Synthesis and Transformations of Functionalized Benzosiloxaboroles

Article abstract of DOI:10.1002/ejoc.201601328

The synthesis and characterization of a series of fluorinated benzosiloxaboroles bearing synthetically useful formyl and cyano groups is reported. These compounds have been obtained by multistep syntheses starting with simple halogenated benzenes. The general synthetic protocol was based on the generation of ortho-boronated aryldimethylsilanes which undergo dehydrogenative cyclization upon hydrolytic workup due to activation of the Si–H bond by the adjacent boronic group. In some cases the synergy of adjacent boron- and silicon-based functionalities resulted in an unexpected hydrosilylation of the CHO group under mild aqueous conditions. The reduction of a benzosiloxaborole derivative bearing the formyl group at the ortho position with respect to the boron atom resulted in a structural transformation reflecting the higher stability of the carboxaborole heterocycle with respect to its silicon counterpart. Thus, a unique heterocyclic system featuring a central 10-membered ring comprising two borasiloxane linkages was isolated.

Full text of DOI:10.1002/ejoc.201601328

A Journal of
Accepted Article
Title: Synthesis and Transformations of Functionalized
Benzosiloxaboroles
Authors: Sergiusz Lulinski, Maja Czub, Krzysztof Durka, Justyna
Łosiewicz, Mateusz Urban, Janusz Serwatowski, and
Krzysztof Woźniak
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601328
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Synthesis and Transformations of Functionalized
Benzosiloxaboroles
Maja Czub,[a] Krzysztof Durka,[a] Sergiusz Luliński,*[a] Justyna Łosiewicz,[a] Janusz Serwatowski,[a]
Mateusz Urban,[a] Krzysztof Woźniak[b]
Abstract: The synthesis and characterization of
a
series of
pyridoxaboroles[8] and benzosiloxaboroles (Scheme 1, II).[9] The
latter heterocycles can be defined as silicon analogues of
benzoxaboroles and can be conveniently obtained by a facile
intramolecular dehydrogenative condensation of arylboronic
acids bearing a SiHR2 group at the ortho position in the
presence of water. This is due to the activation of the Si–H bond
in arylsilanes by the adjacent boronic group.[10] In our search for
fluorinated benzosiloxaboroles bearing the synthetically useful formyl
and cyano groups is reported. These compounds have been
obtained by multistep syntheses starting with simple halogenated
benzenes. The general synthetic protocol was based on the
generation ortho-boronated aryldimethylsilanes which undergo
dehydrogenative cyclization upon hydrolytic workup due to the
activation of the Si–H bond by the adjacent boronic group. In some
cases the synergy of adjacent boron- and silicon-based
functionalities resulted in an unexpected hydrosilylation of CHO
novel
functionalized
benzosiloxaboroles
as
potential
antimicrobial agents we have undertaken the synthesis of
derivatives bearing formyl or cyano groups attached at various
positions of the benzene ring. These studies resulted also in the
discovery that the activation of Si–H bond by the boronic group
enables hydrosilylation[11] of the formyl group under mild
aqueous conditions.
group under mild aqueous conditions. The reduction of
a
benzosiloxaborole derivative bearing the formyl at the ortho position
with respect to the boron atom resulted in the structural
transformation reflecting the higher stability of the carboxaborole
heterocycle with respect to its silicon counterpart. Thus, a unique
heterocyclic system featuring
a
central 10-membered ring
comprising two borasiloxane linkages was isolated.
Introduction
Scheme 1. General structures of benzoxaborole and benzosiloxaborole.
Benzoxaboroles (Chart 1, I) are
a group of boracyclic
compounds known for 70 years.[1] However, they have attracted
a renewed and considerable attention only in the last decade.
This is mainly due to the discovery of potent antimicrobial
activity of functionalized derivatives,[2,3] amply demonstrated by
the recent approval of Tavaborole (trade name Kerydin),4 for the
treatment of onychomycosis - a fungal infection of the nail and
nail bed. Mechanistic studies on the interaction of
benzoxaboroles with biomolecules allowed for a rational design
of other systems, that are currently under clinical trials.[5]
Importantly, benzoxaboroles are stronger Lewis acids than
corresponding arylboronic acids,[6] which is beneficial for the
solubility in water at neutral pH. In general, this is also in line
with their higher affinity and specificity for binding biological
relevant molecules bearing 1,2-diol moiety such as saccharides,
nucleosides and catechol derivatives (e.g., dopamine), which
was exploited for sensing applications.[7] The importance and
potential wide applicability of benzoxaboroles has prompted us
to develop the synthetic routes to their analogues:
Results and Discussion
Synthesis of formyl-substituted benzosiloxaboroles.
Our initial goal was to synthesize a series of formyl-substituted
benzosiloxaboroles. The general synthetic approach to these
compounds consisted of several steps (Scheme 2). In the first
one the starting polyhalogenated benzenes were converted into
corresponding benzaldehydes 1a-e via Br/Li exchange (1a, 1b,
1d) or deprotonative lithiation (1c, 1e) followed by the addition of
DMF and hydrolysis. Obtained products were protected with
HC(OMe)3/MeOH/cat. H2SO4 to give the appropriate dimethyl
acetals 2a-e. The next step involved their deprotonative lithiation
with LDA followed by the addition of Me2Si(H)Cl resulting in the
introduction of the dimethylsilyl group (3a-e). In all cases the
reaction occurred regioselectively at the position between
fluorine and bromine atoms in agreement with the cumulated
ortho-acidifying effect of two halogen substituents.[12] Having
silylated acetals 3a-3e in hand, we have embarked on their
[a]
M. Czub, Dr. K. Durka, Dr. S. Luliński, J. Łosiewicz, Prof. J.
Serwatowski, M.Sc. M. Urban,
conversion
into
respective
benzosiloxaboroles.
Some
Warsaw University of Technology, Faculty of Chemistry, Department
of Physical Chemistry, Noakowskiego 3, 00-664 Warsaw, (Poland).
Fax: +4822 6282741
E-Mail: serek@ch.pw.edu.pl
Homepage: lmt.ch.pw.edu.pl
optimization of reaction conditions was performed. Thus, the
Br/Li exchange was accomplished with t-BuLi in Et2O at –100 °C
followed by trapping a generated aryllithium intermediate with
B(OMe)3 and hydrolysis with dilute aqueous H2SO4. It was
proposed that the formation of the siloxaborole heterocycle
relies on the activation of the Si–H bond due to the interaction of
H atom with the adjacent boron atom.[9,10] Corresponding
[b]
K. Woźniak
Chemistry Department, Biological and Chemical Research Centre,
University of Warsaw, Żwirki i Wigury 101, 02-089 Warszawa,
Poland
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. Synthesis of silylated acetals 3a-3e. Reaction conditions – i: (1) n-BuLi, Et2O, -78 oC, (2) DMF, -78 oC, (3) H3O+; ii: (1) LDA, THF, -78 oC, (2) DMF, -78
oC, (3) H3O+; iii: HC(OMe)3, MeOH, H3O+, reflux; iv: (1) LDA, THF, -78 oC, (2) Me2Si(H)Cl, -78 oC.
Scheme 3. Synthesis of formyl-substituted benzosiloxaboroles 4a-4d and their subsequent reduction to respective hydroxymethyl derivatives 5a-5d. Reaction
conditions – i: (1) t-BuLi, Et2O, -100 oC, (2) B(OMe)3, -100 oC, (3) H3O+; ii: (1) NaBH4, Et2O, (2) H3O+.
benzosiloxaboroles 4a-4d have been obtained in moderate to
good yields as white microcrystalline solids soluble in common
organic solvents (Scheme 3). Unexpectedly, the 1H NMR
spectrum of crude 4b showed that it was contaminated with the
byproduct 5b resulting from reduction of the formyl group. The
pure 4b was isolated by crystallization from CH2Cl2/hexane.
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Compounds 4a-4d have been fully characterized by multinuclear
NMR spectroscopy and HRMS analysis. The structural
formulation of 4d was also confirmed by the X-ray diffraction
analysis (Figure 1). The synthetic utility of obtained formyl
derivatives was demonstrated by an almost quantitative
conversion of 4a-4c to respective hydroxymethyl derivatives 5a-
5c using NaBH4 in THF. Moreover, reductive amination was
successfully employed for the conjugation of 4c with dopamine
(Scheme 4).
