Benzosiloxaboroles: Silicon Benzoxaborole Congeners with Improved Lewis Acidity, High Diol Affinity, and Potent Bioactivity

Article abstract of DOI:10.1021/acs.organomet.5b00265

(Figure Presented). The synthesis and physicochemical properties of benzosiloxaboroles, the silicon analogues of an important class of heterocyclic compounds - benzoxaboroles - is presented. They were prepared by halogen-lithium exchange reactions of (2-b

Full text of DOI:10.1021/acs.organomet.5b00265

Article
pubs.acs.org/Organometallics
Benzosiloxaboroles: Silicon Benzoxaborole Congeners with
Improved Lewis Acidity, High Diol Affinity, and Potent Bioactivity
†
‡
,†
†
§
́
Aleksandra Brzozowska, Paweł Cwik, Krzysztof Durka,* Tomasz Klis, Agnieszka E. Laudy,
́
Sergiusz Lulinski,*,† Janusz Serwatowski,† Stefan Tyski,§,⊥ Mateusz Urban,† and Wojciech Wroblewski‡
†Physical Chemistry Department and Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology,
́
́
‡
Noakowskiego 3, 00-664 Warsaw, Poland
§
̇
Department of Pharmaceutical Microbiology, Medical University of Warsaw, Zwirki i Wigury 61, Warsaw, Poland
⊥National Medicines Institute, ul. Chełmska 30/34, 00-725 Warsaw, Poland
S
* Supporting Information
ABSTRACT: The synthesis and physicochemical properties of benzosiloxaboroles, the silicon analogues of an important class of
heterocyclic compoundsbenzoxaborolesis presented. They were prepared by halogen−lithium exchange reactions of (2-
bromophenyl)boronates with n-BuLi followed by the silylation or boronation of (2-lithiophenyl)dimethylsilanes. The cyclization
of the resulting 2-(dimethylsilyl)phenylboronates apparently occurs through intramolecular dehydrogenative cyclization reaction
in the presence of water. Unlike the case for benzosiloxaborole, the formation of its analogue containing a thiophene ring is
thermodynamically unfavorable, which was confirmed by theoretical calculations. The presence of a B−O−Si linkage results in
increased Lewis acidity with respect to the analogous benzoxaboroles. The acidity is strongly enhanced by fluorination or
introduction of phenyl groups at the silicon atom. Selected compounds show good antifungal activity, and thus they are potential
small-molecule therapeutic agents. They can also serve as effective receptors for biologically relevant diols under neutral pH
conditions.
chemistry.3−5 Their superior diol-binding properties under
INTRODUCTION
■
neutral aqueous conditions have been extensively exploited for
1,3-Dihydro-1-hydroxy-2,1-benzoxaborole (I) and its deriva-
applications in sugar sensing6 and column chromatography for
tives were synthesized and characterized in 1957 (Chart 1).1
separation of the nucleosides or glycoproteins.7 These boron
However, only recently has great attention been paid to this
heterocycles emerged as novel small-molecule therapeutic
agents possessing very good antibacterial,8 antifungal,9 and
group of heterocyclic compounds. Apart from their use as
organoboron partners for Suzuki−Miyaura cross-coupling,2
benzoxaboroles have been successfully employed in medicinal
anti-inflammatory10 bioactivity and concomitant low toxicity.
For instance, 5-fluoro- and 5-chloro-1,3-dihydro-2,1-benzox-
aborole (referred to as AN2690 and AN2718, respectively)
were identified as potent antifungal agents against infection of
the nails (dermatophytic onychomycosis).11 Other benzox-
aboroles are also effective against other important human
diseases, including human African trypanosomiasis (HAT,
known as sleeping sickness),12 malaria,13 and some liver
dysfunctions.14 Recent intensive efforts have resulted in the
Chart 1. General Structures of 1-Hydroxybenzoxaborole and
1-Hydroxybenzosiloxaborole
Received: March 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b00265
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Scheme 1. Synthesis of Benzosiloxaboroles 3a−f
preparation of over 6000 benzoxaborole derivatives. However,
there are only a few examples of related systems where the five-
membered boraheterocycle is fused with a benzene ring. These
include benziodoxaboroles15 with a hypervalent iodine atom as
a part of the borole ring, benzophosphoxaborole featuring a B−
O−O−C peroxo moiety in the pinacol ring,16 and benzox-
adiborolescyclic semianhydrides of 1,2-phenylenediboronic
acidsinvestigated by us in detail recently.17 To extend
chemistry to this rapidly growing area, we have turned our
attention to silicon-based analogues of benzoxaboroles
benzosiloxaboroles (II). Herein, we report on their preparation
and physicochemical characterization, including an evaluation
of Lewis acidity. Specifically, the latter point is relevant to
further studies on the bioanalytical applications and biological
activity of these compounds.
which implies that intermediate (2-bromo-3,4,5,6-
tetrafluorophenyl)diorganosilanes were not isolated prior to
the Br/Li exchange and boronation. The overall reaction yields
for all studied benzosiloxaboroles were in the range 42−62%,
and their structures were confirmed by multinuclear (1H, 13C,
11B, 19F) NMR spectroscopy. The 29Si{1H} NMR spectra were
recorded for 3a,c,e showing resonances at 22.3−23.0 ppm: i.e.,
in the range observed for many C3SiO-type compounds (ca. 0−
50 ppm).19 The downfield shift with respect to the signal for
the compound (Me3SiO)3B also featuring a B−O−Si linkage
(29Si 12.3 ppm20) may be due to the strain of the five-
membered silaheterocycle.
The formation of the siloxaborole heterocycle apparently
occurs via an intramolecular dehydrogenative condensation in
the presence of water. It was already demonstrated that the Si−
H bond in arylsilanes can be activated due to an interaction
with the Lewis acidic boron-based group located at the ortho
position of the aromatic ring.21 The formation of the Si−H···B
bridge makes the silicon atom more susceptible to coordination
with a water molecule. Thus, the elimination of H2 can be
interpreted in terms of an attack of the proton from the
oxonium moiety on the hydrido ligand at the pentacoordinate
silicon center according to the mechanism proposed for
hydrolysis and alcoholysis of 2-(dimesitylboryl)(dimethylsilyl)-
benzene.22 However, the intramolecular cyclization leading to
5-mesityl-2,2-dimethyl-3,4-benzo-1,2,5-oxasilaboracyclopentene
was a minor pathway, as it required the cleavage of a relatively
inert B−mesityl bond. Hence, a dimeric species featuring the
Si−O−Si linkage was formed as a major product. In contrast,
the condensation of BOH and SiOH moieties is apparently
favored.
