Zn-catalyzed hydrohydrazination of propargylamides with BocNHNH₂: a novel entry into the 1,2,4-triazine core

Abstract

Hydrohydrazination of a variety of propargylamides with BocNHNH₂ under Zn(OTf)₂ catalysis, unexpectedly, gave dihydro-1,2,4-triazines with a loss of the protecting group. The initial products can be efficiently aromatized in situ with K₃[Fe(CN)₆]. This provides a new entry into the medicinally important 1,2,4-triazine core.

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Recently, the Beller group reported a facile Zn-catalyzed hydroamination¹ of propargylamides 1 with primary amines 2 leading to high yields of di- and tri-substituted imidazoles 3.² Earlier, a similar reaction with phenylhydrazines 4 (hydrohydrazination³) had been shown to deliver 3-amidoindoles 5 via a domino alkyne-amination-Fischer-indole sequence of events.⁴ In our recent program aimed to identify new heterocyclic scaffolds for medicinal applications (particularly, as anti-infectives⁵) we sought to investigate if a similar hydrohydrazination of 1 with BocNHNH₂ (6), which is not capable of entering a Fischer-type reaction, would deliver N-(Boc)amino imidazoles 7 which would be valuable building blocks for library synthesis of potential antibacterials (Fig. 1).⁶ However, the reaction took an unexpected (and hitherto unprecedented) course, of which we report herein.

Fig. 1 Examples of Zn-catalyzed hydroamination (a) and hydrohydrazination (b) of propargylamides from the Beller group and the variant involving BocNHNH₂ (c) investigated in this work.

A trial reaction of propargyl benzamide 8a and BocNHNH₂ under Zn(OTf)₂ catalysis (25 mol%) demonstrated that the principal product of it was 2,5-dihydro-1,2,4-triazine 9a. While it was isolated by chromatography in modest yield and characterized (see ESI†), its apparent instability (particularly to air oxidation) prompted us to seek an appropriate oxidant to aromatize 9a and thus obtain stable 1,2,4-triazine 10a (the instability of 9a was seen as common to partially aromatized heterocycles; at the same time many 2,5-dihydro-1,2,4-triazines are commercially available⁷). Among the oxidants screened, K₃[Fe(CN)₆]⁸ gave the best isolated yield of 10a (Table 1) and was, therefore, selected for further assessment of the scope of the newly identified method to prepare 1,2,4-triazines.

Table 1 Screening of oxidants to convert 9a to 10a

Oxidant	Solvent (temperature)	Time (h)	Isolated yield (%)
O2	Toluene (110 °C)	8 h	11
MnO2	CH2Cl2 (r. t.)	12 h	32
DDQ	CH2Cl2 (r. t.)	12 h	42
K3[Fe(CN)6]	Benzene/aq. NaOH	12 h	77
KMnO4/SiO2	Acetonitrile (r. t.)	0.5 h	60
10% Pd/C	Benzene (reflux)	4 h	0

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In order to minimize the material losses potentially associated with the chemical instability of 2,5-dihydro-1,2,4-triazines, we tested the possibility of performing the oxidation in situ. This was successfully achieved by adding an alkaline aqueous solution of K₃[Fe(CN)₆] directly into the reaction mixture containing 9a. After stirring the biphasic reaction mixture overnight, an excellent yield of 80% was obtained, which presented a significant improvement of the total yield of 28.5% obtained with interim isolation of 9a (Scheme 1).

Scheme 1 Synthesis of model 1,2,4-triazine 10a with and without the interim isolation of 2,5-dihydro-1,2,4-triazine 9a.

It should be noted that besides the screening of oxidants, several reaction parameters were also altered for the synthesis of 9a (prior to its oxidation to 10a) in an attempt to see if there will be a further improvement of the overall yield. We tried to lower the temperature in the first step from reflux to 80 °C, which led to incomplete conversions even after 48 h. Solvent screening either at reflux temperatures or at 110 °C (benzene, acetonitrile, CH₂Cl₂, THF, DMF, methanol, xylenes) confirmed toluene was an optimal solvent for the synthesis. Interestingly, screening of other Lewis acids at 25 mol% (Cu(OTf)₂, LiOTf, Sc(OTf)₃, Gd(OTf)₃, Yb(OTf)₃, ZnCl₂) provided no conversion of 8a into 9a whatsoever under the same conditions as Zn(OTf)₂ was effective, thereby demonstrating the latter was a fortunate initial finding indeed.^2,4 Likewise, a control reaction performed in the absence of any catalyst demonstrated no conversion of 8a.

Mechanistically, the conversion of 8a into 9a (as well as of the other propargylamides into respective 2,5-dihydro-1,2,4-triazines, vide infra) was likely to proceed via the initial hydrohydrazination of propargyl portion of 8a. Further role of Zn(OTf)₂ (which turned out to be somewhat unique among other Lewis acids) could simply be in facilitating the removal of the Boc protecting group in 11. The resulting hydrazone (12) is likely to undergo cyclodehydration and deliver observed product 9a (Scheme 2). The importance of the Boc group is further substantiated by the fact that benzoic and acetic acid hydrazides did not furnish 2,5-dihydro-1,2,4-triazine products under the same conditions.

Scheme 2 Possible mechanistic pathway from 8a to 9a.

If intermediate 12 could indeed be involved in the formation of 9a, conversion of 8a into 9a should also be possible with unprotected hydrazine. We tested this idea using hydrazine hydrate as well as anhydrous hydrazine (obtained by distillation of the latter). While hydrazine hydrate delivered no product (most likely, due to catalyst hydration and de-activation), anhydrous hydrazine, to our delight, gave compound 9a. After in situ oxidation, compound 10a was isolated in 56% yield (Scheme 3). While this clearly argues for the above mechanistic vision, the yield obtained with Boc-protected hydrazine (6) was superior to that obtained using anhydrous hydrazine.

Scheme 3 Hydrohydrazination of 8a using unprotected hydrazine inputs.

The established protocol of one-pot hydrohydrazination–cyclodehydration–oxidation leading to 1,2,4-triazines was extended to a range of propargylamines (8b–q) prepared by CDI-promoted amidation of the respective carboxylic acids (Scheme 4). This reliably yielded respective 1,2,4-triazines 10b–q in moderate to good yields (Table 2, see ESI† for characterization data). Despite the moderate yields observed in some cases, the method disclosed herein represents a practically simple and attractive, complimentary alternative to the existing methods.⁹ Many of the compounds obtained in this work can be considered as suitable tools for fragment-based drug discovery (especially so, considering the presence of the methyl substituent as producing a suitable signal NMR signal to observe in ligand-based fragment screens).¹⁰ The medicinal importance of the 1,2,4-triazines related to 10a–q in such areas as anti-inflammatory,¹¹ metabolic¹² and neurological¹³ disease (mGluR5 antagonists) has been established. Additionally, 1,2,4-triazines found utility as synthons for cycloaddition reactions¹⁴ and ligands for fluorescent¹⁵ and luminescent¹⁶ transition metal complexes.

Scheme 4 General synthetic approach to 1,2,4-triazines 10a–q developed in this work.

Table 2 Compounds 10b–q prepared in this work^a,b

Compound	Structure	Isolated yield (%)
a Compound 10a is not included in the table as its synthesis has been described in preceding paragraphs related to the method development.b Conditions: Zn(OTf)2 (0.25 mol%), toluene, reflux, 4 h; then – aqueous K3[Fe(CN)6]/NaOH, 12 h.
10b		33
10c		37
10d		42
10e		58
10f		23
10g		61
10h		61
10i		47
10j		62
10k		32
10l		35
10m		37
10n		42
10o		29
10p		42
10q		42

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In summary, we have identified a practically simple, one-pot method to prepare 3,6-disubstituted 1,2,4-triazines via a Zn-catalyzed hydrohydrazination–cyclodehydration–oxidation sequence involving propargylamides and BocNHNH₂, in moderate to good yields. Studies involving other N-nucleophiles in lieu of BocNHNH₂ are currently underway in our laboratories and will be reported on in due course.

Acknowledgements

This research was supported by the Russian Scientific Fund (project grant 14-50-00069). We are grateful to the Center for Chemical Analysis and Materials Research of Saint-Petersburg State University for providing high-resolution mass-spectrometry data.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra12664b

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