Development of Ketone-Based Brominating Agents (KBA) for the Practical Asymmetric α-Bromination of Aldehydes Catalyzed by Tritylpyrrolidine

Article abstract of DOI:10.1021/acscatal.0c01596

Ketone-based brominating agents (KBA), ortho-substituted 2,2,2-tribromoacetophenones, have been developed, and the highly enantioselective and practical α-bromination of aldehydes with KBA was achieved. The reaction could be performed in the presence of only 0.1-1 mol % of catalyst without using a halogenated solvent at 0 °C and was found to be scalable.

Full text of DOI:10.1021/acscatal.0c01596

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Letter
Development of Ketone-Based Brominating Agents (KBA) for the Practical
Asymmetric #-Bromination of Aldehydes Catalyzed by Tritylpyrrolidine
Aika Takeshima, Mio Shimogaki, Taichi Kano, and Keiji Maruoka
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ACS Catalysis
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Development of Ketone-Based Brominating Agents (KBA) for the
Practical Asymmetric α-Bromination of Aldehydes Catalyzed by
Tritylpyrrolidine
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Aika Takeshima,#,† Mio Shimogaki, #,† Taichi Kano,*,†and Keiji Maruoka*,†,‡,§
† Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
‡ Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto 606-8501, Japan
§ School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
ABSTRACT: Ketone-based brominating agents (KBA), ortho-substituted 2,2,2-tribromoacetophenones have been developed, and
the highly enantioselective and practical α-bromination of aldehydes with KBA was achieved. The reaction could be performed in
the presence of only 0.1–1 mol% of catalyst without using a halogenated solvent at 0 °C and was found to be scalable.
KEYWORDS, amine catalyst, asymmetric synthesis, brominating agent, enamine catalysis, organocatalysis
α-Bromocarbonyl compounds can serve as versatile synthetic
intermediates in the formation of carbon–carbon bonds as well
as various carbon–heteroatom bonds because of the high
leaving group ability of bromine atom.1 Asymmetric enamine
catalysis is one of the powerful organocatalytic strategies for
the stereoselective α-halogenation of aldehydes and ketones.2–7
In this area, a number of catalytic asymmetric α-fluorinations
and α-chlorinations of carbonyl compounds have been
developed to date.3–5 On the other hand, only a few asymmetric
α-brominations have been investigated despite high synthetic
utility of the products.6 In the previous attempts for α-
bromination of aldehydes, a high catalyst loading of (R,R)-2 or
(S)-3 (20 mol%) was required, probably due to undesired side
reactions such as bromination of the amine catalyst (Scheme
1a).3e,6a We have also developed the asymmetric α-bromination
of aldehydes catalyzed by the binaphthyl-based secondary
amine (S)-4, in which the amount of catalyst could be reduced,
since the introduction of steric bulkiness into the catalyst
circumvents the catalyst deactivation by the brominating
agent.6b However, both yield and enantioselectivity strongly
depend on the solvent, and use of CH2Cl2 was necessary rather
than industrially usable solvents such as THF and toluene.8 The
low enantioselectivities in non-halogenated solvents might be
attributed to the racemic pathway with the reactive brominating
agent 1. We hypothesized that if a milder brominating agent
suppresses the catalyst deactivation and the non-catalyzed
racemic process, the highly enantioselective bromination would
be promoted by a small amount of chiral amine catalyst even in
a non-halogenated solvent.
Scheme 1. Asymmetric α-Bromination of Aldehydes
Catalyzed by Chiral Secondary Amines
Previous works
a)
O
tBu
+
tBu
O
OH
S
OH
R
NaBH4
cat.
Br
Br
or
solvent
–20 °C
R
R
R
Br Br
1
Jørgensen
Ph
2
(R,R)- (20 mol%)
Ph
CH2Cl2/pentane 72–95%, 68–96% ee (S)
N
H
(1:1)
Ar
Ar
OTMS
N
H
3
(S)- (20 mol%)
CH2Cl2 71–74%, 94–95% ee (S)
Ar = 3,5-(CF3)2-C6H3
Kano and Maruoka
4
(S)- (3-10 mol%)
71–94%, 92–99% ee (R)
64%, 16% ee (R) (R = Bn)
CH2Cl2
THF
toluene 29%, 7% ee (R)
Ph
Ph
Ph
(R = Bn)
N
Ph
OTMS
TMSO
H
This work
b)
O
O
N
Br
O
*
*
Br
+
Br
N
5a
H
In the course of our recent studies on enamine catalysis,
debromination of an α,β-unsaturated tribromomethyl ketone
was observed in the presence of pyrrolidine and an aldehyde.
We realized that this result must be due to the bromination of
the aldehyde and/or pyrrolidine. We first focused on 2,2,2-
tribromoacetophenone (5a) which might show the potential as
a brominating agent. However, rapid amidation of 5a occurred
in the presence of a secondary amine.9 Based on this result,
R
steric protection
catalyst
catalyst deactivation
by Ar–CO rotation
O
*
R''
Br
Br
O
N
Br
R'
Br
R
KBA
R
α-bromination
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Page 2 of 6
ketone-based
brominating
agents
(KBA),
2,2,2-
bromination with pyrrolidine proceeded rapidly. In contrast, the
reaction did not proceed with N-methylpyrrolidine (See SI for
1
tribromoacetophenones bearing ortho-substituents, which may
suppress the catalyst deactivation through the amidation, were
designed (Scheme 1b). It was postulated that the nucleophilic
addition of the secondary amine catalysts to the carbonyl group
along the Bürgi-Dunitz trajectory could be hampered by the
ortho-substituent because the ortho-substituted aryl ring twists
out of the plane of the carbonyl group. Herein, we report the
development of novel brominating agents and their application
to the amine-catalyzed asymmetric α-bromination of aldehydes.
Our strategy could provide a practical solution to circumvent
the high catalyst loading and the use of undesirable solvents.
Several KBAs were prepared via two routes. KBA 5b–5d
could be synthesized from the corresponding aldehydes through
two steps. They were formed by nucleophilic addition of
tribromomethyllithium to the aldehyde, followed by oxidation
of the resulting alcohol (Scheme 2: method A). KBA 5e and 5f
could be prepared in one step from the corresponding ketones
by a simpler method using readily available reagents (Scheme
2: method B).10 The obtained KBAs are relatively stable even
at room temperature, while 5e gradually decomposes into the
corresponding dibromomethyl ketone. KBA 5d could be stored
at –20 °C. KBA 5b, 5c and 5f are bench-stable and have been
maintained for several months without change.
2
3
4
5
6
7
8
9
details).
From
these
results,
ortho-substituted
tribromoacetophenones were confirmed to be promising
brominating agents in enamine catalysis.
O
O
O
O
pyrrolidine
CDCl3, r.t.
or
or
R
N
R
CHBr2
R
OH
R
CBr3
5
6
7
8
(a)
(b)
5
6
10
11
12
13
14
15
16
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60
100
100
50
0
50
0
5 min 40 min 2 h
5 min 40 min 2 h
5 min 40 min 2 h
4 h
4 h
4 h
16 h
40 min 2 h
4 h
16 h
(c)
(d)
100
100
50
0
50
0
Scheme 2. Synthetic Routes for KBA 5b–5f
16 h
5 min 40 min 2 h
4 h
16 h
method A
CHBr3
(e)
(f)
OH
CBr3
O
O
LiHMDS
PCC
100
100
THF
–78 °C
CH2Cl2
reflux
R
R
CBr3
R
Mes-KBA 5b(R = mesityl)
Np-KBA 5c(R = 1-naphthyl)
t-Bu-KBA 5d(R = tert-butyl)
: 59%
: 73%
: 49%
50
0
50
0
(over 2 steps)
method B
HBr
H2O2
16 h
5 min 40 min 2 h
4 h
16 h
O
O
Figure 1. Decomposition of
5
monitored by 1H NMR
1,4-dioxane
reflux
R
R
CBr3
spectroscopy: (a) 5a (R = Ph), (b) 5b (R = Mesityl), (c) 5c (R = 1-
naphthyl), (d) 5d (R = tert-butyl), (e) 5e (R = 2-tolyl), and (f) 5f (R
= 2-chlorophenyl). The ratio of four compounds was determined
with an internal standard.
Tol-KBA 5e(R = 2-tolyl)
: 76%
ClPh-KBA 5f (R = 2-chlorophenyl) : 75%
To evaluate the potential of the newly synthesized
compounds 5 as brominating agent for the enamine catalysis,
we monitored the transformation of 5 in the presence of one
equivalent of pyrrolidine by 1H NMR (Figure 1). Additionally,
they were compared with other standard brominating agents.
Use of 2,2,2-tribromoacetophenone (5a) promptly gave amide
6, which suggests deactivation of the pyrrolidine-based
secondary amine catalyst. In contrast, no or low conversion of
5b–5f to 6 was observed after 16 h. In particular, 5b and 5d
hardly changed in the presence of pyrrolidine. KBA 5c and 5e
were gradually converted to dibromomethyl ketone 7. In the
case of 5f, the corresponding carboxylic acid 8 was obtained.11
Unidentified by-product was observed in some cases. On the
other hand, relatively reactive brominating agents such as N-
bromosuccinimide, N-bromoacetamide and 1,3-dibromo-5,5-
dimethylhydantoin were rapidly decomposed by pyrrolidine. In
the case of the brominating agent 1, the decomposition rate was
faster than that of 5f. After 40 min, 20% of 1 decomposed and
50% remained after 2 h. Furthermore, to confirm whether the
amine-catalyzed bromination proceeds via the enamine
intermediate, the reaction between 3-phenylpropanal (9a) and
5f in the presence of a secondary amine or tertiary amine was
examined in CDCl3 at room temperature. As expected, the α-
The novel brominating agents were applied to the
asymmetric α-bromination of 3-phenylpropanal (9a) in CH2Cl2
in the presence of 10 mol% of a secondary amine catalyst at –
20 °C, and the results are shown in Table 1. Readily available
chiral pyrrolidines were selected as catalysts. Whereas the
reaction with tribromoacetophenone (5a) in the presence of 11
hardly proceeded (entry 1), use of bulky Mes-KBA 5b gave the
bromination product 10a in moderate yield due to suppression
of catalyst deactivation (entry 2). We then examined other
amine catalysts to improve the enantioselectivity (entries 3–9).
The reaction using 3 afforded the product in low yield in spite
of excellent enantioselectivity (entry 3). Use of catalyst 4 led to
excellent yield and high enantioselectivity (entry 4). In the
reactions with catalysts 12–14, low to moderate
enantioselectivities were observed (entries 5–7). In contrast, use
of catalysts 15 and 16 with two substituents in cis configuration
gave 10a in good yield with excellent enantioselectivity due to
the steric effect of the silyloxy group (entries 8 and 9).12 The
catalyst 15 was selected for further study in terms of
accessibility. α-Bromination using the other KBAs was next
investigated (entries 10–13). In most cases examined, 10a was
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ACS Catalysis
obtained in moderate to excellent yields with high
the product in low yield with reduced enantioselectivity (entry
11). The acetophenone framework was found to be important
for the present asymmetric bromination. Regarding
brominating agent, readily available ClPh-KBA 5f was
determined to be the choice. The catalyst loading could be
reduced to 2 mol% without significant loss of enantioselectivity
(entry 14). Incidentally, the reaction using brominating agent 1
under identical conditions did not proceeded at all (entry 15).
The solvent and additive effects were then examined to
optimize the reaction conditions (Table 2). Although CH2Cl2
was the optimal solvent in terms of both yield and
enantioselectivity, 10a was obtained in moderate to high yield
with good enantioselectivity in all solvents tested (entries 1–7).
To avoid halogenated solvents, toluene was selected for further
study. Even when the catalyst loading was reduced to 2 mol%,
the reaction proceeded to give 10a in high yield (entry 8). We
were pleased to find that addition of p-nitrobenzoic acid
drastically accelerated the reaction (entry 9) and the
enantioselectivity was maintained at 0 °C (entry 10). While the
yield was decreased, the reaction proceeded even with 0.5
mol% catalyst loading (entry 11). Use of a reduced amount of
5f (1.1 eq.) at higher concentration led to a good yield and
excellent enantioselectivity (entry 12). The yield was improved
by addition of water, and excellent yield and enantioselectivity
were achieved with low catalyst loading (entry 13). Such a low
catalyst loading is rare not only for organocatalytic
brominations but organocatalysis with secondary amines in
general.13
With low catalyst loading, the asymmetric α-bromination of
several other aldehydes 9 with ClPh-KBA 5f was examined in
toluene at 0 °C, and the results are shown in Table 3. Increasing
the amount of acid could further reduce the catalyst loading
(entry 1). In most cases, the asymmetric α-bromination of
aldehydes proceeded to give the corresponding bromohydrin 10
in good to excellent yields and enantioselectivities with 0.1–1
mol% of catalyst. However, moderate enantioselectivity was
observed in the reaction of 9d (entry 4). The yield was low when
using sterically hindered aldehyde 9f (entry 6). The reaction of
phenylacetaldehyde 9i did not proceed (entry 9). The use of
ketones such as cyclohexanone and diethyl ketone under
identical conditions also resulted in no reaction.
1
enantioselectivities. The reaction using t-Bu- KBA 5d afforded
2
3
4
5
6
7
8
9
Table 1. Asymmetric α-bromination of 3-phenylpropanal
using pyrrolidine-based amine catalystsa
cat. (2 or 10 mol%)
O
O
OH
NaBH4
1
5
or (1.5 eq.)
Br
Bn
Br
CH2Cl2
MeOH
–20 °C
Bn
9a
Bn
10a
–20 °C, 24 h
entry
1
2
3
4
5
6
7
1 or 5
5a
5b
5b
5b
5b
5b
5b
5b
5b
5c
5d
5e
5f
5f
1
cat. (mol %) yield (%)b ee (%)c
11 (10)
11 (10)
3 (10)
trace
61
9
-
36
94
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
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40
41
42
43
44
45
46
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50
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53
54
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56
57
58
59
60
4 (10)
99
83
83
99
87
79
67
15
99
85
81
ndf
–91
28
64
12 (10)
13 (10)
14 (10)
15 (10)
16 (10)
15 (10)
15 (10)
15 (10)
15 (10)
15 (2)
–48
–96
–98
–97
–90
–96
–96
–94
-
8
9
10
11
12
13
14d,e
15d,e
15 (2)
aThe reactions were performed on 0.1 mmol scale in 0.5 mL of
b
c
CH2Cl2. Isolated yield. Determined by HPLC analysis using a
chiral column. dUse of 0.2 mL of CH2Cl2. ePerformed for 83 h. fNot
detected.
X
TBSO
Ph
Ar
Ar
Ar
Ar
N
N
H
N
Ph
OTMS
H
H
Ar
Ar
: X = H, Ar = Ph
15: X = OTBS, Ar = Ph
16
11
12
13
14
: Ar = Ph
: Ar = 3,5-Xy
: X = OTBS, Ar = 3,5-Xy
Table 2. Optimization of reaction conditionsa
15
–
(0.5 10 mol%)
O
O
OH
5f
ClPh-KBA (1.5 eq.)
NaBH4
Br
Bn
Br
solvent
–20 °C
MeOH
–20 °C
Bn
9a
Bn
10a
Table 3. Scope of α-bromination of aldehydesa
15
(0.1–1 mol%)
entry 15 (mol %) solvent
t (h)
24
24
24
24
24
24
24
65
4
yield (%)b ee (%)c
5f
ClPh-KBA (1.1 eq.)
p-NO2-C6H4CO2H (3 mol%)
H2O (2 eq.)
1
2
3
4
5
6
7
10
10
10
10
10
10
10
2
CH2Cl2
CHCl3
PhCF3
THF
CPME
hexane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
99
46
67
52
79
88
89
99
90
99
58
76
96
96
84
90
82
90
83
93
86
92
94
85
97
97
O
O
OH
NaBH4
MeOH
Br
Br
toluene
0 °C
R
R
R
9
10
entry R
15 (mol %) t (h)
yield (%)b
10a 91
10b 87
10c 99
10d 75
10e 76
10f 14
10g 87
10h 84
10i nde
ee (%)c
93
94
97
83
95
92
93
85
1
Bn
0.1
0.5
1
74
24
3
2
Bu
8
9d
3
CH2Cy
Cy
i-Pr
t-Bu
allyl
CH2OBn
Ph
2
2
0.5
0.5
4d
5d
6d
7
1
1
1
1
23
27
24
25
8
10d,e
11d,e
12d,e,f
1
8
4
5
13d,e,f,g 0.5
8
9
1
aThe reactions were performed on 0.1 mmol scale in 0.2 mL of the
1
24
-
solvent. bNMR yield. cDetermined by HPLC analysis using a chiral
aThe reactions were performed on 0.1 mmol scale in 0.1 mL of
d
column. Using three times the amount of p-nitrobenzoic acid to
b
c
e
the catalyst. Performed at 0 °C. fUsing 5f (1.1 eq.) in 0.1 mL of
toluene. Isolated yield. Determined by HPLC analysis using a
chiral column. dPerformed at 10 °C. eNot detected.
toluene. gH2O (2 eq.) was added.
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Arimitsu, S.; Yonamine, T.; Higashi, M. Cinchona-Based Primary
Amine Catalyzed a Proximal Functionalization of Dienamines:
Asymmetric α-Fluorination of α-Branched Enals. ACS Catal. 2017, 7,
4736–4740. (h) Cui, L.; You, Y.; Mi, X., Luo, S. Asymmetric
Fluorination of α-Branched Aldehydes by Chiral Primary Amine
Catalysis: Reagent-Controlled Enantioselectivity Switch. J. Org. Chem.
2018, 83, 4250–4256.
15
(0.5 mol%)
5f
ClPh-KBA (1.1 eq.)
p-NO2-C6H4CO2H (3 mol%)
H2O (2 eq.)
O
O
OH
NaBH4
MeOH
Br
Bn
Br
toluene
0 °C, 52 h
Bn
9a
1.3 g
Bn
10a
1.9 g
(89% yield, 92% ee)
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We performed large scale asymmetric α-bromination using
1.3 g of 3-phenylpropanal (9a). As can be seen from the result
in Scheme 3, the yield and the enantioselectivity were
maintained at the same level, which indicates great possibilities
for practical applications.
In summary, we have developed useful ketone-based
brominating agents (KBA) for asymmetric α-bromination of
aldehydes. With ClPh-KBA, the reaction can be performed
using a low catalyst loading in non-halogenated solvent at the
moderate and practical temperature. This new type of
brominating agents will be of value for other bromination
reactions.
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge via the
Internet at http://pubs.acs.org.
General Information, Preparation of Brominating agents, NMR
spectra, and HPLC spectral.
AUTHOR INFORMATION
Corresponding Author
* E-mail: kano@kuchem.kyoto-u.ac.jp
* E-mail: maruoka@kuchem.kyoto-u.ac.jp
ORCID
Taichi Kano: 0000-0001-5730-3801
Keiji Maruoka: 0000-0002-0044-6411
Author Contributions
#These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported by JSPS KAKENHI Grant Numbers
JP26220803, JP18H01975, JP20H04815 (Hybrid Catalysis) and
JP18J01780. M. S. is grateful for Fellowships for Young Scientists
from the Japan Society for the Promotion of Science (JSPS).
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TBSO
0.1~1 mol%
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O
CPh3
N
H
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Br
Br
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+
Cl
Br
ClPh-KBA
low catalyst loading
toluene
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R
R
non-halogenated solvent
moderate and practical temperature
✓
✓
✓
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