Asymmetric aldol reaction catalyzed by the anion of an ionic liquid

Article abstract of DOI:10.1021/jo300737u

Herein we report the synthesis of a chiral imidazolium salt derived from trans-l-hydroxyproline and its applications as a catalyst for the asymmetric aldol reaction. By performing the aldol reaction in [Bmim]NTf₂ as a solvent, we report excellent isolated yields of the aldol product (up to 99%), as well as modest to excellent selectivities (dr superior to 99:1. ee up to 89%). Mechanistic insights and the origins of the selectivity of the aldol reaction are discussed on the basis of the results obtained with two catalytic imidazolium salts having different H-bonding potential.

Full text of DOI:10.1021/jo300737u

Article
pubs.acs.org/joc
Asymmetric Aldol Reaction Catalyzed by the Anion of an Ionic Liquid
Vincent Gauchot and Andreea R. Schmitzer*
́ ́ ́ ́
Department of Chemistry, Universite de Montreal, C.P. 6128 Succursale Centre-ville, Montreal, Quebec, H3C 3J7, Canada
S
* Supporting Information
ABSTRACT: Herein we report the synthesis of a chiral
imidazolium salt derived from trans-L-hydroxyproline and its
applications as a catalyst for the asymmetric aldol reaction. By
performing the aldol reaction in [Bmim]NTf2 as a solvent, we
report excellent isolated yields of the aldol product (up to 99%), as
well as modest to excellent selectivities (dr superior to 99:1. ee up
to 89%). Mechanistic insights and the origins of the selectivity of
the aldol reaction are discussed on the basis of the results obtained
with two catalytic imidazolium salts having different H-bonding
potential.
functionalization of the carboxylic group of the proline and its
role on the stereoselective outcome of the reaction. Carrying
out the aldol reaction in [Bmim]NTf2 using 30 mol % of
catalyst led to very good results in terms of yields (up to 99%)
and selectivities (dr > 99:1. ee up to 89%). To the best of our
knowledge, this is the second example of an asymmetric aldol
reaction catalyzed by an anion-modified catalytic ionic liquid
providing satisfying conversion and selectivity. The use of ionic
liquids both as solvent and catalyst make this methodology
attractive in terms of atom economy and green chemistry.
INTRODUCTION
■
Organocatalysis, through the use of readily available small chiral
molecules as catalysts, has become a field of major interest in
the stereocontrolled preparation of chiral adducts.1−4 Over the
last 10 years, the wide application range of organocatalysis has
been described through various examples, such as organo-
catalyzed cycloaddition reactions, desymmetrization reactions,
and total synthesis.5−9 The aldol reaction is one of the most
important carbon−carbon bond-forming reactions for the
preparation of small optically active molecules. Since Hajos
and Parrish described the first organocatalyzed aldol reaction
using (S)-proline as the catalyst, various examples involving
proline and its derivatives demonstrated their efficiency as
catalysts for stereoselective organic reactions.10,11 However,
there remain issues regarding the use of environmentally
unfriendly solvents such as DMF or DMSO and the difficulties
of recycling large quantities of catalysts.
Over the past decade, ionic liquids (ILs) have attracted
growing attention as they are becoming greener alternatives to
classical organic solvents.12−14 Several examples have described
efficient aldol reactions carried out in IL as solvents.15−18 More
recently, the design and the use of these ionic liquids in
combination with chiral catalysts has provided excellent yields
and diastereoselectivities. Many examples of functionalized
imidazolium cations as catalytic species have been reported in
the literature,19 but so far only two examples of asymmetric
aldol reactions catalyzed by a chiral anion have been reported.
While the first example reported an enantiomeric excess below
10%,20 Wang et al. recently described an imidazolium salt
catalyst with L-proline as the anion.21 Using their [Emim][Pro]
catalyst, they reported modest to excellent yields and very good
selectivities in the aldol reaction.
RESULTS AND DISCUSSIONS
■
Starting with the readily available trans-L-hydroxyproline, the
carboxylic acid moiety was first esterified under classic
conditions (Scheme 1). Because of solubility issues, protection
of the trans-L-hydroxyproline methyl ester 2 with a Boc group
was necessary in order to proceed to the sulfonation reaction in
CCl4. Sulfonation of the hydroxyl group allowed the
simultaneous deprotection of the Boc group, leading to the
ester zwitterion 4. Crystals of 4 suitable for X-ray crystal
structure determination were obtained by diffusion of ether to a
methanol solution (see the Supporting Information).
Since typical anion metathesis was unsuccessful, the
formation of [Bmim]OH as a nonisolable intermediate was
required for the anion exchange. The preparation of [Bmim]-
OH was performed using an Amberlite IRA-400 hydroxide
form resin, and the anion metathesis was then performed
(Scheme 2).
A typical aldol reaction between p-nitrobenzaldehyde and
cyclohexanone was carried out in several solvents using 30 mol
% catalyst loading, according to the previously described
conditions for this type of reaction.21 Whether the reaction was
carried out in typical organic solvents or IL, a very long reaction
We present here the supramolecular assistance of the anion
of an imidazolium salt in an asymmetric aldol reaction
performed in an ionic liquid medium. Using two differents
catalysts derived from trans-L-hydroxyproline, we discuss
mechanistic insights of the reaction, the importance of the
Received: November 16, 2011
© XXXX American Chemical Society
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Scheme 1. Synthesis of the Anion
Scheme 2. Preparation of the Catalyst
time was required (Table 1). TLC analysis revealed that some
reactions were still incomplete after 5 days.
With the goal of optimizing the reaction conditions, various
acidic additives were tested for the aldol reaction (Table 2).
a
Table 2. Influence of Acidic Additives
Table 1. Solvent Screening
b
d
c
a
b
entry
solvent
yield (%)
dr (anti/syn)
ee (anti) (%)
entry
additive
none
yield (%)
dr (anti/syn)
ee (anti) (%)
d
d
1
2
3
4
5
6
7
8
[Bmim]BF4
[Bmim]PF6
[Bmim]NTf2
MeOH
37 (82)
66:34 (71:29)
76:24 (73:27)
76:24 (75:25)
62:38 (68:32)
75:25 (76:24)
72:28 (64:36)
71:29 (73:27)
59:41 (58:42)
46 (55)
1
2
3
4
5
6
43
6
76:24
57:43
75:25
74:26
71:29
75:25
57
rac
rac
47
41
52
d
d
d
d
d
d
d
d
d
51 (82)
60 (52)
p-TSA
d
d
53 (89)
57 (55)
TFA
11
63
64
d
d
53 (73)
22 (30)
3,5−DNBA
benzoic acid
d
d
DCM
41 (66)
40 (30)
d
d
DMSO
22 (73)
34 (40)
acetic acid
72
d
d
DMF
20 (16)
79 (75)
a
b
1
Determined by H NMR. Determined by chiral HPLC.
d
d
neat
82 (98)
44 (60)
a
Conditions: A solution of cyclohexanone (0.3 mmol) and catalyst (30
mol %) in solvent (0.3 mL) was stirred for 30 min at 4 °C. p-
With the exception of acetic acid, the decrease of selectivity in
spite of a shorter reaction time suggests a kinetic control of the
reaction, where the formation of the racemate is favored,
instead of one particular enantiomer. Another indication of
kinetic control was the lower selectivity observed when
performing the reaction at room temperature. Strong inhibition
of the aldol reaction was observed in the presence of TFA and
p-TSA: these acids are strong enough to protonate the
counteranion of the catalyst (pKa of 0.3 and −2.8, respectively),
leading to anion metathesis and destruction of the catalyst,
explaining the poor yields, and selectivities.
A variation of the medium concentration was also tested
using [Bmim]NTf2 as solvent with catalyst 5. As a general
trend, it was observed that increasing the concentration of the
reaction medium reduced the reaction time was, and led to
better selectivities (Table 3). In an attempt to further decrease
the reaction time, the reaction was carried out at the highest
concentration tested, using acetic acid as additive, and we were
surprised to observe that enantioselectivity plummeted.
Nitrobenzaldehyde (0.1 mmol) was added, and the mixture was stirred
b
c
1
for 72 h at 4 °C. Determined by H NMR. Determined by chiral
d
HPLC. Results in parentheses were obtained when acetic acid was
used as an additive; reaction time was 48 h.
ILs led to better enantioselectivites than common organic
solvents. As it was previously demonstrated that the formation
of the enamine intermediate should be enhanced by a catalytic
source of acid, a solvent screening study was performed using
acetic acid (30 mol %) as an additive. As shown in Table 1, the
overall trend for the addition of acid was to reduce the reaction
time, though selectivity was unchanged. Increasing solvent
polarity had little effect on diastereoselectivity, but generally
offered a slight improvement of ee. Performing the reaction in
neat conditions predictably afforded excellent yields, but poor
selectivity. Within this series, the ionic liquids ([Bmim]BF4,
[Bmim]PF6, and [Bmim]NTf2), offered the best combination
of good yields and selectivities. Best results were achieved in
[Bmim]PF6, and [Bmim]NTf2, but since PF6-derived ILs are
known to release HF,22 we further explored the [Bmim]NTf2
system by improving the reaction conditions and recyclability.
Based on reaction results in neat conditions, we observed
that adding 10 equiv of cyclohexanone instead of 3 allowed the
reaction to be completed in 2 days, with higher dr (86:14) and
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a
used in our model reaction of cyclohexanone with p-
nitrobenzaldehyde, a qualitatively faster reaction was observed,
but with a lower selectivity. Catalyst 5 gave a complexe mixture
of regioisomers when using linear ketones, but using catalyst 7
with 2-butanone as substrate, only one regioisomer was
obtained in good yields and selectivities (entry 14).
Table 3. Concentration Studies
b
c
entry
[aldehyde] (mol·L−1
)
dr (anti/syn)
ee (anti) (%)
In terms of mechanism, our first hypothesis was that the
steric hindrance of the methyl group of the ester moiety on the
anion was the main source of the selectivity of the reaction
when using catalyst 5 (Figure 1 (1)). The methyl group should
be bulky enough to hinder the approach of aldehyde to the
enamine intermediate, and favor the approach by the opposite
face. However, catalyst 7, able to form H-bonds with the
aldehyde (Figure 1 (2)) and direct its approach, led to the same
major enantiomer and a 3-fold shorter reaction time (16 h
instead of 48 h). The amide group, by hydrogen bonding, may
be responsible for directing the approach of the aldehyde
toward the enamine while activating the aldehyde. It is
reasonable to propose a similar transition state using catalyst
5, but steric hindrance of the ester moiety may be the source of
the lower reactivity. None of our experiments confirmed the
implication of the imidazolium cation in the transition state, as
proposed previously.21
1
2
3
4
5
0.33
0.40
0.50
0.66
1
76:24
75:25
76:24
81:19
89:11
71:29
86:14
57
65
71
69
73
29
d
6
1
e
7
1
86
a
b
1
All reactions were arbitrarily stopped after 16 h. Determined by H
NMR. Determined by chiral HPLC. Reaction was carried out using
acetic acid as a additive (30 mol %). 10 equiv of cyclohexanone;
reaction time was 2 days
c
d
e
ee (86%) (entry 7). Using these optimized conditions, a lower
catalyst loading only resulted in a longer reaction time and
lower selectivities (Table 4).
As the major obtained stereoisomers are the same using
either the ester or the amide catalyst, discrimination between
the two faces of the reaction intermediate when approaching
the aldehyde could be attributed to the position of the
imidazolium cation close to the sulfonate group (Figure 1 (3)).
The imidazolium cation, being localized near the negative
charge on the proline derivative, may block the approach of the
aldehyde on this side and allow the formation of the anti
diastereomer.
Molecular modeling was performed to confirm the proposed
transition states and, as shown in Figure 2(2), the resulting
models support the experimental results. The imidazolium
cation is close to the negative charge of the sulfate group (1),
which sterically hinders the approach of the aldehyde (2) on
this side.
Table 4. Influence of Catalyst Loading
a
b
entry catalyst loading (%) yield (%) dr (anti/syn)
ee (anti) (%)
1
2
3
30
20
83
35
17
86:14
83:17
73:27
86
81
75
10
a
b
1
Determined by H NMR. Determined by chiral HPLC.
To broaden the scope of our catalyst 5, we performed the
asymmetric aldol reaction for different cyclic ketones under the
optimized conditions, using o-, m-, or p-nitrobenzaldehydes. As
shown in Table 5 (entries 1−6), apart from cycloheptanone,
the reaction proceeded with good yields and generally good ee
However, when performing the aldol reaction with other
aldehydes, no aldol product was observed, probably due to both
the lower reactivity of these aldehydes and the steric hindrance
induced by the methyl group of the catalyst.
Based on these observations, we designed another catalyst
anion bearing a hydrogen bond donor functional group.
Zwitterion 6 was obtained by dissolving 4 in concentrated
NH4OH, and catalyst 7 was prepared using the same conditions
used for catalyst 5 (Scheme 3). We expected this new catalyst 7
to be more efficient toward less reactive aldehydes through
activation by hydrogen bonding with these aldehydes and to
have the properties required to participate and control the
stereoselectivity of the reaction.
Carrying out the aldol reaction with less activated aldehydes
and catalyst 7 gave access to aldol products that catalyst 5 could
not produce, with good to excellent yields, as well as excellent
selectivities (Table 5, entries 7−13). Less reactive aldehydes,
such as 2-naphtaldehyde or 2-thiophenecarboxaldehyde gave
only low to moderate yields, even after longer reaction times,
but still led to the aldol product with excellent diastereo- and
enantioselectivities. These results highlighted the assistance of
the amide group in the reaction, by activating the aldehydes
through hydrogen bonding. Nonetheless, when catalyst 7 was
The possibility to recycle the catalyst and the ionic liquid was
also proven for cyclohexanone and p-nitrobenzaldehyde
reaction(Table 6). Up to five catalytic runs were achieved,
with only a small decrease in the catalytic efficiency of our
system.
CONCLUSION
■
In conclusion, we report the supramolecular assistance of an
imidazolium-based chiral catalyst in asymmetric organic
synthesis. The mechanistic insights of the asymmetric aldol
reaction allow us to propose that the same proline-based
catalyst can be used in other reactions involving enamine
intermediates, such as the Michael addition. Up to five catalytic
cycles were performed using the same conditions, illustrating
the recyclability of this setup. The ease of switching the anion
encouraged us to develop a new recycling method, as well as
the design of other catalytic anions are currently underway in
our group.
EXPERIMENTAL SECTION
■
Materials. All organic compounds were obtained commercially and
used without further purification. 1H and 13C NMR spectra were
recorded on 400, 300, 100, and 75 MHz spectrometers, respectively, in
the indicated solvent. Chemical shifts are reported in ppm with
internal reference to TMS, and J values are given in Hertz. All HPLC
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Table 5. Substrate Scope
a
b
1
Determined by H NMR. Determined by chiral HPLC.
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Scheme 3. Preparation of Catalyst 7
(m, 2H), 3.76 (s, 3H), 3.28−3.52 (m, 2H), 2.41 (dd, J = 14.1, 7.7 Hz,
1H), 2.12−2.29 (m, 1H). 13C NMR (D2O, 100 MHz): δ = 171, 70.2,
58.9, 54.6, 54.2, 37.4. HRMS (ESI): calcd for C6H12NO3 146.08117,
found 146.08111. Mp: 161.8−162.2 °C.
