Unprecedented rearrangement of 2-(2-aminoethyl)-1-aryl-3,4- dihydropyrazino[1,2-b]indazole-2-ium 6-oxides to 2,3-dihydro-1H-imidazo[1,2-b] indazoles

Article abstract of DOI:10.1021/jo902301x

(Chemical Equation Presented) Easily accessible 2-(2-aminoethyl)-1-aryl-3, 4-dihydropyrazino-[1,2-b]indazole-2-ium 6-oxides rearranged to 2,3-dihydro-1H-imidazo[1,2-b]indazoles under mild conditions. The rearrangement appeared to be general, tolerated a wide range of functional groups, and provided access to an as yet unexplored class of heterocycles. Herein we report the characterization of these heterocycles.

Full text of DOI:10.1021/jo902301x

pubs.acs.org/joc
SCHEME 1. Synthesis of Indazole Oxides1
Unprecedented Rearrangement of 2-(2-Aminoethyl)-
1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-
oxides to 2,3-Dihydro-1H-imidazo[1,2-b]indazoles
ꢀ ꢀꢁ
Jan Kocı, Allen G. Oliver, and Viktor Krchnak*
Department of Chemistry and Biochemistry, 251 Nieuwland
Science Center, University of Notre Dame, Notre Dame,
Indiana 46556
vkrchnak@nd.edu
agents with anti-inflammatory, anticancer,4-6 antimicro-
bial,7,8 antifungal,9,10 and cytotoxic11 activities.
Received October 28, 2009
Indazoles were found to be potent inhibitors of nitric oxide
synthetase,12-14 factor Xa,15 protein kinases,16,17 tubulin,18
reverse transcriptase,19 vascular endothelial growth factor
receptor,20 and TRPV1.21,22 Indazoles were active as male
contraceptives23,24 and 5-HT2C receptor agonists.25
A wide range of biological activities prompted us to extend
our indazole chemistry for traceless solid-phase synthesis of
pyrazino[1,2-b]indazoles26 and 2-(2-aminoethyl)-1-aryl-
3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides.27 Het-
erocycles were synthesized in a very efficient three-step
Easily accessible 2-(2-aminoethyl)-1-aryl-3,4-dihydropyrazino-
[1,2-b]indazole-2-ium 6-oxides rearranged to 2,3-dihy-
dro-1H-imidazo[1,2-b]indazoles under mild conditions.
The rearrangement appeared to be general, tolerated a
wide range of functional groups, and provided access to
an as yet unexplored class of heterocycles. Herein we
report the characterization of these heterocycles.
(7) Yakaiah, T.; Lingaiah, B. P. V.; Narsaiah, B.; Kumar, K. P.; Murthy,
U. S. N. Eur. J. Med. Chem. 2008, 43 (2), 341–347.
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Klinghofer, V.; Johnson, E. F.; Bouska, J.; Olson, A.; Marsh, K. C.; Stoll,
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In continuation of our search for novel and efficient routes
to pharmacologically relevant heterocyclic compounds we
discovered a process for tandem carbon-carbon followed by
nitrogen-nitrogen bond formation yielding indazole oxides
(Scheme 1) of excellent purity.1
Synthetic compounds comprising the indazole core have
recently become an increasingly frequent subject of biologi-
cal studies. A review article by Cerecetto and colleagues2
portrayed the diversity of biological activities exhibited by
indazoles: recent advances in the chemistry of indazoles were
reviewed by Schmidt and colleagues.3 Since then, numerous
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502 J. Org. Chem. 2010, 75, 502–505
Published on Web 12/15/2009
DOI: 10.1021/jo902301x
r
2009 American Chemical Society

ꢀ
Kocı et al.
JOCNote
procedure on solid phase under mild conditions with use of
commercially available building blocks: amines, 2-nitroben-
zenesulfonyl chlorides, and bromoketones.
SCHEME 2. Rearrangement of Indazoles 1a
Here, we report an unprecedented rearrangement of 2-(2-
aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-
ium 6-oxides to 2,3-dihydro-1H-imidazo[1,2-b]indazoles,
formally involving concomitant 5-membered ring-opening,
6- to 5-membered ring contraction, amide formation, and
deoxygenation. The rearrangement proceeded quantita-
tively under mild conditions and provided a route to a very
efficient synthesis of this class of thus far unexplored hetero-
cycles. 2,3-Dihydro-1H-imidazo[1,2-b]indazoles have not
been reported in the literature and we found only one report
related to our fused heterocycles that described the synthesis
of benzimidazoindazoles28 and oxazolo[3,2-b]indazoles.29
During the isolation of 2-(2-aminoethyl)-1-aryl-3,4-
dihydropyrazino[1,2-b]indazole-2-ium 6-oxides, prepared
following our recently published procedure,27 we observed
a quantitative rearrangement of the targeted compounds.
Indazole oxide derivative 1(1,1) (R1 = H, and R2 = Me,
refer to Table 2 for notation), prepared with 2-nitrobenze-
nesulfonyl chloride and 2-bromo-1-p-tolylethanone, was
purified on semipreparative HPLC, using aqueous ammo-
nium acetate buffer and acetonitrile. The purified compound
was isolated after solvent evaporation at elevated tempera-
ture (50 °C) and freeze-drying. The LCMS analysis of
supposedly purified compound revealed that the target
compound had transformed to a new product that exhibited
an identical mass spectrum. However, the retention time had
changed; the new compound was more hydrophobic. Its UV
spectrum was nearly identical with that of compound 1(1,1).
We isolated and fully characterized the unexpected product
by 1D and 2D NMR spectroscopy and high-resolution MS.
In addition, we were able to crystallize the product from
acetonitrile solution and its structure was determined by
a single-crystal X-ray diffraction study (figure in the Sup-
porting Information). The structure of the rearranged pro-
duct was 2,3-dihydro-1H-imidazo[1,2-b]indazole derivative
2(1,1) (Scheme 2).
aReagents and conditions: (i) 50% acetonitrile in 10 mM aqueous
ammonium acetate, 16 h, for temperature, cf, Table 2.
TABLE 1. The Effect of a Base on Conversion to the Rearranged
Product 2a
conversion (%)
entry
aq solution
10 mM NH4OAc
0.1% TFA
10 mM TFA, 10 mM NH4OAc
10 mM TEA, 10 mM HOAc
10 mM NaOAc
21 °C, 15 min 50 °C, 16 h
1
2
3
4
5
6
7
NT
NT
1
100
0
5
50
10
1
100
100
5
10 mM NH2OH HCl
3
entry 3 plus satd soln Na2CO3
1
100
aNote: The compound 1(1,1), ∼0.6 mg, was dissolved in 200 μL of
acetonitrile and 200 μL of aqueous solution was added.
solution containing 10 mM ammonium acetate was heated
to 50 °C for 16 h and a quantitative conversion to 2(1,1) was
observed (Table 1). A solution containing 0.1% TFA, typi-
cally used for HPLC purification, was completely stable
under identical conditions. The data indicated that solutions
at pH above 7 caused a quantitative conversion to 2(1,1).
Crude preparations of 1, obtained after TFA/DCM cleavage
from resin and evaporation of TFA and DCM, still con-
tained residual TFA. Therefore, for practical syntheses of 2,
pH of the solution was adjusted with a saturated solution of
sodium carbonate and exposed to elevated temperature.
To assess the scope and limitation of the rearrangement,
we prepared a set of compounds with building blocks con-
taining both electron-donating and electron-withdrawing
groups. The reaction conditions, temperature and time, for
individual compounds are listed in Table 2. The course of the
reaction and formation of the rearranged product was
monitored by both LC and 1H NMR. A few of the products,
2(2,3), 2(3,3), 2(2,5), and 2(3,5), eluted very close to their
corresponding precursors (Table 2) and monitoring of com-
This unexpected and very clean (and thus potentially very
useful from the preparative point of view) rearrangement
prompted a focused study of this transformation reaction.
The model experiments were carried out with indazole oxide
derivative 1(1,1).
Solutions of 1(1,1) in 50% aqueous acetonitrile were
subjected to seven reaction conditions and the conversion
of 1(1,1) to 2(1,1) was monitored by LCMS analysis. A
1
pletion of the rearrangement by LC was problematic. H
NMR spectra were collected to reliably determine comple-
tion of the reaction. 1H NMR spectra exhibited typical
signals for two methylene groups of the constituent aliphatic
chain (two triplets in the area 4.5-4.0 ppm) and a triplet at
8.5 assigned to the NH proton. The 13C NMR spectrum
revealed the typical CdO resonance at δ 164-166 ppm and it
was used as the indicator for the formation of the products.
All combinations of building blocks afforded the corre-
sponding rearranged products. The analytical data indicated
that the rates of the conversions were not significantly
influenced by the R1 substituent. The effect of the R2
substituent was more pronounced. The rearrangement was
complete to give compounds 2 with electron-donating
groups (R2 = 4-Me, 4-OMe) and 4-Cl (R1 = CF3, NO2) at
50 °C. To observe complete transformation of derivatives 2
with R2 = 4-Cl (R1 = H), 4-CN, the temperature was
(22) Perner, R. J.; DiDomenico, S.; Koenig, J. R.; Gomtsyan, A.;
Bayburt, E. K.; Schmidt, R. G.; Drizin, I.; Zheng, G. Z.; Turner, S. C.;
Jinkerson, T.; Brown, B. S.; Keddy, R. G.; Lukin, K.; McDonald, H. A.;
Honore, P.; Mikusa, J.; Marsh, K. C.; Wetter, J. M.; George, K. S.; Jarvis,
M. F.; Faltynek, C. R.; Lee, C. H. J. Med. Chem. 2007, 50 (15), 3651–3660.
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Georg, G. I. Biol. Reprod. 2008, 78 (6), 1127–1138.
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Hornbaker, K.; Heckert, L. L.; Ozturk, S. B.; Hadden, M. K.; Kinzy, T. G.;
Blagg, B. S. J.; Georg, G. I. Biol. Reprod. 2008, 78 (6), 1139–1152.
(25) Shimada, I.; Maeno, K.; Kazuta, K. I.; Kubota, H.; Kimizuka, T.;
Kimura, Y.; Hatanaka, K. I.; Naitou, Y.; Wanibuchi, F.; Sakamoto, S.;
Tsukamoto, S. I. Bioorg. Med. Chem. 2008, 16 (4), 1966–1982.
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(27) Koci, J.; Krchnak, V. J. Comb. Chem. 2009, In press.
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J. Org. Chem. Vol. 75, No. 2, 2010 503

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TABLE 2. The Effect of R1 and R2 on Formation of 2,3-Dihydro-1H-
SCHEME 3. Proposed Mechanism of 2,3-Dihydro-1H-imidazo-
[1,2-b]indazoles Formation
imidazo[1,2-b]indazoles 2a
Rt of
1a
Rt of purityb yield
entry
R1
R2
4-Me
T (°C)
2a
(%)
(%)
2(1,1)
2(1,2)
2(1,4)
2(1,5)
H
H
H
H
50
50
80
80
50
50
80
80
50
50
80
80
5.13
4.52
4.58
5.23
6.23
7.30
6.15
6.87
5.47
6.57
5.37
6.15
5.70
5.25
5.13
5.75
6.58
7.52
6.47
6.97
5.80
6.77
5.75
6.18
86
97
58
83
94
76
79
85
94
87
72
89
53
65
26
50
71
37
23
67
53
41
41
52
4-OMe
4-CN
c
-
2(2,2) 4-CF3 4-OMe
2(2,3) 4-CF3 4-Cl
2(2,4) 4-CF3 4-CN
c
2(2,5) 4-CF3
-
2(3,2) 4-NO2 4-OMe
2(3,3) 4-NO2 4-Cl
2(3,4) 4-NO2 4-CN
c
2(3,5) 4-NO2
-
aRetention time (min) on analytical C18 column (for conditions, cf.
the Supporting Information). bCalculated from UV response on LC
traces at 200-400 nm. cR2 = 3,5-diCl-4-NH2.
elevated to 80 °C. The LC results showed that, although the
products 2(1,1) and 2(1,5) were complete after 3.5 and 2 h,
respectively, the conversion of compounds 1(R1,3) was only
40% to 70% after 3 h, hence they were allowed to react
overnight.
Starting materials and products of compounds 2(2,5) and
2(3,5) eluted close to each other and 1H NMR spectra,
recorded after overnight reaction, confirmed quantitative
rearrangement. Analyses of LC traces and 1H NMR spectra
confirmed that the rearrangements were very clean. The only
minor impurities we detected were present in 1-7% with
respect to the products and gave MS spectra with ions of m/z
-15, which may supposedly belong to deoxygenated pro-
ducts formed during indazole cyclizations and subsequent
rearrangements.
We propose the following mechanistic explanation of the
rearrangement (Scheme 3). In neutral pH, the iminium 1
closed a five-membered ring and formed the imidazolidine
derivative 3.27 This rearrangement was triggered by an initial
formation of a carbon-oxygen bond by nucleophilic attack
at the quaternary carbon by water with concurrent ring
contraction and formation of imidazolidine 4. The forma-
tion of this new carbon-nitrogen bond was facilitated by the
presence of the N-oxide, responsible for electronic activation
of the electron-deficient nitrogen. Formation of N-hydroxy
derivative 4 was the critical step toward water elimination
that stabilized the intermediate structure by rearomatization
of the indazole core and formation of carboxamide 2.
An alternative reaction mechanism, suggested by one of
the reviewers, included formation of an intermediate 30,
followed by the water attack.
cleanly under mild conditions and tolerated a wide range
of substitution pattern on both aromatic rings. 2,3-Dihydro-
1H-imidazo[1,2-b]indazoles can be regarded as 2,3-substi-
tuted-2H-indazoles with an additional ring closed between
substituents at positions 2 and 3. Synthetic compounds
comprising indazole core have recently become an increas-
ingly frequent subject of biological studies: indazole deriva-
tives possessed significant potency in a wide range of diverse
biological targets.2
Experimental Section
2-(2-Aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-
2-ium 6-Oxides 1. Synthesis of 1 was carried out on solid phase
as described previously.27 After finishing the solid-phase synth-
esis, products were cleaved from the resin with 50% TFA/DCM
for 1 h. The TFA solution was collected. The resin was washed
with 50% TFA/DCM (3ꢀ) and combined extracts were evapo-
rated by a stream of nitrogen.
2,3-Dihydro-1H-imidazo[1,2-b]indazoles 2. After cleavage
from the resin, the crude oily residue, typically ∼100 mg, was
dissolved in 3 mL of acetonitrile then diluted with 3 mL of 10
mM aqueous ammonium acetate and the pH was adjusted to 8
by addition of a saturated solution of Na2CO3. The resulting
solution was heated to 50-80 °C for 16 h. Solvents were
evaporated under reduced pressure. The oily residue was dis-
solved in a minimum volume of acetonitrile and purified by
semipreparative reversed phase HPLC in a gradient formed
from acetonitrile and 10 mM aqueous ammonium acetate.
Products were collected after freeze-drying.
To confirm the essential role of the N-oxide, we prepared
the deoxygenated analogue of 1 using methanesulfonyl
chloride and triethylamine.30 After two days of heating in
ammonium acetate solution at 50 °C no change of the
deoxygenated material was observed.
N-(2-(2,3-Dihydro-1H-imidazo[1,2-b]indazol-1-yl)ethyl)-4-meth-
oxybenzamide 2(1,2). Yield (HPLC purified) 27.3 mg (65%). ESI-
MS m/z 337 [M þ H]þ. 1H NMR (500 MHz, DMSO-d6) δ 8.53 (t,
J = 5.6 Hz, 1 H), 7.75-7.81 (m, 2 H), 7.61 (d, J = 8.4 Hz, 1 H),
7.27 (d, J = 8.8 Hz, 1 H), 7.06 (ddd, J = 1.1, 6.6, 8.9 Hz, 1 H),
6.94-6.99 (m, 2 H), 6.72 (ddd, J = 0.9, 6.6, 8.5 Hz, 1 H), 4.38 (t,
J = 8.4 Hz, 2 H), 4.00 (t, J = 8.4 Hz, 2 H), 3.79 (s, 3 H), 3.52-3.59
(m, 4 H). 13C NMR (126 MHz, DMSO-d6) δ 166.0, 161.5, 152.5,
147.4, 128.9, 126.6, 125.6, 119.6, 117.1, 116.7, 113.4, 103.8, 55.3,
To conclude, we report an unprecedented formation of
2,3-dihydro-1H-imidazo[1,2-b]indazoles by rearrangement
formally involving 5-membered ring-opening, 6- to 5-mem-
bered ring contraction, amide formation, and deoxygena-
tion. In several examples, the rearrangements proceeded
(30) Morimoto, Y.; Kurihara, H.; Yokoe, C.; Kinoshita, T. Chem. Lett.
1998, 8, 829–830.
504 J. Org. Chem. Vol. 75, No. 2, 2010

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54.5, 49.4, 46.5, 37.7 HRMS (FAB) m/z calcd for C19H21N4O2
[M þ H]þ 337.1665, found 337.1666.
reaction mechanism. We appreciate the use of the NMR
facility at the University of Notre Dame.
Acknowledgment. The work was supported by the De-
partment of Chemistry and Biochemistry, University of
Notre Dame and the NIH (GM079576). We are grateful to
Prof. Marvin J. Miller for indispensible insight into the
Supporting Information Available: Spectroscopic and crys-
tallographic data and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 2, 2010 505