A theoretical investigation into chiral phosphoric acid-catalyzed asymmetric Friedel-Crafts reactions of nitroolefins and 4,7-dihydroindoles: reactivity and enantioselectivity

Article abstract of DOI:10.1016/j.tet.2010.02.031

This article mainly focused on high level Density Functional Theory (DFT) studies on the chiral phosphoric acid-catalyzed Friedel-Crafts reactions between 4,7-dihydroindoles and nitroolefins. Firstly, the reactivities of 4,7-dihydroindole and indole in the chiral phosphoric acid-catalyzed Friedel-Crafts reactions with nitroolefin have been compared. The higher reactivity of 4,7-dihydroindole could be attributed to its higher HOMO energy as well as its more suitable trajectory to attack the nitroolefin in the transition state. Secondly, the origin of the enantioselectivity of the chiral phosphoric acid-catalyzed Friedel-Crafts reaction of 4,7-dihydroindole with nitroolefin has been studied using complete models on PBE1PBE/[6-311+G(d,p), 6-31G(d,p)] level. When (S)-1b was used as the catalyst, the enantioselectivity of the reaction is entirely controlled by the steric effect between the catalyst and the substrate. Whereas for catalyst (S)-1c the enantioselectivity is determined by the solvent effect.

Full text of DOI:10.1016/j.tet.2010.02.031

Tetrahedron 66 (2010) 2875–2880
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A theoretical investigation into chiral phosphoric acid-catalyzed asymmetric
Friedel–Crafts reactions of nitroolefins and 4,7-dihydroindoles: reactivity and
enantioselectivity
*
*
Chao Zheng, Yi-Fei Sheng, Yu-Xue Li , Shu-Li You
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
This article mainly focused on high level Density Functional Theory (DFT) studies on the chiral phos-
phoric acid-catalyzed Friedel–Crafts reactions between 4,7-dihydroindoles and nitroolefins. Firstly, the
reactivities of 4,7-dihydroindole and indole in the chiral phosphoric acid-catalyzed Friedel–Crafts re-
actions with nitroolefin have been compared. The higher reactivity of 4,7-dihydroindole could be at-
tributed to its higher HOMO energy as well as its more suitable trajectory to attack the nitroolefin in the
transition state. Secondly, the origin of the enantioselectivity of the chiral phosphoric acid-catalyzed
Friedel–Crafts reaction of 4,7-dihydroindole with nitroolefin has been studied using complete models
on PBE1PBE/[6-311þG(d,p), 6-31G(d,p)] level. When (S)-1b was used as the catalyst, the enantiose-
lectivity of the reaction is entirely controlled by the steric effect between the catalyst and the substrate.
Whereas for catalyst (S)-1c the enantioselectivity is determined by the solvent effect.
Received 16 November 2009
Received in revised form 3 February 2010
Accepted 5 February 2010
Available online 10 February 2010
Keywords:
Chiral phosphoric acid
Friedel–Crafts reaction
Enantioselectivity
Theoretical calculation
DFT
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
important type of carbon–carbon bond-formation reactions, the
chiral phosphoric acid-catalyzed asymmetric Friedel–Crafts re-
Chiral phosphoric acid has received much attention recently as
powerful asymmetric organocatalyst.1 Various reactions, such as
Mannich-type,2 Friedel–Crafts,3 transfer hydrogenation,4 hetero
Diels–Alder5 can be achieved efficiently using this catalyst system
with high ees. These catalysts have also been successfully used in
multi-component, cascade reactions6 and in metal co-catalyzed
reactions.7 It was found in many cases that the chiral phosphoric
acids are bifunctional catalysts bearing both Brønsted-acidic site
and Lewis-basic site that activate two substrates simultaneously.
Computational studies employing this type of catalytic model by
action has not been investigated with computational method.9 The
detailed mechanism of the chiral discrimination process is still
unconfirmed despite that significant progress has been made in
this field recently.
In 2008, Akiyama et al. reported a highly enantioselective Frie-
del–Crafts alkylation of indoles and nitroolefins (Scheme 1).3h (R)-
BINOL derived chiral phosphoric acid 1a was used as the catalyst.
The reactions proceeded smoothly in benzene/1,2-dichloroethane
(1:1) at ꢀ35 ꢁC, with 10 mol % catalyst loading. For most sub-
strates, (R)-products were obtained in excellent ees but with rela-
tively long reaction time.
