Enantioselective Reformatsky Reaction of Ketones Catalyzed by Chiral Indolinylmethanol

Article abstract of DOI:10.1002/ejoc.202000768

A reliable and practical Reformatsky reaction of ethyl iodide acetate with ketones for the synthesis of chiral β-hydroxyl carbonyl compounds in good yields and excellent enantioselectivities is presented. A readily available dihydroindole derivative was u

Full text of DOI:10.1002/ejoc.202000768

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Enantioselective Reformatsky Reaction of Ketones Catalyzed by
Chiral Indolinylmethanol
Authors: Renshi Luo, Miao-Miao Chen, Lu Ouyang, Albert S. C. Chan,
and Gui Lu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000768
Link to VoR: https://doi.org/10.1002/ejoc.202000768
01/2020

10.1002/ejoc.202000768
European Journal of Organic Chemistry
FULL PAPER
Enantioselective Reformatsky Reaction of Ketones Catalyzed by
Chiral Indolinylmethanol
Renshi Luo,[a],[b] Miao-Miao Chen,[a] Lu Ouyang,[b] Albert S. C. Chan[a] and Gui Lu*,[a]
[a]
Department Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University
Guangzhou 510006, P. R. China
[b]
School of Pharmaceutical Sciences, Gannan Medical University
Ganzhou, 341000, Jiangxi Province, P. R. China
E-mail: lugui@mail.sysu.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: A reliable and practical Reformatsky reaction of ethyl
iodide acetate with ketones for the synthesis of chiral β-hydroxyl
carbonyl compound in good yields and excellent enantioselectivities
is presented. Readily available dihydroindole derivative was used as
chiral catalyst, ethyl iodide acetate was the nucleophile, and Me2Zn
was the zinc source. The presence of air was found to be essential
for the efficient construction of new carbon-carbon bond through a
radical pathway.
standpoints, it is highly desirable to develop new method for the
asymmetric Reformatsky reaction with good stereocontrol.
Introduction
Metal-mediated reactions are one of the most effective methods
for the construction of carbon-carbon bonds and have been
discovered and applied to synthesize a rich variety of complex
organic molecules.[1] The classic Reformatsky reaction, which is
the zinc-promoted addition of α-haloesters to carbonyl
compounds to provide β-hydroxy esters, has been the most
useful methods to form carbon-carbon bonds and an important
alternative to the base-induced aldol reaction (Scheme 1).[2] The
wide applicability and great versatility of the Reformatsky
reaction have made it highly useful organic reactions in synthetic
chemistry and laid the foundation for the rapid development of
organic chemistry.[3]
Scheme 2. Complexes and ligands employed in asymmetric Reformatsky
reaction.
Scheme 1. The classic Reformatsky reaction.
However, the asymmetric Reformatsky reaction remained a
great challenge in a long time albeit it has striking applications
for the synthesis of many chiral pharmaceuticals. Considerable
research efforts have been made using different chiral auxiliaries
and ligands, but success has been confined to only a few
examples.[4] For instance, a catalytic enantioselective version of
this transformation has been successfully reported by using
chiral MnCl(salen) complexes,[5] BINOL derivatives,[6] N-
methylephedrine,[7] N-pyrrolidinylnorephedrine,[8] and chiral
Schiff base ligands[9] (Scheme 2). Nevertheless, the low yields
and enantioselectivities, limited substrate scope have restricted
their synthetic utilities. From both fundamental and practical
Scheme 3. Efficient asymmetric reaction involving chiral indolinylmethanols or
derivatives.
As our continuous interests in asymmetric catalysis,[10] we have
developed a highly efficient asymmetric Michael reaction using
indolinylmethanol catalyst (Scheme 3a).[11] Meanwhile,
literatures also documented that chiral indolinylmethanol ligand
played an important role in the stereocontrolled diethylzinc
addition to aldehydes and ketones.[12-14] Under this background,
our group realized the asymmetric zinc powder-promoted
1
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10.1002/ejoc.202000768
European Journal of Organic Chemistry
FULL PAPER
Reformatsky reaction of α-bromoester with ketones using chiral
indolinylmethanol ligands (Scheme 3b).[15] Nonetheless, the
yields and enantioselectivities are only modarate.
but only 56% ee was obtained by using (S)-L10 as the ligand
(Table 1, entries 11 and 10). Longer time was needed and a
slight decrease in enantioselectivity (88% ee) was obtained
when the loading of Me2Zn was decreased to 4.0 equiv. (Table 1,
entry 12).
Me2Zn in the presence of oxygen forms substantial reactive alkyl
peroxides (R1ZnOOR2),[16] which can initiate radical reactions.[17-
18]
Hence, we speculated that an effective catalytic
Table 1. Optimization of ligands in asymmetric Reformatsky reaction.
enantioselective Reformatsky reaction might be realized via the
initiation of Me2Zn and the proper stereocontrol of chiral Zn-
indolinylmethanol complex (Scheme 3c).
Results and Discussion
Synthesis of chiral indolinylmethanols and derivatives
(S)-Indoline-2-carboxylic acid M1 was commercially available,
and was chosen as starting material. The reaction of M1 with
thionyl chloride in methanol, followed by protection with Boc2O
provided the corresponding methyl ester (S)-3 in 85% overall
yield. Treatment of (S)-3 with RMgBr and the subsequent N-Boc
deprotection gave the indolinylmethanols (S)-L1~L8 with
34%~50% overall yields (Scheme 5). Reaction of M1 with
iodomethane in the presence of potassium carbonate provided
the corresponding methyl ester (S)-4 in 95% yield. Treatment of
(S)-4 with PhMgBr under reflux conditions afforded (S)-L9 in
91% yield (Scheme 4).
Entry
1
Ligand
(S)-L1
(S)-L2
(S)-L3
(S)-L4
(S)-L5
(S)-L6
(S)-L7
(S)-L8
(S)-L9
(S)-L10
(S)-L11
(S)-L8
Time [h]
Yield [%][a]
ee [%][b]
71
4
4
75
82
80
76
81
81
92
85
84
91
89
75
2
66
3
4
70
4
4
81
5
4
81
6
4
80
7
4
80
8
4
90
9
4
60
10
11
12c
4
56
4
81
12
88
Scheme 4. Preparation of (S)-L1~L9.
[a] Isolated yield. [b] Determined by OD-H column. [c] 4.0 equiv. Me2Zn.
Effect of Ligands
Conditions optimization of the Reformatsky reaction with
ketones
As we were interested to develop new ligands to promote the
Reformatsky reaction, at the beginning of this study
acetophenone (1a) was chosen as the model reaction substrate
to study the effects of ligands (Table 1). Different side chains of
the chiral indole alcohol derivatives led to different results. With
8.0 equiv. Me2Zn and Et2O as the solvent, 71% ee and 75%
yield were obtained by using (S)-L1 as the ligand (Table 1, entry
1). A slight decrease in enantioselectivity (66% ee) and an
increase in yield (82%) occured when using (S)-L2 as the ligand
(Table 1, entry 2). Almost the same enantioselectivity (70% ee)
was obtained by using (S)-L3 (Table 1, entry 3). With the longer
side chain (S)-L4, increasing enantioselectivity (81% ee) was
observed (Table 1, entry 4). However, no increase in
enantioselectivity (81% ee) was obtained by extending the side
chain to (S)-L5 (Table 1, entry 5). Almost the same
enantioselectivities were achieved when the side chains R were
substituted with n-Pr (S)-L6 or n-Bu (S)-L7 (Table 1, entries 6
and 7). 85% yields and 90% ee were achieved when the side
chain was replaced with phenyl group (Table 1, entry 8). Only
60% ee was obtained when (S)-L9 was empolyed (Table 1,
entry 9), which might be caused by the large steric effect of the
substituents. For better contrast, (S)-L10 and (S)-L11 were also
tested in this reaction. 81% ee was obtained by using (S)-L11,
Several common organic solvents were screened to improve this
catalytic system based on the activities (reactivity and
enantioselectivity) of (S)-L8. We used 20 mol% catalyst and 4.0
equiv. Me2Zn throughout this study. Strong solvent effects were
observed as shown in Table 2. Et2O was the best solvent of this
reaction, providing 75% yield and 88% ee (Table 2, entry 1). A
slight decrease in enantioselectivities (86% ee and 85% ee ) by
using toluene and CH2Cl2 as the solvents (Table 2, entries 2 and
3). Lower yield (66%) and enantioselectivity (82%) were
achieved with the solvent of CHCl3 (Table 2, entry 4). Higher
yields but only moderate enantioselectivities were achieved with
hexane and THF as the solvents (Table 2, entries 5 and 6).
Ligand loading, temperature, and additive were also screened to
achieve the best catalytic activity of (S)-L8. As can be seen in
Table 2, a similar yield but only 62% ee were obtained when the
ligand loading was decreased to 10 mol % (Table 2, entry 7). A
slight increase in enantioselectivity (90% ee) was observed by
using 30 mol% ligand loading (Table 2, entry 8). 90% ee was
acquired when the reaction proceeded at the temperature of -10
oC (Table 2, entry 9). However, only 81% ee was obtained when
o
the reaction temperature was cooled to -20 C (Table 2, entry
2
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10.1002/ejoc.202000768
European Journal of Organic Chemistry
FULL PAPER
10). The literature has demonstrated that Ph3PO is a suitable
additive for accelerating the Reformatsky reaction, particularly
under low temperature.[19] Therefore, 20 mol% of Ph3PO was
added into the reaction, which led to 93.5% ee and 83% yield
after 5 h (Table 2, entry 11).
Table 3. Asymmetric Reformatsky reaction of different ketones.
Table 2. The influence of solvents on asymmetric Reformatsky reaction.
Entry
Substrate
Time [h] Product 3 Yield [%][a] ee [%][b]
1
2
3
4
5
6
5
12
12
8
3a
3b
3c
3d
3e
3f
83
76
73
83
85
82
93.5
87
Entry
1
Solvent
Et2O
L [mol%]
20
Time [h]
12
Yield [%][a]
ee [%][b]
88
75
77
85
66
83
81
80
85
75
73
83
91
2
toluene
DCM
20
12
86
3
20
12
85
86
4
CHCl3
hexane
THF
20
12
82
5
20
12
64
6
20
12
53
5
89
7
Et2O
10
12
62
8
Et2O
30
12
90
9
Et2O[c]
Et2O[d]
Et2O[e]
20
12
90
13
88
10
11
20
12
81
7[c]
13
5
3g
3h
66
87
84
91
20
5
93.5
[a] Isolated yield. [b] Determined by OD-H column. [c] The reaction was
performed at -10 oC. [d] The reaction was performed at -20 oC. [e] 20% Ph3PO
was added and the reaction was performed at -10 oC.
8
9
19
19
19
19
3i
3j
63
71
79
82
97
89
91
64
Chiral indolinylmethanol-mediated asymmetric Reformatsky
reaction of various ketones
10
11
12
Having established 20 mol% (S)-L8 and Ph3PO as effective
ligand and additive, respectively, and Et2O as solvent for the
enantioselective Reformatsky reaction of ketones, we next
investigated the scope of the ketone substrates. A variety of
ketones of aromatic, aliphatic and heterocylic were used in the
Reformatsky reaction, which provided the desired β-hydroxyl
ester products in excellent yields and poor to excellent
enantioselectivities (Table 3, entries 1-16).
3k
3l
13
14
15
16
13
19
13
19
3m
3n
3o
3p
85
87
85
45
65
46
20
5
As can be seen in Table 3, the yields obtained in all reactions
ranged from good to excellent. Compared with aliphatic and
heterocylic ketones (Table 3, entries 11-15), good yields (63%-
87%) and enantioselectivities (84%-97% ee) were acquired for
both electron-rich and electron-poor aryl ketones (Table 3,
entries 1-10). In case of 1-indanone and tetralone (Table 3,
entries 9 and 10), longer reaction time was needed to ensure
good yield. For 1-(4-nitrophenyl)ethanone (Table 3, entry 7), 8.0
equiv. Me2Zn was needed, and the lowest enantioselectivity
(84%) was observed for similar aromatic ketones. Excellent
enantioselectivity and moderate yield (91% ee and 79% yield)
were obtained when acetylthiophene was subjected as substrate
(Table 3, entry 11), while good yield but moderate
enantioselectivity (64% ee) were achieved for furylacetone
(Table 3, entry 12). Only moderate enantioselectivity (65% ee)
was acquired when a larger steric hindrance group at α-carbon
position was employed (Table 3, entry 13). Good yields but low
enantioselectivities (46% ee and 20% ee) were observed with
aliphatic ketones as the substrates (Table 3, entries 14 and 15).
Diarylketones were also compatible in this reaction, but low
yields were obtained (Table 3, entries 16-19). The location of
substituents on the diarylketones determined the
17
18
19
19
19
19
3q
3r
41
43
<5
50
75
3s
n.d.[d]
[a] Isolated yield. [b] Determined by Chiral AD-H, AS-H or OD-H column. [c]
8.0 equiv. Me2Zn was used. [d] n.d. = not determined.
enantioselectivities. For example, a nearly racemic product was
acquired by employing the phenyl(p-tolyl)methanone as the
substrate (Table 3, entry 16). When (2-fluorophenyl)(4-
fluorophenyl)methanone was used in the reaction, 50% ee was
3
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10.1002/ejoc.202000768
European Journal of Organic Chemistry
FULL PAPER
generated (Table 3, entry 17). The electronegative atom (F or
Cl) near the carbonyl was helpful for the nucleophilic addition,
the ee increased to 75% when steric Cl atom near the carbonyl
(Table 3, entry 18). Nearly no product was obtained when
phenyl(o-tolyl)methanone was used in the reaction (Table 3,
entry 19).
The reaction of acetophenone (1a) was also chosen as the
model to examine the recyclability of (S)-L8. After the reaction
was completed, the reaction mixture was quenched by 6 N HCl
and extracted with Et2O for two times. The recovered aqueous
phase was neutralized by 2 N NaOH and extracted by Et2O
again. The combined solution was concentrated to acquire the
recyclable ligand, which was used again in the reaction. As
shown in Table 4, the catalytic activity of (S)-L8 dropped
obviously after one cycle. Only 72% ee was obtained after the
reaction proceeded in 13 h (Table 4, entry 2), which might due to
the racemization of ligand under the treatment of acid.
Scheme 6. Proposed catalytic cycle for the asymmetric Reformatsky reaction.
Conclusion
New indole alcohols were synthesized in moderate yields and
evaluated as chiral ligands in the asymmetric Reformatsky
reaction of ketones. (S)-Indolin-2-yl-diphenylmethanol (S)-L8
facilitated the reaction of a wide range of ketones, especially for
the aromatic ketones, which provided Reformatsky products with
good yields and high enantioselectivities (up to 97% ee). Further
study on the aldehyde substrates and applications in other
enantioselective syntheses is still in progress.
Table 4. Recycling study of (S)-L8.
Cycle
Time [h]
Yield [%][a]
ee [%][b]
1
2
12
13
83
75
91
72
Experimental Section
All reactions were performed under air in the dried flask. All solvents
were purified by standard drying methods. Unless otherwise stated,
commercial reagents were directly used without further purification.
Products were purified by flash chromatography using silica gel (200-300
mesh). 1H NMR spectra were determined by Bruker 400 (400 MHz)
spectrometer with CDCl3 (δ = 7.26 ppm), or with tetramethylsilane (TMS,
δ = 0.00 ppm) as the internal standard. 13C NMR spectra were
determined by Bruker (100 MHz) spectrometer with CDCl3 as the internal
reference (δ = 77.0 ppm). HPLC analyses were performed with Agilent
1100 instrument using Chiralcel OD-H, Chiralpak AD-H or AS-H columns
(0.46 cm diameter × 25 cm length). Optical rotations and MS spectra
were recorded on a Perkin Elmer polarimeter (Model 341) and an ESI-ion
trap Mass spectrometer (Shimadzu LCMS-IT-TOF) separately.
[a] Isolated yield. [b] Determined by OD-H column.
β-hydroxy esters represent a valuable synthons for the synthesis
of various functional molecules which are important in bioactive
molecules and pharmaceuticals agents, such as anti-depressant
medication (R)-tomoxetine and (R)-duloxetine. Therefore, in
order to demonstrate the synthetic utility of this method, the
synthesis of chiral drugs was probed. Benzaldehyde and
thenaldehyde reacted with ethyl iodide acetate under the
standard condition giving 4a and 5a in excellent yield and good
enantioselectivity (Scheme 5). Even more important, (R)-
tomoxetine and (R)-duloxetine was obtained via ammonolysis,
reduction, and condensation.[20]
General procedure for the enantioselective Reformatsky reaction
In a single-neck 25 mL round-bottom flask equipped with a CaCl2 tube,
14.9 mg (S)-L8 (0.05 mmol, 20 mol%) and 13.9 mg (0.05 mmol, 20
mol%) Ph3PO was added at room temperature. The bottle was taken to -
10 oC and Et2O (5 mL) was added and stirred for about 15 min. 60 μL
(0.5 mmol, 2.0 equiv.) ethyl iodide acetate and 0.42 mL Me2Zn (0.5 mmol,
2 equiv., 1.2 M solution in toluene) was added and immediately a solution
of ketone (0.25 mmol) in Et2O (1 mL) was added at one time. After the
addition of ketone, again 0.42 mL Me2Zn (0.5 mmol, 2 equiv., 1.2 M
solution in toluene) was added immediately. The resulting solution was
stirred for 5 h and quenched with saturated NH4Cl (aq.). The organic
phase was separated, and the aqueous phase extracted with Et2O (5
mL×2). The combined organic phases were dried over MgSO4 and
concentrated under reduced pressure, then purified by flash
chromatography on silica gel (EtOAc/petroleum ether 1:10) to afford the
pure product.
Scheme 5. Enantioselective syntheses of (R)-tomoxetine and (R)-duloxetine.
Based on the catalytic cycle proposed by Cozzi for the imino-
Reformatsky reaction[21] and the possible mechanism for the
Reformatsky reaction with aldehydes and ketones proposed by
Feringa,[6a,6b] we supposed a similar radical mechanism for the
reaction with ketones as shown in Scheme 6.
(+)-Ethyl 3-hydroxy-3-phenylbutanoate (3a)
[a]2D0
= +20.7 (c 0.82, CH2Cl2). Known compound, colorless liquid,
isolated yield 83%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.46-7.43 (m, 2H),
4
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10.1002/ejoc.202000768
European Journal of Organic Chemistry
FULL PAPER
7.35-7.31 (m, 2H), 7.26-7.21 (m, 1H), 4.40 (s, 1H), 4.05 (q, J = 7.1 Hz,
2H), 2.98 (d, J = 15.9 Hz, 1H), 2.79 (d, J = 15.9 Hz, 1H), 1.47 (s, 3H),
1.06 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 171.7, 145.8,
127.2, 125.8, 123.4, 71.7, 59.7, 45.4, 29.7, 13.0. The enantiomeric
excess was determined by HPLC using Daicel Chiralcel OD-H column,
hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection at 208 nm, tminor
= 9.49 min, tmajor = 10.48 min, 93% ee.
(+)-Ethyl 3-hydroxy-(4-nitrophenyl)-butanoate (3g)
[a]2D0
= +14.3 (c 0.41, CH2Cl2). Known compound, colorless liquid,
isolated yield 66%.[12] 1H NMR (400 MHz, CDCl3) δ: 8.25-8.16 (m, 2H),
7.67-7.61 (m, 2H), 4.59 (s, 1H), 4.08 (qd, J = 7.1, 4.1 Hz, 2H), 3.00 (d, J
= 16.2 Hz, 1H), 2.85 (d, J = 16.2 Hz, 1H), 1.56 (s, 3H), 1.17 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ: 172.3, 154.3, 125.7, 123.6, 72.7,
61.2, 45.9, 30.5, 14.0. The enantiomeric excess was determined by
HPLC using Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow
rate 1.0 mL/min, UV detection at 208 nm, tminor = 8.09 min, tmajor = 9.10
min, 84% ee.
(+)-Ethyl 3-hydroxy-3-p-tolylbutanoate (3b)
[a]2D0
= +1.8 (c 0.5, CH2Cl2). Known compound, colorless liquid, isolated
yield 76%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 8.2 Hz, 2H), 7.13
(d, J = 8.0 Hz, 2H), 4.33 (s, 1H), 4.06 (qd, J = 7.1, 1.2 Hz, 2H), 2.95 (d, J
= 15.9 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 1.52 (s, 3H), 1.14 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ: 172.7, 144.0, 136.4, 128.9, 124.4,
72.6, 60.7, 46.5, 30.7, 20.9, 14.0. The enantiomeric excess was
determined by HPLC using Daicel Chiralpak AS-H column, hexane/i-
PrOH 99:1, flow rate 1.0 mL/min, UV detection at 208 nm, tminor = 9.27
min, tmajor = 10.70 min, 87% ee.
(+)-Ethyl 3-hydroxy-3-(naphthalen-2-yl)butanoate (3h)
[a]2D0
= +17.6 (c 0.46, CH2Cl2). Known compound, colorless liquid,
isolated yield 87%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.93 (s, 1H), 7.84-
7.79 (m, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.48-7.41 (m, 2H), 4.54 (s, 1H),
4.07-3.98 (m, 2H), 3.07 (d, J = 15.9 Hz, 1H), 2.87 (d, J = 15.9 Hz, 1H),
1.62 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ:
172.7, 144.3, 133.2, 132.4, 128.2, 128.0, 127.5, 126.1, 125.8, 123.2,
123.1, 72.9, 60.8, 46.4, 30.6, 14.0. The enantiomeric excess was
determined by HPLC using Daicel Chiralpak AD-H column, hexane/i-
PrOH 95:5, flow rate 1.0 mL/min, UV detection at 208 nm, tminor = 8.94
min, tmajor = 11.42 min, 91% ee.
(+)-Ethyl 3-hydroxy-3-(4-methoxyphenyl)butanoate (3c)
[a]2D0
= +14.8 (c 0.5, CH2Cl2). Known compound, colorless liquid,
isolated yield 73%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.40-7.32 (m, 2H),
6.89-6.82 (m, 2H), 4.33 (s, 1H), 4.06 (qd, J = 7.1, 0.8 Hz, 2H), 3.79 (s,
3H), 2.94 (d, J = 15.8 Hz, 1H), 2.76 (d, J = 15.8 Hz, 1H), 1.52 (s, 3H),
1.15 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 172.8, 158.4,
139.1, 125.7, 113.5, 72.5, 60.7, 55.2, 46.5, 30.7, 14.0. The enantiomeric
excess was determined by HPLC using Daicel Chiralpak AS-H column,
hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection at 208 nm, tminor
= 18.11 min, tmajor = 21.65 min, 91% ee.
(-)-Ethyl 2-(1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (3i)
[a]2D0
= -17.1 (c 0.65, CH2Cl2). Known compound, colorless liquid,
isolated yield 63%.[6] 1H NMR (400 MHz, CDCl3) δ: 7.57-7.53 (m, 1H),
7.22-7.13 (m, 2H), 7.06 (d, J = 7.0 Hz, 1H), 4.21-4.15 (m, 2H), 4.00 (s,
1H), 2.88-2.71 (m, 4H), 2.12-2.06 (m, 1H), 2.01-1.90 (m, 2H), 1.83-1.72
(m, 1H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 172.5,
140.7, 136.5, 128.9, 127.4, 126.4, 126.3, 71.1, 60.8, 46.1, 36.4, 29.5,
20.0, 14.2. The enantiomeric excess was determined by HPLC using
Daicel Chiralpak AD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min,
UV detection at 208 nm, tminor = 9.65 min, tmajor = 11.94 min, 97% ee.
(+)-Ethyl-3-(4-chlorophenyl)-3-hydroxybutanoate (3d)
[a]2D0
= +15.1 (c 0.42, CH2Cl2). Known compound, colorless liquid,
isolated yield 83%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.40-7.35 (m, 2H),
7.31-7.27 (m, 2H), 4.43 (s, 1H), 4.06 (qd, J = 7.1, 0.9 Hz, 2H), 2.93 (d, J
= 16.0 Hz, 1H), 2.77 (d, J = 16.0 Hz, 1H), 1.51 (s, 3H), 1.15 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ: 172.6, 145.5, 132.7, 128.4, 126.0,
72.5, 60.9, 46.2, 30.6, 14.0. The enantiomeric excess was determined by
HPLC using Daicel Chiralpak AS-H column, hexane/i-PrOH 99:1, flow
rate 1.0 mL/min, UV detection at 208 nm, tminor = 9.92 min, tmajor = 11.42
min, 86% ee.
(+)-(S)-Ethyl 2-(1-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate (3j)
[a]2D0
= +0.8 (c 0.6, CH2Cl2). Known compound, colorless liquid, isolated
yield 71%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.35-7.32 (m, 1H), 7.25-7.19
(m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 4.13 (s, 1H), 3.07-3.00 (m, 1H), 2.90-
2.78 (m, 2H), 2.69 (d, J = 15.8 Hz, 1H), 2.30-2.24 (m, 2H), 1.26 (t, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 172.7, 146.0, 142.7, 128.5, 126.8,
125.0, 122.9, 81.1, 60.9, 44.0, 40.3, 29.4, 14.2. The enantiomeric excess
was determined by HPLC using Daicel Chiralcel OD-H column, hexane/i-
PrOH 95:5, flow rate 1.0 mL/min, UV detection at 210 nm, tminor = 9.63
min, tmajor = 12.13 min, 89% ee.
(+)-Ethyl 3-(4-bromophenyl)-3-hydroxybutanoate (3e)
[a]2D0
= +13.1 (c 0.54, CH2Cl2). Known compound, colorless liquid,
isolated yield 85%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.51-7.40 (m, 2H),
7.38-7.28 (m, 2H), 4.43 (s, 1H), 4.13-4.01 (m, 2H), 2.93 (d, J = 16.0 Hz,
1H), 2.77 (d, J = 16.0 Hz, 1H), 1.51 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ: 172.5, 146.0, 131.3, 126.4, 120.8, 72.5, 60.9,
46.2, 30.6, 14.0. The enantiomeric excess was determined by HPLC
using Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0
mL/min, UV detection at 208 nm, tminor = 5.84 min, tmajor = 6.49 min, 89%
ee.
(+)-Ethyl-3-hydroxy-3-(thiophen-2-yl)butanoate (3k)
[a]2D0
= +14.7 (c 0.81, CH2Cl2). Known compound, yellowish liquid,
isolated yield 79%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.18 (dd, J = 5.0, 1.2
Hz, 1H), 6.92 (dd, J = 5.0, 3.6 Hz, 1H), 6.89 (dd, J = 3.6, 1.2 Hz, 1H),
4.74 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.98 (d, J = 15.9 Hz, 1H), 2.81 (d, J
= 15.9 Hz, 1H), 1.63 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ: 172.4, 152.3, 126.7, 124.0, 122.0, 71.9, 60.9, 47.0, 31.4, 14.0.
The enantiomeric excess was determined by HPLC using Daicel
Chiralpak AS-H column, hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV
detection at 208 nm, tminor = 9.00 min, tmajor = 10.29 min, 91% ee.
(+)-Ethyl 3-(4-fluorophenyl)-3-hydroxybutanoate (3f)
[a]2D0
= +13.2 (c 0.62, CH2Cl2). Known compound, colorless liquid,
isolated yield 82%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.45-7.38 (m, 2H),
7.04-6.97 (m, 2H), 4.44 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 2.94 (d, J = 15.9
Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 1.53 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ: 171.6, 159.3 (d, J = 243 Hz), 141.7 (d, J =
3 Hz), 125.3 (d, J = 8 Hz), 113.9 (d, J = 21 Hz), 71.5, 59.8, 45.5, 29.7,
13.0. The enantiomeric excess was determined by HPLC using Daicel
Chiralcel OD-H column, hexane/i-PrOH 99:1, flow rate 0.5 mL/min, UV
detection at 208 nm, tminor = 15.75 min, tmajor = 19.90 min, 88% ee.
(+)-Ethyl 3-(furan-2-yl)-3-hydroxybutanoate (3l)
[a]2D0
= +6.7 (c 0.3, CH2Cl2). Known compound, colorless liquid, isolated
yield 82%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.32 (d, J = 0.8 Hz, 1H), 6.30
(dd, J = 3.1, 1.8 Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H), 4.35 (s, 1H), 4.13 (q, J
= 7.1 Hz, 2H), 2.98 (d, J = 15.8 Hz, 1H), 2.72 (d, J = 15.8 Hz, 1H), 1.58 (s,
5
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10.1002/ejoc.202000768
European Journal of Organic Chemistry
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3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 172.3, 158.5,
141.5, 110.2, 104.6, 69.7, 60.8, 44.5, 27.6, 14.0. The enantiomeric
excess was determined by HPLC using Daicel Chiralcel OD-H column,
hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection at 208 nm, tmajor
= 13.18 min, tminor = 19.78 min, 64% ee.
Daicel Chiralcel OD-H column, hexane/i-PrOH 99:1, flow rate 1.0 mL/min,
UV detection at 208 nm, tminor = 7.77 min, tmajor = 8.84 min, 50% ee.
(+)-Ethyl-3-(2-chlorophenyl)-3-hydroxy-3-phenylpropanoate (3r)
[a]2D0
= +70.7 (c 0.29, CH2Cl2). Known compound, colorless liquid,
isolated yield 43%.[6] 1H NMR (400 MHz, CDCl3) δ: 7.92 (dd, J = 1.3, 7.9
Hz, 1H), 7.20-7.93 (m, 8H), 5.22 (s, 1H), 4.06-4.11 (m, 2H), 3.64 (d, J =
15.9 Hz, 1H), 3.48 (d, J = 15.9 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ: 173.1, 143.9, 142.2, 132.2, 131.5, 129.0, 128.3,
128.0, 127.4, 126.6, 126.5, 76.5, 61.1, 42.7, 14.0. The enantiomeric
excess was determined by HPLC using Daicel Chiralcel OD-H column,
hexane/i-PrOH 95:5, flow rate 0.5 mL/min, UV detection at 210 nm, tmajor
= 37.71 min, tminor = 34.42 min, 75% ee.
(+)-Ethyl-3-hydroxy-3,4-diphenylbutanoate (3m)
[a]2D0
= +16.0 (c 0.31, CH2Cl2). Colorless liquid, isolated yield 85%. 1H
NMR (400 MHz, CDCl3) δ: 7.07-7.44 (m, 12H), 4.51 (s, 1H), 4.03 (q, J =
7.1 Hz, 2H), 3.04-3.17 (m, 3H), 2.81 (d, J = 15.9 Hz, 1H), 1.12 (t, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 172.9, 145.6, 136.5, 130.9, 128.1,
127.8, 127.0, 126.6, 125.3, 75.4, 60.7, 50.0, 43.8, 13.9. The enantiomeric
excess was determined by HPLC using Daicel Chiralcel OD-H column,
hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection at 208 nm, tmajor
= 9.67 min, tminor = 10.88 min, 65% ee.
(-)-(S)-Ethyl 3-hydroxy-3-phenylpropanoate (4a)
[a]2D0
(-)-(E)-Ethyl 3-hydroxy-3-methyl-5-phenylpent-4-enoate (3n)
= -25.0 (c 1.00, CHCl3). Known compound, colorless liquid,
isolated yield 97%.[6] 1H NMR (400 MHz, CDCl3) δ: 7.41-7.28 (m, 5H),
5.19-5.11 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.39 (d, J = 3.4 Hz, 1H),
2.77-2.73 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ:
172.4, 142.6, 128.6, 127.8, 125.7, 70.3, 60.9, 43.4, 14.2. The
enantiomeric excess was determined by HPLC using Daicel Chiralcel
OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at
220 nm, tmajor = 7.09 min, tminor = 9.84 min, 63% ee.
[a]2D0
= -8.2 (c 0.45, CH2Cl2). Known compound, colorless liquid,
isolated yield 87%.[6] 1H NMR (400 MHz, CDCl3) δ: 7.44-7.41 (m, 2H),
7.38-7.33 (m, 2H), 7.31-7.23 (m, 4H), 7.08 (dd, J = 6.5, 3.0 Hz, 2H), 4.51
(s, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.10 (dt, J = 13.3, 12.2 Hz, 3H), 2.81 (d,
J = 15.9 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ:
172.9, 145.6, 136.5, 131.0, 130.9, 128.1, 128.0, 127.8, 127.0, 126.6,
125.3, 75.4, 60.7, 50.0, 43.8, 14.0. The enantiomeric excess was
determined by HPLC using Daicel Chiralcel OD-H column, hexane/i-
PrOH 95:5, flow rate 1.0 mL/min, UV detection at 208 nm, tminor = 9.12
min, tmajor = 11.72 min, 44% ee.
(-)-(S)-Ethyl 3-hydroxy-3-(thiophen-2-yl)propanoate (5a)
[a]2D0
= -17.9 (c 1.00, CHCl3). Known compound, colorless liquid,
isolated yield 91%.[6] 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 4.7, 1.5
Hz, 1H), 6.98 (q, J = 3.5 Hz, 2H), 5.42-5.32 (m, 1H), 4.20 (q, J = 7.1 Hz,
2H), 3.59 (s, 1H), 2.92-2.81 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 171.9, 146.4, 126.7, 124.9, 123.7, 66.6, 61.0, 43.2,
14.2. The enantiomeric excess was determined by HPLC using Daicel
Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV
detection at 220 nm, tmajor = 11.58 min, tminor = 16.86 min, 71% ee.
(-)-Ethyl 3-hydroxy-3-methyl-5-phenylpentanoate (3o)
[a]2D0
= -0.4 (c 0.58, CH2Cl2). Known compound, colorless liquid,
isolated yield 85%.[15] 1H NMR (400 MHz, CDCl3) δ: 7.32-7.27 (m, 2H),
7.22-7.18 (m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 3.68 (s, 1H), 2.77-2.68 (m,
2H), 2.55 (q, J = 15.6 Hz, 2H), 1.89-1.81 (m, 2H), 1.33 (s, 3H), 1.30 (t, J
= 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 173.0, 142.3, 128.4, 128.3,
125.8, 70.8, 60.7, 45.0, 43.9, 30.3, 26.7, 14.2. The enantiomeric excess
was determined by HPLC using Daicel Chiralcel OD-H column, hexane/i-
PrOH 95:5, flow rate 0.5 mL/min, UV detection at 210 nm, tminor = 16.78
min, tmajor = 19.12 min, 20% ee.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (21562004, 21962004), Jiangxi Provincial Department of
Science and Technology (20192BAB203004), and the
Fundamental Research Funds for Gannan Medical University
(QD201810, YJ202027) for financial support.
Ethyl-3-hydroxy-3-phenyl-3-(p-tolyl)propanoate (3p)
Known compound, colorless liquid, isolated yield 45%.[6] 1H NMR (400
MHz, CDCl3) δ: 7.42 (d, J = 7.6 Hz, 2H), 7.27-7.32 (m, 4H), 7.18-7.24 (m,
1H), 7.10 (d, J = 8.1Hz, 2H), 5.04 (s, 1H), 4.06-4.11 (m, 2H), 3.24 (s, 2H),
2.30 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ:
173.1, 146.3, 143.3, 136.9, 129.1, 128.4, 127.2, 125.8, 125.8, 76.5, 61.1,
45.8, 21.2, 14.2. The enantiomeric excess was determined by HPLC
using Daicel Chiralcel OD-H column, hexane/i-PrOH 99:1, flow rate 1.0
mL/min, UV detection at 208 nm, tminor = 8.85 min, tmajor = 9.69 min, 5%
ee.
Keywords: Asymmetric catalysis • Reformatsky reaction •
Ketones • Dihydroindole derivatives • Chiral β-hydroxyl carbonyl
compound
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7
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European Journal of Organic Chemistry
FULL PAPER
Table of Contents
Reformatsky Reaction
Asymmetric Reformatsky reaction of ethyl iodide acetate with ketones was realized via the initiation of Me2Zn and
the proper stereocontrol of chiral Zn-indolinylmethanol complex. Various chiral β-hydroxyl carbonyl compounds were
obtained in good yields and excellent enantioselectivities (up to 97% ee).
8
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