Development of a Modified Bouveault-Blanc Reduction for the Selective Synthesis of α,α-Dideuterio Alcohols

Article abstract of DOI:10.1021/acs.joc.6b02950

A modified Bouveault-Blanc reduction has been developed for the synthesis of α,α-dideuterio alcohols from carboxylic acid esters. Sodium dispersions are used as the electron donor in this electron transfer reaction, and ethanol-d₁ is employed a

Full text of DOI:10.1021/acs.joc.6b02950

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Note
Development of a Modified Bouveault-Blanc Reduction for
the Selective Synthesis of alpha,alpha-Dideuterio Alcohols
Minhui Han, Xiaodong Ma, Shangchu Yao, Yuxuan Ding, Zihan Yan, ADiLa
ADiJiang, Yufei Wu, Hengzhao Li, Yuntong Zhang, Peng Lei, Yun Ling, and Jie An
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02950 • Publication Date (Web): 28 Dec 2016
Downloaded from http://pubs.acs.org on December 30, 2016
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Development of a Modified Bouveault-Blanc Reduction for the Selective
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Synthesis of α,α-Dideuterio Alcohols
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Minhui Han,† Xiaodong Ma,† Shangchu Yao, Yuxuan Ding, Zihan Yan, ADiLa ADiJiang,
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Yufei Wu, Hengzhao Li, Yuntong Zhang, Peng Lei, Yun Ling and Jie An*
College of Science, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing
100193, China.
*jie_an@cau.edu.cn
†M. Han and X. Ma contributed equally.
ABSTRACT: A modified Bouveault-Blanc reduction has been developed for the synthesis
of α,α-dideuterio alcohols from carboxylic acid esters. Sodium dispersions are used as the
electron donor in this electron transfer reaction and ethanol-d1 is employed as deuterium
source. This reaction uses stable, cheap and commercially-available reagents, is
operationally-simple and results in excellent deuterium incorporation across a broad range of
aliphatic esters, which provides an attractive alternative to reactions mediated by expensive
pyrophoric alkali metal deuterides.
Deuterium incorporation has found increasing applications in the pharmacological industry
to improve metabolism and pharmacokinetic properties of drug candidates.1 A significant
number of deuterated drug candidates has been synthesized and forwarded to clinical trials.2
The FDA is currently considering the approval of the first deuterated drug, deutetrabenazine
(A, Figure 1).3 The cleavage of C-D bonds requires higher activation energy than that of C-H
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bonds, which is known as deuterium isotope effect.4 Some deuterated drugs have been
reported to have a longer half-life and improved toxicity profiles.1-3 Thus, broad applications
of deuterated compounds in the development of safer drugs are expected. Similarly, the
metabolism rate of some deuterated pesticides is significantly slower than that of their
unlabeled counterparts, which could lead to the improvement of their toxicity and insecticidal
activity profiles (B, Figure 1).5 In addition, deuterated compounds have been widely used as
metabolic or pharmacokinetic probes in pharmaceutical studies6, as internal standards in
LC/MS analysis,7 and as tools for studying the mechanisms of organic reactions.8
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Figure 1. Deutetrabenazine: compared with tetrabenazine, A exhibits a significantly better
toxicity profile and longer half-life; [D1]-DDT: the enzyme-catalyzed dehydrochlorination
process of B is 6 times slower than that of the unlabeled DDT.
Scheme 1. (A) Reductive deuteration using LiAlD4; (B) This work: selective reductive
deuteration using sodium dispersions and ethanol-d1.
The increasing demand for deuterium labeled compounds has led to an increased interest in
the development of new synthetic methodologies to introduce deuterium. Generally, three
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strategies are employed in the synthesis of deuterated compounds: (a) Synthesis from
deuterated precursors. The feasibility of this strategy, however, highly depends on the
availability of starting materials and long synthetic routes must often be considered. (b) Post-
synthetic hydrogen/deuterium exchange, including metal catalyzed and pH-dependent
protocols.9 However, a vast majority of reactions of this type requires either expensive
catalysts or harsh reaction conditions, and suffers from limited scope, low levels of deuterium
incorporation, and poor selectivity.9a (c) Reductive deuteration, including reductions mediated
by alkali metal deuterides, such as sodium borodeuteride and lithium aluminum deuteride (A,
Scheme 1).10 Reductive methods of this type can selectively introduce deuterium into the
targeted position and generally result in high levels of deuterium incorporation. However, the
widespread application of these methods is restricted by the requirement of expensive
pyrophoric alkali metal deuterides. In 2014, a SmI2-Et3N-D2O mediated reductive deuteration
method for the selective synthesis of α,α-dideuterio alcohols from carboxylic acids was
reported.11 This very selective reaction represents the first application of single electron
transfer (SET) reaction in direct reductive deuteration of carboxylic acids, and shows the
advantages of selective SET reagents in this field. However, despite advances in deuteration
methodologies, the application of deuterium labeled compounds in industry, especially
pesticide industry, is still restricted by high economic cost.3
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Herein, we report a new and highly selective improved Bouveault-Blanc reduction for the
synthesis of α,α-dideuterio alcohols via electron transfer reaction using low price and
commercially-available reagents: sodium metal dispersion and ethanol-d1 (B, Scheme 1).
Bouveault-Blanc reduction is an important ester reduction method mediated by sodium lump
and absolute ethanol (B, Scheme 1).12 Recently, a new sodium reagent (Na-D15) has been
employed for an improved Bouveault-Blanc reduction. The application of this method was,
13
however, restricted by the limited availability of Na-D15 . Although various bench-stable
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sodium dispersions and reagents have become commercially available, their application as
mild, stable and highly chemoselective single electron donors is underdeveloped.
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Table 1.Optimization of the Reductive Deuteration Mediated by Na/RODa
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entry Na reagent
ROH
ROH
(eq.)
yield [D2]
(%)b
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64
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(%)b
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85
1
dispersion in oilc
MeOD-d4
MeOD-d4
MeOD-d4
EtOD-d1
4.5
6.0
8.0
4.5
6.0
8.0
4.5
6.0
8.0
4.5
6.0
8.0
4.5
4.5
4.5
2
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in oilc
dispersion in paraffind
dispersion in toluenee
Na-SG (I)f
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4
5
EtOD-d1
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EtOD-d1
7
i-PrOD-d1
i-PrOD-d1
i-PrOD-d1
t-BuOD-d1
t-BuOD-d1
t-BuOD-d1
EtOD-d1
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EtOD-d1
EtOD-d1
aConditions: 1a (0.50 mmol, 1.0 equiv), Na reagent (4.5 equiv), hexane, 0 ºC, 5 min. bDetermined by 1H NMR. c40 wt%,
particle size 5-10 µm. 30~35 wt%, average particle size 10 µm. 30 wt%, particle size <100 µm. ~35 wt%, sodium silica
gel stage I.
d
e
f
We started our investigations by studying the effect of various sodium reagents and
deuterium donors on the reductive deuteration of 1a (Table 1). Sodium dispersion in oil
(particle size 5-10 µm, purchased from Alfa Aesar) was chosen as the preferred reducing
reagent as it is a bench-stable commercially-available reagent which is easy to handle in an
open atmosphere. The use of solid state sodium dispersions (entry 13) or dispersions with
larger particle size (entry 14) led to lower yields, which may due to smaller contact surface
between sodium and other reactants. Of note, sodium on silica gel (Na-SG), a stabilized
sodium metal that has been demonstrated to be effective for the reduction of esters,14 failed to
achieve high D2 incorporation in this reaction (entry 15). The presence of approximately
quantitative sodium dispersion in oil15 and MeOD-d4 afforded the alcohol product in 91%
yield with 92.0% D2-incorporation (entry 1). Given the low solubility of MeOD-d4 in hexane,
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other proton donors were screened (entries 1-12). The use of EtOD-d1 (4.5 equiv) led to the
best yield of 2a and 94% D2-incorporation (entry 4). When excess of the proton donor was
used, D2-incorporations only marginally increased, while the yields were lower due to
competing oxidation of sodium by alcohol (entries 5-6).
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Following our optimization studies, a range of esters derived from hydrocinnamic acid was
tested under the optimized conditions (Table 1, entry 4). Methyl, ethyl, i-propyl, t-butyl, n-
butyl, allyl, benzyl and 2-methoxyethyl esters were all converted into the corresponding α,α-
dideuterio alcohols in high yields and with excellent D2-incorporation (Table 2). Even
sterically-hindered ester 1d and allyl ester 1f were reduced in high yields (entries 3 and 5).
