A comparative study of the Au-catalyzed cyclization of hydroxy-substituted allylic alcohols and ethers

Article abstract of DOI:10.3762/bjoc.7.91

The Au(I)-catalyzed cyclization of hydroxyallylic ethers to form tetrahydropyrans is reported. Employing (acetonitrile)[(o-biphenyl) di-tert-butylphosphine]gold(I) hexafluoroantimonate, the cyclization reactions were complete within minutes to hours, depending on the substrate. The reaction progress was monitored by GC, and comparisons between substrates demonstrate that reactions of allylic alcohols are faster than the corresponding ethers. Additionally, it is reported that Reaxa QuadraPure MPA is an efficient scavenging reagent that halts the reaction progress.

Full text of DOI:10.3762/bjoc.7.91

A comparative study of the Au-catalyzed cyclization
of hydroxy-substituted allylic alcohols and ethers
Berenger Biannic, Thomas Ghebreghiorgis and Aaron Aponick*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 802–807.
Department of Chemistry, University of Florida, P.O. Box 117200,
Gainesville, FL 32611, U.S.A
doi:10.3762/bjoc.7.91
Received: 01 April 2011
Accepted: 24 May 2011
Published: 14 June 2011
Email:
Aaron Aponick* - aponick@chem.ufl.edu
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis".
Keywords:
allylic alcohol; allylic ether; Au-catalyzed; SN2'; tetrahydropyran
Guest Editor: F. D. Toste
© 2011 Biannic et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The Au(I)-catalyzed cyclization of hydroxyallylic ethers to form tetrahydropyrans is reported. Employing (acetonitrile)[(o-
biphenyl)di-tert-butylphosphine]gold(I) hexafluoroantimonate, the cyclization reactions were complete within minutes to hours,
depending on the substrate. The reaction progress was monitored by GC, and comparisons between substrates demonstrate that
reactions of allylic alcohols are faster than the corresponding ethers. Additionally, it is reported that Reaxa QuadraPureTM MPA is
an efficient scavenging reagent that halts the reaction progress.
Introduction
Saturated oxygen heterocycles are found in a wide variety of ysis, see [2-10]. Generally, only mild conditions are necessary
biologically interesting and structurally complex natural prod- and these processes are highly chemoselective. While the
ucts [1]. These compounds are typically densely functionalized typical substrates employed in these reactions effect transforma-
and contain numerous stereogenic centers. Many challenges for tions on alkyne, allene, and alkene moieties, recent reports from
the total synthesis of these molecules revolve around issues of our laboratory and others have demonstrated that unsaturated
selectivity and can be complicated by the presence of sensitive alcohols, such as allylic and propargylic alcohols, are reactive
functional groups. While cyclization reactions of highly elabo- substrates that readily participate in dehydrative formal SN2'
rated substrates are desirable, mild chemoselective methods are reactions [11-25]. The formation of tetrahydropyrans is easily
necessary for this endeavor.
accomplished with monoallylic diol substrates, as illustrated in
Scheme 1 [23-25]. The reactions are generally rapid and high
Homogeneous gold-catalyzed reactions have emerged as a yielding with low catalyst loading and can be carried out at low
powerful new methodology for the construction of a diverse reaction temperatures. Additionally, they are stereospecific, as
array of molecular architectures; for recent reviews on Au-catal- changing the olefin geometry provides enantiomeric products
802

Beilstein J. Org. Chem. 2011, 7, 802–807.
(Scheme 1, reaction 1 versus reaction 2) [25], and they are also Au-catalyzed cyclizations with different leaving groups that do
tolerant of highly substituted substrates (Scheme 1, reaction 3) not require deprotection, and data on the reaction progress that
[23].
allows comparison between leaving groups and cis- versus
trans-olefins.
Although these features are attractive from a synthetic point of
view, one potential disadvantage is that both the nucleophile Results and Discussion
and electrophile are alcohols that may require the introduction At the outset, one of the important goals was to be able to make
and cleavage of protecting groups in the preparation of more comparisons between how well different substrates function in
complex substrates. In the course of a synthetic project, we the reaction. Previous papers detail the results with diols and
required a monoallylic diol but encountered difficulty due to an include a variety of substrates with yields and reaction times
errant protecting group scheme. It was surmised that the [23-25]. While the isolated yield is the ultimate measure of how
problem would be solved if the allylic alcohol leaving group did well the system has performed, these data do not provide suffi-
not need to be revealed directly before the cyclization event. cient details to compare accurately between different classes of
This led us to consider the use of alternative substrates where substrates. We also sought to gain more insight into how fast
the allylic alcohol could be deprotected under the reaction the reaction proceeds and to be able to comment on catalyst
conditions, or the use of other “protecting groups” that would lifetime.
also serve as leaving groups and obviate the need for a separate
deprotection step. We reasoned that the best group to introduce To be consistent, we chose to study the simple system shown in
would be one that was not susceptible to cleavage by standard Scheme 2 and to vary the nature of the allylic leaving group and
deprotection conditions and therefore would only be removed olefin geometry. These conditions are slightly different to those
after the desired cyclization reaction. Since alcohols are usually employed in the study of diols [23-25], differing in catalyst
very poor leaving groups, but function extremely well in the identity and loading (1 mol % (Ph3P)AuCl/AgOTf versus
present system, it seemed likely that a fairly robust group could 5 mol % Au[P(t-Bu)2(o-biphenyl)]SbF6).
perform satisfactorily here. Additionally, calculations suggest
that in intermolecular hydroalkoxylation reactions of allenes the As mentioned above, the ability to follow the reaction progress
kinetic allylic ether products are isomerized by Au(I)-NHC was desired but this presented several practical challenges. As
complexes to the regioisomeric thermodynamic (and observed) the reactions are often complete within minutes, a continuous
products [26]. Successful implementation of such a strategy method of analysis would be necessary, or alternatively samples
would offer an alternative to the use of the highly successful could be collected over the course of the reaction with analysis
and well-established set of leaving groups employed in π-allyl- to follow. Initial experiments focused on using 1H NMR, but
metal chemistry [27-32]. Herein we report a study of this raised concerns due to the heterogeneous nature of the reac-
Scheme 1: Au-catalyzed cyclization reactions of monoallylic diols.
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Beilstein J. Org. Chem. 2011, 7, 802–807.
Scheme 2: Reaction conditions for the preparation of 8.
tion mixture, which contained molecular sieves to absorb the
water that was generated. Analysis by GC with decane as an
internal standard was then explored. A standard curve was
prepared with 8, but, due to the fact that Au-complexes are
fairly stable in air and moisture, a quenching method was
needed to obtain accurate results. In a typical experiment, the
reaction is generally filtered through a short plug of silica, but
for small aliquots (25 μL) this was not practical. Instead the
resin bound scavenging agent QuadraPureTM MPA 9 (Figure 1)
was employed.
Figure 2: Quenching experiments using 9. = quenched after 1 min;
= quenched after 3 min; = quenched after 5 min.
5 minutes, respectively. The reaction conditions were otherwise
identical to the reaction shown in black, which proceeded to
96% conversion, while the reactions quenched at 1, 3, and 5
minutes went to 23%, 41%, and 52% conversion, respectively.
Subsequently, a comparison between cis- and trans-diols 10 and
7 was made. As can be seen in Figure 3, both reactions were
fairly rapid, with the cis-diol 10 being only slightly faster in the
Figure 1: QuadraPureTM MPA.
To the best of our knowledge, scavenging reagents such as this
have not previously been employed in homogeneous Au-catal-
ysis and it was necessary to validate this method. In a typical
reaction, the goal was to quench aliquots by injecting them into
vials containing 9 suspended in CH2Cl2. For a detailed protocol
see the Supporting Information File 1. As a test, samples were
continually taken from the reaction illustrated in Scheme 2 and
treated with 9 until TLC analysis indicated that the reaction was
complete. GC analysis of the samples provided the data used to
construct the black curve shown in Figure 2, which shows the
expected behavior and was reproducible. As a control experi-
ment, a sample taken after 3 minutes was diluted with CH2Cl2,
but not exposed to the resin. After 16 h, the reaction had
proceeded to 95% conversion demonstrating that 9 is necessary
to halt the progress of the reaction. The precision of the analysis
also warrants comment. At several points throughout the reac-
tion, the same sample was analyzed 5 times. In each of these
sample sets, the range of percent conversion spanned approxi-
mately 2%. The standard deviation from the mean was 0.92%.
Figure 2 also demonstrates that the reactions can be quenched
with QuadraPureTM MPA. The curves in red, green, and blue
show the results of reactions that were quenched after 1, 3, and
Figure 3: Reaction progress in cis- and trans-diols. Conditions:
5 mol % Au[P(t-Bu)2(o-biphenyl)]SbF6, CH2Cl2, MS 4 Å.
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Beilstein J. Org. Chem. 2011, 7, 802–807.
initial period than 7. Interestingly, the reaction of 7 achieves
higher conversion overall, but both substrates have >90%
conversion after 25 minutes.
The methyl ethers 11 and 12 were explored and proved to be
suitable substrates (Figure 4). While these reactions were
slightly slower in the initial stages than the corresponding diols,
excellent conversions were achieved. This demonstrates that
methyl ethers fit the criteria described above. The methyl group
efficiently shields this functional group under a variety of
commonly used conditions and it can then act as a leaving
group under Au-catalyzed cyclization conditions.
Figure 5: A comparison of commonly used protecting groups. Condi-
tions: 5 mol % Au[P(t-Bu)2(o-biphenyl)]SbF6, CH2Cl2, MS 4 Å.
cis-cyclohexyl-substituted diols (not shown) provide the prod-
ucts in 96% and 92% isolated yields after 40 minutes, respect-
ively [23-25]. While cyclohexyl substituents significantly slow
the reaction, it is likely that other less sterically demanding
substituents will be better tolerated. This is currently under
investigation with more synthetically useful substrates.
Figure 4: Reaction progress in cis- and trans-methyl ethers. Condi-
tions: 5 mol % Au[P(t-Bu)2(o-biphenyl)]SbF6, CH2Cl2, MS 4 Å.
Several additional, commonly used, protecting groups were also
screened under the reaction conditions (Figure 5). From the
graph, it is apparent that benzyl (13), TBDPS (14), and THP
[33] (15) could all be used, but esters such as benzoyl (16) were
unsuitable. This may provide a basis for chemoselective trans-
formations, as allyl esters are readily ionized by Pd0 complexes
and the resulting π-allylpalladium species are alkylated by a
variety of nucleophiles [27,28].
Finally, 1° allylic and 2° allylic ether substrates were compared
(Figure 6). Substitution at the allylic position drastically slows
the reaction. Although the conversion of 17 and 18 is low on the
timescale shown, the reactions continue and after 48 h provide
acceptable, but moderate yields. The corresponding trans- and
Figure 6: Comparison of 1° and 2° allylic ethers. Conditions: 5 mol %
Au[P(t-Bu)2(o-biphenyl)]SbF6, CH2Cl2, MS 4 Å.
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Beilstein J. Org. Chem. 2011, 7, 802–807.
13.Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org. Lett. 2009, 11,
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Conclusion
In conclusion, it has been demonstrated that a variety of allylic
ethers undergo Au-catalyzed formal SN2' reactions to form
tetrahydropyrans. The reaction of allylic alcohols appears to be
faster, although the leaving group is traditionally not consid-
ered to be as good. Reactions of cis-substrates appear to be
slightly faster than the corresponding trans-allylic ethers. While
the difference is small, it suggests that it is better to prepare the
cis-substrates, and this is also very straightforward via a number
of different routes. Further studies on secondary allylic ethers
and on the application of the method in total synthesis are
ongoing and will be reported in due course.
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Supporting Information
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Supporting Information File 1
General procedures and characterization data for all new
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-91-S1.pdf]
24.Aponick, A.; Biannic, B. Synthesis 2008, 3356–3359.
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Acknowledgements
We gratefully acknowledge the Florida Department of Health,
James and Ester King Biomedical Research Program for
funding of this work (09-KN-01-23124). We thank Petra
Research, Inc. for the gift of starting materials and an unre-
stricted research award and Prof. Jon Stewart (UF) for assis-
tance with the GC analysis.
27.Tsuji, J. The Tsuji–Trost Reaction and Related Carbon–Carbon Bond
Formation Reactions: Overview of the Palladium–Catalyzed
Carbon–Carbon Bond Formation via π-Allylpalladium and
Propargylpalladium Intermediates. In Handbook of Organopalladium
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