Cinchonium Betaines as Efficient Catalysts for Asymmetric Proton Transfer Catalysis: The Development of a Practical Enantioselective Isomerization of Trifluoromethyl Imines

Article abstract of DOI:10.1021/jacs.6b08727

We have developed a new class of cinchonium betaine catalysts bearing both a base moiety and an aromatic moiety as an N-substituent of the quinuclidine motif. These cinchonium betaines were found to promote proton transfer catalysis with 1000-5000 turnovers per 24 h, thereby enabling us to realize highly efficient enantioselective isomerization of trifluoromethyl imines to provide a practical access to optically active trifluoromethylated amines.

Full text of DOI:10.1021/jacs.6b08727

Subscriber access provided by United Arab Emirates University | Libraries Deanship
Article
Cinchonium Betaines as Efficient Catalysts for Asymmetric
Proton Transfer Catalysis: The Development of a Practical
Enantioselective Isomerization of Trifluoromethyl Imines
Xiao Zhou, Yongwei Wu, and Li Deng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08727 • Publication Date (Web): 31 Aug 2016
Downloaded from http://pubs.acs.org on August 31, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Cinchonium Betaines as Efficient Catalysts for Asymmetric Proton
Transfer Catalysis: The Development of a Practical Enantioselective
Isomerization of Trifluoromethyl Imines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Xiao Zhou§, Yongwei Wu§ and Li Deng*
Department of Chemistry, Brandeis University, Waltham, MA 02454-9110
Supporting Information Placeholder
ABSTRACT: We have developed a new class of cinchonium betaine catalysts bearing both a base moiety and an aromatic
moiety as an N-substituent of the quinuclidine motif. These cinchonium betains were found to promote proton transfer
catalysis with 1000-5000 turnovers per 24 hours, thereby enabling us to realize highly efficient enantioselective isomeriza-
tion of trifluoromethyl imines to provide a practical access to optically active trifluoromethylated amines.
catalyst loading render this unprecedented, phase transfer
catalysis-mediated enantioselective imine isomerization a
1. Introduction
We1 and others2 demonstrated that chiral organic cata-
practical method for the asymmetric synthesis of trifluo-
romethylated amines.6-9
lysts containing both hydrogen bond donor and acceptor
could facilitate biomimetic 1,3-proton transfer catalysis to
promote highly enantioselective olefin and imine isomer-
izations. These enantioselective isomerizations provide
new access to valuable chiral building blocks such as α,β-
unsaturated butenolides,1a,3 α-amino acids,2c α,β-
unsaturated cyclohexenones1c and trifluoromethylated
amines.1b,2e Among these studies, the realization of the
first highly enantioselective isomerization1b of trifluoro-
Figure 1. Drawbacks of asymmetric isomerization of trifluo-
romethyl imines with acid-base bifunctional catalysts.
methyl imines with DHQ-3 stands as a conceptually sig-
nificant progress as DHQ-3 achieved efficient catalytic
chiral recognition of non-enolate carbanions for asym-
metric reactions (Figure 1).4,5
2. Results and discussion
During our recent studies of C-C bond forming asym-
metric umpolung reaction of imines10, we observed that
certain cinchona alkaloid-derived chiral phase transfer
catalysts promoted isomerization of trifluoromethyl
imines. This observation raised the prospect of develop-
ing a new class of chiral catalysts for the promotion of
asymmetric isomerizations of imines via a fundamentally
different mechanism from those by acid-base bifunctional
catalysts. Although highly enantioselective protonations
of enol derivatives were reported,11 a literature search re-
vealed that phase transfer catalyst-promoted proton
transfer reactions are still rare and only with modest en-
antioselectivity.12
However, the required high catalyst loading (10 mol%)
and long reaction time (48-72 hours) severely hampered
the application of this reaction in asymmetric synthesis.
Moreover, the isomerizations with the pseudoenantio-
meric catalyst DHQD-3 proceeded with significantly low-
er enantioselectivity under optimized conditions (Figure
1). Consequently, this method was not able to provide
useful access to the S enantiomers of chiral trifluoro-
methylated amines. These problems also apply to anoth-
er cinchona alkaloid-derived bifunctional catalyst report-
ed by Shi and coworkers for the same isomerizations.2e
These limitations associated with existing methods high-
lighted both the urgent need and challenges for the de-
velopment of significantly more active and selective chiral
catalysts for this promising asymmetric transformation.
We wish to report in this article the development of new
chiral cinchonium betaine catalysts that afford powerful
enantioselective proton transfer catalysis, which over-
comes the limitations associated with existing chiral cata-
lysts. The general scope, simple protocol for reaction exe-
cution and product isolation and an extraordinarily low
Motivated by the possible discovery of new and pow-
erful catalysts for enantioselective proton transfer cataly-
sis, we began to explore cinchonium salts as catalysts for
the isomerization of trifluoromethyl imine 1. At room
temperature in the presence of aqueous KOH and 0.5
mol% cinchonium salts C-5 and C-6, the model isomeri-
zation was found to proceed in very low enantioselectivity
(Entries 1-2, Table 1). We next examined catalysts C-7,
which presented an electron-rich N-terphenyl group
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
Table 1. Asymmetric isomerization of 1a with cinchonium betaine catalystsa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReactions were run with 1a (0.025 mmol), aqueous KOH (0.3 μL, 50 wt%, 10 mol%) and catalyst in toluene/CHCl3 (7/3
v/v, 0.25 mL) at room temperature. Determined by HPLC analysis. The Betaine catalyst QD-9a was generated in situ
from PQD-9a.
b
c
Figure 2. Working hypotheses.
Table 2. Optimizations of catalyst and reaction conditions for enantioselective isomerization of 1aa
aBetaine catalysts QD-9 and Q-9c were preformed from treatment of the corresponding precursors PQD-9 and PQ-9c
with base (see supporting information for details). Reactions were run with 1a (0.025 mmol) in solvent (0.25 mL) indicat-
ed. The ratio of 2a/4a was determined to be greater than 99/1 by HPLC analysis. bDetermined by HPLC analysis. cAbsolute
configuration was determined to be R. See Supporting Information for details.
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
To further test whether the betaine QD-9 was indeed
that was designed to engage in π-π interaction with the 2-
azaallylanions.10 To our disappointment, C-7 afforded
even worse enantioselectivity (Entry 3, Table 1). Moreo-
ver, imine 1a was found to be transformed into not only
the chiral amine 2a but also the N-(1,1-difluoropropenyl)
imine 4a. The latter, presumably formed by the loss of
fluoride from 2-azaallylanion 10a (Figure 2a), was often
the dominant product.13
responsible for the dramatically improved catalytic activi-
ty and selectivity, we carried out an isomerization with
the preformed betaine QD-9a under base free conditions.
Specifically, we first treated PQD-9a with solid KOH in
toluene/CHCl3 for 15 minutes, when PQD-9a was shown
1
2
3
4
5
6
7
8
1
by H NMR analysis to be converted into the betaine QD-
9a.19 Then the desired amount of the QD-9a solution in
toluene/CHCl3 was added to a solution of imine 1a in tol-
uene/CHCl3. After four hours the isomerization was
shown to proceed to 76% conversion to afford R-2a as the
only detectable product in 92% ee (entry 1, Table 2). Up-
on further optimization by catalyst tuning (entries 2-3,
Table 2), we were able to accomplish the isomerization in
98% conversion and 95% ee by employing betaine QD-9c.
These discouraging results indicated that, with cincho-
nium-based phase transfer catalysts, the enantioselective
protonation of the 2-azaallyl anion 10a proceeded not
only with low enantioselectivity but also too slow to es-
tablish the desired isomerization as the major reaction
pathway (Figure 2a). Moreover, we suspected that the
low enantioselectivity could be attributed to the difficulty
in effectively biasing the two enantiotopic faces of the 2-
azaallylanion 10a towards the intermolecular protonation
by water, a small proton donor. Following these consid-
erations, we concluded that the intermolecular nature of
the protonation step in these cinchonium salts-mediated
isomerizations was largely responsible for the poor cata-
lytic activity and enantioselectivity.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We attempted to further reduce catalyst loading, but
failed to accomplish a completed reaction with 0.2 mol%
of QD-9c (entry 4, Table 2). Subsequently, we found that
the presence of a solid base such as K2CO3 was highly
beneficial for maintaining the activity of the betaine cata-
lyst (entry 5 vs. 4, Table 2). Upon optimizations of sol-
vent, a highly enantioselective and complete isomeriza-
tion of 1a could be consistently accomplished in 24 hours
in toluene with only 0.02 mol% of QD-9c (entry 6, Table
2). Notably, the conversion only suffered very slightly
with 0.01 mol% of QD-9c without compromising enanti-
oselectivity; reaching 97% in 24 hours. These results
showed that the cinchonium betaine catalyst-mediated
asymmetric proton transfer catalysis proceeded with an
extraordinarily high catalyst turnover rate (entry 7, Table
2). Gratifyingly, a highly enantioselective isomerization
of 1a into S-2a could be accomplished with 0.05 mol% of
quinine-derived betaine Q-9c (entry 8, Table 2). Thus, the
cinchonium betaine catalysts not only are far superior to
existing organocatalysts in terms of catalyst efficiency but
also bring a decisive synthetic advantage by offering use-
ful access to either R or S enantiomer of the trifluoro-
methylated amines 2.
We postulated that we might be able to address this
problem by installing an alkoxide functionality into the
cinchonium salt C-7, which bear a π-π interaction moiety.
As illustrated in Figure 2b, we hypothesized that such a
betaine catalyst11c,14-18 could, upon the binding of imine 1a
to the catalyst via π-π interaction, promote both the
deprotonation and the protonation steps in an intramo-
lecular-like setting. The protonation step should be
greatly accelerated as it involved proton transfer between
the alkoxide and the 2-azaallyanion intermediate located
close to each other. More importantly, the spatial rela-
tionship between the phenol as the proton donor and the
2-azaallyanion interacting with the catalyst via π-π and
ion-pair interactions should be confined by the chiral
backbone of the catalyst, thereby providing a more favor-
able setting for achieving fast and highly enantioselective
protonation.
We next investigated the substrate scope. Excellent en-
antioselectivity could be readily accomplished for a varie-
ty of aliphatic trifluoromethyl imines of varying length
(1a-1c) with QD-9c in 0.02-0.10 mol% loading (entries 1-3,
Table 3). For the sterically more hindered cyclohexyl
trifluoromethyl imine 1d, a catalyst loading of 0.50 mol%
was required in order to achieve a highly enantioselective
and complete isomerization in 24 hours (entry 4, Table 3).
Interestingly, we found that QD-9c promoted an unprec-
edented isomerization of α,β-unsaturated imine 1e in
excellent enantioselectivity and yield. It is noteworthy
that the reaction proceeded without the formation of the
1,3-proton transfer product. The scope of the reaction was
readily extended to a wide range of aryl trifluoromethyl
imines (entries 6-12, Table 3). In most cases, a loading of
0.10-0.20 mol% of QD-9c was sufficient in affording a
complete and highly enantioselective isomerization of
imines 1 within 24 hours to generate the corresponding
optically active chiral aryl trifluoromethylated amine 2 in
close to quantitative yields. Aryl trifluoromethyl imines
bearing a strongly electron-withdrawing substituent such
Guided by these considerations, we employed PQD-9a
as a precursor of the cinchonium betaine catalyst QD-9a
(Table 1). Initially, betaine QD-9a was examined for the
isomerizations of 1a under the same conditions as those
applied to catalysts C5-C7. We expected that QD-9a
could be formed in situ via deprotonation of the PQD-9a
by KOH. To our delight, the isomerization of 1a went to
completion in one hour with 0.5 mol% of QD-9a to afford
the desired chiral amine 2a in 91% ee as virtually the only
detectable product (entry 4, Table 1). In contrast, the
quinidine-derived cinchonium salt QD-8 afforded poor
chemoselectivity and enantioselectivity, thereby showing
the critical role played by the phenoxide of QD-9a for the
efficient promotion of the enantioselective isomerization.
The opposite sense of asymmetric induction by QD-9a
versus that by C5-C7 and QD-8 indicated that QD-9a ex-
ercised its enantioselectivity via a distinct mechanism.
This notion is consistent with the working hypothesis of
our catalyst design as outlined in Figure 2.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
Table 3. Isomerization of 1 to 2 catalyzed by QD-9c
and Q-9ca.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Figure 3. H NMR spectra of 2a isolated from labeling exper-
iment in toluene-d8 at 298 K using the standard reaction
conditions.
aBetaine catalysts QD-9c and Q-9c were preformed from
treatment of the corresponding precursors PQD-9c and
PQ-9 with base(see supporting information for details).
Reactions were run with 1 (0.2 mmol) in toluene (2.0 mL).
Results in parentheses were obtained with Q-9c. bIsolated
Figure 4. Isomerization of imines 1a’ and 1a’’ with QD-9c.
oselective 1,3-proton transfer (Figure 2b). To verify that
the π-π interaction between imines 1 and catalyst 9c
played an important role to the catalysis by 9c (Figure
2b), we investigated the isomerizations of both imines
1a’ and 1a”, which were derived by replacing the 4-NO2
benzyl group in 1a with a benzyl group and 4-
carboxylatebenzyl group, respectively (Figure 4). Catalyst
9c was found to be inactive toward the isomerization of
imine 1a’ and afforded significantly worse enantioselectiv-
ity (84% ee vs. 96% ee) and lower conversion (43% vs
100%) for the isomerization of 1a”. These results indicat-
ed that the 4-NO2 benzyl group not only rendered imine
1a more active toward the QD-9c catalyzed isomerization
but also played an important role in the substrate-catalyst
chiral recognition.
c
d
yield. Determined by HPLC analysis. An E/Z mixture of
imine stereoisomers (E/Z = 3.2/1) was used.
as 1m and 1n proved to be more challenging substrates,
nonetheless a quantitative reaction with good enantiose-
lectivity could be mediated by 0.20 mol% of QD-9c. Im-
portantly, isomerizations with betaine Q-9c in similarly
low loading afforded the opposite enantiomer of the chi-
ral trifluoromethylated amine in excellent yield and in
only slightly lower optical purities (Table 3). The isomer-
ization typically proceeded so cleanly that a simple filtra-
tion of the reaction mixture through a plug of deactivated
silica gel followed by solvent removal furnished amines 2
in pure form as determined by NMR analysis. The NMR-
pure isomerization product 2a, without further purifica-
tion, could be hydrolyzed to give the desired chiral tri-
fluoromethylated amine 11a in 86% yield and 96% ee.1b
3. Conclusion
In conclusion, our exploratory studies of cinchonium
betaines have led to the discovery of a new class of cata-
lysts for enantioselective proton transfer catalysis. These
new catalysts afforded remarkably high catalyst turnover
rate for the promotion of asymmetric isomerizations of
trifluoromethyl imines.20 Consequently, a broad range of
alkyl, alkenyl and aryl trifluoromethyl imines could be
converted in a highly enantioselective manner into either
enantiomer of the corresponding optically active trifluo-
romethylated amines with typically 0.02 to 0.10 mol% of
the cinchonium betaines. With a mechanistically distinct
mode of catalysis, this reaction should provide a comple-
mentary approach to existing methods for the asymmetric
synthesis of trifluoromethylated amines.
To validate that the methine hydrogen in 2a came from
one of the benzylic hydrogen in 1a, we first carried out the
QD-9c catalyzed isomerization of 1a in toluene-d8 using
the standard reaction conditions. We next carried out the
same isomerization with dry K2CO3 in anhydrous toluene-
1
d8 in dry box.19 As shown by H NMR analyses (Figure 3
and S-Figure 6 in Supporting Information), we found the
chiral amine 2a was formed without incorporation of deu-
terium. We also investigated a QD-9c catalyzed isomeri-
zation of 1a in toluene-d8 with 40% KOD in D2O, instead
of K2CO3, as the base. We found that 2a was formed in
92% ee and, once again, without incorporation of deuter-
ium.19 These results indicated that the methine hydrogen
in 2a indeed came from the benzylic hydrogen in 1a,
which was consistent with our hypothesis of how a cin-
chonium betain like QD-9c mediated this highly enanti-
4. Experimental Section
4.1 General procedure for the asymmetric isomeri-
zation of alkyl trifluomethyl imines 1a to 1d with cat-
alyst QD-9c. To a solution of catalyst PQD-9c (3.1 μmol,
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
3.0 mg) in toluene (180 μL) was added grounded K2CO3
REFERENCES
1
2
3
4
5
6
7
8
(0.065 mmol, 9.0 mg). The suspension was then stirred
vigorously at room temperature for 2 hours. After stand-
ing for 10 minutes, a portion of the clear solution (90 μL)
was collected and diluted with toluene (810 μL). A portion
of this diluted solution of QD-9c in toluene (0.040 μmol
to 1.0 μmol, 23 μL to 580 μL) was placed into a vial (3.7
mL), to which was added sequentially toluene (1.977 mL
to 1.42 mL), grounded K2CO3 (0.020 mmol, 2.8 mg) and
trifluoromethyl imine 1 (0.20 mmol). Then the mixture
was allowed to stir at room temperature for 24 hours. The
reaction mixture was allowed to pass through a plug of
deactivated silica gel21 to remove the catalyst. The deac-
tivated silica gel plug was then washed with diethyl ether
(2.0-4.0 mL). The filtrate was concentrated in vacuo to
give trifluoromethylated amines 2.
