Efficient synthesis of tertiary α-hydroxy ketones through CO 2-promoted regioselective hydration of propargylic alcohols

Article abstract of DOI:10.1039/c4gc00522h

A carbon dioxide-promoted and silver acetate-catalyzed hydration of propargylic alcohols for the efficient synthesis of tertiary α-hydroxy ketones has been developed. The reaction is proposed to proceed via a tandem process of carbon dioxide incorporation into propargylic alcohols and subsequent hydrolysis. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00522h

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Efficient synthesis of tertiary α-hydroxy ketones
through CO2-promoted regioselective hydration
of propargylic alcohols†
Cite this: Green Chem., 2014, 16,
3729
Received 25th March 2014,
Accepted 5th June 2014
Haitao He,a Chaorong Qi,*a,b Xiaohan Hu,a Yuqi Guana and Huanfeng Jianga
DOI: 10.1039/c4gc00522h
www.rsc.org/greenchem
A carbon dioxide-promoted and silver acetate-catalyzed hydration
of propargylic alcohols for the efficient synthesis of tertiary
α-hydroxy ketones has been developed. The reaction is proposed
to proceed via a tandem process of carbon dioxide incorporation
into propargylic alcohols and subsequent hydrolysis.
Scheme 1 Transformation of propargylic alcohols into tertiary
α-hydroxy ketones.
The catalytic hydration of alkynes is an important and atom-
economic reaction that provides one of the most straight-
forward and efficient methodologies to generate useful carbonyl
compounds.1 Transition-metal-catalyzed hydration of alkynes
has long been known since Kutscheroff found that mercury(II)
salts can efficiently catalyze the hydration of alkynes in
aqueous sulphuric acid solution.2 However, associating with
high toxicity of mercury salts, the Kucherov reaction is not
practical in modern industrial application. Therefore, much
effort has been devoted to developing less toxic and more
efficient catalysts for the reaction in recent years. A wide range
of transition metals including Pd,3 Pt,4 Fe,5 Au,6 Ag,7 Ir8 and
Ru9 have been investigated for the hydration of alkynes. These
catalyst systems are proved to be efficient for simple nonfunc-
tionalized alkynes. However, few of them could be applicable
for efficient hydration of propargylic alcohols. These α-hydroxy
group functionalized alkynes either showed low activity or
led to other reactions including the Meyer–Schuster and Rupe
rearrangements under mercury-free conditions.4c,6a,b,f,7b,c
Thus, the direct hydration of propargylic alcohols remains a
continuing challenge. It should be noted that the mercury-
catalyzed hydration of propargylic alcohols is one of the most
important applications of alkyne hydration of all, because it
offers α-hydroxy ketones as important building blocks for
more elaborated molecules.10 And recently, α-hydroxy ketones
have attracted tremendous interest in biologically active
natural product research and synthetic chemistry.11 Therefore,
the development of novel mercury-free processes for the
efficient hydration of propargylic alcohols to produce
α-hydroxy ketones is highly desirable. Herein, we present a
carbon dioxide (CO2)-promoted and silver acetate-catalyzed
hydration of propargylic alcohols for convenient synthesis of
tertiary α-hydroxy ketones under mild reaction conditions
(Scheme 1).
During the course of our investigation on the optimal reac-
tion conditions for the synthesis of 2,2,5-trimethyl-4-(pyridin-
2-yl)furan-3(2H)-one from 2-methyl-4-(pyridin-2-yl)but-3-yn-2-
ol (1a) and acetonitrile under a CO2 atmosphere, 3-hydroxy-3-
methyl-1-(pyridin-2-yl)butan-2-one (2a) was observed as a by-
product in some cases.12 Surprisingly, the α-hydroxy ketone
was selectively formed in 76% isolated yield when silver
acetate was used as a catalyst under 2 MPa of CO2 at 70 °C in
the presence of 0.5 equiv. of 1,8-diazabicyclo[5.4.0]-undec-7-
ene (DBU) (Table 1, entry 1).
