Asymmetric chlorination of β-keto esters using diaminomethylenemalononitrile organocatalyst

Article abstract of DOI:10.1248/cpb.c16-00722

Diaminomethylenemalononitrile organocatalysts promote the asymmetric chlorination of simple cyclic β-keto esters such as methyl, ethyl, and benzyl esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid. This affords the corresponding chiral α-chlorinated

Full text of DOI:10.1248/cpb.c16-00722

Vol. 64, No. 12
Chem. Pharm. Bull. 64, 1781–1784 (2016)
1781
Note
Asymmetric Chlorination of β-Keto Esters Using
Diaminomethylenemalononitrile Organocatalyst
Takaaki Sakai, Shin-ichi Hirashima, Kosuke Nakashima, Chie Maeda, Akihiro Yoshida,
Yuji Koseki, and Tsuyoshi Miura*
Tokyo University of Pharmacy and Life Sciences; 1432–1 Horinouchi, Hachioji, Tokyo 192–0392, Japan.
Received September 8, 2016; accepted September 23, 2016
Diaminomethylenemalononitrile organocatalysts promote the asymmetric chlorination of simple cyclic
β-keto esters such as methyl, ethyl, and benzyl esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid. This
affords the corresponding chiral α-chlorinated carbonyl products in excellent yields with high enantioselec-
tivities.
Key words organocatalyst; asymmetric chlorination; β-keto ester
Chiral α-chlorinated carbonyl compounds are valuable acid, such as methyl, ethyl, and benzyl esters (6a–c), is very
1
2,18)
building blocks in the production of various biologically ac- rare.
tive compounds.
Among the various chlorine sources, NCS is one of
1–5)
To synthesize enantiomerically enriched the best reagents because of its simple structure and low cost.
α-chlorinated carbonyl compounds, direct chlorination of The α-chlorination of a simple cyclic β-keto ester with NCS,
carbonyl compounds using a chlorine source, such as N-chlo- in the presence of an organocatalyst (ca. 1mol%), is therefore
rosuccinimide (NCS), is a reliable method. Several research highly desirable, and it is one of the most challenging research
groups have reported on the asymmetric chlorination of β-keto topics.
6
–17)
esters using metal catalysts.
Organocatalysis, meanwhile,
Recently, we reported on some asymmetric reactions
has received considerable attention in the area of organic using organocatalysts bearing diaminomethylenemalononitrile
2
5–32)
synthesis because, in comparison to reactions involving metal (DMM) or diaminomethyleneindenedione (DMI) motifs.
catalysts, it is an environmentally benign method. Synthetic In order to further demonstrate the value of DMM organo-
methods for producing α-chlorinated compounds from β-keto catalysts, we attempted to apply them to the asymmetric
18–24)
esters using organocatalysts have also been developed.
Although chiral α-chlorinated β-keto esters are valuable syn-
thetic intermediates, their preparation using organocatalysts Results and Discussion
and NCS with high enantioselectivity (>80% enantiomeric ex- We examined organocatalysts 1–5 (Fig. 1) for an enantiose-
Several methods lective α-chlorination of β-keto ester 6a, as shown in Table 1.
α-chlorination of simple cyclic β-keto esters.
19–21)
cess (ee)) has rarely been reported upon.
for the synthesis of chiral α-chlorinated β-keto esters require DMM organocatalysts 1–3 with tertiary or secondary amine
high catalyst loading (>5mol%), a complex chlorine source, groups provided the desired product 7a in excellent yields
and bulky ester units such as the t-butyl and adamantyl with low enantioselectivities (entries 1–3). Organocatalyst 4,
groups. The highly stereoselective (>80% ee) α-chlorination which bears a chiral primary amine group, accelerates the
of simple esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic α-chlorination of 6a and gives 7a with good enantioselectivity
Fig. 1. Structure of Organocatalysts
*
To whom correspondence should be addressed. e-mail: tmiura@toyaku.ac.jp
©
2016 The Pharmaceutical Society of Japan