(2S,4R)-1-tert-Butyl-2-methyl-4-hydroxypyrrolidine-1,2-dicarbox-
ylate (3). Compound 2 (4 g) was suspended in methylene chloride
and cooled to 0 °C. Triethylamine (9.21 mL, 3 equiv) and di-tert-butyl
dicarbonate (5.29 g, 1.1 equiv) were added, and the mixture was
stirred at room temperature for 2 days. The solution was first washed
with an aqueous solution of 1 N HCl, washed with a saturated aqueous
solution of NaHCO3, and finally washed with brine. The organic phase
was dried on magnesium sulfate, filtered, and concentrated under
vacuum to give the crude product 3 as a pale yellow oil (5.13 g, 95%
crude). 1H NMR (CDCl3, 400 MHz): δ = 4.49 (bs, 1H), 4.40 (t, J = 8
Hz, 1H), 3.74 (s, 3H), 3.44−3.65 (m, 2H), 2.22−2.35 (m, 1H), 3.03−
2.12 (m, 1H). HRMS (ESI): calcd for C11H19NO5Na 268.11554,
found 268.11652.
Figure 1. Proposed transition states.
(3R,5S)-5-(Methoxycarbonyl)pyrrolidin-3-yl Hydrogen Sulfate (4).
Under inert atmosphere, crude 3 (4.835 g) was solubilized in 40 mL of
carbon tetrachloride and then cooled to 0 °C. Chlorosulfonic acid
(1.57 mL, 1.2 equiv) was added dropwise to the reaction mixture
under strong stirring. The reaction medium was then stirred vigorously
at room temperature overnight. The solvent was removed under
vacuum, the residue was triturated in methanol and then filtered to
give 4 as a white powder (2.73 g, 62%). 1H NMR (D2O, 400 MHz): δ
= 5.12 (s, 1H), 4.65 (dd, J = 10.6, 7.9 Hz, 1H), 3.77 (s, 3H), 3.68 (s,
1H), 3.55−3.62 (m, 1H), 2.69−2.79 (m, 1H), 2.37 (s, 1H). 13C NMR
(D2O, 100 MHz): δ = 170.4, 77.83, 58.93, 54.68, 52.44, 35.64. HRMS
(ESI): calcd for C6H12NO6S 226.03798, found 226.03795.
(3R,5S)-5-Carbamoylpyrrolidin-3-yl Hydrogen Sulfate 6. Com-
pound 4 (1 g, 4.44 mmol) was dissolved in concentrated ammonium
hydroxide (10 mL), and the reaction medium was stirred overnight at
room temperature. The solvent was evaporated under vacuum and the
residue was suspended and triturated in methanol. Filtration of the
mixture afforded compound 6 as a white powder (809.2 mg, 87%). 1H
NMR (D2O, 400 MHz): δ = 5.12 (t, J = 4.2 Hz, 1H), 4.45 (dd, J =
10.4, 7.7 Hz, 1H), 3.45−3.66 (m, 2H), 2.74 (dd, J = 14.5, 7.7 Hz, 1H),
2.17−2.29 (m, 1H). 13C NMR (D2O, 100 MHz): δ = 172.8, 79.1, 59.2,
52.6, 37.1. HRMS (ESI): calcd for C5H11N2O5S 211.03832, found
211.03886.
General Procedure for the Synthesis of the Imidazolium
Catalysts. 1-Butyl-3-methylimidazolium bromide (450 mg) was
dissolved in 24 mL of methanol and passed through a glass column
containing 12 g of activated Amberlite IRA400 hydroxide form resin.
The column was then washed twice with 15 mL of methanol. The
collected fractions were assembled in a 100 mL round-bottom flask,
and zwitterion 4 or 6 was added (1.15 equiv). The mixture was
allowed to stir at room temperature overnight. The solvent volume
was reduced under vacuum, cooled down to 0 °C for 3 h, and filtered
through a Celite pad to remove excess zwitterion. The filtrate was
evaporated under vacuum and dried under vacuum overnight to afford
catalyst 5 or 7 as a viscous pale yellow oil (quant.).
Figure 2. Theoretical calculation of the enamine intermediate
obtained with MOPAC, PM6 method. Carbon atoms are represented
in blue, oxygen in red, and sulfur in yellow. The aldehyde is
represented in green and the imidazolium cation in gray.
Table 6. Recycling Studies
a
catalytic run
reaction time (days)
conversion (%)
1
2
3
4
5
2
97
91
87
99
85
2.5
3
3
4
a
Determined by chiral HPLC.
analysis were done using Chiralpak AD or OD columns and absolute
configurations of the aldols products were based on previously
reported literature.23−25 Ionic liquids used as solvents were prepared as
already described.26
Molecular Modeling. In order to assess the energy content for
various molecules designed, semiempirical quantum calculations were
undertaken using the PM6 method in gas phase or in aqueous solution
(MOPAC2009TM; Stewart Computational Chemistry). All structures
were optimized to a gradient inferior to 0.1 using the eigenvector
following method.
