Zeise's dimer-catalyzed regioselective hydration of homopropargyl tertiary ether

Article abstract of DOI:10.1016/j.tetlet.2012.07.010

The regioselective hydroalkoxylation of homopropargyl tertiary ether catalyzed by Zeise's dimer was realized. The desired products were obtained in 61-95% yield with good regioselectivity. This methodology represents a valuable alternative to the aldol reaction or the oxa-Michael reaction to form prochiral tertiary β-hydroxy ketones.

Full text of DOI:10.1016/j.tetlet.2012.07.010

Tetrahedron Letters 53 (2012) 4955–4958
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Tetrahedron Letters
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Zeise’s dimer-catalyzed regioselective hydration of homopropargyl
tertiary ether
Ting Zhou a, Guili Zhu a, Xuan Huang a, Bo Liu a,b,
⇑
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective hydroalkoxylation of homopropargyl tertiary ether catalyzed by Zeise’s dimer was
realized. The desired products were obtained in 61–95% yield with good regioselectivity. This
methodology represents a valuable alternative to the aldol reaction or the oxa-Michael reaction to form
prochiral tertiary b-hydroxy ketones.
Received 31 March 2012
Revised 24 June 2012
Accepted 3 July 2012
Available online 16 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Zeise’s dimer
Homopropargyl tertiary ether
Regioselectivity
Tertiary b-alkoxy ketone
The b-hydroxy ketones are important building blocks and can
be utilized in a variety of natural products.1 The aldol reaction, act-
ing as one of the most powerful tools to construct b-hydroxy car-
bonyl derivatives with high stereochemistry, has experienced an
exponential growth in recent years.2 Relatively, however, within
the direct catalytic aldol realm, the reactions between unmodified
ketones and aldehydes have been only scantly represented.3 The
oxa-Michael reaction, which can be protonated to give b-hydroxy
carbonyl compounds, has attracted increasing attention only in re-
cent years.4 In view of this fact, several efficient strategies have
been developed concerning the formation of b-hydroxy or b-alkoxy
ketones, including the ruthenium-catalyzed regioselective hydrosi-
lylation of propargyl alcohols, as well as an alkyne hydrosilylation-
oxidation strategy to afford b-hydroxy ketone achieved by the
Trost group.5 Other examples include catalytic peroxidation-
of our knowledge, only a few of studies have been conducted on
its direct building.12 The Scheidt group synthesized tertiary b-hy-
droxy amides by enolate additions to acylsilanes,12a,12b while the
Panunzio group provided a general route to furnish 3,3-disubsti-
tuted b-hydroxy acids using N-trimethylsilylbenzaldimine and
acetyl chloride as starting materials.12c With this challenge in
mind, we decided to expand our previous work to the hydration
of homopropargyl tertiary ether. Herein, we would like to report
our research results on this methodology.
We began with the optimization studies on the hydration of
substrate 1a, relying on our previous findings.11 Several different
transition metals were examined with a catalyst loading of
2.5 mol %. Mercury triflate afforded an unfavorable regio-selectiv-
ity, preferring 3a as the major product (0.6:1, 2a/3a; Table 1, entry
1). Zeise’s dimer and platinum chloride provided identical selectiv-
ity (3.3:1, exo/endo; Table 1, entries 2 and 3), while Zeise’s dimer
behaved better with relatively higher reactivity (4 h, 79% yield at
40 °C). However, when the cyclooctadiene coordinated with plati-
num, the catalyst turned inactive even at 60 °C (Table 1, entry 4).
Other gold catalysts, such as sodium tetrachloroaurate(III) dihy-
drate, and gold(I) chloride combined with AgOTf or AgSbF6,
showed almost no activity (Table 1, entries 6–8), although
Au(PPh3)Cl/AgOTf afforded an unfavorable regioselectivity (Table 1,
entry 5). So Zeise’s dimer was the catalyst of choice for this partic-
ular reaction.
hydrogenation of
a -
, b-unsaturated ketones6 and reduction of D2
isoxazolines,7 etc.8 For the tactics with homopropargyl alcohol
derivatives, the Shin group achieved an intramolecular hydroamin-
ation of homopropargyl trichloroacetimidates in 2006,9 and the
Yanik group developed platinum-catalyzed intramolecular hydros-
ilation of homopropargyl alcohols.10 In 2010, our laboratory devel-
oped an one-step, platinum-catalyzed hydration of internal
homopropargyl ether,11 which gives rise to b-alkoxy ketones
regioselectively.
It is no doubt that the construction of tertiary b-hydroxy car-
bonyl is challenging in synthetic organic chemistry. To the best
We then investigated different solvents at room temperature
and found that the nature of the reaction medium significantly af-
fected the catalytic reaction. The use of dimethoxyethane resulted
in the best regioselectivity (exo/endo, 5:1); tetrahydrofuran,
⇑
Corresponding author. Tel./fax: +86 28 8541 3712.
E-mail address: chembliu@scu.edu.cn (B. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.010

4956
T. Zhou et al. / Tetrahedron Letters 53 (2012) 4955–4958
Table 1
Table 2
Investigation of metal catalysts
Beneficial effect of crown ether on the regioselectivity
O
O
nBu
nBu
Ph
Ph
2
2
catalyst
M (2.5 mol-%)
L (5 mol-%)
Ph
Ph
O
Me OH
O
MeOH
2.5 mol-%
+
+
nBu
O
OH
nBu
2a
2a
O
OH
DME
DME
2
nBu
O
nBu
O
2
40 o
C
2
2
2
2
0.1M
0.1M
Ph
Ph
Me
3a
Me
3a
OH
OH
O
O
1a
1a
M: Zeise's dimer; L: 12-crown-4
Entry
Catalyst
Hg(OTf)2
Pt2Cl4(C2H4)2(Zeise’s dimer)
PtCl2
T (°C)
t (h)
Yielda (%)
2a/3ab
Entry
Crown ether
t (h)
Yielda (%)
2a/3ab
1
2
3
4
5
6
7
8
406
40
6
4
71
79
70
0.6:1
3.3:1
3.3:1
—
0.5:1
—
1
2
3
4
5
—
4
79
79
71
3.3:1
14:1
8.3:1
7.7:1
7.1:1
40–60c
40–60c
40–60c
40
12-C-4
15-C-5
18-C-6
DCHI18-C-6
1.5
6.5
3.5
19
PtCl2(COD)
Trace
44(76)e
NRf
Au(PPh3)Cl/AgOTfd
NaAuCl4ꢀ2H2O
AuCl/AgOTfd
82
53(63)c
24
24
40
NRf
—
3.3:1
a
b
c
Isolated yield combining 2a and 3a.
40–60c
Trace
d
AuCl /AgSbF6
Determined by 1H NMR spectroscopy of the mixture.
Based on the recovered starting material.
a
b
c
d
e
f
Isolated yield combining 2a and 3a.
Determined by 1H NMR spectroscopy of the mixture.
The catalytic reaction was stirred at 40 °C for 11 h and 60 °C for 8 h.
The ratio of the two metals is 1:1.
Based on the recovered starting material.
NR = No Reaction.
Table 3
Substrate scope of platinum-catalyzed hydration
M (2.5 mol-%)
O
R1
O
2
1a-1l
0.1M
L (5 mol-%)
dioxane, and ether gave rise to the same moderate regioselectivity,
that is, 3.3:1 (exo/endo); other solvent resulted in inferior regiose-
lectivity. This is probably caused by the chelation between the oxy-
gen atom in the solvent molecule and the metal catalyst. For the
alkoxylation of 1a, the triple bond required an intramolecular addi-
tion, other than the intermolecular addition, in which C4 behaves
more electrophilic than C3 because of the chelation between the
catalyst and the triple bond, as well as the ethereal oxygen (see
Fig. 1). So the chelation effect with the dimethoxyethane molecule
might compete with the above-mentioned chelation and benefit
the intermolecular activation of the alkyne, thus resulting in the
favorable regioselectivity.
R1
2
2
+
R3
R2
3a-l
R2
R3
2a-l
O
OH
O
OH
DME
40 o
C
M: Zeise's dimer; L: 12-crown-4
Entry
Substrate
Time (h)
Yielda (%)
79
2/3b
14:1
Ph
1
2
1.5
nBu
O
OH
OH
2
1a
Ph
Ph
Ph
nPr
1.5
69
9.1:1
O
O
2
2
Based on the solvent effect on regioselectivity, we thought
about the introduction of a crown ether as the ligand to enhance
the chelation with the metal catalyst. Fortunately, the results were
gratifying as shown in Table 2.
1b
3
4
5
6
7
1.5
61
7.7:1
>20:1
8.3:1
7.1:1
>20:1
nEt
OH
It is obvious that notable increase on the ratio of 2a to 3a was
obtained and the regioselectivity ranged from 7.1:1 to 14:1 when
we used different size of crown ethers. Among them, 12-crown-4
acted as the best one. As we proposed in our previous communica-
tion,11 the reason might be the incomplete enclosure of platinum
1c
1.5
80
O
O
OH
OH
2
1d
by 12-crown-4 resulting in greater
p
acidity,13 which made the tri-
Ph
Et
ple bond more electrophilic and led to the higher reactivity.
To clarify the scope of this hydroalkoxylation, a variety of sub-
strates were examined (Table 3). On the whole, the results demon-
strated great synthetic potential. When the substituent adjacent to
the triple bond was switched from ethyl to propyl then to butyl,
the ratios of 2 to 3 ranged from 7.7:1 to 14:1, showing satisfactory
regioselectivity (Table 3, entries 1–3). When the homopropargyl
substituent changed from methyl to ethyl or when the phenyl ring
became substituted, the exo/endo selectivity could still maintain
1.5
70
nBu
2
1e
p-BrC6H4
Ph
1.5
63
nBu
OH
O
2
1f
36
57(65)c
O
OH
Ph
2
1g
Ph
H
R
H
O
R1
O
c
O(CH2)2OH
R3
R2
M
8
9
36
43(74)
>20:1
3.6:1
R1
O
OH C6H4Br-4
O
4
Vs
2
4
3
3
1h
M
R
O
R3
Ph
R2
H
intramolecular attack mode
7-exo-dig vs. 8-endo-dig
intermolecular attack mode
C-4 attack preferred
c
36
42(69)
O
OH C6H4Me-4
2
1i
Figure 1. Two activation modes of the substrate by the metal catalyst.

