Synthesis of alkynyl/alkenyl-substituted pyridine derivatives via heterocyclization and Pd-mediated Sonogashira/Heck coupling process in one-pot: a new MCR strategy

Abstract

A new class of 2-amino-4-(3/2-(alkynyl)/3-(alkenyl)phenyl)-6-phenylnicotinonitriles (6, 7 & 9) has been synthesized with good to excellent isolated yields by the multi-component reaction (MCR) of bromobenzaldehyde (1), malononitrile (2), acetophenone (3), NH₄OAc (4) and a series of terminal alkynes (5)/alkenes (8) in the presence of pyrrolidine and Pd-catalyst in a mixture of H₂O–DME (1 : 4 ratio) under reflux conditions in a single step. The Heck-type coupling with terminal olefins takes place stereoselectively with exclusive formation of E-isomers. This new MCR strategy opens new avenues in the development of (i) a diversity-oriented new cyanopyridine based compound library and (ii) new chemical entities other than the present reported molecules.

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1. Introduction

The pyridine ring system is an ‘important structural motif’ in a large number of natural products and also in clinically useful molecules. Among this plethora of compounds, cyanopyridine derivatives have attracted great attention due to their wide range of biological activities such as antimicrobial,^1,2 antipyretic,³ anti-hyperglycemic properties,⁴ Ca²⁺-channel blockers,⁵ vasodilator,⁶ antitumor,^7,8 anti-diabetic agents.⁹ In addition, they have been evaluated as IKK-β inhibitors,¹⁰ protein kinase B (PKB/Akt) inhibitors,¹¹ protein kinase Cθ (PKCθ) inhibitors,¹² melanin-concentrating hormone receptor 1 (MCH-R1) antagonists,¹³ A_2A adenosine receptor antagonists,¹⁴ carbonic anhydrase inhibitors,¹⁵ dipeptidyl peptidase-IV (DPP-IV) inhibitors with anti-hyperglycemic activity,¹⁶ analgesic agents,¹⁷ monoamine oxidases (MAO), cholinesterase inhibitors for the treatment of Alzheimer's disease,¹⁸ metabotropic glutamate receptor5 (mGluR5) negative allosteric modulators,¹⁹ C-Jun NH₂ terminal kinase (JNKs) inhibitors,²⁰ prion disease therapeutics²¹ and RET tyrosine kinase inhibitors²² and also useful in the development of non-linear optical (NLO) materials²³ and nondoped organic light-emitting devices (OLEDs) too.²⁴ As a result, cyanopyridine derivatives are regarded as “significant structural motif” and a huge number of strategies are developed for their synthesis.^25,26 In addition, the development of multi-component reactions (MCRs) strategies have attracted great attention from organic chemists^27–34 to prepare these useful pyridine frameworks. Multi-component reactions (MCRs) are powerful strategies for the quick synthesis of diverse and complex organic molecules of potential interest particularly in the area of material science and drug discovery.^35–39 MCRs have attracted much attention owing to their excellent synthetic efficiency, intrinsic atom economy, high selectivity, procedural simplicity and environmental friendliness.^40–44 Therefore, the development of new multi-component reaction (MCR) strategies for the preparation of diversity-oriented complex molecules have recently gained considerable interest from the organic chemists.^45–49 In particular, structural elaboration on heterocyclic compounds with terminal alkynyl/alkenyl functionalities using Sonogashira and Heck coupling reactions is quite interesting.^50–56 However, attempts are not made to investigate the structural elaboration of cyanopyridine derivatives using Pd-mediated Sonogashira and Heck coupling reactions via a one-pot multicomponent reaction (MCR).

Herein, we report a new MCR strategy for the synthesis of 2-amino-4-(3/2-(alkynyl)/3-(alkenyl)phenyl)-6-phenylnicotinenitriles (6, 7 & 9) with 80–90% isolated yields via heterocyclization from bromobenzaldehyde (1), malononitrile (2), acetophenone (3) and NH₄OAc (4) in the presence of pyrrolidine followed by Pd-mediated Sonogashira and Heck coupling reactions using a variety of terminal alkynes (5)/alkenes (8) in a mixture of H₂O–DME (1 : 4 ratio) under reflux conditions as shown in Scheme 1. The present communication addresses several challenging issues e.g. (i) MCR based synthesis of alkynyl/alkenyl substituted-heterocyclic molecules via heterocyclization followed by C–C coupling in one-pot, (ii) the optimal base, catalyst system and reaction conditions and (iii) synthesis in view to develop alkynyl/alkenyl substituted heterocyclic compounds based synthetic precursors suitable for further functional group transformations in the development of diversity oriented new compound library.

Scheme 1 Synthesis of 2-amino-4-(3/2-(alkynyl)/3-(alkenyl)phenyl)-6-phenylnicotinenitriles via multi-component reaction.

2. Experimental

Melting points of various products obtained are determined (uncorrected). ¹H and ¹³C NMR spectra are recorded on a Varian 400 MHz. Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The data are reported as follows: chemical shift (ppm) and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad singlet), coupling constant(s) in Hz, integration assignment. High-resolution mass spectra (HRMS) and compound purity data are acquired on a Waters LCT premier XE TOF HRMS single quadrupole system equipped with electro spray ionization (ESI) source. Thin-layer chromatography is performed on 0.25 mm Merck silica gel plates and visualized with UV light. Column chromatography is performed on silica gel (200–300 mesh). Chemicals and solvents are purchased from Sigma-Aldrich and Merck. Isolated compounds are characterized by physical and spectroscopic data.

Typical experimental procedure for the preparation of 2-amino-4-(3-(3-hydroxyprop-1-ynyl)phenyl)-6-phenylnicotinonitrile (6a)

A mixture of 3-bromobenzaldehyde (1) [10.0 mmol], malononitrile (2) [11.0 mmol], acetophenone (3) [11.0 mmol] and NH₄OAc (4) [20.0 mmol] in presence of pyrrolidine (5.0 mmol) in a mixture of H₂O–DME (1 : 4 ratio) (10 vol) is stirred at reflux for 1.0 h. The first phase progress of the reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is cooled to RT and then, prop-2-yn-1-ol 5a [15.0 mmol], PdCl₂(PPh₃)₂ [0.002 mmol] and CuI [0.005 mmol] are added. Again the entire reaction mixture is kept under reflux condition for 3.0 h in open air. Final stage progress is monitored by TLC. After the completion of the reaction, the whole reaction mixture is cooled to RT and the solvent is removed under reduced pressure. The obtained crude product is purified by column chromatography using silica gel and 1 : 9 ratio of EtOAc–petroleum ether (PE) to obtain pure compound 6a. The isolated yield of product 6a is 91%. The same procedure is followed for the preparation of 2-amino-4-(3-(alkynyl)phenyl)-6-phenylnicotinonitrile derivatives (6b–k) listed in Table 2. All the synthesised compounds (6a–k) gave satisfactory spectroscopic data in accordance with their proposed structures.

Typical experimental procedure for the preparation of 2-amino-4-(2-(3-hydroxyprop-1-ynyl)phenyl)-6-phenylnicotinonitrile (7a)

A mixture of 2-bromobenzaldehyde (1a) [10.0 mmol], malononitrile (2) [11.0 mmol], acetophenone (3) [11.0 mmol] and NH₄OAc (4) [20.0 mmol] in the presence of pyrrolidine (5.0 mmol) in a mixture of H₂O–DME (1 : 4 ratio) (10 vol) is stirred at reflux for 1.0 h. The first phase progress of the reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is cooled to RT and then, prop-2-yn-1-ol 5a [17.0 mmol], PdCl₂(PPh₃)₂ [0.002 mmol] and CuI [0.005 mmol] are added. Again the entire reaction mixture is kept under reflux condition for 3.5 h in open air. Final stage progress is monitored by TLC. After the completion of the reaction, the whole reaction mixture is cooled to RT and the solvent is removed under reduced pressure. The obtained crude product is purified by column chromatography using silica gel and 1 : 9 ratio of EtOAc–petroleum ether (PE) to obtain pure product 7a. The isolated yield of product 7a is 80%. The same procedure is followed for the preparation of 2-amino-4-(2-(alkynyl)phenyl)-6-phenylnicotinonitrile derivatives (7b–d) listed in Table 3. Synthesized compounds (7a–d) gave satisfactory spectroscopic data in accordance with their proposed structures.

Typical experimental procedure for the preparation of (E)-methyl 3-(3-(2-amino-3-cyano-6-phenylpyridin-4-yl)phenyl)acrylate (9a)

A mixture of 3-bromobenzaldehyde (1) [10.0 mmol], malononitrile (2) [11.0 mmol], acetophenone (3) [11.0 mmol] and NH₄OAc (4) [20.0 mmol] in presence of pyrrolidine (5.0 mmol) in a mixture of H₂O–DME (1 : 4 ratio) (10 vol) is stirred at reflux for 1.0 h. The first phase progress of the reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is cooled to RT and then, methyl acrylate (8a) [16.0 mmol] and PdCl₂(PPh₃)₂ [0.002 mmol] are added. Again, the entire reaction mixture is kept under reflux condition for 3.0 h in open air. Final stage progress is monitored by TLC. After the completion of the reaction, the whole reaction mixture is cooled to RT and the solvent is removed under reduced pressure. The obtained crude product is purified by column chromatography using silica gel and 1 : 9 ratio of EtOAc–petroleum ether (PE) to obtain pure compound (9a). The isolated yield of product 9a is 88%. The same procedure is followed for the preparation of 2-amino-4-(3-(alkenyl)phenyl)-6-phenylnicotinonitrile derivatives (9b–f) listed in Table 4. Synthesized compounds (9a–f) gave satisfactory spectroscopic data in accordance with their proposed structures. Based on ¹H NMR data, all the prepared alkenes (9a–f) are confirmed as ‘E’ isomers (J = 16.0–16.5 Hz).

3. Results and discussion

In the present study, our initial objective is to identify well-suited reaction conditions for the heterocyclization along with Pd-mediated C–C coupling process in a single step operation. Accordingly, we have studied the effect of bases, solvents, reaction temperature and Pd-catalysts as well as effect of concentration of base for the construction of pyridine frame work followed by Sonogashira/Heck coupling in one-pot. Therefore, in an initial experiment, 3-bromobenzaldehyde (1), malononitrile (2), acetophenone (3) and NH₄OAc (4) in presence of K₂CO₃ in H₂O is stirred at reflux for 10.0 h. After the completion of the reaction, the reaction mixture is cooled to RT and then, prop-2-yn-1-ol [5a], PdCl₂(PPh₃)₂ and CuI are added. After workup and purification, the desired product 2-amino-4-(3-(3-hydroxyprop-1-ynyl)phenyl)-6-phenylnicotinonitrile (6a) is isolated in 5.0% yield (entry 1, Table 1). The obtained yield of the product (6a) is not impressive; this may be due to insolubility of the reactants. To improve the solubility of the reactants and thereby the yield of the product (6a), H₂O is replaced by organic solvents such as THF, dioxane, DME, mixture of H₂O–DME (1 : 4 ratio), DMF and DMSO. The obtained yields are 48%, 56%, 64%, 71% and 62%, respectively (entries 2–7, Table 1). Initial effect of solvent study revealed that mixture of H₂O–DME (1 : 4 ratio) provided acceptable yield (71%) of the product 6a (entry 5). To increase the yield of the product (6a) further, various bases such as Na₂CO₃ (entry 8), Et₃N (entry 9) and pyrrolidine (entry 10) are employed which resulted a yield of 56%, 78% and 91%, respectively in a mixture of H₂O–DME (1 : 4 ratio). The evaluation of suitable base revealed that pyrrolidine is more efficient in producing the maximum yield (91%) of product 6a (entry 10) in a mixture of H₂O–DME (1 : 4 ratio). Subsequently, the effects of temperature, Pd-catalyst and concentration of base and terminal alkyne, prop-2-yn-1-ol (5a) are investigated on the course of MCR. Lower yields (25–72%) are obtained when the same reaction is conducted at less than 80 °C in a mixture of H₂O–DME (1 : 4 ratio). In this case, it is observed that some portions of the reactants are still remaining and resulting lower yields of the desired product (6a). Then, the same reaction has been conducted at reflux temperature and the obtained yield of the product (6a) has dramatically increased to 91%. In order to study the effect of other Pd-catalysts on the course of the C–C coupling reaction, various Pd-catalysts such as Pd(PPh₃)₄, Pd(dppf)Cl₂ and 20% Pd(OH)₂ have been employed which afforded 72%, 68% and 75% yields, respectively (entries 11–14). The results show the superiority of the PdCl₂(PPh₃)₂ catalyst to obtain maximum yield (91%) of the product (6a) within 4.0 h. The effect of pyrrolidine base load is studied on the course of MCR reaction; for example 2.0, 5.0, 10.0, 15.0 and 20.0 mmol of pyrrolidine provided 72%, 91%, 78%, 71% and 65% yields of product (6a), respectively. From the results, it is concluded that 5.0 mmol of pyrrolidine offered best yield (91%) of product (6a). Variation of terminal alkyne concentration also effected the yields significantly; 10.0, 15.0, 20.0 and 25.0 mmol of prop-2-yn-1-ol 5a resulted 68%, 91%, 84% and 78% yields and the optimum concentration of terminal alkyne concentration is 15.0 mmol for maximum yield.

Table 1 Optimization of reaction conditions for the MCR based synthesis of 2-amino-4-(3-(3-hydroxyprop-1-ynyl)phenyl)-6-phenylnicotinonitrile (6a) through heterocyclization followed by Sonogashira reaction^a

Entry	Catalyst	Solvent	Base	Time (h)/temp. (°C)	Yield^b (%)
a Reagents and conditions: 3-bromobenzaldehyde 1 (10.0 mmol), malononitrile 2 (11.0 mmol), acetophenone 3 (11.0 mmol), NH4OAc 4 (20.0 mmol), base (5.0 mmol); prop-2-yn-1-ol 5a (15.0 mmol), PdCl2(PPh3)2 (0.002 mmol) and CuI (0.005 mmol) in a solvent or mixture of solvents (10 vol) at specified temperature.b Isolated yield.c Act as catalyst cum base.
1	PdCl2(PPh3)2	H2O	K2CO3	24.0; reflux	5
2	PdCl2(PPh3)2	THF	K2CO3	16.0; reflux	48
3	PdCl2(PPh3)2	Dioxane	K2CO3	12.0; reflux	56
4	PdCl2(PPh3)2	DME	K2CO3	9.0; reflux	64
5	PdCl2(PPh3)2	H2O–DME (1 : 4 ratio)	K2CO3	7.0; reflux	71
6	PdCl2(PPh3)2	DMF	K2CO3	8.0; 90–100	62
7	PdCl2(PPh3)2	DMSO	K2CO3	6.0; 90–100	65
8	PdCl2(PPh3)2	H2O–DME (1 : 4 ratio)	Na2CO3	9.0; reflux	56
9	PdCl2(PPh3)2	H2O–DME (1 : 4 ratio)	Et3N	6.0; reflux	78
10	PdCl2(PPh3)2	H2O–DME (1 : 4 ratio)	Pyrrolidine	4.0; reflux	91
11	Pd(PPh3)4	H2O–DME (1 : 4 ratio)	Pyrrolidine	10; reflux	68
12	Pd(PPh3)4	H2O–DME (1 : 4 ratio)	Pyrrolidine	8.0; reflux	72
13	Pd(dppf)Cl2	H2O–DME (1 : 4 ratio)	Pyrrolidine	7.0; reflux	68
14	20%Pd(OH)2^c	H2O–DME (1 : 4 ratio)	—	6.0; reflux	75

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Having prepared 2-amino-4-(3-(3-hydroxyprop-1-ynyl)phenyl)-6-phenylnicotinonitrile (6a) through heterocyclization followed by Sonogashira reaction efficiently under optimized reaction conditions, it is further investigate the further substrate scope and generality of this process using various terminal alkynes i.e. 6a–k and the obtained results are presented in Table 2. From this study, it is found that various functional groups of terminal alkyne substrates (6a–k) are well tolerated to the reaction conditions and provided good yields of the desired products (6a–k).

Table 2 MCR based synthesis of 2-amino-4-(3-(alkynyl)phenyl)-6-phenylnicotinonitriles (6) via heterocyclization followed by Sonogashira reaction^a

Entry	R′ of terminal alkyne (5) substrate	Product (6)	Time (h)	Yield^b (%)	Rf^c
a Reagents and conditions: 3-bromobenzaldehyde 1 (10.0 mmol), malononitrile 2 (11.0 mmol), acetophenone 3 (11.0 mmol), NH4OAc 4 (20.0 mmol), pyrrolidine (5.0 mmol); terminal alkynes 5a–k (15.0 mmol), PdCl2(PPh3)2 (0.002 mmol) and CuI (0.005 mmol) in a mixture of H2O–DME (1 : 4 ratio) (10 vol) at reflux.b Isolated yield.c Retention factor: 40% EtOAc in PE.
1	CH2OH (5a)		4.0	91	0.4
2	CH2CH2OH (5b)		4.0	89	0.45
3	CH2CH2CH2OH (5c)		3.5	85	0.5
4	CH2CH2CH2Cl (5d)		3.5	87	0.7
5	CH2CH(OH)CH3 (5e)		4.0	89	0.4
6	(OH)C(CH3)2 (5f)		5.0	85	0.4
7	CH2(CH2)2CH3 (5g)		4.5	88	0.75
8	CH2(CH2)3CH3 (5h)		4.5	86	0.8
9	CH2(CH2)4CH3 (5i)		4.5	88	0.85
10	CH2(CH2)6CH3 (5j)		4.5	87	0.85
11	1-Hydroxy-1-cyclohexyl (5k)		5.0	85	0.45

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The results obtained reveal that 3-bromobezaldehyde (1) can act as an efficient key starting material in the formation of 2-amino-4-(3-(alkynyl)phenyl)-6-phenylnicotinonitriles (6a–k) via heterocyclization followed by Sonogashira reaction (Table 2); further it is found that the scope of the same reaction with 2-bromobenzandehyde (1a) as a key starting material resulted in the production of desired products (7a–d) presented in Table 3. The study reveal that lower yields of final products (7a–d) are obtained due to steric hindrance in the course of the C–C coupling process. It is found that lower yields of products (7a–d) are offered in all cases (entries 1–4, Table 3) irrespective of the nature of substituents present on terminal alkyne substrates (5a, 5b, 5f and 5i) when 2-bromobenzandehyde (1a) is used instead of 3-bromobenzandehyde (1).

Table 3 MCR based synthesis of 2-amino-4-(2-(alkynyl)phenyl)-6-phenylnicotinonitriles (7) via heterocyclization followed by Sonogashira reaction^a

Entry	R′ of terminal alkyne (5) substrate	Product (7)	Time (h)	Yield^b (%)	Rf^c
a Reagents and conditions: 2-bromobenzaldehyde 1a (10.0 mmol), malononitrile 2 (11.0 mmol), acetophenone 3 (11.0 mmol), NH4OAc 4 (20.0 mmol), pyrrolidine (5.0 mmol); terminal alkynes 5a/b/f/i (15.0 mmol), PdCl2(PPh3)2 (0.002 mmol) and CuI (0.005 mmol) in a mixture of H2O–DME (1 : 4 ratio) (10 vol) at reflux.b Isolated yield.c Retention factor: 40% EtOAc in PE.
1	CH2OH (5a)		4.5	81	0.35
2	CH2CH2OH (5b)		4.5	78	0.4
3	(OH)C(CH3)2 (5f)		5.5	76	0.4
4	CH2(CH2)4CH3 (5i)		5.0	79	0.85

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Further substrate scope is investigated to assess the generality of the proposed MCR under Heck reaction conditions as shown in Table 4. Towards this direction, a mixture of 3-bromobenzaldehyde (1) malononitrile (2), acetophenone (3), NH₄OAc (4) and methyl acrylate (8a) in presence of PdCl₂(PPh₃)₂ and pyrrolidine in a mixture of H₂O–DME (1 : 4 ratio) (10 vol) are stirred for 5.0 h at reflux temperature to obtain product 9a. The yield (88%) of product 9a is good (entry 1, Table 4). Further, a series of terminal alkenes i.e. 8b–f are tested for the preparation of desired alkenyl-substituted pyridine derivatives (9b–f) and found that various sensitive functional groups of terminal alkenes (8a–f) are well tolerated to the reaction conditions and provided good yields of the desired products (9b–f) (entries 2–6, Table 4). Based on the obtained ¹H NMR data, all the prepared 2-amino-4-(3-(alkenyl)phenyl)-6-phenylnicotinonitrile derivatives (9a–f) are confirmed as ‘E’ isomers (J = 16.0–16.5 Hz).

Table 4 MCR based synthesis of 2-amino-4-(3-(alkenyl)phenyl)-6-phenylnicotinonitriles (9) via heterocyclization followed by Heck reaction^a

Entry	R′′ of terminal alkene (8) substrate	Product (9)	Time (h)	Yield^b (%)	Rf^c
a Reagents and conditions: 3-bromobenzaldehyde 1 (10.0 mmol), malononitrile 2 (11.0 mmol), acetophenone 3 (11.0 mmol), NH4OAc 4 (20.0 mmol), pyrrolidine (5.0 mmol) and terminal alkenes 8a–f (16.0 mmol), PdCl2(PPh3)2 (0.002 mmol) in a mixture of H2O–DME (1 : 4 ratio) (10 vol) at reflux.b Isolated yield.c Retention factor: 30% EtOAc in PE.
1	COOCH3 (8a)		5.0	88	0.55
2	COOCH2CH3 (8b)		5.5	82	0.55
3	COOC(CH3)3 (8c)		5.0	83	0.6
4	COCH3 (8d)		5.5	86	0.4
5	CONH2 (8e)		5.5	87	0.1
6	CN (8f)		4.5	85	0.3

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4. Conclusions

In summary, general syntheses of a new library of structurally diverse alkynyl/alkenyl-substituted pyridine derivatives (6, 7 & 9) have been accomplished via heterocyclization and subsequent Pd-mediated structural elaboration under Sonogashira and Heck coupling reactions in single step. Interestingly, the Heck coupling with terminal alkenes takes place stereoselectively with exclusive formation of the E-isomers. This MCR strategy offers advantages like easy isolation of products, simple construction of diversity oriented library of highly substituted pyridine derivatives and wide applications in the synthesis of valuable heterocyclic synthetic precursors bearing carbon–carbon triple and double bond functionalities other than the present reported molecules. The prepared synthetic precursors will be suitable for further functional group transformations in the development of new and novel heterocyclic molecules of potential pharmacological interest.

Acknowledgements

We gratefully acknowledge for the financial support from Council of Scientific and Industrial Research (CSIR), New Delhi, Govt of India through a major research project no. 01 (2391)/10/EMR-IIand Department of Atomic Energy-Board of Research in Nuclear Sciences (DAE-BRNS), Mumbai, Govt of India through a major research project no. 2011/37C/52/BRNS/2264.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra01053a

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