Metal-Free Synthesis of Adipic Acid via Organocatalytic Direct Oxidation of Cyclohexane under Ambient Temperature and Pressure

Article abstract of DOI:10.1021/acs.oprd.8b00196

A direct metal-free approach for the production of adipic acid from cyclohexane is reported. The use of N-hydroxyphthalimide (NHPI) as a catalyst in the presence of HNO₃/TFA enables the direct oxidation of cyclohexane to yield adipic acid under ambient temperature and pressure via a simple procedure. This reaction proceeds through an initial oxidation of cyclohexane to cyclohexanone oxime and cyclohexanone followed by a second oxidation of these intermediates to adipic acid. NHPI plays a crucial role in both oxidation steps to achieve a high yield and selectivity for adipic acid.

Full text of DOI:10.1021/acs.oprd.8b00196

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Communication
Metal-free synthesis of adipic acid via organocatalytic direct
oxidation of cyclohexane under ambient temperature and pressure
Yohei Matsumoto, Masami Kuriyama, Kosuke Yamamoto, Koyo Nishida, and Osamu Onomura
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00196 • Publication Date (Web): 07 Sep 2018
Downloaded from http://pubs.acs.org on September 7, 2018
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Metal-free synthesis of adipic acid
via organocatalytic direct oxidation of cyclohexane
under ambient temperature and pressure
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Yohei Matsumoto, Masami Kuriyama, Kosuke Yamamoto, Koyo Nishida, and
Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University,
1
-14 Bunkyo-machi, Nagasaki, Nagasaki 852-8521, Japan
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Table of Contents Graphic
O
cat.
N OH
O
O
OH
n
O
HO
70% HNO , TFA, rt
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n
0
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2% for adipic acid (n = 1)
•
Metal-free direct oxidation of cycloalkanes
•
Ambient temperature and pressure • Simple operating procedure
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ABSTRACT: A direct metal-free approach for the production of adipic acid from cyclohexane
is reported. The use of an N-hydroxyphthalimide (NHPI) catalyst in the presence of HNO /TFA
3
enables the direct oxidation of cyclohexane to yield adipic acid under ambient temperature and
pressure via a simple procedure. This reaction proceeds through an initial oxidation of
cyclohexane to cyclohexanone oxime and cyclohexanone followed by a second oxidation of
these intermediates to adipic acid. NHPI plays a crucial role in both oxidation steps to achieve a
high yield and selectivity of adipic acid.
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Keywords: adipic acid • metal-free reaction • organocatalysis • radical • oxidation
1
. INTRODUCTION
Adipic acid is an important building block in the preparation of nylon-6,6 and other polyesters,
1
and more than 3.5 million tons of adipic acid are employed worldwide each year. Currently, the
most widely-used industrial procedure for adipic acid synthesis is the two-step nitric acid
2
oxidation from cyclohexane (Scheme 1a). In the first step of this process, cyclohexane is
oxidized under air to yield a mixture of cyclohexanone and cyclohexanol (K/A oil). This
transformation requires the presence of metal salts in addition to a high temperature (125–
1
65 °C) and pressure (8–15 atm), and the conversion of cyclohexane must be controlled at only
–11% to achieve a high selectivity (85%). Subsequently, the metal-catalyzed oxidation of K/A
4
oil using nitric acid as the oxidant proceeds with high efficiency to give adipic acid. While a
number of other synthetic strategies for adipic acid have been developed, such as one-step
oxidation methods from cyclohexene and multi-step procedures from non-petroleum
3,4
feedstocks, the single-step oxidation of cyclohexane to give adipic acid in the presence of
5
,6
metal catalysts has also received significant attention in the context of cost and efficiency.
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However, in recent years, focus has shifted to metal-free synthetic processes for environmental
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reasons. For example, in 2014, Hwang reported a direct oxidation of cyclohexane into adipic
8
acid using ozone under UV irradiation (Scheme 1b). While this oxidation process is highly
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simple and efficient, issues regarding the performance of the UV reactors in addition to the
formation of organic peroxide side products should be considered in the context of industrial
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scale applications. Furthermore, although organocatalysis has also been studied for a variety of
1
0
transformations, the organocatalytic oxidation of cyclohexane into adipic acid has received
little attention, and remains a challenge in the context of achieving high conversions and
1
1
selectivities. Thus, we herein report the metal-free direct oxidation of cyclohexane to yield
adipic acid in the presence of the radical precursor N-hydroxyphthalimide (NHPI) as the sole
catalyst (Scheme 1c).
Scheme 1. Synthetic approaches towards the production of adipic acid
(a) Nitric acid process (industrial method)
O
OH
cat. Co/Mn
+
Cu(II), NH VO
4 3
>
125 ºC
50-65% HNO3
O , 8-15 atm
70-90 ºC
2
1
a
K/A oil
conversion 4-11%
ca. 85% selectivity
O
O
OH
OH
+
HO
HO
n
O
O
adipic acid (2a)
(n = 1 or 2)
conversion 100%
93-95% selectivity for 2a
(b) Ozone-UV approach (Hwang)
O
O
UV light
OH
+
HO
HCl aq., O3
rt, 1 atm
O
1a
2a, 75%
8%
O
(
c) Organocatalytic approach (this work)
O
NHPI
OH
N OH
HO
n
7
0% HNO3
TFA (1.0 M)
rt, 1 atm
O
O
1
a
2a (n= 1): 82%
NHPI (C1)
+
2
b (n= 0): 5%
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2
. RESULTS AND DISCUSSION
Upon the treatment of cyclohexane 1a with 3.0 equiv of 70% HNO and 0.2 equiv of NHPI
3
(C1) in trifluoroacetic acid (TFA) at room temperature for 18 h, the desired adipic acid 2a was
obtained in 82% yield along with a small amount (5%) of glutaric acid 2b (Table 1, entry 1).
Inspired by this result, other radical precursors were evaluated in the oxidation of cyclohexane.
However, stoichiometric amount of peroxide reagents, such as 30% hydrogen peroxide and tert-
butyl hydroperoxide, led to complex mixtures (entries 2 and 3). Thus, we then moved on to
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evaluate the effect of the NO source concentration using C1 as the radical precursor.
x
Interestingly, when 99% HNO was employed in the reaction, both the yield and the selectivity
3
of 2a decreased (entry 4), while the use of 60% HNO produced 2a in a lower yield but with
3
improved selectivity (entry 5). The use of 2 equiv of 70% HNO also resulted in a decreased
3
yield (entry 6). Surprisingly, NaNO , which gave the optimal result in our previous study into the
2
1
2
oxidation of cycloalkanols, failed to yield 2a under the conditions employed herein (entry 7).
The choice of the reaction medium was also important to obtain the desired product in a high
yield and selectivity. More specifically, the use of a strong mineral acid (i.e., H SO or HNO )
2
4
3
led to the decomposition of C1 (entries 8 and 9). Other halogenated and nonhalogenated organic
acids were ineffective with the exception of CF CF CO H, affording 2a in decreased yields,
3
2
2
1
3
likely due to their higher pK values and the low solubility of C1 in these acids (entries 10–15).
a
Although the oxidation proceeded without TFA, the yield of 2a decreased drastically (entry 16).
These results indicated that the properties of TFA (i.e., the appropriate pK value and the ability
a
to dissolve C1) could play a crucial role to promote this oxidation efficiently. It is noteworthy
that the presence of C1 and HNO was essential to promote the direct oxidation of 1a to 2a at
3
ambient temperature and pressure, as the reaction was unsuccessful in the absence of these
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components (entries 17–19). Based on these results, we selected a combination of 70% HNO3
and TFA as the optimal NO source and the reaction medium for this transformation.
x
Table 1. Influence of reaction parameters
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radical precursor (0.2 equiv)
NOx source (3.0 equiv)
O
OH
HO
n
acid (1.0 M)
rt, 18 h
O
1a
2a (n = 1) + 2b (n = 0)
a
yield (%)
entry
radical precursor
NO source
acid
x
2
a
2b
1
2
3
4
5
NHPI (C1)
70% HNO3
70% HNO3
70% HNO3
99% HNO3
60% HNO3
70% HNO3
NaNO2
TFA
TFA
TFA
TFA
TFA
TFA
TFA
82
5
b
30% H O2
c.m.
c.m.
61
c.m.
c.m.
5
2
b
TBHP
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
none
C1
79
2
c
6
57
4
7
8
9
n.d.
n.d.
