Synthesis of enantioenriched alkylfluorides by the fluorination of boronate complexes

Article abstract of DOI:10.1021/jacs.5b05848

The enantiospecific conversion of chiral secondary boronic esters into alkylfluorides is reported. Boronate complexes derived from boronic esters and PhLi were used as nucleophiles, with Selectfluor II as the electrophilic fluorinating agent, to afford alkylfluorides in short reaction times. The addition of styrene as a radical trap was found to enhance enantiospecificity. A broad range of alkyl boronic esters were converted into alkylfluorides with almost complete enantiospecificity by this method.

Full text of DOI:10.1021/jacs.5b05848

Communication
pubs.acs.org/JACS
Synthesis of Enantioenriched Alkylfluorides by the Fluorination of
Boronate Complexes
Christopher Sandford, Ramesh Rasappan, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
S
* Supporting Information
Scheme 1. Synthesis of Fluorine-Bearing Stereocenters Distal
to Functional Groups
ABSTRACT: The enantiospecific conversion of chiral
secondary boronic esters into alkylfluorides is reported.
Boronate complexes derived from boronic esters and PhLi
were used as nucleophiles, with Selectfluor II as the
electrophilic fluorinating agent, to afford alkylfluorides in
short reaction times. The addition of styrene as a radical
trap was found to enhance enantiospecificity. A broad
range of alkyl boronic esters were converted into
alkylfluorides with almost complete enantiospecificity by
this method.
rganofluorine compounds are of increasing importance in
Opharmaceuticals, agrochemicals, and functional materials
due to the element’s unique properties.1 In medicinal chemistry,
the incorporation of fluorine into an organic compound can
result in improved metabolic stability and bioavailability and
enhance the binding efficacy when compared to the non-
fluorinated analogue.2 Consequently, ∼20−25% of all pharma-
ceuticals on the market contain fluorine,3 and the development of
novel procedures to introduce fluorine are highly sought after.
Late-stage fluorination techniques are of particular importance
because they can be used to introduce 18F into molecules for
positron emission tomography (PET).4
The high demand for fluorination techniques has resulted in
significant recent progress, particularly in the fluorination of
aromatic compounds.5 However, general techniques for aliphatic
fluorination remain challenging when the desired site for
fluorination is distal to functional groups.6 Specifically, while
enantioselective fluorination7 adjacent to aromatics,8 alkenes,9
heteroatoms,10 or carbonyl11 functional groups has been
achieved successfully, enantioselective fluorination of remote
positions is largely unexplored. The most direct current method
to create such entities is the conversion of chiral secondary
alcohols into alkylfluorides by deoxyfluorination (Scheme 1a),
but the process often suffers from competing elimination.12 This
process has been improved by Ritter with the introduction of
PhenoFluor, a thermally more stable reagent.13 Alternatively,
Gandelman has reported an enantioselective nickel-catalyzed
Suzuki cross-coupling reaction, but the enantioselectivity was
found to be highly substrate dependent (Scheme 1b).14 In this
paper, we demonstrate that enantioenriched boronic esters can
be converted into alkylfluorides in short reaction times and with
high levels of enantiospecificity (Scheme 1d).
Figure 1. Reaction pathways of boronate complexes with electrophiles,
and previous results with diisopropyl azodicarboxylate (DIAD) and N-
bromosuccinimide (NBS) as electrophiles (E+). SET = single-electron
transfer.16a
reaction was found to proceed through a radical mechanism. We
reasoned that if a protocol could be found which proceeded via a
polar (two-electron) pathway rather than a radical pathway, then
enantioenriched alkylfluorides would be obtained. We previously
reported that the addition of an aryllithium to a secondary
boronic ester afforded a boronate complex, which reacted with a
range of electrophiles with high selectivity (Figure 1), the
reactions proceeding by a polar pathway. This enabled the
conversion of the C−B bond into C−I, C−Br, C−Cl, C−N, C−
O, and C−C (bromination exemplified in Figure 1).16 However,
the conversion of the C−B bond into C−F was more challenging,
but has now been realized and is reported herein.
Initially, chiral secondary boronic ester 4a was treated with
phenyllithium to afford the intermediate boronate complex 5a
(Table 1), but no reaction with Selectfluor I (7) was observed in
THF. However, when THF was used for ate complex formation
and then exchanged for acetonitrile for the reaction with
Recently, Li reported the silver-catalyzed fluorination of
primary, secondary, and tertiary alkylboronates with Selectfluor
as the electrophilic fluorinating agent (Scheme 1c).15 The
Received: June 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05848
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(CF3)2C6H3Li (2) significantly increased the enantiospecificity
of the related reaction with diisopropyl azodicarboxylate (DIAD,
Figure 1),16a presumably by reducing the reduction potential of
the boronate complex and favoring the polar (two-electron)
pathway. However, the boronate complex derived from 2 was
found to afford only a small improvement to 47% es in the
fluorination reaction (entry 2).
Table 1. Investigation into the Fluorination of Boronate
Complex 5a
a
Somewhat surprisingly, using an aryl organolithium formed
from 4-bromostyrene increased the enantiospecificity to 59%
(entry 3). To ascertain whether the alkene substituent was
altering the reaction, 1.3 equiv of styrene was added to the
reaction mixture, with phenyllithium being used for ate complex
formation. Pleasingly, product 6a was afforded in 81% yield and
89% es (entry 4). Notably, ate complex 5a is fluorinated within
only 30 min at 0 °C.
Different additives were tested in the model reaction, but no
improvements in enantiospecificity were observed when
compared to styrene (entries 5−10). Specifically, using either
electron-deficient or -rich styrenes had no significant effect on
the level of enantiospecificity; small amounts of 4-tert-
butylcatechol, which are added to commercial styrenes to inhibit
polymerization, were ruled out as the contributing factor.17
When the alkene additive was replaced with toluene or an alkane
such as n-octane, the enantiospecificity was found to be reduced,
signifying the importance of the alkene functionality. It was also
found that the number of equivalents of styrene could be reduced
to 0.5 before the level of enantiospecificity was found to decrease
(entry 11).
To further increase the enantiospecificity, we turned to tuning
the fluorinating agent to favor the desired polar pathway. It was
reported by Banks that the electrophilicity (and, consequently,
the oxidation potential) could be reduced by decreasing the
electron-withdrawing power of the alkyl group attached to
nitrogen (CH2R3).18 Pleasingly, using commercially available
Selectfluor II (8) increased the enantiospecificity to 94% (entry
12).19 When the scale of the reaction was increased to 0.25 mmol
it was found that reducing the equivalents of PhLi to 0.95 was
necessary to maintain high enantiospecificity. Upon final
optimization,20 it was determined that adding molecular sieves
and reducing the temperature to −10 °C gave alkylfluoride 6a in
b
c
entry ArLi
Selectfluor
additive
yield (%) es (%)
1
1
2
3
1
1
1
1
1
1
1
1
1
1
1
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor I
Selectfluor II
Selectfluor II
Selectfluor II
none
none
none
78
61
37
47
59
89
74
87
24
78
46
33
89
94
100
80
2
3
61
4
styrene
81
5
4-MeO styrene
4-CF3 styrene
4-tert-butyl catechol
1-octene
>99
78
6
d
7
67
8
>99
72
9
toluene
10
11
12
13
n-octane
>99
89
e
styrene
e
styrene
72
f
e
g
styrene
83
f
g
14
none
72
a
Reactions were carried out with 0.10 mmol of 4a and 1.3 equiv of
ArLi. Conditions: 1.0 mL of THF for ate complex formation, 2.0 mL
of MeCN (total) for fluorination, PMP = para-methoxy phenyl. Yield
of isolated product. Determined by HPLC analysis. 0.2 equiv of 4-
tert-butylcatechol used. 0.5 equiv of styrene used. 0.25 mmol of 4a
and 0.95 equiv of PhLi. Conditions: Ate complex formation at 0 °C
(30 min) in 2.5 mL of THF, fluorination at −10 °C (2 h) in 5.0 mL of
MeCN (total), with 1.3 equiv of Selectfluor and 3 Å molecular sieves
b
c
d
e
f
g
(powder, 100 mg). Yield based on 0.95 equiv of PhLi.
