A one-pot-three-step route to triazolotriazepinoindazolones from oxazolino-2H-indazoles

Article abstract of DOI:10.1021/ol3015804

A one-pot-three-step method has been developed for the conversion of oxazolino-2H-indazoles into triazolotriazepinoindazolones with three points of diversity. Step one of this process involves a propargyl bromide-initiated ring opening of the oxazolino-2H-indazole (available by the Davis-Beirut reaction) to give an N¹-(propargyl)-N²-(2-bromoethyl)-disubstituted indazolone, which then undergoes -CH₂Br → -CH₂N ₃ displacement (step two) followed by an uncatalyzed intramolecular azide-alkyne 1,3-dipolar cycloaddition (step three) to form the target heterocycle. Employing 7-bromooxazolino-2H-indazole allows for further diversification through, for example, palladium-catalyzed coupling chemistry, as reported here.

Full text of DOI:10.1021/ol3015804

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3870–3873
A One-PotꢀThree-Step Route to
Triazolotriazepinoindazolones from
Oxazolino-2H-indazoles
Wayne E. Conrad,† Kevin X. Rodriguez,† Huy H. Nguyen,† James C. Fettinger,†
Makhluf J. Haddadin,*,‡ and Mark J. Kurth*,†
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States, and Department of Chemistry, American University of
Beirut, Beirut, Lebanon
haddadin@AUB.edu.lb; mjkurth@ucdavis.edu
Received June 7, 2012
ABSTRACT
A one-potꢀthree-step method has been developed for the conversion of oxazolino-2H-indazoles into triazolotriazepinoindazolones with three
points of diversity. Step one of this process involves a propargyl bromide-initiated ring opening of the oxazolino-2H-indazole (available by the
DavisꢀBeirut reaction) to give an N1-(propargyl)-N2-(2-bromoethyl)-disubstituted indazolone, which then undergoes ꢀCH2Br f ꢀCH2N3
displacement (step two) followed by an uncatalyzed intramolecular azideꢀalkyne 1,3-dipolar cycloaddition (step three) to form the target
heterocycle. Employing 7-bromooxazolino-2H-indazole allows for further diversification through, for example, palladium-catalyzed coupling
chemistry, as reported here.
The generation of libraries of structurally complex and
diverse small molecules for high-throughput screening
is a vitally important, integral part in the drug discovery
process.1 Two powerful methods for generating structural
complexity are cycloaddition reactions and one-potꢀ
multistep methods.2 Herein, we present a one-potꢀthree-step
transformation exploiting propargyl bromide-initiated
ring-opening and a subsequent intramolecular azideꢀalkyne
1,3-dipolar cycloaddition (IAAC),3 which converts oxazoli-
no-2H-indazoles into novel triazolotriazepinoindazolone
heterocycles wherein a 1,2,5-triazepine is fused to both an
indazolone and a triazole. In previous reports, we have shown
that oxazolino-2H-indazoles, available via the DavisꢀBeirut
reaction,4 can be converted into N2-substituted indazolones
by treatment with various nucleophiles5 or N1,N2-disubsti-
tuted indazolones by treatment with various electrophiles6
(Scheme 1). The chemistry reported here combines this
electrophilic indazole f indazolone reaction with an IAAC
to provide an efficient route to triazolotriazepinoindazolones
{e.g., 12,13-dihydro[1,2,3]triazolo-[10,50:5,6][1,2,5]triazepino-
[1,2-a]indazol-10(4H)-ones}. An interesting aspect of these
(4) (a) Avila, B.; Solano, D. M.; Haddadin, M. J.; Kurth, M. J. Org.
Lett. 2011, 13, 1060–63. (b) Solano, D. M.; Butler, J. D.; Haddadin,
M. J.; Kurth, M. J. J. Org. Synth. 2010, 87, 339–49. (c) Butler, J. D.;
Solano, D. M.; Robins, L. I.; Haddadin, M. J.; Kurth, M. J. J. Org.
Chem. 2008, 73, 234–40. (d) Mills, A. D.; Maloney, P.; Hassanein, E.;
Haddadin, M. J.; Kurth, M, J. J. Comb. Chem. 2007, 9, 171–77. (e) Mills,
A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J. J. Org. Chem. 2006,
71, 2687–89. (f) Kurth, M. J.; Olmstead, M. M.; Haddadin, M. J. J. Org.
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† University of California.
‡ American University of Beirut.
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r
10.1021/ol3015804
Published on Web 07/23/2012
2012 American Chemical Society