T. Zhou et al. / Tetrahedron Letters 53 (2012) 4955–4958
4957
In general, Zeise’s dimer-catalyzed hydration of homopropargyl
tertiary ether has been developed to afford tertiary b-hydroxy ke-
tones. In addition, the chiral substrates of this reaction are facilely
available since several elegant strategies have been developed on
the asymmetric propargylation of prochiral aliphatic or aromatic
ketones.16 So it is worth considering for organic chemists to ad-
dress chiral tertiary b-hydroxy ketones using our methodology,
thus making it an attractive alternative to the asymmetric version
of aldol reaction or the oxa-Michael reaction. The application of
this methodology in the total synthesis of natural product is under
way in our laboratory.
Table 3 (continued)
Entry
Substrate
Time (h)
36
Yielda (%)
2/3b
Ph
c
10
46(63)
3.3:1
O
OH C6H4OMe-4
2
1j
nBu
OH
11
1.5
12
95
16:1
—
O
2
1k
Ph
12d
Mess
nBu
OTBS
O
2
General procedure for the platinum-catalyzed hydration
1l
a
b
c
Isolated yield combining 2a and 3a.
A solution of Zeise’s dimer (2.5 mol %, 2.3 mg) and 12-crown-4
(5 mol %, 1.4 mg) in dry DME (1.5 ml) was stirred at room temper-
ature for 30 min, and then transferred to a tube containing the sub-
strate (0.15 mmol) in a glove bag. The resulting mixture was stirred
at 40 °C for the indicated time (for 1g–1j: additional 2.3 mg of cat-
Determined by 1H NMR spectroscopy of the mixture.
Based on the recovered starting material.
3.0 equiv of water was added.
d
alyst in 1.5 ml of DME was added after 12 h). Water (25
added, and the mixture was stirred for another 10 min. Subse-
quently, the reaction was quenched with triethylamine (50 L).
After evaporation of the solvent, the residue was purified by flash
chromatography (SiO2) to give the products.
lL) was
more than 7:1 (Table 3, entries 5 and 6). Undoubtedly, the terminal
alkyne 1d should adopt a 7-exo-dig pathway after the coordination
between the catalyst and the terminal alkyne (Table 3, entry 4). As
for phenylacetylene-derived substrates, the regioselectivity proved
to be sensitive to the substituent (Table 3, entries 7–10).When sub-
stituent on the phenyl ring turned more electrondonating, its abil-
ity to stabilize the positive charge at C4 position becomes stronger,
making the C4 position more electrophilic, thus showing preferring
the 8-endo-dig product. In addition, the low reactivity derived from
the bulk size of the aromatic ring led to the lower reactivity. The
aliphatic substrate 1k, to our delight, provided desired products
in excellent yield with good ratio of 16:1 (exo/endo). However, un-
der the same condition, the reaction of compound 1l turned slow
and messy, even though we used 3.0 equiv of water, which eluci-
dates the hydroxyl in the substrate is essential to realize this
transformation.
l
Acknowledgments
We appreciate financial support from the National Natural Sci-
ence Foundation of China (21021001, 21172154), and the Ministry
of Science and Technology of China (2010CB833200). We also
thank the Analytical & Testing Center of Sichuan University for
recording the NMR spectra.
Supplementary data
To illustrate the oxygen source, we did the H218O labeling
experiment of substrate 1d14 (see Fig. 2). Besides the product 2d
due to the existence of the adventitious water in the reaction sys-
tem, the product 2d0 containing the 18O in carbonyl was also gen-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.010.
18
erated15; however, O-labeled compound 2d00 was not detected.
References and notes
This experiment indicated that the oxygen source toward the car-
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the substrate (see Fig. 3).
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Ph
M (2.5 mol-%)
L (5 mol-%)
O
O
O
2
OH
2
2
OH
+
H
18O
O
Ph
O
M1e8OH
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Figure 2. H218O labeling experiment of substrate 1d.
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H
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O
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~H
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LnM
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MLn
R3
LnM
R2
R3
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Figure 3. Mechanism of the hydration of the substrates.

4958
T. Zhou et al. / Tetrahedron Letters 53 (2012) 4955–4958
12. For the related examples, see: (a) Lettan, R. B., II; Reynolds, T. E.; Galliford, C. V.;
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Synlett 1999, 1735–1738.
14. See Supplementary data.
13
15. See the C NMR spectra of 2d and 2d0 in Supplementary data.
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