Brønsted Acid-Thiourea Co-catalysis: Asymmetric Synthesis of Function­alized 1,4-Dihydropyridines from β-Enamino Esters and α,β-Unsaturated ­Aldehydes

Abstract

A Brønsted acid and a novel thiourea derivative co-catalyze the addition of β-enamino esters to α,β-unsaturated aldehydes leading to functionalized 1,4-dihydropyridines with moderate to good enantioselectivity. A regioselective synthesis of 1,2-dihydropyridines from α,β-unsaturated aldehydes is also described.

Key words

asymmetric organocatalysis - Brønsted acid - thiourea - 1,4-dihydropyridines - β-enamino esters - α,β-unsaturated aldehydes

References and Notes

• 1 Rovnyak GC. Kimball SD. Beyer B. Cucinotta G. Dimarco JD. Gougoutas J. Hedberg A. Malley M. McCarthy JP. Zhang R. Mereland S. J. Med. Chem.  1995,  38:  119 
• 2a Hilgeroth A. Mini-Rev. Med. Chem.  2002,  2:  235 
• 2b Hilgeroth A. Lilie H. Eur. J. Med. Chem.  2003,  38:  495 
• 3 Straub T. Boesenberg C. Gekeler V. Boege F. Biochemistry  1997,  36:  10777 
• 4a Robert J. Jarry C. J. Med. Chem.  2003,  46:  4805 
• 4b Avendaño C. Menéndez JC. Med. Chem. Rev. Online  2004,  1:  419 
• 5 Donkor IO. Zhou X. Schmidt J. Agrawal KC. Kishore V. Bioorg. Med. Chem.  1998,  6:  563 
• 6a Lelais G. MacMillan DWC. Aldrichimica Acta  2006,  39:  79 
• 6b You S.-L. Chem. Asian J.  2007,  2:  820 
• 6c Rueping M. Sugiono E. Schoepke FR. Synlett  2010,  852 
• 7a Su W. Li J. Zheng Z. Shen Y. Tetrahedron Lett.  2005,  46:  6037 
• 7b Reddy KR. Reddy CV. Mahesh M. Raju PVK. Reddy VVN. Tetrahedron Lett.  2003,  44:  8173 
• 7c Maiti G. Kundu P. Guin C. Tetrahedron Lett.  2003,  44:  2757 
• 7d Lu J. Ma H. Synlett  2000,  63 
• 7e Hu EH. Sidler DR. Dolling U.-H. J. Org. Chem.  1998,  63:  3454 
• 8a Hantzsch A. Ann. Chem.  1882,  1:  215 
• 8b Vanden Eynde JJ. Mayence A. Molecules  2003,  8:  381 
• 8c Simon C. Constantieux T. Rodriguez J. Eur. J. Org. Chem.  2004,  4957 
• For selected recent reports, see:
• 9a Maiti S. Menendez JC. Synlett  2009,  2249 
• 9b Wan J.-P. Gan S.-F. Sun G.-L. Pan Y.-J. J. Org. Chem.  2009,  74:  2862 
• 9c Kumar A. Marurya RA. Tetrahedron  2008,  64:  3477 
• 9d Bartoli G. Babiuch K. Bosco M. Carlone A. Galzerano P. Melchiorre P. Sambri L. Synlett  2007,  2897 
• 9e Sridharan V. Perumal PT. Avendano C. Menendez JC. Tetrahedron  2007,  63:  4407 
• 9f Ishar MPS. Kumar K. Kaur S. Kumar S. Girdhar NK. Sachar S. Marwaha A. Kapoor A. Org. Lett.  2001,  3:  2133 
• 10 Jie JJ. Yu J. Sun X.-X. Rao Q.-Q. Gong L.-Z. Angew. Chem. Int. Ed.  2008,  47:  2458 
• 11 Moreau J. Duboc A. Hubert C. Hurvois J.-P. Renaud J.-L. Tetrahedron Lett.  2007,  48:  8647 
• For reviews, see:
• 12a Miyabe H. Takemoto Y. Bull. Chem. Soc. Jpn.  2008,  81:  785 
• 12b For related papers, see: Takemoto Y. Org. Biomol. Chem.  2005,  3:  4299 
• 12c Okino T. Hoashi Y. Takemoto Y. J. Am. Chem. Soc.  2003,  125:  12672 
• 12d Okino T. Hoashi Y. Furukawa T. Xu X. Takemoto Y. J. Am. Chem. Soc.  2005,  127:  119 
• 12e Inokuma T. Hoashi Y. Takemoto Y. J. Am. Chem. Soc.  2006,  128:  9413 
• 13a Davis TA. Wilt JC. Johnston JN. J. Am. Chem. Soc.  2010,  132:  2880 
• 13b Nugent BM. Yoder RA. Johnston JN. J. Am. Chem. Soc.  2004,  126:  3418 
• 13c Ishihara K. Nakano K. Akakura M. Org. Lett.  2008,  10:  2893 
• 13d Ishihara K. Nakano K. J. Am. Chem. Soc.  2007,  129:  8930 
• 13e Ishihara K. Nakano K. J. Am. Chem. Soc.  2005,  127:  10504 
• 14a Klausen RS. Jacobsen EN. Org. Lett.  2009,  11:  887 
• 14b Reiseman SE. Doyle AG. Jacobsen EN. J. Am. Chem. Soc.  2008,  130:  7198 
• 14c Raheem IT. Thiara PS. Peterson EA. Jacobsen EN. J. Am. Chem. Soc.  2007,  129:  13404 

15

When 2a (E/Z = 25:75) was reacted with 3a in the presence of DFA-(S,S)-1c, 4aa was obtained in 50% ee (compared
to entry 8 in Table  [¹] ). Therefore we concluded that the stereochemistry of the enamino esters would not effect to the enantioselectivities.

16

The absolute configuration of the thiourea catalysts described has been assigned based on the known configuration of the starting 1,2-diaminocyclohexane or has been established by X-ray-analysis (CCDC768496).

17

In addition to toluene, we tested a chlorinated solvent (CH₂Cl₂) and ethers (THF, Et₂O). Lower temperature (0 ˚C) led to a decrease in yield (<5%), while higher temperatures (50 ˚C) and catalyst loading (20 mol%) led to an increased yield but lower ee (28%, 55% ee). The addition of molecular sieves (3 Å, 4 Å) inhibited the reaction, while other additives (NaSO₄, MgSO₄) led to a decrease in enantioselectivity without improving the yield.

18

Typical Procedure for the Reaction of 2j and 3a Catalyzed by Thiourea 1g - DFA To a solution of cinnamaldehyde (3a, 17.7 mg, 0.10 mmol) in toluene (0.40 mL) were added thiourea 1f (5.4 mg, 0.010 mmol) and 0.1 M difluoroacetic acid in toluene solution (100 µL, 0.010 mmol) at r.t. To this mixture was added dropwise (50 µL/30 min) a solution of 2j (22.0 mg, 0.10 mmol) in toluene (0.50 mL) at r.t. After being stirred at the same temperature for 12 h the reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-EtOAc = 5:1) to give 4ja (30.8 mg, 81%) as a yellow oil.
( R )-Ethyl 1-Benzyl-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (4ja) IR (ATR): 2979, 2925, 1684, 1516 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 8.8 Hz, 2 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.38-7.31 (m, 3 H), 7.22-7.20 (m, 2 H), 6.02 (d, J = 7.6 Hz, 1 H), 4.93 (dd, J = 7.6, 5.5 Hz, 1 H), 4.78 (d, J = 5.5 Hz, 1 H), 4.69 (d, J = 16.8 Hz, 1 H), 4.59 (d, J = 16.8 Hz, 1 H), 3.99 (q, J = 7.1 Hz, 2 H), 2.46 (s, 3 H), 1.09 (t, J = 7.1 Hz, 3 H) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 168.3, 155.9, 149.8, 146.3, 137.6, 130.3, 129.0, 128.1, 127.7, 126.2, 123.6, 106.6, 99.3, 59.5, 53.8, 40.5, 16.0, 14.2. MS (FAB⁺): m/z (%) = 378 (100) [M⁺]. HRMS (FAB⁺):
m/z calcd for C₂₂H₂₂N₂O₄ [M⁺]: 378.1580; found: 378.1578. HPLC (CHIRALCEL AD-H, hexane-2-PrOH = 90:10, flow rate 1.0 mL/min, 254 nm): t _r(minor) = 12.0 min, t _r(major) = 15.3 min. A sample with 80% ee gave [α]_D ^²³ +309.8 (c 1.36, CHCl₃).