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Alkylation of Phenols with ACOA or ACOM Halides
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gave 1.81 g (7%) of 3a as pale green crystals; mp 92–95 °C; one
spot on TLC; Rf 0.21 (CH2Cl2–acetone, 95:5).
1H NMR (CDCl3): d = 7.43 (d, J = 8 Hz, 2 H), 7.14 (br s, 1 H), 7.00
(d, J = 8 Hz, 2 H), 5.73 (s, 2 H), 2.18 (s, 3 H), 2.12 (s, 3 H).
4d
During the isolation of 3d, column fractions containing mixtures of
3d and 4d were combined and concentrated. Compound 4d was iso-
lated from this mixture via crystallization (EtOAc–hexane) as pale-
blue crystals; yield: 0.30 g (2%); mp 105–109 °C (Lit.35 mp 107–
109 °C); one spot on TLC; Rf 0.17 (CH2Cl2–EtOAc, 85:15).
1H NMR (CDCl3): d = 7.49 (d, J = 8 Hz, 2 H), 7.20 (br s, 1 H), 7.03
(d, J = 8 Hz, 2 H), 2.54 (t, J = 8 Hz, 2 H), 2.17 (s, 3 H), 1.75 (m, 2
H), 1.39 (m, 4 H), 0.93 (t, J = 8 Hz, 3 H).
Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C,
58.96; H, 5.84; N, 6.22.
3b (Entry 16)
Scale = 96.7 mmol 2a. Column chromatography (acetone–hexane,
3:7) and subsequent crystallization (Et2O–pentane) gave 3.64 g
(15%) of 3b as colorless crystals; mp 56–59 °C; one spot on TLC;
Rf 0.26 (acetone–hexane, 35:65).
3e and 4e (Entry 13)
Scale = 19.9 mmol 2a.
1H NMR (CDCl3): d = 7.42 (d, J = 8 Hz, 2 H), 7.10 (br s, 1 H) 6.99
(d, J = 8 Hz, 2 H), 5.74 (s, 2 H), 2.39 (q, J = 8 Hz, 2 H), 2.16 (s, 3
H), 1.15 (t, J = 8 Hz, 3 H).
3e
The residue obtained after the workup was chromatographed on sil-
ica gel (gradient = hexane → CH2Cl2 → acetone). In this way, 1.89
g (31%) of 3e was isolated as colorless crystals; mp 53–54 °C; one
spot on TLC; Rf 0.13 (CHCl3–acetone, 97:3).
Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C,
60.85; H, 6.35; N, 5.84.
1H NMR (CDCl3): d = 7.42 (d, J = 8 Hz, 2 H), 7.09 (br s, 1 H), 6.99
(d, J = 8 Hz, 2 H), 5.73 (s, 2 H), 2.35 (t, J = 7 Hz, 2 H), 2.16 (s, 3
H), 1.62 (m, 2 H), 1.26 (quint, J = 7 Hz, 8 H), 0.87 (t, J = 7 Hz, 3 H).
3c (Entry 15)
Scale = 112 mmol 2a. Column chromatography (EtOAc–hexane,
1:1) gave 12.51 g (44%) of 3c as an oil. Crystallization from Et2O–
2-methylbutane gave 7.03 g (25%) of 3c as colorless crystals;
mp 56–58 °C (Lit.13 mp 56–58 °C); one spot on TLC; Rf 0.16
(EtOAc–hexane, 1:1).
1H NMR (CDCl3): d = 7.42 (d, J = 8 Hz, 2 H), 7.13 (br s, 1 H), 6.99
(d, J = 8 Hz, 2 H), 5.74 (s, 2 H), 2.34 (t, J = 7 Hz, 2 H), 2.17 (s, 3
H), 1.65 (m, 2 H), 0.94 (t, J = 7 Hz, 3 H).
Anal. Calcd for C17H25NO4: C, 66.43; H, 8.20; N, 4.56. Found: C,
66.51; H, 8.19; N, 4.55.
4e
In addition to 3e, the chromatography procedure described above
also gave 2.24 g of a solid material composed of a mixture of 3e and
4e in a ratio of 1.3:1.0. This material was recrystallized (EtOAc–
hexane) to give 0.48 g (9%) of 4e as colorless crystals; mp 106–
108 °C (Lit.35 mp 103–105 °C); one spot on TLC; Rf 0.10 (CHCl3–
acetone, 97:3).
Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C,
61.92; H, 6.85; N, 5.52.
