Tuning the Reactivity of Functionalized Diallylic Alcohols: Br?nsted versus Lewis Acid Catalysis

Article abstract of DOI:10.1002/chem.201702601

The chemodivergent reactivity of bifunctional, enol thioether-containing diallylic alcohols in acidic medium is disclosed, highlighting the difference between strong Lewis acid and mild Br?nsted acid catalysis. In the presence of bismuth(III) triflate, allylic alcohol activation affords diversely substituted cyclopentenones in a Nazarov-type electrocyclization, whereas activation of the thioenol ether by p-toluenesulfonic acid provides an entry to α-sulfenylated β,γ-unsaturated ketones. Both methods represent a facile access to the corresponding products under mild conditions, using inexpensive and non-toxic catalytic systems.

Full text of DOI:10.1002/chem.201702601

A Journal of
Accepted Article
Title: Tuning the Reactivity of Functionalized Diallylic Alcohols:
Brønsted Acid vs. Lewis Acid Catalysis
Authors: Elisabet Dunach, Luisa Lempenauer, and Gilles Lemière
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201702601
Link to VoR: http://dx.doi.org/10.1002/chem.201702601
Supported by

10.1002/chem.201702601
Chemistry - A European Journal
COMMUNICATION
Tuning the Reactivity of Functionalized Diallylic Alcohols:
Brønsted Acid vs. Lewis Acid Catalysis
Luisa Lempenauer[a], Elisabet Duñach*[a] and Gilles Lemière*[a]
Abstract: The chemodivergent reactivity of bifunctional, enol
thioether-containing diallylic alcohols in acidic medium is disclosed,
highlighting the difference between strong Lewis acid and mild
Brønsted acid catalysis. In the presence of bismuth(III) triflate, allylic
alcohol activation affords diversely substituted cyclopentenones in a
Nazarov-type electrocyclization, whereas activation of the thioenol
ether by p-toluenesulfonic acid provides an entry to α-sulfenylated
β,γ-unsaturated ketones. Both methods represent a facile access to
the corresponding products under mild conditions, using inexpensive
and non-toxic catalytic systems.
Cyclopentenones are important structural motives present in a
wide range of natural products and powerful building blocks for
the preparation of diversely functionalized five-membered
carbocycles.[1] One of the most prominent strategies facilitating
Scheme 1. Work hypothesis: entry to diversely substituted cyclopentenones.
the construction of the cyclopentenone core by intramolecular
cationic-type cyclization is the classical Nazarov reaction of
divinyl ketones.[2] Other entries to cyclopentenone derivatives
making use of the characteristic oxyallyl cation are the
Rautenstrauch rearrangement of propargyl acetates[3] or the
Piancatelli rearrangement of furyl carbinols.[4] These electro-
cyclizations differ in the choice of the catalyst as well as the nature
of the activated functional group. Since the available methods for
cyclopentenone synthesis still suffer from limitations in terms of
scope and regioselectivity, the development of complementary
methods is of interest. To date, a limited number of methodologies
have been devised to convert readily available α,β-unsaturated
ketones into cyclopentenones by their transformation into
bis(allylic) alcohol derivatives. Tius and coworkers have
developed an elegant strategy lying in cyclizations of β-allenols[5],
but these reactions are restricted to the synthesis of α-alkylidene
cyclopentenones[6] and usually require several equivalents of
alcohol activating agents such as trifluoroacetic or
trifluoromethanesulfonic anhydride (Scheme 1). On the other
hand, the Rautenstrauch rearrangement allows for the synthesis
of cyclopentenones bearing a vicinal sp3 carbon. However, the
scope of this elegant transformation is limited, owing to the
difficulty to install the ester in the case of hindered tertiary alcohols
as well as the sensitivity towards steric constraints in the course
of the cyclization. In addition, 2 to 10 mol% of a noble metal-based
complex are usually required to promote the ester migration.
Recently, we reported a bismuth(III) triflate-catalyzed electro-
cyclic ring rearrangement of dihydropyran-containing diallylic
alcohols (Scheme 1).[7] The key step is the chemoselective
activation of an allylic alcohol in the presence of an enol ether and
the subsequent electrocyclization of the intermediate oxyallyl
cation.[8] The necessity of using a cyclic enol ether imposes the
presence of a hydroxypropyl side chain in the cyclized products
which could be quite restrictive. These results prompted us to
search for a more general approach from acyclic enol ether-
derived substrates to broaden the scope and structural diversity
of the obtained cyclopentenones. We present herein a straight-
forward entry to diversely substituted cyclopentenones by the
direct cyclization of unactivated diallylic alcohols using a cheap,
green and reusable Lewis acid catalyst. The cyclization
precursors are easily accessible from α,β-unsaturated ketones by
simple addition of the lithiated form of a commercially available
vinyl sulfide (Scheme 1).[9]
We anticipated, that allylic alcohols of type 1 could generally
exhibit different behaviors according to the activation site
(Scheme 2).
