Fluorinated aromatic ketones as nucleophiles in the asymmetric organocatalytic formation of C-C and C-N bonds: A facile route to the construction of fluorinated quaternary stereogenic centers

Article abstract of DOI:10.1002/chem.201003761

Highly enantioselective Mannich and α-amination reactions have been successfully developed using α-fluorinated aromatic ketones as fluorocarbon nucleophiles in the presence of a bicyclic chiral guanidine (see scheme; Ms=methanesulfonyl). This method is a

Full text of DOI:10.1002/chem.201003761

COMMUNICATION
DOI: 10.1002/chem.201003761
Fluorinated Aromatic Ketones as Nucleophiles in the Asymmetric
À
À
Organocatalytic Formation of C C and ACTHUNTGRNEUNGC N Bonds: A Facile Route to the
Construction of Fluorinated Quaternary Stereogenic Centers
Yujun Zhao,[a] Yuanhang Pan,[a] Hongjun Liu,[a] Yuanyong Yang,[a]
Zhiyong Jiang,*[b] and Choon-Hong Tan*[a]
The development of a broadly useful platform for the or-
ganocatalytic nucleophilic addition of carbonyl compounds
represents a major research field in asymmetric catalysis.[1]
Recent research efforts have mainly focused on dicarbonyl
compounds such as b-ketoesters and b-ketosulfones, which
are easily activated and widely used in many conjugated ad-
dition reactions.[1,2] Most of the aliphatic ketones and aceto-
phenone nucleophiles used in organocatalytic asymmetric
transformations rely on the formation of highly reactive en-
amine intermediates.[3–5] On the other hand, Brønsted
bases[6] are seldom used as catalysts in reactions of simple
carbonyls because of to the rather low basicity of most orga-
nobases, and thus their inability to activate the carbonyl
group through enolization. Successful strategies are those
that try to increase the acidity of the a-proton.[7] For exam-
ple, activated esters, such as trifluoroethyl thioesters,[7a–c] a-
cyanothioacetates,[7d] a-substituted cyanoacetates,[7e–k] and a-
nitroacetates,[7l–o] are valuable nucleophiles for organic base-
catalyzed reactions because of their enhanced acidity. In
contrast, fused cyclic aromatic ketones are still challenging
substrates to activate as a result of the difficulty in forming
the enamine intermediate and their poor reactivity.[8] To our
knowledge, the use of activated aromatic ketones as nucleo-
philes for Brønsted base-catalyzed reactions is restricted to
several reports which focused on a-cyano ketones.[9]
through an enantioselective fluorination of tertiary carbon
nucleophiles using chiral transition-metal complexes or or-
ganocatalysts.[12] The less explored route is the asymmetric
À
formation of C C bonds by using fluorocarbon nucleo-
philes.[13] Recently, a-fluoro-b-ketoesters have been em-
ployed as fluorocarbon nucleophiles in organocatalytic pro-
cesses, asymmetric Michael, amination, and Mannich reac-
tions.[13a–d,m] The asymmetric alkylation of a-fluoro-b-keto-
AHCTUNGTRENNUNG
esters under phase-transfer conditions,[13e] and asymmetric
Robinson annulations[13f] have been carried out using fluoro-
carbon nucleophiles. Other fluorocarbon nucleophiles such
as 1-fluoro-bis(phenylsulfonyl)methane (FBSM)[13g–i] and 1-
fluoro-1-nitro(phenylsulfonyl)methane (FNSM)[13j] were also
developed. We have also shown that the a-fluoro-b-keto-
ACHUTNGRENeNUG ster and the a-fluoro-b-ketoCAHTUNGTRENNaUGN cyloxazolidinone underwent
guanidine-catalyzed[14] enantioselective Michael and Man-
nich reactions, which resulted in high enantioselectivities.[15]
The use of simple a-fluorinated aromatic ketones as nucleo-
philes has been less studied. However, there were two inde-
pendent reports on the use of phase-transfer catalysts for
asymmetric alkylation reactions of a-fluorotetralone that re-
sulted in unsatisfactory enantioselectivities and yields.[13k,l]
Herein, we present the highly enantioselective formation
À
À
of C N and C C bonds using a-fluorinated aromatic ke-
tones as nucleophiles. Our initial efforts focused on the a-
amination reaction[16] of a-fluorinated aromatic ketones cat-
alyzed by a bicyclic chiral guanidine. To the best of our
knowledge, there are no reports on enantioselective synthe-
sis of nitrogen-substituted fluorinated stereogenic carbons
from a-fluorinated ketones using organocatalytic processes.
However, successful examples using a-fluoro-b-ketoesters
and catalyzed with copper and nickel complexes of Cincho-
na alkaloid derivatives have been reported.[13m,17]
Organofluorine compounds are important in medicinal
and bioorganic chemistry.[10] Enantiopure compounds con-
taining a fluorine atom directly connected to a quaternary
carbon center[11] are nontrivial to prepare. The most
common approach thus far is to generate such compounds
[a] Y. Zhao, Y. Pan, H. Liu, Y. Yang, Prof. Dr. C.-H. Tan
Department of Chemistry, National University of Singapore, 3
Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6779-1691
Direct a-amination of a-fluorinated aromatic cyclic ke-
tones 1d catalyzed by chiral guanidine 2 with azodicarboxy-
lates 3 led to optically active a-hydrozino-a-fluorinated aro-
matic cyclic ketones 4 and 5d. When di-tert-butyl azodicar-
boxylate 3a was used as the nitrogen source (Table 1, en-
tries 1–7), the best result obtained was 84% ee in THF
(Table 1, entry 7). A bulkier version of azodicarboxylate, di-
3-ethylpentan-3-yl azodicarboxylate 3b (EocN=NEoc), was
designed as we are aware that bicyclic guanidine catalyst re-
sponds positively to an increase in the steric demand of the
E-mail: chmtanch@nus.edu.sg
[b] Prof. Dr. Z. Jiang
Provincial Key Laboratory of Natural Medicine
and Immuno-Engineering, Henan University
Jinming Campus, Kaifeng, Henan, 475004 (P.R. China)
Fax : (+86)0378-2864665
E-mail: chmjzy@henu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003761.
Chem. Eur. J. 2011, 17, 3571 – 3574
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3571

Table 1. Reaction optimization for the a-amination of 1d.
Table 2. Asymmetric direct a-amination of a-fluorinated aromatic ke-
tones 1 with azodicarboxylates 3b catalyzed by chiral guanidine 2.
Entry Solvent
3
T [oC] t [h] Product Yield [%][a] ee [%][b]
Entry 1 (a-Fluorinated ketones)
5
T [oC] Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
CH2Cl2 3a
hexane 3a
toluene 3a
acetone 3a
Et2O
THF
THF
THF
RT
RT
RT
RT
RT
RT
24
20
20
5
2
2
4
4
4
4
4
4
80
81
88
92
90
95
92
86
45
72
64
72
75
76
84
94
1
2
1a
1b
5a À20
5b À20
5c À20
88
98
90
96
3a
3a
3a À20
15
30
4
5d
3b
0
[a] Yield of isolated product. [b] Determined by HPLC analysis on a
chiral stationary phase.
3
4
1c
1d
90
86
91
94
5d
5e
0
0
substrate. Azodicarboxylate 3b was easily synthesized from
1,1’-carbonyldiimidazole (CDI) and 3-ethylpentan-3-ol using
a five-step procedure modified from a protocol that is used
to prepare azodicarboxylate 3a (See the Supporting Infor-
mation for details).[18] Azodicarboxylate 3b was obtained as
stable yellow crystals in a good yield. a-Hydrozino-a-fluori-
nated aromatic cyclic ketone 5d was obtained in 94% ee
with 86% yield when this novel azodicarboxylate 3b was
used as the nitrogen source (Table 1, entry 8).
5
1e
94
95
6
7
1 f
1g
5 f À40
5g À20
96
86
90
93
With the optimal reaction conditions in hand, the scope of
the a-amination reaction between a-fluorinated aromatic
cyclic ketones 1a–k and azodicarboxylate 3b was investigat-
ed. A variety of cyclic ketones 1a–g with varying substitu-
ents on the aromatic ring was prepared from a-tetralone de-
rivatives. Excellent yields and high ee values were achieved
irrespective of the electronic nature or positions of the sub-
stituents on the aromatic ring (Table 2, entries 1–7). Sub-
strate 1e, which contains an electron-donating group, under-
went a-amination reaction in 94% yield and 95% ee
(Table 2, entry 5). With substrate 1 f, which contains a strong
electron-withdrawing nitro group at the 7-position of the ar-
omatic ring, the reaction was complete even at À408C
(Table 2, entry 6). Similarly, the a-fluorinated 4-chroma-
nones derivatives also reacted efficiently with azodicarboxy-
late 3b, thus giving the chiral a-hydrozino-a-fluorinated 4-
chromanones derivatives 5h–k in good yields and enantiose-
lectivities (Table 2, entries 8–11). The chromanone moiety
can be found in flavanones and in many natural products
and compounds that are important in medicinal and biologi-
cal chemistry, because of the antitumor and anti-inflamma-
tory properties attributed to the chromanone unit.[19]
8
1h
1i
5h À40
5i À40
5j À40
5k À40
83
93
87
88
92
90
84
86
9[c]
10
11
1j
1k
[a] Yield of isolated product. [b] Determined by HPLC analysis on a
chiral stationary phase. [c] Reaction performed with bicyclic chiral guani-
dine (2; 20 mol%).
mainly of syn-isomers. We also noticed a significant amount
of aldehyde arising from the decomposition of imine 6a;
4 ꢁ molecular sieves (M.S.) were therefore added to reduce
this side product. The syn-7d isomer was formed with high
enantioselectivity and excellent yield; while the observed
diastereoselectivity was moderate. With imine 6a as electro-
phile, a simple study of the substrate scope revealed that ex-
cellent enantioselectivities and high yields can be obtained
regardless of the electronic properties and steric hindrance
of the aromatic ring (Table 3, entries 1–10). The reaction
with fluoronucleophile 2-fluoro-2,3-dihydro-1H-inden-1-one
Excited by the results obtained in the asymmetric a-ami-
nation reaction, we next turned out attention to asymmetric
Mannich reactions[20] with these fluorocarbon nucleophiles.
In preliminary studies, we first examined the Mannich reac-
tion of fluorinated aromatic ketone 1d with N-mesyl (Ms)
imine 6a. The adduct 7d obtained was shown to consist
3572
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3571 – 3574

À
À
Asymmetric Organocatalytic Formation of C C and C N Bonds
COMMUNICATION
(1l), which is reported for the first time, gave the enantio-
pure adduct 7j with good yield (Table 3, entry 10). Ketones
1h–k, which were derived from 4-chromanones, were also
found to be suitable for this Mannich reaction, thereby pro-
viding enantioselectivities of up to 98% ee. The imine 6b,
bearing electron-donating group on its aromatic ring, exhib-
ited relatively lower reactivity. The reaction was thus carried
out at À58C with 20% the chiral guanidine 2. The enantio-
selectivity observed is still high and a reaction yield of 79%
was obtained (Table 3, entry 11). The enantioselectivitie
values for the minor anti-isomers were typically lower than
33%; however, the two diastereoisomers were easily sepa-
rated by flash chromotography.
In summary, a series of a-fluorinated aromatic ketones
have been employed as fluorocarbon nucleophiles for asym-
metric catalysis. It has been found that these a-fluorinated
aromatic ketones are excellent fluorocarbon nucleophiles.
These fluorocarbon nucleophiles have been successfully em-
À
À
ployed for the organocatalytic formation of C N and C C
bonds. Highly enantioselective amination and Mannich addi-
tion reactions were carried out. This synthetic method is a
simple and efficient approach to the construction of nitro-
gen-containing fluorinated quaternary stereogenic centers.
Table 3. Asymmetric Mannich reaction of a-fluorinated aromatic ke-
tones 1 catalyzed by bicyclic chiral guanidine 2.
Experimental Section
Representative procedure for the synthesis of 5d: 2-Fluoro-3,4-dihydro-
naphthalen-1ACTHNUGRTNEUNG(2H)-one 1d (33.0 mg, 0.2 mmol, 4.0 equiv) and 2 (1.12 mg,
Entry 1 (a-Fluorinated ketones)
7
d.r.[a] Yield [%][b] ee [%][c]
0.005 mmol, 0.1 equiv) were dissolved in THF (0.4 mL) and stirred at
08C for 20 min. Di-3-ethylpentan-3-yl azodicarboxylate 3b (17.0 mg,
0.05 mmol, 1.0 equiv) was subsequently added. The reaction mixture was
stirred at 08C and monitored by TLC. After 45 h, upon complete con-
sumption of 3b, the reaction solvent was removed under reduced pres-
sure and the crude product was directly loaded onto a short silica-gel
column. Flash chromatography was performed using gradient elution
with n-hexane/CH2Cl2 mixtures (100:1–10:1). After removing the solvent,
product 5d (21.5 mg) was obtained as a liquid in 86% yield.
1
2
1a
1b
7a 5.2:1 87
7b 3.4:1 92
96 (8)
95 (6)
3
4
1c
1d
7c 3.0:1 90
7d 3.0:1 78
95 (9)
96 (5)
Acknowledgements
This work was supported by the ARF grants R-143-000-337-112 and R-
143-000-342-112 from the National University of Singapore.
5
1e
7e 3.3:1 70
96 (14)
Keywords: amination
· fluorine · Mannich reaction ·
organocatalysis · quaternary stereogenic center
6
7
8
1h
1i
7 f 3.0:1 88
7g 4.6:1 94
7h 3.0:1 88
98 (14)
97 (8)
97 (8)
[1] a) Catalytic Asymmetric Synthesis (Ed.: I. Ojima), Wiley-Blackwell,
New York, 2010; b) A. Berkessel, H. Groger, Asymmetric Organo-
catalysis: From Biomimetic Concepts to Applications in Asymmetric
Synthesis, Wiley-VCH, Weinheim, 2005.
[2] For reviews, see: a) A. Ting, J. M. Goss, N. T. McDougal, S. E.
Schaus, Top. Curr. Chem. 2009, 291, 145–200; b) M. Nielsen, C. B.
Jacobsen, N. Holub, M. W. Paix¼o, K. A. Jørgensen, Angew. Chem.
2010, 122, 2726–2738; Angew. Chem. Int. Ed. 2010, 49, 2668–2679.
[3] For reviews on the activation of ketones in organocatalysis, see:
a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701–1716; b) B. List,
Tetrahedron 2002, 58, 5573–5590; c) W. Notz, F. Tanaka, C. F. Bar-
bas III, Acc. Chem. Res. 2004, 37, 580–591; d) B. List, Chem.
Commun. 2006, 819–824.
[4] For examples of fluoroacetone in organocatalysis, see: a) G. Zhong,
J. Fan, C. F. Barbas III, Tetrahedron Lett. 2004, 45, 5681–5684;
b) X.-Y. Xu, Y.-J. Wang, L.-F. Cun, L.-Z. Gong, Tetrahedron: Asym-
metry 2007, 18, 237–242; c) X.-Y. Xu, Y.-Z. Wang, L.-Z. Gong, Org.
Lett. 2007, 9, 4247–4249; d) T. Hoffmann, G. Zhong, B. List, D.
Shabat, J. Anderson, S. Gramatikova, R. A. Lerner, C. F. III.
Barbas, J. Am. Chem. Soc. 1998, 120, 2768–2779.
[5] For examples of acetophenone and acetone in organocatalysis, see:
a) L. Yue, W. Du, Y.-K. Liu, Y.-C. Chen, Tetrahedron Lett. 2008, 49,
3881–3884; b) X. Jiang, Y. Zhang, A. S. C. Chan, R. Wang, Org.
1j
9
1k
1l
7i 2.4:1 90
7j 3.4:1 87
7k 1.8:1 79
95 (8)
>99 (25)
96 (33)
10
11[d]
1d
[a] d.r.=diastereomeric ratio, determined by 1H NMR analysis. [b] Yield
of isolated product. [c] Determined by HPLC analysis on a chiral station-
ary phase; the ee values of the anti-isomers are in parentheses. [d] Re-
action performed with bicyclic chiral guanidine (20 mol%) at À58C;
imine 6b was used.
Chem. Eur. J. 2011, 17, 3571 – 3574
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3573

C.-H. Tan, Z. Jiang et al.
Lett. 2009, 11, 153–156; c) C. G. Kokotos, G. Kokotos, Adv. Synth.
Catal. 2009, 351, 1355–1362; d) K. Liu, H.-F. Cur, J. Nie; K.-Y.
Dong, X.-J. Li, J.-A. Ma, Org. Lett. 2007, 9, 923–925; K.-Y. Dong,
X.-J. Li, J.-A. Ma, Org. Lett. 2007, 9, 923–925; e) Q. Guo, M. Bha-
nushali, C.-G. Zhao, Angew. Chem. 2010, 122, 9650–9654; Angew.
Chem. Int. Ed. 2010, 49, 9460–9464.
i) S. Brandes, B. Niess, M. Bella, A. Prieto, J. Overgaard, K. A. Jør-
gensen, Chem. Eur. J. 2006, 12, 6039–6052.
[13] a) H. Li, S. Zhang, C. Yu, X. Song, W. Wang, Chem. Commun. 2009,
2136–2138; b) X. Han, J. Luo, C. Liu, Y. Lu, Chem. Commun. 2009,
2044–2046; c) X. Han, J. Kwiatkowski, F. Xue, K-W. Huang, Y. Lu,
Angew. Chem. 2009, 121, 7740–7743; Angew. Chem. Int. Ed. 2009,
48, 7604–7607; d) Y. Oh, S. M. Kim, D. Y. Kim, Tetrahedron Lett.
2009, 50, 4674–4676; e) C. Ding, K. Maruoka, Synlett 2009, 664–
666; f) H.-F. Cui, Y.-Q. Yang, Z. Chai, P. Li, C.-W. Zheng, S.-Z. Zhu,
G. Zhao, J. Org. Chem. 2010, 75, 117–122; g) F. Ullah, G-L. Zhao,
Deiana, L. M. Zhu, P. Dziedzic, I. Ibrahem, P. Hammar, J. Sun, A.
Cꢂrdova, Chem. Eur. J. 2009, 15, 10013–10017; h) T. Furukawa, N.
Shibata, S. Mizuta, S. Nakamura, T. Toru, M. Shiro, Angew. Chem.
2008, 120, 8171–8174; Angew. Chem. Int. Ed. 2008, 47, 8051–8054;
i) S. Mizuta, N. Shibata, Y. Goto, T. Furukawa, S. Nakamura, T.
Toru, J. Am. Chem. Soc. 2007, 129, 6394–6395; j) G. K. S. Prakash,
F. Wang, T. Stewart, T. Mathew, G. A. Olah, Proc. Natl. Acad. Sci.
USA 2009, 106, 4090–4094; k) S. Arai, M. Oku, T. Ishida, T. Shioiri,
Tetrahedron Lett. 1999, 40, 6785–6789; l) B. Thierry, T. Perrard, C.
Audouard, J.-C. Plaquevent, D. Cahard, Synthesis 2001, 1742–1746;
m) X. Han, F. Zhong, Y. Lu, Adv. Synth. Catal. 2010, 352, 2778–
2782.
[14] For recent contributions from other research groups on guanidine-
catalyzed reactions, see: a) Z. Yu, X. Liu, L. Zhou, L. Lin, X. Feng,
Angew. Chem. 2009, 121, 5297–5300; Angew. Chem. Int. Ed. 2009,
48, 5195–5198; b) H. Ube, M. Shimada, M. Terada, Angew. Chem.
2010, 122, 1902–1905; Angew. Chem. Int. Ed. 2010, 49, 1858–1861;
c) T. Misaki, G. Takimoto, T. Sugimura, J. Am. Chem. Soc. 2010,
132, 6286–6287; d) S. Dong, X. Liu, X. Chen, F. Mei, Y. Zhang, B.
Gao, L. Lin, X. Feng, J. Am. Chem. Soc. 2010, 132, 10650–10651.
[15] a) Z. Jiang, Y. Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang, K.-W. Huang,
M. W. Wang, C.-H. Tan, Angew. Chem. 2009, 121, 3681–3685;
Angew. Chem. Int. Ed. 2009, 48, 3627–3631; b) Y. Pan, Y. Zhao, T.
Ma, Y. Yang, H. Liu, Z. Jiang, C.-H. Tan, Chem. Eur. J. 2009, 15,
779–782.
[6] For selected reviews, see: a) D. Leow, C.-H. Tan, Chem. Asian J.
2009, 4, 488–507; b) D. Leow, C.-H. Tan, Synlett 2010, 1589–1605;
c) C. Palomo, M. Oiarbide, R. Lꢂpez, Chem. Soc. Rev. 2009, 38,
632–653; d) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719–
724.
[7] For selected examples using organocatalysts, see: a) D. A. Alonso, S.
Kitagaki, N. Utsumi, C. F. Barbas III, Angew. Chem. 2008, 120,
4664–4667; Angew. Chem. Int. Ed. 2008, 47, 4588–4591; b) N.
Utsumi, S. Kitagaki, C. F. Barbas III, Org. Lett. 2008, 10, 3405–
3408; c) M. C. Kohler, J. M. Yost, M. R. Garnsey, D. M. Coltart,
Org. Lett. 2010, 12, 3376–3379; d) M. Terada, D. Tsushima, M.
Nakano, Adv. Synth. Catal. 2009, 351, 2817–2821; e) C. Guo, M.-X.
Xue, M.-K. Zhu, L.-Z. Gong, Angew. Chem. 2008, 120, 3462–3465;
Angew. Chem. Int. Ed. 2008, 47, 3414–3417; f) F. Marini, S. Sternati-
vo, F. D. Verme, L. Testaferri, M. Tiecco, Adv. Synth. Catal. 2009,
351, 103–106; g) T.-Y. Liu, R. Li, Q. Chai, J. Long, B.-J. Li, Y. Wu,
L.-S. Ding, Y.-C. Chen, Chem. Eur. J. 2007, 13, 319–327; h) S. Saaby,
M. Bella, K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126, 8120–8121;
i) X. Liu, H. Li, L. Deng, Org. Lett. 2005, 7, 167–169; j) X. Wang,
M. Kitamura, K. Maruoka, J. Am. Chem. Soc. 2007, 129, 1038–
1039; k) H. Li, J. Song, X. Liu, L. Deng, J. Am. Chem. Soc. 2005,
127, 8948–8949; l) J. Wang, L. Zu, W. Jiang, W. Duan, W. Wang, J.
Am. Chem. Soc. 2006, 128, 12652–12653; m) H. W. Moon, D. Y.
Kim, Tetrahedron Lett. 2010, 51, 2906–2908; n) A. Prieto, N. Hal-
land, K. A. Jørgensen, Org. Lett. 2005, 7, 3897–3900; o) D. Uragu-
chi, K. Koshimoto, T. Ooi, J. Am. Chem. Soc. 2008, 130, 10878–
10879.
[8] T.-Y. Liu, H.-L. Cui, Y. Zhang, K. Jiang, W. Du, Z.-Q. He, Y.-C.
Chen, Org. Lett. 2007, 9, 3671–3674.
[9] For selected examples, see: a) B. Wang, F. Wu, X. Liu, L. Deng, J.
Am. Chem. Soc. 2007, 129, 768–769; b) Y. Wang, X. Liu, L. Deng, J.
Am. Chem. Soc. 2006, 128, 3928–3930; c) J.-H. Lee, D. Y. Kim, Adv.
Synth. Catal. 2009, 351, 1779–1782; d) S. M. Kim, J. H. Lee, D. Y.
Kim, Synlett 2008, 2659–2662; e) S.-L. Zhao, C.-W. Zheng, H.-F.
Wang, G. Zhao, Adv. Synth. Catal. 2009, 351, 2811–2816.
[16] The reaction between nonfluorinated tetralone and 3a was very
slow under the same reaction conditions.
[17] a) J. Y. Mang, D. G. Kwon, D. Y. Kim, J. Fluorine Chem. 2009, 130,
259–262; b) D. P. Huber, K. Stanek, A. Togni, Tetrahedron: Asym-
metry 2006, 17, 658–664.
[18] a) R. D. Little, R. G. Venegas, Org. Syn. 1983, 61, 17–20; b) L. A.
Carpino, B. A. Carpino, C. A. Giza, P. H. Terry, Org. Syn. 1964, 44,
15–17; c) L. A. Carpino, P. J. Crowley, Org. Syn. 1964, 44, 18–20.
[19] a) The Flavonoids: Advances in Research Since 1980 (Ed.: J. B. Har-
borne), Chapman and Hall, New York, 1994; b) Flavonoid in Biol-
ogy and Medicine III: Proceedings of 3rd International Symposium
on Flavonoids in Biology Medicine (Ed.: N. P. Das), National Uni-
versity of Singapore, Singapore, 1989.
[20] For reviews of asymmetric organocatalytic Mannich reactions, see:
a) A. Ting, S. E. Schaus, Eur. J. Org. Chem. 2007, 5797–5815;
b) J. M. M. Verkade, L. J. C. Hemert, P. J. L. M. Quaedflieg, F. P. J. T.
Ruties, Chem. Soc. Rev. 2008, 37, 29–41.
[10] Fluorine in Medicinal Chemistry and Chemical Biology (Ed.: I.
Ojima), Wiley-Blackwell, New York, 2009.
[11] For a recent review of the organocatalytic formation of quaternary
stereocenters, see: M. Bella, T. Gasperi, Synthesis 2009, 1583–1614.
[12] For highlight articles and recent reviews, see: a) P. M. Pihko, Angew.
Chem. 2006, 118, 558–561; Angew. Chem. Int. Ed. 2006, 45, 544–
547; b) G. K. S. Prakash, P. Beier, Angew. Chem. 2006, 118, 2228–
2230; Angew. Chem. Int. Ed. 2006, 45, 2172–2174; c) V. A. Brunet,
D. OꢃHagan, Angew. Chem. 2008, 120, 1198–1201; Angew. Chem.
Int. Ed. 2008, 47, 1179–1182; d) J.-A. Ma, D. Cahard, Chem. Rev.
2004, 104, 6119–6146; e) N. Shibaba, T. Ishimaru, S. Nakamura, T.
Toru, J. Fluorine Chem. 2007, 128, 469–483; f) H. Ibrahim, A.
Togni, Chem. Commun. 2004, 1147–1155; g) S. Lectard, Y. Hama-
shima, M. Sodeoka, Adv. Synth. Catal. 2010, 352, 2708–2732; h) C.
Bobbio, V. Gouverneur, Org. Biomol. Chem. 2006, 4, 2065–2075;
Received: December 31, 2010
Published online: February 23, 2011
3574
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3571 – 3574