Aldol reaction of trimethylsilyl enolate with aldehyde catalyzed by pyridine N-oxide as a Lewis base catalyst

Article abstract of DOI:10.1055/s-2005-872664

Aldol reaction of trimethylsilyl enolate with aldehydes proceeded in the presence of a catalytic amount of a Lewis base, pyridine N-oxide, and lithium chloride in DMF at room temperature. Not only aryl aldehydes but also alkyl aldehydes provided the aldol

Full text of DOI:10.1055/s-2005-872664

2388
LETTER
Aldol Reaction of Trimethylsilyl Enolate with Aldehyde Catalyzed by Pyridine
N-Oxide as a Lewis Base Catalyst
Aldol Reaction of
i
Trimeth
s
ylsilyl
E
n
a
olate
w
ith
hA
ldehyde iro Hagiwara,*a Hideyuki Inoguchi,a Masakazu Fukushima,a Takashi Hoshi,b Toshio Suzukib
a
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
b
Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
Received 22 July 2005
available and stable trimethylsilyl enolate (Scheme 1). A
simple amine N-oxide was chosen due to its economy, low
toxicity, and availability as a chiral amine.10
Abstract: Aldol reaction of trimethylsilyl enolate with aldehydes
proceeded in the presence of a catalytic amount of a Lewis base, py-
ridine N-oxide, and lithium chloride in DMF at room temperature.
Not only aryl aldehydes but also alkyl aldehydes provided the aldol
products in satisfactory yields. The reaction was mild enough to
apply to aldehydes having HO, AcO, THPO, TBDMSO, MeS,
pyridyl, or olefinic groups.
OTMS
OMe
amine N-oxide (0.1 equiv)
LiCl (0.2 equiv), DMF, r.t.
OH
O
1
Key words: aldol reactions, organomolecular catalysis, pyridine
N-oxide, trimethylsilyl ketene acetal, Lewis base
R
OMe
+
acidic work-up
RCHO 2
3
Scheme 1 Aldol reaction of trimethylsilyl ketene acetal catalyzed
by amine N-oxide
The aldol reaction is a fundamental and important carbon–
carbon bond-forming reaction.1 However, due to its re-
versibility, either under basic or acidic reaction condi-
tions, a classical aldol reaction could not equilibrate The optimum reaction conditions were examined employ-
substrates into aldol products in satisfactory yields. The ing the reaction of trimethylsilyl dimethylketene acetal 1
difficulty in generating an enol or an enolate quantitative- and benzaldehyde (2) (Table 1). The reaction was carried
ly was the major reason for employing such reversible re- out at room temperature in the presence of 0.1 equivalents
action conditions. This issue was solved by Mukaiyama, of amine N-oxide. The resulting silylether of 3 was hydro-
who developed the aldol reaction of trimethylsilyl enolate lyzed during work-up to give 3. Among amine N-oxides
in the presence of a stoichiometric amount of TiCl4.2 In investigated, pyridine N-oxide gave the best result
this reaction, the aldol acceptor is activated by coordina- (Table 1, entry 5).11 The more nucleophilic DMAP N-
oxide12 gave capricious yields during repeated runs
(Table 1, entry 7). Trimethylamine N-oxide suffered from
tion of the Lewis acid. The versatility of the reaction
triggered numerous applications and variants.1,2 Sub-
sequently, Denmark et al. employed a different concept, poor yields probably due to its steric bulkiness (Table 1,
which targeted activation of the silicone atom forming a entry 8).13 The polarity of solvents did not influence the
hypervalent silicate intermediate. They demonstrated the reaction (Table 1, entries 2 and 3). Among the solvents,
utility of a more electropositive trichlorosilyl enol ether in DMF gave the best yield (Table 1, entry 5) due to its
the presence of phosphorane3 or a more strained silacy- highly coordinating nature as exemplified by Mukaiyama
clobutylketene acetal in the absence of Lewis acid.4 Al- et al.8
though the reaction conditions are efficient, use of the
With the optimized amine N-oxide and solvent in hand,
unstable or unusual silyl enol ether created some problems
further effort was devoted to improving the reaction and
for practical application. Subsequently, this concept was
the results are shown in Table 2. In order to enhance the
further developed, and trimethylsilyl or dimethylsilyl eno-
rate of reaction (Table 2, entries 1 and 2), the effect of an
lates were employed in the presence of a catalytic amount
auxiliary reagent was investigated. Fortunately, addition
of a Lewis base such as dimethylsulfoxide,5 phosphine
of a catalytic amount of lithium chloride was effective
oxide,6 or chloride ion7 to activate silylenolate. Mukaiya-
(Table 2, entry 3). Since lithium chloride alone provided
ma et al. also reported the reaction along this line employ-
poor yields (Table 2, entries 1, 4, and 5), lithium chloride
and pyridine N-oxide might operate synergistically to
ing lithium amide8 or acetate as a catalyst.9
In order to develop more efficient and milder aldol reac-
drive the catalytic cycle. On the other hand, addition of
tion conditions, we focused on the catalytic activity of an Hünig’s base, which was anticipated to remove N-oxide
amine N-oxide as an alternative candidate as an organo- from the hypervalent alkoxysilicate intermediate in the
molecular Lewis basic catalyst in the reaction of easily allylation of allyltrichlorosilane,14 was not satisfactory
(Table 2, entry 7).
