NaBH₄-mediated FacileReduction of Esters of Baylis-Hillman Adducts: An EfficientApproach to Substituted Propane-1,3-Diols [1]

Abstract

Reduction of the ester group in the Baylis-Hillman adductsby NaBH₄ reduction is facilitated by the secondary hydroxyl grouppresent at their β-position. This method is efficient forthe preparation of substituted propane-1,3-diols.

Key words

Baylis-Hillman reaction - NaBH₄ - reduction - ester - propane-1,3-diol

1

CDRI Communication No. 6400.

References

• 2 Basavaiah D. Jaganmohan Rao A. Satyanarayana T. Chem.Rev.  2003,  103:  811 
• 3a Batra S. Srinivasan T. Rastogi SK. Kundu B. Patra A. Bhaduri AP. Dikshit M. Bioorg. Med. Chem. Lett.  2002,  12:  1905 
• 3b Patra A. Batra S. Bhaduri AP. Khanna AK. Chander R. Dikshit M. Bioorg. Med. Chem.  2003,  11:  2269 
• 4a Basavaiah D. Kumaragurubaran N. TetrahedronLett.  2001,  42:  477 
• 4b Im YJ. Kim JM. Mun JH. Kim JN. Bull. Korean Chem. Soc.  2001,  22:  349 
• 5a Patra A. Batra S. Kundu B. Joshi BS. Roy R. Bhaduri AP. Synthesis  2001,  276 
• 5b Roy AK. Batra S. Synthesis  2003,  1347 
• 5c Ciganek E. Org.React.  1997,  51:  201 
• 7 Padhi SK. Chadha A. Synlett  2003,  639 
• 8a Periasamy M. Thirumalaikumar M. J.Organomet. Chem.  2000,  609:  137 
• 8b Khanapure SP. Saha G. Sivendran S. Powell WS. Rokacha J. Tetrahedron Lett.  2000,  41:  5653 
• 8c Barnett JEG. Kent PW. J.Chem. Soc.  1963,  2743 
• 8d Tsuboi S. Furutani H. Utaka M. Takeda A. Tetrahedron Lett.  1987,  28:  2709 

1

CDRI Communication No. 6400.

