Copper-free Sonogashira reactions of 4-hydroxycoumarins with alkynes

Article abstract of DOI:10.1016/j.tet.2009.06.089

The palladium-catalyzed direct coupling reactions of 4-hydroxycoumarins with various alkynes under copper-free conditions are described. This transformation is highly effective under mild conditions and the desired products are obtained in good yields.

Full text of DOI:10.1016/j.tet.2009.06.089

Tetrahedron 65 (2009) 6810–6814
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Tetrahedron
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Copper-free Sonogashira reactions of 4-hydroxycoumarins with alkynes
,b,
Yong Luo a, Jie Wu a
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 May 2009
Received in revised form 15 June 2009
Accepted 23 June 2009
Available online 26 June 2009
The palladium-catalyzed direct coupling reactions of 4-hydroxycoumarins with various alkynes under
copper-free conditions are described. This transformation is highly effective under mild conditions and
the desired products are obtained in good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alkyne
Copper-free conditions
4-Hydroxycoumarin
Palladium catalyst
1. Introduction
4-hydroxycoumarins with alkynes. This transformation is highly
effective under copper-free conditions.
Pd-catalyzed cross-coupling reactions can be considered now-
adays to be the most reliable methodology for the formation of
carbon–carbon bonds.1 The types of reactions find increasing ap-
plication in the synthesis of complex organic molecules.2 It is well-
Since a goal of chemical genetics is to find small molecules that
modulate the individual functions of gene products with high po-
tency and high specificity,6 we have developed efficient methods to
build up the libraries of natural product-like compounds.7 Among
the scaffold selected, we identified that coumarin was a universal
skeleton for our chemical genetic approach. Although continuous
efforts toward the coumarin synthesis have been reported due to the
prominence of coumarin in natural products and biologically active
molecules,7j,8–10 developing a novel method for generation of cou-
marin compounds from commercially available 4-hydroxycoumarin
would be of importance. On the other hand, the synthetic potential of
alkynyl fragment in a conjugated enyne system has been demon-
strated as precursor to construct even more complex molecules.11
Since many alkynes are commercially available or synthetically ac-
cessible and the Sonogashira reaction12 is a versatile method for
carbon–carbon bond formation, we start to investigate the direct
cross-coupling reactions of 4-hydroxycoumarins with alkynes.
known that in
a cross-coupling reaction, an electrophile is
combined with a nucleophile to provide the corresponding cou-
pling product. Traditionally, the pre-activated substrates such as
organic (pseudo)halides have to be utilized in these cross-coupling
reactions. Recently, an example of palladium-catalyzed cross-cou-
pling reactions with arylboronic acids via C–OH bond activation of
tautomerizable heterocycles was reported.3 In this reaction, the
phosphonium salts were used as activation reagent, and the pres-
ence of phosphonium salt was proposed to enable an in situ acti-
vation of tautomerizable heterocycle, and then underwent the
subsequent palladium-catalyzed cross-coupling reactions with
arylboronic acids. Afterwhile, Ackermann reported that phenols
could be used as proelectrophiles in ruthenium-catalyzed dehy-
drative direct arylations through functionalizations of C–H and
C–OH bonds.4 In this reaction process, p-toluenesulfonyl chloride
acted as an activator. Meanwhile, we also realized the palladium-
catalyzed cross-coupling reactions of 4-hydroxycoumarins
with arylboronic acids using p-toluenesulfonyl chloride as an ac-
tivation reagent.5 Herein, we would like to disclose another ex-
ample of palladium-catalyzed direct cross-coupling reactions of
2. Results and discussion
The reaction was initially studied with 4-hydroxycoumarin 1a
and phenyl acetylene 2a, which were selected as suitable substrates
for reaction development (Table 1). At the outset, various palladium
catalysts were screened. To our delight, we observed the formation
of the desired product 3a when the reaction was carried out in the
presence of PdCl2 (5 mol %), CuI (10 mol %), p-toluenesulfonyl
i
chloride (1.2 equiv), and Pr2NEt (3.0 equiv) in MeCN at 60 ꢀC (35%
* Corresponding author. Tel.: þ86 21 5566 4619; fax: þ86 21 6510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
yield, Table 1, entry 1). Similar results were obtained when
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.089

Y. Luo, J. Wu / Tetrahedron 65 (2009) 6810–6814
6811
Table 1
Table 2
Palladium-catalyzed direct cross-coupling reaction of 4-hydroxycoumarin 1a with
phenyl acetylene 2a
Palladium-catalyzed direct coupling reaction of 4-hydroxycoumarin 1 with alkyne 2
R2
Ph
OH
PdCl2(PPh3)2
(5 mol %)
Pr2NEt, MeCN
TsCl, 60 °C
OH
R2
R1
+
[Pd] (5 mol%)
R1
i
+
Ph
2a
O
O
base, solvent
additive
O
O
O
O
O
3a
O
1
2
3
1a
Entry
Coumarin 1
Alkyne 2
Product
Yielda (%)
81
Entry [Pd] catalyst Additive
Base
Solvent Yielda
(%)
OH
1
2
3
4
5
6
PdCl2
CuI (10 mol %)/TsCl (1.0 equiv) iPr2NEt MeCN
CuI (10 mol %)/TsCl (1.0 equiv) iPr2NEt MeCN
CuI (10 mol %)/TsCl (1.0 equiv) iPr2NEt MeCN
CuI (10 mol %)/TsCl (1.0 equiv) iPr2NEt MeCN
35
36
43
33
1
2
3a
3b
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
2a
O
O
1a
OMe
PdCl2(PPh3)2 CuI (10 mol %)/TsCl (1.0 equiv) iPr2NEt MeCN
46 (80)b
15
1a
77
PdCl2(dppf)
CuI (10 mol %)/TsCl (1.0 equiv) iPr2NEt MeCN
2b
7b
8b
9b
10b
11b
12b
13b
PdCl2(PPh3)2 TsCl (1.0 equiv)
PdCl2(PPh3)2 CuI (10 mol %)
PdCl2(PPh3)2 TsCl (1.0 equiv)
PdCl2(PPh3)2 TsCl (1.0 equiv)
PdCl2(PPh3)2 TsCl (1.0 equiv)
PdCl2(PPh3)2 MsCl (1.0 equiv)
PdCl2(PPh3)2 TsCl (1.0 equiv)
iPr2NEt MeCN
iPr2NEt MeCN
K2CO3
Na2CO3 MeCN
81
NR
Cl
3
4
5
1a
1a
1a
3c
3d
3e
60
86
71
MeCN
Trace
Trace
56
2c
K3PO4
MeCN
2d
iPr2NEt MeCN
iPr2NEt THF
Trace
58
a
2e
Isolated yield based on 4-hydroxycoumarin.
In the presence of 2.0 equiv of phenyl acetylene.
b
OH
O
6
3f
78
Pd(OAc)2 was used as a replacement (36% yield, Table 1, entry 2).
Further screening revealed that PdCl2(PPh3)2 was the best choice
for this transformation (51% yield, Table 1, entry 5). The yield of 3a
could be increased to 80% when the amount of phenyl acetylene
was increased to 2.0 equiv. Interestingly, in the absence of copper
iodide the reaction also proceeded smoothly to give the desired
product 3a in 81% yield (Table 1, entry 7). The copper-free Sono-
gashira reactions have been investigated in the last few years.13
Addition of an activating agent was essential in the reaction. No
reaction occurred without the addition of p-toluenesulfonyl chlo-
ride (Table 1, entry 8). Other bases were examined in the reaction.
2a
O
1b
1b
7
8
3g
3h
91
81
2d
1b
2e
OH
OMe
9
3i
81
72
48
MeO
1c
O
O
2b
10
11
1c
3j
i
2d
However, Pr2NEt turned out to be the best one (Table 1, entries
OH
O
9–11). Only trace amount of product was detected when meth-
anesulfonyl chloride was used as an additive instead of p-tolue-
nesulfonyl chloride (Table 1, entry 12). When the solvent was
changed to THF, the yield was decreased to 58% (Table 1, entry 13).
