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Cite this: Chem. Commun., 2014, 50, 445 Received 11th October 2013, Accepted 30th October 2013
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Asymmetric synthesis of 3,4-annulated indoles through an organocatalytic cascade approach† Lorenzo Caruana, Mariafrancesca Fochi,* Mauro Comes Franchini, Silvia Ranieri, Andrea Mazzanti and Luca Bernardi*
DOI: 10.1039/c3cc47841f www.rsc.org/chemcomm
Indoles bearing Michael acceptors at the 4-position were engaged in organocatalytic enantioselective cascade reactions with enals. Careful optimisation of the reaction parameters overcame the inherent low reactivity of these substrates, rendering 3,4-ring fused indoles in good yields, excellent enantioselectivities and as single diastereoisomers.
As an alternative to more classic cycloaddition reactions, the construction of enantioenriched carbo- and hetero-cycles by domino organocatalytic processes1 has been the subject of intense research in the last few years. In this context, great focus has been set on the preparation of various benzo-fused heterocycles, such as chromans, thiochromans and hydroquinolines, by using aromatic rings bearing nucleophilic and electrophilic moieties in ortho positions in combination with activated olefins (Scheme 1, top).2 These organocatalytic sequences are generally initiated by a hetero-Michael3 addition of a sulphur, oxygen or nitrogen nucleophile, which triggers the formation of an enolate/enamine that adds to the ortho electrophile terminating the cascade reaction. An elimination step, or even an additional cyclization event, eventually follows. In particular, the merger of iminium ion and enamine catalyses,4 wherein a nucleophilic enamine is formed upon the conjugated addition to an enal or an enone activated by an amine catalyst, has been particularly effective2a–i in these cascade processes. On these grounds, we hypothesized that 4-substituted indoles 1 could be productively engaged in organocatalytic iminium ion– enamine cascade reactions, giving a new synthetic route to 3,4annulated indoles (Scheme 1, bottom). We envisaged that the indole C3 of polyfunctional compounds 1 could act as a nucleophile in an iminium ion promoted Friedel–Crafts (FC)5 process, triggering an intramolecular Michael addition6 of the enamine to the activated Department of Industrial Chemistry ‘‘Toso Montanari’’, School of Science, University of Bologna, V. Risorgimento 4, 40136, Bologna, Italy. E-mail: [email protected], [email protected]; Fax: +39 0512093654; Tel: +39 0512093653 † Electronic supplementary information (ESI) available: Further optimisation results, determination of the relative and absolute configuration, reaction models, experimental details, copies of the NMR spectra and HPLC traces. See DOI: 10.1039/c3cc47841f
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Scheme 1
double bond placed at its ortho position. The resulting all-carbon 3,4-ring fused indole core (1,3,4,5-tetrahydrobenzo[cd]indole) of products 3 is widespread in natural products and/or biologically relevant compounds, as exemplified by the ergot alkaloid family7 and by steroidal indoles.8 It must be stressed that even if several 1,2- and 2,3-annulated indoles have been developed by means of organocatalytic sequential reactions,9 related transformations giving all carbon 3,4-fused indoles are, to our knowledge, unprecedented.10 At the outset of our studies, despite the well proven success of the single reaction step of the planned sequence with simpler substrates (i.e. the FC reaction with 4-unsubstituted indoles5 and intramolecular Michael addition2a–i,6), an open question was posed by the expected poor nucleophilicity of the C3 in indoles 1, caused mainly by conjugation of this carbon with the electron withdrawing C4-acceptor,11 and possibly exacerbated by steric effects. On the other hand, the recourse to a scarcely electron poor acceptor did not seem to be a viable strategy, as the intramolecular Michael addition of the enamine would then be suppressed. We considered a,b-unsaturated ketones as a good compromise, and we selected indole 1a as a substrate for the first attempt (Table 1).12 Furthermore, we opted
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Table 1
ChemComm
Optimisation of the reaction between 1a and acrolein 2aa
Cat. Entry Solvent (mol%) Cocat. 1 2 3 4 5 6 7 8 9 10 11
THF THF THF THF CHCl3 EtOH MTBE Dioxane Dioxane Dioxane Dioxane
4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (10) 4b (10) 4c (10)
PhCO2H 2-NO2PhCO2H TFA TFA TFA TFA TFA TFA TFA TFA TFA
Conv.c eed Additiveb 3a : 3a 0 c (%) (%) None None None MgSO4 MgSO4 MgSO4 MgSO4 MgSO4 MgSO4 MgSO4 MgSO4
— — 57 : 43 >95 : 5 — nd >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5
o10 o10 50 85 o10 nde 76 100 91 >95 >95
— — 98 99 — nd 99 96 94 98 89
a
Conditions: indole derivative 1a (0.06 mmol), catalyst 4 (10–20 mol%), cocatalyst (10–20 mol%), acrolein 2a (0.15 mmol), solvent (0.20 mL), RT, 18 h. In all cases, a single diastereoisomer was observed using 1H NMR spectroscopy in the crude mixture. b 40 mg of MgSO4 were employed. c Determined by 1H NMR spectroscopy on the crude mixture. d Determined by chiral stationary phase HPLC. e Very complex crude mixture.
for the exceedingly reactive acrolein 2a as the enal partner.2e Taking the published asymmetric indole FC alkylation reactions catalyzed by the Jørgensen–Hayashi catalysts13 4a and 4b as the starting point,5b–f we tried to apply similar reaction conditions (MTBE, CH3CN or MeOH as the solvent, with or without basic additives, RT), which led however to very disappointing results (no reaction). Apparently, the 4-substituted indole 1a showed an even lower reactivity than expected. Fortunately, after switching to acidic cocatalysts (Table 1, entries 1–3), we found that the reaction catalysed by 4a proceeded with THF as the solvent, at least with the rather strong acid TFA. Even if the desired 3,4-fused indole 3a was formed as a single trans diastereoisomer and with very good enantioselectivity,14 a considerable amount of ring-open product 3a0 was observed in the crude mixture (Table 1, entry 3). Speculating that water could interfere in the Michael addition step, hydrolysing the enamine and thus stopping the reaction with 3a0 formation, we tested MgSO4 as a mild water-trapping agent. We were pleased to observe not only an enhancement in the conversion, but also the formation of the tricyclic compound 3a as the only product (Table 1, entry 4). Then, we tested the influence of the solvent (Table 1, entries 4–8). Reactions performed in ethereal solvents afforded the best results in terms of conversion and enantioselectivity. In contrast, when the reaction was performed in CHCl3, compound 3a was observed only in trace amounts while EtOH gave a complex crude mixture. Upon selecting dioxane as the solvent and lowering the catalyst loading to 10 mol%, prolinol derived catalysts were evaluated. Diarylprolinols 4a–c (Table 1, entries 9–11) were all able to promote the reaction with high conversion. Compared to its analogues, 4b induced a better enantioselectivity and was thus chosen for further studies.15
446 | Chem. Commun., 2014, 50, 445--447
Table 2
Variation of the indole component 1a
Entry
1
R1
R2
R3
Cat. (mol%)
3-Yieldb (%)
eec (%)
1 2 3 4 5 6 7
1a 1b 1c 1d 1e 1f 1g
Me Ph 4-BrC6H4 4-MeOC6H4 4-NO2C6H4 Me Me
H H H H H H Me
H H H H H Me H
4b (10) 4b (10) 4b (10) 4a (10) 4b (10) 4b (10) 4b (20)
3a-76 3b-75 3c-78 3d-70 3e-71 3f-81 3g-67
98 98 91 >99 96d >99 99
a
Conditions: 1a–g (0.10 mmol), 4a or 4b (10–20 mol%), TFA (10–20 mol%), acrolein 2a (0.25 mmol), 1,4-dioxane (300 mL), MgSO4 (50 mg), RT, 18 h (48 h for entry 7). A single diastereoisomer was observed using 1H NMR spectroscopy in the crude mixture. b Isolated yield. c Determined by chiral stationary phase HPLC. d Determined by 1H NMR spectroscopy using a chiral shift reagent (Pirkle alcohol).
With the optimised conditions in hand, the scope of the reaction was inspected. Variations of the ketone moiety in indoles 1a–e12 afforded the tricyclic compounds 3a–e in good yields and excellent enantioselectivities (Table 2, entries 1–5). Modifications in the indole nucleus12 at N1 and C2 positions in 1f and 1g were also tolerated furnishing 3f and 3g in nearly perfect enantioselectivities, although a slight decrease in yield was observed when the N–Me indole 1g was employed, even at a higher catalyst loading (Table 2, entries 6 and 7). When we tried to employ b-substituted enals in the reaction with 1a, we observed the inability of catalysts 4a–c in promoting the reaction, even under more forcing conditions (temperature, concentration, and catalyst loading), highlighting once again the poor nucleophilicity of 1a. In the search for a more reactive system, we turned to the electrophilicity scale developed by Mayr,16 in which the iminium ion derived from the MacMillan second generation catalyst5a (4d) is about three orders of magnitude more electrophilic than the one derived from prolinol 4b. Indeed, the reaction between 1a and crotonaldehyde 2b catalysed by 4d under the formerly optimised conditions proceeded with high conversion, although with moderate enantioselectivity (see ESI†). Whereas the enantioselectivity could be improved by cooling the reaction and switching to a CH2Cl2–i-PrOH mixture as the solvent, as originally reported for indole alkylations with 4d,5a a related N-alkylated compound invariably formed in various amounts, besides the target NH product. We were not able to discriminate between the FC reaction and the N-alkylation even after decreasing the amount of 2b. Nevertheless, by using the N–Me indole 1g it was possible to obtain product 3h cleanly in satisfactory yield and enantioselectivity,14 and as a single
Scheme 2
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Scheme 3
diastereoisomer (Scheme 2). This protocol could also be applied with good results to cinnamaldehydes 2c and 2d. The possibility of performing synthetic manipulations in the products 3 was briefly explored (Scheme 3). Treatment of 3a under Pinnick conditions5a oxidised both the aldehyde and the indole,17 furnishing the intriguing spirocyclic lactone 5, whereas a Robinson annulation reaction18 rendered the tetracyclic derivative 6 as a mixture of diastereoisomers,14 due to a partial epimerisation of the chiral centre a to the aldehyde during the reaction.19 In summary, we have introduced 4-substituted indoles 1 as useful substrates for asymmetric organocatalytic cascade reactions, resulting in a new synthetic route to 3,4-annulated indoles. The employment of these new substrates in related transformations is currently pursued in our laboratory. We acknowledge support from the University of Bologna (RFO). Donation of chemicals from Dr Reddy’s Chirotech Technology Centre (Cambridge, UK) is gratefully acknowledged. We thank Alessandro Sinisi for the preparation of some of the indoles 1.
6
7
8 9
10
Notes and references 1 For reviews, see: (a) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167; (b) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237; (c) S. Goudedranche, W. Raimondi, X. Bugaut, T. Costantieux, D. Bonne and J. Rodriguez, Synthesis, 2013, 1909; (d) A. M. Walji and D. W. C. MacMillan, Synlett, 2007, 1477; ´, M. Viciano and R. Rios, Curr. Org. (e) A.-N. Alba, X. Companyo Chem., 2009, 13, 1432. See also: ( f ) L. F. Tietze, Chem. Rev., 1996, 96, 115. 2 For a focussed review, see: (a) C. Bhanja, S. Jena, S. Nayak and S. Mohapatra, Beilstein J. Org. Chem., 2012, 8, 1668; early reports disclosing this strategy: (b) W. Wang, H. Li, J. Wang and L. Zu, J. Am. ´n, I. Ibrahem, Chem. Soc., 2006, 128, 10354; (c) R. Rios, H. Sunde ´rdova, Tetrahedron Lett., 2006, G.-L. Zhao, L. Eriksson and A. Co 47, 8679; (d) T. Govender, L. Hojabri, F. M. Moghaddam and P. I. Arvidsson, Tetrahedron: Asymmetry, 2006, 17, 1763; recent reports: (e) C. Wang, X. Yang, G. Raabe and D. Enders, Adv. Synth. Catal., 2012, 354, 2629; ( f ) X. Zhang, S. Zhang and W. Wang, ´man, C. Alvarado, Angew. Chem., Int. Ed., 2010, 49, 1481; ( g) J. Ale ˜ez and J. L. Garcı´a Ruano, Synthesis, 2011, 1840; ´n V. Marcos, A. Nu (h) P. Kotame, B.-C. Hong and J.-H. Liao, Tetrahedron Lett., 2009, 50, 704; (i) W. Hou, H.-B. Hong, P. Kotame, C.-W. Tsai and J.-H. Liao, Org. Lett., 2010, 12, 776; ( j) J. Wang, H. Xie, H. Li, L. Zu and W. Wang, Angew. Chem., Int. Ed., 2008, 47, 4177; (k) W. Hou, B. Zheng, J. Chen and Y. Peng, Org. Lett., 2012, 14, 2378. 3 Two exceptions involving a nitro-Michael reaction have been reported: (a) D. Enders, C. Wang and J. W. Bats, Synlett, 2009, 1777; (b) D. Enders, R. Hahn and I. Atodiresei, Adv. Synth. Catal., 2013, 355, 1126. 4 Landmark reports: (a) Y. Huang, A. M. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 15051; ´n and K. A. Jørgensen, J. Am. (b) M. Marigo, T. Schulte, J. Franze Chem. Soc., 2005, 127, 15710; (c) J. W. Yang, M. T. H. Fonseca and B. List, J. Am. Chem. Soc., 2005, 127, 15036; (d) D. Enders, ¨ttl, C. Grondal and G. Raabe, Nature, 2006, 441, 861. M. R. M. Hu
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11
12 13
14
15
16 17 18 19
Review on enamine/iminium ion catalysis: (e) P. Melchiorre, M. Marigo, A. Carlone and G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138. (a) J. F. Austin and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124, 1172; (b) L. Hong, L. Wang, C. Chen, B. Zhang and R. Wang, Adv. Synth. Catal., 2009, 351, 772; (c) Z.-J. Wang, J.-G. Yang, J. Jin, X. Lv and W. Bao, Synlett, 2009, 3994; (d) Z.-H. Shi, H. Sheng, K.-F. Yang, J.-X. Jiang, G.-Q. Lai, Y. Lu and L.-W. Xu, Eur. J. Org. Chem., 2011, 66; (e) E. Riguet, J. Org. Chem., 2011, 76, 8143; ( f ) D. Enders, C. Wang, M. Mukanova and A. Greb, Chem. Commun., 2010, 46, 2447. Recent reviews: ( g) H.-H. Lu, F. Tan and W.-J. Xiao, Curr. Org. Chem., 2011, 15, 4022; (h) M. Zeng and S.-L. You, Synlett, 2010, 1289; (i) V. Terrasson, R. Marcia de Figueiredo and J. M. Campagne, Eur. J. Org. Chem., 2010, 2635; ( j) M. Rueping and B. J. Nachtsheim, Beilstein J. Org. Chem., 2010, 6, 6. (a) M. T. Hechavarria Fonseca and B. List, Angew. Chem., Int. Ed., 2004, 43, 3958; (b) Y. Hayashi, H. Gotoh, T. Tamura, H. Yamaguchi, R. Masui and M. Shoji, J. Am. Chem. Soc., 2005, 127, 16028; for reviews, see: (c) S. Tsogoeva, Eur. J. Org. Chem., 2007, 1701; ´jera, Tetrahedron: Asymmetry, (d) D. Almas- i, D. A. Alonso and C. Na 2007, 18, 299; (e) J. L. Vicario, D. Badı´a and L. Carillo, Synthesis, 2007, 2065. (a) C. L. Schardl, D. G. Panaccione and P. Tudzynski, in The Alkaloids, ed. G. A. Cordell, Elsevier, 2006, vol. 63, pp. 45–86; (b) M. Somei, Y. Yokoyama, Y. Murakami, I. Ninomiya, T. Kiguchi and T. Naito, in The Alkaloids, ed. G. A. Cordell, Academic Press, San Diego, 2000, vol. 54, pp. 191–257. Q. Xiong, X. Zhu, W. K. Wilson, A. Ganesan and S. P. T. Matsuda, J. Am. Chem. Soc., 2003, 125, 9002. See examples and references in: (a) L. Q. Lu, J.-R. Chen and W.-J. Xiao, Acc. Chem. Res., 2012, 45, 1278; (b) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608; (c) G. Bartoli, G. Bencivenni and R. Dalpozzo, Chem. Soc. Rev., 2010, 39, 4449; (d) C. C. J. Loh, G. Raabe and D. Enders, Chem.–Eur. J., 2012, 18, 13250; (e) D. Enders, A. Greb, K. Deckers, P. Selig and C. Merkens, Chem.–Eur. J., 2012, 18, 10226. Recent non-asymmetric methods delivering 1,3,4,5-tetrahydrobenzo[cd]indole frameworks: (a) D. Shan, Y. Gao and Y. Jia, Angew. Chem., Int. Ed., 2013, 52, 4902; (b) I.-K. Park, J. Park and C.-G. Cho, Angew. Chem., Int. Ed., 2012, 51, 2496; synthesis of lysergic acid: (c) S. Umezaki, S. Yokoshima and T. Fukuyama, Org. Lett., 2013, 15, 4230, and references therein; other types of 3,4-fused indoles: (d) D.-J. Cheng, H.-B. Wu and S.-K. Tian, Org. Lett., 2011, 13, 5636; ¨nherr and J. L. Leighton, Org. Lett., 2012, 14, 2610; (e) H. Scho ( f ) Q.-L. Xu, L.-X. Dai and S.-L. You, Chem. Sci., 2013, 4, 97. An electron withdrawing acceptor in the 1,2-disubstituted benzenes reported in the top of Scheme 1 does not pose particular concerns, as the first nucleophilic addition should proceed through nucleophile deprotonation (at least partial). Compounds 1 were prepared by Wittig olefination of the corresponding aldehydes. See ESI†. (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 794; (b) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212; for reviews, see: (c) L.-W. Xu, L. Li and Z.-H. Shi, Adv. Synth. Catal., 2010, 352, 243; (d) K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht and K. A. Jørgensen, Acc. Chem. Res., 2012, 45, 248. The relative configuration of products 3a, 3h and 6 was determined by NMR experiments. The absolute configuration of 3h was assigned by analogy.5a The absolute configuration of 3a and cis-6 was determined by comparing the calculated (TD-DFT) with the experimental ECD spectra: A. Mazzanti and D. Casarini, WIREs Comp. Mol. Sci., 2012, 2, 613. For details, see ESI†. Other C4-acceptors at the indole were tested. A nitroalkene did not give the FC product, while an a,b-unsaturated ester provided exclusively the open product 3 0 . Thus, as initially assumed the C4-substituent must possess some specific electronic properties for the reaction to occur. H. Mayr, S. Lakhdar, B. Maji and A. R. Ofial, Beilstein J. Org. Chem., 2012, 8, 1458. For a mechanistic proposal of the formation of 5, see ESI†. U. Eder, G. Sauer and R. Wiechert, Angew. Chem., Int. Ed. Engl., 1971, 10, 496. cis-6 shows dynamic behaviour, as observed by NMR. See ESI†.
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COMMUNICATION
Cite this: Chem. Commun., 2014, 50, 445 Received 11th October 2013, Accepted 30th October 2013
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Asymmetric synthesis of 3,4-annulated indoles through an organocatalytic cascade approach† Lorenzo Caruana, Mariafrancesca Fochi,* Mauro Comes Franchini, Silvia Ranieri, Andrea Mazzanti and Luca Bernardi*
DOI: 10.1039/c3cc47841f www.rsc.org/chemcomm
Indoles bearing Michael acceptors at the 4-position were engaged in organocatalytic enantioselective cascade reactions with enals. Careful optimisation of the reaction parameters overcame the inherent low reactivity of these substrates, rendering 3,4-ring fused indoles in good yields, excellent enantioselectivities and as single diastereoisomers.
