Mild and Stereoselective Friedel-Crafts Alkylation of Phenol Derivatives with Vinyloxiranes: A New Access to Cycloalkenobenzofurans

Abstract

The ring opening of vinyloxiranes with aryl borates under very mild and neutral conditions affords new hydroxyphenols with interesting levels of regio- and stereoselectivity. The subsequent Mitsunobu-type cyclodehydration proceeds with a good yield giving a new and easy access to cycloalkenobenzofurans.

Friedel-Crafts - vinyloxiranes - regioselectivity - stereoselectivity - fused-ring systems

References and Notes

For recent examples, see:

1a Kimura M. Mukai R. Tamaki T. Horino Y. Tamaru Y. J. Am. Chem. Soc.  2007,  129:  4122 

1b Brunner B. Stogaitis N. Lautens M. Org. Lett.  2006,  8:  3473 

1c Charrier N. Gravestock D. Zard SZ. Angew. Chem. Int. Ed.  2006,  45:  6520 

1d Restorp P. Somfai P. Eur. J. Org. Chem.  2005,  3946 ; and references cited therein

For a review, see:

2a Olah GA. Krishnamurti R. Prakash SGK. In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  p.293 

For recent examples, see:

2b Bertolini F. Crotti P. Macchia F. Pineschi M. Tetrahedron Lett.  2006,  47:  61 

2c Prakash SGK. Linares-Palomino PJ. Glinton K. Chacko S. Rasul G. Mathew T. Olah GA. Synlett  2007,  1158 

3 Vinyloxiranes have been used in an intramolecular process to control a 7-endo-selective Friedel-Crafts-type cyclization. See: Nagumo S. Miyoshi I. Akita H. Kawahara N. Tetrahedron Lett.  2002,  43:  2223 

4a Taylor SK. Clark DL. Heinz KL. Schramm SB. Westermann CD. Barnell KK. J. Org. Chem.  1983,  48:  592 

4b

The drastic reaction conditions used in this work, allowed direct ring opening of the oxirane ring by the Lewis acid promoter and caused the resulting alcohols to undergo a further Friedel-Crafts alkylation to give diarylated products.

5 For Friedel-Crafts reactions of a sulfonyl-substituted vinylic epoxide with various aromatics promoted by BF₃·Et₂O, see: Brandänge S. Bäckvall J.-E. Leijonmarck H. J. Chem. Soc., Perkin Trans. 1  2001,  2051 

6 For the reactions of methyl 4,5-epoxypentenoate with aryl ethers, see: Ono M. Tanikawa S. Suzuki K. Akita H. Tetrahedron  2004,  60:  10187 ; and references cited therein

7 Pineschi M. Bertolini F. Haak RM. Crotti P. Macchia F. Chem. Commun.  2005,  1426 

8 Tsuji Y. Toteva Garth HA. Richard JP. J. Am. Chem. Soc.  2003,  125:  15455 

For the use of indium salts in Friedel-Crafts-type reactions of heteroarenes with epoxides, see:

9a Yadav JS. Reddy BVS. Parimala G. Synlett  2002,  1143 

9b Bandini M. Cozzi PG. Melchiorre P. Umani-Ronchi A. J. Org. Chem.  2002,  67:  5386 

For the synthesis of tetrahydrobenzofurans, see:

10a Hosokawa T. Miyagi S. Murahashi S.-I. Sonoda A. J. Org. Chem.  1978,  43:  2752 

10b Guzzo PR. Buckle RN. Chou M. Dinn SR. Flaugh ME. Kiefer AD. Ryter KT. Sampognaro AJ. Tregay SW. Xu Y.-C.
J. Org. Chem.  2003,  68:  770 

10c Yamashita M. Inaba T. Nagahama M. Shimizu T. Kosaka S. Kawasaki I. Ohta S. Org. Biomol. Chem.  2005,  3:  2296 

10d Crich D. Sannigrahi M. Tetrahedron  2002,  58:  3319 

For the obtainment of hexahydrodibenzofurans, see:

10e Liu Q. Han B. Zhang W. Yang L. Liu Z.-L. Yu W. Synlett  2005,  2248 

10f Kurono N. Honda E. Komatsu F. Orito K. Tokuda M. Tetrahedron  2004,  60:  1791 

10g Nguyen R.-V. Yao X. Li C.-J. Org. Lett.  2006,  8:  2397 

11a Clive DLJ. Daigneault S. J. Org. Chem.  1991,  56:  5285 

11b Trost BM. Tang W. Toste FD. J. Am. Chem. Soc.  2005,  127:  14785 

12 Aristoff PA. Harrison AW. Huber AM. Tetrahedron Lett.  1984,  25:  3955 

13

Aryl borates 1a,b were prepared from the corresponding commercially available phenols with BH₃·SMe₂,¹⁴ and were used immediately after their preparation.
Typical Procedure for the Preparation of Hydroxy-phenols (Entry 7, Table 1): Under an argon atmosphere, a solution of aryl borate 1b (705 mg, 1.5 mmol) in CH₂Cl₂ (1.0 mL) was added at -78 °C to a stirred solution of vinyloxirane 2a (96 mg, 1.0 mmol) in CH₂Cl₂ (0.5 mL). The mixture was allowed to react for 18 h at -78 °C, then quenched with brine (2.0 mL) and diluted with Et₂O or CH₂Cl₂ (20 mL). Evaporation of the dried (MgSO₄) organic solution afforded a crude reaction mixture which was purified by silica gel column chromatography eluting with hexanes-EtOAc (7:3), to give pure 2-[(1R*,6S*)-6-hydroxycyclohexen-2-yl]-3,5-dimethoxyphenol (4ab; 162 mg, 65%), as a light yellow oil; TLC (hexanes-EtOAc, 1:1): R _f 0.36. ¹H NMR (250 MHz, CDCl₃): δ = 1.70-1.90 (m, 1 H), 2.05-2.18 (m, 1 H), 2.30-2.43 (m, 2 H), 2.50-2.67 (br s, 1 H, CHOH), 3.82 (s, 3 H), 3.83 (s, 3 H), 3.95-4.10 (m, 2 H), 5.67-5.83 (m, 2 H), 5.93-6.05 (m, 1 H), 6.10-6.25 (m, 1 H), 6.50-6.70 (br s, 1 H, ArOH). ¹³C NMR (62.5 MHz, CDCl₃): δ = 24.6, 30.7, 40.6, 55.1, 55.6, 71.2, 91.5, 94.5, 106.1, 107.7, 128.8, 156.9, 159.2, 159.9.
2-[(1 R *,6 S *)-6-Hydroxycyclohexen-2-yl]-3,5-dimethyl-phenol (4aa): yield: 40%; solid; mp 119-122 °C; TLC (hexanes-EtOAc, 7:3): R _f 0.20. ¹H NMR (200 MHz, MeOD): δ = 1.56-1.86 (m, 2 H), 1.93-2.12 (m, 2 H), 2.17 (s, 3 H), 2.27 (s, 3 H), 3.62-3.89 (m, 1 H), 4.12-4.33 (m, 1 H), 5.45 (d, J = 9.8 Hz, 1 H), 5.56-5.71 (m, 1 H), 6.46 (s, 2 H). ¹³C NMR (50 MHz, MeOD): δ = 21.0, 21.2, 26.4, 33.4, 45.3, 71.1, 115.3, 124.2, 125.4, 126.0, 131.7, 137.6, 139.5, 157.1.
2-(1-Hydroxybut-3-en-2-yl)-3,5-dimethylphenol (6aa): yield: 54%; colorless oil; TLC (hexanes-EtOAc, 6:4): R _f 0.31. ¹H NMR (200 MHz, CDCl₃): δ = 2.24 (s, 3 H), 2.28 (s, 3 H), 3.63 (br s, 1 H), 3.81-4.19 (m, 3 H), 5.04-5.24 (m, 2 H), 6.22 (ddd, J ₁ = 16.6 Hz, J ₂ = 10.4 Hz, J ₃ = 5.3 Hz, 1 H), 6.58 (s, 1 H), 6.60 (s, 1 H), 8.26 (br s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 20.7, 44.8, 65.1, 116.1, 116.5, 122.4, 123.6, 136.0, 137.6, 154.7.
2-(1-Hydroxybut-3-en-2-yl)-3,5-dimethoxyphenol (6ab): yield: 75%; colorless oil; TLC (hexanes-EtOAc, 8:2): R _f 0.13. ¹H NMR (200 MHz, CDCl₃): δ = 3.73 (s, 6 H), 3.89 (dd, J ₁ = 10.2 Hz, J ₁ = 3.2 Hz, 1 H), 4.02-4.15 (m, 1 H), 4.16-4.28 (m, 1 H), 5.00-5.19 (m, 2 H), 6.03-6.12 (m, 2 H), 6.13-6.23 (m, 1 H). ¹³C NMR (500 MHz, CDCl₃): δ = 40.0, 54.5, 55.7, 65.7, 91.2, 94.7, 108.0, 116.1, 136.7, 156.6, 158.6, 159.8.
( E )-2-(6-Hydroxynon-4-en-3-yl)-3,5-dimethoxyphenol (6bb): yield: 65%; colorless oil; TLC (hexanes-EtOAc, 7:3): R _f 0.27. ¹H NMR (250 MHz, CDCl₃): δ = 0.79 (t, 3 H), 0.86 (t, J = 7.1 Hz, 3 H), 1.19-1.52 (m, 4 H), 1.62-1.82 (m, 2 H), 2.20 (br s, 1 H, CHOH), 3.69 (s, 3 H), 3.71 (s, 3 H), 3.74-3.89 (m, 1 H), 4.06-4.13 (m, 1 H), 5.55 (dd, J ₁ = 16.3 Hz, J ₂ = 6.7 Hz, 1 H), 5.98-6.18 (m, 3 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 12.3, 13.9, 18.61, 25.49, 38.27, 39.31, 55.1, 55.6, 72.7, 91.4, 94.4, 110.2, 132.6, 134.4, 158.8, 159.1.
(4 S* ,5 S* , E )-Ethyl 5-Hydroxy-4-(2-hydroxy-4,6-dimethylphenyl)oct-2-enoate (6cb): yield: 40%; colorless oil; TLC (hexanes-EtOAc, 7:3): R _f 0.19. ¹H NMR (200 MHz, CDCl₃): δ = 0. 93 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 5.7 Hz, 3 H), 1.33-1.74 (m, 4 H), 3.52 (br s, 1 H, CHOH), 3.74 (s, 6 H), 3.95-4.30 (m, 4 H), 5.78 (d, J = 15.8 Hz, 1 H), 6.04 (s, 1 H), 6.11 (s, 1 H), 7.38 (dd, J ₁ = 15.8 Hz, J ₂ = 7.2 Hz, 1 H), 9.22 (br s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 13.7, 14.1, 19.0, 38.1, 42.3, 55.1, 55.7, 60.3, 75.4, 91.0, 94.8, 108.0, 123.1, 145.2, 156.8, 158.2, 160.1, 167.0.
(1 S* ,2 R* )-2-(2-Hydroxy-4,6-dimethoxyphenyl)cyclo-hept-3-enol (4bb): yield: 58% [obtained as an inseparable mixture with 7% of the corresponding (1S*,2S*)-stereoisomer]; TLC (hexanes-EtOAc, 7:3): R _f 0.16. ¹H NMR (200 MHz, CDCl₃): δ = 1.40-2.42 (m, 6 H), 3.70 (s, 3 H), 3.74 (s, 3 H), 3.93-4.17 (m, 2 H), 5.50-5.61 (m, 1 H), 5.77-5.95 (m, 1 H), 6.01 (d, J = 2.3 Hz, 1 H), (6.06 d, J = 2.3 Hz, 1 H), 6.94-7.03 (br s, 1 H, ArOH). ¹³C NMR (50 MHz, CDCl₃): δ = 24.7, 27.8, 39.8, 43.3, 55.1, 55.6, 71.1, 91.2, 94.4, 109.0, 132.1, 133.0, 156.3, 159.5, 159.7. Typical Procedure for the Preparation of 2,3-Dihydro-benzofuranes via Mitsunobu Cyclodehydration (Scheme 2): Triphenylphosphine (262.3 mg, 1.0 mmol) and diethyl-azodicarboxylate (118 µL, 0.75 mmol) were added to a stirred solution of hydroxyphenol 4ab (125 mg, 0.5 mmol) in anhyd THF (2.0 mL) under argon. The reaction was followed by TLC up to complete consumption of the starting hydroxyphenol and the solvent was removed in vacuo. The crude reaction mixture was purified by silica gel column chromatography to give pure (4aR*,9bR*)-7,9-dimethoxy-3,4,4a,9b-tetrahydrodibenzo[b,d]furan (7ab; 94 mg, 81%) as a light yellow oil. ¹H NMR (200 MHz, CDCl₃): δ = 1.75-2.31 (m, 4 H), 3.75 (s, 3 H), 3.79 (s, 3 H), 3.81-3.88 (m, 1 H), 4.93-5.05 (m, 1 H), 5.73-5.95 (m, 2 H), 6.00 (d, J = 2.0 Hz, 1 H), 6.05 (d, J = 2.0 Hz, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 19.2, 25.1, 39.0, 55.1, 55.4, 82.3, 88.7, 91.0, 110.1, 126.0, 126.7, 156.7, 161.1, 161.5.
(4a R *,9b R *)-7,9-Dimethyl-3,4,4a,9b-tetrahydro-dibenzo[ b , d ]furan (7aa): yield: 83%; colorless oil; TLC (hexanes-Et₂O, 9:1): R _f 0.51. ¹H NMR (200 MHz, CDCl₃): δ = 1.75-2.12 (m, 2 H), 2.19-2.30 (m, 2 H), 2.27 (s, 3 H), 2.30 (s, 3 H), 3.77 (br d, J = 6.9 Hz, 1 H), 4.94-5.00 (m, 1 H), 5.68-5.95 (m, 2 H), 6.48 (s, 1 H), 6.50 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 18.3, 19.0, 21.4, 24.9, 40.1, 81.3, 108.0, 122.6, 125.1, 126.9, 127.8, 134.0, 138.2.
(5a R *,10a R *)-1,3-Dimethoxy-6,7,8,10a-tetrahydro-5a H -benzo[ d ]cyclohepta[ b ]furan (7bb): yield: 80% (obtained as an inseparable mixture with 10% of the corresponding trans stereoisomer); light yellow oil; TLC (hexanes-EtOAc, 9:1): R _f 0.38. ¹H NMR (200 MHz, CDCl₃): δ = 1.55-1.75 (m, 2 H), 1.92-2.07 (m, 2 H), 2.09-2.22 (m, 2 H), 3.76 (s, 3 H), 3.80 (s, 3 H), 4.25 (d, J = 9.8 Hz, 1 H), 4.88 (ddd, J ₁ = 4.5 Hz, J ₂ = 9.8 Hz, 1 H), 5.62-5.68 (m, 2 H), 6.00-6.05 (m, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 19.4, 26.7, 28.7, 42.4, 55.3, 55.5, 85.5, 88.1, 91.1, 127.6, 129.7, 159.0, 160.3, 160.7.
(5a S *,11a S *, Z )-1,3-Dimethoxy-5a,6,7,8,11a-hexa-hydrobenzo[ b ]cycloocta[ d ]furan (7cb): yield: (70%); light yellow oil; TLC (hexanes-EtOAc, 9:1): R _f 0.45. ¹H NMR (200 MHz, CDCl₃): δ = 0.95-2.25 (m, 8 H), 3.72 (s, 3 H), 3.76 (s, 3 H), 4.10-4.26 (m, 1 H), 4.50-4.67 (m, 1 H), 5.11 (dd, J ₁ = 10.6 Hz, J ₂ = 7.0 Hz, 1 H), 5.68-5.88 (m, 1 H), 6.00 (s, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 26.6, 26.7, 28.2, 29.2, 40.4, 55.5 (2 × C), 88.3, 91.3, 91.5, 11.8, 130.5, 133.3, 156.7, 160.5, 161.6.

14 Brown CA. Krishnamurthy S. J. Org. Chem.  1978,  43:  2731