Convenient and easy access to 2-hydroxycyclopent-2-enones from acylcyanohydrins

Article abstract of DOI:10.1016/j.tet.2019.07.010

A convenient access to 2-hydroxycyclopentenones was designed from acylcyanohydrins, by using titanacyclopropane complexes as nucleophilic partners and an intramolecular aldol condensation in basic conditions. The development of a one-pot procedure allows a step- and atom-economic process, and the use of Grignard reagents other than ethylmagnesium bromide provided valuable 3,4-disubstituted 2-hydroxycyclopentenones. The utility of the hydroxy group was illustrated by further functionalization of the α-position using palladium-mediated cross-coupling reactions.

Full text of DOI:10.1016/j.tet.2019.07.010

Accepted Manuscript
Convenient and easy access to 2-hydroxycyclopent-2-enones from acylcyanohydrins
Mathilde Pantin, Florent Bodinier, Jordan Saillour, Yassine M. Youssouf, Fabien
Boeda, Morwenna S.M. Pearson-Long, Philippe Bertus
PII:
S0040-4020(19)30752-5
https://doi.org/10.1016/j.tet.2019.07.010
TET 30452
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 May 2019
Revised Date: 4 July 2019
Accepted Date: 5 July 2019
Please cite this article as: Pantin M, Bodinier F, Saillour J, Youssouf YM, Boeda F, Pearson-Long
MSM, Bertus P, Convenient and easy access to 2-hydroxycyclopent-2-enones from acylcyanohydrins,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.07.010.
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Convenient and easy access to 2-
hydroxycyclopent-2-enones from
acylcyanohydrins
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Mathilde Pantin, Florent Bodinier, Jordan Saillour, Yassine M. Youssouf, Fabien Boeda, Morwenna S. M.
Pearson-Long and Philippe Bertus
Institut des Molécules et Matériaux du Mans (IMMM) – UMR 6283 CNRS, Le Mans Université, Avenue Olivier
Messiaen, 72085 Le Mans Cedex 09, France
O
O
R2
O
MgBr
, Ti(OiPr)4
HO
R1
HO
R1
O
C
NaOH
then
N
O
R2
R2
R1
13 examples

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Convenient and easy access to 2-hydroxycyclopent-2-enones from acylcyanohydrins
Mathilde Pantina, Florent Bodiniera, Jordan Sailloura, Yassine M. Youssoufa, Fabien Boedaa, Morwenna S.
M. Pearson-Longa, and Philippe Bertusa,
a Institut des Molécules et Matériaux du Mans (IMMM)
–
UMR 6283 CNRS, Le Mans Université, Avenue Olivier Messiaen, 72085 Le Mans Cedex 09, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient access to 2-hydroxycyclopentenones was designed from acylcyanohydrins, by
using titanacyclopropane complexes as nucleophilic partners and an intramolecular aldol
condensation in basic conditions. The development of a one-pot procedure allows a step- and
atom-economic process, and the use of Grignard reagents other than ethylmagnesium bromide
provided valuable 3,4-disubstituted 2-hydroxycyclopentenones. The utility of the hydroxy group
was illustrated by further functionalization of the α-position using palladium-mediated cross-
coupling reactions.
Available online
Keywords:
Nitriles
2009 Elsevier Ltd. All rights reserved
.
Grignard reagents
Titanium
Cyclopentenones
———
Corresponding author. Tel.: +33-243-833-096; fax: +33-243-833-902; e-mail: morwenna.pearson@univ-lemans.fr
Corresponding author. Tel.: +33-243-833-323; fax: +33-243-833-902; e-mail: philippe.bertus@univ-lemans.fr

2
Tetrahedron
diketones from acylcyanohydrins.15 The subsequent improvement
ACCEPTED MANUSCRIPT
1. Introduction
in a one-pot procedure affords a higher yielding and step-
economic process and allows the formation of 3,4-disubstituted
2-hydroxycyclopentenones (Scheme 1).
The cyclopenten-2-one moiety is found in several natural and
synthetic compounds with organoleptic properties and biological
activities. For instance, the well-known cis-jasmone (1) is a
fragrant compound of jasmine flowers whereas its synthetic
pyrethroid congener, allethrin I (2),1 is used as the mixture of the
8 stereoisomers as household insecticides (Figure 1). The
naturally occurring (+)-terrein (3) could also be cited for its
interesting inhibition properties towards human tumor cell
growth.2 This scaffold can also display hydroxy function at the
C2-position, as in Coronol® (4), a flavoring agent with caramel
and maple notes.3 These 2-hydroxycyclopentenones, also
referenced as cyclopentane-1,2-diones, can be part of natural
products, like (±)-tylopilusins (5a,b)4 and (±)-suillusine (6),5
extracted from fruiting bodies of Tylopilus eximius and Suillus
granulatus respectively, and are also used as synthetic
intermediates, such as the polycyclic compound 7, a precursor of
the anticancer agent Rocaglamide.6
Scheme 1. One-pot synthesis of 2-hydroxycyclopentenones 9 from
acylcyanohydrins 8.
2. Results and discussion
2.1. Aldol condensation
The 5-hydroxy-1,4-diketones 11, required for the formation of
2-hydroxycyclopentenones, are directly accessible from
cyanohydrins derivatives 8 via the use of titanacyclopropane
reagents, themselves generated from titanium isopropoxide and
Grignard reagents (Scheme 2).15 In this reaction, the formal 1,2-
dianion reactivity of titanacyclopropanes was modulated by the
nature of the solvent. Indeed, by using Et2O as solvent instead of
THF, the formation of dicarbonyl compounds 11 is largely
privileged over the cyclopropylamine derivatives 10, and 5-
hydroxy-1,4-diketones 11 were isolated in up to 74% yield (69%
yield in the case of 11a), after purification. From a mechanistic
point of view, after insertion of the nitrile moiety of 8 into the
titanacyclopropane complex A, the azatitanacyclopentene B
would evolve into a C,N di-metallated intermediate C through a
putative reversible equilibrium. The intramolecular cyclization by
nucleophilic addition onto the ester function would afford the
stable cyclic intermediate D that provides hydroxydiketones 11
after hydrolysis.
Fig. 1. Cyclopenten-2-ones and 2-hydroxycyclopenten-2-ones of
interest
EtMgBr (2.1 equiv.)
Ti(OiPr)4 (1.1 equiv.)
O
H
O
N
R
Due to their biological importance and their interest as
building blocks, cyclopentenones represent an intensive research
field, and biomass is an interesting renewable resource to prepare
these cyclic enones by intramolecular or intermolecular
Piancatelli rearrangement of furans,7 and furfuryl derivatives.8
The Pauson-Khand reaction, i.e. the [2+2+1] cycloaddition
between an alkyne, an alkene and carbon monoxide is largely
used in total syntheses,9 and variants consisting in titanium-
mediated intramolecular coupling of alkynes with α,β-
unsaturated esters or β-ketoesters were reported.10 An important
alternative is the Nazarov cyclization of divinyl ketones, which is
also able to provide 2-hydroxycyclopentenone derivatives when
an enol equivalent or enol ether is conjugated to the ketone
function.11,12 Cyclopentenones were also prepared by cyclization
of 1,4-diketones,7,13 and this approach has already been applied to
the synthesis of 2-hydroxycyclopentenones from carboxylic
esters of 5-hydroxy-1,4-diketones, obtained from convergent
synthesis involving a Stetter reaction with benzaldehydes, and
using acidic conditions13a or basic alcoholic media.13b-d Very
recently, an efficient Suzuki cross-coupling reaction between 3-
bromo-cyclopentenones and arylboronic acids was reported to
functionalize the cyclopentenone ring but the yields do not reach
more than 26% when the 2-hydroxy group was not protected.14
Thus, if cyclopentenones are well described by several synthetic
processes,7-13 the access to 2-hydroxy derivatives is more limited
and such scaffold constitutes an interesting target for synthetic
chemists.
HO
HO
R
R
O
O
N
O
Et2O, rt, 1 h
8
10
11
11a
(
: R = Ph, 69%)
Ti(OiPr)4 + 2 EtMgBr
Ti(OiPr)2
+ 2 iPrOMgBr + Et-H
A
O
O
O
iPrOMgBr
A
N-M
N
R
O
CN
R O
R
O
Ti(OiPr)2
8
B
M
C
M = MgBr, Ti(OiPr)3
O
N-M
O
H2O
HO
R
R
O
OM
D
11
Scheme 2. Titanium-mediated synthesis of 5-hydroxy-1,4-diketones
11.
The intramolecular cyclization of the 5-hydroxy-diketones
was first carried out with the model compound 11a and NaH as a
base in Et2O under argon (Table 1, entry 1). To our delight, the 2-
hydroxycyclopentenone 9a was obtained in 86% yield as the only
product. Obviously, the hydroxy moiety does not interfere in the
cyclization process, and competes with the related protocol
involving methanolate-mediated intramolecular cyclization of the
acetyl ester of 11a (83% yield),13a the latter being prepared by
Stetter reaction. The use of K2CO3 in MeOH also led to complete
conversion and good yield without purification, but required a
longer reaction time (entry 2). In order to perform a one-pot
reaction directly from the cyanohydrins 8 (i.e. without the
In this context, we present a convenient two-step access to 2-
hydroxycyclopenten-2-ones
9
from easily available acyl
cyanohydrins 8 by taking the advantage of the previously
published titanium-mediated formation of 5-hydroxy-1,4-

3
The one-pot method was then performed by adding a
isolation of the diketones 11, vide infra), aqueous media is
required to hydrolyze the metallated imine intermediate D before
performing base-mediated cyclization into 9. A biphasic media
was thus used with diketone 11a in Et2O and 3M NaOH solution
in water. Under these conditions, the reaction was completed
within 30 minutes, but the expected product was isolated in a
lower 75% yield (entry 3). Benzoic acid and 4-oxo-4-
phenylbutanoic acid were also obtained as by-products,
suggesting an aerobic oxidation of the starting material in the
basic reaction media.16 Consequently, the experiment was
reiterated with carefully degassed aqueous solution of NaOH,
affording cyclopentenone 9a in 94% yield without purification
(entry 4). The use of lower amounts of NaOH (1.5 equiv.)
provided 9a in similar yield but required longer reaction time
(entry 5) and catalytic amount of NaOH (0.2 equiv) led only to
13% conversion after 3 days (entry 6), showing that at least one
equiv of base is required. At last, weaker basic media was
ineffective, since sodium hydrogen carbonate, ammonium
hydroxide, sodium carbonate and disodium hydrogen phosphate
aqueous solutions were tested without success (entries 7-10).
ACCEPTED MANUSCRIPT
degassed NaOH 3M aqueous solution to the crude reaction
mixture, obtained after addition of EtMgBr to the nitriles 8 and
Ti(OiPr)4 in Et2O. After 3 h of additional stirring and work-up,
the crude material was purified by chromatography on silicagel to
afford the pure cyclopentenones 9a-d. Apart from the simplicity
of the procedure, the one-pot version was equivalent to the two-
step procedure in terms of efficiency for the phenyl-substituted
compound 9a , even when the reaction was conducted on 12
mmol scale of 8a (entry 1). On the other hand, a significantly
better yield (78% instead of 49%) was obtained for the para-
methoxy derivative 9b by using the one-pot procedure (entry 2)
and an increase of 27-28% in the yield was also observed for
products 9c and 9d (entries 3 and 4). As a result, the one-pot
process was found to outperform the two-step one. The main
reason of this efficiency lies in the difficulty to purify the
diketones by column chromatography in the two-step process.17
This one-pot method was next applied to the synthesis of other
hydroxycyclopentenones from easily available acylcyanohydrins
(entries 5-8). The reaction works well with aliphatic and alkenyl
moieties, giving 9e-h in 63-72% yields. The formation of 9i,
bearing an alkyne moiety was also possible but in lower yield
(entry 9).
Table 1. Study of the base-mediated intramolecular
cyclization of hydroxydiketone 11a.
Table 2. Two-step versus one-pot preparation of
cyclopentenones 9 from acylcyanohydrins 8.
Entry Conditions
Solvent Equiv.a
Time (h)
Conv.b
100%
100%
100%
100%
100%
13%
0
Yieldc
86%
90%
75%d
94%
90%
-
Entry
R
Two-step
Two-step
Yield
One-pota
Yield
1
2
NaH
THF
MeOH
Et2O
Et2O
Et2O
Et2O
Et2O
1.1
4
3
11(Yield)/9(Yield)
1
2
3
4
5
6
7
8
9
Ph
11a(69%) / 9a(90%) 9a (62%)
11b(65%) / 9b(75%) 9b (49%)
9a (60%)b
9b (78%)
9c (80%)
9d (73%)
9e (72%)
9f (68%)
9g (63%)
9h (69%)
9i (21%)
K2CO3
12
0.5
0.5
3
3
NaOH 3M
NaOH 3Me
NaOH 0.5Me
NaOH 0.1Me
Sat. NaHCO3
9
p-MeO-Ph
p-Br-Ph
p-F-Ph
11c(60%) / 9c(87%)
9c (52%)
4
9
11d(60%) / 9d(76%) 9d (46%)
5
1.5
0.2
-
Me
-
-
-
-
-
-
-
-
-
-
6
72
12
12
12
-
n-Pr
iBu
7
-
CH2=CH-C8H16
Ph-C≡C
8
NH4OH 0.8M Et2O
1.5
1.5
-
0
-
a One-pot procedure: after the addition of EtMgBr to a solution of 1 mmol
of nitrile 8 and Ti(OiPr)4 in Et2O, the mixture was stirred for 1 h at room
temperature. A 3M freshly prepared and degassed aqueous NaOH solution
was then added under argon and vigorous stirring was maintained for further
9
Na2CO3 0.5M
Et2O
Et2O
0
-
f
10
Na2HPO4
0
-
a Number of equivalents of base compared to the starting ketone 11a.
b
Conversion was monitored by TLC and calculated by integration of 1H NMR
b
3 h. Reaction undertaken on 12 mmol of substrate 8a (the yield was 64%
signals recorded for the crude residue. c Isolated yield. Unless specified, the
when 1 mmol of 8a was used).
d
product was isolated pure after work-up, without any further purification.
e
Purification by column chromatography was required. The aqueous NaOH
solution was freshly prepared and degassed before use. f Buffer pH 11 used.
The use of substituted ethyl Grignard reagents gives the
opportunity to further functionalize the cyclopentenones (Scheme
3). Interestingly, even though the corresponding diketones 11j-l
were isolated in modest yields in the above Ti-mediated reaction,
they were obtained as a single regioisomer.15a Here also, the one-
pot formation of hydroxycyclopentenones increases the overall
yield of the transformation, providing 3,4-disubstituted 2-
hydroxycyclopentenones 9j-l. Furthermore, the synthetic
applicability was well illustrated by the formation of the
multifunctional scaffold 9m, in only one step from nitrile 8m.
2.2. One-pot synthesis of cyclopentenones
With the above optimized conditions in hand (3M aqueous
degassed NaOH solution), the one-pot version was explored and
compared to the two-step method (Table 2). At first, the
diketones 11b-d displaying methoxy, bromide and fluoride
groups in the para position of the phenyl substituent were
prepared in 60-65% yield from the parent acylcyanohydrins 8b-
d, after aqueous acidic workup and purification by
chromatography on silicagel, according to reported procedure.15b
Subsequent cyclization in aqueous sodium hydroxide solution
efficiently provided 9b-d, giving access to cyclopentenones 9a-d
in 46-62% yields for the two-step preparation from nitriles 8a-d.

