Diastereoselective Passerini Reaction of Chiral 2,3-Epoxy Aldehydes with TosMIC [1]

Abstract

A diastereoselective three-component Passerini reaction (P-3CR) of chiral 2,3-epoxy aldehydes with tosylmethyl isocyanide (TosMIC) under benzoic acid conditions to afford densely substituted products in moderate to good yields and diastereomeric excess is reported.

Key words

diastereoselective Passerini reaction - chiral 2,3-epoxy aldehydes - tosylmethyl isocyanide (TosMIC) - three-component ­reaction (P-3CR) - benzoic acid

1

IICT Communication number: 060606.

References and Notes

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• 5 Radha Krishna P. Krishnarao L. Kannan V. Tetrahedron Lett.  2004,  45:  7847 
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• 7 Dömling A. Chem. Rev.  2006,  106:  17 
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• 13a Radha Krishna P. Ramana Reddy VV. Sharma GVM. Synlett  2003,  1619 
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• 15 Banfi L. Riva R. The Passerini Reaction, In Organic Reactions   Vol. 65:  Overman LE. John Wiley and Sons; New York: 2005.  p.1-140  
• 17 Mihelich ED. Tetrahedron Lett.  1979,  4729 

1

IICT Communication number: 060606.

16

The authors are thankful to the referee who has suggested conducting the Passerini reaction in presence of chiral acids.

18

General Experimental Procedure.
To a stirred solution of the epoxy aldehyde (1.16 mmol) in CH₂Cl₂ (4 mL) was added benzoic acid (1.16 mmol) and TosMIC (1.04 mmol) at r.t. The reaction mixture was stirred for 48 h at the same temperature. After complete consumption of TosMIC, CH₂Cl₂ was removed to obtain a residue, which was purified by column chromatography (silica gel, 60-120 mesh, EtOAc-n-hexane, 8.5:1.5) to afford products 1a-9a in 50-79% yields.

