Diversity Oriented Synthesis of Indoloazepinobenzimidazole and Benzimidazotriazolobenzodiazepine from N1-Alkyne-1,2-diamines

Article abstract of DOI:10.1002/chem.201502956

A one-pot protocol for the diversity oriented synthesis of two N-polyheterocycles indoloazepinobenzimidazole and benzimidazotriazolobenzodiazepine from a common N¹-alkyne-1,2-diamine building block is described. The approach involves sequential formation of benzimidazole through cyclocondensation and oxidation, which is followed by the formation of either an azepine ring (through alkyne activation and 6-endo-dig cyclization, 1,2-migration with ring expansion, and re-aromatization), or diazepine and triazole rings through 1,3-dipolar cycloaddition.

Full text of DOI:10.1002/chem.201502956

DOI: 10.1002/chem.201502956
Full Paper
&
Fused-Ring Systems
Diversity Oriented Synthesis of Indoloazepinobenzimidazole and
Benzimidazotriazolobenzodiazepine from N1-Alkyne-1,2-diamines
Ravi Kumar,[a, b] Rajesh K. Arigela,[a] Srinivas Samala,[a] and Bijoy Kundu*[a, b]
In memory of Richard Heck
Abstract: A one-pot protocol for the diversity oriented syn-
thesis of two N-polyheterocycles indoloazepinobenzimida-
zole and benzimidazotriazolobenzodiazepine from a com-
mon N1-alkyne-1,2-diamine building block is described. The
approach involves sequential formation of benzimidazole
through cyclocondensation and oxidation, which is followed
by the formation of either an azepine ring (through alkyne
activation and 6-endo-dig cyclization, 1,2-migration with ring
expansion, and re-aromatization), or diazepine and triazole
rings through 1,3-dipolar cycloaddition.
Introduction
indole derivatives 2 or with o-azidobenzaldehyde derivatives 8
may facilitate annulations through sequential generation of
rings (five-, six-, and seven-membered) to afford structurally di-
verse annulated N-polyheterocycles. The diamine would react
with the aldehyde to form a tethered benzimidazole[7] with
a pendant internal alkyne that can then undergo either intra-
molecular carbocyclization at the C-2/C-3 of the indole or 1,3-
dipolar cycloaddition with the ortho azide to afford annulated
N-polyheterocylic derivatives. Herein, we report catalyst-driven
diversity oriented synthesis of two annulated N-polyheterocy-
cles from N1-alkyne-1,2-diamine as a common building block in
a one-pot format.
The design of one-pot strategies involving domino reactions[1]
for rapid access to N-polyheterocycles with architectural and
molecular complexity remains a challenging task. The ubiqui-
tous presence of N-polyheterocycles in the vast majority of
drugs and natural products has led to their application as
chemical probes for drug discovery.[2] Among the range of
one-pot strategies reported for their synthesis, the use of
alkyne-based reactants as versatile building blocks that com-
bine both a nucleophile and an electrophile has been report-
ed.[3] In general, these alkyne-based building blocks are con-
densed with another readily available mono/bifunctional reac-
tant, thereby initiating the formation of multiple bonds
through a series of intramolecular ring closures to afford a di-
verse range of annulated structures. Examples of alkyne-based
reactants used extensively by us and others include: 2-alkynyl
benzaldehyde,[4] 2-alkynyl indole,[5] and alkynones/propargyl al-
cohols.[6] All of these compounds contain both nucleophilic
and electrophilic centers, thereby facilitating the formation of
multiple bonds without isolation of intermediates in an atom-
economic mode.
Results and Discussion
Our studies commenced with the synthesis of N1-alkyne-1,2-
phenyl diamine 1a, which was carried out by treating o-phe-
nylenediamine with (3-bromo-1-propynyl)benzene in K2CO3/
acetone for 24 h and resulted in the formation of N1-(3-phenyl-
prop-2-yn-1-yl)benzene-1,2-diamine (1a) in satisfactory yield
(not optimized). We then treated 1a with 3-formyl indole (2a)
in toluene at 110 8C in the presence of AuPPh3Cl and AgOTf
(10 mol%, each), which led to the formation of acyclic inter-
mediate 3aa in 82% isolated yield (Table 1, entry 1) without
formation of the annulated product.
In a continuation of this work, we then studied the ability of
N1-alkyne-1,2-diamine 1 to act as a new alkyne-based substrate
with multiple-bond-forming sites by allowing its condensation
with appropriate mono- or bifunctional reactants in a one-pot
format. We envisaged that condensing 1 with either 3-formyl
This prompted us to employ different gold catalysts that
would facilitate the cyclization of the internal alkyne and the
indole through intramolecular hydroarylation of 3aa. Gold
complexes along with silver salts and iodine have been well
documented to interact with the p-system of double/triple
bonds, thereby leading to their activation towards nucleophilic
attack.[8] Accordingly, we carried out the reaction employing
AuPPh3Cl and AgSbF6 (10 mol%, each) in toluene at 110 8C for
36 h, which resulted in the formation of annulated product
4aa in 48% isolated yield along with 3aa in 22% isolated
yield (Table 1, entry 2). Interestingly, formation of only a seven-
[a] R. Kumar, R. K. Arigela, S. Samala, Dr. B. Kundu
Medicinal and Process Chemistry Division
CSIR-Central Drug Research Institute, Lucknow, 226031 (India)
E-mail: bijoy_kundu@yahoo.com
[b] R. Kumar, Dr. B. Kundu
Academy of Scientific and Innovative Research
New Delhi, 110001 (India)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502956.
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thesized 22 compounds based on 4 by introducing diversity in
both reactants, and the products were obtained in moderate
to good yields (Table 2). Substituting R1 with electron-with-
drawing groups such as nitro and fluoro, produced 4ag and
4bf, respectively, in reduced yields. In contrast, the presence of
an electron-donating methyl substituent as R1 led to an im-
provement in the isolated yield of 4di. Notably, 4-substituted
(R1) diamines 1 produced the corresponding compound 4 as
single regioisomers (4ag, 4aj, 4bf, 4cf–cl, and 4dh–dl). Bulkier
R1 substituents such as Br (1k) and Cl (1l) enhanced the yield
and afforded 4ck, 4cl, 4dk, and 4dl in 69, 67, 80, and 74%
isolated yields, respectively. Replacing R2 in the aromatic ring
of the alkyne component with either electron-donating or elec-
tron-withdrawing groups did not have a significant effect on
the yield of the corresponding product 4.
Table 1. Optimization of the synthesis of dihydroindoloazepinobenzim-
idazole 4aa.[a]
Entry Catalyst (mol%)
Solvent
T [8C]/t [h]
Yield [%][b]
3aa
4aa
1
2
3
4
5
6
7
8
AgOTf/AuPPh3Cl (10)
AgSbF6/AuPPh3Cl (10)
AgSbF6/AuPPh3Cl (10)
AgSbF6/AuPPh3Cl (10)
AgSbF6/AuPPh3Cl (10)
AgSbF6/AuPPh3Cl (10)
AgSbF6/AuPPh3Cl (15)
AgSbF6/AuPPh3Cl (15)
toluene
toluene
DMF
110/12
110/36
110/36
110/36
110/36
130/36
130/24
130/36
130/24
130/24
130/24
130/24
130/24
130/24
130/24
130/24
130/24
130/24
82
22
66
22
15
13
–
–
48
15
trace
62
59
THF
xylene
xylene
xylene
DCE
78
8
43
9
AgSbF6/AuPPh3Cl (15) 1,4 dioxane
ca. 10 trace
10
11
12
13
14[c]
15[d]
16
17
18[e]
AgSbF6/AuPPh3Cl (15)
AgNO3/AuPPh3Cl (15)
Ag2CO3/AuPPh3Cl (15)
AgNTf2/ AuPPh3Cl (15)
AgSbF6 (15)
AuPPh3Cl (15)
AuCl3 (15)
AuPPh3NTf2 (15)
I2 (100)
DMA
n.r.
n.r.
n.r.
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
Table 2. Substrate scope of the reaction for the synthesis of indolobanza-
midazoazapine derivatives 4.[a]
trace
35
58
–
–
trace
n.r.
n.r.
n.r.
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), solvent (5 mL) under
N2. [b] Isolated yield. n.r.=no reaction. [c] Without AuPPh3Cl. [d] Without
AgSbF6. [e] Molecular iodine used as a catalyst.
membered ring annulated to the indole and benzamidazole
was observed; the formation of other regioisomers through 6-
exo-dig cyclization was not observed.
In an attempt to improve the yield of 4aa through complete
conversion of 3aa, we screened several solvents; however, no
significant gain in the yield was achieved (Table 1, entries 3–5).