(1) (a) Wu, Y.; Singh, R. P.; Deng, L. J. Am. Chem. Soc. 2011, 133,
12458. (b) Wu, Y.; Deng, L. J. Am. Chem. Soc. 2012, 134, 14334. (c)
Lee, J. H.; Deng, L. J. Am. Chem. Soc. 2012, 134, 18209.
(2) (a) Liu, H.-J.; Leow, D.-S.; Huang, K.-W.; Tan, C.-H. J. Am.
Chem. Soc. 2009, 131, 7212. (b) Liu, H.; Feng, W.; Kee, C. W.; Le-
ow, D.; Loh, W.-T.; Tan, C.-H. Adv. Synth. Catal. 2010, 352, 3373.
(c) Xiao, X.; Xie, Y.; Su, C.; Liu, M.; Shi, Y. J. Am. Chem. Soc. 2011,
133, 12914. (d) Inokuma, T.; Furukawa, M.; Suzuki, Y.; Kimachi,
T.; Kobayashi, Y.; Takemoto, Y. ChemCatChem 2012, 4, 983. (e)
Liu, M.; Li, J.; Xiao, X.; Xie, Y.; Shi, Y. Chem. Commun. 2013, 49,
1404.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) Hugelshofer, C. L.; Magauer, T. J. Am. Chem. Soc., 2015, 137,
3807.
(4) For early attempts to develop catalytic enantioselective
isomerizations of trifluoromethyl imines, see: (a) Soloshonok, V.
A.; Kirilenko, A. G.; Galushko, S. V.; Kukhar, V. P. Tetrahedron
Lett. 1994, 35, 5063. (b) Soloshonok, V. A.; Ono, T. J. Org. Chem.
1997, 62, 3030. (c) Soloshonok, V. A.; Yasumoto, M. J. Fluorine
Chem. 2007, 128, 170. (d) Michaut, V.; Metz, F.; Paris, J.-M.;
Plaquevent, J.-C. J. Fluorine Chem. 2007, 128, 500.
(5) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2567.
(6) For selected reviews on asymmetric synthesis of fluorinat-
ed molecules, see: (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104,
6119. (b) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev.
2011, 111, 455.
(7) For selected examples of catalytic asymmetric hydrogena-
tion of trifluoromethyl imines or enamides, see: (a) Abe, H.;
Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313. (b) Chen, M.-W.;
Duan, Y.; Chen, Q.-A.; Wang, D.-S.; Yu, C.-B.; Zhou, Y.-G. Org.
Lett. 2010, 12, 5075. (c) Jiang, J.; Lu, W.; Zhang, X. Org. Lett. 2015,
17, 1154.
(8) For selected examples of catalytic asymmetric transfer hy-
drogenation with trifluoromethyl imines, see: (a) Henseler, A.;
Kato, M.; Mori, K.; Akiyama, T. Angew. Chem., Int. Ed. 2011, 50,
8180. (b) Genoni, A.; Benaglia, M.; Massolo, E.; Rossi, S. Chem.
Commun. 2013, 49, 8365. (c) Dai, X. Y.; Cahard, D. Adv. Synth.
Catal. 2014, 356, 1317.
(9) For selected examples of catalytic asymmetric nucleophilic
addition to trifluomethyl aldimines or aldimines, see: (a) Fu-
nabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M. Chem. Commun.
2004, 1928. (b) Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.;
Chen, C.-Y.; Volante, R. P. Org. Lett. 2005, 7, 355. (c) Kawai, H.;
Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N. Angew. Chem.,
Int. Ed. 2009, 48, 6324.
(10) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445.
(11) For examples of phase transfer catalyzed protonation reac-
tions, see: (a) Yamamoto, E.; Nagai, A.; Hamasaki, A.; Tokunaga,
M. Chem. Eur. J. 2011, 17, 7178. (b) Yamamoto, E.; Gokuden, D.;
Nagai, A.; Kamachi, T.; Yoshizawa, K.; Hamasaki, A.; Ishida, T.;
Tokunaga, M. Org. Lett. 2012, 14, 6178. (c) Claraz, A.; Landelle,
G.; Oudeyer, S.; Levacher, V. Eur. J. Org. Chem. 2013, 7693.
(12) For examples of phase transfer catalyzed proton transfer
reactions, see: (a) Oku, M.; Arai, S.; Katayama, K.; Shioiri, T.
Synlett 2000, 493; (b) Shirakawa, S.; Tokuda, T.; Kan, S. B. J.;
Maruoka, K. Org. Chem. Front. 2015, 2, 336. (c) Roy, A.; Bhat, B.
A.; Lepore, S. D. Org. Lett. 2016, 18, 1230.
(13) HF eliminations were previously reported, see: Perosa, A.;
Selva, M.; Tundo, P. J. Chem. Soc., Perkin Trans. 2, 2002, 1033.
(14) For pioneering studies of chiral ammonium betaines, see:
Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130,
10878.
(15) For chiral BINOL-derived ammonium betaines as base
catalysts, see: (a) Uraguchi, D.; Koshimoto, K.; Sanada, C.; Ooi,
T. Tetrahedron: Asymmetry 2010, 21, 1189. (b) Uraguchi, D.; Ko-
shimoto, K.; Ooi, T. Chem. Commun. 2010, 46, 300. (c) Uraguchi,
4.2 General procedure for the asymmetric isomeri-
zation of alkenyl or aryl trifluomethyl imines 1e to 1n
with catalyst QD-9c. To a solution of catalyst PQD-9c
(3.1 μmol, 3.0 mg) in toluene (180 μL) was added ground-
ed K2CO3 (0.065 mmol, 9.0 mg). The suspension was then
stirred vigorously at room temperature for 2 hours. After
standing for 10 minutes, a portion of the clear solution (90
μL) was collected and diluted with toluene (810 μL). A
portion of this diluted solution of QD-9c in toluene (0.20
μmol to 0.80 μmol, 120 μL to 460 μL) was placed into a
vial (3.7 mL), to which was added sequentially toluene
(680 μL to 340 μL) and grounded K2CO3 (0.020 mmol, 2.8
mg). After the mixture was stirred at the designated tem-
perature in Table 3 for 20 minutes, the solution of imine 1
(0.20 mmol) in toluene (1.2 mL) was added in one portion
(the imine solution was also stirred at the specified tem-
perature for 20 minutes). Then the mixture was allowed
to stir at the specified temperature for 24 hours. The reac-
tion mixture was allowed to pass through a plug of deac-
tivated silica gel to remove the catalyst. The deactivated
silica gel plug was then washed with diethyl ether (2.0-4.0
mL). The filtrate was concentrated in vacuo to give tri-
fluoromethylated amines 2.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures; characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
deng@brandeis.edu
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support from National Institutes
of Health (Grant GM-61591) and the Keck Foundation.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
D.; Oyaizu, K.; Ooi, T. Chem. Eur. J. 2012, 18, 8306. (d) Uraguchi,
1
2
3
D.; Oyaizu, K.; Noguchi H.; Ooi, T. Chem. Asian J. 2015, 10, 334.
(e) Oyaizu, K.; Uraguchia, D.; Ooi, T. Chem. Commun., 2015, 51,
4437.
(16) For chiral BINOL-derived ammonium betaines as nucleo-
philic catalysts, see: (a) Uraguchi, D.; Koshimoto, K.; Miyake, S.;
Ooi, T. Angew. Chem. Int. Ed. 2010, 49, 5567. (b) Uraguchi, D.;
Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2012, 134, 6972.
(17) For studies of 6’-OH cinchona alkaloid-derived ammoni-
um salts, see: (a) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng,
L. Chem. Sci. 2011, 2, 1301. (b) Provencher, B. A.; Bartelson, K. J.;
Liu, Y.; Foxman, B. M.; Deng, L. Angew. Chem. Int. Ed. 2011, 50,
10565.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) For cinchonium BINOL-derived betaines as base catalysts,
see: Zhang, W.-Q.; Cheng, L.-F.; Yu, J.; Gong, L.-Z. Angew.
Chem., Int. Ed. 2012, 51, 4085.
(19) See Supporting Information for details.
(20) For a review on low loading organocatalysis, see: Gia-
calone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc.
Rev. 2012, 41, 2406.
(21) The deactivated silica gel was prepared from treating
normal silica gel with NEt3. See supporting information for de-
tails.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
ACS Paragon Plus Environment