Mendeleev Commun., 2016, 26, 3–5
H
N
replacement of KOH with less basic K2CO3 and increase in the
R
R
reaction temperature to 90°C allowed us to synthesize the target
pyrrolobenzimidazoles 3a–f from aldehydes 1a–f regardless of
their substitution pattern in reasonable yields (see Scheme 1).†
Note that in this case the stereoselectivity of final product forma-
tion changes dramatically, and instead of E-isomers of compounds
3 more sterically hindered Z-isomers were formed in all cases. As
it can be seen from the data obtained, replacement of phenyl
group with more electron-withdrawing 2-thienyl or 3,4-difluoro-
phenyl one, as well as introducing two alkyl groups into a-posi-
tion of the starting aldehyde sufficiently facilitate intramolecular
cyclization of benzimidazoles 2, which, most likely, is due to
increase in polarization of the triple bond.
N
Ar
Ar
2
4
– H+
R
N
N
R
E-3
Z-3
H+
R
2
R
Most likely, such significant difference in stereoselectivity
depending on the base used can be explained as follows. In
case of strongly basic KOH, benzimidazoles 2 undergo fast and
complete deprotonation giving anions 4, which was confirmed
by the characteristic upfield shifts of signals of aromatic protons
in benzimidazole system. Then the latter give vinylic anions Z-5
as a result of 5-exo-dig-cyclization. Such stereoselectivity is in
accordance with known data on intramolecular hydroamination
of alkynes under the action of imidazoles17 and indoles18 under
basic conditions. Due to high basicity of KOH–DMSO medium,
these anions have enough time to isomerize into more thermo-
dynamically stable E-5 (such isomerization of vinylic anions
derived from intramolecular addition of N-centered anions to
the triple bond of alkynes in basic medium has been postulated,
see ref. 19), which then trap proton from the reaction medium,
forming E-isomers of 1-arylmethylidenepyrrolobenzimidazoles 3.
If less basic K2CO3 is used, benzimidazoles 2 are deprotonated
only to a little extent, and once intermediates Z-5 are formed, they
are protonated immediately by the action of starting compound
R
N
R
N
N
N
Ar
Z-5
Ar
E-5
Scheme 2
2, generating anions 4, which participate in the next reaction
cycle, and Z-isomers of products 3 (Scheme 2).
Identification of E- and Z-isomers of benzimidazoles 3 was
performed based on the 2D NOESY proton spectra. In case of
E-isomers of 3a and 3b this spectrum shows correlations between
methine proton at double bond and the proton at the 8-position,
as well as between methylene fragment at the 2-position and
o-protons in phenyl group. NOESY spectra of Z-isomers of
compounds 3 exhibit characteristic correlations between olefinic
proton and CH2 fragment at the 2-position, and also between
o-protons in aromatic group and the proton at the 8-position.
In summary, we have developed a new one-pot transition metal-
free synthesis of 1-arylmethylidene-2,3-dihydro-1H-pyrrolo-
[1,2-a]benzimidazoles from alk-4-ynals in DMSO–NH4Br–base
system. Important feature of this method is the possibility of
controlling the stereoselectivilty of five-membered ring closure,
which provides exclusive formation of E- or Z-isomers of target
products depending on the base used.
†
1-Arylmethylidene-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles 3a–f
(general procedure). A solution of o-diaminobenzene (216 mg, 2 mmol)
in 3 ml of anhydrous DMSO was slowly added to a solution of aldehyde
1 (2 mmol) in 3 ml of DMSO. Then, NH4Br (39 mg, 0.4 mmol) was
added, and the resulting mixture was stirred at room temperature for 24 h
in the presence of dry air. Thereafter freshly powdered KOH (180 mg,
3 mmol in case of E-3a and E-3b) or anhydrous K2CO3 (830 mg, 6 mmol,
in case of Z-3a–f) was added, and the resulting suspension was stirred in
argon atmosphere for time and at temperature specified in Scheme 1 (NMR
monitoring). Then, 30 ml of water and 30 ml of Et2O were added, and the
organic layer was separated. The aqueous layer was additionally extracted
with Et2O (3×10 ml). The combined extracts were washed thrice with
water, dried (Na2SO4), and concentrated. Column chromatography of the
residue on silica gel [hexane–Et2O (20:1®5:1) as eluent] gave compounds
E-3a,b or Z-3a–f.
This work was supported by the Russian Foundation for Basic
Research (grant no. 15-03-08195 A).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2016.01.002.
(
1E)-1-Benzylidene-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimid-
azole E-3a was prepared from aldehyde 1a in 56% yield, mp 135–137°C.
1H NMR, d: 1.46 (s, 6H, 2Me), 3.27 (d, 2H, CH2, 4J 2.2 Hz), 6.69 (t, 1H,
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3
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