Figure 6 a possible transition-state structure for the
nitro-Michael addition reaction using sulfonamide-de-
rived tertiary amine organocatalysts 14 and 15 result-
ing in the opposite enantiomer.
As toluene and/or HFB gave us the best yields and
ee values, we applied these solvents for the asym-
metric nitro-Michael addition of different N-unsubsti-
tuted 2-oxindoles to nitrostyrene in the presence of
catalysts 14 and/or 15. The results are summarized in
Table 6.
Starting from rac-3-chloroindolin-2-one (entries 1–
4), the desired product 16 was obtained in up to
99% yield and 76% ee.
3-Benzylated N-unprotected oxindoles were also
utilized as Michael donors for this reaction (entries 5–
10). Interestingly, the use of 2-oxindoles with p-nitro-
benzyl and p-bromobenzyl substituents at C3 gave
the corresponding products 17 and 18 with 44%
yield, 81% ee, and 94% yield, 79% ee, respectively
(entry 5 and entry 6). The application of para-methox-
ybenzyl substituted 2-oxindole led to 68% yield and
80% ee for Michael adduct 19 (entry 7). It was possi-
ble to increase the yield up to 75% and an ee value
of 82% for Michael product 20 (entries 8–10).
Thus, good to high yields (up to 94%), good dia-
stereomeric ratios (up to 87:13 syn/anti) and enantio-
selectivities (up to 87% ee) were achieved in these
reactions.
Figure 6. Calculated and proposed transition-state structures leading to enantiomeric syn
products.
Table 6. Substrate scope for the nitro-Michael addition of different oxindoles to nitro-
styrene.[a]
Notably, in comparison to N-unprotected 3-benzy-
lated 2-oxindole, the N-Boc-protected derivative re-
sulted in slightly lower yield and diastereoselectivity,
but enantioselectivities were over 80% in both cases
(entry 11 and entry 8). Intriguingly, application of N-
benzyl protected substrate resulted only in racemic
product with 12% yield, caused most probably by
unfavorable steric interaction between the benzyl-
protecting group and the catalyst within the transi-
tion-state structure.
Entry
Product
Solvent
Cat.
Yield
[%][b]
dr
ee
(syn/anti)[c]
[%][c]
1[d]
toluene
toluene
toluene
toluene
14
15
15
15
93
95
94
72:28
64:36
68:32
61:39
76[e]
71[e]
76[e]
61[e]
2[d]
3[d,f]
4[d,f,g]
>99
5[h]
toluene
toluene
toluene
14
14
14
44
94
68
85:15
87:13
84:16
81
79
80
Our studies illustrate that the developed method is
more efficient in the nitro-Michael additions of N-un-
protected oxindoles than of N-protected ones.
Conclusions
6
We have successfully performed and investigated
enantioselective nitro-Michael additions of different
N-unprotected 3-substituted 2-oxindoles to nitrostyr-
ene, catalyzed by bifunctional thiourea- or sulfona-
mide-derived tertiary amine organocatalysts 8, 10–
15. These transformations under simple and mild re-
action conditions provide direct access to versatile N-
unsubstituted oxindoles in up to 99% yields, up to
88% ee, and 87:13 dr in the presence of the selected
tertiary amine-sulfonamide catalysts 14 and 15. The
dependence of yields and stereoselectivities on the
7
Based on the above presented DFT computations of the
analogous reaction using Takemoto’s catalyst, we exhibited in
solvent used has been demonstrated. It is shown that, for
a good reaction outcome, the introduction of activating
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Waals interactions were found to play a crucial role
for stereoselectivity.
Table 6. (Continued)
Entry
Product
Solvent
Cat.