12
n.d.
n.d.
trace
5
70% HNO3
70% HNO3
70% HNO3
70% HNO3
70% HNO3
70% HNO3
70% HNO3
70% HNO3
70% HNO3
70% HNO3
none
H SO
2
4
70% HNO3
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
CF CF CO H
75
3
2
2
CCl CO H
31
trace
2
3
2
CHCl CO H
33
2
2
CH ClCO H
n.d.
trace
n.d.
23
n.d.
trace
n.d.
6
2
2
HCO H
2
CH CO H
3
2
d
none
TFA
TFA
trace
n.d.
trace
n.d.
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d
1
9
C1
none
none
n.d.
n.d.
a
1
b
Yields were determined by H NMR spectroscopy using DMF as an internal standard. The
c
d
radical precursor (1.0 equiv) was employed. 70% HNO (2.0 equiv) was employed.
Dichloromethane (1.0 M) was used instead of TFA. c.m. = complex mixture, n.d. = not detected.
3
The catalytic activities of various NHPI derivatives were then evaluated, as the presence of a
1
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0
substituent on the aryl ring of NHPI is known to affect the NO-H bond dissociation energy
14
(
BDE) (Table 2). As indicated, the catalyst bearing an electron-donating methyl group (C2)
was less effective, affording 2a in 67% yield. In addition, although the introduction of electron-
1
4b
withdrawing groups on the NHPI aryl ring has been reported to increase the NO-H BDE to
potentially generate a more reactive N-oxyl species, the introduction of chloro (C3) and ester
(
C4) groups gave 2a in slightly decreased yields (i.e., 75 and 77%, respectively). Interestingly, a
nitro substituted NHPI (C5) also afforded 2a in 70% yield, despite the fact that C5 and other
II
15
nitro-substituted substrates were not tolerated in the NHPI/Co -catalyzed benzylic oxidation.
Furthermore, the catalyst bearing a carboxyl group (C6) provided 2a in a high yield (80%),
although the selectivity towards 2a was poor, potentially due to the higher reactivity of the N-
1
6
oxyl species. Moreover, the use of C7, which gradually generates C1 via hydrolysis resulted in
a significant decrease in selectivity. We also found that N-oxyl precursors derived from
succinimide (C8), cyanuric acid (C9), o-sulfobenzimide (C10), and naphthalimide skeletons
(C11) were ineffective, affording 2a in lower yields. Although the presence of two N-hydroxyl
groups in the catalyst (C12) afforded 2a in a high yield, the selectivity towards 2a was poor.
Based on these results, we therefore selected C1 as the preferred organocatalyst for this
oxidation system.
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a
Table 2. Screening of N-oxyl precursors
N-oxyl precursor (0.2 equiv)
70% HNO3 (3.0 equiv)
O
OH
HO
n
TFA (1.0 M)
rt, 18 h
O
1
a
2a (n = 1) + 2b (n = 0)
0
1
2
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0
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0
O
O
O
Me
Cl
N
OH
N
OH
N
O
OH
O
O
C1
C2
C3
2a: 82%, 2b: 5%
2a: 67%, 2b :2%
2a: 75%, 2b: 2%
O
O
O
MeO C
O N
HO C
2
2
2
N
OH
N
OH
N
OH
O
O
O
C4
a: 77%, 2b: 5%
C5
C6
2
2a: 70%, 2b: 4%
2a: 80%, 2b: 11%
OH
O
O
O
O
O
N
O
CH3
N
N OH
N
N
HO
OH
O
O
O
C9
C7
C8
2
a: 25%, 2b: 3%
2a: 47%, 2b: 3%
2a: 53%, 2b: 6%
O
O
O
O
N
O
OH
N
O
OH
HO
N
N OH
S
O
O
O
C10
2a: 66%, 2b: 3%
C11
2a: 55%, 2b: 6%
C12
2a: 72%, 2b: 9%
a
1
Yields were determined by H NMR spectroscopy using DMF as an internal standard.
With the optimized condition in hand, we examined the scalability of the present reaction. To
our delight, the oxidation of cyclohexane could be performed on a gram-scale, affording adipic
acid 2a in 75% yield (Scheme 2). We also surveyed the effect of the cycloalkane ring size on this
reaction. As shown in scheme 3, cycloalkanes larger than cyclohexane gave the desired
dicarboxylic acids in moderate to good yields, while those yields were prone to decrease with
increasing the cycloalkane ring size.
