gem-Difluorination of Alkenyl N-methyliminodiacetyl Boronates: Synthesis of α- and β-Difluorinated Alkylborons

Article abstract of DOI:10.1002/anie.201810204

Organofluorine compounds are widely used in pharmaceutical, agrochemical, and materials sciences. The syntheses and applications of fluorinated organoborons facilitate the rapid and modular assemblies of fluorine-containing molecules because of the versatility of C?B bonds in diverse chemical transformations. Reported herein is a migratory geminal difluorination of aryl-substituted alkenyl N-methyliminodiacetyl (MIDA) boronates using commercially available Py?HF as the fluorine source and hyperiodine as the oxidant. The protocol offers facile access to α- and β-difluorinated alkylboron compounds, both of which have previously been challenging to prepare. Mild reaction conditions, broad substrate scope, good functional-group tolerance, and moderate to good yields were observed. The utility of these products is demonstrated by further transformations of the C?B bond into other valuable functional groups.

Full text of DOI:10.1002/anie.201810204

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Accepted Article
Title: gem-Difluorination of Alkenyl MIDA Boronates: Synthesis of α-
and β-Difluorinated Alkylborons
Authors: Wen-Xin Lv, Qingjiang Li, Ji-Lin Li, Zhan Li, E Lin, Dong-Hang
Tan, Yuan-Hong Cai, Wen-Xin Fan, and Honggen Wang
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10.1002/anie.201810204
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COMMUNICATION
gem-Difluorination of Alkenyl MIDA Boronates: Synthesis of α-
and β-Difluorinated Alkylborons
Wen-Xin Lv,+ Qingjiang Li,+ Ji-Lin Li, Zhan Li, E Lin, Dong-Hang Tan, Yuan-Hong Cai, Wen-Xin Fan
and Honggen Wang*
Abstract: Organofluorine compounds are widely used in
pharmaceutical, agrochemical and material sciences. The syntheses
and applications of fluorinated organoborons facilitate the rapid and
modular assemblies of fluorine-containing molecules due to the
versatility of C-B bonds in diverse chemical transformations.
Reported herein is a migratory geminal difluorination of aryl-
substituted alkenyl N-methyliminodiacetyl (MIDA) boronates using
commercially available Py·HF as the fluorine source and hyperiodine
as the oxidant. The protocol offers a facile access to α- and β-
difluorinated alkylboron compounds, both of which have previously
been challenging to prepare. Mild reaction conditions, broad
substrate scope, good functional group tolerance, and moderate to
good yields were observed. The utility of these products is
demonstrated by further transformations of the C-B bond to other
valuable functional groups.
an important role in modern organic chemistry.[6] Besides, there
has been an increase in the number of boron-containing drugs in
which the boron motif is the key pharmacophore (Figure 1b).[7]
As such, gem-difluorinated alkylboron compounds[8] should
serve as intriguing synthons for organofluorine synthesis. This
structural motif might also find applications in medicinal
chemistry.
There has been an extraordinary increase in the use of
organofluorines in pharmaceutical, agrochemical and material
industries.[1] The geminal, or 1,1-difluoroalkyl groups,[2]
possessing specific steric and electronic properties, are of
particular importance in medicinal chemistry (Figure 1a). They
can act as chemically and metabolically inert bioisosteres for
alcohols, thiols, and other polar functional groups, bringing about
modulated bioavailability, lipophilicity and improved binding
affinity.[3] As such, substantial research effort has been devoted
to their synthesis.[4] While a number of efficient methods were
known, few methods exist for the synthesis of gem-
difluoroalkanes bearing easily transformable functional groups,
which are important for allowing the rapid assemblies of complex
fluorine-containing molecules in a modular fashion.[5] While
organofluorines are particularly useful, organoborons also play
Scheme 1. Inspirations for the Synthesis of Fluorinated Alkylboranes.
We have been interested in organoboron synthesis via the
oxidative functionalization of an easily accessible alkenyl MIDA
(N-methyliminodiacetyl) boronate.[9] The sp3 hybridized MIDA
boron shows special stability, unique reactivity and was found to
be indispensable in these transformations.[10] Our synthesis of
gem-difluorinated alkylboron compounds was inspired by recent
work from Jacobsen.[11a] In their work, the interaction of the
hypervalent iodoarene (formed in situ via the oxidation of a chiral
aryl iodide) with the styrenyl double bond triggered a sequential
1,2-fluoroiodination and 1,2-aryl migration, leading to an
enantioenriched difluoromethylated product. Yudin[12] and
Burke[13] independently observed a 1,2-boryl migration in their α-
boryl aldehyde synthesis via
a
Lewis acid-promoted
rearrangement of oxiranyl MIDA boronates. It was found that the
MIDA-boryl group migrated in preference to hydride, alkyl and
aryl substituents (Scheme 1b). Based on these elegant works
and the notion that electron-rich sp3-boron centers are capable
of stabilizing the ɑ-cations via hyperconjugation,[14] we
hypothesized that the use of substituted alkenyl MIDA boronates
in the hypervalent iodoarene-mediated 1,1-difluorinative
rearrangement could deliver a difluoromethylated organoboron
via MIDA-boryl migration (Scheme 1c). Interestingly, an
extensive literature review revealed that methods for the
synthesis of β-difluorinated alkylborons were largely
unexplored.[8a] The lack of research regarding this synthesis may
be due to the sensitivity of the C-B(sp2) bond toward both F+ and
F-, when employing a borylated starting material. This can lead
to deborylative fluorination[15] in reaction with F+ and
protodeboronation[16] in reaction with F-. Additionally, syntheses
that begin with a pre-fluorinated substrate, typically via base-
Figure 1. Examples of Bioactive Molecules Containing a CF2 or Boron Moiety.
[*]
[+]
W.-X. Lv,[ +] Prof. Dr. Q. Li,[ +] J.-L. Li, Z. Li, E. Lin, D.-H. Tan, Y.-H.
Cai, W.-X. Fan, Prof. Dr. H. Wang
School of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou, 510006, China
E-mail: wanghg3@mail.sysu.edu.cn
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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14[e]
15[f]
Py·HF (40.0)
Py·HF (40.0)
PIDA
DCM
DCM
70
0
mediated nucleophilic borylation, might result in unproductive β-
F elimination.[17]
mCPBA
To test our working hypothesis, the geminal difluorination
reaction of styrenyl MIDA boronate 1a was first explored by
examining different F sources in the presence of PIFA[18]
(iodosobenzene bis(trifluoroacetate), 1.5 equiv) as the oxidant in
DCM (dichloromethane) at room temperature (Table 1). While
the use of an inorganic F source such as CsF or AgF led to no
reaction (entry 1), the use of Py·HF (20.0 equiv) successfully
produced the corresponding migration product 2a in 62% yield
(entry 2). Further screening revealed that DCM was the
preferred solvent (entries 3-5). Other hypervalent iodine oxidants
such as PIDA (iodobenzene diacetate) or PhIO also worked,
with PIDA producing a slightly higher 65% yield (entries 2, 6 and
7). The loadings of oxidants and fluorine sources were also
examined. Decreasing or increasing the PIDA loading produced
lower yields (28% and 47%; entries 8 and 9). The use of excess
Py·HF, however, improved the yield, with a 40.0 equivalent
loading being optimal (entries 10-13). Remarkably, the reaction
proceeded extremely quickly and was completed within minutes.
Prolonging the reaction time to 5 h, however, resulted in 70%
yields, indicating good product stability (entry 14). Attempts to
use PhI as a catalyst in combination with stoichiometric amounts
of a mCPBA (meta-chloroperoxybenzoic acid) oxidant failed to
give the desired product (entry 15). Instead, an aldehyde was
formed via epoxidation and 1,2-boryl migration.12,13 In addition,
the reaction of sp2 hybridized pinacol styrenylboronates 3 in lieu
of 1a gave fluoroalkene 4, which is assumed to arise from the
elimination of difluorinated intermediate A due to the high
nucleophilicity of the C-B bond, suggesting the importance of
sp3-MIDA boron (eq 1).
[a]General reaction conditions: 1a (0.2 mmol, 1.0 equiv), “F” source, oxidant
(1.5 equiv), solvent (2.0 mL), RT, 1 min. [b]Isolated yield. [c]PIDA (1.2 equiv).
[d]PIDA (2.0 equiv). [e]5 h. [f]PhI (20 mol%) was used. DCE: dichloroethane.
Once the optimized conditions were determined (Table 1,
entry 11), the substrate scope of the gem-difluorination reaction
was explored. The reaction of a series of E-type substituted
styrenyl MIDA boronate were first investigated (Scheme 2). A
number of commonly encountered functional groups such as
halides (2c, 2d, 2e, 2l, 2m, 2n), ester (2f), trifluoromethyl (2g),
and ether (2k) were well tolerated, giving the corresponding
products in moderate to good yields. Unfortunately, the p-NO2
and p-NMe2 substituted substrates failed to give any desired
products (not shown). Of note, a methyl substituent at the ortho
position of the phenyl ring (2o, 2p) did not hamper the reaction
efficiency. Other aryl-substituted alkenyl MIDA boronates, such
as naphthyl (2q) and thienyl-substituted (2r) substrates were
also compatible with the reaction conditions, albeit in lower
yields. It should be noted that for substrates bearing electron-
withdrawing groups, increasing the loading of HF·Py (100 equiv),
prolonging the reaction time, or both were beneficial for ensuring
a higher degree of conversion. Z-Styrenyl MIDA boronate was
also tested and the same product 2a was obtained in 57% yield.
Next, the compatibility of tri-substituted olefins was also
examined (Scheme 2). Surprisingly, substrates substituted with
an additional methyl group (1s-1w) did not delivered the
expected difluoromethylated tertiary alkylboronates. Instead, the
difluoroethyl-substituted benzylic boronates (2s-2w) were
formed. These results indicated that 1,2-aryl migration was
occurring, rather than the expected 1,2-boryl migration. The
diaryl-substituted substrate provided a difluorobenzyl product
(2x) in good yield. The difluoromethylated tertiary alkylboronate
was accessible by installation of a substituent at the position ɑ to
boron (2y).
Table 1. Optimization of the Reaction Conditions.[a]
entry
1
“F” (x equiv)
CsF or AgF (2.0)
Py·HF (20.0)
Py·HF (20.0)
Py·HF (20.0)
Py·HF (20.0)
Py·HF (20.0)
Py·HF (20.0)
Py·HF (20.0)
Py·HF (20.0)
Py·HF (50.0)
Py·HF (40.0)
Py·HF (10.0)
Py·HF (5.0)
oxidant
PIFA
PIFA
PIFA
PIFA
PIFA
PIDA
PhIO
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
solvent
DCM
DCM
DCE
yield (%)[b]
0
2
62
55
45
0
3
4
toluene
MeCN
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
5
6
65
40
28
47
72
75
12
trace
7
8[c]
9[d]
10
11
12
13
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Scheme 2. Synthesis of -Difluorinated Alkylborons. [a]Z-1a was used.
Scheme 4. Synthetic Utility and Product Derivatization. o-DCB: ortho
dichlorobenzene; 1,10-phen: 1,10-phenanthroline; CFL: compact fluorescent
lamp.
[b]HF·Py (100.0 equiv), 10 min. [c]10 min. [d]HF·Py (100.0 equiv), 30 min.
Interestingly, the employment of 1,1-disubstituted alkenyl MIDA
boronates resulted in the chemoselective formation of α-
difluorinated alkylboronates, with no observed formation of -
difluorinated alkylboronates (Scheme 3). It should be noted that
no efficient methods were thus far known to synthesize α-
difluorinated alkylboronates despite their great synthetic
potential.
difluoro-containing compounds. For example, the oxidation of β-
difluorinated alkylboron 2 with H2O2/NaOH gave two α-CF2H
alcohols (8a and 8j) in good yields (Scheme 4b). Ligand
exchanges of 2a were feasible to give the corresponding pinacol
boronic ester 9 and potassium trifluoroboronate 10 in reasonable
yields.19 The oxidative bromination of 10 furnished bromide 11,
which could be applied to nucleophilic substitution reactions to
produce C-N (12 and 13) and C-O (14) bonds. A copper(I)-
catalyzed alkenylation reaction of 11 with styrene also gave an
allylic CF2H-substituted product (15) with good efficiency. In
another vein, trifluoroboronate 10 could undergo a copper-
catalyzed oxidative Heck-type reaction with 1,1-diphenylethene
16.20 And the cross-coupling reaction with bromide 18 was
realized under Molander’s photoredox/nickel dual catalytic
system.21 Likewise, the BMIDA group in ɑ-difluorinated
alkylborons
6
could be converted into its congeners
trifluoroborate 20 and BPin 21 in excellent yields (Scheme 4c).19
21 served as an intriguing synthon for follow-up transformations.
Scheme 3. Synthesis of ɑ-Difluorinated Alkylborons.
A
ɑ-difluorinated alkylbromide 22 was formed via C-B
bromination with CuBr2. The oxidation of 21 with silver(I)
triggered an oxidative radical cyclization of isocyanide 23 to
provide a difluoroalkylated phenanthridine 24. Moreover, a
number of (het)arenes, as represented by benzene (25a),
pyridine (25b), thiophene (25c) and cyclophane (25d), reacted
with 21 to give the benzylic difluorinated arenes by using Ag2O
as the oxidant.22 And as a final example, the use of pinene-
derived iminodiacetic acid ligand rendered a diastereoselective
(dr = 3.8:1) gem-difluorination reaction in good yield (Scheme
4d).
The practicality of the protocol was evidenced by the efficient
gram-scale synthesis of both of the ɑ- and β-difluorinated
alkylboron products under the standard reaction conditions
(Scheme 4a). Synthetic manipulations on the C(sp3)-B(sp3) bond
in the products allowed for the synthesis of diverse
Scheme 5. Mechanistic Studies and Proposed Mechanism.
The reaction of the deuterated alkenyl MIDA boronate 1a
gave
a
difluorinated product with the deuterium atom
incorporated exclusively at the benzylic position (Scheme 5a).
This result unambiguously demonstrated that 1,2-aryl migration
took place. Competition experiments revealed that the MIDA-
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[4]
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boryl group activated the substrate as 1a showed higher
reactivity toward difluorination in comparison with its methyl- (28)
or ester-substituted (29) counterpart (Scheme 5b). Based on
these results and literature precedents,[4c,4e,11,18] the possible
reaction pathways were proposed and outlined in Scheme 5c.
Initially, the interaction between the double bond within styrenyl
MIDA boronate and (difluoroiodo)benzene generated in-situ from
the reaction of PIDA and Py·HF, triggers a regioselective vicinal
fluoroiodination to deliver an intermediate B. The capability of
the aryl group to stabilize the developing benzylic cation
accounts for the observed regioselectivity. Thereafter, the
intramolecular nucleophilic attack of phenyl ring on the C-I bond
leads to the formation of a phenonium ion species C. The
second regioselective fluoride attack results in the ring-opening
of C, which is accompanied by the homotopic 1,2-aryl migration,
providing a β-difluorinated alkylboron. This selectivity may result
from the more eletrophilicity of the carbon bound to a fluorine
atom. Likewise, the reaction of 1,1-disubstituted alkenyl MIDA
boronate first gives arenium cation intermediate D. An open
chain carbocation species E is likely formed before the attack of
fluoride due to the stabilization from both of the attached boron
and fluorine atoms (SN1-like mechanism).
[5]
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In summary, by taking advantage of the unique stability and
reactivity of sp3-MIDA boronates, we developed a regioselective
migratory difluorination reaction of alkenyl MIDA boronates with
Py·HF in the presence of stoichiometric amounts of the oxidant,
PIDA. The protocol enables an unprecedented efficient
construction of both α- and β-difluorinated alkylboron
compounds, depending on the substitution pattern of the starting
materials. Both of these two products are stable to storage for
months under air, and most of them are solid. Broad substrate
scope, good functional-group tolerance and moderate to good
yields were observed. The utility of the products was
demonstrated by further transformations of the C-B bond to
other carbon-carbon and carbon-heteroatom bonds.
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Acknowledgements
Financial support from the National Natural Science Foundation
of China (21472250 and 21502242), the Key Project of Chinese
National Programs for Fundamental Research and Development
(2016YFA0602900) and the National Science and Technology
Major Project of the Ministry of Science and Technology of
China (2018ZX09735010) are gratefully acknowledged.
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Keywords: alkene • difluorination • migration • organoboron •
oxidation
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[19] The corresponding free boronic acids of 2a and 6b are unstable upon
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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W.-X. Lv,+ Q. Li,+ J.-L. Li, Z. Li, E. Lin,
D.-H. Tan, Y.-H. Cai, W.-X. Fan, H.
Wang*
Page No. – Page No.
gem-Difluorination of Alkenyl MIDA
Boronates: Synthesis of α- and β-
Difluorinated Alkylborons
Text for Table of Contents
A migratory geminal difluorination of aryl-substituted alkenyl N-methyliminodiacetyl (MIDA) boronates using commercially
available Py·HF as the fluorine source was reported. The protocol offers an unprecedented opportunity for the synthesis of α-
and β-difluorinated alkylboron compounds, both of which have previously been challenging to prepare. Mild reaction
conditions, broad substrate scope, good functional group tolerance, and moderate to good yields were observed. The utility of
these products is demonstrated by further transformations of the C-B bond to other valuable functional groups.
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