Yield
[%][b]
dr
ee
[%][c]
(syn/anti)[c]
Experimental Section
8
toluene
toluene
HFB
15
15
15
75
64
45
83:17
87:13
81:19
81
82
71
9[g]
10[g,i]
General
THF, DMF, EtOAc, Et2O, and CH3CN were purchased as
anhydrous solvents from Sigma–Aldrich Co. HFB was
purchased from Sigma–Aldrich Co. and was used with-
out further purification. CH2Cl2 was dried by using appro-
priate methods. Column chromatography was performed
on Macherey–Nagel silica gel 60m (0.04–0.063 mm/230–
400 mesh ASTM) and TLC on Macherey–Nagel ALU Gram
SIL G/UV254 plates). 2-Oxindoles were synthesized from
commercially available 2-oxindole,[23] skatole,[24] and ni-
trostyrene.[7d] 1H NMR and 13C NMR spectra were record-
ed at RT on a Bruker Avance 400 and 300 or JEOL JNM
GX 400 spectrometer operating at 400 and 300 MHz by
using the solvent as an internal standard. ESI mass spec-
tra were recorded on a Bruker Daltonik maXis 4G or
a Bruker Daltonik micrOTOF II focus. HPLC measurements
were recorded on an Agilent 1200 Series system.
11
toluene
15
68
80:20
87
12
HFB
14
12
rac
rac
Copies of 1H and 13C NMR spectra of all compounds,
HPLC chromatograms, density-functional calculations (in-
cluding coordinate files and calculated energies) are
available in the Supporting Information.
[a] The reactions were performed with oxindole (1 equiv.), nitroolefin (1.2 equiv.), and
catalyst (10 mol%) in solvent. [b] Yields of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] The reactions were performed in a mixture of
toluene (0.59 mL) and DCM (0.2 mL). [e] The absolute configuration of this product
was not determined. [f] In this reaction 5 mol% catalyst was used. [g] T=508C.
[h] The reaction was performed in a mixture of toluene (0.90 mL) and DCM (0.5 mL).
[i] 1 mL solvent was used.
Typical procedure for the Michael addition of 3-
substituted-2-oxindoles to nitrostyrene 7
To
a solution of the corresponding catalyst (10–
30 mol%) and nitrostyrene 7 (1.2 equiv.) in solvent the
corresponding 3-substituted-2-oxindole (1.0 equiv.) was
added. The reaction mixture was stirred at RT for 44–
48 h. Follow-up, the reaction mixture was directly sub-
jected to flash column chromatography on silica gel (PE/
EtOAc, 2:1; PE=petrol ether) to isolate the corresponding Michael
product.
groups at the nitrogen moiety of 3-substituted 2-oxindoles is
not necessary.
The observed stereoselectivity induced by the Takemoto cat-
alyst 8 is explained by steric interactions of the reactant mole-
cules with the catalyst during the CꢀC bond forming step,
which leads to different activation barriers for different stereo-
isomers. Here, the basic amine and the thiourea moiety of the
catalyst may be viewed as “anchor” groups for the reactant
molecules, and the interplay between the phenyl group of the
catalyst with both the methyl substituent of the oxindole and
the aryl group of the nitrostyrene molecule is responsible for
the observed selectivity. To our knowledge, this is the first ex-
ample of DFT calculations accounting for dispersion interac-
tions in the nitro-Michael addition of N-unprotected 2-oxindole
to nitrostyrene using a bifunctional tertiary amine-thiourea or-
ganocatalyst. It was shown, in contrast to earlier studies,[22]
that in the transition state merely a single oxygen atom of the
nitro group is bound to the thiourea moiety of the catalyst,
rather than both oxygen atoms, if dispersion interactions are
properly taken into account. Moreover, van der Waals interac-
tions induce a higher degree of compactness of the reacting
complexes, which, in turn, causes the above mentioned steric
interactions and thus the stereoselectivities. Thereby, van der
(S)-3-Methyl-3-((R)-2-nitro-1-phenylethyl)indolin-2-one
(9b):[6c]
1H NMR (400 MHz, CDCl3): mixture of diastereomers; d=1.46/1.47
(2ꢄs, 2ꢄ3H), 3.92/3.99 (2ꢄdd, J3.92 =11.3, 4.4 Hz; J3.99 =11.1, 4.5 Hz,
2ꢄ1H), 4.91/4.92 (2ꢄdd, J4.91 =13.4, 4.5 Hz; J4.92 =12.8, 11.3 Hz, 2ꢄ
1H), 5.04/5.06 (2ꢄdd, J5.04 =13.4, 11.1 Hz; J5.06 =12.8 Hz, 4.4 Hz, 2ꢄ
1H), 6.69–7.26 (m, 18H), 7.80/7.95 ppm (s, 2ꢄ1H); 13C NMR
(100 MHz, CDCl3): mixture of diastereomers: d=20.6, 22.4, 49.9,
50.1, 50.6, 50.8, 75.4, 76.0, 109.9, 110.0, 122.7, 124.1 (2ꢄ), 128.0,
128.2, 128.3, 128.5, 128.8, 128.9, 129.0, 131.4, 132.0, 134.9, 139.6,
140.3, 180.1, 180.7 ppm; MS (ESI): m/z=319 ([M+Na]+).
3-Chloro-3-(2-nitro-1-phenylethyl)indolin-2-one (16):[7c] 1H NMR
(400 MHz, CDCl3): mixture of diastereomers: d=4.28/4.43 (2ꢄdd,
J
4.28 =11.3, 3.6 Hz; J4.43 =8.4, 6.5 Hz, 2ꢄ1H), 5.13 (dd, J=13.3,
11.4 Hz, 1H), 5.48 (bs, 1H), 5.50–5.51 (m, 1H), 5.62–5.68 (m, 1H),
6.60 (d, J=7.7 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.87–7.38 (m, 15H),
7.44–7.48 (m, 1H), 7.64/7.69 ppm (2ꢄbs, 2ꢄ1H); 13C NMR
(100 MHz, CDCl3): mixture of diastereomers: d=50.6, 51.5, 65.5,
65.9, 75.4, 75.5, 110.6, 110.6, 123.4, 123.6, 124.8, 126.0, 127.2, 128.6
(3ꢄ), 128.9, 129.1, 129.4, 130.7, 131.1, 132.6 (2ꢄ), 139.1, 139.8,
173.7, 173.9 ppm; MS (ESI): m/z=339 ([M+Na]+).
3-(2-Nitro-1-phenylethyl)-3-(4-nitrobenzyl)indolin-2-one
1H NMR (400 MHz, CDCl3): mixture of diastereomers: d=3.02/3.21
(17):
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(2ꢄd, J3.02 =12.6 Hz; J3.21 =12.6 Hz, 2ꢄ1H), 3.31/3.46 (2ꢄd, J3.31
=
50.7, 70.4, 109.7, 122.7, 123.6, 126.8, 127.4, 128.3, 128.4, 128.7,
128.8, 128.9, 129.0, 130.7, 135.0, 135.1, 142.7, 178.3 ppm.
12.6 Hz; J3.46 =12.6 Hz, 2ꢄ1H), 4.13 (t, J=7.7 Hz, 1H), 4.22 (q, J=
6.0 Hz, 1H), 4.91–4.96 (m, 2H), 4.98 (d, J=7.7 Hz, 2H), 6.44–6.48
(m, 1H), 6.53 (d, J=7.6 Hz, 1H), 6.87–6.98 (m, 4H), 7.01–7.29 (m,
20H), 7.81–7.86 ppm (m, 2ꢄ1H). 13C NMR (100 MHz, CDCl3): mix-
ture of diastereomers: d=40.5, 50.4, 56.6, 76.0, 110.1, 122.9 (2ꢄ),
123.0, 124.5, 128.1, 128.5, 128.6 (2ꢄ), 129.4, 129.5, 129.6, 130.9,
131.0, 134.4, 140.6, 142.5, 147.0, 177.0 ppm; MS (ESI): m/z=440
([M+Na]+).