SYNLETT 2005, No. 15, pp 2388–2390
Advanced online publication: 07.09.2005
DOI: 10.1055/s-2005-872664; Art ID: U23505ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
9
.2
0
0
5
The present reaction conditions (Table 2, entry 3) can be
applied to various aldehydes as shown in Table 3. Not

LETTER
Aldol Reaction of Trimethylsilyl Enolate with Aldehyde
2389
Table 3 Reaction with a Variety of Aldehydesa
Table 1 Investigation of the Optimized Reaction Conditions for the
Lewis Base Catalyzed Aldol Reactiona
Entry
Aldehyde 2
Acetal 1 Time Yieldb
Entry
Amine N-oxide
Pyridine N-oxide
Pyridine N-oxide
Pyridine N-oxide
Pyridine N-oxide
Pyridine N-oxide
–
Solvent
CH2Cl2
MeNO2
Time (h) Yieldb (%)
(equiv)
1.5
1.5
1.5
1.5
3
(h)
23
12
10
10
21
15
15
(%)
87
65
77
44
96
80
79
1
2
3
4
5c
6
7
p-Nitrobenzaldehyde
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
1
2
3
4
5
6
7
8
24
5
0
13
32
36
55
25
60
18
[bmim]PF6 18
DMIc
DMF
DMF
DMF
DMF
5
p-Hydroxybenzaldehyde
p-Acetoxybenzaldehyde
5.5
5
3
p-Tetrahydropyranyloxy-
3
DMAP N-oxide
Me3N N-oxide
5
benzaldehyde
9
8
p-(tert-Butyldimethyl-
siloxy)benzaldehyde
1.5
10
62
a The reaction of trimethylsilyl dimethylketene acetal (1, 1.3 equiv)
with benzaldehyde (2) was carried out in the presence of amine
N-oxide (0.1 equiv) at r.t.
9
p-Methylthiobenzaldehyde
1.5
3
21
15
87
87
b Yield of the isolated pure product.
c 1,3-Dimethyl-2-imidazolidinone.
10
11
12
13
14
15
16
17
Hydrocinnamaldehyde
Hydrocinnamaldehyde
Citronellal
1.5
4.5
1.5
4
10
5
44
80
44
81
43
78
91
only arylaldehydes (Table 3, entries 1–10) but also alkyl-
aldehydes (Table 3, entries 11–17) provided the aldol
products; to date alkylaldehyde had not been a good aldol
partner compared to arylaldehyde under either Lewis acid
or base reaction conditions.2,5,6,8 It is interesting to note
that the reaction proceeded in the absence of lithium
chloride without protection of the acidic phenol (Table 3,
entry 5). Addition of excess trimethylsilyl dimethylketene
acetal (1) accelerated the reaction (Table 3, entries 12, 14,
and 16). The mild nature of the present reaction conditions
is apparent from the successful reactions of aldehydes 2
having acid or base-sensitive protecting groups (Table 3,
entries 6–8). Moreover, pyridinecarboxaldehyde provided
the aldol product (Table 3, entry 10), which hitherto was
not a suitable substrate under Lewis acid reaction condi-
13
5
Citronellal
1-Decanal
1.5
5
20
7
1-Decanal
Perillaldehyde
3
10
a The reaction of trimethylsilyl dimethylketene acetal 1 with aldehyde
2 was carried out in the presence of pyridine N-oxide (0.1 equiv) and
LiCl (0.2 equiv) in DMF at r.t.
b Yield of the isolated pure product.
c Lithium chloride was not added.