Figure 2. The crystal structure of 6d.
Apparently, a specific mechanism accounting for the Si–H
bond reactivity should be invoked for the observed reduction of
the formyl group. First of all, the reduction must be preceded by
the cleavage of dimethoxymethyl group. In this regard, the
choice of solvent seems to be important for the reaction course.
THF is much more hydrophilic than Et2O and thus the
concentration of water in this solvent is relatively high during
hydrolysis. This facilitates hydrolytic cleavage of the CH(OMe)2
group. In fact, when THF was added to a reaction mixture during
the synthesis of 4d prior to final hydrolysis, the mixture of
products was obtained (Scheme 5). The major product 4d was
contaminated by a substantial amount of 7-(dimethylsilyl)-5,6-
difluorobenzoxaborole 7d (the ratio 4d/7d was ca. 2:1). The
formation of 7d can be explained by an initial deprotection of the
formyl group followed by an intermolecular hydride transfer from
another molecule, which may still bear the CH(OMe)2
functionality. However, the formation of 7d could be suppressed
by the addition of excess of propanal, which apparently acted as
an effective hydride acceptor. The isolation of 7d from the
mixture with 4d was accomplished by the addition of NaBH4 in
THF resulting in the conversion of 4d to 6d. Unlike 7d,
compound 6d is essentially insoluble in a mixed solvent
Et2O/hexane (1:1) which enabled separation of these two
compounds.
Scheme 4. Reaction conditions – i: (1) THF / Et3N (2) NaBH4 (3) H3O+.
The reduction of 4d resulted in the structural reorganization and
dimerization of an initial product 5d. The presence of CH2OH
group at the ortho position with respect to the boron atom led to
the cleavage of the siloxaborole heterocycle in favor of the
formation of a carboxaborole ring. However, the liberated
Me2SiOH moiety undergoes condensation with the BOH group
to give compound 6d – a unique centrosymmetric molecule
comprising a central 10-membered ring composed of two
borosiloxane linkages and fused with two benzoxaborole units.
The X-ray diffraction analysis of 6d confirmed the formation of a
centrosymmetric dimer with O1 oxygen atoms pointing toward
the centre of a planar 10-membered heterocyclic ring (Figure 2).
The 29Si NMR spectrum of 6d shows a signal at 2.28 ppm
consistent with a significant upfield shift relative to 4d (δ29Si =
20.76 ppm) which may reflect the release of strain at the silicon
atom.[9]
Scheme 5. Reaction conditions – i: (1) t-BuLi, THF, -100 oC, (2) B(OMe)3, -
100 oC, (3) H3O+. Note that the synthesis was performed in THF instead of
Et2O.
Figure 1. Crystal structure of 4d. An intramolecular O–H…O hydrogen bond
(red dashed line) is formed between the BOH and formyl groups. The
hydrogen bonded centrosymmetric dimeric motif, typically found in the
structures of benzoxaboroles,[2a,c] is not present in this case.
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to synthesize related benzosiloxaboroles 4f and 4g (Scheme 7).
Specifically, the presence of a substituent at the 5-position in
various benzoxaborole derivatives is often beneficial for their
acitivity, and therefore we decided to obtain compound 4g. In
addition there are also various possibilities of transformations
involving cyano groups, which can give rise to more extended
systems. The synthesis of 4f started with 2-bromo-4-
fluorobenzonitrile, which was subjected to deprotonation with
LDA followed by the addition of Me2Si(H)Cl. The resulting
silylated derivative 3f was reacted with t-BuLi in THF at –100 °C
to give corresponding aryllithium, which was trapped with
B(OMe)3. The synthesis of 4g involved the generation of 2-(2′-
Figure 3. The crystal structure of 7d. The formation of a centrosymmetric
hydrogen-bonded dimer is presented.
bromo-4’-cyanophenyl)-6-butyl-1,3,6,2-dioxazaborocan
3g,
which was further subjected to Br/Li exchange reaction with n-
BuLi at –100 oC followed by the addition of Me2Si(H)Cl. The
hydrolytic work-up afforded the expected benzosiloxaboroles 4f
and 4g.
It is interesting to note that compound 7d is relatively stable
and does not eliminate dihydrogen readily. According to the
o
DSC analysis 7d melts at ca. 90 C (Figure S61, ESI). Further
heating is accompanied by its dehydration rather than
dihydrogen elimination. This was confirmed by 1H NMR
spectrum which points to the formation of a dimeric anhydride
featuring the B–O–B moiety and preserving Si(H)Me2 group. It
o
decomposes only at relatively high temperatures (> 200 C). A
relative inertness of the Si–H bond in 7d is apparently due to a
structural rigidity resulting from the incorporation of the boron
atom into the five-membered carboxaborole ring. (Figure 3).
In addition, we have attempted to convert 3e into 4-fluoro-5-
formyl-6-(dihydroxyboryl)benzosiloxaborole 4e by a double Br/Li
exchange followed by boronation and hydrolysis. Both bromine
atoms in 3e were susceptible to the interconversion with an
excess of t-BuLi in THF at –78 °C. The obtained dilithio reagent
was treated with an excess of B(OMe)3. Hydrolysis and
subsequent workup afforded a mixture containing the expected
product 4e as a minor component (ca. 20%). The major product
was the compound 5e resulting from the reduction of the CHO
group in 4e and comprising CH2OB linkage within the fused
oxaborole ring. Addition of NaBH4 to the mixture of 4e and 5e in
THF resulted in the complete reduction of the former compound
affording pure 5e after aqueous acidic workup (Scheme 6). The
formation of 5e can be explained by the hydride transfer from
the silicon atom to the formyl group. This is consistent with the
lack of dihydrogen elimination, which typically occurs during the
formation of a siloxaborole ring.[9]
Scheme 7. Preparation of functionalized benzonitriles 3f–3g and their use for
the synthesis of respective benzosiloxaboroles. Reaction conditions – i: (1)
LDA, THF, –78 oC, (2) Me2Si(H)Cl, –78 oC, (3) H3O+; ii: (1) t-BuLi, THF, –100
oC, (2) B(OMe)3, (3) H3O+; iii (1) n-BuLi, in situ B(OiPr)3, THF/Et2O (1:1), -100
oC, (2) CH3SiCl, –78 oC then (3) 40 oC, (4) N-butyldiethanolamine, Et2O, r.t.; v:
(1) n-BuLi, THF/Et2O (1:1), –90 oC, (2) B(OMe)3, (3) H3O+.
Conclusions
In
a
summary, fluorinated 1,3-dihydro-1,1-dimethyl-1,2,3-
benzosiloxaboroles bearing formyl, hydroxymethyl and cyano
groups have been prepared by multistep protocols starting with
appropriate polyhalogenated benzenes. This work was
stimulated by the recent results confirming potent antimicrobial
properties of fluorinated benzosiloxaboroles.9 It should be
stressed that the presence of additional functional groups opens
synthetic possibilities towards creating more extended systems
as exemplified by the preparation of dopamine conjugate 6c.
Such studies are currently in progress in our research group.
During our work we have found that the reduction of the formyl
group may occur as
a subsequent reaction during final
Scheme 6. Synthesis of 5e. Reaction conditions – i: (1) t-BuLi, THF, –78 oC,
(2) B(OMe)3, –100 oC, (3) H3O+; ii: (1) NaBH4, THF (2) H3O+.
hydrolysis. The reduction is obviously consistent with
a
decreased selectivity and lower yields of formyl-substituted
benzosiloxaboroles. On the other hand, this indicates that the
ortho-B(OH)2 group is able to activate the adjacent Si(H)Me2
group toward reduction of the formyl group. In the presence of
water the reaction proceeds readily at room temperature. Since
Cyano-substituted benzoxaboroles have been previously
reported to exhibit a potent activity[5b,c] and therefore we decided
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4-Bromo-2,6-difluorobenzaldehyde (1c):[14] The solution of LDA was
prepared by the addition of diisopropylamine (10.5 g, 0.104 mol) to a
solution of n-BuLi (10 M, 10 mL, 0,1 mol) in THF (150 mL) at -78 oC.
