Efficient synthesis of 4-hydroxycyclopentenones: Dysprosium(III) triflate catalyzed Piancatelli rearrangement

Article abstract of DOI:10.1016/j.tet.2014.03.007

4-Hydroxycyclopentenones represent a privileged scaffold in chemical synthesis. A dysprosium(III) trifluoromethanesulfonate catalyzed rearrangement of furylcarbinols to 4-hydroxycyclopentenones via a 4π electrocyclization has been developed. The catalytic Piancatelli rearrangement affords a single trans-diastereomer from both aryl and alkyl substituted furylcarbinols.

Full text of DOI:10.1016/j.tet.2014.03.007

Tetrahedron xxx (2014) 1e6
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of 4-hydroxycyclopentenones: dysprosium(III)
triflate catalyzed Piancatelli rearrangement
*
David Fisher, Leoni I. Palmer, Jonathan E. Cook, Jessica E. Davis, Javier Read de Alaniz
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Hydroxycyclopentenones represent a privileged scaffold in chemical synthesis. A dysprosium(III) tri-
Received 16 January 2014
Received in revised form 28 February 2014
Accepted 3 March 2014
Available online xxx
fluoromethanesulfonate catalyzed rearrangement of furylcarbinols to 4-hydroxycyclopentenones via
a 4
p electrocyclization has been developed. The catalytic Piancatelli rearrangement affords a single
trans-diastereomer from both aryl and alkyl substituted furylcarbinols.
Published by Elsevier Ltd.
1. Introduction
structure has become a privileged building block that has been used
to access a wide array of natural products and biologically active
molecules (Fig. 1).2 Among the various methods available to access
the 4-hydroxycyclopentenone core, the Piancatelli rearrangement
The chemistry of 4-hydroxycyclopentenones was fueled in the
1980s by the synthesis of prostaglandins.1 Over the years this core
O
O
O
H
CH3
O
N
H
OH
HO
H
O
O
O
H
Piancatelli rearrangement
HO
H3C
HO
O
F
HO
F
3
bimatoprost
4
5
arglabin
1-step
steps
R
R
lubiprostone
O
O
OH
O
OH
1
2
O
H
O
O
HO
OH
OH
H
O
O
F3C
OH
HO
HO
N
6
7
8
didemnenone A
travoprost
daphnipaxianines A-B
Proposed mechanism of the Piancatelli rearrangement
LA
O
O
H
2
H2O
OH
3
1
O
R
R
R
H2O
O
4
con.
+
O
1
O
O
B
HO
C
H
4
5
OH
R
R
R
HO
R
HO
R
OH
HO
9
HO–LA
A
D
E
2
H
Fig. 1. Representative applications of the Piancatelli rearrangement for the synthesis of 4-hydroxycyclopentenones.
discovered in 1976 remains one of the most direct.3 The cascade
rearrangement transforms a furylcarbinol into a substituted 4-
hydroxycyclopentenone in one-step. The reaction is believed to
proceed through a series of cascading events that terminates with
* Corresponding author. E-mail address: javier@chem.ucsb.edu (J. Read de
Alaniz).
0040-4020/$ e see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.03.007
Please cite this article in press as: Fisher, D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.007

2
D. Fisher et al. / Tetrahedron xxx (2014) 1e6
a 4
p
electrocyclic ring closure of a pentadienyl cation (D),4 analo-
of strategies used for the synthesis of biologically active molecules
that rely on the Piancatelli rearrangement and the current limita-
tions, we directed our efforts toward developing a catalytic cascade
rearrangement using Dy(OTf)3. We envisioned that the milder
catalytic conditions would be compatible with more functionalized
substrates and would result in the exclusive formation of kinetic
isomer 2, which could be transformed into the thermodynamic
isomer 9 under known conditions if desired. It’s important to note
that the initial inspiration for studying the catalytic activity of
Dy(OTf)3 came from a pioneering report by Batey and co-workers in
2007.10 In this report they demonstrated the synthetic potential of
rare earth Lewis acids, including Dy(OTf)3, in a related rearrange-
ment of furfural.
Our initial optimization studies evolved from an observation
made while investigating the oxa-Piancatelli rearrangement.9c,9d
During these studies 4-hydroxycyclopentenone 16 was observed
in 52% yield when 10 equiv of i-PrOH was added to 2-furylcarbinol
15 in the presence of 5 mol % Dy(OTf)3 and heated to 60 ꢀC in
acetonitrile (Scheme 2).
The preference for addition by water, generated in situ during
the formation of oxocarbenium ion A (Fig. 1), in the presence of
excess i-PrOH was surprising as in the aza-Piancatelli reaction
water could be used as a co-solvent without observation of the 4-
hydroxycyclopentenone product. Encouraged by the ability to use
catalytic conditions and based on the importance of 4-
hydroxycyclopentenones as intermediates in synthesis, we de-
cided to explore the rearrangement with water in more detail. The
results from these studies are described herein.
We elected to start by screening alcohol additives in the pres-
ence of water as a co-solvent (Table 1). In all cases examined the
addition of an alcohol had a positive effect on the efficiency of the
Piancatelli rearrangement. Even though the reaction benefited from
the use of phenols, we decided to pursue the use of i-PrOH and t-
BuOH. These alcohols are advantageous for synthesis due to their
low cost and ease of purification. Further optimization revealed
that 10 mol % Dy(OTf)3 in a solvent mixture of t-BuOH/H2O (5:1) at
80 ꢀC gave the best results (entry 8). A side product originating
from i-PrOH acting as a nucleophile was observed when a solvent
system of i-PrOH/H2O (5:1) was used. We never observed any side
product originating from the addition of t-BuOH probably due to its
steric bulk preventing nucleophilic attack. In the absence of an al-
cohol additive the reaction was more sluggish and lower yielding
(entry 10).
gous to the Nazarov cyclization.5 Some of the current drawbacks
with the Piancatelli rearrangement are the use of stoichiometric
quantities of Brønsted or Lewis acid, the product is often isolated in
low yield (40e55%), and the acid catalyzed reaction can result in
the formation of polymeric material that may be difficult to remove,
especially on scale.6 Moreover, the rearrangement often results in
an inseparable mixture of 4-hydroxycyclopentenone isomers (2
and 9), which are typically processed through a second rear-
rangement step into the thermodynamically more stable isomer
(9).
Despite these challenges, the Piancatelli rearrangement still
remains a highly attractive method that is widely used in academia
and industry. For example, Henschke and co-workers demon-
strated the utility of the cascade rearrangement as an integral part
in their strategy for the synthesis of a 4-hydroxycyclopentenone
(12), a common intermediate from which several active pharma-
ceutical ingredients could be accessed.7 The reaction was con-
ducted on multi kilogram scale with superstoichiometric quantities
of ZnCl2 (16 equiv) and despite optimization the reaction resulted
in a 1.0:1.1 mixture of cyclopentenone isomers that were converted
to the thermodynamic isomer in 55% yield over two steps. Recently,
Reiser and co-workers have demonstrated that the Piancatelli
rearrangement can be accelerated at high temperature (240 ꢀC) and
pressure (1000 psi) using a microreactor.8 Under these conditions
higher yields and shorter reaction times were observed. Clearly,
progress is being made in further improving the Piancatelli rear-
rangement however Scheme 1, more research is still required to
reduce the catalyst loading, increase the efficiency and avoid the
formation of cyclopentenone isomer mixtures.
Piancatelli rearrangement: Henschke and co-workers: ref. 7
i-PrO2C
i-PrO2C
i-PrO2C
O
O
ZnCl2
+
O
H2O/Dioxane
OH
OH
HO
11
12
10
ratio = 1.0 : 1.1
Piancatelli rearrangement: Reiser and co-workers: ref. 8
O
O
240 °C,
1000 psi
R
R
R
+
O
H2O
With the optimized reaction conditions in hand, we then in-
vestigated the substrate scope with furylcarbinols substituted with
an aryl group at the 2-position (Scheme 3). Short reaction times and
excellent yields were observed in all cases. Heteroaromatic groups,
such as thiophene 23 were also well tolerated in the reaction. Im-
portantly, the products were isolated exclusively as the trans-di-
OH
OH
OH
1
13
2
ratio = 5–12 : 1
Scheme 1. Recent examples of the Piancatelli rearrangement.
2. Results and discussion
astereomer, which is consistent with the proposed conrotatory 4
electrocyclization (Fig. 1).
p
In our efforts to develop new methods for the synthesis of
substituted cyclopentenones, we recently demonstrated that dys-
prosium triflate (Dy(OTf)3) was an excellent catalyst for the aza-
and oxa-Piancatelli rearrangements.9 These cascade rearrange-
ments were shown to be compatible with aniline and alcohol nu-
cleophiles using 5 mol % Dy(OTf)3 as the catalyst. Given the number
After successfully demonstrating the generality of the Dy(OTf)3
catalyzed Piancatelli reaction with furylcarbinols bearing aromatic
side-chains, we turned our attention to investigate the reaction
with aliphatic side-chains. Disappointingly, the rearrangement
with n-butylfurylcarbinol was exceedingly sluggish and extensive
decomposition was observed. Because prostaglandin analogues
i-Pr
i-Pr
i-Pr
i-Pr
O
O
i-Pr
i-Pr
5 mol % Dy(OTf)3
+
+
OH
O
MeCN, 60 ºC
i-Pr
OH
i-Pr
OH
i-Pr
10 equiv
O
14
15
16
ratio ~ 1:1
17
Scheme 2. Formation of 4-hydroxycyclopentenone via the oxa-Piancatelli rearrangement.
Please cite this article in press as: Fisher, D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.007

D. Fisher et al. / Tetrahedron xxx (2014) 1e6
3
Table 1
but 30 mol % resulted in decomposition. Switching to other sources
of dysprosium, such as Dy(Cl)3 and Dy(OAc)3, proved unsuccessful
(entries 3 and 4). The use of slightly more Lewis acidic Sc(OTf)3
(10 mol %) resulted in 53% yield, but decomposition was still ex-
tensively observed. Unfortunately, under the t-BuOH/H2O (5:1)
solvent mixture stoichiometric ZnCl2 proved ineffective and cata-
lytic trifluoroacetic acid resulted in only modest success (Table 2,
entries 6e8). To our gratification, we found that utilizing a com-
bination of Dy(OTf)3 (10 mol %) and TFA as co-catalysts (5 mol %)
dramatically increased the yield and efficiency (entry 9). Yin and
co-workers also observed that a combination of Lewis and
Brønsted acid afforded optimal results for a related rearrange-
ment.11 A small Brønsted acid screen: potassium dihydrogen
phosphate, acetic acid, phosphoric acid, trifluoromethanesulfonic
acid, and hydrochloric acid, at 5 mol % in combination with
10 mol % Dy(OTf)3 was performed, however, the combination of
TFA with Dy(OTf)3 proved optimal. It is interesting to note that the
efficiency of the Dy(Cl)3 and Dy(OAc)3 catalyzed reaction was also
improved by the addition of 5 mol % TFA, albeit to a smaller extent
(compare entries 3 and 4 to 10 and 11). Further studies are cur-
rently underway to fully elucidate the beneficial effect of the TFA
additive. With optimized reaction conditions (entry 9) in hand for
the rearrangement of a furylcarbinol substituted with an n-butyl
side-chain, the scope was extended to include other aliphatic
derivatives.
Optimization studies with alcohol additives
Me
O
Me
Me
Me
10 mol %
Dy(OTf)3
ROH
+
O
MeCN/H2O (5:1)
80 °C
10 equiv
Me
OH Me
OH
18
19
Entry
ROH
Time (h)
16
4.5
Yield (%)
1
2
3
4
5
6
7
8
9
MeOH
i-PrOH
t-BuOH
F6i-PrOH
76
80
80
76
80
80
80
80
64
70
3.25
7
Phenol
4.5
4.5
3.5
3.5
3.5
p-Nitro phenol
p-Methoxy phenol
5:1 t-BuOH/H2O
5:1 i-PrOH/H2O
d
10
19
O
10 mol% Dy(OTf)3
Ar
OH
Ar
O
t-BuOH/H2O, 80 °C
20
21
OH
5:1
R
O
O
O
S
R
Pleasingly, the dual system proved general for a variety of sub-
strates as illustrated in Scheme 4. Terminal alkenes and branched
alkanes were well tolerated. Moreover, we discovered that the
combination of Lewis and Brønsted acid catalysts was beneficial for
substrates that had previously proved challenging or exceedingly
sluggish under only Lewis acid catalysis. Cyclopentenones 32e34
were accessed from the corresponding substituted furylcarbinol in
moderate to good yield (40e72% yield, Scheme 4).
R
OH
OH
OH
22
19 R = Me, 3.5h, 80%
23
6h, 84%
16 R = i-Pr, 2h, 84%
1h, 72%
O
O
O
O
OH
OH
O
10 mol % Dy(OTf)3
24
5h, 86%
25
3h, 64%
R2
R1
R2
OH
R1
5 mol % TFA
O
t-BuOH/H2O (5:1)
OH
80 °C
Scheme 3. Substrate scope with aromatic groups at the 2-position of the furylcarbinol.
28
29
O
O
O
commonly feature lengthy alkyl side-chains, we sought to over-
come this limitation by screening other Lewis and Brønsted acids
in an attempt to improve both reactivity and efficiency (Table 2).
The use of 10 mol % Dy(OTf)3 gave the desired product in 60% yield,
OH
OH
30
OH
27
31
56%
90%
72%
O
O
O
CN
Ph
Ph
Ph
Table 2
Lewis and Brønsted acid screen
OH
OH
33
OH
34
O
32
64%
40%
(5:1)
72%
Acid Catalyst
O
t-BuOH/H2O (5:1)
OH
26
Scheme 4. Substrate scope under the combination of Dy(OTf)3 and TFA catalysis.
OH
80 °C
27
Entry
Acid
equiv
Time (h)
Yield (%)
Having determined that our Lewis/Brønsted acid catalyst system
can be used to access a range of desirable cyclopentenones, we
wanted to address a key part of the overall strategy for the syn-
thesis of prostaglandin analogues, in controlling the formation of
cyclopentenone isomers. Interestingly, using our catalytic Dy(OTf)3
conditions the more thermodynamically stable isomer was only
observed for compounds 23 and 33 (5% and 6%, respectively).
Presumably this is due to the activating group at the 5-position of
the cyclopentenone, which helps facilitate the rearrangement. To
promote the isomerization we chose to use conditions developed
1
2
3
4
5
6
7
8
Dy(OTf)3
Dy(OTf)3
Dy(Cl)3
Dy(OAc)3
Sc(OTf)3
ZnCl2
TFA
TFA
Dy(OTf)3þTFA
Dy(Cl)3þTFA
Dy(OAc)3þTFA
0.10
0.30
0.10
0.10
0.10
1.00
0.05
0.20
0.10þ0.05
0.10þ0.05
0.10þ0.05
72
d
60
Decomp.
44
No reaction
53
Incomplete
Decomp.
24
90
48
28
146
>240
20
>240
96
18
16
24
168
9
10
11
Please cite this article in press as: Fisher, D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.007

4
D. Fisher et al. / Tetrahedron xxx (2014) 1e6
by Piancatelli.12 Subjection of 27 to basic alumina (Brockman Grade
III) led to complete cyclopentenone isomerization (Scheme 5). This
stepwise approach provides a high yielding and simple synthetic
procedure to both isomers, thus increasing the versatility of the
rearrangement.
mixture was immediately fitted with a reflux condenser and placed
in an oil bath pre-heated to 80 ꢀC. The reaction was monitored by
TLC. Upon completion, the reaction was then quenched with sat-
urated aqueous sodium bicarbonate, diluted with H2O, and
extracted with diethyl ether. The combined organic layers were
dried over MgSO4, filtered, and then concentrated in vacuo. The
residue was purified by column chromatography.
10 mol %
O
O
4.2.1. 4-Hydroxy-5-(2,4,6-triisopropylphenyl)cyclopent-2-en-1-one
Dy(OTf)3
(16). According to general procedure
A Dy(OTf)3 (5 mg,
5 mol % TFA
Al2O3
0.008 mmol, 0.1 equiv) was added to furan-2-yl(2,4,6-triisopropyl)
methanol (25 mg, 0.08 mmol, 1 equiv) in 1.5 mL of t-BuOH and
0.3 mL H2O. The resulting reaction mixture was heated to 80 ꢀC for
2 h. The reaction was then quenched with 1.5 mL of saturated
aqueous sodium bicarbonate, diluted with 3 mL H2O, and extracted
with diethyl ether (3ꢂ7 mL). The combined organic layers were
dried over MgSO4, filtered, and then concentrated in vacuo. The
residue was purified by column chromatography to afford cyclo-
pentenone 16 (21 mg, 84%) as a white solid. 1H NMR (400 MHz,
t-BuOH/H2O (5:1)
O
80 °C
HO
OH
OH
27
35
26
90%
quant
Scheme 5. Efficient access to both cyclopentenone isomers.
3. Conclusion
CDCl3)
d
7.54 (dd, J¼5.8, 1.9 Hz, 1H), 7.26 (s, 1H), 7.03 (d, J¼1.8 Hz,
We have developed an efficient, catalytic method for the rear-
rangement of furylcarbinols to 4-hydroxycyclopentenones. Cata-
lytic Dy(OTf)3 was determined to be optimal for the rearrangement
of furylcarbinols bearing aromatic substituents at the 2-position,
while the combination of TFA and Dy(OTf)3 was required for the
more challenging substrates, such as those with aliphatic side-
chains. This process is mild, operationally simple, and compatible
with a variety of substituted furylcarbinols. In addition, the mild
reaction conditions developed allow for both cyclopentenone iso-
mers to be accessed in high yield using a controlled stepwise
approach.
1H), 6.99 (d, J¼1.9 Hz, 1H), 6.39 (dd, J¼5.8, 1.3 Hz, 1H), 4.94 (dt,
J¼5.9, 1.8 Hz, 1H), 3.99 (d, J¼3.1 Hz, 1H), 3.26e3.16 (m, 1H),
2.92e2.82 (m, 1H), 2.41 (d, J¼5.9 Hz, 1H), 2.02e1.92 (m, 1H), 1.33 (d,
J¼6.6 Hz, 3H), 1.29e1.13 (m, 12H), 1.05 (d, J¼6.5 Hz, 3H); 13C NMR
(150 MHz, CDCl3)
d 205.1, 159.7, 148.4, 148.2, 147.5, 134.6, 128.3,
122.8, 121.3, 79.6, 57.4, 34.3, 30.9, 30.6, 25.2, 24.1, 24.1, 23.9, 23.5; IR
(thin film, cmꢁ1) 3501, 3075, 2959, 2869, 1699, 11þ02, 765; HRMS
(ESI) m/z 323.1973 (323.1987 calcd for C20H28NaO2 ½MNaꢃþ).
4.2.2. 4-Hydroxy-5-mesitylcyclopent-2-en-1-one (19). According to
general procedure A Dy(OTf)3 (7 mg, 0.0115 mmol, 0.1 equiv) was
added to furan-2-yl(mesityl)methanol (25 mg, 0.115 mmol,
1 equiv) in 1.5 mL of t-BuOH and 0.3 mL H2O. The resulting reaction
mixture was heated to 80 ꢀC for 2 h. The reaction was then
quenched with 1.5 mL of saturated aqueous sodium bicarbonate,
diluted with 3 mL H2O, and extracted with diethyl ether (3ꢂ7 mL).
The combined organic layers were dried over MgSO4, filtered, and
then concentrated in vacuo. The residue was purified by column
chromatography to afford cyclopentenone 19 (20 mg, 80%) as
4. Experimental
4.1. Materials and general experimental details
Unless stated otherwise, reactions were conducted in air dried
glassware under an atmosphere of air using reagent grade sol-
vents. Reaction temperatures were controlled using a Heidolph
temperature modulator, and unless stated otherwise, reactions
were performed at room temperature (rt, approximately 23 ꢀC).
Thin-layer chromatography (TLC) was conducted with E. Merck
silica gel 60 F254 pre-coated plates (0.25 mm) and visualized by
exposure to UV light (254 nm) or stained with anisaldehyde and
potassium permanganate. Flash column chromatography was
a yellow oil. 1H NMR (400 MHz, CDCl3)
d
7.56 (dd, J¼5.9, 2.0 Hz,
1H), 6.79 (m, 2H), 6.32 (m, 1H), 5.07e5.04 (m, 1H), 3.89 (d,
J¼3.1 Hz, 1H), 2.39 (s, 3H), 2.26 (s, 4H), 1.90 (s, 3H); 13C NMR
(150 MHz, CDCl3)
d 205.4, 160.3, 138.4, 137.0, 136.1, 134.4, 130.3,
130.1, 129.2, 78.2, 58.3, 21.2, 20.8, 20.3; IR (thin film, cmꢁ1) 3419,
3062, 2963, 2921, 1701, 852; HRMS (ESI) m/z 239.1055 (239.1055
ꢀ
performed using normal phase silica gel (60 A, 230e240 mesh,
calcd for C14H16NaO2 ½MNaꢃþ).
