Chiral scandium-catalyzed enantioselective hydroxymethylation of ketones in water

Article abstract of DOI:10.1002/asia.200900442

Scandium-catalyzed enantioselective hydroxymethylation of ketones has been developed using aqueous formaldehyde (formalin) in water. The addition of a catalytic amount of pyridine enables the use of ketones directly in asymmetric hydroxymethylation reactions. (Chemical equation presented).

Full text of DOI:10.1002/asia.200900442

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DOI: 10.1002/asia.200900442
Chiral Scandium-Catalyzed Enantioselective Hydroxymethylation of Ketones
in Water
Shu Kobayashi,* Masaya Kokubo, Katsuaki Kawasumi, and Takashi Nagano[a]
¯
Dedicated to the 150th anniversary of Japan–UK diplomatic relations
Hydroxymethylation reactions provide one of the most
useful one-carbon extension methods.[1,2] The reactions are
usually carried out using paraformaldehyde or difficult-to-
handle formaldehyde gas in organic solvents.[3] In the course
of our investigations to develop catalytic asymmetric reac-
tions in water,[4,5] we have recently found that scandium–
chiral N-oxide complex catalyzed highly efficient asymmet-
their systems, chemical yields were moderate and substrates
are relatively limited. Therefore, efficient and general asym-
metric hydroxymethylation is desirable. We started to inves-
tigate asymmetric hydroxymethylation of ketones in water,
and in this report, preliminary results using chiral scandium
catalysts are described.
At the outset, several reaction conditions were examined
for the scandium-catalyzed asymmetric reaction of a-meth-
ylindanone (3a) with formalin in water using chiral N-oxide
1a[9] as a ligand (Table 1). Although the reaction proceeded
Table 1. Optimization of reaction conditions.
Scheme 1. Chiral Sc-catalyzed enantioselective hydroxymethylation of sil-
icon enolates.
Entry
Ligand
Additive (mol%)
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
none
Et3N (20)
20
36
37
87
16
60
57
76
76
81
41
27
38
0
46
47
67
70
73
72
ric hydroxymethylation of silicon enolates in water
(Scheme 1).[6] In this reaction, readily available and inexpen-
sive aqueous formaldehyde (formalin) could be successfully
employed. Although this asymmetric hydroxymethylation is
simple and shows high enantioselectivities for a variety of
silicon enolates, direct use of ketones instead of silicon eno-
lates seems to be attractive from an atom economy point of
view. Recently, Cꢀrdova[7] and Yamamoto[8] have reported
organocatalytic asymmetric hydroxymethylation using for-
malin. Although high enantioselectivities were observed in
NaOH (20)
NaOH (50)
2,6-lutidine (20)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (20)
9
10[c]
[a] Yield of isolated product after chromatography. [b] Enantiomeric
excess was determined by chiral HPLC analysis. [c] Reaction for 48 h.
sluggishly in the absence of an additive, the use of a catalytic
amount of triethylamine resulted in improving the yield
with moderate enantioselectivity (entries 1 and 2). Addition
of 20 mol% NaOH also enhanced the rate of the desired re-
action (entry 3). Although further addition of NaOH gave
good yields, no chiral induction was observed, probably be-
[a] Prof. Dr. S. Kobayashi, M. Kokubo, K. Kawasumi, Dr. T. Nagano
Department of Chemistry
School of Science and Graduate School of Pharmaceutical Sciences
The University of Tokyo
The HFRE Division, ERATO, JST
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.sc.jp
cause ScACTHGNURETNNU(G OTf)3 was deactivated and free NaOH catalyzed
490
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Chem. Asian J. 2010, 5, 490 – 492

an achiral pathway (entry 4). Among the organic bases
tested, pyridine was found to be the best additive for the de-
sired asymmetric hydroxymethylation (entry 6). Use of alkyl
amide-type ligand 1b instead of 1a improved enantioselec-
tivity significantly (entry 7), and finally, a cyclopentyl sub-
stituent on the amide moiety (1d) was found to be the best
in terms of both yield and enantioselectivity (entries 7–10).
With the optimized conditions in hand, we then examined
substrate generality of this reaction (Table 2). Introduction
Table 2. Asymmetric hydroxymethylation of ketones in water.[a]
Entry Ketone
Product
Yield [%][b] ee [%][c]
Scheme 2. Asymmetric hydroxymethylation of oxindole.
1
81
72
39
72
72
88
formaldehyde (formalin) in water. The addition of a catalyt-
ic amount of pyridine enabled us to use ketones directly in
asymmetric hydroxymethylation reactions. Further investiga-
tions to clarify the mechanism of the present system as well
as to expand substrate scope by modifying chiral catalysts
are now in progress in our laboratories.
2
3[d]
Experimental Section
A typical experimental procedure is described for the enantioselective
hydroxymethylation of ketones: Ketone (0.3 mmol), ScACHTUNGTRENNUNG(OTf)3
4[d]
29
81
67
(10 mol%), N-oxide 1d (12 mol%), C11H23SO3Na (150 mol%), pyridine
(20 mol%), and formalin (5 equiv) were combined in water (500 mL) at
room temperature. After 24 h, a mixture of sat. aqueous NaHCO3 and
brine (1:1, 5–10 mL) was added, and the aqueous layer was extracted
three times with dichloromethane. The combined organic layers were
dried (Na2SO4), filtrated, and evaporated to afford the crude product,
which was purified by preparative TLC. The enantiomeric excess was de-
termined by chiral HPLC analysis.
5
quant
[a] Conditions: Ketone 3 (0.3 mmol), ScACTHNUTRGNENUG(OTf)3 (10 mol%), N-oxide 1d
(12 mol%), C11H23SO3Na (150 mol%), pyridine (20 mol%), formalin
(5 equiv), water, RT, 24 h. [b] Yield of isolated product after chromatog-
raphy. [c] Enantiomeric excess was determined by chiral HPLC analysis.
[d] Reaction was carried out at 408C for 48 h.
Acknowledgements
of a methyl group at the 6-position of a-methyl indanone
did not retard the chiral induction, resulting in formation of
hydroxymethylated ketone 4b in 72% yield with 72% ee
(entry 2). Ketone 4b is known as a useful intermediate for
the preparation of artificial odorant.[10] Although reactivity
was lower, tetralone 3c and propiophenone (3d) also gave
the desired hydroxymethylated ketones in high enantioselec-
tivities (entries 3 and 4). In the case of a-methylcoumara-
none (3e), the desired product 4e was obtained quantita-
tively with good enantiomeric excess (entry 5). In the hy-
droxymethylation of oxindole, the reaction proceeded
smoothly to afford the desired compound 7 in 82% yield,
albeit no chiral induction was observed unexpectedly. Slight
modification of reaction conditions was performed and it
was finally found that the combination of Sc(DS)3 and chiral
bipyridine ligand 6[11] with SDS gave the desired hydroxyme-
thylated oxindole 7 in 59% yield with 82% ee (Scheme 2).
In summary, we have developed scandium-catalyzed enan-
tioselective hydroxymethylation of ketones using aqueous
This work was partially supported by a Grant-in-Aid for Science Re-
search from the Japan Society for the Promotion of Science (JSPS) and
Global COE Program (Chemistry Innovation through Cooperation of
Science and Engineering), The University of Tokyo, MEXT, Japan.
Keywords: asymmetric catalysis
·
green chemistry
·
hydroxymethylation · scandium · water
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Received: September 10, 2009
Published online: January 8, 2010
492
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Chem. Asian J. 2010, 5, 490 – 492