Imidazole-Fused Enediynes by Selective C5-C4 Alkynylations of 4,5-Dibromoimidazoles

Article abstract of DOI:10.1055/s-0037-1610666

An efficient synthesis of symmetrical 1,2-disubstituted 4,5-dialkynylimidazoles by Sonogashira alkynylation of the corresponding 4,5-dibromo derivatives was developed. Moreover, through a careful tuning of the palladium ligand, unsymmetrical 1,2-disusbtituted 4,5-dialkynylimidazoles were also prepared through a regioselective C5 alkynylation of 4,5-dibromoimidazoles, followed by a second alkynylation involving the 4-bromo derivatives so obtained. This interesting class of imidazole-fused enediynes is also able to give thermal Bergman cycloaromatization (BC), as proved by DSC experiments.

Full text of DOI:10.1055/s-0037-1610666

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
M. Lessi et al.
Paper
Synthesis
Imidazole-Fused Enediynes by Selective C5–C4 Alkynylations of
4,5-Dibromoimidazoles
Marco Lessia
Alessandro Panattonib
Luca Guglielmeroa,c
Pierpaolo Mineia
Br
Br
H
N
N
N
N
R1
R1
(3.0 equiv)
R
R
Fabio Bellina*a
0
0
0
0-
0
0
0
2-4
9
3
9-7
0
0
8
Pd(OAc)2
Xantphos
CuI
DMF/DBU
80 °C, 3 h
H
(60–90%)
(1.5 equiv)
Pd(OAc), DPPF, CuI
DMF/DBU, 80 °C, 3 h
a Dipartimento di Chimica e Chimica Industriale, Università
di Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
fabio.bellina@unipi.it
b Institute of Organic Chemistry and Biochemistry, Academy
of Sciences of the Czech Republic, Gilead & IOCB Research
Center, 16610 Prague 6, Czech Republic
c Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126
Pisa, Italy
Br
N
N
N
N
R1
R1
H
R
(1.5 equiv)
R
(76–88%)
(21–56%)
Received: 18.08.2018
Accepted after revision: 01.10.2018
Published online: 30.10.2018
tion7 of the corresponding 4,5-diiodoimidazoles,8 while the
only preparation of unsymmetrical dialkynylimidazole de-
rivatives was performed by sequential C2–C3 Sonogashira
coupling involving 2-iodo-3-bromoimidazo[1,2-a]pyri-
dine.9
Recently, we reported a synthetic protocol for the selec-
tive one-pot preparation of 2-substituted 5-alkynylimidaz-
oles by regioselective C5 bromination with NBS, followed by
Sonogashira alkynylation of the 5-bromoimidazole ob-
tained in situ (Scheme 1).10
DOI: 10.1055/s-0037-1610666; Art ID: ss-2018-e0555-op
Abstract An efficient synthesis of symmetrical 1,2-disubstituted 4,5-
dialkynylimidazoles by Sonogashira alkynylation of the corresponding
4,5-dibromo derivatives was developed. Moreover, through a careful
tuning of the palladium ligand, unsymmetrical 1,2-disusbtituted 4,5-di-
alkynylimidazoles were also prepared through a regioselective C5 alky-
nylation of 4,5-dibromoimidazoles, followed by a second alkynylation
involving the 4-bromo derivatives so obtained. This interesting class of
imidazole-fused enediynes is also able to give thermal Bergman cy-
cloaromatization (BC), as proved by DSC experiments.
N
N
1) NBS (0.95 equiv)
DMF, r.t., 3 h
R
R
Key words imidazoles, Sonogashira reaction, regioselectivity,
enediynes, Bergman cyclization, palladium, copper, cross-coupling
N
N
Br
Me
Me
Several naturally occurring acetylenes such as chali-
cheamicin and dynemicin display significant antitumor
properties due to their ability to damage the DNA of cancer
cells.1 This biological activity has been attributed to the for-
mation of 1,4-dehydrobenzene diradicals resulting from a
thermal-induced Bergman cyclization2 of an enediyne moi-
ety, which is the common structural trait of this class of
molecules.1c,d,3 However, the strong anticancer activity dis-
played by enediynes is often overbalanced by several nega-
tive effects, such as high toxicity at therapeutic doses, that
seriously impair their clinical use on humans.1b For this rea-
son, the development of methods able to grant the access to
new enediyne-containing molecular entities is an import-
ant synthetic target, aimed at obtaining analogues with im-
proved pharmacological profiles.1d,4
N
N
R1
H
2)
(1.1 equiv)
R
PdCl2(PPh3)2 (2 mol%)
CuI (4 mol%)
piperidine (3.0 equiv)
80 °C, 3 h
Me
51–87%
R1
Scheme 1 Synthesis of 5-alkynylimidazoles by one-pot regioselective
bromination and Sonogashira alkynylation10
During the optimization of the first step of the above re-
ported protocol, we observed that 4,5-dibromo-1,2-di-
methyl-1H-imidazole (2) may be easily obtained simply us-
ing 2.0 equivalents of NBS from commercially available 1,2-
dimethyl-1H-imidazole (1), working in DMF at room tem-
perature (Scheme 2). This convenient route to 2, which rep-
resents a clean improvement over its previously reported
preparation via bromination of 1 with molecular bromine,11
encouraged us to start a study on the viability of using 2 as
a precursor of imidazole-fused enediynes by sequential
double Sonogashira alkynylations.12
Despite the large number of studies devoted to the
preparation of enediynes, to the best of our knowledge very
few papers described the preparation of imidazole-fused
enediynes,5 regardless of the biological relevance of the im-
idazole nucleus itself.6 In particular, symmetrical 4,5-di-
alkynylimidazoles were obtained by Sonogashira alkynyla-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
M. Lessi et al.
Paper
Synthesis
Whereas performing sequential transition-metal-cata-
lyzed carbon–carbon bond-forming reactions involving
polyhalogenated substrates bearing different halogens is
relatively easy, the achievement of the same regioselectivity
using polyhalogenated derivatives containing two or more
halogens of the same type may be a serious challenge.13
However, when the electrophiles are polyhalogenated het-
eroarenes, the presence of the heteroatom(s) may induce a
differentiation among the carbon–halogen bonds sufficient,
after a judicious screening of the reaction system, to grant
regioselective couplings by a kinetically determinant oxida-
tive addition step.
As regards dibromoimidazole 2, the ‘normal’ order of re-
activity should be C5 > C4, considering the higher electro-
philic character of the C–Br bond proximal to the pyrrole-
like nitrogen atom in respect to the C–Br bond adjacent to
the pyridine-like nitrogen atom. A similar reactivity (C5 >
C4) was also observed in sequential Suzuki–Miyaura cou-
plings involving polyhalogenated imidazoles and organobo-
ron derivatives.14 Hence, the selective formation of C5-
alkynylimidazole 4a from the coupling between equimolar
amounts of 2 and 3a was reasonably awaited or, on the con-
trary, an unselective C5,C4 double alkynylation to give the
symmetrical imidazole-fused enediyne 5a could be ob-
served (Figure 1).
Br
NBS (2.0 equiv)
DMF, r.t., 3 h
N
N
N
N
Me
Me
Br
Me
Me
2 (74%)
1
Scheme 2 Synthesis of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2)
Here we summarize the results of this study, which al-
lowed us to find an efficient protocol for the double alky-
nylation of both the C–Br bonds of 2 to obtain symmetrical
compounds featuring two identical alkynyl groups (Scheme
3, Path A). Moreover, through a careful tuning of the catalyst
system, unsymmetrically substituted imidazoles were suc-
cessfully obtained by sequential C5–C4 alkynylations
(Scheme 3, Path B).
R2
Br
N
N
N
N
R2
H
Path A
R1
R1
Cat. system A
Br
R
R
R2
Br
Br
N
N
N
N
2
1)
R
H
R1
R1
Cat. system B
Br
R
R
Ph
R2
Br
N
N
N
N
R3
Me
Me
Path B
R3
H
N
2)
Me
Me
R1
Ph
Ph
4a
5a
Cat. system A
N
R
Figure 1 Chemical structures of imidazoles 4a and 5a
R2
Scheme 3 Symmetrical imidazole-fused enediynes via synthetic Path
A, and unsymmetrical analogues via synthetic Path B
We initially examined the impact of the base/solvent
system on the outcome of the alkynylation (Table S1, Sup-
porting Information), and we found that the best results in
terms of yield and selectivity were obtained when the cou-
pling was carried out in a 9:1 (v:v) mixture of DMF and DBU
at 80 °C for 3 hours, in the presence of 4 mol% PdCl2(PPh3)2
and 2 mol% CuI (Table S1, entry 8). Under these experimen-
tal conditions, C5-alkynylated imidazole 4a was obtained in
53% GLC yield and in 82:18 molar ratio with the corre-
sponding symmetrical enediyne 5a (Scheme 4).