Table 2 Effect of an Additivea
tions due to its highly coordinating character. The sulfide
or double bond remained intact even in the presence of
pyridine N-oxide (Table 3, entries 9, 13, and 17).
Entry
Amine N-oxide and additive
No additive
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
5.5
23
5
55
81
83
32
41
42
59
The generality of the present protocol was further demon-
strated by the reaction of trimethylsilyl enolate of methyl
propanoate (4) or acetophenone (5) (Scheme 2, Table 4).
No additive
LiCl (0.2 equiv)
LiCl (0.2 equiv)c
LiCl (1.2 equiv)c
CaCl2 (0.2 equiv)
(i-Pr)2NEt (0.1equiv)
5
OTMS
OH
O
5
R
OMe
OMe
RCHO 2
pyridine N-oxide
LiCl, DMF, r.t.
4
6
9
or
or
OH
acidic work-up
9
OTMS
O
a The reaction of trimethylsilyl dimethylketene acetal (1, 1.3 equiv)
with benzaldehyde (2) was carried out in the presence of pyridine N-
oxide (0.1 equiv) and the additive in DMF at r.t.
b Yield of the isolated pure product.
R
Ph
Ph
7
5
c Pyridine N-oxide was not added.
Scheme 2 Aldol reaction of trimethylsilyl enolate catalyzed by
pyridine N-oxide.
Synlett 2005, No. 15, 2388–2390 © Thieme Stuttgart · New York

2390
H. Hagiwara et al.
LETTER
Table 4 Reaction with Trimethylsilyl Enolates 4 and 5a
Silyl enolate Time (h) Yieldb (%)
References
Entry Aldehyde 2
(1) (a) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(b) Mahrwald, R. Chem. Rev. 1999, 99, 1095.
(c) Machajewski, T. D.; Wong, C.-H. Angew. Chem. Int. Ed.
2000, 39, 1352.
(2) (a) Mukaiyama, T. Org. React. 1982, 28, 203.
(b) Mukaiyama, T. Angew. Chem. Int. Ed. 2004, 43, 5590.
(3) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am.
Chem. Soc. 1996, 118, 7404.
(4) Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute, M. E.
J. Am. Chem. Soc. 1994, 116, 7026.
(5) Genisson, Y.; Gorrichon, L. Tetrahedron Lett. 2000, 41,
4881.
(6) Matsukawa, S.; Okano, N.; Imamoto, T. Tetrahedron Lett.
2000, 41, 103.
(7) Miura, K.; Nakagawa, T.; Hosomi, A. J. Am. Chem. Soc.
2002, 124, 536.
(8) (a) Mukaiyama, T.; Fujisawa, H.; Nakagawa, T. Helv. Chim.
Acta 2002, 85, 4518. (b) Fujisawa, H.; Mukaiyama, T.
Chem. Lett. 2002, 182. (c) Fujisawa, H.; Mukaiyama, T.
Chem. Lett. 2002, 858. (d) Nakagawa, T.; Fujisawa, H.;
Mukaiyama, T. Chem. Lett. 2003, 32, 462.
4 or 5 (equiv)
1
2
Benzaldehyde
4 (5)c
6
5
85 (56:44)c
95 (54:46)d
p-Nitrobenz-
4 (5)
aldehyde
3
4
5
6
p-Anisaldehyde
Citronellal
4 (5)
4 (5)
5 (5)
5 (4.5)
12
15
24
21
99 (51:49)d
45e
96
Benzaldehyde
p-Nitrobenz-
56
aldehyde
7
8
p-Tetrahydropyran- 5 (5)
yloxybenzaldehyde
24
23
57
60
Citronellal
5 (5)
a The reaction of trimethylsilyl enolate 4 or 5 with aldehyde 2 was
carried out in the presence of pyridine N-oxide (0.1 equiv) and LiCl
(0.2 equiv) in DMF at r.t.
(9) Nakagawa, T.; Fujisawa, H.; Mukaiyama, T. Chem. Lett.
2004, 33, 92.
b Yield of the isolated pure product.
c Ratio E/Z, 79:21.18
(10) (a) Chelucci, G.; Murineddu, G.; Pinna, G. A. Tetrahedron:
Asymmetry 2004, 15, 1373. (b) Hoshi, T.; Katano, M.;
Nozawa, E.; Suzuki, T.; Suzuki, T.; Hagiwara, H.
Tetrahedron Lett. 2004, 45, 3489. (c) Tao, B.; Lo, M. M.-
C.; Fu, G. C. J. Am. Chem. Soc. 2001, 23, 353.
(11) Chiral pyridine N-oxide has been used in enantioselective
aldol reaction of trichlorosilyl enol ether: (a) Denmark, S.
E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
(b) Nakajima, M. J. Synth. Org. Chem., Jpn. 2003, 61, 1081.
(12) Sojka, S. A. J. Org. Chem. 1979, 44, 707.
(13) Retro-aldol reaction was not a problem since the initial
product was a silylether of 3, see: Rodriguez, M. J.; Zweifel,
M. J. Tetrahedron Lett. 1996, 37, 4301.
d Ratio syn/anti.
e An inseparable mixture of diastereomers.
The present reaction could proceed via the same catalytic
cycle proposed by Denmark3 or Mukaiyama.8 After coor-
dination of pyridine N-oxide and DMF to the silicone
atom15 of the silyl ketene acetal to form a hexa-coordinat-
ed hypervalent silicate intermediate, addition to the alde-
hyde proceeded to provide a hypervalent alkoxysilicate
intermediate, from which pyridine N-oxide was pushed
out by lithium chloride and re-used in the catalytic cycle.
(14) Nakajima, M.; Sato, M.; Shiro, M.; Hashimoto, S. J. Am.
Chem. Soc. 1998, 120, 6419.
In summary, we have developed a new protocol for a
Lewis base catalyzed aldol reaction of trimethylsilyl eno-
late employing a catalytic amount of pyridine N-oxide and
lithium chloride in DMF at room temperature.16,17 The
present reaction proceeds via stable trimethylsilyl enolate,
which is the major advantage compared to the previous
works employing trichlorosilyl- or silacyclobutylenolate.
The reaction conditions are so mild that the base- or acid-
sensitive protecting groups on aldehydes 2 survived.
Pyridine N-oxide did not oxidize the sulfide or double
bond. The present reaction is mild, practical, environmen-
tally benign, and less toxic than existing methods, which
would be useful not only for large-scale preparation but
also manipulation of multifunctional substrates for natural
product syntheses.
(15) Sato, K.; Kira, M.; Sakurai, H. Tetrahedron Lett. 1989, 30,
4375.
(16) Typical experimental procedure: To a stirred solution of
pyridine N-oxide (3.8 mg, 0.04 mmol) and LiCl (3.4 mmol,
0.08 mmol) in DMF (1.5 mL) were added benzaldehyde 2
(R = Ph) (42 mL, 0.4 mmol) and trimethylsilyl ketene acetal
1 (105 mL, 0.52 mmol) at r.t. under a nitrogen atmosphere.
After stirring for 5 h, the reaction was quenched by the
addition of 1 N aq HCl. The product was extracted with
EtOAc twice. The combined organic layer was washed with
water, brine, and evaporated to dryness. The residue was
purified by medium-pressure LC (EtOAc–hexane, 1:2) to
afford aldol product 3 (R = Ph) (92 mg, 81%) as a solid.
(17) All new compounds have satisfactory analytical data
including 1H NMR, 13C NMR and IR spectra and HRMS.
(18) Mikami, K.; Matsumoto, S.; Ishida, A.; Takamuku, S.;
Suenobu, T.; Fukuzumi, S. J. Am. Chem. Soc. 1995, 117,
11134.
Acknowledgment
This work was partially supported by Grant-in-Aid for Scientific
Research on Priority Areas (17035031 for H. H.) from The Ministry
of Education, Culture, Sports, Science and Technology (MEXT).
Synlett 2005, No. 15, 2388–2390 © Thieme Stuttgart · New York