N-2-Iodobenzylcinchoninium bromide is effective for catalytic enantioselective trifluoromethylation of azomethine imines in Solkane 365mfc

Article abstract of DOI:10.1016/j.jfluchem.2012.06.008

Solkane 365mfc (1,1,1,3,3-pentafluorobutane, CF₃CH ₂CF₂CH₃) is proven to be an environmental benign alternative solvent for the catalytic enantioselective trifluoromethylation of azomethine imines 1. High chemical yields and enantioselectivities (up to 96% ee) were achieved by employing previously unknown and structurally simple cinchona alkaloid ammonium salt, N-2-iodobenzylcinchoninium bromide 3d as a catalyst.

Full text of DOI:10.1016/j.jfluchem.2012.06.008

Journal of Fluorine Chemistry 143 (2012) 216–219
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
N-2-Iodobenzylcinchoninium bromide is effective for catalytic enantioselective
trifluoromethylation of azomethine imines in Solkane1 365mfc
*
Satoshi Okusu, Hiroyuki Kawai, Xiu-Hua Xu, Etsuko Tokunaga, Norio Shibata
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
A R T I C L E I N F O
A B S T R A C T
Solkane1 365mfc (1,1,1,3,3-pentafluorobutane, CF3CH2CF2CH3) is proven to be an environmental benign
alternative solvent for the catalytic enantioselective trifluoromethylation of azomethine imines 1. High
chemical yields and enantioselectivities (up to 96% ee) were achieved by employing previously unknown
and structurally simple cinchona alkaloid ammonium salt, N-2-iodobenzylcinchoninium bromide 3d as
a catalyst.
Article history:
Received 10 April 2012
Received in revised form 1 June 2012
Accepted 5 June 2012
Available online 19 June 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Solkane1 365mfc
Fluorine
Trifluoromethylation
Green chemistry
Azomethine imines
1. Introduction
formation, and with increasingly tighter restrictions on the use of
organic solvents in industrial synthesis for green chemistry [9], these
The incorporation of a trifluoromethyl group into organic or
inorganic molecules has received considerable attention because
they possess unique physical and chemical properties which are
indispensable in the field of medicinal, agrochemical and material
chemistry [1]. Thereby, tremendous effort has been directed at the
introduction of trifluoromethyl groups into organic molecular
frameworks [2]. Among a variety of synthetic methodologies
available for the preparation of trifluoromethylated compounds,
the nucleophilic trifluoromethylation reaction using the Ruppert–
Prakash reagent ((trifluormethyl)trimethylsilane, Me3SiCF3) is the
most direct method for introducing a CF3 unit into synthetically
useful compounds [2]. Thanks to the great effort of TOSOH-FTEC INC.
in developing a process to make the reagent in up to ton quantities at
about one-fifth of the price using a contained system avoiding
problems with the ozone-depleting starting material [3], now a
number of catalytic systems are available using Me3SiCF3, and
stereoselective variants also have been extensively investigated in
recent years under chiral catalysis. Ever since various catalytic
systems were devised for asymmetric trifluoromethylation using
Me3SiCF3 [4], several examples of enantioselective trifluoromethyla-
tioninvarioussolventshavebeen reported sofar, thatis,usingCH2Cl2
[5], toluene [6], ether solvents [7] or DMF [8] as a solvent. However,
these solvents have some drawbacks such as toxicity and peroxide
facts led us to search for an alternative environmentally benign
solvent for the asymmetric trifluoromethylation reaction. Recently,
wedevelopedthefirstenantioselective trifluoromethylationof imine
equivalents, azomethine imines with Me3SiCF3 in toluene/CH2Cl2 (2/
1) [10]. In this regard, we came up with the idea of investigating
enantioselective trifluoromethylation in commercially available
Solkane1 365mfc (1,1,1,3,3-pentafluorobutane), developed by Sol-
vay Fluor GmbH, as an environmentally friendly liquid [11].