1H NMR (CDCl3): d = 7.50 (d, J = 8 Hz, 2 H), 7.15 (br s, 1 H), 7.03
(d, J = 8 Hz, 2 H), 2.55 (t, J = 8 Hz, 2 H), 2.18 (s, 3 H), 1.75 (m, 2
H), 1.32 (m, 8 H), 0.90 (t, J = 8 Hz, 3 H).
3f (Entry 18)
Scale = 8.5 mmol 2a. Column chromatography (acetone–hexane,
3:7) gave 0.79 g (39%) of 3f as a colorless solid. This solid was re-
crystallized from Et2O–2-methylbutane to give 0.56 g (28%) of 3f
as colorless crystals. Upon heating, 3f displayed an initial melting
point of 82–92 °C. Once this material had cooled to r.t. and solidi-
fied, it was heated again. This time, 3f displayed a sharp melting
point: 81–83 °C; one spot on TLC; Rf 0.20 (acetone–hexane, 3:7).
1H NMR (CDCl3): d = 7.41 (d, J = 9 Hz, 2 H), 7.08 (br s, 1 H), 6.92
(d, J = 9 Hz, 2 H), 6.51 (q, J = 5 Hz, 1 H), 2.16 (s, 3 H), 2.10 (s, 3
H), 1.60 (d, J = 5 Hz, 3 H).
References
(1) Bodor, N.; Sloan, K. B. US Patent 4061753, Chem. Abstr.
1977, 87, 152278.
(2) Sloan, K. B.; Wasdo, S. Med. Res. Rev. 2003, 23, 763.
(3) Mollgaard, B.; Hoelgaard, A.; Bundgaard, H. Int. J. Pharm.
1982, 12, 153.
(4) Roberts, W.; Sloan, K. B. J. Pharm. Sci. 2003, 92, 1028.
(5) Rautio, J.; Nevalainen, T.; Taipale, H.; Vepsalainen, J.;
Gynther, J.; Laine, K.; Jarvinen, T. J. Med. Chem. 2000, 43,
1489.
(6) Stinchcomb, A. L.; Swaan, P.; Ekabo, O.; Harris, K.; Browe,
J.; Hammell, D.; Cooperman, T.; Pearsall, M. J. Pharm. Sci.
2002, 91, 2571.
Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C,
60.69; H, 6.40; N, 5.91.
Product Purification Method B; Isolation of 3 and 4
3d and 4d (Entry 14)
Scale = 52.1 mmol 2a. The crude reaction mixture was filtered and
concentrated in vacuo to give an oily residue.
(7) Abbas, A.; Fadel, P.; Wang, Z.; Arbique, D.; Jialal, I.;
Vongpatanasin, W. Arterioscler. Thromb. Vasc. Biol. 2004,
24, e164.
(8) Thomas, J. D.; Sloan, K. B. Int. J. Pharm. 2007, 346, 80.
(9) Brass, E. Pharmacol. Rev. 2002, 54, 589.
(10) Tabbache, S.; Loubinoux, B. Synthesis 1982, 665.
(11) Sloan, K. B.; Koch, S. J. Org. Chem. 1983, 48, 3777.
(12) Ouyang, H.; Borchardt, R.; Siahaan, T. Tetrahedron Lett.
2002, 43, 577.
(13) Thomas, J.; Sloan, K. B. Tetrahedron Lett. 2006, 47, 8785.
(14) Iyer, R.; Yu, D.; Ho, N.; Agrawal, S. Synth. Commun. 1995,
25, 2739.
(15) Binderup, E.; Hansen, E. T. Synth. Commun. 1984, 14, 857.
(16) Thomas, J. D. Ph.D. Thesis; University of Florida: USA,
2006.
3d
The residue was subjected to column chromatography on silica gel
(gradient = hexane → CH2Cl2 → EtOAc) to give an oil. The oil was
then triturated in pentane (80 mL) to give 2.96 g (20%) of 3d as col-
orless crystals; mp 50–52 °C; one spot on TLC; Rf 0.20 (CH2Cl2–
EtOAc, 85:15).
1H NMR (CDCl3): d = 7.42 (d, J = 8 Hz, 2 H), 7.10 (br s, 1 H), 6.99
(d, J = 8 Hz, 2 H), 5.73 (s, 2 H), 2.35 (t, J = 7 Hz, 2 H), 2.16 (s, 3
H), 1.63 (quint, J = 7 Hz, 2 H), 1.29 (m, 4 H), 0.87 (t, J = 7 Hz, 3 H).
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.54; H, 7.56; N, 4.97.
Synthesis 2008, No. 2, 272–278 © Thieme Stuttgart · New York