The substrate scope investigations demonstrate that high levels of D2-incorporation are
general across a range of aliphatic ester and lactone substrates (Table 3). Significantly, no
impact on the D2 incorporation and yield was observed with sterically-hindered substituents
(entries 7 and 9), which compares favorably with reductions mediated by SmI2/H2O.11a
Substrates bearing both internal and terminal olefins (entries 12, 13 and 16) were well-
tolerated. Aromatic reduction was not observed in the reaction when aromatic substrates were
used (entries 1-8). Sensitive functional groups such as F, OMe, and SMe (entries 2-4) were
tolerated well.
a
Table 2.The Reductive Deuteration of Hydrocinnamic Acid Esters by Na/EtOD-d1
entry ester
R
product
yield
(%)b
[D2]
(%)c
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
Et
2a
2a
2a
2a
2a
2a
2a
97
96
81
94
77
88
98
94
93
95
93
94
95
93
i-Pr
t-Bu
n-Bu
Allyl
Bn
1g
1h
(CH2)2OMe
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b
aConditions: 1 (0.50 mmol, 1.0 equiv ), Na (4.5 equiv), EtOD-d1 (4.5 equiv), hexane, 0 ºC, 5 min. Isolated yields.
3
4
5
cDetermined by 1H NMR.
Interestingly, when 6.5 equiv of sodium was used, 4-chlorophenyl group was sequentially
reduced with 95% D1-Ar-incorporation (Table 3, entry 5). Conjugated alkenyl (1u) and
cyclopropane (1v) groups were also fully reduced to give alcohols 2u and 2v with high
deuterium incorporations (entries 14-15). These results suggest the potential application of
this protocol for the selective introduction of deuterium in tandem sequences via electron
transfer. It is noteworthy that a 20-fold scale up of this reaction (0.50 mmol to 10 mmol)
resulted in excellent yield and D2 incorporation (entry 1). High D2 incorporation (90%) was
also obtained in the reaction carried out in open flask conditions, which demonstrated that
this reaction was relatively insensitive to moisture and atmospheric oxygen.
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a
Table 3.Reductive Deuteration of Esters by Na/EtOD-d1
entry
1d
substrate
product
yield
(%)b
93
[D2]
(%)c
96
2
3
91
81
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92
4
5e
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94f
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77
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91
97
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80
95
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94
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95
78
91
14e
91g
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15e
16
66
85
94h
>98%
aConditions: 1 (0.50 mmol, 1.0 equiv), Na (4.5 equiv), EtOD-d1 (4.5 equiv), hexane, 0 ºC, 5 min. Isolated yields.
cDetermined by 1H NMR. dConditions: 1 (10.0 mmol). eConditions: Na dispersion in oil (6.5 equiv), EtOD-d1 (6.5 equiv). f95%
[D1] at C1. g 94% [D1] at C1, 74% [D1] at C2. h93% [D1] at C1, 89% [D1] at C2.
b
Table 4. The Effect of the Amount and Addition Order of EtOD-d1 and EtOH on the Deuterium Incorporationa
entry EtOD/H
(equiv)
EtOD/H
(ratio)
addition
methodb
yield
(%)c
[D2]
(%)c
1
2
3
4
5
4.5
4.5
4.5
4.5
4.5
1:1
1:1
1:1
2:1
8:1
A
B
C
A
A
94
95
93
96
95
82
50
11
88
91
aConditions: 1a (0.50 mmol, 1.0 equiv), Na (4.5 equiv), hexane, 0 ºC. b A: EtOD-d1 was added followed by EtOH after 10
s; B: EtOD-d1 and EtOH were added together; C: EtOH was added followed by EtOD-d1 after 10 s. cDetermined by 1H NMR.
Next, the effect of proton donors on the reaction was explored by using limiting deuterium
donor (Table 4). The sequential addition of EtOD-d1 (2.25 equiv) and EtOH (2.25 equiv) led
to the formation of 2a in 94% yield and 82% D2-incorporation (entry 1). However, the
reverse addition resulted in the formation of non-deuterium labeled product as the major
product (entry 3). These results indicate that only 2 equiv of the proton donor are involved in
the Bouveault-Blanc reduction under these conditions, while ruling out the four proton
transfer process.16 In addition, the use of pre-mixed EtOD-d1/EtOH (1:1) led to the formation
of 2a in 50% D2 incorporation. The kinetic isotope effect (kH/kD=1.0) determined by this
experiment indicates that the proton transfer is not involved in the rate determine step.8a
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Scheme 2. The Proposed Mechanism for the Reductive Deuteration of Esters Using
Na/EtOD-d1
Control reactions (eq. 1 and 2) demonstrated that: (a) ester reduction by Na/HCl is not
observed (eq. 1); (b) in the reaction with 2.0 equiv of EtOD-d1, Na was all consumed within
30 sec (eq. 2). Moreover, in the presence of 4.0 equiv of Na and 1.0 equiv of EtOD-d1, 2a
was formed in 40% yield and 88% D2-incorporation, while 46% of acyloin 3a was also
formed (eq. 3). Interestingly, in the presence of 2.0 equiv of Na and 1.0 equiv of EtOD-d1,
only 2a was observed (eq. 4). These observations together with the opening of the
cyclopropyl radical clock (Table 3, entry 15) indicate that: (a) the first electron transfer (14)
may be reversible and occurs even without a proton donor17; (b) the second electron transfer
step (45) occurs only in the presence of a proton donor and this process is faster than the
condensation process (47) (Scheme 2); (c) The high levels of deuterium incorporation (eq.
