Palladium catalyzed one-pot synthesis of 2-(pyridin-4-yl) quinolines via a multicomponent unprecedented reaction of pyridine-4-carbaldehyde, 2-iodoaniline and triethylamine

Abstract

Palladium catalyzed synthesis of 2-(pyridin-4-yl) quinolines with an unprecedented participation of Et₃N in moderate to high yields was achieved in a novel multicomponent one-pot cyclization reaction of readily available pyridine-4-carbaldehyde, 2-iodoaniline and triethylamine in refluxing toluene.

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Quinolines are essential structural motif found in plethora classes of antifungal agents, such as 8-hydroxy quinolines, 2-aryl or styryl-quinolines, which showed potent antifungal activities.^1,2 This moiety is also found as prominent substructure in numerous natural and unnatural compounds having biological activities, such as antibacterial,³ HIV-1 replication inhibitors⁴ and most importantly within anti malarial agents⁵ shown in Fig. 1. C-2 pyridinyl substituted quinolines are best MIC₈₀ and MIC₅₀ against the clinically important fungi Candida albicans and non-albicans Candida species and have shown activities against dermatophytes.⁶ Hence, the development of alternative approaches for the preparation of quinolines, have attracted significant interest.^7–9

Fig. 1 Quinoline based natural products.

Multicomponent reactions (MCRs) have emerged in recent times as popular, powerful and useful tools in synthetic, combinatorial, and medicinal chemistry.¹⁰ The significant advantages such as greater efficiency, facileness, atom economy, convergent and structural complexity compared to the conventional linear-type syntheses have made MCRs as prominent strategies for the diverse construction of heterocyclic scaffolds.¹¹ Moreover, MCRs have also been extensively exploited in the synthesis of quinolines.¹² Et₃N is an exceptionally versatile compound in organic chemistry by providing several roles such as base,¹³ reducing agent¹⁴ and catalyst.¹⁵ In this context, we have demonstrated a straightforward synthesis of 2-(pyridin-4-yl) quinolines, some of which have already been characterized with prominent biological activities,^1,2 via a three-component reaction of pyridine-4-carbaldehyde, 2-iodoaniline and triethylamine, involving unprecedented double C–H insertion reactions of Et₃N with the assembling of the quinoline core from [3 + 2 + 1] atom fragments and the formation of three new bonds (Scheme 1).

Scheme 1 Multicomponent approach to quinoline.

We preliminary aimed at the synthesis of benzo[c][2,6]naphthyridine 4a from pyridine-4-carbaldehyde 1 and 2-iodoaniline 2. In this regard, the reaction was conducted with 1a and 2a in the presence of Et₃N (7 equiv.), Pd₂(dba)₃ (5 mol%) and PPh₃ (10 mol%) in dry DMF at 110 °C for 24 h, instead of 4a, 2-(pyridin-4-yl)quinoline 3a was produced solely in 42% yield (Table 1, entry 1). The structure of 3a was confirmed by matching the ¹H, ¹³C NMR spectra and HRMS with the reported data.^2a,16 The cascade reaction herein was unambiguously progressed through the initial formation of more stable E-imine isomer, which offered 3a rather than 4a that would be obtained from less stable Z-imine (Scheme 2). Now because 3a is a biologically prominent compound as per reports,^1,2 we focused on to the synthesis of 2-(pyridin-4-yl) quinolines. Then, exhaustive studies of the reaction conditions for the synthesis of 3a by employing an array of catalytic systems, bases, ligands, temperatures, additives and solvents were conducted (Table 1). It was found that the presence of combined additives of 4 Å MS with MgSO₄ fabricated Pd₂(dba)₃ as the most suitable catalyst for the reaction among others such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, PdCl₂, Pd(MeCN)₂Cl₂ and Pd(OAc)₂ (entries 1–9). The use of toluene as the solvent led the reaction most effectively compared to other solvents like DMF, DMA, DMSO, xylene and mesitylene (entries 10–14).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Ligand	Additive		T/°C	Base (equiv.)	Time/h	Yield^b (%)
				I	II
a Reactions were carried out with 1a (0.654 mmol), 2a (0.687 mmol), Pd-catalyst (5 mol%), ligand (10 mol%), base in 5 mL of solvent. 65 mg of 4 Å MS and additive II (6 equiv.) were used.b Isolated yields.
1	Pd2(dba)3	DMF	PPh3	—	—	110	Et3N(7)	24	42
2	Pd2(dba)3	DMF	PPh3	4 Å MS	—	110	Et3N(7)	24	49
3	Pd2(dba)3	DMF	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	58
4	Pd2(dba)3	DMF	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	53
5	Pd(PPh3)4	DMF	—	4 Å MS	MgSO4	110	Et3N(7)	24	49
6	Pd(PPh3)2Cl2	DMF	—	4 Å MS	MgSO4	110	Et3N(7)	24	48
7	PdCl2	DMF	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	45
8	Pd(MeCN)2Cl2	DMF	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	47
9	Pd(OAc)2	DMF	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	51
10	Pd2(dba)3	DMA	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	53
11	Pd2(dba)3	DMSO	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	50
12	Pd2(dba)3	Toluene	PPh3	4 Å MS	MgSO4	Reflux	Et3N(7)	24	67
13	Pd2(dba)3	Xylene	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	60
14	Pd2(dba)3	Mesitylene	PPh3	4 Å MS	MgSO4	110	Et3N(7)	24	58
15	Pd2(dba)3	Toluene	PCy3	4 Å MS	MgSO4	Reflux	Et3N(7)	24	59
16	Pd2(dba)3	Toluene	Dppp	4 Å MS	MgSO4	Reflux	Et3N(7)	24	64
17	Pd2(dba)3	Toluene	L1	4 Å MS	MgSO4	Reflux	Et3N(7)	24	68
18	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Et3N(7)	24	75
19	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	90	Et3N(7)	24	52
20	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	100	Et3N(7)	24	62
21	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	120	Et3N(7)	24	72
22	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Et3N(3)	24	73
23	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Et3N(2)	24	75
24	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Et3N(1)	24	56
25	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Et3N(2)	12	0
26	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Et3N(2)	18	47
27	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	(Me2CH)2NEt	24	49
28	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Me3N(2)	24	0
29	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	K2CO3	24	0
30	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Cs2CO3	24	0
31	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Na2CO3	24	0
32	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	Li2CO3	24	0
33	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	NaOAc	24	0
34	Pd2(dba)3	Toluene	L2	4 Å MS	MgSO4	Reflux	KOAc	24	0

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Scheme 2 Palladium-catalyzed cyclization reaction.

Then, various phosphine ligands, including PCy₃, dppp and xantphos L₁ were tested, but all produced 3a in lower yields (entries 15–17). When (R)-(+)-Tol-BINAP L₂ was used, 3a was obtained in increased yield of 75% (entry 18). It was observed that the reaction afforded 3a in lower yields on decreasing the temperature below 110 °C (entries 19 and 20), and the elevation of temperature also failed to improve the yield of the product (entry 21). The yield was found to be unbiased until 2 equiv. of triethylamine below which led to a decrease in yield (entries 22–24). The formation of 3a was initiated after 12 h of reaction time (entries 25 and 26). When N,N-diisopropylethylamine (Hunig's base) was used as a base, product 3a was solely obtained in reduced yield of 49% (entry 27). In contrast, when bases having a lack of ethylene source, like Me₃N, K₂CO₃, Cs₂CO₃, Na₂CO₃, Li₂CO₃, NaOAc or KOAc, were used, the formations of 3a was not observed (entries 28–34). Hence, the initial base choice as triethylamine and the arbitrary set of the reaction time at 24 h favoured our reaction to display an unexpected and unmatched result.

To extend the scope and general applicability of the protocol, a range of reactions was conducted with various 2-iodoanilines 2a–f and pyridine-4-carbaldehydes 1a–b (Table 2), under the optimized conditions mentioned above (Table 1, entry 23). They smoothly reacted to produce corresponding quinolines 3 in moderate to high yields with a tolerance of electron-donating, as well as electron-withdrawing groups on aromatic rings. However, a reduced trend of yields was noticed with stronger withdrawal substitution on 2-iodoaniline ring (Table 2). On the other hand 2-iodo-4,6-dimethylaniline 2g, 2-bromoaniline 2h and benzaldehyde 6 failed to afford quinolines 3, although corresponding imines were solely isolated (compounds 5a–b and 7 in Table 3). Similar results were observed on carrying out the reaction for 12 h or in the absence of the Pd-catalyst for 24 h (Table 3, 5c–d). It is clear that pyridinyl nucleus assisted the double C–H insertions of Et₃N (compare the formations of 3a–j and 7), which was not obeyed because of the presence of an extra ortho methyl group forcing 5a not to achieve appropriate geometry for cyclization. It is also elucidated that stronger withdrawal substitution on 2 reduced the yields of the imines 5, from which corresponding quinolines 3 were obtained in lower yields (compare yields for 5a and 5d). Moreover, 2-iodo-4-nitro-aniline 2i failed to afford 3 or 5.

Table 2 Pd-Catalyzed multicomponent synthesis of quinolines^a,b

a All the reactions were carried out with 1 (0.654 mmol), 2 (0.687 mmol), Pd₂(dba)₃ (5 mol%), L₂ (10 mol%), Et₃N (2 equiv.), 65 mg of 4 Å MS and MgSO₄ (6 equiv.) in toluene (5 mL).b Isolated yields.

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Table 3 Isolation of intermediate imine^a,b

a Reactions were carried out with 1 (0.654 mmol), 2 (0.687 mmol), Pd₂(dba)₃ (5 mol%), L₂ (10 mol%), Et₃N (2 equiv.), 65 mg of 4 Å MS and MgSO₄ (6 equiv.) in toluene (5 mL).b Isolated yields.c Reaction time 12 h.d Absence of Pd₂(dba)₃.e Absence of Pd₂(dba)₃.

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A proposed catalytic cycle for the synthesis of quinoline 3 is depicted in Scheme 3. In this mechanism, palladium undergoes oxidative addition to the carbon–iodine bond of imine 5 to form 11. Both the olefinic C–H bonds of vinyl(diethyl)amine 10, produced from triethylamine as per report,¹⁷ can participate in insertion reactions via π-complex. However, a majority of that could proceed by the involvement of the C–H bond β to the nitrogen atom¹⁸ to produce the primary alkylpalladium complex 12. The reaction at the highlighted C–H bond produces seven-membered palladacycle 13. Reductive elimination delivers 14, and subsequent 1,2-elimination of Et₂NH provides 2-(pyridin-4-yl) quinoline 3. There is no direct evidence for the formation of 10 at present; however, it is clear that triethylamine is the only source of the ethylene moiety required for the complete cyclization to afford 3 (compare entries 1–26 and 28–34 in Table 1).

Scheme 3 Proposed mechanism for the synthesis of 2-(pyridin-4-yl) quinolines 3.

In conclusion, we have developed a straightforward synthesis of 2-(pyridin-4-yl) quinolines in one-pot via the multicomponent reaction of pyridine-4-carbaldehyde, 2-iodoaniline and triethylamine. In this reaction, three new bonds are formed with the assembly of [3 + 2 + 1] atom fragments. The reactions deal with longer reaction time. The starting materials are cheap and readily available. The unprecedented double C–H insertions of Et₃N have made this approach novel.

Acknowledgements

We are thankful to CSIR, DST and UGC (New Delhi), India for financial support. We are also grateful to Sk Nurul Islam of Indian Institute of Technology Bombay for providing HRMS.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterization for all final compounds. For ESI see DOI: 10.1039/c4ra08624d

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