novel molecules is their fusion of two heterocycles, each
with well established biological activities. The indazolone
scaffold is found in molecules possessing analgesic, antian-
giogenic, anticancer, antihypertensive, anti-inflammatory,
and antitumor activities,7 and the 1,2,3-triazole scaffold is
known to express antiallergic, anticonvulsant, antifungal,
anti-HIV, antimicrobial, and antiviral activities.3a,8 Triaze-
pines, while less fully evaluated, are reported to have anti-
bacterial, antifungal, antioxidant, and immunosuppressive
activities.9
Figure 1, also revealed an intriguing biplanar conforma-
tion for the indazolone and triazole heterocycles.
Scheme 2. Proposed Pathway for the One-PotꢀThree-Step
Synthesis of Triazolotriazepinoindazolones
Scheme 1. Nucleophilic and Electrophilic Ring-Opening of
Oxazolino-2H-indazoles
To launch the current investigation into a propargyl
bromide initiated ring opening and subsequent intramole-
cular azideꢀalkyne 1,3-dipolar cycloaddition transforma-
tion, we first prepared the requisite indazolone from
oxazolino-2H-indazole (S)-1b by treating it with propargyl
bromide; N1-Alkylation to the oxazolo[3,2-b]indazol-5-
ium bromide followed by nucleophilic (Brꢀ) attack at C2
delivered 4 (Scheme 2). We speculated that, from 4, sub-
sequent bromide f azide conversion would position the
system for an uncatalyzed intramolecular azideꢀalkyne
cycloaddition to afford triazolotriazepinoindazolone 6.
In the event, addition of sodium azide to 4 in DMF at
80 °C converted bromide 4 to triazolotriazepinoindazol-
one 6 in 69% yield from 4. The structure of 6 was estab-
lished by X-ray crystallography, which, as illustrated in
Figure 1. X-ray crystal structure of triazolotriazepinoindazo-
lone 6.
This encouraging result prompted us to investigate
effecting (S)-1b f 6 as a one-potꢀthree-step transforma-
tion. We were indeed pleased to find that treating a 0.1 M
solution of (S)-1b with propargyl bromide (1.5 equiv) at
80 °C led smoothly to the disappearance (TLC)10 of (S)-1b
and formation of 4 (18 h). Atthis point, addition of sodium
azide (1.6 equiv) with continued heating at 80 °C for 16 h
caused a clean conversion of 4 to 6, most likely via the
intermediacy of 5. This one-potꢀthree-step protocol de-
livered 6 in 82% yield.
Withthis protocol in hand, we turned toan investigation
of the scope of this operationally simple, one-pot method
for the construction of triazolo-, triazepino-, and indazo-
lone-fused heterocyles. As outlined in Scheme 3, this one-
potꢀthree-step method accommodates both terminal and
internal alkynes. Regarding the latter, alkyl- as well as
electron-neutral and electron-rich internal aryl-substituted
propargyl bromide analogs all perform equally well.
Attempts at employing internal alkynes conjugated to
electron-poor aryl groups (p-CN, p-CF3) resulted in the
formation of a complicated reaction mixture.
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Libraries Small Molecule Repository (MLSMR) for
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Org. Lett., Vol. 14, No. 15, 2012
3871

Scheme 3. One-PotꢀThree-Step Synthesis of Variously Substi-
Scheme 4. Synthesis of Precursors of 7-Bromo-oxazolino[3,2-b]-
indazole 1d
tuted Triazolotriazepinoindazolones
Scheme 5. Synthesis and Palladium Cross-Coupling Reactions
of 6-Bromotriazolotriazepinoindazolone 17
2-pentyne delivered the targeted 7-bromotriazolotriazepi-
noindazolone 17 in 93% yield (Scheme 5). With the stage
thus set, the aryl bromide moiety of 17 was employed in
two demonstrative palladium cross-coupling reactions;
BuchwaldꢀHartwig amination11 of 17 with pyrrolidine
delivered 20 in 73% yield, and Suzuki cross-coupling12
with 3-methoxyphenylboronic acid gave 21 in 89%
yield. Importantly, the triazolotriazepinoindazolones
depicted in Schemes 3 and 5 have physical properties
high-throughput biological screening, we next set out to
diversify the output of this one-potꢀthree-step reaction by
using palladium cross-coupling reactions on the benzo
ring of the indazolone moiety. As outlined in Scheme 4,
this was achieved by first preparing 7-bromooxazolino-
[3,2-b]indazole 1d. Sandmeyer reaction of aniline 14
delivered aryl bromide 15, and subsequent benzylic
bromination using NBS and catalytic AIBN gave
4-bromo-1-(bromomethyl)-2-nitrobenzene (16). Applying
our standard one-pot DavisꢀBeirut reaction to this
dibromide along with (S)-2-amino-1-propanol gave
7-bromoindazole 1d in 60% yield.
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Employing 1d in a one-potꢀthree-step intramolecular
azideꢀalkyne cycloaddition reaction along with 1-bromo-
3872
Org. Lett., Vol. 14, No. 15, 2012

that are in accordance with Lipinski’s rule-of-five for
drug-likeness; for example, log P values range between
1.18 and 4.25.13
novel triazolotriazepinoindazolones as part of our commit-
ment to the NIH MLSMR.
Acknowledgment. We thank the National Science Foun-
dation (CHE-0910870) and the National Institutes of Health
(GM089153) for generous financial support of this work and
the National Science Foundation (Grant 0840444) for the
Dual source X-ray diffractometer. W.E.C. acknowledges the
United States Department of Education for a GAANN
fellowship. We also thank Ms. Kelli M. Farber in our
laboratory for assistance in the collection of HRMS data.
In summary, we have developed a methodology that
provides ready access to triazolotriazepinoindazolones from
oxazolino-2H-indazoles. The key steps in this one-potꢀ
three-step protocol are (i) propargyl bromide initiated ring
opening of the oxazolino-2H-indazole (available by the
DavisꢀBeirut reaction), (ii) ꢀCH2Br f ꢀCH2N3 displace-
ment, and (iii) uncatalyzed intramolecular azideꢀalkyne
1,3-dipolar cycloaddition. We have also shown that palla-
dium catalyzed cross-coupling reactions can be exploited to
further diversify these previously unreported heterocycles.
By exploiting this reactivity, we have synthesized a set of
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR, IR,
and HRMS) for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(13) (a) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Adv. Drug Delivery Rev. 1997, 23, 3–25. (b) Hann, M. M.; Oprea, T. I.
Curr. Opin. Chem. Biol. 2004, 8, 255–63.
The authors declare no competing financial interest.
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