Reductive cyclization of 2-iminonitrostyrenes (from the condensation of 2-aminostyrenes with an aldehyde and subsequent nitration of the alkene) using a bifunctional thiourea catalyst and tert-butyl-Hantzsch ester leads to an intramolecular conjugate hydride addition nitro-Mannich reaction to give the corresponding cis-2-aryl-3-nitrotetrahydroquinolines as single diastereoisomers in high yields and enantioselectivities

Anderson, JC

Barham, JP

Rundell, CD

UCL Discovery

An Asymmetric Intramolecular Conjugate Addition nitro-Mannich route to cis-2-aryl-3-nitrotetrahydroquinolines  James C. Anderson,* Joshua P. Barham and Christopher D. Rundell Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.  Supporting Information Placeholder  Reductive cyclisation of 2-imino-nitrostyrenes (from the condensation of 2-aminostyrenes with an aldehyde and subsequent nitration of the alkene) using a bifunctional thiourea catalyst and tbutyl-Hantzsch ester leads to an intramolecular conjugate hydride addition nitro-Mannich reaction to give the corresponding cis-2-aryl-3-nitrotetrahydroquinolines as single diastereoisomers, in high yields and enantioselectivities.  Tetrahydroquinolines are present in numerous biologically active natural products and drug substances.1 Natural products (-)-isoschizogaline (1)2 and helquinone (2)3 display antibiotic activity, the drug molecule viratmycin (3)4 is an antiviral antibiotic that also possesses antifungal activity, while drug molecule 45 is an antimalarial (Figure 1).  Figure 1. Biologically active tetrahydroquinolines  The efficient synthesis of functionalised tetrahydroquinolines in enantiomerically pure form continues to be of high importance to synthetic chemists.1 For flexible syntheses in terms of stereochemistry and functionalization, de novo constructions of the heterocycle are the most efficient methods. Of those methods, the intramolecular cyclisation of a resonance stabilized nucleophile onto an imine derived from an aniline has proved most popular.6 In particular, the nitro-Mannich cyclisation of nitronate nucleophiles onto a pendant aniline imine gives highly versatile stereodefined nitro-substituted tetrahydroquinolines (Scheme 1). The nitro group is a versatile synthetic handle and can be transformed into amines, carbonyl groups or be denitrated.7 The nitro-Mannich reaction is an efficient route to stereochemically pure -nitroamines which have been shown to be useful building blocks for amino heterocycles.8 We devised a diastereoselective intramolecular nitro-Mannich route to trans-3-nitrotetrahydroquinolines 5 in racemic form via in situ generation of an imine from 2-(2-nitroethyl)phenylamine (Scheme 1, equation 1).9 This has recently shown to be amenable to asymmetric control through the use of a bifunctional tertiary amine thiourea catalyst that gave products with moderate to good enantioselectivities.10 Other routes to enantiomerically pure nitrotetrahydroquinolines have also taken advantage of organocatalysis. A tandem Michael‒nitro-Mannich sequence gave  cis, trans-nitrotetrahydroquinolines 6 (Scheme 1, equation 2),11 a structural motif that can also be made with the trans, trans stereochemistry by an aza-Michael‒Michael strategy using nitroalkenes.12 The cis-diastereoisomer of 5 can also be prepared by chiral phosphoric acid catalyzed transfer hydrogenation of 2-aryl-3-nitroquinolines, but this is limited by the poor yields of the multistep synthesis required to prepare the quinolines.13 We wish to report an efficient asymmetric synthesis of cis-2-aryl-3-nitrotetrahydroquinolines via an intramolecular nitro-Mannich reaction initiated by an organocatalyzed reduction of the parent nitrostyrene. Scheme 1. Relevant reported work     Following on from our work defining stereoselective nitro-Mannich reactions initiated by conjugate