Cyclization of alk-4-ynals with o-diaminoarenes as a selective one-pot synthesis of arylmethylidene-substituted 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles and 7,8-dihydro-6H-pyrrolo[1’,2’:1,2]imidazo[4,5-b]pyridines

Article abstract of DOI:10.1007/s11172-016-1517-6

A one-pot synthesis of arylmethylidene-substituted 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles based on the reaction of alk-4-ynals with 1,2-diaminobenzenes in DMSO at sequential catalysis with NH₄Br and bases was suggested. The use in these pr

Full text of DOI:10.1007/s11172-016-1517-6

Russian Chemical Bulletin, International Edition, Vol. 65, No. 7, pp. 1829—1838, July, 2016
1829
Cyclization of alkꢀ4ꢀynals with oꢀdiaminoarenes as a selective
oneꢀpot synthesis of arylmethylideneꢀsubstituted
2
,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]benzimidazoles and
,
7
,8ꢀdihydroꢀ6Hꢀpyrrolo[1´,2´:1,2]imidazo[4,5ꢀb]pyridines* **
V. D. Gvozdev, K. N. Shavrin, E. G. Baskir, M. P. Egorov, and O. M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: vgvozdev2006@yandex.ru
A oneꢀpot synthesis of arylmethylideneꢀsubstituted 2,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]ꢀ
benzimidazoles based on the reaction of alkꢀ4ꢀynals with 1,2ꢀdiaminobenzenes in DMSO at
sequential catalysis with NH Br and bases was suggested. The use in these processes of KOH as
4
a base led to the selective formation of Eꢀisomers of the final products in 48—66% yields,
whereas less basic K CO gave the corresponding Zꢀisomers in 32—82% yields. Similar cyclizaꢀ
2
3
tion reactions involving 2,3ꢀdiaminopyridine gave 7,8ꢀdihydroꢀ6Hꢀpyrrolo[1´,2´:1,2]imidꢀ
azo[4,5ꢀb]pyridines in up to 56% yields. The distinguishing feature of the processes under study
is proceeding of their key step that is intramolecular hydroamination of the triple bond, as
a 5ꢀexoꢀdigꢀcyclization. The necessity for the application of drastic conditions required for these
processes is in agreement with the results of quantum chemical calculations of PES of their
most probable rateꢀdetermining step, namely, the cyclization of the corresponding benzimidꢀ
azolide anions to cyclic vinyl anions.
Key words: alkꢀ4ꢀynals, 1,2ꢀdiaminoarenes, 2,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]benzimidazoles,
7
,8ꢀdihydroꢀ6Hꢀpyrrolo[1´,2´:1,2]imidazo[4,5ꢀb]pyridines, hydroamination, anionic cyclizaꢀ
tion, dimethyl sulfoxide, potassium hydroxide, potassium carbonate, quantum chemical calꢀ
culations.
Pyrrolobenzimidazoles play an important role in meꢀ
dicinal chemistry and can be regarded as privileged scafꢀ
folds in pharmaceutical studies. Investigation of their bioꢀ
logical activity began in 1975, when these compounds were
found to possess pronounced analgesic activity. Later, it
was shown that substituted 2,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]ꢀ
Earlier, we have suggested13—15 an original approach
to (arylmethylidene)octahydropyrrolo[1,2ꢀa]pyrimidines
and 5ꢀ(arylmethylidene)hexahydropyrrolo[1,2ꢀa]imidꢀ
azoles based on the reaction of alkꢀ4ꢀynals with aliphatic
diamines upon treatment with strong bases. Later, this
2
1
6
approach was extended to similar processes involving
amino alcohols and amino thiols, which led to the correꢀ
sponding fused oxazoles, oxazines, and thiazoles with an
exocyclic double bond. Further development of these studꢀ
ies showed that the use of oꢀaminobenzylamine and
oꢀaminobenzyl alcohol as binucleophilic reagents in the
reactions with alkꢀ4ꢀynals constitutes a simple, efficient,
and metalꢀfree method for the preparation of 1ꢀarylmethꢀ
ylideneꢀ1,2,3,3aꢀtetrahydroꢀ5Hꢀpyrrolo[1,2ꢀa][3,1]benzꢀ
oxazines and 1ꢀarylmethylideneꢀ1,2,3,3a,4,5ꢀhexahydroꢀ
benzimidazoles can be used as inhibitors of proteinꢀproꢀ
3
4,5
tein interaction and antitumor agents.
The common syntheses of these compounds include
the rhodiumꢀcatalyzed cyclization of Nꢀalkenylbenzimidꢀ
6
azoles, cyclocondensation of pyrrolidones with oꢀbromoꢀ
8
anilines, annulation of benzimidazoles through the intraꢀ
9
molecular nucleophilic substitution, and cyclopropylꢀ
imine rearrangement of 2ꢀcyclopropylbenzimidazolium
salts.10 There are also known syntheses of 2,3ꢀdihydroꢀ
1
7
1
Hꢀpyrrolo[1,2ꢀa]benzimidazoles based on the radical
pyrrolo[1,2ꢀa]quinazolines.
1
1
1
cyclization of different alkylbenzimidazoles and iodoꢀ
cyclization of 2ꢀalkynylbenzimidazoles.12
Recently, we accomplished a oneꢀpot synthesis of
arylmethylideneꢀsubstituted 2,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]ꢀ
benzimidazoles based on the reaction of available alkꢀ4ꢀ
ynals with 1,2ꢀdiaminobenzene, which is catalyzed seꢀ
quentially by ammonium bromide and bases. By the
present time, there are known only several examples of the
*
*
For preliminary communication, see Ref. 1.
* Based on the materials of the IV AllꢀRussian Conference on
Organic Chemistry and XVII Youth SchoolꢀConference on
Organic Chemistry (November 22—27, 2015, Moscow, Russia).
1
2
preparation of such compounds which contain an iodine
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1829—1838, July, 2016.
066ꢀ5285/16/6507ꢀ1829 © 2016 Springer Science+Business Media, Inc.
1

1
830
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Gvozdev et al.
atom, a phenyl and a phenylethynyl group as substituents
in the methylidene fragment, with all of them being obꢀ
tained as less sterically hindered Eꢀisomers. The present
work is devoted to more detailed study of the discovered
process for the preparation of these compounds, revealing
its specific features and synthetic scope.
ture, only 2ꢀ(1,1ꢀdimethylꢀ4ꢀphenylbutꢀ3ꢀynꢀ1ꢀyl)ꢀ2,3ꢀ
dihydroꢀ1Hꢀbenzimidazole, which was an initial product
of cyclocondensation of the starting compounds. Its strucꢀ
ture was established based on characteristic signals, which
are: first of all, a broad singlet at δ 5.02 corresponding to
the aminal proton; a doublet with the spinꢀspin coupling
constant J = 3.4 Hz attributed to two equivalent NH
groups; as well as a multiplet for four protons of the dihyꢀ
drobenzimidazole fragment in the region of δ 6.23—6.37.
The addition of a 1.5ꢀfold molar excess of freshly powꢀ
dered KOH to the solutions of benzimidazoles 3a—d in
DMSO with subsequent stirring of the reaction mixtures
at ~20 °C for 2 h did not cause any changes in contrast to
the earlier studied by us similar processes involving alkyꢀ
nylꢀsubstituted 1,4ꢀdihydroꢀ2Hꢀ3,1ꢀbenzoxazines and
1
Results and Discussion
In the course of the present studies, we found that the
stirring of equimolar amounts of aldehydes 1a—f and
oꢀdiaminobenzenes 2a,b in anhydrous DMSO in the presꢀ
ence of NH Br at ~20 °C led, according to the NMR
4
spectra of the reaction mixtures, to the selective formation
of the corresponding 2ꢀalkynylꢀsubstituted benzimidazoles
a—g (Scheme 1). Earlier,1 a fourꢀfold excess of NH Br
8
1,2,3,4ꢀtetrahydroquinazolines. However, raising temꢀ
17
3
4
was used in similar reactions with aromatic aldehydes,
however, we showed that the process can successfully proꢀ
perature to 50 °C and prolongation the reaction to 12—48 h
led to the complete transformation of compounds 3 into
pyrrolobenzimidazoles 4a—d, which were obtained excluꢀ
sively as Eꢀisomers, as was inferred from the NMR spectra
of the reaction mixtures (see Scheme 1, Table 1). The
latter after aqueous workꢀup of the reaction mixtures were
isolated in 48—66% yields by recrystallization from hexꢀ
ane (for compounds 4a—c) or by chromatography on siliꢀ
ca gel (for compound 4d).
ceed with only 20 mol.% NH Br. In separate experiments,
4
benzimidazoles 3a and 3d were isolated in the individual
state in 68% and 74% yields, respectively.