With this result in hands and having defined an efficient catalytic
system [PdCl2(PPh3)2 (5 mol %), iPr2NEt, TsCl, MeCN], the scope of the
palladium-catalyzed direct cross-coupling reactions of 4-hydroxy-
coumarins 1 with alkynes 2 was next explored. The results obtained
are shown in Table 2. In all cases, 4-alkynylcoumarins 3 were
obtained in moderate to good yields. For instance, reaction of
4-hydroxycoumarin 1a with 4-methoxyphenyl acetylene 2b gave
rise to the desired product 3b in 77% yield (Table 2, entry 2). 86% yield
of compound 3d was observed when ethynylcyclopropane 2d was
employed in the reaction (Table 2, entry 4). When 1-hexyne 2e was
utilized as a replacement in the reaction of 4-hydroxycoumarin 1a,
the transformation also proceeded well to furnish the corresponding
products in good yields (71% yield, Table 2, entry 5). To assess the
impact of the structural and functional motifs on the reaction we
tested the linking units of 4-hydroxycoumarins meanwhile. We
found that the conditions have proven to be useful for various 4-
hydroxycoumarins. Both electron-rich and electron-poor 4-hydroxy-
coumarins were suitable partners in this process. However, better
results were displayed when electron-donating groups attached on
the aromatic ring of 4-hydroxycoumarins. For example, 6,7-di-
methyl-4-hydroxycoumarin 1b reacted with ethynylcyclopropane 2d
leading to the desired product 3g in 91% yield (Table 2, entry 7).
In order to illustrate the reaction process, reaction of 4-tosyl-
oxycoumarin with phenylacetylene 2a under the copper-free
F
3k
2a
O
1d
OMe
12
13
14
1d
1d
1d
3l
60
53
54
2b
3m
3n
2d
2e
OH
O
Cl
15
16
3o
3p
48
45
2a
O
1e
OMe
1e
2b
17
18
1e
1e
3q
3r
58
72
2d
2e
a
Isolated yield based on 4-hydroxycoumarin 1.
conditions was performed [PdCl2(PPh3)2 (5 mol %), iPr2NEt, MeCN].
As expected, the desired product 3a was generated in 80% yield
compared with our previous result.9b Since 4-tosyloxycoumarin
could undergo the 1,4-addition and subsequent
the presence of nucleophile, blank experiment without the
b-elimination in

6812
Y. Luo, J. Wu / Tetrahedron 65 (2009) 6810–6814
addition of palladium catalyst was then examined. However, no
reaction was observed under the conditions. Thus, we proposed the
possible mechanism for the palladium-catalyzed direct coupling
reaction of 4-hydroxycoumarin 1 with alkyne 2 (Scheme 1).
According to the previous reports,13 we reasoned that the presence
of p-toluenesulfonyl chloride would enable an in situ activation of
4-hydroxycoumarin. Therefore, oxidative addition of Pd(0) to 4-
tosyloxycoumarin 4 would generated intermediate A, which then
reacted with alkyne leading to intermediate B. The latter would
undergo subsequent reductive elimination to afford the corre-
sponding product 3.
CH3CN (2.0 mL) was stirred at 60 ꢀC. Subsequently, terminal acety-
lene (0.4 mmol, 2.0 equiv), N,N-diisopropylethyl amine
(0.6 mmol, 3.0 equiv) were added into the mixture. After comple-
tion of the reaction as indicated by TLC, the solvent was diluted
with EtOAc (10 mL), washed with saturated brine (2ꢁ10 mL), and
dried by anhydrous Na2SO4. Evaporation of the solvent followed by
purification on silica gel provided the corresponding compound 3.
2
4.2.1. 4-(Phenylethynyl)-2H-chromen-2-one (3a)9b
1H NMR (500 MHz, CDCl3)
d
7.97 (d, J¼7.5 Hz, 1H), 7.66 (d,
J¼7.5 Hz, 2H), 7.59 (t, J¼8.5, 7.0 Hz, 1H), 7.43–7.52 (m, 3H), 7.37 (t,
J¼8.0 Hz, 2H), 6.64 (s, 1H). 13C NMR (125.7 MHz)
d 160.5, 153.8,
OH
146.7, 137.5, 132.5, 132.4, 130.5, 129.0, 126.9, 124.7, 121.4, 118.6, 117.3,
102.4, 83.4.
R2
R1
TsCl
base
R1
O
1
O
OTs
4.2.2. 4-((4-Methoxyphenyl)ethynyl)-2H-chromen-2-one (3b)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.94 (d, J¼7.8 Hz, 1H),
7.54–7.59 (m, 3H), 7.32–7.36 (m, 2H), 6.93–6.95 (d, J¼8.7 Hz, 2H),
6.58 (s, 1H), 3.90 (s, 3H). 13C NMR (100 MHz)
161.1, 160.4, 153.5,
R1
Pd(0)
O
4
O
d
O
O
137.6, 134.0, 132.1, 126.7, 124.3, 118.4, 117.5, 117.0, 114.4, 113.0, 102.9,
82.1, 55.4. HRMS (ESI) calcd for C18H12O3 [MþH]þ 277.0865, found
277.0858.
3
R2
PdII
O
TsO
PdII
O
R1
R1
4.2.3. 4-((4-Chlorophenyl)ethynyl)-2H-chromen-2-one (3c)
B
A
White solid. 1H NMR (400 MHz, CDCl3)
d
7.91–7.94 (m,1H), 7.56–
7.60 (m, 3H), 7.41–7.43 (m, 2H), 7.34–7.38 (m, 2H), 6.63 (s, 1H). 13C
NMR (100 MHz) 160.1,153.5,136.9,136.5,133.4,132.4,129.1,126.5,
O
O
H
R2
d
2
base
R2
124.5, 119.6, 118.6, 118.2, 117.1, 100.7, 83.6. HRMS (ESI) calcd for
C17H9ClO2 [MþH]þ 281.0369, found 281.0354.
Scheme 1. Possible mechanism for the palladium-catalyzed direct coupling reaction of
4-hydroxycoumarin 1 with alkyne 2.
4.2.4. 4-(Cyclopropylethynyl)-2H-chromen-2-one (3d)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.79 (dd, J¼7.8, 3.4 Hz,
1H), 7.51–7.53 (m, 1H), 7.27–7.30 (m, 2H), 6.43 (s, 1H), 1.59–1.62 (m,
1H), 0.98–1.06 (m, 4H). 13C NMR (100 MHz)
160.4, 153.5, 138.0,
3. Conclusions
d
In conclusion, we have described an efficient method for the
palladium-catalyzed direct cross-coupling reactions of 4-hydroxy-
coumarins 1 with alkynes 2. p-Toluenesulfonyl chloride was used as
an activation reagent in the reaction process. In addition, this
transformation was performed under copper-free conditions which
generated the 4-alkynylcoumarins in good yields. Further in-
vestigation using phenols as substrates in cross-coupling reactions
is ongoing, and the results will be reported in due course.
132.0, 126.7, 124.2, 118.8, 117.8, 116.8, 108.5, 70.1, 9.7, 0.6. HRMS (ESI)
calcd for C14H10O2 [MþNa]þ 233.0579, found 233.0570.
4.2.5. 4-(Hex-1-ynyl)-2H-chromen-2-one (3e)9b
1H NMR (400 MHz, CDCl3)
d
7.84 (dd, J¼7.8, 1.4 Hz, 1H), 7.52–
7.56 (m, 1H), 7.30–7.33 (m, 2H), 6.49 (s, 1H), 2.57 (t, J¼6.9 Hz, 2H),
1.66–1.70 (m, 2H), 1.49–1.55 (m, 2H), 0.99 (t, J¼7.4 Hz, 3H). 13C NMR
(100 MHz) d 160.5, 153.5, 138.1, 132.1, 126.7, 124.3, 118.8, 118.2, 116.9,
105.1, 74.8, 30.2, 22.1, 19.5, 13.5.
4. Experimental section
4.1. General method
4.2.6. 6,7-Dimethyl-4-(phenylethynyl)-2H-chromen-2-one (3f)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.63–7.66 (m, 3H),
7.43–7.46 (m, 3H), 7.11 (s, 1H), 6.54 (s, 1H), 2.35 (s, 3H), 2.39 (s, 3H).
13C NMR (100 MHz)
160.7, 151.9, 142.4, 137.0, 133.2, 132.2, 130.0,
All reactions were performed in reaction tubes under nitrogen
atmosphere. Flash column chromatography was performed using
silica gel (60-Å pore size, 32–63
mm, standard grade). Analytical
d
128.6, 126.5, 121.3, 117.5, 117.3, 116.0, 101.5, 83.0, 20.2, 19.3. HRMS
(ESI) calcd for C19H14O2 [MþH]þ 275.1072, found 275.1059.
thin-layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230–400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography
plates were visualized by exposure to ultraviolet light. Organic
solutions were concentrated on rotary evaporators at w20 Torr
(house vacuum) at 25–35 ꢀC. Commercial reagents and solvents
were used as received. Nuclear magnetic resonance (NMR) spectra
are recorded in parts per million from internal tetramethylsilane
4.2.7. 4-(Cyclopropylethynyl)-6,7-dimethyl-2H-chromen-2-
one (3g)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.48 (s, 1H), 7.06 (s, 1H),
6.35 (s, 1H), 2.31 (s, 3H), 2.34 (s, 3H), 1.60–1.63 (m, 1H), 1.04–1.06
(m, 2H), 0.97–0.99 (m, 2H). 13C NMR (100 MHz)
160.9, 151.8, 142.1,
d
137.9, 133.0, 126.6, 117.4, 116.7, 116.5, 107.9, 70.3, 20.2, 19.3, 9.6, 0.6.
HRMS (ESI) calcd for C16H14O2 [MþH]þ 239.1072, found 239.1060.
on the
d scale.
4.2.8. 4-(Hex-1-ynyl)-6,7-dimethyl-2H-chromen-2-one (3h)
4.2. General procedure for the palladium-catalyzed direct
cross-coupling reactions of 4-hydroxycoumarins 1 with
alkynes 2
White solid. 1H NMR (400 MHz, CDCl3)
d 7.53 (s, 1H), 7.07 (s, 1H),
6.40 (s, 1H), 2.57 (t, J¼7.3 Hz, 2H), 2.32 (s, 3H), 2.35 (s, 3H),1.65–1.70
(m, 2H),1.51–1.56 (m, 2H), 0.99 (t, J¼7.3 Hz 3H). 13C NMR (100 MHz)
d
160.9, 151.8, 142.1, 137.9, 133.0, 126.6, 117.3, 117.0, 116.5, 104.4, 75.0,
A solution of 4-hydroxycoumarin 1 (0.2 mmol), p-toluene-
sulfonyl chloride (0.24 mmol, 1.2 equiv), Pd(PPh3)Cl2 (5 mol %) in
30.2, 22.0, 20.2, 19.5, 19.3, 13.5. HRMS (ESI) calcd for C17H18O2
[MþH]þ 255.1385, found 255.1380.

Y. Luo, J. Wu / Tetrahedron 65 (2009) 6810–6814
6813
4.2.9. 7-Methoxy-4-((4-methoxyphenyl)ethynyl)-2H-chromen-2-
151.9, 136.9, 131.9, 129.7, 126.1, 119.9, 118.6, 118.3, 109.4, 69.6, 9.8, 0.7.
one (3i)9b
HRMS (ESI) calcd for C14H9ClO2 [MþH]þ 245.0369, found 245.0358.
1H NMR (400 MHz, CDCl3)
d
7.81 (d, J¼8.7 Hz, 1H), 7.57 (d,
J¼9.2 Hz, 2H), 6.91–6.95 (m, 3H), 6.81 (d, J¼2.3 Hz, 1H), 6.42 (s, 1H),
3.86 (s, 3H), 3.90 (s, 3H). 13C NMR (100 MHz)
163.0, 161.0, 160.8,
4.2.18. 6-Chloro-4-(hex-1-ynyl)-2H-chromen-2-one (3r)9b
d
1H NMR (400 MHz, CDCl3)
d
7.79 (d, J¼2.3 Hz, 1H), 7.48 (dd,
155.3, 137.5, 134.0, 127.6, 114.3, 114.2, 112.5, 113.2, 112.1, 102.3, 100.7,
82.3, 55.8, 55.4.
J¼9.2, 2.8 Hz, 1H), 7.24–7.26 (m, 1H), 6.51 (m, 1H), 2.58 (t, J¼7.4 Hz,
3H), 1.67–1.71 (m, 2H), 1.51–1.55 (m, 2H), 0.99 (t, J¼7.3 Hz, 3H). 13C
NMR (100 MHz) d 159.8, 151.9, 137.0, 132.0, 129.7, 126.2, 119.9, 119.0,
4.2.10. 4-(Cyclopropylethynyl)-7-methoxy-2H-chromen-2-one (3j)
118.3, 106.0, 74.3, 30.2, 22.1, 19.5, 13.5.
White solid.1HNMR(400 MHz,CDCl3)
d
7.67(d, J¼8.7 Hz,1H), 6.85
(d, J¼8.7 Hz,1H), 6.77 (d, J¼2.8 Hz,1H), 6.28 (s,1H), 3.87 (s, 3H),1.56–
1.59 (m, 1H), 0.96–1.06 (m, 4H). 13C NMR (100 MHz)
162.9, 160.9,
Acknowledgements
d
155.2, 138.0, 127.6, 114.5, 112.5, 112.4, 107.9, 100.6, 70.3, 55.8, 9.6, 0.6.
Financial support from National Natural Science Foundation of
China (20772018), Shanghai Pujiang Program, and Program for New
Century Excellent Talents in University (NCET-07-0208) is grate-
fully acknowledged. This paper is dedicated to Professor Li-Xin Dai
on the occasion of his 85th birthday.
HRMS (ESI) calcd for C15H12O3 [MþH]þ 241.0865, found 241.0860.
4.2.11. 6-Fluoro-4-(phenylethynyl)-2H-chromen-2-one (3k)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.64–7.66 (m, 3H),
7.45–7.47 (m, 3H), 7.26–7.36 (m, 2H), 6.68 (s, 1H). 13C NMR
(100 MHz)
d
160.0, 158.7 (d, J¼222.1 Hz), 149.7, 136.4, 132.3, 130.4,
References and notes
128.7, 120.8, 119.7 (d, J¼24.8 Hz), 119.2, 118.6, 112.2, 102.7, 82.4.
HRMS (ESI) calcd for C17H9FO2 [MþH]þ 265.0665, found 265.0660.
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Chichester, UK, 2004; (b) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-
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4.2.12. 6-Fluoro-4-((4-methoxyphenyl)ethynyl)-2H-chromen-2-
one (3l)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.58–7.61 (m, 3H), 7.26–
7.32 (m, 2H), 6.95–6.96 (m, 2H), 6.62 (s, 1H), 3.90 (s, 3H). 13C NMR
(100 MHz)
d
161.3, 158.8 (d, J¼243.1 Hz), 149.7, 136.7, 134.1, 119.5 (d,
6. (a) Walsh, D. P.; Chang, Y.-T. Chem. Rev. 2006, 106, 2476; (b) Arya, P.; Chou, D. T.
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J¼24.8 Hz),118.5,118.3,114.4,112.7,112.2 (d, J¼24.8 Hz),103.5, 81.7, 55.4.
HRMS (ESI) calcd for C18H11FO3 [MþH]þ 295.0770, found 295.0762.
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Q.; Wu, J. Adv. Synth. Catal. 2008, 350, 1850; (c) Ding, Q.; Wu, J. J. Comb. Chem.
2008, 10, 541; (d) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959; (e) Zhang, L.; Wu, J.
Adv. Synth. Catal. 2007, 349, 1047; (f) Gao, K.; Wu, J. J. Org. Chem. 2007, 72, 8611;
(g) Ding, Q.; Ye, Y.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 5439; (h) Sun, W.; Ding,
Q.; Sun, X.; Fan, R.; Wu, J. J. Comb. Chem. 2007, 9, 690; (i) Wang, Z.; Fan, R.; Wu, J.
