Towards Isocoumarin-Fused Enediyne Systems through the Electrophilic Cyclization of Methyl o-(Buta-1,3-diynyl)benzoates

Article abstract of DOI:10.1002/ejoc.201501262

The synthesis of enediynes fused to an isocoumarin core was achieved through the electrophilic cyclization of o-(buta-1,3-diynyl)benzoates as a key step, followed by the Sonogashira coupling of the resulting 3-ethynyl-4-iodoisocoumarins with acetylenes. T

Full text of DOI:10.1002/ejoc.201501262

DOI: 10.1002/ejoc.201501262
Full Paper
Isocoumarin-Fused Enediynes
Towards Isocoumarin-Fused Enediyne Systems through the
Electrophilic Cyclization of Methyl o-(Buta-1,3-diynyl)benzoates
[a]
[a]
[a,b]
[a]
Natalia A. Danilkina, Larisa Y. Gurskaya, Aleksander V. Vasilyev,
and Irina A. Balova*
Abstract: The synthesis of enediynes fused to an isocoumarin be introduced to both ethynyl moieties with complete regio-
core was achieved through the electrophilic cyclization of o- control. The ability of the isocoumarin-fused enediynes to un-
(
buta-1,3-diynyl)benzoates as a key step, followed by the Sono- dergo Bergman cyclization was studied by differential scanning
gashira coupling of the resulting 3-ethynyl-4-iodoisocoumarins calorimetry.
with acetylenes. This approach allowed different substituents to
Introduction
The electrophilic cyclization of methyl o-ethynylbenzoates
has been investigated in detail, but only a few examples of the
cyclization of methyl o-(buta-1,3-diynyl)benzoates have been
Isocoumarin and its derivatives make up an important class of
oxygen-containing heterocycles, as they occur in many natural
reported. The ICl-induced double cyclization of dimethyl 2,2′-
[
1]
products with a wide range of biological activities. Considera-
ble efforts have been devoted to the synthesis of isocoumar-
[9a]
(
buta-1,3-diyn-1,4-diyl)dibenzoate to give biisocoumarin was
described. The second reported example was a double iodocy-
clization of asymmetrically substituted 1,4-diarylbutadiynes to
give biheterocyclic compounds bearing one isocoumarin
[
1a,2]
ins.
Of the methods for the synthesis of an isocoumarin
core, the electrophilic cyclization of 2-(alk-1-ynyl)benzoic acids
and esters is the most attractive. These reactions can be medi-
[
3]
[12b]
ring.
The formation of 3-ethynyl-4-iodoisocoumarin as an
[
4]
[5]
[6]
ated by Brønsted acids or transition-metal salts (Cu, Hg,
[12b]
intermediate in the double cyclization was observed once.
Recently, we reported the iodocyclization of diacetylene de-
rivatives of thioanisole, anisole, and N,N-dimethylaniline. Only
one of the triple bonds was affected, and heteroindenes bear-
ing an ethynyl moiety and an iodine atom were formed in one
step. This cyclization was used as a key step in a simple and
[
7]
[8]
Pd, Ag ). The corresponding 4-chalcogeno derivatives have
been synthesized using p-NO C H SCl or PhSeCl as electrophilic
2
6 4
[
9a]
reagents. Moreover, the electrophilic cyclization of methyl 2-
ethynylbenzoates has been found to be a general strategy for
the synthesis of 4-haloisocoumarin derivatives. Reagents such
[
9]
[10]
as iodine and ICl or N-iodosuccinimide (NIS)
gave 4-iodo-
convenient approach to acyclic and macrocyclic enediynes
isoscoumarins, whereas bromolactonization of methyl 2-
ethynylbenzoates with N-bromosuccinimide or N-methylpyr-
rolidin-2-one hydrotribromide led to 4-bromoisocoumarins.
It should be noted that depending on the reaction condi-
tions and the structure of the acetylene starting materials, 5-
exo-dig cyclization may take place to give isobenzofuranone by-
[14]
fused to heteroindenes.
In this paper, we extend this ap-
[
10]
proach, and report the synthesis of isocoumarin-fused enedi-
ynes by the electrophilic cyclization of methyl o-(buta-1,3-di-
ynyl)benzoates and subsequent Sonogashira coupling.
It is noteworthy that enediynes are coming to the attention
of the synthetic community as a result of the fact that naturally
occurring enediynes with a (Z)-3-ene-1,5-diyne scaffold incor-
[
11]
[
9a]
products along with the 6-endo-dig ring closure.
Neverthe-
less, many isocoumarins, including naturally occurring com-
pounds, have been synthesized by this approach. For example,
this strategy has been used for the solution-phase synthesis of
a 167-membered library of isocoumarins,
of polyheterocyclic compounds,
synthesis of 4-haloisocoumarin derivatives.
porated into a 9- or 10-membered macrocycle can damage
[15]
DNA.
Thus, enediyne antibiotics represent some of the
strongest antitumor and antibacterial compounds among other
[
12a]
for the synthesis
and for the solid-phase
[16]
natural products.
However, their clinical application is re-
[
12b]
stricted due to their high instability, toxicity, allergenicity, and
structural complexity. This motivates chemists to search for syn-
[
13]
[
17]
thetic analogues of enediynes.
[
a] Institute of Chemistry, Saint Petersburg State University,
Universitetskaya nab. 7/9, Saint Petersburg 199034, Russia
E-mail: i.balova@spbu.ru
http://www.chem.spbu.ru/org_en.php
[
b] Department of Chemistry, Saint Petersburg State Forest Technical
University,
Results and Discussion
Institutsky per. 5, 194021 Saint Petersburg, Russia
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501262.
For the synthesis of starting methyl ortho-(buta-1,3-diynyl)-
[
18]
benzoates 3a–3d, we used the Sonogashira coupling
of 2-
iodobenzoate with terminal diacetylenes or TMS (trimethylsilyl)
Eur. J. Org. Chem. 2016, 739–747
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protected diacetylenes using conditions for one-pot TMS-group
removal and C–C coupling (Table 1).
Table 2. Optimization of reaction conditions for the electrophilic cyclization
of methyl o-(4-phenylbuta-1,3-diynyl)benzoate 3a.
Table 1. Synthesis of methyl o-(buta-1,3-diynyl)benzoates 3a–3d.
Entry
R
X
Diacetylene[a] Conditions[b] Product (isolated
yield [%])
1
2
3
4
Ph
TMS
H
H
TMS
2a
2b
2c
A
A
B
B
3a (75)
3b (48)
3c (84)
3d (77)
C
5
H
11
(CH
2
)
2
OH TMS
2d
Entry Solvent [a]
E (equiv.)
Reaction
time[
Ratio 4a/5/6 or 7/3a[c]
a] Diacetylenes 2a and 2b were synthesized by known procedures,[14a] and
[
b]
3 4
were used in the Sonogashira coupling without purification. [b] A: Pd(PPh )
(
(
(
5 mol-%), CuI (15 mol-%), Et
15 mol-%), diisopropanolamine [DIPA-(OH)
10 equiv.), DMF, 40 °C, 1–2 h.