At the beginning of our study, the same experimental
conditions, which gave excellent results in the in situ
Pd/Cu-catalyzed alkynylation of 5-bromo-1,2-dimethylim-
idazole (Scheme 1, step 2) were tried.10 However, when 4,5-
dibromo-1,2-dimethylimidazole (2) was reacted with 1.1
equivalents of phenylacetylene (3a) employing piperidine
as the base, Pd(PPh3)2Cl2 and CuI as the catalysts in DMF at
80 °C for 3 hours, a complex reaction mixture was obtained,
and the main products resulted those deriving from alkyne
homocouplings12c (data not shown).
Considering this negative result, which clearly proved
the different chemical reactivity of 4,5-dibromoimidazole 2
when compared with the analogous 5-bromo derivative, we
decided to verify the efficiency and the selectivity of a
Sonogashira coupling involving equimolar amounts of 2
and 3a chosen as model coupling partner, in the presence of
catalytic amounts of PdCl2(PPh3)2 and CuI.
PdCl2(PPh3)2 (4 mol%)
CuI (2 mol%)
Ph
+
+
5a
2
4a
(53% GLC)
DMF/DBU (9:1), 80 °C, 3 h
3a
(1.0 equiv)
H
[4a/5a = 82:18 (GLC)]
Scheme 4 PdCl2(PPh3)2-mediated selective alkynylation of 2 with 3a
It is known that the stereoelectronic features of the pal-
ladium ligand may have a significant impact on regioselec-
tive couplings involving heteroarene bearing two or more
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
M. Lessi et al.
Paper
Synthesis
halogens of the same type, due to its influence on the oxi-
dative addition which clearly represents, in these cases, the
selectivity-determining step of the whole catalytic cy-
cle.13a,14b Hence, encouraged by the positive result summa-
rized in Scheme 4, we evaluated the influence of the nature
of the palladium ligand on our model reaction (Table 1). In
order to allow a fast comparison between different ligands,
PdCl2(MeCN)2 was chosen as a convenient palladium prec-
atalyst for this further screening instead of PdCl2(PPh3)2,
while all the other reaction parameters were left unaltered
in respect to those summarized in Scheme 4. It is relevant
to note that at the end of all the reactions phenylacetylene
(3a) was never detected in the reaction mixture, probably
due to its partial transformation into high molecular weight
oligomers, which are common by-products in copper-cata-
lyzed alkynylations.12c Considering also the fact that under
the adopted experimental conditions no degradation of 2
was noticed, the overall yield of 4a + 5a may be reasonably
adopted as a measure of the efficiency of the catalyst sys-
tem.
use of an excess of 3a lowered the 4a:5a ratio from 93:7 to
78:22 (entries 3 and 4). Even worse, the hard PCy3 ligand
displayed poorer selectivity and yield (entry 5).
The activity of a series of bidentate phosphines was
then evaluated (Table 1, entries 6–9). As can be seen from
Table 1, these species generally improved the conversion of
2 into alkynylimidazoles 4a and 5a, apart from DPPE (entry
6). In particular, 1,1-bisdiphenylphosphinoferrocene (DPPF)
was found to show a good selectivity, leading to the
monoalkynylated product 4a in 59% GLC yield, and to 5a in
18% GLC yield (entry 9). The conversion of the alkyne into
products was thus almost quantitative (95%). However,
compound 4a was isolated chemically pure in only 28%
yield, due to difficulties in the separation from unreacted
dibromoimidazole 2. To confirm the C5 regioselectivity of
the alkynylation using DPPF as the ligand, an unambiguous-
ly chemical assignment of the position of the alkynyl moi-
ety of bromoimidazole 4a was set up (Scheme 5). In detail,
4a was debrominated through a metal/halogen exchange
with BuLi at –100 °C, followed by protonolysis with MeOH
1
From the results reported in Table 1, it emerged that the
use of PPh3 gave a very similar reaction outcome than that
obtained with Pd(PPh3)2Cl2 (Table 1, entries 1 and 2). On the
contrary, P(2-furyl)3 taken as an example of soft ligand gave
a lower conversion even if it showed a better selectivity
(entry 3). In order to rise the conversion of 2, 1.5 equiva-
lents of 3a were then employed (entry 4). As expected, a
higher conversion of 2 into 4a and 5a was observed, but the
(Scheme 5). The H NMR spectrum of the resulting debro-
minated imidazole was compared with the spectrum of an
authentic sample of 1,2-dimethyl-5-(phenylethynyl)-1H-
imidazole (6a), previously prepared by us through the one-
pot C-5 bromination/alkynylation reaction on 1,2-dimeth-
yl-1H- imidazole (Scheme 1).10
Br
H
N
N
N
N
1) n-BuLi, THF, –100 °C
Me
Me
2) MeOH
Me
Me
Table 1 Ligand Screening for the Sonogashira Coupling Involving 2
and 3aa
4a
6a
Ph
Ph
Scheme 5 Selective debromination of imidazole 4a
Entry
Pd ligand
Product Yield (%)b
4a:5a
4a
5a
Since the use of DPPF as the palladium ligand led to the
highest chromatographic yield in the monoalkynylated im-
idazole 4a, once again 1.5 equivalents of 3a were employed
to rise the conversion of 2 (Table 1, entry 10). As already ob-
served when P(2-furyl)3 was used as the palladium ligand, a
higher conversion of 2 into 4a and 5a was observed, but the
recorded increase in overall GLC yield was negatively coun-
terbalanced by a lowering in the 4a:5a ratio from 77:23 to
53:47 (entries 9 and 10). Despite a lower GLC yield, 4a was
isolated in 42% yield from the crude reaction mixture due
the fact that the separation of the monalkynylated product
4a from the dialkynylated product 5a resulted easier than
its separation from dibromoimidazole 2.
After recording that the trend of activity of the in situ
formed catalytic system with bidentate phosphines paral-
lels the increasing of the bite angle,15 the effect of 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene(Xantphos),
which displays a bite angle of 108°, was attempted (Table 1,
entry 11). As a result, the use of Xantphos lowered the ki-
netic discrimination between the two C–Br bonds of 2, al-
lowing in this case to observe a slight prevalence (59:41) of
1c
2
–
53
12
16
3
82:18
76:24
93:7
PPh3
51
3
P(2-furyl)3
P(2-furyl)3
PCy3
38
4d
5
40
11
15
4
78:22
53:47
79:21
74:26
74:26
77:23
53:47
41:59
0:100
17
6
DPPE
15
7
DPPB
54
19
18
18
41
38
8
DPEphos
DPPF
50
9
59 (28)
47 (42)
26
10d
11
12e
DPPF
Xantphos
Xantphos
0
100 (90)
a Unless otherwise stated, the reactions were carried out using 2 (1 mmol),
3a (1 mmol), PdCl2(MeCN)2 (4 mol%), CuI (2 mol%), and Pd ligand (8 mol%
if monodentate, 4 mol% if bidentate), in a 9:1 mixture (v:v) of DMF and
DBU (5 mL) for 3 h at 80 °C (oil bath temperature).
b GLC yield. In parentheses, isolated yield.
c PdCl2(PPh3)2 (4 mol%) was employed as the catalyst precursor.
d Reaction carried out using 1.5 mmol of 3a.
e Reaction carried out using 3.0 mmol of 3a.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
M. Lessi et al.
Paper
Synthesis
the dialkynylated product 5a with respect to the
monoalkynylimidazole 4a. Imidazole 5a was recovered
from the crude reaction mixture in 38% yield, along with 4a
(26%). The conversion of this reaction, with respect to the
alkyne 3a, was thus quantitative. The latter trial was finally
repeated with 3.0 equivalents of 3a, resulting in a quantita-
tive conversion into the dialkynylated product 5a, which
was isolated in a satisfactory 90% yield (entry 12).
In summary, the regioselective coupling of 2 with 1.5
equivalents of 3a in the presence of 4 mol% PdCl2(MeCN)2, 4
mol% DPPF, 2 mol% CuI, at 80 °C for 3 hours in a 9:1 mixture
of DMF and DBU allowed us to isolate the pure monoalky-
nylated imidazole 4a in 42% yield (Table 1, entry 10). On the
other hand, the symmetrical imidazole-fused enediyne 5a
was obtained in 90% isolated yield simply replacing DPPF
with Xantphos and doubling the amount of 3a (entry 12).
With these two protocols in hands, we then evaluated
their scope starting from the synthesis of symmetrically
substituted 4,5-dialkynylimidazoles 5, 9, and 10 from the
corresponding 4,5-dibromoimidazoles 2, 7, and 8 according
to the experimental conditions reported in Table 1, entry 12
(Scheme 6).
Table 2 Synthesis of Symmetrical Imidazole-Fused Enediynes 5, 9, and
10a
Entry 4,5-Dibromoimidazole
R1
Alkyne
Product
R
3
R2
Yield
(%)b
1
2
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
3a
3b
3c
3d
3e
3b
3b
3a
3b
3a
Ph
5a
5b
5c
90
80
60
77
72
79
88
72
73
75
2
Me
4-MeOC6H4
4-CO2EtC6H4
n-C10H21
HO(CH2)4
4-MeOC6H4
4-MeOC6H4
Ph
3
2
Me
4
2
Me
5d
5e
9a
9b
9c
5
2
Me
6
7a
7b
7c
7c
8a
4-CO2EtC6H4
4-MeSO2C6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
7
8
9
4-MeOC6H4
Ph
9d
10a
10
a The reactions were carried out using dibromoimidazole 2, 7, or 8 (1 mmol),
3 (3.0 mmol), PdCl2(MeCN)2 (4 mol%), CuI (2 mol%), and Xantphos (4 mol%)
in a 9:1 mixture (v:v) of DMF and DBU (5 mL) for 3 h at 80 °C (oil bath tem-
perature).
b Isolated yield.
Br
N
Free hydroxyl group were well tolerated, as demonstrat-
ed by using hex-5-yn-1-ol (3e). The desired enediyne 5e
was in fact isolated in 72% yield (Table 2, entry 5).
R1
N
Br
R
The precatalyst systems PdCl2(MeCN)2/Xantphos result-
ed also very efficient in promoting the alkynylation of 2-
aryl-4,5-dibromo-1-methylimidazoles 7a–d. To our delight,
the required enediynes 9a–d were in fact isolated in 72–
88% yields (Table 2, entries 6–9). Interestingly, the symmet-
rical enediyne 10a was also obtained in 75% yield by reac-
tion of a typical 1,2-diaryl-4,5-dibromoimidazole, 8a, with
phenylacetylene (3a) (entry 10).
2: R = R1 = Me
R2
7: R = Me; R1 = Ar
PdCl2(MeCN)2 (4 mol%)
8: R = Ph; R1 = Ar
CuI (2 mol%), Xantphos (4 mol%)
N
R1
+
DMF/DBU (9:1), 80 °C, 3 h
R2
N
H
R
R2
5: R = R1 = Me
9: R = Me; R1 = Ar
10: R = Ph; R1 = Ar
3
(3.0 equiv)
O
PPh2
Xantphos
PPh2
Having secured the synthesis of symmetrical enediynes,
our attention was devoted towards the preparation of un-
symmetrical enediynes 11. Considering the results ob-
Scheme 6 Synthesis of symmetrical imidazole-fused enediynes 5, 9,
and 10
Table 3 Synthesis of 5-Alkynyl-4-bromoimidazoles 4 by Regioselective
C5 Alkynylation of 4,5-Dibromoimidazole 2a
As it can be seen from Table 2, where the results ob-
tained in the preparation of compounds 5, 9, and 10 are
summarized, Sonogashira reactions involving 2 and elec-
tron-rich arylalkynes proceeded easily and in excellent
yields. In fact, when 4-ethynylanisole (3b) was employed as
the alkyne, the corresponding dialkynylated product 5b
was isolated in 80% yield (Table 2, entry 2). On the contrary,
the use of the typical electron-poor alkyne 5c gave the re-
quired symmetrical enediyne 5c in a lower 60% yield (entry
3). The reaction proceeded well even when an aliphatic
alkyne was employed. In fact, the symmetrical enediyne 5d
resulting from the coupling involving 2 and dodec-1-yne
(3d) was obtained in 77% isolated yield (entry 4).
Entry
Alkyne
Product
3
R
4
4/5
53/47
Yield (%)b
1
2
3
4
5
a
b
c
Ph
a
b
c
42
51
21c
46
56
4-MeOC6H4
4-CO2EtC6H4
n-C10H21
81/19
100/0
68/32
92/8
d
e
d
e
4-hydroxybutyl
a The reactions were carried out using 2 (1 mmol), 3 (1.5 mmol), Pd-
Cl2(MeCN)2 (4 mol%), CuI (2 mol%), and DPPF (4 mol%, in a 9:1 mixture (v:v)
of DMF and DBU (5 mL) for 3 h at 80 °C (oil bath temperature). Unless oth-
erwise stated, the complete conversion of 2 was observed.
b Isolated yield.
c By GLC and GC-MS analyses of the crude reaction mixture a 2/4c molar
ratio of 53/47 was determined.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

E
M. Lessi et al.
Paper
Synthesis
R1
R1
R2
3 (1.5 equiv)
H
3 (1.5 equiv)
H
Br
Br
Br
PdCl2(MeCN)2 (4 mol%)
N
N
N
N
PdCl2(MeCN)2 (4 mol%)
N
N
Me
Me
Me
CuI (2 mol%)
Xantphos (4 mol%)
CuI (2 mol%)
DPPF (4 mol%)
Me
Me
Me
2
R2
R2
4
DMF/DBU (9:1), 80 °C, 3 h
DMF/DBU (9:1), 80 °C, 3 h
11
Scheme 7 Two-step synthesis of unsymmetrical imidazole-fused enediynes 11
tained using Xantphos as the palladium ligand, we decided
to perform the first, regioselective, alkynylation using DPPF
as the ligand according to the reaction conditions of Table 1,
entry 10 (Scheme 7 and Table 3). Thus, the resulting 5-
alkynyl-4-bromoimidazoles 4 were reacted with a different
alkyne, using Xantphos as the ligand (Scheme 7).
when imidazole 4e was reacted with phenylacetylene (3a),
providing the desired unsymmetrical enediyne 11b
(Scheme 8).
Br
N
Me
N
As can be seen from Table 3, where the results of the re-
Me
R
R1
PdCl2(MeCN)2 (4 mol%)
CuI (2 mol%)
Xantphos (4 mol%)
gioselective C5-alkynylation of 2 are reported, the use of
DPPF as the palladium ligand enabled the regioselective C5-
alkynylation without the necessity of employing substrates
bearing two different halogen atoms, such as the case
reported by Gueffier and co-workers in 2017 working on
2,3-dihalogenoimidazo[1,2-a]pyridines.9 The required 5-
alkynyl-4-bromoimidazoles 4 were recovered in reasonable
yields after 3 hours at 80 °C from mixtures containing also
variable amounts of the corresponding dialkynylimidazole
derivatives 5 (Table 3).
4d: R1 = n-decyl
4e: R1 = 4-hydroxybutyl
N
N
Me
+
H
DMF/DBU (9:1), 80 °C, 3 h
R1
Me
R
(1.5 equiv)
11a: R = n-decyl; R1 = 4-MeOC6H4 (88%)
11b: R = 4-hydroxybutyl; R1 = Ph (76%)
3b: R1 = 4-MeOC6H4
3a: R1 = Ph
Scheme 8 Synthesis of unsymmetrical enediynes 11a and 11b
In detail, when the coupling was performed using aryl-
alkynes such as phenylacetylene (3a) or 4-ethynylanisole
(3b), a complete conversion of dibromide 2 was noticed,
and the desired monoalkynylated products 4a and 4b were
obtained in 42% and 51% isolated yields, respectively (Table
3, entries 1, 2). A similar chemical yield (46%) was observed
when dodec-1-yne (2d) was employed in the reaction with
2, (entry 4). The hydroxy group of hex-5-yn-1-ol (3e) was
well tolerated (entry 5), giving rise also to the highest 4/5
GLC ratio (92/8). In contrast, when ethyl 4-ethynylbenzoate
(3c) was employed as a typical electron-poor arylalkyne,
we experienced an incomplete conversion of 2, and a poor
21% isolated yield of bromoenyne 4c. This low yield was at-
tributed to the tendency of such an alkyne, in the presence
of a less effective catalytic system, to be involved in compet-
itive homocoupling reactions. In fact, it has been recently
demonstrated that Cu-promoted Glaser–Hay-type alkyne
homocouplings, such as those involved in the by-product
formation under Sonogashira conditions,12c are faster when
more acidic alkynes are involved.16
The preparation of unsymmetrical enediynes 11 was
completed by reacting 5-alkynyl-4-bromoimidazoles 4d
and 4e, taken as examples, under the reaction conditions of
Table 1, entry 12. In particular, when compound 4d was
coupled with 1.5 equivalents of 4-ethynylanisole (3b), the
reaction provided the desired compound 11a in 88% isolat-
ed yield (Scheme 8), proving once again the efficacy of the
precatalyst system based on Xantphos for the alkynylation
of bromoimidazoles. A similar yield (76%) was obtained
Finally, the ability of some imidazole-fused enediynes
to be involved in thermal Bergman cyclization (Scheme 9)
was evaluated by differential scanning calorimetry (DSC).
The use of this experimental method to study the behavior
of enediynes under reaction conditions that favor the cy-
clization has been already reported,5 and it seems to us a
practical method to perform a comparison among the reac-
tivity of enediyne analogues.
R2
R2
R2
N
N
N
N
Δ
R1
R1
Me
Me
R2
5 or 9
12
Scheme 9 Benzimidazole 12 via thermal Bergman cyclization involving
enediynes 5 or 9
In particular, 1,2-dimethylimidazoles 5a–d and 2-aryl-
1-methylimidazoles 9a–c were selected for this study. The
onset temperature of the exothermic peak observed in the
DSC thermogram of each enediyne, which represents the
temperature at which the Bergman cyclization occurs, is re-
ported in Table 4. No exothermic peaks were recorded
during a second scanning of the samples (see the thermo-
grams in Supporting Information), which confirmed that an
irreversible process has taken place.17
A quick analysis of the data outlined in Table 4 clearly
reveals the influence of the substituents at both the triple
bonds and the imidazole ring. As regards enediynes 5, while
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
M. Lessi et al.
Paper
Synthesis
Table 4 Bergman Cyclization Temperature (tBC) of Selected Imidazole-
Fused Enediyne 5 or 9
1000 data station. Three types of capillary columns were used: an
Agilent J & W HP-5ms column (30 m × 0.25 mm i.d. × 0.25 μm), an
Agilent J & W DB-5 column (30 m × 0.25 mm i.d. × 1 μm) and an
Alltech AT-35 FSOT column (30 m × 0.25 mm i.d. × 0.25 μm). EI-MS
spectra were recorded at 70 eV by GLC-MS, performed on an Agilent
6890N gas-chromatograph interfaced with an Agilent 5973N mass
detector. The ESI spectra were acquired on a Acquity QDa Water spec-
trometer (Temperature Probe: 600 °C; ESI capillary voltage 1.5 V;
Cone voltage 15 V; mass range 200–1000) coupled with a Acquity
HUPLC Water (Phase A 95/5 H2O/MeCN + 0.1% formic acid, Phase B
5/95 H2O/MeCN + 0.1% formic acid; Column Acquity UPLC 2.1 × 100
mm, BEH C18, 1.7 μm; Flow 0.6 mL/min). Elementar analyses were
acquired with an Elementar Vario Micro Cube in CHNS mode. 1H NMR
spectra were recorded on a Varian Gemini 200 or on a Buker 400 MHz
spectrometer using TMS as an internal standard. Standard notations
were used in order to report NMR spectra. The 13C NMR spectra were
recorded at 50 or 100 MHz, using Varian Gemini or Bruker instru-
ment, respectively, and the spectra were referred to the signal of the
solvent. Differential Scanning Calorimetry (DSC) thermograms were
recorded under N2 atmosphere by a Mettler Toledo DSC 922e Module
Stare apparatus equipped with a liquid N2 cooling system. The DSC
experiments were carried out with 2.8–3.4 mg of samples using cru-
cibles with pierced caps under a N2 atmosphere at a heating/cooling
rate of 20 °C × min–1 from a temperature of 20 °C up to 395 °C, fol-
lowed by cooling to 20 °C and heating to 395 °C for the second time.
Unless otherwise stated, all the reactions were performed under a
positive atmosphere of argon by standard syringe, cannula, and septa
techniques. DMF was dried by distillation at reduced pressure over
CaH2. THF was dried by distillation over LiAlH4. 1-Methyl-1H-imidaz-
ole, 1,2-dimethyl-1H-imidazole (1), and hex-5-yn-1-ol (3e) were pu-
rified by distillation at reduced pressure. Phenylacetylene (3a), dodec-
1-yne (3d), 4-ethynylanisole (3b), Et3N, i-Pr2NEt, tributylamine, 1,4-
diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU), and piperidine were purified by distillation at reduced
pressure over CaH2. 4-Bromoanisole and ethyl 4-bromobenzoate were
degassed just before their use. NBS was purified by crystallization.
Ethyl 4-(4,5-dibromo-1-methyl-1H-imidazol-2-yl)benzoate, 4,5-di-
bromo-2-[4-(methylsulfonyl)phenyl]-methyl-1H-imidazole, 4,5-di-
bromo-1-methyl-2-(4-methylphenyl)-1H-imidazole, and 4,5-dibro-
mo-2-(4-methoxyphenyl)-1-phenyl-1H-imidazole were synthesized
according to literature procedure previously developed by us.22 All the
other commercially available reagents and solvents were used as re-
ceived.
Enediyne 5 or 9
Product
R1
R2
Ph
12
tBC (°C)a
5a
5b
5c
5d
9a
9b
9c
Me
a
b
c
302
280
264
284
319
302
312
Me
4-MeOC6H4
4-CO2EtC6H4
n-C10H21
Me
Me
d
e
f
4-CO2EtC6H4
4-MeSO2C6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
Ph
g
a The onset temperature of the exothermic peak is reported.
the higher reactivity of 5c when compared with the analo-
gous 5a and 5b is expected due to the reported positive ef-
fect on Bergman cyclization exerted by electron-withdraw-
ing substituents on the triple bond(s),18 the fact that 5a re-
sulted less reactive than 5b, which bears the strong
electron-donor methoxyphenyl moiety, is quite unpredict-
ed. We noticed also that the presence of an aryl substituent
on the C2 position of the imidazole ring, either electron-de-
ficient (for enediynes 9a and 9b) or mildly electron-rich (for
enediyne 9c) led to a sharp decrease in reactivity. The onset
BC temperatures recorded for these three enediynes result-
ed in fact 20–30 °C higher than that observed for the corre-
sponding 2-methylimidazole-fused enediynes 5b and 5a,
respectively. It has been proposed that the percentage of
double-bond character of an enediyne double bond could
be involved in the efficiency of Bergman cyclization19 but,
in the literature, there is no clear evidence of this parameter
or on the distance between the two alkynyl moieties20
when acyclic enediynes are involved.21
In conclusion, we have demonstrated that playing with
palladium ligands may be a good way to enhance the chem-
ical difference between vicinal bromine atoms on imidaz-
oles, allowing a regioselective oxidative addition of Pd(0)
species and, consequently, making the catalytic cycle to
start. Not only the best ligand in terms of selectivity is use-
ful, but also the worst one, because its employment opens
the way towards unselective, but not for this reason useless,
multiple alkynylation protocols. We proved also that the
imidazole-fused enediynes so prepared are able to undergo
Bergman cycloaromatization, and studies on the practical
application of this reaction to the preparation of polysubsti-
tuted benzoazoles and on the observed reactivity are in
progress.
4,5-Dibromo-1,2-dimethyl-1H-imidazole (2)
A modification of a literature procedure for the synthesis of the title
compound was adopted.23 A solution of 1,2-dimethyl-1H-imidazole
(1; 1.33 mL, 1.44 g, 15 mmol) and NBS (5.34 g, 30 mmol) in EtOAc or
DMF (75 mL) was stirred overnight in the open air and in the dark at
r.t. The clear orange-yellowish solution thus obtained was washed
with a 10% aq NaOH (2 × 50 mL), 10% aq Na2SO3 (2 × 50 mL), H2O (50
mL), and brine (50 mL). The aqueous phases were back-extracted
with EtOAc (50 mL) and the combined organic phases were dried
(Na2SO4). The solvent was removed under reduced pressure, affording
the title compound as a colorless solid; yield: 2.83 g (74%); mp 86–88
°C (Lit.24 mp 88–90 °C).
1H NMR (200 MHz, CDCl3): δ = 3.54 (s, 3 H), 2.40 (s, 3 H).
EI-MS: m/z (%) = 256 (48), 254 (100), 252 (52), 175 (74), 173 (82), 134
(55), 132 (61), 94 (17), 82 (14), 80 (14), 52 (16).
Melting points were recorded on a hot-stage microscope (Reichert
Thermovar). Precoated silica gel PET foils (Sigma-Aldrich) were used
for TLC analyses. GLC analyses were performed on a Dani GC 1000 in-
strument equipped with a PTV injector and recorded with a Dani DDS
The physical and spectral properties of this compound were in agree-
ment with those reported in the literature.24,25
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
M. Lessi et al.
Paper
Synthesis
Ethyl 4-(4,5-Dibromo-1-methyl-1H-imidazol-2-yl)benzoate (7a)
EI-MS: m/z (%) = 332 (49), 330 (100), 328 (53), 251 (36), 249 (37), 210
(62), 208 (64), 132 (9), 103 (9).
NBS (356 mg, 2 mmol) was added to a solution of ethyl 4-(1-methyl-
1H-imidazol-2-yl)benzoate (230 mg, 1 mmol) in DMF (5 mL) and the
resulting suspension was stirred at r.t. for 48 h. The resulting reaction
mixture was diluted with EtOAc (100 mL), washed with 10% aq NaOH
(2 × 50 mL), 10% aq Na2SO3 (2 × 50 mL), H2O (50 mL), and brine (50
mL). The aqueous phases were back-extracted with EtOAc (50 mL)
and the combined organic phases were dried (Na2SO4). The solvent
was removed under reduced pressure, affording the title compound as
an orange solid; yield: 360 mg (93%); mp 123–125 °C.
Anal. Calcd for C11H10Br2N2: C, 40.03; H, 3.05; N, 8.49. Found: C, 40.29;
H, 3.11; N, 8.71.
4,5-Dibromo-2-(4-methoxyphenyl)-1-phenyl-1H-imidazole (8a)
NBS (356 mg, 2 mmol) was added to a solution of 2-(4-methoxyphe-
nyl)-1-phenyl-1H-imidazole (250 mg, 1 mmol) in DMF (5 mL) and the
resulting reaction mixture was stirred in the dark at r.t. for 24 h. The
mixture was then diluted with EtOAc (100 mL) and washed with 10%
aq NaOH (2 × 50 mL), 10% aq Na2SO3 (2 × 50 mL), H2O (50 mL), and
brine (50 mL). The aqueous phases were back-extracted with EtOAc
(50 mL) and the combined organic phases were dried (Na2SO4). The
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography (95:5, toluene/EtOAc). The title
compound was obtained as a pale organge solid; yield: 220 mg (54%);
mp 135–137 °C.
1H NMR (200 MHz, CDCl3): δ = 8.13 (m, 2 H), 7.67 (m, 2 H), 4.41 (q, J =
7.2 Hz, 2 H), 3.74 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 165.9, 147.4, 133.4, 131.3, 130.0 (2 C),
128.5 (2 C), 117.3, 106.8, 61.4, 35.0, 14.5.
EI-MS: m/z (%) = 390 (50), 389 (18), 388 (100), 386 (52), 209 (20), 307
(20), 268 (53), 266 (54), 134 (19), 132 (22).
Anal. Calcd for C13H12Br2N2O2: C, 40.24; H, 3.12; N, 7.22. Found: C,
40.30; H, 3.11; N, 7.52.
1H NMR (400 MHz, CDCl3): δ = 7.46 (m, 3 H), 7.21 (m, 4 H), 6.70 (m, 2
H), 3.71 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 160.1, 148.3, 136.7, 129.7 (2 C), 129.6
(2 C), 128.2 (2 C), 121.7, 117.8, 113.7 (2 C), 105.9, 55.2.
4,5-Dibromo-2-[4-(methylsulfonyl)phenyl]methyl-1H-imidazole
(7b)
ESI-MS: m/z = 408 [M + H]+1
.
NBS (356 mg, 2 mmol) was added to a solution of 1-methyl-2-(4-
methylsulfonyl)phenyl-1H-imidazole (236 mg, 1 mmol) in DMF (5
mL) and the resulting reaction mixture was stirred in the dark at r.t.
for 48 h. The mixture was then diluted with EtOAc (100 mL) and
washed with 10% aq NaOH (2 × 50 mL), 10% aq Na2SO3 (2 × 50 mL),
H2O (50 mL), and brine (50 mL). The aqueous phases were back-ex-
tracted with EtOAc (50 mL) and the combined organic phases were
dried (Na2SO4). The solvent was removed under reduced pressure, af-
fording the title compound as a colorless solid; yield: 378 mg (96%);
mp 197–199 °C.
Anal. Calcd for C16H12Br2N2: C,47.09; H, 2.96; N, 6.86. Found: C, 46.90;
H, 3.00; N, 6.60.
Procedure for the Screening of the Reaction Conditions for the Pd-
and Cu-Promoted Alkynylation of 4,5-Dibromo-1,2-dimethyl-1H-
imidazole (2) with Phenylacetylene (3a)
A mixture of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2; 0.25 g, 1.0
mmol), phenylacetylene (3a; 0.11 mL, 0.10 g, 1 mmol), Pd catalyst (10
mg, 0.04 mmol), CuI (3 mg, 0.02 mmol), Pd ligand (0.08 mmol if
monodentate, 0.04 mmol if bidentate) in the selected solvent(s) (5
mL) was stirred under argon for 3 h at the temperature reported in
Table 1 and Table S1. After cooling to r.t., the crude reaction mixture
was diluted with EtOAc, and sat. aq NH4Cl (100 mL) was added. The
resulting mixture was stirred in the open air for 0.5 h and then ex-
tracted with EtOAc. The organic extract was washed with H2O (3 × 25
mL) and brine (25 mL), biphenyl was added as internal standard, and
the resulting mixture was analyzed by GLC and GC/MS. Table 1 and
Table S1 summarize the results of this screening.
H NMR (200 MHz, CDCl3): δ = 8.04 (m, 2 H), 7.82 (m, 2 H), 3.77 (s, 3
H), 3.09 (s, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 146.2, 141.0, 134.5, 129.3 (2 C), 127.8
(2 C), 117.6, 107.4,44.5, 35.0.
EI-MS: m/z (%) = 396 (53), 395 (17), 394 (100), 392 (50), 315 (25), 313
(23), 274 (40), 272 (36), 134 (21), 132 (22).
Anal. Calcd for C11H10Br2N2O2S: C, 33.53; H 2.56; N, 7.1; S, 8.14.
Found: C, 33.50; H, 2.58; N, 7.15; S, 7.98..
4,5-Dibromo-1-methyl-2-(4-methylphenyl)-1H-imidazole (7c)
Symmetrical 1,2-Disubstituited 4,5-Dialkynyl-1H-imidazoles 5, 9,
NBS (2.48 g, 13.9 mmol) was added to a solution of 1-methyl-2-(4-
methylphenyl)-1H-imidazole (1.20 g, 6.98 mmol) in DMF (35 mL).
The resulting suspension was stirred for 46 h at r.t. in the dark. EtOAc
(500 mL) was added to the reaction mixture and the organic layer was
washed with 10 aq NaOH (2 × 250 mL). The organic phase was
washed with 5% aq Na2SO3 (2 × 250 mL), then with H2O (3 × 200 mL),
and finally with brine (300 mL). The aqueous phases were extracted
with EtOAc (120 mL). The organic phases were combined, dried
(Na2SO4), and the solvent was removed under reduced pressure af-
fording the title compound as a colorless solid; yield: 1.84 g (80%); mp
96–98 °C.
1H NMR (200 MHz, CDCl3): δ = 7.39 (m, 2 H), 7.19 (m, 2 H), 3.61 (s, 3
H), 2.33 (s, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 148.6, 139.8, 129.4, 128.6, 126.5,
116.4, 105.4, 34.7, 21.5.
and 10; General Procedure
A solution of 4,5-dibromo-1,2-disubstituted-1H-imidazole 2, 7a–e, or
8a (1 mmol) or 5-alkynyl-4-bromo-1,2-dimethyl-1H-imidazole,
alkyne 3 (3 mmol or 1.5 mmol), Pd(MeCN)2Cl2 (10 mg, 0.04 mmol, 4
mol%), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26 mg,
0.04 mmol, 4 mol%), and CuI (3 mg, 0.02 mmol, 2 mol%) in DMF (4.5
mL) and DBU (0.5 mL) was stirred at 80 °C for 3 h. The reaction mix-
ture was then diluted with EtOAc (100 mL) and sat. aq NH4Cl (100 mL)
was added. The resulting mixture was stirred in the open air for 0.5 h
and then extracted with EtOAc. The combined organic extractswere
washed with H2O (3 × 25 mL) and brine (25 mL), dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue was pu-
rified by flash chromatography on silica gel. This procedure was em-
ployed to prepare 1,2-dimethylimidazole-fused enediynes 5a–e, 2-
aryl-1-methylimidazole-fused enediynes 9a–d, and 1,2-diarylimidaz-
ole-fused enediyne 10a (Table 2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
M. Lessi et al.
Paper
Synthesis
1,2-Dimethyl-4,5-bis(phenylethynyl)-1H-imidazole (5a) (Table 2,
entry 1)
mixture of EtOAc and toluene (50:50) as eluent to give 5d as a beige
solid; yield: 326 mg (77%); mp 50–51 °C. GLC analysis showed that 5d
had chemical purity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 3.47 (s, 3 H), 2.48 (t, J = 7.0 Hz, 2 H),
2.41 (t, J = 7.0 Hz, 2 H), 2.30 (s, 3 H), 1.46 (m, 32 H), 0.88 (m, 6 H).
13C NMR (50.3 MHz, CDCl3): δ = 144.4, 126.5, 119.4, 99.7, 92.3, 73.8,
68.9, 31.9 (2 C), 31.1, 29.6 (2 C), 29.4 (2 C), 29.3 (2 C), 29.2, 29.0, 28.8,
28.7, 28.6, 28.5, 22.7 (2 C), 19.8, 19.6, 14.1 (2 C), 13.4.
The crude reaction product obtained by Pd- and Cu-mediated alky-
nylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with phenyl-
acetylene (3a) was purified by flash chromatography on silica gel
with a mixture of EtOAc and toluene (60:40) as eluent to give 5a as a
yellow solid; yield: 266 mg (90%); mp 126–127 °C. GLC analysis
showed that 5a had chemical purity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 7.55 (m, 4 H), 7.30 (m, 6 H), 3.54 (s, 3
H), 2.35 (s, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 146.1, 131.3 (2 C), 131.1 (2 C), 128.6,
128.3 (2 C), 128.1 (2 C), 128.0, 127.0, 123.2, 122.3, 119.8, 99.2, 92.2,
83.0, 77.3, 31.4, 13.5.
EI-MS: m/z (%) = 424 (91), 353 (46), 339 (54), 325 (31), 299 (100), 213
(44), 199 (43), 185 (44).
Anal. Calcd for C29H48N2: C, 82.01; H, 11.39; N, 6.60. Found: C, 81.80;
H, 11.30; N, 6.56.
EI-MS: m/z (%) = 297 (23), 296 (100), 214 (12), 213 (20), 218 (16).
6,6′-(1,2-Dimethyl-1H-imidazol-4,5-diyl)bis(hex-5-yn-1-ol) (5e)
Anal. Calcd for C21H16N2: C, 85.11; H, 5.44; N,9.45. Found: C, 84.80; H,
5.73; N, 9.47.
(Table 2, entry 5)
The crude reaction product obtained by Pd- and Cu-mediated alky-
nylation of 4,5-dibromo-1,2- dimethyl-1H-imidazole (2) with hex-5-
yn-1-ol (3e) was purified by flash chromatography on silica gel with a
mixture of CH2Cl2 and MeOH (97:3) as eluent to give 5e as a beige sol-
id; yield: 207 mg (72%); mp 88–89 °C. GLC analysis showed that 5e
had chemical purity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 3.78 (br s, 2 H), 3.65 (m, 4 H), 3.46 (s, 3
H), 2.53 (m, 2 H), 2.45 (m, 2 H), 2.30 (s, 3 H), 1.70 (m, 6 H), 1.26 (m, 2
H).
4,5-Bis[(4-methoxyphenyl)ethynyl]-1,2-dimethyl-1H-imidazole
(5b) (Table 2, entry 2)
The crude reaction product obtained by Pd- and Cu-mediated alky-
nylation of 4,5-dibromo-1,2- dimethyl-1H-imidazole (2) with 4-ethy-
nylanisole (3b) was purified by flash chromatography on silica gel
with EtOAc as eluent to give 5b as a yellow solid; yield: 285 mg (80%);
mp 143–144 °C. GLC analysis showed that 5b had chemical purity
higher than 98%.
13C NMR (50.3 MHz, CDCl3): δ = 144.7, 126.2, 119.6, 99.9, 92.6, 74.0,
69.0, 61.7, 61.7, 31.9, 31.3, 29.7, 25.0, 25.1, 19.7, 19.4, 13.3.
1H NMR (200 MHz, CDCl3): δ = 7.46 (m, 4 H), 6.84 (m, 4 H), 3.78 (s, 3
H), 3.76 (s, 3 H), 3.53 (s, 3 H), 2.35 (s, 3 H).
EI-MS: m/z (%) = 288 (53), 243 (48), 231 (100), 201 (37), 199 (34), 185
(49), 174 (43), 173 (62), 172 (62), 159 (41).
13C NMR (50.3 MHz, CDCl3): δ = 159.7, 159.3, 145.7, 132.7 (4 C), 126.7,
119.7, 115.3, 114.4, 113.9 (2 C), 113.8 (2 C), 99.0, 91.8, 81.7, 76.1, 55.2,
55.1, 31.3, 13.4.
Anal. Calcd for C17H24N2O: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.55;
H, 8.40; N, 9.76.
EI-MS: m/z (%) = 357 (26), 356 (100), 341 (30), 259 (5), 178 (15).
Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.30;
H, 5.70; N, 7.91.
Ethyl4-{4,5-Bis[(4-methoxyphenyl)ethynyl]-1-methyl-1H-imidaz-
ol-2-yl}benzoate (9a) (Table 2, entry 6)
The crude product obtained by Pd- and Cu-mediated alkynylation of
ethyl 4-(4,5-dibromo-1-methyl-1H-imidazol-2-yl)benzoate (7a) with
4-ethynylanisole (3b) was triturated with a mixture of toluene and
EtOAc (90:10) to afford the title compound 9a as a yellow solid; yield:
387 mg (79%); mp 128–130 °C. GLC analysis showed that 9a had
chemical purity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 8.13 (m, 2 H), 7.79 (m, 2 H), 7.51 (m, 2
H), 7.49 (m, 2 H), 6.89 (m, 2 H), 6.86 (m, 2 H), 4.40 (q, J = 7.0 Hz, 2 H),
3.82 (s, 3 H), 3.81 (s, 6 H), 1.41 (t, J = 7.0 Hz, 3 H).
Diethyl 4,4′-[(1,2-Dimethyl-1H-imidazole-4,5-diyl)]bis(ethyne-
2,1-diyl)dibenzoate (5c) (Table 2, entry 3)
The crude reaction product obtained by Pd- and Cu-mediated alky-
nylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with ethyl 4-
ethynylbenzoate (3c) was purified by flash chromatography on silica
gel with EtOAc as eluent to give 5c as a yellow solid; yield: 264 mg
(60%); mp 165–167 °C. GLC analysis showed that 5c had chemical pu-
rity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 8.04 (m, 4 H), 7.60 (m, 4 H), 4.40 (q, J =
7.0 Hz, 2 H), 4.38 (q, J = 7.0 Hz, 2 H), 3.65 (s, 3 H), 2.41 (s, 3 H), 1.41 (t,
J = 7.0 Hz, 3 H), 1.40 (t, J = 7.0 Hz, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 166.0, 165.6, 131.2 (4 C), 131.0 (4 C),
130.2, 129.7, 129.4 (4 C), 129.3 (4 C), 127.7, 126.8, 99.1, 92.0, 85.7,
80.0, 61.3, 61.2, 31.7, 14.4, 13.7.
13C NMR (50.3 MHz, CDCl3): δ = 1656.0, 160.1, 159.6, 146.9, 133.7,
133.14 (2 C), 133.08 (2 C), 130.8, 129.8, 128.7 (2 C), 128.5 (2 C), 122.3,
115.3, 114.4, 114.2 (2 C), 114.0 (2 C), 100.5, 92.8, 81.3, 76.0, 61.3, 55.5,
55.4, 33.7, 14.5.
Anal. Calcd for C31H26N2O4: C, 75.90; H, 5.34; N, 5.71. Found: C, 75.80;
H, 5.40; N, 5.75.
EI-MS: m/z (%) = 442 (7), 441 (32), 440 (100), 412 (7), 384 (8).
4,5-Bis[(4-methoxyphenyl)ethynyl]-1-methyl-2-[4-(methylsulfo-
nyl)phenyl]-1H-imidazole (9b) (Table 2, entry 7)
Anal. Calcd for C27H24N2O4: C, 73.62; H, 5.49; N, 6.36. Found: C, 73.40
H, 5.40; N, 6.55.
The reaction product obtained by Pd- and Cu-mediated alkynylation
of 4,5-dibromo-1-methyl-2-(4-methylsulfonyl)phenyl-1H-imidazole
(7b) with 4-ethynylanisole (3b) was triturated with a mixture of tolu-
ene and EtOAc (50:50) affording the title compound 9b as a yellow
solid; yield: 436 mg (88%); mp 179–180 °C. GLC analysis showed that
9b had chemical purity higher than 98%.
4,5-Bis(dodec-1-yn-1-yl)-1,2-dimethyl-1H-imidazole (5d) (Table 2,
entry 4)
The crude reaction product obtained by Pd- and Cu-mediated alky-
nylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with dodec-
1-yne (3d) was purified by flash chromatography on silica gel with a
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1H NMR (200 MHz, CDCl3): δ = 8.01 (m, 2 H), 7.92 (m, 2 H), 7.49 (m, 4
H), 6.90 (m, 2 H), 6.87 (m, 2 H), 3.83 (s, 6 H), 3.81 (s, 3 H), 3.07 (s, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 160.2, 159.7, 145.7, 140.6, 134.7,
133.1 (4 C), 129.4 (2 C), 128.8, 127.7 (2 C), 122.8, 115.0, 114.2 (2 C),
114.1, 114.0 (2 C), 100.9, 93.0, 81.0, 75.7, 55.5, 55.4, 44.5, 33.8.
13C NMR (100 MHz, CDCl3): δ = 160.3, 147.7, 136.9, 131.7 (2 C), 131.1
(2 C), 130.2 (2 C), 129.4 (2 C), 129.0, 128.9, 128.6, 128.4 (2 C), 128.3
(3), 127.7 (2 C), 123.3, 122.6, 122.2, 121.8, 113.7 (2C), 99.9, 93.2, 82.8,
78.0, 55.2.
ESI-MS: m/z = 451 [M + H]+.
Anal. Calcd for C29H24N2O4S: C, 70.14; H, 4.87; N, 5.64. Found: C,
69.98; H, 4.88; N, 5.50.
Anal. Calcd forC32H22N2O: C, 85.31; H, 4.92; N, 6.22. Found: C, 85.40;
H, 4.77; N, 6.26
1-Methyl-2-(4-methylphenyl)-4,5-bis(phenylethynyl)-1H-imidaz-
5-Alkynyl-4-bromo-1,2-dimethyl-1H-imidazoles 4; General Proce-
ole (9c) (Table 2, entry 8)
dure
The crude product obtained by Pd- and Cu-mediated alkynylation of
4,5-dibromo-1-methyl-2-(4-methylphenyl)-1H-imidazole (7c) with
phenylacetylene (3a) was purified by flash chromatography on silica
gel with a mixture of toluene and EtOAc (94:6) as eluent. The chro-
matographic fractions containing the product were collected and
concentrated, affording 9c as a pale-yellow solid; yield: 268 mg (72%);
mp 176–179 °C. GLC analysis showed that 9c had chemical purity
higher than 98%.
1H NMR (400 MHz, CDCl3): δ = 7.59 (m, 6 H), 7.32 (m, 8 H), 3.80 (s, 3
H), 2.42 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.7, 139.5, 131.63,131.4, 129.4,
128.8, 128.7, 128.5, 128.5, 128.3, 128.2, 126.7, 123.3, 122.5, 121.6,
100.1, 92.6, 82.9, 77.5, 33.4, 21.4.
A solution of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2; 254 mg, 1
mmol), alkyne 3 (1.5 mmol), Pd(MeCN)2Cl2 (10 mg, 0.04 mmol, 4
mol%), 1,1′-bis(diphenylphosphino)ferrocene (22 mg, 0.04 mmol, 4
mol%), and CuI (3 mg, 0.02 mmol, 2 mol%) in DMF (4.5 mL) and DBU
(0.5 mL) was stirred at 80 °C for 3h. The reaction mixture was then
diluted with EtOAc (100 mL) and sat. aq NH4Cl (100 mL) was added.
The resulting mixture was stirred in the open air for 0.5 h and then
extracted with EtOAc. The combined organic extracts were washed
with H2O (3 × 25 mL) and brine (25 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel. This procedure was employed to
prepare compounds 4a–e (Table 3).
4-Bromo-1,2-dimethyl-5-(phenylethynyl)-1H-imidazole (4a) (Ta-
ble 3, entry 1)
EI-MS: m/z (%) = 373 (28), 372 (100), 213 (15), 204 (10), 186 (7).
Anal. Calcd for C27H20N2: C, 87.07; H, 5.41; N, 7.52. Found: C, 87.15; H,
5.25; N, 7.38.
The crude reaction product obtained by C-5 Pd- and Cu-mediated
alkynylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with
phenylacetylene (3a) was purified by flash chromatography on silica
gel with a mixture of toluene and EtOAc (60:40) as eluent to give 4a as
a beige solid; yield: 116 mg (42%); mp 117–121 °C. GLC analysis
showed that 4a had chemical purity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 7.52 (m, 2 H), 7.35 (m, 3 H), 3.59 (s, 1
H), 2.37 (s, 1 H).
13C NMR (50.3 MHz, CDCl3): δ = 145.8, 131.3 (2 C), 128.7, 128.4 (2 C),
122.4, 119.2, 115.7, 98.7, 76.4, 32.0, 13.7.
4,5-Bis[(4-methoxyphenyl)ethynyl]-1-methyl-2(4-methylphenyl)-
1H-imidazole (9d) (Table 2, entry 9)
The crude product obtained by Pd- and Cu-mediated alkynylation of
4,5-dibromo-1-methyl-2-(4-methylphenyl)-1H-imidazole (7c) with
4-ethynylanisole (3b) was purified by flash chromatography on silica
gel with a mixture of toluene and EtOAc (93:7) as eluent. The chro-
matographic fractions containing the product were collected and
concentrated to afford 9d as a pale-yellow solid; yield: 315 mg (73%);
mp 162–164 °C.
1H NMR (400 MHz, CDCl3): δ = 7.56 (m, 2 H), 7.49 (m, 4 H), 7.24 (m, 2
H), 6.86 (m, 4 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.73 (s, 3 H), 2.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.1, 159.6, 148.3, 139.3, 133.1 (2 C),
133.0 (2 C), 129.3 (2 C), 128.7 (2 C), 128.3, 127.0, 121.5, 115.6, 114.7,
114.2 (2 C), 114.0 (2 C), 99.9, 92.4, 81.8, 76.4, 55.4, 55.3, 33.4, 21.4.
EI-MS: m/z (%) = 277 (14), 276 (96), 275 (25), 274 (100), 273 (10), 142
(20), 139 (11), 128 (30), 127 (26), 56 (12).
Anal. Calcd for C13H11BrN2: C, 56.75; H, 4.03; N, 10.18. Found: C,
57.01; H, 4.06; N, 10.25.
4-Bromo-5-[(4-methoxyphenyl)ethynyl]-1,2-dimethyl-1H-imid-
azole (4b) (Table 3, entry 2)
ESI-MS: m/z = 433 [M + H]+.
The crude reaction product obtained by C-5 Pd- and Cu-mediated
alkynylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with 4-
ethynylanisole (3b) was purified by flash chromatography on silica
gel with a mixture of toluene and EtOAc (60:40) as eluent to give 4b
as a beige solid; yield: 155 mg (51%); mp 107–111 °C. GLC analysis
showed that 4b had chemical purity higher than 98%.
Anal. Calcd for C29H24N2O2: C, 80.53; H, 5.59; N, 6.48. Found: C, 80.79;
H, 5.40; N, 6.50.
2-(4-Methoxyphenyl)-1-phenyl-4,5-bis(phenylethynyl)-1H-imid-
azole (10a) (Table 2, entry 10)
1H NMR (200 MHz, CDCl3): δ = 7.46 (m, 2 H), 6.86 (m, 2 H), 3.83 (s, 3
The crude product obtained by Pd- and Cu-mediated alkynylation of
4,5-dibromo-1-phenyl-2-(4-methoxylphenyl)-1H-imidazole
(8a)
H), 3.58 (s, 3 H), 2.37 (s, 3 H).
with phenylacetylene (3a) was purified by flash chromatography on
silica gel with a mixture of toluene and EtOAc (95:5) as eluent. The
chromatographic fractions containing the product were collected and
concentrated, affording 10 as a colorless solid; yield: 337 mg (75%);
mp 185–187 °C.
13C NMR (50.3 MHz, CDCl3): δ = 160.0, 145.5, 133.0 (2 C), 118.6, 115.9,
114.4, 114.1 (2 C), 98.6, 75.2, 55.4, 32.0, 13.7.
EI-MS: m/z (%) = 307 (16), 306 (98), 305 (18), 304 (100), 291 (61), 290
91 (10), 289 (64), 261 (10), 114 (10), 56 (16).
Anal. Calcd for C14H13BrN2O: C, 55.10; H, 4.29; N, 9.18. Found: C,
55.11; H, 4.38; N, 9.19
1H NMR (400 MHz, CDCl3): δ = 7.62 (m, 2 H), 7.61 (m, 2 H), 7.48 (m, 3
H), 7.36 (m, 8 H), 7.29 (m, 3 H), 6.76 (m, 2 H), 3.77 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
M. Lessi et al.
Paper
Synthesis
Ethyl 4-[(4-Bromo-1,2-dimethyl-1H-imidazol-5-yl)ethynyl]benzo-
ate (4c) (Table 3, entry 3)
(2.25 mL) and DBU (0.25 mL) was stirred at 80 °C for 3 h. The reaction
mixture was then diluted with EtOAc (50 mL) and sat. aq NH4Cl (50
mL) was added. The resulting mixture was stirred in the open air for
0.5 h and then extracted with EtOAc. The combined organic extracts
were washed with H2O (3 × 10 mL) and brine (10 mL), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel with a mixture of hex-
ane and EtOAc (4:6) as eluent to give 11a as a red liquid; yield: 0.086 g
(88%).
1H NMR (200 MHz, CDCl3): δ = 7.46 (m, 2 H), 6.84 (m, 2 H), 3.80 (s, 3
H), 3.52 (s, 3 H), 2.52 (t, J = 6.8 Hz, 2 H), 2.36 (s, 3 H), 1.64 (qt, J = 6.8
Hz, 2 H), 1.48 (m, 2 H), 1.25 (m, 12 H), 0.87 (t, J = 6.4 Hz, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 159.4, 145.1, 133.0 (2 C), 126.2, 120.1,
115.7, 113.7 (2 C), 100.7, 91.5, 81.6, 69.0, 55.3, 32.0, 31.4, 29.75, 29.69,
29.5, 29.3, 29.0, 28.7, 22.8, 20.0, 14.3, 13.6.
The crude reaction product obtained by C-5 Pd- and Cu-mediated
alkynylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with
ethyl 4-ethynylbenzoate (3c) was purified by flash chromatography
on silica gel with a mixture of Et2O and EtOAc (95:5) as eluent to give
4c as a colorless solid; yield: 73 g (21%); mp 130–131 °C. GLC analysis
showed that 4c had chemical purity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 8.03 (m, 2 H), 7.57 (m, 2 H), 4.39 (q, J =
7.3 Hz, 2 H), 3.63 (s, 3 H), 2.41 (s, 3 H), 1.41 (t, J = 7.3 Hz, 3 H).
13C NMR (50.3 MHz, CDCl3): δ = 165.9, 146.3, 131.4 (2 C), 130.2, 129.6
(2 C), 126.9, 120.3, 115.4, 98.3, 79.6, 61.3, 32.1, 14.5, 13.7.
EI-MS: m/z (%) = 349 (17), 348 (99), 347, (19), 346 (100), 320 (35), 319
(10), 318 (36), 303 (15), 301 (15), 56 (16).
Anal. Calcd for C16H15BrN2O2: C, 55.35; H, 4.35; N, 8.07. Found: C,
55.40; H, 3.99; N, 8.09.
EI-MS: m/z (%) = 391 (28), 390 (100), 319 (11), 305 (27), 291 (15), 265
(15), 263 (20), 250 (14).
Anal. Calcd for C26H34N2O: C, 79.96; H, 8.77; N, 7.17. Found: C, 80.01;
H, 8.78; N, 7.00.
4-Bromo-5-(dodec-1-yn-1-yl)-1,2-dimethyl-1H-imidazole (4d)
(Table 3, entry 4)
The crude reaction product obtained by C-5 Pd- and Cu-mediated
alkynylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with do-
dec-1-yne (3d) was purified by flash chromatography on silica gel
with a mixture of toluene and EtOAc (40:60) as eluent to give 4d as a
colorless solid; yield: 156 mg (46%); mp 75–76 °C. GLC analysis
showed that 4d had chemical purity higher than 98%.
1H NMR (200 MHz, CDCl3): δ = 3.51 (s, 3 H), 2.48 (t, J = 7.0 Hz, 2 H),
2.34 (s, 3 H), 1.63 (qt, J = 7.0 Hz, 2 H), 1.46 (m, 2 H), 1.27 (m, 12 H),
0.88 (t, J = 6.4 Hz, 3 H).
6-[1,2-Dimethyl-4-(phenylethynyl)-1H-imidazol-5-yl]hex-5-yn-1-
ol (11b)
A mixture of 6-(4-bromo-1,2-dimethyl-1H-imidazol-5-yl)hex-5-yn-
1-ol (4e; 0.11 g, 0.4 mmol), phenylacetylene (3a; 65 μL, 0.06 g, 0.6
mmol), Pd(MeCN)2Cl2 (4 mg, 0.016 mmol, 4 mol%), Xantphos (10 mg,
0.016 mmol, 4 mol%), and CuI (1.4 mg, 0.008 mmol, 2 mol%) in DMF
(2.25 mL) and DBU (0.25 mL) was stirred at 80 °C for 3 h. The reaction
mixture was then diluted with EtOAc (50 mL) and sat. aq NH4Cl (50
mL) was added. The resulting mixture was stirred in the open air for
0.5 h and then extracted with EtOAc. The combined organic extracts
were washed with H2O (3 × 10 mL) and brine (10 mL), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel with a mixture of tolu-
ene and EtOAc (40:60) as eluent to give 11b as a beige solid; yield:
0.083 g (76%); mp 114–116 °C. GLC analysis showed that 11b had
chemical purity higher than 98%.
13C NMR (50.3 MHz, CDCl3): δ = 144.6, 117.6, 116.1, 100.2, 68.0, 31.9,
31.7, 29.6, 29.5, 29.3, 29.1, 28.8, 28.6, 22.7, 19.8, 14.3, 13.5.
EI-MS: m/z (%) = 340 (38), 338 (39), 259 (100), 215 (38), 213 (80), 211
(46), 147 (36), 134 (82).
Anal. Calcd for C17H27BrN2: C, 60.18; H, 8.02; N, 8.26. Found: C, 60.20;
H, 8.15; N, 8.27
1H NMR (200 MHz, CDCl3): δ = 7.50 (m, 2 H), 7.29 (m, 3 H), 3.69 (t, J =
5.9 Hz, 2 H), 3.45 (s, 3 H), 2.54 (t, J = 6.4 Hz, 2 H), 2.32 (s, 3 H), 1.75 (m,
4 H).
13C NMR (50.3 MHz, CDCl3): δ = 145.2, 131.2 (2 C), 128.1 (2 C), 127.9,
125.3, 123.1, 120.5, 100.6, 91.7, 82.9, 68.7, 61.5, 31.8, 31.3, 24.9, 19.6,
13.3.
6-(4-Bromo-1,2-dimethyl-1H-imidazol-5-yl)hex-5-yn-1-ol (4e)
(Table 3, entry 5)
The crude reaction product obtained by C-5 Pd- and Cu-mediated
alkynylation of 4,5-dibromo-1,2-dimethyl-1H-imidazole (2) with
hex-5-yn-1-ol (3e) was purified by flash chromatography on silica gel
with a mixture of toluene and EtOAc (4:6) as eluent to give 4e as a
yellow solid; yield: 152 mg (56%); mp 94–96 °C. GLC analysis showed
that 4e had chemical purity higher than 98%.
EI-MS: m/z (%) = 293 (22), 292 (100), 291 (25), 235 (75), 233 (47), 165
(20).
1H NMR (200 MHz, CDCl3): δ = 3.73 (t, J = 5.9 Hz, 2 H), 3.51 (s, 3 H),
3.02 (br s, 1 H), 2.53 (t, J = 6.6 Hz, 2 H), 2.34 (s, 3 H), 1.74 (m, 4 H).
Anal. Calcd for C19H20N2O: C, 78.05; H, 6.90; N, 9.58. Found: C, 78.01;
H, 6.95; N, 9.65.
13C NMR (50.3 MHz, CDCl3): δ = 114.9, 117.4, 116.0, 99.9, 68.2, 61.8,
31.9, 31.8, 25.0, 19.6, 13.5.
Funding Information
EI-MS: m/z (%) = 272 (51), 270 (51), 213 (100), 211 (78), 189 (46), 187
(43), 174 (35), 173 (44), 147 (50), 134 (98), 56 (45).
This work was supported by the Regione Toscana under POR-CREO
2014-2020 (project ‘COOLSUN’), the Università di Pisa under PRA
2017 (project No. PRA_2017_28).()
Anal. Calcd for C11H15BrN2O: C, 48.72; H, 5.58; N, 10.33. Found: C,
48.75; H, 5.38; N, 10.35.
5-(Dodec-1-yn-1-yl)-4-[(4-methoxyphenyl)ethynyl]-1,2-dimethyl-
Supporting Information
1H-imidazole (11a)
A mixture of 4-bromo-5-(dodec-1-yn-1-yl)-1,2-dimethyl-1H-imidaz-
ole (4d; 0.08 g, 0.25 mmol), 4-ethynylanisole (3b; 55 μL, 0.05 g, 0.38
mmol), Pd(MeCN)2Cl2 (4 mg, 0.016 mmol, 4 mol%), Xantphos (10 mg,
0.016 mmol, 4 mol%), and CuI (1.4 mg, 0.008 mmol, 2 mol%) in DMF
Supporting information (Table S1, copies of NMR spectra for com-
pounds 4a–e, 5a–e, 9a–d, 10a, and DSC thermograms for compounds
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
M. Lessi et al.
Paper
Synthesis
5a–d and 9a–c) for this article is available online at
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https://doi.org/10.1055/s-0037-1610666.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K