Computational details
All calculations were performed with the Turbomole 6.5 program
suite.[25] We used the BP86 density functional[26] together with the
def2-TZVP basis set[27] and the RI-J approximation.[28] As it is well-
known that standard DFT functionals (like BP86) have severe short-
comings describing noncovalent interactions, empirical van der
Waals corrections according to Grimme (version D3)[29a] were ap-
plied, see Results and Discussion for more details. Geometries were
optimized to a maximum force of 10ꢀ4 au and afterwards checked
by calculating the vibrational frequencies to ensure that the struc-
ture represents either a minimum (no imaginary frequency) or
a transition state (exactly one imaginary frequency) on the poten-
tial energy surface. That a transition state indeed connects the cor-
responding minima was checked by slightly distorting the transi-
tion-state geometry and subsequent geometry optimization using
a steepest descent algorithm with small step size. Free Gibbs ener-
gies were computed for standard conditions (298.15 K and
100 kPa) within the harmonic-oscillator and rigid-rotator approxi-
mations. The convergence with the basis set was tested by per-
forming single-point calculations for all relevant geometries adopt-
ing the def2-QZVPPD basis set.[30] However, differences to the ener-
gies obtained with the def2-TZVP basis set were found to be negli-
gible.
3-(4-Bromobenzyl)-3-(2-nitro-1-phenylethyl)indolin-2-one
1H NMR (400 MHz, CDCl3): mixture of diastereomers: d=2.87/3.08
(2ꢄd, J2.87 =12.8 Hz; J3.08 =12.8 Hz, 2ꢄ1H), 3.16/3.28 (2ꢄd, J3.16
12.8 Hz; J3.26 =12.8 Hz, 2ꢄ1H), 4.09/4.17 (2ꢄdd, J4.09 =9.6, 5.9 Hz;
4.17 =11.0, 4.6 Hz, 2ꢄ1H), 4.81–5.16 (m, 4H), 6.49 (d, J=7.7 Hz,
(18):
=
J
1H), 6.54 (d, J=7.8 Hz, 1H), 6.60–6.66 (m, 4H), 6.97–7.51 (m, 20H),
7.88 (d, J=8.1 Hz, 1H), 7.97 ppm (d, J=8.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3): mixture of diastereomers: d=40.2, 41.4, 49.7,
50.3, 56.7, 75.4, 76.2, 110.1, 111.0, 117.8, 121.0, 122.3, 122.6, 124.1,
124.5, 124.5, 127.5, 128.4 (3ꢄ), 128.5, 128.6, 128.9, 129.1, 129.3,
129.4, 129.5, 130.9 (2ꢄ), 131.5, 131.7 (2ꢄ), 133.5 (2ꢄ), 133.7, 134.6,
140.9, 152.8, 177.8 ppm; MS (ESI): m/z=473 ([M+Na]+).
3-(4-Methoxybenzyl)-3-(2-nitro-1-phenylethyl)indolin-2-one
1H NMR (400 MHz, CDCl3): mixture of diastereomers: d=2.90/3.10
(2ꢄd, J2.90 =13.0 Hz; J3.10 =13.0 Hz, 2ꢄ1H), 3.17/3.27 (2ꢄd, J3.17
13.0 Hz; J3.27 =13.1 Hz, 2ꢄ1H), 3.60–3.64 (m, 6H), 4.09/4.16 (2ꢄdd,
4.09 =10.7, 4.9 Hz; J4.17 =11.0, 4.5 Hz, 2ꢄ1H), 4.88–5.06 (m, 4H),
(19):
=
J
6.44–6.55 (m, 6H), 6.64–6.72 (m, 4H), 6.95–7.27 (m, 16H), 7.38 ppm
(s, 2ꢄ1H); 13C NMR (100 MHz, CDCl3): mixture of diastereomers:
d=40.0, 50.2, 54.9, 56.9, 57.0, 76.3, 109.8, 113.1, 113.2, 122.1, 122.4,
124.6, 125.4, 126.6, 128.1, 128.3 (3ꢄ), 128.5, 129.0, 129.1, 129.4,
131.0, 134.9, 140.3, 141.0, 158.3, 178.0 ppm; MS (ESI): m/z=425
([M+Na]+).