4
Tetrahedron
anhydrous Et2O using the conventional method from the
ACCEPTED MANUSCRIPT
appropriate bromide precursors and Mg turnings, and the
resulting solutions were titrated before use according to the B. E.
Love method.19 The commercially available chemical reagents
were purchased from Sigma-Aldrich and used without
purification. The aqueous NaOH solution used for the cyclization
of diketones was freshly prepared from ultrapure water purified
on Milli-Q® system and was degassed before use.
Analytical TLC were performed on Alugram SIL G/UV254
silica gel sheets (Macherey-Nagel) with detection using ethanolic
potassium permanganate solution. Column chromatographies
were carried out using silica gel 60 (0.040-0.063 mm) from
Merck. Melting points were determined with a Büchi B-540
1
melting point apparatus. H and 13C NMR spectra were recorded
on a Bruker DPX-200 or Bruker AC-400 spectrometer. Chemical
shifts (δ) are expressed in ppm units, relative to the residual
solvent peak. Coupling constants are given in Hz. The
multiplicities are reported as follows: singlet (s), doublet (d),
triplet (t), quadruplet (q), apparent sextuplet (app sx), apparent
nonuplet (app non), multiplet (m), and broad signal (bs). IR
spectra were obtained on a Perkin Elmer Spectrum One
spectrometer on a single-reflection diamond ATR unit. High
resolution mass spectra were recorded on a Waters Micromass
GCT Premier spectrometer. Acylcyanohydrins 8a-d,15b 8e,20 8f-
i,15b and 1,4-diketones 11a-d,15a were prepared according to
previously reported procedures.
Scheme 3. Synthesis of substituted cyclopentenones
2.3. Functionalization of cyclopentenones
The hydroxy moiety of the prepared cyclopentenones can be
used for further modifications, as exemplified below by
palladium-mediated cross-coupling reactions (Scheme 4).
The compound 9a was selectively converted into the
corresponding triflate 12 by using trifluoromethanesulfonyl
anhydride. The subsequent Heck reaction with styrene was
performed under standard conditions to afford the dienone 13 in
good yield.18 Alternatively, the Sonogashira coupling of 12 was
performed with trimethylsilylacetylene and PdCl2(PPh3)3 in THF
to afford the enynone 14 in excellent yield.
4.2. General one-pot procedure to access cyclopentenones 9
To a solution of the appropriate acylcyanohydrin 8 (1 mmol)
in Et2O (5 mL) cooled to 0 °C was added Ti(OiPr)4 (327 ꢀL,
1.1 mmol). A solution of the appropriate Grignard reagent in
Et2O (2.1 mmol) was added dropwise over a period of 15 min
and the mixture was allowed to warm up to room temperature.
After stirring at room temperature for 1 h, a 3M freshly prepared
and degassed aqueous NaOH solution (3 mL) was added under
argon and vigorous stirring was maintained for further 3 h. The
solution was acidified by adding a 3M HCl aqueous solution. The
aqueous phase was extracted with EtOAc (3 × 5 mL) and the
combined organic extracts were washed with brine, and dried
over MgSO4. After filtration, the organic fraction was
concentrated under reduced pressure and the crude residue was
purified by flash chromatography on silica gel to afford the pure
cyclopentenone 9.
Scheme 4. Cross-coupling reactions with triflate derivative of 9a.
4.2.1. 2-Hydroxy-3-phenylcyclopent-2-enone (9a)1 3 b
3. Conclusion
Prepared from acylcyanohydrin 8a (12 mmol) and EtMgBr.
Purification by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9a (1.25
g, 60%) as a beige solid; mp = 188–190 °C (lit: 187–189 °C). 1H
NMR (200 MHz, CDCl3): δ (ppm) 7.93 (m, 2H), 7.53–7.36 (m,
3H), 6.40 (bs, 1H), 2.95–2.86 (m, 2H), 2.62–2.55 (m, 2H). 13C
NMR (50 MHz, CDCl3): δ (ppm) 203.1, 148.4, 138.1, 134.1,
129.6, 128.8, 127.8, 31.2, 23.5.
A general synthesis of 2-hydroxycyclopentenone derivatives
was presented, based on the titanium-mediated conversion of
easily available acyl cyanohydrins to 5-hydroxy-1,4-diketones,
followed by a selective basic cyclization. The direct formation of
the cyclopentenones without prior purification of the diketone
(one-pot method) was proven to be more efficient. The scope of
the reaction was explored, allowing the straightforward synthesis
of 3,4-difunctional 2-hydroxycyclopentenones, and, by
modification of the 2-hydroxy moiety, the preparation of 2,3-
disubstituted cyclopentenones.
4.2.2. 2-Hydroxy-3-(4-methoxyphenyl)cyclopent-2-
1 3 c
enone (9b)
Prepared from acylcyanohydrin 8b and EtMgBr. Purification
by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9b (159
mg, 78%) as a yellow solid; mp = 186–188 °C (lit: 200–201 °C).
1H NMR (200 MHz, CDCl3): δ (ppm) 7.89 (m, 2H), 6.97 (m,
2H), 6.12 (s, 1H), 3.87 (s, 3H), 2.90–2.83 (m, 2H), 2.59–2.53 (m,
2H). 13C NMR (50 MHz, CDCl3): δ (ppm) 202.7, 160.7, 147.2,
138.8, 129.6, 126.9, 114.2, 55.5, 31.1, 23.6.
4. Experimental section
4.1. General remarks
All air- and moisture-sensitive manipulations were carried out
with standard Schlenk techniques under argon. Et2O, THF and
CH2Cl2 were purified by passing through neutral alumina
columns under nitrogen. DMF and Et3N were distilled under
argon before use. The Grignard reagents were prepared in

5
4.2.3. 2-Hydroxy-3-(4-bromophenyl)cyclopent-2-
enone (9c)
mg, 69%) as a beige solid; mp = 164–166 °C. IR (neat) ṽ =
ACCEPTED MANUSCRIPT
3227, 2925, 2854, 1707, 1640, 1395, 1115 cm-1. H NMR (400
1
MHz, CDCl3): δ (ppm) 6.38 (bs, 1H), 5.85–5.75 (m, 1H), 5.02
4.88 (m, 2H), 2.47–2.38 (m, 3H), 2.34 (t, J = 7.5 Hz, 1H), 2.08
–
–
Prepared from acylcyanohydrin 8c and EtMgBr. Purification
by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9c (202
mg, 80%) as a pale yellow solid; mp = 200–202 °C. IR (neat): ṽ
= 3201, 2921, 2884, 1699, 1633, 1583, 1485, 1448, 1384, 1272,
1.98 (m, 2H), 1.68–1.50 (m, 2H), 1.40–1.25 (m, 12H). 13C
NMR (100 MHz, CDCl3): δ (ppm) 203.9, 179.2, 148.9, 139.3,
114.3, 33.9, 32.0, 29.7, 29.4, 29.2, 29.0, 28.8, 27.0, 25.4, 24.8.
HRMS (EI): calcd. for C15H24O2 [M+•] 236.1776; found 236.1774.
1
1204, 1133, 1072 cm-1. H NMR (200 MHz, CDCl3): δ (ppm)
7.79 (m, 2H), 7.58 (m, 2H), 6.49 (bs, 1H), 2.90–2.84 (m, 2H),
2.61–2.55 (m, 2H). 13C NMR (50 MHz, CDCl3): δ (ppm) 202.8,
148.6, 136.6, 132.9, 132.0, 129.3, 123.9, 31.1, 23.4. HRMS (CI-
CH4/NH3): calcd. for C11H10O2Br [M + H]+ 252.9864; found
252.9869.
4.2.9. 2-Hydroxy-3-(phenylethynyl)cyclopent-2-en-
1-one (9i)2 3
Prepared from acylcyanohydrin 8i and EtMgBr. Purification
by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9i (42
mg, 21%) as a colorless oil. 1H NMR (200 MHz, CDCl3):
δ (ppm) 7.54 (m, 2H), 7.38–7.35 (m, 3H), 6.0 (bs, 1H), 2.73–2.68
(m, 2H), 2.55–2.50 (m, 2H). 13C NMR (100 MHz, CDCl3):
δ (ppm) 202.2, 154.0, 132.0, 129.4, 128.6, 122.9, 122.5, 104.9,
83.2, 31.8, 26.0.
4.2.4. 2-Hydroxy-3-(4-fluorophenyl)cyclopent-2-
enone (9d)1 3 c
Prepared from acylcyanohydrin 8d and EtMgBr. Purification
by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9d (141
mg, 73%) as a beige solid; mp = 176–178 °C (lit: 177–178 °C).
1H NMR (200 MHz, CDCl3): δ (ppm) 7.92 (m, 2H), 7.14 (m,
2H), 6.33 (s, 1H), 2.91–2.84 (m, 2H), 2.62–2.55 (m, 2H). 13C
NMR (50 MHz, CDCl3): δ (ppm) 203.1, 163.3 (d, JC-F = 251.0
Hz), 148.1, 137.4, 130.4 (d, JC-F = 3.4 Hz), 129.8 (d, JC-F = 8.3
Hz), 115.8 (d, JC-F = 21.6 Hz), 31.2, 23.6.
4.2.10. 4-Ethyl-2-hydroxy-3-phenylcyclopent-2-en-
1-one (9j)
Prepared from acylcyanohydrin 8a and BuMgBr. Purification
by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9j (89
mg, 44%) as a beige solid; mp = 116–118 °C. IR (neat): ṽ =
3280, 3062, 3021, 2953, 2871, 1738, 1683, 1495, 1455, 1386,
4.2.5. 2-Hydroxy-3-methylcyclopent-2-en-1-one
(9e)2 1
1
1298, 1113 cm-1. H NMR (400 MHz, CDCl3): δ (ppm) 7.81 (m,
2H), 7.45 (m, 2H), 7.36 (m, 1H), 6.42 (s, 1H), 3.30 (dddd, J =
9.0, 6.3, 2.9, 1.2 Hz, 1H), 2.71 (dd, J = 19.2, 6.3 Hz, 1H), 2.27
(dd, J = 19.2, 1.2 Hz, 1H), 1.90 (m, 1H), 1.33 (m, 1H), 0.88 (t, J
= 7.4 Hz, 3H). 13C NMR (50 MHz, CDCl3): δ (ppm) 202.9,
148.3, 143.0, 133.1, 129.2, 128.7, 128.4, 37.7, 36.5, 27.3, 10.8.
