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Domino Prins/pinacol reaction for the stereoselective synthesis of spiro[ pyran-4,4’-quinoline]-2’,3’-dione derivatives† B. V. Subba Reddy,*a S. Gopal Reddy,a,b M. Durgaprasad,a Manika Pal Bhadrab and B. Sridharc A wide array of aldehydes undergo smooth cross-coupling with 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-
Received 28th May 2015, Accepted 8th July 2015
1-methylindolin-2-one in the presence of 10 mol% BF3·OEt2 at 0 °C in dichloromethane to afford the corresponding 2,3,5,6-tetrahydro-1’H-spiro[ pyran-4,4’-quinoline]-2’,3’-dione derivatives in good yields
DOI: 10.1039/c5ob01077b
with excellent diastereoselectivity. This is the first report on the synthesis of tetrahydro-1’H-spiro[ pyran-
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4,4’-quinoline]-2’,3’-dione scaffolds through a cascade of Prins/pinacol reactions.
Introduction Nitrogen containing heterocycles are considered as privileged scaffolds because of their occurrence in natural products and designed pharmaceuticals.1 Among them, quinolones represent an important class of biologically active nitrogen heterocycles.2 On the other hand, the tetrahydropyran ring comprises a core structure of many bioactive natural products.3 In order to generate combinatorial libraries for drug discovery, a large number of hybrid molecules can be generated if these two interesting frameworks are integrated into a complex structure. Indeed, there are some reports on the amalgamation of these two bioactive scaffolds to make another complex structure so as to improve or generate new biological activity.4 Furthermore, spirocycles are important structural scaffolds in medicinal chemistry, which are key components of many bioactive molecules displaying potent pharmacological activity.5 They are often found in drug molecules.6 Moreover, the rigidity of these structures has been explored for the construction of chiral ligands.7 In addition, spiroquinoline/isoquinoline derivatives are known to exhibit a broad spectrum of biological activities such as antiarrhythmic, anti-depressant, and stimulant effects on respiration, analgesic and cardiotonic
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, India. E-mail: [email protected]; Fax: +91-40-27160512; Tel: +91-40-27193535 b Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India c Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad, India † Electronic supplementary information (ESI) available: Copies of 1H and 13C NMR spectra of products. CCDC 1061396. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ob01077b
This journal is © The Royal Society of Chemistry 2015
Fig. 1
Biologically active molecules.
behaviour (Fig. 1).8 As a result, numerous synthetic strategies have been developed for the synthesis of spirocycles.5–7 Among them, pinacol terminated Prins cyclization is an elegant process for the stereoselective construction of spirocarbocycles and oxacycles.9,10 Due to the fascinating molecular architecture and proven biological activity of spirocycles,11 we also reported a few cascade reactions for their synthesis.12
Results and discussion Inspired by the versatility of cascade reactions in organic synthesis,13 we herein report a novel synthesis of spiropyranoquinolinone scaffolds through a Prins/pinacol reaction. The reaction proceeds in two steps but in one-pot through a sequential Prins/pinacol cascade. The required enediol (3) was
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prepared from homopropargyl alcohol (1). Hydrobromination of 1 using PBr3/H2O gave the vinyl bromide (2a), which was then protected as its TBS ether (2). Lithiation of 2 using n-BuLi followed by treatment with N-methylisatin afforded the desired enediol (3) (Scheme 1). As the outset, we attempted the coupling of 3 with pivaldehyde using several Lewis and Brønsted acids in different solvents at various temperatures (Table 1). Lewis acids such as In(OTf )3, Sc(OTf )3, Cu(OTf )2, InCl3, and InBr3 gave the product in low yields (Table 1, entries a–f ). No significant improvement in yield was observed even by increasing the catalyst loading (Table 1, entry b). However, the use of 10 mol% BF3·OEt2 at 0 °C gave the expected product in 80% yield as a single diastereomer (entry i, Table 1), which was confirmed by the 1H NMR spectrum. In addition, TMSOTf was also found to be equally effective. Alternatively, Brønsted acids such as p-TSA and CSA were unsuccessful even at elevated temperature after a long reaction time (Table 1, entries g and h). After several experiments, BF3·OEt2 gave the best results in terms of conversion. Among different solvents, DCM was found to be the best for this cascade reaction. These results prompted us to investigate
Scheme 1 Preparation of the starting material (3). Reagents: (a) PBr3/ H2O, DCM, 40 °C, TEAB; (b) TBSCl, imidazole; (c) n-BuLi, THF, N-methylisatin, −78 °C; and (d) TBAF, THF.
Table 1
Optimization of reaction conditionsa
Entry
Lewis acid
mol%
Temp (°C)
Time (h)
Yieldb (%)
a b c d e f g h i j
In(OTf)3 In(OTf)3 Sc(OTf)3 Cu(OTf)2 InBr3 InCl3 p-TSA CSA BF3·OEt2 TMSOTf
0.3 1.0 0.5 0.5 0.5 1.0 1.0 1.0 0.1 0.1
25 25 25 25 25 25 80 80 0 0
12 12 12 12 12 12 12 12 0.5 0.5
20 40 30 10 30 20 — — 80 75
a
Reaction was performed at the 0.5 mmol scale. b Yield refers to pure products.
Org. Biomol. Chem.
this reaction further with various aldehydes bearing a diverse substitution pattern. In most of the cases, the products were obtained in good to excellent yields with high selectivity. It is worth mentioning that a wide range of functional groups are well tolerated under these reaction conditions (Table 2). The substituent present on the aromatic ring had shown a modest effect on the conversion. It was observed that both electron rich and electron deficient aldehydes gave the products in comparatively lower yields than the corresponding halogenated or alkyl substituted aromatic aldehydes. Furthermore, the reaction was also quite successful with aliphatic aldehydes such as pivaldehyde and propanaldehyde (Table 2, entries a and n), but relatively in lower yields than aromatic counterparts. The relative stereochemistry of 5a was established by X-ray crystallography (Fig. 2).14 The scope of the reaction was further extended to ketones. However, the sterically hindered isatin failed to undergo Prins cyclization under the present reaction conditions. Interestingly, cyclohexanone gave the desired product in good yield with high selectivity (entry r, Table 2). Furthermore, substituted enediols such as 5-chloro-, and 5-methoxy- derivatives participated effectively in this cyclization (entries p and q, Table 2). In addition to N-methyl derivative, the reaction also proceeded with N-allyl enediol (entry o, Table 2). The stereochemistry of different compounds that are reported in Table 2 was confirmed by the analogy of NMR chemical shifts/coupling constants with 5a. Based on our earlier observation, we propose a plausible reaction pathway in Scheme 2. The reaction is assumed to proceed through the formation of an oxocarbenium ion (A) from an aldehyde and alkenol under acidic conditions. A subsequent attack of the olefin on the oxo-carbenium ion leads to the formation of a tertiary carbocation (B), which is terminated by a pinacol 1,2-shift to give the desired spirocycle (5). The expected diastereoselectivity can be explained by a favourable trapping of the carbocation from a less hindered equatorial side in order to avoid unfavourable 1,3-diaxial interactions.15 It is known that all substituents on cyclohexane in the chair conformation occupy an equatorial position to relieve the molecule from torsional strain.3 In the above cyclization, there is a possibility of acyl migration over the aryl group.16 However, in the present case, the aryl migration was observed exclusively due to electronic factors.17
Conclusion In summary, we have developed a novel one-pot strategy for the synthesis of spiropyranoquinolone scaffolds from 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1-methylindolin-2-one and aldehydes through a Prins/pinacol cascade reaction. Noteworthy features of this protocol include mild reaction conditions, a wide substrate scope, good yields and excellent diastereoselectivity, which make it an attractive process for the synthesis of biologically relevant spirocycles in a single-step.
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Table 2
Paper Table 2
Synthesis of spirotetrahydropyranoquinolones
(Contd.)
Entry
a
80
i
85
b
83
j
88
c
82
k
90
d
80
l
92
e
92 m
80
n
75
o
82
p
90
Aldehyde (4)
Product (5)
f
Product (5)
93
g
90
h
87
This journal is © The Royal Society of Chemistry 2015
Aldehyde (4)
Yielda,b (%)
Yielda,b (%)
Entry
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Table 2
Entry
Organic & Biomolecular Chemistry (Contd.)
Aldehyde (4)
Product (5)
Yielda,b (%)
q
85
r
75
Scheme 2
A plausible reaction pathway.
a
Yield refers to pure products after column chromatography. b Reaction was carried out on the 0.5 mmol scale.
(60–120 mesh) using ethyl acetate/hexane as the eluent to afford the pure spirocycle.
Acknowledgements SGR and MD thank CSIR, New Delhi, for the award of fellowships.
Notes and references
Fig. 2
ORTEP diagram of 5a.
Experimental Typical procedure To a stirred solution of 3 (0.5 mmol) and an aldehyde (0.6 mmol) in dry dichloromethane (5 mL) was added 10 mol% BF3·OEt2 at 0 °C. The resulting mixture was stirred at the same temperature under a nitrogen atmosphere for the specified time (Table 2). After completion, as indicated by TLC, the reaction mixture was quenched with sat. NaHCO3 (1.0 mL) and extracted with dichloromethane (2 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography
Org. Biomol. Chem.
1 (a) T. Naito, Chem. Pharm. Bull., 2008, 56, 1367; (b) M. C. Tseng, H. Y. Yang and Y. H. Chu, Org. Biomol. Chem., 2010, 8, 419; (c) G. Dong, S. Wang, Z. Miao, J. Yao, Y. Zhang, Z. Guo, W. Zhang and C. Sheng, J. Med. Chem., 2012, 55, 7593; (d) M. Baumann and I. R. Baxendale, Beilstein J. Org. Chem., 2013, 9, 2265. 2 (a) S. Madapa, Z. Tusi and S. Batra, Curr. Org. Chem., 2008, 12, 1116; (b) S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal and H. D. Patel, RSC Adv., 2014, 4, 24463; (c) S. K. Kandi, S. Manohar, C. E. V. Gerena, B. Zayas, S. V. Malhotra and D. S. Rawat, New J. Chem., 2015, 39, 224; (d) V. Sridharan, P. A. Suryavanshi and J. C. Menendez, Chem. Rev., 2011, 111, 7157. 3 (a) E. A. Crane and K. A. Scheidt, Angew. Chem., Int. Ed., 2010, 49, 8316; (b) M. Pastor and I. M. Yus, Curr. Org. Chem., 2012, 16, 1277; (c) X. Han, G. R. Peh and P. E. Floreancig, Eur. J. Org. Chem., 2013, 1193. 4 (a) H. A. Saadeh, I. M. Mosleh and M. S. Mubarak, Molecules, 2009, 14, 1483; (b) F. W. Muregi and A. Ishih, Drug Dev. Res., 2010, 71, 20.
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5 (a) Y. Zheng, C. M. Tice and S. B. Singh, Bioorg. Med. Chem. Lett., 2014, 24, 3673; (b) B. Yu, D.-Q. Yu and H.-M. Liu, Eur. J. Med. Chem., 2015, 97, 673. 6 M. M. M. Santos, Tetrahedron, 2014, 70, 9735. 7 (a) R. Rios, Chem. Soc. Rev., 2012, 41, 1060; (b) K. Ding, Z. Han and Z. Wang, Chem. – Asian J., 2009, 4, 32. 8 (a) F. Palluotto, G. D. Monache, G. Casini and F. Campagna, Heterocycles, 1997, 45, 1337; (b) L. Wang, Y. Su, X. Xu and W. Zhang, Eur. J. Org. Chem., 2012, 6606; (c) E. A. Markaryan, R. E. Markaryan, Z. S. Arustamyan, G. K. Airapetyan, R. S. Sukasyan, K. Z. Markaryan and T. O. Asatryan, Pharm. Chem. J., 1997, 31, 403; (d) E. W. Warnhoff and W. C. Wildman, J. Am. Chem. Soc., 1960, 82, 1472. 9 (a) P. H. Herrinton, M. H. Hopkins, P. Mishra, M. J. Brown and L. E. Overman, J. Org. Chem., 1987, 52, 3711; (b) L. E. Overman and E. J. Velthuisen, J. Org. Chem., 2006, 71, 1581; (c) G. C. Hirst, P. N. Howard and L. E. Overman, J. Am. Chem. Soc., 1989, 111, 1514; (d) L. E. Overman and J. P. Wolfe, J. Org. Chem., 2002, 67, 6421; (e) A. D. Lebsack, L. E. Overman and R. J. Valentekovich, J. Am. Chem. Soc., 2001, 123, 4851; (f ) S. N. Chavre, U. P. Reddy, S. J. Min, J. K. Lee, A. N. Pae, Y. Kim and Y. S. Cho, Org. Lett., 2009, 11, 3834; (g) B. V. S. Reddy, S. G. Reddy, M. R. Reddy, M. P. Bhadra and A. V. S. Sarma, Org. Biomol. Chem., 2014, 12, 7257. 10 (a) M.-A. Beaulieu, C. Sabot, N. Achache, K. C. Guerard and S. Canesi, Chem. – Eur. J., 2010, 16, 11224; (b) M.-A. Beaulieu, K. C. Guérard, G. Maertens, C. Sabot and S. Canesi, J. Org. Chem., 2011, 76, 9460; (c) Z. Pan, C. Zheng, H. Wang, Y. Chen, Y. Li, B. Cheng and H. Zhai, Org. Lett., 2014, 16, 216.
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11 (a) L. Chen, X.-P. Yin, C.-H. Wang and J. Zhou, Org. Biomol. Chem., 2014, 12, 6033; (b) J.-S. Yu, F.-M. Liao, W.-M. Gao, K. Liao, R.-L. Zuo and J. Zhou, Angew. Chem., Int. Ed., 2015, 54, 7381; (c) X.-P. Yin, X.-P. Zeng, Y.-L. Liu, F.-M. Liao, J.-S. Yu, F. Zhou and J. Zhou, Angew. Chem., Int. Ed., 2014, 53, 13740; (d) Z.-Y. Cao, X. Wang, C. Tan, X.-L. Zhao, J. Zhou and K. Ding, J. Am. Chem. Soc., 2013, 135, 8197; (e) Y.-L. Liu, X. Wang, Y.-L. Zhao, F. Zhu, X.-P. Zeng, L. Chen, C.-H. Wang, X.-L. Zhao and J. Zhou, Angew. Chem., Int. Ed., 2013, 52, 13735. 12 (a) B. V. S. Reddy, V. Swathi, S. Manisha, M. P. Bhadra, B. Sridhar, D. Satyanarayana and B. Jagadeesh, Org. Lett., 2014, 16, 6267; (b) B. V. S. Reddy, M. Durgaprasad and B. Sridhar, J. Org. Chem., 2015, 80, 653; (c) B. V. S. Reddy, M. Durgaprasad and B. Sridhar, J. Org. Chem., 2014, 79, 2289. 13 (a) L. F. Tietze, Chem. Rev., 1996, 96, 115; (b) P. J. Parsons, C. S. Penkett and A. J. Shell, Chem. Rev., 1996, 96, 195; (c) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134; (d) K. C. Nicolaou and J. S. Chen, Chem. Soc. Rev., 2009, 38, 2993. 14 CCDC 1061396 contains supplementary crystallographic data of 5a. 15 A. Diez-Varga, H. Barbero, F. J. Pulido, A. Gonzalez-Ortega and A. Barbero, Chem. – Eur. J., 2014, 20, 14112. 16 (a) M. Betou, L. Male, J. W. Steed and R. S. Grainger, Chem. – Eur. J., 2014, 20, 6505; (b) B. Alcaide, P. Almendros, A. Luna, S. Cembell, M. Arn and L. R. Domingo, Chem. – Eur. J., 2011, 17, 11559. 17 (a) B. Alcaide, P. Almendros, A. Luna and N. Prieto, Org. Biomol. Chem., 2013, 11, 1216; (b) B. Alcaide, P. Almendros, A. Luna, G. G. Campillos and M. R. Torres, J. Org. Chem., 2012, 77, 3549.
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Domino Prins/pinacol reaction for the stereoselective synthesis of spiro[ pyran-4,4’-quinoline]-2’,3’-dione derivatives† B. V. Subba Reddy,*a S. Gopal Reddy,a,b M. Durgaprasad,a Manika Pal Bhadrab and B. Sridharc A wide array of aldehydes undergo smooth cross-coupling with 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-
Received 28th May 2015, Accepted 8th July 2015
1-methylindolin-2-one in the presence of 10 mol% BF3·OEt2 at 0 °C in dichloromethane to afford the corresponding 2,3,5,6-tetrahydro-1’H-spiro[ pyran-4,4’-quinoline]-2’,3’-dione derivatives in good yields
DOI: 10.1039/c5ob01077b
with excellent diastereoselectivity. This is the first report on the synthesis of tetrahydro-1’H-spiro[ pyran-
www.rsc.org/obc
4,4’-quinoline]-2’,3’-dione scaffolds through a cascade of Prins/pinacol reactions.
Introduction Nitrogen containing heterocycles are considered as privileged scaffolds because of their occurrence in natural products and designed pharmaceuticals.1 Among them, quinolones represent an important class of biologically active nitrogen heterocycles.2 On the other hand, the tetrahydropyran ring comprises a core structure of many bioactive natural products.3 In order to generate combinatorial libraries for drug discovery, a large number of hybrid molecules can be generated if these two interesting frameworks are integrated into a complex structure. Indeed, there are some reports on the amalgamation of these two bioactive scaffolds to make another complex structure so as to improve or generate new biological activity.4 Furthermore, spirocycles are important structural scaffolds in medicinal chemistry, which are key components of many bioactive molecules displaying potent pharmacological activity.5 They are often found in drug molecules.6 Moreover, the rigidity of these structures has been explored for the construction of chiral ligands.7 In addition, spiroquinoline/isoquinoline derivatives are known to exhibit a broad spectrum of biological activities such as antiarrhythmic, anti-depressant, and stimulant effects on respiration, analgesic and cardiotonic
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, India. E-mail: [email protected]; Fax: +91-40-27160512; Tel: +91-40-27193535 b Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India c Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad, India † Electronic supplementary information (ESI) available: Copies of 1H and 13C NMR spectra of products. CCDC 1061396. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ob01077b
This journal is © The Royal Society of Chemistry 2015
Fig. 1
Biologically active molecules.
behaviour (Fig. 1).8 As a result, numerous synthetic strategies have been developed for the synthesis of spirocycles.5–7 Among them, pinacol terminated Prins cyclization is an elegant process for the stereoselective construction of spirocarbocycles and oxacycles.9,10 Due to the fascinating molecular architecture and proven biological activity of spirocycles,11 we also reported a few cascade reactions for their synthesis.12
Results and discussion Inspired by the versatility of cascade reactions in organic synthesis,13 we herein report a novel synthesis of spiropyranoquinolinone scaffolds through a Prins/pinacol reaction. The reaction proceeds in two steps but in one-pot through a sequential Prins/pinacol cascade. The required enediol (3) was
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prepared from homopropargyl alcohol (1). Hydrobromination of 1 using PBr3/H2O gave the vinyl bromide (2a), which was then protected as its TBS ether (2). Lithiation of 2 using n-BuLi followed by treatment with N-methylisatin afforded the desired enediol (3) (Scheme 1). As the outset, we attempted the coupling of 3 with pivaldehyde using several Lewis and Brønsted acids in different solvents at various temperatures (Table 1). Lewis acids such as In(OTf )3, Sc(OTf )3, Cu(OTf )2, InCl3, and InBr3 gave the product in low yields (Table 1, entries a–f ). No significant improvement in yield was observed even by increasing the catalyst loading (Table 1, entry b). However, the use of 10 mol% BF3·OEt2 at 0 °C gave the expected product in 80% yield as a single diastereomer (entry i, Table 1), which was confirmed by the 1H NMR spectrum. In addition, TMSOTf was also found to be equally effective. Alternatively, Brønsted acids such as p-TSA and CSA were unsuccessful even at elevated temperature after a long reaction time (Table 1, entries g and h). After several experiments, BF3·OEt2 gave the best results in terms of conversion. Among different solvents, DCM was found to be the best for this cascade reaction. These results prompted us to investigate
Scheme 1 Preparation of the starting material (3). Reagents: (a) PBr3/ H2O, DCM, 40 °C, TEAB; (b) TBSCl, imidazole; (c) n-BuLi, THF, N-methylisatin, −78 °C; and (d) TBAF, THF.
Table 1
Optimization of reaction conditionsa
Entry
Lewis acid
mol%
Temp (°C)
Time (h)
Yieldb (%)
a b c d e f g h i j
In(OTf)3 In(OTf)3 Sc(OTf)3 Cu(OTf)2 InBr3 InCl3 p-TSA CSA BF3·OEt2 TMSOTf
0.3 1.0 0.5 0.5 0.5 1.0 1.0 1.0 0.1 0.1
25 25 25 25 25 25 80 80 0 0
12 12 12 12 12 12 12 12 0.5 0.5
20 40 30 10 30 20 — — 80 75
a
Reaction was performed at the 0.5 mmol scale. b Yield refers to pure products.
Org. Biomol. Chem.
this reaction further with various aldehydes bearing a diverse substitution pattern. In most of the cases, the products were obtained in good to excellent yields with high selectivity. It is worth mentioning that a wide range of functional groups are well tolerated under these reaction conditions (Table 2). The substituent present on the aromatic ring had shown a modest effect on the conversion. It was observed that both electron rich and electron deficient aldehydes gave the products in comparatively lower yields than the corresponding halogenated or alkyl substituted aromatic aldehydes. Furthermore, the reaction was also quite successful with aliphatic aldehydes such as pivaldehyde and propanaldehyde (Table 2, entries a and n), but relatively in lower yields than aromatic counterparts. The relative stereochemistry of 5a was established by X-ray crystallography (Fig. 2).14 The scope of the reaction was further extended to ketones. However, the sterically hindered isatin failed to undergo Prins cyclization under the present reaction conditions. Interestingly, cyclohexanone gave the desired product in good yield with high selectivity (entry r, Table 2). Furthermore, substituted enediols such as 5-chloro-, and 5-methoxy- derivatives participated effectively in this cyclization (entries p and q, Table 2). In addition to N-methyl derivative, the reaction also proceeded with N-allyl enediol (entry o, Table 2). The stereochemistry of different compounds that are reported in Table 2 was confirmed by the analogy of NMR chemical shifts/coupling constants with 5a. Based on our earlier observation, we propose a plausible reaction pathway in Scheme 2. The reaction is assumed to proceed through the formation of an oxocarbenium ion (A) from an aldehyde and alkenol under acidic conditions. A subsequent attack of the olefin on the oxo-carbenium ion leads to the formation of a tertiary carbocation (B), which is terminated by a pinacol 1,2-shift to give the desired spirocycle (5). The expected diastereoselectivity can be explained by a favourable trapping of the carbocation from a less hindered equatorial side in order to avoid unfavourable 1,3-diaxial interactions.15 It is known that all substituents on cyclohexane in the chair conformation occupy an equatorial position to relieve the molecule from torsional strain.3 In the above cyclization, there is a possibility of acyl migration over the aryl group.16 However, in the present case, the aryl migration was observed exclusively due to electronic factors.17
Conclusion In summary, we have developed a novel one-pot strategy for the synthesis of spiropyranoquinolone scaffolds from 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1-methylindolin-2-one and aldehydes through a Prins/pinacol cascade reaction. Noteworthy features of this protocol include mild reaction conditions, a wide substrate scope, good yields and excellent diastereoselectivity, which make it an attractive process for the synthesis of biologically relevant spirocycles in a single-step.
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Table 2
Paper Table 2
Synthesis of spirotetrahydropyranoquinolones
(Contd.)
Entry
a
80
i
85
b
83
j
88
c
82
k
90
d
80
l
92
e
92 m
80
n
75
o
82
p
90
Aldehyde (4)
Product (5)
f
Product (5)
93
g
90
h
87
This journal is © The Royal Society of Chemistry 2015
Aldehyde (4)
Yielda,b (%)
Yielda,b (%)
Entry
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Table 2
Entry
Organic & Biomolecular Chemistry (Contd.)
Aldehyde (4)
Product (5)
Yielda,b (%)
q
85
r
75
Scheme 2
A plausible reaction pathway.
a
Yield refers to pure products after column chromatography. b Reaction was carried out on the 0.5 mmol scale.
(60–120 mesh) using ethyl acetate/hexane as the eluent to afford the pure spirocycle.
Acknowledgements SGR and MD thank CSIR, New Delhi, for the award of fellowships.
Notes and references
Fig. 2
ORTEP diagram of 5a.
Experimental Typical procedure To a stirred solution of 3 (0.5 mmol) and an aldehyde (0.6 mmol) in dry dichloromethane (5 mL) was added 10 mol% BF3·OEt2 at 0 °C. The resulting mixture was stirred at the same temperature under a nitrogen atmosphere for the specified time (Table 2). After completion, as indicated by TLC, the reaction mixture was quenched with sat. NaHCO3 (1.0 mL) and extracted with dichloromethane (2 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography
Org. Biomol. Chem.
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