Convenient Preparation and Structure Determination of Air- and Moisture-Tolerant Difluoromethylborates

Article abstract of DOI:10.1002/asia.202000854

Convenient and reliable synthetic methods for difluoromethylborates have been established. The intermediary generated difluoromethylsilicate species from TMSCF₂H (TMS=trimethylsilyl) and potassium tert-butoxide were allowed to react with pinBPh (Me₄C₂O₂BPh) in the presence of 18-crown-6 to give the corresponding borate compound [pinB(Ph)CF₂H]^?K⁺(18-crown-6) as an air- and moisture-tolerant solid. The unambiguously determined crystal structure of [pinB(Ph)CF₂H]^?K⁺(18-crown-6) revealed that the difluoromethylborate unit partially coordinated on the potassium ion. Reaction of [pinB(Ph)CF₂H]^–K⁺(18-crown-6) with potassium difluoride (KHF₂) in acetic acid enabled substitution of the pinacol unit and phenyl group with fluorides, and gave (difluoromethyl)trifluoroborate [F₃BCF₂H]^–K⁺(18-crown-6) in a good yield. The crystal structure of air- and moisture-tolerant [F₃BCF₂H]^–K⁺(18-crown-6), which would be a promising reagent for synthesis of various difluoromethylboron species, showed a polyrotaxane-like polymeric structure based on the K???F interactions between the K⁺(18-crown-6), CF₂H, and BF₃ units.

Full text of DOI:10.1002/asia.202000854

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Accepted Article
Title: Convenient Preparation and Structure Determination of Air- and
Moisture-Tolerant Difluoromethylborates
Authors: Akitaka Yokawa and Shigekazu Ito
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Chemistry - An Asian Journal
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Convenient Preparation and Structure Determination of Air- and
Moisture-Tolerant Difluoromethylborates
Akitaka Yokawa and Shigekazu Ito*
Dedication ((optional))
A. Yokawa, Prof. Dr. S. Ito
Department of Applied Chemistry, School of Materials and Chemical Technology
Tokyo Institute of Technology
2-12-1-H113 Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
E-mail: ito.s.ao@m.titech.ac.jp
Homepage: http:/www.apc.titech.ac.jp/~sito/
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Convenient and reliable synthetic methods for
science.[4] Recently, boron compounds bearing the fluoroalkyl
difluoromethylborates have been established. The intermediary
group(s) are of interest and useful for novel synthetic
methodologies and materials development. Figure 1 shows
examples of perfluoroalkylborates. Trimethoxy(trifluoromethyl)
generated difluoromethylsilicate species from TMSCF
trimethylsilyl) and potassium tert-butoxide were allowed to react with
pinBPh (Me BPh) in the presence of 18-crown-6 to give the
corresponding borate compound [pinB(Ph)CF
an air- and moisture-tolerant solid. The unambiguously determined
2
H (TMS =
C O
4 2 2
borate
A[5]
can
be
utilized
for
copper-mediated
–
+
trifluoromethylation of aryl iodides[5a,b] and nucleophilic
2
H] K (18-crown-6) as
trifluoromethylation.[ Besides CF
5c]
, various perfluoroalkyl groups
construct the corresponding
and the related boron
3
-borazine derivative B can be prepared via
3
–
+
crystal structure of [pinB(Ph)CF
2
H] K (18-crown-6) revealed that the
are
trimethoxy(perfluroalkyl)borates
compounds.[6] The CF
3 3
activation of fluoroform (HCF ) and is useful as a CF source.
available
to
[
5b]
difluoromethylborate unit partially coordinating on the potassium ion.
–
+
Reaction of [pinB(Ph)CF
KHF ) in acetic acid enabled substitution of the pinacol unit and
phenyl group with fluorides, and gave (difluoromethyl)trifluoroborate
2
H] K (18-crown-6) with potassium difluoride
–
[7]
(
2
The BODIPY derivative C would be useful as a fluorescent
material.[8] The boron 1,3-diketonate D works as a biocompatible
oxidation catalyst of amyloid peptide under near-infrared light
irradiation.[
–
+
[
F
3
BCF
2
H] K (18-crown-6) in a good yield. The crystal structure of air-
–
+
and moisture-tolerant [F
3 2
BCF H] K (18-crown-6), which would be a
9]
promising reagent for synthesis of various difluoromethylboron
species, showed a polyrotaxane-like polymeric structure based on the
+
K···F interactions between the K (18-crown-6), CF
2
H, and BF
3
units.