Solkane1 365mfc is non-toxic and has no impact whatsoever on
the ozone layer. Although Solkane1 365mfc has a flash point below
À27 8C, it is difficult to ignite. The minimum ignition energy is
around 50 times higher than that of n-pentane and is 10.8 mJ
(25 8C, 8 vol% in air at 1 bar). It is used as an insulating and blowing
agent for polyurethane foams, whose main uses are the thermal
insulation of residential and industrial buildings, as well as in cold
storage. Solkane1 365mfc is now produced in a pilot plant with a
capacity of several hundred tons per year. We previously reported
that Solkane1 365mfc can be used as an environmentally benign
alternative solvent for several transformations, namely the
trifluoromethylation of carbonyl compounds [12], the catalytic
asymmetric Friedel–Crafts alkylations of indoles [13], the homo-
coupling reaction of terminal alkynes [14], the trifluoromethane-
sulfonylation of indoles [15] and the Suzuki–Miyaura cross
coupling reaction [16]. As part of our ongoing research project
concerning the enantioselective synthesis of organofluorine
compounds [4,6,10], we required the development of enantiose-
lective trifluoromethylation of azomethine imines with Me3SiCF3
* Corresponding author. Tel.: +81 52 735 7543; fax: +81 52 735 7543.
E-mail address: nozshiba@nitech.ac.jp (N. Shibata).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.06.008

S. Okusu et al. / Journal of Fluorine Chemistry 143 (2012) 216–219
217
cinchoninium bromide (3a) at À10 8C, affording the trifluoromethy-
lated adduct 2a in 96% with 78% ee (Table 1, run 1). This result was
inferior to chiral induction using toluene/CH2Cl2 (2/1) as a solvent
under the same reaction condition (81%, 82% ee, run 2). We next
investigated other additives in an attempt to improve enantioselec-
tivity (runs 3–5); however, none of the additives provided a better
result in terms of reactivity and enantioselectivity. We then turned
our attention to screening a broad range of ammonium bromides
derived from cinchona alkaloids to find a proper catalyst for the
transformation in Solkane1 365mfc (runs 6–10). We were pleased to
find that the reaction with novel N-2-iodobenzylcinchoninium
bromide 3d in Solkane1 365mfc gave a superior result to the ee
value of the reaction catalyzed by either 3a and 3d in toluene/CH2Cl2
(2/1) (87%, 83% ee, run 8 vs. runs 2, 9). The best result was obtained by
treating 1a with Me3SiCF3 (4.0 equiv.) at À20 8C in Solkane1 365mfc
in the presence of 3d (10 mol%) and KOH (6.0 equiv.), leading to the
isolation of 2ain 99% yield with86%ee (run11). Itshould be noted that
the catalyst 3d is very efficient in spite of its simple structure, and can
be prepared in one step from commerically available cinchonine and
o-iodobenzyl bromide. N-2-Trifluoroethoxybenzylcinchoninium bro-
mide 3f also proved to be an almost equally effective catalyst,
affording 2a in 97% yield with 84% ee (run 12).
With conditions optimized, several families of azomethine
imines differing in the nature of their aryl groups were submitted
to the action of our trifluoromethylation system, to explore the
scope of the chiral ammonium bromide 3d/KOH catalyst in
Solkane1 365mfc (Table 2). A series of azomethine imines 1a–h
were nicely converted to the corresponding trifluoromethylated
adducts 2a–h in high yield in 85–99% yield with high enantios-
electivities up to 96% ee, these being almost independent of the
functional groups on the aromatic ring (entries 1–8). What is more,
in a slightly large-scale preparation, the product was isolated by
filtration and distillation to give 2a (86% ee), and 72% yield after
recrystallization, while Solkane1 365mfc was recovered in 72%
(entry 9).
Br
HO
N
H
N
O
O
3d (10 mol%) I
KOH (6.0 equiv)
Solkane® 365mfc, -20 °C
HN
N
Me3SiCF3
N
N
Ar
CF3
Ar
H
(S)−2
1
up to 96% ee
Scheme 1. Enantioselective trifluoromethylation of azomethine imines in Solkane1
365mfc.
using Solkane1 365mfc as a green medium in organic reactions.
This reaction was previously achieved by N-3,5-bis(tert-butylben-
zyl)cinchoninium bromide (3a) as a catalyst in toluene/CH2Cl2
[10]; however, 3a is not efficient enough for this transformation in
Solkane1 365mfc. We herein report that previously unknown N-2-
iodobenzylcinchoninium bromide 3d is effective as a chiral
catalyst for enantioselective trifluoromethylation of azomethine
imines in Solkane1 365mfc. The novel catalyst 3d has a very simple
structure and is readily synthesized in one step from commercially
available cinchonine and o-iodobenzyl bromide in high yield
(Scheme 1).
2. Results and discussion
First, our original catalytic system for enantioselective trifluor-
omethylation of 1a in toluene/CH2Cl2 (2/1) was tested in Solkane1
365mfc as a medium. A stoichiometric amount of KOH was added to a
mixture of 1a and 4.0 equiv. of Me3SiCF3 in Solkane1 365mfc in
the presence of a catalytic amount of N-3,5-bis(tert-butylbenzyl)
Table 1
Optimization of reaction conditions for the enantioselective trifluoromethylation of 1a with Me3SiCF3 in Solkane1 365mfc.
O
O
cat. 3 (10 mol%)
additive (6.0 equiv)
HN
N
Me3SiCF3
(4.0 equiv)
N
N
Solkane®365mfc, temp.
Ph
CF3
Ph
H
(S)-2a
1a
3a : Ar = 3,5-tBu2C6H3
3b : Ar = 3,5-(CF3)2C6H3
3c : Ar = 2-BrC6H4
3d : Ar = 2-IC6H4
Br
HO
N
3e : Ar = 4-IC6H4
H
Ar
N
3f: Ar = 2-CF3OC6H4
Run
Catalyst
Additive
Time (h)
Yield (%)
eea
1
2b
3
3a
3a
3a
3a
3a
3b
3c
3d
3d
3e
3d
3f
KOH
KOH
NaOH
CsF
8
12
16
10
10
15
12
12
7
96
81
15
57
20
76
85
87
70
56
99
97
78
82
80
78
76
11
63
83
82
37
86
84
4
5
KOPh
KOH
KOH
KOH
KOH
KOH
KOH
KOH
6
7
8
9b
10
11c
12c
14
14
12
a
Determined by chiral HPLC.
b
c
Toluene/CH2Cl2 (2/1) was used as solvent.
The reaction was carried out at À20 8C.

218
S. Okusu et al. / Journal of Fluorine Chemistry 143 (2012) 216–219
Table 2
Enantioselective trifluoromethylation of azomethine imines 1a–h with Me3SiCF3 catalyzed by 3d in Solkane1 365mfc.
O
O
cat. 3d (10 mol%)
KOH (6.0 equiv)
HN
N
Me3SiCF3
(4.0 equiv)
N
N
Solkane®365mfc, -20 °C
Ar
CF3
Ar
H
1a− h
(S)-2a− h
Entry
1
R
Time (h)
Yield (%)
eea
1
2b
3b,c
4b
5b
6
7b
8b
9d
1a
1b
1c
1d
1e
1f
Ph
14
10
18
12
12
17
21
21
18
99
80
65
87
95
90
94
84
72
86
84
89
89
86
96
96
74
86e
3-MeOC6H4
4-MeOC6H4
3-MeC6H4
4-MeC6H4
4-iPrC6H4
4-tBuC6H4
4-FC6H4
Ph
1g
1h
1a
a
Determined by chiral HPLC.
b
c
Me3SiCF3 (6.0 equiv.) and KOH (10.0 equiv.) were used.
3f was used instead of 3d.
d
e
The reaction was performed at a slightly large scale and product 2a was isolated by filtration, distillation and recrystallization. Solkane1 365mfc was recovered in 72% yield.
Before recrystallization.
3. Conclusion
0.60 mmol, 6.0 equiv.) in Solkane1 365mfc (1.0 mL) Me3SiCF3
(59.1
L, 0.40 mmol, 4.0 equiv.) was added at À20 8C under a
m
In conclusion, Solkane1 365mfc was introduced as an environ-
mentally benign alternative solvent for the enantioselective trifluor-
omethylation reaction of imine equivalents, azomethine imines 1. The
trifluoromethylated adducts can be readily converted into pharma-
ceutically important trifluoromethylated amines [10]. High chemical
yields and enantioselectivities (up to 96% ee) were achieved by
employing previously unknown N-2-iodobenzylcinchoninium bro-
mide 3d as a chiral catalyst. The novel catalyst 3d has a very simple
structure and is readily synthesized in one step from commercially
available cinchonine and o-iodobenzyl bromide in high yield.
nitrogen atmosphere. After the reaction mixture was stirred at the
same temperature for 14 h, it was quenched with sat. NH4Cl aq. The
aqueous layer was extracted with CH2Cl2, and the combined organic
layers was washed with brine, dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (n-hexane/ethyl acetate = 1/1) to give
trifluoromethylated compounds (S) – 2a (27.2 mg, 99%, 86% ee) as a
white solid; 1H NMR (CDCl3, 200 MHz)
d 1.32 (s, 3H), 1.48 (s, 3H),
1.62, 1.77 (AB quartet, J = 16.1 Hz, 2H), 4.51 (q, J = 8.9 Hz, 1H), 7.35–
7.42 (m, 3H), 7.46–7.51 (m, 2H), 7.58 (brs, 1H); 13C NMR (CD3OD,
150.9 MHz)
J = 280.2 Hz), 130.6, 131.3, 133.2, 133.5, 180.2; 19F NMR (CDCl3,
188 MHz)
1694, 1497, 1455, 1360, 1275, 1242, 1167, 1124, 1088, 1033, 898,
846, 710, 658 cmÀ1; mp = 191–192 8C (CH2Cl2/hexane); MS (EI, m/z)
272 (M+), HRMS calcd. for C13H15F3N2O: 272.1136, Found:
272.1138; the ee of the product was determined by HPLC using
an OJ-H column (n-hexane/i-PrOH = 95/5, flow rate 0.5 mL/min,
d 25.0, 30.9, 44.9, 67.5 (q, J = 28.2 Hz), 67.6 127.7 (q,
4. Experimental
d
À70.7 (d, J = 9.2 Hz, 3F); IR (KBr) 3186, 3086, 2980, 2929,
4.1. Preparation of N-2-iodobenzylcinchoninium bromide 3d
A solution of cinchonine (200 mg, 0.68 mmol) and o-iodobenzyl
bromide (222 mg, 0.75 mmol, 1.1 equiv.) in THF (20 mL)/MeCN
(5 mL) was refluxed under a nitrogen atmosphere. After 12 h, the
reaction mixture was concentrated under reduced pressure and
recrystallized from CH2Cl2/diethyl ether to give 3d (330 mg, 82%)
l
= 254 nm,
tmaj = 16.7 min, tmin = 21.6 min).
as a solid with a bisque color; 1H NMR (CD3OD, 300 MHz)
d 1.07 (m,
Acknowledgments
1H), 1.89–1.96 (m, 4H), 2.47 (t, J = 11.7 Hz, 1H), 2.64 (q, J = 8.3 Hz,
1H), 3.27–3.34 (m, 1H), 3.48 (t, J = 11.3 Hz, 1H), 4.12–4.16 (m, 2H),
4.71–4.77 (m, 1H), 5.26–5.45 (m, 4H), 6.05 (ddd, J = 7.0, 10.4,
17.3 Hz, 1H), 6.69 (s, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz,
1H), 7.84 (t, J = 3.8 Hz, 2H), 7.98 (d, J = 4.8 Hz, 2H), 8.14 (t, J = 9.0 Hz,
2H), 8.42 (d, J = 6.0 Hz, 1H), 8.96 (d, J = 4.5 Hz, 1H); 13C NMR
This study was financially supported in part by Grants-in-Aid
for Scientific Research (24105513, 22106515, Project No. 2304).
We thank Dr. Max Braun, Solvay Fluor GmbH for the generous gift
of Solkane1 365mfc. We thank Tosoh F-Tech Ltd. for the generous
gift of Me3SiCF3. We also thank the Asahi Glass Foundation for
financial support.
(CD3OD, 150.9 MHz)
d 22.3, 24.7, 28.2, 38.9, 57.2, 58.2, 67.1, 67.4,
69.2, 106.4, 117.8, 121.1, 124.5, 126.1, 129.3, 130.2, 131.2, 132.2,
133.4, 136.6, 137.6, 142.7, 147.4, 148.7, 151.0; IR (KBr) 3382, 3163,
3089, 2884, 1639, 1587, 1509, 1459, 1424, 1329, 1281, 1206, 1169,
1130, 1053, 998, 932, 858, 760, 630, 551 cmÀ1; mp = 230 8C
(decomposed) (CH2Cl2/Et2O); MS (ESI, m/z) 511 (M+-Br).
References
[1] (a) R. Filler, Y. Kobayashi, Biomedicinal Aspects of Fluorine Chemistry, Elsevier
Biomedical Press and Kodansya Ltd., Amsterdam, 1982;
(b) R. Filler, Y. Kobayashi, L.M. Yagupolskii, Organofluorine Compounds in Me-
dicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam/New York,
1993;
4.2. Trifluoromethylation of azomethine imine 1a in Solkane1 365mfc
catalyzed by 3d
(c) J.T. Welch, S. Eswarakrishman, Fluorine in Bioorganic Chemistry, Wiley, New
York, 1991;
(d) P. Krisch, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004;
(e) V.P. Kukhar, V.A. Soloshonok, Fluorine-containing Amino Acids. Synthesis and
Properties, Wiley, Chichester, 1995.
Toa stirredsolution ofazomethineimine 1a(20.2 mg, 0.1 mmol),
catalyst 3d (5.9 mg, 0.010 mmol, 10 mol%) and KOH (33.7 mg,

S. Okusu et al. / Journal of Fluorine Chemistry 143 (2012) 216–219
219
[2] (a) G.K.S. Prakash, A.K. Yudin, Chemical Reviews 97 (1997) 757–786;
[7] (a) Y. Kuroki, K. Iseki, Tetrahedron Letters 40 (1999) 8231–8234;
(b) H. Zhao, B. Qin, X. Liu, X. Feng, Tetrahedron 63 (2007) 6822–6826;
(b) R.P. Singh, J.M. Shreeve, Tetrahedron 56 (2000) 7613–7632;
(c) P. Lin, J. Jiang, Tetrahedron 56 (2000) 3635–3671;
(d) G.K.S. Prakash, M. Mandal, Journal of Fluorine Chemistry 112 (2001) 123–131;
(e) B.R. Langlois, T. Billard, S. Roussel, Journal of Fluorine Chemistry 126 (2005)
173–179.
(c) X. Hu, J. Wang, W. Li, L. Lin, X. Liu, X. Feng, Tetrahedron Letters 50 (2009)
4378–4380;
(d) T. Furukawa, T. Nishimine, E. Tokunaga, N. Shibata, Organic Letters 13 (2011)
3972–3975;
[3] A.M. Thayer, Chemical & Engineering News 84 (2006) 15–24.