Akiyama and Yamanaka et al.8a Goodman and Simon,
Himo
8b,c
´
et al.,8d,e Yamanaka and Hirata,8f Shi and Song,8g and Ding and Li
et al.8h on asymmetric transfer hydrogenation, Mannich, hydro-
phosphonylation and Baeyer–Villiger reaction provide good in-
sights into the origin of enantioselectivities of these reactions.
However, all these computational works focused on the reactions in
which various imines were employed as the electrophile, while
those reactions involving other electrophiles have still been un-
touched. On the other hand, high level computation with complete
model has seldom been employed. In addition, as one of the most
SiPh3
Ph
O
O
O
NO2
P
1a (10 mol%)
NO2
OH
+
Ph
N
H
3A MS, DCE/PhH
-35°C, 48h
N
H
SiPh3
(R)-CPA 1a
76% yield
91% ee
Scheme 1. Chiral phosphoric acid-catalyzed Friedel–Crafts reaction of indole with
nitroolefin by Akiyama.3h
Subsequently, we3j demonstrated 4,7-dihydroindoles are also
suitable in chiral phosphoric acid Friedel–Crafts alkylation reactions
of nitroolefins. The Friedel–Crafts reaction together with a sub-
sequent oxidation led to the 2-alkylated indoles in excellent yields
* Corresponding authors.
E-mail address: slyou@mail.sioc.ac.cn (S.-L. You).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.031

2876
C. Zheng et al. / Tetrahedron 66 (2010) 2875–2880
and ees. A dramatic lifting of catalysis turn-over was observed for
most substrates. With 10 mol % of the catalyst, reactions went to
complete in minutes in benzene/dichloromethane (1:1) at room
temperature. By adding the nitroolefin substrate slowly with syringe
pump, the catalyst loading could be reduced to 0.5 mol %. When
chiral phosphoric acid (S)-1b was used, the expected (S)-products
were obtained with 41% ee. Interestingly, when the catalyst was
changed to (S)-1c, the absolute configuration of the major product
was reversed and (R)-products were produced with about 90% ee
(Scheme 2). This is one of few reports10 in which the configuration of
the final products could be switched in chiral phosphoric-acid ca-
talysis by changing 3,30-substitution group on the catalyst.
and 11-membered ring transition states in indole and dihy-
droindole systems, respectively (Fig. 1). These cyclic transition
states are believed necessary for the high enantioselectivities of the
Friedel–Crafts reactions.
R
R
H
H
N
O
N
H
O
O
O
O
O
O
O
Ph
Ph
P
O
P
N
N
O
R
O
H
O
"core" part
R
R = SiPh3
R = SiPh3
9-anthryl
B
O2N
A
1b (1 mol%)
R
NO2
+
Ph
N
H
4A MS, DCM/PhH
rt, 2h
N
H
Ph
Figure 1. (A) 12-Membered ring TS in indole system. (B) 11-Membered ring TS in 4,7-
dihydroindole system. For the complete models used to study the enantioselectivity in
4,7-dihydroindole system, two substrates, and the ‘core’ part of the catalysts were
described by 6-311þG(d, p) basis set while the BINOL skeleton and the R groups were
described by 6-31G(d, p) basis set.
O
O
P
(S) 41% ee
OH
O
R
O2N
1c (0.5 mol%)
(S)-CPA 1b: R=SiPh3
1c: R=9-anthryl
NO2
+
Ph
Unlike other electrophilic partners that are widely used in chiral
phosphoric acid-catalyzed Friedel–Crafts reactions, such as
imine3a,d–g,i or carbonyl16, nitroolefins have more hydrogen bond
receptors and therefore several different activation modes emerge
in which hydrogen bond can be formed with the catalyst in dif-
ferent directions (Fig. 2). In addition, nitroolefin has one pro-chiral
center, and nucleophile attacking from Re- or Si-face will afford (R)-
or (S)-product, respectively. Although in both starting material and
final product, the 2-position of 4,7-dihydroindole and the 3-posi-
tion of indole are not a chiral center, however, in the electrophilic
attacking step, there is a facial-selective issue.
N
H
4A MS, DCM/PhH
rt, 2h
N
H
Ph
(R) 92% ee
Scheme 2. Chiral phosphoric acid-catalyzed Friedel–Crafts reaction of 4,7-dihy-
droindole with nitroolefin by You group.3j
Intrigued by these experimental results, we began to use com-
putational method to address (i) why 4,7-dihydroindole exhibits
much higher reactivity than indole as the nucleophile in chiral
phosphoric acid-catalyzed Friedel–Crafts reactions and (ii) how this
unique enantioselectivity originates. Herein, we report our detailed
computational studies.
a
2. Computational methods
Si face
(S) - product
(R) - product
Re face
Si face
b
∗
O
O
O
O
H
O
N
Density Functional Theory(DFT)calculationswerecarriedoutwith
the Gaussian03 programs.11 To compare the reactivities of indoles and
4,7-dihydrodinles in CPA-catalyzed Friedel–Crafts reactions, all the
structures were located in gas phase with B3LYP12 functional and 6-
31G(d, p) basis set. Frequency analyses were performed to validate
each structure being a minimum (without imaginary vibration) or
a transition state (with only one imaginary vibration).
P
H
O2N
H
N
O
Ph
H
c
Re face
H
H
N
H
O2N
S - Si
H
During the complete model study in 4,7-dihydroindole system,
the PBE1PBE13 functional was used instead of B3LYP. It has been
well established that this functional usually gives good results in
dealing with weak nonbonded interactions.14 Both 6-31G(d, p) and
6-311þG(d, p) basis sets were used (vide infra). Frequency analyses
were performed for all low-energy transition states. Solvent effects
were considered by single point energy calculation using the
R - Re
O2N
H
N
H
H
R - Si
O2N
N
H
H
S - Re
O2N
H
N
H
H
IEFPCM15 model (UAHF radii) in dichloromethane (
on the optimized structures in gas phase.
3
¼8.93) based
Figure 2. Possible activation and reaction modes.
Throughout this article,
energy and Gibbs free energy in gas phase, respectively.
denotes the solvent effect correction to the Gibbs free energy,
denotes the Gibbs free energy of the system in dichloromethane,
S denotes the contribution of S to the Gibbs free energy
D
Egas and
D
Ggas denote the electronic
Gcorr
Gsol
D
D
3.2. The reactivities of 4,7-dihydroindole and indole
It is generallyaccepted that the nucleophilic attack of the aromatic
ring to the electrophilic partner is the rate-determining step (RDS) in
the Friedel–Crafts reaction.17 The following proton transfer is a fast
process. In order to compare the reactivities of 4,7-dihydroindole and
indole, the rate-determining steps were studied with a simplified
biphenyl-derived phosphoric acid (Fig. 3). Based on a conformational
search (See Supplementary data fordetail), the most stable structures
of TS-A and TS-B are located and shown in Figure 4. The sum of the
Gibbs free energies of the catalyst and the two substrates are used as
thezero point reference. In the indole system, the Gibbs freeenergyof
TS-B is 24.2 kcal/mol, whereas for 4,7-dihydroindole, the energy
barrier is much lower (19.4 kcal/mol), indicating much higher re-
activity, which corresponds well with the experiments.
and ꢀT
D
D
(T¼298.15 K).
3. Results and discussion
3.1. The catalyst working model
Both Akiyama et al. and You et al. suggested that the chiral
phosphoric acid acts as a bifunctional catalyst, in which the acid
proton of the catalyst activates the nitroolefin while the phosphoryl
oxygen atom forms hydrogen bond with the N–H moiety of the
nucleophile. This type of arrangement results in 12-membered ring

C. Zheng et al. / Tetrahedron 66 (2010) 2875–2880
2877
3.3. Understanding the origin of the enantioselectivity
In order to understand the origin of the enantioselectivity of the
Friedel–Crafts reactions between 4,7-dihydroindoles and nitro-
olefins, calculations were performed with complete models using
chiral phosphoric acid catalyst (S)-1c. After an exhausted confor-
mational search, 16 distinct transition states to both enantiomers
have been located in gas phase using PBE1PBE functional and 6-
31G(d, p) basis set (Fig. 6). Frequency analyses were carried out for
the six most stable transition states.
O
P
O
O
O
O
O
O
H
O
O
O
P
O
P
P
O
H
O
O
H
O
O
H
N
H
H
N
O
O
N
H
O
O
N
N
H
H
N
H
H
O
O
O
N
N
Ph
H
O
H
Ph
H
Ph
H
Figure 3. The reaction profiles of the rate-determining step of the Friedel–Crafts re-
Ph
H
actions of nitroolefin with 4,7-dihydroindole and indole. The relative Gibbs free en-
ergies in gas phase (
theory.
DGgas) are in kcal/mol. Calculated on B3LYP/6-31G(d, p) level of
R - Si - 2: 0.0 (0.0)
S - Re - 2: -0.5 (-0.3)
R - Si - 3: 1.1 (2.7)
S - Re - 3: 0.7 (1.9)
R - Si - 4: 2.2 (3.9)
S - Re - 4: 2.1 (0.8)
O
R - Si - 1: 3.9
S - Re - 1: 3.2
O
P
O
O
O
O
O
P
H
O
O
P
O
H
O
P
O
H
H
O
O
O
O O
H
O
O
O
O
N
H
N
H
N
Ph
H
N
O
N
H
O
N
H
H
Ph
N
H
H
H
Ph
N
H
H
Ph
O
R - Re - 1: 6.0
S - Si - 1: 6.4
R - Re - 2: 3.4
S - Si - 2: 4.6
R - Re - 3: 3.0
S - Si - 3: 3.7
R - Re - 4: 5.7
S - Si - 4:
5.7
O
O
O
P
=
(S)-1c
O
H
Figure 4. The optimized structures of transition states TS-A and TS-B. Most hydrogen
atoms are omitted for clarity. Distances are in angstrom, angles are in degree. Calcu-
lated on B3LYP/6-31G(d, p) level of theory.
Figure 6. Newman projections of all possible transition states.
DEgas and
D
Ggas (in
parentheses) are in kcal/mol. Calculated at PBE1PBE/6-31G(d, p) level of theory.
We next compared the energies of the Frontier Molecular Or-
bitals (FMO) of all substrates. The energies of the HOMO of 4,7-
dihydrodindole and indole are ꢀ4.4 eV and ꢀ4.6 eV, respectively,
and the energy of the LUMO of (E)-(2-nitrovinyl)benzene is
ꢀ2.2 eV. The energy of the HOMO of 4,7-dihydroindole is closer to
the energy of the LUMO of (E)-(2-nitrovinyl)benzene. Therefore the
higher HOMO energy of 4,7-dihydroindole may account for its
higher reactivity in the Friedel–Crafts reaction.18 In addition, the
structure of the transition state may also affect the energy barriers.
There is a small difference between the nucleophile-attacking angle
to the nitroolefin in TS-A and TS-B (Fig. 4). The angle A(C1–C2–C5)
in TS-A is 109.9ꢁ, 3ꢁ smaller than A(C4–C2–C5) in TS-B (112.9ꢁ). The
4,7-dihydroindole attacks the nitroolefin in a direction closer to
Du¨nitz angle (105ꢂ5ꢁ), the favorite trajectory for a nucleophile to
attack a sp2 carbon atom.19 This difference should be caused by the
different ring sizes in TS-A and TS-B. In the larger 12-membered
transition state TS-B, the constraint of the cyclic structure in-
evitably lead to a larger attacking angle.
The relative electronic energies (DEgas) of these transition states
are quite diverse (Fig. 6). Take the eight transition states affording
(R)-product as example, the energy difference between the most
unstable and the most stable transition state is 6.0 kcal/mol. The 4,7-
dihydroindole preferentially attacks the Re-face of nitroolefin with
its Si-face. The energies of R–Si–n are about 3 kcal/mol lower than
that of R–Re–n. Similar trend could be observed for the transition
stateseries thataccessed tothe(S)-product. Amongthesestructures,
R–Si–2 and its diastereomeric counterpart S–Re–2 are the most fa-
vorite transition states leading to (R)- and (S)-product, respectively.
Both of them have minimized repulsion between the two substrates
and meanwhile maintain suitable orientation for hydrogen bonding.
In order to get more accurate energies, the six most stable tran-
sition states with catalyst (S)-1c were reoptimized using PBE1PBE
method (the model shown in Fig. 1-B). In these models, the two
substrates and the ‘core’ part of the catalysts (O2P(]O)OH) were
described by 6-311þG(d, p) basis set, the BINOL skeleton and the
bulky R groups were described by 6-31G(d, p) basis set. Frequency
analyses were then performed and solvent effects were considered
The regioselectivities between the 2- and 3-position of indole
and 4,7-dihydroindole in the Friedel–Crafts reaction were also in-
vestigated. As expected, the 2-position of 4,7-dihydroindole and
the 3-position of indole are the more active reaction sites. The
energy barrier of the nucleophilic attacking at 2-position of 4,7-
dihydroindole was 7.0 kcal/mol lower than that at 3-position. The
corresponding energetic gap of indole was 7.3 kcal/mol (Fig. 5).
using the IEFPCM model (UAHF radii) in dichloromethane (
The results are summarized in Table 1. The structures of R–Si–2(9-
anthryl) and S–Re–2(9-anthryl) are shown in Figure 7.
3
¼8.93).
Table 1
The calculated relative energies of the six most stable transition states with catalyst
(S)-1c on PBE1PBE/[6-311þG(d,p), 6-31G(d,p)] level of theory. All energies are in
kcal/mol, T¼298.15 K
7.0
0.0
NO2
3-attack
2-attack
7.3
3-attack
2-attack
TS
D
Egas
ꢀT
DS
D
Ggas
D
Gcorr
DGsol
N
H
N
H
indole
Ph
R–Si–2(9-anthryl)
R–Si–3(9-anthryl)
R–Si–4(9-anthryl)
S–Re–2(9-anthryl)
S–Re–3(9-anthryl)
S–Re–4(9-anthryl)
0.0
2.6
2.0
L0.1
2.2
0.7
0.0
1.1
0.5
0.1
1.2
0.1
0.0
3.7
2.2
L0.2
3.2
0.2
0.0
0.4
2.1
0.8
0.6
2.9
0.0
4.1
4.3
0.6
3.8
3.1
0.0
4,7-dihydroindole
Figure 5. The relative energetic barriers of nucleophilic attacking at different position
of 4,7-dihydroindole and indole. The relative Gibbs free energies in gas phase (
are in kcal/mol. Calculated on B3LYP/6-31G(d, p) level of theory.
DGgas)

2878
C. Zheng et al. / Tetrahedron 66 (2010) 2875–2880
most stable transition states R–Si–2(SiPh3) and S–Re–2(SiPh3) were
considered. The results are summarized in Table 2.
Table 2
The calculated relative energies of the two most stable transition states with catalyst
(S)-1b on PBE1PBE/[6-311þG(d, p), 6-31G(d, p)] level of theory. All energies are in
kcal/mol, T¼298.15 K
TS
DEgas
ꢀT
DS
DGgas
DGcorr
DGsol
R–Si–2(SiPh3)
S–Re–2(SiPh3)
0.7
0.0
0.3
0.0
1.4
0.0
ꢀ0.1
1.3
0.0
0.0
Quite different from catalyst (S)-1c, for (S)-1b, S–Re–2(SiPh3)
becomes the more stable transition state, whose Gibbs free energy
is 1.3 kcal/mol lower than that of R–Si–2(SiPh3). Thus the absolute
configuration of the major product switches to S, which is consis-
tent well with the experiment. As shown in Figure 9, in R–Si–
Figure 7. The optimized structures of the transition states R–Si–2(9-anthryl) and S–Re–
2(9-anthryl). The relative Gibbs free energies including solvent effect (DGsol) are in kcal/
mol, distances are in angstroms. Calculated on PBE1PBE/[6-311þG(d,p), 6-31G(d,p)]
level of theory.
As shown in Table 1, the transition states R–Si–2(9-anthryl) and S–
Re–2(9-anthryl) are the most stable ones leading to (R)- and (S)-
product, respectively. The other four structures are much unstable
(more than 3 kcal/mol higher), indicating that their contributions
to the ee value of the product can be omitted.
The transition states R–Si–2(9-anthryl) and S–Re–2(9-anthryl) have
very similar structures and energies. The Gibbs free energy of S–Re–
2(9-anthryl) in gas phase (DGgas) is 0.2 kcal/mol lower than that of
2
(SiPh3), the 4,7-dihydroindole is very close to one phenyl ring of the
left SiPh3 group, which would cause stronger repulsion than that in
S–Re–2(SiPh3). Meanwhile, the more congested structure of R–Si–
2
(SiPh3) is also unfavorable in terms of entropy (the contribution of
S to the Gibbs free energy for R–Si–2(SiPh3) is 0.3 kcal/mol). The
difference of the solvent effect ( Gcorr) of these two transition
D
D
states is only 0.1 kcal/mol, and the electron density surfaces also do
not show obvious distinction in charge distribution (Fig. 10). In this
system the enantioselectivity is determined by the steric effect.
R–Si–2(9-anthryl). However, the solvent effect brings about larger
discrimination to the Gibbs free energies of these two structures
(
D
Gcorr¼0.8 kcal/mol), with R–Si–2(9-anthryl) being the favorite one.
The Gsol suggests that the absolute configuration of the major
D
product is R, which corresponds well with the experiments.
Therefore, for catalyst (S)-1c the enantioselectivity is mainly de-
termined by the solvent effect.
How does the solvation affect the enantioselectivity? The energy
correction of the solvent effect
DGcorr is composed of electrostatic
interaction and nonelectrostatic interaction (including cavitation,
dispersion, and repulsion energies).20 A detailed comparison of these
energetic terms shows that R–Si–2(9-anthryl) can be better stabilized
by larger electrostatic interaction with the solvent compared with
S–Re–2(9-anthryl) (ꢀ8.45 kcal/mol vs ꢀ7.65 kcal/mol). On the other
hand, the nonelectrostatic interactions of these two structures are
nearly the same (<0.1 kcal/mol in difference). Encouraged by these
results, we drew the electron density surfaces of R–Si–2(9-anthryl) and
S–Re–2(9-anthryl) based on the total density (Fig. 8). The most
negatively charged region in the electron density surface is the
nonactivated oxygen atom of the nitro group (red part). In S–Re–
2(9-anthryl), this oxygen atom is just shielded by one anthryl ring of
the catalyst. Whereas in R–Si–2(9-anthryl), this polarized fragment is
exposed to the solvent, leading to larger electrostatic interactions.
Therefore, the difference in electrostatic interactions with the
solvent is caused by the different charge distributions.
Figure 9. The optimized structures of the transition states R–Si–2(SiPh3) and S–Re–
2(SiPh3) Selected hydrogen atoms are omitted for clarity. The relative Gibbs free ener-
gies including solvent effrct (DGsol) are in kcal/mol, distances are in angstroms. Cal-
culated on PBE1PBE/[6-311þG(d, p), 6-31G(d, p)] level of theory.
Figure 8. Electron density surfaces of R–Si–2(9-anthryl) and S–Re–2(9-anthryl) based on
the total density. Red: negative charge; Blue: positive charge; Green: neutral.
Subsequently, the enantioselectivity of the Friedel–Crafts re-
actions between 4,7-dihydroindoles and nitroolefins with catalyst
(S)-1b was studied. Based on the previous calculations, only the two
Figure 10. Electron density surfaces of R–Si–2(SiPh3) and S–Re–2(SiPh3) based on the
total density. Red: negative charge; Blue: positive charge; Green: neutral.

C. Zheng et al. / Tetrahedron 66 (2010) 2875–2880
2879
J. C. Org. Lett. 2007, 9, 2609; (g) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C.
Org. Lett. 2007, 9, 4065; (h) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed.
2008, 47, 4016; (i) Kang, Q.; Zheng, X.-J.; You, S.-L. Chem.dEur. J. 2008, 14, 3539;
(j) Sheng, Y.-F.; Li, G.-Q.; Kang, Q.; Zhang, A.-J.; You, S.-L. Chem.dEur. J. 2009, 15,
3351; (k) Kang, Q.; Zhao, Z.-A.; You, S.-L. Tetrahedron 2009, 65, 1603; (l) Sun, F.-L.;
Zeng, M.; Gu, Q.; You, S.-L. Chem.dEur. J. 2009, 15, 8709.
4. For selected examples: (a) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int.
Ed. 2005, 44, 7424; (b) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte,
M. Org. Lett. 2005, 7, 3781; (c) Rueping, M.; Antonchich, A. P.; Theissmann, T.
Angew. Chem., Int. Ed. 2006, 45, 3683; (d) Rueping, M.; Antonchich, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751; (e) Rueping, M.; Anton-
chich, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562; (f) Li, G.; Liang, Y.; Antilla, J. C.
J. Am. Chem. Soc. 2007, 129, 5830; (g) Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129,
7498; (h) Kang, Q.; Zhao, Z.-A.; You, S.-L. Adv. Synth. Catal. 2007, 349, 1657; (i)
Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759; (j) Kang, Q.;
Zhao, Z.-A.; You, S.-L. Org. Lett. 2008, 10, 2031.
5. For selected examples: (a) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed.
2006, 45, 4796; (b) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006,
128, 13070; (c) Liu, H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett.
2006, 8, 6023; (d) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K. Synlett
2006, 141; (e) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem.,
Int. Ed. 2008, 47, 9236.
6. For selected examples: (a) Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z.
J. Am. Chem. Soc. 2006, 128, 14082; (b) Li, N.; Chen, X.-H.; Song, J.; Luo, S.-W.;
Fan, W.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 15301; (c) Akiyama, T.; Katoh, T.;
Mori, K. Angew. Chem., Int. Ed. 2009, 48, 4226.
Finally, one crucial question remains to be answered is why the
predominant factors that determine the overall enantioselectivities
are different in two very similar catalytic systems? We believe that
in the system of (S)-1b the two SiPh3 groups provide more com-
plete reaction pocket that embraces the substrates better, avoiding
external solvent effects. Thus the enantioselectivity of the reaction
is entirely controlled by the chiral discrimination to the transition
states of the catalyst itself. Given that Akiyama used (R)-1a in the
indole system to afford (R)-product, it is reasonable that in our
system the catalyst (S)-1b affords (S)-product with 4,7-dihy-
droindole as the nucleophile. However, the bulky substitution 9-
anthryl is less steric-demanding than SiPh3. Direct interactions
between 9-anthryl and the substrates should be diminished, giving
nearly identical DGgas for transition states accessing both enantio-
meric products. The relatively less shielded transition state struc-
tures permit more remarkable solvent effects to the whole systems,
and the enantioselectivity originates from this ‘external’ discrimi-
nation eventually.21
4. Conclusion
7. For selected examples: (a) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006,
128, 16448; (b) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317,
496; (c) Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem., Int. Ed. 2007,
46, 6903; (d) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336; (e) Hu, W.-
H.; Xu, X.-F.; Zhou, J.; Liu, W.-J.; Huang, H.-X.; Hu, J.; Yang, L.-P.; Gong, L.-Z. J. Am.
Chem. Soc. 2008, 130, 7782; (f) Li, C.-Q.; Wang, C.; Villa-Marcos, B.; Xiao, J.-L.
J. Am. Chem. Soc. 2008, 130, 14450; (g) Li, C.-Q.; Wang, C.; Villa-Marcos, B.; Xiao,
J.-L. J. Am. Chem. Soc. 2009, 131, 6967; (h) Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2008, 130, 14452; (i) Terada, M.; Toda, Y. J. Am. Chem. Soc. 2009, 131, 6354; (j)
Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J.
J. Am. Chem. Soc. 2009, 131, 10796; (k) Cai, Q.; Zhao, Z.-A.; You, S.-L. Angew. Chem.,
Int. Ed. 2009, 48, 7428; (l) Zhang, Q.-W.; Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.; Zhao,
Y.-M.; Gu, P.; Chen, Z.-M. Angew. Chem., Int. Ed. 2009, 48, 8572; (m) Liu, X.-Y.; Che,
C.-M. Org. Lett. 2009, 11, 4204.
In summary, density functional theory calculations have been
carried out on chiral phosphoric acid-catalyzed Friedel–Crafts re-
action of nitroolefin with 4,7-dihydrodindole/indole. 4,7-Dihy-
droindole is more nucleophilic than indole in the view of frontier
molecular orbital energies. Besides, the 11-membered ring transi-
tion structure also contributes to its high reactivity.
The reversal of the enantioselectivies in the Friedel–Crafts re-
action of 4,7-dihydroindole and nitroolefin caused by switch of
3,30-substituted groups was explained qualitatively. When the
catalyst (S)-1b was used, the transition state leading to (R)-product
suffered from slightly stronger repulsion between the 4,7-dihy-
droindole and one SiPh3 group of the catalyst, which results in the
moderate enantiomeric excess (S) observed experimentally.
Whereas for catalyst (S)-1c, the different solvent effects of the two
transition states became predominant, products of opposite con-
figuration (R) were obtained with high ees.
8. (a) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129,
6756; (b) Simo´n, L.; Goodmann, J. M. J. Am. Chem. Soc. 2008, 130, 8741; (c) Si-
´
mon, L.; Goodmann, J. M. J. Am. Chem. Soc. 2009, 131, 4070; (d) Marcelli, T.;
Hammar, P.; Himo, F. Chem.dEur. J. 2008, 14, 8562; (e) Marcelli, T.; Hammar, P.;
Himo, F. Adv. Synth. Catal. 2009, 351, 525; (f) Yamanaka, M.; Hirata, T. J. Org.
Chem. 2009, 74, 3266; (g) Shi, F.-Q.; Song, B.-A. Org. Biomol. Chem. 2009, 7, 1292;
(h) Xu, S.; Wang, Z.; Li, Y.; Zhang, X.; Wang, H.; Ding, K. Chem.dEur. J., in press.
doi:10.1002/chem.200902698
9. For reviews on asymmetric Friedel–Crafts reactions: (a) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550; (b) Bandini, M.; Melloni,
A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199; (c) Poulsen, T. B.; Jørgen-
sen, K. A. Chem. Rev. 2008, 108, 2903; (d) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc.
Rev. 2009, 38, 2190. After the acceptance of this manuscript, Goodman et al.
reported an excellent theoretical investigation into chiral phosphoric acid-cat-
Acknowledgements
We thank the National Natural Science Foundation of China
(20732006, 20821002, 20872168, 20932008), National Basic Re-
search Program of China (973 Program 2009CB825300) for gener-
ous financial support.
´
alyzed Friedel–Crafts reactions of various imines; (e) Simon, L.; Goodman, J. M.
J. Org. Chem. 2010, 75, 589.
10. For other literature reports in which the configuration of the final products
could be switched in chiral phosphoric-acid catalysis caused only by changes of
3,30-substitution group on the catalyst, please see: Ref. 2b,3e,4e,j,6a,b and
Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485.
Supplementary data
11. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03
(Revision D.01); Gaussian: Wallingford, CT, 2004.
12. (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785; (b) Becke, A. D. Phys.
Rev. A 1988, 38, 3098; (c) Becke, A. D. J. Chem. Phys. 1992, 96, 2155; (d) Becke, A.
D. J. Chem. Phys. 1992, 97, 9173; (e) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
13. (a) Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1996, 77, 3865; (b)
Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1997, 78, 1396.
14. Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2005, 1, 415.
15. (a) Cances, M. T.; Mennucci, V.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032; (b)
Cossi, M.; Barone, V.; Tomasi, J. J. Phys., Lett. 1998, 286, 253.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.02.031.
References and notes
1. Reviews on chiral phosphoric-acid catalysis: (a) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 1520; (b) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999; (c) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45,
3909; (d) Akiyama, T. Chem. Rev. 2007, 107, 5744; (e) Yu, X.; Wang, W. Chem.
Asian J. 2008, 3, 516; (f) Terada, M. Chem. Commun. 2008, 4097.
2. For selected examples: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566; (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356; (c) Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu, Y.; Gong, L.-Z. J.
Am. Chem. Soc. 2007, 129, 3790; (d) Rueping, M.; Sugiono, E.; Schoepke, F. R.
Synlett 2007, 1441; (e) Gridnev, I. D.; Kouchi, M.; Sorimachi, K.; Terada, M.
Tetrahedron Lett. 2007, 48, 497; (f) Itoh, J.; Fuchibe, K.; Akiyama, T. Synthesis
2008, 1319.
3. For selected examples: (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 11804; (b) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2007, 46, 5565; (c) Terada, M.; Sorimachi, K. J. Am. Chem.
Soc. 2007, 129, 292; (d) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129,
1484; (e) Terada, M.; Yokoyama, S.; Sorimachi, K.; Uraguchi, D. Adv. Synth. Catal.
2007, 349, 1863; (f) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman, J. A.; Antilla,
16. Chiral phosphoric acids used in the activation of carbonyl compounds, see: Ref.
6c and (a) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.

2880
C. Zheng et al. / Tetrahedron 66 (2010) 2875–2880
Angew. Chem., Int. Ed. 2007, 46, 2097; (b) Terada, M.; Soga, K.; Momiyama, N.
Angew. Chem., Int. Ed. 2008, 47, 4122.
19. Bu¨rgi, H. B.; Du¨ nitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563.
20. (a)Ben-Naim, A. WaterandAqueousSolutions;Plenum:NewYork,NY,1974;(b)Ben-
Naim, A. J. Phys. Chem. 1978, 82, 792; (c) Ben-Naim, A. Solvation Thermodinamics;
Plenum: New York, NY, 1974; (d) Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027.
21. It has been reported that the configuration of the major product can be re-
versed simply by using different solvents in chiral phosphoric acid-catalyzed
aza-Diels–Alder reaction, see Ref. 5d.
17. Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; Wiley: New
York, NY, 2000; pp 675–681.
18. (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 4th ed.; Kluwer:
New York, NY, 2000; pp 568–571; (b) Pearson, R. G. Proc. Natl. Acad. Sci. U.S.A.
1986, 83, 8440; (c) Zhou, Z.; Parr, R. G. J. Am. Chem. Soc. 1990, 112, 5720.