An expedient route to imidazo[1,4]diazepin-7-ones via a post-Ugi gold-catalyzed heteroannulation

Article abstract of DOI:10.1021/ol400526a

A novel diversity-oriented post-Ugi/gold(I)-catalyzed heteroannulation process for the synthesis of imidazo[1,4]diazepin-7-ones is elaborated. The scope and limitations of the protocol are discussed.

Full text of DOI:10.1021/ol400526a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
An Expedient Route to
Imidazo[1,4]diazepin-7-ones via
A Post-Ugi Gold-Catalyzed
Heteroannulation
Amit Kumar,† Zhenghua Li,† Sunil K. Sharma,‡ Virinder S. Parmar,‡ and
Erik V. Van der Eycken*,†
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of
Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven,
Belgium, and Bioorganic Laboratory, Department of Chemistry, University of Delhi,
Delhi-110 007, India
erik.vandereycken@chem.kuleuven.be
Received February 25, 2013
ABSTRACT
A novel diversity-oriented post-Ugi/gold(I)-catalyzed heteroannulation process for the synthesis of imidazo[1,4]diazepin-7-ones is elaborated. The
scope and limitations of the protocol are discussed.
Homogeneous gold-catalyzed carbocyclization and het-
eroannulation strategies have become a particularly active
research area due to the exceptional ability of gold com-
plexes to activate alkynes, alkenes, and allenes toward
nucleophilic attack.1 The rediscovering of this coinage
metal in homogeneous catalysis allowed a significant
expansion of the current synthetic scenario for selective
manipulations of unactivated unsaturated hydrocarbons.
The gold-catalyzed intramolecular cyclizations of aro-
matic and heteroaromatic compounds with alkynes offer
new pathways for the efficient construction of bioactive
compounds.2,3
† University of Leuven (KU Leuven).
‡ University of Delhi.
€
(1) For selected reviews, see: (a) Furstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410. (b) Hashmi, A. S. K. Chem. Rev. 2007,
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107, 3180. (c) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008,
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Figure 1. Drugs possessing the imidazo[1,4]diazepin-7-one
skeleton.
€
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r
10.1021/ol400526a
XXXX American Chemical Society

The imidazodiazepinone core is ubiquitous in various
natural and synthetic pharmaceuticals4 as well as vital
intermediates in the synthesis of pentostanin5 and
coformycin,6 both naturally occurring anticancer and
antiviral nucleosides. The commercially available drug
bretazenil7 is used as a partial agonist for GABAA receptors
due to its high affinity to the benzodiazepinone binding site.
On the other hand, flumazenil8 is a high-affinity GABAA-BZ
site antagonist that has been used clinically to treat
benzodiazepine intoxication9 (Figure 1). Most synthetic
approaches toward imidazo[1,4]diazepinones involve multi-
ple-step sequences and harsh conditions and are limited in
scope of the substitution pattern of the scaffold.10 Conse-
quently, it would be highly desirable to develop a more
versatile and milder route for these compounds. Through
the years, multicomponent reactions (MCRs)11 have
received increasing attention due to their simplicity, effi-
ciency, atom economy, shortend reaction times, and the
possibilty for diversity-oriented synthesis. The combination
of MCRs with transition metal-catalysis gives access to
Table 1. Optimization of the Reaction Conditionsa
time conversionb
solvent (h) (%) (yield %)
entry
catalyst (mol %)
AuCl (10)
1
2
3
4
5
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
24
24
24
10
24
24
4
100 (80)
100 (72)
20
AuCl3(10)
Au(PPh3)Cl (10)
Au(PPh3)OTf (10)
Au(PPh3)SbF6(10)
100 (96)
60
6c Au(PPh3)BF4(10)
65
7
8
9
Au(PPh3)BF4(10)
Au(PPh3)NTf2(10)
Au(X-PhOS)NTf2(10)
100 (98)
100 (96)
100(92)
100 (90)
100(84)
0
24
12
24
24
24
24
24
6
10 [MeCN(JohnPhos)Au] SbF6 (10) CDCl3
11 AgBF4 (10)
CDCl3
CDCl3
CDCl3
CDCl3
ACN-d3
12 Cu(I)OTf (10)
13 Sc(III)(OTf)3 (10)
14 Bi(III)(OTf)3 (10)
15 Au(PPh3)BF4(10)
16 Au(PPh3)BF4(10)
17 Au(PPh3)BF4(5)
18
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100 (86)
90
THF-d8 24
CDCl3
CDCl3
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24
45
traces
a All reactions were run on a 0.13 mmol scale of 5a in a screw-capped
vial at 70 °C. b Conversion based on 1H NMR analysis; yields given in
parentheses are isolated yields. c Reaction at 50 °C. Tf = Trifluoro-
methanesulfonyl, X-Phos =2-dicyclohexylphosphino-204060-triisopro-
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multistep processes. We have recently developed a sequen-
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B
Org. Lett., Vol. XX, No. XX, XXXX

heteroannulation approach for the synthesis of imidazo-
diazepinones.
Ugi 4-CR11 of imidazole-4-carbaldehyde (1a), p-meth-
oxybenzylamine (2a), 2-butynoic acid (3a), and tert-butyl
isonitrile (4a) in methanol at rt furnishes the corresponding
Ugi adduct 5a in 84% yield. This compound was used to
check the feasibility of the intramolecular heteroannula-
tion. The application of 10 mol % of AuCl or AuCl3 as
catalyst produced imidazodiazepinone 6a in 100% con-
version with a yield of 80 and 72%, respectively, while only
20% conversion was observed with Au(PPh3)Cl (Table 1,
entries 1ꢀ3). The use of Au(PPh3)OTf (10 mol %) gave
100% conversion in 10 h with a yield of 96%, while only
60% conversion was observed with Au(PPh3)SbF6 after
24 h (Table 1, entries 4 and 5). Au(PPh3)BF4 (10 mol %) at
50 °C furnished 65% conversion, while heating at 70 °C
resulted in 100% conversion in just 4 h with a yield of
98% (Table 1, entry 6 and 7). Also Au(PPh3)NTf2, Au(X-
Phos)NTf2, and with Au(PPh3)Cl (Table 1, entries 1ꢀ3).
The use of Au(PPh3)OTf (10 mol %) gave 100% conver-
sionin10h with a yield of 96%, while only 60% conversion
was observed with Au(PPh3)SbF6 after 24 h (Table 1,
entries 4 and 5). Au(PPh3)BF4 (10 mol %) at 50 °C
furnished 65% conversion, while heating at 70 °C resulted
in 100% conversion in just 4 h witha yield of 98% (Table 1,
entry 6 and 7). Also Au(PPh3)NTf2, Au(X-Phos)NTf2,
and [MeCN(JohnPhos)Au]SbF6 gave 100% conversion
with excellent yields but with longer reaction times
(Table 1, entries 8ꢀ10). Although the reaction with the
comparitivily cheaper AgBF4 was found to be feasible,
a longer reaction time was required (Table 1, entry 11).
No amelioration was observed with CuOTf, Sc(OTf)3 or
Bi(OTf)3, (Table 1, entries 12ꢀ14). In the case of cationic
gold-catalysis, changing the solvent into ACN-d3 resulted
in a decreased yield, while in THF-d8 a lower conversion
was obtained (Table 1, entries 15 and 16). Diminishing
the catalyst loading to 5 mol % resulted in a decreased
conversion (Table 1, entry 17). No conversion was ob-
tained without catalyst (Table 1, entry 18).
Table 2. Scope of the Intramolecular Heteroannulation
Reactiona
yield (%)
imidazodi-
Ugi
azepinone
entry R1 R2
R3
PMB
R4
R5
adduct (5)
(6)
a
b
c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me t-Bu
Me Cy
84
82
75
73
62
54
57
63
47
71
70
50
97
63
63
34
85
55
98 (84)b
94 (65)b
90
PMB
PMB
PMB
PMB
Me n-Bu
Et t-Bu
Ph t-Bu
Me Cy
d
e
f
92
82c
Me PMB
79
g
h
i
H
H
piperonyl Me t-Bu
piperonyl Et t-Bu
89
93 (76)b
96 (68)b
86 (74)b
90 (81)b
96
Me piperonyl Me t-Bu
j
H
H
piperonyl Me Cy
k
l
3,4-DMB Me t-Bu
Me 3,4-DMB Me Cy
m
n
o
p
q
r
H
H
3,4-DMB Me Cy
3,4-DMB Et Cy
97
82
Me PMB
Me t-Bu
95
H
H
H
Bn
Me Cy
88
3,4-DMB
PMB
H
t-Bu
75
Me t-Bu
77
a All reactions were run on a 0.25 mmol scale of 5a with Au(PPh3)BF4
(10 mol %) and CHCl3 (2 mL) in a screw capped vial at 70 °C for 4 h.
b The reaction was carried using AgBF4 (10 mol %) at 70 °C for 24ꢀ30 h.
c Au(PPh3)BF4 (20 mol %) was used at 80 °C for 72 h. 3,4-DMB = 3,4-
dimethoxybenzyl.
Scheme 1. Plausible Mechanism for the Gold-Catalyzed
Heteroannulation
To evaluate the scope and limitations of our optimized
protocol (Table 1, entry 7), different Ugi adducts (5aꢀr)
were synthesized from imidazole-4-carbaldehyde (1a) and
subjected to the intramolecular heteroannulation reaction
(Table 2). Various substituents related to the alkyne, the
isonitrile, the imidazole, and the amine are tolerated giving
good to excellent yields. A bulky substituent like a phenyl
group on the alkyne consistently reduced the reaction rate,
increasing the temperature to 80 °C and the time to 72 h
with 20 mol % of catalyst loading, leading to an isolated
yield of 82% (Table 2, 6e). When the Ugi adduct contain-
ing a terminal alkyne was subjected to the optimized
conditions, the exclusive formation of the endo product
was observed in 75% isolated yield (Table 2, 6q).
On the basis of previous investigations of related
cyclizations,2,10ꢀ13 a plausible mechanism for this gold(I)-
catalyzed intramolecular heteroannulation reaction is
depicted in Scheme 1. The coordination of the metal with
the alkyne in the Ugi-adduct 5a generates intermediate A.
Nucleophilic attack of the imidazole on the activated
Org. Lett., Vol. XX, No. XX, XXXX
C

alkyne occurs in an endo-dig fashion generating a 7-mem-
bered ring intermediate B, which upon deprotonation and
protodeauration forms imidazodiazepinone 6a.
In summary, we have elaborated a novel diversity-
oriented approach for the synthesis of interesting imidazo-
[1,4]diazepin-7-ones starting from readily available build-
ing blocks. The first step, the Ugi-4CR, generates diversity,
while the second step, an efficient gold(I)-catalyzed hetero-
annulation, results in the formation of the imidazo[1,4]-
diazepin-7-one scaffold.
of the University of Leuven (KU Leuven) for financial
support. A.K. is thankful to EMA2experts (Erasmus Mun-
dus Action 2, Lot 11 Asia: Experts) for providing a doctoral
exchange scholarship, and Z.L. is thankful to the CSC
(China Scholarship Council) for providing a doctoral
scholarship.
Supporting Information Available. General experimen-
tal details and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the FWO [Fund for Scien-
tific Research - Flanders (Belgium)] and the Research Fund
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX