Highly diastereo- and enantioselective organocatalytic one-pot sequential 1,4-addition/dearomative-fluorination transformation

Article abstract of DOI:10.1002/chem.201202636

Fluorination: A wide range of nitroolefins and pyrazol-5-ones undergo a sequential 1,4-addition/dearomative-fluorination transformation when treated with a catalytic amount of a tertiary-amine-thiourea compound and the terminal electrophile, N-fluorobenzenesulfonimide, to give fluorinated products in 72-95 % yield with up to 99:1 d.r. and 98 % ee. Notably, these products contain adjacent tertiary and α-fluoro quaternary stereocenters (see scheme). Copyright

Full text of DOI:10.1002/chem.201202636

COMMUNICATION
DOI: 10.1002/chem.201202636
Highly Diastereo- and Enantioselective Organocatalytic One-Pot Sequential
1,4-Addition/Dearomative-Fluorination Transformation
Feng Li,[a] Long Sun,[a] Yuou Teng,[b] Peng Yu,[b] John Cong-Gui Zhao,[c] and
Jun-An Ma*[a]
Dearomatization reactions are powerful because they pro-
vide a straightforward access to carbocyclic and heterocyclic
frameworks that are present in a large number of natural
products, pharmaceuticals, and materials. Its synthetic im-
portance has led to the development of many methods for
the dearomatization of arenes, phenols, and heteroaromatic
compounds through oxidation, reduction, complexation, and
cycloaddition.[1] Despite these impressive advances, direct
catalytic dearomative fluorination remains largely untap-
ped.[2] Dearomative fluorination would be significant be-
cause it would lead to fluorinated cyclic nonaromatic com-
pounds, which play an important role in medicinal chemis-
try.[3] On the other hand, given the increasing demand of
pharmaceutically and agrochemically relevant chiral com-
pounds, the development of catalytic asymmetric reactions,
as cost-effective and environmentally friendly methodolo-
gies, has become one of the main themes of contemporary
synthetic chemistry.[4] Therefore, we envisioned that that
asymmtric dearomative fluorination and asymmetric cataly-
sis in one pot would provide a powerful strategy for the
rapid chemical synthesis of fluorinated chiral alicyclic mole-
cules.[5]
Pyrazolone derivatives, an important class of five-mem-
bered lactams, are widely used in organic synthesis and
pharmaceutical chemistry.[6] The reactivity and functionality
of these compounds provide many possibilities for the prep-
aration of heterocyclic structures.[7] We recently found that
chiral thioureas containing tertiary amines can catalyze the
addition of pyrazolones to nitroalkenes to afford highly
enantioenriched pyrazol-5-ol derivatives, which could be fur-
ther fluorinated with concurrent dearomatization. Herein
we report an organocatalytic, asymmetric, one-pot sequen-
tial 1,4-addition/dearomative-fluorination transformation
using pyrazolones as the aromatic partners, thus leading to
optically active fluorine-containing products with two adja-
cent stereogenic centers (Figure 1). Most importantly, this
Figure 1. Catalytic asymmetric one-pot 1,4-addition/dearomative-fluorina-
tion sequence.
one-pot multistep reaction proceeds with excellent chemo-,
diastereo-, and enantiocontrol by the application of a chiral
tertiary-amine—thiourea catalyst and an achiral acid as the
co-catalyst. Furthermore, this enantioselective organocata-
lytic reaction represents a simple and efficient way to pre-
pare a complex chiral molecule containing an a-quaternary
fluorine atom.
To achieve the desired asymmetric sequential transforma-
tion, the reaction of 3-methyl-1-phenylpyrazolone (1a) with
trans-b-nitrostyrene (2a) and N-fluorobenzenesulfonimide
(NSFI) was investigated in the presence of various bifunc-
tional chiral tertiary-amine—thiourea catalysts (A—H;
Figure 2).[8] The results are given in Table 1. The use of sac-
charide-derived catalyst A, developed and studied previous-
ly in our research group,[9] gave the fluorine-containing
product 3a in high yield with good diastereoselectivity.
However, the enantioselectivity of the major isomer was low
(30% ee; Table 1, entry 1). Notably, the product was ob-
tained with higher ee values when this catalyst was used in
combination with external weak acids, such as benzoic acid
(Table 1, entries 2–4). Subsequently, chiral tertiary-amine–
thiourea catalysts B–D were tested under these reaction
conditions (Table 1, entries 5–7). It was found that thiourea
C was the most promising catalyst for the test reaction,
[a] F. Li, L. Sun, Prof. J.-A. Ma
Department of Chemistry, Tianjin University
Tianjin 300072 (P. R. China)
Fax : (+86)22-2740-3475
E-mail: majun_an68@tju.edu.cn
[b] Y. Teng, Prof. P. Yu
College of Bioengineering
Tianjin University of Science and Technology
Tianjin 300457 (P. R. China)
[c] Prof. J. C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio
One UTSA Circle, San Antonio, Texas 78249-0698 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202636.
Chem. Eur. J. 2012, 18, 14255 – 14260
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14255

Table 1. Optimization studies.[a]
Entry
Cat.
Solvent
RCO2H
[mol%]
Yield
[%][b]
d.r.[c]
ee
N
[%][d]
1
A
A
A
A
B
C
D
E
F
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
–
91
95
90
92
88
90
90
95
98
90
93
94
90
91
89
90
93
90
99
99
88
90
94
85:15
87:13
85:15
87:13
85:15
93:7
30
(À)
2
Me (20)
CF3(20)
Ph (20)
Ph (20)
Ph (20)
Ph (20)
Ph (20)
Ph (20)
Ph (20)
Ph (40)
Ph (50)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
Ph (40)
38
(À)
33
3
(À)
4
50
(À)
34
(+)
90
5
6
(À)
7
91:9
45
(+)
48
8
85:15
88:12
80:20
92:8
(À)
Figure 2. Bifunctional tertiary-amine—thiourea catalysts tested in the
one-pot sequential 1,4-addition/ dearomative-fluorination transformation.
9
48
(À)
42
10
11
12
13
14
15
16
17
18
19
20
21[e]
22[f]
23
G
C
C
C
C
C
C
C
C
C
(À)
giving rise to the highest diastereo- and enantioselectivity
(Table 1, entry 6). The tertiary-amine–thiourea catalyst C
was then compared with Takemotoꢁs catalysts E and F,
which contain the achiral N-3,5-bis(trifluoromethyl)phenyl
group and have proven to be very effective catalysts for a
number of transformations.[10] Nevertheless, catalysts E and
F gave only moderate levels of enantioselectivity (Table 1,
entries 8 and 9). In addition, the use of catalyst G, which
does not contain a saccharide motif, resulted in a dramatic
decrease in diastereo- and enantioselectivity (Table 1,
entry 10). These results indicate that the saccharide motif is
crucial for maintaining good levels of stereoselectivity. Fur-
ther optimization of other reaction parameters, such as sol-
vent, temperature, additive, and catalyst loading (Table 1,
entries 11–22), led to the discovery that the best results were
obtained when toluene was used as the solvent and when
the reactions were carried out at room temperature (93%
yield, 93:7 d.r., 96% ee; Table 1, entry 17). Under similar re-
action conditions, the use of l-glucopyranose-derived cata-
lyst H gave products with high levels of stereoselectivity and
with the opposite sense of asymmetric induction (Table 1,
entry 23).
With the optimized reaction conditions established, the
scope of the reaction was explored with respect to both the
nucleophile and the electrophile. The results are summar-
ized in Table 2. Various nitrostyrene derivatives with differ-
ent substitution patterns on the aromatic ring all gave the
expected products 3a–3m in high yields and with excellent
levels of stereoselectivity (Table 2, entries 1–13). Heteroaro-
matic nitroalkene 2n is also a viable substrate, affording the
desired product 3n in high yield and enantioselectivity,
albeit with moderate diastereoselectivity (Table 2, entry 14).
Notably. alkyl-substituted nitroalkenes may also be used as
92
(À)
92
92:8
(À)
93:7
92
(À)
90
97:3
(À)
THF
90:10
92:8
89
(À)
96
Et2O
(À)
toluene
xylene
MeCN
EtOH
93:7
96
(À)
94
93:7
(À)
90:10
91:9
87
(À)
73
C
(10)
C (5)
(À)
toluene
toluene
toluene
93:7
92
(À)
96
C
(10)
H
93:7
(À)
87:13
91
(10)
(+)
[a] Catalyst loading is 10 mol% unless otherwise noted. [b] Yield of iso-
lated product. [c] Determined by 19F NMR analysis of the crude reaction
mixture. [d] The ee value of the main product only, as determined by
HPLC using a chiral stationary phase. [e] Reaction time: 60 h; catalyst
loading: 5 mol%. [f] Reaction carried out at 08C for 60 h. DCE=di-
chloroethane.
reaction partners; the fluorinated products 3o and 3p,
which were derived from linear and branched substrates, re-
spectively, were obtained with excellent levels of stereose-
lectivity (Table 2, entries 15 and 16), albeit in reduced yield
relative to products derived from aryl substrates. Finally,
14256
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14255 – 14260

1,4-Addition/Dearomative-Fluorination Transformation
COMMUNICATION
Table 2. Catalytic asymmetric one-pot sequential 1,4-addition/dearomative-fluorination transformation.
