Protection-, salt-, and metal-free syntheses of [n]-shogaols by use of dimethylammonium dimethyl carbamate (DIMCARB) without protecting groups

Article abstract of DOI:10.1055/s-0029-1218389

Shogaols, the pungent principle of ginger, exhibit interesting bioactivities. Practical preparation of shogaols is highly desired. Here we report the protection/deprotection-, salt-, and metalfree synthesis of shogaol in three steps by use of dimethylammonium dimethyl carbamate (DIMCARB), in which DIMCARB smoothly promoted Mannich-type condensation of the ketone donor with the aldehyde acceptor through the iminium cation intermediate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218389

LETTER
93
Protection-, Salt-, and Metal-Free Syntheses of [n]-Shogaols by Use of
Dimethylammonium Dimethyl Carbamate (DIMCARB) without
Protecting Groups
S
N
ynthese
s
of [n]-S
o
hogaols buyuki Mase,* Norihiko Kitagawa, Kunihiko Takabe*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Fax +81(53)4781196; E-mail: tnmase@ipc.shizuoka.ac.jp; E-mail: tcktaka@ipc.shizuoka.ac.jp
Received 16 September 2009; revised 16 October 2009
Zingerone (3a) is obtained by chemoselective reduction
of 4a. Second direct Mannich-type condensation of 3a
with aldehyde furnished shogaols 2.
Abstract: Shogaols, the pungent principle of ginger, exhibit inter-
esting bioactivities. Practical preparation of shogaols is highly de-
sired. Here we report the protection/deprotection-, salt-, and metal-
free synthesis of shogaol in three steps by use of dimethylammoni-
um dimethyl carbamate (DIMCARB), in which DIMCARB
smoothly promoted Mannich-type condensation of the ketone do-
nor with the aldehyde acceptor through the iminium cation interme-
diate.
Recently, organic transformations via iminium and/or
enamine intermediate catalyzed by metal-free small or-
ganic molecule have received great attention by organic
chemists because of its high versatility, maneuverability,
4
simplicity, and safety. In general, protection of the func-
Key words: shogaols, protection-free synthesis, salt-free synthesis,
metal-free synthesis, cross Mannich-type condensation
tional group is not required in most of organocatalytic re-
actions; therefore, we took these advantages to synthesize
shogaols 2. Iminium cation mediated Mannich-type con-
densation is one of the promising synthetic methods for
direct preparation of benzalacetone derivatives of
aldehydes and enolizable ketones. Kreher and Strauss
reported that dimethylammonium dimethyl carbamate
The pungent principles of fresh ginger are homologous
phenolic ketones known as gingerols 1, which are con-
verted to dehydration products as shogaols 2 during stor-
age or thermal processing (Figure 1). Shogaols 2 are more
pungent than gingerols 1; in addition, recently interesting
bioactivities are reported. For example, trans-[8]-shogaol
showed the highest antifouling activity comparable with
that of tributyltin fluoride (TBTF), which is recognized as
one of the most effective antifouling agents, in the con-
(
DIMCARB, 7) is a recyclable reaction medium and as a
5
catalyst for preparation of benzalacetone derivatives. As
shown in Scheme 2, iminium cation intermediate 8 in situ
derived from the aldehyde 6 and DIMCARB 7 undergoes
Mannich-type condensation with the ketone 9. Subse-
quent elimination of dimethylamine from the Mannich ad-
duct 10 is facile and gives the benzalacetone derivative
1
ventional submerged assay. Further, [6]-shogaol was
more effective than [6]-gingerol in inhibition of PG syn-
1
1. In spite of their useful findings, this procedure was
2
thetase.
6
employed in only a few papers. Strong bases, such as so-
dium hydroxide, are usually employed to prepare benzal-
acetone derivatives in most cases, though formation of
dibenzalacetone derivatives is unavoidable.
O
OH
O
MeO
HO
MeO
HO
R
R
O
[n]-gingerols (1)
[n]-shogaols (2)
O
O
R = Cn–1H2(n–1)+1
R = Cn–1H2(n–1)+1
MeO
HO
a
b
c
H
2
Ar
zingerone (3a)
Ar
Figure 1 [n]-Gingerols 1 and [n]-shogaols 2
4a
vanillin (5a)
Previous syntheses of shogaols 2 contain following prob-
Scheme 1 Three-step synthesis of shogaols 2 without protecting
groups: (a) Mannich-type condensation; (b) reduction; (c) Mannich-
lems: (1) multistep synthesis, (2) use of strong base, (3)
3
low temperature, and (4) wastes, such as salt. Modern or- type condensation
ganic synthesis highly required environmentally friendly
procedure. Herein, we report protection/deprotection-,
First, we carefully investigated the Mannich-type conden-
sation of vanillin (5a) with acetone (12) using DIMCARB
7) as shown in Table 1, since only one example of using
acetone donor was reported. According to original proce-
dure, the reaction was carried out in DIMCARB as reac-
tion medium and catalyst, furnishing the desired enone
salt-, and metal-free synthesis of shogaols 2 under neutral
condition at 25 °C in three steps as shown in Scheme 1.
Benzalacetone derivative 4a is generated from vanillin
(
5
(
5a) employing a direct Mannich-type condensation.
1
3a in moderate yield (entry 1). A series of different sol-
SYNLETT 2010, No. 1, pp 0093–0096
Advanced online publication: 27.11.2009
DOI: 10.1055/s-0029-1218389; Art ID: U09209ST
x
x.
x
x.
2
0
0
9
vent systems was evaluated. In general, in polar solvents
unidentified tailing spots on TLC were observed, while
©
Georg Thieme Verlag Stuttgart · New York

9
4
N. Mase et al.
LETTER
solvents tested; therefore, we mainly chose dichlo-
romethane as a solvent for further study (entry 14).
N
O
–
O
7,8
CO2
N
+
H2
N
+
H
R1
R1
R2
H
The scope of this class of Mannich-type condensations us-
ing DIMCARB was examined with a series of aromatic
aldehyde acceptors 5. Results were shown in Table 2. Sta-
bilizing functional groups in formation of the iminium
cation intermediate 8 enhanced chemical yields (entries
6
DIMCARB (7)
8
9
O
N
O
R2
R1
R2
R1
1
–4). On the other hand, destabilizing groups, such as ni-
10
11
tro group, gave rise to unidentified products; the desired
enone 13f was obtained in 36% yield (entry 6).
Scheme 2 DIMCARB-mediated Mannich-type reaction
Next, chemoselective reduction of the enone 13a to
zingerone (3a) was examined as shown in Table 3. Pd/C-
catalyzed hydrogenation of 13a without additive resulted
in the mixture of the desired product 3a in 88% yield and
overhydrogenated alcohol 14a in 12% yield (entry 1). Ac-
Table 1 Mannich-Type Condensation of Vanillin (5a) with Ace-
tone (12) Using DIMCARB
a
O
DIMCARB
(1 equiv)
MeO
HO
O
O
3c
H
cording to the reported procedure, with 10 mol% of ace-
tic acid as an additive the alcohol 14a was still formed in
37% yield (entry 2), although this additive was highly
effective in the hydrogenation of the enone 13c to give
raspberry ketone 3c used in perfumery, in cosmetics, and
as flavor (entry 5). Recently, Sajiki and co-workers devel-
oped a Pd/C-catalyzed chemoselective hydrogenation us-
+
solvent
Ar
(
0.5 mL)
5 °C
5
a
12
(1 equiv)
13a
2
(
0.5 mmol)
Yield (%)b
Entry
Solvent
Time (h)
24
24
24
24
30
6
1c
2
3
4
5
6
7
8
9
DIMCARB
DMSO
41
25
44
52
52
59
62
26
63
63
42
69
70
81
9
ing diphenylsulfide as a catalyst poison. The enone 13a
was treated in the presence of 1 mol% diphenylsulfide in
ethanol to afford zingerone (3a) in 94% yield (entry 3). In
spite of the high yield of 3, using sulfur compounds would
be avoided preferably in perfumery, in cosmetics, and as
flavor. We found that Lewis base catalyzed conjugate
reduction of 13 using trichlorosilane developed by
Nakajima and co-workers afforded the desired com-
DMF
MeCN
1,4-dioxane
Et O
2
pounds 3.10 The reduction of 13a with HSiCl was per-
THF
30
24
6
3
formed in the presence of HMPA (20 mol%), affording
zingerone (3a) in 87% yield (entry 4). Similarly, raspberry
ketone 3c was obtained in 79% yield (entry 6).
MeOH
2-PrOH
acetone
hexane
toluene
CHCl3
CH Cl
0d
Table 2 Mannich-Type Condensation of Arylaldehyde 5 with Ace-
tone (12) Using DIMCARBa
1
1
1
1
24
6
1
2
3
4
O
O
R2
R2
DIMCARB
(1 equiv)
O
30
48
48
H
+
R1
CH2Cl2
R1
(0.5 mL)
5
12
(1 equiv)
13
2
5 °C, 48 h
1
(0.5 mmol)
2
2
a
Reactions were carried out using vanillin (5a, 0.5 mmol), acetone
12, 0.5 mmol), and DIMCARB (7, 0.5 mmol) in the solvent (0.5 mL)
R1
R2
Yield (%)b 13
Entry
5
(
at 25 °C for 6–48 h, unless otherwise noted.
1
5a
5b
5c
5d
5e
5f
OH
OMe
OH
H
OMe
H
81
75
58
63
76
36
13a
13b
b
Isolated yield.
DIMCARB (2.5 equiv) was used.
Acetone (0.5 mL, 14 equiv) was used.
c
2c
3
d
H
13c
13d
13e
13f
those spots decreased in nonpolar solvents. DMSO, DMF,
and acetonitrile were inferior solvents in terms of product
yield (entries 2–4). Ethers were moderate solvent (entries
4
H
5
Cl
H
5
–7). Methanol is a poor solvent, whereas 2-propanol is a
6
NO2
H
better solvent (entries 8 and 9). Excess acetone donor did
not improve the chemical yield (entry 10). Aromatic hy-
drocarbon solvent, such as toluene, afforded the enone
a
Reactions were carried out using vanillin (5a, 0.5 mmol), acetone
12, 0.5 mmol), and DIMCARB (7, 0.5 mmol) in CH Cl (0.5 mL) at
5 °C for 48 h, unless otherwise noted.
(
2
2
2
1
3a in 69% yield (entry 12). Halogenated solvent, espe-
cially dichloromethane, gave the highest chemical yield
b
Isolated yield.
c
The reaction was carried out in acetone (0.5 mL, 14 equiv) instead
without formation of dibenzalacetone derivatives among of CH Cl for 18 h.
2
2
Synlett 2010, No. 1, 93–96 © Thieme Stuttgart · New York

LETTER
Syntheses of [n]-Shogaols
95
Table 3 Chemoselective Reduction of the Enone 13 to Zingerone
Derivatives 3
Table 4 Mannich-Type Condensation of Hexanal (15a) with the
Ketone 3a Using DIMCARBa
O
O
R1
O
OH
MeO
reduction
O
+
Ar
Ar
HO
3
14
HO
H
Ar
5 11
C H
[6]-shogaol (2a)
3
a
DIMCARB
5 °C, 48 h
1
1
3a: R = OMe
3c: R = H
+
+
2
O
O
Entry
13
Conditions
Pd/C, H2
Yield of 3 Yield of 14
C4H9
(
%)
(%)
12
37
0
H
1
5a
1a
13a
13a
13a
13a
13c
13c
88
58
94
87
99
79
C5H11
1
6
2a,b
3a,c
4d
Pd/C, H , AcOH
2
Entry
1b
2
15a (equiv)
Yield of 2a (%) Yield of 16 (%)
Pd/C, H , Ph S
2
2
1
1
4
48
56
62
74
59
65
77
80
36
5
HSiCl , HMPA
0
3
5a,b
Pd/C, H , AcOH
0
2
3
2
8
6d
HSiCl , HMPA
0
3
4
3
10
24
<5
<5
<5
<5
a
Reactions were carried out using Pd/C (10 mol%) and H (balloon)
2
in MeOH for 24 h at r.t.
5
10
1
b
AcOH (10 mol%) was used.
Ph S (1 mol%) was used.
6c
7c
8c
9c
c
2
d
Reactions were carried out using HSiCl (2 equiv) and HMPA (20
3
1.5
2
mol%) in CH Cl for 2 h at 0 °C.
2
2
Next, we examined syntheses of [6]-shogaol (2a) as
shown in Table 4. There is no report on the DIMCARB-
mediated Mannich-type condensation of the aliphatic al-
3
a
Reactions were carried out using the ketone (3a, 0.3 mmol), hexanal
dehyde acceptor with the ketone donor previously. Con- (15a, 1–10 equiv), and DIMCARB (7, 0.3 mL, 1.47 mmol) at 25 °C
for 48 h, unless otherwise noted.
trol of the formation of self-Mannich product 16 is very
b
Reaction was carried out in CH Cl .
Hexanal (15a) was added by use of syringe pump over 10 h.
important to prepare the desired shogaol 2a. Although
best reaction conditions in Table 1 were applied to the
synthesis of [6]-shogaol 2a, Z-isomer of self-Mannich
product 16 was obtained as a major product (entry 1).
Evaluation of various solvents furnished that DIMCARB
is the best reaction medium (entry 2); hence, further stud-
2
2
c
tions directly afforded desired shogaols 2 in good yields
entries 1–3). It was difficult to add aldehydes with a high-
(
er melting point such as nonyl and undecyl aldehydes via
syringe pump, however, portionwise addition of them af-
forded the shogaols 2 in up to 60% and 77% chemical
yields, respectively (entries 4 and 5). Reactions with aro-
matic aldehydes yielded the shogaol derivatives 2 in good
yield at 80 °C even when 1.0 equivalent of acceptor was
used (entries 6–8), although these reactions did not pro-
ceed at 25 °C.
ies were carried out without addition of conventional or-
ganic solvent.11 Increasing the amount of aldehyde
acceptor improved the chemical yield of 2a up to 74%
along with an increase in formation of self-Mannich prod-
uct 16 (entries 2–5). Keeping low concentration of hexa-
nal acceptor 15a would be a key to suppressing self-
Mannich reaction.1 Addition of 15a by use of syringe
2
pump over 10 hours, the desired [6]-shogaol (2a) was ob- In summary, we have developed the synthesis of shogaols
tained in 59% yield along with 16 in less than 5% yield 2 in three steps by use of DIMCARB. Protection and/or
(
entry 6). Chemical yields were up to 80%, when three deprotection is not required, in addition, waste salts do not
1
3
equivalents of the acceptor 15a were used (entries 7–9).
generate. All transformations were carried out using met-
The DIMCARB-mediated Mannich-type condensation of al-free catalysts. Further studies focusing on the full scope
the aliphatic aldehyde acceptor 15a with the ketone donor of this simple and environmentally friendly synthesis of
3
a for preparing [6]-shogaol (2a) was achieved by easy shogaols 2 are currently under investigation and will be
manipulation under mild conditions, that is, just mixing reported in due course.
the donor and DIMCARB and slow addition of the accep-
tor.
Acknowledgment
The scope of this class of Mannich-type condensations us-
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science.
ing DIMCARB was examined with a series of aldehyde
acceptors. Results were shown in Table 5. With liquid
aliphatic aldehyde acceptors 15 Mannich-type condensa-
Synlett 2010, No. 1, 93–96 © Thieme Stuttgart · New York

9
6
N. Mase et al.
LETTER
(6) (a) Chowdari, N. S.; Barbas, C. F. III. Org. Lett. 2005, 7,
Table 5 Mannich-Type Condensation of the Aldehyde 15 with the
Ketone 3a Using DIMCARB
a
867. (b) Sridhar, G.; Gunasundari, T.; Raghunathan, R.
Tetrahedron Lett. 2007, 48, 319.
7) Typical Procedure
O
(
O
O
MeO
HO
Handling of this class of reaction is very simple. DIMCARB
(7, 101 mL, 0.5 mmol) was added to the solution of vanillin
(5a, 76.1 mg, 0.5 mmol) in CH Cl (0.5 mL) at 25 °C. Gas
DIMCARB
+
H
R
Ar
R
25 °C
2
2
3a
15
2
was evolved. Acetone (12, 36.7 mL, 0.5 mmol) was added in
a single portion. Stirring was continued for 48 h. The solvent
mixture was acidified with 10% HCl aq (2 mL) and extracted
Entry
R
Time (h)
Yield of 2 (%)
1b
with CH Cl (3 × 3 mL). The combined organic fraction was
Pr
48
48
48
48
48
8
70
80
83
60
77
74
76
76
2
2
dried with anhyd Na SO , filtrated, and solvent removed in
2
4
2b
3b
pentyl
heptyl
nonyl
vacuo. Purification with column chromatography (silica gel,
hexane–EtOAc) gave the enone 13a (77.8 mg, 81%) as a
pale yellow solid. Without extraction, the crude reaction
mixture could be directly purified by column chromatog-
raphy in decreasing to 56% chemical yield.
4c
5c
(8) We further investigated decreasing amount of DIMCARB,
but chemical yields also decreased in the Mannich-type
condensation of vanillin(5a) with acetone(12). Amount of
DIMCARB = 1.0 equiv: 81%; 0.5 equiv: 72%; 0.1 equiv:
41%. These results suggested that DIMCARB catalyzed the
Mannich-type condensation; however, due to low catalytic
ability, a stoichiometric amount of DIMCARB was used for
the present reactions.
9) Mori, A.; Miyakawa, Y.; Ohashi, E.; Haga, T.; Maegawa, T.;
Sajiki, H. Org. Lett. 2006, 8, 3279.
(10) Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem.
Commun. 2008, 4309.
(11) Reactions in conventional solvents such as DMSO, DMF,
undecyl
6d
7d
4-HO-3-MeOC H
6
4
18
10
6
4-MeOC H4
8d
Ph
a
Reactions were carried out using the ketone (3a, 0.3 mmol), alde-
hydes (15, 1–3 equiv), and DIMCARB (7, 0.3 mL, 1.47 mmol) at
(
2
5 °C, otherwise noted.
b
Aldehydes 15 were added by use of syringe pump over 10 h.
Aldehydes 15 were added portionwise (3 × 1 equiv).
Reactions were carried out at 80 °C in CH Cl using DIMCARB
c
d
2
2
(
0. 5 equiv) in a pressure-resisted tube.
MeCN, 1,4-dioxane, Et O, THF, MeOH, 2-PrOH, toluene,
2
and CHCl resulted in low chemical yields (2a: 0–19%)
3
along with self-Mannich product in 6–42% yields.
(
12) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
002, 124, 6798.
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(
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R
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