2, 3 and 4) indicate that anions are selectively protonated by the proton donor (cf.
intramolecular proton transfer), which may lead to the development of new selective SET
synthetic protocols using Na dispersion and EtOH.18
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In summary, α,α-dideuterio alcohols can be synthesized from carboxylic acid esters by
using Na dispersion in oil and ethanol-d1. High levels of deuterium incorporation and
excellent yields have been achieved across a broad range of substrates. This study also
provides new insights into the mechanism of the Bouveault-Blanc reduction. Compared with
the reductive deuteration mediated by alkali metal deuterides or SmI2, this protocol is safer,
lower costing and with higher atom economy. The potential for the reductive deuteration of
halides, alkenes and cyclopropanes by tandem sequences has also been demonstrated and will
be the subject of our further studies.
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Experimental Section
Glassware was dried in an oven overnight before use. Thin layer chromatography was carried
out on SIL G/UV254 silica-aluminum plates and plates were visualized using ultra-violet
light (254 nm) and KMnO4 solution. For flash column chromatography, silica gel 60, 35-70 μ
was used. NMR data was collected at 300, 400, or 500 MHz. Data was manipulated directly
from the spectrometer or via a networked PC with appropriate software. All samples were
analyzed in CDCl3 unless otherwise stated. Reference values for residual solvent were taken
as δ = 7.27 (CDCl3) for 1H-NMR; δ = 77.1 (CDCl3) for 13C-NMR. Multiplicities for coupled
signals were designated using the following abbreviations: s = singlet, d = doublet, t = triplet,
q = quartet, quin = quintet, br = broad signal, and are given in Hz.
All compounds used in this study have been described in the literature or are commercially
available. All solvents and reagents were used as supplied. Esters were purchased from
commercial suppliers or prepared by standard methods.11c, 13, 14b
Optimization Studies (Table 1)
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To a solution of ester (0.500 mmol) in anhydrous hexane (2.5 mL), was added anhydrous
ROD (2.25 mmol-4.00 mmol), followed by Na reagent (2.25 mmol) under N2 at 0 ºC and the
resulted solution was stirred vigorously. After 5 min the reaction was quenched by an
aqueous solution of HCl (1.0 mL, 3.0 M) and the reaction mixture was diluted with Et2O (10
mL) and brine (20 mL). The aqueous layer was extracted with Et2O (2 × 10 mL), the organic
layers were combined, dried over MgSO4, filtered and concentrated. Then the sample was
analyzed by 1H NMR (CDCl3, 400/500 MHz) to obtain the deuterium incorporation and yield
using internal standard (MeNO2) and comparison with corresponding samples.
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General Procedure for the Reduction of Esters by Na/EtOD-d1
To a solution of ester (0.500 mmol) in anhydrous hexane (2.5 mL), was added EtOD (2.25
mmol), followed by Na dispersion in oil (40 wt%, 2.25 mmol) under N2 at 0 ºC and the
resulted solution was stirred vigorously. After 5 min at 0 ºC, the temperature was raised to rt.
After the specified time (typically 0-10 min), the reaction was quenched by an aqueous
solution of HCl (1.0 mL, 3.0 M) and the reaction mixture was diluted with Et2O (10 mL) and
brine (20 mL). The aqueous layer was extracted with Et2O (2 × 10 mL), the organic layers
were combined, dried over MgSO4, filtered and concentrated. The crude product was purified
by flash chromatography (silica, 0-30% EtOAc/hexane).
1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 1, entry 4). According to the general
procedure, the reaction of methyl 3-phenylpropanoate (0.50 mmol), EtOD (2.25 mmol) and
Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC, after chromatography (hexanes-10%
EtOAc/hexane), afforded 2a 67 mg in 97% yield as a colorless oil. D2 incorporation = 94%.
1H NMR (500 MHz, CDCl3) δ 7.32 – 7.28 (m, 2H), 7.25-7.17 (m, 3H), 2.72 (t, J = 7.8, 2H),
13
1.91 (t, J = 7.8, 2H); C NMR (125 MHz, CDCl3) δ 141.9, 128.5, 128.5, 126.0, 61.7 (m),
34.1, 32.1.
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1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 2, entry 1). According to the general
procedure, the reaction of ethyl 3-phenylpropanoate (0.500 mmol), EtOD (2.25 mmol) and
Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC, afforded 2a 67 mg in 97% yield as a
colorless oil. D2 incorporation = 94%. Spectroscopic properties matched those previously
described.
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1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 2, entry 2). According to the general
procedure, the reaction of isopropyl 3-phenylpropanoate (0.500 mmol), EtOD (2.25 mmol)
and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 10 min at rt, afforded 2a 66 mg in
96% yield as a colorless oil. D2 incorporation = 93%. Spectroscopic properties matched those
previously described.
1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 2, entry 3). According to the general
procedure, the reaction of tertbutyl 3-phenylpropanoate (0.500 mmol), EtOD (2.25 mmol)
and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 10 min at rt, afforded 2a 56 mg in
81% yield as a colorless oil. D2 incorporation = 95%. Spectroscopic properties matched those
previously described.
1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 2, entry 4). According to the general
procedure, the reaction of n-butyl 3-phenylpropanoate (0.500 mmol), EtOD (2.25 mmol) and
Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC, afforded 2a 65 mg in 94% yield as a
colorless oil. D2 incorporation = 93%. Spectroscopic properties matched those previously
described.
1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 2, entry 5). According to the general
procedure, the reaction of allyl 3-phenylpropanoate (0.500 mmol), EtOD (2.25 mmol) and Na
dispersion in oil (2.25 mmol) for 5 min at 0 ºC, afforded 2a 53 mg in 77% yield as a colorless
oil. D2 incorporation = 94%. Spectroscopic properties matched those previously described.
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1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 2, entry 6). According to the general
procedure, the reaction of benzyl 3-phenylpropanoate (0.500 mmol), EtOD (2.25 mmol) and
Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC, afforded 2a 61 mg in 88% yield as a
colorless oil. D2 incorporation = 95%. Spectroscopic properties matched those previously
described.
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1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 2, entry 7). According to the general
procedure, the reaction of 2-methoxyethyl 3-phenylpropanoate (0.500 mmol), EtOD (2.25
mmol) and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC, afforded 2a 68 mg in 98%
yield as a colorless oil. D2 incorporation = 93%. Spectroscopic properties matched those
previously described.
1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (Table 3, entry 1). According to the general
procedure, the reaction of methyl 3-phenylpropanoate (10.0 mmol), EtOD (45.0 mmol) and
Na dispersion in oil (45.0 mmol) for 5 min at 0 ºC, after chromatography (hexanes-10%
EtOAc/hexane), afforded 2a 1.28 g in 93% yield as a colorless oil. D2 incorporation = 96%.
Spectroscopic properties matched those previously described.
1,1-Dideuterio-3-phenylpropan-1-ol 2a11a (reaction under open flask conditions). To a
solution of methyl 3-phenylpropanoate (1.00 mmol) in anhydrous hexane (5.0 mL), was
added EtOD (4.5. mmol), followed by Na dispersion in oil (4.50 mmol) in an open flask at 0
ºC and the resulted solution was stirred vigorously. After 5 min at 0 ºC, the temperature was
raised to rt. The reaction was quenched by an aqueous solution of HCl (2.0 mL, 3.0 M) and
the reaction mixture was diluted with Et2O (10 mL) and brine (20 mL). The aqueous layer
was extracted with Et2O (2 × 10 mL), the organic layers were combined, dried over MgSO4,
filtered and concentrated. The crude product was purified by flash chromatography (silica, 0-
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10% EtOAc/hexane), afforded 2a 127 mg in 92% yield as a colorless oil. D2 incorporation =
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90%. Spectroscopic properties matched those previously described.
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1,1-Dideuterio-3-(4-methoxyphenyl)propan-1-ol 2i11a (Table 3, entry 2). According to the
general procedure, the reaction of methyl 3-(4-methoxyphenyl)propanoate (0.500 mmol),
EtOD (2.25 mmol) and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt,
after chromatography (hexanes-10% EtOAc/hexane), afforded 2i 76 mg in 91% yield as a
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colorless oil. D2 incorporation = 93%. H NMR (500 MHz, CDCl3) δ 7.16-7.10 (m, 2H),
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6.88-6.82 (m, 2H), 3.80 (s, 3H), 2.66 (t, J = 7.7, 2H), 1.86 (t, J = 7.7, 2H); C NMR (125
MHz, CDCl3) δ 157.9, 133.9, 129.4, 113.9, 61.6 (m), 55.4, 34.3, 31.2.