1-Butyl-3-methylimidazolium (3R,5S)-5-(Methoxycarbonyl)-
1
pyrrolidin-3-yl Sulfate (5). H NMR (D2O, 400 MHz): δ = 8.60 (s,
1H), 7.37 (s, 1H), 7.32 (s, 1H), 4.87−4.97 (m, 1H), 4.09 (t, J = 7.1
Hz, 2H), 4.02 (t, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 3.00−3.20 (m, 2H),
2.33−2.48 (m, 1H), 2.03−2.18 (m, 1H), 1.64−1.81 (m, 2H), 1.21 (d, J
= 7.7 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13C NMR (D2O, 100 MHz): δ
= 175, 135.4, 123, 121.7, 79.6, 57.5, 52.4, 51.5, 48.8, 35.8, 35.1, 30.8,
18.3, 12.1. HRMS (+ESI): calcd for C8H15N2 139.12297, found
139.12347; (-ESI) calcd for C6H10NO6S 224.02343, found 224.02324.
(2S,4R)-Methyl-4-hydroxypyrrolidine-2-carboxylate Hydrochlor-
ide (2). trans-4-Hydroxy-L-proline (5.0 g) was suspended in methanol
(40 mL) and cooled to 0 °C. Acetyl chloride (4.08 mL, 1.5 equiv) was
slowly added, and the reaction was stirred at reflux for 16 h. The
reaction mixture was then cooled to room temperature. Ether was
added and the reaction medium filtered to afford compound 2 (6.92 g,
1
quant) as white crystals. H NMR (D2O, 400 MHz): δ = 4.53−4.66
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1-Butyl-3-methylimidazolium (3R,5S)-5-Carbamoylpyrrolidin-3-yl
mL·min−1, λ = 254 nm) tR (anti isomer) = 39.93 (minor), 19.80
(major), tR (syn isomer) = 14.10 (minor), 16.57 min (major). HRMS
(ESI): calcd for C14H17NO4Na 286.10498, found 286.10443..
(S)-2-((S)-Hydroxy(4-nitrophenyl)methyl)cyclopentanone (10f).
Yellow solid. Yield: 8.5 mg, 71%. Mp: 88−90 °C. dr (anti/syn):
37:63. ee (anti/syn): 16%/rac. 1H NMR (CDCl3, 400 MHz): δ =
8.18−8.28 (m, 2H), 7.49−7.61 (m, 2H), 5.44 (d, J = 2.9 Hz, 1H),
2.35−2.54 (m, 2H), 2.10−2.23 (m, 1H), 1.92−2.09 (m, 1H), 1.68−
1.80 (m, 2H), 1.50−1.63 (m, 1H). HPLC: (Chiralpak AD column,
hexanes/2-propanol =95/5, flow rate =1.0 mL·min−1, λ = 254 nm) tR
(anti isomer) = 42.35 (minor), 45.73 (major), tR (syn isomer) = 33.70
(minor), 23.90 min (major). HRMS (ESI): calcd for C12H13NO4Ag
341.989, found 341.98983.
1
Sulfate (7). H NMR (D2O, 400 MHz): δ = 8.63 (s, 1H), 7.38−7.43
(m, 1H), 7.36 (t, J = 1.7 Hz, 1H), 4.92−4.97 (m, 1H), 4.12 (t, J = 7.1
Hz, 2H), 3.94 (t, J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.05−3.22 (m, 2H),
2.44 (dd, J = 14.5, 7.9 Hz, 1H), 2.00 (ddd, J = 14.3, 9.1, 5.3 Hz, 1H),
1.72−1.83 (m, 2H), 1.19−1.31 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13C
NMR (D2O, 100 MHz): δ = 179.3, 136.40, 124.2, 123.0, 81.6, 59.4,
53.1, 50.0, 37.9, 36.4, 32.0, 19.5, 13.4. HRMS (+ESI): calcd for
C8H15N2 139.12297, found 139.12323; (−ESI) calcd for C5H9N2O5S
209.02377, found 209.02279.
(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanone (10a):
General Representative Procedure for the Asymmetric Aldol
Reaction. Cyclohexanone (103.5 μL, 10 equiv) was introduced in a
vial containing the catalyst (10.9 mg, 30% mol) in [Bmim]NTf2 (0.1
mL), and the mixture was stirred 30 min a 4 °C before p-
nitrobenzaldehyde (15.12 mg, 1 equiv) was added to the reaction
medium. The mixture was vigorously stirred at 4 °C until completion
(monitored by TLC). The mixture was then directly purified by flash
chromatography (hexanes/ethyl acetate: 9/1 then 65/35) to give the
product as a white solid (20.69 mg, 83%, mp: 98−99 °C).
(S)-2-((R)-(2-Chlorophenyl)(hydroxy)methyl)cyclohexanone
(10g). Colorless oil. Yield: 22.1 mg, 93%. dr (anti/syn): >99:1. ee
1
(anti/syn): 89%/−. H NMR (CDCl3, 400 MHz): δ = 7.54−7.60 (m,
1H), 7.30−7.39 (m, 2H), 7.19−7.27 (m, 1H), 5.37 (d, J = 8.2 Hz,
1H), 2.65−2.75 (m, 1H), 2.45−2.54 (m, 1H), 2.31−2.42 (m, 1H),
2.06−2.16 (m, 1H), 1.80−1.88 (m, 1H), 1.51−1.78 (m, 4H). HPLC:
(Chiralpak AD column, hexanes/2-propanol = 90/10, flow rate = 1.0
mL·min−1, λ = 215 nm) tR (anti isomer) = 11.92 (minor), 10.49 min
(major). HRMS (ESI): calcd for C13H15ClO2Na 261.06528, found
261.0649.