1
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Chem. Pharm. Bull.
Vol. 64, No. 12 (2016)
(entry 4). DMI organocatalyst 5 is a poor choice for asym- conditions, therefore, were determined to be 1mol% of 4 and
metric α-chlorination (entry 5). Owing to these results, we 1.5eq of NCS in toluene at −80°C (entry 10). Among the re-
decided to further study its reaction conditions using catalyst ported methods for the synthesis of 7a using organocatalysts,
4
because we found that catalyst 4 provided the best results.
Various reaction conditions were examined for the asym- procedure to obtain 93% ee ; other organocatalytic methods
the method reported by Bartoli et al. was the only successful
18)
2
0)
metric α-chlorination of 6a using catalyst 4, as shown in Table provided moderate enantioselectivities (up to 63% ee).
2
. Among the reaction solvents examined at 0°C, toluene was
Next, we examined chlorine sources such as trichloroisocy-
found to be the most suitable solvent (entries 1–4). The reac- anuric acid and 1,3-dichloro-5,5-dimethylhydantoin, as shown
tion in toluene at −80°C improved the enantioselectivity by in Table 3. Among the chlorine sources examined under the
up to 72% ee (entry 5). Other reaction solvents were examined optimal reaction conditions, NCS was still found to be the
at −80°C, and toluene was again found to be the most suit- most suitable source.
able solvent (entries 5–7). We also attempted to reduce the
With these optimal conditions in mind, the scope and
amount of catalyst loading necessary to achieve the optimal limitations of α-chlorinations of various β-keto esters were
conditions. Enantioselectivity was improved by up to 78% examined (Table 4). An ethyl ester of 1-oxo-2,3-dihydro-1H-
ee without lowering of the yield when catalyst loading was indene-2-carboxylic acid (6b) reacts with NCS to afford the
reduced to 1mol% (entries 8–10). Changes in the amount of corresponding product 7b in an excellent yield with 71% ee
NCS added (2.0 or 1.1eq) resulted in a slight reduction in (entry 2). Meanwhile, the reported methods for synthesizing
enantioselectivity (entries 11, 12, respectively). The optimal 7b using organocatalysts and metal catalysts did not even
13,14,16,24)
provided moderate enantioselectivities (up to 64% ee).
Table 1. Catalyst Screening
The reaction of the benzyl ester 6c with NCS provided the
Table 3. Study of Chlorine Source
a)
b)
Entry
Catalyst
% Yield
% ee
1
2
3
4
5
1
2
3
4
5
99
99
99
99
99
22
−30
−5
69
41
a
a) Isolated yield. b) Determined by chiral HPLC analysis.
One equivalent of chlorine source was used.
Table 2. Study of Reaction Conditions
a)
b)
Entry
Solvent
CH Cl
Temp. (°C)
Catalyst (mol%)
% Yield
% ee
1
2
3
4
5
6
7
8
9
0
0
10
10
10
10
10
10
10
5
95
99
99
96
99
99
98
98
93
99
99
99
24
26
10
33
72
49
32
75
77
78
75
76
2
2
CHCl3
THF
0
Toluene
Toluene
EtOAc
0
−80
−80
−80
−80
−80
−80
−80
−80
Et O
2
Toluene
Toluene
Toluene
Toluene
Toluene
2
10
11
12
1
c)
d)
1
1
a) Isolated yield. b) Determined by chiral HPLC analysis. c) NCS (2eq) was used. d) NCS (1.1eq) was used.

