Facile one-pot assembly of imidazotriazolobenzodiazepines via indium(III)-catalyzed multicomponent reactions

Article abstract of DOI:10.1021/ol402045h

An operationally simple, one-pot multicomponent reaction has been developed for the assembly of 9H-benzo[f]imidazo[1,2-d][1,2,3]triazolo[1,5-a][1,4] diazepines adorned with three diversification points via an atom-economical transformation incorporating α-diketones, o-azidobenzaldehydes, propargylic amines, and ammonium acetate. This process involves tandem InCl ₃-catalyzed cyclocondensation and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions; optimization data, substrate scope, and mechanistic insights are discussed.

Full text of DOI:10.1021/ol402045h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Facile One-Pot Assembly
of Imidazotriazolobenzodiazepines via
Indium(III)-Catalyzed Multicomponent
Reactions
Huy H. Nguyen, Teresa A. Palazzo, and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States
mjkurth@ucdavis.edu
Received July 19, 2013
ABSTRACT
An operationally simple, one-pot multicomponent reaction has been developed for the assembly of 9H-benzo[f]imidazo[1,2-d][1,2,3]triazolo[1,5-
a][1,4]diazepines adorned with three diversification points via an atom-economical transformation incorporating R-diketones, o-azidobenzaldehydes,
propargylic amines, and ammonium acetate. This process involves tandem InCl3-catalyzed cyclocondensation and intramolecular azideÀalkyne
1,3-dipolar cycloaddition reactions; optimization data, substrate scope, and mechanistic insights are discussed.
Imidazoles, triazoles, and benzodiazepines are privi-
leged heterocyclic structures present in various natural
products and synthetic pharmaceuticals. The imidazole
scaffold is widely found in bioactive compounds posses-
sing anti-inflammatory, anticancer, anti-HIV, and antitu-
berculosis activities.1 1,2,3-Triazole-derived molecules are,
for example, reported to have antiprotozoal and antiviral
properties.2 The 1,4-benzodiazepine core is a ubiquitous
motif found in numerous psychoactive pharmaceutical
agents, for instance, diazepam (Valium).3a
Furthermore, fused-ring systems embodying benzodia-
zepine and imidazole and/or triazole substructures have
attracted considerable attention due to their highly potent
biological activities. Two of these pharmaceutically impor-
tant imidazobenzodiazepines are Bretazenil (1)3b and Mid-
azolam (2),3c which are currently used in the treatment of
anxiety, seizure, and insomnia(Figure1). Derived from the
triazolodiazepinone skeleton, the synthetic molecule 3 is
found to show good serine protease inhibition activity.4
Due to the pharmacological significance of the aforemen-
tioned cores, a number of synthetic methods have recently
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r
10.1021/ol402045h
XXXX American Chemical Society

Scheme 2. Our Synthetic Strategy toward Imidazo-
[1,2,3]triazolo[1,4]benzodiazepines
Figure 1. Pharmaceutical examples exploiting bioactive imidazole,
triazole, and benzodiazepine.
and ammonium acetate (Scheme 2). Indeed, there are
numerous procedures for the synthesis of imidazoles.6
Among these, we were especially interested in cyclocon-
densations of R-diketone, aldehyde, 1°-amine, and ammo-
nia reactants; conventionally catalyzed by a variety of
Brønsted/Lewis acids to promote imine formation and
subsequent heterocyclization.7 Our rationale is based on
the idea of assembling a highly substituted imidazole ring
from an R-diketone, an aldehyde substrate bearing azide
functional group, and a 1°-amine substrate bearing an al-
kyne functional group. We envisioned that the resulting
post-cyclocondensation system would preorganize the
azide and alkyne moieties for a subsequent thermally
driven intramolecular 1,3-dipolar cycloaddition.5a,8 The
result of this one-pot, tandem, multicomponent reaction
would be the tetracyclic core of 10 adorned with three di-
versification points (Scheme 2).9
Scheme 1. Previous Work on Imidazole/Triazole/Diazepine-
fused Skeletons
Initial investigations centered on the cyclocondensation
ofbenzil (7d; 1.1equiv), o-azidobenzaldehyde(8a; 1equiv),
propargylamine (9a; 1.1 equiv), and ammonium acetate
(1.1 equiv). Lewis acid screening began with molecular
iodine since it is known to be an efficient catalyst for
the rapid, one-pot formation of 1,2,4,5-tetra-substituted
imidazoles in excellent yields.7e Subjecting the starting
materials and a catalytic amount of I2 (15 mol %) to
stirring in MeOH at 80 °C in a sealed microwave vial for
24 h furnished the desired imidazotriazolobenzodiazepine
CuAAC = copper-catalyzed azideÀalkyne cycloaddition.
been developed for the construction of imidazole/triazole/
diazepine-fused skeletons. Martin5a,b and co-workers
reported an effective route to 1,2,3-triazole-fused 1,4-
benzodiazepines (4) via cascade reductive amination
and intramolecular Huisgen cycloaddition reactions5c
(Scheme 1). In addition, the atom economy, ease of diver-
sification, and operational simplicity of multicomponent
reactions (MCRs) have been extensively exploited to
provide ready accesses to these complex annulated ring
systems from simple building blocks. In that context, Van
der Eycken has reported an expedient post-Ugi intramo-
lecular heteroannulation approach for the synthesis of
imidazo[1,4]diazepin-7-ones, (5; Scheme 1)5d,e and Djuric
has demonstrated an interesting postmodification of the
van Leusen imidazole synthesis using an intramolecular
azideÀalkyne cycloaddition to construct 6, which incor-
porates imidazole, triazole, and diazepine rings in one
scaffold.5f
(6) (a) Bredereck, H.; Theilig, G. Chem. Ber. 1953, 86, 88–96. (b)
Japp, F. R.; Robinson, H. H. Ber. Dtsch. Chem. Ges. 1882, 15, 1268–70.
(c) Radziszewsky, B. Ber. Dtsch. Chem. Ges. 1882, 15, 1493–96. (d)
Debus, H. Justus Liebigs Ann. Chem. 1858, 107, 199–208. (e) Kunckell,
F. Ber. Dtsch. Chem. Ges. 1901, 34, 637–42. (f) van Leusen, A. M.;
Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153–59.
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2008, 49, 2216–20. (b) Sangshetti, J. N.; Kokare, N. D.; Kothrkara,
S. A.; Shinde, D. B. J. Chem. Sci. 2008, 120, 463–7. (c) Samai, S.; Nandi,
G. C.; Singh, P.; Singh, M. S. Tetrahedron 2009, 65, 10155–61. (d)
Sadeghi, B.; Mirjalili, B. B. F.; Hashemi, M. M. Tetrahedron Lett. 2008,
49, 2575–77. (e) Kidwai, M.; Mothsra, P.; Bansal, V.; Somvanshi, R. K.;
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Chem. 2008, 139, 31–33.
(8) For a review, see: (a) Majumdar, K. C.; Ray, K. Synthesis 2011,
23, 3767–83. For recent examples, see: (b) Arigela, R. K.; Mandadapu,
A. K.; Sharma, S. K.; Kumar, B.; Kundu, B. Org. Lett. 2012, 14, 1804–
07. (c) Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan, M. I. Bioorg.
Med. Chem. Lett. 2009, 19, 5241–45. (d) Akritopoulou-Zanze, I.;
Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 8439–41. (e) Oliva,
A. I.; Christmann, U.; Font, D.; Cuevas, F.; Ballester, P.; Buschmann,
H.; Torrens, A.; Yenes, S.; Pericas, M. A. Org. Lett. 2008, 10, 1617–19.
(9) For our group’s recent work in this area, see: (a) Conrad, W. E.;
Rodriguez, K. X.; Nguyen, H. H.; Fettinger, J. C.; Haddadin, M. J.;
Kurth, M. J. Org. Lett. 2012, 14, 3870–73. (b) Guggenheim, K. G.; Toru,
H.; Kurth, M. J. Org. Lett. 2012, 14, 3732–35.
Prompted by the synthetic interest and applications
of imidazole/triazole/diazepine-fused skeletons and en-
couraged by recently reported MCRs of these scaffolds,
we report herein a facile route to the novel imidazo-
[1,2,3]triazolo[1,4]benzodiazepines via the Lewis acid-
catalyzed multicomponent reaction of symmetrical
R-diketones, o-azidobenzaldehydes, propargylic amines,
B
Org. Lett., Vol. XX, No. XX, XXXX

loadings slightly decreased the yield (entries 13À15). MeOH
proved to be better than EtOH and MeCN (entries 16À17)
as solvent. Finally, the structure of 10d was unambiguously
established by X-ray crystallography (Table 1).11
Table 1. Optimization Data: Multicomponent Assembly of 10da
With these optimal conditions in hand, we set out to
explore a method for the preparation and diversification of
the R-diketone, aldehyde, and amine components. Indeed,
each component for this MCR can be accessed via simple
transformations. We utilized a variety of commercial sym-
metrical R-diketones: glyoxal (7a), 2,3-butanedione (7b,c),
and benzil derivatives (7d,e/kÀn: R1 = Ph; 7f: R1 =
o-ClC6H4; 7g: R1 = p-BrC6H4; 7h: R1 = p-MeOC6H4;
7i,j: R1 = p-MeC6H4). The requisite o-azidobenzaldehyde
and derivatives (8aÀd; Scheme 3a) were synthesized in
excellent yields (80À95%) by nucleophilic aromatic sub-
stitution on commercially available o-nitrobenzaldehyde
or o-fluorobenzaldehyde derivatives in HMPA (method
by Driver).12a The propargylamine component was ob-
tained from the corresponding propargyl halide in two
steps (Scheme 3b); e.g., SN2 displacement of bromide from
1-bromopent-2-yne by sodium azide in DMF yielded the
alkyl azide and subsequent in situ Staudinger reduction12b
delivered 9b.
entry Lewis acid (mol %) solvent temp (°C) time (h) yieldb (%)
1
I2 (15)
MeOH
toluene
DMF
80
80
24
24
48
72
72
24
72
72
48
72
72
48
48
72
48
48
48
45
2
I2 (15)
trace
trace
30
31c
0
3
I2 (15)
80
4
I2 (1 equiv)
I2 (1 equiv)
Cu(OAc)2 (20)
FeCl3 (10)
Zn(ClO4)2 (10)
Sc(OTf)3 (10)
CeCl3 (10)
InBr3 (10)
InCl3 (10)
InCl3 (5)
EtOH
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
MeCN
100
100
80
5
6
7
100
100
100
100
100
100
100
80
51
8
58
9
57
10
11
12
13
14
15
16
17
67
52
71
65
InCl3 (5)
51
InCl3 (20)
InCl3 (10)
InCl3 (10)
100
100
100
70
46
Scheme 3. Preparation of o-Azidobenzaldehyde 8 and Pent-2-
yn-1-amine 9b
25
a Optimal reaction condition: benzil (1.1 equiv), o-azidobenzaldehyde
(1 equiv), propargylamine (1.1 equiv), ammonium acetate (1.1 equiv),
InCl3 (10 mol %), MeOH (0.1 M), 100 °C in a sealed microwave vial.
b Isolated yields. c Additives: CuSO4 5H2O (10 mol %), sodium ascorbate
3
(20 mol %). Tf = trifluoromethanesulfonyl.
10d in 45% yield together with a small amount of a free-
azideÀalkyne-tethered intermediate as the main side pro-
duct (Table 1, entry 1). However, switching to toluene or
DMF as solvent under the same conditions failed to deliver
product (entries 2À3). Next, we reasoned that increased
catalyst loading as well as reaction temperature would
enhance the yield of 10d by increasing the rate of both the
cyclocondensation and cycloaddition steps. Interestingly,
the presence of one equivalent of I2 in EtOH/100 °C/72 h
reduced the yield of 10d (45 f 30%; entries 1 vs 4) even
when azideÀalkyne cycloaddition catalysts such as CuSO4
and sodium ascorbate were added (entry 5).10 On the basis
of these results, we examined a series of transition metal
Lewis acids [Cu(OAc)2, FeCl3, Zn(ClO4)2, Sc(OTf)3, CeCl3,
InCl3, InBr3] for their ability to activate 1,2-dicarbonyl
electrophiles (entries 6À12). While most of these Lewis
acids showed better efficacy than I2, the InCl3 reaction
proceeded best and afforded a significant improvement
in product yield (45 f 71%) (entry 12) with complete
conversion of the precycloaddition intermediate to 10d
(as monitored by LC/MS). Further screening established
the optimal catalyst loading as 10 mol %; lower or higher
Next, we examined the substrate scope of this MCR by
subjecting R-diketones 7aÀn, aldehydes 8aÀd, amines
9aÀc, and ammonium acetatetoour optimized conditions.
In all cases, these four components were successfully as-
sembled into the corresponding imidazotriazolobenzodia-
zepines 10aÀn (Scheme 4). The electronic effects of sub-
stituents on each component have a significant impact
on the product yields; that said, trends were not uniform.
For example, when R1 on 7 is phenyl (7d f 10d), the yield
is higher than when R1 is H (7a f 10a) or Me (7b f 10b).
