Organocatalytic direct asymmetric crossed-aldol reactions of acetaldehyde in aqueous media

Article abstract of DOI:10.1021/jo302442g

A new type of diarylprolinol-based catalyst, which contains a dioctylamino group in the presence of a newly developed ionic liquid supported (ILS) benzoic acid as cocatalyst, is shown to be an effective catalytic system for the asymmetric direct crossed-aldol reaction of acetaldehyde in aqueous media using brine. For the reactions studied, the catalyst loading could be reduced to 5 mol %; high yields (up to 97%) and high enantioselectivities (up to 92% ee) were also achieved for a wide variety of aromatic aldehyde.

Full text of DOI:10.1021/jo302442g

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Note
Organocatalytic Direct Asymmetric Crossed-
Aldol Reactions of Acetaldehyde in Aqueous Media
Yupu Qiao, Qiankun Chen, Sirong Lin, Bukuo Ni, and Allan Dave Headley
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302442g • Publication Date (Web): 12 Feb 2013
Downloaded from http://pubs.acs.org on February 17, 2013
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Organocatalytic Direct Asymmetric Crossed-Aldol Reactions of
Acetaldehyde in Aqueous Media
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Yupu Qiao, Qiankun Chen, Sirong Lin, Bukuo Ni*and Allan D. Headley*
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Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA
E-mail: bukuo.ni@tamuc.edu or allan.headley@tamuc.edu
ABSTRACT: A new type of diarylprolinol-based catalyst, which contains a
dioctylamino group, in the presence of a newly developed ionic liquid supported (ILS)
benzoic acid as co-catalyst, is shown to be an effective catalytic system for the
asymmetric direct crossed-aldol reaction of acetaldehyde in aqueous media using brine.
For the reactions studied, the catalyst loading could be reduced to 5 mol%, high yields
(up to 97%) and high enantioselectivities (up to 92% ee) were also achieved for a wide
variety of aromatic aldehyde.
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Owing to the unique properties of water, it is an ideal medium in which to perform
reactions, especially organic reactions. Compared to organic solvents, water is cheap,
safe, and environmentally benign; these combined properties make it a unique green
solvent. In addition, water possesses other extraordinary properties, such as a high
dielectric constant, hydrogen bonding capabilities, and high polarity;1 these properties
make water an ideal solvent for most reactions. There is still however, a big challenge in
carrying out reactions in water because it has the potential to inhibit catalytic activity and
stereocontrol since it has the ability to disrupt hydrogen bonds and other polar
interactions that are important for catalysis of some reactions.2 In the 1930s the Diels-
Alder reaction was reported in aqueous media,3 but the full potential of water as a solvent
for such reactions was not fully realized until in the 1980s, when it was discovered by
Breslow4 that the Diels-Alder reaction could be accelerated in aqueous media, compared
to organic solvents. Since then, a revival of this chemistry was initiated at a breathtaking
pace.
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Recently, different types of organocatalysts have been developed for organic
transformations.5 A major challenge is the development of water-compatible catalysts that
are also effective in aqueous media. Over the years, many types of catalysts were
designed and synthesized and applied in synthesis carried out in aqueous media;6 and our
research group has focused on the development of water-compatible organocatalysts for
asymmetric reactions. The catalysts developed in our research group are unique in that
they contain ionic liquid moieties, which make them extremely effective and versatile. 7
The direct aldol reaction is considered to be one of the key transformations for carbon-
carbon bond formation both in nature and in organic synthesis.8 Within this category of
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reactions, the organocatalyzed direct crossed-aldol reactions are of special importance
since they provide an efficient access to versatile synthetic building blocks for the
synthesis of natural and unnatural compounds of biological interest.8 During the past few
years, various enamine-type catalysts have been developed, which have been successfully
used for a wide range of asymmetric crossed aldol reactions.9 However, limited success
has been achieved so far for the asymmetric crossed-aldol reaction of acetaldehyde. Even
though acetaldehyde is the simplest enolizable carbonyl compounds, the direct crossed-
aldol reaction involving acetaldehyde has been known to be difficult due to the fact that
various undesired side products of poly-aldolization, dehydration, Tishchenko-type
processes, oligomerization are formed.10 Recently, Hayashi et al.11 carried out a highly
enantioselective direct crossed-aldol reaction of acetaldehyde in DMF catalyzed by a
diarylprolinol-based catalyst. Later, Luo group12 reported the primary amine catalyzed
direct crossed-aldol reaction of acetaldehyde in neat condition, but 18 equiv of
acetaldehyde were used to achieve high yield and enantioselectivities. While all of these
reactions were carried out in organic solvents, there is current interest in carrying out
such reactions in water. It is known that Class I aldolase enzymes and aldolase ctalytic
antibodies that catalyze reactions through an enamine reaction mechanism are
accomplished in water.13 Hence, a mimic of such reactions in aqueous environment is
desirable.