Vol. 64, No. 12 (2016)
Chem. Pharm. Bull.
1783
Table 4. Study of Substrate Scope
cyclic β-keto esters, such as methyl ester 6a, ethyl ester 6b,
and benzyl ester 6c acted as good substrates as they provided
relatively higher stereoselectivities than those provided by pre-
vious organocatalytic methods. We have demonstrated that the
organocatalyst bearing DMM motif can function as an effi-
cient catalyst for the stereoselective synthesis of α-chlorinated
carbonyl compounds 7. Further application of the DMM cata-
lyst in the synthesis of bioactive compounds is currently being
investigated in our laboratory.
a)
b)
Entry
1
Product
Time (h) % Yield
% ee
23
99
78
Experimental
General Methods and Materials H- and C-NMR
1
13
2
3
19
96
71
79
spectra were measured with a Bruker DPX 400 spectrometer
1
13
(
400MHz for H-NMR, 100MHz for C-NMR). The chemical
shifts are expressed in ppm downfield from tetramethylsilane
δ=0.00) as an internal standard. Mass spectra were recorded
(
20
99
by an electrospray ionization-time of flight (ESI-TOF) mass
spectrometer (Micromass LCT). For TLC analyses, Merck
precoated TLC plates (silica gel 60 F254) were used. Flash
column chromatography was performed on neutral silica gel
4
5
6
7
21
22
26
96
97
99
55
46
56
19
31)
28)
26)
25)
32)
(
40–50 µm). Organocatalysts 1, 2, 3, 4, and 5 were
prepared by the previous reported methods.
Typical Procedure for α-Chlorination of β-Keto Esters
6
Using Organocatalyst 4 (Table 2) To a solution of meth-
yl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (6a, 38.0mg,
.200mmol) and organocatalyst 4 (0.9mg, 0.002mmol) in
toluene (2.0mL) was added NCS (40.1mg, 0.300mmol) at
80°C. After stirring in closed tube at −80°C for 23h, the
0
−
reaction mixture was directly purified by flash column chro-
matography on silica gel with a 9:1 mixture of hexane and
AcOEt to afford 7a (44.5mg, 99%) as a yellow solid. All the
products 7a–h in the paper are known compounds that ex-
hibited spectroscopic data identical to those reported in the
literature.
23
41
99
5
Methyl
boxylate (7a)
(S)-2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-car-
11,15,24)
c)
d)
8
ND
Enantiomeric excess was determined by HPLC with
ChiralPak AD-H column (hexane–2-propanol=95:5), flow
rate=0.7mL/min; λ=254nm; tmajor=14.4min, tminor=15.4 min.
Ethyl 2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
13)
a) Isolated yield. b) Determined by chiral HPLC analysis. c) Catalyst 4 (10mol%) (7b)
was used. d) Not determined.
Enantiomeric excess was determined by HPLC with
ChiralCel OJ-H column (hexane–2-propanol=95:5), flow
corresponding product 7c in an excellent yield with 79% ee. rate=0.8mL/min; λ=254nm; tmajor=25.3min, tminor=37.1 min.
An organocatalytic synthesis of 7c was reported only by No-
Benzyl
(S)-2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-car-
12,24)
vacek et al., but it could afford moderate enantioselectivities boxylate (7c)
2
4)
(
48% ee). In the reaction of bulky esters, such as t-butyl and
Enantiomeric excess was determined by HPLC with Chi-
adamantyl esters 6d and e, the enantioselectivities decreased ralPak OD-H column (hexane–2-propanol=70:30), flow
entries 4, 5, respectively). Although β-keto esters 6f and g as rate=0.7mL/min; λ=254nm; tminor=8.7min, tmajor=9.7 min.
cyclohexanone derivatives were chlorinated under the optimal tert-Butyl (S)-2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-car-
reaction conditions and gave chiral α-chlorinated compounds boxylate (7d)
f and g in excellent yields, their stereoselectivities were low Enantiomeric excess was determined by HPLC with
to modelate (entries 6, 7, respectively). Ethyl 2-methyl-3-oxo- ChiralCel OJ-H column (hexane–2-propanol=80:20), flow
-phenylpropanoate (6h) gave a low yield for the product 7h rate=0.7mL/min; λ=254nm; tmajor=9.3min, tminor=11.4 min.
entry 8).
Adamantan-1-yl (S)-2-Chloro-1-oxo-2,3-dihydro-1H-indene-
In conclusion, the DMM organocatalyst 4 can efficiently 2-carboxylate (7e)
catalyze the asymmetric chlorination of various cyclic β-keto
Enantiomeric excess was determined by HPLC with
(
12,15,24)
7
3
(
13,24)
esters, such as 6, with low catalyst loading (1mol%) and ChiralPak AD-H column (hexane–2-propanol=95:5), flow
NCS as a simple chlorine source to afford the corresponding rate=0.75mL/min; λ=254nm; tmajor=11.8min, tminor=13.7 min.
products 7 bearing tertiary chiral carbon in excellent yields
with moderate to high enantioselectivities. Particularly, simple

1
784
Chem. Pharm. Bull.
Vol. 64, No. 12 (2016)
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Ethyl 1-Chloro-2-oxocyclohexane-1-carboxylate (7g)
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Acknowledgments This work was supported by JSPS
KAKENHI Grant Number 16K08178. The authors would like
to thank Enago (www.enago.jp) for the English language re-
view.
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Conflict of Interest The authors declare no conflict of
interest.
2
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