Control of Chemical Reactions by Using Molecules that Buffer Non-aqueous Solutions

Article abstract of DOI:10.1002/chem.201903552

Control of chemical reactions is necessary to obtain designer chemical transformation products and for preventing decomposition and isomerization reactions of compounds of interest. For the control of chemical events in aqueous solutions, the use of aqueo

Full text of DOI:10.1002/chem.201903552

A Journal of
Accepted Article
Title: Control of Chemical Reactions Using Molecules that Buffer Non-
aqueous Solutions
Authors: Muhammad Sohail and Fujie Tanaka
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10.1002/chem.201903552
Chemistry - A European Journal
RESEARCH ARTICLE
Control of Chemical Reactions Using Molecules that Buffer Non-
aqueous Solutions
Muhammad Sohail[a] and Fujie Tanaka*[a]
Abstract: Control of chemical reactions is necessary for obtaining
designer chemical transformation products and for preventing
decompositions and isomerizations of compounds of interest. For
the control of chemical events in aqueous solutions, the use of
aqueous buffers is a common practice. However, no molecules that
buffer non-aqueous solutions were commonly used. Here we
demonstrate that 1,3-cyclohexanedione derivatives have buffering
functions in non-aqueous solutions. We also show that these
molecules can be utilized to alter and control chemical reactions.
1,3-Cyclohexanedione derivatives inhibited both acid-catalyzed and
base-catalyzed isomerizations and decompositions in organic
solvents. The reaction products obtained in the presence of the
buffering molecule 2-methyl-1,3-cyclohexanedione differed from
those obtained in the absence of the buffering molecule. The use of
buffering molecules that work in organic solvents provides a strategy
to control chemical reactions and expands the range of compounds
that can be synthesized.
strategies to control and alter chemical reactions. Here, we
report the introduction of the "buffering" concept into the events
that occur in non-aqueous solutions. We report that 1,3-
cyclohexanedione derivatives have buffering functions in non-
aqueous solutions and that the use of these molecules provides
a way to control and alter the direction and products of chemical
reactions (Figure 1).
In aqueous buffers, buffer molecules neutralize both acids
and bases to maintain the pH within certain ranges.[2] Many
types of buffer molecules are used in aqueous solutions. The
buffer molecules used in aqueous solutions, however, usually
cannot be used as buffering molecules in non-aqueous solutions.
This may be because the pKa values of functional groups of
molecules depend on solvent,[5] and thus, molecules that act as
buffering molecules in aqueous solutions do not have the pKa
values required to serve as buffering molecules in non-aqueous
solutions.
• supress racemizations, isomerizations,
decompositions caused by acids or bases
R
Introduction
O
O
O
in the absence of a
buffering molecule
HO
24% ee
Control of chemical reactions is necessary to obtain desired
chemical transformation products and to prevent decompositions
and isomerizations of molecules of interest. As organic synthesis
is important for drug discovery and related areas,[1] there is a
high demand for chemical transformation methods and for
strategies to control chemical reactions. To control chemical
reactions in aqueous solutions or to maintain conditions suitable
for enzyme-catalyzed reactions and for storage of biological
samples such as enzymes and antibodies, the use of buffers is a
common practice.[2] However, no molecules that have buffering
functions in non-aqueous solutions to maintain conditions
suitable for chemical reactions were commonly used. For
chemical transformations in non-aqueous solutions, the
selection of solvents may be the first step to tune the reaction
environment.[3] Reagents and/or catalysts are usually developed
to meet the requirements of the desired chemical
transformations. Scavengers have also been employed to
remove certain molecules in non-aqueous solutions to maintain
the desired conditions.[4] Common scavenger molecules,
however, do not have buffering functions; scavengers that
remove acids cannot be used to remove bases and vice versa.[4]
We hypothesized that the use of molecules that neutralize both
acids and bases in organic solvents and thus have buffering
functions in non-aqueous solutions would provide further
DBU, rt, 10 h
O
R = H, CH3, CH2Ph,
Ph, CPh3, etc.
100% ee
N
in the presence of a
buffering molecule
H
100% ee
acting as buffering
molecules in non-
aqueous solutions
• alter reaction products
R'
R'
O
R'
H
in the absence
of a buffering
molecule
O
H
O
H
HO
H
O
TfOH
O
N
O
in the presence
of a buffering
molecule
N
Ph
N
Ph
Ph
Figure 1. Examples of buffering molecules that function in non-aqueous
solutions reported here and the control of reactions using the buffering
molecules.