[a]
L. Lempenauer, Dr. E. Duñach, Dr. G. Lemière
Université Côte d’Azur
Institut de Chimie de Nice, CNRS
Parc Valrose, 06108 Nice Cedex 2 (France)
Email : dunach@unice.fr, gilles.lemiere@upmc.fr
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. (Thio)enol ether vs. allylic alcohol activation.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702601
Chemistry - A European Journal
COMMUNICATION
Heterolytic cleavage of the hydroxyl group by allylic alcohol
activation may trigger an electrocyclization and expulsion of the
leaving group may then furnish the cyclopentenone (path a). The
competing electrophilic activation of the (thio)enol ether is
expected to initiate a semipinacol rearrangement of a carbenium
intermediate with 1,2-migration of the vinyl group and formation of
a quarternary carbon (path b).[10] This double reactivity could
possibly enable the access to two different product classes from
a single starting material, given that appropriate conditions were
found to chemoselectively activate one function or the other.
During a preliminary evaluation it was noted, that deactivated
aromatic vinylsulfide 1a (R = SPh) displayed a promising, more
tunable reactivity and was thus chosen as the model substrate for
an optimization study (Table 1).
While in less polar THF (entry 7) and toluene (entry 8), the rate
decreased considerably, the product ratio was not much affected.
When the slightly more polar dichloroethane was used, selectivity
shifted in favor of the cyclization and 2a was formed in 69% yield
(entry 9). Acetonitrile was finally identified as the solvent of choice
to efficiently suppress enol thioether activation (entry 10).
From a mechanistic point of view, two observations were made:
(i) While complete conversion of 1a was stated after a few minutes,
a longer reaction time was required to reach the maximum
concentration of 2a, suggesting a stable intermediate en route to
the final cyclopentenone. (ii) Addition of three equivalents of water
resulted in a further improvement of the cyclization reaction and
3a was formed in 91% yield (Table 1, entry 11). Based on these
findings, we propose that initial alcohol elimination and
electrocyclization of B occur rapidly and that proton elimination
from allylic cation C leads to the formation of a stable intermediate
of type D. Slow hydrolysis of D as the rate limiting step finally
furnishes cyclopentenone 2a (Scheme 3).[13]
Table 1. Screening of reaction conditions.
Yield of
2a/3a (%)[c]
Entry
Catalyst[a]
Solvent
Time (h)[b]
1
2
Bi(OTf)3
Al(OTf)3
Sc(OTf)3
In(OTf)3
p-TsOH
TfOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0.5
30
51/19
42/18
43/22
42/21
20/69
49/17
55/26
47/15
69/15
75/1
3
24
4
30
5
0.5
0.5
1.0
5.0[d]
1.0
1.0
1.0
6
Scheme 3. Proposed mechanism for the electrocyclization of 1a.
7
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
8
Toluene
Cl(CH2)2Cl
CH3CN
CH3CN[e]
Gratifyingly, D could be isolated in a non-optimized 62% yield
when the catalyst loading was reduced to 1 mol% and MgSO4
was added to trap the released water, impeding hydrolysis.
In order to explore the scope of this novel electrocyclization,
diverse diallylic alcohols 1a-p were prepared and subjected to the
optimized conditions (Table 2). A range of α,β-dialkylsubstituted
allylic alcohols 1a-d cyclized readily and afforded the
corresponding cyclopentenones 2a-d in good yields (entries 1-4).
Introduction of an additional unsaturation in alcohol 1c derived
from (S)-(–)-perillaldehyde (entry 3) did not have any impact on
the cyclization and cyclopentenone 2c was obtained in 80% yield
as a single diastereomer, indicating a highly stereoselective
hydrolysis of the intermediate cyclopentadiene of type D (Scheme
2). The methyl group at the C1-carbon could be replaced by a
longer alkyl chain, affording 2d from cyclization of 1d (entry 4).
Equally good results were obtained with alcohol 1e, bearing a β-
phenyl group (entry 5). Remarkably, the additional enol ether in
diallylic alcohol 1f did not interfere with thioenol ether-activation
under the Bi(OTf)3-catalyzed conditions and gave the expected
methoxy-substituted cyclopentenone 2f in 72% yield (entry 6).
The structural diversity could be further enlarged using alcohols
derived from cyclic enones (entries 7-10). Cyclohexanol
derivatives 1g and 1h bearing a phenyl and isopropyl group, as
9
10
11
91/1
[a] General screening procedure: 5 mol% of catalyst were added to a 0.1 M
solution of 1a in anhydrous solvent at room temperature. [b] Time until
complete conversion of 1a. [c] GC-yields. [d] Complete conversion was not
reached. [e] 3.0 equivalents of water were added.
A range of metal triflates afforded a mixture of products 2a and 3a
in an approximate 2:1 ratio (entries 1-4). The highest yield for 2a
was reached with Bi(OTf)3 and the reaction was complete after 30
minutes (entry 1). Other metal triflates gave slightly lower yields
and required longer reaction times (entries 2-4). Interestingly, the
chemoselectivity was inverted by the use of p-toluenesulfonic acid,
giving 3a as the major product (entry 5). Unexpectedly, triflic acid
(entry 6) however gave similar results as the corresponding metal
salts but was not further pursued due to its corrosiveness.[11]
Inexpensive, non-toxic[12] and easy-to-handle bismuth(III) triflate
was chosen for further optimization of the reaction conditions. The
product selectivity was found to be dependent on solvent effects.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702601
Chemistry - A European Journal
COMMUNICATION
Table 2. Scope of the Bi(OTf)3-catalyzed cyclization of alcohols 1.
Entry
1
Substrate
Product
Yield (%)[a]
Entry
9
Substrate
Product
Yield (%)[a]
75
87
2
3
79
10
11
81
80[b]
53[c]
4
69
12
52[c]
5
6
7
78
72
77
13
14
15
69[c]
53[c]
77% (E)[c]
38% (Z)[c]
8
83
16
87%[c],[d]
[a] Isolated yields. [b] 2c was obtained as a single diastereomer from a 1:1 diastereomeric mixture of 1c. The absolute configuration was determined by 1H-
NOESY correlations. [c] The reaction was conducted at 60 °C. [d] 1p was used as a mixture of diastereomers with respect to the configuration of the thioenol
ether (dr = 7:1, determined by gas chromatography); 2p was obtained as a mixture of diastereomers dr (trans:cis) = 6:1.
well as cycloheptanol 1i, led to the corresponding products in
excellent yields (entries 7-9). To our delight, the methodology
could be successfully extended to challenging β,β-disubstituted
substrates 2j-2o (entries 11-15), which represent one of the
limitations of the Rautenstrauch rearrangement. In these cases,
heating (60 °C) was required to promote the cyclization.
Pulegone-derived precursor 1j, featuring a tetrasubstituted olefin,
readily afforded bicyclic enone 2j with the final double bond
placed at the fused ring junction (entry 10). In the same manner,
cyclohexylidene derivative 1k, alkyl-substituted alcohols 1l and
1m and benzylic alcohol 1n gave the corresponding cyclic and
spirobicyclic ketones 2k-n in satisfactory 52-69% yields (entries
11-14). Additional substituents at the termini of the π-system
involved in the electrocyclization induce steric constraints,
especially in the case of internal β-substituents, where the
required planar configuration of the pentadienyl cation suffers
from strong steric hindrance.[14] This was demonstrated for
phenyl-substituted precursor 1o, where the (Z)-isomer afforded
cyclopentenone 2o in 77% yield, whereas (E)-1o reacted
reluctantly even at elevated temperature and led only to 38% of
cyclized product (entry 15). Satisfactorily, substituents on the
thioenol ether β-carbon are compatible with the cyclization. Alkyl-
substituted thioenol ether 1p cyclized readily and tetrasubstituted
cyclopentenone 2p was obtained in 87% yield as a 6:1-mixture of
diastereomers (entry 16).
As mentioned above, changing from strongly Lewis acidic
bismuth(III) triflate to mildly acidic protic medium had a significant
effect on the chemoselectivity of the reaction (Table 1, entries 5
vs. 11). In the presence of 5 mol% p-toluenesulfonic acid a
selection of (bis)allylic alcohols of type 1 underwent the
semipinacol rearrangement and afforded α-sulfenylated ketones
3 in good to excellent yields under mild conditions (Table 3).
In summary, the reactivity of challenging, bifunctional substrates
was investigated. It was shown, that the chemoselectivity of
substrate activation can be tuned by the choice of the catalyst and
two different products are directly available from a single starting
This article is protected by copyright. All rights reserved.

10.1002/chem.201702601
Chemistry - A European Journal
COMMUNICATION
Table 3. Scope of semipinacol rearrangement of alcohols 1.[a]
S. E. Lewis, N. Mainolfi, J. Organomet. Chem. 2004, 689, 3873–3890; d)
S. M. Roberts, M. G. Santoro, E. S. Sickle, J. Chem. Soc., Perkin Trans.
1 2002, 1735–1742;
Entry
1
Substrate
Product
Yield (%)[b]
[2]
[3]
I. N. Nazarov, I. I. Zaretskaya, Izv. Akad. Nauk. SSSR, Ser.Khim. 1941,
211–224. For more recent reviews, see: a) D. R. Wenz, J. R. de Alaniz,
Eur. J. Org. Chem. 2015, 23–37; b) T. Vaidya, R. Eisenberg, A. J.
Frontier, ChemCatChem 2011, 3, 1531–1548.
63
a) C. Bürki, A. Whyte, S. Arndt, A. S. K. Hashmi, M. Lautens, Org. Lett.
2016, 18, 5058–5061; b) W. Zi, H. Wu, F. D. Toste, J. Am. Chem. Soc.
2015, 137, 3225–3228; c) O. N. Faza, C. S. Lopez, R. Alvarez, A. R. de
Lera, J. Am. Chem. Soc. 2006, 128, 2434–2437; d) X. Shi, D. Gorin, F.
D. Toste, J. Am. Chem. Soc. 2005, 127, 5802–5803; e) P. A. Caruana,
A. J. Frontier, Tetrahedron 2007, 63, 10646–10656; f) V. Rautenstrauch,
J. Org. Chem. 1984, 49, 950–952.
2
3
67
80
[4]
a) L. Marin, V. Gandon, E. Schulz, D. Lebœuf, Adv. Synth. Catal. 2017,
359, 1157–1163; b) H. Li, R. Tong, J. Sun, Angew. Chem. Int. Ed. 2016,
55, 15125–15128; c) Y. Cai, Y. Tang, I. Atodiresei, M. Rueping, Angew.
Chem. Int. Ed. 2016, 55, 14126–14130; d) D. Lebœuf, E. Schulz, V.
Gandon, Org. Lett. 2014, 16, 6464–6467-1163; e) G. Piancatelli, A.
Scettri, S. Barbadoro, Tet. Lett. 1976, 17, 3555–3558.
4
98[c]
[5]
[6]
a) L. Wan, M. A. Tius, Org. Lett. 2007, 9, 647–650; M. A. Tius, D. J.
Drake, Tetrahedron 1996, 52, 14651–14660; b) M. A. Tius, S. Trehan, J.
Org. Chem. 1989, 54, 46–51; c) M. A. Tius, D. P. Astrab, A. H. Fauq, J.-
B. Ousset, S. Trehan, J. Am. Chem. Soc. 1986, 108, 3438–3442.
For an exception, see: P. E. Harrington, L. Li, M. A. Tius, J. Org. Chem.
1999, 64, 4025–4029.
5
6
7
71
92
84
[7]
[8]
L. Lempenauer, E. Duñach, G. Lemière, Org. Lett. 2016, 18, 1326–1329.
For the use of allylic alcohols in Nazarov-type reactions, see: a) Z. Wang,
X. Xu, Z. Gu, W. Feng, H. Qian, Z. Li, X. Sun, O. Kwon, Chem. Comm.
2016, 52, 2811–2814; b) H. Yamamoto, D. L. Usanov, Org. Lett. 2012,
14, 414–417; c) X. Liu, X. Xu, L. Pan, Q. Zhang, Q. Liu, Org. Biomol.
Chem. 2013, 11, 6703–6706; d) R. L. Halterman, A. Tretyakov,
Tetrahedron 1995, 51, 4371–4382; e) D. Dytnerski, K. Ranganayakulu,
B. P. Singh, T. S. Sorensen, J. Org. Chem. 1983, 48, 309–315.
a) M.-G. Braun, B. Quiclet-Sire, S. Z. Zard, J. Am. Chem. Soc. 2011, 133,
15954–15957; b) H. D. Verkruijsse, L. Brandsma, P. Von R. Schleyer, J.
Organomet. Chem. 1987, 99-103.
[a] Conditions: 5 mol% of pTsOH were added to a stirred solution of alcohols
1 in anhydrous CH2Cl2 (0.1 M) at room temperature. [b] Isolated yields. [c]
1l and 3l: dr (E/Z) = 5:1.
