Asymmetric synthesis of β-amino ketones by using cinchona alkaloid-based chiral phase transfer catalysts

Article abstract of DOI:10.1039/c8ob02484g

A highly enantioselective nucleophilic addition of ketones to imines catalyzed by chiral phase-transfer catalysts (N-quaternised cinchona alkaloid ammonium salts) has been developed, and the process affords the Mannich reaction products with tertiary stereocenters in good to high yields (up to 95%) with excellent enantioselectivities (up to 97% ee).

Full text of DOI:10.1039/c8ob02484g

Organic &
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Asymmetric synthesis of β-amino ketones by using
cinchona alkaloid-based chiral phase transfer
catalysts†
Cite this: Org. Biomol. Chem., 2018,
16, 8704
Received 6th October 2018,
Accepted 31st October 2018
Weihua Li,
Yifeng Wang and Danqian Xu
*
DOI: 10.1039/c8ob02484g
rsc.li/obc
A
highly enantioselective nucleophilic addition of ketones to synthesis of enantiomerically enriched β-amino ketones is an
imines catalyzed by chiral phase-transfer catalysts (N-quaternised emerging area in organic chemistry; nonetheless, the asym-
cinchona alkaloid ammonium salts) has been developed, and the metric synthesis of β-amino ketones and their derivatives has
process affords the Mannich reaction products with tertiary stereo- long been a challenging topic despite the many methods that
centers in good to high yields (up to 95%) with excellent enantio- have been developed.5–7 Herein, we report a straightforward
selectivities (up to 97% ee).
organocatalytic enantioselective Mannich reaction of various
imines catalyzed by a cinchona alkaloid-based chiral phase-
transfer catalyst, and a wide range of β-amino ketones were
obtained with excellent enantioselectivities (up to 97% ee) and
high yields (up to 95%).
In our initial exploration, the addition of 1-(2-fluorophe-
nyl)-N-(6-methoxybenzo[d]thiazol-2-yl) methanimine 1a to
acetophenone 2a was set as the model reaction for catalyst
screening. Quinine and quinidine, a type of commercial cinch-
ona alkaloid, were screened in the presence of an alkali metal
carbonate (sodium carbonate), but a reaction was hardly trig-
gered (Table 1, entries 1 and 2); seven cinchona alkaloid-based
N-quaternized ammonium salts, Q-1 to Q-7, were investigated
in their use as phase-transfer catalysts together with a 10%
potassium hydroxide aqueous solution as the water phase
β-Amino ketones can serve as a key synthetic intermediate of
numerous drugs and natural products (e.g. β-amino acids,
β-amino alcohols and β-lactams).1 Moreover, β-amino ketones
and their derivatives are important compounds exhibiting
various and useful bioactivities, and they are extensively used
with functionalities spanning anti-inflammatory, antibacterial,
antimycobacterial, analgesic, antidiabetic, and antitumor
activities and so on.2 Marketed β-aminoketone drugs are
widely applied in clinics, for example, Mydocalm (Tolperisone
Hydrochloride) and Myonal (Eperisone Hydrochloride) are
commonly used for spastic paralysis disease control (antispas-
modic); Ondansetron is a medication used to prevent nausea
and vomiting caused by cancer chemotherapy and radiation
therapy; and Lobeline (Alpha-Lobeline Hydrochloride) finds
application in the treatment of medullary respiratory center
stimulating (Fig. 1).3
Optically active β-amino ketones are also useful building
blocks for preparing pharmaceutical targets.4 The biological
activity of compounds containing the β-amino ketone moiety
depends on the absolute configurations of the compounds,
such as L-asparagine bearing an important clinical application
of nutritional supplementation, and also for treating dietary
shortage or imbalance; nevertheless, D-asparagine does not
show the same potency in these respects (Fig. 2). Thus, the
Fig. 1 Representative marketed β-aminoketone drugs.
State Key Laboratory Breeding Base of Green Chemistry Synthesis Technology,
Key Laboratory of Green Pesticides and Cleaner Production Technology of Zhejiang
Province, Zhejiang University of Technology, Hangzhou 310014, China.
E-mail: chrc@zjut.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1867988. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02484g
Fig. 2 The stereo-configurations of asparagine (β-amino ketone struc-
ture included).
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Table 1 Screening of catalystsa
Table 2 Screening of bases and reaction temperaturea
Entry
Base
Time [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
50% K2CO3 aq.
50% Cs2CO3 aq.
10% KOH aq.
10% NaOH aq.
10% KOAc aq.
TMAOH·5H2O
50% K2CO3 aq.
50% Cs2CO3 aq.
5% KOH aq.
10% KOH aq.
20% KOH aq.
10% KOH aq.
10% KOH aq.
60
24
12
12
48
12
60
60
48
24
12
48
24
60
58
60
57
Trace
80
55
52
80
80
65
70
85
93
94
90
75
—
77
91
90
95
96
91
97
92
7d
8d
9d
10d
11d
12e
13f
Entry
Cat.
Time [h]
Yieldb [%]
eec [%]
1d
2d
3
4
5
6
7
8
9
Quinine
Quinidine
Q-1
Q-2
Q-3
Q-4
Q-5
Q-6
Q-7
48
48
12
24
24
12
12
12
24
Trace
Trace
70
40
50
70
60
75
70
—
—
a Unless otherwise noted, the reactions were conducted with 1a
(0.05 mmol), 2a (0.075 mmol) and 10 mol% of catalyst in 1.5 mL
toluene at room temperature for a definite time. b Isolated yields.
c Detected by chiral HPLC analysis. d −20 °C. e −30 °C. f 0 °C.
55
70
37
−46
90
77
78
a Unless otherwise noted, the reactions were conducted with 1a
(0.05 mmol), 2a (0.075 mmol) and 10 mol% of catalyst in 1.5 mL
toluene at room temperature for a definite time. b Isolated yields.
c Detected by chiral HPLC analysis. d Solid Na2CO3 as the base.
(Table 2, entry 5), and this was due to its own relatively weak
basicity. However, TMAOH·5H2O revealed the highest yield
(80%) among these six bases. We further investigated the cata-
lytic properties at a low temperature of three types of bases
which could afford higher enantioselectivities at ambient
system. Q-1, obtained by the reaction of quinine and benzyl temperature, as an integrated comparison, and the 10% pot-
bromide, shows moderate enantiomeric excess and yield assium hydroxide aqueous solution exhibited better catalytic
(Table 1, entry 3); further exploration of catalysts showed that performance than the other two (Table 2, entries 7–8 and 10
the quinine-based PTC containing a 3,5-bis(trifluoromethyl) respectively). Three different concentrations of potassium
benzyl group demonstrated the most effective catalytic pro- hydroxide aqueous solutions (5%, 10%, and 20%) were investi-
perties (Table 1, entry 7, 90% ee). Thus, PTC Q-5 was our solid gated and assessed (Table 2, entries 9–11), and results of the
choice for the following experiments. PTC Q-4 is a diastereo- integrated effect comparison showed that the 10% concen-
mer of PCT Q-5; however, it did not afford a comparable tration solution was superior (shorter reaction time, higher
enantioselectivity with Q-5 despite it providing a slightly yield, and comparable ee value) to the other two. The possible
higher yield (Table 1, entry 6).
reason for the yield obviously dropping when the concen-
Based on initial exploration, we believed that the base may tration of the base aqueous solution is increased up to 20%
play a key role in this type of Mannich reaction; so we selected could be imine decomposition. The enantiomeric excess
six different bases, 50% potassium carbonate aqueous solu- increased significantly with the decrease in the reaction temp-
tion, 50% cesium carbonate aqueous solution, 10% potassium erature, despite the longer reaction time needed and the slight
hydroxide aqueous solution, 10% sodium hydroxide aqueous decrease in the yield (Table 2, entries 3, 13, 10 and 12);
solution, 10% potassium acetate aqueous solution and however, the difference between −30 °C and −20 °C is minus-
TMAOH·5H2O (tetramethylammonium hydroxide penta- cule (in terms of detected ee value, there is only 1% difference
hydrate), for our subsequent screening investigation. 10% between −30 °C and −20 °C), and −20 °C led to higher yield;
sodium hydroxide aqueous solution and TMAOH·5H2O pro- thus −20 °C was our final consideration.
vided moderate enantioselectivities (Table 2, entries 4 and 6
While further optimizing the reaction conditions, non-pro-
respectively). The desired enantioselectivities (90%–94% ee) tonic solvents, such as DCM, THF, xylene, n-hexane and
were gained when 10% potassium hydroxide aqueous solution, toluene, were used for organic phase screening. A high yield
50% potassium carbonate aqueous solution and 50% cesium (69%) and excellent enantioselectivity (90% ee) were achieved
carbonate aqueous solution were employed separately though when toluene was applied as the organic phase solvent
moderate yields (58%–60%) were obtained (Table 2, entries (Table 3, entry 1); compared with toluene, xylene could afford
1–3). The reaction barely proceeded in the presence of 10% comparable enantioselectivity, but the yield is slightly inferior
potassium acetate aqueous solution as the water phase system (Table 3, entry 5); the same phenomenon was revealed at low
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Table 3 Screening of organic phase solvents and catalyst loadinga
4). Different catalyst loading levels, including 5, 10 and
20 mol%, were applied to the model reaction for investigation;
the enantioselectivity and yield decreased visibly when the
loading of catalyst Q-5 was reduced to 5 mol% (Table 3, entry
7). Between the catalytic performances at 10 and 20 mol%
loading, there was no significant difference noted in the yield
and enantioselectivity (Table 3, entries 1 and 8, respectively).
With the appropriate reaction conditions in hand (10 mol%
Q-5 loading, toluene/10% KOH aq. as a biphasic system, and a
low-temperature of −20 °C), we explored the substrate scope of
various imines and aromatic/aliphatic ketones. The Mannich
reactions of 1a and 1g (1-(2-fluorophenyl)-N-(4-methyl-benzo[d]
thiazol-2-yl)methanimine) were found to smoothly provide
comparable yields and enantioselectivities, although different
aromatic ketones were used as nucleophilic agents (Table 4,
entries 1–5 and 21–25). Substrate 1b (1-(2-chlorophenyl)-N-
(6-methoxybenzo[d] thiazol-2-yl)methanimine) with different
substituent group (Chlorine) on the benzene ring of imine
aldehydic part was explored also, it revealed comparable yield
with substrate 1a and 1g no matter what R3 are substituted or
unsubstituted phenyl groups, but it encountered enantio-
selectivities decreased slightly when R3 are substituted phenyl
groups (Table 4, entries 1–3, 13–15 and 21–23). Meanwhile,
various substituted groups on the benzene ring of aromatic
Entry
Solvent
RT [h]
Yieldb [%]
eec [%]
1
2
3
4
Toluene
DCM
THF
n-Hexane
Xylene
Xylene
Toluene
Toluene
12
12
24
24
12
24
12
12
69
30
N.D.
N.D.
60
65
65
68
90
79
—
—
89
93
85
91
5
6d
7e
8f
a Unless otherwise noted, the reactions were conducted with 1a
(0.05 mmol), 2a (0.075 mmol) and 10 mol% of catalyst in 1.5 mL
screening solvent at room temperature for a specified time. b Isolated
yields. c Detected by chiral HPLC analysis. d 0 °C. e 5 mol% catalyst
loading. f 20 mol% catalyst loading.
reaction temperature (Table 3, entry 6 and Table 2, entry 13).
The reaction was hardly triggered when THF and n-hexane
were used as the organic phase solvents (Table 3, entries 3 and
Table 4 Substrate scope of β-aminoketonea
Entry
R1
R2
Subs. 1
R3
Subs.2
RT [h]
Yieldb [%]
eec [%]
1d
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
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
6-OMe
4-Me
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-Furyl
2-Thienyl
3-FC6H4
4-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1d
1e
1f
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
48
48
48
48
48
48
48
48
48
48
24
48
48
48
48
60
60
60
60
48
24
24
24
24
24
24
83
81
85
84
86
95
86
90
75
85
80
79
85
83
86
71
70
66
70
81
81
86
83
85
79
78
96
94
93
94
91
92
77
82
94
94
91
75
96
87
87
75
66
78
74
95
95
94
95
97
96
96
2′-FC6H4
4′-FC6H4
2′-ClC6H4
2′-BrC6H4
3′-ClC6H4
2′-NO2C6H4
4′-NO2C6H4
3′-CH3C6H4
3′-OCH3C6H4
3′,4′-(CH3)2C6H3
1′-Naphthalene
C6H5
2′-FC6H4
4′-FC6H4
C6H5
C6H5
C6H5
C6H5
CH3
C6H5
2′-FC6H4
4′-FC6H4
2′-ClC6H4
2′-BrC6H4
C6H5
2j
2k
2l
2a
2b
2c
2a
2a
2a
2a
2m
2a
2b
2c
2d
2e
2a
1a
1g
1g
1g
1g
1g
1h
4-Me
4-Me
4-Me
4-Me
H
a Unless otherwise noted, the reactions were conducted with 1a–1h (0.05 mmol), 2a–2m (0.075 mmol), 10 mol% of PTC Q-5 and 1.5 equiv. 10%
aq. KOH in 1.5 mL toluene at −20 °C for 24 or 60 h; subs. is the abbreviation of substrate. b Isolated yields. c Determined by chiral HPLC analysis.
d We implemented this straightforward protocol to a gram reaction (1.0 g) successfully, and almost identical yield (80%) and enantioselectivity
(94% ee) can be obtained (for details refer to ESI).
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Fig. 3 Proposed transition state model of the Mannich reaction product 3a.
ketones were also investigated, on the basis of the detected ee, a catalyst for the Mannich reaction of an imine and an aro-
and we found no conspicuous difference when electron- matic ketone is shown in Fig. 3. We believed that the imine
drawing groups (F, Cl, and Br) and electron-donating groups was activated by hydrogen bonding from the chiral acidic
(–CH3 and –OCH3) were introduced to the benzene ring of aro- hydroxyl group in the PTC. Normally the acetophenone is in
matic ketones (Table 4, entries 2–6 and 9–11); nevertheless, equilibrium with its keto and enol forms (keto–enol tautomer-
the enantioselectivities dropped visibly when stronger elec- ism equilibrium),11 and at room temperature the equilibrium
tron-withdrawing groups (e.g. nitro-) were employed (Table 4, heavily favours the formation of the keto form. This equili-
entries 7 and 8). An acetonaphthone framework was also suit- brium can be influenced/catalyzed by the presence of a base
able for the addition and gave the corresponding yield (79%) (mechanism for base-catalyzed enolization) and the content of
and enantioselectivity (75%) (Table 4, entry 12). We also the enol form would rely heavily on the activity of carbonyl α
observed that in the case of an aromatic ketone with the same hydrogen (acidic) and the stability of the formed carbon
substituted group at a different position of the benzene ring, anion.12 In addition, the carbon anion is also considered as
the substituted group did not cause remarkable ee variation the actual nucleophilic species of the keto form rather than an
(Table 4, entries 2–4, 6–8, 14, 15, 22 and 23). The yield and enolate under basic conditions. Therefore, the exposed oxygen
enantioselectivity had partly dropped when aromatic hetero- anion of enolates could be efficiently ion-paired with the
cyclic groups were introduced to the aldehydic part of imine ammonium cation of quinuclidine in the PTC. Then, the
(R2) (Table 4, entries 16 and 17). Meanwhile, the R2 with meta- desired product was produced by the Re face attack of the acti-
and para-fluorine substituted phenyl groups were employed vated imine (electrophilic azomethine carbon). However, for
for assessment, and a positive result could be presented, but certainty, we considered this chiral cinchona alkaloid-based
they were slightly worse than the ortho-fluorine substituted PTC to act as a bi-functional organocatalyst.
phenyl group (Table 4, entries 1, 18 and 19). Acetone was used
as a nucleophilic agent for investigation, and we found that it
can afford comparable yield and enantioselectivity with aro-
matic ketones (Table 4, entries 20 and 1). The amine part of
Conclusions
the imine without any substituted group (substrate 1h) was In summary, we established a convenient organocatalytic strat-
also explored, and high yield and excellent enantioselectivity egy for the Mannich reaction of benzothiazole imines through
were achieved (Table 4, entry 26). However, 6-methoxyl substi- a marketed and inexpensive quinine-derived chiral phase-
tuted benzothiazole imines (R1 = 6-OCH3) needed a longer transfer catalyst (N-quaternized cinchona alkaloid ammonium
reaction time than benzothiazole imines with R1 being 4-CH3 salts) and ketones as nucleophilic agents. This simple proto-
or H to get an identical catalytic effect. Enantiomerically col, which leads to β-amino ketones with tertiary stereocenters
enriched β-amino ketones can be converted into their corres- in high yields (up to 95%) and with excellent enantioselectivi-
ponding γ-amino alcohols and β-lactams and/or useful inter- ties (up to 97%), makes this asymmetric synthesis important
mediates for synthesizing amino-peptides without any signifi- and extends the universality of the catalytic enantioselective
cant loss of enantioselectivity by some of strategies mentioned Mannich reaction. We can also apply this straightforward pro-
in these cited literatures.7,8
tocol to gram scale reactions (1.0 g) effectively.
The absolute configuration of product 3a was determined
unambiguously by X-ray analysis (Fig. 3).9 Based on the
assumption stereochemical models that were proposed by
Plaquevent group and Palomo group on previously published
Conflicts of interest
literatures,10 a mechanistic proposal for the role of PTC Q-5 as There are no conflicts to declare.
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Acknowledgements
The research was supported by the National Key R&D Program
of China (2017YFB0307200) and National Natural Science
Foundation of China (21402176).
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