Mannich Reactions of Carbohydrate Derivatives with Ketones to Afford Polyoxy-Functionalized Piperidines

Article abstract of DOI:10.1021/acs.orglett.9b00105

Mannich reactions of carbohydrate derivatives with ketones that afford polyoxy-functionalized piperidines are reported. Ketone nucleophiles (enamines/enolates) were generated in the presence of the amines used for the formation of the iminium ions of suga

Full text of DOI:10.1021/acs.orglett.9b00105

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mannich Reactions of Carbohydrate Derivatives with Ketones To
Afford Polyoxy-Functionalized Piperidines
Lingaiah Maram and Fujie Tanaka*
Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha,
Onna, Okinawa 904-0495, Japan
S
* Supporting Information
ABSTRACT: Mannich reactions of carbohydrate derivatives
with ketones that afford polyoxy-functionalized piperidines are
reported. Ketone nucleophiles (enamines/enolates) were
generated in the presence of the amines used for the
formation of the iminium ions of sugar derivatives with or
without an additive. Conditions to preferentially generate
piperidine derivatives rather than tetrahydrofurans were
identified. Products from the reactions of allyl ketones were
readily transformed to bicyclic piperidines.
olyoxy-functionalized piperidine derivatives are found in
pharmaceuticals, probes, and their building blocks.1
type reactions of simple cyclic imines and of simple cyclic
nitrones with ketones have been reported.2a,c These reactions
cannot provide polyoxy-substituted piperidines, however. We
reasoned that the use of ketones as nucleophiles in the
reactions with the iminium ions generated in situ from sugar
derivatives would provide a direct route to ketone- and
polyoxy-functionalized piperidine derivatives (Scheme 1).
Whereas iminium ions derived from sugar derivatives have
been used in reactions with various nucleophiles,4 reactions
with ketones that provide piperidines have not been realized
previously.5
Compounds bearing primary amines have been used as
catalysts and components of catalyst systems for the reactions
involving ketone nucleophiles under certain conditions.6
Therefore, we hypothesized that amines (for example,
R1NH2 = benzylamine in Scheme 1) used for the formation
of the iminium ions would also act as catalysts for the Mannich
reactions of the iminium ions with ketones via the formation of
enamines/enolates of ketones under appropriate conditions
(Scheme 1). When sugar derivatives are used as reactants,
there are potential side reactions that must be avoided to afford
piperidines (Scheme 2). A hydroxy group can be generated
from the hemiacetal group of the sugar molecule during the
Mannich reaction, and the hydroxy group may lead to
oxacyclization, which results in the formation of tetrahydrofur-
an derivative. Formation of the iminium ions in situ
cogenerates water molecules, and these water molecules may
hydrolyze the iminium ions. Subsequent reaction of the
aldehyde group with the ketone followed by oxacyclization
may also result in the formation of tetrahydrofuran derivatives.
P
Therefore, the development of methods for the synthesis of
polyoxy-functionalized piperidine derivatives is of interest in
drug discovery and related areas. Whereas various reaction
methods for the synthesis of piperidine derivatives have been
reported, most provide piperidines bearing only mono- and
disubstitutions on the carbons of the piperidine rings.2 For the
synthesis of polyoxy-functionalized piperidines, strategies that
are different from those used for the synthesis of simple
piperidines are required. Here, we report the Mannich
reactions of sugar derivatives with ketones that afford
polyoxy-substituted piperidine derivatives bearing ketone
groups (Scheme 1).
Piperidines bearing ketone functional groups are used for the
synthesis of various functionalized piperidine derivatives.2a−g,3
The introduction of a substituent bearing a ketone group to a
piperidine often requires several steps.2b,d,e For the synthesis of
simple piperidines bearing ketone group moieties, Mannich-
Scheme 1. Mannich Reactions of Sugar Derivatives with
Ketones That Afford Polyoxy-Functionalized Piperidine
Derivatives
Received: January 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00105
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Next, the stability of 3a and the conversions of 3a to 3aA
and of 3aA to 3a were analyzed (Tables 1 and 2). Whereas 3a
Scheme 2. Potential Side Reactions That May Occur during
the Mannich Reactions
Table 1. Stability of 3a and Conversion of 3a to 3aA
entry
conditions
60 °C in toluene, 24 h
TsOH (0.5 equiv), 60 °C in CHCl3, 24 h
TsOH (0.5 equiv), 25 °C in CH2Cl2, 24 h
PhCH2NH2 (1.0 equiv), 60 °C in toluene, 2 h 3aA 85% (isolated)
PhCH2NH2 (1.0 equiv), 25 °C in CDCl3, 48 h 3a >95% unchanged
pyrrolidine (0.2 equiv), 60 °C in CDCl3, 4 h 3a:3aA = 1:1
pyrrolidine (0.2 equiv), 25 °C in CDCl3, 48 h 3a >95% unchanged
results
1
2
3
4
5
6
7
8
3a unchanged
3aA 80% (isolated)
3a >95% unchanged
Incomplete iminium ion formation may also provide the
tetrahydrofuran derivatives. Interconversion between the
piperidine derivatives and the tetrahydrofuran derivatives
may also occur. In fact, previously reported reactions of
iminium ions derived from sugar derivatives with ketones
afforded tetrahydrofuran derivatives.7
To identify conditions suitable for the formation of
piperidine derivatives, we first examined the reaction of D-
ribose derivative 1a4b−d with acetone (2a) to afford piperidine
derivative 3a (Scheme 3). When an iminium ion was formed
DBU (0.3 equiv), 25 °C in CDCl3, 24 h
3a >95% unchanged
Table 2. Stability of 3aA and Conversion of 3aA to 3a
Scheme 3. Mannich Reaction of 1a with 2a To Afford 3a
entry
1
conditions
results
pyrrolidine (0.2 equiv), 25 °C in CDCl3 3a:3aA = 3:7 at 15 h,
1:1 at 40 h
2
3
4
5
pyrrolidine (0.5 equiv), 25 °C in CH2Cl2, 3a 45% (isolated)
20 h
pyrrolidine (0.2 equiv), 60 °C in CDCl3 3a:3aA = 1:3 at 2 h,
1:1 at 4 h
PhCH2NH2 (0.2 equiv), 25 °C in CH2Cl2, 3aA >90% unchanged
48 h
PhCH2NH2 (1.0 equiv), 25 °C in CH2Cl2, 3a:3aA = 2:3
48 h
6
7
TsOH (0.5 equiv), 25 °C in CH2Cl2, 24 h 3aA >90% unchanged
PhCH2NH2 (0.5 equiv),
TsOH (0.2 equiv), 25 °C in CH2Cl2,
24 h
3a:3aA = 1:1
8
PhCH2NH2 (1.0 equiv), DBU (0.5 equiv), 3a:3aA = ∼1:1
25 °C in CH2Cl2, 14 h
9
DBU (0.5 equiv), 25 °C in CH2Cl2, 24 h 3a:3aA = ∼1:1
10
11
100 °C, toluene, 2 h
TsOH (0.5 equiv), 60 °C in CH2Cl2
3a:3aA = 3:1
3a:3aA = 1:3
at 2, 4, and 24 h
was unchanged in toluene at 60 °C for at least 24 h in the
absence of amine or acid (Table 1, entry 1), heating of 3a at 60
°C in the presence of TsOH, benzylamine, or pyrrolidine
resulted in the formation of 3aA in significant yields (Table 1,
entries 2, 4, and 6). Piperidine derivative 3a was stable (<5%
conversion) at 25 °C in the presence of TsOH, benzylamine,
pyrrolidine, or DBU at least for 24 h (Table 1, entries 3, 5, 7,
and 8).
In contrast, furan derivative 3aA was partly converted to 3a
at 25 °C in the presence of pyrrolidine (Table 2, entries 1 and
2). Heating of 3aA at 60 °C or at 100 °C also caused partial
formation of 3a in the presence and absence of pyrrolidine or
TsOH (Table 2, entries 3, 10, and 11). At 25 °C, benzylamine
also isomerized 3aA to 3a, depending on its loading amount
(Table 2, entries 4 and 5). In the presence of benzylamine−
from 1a (1.0 equiv) with benzylamine (2.0 equiv) in situ and
was reacted with acetone at room temperature (25 °C) in one
pot, product 3a was obtained in 90% from 1a as a single
diastereomer (Scheme 3a). The use of less benzylamine also
afforded 3a; for example, in the reaction with 1.2 equiv of
benzylamine to 1a, product 3a was obtained in 65% after 14 h
(Scheme 3a). Reactions at 60 °C led the formation of
tetrahydrofuran derivative 3aA7 as well as piperidine derivative
3a (Scheme 3b,c).
B
DOI: 10.1021/acs.orglett.9b00105
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
TsOH, benzylamine−DBU, or DBU alone, the formation of 3a
from 3aA was also observed at 25 °C (Table 2, entries 7−9).
The isomerization of 3aA to 3a in the presence of benzylamine
(Table 2, entries 4 and 5) at 25 °C was significantly slower
than the formation of 3a in the ketone reaction step of the
reaction of 1a shown in Scheme 3a. Thus, in terms of yield of
piperidine derivative 3a, the direct formation of 3a from 1a as
shown in Scheme 3a was superior to the isomerization of 3aA
to 3a. For the avoidance of the formation of 3aA, it was
necessary to conduct the reaction with the ketone at 25 °C (no
heating).
Scheme 5. Mannich Reactions of 1a with Allyl Phenyl
Ketone
Using conditions of Scheme 3a, piperidine derivatives 3 were
synthesized using various alkyl and functionalized alkyl ketones
2 (Scheme 4). For the reaction with 2-butanone, the C−C
a
Scheme 4. Mannich Reactions To Afford 3 from 1a
Scheme 6. Mannich Reactions of 1a with Allyl Ketones To
a
Afford 6
a
Conditions: 1a (1.0 mmol, 1.0 equiv) and PhCH2NH2 (1.2 equiv) in
a
Conditions: D-ribose tosylate 1a (0.45 mmol, 1.0 equiv) and
CH2Cl2 (5.0 mL) at rt (25 °C) for 3 h; then, allyl ketone (1.2 equiv).
Products 6 were isolated as single diastereomers.
PhCH2NH2 (2.0 equiv) in CH2Cl2 (2.0 mL) at room temperature (rt;
25 °C) for 3 h; then, addition of ketone 2 (5.0 equiv). Products 3
were isolated as single diastereomers (diastereomeric ratio, dr >20:1).
bL-Ribose-derived starting material was used, and the product was an
c
opposite enantiomer of the structure shown. The stereochemistry of
the methoxy-substituted carbon is tentatively assigned (see the
Supporting Information).
For the reaction of 1a with acetophenone derivatives, the
use of DBU9 (0.2 equiv) as additive at the ketone reaction step
led to the formation of Mannich products 7 (Scheme 7).
Scheme 7. Mannich Reactions of 1a with Aryl Methyl
Ketones To Afford 7
a
bond formation occurred at the methyl group of the ketone
(formation of 3b). In the reaction with methoxyacetone, the
C−C bond formed at the methoxy-substituted carbon
(formation of 3e).
In the case of the reaction of allyl phenyl ketone (4a),8 the
use of 2.0 equiv of benzylamine (relative to 1a) resulted in the
formation of product 5a in 20%; the C−C bond formation
occurred at the α-position of the allyl ketone (Scheme 5).
When the loading of benzylamine was reduced to 1.2 equiv,
product 6a, which was formed from the C−C bond formation
at the γ-position of the allyl ketone, was obtained as the major
product in 65%, and α-adduct 5a was obtained in 15%
(Scheme 5). With the use of 1.2 equiv of benzylamine, various
Mannich products 6 were obtained as the major products from
the bond formation at the γ-position of the allyl ketones
(Scheme 6). Note that Mannich reactions at the γ-position of
the allyl ketones have not been readily achieved previously.8c
a
Conditions: 1a (0.45 mmol, 1.0 equiv) and PhCH2NH2 (2.0 equiv)
in CH2Cl2 (2.0 mL) at rt (25 °C) for 3 h; then, addition of aryl
methyl ketone (1.5 equiv) and DBU (0.2 equiv). Products 7 were
isolated as single diastereomers.
C
DOI: 10.1021/acs.orglett.9b00105
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The Mannich reaction strategy to afford piperidine
derivatives was further evaluated in the reactions of various
sugar derivatives (Scheme 8). From the reactions of D-lyxose
Scheme 9. Transformations of the Mannich Products
Scheme 8. Mannich Reactions of Various Sugar Derivatives
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00105.
Additional discussion, experimental procedures, charac-
terization of products, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ftanaka@oist.jp.
ORCID
derivative 8,10 piperidine derivatives 9 were obtained (Scheme
8a,b). For product 9b, the isomer obtained had the syn
configuration between the formed C−C bond and the hydroxy
group at the original 2-position of lyxose when initially
isolated. The dr became 1:1 when 9b was stored at rt (25 °C).
These results suggest that product stereochemistry observed is
the result of the steric effects during the C−C bond formation
and is influenced by the thermodynamic stability of the
product (see the Supporting Information). From L-rhamnose
derivative 10,11 pyrrolidine derivatives 11 were also synthe-
sized (Scheme 8c). In these reactions, the iminium ion
formation step was heated to 80 °C, but reaction with the
ketone was performed at rt (25 °C). From 12, which had
acetonide protection of the trans-hydroxy groups, piperidine
derivative 13 was obtained, although the yield was moderate
(Scheme 8d, not optimized).
Fujie Tanaka: 0000-0001-6388-9343
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 and in part by the MEXT/JSPS (Japan)
Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysts”
(26105757).
The utility of the Mannich reaction methods was
demonstrated by transformations of the products (Scheme
9). Deprotection of the benzyl and the acetonide groups of 3i
afforded 14. Chloride derivative 15 was obtained from 3a by
treating with tosyl chloride in the presence of Et3N through the
retention of the stereochemistry of the hydroxy group of 3a.
Mannich reaction products 6a and 6b were transformed to
quinolizine derivatives1f,4c,11 16 and 17, respectively, in one
pot. After deprotection of the acetonide group, polyhydroxy-
functionalized quinolizines 18 and 19 were obtained.
In summary, we have developed Mannich reactions of sugar
derivatives with ketones to afford polyoxy-functionalized
piperidine derivatives. The conditions leading to the formation
of piperidine derivatives rather than tetrahydrofuran derivatives
were identified. Further, with the use of developed Mannich
reactions, polyhydroxy-functionalized bicyclic piperidine de-
rivatives were readily accessed.
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