Organocatalytic enantioselective Friedel-Crafts alkylation of simple phenols with trifluoropyruvate

Article abstract of DOI:10.1016/j.tetlet.2007.12.129

Enantioselective Friedel-Crafts alkylation of simple phenols (4a-j) with 3,3,3-trifluoropyruvate (3) was accomplished by using chiral cinchona alkaloid catalyst 2h (10 mol %). High yields and enantioselectivities (71-94% ee) of the Friedel-Crafts alkylati

Full text of DOI:10.1016/j.tetlet.2007.12.129

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1476–1479
Organocatalytic enantioselective Friedel–Crafts alkylation
of simple phenols with trifluoropyruvate
Jun-Ling Zhao, Li Liu *, Chun-Ling Gu, Dong Wang, Yong-Jun Chen *
Beijing National Laboratory for Molecular Sciences (BNLMS), Center for Chemical Biology, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
Received 11 October 2007; revised 20 December 2007; accepted 25 December 2007
Available online 8 January 2008
Abstract
Enantioselective Friedel–Crafts alkylation of simple phenols (4a–j) with 3,3,3-trifluoropyruvate (3) was accomplished by using chiral
cinchona alkaloid catalyst 2h (10 mol %). High yields and enantioselectivities (71–94% ee) of the Friedel–Crafts alkylation products were
obtained.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Organocatalysis; Enantioselective Friedel–Crafts alkylation; Phenol; Trifluoropyruvate
Friedel–Crafts alkylation of aromatic and heteroaro-
matic compounds with carbonyls is one of the most impor-
tant carbon–carbon bond forming reactions.1 There have
been tremendous progress in recent years with reactions
now proceeding in an enantioselective manner, which can
provide optically active aromatic compounds possessing
biological and pharmaceutical activities. Both electron-rich
aromatic and heteroaromatic compounds as well as less
active aromatic compounds, for example, anisole deriva-
tives have been shown to be good C-nucleophiles catalyzed
by chiral Lewis acids.2 In 1990 Erker reported the first
example of the asymmetric Friedel–Crafts alkylation of
1-naphthol with pyruvate catalyzed by chiral zirconium
complex.3 However, since then, enantioselective Friedel–
Crafts reactions of directly using phenols as C-nucleophiles
have been less studied. It could be attributed to the rela-
tively low reactivities of simple phenol compounds as
C-nucleophiles and strong interaction of unprotected
hydroxyl group with metallic catalysts as well as the diffi-
culty in controlling stereochemistry of transition states.
Recently, organocatalysis for asymmetric synthesis has
attracted considerable attention in terms of its unique
properties.4 Limited studies on organocatalytic enantiose-
lective Friedel–Crafts alkylations were also reported.
Among them, bifunctional cinchona alkaloid derivatives
have been demonstrated to be efficient catalyst for the
enantioselective Friedel–Crafts alkylation of indoles5 and
2-naphthol.6 However, to the best of our knowledge, the
catalytic enantioselective Friedel–Crafts alkylation of
phenol compounds, especially simple phenols is still a
challenge and has not been reported up to now. We
speculated that the use of organocatalysts would provide
an opportunity to solve the problem encountered in the
enantioselective Friedel–Crafts alkylation of phenols. To
continue our interest in catalytic enantioselective Friedel–
Crafts alkylation for generating optically active CF3-con-
taining compounds for biological application,7 herein we
would like to report an organocatalyzed enantioselective
Friedel–Crafts alkylation of simple phenols with trifluoro-
pyruvate under mild conditions.
Recently, we reported a highly enantioselective Friedel–
Crafts alkylation of aromatic ether, for example, anisole,
with trifluoropyruvate catalyzed by chiral (4R,5S)-BOX-
DiPh-Cu(OTf)2 (1) to give the product in 90% yield with
*
Corresponding authors. Tel.: +86 10 6255 4614; fax: +86 10 6255 4449.
E-mail addresses: lliu@iccas.ac.cn (L. Liu), yjchen@iccas.ac.cn (Y.-J.
Chen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.129

J.-L. Zhao et al. / Tetrahedron Letters 49 (2008) 1476–1479
1477
up to 93% ee.8 However, when the chiral catalyst 1 was
Table 1
Screening catalyst by reaction of 3 with 4b
employed in the reaction of phenol 4a with ethyl 3,3,3-tri-
fluoropyruvate 3 at ꢀ25 °C for 48 h, only trace amount of
product 5a was detected by TLC (Fig. 1, Scheme 1). As a
result, we focused on the enantioselective Friedel–Crafts
alkylation catalyzed by organocatalyst. Thus, natural cin-
chona alkaloids such as cinchonidine (2a), quinine (2b),
and quinidine (2c) served as bifunctional chiral organo-
catalyst in the Friedel–Crafts alkylation of 2,6-dimethyl-
phenol 4b with 3 in dichloromethane (DCM) under the
given conditions, respectively (Table 1). By using the stan-
dard conditions (10 mol % catalyst loading), product 5b,
ethyl 3,3,3-trifluoro-2-hydroxy-2-(4-hydoxy-3,5-dimethyl-
phenyl) propanoate, was obtained in good yields (65–
96%). Although it was shown by Torok et al.5a that 2a
and 2b (or 2c) are efficient catalysts for the highly enantio-
selective reaction of indoles with 3, only modest enantio-
selectivities were obtained in the reaction of phenol
compound 4b with 3 (36–44% ee) (Table 1, entries 1 and
2). To improve the enantioselectivity, a series of cinchona
alkaloid derivatives (2d–i) were prepared (Fig. 1), and
employed as catalysts in the reaction of 4b with 3. If both
60-OH and 9-OH were blocked by methyl and benzyl
groups, respectively, lower ability of catalyst (2d) and poor
enantioselectivity of product 5b were observed (entry 4).
OH
OH
O
10 mol % cat
DCM
+
COOEt
OH
F3C
COOEt
∗
F3C
5b
4b
3
Entry
Cata
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
a
2a
2b
2c
2d
2e
2f
25
25
25
23
23
24
24
24
16
24
16
48
96
85
81
65
85
95
85
88
30
44
36
ꢀ30
25
15
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ4
72
58
92
ꢀ11
2g
2h
2i
Catalyst loading: 10 mol %.
Isolated yield.
Determined by chiral HPLC.
b
c
Furthermore, for unprotected 60-OH and 9-OH, catalyst
2e afforded very low enantioselectivity (entry 5). The poor
enantioselectivity could be due to the fact that both hydro-
xyl groups could participate in forming hydrogen bonding
with substrates and resulted in the loss of selectivity. When
60-OH was free and 9-OH was blocked (2f–h), the ee values
of 5b increased significantly. To our delight, with a bulky
phenanthrene (PHN) group in 9-OR (2h) the enantioselec-
tivity of 5b reached 92% ee (entry 8).9 An attempt to
increase the enantioselectivity by introducing a thiourea
group at 9-position (2i) was not successful (entry 9).
When the catalyst loading was reduced from 10 mol %
to 5 mol %, 2 mol % and 1 mol %, respectively, the yields
decreased noticeably and the ee lowered slightly (Table 2,
entries 1–3). The reaction temperature also affected the
enantioselectivities. At 0 °C, the reaction between 4b and
3 gave the product 5b with 84% ee, while the enantioselec-
tivity was increased to 92% at ꢀ10 °C and 94% at ꢀ40 °C,
with a prolonged reaction time (entries 4–6).
N
N
HO
HO
O
O
H
H
Ph
Ph
N
N
MeO
Cu
TfO OTf
Ph
Ph
N
2a
N
1
2b
N
N
N
RO
HO
BnO
H
H
H
MeO
MeO
HO
N
N
N
2c
2d
2e. R=H, 2f. R=Bn
2g. R=Bz
Subsequently, various phenols (4a–j) were reacted with 3
in the presence of chiral organocatalyst 2h (10 mol %) in
DCM under given reaction conditions (Scheme 1, Table
3).10 Moderate to high yields (58–96%) and high enantio-
CF3
N
H
2h. R=
H
N
N
H
S
MeO
CF3
N
2i. Ar=3,5-(CF3)2C6H3
Table 2
Fig. 1. Chiral catalysts 1 and 2a–i.
Effects of temperature and catalyst loading on the reaction of 4b and 3
Entry
Cata (mol %)
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
a
5
2
1
10
10
10
ꢀ10
ꢀ10
ꢀ10
0
24
24
48
6
16
72
86
76
21
96
88
78
88
85
83
84
92
94
OH
OH
R
O
2h (10 mol %)
ꢀ10
R
COOEt
F3C
COOEt
DCM
∗
ꢀ40
F3C
OH
5a-j
Catalyst: 2h.
Isolated yield.
Determined by chiral HPLC.
4a-j
3
b
c
Scheme 1.

1478
J.-L. Zhao et al. / Tetrahedron Letters 49 (2008) 1476–1479
Table 3
Organocatalytic enantioselective Friedel–Crafts alkylation of phenols (4a–j) with 3a
Entry
1
Phenol
Temp (°C)
Time (h)
Productb
Yieldc (%)
76
eed (%)
86
OH
OH
4a
4b
ꢀ25
72
5a
5b
X
OH
OH
2
ꢀ40
72
78
94
X
OH
OH
3
4
5
6
7
8
9
4c
4d
4e
4f
4g
4h
4i
ꢀ20
ꢀ30
ꢀ20
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ20
24
72
24
60
68
60
48
24
5c
5d
5e
5f
5g
5h
5i
83
75
96
88
67
87
82
58
88
86
81
86
75
71
78
91
X
OH
OH
X
OH
OH
X
OH
OH
OH
OH
OH
OH
X
OH
Ph
Ph
X
OH
OMe
OH
OMe
OH
X
OH
X
OH
10
4j
5j
X
a
Catalyst: 2h (10 mol %) in DCM.
X: F3CC(OH)CO2Et.
Isolated yield.
b
c
d
Determined by chiral HPLC.
selectivities (71–94% ee) were obtained in each case (Table
3). The H NMR spectra of the products showed that the
Friedel–Crafts alkylation of phenols has excellent para
regioselectivity, even in the case of 2-methoxyphenol 4h,
the alkylation reaction occurred at the para-position of
hydroxyl group exclusively, but not at the para-position
of methoxyl group. On the other hand, the reaction
between anisole (6) with 3 did not proceed under the same
reaction conditions, and the starting materials were
recovered completely.
1

J.-L. Zhao et al. / Tetrahedron Letters 49 (2008) 1476–1479
1479
K. J. Org. Chem. 2004, 69, 146; (c) Gathergood, N.; Zhuang, W.;
Jogensen, K. A. J. Am. Chem. Soc. 2000, 122, 12517; (d) Zhuang, W.;
Gathergood, N.; Hazell, R. G.; Jogensen, K. A. J. Org. Chem. 2001,
66, 1009.
OH
OMe
1) K2CO3, THF
2) CH3I
COOEt
OH
5a
COOEt
OH
(S)-7
3. Erker, G.; van der Zeijden, A. A. H. Angew. Chem., Int. Ed. 1990, 29,
512.
4. For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138; (b) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2006, 45, 1520; (c) Special issue on organocatalysis: Houk, K. N.,
List, B., Eds.; Acc. Chem. Res. 2004, 37, 487.
F3C
F3C
Scheme 2.
5. (a) Torok, B.; Abid, M.; London, G. Angew. Chem., Int. Ed. 2005, 44,
3086; (b) Li, H.; Wang, Y. Q.; Deng, L. Org. Lett. 2006, 8, 4063.
6. (a) Brandes, S.; Bella, M.; Kjarsgaard, A.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2006, 45, 1147; (b) Liu, T. Y.; Cui, H. L.; Chai, Q.;
Long, J.; Li, B. J.; Wu, Y.; Ding, L. S.; Chen, Y. C. Chem. Commun.
2007, 2228.
To assign the absolute configuration, 5a was converted
to corresponding methylation product 7 under mild condi-
tions (Scheme 2). Compared the rotation sign of 7 ([a]D
+17.1) with the known compound,8 the absolute configura-
tion of 5a was assigned as S.
7. (a) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001, 66,
2572; (b) Surya Prakash, G. K.; Manadal, M.; Olah, G. A. Angew.
Chem., Int. Ed. 2001, 40, 589; (c) Bravo, P.; Crucianelli, M.; Vergani,
B.; Zanda, M. Tetrahedron Lett. 1998, 39, 9151.
8. Zhao, J. L.; Liu, L.; Sui, Y.; Liu, Y. L.; Wang, D.; Chen, Y. J. Org.
Lett. 2006, 8, 6127.
9. The examples of 6-OH cinchona alkaloid bearing 90-OR type
catalysts, see: (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem.
Soc. 2004, 126, 9906; (b) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am.
Chem. Soc. 2005, 127, 8948; (c) Li, H.; Wang, Y.; Tang, L.; Wu, F.;
Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed.
2005, 44, 105; (d) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J.
Am. Chem. Soc. 2006, 128, 8156; (e) Li, H.; Wang, B.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 732; (f) Wang, Y.; Liu, X.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 3928.
In conclusion, an enantioselective Friedel–Crafts alkyl-
ation of simple phenols with trifluoropyruvate catalyzed
by cinchona alkaloid derivatives was achieved. The method
provides a practical synthetic approach to optically active
CF3-containing a-hydoxyl-a-aryl-carboxylate compounds
bearing functional phenolic hydroxyl groups.
Acknowledgments
We thank the National Natural Science Foundation of
China and The Chinese Academy of Sciences for financial
support.
10. Typical experimental procedure: To
a solution of 2h (7.2 mg,
References and notes
0.015 mmol) in freshly distilled CH2Cl2 (0.3 mL) phenol 4a
(14.1 mg, 0.15 mmol) was added at ambient temperature, followed
by stirring at ꢀ25 °C for 10 min. Ethyl trifluoro- pyruvate 3 (24 lL,
30.6 mg, 0.18 mmol) was injected under Ar atmosphere. The mixture
was stirred at the same temperature for 72 h. The mixture was purified
by flash chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 8:1 v/v) to give 5a as a colorless oil (30.1 mg, 76% yield with
86% ee).
1. For reviews, see: Olah, G. A.; Khrisnamurti, R.; Surya Prakashi, G.
K. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
New York, 1991; Vol. 3, pp 293–339.
2. For examples of Lewis acid-catalyzed asymmetric Friedel–Crafts
alkylation, see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 550; (b) Yuan, Y.; Wang, X.; Ding,