Then a solution of 1-dibromo-3,5-difluorobenzene (19.3 g, 0,1 mol) in
Et2O (50 mL) was added dropwise at –80 oC during 30 min. The mixture
was stirred for 15 min followed by a dropwise addition of a solution of
anhydrous DMF (8.0 g, 0.11 mol) in Et2O (20 mL). The resulting pale
the reported preliminary observations may have a significant
synthetic potential, we have undertaken further comprehensive
studies on the scope and selectivity of the observed boronic
group-assisted hydrosilylation supported by theoretical studies
on its plausible mechanism. Those results will be reported in due
course.
o
yellow solution was stirred for 15 min at –78 C and then it was allowed
to warm to ca. –50 °C. 1 M aqueous H2SO4 (180 mL) was added with
stirring. Further workup was carried out as described for 1a. The product
was obtained as a colorless crystalline material, m.p. 75-77 °C. Yield
19.7 g (89%). 1H NMR (400 MHz, CDCl3) δ 10.25 (t, J = 1.0 Hz, 1H), 7.19
(d, J = 8.1 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 183.43 (t, J = 4.3
Hz), 162.75 (dd, J = 267.0, 6.8 Hz), 129.36 (t, J = 13.0 Hz), 116.76–
116.45 (m), 113.18 (t, J = 11.0 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ -
113.27 (d, J = 8.1 Hz). Anal. Calcd for C7H3BrF2O (221.00): C, 38.04; H,
1.37. Found: C, 37.95; H, 1.34.
Experimental Section
General comments. Solvents used for reactions were dried by heating
to reflux with sodium/benzophenone and distilled under argon. Starting
materials including various benzene derivatives, Me2(H)SiCl, B(OMe)3
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, and 13C NMR chemical shifts are given relative to TMS using
residual solvent resonances. 11B, 19F and 29Si NMR chemical shifts are
given relative to BF3∙Et2O, CFCl3, and TMS, respectively. The syntheses
of 1a,[13] 1c,[14] 1d,[15] 2a,[16] and 2b[17] were reported previously. However,
published procedures lack experimental and analytical details and
therefore we have decided to include a full information regarding
synthetic protocols and characterization for the mentioned compounds.
3-bromo-4-iodobenzonitrile was synthesised according to previously
reported protocol.[18]
2-Bromo-4,5-difluorobenzaldehyde (1d):[15] This compound was
obtained from 1,2-dibromo-4,5-fluorobenzene using the procedure
described for 1a. However, the reactions were performed at -110 °C and
THF was used as a solvent for the preparation of a solution of n-BuLi.
The product was isolated from the crude reaction mixture by fractional
distillation under reduced pressure, b.p. 62-66 °C (1 Tr). Crystallization
from hexane (50 mL) afforded a white solid, m.p. 48-50 °C. Yield 11.1 g
(50%). 1H NMR (300 MHz, CDCl3) δ 10.24 (d, J = 3.1 Hz, 1H), 7.78 (dd, J
= 10.0, 8.3 Hz, 1H), 7.53 (dd, J = 9.1, 6.7 Hz, 1H) ppm. 13C NMR (101
MHz, CDCl3) δ 189.26 (t, J = 1.1 Hz), 153.92 (dd, J = 263.5, 14.0 Hz),
150.27 (dd, J = 253.6, 12.9 Hz), 130.57 (t, J = 4.0 Hz), 122.85 (d, J =
20.6 Hz), 121.37 (dd, J = 8.1, 3.5 Hz), 118.26 (dd, J = 19.0, 2.2 Hz) ppm.
19F NMR (376 MHz, CDCl3) δ -124.64 (dt, J = 20.6, 8.7 Hz), -135.61 – -
135.73 (m) ppm. Anal. Calcd for C7H3BrF2O (221.00): C, 38.04; H, 1.37.
Found: C, 37.82; H, 1.27.
Synthetic procedures.
4-Bromo-2-fluorobenzaldehyde (1a):[13] A solution of 1,4-dibromo-2-
fluorobenzene (25.4 g, 0.1 mol) in Et2O (100 mL) was added dropwise to
the stirred solution of n-BuLi (10 M, 10 mL, 0.1 mol) in Et2O (200 mL) at –
100 oC during 30 min. The mixture was stirred for 15 min followed by a
dropwise addition of a solution of anhydrous DMF (8.0 g, 0.11 mol) in
Et2O (20 mL). The resulting pale yellow solution was stirred for 15 min
below –90 oC and then it was allowed to warm to ca. –50 °C. 1 M
aqueous H2SO4 (120 mL) was added with stirring. The organic phase
was separated. The water phase was washed with Et2O (2 × 50 mL). The
combined organic phase was dried over anhydrous MgSO4. It was
filtered and evaporated under reduced pressure to leave a pale yellow
solid. It was recrystallized by dissolving it in warm hexane (100 mL)
followed by cooling the obtained solution to ca. -50 °C. The product was
obtained as colorless crystals, m.p. 60-63 °C. Yield 17.5 g (86%). 1H
NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.76–7.72 (m, 1H), 7.45–7.41 (m,
1H), 7.39 (dd, J = 9.7, 1.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 186.03
(d, J = 6.2 Hz), 164.10 (d, J = 262.9 Hz), 130.17 (d, J = 9.9 Hz), 129.62
(d, J = 2.6 Hz), 128.39 (d, J = 3.8 Hz), 123.06 (d, J = 8.3 Hz), 120.24 (d,
J = 23.7 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ -119.79 (dd, J = 9.7, 7.5
Hz) ppm. Anal. Calcd for C7H4BrFO (203.01): C, 41.41; H, 1.99. Found:
C, 41.65, H, 1.88.
2,4-Dibromo-6-fluorobenzaldehyde (1e): This compound was obtained
from 1,3-dibromo-5-fluorobenzene using the procedure described for 1c.
The product was obtained as a pale beige solid, m.p. 56-59 °C. Yield
23.7 g (84%). 1H NMR (300 MHz, CDCl3) δ 10.28–10.27 (m, 1H), 7.67 (m,
1H), 7.37–7.32 (m, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 187.31 (d, J
= 2.3 Hz), 162.60 (d, J = 270.2 Hz), 132.86 (d, J = 3.9 Hz), 128.79 (d, J =
11.4 Hz), 125.80 (d, J = 3.7 Hz), 121.68 (d, J = 9.2 Hz), 120.12 (d, J =
24.6 Hz) ppm. 19F NMR (282 MHz, CDCl3) δ -112.48 (d, J = 9.7 Hz) ppm.
Anal. Calcd for C7H3Br2FO (281.90): C, 29.82; H, 1.07. Found: C, 29.70;
H, 1.14.
1-Bromo-4-(dimethoxymethyl)-3-fluorobenzene (2a):[16] The mixture of
4-bromo-2-fluorobenzaldehyde 1a (10.2 g, 50 mmol), trimethyl
orthoformate (7.0 g, 66 mmol) and methanol (5 mL) to which 1 drop of
conc. H2SO4 was added, was refluxed for 1 hr at 60 C (bath temp.).
After neutralization with sodium methoxide (25wt% solution in MeOH)
and concentration, the residue was distilled in vacuo to give the title
compound as a colorless liquid, b.p. 65–68 C (1 Tr). Yield 11.8 g (95%)
1H NMR (400 MHz, CDCl3) δ 7.43 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 8.2,
1.7 Hz, 1H), 7.23 (dd, J = 9.6, 1.7 Hz, 1H), 5.54 (s, 1H), 3.34 (s, 6H) ppm.
13C NMR (101 MHz, CDCl3) δ 160.26 (d, J = 253.3 Hz), 129.51 (d, J =
4.5 Hz), 127.34 (d, J = 3.6 Hz), 124.76 (d, J = 12.7 Hz), 122.89 (d, J =
9.6 Hz), 119.20 (d, J = 24.7 Hz), 98.26 (d, J = 2.6 Hz), 53.61 ppm. 19F
NMR (376 MHz, CDCl3) δ -116.54 (m) ppm. Anal. Calcd for C9H10BrFO2
(249.08): C, 43.40; H, 4.05. Found: C, 43.15; H, 4.14.
3-Bromo-5-fluorobenzaldehyde (1b): This compound was obtained
from 1,3-dibromo-5-fluorobenzene using the procedure described for 1a.
However, the reactions were performed at -78 °C. The product was
obtained as a pale yellow solid, m.p. 40-42 °C. Yield 16.1 g (80%). 1H
NMR (400 MHz, CDCl3) δ 9.98 – 9.84 (m, 1H, CHO), 7.82–7.74 (m, 1H,
Ph), 7.58 – 7.42 (m, 2H, Ph) ppm. 19F NMR (376 MHz, CDCl3) δ -108.55
(t, J = 7.9 Hz) ppm. 13C NMR (100.6 MHz, CDCl3) δ 189.20 (d, J = 2.3
Hz), 162.81 (d, J = 254.4 Hz), 139.10 (d, J = 6.5 Hz), 128.87 (d, J = 3.2
Hz), 124.80 (d, J = 24.9 Hz), 123.57 (d, J = 8.8 Hz), 114.56 (d, J = 21.9
Hz) ppm . Anal. Calcd for C7H4BrFO (203.01): C, 41.41; H, 1.99. Found:
C, 41.27, H, 2.06.
1-Bromo-3-(dimethoxymethyl)-5-fluorobenzene
(2b):[17]
This
compound, b.p. 62–66 C (1 Tr), was obtained as described for 2a
starting with 1b. Yield 12.0 g (96%). 1H NMR (400 MHz, CDCl3) δ 7.39 (d,
J = 0.4 Hz, 1H), 7.17 (ddd, J = 8.0, 3.0, 1.1 Hz, 1H), 7.11 (ddd, J = 9.2,
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1.2, 0.6 Hz, 1H), 5.33 (s, 1H), 3.29 (s, 6H). ppm. 13C NMR (101 MHz,
CDCl3) δ 162.64 (d, J = 250.6 Hz), 142.42 (d, J = 7.3 Hz), 125.91 (d, J =
3.1 Hz), 122.49 (d, J = 9.5 Hz), 119.01 (d, J = 24.5 Hz), 112.98 (d, J =
22.4 Hz), 101.17 (d, J = 2.2 Hz), 52.56 ppm. 19F NMR (376 MHz, CDCl3)
δ -110.65 (t, J = 8.6 Hz) ppm. Anal. Calcd for C9H10BrFO2 (249.08): C,
43.40; H, 4.05. Found: C, 43.19; H, 3.90.
0.46–0.43 (m, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ 167.08 (d, J =
245.8 Hz), 143.33 (d, J = 8.5 Hz), 130.21 (d, J = 12.2 Hz), 127.20 (d, J =
3.0 Hz), 112.54 (d, J = 28.4 Hz), 101.11 (d, J = 2.3 Hz), 52.62, -3.25 (d, J
= 4.1 Hz) ppm. 19F NMR (282 MHz, CDCl3) δ -95.43 (m) ppm. 29Si{1H}
NMR (99 MHz, CDCl3) δ -19.42 ppm. Anal. Calcd for C11H16BrFO2Si
(307.23): C, 43.00; H, 5.25. Found: C, 42.94; H, 5.40.
1-Bromo-3,5-difluoro-4-(dimethoxymethyl)benzene
(2c):
This
1-Bromo-3,5-difluoro-4-(dimethoxymethyl)-2-(dimethylsilyl)benzene
(3c): This compound, b.p. 102–106 C (1 Tr), was obtained as described
for 3a starting with 2c. Yield 8.6 g (88%). 1H NMR (300 MHz, CDCl3) δ
7.18 (dd, J = 9.5, 1.7 Hz, 1H), 5.54 (s, 1H), 4.79–4.70 (m, 1H), 3.47 (s,
6H), 0.45 (dd, J = 3.9, 1.9 Hz, 6H) ppm. 13C NMR (100.6 MHz, CDCl3) δ
164.95 (dd, J = 250.2, 8.6 Hz), 161.58 (dd, J = 257.4, 9.9 Hz), 130.33 (dd,
J = 15.9, 12.3 Hz), 122.07 (d, J = 34.6 Hz), 117.28 (dd, J = 24.9, 3.1 Hz),
113.24 (dd, J = 21.3, 15.1 Hz), 99.37, 55.15 (d, J = 4.3 Hz), -3.26 (d, J =
4.3 Hz) ppm. 19F NMR (282 MHz, CDCl3) δ -96.50 – -96.62 (m), -110.84
– -110.95 (m) ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ -18.88 ppm. Anal.
Calcd for C11H15BrF2O2Si (325.22): C, 40.62; H, 4.65. Found: C, 40.47; H,
4.52.
compound, b.p. 60–63 C (1 Tr), was obtained as described for 2a
1
starting with 1c. Yield 12.4 g (93%). H NMR (300 MHz, CDCl3) δ 7.16–
7.07 (m, 2H), 5.56 (s, 1H), 3.46 (t, J = 0.4 Hz, 6H) ppm. 13C NMR (101
MHz, CDCl3) δ 160.75 (dd, J = 256.0, 9.0 Hz), 122.46 (t, J = 12.6 Hz),
115.93–115.53 (m), 113.79 (t, J = 16.3 Hz), 98.97 (t, J = 2.7 Hz), 54.94
ppm. 19F NMR (376 MHz, CDCl3) δ -111.49 – -111.56 (m) ppm. Anal.
Calcd for C9H9BrF2O2 (267.07): C, 40.48; H, 3.40. Found: C, 40.25; H,
3.23.
1-Bromo-4,5-difluoro-2-(dimethoxymethyl)benzene
(2d):
This
compound, b.p. 64–68 C (1 Tr), was obtained as described for 2a
starting with 1d. Yield 12.1 g (91%). 1H NMR (300 MHz, CDCl3) δ 7.46
(dd, J = 11.1, 8.5 Hz, 1H), 7.38 (dd, J = 9.5, 7.2 Hz, 1H), 5.46–5.44 (m,
1H), 3.36 (s, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ 149.98 (dd, J =
254.0, 13.7 Hz), 149.45 (dd, J = 249.5, 12.3 Hz), 134.15 (dd, J = 4.8, 3.9
Hz), 121.61 (d, J = 20.1 Hz), 117.29 (dd, J = 19.7, 0.9 Hz), 116.03 (dd, J
= 7.4, 3.7 Hz), 101.74, 53.67 ppm. 19F NMR (282 MHz, CDCl3) δ -134.84
– -134.98 (m), -138.00 (dddd, J = 21.1, 11.1, 7.3, 1.1 Hz) ppm. Anal.
Calcd for C9H9BrF2O2 (267.07): C, 40.48; H, 3.40. Found: C, 40.37; H,
3.43.
2-Bromo-4,5-difluoro-1-(dimethoxymethyl)-3-(dimethylsilyl)benzene
(3d): This compound, b.p. 107–110 C (1 Tr), was obtained as described
for 3a starting with 2d. Yield 8.7 g (90%). 1H NMR (300 MHz, CDCl3) δ
7.47 (dd, J = 10.8, 8.8 Hz, 1H), 5.50 (d, J = 1.2 Hz, 1H), 4.84–4.74 (m,
1H), 3.38 (s, 6H), 0.48 (dd, J = 3.9, 1.9 Hz, 6H) ppm. 13C NMR (101 MHz,
CDCl3) δ 154.33 (dd, J = 247.6, 12.3 Hz), 149.47 (dd, J = 251.7, 16.9 Hz),
134.81 (t, J = 4.0 Hz), 129.40 (dd, J = 27.2, 1.9 Hz), 123.61 (dd, J = 10.0,
3.8 Hz), 118.44 (dd, J = 19.8, 1.6 Hz), 102.72, 54.20, -3.06 (d, J = 4.6
Hz) ppm. 19F NMR (282 MHz, CDCl3) δ -120.68 – -120.88 (m), -138.48
(dd, J = 23.1, 10.8 Hz) ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ -18.85 (J =
2.6 Hz) ppm. Anal. Calcd for C11H15BrF2O2Si (325.22): C, 40.62; H, 4.65.
Found: C, 40.70; H, 4.43.
1,5-Dibromo-2-(dimethoxymethyl)-3-fluorobenzene
(2e):
This
compound, b.p. 93–96 C (1 Tr), was obtained as described for 2a
1
starting with 1e. Yield 15.4 g (95%). H NMR (400 MHz, CDCl3) δ 7.52–
7.50 (m, 1H), 7.20 (dd, J = 9.9, 1.9 Hz, 1H), 5.60 (d, J = 1.2 Hz, 1H), 3.42
(s, 6H) ppm.13C NMR (101 MHz, CDCl3) δ 160.91 (d, J = 260.9 Hz),
131.54 (d, J = 3.9 Hz), 124.53 (d, J = 14.5 Hz), 123.85 (d, J = 6.4 Hz),
1,5-Dibromo-2-(dimethoxymethyl)-4-(dimethylsilyl)-3-fluorobenzene
(3e): This compound, b.p. 134–137 C (1 Tr), was obtained as described
for 3a starting with 2e. Yield 9.6 g (83%). 1H NMR (400 MHz, CDCl3) δ
7.59 (d, J = 1.4 Hz, 1H), 5.61 (d, J = 1.4 Hz, 1H), 4.75–4.67 (m, 1H), 3.46
(s, 6H), 0.43 (dd, J = 3.9, 1.9 Hz, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ
165.08 (d, J = 255.0 Hz), 132.96 (d, J = 3.8 Hz), 130.77 (d, J = 14.2 Hz),
125.22 (d, J = 7.4 Hz), 123.97 (d, J = 19.8 Hz), 104.63, 55.90, -3.20 (d, J
= 4.6 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ -94.09 ppm. 29Si{1H} NMR
(99 MHz, CDCl3) δ -18.30 ppm. Anal. Calcd for C11H15Br2FO2Si (386.13):
C, 34.22; H, 3.92. Found: C, 34.11; H, 3.76.
122.92 (d, J = 10.9 Hz), 119.64 (d, J = 26.4 Hz), 104.20, 55.44 ppm. 19
F
NMR (376 MHz, CDCl3) δ -108.84 (d, J = 9.9 Hz) ppm. Anal. Calcd for
C9H9Br2FO2 (325.90): C, 32.96; H, 2.77. Found: C, 32.77; H, 2.70.
1-Bromo-4-(dimethoxymethyl)-2-(dimethylsilyl)-3-fluorobenzene
(3a): A solution of 2a (7.5 g, 30 mmol) in Et2O (20 mL) was added at –
75 °C to
a
stirred solution of LDA, freshly
prepared from
diisopropylamine (3.2 g, 32 mmol) and nBuLi (10 M, 3 mL, 30 mmol) in
THF (50 mL). After ca 30 min stirring at ca –75 °C Me2Si(H)Cl (3.0 g,
31.5 mmol) was added slowly. The mixture was stirred for 30 min at –
75 °C and was then allowed to warm to the room temperature. Solvents
were removed under reduced pressure and the residue was dissolved in
hexane. The mixture was filtered under argon through a Celite pad to
remove LiCl byproduct. The filtrate was concentrated and the residue
was subjected to a fractional distillation under reduced pressure. The
product was obtained as a colorless liquid, b.p. 102-105 °C (1 Tr). Yield
2-Bromo-4-fluoro-3-(dimethylsilyl)benzonitrile (3f): This compound,
b.p. 95-97 C (1 Tr), was obtained as described for 3a starting with 2-
bromo-4-fluorobenzonitrile. LTMP freshly prepared from 2,2,6,6-
tetramethylpiperidine and n-BuLi, was used as lithiating agent instead of
LDA. Yield 8.3 g (62%). 1H NMR (300 MHz, CDCl3) δ 7.69 (dd, J = 8.6,
5.8 Hz, 1H, Ph), 7.15–7.06 (m, 1H, Ph), 4.90–4.69 (m, 1H, SiMe2H), 0.50
(dd, J = 3.9, 1.9 Hz, 6H, SiMe2H) ppm. 13C NMR (100.6 MHz, CDCl3) δ
168.72 (d, J = 255.3 Hz), 136.92 (d, J = 10.9 Hz), 133.66 (d, J = 13.2 Hz),
129.09 (d, J = 33.3 Hz), 117.12, 115.16 (d, J = 28.6 Hz), 113.31 (d, J =
3.8 Hz), -3.22 (d, J = 4.4 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ -85.19 –
-85.30 (m) ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ -19.22 ppm. Anal.
Calcd for C9H9BrFNSi (258.16): C, 41.87; H, 3.52. Found: C, 42.10; H,
3.40.
1
7.8 g (85%). H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.9 Hz, 1H), 7.36
(d, J = 8.2 Hz, 1H), 5.52 (s, 1H), 4.79–4.71 (m, 1H), 3.36 (s, 6H), 0.45
(dd, J = 3.9, 1.8 Hz, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ 164.52 (d, J
= 248.0 Hz), 130.74 (d, J = 12.4 Hz), 130.62 (d, J = 5.2 Hz), 128.86 (d, J
= 3.5 Hz), 125.95 (d, J = 32.8 Hz), 124.25 (d, J = 17.4 Hz), 98.60 (d, J =
3.8 Hz), 53.78, -3.02 (d, J = 4.4 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ -
101.77 ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ -19.17 ppm. Anal. Calcd
for C11H16BrFO2Si (307.23): C, 43.00; H, 5.25. Found: C, 43.12; H, 5.33.
6-Butyl-2-(2'-bromo-4'-cyanophenyl)-(N-B)-1,3,6,2-dioxazaborocan
(3g): A n-BuLi solution in hexane (2.5 M, 20.0 mL, 0.050 mol) was slowly
added to a stirred solution of 3-bromo-4-iodobenzonitrile18 (15.06 g,
0.049 mol) and B(OiPr)3 (11.5 mL, 0.050 mol) in THF/Et2O (2:1, 300 mL)
at -100 oC. After 30 min of stirring, the mixture was slowly warmed to -78
oC and Me3SiCl (22.4 mL, 0.176 mol) was added dropwise. The reaction
1-Bromo-5-(dimethoxymethyl)-2-(dimethylsilyl)-3-fluorobenzene
(3b): This compound, b.p. 105–108 C (1 Tr), was obtained as described
for 3a starting with 2b. Yield 7.6 g (82%). 1H NMR (400 MHz, CDCl3) δ
7.46 (s, 1H), 7.06 (d, J = 9.4 Hz, 1H), 4.79–4.69 (m, 1H), 3.32 (s, 6H),
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10.1002/ejoc.201601328
European Journal of Organic Chemistry
FULL PAPER
was warmed to 40 oC, stirred for 5 h and cooled to room temperature.
The precipitation of white solid (LiCl) was observed. It was removed by
filtration under argon, and the solvents were evaporated from the filtrate
to give a crude diisopropoxyboryl ester which was used for the next step
without purification. Thus, it was dissolved in Et2O (70 mL) followed by
the addition of N-butyldiethanolamine (8.2 mL, 0.049 mol). The resulting
dark-red solution was concentrated. The precipitated product was
washed with Et2O (ca. 40 mL) and filtered under argon to give the title
compound as a white powder. Yield: 11.2 g (65%). 1H NMR (300 MHz,
CDCl3) δ 7.95 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.52 (dd, J =
7.8, 1.6 Hz, 1H), 4.29 – 4.09 (m, 4H), 3.40 – 3.24 (m, 2H), 3.19 – 3.03 (m,
2H), 2.73 – 2.51 (m, 2H), 1.71 – 1.50 (m, 2H), 1.31 – 1.12 (m, 3H), 0.87
(t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 137.33, 136.17, 129.51,
129.20, 118.02, 112.83, 63.18, 58.61, 58.57, 26.92, 20.12, 13.69 ppm.
11B NMR (96 MHz, CDCl3) δ 11.63 ppm. Anal. Calcd for C15H20BBrN2O2
(350.08): C, 51.32; H, 3.74; N, 7.89. Found: C, 51.37; H, 3.79; N, 7.81.
The product hydrolyzes rapidly when exposed to moist air and should be
stored and handled under argon.
acetone-d6) δ 20.38 ppm. HRMS (EI): calcd. for C9H9BF2O3Si [M]+
242.0382; found 242.0378.
4,5-Difluoro-7-formyl-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-
benzosiloxaborole (4d): This compound was obtained as described for
4a starting with 3d. White powder, m.p. 134–137 C. Yield 1.75 g (72%).
1H NMR (300 MHz, acetone-d6) δ 10.41 (d, J = 1.5 Hz, 1H), 9.07 (s, 1H),
8.02 (dd, J = 10.9, 7.4 Hz, 1H), 0.52 (s, 6H) ppm. 13C NMR (101 MHz,
acetone-d6) δ 194.53, 155.35 (dd, J = 253.6, 11.5 Hz), 152.25 (dd, J =
255.7, 16.3 Hz), 141.57 (d, J = 29.2 Hz), 139.22 (t, J = 3.5 Hz), 123.33 (d,
J = 18.3 Hz), -0.92 ppm. 19F NMR (471 MHz, acetone-d6) δ -122.61 (dd,
J = 23.8, 7.4 Hz), -136.53 (ddd, J = 23.8, 11.0, 1.7 Hz) ppm. 11B NMR (96
MHz, acetone-d6) δ 28.7 ppm. 29Si{1H} NMR (99 MHz, acetone-d6) δ
20.76 ppm. HRMS (EI): calcd. for C9H9BF2O3Si [M]+ 242.0382; found
242.0384.
7-Cyano-4-fluoro-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-
benzosiloxaborole (4f): This compound was obtained as described for
4a starting with 3f. White powder, m.p. 119–122 C. Yield 0.28 g (65%).
1H NMR (400 MHz, CDCl3) δ 7.77 (ddd, J = 8.3, 4.7, 0.9 Hz, 1H, Ph),
7.19 (ddd, J = 8.3, 6.5, 1.0 Hz, 1H, Ph), 5.51 (br, 1H, OH), 0.52 (s, 6H,
SiMe2) ppm. 13C NMR (100.6 MHz, CDCl3) δ 166.57 (d, J = 255.0 Hz),
161.35 (d, J = 12.7 Hz), 137.48 (d, J = 7.9 Hz), 134.60 (d, J = 11.3 Hz),
117.97 (d, J = 26.2 Hz), 110.83, 108.25 (d, J = 23.3 Hz), 103.86 (d, J =
25.1 Hz), -1.04 ppm. 19F NMR (376 MHz, CDCl3) δ -94.18 (t, J = 5.3 Hz)
ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ 20.92 ppm. Anal. Calcd for
C9H9BFNO2Si (221.07): C, 48.90; H, 4.10. Found: C, 49.28; H, 3.64.
HRMS (EI): calcd. for C9H9BFNO2Si [M]+ 221.0480; found 221.0484.
4-Fluoro-5-formyl-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-
benzosiloxaborole (4a): A solution of 3a (3.07 g, 0.01 mol) in Et2O (15
mL) was added dropwise to a solution of t-BuLi (1.7 M in pentane, 12 mL,
0.02 mol) in Et2O (30 mL) and cooled to –100 °C. After 30 min of stirring
at –100 °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 aq. H2SO4 to reach
the pH = 2-3 and stirred at room temperature until evolution of H2 ceased.
The aqueous phase was separated followed by the extraction with Et2O
(2 × 20 mL). The extracts were added to the organic phase, which was
concentrated under reduced pressure. Water acidified with a few drops of
conc. aqueous HCl was added and the mixture was heated at ca. 60 °C
under reduced pressure. The white solid precipitated during the
evaporation. It was filtered, washed with CH2Cl2 (5 mL), hexane (2 × 5
mL) and dried in vacuo to give 4a, m.p. 164–167 °C. Yield 1.85 g (82%).
1H NMR (400 MHz, acetone-d6) δ 10.38 (s, 1H), 7.94 (dd, J = 7.3, 6.7 Hz,
1H), 7.77 (ddd, J = 7.3, 1.6, 0.6 Hz, 1H), 0.49 (s, 6H) ppm. 13C NMR (101
MHz, acetone-d6) δ 188.09 (d, J = 5.1 Hz), 166.55 (d, J = 255.9 Hz),
137.57 (d, J = 31.2 Hz), 131.81, 128.70 (d, J = 3.5 Hz), 125.79 (d, J =
11.1 Hz), -0.74 ppm. 11B NMR (96 MHz, CDCl3) δ 29.3 ppm. 19F NMR
(376 MHz, acetone-d6) δ -114.31 (dd, J = 6.7, 1.6 Hz) ppm. 29Si{1H} NMR
(99 MHz, acetone-d6) δ 19.94 ppm. HRMS (EI): calcd. for C9H10BFO3Si
[M]+ 224.0476; found 224.0477.
5-Cyano-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-
benzosiloxaborole (4g): A solution of 3g (2.04 g, 6 mmol) in THF (15
mL) was slowly added to a stirred solution of n-BuLi (1.6 M, 3.8 mL, 6
mmol) in THF (20 mL) at –90 oC. After 1 h of stirring the solution of
Me2Si(H)Cl (0.65 mL, 6 mmol) in THF (5 mL) was added dropwise. The
solution was warmed to –30 °C and hydrolyzed with 1.5 M H2SO4. After
the hydrogen evolution ceased the water phase was separated followed
by extraction with Et2O (20 mL), the organic phase was washed with 0.5
M H2SO4 and brine (20 mL). Organic phases were combined and
concentrated under reduced pressure. The solid residue was crystallized
from hexane/ chloroform (10:10 ml). White powder, m.p. 129–130 C.
Yield 0.67 g (57%).1H NMR (300 MHz CDCl3) δ 7.93 (dd, J = 7.6, 0.9 Hz,
1H), 7.90 (dd, J = 1.5, 0.9 Hz, 1H), 7.74 (dd, J = 7.6, 1.5 Hz, 1H), 0.48 (s,
6H). 13C NMR (101 MHz, CDCl3) δ 151.12, 133.89, 132.80, 131.70,
119.03, 114.32, -0.78 ppm.11B NMR (96 MHz, CDCl3) δ 29.3 ppm.
4-Fluoro-6-formyl-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-
benzosiloxaborole (4b): This compound was obtained as described for
4a starting with 3b. White powder, m.p. 102–105 C. Yield 0.95 g (42%).
1H NMR (300 MHz, CDCl3) δ 10.09 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.62
(dd, J = 7.0, 0.9 Hz, 1H), 0.56 (s, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ
191.62, 164.96 (d, J = 248.2 Hz), 144.5 (broad), 142.86 (d, J = 32.0 Hz),
140.78 (d, J = 5.0 Hz), 129.64, 116.36 (d, J = 25.4 Hz), -0.95 ppm. 11B
NMR (96 MHz, CDCl3) δ 29.5 ppm. 19F NMR (282 MHz, CDCl3) δ -103.02
ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ 22.00 ppm. HRMS (EI): calcd. for
C9H10BFO3Si [M]+ 224.0476; found 224.0477.
29Si{1H} NMR (99 MHz, CDCl3)
δ 22.34 ppm. Anal. Calcd for
C9H9BFNO2Si (203.08): C, 53.23; H, 4.96; N, 6,90. Found: C, 53.19; H,
4.80; N, 6,75. HRMS (EI): calcd. for C9H10BNO2Si [M]+ 203.0574; found
203.0577.
4-Fluoro-5-(hydroxymethyl)-1,3-dihydro-3-hydroxy-1,1-dimethyl-
1,2,3-benzosiloxaborole (5a). Compound 4a (230 mg, 1.03 mmol) was
dissolved in THF (5 mL). The solution was cooled to 0 °C. Then NaBH4
(50 mg, 1.25 mmol) was added and a vigorous evolution of H2 was
observed. The mixture was stirred for 30 min at room temperature and
hydrolyzed with 1.5 M aq. H2SO4. The aqueous phase was separated
followed by the extraction with Et2O (2 × 20 mL). The extracts were
added to the organic phase, which was dried with CaCl2 and
concentrated to leave a white solid. It was washed with acetone (2 × 5
mL) and dried in vacuo to give 5a, m.p. 285–290 °C. Yield 205 mg (90%).
1H NMR (300 MHz, dmso-d6+D2O) δ 9.23 (s, 1H), 7.62 (dd, J = 7.3, 2.2
Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 4.57 (s, 2H), 0.40 (s, 6H) ppm. 13C NMR
(101 MHz, dmso-d6+D2O) δ 161.79 (d, J = 243.3 Hz), 143.08, 134.47 (d,
J = 31.4 Hz), 132.09 (d, J = 3.4 Hz), 131.22 (d, J = 17.6 Hz), 128.20 (d, J
= 3.0 Hz), 57.15 (d, J = 3.4 Hz), -0.20 ppm. 19F NMR (282 MHz, dmso-
4,6-Difluoro-5-formyl-1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-
benzosiloxaborole (4c): This compound was obtained as described for
4a starting with 3c. White powder, m.p. 167–170 C. Yield 1.95 g (80%).
1H NMR (300 MHz, acetone-d6) δ 10.40–10.38 (m, 1H), 7.50 (d, J = 9.6
Hz, 1H), 0.50 (s, 6H) ppm. 13C NMR (101 MHz, acetone-d6) δ 184.53 (dd,
J = 5.0, 3.5 Hz), 164.78 (dd, J = 264.3, 3.4 Hz), 164.01 (dd, J = 260.1,
5.1 Hz), 152.1 (broad), 131.42 (d, J = 31.9 Hz), 114.94 (dd, J = 18.6, 3.8
Hz), 114.78 (dd, J = 14.2, 11.3 Hz), -1.66 ppm. 11B NMR (96 MHz,
acetone-d6) δ 29.7 ppm. 19F NMR (376 MHz, acetone-d6) δ -106.77 (d, J
= 5.5 Hz), -114.63 (dd, J = 9.5, 5.5 Hz) ppm. 29Si{1H} NMR (99 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601328
European Journal of Organic Chemistry
FULL PAPER
d6+D2O) δ -111.01 ppm. 29Si{1H} NMR (99 MHz, dmso-d6+D2O) δ 19.58
ppm. HRMS (EI): calcd. for C9H12BFO3Si [M]+ 226.0633; found 226.0639.
Hz) ppm. HRMS (EI): calcd. for C18H18B2F2O4Si2 [M]+ 452.0866; found
452.0869.
4-Fluoro-6-(hydroxymethyl)-1,3-dihydro-3-hydroxy-1,1-dimethyl-
1,2,3-benzosiloxaborole (5b). This compound was obtained as
described for 5a starting with 4b. White powder, m.p. 278–281 °C. Yield
190 mg (85%). 1H NMR (300 MHz, acetone-d6+D2O) δ 7.64–7.58 (m, 1H),
7.16–7.09 (m, 1H), 4.65 (s, 2H), 0.38 (s, 6H) ppm. 13C NMR (101 MHz,
acetone-d6+D2O) δ 164.82 (d, J = 243.0 Hz), 148.32 (d, J = 5.4 Hz),
132.69 (d, J = 31.2 Hz), 125.53 (d, J = 2.6 Hz), 114.73 (d, J = 25.1 Hz),
62.85 (d, J = 1.9 Hz), -1.38 ppm. 19F NMR (282 MHz, acetone-d6+D2O) δ
-106.01 ppm. 29Si{1H} NMR (99 MHz, acetone-d6+D2O) δ 21.37 ppm.
HRMS (EI): calcd. for C9H12BFO3Si [M]+ 226.0633; found 226.0635.
5,6-Difluoro-7-(dimethylsilyl)-1,3-dihydro-3-hydroxy-1,1-dimethyl-
1,2,3-benzosiloxaborole (7d). The synthesis was carried out as
described for 4d except that THF (30 mL) was added to the reaction
mixture prior to hydrolysis. The crude product consisting of 4d (ca. 65%)
and 7d (ca. 35%) was dissolved in THF (20 mL). The solution was cooled
to 0 °C. Then NaBH4 (100 mg) was added in a few portions. A vigorous
evolution of H2 was observed. The mixture was stirred for 1 hr at room
temperature and hydrolyzed with 1.5 M aq. H2SO4. The standard workup
gave a white solid, which was filtered washed with water (3 × 5 mL) and
dried in vacuo. Then it was triturated with cold Et2O/hexane (1:1, 10 mL).
The resulting suspension was filtered; the white solid was washed with
hexane (5 mL) and dried to give 5d (yield 0.90 g, 40%). The filtrate was
evaporated and the residue was crystallized from boiling hexane (20 mL)
to afford 7d as colorless needles, m.p. 99–101 C. Yield 0.35 g (15%). 1H
NMR (400 MHz, CDCl3) δ 7.13 (dd, J = 9.7, 7.0 Hz, 1H), 5.04 (s, 2H),
4.78–4.69 (m, 1H), 0.46 (dd, J = 3.8, 0.9 Hz, 6H) ppm. 13C NMR (101
MHz, CDCl3) δ 154.87 (d, J = 241.5, 11.9 Hz), 152.40 (d, J = 257.0, 18.2
Hz), 150.58 (m), 130.44 (d, J = 24.4 Hz), 111.24 (d, J = 18.2 Hz), 70.26
(d, J = 2.4 Hz), -3.24 (d, J = 2.8 Hz) ppm. 11B NMR (96 MHz, CDCl3) δ
32.3 ppm.19F NMR (376 MHz, CDCl3) δ -127.58 (d, J = 21.7 Hz), -132.78
(dd, J = 21.9, 9.7 Hz) ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ -22.23 (dd,
J = 7.8, 3.4 Hz) ppm. HRMS (EI): calcd. for C9H11BF2O2Si [M]+ 228.0589;
found 228.0582.
4,6-Difluoro-5-(hydroxymethyl)-1,3-dihydro-3-hydroxy-1,1-dimethyl-
1,2,3-benzosiloxaborole (5c). This compound was obtained as
described for 5a starting with 4c. The product contains acetone (ca
1.5wt%) used for final crystallization which could not be removed even
under reduced pressure at 90 C. White powder, m.p. 330–335 °C. Yield
1
225 mg (94%). H NMR (400 MHz, dmso-d6+D2O) δ 7.43 (d, J = 8.6 Hz,
1H), 4.51 (s, 2H), 0.40 (s, 6H) ppm. 13C NMR (101 MHz, dmso-d6+D2O) δ
163.63 (dd, J = 251.0, 6.2 Hz), 163.00 (dd, J = 247.0, 7.7 Hz), 144.71
(broad), 130.24 (d, J = 32.8 Hz), 118.87 (t, J = 21.5 Hz), 114.64 (dd, J =
19.8, 3.3 Hz), 51.09 (t, J = 3.6 Hz), -0.29 ppm. 19F NMR (282 MHz,
dmso-d6+D2O) δ -106.48 (d, J = 9.3 Hz), -113.03 (d, J = 9.3 Hz) ppm.
29Si{1H} NMR (99 MHz, dmso-d6+D2O) δ 19.25 ppm. HRMS (EI): calcd.
for C9H11BF2O3Si [M]+ 244.0539; found 244.0538.
Compound 5e: This compound was obtained as described for 4a
starting with 3e. The crude product containing ca. 20% of 4e (1H and 19
F
4,6-Difluoro-5-{N-[2-(3,4-dihydroxyphenyl)ethyl]aminomethyl}-1,3-
NMR spectra point that 4e exists in solution as a ca. 1:1 mixture of two
tautomers: a species with free CHO and B(OH)2 groups and a second
cyclic form, where these groups interact to form the carboxaborole ring)19
was dissolved in THF (20 mL). The solution was cooled to 0 °C. Then
NaBH4 (0.1 g) was added in a few portions. A vigorous evolution of H2
was initially observed. The mixture was stirred for 1 hr at room
temperature and hydrolyzed with 1.5 M aq. H2SO4. The standard workup
gave a white solid, which was filtered, washed with water (2 × 5 mL),
CH2Cl2 (5 mL) and dried in vacuo to give 5e as a white powder, m.p.
dihydro-3-hydroxy-1,1-dimethyl-1,2,3-benzosiloxaborole
(6c).
Compound 4c (242 mg, 1 mmol) and 3-hydroxytyramine hydrobromide
(245 mg, 1.03 mmol) were suspended in THF (10 mL) followed by the
addition of Et3N (303 mg, 3.0 mmol). A mixture was stirred for 1 h at 50
°C and a grayish viscous oil separated at the bottom of the flask. The
mixture was cooled to 5 °C and NaBH4 (120 mg, 3 mmol) was added in a
few portions. The resulting mixture was stirred for 1 h at ambient
temperature and concentrated under reduced pressure. A white waxy
residue was triturated with Et2O (10 mL) and the obtained suspension
was hydrolyzed by a dropwise addition 1.5 M H2SO4 so that the final pH
was adjusted to ca. 4-5. The precipitated product was filtered, washed
with water and acetone (2 × 5 mL), and dried in vacuo. The obtained
material contained a small amount of Et3N which could not be removed
by repeated washing and drying under reduced pressure. White powder,
m.p. 225–227 °C. Yield 276 mg (73%). 1H NMR (400 MHz, dmso-
d6+CF3SO3D+D2O) δ 8.93 (broad, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.66 (d,
J = 8.0 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 6.48 (dd, J = 8.0, 2.1 Hz, 1H),
4.26 (broad, 2H), 3.15 (broad, 2H), 2.78–2.71 (m, 2H). 0.42 (s, 6H) ppm.
13C NMR (101 MHz, dmso-d6+CF3SO3D+D2O) δ 163.56 (d, J = 250.2
Hz), 163.01 (d, J = 251.0 Hz), 147.85 (broad), 145.65, 144.48, 130.56 (d,
J = 32.0 Hz), 127.89, 122.67, 119.77, 119.46, 116.25 (d, J = 31.4 Hz),
114.90 (d, J = 19.2 Hz), 49.06 (t, J = 8.7 Hz), 38.30, 31.26, -0.22 ppm.
19F NMR (376 MHz, dmso-d6+CF3SO3D+D2O) δ -102.43, -108.95 ppm.
29Si{1H} NMR (99 MHz, dmso-d6+CF3SO3D+D2O) δ 18.95 ppm. HRMS
(EI): calcd. for C17H20BF2NO4Si [M]+ 379.1223; found 379.1221.
1
164–167 °C. Yield 2.05 g (81%). H NMR (400 MHz, acetone-d6) δ 8.39
(broad, 1H), 8.17 (broad, 1H), 8.00 (d, J = 3.8 Hz, 1H), 5.11 (s, 2H), 0.45
(s, 6H) ppm. 13C NMR (101 MHz, acetone-d6) δ 159.86 (d, J = 246.1 Hz),
142.34 (d, J = 18.2 Hz), 138.08 (d, J = 29.3 Hz), 130.75 (d, J = 3.2 Hz),
68.05 (d, J = 1.6 Hz), -0.58 ppm. 11B NMR (96 MHz, acetone-d6) δ 31.8,
30.1 ppm. 19F NMR (376 MHz, acetone-d6) δ -114.01 (d, J = 3.5 Hz) ppm.
HRMS (EI): calcd. for C9H11B2FO4Si [M]+ 252.0597; found 252.0598.
Structural measurement and refinement details. The single crystals of
was measured at 100 K on SuperNova diffractometer equipped with
Atlas detector (Cu-Kα radiation, λ = 1.54184 Å). The structures of 6d, 7d
were determined on SuperNova diffractometer equipped with an EOS
measurement device type (Mo-Kα radiation,
λ = 0.7107 Å). Data
reduction and analysis were carried out with the CrysAlisPro program.[20]
All structures were solved by direct methods using SHELXS-97[21] and
refined using SHELXL-2014.[22] All non-hydrogen atoms were refined
anisotropically. All structures except for 4d were measured at 100 K.
Single crystals of 4d collapsed during cooling which is probably due to
phase transition and therefore the diffraction experiment was performed
Compound 6d. This compound was obtained as described for 5a
starting with 4d. White powder, m.p. 195–197 °C. Yield 212 mg (94%).
1H NMR (400 MHz, CDCl3) δ 7.18–7.10 (m, 2H), 4.99 (s, 4H), 0.62 (d, J =
2.2 Hz, 12H) ppm. 13C NMR (101 MHz, CDCl3) δ 154.28 (dd, J = 240.6,
11.9 Hz), 152.09 (dd, J = 255.6, 18.2 Hz), 151.41 (dd, J = 5.9, 2.2 Hz),
131.85 (d, J = 23.5 Hz), 111.24 (d, J = 17.4 Hz), 69.64 (d, J = 2.3 Hz),
1.62 (d, J = 2.9 Hz) ppm. 11B NMR (96 MHz, CDCl3) δ 30.1 ppm. 19F
NMR (376 MHz, CDCl3) δ -127.98– -128.10 (m), -133.79 (dd, J = 22.0,
9.7 Hz) ppm. 29Si{1H} NMR (99 MHz, CDCl3) δ 2.28 (dd, J = 10.0, 4.3
at
room
temperature.
CCDC-1047174-1047176
contain
the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
4d: C9H9BF2O3Si, Mr = 242.06 a.u.; T = 298 K; orthorhombic space group,
Pbcm, a = 11.7006 (7) Å, b = 14.2170 (6) Å, c = 7.0010 (5) Å, V =
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10.1002/ejoc.201601328
European Journal of Organic Chemistry
FULL PAPER
1164.60 (12) Å3, Z = 4; dcalc = 1.381 gcm−3; μ = 1.97 mm−1; F(000) = 496;
crystal size = 0.07_0.07_0.01; θ range: 3.78°–67.68°; index ranges: –13
< h < 13, –16 < k <16, –8 < l < 6; absorption correction: multiscan;
number of collected / independent / unique reflection (Rint = 3.7%) =
6210 / 1128 / 738; GooF = 1.019, R1 / wR1 (I ≥ 3σ(I)) = 4.5% / 12.0%; R2
S. A. Martinis, S. J. Benkovic, S. Cusack, M. R. K. Alley, Science, 2007,
316, 31759–31761; b) T. Akama, S. J. Baker, Y. -K. Zhang, V. Hernandez,
H. Zhou, V. Sanders, Y. Freund, R. Kimura, K. R. Maples, J. Plattner,
Bioorg. Med. Chem. Lett. 2009, 19, 2129–2132; c) Y. R. Freund, T.
Akama, M. R. K. Alley, J. Antunes, C. Dong, K. Jarnagin, R. Kimura, J. A.
Nieman, K. R. Maples, J. J. Plattner, F. Rock, R. Sharma, R. Singh, V.
Sanders, Y. Zhou, FEBS Lett. 2012, 586, 3410-3414; d) E. Seiradake, W.
Mao, V. Hernandez, S. J. Baker, J. J. Plattner, M. R. K. Alley, S. Cusack,
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/ wR2 (all data) = 7.5% / 13.8%; ∆ϱres(min/max) = −0.17 / +0.13 eÅ−3
.
6d: C18H18B2F4O4Si2, Mr = 452.12 a.u.; T = 100 K; monoclinic space
group, P21/c, a = 8.5267 (2) Å, b = 11.5577 (2) Å, c = 10.1858 (2) Å,  =
100.476 (2) o; V = 987.07(4) Å3; Z = 2; dcalc = 1.521 gcm−3; μ = 0.241
mm−1; F(000) = 464; crystal size = 0.10_0.09_0.09; θ range: 2.32°–
32.70°; index ranges: –9 < h < 9, –13 < k <13, –14 < l < 14; absorption
correction: multiscan; number of collected / independent / unique
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reflection (Rint = 4.1%) = 39804 / 4111 / 3435, R1 / wR1 (I ≥ 3σ(I)) = 3.8%
(min/max)
/ 10.8%, R2 / wR2 (all data) = 4.8% / 11.9%, ∆ϱres
eÅ−3
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7d: C9H11BF2O2Si, Mr = 228.08 a.u.; T = 100 K; triclinic space group, P-1,
a = 6.4605 (7) Å, b = 9.2182 (7) Å, c = 9.5147 (9) Å,  = 110.238 (8) o, 
= 99.365 (9) o,  = 92.087 (8) o; V = 521.93(9) Å3; Z = 2; dcalc = 1.451
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absorption correction: multiscan; number of collected / independent /
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.
Acknowledgements
This work was supported by Warsaw University of Technology.
The X-ray measurements were undertaken in the
Crystallographic Unit of the Physical Chemistry Laboratory at the
Chemistry Department of the University of Warsaw. We
gratefully acknowledge the Aldrich Chemical Co., Milwaukee, WI,
U.S.A. for a long-term collaboration.
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Keywords: heterocycles • boron • arylsilanes •
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Entry for the Table of Contents
FULL PAPER
Boracycles
Maja Czub, Krzysztof Durka, Sergiusz
Luliński, Justyna Łosiewicz, Janusz
Serwatowski, Mateusz Urban, Krzysztof
Woźniak
Page No. – Page No.
The synthesis and characterization of a series of fluorinated benzosiloxaboroles
bearing the synthetically useful formyl, hydroxymethyl and cyano groups is
reported. These compounds have been obtained by multistep syntheses starting
with simple halogenated benzenes. In some cases the synergy of adjacent boron
and silicon centres resulted in an unexpected hydrosilylation of CHO group under
mild aqueous conditions.
Synthesis and Transformations of
Functionalized Benzosiloxaboroles
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