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a
Scheme 2. Gram-scale experiment for the production of adipic acid
C1 (0.2 equiv)
0% HNO3 (3.0 equiv)
O
7
OH
HO
n
TFA (1.0 M)
rt, 18 h
O
1
a
2a (n = 1): 75% (61%)
+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
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5
5
5
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0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12.0 mmol
2
b (n = 0): 5%
a
1
Yields were determined by H NMR spectroscopy using DMF as an internal standard. Isolated
yield after single recrystallization is shown in parentheses.
a
Scheme 3. The effect of the ring size on the metal-free direct oxidation of cycloalkanes
C1 (0.2 equiv)
70% HNO3 (3.0 equiv)
O
OH
HO
n
TFA (1.0 M)
rt, 18 h
n
O
1
1
c (n = 2)
2c (n = 2): 64%
d (n = 3)
2d (n = 3): 44%
a
1
Yields were determined by H NMR spectroscopy using DMF as an internal standard.
Finally, control experiments were then conducted to gain an improved understanding of the
reaction mechanism involved in this transformation. The present oxidation reaction was
completely inhibited by 3,5-di-tert-4-butylhydroxytoluene (BHT), which is known as a free
radical scavenger. The result indicated that this oxidation might proceed via a radical pathway
(
Scheme 4). When the reaction was performed in the presence of 0.2 equiv of C1 and 0.2 equiv
of 70% HNO , cyclohexanone oxime 3 was obtained in 20% yield along with a small amount of
3
17
cyclohexanone 4 (Scheme 5). Next, compounds 3 and 4 were independently subjected to
further control experiments (Scheme 6). Both compounds, in contrast to cyclohexane 1a, were
oxidized to adipic acid 2a under the HNO /TFA system, and a higher yield was obtained by
3
employing oxime 3 as a starting material (entries 1 and 3). When the same reactions were
conducted with C1, the yield of 2a from 3 was dropped from 74% to 51%, whereas that from 4
was increased from 33% to 85% (entries 2 and 4). The deteriorated yield from 3 in the presence
of C1 was likely due to the too high reactivity of 3 towards the C1/HNO /TFA system, because
3
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many unidentified byproducts were observed under the reaction conditions. In fact, the oxidation
of 3 proceeded even at 0 °C under the C1/HNO /TFA system, providing 2a in a restored yield.
3
On the other hand, cyclohexanone 4 gave trace amount of 2a under the same reaction conditions
0
1
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(entries 3 and 6). These results indicate that C1 might play an important role in the nitric acid
oxidation of 3 and 4, and oxime 3 would be more tend to undergo oxidation under this reaction
conditions. Moreover, these two intermediates might transform into adipic acid through two
distinct oxidation pathways.
Scheme 4. Effect of a free radical scavenger
BHT (1.0 equiv)
C1 (0.2 equiv)
0% HNO3 (3.0 equiv)
O
7
OH
HO
n
TFA (1.0 M)
rt, 18 h
O
1
a
2a (n= 1): not detected
+
2
b (n= 0): not detected
BHT: 3,5-di-tert-4-butylhydroxytoluene
Scheme 5. Investigation of intermediates
OH
C1 (0.2 equiv)
N
O
70% HNO3 (0.2 equiv)
+
TFA (1.0 M)
rt, 18 h
1
a
3
4
0% (18%)a
6% (4%)a
2
a
with 4.2 equiv of H O
2
Scheme 6. Control experiments using oxime 3 or ketone 4 as a starting material
OH
N
O
C1
O
7
0% HNO3 (3.0 equiv)
OH
or
HO
n
TFA (1.0 M)
temp, 18 h
O
3
4
2
entry substrate C1 (equiv) temp (ºC) 2a (n = 1) 2b (n = 0)
1
2
3
4
5
6
3
3
3
4
4
4
0
rt
rt
0
rt
rt
0
74%
51%
78%
33%
85%
trace
14%
7%
0.2
0.2
0
trace
3%
5%
n.d.