Entry
Product 3
Yield
[%][a]
d.r.[b]
ee
Entry
12
Product 3
Yield
[%][a]
d.r.[b]
ee
[%][c]
[%][c]
1
93
90
93:7
96
96
88
83
>99:1
94
93
2
97:3
13
>99:1
3
4
5
6
7
94
93
92
94
85
90:10
>99:1
95:5
92
91
96
96
94
14
15
16
17
18
90
72
75
82
81
73:27
>99:1
>99:1
>99:1
>99:1
95
91
90
91
92
97:3
>99:1
8
9
93
92
90:10
95:5
91
98
19
78
>99:1
87
20
21
95
86
99:1
99:1
92
91
10
11
92
95
90:10
90:10
91
94
[a] Yield of isolated product. [b] Determined by 19F NMR analysis of the crude reaction mixture. [c] The ee value was determined by HPLC using a
chiral stationary phase and the absolute configuration of other fluorinated products were assigned on the basis of analogy with 3m (Figure 3).
other nucleophilic donors were tested for the sequential re-
action. To our delight, the similarly high levels of reactivity
and stereocontrol were observed (Table 2, entries 17–21).
Compound 3m proved to be crystalline, thus allowing the
determination of the absolute configuration of the two adja-
cent stereogenic centers by using X-ray crystallographic
analysis; (4S, 1’S; Figure 3).[11]
4-Nonsubstituted pyrazolones commonly exist as the OH/
CH/NH tautomeric form.[12] Treatment of 1a with CF3CO2D
in C6D6 at room temperature for 2 hours gave the deuterat-
Chem. Eur. J. 2012, 18, 14255 – 14260
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14257

J.-A. Ma et al.
both 1H-pyrazol-5-yl acetate and 5-methoxy-1H-pyrazole
were employed as substrates, no reaction was observed, thus
demonstrating that access to the keto tautomer of pyrazolin-
5-one is crucial for activation of the reactant by protonated
tertiary-amine–thiourea catalysts. Thus, this catalyst pro-
vides a chiral environment, as well as positioning the reac-
tion partners in close proximity and with the correct relative
geometry to facilitate this reaction. Interestingly, the hy-
droxy group in intermediates INa-c can be methylated and
acylated leading to products 4–6 without loss of enantiopuri-
ty. Subjecting intermediates INa–c to triethylamine and N-
fluorobenzenesulfonimide afforded dearomatization–fluori-
nation products 3a, 3 f, and 3l in high yields with relatively
lower levels of diastereoselectivity (Scheme 1, bottom). In
addition, using catalyst H, the intermediate INa could also
be transformed into the dearomatization–fluorination prod-
uct 3a in 90% yield with 88:12 d.r. and 90% ee. These re-
sults indicated that the chiral catalyst not only controls the
stereochemistry in the first step, it is also essential for the
À
highly diastereoselective formation of the C F bond in the
subsequent transformation.
Figure 3. X-ray structures of 3m, INc, and 6. Thermal ellipsoids are
shown at 50% probability and hydrogen atoms are omitted for clarity.
A possible mechanism for the one-pot sequential 1,4-addi-
tion/dearomative-fluorination transformation, which con-
tains two catalytic cycles, is outlined in Figure 4. In the first
cycle, the nitroalkene forms a complex with the thiourea
group of the chiral catalyst through hydrogen bonding; the
pyrazolone substrate, in its enol form, coordinates to the
ammonium center of the chiral catalyst through hydrogen
bonding. General-base-assisted addition of the enol form of
the pyrazolone substrate to the nitroalkene proceeds
through a highly organized open transition state (the conju-
gated base of the acid additive acts as the general base). In
the subsequent electrophilic-fluorination step, the pyrazol-5-
ol intermediate, which is formed in the first reaction se-
quence, reassociates with the catalyst through hydrogen
bonding to form a highly organized structure and then un-
dergoes general-base-assisted reaction with the fluorinating
reagent.