RESULTS AND DISCUSSION
■
Synthesis. Two general approaches for the preparation of
benzosiloxaboroles were elaborated. The first method involved
the addition of R2Si(H)Cl (R = Me, Ph) to 2-(2′-lithiophenyl)-
butyl-1,3,6,2-dioxazaborocan or its fluorinated analogue (both
generated by Br/Li exchange reactions as described pre-
viously17,18) at −90 °C (Scheme 1). Alternatively, (2-
bromophenyl)dimethylsilane (1a) and its fluorinated derivative
1b were subjected to Br/Li exchange reactions followed by
boronation. The resultant (2-(diorganosilyl)phenyl)boronates
were hydrolyzed with dilute acid to give the final benzosilox-
aboroles with concomitant evolution of dihydrogen. The
isolation of pure siloxaboroles 3a−c from hydrolyzed reaction
mixtures was aided by the precipitation of the respective chelate
complexes 2a−c with 2-(N,N-dimethylamino)ethanol
(DMAE). The formation of complex 2a was confirmed by X-
ray diffraction (Figure S54a, Supporting Information). Com-
plexes 2a−c can be then deprotected with dilute acid to recover
the sufficiently pure products 3a−c in good yields. 5,6-
Difluorobenzosiloxaborole 3d was obtained without the need
for the isolation of an intermediate DMAE complex. 4,5,6,7-
Tetrafluorobenzosiloxaboroles 3e,f were accessible via a simple
one-pot synthesis from 1,2-dibromo-3,4,5,6-tetrafluorobenzene,
It seems that the close vicinity of these groups is crucial for
the formation of the siloxaborole heterocycle. This was
confirmed by theoretical calculations (B3LYP/aug-cc-pVDZ),
which indicate that the dehydrative cyclization leading to 3a,e is
thermodynamically favored (Table 1). A similar effect is
observed for the corresponding benzoxaboroles. However,
this is in contrast with the case for the thiophene-based
analogue 4 (Scheme 2), where boron and silicon atoms are
B
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Article
Table 1. Results of Quantum-Chemical Calculations
(B3LYP/aug-cc-pVDZ) of Dehydrative Cyclization versus
Dimerization in Selected Benzoxaboroles snd
a
Benzosiloxaboroles
Figure 1. Superimposed 19F NMR spectra of 3c in D2O solutions
under varying pH conditions.
3a
3e
4
BnBO
4FBnBO
ΔG1
ΔG2
−23.7
−29.3
10.0
−28.3
−31.2
2.1
3.8
−19.4
25.2
27.0
Cleavage of Siloxaborole Ring. It was reported that
ortho-silylated phenylboranes act as bidentate Lewis acids
capable of binding the fluoride anion through the formation of
a B−F−Si bridge, which is driven by the high thermodynamic
strength of B−F and Si−F bonds.23 This has prompted us to
investigate the interaction between the selected benzosilox-
aborole 3d and aqueous KHF2 as a source of F−. Specifically, it
was interesting to check whether the B−O−Si linkage will be
cleaved upon the addition of KHF2. Indeed, we found that both
the boron and silicon atoms were effectively fluorinated to give
the fluoroborate salt [2-(FMe2Si)-4,5-F2C6H2BF3]K (6) as the
sole product in good yield (Scheme 3). The 29Si{1H} NMR
a
ΔG values are given in kJ/mol.
Scheme 2. Synthesis of 2-
[(Hydroxy)diphenylsilyl]thiophene-3-boronic Acid 4 and Its
BDEA Ester 5
Scheme 3. Cleavage of Siloxaborole Ring in 3d with KHF2
more separated due to a wider angle between C−B and C−Si
vectors. Thus, the cyclization through the formation of a B−
O−Si linkage is disfavored in this case, as it would introduce a
remarkable strain to the resulting structure. On the basis of the
calculations, 4 tends to form a diboronic acid via formation of a
siloxane linkage, but it could not be isolated in a well-defined
form. However, we obtained its crystalline complex 5 with N-
butyldiethanolamine (BDEA) featuring a (hydroxyl)-
diphenylsilyl group (for details on its crystal structure see the
Supporting Information).
spectrum of 6 in acetone-d6 shows a doublet (1JSiF = 267.0 Hz)
at 18.0 ppm: i.e., in the range expected for a tetracoordinate
silicon atom. It is noticeable that in the 1H NMR spectrum of 6
the signal of methyl groups appears as a doublet of quartets due
to a vicinal coupling (3JHF = 8.0 Hz) with the Si-bound fluorine
and an apparent through-space coupling (6JHF = 1.5 Hz) with
the B-bound fluorine atoms. Accordingly, a doublet of quartets
The chemical integrity of siloxaborole ring in D2O solutions
1
was studied by performing H and 19F NMR analyses of 3c
over a wide range of pH (Figure 1). The 19F NMR spectrum of
3c under acidic conditions exhibits a signal at −104.3 ppm
corresponding to the neutral form of 3c. In pure D2O the major
peak at −104.3 ppm is accompanied by a less intense resonance
at −106.3 ppm, which indicates that 3c coexists in the
equilibrium with its anionic form (3c·OH−) in a proportion of
5
(2JCF = 17.0 Hz, JCF = 4.5 Hz) of the methyl carbon at −0.1
ppm is observed in the 13C NMR spectrum. This may suggest
that the preferred conformation features intramolecular (Si)C−
H···F−B contacts. It should be stressed that there is no
evidence for the formation of a Si···F−B bridge even at lower
1
5:1. The H NMR spectrum features broad signals of aromatic
−
and methyl hydrogen atoms. Under weakly basic conditions
(D2O/NaHCO3), the anionic form strongly prevails. In D2O/
NaOH a single 19F NMR resonance of 3c·OH− at −105.7 ppm
is observed and, accordingly, well-resolved resonances appear in
temperature (−50 °C). However, the signal of BF3 fluorine
atoms in the 19F NMR spectrum becomes broad and loses its
quartet structure, which may point to the partially restricted
rotation of the trifluoroborate group around the C−B bond at a
lower temperature. The crystal structure of 6 features the
presence of two molecules in the asymmetric part of the unit
cell, which differ mainly in the conformation of the SiMe2F
group (Figure S55 in the Supporting Information). The first
conformer supports the structure formulation based upon
1
the H NMR spectrum. The presence of a tetracoordinate
boron atom is supported by a single 11B NMR resonance at 5.4
ppm. It is worth noting that no changes in the spectra were
observed when the samples were analyzed after a few days,
which indicates that the studied compound is quite stable in
aqueous solutions over a wide range of pH.
−
NMR studies with one of the fluorine atoms from the BF3
C
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Article
group interacting with Si-bound methyl groups (dC16···F2
3.135(1) Å, dH16B···F9 = 2.51 Å; dC15···F2 = 3.202(1) Å, dH15C···F9
2.60 Å). In the second conformer the SiMe2F group is twisted
around the C−Si bond with the fluorine atom facing the BF3
group, which provides a stronger coordination to the potassium
cation.
=
=
observed when fluorine substituents are attached to the
benzene ring, as the pKa values for mono- (3c), di- (3d), and
tetrafluorinated (3e) derivatives are equal to 7.2, 6.8 and 4.7,
respectively. Cumulation of these two effects in 3f results in the
most acidic (pKa = 4.2) oxaborole system known to date. This
is (also quantitatively) in line with our recent observations
regarding a strong acidifying effect (by 3.0 pKa units) of ring
perfluorination in 1,2-phenylenediboronic acid.17 However, it
should be stressed that the formation of a siloxaborole
heterocycle is crucial for the acidity enhancement. The pKa of
boronated thienylsilanol 4 was estimated to be 9.2: i.e., it is
higher by 2.4 pKa units with respect to the related compound
3b and is comparable to the value reported for phenylboronic
acid (pKa = 8.8).27
−
Crystal Structure of 3e. An analysis of the crystal structure
of 3e (Figure 2) shows that the B−C bond length is slightly
Interaction of Benzosiloxaboroles with Diols. Consid-
ering the strong interest in organoboranes as receptors for
biologically relevant molecules, we have determined the
association constants Ks of two selected derivatives (3c,d)
with target compounds including dopamine, monosaccharides,
and adenosine and its monophosphate (AMP). For this
purpose, the method proposed by Springsteen and Wang,
utilizing Alizarin Red S (ARS) as a fluorescent probe, was
used.28 The results are given in Table 3. Usually 3c exhibits a
Figure 2. Molecular structure of 3e.
