Platinum-catalyzed regioselective formation of pss-alkoxy ketones from internal alkynes

Article abstract of DOI:10.1002/ejoc.201000484

A catalytic amount of Zeise's dimer and 15-crown-5 were combined to effectively promote the regioselective formation of p-alkoxy ketones from 2-(homopropargyloxy)ethanols in dimethoxyethane, The desired products were obtained in 59-98% yields with up to 17:1 exo/endo regioselectivity. The methodology allows access to ss-hydroxy ketones as an aldol reaction alternative.

Full text of DOI:10.1002/ejoc.201000484

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000484
Platinum-Catalyzed Regioselective Formation of β-Alkoxy Ketones from
Internal Alkynes
Daxin Yang,[a] Jianfeng Huang,[a] and Bo Liu*[a,b]
Keywords: Platinum / Alkynes / Ketones / Regioselectivity / Cyclization
A catalytic amount of Zeise’s dimer and 15-crown-5 were
combined to effectively promote the regioselective formation
of β-alkoxy ketones from 2-(homopropargyloxy)ethanols in
dimethoxyethane. The desired products were obtained in 59–
98% yields with up to 17:1 exo/endo regioselectivity. The
methodology allows access to β-hydroxy ketones as an aldol
reaction alternative.
metal-catalyzed tactics in homopropargyl alcohols, several
elegant strategies have also been developed that involve a
regioselective metal-catalyzed process.[7] In 2006, the Shin
group achieved an intramolecular hydroamination of
homopropargyl trichloroacetimidates, which works well for
both internal and terminal alkynes.[7a] In the same year,
gold-catalyzed cyclization of tert-butyl carbonates of ter-
minal alkynes was completed by the same group.[7b] In ad-
dition, platinum-catalyzed synthesis from homopropargylic
alcohols of internal and terminal alkynes was achieved by
intramolecular hydrosilation.[8] However, a one-step, metal-
catalyzed synthesis of β-alkoxy ketones from homopropar-
gyl alcohol derivatives of internal alkynes had not shown
up yet. We envisioned that this kind of transformation
might be realized through regioselective hydration with a
homopropargyl directing group. Herein, we would like to
present our research results on this methodology. Such re-
gioselective results are easy to understand if one considers
the unequal distribution of positive charges between C-3
and C-4 led by simultaneous coordination of the triple
bond and the homopropargyl oxygen atom with the metal
catalyst.
Introduction
Polyketides are ubiquitous in natural products or active
pharmaceutical intermediates (APIs), most of which exhibit
significant bioactivities. Undoubtedly, the aldol reaction
acts as the most straightforward tool to construct poly-
ketide motifs.[1] The application of an alkyne moiety as a
latent functionality of a ketone in organic synthesis is ap-
pealing as a result of the relative insensitivity of alkynes and
the facile accessibility of chiral homopropargyl alcohols.[2]
Platinum and gold catalysts, enabling powerful atom-econ-
omic reactions to be effected, have initiated an explosion in
their utilization in recent years.[3] Thus, it is beyond doubt
that hydration or alkoxylation of alkynes catalyzed by tran-
sition metals should be a potentially powerful strategy to
construct the β-hydroxy ketone motif, the iterative sub-
structure of polyketides. However, to the best of our knowl-
edge, whereas gold-catalyzed 5-exo-dig cyclizations of pro-
pargylic tert-butyl carbonates[4]and the Meyer–Schuster re-
action have been explored already,[5] few successful exam-
ples of the metal-catalyzed formation of β-hydroxy ketones
from propargyl alcohols have been reported.[6] The Trost
group achieved a ruthenium-catalyzed regioselective hydro-
silylation, followed by debenzylation and Fleming–Tamao
oxidation to afford hydroxy ketones.[6a,6b] Other examples
include the gold-catalyzed cyclization of 1,4-diynes (ter-
minal alkynes) to seven-membered heterocycles[6c] and the
cyclization of 1-alkynyl cyclopropyl tert-butyl carbonate,[6d]
but both methods could only be applied to structurally spe-
cial substrates. To illustrate the applicability with similar
Results and Discussion
In a preliminary study, a variety of directing groups was
evaluated with different transition metal catalysts in various
solvents in the presence of water or methanol.[9] All these
endeavors afforded substituted γ-hydroxy ketones as the
major or sole product, which indicates that the π activation
of the triple bond with metal catalysts, directed by the
homopropargyl oxygen-containing functional groups,
should facilitate attack at C-4 by the nucleophilic reagent.
Obstructed by the unfavorable selectivity of intermo-
lecular hydration and hydroalkoxylation, we focused our at-
tention on an intramolecular hydroalkoxylation tethered by
a homopropargyl ether. With compound 1 as the test sub-
[a] Key Laboratory of Green Chemistry & Technology of Ministry
of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China
Fax: +86-28-85413712
E-mail: chembliu@scu.edu.cn
[b] Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, CAS,
345 Lingling Road, Shanghai 200032, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000484.
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D. Yang, J. Huang, B. Liu
SHORT COMMUNICATION
strate, the catalytic activity and regioselectivity of different be considered only in the trans activation mode. To simplify
transition metals were evaluated with a catalyst loading of the possible reaction pathways and to probe the inherent
5 mol-%. In sharp contrast to the gold-catalyzed hydro- exo/endo selectivity, a dominant trans activation mode was
alkoxylation of conjugated alkynoates reported recently,[10] favorable. We speculated that application of ligands that are
simple gold catalysts, such as gold(I) chloride, gold(III) able to enclose a platinum atom might efficiently suppress
chloride, and sodium tetrachloroaurate(III) dihydrate, do the chelation between the substrate and the metal catalyst
not show any activity even at 60 °C, and Au(PPh3)Cl/Ag- in a cis activation mode, and thus benefit trans activation
OTf afforded 3a as the only detectable product (Table 1, of the alkyne, promoting, in principle, the exo/endo regiose-
Entries 1–4).[11] Mercury triflate displayed the same unfa- lectivity.[13]
vorable regioselectivity, preferring an 8-endo-dig product
(Table 1, Entry 5). The Nishizawa group reported a regiose-
lective Hg(OTf)2-catalyzed hydration of undec-6-yn-1-ol in
aqueous MeCN, favoring a 7-exo-dig product (3:1, 7-exo/
8-endo);[12] however, when we treated compound 1a under
identical reaction conditions to those used by the Nishizawa
group, ketone 3a was obtained as the dominant 8-endo-dig
product (1:5, 2a/3a). This shows that the oxygen atom at
the homopropargyl position in 1a plays a very important
role in the catalytic process. Interestingly, platinum chloride
showed moderate selectivity (3.6:1, exo/endo; Table 1, En-
Figure 1. Two activation modes of the substrate by the metal cata-
lyst.
try 6) in 61% yield at 60 °C. Zeise’s dimer behaved better,
affording similar selectivity at 35 °C (Table 1, Entry 7).
However, platinum catalysts with other ligand, such as PPh3
or cyclooctadiene, proved totally inactive even at 60 °C
(Table 1, Entries 8 and 9).
Table 1. Investigation of metal catalysts.
Scheme 1. 1,4-Difuctionalization of homopropargyl alcohol deriva-
Entry
Catalyst
T
[°C]
t
[h]
Yield[a] 2a/3a[b]
[%]
tives catalyzed by transition metals; DG: directing group = Ac, Me,
CONHBn, CH2CO2Et, etc.; metal cat.: HgII, PtII, AuI, AuIII, HgII,
etc.; solvent: DCM, THF, MeCN, etc.
1
2
3
4
AuCl
AuCl3
NaAuCl4·2H2O
Au(PPh3)Cl/AgOTf
(1:1)
60
60
60
60
6
6
6
6
NR
NR
NR
23
–
–
–
Ͻ1:20
Table 2. Beneficial effect of crown ether on the regioselectivity.
5
6
7
Hg(OTf)2
PtCl2
Pt2Cl4(C2H4)2
(Zeise’s dimer)[c]
PtCl2(PPh3)2
PtCl2(COD)
35
60
35
4
6
10
44
61
87
Ͻ1:20
3.6:1
4:1
8
9
60
60
6
6
NR
NR
–
–
[a] Isolated yield combining 2a and 3a. [b] Determined by 1H NMR
spectroscopy of the crude mixture. [c] A catalyst loading of 2.5 mol-
% was used.
Entry
Crown ether
t [h]
Yield[a] [%]
2a/3a[b]
For metal-catalyzed intramolecular alkoxylation of 1,
two activation modes of the triple bond with the metal, that
is, cis activation and trans activation, are present in the reac-
tion process, which complicate the regioselectivity of the re-
action. As illustrated in Figure 1, for a cis activation case,
homopropargylic oxygen directed intramolecular alk-
oxylation might strongly prefer 8-endo-dig selectivity, as an
intramolecular version of the case illustrated in Scheme 1.
