Direct asymmetric α-hydroxymethylation of ketones in homogeneous aqueous solvents

Article abstract of DOI:10.1016/j.tetlet.2010.05.134

A chiral prolinamide-based zinc complex promotes the aldol reaction of ketones with aqueous formaldehyde, giving the corresponding adducts in good yields and high ees. The efficient direct aldol reaction of formaldehyde with ketones in homogeneous aqueous

Full text of DOI:10.1016/j.tetlet.2010.05.134

Tetrahedron Letters 51 (2010) 4088–4090
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct asymmetric
a-hydroxymethylation of ketones in homogeneous
aqueous solvents
a
b
b
a,b,
*
´
Monika Pasternak , Joanna Paradowska , Maria Rogozinska , Jacek Mlynarski
a Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A chiral prolinamide-based zinc complex promotes the aldol reaction of ketones with aqueous formalde-
hyde, giving the corresponding adducts in good yields and high ees. The efficient direct aldol reaction of
formaldehyde with ketones in homogeneous aqueous solution is presented for the first time.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 April 2010
Revised 12 May 2010
Accepted 28 May 2010
Available online 2 June 2010
The direct catalytic asymmetric aldol reaction is a powerful and
leading methodology,1 even for the synthesis of chiral b-carbonyl
compounds.2 Following the pioneering work of Shibasaki,3 consid-
erable attention has been paid to in situ activation of carbonyl
compounds as nucleophiles, and direct aldol reactions represent
the current state of art in the area.4 Although many chiral catalysts
have been developed for the reactions of various donors and accep-
tors, their application to the direct aldol reaction of formaldehyde
is still limited to only a few examples.5
Hydroxymethylation reactions represent one of the most useful
one-carbon extension methods,6 but the use of formaldehyde as a
C1-unit in direct catalytic asymmetric aldol reactions of ketones is
surprisingly neglected, possibly due to its high reactivity and small
and symmetrical structure. The direct use of commercially available
aqueous formaldehyde (formalin) solution gives the safest and most
economically attractive reaction conditions. This is another impor-
tant issue, as an aqueous medium is not compatible with most of
the known chiral metal complexes and organocatalysts.
Several interesting reactions with unique reactivity and selec-
tivity have been demonstrated to proceed in water or water–or-
ganic solvents,7 but the development of an asymmetric aqueous
aldol reaction is still ongoing.8 Most published examples using
water as a solvent are carried out ‘in the presence of water’, and
the organic substrates (aromatic ketones and cyclohexanone) and
catalyst are not dissolved in water, the reaction proceeding in
the organic phase.8b,9
the synthetic utility of the asymmetric aldol reaction, there has
been increased interest in the search for better-defined organic
catalysts that can promote effectively this reaction in homoge-
neous water solution.11–13 Understanding such a process is an
important issue.
Formaldehyde, having a high affinity for water, was beyond the
reach of known water-compatible chiral catalysts for a long time.
Whereas asymmetric aqueous hydroxymethylation of an enolate
component with formaldehyde is known,14 the direct use of ke-
tones instead of silicon enolates in water still needs further inves-
tigations. Recently, two examples of organocatalytic asymmetric
hydroxymethylation using formalin in the presence of a small
amount of water were reported.5a,15 In both cases, the chemical
yields were moderate, and the substrate scope was limited to a sin-
gle example, cyclohexanone, which is insoluble in water.
We recently demonstrated that zinc triflate and the chiral C2-
symmetrical prolinamide ligand 1 presented in Figure 1 was an
efficient catalyst system for asymmetric aldol reactions of acetone
and cyclic ketones in water, and in the presence of water.11 The
protonated ligand 1 (with trifluoroacetic acid) also catalyzed direct
aldol reactions, as an organocatalyst with excellent diastereo- and
enantiocontrol. Thus, this study reveals an interesting overlap in
aqueous asymmetric aldol reactions between the application of
metal complexes and organocatalysis.
Recent progress in the area has initiated constructive discussion
on the role and practical merits of water as a solvent.10 Water and
water-based reactions were debated with regard to terminology
(i.e., whether a reaction is carried out ‘in water’, ‘in the presence
of water’, or ‘in the presence of a large excess of water’).9 Given
O
N
H
NH
O
N
H
NH
OH
H
N
O
2
(S)-proline
1
* Corresponding author. Tel.: +48 12 663 2035; fax: +48 12 634 0515.
E-mail address: jacek.mlynarski@gmail.com (J. Mlynarski).
URL: http://www.jacekmlynarski.pl (Jacek Mlynarski).
Figure 1. Structure of the proline-based ligand 1 used in this study.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.134

M. Pasternak et al. / Tetrahedron Letters 51 (2010) 4088–4090
4089
To improve the flexibility of the previously elaborated catalytic
system and to highlight the discussion on homogeneous aqueous
catalysis, we herein communicate our recent research on the direct
aldol reaction of formaldehyde promoted by a Zn complex of pro-
linamide 1 in a homogeneous aqueous environment.
Initial optimization studies using cyclohexanone and formalin
as model substrates are summarized in Table 1. Both molecules
are of different hydrophobic/hydrophilic nature and are symmetri-
cal thereby making the desired asymmetric reaction even more
challenging.
with previously published results in aqueous systems.17 Only a
twofold excess of ketone was necessary for good substrate
conversion.
The use of an ethanol–water solution instead of THF–water
mixtures improved the reaction further (Table 1, entry 11), and fi-
nally, at higher concentration and still at room temperature, the
reaction proceeded in higher yield and with high selectivity (Table
2, entry 1).
Comparison of the HPLC analysis, on a chiral stationary phase,
of the benzoyl derivative of the product with that reported in the
literature14a revealed that both (S)-proline and catalyst 1 provided
(S)-2-hydroxymethyl cyclohexanone.
The new catalyst incorporates a metal center that can act as a
Lewis acid in water and mimics the mode of action of type II aldol-
ases. On the other hand, the complex could also form an enamine
intermediate, in analogy to type I aldolases. The fact that proline
alone is not an efficient catalyst supports only the expectation that
enamine formation is unfavorable under the aqueous reaction con-
ditions.9a The zinc complex gave the S enantiomer of the aldol
product in excess, and with proline alone, the same S enantiomer
was also predominant. Thus we postulate a mechanism involving
organocatalytic enamine formation, where zinc complexation only
stabilizes the formation of an enamine intermediate in water.
Using the optimized conditions, we next examined other sub-
strates and were delighted to find that various ketones could be
successfully employed (Table 2). Again, the same level of enanti-
oselectivity could be reached with 10% and 50% of water in the
homogeneous reaction mixture (Table 2, entry 1).18
In an initial experiment, cyclohexanone (1.5 mmol), aqueous
formaldehyde (0.75 mmol), and 10 mol % of (S)-proline were
mixed in DMSO following a literature protocol (Table 1, entry
1).5b After stirring for 20 h,
a-hydroxymethyl ketone was isolated
in 15% yield and 84% ee. Although not as promising as in the pub-
lished example (47% yield, 99% ee), this aldol reaction in our hands
afforded the product with a good level of enantioselectivity. At the
outset, several aqueous solvents were examined for the proline–
catalyzed reaction of cyclohexanone and formalin, but the reaction
product was not detected or was present in only a trace amount
(5%) in the reaction mixture (Table 1, entries 2 and 3).
This confirms our knowledge that proline catalyzes direct aldol
reactions with high enantioselectivity in polar organic solvents
such as DMSO and DMF, but water or an aqueous solution is not
acceptable as reaction media.16
Next, we tested the catalytic activity of the bis(prolinamide)
catalyst 1 for the same reaction. Only a trace amount of the product
was obtained in DMSO while brine was more promising (entries 4
and 5). Unfortunately, the use of a homogeneous aqueous solution
affected the enantioselectivity. Although the reaction proceeded
sluggishly in the absence of an additive (entries 4–6), the use of
a catalytic amount of zinc triflate resulted in an improved yield
and enantioselectivity (entry 7).
As far as we are aware, there are no other examples in which
this reaction proceeds with high enantioselectivity in aqueous
solution, with all the reagents and catalyst dissolved homoge-
neously in the reaction mixture. For the present catalytic system
the same level of enantioselectivity can be reached with 10–50%
of water present in the reaction mixture (entries 7 and 8). The reac-
tion in brine or in water is less efficient, but still compares well
The Zn-prolinamide-catalyzed
a-hydroxymethylation afforded
products with excellent enantioselectivity (entries 1–5). High ste-
reocontrol was maintained with five- and seven-membered rings.
With 2-methylcyclohexanone we observed high regioselectivity
but the yield of the product was low because of the formation of
a sterically hindered product (entry 4). The predominance of one
stereoisomer in the reaction of 4-methylcyclohexanone resulted
from a match and mismatch interaction between the chiral catalyst
and substrate (entry 5).19
Table 2
Direct catalytic asymmetric aldol reaction of various ketones with formaldehydea
O
O
1/Zn(OTf)2
Table 1
Optimization of the reaction conditionsa
(10 mol%)
OH
+ aq. HCHO
R
R'
R
R'
EtOH-H2O (9/1)
rt, 24 h
O
O
catalyst
1.5 mmol 0.75 mmol
(10 mol%)
OH
+ aq. HCHO
(S)
% eeb
solvent, rt, 20 h
Entry
1
Ketone
% Yield
1.5 mmol 0.75 mmol
9418
94c
O
60
52
O
O
2
3
58
59
98
93
O
O
O
4
5
6
<10
63
95
94 (dr 3/2)
—
n.d.
a
The reaction was performed employing formalin (0.75 mmol, 37% in water),
a
The reaction was performed employing formalin (0.75 mmol, 37% in water),
cyclohexanone (1.5 mmol), catalyst (10 mol %), and solvent (1 mL). Additives:
Zn(OTf)2 (10 mol %), TFA (20 mol %).
ketone (1.5 mmol), catalyst (10 mol %), and EtOH/H2O (9:1, 0.5 mL).
b
b
Isolated yield. Ee determined by HPLC analysis of the benzoate ester on a chiral
Isolated yield.
c
phase (Daicel AD-H and OD-H columns).
Ee determined by HPLC analysis of the benzoate ester on a chiral phase (Daicel
c
Reaction performed in EtOH/H2O (1:1, 0.5 mL).
OD-H column).

4090
M. Pasternak et al. / Tetrahedron Letters 51 (2010) 4088–4090
10. Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed.
In conclusion, we have reported the novel direct catalytic asym-
metric
2007, 46, 3798.
a-hydroxymethylation of unmodified ketones in wet sol-
11. Paradowska, J.; Stodulski, M.; Mlynarski, J. Adv. Synth. Catal. 2007, 349, 1041.
12. Aratake, S.; Itoh, T.; Okano, T.; Usui, T.; Shoji, M.; Hayashi, Y. Chem. Commun.
2007, 2524.
vents. It is not yet another aldol reaction in water—to date these
are the best results reported for the direct aqueous reaction of
formaldehyde catalyzed by a small synthetic metal complex.20
Though there is still room for improvement in terms of yield and
generality, the present reaction is the first example of the direct
asymmetric hydroxymethylation in homogeneous aqueous
solvents.
13. Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593.
14. (a) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 12236; (b) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.;
Manabe, K. Org. Lett. 2005, 7, 4729; (c) Kokubo, M.; Ogawa, Ch.; Kobayashi, S.
Angew. Chem., Int. Ed. 2008, 47, 9609.
15. Aratake, S.; Itoh, T.; Okano, T.; Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y.
Chem. Eur. J. 2007, 13, 10246.
Further studies to clarify the mechanism of the present system
and to expand the substrate scope by modifying the chiral catalyst
are now in progress in our laboratory.
16. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123,
5260; (b) Córdova, A.; Notz, W.; Barbas, C. F., III Chem. Commun. 2002, 3024.
17. For comparison, see Ref. 15: 37% yield, 96% ee, reaction medium: ketone with
18 equiv of water, 90 h; and Ref. 5a: 40% yield, 99% ee, reaction medium MeCN,
and buffer.
18. (S)-2-(Hydroxymethyl)cyclohexanone (Table 2, entry 2): Prolinamide
1
Acknowledgment
(30.5 mg, 0.075 mmol, 10 mol %) and Zn(OTf)2 (27.3 mg, 0.075 mmol,
10 mol %) were stirred for 5 min in the EtOH–H2O (9/1, 0.5 mL). To the
resulting solution cyclohexanone (1.5 mmol, or the same amount of another
ketone) and formaldehyde (0.75 mmol, 37% in water) were added at room
temperature and the mixture was stirred for 20 h. The mixture was extracted
with CH2Cl2, and the combined organic layer was dried over anhydrous
Mg2SO4. The solvents were evaporated, and the residue was purified by
chromatography (silica gel, hexane/EtOAc (1/1)) to give the product in 60%
yield. 1H NMR (300 MHz, CDCl3) d 1.50–2.10 (m, 6H), 2.22–2.52 (m, 3H), 2.56
(s, 1H), 3.50–3.60 (m, 1H), 3.62–3.72 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3) d
25.4, 28.2, 30.7, 42.9, 52.9, 63.5, 215.4. The enantiomeric excess of the product
was determined by chiral HPLC analysis of the corresponding benzoate
derivative. [(S)-2-Oxocyclohexyl]methyl benzoate:14a to a solution of (S)-2-
(hydroxymethyl)cyclohexanone (12 mg, 0.094 mmol) in CH2Cl2 (1 mL) were
Financial support from the Polish State Committee for Scientific
Research (KBN Grant N N204 093 135) is gratefully acknowledged.
References and notes
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1H), 2.07–2.16 (m, 1H), 2.26–2.40 (m, 2H), 2.44–2.49 (m, 1H), 2.79–2.87 (m,
1H), 4.32 (dd, 1H, J = 11.6, 6.7 Hz), 4.66 (dd, 1H, J = 11.6, 5.8 Hz), 7.41–7.45 (m,
2H), 7.53–7.57 (m, 1H), 8.01–8.03 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3): d
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HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH = 98:2, flow rate = 1.0 mL/min,
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