Table 3. Stability Constants (Ks, M−1) of Complexes Formed
between 3c,d and Biologically Relevant Target Compounds
longer than that in 1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(BnBO; 1.581(2) Å versus 1.496÷1.550 Å), whereas B−O
bond lengths are slightly shorter (endocyclic, 1.388(2) Å versus
1.401−1.412 Å; exocyclic, 1.337(2) Å versus 1.348÷1.372 Å).24
Such a discrepancy can be attributed to longer Si−O versus C−
O bond lengths. This also leads to an increase in the endocyclic
C−B−O bond angle (111.7(1)° in 3e, 108.0−110.5° in
BnBO), which partially alleviates the oxaborole ring strain.
The increase of the endocyclic bond angle on the B atom can
also be attributed to the known gem-dimethyl effect.25 This is
also consistent with the effect of two methyl groups at the 3-
position observed for 1,3-dihydro-1-hydroxy-3,3-dimethyl-2,1-
benzoxaborole (3,3-dMe-BnOB).26 The basic structural motif
ARS
dopamine
ribose
adenosine
AMP
sorbitol
3c
7770
4480
13700
11600
fructose
4830
214
2030
214
4960
289
822
680
3d
PEA
362
29.6
glucose
glucosamine
711
33.1
galactose
3c
582
287
45.9
13.1
36.3
19.7
3d
higher affinity toward all examined compounds, including ARS.
Different Ks values for compounds of comparable acidity can be
explained on the basis of the binding mechanism presented by
Tomsho and Benkovic.29 According to this report, related
benzoxaboroles bind ARS most readily in their neutral form
(while one hydroxyl group of ARS is deprotonated). Under
conditions used in our studies (pH 7.0), benzosiloxaboroles
3c,d remain in their neutral forms in amounts of ca. 60% and
40%, respectively. Although the general trend of Ks change as a
function of boron atom acidity was consistent with Tomsho
and Benkovic theory, the extent of the observed differences was
much greater than could be expected. Moreover, the very high
affinity of benzosiloxaboroles toward dopamine is surprising.
Taking into account the reactivity of neutral benzosiloxaborole
with catecholates, the affinity toward dopamine should be lower
than that for ARS (the influence of the amine moiety seems to
be insignificant, since the Ks values for both benzosiloxaborole−
2-phenylethylamine (PEA) complexes are very low in
comparison to those for dopamine complexes). Therefore,
the mechanism of interactions between benzosiloxaboroles and
diols (in particular catechols) should be further elucidated.
Finally, the great differences in the affinities of benzosiloxabor-
ole 3c,d to ribose and related compounds (adenosine and
in 3e is based on centrosymmetric H-bonded dimers (dO1···O2
=
2.774(1) Å, dH1···O2 = 1.94 Å) resembling those typical of
benzoxaboroles.3
Acidity of Benzosiloxaboroles. We have measured the
pKa values for all studied systems (3a−f, 4) in water/methanol
solution (1/1) and compared them with those reported for the
related benzoxaboroles BnOB and 3,3-dMe-BnOB (Table 2).
The pKa of 3a is 7.9: i.e., it is lower than that reported for 3,3-
diMe-BnOB (pKa = 8.3).26 Apparently, the boron atom in 3a is
less saturated by the endocyclic oxygen lone pairs in
comparison with 3,3-diMe-BnOB, which is likely due to the
competition with the distinctive Si−O bond conjugation effect.
On the other hand, 3a is less acidic than BnOB (pKa = 7.2),6b,26
which could be attributed to a positive inductive effect of
methyl groups. In addition, the endocyclic C−B−O angle is
slightly larger than that in BnOB, which in turn disfavors
ionization in aqueous solutions (i.e., acceptance of the
hydroxide anion). Conversely, the introduction of electron-
withdrawing phenyl groups at the silicon atom significantly
increases the acidity (3b: pKa = 6.8). The same effect is
Table 2. Acidities (pKa Values) of Benzosiloxaboroles Studied
BnOB24
7.2
3,3-diMe-BnOB23
8.3
3a
3b
3c
3d
3e
3f
4
pKa
7.9
6.8
7.2
6.8
4.7
4.2
9.2
D
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AMP) should be emphasized. This is not consistent with results
reported for complexes of benzoxaboroles with AMP
derivatives.26 Therefore, the binding mechanism of ribose and
its derivatives by benzosiloxaboroles seems to be significantly
different from that observed for benzoxaboroles. On the other
hand, the effect of increased acidity of boron atom (3d vs 3c)
on the binding of nitrogen-containing species (i.e., glucos-
amine, PEA) is related to electron donor−acceptor interactions.
Upon binding hydroxyl anion, the boron atom loses its ability
to bind an electron-donating nitrogen atom.
This can be explained by the Si−O conjugation weakening the
B−O back-bonding. In addition, the Lewis acidity of
benzosiloxaboroles is greatly enhanced by the fluorination of
the benzene ring and by the replacement of methyl with phenyl
groups at the silicon atom. Under neutral pH conditions, both
studied benzosiloxaboroles 3c,d very strongly bind dopamine.
However, 3c is a much more effective receptor for sugars and
related compounds. Specifically, high Ks values were
determined for the complexation of ribose and AMP.
Moreover, initial screenings revealed that benzosiloxaboroles
(especially 3d) show promising antifungal activity. Hence, the
potential applications of these compounds in bioanalytical and
medicinal chemistry should be considered. Further work on
structure−property relationships for this group of compounds
is currently in progress. Specifically, it is aimed at the design of
systems which could be employed as selective sensors for
important bioanalytes or potent antimicrobial agents.
1
In addition, the H NMR spectrum of an equimolar mixture
of 3c and adenosine in DMSO-d6 revealed that complexation
products exist in the equilibrium with substrates, which is
manifested by the broadening of the peaks from the ribose
fragment (Figures S44 and S45 in the Supporting Information).
A more detailed examination of the interaction of siloxaboroles
with diols will be given in due course.
Biological Activity. Further investigation has been under-
taken in order to estimate the antimicrobial potency of the
obtained compounds. Three (3c−e) of the six compounds
were investigated, as the solubilities of the remaining
compounds were too low. A total of 14 bacterial and 7 yeast
standard strains were used in this step of the study. Minimal
inhibitory concentration (MIC) and minimal bactericidal
concentration (MBC) were evaluated according to CLSI and
EUCAST recommendations.30 All tested fluoro-substituted
compounds showed the highest activity against bacteria from
Staphylococcus genus: MIC range 25−100 mg/L (Table S2 in
the Supporting Information). However, MBCs for tested
compounds against all bacterial strains were highover 400
mg/L. Thus, the analyzed compounds should be considered as
bacteriostatic rather than bactericidal agents. On the basis of
the methodology31 it has also been proven that compounds
3c−e were probably actively removed from Gram-negative rods
by the cell wall efflux systems. On the other hand, the studied
compounds (especially 3d) are significantly more active against
yeast strains than against bacteria (MIC range 0.78−200 mg/L,
Table 4), which indicates their potential as antifungal agents.
EXPERIMENTAL SECTION
■
General Comments. Solvents used for reactions were dried by
heating to reflux with sodium/benzophenone and distilled under
argon. Starting materials, including halogenated benzenes, trialkylbo-
rates, chlorodiorganosilanes R2(H)SiCl (R = Me, Ph), DMAE, and
BDEA, were used as received without further purification. In the 13C
NMR spectra the resonances of boron-bound carbon atoms were not
observed in most cases as a result of their broadening by a quadrupolar
boron nucleus. 1H, 13C, and 29Si NMR chemical shifts are given
relative to TMS using residual solvent resonances. 11B and 19F NMR
chemical shifts are given relative to BF3·Et2O and CFCl3, respectively.
Synthesis. 1-Bromo-2-(dimethylsilyl)benzene (1a). n-BuLi in
hexane (2.5 M; 20.8 mL, 0.052 mol of n-BuLi) was added dropwise
to a stirred solution of 1,2-dibromobenzene (11.8 g, 0.05 mol) in
THF/Et2O (1/1, 150 mL) at −110 °C over 1 h. The resulting white
slurry was stirred for 15 min, followed by a slow addition of
Me2(H)SiCl (5.4 mL, 0.052 mol) in Et2O (5 mL). The resulting
mixture was warmed to −80 °C and stirred for 15 min. The cooling
bath was removed and the mixture was slowly warmed to room
temperature. The resultant suspension was filtered under argon and
concentrated. The oily residue was distilled under reduced pressure
1
(bp 83−88 °C/2 Torr) to give 1a in 77% (8.7 g) yield. H NMR
(CDCl3, 400.1 MHz): δ 7.55 (dd, J = 8.0, 1.0 Hz, 1H, Ph), 7.49 (dd, J
= 7.0, 2.0 Hz, 1H, Ph), 7.30 (td, J = 7.0, 1.0 Hz, 1H, Ph), 7.24 (td, J =
8.0, 2.0 Hz, 1H, Ph), 4.55 (sp, J = 4.0 Hz, 1H, SiH), 0.46 (d, 6H, J =
4.0 Hz, SiMe2) ppm. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 139.3
(Ph), 136.6 (Ph), 132.4 (Ph), 131.1 (Ph), 130.8 (Ph), 126.6 (Ph),
−3.6 (SiH(CH3)2) ppm. Anal. Calcd for C8H10BrSi (214.15): C,
44.87, H, 4.71. Found: C, 44.75, H, 4.63.
Table 4. Antifungal Activity of Selected Benzosiloxaboroles
MIC (mg/L)
yeast strain
3c
50
3d
50
3e
200
C. albicans ATCC 90028
C. parapsilosis ATCC 22019
C. krusei ATCC 6258
C. quilliermondii IBA 155
C. tropicalis IBA 171
100
50
100
50
50
200
50
1-Bromo-3-fluoro-2-(dimethylsilyl)benzene (1b). A solution of 1-
bromo-3-fluorobenzene (1.75 g, 10 mmol) in THF (10 mL) was
added to a stirred solution of LDA (10 mmol) freshly prepared from
n-BuLi (10 M, 1.0 mL, 10 mmol) in THF (30 mL) at −78 °C. The
resultant white solution was stirred for 1 h to give a colorless
precipitate. The electrophile SiHMe2Cl (0.95 g, 10 mmol) was then
added to the stirred mixture to give a colorless solution, which was
stirred for 1 h and then hydrolyzed with H2O (100 mL). Dilute
aqueous H2SO4 was added until the pH was slightly acidic. Et2O (50
mL) was next added and the mixture was stirred for 10 min. The
organic phase was separated and the aqueous phase extracted with
Et2O (20 mL). The combined organic solutions were dried over
MgSO4 and evaporated to give a residue which was distilled under
reduced pressure (bp 60−63 °C/1 Torr) to give 1b as a colorless
12.5
50
6.25
3.13
6.25
0.78
3.13
1.56
1.56
S. cerevisiae ATCC 9763
S. cerevisiae IBA 198
25
50
CONCLUSIONS
■
In a summary, a series of 1,3-dihydro-1,1-diorgano-1,2,3-
benzosiloxaboroles was prepared using two general synthetic
strategies. Irrespective of the used method, the introduction of
the SiHR2 group to the aromatic ring is straightforward.
Furthermore, the ortho assistance of the boronic group enables
the rapid hydrolytic cleavage of the Si−H bond under mild
conditions. Thus, benzosiloxaboroles with diverse substitution
patterns are readily accessible. On the basis of a comparison
between 3a and 3,3-diMe-BnOB, these boraheterocycles seem
to be stronger Lewis acids than their nonsilicon counterparts.
1
liquid. Yield: 2.18 g (94%). H NMR (CDCl3, 400.1 MHz): δ 7.34
(dd, J = 8.0, 0.5 Hz, 1H), 7.19 (td, J = 8.0, 6.5 Hz, 1H), 6.95 (td, J =
8.0, 1.0 Hz, 1H), 4.75 (sp, J = 4.0 Hz, 1H, SiH(CH3)2), 0.45 (d, J = 4.0
Hz, 6H, SiH(CH3)2). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 167.1
(d, J = 246.0 Hz), 132.1 (d, J = 10.0 Hz), 130.3 (d, J = 12.0 Hz), 128.9
(d, J = 3.0 Hz), 125.9 (d, J = 31.0 Hz), 114.0 (d, J = 27.0 Hz), −3.2
E
DOI: 10.1021/acs.organomet.5b00265
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
ppm. Anal. Calcd for C8H9BrFSi (232.15): C, 41.39, H, 3.91. Found:
C, 41.20, H, 3.68.
(CDCl3, 99.3 MHz): δ 22.3 ppm. HRMS (EI): calcd for
C16H20B2O3Si2 [M]+ 338.1137 (diboroxane formed upon dehydra-
tion), found 338.1143.
3-[2-(N,N-Dimethylamino)ethanolato]-1,3-dihydro-1,1-dimethyl-
1,2,3-benzosiloxaborole (2a). Method A. A solution of 2-(2′-
bromophenyl)-6-butyl-1,3,6,2-dioxazaborocan (16.2 g, 0.05 mol) in
THF (40 mL) was added to a solution of n-BuLi (10 M solution in
hexanes, 5.2 ml, 0.052 mol) in THF (150 mL) at −90 °C. During the
addition the reaction mixture was warmed to −80 °C. After 20 min of
stirring it was again cooled to −90 °C. Then Me2(H)SiCl was slowly
added (5.4 mL, 0.052 mol) and a thick slurry was formed. It was
warmed to −30 °C, quenched with 1.5 M aqueous H2SO4 to reach a
pH of ca. 4−5, and stirred at room temperature until evolution of H2
ceased. The aqueous phase was separated followed by the extraction
with Et2O (3 × 20 mL). The extracts were added to the organic phase,
which was concentrated under reduced pressure. Then a solution of
DMAE (5.1 mL, 0.051 mol) in Et2O (10 mL) was added, resulting in
precipitation of a white solid. It was filtered and washed with hexane
(10 mL). Drying in vacuo afforded 2a as a white powder. Mp: 131−
1,3-Dihydro-3-hydroxy-1,1-diphenyl-1,2,3-benzosiloxaborole
(3b). This compound was prepared as described for 3a. A crystalline
1
solid was obtained. Mp: 163−165 °C. Yield: 2.23 g (74%). H NMR
(CDCl3, 300.2 MHz): δ 7.89 (m, 1H, Ph), 7.80 (m, 1H, Ph), 7.67 (dd,
J = 8.0, 1.5 Hz, 4H, SiPh2), 7.54 (m, 2H, Ph), 7.40 (m, 6H, SiPh2),
5.07 (broad, 1H, OH) ppm. 11B NMR (CDCl3, 96.3 MHz): δ 32.4
ppm. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 146.8 (Ph), 134.9 (Ph),
132.5 (Ph), 131.9 (Ph), 131.6 (Ph), 131.2 (Ph), 130.8 (Ph), 130.1
(Ph), 128.1 (Ph), 127.6 (Ph) ppm. HRMS (EI): calcd for
C18H15BO2Si [M]+ 302.0934, found 302.0939.
7-Fluoro-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-benzosiloxa-
borole (3c). This compound was prepared as described for 3a, starting
with 2c (2.67 g, 10 mmol). The product was isolated as a white
1
crystalline solid. Yield: 1.39 g (71%). Mp: 109−110 °C. H NMR
(400.1 MHz, CDCl3): δ 7.63 (dd, J = 7.0, 2.5 Hz, 1H, Ph), 7.48 (m,
1H, Ph), 7.10 (t, J = 7.0 Hz, 1H, Ph), 6.47 (br, 1H, B−OH), 0.52 (s,
6H, Si(CH3)2). 13C{1H} NMR (100.6 MHz, CDCl3): δ 164.7 (d, J =
245.0 Hz, Ph), 143.2 (br, Ph), 134.5 (d, J = 30.5 Hz, Ph), 132.7 (d, J =
7.0 Hz, Ph), 127.5 (d, J = 3.0 Hz, Ph), 117.2 (d, J = 24.5 Hz, Ph), −0.7
(Si(CH3)2) ppm. 19F NMR (376.5 MHz, CDCl3): δ −104.70 ppm.
11B NMR (CDCl3, 96.3 MHz): δ 29.9 ppm. 29Si{1H} NMR (CDCl3,
1
135 °C. Yield: 6.8 g (55%). H NMR (CDCl3, 300.2 MHz): δ 7.55
(broad, 2H, Ph), 7.33 (broad, 2H, Ph), 4.2 (broad, 2H, OCH2), 3.2
(broad, 2H, CH2N), 2.5 (broad, 6H, NMe2), 0.35 (broad, 6H, SiMe2)
ppm. 11B NMR (CDCl3, 96.3 MHz): δ 10.8 ppm. 13C{1H} NMR
(CDCl3, 100.6 MHz): δ 148.7 (Ph), 131.0 (Ph), 130.0 (Ph), 128.3
(Ph), 127.3 (Ph), 59.8 (CH2O), 58.6 (CH2N), 45.8 (N(CH3)2), 1.0
(Si(CH3)2) ppm. HRMS (EI): calcdfor C12H20BNO2Si [M]+
249.1356, found 249.1364.
99.3 MHz): δ 22.4 ppm. 19F NMR (376.5 MHz, D2O + HCl, pH ∼0):
δ −104.35 (3c) ppm. 19F NMR (376.5 MHz, D2O, pH ∼7): δ
−104.33 (3c, 85%), −106.26 (3c·OH−, 15%) ppm. 19F NMR (376.5
MHz, D2O + NaHCO3, pH ∼9): δ −104.55 (3c, 7%), −105.75 (3c·
OH−, 93%) ppm. 19F NMR (376.5 MHz, D2O + NaOH, pH ∼14): δ
−105.72 (3c·OH−) ppm. HRMS (EI): calcd for C8H10BFO2Si [M]+
196.0527, found 196.0533.
5,6-Difluoro-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-benzsilox-
aborole (3d). A solution of 2-(2′-bromo-4′,5′-difluorophenyl)-6-butyl-
1,3,6,2-dioxazaborocan17b (3.66 g, 10 mmol) in THF (15 mL) was
added to a previously prepared solution of n-BuLi (10 M solution in
hexanes, 1.10 mL, 11 mmol) in Et2O (80 mL) at −90 °C. After 20 min
of stirring Me2(H)SiCl (1.3 mL, 12 mmol) was slowly added to the
resulting grayish suspension and a clear colorless solution was formed.
This was then warmed gradually to −20 °C, which resulted in a white,
thick slurry. It was quenched with H2SO4 (1.5 M) to pH 4 and stirred
at room temperature until hydrogen evolution ceased. The water
phase was separated followed by extraction with Et2O (2 × 20 mL).
The extracts were added to the organic phase, which was concentrated
under reduced pressure, to give a white waxy residue. It was
crystallized from hexane (20 mL) to give 3d as a white powder. Mp:
69−71 °C. Yield: 1.1 g (51%). 1H NMR (300.2 MHz, CDCl3): δ 7.62
(dd, J = 10.0, 7.5 Hz, 1H, Ph), 7.38 (dd, J = 10.0, 7.5 Hz, 1H, Ph), 0.47
(s, 6H, Si(CH3)2) ppm. 11B NMR (CDCl3, 96.3 MHz): δ 30.3 ppm.
13C NMR (CDCl3, 100.6 MHz): δ 153.0 (dd, J = 256.0, 13.0 Hz, Ph),
Method B. A solution of 1a (2.15, 0.01 mol) in Et2O (5 mL) was
slowly added to a stirred solution of t-BuLi (1.7 M, 12.5 mL, 0.021
mol) in Et2O (50 mL) at −70 °C. The lithiate was stirred for 30 min at
−50 °C. Then it was cooled to −70 °C and B(OEt)3 (2.4 mL, 0.014
mol) was added dropwise. The reaction mixture was hydrolyzed with
H2SO4 (1.5 M). The workup was carried out as described for method
A. Yield: 1.8 g (73%). Mp: 133−135 °C.
3-[2-(N,N-Dimethylamino)ethanolato]-1,3-dihydro-1,1-diphenyl-
1,2,3-benzosiloxaborole (2b). This compound was prepared as
described for 2a (method A) using Ph2Si(H)Cl instead of Me2(H)-
1
SiCl. Mp: 154−158 °C. Yield: 2.2 g (62%). H NMR (CDCl3, 300.2
MHz): δ 7.68 (m, 6H, Ph), 7.34 (m, 8H, Ph), 4.2 (broad, 2H, OCH2),
3.2 (broad, 2H, CH2N), 2.4 (broad, 6H, NMe2) ppm. 11B NMR
(CDCl3, 96.3 MHz): δ 11.2 ppm. 13C{1H} NMR (CDCl3, 100.6
MHz): δ 144.85 (broad, Ph), 136.66 (broad, Ph), 135.0 (Ph), 134.3
(Ph), 131.8 (Ph), 131.1 (Ph), 129.6 (Ph), 128.8 (Ph), 127.7 (Ph),
127.6 (Ph), 59.9 (broad, CH2O), 58.8 (broad, CH2N), 46.0 (broad,
N(CH3)2) ppm. HRMS (EI): calcd for C22H24BNO2Si [M]+
373.1669, found 373.1660.
3-[2-(N,N-Dimethylamino)ethanolato]-7-fluoro-1,3-dihydro-1,1-
dimethyl-1,2,3-benzosiloxaborole (2c). The product was prepared as
described for 2a (method B) starting with 1b (2.32 g, 10 mmol), as
1
colorless crystals. Yield: 2.16 g (81%). Mp: 168−169 °C. H NMR
(acetone-d6, 400.2 MHz): δ 7.30 (m, 2H, Ph), 6.84 (td, J = 7.0, 1.5 Hz,
1H), 3.95 (broad, 2H, CH2O), 3.18 (broad, 2H, CH2N), 2.52 (broad,
6H, N(CH3)2), 0.27 (s, 6H, Si(CH3)2). 13C{1H} NMR (acetone-d6,
100.6 MHz): δ 165.5 (d, J = 241.0 Hz, Ph), 133.8 (d, J = 31.0 Hz, Ph),
131.5 (d, J = 6.0 Hz, Ph), 128.2 (Ph), 113.3 (d, J = 25.0 Hz, Ph), 60.2
(CH2O), 59.0 (CH2N), 45.8 (N(CH3)2), 1.2 (Si(CH3)2) ppm. 19F
NMR (acetone-d6, 376.5 MHz): δ −103.54. 11B NMR (acetone-d6,
96.3 MHz) δ 11.4 ppm. HRMS (EI): calcd for C12H19BFNO2Si [M]+
267.1262, found 267.1256.
1,3-Dihydro-3-hydroxy-1,1-dimethyl-1,2,3-benzosiloxaborole
(3a). 2a (2.5 g, 0.01 mol) was dissolved in Et2O (20 mL), and H2SO4
(1.5 M) was added dropwise to reach pH 2. The reaction mixture was
refluxed for 30 min. After the mixture was cooled to room
temperature, the water phase was separated and washed with Et2O
(4 × 5 mL). The organic phases were combined and concentrated
under reduced pressure to give 3a as a colorless viscous oil. Yield: 1.5 g
(83%). 1H NMR (CDCl3, 400.1 MHz): δ 7.85 (m, 1H, Ph), 7.63 (m,
1H, Ph), 7.49 (m, 2H, Ph), 6.03 (broad, 1H, B−OH), 0.46 (s, 6H,
Si(CH3)2) ppm. 11B NMR (CDCl3, 96.3 MHz): δ 30.9 ppm. 13C{1H}
NMR (CDCl3, 100.6 MHz): δ 149.9 (Ph), 131.7 (Ph), 130.9 (Ph),
130.5 (Ph), 129.8 (Ph), −0.4 (Si(CH3)2) ppm. 29Si{1H} NMR
152.1 (dd, J = 256.0, 13.0 Hz, Ph), 147.0 (Ph), 120.1 (d, J = 14.5 Hz,
Ph), 119.0 (d, J = 15.1 Hz, Ph), −0.7 (Si(CH3)2) ppm. 19F NMR
(CDCl3, 375.5 MHz): δ −134.12 (ddd, J = 17.0, 11.5, 8.5 Hz),
−135.90 to −136.14 (m) ppm. HRMS (EI): calcd for C8H9BF2O2Si
[M]+ 214.0433, found 214.0425.
4,5,6,7-Tetrafluoro-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-
benzosiloxaborole (3e). 1,2-Dibromo-3,4,5,6-tetrafluorobenzene (6.2
g, 0.02 mol) was dissolved in Et2O (50 mL) and cooled to −70 °C.
Then n-BuLi (2.8 M solution in hexanes, 7 mL, 0.02 mol) was added
dropwise and the reaction mixture turned green. Subsequently,
Me2(H)SiCl was added (2.2 mL, 0.02 mol) followed by the addition
of another portion of n-BuLi (2.8 M, 7 mL, 0.02 mol) and THF (5
mL). After 30 min of stirring at −60 °C, B(OMe)3 (2.2 mL, 0.02 mol)
was added and the reaction mixture was warmed to −30 °C, quenched
with 1.5 M aqueous H2SO4 to reach the pH 2−3, and stirred at room
temperature until evolution of H2 ceased. The aqueous phase was
separated followed by extraction with Et2O (2 × 20 mL). The extracts
were added to the organic phase, which was concentrated under
reduced pressure. Then hexane (20 mL) was added and a white solid
precipitated. It was filtered, washed with hexane (2 × 5 mL), and dried
1
in vacuo to give 3e. Mp: 112−115 °C. Yield: 2.95 g (59%). H NMR
F
DOI: 10.1021/acs.organomet.5b00265
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(CDCl3, 300.2 MHz): δ 5.17 (broad, 1H, B−OH), 0.53 (s, 6H,
Si(CH3)2) ppm. 11B NMR (CDCl3, 96.3 MHz): δ 28.8 ppm. 13C{1H}
NMR (CDCl3, 100.6 MHz): δ 149.8 (ddd, J = 254.0, 9.5, 3.0 Hz, Ph),
148.1 (ddd, J = 245.0, 9.5, 2.0 Hz, Ph), 143.3 (dddd, J = 75.0, 19.0,
13.0, 2.5 Hz, Ph), 140.8 (dddd, J = 71.0, 19.0, 13.0, 2.5 Hz, Ph), 130.4
(d, J = 30 Hz, Ph), −1.0 (Si(CH3)2) ppm. 19F NMR (CDCl3, 282.4
MHz): δ −128.0 (ddd, J = 24.0, 21.5, 5.5 Hz, 1F), −131.5 (td, J = 21.5,
5.5 Hz, 1F), −149.0 (ddd, J = 24.0, 18.0, 5.5 Hz, 1F), −151.3 (ddd, J =
21.5, 18.0, 5.5 Hz, 1F) ppm. 29Si{1H} NMR (CDCl3, 99.3 MHz): δ
23.0 ppm. HRMS (EI): calcd for C8H7BF4O2Si [M]+ 250.0245, found
250.0235.
4,5,6,7-Tetrafluoro-1,3-dihydro-3-hydroxy-1,1-diphenyl-1,2,3-
benzsiloxaborole (3f). This compound was prepared as described for
3e using Ph2(H)SiCl instead of Me2(H)SiCl. The obtained crude
product was contaminated with the byproduct n-BuB(OH)2. It was
purified by recrystallization from CHCl3/hexane (10 mL, 1/1) to
afford a white crystalline solid. Mp: 82−84 °C. Yield: 2.2 g (62%). 1H
NMR (CDCl3, 300.2 MHz): δ 7.68 (m, 4H, Ph), 7.51 (m, 2H, Ph),
7.43 (m, 4H, Ph), ppm. 11B NMR (CDCl3, 96.3 MHz): δ 29.1 ppm.
13C{1H} NMR (CDCl3, 100.6 MHz): δ 150.0 (dd, J = 256.0, 8.0 Hz,
Ph), 148.5 (dd, J = 246.5, 7.5 Hz, Ph), 143.8 (dddd, J = 18.5, 15.5,
12.5, 2.5 Hz, Ph), 141.2 (dddd, J = 19.0, 15.5, 12.5, 2.0 Hz, Ph), 134.6
(d, J = 0.5 Hz, SiPh2), 131.6 (SiPh2), 130.0 (SiPh2), 128.4 (SiPh2),
128.3 (d, J = 12.5 Hz, Ph) ppm. 19F NMR (CDCl3, 282.4 MHz): δ
−124.56 (ddd, J = 23.5, 21.0, 6.0 Hz, 1F), −130.85 (td, J = 21.0, 7.5
Hz, 1F), −147.71 (ddd, J = 23.5, 18.0, 7.5 Hz, 1F), −150.08 (ddd, J =
21.5, 18.0, 6.0 Hz, 1F) ppm. HRMS (EI): calcd for C18H11BF4O2Si
[M]+ 374.0558, found 374.0572.
temperature. After ca. 5 min a white solid precipitated; it was filtered
off, washed with diethyl ether (2 × 1 mL), and dried in vacuo to give
the title compound. Mp: 303−305 °C. Yield: 0.075 g (85%). 1H NMR
(acetone-d6, 300.2 MHz): δ 7.40−7.30 (m, 2H), 0.41 (dq, J = 8.0, 1.5
Hz, 6H, Si(CH3)2) ppm. 11B NMR (acetone-d6, 96.3 MHz): δ 2.9 (q, J
= 50 Hz) ppm. 13C{1H} NMR (acetone-d6, 100.6 MHz): δ 150.4 (dd,
J = 247.0, 11.5 Hz, Ph), 148.1 (dd, J = 243.0, 12.5 Hz, Ph), 136.4 (d, J
= 14.5 Hz, Ph), 120.5 (dd, J = 12.5, 8.0 Hz, Ph), 119.8 (d, J = 11.5 Hz,
Ph), −0.1 (dq, J = 17.0, 4.5 Hz, Si(CH3)2) ppm. 19F NMR (acetone-
d6, 282.4 MHz): δ −136 (m, 3F, BF3K), −143.3 (m, 1F, Ph), −147.6
(m, 1F, Ph), −157.3 (sp, J = 8.0 Hz, 1F, SiF(CH3)2) ppm. 29Si{1H}
1
NMR (acetone-d6, 99.3 MHz): δ 18.0 (d, J = 267.0 Hz). H NMR
(acetone-d6, 300.2 MHz, T = −50 °C): δ 7.37−7.27 (m, 2H), 0.37 (m,
6H, Si(CH3)2) ppm. 19F NMR (acetone-d6, 282.4 MHz, T = −50 °C):
δ −135.9 (broad, 3F, BF3K), −142.6 (m, 1F, Ph), −146.6 (m, 1F, Ph),
−157.3 (sp, J = 8.0 Hz, 1F, SiF(CH3)2) ppm. 29Si{1H} NMR (acetone-
d6, 99.3 MHz, T = −50 °C): δ 18.5 (d, J = 266.0 Hz) ppm. Anal. Calcd
for C8H8BF6KSi (296.13): C, 32.45, H, 2.72. Found: C, 32.22, H, 2.61.
Structural Measurement and Refinement Details. A single
crystal of 3e was measured at 100 K on a SuperNova diffractometer
equipped with an Atlas detector (Cu Kα radiation, λ = 1.54184 Å). X-
ray diffraction data sets for single crystals of 2a, 5, and 6 were collected
at 100 K on a SuperNova diffractometer equipped with an Eos CCD
detector (Mo Kα radiation, λ = 0.71073 Å). Data reduction and
analysis were carried out with the CrysAlisPro program.32 All
structures were solved by direct methods using SHELXS-97 and
refined using SHELXL-2013.33 All non-hydrogen atoms were refined
anisotropically. CCDC depository numbers: 1047174 (2a), 1047175
(3e), 1047176 (5), 1400000 (6).
2-[(Hydroxy)diphenylsilyl]thiophene-3-boronic Acid (4). A solu-
tion of 6-butyl-2-[3′-thienyl]-1,3,6,2-dioxazaborocan (1.75 g, 0.03
mol) in THF (10 mL) was added to a stirred solution of LDA (0.031
mol) freshly prepared from n-BuLi (10 M, 3.1 mL, 0.031 mol) in THF
(50 mL) at −78 °C. The resultant colorless solution was stirred for 1 h
to give a colorless precipitate. The electrophile Ph2(H)SiCl (7.94 g,
0.032 mol) was then added to the stirred mixture to give a colorless
solution, which was warmed to −30 °C, quenched with 1.5 M aqueous
H2SO4 to reach a pH of ca. 4−5, and stirred at room temperature until
evolution of H2 ceased. The aqueous phase was separated, followed by
extraction with Et2O (3 × 20 mL). The extracts were added to the
organic phase, which was concentrated under reduced pressure to give
Crystal data for 2a: C H BNO Si, M = 249.19 au; triclinic; P1; a
̅
12 20
2
r
= 8.853(1) Å, b = 8.961(1) Å, c = 17.416(1) Å, α = 77.09(1)°, β =
89.02(1)°, γ = 86.32(1)°, V = 1344.0(2) Å3; dcalc = 1.231 g cm−3; μ =
0.16 mm−1; Z = 4; F(000) = 536; number of collected/unique
reflections (Rint = 6.3%) 20831/7336, R[F]/Rw[F] (I ≥ 3σ(I)) =
6.5%/14.0%, Δϱres(min/max) = +0.69/−0.45 e Å−3.
Crystal data for 3e: C H BF O Si, M = 250.04 au; triclinic; P1; a
̅
8
7
4
2
r
= 7.059(1) Å, b = 8.246(1) Å, c = 9.243(1) Å, α = 85.36(1)°, β =
86.53(1)°, γ = 85.64(1)°, V = 533.9(1) Å3; dcalc = 1.555 g cm−3; μ =
2.37 mm−1; Z = 2; F(000) = 252; number of collected/unique
reflections (Rint = 1.9%) 6978/2208, R[F]/Rw[F] (I ≥ 3σ(I)) = 3.4%/
9.7%, Δϱres(min/max) = −0.36/+0.46 e Å−3.
1
the product as a viscous oil. Yield: 4.31 g (44%). H NMR (CDCl3,
300.2 MHz): δ 7.70−7.60 (m, 4H, Ph), 7.49−7.31 (m, 8H, Ph, Th),
2.32 (broad, 2H, B−OH) ppm. 11B NMR (CDCl3, 96.3 MHz): δ 29.0
ppm. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 135.0 (Ph), 131.8 (Th),
131.3 (Th), 130.0 (Ph), 129.7 (Ph), 127.9 (Ph), 127.7 (Th) ppm.
Anal. Calcd for C16H15BO3SSi (326.25): C, 58.90, H, 4.63. Found: C,
58.59, H, 4.91.
Crystal data for 5: C24H30BNO3SSi, Mr = 451.45 au;
orthorhombic; P212121; a = 11.393(1) Å, b = 12.124(1) Å, c =
16.833(1) Å, V = 2325.0(1) Å3; dcalc = 1.290 g cm−3; μ = 0.22 mm−1; Z
= 4; F(000) = 960; number of collected/unique reflections (Rint
=
3.4%) = 46116/9589, R[F]/Rw[F] (I ≥ 3σ(I)) = 3.3%/8.6%,
Δϱres(min/max) = +0.36/−0.21 e Å−3.
6-Butyl-2-[2′-((hydroxy)diphenylsilyl)-3′-thienyl]-1,3,6,2-dioxaza-
borocan (5). A solution of N-butyldiethanolamine (0.58 g, 0.005 mol)
in diethyl ether (5 mL) was added to a stirred solution of 4 (1.53 g,
0.005 mol) in Et2O (10 mL). A white crystalline precipitate was
formed, and the resulting suspension was stirred for 1 h at room
temperature. The crystalline product was collected by filtration,
washed with Et2O (2 × 5 mL), and dried to give 5. Yield: 1.18 g (69%,
1.55 g). Mp: 105−108 °C. 1H NMR (CDCl3, 300.2 MHz): δ 7.71 (dd,
J = 8.0, 1.5 Hz, 4H, Ph), 7.56 (d, J = 4.5 Hz, 1H, Th), 7.40 (d, J = 4.5
Hz, 1H, Th), 7.46−7.32 (m, 6H, Ph), 4.19−3.93 (m, 4H, CH2O), 2.77
(m, 2H, CH2N), 2.66 (broad, 2H, H2O, SiOH), 2.34 (m, 2H, CH2N),
2. 07 (m, 2H, NCH2 CH2 CH2 CH3 ), 1. 19 (m, 2H,
NCH2CH2CH2CH3), 1.04 (m, 2H, NCH2CH2CH2CH3), 0.82 (t, J
= 7.0 Hz, 3H, NCH2CH2CH2CH3). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 135.5 (Th), 135.4 (Th), 135.0 (Ph), 129.9 (Ph), 129.2 (Ph),
127.8, 127.4 (Th), 59.6 (CH2O), 56.0 (CH2N), 54.5
(NCH2 CH2 CH2 CH3 ), 29.1 (NCH2 CH2 CH2 CH3 ), 20.5
(NCH2CH2CH2CH3), 14.0 (NCH2CH2CH2CH3) ppm. 11B NMR
(CDCl3, 96.3 MHz): δ 11.1 ppm. Anal. Calcd for C24H30BNO3SSi
(451.46): C, 63.85, H, 6.70. Found: C, 63.61, H, 6.44.
Crystal data for 6: 2•C8H8BF6KSi, Mr = 296.16 au; orthorhombic;
P212121; a = 7.0742(1) Å, b = 10.7508(2) Å, c = 15.0965(4) Å, V =
1136.15 (4) Å3; dcalc = 1.731 g cm−3; μ = 0.62 mm−1; Z = 2; F(000) =
592; number of collected/unique reflections (Rint = 2.1%) 25149/
9326, R[F]/Rw[F] (I ≥ 3σ(I)) = 2.5%/6.5%, Δϱres(min/max) =
+0.53/−0.27 e Å−3.
Computational Methods. All geometry optimizations and
frequency calculations were carried out with the GAUSSIAN09 suite
of programs34 and B3LYP functional35 using aug-cc-pVDZ36 basis sets.
The minima were confirmed by vibrational frequency calculations
within the harmonic approximation (no imaginary frequencies). In
optimization processes no symmetry constraints were applied.
Determination of Stability Constants of Complexes Formed
between Organoboron Derivatives (OB) and Selected Target
Compounds (TC). Fluorescence measurements were taken with a
Synergy Mx Microplate Reader (BioTek Instruments Inc.). pH
Measurements were performed using an MA 234 pH/Ion Analyzer
(Mettler Toledo). Three stock solutions have been prepared. Solution
A contained 90 μM ARS in 0.01 M HEPES buffer, while solutions B
and C contained 4.5 mM of compounds 3c,d, respectively, both in
0.01 M HEPES buffer. The pH of all solutions was adjusted to 7.0
using 3 M NaOH. Solution D was prepared by 10-fold dilution of
solution A with an appropriate volume of solution B adequate to
Potassium [2-(Fluorodimethylsilyl)phenyl]trifluoroborate (6). A
saturated aqueous solution of KHF2 (0.117 g, 1.5 mmol) was added to
a stirred solution of 3d (0.064 g, 0.3 mmol) in MeOH (1 mL) at room
G
DOI: 10.1021/acs.organomet.5b00265
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obtain a 50-fold molar equivalent of 3c with respect to ARS. Solution
E was prepared in the same manner, except for the use of solution C
instead of B, and the molar excess of 3d was 100-fold. Both solutions
were diluted with 0.01 M HEPES buffer, and the pH was adjusted to
7.0. Solutions D and E were mixed with different volumes of 9 μM
ARS (0.01 M HEPES buffer, pH 7.0) to obtain a series of solutions
with a fixed concentration of ARS and various concentrations of OB
(i.e., various molar ratios of OB to ARS). The fluorescence spectra
were taken after assessing an optimal excitation wavelength for both
solutions D and E, i.e., 468 and 440 nm, respectively. The maximum
fluorescence intensities were plotted against the concentration of both
OBs (Figures S63 and S64 in the Supporting Information) in order to
assess the optimal concentration of OBs (0.45 and 0.72 mM for 3c,d,
respectively) during further studies. The stability constants of OB-ARS
complexes K1 have been calculated according to the Benesi−
Hildebrand method by dividing an intercept by a slope in the 1/ΔF
vs 1/CBC plot (Figure S65 in the Supporting Information). Every point
taken into calculations was an average of measurements made for four
individual solutions. The stability constants of OB-TC complexes Ks
were determined by the titration of an OB-ARS complex solution with
a chosen TC. Solutions F and G containing 0.45 and 0.72 mM of
compounds 3c,d, respectively, 9 μM ARS, and a portion of TC were
obtained. The added portions of TC were tuned to reduce the
fluorescence intensity to the level of 25−35% of the value obtained for
an original solution. The series of solutions with fixed OB and ARS
concentration and a range of TC concentrations were prepared by
mixing solutions D and E with solutions F and G in various ratios,
respectively. The fluorescence spectra were recorded as described
above for determination of K1 constants. As previously, each point
taken for calculations was an average of four individual measurements.
The Ks values were calculated by plotting [TC0]/P vs Q, where [TC0]
is the total concentration of TC, Q is a quotient of concentrations of
free and bound ARS (calculated from fluorescence data), and P is
defined by the equation
Mathematical and Computational Modelling in Warsaw (Grant
No. G33-14). The authors thank Prof. K. Wozniak (University
́
of Warsaw, Laboratory of Structural Research) for providing
access to X-ray diffraction facilities.
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