1
Diastereomeric ratio (89:11) was determined by H NMR spectros-
copy and enantiomeric excess (syn/anti: 4%/86%) was determined by
chiral HPLC (Chiralpak AD column, hexanes/2-propanol 90/10, flow
rate: 1.0 mL·min−1, λ = 254 nm). tR (syn isomer) = 18.07 (minor),
22.24 (major); tR (anti isomer) = 24.48 (minor), 32.45 min (major).
1H NMR (CDCl3, 400 MHz): δ = 8.19−8.27 (m, 2H), 7.47−7.58 (m,
2H), 4.92 (d, J = 8.4 Hz, 1H), 2.57−2.66 (m, 1H), 2.48−2.57 (m,
1H), 2.33−2.44 (m, 1H), 2.09−2.18 (m, 1H), 1.81−1.92 (m, 1H),
1.66−1.79 (m, 1H), 1.51−1.66 (m, 2H), 1.36−1.47 (m, 1H). HPLC:
(Chiralpak AD column, hexanes/2-propanol = 90/10, flow rate = 1.0
mL·min−1, λ = 254 nm) tR (anti isomer) = 22.01 (minor), 29.76
(major), tR (syn isomer) = 16.08 (minor), 19.75 min (major). HRMS
(ESI): calcd for C13H15NO4Na 272.08933, found 272.08959.
(S)-2-((R)-Hydroxy(thiophene-2-yl)methyl)cyclohexanone (10h).
Pale yellow oil. Yield: 2.4 mg, 11%. dr (anti/syn): 95:5. ee (anti/
1
syn): 85%/−. H NMR (CDCl3, 400 MHz): δ = 7.27−7.33 (m, 1H),
6.96−7.01 (m, 2H), 5.10 (d, J = 8.4 Hz, 1H), 2.64−2.73 (m, 1H),
2.47−2.55 (m, 1H), 2.33−2.44 (m, 1H), 2.09−2.18 (m, 1H), 1.56−
1.89 (m, 4H), 1.37 (qd, J = 12.8, 3.7 Hz, 1H). HPLC: (Chiralpak AD
column, hexanes/2-propanol = 90/10, flow rate = 1.0 mL·min−1, λ =
215 nm) tR (anti isomer) = 15.18 (minor), 13.75 min (major). HRMS
(ESI): calcd for C11H14O2SNa 233.06067, found 233.06033.
(S)-2-((R)-Hydroxy(perfluorophenyl)methyl)cyclohexanone (10i).
White solid. Yield: 27 mg, 92%. Mp: 85−87 °C. dr (anti/syn): >99:1.
(S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexanone (10b).
White solid. Yield: 20.4 mg, 82%. Mp: 116−118 °C. dr (anti/syn):
1
ee (anti/syn): 88%/−. H NMR (CDCl3, 400 MHz): δ = 5.34 (d, J =
1
97:3, ee (anti/syn): 69%/−. H NMR (CDCl3, 400 MHz): δ = 7.87
9.7 Hz, 1H), 2.96−3.08 (m, 1H), 2.50−2.59 (m, 1H), 2.42 (td, J =
13.0, 6.2 Hz, 1H), 2.09−2.25 (m, 1H), 1.82−1.96 (m, 1H), 1.55−1.77
(m, 3H), 1.35 (qd, J = 12.6, 3.7 Hz, 1H). HPLC: (Chiralpak AD
column, hexanes/2-propanol = 90/10, flow rate = 0.5 mL·min−1, λ =
215 nm) tR (anti isomer) = 18.74 (minor), 14.86 min (major). HRMS
(ESI): calcd for C13H11F5O2Na 317.05714, found 317.0561.
(dd, J = 8.1, 1.3 Hz, 1H), 7.79 (dd, J = 8.0, 1.4 Hz, 1H), 7.62−7.71 (m,
1H), 7.40−7.51 (m, 1H), 5.47 (d, J = 7.0 Hz, 1H), 2.72−2.84 (m,
1H), 2.43−2.53 (m, 1H), 2.30−2.42 (m, 1H), 2.07−2.20 (m, 1H),
1.83−1.94 (m, 1H), 1.48−1.83 (m, 4H). HPLC: (Chiralpak AD
column, hexanes/2-propanol = 85/15, flow rate = 0.5 mL·min−1, λ =
254 nm) tR (anti isomer) = 26.38 (minor), 24.52 min (major). HRMS
(ESI): calcd for C13H15NO4Na 272.08933, found 272.08995.
(S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexanone (10c).
Pale yellow solid. Yield: 18.9 mg, 77%. Mp: 69−71 °C. dr (anti/
syn): 85:15. ee (anti/syn): 67%/15%. 1H NMR (CDCl3, 400 MHz): δ
= 8.10−8.28 (m, 2H), 7.64−7.74 (m, 1H), 7.50−7.61 (m, 1H), 4.92
(d, J = 8.4 Hz, 1H), 2.60−2.71 (m, 1H), 2.48−2.56 (m, 1H), 2.33−
2.47 (m, 1H), 2.08−2.19 (m, 1H), 1.81−1.93 (m, 1H), 1.52−1.79 (m,
3H), 1.34−1.48 (m, 1H). HPLC: (Chiralpak AD column, hexanes/2-
propanol = 92/8, flow rate = 1.0 mL·min−1, λ = 254 nm) tR (anti
isomer) = 27.91 (minor), 21.90 (major), tR (syn isomer) = 17.87
(minor), 19.70 min (major). HRMS (ESI): calcd for C13H15NO4Na
272.08933, found 272.09007.
(S)-2-((R)-Hydroxy(naphthalen-3-yl)methyl)cyclohexanone (10j).
Colorless oil. Yield: 9.6 mg, 38%. dr (anti/syn): 84:16. ee (anti/syn):
77%/17%. 1H NMR (CDCl3, 400 MHz): δ = 7.82−7.90 (m, 3H), 7.78
(s, 1H), 7.46−7.54 (m, 3H), 4.99 (d, J = 8.8 Hz, 1H), 2.75 (ddd, J =
13.1, 7.9, 5.1 Hz, 1H), 2.50−2.57 (m, 1H), 2.35−2.47 (m, 1H), 2.06−
2.16 (m, 1H), 1.49−1.84 (m, 4H), 1.32−1.43 (m, 1H). HPLC:
(Chiralpak OD column, hexanes/2-propanol = 85/15, flow rate = 1.0
mL·min−1, λ = 210 nm) tR (anti isomer) = 15.18 (minor), 12.10
(major), tR (syn isomer) = 6.67 (minor), 10.62 min (major). HRMS
(ESI): calcd for C17H18O2Na 277.1199, found 277.11917.
(S)-2-((R)-(4-Bromophenyl)(hydroxymethyl)cyclohexanone (10k).
Colorless oil. Yield: 13.9 mg, 49%. dr (anti/syn): 98:2. ee (anti/syn):
83%/−. 1H NMR (CDCl3, 400 MHz): δ = 7.46−7.52 (m, 2H), 7.19−
7.25 (m, 2H), 4.77 (d, J = 8.8 Hz, 1H), 2.54−2.63 (m, 1H), 2.47−2.54
(m, 1H), 2.32−2.43 (m, 1H), 2.07−2.16 (m, 1H), 1.78−1.87 (m, 1H),
1.50−1.75 (m, 3H), 1.27−1.38 (m, 1H). HPLC: (Chiralpak AD
column, hexanes/2-propanol = 90/10, flow rate = 0.8 mL·min−1, λ =
215 nm) tR (anti isomer) = 18.64 (minor), 22.70 min (major). HRMS
(ESI): calcd for C13H15BrO2Na 305.01476, found 305.01351.
(S)-2-((R)-(3-Bromophenyl)(hydroxymethyl)cyclohexanone (10l).
Colorless oil. Yield: 19.8 mg, 70%. dr (anti/syn): 78:22. ee (anti/syn):
75%/13%. 1H NMR (CDCl3, 400 MHz): δ = 7.51 (d, J = 1.8 Hz, 1H),
7.44 (dt, J = 7.1, 1.9 Hz, 1H), 7.21−7.26 (m, 2H), 4.76 (d, J = 8.8 Hz,
1H), 2.55−2.64 (m, 1H), 2.47−2.54 (m, 1H), 2.32−2.44 (m, 1H),
2.08−2.16 (m, 1H), 1.79−1.88 (m, 1H), 1.51−1.77 (m, 4H), 1.29−
1.39 (m, 1H). HPLC: (Chiralpak AD column, hexanes/2-propanol =
98/2, flow rate = 0.5 mL·min−1, λ = 215 nm) tR (anti isomer) = 74.51
(minor), 69.73 (major), tR (syn isomer) = 47.75 (minor), 39.50 min
(S)-Tetrahydro-3-((R)-hydroxy(4-nitrophenyl)methyl)pyran-4-one
(10d). Pale yellow oil.Yield: 24.9 mg, 99%. dr (anti/syn): 83:17. ee
1
(anti/syn): 67%/15%. H NMR (CDCl3, 400 MHz): δ = 8.19−8.29
(m, 2H), 7.48−7.59 (m, 2H), 5.01 (d, J = 8.1 Hz, 1H), 4.17−4.35 (m,
1H), 3.68−3.83 (m, 2H), 3.48 (dd, J = 11.3, 9.9 Hz, 1H), 2.87−3.00
(m, 1H), 2.65−2.80 (m, 1H), 2.44−2.61 (m, 1H). HPLC: (Chiralpak
AD column, hexanes/2-propanol = 90/10, flow rate = 1.0 mL·min−1, λ
= 254 nm) tR (anti isomer) = 48.72 (minor), 57.36 (major), tR (syn
isomer) = 30.63 (minor), 37.60 min (major). HRMS (ESI): calcd for
C12H13NO5Na 274.06859, found 274.06922.
(R)-2-((S)-Hydroxy(4-nitrophenyl)methyl)cycloheptanone (10e).
Colorless oil. Yield: 8.5 mg, 32%. dr (anti/syn): 66:34. ee (anti/syn):
16%/9%. 1H NMR (CDCl3, 400 MHz): δ = 8.24 (d, J = 8.8 Hz, 2H),
7.55 (d, J = 8.8 Hz, 2H), 5.32 (d, J = 2.0 Hz, 1H), 2.89 (dt, J = 10.5,
2.8 Hz, 1H), 2.41−2.75 (m, 2H), 1.18−2.00 (m, 8H). HPLC:
(Chiralpak AD column, hexanes/2-propanol = 80/20, flow rate = 0.5
F
dx.doi.org/10.1021/jo300737u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(major). HRMS (ESI): calcd for C13H15BrO2Na 305.01476, found
305.01424.
(12) Welton, T. Chem. Rev. 1999, 99, 2071−2084.
(13) Parvulescu, V. I.; Hardacre, C. Chem. Rev. 2007, 107, 2615−
(S)-2-((R)-(2,4-Bis(trifluoromethyl)phenyl)(hydroxymethyl)-
2665.
cyclohexanone (10m). Colorless oil. Yield: 27.1 mg, 80%. dr (anti/
(14) Sowmiah, S.; Srinivasadesikan, V.; Tseng, M.-C.; Chu, Y.-H.
Molecules 2009, 14, 3780−3813.
1
syn): >99:1. ee (anti/syn): 88%/−. H NMR (CDCl3, 400 MHz): δ =
7.85−7.95 (m, 3H), 5.32−5.39 (m, 1H), 2.70−2.81 (m, 1H), 2.50−
2.59 (m, 1H), 2.34−2.46 (m, 1H), 2.08−2.19 (m, 1H), 1.82 (dd, J =
13.2, 1.3 Hz, 1H), 1.70 (qt, J = 13.0, 3.9 Hz, 1H), 1.50−1.63 (m, 1H),
1.36−1.48 (m, 2H). 13C NMR (CD3OD, 100 MHz): δ =212.6, 146.6,
130.7, 130.3−130 (d, J = 24.7 Hz), 129.4 (d, J = 2.3 Hz), 128.9−128.6
(d, J = 23.2 Hz), 125.3−125.2 (d, J = 7.7 Hz), 1226−122.5 (d, J = 6.1
Hz), 122.3, 67.4, 57.9, 42.6, 31.5, 28.7, 24.8. HPLC: (Chiralpak AD
column, hexanes/2-propanol = 90/10, flow rate = 1.0 mL·min−1, λ =
215 nm) tR (anti isomer) = 6.92 (minor), 8.08 min (major). HRMS
(ESI): calcd for C15H14F6O2Na 363.07902, found 363.07848.
́
(15) Pegot, B.; Vo-Thanh, G.; Gori, D.; Loupy, A. Tetrahedron Lett.
2004, 45, 6425−6428.
(16) Gausepohl, R.; Buskens, P.; Kleinen, J.; Bruckmann, A.;
Lehmann, C. W.; Klankermayer, J.; Leitner, W. Angew. Chem., Int.
Ed. 2006, 45, 3689−3692.
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(18) Guo, H. M.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.
Chem. Commun. 2005, 11, 1450−1452.
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3677.
(3S,4R)-4-Hydroxy-3-methyl-4-(4-nitrophenyl)butan-2-one (10n).
Colorless oil. Yield: 12.9 mg, 58%. dr (anti/syn): 62:38. ee (anti/syn):
76%/42%. 1H NMR (CDCl3, 400 MHz): δ = 8.22−8.25 (m, 2H), 7.53
−7.57 (m, 2H), 4.89 (d, J = 7.8 Hz, 1H), 2.93 (qt, 1H), 2.83−2.85 (m,
1H), 2.49−2.51 (m, 1H), 2.23 (s, 3H), 1.05 (t, J = 7.4 Hz, 3H),
HPLC: (Chiralpak AD column, hexanes/2-propanol = 70/30, flow
rate = 0.5 mL·min−1, λ = 215 nm) tR (anti isomer) = 22.01 (minor),
18.19 (major), tR (syn isomer) = 16.78 (minor), 20.83 min (major).
HRMS (ESI): calcd for C11H13NO4Na 246.07368, found 246.07356.
(22) Swatloski, R. P.; Holbrey, J. D.; Rogers, R. D. Green Chem. 2003,
5, 361−363.
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ASSOCIATED CONTENT
(26) Gauchot, V.; Kroutil, W.; Schmitzer, A. R. Chem.Eur. J. 2010,
■
16, 6748−6751.
S
* Supporting Information
1H and 13C NMR spectra, HPLC traces, and crystallographic
data for compound 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ar.schmitzer@umontreal.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Natural Sciences and
Engineering Research Council of Canada, the Fonds Queb
de la Recherche sur la Nature et les Technologies, the Centre of
■
́
ec
́
ois
Green Chemistry and Catalysis, the Canada Foundation for
Innovation, and the Universite
́ ́
de Montreal. We thank Augusto
Cesar Hernandez Perez for the 2-naphthaldehyde and our
́
colleagues for careful discussions of this manuscript.
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dx.doi.org/10.1021/jo300737u | J. Org. Chem. XXXX, XXX, XXX−XXX