3
N, 40 °C, 3–18 h; B: Pd(PPh
3
)
4
(5 mol-%), CuI
1
2
3
4
MeCN
MeCN
MeCN
MeCN
I2 (3)
I2 (1)
NIS (1)
5 d
28 h
5 d
1:0.8:0.25:0.05
1:–:2:0.1
1:0.3:0.2:1
1:–:0.2:1.5
2
] (4 equiv.), KF (5 equiv.), MeOH
I
(
2
/CAN
20 h
1:1.1)[
d]
Thus phenylbuta-1,3-diyne (2a) and (trimethylsilyl)buta-1,3-
5
6
7
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
I
I
I
2
(1)
(1.5)
(1.2)
28 h
20 h
20 h
1:<0.05:–:0.1
1:0.16:–: <0.05
1:–:–: <0.05
diyne (2b), derived from 2-methyl-6-phenylpenta-3,5-diyn-2-ol
and 1,4-bis(trimethylsilyl)butadiyne, respectively, were easily
coupled with methyl 2-iodobenzoate (1) under the Sonogashira
reaction conditions (A) that has been used previously for the
2
2
[
a] Reactions were carried out at 40 °C. [b] Reaction times were evaluated by
H NMR spectroscopy because of the close R values of compounds 3–7.
f
1
[
14a]
1
synthesis of other o-functionalized aryldiacetylenes
(Table 1,
[c] The ratio was determined by H NMR spectroscopy. [d] The experiment
was run at room temp.
entries 1 and 2).
For the introduction of diacetylene moieties with alkyl and
hydroxyalkyl substituents, another method (B) was used. In this
We then examined other electrophilic agents. Unfortunately,
case, TMS-group removal and Sonogashira coupling were car- neither NIS nor an I /CAN system, which have been used previ-
2
[
10,20]
ried out in one pot. This technique has been used previously ously for the O-cyclization of monoacetylenes,
with Ag /Pd catalysts, and with K CO /MeOH acting as both the desired product (4a) without iodinated by-products. More-
gave only
I
0
2
3
a TMS-deprotection reagent and a base for the Sonogashira over the conversion of ester 3a was still low (Table 2, entries 3
[
19]
coupling.
We found that a similar approach using Cu /Pd in the pres-
ence of K CO /MeOH or a milder KF/MeOH system was very o-(buta-1,3-diynyl)thioanisoles and -N,N-dimethylanilynes was
and 4).
I
0
Bearing in mind the fact that the rate of iodocyclization of
2
3
efficient in the synthesis of aryl diacetylenic alcohols, and for higher when CH Cl was used as a solvent rather than aceto-
2
2
the introduction of eneyne scaffolds.[14a,14d]
nitrile,
[14a]
we next tested CH Cl as a solvent. We found that
2 2
The Sonogashira coupling of diynes 2c and 2d using KF/ when the cyclization was carried out in CH
Cl with an equimo-
2 2
MeOH for one-pot TMS-group removal gave diacetylenes 3c lar amount of iodine, iodination of a triple bond in starting
and 3d in high yields, without affecting the ester group ester 3a was avoided, the formation of by-product 5 decreased
(
Table 1, entries 3 and 4).
significantly, and the conversion of ester 3a into iodoisocouma-
Electrophilic cyclization of methyl o-(4-phenylbuta-1,3-di- rin 4a increased (Table 2, entry 5). To reach full conversion, an
ynyl)benzoate (3a) with iodine (3 equiv.) in MeCN at 40 °C gave excess of iodine (1.5 equiv.) was used. But despite the fact that
a mixture of products. The mixture was separated by prepara- almost full conversion was obtained, these conditions led to
tive TLC, and analysed by MS. On the basis of the analytical increased amounts of isocoumarin with an iodinated triple
data, the desired isocoumarin (4a), an isocoumarin with an iodi- bond 5 (Table 2, entry 6).
nated triple bond 5, and an iodinated starting ester 6 (or 7)
were identified along with the starting diyne (3a), which was (1.2 equiv.) in CH
Finally, optimal conditions were found. The use of iodine
Cl at 40 °C gave only traces of unconverted
2
2
detected in the reaction mixture even after 5 d (Table 2, en- ester 3a, and did not give iodinated by-products (Table 2, en-
try 1). To avoid iodination of the triple bonds, starting ester 3a try 7). Under these conditions, compound 4a was isolated in
and I were used in an equimolar ratio (Table 2, entry 2). How- 64 % yield (Table 3, entry 1).
2
ever, the conversion of the ester to the desired iodoisocoumarin
For the reactions shown in Table 3, entries 2–4, the amount
(
4a) was poor, and iodination of a triple bond in the starting of iodine was reduced to 1.1 equiv. Iodocyclization of methyl
material (3a) occurred again.
o-(buta-1,3-diynyl)benzoates 3c and 3d gave the desired pro-
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Table 3. Electrophilic cyclization of methyl o-(buta-1,3-diynyl)benzoates 3a–
d.
Table 4. Optimization of reaction conditions for the synthesis of isocoumarin-
fused enediynes.
3
Entry
R
Ester
Reaction
time
Ratio
4/3
Product
(isolated yield [%])
Base[a]
Entry Acetylene, R
CuI,
[
Product
(isolated yield [%])
[
a]
mol-%[b]
]
1
2
3
4
Ph
TMS
3a
3b
3c
3d
20[b]
24
21
1:0.05
4a (64)
(–)
4b (59)
4c (40)
1
2
3
4
5
8a, Bu
8b, CH
8b, CH
8b, CH
DIPA-(OH)
2
15
15
15
5
9 (27)
9 (9)
10a (17)
10a (62)
9 (22), 10a (24)
[
c]
2
2
2
OH
OH
OH
Et
3
N
C
5
H
11
1:0.07
1:0.25
DIPA
DIPA
DIPA-(OH)2
(CH
2
)
2
OH
24
1
8b, CH OH
5
[
a] The ratio was determined by H NMR spectroscopy. [b] 1.2 equiv. of I
2
was
2
used. [c] The ratio was not determined; a complex mixture was obtained.
[
a] DIPA-(OH)
ditions: entries 1 and 3–5, (A): PdCl
entry 2, (B): Pd(PPh (5 mol-%), THF, 50 °C, 24 h.
2
= diisopropanolamine; DIPA = diisopropylamine. [b] Other con-
2
(PPh (5 mol-%), DMF, 50 °C, 1–5 h;
3 2
)
3 4
)
ducts (i.e., 4b and 4c, respectively), and the formation of iodin-
ated isocoumarins did not take place. However in the case of
the hydroxyalkyl substituent, the electrophilic cyclization pro-
ceeded with a worse conversion of the starting material under
these conditions, and the corresponding isocoumarin (4c) was
formed in only moderate yield (Table 3, entry 4). Unfortunately,
all attempts to induce TMS-substituted diacetylene ester 3b to
undergo cyclization gave complex mixtures of unidentified pro-
ducts and unconverted starting material (Table 3, entry 2).
Despite the fact that according to Baldwin's rules, digonal
These results show that both the amount of CuI and the nature
of the base affect the reaction. Therefore, the best conditions
(
Table 4, entry 4) were used for the synthesis of other enedi-
ynes.
These optimized conditions allowed enediynes fused to an
isocoumarin ring 10a–10h to be obtained in yields from mod-
erate to high (Table 5). Moreover, TMS, hydroxyalkyl, and alk-
oxyalkyl substituents, which are very important functional
groups for the further transformation into macrocyclic enedi-
ynes, were introduced into the molecules in this step.
[
21]
ring closures are generally of the endo type,
the formation
of both 5-exo-dig and 6-endo-dig products have been observed
[
9a]
with o-ethynylbenzoates.
We found that all the reactions of
diacetylene derivatives 3 proceeded regioselectively as 6-endo-
dig processes with the formation of only the isocoumarin
ring.
Table 5. Sonogashira coupling in the synthesis of enediynes fused to an iso-
coumarin core 10a–10h.
[
22]
Next, iodoisocoumarins 4a–4c were used as substrates for
the synthesis of acyclic enediyne systems fused to an isocouma-
rin core by Sonogashira coupling with terminal acetylenes 8.
Iodoisocoumarin 4a was chosen for optimization of the condi-
tions (Table 4).
Surprisingly, the reaction of iodoisocoumarin 4a with hexyne
(
8a) under conditions used recently for the synthesis of enedi-
[
14a]
ynes fused to heteroindenes
gave only reduced isocoumarin
Entry
Substrate, R1
Alkyne, R2
Reaction
time [h]
Product
(isolated yield [%])
9
in low yield (Table 4, entry 1). Similar results were obtained
when the reaction was carried out in THF using Et N instead of
DIPA-(OH) (Table 4, entry 2). Switching to diisopropylamine as
3
1
2
3
4
5
6
7
8
4a, Ph
4a, Ph
4a, Ph
4b, C5H11
8b, CH
8a, Bu
2
OH
1
20
2
1
3
22
2
22
10a (68)
10b (72)
10c (90)
10d (90)
10e (76)
10f (63)
10g (68)
10h (36)
2
the base gave the desired cross-coupling product, but the yield
was low (Table 4, entry 3).
Taking into account the fact that the cross-coupling of 4-
iodoisocoumarins with various terminal acetylenes has previ-
ously been carried out successfully in the synthesis of a combi-
8c, TMS
8d, Ph
8c, TMS
4b, C
4b, C
5
H
H
11
5
11
8e, (CH
2
)
2
OH
4c, (CH
4c, (CH
2
)
)
2
OH
OH
8d, Ph
2
2
8f, CH
2
OMe
[
12a]
natorial library of isocoumarins,
were carried out in the presence of a smaller amount of CuI
2 mol-%) as a cocatalyst, we decided to decrease the amount
and that these reactions
(
The structure of enediynes 10b–10d was verified by X-ray
[
23]
of CuI used. When we used less CuI, together with diisopropyl- analysis (Figure 1). The data obtained confirmed that the iso-
amine as a base, the yield of target compound 10a increased coumarin structures of the electrophilic cyclization products de-
to 62 % (Table 4, entry 4). However, when the Sonogashira cou- termined by NMR spectroscopy are correct. Moreover, these
pling was run with diisopropanolamine, a mixture of enediyne data gave values for bond angles (1 and 2) and cd-distances for
1
0a and reduced product 9 was again formed (Table 4, entry 5). the enediyne molecules (Table 6). These are important struc-
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tural parameters of enediynes in evaluating their ability to un- oxidation of the sample by residual oxygen in the sealed
dergo Bergman cyclization (BC).[24]
pan.
[26]
Table 7. Studying the reactivity of enediynes 10a–10g in Bergman cyclization
by DSC.[
a]
Figure 1. Molecular structures of isocoumarin-fused enediynes 10b (left), 10c
(
middle), and 10d (right).
Entry
Enediyne
R1
R2
T
BC [°C][b]
Table 6. Selected X-ray structural data of enediynes 10b–10d.
1
2
3
4
5
6
7
10a
10b
10c
10d
10e
10f
Ph
Ph
Ph
CH
Bu
TMS
Ph
TMS
(CH
Ph
2
OH
192 (198)
164
154
148
220
C
5
C
5
C
5
H
H
H
11
11
11
2
)
2
OH
164
162 (167)
10g
(CH
2
)
2
OH
[
a] Polymeric structure of Bergman cyclization products obtained by heating
of acyclic enediynes in a heating bath set at their peak DSC temperature has
R1
R2
been reported.[27b] [b] Peak separation procedure for the obtained curves
1 [°]
2 [°]
cd [Å]
gave the values of the Bergman cyclization temperatures (TBC). The onset
temperatures of exothermic peaks from the experiments with closed high-
pressure steel pans are given; onset temperatures from the DSC measure-
ments in pans with pierced lids for enediynes 10a and 10g are given in
parentheses.
10b
10c
10d
Ph
Ph
C H
5 11
Bu
TMS
Ph
120.8
120.5
119.9
125.8
125.4
125.0
4.35
4.25
4.15
Finally the reactivity of enediynes 10a–10g in Bergman cycli-
zation was studied by differential scanning calorimetry (DSC),
As expected, the observed values of the Bergman cyclization
which is known to be an efficient, rapid method for this pur- temperatures (TBC) for isocoumarin-fused enediynes (148–
[
25]
pose.
pounds were tested by thermogravimetric analysis (TGA). This heteroindenes (200–266 °C).
Before running the DSC measurements, all the com- 220 °C) are much lower than the TBC for enediynes fused to
[
14a]
This fact can be explained by
showed significant loss of mass for enediynes 10b–10f at tem- the structural and electronic properties of the enediynes syn-
peratures around 200 °C, connected to vaporization of the sam- thesized.
ple before complete Bergman cyclization of all the sample vol-
ume had taken place.
It has been shown that if the ring-strain energy does not
[
26]
Only two enediynes, 10a and 10g, influence the reactivity of endiynes,[28] then their ability to un-
bearing phenyl and hydroxyalkyl substituents at both ethynyl dergo Bergman cyclization strongly depends on the distance
[
29]
moieties, did not evaporate during the heating to 350 °C, and between the interacting Csp atoms (cd-distance). For the iso-
were therefore investigated by the conventional DSC technique coumarin-fused enediynes, angles 1 and 2 were found to be
using aluminium pans with pierced lids. Thus, the exothermic smaller by 3–7° than the corresponding angles in acyclic enedi-
[
14a]
peaks observed in the thermograms (198 °C for 10a, and 167 °C ynes fused to heteroindenes synthesized earlier (Table 6).
for 10g, onset temperatures) obviously show that the Bergman As a result, the cd-distances in the isocoumarin-annulated ene-
cyclization of compounds 10a and 10g took place.[ Addi- diynes became significantly smaller (4.1–4.3 Å) than the cd-dis-
tional evidence suggesting that irreversible Bergman cyclization tances in heteroindene-fused molecules (4.5–4.7 Å), and ex-
26]
[
27]
followed by polymerization
occurred comes from the fact plains the increased reactivity of the isocoumarin-fused enedi-
that neither endothermic nor exothermic features were ob- ynes. Furthermore, for enediynes 10b–10d, the values of the
served when the thermolysed samples were scanned a second cd-distance obtained from the X-ray data (Table 6) are consist-
time.
ent with the values of TBC (Table 7, entries 2–4). Thus, an in-
To evaluate the ability of the other compounds to undergo crease in the cd-distance of 0.1 Å corresponds to in an increase
Bergman cyclization, the DSC measurements were carried out in TBC of 6–10 °C.
in closed high-pressure steel pans (Table 7). It should be noted
that under these conditions, the onset temperatures of the exo- known that annulation of an electron-deficient heterocycle
Regarding the electronic properties of the enediynes, it is
[
30]
[
31]
thermic peaks for compounds 10a and 10g were found to be or a benzene ring with electron-withdrawing substituents to
close to the temperatures obtained using aluminium pans with an enediyne system results in a more reactive species in ther-
pierced lids (Table 7, entries 1 and 7). However, running the mally induced cycloaromatization. Therefore, replacing the elec-
DSC measurements in closed pans led to a second exothermic tron-rich heteroindene rings with an isocoumarin core in the
effect at temperatures higher than those for the Bergman cycli- heterocycle-fused enediynes might also result in a decrease in
zation. The new exothermic effect observed could be due to their TBC.
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Conclusions
was carried out using Netzsch Peak Separation software. X-ray anal-
ysis of single crystals of compounds 10b–10d was carried out with
The electrophilic cyclization of methyl 2-(buta-1,3-diynyl)benzo- a SuperNova, Dual, Cu at zero, Atlas diffractometer. A suitable crys-
ates was found to proceed regioselectively as a 6-endo-dig cycli- tal was kept at 100(2) K during data collection. Using Olex2,[ the
35]
structure was solved with the Superflip structure-solution pro-
zation to give 3-ethynyl-4-iodoisocoumarins. The Sonogashira
coupling of the resulting iodoethynylisocoumarins with acet-
ylenes led to enediynes fused to an isocoumarin core. We found
[
36]
gram
using charge flipping, and refined with the ShelXL refine-
[
37]
ment package
using least-squares minimization.
that the amount of CuI used as cocatalyst and the nature of 4-Phenylbuta-1,3-diyne (2a): Well-ground NaOH (12.1 mmol,
the base both strongly affected the results of the Sonogashira 485 mg) was added to a solution of 2-methyl-6-phenylhexa-3,5-
coupling and the formation of by-products due to the reduc- diyn-2-ol (4.02 mmol, 740 mg) in benzene (22.0 mL). The reaction
mixture was stirred under Ar at 70 °C for 50 min. Then, the reaction
mixture was cooled to room temperature, filtered, and washed with
water until pH 7. The combined aqueous layers were extracted with
ethyl acetate. The combined organic layers were dried with anhy-
drous Na SO , and evaporated to give a solution of 4-phenylbuta-
tion of 4-iodoisocoumarins. Using this approach, asymmetrically
substituted isocoumarin-fused enediynes were obtained in
three synthetic steps. The results of DSC analysis demonstrated
that the isocoumarin-fused enediynes were more reactive than
acyclic enediynes fused to heteroindenes in Bergman cycliza-
tions.
2
4
1,3-diyne (2a) in a mixture of benzene and ethyl acetate (ca. 10 mL),
which was used in the Sonogashira coupling without further purifi-
cation.
Trimethylsilylbuta-1,3-diyne (2b): MeLi·LiBr complex (2.20
tion in diethyl ether; 14.8 mmol, 6.7 mL) was added dropwise to a
cooled (0 °C) stirred solution of 1,3-bis(trimethylsilyl)buta-1,3-diyne
M solu-
Experimental Section
General Remarks: Solvents, reagents, and chemicals [1,3-bis(tri-
methylsilyl)buta-1,3-diyne and terminal acetylenes 8a–8e] were
purchased from commercial suppliers, and were used without fur-
ther purification. Catalysts Pd(PPh ) , and PdCl (PPh ) were pur-
(6.0 mmol, 1.17 g) in absolute diethyl ether (60 mL). The reaction
mixture was warmed to room temperature, and was stirred at room
temperature for 6 h. Then, the reaction mixture was cooled to 0 °C,
quenched with water (4.0 mL), and diluted with brine. The organic
layer was separated, and the aqueous layer was acidified with HCl
3
4
2
3 2
chased from Sigma–Aldrich. Solvents were dried under standard
[32]
conditions. Methyl o-iodobenzoate (1),
2-methyl-6-phenylhexa-
,5-diyn-2-ol (2a),[14a] trimethyl(nona-1,3-diynyl)silane (2c),
[33]
(10 % aq.), and extracted with Et
were washed with brine until pH 7, dried with anhydrous Na
2
O. The combined organic layers
SO
3
6-tri-
[14a]
2
,
4
methylsilylhexa-3,5-diyn-1-ol (2d),
and 3-methoxyprop-1-yne
8f)[ were synthesized by known procedures without any modifi-
34]
and evaporated under reduced pressure (not lower than 700 Torr).
This gave a solution of trimethylsilyldiacetylene (2b) in Et O (ca.
(
2
cation. All reactions were carried out under Ar in flame-dried glass-
ware. Evaporation of solvents and concentration of reaction mix-
tures were carried out under vacuum at 30–40 °C on a rotary evapo-
rator. Thin-layer chromatography (TLC) was carried out on silica gel
plates (silica gel 60, F254), with detection by UV light. Normal-phase
silica gel (silica gel 60, 230–400 mesh) was used for preparative
6
mL), which was used in the Sonogashira coupling without further
purification.
General Procedures for the Sonogashira Coupling of Methyl 2-
Iodobenzoate 1 with Terminal Diacetylenes 2a and 2b, and
TMS-Substituted Diacetylenes 2c and 2d
1
13
chromatography. H and C NMR spectra were recorded at 400 and
Method A: Methyl 2-iodobenzoate (1; 1.00 equiv.) was dissolved in
triethylamine, and a solution of terminal diacetylene 2a or 2b (2–
1
00 MHz in CDCl (3a–3d, 4a–4c, 10a, 10c–10h) or [D ]DMSO (10b)
3
6
1
without any internal standard. H NMR spectroscopic data are re-
ported as follows: chemical shift (δ), multiplicity (s, singlet; d, dou-
blet; t, triplet; q, quartet; m, multiplet; br., broad), coupling con-
stants (J, given in Hz), and number of protons. C NMR spectro-
scopic data are reported as follows: chemical shift (δ) and type of
carbon (p, primary; s, secondary; t, tertiary; q, quaternary), as deter-
mined from DEPT experiments. Chemical shifts are reported as δ
values (ppm), and were referenced to residual solvent signals [δ =
2
.5 equiv.; see above) was added, followed by PPh (10 mol-%) and
3
Pd(PPh3)4 (5 mol-%). The resulting solution was evacuated and
flushed with Ar several times. Then, CuI (15 mol-%) was added. The
reaction mixture was evacuated and flushed with Ar once again,
and then stirred at 40–45 °C. When TLC showed that the reaction
was complete, the reaction mixture was poured into saturated
1
3
aqueous NH Cl. The mixture was extracted with ethyl acetate. The
4
1
organic phase was washed with saturated aqueous NH Cl, and
7
.26 (CHCl ) or 2.50 ([D ]DMSO) ppm for H; δ = 77.00 (CDCl ) or
4
3
5
3
1
3
brine, dried with anhydrous Na SO , and concentrated under re-
2 4
duced pressure. The crude product was purified by column chroma-
tography on silica gel.
3
9.52 ([D ]DMSO) ppm for C]. High-resolution mass spectra
6
(HRMS) were measured using the electrospray ionization (ESI) tech-
nique in positive-ion mode using time-of-flight (TOF) MS. Thermo-
gravimetric analysis (TGA) for compounds 10a–10g was carried out
using a TG 209 F1 Libra thermogravimetric analyser (Netzsch). Sam-
ples (0.15–1.19 mg) were heated in aluminium pans under a flow
Method B: Methyl 2-iodobenzoate (1; 1 equiv.) was dissolved in
DMF, and Pd(PPh ) (5 mol-%), DIPA-(OH) (4 equiv.), CuI (15 mol-
3
4
2
%
), and KF (5 equiv.) were added. The reaction vial was evacuated
and flushed with Ar several times, then it was sealed and MeOH
10 equiv.) was added, followed by TMS-substituted diacetylene 2c
or 2d (1.0–1.5 equiv). The reaction mixture was stirred at 40 °C for
–2 h (monitored by TLC). The reaction mixture was then allowed
3
of argon (90 cm /min) at a rate of 5 °C/min from 20 °C to 380 °C.
Differential scanning calorimetry (DSC) for compounds 10a–10g
was carried out with a DSC 204 F1 Phoenix (Netzsch) calorimeter.
The measurements for enediynes 10a and 10g were carried out in
(
1
4
0 μL aluminium crucibles with pierced lids. Then compounds 10a–
0g were analysed in closed high-pressure steel pans with a de-
composition pressure of 100 bar. DSC samples (0.12–0.27 mg) were
to cool, and worked up as described for method A.
1
Methyl 2-(Phenylbuta-1,3-diynyl)benzoate (3a): Compound 3a
investigated at a heating rate of 10 °C/min under a flow of argon was synthesized following method A in Et N (8 mL) from methyl 2-
3
(
70 mL/min). Samples precooled to 20 °C were heated to 400 °C,
iodobenzoate (1; 1.64 mmol, 430 mg) and a solution of 4-phenyl-
buta-1,3-diyne (2a), obtained as described above from 2-methyl-6-
then cooled to 20 °C, and heated to 400 °C again. Peak separation
Eur. J. Org. Chem. 2016, 739–747
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
phenylhexa-3,5-diyn-2-ol (4.02 mmol, 740 mg). Purification of the
crude product by column chromatography on silica gel (petroleum
reaction mixture by TLC analysis (hexane/ethyl acetate, 20:1). Then,
the mixture was cooled to room temperature, diluted with Na S O
2 3
2
ether/ethyl acetate, 30:1) gave 3a (320 mg, 75 %) as a white solid,
(5 % aq.), and extracted with CH Cl . The combined organic layers
were washed with H O, dried with anhydrous Na SO , and concen-
2 2 4
2 2
1
m.p. 79–81 °C. H NMR (400 MHz, CDCl ): δ = 7.99 (dd, J = 7.8, J =
3
0
7
.8 Hz, 1 H), 7.66 (dd, J = 7.6, J = 0.6 Hz, 1 H), 7.53–7.55 (m, 2 H),
trated under reduced pressure. The crude mixture was subjected to
column chromatography on silica gel (hexane/ethyl acetate, 20:1),
followed by fine separation by preparative TLC (hexane/acetone,
3:1) to give iodoisocoumarin 4a (70.0 mg, 34 %); MS (ESI): calcd. for
.48–7.51 (m, 1 H), 7.40–7.44 (m, 1 H), 7.32–7.38 (m, 3 H), 3.97 (s, 3
13
H) ppm. C NMR (100 MHz, CDCl ): δ = 166.2 (q), 135.3 (t), 132.8
3
(
(
(
q), 132.7 (t), 132.0 (t), 130.7 (t), 129.4 (t), 128.8 (t), 128.6 (t), 122.8
q), 121.9 (q), 83.4 (q), 79.9 (q), 79.0 (q), 74.3 (q), 52.7 (p) ppm. HRMS
ESI): calcd. for C H O [M + H] 261.0916; found 261.0902.
+
C H IO [M + H] 372.97; found 372.97. Also isocoumarin with
17
10
2
+
iodinated triple bond 5 (60 mg, 17 %); MS (ESI): calcd. for C H I O
18
13
2
17 10 3
2
+
[
M + H] 626.76; found 626.76. Also a mixture of iodoisocoumarin
Methyl 2-[(Trimethylsilyl)buta-1,3-diynyl]benzoate (3b): Com-
pound 3b was synthesized following method A in Et N (9 mL) from
methyl 2-iodobenzoate (1; 2.2 mmol, 590 mg) and a solution of cation of all the components allowed the composition of the crude
trimethylsilylbuta-1,3-diyne (2b) in diethyl ether, obtained as de-
scribed above from bis(trimethylsilyl)diacetylene (6.0 mmol, 1.17 g).
Purification of the crude product by column chromatography on
silica gel (petroleum ether, then petroleum ether/ethyl acetate, 90:1
4a with diiodide 6 (or 7) (20 mg); MS (ESI): calcd. for C H I O K
18 12 2 2
+
3
[M + K] 552.86; found 552.86; ratio 4a/6 (or 7) = 1:0.5. The identifi-
1
mixture to be calculated from its H NMR spectrum: 4a/5/6 (or 7)/
3a = 1:0.8:0.25:0.05.
General Procedure for the Electrophilic Cyclization of Methyl 2-
(Buta-1,3-diynyl)benzoates: A solution of iodine (1.1–1.2 equiv.)
1
then 70:1) gave 3b (0.28 g, 48 %) as a brown oil. H NMR (400 MHz,
CDCl ): δ = 7.97 (dd, J = 7.8, J = 1.0 Hz, 1 H), 7.62 (d, J = 7.6 Hz, 1
in CH
2
Cl
2
was added dropwise to an argon-flushed solution of
3
H), 7.45–7.49 (m, 1 H), 7.38–7.43 (m, 1 H), 3.94 (s, 3 H), 0.23 (s, 9 H)
methyl 2-(buta-1,3-diynyl)benzoate (3, 1 equiv.) in CH
tion mixture was stirred under reflux until the reaction was com-
plete (see Table 3). To monitor the reaction, an aliquot of the reac-
2
Cl . The reac-
2
ppm. 13C NMR (100 MHz, CDCl ): δ = 166.1 (q), 135.6 (t), 133.0 (q),
3
1
32.0 (t), 130.7 (t), 128.9 (t), 122.4 (q), 92.6 (q), 88.0 (q), 79.1 (q), 74.9
(
q), 52.5 (p), –0.26 (p) ppm. HRMS (ESI): calcd. for C H O Si [M +
tion mixture was passed through a layer of Na S O , evaporated to
2 2 3
1
5 17 2
+
1
H] 257.0992; found 257.0994.
dryness, and analysed by H NMR spectroscopy. When the reaction
was complete, the mixture was cooled to room temperature, diluted
with Na S O (5 % aq.), and extracted with CH Cl . The combined
Methyl 2-(Nona-1,3-diynyl)benzoate (3c): Diacetylene 3c was
synthesized following method B from methyl 2-iodobenzoate (1;
2
2
3
2
2
organic layers were washed with H O, dried with anhydrous Na SO ,
2
2
4
2
.0 mmol, 524 mg) and trimethyl(nona-1,3-diynyl)silane (2c;
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel.
3.0 mmol, 576 mg). Purification of the crude product by column
chromatography (petroleum ether/ethyl acetate, 90:1 then 70:1)
1
gave 3c (420 mg, 84 %) as a yellow oil. H NMR (400 MHz, CDCl ):
4-Iodo-3-(phenylethynyl)-1H-isochromen-1-one (4a): Compound
4a was prepared following the general procedure from diyne (3a,
3
δ = 7.95 (dd, J = 7.8, J = 1.1 Hz, 1 H), 7.60 (dd, J = 7.6, J = 1.3 Hz,
1
7
3
H), 7.43–7.47 (m, 1 H), 7.35–7.39 (m, 1 H), 3.94 (s, 3 H), 2.37 (t, J =
1.54 mmol, 400 mg) in CH
2 2 2
Cl (23 mL), and I (1.85 mmol, 468 mg)
.1 Hz, 2 H), 1.55–1.60 (m, 2 H), 1.29–1.43 (m, 4 H), 0.91 (t, J = 7.2 Hz,
in CH Cl (30 mL). The reaction time was 20 h (Table 2, entry 1).
