KO^tBu-promoted synthesis of multi-substituted 4-aminopyrimidines from benzonitriles and aliphatic amides

Abstract

Multi-substituted 4-aminopyrimidines have been prepared from commercially-available benzonitriles and aliphatic amides under transition-metal-free conditions. With KO^tBu as the only promoter, the desired pyrimidines were isolated in moderate to excellent yields.

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Pyrimidine and its derivatives are ubiquitous in natural products, functional materials, etc.¹ Various biological activities, including anticonvulsant,² antitumor,³ anticancer,⁴ antiflammatory⁵ and antimicrobial activities⁶ have been reported. Representative examples of pharmaceuticals containing a pyrimidine moiety as the core structure, i.e. trimethoprim,⁷ capecitabine⁸ and imatinib,⁹ are shown in Scheme 1.

Scheme 1 Selected examples of pharmaceuticals containing a pyrimidine core.

Considering the importance of pyrimidines, a variety of elegant approaches have been developed.¹⁰ Examples of transition metal catalyst-based procedures are gold-catalyzed cycloadditions of ynamides with two nitriles,¹¹ iron-catalyzed construction of 2-aminopyrimidines from alkynenitriles and cyanamides,¹² iridium-catalyzed multi-component synthesis of pyrimidines from amidines and alcohols¹³ and niobium-catalyzed cycloaddition of alkynes and nitriles.¹⁴ Transition metal-free procedures have also been developed.¹⁵ Among these methodologies, the use of Tf₂O as a promoter to prepare pyrimidines from nitriles and methyl ketones has been established and applied. Here, we wish to report a new reaction pathway for the synthesis of pyrimidines from nitriles and amides. In our new procedure, KO^tBu has been applied as the promoter. Various 4-aminopyrimidines were isolated in moderate to excellent yields.

Initially, various inorganic bases were examined in 2 mL of DMAc with benzonitrile at 100 °C (Table 1, entries 1–7). To our delight, 68% of the target product was produced with KO^tBu as the base (Table 1, entry 1). The other tested bases, which included NaO^tBu, K₂CO₃, KOAc, K₃PO₄ and KOH, were ineffective here. No improvement in yield could be obtained when the amount of KO^tBu was lowered or increased (Table 1, entries 8 and 9). However, 84% of the desired product was isolated when the reaction was conducted at 110 °C (Table 1, entry 11).

Table 1 Optimization of conditions for the synthesis of N,N-dimethyl-2,6-diphenylpyrimidin-4-amine^a

Entry	Base (equiv.)	T (°C)	Yield^b (%)
a Reaction conditions: benzonitrile (3 equiv.), base, DMAc (2 mL), 16 h.b GC yield, with hexadecane used as the internal standard.c Isolated yield.
1	KO^tBu (2)	100	68
2	NaO^tBu (2)	100	0
3	K2CO3 (2)	100	0
4	K3PO4 (2)	100	0
5	KOH (2)	100	0
6	NaOMe (2)	100	5
7	KOAc (2)	100	0
8	KO^tBu (1)	100	27
9	KO^tBu (3)	100	60
10	KO^tBu (2)	80	19
11	KO^tBu (2)	110	86 (84)^c
12	KO^tBu (2)	120	73

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With the best reaction conditions in hand (Table 1, entry 11), we investigated the generality of this reaction. As shown in Table 2, electron-donating and electron-withdrawing substituents and even heterocyclic aromatic nitriles can be applied as the substrates in this new procedure. 71% of the desired pyrimidine (3ba) was produced from 4-methylbenzonitrile and DMAc. However, the yield decreased to 10% when the methyl group was substituted at the ortho position, which can be explained by steric hindrance. Ether and thioether groups can be well tolerated, and gave the corresponding pyrimidines in good to excellent yields (3da–3ga). Naphthonitriles were also tested under our conditions and gave the desired products in good yields (3ha–3ja). In the cases of halogen-substituted benzonitriles, the yields of the target pyrimidines decreased. This phenomenon can be explained by the nucleophilic substitution between the halogen groups and DMAc-decomposed N,N-dimethyl amine to give the corresponding N,N-dimethylaniline derivatives. To our delight, 90% of N,N-dimethyl-2,6-di(pyridin-3-yl)pyrimidin-4-amine (3ra) was isolated when nicotinonitrile was applied as the starting material. However, aliphatic nitriles failed here and no desired products could be obtained.

Table 2 Synthesis of pyrimidines from benzonitriles and DMAc^a

a Reaction conditions: 1 (3 equiv.), K^tOBu (2 equiv.), DMAc (2 mL), 110 °C, 16 h, isolated yield.

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Subsequently, various DMAc derivatives were examined with benzonitrile. As illustrated in Table 3, moderate to good yields were achieved in all cases. A limitation of this procedure is that no primary and secondary amides can be applied. Additionally, besides amides, acetone, acetophenone, 2-phenylacetophenone, 1-cyclopropylethan-1-one, DMSO, etc. were tested as well. Rather than the desired pyrimidines, enaminones were obtained as the main products (3ai). From a synthetic point of view, it’s interesting to prepare cross-cyclized pyrimidines. Hence, we applied 3-cyanopyridine (1.5 equiv.) and p-methylbenzonitrile (1.5 equiv.) as two different starting materials in DMAc under our best reaction conditions (Scheme 2). From the obtained results, we see that no selectivity could be achieved here.

Table 3 Synthesis of pyrimidines from DMAc derivatives^a

a Reaction conditions: 1 (3 equiv.), K^tOBu (2 equiv.), 2 (2 mL), 110 °C, 16 h, isolated yield.

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Scheme 2 Synthesis of different 2,6-substituted pyrimidines.

Interestingly, when quinoline-3-carbonitrile was tested as substrate under our conditions, only 2-(3-cyanoquinolin-2-yl)-N,N-dimethylacetamide was formed and isolated. After further optimization, the yield was improved to 90% with 3 equiv. of KOtBu. Instead of DMAc, N,N-diethylacetamide and 1-morpholinoethan-1-one are suitable solvent and substrates as well (Scheme 3).

Scheme 3 Direct functionalization of quinoline-3-carbonitrile.

Based on the obtained results, a possible reaction pathway is proposed (Scheme 4). In the presence of KO^tBu, the activated α-H of DMAc could be trapped and transformed into a carbon anion, I. Then, nucleophilic addition of the in situ-formed carbon anion to the nitrile group could take place and afford the intermediate enaminone, II. The amidine intermediate, III, could be formed after enaminone II reacts with another molecule of benzonitrile. The nitrogen anion in amidine intermediate III could then go through intramolecular nucleophilic addition to the carbonyl group to give the target molecule, through nucleophilic addition to the enol form of III.

Scheme 4 Proposed reaction mechanism.

Conclusions

In conclusion, we have presented a new pathway for the synthesis of pyrimidine derivatives. This procedure has advantages which include being highly economical, efficient and convenient. All the reactions were conducted in a one-pot, one-step manner, and without the addition of transition metal catalysts. The desired multi-substituted 4-aminopyrimidines were isolated in moderate to excellent yields from commercially-available benzonitriles and aliphatic amides, with KO^tBu as the only promoter.

Acknowledgements

The authors thank the state of Mecklenburg-Vorpommern, the Bundesministerium für Bildung und Forschung (BMBF) and the Deutsche Forschungsgemeinschaft for financial support. In addition, the research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (CHEM21) under grant agreement no. 115360, resources of which are composed of a financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies in kind contribution. We also thank Dr C. Fischer, S. Schareina, and Dr W. Baumann for their excellent technical and analytical support. We also appreciate the general support from Prof. Matthias Beller.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General procedure, analytic data and NMR spectra. See DOI: 10.1039/c5ra24292d

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