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Despite the difficulties encountered in the use of acetaldehyde as a reactant, we report
in the research our success for the highly water-compatible organocatalytic direct
crossed-aldol reactions of acetaldehyde in aqueous media without any organic co-solvent
afforded the desired products in moderate to high yields and high enantioselectivities.
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The direct crossed-aldol reaction of acetaldehyde and p-nitrobenzyaldehyde was selected
as the model reaction. Diarylprolinol-based catalyst 3 was first investigated, as shown in
Table 1. For the majority of reactions studied, Brønsted acids have been used extensively
as additives for the amine-catalyzed organic reactions of carbonyl groups due to their
ability to activate the carbonyl group and the amine catalyst through the formation of
iminium and enamine intermediates; as a result, improved stereoselectivity of the
products is observed. Another major function of the acid in this catalytic system is to
protonate the amine functionality of the organocatalyst. These organocatalysts that
contain the amine functionality exhibit unique properties upon protonation since they
result in ammonium salts.
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The first Brønsted acid selected was benzoic acid and various acid concentrations
were first evaluated. Initially, the aldol reaction was conducted in brine with 10 mol % of
catalyst 3 and 10 mol % of benzoic acid as additive, 89% yield and 79%
enantioselectivity were obtained in 19 h at room temperature (Table 1, entry 1). When the
amount of benzoic acid was increased to 20 mol %, the reaction yields were slightly
increased to 90% with 83% ee (Table 1, entry 2). Unfortunately, the reaction rate was
greatly reduced when the amount of the benzoic acid was increased from 30 mol% to 200
mol% (Table 1, entries 3-7). With the best loading of acid in hand, different solvents
were then examined. The activity of the reaction was found to be highly solvent-
dependent, when water was used as the reaction medium, 50% yield and 85% ee were
observed (Table 1, entry 8). Organic solvents such as DMF, NMP were ineffective, only
trace products were obtained (Table 1, entry 9, 10). The mixtures of the solvents were
also tested to further increase the activity of the catalytic system, but no solvent was more
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efficient than brine, only moderate yields were obtained, while the enantioselectivities
remained the same (Table 1, entry 11, 12). Next, different types of organocatalysts
Table 1 Optimization of the reaction conditions.a
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entry
Catalyst
Solvent
Brine
Brine
Brine
Brine
Brine
Brine
Acid x mol%b Yield (%)c
ee (%)d
79
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3
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20
89
90
83
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57
50
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73
100
150
14
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trace
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1
Brine
H2O
200
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trace
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DMF
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16e
17f
18f
19f
NMP
trace
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H2O:iPrOH=3:1
H2O:iPrOH=4:1
Brine
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89
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75
37
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Brine
13
Brine
89
Brine
90
Brine
86
-
43
Brine
10
a
The reactions were carried out with 0.4 mmol of aromatic aldehyde, 4 mmol of
acetaldehyde, indicated amount of acid and 0.04 mmol of catalyst in 400 μL of solvent at
o
25 C. entries 1-16, PhCOOH; entries 17-19, ILS-benzoic acid 5. Isolated yield.
b
c
d
f
e
Determined by chiral HPLC. 5 mol% catalyst was used, the reaction time was 28h.