It should be noted that carrying out the reaction of
aldehydes 1 with aromatic diamines with contact of the
reaction mixture with air is a necessary condition for
benzimidazoles 3 to be formed. A control reaction of aldeꢀ
hyde 1a and oꢀdiaminobenzene 2a under argon for 24 h
gave, according to the NMR spectra of the reaction mixꢀ
Unfortunately, our attempts to involve alkꢀ4ꢀynals with
hydrogen atoms at αꢀposition to the carbonyl group in
Scheme 1
Compound 1
R1
Ph
2ꢀthienyl
Ph
R2
Me
Me
Compound 3, 4
R1
Ph
Ph
R2
Me
Me
R3
H
Me
H
H
H
a
b
c
d
e
f
a
b
c
d
e
f
—(CH ) —
2ꢀthienyl
Ph
Me
2
5
Ph
H
H
Me
—(CH ) —
2
5
3,4ꢀF C H
Ph
H
H
Me
2
6
3
3
3,4ꢀF C H
3,4ꢀF C H
H
H
2
6
2
6
3
3
g
3,4ꢀF C H
2
6
3
2
: R = H (a), Me (b)
Conditions and reagents: i. DMSO, NH Br, 24 h, 20 °C; ii. KOH, DMSO, 50 °C; iii. K CO , DMSO, 90 °C.
4
2
3

Cyclization of alkꢀ4ꢀynals with oꢀdiaminoarenes
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1831
a
Table 1. Reactions of alkꢀ4ꢀynals 1a—f with diamines 2a—e in DMSO sequentially catalyzed by NH Br and bases
4
Alkynal
Diamine
T1/°C
Cyclization of intermediates 3
Product
yield (%)
Base
τ/h
T2/°C
b
1
1
1
1
1
1
1
a
a
a
a
a
a
a
2a
2b
2c
2a
2b
2c
2d
20
20
20
20
20
20
20
KOH
KOH
KOH
48
60
48
72
48
72
48
50
50
50
90
90
90
90
Eꢀ4a (56 )
b
Eꢀ4b (66 )
b
Eꢀ4h (62 )
b
K CO3
Zꢀ4a (75 )
2
b
K CO3
Zꢀ4b (82 )
2
b
K CO3
Zꢀ4h (69 )
2
K CO3
Zꢀ4i : Zꢀ4j =
2
d
c
=
1.1 : 1 (78 )
b
1
1
1
1
1
1
1
1
1
1
a
b
b
b
c
c
d
d
e
f
2e
2a
2a
2e
2a
2a
2a
2a
2a
2a
90
20
20
90
20
20
20
20
20
20
K CO3
24
12
12
12
24
24
24
240
24
12
90
50
90
90
50
90
50
90
90
90
Zꢀ8a (56 )
2
b
KOH
Eꢀ4c (59 )
b
K CO3
Zꢀ4c (78 )
2
b
K CO3
Zꢀ8b (51 )
2
с
KOH
Eꢀ4d (48 )
b
K CO3
Zꢀ4d (52 )
2
e
KOH
—
b
K CO3
Zꢀ4e (37 )
2
b
K CO3
Zꢀ4f (32 )
2
b
K CO3
Zꢀ4g (57 )
2
a
The molar ratio of alkynal : diamine = 1 : 1; T is the temperature of the reaction carried out upon treatment with
1
NH Br, T is the temperature of cyclization.
4
2
b
c
d
e
After recrystallization from hexane.
After column chromatography.
According to the H NMR spectral data of isolated mixtures of products.
1
A complete resinification of the reaction mixture was observed.
these processes were unsuccessful. Thus, the addition of
KOH to a solution of benzimidazole 3e obtained by the
reaction of aldehyde 1d with diamine 2a led to the formaꢀ
tion of only polymeric products. Probably, this is explained
by side processes involving acidic enough hydrogen atoms
in the corresponding benzimidazole 3e, which proceed
much faster than the intramolecular hydroamination of
the triple bond.
The use of less strong base (anhydrous potassium carꢀ
bonate) instead of KOH with simultaneous increase in
temperature to 90 °C allowed us to synthesize pyrrolobenꢀ
zimidazoles 4a—g from aldehydes 1a—f irrespective of the
presence in the latter of substituents at αꢀposition to the
carbonyl group. The yields of the final products varied
within the range of 32—82% (see Table 1). Very interestꢀ
ing and unexpected is the fact that the use of these cyclizaꢀ
tion conditions leads to a dramatic change in the stereoseꢀ
lectivity of the formation of pyrrolobenzimidazoles 4,
which, in contrast to the case with KOH, are formed exꢀ
clusively as more sterically hindered Zꢀisomers.
due to the increase in polarization of the triple bond and,
respectively, to its ability to undergo nucleophilic addition.
The reaction of aldehyde 1a with 1,2ꢀdiaminoꢀ3ꢀmeꢀ
thylbenzene (2c) in DMSO in the presence of NH Br and
4
subsequent cyclization of obtained benzimidazole 3h upon
treatment with K CO led to the selective formation of
2
3
pyrrolobenzimidazole Zꢀ4h in 69% yield (Scheme 2). The
presence in its structure of methyl substituent at position 5,
1
rather than at position 8, was inferred from the H NMR
spectrum, which exhibited a signal characteristic of the
proton H(8) at δ 5.67 correlating well with similar signals
in the spectra of other Zꢀisomers of pyrrolobenzimidꢀ
azoles 4. The use of KOH for cyclization of benzimidazole
3h also led to the only product in 62% yield, which based
on a combination of spectral data was characterized as the
Eꢀisomer of compound 4h (see Scheme 2). Apparently,
the steric and electronic influence of the methyl substituꢀ
ent at orthoꢀposition to the fiveꢀmembered ring in benzꢀ
imidazole 3h turned out to be enough for the 5ꢀexoꢀdigꢀ
hydroamination proceeding exclusively with the involveꢀ
ment of the most remote from it nitrogen atom.
At the same time, the use of 1,2ꢀdiaminoꢀ4ꢀmethylꢀ
benzene (2d) in a similar reaction leads to a mixture of
isomers Zꢀ4i and Zꢀ4j in the ratio of 1.1 : 1 in 78% total
yield, which were characterized without separation. The
absence of selectivity in this case indicates that the methyl
As can be seen from the given data (see Table 1), the
replacement of a phenyl group with more electronꢀwithꢀ
drawing thienyl or 3,4ꢀdifluorophenyl one considerably
accelerates cyclization of benzimidazoles 3. A similar efꢀ
fect is observed when two alkyl substituents are introduced
at αꢀposition of the starting aldehyde, that, most likely, is

1
832
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Gvozdev et al.
Scheme 2
Conditions and reagents: i. DMSO, NH Br, 24 h, 20 °C; ii. K CO , DMSO, 90 °C; iii. KOH, DMSO, 50 °C.
4
2
3
group has little effect on the relative reactivities of nitroꢀ
gen atoms in benzimidazole 3i (Scheme 3). Compounds 4i
and 4j were identified based on the analysis of the splitting
pattern of the signal for the proton H(8). In the predomiꢀ
nant isomer 4i, this signal was found as a broad singlet,
whereas in the minor isomer 4j it is a doublet with the
spinꢀspin coupling constant of 8.4 Hz due to the interacꢀ
tion with the neighboring proton.
methylene fragment at position 2 and the signals for the
orthoꢀprotons of the aromatic substituent at the double
bond. At the same time, the correlations between the signals
for the protons of the aromatic substituent and the signal
for the proton at position 8 are completely absent. Converꢀ
sely, they are quite pronounced for isomers Zꢀ4. There are
also present characteristic correlations between the signals
for the olefin proton and the CH fragment at position 2
2
The Eꢀ and Zꢀisomers of pyrrolobenzimidazoles 4 were
identified based on the 2D proton NOESY spectra. In the
case of Eꢀisomers, they exhibited correlations between the
signals for the methine proton at the double bond and the
proton at position 8, as well as between the signals for the
(Fig. 1). Apart from that, the spectra of isomers Zꢀ4 are charꢀ
acterized by a strong upfield shift of the signal for the proton
H(8) (δ 5.3—5.9), most likely, attributed to the shielding
effect of a nearby aryl substituent, whose plane is perpenꢀ
dicular to the plane of the pyrrolobenzimidazole core.
Scheme 3
7
8% total yield
Conditions and reagents: i. DMSO, NH Br, 24 h, 20 °C; ii. K CO , DMSO, 90 °C.
4
2
3

Cyclization of alkꢀ4ꢀynals with oꢀdiaminoarenes
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1833
hydroamination of alkynes upon treatment with imidꢀ
1
9
20
azoles and indoles. Because of the high basicity of the
KOH—DMSO system, these anions live long enough to
undergo isomerization to more thermodynamically stable
anions Eꢀ6 (according to our calculations, the energy difꢀ
–
1
ference is ~2.5—2.7 kcal mol ). Note that similar proꢀ
cesses for vinyl anions obtained by the intramolecular adꢀ
dition of Nꢀcentered anions to triple bonds were described
2
1
in the work. In the final step, anions Eꢀ6 add a proton
from the reaction medium to form Eꢀisomers of pyrꢀ
rolobenzimidazoles 4 (Scheme 4).
In the case of less basic K CO , the starting alkynylꢀ
2
3
benzimidazoles 3 undergo deprotonation only to a little
extent. As soon as anions 5 cyclize to anions Zꢀ6, the
latter are immediately protonated upon action of the exꢀ
cessive starting compound 3, regenerating anions 5, which
enter the next reaction cycle, and giving rise to Zꢀisomers
of products 4 (see Scheme 4).
The present studies showed that besides oꢀdiaminobenzꢀ
enes 2a—d, 2,3ꢀdiaminopyridine (2e) can be also involved
in similar cyclization reactions with alkꢀ4ꢀynals. In this
case, the first step of the process, i.e., the oxidative cyclizaꢀ
tion to the corresponding imidazopyridines 7a,b, proceeds
considerably slower and requires heating for 12 h at 90 °C to
reach completion. The addition of a threeꢀfold molar excess
of anhydrous K CO to the thus obtained solutions of
imidazopyridines 7a,b in DMSO with subsequent stirring of
the reaction mixtures for 12—24 h at 90 °C led to a complete
consumption of the starting compounds with the formaꢀ
tion of arylmethylideneꢀsubstituted 7,8ꢀdihydroꢀ6Hꢀpyrrꢀ
olo[1´,2´:1,2]imidazo[4,5ꢀb]pyridines Zꢀ8a,b. The latter
after aqueous workꢀup of the reaction mixture were isolated
in the individual state by recrystallization from hexane in
56 and 51% yields, respectively (Scheme 5, see Table 1).
Fig. 1. Key NOEꢀinteractions in compounds Eꢀ4a and Zꢀ4a.
The large difference in the stereoselectivity of the forꢀ
mation of pyrrolobenzimidazoles 4 depending on the naꢀ
ture of the base used is most likely explained as follows. In
the case of strongly basic KOH, the starting alkynylbenzꢀ
imidazoles 3 undergo fast and complete deprotonation
with the formation of the corresponding anions 5. This
fact was confirmed by characteristic upfield shifts of the
signals for the aromatic protons in the spectra of solutions
of compounds 3 in DMSO after addition of KOH. Then,
anions 5 as a result of 5ꢀexoꢀdigꢀcyclization are converted
to vinyl anions Zꢀ6, that agrees with the literature data on
2
3
Scheme 4

1
834
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Gvozdev et al.
Scheme 5
1
1
, 7, 8: R = Ph (a), 2ꢀthienyl (b)
Conditions and reagents: i. DMSO, NH Br, 12 h, 90 °C; ii. K CO , DMSO, 90 °C.
4
2
3
1
Their H NMR spectra exhibit signals at δ 5.62—6.02
corresponding to the protons at position 4 of the tricyclic
system, which are located in the same region as the signals
of similar protons in pyrrolobenzimidazoles 4 (δ 5.3—5.9).
This indicates that these products have the structure in
which the pyridine nitrogen atom is at position remote
from the arylmethylidene group. Thus, under conditions
of anionic cyclization of compounds 7 the nitrogen atom
of the imidazole ring which is farther from the pyridine
nitrogen atom possesses considerably higher reactivity with
respect to the triple bond. Note that such a regioselectivity
crucially differs from the regioselectivity of similar cyclizaꢀ
tions22 carried out upon heating in polar solvent, which
proceed exclusively as 6ꢀendoꢀdigꢀprocesses with the forꢀ
mation of sixꢀmembered rings.
Scheme 6
1
2
1
2
1
2
9
, 10: R = H, R = H (a), R = Me, R = H (b), R = H, R = F (c)
To explain the strong differences in conditions required
for the intramolecular cyclization of alkynylꢀsubstituted
benzimidazoles 3 upon treatment with KOH in DMSO
Fig. 2), in this case the process is endothermic (ΔE =
0
–1
=
12.9—18.4 kcal mol ) and has a high activation barrier.
This agrees with the experimentally observed necessity for
rather drastic conditions (see Table 1) for carrying out the
cyclization of benzimidazoles 3 to pyrrolobenzimidazoles 4.
The formation of the latter upon heating of solutions of
benzimidazoles 3 in DMSO in the presence of bases is
a slow process, apparently, because of the very low equilibꢀ
rium concentration of the corresponding cyclic anions 6.
The introduction of the methyl groups at αꢀposition of
the alkynyl fragment (compound 5b) or the fluorine atoms
in benzene ring (compound 5c) leads to some decrease in
(
12—60 h at 50 °C, see Table 1) and the earlier studied
similar processes involving related 1,2,3,4ꢀtetrahydroꢀ
1
7
quinazolines (0.5—2 h at ~20 °C), we carried out quanꢀ
tum chemical calculations of the key step of these transꢀ
formations, that is, the intramolecular addition of the corꢀ
responding amide anions at the triple bond.
It is known23 that the energy parameters of intraꢀ
molecular cyclization reactions, including those involvꢀ
ing anions obtained from the results of the B3LYP/6ꢀ
3
1+G(d,p) calculations, are in good agreement with the
the activation energy of the direct reaction (from 25.2 to
experimental results. The use of similar procedure for calꢀ
culations of the potential energy surface (PES) of the transꢀ
formations of Nꢀanions 9a—c, formed as the intermediate
products in the reaction of alkꢀ4ꢀynals with oꢀaminoꢀ
benzylamine,17 to anions 10a—c (Scheme 6, Fig. 2)
–1
2
2.6—23.3 kcal mol ) and an increase in the reverse reꢀ
–1
action barrier (from 6.8 kcal mol in the case of Zꢀ6a to
ΔE /kcal mol–
1
0
TSa
TSc
2
0
0
0
TSb
showed that this process is weakly exothermic (ΔE =
0
–
1
=
–(0.4—1.4) kcal mol ).
20.3
19.1
18.5
Similar method was used to calculate the PES of the
1
cyclization of benzimidazolide anions 5a—c to the correꢀ
sponding vinyl anions Zꢀ6a—c and Eꢀ6a—c, which most
likely is a rateꢀdetermining step in the transformation of
benzimidazoles 3 to pyrrolobenzimidazoles 4 (see Schemes 4
and 7, Fig. 3). The calculations showed that, in contrast
to similar transformation of anions 9 to anions 10 (see
9a
10a 9b
10b 9c
–1.4 10c
–0.5
–0.4
Fig. 2. Energy profile of cyclization of Nꢀanions 9a—c to anions
10a—c.

Cyclization of alkꢀ4ꢀynals with oꢀdiaminoarenes
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1835
Scheme 7
1
2
1
2
1
2
5
,6: R = H, R = H (a), R = Me, R = H (b), R = H, R = F (c)
ΔE /kcal mol–1
recorded on a Bruker ACꢀ200p spectrometer in CDCl , using
0
3
SiMe4 as an internal standard. NMR monitoring of reaction
progress was carried out by recording spectra of the samples of
reaction mixtures.
