Chiral phosphoric acid catalyzed oxidative kinetic resolution of cyclic secondary amine derivatives including tetrahydroquinolines by hydrogen transfer to imines

Article abstract of DOI:10.1039/c5cc06436h

A chiral Bronsted acid catalyzed dehydrogenative kinetic resolution of tetrahydroquinoline derivatives, which are representative of cyclic secondary amines, based on their hydrogen transfer to aromatic imines was efficiently achieved with high enantioselectivities. This hydrogen transfer of tetrahydroquinolines to imines was not driven by their aromatization to quinolines. This dehydrogenative kinetic resolution could be also applied to the asymmetric synthesis of various benzofused heterocycles containing secondary amine cores.

Full text of DOI:10.1039/c5cc06436h

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ARTICLE
Chiral Phosphoric Acid Catalyzed Oxidative Kinetic Resolution of
Cyclic Secondary Amine Derivatives including
Tetrahydroquinolines by Hydrogen Transfer to Imines
Received 00th January 20xx,
Accepted 00th January 20xx
Kodai Saito,a Hiromitsu Miyashitaa and Takahiko Akiyama*a
DOI: 10.1039/x0xx00000x
A chiral Brønsted acid catalyzed dehydrogenative kinetic resolution of tetrahydroquinoline derivatives, which are
representative cyclic secondary amines, based on their hydrogen transfer to aromatic imines was efficiently achieved with
high enantioselectivities. This hydrogen transfer of tetrahydroquinolines to imines was not driven by their aromatization to
quinolines. This dehydrogenative kinetic resolution could be also applied to the asymmetric synthesis of various
www.rsc.org/
benzofused
heterocycles
containing
secondary
amine
cores.
Enantiomerically pure amines are key components of scope.
pharmaceuticals and agrochemicals.1 Thus, the development
Previous Work Dehydrogenative kinetic resolution of indoline
of new strategies for the enantioselective construction of
carbon-nitrogen skeletons has captured the attention of
synthetic organic chemists.2 The kinetic resolution of racemic
starting materials using either chemical reagents or
biotechnological approaches is one of the most important
methods to afford chiral compounds.3
cat. CPA
NAr'
H
N
H
N
H
N
NHAr'
Ar
R
R
R
Ar
indolines
(racemic)
indolines
(chiral)
indoles
(aromatic compounds)
This work
cat. CPA
NAr'
The 2-substituted tetrahydroquinoline structure is often
H
N
H
N
R'
n
R'
n
found in
a
variety of natural and biologically active
N
X
R'
n
NHAr'
Ar
compounds. Many research groups have recently reported the
asymmetric synthesis of tetrahydroquinoline derivatives based
on the enantioselective hydrogenation using transition-metal
catalysts with high-pressure molecular hydrogen6 or the
organocatalyzed transfer hydrogenation using Hantzsch ester.7
Nevertheless, there are few reports of the catalytic synthesis
of tetrahydroquinolines in a highly enantioselective manner
based on kinetic resolution.8 As an initial work, Krasnov et al.
reported the kinetic resolution of 2-methyltetrahydroquinoline
based on an acylation reaction using a chiral acylating
reagent,8a in which use of more than half amount of the chiral
reagent was required. More recently, although the Toste
group has elegantly developed a chiral phosphoric acid
catalyzed synthesis of 2-substituted tetrahydroquinoline
derivatives by the dehydrogenative deracemization of racemic
tetrahydroquinolines, the use of excess amounts oxidant and
hydrogen donor was needed, and this method was limited to
2-aryl-substituted tetrahydroquinolines.8c Clearly, there is a
great demand for the development of a catalytic kinetic
resolution of tetrahydroquinolines having a wide substrate
Ar
X
X
tetrahydroquinolines
(racemic)
tetrahydroquinolines
non-aromatic compounds
H
H
N
O
R'
N
R'
O
O
P
tetrahydroquinoline dihydrobenzoxazine
O
OH
H
N
H
R'
R'
N
S
Chiral phosphoric acid
dihydrobenzothiazine
tetrahydroazepine
(CPA, 1)
Figure 1 Concept of this work and target compounds for this
OKR
We have recently developed a chiral phosphoric acid9
catalyzed oxidative kinetic resolution of 2-substituted indoline
derivatives based on the hydrogen transfer to imines,10
wherein one hydrogen molecule was transferred to imine to
afford amine accompanied by the formation of indole. This
hydrogen transfer would be strongly driven by the
aromatization of indoline to indole. In contrast, the
dehydrogenation
of
one
hydrogen
molecule
of
tetrahydroquinolines gives dihydroquinolines, which are not
aromatic compounds. The dehydrogenation reaction of
tetrahydroquinolines is thus expected to be more difficult in
terms of thermodynamic stability. We hypothesized that the
amine in the products has lower hydrogen donating ability to
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Journal Name
(R)-1 (10 mol%)
3c (1 equiv)
cyclic ketimine and the equilibrium would be biased to the
products. To achieve the dehydrogenative kinetic resolution,
we should be able to access various chiral heterocycles that
show promising functions in medicinal chemistry. We wish to
report herein the chiral phosphoric acid catalyzed asymmetric
hydrogen transfer reaction of tetrahydroquinolines and cyclic
amines employing imines as hydrogen acceptors, which would
be a good example of an efficient OKR of secondary amine.
H
H
N
Ar
N
Ar
R'
R'
5Å MS, toluene
110 oC
rac-2
ent-2
H
N
H
H
n-C4H9
N
c-C6H11
N
n-C5H11
2b
2c
2a
50%, 98% ee
(s = 458)
47%, 61% ee
(s = 6)
46%, 98% ee
(s = 50)
Table 1 Examination of reaction conditions
O
H
N
O
2d
53%, 97% ee
O
(R)-1 (10 mol%)
H
N
H
N
O
O
P
nBu
imine 3
nBu
H
H
OH
H
N
PMP
N
p-Tol
N
Ph
5Å MS, toluene
temperature, 3 d
rac-2a
(R)-2a
2g
2e
2f
55%, 96% ee
52%, 99% ee
50%, 81% ee
(s = 24)
(R)-1
Entry
Imine
(1 equiv)
T/oC
Yielda/%
53
Eeb/% ee
Cl
Ph
H
N
H
N
NPMP
1
2
50
24
Ph
2h
2i
3a
NPMP
56%, 95% ee
44%, 89% ee
50
85
24
(s = 16)
H
H
N
Ph
H
N
N
MMP
OMP
3b
3b
3
4
110
110
57
46
77
98
NTMP
2j
2k
2l
53%, 98% ee
52%, 77% ee
(s = 26)
50%, 97% ee
(s = 278)
Ph
3c
H
N
H
N
a Isolated yields. b Enantiomer ratios were determined by HPLC
analysis on a chiral stationary phase. PMP = p-methoxyphenyl,
TMP = 3,4,5-trimethoxyphenyl.
Ph
p-Tol
2m
2n
46%, 97% ee
(s = 43)
49%, >99% ee
(s = 211)
As an initial examination, we treated racemic 2-
butyltetrahydroquinoline 2a with 1.0 equiv of N-PMP aldimine
3a in the presence of a catalytic amount of phosphoric acid
(R)-111 and molecular sieves 5Å (5Å MS) at 50 oC (Table 1, entry
1). Transfer hydrogenation from 2a to 3a proceeded to furnish
(R)-2a in 53% yield with 24% ee. Use of ketimine 3b improved
the selectivity with lower conversion (entry 2). Raising the
reaction temperature resulted in high conversion and good ee
(entry 3). Use of ketimine 3c bearing a 3,4,5-trimethoxyphenyl
group on nitrogen further improved ee of 2a to 98%, and
amine 4c was obtained in 63% yield with 93% ee.12
N
n-C5H11
(R)-Angustureine
(R)-2b
(98% ee)
K2CO3 (4 equiv)
MeI (2.5 equiv)
2ba
82%, 98% ee
O
O
THF, 65 oC, 22 h
(R)-2d
N
(97% ee)
(R)-Galipinine
2da
86%, 98% ee
a Isolated yields. b Enantiomer ratios were determined by HPLC
analysis on a chiral stationary phase. Tol = tolyl, PMP = p-
Scheme
2 Substrate scope of CPA-catalyzed OKR of
methoxyphenyl, MMP
methoxyphenyl.
= m-methoxyphenyl, OMP = o-
tetrahydroquinolines and derivatizationa,b
Next, we explored the scope of the CPA-catalyzed oxidative
kinetic resolution of a range of tetrahydroquinoline derivatives
under the optimum reaction conditions (Scheme 2). Although
tetrahydroquinolines bearing pentyl (2b) or arylethyl (2d
)
group proved to be suitable substrates, the substitution of
cyclohexyl group at 2-position gave inferior results. For
substrates having various aryl groups at 2-position, phenyl
group (2e) and electron-donating (2f and 2g) or –withdrawing
2 | J. Name., 2012, 00, 1-3
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2h and 2i) substitution at p-position of the aromatic ring at 2-
ARTICLE
was slow, (R)-isomer rapidly underwent transfer
hydrogenation with ketimine to furnish 8j and 9j. Subsequet
reduction of 8j proceeded highly enantioselective manner to
give (S)-2j as a single enantiomer. Interestingly, extremely low
conversion was observed when we examined kinetic
resolution of acyclic secondary amine 7, which clearly shows
that the cyclic structure of secondary amine is also important
for this hydrogen transfer reaction to ketimines.
(
position had marginal effects, and high enantioselectivities
were obtained with efficient conversions. The m- , o-, and 3,5-
substitutions of the aromatic ring were also effective for
enantiocontrol
(2j-2l). In addition, we examined
tetrahydroquinoline substrates having a substituent on their
aromatic rings. Substrates 2m and 2n having a methyl group at
6-position were also suitable for this OKR, and excellent
enantiomeric excesses were realized with good conversion.
Products (R)-2b and (R)-2d were efficiently transformed into
methylated natural products, (R)-angustureine ((R)-2ba) and
(R)-galipinine ((R)-2da) without loss of optical purity.
Scheme 4 Probing the reaction mechanism
(R)-1 (0.01 mmol)
H
N
MMP
NHTMP
3c (0.1 mmol)
(S)-2j
(1)
(2)
5Å MS, toluene
110 oC, 3 d
Ph
70%, >99% ee
(0.035 mmol)
(R)-4c
(S)-2j
(0.05 mmol)
As an extension of this work, we investigated OKR of other
cyclic secondary amines (Scheme 3). When the reaction was
performed under the same optimum conditions using 2-
phenyldihydrooxazine13 5a, the product was isolated in 53%
yield with 84% ee. 5b bearing a para-methoxy group at 2-
position and dihydrothiazine13 5c also participated in this OKR.
Next, tetrahydrodiazepine 5d, which has a seven-membered
cyclic secondary amine structure, could be used for this OKR
albeit with lower conversion. It should be noted that the
present OKR is the few example of the catalytic synthesis of
chiral tetrahydroazepines.14
23%, 74% ee
(R)-1 (0.01 mmol)
3c (0.1 mmol)
H
NHTMP
N
MMP
(S)-2j
5Å MS, toluene
110 oC, 3 d
Ph
26%, >99% ee
(0.013 mmol)
(R)-4c
(R)-2j
49%, 90% ee
(0.05 mmol)
N
Ph
(R)-4c (1.0 equiv)
or
(S)-4c (1.0 equiv)
(R)-1 (10 mol%)
(3)
(4)
No reaction
5Å MS, toluene
110 oC, 7 d
O
6
(R)-1 (10 mol%)
3c (1.0 equiv)
H
N
Ph
No reaction
Scheme 3 Substrate scope of CPA-catalyzed OKR of cyclic
5Å MS, toluene
110 oC, 7 d
secondary amines
(R)-1 (10 mol%)
3c (1.0 equiv)
7
Reaction mechanism for inversion of stereochemistry of (R)-2j
ent-5
rac-5
(R)-1
3c
H
N
5Å MS, toluene
110 oC
NHTMP
MMP
N
MMP
Ph
(R)-2j
reactive
8j
H
H
H
N
PMP
N
R
N
PMP
H
hydrogen transfer
MMP
N
MMP
N
O
S
5c
5a (R = Ph)
53%, 84% ee
(s = 98)
(S)-2j
9j
5d
48%, 73% ee
(s = 11)
less reactive
55%, 62% ee
(s = 13)
10j
5b (R = PMP)
40%, 72% ee
(s = 5.9)
In conclusion, we have developed highly efficient OKR of a
series of 2-substituted cyclic secondary amine derivatives,
involving asymmetric transfer hydrogenation in high yields
with high to excellent enantioselectivities. This method
features an efficient dehydrogenative kinetic resolution
catalyzed by chiral phosphoric acid based on asymmetric
hydrogen transfer to ketimine derivative.
a Isolated yields. b Enantiomer ratios were determined by HPLC
analysis on a chiral stationary phase. PMP = p-methoxyphenyl.
To gain further insight of the reaction mechanism of this
OKR process, we compared the reactivity of both enantiomers
of tetrahydroquinoline 2j by means of (R)-
difference of the hydrogen donating ability was observed
between the enantiomers of 2j Whereas (S)-2j underwent
1. Remarkable
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced
Transformation by Organocatalysis” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
.
hydrogen transfer slowly to give 4c in 23% with 74% ee,15
accompanied by the recovery of (S)-2j in 70% (Scheme 4, Eq 1),
(R)-2j reacted smoothly with 3c to give (S)-2j and (R)-4c in 26%,
>99% ee, and 49%, 90% ee, respectively (Eq 2). Quite
interestingly, inversion of the stereochemistry of 2j was
observed, which could be explained by considering that
dihydroquinoline 8j was hydrogenated by the isomerized 9j to
give (S)-2j, resulting in the inversion of the stereochemistry of
Notes and references
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2
3
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2j 16
(Eq 3).17 Neither of the enantiomers of 4c furnished the
reduction product of , which clearly indicated that the
.
Next, we examined the reverse reaction of ent-4c with 6
6
hydrogen transfer reaction would not exist between the
dihydroquinoline and 4c in this kinetic resolution. These results
suggest that although transfer hydrogenation of (S)-isomer
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ARTICLE
Palovics, V. Kiss, Org. Biomol. Chem., 2006,
Journal Name
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6
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synthesis
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7
2007,
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5
, 3407-3417; (d) S. G. Ouellet, A. M. Walji, D. W. C. 15 The low enantioselective transfer hydrogenation of imine 3c
by the less reactive enantiomer of hydrogen donor was also
observed in our previous work (ref. 10).
16 The similar phenomenon was observed in the asymmetric
transfer hydrogenation of dihydroquinoxalines, see: Q.-A.
Chen, D.-S. Wang, Y.-G. Zhou, Y. Duan, H.-J. Fan, Z. Zhang, J.
Am. Chem. Soc., 2011, 133, 6126-6129.
3
,
Theissmann, Angew. Chem., Int. Ed., 2006, 45, 3683-3686; 17 Examination of the reverse reaction using dihydroquinoline
8
(h) M. Rueping, E. Sugiono, F. R. Schoepke, Synlett, 2010,
852-865; (i) R.-N. Guo, Z.-P. Chen, X.-F. Cai, Y.-G. Zhou,
Synthesis, 2014, 46, 2751-2756; (j) X.-F. Cai, R.-N. Guo, G.-S.
was difficult because 8 readily aromatizes to quinoline 10.
4 | J. Name., 2012, 00, 1-3
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