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Stereoselective tandem synthesis of thiazolo fused naphthyridines and thienopyridines from o-alkynylaldehydes via Au(III)-catalyzed regioselective 6-endo-dig ring closure† Rajeev R. Jha, Rakesh K. Saunthwal and Akhilesh K. Verma*
An operationally simple approach for the stereoselective tandem synthesis of novel thiazolo fused naphthyridines 5a–o and thienopyridines 8a–e by the reaction of o-alkynylaldehydes with L-cystine
methyl ester hydrochloride via Au(III)-catalyzed regio-
selective 6-endo-dig ring closure under mild reaction conditions is described. It is noteworthy that alkynes bearing an alkyl and a strong electron-withdrawing nitro group successfully afforded the desired products in good yields.
A wide variety of biologically active natural and synthetic compounds are known to have substituted heterocycles in their core.1 Similarly, their sulphur analogues like thiazolines are signature metal binding motifs common to clinically important non-ribosomally derived macrocyclic peptides.2 These optically active thiazolines are also widely applicable in asymmetric synthesis as chiral templates and ligands.3 The chiral compounds have emerging significance owing to the difference in biological activity of each isomer.4 The significance of these heterocyclic derivatives justifies a need to develop new synthetic strategies for these molecules.5 A literature search revealed that tandem6 and domino7 reactions have emerged as an efficient tool for the synthesis of fused heterocycles. More recently, o-alkynylaldehydes have been widely explored as versatile building blocks for the assembly of a wide variety of heterocyclic scaffolds.8 The literature search revealed that the stereoselective synthesis of heterocycles from o-alkynylaldehydes has not been explored. In continuation of our work on the synthesis of heterocycles9 from aldehydes/o-alkynylaldehydes, and the application of o-alkynylaldehydes as building blocks in the synthesis of a variety of heterocyclic scaffolds (Scheme 1),10 we hypothesized that the reaction of o-alkynylaldehydes with L-cystine methyl ester hydrochloride might offer an opportunity for the
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India. E-mail: [email protected]; Tel: +91-11-27666272(Ext. 175) † Electronic supplementary information (ESI) available. See 10.1039/c3ob42035c
552 | Org. Biomol. Chem., 2014, 12, 552–556
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Scheme 1
Synthesis of racemic heterocycles.
Scheme 2 Au-catalyzed stereoselective synthesis of thiazolo-fusednaphthyridines and thienopyridines via 6-endo-dig cyclization.
diastereoselective synthesis of thiazolo fused heterocycles (Scheme 2). To identify the optimal conditions for the reaction, a previously reported catalyst of Ag(I) for cyclization was scrutinized in the reaction of o-alkynylaldehyde 1a with L-cystine methyl
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Table 1
Communication
Optimization of reaction conditionsa
Entry
Solvent
Cat. (mol%)
T (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
H2O H2O H2O EtOH THF MeOH CHCl3 DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE
AgNO3/5 AgNO3/5 AgNO3/10 AgNO3/10 AgNO3/10 AgNO3/10 AgNO3/10 AgNO3/10 AgOAc/10 AgOTf/10 AuCl3/10 AuCl3/10 AuCl3/5 AuCl3/10 Cu(OTf)2/10 CuI/10 PdCl2/10 —
3 3 3 3 3 3 3 3 3 3 3 6 3 1 3 3 3 3
05c 13 20 37 23 31 39 44 53 78 85 83 59 46 63 13 00 00
Fig. 1
NOESY studies of compound 5a.
a Reactions were performed using 0.5 mmol of 1a, 1.1 equiv. of 4, 1.1 equiv. of Et3N, catalyst in 2.0 mL solvent at 70 °C unless otherwise noted. b Isolated yield. c At 25 °C. DCE = 1,2-dichloroethane.
ester hydrochloride 4 in the presence of 1.1 equiv. of Et3N (Table 1). When 5 mol% of AgNO3 was used as a catalyst in H2O at 25 °C for 3 h, thiazolo fused-naphthyridine 5a was obtained in only 5% yield (entry 1). An increase in the temperature to 70 °C provided the product 5a in 13% yield (entry 2). Increasing the catalyst loading from 5 to 10 mol% afforded the products 5a in 20% yields (entry 3). Upon screening of various solvents, 1,2-dichloroethane was found to be most suitable for the reaction (entries 3–8). Use of AgOAc and AgOTf was found effective for the reaction and afforded the desired product 5a in 53 and 78% yields respectively (entries 9–10). Use of gold(III) chloride improved the yield of the product, and afforded the 6-endo-dig cyclized product 5a in 85% yield (entry 11). The yield of the product remained almost the same when the reaction was run for 6 h (entry 12). Further lowering of the catalyst loading and time of the reaction decreases the yield of the product (entries 13–14). Use of Cu(OTf )2 provided the product 5a in 63% yield (entry 15); however, CuI and PdCl2 were found ineffective (entries 16–17). No product was observed when the reaction was allowed to proceed in the absence of a catalyst (entry 18). After screening various reaction conditions it was found that 10 mol% of AuCl3 in EDC was found to be the best for obtaining the desired product 5a (entry 10). The structure of the product 5a was fully characterized by the 1H NMR, 13C NMR and by NOESY experiment. Use of L-cystine methyl ester controls the chirality in the product and afforded the 6-endo-dig cyclized product with high diastereoselectivity. The relative configuration of the new stereogenic center at Hb in product 5a was determined by NOESY experiments (Fig. 1).11–13
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Scheme 3 Gold-catalyzed diastereoselective synthesis of 6-endo dig thiazolo fused naphthyridines. Reactions were performed using 0.5 mmol of 1, 1.1 equiv. of 4, 1.1 equiv. of Et3N, 10 mol% AuCl3 in 2.0 mL DCE at 70 °C for 3–5 h.
H NMR spectra of 5a show that Hb appears at 6.39 as a singlet and Ha at 4.29–4.27 ppm as a multiplet. No distinct NOE effect was observed between Hb and Ha in compound 5a. This suggests that Hb and Ha are located in trans-orientation. With an optimized condition in hand (Table 1, entry 11) we investigated the scope of the developed chemistry using a variety of ortho-alkynylquinoline-3-carbaldehydes 1a–o and L-cystine methyl ester hydrochloride 4 for the selective synthesis of 6-endo-dig cyclized products 5a–o (Scheme 3). Substrate 1a bearing phenyl substituent at R2 provided the product 5a in 80% yield. Alkynes bearing electron-rich substituents at R2 on reaction with 4 afforded the desired products 5b–e in 79–85% yields with high diastereoselectivity. Substrates 1f–g 1
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bearing substitution at the meta position of the phenyl ring afforded the desired products 5f–g comparatively in lower yields with high diastereomeric ratios (dr). The majority of the reported syntheses of heterocycles using o-alkynylaldehydes were not successful with alkynes bearing strong electron-withdrawing groups.10a,b,14 It is noteworthy that alkynes 1h bearing a strong electron-withdrawing nitro group at the 4-position of the phenyl ring were found successful for the reaction and afforded the desired product 5h in 63% yield with high diastereoselectivity. The probable reason could be the strong nucleophilicity of the thiol group. Substrates 1i–k bearing a cyclohexyl, cyclopropyl and n-hexyne group were found successful for the reaction and provided the diastereomeric mixture of desired products 5i–k in 60–68% yields. Reaction of 6-methoxy substituted o-alkynylaldehydes 1l–m afforded the mixture of diastereomeric product 5l–m in 68–75% yields. Reaction of 6-methyl substituted o-alkynylaldehydes 1o with 4 provided the single diastereomeric product 5o in good yield. Reaction of 2-((4-(tert-butyl)phenyl)ethynyl)benzaldehyde (2) afforded the desired product 6 in 48% yield (Scheme 4). The low yield of the product 6 is due to the formation of a byproduct in 42% yield. The byproduct was assigned to be 3-(4-(tert-butyl)phenyl)isoquinoline 7 as compared with the NMR spectra of the authentic sample. The possible formation of phenylisoquinoline 7 ( path b) along with product 6 ( path a) is explained in Scheme 3. We further extended the scope of the developed chemistry for the synthesis of another very important class of heterocyclic scaffold dihydro-2H-benzo[4,5]thieno[2,3-c]thiazolo[3,2-a]pyridine which is known as sulfur analogue of the β-carbolines (Scheme 5). Using the optimized reaction conditions (Table 1, entry 11), reaction of 3-(arylethynyl)benzo[b]thiophene-2-carbaldehydes 3a–e with L-cystine methyl ester hydrochloride 4 provided the thiazolo-pyridines 8a–e in good to moderate yields. All thiazolo-pyridines 8a–e were obtained as a mixture of diastereomers. The possible reason for the lower diastereoselectivities could be due to the structural difference between ortho-alkynylquinoline-3-carbaldehydes 1a–o and 3-alkynyl-benzothiophene-2-carbaldehydes 3a–e. Possibly in the case of quinoline substrates the presence of C-4 hydrogen restricts the attack of the SH group from below the plane; however, in the case of
Organic & Biomolecular Chemistry
Scheme 5 Gold-catalyzed synthesis of thiazolo fused pyridines 8. Reactions were performed using 0.5 mmol of 3, 1.1 equiv. of 4, 1.1 equiv. of Et3N, 10 mol% AuCl3 in 2.0 mL EDC at 70 °C for 3–5 h.
Fig. 2
Possible reason for the distereoselectivity.
Scheme 6
Scheme 4 Possible formation of thiazolo-fused isoquinoline 6 and isoquinoline 7.
554 | Org. Biomol. Chem., 2014, 12, 552–556
Plausible mechanism.
benzothiophene (no hindrance on imine carbon) the –SH group can attack on imine carbon from both the sides (Fig. 2). A plausible mechanism for the designed tandem approach is proposed in Scheme 6. Initially, the reaction of alkyne 1–3 and L-cystine methyl ester 4 generates key intermediate imine P. From intermediate P, two possibilities exist for the
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formation of product 5 (i.e., either thiazole ring from first or isoquinoline ring or vice versa). Intermediate Q could be formed by the intramolecular attack of the –SH group onto imine carbon ( path a), which upon π-complexation with AuCl3, would undergo a second intramolecular nucleophilic attack of the –NH onto triple bond to afford the desired product 5. Alternatively, the isoquinoline ring (intermediate R) could be generated by the intramolecular attack of the imine on the activated alkyne ( path b), which (R) on successive second intramolecular nucleophilic attack of the –SH group onto the quinolinium ring will furnish the desired product 5. In summary, for the first time we have described a stereoselective tandem synthesis of thiazolo fused naphthyridines and thienopyridines by the reaction o-alkynylaldehydes with inexpensive L-cystine methyl ester hydrochloride under mild reaction conditions. Structure and stereochemistry of the 6-endo-dig cyclized products were supported by the NOESY studies. Alkynes bearing electron-releasing, electron-withdrawing, alkyl and acyl groups successfully afforded the desired products in good yields. The tandem approach developed herein is general and expands the application of o-alkynylaldehydes for the synthesis of diastereoselective compounds, which are of high importance in medicinal chemistry. Further investigations of this synthetic protocol are under progress and will be reported in due course.
Acknowledgements We thank Department of Science and Technology (SR/S1/ OC-66/2010), DU-DST-PURSE University of Delhi for the financial support and USIC for providing instrumentation facility. R. R. J. and R. K. S. are thankful to CSIR and UGC for the fellowship.
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4 5
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Notes and references 1 (a) S. Antoniotti and E. Dunach, Tetrahedron Lett., 2002, 43, 3971; (b) R. Dua, S. Shrivastava, S. K. Sonwane and S. K. Srivastava, Adv. Biol. Res., 2011, 5, 120; (c) C. Gil and S. Bräse, J. Comb. Chem., 2009, 11, 175; (d) K. Bhadra and S. Kumar, Med. Res. Rev., 2011, 31, 821; (e) H. Fan, J. Peng, M. T. Hamann and J.-F. Hu, Chem. Rev., 2008, 108, 264; (f ) G. Vincent and R. M. Williams, Angew. Chem., Int. Ed., 2007, 46, 1517; (g) K. W. Bentley, Nat. Prod. Rep., 2006, 23, 444; (h) P. L. McGrane and T. Livinghouse, J. Am. Chem. Soc., 1993, 115, 11485; (i) J. C. Kwan, R. Ratnayake, K. A. Abboud, V. J. Paul and H. Luesch, J. Org. Chem., 2010, 75, 8012; ( j) S. Agarwal, S. Cämmerer, S. Filali, W. Fröhner, J. Knöll, M. P. Krahl, K. R. Reddy and H.-N. Knolker, Curr. Org. Chem., 2005, 9, 1601. 2 (a) M. C. Bagley, J. W. Dale, E. A. Merritt and X. Xiong, Chem. Rev., 2005, 105, 685; (b) J. Berdy, Adv. Appl. Microbiol., 1974, 18, 309; (c) M. Sellstedt and F. Almqvist, Org. Lett., 2008, 10, 4005; (d) V. Gududuru, E. Hurh, J. T. Dalton
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and D. D. Miller, J. Med. Chem., 2005, 48, 2584; (e) C. M. Marson, C. J. Matthews, E. Yiannaki, S. J. Atkinson, P. E. Soden, L. Shukla, N. Lamadema and N. S. B. Thomas, J. Med. Chem., 2013, 56, 6156. (a) P. Saravanan and E. J. Corey, J. Org. Chem., 2003, 68, 2760; (b) G. Cardillo, L. Gentilucci and A. Tolomelli, Aldrichimica Acta, 2003, 36, 39; (c) A. I. Meyers, J. Org. Chem., 2005, 70, 6137; (d) Y. Gnas and F. Glorius, Synthesis, 2006, 1899; (e) A. K. Ghosh, P. Mathivanan and J. Cappiello, Tetrahedron: Asymmetry, 1998, 9, 1; (f ) M. Gómez, G. Muller and M. Rocamora, Coord. Chem. Rev., 1999, 193, 769; (g) J. S. Johnson and D. A. Evans, Acc. Chem. Res., 2000, 33, 325; (h) P. Braunstein and F. Naud, Angew. Chem., Int. Ed., 2001, 40, 680; (i) D. Rechavi and M. Lemaire, Chem. Rev., 2002, 102, 3467; ( j) H. A. McManus and P. J. Guiry, Chem. Rev., 2004, 104, 4151; (k) M. Calmes, F. Escale and F. Paolini, Tetrahedron: Asymmetry, 1997, 8, 3691; (l) R. J. Bergeron, J. Wiegand, J. S. McManis, W. R. Weimar, J.-H. Park, E. E. McManis, J. Bergeron and G. M. Brittenham, J. Med. Chem., 2005, 48, 821; (m) M. Mellah, A. Voituriez and E. Schulz, Chem. Rev., 2007, 107, 5133. E. J. Ariens, Med. Res. Rev., 1986, 6, 451. (a) M. Juhász, L. Lázár and F. Fülöp, Tetrahedron: Asymmetry, 2011, 22, 2012; (b) T. H. Graham, Org. Lett., 2010, 12, 3614; (c) A.-C. Gaumont, M. Gulea and J. Levillain, Chem. Rev., 2009, 109, 1371; (d) T. Fukuhara, C. Hasegawa and S. Hara, Synthesis, 2007, 1528. (a) X. Yu and J. Wu, J. Comb. Chem., 2010, 12, 238; (b) N. T. Patil, A. K. Mutyala, P. G. V. V. Lakshmi, P. V. K. Raju and B. Sridhar, Eur. J. Org. Chem., 2010, 1999; (c) R. Yanada, S. Obika, H. Kono and Y. Takemoto, Angew. Chem., Int. Ed., 2006, 45, 3822. (a) H. Pellissier, Chem. Rev., 2013, 113, 442; (b) A. A. Friedman, J. Panteleev, J. Tsoung, V. Huynh and M. Lautens, Angew. Chem., Int. Ed., 2013, 52, 9755; (c) L. F. Tietze, T. Hungerland, C. Eichhorst, A. Dufert, C. Maab and D. Stalke, Angew. Chem., Int. Ed., 2013, 52, 3668; (d) A. Grossmann and D. Enders, Angew. Chem., Int. Ed., 2012, 51, 314; (e) H. Liu, M. El-Salfiti and M. Lautens, Angew. Chem., Int. Ed., 2012, 51, 9846; (f ) L. F. Tietze, G. Brasche and K. M. Gericke, Angew. Chem., Int. Ed., 2007, 46, 2977; (g) L. F. Tietze, Chem. Rev., 1996, 96, 115. (a) H.-C. Ouyang, R.-Y. Tang, P. Zhong, X.-G. Zhang and J.-H. Li, J. Org. Chem., 2011, 76, 223; (b) Y. Ohta, Y. Kubota, T. Watabe, S. Chiba, H. Oishi, S. Fujii and H. Ohno, J. Org. Chem., 2009, 74, 6299; (c) M. Yu, Y. Wang, C.-J. Li and X. Yao, Tetrahedron Lett., 2009, 50, 6791; (d) Y. Ye, Q. Ding and J. Wu, Tetrahedron, 2008, 64, 1378; (e) K. Gao and J. Wu, J. Org. Chem., 2007, 72, 8611; (f ) Q. Ding and J. Wu, Org. Lett., 2007, 9, 4959; (g) N. Asao, K. Iso and Y. S. Salprima, Org. Lett., 2006, 8, 4149; (h) N. Asao, Y. S. Salprima, T. Nogami and Y. Yamamoto, Angew. Chem., Int. Ed., 2005, 44, 5526; (i) D. Yue, N. Della Ca and R. C. Larock, Org. Lett., 2004, 6, 1581; ( j) T. Yao, M. A. Campo and R. C. Larock, Org. Lett., 2004, 6, 2677.
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9 (a) A. K. Verma, R. R. Jha, V. K. Shankar, T. Aggarwal, R. P. Singh and R. Chandra, Eur. J. Org. Chem., 2011, 6998; (b) A. K. Verma, R. R. Jha, V. K. Shankar and R. P. Singh, Tetrahedron Lett., 2013, 54, 5984; (c) R. K. Tiwari, J. Singh, D. Singh, A. K. Verma and R. Chandra, Tetrahedron, 2005, 61, 9513; (d) A. R. Katritzky, A. K. Verma, H.-Y. He and R. Chandra, J. Org. Chem., 2003, 68, 4938. 10 (a) A. K. Verma, D. Choudhary, R. K. Saunthwal, V. Rustagi, M. Patel and R. K. Tiwari, J. Org. Chem., 2013, 78, 6657; (b) A. K. Verma, S. K. R. Kotla, D. Choudhary, M. Patel and R. K. Tiwari, J. Org. Chem., 2013, 78, 4386; (c) S. P. Shukla, R. Tiwari and A. K. Verma, Tetrahedron, 2012, 68, 9035; (d) T. Aggarwal, R. R. Jha, R. K. Tiwari, S. Kumar, S. K. R. Kotla, S. Kumar and A. K. Verma, Org. Lett., 2012, 14, 5184; (e) A. K. Verma, V. Rustagi, T. Aggarwal and A. P. Singh, J. Org. Chem., 2010, 75, 7691; (f) V. Rustagi, R. K. Tiwari and A. K. Verma, Eur. J. Org. Chem., 2012,
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12 13
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4590; (g) V. Rustagi, T. Aggarwal and A. K. Verma, Green Chem., 2011, 13, 1640. (a) A. R. Katritzky, H.-Y. He and A. K. Verma, Tetrahedron: Asymmetry, 2002, 13, 933; (b) A. R. Katritzky, Y.-J. Xu, H.-Y. He and P. J. Steel, J. Chem. Soc., Perkin Trans. 1, 2001, 1767. See ESI.† (a) The stereochemistry of the products 5a–o was assigned based on the NOESY and optical rotation of 5a and the similarity in the 1H NMR spectral pattern of 5a–o (b) The stereochemistry of the products 8a–e was assigned based on the optical rotation and the similarity in the 1H NMR spectral pattern of 8a–e. (a) N. A. Markina, R. Mancuso, B. Neuenswander, G. H. Lushington and R. C. Larock, ACS Comb. Sci., 2011, 13, 265; (b) J. P. Waldo, S. Mehta, B. Neuenswander, G. H. Lushington and R. C. Larock, J. Comb. Chem., 2008, 10, 658.
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Cite this: Org. Biomol. Chem., 2014, 12, 552 Received 11th October 2013, Accepted 8th November 2013 DOI: 10.1039/c3ob42035c www.rsc.org/obc
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Stereoselective tandem synthesis of thiazolo fused naphthyridines and thienopyridines from o-alkynylaldehydes via Au(III)-catalyzed regioselective 6-endo-dig ring closure† Rajeev R. Jha, Rakesh K. Saunthwal and Akhilesh K. Verma*
An operationally simple approach for the stereoselective tandem synthesis of novel thiazolo fused naphthyridines 5a–o and thienopyridines 8a–e by the reaction of o-alkynylaldehydes with L-cystine
methyl ester hydrochloride via Au(III)-catalyzed regio-
selective 6-endo-dig ring closure under mild reaction conditions is described. It is noteworthy that alkynes bearing an alkyl and a strong electron-withdrawing nitro group successfully afforded the desired products in good yields.
A wide variety of biologically active natural and synthetic compounds are known to have substituted heterocycles in their core.1 Similarly, their sulphur analogues like thiazolines are signature metal binding motifs common to clinically important non-ribosomally derived macrocyclic peptides.2 These optically active thiazolines are also widely applicable in asymmetric synthesis as chiral templates and ligands.3 The chiral compounds have emerging significance owing to the difference in biological activity of each isomer.4 The significance of these heterocyclic derivatives justifies a need to develop new synthetic strategies for these molecules.5 A literature search revealed that tandem6 and domino7 reactions have emerged as an efficient tool for the synthesis of fused heterocycles. More recently, o-alkynylaldehydes have been widely explored as versatile building blocks for the assembly of a wide variety of heterocyclic scaffolds.8 The literature search revealed that the stereoselective synthesis of heterocycles from o-alkynylaldehydes has not been explored. In continuation of our work on the synthesis of heterocycles9 from aldehydes/o-alkynylaldehydes, and the application of o-alkynylaldehydes as building blocks in the synthesis of a variety of heterocyclic scaffolds (Scheme 1),10 we hypothesized that the reaction of o-alkynylaldehydes with L-cystine methyl ester hydrochloride might offer an opportunity for the
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India. E-mail: [email protected]; Tel: +91-11-27666272(Ext. 175) † Electronic supplementary information (ESI) available. See 10.1039/c3ob42035c
552 | Org. Biomol. Chem., 2014, 12, 552–556
DOI:
Scheme 1
Synthesis of racemic heterocycles.
Scheme 2 Au-catalyzed stereoselective synthesis of thiazolo-fusednaphthyridines and thienopyridines via 6-endo-dig cyclization.
diastereoselective synthesis of thiazolo fused heterocycles (Scheme 2). To identify the optimal conditions for the reaction, a previously reported catalyst of Ag(I) for cyclization was scrutinized in the reaction of o-alkynylaldehyde 1a with L-cystine methyl
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Table 1
Communication
Optimization of reaction conditionsa
Entry
Solvent
Cat. (mol%)
T (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
H2O H2O H2O EtOH THF MeOH CHCl3 DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE
AgNO3/5 AgNO3/5 AgNO3/10 AgNO3/10 AgNO3/10 AgNO3/10 AgNO3/10 AgNO3/10 AgOAc/10 AgOTf/10 AuCl3/10 AuCl3/10 AuCl3/5 AuCl3/10 Cu(OTf)2/10 CuI/10 PdCl2/10 —
3 3 3 3 3 3 3 3 3 3 3 6 3 1 3 3 3 3
05c 13 20 37 23 31 39 44 53 78 85 83 59 46 63 13 00 00
Fig. 1
NOESY studies of compound 5a.
a Reactions were performed using 0.5 mmol of 1a, 1.1 equiv. of 4, 1.1 equiv. of Et3N, catalyst in 2.0 mL solvent at 70 °C unless otherwise noted. b Isolated yield. c At 25 °C. DCE = 1,2-dichloroethane.
ester hydrochloride 4 in the presence of 1.1 equiv. of Et3N (Table 1). When 5 mol% of AgNO3 was used as a catalyst in H2O at 25 °C for 3 h, thiazolo fused-naphthyridine 5a was obtained in only 5% yield (entry 1). An increase in the temperature to 70 °C provided the product 5a in 13% yield (entry 2). Increasing the catalyst loading from 5 to 10 mol% afforded the products 5a in 20% yields (entry 3). Upon screening of various solvents, 1,2-dichloroethane was found to be most suitable for the reaction (entries 3–8). Use of AgOAc and AgOTf was found effective for the reaction and afforded the desired product 5a in 53 and 78% yields respectively (entries 9–10). Use of gold(III) chloride improved the yield of the product, and afforded the 6-endo-dig cyclized product 5a in 85% yield (entry 11). The yield of the product remained almost the same when the reaction was run for 6 h (entry 12). Further lowering of the catalyst loading and time of the reaction decreases the yield of the product (entries 13–14). Use of Cu(OTf )2 provided the product 5a in 63% yield (entry 15); however, CuI and PdCl2 were found ineffective (entries 16–17). No product was observed when the reaction was allowed to proceed in the absence of a catalyst (entry 18). After screening various reaction conditions it was found that 10 mol% of AuCl3 in EDC was found to be the best for obtaining the desired product 5a (entry 10). The structure of the product 5a was fully characterized by the 1H NMR, 13C NMR and by NOESY experiment. Use of L-cystine methyl ester controls the chirality in the product and afforded the 6-endo-dig cyclized product with high diastereoselectivity. The relative configuration of the new stereogenic center at Hb in product 5a was determined by NOESY experiments (Fig. 1).11–13
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Scheme 3 Gold-catalyzed diastereoselective synthesis of 6-endo dig thiazolo fused naphthyridines. Reactions were performed using 0.5 mmol of 1, 1.1 equiv. of 4, 1.1 equiv. of Et3N, 10 mol% AuCl3 in 2.0 mL DCE at 70 °C for 3–5 h.
H NMR spectra of 5a show that Hb appears at 6.39 as a singlet and Ha at 4.29–4.27 ppm as a multiplet. No distinct NOE effect was observed between Hb and Ha in compound 5a. This suggests that Hb and Ha are located in trans-orientation. With an optimized condition in hand (Table 1, entry 11) we investigated the scope of the developed chemistry using a variety of ortho-alkynylquinoline-3-carbaldehydes 1a–o and L-cystine methyl ester hydrochloride 4 for the selective synthesis of 6-endo-dig cyclized products 5a–o (Scheme 3). Substrate 1a bearing phenyl substituent at R2 provided the product 5a in 80% yield. Alkynes bearing electron-rich substituents at R2 on reaction with 4 afforded the desired products 5b–e in 79–85% yields with high diastereoselectivity. Substrates 1f–g 1
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bearing substitution at the meta position of the phenyl ring afforded the desired products 5f–g comparatively in lower yields with high diastereomeric ratios (dr). The majority of the reported syntheses of heterocycles using o-alkynylaldehydes were not successful with alkynes bearing strong electron-withdrawing groups.10a,b,14 It is noteworthy that alkynes 1h bearing a strong electron-withdrawing nitro group at the 4-position of the phenyl ring were found successful for the reaction and afforded the desired product 5h in 63% yield with high diastereoselectivity. The probable reason could be the strong nucleophilicity of the thiol group. Substrates 1i–k bearing a cyclohexyl, cyclopropyl and n-hexyne group were found successful for the reaction and provided the diastereomeric mixture of desired products 5i–k in 60–68% yields. Reaction of 6-methoxy substituted o-alkynylaldehydes 1l–m afforded the mixture of diastereomeric product 5l–m in 68–75% yields. Reaction of 6-methyl substituted o-alkynylaldehydes 1o with 4 provided the single diastereomeric product 5o in good yield. Reaction of 2-((4-(tert-butyl)phenyl)ethynyl)benzaldehyde (2) afforded the desired product 6 in 48% yield (Scheme 4). The low yield of the product 6 is due to the formation of a byproduct in 42% yield. The byproduct was assigned to be 3-(4-(tert-butyl)phenyl)isoquinoline 7 as compared with the NMR spectra of the authentic sample. The possible formation of phenylisoquinoline 7 ( path b) along with product 6 ( path a) is explained in Scheme 3. We further extended the scope of the developed chemistry for the synthesis of another very important class of heterocyclic scaffold dihydro-2H-benzo[4,5]thieno[2,3-c]thiazolo[3,2-a]pyridine which is known as sulfur analogue of the β-carbolines (Scheme 5). Using the optimized reaction conditions (Table 1, entry 11), reaction of 3-(arylethynyl)benzo[b]thiophene-2-carbaldehydes 3a–e with L-cystine methyl ester hydrochloride 4 provided the thiazolo-pyridines 8a–e in good to moderate yields. All thiazolo-pyridines 8a–e were obtained as a mixture of diastereomers. The possible reason for the lower diastereoselectivities could be due to the structural difference between ortho-alkynylquinoline-3-carbaldehydes 1a–o and 3-alkynyl-benzothiophene-2-carbaldehydes 3a–e. Possibly in the case of quinoline substrates the presence of C-4 hydrogen restricts the attack of the SH group from below the plane; however, in the case of
Organic & Biomolecular Chemistry
Scheme 5 Gold-catalyzed synthesis of thiazolo fused pyridines 8. Reactions were performed using 0.5 mmol of 3, 1.1 equiv. of 4, 1.1 equiv. of Et3N, 10 mol% AuCl3 in 2.0 mL EDC at 70 °C for 3–5 h.
Fig. 2
Possible reason for the distereoselectivity.
Scheme 6
Scheme 4 Possible formation of thiazolo-fused isoquinoline 6 and isoquinoline 7.
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Plausible mechanism.
benzothiophene (no hindrance on imine carbon) the –SH group can attack on imine carbon from both the sides (Fig. 2). A plausible mechanism for the designed tandem approach is proposed in Scheme 6. Initially, the reaction of alkyne 1–3 and L-cystine methyl ester 4 generates key intermediate imine P. From intermediate P, two possibilities exist for the
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formation of product 5 (i.e., either thiazole ring from first or isoquinoline ring or vice versa). Intermediate Q could be formed by the intramolecular attack of the –SH group onto imine carbon ( path a), which upon π-complexation with AuCl3, would undergo a second intramolecular nucleophilic attack of the –NH onto triple bond to afford the desired product 5. Alternatively, the isoquinoline ring (intermediate R) could be generated by the intramolecular attack of the imine on the activated alkyne ( path b), which (R) on successive second intramolecular nucleophilic attack of the –SH group onto the quinolinium ring will furnish the desired product 5. In summary, for the first time we have described a stereoselective tandem synthesis of thiazolo fused naphthyridines and thienopyridines by the reaction o-alkynylaldehydes with inexpensive L-cystine methyl ester hydrochloride under mild reaction conditions. Structure and stereochemistry of the 6-endo-dig cyclized products were supported by the NOESY studies. Alkynes bearing electron-releasing, electron-withdrawing, alkyl and acyl groups successfully afforded the desired products in good yields. The tandem approach developed herein is general and expands the application of o-alkynylaldehydes for the synthesis of diastereoselective compounds, which are of high importance in medicinal chemistry. Further investigations of this synthetic protocol are under progress and will be reported in due course.
Acknowledgements We thank Department of Science and Technology (SR/S1/ OC-66/2010), DU-DST-PURSE University of Delhi for the financial support and USIC for providing instrumentation facility. R. R. J. and R. K. S. are thankful to CSIR and UGC for the fellowship.
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