Base-mediated synthesis of highly functionalized 2-aminonicotinonitriles from α-keto vinyl azides and α,α-dicyanoalkenes

Abstract

A novel access to highly functionalized 2-aminonicotinonitriles via efficient annulations of α-keto vinyl azides and α,α-dicyanoalkenes is described. This annulation was achieved via base-mediated ring-openings and intramolecular rearrangements. A possible mechanism is also proposed.

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As the most popular N-heterocycles, pyridine scaffolds play an important role in numerous areas of chemistry, biology and pharmaceuticals.¹ Among these, 2-aminonicotinonitrile derivatives attract much more attention over others because of their significant biological activities, such as anticancer,^2a anti-inflammatory,^2b and anti-prion disease,^2c as well as serving as A_2A adenosine receptor antagonists,^2d IKK-β inhibitors,^2e and HIV-1 integrase inhibitors.^2f Moreover, 2-aminonicotinonitriles possess a nucleophilic nature from the amino group and electrophilic nature from the cyano group. Because of their unique chemical reactivity, 2-aminonicotinonitriles could be used to construct other complex heterocycles.³ In light of the pyridine scaffold's importance, a great deal of attention has been given to its organic synthesis.⁴ The classical strategy to afford multifunctionalized 2-aminonicotinonitriles was through the Chichibabin reactions of ketones with an aryl aldehyde, malononitrile, and ammonium^5a (Scheme 1-A, eqn (1)) but with poor yields. During the previous decades, numerous methods have been reported,^5b–f including using microwave irradiation^5b or transition metal catalysts^5c,d (Scheme 1-A, eqn (2)). Other methods have also been reported,^5g–k such as reacting 2-(1-phenylethylidene)propanedinitriles with dimethyl N-cyanodithioiminocarbonate^5g (Scheme 1-A, eqn (3)) or modifying pyridine precursors directly^5h,i (Scheme 1-A, eqn (4)). However, the construction of complex 2-aminonicotinonitriles is still challenging. Therefore, an efficient and facile approach for the construction of highly functionalized 2-amino nicotinonitriles is in demand.

Scheme 1 The synthesis of 2-aminonicotinonitriles.

The vinyl azides are reported to be versatile three-atom synthons for the synthesis of diverse N-heterocycles.^6,7 α,α-Dicyanoalkenes bear specific functionalities that could be involved in a plurality of cascade reactions with Michael acceptors.⁸ The continued interest in the reactivity of vinyl azides motivates us to investigate the reaction between α-keto vinyl azides 1 and α,α-dicyanoalkenes 2 (Scheme 1-B).

Initially, we treated (Z)-2-azido-1-(4-chlorophenyl)-3-phenylprop-2-en-1-one 1a (1.0 equiv.) and 2-(1-phenylethylidene)-malononitrile 2a (1.0 equiv.) with Cs₂CO₃ (0.5 equiv.) in toluene at 90 °C for 3 h. This reaction interestingly led to the formation of the highly functionalized 2-aminonicotinonitrile 3a, which was confirmed by HRMS, ¹H NMR, and ¹³C NMR, as well as X-ray crystal structure analysis (Fig. 1), in an acceptable yield (Table 1, entry 1).

Fig. 1 X-ray crystal structure of 3a.⁹

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Base (equiv.)	T/°C	Conversion^b/%
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv.) and 2a (0.1 mmol, 1.0 equiv.) in various solvents (3 mL, well-sealed tubes) at selected temperature in the presence of the base for 3 h.b The conversion rate was determined by HPLC, based on the disappearance of the starting α-keto vinyl azides 1a.c Isolated yield. n.r. = no reaction.
1	Toluene	Cs2CO3 (0.5)	90	44 (40)^c
2	DCM	Cs2CO3 (0.5)	90	50
3	THF	Cs2CO3 (0.5)	90	31
4	EtOH	Cs2CO3 (0.5)	90	Trace
5	DMF	Cs2CO3 (0.5)	90	Trace
6	ACN	Cs2CO3 (0.5)	90	Trace
7	DCE	Cs2CO3 (0.5)	90	56
8	1,4-Dioxane	Cs2CO3 (0.5)	90	24
9	DCE	Et3N (0.5)	90	n.r.
10	DCE	NaOH (0.5)	90	19
11	DCE	K2CO3 (0.5)	90	20
12	DCE	MeONa (0.5)	90	61 (59)^c
13	DCE	MeONa (0.5)	rt	n.r.
14	DCE	MeONa (0.5)	60	n.r.
15	DCE	MeONa (0.5)	120	83 (80)^c
16	DCE	—	120	n.r.
17	DCE	MeONa (0.1)	120	17
18	DCE	MeONa (1.0)	120	25
19	DCE	MeONa (2.0)	120	26

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Further studies found that the reaction solvent and base have a significant impact on the formation of 3a. When the reaction was performed in DCM or DCE, the conversion of 3a was slightly improved to 50% and 56%, respectively (Table 1, entry 2 and 7). Moreover, only a trace amount of 3a could be detected via LC-MS when performed in EtOH, DMF or ACN (Table 1, entry 4–6). The screening of bases showed that MeONa worked more efficiently, thus giving 3a in 59% yield (Table 1, entry 7 and entries 9–12). Optimization of temperature demonstrated that room temperature or 60 °C failed to obtain the desired product, whereas increasing to 120 °C could lead to an increased yield of 3a of 80% (Table 1, entries 12–15). Subsequent screening of the equivalents of MeONa showed that 0.5 equivalent was the best (Table 1, entries 15–19). As shown in Table 1, the optimal reaction condition was obtained in DCE with well-sealed tubes at 120 °C when 0.5 equivalent of MeONa was employed (Table 1, entry 15).

With the optimized reaction conditions in hand, the generality for the synthesis of highly functionalized 2-aminonicotinonitriles was explored. As shown in Table 2, α-keto vinyl azides 1 worked efficiently with α,α-dicyanoalkenes 2 to provide the desired products in moderate to good yields (3b–3i, 74–82%), regardless of whether an electron-withdrawing group (–Cl, –Br) or electron-donating group (–OMe) was borne at the R¹ position on the aromatic ring or just an alkyl group. Moreover, the steric hindrance has a slightly effect on the reaction yields (3d–3f). Furthermore, most of the substituents R² were found to be compatible in this reaction, including both the aromatic and heteroaromatic rings (3a, 3j–3o) and alkyl group (3y), with the exception being the hydrogen atom (3p). We failed to obtain the product 3p even after heating for 24 hours. In addition to these, the scope of various α,α-dicyanoalkenes 2 were also examined in this synthesis. Likewise, the installation of electron-deficient (3b, 3j–3k, 3o, 3w) and -rich benzene rings (3q, 3s–3t, 3x) or heteroaromatic rings (3r) as the substituent R³ were all well tolerated under the optimized reaction conditions. When R³ was replaced with alkyl groups (t-Bu- or Me-), the desired products were only detected via LC-MS in trace under the above-stated reaction condition. However, much higher isolated yields could be achieved when the reaction was performed for a longer period of time along with 1.5 equivalents of MeONa (3u and 3v), and the structure of 3v was further confirmed by ¹H NMR, ¹³C NMR, HRMS and ¹³C–¹H HMBC spectra (in ESI†).

Table 2 Scope of 2-aminonicotinonitrile from vinyl azides 1 and α,α-dicyanoalkenes 2^a

a Reaction conditions: α-keto vinyl azides 1 (1.0 mmol, 1.0 equiv.), α,α-dicyanoalkenes 2 (1.0 mmol, 1.0 equiv.), and MeONa (0.5 mmol, 0.5 equiv.) in DCE, heated in a well-sealed tube (120 °C). Yields shown are those of the isolated products.b 1.5 equivalents of MeONa were used.

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On the basis of the above mentioned investigation, a possible mechanism for this annulation is proposed in Scheme 2. First, the α-keto vinyl azide 1 could undergo thermolysis to give 2H-azirine A under the stated reaction conditions.⁶ⁱ In the presence of base, the α,α-dicyanoalkene 2 is converted to the vinylogous carbanion B via a facile deprotonation.^8h Then, a nucleophilic attack would occur between B and 2H-azirine A, leading to the adduct product C, which then turned into D through an intramolecular nucleophilic attack between the nitrogen of the aziridine and a cyano group. A possible 4-endo-tet cyclization¹⁰ affording the adduct F may occur after deprotonation of D at the methylene. Then, F undergoes a facile ring opening of the strained four-membered ring to obtain G via a C–N bond cleavage. Finally, the desired product 3 is achieved through aromatization of G.

Scheme 2 The possible reaction mechanism.

In summary, we have developed an efficient strategy for preparing highly functionalized 2-aminonicotinonitriles from readily available α-keto vinyl azides and α,α-dicyanoalkenes. These base-mediated annulations can be realized via intramolecular rearrangement and ring openings in good yields. This methodology also provides an attractive guidance for medicinal chemistry and pharmaceutical applications.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81273356 and 81473074), National Science & Technology Major Projects for “Major New Drugs Innovation and Development” of China (2014ZX09304002-007), the Program for Zhejiang Leading Team of S&T Innovation Team (2011R50014), and Arthritis & Chronic Pain Research Institute, USA to Y. Y.; and National Natural Science Foundation of China (No. 81402778) to W. C.

Notes and references

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9. ESI.†.
10. This possible mechanism contains an unfavorable 4-endo-tet cyclization and further investigation on the reaction mechanism is underway.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization, spectral data of the final products, ¹³C–¹H HMBC spectra of 3v and crystallographic data for compound 3a. CCDC 1431902. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra04669j

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