Novel carbocationic rearrangements of 1-styrylpropargyl alcohols

Article abstract of DOI:10.3762/bjoc.11.114

The dehydration and subsequent cyclization reactions of 1-styrylpropargyl alcohols was examined. In the course of these studies, numerous scaffolds were synthesized, including a furan, a cyclopentenone, an acyclic enone and even a naphthalenone. The diversity of these structural motifs lies in novel cascades of reactions originating from a common carbocationic manifold.

Full text of DOI:10.3762/bjoc.11.114

Novel carbocationic rearrangements of
1-styrylpropargyl alcohols
Christine Basmadjian, Fan Zhang and Laurent Désaubry*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1017–1022.
Laboratory of Therapeutic Innovation (UMR 7200), University of
Strasbourg - CNRS, Faculty of Pharmacy, 67401 Illkirch, France
doi:10.3762/bjoc.11.114
Received: 10 March 2015
Accepted: 27 May 2015
Published: 15 June 2015
Email:
Laurent Désaubry* - desaubry@unistra.fr
* Corresponding author
Associate Editor: J. A. Murphy
Keywords:
© 2015 Basmadjian et al; licensee Beilstein-Institut.
License and terms: see end of document.
carbocationic rearrangement; cyclopentenones; furans; propargyl
alcohols
Abstract
The dehydration and subsequent cyclization reactions of 1-styrylpropargyl alcohols was examined. In the course of these studies,
numerous scaffolds were synthesized, including a furan, a cyclopentenone, an acyclic enone and even a naphthalenone. The diver-
sity of these structural motifs lies in novel cascades of reactions originating from a common carbocationic manifold.
Introduction
In the course of our medicinal program on a new class of anti- alternative to the Rautenstrauch rearrangement, the main
cancer agents [1-3], we developed a novel synthesis of limitation of which lies on the necessity to have the alcohol
cyclopentenones substituted by three different aryl groups esterified (Scheme 2) [8]. Indeed, in many cases, this esterifica-
(Scheme 1) [4]. This approach combines a molybdenum(VI)- tion occurs in low yield, or may even be impossible to achieve
catalyzed etherification of allylic alcohol with a gold(I)- [4,8,9].
catalyzed intramolecular cyclization process [5,6].
The importance of cyclopentenones as intermediates to the syn-
During the optimization process of this synthesis, we examined thesis of bioactive compounds prompted us to explore the syn-
several catalysts to transform allylic alcohol 1 into ether 2, thetic potential of this novel rearrangement of 1-styryl-
including Re2O7, which is described to efficiently catalyze this propargyl alcohols (Table 1). Toward this purpose, a number of
type of transformation [7]. Unexpectedly, instead of obtaining other substrates were synthesized from the readily prepared acyl
ether 2, we observed the formation of cyclopentenone 4 in chloride 5 and ketone 6 [4] (Scheme 3).
32% yield. We noticed that this reaction only occurs when
Re2O7 is heated at 45 °C for 15 minutes in MeOH prior to the Results and Discussion
addition of the substrate. As far as we know, this type of We began our study by applying the reaction conditions devel-
reaction has not been described before. It provides a useful oped for alcohol 1 using Re2O7 (1.5%), MeOH (8 equiv) at
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Beilstein J. Org. Chem. 2015, 11, 1017–1022.
Scheme 1: Described synthesis of cyclopentenone 4 using a combination of Mo(VI) and Au(I)-catalyzed reactions and serendipitous discovery of a
direct conversion of alcohol 1 into 4 [4].
thesis). Along with cyclopentenone 4, we observed the forma-
tion of furan 13 (27% isolated yield).
The proposed mechanism for this reaction is shown in
Scheme 4. Both 4 and 13 are expected to arise through the for-
mation of the stabilized carbocation 11 that may evolve through
two pathways. This intermediate may either undergo a ring
Scheme 2: The Rautenstrauch rearrangement.
closure due to the nucleophilic character of the silylated alkyne
(pathway A) or react with an oxygenated nucleophile, such as
45 °C in DCE (entry 1, Table 1). Gratifyingly, replacing the the perrhenate anion, to generate the transient intermediate 12
TMS group by a TBS group improved the yield to 44% (which that undergoes an oxo-cyclization to afford an oxonium en route
is superior to the overall yield of the previous three steps syn- to furan 13 (pathway B). Alternatively, intermediate 12 may
Scheme 3: Synthesis of 1-styrylpropargyl alcohols.
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Beilstein J. Org. Chem. 2015, 11, 1017–1022.
Table 1: Rearrangement of 1-styrylpropargyl alcohols 7–10, 15, and 16.
Entry
R
Isolated productsa
Yield (%)b
1
44
10c
4
27
20
13
2
15c
14
Ph
16c
3
4
35
54
17
18
H
7
n-Bu
8
5
6
47
31
19
20
9
aRe2O7 (1.5%), MeOH (8 equiv), 45 °C, DCE, 16 h. bIsolated yields. cSynthesis described in ref [4]. An = p-anisyl.
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Beilstein J. Org. Chem. 2015, 11, 1017–1022.
Scheme 4: Postulated mechanism for the formation of cyclopentenone 4 and furan 13 (entry 1, Table 1; An= p-anisyl).
result from the allylic [1,3]-transposition of a perrhenate ester ingly, substitution of the carbinol part by an n-butyl substituent
[10].
provided an alternate type of product: the acyclic enone was the
sole product isolated from the reaction medium (47% yield,
Replacement of the highly electron-donating 2,4,6- entry 5, Table 1). It could be envisioned that this compound
trimethoxyphenyl group by a 4-chlorophenyl substituent results from the rearrangement of an allene oxide (Scheme 5).
reduced the yield of cyclopentenone formation to 20% (entry 2, Interestingly the dipropargylic alcohol 9 afforded the rearranged
Table 1). No furan or other compound could be isolated. As a allylic ether 20 as the only isolated product (entry 6, Table 1).
result, we turned to the examination of substrate 16 [4], whose
unsubstituted phenyl ring is even less amenable to stabilize a In order to improve the yields of these reactions and gain
carbocationic intermediate. Unsurprisingly, we could not detect insight in the reaction mechanisms, we explored different reac-
any cyclopentenone. Instead, we were amazed to isolate the tion conditions starting from alcohol 21 (Table 2). 1,2-
rearranged ketone 17 (entry 3, Table 1). Indeed, 4,4-diarylnaph- Dichloroethane and dichloromethane (entries 1 and 2, Table 2)
thalen-1-ones are highly unusual compounds, whose synthesis gave better yields (27–31% for 22 and 10–16% for 23)
is rarely described in literature [11]. The structure of 17 was compared to THF (entry 3, Table 2). In an effort to understand
confirmed by NOE and key HMBC correlations (Figure S1, the role of Re2O7, the catalyst was changed to ReO4SiPh3
Supporting Information File 1). Although highly speculative (entry 5, Table 2) and ReO4H (entry 6, Table 2). In both cases,
and without any experimental support, a putative mechanism the results were similar to those obtained with Re2O7. Removal
for this unprecedented reaction is proposed in Supporting Infor- of methanol from the medium suppressed the formation of 22
mation File 1 (Scheme S1).
(entry 7, Table 2). In this case only furan 23 and rearranged
alcohol 25 could be isolated as traces (5%).
Remarkably, removal of the trimethoxyphenyl group
suppressed the formation of cyclopentanone but promoted the To confirm that the reaction is catalyzed by an acid, we changed
formation of furan 18 (54% yield, entry 4, Table 1). Interest- its nature and tested two Brønsted acids. With F3CSO3H (entry
Scheme 5: Proposed mechanism for the formation of enone 19.
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Beilstein J. Org. Chem. 2015, 11, 1017–1022.
Table 2: Optimization of the acid-catalyzed rearrangements of enynol 2.
Entry
R
Catalyst
Solvent
T (°C)
22 (%)a
23 (%)a
24 (%)a
25 (%)a
26 (%)a
1
2
CH3
CH3
CH3
CH3
CH3
CH3
–
Re2O7
Re2O7
DCE
CH2Cl2
THF
45
45
45
rt
31
27
11
12
28
30
–
16
10
9
–
–
–
–
6
–
–
–
–
–
–
–
–
–
–
–
–
3
Re2O7
12
4
–
4
Re2O7
THF
–
–
5
ReO4SiPh3
ReO4H
DCE
45
45
45
45
45
45
45
45
rt
17
17
5
–
–
6
DCE
–
–
7
ReO4H
DCE
5b
–
–
8
CH3
CH3
–
F3CSO3H
AcOH
DCE
36
–
12
–
–
9
DCE
51
–
47
–
10c
11c
11
12c
F3CSO3H
F3CSO3H
F3CSO3H
F3CSO3H
DCE
–
–
CF3CH3
CH3
CH3
DCE
–
–
–
–
CH3NO2
CH3NO2
30
–
–
–
–
–
–
–
aIsolated yields. bAn allylic alcohol is generated (25, R = H). cDegradation of the reaction mixture.
8, Table 2), we obtained comparable yields with 36% of To determine whether the protection of the alkyne group was
cyclopentenone 22 and 12% of furan 23. When using a weaker necessary for a rearrangement to take place, the reaction was
acid such as acetic acid (entry 9, Table 2) only the two acyclic carried out on compound 27. In the presence of perrhenic acid,
ethers 25 and 26 were isolated. This observation strongly 16% of the starting material was recovered along with 36% of
suggests that perrhenic acid is the active reagent generated from diketone 28 (Scheme 6). No cyclization product was isolated.
Re2O7 by methanolysis or hydrolysis with traces of water [12].
This observation strengthened the hypothesis that the silyl
group stabilizes the carbocation intermediate which seems
When removing methanol or replacing it with trifluoroethanol, necessary for the cyclization step.
the reaction mixture degraded in presence of triflic acid (entries
10 and 11, Table 2). Thus, the presence of methanol seems Conclusion
necessary for the cyclization to occur, perhaps by stabilizing an The discovery of new reaction manifolds often provides a good
intermediate. Replacement of dichloroethane by nitromethane opportunity to discover novel reactivity in related systems. In
slightly decreased the yield of 22, and suppressed the formation this article, we demonstrate the delicate balance among several
of furan 23.
mechanistic pathways by a minor change of substrate in acid-
Scheme 6: Rearrangement of unprotected propargylic carbinol 27.
1021

Beilstein J. Org. Chem. 2015, 11, 1017–1022.
catalyzed rearrangements of 1-styrylpropargyl alcohols. Indeed,
these compounds may generate a furan (18), an enone (19), an
allylic ether or even a naphthalenone (17). The formation of the
latter is quite intriguing because it suggests an unprecedented
cascade of reactions.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Supporting Information
Supporting Information File 1
Experimental procedures for the synthesis of compounds
7–9, 13, 14 and 17–28.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-114-S1.pdf]
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.11.114
Acknowledgements
L.D. was supported by the "Association pour la Recherche sur
le Cancer" (ARC). We are also grateful to AAREC Filia
Research and ANRT for fellowships to C.B.
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