Regioselective synthesis of 7,8-dihydroimidazo [5,1-c][1,2,4]triazine-3, 6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold

Article abstract of DOI:10.3762/bjoc.8.181

Dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives were prepared by successive N3- and N1-alkylation of hydantoins, followed by regioselective thionation and subsequent cyclization under mild conditions. In a final alkylation step a further substituent may be introduced. The synthetic strategy allows broad structural variation of this new drug-like heterobicyclic scaffold. In addition to extensive NMR and MS analyses, the structure of one derivative was confirmed by X-ray crystallography.

Full text of DOI:10.3762/bjoc.8.181

Regioselective synthesis of 7,8-dihydroimidazo
[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives:
A new drug-like heterocyclic scaffold
Nikolay T. Tzvetkov1, Harald Euler2 and Christa E. Müller*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1584–1593.
1PharmaCenter Bonn, Pharmaceutical Sciences Bonn (PSB),
University of Bonn, Pharmaceutical Institute, An der Immenburg 4,
53121 Bonn, Germany and 2University of Bonn, Steinmann-Institute
of Mineralogy, Poppelsdorfer Schloss, 53115 Bonn, Germany
doi:10.3762/bjoc.8.181
Received: 05 May 2012
Accepted: 16 August 2012
Published: 20 September 2012
Email:
Christa E. Müller* - christa.mueller@uni-bonn.de
This article is part of the Thematic Series "Synthetic probes for the study
of biological function".
* Corresponding author
Guest Editor: J. Aube
Keywords:
hydantoins; hydrazides; imidazotriazines; N-alkylation; regio- and
chemoselective reaction; thionation; X-ray structure
© 2012 Tzvetkov et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives were prepared by successive N3- and N1-alkylation of
hydantoins, followed by regioselective thionation and subsequent cyclization under mild conditions. In a final alkylation step a
further substituent may be introduced. The synthetic strategy allows broad structural variation of this new drug-like heterobicyclic
scaffold. In addition to extensive NMR and MS analyses, the structure of one derivative was confirmed by X-ray crystallography.
Introduction
Imidazotriazines represent an important class of condensed general structure 1 (Figure 1) have been developed as selective
heterobicycles that display a variety of significant biological ligands for γ-aminobutyric acid type A (GABAA) receptors and
activities, including anticancer [1], antimicrobial [2], anti- are therefore of benefit in the treatment and prevention of
inflammatory [3] and neuroprotective [4] properties. The adverse conditions of the central nervous system (CNS),
impressive array of biological effects of these compounds is including anxiety, convulsions and cognitive disorders [7].
associated with the 1,2,4-triazine ring as the core structural Novel fused 1,2,4-triazine-4(6H)-ones 2 showed selective cyto-
moiety, which also occurs in a number of natural products [5]. toxicity at micromolar concentrations against a wide range of
In addition, the 1,2,4-triazine scaffold has found application in cancer cells [1,8], while other derivatives of 2 exhibited anal-
pharmaceuticals and agrochemicals [6]. For example, some gesic [9], antibacterial, and antiviral activities [2]. Compounds
7-phenylimidazo-[1,2.b][1,2,4]triazine derivatives of the with the 1,2,3,4-tetrahydroimidazo[1,2-b][1,2,4]triazine frame-
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work 3 were reported to be potentially useful as interleukin-1 We have been interested in expanding the medicinal-chemical
(IL-1) and tumour necrosis factor (TNF) inhibitors for prophy- space of synthetic drug-like small molecules focusing on 6,5-
lactic and therapeutic treatment of chronic inflammatory heterobicyclic ring systems in order to increase the diversity of
diseases in which these cytokines are involved [3]. Recently, our proprietary compound library [13]. Criteria for selection of
specifically substituted imidazo[1,5-f][1,2,4]triazines (4) have the target structures include the potential for biological activity
been developed as polo-like kinase (PLK) inhibitors with poten- and bioavailability (peroral, and possibly central nervous
tial as anticancer therapeutics [10]. The 1,2,4-triazines 4 also system), structural novelty, synthetic accessibility, and the
exhibited inhibitory activities against glycogen synthase kinase possibility for broad structural variations. In particular, we
3 (GSK3β), and may therefore be developed for the treatment of planned to introduce sp3-hybridized carbon atoms, to avoid
haematological diseases, and inhibition of phosphodiesterase 10 completely flat aromatic structures that are prone to low solu-
(PDE10), which is potentially useful for the treatment of bility in water due to π-stacking effects.
neurodegenerative diseases, especially Parkinson’s disease [11].