Selectfluor (acetonitrile used to solubilize Selectfluor), the
corresponding secondary alkylfluoride 6a was formed in 78%
yield and 37% es (entry 1). Reasoning that a single-electron
transfer (SET) process was dominating because of the high
oxidation potential of Selectfluor I, we attempted to tune the
reactivity by altering the nature of the aryl group on boron. We
have previously reported that replacing PhLi (1) with 3,5-
a
Scheme 2. Scope of the Fluorination Reaction
a
Reactions were carried out with 0.25 mmol of boronic ester and 0.95 equiv of PhLi. Conditions: 2.5 mL of THF for ate complex formation, 5.0 mL
of MeCN (total) for fluorination, 3 Å molecular sieves (powder, 100 mg), unless stated otherwise. Yields recorded are those of isolated material
b
c
based on 0.95 equiv of PhLi; es determined by HPLC or GC analysis; dr determined by 19F NMR analysis. Yield after 16 h reaction. Selectfluor I
d
(7, 1.3 equiv), no styrene or molecular sieves, MeCN, rt, 1 h. Fluorination in 4:1 MeCN/THF mixture (5.0 mL total).
B
DOI: 10.1021/jacs.5b05848
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Journal of the American Chemical Society
Communication
a
Based on these results, we propose that styrene acts as a radical
scavenger.25 However, because the yield of this transformation is
not diminished by the presence of styrene, it seems probable that
styrene is trapping a radical propagating species (Figure 2). We
propose that boronate 5 reacts with Selectfluor predominantly
through a polar SE2inv pathway giving the alkylfluoride in high
enantiospecificity. A slower SET reaction also competes.
However, once the nucleophilic radical 10 is formed it combines
rapidly with the fluorine atom within the solvent cage leading to
racemic alkylfluoride 6. Alternatively, alkyl radical 10 can escape
the solvent cage (11) and then rapidly abstract a fluorine atom
from Selectfluor, forming the racemic product and amine radical
cation 12.6g−i This radical cation then undergoes rapid SET with
a new boronate 5 to regenerate radical 11 and complete a
propagation cycle. It is possible that this cycle is inhibited by the
addition of styrene, which traps radical 11 to afford 13, thus
preventing propagation.26 In the case of the free-radical clock
substrate 4n, if 10 escapes the solvent cage it can undergo ring
opening to afford 9n, unless it is trapped by styrene or
Selectfluor. However, Wong has shown that cyclopropyl radicals
often remain intact rather than undergoing ring opening owing
to their high rate of reaction with Selectfluor.27 The low levels of
enantiospecificity for this substrate presumably result from a
slower rate of SE2inv, with the radical combination following SET
contributing significantly. Because the effect of added styrene is
small, it suggests that radical propagation is not the primary cause
of the low levels of enantiospecificity in this case.
Table 2. Radical Clock Experiment
b
c
temp/°C
(time)
yield
(%)
ratio
d
entry
additive
6n:9n
es (6n) (%)
1
2
3
4
25 (1 h)
25 (1 h)
none
62
69
52
74
95:5
>99:1
97:3
52
56
56
64
styrene
none
−30 (16 h)
−30 (16 h)
styrene
>99:1
a
Reactions were carried out with 0.25 mmol of 4n and 0.95 equiv of
PhLi. Conditions: 2.5 mL of THF for ate complex formation, 5.0 mL
of MeCN (total) for fluorination, 3 Å molecular sieves (powder, 100
b
mg). Yield of isolated product based on 0.95 equiv of PhLi.
c
d
Determined by 19F NMR analysis. Determined by HPLC analysis.
83% yield with complete enantiospecificity (100% es, 91% ee,
entry 13). Under these optimized conditions, but without
styrene, the enantiospecificity was only 80% (entry 14).
With optimized conditions established for the model reaction,
the scope of the transformation was investigated (Scheme 2).
Upon changing the methyl substituent at the stereogenic center
for ethyl, the es of the reaction was found to drop to 81%.
Pleasingly, 99% es was achieved by simply decreasing the
temperature to −30 °C, albeit with a slightly reduced yield. The
two methods (A and B) were thus used to exemplify the high
reactivity and enantiospecificity, respectively, allowing the
conditions to be chosen depending on the application of the
procedure.
To probe the presence of amine radical cation 12, we
considered its application to the fluorination of sp3 C−H bonds.
Lectka has demonstrated that intermediate 12 is capable of
abstracting a H atom from adamantane, with the corresponding
radical reacting with Selectfluor to form 1-fluoroadamantane and
regenerate 12.6g,h When adamantane was added to our system
(Scheme 3), we observed the formation of 1-fluoroadamantane
14 in 4.4% yield after 3 h at rt. The formation of 14 was reduced
to 1.0% upon the addition of 1.3 equiv of styrene, demonstrating
its ability to inhibit the radical propagation cycle.
The reaction scope shows that the conditions tolerate a range
of functional groups including azides, protected alcohols,
alkenes, and tert-butyl esters. Additionally, the reaction can be
used to afford a benzylic alkylfluoride with high enantioenrich-
ment (6j). Given that the SE2inv pathway is highly dependent on
sterics, chiral tertiary boronic esters give rise to racemic products.
However, compound 6l could be obtained in 67% yield within
1 h at rt using Selectfluor I (7), and hence this transformation
provides a rapid late-stage method to obtain such functionality.
Furthermore, the fluorination of complex boronic ester
structures with additional stereogenic centers,21 including a
derivative of cholesterol, was achieved, the products being
formed as essentially single diastereoisomers (6k and 6m).22
The mechanism, and in particular the role of styrene, was
briefly explored. Styrene was not consumed at a detectable level
during the course of the reaction, and no reaction between
styrene and Selectfluor was observed under the reaction
conditions in the absence of the boronate complex. Because
styrene is a known radical scavenger23 and because Selectfluor19
is known to react by either SN2 or SET, we probed the possibility
of radical intermediates being responsible for the erosion in es
(Table 2).6c,g,24 It was expected that if SET competed with the
polar pathway then cyclopropyl substrate 4n would give ring-
opened homoallylic alkylfluoride 9n together with the
fluorinated cyclopropane 6n in high enantiospecificity. In
practice, in the absence of styrene, very little ring-opened
product 9n was observed, but in the presence of styrene,
formation of 9n was completely suppressed. However, the levels
of enantiospecificity for this substrate were lower than those for
all the other boronic esters tested (in agreement with previous
reactions with DIAD16a), thus implicating the existence of a
second racemic pathway (see below).
Figure 2. Proposed pathways for the reaction of boronate complex 5
with Selectfluor (8, F−+NR3).
a
Scheme 3. Radical Fluorination of sp3 C−H Bonds
a
Reactions were carried out with 0.25 mmol of boronic ester and 0.95
equiv of PhLi. Conditions: 2.5 mL of THF for ate complex formation,
5.0 mL of MeCN (total) for fluorination. Yields determined by crude
19F NMR analysis. Ar = C6H4OMe or C6H3FOMe (∼11:1 mixture).
C
DOI: 10.1021/jacs.5b05848
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Journal of the American Chemical Society
Communication
136, 6842. (c) Talbot, E. P. A.; Fernandes, T. D. A.; McKenna, J. M.;
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In conclusion, we have developed the first enantiospecific
method to convert chiral secondary boronic esters into
alkylfluorides. Very high levels of enantiospecificity can be
afforded at low temperatures using styrene, an additive which we
believe acts as a radical trap that prevents a radical propagation
cycle. Alternatively, the reaction can be conducted at higher
temperature to achieve reaction times of 30 min. The
transformation reported herein represents a significant addition
to the range of aliphatic fluorination reactions because it enables
the introduction of fluorine-bearing stereogenic centers at
remote positions, which were previously challenging to obtain.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b05848.
(12) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (b) Messina, P.
A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137.
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H.; Heasley, V. L. J. Chem. Soc., Perkin Trans. 2 1996, 973. (d) Lal, G. S.;
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LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J.
Org. Chem. 2010, 75, 3401. Triflates can be displaced by fluoride, but
elimination also often occurs; see: (f) Hunter, L.; O'Hagan, D.; Slawin,
A. M. Z. J. Am. Chem. Soc. 2006, 128, 16422. (g) Keddie, N. S.; Slawin, A.
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AUTHOR INFORMATION
Corresponding Author
*v.aggarwal@bristol.ac.uk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank EPSRC (EP/I038071/1) and Bristol University for
financial support, Dr. E. Myers and Dr. D. Leonori for valuable
discussions, and Dr. H. Sparkes for X-ray analysis of 6m.
(14) (a) Jiang, X.; Sakthivel, S.; Kulbitski, K.; Nisnevich, G.;
Gandelman, M. J. Am. Chem. Soc. 2014, 136, 9548. (b) Jiang, X.;
Gandelman, M. J. Am. Chem. Soc. 2015, 137, 2542.
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DOI: 10.1021/jacs.5b05848
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