LETTER
Microwave-Assisted Cleavage of Aryl Methyl Ethers with Lithium Thioethoxide
1997
(32) Evans, D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.;
Barrow, J. C. J. Am. Chem. Soc. 1997, 119, 3417.
(33) Inaba, T.; Umezawa, I.; Yuasa, M.; Inoue, T.; Mihashi, S.;
Itokawa, H.; Ogura, K. J. Org. Chem. 1987, 52, 2957.
(34) For a review, see: Schmalz, H.-G.; Gotov, B.; Böttcher, A.
In Arene Metal Complexes. Topics in Organometallic
Chemistry, Vol. 7; Kündig, E. P., Ed.; Springer: Berlin,
2004, 157.
(35) (a) Geller, T. PhD Dissertation; TU-Berlin: Germany,
1998. (b) Majdalani, A.; Schmalz, H.-G. Synlett 1997,
1303. (c) Majdalani, A.; Schmalz, H.-G. Tetrahedron Lett.
1997, 38, 4545. (d) Geller, T.; Schmalz, H.-G.; Bats, J. W.
Tetrahedron Lett. 1998, 39, 1537. (e) Dehmel, F.; Schmalz,
H.-G. Org. Lett. 2001, 3, 3579. (f) Dehmel, F.; Lex, J.;
Schmalz, H.-G. Org. Lett. 2002, 4, 3915.
mL, 160 mmol) was diluted with hexane (150 mL) under an
argon atmosphere. The solution was cooled to 0 °C and
under rapid stirring EtSH (200 mmol, 1.25 equiv, 15 mL)
was added dropwise, whereupon a white precipitate formed.
The reaction mixture was stirred at 0 °C for 10 min and at r.t.
for 30 min. After removal of the solvent (always ensuring
inert conditions) the residue was dried in vacuo to give LiSEt
as a white solid (10.6 g, 156 mmol, 97%). The product was
stored under argon at ambient temperature. C2H5SLi; M =
68.06 g/mol. 1H NMR (250 MHz, DMSO): d = 1.06 (t, 3J =
7.2 Hz, 3 H, H2), 2.27 (q, 3J = 7.3 Hz, 2 H, H1).
General Procedure: The substrate (0.6 mmol, 1 equiv) and
LiSEt (1.2 mmol, 2 equiv) were weighed into the reaction
vessel (either a Schlenk tube or a microwave reactor), which
was then evacuated and flushed with argon three times
before DMF (5 mL) was added and the reaction mixture was
heated/irradiated as specified in Table 1. Reactions were
monitored by TLC and/or GC–MS. For workup, the mixture
was cooled to r.t. and partitioned between 2 N aq HCl (5 mL)
and MTBE (5 mL). The aqueous layer was re-extracted with
MTBE (3 × 10 mL). The combined organic layers were
washed with brine (20 mL), dried over MgSO4, filtered
through a pad of silica and solvents were evaporated. The
residue was flash chromatographed on silica gel with
c-hexane–EtOAc (4:1).
(36) For an efficient entry to stilbene 5 by cross-metathesis, see:
Velder, J.; Ritter, S.; Lex, J.; Schmalz, H.-G. Synthesis 2006,
273.
(37) (a) Polunin, K. E.; Polunina, I. A.; Schmalz, H.-G.
Mendeleev Commun. 2002, 12, 178. (b) Polunin, K. E.;
Schmalz, H.-G. Russ. J. Coord. Chem. 2004, 30, 252.
(38) (a) For synthetic approaches towards pestatone, see: Cueto,
M.; Jensen, P. R.; Kaufmann, C.; Fenical, W.; Lobkovsky,
E.; Clardy, J. J. Nat. Prod. 2001, 64, 1444. (b) Kaiser, F.;
Schmalz, H.-G. Tetrahedron 2003, 59, 7345. (c) Iijima, D.;
Tanaka, D.; Hamada, M.; Ogamino, T.; Ishikawa, Y.;
Nishiyama, S. Tetrahedron Lett. 2004, 45, 5469.
(39) For a review on colchicine total synthesis, see:
(a) Graening, T.; Schmalz, H.-G. Angew. Chem. Int. Ed.
2003, 42, 2580; Angew. Chem. 2003, 115, 2684. (b) For a
recent work from this laboratory, see: Graening, T.; Bette,
V.; Neudörfl, J.; Lex, J.; Schmalz, H.-G. Org. Lett. 2005, 7,
4317.
(40) For previous examples of selective O-demethylation
reactions with thiolate-based reagents which, however,
require harsh reaction conditions, long reaction times and/or
the use of HMPT as a toxic additive, see: (a) Moos, W. H.;
Gless, R. D.; Rapoport, H. J. Org. Chem. 1982, 47, 1831.
(b) Lal, K.; Zarate, E. A.; Youngs, W. J.; Salomon, R. G.
J. Am. Chem. Soc. 1986, 108, 1311. (c) Dodge, J. A.;
Stocksdale, M. G.; Fahey, K. J.; Jones, C. D. J. Org. Chem.
1995, 60, 739. (d) Loubinoux, B.; Coudert, G.; Guillaumet,
G. Synthesis 1980, 638. (e) Lal, K.; Ghosh, S.; Salomon, R.
G. J. Org. Chem. 1987, 52, 1072.
(41) (a) Kappe, C. O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005.