We hypothesized that 1,3-cyclohexanedione derivatives
would have buffering functions in organic solvents based on the
reactions of 1,3-cyclohexanedione: When 1,3-cyclohexanedione
was used as a reactant in organic solvents, an increase in the
equivalents of 1,3-cyclohexanedione relative to the reaction
partner substrates did not enhance the reaction rates or even
slowed the reactions.[6] This was unusual as reaction rates
usually increase as the loading (and thus the concentration) of a
reactant is increased. In organocatalytic and other catalytic
reactions that use simple ketones (such as acetone and
cyclohexane) as a reactant, the ketones are often used in
excess (5 equivalents or more relative to the partner
reactants).[7-9] The excess loadings of the simple ketones in the
reactions are often desired and/or required to enhance the
reaction rates and/or to obtain the desired products.[7-9] In our
survey of the literature on the reactions of 1,3-cyclohexanedione
derivatives reported by other research groups, we found that the
[a]
Dr. M. Sohail, Prof. Dr. F. Tanaka
Chemistry and Chemical Bioengineering Unit
Okinawa Institute of Science and Technology Graduate University
1919-1 Tancha, Onna, Okinawa 904-0495 (Japan)
E-mail: ftanaka@oist.jp
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903552
Chemistry - A European Journal
RESEARCH ARTICLE
loading amounts of 1,3-cyclohexanedione were not in excess in
most cases.[10,11] We reasoned that high loadings of 1,3-
cycohexanedione might partially neutralize bases or acids
depending on the reaction and that 1,3-cycohexanedione was
essentially functioning as a buffering molecule in organic
solvents. We hypothesized that the buffering function of 1,3-
cyclohexanedione and related compounds could be used for
adjusting conditions to control chemical events in non-aqueous
solutions (Figure 1). The data reported here support that
hypothesis.
For the isomerization of 2 catalyzed by DBU, the ratio of
compound 2 to compound 3 was 24:76 at 5 min after the
addition of DBU (Table 1, entry 2). In the presence of compound
1a (1.0 equivalent relative to 2), compound 2 was unchanged or
was not isomerized by the addition of DBU (Table 1, entry 3);
formation of 3 was less than 1% even after 3 days in the
presence of 1a. Similarly, in the presence of 1a, compound 2 did
not isomerize to 3 by the addition of TfOH (Table 1, entry 8).
Compound 1a blocked both the DBU-catalyzed and the TfOH-
catalyzed isomerization of 2, indicating that 1a neutralized both
the base and the acid. Acetic acid suppressed only the base-
catalyzed isomerization (Table 1, entries
4 and 9), and
benzylamine suppressed only the acid-catalyzed isomerization
(Table 1, entries 5 and 10); that is, acetic acid neutralized only
the base, and benzylamine neutralized only the acid. Thus, the
effect of compound 1a on both the base and the acid in an
organic solvent (Table 1, entries 3 and 8) is novel; the results
suggest that compound 1a has a buffering function in non-
aqueous solutions.
Results and Discussion
Evaluation of 1,3-cyclohexanedione to inhibit acid- and
base-catalyzed isomerization in organic solvents. To test our
hypothesis that 1,3-cyclohexanedione has a buffering function
and neutralizes both acids and bases in non-aqueous solutions,
we first examined whether 1,3-cyclohexanedione (1a) inhibited
the isomerization of 2[12] to 3[12,13] catalyzed by 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) at 25 °C and by
trifluoromethanesulfonic acid (TfOH) at 60 °C in CDCl3 (Table 1).
Compound 2 is a useful synthetic intermediate in the formation
of spirooxindole polycycles and is readily isomerized to 3 under
acidic or basic conditions.[12,13] The ratio of 2 to 3 can be easily
determined.[12,13]
Next, the capability of compound 1a to neutralize various
bases and acids in an organic solvent was analyzed by
evaluating the effect of 1a on the isomerization reaction of 2 to 3
catalyzed by various bases and acids (Supporting Information
Table S1). Although the degree of isomerization catalyzed by
the bases and acids varied depending on the base or acid,
compound 1a completely or almost completely suppressed the
isomerization of
2 catalyzed by various bases such as
Table 1. The effect of cyclohexane-1,3-dione (1a) in the DBU- and TfOH-
catalyzed isomerization of 2 to 3.[a]
potassium tert-butoxide and 1,1,3,3-tetramethylguanidine and by
various acids such as methanesulfonic acid and p-
toluenesulfonic acid. That is, the buffering function of compound
1a was observed in non-aqueous solutions against various
bases and acids.
O
O
O
H
H
H
H
H
nPr
O
H
H
nPr
O
H
H
nPr
O
DBU
or TfOH
+
O
O
O
N
N
N
compound
to test
CDCl3
O
O
O
Ph
Ph
Ph
The scope of the inhibition function of 1a on the
isomerization of 2 to 3, or the buffering function of 1a, was also
investigated in various solvents (Supporting Information Tables
S2 and S3). In all solvents tested, the isomerization of 2 to 3 by
DBU or by TfOH was observed to some degree in the absence
of 1a. In the presence of 1a, no isomerization of 2 was detected
in chloroform or in toluene. In acetonitrile, acetone, 2-propanol,
1,4-dioxane, and tetrahydrofuran (THF), the isomerization of 2 to
3 was almost completely suppressed (less than 5%) in the
presence of 1a. In dimethylsulfoxide (DMSO), the isomerization
was partially inhibited by 1a. In polar solvents, changes in the
pKa values of the base, of the acid, and of 1a from those in non-
polar solvents may affect the neutralizing function of 1a, or the
formation of hydrogen bonds between solvent molecules and 1a
may prevent the interaction of 1a with the base or acid, resulting
in a reduction of the buffering function of 1a. Although the
buffering function of 1a did not work in some polar solvents,
compound 1a buffered various organic solvents, including 2-
propanol.
2
2
3
DBU or TfOH
(condition)
entry
compound to test
2:3
1
2
3
– (A)
–
>99.5:0.5
DBU (A)
DBU (A)
–
24:76 (24:76)b
>99.5:0.5 (>99:1)[b]
>99:1[c]
,
1a
4
DBU (A)
DBU (A)
– (B)
CH3COOH
>99:1
5
PhCH2NH2
24:76
6
–
>99.5:0.5
29:71
7
TfOH (B)
TfOH (B)
TfOH (B)
TfOH (B)
–
8
1a
>99.5:0.5
24:76
9
CH3COOH
PhCH2NH2
10
96:4
Compound 1a also inhibited the acid- and base-catalyzed
isomerization of 2 to 3 over a wide range of concentrations
(Supporting Information Tables S4 and S5). When the DBU-
catalyzed and TfOH-catalyzed isomerization reactions of 2 to 3
in CDCl3 were analyzed over various concentrations of 2 in the
presence of one equivalent of 1a, the isomerization was
[a] A mixture of 2 (2:3 >99.5:0.5, 1.0 equiv) and the test compound (1.0 equiv)
in CDCl3 was stirred in the presence of DBU (0.01 equiv) under condition A or
TfOH (0.1 equiv) under condition B, and the ratio of 2:3 was determined by 1H
NMR analysis at rt. Condition A: rt (25 °C) for 5 min; Condition B: 60 °C for 1
h. [b] Data after 3 days. [c] With DBU (0.1 equiv).
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10.1002/chem.201903552
Chemistry - A European Journal
RESEARCH ARTICLE
suppressed to less than 1% in the range from 0.003 M to 0.14 M. completely inhibited the isomerization of 2, as did 1a, indicating
Further, even when 1a was present at less than one equivalent
relative to 2, the buffering function of 1a was observed
(Supporting Information Tables S6 and S7). Further, the
buffering function of 1a was retained in the solution for more
than 3 days, even at 60 °C, in the presence of TfOH (Supporting
Information Table S8). Compound 1a has a buffering function
over a wide range of conditions in non-aqueous solutions.
that mono substitutions with methyl, benzyl, or phenyl groups at
the 2-position of 1,3-cyclohexanedione and methyl substitutions
at the 4- and 6-positions of 1,3-cyclohexanedione did not affect
the buffering function (Table 2). In the presence of the 1,3-
cyclohexanedione derivative bearing an isopropyl group at the 2-
position (compound 1f), the isomerization of 2 was less than 1%.
The 1,3-cyclohexanedione derivatives with mono- or di-
substitutions at the 5-position (compounds 1g-1i) also inhibited
Identification of other molecules that show buffering
functions in non-aqueous solutions. We then sought to
identify other molecules with buffering functions in organic
solvents. We evaluated the effects of 1,3-cyclohexanedione
derivatives and related molecules on the DBU-catalyzed and
TfOH-catalyzed isomerization reactions of 2 to 3 (Table 2; see
also SI Table S9). 1,3-Cyclohexanedione derivatives 1b-1e
the isomerization to
a
similar extent to 1f. 1,3-
Cyclohexanediones bearing cyclohexyl or triphenylmethyl
groups, which are bulkier substituents than the isopropyl group,
at the 2-position (compounds 1j and 1k, respectively) had a
slightly reduced effect to inhibit the isomerization relative to 1f.
1,3-Cyclohexanedione conjugated to resin beads (resin-
conjugated 1b) also inhibited the isomerization.
Table 2. Effects of 1,3-cyclohexanedione derivatives and related compounds 1 in the DBU-catalyzed and TfOH-catalyzed isomerization of 2 to 3.[a]
O
O
O
H
H
H
H
H
nPr
O
H
H
nPr
O
DBU
or TfOH
H
H
nPr
O
+
O
O
O
N
N
N
1
CDCl3
O
O
O
2:3 (reaction with DBU)
2:3 (reaction with TfOH)
Ph
Ph
Ph
2
3
2
Ph
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Ph
1a
>99.5:0.5
>99.5:0.5
1b
>99.5:0.5
1c
>99.5:0.5
>99.5:0.5
1e
>99.5:0.5
1d
>99.5:0.5
1f
>99:1
1g
>99:1
1h
>99.5:0.5
1i
>99.5:0.5
>99:1
>99:1
>99:1
>99:1
>99.5:0.5
>99.5:0.5
>99.5:0.5
O
Ph
O
O
Ph
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Ph
O
1p
23:77
43:57
1s
24:76
33:66
1q
28:72
75:25
1r
26:74
48:52
1j
1k
1l
1m
90:10
93:7
1n
26:74
33:67
1o
24:76
84:16
97:3
96:4
94:6
99:1
97:3
>99:1
resin-linker
O
CF3
CF3
O
OH
HO
OH
HO
OH
OH
O
OH
S
N
N
CF3
N
H
N
H
CF3
O
1y
resin-conjugated 1b
>99:1
1t
1u
1v
1w
1x
1z
>99.5:0.5
78:22
24:76
35:65
23:77
72:28
24:76
92:8
26:74
53:47
97:3
24:76
63:37
38:62
>99:1
[a] A solution of 2 (2:3 >99.5:0.5, 1.0 equiv) and 1 (1.0 equiv) in CDCl3 was stirred at room temperature (25 °C) for 5 min in the presence of DBU (0.01 equiv) or at
60 °C for 1 h in the presence of TfOH (0.1 equiv). The 2:3 ratio was determined by 1H NMR analysis at room temperature and is shown in magenta for the
reaction with DBU and in blue for the reaction with TfOH.
1,3-Cyclopentanedione
(1l)
and
2-acetyl-1,3-
These results indicate that compounds 1a-1e are the most
effective buffering molecules of the compounds tested.
Compound 1a can act as a nucleophile, as compound 2 is
synthesized by the reaction with 1a.[12] The use of compounds
1b-1d may be suitable for providing buffering functions to avoid
the use of 1a, which has a reactive methylene group at the 2-
position. Compounds 1f, 1j, and 1k may also be suitable for
various applications that require buffering function. Similarly,
resin bead-attached 1,3-cyclohexanedione (resin-conjugated 1b)
may also be suitable for various uses to provide buffering
functions.
cyclohexanedione (1m) also had some buffering function in the
DBU-catalyzed and TfOH-catalyzed isomerization reactions of 2.
On the other hand, 1,2-cyclohexanedione (1n), 1,4-
cyclohexanedione (1o), and 2,2-dimethyl-1,3-cyclohexanedione
(1p) did not have
a buffering function to suppress the
isomerization. Acyclic molecule 2,4-pentanedione (1q) also did
not inhibit the isomerization. Molecules that are used as buffers
in
aqueous
solutions,
such
as
2-[bis(2-
hydroxy)amino]ethanesulfonic acid (BES), also did not inhibit the
isomerization (Supporting Information Table S9).
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10.1002/chem.201903552
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RESEARCH ARTICLE
Effects of 1,3-cyclohexanedione derivatives to inhibit
acid- and base-catalyzed isomerization and decomposition.
conditions, and the acidic conditions caused the formation of
elimination product 6[16] (Scheme 1a(ii)). Compound 1b also
prevented the acid-catalyzed racemization and the elimination
reactions of 4 (Scheme 1a(ii)).
Compounds
1 were then evaluated in isomerization and
decomposition reactions of aldol products or β-hydroxyketones
(Scheme 1a, b). Aldol 4[7p,14] is readily racemized under basic
conditions,[15] and the basic conditions also cause a retro-aldol
reaction of 4 to generate 5 (Scheme 1a(i)). The addition of 2-
methyl-1,3-cyclohexanedione (1b) to the solution of aldol 4
blocked the base-catalyzed racemization and the retro-aldol
reaction of 4 (Scheme 1a(i), Supporting Information Tables S10-
S13). Resin-supported 1b also completely inhibited the
racemization and the decomposition. The addition of 2-
pyridinecarboxylic acid, N,N-dimethylglycine, or glycine instead
of 1a was unable to prevent the racemization (Supporting
Information Table S11). Aldol 4 was also racemized under acidic
Similarly, 1,3-cyclohexanedione derivatives 1b and 1k also
completely inhibited the racemization of β-hydroxyketone 7 and
the decomposition of 7[7d,e] that generated 8 and 9 (Scheme 1b).
Isomerization of Mannich reaction product or amino
aldehyde derivative 10 to 11[8d] in the presence of DBU was also
prevented by the addition of 1b (Scheme 1c). Decomposition
reactions of β-hydroxy-α-amino acid derivative or protected
threonine derivative 12 by dehydration that resulted in the
formation of 13 and by hydrolysis leading to the generation of
benzyl alcohol were also inhibited by 1b (Scheme 1d).
a
b
(i)
O
(i)
OH
O
OH
O
O
O
HO
HO
DBU (0.1 equiv)
CDCl3, rt, 12 h
DBU (0.1 equiv)
CD3CN, rt
+
O
O
O
7
Br
Br
N
H
N
H
N
H
O
O
(R)-7 (100% ee)
4
5
(S)-4 (100% ee)
10 h: 4:5 = 94:6; 4 (24% ee)
72 h: 4:5 = 81:19; 4 (17% ee)
H
+
+
DBU (0.1 equiv)
Br
Br
8
9
1b (1.0 equiv)
10 h: 4:5 = 100:0; 4 (100% ee)
72 h: 4:5 = 100:0; 4 (>99.9% ee)
7:8:9 = 94:4:2; 7 (99% ee)
CD3CN, rt
DBU (0.1 equiv)
1b or 1k (1.0 equiv)
DBU (0.1 equiv)
resin-conjugated 1b (1.0 equiv)
7:8:9 = 100:0:0; 7 (100% ee)
CDCl3, rt, 12 h
10 h: 4:5 = 100:0; 4 (100% ee)
72 h: 4:5 = 100:0; 4 (>99.9% ee)
(ii)
OH
O
CD3CN, rt
TfOH (0.1 equiv)
CDCl3, rt, 6 h
7:8:9 = 88:2:10; 7 (93% ee)
7:8:9 = 100:0:0; 7 (100% ee)
O
(ii)
O
O
Br
HO
HO
(R)-7 (100% ee)
TfOH (0.1 equiv)
TfOH (0.1 equiv)
O
1b or 1k (1.0 equiv)
+
O
O
CD3CN, rt
N
H
N
H
CDCl3, rt, 6 h
N
H
4
6
(S)-4 (100% ee)
72 h: 4:6 = 90:10; 4 (94% ee)
d
(i)
O
OH
O
OH
O
TfOH (0.1 equiv)
DBU
(0.1 equiv)
1b (1.0 equiv)
72 h: 4:6 >99:1; 4 (100% ee)
+
OCH2Ph
OCH2Ph
OCH2Ph
NHCbz
CD3CN, rt
CDCl3, rt, 1 h
NHCbz
NHCbz
12
13
12
TfOH (0.1 equiv)
resin-conjugated 1b (1.0 equiv)
12:13 = 85:15, 12 (purity >95%)
DBU
(0.1 equiv)
72 h: 4:6 >99:1; 4 (100% ee)
12:13 = 100:0, 12 (purity >99%)
CD3CN, rt
1b (1.0 equiv)
CDCl3, rt, 1 h
c
(ii)
OH
O
OH
O
DBU (0.1 equiv)
TfOH
(0.1 equiv)
O
NHPMP
COOEt
O
NHPMP
COOEt
10:11 = 55:45
10:11 = 86:14
+
+
CDCl3, rt, 10 h
PhCH2OH
OCH2Ph
OCH2Ph
NHCbz
H
H
CDCl3, rt, 12 h
NHCbz
12
DBU (0.1 equiv)
12
TfOH
(0.1 equiv)
12:PhCH2OH = 92:8
12:PhCH2OH = 100:0
10
11
1b (1.0 equiv)
10:11 = 86:14
CDCl3, rt, 10 h
1b (1.0 equiv)
CDCl3, rt, 12 h
Scheme 1. Effects of 2-methyl-1,3-cyclohexanedione (1b) and related 1,3-cyclohexanedione derivatives on the isomerizations and decompositions of
compounds. a, Effects on the racemization and decomposition of β-hydroxyketone derivative (aldol) 4. b, Effects on the racemization and decomposition of β-
hydroxyketone derivative (aldol) 7. c, Effects on the isomerization of amino aldehyde derivatives (Mannich reaction products) 10 and 11. d, Effects on the
isomerization and decomposition of β-hydroxy α-amino acid derivative 12.
Effects of 1,3-cyclohexanedione derivatives to alter and
control chemical transformations. The use of 2-methyl-1,3-
cyclohexanedione (1b) was not limited to the prevention of
isomerization and decomposition of compounds by buffering.
The use of 1b also altered the products of the chemical
transformations (Schemes 2-4). For the protection of the
hydroxy group of aldol 14, when 14 was treated with TMSCN[17]
in the presence of DBU as a base at 60 °C, products 15, 16, and
17 were obtained; selective formation of 15 in a high yield was
not achieved (Scheme 2). When the same reaction was
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10.1002/chem.201903552
Chemistry - A European Journal
RESEARCH ARTICLE
performed but with the addition of 1b, product 15 was obtained
in a high yield, and the enantiopurity of the starting material was
retained in the product (Scheme 2). In the absence of 1b, the
cyanide anion generated from TMSCN reacted with 14 to give
16 and 17. In the presence of 1b, the cyanide anion may be
protonated, preventing it from acting as a nucleophile.
The reaction of β-hydroxyenone derivative 18 with furan was
also altered by the addition of 1b (Scheme 3a). Under acidic
conditions, compound 18 was readily converted to oxa-Michael
cyclization product 19.[18] Neat conditions for the reaction of 18
with furan using TfOH as catalyst resulted in the formation of a
complex mixture containing more than six new spots on TLC
analysis; none of them were 20 or 21. In contrast, the reaction
under the same neat conditions but in the presence of 1b
afforded furan-added products 20 (keto form) and 21 (enol form)
(Scheme 3a). Similarly, TfOH-catalyzed reactions of β-
hydroxyenone derivative 22 with furan in the presence of 1b
afforded corresponding addition products 23 and 24 (Scheme
3b), and the reaction of 14 under these conditions yielded 25
(Scheme 3c). The TfOH-catalyzed reactions of 18 with
thiophene or benzofuran in the presence of 1b afforded
corresponding addition products 26 and 27, respectively
(Scheme 3d).
nPr
nPr
nPr
OTMS
CN
TMSCN
DBU
(0.1 equiv)
CHCl3
60 °C, 1 h
HO
TMSO
TMSO
O
O
+
O
O
O
N
H
N
H
N
H
16
29%
15
29%
nPr
CN
14
TMSO
O
O
+
N
H
17
34%
nPr
nPr
HO
TMSO
TMSCN
O
O
DBU (0.1 equiv)
1b (1.0 equiv)
CHCl3, 60 °C, 1.5 h
O
O
N
H
N
H
(R)-14
(100% ee)
15
96% (100% ee)
Scheme 2. Effects of 2-methyl-1,3-cyclohexanedione (1b) on chemical
transformations; protection of hydroxy groups.
a
b
nPr
nPr
Ph
Ph
Ph
O
O
(3 equiv)
O
O
O
TfOH (0.1 equiv)
CDCl3, 60 °C, 1 h
(48 equiv)
HO
HO
O
O
O
O
TfOH (0.1 equiv)
O
OH
+
N
O
O
O
1b (1.0 equiv)
neat, 60 °C, 1 h
O
N
22
N
N
Ph
19
N
100% (1H NMR analysis)
Ph
Ph
Ph
(48 equiv)
O
TfOH (0.1 equiv)
18
23
24
Ph
96% (23 + 24), 23:24 = 55:45
more than 6 products on TLC
neat, 60 °C, 1 h
nPr
nPr
d
nPr
nPr
O
O
S
(48 equiv)
O
TfOH (0.1 equiv)
S
TfOH (0.1 equiv)
O
OH
HO
O
O
+
O
O
1b (1.0 equiv)
neat, 60 °C, 1 h
1b (1.0 equiv)
O
O
N
N
N
neat, 60 °C, 1 h
N
18
Ph
20
98% (20 + 21), 20:21 = 35:65
Ph
21
Ph
Ph
26
88%
(48 equiv)
O
no reaction (18 remained)
nPr
1b (1.0 equiv)
neat, 60 °C, 24 h
O
c
nPr
nPr
O
TfOH (0.1 equiv)
OH
O
O
N
(48 equiv)
1b (1.0 equiv)
neat, 60 °C, 5 h
O
TfOH (0.1 equiv)
HO
O
O
Ph
1b (1.0 equiv)
neat, 60 °C, 1 h
27
45%
O
O
N
H
N
H
25
92%
14
Scheme 3. Effects of 2-methyl-1,3-cyclohexanedione (1b) on chemical transformations; addition reactions.
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10.1002/chem.201903552
Chemistry - A European Journal
RESEARCH ARTICLE
a
b
nPr
nPr
R1
R1
O
R1
O
H
O
O
H
TfOH (0.1 equiv)
TfOH (0.1 equiv)
HO
HO
O
O
O
TfOH (0.1 equiv)
H
O
H
CHCl3
60 °C, 1 h
1b (1.0 equiv)
CHCl3, 60 °C
12 h
N
1b (1.0 equiv)
CHCl3, 60 °C, 12 h
O
O
N
R2
O
N
N
R2
Ph
N
R2
19
100% (1H NMR analysis)
Ph
29: R1 = n-hexyl, R2 = CH2Ph
30: R1 = i-Pr, R2 = CH2Ph
31: R1 = n-Pr, R2 = Ph
18
32-34
nPr
nPr
H
O
nhexyl
nPr
TfOH (0.1 equiv)
nhexyl
nPr
1b (1.0 equiv)
CHCl3, 60 °C, 12 h
H
O
H
O
H
H
O
H
H
O
H
O
H
H
O
O
O
O
O
N
O
O
H
H
H
H
H
H
N
Ph
O
O
N
O
N
Ph
N
N
N
N
Ph
Ph
28
65%
Ph
Ph
34
61%
Ph
Ph
32
71%
33
67%
Scheme 4. Effects of 2-methyl-1,3-cyclohexanedione (1b) on chemical transformations; dimerization reactions of isatin aldol derivatives to afford spirooxindole
octahydropentalenes.
Further, the use of the buffering function of 1b allowed the
synthesis of complex spirooxindole derivatives (Scheme 4).
Spirooxindoles bearing fused ring systems are of interest for the
development of pharmaceuticals and related molecules.[12,13,19]
Concise construction of functionalized fused ring systems is a
challenge,[12,13,19,20] however. Under acidic conditions with TfOH,
compound 18 was transformed to oxa-cyclization product 19.[18]
The same reaction but with the addition of 1b led to the
dimerization of 18, resulting in the formation of spirooxindole
octahydropentalene derivative 28 (Scheme 4a). The relative
stereochemistry of 28 was determined by X-ray crystal structural
analysis.[21] Note that treatment of spirooxindole tetrahydropyran
19 under the conditions used for the formation of 28 (i.e., with
TfOH and 1b) did not form 28. The treatment of 18 with 1b alone
without TfOH did not lead to the formation of 19 or 28. Milder
acids such as acetic acid and trifluoroacetic acid also did not
catalyze the formation of 28 from 18. These results suggest that
the use of compound 1b in the TfOH-catalyzed reaction tunes
the reaction conditions for the formation of 28 or that compound
1b makes the TfOH-catalyzed reaction environment less acidic
allowing the formation of the enolate from 18, which is
necessary for the C-C bond formation that leads to the formation
of 28. Similarly, the TfOH-catalyzed reactions of 29-31 in the
presence of 1b afforded 32-34, respectively (Scheme 4b). The
buffering function of 1b enabled the synthesis of complex
spirooxindole octahydropentalenes.
significantly higher than that of cyclohexanone.[24] Bases easily
abstract the proton from 1,3-cyclohexanedione derivatives. The
lone pair of the ketone carbonyl oxygen of 1,3-cyclohexanedione
derivatives may act as a Lewis base to react with acids. Thus,
acids and bases added to the reaction mixtures protonate and
deprotonate the 1,3-cyclohexanedione derivatives, respectively.
As a result, the acidic/basic environments of the solutions
containing acids (such as TfOH) or bases (such as DBU) in the
presence of 1,3-cyclohexanedione derivatives with buffering
functions may be similar to those that the 1,3-cyclohexanedione
derivatives provide, apart from the conditions that the acids
(such as TfOH, the pKa is 0.3 in DMSO[6]) or bases (such as
DBU) originally create.
Conclusion
We have developed strategies to control chemical reactions.
The strategies use molecules that have buffering functions in
non-aqueous solutions. We have demonstrated that 1,3-
cyclohexanedione derivatives have buffering functions in non-
aqueous solutions and that the buffering functions of these
molecules in non-aqueous solutions can be used for tuning the
conditions to control chemical events. Addition of the buffering
molecule or its resin-conjugated version in storage solutions of
molecules of interest can prevent decompositions and/or
isomerizations of the molecules. To suppress decompositions
and isomerizations of the molecules by using the buffering
molecules that we have disclosed, there is no need to consider
whether the decomposition and/or isomerization is caused by a
base or an acid or which type of base or acid is causing the
decomposition, isomerization, and/or racemization. Additionally,
simply adding the buffering molecule to reaction mixtures can
completely alter the pathways of the reactions. No such simple
operations to control chemical reactions were demonstrated
previously, to the best of our knowledge. By introducing the
Mechanisms underlying the buffering functions of 1,3-
cyclohexanedione derivatives. The buffering functions of 1,3-
cyclohexanedione derivatives may be explained by their pKa
values, which are associated with the tautomerization
equilibrium of these molecules and the fast dynamics of the
equilibrium. The pKa of 1a has been experimentally determined
to be 10.3 in DMSO[22] and has been theoretically predicted to
be 8.0 using MP2 and 5.5 using B3LYP.[23] It has also been
reported that 1,3-cyclohexanedione has the proton affinity
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10.1002/chem.201903552
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RESEARCH ARTICLE
[8]
Examples in Mannich and related reactions: a) G. List, J. Am. Chem.
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concept of buffering in non-aqueous solutions, simple ways to
control chemical reactions have been realized.
The buffering molecules suppress isomerization and
decomposition reactions of various compounds and alter the
products of chemical transformations in non-aqueous solutions,
allowing access to products that are not generated in the
absence of buffering molecules. The use of buffering molecules
in non-aqueous solvents provides a strategy to control chemical
reactions and expands the range of compounds that can be
synthesized.
[9]
Examples in Michael and other reactions: a) H. Huang, E. N. Jacobsen,
J. Am. Chem. Soc. 2006, 128, 7170; b) S. V. Pansare, K. Pandya, J.
Am. Chem. Soc. 2006, 128, 9624; c) C. L. Cao, M.-C. Ye, X.-L. Sun, Y.
Tang, Org. Lett. 2006, 8, 2901; d) S. H. McCooey, S. J. Connon, Org.
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Ma, Org. Lett. 2007, 9, 923; f) B. Tang, X. Zeng, Y. Lu, P. J. Chua, G.
Zhong, Org. Lett. 2009, 9, 1927.
Acknowledgements
We thank Dr. Michael Chandro Roy, Research Support Division,
Okinawa Institute of Science and Technology Graduate
University for mass analyses. This study was supported by the
Okinawa Institute of Science and Technology Graduate
University.
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Keywords: aldol reaction • organocatalysis • Michael addition •
reaction control • spiro compounds
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10.1002/chem.201903552
Chemistry - A European Journal
RESEARCH ARTICLE
Entry for the Table of Contents
Layout 2:
RESEARCH ARTICLE
Muhammad Sohail and Fujie Tanaka*
R'
R'
O
R
O
R'
H
in the absence
of a buffering
molecule
O
O
HO
O
H
TfOH
Page No. – Page No.
O
24% ee
O
H
DBU, rt, 10 h
H
O
in the presence
of a buffering
molecule
HO
buffering
molecules
that act in
non-aqueous
solutions
100% ee
N
Control of Chemical Reactions Using
Molecules that Buffer Non-aqueous
Solutions
O
in the presence
of a buffering
molecule
N
H
100% ee
O
N
Ph
N
Ph
Ph
A strategy to control chemical reactions was developed with the discovery that 1,3-
cyclohexanone derivatives act as buffering molecules in non-aqueous solutions.
With the buffering molecules, undesired isomerization and decomposition of
molecules of interest were suppressed. The use of the buffering molecules altered
the chemical transformation products and expanded the range of molecules that
were able to be accessed.
This article is protected by copyright. All rights reserved.