L.-C. Donget al. / Tetrahedron Letters 45 (2004) 2731–2733
2733
8. Chen, G. T.; King, M.; Gusovsky, F.; Creveling, C. R.;
Daly, J. W.; Chen, B.-H.; Nie, J.-Y.; Kirk, K. L. J. Med.
Chem. 1993, 36, 3947–3955.
ed.; Fresenius, W., Huber, J. F. K., Pungor, E., Rechnitz,
G. A., Simon, W., West, T. S., Eds.; Springer: Berlin,
1989; p H155.
9. Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am.
Chem. Soc. 1960, 82, 543–551; Dmowski, W.; Wiszniew-
ski, W. J. Fluorine Chem. 1997, 82, 163–165.
18. The separation of enantiomers via recrystallization is a
phenomenon that has been previously observed. See: Oi,
R.; Sharpless, K. B. Org. Synth. 1995, 73, 1.
10. Tanabe, Y.; Matsuo, N.; Ohno, N. J. Org. Chem. 1988, 53,
4582–4585.
11. Ono, T.; Umemoto, T. J. Fluorine Chem. 1996, 80, 163–
166.
19. General experimental procedure for 1R: To a 25 mL round
bottom flask equipped with a stir bar was added (R)-1-
(3,4-dimethoxy-2-trifluoromethylphenyl)-2-methylamino-
ethanol (9R, 190 mg, 0.68 mmol) in CH2Cl2 (1.5 mL) with
stirring under an atmosphere of argon. The solution was
cooled to )78 ꢀC followed by the slow addition of boron
tribromide (1 M in CH2Cl2, 2.5 mL, 2.5 mmol) via a glass
syringe. The solution was warmed to room temperature,
stirred overnight, cooled to )78 ꢀC, and quenched with
methanol (3 mL, 74 mmol). A referee noted the possibility
of solvolysis with racemization upon boron tribromide
demethylation of 9R. We have performed the quenching of
the boron tribromide de-O-methylation reaction using
water and observed partial inversion of configuration of
the carbon containing the benzylic alcohol. This inversion,
however, was prevented upon quenching the de-O-meth-
ylation reaction in methanol. When using methanol we
observed a small amount of benzylic methyl ether forma-
tion, as evident by LCMS (APCI) analysis, in addition to
optically pure 1R. Upon warming the methanolic solution,
the epinephrine derivative was purified using reversed
12. May, D. D. Process for Trifluoromethylation of Aromatic
Compounds. U.S. Patent 5,233,104, 1993; Burton, D. J.;
Wiemers, D. M.; Easdon, J. C. Method of Preparation of
Trifluoromethyl Copper and Trifluoromethyl Aromatics.
U.S. Patent 4,749,802, 1988.
13. Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett.
1981, 1719–1720; Carr, G. E.; Chambers, R. D.; Holmes,
T. F.; Parker, D. G. J. Chem. Soc., Perkin Trans. 1 1988,
921–926; McClinton, M. A.; McClinton, D. A. Tetrahe-
dron 1992, 48, 6555–6666.
14. Markovich, K. M.; Tantishaiyakul, V.; Hamada, A.;
Miller, D. D.; Romstedt, K. J.; Shams, G.; Shin, Y.;
Fraundorfer, P. F.; Doyle, K.; Feller, D. R. J. Med. Chem.
1992, 35, 466–479.
15. General experimental procedure: To a 1000 mL three neck
flask equipped with a stir bar, argon gas inlet adapter,
thermometer to measure internal temperature, and a
mineral oil bubbler, was added N-methyl-2-pyrrolidinone
(360 mL) via a double ended cannula needle. The solvent
was kept under streaming argon while 3,4-dimethoxy-2-
iodo-benzaldehyde (4, 18.48 g, 63.3 mmol), CuI (24.11 g,
127 mmol), and sodium trifluoroacetate (34.43 g,
253 mmol) were quickly added. The flask was submerged
in an oil bath preheated to 185 ꢀC and heated to an
internal temperature of 175 ꢀC for 4 h with stirring. The
contents of the flask were allowed to cool to rt and poured
into a flask containing water (700 mL) with stirring for
0.5 h, which generated a light brown precipitate. The
precipitate was removed by centrifugation (25 ꢀC,
3700 rpm, 15 min) and the mother liquor was extracted
with hexane (3 · 500 mL). The hexane extracts were
combined and washed with an equal volume of water,
dried over MgSO4, and filtered. The solvent was removed
in vacuo to afford 3.72g (15.9 mmol, 25.1%) of 5 as a
yellow oil that was used without further purification.
16. In our attempt to optimize the asymmetric synthesis of 6R
and 6S, we performed the addition of aldehyde 5 and
TMSCN to the catalysts at an elevated temperature (rt)
followed by stirring for 18 h. Reduction of the silyl
cyanohydrins 6R and 6S yielded moderate to poor ee of
b-aminoethanols 7R and 7S.
phase
semi-preparative
HPLC
yielding
149 mg
(0.41 mmol, 60.0%) of a light green solid. The ee of 1R
and 1S was determined by HPLC analysis with UV
detection at 290 nm on a Cyclobond I 2000 RSP chiral
column (4.6 · 250 mm) using aqueous (NH4)H2PO4
(pH ¼ 4, 100 mM) at a flow of 1 mL/min. The absolute
configuration of 1R and 1S was determined by compar-
ison of the elution order of authentic (R)-epinephrine and
racemic epinephrine using identical chiral HPLC condi-
tions.
1H NMR for 1R trifluoroacetate salt (300 MHz, D2O, d)
7.12(d, 1H, J ¼ 8.5 Hz), 7.04 (d, 1H, J ¼ 8.5 Hz), 5.30 (d,
1H, J ¼ 7.2 Hz), 3.20–3.07 (m, 2H), 2.73 (s, 3H). 13C NMR
(75.6 MHz, D2O, d) 163.1 (q, J ¼ 35 Hz, trifluoroacetate),
145.5, 143.7, 130.3, 124.8 (q, J ¼ 275 Hz), 119.2, 118.6,
116.5 (q, J ¼ 291 Hz, trifluoroacetate), 114.4 (q,
J ¼ 29 Hz), 64.9, 55.1, 33.0. 19F NMR (282.8 MHz, D2O,
d) )53.0, )75.4 (trifluoroacetate). LCMS (APCI) m=z:
[M+H]þ 252. HRMS (ESI) calcd for [M+H]þ
C10H13F3NO3,
252.0848;
Found
252.0849.
tR
25
D
1R ¼ 4.6 min. ½aꢁ )33.8 (c 2.1, H2O), mp ¼ 61–63 ꢀC.
1H NMR for 1S trifluoroacetate salt (300 MHz, D2O, d)
7.17 (d, 1H, J ¼ 8.5 Hz), 7.10 (d, 1H, J ¼ 8.5 Hz), 5.33 (dd,
1H, J ¼ 2.2, 9.1 Hz), 3.24–3.11 (m, 2H), 2.74 (s, 3H). 13C
NMR (75.6 MHz, D2O, d) 163.2(q, J ¼ 34 Hz, trifluoro-
acetate), 145.5, 143.7, 130.3, 124.6 (q, J ¼ 275 Hz), 119.3,
118.6, 116.6 (q, J ¼ 292 Hz, trifluoroacetate), 114.4 (q,
J ¼ 29 Hz), 65.0, 54.8, 33.0. 19F NMR (282.8 MHz, D2O,
d) )53.2, )5.4 (trifluoroacetate). LCMS (APCI) m=z:
[M+H]þ 252. HRMS (ESI) calcd for [M+H]þ
C1205H13F3NO3, 252.0848; Found 252.0852. tR 1S ¼ 4.8 min.
17. We observed s-cis and s-trans isomers of both 8R and 8S
1
by H NMR, most likely due to slow rotation around the
CO–N bond. The ratio of s-cis to s-trans for each
enantiomer was ꢀ4:1 using the benzylic proton as the
integration indicator. The detection of monosubstituted
formamide isomers by NMR is noted in: Pretsch, E.;
Clerc, T.; Seibl, J.; Simon, W. In Tables of Spectral Data
for Structure Determination of Organic Compounds, 2 nd
½aꢁ +32.9 (c 2.2, H2O), mp ¼ 61–66 ꢀC.
D