A. S. Capes et al. / Tetrahedron Letters 52 (2011) 7091–7094
7093
H
TBDPSO
O
TBDPSO
TBDPSO
O
O
Cu(BF4)2
TrCl
H
HO
HO
+
+
+
TBDPSO
OH
TBDPSO
OH
OTr
Scheme 4. Example of the trityl chloride method for removing excess alcohol.
and therefore the nucleophile would be less available to attack the
epoxide.27–29
26.7 (CH3), 24.3 (CH2), 24.0 (CH2), 19.3 (C) ppm. HRMS calcd mass
for C26H39O3Si (M+H+): 427.2663, found: 427.2645 (4.3 ppm).
Although the solvent must allow some of the copper catalyst to
dissolve, it was observed that the negative effects of a polar solvent
far outweighed the benefit of having more catalyst in solution. How-
ever, some of the more polar but lower yielding solvents may be use-
ful where substrate solubility is an issue. These results show that
there are several other solvents that are suitable for this reaction,
which may extend the type of substrates that can be used. There is
certainly more scope for exploring solvents for this reaction.
A further complication arises because the reaction works best
with four equivalents of alcohol. In a number of instances, the
product and the alcohol reagent had similar polarity, which made
separation of the product and the alcohol problematic. Previously,
this problem has been overcome either by using volatile alcohols
which could be removed in vacuo, by washing with water,24 or
by acetylating the reaction mixture before performing column
chromatography, and then deacetylating the purified material.30
The first two options were not available because none of the
alcohols used in this study are volatile or water soluble, and the
third option is laborious because it adds two steps to a synthesis.
We developed an alternative and shorter procedure using trityl
chloride to remove the excess of primary alcohol substrate, leaving
the secondary alcohol product untouched. The crude reaction mix-
ture was treated with trityl chloride, allowing facile chromato-
graphic separation of the product from the reagents and removing
the need for a further deprotection step (Scheme 4), thereby short-
ening the synthetic procedure. The required product was obtained
in 78% yield over two steps with this method, which was used for
all compounds in Table 1, except for Table 1, entry 4.
General ring-opening method, as exemplified by trans-2-{3-
[(tert-butyldiphenylsilyl)oxy]propoxy}cyclohexanol (Table 1,
entry 3)
Cyclohexene oxide (0.159 mL, 1.574 mmol, 1 equiv), 3-[(tert-
butyldiphenylsilyl)oxy]propan-1-ol
(1.980 mg,
6.296 mmol,
4 equiv) and Cu(BF4)2 (4 mg, 0.016 mmol, 0.01 equiv) were dis-
solved in CH2Cl2 (10 mL) using sonication (1 min). The mixture
was stirred under argon overnight at room temperature. The mix-
ture was diluted with H2O (20 mL), extracted with CH2Cl2
(3 Â 15 mL) and then the combined organic extracts were washed
with brine (50 mL) and filtered through cotton wool. The solvent
was removed to leave a residue.
General tritylation method as exemplified by trans-2-{3-[(tert-
butyldiphenylsilyl)oxy]propoxy})cyclohexanol
The crude mixture was dissolved in pyridine (4 mL) and added
to TrCl (1.755 g, 6.296 mmol, 4 equiv). The resulting mixture was
stirred at 70 °C for 16 h. The pyridine was removed by co-evapora-
tion with toluene and the residue resuspended in EtOAc (50 mL).
The organic phase was washed with H2O (50 mL), and the aqueous
layer extracted with EtOAc (2 Â 50 mL). The combined organic ex-
tracts were washed with H2O (100 mL) and brine (100 mL) and
then filtered through cotton wool. The solvent was removed and
the crude purified by column chromatography (Et2O/hexane,
0:100 to 2:3) to afford the product as a clear oil (531 mg, 78%).
1H NMR (500 MHz, CDCl3) dH 7.67 (4H, dd, J = 7.8, 1.4 Hz), 7.43–
7.35 (6H, m), 3.80–3.74 (3H, m), 3.53–3.48 (1H, m), 3.41–3.36 (1H,
m), 3.03–2.98 (1H, m), 2.07–1.98 (2H, m), 1.81 (2H, quin,
J = 6.2 Hz), 1.72–1.67 (2H, m), 1.29–1.09 (4H, m), 1.05 (9H, s)
ppm. 13C NMR (125 MHz, CDCl3) dC 135.6 (CH), 133.9 (C), 133.9
(C), 129.6 (CH), 127.7 (CH), 127.6 (CH), 83.7 (CH), 73.8 (CH), 65.3
(CH2), 60.8 (CH2), 33.1 (CH2), 32.0 (CH2), 29.2 (CH2), 26.9 (CH3),
24.3 (CH2), 24.0 (CH2), 19.2 (C) ppm. HRMS calcd mass for
In conclusion, a novel selection of alcohols has been used to ex-
tend the scope of the Cu(BF4)2 catalysed epoxide opening reaction.
A solvent study has shown several alternatives to CH2Cl2, which
may allow new substrates to be used with the reaction. Further-
more, a method for removal of excess primary alcohol in a single,
simple step has been outlined.
Solvent study ring opening method for trans-2-{4-[(tert-
butyldiphenylsilyl)oxy]butoxy}cyclohexanol
C
25H37O3Si (M+H+): 413.2506, found: 413.2498 (2.1 ppm).
Cyclohexene oxide (50 lL, 0.495 mmol, 1 equiv), 4-[(tert-butyl-
Acknowledgements
diphenylsilyl)oxy]butan-1-ol31 (651 mg, 1.982 mmol, 4 equiv) and
Cu(BF4)2 (14 mg, 0.071 mmol, 0.1 equiv) were dissolved in the sol-
vent (3 mL). The reaction mixture was stirred under argon over-
night at room temperature, diluted with CH2Cl2 (5 mL) then
washed with H2O (15 mL), and passed down a phase separator.
The solvent was removed in vacuo, and the crude purified by ra-
dial-band chromatography (100% hexane to 10:1 Et2O/hexane).
The identity of the product was confirmed by NMR.
We would like to acknowledge the MRC for a PhD studentship
(A.S.C.) and the Wellcome Trust (grants 085622 and 083481) for
funding.
References and notes
1. Lewars, E. G. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
R., Eds.; Pergamon: Oxford, 1984; pp 95–129.
2. Padwa, A.; Murphree, S. S. Arkivoc 2006, iii, 6.
3. Robinson, M. W. C.; Davies, A. M.; Mabbett, I.; Apperley, D. C.; Taylor, S. H.;
Graham, A. E. J. Mol. Catal. A: Chem. 2009, 314, 10.
4. Jafarpour, M.; Rezaeifard, A.; Aliabadi, M. Helv. Chim. Acta 2010, 93, 405.
5. Mogadam, M.; Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-Baltork, I.;
Taghavi, S. A. Catal. Commun. 2007, 8, 2087.
1H NMR (500 MHz, CDCl3) dH 7.68–7.65 (4H, m), 7.44–7.36 (6H,
m), 3.71–3.60 (3H, m), 3.42–3.32 (2H, m), 3.07–2.96 (1H, m), 2.42
(1H, br s), 2.06–1.98 (2H, m), 1.72–1.60 (6H, m,), 1.28–1.17 (4H,
m), 1.05 (9H, s) ppm. 13C NMR (125 MHz, CDCl3) dC 135.6 (CH),
134.0 (C), 133.7 (C), 129.7 (CH), 129.6 (CH), 127.7 (CH), 127.6
(CH), 83.7 (CH), 73.8 (CH), 68.6 (CH2), 64.0 (CH2), 63.7 (CH2), 62.8
(CH2), 32.0 (CH2), 29.9 (CH2), 29.3 (CH2), 29.2 (CH2), 26.9 (CH3),
6. Han, J. H.; Hong, S. J.; Lee, E. Y.; Lee, J. H.; Kim, H. J.; Kwak, H.; Kim, C. Bull.
Korean Chem. Soc. 2005, 26, 1434.