addition to nitroalkenes,14 we reasoned that conjugate addition of a nucleophile to an imino-nitrostyrene would trigger an intramolecular nitro-Mannich reaction to form contiguous stereocentres, with high diastereo- and enantiocontrol (Scheme 2). Scheme 2. Proposed reaction  To investigate this reaction, a synthesis of the 2-imino-nitrostyrene precursors was required. The most direct method would be from a 2-amino-β-nitrostyrene and an aldehyde. Attempts at the chemoselective reduction of 2-nitro--nitrostyrene were unsuccessful, suffering from reduction of the nitrostyrene. This suggested to us that the reactive nitrostyrene group should be introduced last. After some optimization, our initial approach involved imine formation from the intermediate Henry product between nitromethane and 2-aminobenzaldehyde (7, Scheme 3). Selective reduction of the aromatic nitro group of 7 was reliably achieved on a gramme scale using a mixture of palladium on charcoal and Pearlman’s catalyst to give 8 in 77% yield after recrystallization.15 Formation of the imine in situ was followed by dehydration of the nitroalcohol to form the desired 2-imino nitrostyrene. Many dehydrating systems were investigated and we found that careful treatment of 8 with trifluoroacetic anhydride and triethylamine minimised retro-Henry reaction and formation of by-product 9 and gave 10a in good 67% isolated yield. Unfortunately, this sequence gave poor yields (20-30%) with electron rich and poor aldehydes, presumably because with the former the amine lone pair is not nucleophilic enough due to the electron withdrawing nitrostyrene group, and the latter giving mainly byproducts like 9 due to the increased electrophilicity of the formed imine towards cyclisation. Scheme 3: Initial approach  To circumvent this, the desired 2-imino-nitrostyrenes 10a-m from quantitative imine formation were subjected to late stage nitration.16 The stereoselective nitration of styrene alkenes had been disclosed by Maiti et al. and had been reported to be tolerant of various functional groups.17 Our results suggest that aromatic imines are also stable to the mild reaction conditions of AgNO2/TEMPO. For the imine derived from pentanal, imine formation proceeded as expected, but nitration unfortunately led to decomposition. Various 2-imino-nitrostyrenes were synthesized according to this procedure (Figure 1) in excellent yield. Substituents on the styrene partner were limited due to the availability of the starting materials. The 5-chloro substituent was tolerated (10m), but other electron withdrawing groups in this position (CN, F) were unable to form the imine. This was also true of the 4-chloro analogue and 2-amino-3-vinylpyridine.  However a wide variety of electron rich and poor imines were prepared in good yield.  Figure 1. Synthesis of nitrostyrene substrates    10a, 97% yield   10b, 94% yield  10c, 95% yield  10d, 44% yield    10e, 94% yield 10f, 95% yield  10g, 51% yield  10h, 82% yield  10i, 86% yield  10j, 88% yield  10k, 73% yield  10l, 15% yield  10m, 93% yield Initially, cyclisation of 10a was investigated using the conditions previously described by us for the enantioselective tandem reduction/nitro-Mannich reaction.14e Using tbutyl-Hantzsch ester (11) as a transfer hydrogenation agent in the presence of thiourea catalyst 1214e the desired tetrahydroquinoline 13a was isolated in quantitative yield, as a single diastereoisomer by 1H NMR in 94% ee (Table 1). No reduction of the imine was observed. Decreasing the temperature from rt to 0 C gave a small increase in ee with increased reaction time (entry 2). Using an equimolar quantity of 11 gave the same yield, ee and dr. Table 1. Investigation into cyclisation conditionsa   entry  t  (°C) 11  (eq) T  (h) yield  (%)b ee  (%)c drd  1 rt 2 12 99 94 >95:5 2 0 2 18 99 97 >95:5 3 0 1 18 99 97 >95:5 aReaction scale (0.1 mmol), PhMe (1 mL). bIsolated yield. cDetermined by chiral HPLC (OD column). dDetermined by 1H NMR analysis of crude product. The generality of the procedure for the synthesis of cis-2-aryl-3-nitrotetrahydroquinolines 13 was investigated (Figure 3). All cis-tetrahydroquinolines 13 were made in good yield, high ee and essentially as a single diastereoisomer by 1H NMR. The sense of diastereoselectivity was determined by inspection of 3J coupling constants between the vicinal protons adjacent to the pendant phenyl ring and the nitro function where 3Jcis ~4 Hz.18 The absolute configuration was assigned as 2R, 3R by comparison to the optical rotations reported by Zhou et al.13,19,20 The diastereoselectivity can be attributed to the cis-diastereoisomer being the kinetic product as treatment of cis-tetrahydroquinoline 13a with DBU (1 equiv) in CH2Cl2 for 16 h at rt gave a 9:1 mixture in favour of the thermodynamic trans-diastereoisomer.21 This was isolated in 72% yield and possessed identical enantioselectivity to the starting material.22 This route to the trans-products would deliver superior enantioselectivites than other methods.10 The presence of groups on the meta- or para- position led to an increase in ee but no obvious stereoelectronic preference could be discerned. When Ar = p-NO2C6H5 the desired product 13h was not observed, the product from conjugate reduction of the nitrostyrene was isolated instead. This is most probably due to the imine function not participating in the nitro-Mannich reaction due to the lower reactivity of the imine lone pair, the protonation of which is required for the nitro-Mannich reaction to proceed.21 Figure 3. Asymmetric Tandem reductive intramolecular nitro-Mannich reactiona     13a, 93% yield, 97% ee   13b, 100% yield, >99% ee    13c, 95% yield, >99% ee 13d, 99% yield, 98% ee  13e, 100% yield, >99% ee  13f, 100% yield, 96% ee   13g, 97% yield, 99% ee  13i, 97% yield, 99% ee   13j, 88% yield, 88% ee  13k, 100% yield, 98% ee   13l, 93% yield, 93% ee  13m, 88% yieldb aReaction scale (0.1 mmol) in PhMe (1 mL), isolated yield is given in all cases, ee was determined by chiral HPLC (OD column) and diastereoselectivity by 1H NMR analysis. bProduct unstable to HPLC conditions.  In summary we have developed an expedient synthesis of sensitive 2-imino-nitrostyrenes 10 through the use of radical alkene nitration, which exemplifies the mild nature and further scope of this reaction. These can be cyclised by an organocatalytic tandem reductive nitro-Mannich reaction in high yield to give a single cis-2-aryl-3-nitrotetrahydroquinolines 13 in high yield and enantioselectivity. Further investigation is ongoing into the utility of these nitrostyrenes for the synthesis of densely functionalized tetrahydroquinolines of biological interest. ASSOCIATED CONTENT  Supporting Information Detailed experimental procedure, characterization data, NMR spectra for new compounds and HPLC analysis. This material is available free of charge via the Internet at http://pubs.acs.org.  AUTHOR INFORMATION Corresponding Author * j.c.anderson@ucl.ac.uk ACKNOWLEDGMENT  The preliminary work was taken from the Masters research project of JB and the main work is part of the PhD of CDR. We thank the Engineering and Physical Sciences Research Council (DTA), University College London (UCL) and AstraZeneca for funding, Dr. V.J. Gray (UCL) for mass spectra and Mrs. J. Maxwell (UCL) for microanalytical data. REFERENCES  1. For reviews, see: (a) Nammalwar, B.; Bunce, R.A. Molecules 2014, 19, 204. (b) Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Chem. Rev. 2011, 111, 7157. (c) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357. (d) Mitchinson, A.; Nadin, A. J. Chem. Soc. Perkin Trans. 1 2000, 2862. (e) Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A. J. Heterocycl. Chem. 1998, 35, 761. (f) Katrizky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031. 2. Asolkar, R.N.; Schroeder, D.; Heckmann, R.; Lang, S.; Wagner-Doebler, I.; Laatsch, H. J. Antibiot. 2004, 57, 17. 3. Magomedov, N.A. Org. Lett. 2003, 5, 2509. 4. (a) Keck, D.; Vanderheiden, S.; Brase, S. A. Eur. J. Org. Chem. 2006, 4916.(b) Ori, M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H. Tetrahedron 2005, 61, 2075. (c) Steinhagen, H.; Corey, E.J.  Org. Lett. 1999, 1, 823. (d) Back, T.G.; Wulff, J.E. Angew. Chem. Int. Ed. 2004, 43, 6493. 5. Nallan, L.; Bauer, K.D.; Bendale, P.; Rivas, K.; Yokoyama, K.; Horney, C.P.; Rao, P.P. J. Med. Chem. 2005, 48, 3704. 6. For examples, (a) Jia, Z.-X.; Luo, Y.-C.; Wang, Y.; Chen, L.; Xu, P.-F.; Wang, B. Chem. Eur. J. 2012, 18, 12958. (b) Wang, K.-T.; Kim, S.-G. Synthesis 2014, 3365. (c) Kang, Y. K.; Kim, S. M.; Kim, D. Y.  J. Am. Chem. Soc. 2010, 132, 11847. (d) Suh, C. W. Kim, D. Y. Org. Lett. 2014, 16, 5374. (e) Cao, W.; Liu, X.; Guo, J.; Liu, L.; Feng, X. Chem. Eur. J. 2015, 21, 1632. 7. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001. 8. Noble, A.; Anderson, J. C. Chem. Rev., 2013, 113, 2887. 9. Anderson, J. C.; Noble, A.; Ribelles Torres, P. Tetrahedron Lett. 2012, 53, 5707. 10. Maity, R.; Pan, S. C. Org. Biomol. Chem. 2015, 13, 6825. 11. Jia, Z.-X.; Luo, Y.-C.; Xu, P.-F. Org. Lett. 2011, 13, 832. 12. 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Using a 1:1 mixture of 10% Pd/C and Pearlman's catalyst, which has been reported to give superior results for N- and O- hydrogenolysis of benzyl groups (Li, Y.; Manickam, G.; Ghoshal, A.; Subramaniam, P. Synth. Commun. 2006, 36, 925), gave little change in yield. 16. The 2-amino-styrenes were prepared from the corresponding 2-nitrophenylacetic acids by the sequence of: reduction of the carboxylic acid to the alcohol with borane, reduction of the nitro group to the amine with Zn, CaCl2 and H2O, and dehydration by heating with KOH. See Supporting Information. Other structurally diverse substrates have been prepared in the literature by a modified Suzuki reaction between 2-bromoanilines and potassium  vinyltrifluoroborate, see: a)  Ascic, E.; Buchwald, S.L. J. Am. Chem. Soc. 2015, 137, 4666. (b) Li, B.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2013, 135, 1125.   17. Maity, S.; Manna, S.; Rana, S.; Naveen, T.; Mallick, A.; Maiti, D. J. Am. Chem. Soc. 2013, 135, 3355. 18. Compared to 3Jtrans ~8 Hz, see ref 9. 19. Comparison of optical rotations gives the opposite sign and similar values to those in ref 13. Novel tetrahydroquinolines were assigned the same 2R, 3R stereochemistry by the sign of their optical rotation. See Supporting Information. 20. A transition state model to account for the sense of enantioselectivity would be similar to that proposed by us for the acyclic tandem reduction/nitro-Mannich reaction of nitroalkenes (see SI of ref 13e). 21. We have presented a transition state model to account for the kinetic cis-diastereoselectivity versus the thermodynamic trans-stereochemistry previously (ref 9). 22. Retention of enantioselectivity in the epimerisation of this substrate was also documented by Zhou et al. ref 13 in 74% yield.     

Asymmetric Intramolecular Conjugate Addition Nitro-Mannich Route to cis-2-Aryl-3-nitrotetrahydroquinolines

James C. Anderson

Joshua P. Barham

Christopher D. Rundell

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Organic Letters

Asymmetric Intramolecular Conjugate Addition Nitro-Mannich Route to <i>cis</i>-2-Aryl-3-nitrotetrahydroquinolines

http://discovery.ucl.ac.uk/1472075/1/Accepted%20manuscript%20OL%202015%20%2817%29%204090.pdf

Asymmetric Intramolecular Conjugate Addition Nitro-Mannich Route to cis-2-Aryl-3-nitrotetrahydroquinolines

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