ILS-benzoic acid 5 was used, 5 mol% catalyst, the reaction time was 28h.
were examined using the best reaction conditions. When diarylprolinol catalyst 1 was
used as the catalyst, only 58% yield and 74% ee were obtained (Table 1, entry 13). When
the water-compatible catalyst 2 was used for the screening, it gave the final product in
even lower yield, 13%, and moderate enantioselectivity 60% ee (Table 1, entry 14).
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Catalyst 4, which contains long alkyl chains, was used for this reaction, the desired
product was produced in 89% yield and a slightly higher enantioselectivity 85% ee
observed (Table 1, entry 15). Moreover, if the catalyst loading was decreased to 5 mol%,
in 28h, the yield of the desired product was increased to 90% while the enantioselectivity
was maintained (Table 1, entry 16). These results may be due to the fact that the catalytic
system forms a hydrophobic active site that diminishes contact between bulk water and
the reaction transition states.14 Surprisingly, when the co-catalyst was changed to the ionic
liquid supported (ILS) benzoic acid 5, comparable yield and a slightly higher
enantioselectivity (89% ee) were obtained (Table 1, entry 17). It is interesting to note that
without brine, the yield was dramatically reduced to 43%, indicating the great effect that
brine has on the reaction in the presence of this newly developed catalytic system (Table
1, entry 18). When diphenylprolinol catalyst 1 in combination with the ionic liquid
supported (ILS) benzoic acid 5 was used, only 10% yield was obtained with 75% ee
(Table 1, entry 19).
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Table 2 The substrate scope of organocatalytic direct crossed-aldol reactions of
acetaldehyde.a
Entry
R
Time (h)
Yield (%)b
6a/86
ee (%)c
89
1
2
3
4-NO2
2-NO2
3-NO2
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45
6b/97
90
6c/77
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4-CF3
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96
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120
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6d/94
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2-CF3
4-CN
2-Br
4-Br
3-Br
2-Cl
H
6e/74
6f/84
6g/81
6h/55
6i/62
6j/45
6k/35
6l/30
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Naph
a
The reactions were carried out with 0.4 mmol of aromatic aldehyde, 4 mmol of
acetaldehyde, 0.02 mmol of catalyst 4 and 0.04 mmol of 5 (ILS-PhCOOH) in 400 μL of
Brine at 25 oC. b Isolated yield. c Determined by chiral HPLC.
To further demonstrate the potentials of the catalytic system, the scope of the reaction
with different substituted aromatic aldehydes were examined using catalyst 4 in brine. As
shown in Table 2, the reaction proceeded very well with aromatic aldehydes with
electron-withdrawing substituents, and the aldol products could be generated in moderate
to excellent yields and high enantioselectivities (Table 2, Entry 1-10), demonstrating the
high efficiency of the catalytic system. The reaction of non-activated aldehydes, such as
benzaldehyde and 2-naphthaldehyde, also proceeded smoothly with moderate yield and
high ee (Table 2, Entry 11, 12). The absolute stereochemistry of the aldol products were
determined by comparing its optical rotation with literature values.11-12 The high
enantioselectivities of the products resulting from reactions with catalyst 4 can be
explained by related transition state models discussed previously by using (S)-
diphenylprolinol as catalyst.11
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In summary, we have developed a highly efficient organocatalytic system for the
direct asymmetric crossed-aldol reaction of acetaldehyde that can be performed in brine
without addition of any organic solvents. Furthermore, the catalyst loading could be
lowered to 5 mol%, even though the diarylprolinol-based catalystic system demonstrated
high reactivity and enantioselectivity for a broad range of aromatic aldehydes.
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Experimental Section
General information: Commercially available chemicals were used as received. Catalyst
2, 3, 4 were prepared according to previously reported procedures.7b 1H and 13C NMR
spectra were recorded on the Varian-400. Chemical shifts in NMR were reported in ppm
(δ), relative to the internal standard of tetramethylsilane (TMS). The signals observed
were described as s (singlet), d (doublet), t (triplet), dd(double doublet), m (multiplets), br
(board). The number of protons (n) for a given resonance is indicated as nH. Coupling
constants were reported as J in hertz. The high resolution mass spectra were analyzed by
using ESI-TOF high-acc from the Scripps Research Institute. All the compounds
synthesized (shown in Table 1 and 2) in the manuscript are known compounds.11-12 Their
relative and absolute configurations of the products were determined by comparison with
known optical rotation values. Optical rotations were measured using a 1 mL cell with a 1
dm path length and reported as follows: [α] 25 (c in g per 100 mL of solvent). HPLC
D
analysis was performed using ChiralPak columns.