ed pyrazol-5-ol, thus indicating the facile enolization of 1a
in the presence of organic acid (Scheme 1, top). Notably, in
the presence of the tertiary-amine–thiourea catalyst and
benzoic acid, compound 1a was transformed into the C-sub-
stituted intermediates (INa—c; Scheme 1), which were iso-
lated in almost quantitative yields with excellent levels of
enantioselectivity (Scheme 1, middle).[11] However, when
In summary, we have successfully developed an organoca-
talytic
sequential
1,4-addition/dearomative-fluorination
transformation of pyrazolones and nitroolefins in the pres-
ence of NFSI. The transformation is catalyzed by a chiral
tertiary-amine–thiourea compound and benzoic acid and
can be performed effectively with a broad range of conju-
gate acceptors and donors to afford the products, which con-
tain adjacent tertiary and fluorine-bearing-quaternary ster-
eocenters. Further extension of this one-pot sequential reac-
tion to other halogenating reagents and different substrates,
as well as the application of this process to the synthesis of
bioactive products are ongoing in our laboratory and will be
reported in due course.
Experimental Section
Scheme 1. Deuteration of pyrazolone 1a; the isolation and further trans-
formation of C-substituted intermediates INa–c. Ad=adamantyl,
DIAD=diisopropyl azodicarboxlate.
General procedure: Pyrazolone 1 (0.15 mmol.), nitroolefin 2 (0.1 mmol.),
PhCO2H (0.04 mmol), and the tertiary-amine–thiourea catalyst
14258
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14255 – 14260

1,4-Addition/Dearomative-Fluorination Transformation
COMMUNICATION
co Jr., Angew. Chem. 2011, 123,
4154; Angew. Chem. Int. Ed.
2011, 50, 4068; for selected recent
examples on catalytic asymmetric
dearomatization, see: h) T. Dohi,
A. Maruyama, N. Takenaga, K.
Senami, Y. Minamistsuji, H. Fu-
jioka, S. B. Caemmerer, Y. Kita,
Angew. Chem. 2008, 120, 3847;
Angew. Chem. Int. Ed. 2008, 47,
3787; i) S. Quideau, G. Lyvinec,
M. Marguerit, K. Bathany, A.
Ozanne-Beaudenon, T. Buffe-
teau, D. Cavagnat, A. Chꢄnedꢄ,
Angew. Chem. 2009, 121, 4675;
Angew. Chem. Int. Ed. 2009, 48,
4605; j) J. Garcia-Fortanet, F.
Kessler, S. L. Buchwald, J. Am.
Chem. Soc. 2009, 131, 6676; k) J.
Qi, A. B. Beeler, Q. Zhang, J. A.
Porco Jr., J. Am. Chem. Soc.
2010, 132, 13642; l) M. Uyanik, T.
Yasui, K. Ishihara, Angew. Chem.
2010, 122, 2221; Angew. Chem.
Int. Ed. 2010, 49, 2175; m) D.-S.
Wang, Q.-A. Chen, W. Li, C.-B.
Yu, Y.-G. Zhou, X. Zhang, J. Am.
Chem. Soc. 2010, 132, 8909; n) Q.
Gu, Z.-Q. Rong, C. Zheng, S.-L.
You, J. Am. Chem. Soc. 2010,
132, 4056; o) Q.-A. Chen, D.-S.
Wang, Y.-G. Zhou, Y. Duan, H.-J.
Fan, Y. Yang, Z. Zhang, J. Am.
Chem. Soc. 2011, 133, 6126;
Figure 4. Proposed mechanism for the one-pot sequential transformation. Bz=benzoyl.
p) Q.-F. Wu, W.-B. Liu, C.-X.
Zhuo, Z.-Q. Rong, K.-Y. Ye, S.-L.
You, Angew. Chem. 2011, 123,
(0.01 mmol) were added to a 10 mL Schlenk flask equipped with a stir-
ring bar. The vial was evacuated and filled with Ar three times. Toluene
(1 mL) was added and the resulting mixture was stirred at room tempera-
ture under Ar until 2 was consumed (40–48 h; monitored by TLC). Then
NFSI (0.2 mmol) was added and the mixture was stirred at the same tem-
perature for 12–24 h (monitored by TLC). The reaction solution was con-
centrated in vacuo and the crude was purified by flash chromatography
with ethyl acetate/hexane (1:20, v/v) to afford the fluorinated product 3.
4547; Angew. Chem. Int. Ed. 2011, 50, 4455; q) A. Rudolph, P. H.