Raising the temperature in xylene to 1308C also had minimal
effect on the yield of 4aa (entry 6). Finally, an increase in the
catalyst loading from 10 to 15 mol% led to complete conver-
sion and afforded 4aa in 78% isolated yield as the only prod-
uct (entry 7). Replacing xylene with other solvents such as 1,2-
dichloroethane (DCE), dioxane, or dimethylacetamide (DMA)
with 15 mol% catalyst loading had little effect (entries 8–10),
whereas employing other silver salts such as AgNO3, Ag2CO3,
or AgNTf2 either failed to promote the reaction or produced
3aa in trace amounts (entries 11–13). Carrying out reaction in
the presence of only silver or gold salts afforded 3aa as the
major product with either no or trace amounts of 4aa (en-
tries 14–17). In an attempt to replace the Au/Ag complex, in-
troduction of iodine failed to promote the reaction (entry 18).
Thus, use of 15 mol% each of AuPPh3Cl and AgSbF6 in xylene
at 1308C was found to be the optimal conditions for the one-
pot synthesis of indoloazepinobenzimidazole 4aa. Although
gold complexes may decompose at higher temperature, a prec-
edence exists for the employment of gold complexes at elevat-
ed temperatures.[9]
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), AuPPh3Cl (15 mol%),
AgSbF6 (15 mol%), xylene (5 mL), 1308C, 24–36 h, under N2.
With the optimized reaction conditions in hand, we then ex-
amined the scope and limitations of the methodology. We syn-
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Replacing the aromatic ring on the alkyne with a napthalene
resulted in the formation of 4ad, 4bd, and 4dd, albeit in di-
minished yields. However, the use of indole with no substitu-
ent (R3 =H) led to a smooth transformation without compro-
mising the yield of 4. Substituting R3 with benzyloxy and Br af-
forded 4 in marginally reduced yield. However, replacing R3
with a methoxy group in the aromatic ring of 2 led to an en-
hanced isolated yield of 4. Replacement of N-H indole in sub-
strate 2 with N-substituted indoles such as N-Me led to the
corresponding annulated product 4ea in 70% yield; however,
the use of N-Ac or N-Ts indoles either led to acyclic product
3 fa or failed to initiate the reaction (Table 2).
To understand the reaction mechanism, we carried out a con-
trol experiment in which intermediate 3aa was allowed to cy-
clize under the standard conditions. As expected, the cyclized
product 4aa was obtained in 80% isolated yield (Scheme 1).
Based on the above experimental observation and on previ-
ous reports,[10] we propose a plausible mechanism shown in
Figure 1. Initially, oxidative cyclocondensation between dia-
mine 1a and 3-formyl indole 2a affords indolobenzimidazole
(3aa) containing a pendent internal alkyne. The alkyne in 3aa
then undergoes activation following p-complexation with the
aid of a cationic gold species that is formed in situ from
AuPPh3Cl/AgSbF6 to afford intermediate I. The latter undergoes
intramolecular nucleophilic attack at C-3 of the indole to afford
the spirocyclic[10a–f] intermediate II through 6-endo-dig cycliza-
tion. This is then followed by 1,2-migration along with ring ex-
pansion to give intermediate III, which, after deprotonation,
produces intermediate IV. In the last step, intermediate IV un-
dergoes protodeauration and releases the final product 4aa
along with regeneration of the active gold catalyst.
Attempts to replace 3-formyl indole with pyrrole-2-carboxal-
dehyde failed to furnish the corresponding annulated product
5a (Table 2); instead, the intermediate corresponding to 3 was
isolated as the only product.
To further expand the utility of substrate 1, we then treated
it with o-azidobenzaldehyde (8a) in a one-pot format. Our in-
vestigation commenced by treating N1-alkyne-1,2-diamine 1a
with 8a in the presence of 10 mol% AuPPh3Cl and AgSbF6,
which failed to give the desired product (Table 3, entry 1). We
then turned our attention towards the use of iodine as a cata-
lyst. Gratifyingly the use of 10 mol% I2 in MeOH at 508C afford-
ed the desired product 9aa in 86% isolated yield in 2.0 h
(entry 2). Various solvents and loading of iodine were screened
(entries 3–20) and best conditions were found to involve
10 mol% iodine in MeOH at 508C for 2 h. With the optimized
conditions in hand, we next turned our attention to the scope
and limitations of the reaction.