(S)-bis(4-(dimethylamino)phenyl)(pyrrolidin-2-yl)methanol (2): purified by flash
chromatography using Ethyl acetate/triethylamine = 200/1-100/1 to give compound 2 as
white solid( 0.653g, yield 62% (for 2 steps)). [α]25D = -71.6 (c = 0.52, MeOH), 1H NMR
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(400 MHz, CDCl3) δ = 7.41 (d, J =8Hz, 2H), 7.33 (d, J =12Hz, 2H), 6.68 (d, J =8Hz,
2H), 6.65 (d, J =8Hz, 2H), 4.15 (d, J =8Hz, 1H), 3.02 (s, 4H), 2.90 (s, 6H), 2.89 (s, 6H),
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1.72-1.58 (m, 4H); C NMR (100 MHz, CDCl3) δ =149.0, 148.9, 136.9, 134.5, 126.5,
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126.2, 112.4, 112.1, 76.5, 64.7, 46.7, 40.6, 26.2, 25.5. HRMS (ESI-TOF high-acc) m/z
calcd for C21H29N3O (MH+): 340.2383, found: 340.2388.
(S)-bis(4-((dimethylamino)methyl)phenyl)(pyrrolidin-2-yl)methanol (3): purified by
flash chromatography using Ethyl acetate/triethylamine = 200/1-50/1 to give compound 3
1
as an oil( 0.8964g, yield 59% (for 2 steps)), [α]25 = -34.7 (c = 0.5, MeOH). H NMR
D
(400 MHz, CDCl3) δ = 7.51(d, J =8 Hz, 2H), 7.42 (d, J =8.4Hz, 2H), 7.21 (t, J =8Hz,
4H), 4.22 (t, J =7.6Hz, 1H), 3.35 (s, 4H), 3.05-2.92 (m, 2H), 2.20 (s, 6H), 2.19 (s, 6H),
13
1.74-1.52 (m, 5H); C NMR (100 MHz, CDCl3) δ =147.2, 144.5, 137.2, 137.0, 129.1,
128.9, 126.0, 125.6, 77.2, 64.8, 64.3, 64.2, 46.9, 45.7, 45.6, 26.5, 25.7; HRMS (ESI-TOF
high-acc) m/z calcd for C23H33N3O (MH+): 368.2696, found: 368.2692.
(S)-bis(4-((dioctylamino)methyl)phenyl)(pyrrolidin-2-yl)methanol 4: purified by flash
chromatography using Ethyl acetate/triethylamine = 200/1 to give compound 4 as an oil (
1
0.9245g, yield 51% (for 2 steps)), [α] 25 = -43.1 (c 0.5, EtOAc). H NMR (400 MHz,
D
CDCl3) δ = 7.48 (d, J =8Hz, 2H), 7.40 (d, J =8Hz, 2H), 7.21 (t, J= 8.4Hz, 4H), 4.52 (s,
1H), 4.20 (t, J= 7.2Hz, 1H), 3.47 (s, 4H), 3.04-2.92 (m, 2H), 2.37-2.33 (m, 8H), 1.74-
13
1.62 (m, 5H), 1.42 (s, 8H), 1.31-1.23 (m, 40H), 0.88 (t, J= 7.2Hz, 12H); C NMR (100
MHz, CDCl3) δ =146.5, 143.8, 138.3, 138.1, 128.5, 128.3, 125.5, 125.2, 76.9, 64.7, 58.3,
58.1, 53.8, 53.7, 46.7, 31.8, 29.5, 29.5, 29.3, 27.4, 27.0, 26.2, 25.4, 22.6, 14.1; HRMS
(ESI-TOF high-acc) m/z calcd for C51H89N3O (MH+): 760.7078, found: 760.7073.
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Typical procedure for the Aldol reactions: Acetaldehyde (4 mmol) was added to a
mixture of aromatic aldehyde (0.4 mmol), Catalyst 4 (0.02 mmol) and ILS-PhCO2H 5
(0.04 mmol) in brine (0.4 mL) at room temperature. The resulting mixture was stirred for
the time indicated in Table 2 and then quenched with 1M HCl. The organic materials
were extracted three times with dichloromethane. The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated in vacuo. NaBH4 (2 mmol) was added to
the mixture in methanol (3 mL) at 0 oC and the mixture was stirred for additional 30 min
before quenching with water. The products were extracted three times with
dichloromethane, and the combined organic phase was dried over anhydrous Na2SO4 and
concentrated under vacuo. The residue was purified by flash chromatograph on silica gel
to afford the desired products 6a-l.
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(R)-1-(4-nitrophenyl)propane-1,3-diol (6a): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/1-2/1) gave 6a (67.8 mg, 86%, 0.4 mmol scale) as a colorless oil.
[α]25 = 19.1 (c = 0.86, MeOH). Lit. 11, 12) [α]25 = 21.6 (c = 0.87, MeOH), [α]20 = 20.2
D
D
D
(c = 0.5, MeOH). enantiomeric excess 89%, HPLC analysis Chiralpak IC, i-
propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (minor) = 36.63 min, tR (major) = 41.18
1
min; H NMR (400 MHz, CDCl3) δ = 8.21 (d, J= 8.4Hz, 2H), 7.56 (d, J= 8.8Hz, 2H),
5.12-5.09 (m, 1H), 3.92 (t, J= 4.8 Hz, 2H), 3.52 (d, J= 2.8 Hz, 1H), 2.21 (s, 1H), 2.00-
13
1.96 (m, 2H); C NMR (100 MHz, CDCl3) δ = 151.7, 147.2, 126.4, 123.7, 73.3, 61.3,
40.2.
(R)-1-(2-nitrophenyl)propane-1,3-diol (6b): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/1) gave 6b (76.5 mg, 97%, 0.4 mmol scale) as a colorless oil. [α]25
=
D
-57.1 (c = 0.92, MeOH). enantiomeric excess 90%, HPLC analysis Chiralpak IC, i-
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propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (major) = 48.49 min, tR (minor) = 80.28
5
6
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min; H NMR (400 MHz, CDCl3) δ = 7.92-7.88 (m, 2H), 7.68-7.64 (m, 1H), 7.44-7.40
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(m, 1H), 5.49 (d, J = 8.8Hz, 1H), 3.97-3.90 (m, 2H), 2.84 (s, 1H), 2.11-1.90 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ = 147.3, 139.8, 133.6, 128.1, 128.1, 124.3, 69.6, 61.7, 39.5.
(R)-1-(3-nitrophenyl)propane-1,3-diol (6c): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/1-2/1) gave 6c (60.7 mg, 77%, 0.4 mmol scale) as a colorless oil.
[α]25D = 29.2 (c = 0.79, MeOH). enantiomeric excess 86%, HPLC analysis Chiralpak IC,
i-propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (minor) = 62.15 min, tR (major) = 71.94
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min; H NMR (400 MHz, CDCl3) δ = 8.25(s, 1H), 8.14-8.11 (m, 1H), 7.71 (d, J = 8Hz,
1H), 7.53 (t, J = 8Hz, 1H), 5.10 (t, J = 6.4Hz, 1H), 3.92 (t, J = 5.6 Hz, 2H), 3.73 (s, 1H),
13
2.45 (s, 1H), 2.01-1.94 (m, 2H); C NMR (100 MHz, CDCl3) δ = 148.3, 146.5, 131.8,
129.4, 122.4, 120.6, 73.2, 61.3, 40.2.
(R)-1-(4-(trifluoromethyl)phenyl)propane-1,3-diol
(6d):
Silica
gel
column
chromatography (Ethyl acetate/Hexane = 1/1) gave 6d (82.8 mg, 94%, 0.4 mmol scale) as
a colorless oil. [α]25D = 25.0 (c = 0.35, MeOH). enantiomeric excess 86%, HPLC analysis
Chiralpak IC, i-propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (minor) = 10.52 min, tR
(major) = 11.90 min; 1H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8Hz, 2H), 7.47 (d, J =
8Hz, 2H), 5.01 (d, J = 2.8Hz, 1H), 3.88-3.85 (m, 2H), 3.59 (s, 1H), 2.63 (s, 1H), 1.98-
13
1.91 (m, 2H); C NMR (100 MHz, CDCl3) δ = 148.3, 129.5, 125.9, 125.4, 125.3, 73.6,
61.2, 40.3.
