The β-Silyl Effect on the Memory of Chirality in Friedel-Crafts Alkylation Using Chiral α-Aryl Alcohols

Article abstract of DOI:10.1021/acs.orglett.5b01582

Iron salt-catalyzed Friedel-Crafts alkylation of chiral α-aryl alcohols with a trimethylsilyl group was found to proceed with retention of the configuration of the hydroxyl group as a leaving group. The memory of chirality of this system stems from the β-

Full text of DOI:10.1021/acs.orglett.5b01582

Letter
pubs.acs.org/OrgLett
The β‑Silyl Effect on the Memory of Chirality in Friedel−Crafts
Alkylation Using Chiral α‑Aryl Alcohols
Toshiki Nokami,†,‡ Yu Yamane,† Shunsuke Oshitani,† Jun-ka Kobayashi,† Shin-ichiro Matsui,†
Takashi Nishihara,† Hidemitsu Uno,§ Shuichi Hayase,†,‡ and Toshiyuki Itoh*,†,‡
‡
†Department of Chemistry and Biotechnology, Center for Research on Green Sustainable Chemistry, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori City 680-8552, Tottori, Japan
§Department of Chemistry and Biology, Graduate School of Science and Engineering, Ehime University, 2-5 Bunkyo-cho, Matsuyama
City 790-8577, Ehime, Japan
S
* Supporting Information
ABSTRACT: Iron salt-catalyzed Friedel−Crafts alkylation of
chiral α-aryl alcohols with a trimethylsilyl group was found to
proceed with retention of the configuration of the hydroxyl
group as a leaving group. The memory of chirality of this
system stems from the β-silyl effect of the trimethylsilyl group
on the carbocation intermediate.
symmetric synthesis based on the memory of chirality
1
A(MOC) is quite useful in carbanion chemistry. MOC in
carbocation chemistry2 is rare and there is no general method
to achieve it.
During the course of our studies on development of iron salt
catalyzed reactions,3 we were interested in Friedel−Crafts
alkylation using α-aryl alcohols as alkylating agents.4,5 Here, we
Figure 2. Retentive electrophilic substitution of α-substituted
report a significant effect of a silyl group at the β-position on
the MOC in the iron salt catalyzed Friedel−Crafts alkylation of
aromatic compounds (Figure 1).
alkylferrocenes.
conformational stability of carbocation intermediates is a crucial
property to achieve the MOC.
Figure 3. Retentive electrophilic substitution of the electrochemically
generated N-acyliminium ion.
Figure 1. A silyl group effect on the MOC in the Friedel−Crafts type
alkylation using chiral α-aryl alcohols as alkylating agents.
We initiated our study from the Friedel−Crafts alkylation of
indole (1) with β-silyl alcohols 2−4 to optimize an acid catalyst
(Table 1). Conventional Lewis acids such as AlCl3 and FeCl3
gave the corresponding alkylation products 5 in moderate
yields (entries 1 and 2). Although sulfuric acid, which is a
typical Brønsted acid, also catalyzed the reaction, the yield of 5
Electrophilic substitutions of chiral starting materials having a
leaving group at the chiral carbon center give racemic products
via a carbocation intermediate; however, the reaction of chiral
ferrocene derivatives is a known exception (Figure 2). Ugi and
co-workers reported the retentive electrophilic substitution of
the α-substituted alkylferrocenes.6 Another example is the
electrochemical generation of the N-acyliminium ion and the in
situ trap with a nucleophile (Figure 3).7,8 In both cases, the
Received: May 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01582
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Letter
single crystal (>99% ee, see the Supporting Information for
HPLC profiles) after recrystallization from hexane, and the
absolute configuration of (+)-7 was determined by X-ray single
crystal structure analysis to be (R) (Figure 5).12,13 These results
Table 1. Optimization of Reaction Conditions
entry
Ar
acid catalyst
AlCl3
solvent
yield (%)
1
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-thienyl
2-thienyl
phenyl
phenyl
neat
neat
neat
neat
neat
neat
H2O
CH3CN
neat
neat
neat
neat
45
49
33
66
96
49
2
2
FeCl3
3
H2SO4
4
Sc(OTf)3
5
Fe(BF4)2·6H2O
Fe(ClO4)3·nH2O
Fe(BF4)2·6H2O
Fe(BF4)2·6H2O
Fe(ClO4)3·nH2O
Fe(BF4)2·6H2O
Fe(ClO4)3·nH2O
Fe(BF4)2·6H2O
Figure 5. Crystal structure of the alkylation product (R)-7.
6
7
indicate that the Friedel−Crafts alkylation of chiral β-silyl
alcohols proceeded with retention of the configuration. The
same level of MOC was observed with other conventional
Lewis acids such as AlCl3, FeCl3, and Sc(OTf)3, although the
yields were lower than those using the best catalyst (see the
Supporting Information for details). Thus, the choice of catalyst
is not crucial for MOC in this system. We were also surprised
that MOC was achieved with retention of the configuration. It
is hard to propose a mechanism in which the Lewis acid catalyst
activates the hydroxyl group and directs the nucleophile at the
same time. Therefore, a reaction mechanism via the carbocation
intermediate cannot be ruled out.
8
23
69
96
70
57
9
10
11
12
was again moderate (entry 3). Sc(OTf)3 was more effective
(entry 4); however, the cationic iron salt Fe(BF4)2·6H2O3 was
found to be much more effective as a catalyst (entry 5). Further
investigation of iron salts and addition of solvents did not
improve the yields of 5 (entries 6−8). The choice of iron salts
depends on the aryl substituents. With 2-furyl and 2-thienyl
derivatives 2 and 3, Fe(BF4)2·6H2O was the best catalyst
(entries 9 and 10). On the other hand, Fe(ClO4)3·nH2O gave
better results with the phenyl derivative of β-silyl alcohol 4
(entries 11 and 12).
The effect of trimethylsilyl on both reactivity and MOC was
significant (Figure 6). (S)-1-Phenylethanol ((S)-8) did not
Next, we investigated chiral β-silyl alcohols as alkylating
agents to confirm the generation of a carbocation intermediate.
The astonishing thing is that chiral alkylation product (+)-6
(66% ee) was obtained when we subjected chiral β-silyl alcohol
(+)-3 (77% ee)9 to the reaction (Figure 4). Even better
chirality transfer was attained in the reaction of chiral β-silyl
alcohol (S)-(+)-4:10,11 the chiral product (R)-(+)-7 (91% ee)
was afforded in 67% yield when (S)-(+)-4 (93% ee) was
subjected to the reaction with indole in the presence of 5 mol %
of Fe(ClO4)3·nH2O. Fortunately, (+)-7 was obtained as a pure
Figure 6. Friedel−Crafts type alkylation using chiral alcohols (S)-8
and (S)-9 as alkylating agents.
afford the corresponding alkylation product at all under the
optimized reaction conditions (Table 1, entry 11). In contrast,
(S)-1-(thien-2-yl)ethanol ((S)-9) gave alkylation product
(+)-10 in 60% yield; however, the alkylation product (+)-10
thus obtained was almost a racemic mixture (3% ee).
Therefore, Friedel−Crafts alkylation reactions must proceed
via a carbocation intermediate. These results indicate that the
trimethylsilyl group plays a crucial role in MOC.
Bach and co-workers have reported the syn-selective Friedel−
Crafts alkylation at the benzylic position of 2,3,3-trimethyl-1-
phenylbutan-1-ol via a benzylic carbocation intermediate using
a strong Lewis or a Brønsted acid.5b They have revealed that
the substituent at the β-position plays a crucial role in the
diastereoselectivity and the steric outcome of the reaction is
Figure 4. Friedel−Crafts type alkylation using chiral β-silyl alcohols
(+)-3 and (S)-(+)-4 as alkylating agents.
B
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Letter
determined by a conformational restriction in the benzylic
carbocation intermediate. Several diastereoselective reactions
via carbocation intermediates have also been reported.14,15
On the basis of the pioneering works, we assume that the
origin of the MOC stems from the carbocation intermediate
which is conformationally stable (Figure 7). In the first step, a
was observed at 97° where the C−Si σ-bond is almost
perpendicular to the plane of the cationic carbon. For
comparison, the methyl analogue of intermediate 12 was also
calculated (Figure 8, dashed line). The energy minimum was
observed at 120° where one of the two C−H σ-bonds is
perpendicular to the plane of the cationic carbon. In this case,
the C−H σ-bond works as an electron donor toward the
cationic carbon; however, its ability as an electron donor is
much weaker than that of the C−Si σ-bond. This significant
difference in the conformational energy can be explained by the
hyperconjugation of the C−Si σ-bond to stabilize the
carbocation intermediate 11. Moreover, during the formation
of the carbocation intermediate, the leaving hydroxyl group and
the trimethylsilyl group are in the antiperiplanar conformation
(see the Supporting Information for details). These results
support our mechanistic proposal.
In conclusion, we have found that a silyl group has a
significant effect on the MOC in Friedel−Crafts alkylations
using chiral α-aryl alcohols as alkylating agents. Although Lewis
acids do not affect the MOC, the introduction of a silyl
substituent at the β-position of the hydroxyl group is crucial.
This is the first example of MOC based on the conformational
stability of the carbocation intermediate supported by a flexible
silyl substituent. Further transformations of the alkylation
products including the scope of silyl groups and their
application for the synthesis of functional molecules are in
progress in our laboratory.
Figure 7. Proposed mechanism of the Friedel−Crafts type alkylation
with retention configuration using the chiral β-silyl alcohol (S)-4.
catalytic amount of iron salt generates conformationally stable
carbocation intermediate 11 from chiral β-silyl alcohol (S)-4.
The trimethylsilyl group occupies the opposite face of the
leaving hydroxyl group in this carbocation intermediate 11. In
the second step, a nucleophile attacks the cationic carbon from
the opposite face of the trimethylsilyl group and affords the
alkylation product (R)-7 with retention of configuration.
To support our mechanistic proposal, we investigated the
conformational stability of the carbocation intermediate using
density functional theory (DFT) calculations.16 To estimate the
possibility of conformational change of carbocation intermedi-
ate 11, the relationship between the free energy and the
conformation of the carbocation intermediate was calculated
(Figure 8, solid line). We found that the dihedral angle between
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, results of DFT calculations, and
spectroscopic data of compounds. The Supporting Information
is available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01582.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: titoh@chem.tottori-u.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
All of the calculations with Gaussian09 were performed using
the Research Center for Computational Science (RCCS) in
Okazaki (Nagoya, Japan). The authors thank the RCCS for
their permission to access their computer resources.
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