We therefore identified the 1,2,4-triazine-containing scaffolds
The scaffolds 1–4 consist of a 1,2,4-triazine core, which arises IV and VIII as promising novel target structures (Scheme 1).
from the ring fusion of C4a–N8 (1, 3 and 4) or C8a–N5 atoms Depending on the starting material used, e.g., hydantoin I, or
(2), and differ in the arrangement of the substitution pattern of pyrazolidine-3,5-dione V, respectively, either 7,8-dihydro-
the imidazotriazine framework (Figure 1).
imidazo[5,1-c][1,2,4]triazine-3,6-diones IV (route A) or
6,8-dihydropyrazolo[5,1-c][1,2,4]triazine-3,7-dione derivatives
The structural variation of imidazo[1,2,4]triazine derivatives VIII (route B) should be accessible. In either case two nitrogen
poses a significant challenge, particularly if a broad variety of atoms, N7/N6 and N2, may be substituted with a variety of
substituents is to be introduced. Several synthetic strategies residues; e.g., alkylation of N2 (R5) in the very last step should
involving combinatorial and sequential approaches, in particu- allow an easy access to a library of compounds. Route B would
lar intramolecular cyclocondensation reactions of functional- proceed in four steps yielding product VIII starting from V,
ized 1,2,4-triazole and imidazole precursors, have been devel- which may be obtained from the corresponding malonyl dichlo-
oped [5,6,12].
ride and hydrazine derivatives.
Figure 1: Biologically active imidazo[1,2,4]triazine scaffolds 1–4.
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Scheme 1: Retrosynthetic approaches towards novel 7,8-dihydroimidazo-[5,1-c][1,2,4]-triazine-3,6-diones IV and
6,8-dihydropyrazolo[5,1-c][1,2,4]triazine-3,7-diones VIII.
In the present study we focussed on synthetic route A starting fully conducted N3-alkylation of hydantoins 5 and 6 with
from the commercially available hydantoins I, which would various alkyl halides are shown in Table 1.
allow very broad structural diversity by introducing a variety of
substituents and functionalities at different stages of the syn- Alkylation of the thermodynamically preferred N3-position was
thesis. As a first step ethyl (2,5-dioxoimidazolidin-1-yl)acetate achieved following a modified literature procedure, and the
derivative II is formed from hydantoins I. The condensation products could be obtained on a multigram scale [18]. In
reaction of II with hydrazine, followed by a regioselective general, 1.1 equivalents of the corresponding alkylation reagent
intramolecular heterocyclization, formally by dehydration, and potassium carbonate as a base in dry dimethylformamide
would afford the 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6- (DMF) were used. The best yield (92%) was achieved with
diones III. The success of this route, however, depends on two ethyl 2-bromopropionate and benzyl bromide as alkylating
factors: (i) the preferred regioselectivity of the successive reagents. Although this procedure led to the direct formation of
N-alkylation steps for the formation of II; and (ii) the regiose- the desired N3-substituted products, the regioselectivity
lective cyclization of 2,5-dioxoimidazolidines II to the desired depended on the substitution pattern of 6, due to the directing
product III, which is expected to be favoured in the case of effect of the methyl groups. Thus, traces of a N1-substituted
dimethylhydantoin derivatives (R1 = R2 = Me).
regioisomer were detected by LC/ESI-MS analysis in the
conversion of 5 to product 7 (N3/N1-alkylation ratio 15:1).
Direct N1,N3-dialkylation of 5, however, was not observed.
Alkylation with benzyl bromide was carried out in order to
Results and Discussion
Chemistry
Following the proposed strategy for the formation of 7,8-dihy- verify the N3-substitution yielding 11, which had already been
droimidazo[5,1-c][1,2,4]triazine-3,6-dione derivatives described in the literature [14]. 3-Benzyl-5,5-dimethylhydan-
possessing aryl (R4 = 3,4-dichlorobenzyl) and alkyl/alkynyl toin (11) was obtained in 92% isolated yield (see Section
(R5 = Me, propargyl) substituents at their nitrogen atoms 7 and Experimental in Supporting Information File 1), in comparison
2, respectively, we started from the differently substituted to 80% obtained by the literature procedure [14]. Compounds
hydantoins (R1 = R2 = H or Me) 5 and 6. N3- and subsequent 7–11 were isolated after chromatographic purification in good
N1-alkylation led to the N1,N3-dialkylated hydantoin deriva- to excellent yields and analyzed by NMR spectroscopy (1H and
tives 12–18. Alkylation reactions of hydantoins are well docu- 13C) and LC/ESI-MS. In addition, we obtained an X-ray crystal
mented in the literature [14-18]. Depending on the alkylation structure of 11 [18], which confirmed the alkylation at the
reagents and reaction conditions, either N1- or N3-substituted N3-position of 5,5-dimethylhydantoin (6). The subsequent
hydantoins are accessible [14-17]. The details of the success- N1-alkylation of 2,5-dioxoimidazolidines 7–10 to the corres-
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Table 1: Yields and reaction conditions for the N3-alkylation of hydantoin derivatives 5 and 6.
starting compound
R2–X (1.1 equiv)
conditions
product
yield (%)
89
1.1 equiv K2CO3
DMF, 85 °C, 42 h
5
7a
1.1 equiv K2CO3
DMF, 80 °C, 56 h
6
6
76
92
8a
1.1 equiv K2CO3
DMF, 85 °C, 90 h
9a
1.1 equiv K2CO3
DMF, 85 °C, 28 h
6
6
56
92
= POM-Cl
10
1.1 equiv K2CO3
DMF, 85 °C, 6 h
11b
aCompounds 7 [19], 8 [19,20], 9 [19] have been described in the literature without detailed analytical data. bAnalytical data for 11 [14] are in accor-
dance with literature data.
ponding N,N-disubstituted hydantoins 12–18 was performed 12–18 were isolated after chromatographic purification
with 1.0–1.2 equiv of the appropriate alkylating reagent by (Table 2).
using sodium hydride as a base in dry dimethylformamide
(DMF) (Table 2). However, under these conditions the forma- In order to demonstrate the tractability of the successive N1,N3-
tion of compounds 12–18 strongly depended on the nature of alkylation of hydantoin 6 we applied a three-step synthetic route
the alkylating reagent, and therefore varying yields of dialkyl- to obtain compound 19 [17]. N3-Unsubstituted, N1-substituted
ated products were obtained. The reactions of 9 and 10 with hydantoins were obtained by a three-step synthetic procedure by
3,4-dichlorobenzyl bromide and phenethyl bromide, respective- reaction of 6 with pivaloyloxymethyl chloride (POM-Cl) to
ly, led to the formation of 15, 16, and 18 in poor to moderate introduce a protecting group prior to N1-alkylation. Subse-
yields. The alkylation with benzyl bromide worked well not quently, the ester can easily be cleaved with lithium hydroxide
only with sodium hydride (method 1) but also in the presence of in a methanol/tetrahydrofuran mixture at room temperature to
potassium carbonate (method 2) as a base and gave rise to the afford 1-benzyl-5,5-dimethylimidazolidine-2,4-dione (19)
disubstituted derivatives 12–14 and 17 in good yields. Products (Scheme 2).
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Table 2: Yields and reaction conditions of N1-alkylation of N3-substituted hydantoins 7–10.
starting compound
R3–X (1.0–1.2 equiv)
conditions
product
yield (%)
1.2 equiv NaH
DMF, 85 °C, 66 ha
7
70
12
1.0 equiv NaH
DMF, 80 °C, 72 ha
8
9
80
13
(1) 1.2 equiv NaHa
DMF, 85 °C, 80 h
79a
60b
(2) 1.1 equiv K2CO3
DMF, 80 °C, 72 hb
14
1.2 equiv NaH
DMF, 85 °C, 120 ha
9
37
15
1.1 equiv NaH
DMF, 85 °C, 68 ha
9
18
16
1.2 equiv K2CO3
DMF, 85 °C, 72 hb
10
62
17
1.2 equiv K2CO3
DMF, 85 °C, 69 hb
10
28
18
aMethod 1. bMethod 2.
According to our retrosynthetic analysis (Scheme 1), cedure for the synthesis of differently substituted
and based on an efficient protocol for the regioselective 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6-diones 23–29
N-alkylation of hydantoins, we applied a four-step pro- (Scheme 3).
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Scheme 2: Synthesis of N3-unsubstituted, N1-substituted hydantoin 19 by using a protection strategy.
Scheme 3: Synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6-diones 23–29. Reagents and conditions: (i) P2S5, dioxane, reflux, 24 h; (ii)
hydrazine monohydrate (20 equiv), EtOH, reflux 5–10 h; (iii) MeI (for 26) or methyl methanesulfonate (for 27), NaH, DMF, r.t.; (iv) propargyl bromide
(80% in toluene), NaH, 85 °C, 48 h.
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The main challenge in the synthesis of 23–25 was the construc- of molecular sieves (4 Å) to the reaction medium greatly
tion of the 1,2,4-triazine ring. Direct reaction of 13–15 with improved the yields of condensed products 23–25.
hydrazine hydrate failed, and only the corresponding hydrazides The regioselective two-step cyclization of 14 yielding
were formed. Therefore, the C5 carbonyl group of 13–15 was imidazo[5,1-c][1,2,4]triazine-3,6-dione (24, pathway A) via an
regioselectively thionated with phosphorus pentasulfide in N5–C5 ring fusion is outlined in Scheme 4. Precursors 13 and
dioxane under reflux [21] (Scheme 4). The products were puri- 15 follow the same pathway A. A dehydrothionated intermedi-
fied chromatographically and the preferred regioselectivity (C5 ate (e.g., 30 in the preparation of 24) is formed. Obviously,
versus C2) was confirmed by NMR spectroscopy. The forma- N1–C2 cyclization (pathway B) via 31 is not favoured, and 32
tion of C2-thiocarbonyl by-products was not observed under is not formed starting from 21. The products 23–25 were puri-
these reaction conditions. The highly regioselective formation fied by column chromatography and obtained on a multigram
of thioketones 20–22 may be due to electronic effects and scale. Finally, the imidazotriazines were further functionalized
prevention of the formation of certain tautomers by the by an N-alkylation reaction using different alkylating reagents
C4-methyl groups in compounds 13–15 [22]. To investigate the under basic conditions (Scheme 3). Alkylation of 24 with
influence of the C4-methyl groups on the regioselective thiona- methyl iodide led to 26, whereas methyl methanesufonate was
tion reaction, we treated unsubstituted 5,5-dimethylhydantoin 6 used as an alkylating reagent for the methylation of 25 yielding
with phosphorus pentasulfide in dioxane for four hours. As 27. Reaction of 24 and 25 with propargyl bromide (80% in
reported in the literature, we observed only the preferred C4 toluene) under basic conditions at 85 °C yielded the
thiocarbonyl product while the thionation of 5-unsubstituted N-propargyl derivatives 28 and 29 (Scheme 3). The final prod-
hydantoin yields a mixture of 2- and 4-thionated products, indi- ucts 26–29 were purified by column chromatography followed
cating that the 5-dimethyl substitution was responsible for by preparative RP-HPLC, or by recrystallization; the pure prod-
regioselective thionation [21].
ucts were obtained in good yields.
The proposed intramolecular N1–C5 heterocondensation as a Structural analyses
key step to form the desired imidazo[5,1-c][1,2,4]triazine-3,6- Regioselectivity of the thionation reaction of the C5-carbonyl
diones 23–25 was accomplished by reaction of the thioxoimida- group was an essential precondition for a successful heterocon-
zolidines 20–22 with hydrazine hydrate [23-26]. Different reac- densation step yielding the desired imidazo[5,1-c][1,2,4]tri-
tion conditions were applied, e.g., variation of the solvent or the azine-3,6-dione derivatives 23–25. The structural assignment
amount of hydrazine monohydrate that was used. The highest of the precursors (2,5-dioxoimidazolidines 13–15 and their
yields of compounds 23–25 (almost 90% on average) were thiocarbonyl analogues 20–22) reported herein is based on
obtained when the condensation was performed in ethanol with their spectral data and, if necessary, supported by MMFF94
a large excess of hydrazine hydrate (20 equiv) under reflux for force field conformational analytical data [27]. The most impor-
the appropriate reaction time. We observed that the adding tant 13C NMR chemical shifts δ (ppm) are reported in Table 3.
Scheme 4: Proposed regioselective two-step cyclization pathway to form 24 from 14.
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Table 3: 13C NMR chemical shifts (determined at 125 MHz in DMSO-d6) before and after thionation: comparison of 13–15 and 20–22.
13C assignment 13
14
15
20
21
22
C2
C4
C5
154.6
154.5
61.8
154.6
61.9
154.1
70.9
153.9
70.8
154.0
70.8
62.2
175.9
175.7
175.6
209.2
208.5
208.4
In the case of C5-thionation, the 13C NMR signal for this mation File 1). The analysis of two HMBC spectra of 24 and 25
carbon atom is shifted from about 176 to 208–209 ppm. In showed key correlations between C8 and HC/HD as well as
addition, the C4 signal is shifted from ca. 62 to 71 ppm upon between C6 and HC/HD methylene protons. In the case of an
thionation.
alternative N1–C2 ring fusion (structure 32 in Scheme 4) such a
correlation between the carbonyl C5-function and the meth-
The structure determination of the condensed key products 24 ylene protons HC/HD would be not possible. The structure was
and 25 was carried out by heteronuclear correlation NMR additionally confirmed by X-ray analysis of 24 (Figure 3) [28].
(HSQC and HMBC) in combination with 1H and 13C NMR, and The molecules in the crystal are held together by one type of
additionally by LC/ESI-MS (m/z 287 [M + H]+/285 [M − H]− intermolecular hydrogen bond, located between O2 and the
for 24, 355 [M + H]+/353 [M − H]− for 25). Molecular model- hydrogen H1 of the N2, with a distance of d(O···H1–N2) =
ling was performed to calculate the respective geometries by 1.9437(2) Å, d(H1–N2) = 0.93(2) Å and an angle of
using the MMFF95 force field [27] assuming an N1–C5 ring
fusion during the intramolecular condensation reaction yielding
24 and 25 (Figure 2).
(O2–H1–N2) = 155(2)°.
Physicochemical properties
In order to assess the physicochemical properties of
The structural assignments of 24 and 25 were confirmed by imidazo[5,1-c][1,2,4]triazine-3,6-dione derivatives we deter-
HSQC and, most importantly, by HMBC (see Supporting Infor- mined water-solubility, log P, and pKa values for compound 25
Figure 2: Optimized structure (MMFF95) and key HMBC correlations of imidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-diones 24 and 25.
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Figure 3: ORTEP diagram of 24 showing the atomic numbering. The thermal ellipsoids are drawn at the 50% probability level.
as a representative of this new class of heterocyclic compounds. related heterobicyclic systems possessing different ring-
Water solubility at physiological pH of 7.4 was found to be members, ring sizes, and a variety of substituents.
47 µg/mL, which is a suitable range for perorally active drugs.
A pKa value of 10.0, and a logP value of 3 was determined.
Supporting Information
Thus, the molecule will be uncharged under physiological
conditions and the logP value is in a range which allows us to
Supporting Information File 1
predict oral bioavailability [29].
Assays for determination of physicochemical properties of
25, experimental details and copies of NMR (1D and 2D)
and LC/ESI-MS spectra of compounds 24 and 25.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-181-S1.pdf]
Conclusion
In conclusion, we have designed and synthesized novel fused
7,8-dihydroimidazo-[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione
derivatives, i.e., a novel class of small heterocyclic molecules
with drug-like properties, thereby expanding the druggable
chemical space. For this purpose, we have developed a
four-step convergent synthetic concept to access the
imidazo[5,1-c][1,2,4]triazine frameworks starting from the
commercially available 5,5-dimethylhydantoin 6. The reaction
sequence involves successive N-alkylations of the corres-
ponding hydantoin, followed by C5-thionation and an intramol-
ecular heterocondensation reaction with hydrazine hydrate as a
key step affording the imidazo[5,1-c][1,2,4]triazine-3,6-dione
derivatives 23–25 in a regioselective manner. The synthetic
procedure was optimized for all steps and can easily be carried
out on a multigram scale. The experimentally determined
physicochemical properties of prototypic compound 25 are in-
Acknowledgements
A. Reiner, S. Terhart-Krabbe, M. Schneider and H. Passgang
are gratefully acknowledged for skillful technical assistance.
Dr. G. Schnakenburg and C. Rödde, Department for X-ray
Single Crystal Structure Solution, Institute for Inorganic Chem-
istry, are acknowledged for collecting the dataset of compound
24. Dr. F. Pineda and Dr. M. Wiese are acknowledged for the
determination of physicochemical data of compound 25. We are
grateful to the German Federal Ministry of Education and
Research (BMBF) and UCB Pharma for financial support
(BIOPHARMA Neuroallianz project).
dicative of drug-like properties suitable for peroral application. Dedication
Alkylation in the final step allows the introduction of additional Dedicated to the late Dr. Frédéric Denonne, who inspired this
diversity and the preparation of compound libraries. The new work: to a great medicinal chemist, a fantastic colleague, and a
synthetic strategy should also allow for the preparation of other, wonderful person who died much too young.
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20.Curtin, L. M.; Dai, Y.; Davidsen, S. K.; Dellaria, J. F., Jr.;
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