As an alternative to more classic cycloaddition reactions, the construction of enantioenriched carbo- and hetero-cycles by domino organocatalytic processes1 has been the subject of intense research in the last few years. In this context, great focus has been set on the preparation of various benzo-fused heterocycles, such as chromans, thiochromans and hydroquinolines, by using aromatic rings bearing nucleophilic and electrophilic moieties in ortho positions in combination with activated olefins (Scheme 1, top).2 These organocatalytic sequences are generally initiated by a hetero-Michael3 addition of a sulphur, oxygen or nitrogen nucleophile, which triggers the formation of an enolate/enamine that adds to the ortho electrophile terminating the cascade reaction. An elimination step, or even an additional cyclization event, eventually follows. In particular, the merger of iminium ion and enamine catalyses,4 wherein a nucleophilic enamine is formed upon the conjugated addition to an enal or an enone activated by an amine catalyst, has been particularly effective2a–i in these cascade processes. On these grounds, we hypothesized that 4-substituted indoles 1 could be productively engaged in organocatalytic iminium ion– enamine cascade reactions, giving a new synthetic route to 3,4annulated indoles (Scheme 1, bottom). We envisaged that the indole C3 of polyfunctional compounds 1 could act as a nucleophile in an iminium ion promoted Friedel–Crafts (FC)5 process, triggering an intramolecular Michael addition6 of the enamine to the activated Department of Industrial Chemistry ‘‘Toso Montanari’’, School of Science, University of Bologna, V. Risorgimento 4, 40136, Bologna, Italy. E-mail: [email protected], [email protected]; Fax: +39 0512093654; Tel: +39 0512093653 † Electronic supplementary information (ESI) available: Further optimisation results, determination of the relative and absolute configuration, reaction models, experimental details, copies of the NMR spectra and HPLC traces. See DOI: 10.1039/c3cc47841f
This journal is © The Royal Society of Chemistry 2014
Scheme 1
double bond placed at its ortho position. The resulting all-carbon 3,4-ring fused indole core (1,3,4,5-tetrahydrobenzo[cd]indole) of products 3 is widespread in natural products and/or biologically relevant compounds, as exemplified by the ergot alkaloid family7 and by steroidal indoles.8 It must be stressed that even if several 1,2- and 2,3-annulated indoles have been developed by means of organocatalytic sequential reactions,9 related transformations giving all carbon 3,4-fused indoles are, to our knowledge, unprecedented.10 At the outset of our studies, despite the well proven success of the single reaction step of the planned sequence with simpler substrates (i.e. the FC reaction with 4-unsubstituted indoles5 and intramolecular Michael addition2a–i,6), an open question was posed by the expected poor nucleophilicity of the C3 in indoles 1, caused mainly by conjugation of this carbon with the electron withdrawing C4-acceptor,11 and possibly exacerbated by steric effects. On the other hand, the recourse to a scarcely electron poor acceptor did not seem to be a viable strategy, as the intramolecular Michael addition of the enamine would then be suppressed. We considered a,b-unsaturated ketones as a good compromise, and we selected indole 1a as a substrate for the first attempt (Table 1).12 Furthermore, we opted
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Table 1
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Optimisation of the reaction between 1a and acrolein 2aa
Cat. Entry Solvent (mol%) Cocat. 1 2 3 4 5 6 7 8 9 10 11
THF THF THF THF CHCl3 EtOH MTBE Dioxane Dioxane Dioxane Dioxane
4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (20) 4a (10) 4b (10) 4c (10)
PhCO2H 2-NO2PhCO2H TFA TFA TFA TFA TFA TFA TFA TFA TFA
Conv.c eed Additiveb 3a : 3a 0 c (%) (%) None None None MgSO4 MgSO4 MgSO4 MgSO4 MgSO4 MgSO4 MgSO4 MgSO4
— — 57 : 43 >95 : 5 — nd >95 : 5 >95 : 5 >95 : 5 >95 : 5 >95 : 5
o10 o10 50 85 o10 nde 76 100 91 >95 >95
— — 98 99 — nd 99 96 94 98 89
a
Conditions: indole derivative 1a (0.06 mmol), catalyst 4 (10–20 mol%), cocatalyst (10–20 mol%), acrolein 2a (0.15 mmol), solvent (0.20 mL), RT, 18 h. In all cases, a single diastereoisomer was observed using 1H NMR spectroscopy in the crude mixture. b 40 mg of MgSO4 were employed. c Determined by 1H NMR spectroscopy on the crude mixture. d Determined by chiral stationary phase HPLC. e Very complex crude mixture.
for the exceedingly reactive acrolein 2a as the enal partner.2e Taking the published asymmetric indole FC alkylation reactions catalyzed by the Jørgensen–Hayashi catalysts13 4a and 4b as the starting point,5b–f we tried to apply similar reaction conditions (MTBE, CH3CN or MeOH as the solvent, with or without basic additives, RT), which led however to very disappointing results (no reaction). Apparently, the 4-substituted indole 1a showed an even lower reactivity than expected. Fortunately, after switching to acidic cocatalysts (Table 1, entries 1–3), we found that the reaction catalysed by 4a proceeded with THF as the solvent, at least with the rather strong acid TFA. Even if the desired 3,4-fused indole 3a was formed as a single trans diastereoisomer and with very good enantioselectivity,14 a considerable amount of ring-open product 3a0 was observed in the crude mixture (Table 1, entry 3). Speculating that water could interfere in the Michael addition step, hydrolysing the enamine and thus stopping the reaction with 3a0 formation, we tested MgSO4 as a mild water-trapping agent. We were pleased to observe not only an enhancement in the conversion, but also the formation of the tricyclic compound 3a as the only product (Table 1, entry 4). Then, we tested the influence of the solvent (Table 1, entries 4–8). Reactions performed in ethereal solvents afforded the best results in terms of conversion and enantioselectivity. In contrast, when the reaction was performed in CHCl3, compound 3a was observed only in trace amounts while EtOH gave a complex crude mixture. Upon selecting dioxane as the solvent and lowering the catalyst loading to 10 mol%, prolinol derived catalysts were evaluated. Diarylprolinols 4a–c (Table 1, entries 9–11) were all able to promote the reaction with high conversion. Compared to its analogues, 4b induced a better enantioselectivity and was thus chosen for further studies.15
446 | Chem. Commun., 2014, 50, 445--447
Table 2
Variation of the indole component 1a
Entry
1
R1
R2
R3
Cat. (mol%)
3-Yieldb (%)
eec (%)
1 2 3 4 5 6 7
1a 1b 1c 1d 1e 1f 1g
Me Ph 4-BrC6H4 4-MeOC6H4 4-NO2C6H4 Me Me
H H H H H H Me
H H H H H Me H
4b (10) 4b (10) 4b (10) 4a (10) 4b (10) 4b (10) 4b (20)
3a-76 3b-75 3c-78 3d-70 3e-71 3f-81 3g-67
98 98 91 >99 96d >99 99
a
Conditions: 1a–g (0.10 mmol), 4a or 4b (10–20 mol%), TFA (10–20 mol%), acrolein 2a (0.25 mmol), 1,4-dioxane (300 mL), MgSO4 (50 mg), RT, 18 h (48 h for entry 7). A single diastereoisomer was observed using 1H NMR spectroscopy in the crude mixture. b Isolated yield. c Determined by chiral stationary phase HPLC. d Determined by 1H NMR spectroscopy using a chiral shift reagent (Pirkle alcohol).
With the optimised conditions in hand, the scope of the reaction was inspected. Variations of the ketone moiety in indoles 1a–e12 afforded the tricyclic compounds 3a–e in good yields and excellent enantioselectivities (Table 2, entries 1–5). Modifications in the indole nucleus12 at N1 and C2 positions in 1f and 1g were also tolerated furnishing 3f and 3g in nearly perfect enantioselectivities, although a slight decrease in yield was observed when the N–Me indole 1g was employed, even at a higher catalyst loading (Table 2, entries 6 and 7). When we tried to employ b-substituted enals in the reaction with 1a, we observed the inability of catalysts 4a–c in promoting the reaction, even under more forcing conditions (temperature, concentration, and catalyst loading), highlighting once again the poor nucleophilicity of 1a. In the search for a more reactive system, we turned to the electrophilicity scale developed by Mayr,16 in which the iminium ion derived from the MacMillan second generation catalyst5a (4d) is about three orders of magnitude more electrophilic than the one derived from prolinol 4b. Indeed, the reaction between 1a and crotonaldehyde 2b catalysed by 4d under the formerly optimised conditions proceeded with high conversion, although with moderate enantioselectivity (see ESI†). Whereas the enantioselectivity could be improved by cooling the reaction and switching to a CH2Cl2–i-PrOH mixture as the solvent, as originally reported for indole alkylations with 4d,5a a related N-alkylated compound invariably formed in various amounts, besides the target NH product. We were not able to discriminate between the FC reaction and the N-alkylation even after decreasing the amount of 2b. Nevertheless, by using the N–Me indole 1g it was possible to obtain product 3h cleanly in satisfactory yield and enantioselectivity,14 and as a single
Scheme 2
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Scheme 3
diastereoisomer (Scheme 2). This protocol could also be applied with good results to cinnamaldehydes 2c and 2d. The possibility of performing synthetic manipulations in the products 3 was briefly explored (Scheme 3). Treatment of 3a under Pinnick conditions5a oxidised both the aldehyde and the indole,17 furnishing the intriguing spirocyclic lactone 5, whereas a Robinson annulation reaction18 rendered the tetracyclic derivative 6 as a mixture of diastereoisomers,14 due to a partial epimerisation of the chiral centre a to the aldehyde during the reaction.19 In summary, we have introduced 4-substituted indoles 1 as useful substrates for asymmetric organocatalytic cascade reactions, resulting in a new synthetic route to 3,4-annulated indoles. The employment of these new substrates in related transformations is currently pursued in our laboratory. We acknowledge support from the University of Bologna (RFO). Donation of chemicals from Dr Reddy’s Chirotech Technology Centre (Cambridge, UK) is gratefully acknowledged. We thank Alessandro Sinisi for the preparation of some of the indoles 1.
6
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Notes and references 1 For reviews, see: (a) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167; (b) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237; (c) S. Goudedranche, W. Raimondi, X. Bugaut, T. Costantieux, D. Bonne and J. Rodriguez, Synthesis, 2013, 1909; (d) A. M. Walji and D. W. C. MacMillan, Synlett, 2007, 1477; ´, M. Viciano and R. Rios, Curr. Org. (e) A.-N. Alba, X. Companyo Chem., 2009, 13, 1432. See also: ( f ) L. F. Tietze, Chem. Rev., 1996, 96, 115. 2 For a focussed review, see: (a) C. Bhanja, S. Jena, S. Nayak and S. Mohapatra, Beilstein J. Org. Chem., 2012, 8, 1668; early reports disclosing this strategy: (b) W. Wang, H. Li, J. Wang and L. Zu, J. Am. ´n, I. Ibrahem, Chem. Soc., 2006, 128, 10354; (c) R. Rios, H. Sunde ´rdova, Tetrahedron Lett., 2006, G.-L. Zhao, L. Eriksson and A. Co 47, 8679; (d) T. Govender, L. Hojabri, F. M. Moghaddam and P. I. Arvidsson, Tetrahedron: Asymmetry, 2006, 17, 1763; recent reports: (e) C. Wang, X. Yang, G. Raabe and D. Enders, Adv. Synth. Catal., 2012, 354, 2629; ( f ) X. Zhang, S. Zhang and W. Wang, ´man, C. Alvarado, Angew. Chem., Int. Ed., 2010, 49, 1481; ( g) J. Ale ˜ez and J. L. Garcı´a Ruano, Synthesis, 2011, 1840; ´n V. Marcos, A. Nu (h) P. Kotame, B.-C. Hong and J.-H. Liao, Tetrahedron Lett., 2009, 50, 704; (i) W. Hou, H.-B. Hong, P. Kotame, C.-W. Tsai and J.-H. Liao, Org. Lett., 2010, 12, 776; ( j) J. Wang, H. Xie, H. Li, L. Zu and W. Wang, Angew. Chem., Int. Ed., 2008, 47, 4177; (k) W. Hou, B. Zheng, J. Chen and Y. Peng, Org. Lett., 2012, 14, 2378. 3 Two exceptions involving a nitro-Michael reaction have been reported: (a) D. Enders, C. Wang and J. W. Bats, Synlett, 2009, 1777; (b) D. Enders, R. Hahn and I. Atodiresei, Adv. Synth. Catal., 2013, 355, 1126. 4 Landmark reports: (a) Y. Huang, A. M. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 15051; ´n and K. A. Jørgensen, J. Am. (b) M. Marigo, T. Schulte, J. Franze Chem. Soc., 2005, 127, 15710; (c) J. W. Yang, M. T. H. Fonseca and B. List, J. Am. Chem. Soc., 2005, 127, 15036; (d) D. Enders, ¨ttl, C. Grondal and G. Raabe, Nature, 2006, 441, 861. M. R. M. Hu
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