Divergent, Stereospecific Mono- and Difluoromethylation of Boronic Esters

Article abstract of DOI:10.1002/anie.202002246

There is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH₂F and CHF₂ groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α-fluoro-boronic esters. These unique intermediates can be readily transformed into the corresponding mono- or difluoromethylated compounds through proto- or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2-migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.

Full text of DOI:10.1002/anie.202002246

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Accepted Article
Title: Divergent, stereospecific mono- and difluoromethylation of
boronic esters
Authors: Varinder Kumar Aggarwal, Valerio Fasano, Nils Winter, and
Adam Noble
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002246
Angew. Chem. 10.1002/ange.202002246
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Angewandte Chemie International Edition
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COMMUNICATION
Divergent, stereospecific mono- and difluoromethylation of
boronic esters
‡
‡
[a]
Valerio Fasano, Nils Winter, Adam Noble, and Varinder K. Aggarwal*
Abstract: There is considerable interest in incorporating fluorine in
agrochemicals and pharmaceuticals to improve their biological
properties. Whilst a number of methods have been reported for
2 2
Since CH F and CHF groups are bioisosteric with methyl and
hydroxyl groups, respectively, their stereoselective incorporation
into organic molecules is highly desirable.1
2-14
We considered the
installing CH
2
F and CHF
2
groups, they are mainly limited to radical
possibility of transforming enantioenriched boronic esters into
CH or CHF groups by stereospecific Matteson-type
homologation (via 1,2-migration)
carbenoid precursor, followed by subsequent removal of the
boron moiety (Scheme 1b). These transformations would require
reactions which are invariably racemic. Herein, we report the
divergent, stereospecific reaction of fluoroiodomethyllithium with
boronic esters which give α-fluoro-boronic esters. These unique
intermediates can be readily transformed into the corresponding
mono- or difluoromethylated compounds, via proto- or
fluorodeboronation, respectively. The use of the highly unstable
fluoroiodomethyllithium was key to allowing rapid 1,2-migration over
competing decomposition of the carbanion. DFT calculations
informed and supported the experimental findings.
2
F
2
a
1
5-16
with a mono- or difluorinated
2
fluorocarbenoids such as LiCH(F)X and LiCF X. However, such
entities are highly unstable reagents, being prone to carbene
formation,1
7-20
and so careful consideration of suitable leaving
groups (X) was required. There were three main factors governing
the nature of X that we needed to consider: (i) X must be a good
leaving group to promote 1,2-migration but not too good that it
results in elimination of LiX with formation of a fluorine-stabilized
carbene (ii) X must not stabilize the lithiated species otherwise
dissociation of the boronate complex back to its constituents will
occur leading to decomposition of the carbanion (iii) X must not
stabilize the potential carbene as this will promote α-elimination
of LiF leading to decomposition of the carbanion. DFT calculations
were performed to help guide and understand the effect of the X
substituent on the homologation process (M06-2X/6–
Organofluorine compounds are finding increasing applications,
particularly in medicinal chemistry, where replacing a C–H bond
with a C–F bond often provides more potent lead molecules. For
example, mono-, di- and trifluoromethyl groups are frequently
introduced in agrochemicals and pharmaceuticals to enhance
their metabolic stability, lipophilicity, as well as to increase their
binding affinity.1-4 Of these fluoromethyl groups, the introduction
of CF is the most common because of the well-established
3
reactivity of various commercially available reagents (e.g.
Umemoto, Ruppert-Prakash, or Langlois). However, synthetic
routes for direct mono- and difluoromethylation are more limited
3
11G(d,p)+LANL2DZ (5d, 7f), with a polarisable continuum model
-
of solvation [PCM,THF]). MeBpin and [CH(F)Br] were chosen for
the model reaction (Scheme 2A). The lithium cation was not
modelled explicitly as a previous report on related 1,2-migrations
5
(
Scheme 1a). The introduction of CH
2
F or CHF
2
groups at sp2
observed minimal structural differences between the optimized
structures of boronate complexes with and without the cation.21
6
centres usually involves metal catalyzed cross-couplings, while
installation on sp -carbons is mainly achieved by radical mono-
3
and difluoromethylation of alkenes.7-9 As radicals are involved in
these processes, controlling asymmetry is especially
challenging.10-11
Scheme 1. A) Reagents for direct fluoromethylation. B) Initial proposed
stereospecific mono- and difluoromethylation of boronic esters.
[
a]
Dr. V. Fasano, Dr. N. Winter, Dr. A. Noble, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’sClose,Bristol,BS8 1TS (UK)
-
E-mail: v.aggarwal@bristol.ac.uk
Equal contribution
Scheme 2. A) Energy profile for MeBPin homologation with [CH(F)Br] . B) The
relative values using [CH
‡
-
-
-
-
2 2
Br] , [CH(F)Br] and [CF Br] . C) Stability of [CH(F)X]
Supporting information for this article is given via a link at the end of the
document.
towards fluoride elimination.
1
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The DFT calculations suggested that boronate complex IHF would
undergo 1,2-migration (ΔG# = 11.7 kcal mol ) affording the
thermodynamically stable, homologated product IIHF. Boronate IHF
resulted in recovery of the starting material at room temperature
or decomposition at elevated temperatures (100 °C).27 This
indicated that, unlike an aromatic ring, fluorine was not able to
stabilize an incipient negative charge.28 Acidic conditions
-1
can also potentially dissociate back to the carbanion IIIHF
.
2 3 4
(treatment with EtCO H or H PO
)29 were also unsuccessful and
Although we were unable to find a transition state for this
dissociation, it must be higher than the energy of the anion loosely
led mainly to α-elimination. We then considered a radical-based
approach since it is known that fluorine can stabilize an adjacent
radical.30 In particular, Renaud had shown that pinacol boronic
esters could undergo radical-mediated protodeboronation by acid
catalysed transesterification to a catechol boronic ester followed
by oxidation and hydrogen atom transfer.31 To our delight,
following screening of different acid and solvent combinations
(see Table T2 in the SI for full optimisation) we found that using
-1
bound to MeBpin (ΔG = 21.7 kcal mol ), and so homologation
should occur. Calculations were also conducted for difluorinated
-
-
2 2
and non-fluorinated carbenoids [CF Br] and [CH Br] (IIIF2 and
IIIH2, respectively), and clear trends emerged: the more fluorine
atoms attached to carbon the higher the barrier to 1,2-migration
and the lower the barrier to dissociation (Scheme 2B). In fact,
LiCF
making it an unsuitable reagent for the proposed homologation
reaction. Having identified the monofluoro-carbenoid as
2
Br underwent dissociation in preference to 1,2-migration
2 2
TFA and 4-tBu-catechol in CH Cl gave the corresponding
a
alkylfluoride 3 in high yield (Scheme 4). Notably, the reaction had
to be performed under an inert atmosphere otherwise oxidation of
the boronic ester occurred, with subsequent HF elimination
providing the corresponding aldehyde product.
promising candidate, the effect of the X group on α-elimination of
fluoride was evaluated. DFT calculations were performed to
determine ΔG for the equation in Scheme 2C as this would give
an indication of the relative propensity for carbene formation for
different X groups. For the second period elements N, O and F, it
was found that α-elimination of fluoride followed the order N>O>F,
making the most electronegative halide optimum. Moving down
the halogen series, α-elimination of fluoride was less and less
favoured (the reaction became more endothermic), making iodide
optimum. The trend mirrors the mesomeric effect of X to stabilise
a carbene by donating electron density into the empty p-orbital of
Scheme 4. Protodeboronation of 2.
2
the carbene carbon (NR > OR > F > Cl > Br > I). Thus,
fluoroiodomethyllithium emerged as the ideal candidate for the
homologation since (i) iodide is least able to stabilise the carbene,
thereby promoting stability of the carbanion and (ii) iodide is the
optimum leaving group, thereby promoting 1,2-migration. In fact,
Luisi and Pace recently found that fluoroiodomethyllithium was
able to add to carbonyl compounds under Barbier conditions and
gave higher yields than LiCH(F)Br.22
Guided by our computational analysis and the literature
precedent,22-23 we began our investigation by treating a mixture of
boronic ester 1 and fluoroiodomethane with LDA at –78 °C
With our optimised conditions in hand, the substrate scope of the
homologation-protodeboronation sequence was explored,
without purification of the intermediate α-fluoro-boronic ester
(
Scheme 5). NMR and isolated yields over two steps are reported,
with the latter usually being lower due to the increased volatility
caused by the replacement of the boryl moiety with the CH
2
F
group.4 Primary boronic esters bearing different aromatic rings
were initially explored. The two-step process tolerated electron-
poor/neutral (3a-3e) and electron-rich aromatics (3f-3i). Notably,
we observed no competing addition of LiCH(F)I to electrophilic
functional groups, such as methyl esters (3b) and nitriles (3c).22
The homologation-protodeboronation sequence was also
successfully applied to the synthesis of perfluorinated product 3j
but its high volatility complicated its isolation. Amino acid
derivatives were also suitable substrates giving 3k and 3l, the
latter without racemization. Notably, the acid sensitive Boc group
was tolerated during the acidic protodeboronation step. The
methodology could also be extended to secondary boronic esters,
as demonstrated by 3m-3o, although yields tended to be slightly
lower (compare 3f with 3o). Complete stereospecificity was
observed with 3o, thereby providing a route to a chiral fluorinated
isopropyl group. The homologation-protodeboronation sequence
was also applied to biologically relevant molecules such as
derivatives of cholesterol, diosgenin, and lithocholic acid (3p, 3q,
and 3r, respectively). Again, no loss in diastereoselectivity was
observed for 3p and 3q, indicating the stereospecificity of the 1,2-
migration.15-16 Furthermore, functional groups such as alkenes
(
Scheme 3). After optimization we obtained boronic ester 2 in 90%
yield (see Table T1 in the SI for full optimisation). Fluoroboronic
ester 2 was unstable to chromatography, but a simple aqueous
work up gave material of sufficient purity to be used directly in the
subsequent transformations. It should be noted that 2 represents
a unique example of an isolated alkyl α-fluoroboronic ester
outside the tetracoordinated MIDAand trifluoroboronates.24-26 The
ready preparation of these intermediates will now enable their
broader applications in synthesis.
Scheme 3. Homologation of 1 with in-situ generated fluoroiodomethyllithium.
(
3p and 3q), acetals (3q) and silyl ethers (3r) were well tolerated
Having identified
homologation, our attention focused on the subsequent
protodeboronation step which would give access to the CH
functionality. Benzylic boronic esters undergo protodeboronation
using XF/H O (X = Cs, nBu N) but application of these conditions
a suitable reagent and conditions for
under the reaction conditions. However, tertiary boronic esters
were unreactive, probably reflecting a slower rate of boronate
formation and competing decomposition of LiCH(F)I.
2
F
2
4
2
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COMMUNICATION
well (4a-4c), electron deficient aromatics resulted in diminished
reactivity, and so further optimization was conducted (see Table
T4 in the SI for full optimization).
Scheme 6. Fluorodeboronation of 2.
By increasing the stoichiometry of selectfluor and using AgOAc in
place of AgNO enabled the homologation-fluorodeboronation
3
sequence to be extended to primary boronic ester substrates
containing electron-poor aromatic rings (4d-4g) and a range of
other functional groups (4h-4i). A notable example is amino acid
4
h, a bioisostere of homoserine in which the hydroxyl group has
been replaced with the lipophilic H-bond donor CHF . The
2
reaction was also extended to a lithocholic acid-derived boronic
ester, leading to 4i. These conditions were also successfully
applied to secondary boronic esters (4j-4m). Furthermore, the
reaction was fully stereospecific as shown by transforming an
enantioenriched secondary boronic ester into difluoromethylated
product 4l in high enantiomeric excess. The stereospecificity was
also demonstrated in the transformation of a cyclic boronic ester
into 4m. The yield and substrate scope of the homologation-
fluorodeboronation sequence is more limited than the
homologation-protodeboronation, and further methodology
development is currently ongoing in our lab.
Scheme 5. Homologation-protodeboronation scope. 19F NMR yields over two
steps using 1-fluoropentane as standard (in brackets, isolated yields). For 3i,
.
1.5 equiv. of FCH
2
I / LDA and 1 equiv. of MgBr
2
OEt
2
were used in the
homologation, and 1.2 equiv. of TFA were used in the protodeboronation. For
k, the amino alcohol protecting group was lost during the reaction sequence.
3
We then turned our attention to the fluorodeboronation of 2 which
would give access to the CHF functionality. Two procedures
have been reported for the fluorodeboronation of boronic esters:
i) reaction of arylboronate complexes with selectfluor32 and (ii)
reaction of pinacol boronic esters with selectfluor and AgNO
.33
2
(
3
Whilst the first method was unsuccessful, the second method
bore fruit. Through modification of the reported conditions (see
Table T3 in the SI for full optimization) fluorodeboronation of 2 to
the desired product 4 could be realized (Scheme 6). Notably,
reducing the reaction time (usually to 3-4 hours) avoided
unwanted benzylic oxidation of the product 4. Having identified
suitable conditions, we explored the substrate scope of the
homologation-fluorodeboronation sequence, again without
purification of the intermediate α-fluoro-boronic ester (Scheme 7).
Primary boronic esters bearing different aromatic rings were
initially explored. Whilst electron neutral/rich aromatics worked
Scheme 7. Homologation-fluorodeboronation scope. 19F NMR yields over two
steps using 1-fluoropentane as standard (in brackets, isolated yields).
a
b
Selectfluor (2 equiv.), AgNO
3
(20 mol %), TFA (1 equiv.), 4 h. Selectfluor (3
equiv.), AgOAc (1.2 equiv.), 18 hr. c Selectfluor (3 equiv.), AgOAc (3.0 equiv.),
8 hr.
1
3
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COMMUNICATION
In conclusion, a novel conversion of boronic esters into mono- and
difluoromethyl groups has been reported. Guided by DFT
calculations on a series of potential fluorinated carbenoids,
fluoroiodomethyllithium was selected as the ideal reagent for
stereospecific homologation of boronic esters to generate unique
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Keywords: Fluoromethylation • Boronic esters • 1,2-migration •
fluorocarbanion • stereospecificity
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4
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Entry for the Table of Contents
Fluoro divergence: Upon homologation of a boronic ester with fluoroiodomethyllithium, the intermediate α-fluoro-boronic ester can be
converted into -CH F (via protodeboronation) or -CHF (via fluorodeboronation). The choice of the fluorocarbenoid was key to success,
2
2
requiring a substituent that was both a good leaving group and poor at stabilizing a carbene. Exploiting the stereospecificity of the 1,2-
migration, this approach enables complete control of asymmetry.
Researcher Twitter usernames: @AggarwalLab
5
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