Vinyl nosylates as partner in copper and silver co-catalyzed Sonogashira cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2018.10.017

Vinyl nosylates, readily obtained from β-dicarbonyl derivatives, could be efficiently engaged in Sonogashira cross-coupling reactions, either cocatalyzed by copper or silver salts. The para-nitrobenzenesulfonate (nosylate) group allows this coupling to be performed under very mild conditions (room temperature). These new leaving group and mild conditions could be applied to the synthesis of acetylenic coumarinyl derivatives and to the total synthesis of an acetylenic monoterpene natural product, named cleviolide.

Full text of DOI:10.1016/j.tet.2018.10.017

Accepted Manuscript
Vinyl nosylates as partner in copper and silver co-catalyzed Sonogashira cross-
coupling reactions
Nicolas P. Cheval, Barbara Hoffmann, Anna Dikova, Fatih Sirindil, Philippe Bertus,
Aurélien Blanc, Jean-Marc Weibel, Patrick Pale
PII:
S0040-4020(18)31211-0
https://doi.org/10.1016/j.tet.2018.10.017
TET 29850
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 July 2018
Revised Date: 9 October 2018
Accepted Date: 10 October 2018
Please cite this article as: Cheval NP, Hoffmann B, Dikova A, Sirindil F, Bertus P, Blanc Auré, Weibel
J-M, Pale P, Vinyl nosylates as partner in copper and silver co-catalyzed Sonogashira cross-coupling
reactions, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.10.017.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Vinyl Nosylates as Partner in Copper and
Silver Co-Catalyzed Sonogashira Cross-
Coupling Reactions
Leave this area blank for abstract info.
Nicolas P. Cheval,a Barbara Hoffmann,a Anna Dikova,a Fatih Sirindil,a Philippe Bertus,b Aurélien Blanc,a Jean-
Marc Weibel*a and Patrick Pale.*a
a Laboratoire de Synthèse, Réactivité Organiques et Catalyse, Institut de Chimie, UMR 7177 - CNRS, Université
de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France.
b Institut des Molécules et Matériaux du Mans, Université du Maine, Avenue Olivier Messiaen, 72085 Le Mans

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Vinyl Nosylates as Partner in Copper and Silver Co-Catalyzed Sonogashira Cross-
Coupling Reactions
Nicolas P. Cheval,a Barbara Hoffmann,a Anna Dikova,a Fatih Sirindil,a Philippe Bertus,b Aurélien Blanc,a
Jean-Marc Weibel*a and Patrick Pale*a
a Laboratoire de Synthèse, Réactivité Organiques et Catalyse, Institut de Chimie, UMR 7177 - CNRS, Université de Strasbourg, 4 rue Blaise Pascal, 67070
Strasbourg, France.
b Institut des Molécules et Matériaux du Mans, Université du Maine, Avenue Olivier Messiaen, 72085 Le Mans
Dedicated to Prof. Leon Ghosez, for his humanism, his numerous achievements in organic chemistry and in the promotion of organic chemistry
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Vinyl nosylates, readily obtained from β-dicarbonyl derivatives, could be efficiently engaged in
Sonogashira cross-coupling reactions, either cocatalyzed by copper or silver salts. The para-
nitrobenzenesulfonate (nosylate) group allows this coupling to be performed under very mild
conditions (room temperature). These new leaving group and mild conditions could be applied
to the synthesis of acetylenic coumarinyl derivatives and to the total synthesis of an acetylenic
monoterpene natural product, named cleviolide.
Available online
Keywords:
Vinyl nosylates
Sonogashira
2009 Elsevier Ltd. All rights reserved
.
para-Nitrobenzenesulfonate
Cross-Coupling
Palladium
1. Introduction
compounds have indeed been studied with other leaving groups,
such as the classical halides and triflate, but also tosylates,
mesylates and phosphates.8 We also investigated the vinyl
nosylates 4-5 in connection with various total synthesis projects,
including our approach to dienediyne synthesis (Figure 1).9 To
demonstrate the usefulness of nosylates in Sonogashira coupling
reaction, we also report here the synthesis of cleviolide, the only
naturally occurring acetylenic monoterpene.
The Sonogashira reaction is one of the four most well-known
palladium-catalyzed cross-coupling reactions beside Mizoroki-
Heck, Stille and Suzuki-Miyaura couplings.1 This reaction has
been extensively applied to many areas, from total synthesis2 to
OFET, OLED and related materials synthesis.3 As a result, a
wide panel of substrates has been engaged in this coupling
reaction, but most of them are vinyl or aryl halides and triflates.
Although quite reactive in such coupling reactions, triflates
require specific conditions for their introduction due to the use of
the sensitive and expensive triflic anhydride. Therefore,
convenient and cheaper alternatives to triflates are highly sought.
In this context, various other electrophiles,4 such as phosphates5
and a few sulfonates6 have been investigated. As we recently
showed that para-nitrobenzenesulfonate or nosylates (NsO)
derivatives are very interesting, cheap and stable electrophilic
coupling partners in various palladium-catalyzed cross-coupling
reactions,7 we further explored the behavior of such leaving
group in the Sonogashira reaction (Scheme 1). We report here a
full account of the results we gained specifically for the
Sonogashira reaction with a series of challenging compounds.
Scheme 1. Sonogashira coupling of vinyl nosylates
highlighted in this work (Ns = para-nitrobenzenesulfonyl or
nosyl)
In this work, we mostly focused on nosylates derived from 4-
hydroxycoumarin 1, dimedone 2, and 4-hydroxy-5(H)-furan-2-
one 3 as models for comparison purposes (Scheme 1). These

2
Tetrahedron
2. Results and discussion
Under the conditions previously set for silver-cocatalyzed
ACCEPTED MANUSCRIPT
Sonogashira coupling,9,10 the E-nosylate
4 derived from
2.1. Nosylate formations
acetylacetone readily reacted with various alkynes, functionalized
or not, and provided the corresponding E-enynones 6-8 in
reasonable to high yields, depending on the sensitivity of the
compound (entries 3, 7 and 11). With copper iodide as co-
catalyst, the E-enynones 6-8 were obtained in good to high yields
(entries 4, 8 and 12). As expected from the lower reactivity of
silver acetylides,14 reaction times were longer, and yields were
thus often lower with the silver Sonogashira reaction as
compared to the classical copper version (entries 3 vs 4, 7 vs 8
and 11 vs 12). More surprising was the lack of reaction starting
from the corresponding Z isomer of 4, even after prolonged
reaction time (entries 1-2, 5-6). It nevertheless reacted with the
silyl protected Z-pent-3-en-4-yn-1-ol, but after prolonged
reaction time, whatever the copper or silver conditions applied.
The yields were modest, with a large difference between those
achieved starting from the E isomer (entries 9-10 vs 11-12).
Vinyl nosylates are readily obtained after treating β-
dicarbonyl derivatives with nosyl chloride in the presence of mild
bases.7b For cyclic compounds 1-2, the most appropriate base and
solvent were diisopropylethylamine and dichloromethane at room
temperature (96 and 88 % isolated yields), although potassium
carbonate and acetonitrile were as effective. In the case of the
more sensitive 3, potassium carbonate and acetonitrile were
required.
With acyclic dicarbonyl derivatives, these conditions could
not be applied and only strong bases, such as Na- or K-HMDS, in
THF allowed the formation of the corresponding nosylates 4-5,
but the use of HMPA was mandatory. Under such conditions, a
1:1 mixture of E and Z isomers were always obtained, but they
can be readily separated by chromatography (Scheme 2).
Table 1. E or Z Vinyl nosylate in Ag- vs Cu-cocatalyzed
O2N
SO2Cl
= NsCl
O
ONs
Sonogashira reactions with various alkynes.
O
O
R3
R2
O
R2
X
O
X
Conditions
AgI or CuI 0.2 equiv
R1
ONs
R1
Pd(PPh3)4 0.1 equiv
NEt(i-Pr)2 1.25 equiv
R3
ONs
O
ONs
O
E or Z
E or Z
NsCl
1.05 equiv
DMF, rt
NEt(i-Pr)2
CH2Cl2, rt
O
Entry Nosylate
Alkyne
Co-
Cat.
AgI
CuI
AgI
Product
Time Yielda
X
O
O
(h)
24
24
4
(%)
0b
0b
1
96%
2
3
88%
1
2
3
-
NsCl
1.1 equiv
NsO
NsO
HO
O
50
O
73%
K2CO3
MeCN, rt
O
O
O
4
CuI
2
58
5
6
7
AgI
CuI
AgI
24
24
4
0b
0b
-
O
O
R1
O
NaHMDS
68
R1
R2
R1
R2 NsO
1:1
R2
HMPA
THF - 78°C
8
9
CuI
AgI
1
84
38
then NsCl
4
R1, R2 = Me
50%
24
5
R1 = Me, R2 = Ph 89%
CuI
AgI
10
24
45
Scheme 2. Standard procedures for the preparation of vinyl
nosylate derivatives 1-5 using NsCl.
11
12
4
4
57
77
CuI
2.2. Silver vs copper co-catalyzed Sonogashira coupling with
vinyl nosylates
a Yields of isolated pure products unless otherwise stated.
b No reaction.
Some years ago, our group developed a variant of the
Sonogashira coupling based on silver salts as co-catalyst, silver
iodide in DMF being the best, starting from triflate derivatives.9,10
The purpose of this variant was to suppress alkyne
As the oxidative addition of palladium species to the carbon-
nosylate bond obviously occurred for the E isomer, the problems
observed for the other isomer clearly imply specific phenomenon.
The lack of reaction or the very slow reaction for the Z isomer
could be due to either competitive chelation or special stability of
the insertion complex. The Z starting material could act as a kind
of acac ligand, strongly chelating palladium and thus inhibiting
further transformation (Scheme 3, top left). It is worth noting
that, due to the sulfonate structure, such β-keto nosylate could
also act as a tridentate ligand nicely complementing the Pd0
coordination sphere (Scheme 3, top right). Furthermore, the
complex formed upon oxidative addition could be stabilized by
chelation with the adjacent carbonyl group (Scheme 3, bottom).
Upon work-up, this complex could be simply hydrolyzed, leading
to the corresponding enone, or converted to a new hydroxo
complex,16 which could provide back the diketone.
homocoupling,
a common side-reaction of the classical
Sonogashira reaction, but also to limit self-addition of certain
substrates.11 The former side-reaction results from the well-
known Glaser reaction,12 while the latter is due to the
nucleophilic character of the in situ formed copper acetylide.13 As
silver acetylides are less prone to oxidative coupling and less
nucleophilic than their copper analogs14 but can still
transmetalate to palladium,15 the corresponding side-products
become totally absent or negligible in the silver version of the
Sonogashira coupling.
Within this frame, we decided to explore the behavior of vinyl
nosylates in our silver-cocatalyzed Sonogashira coupling. For
comparison purposes, both silver and copper-cocatalyzed
versions were evaluated with the nosylates 4 (Table 1).

3
L
Table 2. Optimization of the Sonogashira coupling
ACCEPTED MANUSCRIPT
O
S
R1
conditions.
R2
R1
Ns
Pd
O
O
O
O
O
O
O
Pd°L 2
Pd°L 2
O
O
ONs
Ar
Pd
Ns
O
ONs
R1
R2
[Pd] [Cu] cat.
R2
R
R2
R1
R
NEt(i-Pr)2 1.25 equiv
solvent, rt
OH
Pd
Pd°L 2
O
O
10, R = SiMe3
11, R = C4H9
O
OH
L
R3
O
1
ONs
Pd
R1
R2
R1
R2
Entry
R
[Pd] (mol%)
[Cu]
(mol%)
CuI
(20)
AgI
Solvent Time Yielda
R3
LPd°
O
L
O
m
H2O
(h)
6
(%)
-
O
H
R1
b
R2
R1
R2
HO Pd ONs
1
2
3
SiMe3 Pd(PPh3)4 (10)
SiMe3 Pd(PPh3)4 (10)
n-C4H9 Pd(PPh3)4 (10)
DMF
DMF
DMF
R1
R2
b
Scheme 3. Possible explanations for the lack or poor
reactivity of Z-β-keto nosylates.
6
6
-
(20)
CuI
b
-
(20)
To check these possibilities, we engaged a 1:1 mixture of 5E
and 5Z in copper or silver Sonogashira coupling reactions with 1-
hexyne (Scheme 4). Whatever the conditions and as expected
from the above results, only the E coupling product 9E coming
from the E isomer 5E could be isolated. Interestingly, the
corresponding diketone was also isolated. The presence of this
compound thus tends to support the second hypothesis, involving
a stable insertion complex and the hydroxo complex mechanism
with the starting Z isomer 4 or 5.
c
4
5
6
7
8
9
n-C4H9 PdCl2(MeCN)2 (2) CuI (4)
n-C4H9 PdCl2(MeCN)2 (2) CuI (4)
THF
DMF
THF
CH3CN
CH3CN
CH3CN
1
1
24
1
1
-
c
-
d
n-C4H9 PdCl2(dppf) (2)
n-C4H9 PdCl2(PPh3)2 (5)
SiMe3 PdCl2(PPh3)2 (5)
CuI (4)
CuI (5)
CuI (5)
-
91
98
c
SiMe3 PdCl2(MeCN)2 (2) CuI (4)
a Yields of isolated pure products unless otherwise stated.
2
-
b
1
Trace of the product was observed on the crude H NMR
spectrum.
c Degradation occurs leading to unidentified by-products.
d Starting material was recovered untouched.
Bu
O
AgI or CuI 0.2 equiv
O
O
ONs
O
O
+
Ph
Pd(PPh3)4 0.1 equiv
NEt(i-Pr)2 1.25 equiv
Ph
ONs Ph
Ph
Bu
5E and Z 1:1
9E 50%
40%
DMF, rt
Scheme 4. Competitive experiment set to decipher the
possible reasons for the non-coupling of Z-β-keto nosylates.
Acetonitrile was the key to success, because in this solvent,
the coupling with PdCl2(PPh3)2 together with CuI as catalysts
afforded the expected product 11 in only 2 hours at room
temperature in high yields (91%; entry 7). Under the same
conditions, trimethysilylacetylene quantitatively afforded the
corresponding product 10 in 1 hour (98%; entry 8). However,
triphenylphosphine proved essential as ligand, as a phosphine-
free catalyst led to a messy reaction (entry 9).
With these surprising results, we then mostly focused on the
classical Sonogashira reaction, trying to adjust conditions to
nosylate derivatives as substrates.
2.3. Copper co-catalyzed Sonogashira reaction with vinyl
nosylates
It is worth mentioning here that these results are highly
competitive regarding the few examples of Sonogashira reaction
involving coumarinyl derivatives (Table 3). Triflates derived
from activated methoxylated coumarins readily reacted with
trimethylsilylacetylene within two hours giving the expected
coupling product in good to high yields (77-85%).20 In sharp
contrast, the tosylate of coumarin required a very long reaction
time (48h) to react with trimethylsilylacetylene producing the
coupling product in good yields (68%).19 It has been reported
that the 4-chloro-3-nitrocoumarin also required long reaction
times (24h) to provide coupling products in good yields (73%).8c
We selected the nosylate 1 derived from coumarin as our first
but challenging starting material. Indeed, the analog triflate is
known to be unstable,17 except when α-substituted,18 and
phosphates have been reported as unreactive.19 Since the halide
and tosylate derived from coumarin have been described and
engaged in cross-coupling reactions, Sonogashira reaction with 1
would serve as benchmark to qualify nosylate as effective partner
in such coupling reaction.
We first studied the Sonogashira coupling of 1 with 1-hexyne
and trimethylsilylacetylene, and diisopropylethylamine as base
(Table 2). Under the classical conditions (10 mol% of Pd(PPh3)4
and 20 mol% of CuI) with trimethylsilylacetylene, only traces of
Table 3. Comparison of Sonogashira coupling reactions
performed with coumarinyl derivatives carrying different
1
the expected product 10 could be detected by H NMR of the
leaving group.
crude (entry 1). The use of silver salt instead of copper led to
similar results (entry 2). Assuming that the product was sensitive,
we switched to 1-hexyne as alkyne. However, the same problem
occurred, with the product 11 detected in the crude but not much
after work-up and purification (entry 3). We then turned to
PdCl2(MeCN)2 as catalyst while lowering the catalyst loading to
2 mol%, but both modifications led to degradation in THF (entry
4), and to an even more complex crude in DMF (entry 5). In
sharp contrast, switching to PdCl2(dppf)7 with CuI as catalysts
were not effective, only leaving unchanged the starting material
even after prolonged reaction time (entry 6).
SiMe3
LG
R2
O
R2
O
SiMe3
R1
R1
[Pd][Cu] cat.
O
O
Entry LG
R1
H
H
OMe
H
R2
H
H
H
H
Yield (%)
Ref.
this work
1
2
3
4
5
6
ONs
OTf
OTf
OTs
Cl
98
deg.
77-89
68
73
0
17
20
19
8c
19
H
H
NO2
H
OP(O)(OEt) 2

4
Tetrahedron
ACCEPTED MANUSCRIPT
With optimal reaction conditions identified, the scope and
(entries 4 and 5). The more sensitive nosylate 3 derived from 4-
limitations of this coupling reaction were investigated through
the coupling of various alkynes first with the same coumarinyl
nosylate 1 (Table 4). Simple linear and cyclic aliphatic alkynes,
even the gaseous propyne, were efficiently coupled, leading to
the desired products 12-14 in good to high yields (54-92%,
entries 1-3). More functionalized alkynes could also be engaged
in coupling reaction with nosylate 1, with usually good results. 1-
Ethynylcyclohex-1-ene yielded the dienynone 15 in 87% yield
(entry 4), whereas the coupling product with 2-methylbut-1-en-3-
yne 16 could not be isolated, presumably due to its fragility
(entry 5). Not so surprisingly, propargyl alcohol led to the
isolation of the coupling product 17 only in low yield, due to its
instability (entry 6). It is worth mentioning that the same issue
was observed on a similar substrate by Fairlamb et al..21 Upon
protection of the hydroxy group, the expected product 18 could
be isolated in good yield (entry 7). Upon substitution at the
propargylic position with two methyl or an isopropyl group,
protection of the alcohol was no longer required to isolate the
corresponding products 19 and 20 with 89% and 77% yield
respectively (entries 8-9). With longer alkyl chain between the
hydroxy group and the alkyne, the coupling product was readily
produced, again without the requirement for a protecting group
and 21 could be isolated in good yield (entry 10). Not
unexpectedly, amino-substituted alkynes required a protecting
group, as shown with but-3-ynamine for which its N-but-1-ynyl
phtalimide derivative yielded the expected coupling product 22 in
69% yield (entry 11).
hydroxy-2,5-dihydrofuran-2-one could also be successfully
engaged in this procedure and its coupling with 1-hexyne and
propyne yielded the corresponding products 28 and 29 in 83%
and 58% yield respectively (entries 6 and 7).
Table 5. Vinyl nosylate scope with various alkynes.
O
ONs
PdCl2(PPh3)2 5 mol%
CuI 5 mol%
R
R
+
NEt(i-Pr)2 1.25 equiv
CH3CN, rt
n
n
O
23-27
1.2 equiv
Entry
Vinyl
R
Product
Time Yielda
Nosylate
(h)
(%)
1
2
3
2
2
2
n-C4H9
CH2OH
CH3
23
2
88
24
25
1
2
99
78
4
5
5E
5E
n-C3H7
Cy
26
27
2
2
54
63
6
7
3
3
n-C4H9
CH3
28
29
4
4
83
58
Table 4. Alkyne scope in Sonogashira coupling with
coumarinyl nosylate 1.
a Isolated yields.
O
ONs
PdCl2(PPh3)2 5 mol%
CuI 5 mol%
O
R
R
+
The latter was selected, because the 2,5-dihydrofuran-2-one
((5H)-furan-2-one) motif can be found in various natural
products from different families,22 but also used as building
blocks for the total synthesis of natural products.23 (5H)-Furan-2-
one could be found in neoclerodanes, cardenolides as well as
simple mono- or diterpenes (Scheme 5), compounds which often
exhibit strong and useful biological activities.24 To illustrate the
usefulness of the coupling method described here, we embarked
in the total synthesis of one of these monoterpenes, i.e.
cleviolide.
NEt(i-Pr)2 1.25 equiv
CH3CN, rt
O
O
1.2 equiv
1
12-23
Entry
R
Product
12
Time (h)
Yielda (%)
1
2
3
n-C3H7
CH3
5
2
1
70
54
92
13
14
4
5
15
16
2
6
87
b
-
O
O
6
7
CH2OH
17
18
19
20
21
22
14
14
4
10
67
89
77
71
69
O
O
CH2OTBDPS
C(CH3)2OH
CH(OH)iPr
(CH2)4OH
8
O
O
9
6
H
OH
R"
R'
H
Cleviolide25
10
11
6
H
OH
(CH2)2NPht
6
OR'
a Isolated yields.
RO
O
OR
2
O
O
Scutolides A-L24a
Scutebartines C-D24b
Vallarisoside24c
Strebloside24d
b Degradation occurs leading to unidentified by-products.
Furospongolide24e
We then briefly examined the vinyl nosylate scope with other
challenging compounds (Table 5). Vinyl nosylate 2 obtained
from dimedone was efficiently coupled under the best conditions
set above, and the expected enynone 23 was isolated in high yield
(88%; entry 1). Interestingly, in this case, the coupling with
propargyl alcohol proceeded efficiently without protection and
the resulting product 24 was even obtained quantitatively (entry
2), providing further insights into the instability of 17 (Table 2,
entry 6). Gaseous propyne was also efficient in this coupling and
provided the enynone 25 in high yield (78%; entry 3). Starting
from E-β-keto nosylate 5E, coupling compounds 26 and 27 could
be obtained in good yields, even if substantial amount of
unidentifiable by-products was also formed during the reactions
Scheme 5. Various natural products containing the 2,5-
dihydrofuran-2-one motif.
Cleviolide was isolated as the first acetylenic monoterpene
from the plant Senecio clevelandii.25 In contrast to other
syntheses,26 and related works,27 we used nosylate 3 as starting
material and we were able to engage 3 under our coupling
conditions directly in the presence of 4-methylpent-1-yn-3-ol as
terminal alkyne (Scheme 6).

5
4.1. General Procedure for Copper Co-Catalyzed Sonogashira
Cross-Coupling of Vinyl Nosylates in acetonitrile
ACCEPTED MANUSCRIPT
PdCl2(PPh3)2 (5 mol%), CuI (5 mol%) and the alkyne (1.2
equiv) were successively added at room temperature to a solution
of vinyl nosylate (1 equiv, 0.5 mmol) in degassed and anhydrous
Scheme 6. Synthesis of cleviolide from vinyl nosylate 3.
acetonitrile
(5
mL,
10
mL/mmol)
under
argon.
Diisopropylethylamine (DIPEA) (1.25 equiv) was then added
dropwise. The reaction mixture was stirred at room temperature
until consumption of the starting material (TLC). The suspension
was then diluted with Et2O (9 mL), filtered over a pad of Celite®
(elution with Et2O), then on a silica gel pad. The filtrate was
evaporated to dryness and chromatographed over silica gel to
afford the product.
The expected product 30 was isolated in good yield despite its
sensitivity (67%). The latter was then very efficiently dehydrated
with diphosphorous pentoxide according to the procedure
reported by Boukouvalas et al..26d The natural product 31 was
thus isolated in high yield (81%). This sequence thus offers a
three-step synthesis of this naturally occurring acetylenic
monoterpene starting from the commercially available 5-
hydroxy-(5H)-furan-2-one (tetronic acid) with an overall yield of
40%. It is worth to note that the coupling step here was more
efficient than those reported from stannyl furanone and 1-
iodoalkyne (37%),26a from iodofuranone and stannylalkyne
(52%)27d but similar to the routes from bromofuranone and
4.1.1. 4-(Trimethylsilylethynyl)-2H-chromen-2-one
(10)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), ethynyltrimethylsilane (92
ꢀL, 0.65 mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at
room temperature during 1 h and gave 10 (119 mg, 4.91 mmol,
stannyl
alkyne26c
,
free
alkyne26d
or
potassium
alkynyltrifluoroborates27c
.
1
98 %) as a yellow powder. H NMR (400 MHz, CDCl3) δ (ppm)
0.34 (s, 9H), 6.56 (s, 1H), 7.32 (dd, J = 7.8 and 1.2 Hz, 1H), 7.33
(ddd, J = 8.2, 7.8 and 1.2 Hz, 1H), 7.55 (ddd, J =8.2, 7.8 and 1.6
Hz, 1H), 7.84 (dd, J = 8.2 and 1.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm) -0.2, 97.7, 109.7, 117.2, 118.5, 119.4, 124.7,
126.9, 132.9, 137.1, 153.8, 160.4; consistent with literature
data.19
3. Conclusion
In the present work, we showed that the para-
nitrobenzenesulfonate (nosylate) group acts as an excellent
partner in Sonogashira cross-coupling reaction, whatever the
cocatalyst (copper or silver) used. We were also able to set up
very mild conditions (room temperature) allowing sensitive
compounds and products such as enynes to be engaged or formed
under these conditions. We demonstrated that these nosylate
leaving group and mild conditions perfectly combine to
efficiently produce coumarinyl products. We also applied these
new leaving group and mild conditions to the total synthesis of
an acetylenic monoterpene natural product.
4.1.2. 4-(Hex-1-ynyl)-2H-chromen-2-one (11)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), 1-hexyne (72 ꢀL, 0.63
mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at room
temperature during 4h and gave 11 (103 mg, 0.455 mmol, 91 %)
1
as a brown oil. H NMR (400 MHz, CDCl3) δ (ppm) 0.99 (t, J =
7.3 Hz, 3H), 1.53 (m, J = 7.3 Hz, 2H), 1.68 (tt, J = 7.3 and 7.1
Hz, 2H), 2.57 (t, J = 7.1 Hz, 2H), 6.49 (s, 1H), 7.28-7.33 (m, 2H),
7.54 (ddd, J = 8.2, 7.5 and 1.6 Hz, 1H), 7.84 (dd, J = 8.2 and 1.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 13.6 19.5, 22.1,
30.3, 74.8, 105.0, 116.9, 118.2, 118.8, 124.3, 126.7, 127.8, 132.0,
138.0, 153.5; consistent with literature data.27c
4. Experimental section
Proton (1H NMR) and Carbon (13C NMR) nuclear magnetic
resonance spectra were recorded on the following 300, 400 or
500 MHz instruments. The chemical shifts are given in part per
million on the delta scale. The solvent peak was used as reference
values. For 1H NMR: CHCl3 = 7.26 ppm. For 13C NMR: CDCl3 =
77.16 ppm. Data are presented as follow; chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint
= quintet, m = multiplet, b = broad), coupling constants (J/Hz)
and integration. IR spectra were recorded as neat sample on a
Brucker Alpha spectrophotometer. High-resolution mass spectra
(HRMS) were recorded by Electrospray Ionisation (ESI) on an
Agilent 6520 Accurate Mass Q-TOF. Analytical thin layer
chromatography (TLC) was carried out on silica gel 60 F254
plates with visualization by ultraviolet light, para-anisaldehyde
or potassium permanganate dip. Flash column chromatography
was carried out using silica gel 60 (40–63 ꢀm) and the procedure
included the subsequent evaporation of solvents in vacuo.
Reagents and solvents were purified using standard means.
Tetrahydrofuran was dried using Glasstechnology DryStation
ST100 purification system (filtration over alumina) under an
argon atmosphere. Acetonitrile and N,N-diisopropylethylamine
(DIPEA) were distilled from CaH2 and stored under an argon
atmosphere. Anhydrous reactions were carried out in flame-dried
glassware and under an argon atmosphere. All extractive
procedures were performed using non-distilled solvents and all
aqueous solutions used were saturated unless details are given.
Vinyl nosylate derivatives 1-3 were prepared according reported
procedures.7b
4.1.3. 4-(Pent-1-ynyl)-2H-chromen-2-one (12)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), 1-pentyne (59 ꢀL, 0.6
mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at room
temperature during 5 h and gave 12 (74 mg, 0.35 mmol, 70 %) as
1
a brown solid. TLC Rf 0.23 (Cyclohexane/EtOAc 9/1); H NMR
(300 MHz, CDCl3) δ (ppm) 1.10 (t, J = 7.3 Hz, 3H), 1.73 (m, J =
7.3 Hz, 2H), 2.55 (t, J = 7.3 Hz, 2H), 6.48 (s, 1H), 7.27- 7.33 (m,
2H), 7.53 (ddd, J = 7.8, 7.8 and 1.6 Hz, 1H), 7.85 (dd, J = 8.1 and
1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm) 13.8, 22.0,
22.0, 75.2, 105.0, 117.1, 118.5, 119.1, 124.5, 126.9, 132.3, 138.3,
153.8, 160.6; HR-MS 235.073 (C14H12O2 + Na+ calcd 235.073).
4.1.4. 4-(Prop-1-ynyl)-2H-chromen-2-one (13)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), propyne (1-2 bar, recharged
after 1 h) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at room
temperature during 2 h and gave 13 (49 mg, 0.27 mmol, 54 %) as
1
a brown solid. TLC Rf 0.19 (Cyclohexane/EtOAc 9/1); H NMR
(300 MHz, CDCl3) δ (ppm) 2.23 (s, 3H), 6.49 (s, 1H), 7.27-7.34
(m, 2H), 7.54 (ddd, J = 7.8, 7.8 and 1.6 Hz, 1H), 7.86 (dd, J = 8.1
and 1.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm) 5.2, 74.2,

6
Tetrahedron
ACCEPTED MANUSCRIPT
100.7, 117.1, 118.5, 119.0, 124.5, 127.0, 132.3, 138.3, 153.7,
1H), 7.26 (ddd, J = 7.9, 7.3 and 1.2 Hz, 1H), 7.31 (dd, J = 8.3 and
160.7; HR-MS 207.044 (C12H8O2 + Na+ calcd 207.042).
1.2 Hz, 1H), 7.38-7.48 (m, 6H), 7.54 (ddd, J = 8.3, 7.3 and 1.4
Hz, 1H), 7.70 (dd, J = 7.9 and 1.4 Hz, 1H), 7.72-7.77 (m, 4H);
13C NMR (100 MHz, CDCl3) δ (ppm) 19.4, 26.9, 53.3, 79.0,
101.1, 117.1, 118.5, 119.1, 124.6, 126.9, 128.1, 130.3, 132.4,
132.9, 135.9, 137.1, 153.7, 160.3; HR-MS 461.154 (C28H26O3Si
+ Na+ calcd 461.154).
4.1.5. 4-(Cyclohexylethynyl)-2H-chromen-2-one
(14)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), cyclohexylacetylene (79
ꢀL, 0.6 mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at
room temperature during 1 h and gave 14 (116 mg, 0.46 mmol,
92 %) as a brown solid. TLC Rf 0.28 (Cyclohexane/EtOAc 9/1);
mp 60-61°C; IR νmax 3064, 2933, 2924, 2845, 2221, 2209, 1718,
1603, 1555, 1484, 1460, 1448, 1369, 1323, 1302, 1273, 1251,
1238, 1174, 1152, 1139, 1105, 1030, 980, 950, 922, 887, 871,
4.1.9. 4-(3-Hydroxy-3-methylbut-1-ynyl)-2H-
chromen-2-one (19)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), 2-methyl-3-butyn-2-ol (63
ꢀL, 0.65 mmol) and DIPEA (109 ꢀL, 0.625 mmol) %) were
stirred at room temperature during 4 h and gave 19 (102 mg, 4.45
843, 818 cm-1; H NMR (400 MHz, CDCl3) δ (ppm) 1.35-1.48
1
(m, 3H), 1.55-1.68 (m, 3H), 1.73-1.84 (m, 2H), 1.90-2.00 (m,
2H), 2.76 (m, 1H), 6.48 (s, 1H), 7.28-7.33 (m, 2H), 7.53 (ddd, J =
8.3, 7.4 and 1.6 Hz, 1H), 7.84 (dd, J = 8.3 and 1.6, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 25.0, 25.9, 30.3, 32.4, 75.0,
109.1, 117.1, 118.3, 119.1, 124.5, 126.9, 132.2, 138.3, 153.8,
160.7; HR-MS 253.124 (C17H16O2S calcd 253.122).
mmol, 89 %) as
(Cyclohexane/Et2O 7/3); mp 93-94°C; IR νmax 3422, 3199, 2983,
a
yellow powder. TLC Rf 0.25
1690, 1600, 1554, 1487, 1445, 1396, 1364, 1326, 1273,
1245,1210, 1169, 1128, 1029, 964, 947, 894, 858, 843 cm-1; H
1
NMR (500 MHz, CDCl3) δ (ppm) 1.70 (s, 6H), 1.94 (bs, 1H),
6.53 (s, 1H), 7.32 (ddd, J = 7.4, 7.1 and 1.6 Hz, 1H), 7.32 (dd, J
= 7.1 and 1.6 Hz, 1H), 7.55 (ddd, J = 8.1, 7.4 and 1.6 Hz, 1H),
7.80 (dd, J = 8.1 and 1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
(ppm) 31.3, 76.1, 84.2, 107.0, 117.2, 118.5, 119.1, 124.7, 126.8,
132.6, 137.0, 153.8, 160.3; HR-MS 251.067 (C14H12O2 + Na+
calcd 251.068).
4.1.6. 4-(Cyclohex-1-enylethynyl)-2H-chromen-2-
one (15)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), 1-ethynylcyclohexene (76
ꢀL, 0.65 mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at
room temperature during 2 h and gave 15 (109 mg, 0.43 mmol,
4.1.10. 4-(3-Hydroxy-4-methylpent-1-ynyl)-2H-
chromen-2-one (20)
1
87 %) as a brown solid. mp 92-93°C; H NMR (500 MHz,
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), 4-methylpent-1-yn-3-ol (64
ꢀL, 0.6 mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at
room temperature during 6h and gave 20 (94 mg, 0.39 mmol, 77
%) as a yellow powder. TLC Rf 0.23 (Cyclohexane/EtOAc 7/3);
mp 83-84°C; IR νmax 3505, 3071, 2967, 2932, 2872, 2225, 1710,
1606, 1556, 1487, 1472, 1452, 1373, 1326, 1275, 1253, 1235,
1182, 1144, 1113, 1100, 1032, 959, 940, 896, 860, 836, 808 cm-1;
1H NMR (500 MHz, CDCl3) δ (ppm) 1.11 (d, J = 6.8 Hz, 3H),
1.13 (d, J = 6.8 Hz, 3H), 2.08 (dm, J = 6.8 and 5.6 Hz, 1H), 2.17
(bs, 1H), 4.53 (d, J = 5.6 Hz, 1H), 6.55 (s, 1H), 7.31 (ddd, J =
7.6, 7.5 and 1.6 Hz, 1H), 7.32 (dd, J = 7.5 and 1.6 Hz, 1H), 7.55
(ddd, J = 8.0, 7.6 and 1.6 Hz, 1H), 7.82 (dd, J = 8.0 and 1.6 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ (ppm) 17.9, 18.4, 34.8, 68.6,
79.3, 102.6, 117.3, 118.5, 119.3, 124.7, 126.8, 132.6, 137.1,
153.8, 160.3; HR-MS 265.084 (C15H14O3 calcd + Na+ 265.084).
CDCl3) δ (ppm) 1.64-1.70 (m, 2H), 1.70-1.76 (m, 2H), 2.19-2.26
(m, 2H), 2.27-2.33 (m, 2H), 6.47 (tt, J = 4.2 and 1.9 Hz, 1H),
6.50 (s, 1H), 7.31 (ddd, J = 8.4, 7.3 and 1.6 Hz, 1H), 7.32 (dd, J
= 7.7 and 1.6 Hz, 1H), 7.54 (ddd, J = 8.4, 7.3 and 1.6 Hz, 1H),
7.84 (dd, J = 7.7 and 1.6 Hz, 1H) 13C NMR (125 MHz, CDCl3) δ
(ppm) 21.5, 22.3, 26.3, 29.0, 80.9, 117.2, 118.8, 120.1, 124.5,
126.9, 132.3, 138.0, 140.3; HR-MS 273.090 (C17H14O2 + Na+
calcd 273.089).
4.1.7. 4-(3-Hydroxyprop-1-ynyl)-2H-chromen-2-one
(17)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), propargyl alcohol (38 ꢀL,
0.65 mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at
room temperature during 14 h and gave 17 (10 mg, 0.05 mmol,
10 %) as a yellow powder. TLC Rf 0.23 (Cyclohexane/Et2O 7/3);
mp 89-91°C; IR νmax 3265, 2924, 2851, 1671, 1604, 1557, 1530,
1442, 1372, 1349, 1278, 1260, 1229, 1191, 1138, 1100, 1016,
970, 950, 914, 877, 856, 811 cm-1; 1H NMR (500 MHz, CDCl3) δ
(ppm) 4.64 (s, 2H), 6.56 (s, 1H), 7.32 (ddd, J = 8.3, 7.7 and 1.3
Hz, 1H), 7.33 (dd, J = 7.2 and 1.3 Hz, 1H), 7.56 (ddd, J = 8.3, 7.2
and 1.3 Hz, 1H), 7.85(dd, J = 7.7 and 1.3 Hz, 1H); HR-MS
223.036 (C12H8O3 + Na+ calcd 223.037).
4.1.11. 4-(6-Hydroxyhex-1-ynyl)-2H-chromen-2-one
(21)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), 5-hexyn-1-ol (72 ꢀL, 0.65
mmol) and DIPEA (109 ꢀL, 0.625 mmol) were stirred at room
temperature during 6 h and gave 21 (86 mg, 0.36 mmol, 71 %) as
a white solid. TLC Rf 0.13 (Cyclohexane/EtOAc 7/3); mp 50-
51°C; IR νmax 3321, 3068, 2940, 2223, 1711, 1682, 1603, 1555,
1485, 1449, 1420, 1373, 1329, 1273, 1256, 1179, 1136, 1103,
1049, 1031, 984, 936, 858, 813 cm-1; 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.74- 1.84 (m, 4H), 2.62 (t, J = 6.8 Hz, 2H), 3.74
(t, J = 5.7 Hz, 2H), 6.48 (s, 1H), 7.27-7.33 (m, 2H), 7.53 (ddd, J
4.1.8. 4-(3-(tert-Butyldiphenylsilyloxy)prop-1-
ynyl)-2H-chromen-2-one (18)
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), tert-butyldiphenyl(prop-2-
yn-1-yloxy)silane (191 mg, 0.65 mmol) and DIPEA (109 ꢀL,
0.625 mmol) were stirred at room temperature during 14 h and
gave 18 (147 mg, 3.3 mmol, 67 %) as a brown oil. TLC Rf 0.20
(Cyclohexane/Et2O 8/2); IR νmax 3070, 2929, 2856, 1721, 1605,
1557, 1488, 1471, 1450, 1427, 1369, 1323, 1274, 1253, 1230,
1178, 1137, 1105, 1075, 1031, 997, 932, 860, 822 cm-1; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.10 (s, 9H), 4.67 (s, 2H), 6.40 (s,
= 8.3, 7.4 and 2.0 Hz, 1H), 7.83 (dd, J = 8.1 and 2.0 Hz, 1H); 13
NMR (100 MHz, CDCl3) δ (ppm) 19.9, 24.9, 32.1, 62.4, 75.3,
104.7, 117.1, 118.5, 118.9, 124.6, 126.9, 132.3, 138.2, 153.7,
160.6; HR-MS 265.084 (C15H14O3 + Na+ calcd 265.084).
C
4.1.12. 2-(4-(2-Oxo-2H-chromen-4-yl)but-3-
ynyl)isoindoline-1,3-dione (22)

7
Following the general procedure, 2-oxo-2H-chromen-4-yl 4-
nitrobenzenesulfonate 1 (173 mg, 0.5 mmol), PdCl2(PPh3)2 (17.5
mg, 5 mol%), CuI (4.7 mg, 5 mol%), N-(3-butynyl)phthalimide
(129 mg, 0.65 mmol) and DIPEA (109 ꢀL, 0.625 mmol) were
stirred at room temperature during 6 h and gave 22 (119 mg, 3.45
mmol, 69 %) as a white solid. TLC Rf 0.13 (Cyclohexane/EtOAc
7/3); mp 169-170°C; IR νmax 3035, 2227, 1767, 1701, 1608,
1558, 1487, 1463, 1397, 1374, 1359, 1346, 1298, 1277, 1252,
1233, 1159, 1115, 1089, 1072, 1032, 1020, 986, 963, 934, 884,
at room temperature during 2 h and gave 26 (8.9 mg, 42.0
ACCEPTED MANUSCRIPT
µmol, 54 %) as brown oil. TLC Rf 0.48 (Cyclohexane/EtOAc
8/2); IR νmax ;1H NMR (400 MHz, CDCl3) δ (ppm) 1.03 (t, J =
7.3 Hz, 3H), 1.62 (p, J = 7.3 Hz, 2H), 2.33 (d, J = 1.4 Hz, 3H),
2.38 (t, J = 7.0 Hz, 2H), 7.08 (d, J = 1.7 Hz, 1H), 7.46 (t, J = 7.5
Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.90-7.96 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 13.7, 21.3, 21.8, 22.1, 84.3, 96.7,
127.3, 128.3 (x2), 128.7 (x2), 132.8, 138.9, 139.1, 190.9. HR-MS
213.1289 (C15H16O + H+ calcd 213.1274).
852 cm-1; H NMR (500 MHz, CDCl3) δ (ppm) 3.01 (t, J = 6.8
1
4.1.17. (E)-5-Cyclohexyl-3-methyl-1-phenylpent-2-
en-4-ynone (27)
Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 6.44 (s, 1H), 7.23 (ddd, J = 8.1,
7.4 and 1.2 Hz, 1H), 7.28 (dd, J = 8.1 and 1.2 Hz, 1H), 7.52 (ddd,
J = 8.2, 7.4 and 1.7 Hz, 1H), 7.73-7.76 (m, 3H), 7.86-7.90 (m,
2H); 13C NMR (125 MHz, CDCl3) δ (ppm) 20.1, 36.3, 76.6,
100.0, 117.1, 118.7, 119.2, 123.7, 124.5, 127.0, 132.1, 132.4,
137.5, 153.7, 160.4, 168.0; HR-MS 366.075 (C21H13NO4 + Na+
calcd 366.074).
Following the general procedure, (E)-4-oxo-4-phenylbut-2-
en-2-yl 4-nitrobenzenesulfonate 5E (37 mg, 106.5 µmol),
PdCl2(PPh3)2 (3.9 mg, 5 mol%), CuI (1.1 mg, 5 mol%),
cyclohexylacetylene (18 ꢀL, 128 µmol) and DIPEA (25 ꢀL, 133
µmol) were stirred at room temperature during 2 h and gave 27
(17.5 mg, 69 µmol, 63 %) as brown oil. TLC Rf 0.47
(Cyclohexane/EtOAc 8/2); IR νmax ; 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.34 (td, J = 10.3 and 4.1 Hz, 4H), 1.51 (tdd, J = 12.5,
5.2 and 3.0 Hz, 2H), 1.73 (dtd, J = 11.5, 7.7, 6.6 and 3.5 Hz, 2H),
1.85 (dq, J = 12.6 and 3.5 Hz, 2H), 2.34 (d, J = 1.4 Hz, 3H), 2.57
(tt, J = 8.3 and 3.5 Hz, 1H), 7.07 (q, J = 1.5 Hz, 1H), 7.43-7.48
(m, 2H), 7.50-7.57 (m, 1H), 7.92- 7.96 (m, 2H).; 13C NMR (100
MHz, CDCl3) δ (ppm) 21.5, 25.0, 25.9, 29.9, 30.0, 32.5, 84.1,
100.9, 127.2, 128.3 (x2), 128.7 (x2), 132.7, 139.0, 139.3, 190.9.
HR-MS 253.1580 (C18H20O + H+ calcd 253.1587).
4.1.13. 3-(Hex-1-ynyl)-5,5-dimethylcyclohex-2-
enone (23)
Following
the
general
procedure,
5,5-dimethyl-3-
oxocyclohex-1-en-1-yl 4-nitrobenzenesulfonate 2 (162 mg, 0.5
mmol), PdCl2(PPh3)2 (17.5 mg, 5 mol%), CuI (4.7 mg, 5 mol%),
1-hexyne (72 ꢀL, 0.63 mmol) and DIPEA (109 ꢀL, 0.625 mmol)
were stirred at room temperature during 2 h and gave 23 (90 mg,
1
0.44 mmol, 88 %) as a brown oil. H NMR (400 MHz, CDCl3) δ
(ppm) 0.93 (t, J = 7.3 Hz, 3H), 1.05 (s, 6H), 1.43 (m, J = 7.3 Hz,
2H), 1.55 (tt, J = 7.3 and 7.1 Hz, 2H), 2.23 (s, 2H), 2.29 (d, J =
1.6 Hz, 2H), 2.40 (t, J = 7.1 Hz, 2H), 6.13 (t, J = 1.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 13.8, 19.7, 22.2, 28.3, 30.6,
33.9, 45.0, 51.3, 80.9, 102.2, 131.0, 142.6, 190.4, 199.4;
consistent with literature data.28
4.1.18. 4-(Hex-1-ynyl)-2(5H)-furanone (28)
Following the general procedure, 5-oxo-2,5-dihydrofuran-3-
yl 4-nitrobenzenesulfonate 3 (142 mg, 0.5 mmol), PdCl2(PPh3)2
(17.5 mg, 5 mol%), CuI (4.7 mg, 5 mol%), 1-hexyne (75 ꢀL,
0.65 mmol), and DIPEA (109 ꢀL, 0.625 mmol) were stirred at
room temperature during 2 h and gave 28 (68 mg, 0.415 mmol,
4.1.14. 3-(3-Hydroxyprop-1-ynyl)-5,5-
dimethylcyclohex-2-enone (24)
1
83 %) as a brown oil. H NMR (400 MHz, CDCl3) δ (ppm) 0.94
Following
the
general
procedure,
5,5-dimethyl-3-
(t, J = 7.3 Hz, 3H), 1.43 (m, J = 7.3 Hz, 2H), 1.58 (tt, J = 7.3 and
7.1 Hz, 2H), 2.45 (t, J = 7.1 Hz, 2H), 4.76 (d, J =1.9 Hz, 2H),
6.08 (t, J = 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm)
13.7, 19.8, 22.2, 30.2, 71.7, 73.5, 108.4, 121.6, 148.4, 158.8;
consistent with literature data.27a
oxocyclohex-1-en-1-yl 4-nitrobenzenesulfonate 2 (162 mg, 0.5
mmol), PdCl2(PPh3)2 (17.5 mg, 5 mol%), CuI (4.7 mg, 5 mol%),
propargyl alcohol (38 ꢀL, 0.65 mmol), and DIPEA (109 ꢀL,
0.625 mmol) were stirred at room temperature during 1 h and
gave 24 (88 mg, 0.494 mmol, 99 %) as a clear oil. TLC Rf 0.21
(Cyclohexane/EtOAc 7/3); IR νmax 3407, 2958, 2218, 1657, 1594,
1470, 1355, 1278, 1243, 1213, 1164, 1143, 1120, 1034, 997, 967,
901, 870, 849 cm-1; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.05 (s,
6H), 2.26 (s, 2H), 2.32 (d, J = 1.6 Hz, 2H), 2.68 (bs, 1H), 4.47 (d,
J = 5.8 Hz , 2H), 6.21 (t, J = 1.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 28.3, 34.0, 44.4, 51.1, 51.5, 84.8, 98.3, 131.7,
141.3, 199.7; HR-MS 201.088 (C11H14O2 + Na+ calcd 201.089).
4.1.19. 4-(Prop-1-ynyl)-2(5H)-furanone (29)
Following the general procedure, 5-oxo-2,5-dihydrofuran-3-
yl 4-nitrobenzenesulfonate 3 (142 mg, 0.5 mmol), PdCl2(PPh3)2
(17.5 mg, 5 mol%), CuI (4.7 mg, 5 mol%), propyne (1-2 bar),
and DIPEA (109 ꢀL, 0.625 mmol) were stirred at room
temperature during 4 h and gave 29 (65 mg, 0.265 mmol, 58 %)
as a brown oil. TLC Rf 0.27 (Cyclohexane/EtOAc 8/2); 1H NMR
(300 MHz, CDCl3) δ (ppm) 2.12 (s, 3H), 4.76 (d, J = 2.0 Hz,
2H), 6.09 (t, J = 2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 5.2, 71.0, 73.4, 104.0, 121.7, 148.4, 173.9; HR-MS
145.026 (C7H6O2 + Na+ calcd 145.026).
4.1.15. 3-(Prop-1-ynyl)-5,5-dimethylcyclohex-2-
enone (25)
Following
the
general
procedure,
5,5-dimethyl-3-
oxocyclohex-1-en-1-yl 4-nitrobenzenesulfonate 2 (162 mg, 0.5
mmol), PdCl2(PPh3)2 (17.5 mg, 5 mol%), CuI (4.7 mg, 5 mol%),
propyne (1-2 bar) and DIPEA (109 ꢀL, 0.625 mmol) were stirred
at room temperature during 2 h and gave 25 (63 mg, 0.39 mmol,
4.1.20. 4-(3-Hydroxy-4-methylpent-1-ynyl)-2(5H)-
furanone (30)
Following the general procedure, 5-oxo-2,5-dihydrofuran-3-
yl 4- nitrobenzenesulfonate 3 (142 mg, 0.5 mmol), PdCl2(PPh3)2
(17.5 mg, 5 mol%), CuI (4.7 mg, 5 mol%), 4-methylpent-1-yn-3-
ol (69 ꢀL, 0.65 mmol) and DIPEA (109 ꢀL, 0.625 mmol) were
stirred at room temperature during 5 h and gave 30 (66 mg, 3.65
1
78 %) as a yellow liquid. H NMR (300 MHz, CDCl3) δ (ppm)
1.04 (s, 6H), 2.05 (s, 3H), 2.23 (s, 2H), 2.23 (d, J = 1.8 Hz, 2H),
6.13 (t, J = 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm) 5.1,
28.3, 33.9, 44.8, 51.2, 80.0, 97.7, 131.1, 142.6, 199.6; HR-MS
185.094 (C11H14O + Na+ calcd 185.094).
1
mmol, 73 %) as a brown oil. H NMR (400 MHz, CDCl3) δ
(ppm) 1.02 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.97 (m,
J = 6.8 Hz, 1H), 2.31 (d, J = 5.6 Hz, 1H), 4.40 (t, J = 5.6 Hz,
1H), 4.80 (d, J = 2.0 Hz, 2H), 6.18 (t, J = 2.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 18.0, 18.2, 34.6, 68.5, 73.2, 75.8,
105.9, 123.0, 147.0, 173.4.
4.1.16. (E)-3-Methyl-1-phenyloct-2-en-4-ynone (26)
Following the general procedure, (E)-4-oxo-4-phenylbut-2-
en-2-yl 4-nitrobenzenesulfonate 5E (27 mg, 77.7 µmol),
PdCl2(PPh3)2 (2.8 mg, 5 mol%), CuI (0.8 mg, 5 mol%), pentyne
(10 ꢀL, 93.3 µmol) and DIPEA (17 ꢀL, 97.2 µmol) were stirred
4.1.21. Cleviolide (31)

8
Tetrahedron
ACCEPTED MANUSCRIPT
12. (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422;
Phosphorous pentoxide (2.5 equiv) was portionwise added to
(b) For a review, see: Siemsen, P.; Livingston, R. C.; Diederich, F.
Angew. Chem. Int. Ed. 2000, 39, 2632.
a solution of 30 (0.2 mmol) in benzene (3 mL). The mixture was
stirred at reflux during 2 h and was then allowed to cool to room
temperature. The mixture was filtered over celite and the solvent
evaporated to dryness. Crude was recrystallized from
13. (a) U. Halbes-Letinois, P. Pale, S. Berger, Magn. Reson. Chem.
2004, 42, 831; (b) U. Halbes-Letinois, P. Pale, S. Berger, J. Org.
Chem. 2005, 70, 9185.
14. Halbes-Letinois, U., Weibel, J.-M., Pale, P. Chem. Soc. Rev.
2007, 36, 759.
15. Bertus, P., Dillinger, S., Pale, P. Org. Lett. 2001, 3, 1661.
16. (a) Grushin, V.; Alper, H. Organometallics 1996, 15, 5242;
(b) Ruiz, J.; Rodriguez, V.; Lopez, G.; Chaloner, P. A.; Hitchcock,
P. B. J. Chem. Soc., Dalton Trans. 1997, 4271;
(c) Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J. 2011, 17,
2492.
1
AcOEt:hexane to afford cleviolide 31 (81 %). H NMR (500
MHz, CDCl3) δ (ppm) 1.91 (d, J = 1.2 Hz 3H), 1.96 (s, 3H), 4.82
(d, J = 2.0 Hz, 2H), 5.49 (q, J = 1.2 Hz, 1H), 6.11 (t, J = 2.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ (ppm) 21.9, 25.6, 73.2, 81.9,
104.2, 104.4, 120.7, 148.0, 155.4, 173.9; consistent with
literature data.26c-d
17. Schio, L.; Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41,
1543.
Acknowledgments
18. (a) Wang, Z.; Xue, L.; He, Y.; Weng, L.; Fang, L. J. Org. Chem.
2014, 79, 9628;
We gratefully acknowledge the French Ministry of Research
and the CNRS for financial supports. NPC thanks the French
Agency of Research (ANR 09-BLAN-0329 CADISCOM). AD
thanks the French Ministry of Research for a PhD fellowship.
(b) Ngo, T. N.; Akrawi, O. A.; Dang, T. T.; Villinger, A.; Langer,
P. Tetrahedron Lett. 2015, 56, 86.
19. Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642.
20. Nyuchev, A. V.; Sharonova, E. A.; Lenshina, N. A.; Shavyrin, A.
S.; Lopatin, M. A.; Balalaeva, I. V.; Beletskaya, I. P.; Fedorov, A.
Y. Tetrahedron Lett. 2011, 52, 4196.
21. Marrison, L. R.; Dickinson, J. M.; Ahmed, R.; Fairlamb, I. J. S.
Tetrahedron Lett. 2002, 43, 8853.
22. For a review, see: Figadère, B. Acc. Chem. Res. 1995, 28, 359.
23. For a recent example, see: Gomes, J.; Daeppen, C.; Liffert, R.;
Roesslein, J.; Kaufmann, E.; Heikinheimo, A.; Neuburger, M.;
Gademann, K. J. Org. Chem. 2016, 81, 11017.
Appendix A. Supplementary data
Supplementary data related to this article can be found at …
References and notes
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12.

Furanone Natural Products
ACCEPTED MANUSCRIPT
O
O
O
O
R
LG
O
or
Cleviolide
O
H
m
OH
R
O
OR'
O
O
OR
Furospongolide
Scutolides A-L
Scutebartines C-D
Dienediyne Natural Products
O
O
O
O
R'
MeO
OH
OH
O
HO
O
O
Z
O
LG
O
Z'
MeNH
OH
OH
O
LG'
HO
R
O
HO
NCS-Chrom
O
Cl
MeO
N1999A2
+ Kedarcidin, Maduropeptin, C1027