Although α-hydroxy ketones as by-products were also
observed in previous research on the coupling reaction of pro-
pargylic alcohols and CO2 under other catalytic conditions,13
their formation mechanism and synthetic application have
long been ignored. Notably, Yamada and co-workers have
recently showed that optically active α-hydroxy ketone could be
obtained through the hydrolysis of the corresponding cyclic
carbonate.14 To gain more information on the reaction mech-
anism and develop a facile mercury-free route to access
α-hydroxy ketones from readily available propargylic alcohols,
we further investigated the reaction with 2-methyl-4-(pyridin-2-
yl)but-3-yn-2-ol (1a) as a model substrate in the presence of
silver salts as catalysts. Gratifyingly, when the reaction of 1a
aSchool of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, P.R. China. E-mail: crqi@scut.edu.cn;
Fax: +86 20 97112906; Tel: +86 20 97112906
bState Key Lab of Luminescent Materials and Devices, South China University of
Technology, Guangzhou 510640, P.R. China. E-mail: crqi@scut.edu.cn;
Fax: +86 20 97112906; Tel: +86 20 97112906
†Electronic supplementary information (ESI) available: Experimental section
and analytical details of the products. See DOI: 10.1039/c4gc00522h
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Table 1 Optimization of reaction conditionsa
Table 2 Synthesis of various α-hydroxy ketonesa,b
Entry
Catalyst
Base
Solvent v/v
Yieldb/%
1c
2
AgOAc
AgOAc
AgOAc
AgCl
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DIEA
DABCO
Et3N
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
—
MeCN
76
91
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
1,4-Dioxane–H2O = 10 : 3
THF–H2O = 10 : 3
CH2Cl2–H2O = 10 : 3
DMF–H2O = 10 : 3
H2O
3d
4
72
18e
5
6
7
8
AgNO3
Ag2CO3
AgBF4
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
—
8f
17
14
9g
9
27
49
30
10
Trace
Trace
24
10
11
12
13
14
15
16h
17i
18j
19
20
—
11
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
MeCN–H2O = 10 : 3
73
n.r.k
n.r.
n.r.
DBU
a Reaction conditions: 1a (0.5 mmol), catalyst (10 mol%), base
(0.25 mmol), solvent (1.3 mL), CO2 (2 MPa), 90 °C, 24 h. b Isolated
yield. c Ref. 12, catalyst (10 mol%), H2O (1 mmol), MeCN (1 ml), 70 °C.
d The reaction was carried out at 120 °C. e 66% of 1a was recovered
and 8% yield of 2,2,5-trimethyl-4-(pyridin-2-yl)furan-3(2H)-one was
isolated. f 61% of 1a was recovered and 12% yield of 2,2,5-trimethyl-4-
(pyridin-2-yl)furan-3(2H)-one was isolated. g 36% yield of (Z)-4,4-
dimethyl-5-((pyridin-2-yl)methylene)-1,3-dioxolan-2-one was obtained
as a major product. h 1 mmol of H2O was added. i At 1 MPa of CO2.
a Reaction conditions:
1 (0.5 mmol), AgOAc (10 mol%), DBU
(0.25 mmol), MeCN–H2O (1.3 mL, v/v = 10 : 3), CO2 (2 MPa), 90 °C,
j The reaction was carried out under a nitrogen pressure of 2 MPa in 24 h. b Isolated yield. c At 120 °C.
the absence of CO2. k No reaction.
that a decrease in the pressure of CO2 led to a decrease in the
yield of the product (entry 17). Although silver salts have pre-
viously been reported to be efficient catalysts for the hydration
of terminal alkynes,7 no reaction occurred when the procedure
was performed under a N2 atmosphere instead of CO2 in our
case (entry 18), suggesting that CO2 was involved in the
product-forming step. Two more control experiments showed
that both silver salt and organic base are essential for this reac-
tion (entries 19 and 20).
