A practical protocol for three-component, one-pot, stepwise sonogashira-heterocyclization-heck couplings

Article abstract of DOI:10.1055/s-0033-1338873

A three-component, one-pot, stepwise Sonogashira-heterocyclization-Heck- coupling process was developed starting from either haloarenecarboxamides, halophenols or haloanilines, terminal alkynes and electron-deficient alkenes. Cyclic imidate-, benzofuran-,

Full text of DOI:10.1055/s-0033-1338873

PAPER
▌2009
paper
A Practical Protocol for Three-Component, One-Pot, Stepwise
Sonogashira–Heterocyclization–Heck Couplings
A Protocol for Sonogashira–Heterocyclization–Heck Couplings
Youssef Madich,1,a,c J. Gabriel Denis,1,b Aitor Ortega,a Claudio Martínez,b Abdellatif Matrane,c Larbi Belachemi,c
Angel R. de Lera,b Rosana Alvarez,*b José M. Aurrecoechea*a
a
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco UPV/EHU, Apartado 644,
48080 Bilbao, Spain
Fax +34(94)6013500; E-mail: jm.aurrecoechea@ehu.es
b
Departamento de Química Orgánica, Facultad de Química, Universidade de Vigo, Campus As Lagoas-Marcosende, 36310 Vigo, Spain
Fax +34(986)818622; E-mail: rar@uvigo.es
c
Laboratoire de Chimie Organométallique et Macromoléculaire - Matériaux Composites (CO2MC), Département de Sciences Chimiques,
Faculté des Sciences et Techniques, Université Cadi Ayyad, Avenue Abdelkarim Khattabi, BP 549, Marrakech, Morocco
Fax +212(524)433170; E-mail: belachemi@yahoo.fr
Received: 19.03.2013; Accepted after revision: 30.04.2013
procedure, fewer purifications, and often, higher overall
Abstract: A three-component, one-pot, stepwise Sonogashira–
yields. When the consecutive steps in a multicomponent
heterocyclization–Heck-coupling process was developed starting
process include metal-catalyzed reactions,6,10–19 one par-
from either haloarenecarboxamides, halophenols or haloanilines,
terminal alkynes and electron-deficient alkenes. Cyclic imidate-,
ticular challenge is the finding of a so-called ‘multitask
benzofuran-, or indole-type products are obtained, respectively, in catalyst’4,6 that is suitable for all the different steps in-
useful yields, being typically better than those obtained with isola-
tion of the intermediate Sonogashira adducts. Very high 6-endo se-
volved in the overall transformation. For example, one-
pot, consecutive Sonogashira–cycloisomerization reac-
lectivity is maintained with imidate-type coupling products despite
tions have been employed extensively.20 However, reports
the presence of copper salts carried over from the Sonogashira cou-
on the related process involving an additional coupling af-
pling.
ter the cyclization step (Sonogashira–cyclization–cou-
Key words: cyclization, Sonogashira reaction, Heck reactions, pal-
pling) are scarce,3,5,7–11 particularly when the new
ladium, regioselectivity
coupling takes place under oxidative conditions.7,8,10a,21
A
key problem in this case is the difficulty in running the air-
sensitive Sonogashira reaction and an oxidative coupling
process (e.g., Heck) under a unique set of conditions, a sit-
uation where a one-pot, stepwise procedure may be ad-
vantageous. One such case is the formation of tricyclic
products 4 from 2-iodobenzamides 1 and alkyne 2, in-
volving consecutive Sonogashira and cascade cycliza-
tion–intramolecular oxidative Heck reactions. The
reaction is performed in a one-pot, stepwise fashion with-
out isolation of the intermediate Sonogashira adduct 3
(Scheme 1).8 The same strategy has been employed in the
preparation of 3-(1-alkenyl)benzofurans in a microwave-
assisted process.10a
Multistep syntheses can often be simplified by running
two or more consecutive steps without isolation of inter-
mediates. Ideally, these one-pot multicomponent proce-
dures would simply involve the mixing of reagents, which
then participate chemoselectively in a particular sequence
of events leading to the final product.2 Alternatively, a
one-pot, stepwise procedure may be adopted where some
additional external manipulation is needed. For example,
the sequential introduction of reagents in a certain order
may be a requirement for success.3–9 Whatever the actual
protocol, the advantages of these types of operational
strategies usually include lower costs, a more expeditious
I
R1
CO2Et
O
EtO2C
NHR2
Pd(II),
1
O2, MA,
catechol
R1
Cu(I)
R1
+
O
NR2
O
NHR2
( )3
CO2Et
4
2
3
MA = maleic anhydride
Scheme 1
SYNTHESIS 2013, 45, 2009–2017
Advanced online publication: 21.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338873; Art ID: SS-2013-T0225-OP
© Georg Thieme Verlag Stuttgart · New York

2010
Y. Madich et al.
PAPER
In fact, the cyclic imidate substructure embedded in prod- termediate 2-alkynylbenzamides
3
undergo highly
ucts 4 has been the subject of significant attention in the selective 6-endo-cyclizations,8,31 whereas an alternative
literature.22–29 While this is due in part to some interesting coupling with aryl halides has been reported with 5-exo
biological activities displayed by five- and six-membered regioselectivity,26 and reactions cocatalyzed by palladium
cyclic imidates25,29 and to their use as ligands in asymmet- and copper led to oxidative dimerization products, also
ric catalysis,30 it is also noted that the preparation of these with 5-exo regiochemistry.27 Significantly, in the one-pot
compounds has revealed a rather unexpected strong ten- preparation of 4, the formation of side-products, presum-
dency of 2-alkynylbenzamides to undergo O-cyclization ably regioisomers and/or dimers, was suppressed with the
in palladium-catalyzed processes.8,26,27,31,32 Furthermore, addition of catechol, which was suspected to act as a cop-
the regiochemistry of the cyclization has been found to be per scavenger.8,33,34 In this particular case, it is also likely
variable, depending on the reaction conditions. For exam- that the intramolecular nature of the Heck coupling con-
ple, under the oxidative Heck conditions of Scheme 1, in- tributed such that it prevailed over the alternative compet-
Table 1 One-Pot, Stepwise Sonogashira–Cascade Oxycyclization–Oxidative Coupling from Halocarboxamides 5, Alkynes 6 and Ethyl
Acrylatea
CO2Et
R2
X
R2
Pd(II), Cu(I)
Ar
Ar
Ar
O
O
O
R2
6
NHR1
N
NHR1
R1
5
8
CO2Et
7
9
method A or B
Entry
Halocarboxamide
R1
Ph
R2
Method
Product
Yield (%)b
1
2
3
4
5
6
7
8
5a
5b
5a
5c
5c
5c
5c
5d
Ph (6a)
A
A
A
A
B
9a
9b
9c
9d
9d
9e
9e
9f
82 (72)
75 (66)
67
4-MeOC6H4
Ph
Ph (6a)
4-MeOC6H4 (6b)
n-Hex (6c)
n-Hex (6c)
thien-3-yl (6d)
thien-3-yl (6d)
n-Hex (6c)
I
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
n-Bu
78
O
75
NHR1
A
B
69
56
Ac
68
Cl
I
9
5e
5e
Ph
Ph
Ph (6a)
A
A
9g
9h
79
74
O
10
n-Hex (6c)
NHR1
11
12
13
14
5f
5f
5f
5g
Ph
Ph (6a)
A
A
B
A
9i
54
47
50
64
MeO
MeO
I
Ph
n-Hex (6c)
n-Hex (6c)
n-Hex (6c)
9j
9j
9k
O
Ph
NHR1
n-Bu
Br
O
15
5h
Ph
n-Hex (6c)
Ad
9l
52
NHR1
S
a Reaction conditions: Method A: (i) PdCl2(PPh3)2, (5 mol%), CuI (1 mol%), 6 (1.2 equiv), Et3N (8.6 mL/mmol), 55 °C, Ar, 2–5 h; (ii) evapo-
ration of Et3N; (iii) ethyl acrylate (6 equiv), DMF, 80 °C, air, 16–24 h. Method B: (i) PdCl2(PPh3)2 (5 mol%), CuI (20 mol%), Ph3P (5 mol%),
6 (2 equiv), ethyl acrylate (2 equiv), Et3N (2 equiv), DMF (3 mL/mmol), 60 °C, Ar, 21–24 h; (ii) 60 °C (except entry 7, 80 °C), air, 19–24 h.
b Yield in parentheses is that over the two steps with isolation and purification of the intermediate Sonogashira product.31
c Catalyst (2%) and pyridine (1 equiv) were used; 42 h for step (iii).
d Steps (i) and (iii) were conducted at 80 °C and 100 °C, respectively.
Synthesis 2013, 45, 2009–2017
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Protocol for Sonogashira–Heterocyclization–Heck Couplings
2011
itive oxidative dimerization.27 Based on these precedents, ethyl acrylate).31 The results on the application of the
it was considered interesting to study the possibility of ap- same conditions to a collection of 2-halobenzamide-type
plying the stepwise protocol of Scheme 1 to the corre- substrates 5 and alkynes 6 are shown in Table 1. We used
sponding
three-component
process
using the preparation of known compounds 9a and 9b31 to con-
halobenzamides, alkynes and ethyl acrylate, without iso- firm both the validity of the structural assignments, and
lation of intermediate Sonogashira adducts. The cycliza- the yield advantage realized when performing the whole
tion–intermolecular Heck coupling cascade of 2- sequence without isolation of intermediates (Table 1, en-
alkynylbenzamides and alkenes has been shown to also tries 1 and 2). The remainder of compounds 9 are new
provide cyclic amidates in a 6-endo-selective manner.31 structures incorporating various combinations of aryl and
By performing the coupling in the presence of the copper alkyl groups at R1 and R2, as well as substitution on the
salts carried over from the Sonogashira coupling, the ef- aryl ring of the starting haloarenecarboxamide 5 (Table 1,
fect of copper on the regiochemistry and coupling effi- entries 9–15). Additionally, heterocyclic moieties have
ciency would be evaluated in the absence of any also been introduced at various positions (Table 1, entries
intramolecular bias. We now report that the three-compo- 6, 7 and 15). Structural assignments for new products
nent process from haloarenecarboxamides 1 (and related were initially made by analogy with known compounds
substrates), terminal alkynes and ethyl acrylate is also ef- 9a and 9b, and were confirmed by X-ray analysis of 9g
fective without isolation of the intermediate Sonogashira (see the Supporting Information, Figure 1).
adducts, and that cyclic imidate type coupling products
are obtained with very high 6-endo selectivity. In contrast
with the variant shown in Scheme 1, this new protocol
Additionally, reaction conditions were developed in
which the triethylamine evaporation step was avoided by
reducing the relative amount of the amine and by using tri-
does not require the use of additives such as maleic anhy-
phenylphosphine (Ph3P) as an additive (method B). The
dride and catechol. Nevertheless, the isolated yields are
yields were similar to those obtained using method A (Ta-
improved compared to those reported via the two-step
ble 1, entries 5, 7 and 13). Besides, it was interesting that
procedure, and some new substitution patterns have been
haloarenecarboxamides 5 underwent Sonogashira cou-
pling with alkynes 6 selectively, even in the presence of
excess ethyl acrylate, without any apparent interference
incorporated successfully. Examples of derivatization by
functional group manipulation of the products are also de-
scribed. Additionally, extension of this one-pot process to
from the alternative Heck coupling with the alkene. Also,
the similar use of 2-iodo-phenols and -anilines is also
it is worth noting that in the presence of both palladium
and copper complexes, the intermolecular Heck coupling
demonstrated.
Iodobenzamide 5a (Ar = C6H4, R1 = Ph, Table 1) was used competes effectively with the alternative oxidative dimer-
as a test substrate, and was subjected initially to ization,27 thus ruling out the need for an intramolecular
Sonogashira conditions with phenylacetylene (6a) in the bias to perform these reactions. It is also noted that the re-
presence of excess ethyl acrylate (7). A stoichiometric giochemistry of the cyclization is 6-endo-selective, even
amount of copper(II) chloride (CuCl2)33 was used in an at- in the presence of copper salts, implying that copper-
tempt to provide the oxidant to generate the palladium(II) catalyzed 5-exo-cyclization processes are not operating in
needed for the cyclization–Heck coupling after the initial these reactions.27,33,34
palladium(0)-promoted Sonogashira reaction. In this
manner, the coupling product 9a would be synthesized in
(a)
CO2Et
CO2Et
a one-pot, three-component coupling. In the event, the
corresponding Sonogashira adduct 8a31 was formed read-
ily, as judged by TLC, but did not react further. Formation
of the desired cascade product 9a took place only when air
was allowed to enter the system and replace the initial ar-
gon atmosphere. Following this procedure, product 9a
was obtained in 40% yield accompanied by other uniden-
tified coupling products. The yield of 9a was improved to
82% when triethylamine was evaporated before carrying
out the cyclization–Heck cascade (Table 1, entry 1, meth-
od A). Therefore, as previously observed in the corre-
sponding intramolecular Heck processes,8 the presence of
triethylamine had a deleterious effect on the formation of
9. Remarkably, the maleic anhydride and catechol addi-
tives found necessary in those reactions were not required
in this case. The yield of 9a (82%) compares favorably
with the 72% overall yield obtained when the reaction was
performed in two steps, with isolation of Sonogashira ad-
duct 8a, and starting from the same substrates (5a, 6a and
Ph
O
Ph
O
3 M HCl, EtOH
25 °C
0
(54%)
N
O
10
Ph
9a
(b)
CO2Et
CO2H
MeO
R2
LiOH•H2O
MeO
MeO
R2
THF–H2O, 50 °C
O
O
MeO
N
N
Ph
Ph
9i R2 = Ph
9j R2 = n-Hex
11a (89%)
11b (88%)
Scheme 2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2009–2017

2012
Y. Madich et al.
PAPER
Table 2 One-Pot, Stepwise Sonogashira–Cascade Heterocyclization–Oxidative Coupling of Iodophenol 12 or Iodoanilines 13, Alkyne 14 and
Alkenes 15a
14
A
A
R1
I
15
R1
Pd(II), CuI(I)
4-Tol
XH
12 X = O
13 X = NH
X
16 X = O
17 X = NH
method A or B
Entry
Substrate
R1
A
Method
Temp (°C)
Product
Yield (%)b
1
2
3
4
5
6
7
12a
12a
12a
12b
13a
13a
13b
H
CO2n-Bu
CO2n-Bu
COMe
A
B
A
B
A
B
A
80
50
16a
16a
16b
16c
17a
17a
17b
97 (90)
60 (90)
64 (90)
80
H
H
80
MeO
H
CO2n-Bu
CO2n-Bu
CO2n-Bu
CO2n-Bu
50
100
50
78 (73)
80 (73)
74 (48)
H
Me
100
a Reaction conditions: Method A: (i) PdCl2(PPh3)2, (2 mol%), CuI (4 mol%), 14 (1.3 equiv), Et3N (3 equiv), DMF, 25 °C, Ar, 2 h; (ii) evapo-
ration of Et3N; (iii) 15 (6 equiv), air, 20 h. Method B: (i) PdCl2(PPh3)2 (5 mol%), CuI (20 mol%), Ph3P (5 mol%), 14 (2 equiv), 15 (2 equiv),
Et3N (2 equiv), DMF (3 mL/mmol), 50 °C, Ar, 1.5 h; (ii) air, 50 °C, 5 h.
b Yield in parentheses is that over the two steps with isolation of the corresponding intermediate Sonogashira product.31
The imino functionality of products 9 was sensitive to
acidic conditions, as shown by the conversion of 9a into
lactone 1035,36 (Scheme 2, a), but products 9 were other-
wise reasonably stable and they could be purified by silica
gel chromatography, provided that the silica was first sat-
urated with triethylamine. Alternatively, as exemplified in
Scheme 2 (b), selective hydrolysis of the ester function
was possible to afford the corresponding acids 11a,b,
which were also stable compounds.
Table 3 One-Pot, Stepwise Sonogashira–Cascade Heterocycliza-
tion–Oxidative Coupling of Iodophenols 12 or Iodoaniline 13 and
Alkynes 2 or 18a
A
A
2 A = CO2Et
18 A = COMe
R1
R2
I
R1
R2
Pd(II), Cu(I)
method B
X
XH
12 X = O
19 X = O
Next, the extension of this one-pot, stepwise protocol to
phenol- and aniline-type substrates was investigated and
found to be similarly effective, as shown by the prepara-
tion of benzofurans 16 and indoles 17 (Table 2), with
yields, that in most cases, were improved compared to
those reported with isolation of the intermediate
Sonogashira adducts.31 In the case of benzofurans 16, the
employed conditions offer a practical alternative to the re-
cently reported microwave-assisted preparation.10a
13 X = NH
20 X = NH
Entry Substrate R1
R2
Alkyne Product Yield (%)b
1
12a
12a
12b
12c
13
H
H
2
18
2
19a
19b
19c
19d
20
72 (88)
72 (58)
55 (60)
47 (40)
56
2
H
H
3
MeO
H
H
4c
5
MeO
H
2
Finally, encouraged by these results, we also studied the
corresponding reactions of iodophenols 12 and iodoani-
line 13 with functionalized alkynes 2 and 18 (Table 3). In
these cases, only the conditions of method B were found
to give useful results. However, in line with the results
displayed in Tables 1 and 2, the yields of benzofurans 19
and indole 20 were often improved compared with those
previously reported,8 and the advantages in simplicity of
this new protocol were maintained.
H
2
a Reaction conditions: Method B: (i) Pd(PPh3)2Cl2 (5 mol%), CuI (20
mol%), Ph3P (5 mol%), Et3N (2 equiv), alkyne (2 equiv), DMF (3
mL/mmol), 50 °C, Ar, 0.5 h; (ii) air, 50 °C, 17–22 h.
b Yield in parentheses is that over the two steps with isolation of the
corresponding intermediate Sonogashira product.8
c Reaction run at 60 °C (both steps), 5 h for step (i), 3 h for step (ii).
tion–Heck-type coupling reactions has been demonstrated
starting from terminal alkynes, electron-deficient alkenes
and 2-halobenzamide-, 2-iodophenol- or 2-iodoaniline-
In conclusion, a three-component, stepwise, one-pot pro-
tocol involving Sonogashira and cascade heterocycliza-
Synthesis 2013, 45, 2009–2017
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Protocol for Sonogashira–Heterocyclization–Heck Couplings
2013
Mp 172–173 °C.
IR (film): 1653 (s), 1600 (s) cm–1.
1H NMR (300.13 MHz, acetone-d6): δ = 7.18 (t, J = 7.4 Hz, 1 H),
7.41 (t, J = 7.8 Hz, 2 H), 7.57 (s, 1 H), 7.83 (d, J = 7.8 Hz, 2 H), 8.00
type substrates. This protocol is useful for the preparation
of alkene-substituted isochromenimines, benzofurans and
indoles. Where comparisons are available, the yields were
generally improved compared to those reported using
analogous procedures with isolation of the intermediate (s, 1 H), 9.55 (s, 1 H).
13C NMR (75.47 MHz, acetone-d6): δ = 93.8 (C), 120.6 (2 × CH),
124.9 (CH), 129.1 (CH), 129.6 (2 × CH), 130.0 (CH), 136.0 (C),
139.5 (CH), 139.9 (C), 143.0 (C), 167.4 (C).
MS (EI): m/z (%) = 359 (7) [37Cl, M]+, 357 (20) [35Cl, M]+, 267 (25),
265 (base).
HRMS (EI): m/z [M]+ calcd for C13H935ClINO: 356.9417; found:
356.9423; m/z [M]+ calcd for C13H937ClINO: 358.9388; found:
358.9385.
Sonogashira adducts. In the case of benzamide substrates,
the scope has been expanded with the incorporation of
new substitution patterns. Besides the usual benefits de-
rived from increased simplicity, the new procedures avoid
the use of the additives, which are required when the reac-
tions are performed using the isolated Sonogashira ad-
ducts.
All reactions involving air- and moisture-sensitive materials were
performed under an argon atmosphere. Et3N, CH2Cl2, and toluene
were distilled from CaH2 and purged with Ar. ACS-Grade DMF
was stored over 4 Å MS under Ar. All other reagents were commer-
cial compounds of the highest purity available. Analytical thin-layer
chromatography (TLC) was performed on Merck Kieselgel 60F254
aluminum plates, which were made visual with UV irradiation (254
nm), or by staining with an ethanolic solution of phosphomolybdic
acid. Flash column chromatography was performed on Merck Kie-
selgel 60 silica gel (230–400 mesh). Melting points were recorded
on a Buchi B-540 apparatus and are uncorrected. Infrared spectra
(IR) were obtained from a thin film deposited onto an NaCl glass
plate using a JASCO FT/IR-400 spectrometer; data include only
characteristic absorptions. 1H NMR spectra were obtained on Bruk-
er AV-300 or AMX-400 spectrometers at 300.13 or 400.16 MHz in
CDCl3 at ambient temperature, with the residual protic solvent as
the internal reference (δH = 7.26 for CHCl3, and δH = 2.05 for ace-
tone-d6). 13C NMR spectra were recorded on the same spectrome-
ters at 75.47 or 100.62 MHz in CDCl3 at ambient temperature, with
the central peak of the solvent (δC = 77.0 for CDCl3, and δC = 29.8
for acetone-d6) as the internal reference. The DEPT sequence was
routinely used for 13C multiplicity assignment. In addition, COSY,
NOE, HSQC and HMBC data were recorded to confirm the struc-
tural assignments. Electron impact (EI) mass spectra were acquired
on a Hewlett-Packard HP59970 instrument operating at 70 eV;
chemical ionization (CI) mass spectra were acquired on an Agilent
6890N gas chromatograph coupled to a mass spectrometer with a
Micromass GCT Time of Flight (TOF) analyzer; electrospray ion-
ization (ESI) mass spectra were acquired on a micrOTOF focus
mass spectrometer (Bruker Daltonics) using an ApolloII (ESI)
source with a voltage of 4500 V applied to the needle, and a counter
voltage between 100 and 150 V applied to the capillary. Iodoamides
5a–g were prepared from the corresponding acids according to a lit-
erature procedure,37 but modified by using toluene in place of ben-
zene. Compounds 5a,38 5b,38 5c,39 5d,40 5f8 and 5h41 were
characterized by comparison with literature data.
N-Butyl-2-iodo-4,5-dimethoxybenzamide (5g)
The above procedure was followed using 2-iodo-4,5-dimethoxy-
benzoic acid (2.03 g, 6.59 mmol) and n-butylamine (651 μL, 6.59
mmol). The crude amide 5g (2.34 g, 98%) was used without further
purification.
Mp 112–114 °C.
IR (film): 3275 (m), 1635 (s), 1593 (s), 1539 (s), 1496 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 0.97 (t, J = 7.3 Hz, 3 H), 1.39–
1.51 (m, 2 H), 1.58–1.68 (m, 2 H), 3.41–3.48 (m, 2 H), 3.86 and
3.87 (2 s, 6 H), 5.84 (br s, 1 H, NH), 7.00 (s, 1 H), 7.20 (s, 1 H).
13C NMR (75.47 MHz, CDCl3): δ = 13.7 (CH3), 20.2 (CH2), 31.2
(CH2), 39.8 (CH2), 56.0 (CH3), 56.2 (CH3), 80.7 (C), 111.8 (CH),
121.8 (CH), 134.6 (C), 149.1 (C), 150.3 (C), 168.7 (C).
MS (CI): m/z (%) = 364 (base) [M + H]+, 363 (28).
HRMS (CI): m/z [M + H]+ calcd for C13H19INO3: 364.0410; found:
364.0418.
Products 9; Typical Procedures
Method A
To a soln of 5 (1.55 mmol) and alkyne 6 (1.86 mmol) in Et3N (13
mL) were added PdCl2(PPh3)2 (54 mg, 77 μmol) and CuI (3.0 mg,
15 μmol). The resulting mixture was heated under Ar at 55 °C for
2–5 h and then the Et3N was removed in vacuo. DMF (13 mL) and
ethyl acrylate (7) (1.01 mL, 9.28 mmol) were added and the mixture
was stirred at 80 °C for 16–24 h. The mixture was allowed to cool
to 25 °C and a sat. aq NaHCO3 soln (25 mL) was added. The mix-
ture was extracted with EtOAc (3 × 50 mL), and the combined or-
ganic extracts were washed with H2O (15 mL), dried (Na2SO4) and
the solvent removed. The residue was purified as indicated below
for the individual cases.
Method B
To a soln of 5 (0.140 mmol) and alkyne 6 (0.280 mmol) in DMF
(420 μL) were added PdCl2(PPh3)2 (4.9 mg, 7.0 μmol), CuI (5.3 mg,
28 μmol), Ph3P (1.8 mg, 6.9 μmol), Et3N (39 μL, 0.28 mmol) and
ethyl acrylate (7) (30 μL, 0.28 mmol), and the resulting mixture was
stirred under Ar at 60 °C. After 21–24 h, air was allowed to enter
the system, and the mixture was stirred at 60 °C (Table 1, entries 5
and 13) or at 80 °C (Table 1, entry 7) for 19–24 h. The work-up pro-
cedure described in method A above was then followed.
4-Chloro-2-iodo-N-phenylbenzamide (5e)
DMF (2 drops) and oxalyl chloride (180 μL, 2.12 mmol) were add-
ed to a suspension of 4-chloro-2-iodobenzoic acid (0.400 g, 1.42
mmol) in toluene (5 mL). After the acid had dissolved and evolution
of gas had ceased, the mixture was concentrated under vacuum to
afford the crude acyl chloride, which was used without further pu-
rification. To a soln of this crude acyl chloride in CH2Cl2 (6 mL)
was added a soln of Et3N (592 μL, 4.25 mmol) and aniline (129 μL,
1.42 mmol) in CH2Cl2 (6 mL). The mixture was stirred for 1 h and
then sat. aq NH4Cl soln (5 mL) was added. The aq layer was extract-
ed with CH2Cl2 (3 × 5 mL) and the combined organic layers dried
(Na2SO4) and evaporated. The crude residue was purified by flash
chromatography (hexanes–EtOAc, 90:10 to 85:15), to afford 5e
(400 mg, 79%) as a white solid.
Ethyl (E)-3-[(Z)-3-Phenyl-1-(phenylimino)-1H-isochromen-4-
yl]acrylate (9a)
Prepared from 5a38 (500 mg, 1.55 mmol) and phenylacetylene (6a)
(204 μL, 1.86 mmol). The crude residue was purified by flash chro-
matography on silica gel saturated with Et3N, (hexanes–EtOAc–
Et3N, 98.5:0.5:1 to 97.5:1.5:1), to afford 9a (502 mg, 82%). The
product was characterized by comparison of its 1H NMR spectrum
with reported data.31
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2009–2017

2014
Y. Madich et al.
PAPER
Ethyl (E)-3-[(Z)-1-(4-Methoxyphenylimino)-3-phenyl-1H-iso-
chromen-4-yl]acrylate (9b)
IR (film): 1738 (s), 1717 (s), 1647 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.36 (t, J = 7.0 Hz, 3 H), 4.30
(q, J = 7.0 Hz, 2 H), 6.34 (d, J = 16.1 Hz, 1 H), 7.14–7.22 (m, 3 H),
7.31–7.33 (m, 3 H), 7.45–7.50 (m, 2 H), 7.59–7.77 (m, 3 H), 8.44
(d, J = 7.5 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): δ = 14.3 (CH3), 60.8 (CH2), 109.7
(C), 123.2 (C), 123.7 (CH), 123.9 (2 × CH), 125.4 (CH), 126.0
(CH), 127.2 (CH), 127.9 (2 × CH), 128.4 (CH), 128.7 (2 × CH),
128.8 (C), 132.5 (C), 132.6 (CH), 133.6 (C), 138.6 (CH), 144.9 (C),
147.1 (C), 148.9 (C), 166.2 (C).
Prepared from 5b38 (500 mg, 1.42 mmol) and phenylacetylene (6a)
(186 μL, 1.70 mmol). The crude residue was purified by flash chro-
matography on silica gel saturated with Et3N (hexanes–EtOAc–
Et3N, 98:1:1 to 91:8:1), to afford 9b (450 mg, 75%). The product
was characterized by comparison of its 1H NMR spectrum with re-
ported data.31
Ethyl (E)-3-[(Z)-3-(4-Methoxyphenyl)-1-(phenylimino)-1H-iso-
chromen-4-yl]acrylate (9c)
Prepared from 5a38 (0.150 g, 0.464 mmol) and 4-ethynylanisole
(6b) (72 μL, 0.56 mmol). The crude residue was purified by flash
chromatography on silica gel saturated with Et3N (hexanes–
EtOAc–Et3N, 94:5:1 to 70:29:1), to afford 9c (0.132 g, 67%) as a
yellow solid.
MS (CI): m/z (%) = 436 (base) [M + H]+, 435 (54).
HRMS (CI): m/z [M + H]+ calcd for C24H1935ClNO3S: 436.0774;
found: 436.0772; m/z [M + H]+ calcd for C24H1937ClNO3S:
438.0745; found: 438.0754.
Mp 125–127 °C.
IR (film): 1710 (s), 1650 (s), 1591 (s) cm–1.
Ethyl (E)-3-[(Z)-1-(Butylimino)-3-hexyl-1H-isochromen-4-
yl]acrylate (9f)
Prepared from 5d40 (0.150 g, 0.495 mmol) and oct-1-yne (6c) (88
μL, 0.59 mmol). The standard procedure was modified as follows:
the amount of PdCl2(PPh3)2 was 2 mol% and py (40 μL, 0.495
mmol) was used as an additive in the last step. The crude residue
was purified by flash chromatography on silica gel saturated with
Et3N (hexanes–Et3N, 98:2), to afford 9f (0.130 g, 68%) as a yellow
oil.
1H NMR (300.13 MHz, CDCl3): δ = 1.33 (t, J = 7.1 Hz, 3 H), 3.82
(s, 3 H), 4.27 (q, J = 7.1 Hz, 2 H), 6.28 (d, J = 16.3 Hz, 1 H), 6.87
(d, J = 8.9 Hz, 2 H), 7.09 (t, J = 7.3 Hz, 1 H), 7.20–7.23 (m, 2 H),
7.31–7.49 (m, 5 H), 7.57–7.63 (m, 1 H), 7.67 (d, J = 16.3 Hz, 1 H),
7.74 (d, J = 8.0 Hz, 1 H), 8.47 (d, J = 7.9 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): δ = 14.3 (CH3), 55.3 (CH3), 60.6
(CH2), 109.0 (C), 113.7 (2 × CH), 122.7 (2 × CH), 123.5 (CH),
123.7 (CH), 123.9 (CH), 124.9 (C), 127.9 (CH), 128.2 (CH), 128.6
(2 × CH), 130.9 (2 × CH), 132.3 (CH), 132.6 (C), 139.3 (CH),
146.2 (C), 148.6 (C), 152.5 (C), 160.8 (C), 166.5 (C).
IR (film): 1716 (s), 1665 (s), 1636 (s) cm–1.
1H NMR (300.13 MHz, acetone-d6): δ = 0.92 (t, J = 6.9 Hz, 3 H),
0.99 (t, J = 7.3 Hz, 3 H), 1.32–1.56 (m, 11 H), 1.62–1.71 (m, 2 H),
1.72–1.82 (m, 2 H), 2.68 (t, J = 7.4 Hz, 2 H), 3.52 (t, J = 6.9 Hz, 2
H), 4.28 (q, J = 7.1 Hz, 2 H), 6.22 (d, J = 16.0 Hz, 1 H), 7.38–7.43
(m, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.56–7.61 (m, 1 H), 7.69 (d, J =
16.0 Hz, 1 H), 8.20 (dd, J = 7.9, 1.0 Hz, 1 H).
MS (CI): m/z (%) = 426 (base) [M + H]+, 425 (76).
HRMS (CI): m/z [M + H]+ calcd for C27H24NO4: 426.1705; found:
426.1686.
13C NMR (75.47 MHz, acetone-d6): δ = 14.3 (CH3), 14.6 (CH3),
21.4 (CH2), 23.2 (CH2), 28.1 (CH2), 29.3 (CH2), 31.8 (CH2), 32.3
(CH2), 33.8 (CH2), 46.3 (CH2), 61.0 (CH2), 109.5 (C), 123.7 (CH),
124.7 (C), 124.9 (CH), 127.5 (CH), 128.4 (CH), 132.5 (CH), 132.7
(C), 138.8 (CH), 148.0 (C), 156.9 (C), 166.5 (C).
MS (EI): m/z (%) = 383 (27) [M]+, 362 (36), 340 (30), 336 (37), 313
(24), 310 (79), 306 (28), 298 (base), 294 (32), 287 (59), 286 (37),
282 (21), 280 (39), 270 (37), 268 (38), 254 (25), 252 (76), 242 (18),
241 (21), 228 (18), 226 (20), 224 (46), 214 (43), 213 (26), 212 (61),
211 (35), 200 (26), 198 (35), 197 (23), 196 (57), 186 (32), 185 (54),
184 (73), 183 (46), 182 (53), 172 (25), 171 (24), 170 (37), 169 (26),
168 (22), 167 (22), 160 (24), 158 (34), 157 (20), 156 (37), 154 (27),
143 (20), 141 (22), 140 (53).
Ethyl (E)-3-[(Z)-1-(4-Chlorophenylimino)-3-hexyl-1H-isochro-
men-4-yl]acrylate (9d)
Prepared from 5c39 (0.500 g, 1.40 mmol) and oct-1-yne (6c) (247
μL, 1.68 mmol). The crude residue was purified by flash chroma-
tography on silica gel saturated with Et3N (hexanes–EtOAc–Et3N,
98:1:1 to 97:2:1), to afford 9d (478 mg, 78%) as a yellowish oil.
IR (film): 1715 (s), 1652 (s), 1635 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 0.85–0.89 (m, 3 H), 1.24–1.31
(m, 6 H), 1.36 (t, J = 7.1 Hz, 3 H), 1.48–1.57 (m, 2 H), 2.51 (t, J =
7.4 Hz, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 6.15 (d, J = 16.1 Hz, 1 H),
7.09 (d, J = 8.7 Hz, 2 H), 7.30 (d, J = 8.7 Hz, 2 H), 7.41–7.48 (m, 2
H), 7.55–7.64 (m, 1 H), 7.66 (d, J = 16.0 Hz, 1 H), 8.37 (d, J = 7.8
Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): δ = 14.0 (CH3), 14.3 (CH3), 22.3
(CH2), 27.3 (CH2), 28.6 (CH2), 31.0 (CH2), 31.4 (CH2), 60.7 (CH2),
109.7 (C), 123.0 (C), 123.1 (CH), 124.0 (2 × CH), 124.7 (CH),
127.7 (CH), 128.0 (CH), 128.6 (2 × CH), 128.7 (C), 132.5 (CH),
132.7 (C), 137.9 (CH), 145.0 (C), 149.4 (C), 155.5 (C), 166.3 (C).
MS (EI): m/z (%) = 439 (26) [37Cl, M]+, 438 (19), 437 (74) [35Cl,
M]+, 367 (22), 366 (22), 365 (27), 364 (32), 352 (22), 350 (38), 308
(31), 294 (25), 282 (20), 280 (60), 279 (26), 266 (23), 254 (25), 253
(35), 252 (71), 251 (26), 230 (21), 217 (base), 216 (64).
HRMS (EI): m/z [M]+ calcd for C26H2835ClNO3: 437.1758; found:
437.1752; m/z [M]+ calcd for C26H2837ClNO3: 439.1728; found:
439.1717.
HRMS (EI): m/z [M]+ calcd for C24H33NO3: 383.2460; found:
383.2463.
Ethyl (E)-3-[(Z)-6-Chloro-3-phenyl-1-(phenylimino)-1H-iso-
chromen-4-yl]acrylate (9g)
Prepared from 5e (0.100 g, 0.280 mmol) and phenylacetylene (6a)
(37 μL, 0.34 mmol). The crude residue was stirred for 24 h in hex-
ane (20 mL). The solvent was decanted and the solid residue was
dissolved in CH2Cl2 (5 mL) and eluted through a short column of
silica gel (35–70 μm, 2.5 × 6 cm) saturated with Et3N (CH2Cl2–
Et3N, 95:5). Finally, a soln of the residue in CH2Cl2 (10 mL) was
washed with NaOH (1 M, 5 mL) and H2O (5 mL), and dried
(Na2SO4) to afford, after evaporation of the solvent, 9g (95 mg,
79%) as a yellow solid.
Ethyl (E)-3-[(Z)-1-(4-Chlorophenylimino)-3-thien-3-yl-1H-iso-
chromen-4-yl]acrylate (9e)
Mp 185–187 °C.
IR (film): 1711 (s), 1636 (s), 1588 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.33 (t, J = 7.1 Hz, 3 H), 4.26
(q, J = 7.1 Hz, 2 H), 6.20 (d, J = 16.3 Hz, 1 H), 7.09 (t, J = 7.2 Hz,
1 H), 7.21 (d, J = 7.4 Hz, 2 H), 7.31 (d, J = 7.4 Hz, 2 H), 7.35–7.40
(m, 3 H), 7.45 (d, J = 7.9 Hz, 3 H), 7.60 (d, J = 16.3 Hz, 1 H), 7.66
(d, J = 1.8 Hz, 1 H), 8.42 (d, J = 8.5 Hz, 1 H).
Prepared from 5c39 (0.100 g, 0.280 mmol) and 3-ethynylthiophene
(6d) (33 μL, 0.34 mmol). The crude residue was purified by flash
chromatography on silica gel saturated with Et3N (hexanes–
EtOAc–Et3N, 94:5:1 to 88:11:1), to afford 9e (84 mg, 69%) as a yel-
low-orange solid.
Mp 143–145 °C.
Synthesis 2013, 45, 2009–2017
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Protocol for Sonogashira–Heterocyclization–Heck Couplings
IR (film): 1712 (s), 1635 (s), 1589 (s), 1517 (s) cm–1.
2015
13C NMR (75.47 MHz, CDCl3): δ = 14.2 (CH3), 60.8 (CH2), 109.2
(C), 122.2 (C), 122.8 (2 × CH), 123.4 (CH), 124.1 (CH), 125.1
(CH), 128.3 (2 × CH), 128.7 (2 × CH), 128.8 (CH), 129.3 (2 × CH),
129.6 (CH), 130.1 (CH), 132.2 (C), 134.1 (C), 138.2 (CH), 139.0
(C), 145.6 (C), 147.5 (C), 153.3 (C), 166.1 (C).
1H NMR (300.13 MHz, CDCl3): δ = 0.83–0.88 (m, 3 H), 1.19–1.30
(m, 6 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.46–1.53 (m, 2 H), 2.49 (t, J =
7.6 Hz, 2 H), 3.96 and 4.01 (2 s, 6 H), 4.29 (q, J = 7.3 Hz, 2 H), 6.15
(d, J = 16.0 Hz, 1 H), 6.85 (s, 1 H), 7.05–7.15 (m, 3 H), 7.30–7.35
(m, 2 H), 7.66 (d, J = 16.0 Hz, 1 H), 7.83 (s, 1 H).
MS (EI): m/z (%) = 431 (7) [37Cl, M]+, 429 (22) [35Cl, M]+, 357 (20),
105 (base), 77 (30).
13C NMR (75.47 MHz, CDCl3): δ = 14.0 (CH3), 14.3 (CH3), 22.4
(CH2), 27.4 (CH2), 28.6 (CH2), 31.0 (CH2), 31.4 (CH2), 56.2 (CH3),
56.3 (CH3), 60.8 (CH2), 104.7 (CH), 108.6 (CH), 109.3 (C), 116.3
(C), 122.6 (2 × CH), 123.3 (CH), 124.2 (CH), 127.4 (C), 128.6
(2 × CH), 138.4 (CH), 146.8 (C), 149.1 (C), 149.3 (C), 153.0 (C),
154.8 (C), 166.4 (C).
MS (EI): m/z (%) = 463 (84) [M]+, 390 (30), 351 (36), 306 (29), 304
(21), 279 (30), 278 (base), 263 (25), 262 (21), 247 (36).
HRMS (EI): m/z [M]+ calcd for C28H33NO5: 463.2359; found:
463.2362.
HRMS (EI): m/z [M]+ calcd for C26H2035ClNO3: 429.1132; found:
429.1122; m/z [M]+ calcd for C26H2037ClNO3: 431.1102; found:
431.1108.
Ethyl (E)-3-[(Z)-6-Chloro-3-hexyl-1-(phenylimino)-1H-isochro-
men-4-yl]acrylate (9h)
Prepared from 5e (0.150 g, 0.419 mmol) and oct-1-yne (6c) (74 μL,
0.50 mmol). The crude residue was purified by flash chromatogra-
phy on silica gel saturated with Et3N (hexanes–EtOAc–Et3N, 98:1:1
to 97:2:1), to afford 9h (0.136 g, 74%) as a yellow oil.
IR (film): 1715 (s), 1657 (s), 1637 (s), 1590 (s) cm–1.
Ethyl (E)-3-[(Z)-1-(Butylimino)-3-hexyl-6,7-dimethoxy-1H-iso-
chromen-4-yl]acrylate (9k)
Prepared from 5g (0.150 g, 0.413 mmol) and oct-1-yne (6c) (73 μL,
0.50 mmol). The crude residue was purified by flash chromatogra-
phy on silica gel saturated with Et3N (hexanes–EtOAc–Et3N,
90:9:1), to afford 9k (0.118 g, 64%) as a viscous oil.
1H NMR (300.13 MHz, CDCl3): δ = 0.84–0.88 (m, 3 H), 1.20–1.30
(m, 6 H), 1.37 (t, J = 7.1 Hz, 3 H), 1.47–1.54 (m, 2 H), 2.49 (t, J =
7.4 Hz, 2 H), 4.31 (q, J = 7.1 Hz, 2 H), 6.15 (d, J = 16.1 Hz, 1 H),
7.10–7.16 (m, 3 H), 7.32–7.41 (m, 4 H), 7.59 (d, J = 16.1 Hz, 1 H),
8.32 (d, J = 8.4 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): δ = 14.0 (CH3), 14.3 (CH3), 22.3
(CH2), 27.2 (CH2), 28.5 (CH2), 31.1 (CH2), 31.3 (CH2), 60.8 (CH2),
108.6 (C), 121.7 (C), 122.5 (2 × CH), 122.7 (CH), 123.8 (CH),
125.0 (CH), 128.1 (CH), 128.6 (2 × CH), 129.3 (CH), 134.3 (C),
137.3 (CH), 138.9 (C), 145.9 (C), 147.9 (C), 156.8 (C), 166.1 (C).
MS (EI): m/z (%) = 439 (22) [37Cl, M]+, 438 (17), 437 (69) [35Cl,
M]+, 433 (25), 377 (26), 367 (21), 365 (30), 364 (25), 350 (32), 308
(22), 294 (20), 282 (20), 280 (40), 266 (28), 257 (20), 254 (34), 253
(45), 252 (73), 251 (28), 218 (24), 217 (base), 216 (34).
IR (film): 1707 (s), 1661 (s), 1516 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 0.87–1.03 (m, 6 H), 1.32–1.48
(m, 11 H), 1.61–1.73 (m, 4 H), 2.58 (t, J = 6.7 Hz, 2 H), 3.48 (t, J =
6.9 Hz, 2 H), 3.91 and 3.94 (2 s, 6 H), 4.29 (q, J = 7.0 Hz, 2 H), 6.14
(d, J = 16.0 Hz, 1 H), 6.81 (s, 1 H), 7.63–7.69 (m, 2 H).
13C NMR (75.47 MHz, CDCl3): δ = 14.0 (CH3), 14.1 (CH3), 14.3
(CH3), 20.9 (CH2), 22.5 (CH2), 27.5 (CH2), 28.8 (CH2), 31.3 (CH2),
31.5 (CH2), 33.0 (CH2), 46.0 (CH2), 56.1 (CH3), 56.2 (CH3), 60.7
(CH2), 104.8 (CH), 108.1 (CH), 108.5 (C), 117.0 (C), 123.4 (CH),
126.2 (C), 138.9 (CH), 148.9 (C), 149.3 (C), 152.1 (C), 155.1 (C),
166.6 (C).
HRMS (EI): m/z [M]+ calcd for C26H2835ClNO3: 437.1758; found:
437.1748; m/z [M]+ calcd for C26H2837ClNO3: 439.1728; found:
439.1748.
MS (EI): m/z (%) = 443 (11) [M]+, 358 (24), 155 (base), 127 (26),
85 (22), 81 (20), 71 (32).
HRMS (EI): m/z [M]+ calcd for C26H37NO5: 443.2672; found:
443.2679.
Ethyl (E)-3-[(Z)-6,7-Dimethoxy-3-phenyl-1-(phenylimino)-1H-
isochromen-4-yl]acrylate (9i)
Prepared from 5f8 (0.100 g, 0.261 mmol) and phenylacetylene (6a)
(34 μL, 0.31 mmol). The crude residue was purified by flash chro-
matography on silica gel saturated with Et3N (hexanes–EtOAc–
Et3N, 90:9:1), to afford 9i (64 mg, 54%) as a yellow solid.
Ethyl (E)-3-[(Z)-3-Hexyl-1-(phenylimino)-1H-benzo[4,5]thie-
no[2,3-c]pyran-4-yl]acrylate (9l)
Prepared from 5h41 (0.100 g, 0.301 mmol) and oct-1-yne (6c) (76
μL, 0.51 mmol). The crude residue was purified by flash chroma-
tography on silica gel saturated with Et3N (hexanes–EtOAc–Et3N,
99.5:0:0.5 to 99:0.5:0.5), to afford 9l (72 mg, 52%) as a yellow sol-
id.
Mp 171–173 °C.
IR (film): 1702 (s), 1647 (s), 1588 (s), 1512 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.30 (t, J = 7.0 Hz, 3 H), 3.98
(s, 3 H), 4.04 (s, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 6.24 (d, J = 16.4 Hz,
1 H), 7.06 (t, J = 6.9 Hz, 1 H), 7.12 (s, 1 H), 7.20–7.42 (m, 9 H),
7.67 (d, J = 16.4 Hz, 1 H), 7.91 (s, 1 H).
Mp 90–92 °C.
IR (film): 1715 (s), 1638 (s), 1589 (s) cm–1.
13C NMR (75.47 MHz, CDCl3): δ = 14.0 (CH3), 56.1 (CH3), 56.3
(CH3), 60.6 (CH2), 105.3 (CH), 108.8 (CH), 109.8 (C), 117.0 (C),
122.7 (2 × CH), 123.5 (CH), 124.3 (CH), 127.0 (C), 128.2
(2 × CH), 128.6 (2 × CH), 129.3 (2 × CH), 129.7 (CH), 132.6 (C),
139.4 (CH), 146.4 (C), 148.6 (C), 149.7 (C), 151.4 (C), 152.9 (C),
166.3 (C).
MS (EI): m/z (%) = 455 (32) [M]+, 287 (25), 105 (base).
HRMS (EI): m/z [M]+ calcd for C28H25NO5: 455.1733; found:
1H NMR (300.13 MHz, CDCl3): δ = 0.86–0.90 (m, 3 H), 1.26–1.34
(m, 7 H), 1.40 (t, J = 7.1 Hz, 3 H), 1.57–1.67 (m, 2 H), 2.60 (t, J =
7.4 Hz, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 6.15 (d, J = 15.9 Hz, 1 H),
7.11 (t, J = 7.2 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 2 H), 7.33–7.50 (m, 4
H), 7.91 (d, J = 7.8 Hz, 1 H), 7.98 (d, J = 15.9 Hz, 1 H), 8.06 (d, J =
7.8 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): δ = 14.0 (CH3), 14.3 (CH3), 22.4
(CH2), 27.9 (CH2), 28.7 (CH2), 30.6 (CH2), 31.4 (CH2), 60.9 (CH2),
110.0 (C), 123.2 (2 × CH), 123.3 (CH), 123.9 (CH), 124.9 (CH),
125.0 (CH), 125.3 (CH), 127.1 (CH), 127.4 (C), 128.6 (2 × CH),
135.0 (C), 135.3 (C), 139.0 (CH), 142.4 (C), 145.7 (C), 146.9 (C),
156.5 (C), 166.0 (C).
455.1732.
Ethyl (E)-3-[(Z)-3-Hexyl-6,7-dimethoxy-1-(phenylimino)-1H-
isochromen-4-yl]acrylate (9j)
Prepared from 5f8 (0.400 g, 1.04 mmol) and oct-1-yne (6c) (185 μL,
1.25 mmol). The crude residue was purified by flash chromatogra-
phy on silica gel saturated with Et3N (hexanes–EtOAc–Et3N,
89:10:1), to afford 9j (0.209 g, 47%) as a yellow solid.
MS (CI): m/z (%) = 460 (base) [M + H]+, 459 (45).
HRMS (CI): m/z [M + H]+ calcd for C28H30NO3S: 460.1946; found:
460.1941.
Mp 87–89 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2009–2017

2016
Y. Madich et al.
PAPER
Ethyl (E)-3-[1-Oxo-3-phenyl-1H-isochromen-4-yl]acrylate (10)
To 9a (32 mg, 81 μmol) in EtOH (290 μL) at 0 °C was added HCl
(3 M, 280 μL) and the resulting suspension was stirred for 5 h at r.t.
The mixture was diluted with HCl (1 M, 3 mL) and extracted with
EtOAc (3 × 5 mL). The combined organic extracts were washed
with sat. aq NaHCO3 soln (3 mL) and brine (3 mL), and dried
(Na2SO4). The crude residue was purified by flash chromatography
on silica gel (hexanes–EtOAc, 95:5 to 91:9), to afford 10 (14 mg,
mmol), and the mixture was stirred at 25 °C for 2 h. After evapora-
tion of Et3N, alkene 15 (1.38 mmol) was added, air was allowed to
enter the system, and the mixture was stirred at the indicated tem-
perature (Table 2) for 20 h. H2O (10 mL) was added and the mixture
was extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were dried (Na2SO4) and the solvent was removed. The residue
was purified by column chromatography on silica gel (hexane–EtO-
Ac mixtures) to afford 16 or 17.
1
54%). The product was identified by comparison of its H NMR
spectrum with the corresponding reported data.35
Method B
To a soln of 12 or 13 (0.114 mmol) in DMF (340 μL) was added
PdCl2(PPh3)2 (4.0 mg, 5.7 μmol), CuI (5.0 mg, 23 μmol), Ph3P (2.0
mg, 5.7 μmol), Et3N (320 μL, 0.228 mmol), 1-ethynyl-4-methyl-
benzene (14) (29 μL, 0.23 mmol) and alkene 15 (0.228 mmol), and
the mixture was stirred at 50 °C for 1.5 h. Air was allowed to enter
the system and the mixture was stirred for a further 3 h at 50 °C. The
work-up procedure described in method A above was then fol-
lowed. Products 16a,b and 17a,b were characterized by comparison
of their spectroscopic data with those previously reported for the
same compounds.31
(E)-3-[(Z)-6,7-Dimethoxy-3-phenyl-1-(phenylimino)-1H-iso-
chromen-4-yl]acrylic Acid (11a)
A mixture of 9i (36 mg, 79 μmol), LiOH·H2O (66 mg, 1.6 mmol)
and THF–H2O (1:1, 2 mL) was stirred at 50 °C for 4 h, cooled to r.t.
and then evaporated under reduced pressure. H2O (3 mL) was added
to the residue, which was extracted with EtOAc (3 × 5 mL). The aq
phase and remaining solid were cooled to 0 °C and 10% H2SO4 was
added until the liquid was acidic. The mixture was then extracted
with CH2Cl2 (3 × 10 mL), and the combined organic extracts
washed with H2O (5 mL) and dried (Na2SO4). Filtration and evapo-
ration afforded 11a (30 mg, 89%) as a yellow solid.
Butyl (E)-3-(5-Methoxy-2-p-tolylbenzofuran-3-yl)acrylate (16c)
The procedure described above was followed starting from 12b (43
mg, 0.20 mmol) to yield 16c (58 mg, 80%) as a white solid.
IR (film): 2958 (w), 2933 (w), 2872 (w), 2832 (w), 1709 (s) cm–1.
Mp 228–230 °C.
IR (film): 3011 (s), 1702 (s), 1651 (s), 1589 (s), 1513 (s) cm–1.
1H NMR (300.13 MHz, acetone-d6): δ = 4.02 (s, 6 H), 6.29 (d, J =
16.3 Hz, 1 H), 7.06 (t, J = 7.2 Hz, 1 H), 7.24–7.37 (m, 5 H), 7.45–
7.47 (m, 3 H), 7.57–7.60 (m, 2 H), 7.68 (d, J = 16.3 Hz, 1 H), 7.94
(s, 1 H).
13C NMR (75.47 MHz, acetone-d6): δ = 55.4 (CH3), 105.8 (CH),
108.6 (CH), 110.1 (C), 116.7 (C), 122.7 (2 × CH), 123.1 (CH),
125.0 (CH), 127.0 (C), 128.2 (2 × CH), 128.5 (2 × CH), 129.4
(2 × CH), 129.7 (CH), 133.0 (C), 138.9 (CH), 146.9 (C), 148.3 (C),
150.2 (C), 151.3 (C), 153.6 (C), 166.2 (C).
1H NMR (400.16 MHz, CDCl3): δ = 0.99 (t, J = 7.4 Hz, 3 H), 1.42–
1.50 (m, 2 H), 1.73–1.89 (m, 2 H), 2.44 (s, 3 H), 3.91 (s, 3 H), 4.24
(t, J = 6.7 Hz, 2 H), 6.58 (d, J = 16.1 Hz, 1 H), 6.96 (dd, J = 8.9,
2.6 Hz, 1 H), 7.30 (d, J = 2.5 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 2 H),
7.44 (d, J = 8.9 Hz, 1 H), 7.65 (d, J = 8.2 Hz, 2 H), 8.02 (d, J = 16.1
Hz, 1 H).
13C NMR (100.62 MHz, CDCl3): δ = 13.8 (CH3), 19.2 (CH2), 21.5
(CH3), 30.8 (CH2), 56.2 (CH3), 64.4 (CH2), 104.1 (CH), 111.9 (CH),
112.3 (C), 113.2 (CH), 118.5 (CH), 126.9 (C), 127.4 (C), 128.4
(2 × CH), 129.6 (2 × CH), 136.2 (CH), 140.0 (C), 149.4 (C), 156.6
(C), 158.7 (C), 167.5 (C).
MS (EI): m/z (%) = 427 (13) [M]+, 383 (base), 314 (21), 306 (47),
167 (20), 149 (39), 137 (20), 111 (30), 110 (22), 105 (57).
HRMS (EI): m/z [M]+ calcd for C26H21NO5: 427.1420; found:
427.1425.
MS (EI): m/z (%) = 364 (53) [M]+, 263 (100), 262 (33), 248 (36).
HRMS (EI): m/z [M]+ calcd for C23H24O4: 364.1675; found:
364.1670.
(E)-3-[(Z)-3-Hexyl-6,7-dimethoxy-1-(phenylimino)-1H-isochro-
men-4-yl]acrylic Acid (11b)
The procedure described above for 11a was followed starting from
9j (40.5 mg, 0.087 mmol) to yield 11b (33.4 mg, 88%) as a yellow
solid.
Benzofurans 19 and Indole 20; Typical Procedure
To a soln of 12 or 13 (0.114 mmol) in DMF (340 μL) was added
PdCl2(PPh3)2 (4.0 mg, 5.7 μmol), CuI (5.0 mg, 23 μmol), Ph3P (2.0
mg, 5.7 μmol), Et3N (32 μL, 0.23 mmol) and alkyne 2 or 18 (0.228
mmol), and the resulting mixture was stirred at 50 °C for 0.5 h (5 h
at 60 °C for 19d). Air was allowed to enter the system and the mix-
ture was stirred for a further 20 h at 50 °C (3 h at 60 °C for 19d).
The work-up procedure described above was then followed. Prod-
ucts 19 were characterized by comparison of their spectroscopic
data with those previously reported for the same compounds.8
Mp 168–170 °C.
IR (film): 2929 (s), 1694 (s), 1645 (s), 1589 (s), 1515 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 0.84–0.88 (m, 3 H), 1.18–1.32
(m, 7 H), 1.48–1.55 (m, 2 H), 2.51 (t, J = 7.4 Hz, 2 H), 3.97 (s, 3 H),
4.01 (s, 3 H), 6.21 (d, J = 16.0 Hz, 1 H), 6.88 (s, 1 H), 7.07–7.15 (m,
3 H), 7.34 (t, J = 7.7 Hz, 2 H), 7.80 (d, J = 16.0 Hz, 1 H), 7.84 (s, 1
H).
13C NMR (75.47 MHz, CDCl3): δ = 14.0 (CH3), 22.4 (CH2), 27.4
(CH2), 28.6 (CH2), 31.1 (CH2), 31.4 (CH2), 56.1 (CH3), 56.3 (CH3),
104.6 (CH), 108.7 (CH), 109.1 (C), 116.4 (C), 122.6 (2 × CH),
123.4 (CH), 127.1 (C), 128.6 (2 × CH), 140.9 (CH), 146.6 (C),
149.0 (C), 149.4 (C), 153.0 (C), 155.7 (C), 170.8 (C).
Ethyl (E)-2-[2,3-Dihydro-1H-carbazol-4(9H)-ylidene]acetate
(20)
The above procedure was followed starting from 13 (25 mg, 0.23
mmol) to yield 20 (33 mg, 56%) as a white solid.
Mp 160 °C.
IR (film) 3267 (s), 2979 (w), 2925 (w), 2860 (w), 1675 (s), 1591 (s)
cm–1.
MS (EI): m/z (%) = 435 (10) [M]+, 391 (23), 307 (21), 306 (base).
HRMS (EI): m/z [M]+ calcd for C26H29NO5: 435.2046; found:
435.2043.
1H NMR (400.16 MHz, acetone-d6): δ = 1.27 (t, J = 7.1 Hz, 3 H),
1.98 (q, J = 6.2 Hz, 2 H), 2.92 (t, J = 6.2 Hz, 2 H), 3.21–3.38 (m, 2
H), 4.14 (q, J = 7.1 Hz, 2 H), 6.30 (s, 1 H), 7.10–7.20 (m, 2 H), 7.34–
7.40 (m, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 10.62 (s, 1 H).
Benzofurans 16 and Indoles 17; Typical Procedures
13C NMR (100.62 MHz, CDCl3): δ = 14.5 (CH3), 23.1 (CH2), 23.8
(CH2), 27.3 (CH2), 59.3 (CH2), 107.1 (CH), 111.0 (C), 120.5 (CH),
121.3 (CH), 122.3 (CH), 124.8 (C), 136.2 (C), 142.9 (C), 153.1 (C),
168.2 (C).
Method A
To a soln of 12 or 13 (0.230 mmol) in DMF (3 mL) was added
PdCl2(PPh3)2 (3.2 mg, 4.6 μmol), CuI (2.0 mg, 9.2 μmol), Et3N (96
μL, 0.69 mmol) and 1-ethynyl-4-methylbenzene (14) (38 μL, 0.30
Synthesis 2013, 45, 2009–2017
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Protocol for Sonogashira–Heterocyclization–Heck Couplings
2017
MS (EI): m/z (%) = 255 (42) [M]+, 210 (46), 183 (74), 180 (45), 167
(22), 113 (24), 99 (30), 97 (23), 85 (82), 83 (24), 71 (30).
(19) Ohno, H. Asian J. Org. Chem. 2013, 2, 18.
(20) Muller, T. J. J. Synthesis 2012, 44, 159.
(21) For recent reviews on metal-catalyzed oxidative couplings,
see: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. (b) Jensen, K.
H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083.
(c) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009,
3854. (d) Karimi, B.; Behzadnia, H.; Elhamifar, D.;
Akhavan, P. F.; Esfahani, F. K.; Zamani, A. Synthesis 2010,
1399. (e) Liu, C.; Jin, L. Q.; Lei, A. W. Synlett 2010, 2527.
(f) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170.
(g) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(h) Shi, W.; Liu, C.; Lei, A. W. Chem. Soc. Rev. 2011, 40,
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HRMS (EI): m/z [M]+ calcd for C16H17NO2: 255.1259; found:
255.1263.
Acknowledgment
We thank the Spanish Ministerio de Economía y Competitividad
(Grants CTQ2009-14186 and CTQ2012-37734, FEDER), AECID
(Grant A/025378/09), Universidad del País Vasco (fellowship to
Y.M.), and Universidade de Vigo (fellowship to J.G.D.) for finan-
cial support. We also thank SGIker UPV/EHU for technical support
(NMR facilities, HRMS and X-ray analyses).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(22) Liu, G. N.; Zhou, Y.; Ye, D. J.; Zhang, D. Y.; Ding, X.;
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2009–2017