CF3
B
N
B
N
B
(
MeO) B CF
3
3
N
N
B
Introduction
N
F CF3
Developing synthetic methodologies for organofluorine
compounds has been important because introduction of the
fluorinated functional groups has been quite useful for medicinal,
agrochemical, and materials researches. The introduction of
fluoro-functional groups into the lead or seed organic compounds
has been one of the required approaches to improve/express the
desired properties.[1] For example, the C–F bond length of 1.39 Å
is much smaller than that of the C–C bond of 1.54 Å, and is
comparable with the C–O bond. Such structural property of the
C–F bond has been utilized as an isosteric and isopolar
replacement for the hydroxy (OH) group in biologically relevant
A
B
C
N
N
CO H
2
5
Br
O
O
B
F C2F5
D
2
molecules. Similarly, the difluoromethyl (CF H) group has been
Figure 1. Examples of perfluoroalkylated borates.
used as isosteric and isopolar replacement with respect to
carbonyl group, and furthermore, bioisosteric and isopolar with
respect to the hydroxy and thiohydroxy (SH) groups. In addition,
the difluoromethyl-substituted compounds exhibit enhanced
hydrophobicity and lipophilicity leading to unique physicochemical
and biological properties.[2]
On the other hand, examples of the difluoromethyl-substituted
borate derivatives have been limited so far. Reaction of
icosahedral dicarba-closo-dodecaborane with difluorocarbene
[10]
was reported in 1987.
Recently, Szymczak and co-workers
Also, chemistry of organoboron compounds has been of great
interest from the views of organic synthesis[3] and materials
synthesized difluromethylborazine E and azaborinines F via
activation of difluoromethane (Figure 2).[11] In contrast to B, E did
1
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Chemistry - An Asian Journal
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not work as the fluoroalkyl source well, and only the unsaturated
version of F permitted transfer of CF
2
H– into the palladium(II)
be responsible to provide the difluoromethylborate product.
Subsequent screening of the reaction time (Entries 10-13)
centre.
concluded that the reaction time of 1 h was optimal for the reaction
–
of 2 and the [Me
3
Si(CF
2
H)
2
] intermediate, and 3 was generated
almost quantitatively and isolated in 82% yield (Entry 11).
Reduction of the reaction time decreased the yield of 3 (Entries
CF H
2
CF H
CF H
B
2
2
N
B
N
B
12, 13). The reaction in the absence of 18-crown-6 could not
B
N
B
N
Dipp
Dipp
–
N
3 2 2
generate 3 probably due to the instability of [Me Si(CF H) ]
N
(
Entry 14). Attempted synthesis of 3 by using E and 2f has been
unsuccessful.
E
F
G
Figure 2. Difluromethylborates E and F, and difluoromethylborane G. Dipp =
,6-iPr
2
2 6 3
C H .
Table 1. Reactions of difluoromethyltrimethylsilane (1) and boron reagents.
The limited examples of difluoromethylborates prompted us to
synthesize novel CF H-substituted borates that are useful for
synthesis of difluoromethyl-substituted compounds. In addition,
the BCF H moiety would be useful for developing biologically
t
KO Bu (1 eq)
2
1
8-crown-6 (1 eq)
TMSCF H
+
BX3
X B–CF H
2
2
2
THF
2
1
Temp., Time
1
eq
relevant molecules. We previously reported synthesis of the
2
eq
difluoromethylboron compound G by using the borylanion for the
C–F activation process,[12] but conversion of
G
into the
Entry]
BX
3
Temp.
Time
2 h
Result
corresponding borates have been difficult probably due to the
sterically bulky N-containing unsaturated heterocyclic system
1
2
3
4
5
6
7
8
9
B(OMe)
3
(2a)
–78 °C
decomp.
decomp.
decomp.
decomp.
decomp.
protecting the B–CF
alternative and
difluoromethylborates.
