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A.J. Cresswell et al. / Tetrahedron Letters 56 (2015) 3373–3377
a solution of epoxide 2 in CH2Cl2 at À20 °C for 5 min, then
BF3•OEt2
BF3
Me
quenched by the addition of satd aq NaHCO3 (i.e., analogous to
the conditions that we have previously employed to effect the
ring-opening fluorination of trans-b-substituted aryl epoxides
using BF3ÁOEt2 alone),12 and the product distribution was then
analysed by 1H NMR spectroscopy. These reactions all gave rise
to mixtures of products, of which the three main components were
identified as fluorohydrin 8, ketone 12 and the corresponding ether
13 (it being crucial that there was no evidence of fluorohydrin 8 in
either the 1H or 19F NMR spectra of the crude product mixture of
the analogous reaction employing BF3ÁOEt2 alone). It was noted
that integration of the resonance associated with the C(1)H proton
(i.e., CHF) within fluorohydrin 8 at dH 5.12 ppm (1H, dd, J 48.1, 7.3)
against the combined ArCH3 resonances associated with all com-
pounds present in the mixture (collection of singlet resonances
at dH ꢀ2.3–2.4 ppm) allowed quantification of the amount of
fluorohydrin 8 in the mixture (‘NMR yield’) which gave excellent
correlation with the isolated yield of fluorohydrin 8. For example,
treatment of epoxide 2 (92:8 dr) with a 2:1 mixture of BF3ÁOEt2
and B(OMe)3 (0.35 equiv and 0.18 equiv, respectively) gave fluor-
ohydrin 8, ketone 12, and ether 13a in the ratio of 28:34:38,
respectively; chromatographic purification provided 8 in 22% yield
(>95:5 dr), 12 in 26% yield, and 13a in 31% yield (>95:5 dr). The rel-
ative syn-configuration within fluorohydrin 8 was assigned from
the diagnostic value of the 1H NMR 3J coupling constant between
C(1)H and C(2)H (3J1,2 = 7.3 Hz),12 but the relative configuration
within ether 13a was not assigned.30 The relative syn-configuration
within 8 is also consistent with the stereochemical outcome of the
ring-opening fluorination of related trans-b-substituted aryl
epoxides with BF3ÁOEt2 that we have previously reported:12 the
stereochemical outcome of this process has been unambiguously
established by single crystal X-ray diffraction analysis in several
cases (including that of 1 giving 7).12 Increasing the quantity of
BF3ÁOEt2 and B(OMe)3 (to 0.70 and 0.35 equiv, respectively) in an
effort to promote the ring-opening fluorination reaction in fact
led to production of a decreased amount of fluorohydrin 8: under
these conditions a 5:49:46 mixture of 8, 12 and 13a, respectively,
was produced. Of all the conditions examined, the use of 0.70 equiv
of B(OiPr)3 and 0.35 equiv of BF3ÁOEt2 [i.e., 1.05 equiv of the
putative (iPrO)2BF complex] proved the most efficacious, and
delivered a 53:28:19 mixture of fluorohydrin 8, ketone 12 and
ether 13c, from which 8 was isolated in 41% yield and >95:5 dr.
Attempted optimisation of the temperature of this reaction did
not prove particularly fruitful: between À50 °C and 10 °C, increas-
ing the temperature in 10 °C intervals, gave a maximum 46% ‘NMR
yield’ of fluorohydrin 8 when the reaction was conducted at
À10 °C, although a significant decrease in the conversion to 8 (only
3% ‘NMR yield’) was noted when the reaction was run at 10 °C
(Scheme 2).
O
O
Me
Ar
Ar
1, Ar = Ph, >99:1 dr
3, Ar = Ph
2, Ar = p-Tol, 90:10 dr
4, Ar = p-Tol
epoxide
cleavage
F
F
C–C bond
Me
rotation
B
H
F
OBF3
O
H
Ar
H
k2
Me
H
Ar
9, Ar =Ph
5, Ar = Ph
10, Ar = p-Tol
6, Ar = p-Tol
fluoride
transfer
[1,2]-H shift
Me
k1
F
Ar
Me
Ar
O
OH
7, Ar = Ph, 81%, >99:1 dr
8, Ar = -Tol, not detected
11, Ar = Ph
12, Ar = -Tol, 38%
p
p
Scheme 1. p-Tol = para-tolyl.
1:2 ratio] is a convenient reagent for the SN2-type ring-opening
bromination of epoxides.22 Similarly, Guindon and co-workers
have shown that Me2BBr is a generally effective and highly chemo-
selective reagent for the SN2-type ring-opening bromination of
epoxides and other cyclic ethers.23 In addition, Brown and
co-workers have described the utility of (MeO)2BCl24 and (MeO)2BBr25
[prepared in situ by pre-mixing BCl3 or BBr3 respectively with
B(OMe)3] as reagents for the SN2-type ring-opening chlorination
and bromination of epoxides. Inclusion of alkoxy substituents on
6-B-317 fluoroboranes is known to decrease their Lewis acidity,
and for example the fluoride affinities of a range of (methoxy)(flu-
oro)boranes have been shown to be: (MeO)3B < (MeO)2BF < BF3,26
although ring-opening fluorination reactions of epoxides using
modified fluoroborane reagents are conspicuous by their paucity
in the literature.27 Nonetheless, the efficient ring-opening fluorina-
tion of epoxides such as 1 with 0.33 equiv of BF3ÁOEt2 implies that
the putative alkoxydifluoroborane [ROBF2] and dialkoxyfluorobo-
rane [(RO)2BF] intermediates formed during this process transfer
fluoride in preference to their alkoxy group(s). Building on this
hypothesis, we resolved to investigate the ability of a range of alk-
oxy-substituted fluoroborane reagents to facilitate the successful
ring-opening fluorination of trans-b-methyl-substituted aryl epox-
ides. We report herein our findings within this area, which culmi-
nate in the identification of pinacolatoboron fluoride (pinBF) as an
efficient fluoride donor for this stereoselective ring-opening fluori-
nation reaction.
As with alkoxy-substituted chloro- and bromoboranes,
alkoxydifluoroboranes [ROBF2] and dialkoxyfluoroboranes [(RO)2BF]
have previously been prepared by a redistribution process involv-
ing the treatment of B(OR)3 with BF3 or BF3ÁOEt2 (in the appropri-
ate stoichiometry), followed by distillation.28,29 Encouraged by this
precedent, and with the development of an operationally simple
protocol in mind, a variety of B(OR)3 additives, bearing alkoxy
groups with increasing steric demand, were screened to assess
their efficacy at promoting ring-opening fluorination of epoxide 2
in conjunction with BF3ÁOEt2. In each case, the requisite fluorinat-
ing agent was prepared in a separate reaction vessel by pre-mixing
the requisite amount of B(OR)3 with 0.35 equiv of BF3ÁOEt2 (i.e.,
giving 1.05 equiv of fluoride ion available for reaction in each case)
in CH2Cl2 for 5 min at rt.12 The resultant mixture was then added to
In an effort to suppress unwanted alkoxy transfer competing
with the desired fluoride transfer, the efficacy of cyclic B(2)-flu-
oro-1,3-dioxa-2-boracycles as fluorinating agents was next
explored. B-Chloro-1,3-dioxa-2-boracyclopentane,31,32 B-chloro-
4,4,5,5-tetramethyl-1,3-dioxa-2-boracyclopentane (pinBCl)33 and
B-chloro-1,3-dioxa-2-boracyclohexane34 have previously been
prepared by treatment of the corresponding diols with BCl3,
although the analogous preparation of the fluorine analogues has
not been reported. In the event, initial attempts at the use of this
protocol with BF3ÁOEt2 were not successful, and therefore an alter-
native was sought. Aldridge and co-workers have pioneered a con-
venient metathesis approach to alkoxy-substituted fluoroboranes,
in which trimethylsilyl ethers serve as latent B-alkoxy ligands,35
and a variant of this approach has also been demonstrated by
Yamamoto and co-workers to access a B-ethynyl boronic ester.36
Encouraged by this precedent, a range of bis(O-trimethylsilyl)
ethers 14–20 were prepared by disilylation of the corresponding