Synthesis of indole–cycloalkyl[b]pyridine hybrids via a four-component six-step tandem process

The one-pot four-component reaction of 3-(1H-indol-3-yl)-3-oxopropanenitriles, aromatic aldehydes, cycloalkanones and ammonium acetate occurred via a six-step tandem Knoevenagel condensation–nucleophilic addition to carbonyl–Michael addition–N-cyclization–elimination–air oxidation sequence to afford structurally intriguing indole–cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles in excellent yields.


Introduction
The syntheses of novel heterocycles through greener protocols have received a great deal of attention of the synthetic organic chemists in view of environmental concerns [1][2][3]. The multicomponent tandem/domino reaction is one among several green chemical protocols widely employed for the synthesis of myriad of natural products and hybrid heterocycles [4][5][6][7][8][9][10][11][12][13]. These reactions are one-pot processes involving several bond forming steps under identical reaction conditions affording the desired product in a single transformation [14][15][16][17][18][19][20][21][22]. Hence, multicomponent tandem reactions minimize the number of steps to synthe-size complex heterocycles, avoid the isolation and purification of the intermediates, allow less waste to the environment, shorten the reaction time and are also cost effective.
Carbocyclic or heterocyclic fused pyridine derivatives are an important class of compounds omnipresent in natural products and biologically relevant synthetic compounds [23][24][25][26][27]. For example, imiquimod is an immune response modifier used to treat warts on the skin and certain type of skin cancer called superficial basal cell carcinoma ( Figure 1) [28,29]. Loratadine is a second-generation histamine H1 receptor antagonist used to treat allergic rhinitis and urticarial [30,31]. Blonanserin is an atypical antipsychotic drug used to treat schizophrenia [32], whereas the decahydrocyclododeca[b]pyridine has been reported as inhibitors of cytochrome P450 [33]. Furthermore, muscopyridine is being used in perfume industry [34].

Results and Discussion
Initially the precursors viz. 3-(1H-indol-3-yl)-3-oxopropanenitriles 3 were synthesized from the reaction of indoles 1 and 2-cyanoacetic acid (2) in acetic anhydride under heating conditions (Scheme 1) [73]. Subsequently the one-pot four-component reaction of 3-(1Hindol-3-yl)-3-oxopropanenitrile (3a), 4-chlorobenzaldehyde (4f), cyclododecanone (5a) and ammonium acetate (6) was chosen as a model in order to identify the optimum conditions for this reaction (Table 1). To begin with, a 1:1:1:2 mixture of the above reactants was refluxed in toluene for 4 h which led to the formation of indole-cyclododeca[b]pyridine-3-carbonitrile 7f and the intermediate (E)-3-(4-chlorophenyl)-2-(1H-indole-3carbonyl)acrylonitrile (8) in 10 and 80% yields, respectively. Intermediate 8 was formed exclusively when the reaction was carried out in refluxing acetonitrile or isopropanol. The yield of 7f increased up to 60% in refluxing methanol. However, the same reaction in refluxing ethanol afforded solely the desired product 7f in 93% yield within 2 h (Table 1). Furthermore, after completion of the reaction as evident from the TLC, the mixture was set aside for 6 h and the resultant precipitate was filtered, washed with ethanol and dried under vacuum to obtain pure 7f without the need for additional purification methods.
The structure of 7f was elucidated with the help of one-and two-dimensional NMR spectroscopy. In the 1 H NMR of 7f the 5-and 14-CH 2 protons appeared as triplets at 2.56 and 3.01 ppm (J = 9.0 Hz), respectively. From the H,H-COSY correlation of 14-CH 2 protons, the multiplets in the range 2.03-2.18 ppm was assigned to the 13-CH 2 protons. The CH 2 protons of C-6 to C-12 appeared as multiplets in the range 1.27-1.58 ppm. The H,H-COSY spectrum revealed that the NH proton of indole ring, which appeared as a broad singlet at 8.58 ppm is coupled to a doublet at 8.16 ppm (J = 3.0 Hz) due to 2′-CH proton.
Furthermore, the analysis of 1 H NMR spectra revealed that the indole-cyclododeca[b]pyridine-3-carbonitriles 7 with ortho/ortho-para/ortho-meta substituted phenyl ring at C-4, exhibited axial chirality. For instance, in the case of 7f with p-Cl substituted phenyl ring at C-4, the 5-and 14-CH 2 protons appeared as triplets at 2.56 and 3.01 ppm, respectively. However, in 7l wherein C-4 is bearing an o-Br substituted phenyl, the 5-CH 2 protons appeared as multiplets in the range of 2.37-2.46 and 2.61-2.71 ppm, whereas the 14-CH 2 protons appeared as multiplets in the range of 2.91-3.01 and 3.06-3.16 ppm. The diastereotopic behavior of 5-and 14-CH 2 protons of indole-cyclododeca[b]pyridine-3-carbonitrile hybrid heterocycles 7 with an ortho/ortho-para/ortho-meta substituted phenyl ring at C-4 may be attributed to the axial chirality in- duced in these molecules due to the restricted rotation of the C-C single bond. The steric hindrance exerted between the nitrile group at C-3 and the ortho/ortho-para/ortho-meta substitution in the phenyl ring at C-4 restricts the free rotation of the C-4-phenyl C-C single bond thereby inducing axial chirality in these molecules (representative examples, Figure 2).
Interestingly in some cases this reaction afforded the unaromatized indole-cyclododeca[b]pyridine-3-carbonitriles 12 (Table 3). These experiments were repeated thrice in order to ascertain the exclusive formation of 12. The structure of 12 was confirmed from the 1 H NMR spectra, wherein the characteristic singlet around 4.6-5.1 ppm due to the 4-CH proton was observed. In addition, in the case of 12r the structure was confirmed from the single crystal X-ray studies (Figure 3) [74]. A careful analysis of the reaction progress revealed that in these reactions the corresponding product 12 precipitated from the reaction mixture within 2 h of reflux (Table 3), which was also an indication of the completion of the reaction. Further increment in the reaction time had no influence on the reaction to  afford the aromatized product 7. However, in other cases ( Table 2) the reaction was complete within 2 h (TLC analysis) but the product 7 precipitated after 6-8 h.
Gratified by the above results and, also to demonstrate the general applicability of this protocol, the reaction of 3-(1Hindol-3-yl)-3-oxopropanenitriles 3, aromatic aldehydes 4 and  ammonium acetate (6) with lower ring-size cycloalkanones, viz. cyclooctanone (5b), cycloheptanone (5c) and cyclohexanone (5d) was investigated (Scheme 4). Under the previously established conditions, the reaction led to the formation of the respective cycloalkane-fused pyridine-indole hybrid heterocycles in excellent yields (80-95%). However, the reaction failed to occur with cyclopentanone. In total thirty-five indole-cycloalkyl[b]pyridine-3-carbonitrile hybrids 15-18 were isolated ( Table 4). The structure of all the hybrid heterocycles 15-18 was elucidated using NMR spectroscopy and in the case of 16f the structure was further confirmed from single crystal X-ray studies ( Figure 4) [74].

Conclusion
The syntheses of a library of novel indole-cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles have been achieved through a facile one-pot four-component strategy. This reaction occurred through a six-step tandem Hantzsch-like process involving Knoevenagel-Michael-nucleophilic addition-intramolecular cyclization-elimination-oxidative aromatization sequence of reactions in a single transformation leading to the formation of two new C-N and C-C bonds. The structure of all the indole-cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles was elucidated with the help of NMR spectroscopy and supported by single crystal X-ray studies for two compounds. The indole-cycloalkyl[b]pyridine-3-carbonitriles comprising ortho/ortho-para/ortho-meta substituted phenyl rings exhibited axial chirality due to restricted C-C single bond rotation.

Supporting Information
Supporting Information File 1 Experimental procedure, compound characterization data and copies of NMR spectra.