Diastereoselective Friedel-Crafts Alkylation Reactions Employing Chiral Cation Precursors with Polar α-Substituents

Abstract

Precursors 5-7 of chiral para-methoxybenzyl cations (2-4), which carry a polar substituent (NO₂, CN, OH) at the stereogenic α-carbon atom, reacted under acidic conditions with high facial diastereoselectivity (dr = 75:25 to >95:5) to the corresponding 1,1-diarylalkanes threo-9 (50-87% yield). Catalytic amounts of Sc(OTf)₃ as Lewis acid were sufficient to convert epoxide 7 into the corresponding alcohols threo-9ca and threo-9cb.

Key words

carbocations - stereoselective synthesis - electrophilic aromatic substitutions - alkylations - diastereoselectivity

References and Notes

• 2a Olah GA. Krishnamurti GA. Prakash GKS. In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.293 
• 2b Olah GA. Friedel-Crafts Chemistry   John Wiley & Sons; New York: 1973. 
• 2c Friedel-Crafts and Related Reactions   Vol. 2:  Olah GA. Interscience Publishers; New York: 1963. 
• 3a Price CC. Lund M. J. Am. Chem. Soc.  1940,  62:  3105 
• 3b Streitwieser A. Stang PJ. J. Am. Chem. Soc.  1965,  87:  4953 
• 4a Mühlthau F. Schuster O. Bach T. J. Am. Chem. Soc.  2005,  127:  9348 
• 4b Mühlthau F. Stadler D. Goeppert A. Olah GA. Prakash GKS. Bach T. J. Am. Chem. Soc.  2006,  128:  9668-9675 
• 5 For an early example possibly involving cations related to 2, see: Hodge EB. J. Am. Chem. Soc.  1951,  73:  2341 
• Alcohol 5:
• 6a Desai UV. Pore DM. Mane RB. Solabannavar SB. Wadgaonkar PP. Synth. Commun.  2004,  34:  19 
• 6b Dumez E. Faure R. Dulcère J.-P. Eur. J. Org. Chem.  2001,  2557 
• Alcohol 6:
• 7a Das B. Banerjee J. Majhi A. Mahender G. Tetrahedron Lett.  2004,  45:  9225 
• 7b Zhong B. Lu X. Silverman RB. Bioorg. Med. Chem.  1998,  6:  2405 
• 8 Mohan RS. Whalen DL. J. Org. Chem.  1993,  58:  2663 
• 11 Examples for stereoconvergent reactions include the reaction 5 → 9aa, in which the starting material 5 was used in varying anti/syn ratios (62:38 to 86:14) yielding product 9aa with identical selectivity (dr = 91:9), and the BF₃-promoted reaction 7 → 9ca, in which the trans/cis ratio of the epoxide 7 varied from <5:95 to >95:5 while the product selectivity (dr = 88:12) remained constant
• The sequence included
• 14a

  reduction to the aldehyde [DIBAL-H, -78 °C → r.t. (THF), 69%]

• 14b

  oxidation to the free acid [NaClO₂, 2-methylbutene, 0 °C → r.t. (t-BuOH-H₂O), 76%], and

• 14c

  intramolecular Friedel-Crafts acylation [i) (COCl)₂, r.t. (CH₂Cl₂), ii) AlCl₃, 130 °C (PhCl), 53% (two steps)].

• 15 Iwasawa N. Matsuo T. Iwamoto M. Ikeno T. J. Am. Chem. Soc.  1998,  120:  3903 
• 16 Eliel EL. Wilen SH. Stereochemistry of Organic Compounds   John Wiley & Sons; New York: 1994. 
• 18 Hoffmann RW. Chem. Rev.  1989,  89:  1841 
• FeCl₃:
• 19a Review: Iovel I. Mertins K. Kischel J. Zapf A. Beller M. Angew. Chem. Int. Ed.  2005,  44:  3913 
• 19b Kischel J. Jovel I. Mertins K. Zapf A. Beller M. Org. Lett.  2006,  8:  19 
• Sc(OTf)₃:
• 19c Tsuchimoto T. Tobita K. Hiyama T. Fukuzawa S. J. Org. Chem.  1997,  62:  6997 
• 19d Noji M. Ohno T. Fuji K. Futaba N. Tajima H. Ishii K. J. Org. Chem.  2003,  68:  9340 
• 19e B(C₆F₅)₃: Rubin M. Gevorgyan V. Org. Lett.  2001,  3:  2705 

1

To whom inquiries regarding the X-ray crystallographic data should be directed.

9

Representative Procedure: 1-(4-Methoxyphenyl)-2-nitropropane-1-ol (5; 106 mg, 0.50 mmol) was placed in a flame-dried flask, dissolved in anhyd CH₂Cl₂ (10 mL) and cooled to -78 °C. After addition of HBF₄·OEt₂ (86.0 µL, 102 mg, 0.63 mmol) and stirring for 5 min, N-tosylpyrrole (8c; 443 mg, 2.00 mmol) was added and the solution was allowed to warm to r.t. over a period of 15 min. Then the reaction was stopped by adding sat. aq NaHCO₃ solution (20 mL), the mixture was diluted with Et₂O (20 mL) and the separated organic layer was washed with sat. aq NaHCO₃ (20 mL) and sat. aq NaCl solution (20 mL). After drying with Na₂SO₄, it was filtered and the solvent was evaporated under reduced pressure. Column chromatography (pentane-Et₂O, 9:1) yielded the product 9ac (162 mg, 0.39 mmol, 78%) in a diastereomeric ratio of threo/erythro >95:5. R _f 0.10 (pentane-Et₂O, 8:2). ¹H NMR (360 MHz, CDCl₃): δ = 1.38 (d, ³ J = 6.6 Hz, 3 H), 2.35 (s, 3 H), 3.77 (s, 3 H), 4.95 (dq, ³ J = 11.3 Hz, ³ J = 6.6 Hz, 1 H), 5.10 (d, ³ J = 11.3 Hz, 1 H), 6.24 (t, ³ J = 3.4 Hz, 1 H), 6.41-6.46 (m, 1 H), 6.76 (d, ³ J = 8.6 Hz, 2 H), 7.08 (d, ³ J = 8.6 Hz, 2 H), 7.14 (d, ³ J = 8.2 Hz, 2 H), 7.20 (dd, ³ J = 3.4 Hz, ⁴ J = 1.6 Hz, 1 H), 7.40 (d, ³ J = 8.2 Hz, 2 H). ¹³C NMR (90.6 MHz, CDCl₃): δ = 19.5 (q), 21.7 (q), 46.8 (d), 55.4 (q), 86.5 (d), 111.8 (d), 112.0 (d), 114.1 (d), 124.0 (d), 126.7 (d), 129.0 (s), 129.8 (d), 130.3 (d), 133.8 (s), 136.3 (s), 144.7 (s), 159.3 (s). Anal. Calcd for C₂₁H₂₂N₂O₅S (414.5): C, 60.85; H, 5.35; N, 6.76; S, 7.74. Found: C, 60.77; H, 5.20; N, 6.74; S, 7.65.

10

Representative Procedure: 2-(4-Methoxyphenyl)-3-methyloxirane (7; 82.1 mg, 0.50 mmol) was placed in a flame-dried flask, dissolved in anhyd CH₂Cl₂ (10 mL) and cooled to -78 °C. After addition of 2-methylthiophene (8a; 0.19 mL, 196 mg, 2.00 mmol) and BF₃·OEt₂ (79.2 µL, 88.7 mg, 0.63 mmol) the solution was stirred for 30 min at -78 °C and for 1 h at r.t. Identical workup as in the previous procedure⁹ and column chromatography (pentane-Et₂O, 7:3) yielded the product 9ca (114 mg, 0.44 mmol, 87%) in a diastereomeric ratio of threo/erythro = 88:12. Data for the major diastereoisomer: R _f 0.18 (pentane-Et₂O, 7:3). ¹H NMR (360 MHz, CDCl₃): δ = 1.15 (d, ³ J = 6.1 Hz, 3 H), 1.92 (s, 1 H), 2.42 (d, ⁴ J = 1.0 Hz, 3 H), 3.78 (s, 3 H), 3.92 (d, ³ J = 8.2 Hz, 1 H), 4.28 (qd, ³ J = 6.1 Hz, ³ J = 8.2 Hz, 1 H), 6.59-6.60 (m, 1 H), 6.77 (d, ³ J = 3.4 Hz, 1 H), 6.85 (d, ³ J = 8.7 Hz, 2 H), 7.22 (d, ³ J = 8.7 Hz, 2 H). ¹³C NMR (90.6 MHz, CDCl₃): δ = 15.2 (q), 21.1 (q), 55.2 (d), 55.3 (q), 71.2 (d), 114.0 (d), 124.7 (d), 125.2 (d), 129.0 (d), 134.2 (s), 139.0 (s), 142.7 (s), 158.4 (s). Anal. Calcd for C₁₅H₁₈O₂S (262.4): C, 68.67; H, 6.92. Found: C, 68.63; H, 6.92.

12

Crystal data for 9ac: C₂₁H₂₂N₂O₅S, M_r = 414.48, orthorhombic, space group Pna2₁, Final R indices [I > 2σ (I)], R1 = 0.0241, (all data) wR2 = 0.0613, a = 13.8819 (2) Å, b = 7.5952 (1) Å, c = 18.9277 (2) Å, V = 1994.95 (4) ų, T = 123 K, Z = 4, reflections collected/unique: 49268/3432 (R _int = 0.038), number of observations [>2σ (I)] 3296, parameters 351. Crystallographic data (excluding structure factors) for 9ac have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-604901.

13

Crystal data for the nitrobenzoate of 9ca: C₂₂H₂₀N₂O₇S, M_r = 456.47, orthorhombic, space group Pna2₁, Final R indices [I > 2σ(I)], R1 = 0.0353, (all data) wR2 = 0.0873, a = 34.8337 (3) Å, b = 5.5220 (1) Å, c = 21.9007 (2) Å, V = 4212.64 (9) ų, T = 173 K, Z = 8, reflections collected/unique: 764938/7730 (R _int = 0.053), number of observations [>2σ (I)] 6128, parameters 584. Crystallographic data (excluding structure factors) for 9ca have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-604902.

17

Strictly speaking, the corresponding OBF₃-substituted carbenium ion must be considered instead of 4 (X = OH) but it is known that the steric demand of an OR group is not heavily dependent on the R group.¹⁶ Indeed, the diastereoselectivity does not differ much for either catalyst HBF₄·OEt₂ or BF₃·OEt₂ (entries 7 and 8 in Table [1] ).

20

Representative Procedure: 2-(4-Methoxyphenyl)-3-methyloxirane (7; 82.1 mg, 0.50 mmol) was placed in a flame-dried flask, dissolved in nitromethane (5 mL) at ambient temperature. After addition of 2-methylthiophene (8a; 0.19 mL, 196 mg, 2.00 mmol) and Sc(OTf)₃ (2.5 mg, 5 µmol) the solution was stirred for 21 h. Identical workup as in the previous procedure⁹ and column chromatography (pentane-Et₂O, 7:3) yielded the product 9ca (88.0 mg, 0.34 mmol, 67%) in a diastereomeric ratio of threo/erythro 87:13.