6

General Procedurefor Reaction of NaBH ₄ with Baylis-Hillmanadducts. To the solution of appropriate Baylis-Hillmanadduct (2 mmol) in solvent (5 mL) was added NaBH₄ (Aldrich,pellet 7/16′′, 98%) (0.12 g,3 mmol) with stirring at 0-5 °C. After additionof NaBH₄, the reaction was allowed to continue for appropriatetime (Table [1] )at r.t. Thereafter, the reaction mixture was quenched with water andextracted with ethyl acetate (2 × 25 mL). The organic layerswere pooled, washed with brine (30 mL), dried (Na₂SO₄)and concentrated in vacuum to obtain an oily residue. This residuewas passed through a small band of silica gel using hexane:ethylacetate (3:2, v/v) to furnish diasteroisomeric mixtureof 1,3-diols. The HPLC profile of representative diols show onlysingle peak in a gradient system of 0% acetonitrile inwater to 100% acetonitrile in water containing 0.1% ofTFA over a period of 25 min on RP-18e column (150 × 4.6mm) at λ = 220 nm and 254 nm.
2-Methyl-1-(3-nitro-phenyl)-propane-1,3-diol (entries1-5): IR (Neat, cm^-1) 3379(OH); ¹H NMR (CDCl₃, 300 MHz) δ 0.75,0.77 (d, 3 H, J = 7.0 Hz, CH₃),0.81, 0.83 (d, 3H, J = 7.0 Hz,CH₃), 1.98-2.09 (m, 2 H, 2 × CH), 2.69(s, 2 H, 2 × OH, exchangeable with D₂O), 3.68-3.91(m, 4 H, 2 × CH₂), 3.96 (s, 2 H, 2 × OH,exchangeable with D₂O), 4.69, 4.71 (d, 1 H, J = 7.5 Hz, CH), 5.24 (s, 1H, CH), 7.52 (dt, 2 H, J ₁ = 2.4Hz, J ₂ = 7.8 Hz,2 × Ar-H), 7.68, 7.71 (d, 2 H, J = 7.7Hz, 2 × Ar-H), 8.13 (dt almost merged, 2 H, J ₁ = 2.0 Hz, J ₂ = 7.8 Hz, 2 × Ar-H),8.23 (s, 2 H, 2 × Ar-H); ¹³CNMR (CDCl₃, 75.46 Hz) δ 9.8 (CH₃),13.6 (CH₃), 41.0 (CH), 41.4 (CH), 66.3 (CH₂),67.4 (CH₂), 75.0 (CH), 79.4 (CH), 120.09 (CH), 121.6(CH), 122.0 (CH), 122.6 (CH), 129.0 (CH), 129.3 (CH), 132.4 (CH),132.9 (CH), 145.2 (C), 145.5 (C), 148 (2 × C); Mass (FAB+) m/z 212 (M⁺ + 1).Anal. calcd for C₁₀H₁₃NO₄: C, 56.86;H, 6.20; N, 6.63. Found: C, 57.01; H, 6.30; N, 6.55%.
2-Methyl-1-(4-trifluoromethyl-phenyl)-propane-1,3-diol (entry6): IR (Neat, cm^-1) 3396 (OH); ¹HNMR (CDCl₃, 200 MHz) δ 0.73, 0.76 (d, 3 H, J = 7.0 Hz, CH₃),0.81, 0.84 (d, 3 H, J = 7.0Hz, CH₃), 1.97-2.10 (m, 2 H, 2 × CH),2.58, 2.60 (d, 2 H, J = 4.4Hz, OH), 3.42 (br s, 2 H, OH), 3.71-3.84 (m, 4 H, 2 × CH₂),4.62, 4.66 (d, 1 H, J = 6.9Hz, CH), 5.06 (brs, 1 H, CH), 7.44, 7.88 (d, 4 H, J = 8.0Hz, 2 × 2Ar-H), 7.59, 7.63 (d, 4 H, J = 8.0Hz, 2 × 2 Ar-H); Mass (FAB+) m/z 235 (M⁺ + 1).Anal. calcd for C₁₅H₁₃F₃O₂:C, 56.41; H, 5.59. Found: C, 56.60; H, 5.77%.
2-Methyl-1-(3-phenyl-isoxazol-5-yl)-propane-1,3-diol (entry7): HPLC (t _R = 13.01min); IR (Neat, cm^-1) 3369 (OH); ¹HNMR (CDCl₃, 200 MHz) δ 0.93, 0.97 (d, 3 H, J = 7.0 Hz, CH₃),0.99, 1.02 (d, 3 H, J = 7.0Hz, CH₃), 2.22-2.38 (m, 2 H, 2 × CH),3.68-3.90 (m, 6 H, 2 × CH₂ and 2 × OH), 4.86,4.89 (d, 1 H, J = 6.8 Hz, CH),5.16 (d, 1 H, J = 2.8 Hz, CH),6.59 (s, 2 H, 2 × =CH), 7.43-7.46 (m,6 H, 2 × 3Ar-H), 7.79-7.82 (m, 4 H, 2 × 2Ar-H); ¹³C NMR (CDCl₃, 50.32 MHz)11.05 (CH₃), 13.68 (CH₃), 39.76 (CH), 39.95(CH), 66.21 (CH₂), 66.78 (CH₂), 70.55 (CH),72.43 (CH), 100.22 (CH), 100.35 (CH), 127.22 (4 × CH),129.21 (C), 129.25 (C), 129.3 (4 × CH), 130.4 (2 × CH),162.6 (C), 162.7 (C), 174.8 (C), 174.9 (C); Mass (FAB+) m/z 234 (M⁺ + 1).Anal. calcd for C₁₄H₁₂NO₂: C, 67.45;H, 7.68; N, 5.62. Found C, 67.36; H, 7.64; N, 6.00%.
2-Methyl-1-(3- p -tolyl-isoxazol-5-yl)-propane-1,3-diol (entries8 and 9): HPLC (t _R = 14.68min); IR (Neat, cm^-1) 3401 (OH); ¹HNMR (CDCl₃, 200 MHz) δ 0.88, 0.92 (d, 3 H, J = 7.0 Hz, CH₃),0.93, 0.97 (d, 3 H, J = 7.0Hz, CH₃), 2.21-2.29 (m, 2 H, 2 × CH),2.37 (s, 6 H, 2 × CH₃), 3.05 (br s, 2 H, 2 × OH,exchangeable with D₂O), 3.69-3.80 (m, 4 H, 2 × CH₂),4.37 (br s, 2 H, 2 × OH, exchangeable with D₂O), 4.81,4.84 (d, 2 H, J = 7.0 Hz, 2 × CH),5.12, 5.13 (d, 2 H, J = 2.6Hz, 2 × CH), 6.53 (s, 2 H, 2 × =CH),7.21, 7.25 (d, 4 H, J = 8.0Hz, 2 × 2Ar-H), 7.63, 7.67 (d, 4 H, J = 8.0Hz, 2 × 2 Ar-H); Mass (FAB+) m/z 248(M⁺ + 1). Anal. calcd for C₁₄H₁₇NO₃:C, 68.00; H, 6.93; N, 5.66. Found C, 67.96; H, 6.84; N, 6.00%.
1-[3-(2-Chloro-phenyl)-isoxazol-5-yl]-2-methyl-propane-1,3-diol (entry10): IR (Neat, cm^-1) 3373 (OH); ¹H NMR(CDCl₃, 200 MHz) δ 0.95, 0.99 (d, 3 H, J = 7.0 Hz, CH₃),1.00, 1.04 (d, 3 H, J = 7.0Hz, CH₃), 2.11 (br s, 1 H, OH), 2.27-2.36 (m,2 H, 2 × CH), 3.51, 3.54 (d, 1 H, OH), 3.74-3.88(m, 4 H, 2 × CH₂), 4.87-4.93 (m, 1H, CH), 5.19 (br s, 1 H, CH), 6.73, 6.74 (2 s almost merged, 2 H,2 × =CH), 7.34-7.52 (m, 6 H, 2 × 3Ar-H),7.52-7.75 (m, 2 H, 2 × Ar-H); Mass (FAB+) m/z 268 (M⁺ + 1).Anal. calcd for C₁₃H₁₄ClNO₃: C,58.32; H, 5.27; N, 5.23. Found: C, 58.09; H, 4.99; N, 5.00%.
1-[3-(2,4-Dichloro-phenyl)-isoxazol-5-yl]-2-methyl-propane-1,3-diol (entry11): IR (Neat, cm^-1) 3374 (OH); ¹H NMR(CDCl₃, 200 MHz) δ 0.94, 0.98 (d, 3 H, J = 7.0 Hz, CH₃),0.99, 1.03 (d, 3 H, J = 7.0Hz, CH₃), 1.98 (br s, 2 H, 2 × OH), 2.23-2.38(m, 2 H, 2 × CH), 3.69-3.91 (br s merged withm, 6 H, 2 × CH₂ and OH), 4.87, 4.91 (d, 1 H, J = 7.0 Hz, CH), 5.18, 5.19(d, 1 H, J = 2.4 Hz, CH), 6.72,6.73 (2 s almost merged, 2 H, 2 × =CH), 7.31-7.36(m, 2 H, 2 × Ar-H), 7.51,7.52 (2 s almost merged, 2 H,2 × Ar-H), 7.66, 7.70 (2 s, 2 H, 2 × Ar-H); Mass(FAB+) m/z 302 (M⁺ + 1).Anal. calcd for C₁₃H₁₃Cl₂NO₃:C, 51.68; H, 4.34; N, 4.64. Found: C, 51.89; H, 4.51; N, 4.40%.
1-[3-(4-Benzyloxy-phenyl)-isoxazol-5-yl]-2-methyl-propane-1,3-diol (entry12): HPLC (t _R = 17.68min); IR (KBr, cm^-1) 3382 (OH); ¹HNMR (CDCl₃, 200 MHz) δ 0.91, 0.94 (d, 3 H, J = 7.0 Hz, CH₃),0.96, 1.00 (d, 3 H, J = 7.0Hz, CH₃), 2.04 (br s, 2 H, 2 × OH), 2.29-2.30(m, 2 H, 2 × CH), 3.66-3.87 (m, 4 H, 2 × CH₂),4.15 (s, 2 H, 2 × OH), 2.95 (s, 1 H, OH), 4.82, 4.85 (d,1 H, J = 7.0 Hz, CH), 5.09,5.11 (m, 5 H, s of 2 × OCH₂ merged with m ofCH), 6.51 (s, 2 H, 2 × =CH), 7.01, 7.05 (d, 4H, J = 8.8 Hz, 2 × 2Ar-H),7.29-7.41 (m, 10 H, 2 × 5Ar-H), 7.70, 7.74 (d,4 H, J = 8.8 Hz, 2 × 2 Ar-H);Mass (FAB+) m/z 339(M⁺ + 1). Anal. calcd for C₂₀H₂₁NO₄:C, 70.78; H, 6.24; N, 4.13. Found: C, 70.58; H, 5.99; N, 4.14%.
2-Methyl-1-(5-methyl-3-p-tolyl-isoxazol-4-yl)-propane-1,3-diol (entry13): IR (Neat, cm^-1) 3403 (OH); ¹HNMR (CDCl₃, 200 MHz) δ 0.49, 0.53 (d, 3 H, J = 7.0 Hz, CH₃), 0.90,0.94 (d, 3 H, J = 7.0 Hz, CH₃),1.77-1.86 (m, 2 H, 2 × CH), 2.04 (s, 2 H, 2 × OH),2.38 (s, 6 H, 2 × CH₃), 2.49 (s, 3 H, CH₃),2.55 (s, 3 H, CH₃), 2.98 (br s, 2 H, 2 × OH),3.50-3.62 (m, 4 H, 2 × CH₂), 4.55,4.60 (d, 1 H, J = 9.4 Hz, CH), 4.95,4.98 (d, 1 H, J = 5.0 Hz, CH),7.20-7.23 (m, 4 H, 2 × 2Ar-H), 7.43, 7.47 (d,2 H, J = 8.0 Hz, 2 Ar-H), 7.54,7.58 (d, 2 H, J = 8.0 Hz, 2Ar-H); Mass (FAB+) m/z 262(M⁺ + 1). Anal. calcd for C₁₅H₁₉NO₄:C, 68.94; H, 7.33; N, 5.36. Found: C, 69.18; H, 7.22; N, 5.14%.
1-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-propane-1,3-diol (entry14): IR (Neat, cm^-1) 3377 (OH); ¹H NMR(CDCl₃, 200 MHz) δ 0.55, 0.58 (d, 3 H, J = 7.0 Hz, CH₃),0.88, 0.91 (d, 3 H, J = 7.0Hz, CH₃), 1.67-1.72 (m, 1 H, CH), 1.93-1.97(m, 1 H, CH), 2.57 (s, 3 H, CH₃), 2.59 (s, 3 H, CH₃),3.07 (s, 2 H, 2 × OH), 3.51-3.65 (m, 4 H, 2 × CH₂),4.33, 4.38 (d, 1 H, J = 9.6Hz, CH), 4.73, 4.75 (d, 1 H, J = 4.4Hz, CH), 7.35-7.52 (m, 8 H, 2 × 4Ar-H); Mass (FAB+) m/z 282 (M⁺ + 1).Anal. calcd for C₁₃H₁₄ClNO₃: C, 58.32;H, 5.27; N, 5.23. Found C, 58.31; H, 5.22; N, 5.44%.
1-[3-(2,4-Dichloro-phenyl)-5-methyl-isoxazol-4-yl]-propane-1,3-diol (entry15): IR (Neat, cm^-1) 3402 (OH); ¹H NMR(CDCl₃, 200 MHz) δ 0.54, 0.58 (d, 3 H, J = 7.0 Hz, CH₃),0.87, 0.91 (d, 3 H, J = 7.0Hz, CH₃), 1.83-2.10 (m, 2 H, 2 × CH),2.55 (s, 3 H, CH₃), 2.58 (s, 3 H, CH₃), 2.73(br s, 2 H, 2 × OH), 3.34 (br s, 2 H, 2 × OH),3.46-3.72 (m, 4 H, 2 × CH₂), 4.33,4.38 (d, 1 H, J = 9.6 Hz, CH),4.72, 4.74 (d, 1 H, J = 4.4Hz, CH), 7.31-7.35 (m, 4 H, 2 × 2Ar-H), 7.51, 7.52(2 s almost merged, 2 H, 2 × Ar-H); Mass (FAB+) m/z 316 (M⁺ + 1).Anal. calcd for C₁₃H₁₃Cl₂NO₃:C, 51.68; H, 4.34; N, 4.64. Found: C, 51.51; H, 4.39; N, 4.50%.

9

General Procedurefor DABCO-mediated Reaction of NaBH ₄ with Acetate of Baylis-Hillman Adducts. To the solution of appropriateacetate (2 mmol) obtained from the Baylis-Hillman adductsin THF:water (3 mL, 1:1, v/v) was added DABCO (0.22 g,2 mmol) and the reaction was allowed to proceed at r.t. As soonas the solution becomes clear (ca 15 min), NaBH₄ (0.08g, 2 mmol) was added with stirring. The reaction was complete in15 min., after which the reaction mixture was extracted with ethylacetate and usual work up of the organic layer furnished a residue.This residue upon filtration through a small band of silica gel affordedthe desired compounds as oils. These compounds were subjected toreduction with NaBH₄ as described earlier.
2-(3-Nitro-benzyl)-acrylic acid ethyl ester(5a) Yield: 94% as pale yellowoil; IR (Neat, cm^-1) 1718 (CO₂Et); ¹HNMR (CDCl₃, 200 MHz) δ 1.26 (t, 3 H, J = 7.0 Hz, CH₃),3.73 (s, 2 H, CH₂), 4.18 (q, 2 H, J = 7.0Hz, CO₂CH₂), 5.59 (s, 1 H, =CH₂),6.31 (s, 1 H, =CH₂), 7.42-7.58 (m,2 H, Ar-H), 8.09 (s, 2 H, Ar-H); ¹³CNMR (CDCl₃, 50.32 Hz) δ 14.45 (CH), 38.29 (CH₂),61.34 (CH₂), 121.88 (CH), 124.12 (CH), 127.46 (CH₂),129.64 (CH), 135.58 (CH), 139.43 (C), 141.50 (C), 148.73 (C), 166.60(C); Mass (FAB+) m/z 236 (M⁺+1).Anal. calcd for C₁₂H₁₃NO₄: C, 61.27;H, 5.57; N, 5.95. Found: C, 60.99; H, 5.61; N, 6.04%.
2-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-acrylicacid methyl ester(5b) Yield: 92% aspale yellow oil; IR (Neat, cm^-1) 1722(CO₂Me); ¹H NMR (CDCl₃,200 MHz) δ 2.42 (s, 3 H, CH₃), 3.33 (s, 2 H,CH₂), 3.67 (s, 3 H, CO₂Me), 5.14 (s, 1 H, =CH₂),6.02 (s, 1 H, =CH₂), 7.29-7.49 (m,4 H, Ar-H); Mass (FAB+) m/z 292(M⁺ + 1). Anal. calcd for C₁₅H₁₄ClNO₃:C, 61.76; H, 4.84; N, 4.80. Found: C, 61.56; H, 4.99; N, 5.04%.
2-Methyl-3-(3-nitro-phenyl)-propionic acid methyl ester(6a) Yield: 77% as pale yellowoil; IR (Neat, cm^-1) 1717 (CO₂Me); ¹HNMR (CDCl₃, 200 MHz) δ 1.91, 1.22 (d, 3 H, J = 6.6 Hz, CH₃),2.77-2.86 (m, 2 H, CH₂), 3.06-3.14 (m,1 H, CH), 3.65 (s, 3 H, CO₂Me), 7.45-7.88 (m,2 H, Ar-H), 8.05-8.10 (d merged into s, 2 H, Ar-H); Mass(FAB+) m/z 224 (M⁺ + 1).Anal. calcd for C₁₂H₁₃NO₄: C, 61.27;H, 5.57; N, 5.95. Found: C, 60.99; H, 5.61; N, 6.04%.
3-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-2-methyl-propionicacid methyl ester(6b) Yield: 88% as paleyellow oil; IR (Neat, cm^-1) 1722 (CO₂Me); ¹HNMR (CDCl₃, 200 MHz) δ 0.88, 0.91 (d, 3 H, J = 6.6 Hz, CH₃), 1.15-1.19(m, 1 H, CH), 2.18-2.39 (m, 4 H, s of CH₃ merged withm of 1 H of CH₂), 2.55-2.70 (m, 1 H of CH₂),3.57 (s, 3 H, CO₂Me), 7.20-7.39 (m, 4 H, Ar-H);Mass (FAB+) m/z 294(M⁺ + 1). Anal. calcd for C₁₅H₁₆ClNO₃:C, 61.33; H, 5.49; N, 4.77. Found: C, 61.21; H, 5.38; N, 4.87%.

10

3-Hydroxy-2-(4-methyl-piperazin-1-ylmethyl)-3-(3-nitro-phenyl)-propionicacid ethyl ester(7) Yield: 97% as paleyellow oil; IR (Neat, cm^-1) 1727 (CO₂Et); ¹HNMR (CDCl₃, 200 MHz) δ 0.95 (2t merged, 6 H, J = 7.0 Hz, 2 × CH₃),2.31 (s, 6 H, 2 × NCH₃), 2.52-3.13(m, 20 H, 2 × 5CH₂), 3.89 (q, 4 H, J = 7.0 Hz, CO₂CH₂),5.08, 5.13 (d, 1 H, J = 8.8Hz, CH), 5.44, 5.46 (d, 1 H, J = 4.4Hz, CH), 7.44-7.70 (m, 4 H,2 × 2Ar-H), 8.12, 8.16(d 2 H, J = 8.0 Hz, 2 × Ar-H),8.28 (s, 2 H, 2 × Ar-H); Mass (FAB+) m/z 224 (M⁺ + 1).Anal. calcd for C₁₇H₂₅N₃O₅:C, 58.11; H, 7.17; N, 11.96. Found: C, 57.91; H, 7.57; N, 12.08%.
2-(4-Methyl-piperazin-1-ylmethyl)-1-(3-nitro-phenyl)-propane-1,3-diol(8) Yield: 82% as pale red yellowoil; IR (Neat, cm^-1) 3345 (OH); ¹HNMR (CDCl₃, 200 MHz) δ 1.99-2.06 (m,1 H, CH), 2.27 (s, 3 H, CH₃), 2.32-2.91 (m, 10H, 5 × N-CH₂), 3.36-3.48 (m, 2 H, CH₂),4.86, 4.90 (d, 1 H, J = 8.0Hz, CH), 7.50 (t, 1 H, J = 8.0Hz, Ar-H), 7.69, 7.73 (d, 1 H, J = 8.0Hz, Ar-H), 8.10, 8.14 (dt, 1 H, J ₁ = 2.0Hz, J ₂ = 8.0 Hz,Ar-H), 8.25 (s, 1 H, Ar-H); ¹³C NMR(CDCl₃, 50.32 Hz) δ 43.60 (CH), 46.23 (CH₃),53.83 (CH₂), 55.37 (2 × CH₂), 61.13(2 × CH₂), 63.29 (CH₂), 76.47 (CH),122.13 (CH), 122.94 (CH), 129.57 (CH), 133.34 (CH), 145.94 (C), 148.74(C); Mass (FAB+) m/z 310(M⁺ + 1). Anal. calcd for C₁₅H₂₃N₃O₄:C, 58.24; H, 7.49; N, 13.58. Found: C, 57.99; H, 7.38; N, 13.76%.