Acknowledgements
S.B.T. is grateful to the Dr. Hertha & Helmut Schmauser-Stiftung
and Deutsche Forschungsgemeinschaft (DFG) for research sup-
port. B.S., C.N., and A.G. gratefully acknowledge financial support
by the DFG through the Cluster of Excellence Engineering of Ad-
vanced Materials (http://www.eam.uni-erlangen.de) at the Uni-
versity of Erlangen-Nuremberg. We also thank Christina Heckel
(University of Erlangen-Nuremberg, Germany) for the preparation
of catalyst 13.
3-benzyl-3-(2-nitro-1-phenylethyl)indolin-2-one (20):[7a] 1H NMR
(300 MHz, CDCl3): mixture of diastereomers: d=2.96/3.15 (2ꢄd,
J
J
2.96 =12.7 Hz; J3.15 =12.7 Hz, 2ꢄ1H), 3.23/3.35 (2ꢄd, J3.23 =12.7 Hz;
3.35 =12.7 Hz, 2ꢄ1H), 4.12/4.19 (2ꢄdd, J4.12 =10.1, 5.5 Hz; J4.19
=
10.8, 4.8 Hz, 2ꢄ1H), 4.91–5.09 (m, 4H), 6.41–6.52 (m, 2H), 6.73–
6.81 (m, 2H), 6.91–7.32 ppm (m, 26H); 13C NMR (100 MHz, CDCl3):
mixture of diastereomers: d=40.9, 42.1, 49.7, 50.3, 56.9 (2ꢄ), 75.5,
76.3, 109.6, 109.8, 122.2, 122.4, 124.7, 125.4, 126.8 (2ꢄ), 127.8 (2ꢄ),
128.2, 128.3, 128.4, 128.6, 128.7, 129.0, 129.1, 129.4, 130.1, 134.5,
134.9, 140.2, 140.9, 177.8, 179.1 ppm; MS (ESI): m/z=395 ([M+Na]+
).
Keywords: density functional calculations · enantioselectivity ·
Michael addition · noncovalent interactions · organocatalysis
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1H NMR (400 MHz, CDCl3): mixture of diastereomers: d=1.54 (2ꢄs,
2ꢄ3H), 3.48–3.54 (m, 1H), 4.06 (dd, J=11.4, 4.3 Hz, 1H), 4.10 (d,
J=7.2 Hz, 1H), 4.41 (d, J=15.8 Hz, 1H), 4.83–5.01 (m, 5H), 5.12
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(100 MHz, CDCl3): mixture of diastereomers: d=21.6, 43.6, 50.0,
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Received: December 9, 2013
Published online on && &&, 0000
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 10
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9
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These are not the final page numbers!

FULL PAPERS
C. Reiter, S. Lꢀpez-Molina, B. Schmid,
C. Neiss, A. Gçrling,* S. B. Tsogoeva*
The importance of being dispersed: Bi-
functional thiourea- or sulfonamide-de-
rived tertiary amines such as Takemoto’s
catalyst catalyze the enantioselective
nitro-Michael addition of N-unprotected
3-substituted 2-oxindoles to nitrosty-
rene in high yields and enantiomeric
and diastereomeric ratios. DFT calcula-
tions including van der Waals correc-
tions are performed for the stereoiso-
mers.
&& – &&
Michael Addition of N-Unprotected 2-
Oxindoles to Nitrostyrene Catalyzed
by Bifunctional Tertiary Amines:
Crucial Role of Dispersion Interactions
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 10
&10
&
ÞÞ
These are not the final page numbers!