Lewis acid catalysis in water with a hydrophilic substrate: Scandium-catalyzed hydroxymethylation with aqueous formaldehyde in water

Article abstract of DOI:10.1002/anie.200801849

(Chemical Equation Presented) Synthesis in deep water: For the title reaction, which proceeds with high selectivities, acid-base interactions between the Sc catalyst and HCHO are important. The reaction was used in the synthesis of an odorant to demonstra

Full text of DOI:10.1002/anie.200801849

Angewandte
Chemie
DOI: 10.1002/anie.200801849
Water Chemistry
Lewis Acid Catalysis in Water with a Hydrophilic Substrate: Scandium-
Catalyzed Hydroxymethylation with Aqueous Formaldehyde in
Water**
Masaya Kokubo, Chikako Ogawa, and Shu¯ Kobayashi*
The use of Lewis acids as catalysts is one of the most powerful
strategies in organic chemistry.[1] In general, conventional
Lewis acids such as AlCl3, TiCl4, BF3·OEt2, SnCl4, etc.,
require strictly anhydrous conditions because they immedi-
ately react with water in preference to the substrates, resulting
in serious decomposition of the catalysts or the substrates. To
address this issue, water-compatible Lewis acid catalyzed
organic reactions have been intensively studied in the past
decade.[2] Considering the growing concern over environ-
mental pollution, water is an ever more desirable alternative
to organic solvents, as water is a clean, safe, and inexpensive
solvent.[3] Several surfactant-type catalysts derived from
water-compatible Lewis acids have been developed,[4] and
catalytic asymmetric reactions have been achieved in water
Figure 1. Hydroxymethylation of 1. a) Changes in yield as a function of
the number of equivalents of HCHO at different catalyst loadings for a
without requiring any organic cosolvents.[5] These reactions
proceeded smoothly by creating hydrophobic domains in the
water to stabilize and concentrate the organic substrates, or
by suppressing undesired reaction pathways that may occur in
water. One of the key factors for these successes is the
hydrophobicity of the substrates.
1.0m solution monitored over 1 hour. b) Changes in yield as a function
of concentration at different catalyst loadings for reaction containing
5.0 equivalents of HCHO monitored over 8 hours.
increased amounts of the desired product (Figure 1a, navy
blue). Gratifyingly, while optimizing the reaction conditions,
we found that desired product 2 was obtained in 82% yield by
using 5 equivalents of aq. HCHO and by extending the
reaction time to 8 hours. Notably, under these conditions the
competitive hydrolysis of silicon enolate 1 was observed. The
loading levels of the catalyst also has an effect on the yield;
the yield of 2 showed good correlations to the amount of
Sc(DS)3 used, which ranged from 2, 5, 10, to 20 mol%. To
improve the yield, we also investigated the concentration
effect of aq. HCHO for each of the different Sc(DS)3 loadings
(2, 5, 10, or 20 mol%) in the presence of 5 equivalents of aq.
HCHO (Figure 1b). In the presence of 10 and 20 mol% of
Sc(DS)3, the yields were improved to more than 80% as the
concentrations increased to 2.0m, however, no additional
improvement was observed when the concentration was
increased to more than 2.0m. In the cases of 2 and 5 mol%
of Sc(DS)3, the yields leveled off at much lower concentra-
tions of 0.5m and 1.0m, respectively. These results indicated
that Sc(DS)3 might be saturated by aq. HCHO. On the basis
of the experiments described above, it can be said that despite
the good solubility of HCHO in water, the amount of HCHO
in the hydrophobic environment increases in the presence of
Sc(DS)3 because of Lewis acid–Lewis base interactions
between Sc(DS)3 and HCHO, therefore, allowing the reaction
of HCHO with silicon enolate 1 to proceed smoothly in water.
After tuning the reaction conditions, we found that
several silicon enolates reacted with aq. HCHO (5.0 equiv)
in the presence of 5 mol% of Sc(DS)3 in water (1.0m) at 208C
Aqueous formaldehyde solutions (i.e. formalin) are one of
the most important single carbon electrophiles and are
representative of a hydrophilic substrate. As mentioned
above, the hydrophobicity of the substrates is very important
for organic reactions in water and hydrophilic substrates are
often difficult to handle in water.[6–8] Herein, we address this
issue and describe a catalytic hydroxymethylation reaction
with aqueous formaldehyde in which water is the sole solvent.
First, we carried out the hydroxymethylation of silicon
enolate 1 with 1 equivalent of formaldehyde (36% aqueous
solution; aq. HCHO) in the presence of 2 mol% of scandium
tris(dodecyl sulfate) (Sc(DS)3)[4] at a 1.0m concentration at
208C for 1 hour in water. The reaction proceeded sluggishly
and afforded desired product 2 in poor yield. Increasing the
amount of aq. HCHO to 3 equivalents improved the yield to
25%, but addition of more aq. HCHO did not result in
[*] M. Kokubo, Dr. C. Ogawa, Prof. Dr. S. Kobayashi
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 113-0030 (Japan)
Fax: (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801849.
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Communications
Table 2: Asymmetric hydroxymethylation.
to afford the corresponding hydroxymethylated ketones in
high yields (Figure 2 and Table 1). Notably, the catalyst
system can be applied to hydrophilic substrates as well as
hydrophobic substrates.
Entry
Enolate
Conditions[a]
Yield [%][b]
ee [%][c]
The Lewis acid catalyzed asymmetric reactions of hydro-
philic substrates in water are recognized to be highly
challenging[9] because of the importance of the Lewis acid–
Lewis base interactions; Lewis acids loose their acidity upon
coordination with chiral ligands. Additionally, chiral ligands
compete with substrates and water molecules for the coordi-
nation to Lewis acids. Therefore, the development of chiral
Lewis acid catalyzed hydroxymethylation by using aq. HCHO
in water would have a high impact in the field.
Encouraged by the promising results in Table 1, asym-
metric variants of the hydroxymethylation reaction by using
aq. HCHO were investigated (Figure 2 and Table 2). The
addition of a chiral ligand and a small amount of a surfactant
suppressed the competitive hydrolysis of the silicon enolates.
After optimization of the reaction conditions, catalytic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1
1
3
4
5
5
6
8
9
10
10
11
12
13
13
13
14
15
16
17
A
B
B
B
B
C
B
A
B
B
C
B
B
B
C
D
B
B
A
A
81
85
83
85
85
82
84
73
86
82
82
91
92
83
83
83
90
84
73
65
91 (R)
90 (S)
94
91 (R)
90
91 (R)
92
90
85
96
96
91 (R)
90
94
94
90
92
91
91 (S)
90
[a] Conditions A: Sc(DS)3 (10 mol%), L1 (12 mol%), Triton X-705, RT,
20 h. Conditions B: Sc[O3S(CH2)10CH3]3 (10 mol%), L2 (12 mol%),
CH3(CH2)10SO3Na, 58C, 48 h. Conditions C: Sc[O3S(CH2)10CH3]3
(2 mol%), L2 (2.4 mol%), CH3(CH2)10SO3Na, 58C, 96–110 h.
Conditions D: Sc[O3S(CH2)10CH3]3 (1 mol%), L2 (1.2 mol%), CH3-
(CH2)10SO3Na, 58C, 81 h. [b] Yield of isolated product. [c] Determined
by chiral HPLC analysis.
asymmetric hydroxymethylation reactions were successfully
carried with 10 mol% of Sc(DS)3 and 12 mol% of chiral
ligand L1[10] in the presence of Triton X-705 (Conditions A),
or with 10 mol% of Sc[O3S(CH2)10CH3]3 and 12 mol% of
chiral ligand L2[11] in the presence of CH3(CH2)10SO3Na
(Conditions B) to afford the desired products in good to high
yields with high selectivities. Awide variety of silicon enolates
reacted smoothly and high levels of enantioselectivities
(>90% ee) were attained in most cases. Moreover, by using
2 mol% or 1 mol% of the catalyst (Conditions C and D) led
to the same range in yields and enantioselectivities as those
reactions employing 10 mol% of the catalyst. Notably,
thioketene silyl acetals such as 16 and 17, which are known
to be much less stable than silyl enol ethers (ketone-derived
silicon enolates) in water, reacted smoothly under the
reaction conditions to afford the desired hydroxymethylated
adducts in good yields with high enantioselectivities.
Figure 2. Substrates and ligands used.
Table 1: Sc(DS)3-Catalyzed hydroxymethylation.
This method was applied to the synthesis of artificial
odorant 18 (Scheme 1).[12] Hydroxymethylation of 1 was
performed by using Sc(DS)3–L1 as the catalyst. After the
reaction was complete, the reaction mixture was centrifuged
(3000 rpm, 20 min) to separate the colloidal white dispersion
into three phases. The upper phase was the water layer, the
middle phase was surfactant, and the lower phase contained
organic compounds. The bottom phase was removed and
subjected to hydrogenation in the presence of polymer
incarcerated palladium (PI-Pd)[13] in benzotrifluoride (BTF)
to give compound 18 in 56% yield with 91% ee over 2 steps.
Entry
Silicon enolate
Yield [%][a]
1
2
3
4
5
6
7
1
3
4
5
6
7
9
87
88
89
94
75
68
69[b,c]
[a] Yield of isolated product. [b] Portionwise addition of the silicon
enolate (0 h and 3 h, 0.5 equiv each). [c] Yield was determined after
benzoylation.
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Chemie
(Daicel Chiralpak AD, n-hexane/iPrOH = 40:1, flow rate
1.0 mLminÀ1): tR = 11.8 min (major, S), tR = 14.6 min (minor, R).
Received: April 21, 2008
Revised: June 9, 2008
Published online: July 29, 2008
Keywords: asymmetric catalysis · enolates · Lewis acids ·
.
sustainable chemistry · synthetic methods
[1] Lewis Acids in Organic Synthesis (Ed.: H. Yamamoto), Wiley-
VCH, Weinheim, 2000.
Scheme 1. Synthesis of an odorant without using an organic solvent
workup. The pictures show the solution before centrifugation (left) and
the separated phases after centrifugation of the hydroxymethylation
reaction mixture (right).
[2] a) S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc.
1998, 120, 8287; b) S. Kobayashi, C. Ogawa, Chem. Eur. J. 2006,
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[3] a) Organic Reactions in water (Ed.: U. M. Lindström), Black-
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[4] a) S. Kobayashi, T. Wakabayashi, Tetrahedron Lett. 1998, 39,
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Notably, the synthesis was accomplished by using a catalytic
asymmetric reaction in water and a hydrogenation reaction
including an immobilized catalyst, both of which are suitable
for green and sustainable chemistry.[3,14]
In conclusion, we have developed a scandium-catalyzed
hydroxymethylation reaction with aqueous HCHO in water.
The achiral and asymmetric hydroxymethylations both pro-
ceeded smoothly with high selectivities. Contrary to our
previous results, hydrophilic HCHO reacted well in the
hydrophobic system. Lewis acid–Lewis base interactions
between the scandium catalyst and HCHO were suggested
to be crucial based on several experiments. We also applied
this reaction to the synthesis of an odorant. Reported herein is
the first example of a catalytic hydroxymethylation of silicon
enolates with aqueous HCHO in water that does not require
organic solvents. These results provide a foundation for
conducting organic reactions, even with hydrophilic com-
pounds, in the hydrophobic systems.
[5] C. Ogawa, N. Wang, M. Boudou, S. Azoulay, K. Manabe, S.
Kobayashi, Heterocycles 2007, 72, 589, and references therein.
[6] Asymmetric hydroxymethylation by using aqueous formalde-
hyde solution in water/organic solvent systems has been inves-
tigated: a) S. Ishikawa, T. Hamada, K. Manabe, S. Kobayashi, J.
Am. Chem. Soc. 2004, 126, 12236; b) H. Torii, M. Nakadai, K.
Ishihara, S. Saito, H. Yamamoto, Angew. Chem. 2004, 116, 2017;
Angew. Chem. Int. Ed. 2004, 43, 1983; c) S. Kobayashi, T. Ogino,
H. Shimizu, S. Ishikawa, T. Hamada, K. Manabe, Org. Lett. 2005,
7, 4729, and references therein.
[7] For Mukaiyama aldol reaction in aqueous media, see a) S.
Kobayashi, S. Nagayama, T. Busujima, Chem. Lett. 1999, 71; b) S.
Kobayashi, S. Nagayama, T. Busujima, Tetrahedron 1999, 55,
8739; c) S. Nagayama, S. Kobayashi, J. Am. Chem. Soc. 2000,
122, 11531; d) T. Hamada, K. Manabe, S. Ishikawa, S. Nagayama,
M. Shiro, S. Kobayashi, J. Am. Chem. Soc. 2003, 125, 2989; e) H.-
J. Li, H.-Y. Tian, Y.-C. Wu, Y.-J. Chen, L. Liu, D. Wang, C.-J. Li,
Adv. Synth. Catal. 2005, 347, 1247; f) J. Jankowska, J. Para-
dowska, B. Rakiel, J. Mlynarski, J. Org. Chem. 2007, 72, 2228.
[8] For hydrophobic interactions, see U. M. Lindström, F. Ander-
sson, Angew. Chem. 2006, 118, 562; Angew. Chem. Int. Ed. 2006,
45, 548.
[9] “Chiral Lewis Acid Catalysis in Aqueous Media”: S. Kobayashi,
C. Ogawa in Asymmetric Synthesis—The Essentials (Eds.: M.
Christmann, S. Bräse), Wiley-VCH, Weinheim, 2007, pp. 110 –
115.
[10] a) C. Bolm, M. Zehnder, D. Bur, Angew. Chem. 1990, 102, 206;
Angew. Chem. Int. Ed. Engl. 1990, 29, 205; b) C. Bolm, M.
Ewald, M. Felder, G. Schlingloff, Chem. Ber. 1992, 125, 1169;
c) S. Ishikawa, T. Hamada, K. Manabe, S. Kobayashi, Synthesis
2005, 2176.
Experimental Section
Synthesis of (S)-2,3-Dihydro-2-(hydroxymethyl)-2,5-dimethylindane
(18): A mixture of Sc(DS)3 (25 mg, 0.030 mmol) and chiral ligand L1
(12 mg, 0.036 mmol) in water (0.3 mL) was stirred for 1 h at 208C.
Aqueous HCHO (125 mg, 1.5 mmol) and silicon enolate 1 (69.7 mg,
0.3 mmol) were then added to the reaction mixture, which was then
stirred for 20 h at 208C. The resulting mixture was then centrifuged
(3000 rpm, 20 min). The bottom layer was separated, and then
dissolved in a, a, a-trifluorotoluene (BTF, 2 mL). Polymer incarcer-
ated Pd (PI-Pd, 0.668 mmolgÀ1, 45 mg, 0.030 mmol) was added to the
solution under Ar, and the reaction mixture was then stirred for 8 h at
808C under a hydrogen atmosphere (1 atm). After cooling the
reaction mixture to room temperature, it was filtered through Celite
and the filtrate was concentrated under reduced pressure. The residue
was purified by preparative TLC (elution with n-hexane/AcOEt =
3:2) to give 4 (56% in 2 steps) as a colorless oil.
[11] a) D. Shang, J. Xin, Y. Liu, X. Zhou, X. Liu, X. Feng, J. Org.
Chem. 2008, 73, 630; b) M. Nakajima, Y. Yamaguchi, S.
Hashimoto, Chem. Commun. 2001, 1596.
[12] a) C. Vial, G. Bernardinelli, P. Schneider, M. Aizenberg, B.
Winter, Helv. Chim. Acta 2005, 88, 3109; b) B. Winter, S. Gallo-
Flꢀckiger, Helv. Chim. Acta 2005, 88, 3118.
[13] a) R. Akiyama, S. Kobayashi, J. Am. Chem. Soc. 2003, 125, 3412;
b) K. Okamoto, R. Akiyama, H. Yoshida, T. Yoshida, S.
Kobayashi, J. Am. Chem. Soc. 2005, 127, 2125.
1H NMR d = 1.17 (s, 3H), 1.55 (brs, 1H), 2.31 (s, 3H), 2.63 (d, J =
15.6 Hz, 2H), 2.86 (d, J = 15.6 Hz, 1H), 2.87 (d, J = 15.6 Hz, 1H), 3.51
(s, 2H), 6.94(d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 7.04ppm (d, J = 7.6 Hz,
1H); 13C NMR d = 21.2, 24.0, 42.4, 42.7, 45.0, 70.7, 124.5, 125.5, 127.0,
135.8, 139.4, 142.6 ppm; FT-IR (neat) n˜ = 3186, 3007, 2866, 1493, 1454,
1377, 1298, 1225, 1137, 1094, 1036, 977, 812, 794, 699 cmÀ1; [a]23
D
+ 2.7 degcm3 gÀ 1dmÀ1 (c 0.750 gcmÀ3, CHCl3) (91% ee, S), lit. [a]20
D
[14] S. Kobayashi, R. Akiyama, Chem. Commun. 2003, 449.
+ 3.2 degcm3 gÀ 1dmÀ1 (c 1.50 gcmÀ3 CHCl3) (> 99% ee, S); HPLC
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