Adv. Synth. Catal. 2007, 349, 1943; (j) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org.
Chem. 2007, 72, 7279; (k) Wang, Z.; Wang, B.; Wu, J. J. Comb. Chem. 2007, 9, 811;
(l) Ding, Q.; Wang, Z.; Wu, J. J. Org. Chem. 2009, 74, 921.
8. For selected examples, see: (a) von Pechmann, H.; Duisberg, C. Chem. Ber. 1884,
17, 929; (b) Johnson, J. R. Org. React. 1942, 1, 210; (c) Jones, G. Org. React. 1967, 15,
204; (d) Brufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1996, 43,
1257; (e) Shirner, R. L. Org. React. 1942, 1, 1; (f) Narasimhan, N. S.; Mali, R. S.;
Barve, M. V. Synthesis 1979, 906; (g) Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A.
Tetrahedron Lett. 1998, 39, 2391; (h) Cartwright, G. A.; McNab, W. J. Chem. Res.,
Synop. 1997, 296; (i) Alexander, V. M.; Bhat, R. P.; Samant, S. D. Tetrahedron Lett.
2005, 46, 6957 and references cited therein; (j) Sengh, V.; Sengh, J.; Kaur, K. P.;
Kad, G. L. J. Chem. Res., Synop. 1997, 58; (k) Frere, S.; Thiery, V.; Besson, T. Tet-
rahedron Lett. 2001, 42, 2791; (l) John, E. V. O.; Israelstam, S. S. J. Org. Chem. 1961,
26, 240; (m) Hoefnagel, A. J.; Gennewagh, E. A.; Downing, R. S.; Bekkum, H. V. J.
Chem. Soc., Chem. Commun. 1995, 225; (n) Wu, J.; Diao, T.-N.; Sun, W.; Li, Y.
Synth. Commun. 2006, 36, 2949; (o) Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.;
Krishna, P. R. Tetrahedron Lett. 2005, 46, 6119.
4.2.13. 4-(Cyclopropylethynyl)-6-fluoro-2H-chromen-2-one (3m)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.48 (dd, J¼7.3, 2.3 Hz,
1H), 7.25–7.28 (m, 2H), 6.48 (s, 1H), 1.60 (m, 1H), 1.05–1.08 (m, 2H),
0.98–1.00 (m, 2H). 13C NMR (100 MHz)
160.1, 158.8 (d,
d
J¼243.1 Hz), 149.6, 137.2, 119.7, 119.4 (d, J¼24.8 Hz), 118.6, 118.4,
112.2 (d, J¼24.8 Hz), 109.2, 69.7, 9.7, 0.6. HRMS (ESI) calcd for
C14H9FO2 [MþH]þ 229.0665, found 229.0658.
4.2.14. 6-Fluoro-4-(hex-1-ynyl)-2H-chromen-2-one (3n)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.51 (dd, J¼7.3, 2.3 Hz,
1H), 7.25–7.29 (m, 2H), 6.53 (s, 1H), 2.57 (t, J¼6.9 Hz, 2H), 1.67–1.71
(m, 2H),1.50–1.55 (m, 2H), 0.99 (t, J¼7.3 Hz, 3H).13C NMR (100 MHz)
d
160.1,158.8 (d, J¼243.1 Hz),149.6,137.2,119.8,119.4 (d, J¼24.8 Hz),
119.0, 118.4, 112.3 (d, J¼24.8 Hz), 105.7, 74.4, 30.2, 22.1, 19.5, 13.5.
HRMS (ESI) calcd for C15H13FO2 [MþH]þ 245.0978, found 245.0982.
9. For examples, see: (a) Tang, Z. Y.; Hu, Q.-S. Adv. Synth. Catal. 2004, 346, 1635; (b)
Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642; (c) Lei, J.-G.; Xu, M.-H.; Lin,
G.-Q. Synlett 2004, 2364; (d) Wu, J.; Wang, L.; Fathi, R.; Yang, Z. Tetrahedron Lett.
