Highly efficient and tunable synthesis of dioxabicyclo[4.2.1] ketals and tetrahydropyrans via gold-catalyzed cycloisomerization of 2-alkynyl-1,5-diols

Article abstract of DOI:10.1021/ol902215n

A highly efficient gold(l) chloride catalyzed cycloisomerization of 2-alkynyl-1,5-diol (1) to dioxabicyclo[4.2.1] ketal (2) and its further transformation to tetrahydropyran (3) are reported. The diol Is readily obtained by the reduction of 2-alkynyl-subs

Full text of DOI:10.1021/ol902215n

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5090-5092
Highly Efficient and Tunable Synthesis
of Dioxabicyclo[4.2.1] Ketals and
Tetrahydropyrans via Gold-Catalyzed
Cycloisomerization of 2-Alkynyl-1,5-diols
Le-Ping Liu* and Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky, 40292
leping.liu@louisVille.edu; gb.hammond@louisVille.edu
Received September 24, 2009
ABSTRACT
A highly efficient gold(I) chloride catalyzed cycloisomerization of 2-alkynyl-1,5-diol (1) to dioxabicyclo[4.2.1] ketal (2) and its further transformation
to tetrahydropyran (3) are reported. The diol is readily obtained by the reduction of 2-alkynyl-substituted glutarates, isolated from the Michael
addition of allenoates to methyl acrylate. These reactions proceeded smoothly under very mild conditions. A plausible mechanism for the
formation of the said tetrahydropyran from the corresponding ketal is proposed.
A contemporary challenge in organic synthesis is the mapping
of new chemical spaces through cascade reactions in an atom-
economical fashion. This effort requires robust building blocks
and powerful transition-metal-catalyzed processes. In this regard,
bicyclic ketals or their heterobicyclic counterparts1 are intriguing
structural motifs, not only from the perspective of chemical
diversity or biological potential2 but also because of the
stimulating transformations that they could engender. During
our investigations on the regioselective functionalization of
allenoates3 we pondered whether these could also open up a
manifold of nontrivial transformations, illustrated in Scheme
1. As can be seen from the disconnection strategy, bicyclo-
[m+1.n+1.0] or [m+1.n+1.1] compounds could be obtained
from transition-metal-catalyzed double cyclization reactions of
alkynes bearing two nucleophiles. The latter are easily prepared
from the corresponding allenoates using our reported procedure.3
Scheme 1
.
Disconnection of Heterobicyclic Systems Starting
from Functionalized Allenes
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Given gold’s affinity toward alkynes and allenes,4,5 we
envisaged that a gold-catalyzed cycloisomerization of un-
10.1021/ol902215n CCC: $40.75
Published on Web 10/08/2009
 2009 American Chemical Society

strained dioxabicyclic ketals6a and screened various gold salts
and other metal catalysts using 2-methyl-2-n-octynyl-1,5-
diol 1a, which is promptly obtained by LAH reduction of
the parent diester.3b
Scheme 2. Synthesis of 2-Alkynyl-1,5-diol 1 and Its
Transformations Through a Gold-Catalyzed Cycloisomerization
Table 1. Optimum Conditions for Cycloisomerization of
2-Alkynyl-1,5-diol 1a to Dioxabicyclo[4.2.1] Ketal 2aa
entry
catalyst
AuCl
AuCl3
AuBr3
(PPh3)AuOTfc
AgOTf
PtCl2
AuCl
AuCl
AuCl
AuCl
solvent
yield [%]b
1
2
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CHCl3
Toluene
THF
91
88
78
59
76
80
88
90
87
73
45
12
4
5d
6d
7
symmetrical 2-alkynyl-1,5-diols could lead to bicyclo[4.2.1]
ketals6 or functionalized tetrahydropyrans2a,b (Scheme 2).
The starting diols are readily obtained from the reduction of
2-alkynyl-substituted glutarates isolated from the Michael
addition of allenoates to methyl acrylate. Herein, we wish
to report that the gold-catalyzed cycloisomerization of
2-alkynyl-1,5-diols to dioxabicyclo[4.2.1] ketals can also be
directed toward the synthesis of the corresponding tetrahy-
dropyrans; all of these processes occur in high yields and
under mild conditions.
8
9
10
11
12
AuCl
AuCl
CH3CN
MeOH
a General conditions: 2-alkynyl-1,5-diol 1a 0.20 mmol, solvent 1.0 mL.
b Isolated yields. c In situ generated from the mixture of (PPh3)AuCl and
AgOTf. d Reaction time was prolonged to 24 h.
We took a cue from Genet and co-workers’ gold-catalyzed
cycloisomerization of bishomopropargylic diols to yield
To our satisfaction, with gold(I) chloride, the reaction
proceeded very smoothlysin dichloromethane at room
temperaturesand was completed in 10 min; the desired
dioxabicyclo[4.2.1] ketal 2a was isolated in 91% yield (Table
1, entry 1). Other metal catalysts as well as solvent effects
were investigated. Gold(III) chloride, gold(III) bromide, and
triphenylphosphine gold(I) triflate also catalyzed the cycloi-
somerization efficiently (Table 1, entries 2-4). Silver triflate
and platinum(II) chloride could catalyze the reaction too, but
in these cases prolonged reaction times (24 h) were needed
(Table 1, entries 5 and 6). The reaction with gold(I) chloride
proceeded smoothly in 1,2-dichloroethane, chloroform, tolu-
ene, and tetrahydrofuran (Table 1, entries 7-10). However,
in contrast with Genet’s report,6a the lowest yield was
obtained using methanol as the solvent (Table 1, entry 12),
perhaps due to the low stability of the product in the reaction
or isolation process.
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To examine the scope of this reaction, we investigated
other aliphatic and aromatic 2-alkynyl-1,5-diols 1. The results
are outlined in Table 2.
In all cases, the reactions proceeded smoothly under mild
conditions, and the desired products were isolated in moder-
(5) For selected recent articles on Au-catalyzed reactions of carbon-carbon
multiple bonds, see:(a) Escribano-Cuesta, A.; Lopez-Carrillo, V.; Janssen,
D.; Echavarren, A. M. Chem.sEur. J. 2009, 15, 5646. (b) Li, H.;
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Org. Lett., Vol. 11, No. 21, 2009
5091

1,5-diols, were employed in this interesting transformation,
and the tetrahydropyran products 3 were obtained in good
yields (Table 2).
Table 2. Gold-Catalyzed Cycloisomerization of
2-Alkynyl-1,5-diols 1 to Dioxabicyclo[4.2.1] Ketals 2 or
Tetrahydropyrans 3a
Scheme 3. Plausible Mechanism for the Transformation of
Dioxabicyclo[4.2.1] Ketal 2 to Tetrahydropyran 3
entry
R1/R2/R3/R4
x mol %/time
yield [%]b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
n-C6H13/Me/H/H 1a
t-Bu/Me/H/H 1b
1b
CypCH2/Me/H/H 1c
1c
C6H5/Me/H/H 1d
1d
p-CH3OC6H4/Me/H/H 1e
1e
6/24 h
2/10 min
6/24 h
2/10 min
6/24 h
2/10 min
6/24 h
2/10 min
6/24 h
2/10 min
6/24 h
2/10 min
2/10 min
2/10 min
2/10 min
2/10 min
2/10 min
3a, 91
2b, 52
3b, 52
2c, 87
3c, 83
2d, 84
3d, 88
2e, 80
3e, 86
2f, 77
3f, 65
2g, 46
2h, 75
2i, 82
2j, 86
2kc, 68
2ld, 79
p-ClC6H4/Me/H/H 1f
1f
Me/Me/H/H 1g
i-Pr/Me/H/H 1h
Bn/Me/H/H 1i
n-C6H13/Et/H/H 1j
n-C6H13/Me/C6H5/H 1k
n-C6H13/Me/H/Me 1l
A plausible mechanism for the gold-catalyzed transforma-
tion of dioxabicyclo[4.2.1] ketal 2 to tetrahydropyran 3 is
outlined in Scheme 3. Gold catalyst activates one of the
oxygen atoms to form the intermediate A or B, which may
rearrange to the oxonium intermediate C or D, respectively.
Both of the intermediates would undergo an intramolecular
attack to give intermediate E, which produces the tetrahy-
dropyran product 3 and regenerates the gold catalyst. We
asked ourselves if water could help in the transformation;
however, no rate differences were found using wet dichlo-
romethane or dry dichloromethane as the solvent, and the
reaction was retarded when 1 equiv of water was added to
the reaction mixture: no tetrahydropyran was found.
In summary, we have found a highly efficient gold(I)
chloride catalyzed cycloisomerization of 2-alkynyl-1,5-diol
to dioxabicyclo[4.2.1] ketal and its transformation to tet-
rahydropyran under very mild conditions. A plausible
mechanism for the formation of tetrahydropyran 3 has been
proposed. Other applications derived from this methodology
are under consideration.
a General conditions: 2-alkynyl-1,5-diols 1 0.20 mmol, AuCl 1.0 mg (2
mol %), CH2Cl2 1.0 mL, or 2-alkynyl-1,5-diols 1 0.20 mmol, AuCl 3.0 mg
(6 mol %), CH2Cl2 1.0 mL. b Isolated yields. c Mixture of diastereoisomers
in 1.4:1 ratio. d Mixture of diastereoisomers in 1:1 ratio.
1
ate to good yields. The H and 13C NMR spectra of the
reaction mixture showed that the reaction was completed
after 10 min, and the dioxabicyclo[4.2.1] ketal 2 was the
only product observed.
During these investigations, we also found that the
tetrahydropyran derivative 3a accompanied the formation of
2a when the reaction time was prolonged. Initially, we
thought that this rearrangement could be induced by acidic
conditions,7 but no tetrahydropyran was observed when
various Brønsted acids were employed to catalyze the
conversion of 2a to 3a. Using trifluoroacetic acid as the
catalyst, traces of 3a were found by TLC when the reaction
was conducted at 80 °C in toluene. Oxophilic transition metal
catalysts, such as PdCl2, PdCl2(CH3CN)2, and [Rh(cod)Cl]2,
were tested, but PdCl2(CH3CN)2 was the only effective
catalyst for the reaction (see Supporting Information). We
were pleasantly surprised to discover that tetrahydropyran
3a could be obtained in excellent yield by simply increasing
the gold catalyst loading and prolonging the reaction time.
Various substrates, both alphatic and aromatic 2-alkynyl-
Acknowledgment. We are grateful to the National Science
Foundation for financial support (CHE-0809683).
1
Supporting Information Available: The H and 13C
NMR spectroscopic data, MS, IR, and elemental analysis of
the new compounds shown in Tables 1 and 2 and a detailed
description of experimental procedures This material is
available free of charge via the Internet at http://pubs.acs.org.
(7) Frantisek, L.; Jiri, F.; Petr, T.; Miroslav, V. Collect. Czech. Chem.
Commun. 1989, 54, 3278.
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