Pd catalyzed facile synthesis of cyclopenta[b]quinolin-1-one via sequential Sonogashira coupling and annulation. An unusual mode of ring closure, using sulphur as a soft nucleophile

Abstract

Pd mediated one pot sequential Sonogashira coupling followed by annulation using o-alkynyl aldehyde is reported. Contrary to the established modes of ring closures, an unusual mode of the initial attack of sulphur across the triple bond occurs leading to a cascade of reactions. The protocol requires just single column chromatography, delivering cyclopenta[b]quinolin-1-one in high yields. Furthermore chemoselective transformations were carried out across annulated precursors.

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Aza aromatics are a privileged class of skeletons present in a number of natural products and biologically active molecules, with pyridine annulated fused rings being the most common architectural feature.¹ In particular cyclopentenone fused pyridine and quinoline analogues have found frequent appearance in natural products along with a wide spectrum of biological activities.² Prominent amongst them are anticancer,^2a,d topoisomerase inhibitory activities,^2b,h anti tuberculosis,^2c DNA ligands^2g and drug like properties.^2e However, in spite of having such activities, less synthetic attention has been given towards the development of protocols for construction of these important skeletons.³ Recently Gao has carried out photoinduced radical cyclization for synthesis of these scaffolds.^3a Yao has developed reductive cyclization towards this end.^3e Our group has also reported Pd-catalyzed synthesis of 1-oxo, 3-methyl-2,3-dihydro-cyclopenta[b]quinolin via intramolecular Heck reactions of 2-chloroquinolin-3-yl-(1-homoallyl)alcohols.^3g With a prominent void in the development of efficient protocols for these skeletons, we became interested in developing a robust method utilizing our research interest in the area of coupling and cyclization reactions for synthesis of various pyridine/quinoline annulated molecules.^4,5

ortho-Alkynyl aldehyde (Fig. 1) has emerged as a valuable synthon in recent years, for the development of a wide range of protocols towards synthesis of various cyclic skeletons. With dual functional groups in close proximity they serve as an ideal platform for various nucleophile triggered cascade reactions.⁶ Previously we have used 2-(alkynyl)quinoline-3-carbaldehydes as precursors for synthesis of pyrano-quinoline where methoxide acted as a hard nucleophile triggering the domino sequence for cyclization (eqn (1), Fig. 1).^7a Contributions from the lab of Zhao & Wang^7b (eqn (2)), Li^7c (eqn (3)) and others⁶ have also led to the domino reaction initiated by a nucleophilic attack over aldehydes. However a soft nucleophile such as sulphur has not been studied. We envisioned that the sulphur anion may undergo initial attack across the C–C π bond, a soft electrophile rather than aldehydes, which could be trapped by a tethered carbonyl moiety (eqn (4)).

Fig. 1 Different modes of cyclization and present work.

It is worth mentioning here that this would be contrary to the well-established predominant mode of initial attack where various nucleophiles have been added on aldehydes⁶ and other polarized functional groups such as imines,⁸ nitriles⁹ and Michael acceptors¹⁰ followed by cyclization on triple bonds.

Development of protocols which leads to rapid synthesis of the desired product with a minimum number of steps involved has been a central theme in green chemistry. The advantages offered are obvious in terms of cost and economical concerns. Herein we report the palladium catalyzed synthesis of the cyclopenta[b]quinolin-1-one skeleton via sequential Sonogashira coupling and annulation. The protocol involves just single column chromatography (even including the synthesis of precursor)¹¹ along with different substitution patterns. We initiated our studies with the synthesis of the required precursor via Sonogashira coupling (Scheme 1).¹² Initially, we examined the palladium-catalyzed reaction of 2a with Na₂S.^7a

Scheme 1 Synthesis of required precursor 2a.

Thus, substrate 2a (0.50 mmol) was treated with 10 mol% of Pd(OAc)₂, 20 mol% of PPh₃ and 2 eq. Na₂S, in methanol at 80 °C under an open atmosphere followed by quenching with benzyl chloride (Table 1, entry 1). The isolated product was characterized as 3-benzylsulfanyl-2-phenyl-cyclopenta[b]quinolin-1-ones 3a from its spectral and analytical data and furthermore unambiguously confirmed by single crystal X-ray analysis (Fig. 2).¹³

Fig. 2 ORTEP diagram of 3a.

Table 1 Optimization of reaction conditions for the annulation step

Entry	Catalyst (mol%)	Ligand (mol%)	Solvent	Time (min)	Yield^a (%)
a All reactions were carried out using 0.5 mmol of 2a. Isolated yield. b Reaction at 60 °C. c Reaction at 100 °C.
1	Pd(OAc)2 (10)	Ph3P (20)	MeOH	90	45
2	Pd(OAc)2 (5)	Ph3P (10)	MeOH	90	56
3	Pd(OAc)2 (5)	Ph3P (10)	DMF	15	82
4	Pd(OAc) 2 (2.5)	Ph 3 P (5)	DMF	15	88
5	Pd(OAc)2 (1.0)	Ph3P (2.5)	DMF	30	72
6^b	Pd(OAc)2 (2.5)	Ph3P (5)	DMF	15	42
7^b	Pd(OAc)2 (2.5)	Ph3P (5)	DMF	45	72
8^c	Pd(OAc)2 (2.5)	Ph3P (5)	DMF	15	60
9	PdCl2 (2.5)	Ph3P (5)	DMF	30	70
10	Pd(dba)2 (2.5)	Ph3P (5)	DMF	55	65
11	Pd(OAc)2 (2.5)	Cy3P (5)	DMF	65	69
12	Pd(OAc)2 (2.5)	BINAP (2.5)	DMF	40	55
13	Pd(OAc)2 (2.5)	BINAP (5)	DMF	40	58
14	Pd(OAc)2 (2.5)	TMEDA (5)	DMF	90	50
15	Pd(OAc)2 (2.5)	Ph3P (5)	CH3CN	60	60
16	Pd(OAc)2 (2.5)	Ph3P (5)	THF	75	60
17	Pd(OAc)2 (2.5)	Ph3P (5)	Dioxane	70	62
18	Pd(OAc)2 (2.5)	Ph3P (5)	DMSO	50	72
19	CuI (2.5)	Ph3P (5)	DMF	45	—
20	AgOAc (2.5)	Ph3P (5)	DMF	30	—

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The formation of this product revealed that the preferred attack of sulphide takes over the alkyne rather than the carbonyl. This was rewarding as it leads to a new trend of cyclization and also delivered the highly substituted fused cyclopentenone annulated quinoline derivative. Inspired by the new result, we next considered finding optimal conditions. The results are summarized in Table 1. Lowering the mol% of Pd(OAc)₂ and Ph₃P to 5% and 10% respectively resulted in an increase of yield (56%, entry 2). Changing the solvent from methanol to DMF, the reaction was completed in 15 minutes along with enhanced yield to 82% (entry 3). On further decreasing the mol% ratio of the catalyst and ligand to 2.5% and 5% respectively, the yield of 3a further increased to 88% (entry 4). However further reduction in loading was not helpful (entry 5). Decreasing temperature leads to longer reaction times and decrease in yield (entries 6 & 7). Increasing reaction temperature lowered the yields (entry 8). Other available palladium catalysts such as PdCl₂ and Pd(dba)₂ were found less effective (entries 9 and 10). Ligands such as Cy₃P, bidentate BINAP and nitrogen ligand TMEDA were also examined with Pd(OAc)₂ (entries 11–14), but were found less effective than PPh₃. The influence of other solvents such as CH₃CN, THF, dioxane and DMSO (entries 15–18) was found less effective than DMF. Use of other metals such as CuI and AgOAc, didn't lead to product formation (entries 19 & 20). This could be attributed to the better electrophilic character of the palladium complex. Thus, the combination of 0.5 mmol of 2a with 2.5 mol% of Pd(OAc)₂, 5 mol% of Ph₃P, 2 eq. each of sodium sulphide and benzyl chloride in DMF at 80 °C, under an aerobic atmosphere was identified as the optimal reaction conditions (entry 4). As the Sonogashira and annulation steps were Pd catalyzed, we envisioned the possibility of a one pot sequence of both reactions. This would save time and solvent and avoid column chromatography purification of 2a. Thus, a mixture of 1a (0.5 mmol) and phenylacetylene (0.6 mmol) was treated with 5 mol% of Pd(OAc)₂, 10 mol% of PPh₃ and 2 eq. Et₃N in acetonitrile at 80 °C for 5 h under a N₂ atm. Subsequently volatiles were removed under reduced pressure. DMF along with 2.5 mol% of Pd(OAc)₂, 5 mol% of Ph₃P and 2 eq. of Na₂S were added to the reaction mixture and it was heated at 80 °C under an open atm for 15 minutes. Quenching with 2 eq. of benzyl chloride, led to the formation of 3a in 82% overall yield (Scheme 2). With the one-pot optimal reaction conditions in hand, we next examined the generality of this reaction. Initially we extended the scope to various alkynes (Table 2). All reactions proceeded smoothly and were completed in 10–25 min. The corresponding cyclized products 3a–3e were obtained in 70–81% yields. No significant variation in the yields was found with phenylacetylene bearing electron donating or electron withdrawing groups. 3-Ethynyl-thiophene also afforded the cyclized product 3e in 70% yield. The generality of the reaction was further examined with various quinoline precursors. All the reactions proceeded smoothly and were completed in 10–25 min affording the corresponding cyclized products 3f–3k in 68–79% yields (Table 2). The reaction was also examined on the pyridine precursor which afforded the cyclized product 3l in 80% yield. Next, we extended the reaction scope by using different alkyl halides along with sodium sulphide. The reactions proceeded smoothly and afforded the product in good yields 3m–3r. Furthermore, quenching of the reaction with water instead of alkyl halide gave 3s in 72% yield. With the presence of multifunctional groups in cyclopentenone-fused quinoline 3, we further explored the possible transformation of these functionalities (Scheme 3). The 3-benzylsulfanyl group in 3 could be substituted by nucleophiles such as amines (primary and secondary) and alcohols to afford products 4, 5 and 6 in 87%, 85%, and 90% yields respectively. Similarly, the carbonyl group could also be converted to a tertiary alcohol using the Barbier reaction and afforded the allylated product 7 in 80% yield. It is worth mentioning here that in spite of different reactive sites on the periphery of the ring, all the transformations were chemoselective and delivered the products in high yields.

Scheme 2 Sequential Sonogashira coupling and annulation.

Scheme 3 Synthetic transformations of 3.

Table 2 Reaction scope for the synthesis of 2,3-disubstituted cyclopenta[b]quinolin-1-one^a

a (i) Sonogashira coupling: 5 mol% Pd(OAc)₂, 10 mol% Ph₃P, 2 eq. Et₃N, CH₃CN, 80 °C, N₂ atm; (ii) annulation: 2.5 mol% Pd(OAc)₂, 5 mol% Ph₃P, 2 eq. each of Na₂S and R′′X, DMF, 80 °C, air. (iii) Overall yield over 2 steps and reaction time for each step are mentioned respectively.

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With a view of gaining further understanding about the path of the reaction, 2a was treated with ethane thiol and K₂CO₃ under optimized conditions. The reaction was completed in 1 h, however the isolated product didn't turn out to be a cyclized product. Instead it was characterized as 8 (Scheme 4). Lack of formation of the cyclized product suggested that the reaction initially proceeded via addition across triple bonds in Michael fashion which failed to further cyclize.¹⁴ A possible mechanism of the reaction is depicted in Fig. 3. Initial coordination of the triple bond with Pd(OAc)₂ leads to activation. This could undergo nucleophilic attack either by aldehydic oxygen followed by the sulphide anion¹⁵ to give C (path A) or directly via the sulphide anion to give C (path B). Subsequent thiirane formation followed by nucleophilic attack on aldehydes gives D. Proton transfer followed by double bond formation and thiirane ring opening leads to expulsion of Pd⁰ which upon aerial oxidation gets converted to Pd(II). Finally proton abstraction and quenching with RX give the required product.

Scheme 4 Addition of ethane thiol across the triple bond.

Fig. 3 Possible mechanism.

In conclusion, an efficient methodology has been developed for the synthesis of highly functionalized 3-alkylsulfanyl-2-aryl-cyclopenta[b]quinolin-1-ones via one pot two step sequential palladium-catalyzed Sonogashira coupling and annulation reactions as key steps. Furthermore, the synthetic potential of the annulated product was demonstrated by several chemoselective transformations.

Acknowledgements

RK and TG are thankful to UGC for the fellowship. KCB is thankful to DST for the fellowship. RMS is thankful to CSIR for funding (02(0073)/12EMR-II) and director CBMR Lucknow for the HRMS spectra. The authors are thankful to Deepak Joshi for solving crystallographic data. RMS is thankful to Prof. Y. D. Vankar, IIT Kanpur for fruitful suggestions in mechanism.

Notes and references

1. (a) E. Pan, S. Cao, P. J. Brodie, M. W. Callmander, R. Randrianaivo, S. Rakotonandrasana, E. Rakotobe, V. E. Rasamison, K. TenDyke, Y. Shen, E. M. Suh and D. G. I. Kingston, J. Nat. Prod., 2011, 74, 1169; (b) M.-H. Yan, P. Cheng, Z.-Y. Jiang, Y.-B. Ma, X.-M. Zhang, F.-X. Zhang, L.-M. Yang, Y.-T. Zheng and J.-J. Chen, J. Nat. Prod., 2008, 71, 760; (c) C. Dan, Y. Zhou, D. Ye, S. Peng, L. Ding, M. L. Gross and S. X. Qiu, Org. Lett., 2007, 9, 1813; (d) T.-S. Wu and F.-W. Lin, J. Nat. Prod., 2001, 64, 1404.
2. (a) L. Goswami, S. Gogoi, J. Gogoi, R. K. Boruah, R. C. Boruah and P. Gogoi, ACS Comb. Sci., 2016, 18, 253; (b) E. Kiselev, D. Sooryakumar, K. Agama, M. Cushman and Y. Pommier, J. Med. Chem., 2014, 57, 1289; (c) G. C. Muscia, G. Y. Buldain and S. E. Asís, Eur. J. Med. Chem., 2014, 73, 243; (d) S. Chakrabarty, M. S. Croft, M. G. Marko and G. Moyna, Bioorg. Med. Chem., 2013, 21, 1143; (e) D. Camp, R. A. Davis, M. Campitelli, J. Ebdon and R. J. Quinn, J. Nat. Prod., 2012, 75, 72; (f) R. Miri, O. Firuzi, P. Peymani, M. Zamani, A. R. Mehdipour, Z. Heydari, M. M. Farahani and A. Shafiee, Chem. Biol. Drug Des., 2012, 79, 68; (g) N. Malecki, P. Carato, B. Rigo, J.-F. Goossens, R. Houssin, C. Bailly and J.-P. Hénichart, Bioorg. Med. Chem., 2004, 12, 641; (h) L. W. Deady, A. J. Kaye, G. J. Finlay, B. C. Baguley and W. A. Denny, J. Med. Chem., 1997, 40, 2040; (i) Y.-C. Wu and C.-Y. Duh, J. Nat. Prod., 1990, 5, 1327.
3. (a) S. Cai, Z. Xiao, J. Ou, Y. Shi and S. Gao, Org. Chem. Front., 2016, 3, 354; (b) M. Zheng, P. Chen, W. Wu and H. Jiang, Chem. Commun., 2016, 52, 84; (c) J. K. Laha, K. P. Jethava and S. Patel, Org. Lett., 2015, 17, 5890; (d) N. Marquise, V. Dorcet, F. Chevallier and F. Mongin, Org. Biomol. Chem., 2014, 12, 8138; (e) R. R. Rajawinslin, S. D. Gawande, V. Kavala, Y.-H. Huang, C.-W. Kuo, T.-S. Kuo, M.-L. Chen, C.-H. He and C.-F. Yao, RSC Adv., 2014, 4, 37806; (f) S. Dhara, A. A. S. Nandi, S. Baitalik and J. K. Ray, Tetrahedron Lett., 2013, 54, 63; (g) R. M. Singh, A. Chandra, N. Sharma, B. Singh and R. Kumar, Tetrahedron, 2012, 68, 9206; (h) G. Oppermann, M. Stranberg, H. W. Moore, E. Schaumann and G. Adiwidjaja, Synthesis, 2010, 2027.
4. (a) J. B. Singh, K. C. Bharadwaj, T. Gupta and R. M. Singh, RSC Adv., 2016, 6, 26993; (b) M. Asthana, J. B. Singh and R. M. Singh, Tetrahedron Lett., 2016, 57, 615; (c) M. Asthana, R. Kumar, T. Gupta and R. M. Singh, Tetrahedron Lett., 2015, 56, 907; (d) M. Asthana, N. Sharma, R. Kumar, J. B. Singh and R. M. Singh, Tetrahedron Lett., 2014, 55, 4378; (e) M. Asthana, N. Sharma and R. M. Singh, Tetrahedron, 2014, 70, 7996; (f) D. Nandini, M. Asthana, T. Gupta, R. P. Singh and R. M. Singh, Tetrahedron, 2014, 70, 8592; (g) R. M. Singh, K. C. Bharadwaj and D. K. Tiwari, Beilstein J. Org. Chem., 2014, 10, 2975; (h) D. Nandini, M. Asthana, K. Mishra, R. P. Singh and R. M. Singh, Tetrahedron Lett., 2014, 55, 6257.
5. (a) P. Zhao, Y. Liu and C. Xi, Org. Lett., 2015, 17, 4388; (b) Y. Wang, C. Chen, S. Zhang, Z. Lou, X. Su, L. Wen and M. Li, Org. Lett., 2013, 15, 4794; (c) Y. Wang, C. Chen, J. Peng and M. Li, Angew. Chem., Int. Ed., 2013, 52, 5323.
6. (a) M. D. Acqua, B. Castano, C. Cecchini, T. Pedrazzini, V. Pirovano, E. Rossi, A. Caselli and G. Abbiati, J. Org. Chem., 2014, 79, 3494; (b) D. Malhotra, L.-P. Liu, M. S. Mashuta and G. B. Hammond, Chem. – Eur. J., 2013, 19, 4043; (c) E. Parker, N. Leconte, T. Godet and P. Belmont, Chem. Commun., 2011, 47, 343; (d) X. Bantreil, C. Vaxelaire, T. Godet, E. Parker, C. Sauer and P. Belmont, Org. Biomol. Chem., 2011, 9, 4831; (e) A. B. Beeler, S. Su, C. A. Singleton and J. A. Porco Jr., J. Am. Chem. Soc., 2007, 129, 1413; (f) T. Godet, C. Vaxelaire, C. Michel, A. Milet and P. Belmont, Chem. – Eur. J., 2007, 13, 5632; (g) N. T. Patil and Y. Yamamoto, J. Org. Chem., 2004, 69, 5139.
7. (a) A. Chandra, B. Singh, R. S. Khanna and R. M. Singh, J. Org. Chem., 2009, 74, 5664; (b) Z. Chai, Z. F. Xie, X.-Y. Liu, G. Zhao and J.-D. Wang, J. Org. Chem., 2008, 73, 2947; (c) X. Yao and C.-J. Li, Org. Lett., 2006, 8, 1953.
8. (a) Z. Guo, M. Cai, J. Jiang, L. Yang and W. Hu, Org. Lett., 2010, 12, 652; (b) S. Obika, H. Kono, Y. Yasui, R. Yanada and Y. Takemoto, J. Org. Chem., 2007, 72, 4462; (c) R. Yanada, S. Obika, H. Kono and Y. Takemoto, Angew. Chem., Int. Ed., 2006, 45, 3822; (d) N. S. Asao, S. Y. S. T. Nogami and Y. Yamamoto, Angew. Chem., Int. Ed., 2005, 44, 5526.
9. (a) R. M. Singh, R. Kumar, N. Sharma and M. Asthana, Tetrahedron, 2013, 69, 9443; (b) L.-M. Wei, C.-F. Lin and M.-J. Wu, Tetrahedron Lett., 2000, 41, 1215; (c) R. C. Larock, Q. Tian and A. A. Pletnev, J. Am. Chem. Soc., 1999, 121, 3238.
10. (a) G. Qiu, Q. Ding, K. Gao, Y. Peng and J. Wu, ACS Comb. Sci., 2011, 13, 13; (b) L. Liu, L. Wei, Y. Lu and J. Zhang, Chem. – Eur. J., 2010, 16, 11813.
11. (a) A. Srivastava and R. M. Singh, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 2005, 44, 1868.
12. (a) D. Wang and S. Gao, Org. Chem. Front., 2014, 1, 556; (b) R. Chinchilla and C. Nájera, Chem. Soc. Rev., 2011, 40, 5084; (c) R. Chinchilla and C. Nájera, Chem. Rev., 2007, 107, 874; (d) H. Doucet and J.-C. Hierso, Angew. Chem., Int. Ed., 2007, 46, 834.
13. CCDC no. 1046365.
14. H. Tsukamoto, T. Ueno and Y. Kondo, Org. Lett., 2007, 9, 3033.
15. (a) I. Talbi, C. Alayrac, J.-F. Lohier, S. Touil and B. Witulski, Org. Lett., 2016, 18, 2656; (b) S. Zheng, W. Huang, N. Gao, R. Cui, M. Zhang and X. Zhao, Chem. Commun., 2011, 47, 6969; (c) L.-L. Sun, C.-L. Deng, R.-Y. Tang and X.-G. Zhang, J. Org. Chem., 2011, 76, 7546.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterisation data and copies of ¹H & ¹³C NMR spectra. CCDC 1046365. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00203j

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