Transformation of Alkynes into Chiral Alcohols via TfOH-Catalyzed Hydration and Ru-Catalyzed Tandem Asymmetric Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.8b00034

A novel full atom-economic process for the transformation of alkynes into chiral alcohols by TfOH-catalyzed hydration coupled with Ru-catalyzed tandem asymmetric hydrogenation in TFE under simple conditions has been developed. A range of chiral alcohols was obtained with broad functional group tolerance, good yields, and excellent stereoselectivities.

Full text of DOI:10.1021/acs.orglett.8b00034

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transformation of Alkynes into Chiral Alcohols via TfOH-Catalyzed
Hydration and Ru-Catalyzed Tandem Asymmetric Hydrogenation
Sensheng Liu,† Huan Liu,† Haifeng Zhou,*,†,‡ Qixing Liu,† and Jinliang Lv*,‡
†Research Center of Green Pharmaceutical Technology and Process, Hubei Key Laboratory of Natural Products Research and
Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China
‡Yichang Humanwell Pharmaceutical Co., Ltd., Yichang, 443005, China
S
* Supporting Information
ABSTRACT: A novel full atom-economic process for the
transformation of alkynes into chiral alcohols by TfOH-
catalyzed hydration coupled with Ru-catalyzed tandem
asymmetric hydrogenation in TFE under simple conditions
has been developed. A range of chiral alcohols was obtained
with broad functional group tolerance, good yields, and
excellent stereoselectivities.
he transformation of alkynes is of great importance in
Torganic synthesis, because of the wide availability of
alkynyl substrates, as well as the fundamental importance of the
functionalized compounds. Much effort has been devoted to
the conversion of alkynes into carbonyl compounds through
hydration.1−4 Alkynes can also be converted to alcohols by
hydroboration reactions5 or hydration/reduction processes.6
However, the one-pot direct transformation of alkynes into
alcohols via hydration/reduction is challenging, because of the
incompatibility of the catalysts and reaction conditions of the
two steps. So far, examples of direct transformation of alkynes
into alcohols are very rare.6−11 In 2013, Xiao and co-workers
reported the first enantioselective transformation of alkynes
into chiral alcohols by formic acid-mediated hydration coupled
with Rh-catalyzed asymmetric transfer hydrogenation (ATH).7
However, the hydration step needs an excess amount of formic
acid as solvent and high temperature (100 °C), and the second
ATH reaction must adjust the pH to 7 by adding a large
amount of NaOH. Subsequently, several examples about the
synthesis of chiral alcohols via one-pot sequential hydration−
ATH reactions from alkynes catalyzed by the combination of
bimetallic complexes, such as [(IPr)AuX]/Ru-TsDPEN (X =
NTf2 or BF4),8 [(IPr)AuCl]/Rh-TsDPEN,9 Co-Salen/Ru-
TsDPEN,10 and Co-Porphyrin/Rh-TsDPEN11 have also been
reported. Despite these advances, to develop a novel process
with a simple catalyst system and mild reaction conditions for
the alkyne-to-chiral alcohol transformation is highly desirable,
from both a practical standpoint and an environmental point of
view.
ketones14 and heteroaromatics.15 Very recently, Li’s group
reported a metal-free Markovnikov-type alkyne hydration, using
TfOH as the catalyst and 2,2,2-trifluoroethanol (TFE) as the
solvent under mild conditions.4 Notably, the reaction
conditions (20 mol % TfOH, 2 equiv H2O, 1 mL TFE, 25
°C) are not only simple but also compatible with the cationic
chiral Ru(II) diamine triflate-catalyzed AH of ketones. In
addition, it was reported that the stereoselectivities can be
enhanced in asymmetric synthesis using fluorinated solvents.16
Therefore, we reason that the alkynes could be converted to
chiral alcohols via sequential hydration−AH catalyzed by the
combination of TfOH and cationic chiral Ru(II) diamine
triflate in TFE (see Scheme 1).
