Asymmetric Synthesis of α-Amino Ketones by Bronsted Acid Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b01972

The highly efficient, regioselective, and enantioselective transfer hydrogenation of α-keto ketimines and reductive amination of diketones by Bronsted acid catalysis is described. A series of chiral α-amino ketones is prepared in high yields (up to >99%), excellent regioselectivities (up to >99:1), and enantioselectivities (up to 98% ee). This method has broad substrate scope.

Full text of DOI:10.1021/acs.orglett.5b01972

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of α‑Amino Ketones by Brønsted Acid
Catalysis
Wei Wen, Yu Zeng, Li-Yu Peng, Li-Na Fu, and Qi-Xiang Guo*
School of Chemistry and Chemical Engineering, Southwest University, Beibei, Chongqing 400715, China
S
* Supporting Information
ABSTRACT: The highly efficient, regioselective, and enan-
tioselective transfer hydrogenation of α-keto ketimines and
reductive amination of diketones by Brønsted acid catalysis is
described. A series of chiral α-amino ketones is prepared in
high yields (up to >99%), excellent regioselectivities (up to
>99:1), and enantioselectivities (up to 98% ee). This method
has broad substrate scope.
he development of new methods for the asymmetric
synthesis of useful building blocks and the key structural
carbene-catalyzed cross coupling of aldehydes with imines.7 The
research groups of Hashimoto,8 Zhang,9 Zhou,10 Wulff,11 and
several other investigators12 have also reported their work toward
the synthesis of optically active α-amino ketones by asymmetric
catalysis. Theoretically, the chiral α-amino ketones can be readily
prepared via the catalytic asymmetric transfer hydrogenation of
α-keto ketimines; however, there have been very few examples of
this procedure in the literature. In fact, the only successful
reported example of the utilization of this strategy was provided
by Zhang’s group in 2014, where they used chiral Lewis bases as
catalysts to give the desired α-amino ketones in good yields and
moderate to high enantioselectivities.13 With this in mind,
further work is required on this reaction to develop efficient and
robust methods for the catalytic asymmetric transfer hydro-
genation of α-keto ketimines. Given that chiral Brønsted acid
catalysis14 has been successfully used for the transfer hydro-
genation of ketimines,15 aldimines,16 and α-ketimine esters,17 we
envisioned that Brønsted acids could be used as reasonable
catalysts for the transfer hydrogenation of α-keto ketimines.
Herein, we report the development of the first Brønsted acid
catalyzed transfer hydrogenation of the prepared or in situ
formed α-keto ketimines to give the corresponding α-amino
ketones in high yields and excellent stereoselectivities. Notably,
this reaction exhibited a broad substrate scope.
T
units of biologically active compounds is one of the most
important tasks currently facing organic chemists. α-Amino
ketones are useful scaffolds in both synthetic and medicinal
chemistry because they play a vital role in many biologically
active natural products and pharmaceuticals1 as well as being
useful for the construction of structural diverse molecules.2
Important examples of natural products containing a chiral α-
amino ketone moiety include cathinone, which is a monoamine
alkaloid isolated from Khat,3a and gelsemoxonine, which is an
alkaloid found in Gelsemium elegans.3b Pharmaceutical com-
pounds containing an α-amino ketone moiety include ketamine,
which is used as an anesthetic,3c and Keto-ACE, which is an
efficient agent for the treatment of hypertension3d (Figure 1). α-
Figure 1. Representative biologically active compounds and pharma-
ceuticals containing α-amino ketone units.
We first evaluated the transfer hydrogenation of α-keto
ketimine 1a with dihydropyridine 2a in the presence of a catalytic
amount of phosphoric acid 3a (10 mol %). As expected, the
target product α-amino ketone 4a was obtained in 92% yield,
albeit with a low enantioselectivity of 26% (Table 1, entry 1). In
an attempt to improve the enantioselectivity of 4a, we adjusted
the substituents at the 3,3′-positions of the catalyst 3. As shown
in Table 1, the introduction of a bulky electron-donating
substituent at the 3,3′-postitions of the catalyst gave catalyst 3b,
which gave a good yield for the reaction but a lower
enantioselectivity of 20% (Table 1, entry 2). Catalysts 3c−f
Amino ketones can also be used as versatile building blocks for
the synthesis of nitrogen- and oxygen-containing molecules,
including 1,2-amino alcohols, which are used extensively in
organic synthesis as chiral auxiliaries, ligands, and resolving
reagents.4 In light of their importance to synthetic and medicinal
chemistry, the development of efficient new methods for the
preparation of chiral α-amino ketones is of critical importance.5
Several excellent methods have been developed for the
preparation of chiral α-amino ketones. In 2001, Maruoka and
co-workers reported the development of the chiral quaternary
ammonium salt-catalyzed Neber rearrangement of ketoximes for
the construction of enantioenriched α-amino ketones.6 Follow-
ing on from this work, Miller and Ye developed new methods for
the preparation of optically active α-amino ketones via the chiral
Received: July 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01972
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Organic Letters
Letter
95% ee) were obtained when the reaction was conducted at 30
°C (Table 1, entry 14).
Table 1. Catalyst Screening and Optimization of the Reaction
Conditions (PMP = p-Methoxyphenyl)
a
With the optimal reaction conditions in hand, we proceeded to
examine the substrate scope of this reaction using a series of α-
keto ketimines bearing diaryl substituents (Table 2). First, the α-
a
Table 2. Substrate Scope of Diaryl α-Keto Ketimines
b
c
entry
1
4
Ar1; Ar2
yield (%)
ee (%)
b
c
entry
3
2
time (h)
yield (%)
ee (%)
1
1a
1b
1c
1d
1e
1f
4a
4b
4c
4d
4e
4f
Ph
92
91
94
89
95
88
97
85
90
96
92
61
81
75
92
95
95
95
96
96
92
93
94
90
90
94
93
91
96
93
1
3a
3b
3c
3d
3e
3f
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
2e
2e
24
24
24
24
24
24
24
3
92
86
26
20
<5
<5
<5
2
4-FC6H4
2
3
4-ClC6H4
3
44
4
4-BrC6H4
4
51
5
4-MeC6H4
3-FC6H4
5
49
6
6
trace
46
7
1g
1h
1i
4g
4h
4i
3-ClC6H4
7
3g
3g
3g
3g
3g
3g
3g
3g
95
89
89
78
93
8
3-MeC6H4
3,4-2ClC6H3
2-naphthyl
C6H5
8
71
9
9
3
86
10
11
12
13
14
15
1j
4j
d
10
11
12
13
14
3
51
1k
1l
4k
4l
3
90
4-FC6H4; Ph
4-ClC6H4; Ph
4-BrC6H4; Ph
4-MeOC6H4; Ph
d
3
94
93
1m
1n
1o
4m
4n
4o
d
d
,
,
e
f
4
90
90
95
4.5
92
a
a
Reaction conditions: α-keto ketimine 1a (0.1 mmol), hydrogen
donor 2a−e (0.15 mmol), (R)-3 (10 mol %), PhCH3 (1 mL) at 50 °C;
Reaction conditions: α-keto ketimines 1 (0.2 mmol), hydrogen donor
2e (0.3 mmol) and (R)-3g (10 mol %) in PhCH3 (1 mL) at 30 °C.
Isolated yield. Determined by chiral HPLC. The 4-CH3OC6H4
b
c
d
b
c
d
Isolated yield. Determined by chiral HPLC. Reaction conditions: α-
keto ketimine 1a (0.2 mmol), hydrogen donor 2e (0.3 mmol), (R)-3g
group of 1 was replaced by 4-(4-ClC6H4O)C6H4.
e
(10 mol %), PhCH3 (1 mL) at 50 °C. 5 mol % of 3g was used.
f
Reaction conducted at 30 °C.
keto ketimines (1b−k) derived from symmetrical diaryl ketones
were investigated. The results revealed that α-keto ketimines
bearing para-substituted phenyl rings were excellent substrates
for this transformation, regardless of the electronic properties of
their substituents. For example, α-keto ketimine substrates
bearing a para-substituted F, Cl, Br, or Me phenyl ring reacted
smoothly to give the corresponding α-amino ketone products
4b−e in excellent yields (89−95%) and enantioselectivities (95−
96% ee) (Table 2, entries 2−5). α-Keto ketimine substrates
bearing a meta-substituted phenyl ring (4f−h) were also
converted to the corresponding α-amino ketones in excellent
yields and enantioselectivities (Table 2, entries 6−8). The 3,4-
2Cl phenyl- and 2-naphthyl-substituted α-keto ketimine
substrates were readily hydrogenated under the optimal reaction
conditions to give the corresponding α-amino ketones 4i,j in
excellent yields and enantioselectivities (Table 2, entries 9 and
10). Notably, the N-(4-chlorophenoxy)phenyl-substituted α-
keto ketimine 1k produced the target product 4k in both
excellent yield (92%) and enantioselectivity (94%) (Table 2,
entry 11). As illustrated by Zhang’s work,13 the α-amino ketone
4k can be used as a key intermediate for the synthesis of a
cannabinoid receptor 1 (CBA) inhibitor. We found that the α-
keto ketimine substrates bearing ortho-substituted phenyl rings
did not perform well in this transformation, most likely because
of steric hindrance from the ortho substituents on the phenyl
rings. Second, we evaluated the suitability of a series of α-keto
ketimines bearing different aryl substituents as substrates for the
preparation of chiral α-amino ketones. Pleasingly, all of these
substrates 1l−o were converted to the corresponding products
4l−o in high yields (61−92%) and excellent enantioselectivities
also worked well for this reaction but gave the desired product 4a
in moderate yields with poor enantioselectivities (Table 1,
entries 3−5). The phosphoric acid catalyst 3f bearing a
triphenylsilane group was found to be unsuitable as a catalyst
for this reaction (Table 1, entry 6). Pleasingly, the 2,4,6-
triisopropylphenyl-substituted phosphoric acid 3g was found to
be a good catalyst for this reaction in terms of the
enantioselectivity of 4a (95% ee), although the yield was
moderate (Table 1, entry 7). A further period of optimization was
then conducted in an attempt to improve the yield of this
reaction. Dihydrobenzothiazoles have been reported to be
efficient hydrogen donors in a wide range of transfer hydro-
genation reactions.18 With this in mind, we investigated the use
of the 2-aryl-substituted dihydrobenzothiazoles 2b−e as
potential hydrogen sources for this transformation. The results
of these experiments revealed that these alternative hydrogen
sources significantly improved the rate of the reaction and gave
the desired product 4a with high yields and high enantiose-
lectivities (Table 1, entries 8−11). The 2-naphthyl
dihydrobenzo[d]thiazole (2e), in particular, was identified as
the best hydrogen source for this reaction because it gave the
desired product 4a in 90% yield and 93% ee. The yield of 4a
could be further improved by increasing the concentration of the
reaction (Table 1, entry 12). The catalyst loading and reaction
temperature also affected the reaction results. For example, a
reduction in the loading of the catalyst from 10 to 5 mol % led to
a decrease in the yield and enantioselectivity of 4a (Table 1, entry
13). The optimum results for the preparation of 4a (92% yield,
B
DOI: 10.1021/acs.orglett.5b01972
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Organic Letters
Letter
(91−94%). The absolute configuration of compound 4a was
assigned as R on the basis of a comparison of its optical rotation
data with those reported in the literature.11 The stereo-
chemistries of products 4b−o were assigned by analogy with
that of 4a.
We then proceeded to investigate the use of a series of 1,2-
diketones bearing alkyl substituents (5a−n) as substrates in this
reaction (Table 3). Our initial efforts were focused on the
regioselectivity was attributed to the electrophilicity of the
carbonyl group adjacent to an electron-rich phenyl being lower
than that of a carbonyl group adjacent to an electron-deficient
phenyl, making it no more attractive to nucleophiles than the
carbonyl on the alkyl side. Dialkyl diketones were also shown to
be suitable substrates for this transformation. Under the optimal
reaction conditions, we successfully prepared the α-amino
ketones of substrates 5j−n in high yields, good to excellent
enantioselectivities, and high regioselectivities (Table 3, entries
10−14). To the best of our knowledge, this work represents the
first reported example of the use of an alkyl-substituted 1,2-
diketone in an organocatalyzed asymmetric reductive amination
reaction. The absolute configuration of compound 6o was
assigned as R on the basis of a comparison of its optical rotation
data with data reported in the literature.12e The stereochemistries
of products 6a−n were assigned by analogy with that of 6o.
We carried out the asymmetric transfer hydrogenation of α-
keto ketimine 1a and the reduction amination of diketone 5a on a
gram scale (Scheme 1, eqs 1 and 2). The results of these reactions
a
Table 3. Substrate Scope of Alkyl-Substituted Diketones
b
c
d
entry
5
6
R1
C6H5
y ield (%)
6:7
ee (%)
1
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
85
67
91
91
93
74
72
80
71
84
75
69
77
89
>99
>99:1
97:3
98
98
95
98
97
96
98
98
96
75
95
97
95
92
79
2
4-ClC6H4
4-CF3C6H4
4-MeC6H4
4-MeOC6H4
3-FC6H4
3-CF3C6H4
3-MeC6H4
2-Naphthyl
Me
3
91:9
Scheme 1. Gram-Scale Synthesis of α-Amino Ketones 4a and
6a and the Asymmetric Synthesis of Amino Alcohol 8a from 6a
4
>99:1
>99:1
98:2
5
6
7
5g
5h
5i
6g
6h
6i
98:2
8
>99:1
99:1
9
10
11
12
13
14
15
5j
6j
5k
5l
6k
6l
Et
n‑Pr
n‑Bu
89:11
93:7
93:7
5m
5n
5a
6m
6n
Et
e
6o
C6H5
a
Reaction conditions: 1, 2-diketones 5 (0.3 mmol), PMPNH2 (0.2
mmol), hydrogen donor 2e (0.3 mmol), (R)-3g (10 mol %), and 5 Å
b
MS (200 mg) in PhCH3 (1 mL) at 30 °C. Isolated yield.
c
d
e
Determined by 1H NMR. Determined by chiral HPLC. The aniline
was used instead of p-methoxyaniline.
revealed that the catalyst loading and hydrogen donor equivalent
could be decreased in these large-scale preparations. Notably, the
highly optically active N-PMP-protected (R)-cathinone deriva-
tive 6a could be produced on a gram scale in the presence of only
2 mol % of 3g and 1.2 equiv of the hydrogen donor 2e (Scheme 1,
eq 2). Moreover, compound 6a could be converted to the
corresponding N-PMP-protected norephedrine compound 8a in
excellent yield, diastereoselectivity, and enantioselectivity
(Scheme 1, eq 3).
In conclusion, we have developed a new method for the
efficient asymmetric transfer hydrogenation of α-keto ketimines
and the reductive amination of diketones for the synthesis of
optically active α-amino ketones. This reaction was found to be
amenable to both symmetrical and unsymmetrical diaryl α-keto
ketimines, including aryl alkyl- and dialkyl-substituted diketones,
with the corresponding α-amino ketones being produced in
excellent yields and high stereoselectivities. These α-amino
ketone products are useful intermediates for the preparation of
optically active amino alcohols, and some of them could be used
to synthesize chiral natural alkaloid derivatives.
preparation of α-keto ketimines from alkyl-substituted 1,2-
diketones. Unfortunately, however, the target imines were found
to be unstable, which meant that they could not be efficiently
isolated from the reaction mixture. Given that α-keto ketimines
can be regioselectively prepared at the alkyl side of 1,2-diketones
under mild reaction conditions,19 we envisioned that it would be
possible to achieve the catalytic asymmetric transfer hydro-
genation of in situ generated α-keto ketimines. With this in mind,
we evaluated the reaction of 1-phenylpropane-1, 2-dione 5a with
4-methoxyaniline (PMPNH2) and 2-naphthyldihydrobenzo[d]-
thiazole 2e under the optimal reaction conditions (200 mg of 5 Å
MS was used as additive). As expected, the N-PMP-protected
cathinone derivative 6a was generated in high yield and excellent
enantioselectivity (Table 3, entry 1). Based on this result, we
went on to investigate several other diketones bearing alkyl
groups in this reductive amination reaction. As shown in Table 3,
aryl methyl diketones were excellent substrates for this
transformation. For example, aryl methyl diketones bearing an
electron-donating or electron-withdrawing substituent on their
phenyl ring reacted smoothly to give the corresponding products
in 67−93% yield and 95−98% ee (Table 3, entries 2−9). We
noticed that the substrates bearing an electron-donating
substituent of their phenyl ring gave better regioselectivities
than those bearing an electron-withdrawing substituent (Table 3,
entries 4, 5, and 8 vs 2, 3, 6 and 7). This difference in the
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01972.
C
DOI: 10.1021/acs.orglett.5b01972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Experimental procedures, characterization, and 1H NMR,
Chem., Int. Ed. 2005, 44, 7424. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.;
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13C NMR, and HPLC spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: qxguo@swu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from NSFC (21272002,
21472150), the Fundamental Research Funds for the Central
Universities (XDJK2013B028), and the Program for New
Century Excellent Talents in Universities (NCET-12-0929).
(19) Alcaide, B.; Escobar, G.; Perez-Ossorio, R.; Rodriguez, I. M. An.
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DOI: 10.1021/acs.orglett.5b01972
Org. Lett. XXXX, XXX, XXX−XXX