With the optimized conditions in hand (Table 1, entry 2),
we turned our attention to examine the scope and limitation
of our synthetic protocol by using a series of structurally and
functionally diverse propargylic alcohols (Table 2). Gratifyingly,
various internal tertiary propargylic alcohols with a 2-pyridyl
substituent at the acetylenic terminus could be efficiently con-
verted into the corresponding α-hydroxy ketones in moderate
to excellent yields (2a–2j). The data showed that sterically less
bulky propargylic alcohols were favourable to the transform-
ation. When the substrate bearing a bulky alkyl group (1e) or a
phenyl group (1h) at the propargylic position was employed,
lower yield was observed (62% and 69%, respectively). The
reaction of five- or six-membered-ring-substituted propargylic
alcohols proceeded smoothly under the optimized conditions
was conducted in a mixed MeCN–H2O (10 : 3) solvent at 90 °C
in the presence of 10 mol% of AgOAc and 0.5 equiv. of DBU,
the yield of the desired product 2a sharply increased to 91%
(Table 1, entry 2). However, raising the temperature to 120 °C
led to a dramatic decrease in the yield of the product (entry 3).
Further optimization revealed that the silver source was critical
for the success of this reaction, and other silver catalysts such
as AgCl, AgNO3, Ag2CO3 and AgBF4 were proved to be less
effective than AgOAc (entries 4–7). Screening of different bases
showed that the base plays an important role in this trans-
formation. Other organic bases, such as N,N-diisopropyl-
ethylamine (DIEA), 4-diazabicyclo[2.2.2]octane (DABCO) and
triethylamine, were ineffective (entries 8–10). Among various
solvents investigated, the mixed solvent MeCN–H2O (10 : 3)
was found to be the best choice in the formation of the
desired product. Specifically, replacement of MeCN with 1,4-
dioxane or THF made the reaction sluggish, while CH2Cl2 and
DMF resulted in the formation of a complex mixture of pro-
ducts (entries 11–14). With the use of H2O as both a reagent
and a solvent or under solvent-free conditions, the reaction
gave low yield of 2a along with a large amount of unidentified
by-products (entries 15 and 16). Further optimization showed
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to afford the corresponding product in high yields (2i–2j).
Interestingly, even propargylic alcohols bearing a 2-thiophenyl
group at the acetylenic terminus were well tolerated, and
afforded the desired products 2k–2m in reasonable to good
yields at an elevated reaction temperature. A series of aryl-sub-
stituted propargylic alcohols were also investigated and the
results showed that our method was remarkably compatible
with a variety of valuable functional groups at the 4-position of
phenyl ring of the propargylic alcohols, including halogen,
acetyl, ester, nitro, cyano and methoxy groups (2n1–2n8). It was
found that the electronic effect on the phenyl ring of the pro-
pargylic alcohols had a significant influence on the formation
of the desired α-hydroxy ketones. In general, aryl rings substi-
tuted with electron-withdrawing groups furnished the desired
products (2n2–2n7) in higher yields than those with electron-
neutral or electron-donating ones (2n1 and 2n8). Importantly,
propargylic alcohols with functional groups at the 2- or 3-posi-
tion of the phenyl ring were also successfully transformed into
desired products in high yields (2o–2p). Gratifyingly, less reac-
tive alkyl-substituted propargylic alcohol 1q could also afford
the desired product 2q in 46% yield. As expected, terminal ter-
tiary propargylic alcohols could also undergo the reaction
smoothly to afford the corresponding products in high yields
(2r–2t). However, when primary or secondary propargylic alco-
hols were employed as the substrates, no desired products
were observed and the starting materials were recovered,15
indicating that the synthetic protocol is suitable for the syn-
thesis of α-hydroxy ketones arising from tertiary propargylic
alcohols.
Scheme 2 Further demonstration of the synthetic application of the
α-hydroxy ketones. Reaction conditions: (i) 2n4 (0.25 mmol), PhB(OH)2
(1.5 equiv.), Pd(OAc)2 (5 mol%), K3PO4 (3.0 equiv.), PPh3 (10 mol%),
toluene (5 mL), 110 °C, 9 h. (ii) 2n6 (0.25 mmol), zinc dust (6.0 equiv.),
water (6 mmol), CO2 (12 MPa), 80 °C, 9 h. (iii) A mixture of 2n6
(0.25 mmol), NaBH4 (1.5 equiv.) and PhCO2H (1.0 equiv.) was ground in
an agate mortar and pestle at room temperature for 30 minutes.
Scheme 3 Synthesis of 2a on a larger scale. Reaction conditions:
AgOAc (10 mol%), DBU (2.5 mmol), MeCN–H2O (3 mL, v/v = 10 : 3), CO2
(2 MPa), 90 °C, 24 h.
To further demonstrate the synthetic application of this
protocol, the newly formed 2n4 and 2n6 were employed for
further transformations to prepare a series of functionalized
products. As can be seen from Scheme 2, the α-hydroxy ketone
2n4, which has a –Br group on its phenyl ring, could efficiently
undergo Suzuki–Miyaura cross-coupling reaction to afford 3
in high yield. For the α-hydroxy ketone 2n6, the attached nitro
group could be selectively reduced to the amino group using
our previously developed Zn–H2O–CO2 system,16 affording the
product 4 in almost quantitative yield. Moreover, the use
of NaBH4 under solvent-free conditions17 led to exclusive
reduction of the carbonyl group of 2n6, giving 3-methyl-1-(4-
nitrophenyl)butane-2,3-diol (5) in 70% yield upon isolation.
The reaction is practical and scalable since a satisfactory
yield (85%) was obtained when the silver-catalyzed and CO2-
promoted hydration reaction of 1a was performed on 5 mmol
scale (Scheme 3).
In order to clarify the reaction mechanism, a two-step
process for the synthesis of 2a was investigated (Scheme 4).
Firstly, treatment of 1a with 10 mol% AgOAc in the presence of
0.5 equiv. of DBU at 25 °C in MeCN under 2 MPa of CO2
pressure for 24 h gave cyclic carbonate 6a in 96% yield. Sub-
sequently, 6a was heated to 90 °C for 18 h in a MeCN–H2O
(10 : 3) solvent system in the presence of 0.5 equiv. of DBU,
and the desired product 2a was isolated in excellent yield.
Based on the above-described results and previous
reports,12,14,15,18 a plausible mechanism for the reaction is pos-
tulated in Scheme 5. Firstly, Z-alkylidene cyclic carbonate 6 is
formed by the incorporation of CO2 into propargylic alcohol 1
in the presence of the binary catalyst system AgOAc/DBU via
intermediates 7 and 8. Then, the nucleophilic attack of a water
molecule to such a carbonate 6 occurs at the carbonyl group to
Scheme 4 A two-step process for the synthesis of 2a.
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Scheme 5 Reaction mechanism of the formation of α-hydroxy
ketones.
give the alkylcarbonic acid intermediate 9, followed by the
keto–enol tautomerization and the release of CO2 to afford the
corresponding α-hydroxy ketone 2.
Conclusions
We have established a facile and efficient method to synthesize
tertiary α-hydroxy ketones via a tandem incorporation of CO2
into propargylic alcohols/hydrolysis process. The hydration
avoids the use of toxic mercury salts as catalysts and exhibits
complete regioselectivity and high functional group tolerance,
affording a variety of α-hydroxy ketones in moderate to excel-
lent yields. These features may render this new protocol poten-
tially attractive in synthetic organic chemistry. Now, studies are
ongoing in our laboratory to better understand the reaction
mechanism and apply this method to the synthesis of other
useful heterocyclic compounds.
Acknowledgements
We thank the National Basic Research Program of China (973
program) (2010CB732206), the National Natural Science Foun-
dation of China (21172078), the Guangdong Natural Science
Foundation (10351064101000000), and the Fundamental
Research Funds for the Central Universities (2013ZM0061) for
financial support.
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