Scheme 1. Comparison of Previous Work and This Work
The chiral η6-arene/N-tosylethylenediamine-Ru(II) chloride
complexes were famous catalysts for ATH developed by
Noyori.12 Interestingly, the cationic chiral Ru(II) diamine
catalysts, prepared by cleavage of the Ru−Cl bond with base
and adding CF3SO3H (TfOH), can also be used for asymmetric
hydrogenation (AH).13 The cationic chiral Ru(II) diamine
triflate ion pairs have been proved to be ideal AH catalysts for
Received: January 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00034
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To test our hypothesis, phenylacetylene was selected as the
model substrate. The hydration reaction was conducted with 20
mol % TfOH as the catalyst and 1 mL of TFE as the solvent in
the presence of 2 equiv of H2O.4 It was found that the
phenylacetylene could be converted to acetophenone com-
pletely at 40 °C for 6 h, as monitored by gas chromatography
(GC).17 Then, 0.5 equiv of KOH and 1 mol % (S,S)-1a were
added to the reaction tube, which was put into a stainless steel
autoclave. The AH was conducted at 40 °C under 40 atm of
hydrogen for 24 h, affording the desired (S)-1-phenylethanol in
30% yield and 63% enantiometric excess (ee) (Table 1, entry
apparently with 10 atm of hydrogen (entries 11 and 12 in
Table 1). Next, the hexafluoro-2-propanol (HFIP) as the twin
of TFE could also give the desired product but in relatively
lower yield and ee (entry 13 in Table 1). Finally, high yield and
excellent ee remained even if the catalyst loading was reduced
to 0.5 mol % (entry 14 in Table 1).
To expand the scope of this novel sequential hydration−AH
process, a range of alkynes with different functional groups
were investigated, and the results have been summarized in
Table 2. All the tested alkynes could be converted to the
Table 2. Substrate Scope for the Transformation of Alkynes
into Chiral Alcohols
a
a
Table 1. Optimization of the Reaction Conditions
entry
cat.
additive
H2, atm yield (%) ee (%)
entry
1
substrate
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
(S,S)-1a
(S,S)-1b
(S,S)-1c
(S,S)-1d
(S,S)-1e
(S,S)-1f
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
KOH (0.5 equiv)
KOH (0.5 equiv)
KOH (0.5 equiv)
KOH (0.5 equiv)
KOH (0.5 equiv)
KOH (0.5 equiv)
KOH (0.25 equiv)
KOH (0.20 equiv)
40
40
40
40
40
40
40
40
40
40
20
10
2
30
35
97
85
46
57
96
0
63
91
98
89
80
61
98
0
2a: R = H, R′ = H
3a
3b
3c
3d
3e
3f
96
90
81
96
94
79
82
89
62
85
82
83
87
90
79
72
75
83
99
93
99
95
91
87
95
97
81
99
99
97
97
93
99
93
94
97
b
2
2b: R = 2-F, R′ = H
2c: R = 3-F, R′ = H
2d: R = 4-F, R′ = H
2e: R = 4-Cl, R′ = H
2f: R = 2, 5-Cl, R′ = H
2g: R = 3-Br, R′ = H
2h: R = 4-Br, R′ = H
2i: R = 4-NO2, R′ = H
2j: R = 4-Me, R′ = H
2k: R = 4-Et, R′ = H
2l: R = 4-n-Pr, R′ = H
2m: R = 4-MeO, R′ = H
2n: 2-ethynylnaphthalene
2o: R = H, R′ = Me
2p: R = H, R′ = Et
b
3
b
4
b
5
b
6
b
7
3g
3h
3i
b
8
0
0
c
b
9
10
KOH (0.25 equiv)
KOH (0.25 equiv)
KOH (0.25 equiv)
KOH (0.25 equiv)
KOH (0.25 equiv)
0
0
10
11
12
13
14
3j
11
12
97
52
63
96
99
99
90
99
3k
3l
c
13
d
3m
3n
3o
3p
3q
3r
14
20
d
15
d
16
d
17
2q: R = H, R′ = n-Bu
2r: R = H, R′ = Ph
d
18
a
Standard reaction conditions: alkyne (0.5 mmol), TfOH (20 mol %),
H2O (2 equiv), TFE (1 mL), 40 °C, 6 h, then add 0.5 mol % (S,S)-1c,
KOH (0.25 equiv), H2 (20 atm), 40 °C, 24 h; isolated yield; the ee
values were determined by HPLC analysis. Please refer to the
b
Supporting Information for the details of each substrate. Conditions
c
were 70 °C and 12 h for the hydration step. HFIP was used as a
solvent. Conditions were 70 °C and 48 h for hydration step.
Conditions were 40 °C and 48 h for hydration step.
a
Reaction conditions: phenylacetylene (0.5 mmol), TfOH (20 mol
%), H2O (2 equiv), TFE (1 mL), 40 °C, 1 mol % catalyst, the yields
were determined by GC with an internal standard (mesitylene), the ee
d
b
values were determined by HPLC analysis. In the absence of
corresponding chiral alcohols with high yields and excellent ee
values. As for the phenylacetylene derivatives bearing electron-
withdrawing groups such as F (2b−2d), Cl (2e and 2f), and Br
(2g and 2h), a higher temperature (70 °C) and longer time (12
h) were required for the hydration step. By contrast, in the case
of electron-deficient 4-nitrophenylacetylene (2i), HFIP was
used as a solvent instead of TFE, because of its poor solubility,
and the hydration step was conducted at 70 °C for 48 h. The
electron-rich phenylacetylene derivatives 2j−2m gave the
corresponding alcohols 3j−3m in 82%−87% yield and 97%−
99% ee under standard conditions. In addition, 2-
ethynylnaphthalene(2n) could also be converted to (S)-1-
naphthylethanol (3n) in 90% yield and 93% ee under standard
conditions. Notably, this novel procedure was also applicable to
internal arylalkynes. For example, the internal arylalkynes 2o−
2r were transformed to the corresponding alcohols 3o−3r in
c
hydrogen gas. Hexafluoro-2-propanol (HFIP) was used as a solvent.
d
0.5 mol % (S,S)-1c was used.
1). Then, AH catalysts, such as chiral diamine ruthenium
complexes 1a−1d, rhodium complex 1e, and iridium complex
1f, were screened. It was found that (S,S)-1c is the best one,
giving 97% yield and 98% ee (see entries 2−6 in Table 1). If the
amount of KOH was reduced to 0.25 equiv, there is no effect
on the results (entry 7 in Table 1). However, the hydro-
genation step did not occur when no more than 0.20 equiv of
KOH was added (see entries 8 and 9 in Table 1).18 In addition,
the desired alcohol was not detected in the absence of
hydrogen gas, indicating that the reductive step is AH rather
than ATH (entry 10 in Table 1). The enantioselectivity was
insensitive to the H2 pressure, but the yield decreased
B
DOI: 10.1021/acs.orglett.8b00034
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Letter
72%−83% yield and 92%−99% ee. Furthermore, other alkynes
including 2-ethynylpyridine, 3-ethynylpyridine, methyl propio-
late, and propargylic alcohol were also attempted. Unfortu-
nately, this protocol is not applicable to these alkynes.
Most importantly, this novel hydration−AH process was also
applicable to multiethynylbenzenes. As shown in Scheme 2, the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00034.
■
S
Experimental details and characterization data (PDF)
Scheme 2. Conversion of Multiethynylbenzenes to Chiral
a
Alcohols
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhouhf@ctgu.edu.cn
*E-mail: lvjinliang@renfu.com.cn
ORCID
Haifeng Zhou: 0000-0002-2710-9570
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from National Natural
Science Foundation of China (No. 21202092), grants from
China Three Gorges University (Nos. KJ2012B080,
KJ2014H008), a research fund for excellent dissertation of
China Three Gorges University (No. 2017YPY083), and a joint
research fund from Yichang Humanwell Pharmaceutical Co.,
Ltd. (No. SDHZ2015003).
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Scheme 3. Gram-Scale Reaction
reaction of phenylacetylene (2a, 1.2 g) was conducted. The
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(17) Based on Li’s procedure in ref 4, the reaction conditions were
improved by enhancing the temperature and shortening the time.
Please refer to the Supporting Information for the details of each
substrate.
(18) According to refs 12−14, the AH of ketones with prepared
chiral ruthenium(II) diamine triflate as a catalyst was operated under
neutral or slightly acidic conditions. However, in this sequential
procedure, 0.2 equiv of base was required to convert TfOH into
triflate. In addition, the cleavage of the Ru−Cl bond to prepare
cationic chiral Ru(II) diamine catalyst in situ need base. Practically, an
excess of base was necessary due to the solubility and dissociation
equilibrium of KOH in TFE.
D
DOI: 10.1021/acs.orglett.8b00034
Org. Lett. XXXX, XXX, XXX−XXX