Asymmetrie binary-acid catalysis with chiral phosphoric acid and MgF 2: Catalytic enantioselective Friedel- Crafts reactions of β,γ-unsaturated α-ketoesters

Article abstract of DOI:10.1021/ol1000928

(Figure Presented) A unique binary chiral phosphoric acid 1a/MgF ₂ catalyst that enables effective catalysis of asymmetric Friedel-Crafts reactions of phenols with up to 82% yield and >99% ee Is presented. A dramatic synergistic effect has been observed In the combinations of two types of acids, wherein a highly active binary-acid catalyst can be generated from two individually inert acids.

Full text of DOI:10.1021/ol1000928

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1096-1099
Asymmetric Binary-Acid Catalysis with
Chiral Phosphoric Acid and MgF2:
Catalytic Enantioselective
Friedel-Crafts Reactions of
ꢀ,γ-Unsaturated r-Ketoesters
Jian Lv, Xin Li, Long Zhong, Sanzhong Luo,* and Jin-Pei Cheng
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
luosz@iccas.ac.cn
Received January 14, 2010
ABSTRACT
A unique binary chiral phosphoric acid 1a/MgF2 catalyst that enables effective catalysis of asymmetric Friedel-Crafts reactions of phenols
with up to 82% yield and >99% ee is presented. A dramatic synergistic effect has been observed in the combinations of two types of acids,
wherein a highly active binary-acid catalyst can be generated from two individually inert acids.
In the context of the extraordinary pace in exploring chiral
acid catalysis, the development of new catalysts, particularly
those with enhanced efficiency to address difficult substrates
and transformations, remains a challenging task.1 For
example, although a number of chiral acid catalysts for the
asymmetric Friedel-Crafts reaction of activated aromatics,
such as indoles and pyrroles, have been reported,2 the
reactions with less active aromatic substrates (e.g., parent
phenols) have only been explored with very limited success.3
One conceivable way to address this problem is to design
chiral acids with sufficient acidity, since it is known that
strong acids can promote this and similar types of Friedel-
Crafts reactions.4 Previous efforts in this regard by
Yamamoto,5 Ishihara,6 and List7 have shown that chiral
Brønsted acids with stronger acidity could indeed enable
activations of less active substrates such as simple
aldehydes, leading to asymmetric catalysis beyond the
(2) For reviews, see: (a) Poulsen, T.; Jørgensen, K. A. Chem. ReV. 2008,
108, 2903. (b) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. ReV. 2009, 38,
2190. For recent examples with chiral Lewis acid catalysis, see: (c)
Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.sEur. J. 2008,
14, 3630. (d) Liu, Y.; Shang, D.; Zhou, X.; Zhu, Y.; Lin, L.; Liu, X.; Feng,
X. Org. Lett. 2010, 12, 180. For recent examples with Brønsted acid, see:
(e) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2007, 46, 5565. (f) Kang, Q.; Zhang, X.-J.; You, S.-L.
Chem.sEur. J. 2008, 14, 3539. (g) Rowland, G. B.; Rowland, E. G.; Liang,
Y.; Perman, J. A.; Antilla, J. C. Org. Lett. 2007, 9, 2609. (h) Itoh, J.;
Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016.
(3) For an example on reactions of 2-naphthol with nitrostyrenes, see:
Liu, T.; Cui, H.; Chai, Q.; Long, J.; Li, B.; Wu, Y.; Ding, L.; Chen, Y. C.
Chem. Commun. 2007, 2228.
(1) (a) Acid Catalysis in Modern Organic Synthesis; Yamamoto, H.,
Ishihara, K., Eds.; Wiley-VCH: Weinheim, Germany, 2008. (b) Akiyama,
T. Chem. ReV. 2007, 107, 5744–5758. (c) Terada, M. Chem. Commun. 2008,
4097. (d) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713.
(4) Olah, G. A.; Krishnamurit, R.; Prakash Friedel-Crafts Alkylation in
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 3, 293.
10.1021/ol1000928  2010 American Chemical Society
Published on Web 02/04/2010

reach of weak acids. Nevertheless, a new strategy and
catalyst design to achieve asymmetric strong acid catalysis
is still highly desirable.
Table 1. Selected Screening and Optimization Resultsa
In the present work, we propose a combinatorial approach
for asymmetric strong acid catalysis by simply combining
known chiral Brønsted acids with classical Lewis acids. In
this binary-acid strategy, enhanced acidity of either the
Brønsted acid, Lewis acid, or both would be expected
according to Yamamoto’s combined acid principles.8 Most
importantly, the resulting multiacidic centers may induce a
synergistic effect for catalysis by judicious selection of each
acid component and their combinations (Figure 1).9 Our
entry
Brønsted acid
Lewis acid
yield (%)b
ee (%)c
1
2
none
1a
Mg(OTf)2
none
trace/90%g
no reaction
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19d
20e
21f
1a
1b
1c
1d
1e
1f
1a
1a
1a
1a
1a
1a
1a
1a
1a
none
1a
1a
1a
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(ClO4)2
MgSO4
MgF2
MgI2
Cu(OTf)2
InBr3
Zn(OTf)2
Bi(OTf)3
Ni(OTf)2
MgF2
70
92
40
trace
no reaction
no reaction
71
74
79
75
78
72
75
95
68
88
70
38
Figure 1. Asymmetric binary-acid catalysts.
88
90
95
80
30
46
70
40
86
current study indicates that such binary-acid catalysis is
indeed possible and a successful example combining chiral
phosphoric acid and MgF2 is presented herein.
Preliminary studies started with the examination of
binary-acids catalyzed addition of 3-methoxyphenol 2a
to the ꢀ,γ-unsaturated R-ketoester 3a, for which asym-
metric catalysis has not been achieved.10 While no
reactions were observed when weak Brønsted acids, such
as thioureas, BINOL, and BINOL-derived phosphoric
acids (e.g.,1a, Table 1, entry 2), were used, the joint use
of 1a and catalytic amounts of Mg(OTf)2, which is a quite
active catalyst itself (Table 1, entry 1), led to chemo- and
regioselective formation of adduct 4a with 70% yield and
88% ee (Table 1, entry 3). It is noted that the reaction
could not proceed with phosphoric acid salts of 1a such
as sodium salt 1e and pyridinium salt 1f (Table 1, entries
7 and 8), suggesting that the use of free acid is essential
for effective catalysis and that the role played by the acid
may be very likely beyond simply as chiral counteran-
ions11 or phosphate ligands12 as previously observed in
phosphoric acid-metal combined catalysis.13
no reactionh
61
40
21
MgF2
MgF2
MgF2
92
91
90
a General conditions: 2a (0.12 mmol), 3a (0.10 mmol), 1 (20 mol %),
Lewis acid (5 mol %), and 4 Å MS (40 mg) at -70 °C in CH2Cl2, 36 h; for
entries 13-17, 24 h. b Isolated yield. c Enantioselectivities were determined
by HPLC analysis. d 1a (15 mol %). e 1a (10 mol %). f 1a (5 mol %). g Yield
at rt. h Both at rt and -70 °C.
A quick survey of different phosphoric acids such as 1a-d
was then followed and the best results were obtained in the
presence of 1a (Table 1, entries 3-6), whereas others resulted
in either low activity or poor enantioselectivity. With
phosphoric acid 1a, the use of different Lewis acids was next
(11) For examples, see: (a) Mukherjee, S.; List, B. J. Am. Chem. Soc.
2007, 129, 11336. (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) Li, C.; Wang, C.; Villa-
Marcos, B.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 14450.
(5) (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626. (b) Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.;
Yamamoto, H. Org. Lett. 2006, 8, 3175.
(12) For examples, see: (a) Suzuki, S.; Furono, H.; Yokoyama, Y.;
Inanaga, J. Tetrahedron: Asymmetry 2006, 17, 504. (b) Yue, T.; Wang,
M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. J. Org. Chem. 2009, 74, 8396.
(c) After our original submission, Xia and Huang reported the enantioselective
addition of indole nucleophiles to unsaturated R-hydroxy ketones using a chiral
phosphoric acid-iron(III) system. The phosphoric acid is also a phosphate
ligand for the metal according to this study: Yang, L.; Zhu, Q.; Guo, S.; Qian,
B.; Xia, C.; Huang, H. Chem.;Eur. J. 2010, 16, 1638.
(6) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara, K. J. Am.
Chem. Soc. 2008, 130, 16858.
(7) Garc´ıa-Garc´ıa, P.; Lay, F.; Garc´ıa-Garc´ıa, P.; Rabalakos, C.; List,
B. Angew. Chem., Int. Ed. 2009, 48, 4363.
(8) Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924.
(9) The combination of chiral Brønsted acid and boron Lewis acid has
recently been reported as a new Brønsted acid of singular structure: (a)
Gao, L.; Hwang, G.-S.; Lee, M. Y.; Ryu, D. H. Chem. Commun. 2009,
5460. (b) Hu, G.; Huang, L.; Huang, R.; Wulff, W. D. J. Am. Chem. Soc.
2009, 131, 15615.
(13) For other recent examples using the combined chiral Brønsted acid
and transition metal, see: (a) Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang,
H.; Hu, J.; Yang, L.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (b)
Xu, X.; Zhou, J.; Yang, L.; Hu, W. Chem. Commun. 2008, 6564. (c) Guo,
Z.; Shi, T.; Jiang, J.; Yang, L.; Hu, W. Org. Biomol. Chem. 2009, 5028.
(d) Tetrade, M.; Toda, Y. J. Am. Chem. Soc. 2009, 131, 6354. (e) Lu, Y.;
Johnstone, T. C.; Arndtsen, B. A. J. Am. Chem. Soc. 2009, 131, 11284.
(10) For examples with 1,3-dimethoxybenzene, see: (a) Jensen, K. B.;
Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001,
40, 160. (b) Lingen, H. L.; Zhuang, W.; Hansen, T.; Rutjes, P. J. T.;
Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 1953.
Org. Lett., Vol. 12, No. 5, 2010
1097

probed and some selected results were listed in Table 1. In
all the cases, the reactions proceeded very well in the
presence of binary-acids while the activity and enantiose-
lectivity varied significantly with different Lewis acid such
as MgII, CuII, InIII, ZnII, BiIII, and NiII salts (Table 1, entries
9-17). To our delight, Group IIA metal MgII Lewis acids
generally exhibited superior performance in terms of both
activity and stereoselectivity. Among a myriad of MgII salts
examined, MgF2 was identified to be the optimal Lewis acid,
giving 79% yield and 95% ee (Table 1, entry 11). This result
is quite beyond our expectation since there has been no report
on the use of MgF2 as homogeneous Lewis acid in asym-
metric catalysis.14,15 More surprisingly, MgF216 itself turned
out to be an inert catalyst for the reaction in the absence of
chiral phosphoric acid 1a even at rt (Table 1, entry 18). These
intriguing findings further prove the synergistic function of
chiral Brønsted acids and Lewis acids, causing a concertedly
activated complex formation for effective catalysis. The
impact of the ratio of two acids was also examined. While
the enantioselectivity was maintained at a similar level by
increasing the ratio of 1a/MgF2 from 1:1 to 4:1, the activity
was considerably improved with higher ratio (Table 1, entries
19-21). Further increasing the ratio did not lead to much
improvement. An optimal 4:1 ratio of 1a/MgF2 was used in
our subsequent experiments.17
Table 2. Friedel-Crafts Alkylation Reactions of 2a,b and
ꢀ,γ-Unsaturated R-Ketoestersa
R2 yield (%)b ee (%)c d
,
entry product
R
R1
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me Ph
Et Ph
Me 4-ClC6H4
Et 4-ClC6H4
Me 3,4-Cl2C6H3 Me
Me 3,4-Cl2C6H3 Et
Me 2-FC6H4
Me 4-MeC6H4
Me 3-MeC6H4
Me 4-PhC6H4
Me
Me
Me
Me
79
80
70
65
81
76
82
57
75
59
95
90
96
95
>99
86
97
82
84
79
Me
Me
Me
Me
4j
a General conditions: 2a (0.12 mmol), 3a (0.10 mmol), 1 (20 mol %),
MgF2 (5 mol %) and 4 Å MS (40 mg) at -70 °C in CH2Cl2. b Isolated
yield. c Enantioselectivities were determined by HPLC analysis. d The
absolute configurations were assigned by analogy with the known indole
adducts.10a,20
With optimal conditions established, the scope of an
asymmetric binary-acid-catalyzed enantioselective Friedel-
Crafts alkylation reaction was next explored with 1a/MgF2
in dichloromethane at -70 °C. The results are presented
in Table 2. A variety of ꢀ,γ-unsaturated-R-ketoesters can
be applied in the reactions with free phenols 2a and 2b
to give the desired Friedel-Crafts alkylation products
4a-j in good yields and with up to 99% ee (Table 2).
Interestingly, no reaction was observed when 1,3-
dimethoxybenzene was used.
Table 3. Friedel-Crafts Alkylation Reactions of Different
Indoles2c-e and ꢀ,γ-Unsaturated R-Ketoestersa
entry product
R
R1
yield (%)b ee (%)c
1
2
3
4
5
6
4k
4l
H
H
H
H
H
H
Ph
2-FC6H4
4-ClC6H4
3,4-ClC6H4
4-MeC6H4
4-PhC6H4
82
87
82
80
78
81
90
81
83
64
90 (R)d
94
83
88
87
82
92
84
92
Not only free phenols but also the asymmetric binary-
acid catalytic system 1a/MgF2 could also be successfully
applied in similar Friedel-Crafts reactions of indoles.
Remarkably, 0.5 mol % of MgF2 suffices for effective
catalysis and the reactions work well with a range of indole
derivatives and ꢀ,γ-unsaturated-R-ketoesters, affording the
desired 1,4-addition adducts in good yields with 82-94%
ee (Table 3).18 Previously, simple phosphoric acids have been
shown to be unable to catalyze similar reactions and therefore
a specially designed N-triflylphosphoramide acid with strong
4m
4n
4o
4p
4q
4q
4r
7
5-MeO Ph
5-MeO Ph
6-Cl
8e
9
Ph
10f
4s
6-Cl
3,4-Cl2C6H4
91
a General conditions: 2c (0.10 mmol), 3a (0.12 mmol), 1a (2 mol %),
MgF2 (0.5 mol %) and 4 Å MS (40 mg) at -70 °C in CH2Cl2. b Isolated
yield. c Enantioselectivities were determined by HPLC analysis. d The
absolute configuration was determined by comparing the optical rotation
with that reported in ref 10a. e MgF2 was not used. f For 72 h.
(14) For a review on magnesium Lewis acid, see: Zhang, X.; Li, W.
Chin. J. Org. Chem. 2003, 23, 1185
.
(15) For a review on metal fluoride complexes in asymmetric catalysis,
see: Pagenkopf, B. L.; Carreira, E. M. Chem.;Eur. J. 1999, 5, 3437. For
one recent example, see: Hamada, T.; Manabe, K.; Kobayashi, S.
acidity was required for such catalysis.19 From our studies,
it was found that phosphoric acid 1a was actually a viable
catalyst for this reaction20 (Table 3, entry 8) and the
combination of 1a with MgF2 could further improve the
catalysis with better activity and stereocontrol (Table 3, entry
Chem.;Eur. J. 2006, 12, 1205
.
(16) Solubility of MgF2 in CH2Cl2 was determined to be around 10 mg/
100 mL at room temperature. Therefore, solubility would not be the major
reason for inertness of MgF2 (0.31 mg/2 mL of CH2Cl2) in the control
reaction at rt. On the other hand, the binary-acid 1a/MgF2 is very soluble
under the reaction conditions and homogeneous reactions were generally
observed in our experiments.
(17) The real active catalytic species remains unclear and awaits further
study.
(18) N-Methylindole has also been examined. Instead of the desired 1,4-
addition product, this reaction gave regioselectively 1,2-addition product.
Further exploration along this line is underway.
(19) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew.
Chem., Int. Ed. 2008, 47, 593.
1098
Org. Lett., Vol. 12, No. 5, 2010

7 vs 8), thus highlighting again the beneficial features of
this binary-acid catalytic system.
highly active binary-acid catalyst can be generated from two
individually inert acids. This beneficial feature together with
the modular and combinatorial flexibility promise wide
application of such asymmetric binary-acid catalysis in many
other strong acid-catalyzed reactions. A detailed mechanism
study and further investigations in this field of catalysis are
ongoing and will be reported in due course.
In summary, we have developed a combinatorial approach
for chiral strong acid catalysis by simply combining the
known chiral Brønsted acids with typical Lewis acids. A
unique binary-acid 1a/MgF2 was identified via this approach
and the catalyst was found to enable effective catalysis of
asymmetric Friedel-Crafts reactions of phenols and indoles
with good activity and high to excellent enantioselectivity.
A dramatic synergistic effect has been observed in the
combinations of two types of acids, demonstrating that a
Acknowledgment. The project was supported by the
Natural Science Foundation (NSFC 20632060 and 20972163)
and MOST (2008CB617501, 2009ZX09501-018). J.L. and
X.L. thank China Postdoctoral Science Foundation for
support.
(20) Compared with inertness in the reaction of phenol, the activity of
phosphoric acid 1a in this case may be a result of high reactivity of indoles.
In a control reaction, 3-methoxyphenol 2a and indole were treated with 3g
in one pot in the presence of 1a (20 mol %)/MgF2 (5 mol %). The reaction
afforded the desired products 4g and 4l with 94% and 94% ee, respectively,
almost the same as listed in Table 2 (entry 7) and Table 3 (entry 2),
suggesting a common stereocontrol mode in these two reactions. In this
instance, indole was consumed in less than 1 h, but there was only ca. 10%
conversion for phenol 2a.
Supporting Information Available: Experimental pro-
cedures and spectral data for compound4. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL1000928
Org. Lett., Vol. 12, No. 5, 2010
1099