0.2
0.2
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12a,18
On the basis of the literature reports
and the results of our control experiments, a plausible
reaction mechanism for the direct oxidation of cyclohexane to adipic acid is proposed, as shown
in Figure 1. In this mechanism, initial reaction of C1 with HNO affords the phthalimide N-oxyl
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
radical (PINO) and NO . Subsequently, PINO abstracts a hydrogen atom from cyclohexane 1a to
2
yield cyclohexyl radical I. Although Ishii reported the nitration of cyclohexane with in-situ
1
8b
generated NO in trifluorotoluene at 60 ºC using NHPI/HNO system, trace amount of
2
3
1
nitrocyclohexane was observed by H NMR spectroscopy. Under our conditions, in-situ
19
generated NO would undergo rapid equilibration between NO and N O , and hydrolysis of
2
2
2
4
N O followed by disproportionation of HNO provide reactive NO radical. Then, radical
2
4
2
coupling reaction of cyclohexyl radical I with NO radical afford nitrosocyclohexane II, which
tautomerize to cyclohexanone oxime 3. Radical I might also react with molecular oxygen to
generate peroxy radical III, which leads to the formation of cyclohexanone 4. Hydrolysis of 3
might be a conceivable route for the cyclohexanone formation. These two intermediates would
20
be individually oxidized to adipic acid 2a in the presence of C1 and HNO3.
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O
H
N
OH
HNO3
O
NHPI (C1)
1a
O
0
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0
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N
O
NO + H O
2 2
I
O
PINO
2
NO2
N O
2 4
N O + H O
HNO2 + HNO3
NO + HNO3 + H O
2
4
2
3
HNO2
2
2
O
OH
N
N
NO
II
3
CO H
2
H O
2
CO H
2
O
O
O
2a
O2
III
4
Figure 1. Plausible reaction mechanism for the direct oxidation of cyclohexane to adipic acid.
3
. CONCLUSION
We successfully developed a metal-free direct oxidation method for the production of adipic
acid from cyclohexane in an excellent yield and selectivity. The NHPI/HNO /TFA system
3
described herein was applied to the oxidation of other cycloalkanes affording corresponding
dicarboxylic acids. This reaction could be operated under ambient temperature and pressure
without any special techniques or experimental manipulations. We therefore believe this reaction
could be considered an alternative process for the synthesis of adipic acid. Further studies aimed
at improving the yields and selectivities in addition to expanding the substrate scope are
currently underway in our laboratory and the results will be presented in due course.
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4
. EXPERIMENTAL SECTION
General Methods and Materials. Unless otherwise noted, all reactions were performed in a
heavy-wall glass tube (Ace Glass, Inc. approximate total capacity: 35 mL) equipped with a
1
1
1
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1
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0
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0
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0
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23
24
magnetic stir bar at room temperature under air. Catalysts C2-3 , C6 , C7 , C9 , C10 , and
2
5
C12 were synthesized according to reported methods. All other chemicals were used as
received without further purifications.
All melting points were determined using Yanako micro melting point apparatus without
correction. Infrared (IR) spectra were recorded on a Shimadzu IRAffinity-1 spectrophotometer.
-
1
1
13
Data were expressed as frequency of absorption (cm ). H and C NMR spectra were recorded
1
13
on JEOL JNM-AL400 spectrometer (400 MHz for H NMR and 100 MHz for C NMR).
Chemical shift values are expressed in ppm relative to internal TMS (δ 0.00 ppm) or DMSO-d6
1
13
(
δ 2.50 ppm) for H NMR and DMSO-d (δ 39.5 ppm) for C NMR. Splitting patterns are
6
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. High-
resolution mass spectra (HRMS) were recorded using electron impact ionization (EI) mass
spectrometry or fast atom bombardment (FAB) mass spectrometry.
General Procedure for the Metal-free Oxidation of Cycloalkanes. To a pressure tube vessel
(
Ace glass, Inc. approximate total capacity: 35 mL) equipped with magnetic stirring bar was
added cycloalkane 1 (2.0 mmol), NHPI (C1) (65.2 mg, 0.4 mmol, 20 mol%), and trifluoroacetic
acid (2.0 mL). To the resultant mixture was added 70% HNO (540 mg, 6.0 mmol), and the
3
vessel was tightly closed with a PTFE plug. After stirring for 18 h, the solvent was removed
under reduced pressure (approximately 30 mmHg). The residual solid was treated with 5%
3 2 2
NaHCO solution and washed with CH Cl . The aqueous layer was acidified with 10% HCl
4
solution, and extracted with ethyl acetate. The organic layer was dried over MgSO , and
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concentrated under reduced pressure to give a mixture of dicarboxylic acid 2 and C1 as a yellow
1
solid. The yield was determined by H NMR spectroscopy using DMF as an internal standard.
Recrystallization from hot ethyl acetate afforded the desired product.
0
1
2
3
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9
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Adipic acid (2a). The reaction was performed according to the general procedure using
cyclohexane 1a (168 mg, 2.0 mmol). Recrystallization from ethyl acetate afforded pure 2a (193
mg, 66%) as a white solid of mp 152 °C. Compound 2a was isolated in 63% yield by a
simplified procedure avoiding an extraction step. For detail, see the simplified procedure for the
1
Metal-free Oxidation of Cyclohexane described below. H NMR (400 MHz, DMSO-d
6
): δ 1.46-
1
3
1
.54 (m, 4H), 2.15-2.23 (m, 4H), 12.03 (s, 2H). C NMR (100 MHz, DMSO-d
6
): δ 23.93, 33.28,
-
1
-
174.22. IR (ATR): 1683, 2951 cm . HRMS (FAB) m/z: calcd for C
6
H
9
O
4
([M–H] ) 145.0501,
found 145.0502.
Simplified Procedure for the Metal-free Oxidation of Cyclohexane. To a pressure tube
vessel (Ace glass, Inc. approximate total capacity: 35 mL) equipped with magnetic stirring bar
was added cyclohexane 1a (168 mg, 2.0 mmol), NHPI (C1) (65.2 mg, 0.4 mmol, 20 mol%), and
3
trifluoroacetic acid (2.0 mL). To the resultant mixture was added 70% HNO (540 mg, 6.0
mmol), and the vessel was tightly closed with a PTFE plug. After stirring for 18 h, the solvent
was removed under reduced pressure, and the residual solid was dried in vacuo. Recrystallization
from hot ethyl acetate afforded the desired product 2a as a colorless solid (184 mg, 63%).
Gram-scale experiment. To a glass lined stainless autoclave (approximate total capacity: 120
mL) equipped with magnetic stirring bar was added cycloalkane 1 (1.01 g, 12.0 mmol), NHPI
(C1) (391 mg, 2.4 mmol, 20 mol%), and trifluoroacetic acid (12.0 mL). To the resultant mixture
was added 70% HNO (3.24 g, 36.0 mmol), and the reaction vessel was tightly closed with
3
stainless reactor lid. After stirring for 18 h, the solvent was removed under reduced pressure
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(
approximately 30 mmHg). The residual solid was treated with 5% NaHCO solution and
3
washed with CH Cl . The aqueous layer was acidified with 10% HCl solution, and extracted with
2
2
ethyl acetate. The organic layer was dried over MgSO , and concentrated under reduced pressure
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
4
4
4
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5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to give a mixture of dicarboxylic acid 2 and C1 as a yellow solid. The yield of 75% for 2a and
1
5
% for 2b was determined by H NMR spectroscopy using DMF as an internal standard.
Recrystallization from hot ethyl acetate afforded pure 2a in 61% as a white solid (1.07 g).
ASSOCIATED CONTENT
Supporting Information.
The following files are available free of charge.
1
13
Experimental details and H and C NMR spectrum of the products (PDF)
AUTHOR INFORMATION
Corresponding Author
*
E-mail: onomura@nagasaki-u.ac.jp. TEL: (+81)-95-819-2429.
Notes
The authors declare no conflict of interest.
ACKNOWLEDGMENT
This work was supported by MEXT Grant-in-Aid for Scientific Research on Innovative Areas
“
Advanced Molecular Transformations by Organocatalysts” (No. 26105746) and JSPS Grant-in-
Aid for Scientific Research (C) (No. 16K08167).
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3
2
a
2
a
a
a
a
(
pK = 3.75) ; CH ClCO H (pK = 2.85) ; CHCl CO H (pK = 1.35) ; CCl CO H (pK = 0.64) ;
a 2 2 a 2 2 a 3 2 a
a
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