2002, 43, 4395; (e) Schio, L.; Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41,
1543; (f) Yao, M.-L.; Deng, M.-Z. Heteroat. Chem. 2000, 11, 380; (g) Wu, J.; Yang,
Z. J. Org. Chem. 2001, 66, 7875; (h) Wu, J.; Zhang, L.; Gao, K. Eur. J. Org. Chem.
2006, 5260; (i) Wu, J.; Wang, X. Org. Biomol. Chem. 2006, 4, 1348; (j) Wu, J.;
Zhang, L.; Xia, H.-G. Tetrahedron Lett. 2006, 47, 1525; (k) Wu, J.; Zhang, L.; Luo, Y.
Tetrahedron Lett. 2006, 47, 6747.
4.2.15. 6-Chloro-4-(phenylethynyl)-2H-chromen-2-one (3o)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.89 (d, J¼2.3 Hz, 1H),
7.65–7.67 (m, 2H), 7.45–7.52 (m, 4H), 7.26–7.30 (1H), 6.66 (s, 1H).
13C NMR (100 MHz)
159.6, 151.9, 136.2, 132.3, 132.2, 130.4, 129.9,
d
128.8, 126.1, 120.8, 119.5, 119.2, 118.5, 102.9, 82.2. HRMS (ESI) calcd
for C17H9ClO2 [MþNa]þ 303.0191, found 303.0200.
10. (a) Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669 and references cited therein; (b)
Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu, W. J.; Kitamura, T.; Fujiwara, Y. Science
2000, 287, 1992; (c) Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264; (d)
Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055; (e) Youn, S. W.;
Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581; (f) Gabriele, B.; Mancuso, R.;
Salerno, G.; Plastina, P. J. Org. Chem. 2008, 73, 756.
11. For selected examples, see: (a) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.;
Tando, K.; Yamamota, Y. J. Am. Chem. Soc.1996,118, 3970; (b) Gevorgyan, V.; Quan,
L. G.; Yamamoto, Y. J. Org. Chem. 2000, 65, 568; (c) Saito, S.; Chounan, Y.; Nogami,
T.; Fukushi, T.; Tsuboya, N.; Yamada, Y.; Kitahara, H.; Yamamota, Y. Y. J. Org. Chem.
2000, 65, 5350; (d) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
12. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467; (b)
Sonogashira, K. In Comprehesive Organic Synthesis; Trost, B. M., Fleming, L., Eds.;
Pergamon: New York, NY, 1991; Vol. 3, Chapter 2.4.
4.2.16. 6-Chloro-4-((4-methoxyphenyl)ethynyl)-2H-chromen-2-
one (3p)
White solid. 1H NMR (400 MHz, CDCl3)
d
7.89 (d, J¼2.3 Hz, 1H),
7.59 (d, J¼9.2 Hz, 2H), 7.49–7.51 (m, 1H), 7.28 (d, J¼9.2 Hz, 1H),
6.95–6.97 (m, 2H), 6.61 (s, 1H), 3.88 (s, 3H). 13C NMR (100 MHz)
d
161.3, 159.8, 151.9, 136.5, 134.1, 132.1, 129.8, 126.1, 119.6, 118.5,
118.3, 114.4, 112.7, 103.7, 81.6, 55.4. HRMS (ESI) calcd for C18H11ClO3
[MþH]þ 311.0475, found 311.0480.
4.2.17. 6-Chloro-4-(cyclopropylethynyl)-2H-chromen-2-one (3q)
White solid.1H NMR (400 MHz, CDCl3)
d
7.75 (d, J¼2.3 Hz,1H), 7.47
(dd, J¼7.3, 2.7 Hz, 1H), 7.23–7.26 (m, 1H), 6.47 (s, 1H), 1.60–1.61 (m,
1H),1.05–1.09 (m, 2H), 0.98–1.01 (m, 2H).13C NMR (100 MHz)
159.8,
13. For selected copper-free Sonogashira reactions, see: (a) Gelman, D.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2003, 42, 5993; (b) Anderson, K. W.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2005, 44, 6173; (c) Gonzalez-Arellano, C.; Abad, A.;
d

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