[4] (a) N. Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry 19 (2008) 2633–
2644;
(b) J.-A. Ma, D. Cahard, Chemical Reviews 108 (2008) PR1–PR43.
[5] (a) S. Caron, N.M. Do, P. Arpin, A. Larive´e, Synthesis 35 (2003) 1693–1698;
(b) S. Caron, N.M. Do, J.E. Sieser, P. Arpin, E. Vazquez, Organic Process Research &
Development 11 (2007) 1015–1024;
(c) H. Nagao, Y. Kawano, T. Mukaiyama, Bulletin of the Chemical Society of Japan
80 (2007) 2406–2412.
[6] (a) K. Iseki, T. Nagai, Y. Kobayashi, Tetrahedron Letters 35 (1994) 3137–3138;
(b) S. Mizuta, N. Shibata, M. Hibino, S. Nagano, S. Nakamura, T. Toru, Tetrahedron
63 (2007) 8521–8528;
(e) Y. Li, F. Liang, Q. Li, Y.-C. Xu, Q.-R. Wang, L. Jiang, Organic Letters 13 (2011)
6082–6085.
[8] T. Hagiwara, T. Kobayashi, T. Fuchigami, Main Group Chemistry 2 (1997) 13–15.
[9] (a) P.T.Anastas,M.M.Kirchhoff,AccountsofChemicalResearch35(2002)686–694;
(b) M. Doble, A.K. Kruthiventi, Green Chemistry and Processes, Academic Press,
Burlington, MA, 2007;
(c) V.K. Ahluwalia, Green Chemistry: Environmentally: Environmentally Benign
Reactions, CRC, Taylor & Francis, Boca Raton, FL, 2008.
[10] H. Kawai, A. Kusuda, S. Nakamura, M. Shiro, N. Shibata, Angewandte Chemie-
International Edition 48 (2009) 6324–6327.
[11] See Solvay Solkane365mfc brochure, http://www.solvaychemicals.com/EN/pro-
ducts/Fluor/Hydrofluorocarbons_HFC/Solkane365mfc.aspx (accessed April 2012);
thiswebaddressmightnotbeaccessibleorcouldchangeinthefuture. Ifthiswereto
happen, this information is available directly from the authors by e-mail.
[12] A. Kusuda, H. Kawai, S. Nakamura, N. Shibata, Green Chemistry 11 (2009) 1733–
1735.
[13] X.-H. Xu, A. Kusuda, E. Tokunaga, N. Shibata, Green Chemistry 13 (2011) 46–50.
[14] A. Kusuda, X.-H. Xu, X. Wang, E. Tokunaga, N. Shibata, Green Chemistry 13 (2011)
1733–1735.
(c) H. Nagao, Y. Yamane, T. Mukaiyama, Chemistry Letters 36 (2007) 666–667;
(d) S. Mizuta, N. Shibata, S. Akiti, H. Fujimoto, S. Nakamura, T. Toru, Organic
Letters 9 (2007) 3707–3710;
(e) L. Bernardi, E. Indrigo, S. Pollicino, A. Ricci, Chemical Communications 48
(2012) 1428–1430;
(f) H. Kawai, A. Kusuda, S. Mizuta, S. Nakamura, Y. Funahashi, H. Masuda, N.
Shibata, Journal of Fluorine Chemistry 130 (2009) 762–765;
(g) H. Kawai, K. Tachi, E. Tokunaga, M. Shiro, N. Shibata, Organic Letters 12 (2010)
5104–5107;
[15] X.-H. Xu, G.-K. Liu, A. Azuma, E. Tokunaga, N. Shibata, Organic Letters 13 (2011)
4854–4857.
(h) H. Kawai, T. Kitayama, E. Tokunaga, N. Shibata, European Journal of Organic
Chemistry (2011) 5959–5961.
[16] X.-H. Xu, A. Azuma, A. Kusuda, E. Tokunaga, N. Shibata, European Journal of
Organic Chemistry (2012) 1504–1508.