3-(4-(Methylthio)phenyl)propan-1,1-d2-1-ol 2j11a (Table 3, entry 3). According to the
general procedure, the reaction of methyl 3-(4-(methylthio)phenyl)propanoate (0.500 mmol),
EtOD (2.25 mmol) and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt,
after chromatography (hexanes-10% EtOAc/hexane), afforded 2j 75 mg in 81% yield as a
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colorless oil. D2 incorporation = 92%. H NMR (400 MHz, CDCl3) δ 7.25 – 7.18 (m, 2H),
7.17 – 7.11 (m, 2H), 2.68 (t, J = 7.7, 2H), 2.48 (s, 3H), 1.86 (t, J = 7.7, 2H), 1.48 (br, 1H); 13C
NMR (100 MHz, CDCl3) δ 139.0, 135.4, 129.0, 127.1, 61.5 (m), 34.0, 31.5, 16.3.
1,1-Dideuterio-3-(4-fluorophenyl)propan-1-ol 2k11a (Table 3, entry 4). According to the
general procedure, the reaction of methyl 3-(4-fluorophenyl)propanoate (0.500 mmol), EtOD
(2.25 mmol) and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after
chromatography (hexanes-10% EtOAc/hexane), afforded 2k 68 mg in 87% yield as a
1
colorless oil. D2 incorporation = 94%. H NMR (500 MHz, CDCl3) δ 7.19 – 7.12 (m, 2H),
13
7.01 – 6.94 (m, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.87 (t, J = 7.8, 2H), 1.42 (br, 1H); C NMR
(125 MHz, CDCl3) δ 161.4 (d, J (C-F) = 243.4), 137.5 (d, J (C-F) = 3.2), 129.8 (d, J(C-F) = 7.8),
115.2 (d, J(C-F) = 21.1), 61.4 (m), 34.2, 32.3.
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3-(Phenyl-4-d)propan-1,1-d2-1-ol 2l11a (Table 3, entry 5).
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According to the general procedure, the reaction of methyl 3-(4-chlorophenyl)propanoate
(0.500 mmol), EtOD (3.25 mmol) and Na dispersion in oil (3.25 mmol) for 5 min at 0 ºC and
5 min at rt, after chromatography (hexanes-10% EtOAc/hexane), afforded 2l 56 mg in 81%
yield as a colorless oil. D2 incorporation = 94% and D1 incorporation = 95% at C1. 1H NMR
(400 MHz, CDCl3) δ 7.34 – 7.28 (m, 2H), 7.25 – 7.19 (m, 2H), 2.73 (t, J = 7.7, 2H), 1.90 (t, J
13
= 7.7, 2H), 1.48 (br, 1H); C NMR (100 MHz, CDCl3) δ 141.9, 128.5, 128.4, 125.6 (t, J(C-D)
= 24.4), 61.6 (m), 34.1, 32.1.
2-(4-Isobutylphenyl)propan-1,1-d2-1-ol 2m11a (Table 3, entry 6). According to the general
procedure, the reaction of methyl 2-(4-isobutylphenyl)propanoate (0.500 mmol), EtOD (2.25
mmol) and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after
chromatography (hexanes-10% EtOAc/hexane), afforded 2m 89 mg in 92% yield as a
colorless oil. D2 incorporation = 95%. 1H NMR (500 MHz, CDCl3) δ 7.18-7.09 (m, 4H), 2.92
(q, J = 7.0, 1H), 2.46 (d, J = 7.2, 2H), 1.85 (m, 1H), 1.28 (d, J = 7.0, 3H), 0.92 (d, J = 6.6,
13
6H); C NMR (125 MHz, CDCl3) δ 140.8, 140.2, 129.5, 127.2, 68.1 (m), 45.1, 41.9, 30.3,
22.5, 17.7.
(1-Phenylcyclopentyl)methan-d2-ol 2n13 (Table 3, entry 7). According to the general
procedure, the reaction of methyl 1-phenylcyclopentanecarboxylate (0.500 mmol), EtOD
(2.25 mmol) and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after
chromatography (hexanes-10% EtOAc/hexane), afforded 2n 85 mg in 95% yield as a
1
colorless oil. D2 incorporation = 96%. H NMR (400 MHz, CDCl3) δ 7.32-7.23 (m, 4H),
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7.19-7.15 (m, 1H), 2.02 – 1.92 (m, 2H), 1.87 – 1.77 (m, 2H), 1.75 – 1.61 (m, 4H), 1.19 (br,
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1H); 13C NMR (100 MHz, CDCl3) δ 146.8, 128.4, 127.4, 126.3, 69.6 (m), 53.2, 34.3, 23.9.
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2-(3-Hydroxypropyl-3,3-d2)phenol 2o13 (Table 3, entry 8). According to the general
procedure, the reaction of methyl chroman-2-one (0.500 mmol), EtOD (2.25 mmol) and Na
dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after chromatography
(hexanes-30% EtOAc/hexane), afforded 2o 59 mg in 77% yield as a colorless oil. D2
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incorporation = 91%. H NMR (500 MHz, CDCl3) δ 7.16-7.07 (m, 2H), 6.92-6.82 (m, 2H),
2.79 (t, J = 6.8, 2H), 1.88 (t, J = 6.8, 2H); 13C NMR (125 MHz, CDCl3) δ 154.7, 130.7, 127.7,
127.2, 120.9, 116.3, 60.4 (m), 32.1, 25.2.
1-Dideuterio-adamantanemethanol 2p13 (Table 3, entry 9). According to the general
procedure, the reaction of methyl adamantane-1-carboxylate (0.500 mmol), EtOD (2.25
mmol) and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC, after chromatography
(hexanes-10% EtOAc/hexane), afforded 2p 80 mg in 95% yield as a white solid. D2
1
incorporation = 97%. H NMR (500 MHz, CDCl3) δ 2.00 (m, 3H), 1.74 (m, 3H), 1.65 (m,
3H), 1.51 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 73.2 (m), 39.1, 37.3, 34.6, 28.3.
2-Butyloctan-1,1-d2-1-ol 2q13 (Table 3, entry 10). According to the general procedure, the
reaction of methyl 2-butyloctanoate (0.500 mmol), EtOD (2.25 mmol) and Na dispersion in
oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after chromatography (hexanes-10%
EtOAc/hexane), afforded 2q 71 mg in 75% yield as a colorless oil. D2 incorporation = 95%.
1H NMR (400 MHz, CDCl3) δ 1.51-1.40 (s, 1H), 1.38 – 1.22 (m, 16H), 0.97-0.80 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 65.1 (m), 40.4, 32.0, 31.0, 30.7, 29.8, 29.2, 27.0, 23.2, 22.8,
14.2×2.
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3-Cyclopentylpropan-1,1-d2-1-ol 2r (Table 3, entry 11). According to the general
procedure, the reaction of methyl 3-cyclopentylpropanoate (0.500 mmol), EtOD (2.25 mmol)
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and Na dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after chromatography
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(hexanes-10% EtOAc/hexane), afforded 2r 52 mg in 80% yield as a colorless oil. D2
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incorporation = 97%. H NMR (400 MHz, CDCl3) δ 1.83 – 1.69 (m, 3H), 1.65 – 1.30 (m,
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9H), 1.15 – 1.00 (m, 2H); C NMR (100 MHz, CDCl3) δ 62.7 (m), 40.0, 32.8, 32.2, 31.9,
25.2.
1,1-Dideuterioundec-10-en-1-ol 2s13 (Table 3, entry 12). According to the general
procedure, the reaction of methyl undec-10-enoate (0.500 mmol), EtOD (2.25 mmol) and Na
dispersion in oil (2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after chromatography
(hexanes-10% EtOAc/hexane), afforded 2s 82 mg in 95% yield as a colorless oil. D2
incorporation = 94%. 1H NMR (400 MHz, CDCl3) δ 5.82 (m, 1H), 5.04 - 4.89 (m, 2H), 2.04
13
(m, 2H), 1.56 (m, 2H), 1.44 - 1.20 (m, 12H); C NMR (100 MHz, CDCl3) δ 139.3, 114.2,
62.4 (m), 33.9, 32.7, 29.6, 29.5, 29.5, 29.2, 29.0, 25.7.
(Z)-Octadec-9-en-1,1-d2-1-ol 2t13 (Table 3, entry 13). According to the general procedure,
the reaction of methyl oleate (0.500 mmol), EtOD (2.25 mmol) and Na dispersion in oil (2.25
mmol) for 5 min at 0 ºC and 5 min at rt, after chromatography (hexanes-10% EtOAc/hexane),
1
afforded 2t 128 mg in 95% yield as a colorless oil. D2 incorporation = 91%. H NMR (500
MHz, CDCl3) δ 5.36 (m, 2H), 2.02 (m, 4H), 1.56 (t, J = 7.4, 2H), 1.41-1.19 (m, 22H), 0.89 (t,
13
J = 7.0, 3H); C NMR (125 MHz, CDCl3) δ 130.1, 129.9, 62.6 (m), 32.7, 32.0, 29.9, 29.8,
29.6, 29.6, 29.5, 29.4×2, 29.3, 27.3, 27.3, 25.8, 22.8, 14.2.
