An efficient solution phase synthesis of triazadibenzoazulenones: 'designer isonitrile free' methodology enabled by microwaves

Article abstract of DOI:10.1016/j.tetlet.2009.02.099

A novel two-step solution phase protocol for the synthesis of arrays of triazadibenzoazulenones is reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables two tandem ring closing transformations. The ord

Full text of DOI:10.1016/j.tetlet.2009.02.099

Tetrahedron Letters 50 (2009) 1939–1942
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Tetrahedron Letters
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An efficient solution phase synthesis of triazadibenzoazulenones: ‘designer
isonitrile free’ methodology enabled by microwaves
a
a
b
a
Christopher Hulme a, , Shashi Chappeta , Chris Griffith , Yeon-Sun Lee , Justin Dietrich
*
a College of Pharmacy, Department of Pharm/Tox, Divisions of Medicinal Chemistry and Organic Chemistry, BIO5 Institute, United States
b Department of Chemistry, University of Arizona, Tucson, AZ 85721, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel two-step solution phase protocol for the synthesis of arrays of triazadibenzoazulenones is
reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment
enables two tandem ring closing transformations. The order of ring closure is shown to be key for optimal
conversion to the desired tetra-cyclic product and initially proceeds through a benzimidazole intermedi-
ate, followed by second ring closure to give the desired fused benzodiazepine. The two-step protocol is
further facilitated by microwave irradiation. Prudent selection of the isonitrile reagent enables the correct
order of ring forming events. As such the methodology represents the first example of a post-condensa-
tion Ugi modification that employs two internal amino nucleophiles.
Received 28 January 2009
Accepted 5 February 2009
Available online 20 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
With the development of high speed parallel synthesis and dra-
matic need for new molecular probes, the multi-component reac-
tion (MCR) has witnessed a resurgence of interest.1 In particular,
isonitrile-based MCRs have been at the forefront with highly sig-
nificant advances in library methodology development utilizing
both the Ugi2 and Passerini3 reactions as the initial diversity
assembling methodology. The first report from this laboratory
detailed a succinct two-step route to fully functionalized diketopi-
perazine libraries4 and further routes to several widely employed
scaffolds in the pharmaceutical sector were subsequently devel-
oped.5 Moreover, the methodology (coined UDC—Ugi/de-protect/
cyclize) has delivered several examples where initial hits have
progressed along the drug discovery value chain into clinical trials
for the treatment of both HIV infection6 and pre-term labor,7
importantly without the need to ‘scaffold hop’. In many ways these
vignettes are representative of the original ‘Holy Grail’ of combina-
torial chemistry—clinical candidates residing in the virtual space of
the initial hit generation library. Subsequently rigidifying the Ugi
skeleton with the arsenal of available organic methodology via
judicious placement of complementary reactive functionality,
several groups have produced scaffolds of impressive molecular
complexity.8 Herein, we report a novel solution phase synthesis
of tetra-cyclic triazadibenzoazulenones9 4 which represents the
first example of a post-condensation Ugi modification employing
two internal nucleophiles, Scheme 1.
sal isonitrile’ 310 and supporting aldehydes, followed by acid
treatment of 4 to unmask internal amino nucleophiles and to acti-
vate the isonitrile derived carbonyl to nucleophilic attack. A retro-
synthetic analysis describes the two tandem ring forming reac-
tions, Scheme 2. Note that precedents for both individual ring clo-
sures have been demonstrated in this laboratory.11 Thus, for
preliminary development work the solid odorless 4-phenyl-cyclo-
hexynl isonitrile 8 was selected for the role of convertible isoni-
trile, and was prepared in two steps.12 Condensation proceeded
in good yield 9 (80%) and treatment with acid resulted in forma-
tion of three products. Encouragingly, the desired triazadiben-
zoazulenone 12 was observed albeit in low yield (ꢀ10%) along
with the two monocyclic products 10 and 11. The carboxamide
11 is presumably formed when water released after benzimid-
azole formation, hydrolyzes the activated N-acyliminium ion
intermediate 13 (see Scheme 3).
In an attempt to elucidate the order of ring forming events that
result in 12, prolonged heating of 10 resulted in formation of its
trifluoroacetamide congener 14 with no other products observed.
This is consistent with earlier literature reporting extreme diffi-
culty in performing amino-cyclodehydrations onto benzylic ter-
tiary cyclic amides with a variety of acids.13 Prolonged heating of
11 under acidic conditions showed substantial conversion (>70%)
to the desired product 12. The combined results suggest that the
target molecule is derived from a sequential benzimidazole benzo-
diazepine ring forming sequence. Thus to avoid initial formation of
10, experiments were performed to attenuate the reactivity of the
isonitrile derived carbonyl, in such a way that would dramatically
slow formation of 10 relative to the benzimidazole 11. Moreover,
this required a strategy devoid of a designer isonitrile, in favor of
a cheap, sterically unencumbered readily available analog that
It was envisioned that the scaffold would be accessible in two
steps: an Ugi reaction utilizing mono-Boc protected phenylene
diamines 1, Boc-protected anthranilic acids 2, a designer ‘univer-
* Corresponding author. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.099

1940
C. Hulme et al. / Tetrahedron Letters 50 (2009) 1939–1942
R3
R3
CO2H
R1
N
N
+
MeOH
uwave
NH2
BocHN
H
R4 NC
R3
H
N
R1 CHO
R2
+
+
+
O
N
R4
R2
NHBoc
NHBoc
uwave
NH
R1
BocHN
O
O
4
5
3
2
1
R2
Scheme 1.
1. Benzimidazole formation
2. Benzodiazepine formation
Isonitrile Scan
2.
N
O
NH
NC
2 H
NC
NC
NC
N
O
H2N
N
R4
19
O
N
NH
O
17, 11%
18, 71%
17, 70%
18, 20%
17, 47%
18, n.d.
17, 53%
18, n.d.
1.
O
7
6
Scheme 2.
Figure 1. Isonitrile scan.
results in a condensation product containing a CONH moiety of
reduced electrophilic character. Thus the microwave facilitated
conditions,14 Scheme 4, were deployed for four readily available
isonitriles, Figure 1. Exposure of 15 to acid catalyzed dehydration
conditions enabled clean transformation (as judged by thin layer
chromatography) to benzimidazole 16 characterized by a typically
clear to red color change associated with increased conjugation.
The reaction mixtures were then subjected to further irradiation
for 10 min at elevated temperatures (130 °C) to afford desired
product 17 and the trifluoroacetylated benzimidazole 18. Recycling
the latter was straightforward with ammonia induced deacetyla-
tion and further TFA treatment improving yields of 17. Noticeably,
the ratio of 17 to 18 was dependent on the steric bulk of the isoni-
trile under investigation, Figure 1.
This is dramatically exemplified by the difference in isolated
yields of triazadibenzoazulenone between use of t-butyl isonitrile
(17, 11% yield) and n-butyl isonitrile 19 (17, 70% yield). The methyl
ester and benzyl isocyanide were also evaluated. Interestingly,
neither showed complete disappearance of the benzimidazole
under these conditions and isolated yields of 17 were thus signifi-
cantly lower. Yields of 18 were not determined for the latter two
examples. Satisfied with the selection of inexpensive n-butyl
isonitrile the double deprotection and tandem cyclization was
H2N
N
N
H
O
+
H
NH
O
- H2O
10% TFA, toluene, 120oC, 12 h
13
H2N
CO2H
CHO
N
N
N
O
+
10% TFA, DCE, rt, 6 hr
BocHN
MeOH, rt, 16h
H
N
N
N
NHBoc
NH2
+
NH2
+
NH
O
N
NH2
BocHN
O
N
O
O
+
O
H
NC
NHBoc
51% 10
30% 11
10% 12
80% 9
8
O
10% TFA, toluene, 120oC, 48 h
N
NHCOCF3
14
N
H
O
Scheme 3.
N
N
NH
N
10% TFA, DCE,
90 ºC, 5 min,
microwave
17
H2N
O
N
BocHN
H
N
10% TFA, DCE
130 ºC, 10 min,
microwave
(i) 2M NH3, MeOH
H
N
N
R
(ii) 10% TFA, DCE
N
O
N
R
O
130 ºC, 20 min, microwave
O
BocHN
O
CF3
N
H
H
N
15
16
R
O
18
Scheme 4.

C. Hulme et al. / Tetrahedron Letters 50 (2009) 1939–1942
1941
NH2
CHO
N
N
10% TFA, DCE,
130 ºC, 20 min
BocHN
100 ºC, 5 min, uwave
MeOH
H
N
NHBoc
O
N
NH
CO2H
BocHN
O
O
NC
NHBoc
15, 63%
17, 70%
Scheme 5.
O
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
NH
O
NH
O
O
O
O
O
48%, 23
64%, 22
70%, 17
70%, 19
61%, 20
22%, 21
O
N
N
N
N
F
N
N
N
N
N
Cl
N
N
N
N
NH
NH
NH
NH
NH
O
O
O
N
O
O
O
68%, 25
56%, 26
52%, 27
72%, 28
< 5%, 29
50%, 24
Figure 2.
evaluated in one step (130 °C, 20 min, microwave).15 Product dis-
tribution and yield was found to be essentially the same as heating
in two distinct operations, Scheme 5.
Representative scope of the protocol was then evaluated with a
selection of different reagents. Reactions with purified Ugi
products were assembled on a Biotage8 InitiatorÒ and run in a
sequential automated fashion. Products were then purified
sequentially with a Biotage IsoleraÒ system. Twelve examples
(17, 19 to 29 are shown) with isolated yields ranging from <5%
to 72%, Figure 2. The N-methylated anthranilic acid was noticeably
a poor performer, 29.
In summary, a concise two-step solution phase synthesis of
triazadibenzoazulenones has been reported. The methodology
has been shown to be amenable to high-throughput technologies,
and is expected to be embraced by the lead generation community.
The route also compares favorably to only one other reported six-
step solid phase synthesis of this scaffold.9 Significantly the meth-
odology represents the first example of two amino internal nucle-
ophiles being employed to constrain the Ugi product. The latter
cyclization may be viewed as the first post-UDC modification.
Control over the order of ring formation was required and in doing
so it became evident that with the advent of microwave irradiation
and 5 min reaction times, ‘designer convertible isonitriles’ are
potentially rendered partially obsolete for UDC-like methodolo-
gies. Current efforts to improve the methodology are on-going by
use of methyl isocyanide and investigations into alternate scaffolds
derived from similar approaches, will be reported in due course.
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Acknowledgement
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ented Synthesis group for support via a New Faculty Award to C.H.
References and notes
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(438 mg, 2.1 mmol), n-butylisonitrile dissolved in methanol (4 ml) (175 mg,
2.1 mmol), and 2-(tert-butoxycarbonylamino)benzoic acid (500 mg, 2.1 mmol).
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condensation product purified with a
Biotage IsoleraÒ to afford the Ugi
condensation product (755 mg, 63%) as a white solid. This product (100 mg,
0.17 mmol) was dissolved in a solution of 10% TFA in dichloroethane (2 ml),
and was irradiated in a 2.0–5.0 ml microwave vial for 20 min at 130 °C. The
solvent was evaporated in vacuo and crude material partitioned between
NaHCO3 (20 ml) and ethyl acetate (20 ml). Organic layer was washed with
brine (20 ml), dried (MgSO4), and pre-absorbed onto flash silica. Automated
purification afforded the desired triazadibenzoazulenone 17, in 70% yield
(41 mg, 1.41 mmol). Structural characterization: 1H NMR (300 MHz, DMSO-d6)
d 10.81 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.92 (m, 1H), 7.76 (m, 1H), 7.56 (t,
J = 7.5 Hz, 1H), 7.29–7.36 (m, 4H), 5.46 (t, J = 7.6 Hz, 1H), 1.46–1.54 (m, 1H),
1.67–1.75 (m, 1H), 0.92–1.00 (m, 1H), 1.08–1.20 (m, 1H), 0.68 (t, J = 7.2 Hz, 3H).
13C NMR (75 MHz, CDCl3) 168.9, 148.6, 142.2, 135.4, 135.3, 131.7, 129.8, 124.4,
123.0 (2 peaks overlapped), 121.1, 120.0, 118.9, 110.3, 59.6, 31.1, 18.5, 13.1.
Mass: MH+ 292; HRMS calculated 292.1444, observed 292.1446. Rf = 0.34
(ethyl acetate/hexane = 1:1).
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