Evaluating the Baylis-Hillman Reaction of Cyclic Enones Using Surfactants in Water

Abstract

Conjugated cyclic enones react smoothly in water with a variety of aldehydes (Baylis-Hillman reaction) in the presence of surfactants above their critical micelle concentrations (CMC).

Key words

Baylis-Hillman reaction - cyclic enones - surfactant - green chemistry - aldehydes - aqueous media

References

• 1a Organic Syntheses in Water   Grieco PA. Blackie Academic and Professional; London: 1998. 
• 1b Li C.-J. Chan T.-H. Organic Reactions in Aqueous Media   John Wiley and Sons; New York: 1997. 
• 1c Klijn JE. Engberts JBFN. Nature (London)  2005,  435:  746 
• 2a Barnes GT. Gentle IR. Interfacial Science: An Introduction   Oxford University Press; Oxford: 2005. 
• 2b Fendler JH. Fendler EJ. Catalysis in Micellar and Macromolecular Systems   Academic Press; London: 1975. 
• See for example:
• 3a Manabe K. Mori Y. Wakabayashi T. Nagayama S. Kobayashi S. J. Am. Chem. Soc.  2000,  122:  7202 ; and references therein
• 3b Tian H.-Y. Li H.-J. Chen Y.-J. Wang D. Li C.-J. Ind. Eng. Chem. Res.  2002,  41:  4523 ; and references therein
• 4 Heim R. Wiedemann S. Williams CM. Bernhardt PV. Org. Lett.  2005,  7:  1327 
• 5 Rezgui F. El Gaïed MM. Tetrahedron Lett.  1998,  39:  5965 
• 6a Baylis AB, and Hillman MED. inventors; German Patent  2,155,113.  ; Chem. Abstr. 1972, 77, 341174q
• 6b Basavaiah D. Rao AJ. Satyanarayana T. Chem. Rev.  2003,  103:  811 
• 7 Gatri R. El Gaïed MM. Tetrahedron Lett.  2002,  43:  7835 
• 8 Aggarwal VK. Dean DK. Mereu A. Williams R. J. Org. Chem.  2002,  67:  510 
• 9 Luo S. Wang PG. Cheng J.-P. J. Org. Chem.  2004,  69:  555 
• 12 Santos LS. Pavam CH. Almeida WP. Coelho F. Eberlin MN. Angew. Chem. Int. Ed.  2004,  43:  4330 
• Experimental Procedure. To a solution of glucose (3.6 g, 20 mmol) in 1-octanol (200 mL) was added TMSCl (20 mL) and the reaction mixture stirred for 3 d at r.t. The mixture was then diluted with CH₂Cl₂ (200 mL) and extracted with brine (2 × 100 mL). The combined organic layers were then evaporated (CH₂Cl₂) and concentrated under high vacuum. The residue was further purified by column chromatography (CHCl₃-MeOH 5:1, R _f = 0.3) to yield α-octylglucoside (3 g, 50%) as a white solid (ratio α/β = 6:1). ¹H NMR (400 MHz, MeOD): δ = 4.72 (d, 0.86 H, J = 3.76 Hz, H-α), 4.20 (d, 0.14 H, J = 7.80 Hz, H-β). Ratio of α/β anomers were determined by ¹H NMR. ¹H NMR data matched those in the literature. See:
• 13a Straathof AJJ. Romein J. van Rontwijk F. Kieboom APG. van Beekum H. Starch/Staerke  1987,  39:  362 
• 13b Straathof AJJ. van Beekum H. Kieboom APG. Starch/Staerke  1988,  40:  229 
• 13c Brown GM. Dubreuil P. Ichhaporia FM. Desnoyers JE. Can. J. Chem.  1970,  48:  2525 
• 14 Rosen MJ. Surfactants and Interfacial Phenomena   3rd ed:  John Wiley and Sons; New York: 2004. 
• 20 For a non-aqueous comparison, see: You J. Xu J. Verkade JG. Angew. Chem. Int. Ed.  2003,  42:  5054 

10

Isolated yield 32%. Yield based on starting material recovery, 43%.

11

Tilly, D. P.; Williams, C. M.; Bernhardt, P. V. Org. Lett., accepted.

15

A) Representative Procedure for Reactions with Formalin and DMAP.
To a mixture of H₂O (200 µL) and 1 (40 mg, 0.208 mmol) were added SDS (6 mg, 0.02 mmol) and DMAP (25 mg, 0.2 mmol). After stirring for 15 min formalin (200 µL) was added and stirred for 16 h at r.t. The mixture was then quenched with brine (1 mL) and extracted with EtOAc (2 × 3 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. Then the residue was purified by column chromatography (PE-EtOAc 2:1, R _f = 0.33) to give 2 (39 mg, 85%) as a colorless liquid.
B) Representative Procedure for Reactions with Formalin and Imidazole.
To a mixture of 1 M NaHCO₃ (200 µL) and 1 (40 mg, 0.208 mmol) were added CTAB (8 mg, 0.02 mmol) and imidazole (14 mg, 0.2 mmol). After stirring for 15 min formalin (200 µL) was added and stirred for 16 h at r.t. The mixture was then quenched with brine (1 mL) and extracted with EtOAc (2 × 3 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography (PE-EtOAc 2:1, R _f = 0.33) to give 2 (30 mg, 65%) as a colorless liquid.

16

Representative Procedure for Reactions with Formalin and DMAP.
To a mixture of H₂O (3 mL) and of dimethylcyclohexenone (372 mg, 3 mmol) were added SDS (80 mg, 0.3 mmol) and DMAP (366 mg, 3 mmol). After stirring for 15 min formalin (3 mL) was added and stirred for 45 min at r.t. The mixture was then quenched with brine (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography (PE-EtOAc 2:1, R _f = 0.36) to give 2-(hydroxymethyl)-4,4-dimethylcyclo-hex-2-enone (4c, 305 mg, 67%) as a colorless liquid.

17

We were unable to obtain the reported yield (99%, ref. 8).

18

Representative Procedure for Reactions with Various Aldehydes in Water.
To a mixture of H₂O (6 mL) and cyclohexenone (300 mg, 3 mmol) were added SDS (80 mg, 0.3 mmol) and DMAP (366 mg, 3 mmol). After stirring for 15 min, p-nitrobenzaldehyde (538 mg, 3.6 mmol) was added and stirring continued for 16 h at r.t. The mixture was then quenched with brine (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography (PE-EtOAc 2:1, R _f = 0.36) to give 2-[(4-nitrophenyl)(hy-droxy)methyl]cyclohex-2-enone (6d, 500 mg, 68%) as a yellow syrup.

19

Spectroscopic Data for New Compounds.
Compound 4c: ¹H NMR (400 MHz, CDCl₃): δ = 1.17 (s, 6 H), 1.86 (t, 2 H, J = 6.7 Hz), 2.48 (t, 2 H, J = 6.7 Hz), 3.00 (br s, 1 H), 4.21 (s, 2 H), 6.63 (s, 1 H). ¹³C NMR: δ = 27.7, 32.7, 34.5, 35.8, 61.5, 135.0, 155.8, 200.3. MS (EI):
m/z (%) = 154 (25) [M⁺ ], 139 (26), 136 (8), 125 (37), 121 (17), 111 (22), 97 (24), 79 (29), 69 (30), 57 (20), 55 (41), 43 (100). HRMS: m/z calcd for C₉H₁₄O₂: 154.0994; found: 154.0993.
Compound 6c: ¹H NMR (400 MHz, CDCl₃): δ = 1.93-1.96 (m, 2 H), 2.33-2.41 (m, 4 H), 3.58 (br s, 1 H), 5.45 (s, 1 H), 6.72-6.74 (m, 1 H), 7.18-7.20 (m, 2 H), 7.40-7.42 (m, 2 H). ¹³C NMR: δ = 22.4, 25.7, 38.4, 71.7, 121.2, 128.2, 131.3, 140.7, 140.9, 147.5, 200.2. MS (EI): m/z (%) = 282 (38) [M⁺ ], 281 (58), 280 (42) [M⁺ ], 279 (51), 264 (2), 262 (2), 236 (2), 219 (2), 208 (13), 206 (12), 202 (15), 201 (100), 195 (3), 185 (25), 183 (23), 169 (1), 157 (12), 155 (28), 145 (15), 131 (10), 129 (10), 128 (14), 125 (13), 123 (19), 116 (16), 97 (17), 96 (40), 95 (19), 79 (11), 78 (19), 77 (61). HRMS: m/z calcd for C₁₃H₁₃BrO₂: 280.0099; found: 280.0104 for (⁷⁹Br).
Compound 6f: ¹H NMR (400 MHz, CDCl₃): δ = 1.95-2.01 (m, 2 H), 2.37-2.47 (m, 4 H), 3.40 (br s, 1 H), 5.06 (d, 1 H, J = 5.9 Hz), 6.29 (dd, 1 H, J = 6.3, 15.9 Hz), 6.62 (d, 1 H, J = 15.9 Hz), 6.97 (t, 1 H, J = 4.2 Hz), 7.19-7.37 (m, 5 H). ¹³C NMR: δ = 22.5, 25.7, 38.5, 71.6, 126.5, 127.6, 128.6, 129.6, 130.6, 136.6, 140.2, 147.0, 200.3. MS (EI): m/z (%) = 228 [M⁺ ] (43), 210 (12), 200 (10), 182 (5), 172 (11), 167 (5), 153 (5), 137 (17), 131 (12), 128 (15), 124 (19), 123 (18), 115 (23), 105 (18), 104 (17), 103 (18), 96 (100), 95 (21), 91 (37), 77 (37). HRMS: m/z calcd for C₁₅H₁₆O₂: 228.1150; found: 228.1151.
Compound 6g: ¹H NMR (400 MHz, CDCl₃): δ = 1.17 (s, 6 H), 1.84 (t, 2 H, J = 6.7 Hz), 2.47 (t, 2 H, J = 6.7 Hz), 3.30 (br s, 1 H), 5.00 (d, 1 H, J = 5.9 Hz), 6.26 (dd, 1 H, J = 6.3, 15.9 Hz), 6.60 (m, 2 H), 7.38-7.19 (m, 5 H). ¹³C NMR: δ = 27.6, 27.8, 32.9, 34.9, 35.6, 71.7, 126.5, 127.6, 128.5, 129.6, 130.8, 136.6, 136.8, 155.8, 200.2. MS (EI): m/z (%) = 256 [M⁺ ] (29), 223 (5), 201 (16), 200(100), 181 (5), 172 (28), 165 (5), 158 (5), 151 (14), 137 (11), 131 (22), 124 (29), 115 (18), 109 (35), 104 (20), 91 (33), 77 (30). HRMS: m/z calcd for C₁₇H₂₀O₂: 256.1463; found: 256.1458.