HRMS (CI-CH4/NH3): calcd. for C13H15O2 [M + H]+ 203.1072;
found 203.1084.
Prepared from acylcyanohydrin 8e and EtMgBr. Purification
by flash chromatography on silica gel (20% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9e (81
mg, 72%) as a white solid; mp = 102–104 °C (lit: 103–105 °C).
IR (neat): ṽ = 3320, 2918, 1704, 1644, 1402, 1208, 1115, 959 cm-
1. 1H NMR (400 MHz, CDCl3): δ (ppm) 6.57 (bs, 1H), 2.44–2.34
(m, 4H), 1.99 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm)
203.4, 149.3, 145.1, 32.1, 27.3, 14.4.
4.2.11. 4-Benzyl-2-hydroxy-3-phenylcyclopent-2-en-
1-one (9k)
4.2.6. 2-Hydroxy-3-propylcyclopent-2-en-1-one
(9f)2 2
Prepared from acylcyanohydrin 8a and Ph(CH2)3MgBr.
Purification by flash chromatography on silica gel (5% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9k (79
mg, 30%) as a beige solid; mp = 147–149 °C. IR (neat): ṽ =
3295, 2918, 1675, 1623, 1493, 1449, 1386, 1294, 1130, 1029 cm-
Prepared from acylcyanohydrin 8f and EtMgBr. Purification
by flash chromatography on silica gel (20% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9f (95
mg, 68%) as orange crystals; mp = 51–53 °C (lit: 56–58 °C). IR
1
1. H NMR (400 MHz, CDCl3): δ (ppm) 7.93 (m, 2H), 7.49 (m,
(neat): ṽ = 3253, 2959, 2929, 2869, 1698, 1655, 1398, 1227,
1
1119, 966 cm-1. H NMR (400 MHz, CDCl3): δ (ppm) 6.19 (bs,
2H), 7.39 (m, 1H), 7.27 (m, 2H), 7.21 (m, 1H), 7.13 (m, 2H),
6.88 (s, 1H), 3.65 (m, 1H), 3.24 (dd, J = 14.1, 3.3 Hz, 1H), 2.55
(dd, J = 19.3, 6.1 Hz, 1H), 2.40 (dd, J = 14.1, 9.9 Hz, 1H), 2.34
(d, J = 19.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm)
202.4, 148.7, 142.3, 139.1, 132.9, 129.4, 129.0, 128.9, 128.6,
128.4, 126.6, 40.9, 37.5, 36.7. HRMS (EI): calcd. for C18H16O2
[M+•] 264.1150; found 264.1159.
1H), 2.44–2.37 (m, 6H), 1.58 (app sx, J = 7.5 Hz, 2H), 0.95 (t, J
= 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 203.5,
149.0, 148.4, 32.0, 30.8, 25.3, 20.3, 14.2. HRMS (CI-CH4/NH3):
calcd. for C8H13O2 [M + H]+ 141.0916; found 141.0914.
4.2.7. 2-Hydroxy-3-isobutylcyclopent-2-en-1-one
(9g)
Prepared from acylcyanohydrin 8g and EtMgBr. Purification
by flash chromatography on silica gel (20% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9g (97
mg, 63%) as a beige solid; mp = 78–80 °C. IR (neat): ṽ = 3260,
4.2.12. 4-Allyl-2-hydroxy-3-phenylcyclopent-2-en-
1-one (9l)
Prepared from acylcyanohydrin 8a and H2C=CH(CH2)3MgBr.
Purification by flash chromatography on silica gel (5% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9l (75
mg, 35%) as a white solid; mp = 106–108 °C. IR (neat): ṽ =
1
2955, 2921, 1704, 1659, 1410, 1238, 1108, 978 cm-1. H NMR
(400 MHz, CDCl3): δ (ppm) 6.04 (bs, 1H), 2.45–2.39 (m, 4H),
2.29 (d, J = 7.4 Hz, 2H), 1.97 (app non, J = 6.6 Hz, 1H), 0.94 (d,
J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm) 203.4,
149.5, 147.6, 38.1, 32.0, 27.1, 25.8, 22.9. HRMS (EI): calcd. for
C9H14O2 [M+•] 154.0994; found 154.0996.
1
3267, 2931, 2912, 1681, 1638, 1443, 1382, 1118 cm-1. H NMR
(200 MHz, CDCl3): δ (ppm) 7.84 (m, 2H), 7.52–7.32 (m, 3H),
6.78 (s, 1H), 5.71 (m, 1H), 5.09–4.98 (m, 2H), 3.45 (m, 1H), 2.69
(dd, J = 19.3, 6.1 Hz, 1H), 2.59 (m, 1H), 2.34 (dd, J = 19.3, 1.2
Hz, 1H), 2.07 (m, 1H). 13C NMR (50 MHz, CDCl3): δ (ppm)
202.5, 148.5, 142.1, 134.7, 132.8, 129.3, 128.8, 128.3, 117.8,
38.6, 37.5, 34.6. HRMS (EI): calcd. for C14H14O2 [M+•] 214.0994;
found 214.1004.
4.2.8. 3-(Dec-9-en-1-yl)-2-hydroxycyclopent-2-en-
1-one (9h)
Prepared from acylcyanohydrin 8h and EtMgBr. Purification
by flash chromatography on silica gel (20% ethyl
acetate/cyclohexane) provided the pure cyclopentenone 9h (163

6
Tetrahedron
ACCEPTED MANUSCRIPT
To a solution of triflate 12 (153 mg, 0.5 mmol) in THF
(10 mL) under argon were successively added PdCl2(PPh3)2 (18
mg, 0.025 mmol, 5 mol%), CuI (9.5 mg, 0.05 mmol, 10 mol%),
freshly distilled iPr2NEt (85 µL, 0.5 mmol) and
trimethylsilylacetylene (80 µL, 0.55 mmol). The mixture was
stirred overnight at 53 °C then cooled down to room temperature.
After filtration through a pad of Celite® and evaporation of the
solvents under reduced pressure, the crude residue was purified
by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) to afford the alkynyl-derivative 14 (120 mg,
94%) as a white solid; mp = 201–203 °C. IR (neat): ṽ = 3569,
4.2.13. 4-Allyl-2-hydroxy-3-(4-((trimethylsilyl)-
ethynyl)phenyl)cyclopent-2-en-1-one (9m)
Prepared
from
acylcyanohydrin
8m
and
H2C=CH(CH2)3MgBr. Purification by flash chromatography on
silica gel (5% ethyl acetate/cyclohexane) provided the pure
cyclopentenone 9m (81 mg, 34%) as a colorless oil. IR (neat): ṽ
= 3301, 3238, 2955, 2925, 2854, 2106, 1681, 1629, 1447, 1391,
1
1305, 1275, 1120 cm-1. H NMR (400 MHz, CDCl3): δ (ppm)
7.79 (m, 2H), 7.57 (m, 2H), 6.64 (s, 1H), 5.68 (ddt, J = 17.2,
10.3, 6.9 Hz, 1H), 5.09–4.99 (m, 2H), 3.42 (m, 1H), 3.18 (s, 1H),
2.68 (dd, J = 19.3, 6.3 Hz, 1H), 2.56 (m, 1H), 2.34 (dd, J = 19.3,
1.2 Hz, 1H), 2.05 (m, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm)
202.2, 148.8, 140.5, 134.5, 133.2, 132.5, 128.2, 122.8, 118.0,
83.6, 78.9, 38.5, 37.5, 34.5. HRMS (EI): calcd. for C16H14O2
[M+•] 238.0994; found 238.0990.
1
2925, 1707, 1603, 1261, 1235, 1175, 1037 cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 8.16 (m, 2H), 7.53–7.41 (m, 3H), 3.06
(ddd, J = 5.2, 2.6, 2.6 Hz, 2H), 2.58 (ddd, J = 5.2, 2.6, 2.6 Hz,
2H), 0.27 (s, 9H). 13C NMR (100 MHz, CDCl3): δ (ppm) 205.6,
171.9, 134.5, 131.6, 128.6, 127.9, 122.9, 106.6, 97.7, 34.2, 28.5,
–0.2. HRMS (CI-CH4/NH3): calcd. for C16H19OSi [M + H]+
255.1205; found 255.1214.
4.3. 5-Oxo-2-phenyl-cyclopent-1-en-1-yl-trifluoromethane
sulfonate (12)
Acknowledgments
The authors thank S. Bricaud, P. Gangnery, F. Legros, C.
Jacquemmoz and E. Mebold for technical assistance and
analyses. M. Pantin thanks the “Université Bretagne Loire” for
postdoctoral grant.
To a solution of triflic anhydride (0.18 mL, 1.1 mmol) in
CH2Cl2 (6 mL) cooled to 0 °C under argon, was slowly added a
solution of cyclopentenone 9a (174 mg, 1 mmol) and pyridine
(0.16 mL, 2 mmol) in CH2Cl2 (6 mL). The mixture was stirred at
0 °C for 2 h then water (10 mL) was added. The phases were
separated and the aqueous fraction was extracted with CH2Cl2 (2
× 15 mL). The combined organic layers were washed with water
(2 × 25 mL), dried over MgSO4 and filtered. After concentration
under reduced pressure, the residue was purified by flash
chromatography on silica gel (15% ethyl acetate/cyclohexane) to
afford triflate 12 (257 mg, 84%) as a beige solid; mp = 87–89 °C.
IR (neat): ṽ = 1722, 1633, 1424, 1410, 1227, 1205, 1134, 1041
References and notes
1. World Health Organization Geneva, WHO Specifications and
Evaluations for Public Health Pesticides : d-Allethrin 2002. a)
Katsuda, Y.; In Pyrethroids. Topics in Current Chemistry.
Matsuo, N.; Mori, T., Eds.; Springer Verlag Berlin Heidenberg,
2012; Vol. 314, pp 1–30. b) Ujihara, K.; Mori, T.; Matsuo, N. In
Pyrethroids. Topics in Current Chemistry. Matsuo, N.; Mori, T.,
Eds.; Springer Verlag Berlin Heidenberg, 2012; Vol. 314, pp 31–
48.
1
cm-1. H NMR (400 MHz, CDCl3): δ (ppm) 7.73 (m, 2H), 7.55–
7.48 (m, 3H), 3.12–3.08 (m, 2H), 2.67–2.62 (m, 2H). 19F NMR
(375 MHz, CDCl3): δ (ppm) -73.52 (s, 3F). 13C NMR (100 MHz,
CDCl3): δ (ppm) 197.1, 158.5, 143.0, 132.1, 129.2, 127.9, 120.0,
116.8, 31.3, 25.5. HRMS (ESI): calcd. for C12H10F3O4S [M + H]+
307.0246; found 307.0242.
2. a) Porameesanaporn, Y.; Uthaisang-Tanechpongtamb, W.;
Jarintanan,
F.;
Jongrungruangchok,
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4. Fukuda, T.; Nagai, K.; Tomoda, H. J. Nat. Prod. 2012, 75, 2228-
2231.
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Nat. Prod. 2001, 64, 1230–1231. b) Zhang, M. Y.; Malins, L. R.;
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889, and references cited therein.
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8729–8730. b) Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc.
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To a solution of triflate 12 (53 mg, 0.17 mmol) in DMF
(3.4 mL) under argon were successively added freshly distilled
triethylamine (23 ꢀL, 0.17 mmol), Pd(OAc)2 (1.6 mg, 6.9 µmol,
4 mol%), triphenylphosphine (0.9 mg, 3.5 µmol, 2 mol%) and
styrene (20 ꢀL, 0.17 mmol). The mixture was stirred at 70 °C for
16 h then water (5 mL) was added. The aqueous phase was
extracted with Et2O (3 × 5 mL) and the combined organic layers
were washed with brine (3 × 5 mL), dried over MgSO4 and
filtered. After concentration under reduced pressure, the residue
was purified by flash chromatography on silica gel (10% ethyl
acetate/cyclohexane) to afford the styrenyl-derivative 13 (36 mg,
81%) as an orange oil. IR (neat): ṽ = 2925, 2363, 1700, 1588,
1
1447, 1365, 1074 cm-1. H NMR (400 MHz, CDCl3): δ (ppm)
7.88 (d, J = 16.2 Hz, 1H), 7.53–7.42 (m, 7H), 7.33–7.26 (m, 2H),
7.25–7.19 (m, 1H), 6.89 (dt, J = 16.2, 0.9 Hz, 1H), 2.97–2.92 (m,
2H), 2.65–2.60 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm)
207.9, 168.6, 137.8, 136.6, 134.6, 133.9, 129.8, 128.8, 128.7,
128.6, 128.1, 127.9, 126.8, 118.4, 35.5, 29.6. HRMS (EI): calcd.
for C19H16O [M+•] 260.1201; found 260.1193.
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4.5. 3-Phenyl-2-((trimethylsilyl)ethynyl)cyclopent-2-en-1-one
(14)

7
Hormn, C. B.; Gardner, K. A.; Ball, D. W.; Johnson, J. E. B.;
22. Ito, S.; Saito, N.; Hatakeda, K.; Asano, T. Yukagaku 1976, 25,
ACCEPTED MANUSCRIPT
Iacono, S. T.; Balaich, G. J. J. Org. Chem. 2012, 77, 6371–6376.
14. Lopušanskaja, E.; Paju, A.; Järving, I.; Lopp, M. Synthesis 2018,
1883–1890.
326–328.
23. Paju, A.; Kanger, T.; Müürisepp, A.-M.; Aid, T.; Pehk, T.; Lopp,
M. Tetrahedron 2014, 70, 5843–5848.
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P. Angew. Chem., Int. Ed. 2010, 4, 8691–8694. b) Setzer, P.;
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A. H. Steroids 2006, 71, 34–41. b) Maljutenko, K.; Borovkov, V.;
Kananovich, D.; Järving, I.; Lopp, M. Tetrahedron 2018, 74, 661-
664.
17. Some degradation of the diketones 11 may occur during the
purification process. For instance, the diketone 11a was estimated
to be formed in 86% yield in the crude NMR, but it was isolated in
only 69% yield after column chromatography.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
18. All attempts to couple triflate 12 with ethyl acrylate using
different solvents (DMF, THF) and conditions (Pd(PPh3)4,
Pd(OAc)2, triethylamine, ethyldiisopropylamine, …) failed.
19. Love, B. E.; Jones, E. J. J. Org. Chem. 1999, 64, 3755–3756.
20. Caille, J.; Pantin, M.; Boeda, F.; Pearson-Long, M. S. M.; Bertus,
P. Synthesis 2019, 51, 1329–1341.
21. Leir, C. M. J. Org. Chem. 1970, 35, 3203–3205.

ACCEPTED MANUSCRIPT
Original substituted 2-hydroxycyclopentenones by using titanacyclopropane complexes