Aldol Synthesis with an Aqueous Solution of Formalin

Article abstract of DOI:10.1055/s-2003-42089

With an aqueous solution of formalin, aldol reaction of trimethylsilyl enol ether proceeds moderately using tetrabutylammonium fluoride (TBAF). Furthermore, catalytic asymmetric hydroxymethylation with trimethoxysilyl enol ether using water tolerant (R)-B

Full text of DOI:10.1055/s-2003-42089

LETTER
2219
Aldol Synthesis with an Aqueous Solution of Formalin
Aldol Synthesis
w
o
ith an Aqueo
b
us Solution
o
u
f
Formalin ko Ozasa,a Manabu Wadamoto,b Kazuaki Ishihara,a Hisashi Yamamoto*b
a
Graduate School of Engineering, Nagoya University,
SORST, Japan Science and Technology Corporation (JST), , Chikusa, Nagoya 464-8603, Japan
b
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
Fax +1(773)7020805; E-mail: yamamoto@uchicago.edu
Received 2 May 2003
hydroxymethyl ketone with high yield. Other fluoride
sources such as tris(dimethylamino)sulfur (trimethylsi-
lyl)difluoride (TAS-F) or KF did not give good activating
effect because of the low solubility in THF. The useful-
Abstract: With an aqueous solution of formalin, aldol reaction of
trimethylsilyl enol ether proceeds moderately using tetrabutyl-
ammonium fluoride (TBAF). Furthermore, catalytic asymmetric
hydroxymethylation with trimethoxysilyl enol ether using water
tolerant (R)-BINAP–AgOTf as Lewis acid and KF as Lewis base ness of the new process is apparent from Table 1, which
has been achieved in aqueous media.
summarizes aldol reaction with various silyl enol ethers in
the presence of TBAF. Most of the reactions proceeded
smoothly at –20 °C in THF.
Key words: aldol reaction, silyl enol ether, enantioselective,
BINAP–AgOTf catalyst, formalin aqueous solution
Previously, we developed the stereoselective Sakurai–
Hosomi allylation and Mukaiyama aldol synthesis of al-
lylsilane and silyl enol ether, respectively, to aldehydes
catalyzed by (R)-BINAP, AgOTf, KF and 18-crown-6 in
Although formaldehyde is a useful component for organic
synthesis, there are some limitations in developing a gen-
eral methodology for using formaldehyde for aldol syn-
thesis. In fact, generation of formaldehyde monomer is
still quite tedious, and formalin (aq soln), which is readily
available and consists of formaldehyde oligomers, cannot
be used for aldol synthesis with usual Lewis acid catalysts
due to their instability in the presence of water. Therefore,
only a few aldol reactions have been reported using for-
malin (aq soln) with silyl enol ethers catalyzed by Lewis
acid or Lewis base.1 Since our previous observations
show that fluoride ion can activate silyl enol ether effec-
tively even in protic solvent,2 we attempted to apply this
methodology to the aldol synthesis using formaldehyde
(aq soln).
Table 1 Aldol Reaction of Trimethylsilyl Enol Ethers with
Formalin (Aq Soln) Activated by TBAF
OSiMe3
R3
R1
R2
O
aq. HCHO
1)
CH2OH
R3
TBAF (5 equiv)
–20 °C, 1 h
R1
THF
R2
Entry
1
Silyl enolate
Yield (%)a
71
OSiMe3
OSiMe3
+
aq. HCHO (5 equiv)
F– additive
2
3
4
72
OSiMe3
OSiMe3
OSiMe3
O
CH2OH
1
83 (31/69)b
THF, –20 °C, 1 h
F- additive, Yield = TBAF (5 equiv), 71
TBAF (0.05 equiv), trace
TAS-F (5 equiv), 22
89
KF (5 equiv), 0
Equation 1
5
6
79
59
OSiMe3
Various fluoride sources were tested in the reaction be-
tween trimethylsilyl enol ether of cyclohexanone 1
(Equation 1) and formalin (aq soln).3 Among them, tet-
rabutylammonium fluoride (TBAF) smoothly gave the
OSiMe3
(Z/E > 99/1)
Ph
SYNLETT 2003, No. 14, pp 2219–2221
0
6
.1
1
.2
0
0
3
a Isolated yield.
b Diastereomer ratio.
Advanced online publication: 15.10.2003
DOI: 10.1055/s-2003-42089; Art ID: U08403ST.pdf
© Georg Thieme Verlag Stuttgart · New York

2220
N. Ozasa et al.
LETTER
THF.4 In this reaction (R)-BINAP·AgOTf complex with In conclusion, a fluoride source functioned as an activator
fluoride anion showed both Lewis acid and Lewis base ac- for the aldol reaction using an aqueous solution of forma-
tivities. Furthermore silver salts are one of the water-sta- lin and the bifunctional system (R)-BINAP·AgOTf com-
ble Lewis acids and have already been used in some plex with a fluoride source was useful for asymmetric
reactions in aq or alcoholic media.5 Taken together with synthesis. Although there is room for improving the yield
these properties and the results of the hydroxymethylation and selectivity, this approach will play a crucial role in the
process, we tried to extend our bifunctional catalysis for development of asymmetric aldol synthesis using form-
hydroxymethylation reactions in the presence of water aldehyde.
(Equation 2).6 It should be noted that because of small and
symmetrical structure of formaldehyde, there are not
many reports about the asymmetric hydroxymethylation
of carbonyl compounds.
General Procedure: Formalin (aq soln) (37% aq, 187.4 mL, 2.50
mmol) was dissolved in anhyd THF (6 mL) under Ar atmosphere
with direct light excluded, and stirred at 20 °C for 10 min. To this
solution were added trimethylsilyl enol ether (0.50 mmol) and
TBAF (2.5 mL, 1.0 M in THF) successively at –20 °C. The mixture
was stirred for 1 h at this temperature and then treated with brine (6
mL) and solid KF (ca. 1 g) at ambient temperature for 10 min. The
resulting precipitate was filtered off by a glass filter funnel filled
with Celite® and silica gel and the filterate was extracted with Et2O.
The organic extracts were dried over Na2SO4 and concentrated un-
der reduced pressure after filtration. The residual crude product was
purified by column chromatography on silica gel (hexane–Et2O, 3:1
as the eluent) to afford a mixture of the aldol adducts.
(R)-BINAP (6 mol%)
AgOTf (10 mol%)
O
OSiR3
+
F- additive (5 equiv)
solvent
CH2OH
aq. HCHO
Equation 2
(R)-BINAP (6 mol%)·AgOTf (10 mol%) with TBAF were
added for the reaction between trimethyl silyl enol ether
of cyclohexanone 1 and formalin aq solution in THF, but
no significant induction was observed (–20 °C, 1 h; 59%
yield, 7% ee). This result indicated that the reaction pro-
ceeded without (R)-BINAP AgOTf complex. Using KF as
a mild fluoride source, instead of TBAF, gave no desired
product at –20 °C for 6 h. Trimethoxysilyl enol ether of
cyclohexanone 2a can be expected to possess higher reac-
tivity due to its lower HOMO energy level and easier for-
mation of silicate with fluoride anion. Thus 2a gave 2-
hydromethylketone 3a in the presence of (R)-BINAP Ag-
OTf and KF (–20 °C, 6 h; 46% yield, racemic). Addition
of 18-crown-6 to improved the solubility of KF but had
little success (–20 °C, 1 h; 41% yield, 6% ee). Finally, we
found that the mixed solvent of water and THF gave the
highest enantioselectivity in this reaction. The reaction of
trimethoxysilyl enol ether of cyclohexanone 2a (0.5
mmol) and formalin (37% aq solution, 5 equiv) in the
presence of KF (5 equiv) at –40 °C in THF (12 mL)–H2O
(2 mL) gave 3a in 31% yield and 57% ee (Scheme 1).7 a-
Tetralone also gave high enantioselectivity.8,9
References
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(R)-BINAP (6 mol%)
AgOTf (10 mol%)
KF (5 equiv)
OSi(OMe)3
H
O
CH2OH
R1
R1
+
aq. HCHO
R2
3a,b
R2
H
THF : H2O = 6 : 1, –40 °C, 6 h
O
2a,b
O
CH2OH
CH2OH
3a 31% yield, 57% ee (S)
3b 18% yield, 57% ee (S)
Scheme 1 Asymmetric aldol reaction of trimethoxylsilyl enol ethers with formalin aq solution activated by bifunctional system.
Synlett 2003, No. 14, 2219–2221 © Thieme Stuttgart · New York

LETTER
Kameda, M.; Maruoka, K. Org. Lett. 2001, 3, 1273. (e) See
Aldol Synthesis with an Aqueous Solution of Formalin
2221
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(9) The reaction mixture is barely stirrable without being
unfrozen.
Synlett 2003, No. 14, 2219–2221 © Thieme Stuttgart · New York