One-pot four-component synthesis of pyrimidyl and pyrazolyl substituted azulenes by glyoxylation–decarbonylative alkynylation–cyclocondensation sequences

A novel one-pot four-component synthesis of pyrimidyl- and pyrazolylazulenes through the use of glyoxylation–decarbonylative alkynylation–cyclocondensation sequences starting from azulene or guaiazulene as substrates, gives rise to the formation of the target compounds in moderate to good yields.


Introduction
Diversity-oriented synthesis has become an important field in organic chemistry, initiated by the increasing demand for new scaffolds for pharmaceuticals and biologically active compounds over the past decades [1][2][3].Herein, multicomponent reactions adopt a central position since each component can be varied within a wide range of functionalities and substituents [4][5][6][7][8].Furthermore, these one-pot processes are highly advantageous because they combine shortened reaction times and resource efficiency with diminished waste production in com-parison to traditional multistep syntheses.Thus, they can be considered to be economically and ecologically efficient [9,10].
In particular, multicomponent syntheses of heterocycles initiated by transition metal catalysis received increasing attention in the past decade [11].As a one-pot synthetic methodology, this novel concept combines the unique reactivity patterns of transition metal catalysis with fundamental organic reactivity, in a sequential or consecutive fashion.Over the years, we have contributed to this concept through Pd/Cu-catalyzed accesses to enones and ynones and the in situ transformation of these intermediates into many classes of heterocycles [12][13][14][15].These novel MCRs nicely correspond with diversity-oriented strategies towards functional organic chromophores [1,2].
The striking blue color of azulene (1a) (from the Spanish word "azul" = blue) has aroused scientific attention for a long time [16,17].This prominent appearance results from the electronic transition between the S 0 and S 1 state [18], as a consequence of low energy frontier molecular orbital transitions [19].The bicyclic structure of this nonbenzoid hydrocarbon results from a five-seven ring annulation with a planar, cyclic conjugation of 10 π-electrons.The dipole moment of 1a at μ = 1.08 D [20] is astoundingly large in comparison to that of naphthalene at μ = 0 D and can be rationalized by a significant contribution of cyclopentadienyl anion/tropylium cation resonance structures (Scheme 1) [19].
N-Heteroaryl-substituted azulenes can be accessed by stoichiometric [40,41] as well as Pd-catalyzed cross-coupling processes [42][43][44].However, these methods have only delivered a narrow range of derivatives.Prior to application in Pd-catalyzed processes, azulenes must be functionalized, either by halogenation or borylation, and some of these derivatives were found to be quite unstable [45,46].To the best of our knowledge, no diversity-oriented multicomponent syntheses of azulenyl heterocycles have been reported so far.Here, we report the development of one-pot four-component syntheses toward pyrimidyl-and pyrazolylazulenes.

Results and Discussion
Recently, we reported a three-component synthesis leading to the formation of ynones by a conceptually novel glyoxylationdecarbonylative Sonogashira coupling sequence (Scheme 2) [47].The Lewis acid free glyoxylation of electron rich N-heterocycles, such as indoles and pyrroles, leads to the formation of glyoxylyl chlorides, which can be reacted without isolation by decarbonylative Sonogashira coupling to form the desired ynones.So far, only one example of the synthesis of azulenylynones has been described [48].
Our retrosynthetic analysis (Scheme 3) suggests that a wide range of N-heterocycle-substituted azulenes should be accessible through Michael addition-cyclocondensation of azulenylynones with binucleophiles.Azulenylynones in turn could be simply disconnected by our glyoxylation-decarbonylative alkynylation transform [47] back to azulenes.Scheme 3: Retrosynthetic analysis of N-heterocyclic substituted azulenes by a one-pot four-component approach.a The reactions were performed on a 2.00 mmol scale in 10 mL of THF as a solvent (c (1b) = 0.2 M); b isolated yield; c 1,4-Dioxane was used as a solvent (c (1b) = 0.2 M).
Previously, glyoxylation of azulene (1a), with oxalyl chloride in 1-position was reported to be essentially complete within 5 min [39].Oxalyl bromide could be equally used as a glyoxylating agent [49,50].Likewise, the glyoxylation of 1b has been reported to proceed in 3-position with both reagents, yet with lower reactivity, and its conversion was found to be incomplete even after 2 h.In addition, the formation of side products [51] and decarbonylation [52] was observed, presumably caused by the steric hindrance of the methyl group in 4-position.
Initially, the optimized conditions for the glyoxylation-decarbonylative alkynylation of indoles were applied [47], except for the addition of one equivalent of triethylamine in the glyoxylation step for scavenging the generated hydrogen chloride (Table 1, entry 1).However, the use of the amine base in the first step was unsatisfactory (Table 1, entry 2).Prolonged reaction times in the first step did not affect the yield.According to monitoring by TLC, glyoxylation of guaiazulene (1b) was incomplete even after 24 h reaction time (Table 1, entry 3).Shorter reaction times in the first step caused a substantial decrease of the yield (Table 1, entry 4), whereas longer reaction times in the Sonogashira coupling had no effect on the yield (Table 1, entry 5).Rising the reaction temperature of the glyoxylation step to 50 °C considerably diminished the yield (Table 1, entry 6).However, doubling the catalyst loading furnished significantly higher yields (Table 1, entry 7).1,4-Dioxane was equally well employed as a solvent (Table 1, entry 8).From this optimization study, the conditions of entry 7 (Table 1) were considered to be optimal and were applied in the three-component synthesis of the azulenylynones 3 (Scheme 4, Table 2) (for experimental details, see Supporting Information File 1).Their structures were unambiguously supported by NMR spectroscopy, mass spectrometry, and combustion analysis.
Azulene (1a) and guaiazulene (1b) were both applied as substrates in the reaction sequence, giving rise to azulenyland guaiazulenylynones 3. The azulenyl derivatives 3a and 3b were obtained in higher yields compared to the guaiazulenylynones 3c-n.A variety of substituted arylacetylenes were utilized in the reaction sequence.Electron neutral (Table 2, entries 1 and 3), electron withdrawing (Table 2, entries 5-7), and electron donating (Table 2, entries 4 and 8) substituents were equally well tolerated.In addition, heteroaryl-substituted acetylenes (Table 2, entries 9 and 10) as well as simple aliphatic acetylenes (Table 2, entries 2, 11, and 12) were successfully employed.Finally, propargylaldehyde diethylacetal (Table 2, entry 13) and TIPS-protected acetylene (Table 2, entry 14) also participated in the sequence, although relatively low yields were achieved.With this versatile three-component synthesis of azulenylynones in hand, the stage was set to expand the sequence to a four-component access to pyrimidyl-and pyrazolyl-substituted azulenes.Hence, the conditions for the terminating Michael addition-cyclocondensation step, adopted from a recent work [54], were only slightly adjusted as a consequence of the lower electrophilicity of azulenylynones in comparison to aryl-and heteroaryl-substituted ynones that we have previously synthesized.Therefore, upon the subsequent reaction of the azulenes 1 with oxalyl chloride, followed by Pd/Cu-catalyzed decarbonylative alkynylation with terminal alkynes 2, and finally by cyclocondensation of the ynone intermediates with substituted amidine hydrochlorides 4, pyrimidylazulenes 5 were obtained in moderate to good yields in a one-pot fashion (Scheme 5) (for experimental details, see Supporting Information File 1).
The diversity-oriented nature of this four-component approach to pyrimidylazulenes 5 is underlined by flexible variation of the Scheme 6: Four-component synthesis of pyrazolylazulenes 7 by glyoxylation-decarbonylative Sonogashira coupling-cyclocondensation sequence (yields refer to isolated and purified compounds).
Likewise, pyrazolylazulenes were obtained in the course of a consecutive glyoxylation-decarbonylative Sonogashira coupling, followed by a cyclocondensation with methylhydrazine ( 6) to furnish two N-methylpyrazoles 7 in moderate yields (Scheme 6) (for experimental details, see Supporting Information File 1).
Attempts to employ phenylhydrazine, N-Boc-hydrazine, and hydrazine hydrate under standard conditions were met with failure.Based upon previous syntheses of N-methylpyrazoles from ynones and methylhydrazine [55,56] and the appearance of a single set of resonances in the proton and carbon NMR spectra, it is obvious that only a single regioisomer was formed.
Although the synthesis of similarly substituted pyrazolylazulenes has already been described [57], our one-pot four-component approach utilizes readily available starting materials as well as a simple catalyst system.In addition, it avoids tedious multiple workup and purification operations.

Conclusion
In conclusion, we have developed a one-pot four-component process for the synthesis of novel pyrimidyl-and pyrazolylazulenes.A wide range of substituents can be introduced by this modular approach to N-heterocyclic azulene derivatives.The key step of this diversity-oriented synthesis is the generation of azulenylynones by the glyoxylation-decarbonylative alkynylation sequence with azulene or guaiazulene as substrates.
Undoubtedly, this novel four-component approach to heterocyclic derivatives of azulene is well suited for the development of functional chromophores with extended π-conjugation.

Table 1 :
Optimization studies for the synthesis of ynone 3k. a