2
H unit. Therefore, we decided to explore
reliable synthetic methods for
i
pinB-OPr(2b)
–40 °C to r.t.
–40 °C to r.t.
–40 °C to r.t.
–40 °C to r.t.
–40 °C to r.t
–40 °C to 0 °C
–40 °C to –20 °C
–40 °C to r.t
–40 °C to 0 °C
–40 °C to 0 °C
–40 °C to 0 °C
–40 °C to 0 °C
–40 °C to r.t.
2 h
2c
2 h
In this paper, we demonstrate efficient and convenient synthetic
procedures for novel difluoromethylborates that are promising for
B(OPh)
3
(2d)
2 h
developing
novel
difluromethylation
and
functional
catB-Ph (2e)
2 h
difluoromethylboron compounds. Crystal structures of the
difluoromethylborate derivatives showing such as the
polyrotaxane-like assembly are also discussed.
pinB-Ph (2f)
2 h
3 (80% yield)[a]
3 (86% yield)[a]
2f
2 h
2f
2 h
3 (68% yield)[a]
3 (30% yield)[a]
3 (82% yield)[a]
2f[b]
2f
2 h
Results and Discussion
10
11
12
1.5 h
1 h
In the synthesis of A, trifluoromethyltrimethylsilane (Ruppert-
2f
3 (97 yield)[a,c]
Prakash reagent, TMSCF
3
) has been utilized. Analogously, we
commenced to examine reactions of difluoromethyltrimethylsilane
3 (68% yield)[a]
2f
30 min
15 min
2 h
(
(
1) and B(OMe)
KO Bu) and 18-crown-6
3
(2a) in the presence of potassium tert-butoxide
3 (76% yield)[a]
t
[13]
13
2f
over the period of 2 h. In these
conditions, the desired difluoromethylborate compound was not
obtained, and the decomposition product (difluoromethane,
14
2f[d]
decomp.
2 2
CF H ) was observed in the reaction mixture (Table 1, Entry 1).
a] Determined by 19F NMR. [b] 1 eq of 1 was used. [c] 82% isolated yield. [d]
[
Screening the base reagents for reaction of 1 and 2a resulted in
fail (Table S1). Because 2a was not suitable for synthesis of
difluoromethylborates, we next employed several boron reagents
Without 18-crown-6.
t
in the presence of 1, KO Bu, and 18-crown-6. As shown in Table
OMe
i
O
O
O
1
, pinBOPr (2b) methoxy boroxine (2c), B(OPh)
3
(2d), and
B
B R
O
O
B
O
B Ph
catBPh (2e) did not give the corresponding difluoromethylborate
compounds (Entries 2-5). On the other hand, to our delight,
reaction of 1 with pinBPh (2f) gave the desired difluoromethylation
product 3 in 80% yield (Entry 6). Screening the temperatures was
successful (Entries 7,8) to improve the yield up to 86% (Entry 7),
indicating that the temperatures between –40 °C to 0 °C were
suitable for the interaction between 2f and the
difluoromethylsilicate species. Reduction of the amount of 1
reduced the yield (Entry 9), indicating that only the
B
MeO
O
OMe
i
2
2
b: R = OPr
f: R = Ph
2c
2e
O
O
Ph
MeO
+
Ph
K (18-crown-6)
B
B
K+
CF2H
MeO CF3
–
[13]
bis(difluoromethyl)silicate [Me
3
Si(CF
2
H)
2
]
intermediate
might
3
4
2
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Chemistry - An Asian Journal
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FULL PAPER
a)
b)
The difluoromethylborate-potassium salt
3
is
a
colorless
O
O
Ph
KHF2 (6.5 eq)
F
F
F
B
B
crystalline compound, and can be handled in air and moisture. In
contrast to A, 3 was not hygroscopic. The structure of 3 was
characterized by the spectroscopic data. Furthermore,
recrystallization from toluene and hexane was successful, and the
crystal structure of 3 was confirmed by X-ray diffraction analysis
CF2H
AcOH
50 °C to 80 °C, 4 h
CF H
2
+
+
K (18-crown-6)
K (18-crown-6)
84%
3
5
O
Ph
(
Figure 3). Whereas all the oxygen and fluorine atoms in 4
O
F
Ph
H+
F–
B
F
Ph
B
3
showed interactions with the potassium cations in the crystalline
B
O
H
CF2H
CF H
2
state,[14] only two heteroatoms in the pinBCF
H unit of 3
OH
–pinacol F CF H
2
2
+
coordinate on the K (18-crown-6) ion. One of the oxygen atoms
in the 5-membered ring (O1) coordinates on the potassium ion,
and correspondingly the B1–O1 distance is elongated compared
with the B1–O2 bond. The C1–F1 distance is slightly larger than
the C1–F2 length due to the F1···K1 interaction.
H+
F–
C H
F
F
H
B
5
–
6
6
CF H
2
Scheme 1. A) Preparation of (difluoromethyl)trfluoroborate 5 from 3. b) Possible
reaction mechanisms for the substitution process providing 5 under the acidic
conditions.
The structure of 5 was characterized by the spectroscopic data.
Table 2 indicates that the experimentally determined NMR
parameters of 5 are comparable with the GIAO chemical shifts of
[
F
3
BCF
2
H]–.
Thus,
5
would
provide
the
(
difluoromethyl)trifluoromethyl anion in the homogeneous solution.
Furthermore, the crystal structure of 5 was confirmed by X-ray
diffraction analysis. Figure 4a displays the principal unit for the
one-dimensional polymeric structure of 5 in the crystalline state.
2 3
Both the CF H and BF groups interact with the potassium ions to
generate the string, and the 18-crown-6 rings construct the
polyrotaxane-like structure (Figure 4b). Two fluorine atoms in the
Figure 3. Molecular structure of 3 (40% probability level). Hydrogen atoms
except for H1 are omitted for clarity. The oxygen atoms in the crown ether ring
are displayed as reddish balls. Selected bond lengths (Å): B1–C1 1.619(7), B1–
C8 1.624 (6), B1–O1 1.498(6), B1–O2 1.475(6), C1–F1 1.406(5), C1–F2
3
BF unit interact with the potassium ion. The potassium-
coordinated fluorine atoms in the difluoromethyl groups are
disordered, and the metric parameters should not be discussed in
detail. Nevertheless, it is obvious that the one-dimensional
coordination polymer structure is constructed by the F···K
interactions. In addition, the crystal structure of 5 would be helpful
not only to understand the physical and chemical properties but
also to design novel functional materials based on the linearly
assembled difluoromethylboron units accompanying the 18-
crown-6 rings.
1.399(5), O1–K1 2.637(3), F1–K1 3.020(3).
The difluoromethylborate-potassium salt 3 is a promising reagent
for the difluoromethylation reactions. Also, 3 would be useful for
synthesis of organoboron compounds bearing the BCF
In this study, we attempted conversion of the pinBPh unit in 3
affording the BF moiety. To our delight, treatment of 3 with
potassium bifluoride (KHF ) in acetic acid afforded the desired
2
H unit(s).
3
2
product 5 in a good yield (Scheme 1a). In this reaction, even the
phenyl group was eliminated as benzene probably due to the
proton, and the substitution reaction with fluorides proceeded to
Table 2. Experimental NMR chemical shifts and GIAO results for 5
give
the
trifluoroborate
unit
(Scheme
1b).
The
Experimental[a]
GIAO[b]
(
difluoromethyl)trifluoroborate-potassium salt 5 is an air- and
moisture-tolerant solid, and no decomposition of crystalline 5 was
observed under 1 week exposure to air and moisture.

F

F

B

H
(CF
2
H)
–141.2[c]
–156.7
–0.53[d]
5.55
–149.8
–169.5
–1.06
5.53
(BF
3
)
2
(CF H)
–
[
3
a] In CDCl
11+G(d), IEFPCM = chloroform. [c] Average of –141.9 - –142.5 (m). [d]
Average of +0.76 - –1.29 (m).
3 3 2
at 298 K. [b] [BF CF H] : B97XD/6-311++G(2d,p)//B97XD/6-
3
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Chemistry - An Asian Journal
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FULL PAPER
a)
to –60 °C. Potassium tert-butoxide (112 mg, 1.0 mmol) was added in one
portion, and the mixture rapidly stirred for 20 min. 4,4,5,5-Tetramethyl-2-
phenyl-1,3,2-dioxaborolane (2f, 204 mg, 1.0 mmol) was added and the
solution stirred at 0 °C for 1 h. The solution was poured into 20 mL hexane
and stirred at room temperature for 5 min. The suspension was filtered and
washed with hexane (20 mL x 2) twice. After the residue was dried in vacuo,
recrystallization from toluene to afford the title compound as colorless
needles (452 mg, 82%). Single crystals for X-ray crystallography were
obtained by recrystallization from toluene/hexane (1:1). 1H NMR (CDCl
,
3
b)
2
3
00 MHz)  0.98 (s, 6H), 1.19 (s, 6H), 3.55 (s, 24H), 5.68 (t, JHF = 50.6
19
Hz, 1H), 6.97–7.13 (m, 3H), 7.67–7.69 (m, 2H); F NMR (CDCl
3
, 282
, 96 MHz)  2.92
, 75 MHz)  26.5, 26.6, 70.0, 78.3, 123.8, 125.9,
H and Cipso were not determined). HRMS (ESI) calcd for
[M+K(C12
)]+ 861.3788, found 861.3927.
MHz)  –132.1 (d, JFH = 50.0 Hz); 11B{ H} NMR (CDCl
2
1
3
13
1
(
brs); C{ H} NMR (CDCl
3
1
32.7 (CF
2
C H66BO14F K
37 2 2
24 6
H O
Figure 4. a) A drawing of the principal unit of 5 (40% probability level). Hydrogen
atoms are omitted for clarity. The oxygen atoms in the crown ether ring are
displayed as reddish balls. The potassium-coordinated fluorine atoms in the
CF H groups are disordered, and one of the atoms are displayed. b)
2
Coordination polymer structure along the a axis.
Preparation of 5: A solution of KHF
2
(240 mg, 3.1 mmol) and 3 (279 mg,
0.50 mmol) in glacial acetic acid (3 mL) was stirred at 50 °C for 1 h and
then for 3 h at 80 °C. All volatiles were removed in vacuo. The solution was
poured into 20 mL hexane and stirred at room temperature for 5 min to
remove residual AcOH. The suspension was filtered and washed with
hexane. After the residue was dried in vacuo, to the residue was added
2 2
CH Cl (10 mL). The resulting suspension was filtered through a pad of
Celite. After the solvent was removed in vacuo, 5 was obtained as
colorless powder (177 mg, 84%). Single crystals of 5 were obtained by
Conclusion
In conclusion, we have developed convenient and reliable
synthetic methods for difluoromethylborates. Using TMSCF H (1)
2
adding hexane to diffuse into a saturated solution of 5 in CH
CDCl
, 300 MHz)  5.55 (t, 2 HF = 48.9 Hz, 1H); 19F NMR (CDCl
MHz)  –141.9 - –142.5 (m, 2F), –156.7 (q, 1JFB = 47.4 Hz, 3F); B{ H}
2 2
Cl
. 1H NMR
, 282
(
3
J
3
11
1
and pinBPh (2f) as the difluoromethyl and borate source,
respectively, reaction in the presence of potassium tert-butoxide
and 18-crown-6 provided the air- and moisture-tolerant crystalline
13
1
NMR (CDCl
70.2 (CF H was not determined); HRMS (ESI) calcd for C25
M+K(C12
)]+ 725.2511, found 725.2478.
3 3
, 96 MHz)  0.76 - –1.29 (m); C{ H} NMR (CDCl , 75 MHz)

2
5 2
H49BO12F K
[
24 6
H O
–
+
difluoromethylborate-potassium
salt
2
[pinB(Ph)CF H] K (18-
crown-6) (3). The structure of 3 was unambiguously determined.
Reaction of 3 with potassium difluoride under the acidic conditions
provided the (difluoromethyl)trifluoroborate-potassium salt
X-ray crystallographic data of 3: C25
dimensions = 0.240 x 0.190 x 0.180 mm , orthorhombic, Pna2
25.3335(13), b = 11.0549(5), c = 10.5058(5) Å, V = 2942.2(2) Å
= 166 K,  = 0.71075 Å, calc = 1.261 g m–3, µMoK = 0.236 mm–1, F000
1192, –32≤h≤32, –14≤k≤14, –13≤l≤13, 46413 total reflections (2max
H
42BF
2
KO
8
M
W
= 558.49, crystal
(#33), a =
, Z = 4, T
3
1
3
–
+
[
F
3
BCF
2
H] K (18-crown-6) (5). The X-ray diffraction data of 5
=
=
revealed the polyrotaxane-like pone-dimensional polymer
structure via the K···F interactions accompanying the 18-crown-6
rings. Attempted difluoromethylation and synthesis of
difluoromethylboron compounds starting from 3 and 5 are in
progress.
54.97°), 6652 unique (Rint = 0.1068), R = 0.0552 (>2(I)), 0.0847 (all
data), wR2 = 0.1379 (>2(I)), 0.1513 (all data), S = 0.788 (338
parameters). CCDC-2017876.
X-ray crystallographic data of 5: C13
H
25BF
5
KO
6
M
W
= 422.24, crystal
/c (#14), a =
3
dimensions = 0.230 x 0.210 x 0.090 mm , monoclinic, P2
1
1
5,6623(11), b = 16.2557(11), c = 17.1082(18) Å,  = 117.174(2)°, V =
3
–3
Experimental Section

3875.0(6) Å , Z = 8, T = 172 K,  = 0.71075 Å, calc = 1.448 g m , µMoK =
–1
0.346mm , F000 = 1760, –18≤h≤20, –21≤k≤20, –22≤l≤22, 60325 total
reflections (2max = 54.97°), 8615 unique (Rint = 0.0474), R = 0.0666
(>2(I)), 0.1041 (all data), wR2 = 0.1608 (>2(I)), 0.1890 (all data), S =
1.053 (489 parameters). CCDC-2017877.
All experiments were carried out under inert atmosphere (argon) unless
otherwise noted. 1H NMR, 13C NMR, 19F NMR, and 11B NMR spectra were
measured on a Bruker Avance 300 spectrometer. Chemical shifts of 1H
NMR were expressed in parts per million downfield from CHCl
internal standard ( = 7.26) in CDCl , C as an internal standard ( =
. Chemical shifts of C NMR were expressed in parts per
million downfield from CDCl as an internal standard ( = 77.16) in CDCl
as an internal standard ( = 128.4). Chemical shifts of 19F NMR were
expressed in parts per million downfield from benzotrifluoride as an internal
standard ( = –63.24) in CDCl
. Chemical shifts of 11B NMR were
expressed in parts per million downfield from BF /OEt as an external
standard ( = 0) in CDCl . Mass spectra were measured on a JEOL JMS-
T100LC spectrometer. TMSCF (1) was prepared from TMSCF
3
as an
3
6 6
H
1
3
7
6 6
.16) in C D
Acknowledgements
3
3
,
6 6
C D
This work was supported in part by Grants-in-Aid for Scientific
Research (No. 19H02685) from the Ministry of Education, Culture,
Sports, Science and Technology, and Nissan Chemical
Corporation.
3
3
2
3
2
H
3
[
15]
according to the literature. X-ray diffraction data were measured on a
Rigaku RAXIS-RAPID diffractometer. The structures were solved by a
direct method (SHELXL-2014).[16] The X-ray structure solution and
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Keywords: difluoromethyl compounds • borates • substitution
reactions • crystal structures • coordination polymers
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Entry for the Table of Contents
t
TMSCF H
2
KO Bu
O
O
Ph
18-crown-6
KHF2
F
F
+
B
F
K+
F B C
F
O
THF
CF H AcOH
2
H
B-Ph
+
n
K (18-crown-6)
O
t
2
The difluoromethylsilicate species, generated from TMSCF H and KO Bu, reacts with pinB-Ph in the presence of 18-crown-6 to give
–
+
–
+
[
pinB(Ph)CF
2 2 2
H] K (18-crown-6) as an air- and moisture-tolerant solid. Reaction of [pinB(Ph)CF H] K (18-crown-6) with KHF in acetic
–
+
acid gave the difluoromethylated trifluoroborate [F
3
BCF
2
H] K (18-crown-6) showing the polyrotaxane-like linear structure.
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