(R)-1-(2-(trifluoromethyl)phenyl)propane-1,3-diol
(6e):
Silica
gel
column
chromatography (Ethyl acetate/Hexane = 1/2) gave 6e (65.2 mg, 74%, 0.4 mmol scale) as
a colorless oil. [α]25 = 42.4 (c = 1.4, MeOH). enantiomeric excess 85%, HPLC analysis
D
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Chiralpak OJ-H, i-propanol/hexane = 10/90, 1.0 mL/min, 254nm, tR (minor) = 5.44 min,
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6
1
tR (major) = 5.94 min; H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 8Hz, 1H), 7.63-7.58
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(m, 2H), 7.40-7.36 (m, 1H), 5.36 (d, J = 9.2Hz, 1H), 3.96-3.86 (m, 2H), 3.50 (s, 1H),
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2.76 (s, 1H), 2.00-1.85 (m, 1H); C NMR (100 MHz, CDCl3) δ = 143.4, 132.3, 127.7,
127.4, 125.4, 125.4, 125.3, 70.1, 61.9, 40.6.
(R)-4-(1,3-dihydroxypropyl)benzonitrile (6f): Silica gel column chromatography (Ethyl
acetate/Hexane = 2/1) gave 6f (59.5 mg, 84%, 0.4 mmol scale) as a colorless oil. [α]25
=
D
15.8 (c = 0.22, MeOH). enantiomeric excess 86%, HPLC analysis Chiralpak IC, i-
propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (minor) = 59.42 min, tR (major) = 68.56
min; 1H NMR (400 MHz, CDCl3) δ = 7.65 (d, J = 8Hz, 2H), 7.50 (d, J = 8Hz, 2H), 5.05
(t, J = 6Hz, 2H), 2.17 (s, 2H), 1.97-1.93 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 149.7,
132.3, 126.3, 118.8, 111.1, 73.5, 61.3, 40.2.
(R)-1-(2-bromophenyl)propane-1,3-diol (6g): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/2) gave 6g (74.9 mg, 81%, 0.4 mmol scale) as a colorless oil. [α]25
=
D
44.9 (c = 0.54, MeOH). enantiomeric excess 80%, HPLC analysis Chiralpak IC, i-
propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (minor) = 18.73 min, tR (major) = 21.51
1
min. H NMR (400 MHz, CDCl3) δ = 7.62 (d, J = 9.6Hz, 1H), 7.51 (d, J =8.8Hz, 1H),
7.37-7.26 (m, 1H), 7.15-7.11(m, 1H), 5.30-5.28(m, 1H), 3.95-3.88 (m, 2H), 3.49 (s, 1H),
13
2.70 (s, 1H), 2.08-2.02 (m, 1H), 1.92-1.84 (m, 1H); C NMR (100 MHz, CDCl3) δ =
143.0, 132.5, 128.7, 127.7, 127.3, 121.4, 73.1, 61.5, 38.4.
(R)-1-(4-bromophenyl)propane-1,3-diol (6h): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/1) gave 6h (50.8 mg, 55%, 0.4 mmol scale) as a colorless oil. [α]25
=
D
14.4 (c = 0.20, MeOH). enantiomeric excess 82%, HPLC analysis Chiralpak IC, i-
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propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (minor) = 18.18 min, tR (major) = 20.97
5
6
1
min. H NMR (400 MHz, CDCl3) δ = 7.47 (d, J = 6.8Hz, 2H), 7.25 (d, J =8.4Hz, 2H),
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4.95-4.92 (dd, J = 3.6Hz, 8.4Hz, 1H), 3.87-3.84 (m, 2H), 3.20 (s, 1H), 2.40 (s, 1H), 1.97-
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1.90 (m, 2H); C NMR (100 MHz, CDCl3) δ = 143.3, 131.5, 127.4, 121.2, 73.6, 61.3,
40.4.
(R)-1-(3-bromophenyl)propane-1,3-diol (6i): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/1) gave 6i (57.3 mg, 62%, 0.4 mmol scale) as a colorless oil. [α]25
=
D
22.5 (c = 0.95, MeOH). enantiomeric excess 82%, HPLC analysis Chiralpak OJ-H, i-
propanol/hexane = 10/90, 1.0 mL/min, 254nm, tR (minor) = 8.55 min, tR (major) = 9.23
min; 1H NMR (400 MHz, CDCl3) δ = 7.52 (s, 1H), 7.41-7.38 (m, 2H), 7.27-7.21 (m, 1H),
4.92-4.89 (m, 1H), 3.83 (d, J = 3.2Hz, 2H), 3.56 (s, 1H), 2.76 (s, 1H), 1.99-1.87 (m, 2H);
13C NMR (100 MHz, CDCl3) δ = 146.6, 130.5, 130.0, 128.7, 124.2, 122.6, 73.4, 61.2,
40.2.
(R)-1-(2-chlorophenyl)propane-1,3-diol (6j): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/2) gave 6j (33.6 mg, 45%, 0.4 mmol scale) as a colorless oil. [α]25
=
D
54.3 (c = 1.90, MeOH). enantiomeric excess 92%, HPLC analysis Chiralpak IC, i-
propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (major) = 10.67 min, tR (minor) = 11.91
1
min; H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 8.8Hz, 1H), 7.36-7.22 (m, 3H), 5.40-
5.37 (dd, J =3.2Hz, 8.8Hz, 1H), 3.97-3.88 (m, 2H), 3.52 (s, 1H), 2.74 (s, 1H), 2.12-2.05
(m, 1H), 1.95-1.89 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 141.6, 131.3, 129.3, 128.4,
127.1, 127.0, 71.0, 61.7, 38.4.
(R)-1-phenylpropane-1,3-diol (6k): Silica gel column chromatography (Ethyl
acetate/Hexane = 1/1) gave 6k (21.3 mg, 35%, 0.4 mmol scale) as a colorless oil. [α]25
=
D
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23.5 (c = 0.17, MeOH). enantiomeric excess 83%, HPLC analysis Chiralpak IC, i-
propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (major) = 19.47 min, tR (minor) = 20.79
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8
1
min. H NMR (400 MHz, CDCl3) δ = 7.38-7.26 (m, 5H), 4.99-4.96 (dd, J = 3.6Hz,
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8.4Hz, 1H), 3.87 (t, J = 5.6Hz, 2H), 2.96 (s, 1H), 2.44 (s, 1H), 2.05-1.92 (m, 2H); C
NMR (100 MHz, CDCl3) δ = 144.3, 128.5, 127.6, 125.6, 74.4, 61.5, 40.5.
(R)-1-(naphthalen-2-yl)propane-1,3-diol (6l): Silica gel column chromatography (Ethyl
acetate/Hexane = 1.5/1) gave 6l (24.3 mg, 30%, 0.4 mmol scale) as a White solid. [α]25
D
= 21.5 (c = 0.52, MeOH). enantiomeric excess 82%, HPLC analysis Chiralpak IC, i-
propanol/hexane = 5/95, 1.0 mL/min, 254nm, tR (minor) = 33.52 min, tR (major) = 45.90
1
min; H NMR (400 MHz, CDCl3) δ = 7.84-7.82 (m, 4H), 7.50-7.46 (m, 3H), 5.14-5.11
(m, 1H), 3.89 (t, J = 5.2Hz, 2H), 3.07 (s, 1H), 2.45 (s, 1H), 2.11-1.99 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ = 141.6, 133.2, 132.9, 128.3, 127.9, 127.7, 126.2, 125.9, 124.2,
123.8, 74.4, 61.5, 40.3.
ACKNOWLEDGMENTS
We are grateful to the National Science Foundation for financial support of this research
(CHE-1213287).
Supporting Information
1 13
Full optimization details, H and C NMR spectra, and HPLC data. This material is
available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
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