Accordingly, five compounds (9aa–pc) based on 9 were syn-
thesized with high isolated yields (Table 4). Next, with a view
to establishing the generality of our methodology, N1-(prop-2-
yn-1-yl)benzene-1,2-diamine derivatives 10 were synthesized
Table 3. Optimization for the synthesis of benzimidazolotriazolobenzo-
diazepine 9aa.[a]
Scheme 1. Transformation of 3aa into 4aa under standard conditions.
Entry
Catalyst (10 mol%)
Solvent
T [8C]/t [h]
Yield [%][b]
1[c]
2
Au(PPh)3Cl/AgSbF6
CH2Cl2
MeOH
MeOH
MeOH
MeOH
EtOH
tBuOH
H2O
acetone
EtOAc
DMF
50/2.0
50/2.0
50/1.5
50/2.0
40/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
50/2.0
n.r.
86
68
79
47
82
58
trace
38
70
69
72
47
29
trace
55
62
n.r.
n.r.
n.r.
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
3
4[d]
5[e]
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
DMA
CHCl3
CH2Cl2
THF
DCE
MeCN
toluene
dioxane
DMSO
[a] Reaction conditions: 1a (0.5 mmol), 8a (0.5 mmol), I2 (10 mol%), sol-
vent (5 mL). [b] Isolated yield. n.r.=no reaction. [c] 10 mol% of each Au/
Ag salts was used. [d] 50 mol% of I2 was used. [e] Reaction performed at
408C.
Figure 1. Plausible mechanism for the formation of 4aa.
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Table 4. Substrate scope of the reaction with internal alkyne 1 for the
synthesis of benzimidazolotriazolobenzodiazepine derivatives 9.[a]
Table 5. Substrate scope of the reaction with terminal alkyne 10/11 for
the synthesis of benzimidazolotriazolobenzodiazepine derivatives 12/
13.[a]
[a] Reaction conditions: 1 (0.5 mmol), 8 (0.5 mmol), I2 (10 mol%), MeOH
(5 mL), 508C, 2 h.
as a variant of substrate 1 containing a terminal alkyne group,
and these were reacted with o-azidobenzaldehyde derivatives
8 under the optimized conditions. Gratifyingly, the desired
benzimidazolotriazolobenzodiazepine derivatives 12 were iso-
lated in moderate to good yields (Table 5).
Various functional groups were tolerated and substituents
with either an electron-donating or an electron-withdrawing
group afforded the corresponding product 12 with minimal
variation in yields. Substrates with an electron-donating sub-
stituent gave better yields than those with electron-withdraw-
ing substituents (Table 5). Monomethyl and dimethyl groups
on 10 were subjected to the reaction conditions and afforded
12ha–ic in 70–87% isolated yield. However, use of a substrate
with a 4-methyl substituent gave regioisomers 12ia/12ia’ in
1:1 ratio and 12ic/12ic’ in 1.5:1 ratio (based on HPLC analysis).
An electron-withdrawing group on 10 such as a 4-chloro,
4-fluoro, or a 4-trifluoromethyl group led to the corresponding
product 12 in satisfactory isolated yields ranging from 67 to
80%. Replacing the arene ring in 10 with a pyridine ring (11)
resulted in the formation of 13aa and 13ab, with reduced
yield. The use of azido benzaldehyde 8 containing either elec-
tron-donating or electron-withdrawing groups gave similar
yields of 12 and 13.
[a] Reaction conditions: 10/11 (0.5 mmol), 8 (0.5 mmol), I2 (10 mol%),
MeOH (5 mL), 508C, 2 h.
A possible reaction mechanism is shown in Figure 2. Initially,
activation of the carbonyl group with the aid of molecular
iodine results in the formation of intermediate A, which, upon
cyclocondensation with amine groups of 1 or 10, forms C. The
latter undergoes formal [3+2] cycloaddition to give the final
product 9 or 12 after aerial oxidation.
Conclusions
After successfully demonstrating the efficacy of 1, attempts
were made to diversify the reaction further by replacing the in-
ternal alkyne with N1-(prop-2-yn-1-yl)naphthalene-1,8-diamine
(14a). Its treatment with substituted 8 furnished 15aa and
15ad with good isolated yields (Table 5). Notably, in this case,
aerial oxidation did not occur and the dihydro compounds
were obtained.
We have demonstrated a one-pot cascade protocol for the
synthesis of highly substituted dihydroindoloazepinobenzim-
idazole and benzimidazotriazolobenzodiazepine from
a
common building block under different catalytic systems. The
strategy is expected to find applications in the synthesis of
biologically important motifs and further studies to synthesize
new molecules by utilizing this novel substrate are in progress.
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was added and the flask was placed in an oil bath that was pre-
heated at 1308C. AuPPh3Cl (15 mol%) and AgSbF6 (15 mol%) were
then added and the reaction was stirred for the given time under
a nitrogen environment. Upon completion of reaction (which was
monitored by TLC), the resulting mixture was cooled to RT, diluted
with water, and extracted with EtOAc (3”20 mL). The combined
organic layers were washed with brine and dried over Na2SO4. The
solvent was evaporated in vacuo and the remaining residue was
purified by column chromatography on silica gel (n-hexanes/
EtOAc, 5:1) to give the product.
General procedure for the synthesis of benzimidazotriazoloben-
zodiazepine derivatives 9: The appropriate N1-(3-phenylprop-2-
yn-1-yl)benzene-1,2-diamine (1.0 equiv) and 2-azidobenzaldehyde
8 (1.0 mmol) were added to MeOH (5.0 mL) in an oven-dried
round-bottomed flask equipped with a stir bar. Molecular iodine
(10 mol%) was added and the flask was transferred to an oil bath
that was preheated at 508C. Upon completion of reaction (which
was monitored by TLC), the resulting mixture was cooled to RT, di-
luted with water, and extracted with EtOAc (3”20 mL). The com-
bined organic layers were washed with brine and dried over
Na2SO4. The solvent was evaporated in vacuo and the remaining
residue was purified by column chromatography on silica gel
(n-hexanes/EtOAc) to give the product.
Figure 2. Plausible mechanism for the formation of 9 or 12/13.
Experimental Section
General information and methods
All reagents and solvents were purchased from commercial sources
and used without purification. NMR spectra were recorded with
Bruker/Ascend 400 spectrometers, at 400 MHz for 1H NMR and
100 MHz for 13C NMR. HRMS were obtained with an Agilent 6520/
QTOF-MS/MS by using the electrospray ionization (ESI) technique
and a time-of-flight (TOF) analyzer. Column chromatography was
performed by using silica gel (100–200 mesh) as the stationary
phase. All reactions were monitored by thin-layer chromatography
(TLC). The purity and characterization of these compounds were
further established base on HRMS (ESI) analysis with an Agilent
6520/QTOF-MS/MS mass spectrometer. Melting points were mea-
sured with a BESTO capillary melting-point apparatus and are un-
corrected. For further details, see the Supporting Information.
Acknowledgements
R.K. thanks the UGC, and R.K.A. and S.S. are thankful to the
CSIR, New Delhi, India for fellowships. The authors would like
to thank SAIF, CSIR-CDRI, India for providing NMR data. CDRI
communication number: 9077.
Synthesis
Keywords: CÀC activation
·
cycloaddition
·
fused-ring
General procedure for the preparation of N1-(3-phenylprop-2-
ynyl)benzene-1,2-diamine (1) and N1-(prop-2-ynyl)benzene-1,2-
diamine (10): Starting materials 1a–p and 10a–i/11 a and 14a
were prepared by treating the appropriate diamine (1.0 g,
1.0 equiv), K2CO3 (1.1 equiv), and substituted 3-bromo-1-phenylpro-
pyne (1.0 equiv) or propargyl bromide (1.0 equiv) in case of 10/11
and 14 and stirring for 24 h at 508C. After completion of reaction,
which was monitored by TLC, the solvent was evaporated in vacuo
and the resulting mixture was diluted with water and extracted
with EtOAc (3”20 mL). The combined organic layers were washed
with brine and dried over Na2SO4. The solvent was evaporated in
vacuo and the remaining residue was purified by column chroma-
tography on silica gel (n-hexanes/EtOAc, 5:1) to give the product.
Yields were not optimized.
systems · heterocycles · rearrangement
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General procedure for the synthesis of dihydroindolo[3’,2’:3,4]a-
zepino[1,2-a]benzimidazole derivatives 4: The appropriate
3-formyl indole 2 (0.5 mmol) was added to xylene (5.0 mL) in an
oven-dried round-bottomed flask equipped with a stir bar. Substi-
tuted N1-(3-phenylprop-2-yn-1-yl)benzene-1,2-diamine 1 (1.0 equiv)
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Received: July 28, 2015
Revised: September 14, 2015
Published online on November 3, 2015
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Chem. Eur. J. 2015, 21, 18828 – 18833
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