19

Spectral Data of Selected Compounds. Compound 1a: ¹H NMR (300 MHz, CDCl₃): δ = 8.08 (d, 2 H, J = 6.80 Hz, ArH), 8.06 (d, 1 H, J = 4.90 Hz, ArH), 7.76 (d, 1.6 H, J = 7.90 Hz, ArH), 7.70 (d, 0.4 H, J = 8.30 Hz, ArH), 7.58 (d, 1 H, J = 6.80 Hz, ArH), 7.48-7.40 (m, 4 H, NH, ArH), 7.25 (d, 5 H, J = 5.70 Hz, ArH), 5.15 (d, 0.2 H, J = 6.90 Hz, OCH), 5.10 (d, 0.8 H, J = 7.90 Hz, OCH), 4.69-4.46 (m, 4 H, NCH₂, benzylic CH₂), 3.83 (d, 0.4 H, J = 4.90 Hz, OCH₂), 3.76 (d, 1.6 H, J = 4.50 Hz, OCH₂), 3.33-3.15 (m, 2 H, epoxide CH₂), 2.40 (s, 0.6 H, CH₃), 2.38 (s, 2.4 H, CH₃). IR (KBr): 3360, 2932, 2857, 1712, 1622, 1520, 1330 cm^-1. MS (ES): m/z (%) = 510 (28) [M + 1]. Anal. Calcd (%) for C₂₇H₂₇NO₇S: C, 63.64; H, 5.34. Found: C, 63.63; H, 5.36.
Compound 3a: ¹H NMR (200 MHz, CDCl₃): δ = 8.12-8.07 (m, 3 H, ArH), 7.61 (d, 2 H, J = 6.94 Hz, ArH), 7.57 (d, 1 H, J = 7.81 Hz, ArH), 7.51-7.43 (m, 3 H, NH, ArH), 7.36-7.27 (m, 1 H, ArH), 5.42 (d, 0.85 H, J = 3.50 Hz, OCH), 5.24 (d, 0.15 H, J = 5.20 Hz, OCH), 4.68 (d, 2 H, J = 8.70 Hz, NCH₂), 4.13-4.02 (m, 2 H, OCH₂), 3.83-3.79 (m, 1 H, OCH), 3.33-3.30 (m, 1 H, epoxy-H), 3.12-2.92 (m, 1 H, epoxy-H), 2.45 (br s, 3 H, CH₃), 1.42-1.31 (m, 6 H, acetonide). IR (KBr): 3377, 2925, 2855, 1713, 1598, 1526, 1379 cm^-1. MS (ES): m/z (%) = 508 (35) [M⁺ + Na]. Anal. Calcd (%) for C₂₄H₂₇NO₈S: C, 58.88; H, 5.56. Found: C, 58.77; H, 5.51.
Compound 4a: ¹H NMR (300 MHz, CDCl₃): δ = 8.12 (d, 2.5 H, J = 7.60 Hz, ArH), 8.07 (d, 0.5 H, J = 7.90 Hz, ArH), 7.74 (d, 1 H, J = 7.93 Hz, ArH), 7.61-7.53 (m, 2 H, ArH), 7.48-7.40 (m, 3 H, NH, ArH), 7.30 (d, 1 H, J = 7.93 Hz, ArH), 5.16 (d, 0.17 H, J = 7.55 Hz, OCH), 5.14 (d, 0.83 H, J = 9.44 Hz, OCH), 4.78-4.69 (m, 1 H, NCH₂), 4.54-4.47 (m, 1 H, NCH₂), 4.36-4.30 (m, 1 H, OCH), 4.10 (d, 2 H, J = 5.70 Hz, OCH₂), 3.32-3.29 (m, 0.34 H, epoxy-H), 3.23-3.15 (m, 1.66 H, epoxy-H), 2.59 (br s, 0.5 H, CH₃), 2.49 (s, 2.5 H, CH₃), 1.50 (d, 3 H, J = 17.5 Hz, acetonide), 1.30-1.24 (m, 3 H, acetonide). IR (KBr): 3376, 2922, 2857, 1719, 1588, 1520, 1369 cm^-1. MS (ES): m/z (%) = 508 (32) [M⁺ + Na]. Anal. Calcd (%) for C₂₄H₂₇NO₈S: C, 58.88; H, 5.56. Found: C, 58.79; H, 5.47.
Compound 5a: ¹H NMR (200 MHz, CDCl₃): δ = 8.05 (d, 2 H, J = 7.00 Hz, ArH), 7.70 (d, 2 H, J = 8.60 Hz, ArH), 7.55 (d, 1 H, J = 7.00 Hz, ArH), 7.44 (d, 1.5 H, J = 7.80 Hz, ArH), 7.03 (d, 0.5 H, J = 7.00 Hz, ArH), 7.27-7.20 (m, 8 H, NH, ArH), 5.23 (d, 0.75 H, J = 3.90 Hz, OCH), 5.15 (d, 0.25 H, J = 5.50 Hz, OCH), 4.64-4.59 (m, 2 H, NCH₂), 4.46 (s, 2 H, CH ₂Ph), 3.46-3.43 (m, 2 H, OCH₂), 3.04-2.94 (m, 2 H, epoxy-H), 2.39 (s, 3 H, CH₃), 1.71-1.60 (m, 4 H, CH₂). IR (KBr): 3354, 3065, 2924, 2854, 1690, 1601, 1526, 1452 cm^-1. MS (ES): m/z (%) = 533 (27) [M + H]. Anal. Calcd (%) for C₂₉H₃₁NO₇S: C, 64.79; H, 5.81. Found: C, 64.71; H, 5.79.
Compound 6a: ¹H NMR (200 MHz, CDCl₃): δ = 8.07 (d, 3 H, J = 6.80 Hz, ArH), 7.63-7.56 (m, 1 H, ArH), 7.46-7.39 (m, 4 H, NH, ArH), 7.28-7.25 (m, 7 H, ArH), 5.32 (d, 0.27 H, J = 4.20 Hz, OCH), 5.24 (d, 0.73 H, J = 5.70 Hz, OCH), 4.66-4.60 (m, 2 H, NCH₂), 4.46 (s, 2 H, CH ₂Ph), 3.48-3.44 (m, 2 H, OCH₂), 3.08-2.94 (m, 2 H, epoxy-H), 2.38 (s, 3 H, CH₃), 1.69-1.58 (m, 4 H, CH₂). IR (KBr): 3356, 3061, 2925, 2862, 1692, 1621, 1526, 1458 cm^-1. MS (ES): m/z (%) = 533 (28) [M + H]. Anal. Calcd (%) for C₂₉H₃₁NO₇S: C, 64.79; H, 5.81. Found: C, 64.71; H, 5.77.