1
2
3
4
–
12-C-4
15-C-5
18-C-6
DCH-18-C-6
–
10
2
2
24
10
4
87
84
98
88
92
73
4:1
5.5:1
12:1
9:1
12:1
10:1
5
6[c]
[a] Isolated yield combining 2a and 3a. [b] Determined by 1H NMR
spectroscopy of the crude mixture. [c] Diglyme was used as the sol-
vent and no crown ether was added. DCH-18-C-6: dicyclohexyl-
Nevertheless, the inherent 7-exo/8-endo selectivity needs to 18-crown-6.
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Pt-Catalyzed Regioselective Formation of β-Alkoxy Ketones
To our delight, the introduction of a crown ether as the Actually, a platinum-catalyzed reaction in diglyme without
ligand did significantly promote the regioselectivity crown ether gave an excellent 10:1 regioselectivity (Table 2,
(Table 2). The ratio of 2a to 3a was as impressive as 12:1 Entry 6), indicating that diglyme may be able to act as a
when DCH-18-crown-6 and 15-crown-5 were used (Table 2, multidentate ligand as well as a mimic for a crown ether.
Entries 3–5). It deserves noting that the combination of Zei-
To clarify the scope of this intramolecular hydroalkoxyl-
se’s dimer with 15-crown-5 showed better catalytic activity, ation, a variety of substrates were examined (Table 3). The
probably because the incomplete enclosure of platinum by regioselectivity proved to be sensitive to the size of the sub-
15-crown-5 resulted in greater π acidity,[14] which made the stitution adjacent to the triple bond. When the substituent
triple bond more electrophilic and led to a quicker reaction. was switched from butyl to propyl then to ethyl, the ratios
of 2 to 3 diminished from 12:1 to 7:1 to 4:1 (Table 3, En-
tries 1–3). As for a phenylacetylene-derived substrate, the
regioselectivity could reach a ratio as good as 7:1 (Table 3,
Table 3. Substrate scope of platinum-catalyzed alkoxylation.
Entry 4). The substituent at the homopropargyl position
also played an important role on the selectivity. When the
phenyl group in 1a was replaced by a methyl group, the
exo/endo ratio dramatically decreased to 3:1 (Table 3, En-
try 5). However, the ratio increased to 12:1 again once a
substrate with a bulkier butyl group was tested (Table 3,
Entry 6). The electronic effects showed an obvious impact
on this reaction, which could be verified by varying the sub-
stituent on the phenyl ring. The results showed that sub-
strates with electron-deficient aromatic acetylenes afforded
more 7-exo-dig product, probably as a result of the lower
degree of stabilization of the positive charge at C-4. This
reaction could also be extended to 2-(phenylethylenyl)cyclo-
hexanol (1j) with moderate 2.6:1 to 4:1 regioselectivity
(Table 3, Entries 10 and 11). In addition, secondary and ter-
tiary alcohols, 1k and 1l, also proved to be suitable sub-
strates, showing good exo/endo selectivity. Major products
2k and 2l could be facilely transformed into β-hydroxy
ketones (Scheme 2) according to a known method,[15] which
reveals the potential application of this methodology.
Scheme 2. Conversion of the products into β-hydroxy ketones.
Conclusions
In general, we have developed an ether-tethered intramo-
lecular regioselective alkoxylation to form useful β-alkoxy
ketones in the presence of a catalytic amount of Zeise’s di-
mer and a crown ether. Detailed mechanistic investigations
and application of this methodology are underway in our
laboratory.
Experimental Section
1
General Procedure for the Platinum-Catalyzed Reaction: Under an
atmosphere of argon, a solution of Zeise’s dimer (2.5 mol-%,
2.3 mg) and 15-crown-5 (5 mol-%, 1.6 mg) in dry DME (1.5 mL)
[a] Isolated yield combining 2 and 3. [b] Determined by H NMR
spectroscopy of the crude mixture. [c] DCH-18-C-6 was employed
instead of 15-C-5.
Eur. J. Org. Chem. 2010, 4185–4188
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D. Yang, J. Huang, B. Liu
SHORT COMMUNICATION
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Acknowledgments
We appreciate financial support from the National Natural Science
Foundation of China (20702032, 20872098), the Ministry of Edu-
cation of China (IRT0846), and the Ministry of Science and Tech-
nology of China (2010CB833200). We also thank the Analytical &
Testing Center of Sichuan University for recording the NMR spec-
tra.
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Received: April 9, 2010
Published Online: June 23, 2010
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