Organocatalytic Enantioselective Friedel-Crafts alkylation of sesamol with nitro olefins

Article abstract of DOI:10.1002/ejoc.201000271

A bifunctional chiral thiourea-tertiary amine organocatalyst derived from cinchonine was employed to promote the enantioselective Friedel-Crafts alkylation of sesamol and 2-substituted sesamols with various aromatic nitro olefins. The reactions proceeded smoothly to provide the corresponding products in good, yields (up to 97%) and good, enantioselectivities (up to 90% ee).

Full text of DOI:10.1002/ejoc.201000271

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000271
Organocatalytic Enantioselective Friedel–Crafts Alkylation of Sesamol with
Nitro Olefins
Hui Zhang,[a,b] Yu-Hua Liao,[a,b] Wei-Cheng Yuan,[a] and Xiao-Mei Zhang*[a]
Keywords: Alkenes / Organocatalysis / Alkylation / Enantioselectivity
A bifunctional chiral thiourea–tertiary amine organocatalyst
actions proceeded smoothly to provide the corresponding
derived from cinchonine was employed to promote the enan- products in good yields (up to 97%) and good enantio-
tioselective Friedel–Crafts alkylation of sesamol and 2-sub-
stituted sesamols with various aromatic nitro olefins. The re-
selectivities (up to 90%ee).
F–C reactions to construct complex natural products.[7]
However, to the best of our knowledge, systematic research
on asymmetric F–C alkylations of sesamol has not been
reported.
Herein we describe the first enantioselective F–C alk-
ylations of sesamol or 2-substituted sesamols with a wide
variety of nitro olefins promoted by bifunctional chiral
thiourea–tertiary amine organocatalysts. The reactions pro-
ceeded smoothly in the presence of only 5 mol-% of the
optimal organocatalyst to provide the desired products in
good yields (up to 97%) and good enantioselectivities (up
to 90%ee).
Introduction
The Friedel–Crafts (F–C) reaction of electron-rich aro-
matic compounds represents an important C–C bond-form-
ing process for the synthesis of valuable building blocks of
biologically active compounds. Recently, organocatalytic
enantioselective Friedel–Crafts alkylation reactions have at-
tracted much attention due to the significance of this trans-
formation for the synthesis of optically active aromatic
compounds.[1] In 2004, Terada and co-workers first em-
ployed chiral phosphoric acid to promote the F–C alk-
ylation of 2-methoxyfuran with N-Boc aldimines and furan-
2-ylamines were obtained in excellent chemical yields and
enantioselectivities.[2] Since then, many efforts have been de-
voted to enantioselective organocatalytic F–C alkylations
of electron-rich arenes such as indole derivatives,[3] pyrrole
derivatives,[4] and phenol derivatives[5] with various electro-
Results and Discussion
First, 5 mol-% of bifunctional chiral thiourea–tertiary
philes. For example, Chen and co-workers reported the first amine organocatalyst 1a[8a] (Figure 1) was employed in the
highly enantioselective F–C alkylation of 1- and 2-naphth- F–C alkylation of sesamol (2a) with nitrostyrene (3a) in tol-
ols with nitro olefins catalyzed by bifunctional chiral uene at –15 °C. The reaction proceeded for 48 h to give al-
thiourea–tertiary amine organocatalysts.[5c] However, up to most quantitative yield of product 4a in 60%ee (Table 1,
now, phenols other than naphthols were rarely utilized in
enantioselective organocatalytic F–C alkylations[5a] so that
the synthetic potential of this methodology was limited to
some extent. Therefore, expansion of the scope of phenols
in the above-mentioned reactions is of interest.
Sesamol is one of the representative structural motifs
often observed in natural alkaloids and biologically active
compounds.[6] Being electron-rich phenols, sesamol and its
derivatives are good nucleophiles that can be employed in
[a] Key Laboratory for Asymmetric Synthesis and
Chiraltechnology of Sichuan Province, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, P. R. China
Fax: +86-28-85229250
E-mail: xmzhang@cioc.ac.cn
[b] Graduate School of Chinese Academy of Sciences,
Beijing 100049, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000271.
Figure 1. Organocatalysts evaluated in this study.
Eur. J. Org. Chem. 2010, 3215–3218
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H. Zhang, Y.-H. Liao, W.-C. Yuan, X.-M. Zhang
SHORT COMMUNICATION
Entry 1). Encouraged by this result, several bifunctional or- be in vain (Table 1, Entries 9–11) The survey of solvents
ganocatalysts were screened in the titled reaction. All of revealed that nonpolar solvents were appropriate to the re-
these catalysts promoted the reaction efficiently to afford action in terms of yield and enantioselectivity. Chlorinated
the products in almost quantitative yields. Catalysts 1a– solvents led to good yields but inferior ee values (Table 1,
d[8a,8b] derived from cinchona alkaloids[9] resulted in close Entries 14–16). Meanwhile, trace amounts of products or
ee values (Table 1, Entries 1–4), in which 1a delivered the no reaction at all was observed in polar solvents (Table 1,
best ee. However, catalyst 1e[8c] derived from (1R, 2R)-cy- Entries 17–19), perhaps due to the competitive coordination
clohexane-1,2-diamine resulted in much lower enantio- of the solvents with the catalyst. Among the non-polar sol-
selectivity (Table 1, Entry 5). Cinchonine (1f) and quinine vents, mesitylene proved to be the most favorable one
(1g) gave very poor ee values as well (Table 1, Entries 6 and (Table 1, Entry 13). Reducing the catalyst loading from 5 to
7).
2.5 mol-% gave rise to almost the same yield and ee value
(Table 1, Entry 20), whereas enhancing the catalyst loading
to 10 mol-% did not benefit the enantioselectivity at all
(Table 1, Entry 21). Finally, we found that the concentra-
tion had an obvious influence on the reaction. High con-
centrations were deleterious to both yields and ee values
(Table 1, Entry 22). To our delight, low concentrations were
advantageous to the reaction (Table 1, Entries 23–25).
When the reaction was conducted in 4 mL of mesitylene,
the enantioselectivity increased to 84% (Table 1, Entry 25).
Having established the optimal conditions, the enantiose-
lective F–C alkylation was expanded to a wide variety of
nitro olefins and two 2-substituted sesamols. The results are
summarized in Table 2. Generally, the F–C alkylation of
Table 1. Enantioselective F–C alkylation of sesamol (2a) with
nitro olefin 3a.
Entry[a]
Catalyst
(mol-%)
Solvent
T [°C]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
1a (5)
1b (5)
1c (5)
1d (5)
1e (5)
1f (5)
1g (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (2.5)
1a (10)
1a (5)
1a (5)
1a (5)
1a (5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
mesitylene
CH2Cl2
ClCH2CH2Cl –40
CHCl3
Et2O
THF
–15
–15
–15
–15
–15
–15
–15
–40
–40
–40
–40
–40
–40
–40
98
97
98
98
93
98
99
98
97
87
98
86
91
89
84
87
11
NR
NR
91
97
81
92
93
92
60
53
–56
–57
–29
–19
24
75
69
67
68
76
81
73
67
78
62
–
Table 2. Enantioselective F–C alkylation of sesamol or 2-substi-
tuted sesamols 2a–c with nitro olefins 3a–q.
9[d]
10[e]
11[f]
12
13
14
15
16
17
18
19
20
21
22[g]
23[h]
24[i]
25[j]
Entry[a] R1 (2)
R2 (3)
4
Yield
[%][b]
ee
Config.
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
[%][c]
1
2
3
4
5
6
7
8
H (2a)
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
92
97
81
92
91
92
86
75
96
89
93
96
87
85
85
80
96
88
88
84
85
76
82
83
83
83
85
88
59
75
86
86
65
83
77
82
83
90
S (–)[d]
(+)
(+)
(+)
(–)
(–)
(–)
(+)
(–)
(–)
(–)
(–)
(–)
(+)
(+)
(–)
(–)
(–)
EtOH
–
H (2a) 4-MeOC6H4
H (2a) 2-MeOC6H4
H (2a) 4-BnOC6H4
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
80
80
78
81
83
84
4-MeC6H4
3-MeC6H4
4-FC6H4
3-FC6H4
4-ClC6H4
2-ClC6H4
[a] Unless specified otherwise, reactions were carried out with 2a
(0.2 mmol), 3a (0.3 mmol), and the catalyst in the solvent (0.5 mL)
at –15 °C for 48 h or at –40 °C for 96 h. [b] Isolated yield based on
2a. [c] The ee values were determined by using chiral HPLC.
[d] With 3 Å MS as additive. [e] With 4 Å MS as additive. [f] With
5 Å MS as additive. [g] In 0.25 mL of mesitylene. [h] In 1 mL of
mesitylene. [i] In 2 mL of mesitylene. [j] In 4 mL of mesitylene.
9
10
11
12
13
14
15
16
17
18
19
H (2a) 2,4-Cl2C6H3
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
Me (2b)
I (2c)
4-BrC6H4
3-BrC6H4
2-BrC6H4
3-CF3C6H4
2-naphthyl
2-furanyl
Ph
Therefore, 1a was determined as the optimal catalyst and
was employed in further investigations. Various reaction
conditions involving temperature, additives, solvents, and
concentrations were tested in search of the optimal condi-
tions. Lowering the temperature to –40 °C gave rise to an
obvious increase in the ee value (Table 1, Entry 8). How-
ever, attempts to further improve the ee values by adding 3,
Ph
(–)
[a] Unless specified otherwise, reactions were carried out with 2
(0.2 mmol), 3 (0.3 mmol), and catalyst 1a (5 mol-%) in mesitylene
(4 mL) at –40 °C for 96 h. [b] Isolated yield based on 2. [c] The
ee values were determined by using chiral HPLC. [d] The absolute
configuration of 4a was determined by X-ray analysis of the ester
4, or 5 Å molecular sieves to the reaction system proved to derived from 4a and (–)-camphanic acid.
3216 Eur. J. Org. Chem. 2010, 3215–3218
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Enantioselective Friedel–Crafts Alkylation of Sesamol with Nitro Olefins
aromatic nitro olefins bearing substituents in the para or methodology, a wide variety of chiral sesamol derivatives
meta position of the phenyl groups with sesamol proceeded were synthesized in good yields (up to 97%) and good
smoothly to provide the corresponding products in good enantioselectivities (up to 90%ee). The absolute configura-
enantioselectivities (Ͼ80%ee), no matter whether the sub- tion of product 4a was determined as (S) by X-ray crystal-
stituents were electron donating or electron withdrawing. lographic analysis of ester 5 derived from 4a and (–)-
However, aromatic nitro olefins bearing substituents in the camphanic acid. Further work is in progress to utilize this
ortho position of the phenyl groups reacted with sesamol in reaction in the construction of complex natural or unnatu-
inferior enantioselectivities (Table 2, Entries 3, 10, 11, and ral products.
14). Perhaps the ortho substitution on the phenyl group
made the nitro olefins sterically more hindered so that they
displayed lower enantioselectivities. Inferior enantio-
selectivity was observed with (E)-2-(2-nitrovinyl)naphth-
Experimental Section
General Procedure of the Enantioselective F–C Alkylation of Sesa-
mol with Nitro Olefin: Catalyst 1a (5.6 mg, 0.01 mmol, 5 mol-%),
sesamol (2; 0.2 mmol), and nitro olefin 3 (0.3 mmol) were added to
a 10-mL tube and cooled to –40 °C under an atmosphere of argon.
Then, dry mesitylene (4.0 mL) was added. After the reaction was
conducted for 96 h, the mixture was subjected to flash chromatog-
raphy on silica gel to give pure product 4.
alene (3p) as well (Table 2, Entry 16). Heteroaryl-substi-
tuted nitro olefin 3q exhibited excellent reactivity and gave
almost quantitative product with good enantioselectivity
(Table 2, Entry 17). Furthermore, 2-methylsesamol (2b) and
2-iodosesamol (2c) were also subjected to the enantioselec-
tive F–C alkylation with nitro olefin 3a. Compound 2b
underwent the reaction with good yield and ee value
(Table 2, Entry 18). Gratifyingly, reaction of 2c and 3a pro-
vided the highest enantioselectivity (90%ee; Table 2, En-
try 19).
Supporting Information (see footnote on the first page of this arti-
cle): Representative procedures for the enantioselective F–C alky-
lation of sesamol and 2-substituted sesamols with nitro olefins;
spectroscopic data of products 4a–s; HPLC chromatograms of 4a–s.
Afterwards, product 4a was acylated with (1S)-(–)-
camphanic acid to give ester 5. The absolute configuration
of 4a was assigned as (S) by X-ray crystallographic analysis Acknowledgments
of 5 (Figure 2).[10]
We are grateful for the financial support of the National Sciences
Foundation of China (20772122) and National Basic Research Pro-
gram of China (973 Program, 2010CB833301).
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Figure 2. X-ray structure of ester 5.
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H. Zhang, Y.-H. Liao, W.-C. Yuan, X.-M. Zhang
SHORT COMMUNICATION
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Received: February 27, 2010
Published Online: May 6, 2010
3218
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Eur. J. Org. Chem. 2010, 3215–3218