Bos, A. Meetsma, A. J. Minnaard, B. L. Feringa, Angew. Chem.
2011, 123, 5956; Angew. Chem. Int. Ed. 2011, 50, 5834; r) D.-S.
Wang, Z.-S. Ye, Q.-A. Chen, Y.-G. Zhou, C.-B. Yu, H.-J. Fan, Y.
Duan, J. Am. Chem. Soc. 2011, 133, 8866; s) Q. Gu, S.-L. You,
Chem. Sci. 2011, 2, 1519.
[2] For a single elegant example of an asymmetric oxidative dearomati-
zation/Michael addition/fluorination to afford the fluorinated deca-
lin, see: N. T. Vo, R. D. M. Pace, F. OꢁHara, M. J. Gaunt, J. Am.
Chem. Soc. 2008, 130, 404.
[3] a) C. Isanbor, D. OꢁHagan, J. Fluorine Chem. 2006, 127, 303; b) G.
Sandford, J. Fluorine Chem. 2007, 128, 90; c) S. Purser, P. R. Moore,
S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; d) S. C.
Wilkinson, R. Salmon, V. Gouverneur, Future Med. Chem. 2009, 1,
847.
[4] a) R. Noyori, Chem. Soc. Rev. 1989, 18, 187; b) Comprehensive
Asymmetric Catalysis (Eds: E. N. Jacobsen, A. Pfaltz, H. Yamamo-
to), Springer, Berlin, 1999; c) Catalytic Asymmetric Synthesis (Ed.: I.
Ojima), Wiley-VCH, New York, 2000; d) A. Thayer, Chem. Eng.
News 2005, 83, 40.
Acknowledgements
This work was supported financially by NSFC (No. 20972110 and
20902067). We also thank Professor Yoshiji Takemoto (Kyoto University,
Japan) and Qingwei Yao (Sphinx Scientific Laboratory) for his helpful
suggestions.
[5] For selected reviews on catalytic asymmetric fluorination, see: a) K.
Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 2004, 104, 1; b) R. D.
Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, U. K.
2004; c) A. M. Thayer, Chem. Eng. News 2006, 84, 15; d) J.-A. Ma,
D. Cahard, Chem. Rev. 2008, 108, PR1; e) K. L. Kirk, Org. Process
Res. Dev. 2008, 12, 305; f) J. Hu, W. Zhang, F. Wang, Chem.
Commun. 2009, 7465; g) D. Cahard, X. Xu, S. Couve-Bonnaire, X.
Pannecoucke, Chem. Soc. Rev. 2010, 39, 558; h) S. Lectard, Y. Ha-
mashima, M. Sodeoka, Adv. Synth. Catal. 2010, 352, 2708.
[6] For selected examples, see: a) R. K. Boeckman, Jr., J. E. Reed, P.
Ge, Org. Lett. 2001, 3, 3651; b) M. Abass, B. B. Mostafa, Bioorg.
Med. Chem. 2005, 13, 6133; c) M. S. Chande, P. A. Barve, V. Surya-
Keywords: 1,4-addition reactions · asymmetric catalysis ·
organocatalysis · pyrazolones · thiourea catalysts
[1] For recent reviews, see: a) A. R. Pape, K. P. Kaliappan, P. Kꢂndig,
Chem. Rev. 2000, 100, 2917; b) G. S. R. Subba Rao, Pure Appl.
Chem. 2003, 75, 1443; c) W. D. Harman, Top. Organomet. Chem.
2004, 7, 95; d) F. Lꢃpez Ortiz, M. Josꢄ Iglesias, I. Fernꢅndez, C. M.
Andffljar Sꢅnchez, G. Ruiz Gçmez, Chem. Rev. 2007, 107, 1580;
e) Y.-G. Zhou, Acc. Chem. Res. 2007, 40, 1357; f) S. Quideau, L.
Pouysꢄgu, D. Deffieux, Synlett 2008, 467; g) S. P. Roche, J. A. Por-
Chem. Eur. J. 2012, 18, 14255 – 14260
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14259

J.-A. Ma et al.
narayan, J. Heterocycl. Chem. 2007, 44, 49; d) G. Mariappan, B. P.
Saha, N. R. Bhuyan, P. R. Bharti, D. Kumar, J. Adv. Pharm. Tech.
Res. 2010, 1, 260; e) R. Ma, J. Zhu, J. Liu, L. Chen, X. Shen, H.
Jiang, J. Li, Molecules 2010, 15, 3593; f) Y.-H. Liao, W.-B. Chen, Z.-
J. Wu, X.-L. Du, L.-F. Cun, X.-M. Zhang, W.-C. Yuan, Adv. Synth.
Catal. 2010, 352, 827; g) S. Gogoi, C.-G. Zhao, Tetrahedron Lett.
2009, 50, 2252; h) M. Radi, V. Bernardo, B. Bechi, D. Castagnolo,
M. Pagano, M. Botta, Tetrahedron Lett. 2009, 50, 6572; i) S. Gogoi,
C.-G. Zhao, D. Ding, Org. Lett. 2009, 11, 2249; j) Z. G. Yang, Z.
Wang, S. Bai, X. Liu, L. Lin, X. Feng, Org. Lett. 2011, 13, 596;
k) A. N. Alba, A. Zea, G. Valero, T. Calbet, M. Font-Bardía, A.
Mazzanti, A. Moyano, R. Rios, Eur. J. Org. Chem. 2011, 1318; l) Z.
Wang, Z. Yang, D. Chen, X. Liu, L. Lin, X. Feng, Angew. Chem.
2011, 123, 5030; Angew. Chem. Int. Ed. 2011, 50, 4928.
[10] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672; b) T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Org.
Lett. 2004, 6, 625; c) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y.
Takemoto, J. Am. Chem. Soc. 2005, 127, 119; d) Y. Hoashi, T.
Okino, Y. Takemoto, Angew. Chem. 2005, 117, 4100; Angew. Chem.
Int. Ed. 2005, 44, 4032; e) T. Inokuma, Y. Hoashi, Y. Takemoto, J.
Am. Chem. Soc. 2006, 128, 9413; f) X. Xu, T. Furukawa, T. Okino,
H. Miyabe, Y. Takemoto, Chem. Eur. J. 2006, 12, 466; g) Y. Yamao-
ka, H. Miyabe, Y. Takemoto, J. Am. Chem. Soc. 2007, 129, 6686;
h) T. Inokuma, K. Takasu, T. Sakaeda, Y. Takemoto, Org. Lett. 2009,
11, 2425; i) K. Yoshida, T. Inokuma, K. Takasu, Y. Takemoto, Synlett
2010, 1865; j) S. Sakamoto, T. Inokuma, Y. Takemoto, Org. Lett.
2011, 13, 6374.
[11] The relative and absolute configuration of 3m was confirmed by X-
ray crystal structure analysis, with all fluorinated products assigned
by analogy. See the Supporting Information for further details. Com-
pounds INc and 6 were also characterized by X-ray crystallography.
The intramolecular hydrogen bond between the OH and nitro
groups in the intermediate INc was not observed. CCDC-828255
(3m), 818996 (INc) and 809060 (6) contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[7] For reviews on pyrazolines, see: a) A. Lꢄavai, J. Heterocycl. Chem.
2002, 39, 1; b) S. Kumar, S. Bawa, S. Drabu, R. Kumar, H. Gupta,
Recent Pat. Anti-Infective Drug Discovery 2009, 4, 154; c) M. Kis-
sane, A. R. Maguire, Chem. Soc. Rev. 2010, 39, 845; d) C.-H. Kꢂ-
chenthal, W. Maison, Synthesis 2010, 5, 719.
[8] For recent reviews on the chiral thiourea catalysts, see: a) Y. Take-
moto, Org. Biomol. Chem. 2005, 3, 4299; b) S. J. Connon, Chem.
Eur. J. 2006, 12, 5418; c) M. S. Taylor, E. N. Jacobsen, Angew. Chem.
2006, 118, 1550; Angew. Chem. Int. Ed. 2006, 45, 1520; d) Y. Take-
moto, Chem. Pharm. Bull. 2010, 58, 593.
[12] J. Elguero, Comprehensive Heterocyclic Chemistry II Vol. 3: Pyra-
zoles (Eds: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon,
Oxford, 1996, pp. 1–7.
[9] a) K. Liu, H.-F. Cui, J. Nie, K.-Y. Dong, X.-J. Li, J.-A. Ma, Org. Lett.
2007, 9, 923; b) X.-J. Li, K. Liu, H. Ma, J. Nie, J.-A. Ma, Synlett
2008, 3242; c) H. Ma, K. Liu, F.-G. Zhang, C.-L. Zhu, J. Nie, J.-A.
Ma, J. Org. Chem. 2010, 75, 1402.
Received: July 25, 2012
Revised: September 6, 2012
Published online: October 9, 2012
14260
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14255 – 14260