[9]
material. A new, efficient and versatile entry to substituted
cyclopentenones in two steps from readily available α,β-
unsaturated ketones was developed. The key electrocyclization is
catalyzed under mild conditions by inexpensive and non-toxic
bismuth(III) triflate, in wet solvent and without the need for inert
conditions. The final cyclopentenone is generated in situ through
hydrolysis of a sulfenyl-diene intermediate, which can be isolated
and constitutes a synthetically useful precursor for further
functionalization of the cyclopentadiene core. Finally, switching
from a strong Lewis acid to a mild Brønsted acid catalyst led to a
totally different scenario where α-sulfenylated β,γ-unsaturated
ketones, difficult to make by other methods,[15] are obtained.
[10] For selected examples of electrophile-promoted semipinacol rearrange-
ments involving enol ethers, see: a) Z.-M. Chen, W. Bai, S.-H. Wang, B.-
M. Yang, Y.-Q. Tu, F.-M. Zhang, Angew. Chem. Int. Ed. 2013, 52, 9781–
9785; b) Z.-M. Chen, Q.-W. Zhang, Z.-H. Chen, H. Li, Y.-Q. Tu, F.-M.
Zhang, J.-M. Tian, J. Am. Chem. Soc. 2011, 133, 8818–8821; c) Q.-W.
Zhang, C.-A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao, P. Gu, Z.-M. Chen,
Angew. Chem. Int. Ed. 2009, 48, 8572–8574; d) L. A. Paquette, D. R.
Owen, R. T. Bibart, C. K. Seekamp, A. L. Kahane, J. C. Lanter, M.
Alvarez Corral, J. Org. Chem. 2001, 66, 2828–2834; e) L. A. Paquette,
J. C. Lanter, J. N. Johnston, J. Org. Chem. 1997, 62, 1702–1712.
[11] The role of triflic acid in reactions catalyzed by metal triflates is still a
matter of debate. See leading references: a) J. Godeau, F. Fontaine-
Vive, S. Antoniotti, E. Duñach, Chem. Eur. J. 2012, 18, 16815–16822; b)
R. F. Lambert, R. J. Hinkle, S. E. Ammann, Y. Lian, J. Liu, S. E. Lewis,
R. D. Pike, J. Org. Chem. 2011, 76, 9269–9277; c) T. T. Dang, F. Boeck,
L. Hintermann, J. Org. Chem. 2011, 76, 9353–9361; d) A. Dzudza, T. J.
Marks, Chem. Eur. J. 2010, 16, 3403–3422; e) D. C. Rosenfeld, S.
Shekhar, A. Takemiya, M. Utsunomiya, J. F. Hartwig, Org. Lett. 2006, 8,
4179–4182; f) T. C. Wabnitz, J.-Q. Yu, J. B. Spencer, Chem. Eur. J.
2004, 10, 484–493.
Acknowledgements
We thank the French Ministry of Research and Education for the
PhD grant to L. L..
[12] R. Mohan, Nat. Chem. 2010, 2, 336–336.
[13] In
a control experiment using TfOH in dry acetonitrile at room
Keywords: bismuth(III) triflate • electrocyclization • cyclo-
pentenone • chemodivergence • α-sulfenylated ketones
temperature, neither 2a nor 3a were observed and the reaction led to
exclusive formation of intermediate D. Addition of water (3.0 eq.) resulted
in a maximum yield of 23% (GC) of 2a after 15 hours.
[14] S. E. Denmark, R. C. Klix, Tetrahedron 1988, 44, 4043–4060.
[1]
a) S. P. Simeonov, J. P. M. Nunes, K. Guerra, V. B. Kurteva, Carlos A.
M. Afonso, Chem. Rev. 2016, 116, 5744–5893; b) D. Aitken, H. Eijsberg,
A. Frongia, J. Ollivier, P. P. Piras, Synthesis 2014, 46, 1–24; S. P. Roche,
D. J. Aitken, Eur. J. Org. Chem. 2010, 2010, 5339–5358; c) S. E. Gibson,
̈
[15] a) A. Cadu, R. A. Watile, S. Biswas, A. Orthaber, P. J. R. Sjoberg, J. S.
M. Samec, Org. Lett. 2014, 16, 5556−5559; b) S. Biswas, R. A. Watile,
J. S. M. Samec, Chem. Eur. J. 2014, 20, 2159−2163.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702601
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
Luisa Lempenauer, Elisabet Duñach,
Gilles Lemière
Page No. – Page No.
Tuning the Reactivity of
Functionalized Diallylic Alcohols:
Brønsted Acid vs. Lewis Acid
Catalysis
Chemoselectivity tuned by the catalyst: the chemodivergent reactivity of
bifunctional enol thioether-containing diallylic alcohols is described, hereby
highlighting the difference between mild Brønsted acid and strong Lewis acid
catalysis.
This article is protected by copyright. All rights reserved.