3-(4-Methoxyphenyl)propan-1,1,2,3-d4-1-ol 2u13 (Table 3, entry 14).
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According to the general procedure (but a mixture of hexane (2.5 mL) an Et2O (2.0 mL) was
used as the solvent), the reaction of methyl (E)-3-(4-methoxyphenyl)acrylate (0.500 mmol),
EtOD (3.25 mmol) and Na dispersion in oil (3.25 mmol) for 5 min at 0 ºC and 5 min at rt,
after chromatography (hexanes-10% EtOAc/hexane), afforded 2u 66 mg in 78% yield as a
colorless oil. D2 incorporation = 91%; D1 incorporation = 94% at C1; and D1 incorporation =
74% at C2. 1H NMR (400 MHz, CDCl3) δ 7.16 – 7.09 (m, 2H), 6.87 – 6.81 (m, 2H), 3.80 (s,
3H), 2.69 – 2.60 (m, 1H), 1.89 – 1.78 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 157.8, 133.9,
129.4, 113.8, 61.7 (m), 55.3, 33.8 (m), 30.7 (m).
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4-phenylbutan-1,1,2,4-d4-1-ol 2v11d (Table 3, entry 15).
According to the general procedure, the reaction of methyl 2-phenylcyclopropane-1-
carboxylate (0.500 mmol), EtOD (3.25 mmol) and Na dispersion in oil (3.25 mmol) for 5 min
at 0 ºC and 5 min at rt, after chromatography (hexanes-10% EtOAc/hexane), afforded 2v 51
mg in 66% yield as a colorless oil. D2 incorporation = 94%; D1 incorporation =93% at C1;
and D1 incorporation = 89% at C2. 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.25 (m, 2H), 7.23 –
7.15 (m, 3H), 2.69 – 2.59 (m, 1H), 1.74 – 1.64 (m, 2H), 1.64 – 1.55 (m, 1H), 1.42 (br, 1H);
13C NMR (100 MHz, CDCl3) δ 142.4, 128.5, 128.4, 125.8, 62.1 (m), 35.3 (t, J(C-D) = 19.4),
31.8 (t, J(C-D) = 19.0), 27.4.
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Pent-4-en-1,1-d2-1-ol 2w (Table 3, entry 16). According to the general procedure, the
reaction of methyl pent-4-enoate (0.500 mmol), EtOD (2.25 mmol) and Na dispersion in oil
(2.25 mmol) for 5 min at 0 ºC and 5 min at rt, after chromatography (hexanes-Et2O), afforded
1
2w 37 mg in 85% yield as a colorless oil. D2 incorporation >98%. H NMR (300 MHz,
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CDCl3) δ 5.79 (m, 1H), 5.06 – 4.87 (m, 2H), 2.88 (br, 1H), 2.08 (m, 2H), 1.60 (t, J = 7.5 Hz,
5
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2H); 13C NMR (75 MHz, CDCl3) δ 138.2, 114.7, 61.2 (m), 31.5, 29.9.
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Acknowledgments
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We thank NSFC (No. 21602248 and No. 21472236), and Chinese Universities Scientific
Fund for financial support. We thank Professor Ohyun Kwon from UCLA for useful
discussions.
Supporting Information
13
1H and C NMR spectra for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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The Journal of Organic Chemistry
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(13)An, J.; Work, D. N.; Kenyon, C.; Procter, D. J. J. Org. Chem. 2014, 79, 6743.
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(14) (a) Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson, J. E.; Lefenfeld, M. J.
Am. Chem. Soc. 2005, 127, 9338. (b) Bodnar, B. S.; Vogt, P. F. J. Org. Chem. 2009, 74, 2598.
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(15) The reduction of esters using sodium is a four-electron process.
(16) Barrett, A. G. M. Reduction of Carboxylic Acid Derivatives to Alcohols, Ethers and
Amines. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Elsevier
Science Ltd, 1991; pp 236–257.
(17) Shi, S.; Szostak, R.; Szostak, M. Org. Biomol. Chem. 2016, 14 , 9151.
(18) For alkali-metal-promoted cyclization reactions, see: Cossy, J.; Gille, B.; Bellosta, V. J.
Org. Chem. 1998, 63, 3141.
(19) Bartlett, P. D.; Trahanovsky, W. S.; Bolon, D. A.; Schmid, G. H. J. Am. Chem. Soc.
1965, 87, 1314.
(20)Tagge, C. D.; Simpson, R. D.; Bergman, R. G.; Hosteller, M. J.; Girolami, G. S.; Nuzzo,
R. G. J. Am. Chem. Soc. 1996, 118, 2634.
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