3
0
0
0
0
TSa
5.2
TSc
3.3
TSb
2
High resolution mass spectra were recorded on a Bruker
micrOTOF II instrument with electrospray ionization (ESI). The
measurements were performed on positive ions (capillary voltꢀ
age 4500 V). The range of scanned masses m/z from 50 to 3000 Da,
external or internal calibration (Electrospray Calibrant Soluꢀ
tion, Fluka). Compounds were syringed as solutions in acetoꢀ
2
2
1
Zꢀ6a
Eꢀ6a
22.6
1
1
8.4
5.6
Zꢀ6b
Eꢀ6b
Zꢀ6c
Eꢀ6c
1
1
5.5
3.0
15.7
12.9
–
1
nitrile, the flow rate was 3 μL min . Nebulizer gas was nitrogen
(
4 L min–1), interface temperature 180 °C.
5
a
5b
5c
Quantum chemical calculations of structure, vibrational freꢀ
quencies, and potential energy surface (PES) were carried out by
2
4,25
density functional theory (DFT) on the B3LYP
level in the
Fig. 3. Energy profile of cyclization of benzimidazolide anions
a—c to anions 6a—c.
6
ꢀ31+G (d,p) basis, using the GAUSSIANꢀ09, Rev/D 01 softꢀ
5
2
6
ware package. The character of found stationary points (the
minimum or saddle point) was determined by the calculation of
the eigenvalues of the energy second derivatives matrix. The
belonging of a transition state (TS) to a certain transformation
was controlled using results of the calculations of the internal
7
.1—7.6 kcal mol–1 in cases of Zꢀ6b,c, Scheme 7, see
Fig. 3). These results agree with the experimentally obꢀ
served dependence of the reaction time required for the
complete conversion of the corresponding benzimidazoles
27
reaction coordinate (IRC). The allowance for the solvation
effect of DMSO was made using the polarizable continuum model
2
8
3
to products 4 (see Table 1).
(PCM) in the selfꢀconsistent reaction field (SCRF) method.
In conclusion, we have developed a convenient oneꢀ
The starting alkynals 1a—c,f were synthesized from the corꢀ
responding propargyl chlorides (1ꢀchloroꢀ3ꢀphenylpropꢀ2ꢀyne,
pot synthesis of arylmethylideneꢀsubstituted 2,3ꢀdihydroꢀ
Hꢀpyrrolo[1,2ꢀa]benzimidazoles and 7,8ꢀdihydroꢀ6Hꢀ
pyrrolo[1´,2´:1,2]imidazo[4,5ꢀb]pyridines by the reaction
1
ꢀchloroꢀ3ꢀ(2ꢀthienyl)propꢀ2ꢀyne, 1ꢀchloroꢀ3ꢀ(3,4ꢀdifluoroꢀ
1
phenyl)propꢀ2ꢀyne) and aldehydes (isobutyric aldehyde and
cyclohexanecarbaldehyde) according to the procedures described
of available alkꢀ4ꢀynals with aromatic diamines at sequenꢀ
1
5
in the work. Alkynal 1d was obtained by crossꢀcoupling of
tial catalysis with NH Br and bases. A distinguishing feaꢀ
4
iodobenzene with pentꢀ4ꢀynꢀ1ꢀol upon treatment with a mixꢀ
ture of this approach is a possibility of directing stereoꢀ
selectivity of the reaction by changing the type of the base
used, depending on which Zꢀ or Eꢀisomers of the final
products can be selectively obtained. The final compounds
seem promising for medicinal chemistry.
29
ture of Pd(PPh ) Cl —CuI in anhydrous triethylamine with
3
2
2
subsequent Swern oxidation of formed 5ꢀphenylpentꢀ4ꢀynꢀ1ꢀol
(a total yield on two steps was 62%). The spectral data of the
product agree with those published earlier.30 Alkynal 1e was
obtained by similar crossꢀcoupling from 4ꢀbromoꢀ1,2ꢀdifluoroꢀ
benzene, using Pd(PPh ) as the catalyst, in 55% total yield on
3
4
two steps.
Experimental
Synthesis of 2ꢀ(alkꢀ3ꢀynyl)benzimidazoles 3a,d from aldehydes
1
a,c and oꢀdiaminobenzene 2a (general procedure). A solution of
Starting compounds and obtained products were analyzed by
GC using a HewlettꢀPackard 5890 Series II instrument with an
HPꢀ1 capillary column (30 m×0.153 mm) and an HewlettꢀPackꢀ
oꢀdiaminobenzene 2a (216 mg, 2 mmol) in DMSO (3 mL) was
slowly added to a solution of the corresponding aldehyde 1
(2 mmol) in DMSO (3 mL), followed by the addition of NH Br
4
1
13
ard 3396A automated integrator. H and C NMR spectra were
(39 mg, 0.4 mmol). The mixture obtained was stirred for 24 h at

1
836
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Gvozdev et al.
~
20 °C under dry air. Then, water (30 mL) and CH Cl (50 mL)
(1Z)ꢀ1ꢀBenzylideneꢀ3,3ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀpyrroloꢀ
[1,2ꢀa]benzimidazole (Zꢀ4a) was obtained from aldehyde 1a and
diamine 2a and isolated in 75% yield by recrystallization from
2
2
were added, the organic layer was separated. The aqueous layer
was additionally extracted with CH Cl (3×10 mL). The comꢀ
bined organic layers were washed thrice with water, dried with
anhydrous Na SO , the solvent was evaporated, and the residue
2
2
1
hexane, m.p. 121—122 °C. H NMR, δ: 1.57 (s, 6 H, 2 Me); 3.13
4
3
(d, 2 H, CH , J = 1.5 Hz); 5.76 (d, 1 H, C(8)H, J = 8.2 Hz);
2
4
2
was recrystallized from a mixture of light petroleum ether—THF
to isolate products 3a,d.
6.18 (br.s, 1 H, PhCH=); 6.77—6.89 (m, 1 H, C(7)H); 7.08—7.19
(m, 1 H, C(6)H); 7.13—7.25 (m, 2 H, Ph); 7.26—7.41 (m, 3 H,
3
13
2
ꢀ(1,1ꢀDimethylꢀ4ꢀphenylbutꢀ3ꢀynꢀ1ꢀyl)ꢀ1Hꢀbenzimidazole
Ph); 7.67 (d, 1 H, C(5)H, J = 8.1 Hz). C NMR, δ: 26.4 (2 Me);
36.5 (C(3)); 51.6 (C(2)); 108.4 (PhCH=), 114.4 (C(8)); 119.4,
122.0, 122.5 (C(5), C(6), C(7)); 127.2, 128.2, 129.6 (Ph); 130.3
(C(8a)); 133.7, 135.9 (C(1), Ph; C(1)); 148.0 (C(4a)); 168.8
(C(3a)). MS (ESI), found: m/z 275.1538, calculated for C H N ,
(
3a) was obtained from aldehyde 1a in 68% yield, m.p. 250—251 °C.
1
H NMR, δ: 1.55 (s, 6 H, 2 Me); 2.90 (s, 2 H, CH ); 7.05—7.15
2
(
(
m, 2 H, C(5)H, C(6)H); 7.20—7.25 (m, 5 H, Ph); 7.45—7.55
m, 2 H, C(4)H, C(7)H); 11.90 (br.s, 1 H, NH). 1 C NMR,
3
19
18
2
+
δ: 25.0 (2 CH ); 30.9 (CH ); 35.4 (CMe ); 81.0, 85.8 (C≡C), 113.1
[M + H] : m/z 275.1543.
3
2
2
(
(
br., C(4), C(7)); 119.9 (C(5), C(6)); 121.8 (C(1), Ph), 126.2
C(4), Ph), 126.7, 129.7 (C(2), C(3), C(5), C(6), Ph), 136.8 (br.,
(1E)ꢀ1ꢀBenzylideneꢀ3,3,6,7ꢀtetramethylꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrrolo[1,2ꢀa]benzimidazole (Eꢀ4b) was obtained from aldehyde
1a and diamine 2b and isolated in 66% yield by recrystallization
C(3a), C(7a)); 158.8 (C(2)). MS (ESI), found: m/z 275.1549,
calculated for C H N , [M + H] : m/z 275.1543.
+
1
from hexane, m.p. 151—153 °C. H NMR, δ: 1.52 (s, 6 H, 2 Me);
19
18
2
4
2
ꢀ[1ꢀ(3ꢀPhenylpropꢀ2ꢀynꢀ1ꢀyl)cyclohexyl]ꢀ1Hꢀbenzimidꢀ
2.38 (s, 3 H, Me); 2.43 (s, 3 H, Me); 3.34 (d, 2 H, CH , J = 2.2 Hz);
2
4
azole (3d) was obtained from aldehyde 1c in 74% yield, m.p.
2
2
6.72 (t, 1 H, PhCH=, J = 2.2 Hz); 7.20—7.32 (m, 1 H, Ph);
1
38—239 °C. H NMR, δ: 1.23—1.96 (m, 8 H, cycloꢀC );
7.35—7.44 (m, 4 H, Ph); 7.52 (br.s, 2 H, C(5)H, C(8)H).
6
13
.52—2.67 (m, 2 H, cycloꢀC ); 2.86 (s, 2 H, CH C≡C); 7.14—7.25
C NMR, δ: 20.3 (Me); 20.5 (Me); 27.4 (2 Me), 36.3 (C(3));
6
2
(
(
m, 2 H, C(5)H, C(6)H); 7.25—7.41 (m, 5 H, Ph); 7.58—7.70
m, 2 H, C(4)H, C(7)H); 12.08 (br.s, 1 H, NH). 1 C NMR,
47.9 (C(2)); 108.2 (PhCH=); 111.8 (C(8)); 120.3 (C(5)); 126.3,
127.8, 128.6 (Ph); 128.4, 131.8, 131.9 (C(6), C(7), C(8a)); 135.6,
136.2 (C(1), Ph; C(1)); 147.5 (C(4a)); 166.2 (C(3a)). MS (ESI),
3
δ: 22.1 (C(3), C(5), cycloꢀC(6)); 25.0 (C(4), cycloꢀC ); 32.3
(
6
+
C≡CCH ); 33.9 (C(2), C(6), cycloꢀC ); 40.7 (C(1), cycloꢀC );
found: m/z 303.1857, calculated for C H N , [M + H] : m/z
2
6
6
21 22
2
8
1
2.6, 86.9 (C≡C), 114.0 (br., C(4), C(7)); 120.6 (C(5), C(6));
23.0 (C(1), Ph), 127.3 (C(4), Ph); 127.8, 130.9 (C(2), C(3),
303.1856.
(1Z)ꢀ1ꢀBenzylideneꢀ3,3,6,7ꢀtetramethylꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrrolo[1,2ꢀa]benzimidazole (Zꢀ4b) was obtained from aldehyde
1a and diamine 2b and isolated in 82% yield by recrystallization
C(5), C(6), Ph); 135.9 (br., C(3a), C(7a)); 158.3 (C(2)). MS
+
(
ESI), found: m/z 315.1851, calculated for C H N , [M + H] :
22 22 2
1
m/z 315.1856.
from a mixture of hexane—THF, m.p. 157—158 °C. H NMR,
Synthesis of 1ꢀarylmethylideneꢀ2,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]ꢀ
benzimidazoles (4a—j) and 6ꢀarylmethylideneꢀ7,8ꢀdihydroꢀ6Hꢀ
pyrrolo[1´,2´:1,2]imidazo[4,5ꢀb]pyridines (8a,b) (general proꢀ
cedure). A solution of the corresponding aromatic diamine 2
δ: 1.55 (s, 6 H, 2 Me); 1.95 (s, 3 H, Me); 2.26 (s, 3 H, Me); 3.12
4
(d, 2 H, CH , J = 1.6 Hz); 5.36 (s, 1 H, C(8)H); 6.15 (br.s, 1 H,
2
PhCH=); 7.15—7.26 (m, 2 H, Ph); 7.29—7.38 (m, 3 H, Ph);
13
7.40 (s, 1 H, C(5)H). C NMR, δ: 20.0 (Me); 20.1 (Me); 26.5
(2 Me); 36.4 (C(3)); 50.9 (C(2)); 107.6 (PhCH=); 115.0 (C(8));
119.4 (C(5)); 127.0, 128.2, 129.9 (Ph); 128.7, 130.6, 131.2 (C(6),
C(7), C(8a)); 134.1, 136.3 (C(1), Ph; C(1)); 146.4 (C(4a)); 168.0
(C(3a)). MS (ESI), found: m/z 303.1860, calculated for C H N ,
(
1 mmol) in DMSO (3 mL) was added to a solution of the correꢀ
sponding aldehyde 1 (1 mmol) in anhydrous DMSO (3 mL) with
stirring, followed by the addition of NH Br (19 mg, 0.2 mmol) to
4
the resulting mixture, which then was stirred under dry air and
conditions indicated in Table 1. Then, freshly powdered KOH
21
22
2
+
[M + H] : m/z 303.1856.
(
84 mg, 1.5 mmol) was added (for the preparation of Eꢀ4a—d,h)
(1E)ꢀ3,3ꢀDimethylꢀ1ꢀ(2ꢀthienylmethylidene)ꢀ2,3ꢀdihydroꢀ
1Hꢀpyrrolo[1,2ꢀa]benzimidazole (Eꢀ4c) was obtained from aldeꢀ
hyde 1b and diamine 1a and isolated in 59% yield by recrystalliꢀ
or anhydrous K CO (414 mg, 3 mmol) (for the preparation of
Zꢀ4a—j) and the resulting suspension was stirred under argon until
reaction reached completion ( H NMR monitoring, the reacꢀ
tion time and temperature are given in Table 1). Then, water (40 mL)
2
3
1
1
zation from hexane, m.p. 141—143 °C. H NMR, δ: 1.47 (s, 6 H,
4
2 Me); 3.26 (d, 2 H, CH , J = 2.2 Hz); 6.87 (t, 1 H, ThiCH=,
2
4
and Et O (30 mL) were added to the reaction mixture, the organic
J = 2.2 Hz); 6.94—7.01 (m, 2 H, thienyl); 7.15—7.26 (m, 3 H,
2
layer was separated, whereas the aqueous phase was extracted
thienyl, C(5)H, C(6)H); 7.58—7.70 (m, 2 H, C(7)H, C(8)H).
C NMR, δ: 27.7 (2 Me); 36.5 (C(3)); 47.9 (C(2)); 102.4
1
3
with Et O (3×10 mL). The combined organic layers were washed
2
with water thrice and dried with anhydrous K CO , the solvent
was evaporated, the residue was purified by recrystallization or
column chromatography to isolate a product (see Table 1).
(ThiCH=); 111.4 (C(8)); 120.2, 123.0, 123.3 (C(5), C(6), C(7));
124.4, 126.0, 129.7 (Thi); 129.7 (C(8a)); 134.1, 139.3 (C(1),
Thi; C(1)); 149.0 (C(4a)); 167.3 (C(3a)). MS (ESI), found: m/z
2
3
+
(
1E)ꢀ1ꢀBenzylideneꢀ3,3ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀpyrroloꢀ
281.1114, calculated for C H N S, [M + H] : m/z 281.1107.
17
16
2
[
1,2ꢀa]benzimidazole (Eꢀ4a) was obtained from aldehyde 1a and
(1Z)ꢀ3,3ꢀDimethylꢀ1ꢀ(2ꢀthienylmethylidene)ꢀ2,3ꢀdihydroꢀ
1Hꢀpyrrolo[1,2ꢀa]benzimidazole (Zꢀ4c) was obtained from aldeꢀ
hyde 1b and diamine 1a and isolated in 78% yield by recrystalliꢀ
diamine 2a and isolated in 56% yield by recrystallization from
hexane, m.p. 135—137 °C. H NMR, δ: 1.46 (s, 6 H, 2 Me); 3.27
1
4
4
1
(
d, 2 H, CH , J = 2.2 Hz); 6.69 (t, 1 H, PhCH=, J = 2.2 Hz);
zation from hexane, m.p. 83—85 °C. H NMR, δ: 1.55 (s, 6 H,
2
4
7
.10—7.36 (m, 7 H, Ph, C(5)H, C(6)H); 7.63—7.72 (m, 2 H,
2 Me); 3.11 (d, 2 H, CH , J = 1.7 Hz); 5.91 (d, 1 H, C(8)H,
2
13
3
C(7)H, C(8)H). C NMR, δ: 27.4 (2 Me), 36.4 (C(3)); 47.9
C(2)); 108.9 (PhCH=); 111.4 (C(8)); 120.1, 122.9, 123.2 (C(5),
C(6), C(7)); 126.5, 127.9, 128.7 (Ph), 129.9 (C(8a)); 135.5, 136.0
C(1), Ph; C(1)); 149.0 (C(4a)); 167.0 (C(3a)). MS (ESI), found:
J = 8.1 Hz), 6.07 (br.s, 1 H, ThiCH=); 6.76 (dd, 1 H, thienyl,
3
4
(
J = 3.5 Hz, J = 1.2 Hz); 6.87—6.98 (m, 1 H, C(7)H); 7.00 (dd,
3
3
1 H, thienyl, J = 5.2 Hz, J = 3.5 Hz); 7.12—7.22 (m, 1 H,
C(6)H); 7.31 (dd, 1 H, thienyl, J = 5.2 Hz, J = 1.2 Hz); 7.67
(d, 1 H, C(5)H, J = 8.1 Hz). C NMR, δ: 26.4 (2 Me); 36.4
3
4
(
+
3
13
m/z 275.1545, calculated for C H N , [M + H] : m/z 275.1543.
19
18
2

Cyclization of alkꢀ4ꢀynals with oꢀdiaminoarenes
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1837
(
1
C(3)); 50.8 (C(2)); 100.3 (ThiCH=); 114.2 (C(8)); 119.4, 122.3,
22.7 (C(5), C(6), C(7)); 125.5, 127.0, 128.3 (thienyl); 130.2
C(8a)); 135.9, 137.0 (C(1), thienyl; C(1)); 148.0 (C(4a)); 168.7
(1Z)ꢀ1ꢀ(3,4ꢀDifluorobenzylidene)ꢀ3,3ꢀdimethylꢀ2,3ꢀdihydroꢀ
1Hꢀpyrrolo[1,2ꢀa]benzimidazole (Zꢀ4g) was obtained from aldeꢀ
hyde 1d and isolated in 57% yield by recrystallization from
(
(
[
1
C(3a)). MS (ESI), found: m/z 281.1105, calculated for C H N S,
hexane, m.p. 124—126 °C. H NMR, δ: 1.58 (s, 6 H, 2 Me); 3.12
17
16
2
+
4
3
M + H] : m/z 281.1107.
1´E)ꢀ1´ꢀBenzylideneꢀ1´,2´ꢀdihydrospiro[cyclohexaneꢀ1,3´ꢀ
pyrrolo[1,2ꢀa]benzimidazole] (Eꢀ4d) was obtained from aldehyde
c and diamine 2a and isolated in 48% yield by recrystallization
(d, 2 H, CH , J = 1.5 Hz); 5.87 (d, 1 H, C(8)H, J = 8.2 Hz);
2
(
6.07 (br.s, 1 H, C H F CH=); 6.86—6.97 (m, 1 H, C(7)H);
6
3 2
7.11—7.21 (m, 1 H, C(6)H); 6.83—7.12 (m, 3 H, C H F ); 7.69
6
3 2
3
13
1
(d, 1 H, C(5)H, J = 8.1 Hz). C NMR, δ: 26.4 (2 Me); 36.6
(C(3)); 51.3 (C(2)); 106.3 (PhCH=); 113.9 (C(8)); 119.7, 122.4,
122.9 (C(5), C(6), C(7)); 117.1 (d, C(5), C H F , J = 17.1 Hz);
1
from hexane, m.p. 119—120 °C. H NMR, δ: 1.40—1.83 (m, 6 H,
cycloꢀC ); 1.85—2.16 (m, 4 H, cycloꢀC ); 3.38 (d, 2 H, CH ,
6
6
2
6
3
2
CF
4
4
J = 2.2 Hz); 6.78 (t, 1 H, PhCH=, J = 2.2 Hz); 7.00—7.48 (m,
118.3 (d, C(2), C H F , J
= 17.1 Hz); 125.9 (dd, C(6),
CF
6
3
2
7
H, Ph, C(5´)H, C(6´)H); 7.70—7.88 (m, 2 H, C(7´)H, C(8´)H).
C NMR, δ: 22.7 (C(3), C(5), cycloꢀC ); 25.3 (C(4), cycloꢀC );
C H F , J = 6.1 Hz, JCF = 3.3 Hz); 130.1 (C(8a)); 132.8 (dd,
6 3 2 CF
1
3
C(1), C H F , J = 6.1 Hz, JCF = 4.1 Hz); 134.7 (C(1)); 148.0
6
6
6
3
2
CF
3
5.8 (C(2), C(6), cycloꢀC ); 40.5 (C(1,3´)); 44.3 (C(2´)); 108.5
(C(4a)); 149.3 (dd, C(3), C H F , J = 248.5 Hz, JCF = 12.1 Hz);
6 3 2 CF
6
(
PhCH=); 111.4 (C(8´)); 120.1, 122.8, 123.1 (C(5´), C(6´),
C(7´)); 126.4, 127.8, 128.7 (Ph); 129.5 (C(8a´)); 135.8, 136.1
C(1), Ph; C(1´)); 148.7 (C(4a´)); 166.8 (C(3a´)). MS (ESI),
149.9 (dd, C(4), C H F , J = 248.8 Hz, JCF = 12.1 Hz);
6 3 2 CF
168.8 (C(3a)). MS (ESI), found: m/z 311.1344, calculated for
+
(
C H F N , [M + H] : m/z 311.1354.
19
16
2
2
+
found: m/z 315,1852, calculated for C H N , [M + H] : m/z
(1E)ꢀ1ꢀBenzylideneꢀ3,3,5ꢀtrimethylꢀ2,3ꢀdihydroꢀ1Hꢀpyrroꢀ
2
2
22
2
3
15.1856.
1´Z)ꢀ1´ꢀBenzylideneꢀ1´,2´ꢀdihydrospiro[cyclohexaneꢀ1,3´ꢀ
pyrrolo[1,2ꢀa]benzimidazole] (Zꢀ4d) was obtained from aldehyde
c and diamine 2a and isolated in 52% yield by chromatography
lo[1,2ꢀa]benzimidazole (Eꢀ4h) was obtained from aldehyde 1a
and diamine 2c and isolated in 62% yield by recrystallization
(
1
from hexane, m.p. 118—120 °C. H NMR, δ: 1.55 (s, 6 H, 2 Me);
4
1
2.72 (s, 3 H, Me); 3.39 (d, 2 H, CH , J = 2.1 Hz); 6.78 (t, 1 H,
2
4
3
on SiO (eluent hexane—THF, 10 : 1→5 : 1) as a dense liquid.
PhCH=, J = 2.1 Hz); 7.15 (br.d, 1 H, C(6)H, J = 7.3 Hz);
2
1
H NMR, δ: 1.40—1.83 (m, 6 H, cycloꢀC ); 1.85—2.18 (m, 4 H,
7.20—7.32 (m, 2 H, C(4), Ph; C(7)H); 7.35—7.48 (m, 4 H, Ph);
6
4
3
13
cycloꢀC ); 3.15 (d, 2 H, CH , J = 1.6 Hz); 5.77 (d, 1 H, C(8´)H,
7.60 (br.d, 1 H, C(8)H, J = 7.7 Hz). C NMR, δ: 17.2 (Me);
27.5 (2 Me); 36.6 (C(3)); 48.2 (C(2)); 108.6, 108.9 (C(8),
PhCH=); 122.7, 123.8 (C(6), C(7)); 126.4, 127.9, 128.6 (Ph),
129.4, 130.1 (C(5), C(8a)); 135.6, 136.1 (C(1), Ph; C(1)); 148.2
(C(4a)); 166.1 (C(3a)). MS (ESI), found: m/z 289.1698, calcuꢀ
6
2
3
J = 8.2 Hz); 6.16 (br.s, 1 H, PhCH=); 6.77—6.87 (m, 1 H,
C(7´)H); 7.09—7.18 (m, 1 H, C(6´)H); 7.14—7.40 (m, 5 H, Ph);
3
13
7
.71 (d, 1 H, C(5´)H, J = 8.0 Hz). C NMR, δ: 22.8 (C(3),
C(5), cycloꢀC ); 25.4 (C(4), cycloꢀC ); 35.0 (C(2), C(6), cycloꢀ
C ); 40.5 (C(1,3´)); 47.4 (C(2´)); 108.1 (PhCH=); 114.3 (C(8´));
6
6
+
lated for C H N , [M + H] : m/z 289.1699.
6
20 20
2
1
19.3, 121.8, 122.3 (C(5´), C(6´), C(7´)); 127.0, 128.0, 129.5
(1Z)ꢀ1ꢀBenzylideneꢀ3,3,5ꢀtrimethylꢀ2,3ꢀdihydroꢀ1Hꢀpyrroꢀ
lo[1,2ꢀa]benzimidazole (Zꢀ4h) was obtained from aldehyde 1a
and diamine 2c and isolated in 69% yield by recrystallization
(
(
Ph), 129.9 (C(8a´)); 133.8, 135.9 (C(1), Ph; C(1´)); 147.8
C(4a´)); 168.6 (C(3a´)). MS (ESI), found: m/z 315.1850, calcuꢀ
+
1
lated for C H N , [M + H] : m/z 315.1856.
from hexane, m.p. 129—132 °C. H NMR, δ: 1.62 (s, 6 H, 2 Me);
2
2
22
2
4
(
1Z)ꢀ1ꢀBenzylideneꢀ2,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]benzꢀ
2.68 (s, 3 H, Me); 3.15 (d, 2 H, CH , J = 1.6 Hz); 5.67 (d, 1 H,
2
3
imidazole (Zꢀ4e) was obtained from aldehyde 1d and diamine 2a
and isolated in 37% yield by recrystallization from hexane, m.p.
1
C(8)H, J = 8.2 Hz); 6.20 (br.s, 1 H, PhCH=); 6.71—6.81 (m, 1 H,
3
C(7)H); 6.98 (d, 1 H, C(6)H, J = 7.4 Hz); 7.19—7.26 (m, 2 H,
1
13
52—154 °C. H NMR, δ: 3.12—3.23 (m, 2 H, CH ); 3.29—3.41
Ph); 7.30—7.42 (m, 3 H, Ph). C NMR, δ: 17.1 (Me); 26.4
2
3
(
m, 2 H, CH ); 5.75 (d, 1 H, C(8)H, J = 8.1 Hz); 6.18 (br.s,
(2 Me); 36.7 (C(3)); 51.5 (C(2)); 108.3 (PhCH=); 112.0 (C(8));
121.7, 123.1 (C(6), C(7)); 127.1, 128.2, 129.6 (Ph); 129.2, 130.0
(C(5), C(8a)); 133.7, 136.0 (C(1), Ph; C(1)); 147.1 (C(4a));
168.0 (C(3a)). MS (ESI), found: m/z 289.1696, calculated for
2
1
H, Ph CH=); 6.78—6.88 (m, 1 H, C(7)H); 7.09—7.19 (m, 1 H,
C(6)H); 7.17—7.27 (m, 2 H, Ph); 7.26—7.39 (m, 3 H, Ph); 7.65
3
13
(
(
d, 1 H, C(5)H, J = 8.1 Hz). C NMR, δ: 23.1 (C(3)); 34.7
C(2)); 107.6 (PhCH=); 114.4 (C(8)); 119.2, 121.9, 122.5 (C(5),
+
C H N , [M + H] : m/z 289.1699.
2
0
20
2
C(6), C(7)); 127.2, 128.2, 129.7 (Ph); 130.5(C(8a)); 135.0, 136.0
C(1), Ph; C(1)); 148.4 (C(4a)); 163.0 (C(3a)). MS (ESI), found:
(1Z)ꢀ1ꢀBenzylideneꢀ3,3,7ꢀtrimethylꢀ2,3ꢀdihydroꢀ1Hꢀpyrroꢀ
(
lo[1,2ꢀa]benzimidazole (Zꢀ4i) and (1Z)ꢀ1ꢀbenzylideneꢀ3,3,6ꢀtriꢀ
methylꢀ2,3ꢀdihydroꢀ1Hꢀpyrrolo[1,2ꢀa]benzimidazole (Zꢀ4j) were
obtained as a mixture (the ratio 1.1 : 1) from aldehyde 1a and
diamine 2c in 78% total yield, isolated by chromatography on
+
m/z 247.1231, calculated for C H N , [M + H] : m/z 247.1230.
17
14
2
(
1Z)ꢀ1ꢀ(3,4ꢀDifluorobenzylidene)ꢀ2,3ꢀdihydroꢀ1Hꢀpyrroꢀ
lo[1,2ꢀa]benzimidazole (Zꢀ4f) was obtained from aldehyde 1e
and isolated in 32% yield by recrystallization from hexane, m.p.
SiO (eluent hexane—THF, 10 : 1) as a dense liquid, and charꢀ
acterized without separation. Compound Zꢀ4i. H NMR, δ: 1.56
2
1
1
1
26—128 °C. H NMR, δ: 3.12—3.24 (m, 2 H, CH ); 3.28—3.40
2
3
(
m, 2 H, CH ); 5.85 (d, 1 H, C(8)H, J = 8.2 Hz); 6.06 (br.s,
(s, 6 H, 2 Me); 2.06 (s, 3 H, Me); 3.10 (br.s, 2 H, CH ); 5.40
2
2
1
7
H, C H F CH=); 6.83—7.30 (m, 5 H, C(7)H, C(6)H, C H F );
.66 (d, 1 H, C(5)H, J = 8.1 Hz). C NMR, δ: 23.1 (C(3)); 34.9
(br.s, 1 H, C(8)H); 6.16 (br.s, 1 H, PhCH=); 6.96 (d, 1 H,
6
3
2
6
3 2
3
13
3
C(6)H, J = 8.2 Hz); 7.12—7.23 (m, 2 H, Ph); 7.25—7.41 (m, 3 H,
3
13
(
C(2)); 105.4 (C H F CH=); 113.9 (C(8)); 119.5, 122.3, 123.0
Ph); 7.53 (d, 1 H, C(5)H, J = 8.2 Hz). C NMR, δ: 21.3 (Me);
26.4 (2 Me); 36.3 (C(3)); 50.8 (C(2)); 108.0 (PhCH=); 114.7
(C(8)); 118.6, 123.6 (C(5), C(6)); 127.0, 128.0, 129.8 (Ph); 128.3,
131.5 (C(7), C(8a)); 133.9, 136.1 (C(1), Ph; C(1)); 148.2 (C(4a));
6
3 2
(
C(5), C(6), C(7)); 117.1 (d, C(5), C H F , J = 17.3 Hz);
6 3 2 CF
1
18.4 (d, C(2), C H F , J
= 17.1 Hz); 126.0 (dd, C(6),
CF
6
3
2
C H F , J = 5.7 Hz, JCF = 3.3 Hz); 130.3 (C(8a)); 132.9 (dd,
C(1), C H F , J = 6.1 Hz, JCF = 4.1 Hz); 135.9 (C(1)); 148.5
6
3
2
CF
1
168.8 (C(3a)). Compound Zꢀ4j. H NMR, δ: 1.56 (s, 6 H, 2 Me);
6
3
2
CF
(
1
1
C(4a)); 149.2 (dd, C(3), C H F , J = 248.5 Hz, JCF = 12.1 Hz);
2.36 (s, 3 H, Me); 3.10 (br.s, 2 H, CH ); 5.62 (d, 1 H, C(8)H,
6
3
2
CF
2
3
49.8 (dd, C(4), C H F , J = 248.8 Hz, JCF = 12.1 Hz);
J = 8.4 Hz); 6.13 (br.s, 1 H, PhCH=); 6.65 (d, 1 H, C(7)H,
6
3
2
CF
3
63.0 (C(3a)). MS (ESI), found: m/z 283.1042, calculated for
J = 8.2 Hz); 7.12—7.23 (m, 2 H, Ph); 7.25—7.41 (m, 3 H, Ph);
+
13
C H F N , [M + H] : m/z 283.1041.
7.46 (br.s, 1 H, C(5)H). C NMR, δ: 21.3 (Me); 26.3 (2 Me);
17
12
2
2

1
838
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Gvozdev et al.
3
1
6.4 (C(3)); 51.0 (C(2)); 108.0 (PhCH=); 113.8 (C(8)); 119.2,
23.2 (C(5), C(7)); 127.1, 128.1, 129.5 (Ph); 130.3, 132.2 (C(7),
12. X. Zhang, Y. Zhou, H. Wang, D. Guo, D. Ye, Y. Xu, H. Jiang,
H. Liu, Adv. Synth. Catal., 2011, 353, 1429.
C(8a)); 133.6, 135.9 (C(1), Ph; C(1)); 145.8 (C(4a)); 168.2 (C(3a)).
8Z)ꢀ8ꢀBenzylideneꢀ6,6ꢀdimethylꢀ7,8ꢀdihydroꢀ6Hꢀpyrroꢀ
13. K. N. Shavrin, V. D. Gvozdev, O. M. Nefedov, Russ. Chem.
Bull. (Int. Ed.), 2010, 59, 1451 [Izv. Akad. Nauk, Ser. Khim.,
2010, 1418].
14. K. N. Shavrin, V. D. Gvozdev, O. M. Nefedov, Mendeleev
Commun., 2013, 23, 140.
15. V. D. Gvozdev, K. N. Shavrin, O. M. Nefedov, Russ. Chem.
Bull. (Int. Ed.), 2013, 62, 2430 [Izv. Akad. Nauk, Ser. Khim.,
2013, 2430].
16. V. D. Gvozdev, K. N. Shavrin, O. M. Nefedov, Russ. Chem.
Bull. (Int. Ed.), 2014, 63, 409 [Izv. Akad. Nauk, Ser. Khim.,
2014, 409].
17. V. D. Gvozdev, K. N. Shavrin, M. P. Egorov, O. M. Nefeꢀ
dov, Mendeleev Commun., 2015, 25, 329.
18. B. C. Raju, N. D. Theja, J. A. Kumar, Synth. Commun.,
2009, 39, 175.
19. M. Patel, R. K. Saunthawal, A. K. Verma, Tetrahedron Lett.,
2014, 55, 1310.
(
lo[2´,1´:2,3]imidazo[4,5ꢀb]pyridine (Zꢀ8a) was obtained from
aldehyde 1a and diamine 2e and isolated in 56% yield by recrysꢀ
1
tallization from hexane, m.p. 134—136 °C. H NMR, δ: 1.58
4
(
s, 6 H, 2 Me); 3.12 (d, 2 H, CH , J = 1.7 Hz); 5.62 (dd, 1 H,
2
3
4
C(4)H, J = 8.2 Hz, J = 1.6 Hz); 6.23 (br.s, 1 H, PhCH=); 6.72
dd, 1 H, C(3)H, J = 8.2 Hz, J = 4.8 Hz); 7.12—7.23 (m, 2 H,
Ph); 7.27—7.38 (m, 3 H, Ph); 8.32 (dd, 1 H, C(2)H, J = 4.8 Hz,
J = 1.6 Hz). C NMR, δ: 26.4 (2 Me); 37.2 (C(3)); 49.8 (C(7));
3
3
(
3
4
13
1
1
1
2
2
09.1 (PhCH=); 117.2, 121.7 (C(3), C(4)); 123.5 (C(9a)); 127.5,
28.4, 129.6 (Ph); 134.1, 135.7 (C(1), Ph; C(8)); 144.2 (C(2));
59.8 (C(4a)); 170.7 (C(5a)). MS (ESI), found: m/z 276.1506,
+
98.1316, 314.1054, calculated for C H N , [M + H] : m/z
1
8
17
3
+
+
76.1495, [M + Na] : m/z 298.1315, [M + K] : m/z 314.1054.
8Z)ꢀ6,6ꢀDimethylꢀ8ꢀ(2ꢀthienylmethylidene)ꢀ7,8ꢀdihydroꢀ
Hꢀpyrrolo[2´,1´:2,3]imidazo[4,5ꢀb]pyridine (Zꢀ8b) was obꢀ
(
6
tained from aldehyde 1b and diamine 2e and isolated in 51%
yield by recrystallization from hexane, m.p. 124—126 °C.
20. A. K. Verma, M. Patel, M. Joshi, P. R. Likhar, R. K. Tiwari,
K. Parang, J. Org. Chem., 2014, 79, 172.
21. C. Kanazawa, M. Terada, Chem. Asian. J., 2009, 4, 1668.
22. T. K. Chaitanya, K.S. Prakash, R. Nagarajan, Tetrahedron,
2011, 67, 6934.
23. I. V. Alabugin, K Gilmore, M. Manoharan, J. Am. Chem.
Soc., 2011, 133, 12608.
24. A. D. Becke, Phys. Rev. A, 1988, 38, 3098.
25. C. T. Lee, W. T. Yang, R. G. Parr, Phys. Rev. B, 1988,
37, 785.
1
4
H NMR, δ: 1.58 (s, 6 H, 2 Me); 3.13 (d, 2 H, CH , J = 1.7 Hz);
2
3
4
6
.02 (dd, 1 H, C(4)H, J = 8.2 Hz, J = 1.4 Hz); 6.13 (br.s, 1 H,
ThiCH=); 6.77 (d, 1 H, thienyl, J = 3.5 Hz); 6.85 (dd, 1 H,
C(3)H, J= 8.2 Hz, J = 4.8 Hz); 7.03 (dd, 1 H, thienyl, J = 5.2 Hz,
J = 3.5 Hz); 7.35 (d, 1 H, thienyl, J = 5.2 Hz); 8.32 (dd, 1 H,
C(2)H, J = 4.8 Hz, J = 1.4 Hz). C NMR, δ: 26.5 (2 Me); 37.2
C(3)); 49.7 (C(7)); 101.0 (ThiCH=); 117.6, 121.9 (C(3), C(4));
23.7 (C(9a)); 126.1, 127.2, 128.5 (Thi); 136.7, 136.8 (C(1),
3
3
3
3
3
3
3
4
13
(
1
Thi; C(8)); 144.3 (C(2)); 159.9 (C(4a)); 170.9 (C(5a)). MS (ESI),
26. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Ada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin,
V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E.
Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Moroꢀ
kuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Danꢀ
nenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresꢀ
man, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, Reviꢀ
sion D.01, Gaussian Inc., Wallingford (CT), 2013.
found: m/z 282.1069, 304.0881, 320.0621, calculated for C H N S,
1
6
15
3
+
+
+
[
M + H] : m/z 282.1059, [M + Na] : m/z 304.0879, [M + K] :
m/z 320.0618.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 15ꢀ03ꢀ08195 A).
References
1
. V. D. Gvozdev, K. N. Shavrin, M. P. Egorov, O. M. Nefeꢀ
dov, Mendeleev Commun., 2016, 26, 3.
2
3
. A. J. Charlson, J. S. Harrington, Carbohydr. Res., 1975, 43, 383.
. D. H. H. Tsao, A. G. Sutherland, L. D. Jennings, Y. Li, T. S.
Rush, J. C. Alvarez, W. Ding, E. G. Dushin, R. G. Dushin,
S. A. Haney, C. H. Kenny, A. K. Malakian, R. Nilakantan,
L. Mosyak, Bioorg. Med. Chem., 2006, 14, 7953.
4
5
. H. Uchida, A. Asagarasu, T. Matsui, US Pat. 2013/0079306 A1.
. E. B. Skibo, US Pat. 6998413, 2006; Chem. Abstr., 2006, 133,
2
7. J. B. Foresman, A. Frisch, Exploring Chemistry with Elecꢀ
tronic Structure Methods, Gaussian Inc., Pittsburgh (PA),
1
2985.
. K. L. Tan, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.,
001, 123, 2685.
1
996.
8. J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev., 2005,
05, 2999.
9. K. M. Gericke, D. I. Chai, M. Lautens, Tetrahedron, 2008,
4, 6002.
0. R. Jana, J. A. Tunge, Org. Lett., 2009, 11, 971.
6
7
8
9
2
2
3
2
1
. A. S. Tsai, R. M. Wilson, H. Harada, R. G. Bergman, J. A.
Ellman, Chem. Comm., 2009, 3910.
. K. Liubchak, K. Nazarenko, A. Tolmachev, Tetrahedron,
6
2
012, 68, 2993.
. G. Bastug, C. Eviolitte, I. E. Marko, Org. Lett., 2012, 14, 3502.
1
1
0. Y. V. Tomilov, D. N. Platonov, A. E. Frumkin, D. L. Lipiꢀ
lin, R. F. Salikov, Tetrahedron Lett., 2010, 51, 5120.
1. S. M. Allin, W. R. Bowman, R. Karima, S. S. Rahman,
Tetrahedron Lett., 2006, 62, 4306.
Received March 28, 2016;
in revised form April 29, 2016