D. Kuzuhara et al. / Tetrahedron Letters 56 (2015) 5564–5567
5565
Table 1
Reaction conditions of acid cyclization reaction
Entry
Acid (equiv)
Time (h)
Yield (%)
4a (%)
1
2
3
4
5
6
7
8
9
pTsOH (1)
pTsOH (5)
pTsOH (10)
TFA (1)
TFA (5)
TFA (10)
TCA (1)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
3
6
1
81
21
0
90
11
0
98
86
14
0
Trace
63
17
0
3
20
0
TCA (5)
TCA (50)
BF3ÁOEt2 (10)
FeCl3 (10)
AlCl3 (10)
10
11
12
3
3
3
0
0
0
0
Acid cyclization reactions were carried out with 4a (0.06 mmol) and acid in refluxed
CH2Cl2 (3 ml).
were attempted. With 1 equiv of trifluoroacetic acid (TFA), 5a
was obtained only in a trace amount (entry 4). However, with
5 equiv of TFA, the yield of 5a was drastically improved to 63%
(entry 5). On the other hand, 10 equiv of TFA lowered the yield
to 17% (entry 6). For trichloroacetic acid (TCA), 50 equiv of the acid
was necessary to complete the reaction due to the lower acidity of
TCA than that of TFA (entries 7–9). Lewis acids only gave the
decomposed or polymeric products (entries 10–12), which sug-
gested the protonation at pyrrole is necessary for the cyclization
reaction. A plausible reaction mechanism is shown in Scheme S1.
On the basis of the optimized conditions, this acid-cyclization
method was adapted to 4,5-substituted 1,2-di(1H-pyrrol-2-yl)ben-
zenes (4b–4d) and di(1H-pyrrol-2-yl)pyridines (7 and 10)
(Scheme 3). Compounds 4b, 4c, and 4d were synthesized by
Suzuki–Miyaura coupling conditions the same as 4a from the cor-
responding o-dibromobenzenes. The acid-induced cyclization reac-
tions of 4b and 4c proceeded by the similar conditions to
synthesize 5a, giving corresponding INIs 5b (46%) and 5c (28%),
respectively. However, 5c was gradually decomposed under
ambient conditions in solution and in solid state. On the other
hand, 1,2-di(1H-pyrrol-2-yl)benzene 4d with electron-withdraw-
ing group showed lower reactivity compared with 4a. When using
5 equiv of TFA, 5d was obtained in a very low yield, while using
10 equiv of TFA, the yield of 5d increased up to 39%. Subsequently,
we have attempted the synthesis of nitrogen atoms incorporated
azaINIs 8 and 11 from 3,4-di(1H-pyrrol-2-yl)pyridine 7 and 2,3-
di(1H-pyrrol-2-yl)pyridine 10. Compounds 7 and 10 were prepared
from 6 and 9 by Suzuki–Miyaura coupling. The crystal structure of
7 is shown in Figure S4. Firstly, the cyclization reaction was exam-
ined with TFA in CH2Cl2 the same as 5a, but starting material was
only recovered. Secondly, pTsOH was used instead of TFA because
pTsOH is a stronger acid than TFA, but this reaction also gave only
starting material. Finally, we found that the cyclization reactions of
7 and 10 proceeded in the presence of pTsOH (20 equiv) in 1,2-
dichloroethane under reflux conditions. Although these substrates
of 7 and 10 are possible to form two regioisomeric compounds 8a
and 8b, and 11a and 11b, respectively, these reactions gave only 8a
and 11a in 6% and 3%, respectively, and compounds 8b and 11b
were not obtained.
Scheme 1. Synthetic routes of INI derivatives.
Synthesis and characterizations
Scheme 2 shows the synthetic route of INI 5a from 1,2-dibro-
mobenzene 1a. The key intermediate of 1,2-di(1H-pyrrol-2-yl)ben-
zene 4a was synthesized from 1,2-dihalobenzenes (X = Br or I),
independently reported by three groups.14–16 We have modified
the reaction conditions for improvement of the yields of 4a. o-Bis
[1-(t-butoxycarbonyl)-pyrrolyl]benzene 3a was prepared by a
Suzuki–Miyaura coupling reaction of 1a with 1-(t-butoxycar-
bonyl)-pyrrole-2-boronic acid 2. The optimized reaction conditions
using 2 (5 equiv), PdCl2(PPh3)2, and 1.0 M K2CO3 aq in DMF at 80 °C
afforded 3a in 90% yield. Deprotection of Boc groups at 160 °C in
ethylene glycol gave 4a in 95% yield. The structure of 4a was con-
firmed by single crystal X-ray diffraction analysis (Fig. S1). The
addition of p-toluenesulfonic acid (pTsOH; 5 equiv) to a solution
of 4a in CH2Cl2 gave a yellow-colored compound after purification
by silica gel column chromatography eluted with hexane. From 1H
and 13C NMR spectra, 1H–1H COSY spectrum and mass spectrum,
we assigned this yellow compound as INI 5a (Table 1, entry 2).
Finally, the structure of 5a was confirmed by single crystal X-ray
diffraction analysis (Fig. S2). In order to improve the yields, various
acidic conditions have been investigated (Table 1). When decreas-
ing the amount of pTsOH to 1 equiv (entry 1), the reaction did not
proceed and 4a was recovered in 81% yield. In contrast, when the
amount of pTsOH was increased to 10 equiv (entry 3), 4a was con-
sumed. However, 5a was obtained only in 1% probably because of
the decomposition of generated INI. Next, other Brønsted acids
The UV–vis absorption and emission spectra of the obtained INI
derivatives in CH2Cl2 are shown in Figure 1 and Table 2. The
absorption peaks of 5b were observed at 425 nm and 448 nm,
which were red-shifted by 1 nm from 5a, while the absorption of
5c blue-shifted by 3 nm in CH2Cl2. The absorption of azaINIs of
8a and 11a exhibited hypsochromic shift that the longest absorp-
tion peaks were observed at 430 nm for 8a and 440 nm for 11a.
The newly prepared INI derivatives showed fluorescence and
the trends of maximum peak positions were similar to absorption
Scheme 2. Synthesis of INI 5a.