2
2
H) ppm. 13C NMR (100 MHz, CDCl ): δ = 166.4 (q), 135.3 (t), 132.9
Purification of the crude product by column chromatography on
silica gel (petroleum ether/acetone, 3:1) gave pure isochromene 4a
(365 mg, 64 %), along with a mixture of 4a and 3a (71.0 mg); ratio
3
(q), 131.8 (t), 130.6 (t), 123.1 (q), 86.9 (q), 79.6 (q), 73.0 (q), 65.4 (q),
5
2.4 (p), 31.2 (s), 28.0 (s), 22.3 (s), 19.8 (s), 14.0 (p) ppm. HRMS: calcd.
+
1
for C H O [M + H] 255.1380; found 255.1381.
4a/3a = 3:1 according to H NMR spectroscopy. The total yield of
17 19 2
4
a was calculated to be 74 %. Data for 4a: White solid, m.p. 138–
1
Methyl 2-(6-Hydroxyhexa-1,3-diynyl)benzoate (3d): Diacetylene
141 °C. H NMR (400 MHz, CDCl ): δ = 8.27 (d, J = 7.9 Hz, 1 H), 7.78–
3
3
d was synthesized following method B from methyl 2-iodobenzo- 7.82 (m, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.61–7.64 (m, 2 H), 7.55–7.59
(m, 1 H), 7.38–7.46 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl ): δ =
ate (1; 2.0 mmol, 524 mg) and 6-(trimethylsilyl)hexa-3,5-diyn-1-ol
3
(
2d; 2.1 mmol, 349 mg) dissolved in DMF (2 mL). Purification of the
160.9 (q), 140.7 (q), 137.6 (q), 135.9 (t), 132.2 (t), 131.5 (t), 130.14 (t),
130.09 (t), 129.9 (t), 128.7 (t), 121.2 (q), 121.0 (q), 97.6 (q), 84.9 (q),
crude product by column chromatography (petroleum ether/ethyl
acetate, 3:1) gave 3d (350 mg, 77 %) as a yellow oil. 1H NMR
+
83.6 (q) ppm. HRMS: calcd. for C H IO [M + H] 372.9725; found
17
10
2
(
400 MHz, CDCl ): δ = 7.95 (d, J = 7.4 Hz, 1 H), 7.60 (d, J = 7.6 Hz,
372.9707.
3
1
H), 7.44–7.48 (m, 1 H), 7.37–7.41 (m, 1 H), 3.93 (s, 3 H), 3.78–3.82
m, 2 H), 2.66 (t, J = 6.3 Hz, 2 H), 1.97 (br. s, 1 H) ppm. 13C NMR
100 MHz, CDCl ): δ = 166.2 (q), 135.4 (t), 132.9 (q), 131.9 (t), 130.7 4b was synthesized following the general procedure from diyne 3c
(
(
(
3-(Hept-1-ynyl)-4-iodo-1H-isochromen-1-one (4b): Compound
3
t), 128.7 (t), 122.8 (q), 83.0 (q), 79.1 (q), 73.7 (q), 67.2 (q), 60.9 (s),
(0.79 mmol, 200 mg) in CH Cl
(0.87 mmol, 221 mg) in CH Cl (17 mL). The reaction time was 21 h
2
2
2
(15 mL), and a solution of I
2
+
5
2.5 (p), 24.3 (s) ppm. HRMS: calcd. for C H O [M + H] 229.0859;
2
1
4 13 3
found 229.0759.
(Table 2, entry 3). Purification of the crude product by column
chromatography on silica gel (petroleum ether/ethyl acetate, 70:1)
followed by recrystallization from petroleum ether gave 4b
Optimization of Conditions for the Electrophilic Cyclization of
Methyl 2-(Buta-1,3-diynyl)benzoate (3a): (Table 2, entry 1): A so-
lution of iodine (0.550 mmol, 141 mg) in MeCN (2 mL) was added
1
(173 mg, 59 %) as a white solid, m.p. 78–79 °C. H NMR (400 MHz,
CDCl ): δ = 8.20 (d, J = 7.9 Hz, 1 H), 7.73–7.77 (m, 1 H), 7.66 (d, J =
3
to an argon-flushed solution of methyl 2-(phenylbuta-1,3-di- 8 Hz, 1 H), 7.49–7.54 (m, 1 H), 2.52 (t, J = 6.9 Hz, 2 H), 1.62–1.68 (m,
ynyl)benzoate (3a; 0.550 mmol, 144 mg) in MeCN (7 mL). The reac- 2 H), 1.42–1.51 (m, 2 H), 1.32–1.39 (m, 2 H), 0.92 (t, J = 7.2 Hz, 3 H)
tion mixture was stirred at 40 °C for 2 d. Then, additional iodine
0.550 mmol, 144 mg) was added. The reaction mixture was heated
at 40 °C for a further 24 h, then a third portion of iodine
0.550 mmol, 144 mg) was added. The resulting mixture was stirred
at 40 °C for 2 d. Only the starting ester (i.e., 3a) was detected in the
ppm. 13C NMR (100 MHz, CDCl ): δ = 161.1 (q), 140.8 (q), 137.8 (q),
3
(
135.8 (t), 131.4 (t), 130.0 (t), 129.5 (t), 121.1 (q), 100.7 (q), 82.3 (q),
31.2 (s), 27.7 (s), 22.3 (s), 19.7 (s), 14.1 (p) [one C (q) signal overlaps
+
(
with CDCl ] ppm. HRMS: calcd. for C H O INa [M + Na] 389.0009;
3
16 15 2
found 389.0024.
Eur. J. Org. Chem. 2016, 739–747
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744
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
-(4-Hydroxybut-1-ynyl)-4-iodo-1H-isochromen-1-one
(4c):
4-(Hex-1-ynyl)-3-(phenylethynyl)-1H-isochromen-1-one (10b):
Compound 10b was synthesized following the general method
Compound 4c was prepared following the general procedure from
diyne 3d (0.70 mmol, 159 mg) in CH Cl (9 mL), and I (0.76 mmol, from isochromenone 4a (0.13 mmol, 48.0 mg) and hex-1-yne (8a;
2
2
2
1
94 mg) in CH Cl (11 mL). The reaction time was 24 h (Table 2,
0.52 mmol, 42.7 mg). The reaction time was 20 h. Purification of the
entry 4). Purification of the crude product by column chromatogra- crude product by column chromatography on silica gel (petroleum
phy on silica gel (petroleum ether/ethyl acetate, 3:1) gave a mixture ether/acetone, 60:1) gave 10b (31.4 mg, 72 %) as a white solid, m.p.
2
2
1
of 4c and starting material 3d (120 mg); ratio 4c/3d = 1:0.25 accord- 108–109 °C. H NMR (400 MHz, CDCl ): δ = 8.29 (d, J = 7.9 Hz, 1 H),
ing to H NMR spectroscopy. Recrystallization of the mixture from
3
1
7.87 (d, J = 7.8 Hz, 1 H), 7.77–7.82 (m, 1 H), 7.54–7.59 (m, 3 H), 7.36–
petroleum ether/CH Cl (3:1) gave 4c (95.0 mg, 40 %) as a white
7.44 (m, 3 H), 2.60 (t, J = 7.0 Hz, 2 H), 1.65–1.71 (m, 2 H), 1.53–1.61
(m, 2 H), 0.95 (t, J = 7.3 Hz, 3 H) ppm. C NMR (100 MHz, CDCl3):
2
2
1
13
solid, m.p. 120–122 °C. H NMR (400 MHz, CDCl ): δ = 8.24 (d, J =
3
7
(
1
.9 Hz, 1 H), 7.76–7.80 (m, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.53–7.57
m, 1 H), 3.90 (t, J = 6.1 Hz, 2 H), 2.83 (t, J = 6.2 Hz, 2 H), 1.99 (br. s,
H) ppm. 13C NMR (100 MHz, CDCl ): δ = 160.9 (q), 140.4 (q), 137.5
δ = 160.8 (q), 141.0 (q), 136.6 (q), 135.2 (t), 132.2 (t), 129.83 (t),
129.81 (t), 129.3 (t), 128.7 (t), 125.6 (t), 121.6 (q), 120.8 (q), 108.4 (q),
100.9 (q), 97.9 (q), 82.4 (q), 72.7 (q), 30.9 (s), 22.2 (s), 19.7 (s), 13.7 (p)
3
+
(q), 135.9 (t), 131.5 (t), 130.1 (t), 129.9 (t), 121.3 (q), 96.8 (q), 83.2 (q),
ppm. HRMS: calcd. for C H O [M + H] 327.1382; found 327.1380.
23 19 2
+
7
3
8.3 (q), 60.6 (s), 24.2 (s) ppm. HRMS: calcd. for C H O I [M + H]
13 10 3
3
-(Phenylethynyl)-4-[(trimethylsilyl)ethynyl]-1H-isochromen-1-
40.9669; found 340.9669.
one (10c): Compound 10c was synthesized following the general
method from isochromenone 4a (0.13 mmol, 48.0 mg) and trimeth-
ylsilylacetylene (8c, 0.52 mmol, 51.1 mg). Reaction time was 2 h.
Purification of the crude product by column chromatography on
3
3
-(Phenylethynyl)-1H-isochromen-1-one (9): A stirred solution of
-phenylethynyl-4-iodoisochromene (4a, 0.13 mmol, 48.4 mg), dii-
sopropanolamine (0.54 mmol, 72.0 mg), Pd(PPh3)4 (0.007 mmol,
.8 mg), and PPh (0.013 mmol, 3.5 mg) in DMF (2 mL) was evacu-
silica gel using petroleum ether/acetone (60:1) gave 40.0 mg (90 %)
7
3
1
of 10c as a white solid, m.p. 128–129 °C. H NMR (400 MHz, CDCl ):
3
ated and flushed with Ar several times. Then CuI (0.020 mmol,
.8 mg) was added, and the reaction mixture was evacuated and
flushed with Ar once again. The vial was sealed, and warmed up to
0 °C. Hex-1-yne (8a; 0.27 mmol, 22.0 mg) was added to the reac-
δ = 8.29 (d, J = 7.8 Hz, 1 H), 7.87 (d, J = 7.4 Hz, 1 H), 7.80–7.84 (m,
3
1
3
1
H), 7.55–7.60 (m, 3 H), 7.37–7.45 (m, 3 H), 0.34 (s, 9 H) ppm.
C
NMR (100 MHz, CDCl ): δ = 160.5 (q), 142.2 (q), 135.9 (q), 135.3 (t),
3
5
1
1
32.1 (t), 130.0 (t), 129.9 (t), 129.5 (t), 128.7 (t), 125.5 (t), 121.4 (q),
tion mixture, and the vial was heated with stirring for 5 h. After this
time, the mixture was cooled, and the reaction mixture was worked
up as described for compounds 3. Purification of the crude product
20.6 (q), 107.7 (q), 105.4 (q), 98.7 (q), 96.5 (q), 82.2 (q), 0.1 (p) ppm.
+
HRMS: calcd. for C H O Si [M + H] 343.1148; found 343.1149.
22 19 2
by column chromatography on silica gel (petroleum ether/acetone,
3-(Hept-1-ynyl)-4-(phenylethynyl)-1H-isochromen-1-one (10d):
Compound 10d was synthesized following the general method
from isochromenone 4b (0.14 mmol, 50.0 mg) and phenylacetylene
(8d; 0.56 mmol, 57.2 mg). The reaction time was 1 h. Purification of
the crude product by column chromatography on silica gel (light
1
2
0:1) gave 9 (9.0 mg, 27 %) as a white solid, m.p. 118–119 °C. H
NMR (400 MHz, CDCl ): δ = 8.30 (d, J = 7.9 Hz, 1 H), 7.70–7.75 (m,
3
1
6
H), 7.51–7.57 (m, 3 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.36–7.41 (m, 3 H),
.82 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl ): δ = 161.9 (q), 138.4
3
(
(
q), 136.8 (q), 135.1 (t), 132.3 (t), 132.0 (t), 130.0 (t), 129.8 (t), 129.2
t), 128.7 (t), 125.9 (t), 121.6 (q), 121.3 (q), 111.4 (t), 93.8 (q), 82.1 (q)
petroleum/acetone, 60:1) gave 10d (43.0 mg, 90 %) as a white solid,
1
m.p. 91–92 °C. H NMR (400 MHz, CDCl
): δ = 8.29 (dd, J = 0.6, J =
3
ppm. HRMS: calcd. for C H O [M + H]+ 247.0759; found
7.9 Hz, 1 H), 7.92 (d, J = 7.9 Hz, 1 H), 7.79–7.83 (m, 1 H), 7.54–7.60
(m, 3 H), 7.38–7.40 (m, 3 H), 2.55 (t, J = 7.0 Hz, 2 H, CH ), 1.63–1.70
m, 2 H), 1.43–1.50 (m, 2 H), 1.30–1.37 (m, 2 H), 0.87 (t, J = 7.3 Hz,
1
7 11 2
2
47.0731.
2
(
13
General Method for the Synthesis of Isocoumarin-Fused Enedi- 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 160.8 (q), 141.7 (q), 136.2
3
ynes 10 by Sonogashira Coupling: A stirred solution of 3-ethynyl-
(q), 135.2 (t), 131.8 (t), 129.9 (t), 129.2 (t), 129.0 (t), 128.6 (t), 125.3
(t), 122.9 (q), 120.6 (q), 106.8 (q), 101.8 (q), 98.1 (q), 81.6 (q), 74.1
4
-iodo-1H-isochromen-1-one (4, 1 equiv.) and PdCl (PPh ) (5 mol-
2 3 2
%
) in DMF was evacuated and flushed with Ar several times. Then
(q), 31.1 (s), 27.9 (s), 22.3 (s), 19.9 (s), 14.0 (p) ppm. HRMS: calcd. for
+
CuI (5 mol-%) was added, and the reaction mixture was evacuated C H O [M + H] 341.1536; found 341.1541.
24 21 2
and flushed with Ar once again. The reaction vial was sealed, and
diisopropylamine (4 equiv.) was added. The reaction mixture was
warmed up to 50 °C, and a terminal acetylene (4 equiv.) was added.
The reaction mixture was heated with stirring for the appropriate
time (Table 3). The mixture was then cooled, and worked up as
described for compounds 3.
3
-(Hept-1-ynyl)-4-[(trimethylsilyl)ethynyl]-1H-isochromen-1-
one (10e): Compound 10e was synthesized following the general
method from isochromenone 4b (0.14 mmol, 50.0 mg) and trimeth-
ylsilylacetylene (8c; 0.56 mmol, 54.9 mg). The reaction time was 3 h.
Purification of the crude product by column chromatography on
silica gel (petroleum ether/acetone, 60:1) gave 10e (36.0 mg, 76 %)
as a yellow oil. H NMR (400 MHz, CDCl ): δ = 8.25 (d, J = 7.8 Hz, 1
1
3
4
-(3-Hydroxyprop-1-ynyl)-3-(phenylethynyl)-1H-isochromen-1-
H), 7.76–7.83 (m, 2 H), 7.55–7.51 (m, 1 H), 2.52 (t, J = 7.1 Hz, 2 H),
one (10a): Compound 10a was synthesized following the general
method from isochromenone 4a (0.13 mmol, 48.0 mg) and prop-
argyl alcohol (8b; 0.52 mmol, 29.0 mg) in DMF (2 mL). The reaction
time was 1 h. Purification of the crude product by column chroma-
tography on silica gel (petroleum ether/ethyl acetate, 3:1 then 1:1)
1.62–1.70 (m, 2 H), 1.43–1.50 (m, 2 H), 01.32–1.41 (m, 2 H), 0.93 (t,
13
J = 7.2 Hz, 3 H), 0.31 (s, 9 H) ppm. C NMR (100 MHz, CDCl ): δ =
3
1
1
60.7 (q), 142.6 (q), 136.1 (q), 135.2 (t), 129.8 (t), 129.1 (t), 125.3 (t),
20.5 (q), 106.7 (q), 104.4 (q), 101.6 (q), 96.8 (q), 74.0 (q), 31.2 (s),
1
27.9 (s), 22.3 (s), 19.8 (s), 14.0 (p), 0.0 (p) ppm. HRMS: calcd. for
C H O Si [M + H] 337.1618; found 337.1624.
gave 10a (26.5 mg, 68 %) as a white solid, m.p. 188–189 °C. H NMR
+
21 25 2
(
400 MHz, [D ]DMSO): δ = 8.20 (d, J = 7.9 Hz, 1 H), 7.96–7.99 (m, 1
6
H), 7.87 (d, J = 7.9 Hz, 1 H), 7.61–7.76 (m, 3 H), 7.44–7.60 (m, 3 H),
.58 (t, J = 6.0 Hz, 1 H), 4.50 (d, J = 6.0 Hz, 2 H) ppm. 13C NMR
100 MHz, CDCl ): δ = 160.0 (q), 140.6 (q), 136.2 (t), 135.4 (q), 132.1
3-(Hept-1-ynyl)-4-(4-hydroxybut-1-ynyl)-1H-isochromen-1-one
(10f): Compound 10f was synthesized following the general
method from isochromenone 4b (0.14 mmol, 50.0 mg) and but-3-
5
(
(
(
3
t), 130.8 (t), 130.5 (t), 129.7 (t), 129.4 (t), 125.4 (t), 120.36 (q), 120.34 yn-1-ol 8e (0.56 mmol, 39.2 mg). The reaction time was 22 h. Purifi-
q), 107.7 (q), 100.2 (q), 98.4 (q), 82.1 (q), 75.8 (q), 50.0 (s) ppm. cation of the crude product by column chromatography on silica
+
HRMS: calcd. for C H O [M + H] 301.0859; found 301.0847.
gel (petroleum ether/ethyl acetate, 3:1) gave 10f (27.0 mg, 63 %) as
2
0 13 3
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1
a yellow oil. H NMR (400 MHz, CDCl ): δ = 8.24 (d, J = 7.9 Hz, 1 H), 14-03-31761). We are grateful to Ms Elizaveta Gorbunova for
3
7
.73–7.81 (m, 2 H), 7.50–7.53 (m, 1 H), 3.88 (t, J = 6.2 Hz, 2 H), 2.81
t, J = 6.2 Hz, 2 H), 2.51 (t, J = 7.1 Hz, 2 H), 2.12 (br. s, 1 H), 1.63–
testing electrophilic cyclization reactions.
(
1
7
.68 (m, 2 H), 1.40–1.49 (m, 2 H), 1.31–1.40 (m, 2 H), 0.92 (t, J =
.2 Hz, 3 H) ppm. 1 C NMR (100 MHz, CDCl ): δ = 160.8 (q), 141.7
3
Keywords: Alkynes · Enediynes · Cyclization · Cross-
3
(
(
q), 136.3 (q), 135.2 (t), 129.8 (t), 129.1 (t), 125.2 (t), 120.6 (q), 106.7 coupling · Oxygen heterocycles
q), 101.0 (q), 95.8 (q), 74.9 (q), 74.1 (q), 61.1 (s), 31.1 (s), 27.9 (s),
2
4.4 (s), 22.3 (s), 19.8 (s), 14.0 (p) ppm. HRMS: calcd. for C H O
20 21 3
+
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-(4-Hydroxybut-1-ynyl)-4-(phenylethynyl)-1H-isochromen-1-
1
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6
[
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h. Purification of the crude product by column chromatography
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9
974.
1
6
8 %) as a white solid, m.p. 128–129 °C. H NMR (400 MHz, CDCl ):
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1
2
H), 7.54–7.60 (m, 3 H), 7.39–7.41 (m, 3 H), 3.88 (t, J = 6.2 Hz, 2 H),
1
3
.82 (t, J = 6.2 Hz, 2 H), 1.98 (br. s, 1 H) ppm. C NMR (100 MHz,
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3
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(
(
t), 129.4 (t), 129.2 (t), 128.7 (t), 125.3 (t), 122.6 (q), 120.7 (q), 107.6
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6
[
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calcd. for C H O [M + H] 315.1016; found 315.1022.
21 15 3
3
-(4-Hydroxybut-1-ynyl)-4-(3-methoxyprop-1-ynyl)-1H-iso-
[
[
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(
of the crude product by column chromatography on silica gel (pe-
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solid, m.p. 44–45 °C. H NMR (400 MHz, CDCl ): δ = 8.27 (d, J =
3
7
2
.9 Hz, 1 H), 7.76–7.82 (m, 2 H), 7.56 (ddd, J = 8.2, J = 6.4 Hz, J =
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1
1
3
(
t, J = 6.0 Hz, 2 H), 2.29 (br. s, 1 H) ppm. C NMR (100 MHz, CDCl3):
δ = 160.4 (q), 141.8 (q), 135.8 (q), 135.3 (t), 129.9 (t), 129.5 (t), 125.2
t), 120.6 (q), 106.8 (q), 97.9 (q), 94.2 (q), 78.7 (q), 75.4 (q), 60.7 (s),
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7 15 4
2
83.0965; found 283.0968.
Supporting Information (see footnote on the first page of this
1
13
article): Copies of H and C NMR spectra for all compounds; copies
of HMBC and COSY spectra for iodoisocoumarins 4; structural eluci-
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(
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to Dr. Mihail Chislov for the helpful discussion of results of DSC
studies), and Centre for X-ray Diffraction Studies. N. A. D.
acknowledges the President of the Russian Federation for a re-
search grant for young scientists (grant number MK-
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can be obtained free of charge from The Cambridge Crystallographic
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[
3322.2014.3) and the Russian Foundation for Basic Research
(
RFBR) for a research grant for young scientists (grant number
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Published Online: December 21, 2015
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim