Remarkable Differences in Reactivity between Benzothiazoline and Hantzsch Ester as a Hydrogen Donor in Chiral Phosphoric Acid Catalyzed Asymmetric Reductive Amination of Ketones

Article abstract of DOI:10.1002/asia.201501020

Described herein are differences in behavior between a Hantzsch ester and a benzothiazoline as hydrogen donors in the chiral phosphoric acid catalyzed asymmetric reductive amination of ketones with p-anisidine. The asymmetric reductive amination of ketone

Full text of DOI:10.1002/asia.201501020

DOI: 10.1002/asia.201501020
Full Paper
Reductive Amination
Remarkable Differences in Reactivity between Benzothiazoline
and Hantzsch Ester as a Hydrogen Donor in Chiral Phosphoric
Acid Catalyzed Asymmetric Reductive Amination of Ketones
Kyung-Hee Kim,[a] Takahiko Akiyama,*[b] and Cheol-Hong Cheon*[a]
Abstract: Described herein are differences in behavior be-
tween a Hantzsch ester and a benzothiazoline as hydrogen
donors in the chiral phosphoric acid catalyzed asymmetric
reductive amination of ketones with p-anisidine. The asym-
metric reductive amination of ketones with a Hantzsch ester
as a hydrogen donor provided the corresponding chiral
amines exclusively, regardless of the structures of the ke-
tones, whereas a similar transformation with a benzothiazo-
line provided chiral amines and p-methoxyphenyl-protected
primary amines in variable yields, depending on the struc-
tures of both the ketones and benzothiazolines. Because
a benzothiazoline has an N,S-acetal moiety that is vulnerable
to p-anisidine, the primary amine can be formed through
transimination of the benzothiazoline with p-anisidine fol-
lowed by reduction of the resulting aldimine with remaining
benzothiazoline.
Introduction
of ketimines, the development of a new type of hydrogen
donors with high efficacies has been in demand in the chiral
phosphoric acid catalyzed asymmetric reduction of ketimines.
Based on this demand, the group of Akiyama first intro-
duced benzothiazoline 2 (Figure 1) as a new type of hydrogen
donor in the chiral phosphoric acid catalyzed asymmetric re-
duction of ketimines and demonstrated that benzothiazoline 2
was as effective as Hantzsch ester 1 in these transforma-
tions.[6–8] Since then, several excellent protocols for the chiral
phosphoric acid catalyzed asymmetric reduction of ketimines
with benzothiazoline 2 as a hydrogen donor have been devel-
oped.[9–11]
Ever since seminal reports by the groups of Akiyama and
Terada,[1] chiral phosphoric acid catalysis has become one of
the most rapidly growing fields in asymmetric catalysis, and
a number of synthetic protocols have been developed through
the addition of nucleophiles to imines activated by a chiral
phosphoric acid.[2] Among the various reactions developed
with chiral phosphoric acid catalysts, the enantioselective re-
duction of ketimines with Hantzsch ester 1 (Figure 1) as a hy-
drogen donor has been extensively studied, and become one
of the most popular reactions in chiral phosphoric acid cataly-
sis.[3–5] However, because the choice of hydrogen donor has
a strong influence on the outcomes of asymmetric reductions
Most previous examples of chiral phosphoric acid catalyzed
transfer hydrogenation reactions have been developed by
using pregenerated ketimines I, derived from ketones and p-
anisidine (3), in the presence of a hydrogen donor.[5] In these
examples, benzothiazoline 2 displays a similar efficiency to
that of Hantzsch ester 1, and even acts as a better hydrogen
donor than 1 in some cases (Scheme 1a).[12] However, there
has been no direct comparison of the reactivity of 1 and 2 in
the chiral phosphoric acid catalyzed reductive amination of ke-
tones, although a few examples of asymmetric reductive ami-
nation of ketones in the presence of a chiral phosphoric acid
have been reported.[3c,11]
Figure 1. Structures of hydrogen donors used in chiral phosphoric acid cata-
lyzed asymmetric reduction.
Herein, we present the difference in reactivity between
1 and 2 as hydrogen donors in the chiral phosphoric acid cata-
lyzed reductive amination of ketones II with 3 (Scheme 1b).
Enantioselective reductive amination of ketones II with 1 as
a hydrogen donor provided the corresponding chiral amines A
exclusively, regardless of the structures of ketones II, whereas
the same transformation with 2 provided PMP-protected pri-
mary amines B and chiral amines A in variable ratios, depend-
ing on the structures of ketones II. In contrast to Hantzsch
[a] K.-H. Kim, Prof. Dr. C.-H. Cheon
Department of Chemistry, Korea University
145 Anam-ro, Seongbuk-gu, Seoul 02841 (Republic of Korea)
E-mail: cheon@korea.ac.kr
[b] Prof. Dr. T. Akiyama
Department of Chemistry, Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
E-mail: takahiko.akiyama@gakushuin.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201501020.
Chem. Asian J. 2016, 11, 274 – 279
274
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
a few examples of asymmetric reductive amination of ketones
with benzothiazoline as a hydrogen donor,[11] benzothiazoline
2a was explored as an alternative hydrogen donor for 1 in this
transformation (Scheme 2b). When the same transformation
was carried out with benzothiazoline 2a instead of 1, rather
surprisingly, the expected b-aryl amine 5 was not observed at
all, although benzothiazoline 2a was completely consumed
and the formation of the corresponding benzothiazole was ob-
served in the reaction mixture. Instead, PMP-protected (1-
naphthyl)methylamine 6a was obtained as the major product,
along with byproduct benzothiazoline 7 from 4 in the reaction
mixture.
Although there have been a few reports on the chiral phos-
phoric acid catalyzed enantioselective reductive amination of
ketones with benzothiazoline 2,[11] this type of transformation
has rarely been reported.[14] Thus, we further investigated other
reaction parameters for the formation of the PMP-protected
primary amine 6a (Table 1). First, the effect of the amount of
Scheme 1. Comparison of the reactivity of Hantzsch ester 1 and benzothia-
zoline 2 as a hydrogen donor in a) chiral phosphoric acid catalyzed enantio-
selective reduction of ketimines and b) reductive amination of ketones.
PMP=para-methoxyphenyl.
Table 1. Investigation into the reaction parameters for the reductive ami-
nation of ketone 3.
ester 1, benzothiazoline 2 has an N,S-acetal moiety that is vul-
nerable toward 3, and thus, compound 3 would react with
either ketones II or benzothiazoline 2, leading to the corre-
sponding ketimines or the PMP-protected primary aldimines.
Subsequent reduction of the resulting ketimines or PMP aldi-
mines with the remaining benzothiazoline afforded either
chiral amines A or PMP-protected primary amines B.
Entry
Benzothiazoline (2)
T
Yield [%][a]
[8C]
5
6
7
1[b]
2
3[c]
4[d]
5[e]
6
7
8
9
10
11
12
13
14
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
100
100
100
100
100
100
100
100
100
40
0
0
0
0
0
0
0
0
0
0
0
0
0
0
70
82
67
84
36
62
48
–
Results and Discussion
[f]
–
62
48
61
58
51
46
62
58
56
42
Recently, we developed a protocol for the synthesis of chiral b-
aryl amines through the chiral phosphoric acid catalyzed asym-
metric reductive amination of benzyl methyl ketone derivatives
with 3 and 1 as a hydrogen donor (Scheme 2a).[13] Because
benzothiazoline 2 was a better hydrogen donor than 1 in sev-
eral previous reports on the chiral phosphoric acid catalyzed
asymmetric reduction of ketimines,[10] and there have been
77
86
86
72
86
82
78
88
78
40
40
40
40
[a] Yield of product isolated. [b] 1.5 equivalents of 2a was used. [c] In the
absence of 4 A MS. [d] In the absence of 4. [e] In the absence of PA.
[f] The corresponding PMP–aldimine was obtained as the major product.
2a on this transformation was explored (Table 1, entries 1 and
2). The amount of 2a did not have any beneficial influence on
the formation of chiral b-aryl amine 5. No b-aryl amine 5 was
formed, even with two equivalents of 2a; instead, the yields of
6a and benzothiazoline 7 slightly increased under these condi-
tions. Next, the effect of water on this transformation was ex-
amined. The presence of water had a slight effect on this trans-
formation; b-aryl amine 5 was not formed, regardless of the
presence of water, and PMP-protected primary amine 6a was
obtained in slightly lower yield (Table 1, entries 2 and 3). When
the reaction was performed in the absence of ketone 4, benzo-
thiazoline 2a completely disappeared and primary amine 6a
Scheme 2. Difference in reactivity of Hantzsch ester 1 and benzothiazoline 2
in the enantioselective reductive amination of benzyl methyl ketone (4) with
3. 4 A MS=4 Š molecular sieves.
Chem. Asian J. 2016, 11, 274 – 279
www.chemasianj.org
275
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
was obtained with a similar level of efficiency under reductive
amination conditions (Table 1, entries 2 and 4). Surprisingly, the
transimination of benzothiazoline 2a with 3 occurred even in
the absence of chiral phosphoric acid PA (Table 1, entry 5).
When this transformation was performed in the absence of PA,
transimination of benzothiazoline 2a with 3 took place to
afford the corresponding PMP–aldimine. However, primary
amine 6a was not observed in the reaction mixture because
reduction of the resulting aldimine with remaining 2a did not
occur without PA.
Because a bulky 1-naphthyl substituent at the 2-position of
benzothiazoline 2a might play some role in this transforma-
tion, we further investigated other benzothiazolines 2 with dif-
ferent aryl substituents at the 2-position as hydrogen donors
in this transformation (Table 1, entries 2, 6–9). None of benzo-
thiazolines 2 tested provided the expected chiral amine 5; pri-
mary amines 6 were obtained along with benzothiazoline 7.
With these results in hand, we suspected that the relatively
harsh reaction conditions (1008C) might be responsible for the
expected formation of primary amines 6 in the transformation
with benzothiazoline 2. Thus, we attempted to carry out the
same transformation under mild reaction conditions. When 4
and 3 were subjected to the reductive amination reaction with
2 at 408C, no formation of 5 was observed and primary
amines 6 were still obtained as the major products (Table 1,
entries 10–14).
tected primary amine 6. In addition, the condensation of re-
sulting 8 with remaining 4 could lead to the formation of ben-
zothiazoline 7.[15]
Although these two pathways might be competing, the
transimination of 2 with 3 (pathway b in Scheme 3) would be
significantly faster than imine formation with 4 (pathway a).
Under such circumstances, primary amines 6 would be expect-
ed to be predominantly formed without any formation of
chiral b-aryl amine 5.
With this rather unexpected result with 4, we further investi-
gated whether such differences in reactivity between 1 and 2
would exist in the reductive amination of other types of ke-
tones, such as aryl methyl ketones (Table 2). Enantioselective
Table 2. The effect of hydrogen donors on the reductive amination of
ketone 9.
Entry
2
Yield of
6
Yield of
10[a] [%]
ee of
10[b] [%]
[a] [%]
1[c]
2
3
4
5
6
–
–
81
12
14
64
43
46
80
94
92
86
93
87
2a
2b
2c
2d
2e
78
72
28
54
48
With these unexpected results in hand, we attempted to ra-
tionalize these results under conditions for the chiral phospho-
ric acid catalyzed reductive amination of 4 with 3 by using
benzothiazolines 2 as hydrogen donors: there was no forma-
tion of 5, but only compounds 6 and 7 were detected
[a] Yield of product isolated. [b] Enantiomeric excess (ee) was determined
by chiral HPLC analysis. [c] Hantzsch ester 1 was used instead.
reductive amination of acetophenone (9) with 1 provided de-
sired chiral amine 10 in good yield and enantioselectivity
(Table 2, entry 1).[3c] When benzothiazolines 2 were used as hy-
drogen donors instead of 1, PMP-protected primary amines 6
and chiral a-aryl amine 10 were obtained in variable yields. A
substituent at the 2-position of 2 had an influence on the
yields of the resulting chiral amine 10 in the reductive amina-
tion of 9, although the enantioselectivity of the resulting chiral
amine 10 showed relatively little dependence on the structure
of the aryl substituent (Table 2, entries 2–6). Benzothiazolines
2a and 2b, containing bulky naphthyl substituents, were more
likely to undergo transamination with 3, leading to primary
amines 6 in good yields, along with chiral amine 10 in low
yields (Table 2, entries 2 and 3). However, benzothiazolines, de-
rived from benzaldehyde derivatives, provided chiral amines
10 in much better yield, regardless of the electronic natures of
substituents (Table 2, entries 4–6). In contrast to reactions with
4, compound 8, which was generated by the transimination of
benzothiazolines 2 with 3, did not react with 9 and remained
unreacted in the reaction mixture.
Scheme 3. Plausible reaction pathways for the formation of compounds 6
and 7.
(Scheme 3). Compound 3 could undergo two competing path-
ways. One would be the formation of ketimine I from 4 and
subsequent reduction of the resulting ketimine I with benzo-
thiazoline 2 to provide the expected chiral b-aryl amine 5
(pathway a in Scheme 3). On the other hand, compound 3
could react with benzothiazoline 2 to generate aldimine I’ and
o-aminothiophenol (8; pathway b). The subsequent reduction
of the resulting aldimine I’ with remaining 2 provides PMP-pro-
These results strongly suggest that there would be a signifi-
cant difference in the reactivities of 1 and 2 as hydrogen
donors in chiral phosphoric acid catalyzed reductive amination
of ketones with 3. The reductive amination reactions of ke-
Chem. Asian J. 2016, 11, 274 – 279
www.chemasianj.org
276
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tones with 3, by using 1 as a hydrogen donor, provided chiral
amines exclusively, regardless of the structures of ketones,
whereas the reactions with benzothiazolines 2 afforded both
the expected chiral amines and PMP-protected primary amines
in variable yields, depending on the structures of ketones.
This large difference in reactivity between 1 and 2 in the re-
ductive amination of ketones with 3 could be explained based
on the intrinsic reactivity difference between the two hydro-
gen donors toward 3 (Scheme 4). Because 3 has no reactivity
tion predominantly took place to afford PMP aldimines I’ with-
out the concomitant formation of the corresponding ketimine
I. Subsequent reduction of the resulting aldimines I’ with the
remaining benzothiazoline provided only PMP-protected pri-
mary amines 6. On the other hand, the rate of imine formation
of 9 would be comparable to that of transimination (i.e., k1 ꢀ
k2), leading to concomitant formation of the corresponding ke-
timine and the PMP–aldimines. The reduction of the resulting
aldimines and ketimine with remaining benzothiazoline provid-
ed the primary and secondary amines simultaneously.
In addition, in the reductive amination of 9 with benzothia-
zolines 2, the yields of primary amines 6 and chiral secondary
amine 10 showed a dependence on the choice of benzothiazo-
line, particularly the structure of a substituent at the 2-position
(Table 2). This result was presumably obtained because the
substituent at the 2-position in benzothiazoline 2 might have
an influence on the relative rate of transimination with 3.
Conclusion
We described differences in behavior between 1 and 2 as hy-
drogen donors in the chiral phosphoric acid catalyzed reduc-
tive amination of ketones with 3. Hantzsch ester 1 acted as an
efficient hydrogen donor in the reductive animation of ke-
tones, leading to the expected chiral amines, regardless of the
structures of the ketones, whereas 2 provided the expected
chiral amines and unexpected PMP-protected primary amines
in variable ratios, depending on the structures of the ketones.
Unlike 1, compound 2 possesses an N,S-acetal moiety that is
vulnerable to 3, and the transimination of benzothiazoline
with 3 generates the corresponding PMP–aldimine. Subse-
quent reduction of the resulting aldimine with remaining 2
provided the unexpected PMP-protected primary amine.
Although there have been several examples of the enantio-
selective reductive amination of ketones with benzothiazolines
in chiral phosphoric acid catalysis,[11] this study strongly sug-
gests that these previous examples would only be possible
when ketimine formation from ketones with 3 was significantly
faster than the transimination of 2 with 3, leading to the for-
mation of the desired ketimines without any concomitant for-
mation of PMP–aldimines.
Scheme 4. Rationalization of reactivity differences between 1 and 2 in the
chiral phosphoric acid catalyzed enantioselective reductive amination of ke-
tones with 3.
toward 1, compound 3 only undergoes a reaction with the
ketone (4 or 9) to form imine I, and subsequent reduction of
imine I with 1 yields the desired chiral amines (Scheme 4a). On
the other hand, because benzothiazolines 2 have an N,S-acetal
moiety that is vulnerable toward 3, compound 3 could under-
go either imine formation with ketones or transimination with
2, leading to ketimines I or PMP–aldimines I’, respectively. The
subsequent reduction of the resulting aldimines I’ or ketimines
I with the remaining benzothiazoline 2 provided the PMP-pro-
tected primary amines 6 or chiral secondary amines, respec-
tively (Scheme 4b).
Based on this rationalization, we could explain several exper-
imental results observed in Tables 1 and 2. First, in the direct
reductive amination of ketones (4 or 9) with benzothiazolines
2, the structures of the ketones (4 or 9) strongly affected the
outcomes of this transformation; reductive amination of 4 with
benzothiazolines 2 produced PMP-protected primary amines 6
exclusively without concomitant formation of chiral amine 5
(Table 1), whereas the same transformation with 9 provided
the expected chiral amine 10 and PMP-protected primary
amines 6, simultaneously (Table 2).
These results could be explained based on the relative reac-
tion rate of 3 toward ketones (4 or 9) and benzothiazolines 2.
Because the structures of the ketones had an influence on the
rate of imine formation, the ratio of ketimines to aldimines
might be variable, depending on the structures of ketones.
With 4, the imine formation reaction might be much slower
than that of transimination (i.e., k1 !k2), and thus, transimina-
Experimental Section
General
All reactions were carried out in oven-dried glassware under an
argon atmosphere, unless otherwise noted. Except as otherwise in-
dicated, all reactions were magnetically stirred and monitored by
analytical TLC on precoated silica gel glass plates (0.25 mm) with
F254 indicator. Visualization was accomplished by UV light (l=
254 nm), with a combination of potassium permanganate and/or
a solution of phosphomolybdic acid as an indicator. Flash column
chromatography was performed on silica gel 60 (230–400 mesh).
Yields refer to chromatographically and spectrographically pure
compounds, unless otherwise noted. Commercial-grade reagents
and solvents were used without further purification. Benzothiazo-
lines 2 were prepared by following literature protocols from 2-ami-
Chem. Asian J. 2016, 11, 274 – 279
www.chemasianj.org
277
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
nothiophenol and the appropriate aldehyde.[6] 1H and 13C NMR
spectra were recorded on 300/400 and 100 MHz NMR spectrome-
ters, respectively. Tetramethylsilane (TMS) and CDCl3 were used as
internal standards for 1H (d=0.0 ppm) and 13C NMR (d=
77.16 ppm), respectively. Multiplicities are indicated by s (singlet), d
(doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multip-
let), and br (broad). The enantiopurity of the chiral compounds
was determined by HPLC analysis by using chiral columns with
a mixture of 2-propanol and hexanes as the eluent.
4-Methoxy-N-(4-methoxybenzyl)aniline (6d)
The product was obtained as a light-yellow solid (88%, 43 mg).
The spectroscopic data were in good agreement with those report-
ed in the literature.[11c] 1H NMR (300 MHz, CDCl3): d=7.29 (d, J=
8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.61 (d,
J=9.1 Hz, 2H), 4.21 (s, 2H), 3.80 (s, 3H), 3.74 ppm (s, 3H).
4-Methoxy-N-(4-nitrobenzyl)aniline (6e)
The product was obtained as a red oil (78%, 41 mg). The spectro-
scopic data were in good agreement with those reported in the lit-
erature.[11c] 1H NMR (300 MHz, CDCl3): d=8.19 (d, J=8.5 Hz, 2H),
7.54 (d, J=8.5 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.54 (d, J=8.8 Hz,
2H), 4.43 (s, 2H), 3.73 ppm (s, 3H).
General Procedure for the Chiral Phosphoric Acid Catalyzed
Reductive Amination of Ketones (4 or 9) with 3 (Tables 1 and
2)
A test tube equipped with a stirrer bar was charged with a ketone
derivative (either 4 or 9; 0.20 mmol; 1.0 equiv), 3 (0.24 mmol;
1.2 equiv), a hydrogen donor (either Hantzsch ester 1 or benzothia-
zoline 2; 0.40 mmol; 2.0 equiv), chiral phosphoric acid PA
(0.020 mmol; 10 mol%), and 4 A MS (200 mg). Toluene was then
added to this mixture. The reaction mixture was allowed to stir at
408C under an argon atmosphere and monitored by TLC. After
consumption of starting materials, the reaction mixture was cooled
to room temperature and filtered to remove 4 A MS. The filtrate
was further purified by column chromatography on silica gel by
using hexanes/CH2Cl2 (1:1) as the eluent.
2-Benzyl-2-methyl-2,3-dihydrobenzo[d]thiazole (7)
The product was obtained as a yellow oil in variable yield, depend-
ing on the structure of 2. The spectroscopic data were in good
agreement with those reported in the literature.[15] 1H NMR
(300 MHz, CDCl3): d=7.34–7.23 (m, 5H), 7.08 (d, J=7.4 Hz, 1H),
6.96–6.91 (m, 1H), 6.76 (t, J=7.6 Hz, 1H), 6.66 (d, J=7.7 Hz, 1H),
4.05 (br, 1H), 3.32 (d, J=13.2 Hz, 1H), 3.11 (d, J=13.2 Hz, 1H),
1.65 ppm (s, 3H).
4-Methoxy-N-(1-phenylethyl)aniline (10)
4-Methoxy-N-(1-phenylpropan-2-yl)aniline (5)
The product was obtained as a yellow oil. The yield and enantiose-
lectivity were variable, depending on the structures of 2. The spec-
troscopic data were in good agreement with those reported in the
literature.[7] 1H NMR (300 MHz, CDCl3): d=7.38–7.22 (m, 5H), 6.69
(d, J=9.1 Hz, 2H), 6.47 (d, J=8.8 Hz, 2H), 4.41 (q, J=6.6 Hz, 1H),
3.69 (s, 3H), 3.71–3.65 (m, 1H), 1.50 ppm (d, J=6.6 Hz, 3H). The ee
was determined by HPLC with a Chiralcel OD-H column (hexanes/
2-propanol=95:5, flow rate=1.0 mLminÀ1, l=300 nm), tr(major)=
7.7 min., tr(minor)=8.8 min.
The product was obtained as yellow oil (83%, 39 mg, 80% ee). The
spectroscopic data were in good agreement with those reported
in the literature.[13] 1H NMR (300 MHz, CDCl3): d=7.32–7.17 (m, 5H),
6.80 (d, J=9.1 Hz, 2H), 6.60 (d, J=8.8 Hz, 2H), 3.76 (s, 3H), 3.71–
3.65 (m, 1H), 2.93 (dd, J=13.5, 4.7 Hz, 1H), 2.67 (dd, J=13.3,
7.3 Hz, 1H), 1.14 ppm (d, J=6.3 Hz, 3H). The ee was determined by
HPLC with a Chiralcel OJ-H column (hexanes/2-propanol=95:5,
flow
tr(minor)=27.6 min.
rate=1.0 mLminÀ1
,
l=254 nm),
tr(major)=22.7 min.,
Acknowledgements
4-Methoxy-N-(naphthalen-1-ylmethyl)aniline (6a)
This work was supported by the National Research Foundation
of Korea (NRF) grants funded by the Korean Government (NRF-
2013R1A1A1008434 and NRF-20100020209). C.-H.C. also thanks
financial support from an NRF grant funded by the Korean
Government (NRF-2014-011165, Center for New Directions in
Organic Synthesis).
The product was obtained as yellow oil (86%, 45 mg). The spectro-
scopic data were in good agreement with those reported in the lit-
erature.[16] 1H NMR (300 MHz, CDCl3): d=8.10–8.08 (m, 1H), 7.89
(dd, J=6.1, 2.9 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.54–7.51 (m, 3H),
7.50–7.41 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.67 (d, J=9.0 Hz, 2H),
4.70 (s, 2H), 3.76 ppm (s, 3H).
Keywords: benzothiazolines · chiral phosphoric acid catalysis ·
enantioselective reductive amination · Hantzsch ester · organic
hydrogen donor
4-Methoxy-N-(naphthalen-2-ylmethyl)aniline (6b)
The product was obtained as yellow solid in (82%, 43 mg). The
spectroscopic data were in good agreement with those reported
in the literature.[11c] 1H NMR (300 MHz, CDCl3): d=7.84–7.79 (m,
4H), 7.51–7.45 (m, 3H), 6.78 (d, J=8.8 Hz, 2H), 6.65 (d, J=9.1 Hz,
2H), 4.46 (s, 2H), 3.74 ppm (s, 3H).
[1] For seminal reports on chiral phosphoric acid catalyzed asymmetric re-
actions, see: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem.
Int. Ed. 2004, 43, 1566; Angew. Chem. 2004, 116, 1592; b) D. Uraguchi,
M. Terada, J. Am. Chem. Soc. 2004, 126, 5356.
[2] For reviews on chiral phosphoric acid catalysis, see: a) T. Akiyama,
Chem. Rev. 2007, 107, 5744; b) M. Terada, Chem. Commun. 2008, 4097;
c) M. Terada, Synthesis 2010, 1929; d) D. Parmar, E. Sugiono, S. Raja, M.
Rueping, Chem. Rev. 2014, 114, 9047.
[3] For seminal reports on the asymmetric reduction of ketimines with
a Hantzsch ester catalyzed by a chiral phosphoric acid, see: a) M. Ruep-
ing, E. Sugiono, C. Azap, T. Theissmann, M. Bolte, Org. Lett. 2005, 7,
3781; b) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem. Int. Ed. 2005,
N-Benzyl-4-methoxyaniline (6c)
The product was obtained as a dark-yellow oil in (78%, 34 mg).
The spectroscopic data were in good agreement with those report-
ed in the literature.[11c] 1H NMR (300 MHz, CDCl3): d=7.38–7.27 (m,
5H), 6.78 (d, J=8.6 Hz, 2H), 6.61 (d, J=8.6 Hz, 2H), 4.29 (s, 2H),
3.74 ppm (s, 3H).
Chem. Asian J. 2016, 11, 274 – 279
www.chemasianj.org
278
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
44, 7424; Angew. Chem. 2005, 117, 7590; c) R. I. Storer, D. E. Carrera, Y.
Ni, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 84.
[9] For reviews on benzothiazoline as a versatile hydrogen donor for orga-
nocatalytic reductive amination, see: a) C. Zhu, J. R. Falck, ChemCatCh-
em 2011, 3, 1850; b) C. Zhu, K. Saito, M. Yamanaka, T. Akiyama, Acc.
Chem. Res. 2015, 48, 388.
[4] For reviews on enantioselective reductions with Hantzsch ester deriva-
tives as hydrogen donors, see: a) S. G. Ouellet, A. M. Walji, D. W. C. Mac-
Millan, Acc. Chem. Res. 2007, 40, 1327; b) S. J. Connon, Org. Biomol.
Chem. 2007, 5, 3407; c) S.-L. You, Chem. Asian J. 2007, 2, 820; d) M.
Rueping, J. Dufour, F. R. Schoepke, Green Chem. 2011, 13, 1084; e) C.
Zheng, S.-L. You, Chem. Soc. Rev. 2012, 41, 2498.
[5] For selected recent examples, see: a) T. B. Nguyen, H. Bousserouel, Q.
Wang, F. Gueritte, Org. Lett. 2010, 12, 4705; b) V. N. Wakchaure, J. Zhou,
S. Hoffmann, B. List, Angew. Chem. Int. Ed. 2010, 49, 4612; Angew. Chem.
2010, 122, 4716; c) M. Rueping, C. Brinkmann, A. P. Antonchick, I. Atodir-
esei, Org. Lett. 2010, 12, 4604; d) Q.-A. Chen, M.-W. Chen, C.-B. Yu, L. Shi,
D.-S. Wang, Y. Yang, Y.-G. Zhou, J. Am. Chem. Soc. 2011, 133, 16432;
e) M.-W. Chen, Q.-A. Chen, Y. Duan, Z.-S. Ye, Y.-G. Zhou, Chem. Commun.
2012, 48, 1698; f) Q. Yin, S.-G. Wang, S.-L. You, Org. Lett. 2013, 15, 2688;
g) K. Saito, Y. Kajiwara, T. Akiyama, Angew. Chem. Int. Ed. 2013, 52,
13284; Angew. Chem. 2013, 125, 13526; h) Z.-P. Chen, M.-W. Chen, R.-N.
Guo, Y.-G. Zhou, Org. Lett. 2014, 16, 1406; i) X.-F. Cai, R.-N. Guo, G.-S.
Feng, B. Wu, Y.-G. Zhou, Org. Lett. 2014, 16, 2680; j) M. Terada, F. Li, Y.
Toda, Angew. Chem. Int. Ed. 2014, 53, 235.
[10] For examples of the use of benzothiazolines as hydrogen donors in the
chiral phosphoric acid catalyzed asymmetric reduction of ketimines,
see: a) C. Zhu, T. Akiyama, Adv. Synth. Catal. 2010, 352, 1846; b) A. Hens-
eler, M. Kato, K. Mori, T. Akiyama, Angew. Chem. Int. Ed. 2011, 50, 8180;
Angew. Chem. 2011, 123, 8330; c) T. Sakamoto, K. Mori, T. Akiyama, Org.
Lett. 2012, 14, 3312; d) T. Sakamoto, K. Horiguchi, K. Saito, K. Mori, T.
Akiyama, Asian J. Org. Chem. 2013, 2, 943; e) J.-Q. Zhou, W.-J. Sheng, J.-
H. Jia, Q. Ye, J.-R. Gao, Y.-X. Jia, Tetrahedron Lett. 2013, 54, 3082; f) K.
Saito, K. Horiguchi, Y. Shibata, M. Yamanaka, T. Akiyama, Chem. Eur. J.
2014, 20, 7616.
[11] For examples on the use of benzothiazolines as hydrogen donors in the
chiral phosphoric acid catalyzed direct asymmetric reductive amination
of ketones, see: a) D. Enders, J. X. Liebich, G. Raabe, Chem. Eur. J. 2010,
16, 9763; b) K. Saito, T. Akiyama, Chem. Commun. 2012, 48, 4573; c) For
reductive amination of aldehydes: C. Zhu, T. Akiyama, Synlett 2011,
1251; d) W. Wen, Y. Zeng, L.-Y. Peng, L.-N. Fu, Q.-X. Guo, Org. Lett. 2015,
17, 3922.
[6] For seminal examples of the application of benzothiazolines as non-bio-
mimetic organic hydrogen donors, see: a) H. Chikashita, M. Miyazaki, K.
Itoh, Synthesis 1984, 308; b) H. Chikashita, M. Miyazaki, K. Itoh, J. Chem.
Soc. Perkin Trans. 1 1987, 699.
[7] For a seminal report on the use of benzothiazolines in the chiral phos-
phoric acid catalyzed asymmetric reduction of ketimines, see: a) C. Zhu,
T. Akiyama, Org. Lett. 2009, 11, 4180.
[8] The group of Akiyama successfully demonstrated that other benzo-
fused nitrogen-containing heterocycles could also be employed as hy-
drogen donors in chiral phosphoric acid catalyzed transfer hydrogena-
tion reactions; for indolines as hydrogen donors, see: a) K. Saito, Y. Shi-
bata, M. Yamanaka, T. Akiyama, J. Am. Chem. Soc. 2013, 135, 11740; b) K.
Saito, H. Miyashita, T. Akiyama, Org. Lett. 2014, 16, 5312; for tetrahydro-
quinolines as hydrogen donors, see: c) K. Saito, H. Miyashita, T. Akiyama,
Chem. Commun. DOI: 10.1039/C5CC06436H.
[12] For a comparison of the reactivity between a Hantzsch ester and ben-
zothiazolines in the asymmetric reduction of ketimines, see ref. [10].
[13] K.-H. Kim, C.-Y. Lee, C.-H. Cheon, J. Org. Chem. 2015, 80, 6367.
[14] There is one report on the formation of a similar side product in the
chiral phosphoric acid catalyzed asymmetric reduction of ketimines
with benzothiazolines; see ref. [10c].
[15] G. Li, L. Wu, G. Lv, H. Liu, Q. Fu, X. Zhang, Z. Tang, Chem. Commun.
2014, 50, 6246.
[16] P. N. Banedar, Pharma Chem. 2011, 3, 105.
Manuscript received: September 22, 2015
Accepted Article published: October 20, 2015
Final Article published: November 16, 2015
Chem. Asian J. 2016, 11, 274 – 279
www.chemasianj.org
279
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim