Asymmetric Synthesis of Functionalized 3,4-Dihydronaphthalenes via an Organocatalytic Domino Nitroalkane-Michael/Aldol Condensation Reaction

Abstract

An organocatalytic domino nitroalkane-Michael addition/aldol condensation reaction has been developed. This process provides an efficient asymmetric synthesis of trisubstituted 3,4-dihydronaphthalenes in moderate to good yields (40-75%) and high stereoselectivities (de >98%, ee = 91 to >99%).

After intense research in recent years, the field of organocatalysis [¹] has grown with breathtaking speed and is now considered as one of the main branches of asymmetric synthesis. Currently, a focal point at the forefront is the development of organocatalytic domino reactions, [²] which are characterized by the efficient and stereoselective construction of complex molecules from simple precursors in a single operation, thereby avoiding common drawbacks of classical synthesis. Consequently, organocatalytic domino reactions have been intensively investigated during the past few years and a large number of interesting ­reactions have been developed. [³] [4] For example, our group reported recently a secondary amine catalyzed domino Michael/nitroalkane-Michael/aldol condensation reaction for the stereoselective synthesis of tri- and tetrasubstituted cyclohexene carbaldehydes. [4c] [e] [n] In a continuation of our investigations in this field, we envisaged 2-(nitromethyl)benzaldehyde (1) and α,β-unsaturated aldehydes 2 as potential substrates for a domino nitroalkane-Michael addition [5-7] /aldol condensation [8-¹0] reaction, which should provide access to 3-substituted 3,4-dihydronaphthalenes 3 with two stereogenic centers and synthetically valuable aldehyde and nitro groups (Scheme  [¹] ).

In the first instance, we performed the reaction between 2-(nitromethyl)benzaldehyde (1) and cinnamaldehyde (2a) in toluene at room temperature utilizing (S)-diphenylprolinol TMS-ether [¹¹] [(S)-4; 10 mol%] as catalyst. The reaction was found to be completed within five hours, affording dihydronaphthalene 3a in moderate yield (40%) and high diastereo- and enantioselectivity (>98% de, 94% ee, Table  [¹] , entry 1). Encouraged by this initial result, a brief solvent-screening was undertaken and it was found that high stereoselectivity (>98% de, 82-96% ee, Table  [¹] ) was achieved in every solvent used. The optimal result with respect to yield (77%) and stereoselectivity (>98% de, 96% ee) was obtained when the domino reaction was performed in diethyl ether (Table  [¹] , entry 5). Under a lower catalysis load (5 mol%), no significant decrease in yield or stereoselectivity was observed (Table  [¹] , entry 6).

Based on these results, we investigated the scope of the ­reaction by varying the structure of enal 2. In the case of substituted aromatic enals, the dihydronaphthalenes 3b, 3c and 3d were readily synthesized at room temperature in good yields (57-75%) and excellent stereoselectivities (>98% de, 94 to >99% ee, Table  [²] ). The electronic features and the position of the substituent on the aromatic ring had no significant influence on the stereoselectivity of the reaction. Employing the heteroaromatic furyl-­acrolein led to the formation of 3e in good yield (57%) and excellent stereoselectivity (>98% de, 93% ee).

When aliphatic enals 2f and 2g were used as the Michael acceptors the reactions were performed at -5 ˚C affording the desired domino products 3f and 3g in moderate yields (40-41%) and high stereoselectivities (>98% de, 91-93% ee).

The 3,4-dihydronaphthalene 3c was determined to be trans-configured by both Röntgen crystal structure analysis (Figure  [¹] ) [¹²] and NOESY measurements. According to the obtained results in other (S)-diphenylprolinol TMS-ether [(S)-4] catalyzed Michael additions to enals under iminium activation, [4] [6] [7] the absolute configuration of the C-3 stereogenic center was always assigned to be R, if C-4, C-2 and C-1′ possess a descending priority according to the CIP-rules. Based on these results, the absolute configuration of the 3,4-dihydronaphthalenes 3 was assigned as 3R,4S.

A plausible catalytic cycle is given in Scheme  [²] . The ­reaction starts with iminium activation of the enal 2 by the chiral amine catalyst (S)-4. In the next step, the nitroaldehyde 1 performs an intermolecular Michael addition to the generated iminiumion 5. The resulting enamine 6 undergoes an intramolecular aldol reaction affording intermediate 7. Subsequent hydrolysis regenerates the catalyst (S)-4 for the next catalytic cycle and the alcohol 8 dehydrates to the 3,4-dihydronaphthalene products 3.

In summary, we have developed a domino nitroalkane-Michael addition/aldol condensation reaction of 2-(nitromethyl)benzaldehyde (1) and α,β-unsaturated aldehydes 2. This process is efficiently catalyzed by (S)-diphenylprolinol TMS-ether [(S)-4; 5 mol%] to afford functionalized 3,4-dihydronaphthalenes 3 with two stereogenic centers in moderate to good yields (40-75%) and excellent stereoselectivities (>98% de, 91 to >99% ee). [¹³]

Acknowledgment

This work was supported by the Deutsche Forschungsgemeinschaft (priority program Organocatalysis) and the Fonds der Chemischen Industrie. We thank the former Degussa AG and BASF AG for the donation of chemicals.

References and Notes

• For recent reviews on organocatalysis, see:
• 1a Berkessel A. Gröger H. Asymmetric Organocatalysis   Wiley-VCH; Weinheim: 2005. 
• 1b Dalko PI. Enantioselective Organocatalysis   Wiley-VCH; Weinheim: 2007. 
• 1c Special issue on organocatalysis: Chem. Rev.  2007,  107:  issue 12 
• 1d Pellissier H. Tetrahedron  2007,  63:  9267 
  Search in Google Scholar
• 1e Dondoni A. Massi A. Angew. Chem. Int. Ed.  2008,  47:  4638 ; Angew. Chem. 2008, 120, 4716
  Search in Google Scholar
• 1f Kotsuki H. Ikishima H. Okuyama A. Heterocycles  2008,  75:  493 
  Search in Google Scholar
• 1g Kotsuki H. Ikishima H. Okuyama A. Heterocycles  2008,  75:  757 
  Search in Google Scholar
• 1h Enders D. Narine AA. J. Org. Chem.  2008,  73:  7857 
  Search in Google Scholar
• 1i Melchiorre P. Marigo M. Carlone A. Bartoli G. Angew. Chem. Int. Ed.  2008,  47:  6138 ; Angew. Chem. 2008, 120, 6232
  Search in Google Scholar
• For recent reviews on domino reactions, see:
• 2a Tietze LF. Chem. Rev.  1996,  96:  115 
  Search in Google Scholar
• 2b Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis   Wiley-VCH; Weinheim: 2006. 
• 2c Pellissier H. Tetrahedron  2006,  62:  1619 
  Search in Google Scholar
• 2d Pellissier H. Tetrahedron  2006,  62:  2143 
  Search in Google Scholar
• 2e Nicolaou KC. Edmonds DJ. Bulger PG. Angew. Chem. Int. Ed.  2006,  45:  7134 ; Angew. Chem. 2006, 118, 7292
  Search in Google Scholar
• 2f Chapman CJ. Frost CG. Synthesis  2007,  1 
• For reviews on organocatalytic domino reactions, see:
• 3a Enders D. Grondal C. Hüttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 ; Angew. Chem. 2007, 119, 1590
  Search in Google Scholar
• 3b Yu X. Wang W. Org. Biomol. Chem.  2008,  6:  2037 
  Search in Google Scholar
• For selected examples of organocatalytic domino reactions, see:
• 4a Yang JW. Fonseca MTH. List B. J. Am. Chem. Soc.  2005,  127:  15036 
  Search in Google Scholar
• 4b Huang Y. Walji AM. Larsen CH. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  15051 
  Search in Google Scholar
• 4c Enders D. Hüttl MRM. Grondal C. Raabe G. Nature  2006,  441:  861 
  Search in Google Scholar
• 4d Wang W. Li H. Wang J. Zu L. J. Am. Chem. Soc.  2006,  128:  10354 
  Search in Google Scholar
• 4e Enders D. Hüttl MRM. Runsink J. Raabe G. Wendt B. Angew. Chem. Int. Ed.  2007,  46:  467 ; Angew. Chem. 2007, 119, 471
  Search in Google Scholar
• 4f Enders D. Narine AA. Benninghaus TR. Raabe G. Synlett  2007,  1667 
• 4g Carlone A. Cabrera S. Marigo M. Jørgensen KA. Angew. Chem. Int. Ed.  2007,  46:  1101 ; Angew. Chem. 2007, 119, 1119
  Search in Google Scholar
• 4h Hayashi Y. Okano T. Aratake S. Hazelard D. Angew. Chem. Int. Ed.  2007,  46:  4922 ; Angew. Chem. 2007, 119, 5010
  Search in Google Scholar
• 4i Vicario JL. Reboredo L. Badía D. Carrillo L. Angew. Chem. Int. Ed.  2007,  46:  5168 ; Angew. Chem. 2007, 119, 5260
  Search in Google Scholar
• 4j Rueping M. Sugiono E. Merino E. Angew. Chem. Int. Ed.  2008,  47:  3046 ; Angew. Chem. 2008, 120, 3089
  Search in Google Scholar
• 4k Enders D. Wang C. Bats JW. Angew. Chem. Int. Ed.  2008,  47:  7539 ; Angew. Chem. 2008, 120, 7649
  Search in Google Scholar
• 4l Zhao G.-L. Rios R. Vesley J. Eriksson L. Córdova A. Angew. Chem. Int. Ed.  2008,  47:  8468 ; Angew. Chem. 2008, 120, 8596
  Search in Google Scholar
• 4m Lu M. Zhu D. Lu Y. Hou Y. Tan B. Zhong G. Angew. Chem. Int. Ed.  2008,  47:  10187 ; Angew. Chem. 2008, 120, 10341
  Search in Google Scholar
• 4n Enders D. Hüttl MRM. Raabe G. Bats JW. Adv. Synth. Catal.  2008,  350:  267 
  Search in Google Scholar
• 4o Kotame P. Hong B.-C. Liao J.-H. Tetrahedron Lett.  2009,  50:  704 
  Search in Google Scholar
• 4p Franzén J. Fisher A. Angew. Chem. Int. Ed.  2009,  48:  787 ; Angew. Chem. 2009, 121, 801
  Search in Google Scholar
• For reviews on organocatalytic Michael additions, see:
• 5a Tsogoeva SB. Eur. J. Org. Chem.  2007,  1701 
• 5b Sulzer-Mossé S. Alexakis A. Chem. Commun.  2007,  3123 
• 5c Vicario JL. Badía D. Carrillo L. Synthesis  2007,  2065 
• 5d Almaºi D. Alonso DA. Nájera C. Tetrahedron: Asymmetry  2007,  18:  299 
  Search in Google Scholar
• For selected examples of organocatalytic nitroalkane-Michael additions with enals or enones as electrophile, see:
• 6a Hanessian S. Pham V. Org. Lett.  2000,  2:  2975 
  Search in Google Scholar
• 6b Corey EJ. Zhang F.-Y. Org. Lett.  2000,  2:  4257 
  Search in Google Scholar
• 6c Halland N. Hazell RG. Jørgensen KA. J. Org. Chem.  2002,  67:  8331 
  Search in Google Scholar
• 6d Tsogoeva SB. Jagtap SB. Ardemasova ZA. Kalikhevich VN. Eur. J. Org. Chem.  2004,  4014 
• 6e Vukalya B. Varga S. Csámpai A. Soós T. Org. Lett.  2005,  7:  1967 
  Search in Google Scholar
• 6f Mitchell CET. Brenner SE. Ley SV. Chem. Commun.  2005,  5346 
• 6g Prieto A. Halland N. Jørgensen KA. Org. Lett.  2005,  7:  3897 
  Search in Google Scholar
• 6h Ooi T. Takada S. Fujioka S. Maruoka K. Org. Lett.  2005,  7:  5143 
  Search in Google Scholar
• 6i Mitchell CET. Brenner SE. García-Fortanet J. Ley SV. Org. Biomol. Chem.  2006,  4:  2039 
  Search in Google Scholar
• 6j Hanessian S. Shao Z. Warrier JS. Org. Lett.  2006,  8:  4787 
  Search in Google Scholar
• 6k Tsogoeva SB. Jagtap SB. Ardemasova ZA. Tetrahedron: Asymmetry  2006,  17:  989 
  Search in Google Scholar
• 6l Gotoh H. Ishikawa H. Hayashi Y. Org. Lett.  2007,  9:  5307 
  Search in Google Scholar
• 6m Hojabri L. Hartikka L. Moghaddam FM. Arvidsson PI. Adv. Synth. Catal.  2007,  349:  740 
  Search in Google Scholar
• 6n Vakulya B. Varga S. Soós T. J. Org. Chem.  2008,  73:  3475 
  Search in Google Scholar
• 6o Li P. Wang Y. Liang X. Ye J. Chem. Commun.  2008,  3302 
• 6p Zhong S. Chen Y. Petersen JL. Akhmedov NG. Shi X. Angew. Chem. Int. Ed.  2009,  48:  1279 ; Angew. Chem. 2009, 121, 1305
  Search in Google Scholar
• For selected examples of organocatalytic domino reactions involving nitroalkane-Michael additions with enals or enones as electrophiles, see refs 4c, 4e, 4g, 4n, 4o, and:
• 7a Reyes E. Jiang H. Milelli A. Elsner P. Hazell RG. Jørgensen KA. Angew. Chem. Int. Ed.  2007,  46:  9202 ; Angew. Chem. 2007, 119, 9362
  Search in Google Scholar
• 7b Zhao G.-L. Ibrahem I. Dziedzic P. Sun J. Bonneau C. Córdova A. Chem. Eur. J.  2008,  14:  10007 
  Search in Google Scholar
• 7c Lv J. Zhang J. Lin Z. Wang Y. Chem. Eur. J.  2009,  15:  972 
  Search in Google Scholar
• 7d Zu L. Zhang S. Xie H. Wang W. Org. Lett.  2009,  11:  1627 
  Search in Google Scholar
• 8 For a review on organocatalytic aldol reactions, see: Guillena G. Nájera C. Ramón DJ. Tetrahedron: Asymmetry  2007,  18:  2249 
  CrossrefSearch in Google Scholar
• For selected examples of organocatalytic intramolecular aldol reactions, see:
• 9a Pidathala C. Hoang L. Vignola N. List B. Angew. Chem. Int. Ed.  2003,  42:  2785 ; Angew. Chem. 2003, 115, 2891
  Search in Google Scholar
• 9b Kriis K. Kanger T. Laars M. Müürisepp A.-M. Pehk T. Lopp M. Synlett  2006,  1699 
• 9c Enders D. Niemeier O. Straver L. Synlett  2006,  3399 
• 9d Hayashi Y. Sekiziwa H. Yamaguchi J. Gotoh H. J. Org. Chem.  2007,  72:  6493 
  Search in Google Scholar
• 9e Yoshitomi Y. Makino K. Hamada Y. Org. Lett.  2007,  9:  2457 
  Search in Google Scholar
• For selected examples of organocatalytic domino reactions involving intramolecular aldol reactions, see refs 4c-g, 4n, 4o and:
• 10a Halland N. Abruel PS. Jørgensen KA. Angew. Chem. Int. Ed.  2004,  43:  1272 ; Angew. Chem. 2004, 116, 1292
  Search in Google Scholar
• 10b Brandau B. Maerten E. Jørgensen KA.
  J. Am. Chem. Soc.  2006,  128:  14986 
  Search in Google Scholar
• 10c Govender T. Hojbri L. Moghaddam FM. Arvidsson PI. Tetrahedron: Asymmetry  2006,  17:  1763 
  Search in Google Scholar
• 10d Wang J. Li H. Xie H. Zu L. Shen X. Wang W. Angew. Chem. Int. Ed.  2007,  46:  9050 ; Angew. Chem. 2007, 119, 9208
  Search in Google Scholar
• 10e Li H. Wang J. Xie H. Zu L. Jiang W. Duesler EN. Wang W. Org. Lett.  2007,  9:  965 
  Search in Google Scholar
• 10f Hong B.-C. Nimje RY. Sadani AA. Liao J.-H. Org. Lett.  2008,  10:  2345 
  Search in Google Scholar
• 10g Penon O. Carlone A. Mazzanti A. Locatelli M. Sambri L. Bartoli G. Melchiorre P. Chem. Eur. J.  2008,  14:  4788 
  Search in Google Scholar
• For reviews on diphenylprolinol TMS-ether, see:
• 11a Palomo C. Mielgo A. Angew. Chem. Int. Ed.  2006,  45:  7876 ; Angew. Chem. 2006, 118, 8042
  Search in Google Scholar
• 11b Mielgo A. Palomo C. Chem. Asian J.  2008,  922 

Compound 3c: CCDC-725063 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

General Procedure: To a solution of 2-(nitromethyl)-benzaldehyde (1; 1.0 mmol) and α,β-unsatured aldehyde 2 (1.1 mmol, 1.1 equiv) in Et₂O (2 mL), was added (S)-di-phenylprolinol TMS-ether [(S)-4; 0.05 mmol, 5 mol%]. The reaction mixture was stirred at the temperature and for the time displayed in Table  [²] .
Workup A: Direct purification of the reaction mixture by flash chromatography afforded 3,4-dihydronaphthalenes 3 (pentane-Et₂O, 2-10:1).
Workup B: Direct suction through a funnel followed by washing with Et₂O afforded 3c.
Workup C: The reaction mixture was suctioned through a funnel and washed with Et₂O. Purification of the obtained solid by flash chromatography (silica gel, pentane-Et₂O, 1:3) afforded 3d.
(3 R ,4 S )-3-(2-Methoxyphenyl)-4-nitro-3,4-dihydro-naphthalene-2-carbaldehyde (3c; Figure 2): Isolated as a colorless solid (206 mg, 67%). The ee (>99%) was determined by HPLC on a chiral stationary phase [Chiralcel OD; n-heptane-i-PrOH (8:2); 1.0 mL/min, t _R  = 9.04 min(major), 10.29 min (minor, based on the racemic mixture)]; mp 182 ˚C; [α]_D ^²0 -482 (c 1.0, CHCl₃); IR (KBr): 3310 (w), 3000 (w), 2946 (w), 2823 (m), 2728 (w), 2324 (w), 2268 (w), 2184 (w), 2048 (w), 1989 (w), 1942 (w), 1735 (w), 1701 (w), 1663 (vs), 1627 (s), 1599 (m), 1570 (m), 1538 (vs), 1489 (s), 1460 (s), 1435 (m), 1399 (s), 1358 (s), 1327 (m), 1289 (s), 1273 (s), 1245 (vs), 1192 (w), 1158 (vs), 1105 (s), 1052 (s), 1028 (s), 961 (w), 924 (s), 855 (m), 819 (m), 755 (vs), 704 (s) cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 3.95 (s, 3 H, OCH₃), 5.48 (br s, J = <2 Hz, 1 H, H-3), 5.62 (br s, J = <2 Hz, 1 H, H-4), 6.60 (dd, J = 7.6, 1.6 Hz, 1 H, H-6′), 6.65 (td, J = 7.6, 0.8 Hz, 1 H, H-5′), 6.91 (d, J = 7.6 Hz, 1 H, H-3′), 7.19 (td, J = 7.6, 1.6 Hz, 1 H, H-4′), 7.36-7.42 (m, 2 H, H-5,7), 7.48-7.54 (m, 2 H, H-6,8), 7.68 (s, 1 H, H-1), 9.73 (s, 1 H, CHO); ^¹³C NMR (101 MHz, CDCl₃): δ = 34.5 (C-3), 55.6 (OCH₃), 86.4 (C-4), 110.8 (C-3′), 120.3 (C-5′), 122.5 (C-1′), 126.9 (C-6′), 128.0 (C-9), 129.0 (C-4′), 129.4 (C-8), 130.9 (C-6), 131.3 (C-5), 131.6 (C-7), 131.7 (C-10), 137.8 (C-2), 144.1 (C-1), 156.7 (C-2′), 190.7 (CHO); MS (EI, 70 eV): m/z (%) = 309.4 (5.8) [M⁺], 277.3 (2.2), 263.3 (74), 245.3 (50), 235.4 (100), 231.4 (24), 202.3 (65), 189.3 (19), 176.3 (2.7), 165.3 (8.8), 155.3 (7.5), 152.3 (2.7), 127.3 (9.5), 117.6 (9.1), 101.3 (19), 94.8 (7.2), 83.1 (4.7), 77.4 (10), 57.4 (2.2), 51.4 (4.0), 43.3 (2.2); Anal. Calcd for C₁₈H₁₅NO₄: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.92; H, 4.94; N, 4.50.

References and Notes

• For recent reviews on organocatalysis, see:
• 1a Berkessel A. Gröger H. Asymmetric Organocatalysis   Wiley-VCH; Weinheim: 2005. 
• 1b Dalko PI. Enantioselective Organocatalysis   Wiley-VCH; Weinheim: 2007. 
• 1c Special issue on organocatalysis: Chem. Rev.  2007,  107:  issue 12 
• 1d Pellissier H. Tetrahedron  2007,  63:  9267 
  Search in Google Scholar
• 1e Dondoni A. Massi A. Angew. Chem. Int. Ed.  2008,  47:  4638 ; Angew. Chem. 2008, 120, 4716
  Search in Google Scholar
• 1f Kotsuki H. Ikishima H. Okuyama A. Heterocycles  2008,  75:  493 
  Search in Google Scholar
• 1g Kotsuki H. Ikishima H. Okuyama A. Heterocycles  2008,  75:  757 
  Search in Google Scholar
• 1h Enders D. Narine AA. J. Org. Chem.  2008,  73:  7857 
  Search in Google Scholar
• 1i Melchiorre P. Marigo M. Carlone A. Bartoli G. Angew. Chem. Int. Ed.  2008,  47:  6138 ; Angew. Chem. 2008, 120, 6232
  Search in Google Scholar
• For recent reviews on domino reactions, see:
• 2a Tietze LF. Chem. Rev.  1996,  96:  115 
  Search in Google Scholar
• 2b Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis   Wiley-VCH; Weinheim: 2006. 
• 2c Pellissier H. Tetrahedron  2006,  62:  1619 
  Search in Google Scholar
• 2d Pellissier H. Tetrahedron  2006,  62:  2143 
  Search in Google Scholar
• 2e Nicolaou KC. Edmonds DJ. Bulger PG. Angew. Chem. Int. Ed.  2006,  45:  7134 ; Angew. Chem. 2006, 118, 7292
  Search in Google Scholar
• 2f Chapman CJ. Frost CG. Synthesis  2007,  1 
• For reviews on organocatalytic domino reactions, see:
• 3a Enders D. Grondal C. Hüttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 ; Angew. Chem. 2007, 119, 1590
  Search in Google Scholar
• 3b Yu X. Wang W. Org. Biomol. Chem.  2008,  6:  2037 
  Search in Google Scholar
• For selected examples of organocatalytic domino reactions, see:
• 4a Yang JW. Fonseca MTH. List B. J. Am. Chem. Soc.  2005,  127:  15036 
  Search in Google Scholar
• 4b Huang Y. Walji AM. Larsen CH. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  15051 
  Search in Google Scholar
• 4c Enders D. Hüttl MRM. Grondal C. Raabe G. Nature  2006,  441:  861 
  Search in Google Scholar
• 4d Wang W. Li H. Wang J. Zu L. J. Am. Chem. Soc.  2006,  128:  10354 
  Search in Google Scholar
• 4e Enders D. Hüttl MRM. Runsink J. Raabe G. Wendt B. Angew. Chem. Int. Ed.  2007,  46:  467 ; Angew. Chem. 2007, 119, 471
  Search in Google Scholar
• 4f Enders D. Narine AA. Benninghaus TR. Raabe G. Synlett  2007,  1667 
• 4g Carlone A. Cabrera S. Marigo M. Jørgensen KA. Angew. Chem. Int. Ed.  2007,  46:  1101 ; Angew. Chem. 2007, 119, 1119
  Search in Google Scholar
• 4h Hayashi Y. Okano T. Aratake S. Hazelard D. Angew. Chem. Int. Ed.  2007,  46:  4922 ; Angew. Chem. 2007, 119, 5010
  Search in Google Scholar
• 4i Vicario JL. Reboredo L. Badía D. Carrillo L. Angew. Chem. Int. Ed.  2007,  46:  5168 ; Angew. Chem. 2007, 119, 5260
  Search in Google Scholar
• 4j Rueping M. Sugiono E. Merino E. Angew. Chem. Int. Ed.  2008,  47:  3046 ; Angew. Chem. 2008, 120, 3089
  Search in Google Scholar
• 4k Enders D. Wang C. Bats JW. Angew. Chem. Int. Ed.  2008,  47:  7539 ; Angew. Chem. 2008, 120, 7649
  Search in Google Scholar
• 4l Zhao G.-L. Rios R. Vesley J. Eriksson L. Córdova A. Angew. Chem. Int. Ed.  2008,  47:  8468 ; Angew. Chem. 2008, 120, 8596
  Search in Google Scholar
• 4m Lu M. Zhu D. Lu Y. Hou Y. Tan B. Zhong G. Angew. Chem. Int. Ed.  2008,  47:  10187 ; Angew. Chem. 2008, 120, 10341
  Search in Google Scholar
• 4n Enders D. Hüttl MRM. Raabe G. Bats JW. Adv. Synth. Catal.  2008,  350:  267 
  Search in Google Scholar
• 4o Kotame P. Hong B.-C. Liao J.-H. Tetrahedron Lett.  2009,  50:  704 
  Search in Google Scholar
• 4p Franzén J. Fisher A. Angew. Chem. Int. Ed.  2009,  48:  787 ; Angew. Chem. 2009, 121, 801
  Search in Google Scholar
• For reviews on organocatalytic Michael additions, see:
• 5a Tsogoeva SB. Eur. J. Org. Chem.  2007,  1701 
• 5b Sulzer-Mossé S. Alexakis A. Chem. Commun.  2007,  3123 
• 5c Vicario JL. Badía D. Carrillo L. Synthesis  2007,  2065 
• 5d Almaºi D. Alonso DA. Nájera C. Tetrahedron: Asymmetry  2007,  18:  299 
  Search in Google Scholar
• For selected examples of organocatalytic nitroalkane-Michael additions with enals or enones as electrophile, see:
• 6a Hanessian S. Pham V. Org. Lett.  2000,  2:  2975 
  Search in Google Scholar
• 6b Corey EJ. Zhang F.-Y. Org. Lett.  2000,  2:  4257 
  Search in Google Scholar
• 6c Halland N. Hazell RG. Jørgensen KA. J. Org. Chem.  2002,  67:  8331 
  Search in Google Scholar
• 6d Tsogoeva SB. Jagtap SB. Ardemasova ZA. Kalikhevich VN. Eur. J. Org. Chem.  2004,  4014 
• 6e Vukalya B. Varga S. Csámpai A. Soós T. Org. Lett.  2005,  7:  1967 
  Search in Google Scholar
• 6f Mitchell CET. Brenner SE. Ley SV. Chem. Commun.  2005,  5346 
• 6g Prieto A. Halland N. Jørgensen KA. Org. Lett.  2005,  7:  3897 
  Search in Google Scholar
• 6h Ooi T. Takada S. Fujioka S. Maruoka K. Org. Lett.  2005,  7:  5143 
  Search in Google Scholar
• 6i Mitchell CET. Brenner SE. García-Fortanet J. Ley SV. Org. Biomol. Chem.  2006,  4:  2039 
  Search in Google Scholar
• 6j Hanessian S. Shao Z. Warrier JS. Org. Lett.  2006,  8:  4787 
  Search in Google Scholar
• 6k Tsogoeva SB. Jagtap SB. Ardemasova ZA. Tetrahedron: Asymmetry  2006,  17:  989 
  Search in Google Scholar
• 6l Gotoh H. Ishikawa H. Hayashi Y. Org. Lett.  2007,  9:  5307 
  Search in Google Scholar
• 6m Hojabri L. Hartikka L. Moghaddam FM. Arvidsson PI. Adv. Synth. Catal.  2007,  349:  740 
  Search in Google Scholar
• 6n Vakulya B. Varga S. Soós T. J. Org. Chem.  2008,  73:  3475 
  Search in Google Scholar
• 6o Li P. Wang Y. Liang X. Ye J. Chem. Commun.  2008,  3302 
• 6p Zhong S. Chen Y. Petersen JL. Akhmedov NG. Shi X. Angew. Chem. Int. Ed.  2009,  48:  1279 ; Angew. Chem. 2009, 121, 1305
  Search in Google Scholar
• For selected examples of organocatalytic domino reactions involving nitroalkane-Michael additions with enals or enones as electrophiles, see refs 4c, 4e, 4g, 4n, 4o, and:
• 7a Reyes E. Jiang H. Milelli A. Elsner P. Hazell RG. Jørgensen KA. Angew. Chem. Int. Ed.  2007,  46:  9202 ; Angew. Chem. 2007, 119, 9362
  Search in Google Scholar
• 7b Zhao G.-L. Ibrahem I. Dziedzic P. Sun J. Bonneau C. Córdova A. Chem. Eur. J.  2008,  14:  10007 
  Search in Google Scholar
• 7c Lv J. Zhang J. Lin Z. Wang Y. Chem. Eur. J.  2009,  15:  972 
  Search in Google Scholar
• 7d Zu L. Zhang S. Xie H. Wang W. Org. Lett.  2009,  11:  1627 
  Search in Google Scholar
• 8 For a review on organocatalytic aldol reactions, see: Guillena G. Nájera C. Ramón DJ. Tetrahedron: Asymmetry  2007,  18:  2249 
  CrossrefSearch in Google Scholar
• For selected examples of organocatalytic intramolecular aldol reactions, see:
• 9a Pidathala C. Hoang L. Vignola N. List B. Angew. Chem. Int. Ed.  2003,  42:  2785 ; Angew. Chem. 2003, 115, 2891
  Search in Google Scholar
• 9b Kriis K. Kanger T. Laars M. Müürisepp A.-M. Pehk T. Lopp M. Synlett  2006,  1699 
• 9c Enders D. Niemeier O. Straver L. Synlett  2006,  3399 
• 9d Hayashi Y. Sekiziwa H. Yamaguchi J. Gotoh H. J. Org. Chem.  2007,  72:  6493 
  Search in Google Scholar
• 9e Yoshitomi Y. Makino K. Hamada Y. Org. Lett.  2007,  9:  2457 
  Search in Google Scholar
• For selected examples of organocatalytic domino reactions involving intramolecular aldol reactions, see refs 4c-g, 4n, 4o and:
• 10a Halland N. Abruel PS. Jørgensen KA. Angew. Chem. Int. Ed.  2004,  43:  1272 ; Angew. Chem. 2004, 116, 1292
  Search in Google Scholar
• 10b Brandau B. Maerten E. Jørgensen KA.
  J. Am. Chem. Soc.  2006,  128:  14986 
  Search in Google Scholar
• 10c Govender T. Hojbri L. Moghaddam FM. Arvidsson PI. Tetrahedron: Asymmetry  2006,  17:  1763 
  Search in Google Scholar
• 10d Wang J. Li H. Xie H. Zu L. Shen X. Wang W. Angew. Chem. Int. Ed.  2007,  46:  9050 ; Angew. Chem. 2007, 119, 9208
  Search in Google Scholar
• 10e Li H. Wang J. Xie H. Zu L. Jiang W. Duesler EN. Wang W. Org. Lett.  2007,  9:  965 
  Search in Google Scholar
• 10f Hong B.-C. Nimje RY. Sadani AA. Liao J.-H. Org. Lett.  2008,  10:  2345 
  Search in Google Scholar
• 10g Penon O. Carlone A. Mazzanti A. Locatelli M. Sambri L. Bartoli G. Melchiorre P. Chem. Eur. J.  2008,  14:  4788 
  Search in Google Scholar
• For reviews on diphenylprolinol TMS-ether, see:
• 11a Palomo C. Mielgo A. Angew. Chem. Int. Ed.  2006,  45:  7876 ; Angew. Chem. 2006, 118, 8042
  Search in Google Scholar
• 11b Mielgo A. Palomo C. Chem. Asian J.  2008,  922 

Compound 3c: CCDC-725063 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

General Procedure: To a solution of 2-(nitromethyl)-benzaldehyde (1; 1.0 mmol) and α,β-unsatured aldehyde 2 (1.1 mmol, 1.1 equiv) in Et₂O (2 mL), was added (S)-di-phenylprolinol TMS-ether [(S)-4; 0.05 mmol, 5 mol%]. The reaction mixture was stirred at the temperature and for the time displayed in Table  [²] .
Workup A: Direct purification of the reaction mixture by flash chromatography afforded 3,4-dihydronaphthalenes 3 (pentane-Et₂O, 2-10:1).
Workup B: Direct suction through a funnel followed by washing with Et₂O afforded 3c.
Workup C: The reaction mixture was suctioned through a funnel and washed with Et₂O. Purification of the obtained solid by flash chromatography (silica gel, pentane-Et₂O, 1:3) afforded 3d.
(3 R ,4 S )-3-(2-Methoxyphenyl)-4-nitro-3,4-dihydro-naphthalene-2-carbaldehyde (3c; Figure 2): Isolated as a colorless solid (206 mg, 67%). The ee (>99%) was determined by HPLC on a chiral stationary phase [Chiralcel OD; n-heptane-i-PrOH (8:2); 1.0 mL/min, t _R  = 9.04 min(major), 10.29 min (minor, based on the racemic mixture)]; mp 182 ˚C; [α]_D ^²0 -482 (c 1.0, CHCl₃); IR (KBr): 3310 (w), 3000 (w), 2946 (w), 2823 (m), 2728 (w), 2324 (w), 2268 (w), 2184 (w), 2048 (w), 1989 (w), 1942 (w), 1735 (w), 1701 (w), 1663 (vs), 1627 (s), 1599 (m), 1570 (m), 1538 (vs), 1489 (s), 1460 (s), 1435 (m), 1399 (s), 1358 (s), 1327 (m), 1289 (s), 1273 (s), 1245 (vs), 1192 (w), 1158 (vs), 1105 (s), 1052 (s), 1028 (s), 961 (w), 924 (s), 855 (m), 819 (m), 755 (vs), 704 (s) cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 3.95 (s, 3 H, OCH₃), 5.48 (br s, J = <2 Hz, 1 H, H-3), 5.62 (br s, J = <2 Hz, 1 H, H-4), 6.60 (dd, J = 7.6, 1.6 Hz, 1 H, H-6′), 6.65 (td, J = 7.6, 0.8 Hz, 1 H, H-5′), 6.91 (d, J = 7.6 Hz, 1 H, H-3′), 7.19 (td, J = 7.6, 1.6 Hz, 1 H, H-4′), 7.36-7.42 (m, 2 H, H-5,7), 7.48-7.54 (m, 2 H, H-6,8), 7.68 (s, 1 H, H-1), 9.73 (s, 1 H, CHO); ^¹³C NMR (101 MHz, CDCl₃): δ = 34.5 (C-3), 55.6 (OCH₃), 86.4 (C-4), 110.8 (C-3′), 120.3 (C-5′), 122.5 (C-1′), 126.9 (C-6′), 128.0 (C-9), 129.0 (C-4′), 129.4 (C-8), 130.9 (C-6), 131.3 (C-5), 131.6 (C-7), 131.7 (C-10), 137.8 (C-2), 144.1 (C-1), 156.7 (C-2′), 190.7 (CHO); MS (EI, 70 eV): m/z (%) = 309.4 (5.8) [M⁺], 277.3 (2.2), 263.3 (74), 245.3 (50), 235.4 (100), 231.4 (24), 202.3 (65), 189.3 (19), 176.3 (2.7), 165.3 (8.8), 155.3 (7.5), 152.3 (2.7), 127.3 (9.5), 117.6 (9.1), 101.3 (19), 94.8 (7.2), 83.1 (4.7), 77.4 (10), 57.4 (2.2), 51.4 (4.0), 43.3 (2.2); Anal. Calcd for C₁₈H₁₅NO₄: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.92; H, 4.94; N, 4.50.