A Direct Catalytic and Diastereoselective Aldol Route to Protected α,β-Dihydroxyketones

Abstract

The combination of Mg(ClO₄)₂, bipyridine (bipy) and N-methyl morpholine generates an effective catalyst for the direct addition of α-carbonate substituted ketones to aromatic aldehydes. The diol containing products undergo direct cyclic carbonate ­formation to provide protected adducts in good yield with high syn-aldol diastereoselectivity.

Key words

aldol reactions - Lewis acids - magnesium - protecting groups

References

• 1a For example, the dihydroxylation of alkenes: Kolb HC. van Nieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 
• 1b For the asymmetric alkoxy allylation of aldehydes, see: Hunt JA. Roush WR. J. Org. Chem.  1997,  62:  1112 
• 1c Catalytic enantioselective hydrolytic ring-opening of epoxides: Jacobsen EN. Acc. Chem. Res.  2000,  33:  421 
• For recent examples, see:
• 2a Carda M. Falomir E. Murga J. Castillo E. González F. Marco JA. Tetrahedron Lett.  1999,  40:  6845 
• 2b Sasaki S. Hamada Y. Shioiri T. Tetrahedron Lett.  1999,  40:  3187 
• 2c Andrus MB. Meredith EL. Sekhar BVS. Org. Lett.  2001,  3:  259 
• 2d Roush WR. Pfeifer LA. Marron TG. J. Org. Chem.  1998,  63:  2064 
• 2e Crimmins MT. Choy AL. J. Am. Chem. Soc.  1999,  121:  5653 
• 3a Kobayashi S. Kawasuji T. Synlett  1993,  911 
• 3b Mukaiyama T. Shiina I. Uchiro H. Kobayashi S. Bull. Chem. Soc. Jpn.  1994,  67:  1708 
• For examples of direct catalytic aldol reactions using α-oxygenated carbonyls, see:
• 4a Notz W. List B. J. Am. Chem. Soc.  2000,  122:  7386 
• 4b Trost BM. Ito H. Silcoff ER. J. Am. Chem. Soc.  2001,  123:  3367 
• 4c Yoshikawa N. Suzuki T. Shibasaki M. J. Org. Chem.  2002,  67:  2556 
• For recent examples, see:
• 5a Ji J. Barnes DM. Zhang J. King SA. Wittenberger SJ. Morton HE. J. Am. Chem. Soc.  1999,  121:  10215 
• 5b Evans DA. Downey CW. Hubbs JL. J. Am. Chem. Soc.  2003,  125:  8706 
• 6 For the use of α-carbonate substituted ketones and esters in palladium catalysed cyclopropanation, see: Ogoshi S. Morimoto T. Nishio K. Ohe K. Murai S. J. Org. Chem.  1993,  58:  9 
• 8 Willis MC. Piccio VJ.-D. Synlett  2002,  1625 
• 11 (4R*,5S*)-4-Benzoyl-5-phenyl-[1,3]dioxolan-2-one is a known compound: Keshava Murthy KS. Dhar DN. J. Heterocycl. Chem.  1984,  21:  1721 

7

Alternative Lewis acids such as Cu(OTf)₂ and Sn(OTf)₂ produced minimal reaction, while Zn(OTf)₂ and Sc(OTf)₃ resulted in complex reaction mixtures.

9

For a recent example of a Lewis acid catalysed process in which the addition of an external ligand was needed to achieve reaction, see ref. 5a.

10

General Procedure for the Direct Aldol Addition of Carbonates 1 to Aromatic Aldehydes: 4,4′-bipyridine (31.0 mg, 0.2 mmol), 4 Å molecular sieves (200 mg), and Mg(ClO₄)₂ (44.5 mg, 0.2 mmol) were stirred for 30 min in dry THF (2.5 mL) under a nitrogen atmosphere at ambient temperature. The suspension formed was then treated with the carbonate starting material (2 mmol) in THF (2.5 mL). After 10 min the aldehyde (1 mmol) and N-methyl-morpholine (0.055 mL, 0.5 mmol) were added dropwise. The reaction was monitored by thin layer chromatography. After 18-48 h the reaction mixture was filtered through celite and quenched with a saturated aqueous solution of NH₄Cl (10 mL) and extracted with EtOAc (2 ¥ 30 mL). The organic layers were washed with a sat. aq solution of CuSO₄ (10 mL) followed by H₂O (30 mL) and brine (30 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo. The crude mixture of dioxolan-2-one diastereomers was purified by flash column chromatography on silica gel (50:1).

12

All new compounds were fully characterised. Selected data for novel compounds: (4 R *,5 S *)-4-Benzoyl-5- p -tolyl-[1,3]-dioxolan-2-one, colourless oil (259 mg, 92%). ¹H NMR (300 MHz, CDCl₃): δ = 7.92-7.99 (2 H, m, Ar-H), 7.63-7.70 (1 H, m, Ar-H), 7.47-7.55 (2 H, m, Ar-H), 7.24-7.35 (4 H, m, Ar-H), 5.92 [1 H, d, J = 6.3 Hz, Ph(C=O)CH], 5.59 (1 H, d, J = 6.3 Hz, ArCH), 2.40 (3 H, s, CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 191.2, 153.2, 140.1, 135.0, 133.4, 132.7, 130.0, 129.4, 129.1, 126.1, 82.0, 79.1, 21.3. HRMS (ES+): C₁₇H₁₈NO₄, [M + NH₄]⁺ requires 300.1230. Found: 300.1227. (4 R *,5 S *)-4-Benzoyl-5-(4-methoxy-phenyl)-[1,3]-dioxolan-2-one, pale yellow oil (208 mg, 86%). ¹H NMR (300 MHz, CDCl₃): δ = 7.90-7.97 (2 H, m, Ar-H), 7.62-7.70 (1 H, m, Ar-H), 7.46-7.54 (2 H, m, Ar-H), 7.36 (2 H, d, J = 8.6 Hz, Ar-H), 6.97 (2 H, d, J = 8.6 Hz, Ar-H), 5.88 [1 H, d, J = 6.3 Hz, Ph(C=O)CH], 5.61 (1 H, d, J = 6.3 Hz, ArCH), 3.84 (3 H, s, OCH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 191.2, 160.9, 153.2, 134.9, 133.3, 129.3, 129.1, 127.9, 127.4, 114.8, 81.9, 79.2, 55.4. HRMS (ES+): C₁₇H₁₈NO₅, [M + NH₄]⁺ requires 316.1179. Found: 316.1181. (4 R *,5 S *)-4-Benzoyl-5-(4-trifluoromethyl-phenyl)-[1,3]-dioxolan-2-one, white solid (202 mg, 60%); mp 91-92 °C [from CH₂Cl₂/light petroleum (bp 40-60 °C)]. ¹H NMR (400 MHz, CDCl₃): δ = 7.97-8.04 (2 H, m, Ar-H), 7.65-7.77 (3 H, m, Ar-H), 7.50-7.62 (4 H, m, Ar-H), 6.16 [1 H, d, J = 6.5 Hz, Ph(C=O)CH], 5.49 (1 H, d, J = 6.5 Hz, ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 191.0, 152.6, 139.7, 135.2, 133.9, 132.0 (q, ² J _CF = 32.9 Hz), 129.6, 129.2, 126.4 (q, ³ J _CF = 3.8 Hz), 123.6 (q, ¹ J _CF = 272.4 Hz), 81.9, 77.9. HRMS (ES+): C₁₇H₁₅F₃NO₄, [M + NH₄]⁺ requires 354.0948. Found: 354.0945. (4 R *,5 S *)-4-(5-Benzoyl-2-oxo-[1,3]-dioxolan-4-yl)-benzonitrile, white solid (201 mg, 69%); mp 111 °C [from Et₂O/light petroleum (bp 40-60 °C)]. ¹H NMR (300 MHz, CDCl₃): δ = 8.00-8.03 (2 H, m, Ar-H), 7.68-7.79 (3 H, m, Ar-H), 7.52-7.60 (4 H, m, Ar-H), 6.18 [1 H, d, J = 6.8 Hz, Ph(C=O)CH], 5.45 (1 H, d, J = 6.8 Hz, ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 190.9, 152.3, 140.7, 135.3, 133.2, 133.1, 129.6, 129.2, 126.4, 117.9, 113.7, 81.8, 77.6. HRMS (ES+): C₁₇H₁₅N₂O₄, [M + NH₄]⁺ requires 311.1026. Found: 311.1027. (4 R *,5 S *)-4-(Naphthalene-2-carbonyl)-5-phenyl-[1,3]-dioxolan-2-one, white solid (228 mg, 72%); mp 127 °C [from CH₂Cl₂/light petroleum (bp 40-60 °C)]. ¹H NMR (400 MHz, CDCl₃): δ = 8.41 (1 H, s, Ar-H), 7.88-8.04 (4 H, m, Ar-H), 7.56-7.69 (3 H, m, Ar-H), 7.47-7.57 (4 H, m, Ar-H), 6.05 [1 H, d, J = 6.2 Hz, Ar(C=O)CH], 5.74 (1 H, d, J = 6.2 Hz, PhCH). ¹³C NMR (75 MHz, CDCl₃): δ = 191.0, 153.2, 136.3, 135.8, 132.2 × 2, 130.7, 130.0, 129.9, 129.7, 129.4, 129.2, 128.0, 127.4, 126.1, 123.9, 82.2, 79.2. HRMS (ES+): C₂₀H₁₈NO₄, [M + NH₄]⁺ requires 336.1230. Found: 336.1236. (4 R *,5 S *)-4-(Naphthalene-2-carbonyl)-5- p -tolyl-[1,3]-dioxolan-2-one, white solid (238 mg, 71%); mp 143-144 °C [from CH₂Cl₂/light petroleum (bp 40-60 °C)]. ¹H NMR (300 MHz, CDCl₃): δ = 8.40 (1 H, s, Ar-H), 7.86-8.04 (4 H, m, Ar-H), 7.56-7.70 (2 H, m, Ar-H), 7.27-7.38 (4 H, m, Ar-H), 5.98 [1 H, d, J = 6.3 Hz, Ar(C=O)CH], 5.73 (1 H, d, J = 6.3 Hz, ArCH), 2.41 (3 H, s, CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 191.0, 153.3, 140.1, 136.3, 132.7, 132.2, 132.1, 130.7, 130.1, 129.9, 129.7, 129.2, 127.9, 127.3, 126.2, 123.9, 82.2, 79.3, 21.3. HRMS (ES+): C₂₁H₂₀NO₄, [M + NH₄]⁺ requires 350.1387. Found: 350.1384. (4 R *,5 S *)-4-(4-Methoxy-phenyl)-5-(naphthalene-2-carbonyl)-[1,3]-dioxolan-2-one, pale yellow solid (235 mg, 67%); mp 108 °C [from CH₂Cl₂/light petroleum (bp 40-60 °C)]. ¹H NMR (300 MHz, CDCl₃): δ = 8.38 (1 H, s, Ar-H), 7.86-8.04 (4 H, m, Ar-H), 7.56-7.70 (2 H, m, Ar-H), 7.36-7.42 (2 H, m, Ar-H), 6.96-7.02 (2 H, m, Ar-H), 5.93 [1 H, d, J = 6.9 Hz, Ar(C=O)CH], 5.75 (1 H, d, J = 6.9 Hz, ArCH), 3.85 (3 H, s, OCH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 191.0, 160.9, 153.3, 136.3, 132.2, 132.1, 130.7, 129.9, 129.7, 129.2, 128.0, 127.9, 127.4 × 2, 123.9, 114.8, 82.1, 79.4, 55.5. HRMS (ES+): C₂₁H₂₀NO₅, [M + NH₄]⁺ requires 366.1336. Found: 366.1337. (4 R *,5 S *)-4-(Naphthalene-2-carbonyl)-5-(4-trifluoromethyl-phenyl)-[1,3]-dioxolan-2-one, white solid (669 mg, 87%); mp 133 °C [(from CH₂Cl₂/light petroleum (bp 40-60 °C)]. ¹H NMR (300 MHz, CDCl₃): δ = 8.50 (1 H, s, Ar-H), 8.01-8.07 (1 H, m, Ar-H), 7.88-7.98 (3 H, m, Ar-H), 7.57-7.77 (6 H, m, Ar-H), 6.22 [1 H, d, J = 6.5 Hz, Ar(C=O)CH], 5.64 (1 H, d, J = 6.5 Hz, ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 190.8, 152.7, 139.7, 136.4, 132.4, 132.2, 132.0 (q, ² J _CF = 32.9 Hz), 130.6, 130.0, 129.8, 129.2, 128.0, 127.5, 126.4 (q, ³ J _CF = 3.7 Hz), 126.3 × 2, 123.7 (q, ¹ J _CF = 273.1 Hz), 123.9, 82.0, 78.0. HRMS (ES+): C₂₁H₁₇F₃NO₄, [M + NH₄]⁺ requires 404.1104. Found: 404.1100. (4 R *,5 S *)-4-[5-(Naphthalene-2-carbonyl)-2-oxo-[1,3]-dioxolan-4-yl]-benzonitrile, white solid (467 mg, 68%); mp 147 °C (from CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 8.53 (1 H, s, Ar-H), 7.89-8.07 (4 H, m, Ar-H), 7.76-7.80 (2 H, m, Ar-H), 7.66-7.72 (1 H, m, Ar-H), 7.58-7.66 (3 H, m, Ar-H), 6.25 [1 H, d, J = 6.9 Hz, Ar(C=O)CH], 5.59 (1 H, d, J = 6.9 Hz, ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 190.7, 152.4, 140.8, 136.4, 133.1, 132.6, 132.2, 130.6, 130 × 2, 129.3, 128.0, 127.5, 126.4, 123.9, 117.9, 113.8, 82.0, 77.7. HRMS (ES+): C₂₁H₁₇N₂O₄, [M + NH₄]⁺ requires 361.1183. Found: 361.1184.

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These observations are based on the isolation of the individual diastereomeric aldol adducts and cyclic carbonates and resubjection of these components to the reaction conditions.

14

For Baeyer-Villiger reactions on similar compounds, see ref. 4c.

15

Baeyer-Villiger oxidation of the phenyl ketone produced an 8:1 mixture of regioisomers, with the desired phenyl ester predominating.