Enantioselective Direct anti-Selective Mannich-type Reactions Catalyzed by 3-Pyrrolidinecarboxylic Acid in the Presence of Potassium Carbonate: Addition of Potassium Carbonate Improves Enantioselectivities

Article abstract of DOI:10.1021/acs.orglett.0c01561

Mannich-type reactions of cyclohexanone and related six-membered-ring ketones with N-p-methoxyphenyl-protected imines of arylaldehydes catalyzed by 3-pyrrolidinecarboxylic acid in the presence of K2CO3 that afford anti-isomers of the Mannich products with

Full text of DOI:10.1021/acs.orglett.0c01561

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Letter
Enantioselective Direct anti-Selective Mannich-type Reactions
Catalyzed by 3‑Pyrrolidinecarboxylic Acid in the Presence of
Potassium Carbonate: Addition of Potassium Carbonate Improves
Enantioselectivities
Yuvraj Garg and Fujie Tanaka*
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ABSTRACT: Mannich-type reactions of cyclohexanone and related
six-membered-ring ketones with N-p-methoxyphenyl-protected imines
of arylaldehydes catalyzed by 3-pyrrolidinecarboxylic acid in the
presence of K2CO3 that afford anti-isomers of the Mannich products
with high diastereo- and enantioselectivities are reported. Addition of
K2CO3 improved the enantioselectivities of the reactions catalyzed by
3-pyrrolidinecarboxylic acid while retaining the anti-selectivity of the
reaction. Thus, the use of K2CO3 expands the scope of these
organocatalytic reactions for providing the products with high
enantioselectivities.
symmetric Mannich and Mannich-type reactions of
ketones with imines are important transformations to
Scheme 1. Mannich-type Reactions Catalyzed by 3-
Pyrrolidinecarboxylic Acid
A
synthesize enantiomerically enriched amino ketones, amino
alcohols, and their related derivatives, which are used for the
development of bioactive molecules and related research.1−4
Various types of catalysts, including metal-based catalysts and
organocatalysts, have been used for providing the Mannich
products with high diastereo- and enantioselectivities.1−4
However, each catalyst system has a certain scope. To expand
or alter the scope, different catalysts are usually required. The
design and the synthesis of new catalysts are important for the
development of reaction methods, but we sought an alternative
way to expand the scope and improve stereoselectivities of the
reactions catalyzed by certain catalysts. We hypothesized that
the use of additives, such as alkali metal salts,5,6 in the reactions
catalyzed by organocatalysts would tune the transition states of
the reactions to expand or alter the scope of the catalyzed
reactions for leading to the products with high enantiose-
lectivities.
Homochiral 3-pyrrolidinecarboxylic acid (or β-proline) has
been used for catalyzing direct Mannich-type reactions of
ketones or aldehydes with N-p-methoxyphenyl (PMP)-
protected imine of glyoxylates to afford anti-isomers of
Mannich products with high diastero- and enantioselectivities
(Scheme 1a).4 However, the 3-pyrrolidinecarboxylic acid-
catalyzed reactions of cyclohexanone with PMP-protected
imines of arylaldehydes previously provided the anti-isomers of
the Mannich products with low or moderate enantioselectiv-
ities (Scheme 1b).4a Whereas highly enantioselective Mannich
and Mannich-type reactions of cyclohexanone with arylimines
to afford the syn-isomers of the Mannich products with high
Received: May 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01561
Org. Lett. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Organic Letters
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Letter
enantioselectivities have been reported using various catalysts,2
few examples of the reactions that afford the corresponding
anti-isomers of the Mannich products with high diastereo- and
enantioselectivities have been reported.3 Here, we report anti-
selective Mannich-type reactions of cyclohexanone and related
ketones with PMP-protected imines of arylaldehydes catalyzed
by 3-pyrrolidinecarboxylic acid in the presence of K2CO3
(Scheme 1c). We report that the use of K2CO3 as additive
improves the enantioselectivities of the reactions catalyzed by
3-pyrrolidinecarboxylic acid with retaining the anti-selectivities.
In the previously reported 3-pyrrolidinecarboxylic acid-
catalyzed reactions of ketones or aldehydes with the imine of
ethyl glyoxylate, the hydrogen bonds between the carboxylic
acid of the catalyst and the imine or the hydrogen transfer from
the carboxylic acid to the imine can locate the glyoxylate
imines at the position suitable for the C−C bond formation
and control the stereochemistries of the products, leading to
the formation of the anti-Mannich products (Figure 1a).4a In
formation with high enantioselectivities while retaining the
anti-selectivity (Figure 1c). The O−K and the N−K bonds are
longer than the O−H and the N−H bonds in the O−H−N
hydrogen bond;8 the longer bonds would allow the positioning
of the reactants in the transition state for the C−C bond
formation to form the product in a stereocontrolled way.
First, we evaluated various alkali metal salts, alkaline earth
metal salts, and tetraalkylammonium salts as additives in the
(S)-3-pyrrolidinecarboxylic acid-catalyzed Mannich-type reac-
tion of cyclohexanone (1a) with PMP-protected imine 2a to
afford anti-3a with high diastereo- and enantioselectivities
(Table 1, see also Supporting Information). Of additives tested
Table 1. Evaluation of Additives for the (S)-3-
Pyrrolidinecarboxylic Acid-Catalyzed Mannich-type
a
Reaction of 1a with 2a to Afford 3a
b
b
c
entry
additive
time (h)
yield (%)
anti/syn
er
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
none
20
20
20
20
48
20
20
20
20
20
20
20
20
192
168
168
192
40
70
44
55
90
12
43
57
59
68
62
83
77
92
82
98
>20:1
>20:1
>20:1
9:1
9:1
ND
8:1
5:1
9:1
>20:1
>20:1
>20:1
4:1
>20:1
12:1
>20:1
18:1
71:29
68:32
81:19
90:10
90:10
ND
87:13
87:13
89:11
70:30
70:30
68:32
76:24
75:25
94:6
Li2CO3
Na2CO3
K2CO3
K2CO3
Rb2CO3
Rb2CO3
Cs2CO3
MgCO3
CaCO3
SrCO3
BaCO3
Bu4NOH
none
d
d
Figure 1. A schematic representation of the transition states. (a) The
transition state of the Mannich-type reaction of cyclohexanone with
the ethyl glyoxylate imine catalyzed by (R)-3-pyrrolidinecarboxylic
acid, drawn based on previous reports.4 (b) (R)-3-Pyrrolidinecarbox-
ylic acid alone as catalyst may not lead the transition state that results
in the formation of the anti-Mannich products with high
enantioselectivities in the reactions of the imines of arylaldehydes.
(c) Proposed transition state of the Mannich-type reactions of
cyclohexanone with the imines of arylaldehydes catalyzed by (R)-3-
pyrrolidinecarboxylic acid in the presence K2CO3, which affords the
anti-Mannich products with high enantioselectivities.
e
e
K2CO3
none
K2CO3
ef
,
16
17
76:24
95:5
ef
,
g
91 (81)
a
Conditions: A mixture of (S)-3-pyrrolidinecarboxylic acid (0.1
mmol) and additive (0.1 mmol) in N-methylpyrrolidone (NMP) (0.3
mL) was stirred at rt (25 °C) for 1 h. To the mixture, CHCl3 (0.7
mL) and 1a (10 mmol) were added at the same temperature, followed
contrast, in the same catalyst-catalyzed reactions of ketones
with the imines of arylaldehydes, the hydrogen bonds or the
hydrogen transfer between the carboxylic acid and the imines
may not locate the imines at the positions suitable for the C−C
bond formation or may locate the imines at the position a little
far from that suited for the C−C bond formation (Figure 1b).
Accordingly, the C−C bond formation may occur without the
involvement of the hydrogen bonds or the hydrogen transfer,
resulting the formation of the products with moderate to low
enantioselectivities. The differences between the reactions of
the ethyl glyoxylate imine and of the arylaldehydes imines may
originate from the electron-withdrawing feature and/or the
structure of the ester group of the glyoxylate imine. The
electron-withdrawing group may affect the length of the
hydrogen bonds in the transition state.7 We hypothesized that
addition of alkali metal salts, alkaline earth metal salts, and
other additives (such as nontransition metals and ammonium
salts) would tune the positioning of the imines in the transition
state for the C−C bond formation, leading to the product
b
by 2a (1.0 mmol). Determined by 1H NMR analysis before
c
purification. ND = not determined. The er of anti-3a; determined by
d
HPLC analysis after purification. Additive (0.05 mmol, 0.05 equiv).
e
f
The reaction at 0 °C. CF3SO2NH2 (0.1 mmol) was added before
g
addition of CHCl3. Isolated yield of anti-3a in parentheses.
in the reaction at room temperature (rt, 25 °C), K2CO3 most
improved the enantioselectivity (Table 1, entries 4 and 5). The
reaction in the presence of K2CO3 at 0 °C gave the product
with enantiomer ratio (er) 94:6 (Table 1, entry 15). The (S)-
3-pyrrolidinecarboxylic acid-catalyzed reaction in the presence
of K2CO3 with further addition of CF3SO2NH2 afforded anti-
3a in a high yield with high dr (anti/syn = 18:1) with high
enantioselectivity (er 95:5) (Table 1, entry 17). We expected
CF3SO2NH2 acts to maintain the neutral environment9 for the
reaction in the presence of K2CO3, suppressing potential side
reactions and background reactions caused by basic conditions.
B
https://dx.doi.org/10.1021/acs.orglett.0c01561
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Next, the best conditions identified (i.e., conditions of Table
1, entry 17) were used for the synthesis of various Mannich
products 3 (Scheme 2). The reactions catalyzed by (S)-3-
pyrrolidinecarboxylic acid in the presence of K2CO3 afforded
the anti-products in good to high yields with high diastereo-
and enantioselectivities in most cases. The anti-Mannich
products synthesized from the imines of benzaldehydes bearing
electron-withdrawing groups at p- or m-positions and of the
imine of 3-pyridinecarboxyaldehyde were obtained with high
enantioselectivities (er 96:4−94:6 for 3a, 3b, 3c, 3d, 3h, 3i, 3j,
and 3o). In the absence of K2CO3, the same products were
obtained with moderate enantioselectivities (er 86:14−76:24).
The products derived from imines of benzaldehyde, 4-
methylbenzaldehyde, 2-naphthaldehyde, and heteroarylalde-
hydes were obtained with er 93:7−90:10 (3e, 3f, 3m, 3n, and
3p); for these cases, the same products were obtained with er
78:22−68:32 in the absence of K2CO3. For the reactions with
the imines bearing p-methoxy group or an o-substituent on the
phenyl group and with the imine of 1-naphthylaldehyde, the
products were obtained with moderate enantioselectivities (er
80:20−73:27 for 3g, 3k, and 3l); for these reactions, the
enantioselectivities in the presence of K2CO3 were also higher
than those observed in the reactions performed in the absence
of K2CO3.
Scheme 2. Scope of the Mannich-type Reactions Catalyzed
a
by the (S)-3-Pyrrolidinecarboxylic Acid−K2CO3 System
The (S)-3-pyrrolidinecarboxylic acid−K2CO3 catalyst sys-
tem was also useful for affording anti-Mannich products 4 from
the reactions of cyclohexanone derivatives and of heteroatom-
containing cyclic ketones (Scheme 3). Addition of K2CO3 also
improved the enantioselectivities of the 3-pyrrolidinecarboxylic
acid-catalyzed reactions.
The reaction catalyzed by the (S)-3-pyrrolidinecarboxylic
acid−K2CO3 catalyst system was readily scaled up. From a 3
mmol reaction, product 3c (anti-isomer, 960 mg, 85%) was
obtained with er 95:5.
Scheme 3. Ketone Variations in the Mannich-type Reactions
Catalyzed by the (S)-3-Pyrrolidinecarboxylic Acid−K2CO3
a
System
a
Conditions: 1a (10 mmol), 2 (1.0 mmol), (S)-3-pyrrolidinecarbox-
ylic acid (0.1 mmol), K2CO3 (0.1 mmol), and CF3SO2NH2 (0.1
mmol) in NMP (0.3 mL)−CHCl3 (0.7 mL) at 0 °C. See Supporting
Information. Reaction time, isolated yield containing anti- and syn-
a
Conditions: 1 (10 mmol), 2 (1.0 mmol), (S)-3-pyrrolidinecarboxylic
acid (0.1 mmol), K2CO3 (0.1 mmol), and CF3SO2NH2 (0.1 mmol) in
NMP (0.3 mL)−CHCl3 (0.7 mL). See Supporting Information.
Reaction time, isolated yield containing anti- and syn-isomers, dr =
anti/syn determined by 1H NMR analysis of the isolated product, and
er of the anti-isomer determined by HPLC analysis, except where
1
isomers except where noted, dr = anti/syn determined by H NMR
analysis of the isolated product, and er of the anti-isomer determined
b
by HPLC analysis are shown. Results of 3a are from Table 1. Data
c
before purification. Data of the reaction performed in the absence of
d
b
c
K2CO3. Reaction was not completed at the indicated time.
noted, are shown. Data before purification. Data of the reaction
performed in the absence of K2CO3. Isolated yield of the most major
e
d
Obtained from the reaction using (R)-3-pyrrolidinecarboxylic acid
instead of the (S)-3-pyrrolidinecarboxylic acid.
isomer (the major isomer of the anti-isomers).
C
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To understand the mechanism of the reactions catalyzed by
the (S)-3-pyrrolidinecarboxylic acid−K2CO3 catalyst system, in
the reaction to afford 3a, the product er was analyzed at
various time points. From the initial stage of the reaction (such
as at the 15% conversion) to the stage at more than 90%
conversion, the dr (anti/syn) of 3a was >18:1 and the er of the
anti-isomer of 3a was 95:5. No changes in the dr and the er
values were observed during the reaction, indicating that the
Mannich product is kinetically formed.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01561.
■
sı
Experimental procedures, additional information of the
results, characterization data of compounds, NMR
spectra, and HPLC chromatograms (PDF)
The utility of the (S)-3-pyrrolidinecarboxylic acid−K2CO3
catalyst system was further demonstrated by transformations of
the Mannich products (Scheme 4). Mannich product 3c was
AUTHOR INFORMATION
Corresponding Author
■
Fujie Tanaka − Chemistry and Chemical Bioengineering Unit,
Okinawa Institute of Science and Technology Graduate
University, Onna, Okinawa 904-0495, Japan; orcid.org/
0000-0001-6388-9343; Email: ftanaka@oist.jp
Scheme 4. Transformations of the Mannich Products
Author
Yuvraj Garg − Chemistry and Chemical Bioengineering Unit,
Okinawa Institute of Science and Technology Graduate
University, Onna, Okinawa 904-0495, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01561
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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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