þ
Merck KGA).
1H NMR spectra were recorded on Varian spectrometers (at 400,
500 or 600 MHz) and are reported relative to deuterated solvent
signals. Data for 1H NMR spectra are reported as follows: chemical
4.2.3. 4-Hydroxy-5-phenylcyclopent-2-en-1-one (22). According to
general procedure A Dy(OTf)3 (8.7 mg, 0.014 mmol, 0.1 equiv) was
added to furan-2-yl(phenyl)methanol (25 mg, 0.14 mmol, 1 equiv)
in 1.5 mL of t-BuOH and 0.3 mL H2O. The resulting reaction mixture
was heated to 80 ꢀC for 6.5 h. The reaction was then quenched with
1.5 mL of saturated aqueous sodium bicarbonate, diluted with 3 mL
H2O, and extracted with diethyl ether (3ꢂ7 mL). The combined
organic layers were dried over MgSO4, filtered, and then concen-
trated in vacuo. The residue was purified by column chromatog-
raphy to afford cyclopentenone 22 (21 mg, 84%) as brown oil.
Spectral data for 22 were consistent with those previously
reported.8a
shift (d ppm), multiplicity, coupling constant (Hz), and integration.
13C NMR spectra were recorded on Varian spectrometers (125 or
150 MHz). Data for 13C NMR spectra are reported as follows:
chemical shift (d ppm), multiplicity, and coupling constant (Hz). IR
spectra were recorded on a Perkin Elmer Spectrum Two FT-IR
spectrometer and are reported in terms of frequency of absorp-
tion (cmꢁ1). Mass spectra were obtained from the UC Santa Barbara
Mass Spectrometry Facility on a (Waters Corp.) Micromass QTOF2
with an electrospray ionization source.
Furylcarbinols were prepared according to literature precedent
by reacting furfural with the corresponding Grignard reagent.
4.2.4. 4-Hydroxy-5-(thiophen-2-yl)cyclopent-2-en-1-one
(23). According to general procedure
A Dy(OTf)3 (8.5 mg,
4.2. General experimental procedure A: Scheme 3
0.014 mmol, 0.1 equiv) was added to furan-2-yl(thiophen)metha-
nol (25 mg, 0.14 mmol, 1 equiv) in 1.5 mL of t-BuOH and 0.3 mL
H2O. The resulting reaction mixture was heated to 80 ꢀC for 1 h.
The reaction was then quenched with 1.5 mL of saturated aqueous
Furylcarbinol was dissolved in a solution of t-BuOH/H2O. To the
reaction mixture at rt was added 10 mol % of Dy(OTf)3. The reaction
Please cite this article in press as: Fisher, D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.007

D. Fisher et al. / Tetrahedron xxx (2014) 1e6
5
sodium bicarbonate, diluted with 3 mL H2O, and extracted with
diethyl ether (3ꢂ7 mL). The combined organic layers were dried
over MgSO4, filtered, and then concentrated in vacuo. The residue
was purified by column chromatography to afford cyclopentenone
4.3.1. 5-Butyl-4-hydroxycyclopent-2-en-1-one (27). According to
general procedure B Dy(OTf)3 (10 mg, 0.016 mmol, 0.1 equiv) was
added to (furan-2-yl)pentan-1-ol (25 mg, 0.16 mmol, 1 equiv) in
1.5 mL of t-BuOH and 0.3 mL H2O. The resulting reaction mixture
23 (18 mg, 72%) as an orange oil. 1H NMR (600 MHz, CDCl3)
d
7.58
was treated with trifluoroacetic acid (0.6 mL, 0.008 mmol,
(dd, J¼5.9, 2.1 Hz, 1H), 7.25 (dd, J¼5.2, 1.3 Hz, 1H), 7.03e7.00 (m,
1H), 7.00e6.97 (m, 1H), 6.31 (dd, J¼5.9, 1.5 Hz, 1H), 5.09e5.03 (m,
1H), 3.74 (d, J¼3.0 Hz, 1H), 2.63 (d, J¼6.1 Hz, 1H); 13C NMR
0.05 equiv) and heated to 80 ꢀC for 16 h. The reaction was then
quenched with 1.5 mL of saturated aqueous sodium bicarbonate,
diluted with 3 mL H2O, and extracted with diethyl ether (3ꢂ7 mL).
The combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chro-
matography to afford cyclopentenone 27 (22 mg, 90%) as a yellow
(150 MHz, CDCl3)
d 203.1, 161.3, 137.7, 133.8, 127.3, 126.1, 125.0,
79.0, 57.1; IR (thin film, cmꢁ1) 3397, 3106, 2889, 1696, 1027,
697; HRMS (ESI) m/z 203.0130 (203.0143 calcd for
C9H8NaO2Sþ½MNaꢃþ).
oil. 1H NMR (400 MHz, CDCl3)
d
7.49 (dd, J¼5.8, 2.2 Hz, 1H), 6.20 (d,
J¼5.7 Hz, 1H), 4.70 (t, J¼2.7 Hz, 1H), 2.32e2.17 (m, 1H), 2.00 (s, 1H),
4.2.5. 4-Hydroxy-5-(naphthalen-2-yl)cyclopent-2-en-1-one
1.92e1.81 (m, 1H), 1.51e1.31 (m, 5H), 0.92 (t, J¼7.1 Hz, 3H); 13C NMR
(24). According to general procedure
A
Dy(OTf)3 (6.8 mg,
(150 MHz, CDCl3) d 208.2, 161.6, 134.5, 76.8, 55.6, 29.6, 28.5, 22.9,
0.012 mmol, 0.1 equiv) was added to furan-2-yl(naphthalen)
methanol (25 mg, 0.12 mmol, 1 equiv) in 1.5 mL of t-BuOH and
0.3 mL H2O. The resulting reaction mixture was heated to 80 ꢀC for
5 h. The reaction was then quenched with 1.5 mL of saturated
aqueous sodium bicarbonate, diluted with 3 mL H2O, and extracted
with diethyl ether (3ꢂ7 mL). The combined organic layers were
dried over MgSO4, filtered, and then concentrated in vacuo. The
residue was purified by column chromatography to afford cyclo-
pentenone 24 (22 mg, 86%) as yellow oil. 1H NMR (600 MHz, CDCl3)
14.1; IR (thin film, cmꢁ1) 3407, 2957, 2860,1þ694,1098; HRMS (FI) m/
z 154.0991 (154.0994 calcd for C9H14NaO2 ½MNaꢃþ).
4.3.2. 5-Allyl-4-hydroxycyclopent-2-en-1-one (30). According to
general procedure B Dy(OTf)3 (11 mg, 0.018 mmol, 0.1 equiv) was
added to (furan-2-yl)but-3-en-1-ol (25 mg, 0.18 mmol, 1 equiv) in
1.5 mL of t-BuOH and 0.3 mL H2O. The resulting reaction mixture was
treated with trifluoroacetic acid (0.7 mL, 0.009 mmol, 0.05 equiv) and
heated to 80 ꢀC for 15 h. The reaction was then quenched with 1.5 mL
of saturated aqueous sodium bicarbonate, diluted with 3 mL H2O,
and extracted with diethyl ether (3ꢂ7 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography to afford
cyclopentenone 30 (18 mg, 72%) as a brown oil. Spectral data for 30
were consistent with those previously reported.13
d
7.81 (dd, J¼9.0, 2.5 Hz, 2H), 7.79e7.76 (m, 1H), 7.64e7.61 (m, 1H),
7.60 (dd, J¼5.8, 2.1 Hz, 1H), 7.48 (qd, J¼7.0, 3.4 Hz, 2H), 7.14 (dd,
J¼8.4, 1.8 Hz, 1H), 6.33 (dd, J¼5.8, 1.4 Hz, 1H), 5.01 (s, 1H), 3.57 (d,
J¼2.8 Hz, 1H), 2.66 (d, J¼5.7 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d
205.5, 162.0, 134.6, 134.2, 133.6, 132.7, 129.0, 127.8, 127.8, 126.5,
126.2, 125.8, 79.0, 62.4; IR (thin film, cmꢁ1) 3397, 3054, 2902, 1697,
1035, 745; þHRMS (ESI) m/z 247.0724 (247.0735 calcd for
C
15H12NaO2 ½MNaꢃþ).
4.3.3. 4-Hydroxy-5-isopropylcyclopent-2-en-1-one (31). According
to the general procedure B Dy(OTf)3 (11 mg, 0.018 mmol, 0.1 equiv)
was added to (furan-2-yl)-2-methyl-propanol (25 mg, 0.178 mmol,
1 equiv) in 1.5 mL of t-BuOH and 0.3 mL H2O. The resulting reaction
4.2.6. 4-Hydroxy-5-(6-vinylbenzo[d][1,3]dioxol-5-yl)cyclopent-2-en-
1-one (25). According to the general procedure A Dy(OTf)3 (6 mg,
0.010 mmol, 0.1 equiv) was added to furan-2-yl(6-vinylbenzo[d]
[1,3]dioxol)methanol (25 mg, 0.102 mmol, 1 equiv) in 1.5 mL of t-
BuOH and 0.3 mL H2O. The resulting reaction mixture was heated to
80 ꢀC for 3 h. The reaction was then quenched with 1.5 mL of sat-
urated aqueous sodium bicarbonate, diluted with 3 mL H2O, and
extracted with diethyl ether (3ꢂ7 mL). The combined organic layers
were dried over MgSO4, filtered, and then concentrated in vacuo.
The residue was purified by column chromatography to afford
cyclopentenone 25 (16 mg, 64%) as a brown oil. 1H NMR (400 MHz,
mixture was treated with trifluoroacetic acid (0.7 mL, 0.009 mmol,
0.05 equiv) and heated to 80 ꢀC for 34 h. The reaction was then
quenched with 1.5 mL of saturated aqueous sodium bicarbonate,
diluted with 3 mL H2O, and extracted with diethyl ether (3ꢂ7 mL).
The combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chro-
matography to afford cyclopentenone 31 (14 mg, 56%) as an oil.
Spectral data for 31 were consistent with those previously
reported.14
CDCl3)
d
7.59 (dd, J¼5.8, 2.2 Hz, 1H), 7.00 (s, 1H), 6.73 (dd, J¼17.1,
10.9 Hz,1H), 6.39 (s,1H), 6.37 (dd, J¼5.87,1.39,1H), 5.94 (dd, J¼6.84,
1.5, 2H), 5.54 (dd, J¼17.4, 1.3 Hz, 1H), 5.24 (dd, J¼10.9, 1.2 Hz, 1H),
4.3.4. 4-Hydroxy-5,5-diphenylcyclopent-2-en-1-one (32). According
to general procedure B Dy(OTf)3 (6 mg, 0.010 mmol, 0.1 equiv) was
added to furan-2,2-yl(diphenyl)methanol (25 mg, 0.10 mmol,
1 equiv) in 1.5 mL of t-BuOH and 0.3 mL H2O. The resulting reaction
4.99e4.86 (m, 1H), 3.69 (d, J¼2.9 Hz, 1H), 2.43 (d, J¼5.9 Hz, 1H); 13
C
NMR (150 MHz, CDCl3) d 205.6, 161.4, 147.9, 147.5, 134.8, 134.1, 132.1,
128.2, 116.2, 108.6, 106.6, 101.4, 79.4, 59.6; IR (thin film, cmꢁ1) 3406,
3084, 2902, 1698, 1483, 1036,þ733; HRMS (ESI) m/z 267.0615
(267.0633 calcd for C14H12NaO4 ½MNaꢃþ).
mixture was treated with trifluoroacetic acid (0.4 mL, 0.005 mmol,
0.05 equiv) and heated to 80 ꢀC for 43 h. The reaction was then
quenched with 1.5 mL of saturated aqueous sodium bicarbonate,
diluted with 3 mL H2O, and extracted with diethyl ether (3ꢂ7 mL).
The combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by column chro-
matography to afford cyclopentenone 32 (16 mg, 64%) as a brown
4.3. General experimental procedure B: Scheme 4
Furylcarbinol was dissolved in a solution of t-BuOH/H2O. To the
reaction mixture at rt were added 10 mol % of Dy(OTf)3 and 5 mol %
TFA. The reaction mixture was immediately fitted with a reflux
condenser and placed in an oil bath pre-heated to 80 ꢀC. The re-
action was monitored by TLC. Upon completion, the reaction was
then quenched with saturated aqueous sodium bicarbonate, di-
luted with H2O, and extracted with diethyl ether. The combined
organic layers were dried over MgSO4, filtered, and then concen-
trated in vacuo. The residue was purified by column
chromatography.
oil. 1H NMR (400 MHz, CDCl3)
d
7.61 (dd, J¼5.8, 2.5 Hz, 1H),
7.49e7.40 (m, 2H), 7.40e7.27 (m, 6H), 7.16e7.07 (m, 2H), 6.43 (dd,
J¼5.8, 1.3 Hz, 1H), 5.54 (dt, J¼7.9, 1.9 Hz, 1H), 1.59 (d, J¼8.5 Hz, 1H);
13C NMR (150 MHz, CDCl3)
d 205.9, 161.7, 140.5, 139.6, 134.7, 129.9,
128.8, 128.6, 128.5, 127.7, 127.5, 78.8, 65.7; IR (thin film, cmꢁ1) 3418,
3059, 2983, 1705, 1044, 697; HRMS (ESI) m/z 273.0881 (273.0891
calcd for C17H14NaO2 ½MNaꢃþ).
þ
4.3.5. 4-Hydroxy-4-methyl-5-phenylcyclopent-2-en-1-one
(33). According to general procedure
B Dy(OTf)3 (8.1 mg,
Please cite this article in press as: Fisher, D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.007

6
D. Fisher et al. / Tetrahedron xxx (2014) 1e6
0.013 mmol, 0.1 equiv) was added to 5-methylfuran-2-yl(phenyl)
methanol (25 mg, 0.132 mmol, 1 equiv) in 1.5 mL of t-BuOH and
0.3 mL H2O. The resulting reaction mixture was treated with tri-
vacuo to afford cyclopentenone 35 (25 mg, 100%) as an oil. Spectral
data matched literature precedent.16
fluoroacetic acid (0.6 mL, 0.007 mmol, 0.05 equiv) and heated to
Acknowledgements
80 ꢀC for 15.5 h. The reaction was then quenched with 1.5 mL of
saturated aqueous sodium bicarbonate, diluted with 3 mL H2O, and
extracted with diethyl ether (3ꢂ7 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography to afford cyclo-
pentenone 33 (10 mg, 40%) as an oil. Spectral data for 33 were
consistent with those previously reported and was found to have
a 5:1 ratio of diastereomers.15
This work was supported by UCSB and the National Science
Foundation (Career Award CHE-1057180).
References and notes
1. (a) Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533; (b) Das, S.; Chan-
drasekhar, S.; Yadav, J. S.; Gree, R. Chem. Rev. 2007, 107, 3286.
ꢁ
2. (a) Roche, S. P.; Aitken, D. J. Eur. J. Org. Chem. 2010, 5339; (b) Singh, G.; Meyer,
ꢁ
A.; Aube, J. J. Org. Chem. 2013, 79, 452.
4.3.6. 4-(2-Hydroxy-5-oxocyclopent-3-en-1-yl)benzonitrile
(34). According to the general procedure B Dy(OTf)3 (7.6 mg,
0.013 mmol, 0.1 equiv) was added to 4-(furan-2-yl(hydroxy)
methyl)benzonitrile (25 mg, 0.125 mmol, 1 equiv) in 1.5 mL of t-
BuOH and 0.3 mL H2O. The resulting reaction mixture was treated
3. (a) Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett. 1976, 17, 3555; (b)
Piancatelli, G.; Dauria, M.; Donofrio, F. Synthesis 1994, 867; (c) Piutti, C.;
Quartieri, F. Molecules 2013, 18, 12290e12312.
4. Yu, D.; Thai, V. T.; Palmer, L. I.; Veits, G. K.; Cook, J. E.; Read de Alaniz, J.; Hein, J.
E. J. Org. Chem. 2013, 78, 12784.
5. (a) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577; (b) Pellissier, H. Tet-
rahedron 2005, 61, 6479; (c) Tius, M. A. Eur. J. Org. Chem. 2005, 2193; (d) Vaidya,
T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3, 1531.
6. (a) Curran, T. T.; Hay, D. A.; Koegel, C. P.; Evans, J. C. Tetrahedron 1997, 53, 1983;
(b) Ghorpade, S. R.; Bastawade, K. B.; Gokhale, D. V.; Shinde, P. D.; Mahajan, V.
A.; Kalkote, U. R.; Ravindranathan, T. Tetrahedron: Asymmetry 1999, 10, 4115.
7. Henschke, J. P.; Liu, Y.; Huang, X.; Chen, Y.; Meng, D.; Xia, L.; Wei, X.; Xie, A.; Li,
D.; Huang, Q.; Sun, T.; Wang, J.; Gu, X.; Huang, X.; Wang, L.; Xiao, J.; Qiu, S. Org.
Process Res. Dev. 2012, 16, 1905.
8. (a) Ulbrich, K.; Kreitmeier, P.; Reiser, O. Synlett 2010, 2037; (b) Kumaraguru, T.;
Babita, P.; Sheelu, G.; Lavanya, K.; Fadnavis, N. W. Org. Process Res. Dev. 2013, 17,
1526.
9. (a) Veits, G. K.; Wenz, D. R.; Read de Alaniz, J. Angew. Chem., Int. Ed. 2010, 49, 9484;
(b) Palmer, L. I.; Read de Alaniz, J. Angew. Chem., Int. Ed. 2011, 50, 7167; (c) Palmer,
L. I.; Read de Alaniz, J. Org. Lett. 2013, 15, 476; (d) Palmer, L. I.; Veits, G. K.; Read de
Alaniz, J. Eur. J. Org. Chem. 2013, 6237; (e) Wenz, D. R.; Read de Alaniz, J. Org. Lett.
2013, 15, 3250; (f) Palmer, L. I.; Read de Alaniz, J. Synlett 2014, 08.
10. Li, S. W.; Batey, R. A. Chem. Commun. 2007, 3759.
with trifluoroacetic acid (0.5
mL, 0.006 mmol, 0.05 equiv) and
heated to 80 ꢀC for 18 h. The reaction was then quenched with
1.5 mL of saturated aqueous sodium bicarbonate, diluted with
3 mL H2O and extracted with diethyl ether (3ꢂ7 mL). The com-
bined organic layers were dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by column
chromatography to afford cyclopentenone 34 (18 mg, 72%) as an
oil. 1H NMR (400 MHz, CDCl3)
d
7.66 (dd, J¼5.8, 2.1 Hz, 1H), 7.62 (d,
J¼8.2 Hz, 2H), 7.28 (d, J¼8.2 Hz, 2H), 6.36 (dd, J¼5.8, 1.3 Hz, 1H),
5.01 (s, 1H), 3.55 (d, J¼3.0 Hz, 1H), 2.66 (s, 1H); 13C NMR (150 MHz,
CDCl3)
d
¼203.5, 161.8, 142.2, 134.3, 132.6, 129.2, 128.1, 118.5, 111.3,
105.0, 61.8 IR (thin film, cmꢁ1) 3537, 3057, 2917, 2849, 2228,
1693, 1104; þHRMS (ESI) m/z 222.0523 (222.0531 calcd for
12H9NNaO2 ½MNaꢃþ).
11. (a) Yin, B.-L.; Lai, J.-Q.; Zhang, Z.-R.; Jiang, H.-F. Adv. Synth. Catal. 2011, 353,
1961; (b) Yin, B.; Huang, L.; Zhang, X.; Ji, F.; Jiang, H. J. Org. Chem. 2012, 77,
6365.
C
4.4. 2-Butyl-4-hydroxycyclopent-2-en-1-one (35)
12. Ficini, J.; Pouliquen, J. Tetrahedron Lett. 1972, 13, 1131.
13. Barker, A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1983, 1885.
14. Li, C.-C.; Wang, C.-H.; Liang, B.; Zhang, X.-H.; Deng, L.-J.; Liang, S.; Chen, J.-H.;
Wu, Y.-D.; Yang, Z. J. Org. Chem. 2006, 71, 6892.
15. D’Auria, M. Heterocycles 2000, 52, 185.
16. Cooper, G. K.; Dolby, L. J. Tetrahedron Lett. 1976, 17, 4675.
4-Hydroxy-5-butylcyclopent-2-enone (25 mg, 0.162 mmol) was
adsorbed on alumina (850 mg, Brockman grade III) for 23 h and
eluted with 4:1 benzene/diethyl ether, which was concentrated in
Please cite this article in press as: Fisher, D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.007