(b) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(c) Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discovery
2006, 5, 51.
(42) For the use of microwave irradiation in the cleavage or trans
protection of aryl methyl ether using different reagents, see:
(a) Fredriksson, A.; Stone-Elander, S. J. Labelled Compd.
Radiopharm. 2002, 45, 529. (b) Marette, C.; Larrouquet, C.;
Tisne’s, P.; Deloyeb, J.-B.; Grasa, E. Tetrahedron Lett.
2006, 47, 6947.
3-Methoxyphenol (10): colorless oil. 1H NMR (CDCl3): d =
3.76 (s, 3 H), 5.03 (br s, 1 H), 6.40–6.43, 6.46–6.50 (m, 3 H),
7.09–7.14 (m, 1 H). 13C NMR (CDCl3): d = 55.3 (q), 101.5,
106.4, 107.9 (3 × d), 130.1 (d), 156.7 (s), 160.9 (s). HRMS
(EI, 70 eV): m/z calcd for C7H8O2: 124.0524; found:
124.053.
3-Methoxy-2-methylphenol (12): white solid; mp 42–43
°C. 1H NMR (CDCl3): d = 2.11 (s, 3 H), 3.81 (s, 3 H), 4.80
(s, 1 H), 6.44 (d, 3J = 8.5 Hz, 1 H), 6.47 (d, 3J = 8.5 Hz, 1 H),
7.02 (yt, 3J = 8.5 Hz, 1 H). 13C NMR (CDCl3): d = 7.9 (q),
55.6 (q), 103.0 (d), 108.0 (d), 112.1 (s), 126.4 (d), 154.3 (q),
158.6 (q). HRMS (EI, 70 eV): m/z calcd for C8H10O2:
138.0681; found: 138.068.
2-Hydroxy-6-methoxybenzonitrile (14): white solid; mp
163–164 °C. 1H NMR (CD3OD): d = 3.87 (s, 3 H), 6.50 (d,
3J = 8.4 Hz, 1 H), 6.52 (d, 3J = 8.4 Hz, 1 H), 7.34 (yt, 3J =
8.5 Hz, 1 H). 13C NMR (CD3OD): d = 56.7 (q), 90.6 (s),
102.9 (d), 109.0 (d), 115.4 (s), 136.1 (d), 163.0 (s), 163.9 (s).
IR (ATR): 3220 (br m), 2230 (s), 1607 (s), 1594 (s), 1476 (s)
cm–1. HRMS (EI, 70 eV): m/z calcd for C8H7NO2: 149.0477;
found: 149.047.
3,5-Dimethoxybenzoic acid (16): GC–MS and NMR data
matched those of an authentic(commercial) sample.
1-(4-Hydroxy-3,5-dimethoxyphenyl)ethanone (20):
colorless oil. 1H NMR (CDCl3): d = 2.54 (s, 3 H), 3.92 (s, 6
H), 6.03 (br s, 1 H), 7.22 (s, 2 H). 13C NMR (CDCl3): d =
26.2 (q), 56.4 (q), 105.7 (d), 128.8 (s), 139.7 (s), 146.7 (s),
200.3 (s). IR (ATR): 3350 (br m), 1728 (s) cm–1. HRMS:
m/z calcd for C10H12O4: 196.0736; found: 196.074.
5-Bromo-2,3-dimethoxyphenol (22a): white solid; mp 68–
70 °C. 1H NMR (CDCl3): d = 3.82 (s, 3 H), 3.85 (s, 3 H), 5.83
(br s, 1 H), 6.59 (d, 4J = 2.1 Hz, 1 H), 6.75 (d, 4J = 2.1 Hz, 1
H). 13C NMR (CDCl3): d = 56.5 (q), 60.9 (q), 107.9 (d),
111.6 (d), 116.4 (s), 134.8 (s), 149.9 (s), 152.8 (s). MS (EI,
70 eV; isotope pattern reflected a molecule with one bromine
atom): m/z (%) = 234 (95) [M]+, 232 (100) [M]+, 219 (95),
217 (97), 191 (46), 189 (55), 173 (29), 171 (31), 110 (14), 67
(41). HRMS: m/z calcd for C8H9O379Br: 231.9735; found:
231.974.
(43) DMF (99.8%, Fluka) was stored over molecular sieves. GC–
MS measurements were carried out on an Agilent HP6890
instrument with MS detector 5937 N using an Optima 1 MS
(Macherey–Nagel) 30 m × 0.25 mm capillary column with
H2 as carrier gas. NMR data were measured on Bruker DPX
300 and AC 250 instruments. Chemical shifts (d) are given
in ppm relative to the solvent reference as the internal
standard. Reactions under microwave irradiation were
performed in a CEM Discover instrument (300 W) in glass
tubes with temperature and pressure control.
4-Bromo-2,6-dimethoxyphenol (22b): white solid; mp 90–
92 °C. 1H NMR (CDCl3): d = 3.86 (s, 6 H), 5.42 (br s, 1 H),
6.70 (s, 2 H). 13C NMR (CDCl3): d = 56.4 (q), 108.4 (d),
Preparation of the Reagent (LiSEt): In a dry 500-mL
Schlenk flask a solution of n-BuLi (1.3 M) in hexane (120
Synlett 2008, No. 13, 1993–1998 © Thieme Stuttgart · New York