Surprisingly, the presence of either e-donating or e-
withdrawing groups on R1 aryls (7fÀh f 10fÀh) generally
p-MeC6H4 (7i f 10i; 72%)]. Similarly, when R2 is an
e-donating substituent (dioxole; 8b f 10j), the yield is
slightly improved compared to an e-withdrawing substi-
tuent (R2 = CO2Me; 8c f 10e). That said, ester moieties in
10c/e/m were tolerated with no transamination detected.
suppressed the yield [except for the case of R1
=
(11) Compound 10d crystallized in the monoclinic space group P21/n
with a final R1 value of 3.40% for all reflections >2σ.
(12) (a) Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011,
133, 4702–5. (b) Roy, S.; Anoop, A.; Biradha, K.; Basak, A. Angew.
Chem., Int. Ed. 2011, 50, 8316–19.
(10) Iodine might have an adverse effect on the intramolecular
azideÀalkyne cycloaddition, as monitoring by LC/MS showed an un-
changed ratio between product 10d and its pre-cycloaddition
intermediate.
Org. Lett., Vol. XX, No. XX, XXXX
C

a lesser extent, the diketo reactants), it is conceivable that
R-diimine or R-ketoimine intermediates (Scheme 5b) may
compete with the formation of C. These added options might
explain the somewhat lower yield of glyoxal-derived 10a.
Scheme 4. Examples of Imidazotriazolobenzodiazepinesa
Scheme 5. Proposed Mechanism for the Formation of 10ba
a As judged by LC/MS, the formation of intermediate D is somewhat
accelerated under microwave irradiation compared to that under ther-
mal heating. However, the overall time required for the reaction is
comparable in both methods.
a Reaction condition: R-diketone (1.1 equiv), aldehyde (1 equiv),
amine (1.1 equiv), ammonium acetate (1.1 equiv), InCl3 (10 mol %),
MeOH (0.1 M), 60À100 °C in sealed microwave vials. Isolated yields.
b Reactions were performed at 80 °C. c Reaction performed at 60 °C.
In summary, we have developed a versatile MCR for the
synthesis of substituted imidazotriazolobenzodiazepines
that proceed by tandem InCl3-catalyzed cyclocondensa-
tion and intramolecular Huisgen 1,3-dipolar cycloaddition
reactions. This method incorporates two-step cascade
reactions in an operationally simple, one-pot procedure
that affords a highly atom-economical transformation
engaging four starting materials, allowing for easy diversi-
fication of the final products. This method accommo-
dates a wide scope of R-diketones, various substituted
o-azidobenzaldehydes, as well as modification of the pro-
pargylic amine and affords good functional group tolerance.
Employing internal alkynylamines (9b f 10kÀm;
9c f 10n) in place of propargylamine resulted in somewhat
lower yields (cf., 10e in 45% vs 10m in 38%), and the
increased formation of unidentified side products compli-
cated purification. With targets 10kÀn, lowering the reac-
tion temperature improved product yields (cf., 10k in 42%
at 80 °C vs 30% at 100 °C). Finally, we note that the
aryl halide moieties in 10f/g/l and the ester moieties in
10c/e/m set the stage for subsequent synthetic modifica-
tion; for example, SuzukiÀMiyaura cross-coupling13 or
BuchwaldÀHartwig aminations9a and amide coupling
reactions, respectively.
While a number of mechanisms can be envisioned for
thisindium(III)-catalyzed MCR, the sequencepresented in
Scheme 5a for formation of 10b is illustrative. Here, the
tandem process ensues by initial InCl3-catalyzed imine
formation (A f B) followed by nucleophilic addition of
propargylamine to the resulting imine (B f C). From
intermediate C, there are two feasible pathways to 10b with
the difference being the order in which the steps occur:
C f D f 10b proceeds with imidazole formation first,
while C f E f 10b proceeds with triazole formation first.
In the case of the less hindered dicarbonyl glyoxal (and, to
Acknowledgment. We thank the National Institutes of
Health (GM089153) for generous financial support of this
work and the National Science Foundation (CHE-080444)
for the Dual source X-ray diffractometer. We also thank
Professor Makhluf J. Haddadin (American University of
Beirut, Lebanon) for helpful discussions and Kelli M.
Farber (UC Davis; Kurth Group) for assistance in the
collection of HRMS data.
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR,
IR, HRMS, and mp) of all novel compounds; X-ray
crystal data for compound 10d. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Kudo, M.; Perseghini, G.; Fu, C. Angew. Chem., Int. Ed. 2006,
45, 1282–84.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX