Straightforward synthesis and crystal structures of the 3-piperazine-bisbenzoxaboroles and their boronic acid analogs

Article abstract of DOI:10.1016/j.tet.2013.07.102

The straightforward synthesis of a highly biologically active 3-piperazine-bisbenzoxaborole and its fluorine analog has been described. The obtained bisbenzoxaboroles have been used in the synthesis of their phenylboronic acids analogs. One diboronic acid has been also isolated as hydrochloride salt as well as its methyl monoester. All the described compounds display unique molecular architectures, which have been determined by X-ray measurements.

Full text of DOI:10.1016/j.tet.2013.07.102

Accepted Manuscript
Straightforward synthesis and crystal structures of the 3-piperazine-
bisbenzoxaboroles and their boronic acid analogs
Agnieszka Adamczyk-Woźniak, Krzysztof M. Borys, Izabela D. Madura, Stanisław
Michałek, Alicja Pawełko
PII:
S0040-4020(13)01236-2
10.1016/j.tet.2013.07.102
TET 24684
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 May 2013
Revised Date: 11 July 2013
Accepted Date: 22 July 2013
Please cite this article as: Adamczyk-Woźniak A, Borys KM, Madura ID, Michałek S, Pawełko A,
Straightforward synthesis and crystal structures of the 3-piperazine-bisbenzoxaboroles and their boronic
acid analogs, Tetrahedron (2013), doi: 10.1016/j.tet.2013.07.102.
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ACCEPTED MANUSCRIPT
Straightforward synthesis and crystal structures of the 3-piperazine-bisbenzoxaboroles
and their boronic acid analogs
Agnieszka Adamczyk-Woźniak*, Krzysztof M. Borys, Izabela D. Madura, Stanisław
Michałek, Alicja Pawełko
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw,
Poland
Keywords: benzoxaborole, diboronic, bisboronic, monoester, piperazine, boronic acid
Abstract
The straightforward synthesis of a highly biologically active 3-piperazine-bisbenzoxaborole
and its fluorine analog has been described. The obtained bisbenzoxaboroles have been used in
the synthesis of their phenylboronic acids analogs. One diboronic acid has been also isolated
as hydrochloride salt as well as its methyl monoester. All the described compounds display
unique molecular architectures, which have been determined by X-Ray measurements.
Graphical abstract
1. Introduction
Benzoxaboroles emerged lately as compounds that possess interesting properties and have many
applications in organic synthesis, medicine and materials science.1 Recent development in
benzoxaborole chemistry is connected first of all with their biological action. Libraries of
benzoxaboroles have been investigated as antifungal agents and screened for antitrypanosomal
activity, resulting in several new leads.2 The formation of the tetrahedral adduct via a dative bond
has been postulated as the mechanism by which benzoxaboroles act as enzyme inhibitors.3 The
* Corresponding author, phone: +48222346147, fax: +48226282741, e-mail address:
agnieszka@ch.pw.edu.pl (Agnieszka Adamczyk-Woźniak).
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first 3-amino-substituted benzoxaborole was reported several years ago4 and some of its
physicochemical properties have been recently studied.5 Further studies enabled the synthesis
of several other 3-amino-substituted benzoxaboroles.6 A recent contribution describes sugar
receptor activity of those compounds.7 The biological action of several 3-amino-substituted
benzoxaboroles and other phenylboronic compounds has been also evaluated.8
The boronic acid moiety, which is able to reversibly form complexes with hydroxyl
compounds, can be responsible for binding to specific biomolecules.9 The proximity of the
nitrogen atom increases the affinity of the boronic acid towards hydroxyl compounds,
enabling their binding at physiological pH.10
The introduction of a second boronic unit into the receptor scaffold is used to achieve
selective sugar binding.11-14 Diboronic acids have also been used in materials science e.g. in
the formation of self-healing polymers15 or selective membrane transport of sugars.16
Diboronic acids are especially valued due to their higher affinity towards glucose in
comparison with fructose.11,17,18 This fact is of crucial importance in the development of
glucose sensors for use in the diagnosis and management of diabetes, a disease that is
emerging as a major global health concern. The diversity of the reported compounds is large,
yet only one crystal structure of the diboronic acid sugar receptor has been reported.19
The piperazine scaffold is frequently found in biologically active compounds, perhaps thanks
to its high affinity to various receptors.20-26 The piperazine-containing potent anticancer drug
(Imatinib) is the first to be found to act by inhibiting a specific enzyme rather than by killing
all of the rapidly dividing cells.27 Similar action is displayed by the recently developed
boronic anticancer drug Bortezomib, inhibiting the Proteasome 26S receptor.28 Despite the
potential importance of molecules that combine piperazine and boronic scaffolds, only a few
such phenylboronic derivatives have been obtained and studied so far.29 The present
contribution describes the straightforward synthesis of several species containing two
benzoxaborole or phenylboronic acid units linked to a piperazine scaffold placed at ortho
position.
2. Results and discussion
Current work deals with the straightforward synthesis, molecular structure and spectroscopic
investigation of piperazine derivatives of phenylboronic acids.
2.1. Synthesis
Compounds 1 – 4 have been obtained by relatively simple synthetic methods (Scheme 1).
Molecules 1a and 1b contain two oxaborole functions that may lead to useful properties.
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Compound 1a indeed has recently shown an exceptional biological action against
Mycobacterium luteum, Aspergillus niger and Candida tenuis, no details of its synthesis or
characterization data have been yet reported.8 Compounds 1a and 1b have been obtained by the
amination of 2-formylphenylboronic acid or its fluorinated analog with piperazine. Very low
solubility of 1a and 1b in the employed reaction solvents’ mixture (diethyl ether or diethyl
ether/THF ) caused precipitation of the products. It allowed for the removal of the products from
the reaction mixtures, driving the reaction to completion. The application of a drying agent,
essential in the synthesis of other 3-amino-substituted benzoxaboroles was not needed in this
case.6,30
R
HO
OH
B
R
HO
H
N
B OH
O
CHO
Et2O
B
O
N
+
2
HN
NH
H
94% (1a), 86% (1b)
R = H or F
1a (R = H), 1b (R = F)
R
1. NaBH4/MeOH
2. HClaq
1. NaBH4/MeOH
2. H2O
1. NaBH4/MeOH
2. H2O
73% (R = H)
74% (2a), 65% (2b)
87% (2a), 45% (2b)
R
OH
Cl
B
OH
B
OH
N
R
N
HO
OH
1,5 M HCl aq
R = H (47%)
NH
NH
Cl
HO
B
HO
B
HO
3
crystallization
from MeOH
2a (R = H), 2b (R = F)
Cl
OH
B
O
NH
NH
Cl
O
B
HO
4
Scheme 1. Synthesis of compounds 1a-4, 1b and 2b.
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Benzoxaboroles 1a and 1b contain two asymmetric carbon atoms and according to the 2n rule,
four different diastereomers are possible (Figure 1). The 1H NMR spectra of 1a and 1b measured
in DMSO-d6 show two sets of signals of equal intensity, corresponding to two pairs of
enantiomers. After several days at room temperature, the spectra did not alter, which proves high
stability of 1a and 1b in DMSO solution. Signals corresponding to the diastereomers are
indistinguishable in the spectra recorded in CD3OD.
R
R
HO
H
B OH
O
HO
H
B OH
*
O
B
B
*
N
O
N
N
O
N
*
H
*
H
S
R
S
S
R
R
R
R
R
S
R
R
H
H
*
*
N
O
N
O
N
N
B
B
O
*
O
H
OH
B
H
B OH
*
HO
HO
R
R
Fig. 1. Diastereomers of 1a and 1b.
The reduction of benzoxaboroles 1a and 1b with NaBH4 in methanol and subsequent
hydrolysis with water afforded the corresponding diboronic acids 2a and 2b in high yields. A
one-pot amination-reduction protocol for 2 followed by hydrolysis with water resulted in
remarkably lower yield of 2b. In contrast, in the case of 2a the one-pot protocol provided a
higher yield of the product than the synthesis via benzoxaborole reduction. Changing the
hydrolysing agent from water to aqueous hydrochloric acid results in a high yield (73%) of
diboronic acid hydrochloride salt (3), a single crystal of which has been obtained by
crystallization from a water:acetonitrile mixture. Crystallization of 3 from methanol resulted
in its methyl monoester (4).
2.2. X-Ray studies
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Benzoxaboroles usually form dimeric units in the solid state.1,6,31-33 It was of interest to
determine if this pattern will be present also in the obtained bisbenzoxaborole. Single crystals of
1a were obtained by crystallization from dimethyl sulfoxide (DMSO). Molecules of 1a
crystallize in the centrosymmetric space group symmetry of the triclinic system (Table S1 in
ESI) with a half of the bisbenzoxaborole molecule (1a) and one DMSO molecule in the
asymmetric unit. Hence, the molecule of 1a generated by crystallographic inversion center is
an R,S-isomer in the solid state (Figure 2).
Fig. 2. Molecule of 1a with O-H…O hydrogen bonded DMSO molecules (dashed lines).
Ellipsoids with 50% probability and atom numbering scheme are given.
The boron atom has a flat trigonal coordination and deviates only by 0.006(2) Ǻ from the
plane defined by O1O2C1 atoms. Similarly to the other structurally characterized
benzoxaboroles,4,6,31-33,35-42 the fused six-(phenyl) and five-(borole) membered ring is flat with
the largest deviation from the l.s. plane being only 0.033(1) Ǻ. The length of C7–N1 bond
linking the borole unit with the piperazine ring is equal to 1.435(3) Ǻ. The piperazine ring
shows a chair conformation with benzoxaborole moieties in an equatorial disposition. The
relevant orientation of the piperazine unit and the plane containing fused aromatic moiety is
almost perpendicular (the dihedral angle equals to 81.87(5)º). Moreover, the boronic group is
positioned trans towards the nitrogen lone electron pair with torsion angle C1C2C7N1
amounting to 127.2(2)º. Therefore, the O-H group is pointing outside the molecule and
achieving the anti conformation. This rare conformation in benzoxaborole crystals is forced
here by the presence of the solvent molecule containing a relatively strong hydrogen bond
acceptor. In 1a, instead of typical dimeric R2 (8) O-H…O hydrogen bond motif,4,6,31,32,35-37,40-
2
42
the boronic hydroxyl group interacts with oxygen atom of the DMSO molecule. The
resultant O(1)–H(1)…O(3) bond is almost linear (the distances O…O, H…O and the O–
H…O angle equal to 2.711(2), 1.88 Ǻ and 179º, respectively) and form a finite structure with
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the D(3) graph descriptor43 (Figure 2). It is worth mentioning that such an anti conformation
has previously been observed only in one benzoxaborole derivative, namely 3-ethyl-1-
hydroxy-3-(4-hydroxybenzoyl)-2,1-benzoxaborolane,38 where the boronic O-H donor bounds
to the carbonyl oxygen acceptor present in the substituent. Since there are no other strong
hydrogen bond donors in 1a, the numerous weaker interaction are responsible for 3-D
structure formation. Single crystals of 2a were obtained by crystallization from dimethyl
sulfoxide. Molecules of 2a crystallize in P21/c space group symmetry of the monoclinic
system (Table 1 in ESI). Similarly to 1a, the molecules of 2a are generated by an inversion
center (Fig. 3).
Fig. 3. The hydrogen bonded infinite chain structure of 2a. The 50% probability thermal
ellipsoids and atom numbering scheme are shown. Hydrogen bonds are shown as dashed or
dotted lines.
No solvent molecules or solvent accessible voids were detected. The boron atom is in trigonal
environment with the deviation from the plane defined by O1O2C1 atoms amounting to
0.018(1) Ǻ. The boronic B(OH)2 moiety is twisted by 25.37(5)º with respect to the phenyl
ring and adopts syn-anti conformation of OH groups. Such conformation, although frequently
observed in crystals of boronic acids, is enhanced here by the formation of intramolecular O–
H…N hydrogen bond (H…N and O…N distances equal to 1.80(2) and 2.605(1) Ǻ,
respectively, while O–H…N angle equals to 169.2(7)º). The presence of the B-O-H…N
intramolecular hydrogen bond was previously observed for other aminomethylphenylboronic
acid derivatives characterized by X-ray diffraction methods10,19,44-49 except for the derivative50
where charge assisted intermolecular hydrogen bonds with trifluoroacetate anion were detected.
Moreover, the presence of such intramolecular H-bond in 2a forces the twist of the boronic
unit on C7–N1 bond (C1C2C7N1 torsion angle equals to 60.8(1)º). Thus, its orientation
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towards nitrogen's lone electron pair is synplanar, oppositely to 1a where the trans
conformation is observed. The linking C7–N1 bond is elongated in 2a by 0.045 Ǻ in
comparison to the relevant bond in 1a. The piperazine fragment is similar in 1a and 2a. Also
the close to perpendicular orientation of the piperazine ring and the phenyl moiety is observed
(the relevant dihedral angle equals to 87.0387(3)º). Although one OH group is involved in
intramolecular H-bond formation, the second one forms typical dimeric R2 (8) O-H…O
2
hydrogen bond motif. However, the molecule of 2a is centrosymmetric and therefore the
creation of an infinite supramolecular chain propagating along crystallographic a axis is
observed (Fig. 3). An analogous chain motif was also observed in case of ortho substituted
diboronic acid derivative with 4,4'-bipyridinium linker,51 while in structures with bis(N-(1-
phenylethyl)aminomethylanthracene)19 and ethynylene52 ortho bridges supramolecular dimers
and layers are formed, respectively. The H-bonded chains in 2a are further joined by weaker
C-H…O and C-H…π interactions. The molecules of 3 (Fig. 4) crystallize in P21/c space
group symmetry of the monoclinic system (Table 1 in ESI), and as in 1a and 2a they are
generated by an inversion center. The diboronic acid molecule is in this case protonated on
nitrogen atom and therefore the intramolecular O-H…N hydrogen bond is not formed.
Instead, N-H…O intramolecular interaction is observed, with the syn oriented OH group
acting as an acceptor (N…O, H…O distances equal to 2.812(1) and 2.13 Ǻ, respectively,
while N-H…O angle equals to 136º). The poorer geometry of this intramolecular interaction
may result for the bigger twist on B1-C1 bond comparing to 2a, which amounts to 35.1(1)º in
3. Nevertheless this interaction also forces the synplanar orientation of B(OH)2 moiety
towards nitrogen lone pair (protonated in 3) as in 2a. The protonation of nitrogen atom causes
also the elongation of C7-N1 bond length to 1.522 Ǻ. The comparison of other geometrical
parameters of 2a and 3 revealed no significant differences. In turn, the dramatic change is
observed in supramolecular architecture. Even though two OH donors are capable of
extending the structure via hydrogen bonds, the observed motif is a finite one. Both the
chloride anion and solvent water molecule serve as acceptors for boronic OH donors (Fig. 4).
Further, numerous hydrogen bonds join molecules of 3 into 3-D structure. The hydrophilic
zigzag channels along [010] direction are observed.
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Fig. 4. The molecule of 3 with 50% probability thermal ellipsoids and atom numbering
scheme are shown. The intra- and intermolecular hydrogen bonds involving boronic moieties
are denoted as dotted and dashed lines, respectively.
Crystallization of the pure product from methanol resulted in a species in which one of the
OH group in each boronic unit was esterified with methanol (4). Not many examples of
phenylboronic acids methanol hemiesters have been reported so far.53-55 The molecules of
hemiester 4 (Fig. 5) are also centrosymmetric and crystallize in monoclinic system in P21/c
space group symmetry (Table 1, ESI). Similarly to 3, the diboronic moiety is cationic with
protonated nitrogen atoms. Also the change from OH in 3 to OCH3 group in 4 does not
change their conformation towards B1-C1 bond, i.e. the ester moiety is in syn conformation
while OH in the anti one. Hence, in contrast to 3 no intramolecular hydrogen bond is formed
in 4. The absence of this H-bond leads to the twist of the piperazine moiety and thus the
relevant orientation of the phenyl ring and the N-H group is like in benzoxaborole 1a, i.e.
trans. Similarly to 3, the C7-N1 bond is elongated comparing to the value of unprotonated
amines. No substantial differences are found in the geometry of piperazine unit, while in
boronic moiety the dihedral angle between planes comprising B(OH)(OCH3) group or phenyl
ring is much smaller than in 3 and equals to 22.3(9)º. Besides, the B1-C1 bond slightly
elongates upon esterification and amounts to 1.590(1) Ǻ. Lack of intramolecular hydrogen
bond results also in different supramolecular structure. In the case of 4 both OH and NH
donors interact with chloride anion resulting in infinite chain structure. The detected solvent
accessible voids are propagating along a axis. No reliable solvent model was applied during
refinement.
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Fig. 5. The molecule of 4 with 50% probability thermal ellipsoids and atom numbering
scheme are shown. Intermolecular hydrogen bonds with chloride anions are given as dashed
lines.
3. Conclusions
A straightforward synthesis of a highly biologically active 3-piperazine-bisbenzoxaborole
(1a) and its fluorine analog (1b) has been described. The obtained bisbenzoxaboroles have
been used in the synthesis of their boronic acids analogs (2a, 2b). Compound 2a has been also
isolated in the form of the hydrochloride (3) as well as its methoxy hemiester (4). The
obtained products display unique molecular architectures, which have been determined by X-
Ray measurements. The crystal structure analysis of compounds 1a-4 revealed the presence of
centrosymmetric molecules in the crystalline state. The relevant orientation of piperazine
nitrogen lone pair or NH group towards boronic BO2 group was found to be labile and
dependent on intramolecular hydrogen bond formation. The influence of the intermolecular
hydrogen bonds on boronic hydroxyl groups’ conformation was detected.
4. Experimental section
4.1. General information
All reactions were set up under air and using undistilled solvents. The reagents were
purchased from commercial sources and used without further purification. The reported yields
refer to pure isolated products. NMR spectra were recorded on a Varian Inova 500 MHz
spectrometer in deuterated solvents. Elemental analyses were obtained by means of a Perkin
Elmer 2400 apparatus. All melting points (m.p.) are given uncorrected. The IR spectra were
recorded on a Perkin Elmer 2000 with a diamond Gladi ATR optics.
4.2. Experimental procedures and characterization data
4.2.1. 3,3'-(Piperazine-1,4-diyl)bis(benzo[c][1,2]oxaborol-1(3H)-ol) (1a)
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The solution 2-formylphenylboronic acid (4.80 g, 32 mmol) in diethyl ether (200 mL) was
prepared in a 500 mL round-bottomed flask equipped with magnetic stirrer and dropping
funnel. A solution of piperazine (1.345 g, 15.6 mmol) in diethyl ether (180 mL) was dropped
slowly (about 1 drop per second) into the 2-formylphenylboronic acid solution while stirring.
After addition of about 10% of the piperazine solution, a fine white solid precipitated. The
whole piperazine solution was then dropped-in to the suspension and the reaction mixture was
left for 24 hours at room temperature. The solid was filtered off and dried on air resulting in
5.27 g (94% yield) of 1a as white solid, m.p. 220 °C (dec.); [Found: C, 61.64; H, 5.69, N:
7.93. C18H20B2N2O4 requires C, 61.77; H, 5.76; N, 8.00%]; νmax = 3295 (br), 1611, 1443,
1343, 1171, 1137, 1010, 818, 754, 726, 631 cm-1; δH (500 MHz, CD3OD) 7.53-7.25 (8 H, m,
Ph); 5.90 (2 H, s, CH); 3.01-2.90 (8 H, m, CH2); δC (126 MHz, CD3OD) 149.7, 130.2, 128.8,
128.6, 123.5, 104.9, 45.1; δB (64 MHz CD3OD) 13.6; δH (500 MHz, DMSO-d6) 9.14 (0.5 H, s,
BOH), 9.11 (0.5 H, s, BOH), 7.71-7.30 (8 H, m, Ph), 5.84 (0.5 H, s, CH), 5.79 (0.5 H, s, CH),
2.13 (4 H, m, br, CH2CH2), 1.96 (4 H, m, br, CH2CH2); δC (126 MHz, DMSO-d6) 152.6,
152.5, 132.3, 130.9, 130.8, 130.2, 130.1, 128.1, 128.0, 122.5, 122.4, 95.7, 95.6, 46.4.
Crystallization of an analytical sample from DMSO resulted in crystals of 1a suitable for
X-Ray measurements.
4.2.2. 3,3'-(Piperazine-1,4-diyl)bis(5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol) (1b)
To a stirred solution of 4-fluoro-2-formylphenylboronic acid (500 mg, 2.98 mmol) in diethyl
ether (15 mL) and tetrahydrofuran (5 mL), a solution of piperazine (125 mg, 1.45 mmol) in
diethyl ether (17 mL) was added dropwise. After addition of ca. 1/2 of the piperazine solution,
a white fine precipitate started to form. When the addition was finished, stirring was turned
off and the reaction mixture was left at room temperature for 24 hours. The precipitate was
filtered and dried in air for 4 days. The product was obtained (481 mg, 1.25 mmol, 86%) as a
white powder, m.p. 222 °C (dec.); [Found: C, 56.20; H, 4.88; N, 7.13. C18H18B2F2N2O4
requires C, 56.01; H, 4.70; N, 7.26%]; νmax = 3312 (br), 1614, 1434, 1421, 1344, 1181, 1015,
839, 824, 806, 701, 629 cm-1; δH (500 MHz, CD3OD) 7.55-6.94 (6 H, m, Ph), 5.87 (2 H, s,
CH), 3.09-2.91 (8 H, m, CH2CH2); δF (470 MHz, CD3OD) –109.44, –109.55; δB (160 MHz,
CD3OD) 14.9; δH (500 MHz, DMSO-d6) 9.22 (1 H, s, B-OH), 9.20 (1 H, s, B-OH), 7.75-7.72
(1 H, m, Ph), 7.70-7.68 (1 H, m, Ph), 7.25-7.16 (2 H, m, Ph), 7.12-7.06 (2 H, m, Ph), 5.83 (1
H, s, CH), 5.79 (1 H, s, CH), 2.60 (4 H, s, br, CH2CH2), 2.43 (4 H, s, br, CH2CH2); δc (126
MHz, DMSO-d6) 166.4, 166.4, 164.5, 164.3, 156.5, 156.5, 156.3, 156.3, 133.4, 133.3, 133.4,
133.2, 116.9, 116.7, 116.6, 116.7, 110.5, 110.3, 110.2, 110.2, 95.7, 95.7, 95.8, 47.2.
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4.2.3. Piperazine-1,4-diylbis(methylene))bis(2,1-phenylene))diboronic acid (2a)
4.2.3.1. Synthesis of 2a via reduction of benzoxaborole (1a)
Solution of 1a (0.25 g, 0.71 mmol) in methanol (20 mL) was placed in a 50 mL round-
bottomed flask. NaBH4 (0.09 g, 2.4 mmol) was added portionwise while stirring. The mixture
was stirred for 1 h at room temperature. After that time, distilled water (15 mL) was added
resulting in white solid. The solid was filtered off and dried on air resulting in 0.221 g (87%
yield) of 2a. δH (500 MHz, CD3OD) 7.53-7.51 (2 H, m, Ph), 7.25-7.15 (6 H, m, Ph), 3.89 (4
H, s, 2*CH2), 2.85 (8 H, s, 2*CH2CH2). Crystallization of the analytical sample from DMSO
resulted in 2a crystals suitable for X-Ray measurements.
4.2.3.2. Synthesis of 2a via one-pot amination-reduction
Piperazine (1.17 g, 13.6 mmol) was dissolved in methanol (375 mL) in a 1000 mL round-
bottomed flask equipped with magnetic stirrer and a cooling bath (ice/NaCl).
2-Formylphenylboronic acid (4.03 g, 26.9 mmol) was added resulting in clear solution. The
reaction mixture was cooled down to -10 °C. While intense stirring, NaBH4 (4.70 g, 0.12 mol)
was added portionwise. The stirring was continued for another 20 min at -10 °C. Distilled
water (280 mL) was added dropwise to the resulting post-reaction mixture at room
temperature. After addition of about 70 mL of water, white precipitate appeared. The
suspension was left for 24 h at room temperature. The solid was filtered off after that time and
dried under vacuum to give 2a (3.52 g, 74%) as a white powder, m.p. 226 °C; [Found: C,
60.28; H, 6.92; N, 7.92. 3*C18H24B2N2O4*H2O requires C, 60.05; H, 6.91; N, 7.78%]; νmax
=
3262 (br), 1318, 1345, 1318, 1144, 1031, 990, 826, 768, 750, 658, 425 cm-1; δH (500 MHz,
CD3OD) 7.54-7.51 (2 H, m, Ph), 7.25-7.21 (4 H, m, Ph), 7.18-7.15 (2 H, m, Ph) 3.89 (4 H,
2*CH2); 2.88 (8 H, s, br, 2*CH2CH2); δc (126 MHz, CD3OD) 140.4, 130.0, 128.9, 128.7,
128.2, 62.4, 50.9; δB (64MHz, CD3OD) 19.0.
4.2.4. ((Piperazine-1,4-diylbis(methylene))bis(4-fluoro-2,1-phenylene))diboronic acid
(2b)
4.2.4.1. Synthesis of 2b via reduction of benzoxaborole 1b.
To a stirred solution of 1b (72 mg, 0.187 mmol) in methanol (8.0 mL), sodium borohydride
(24 mg, 0.636 mmol) was added portionwise at room temperature. The mixture was stirred for
1.5 h at room temperature. Distilled water (12 mL) was added resulting in the formation of a
white fine precipitate after ca. 2 minutes. The solid was filtered off and dried in air for 2 days
at ca. 35 °C. The product was obtained as a white solid (33 mg, 0.085 mmol, 45%).
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δH (500 MHz, CD3OD) 7.50-7.47 (2 H, m, Ph), 6.98-6.94 (4 H, m, Ph), 3.90 (4 H, s, 2*CH2),
2.87 (8 H, s, 2*CH2CH2); δF (470 MHz, CD3OD) –116.72.
4.2.4.2. Synthesis of 2b via one-pot amination-reduction.
To a stirred solution of piperazine (126 mg, 1.462 mmol, 1.00 eq) in methanol (40 mL), 4-
fluoro-2-formylphenylboronic acid (491 mg, 2.924 mmol, 2.00 eq) was added in one portion
at room temperature. The resulting mixture was cooled to –10 °C with sodium chloride/ice
bath. Sodium borohydride (489 mg, 12.866 mmol, 8.80 eq) was added portionwise over 10
minutes, maintaining the temperature of –10 °C, and the reaction mixture was stirred for the
next 35 minutes at –10 °C. The cooling bath was removed and distilled water (30 mL) was
added to the mixture, resulting in the formation a white fine precipitate after ca. 5 minutes.
The solid was filtered and dried: firstly for 2 hours at ca. 35 °C, then at room temperature for
2 days. The product 2b was afforded as a white solid (386 mg, 0.944 mmol, 65%), m.p. 226
°C; [Found: C, 55.35; H, 5.74; N, 7.23. C18H22B2F2N2O4 requires C, 55.43; H, 5.69; N,
7.18%]; νmax = 3297 (br), 1739 (br), 1368, 1228, 1146, 1033, 999, 823, 640, 544 cm-1; δH (500
MHz, CD3OD) 7.50-7.47 (2 H, m, Ph), 6.98-6.95 (4 H, m, Ph), 3.89 (4 H, s, 2*CH2), 2.87 (8
H, s, 2*CH2CH2); δC (126 MHz, DMSO-d6) 165.1, 163.1, 143.5, 135.6, 115.1, 114.6, 114.6,
61.5, 50.1; δF (470 MHz, CD3OD) –116.56; δB (160 MHz, CD3OD) 19.3.
4.2.5. ((Piperazine-1,4-diylbis(methylene))bis(4-fluoro-2,1-phenylene))diboronic acid
hydrochloride (3)
4.2.5.1 Synthesis of 3 in an amination-reduction reaction
Piperazine (1.15 g, 13.4 mmol) was dissolved in MeOH (70 mL) and stirred at -10ºC. 2-
Formylphenylboronic acid (4.00 g, 26.7 mmol) was added resulting in clear solution. NaBH4
(4.70 g, 13.4 mmol) was added and intense stirring was continued for 20 minutes. HCl aq (3
M, 25 mL) was added (pH~1) and the mixture was stirred for 10 minutes. Diethyl ether (40
mL) was poured into the solution resulting in precipitation of a white solid that was left for 18
hours at room temperature, filtered off and dried on air giving 4.24 g (73%) of the diboronic
product hydrochloride (3). Crystallization of the analytical sample of the product from a
water:acetonitrile mixture resulted in monocrystals of 3 suitable for X-Ray analysis.
Crystallization from MeOH resulted in monocrystals of 4 suitable for X-Ray analysis.
4.2.5.2 Synthesis of 3 starting from the acid 2a
Diboronic acid 2a (0.300 g) and distilled water (4 mL) were placed in a 15 mL beaker.
Hydrochloric acid (3 M, 4 mL) was added to the white suspension while intense stirring. In
few seconds, the solid dissolved and considerable amount of a white solid of the
hydrochloride appeared. The mixture was left for two hours on stirring at room temperature
12

ACCEPTED MANUSCRIPT
and than the solid was filtered off. The solid was washed with distilled water till the pH of the
rinse solution was not acidic. The resulting solid was dried on air to give 3 hexahydrate (0.170
g, 47%) as a white solid, m.p. 252 °C (dec.); [Found C, 40.42; H, 7.10; N, 5.24.
C18H38B2Cl2N2O10 requires C, 40.41; H, 7.16; N, 5.24%]; νmax = 3442 (br), 3246 (br), 3106,
3015, 1738, 1365, 1202, 1155, 1100, 938, 641, 527 cm-1; δH (500 MHz, CD3OD) 7.89 (2 H, d,
J 5.9 Hz, Ph), 7.58-7.48 (6 H, m, Ph), 4.65 (4 H, s, br., 2*Ph-CH2-N), 3.68 (8 H, s, br., 2*N-
CH2-CH2-N), δB (160 MHz, CD3OD) 30.0; δH (500 MHz, (CD3)2SO) 7.81 (2 H, d, J 7.0 Hz,
Ph); 7.63 (2 H, d, J 7.5 Hz, Ph), 7.48-7.40 (4 H, m, Ph), 4.50 (4 H, s, br., 2*Ph-CH2-N), 3.44
(8 H, s, br., 2*N-CH2-CH2-N); δC (125.7 MHz, (CD3)2SO) 136.5, 135.3, 134.4, 131.7, 129.9,
128.6, 59.0, 47.9.
4.3. X-ray diffraction measurements
Single crystal data for 1a-4 (Table 1) were collected on Gemini A Ultra Diffractometer
(Agilent Technologies) with mirror monochromated Cu/Kα radiation (λ = 1.5418 Å). The
CrysAlisPro56 program was used for data collection, cell refinement, data reduction and the
empirical absorption corrections using spherical harmonics, implemented in multi-scan
scaling algorithm. The structures were solved using direct methods, and refined with the full-
matrix least-squares technique using the SHELXS97 and SHELXL97 programs,
respectively,57 both implemented in OLEX2 program.58 All non-hydrogen atoms were refined
with anisotropic temperature factors. The positions of hydrogen atoms bonded to oxygen or
nitrogen atoms were refined freely with fixed isotropic thermal parameters equal to 1.2 ×Ueq
of appropriate atom. The hydrogen atoms bonded to carbon atoms were introduced in
geometrically idealized positions and refined with a riding model with Uiso(H) values of 1.2
×Ueq(C) or 1.5 ×Ueq(C) for methyl groups in 1a. In case of 4, all atoms of the phenylboronic
acid moiety can be located and refined satisfactorily to give R1 ca. 11% and wR2 ca. 30%.
Residual electron density remains, distributed throughout the channels (along the a direction)
and calculated total solvent accesible volume per unit cell amounted to 234.5 Å3 (~18%). This
cannot be resolved into any meaningful atomic positions and was treated, therefore, using the
MASK procedure59 implemented in OLEX2 program.58 The electron density was estimated to
be 51 electrons per unit cell, and correction of the Fobs data to remove its contribution resulted
in R1 and wR2 falling to 3.05% and 7.91%, respectively, and the residual electron density
below 0.4 e/Å3. Figures presenting molecular structures with basic H-bonded motives were
generated using ORTEP-3 for Windows.34 The geometric calculations were done by
13

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PLATON package.60 Values involving hydrogen atoms in the calculated positions are given
without estimated standard deviations.
Table 1. Crystal data.
Parameters
1a
2a
3
4
Empirical formula
Formula moiety
C22H32B2N2O6S2 C18H24B2N2O4
C18H20B2N2O4, C18H24B2N2O4
2 (C2H6SO)
C18H38B2Cl2N2O10 C20H30B2Cl2N2O4
+
+
C18H26B2N2O4 ,
C20H30B2N2O4 ,
2Cl–, 6H2O
2Cl–
Formula weight
Temperature/K
Crystal system
Space group
506.24
354.01
100.0
535.02
454.98
100.0
100.0
100.0
Triclinic
P–1
monoclinic
P21/c
monoclinic
P21/c
Monoclinic
P21/c
a /Å, b /Å, c /Å
5.7946(8),
8.1940(12),
13.093(2)
89.403(13)
87.300(13)
88.998(12)
620.85(16)
1
6.03695(17)
7.74920(18)
19.9827(4)
90
11.57123(16)
16.19904(18)
7.14661(11)
90
7.11214(7)
17.23967(12)
11.10757(10)
90
α /°, β /°, γ /°
92.895(2)
90
107.9826(15)
90
107.9866(10)
90
Volume /Å3
Z
933.63(4)
2
1274.14(3)
2
1295.35(2)
2
ρcalc /mg mm–3
ꢀ /mm–1
1.354
1.259
1.395
1.166
2.286
0.702
2.761
2.462
F(000)
268
376
568
480
Index ranges
–6 ≤ h ≤ 6,
–9 ≤ k ≤ 9,
–15 ≤ l ≤ 15
–7
–9
≤
≤
h
k
≤
≤
6, –13
9, –19
≤
≤
h
k
≤
≤
13, –8
≤
h
≤
7,
19, –20 ≤ k ≤ 20,
–13 ≤ l ≤ 13
–23 ≤ l ≤ 23
5577
–8 ≤ l ≤ 8
Reflections collected 30583
32254
46051
Independent
reflections
2198[R(int)
0.078]
= 1662[R(int)
0.016]
= 2282[R(int) = 0.039] 2318[R(int)
=
0.0345]
Data/restraints/parame 2198/0/159
1662/0/124
2282/0/181
2318/0/143
ters
Goodness-of-fit on F2 1.063
1.051
1.063
1.077
Final
R
indexes [I R1
wR2 = 0.0973
0.0476, R1 = 0.0370, wR2 R1 = 0.0288, wR2 = R1 = 0.0312, wR2
wR2 = 0.1015 = 0.0941 0.0721 = 0.0793
=
0.0405, R1 = 0.0356, wR2 R1 = 0.0271, wR2 = R1 = 0.0305, wR2
>2σ(I)]
= 0.0930 0.0708 = 0.0787
Final R indexes [all R1
data]
=
14

ACCEPTED MANUSCRIPT
Largest
diff. 0.41/–0.29
0.28/–0.21
0.30/–0.19
0.26/–0.22
peak/hole/e Å–3
Acknowledgements: The work has been supported by Warsaw University of Technology.
Agnieszka Adamczyk-Woźniak acknowledges financial support by Warsaw University of
Technology within the Dean’s grant (2011-2012).
Supplementary data
Supplementary data related to this article can be found online at [link]. Crystallographic data
(excluding structure factors) for the structure reported in this paper has been deposited with
the Cambridge Crystallographic Data Centre as deposit numbers CCDC 940237-940240.
Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Rd,
Cambridge CB2IEZ UK (fax: +44 (1223) 336 033; e-mail: deposit@ccdc.cam.ac.uk.
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Supplementary data
Straightforward synthesis and crystal structures of the 3-piperazine-bisbenzoxaboroles
and their boronic acid analogs
Agnieszka Adamczyk-Woźniak*, Krzysztof M. Borys, Izabela D. Madura, Stanisław
Michałek, Alicja Pawełko
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw,
Poland
Table S1. Bond lengths for compounds 1a, 2a, 3 and 4, Å.
Table S2. Bond angles for compounds 1a, 2a, 3 and 4, º
Table S3. Torsion angles for compounds 1a, 2a, 3 and 4, º.
page 2
page 2
page 3
page 4
.
Table S4. Hydrogen bonds geometry for compounds 1a, 2a, 3 and 4, Å,º.
Cl
Cl
OH
OH
OH
B
B
B
HO
H
N
B
OH
O
OH
OH
NH
O
N
B
NH
Cl
HO
N
HO
NH
NH
Cl
O
O
N
B
B
HO
B
HO
H
HO
*2 DMSO
* 6 H2O
1a
2a
3
4
Figure. Structures determined by X-Ray.
* Corresponding author, phone: +48222346147, fax: +48226282741, e-mail address:
agnieszka@ch.pw.edu.pl (Agnieszka Adamczyk-Woźniak).
1

ACCEPTED MANUSCRIPT
Table S1. Bond lengths for compounds 1a, 2a, 3 and 4, Å
1a
2a
3
4
O1–B1
O2–B1
O1–C7
O1–C10
C1–B1
N1–C7
N1–C8
N1–C9
C8–C9x
C1–C2
C1–C6
C2–C3
C2–C7
C3–C4
C4–C5
C5–C6
S1–O3
S1–C10
S1–C11
1.379(3)
1.350(3)
1.465(2)
1.365(2)
1.354(2)
1.367(2)
1.356(2)
1.366(2)
1.352(2)
1.436(2)
1.590(2)
1.514(2)
1.500(2)
1.499(2)
1.516(2)
1.409(2)
1.402(2)
1.396(2)
1.511(2)
1.383(2)
1.381(2)
1.391(2)
1.565(3)
1.435(3)
1.467(2)
1.467(3)
1.520(3)
1.400(3)
1.401(3)
1.381(3)
1.508(3)
1.388(3)
1.396(3)
1.381(3)
1.516(2)
1.786(2)
1.786(2)
1.586(2)
1.480(1)
1.468(2)
1.471(1)
1.516(2)
1.414(2)
1.400(2)
1.394(2)
1.517(2)
1.386(2)
1.385(2)
1.388(2)
1.579(2)
1.522(2)
1.498(2)
1.497(2)
1.511(2)
1.409(2)
1.399(2)
1.392(2)
1.512(2)
1.390(2)
1.384(2)
1.385(2)
Symmetry operation (x) for (1a) 1–x, 1–y, 2–z; (2a, 4) 2–x, 1–y, 1–z; (3) 2–x, 1–y, –z.
Table S2. Bond angles for compounds 1a, 2a, 3 and 4, º
1a
2a
3
4
O2–B1–O1
O1–B1–C1
O2–B1–C1
B1–O1–C7
B1–O1–C10
C7–N1–C8
C7–N1–C9
C8–N1–C9
O1–C7–C2
N1–C7–O1
N1–C7–C2
N1–C8–C9x
N1–C9–C8x
C2–C1–C6
C2–C1–B1
C6–C1–B1
C1–C2–C7
C3–C2–C1
C3–C2–C7
C2–C3–C4
C3–C4–C5
C4–C5–C6
C5–C6–C1
O3–S1–C10
O3–S1–C11
C10–S1–C11
119.5(2)
108.4(2)
132.0(2)
110.7(2)
119.6(1)
122.8(1)
117.6(1)
119.5(1)
118.1(1)
122.5(1)
118.1(1)
118.9(1)
123.0(1)
119.3(1)
110.3(1)
111.9(1)
110.0(1)
113.5(2)
112.5(2)
110.1(2)
105.0(2)
113.3(2)
113.7(2)
109.8(2)
110.3(2)
118.6(2)
104.8(2)
136.5(2)
110.9(2)
122.2(2)
126.8(2)
118.3(2)
120.5(2)
120.8(2)
119.5(2)
105.9(1)
105.6(1)
97.7(1)
112.3(1)
110.5(1)
109.7(1)
109.8(1)
111.7(1)
108.9(1)
113.6(1)
110.1(1)
110.4(1)
117.5(1)
126.1(1)
116.4(1)
122.5(1)
119.8(1)
117.6(1)
121.1(1)
119.9(1)
119.2(1)
122.4(1)
111.9(1)
111.3(1)
111.8(1)
117.7(1)
123.4(1)
118.9(1)
122.0(1)
120.2(1)
117.8(1)
120.7(1)
119.7(1)
119.6(1)
122.0(1)
111.2(1)
110.8(1)
110.8(1)
117.1(1)
125.6(1)
117.3(1)
123.2(1)
120.3(1)
116.5(1)
121.1(1)
119.6(1)
119.6(1)
122.3(1)
Symmetry operation (x) for (1a) 1–x, 1–y, 2–z; (2a, 4) 2–x, 1–y, 1–z; (3) 2–x, 1–y, –z.
2

ACCEPTED MANUSCRIPT
Table S3. Torsion angles for compounds 1a, 2a, 3 and 4, º
1a
–2.4(2)
176.7(2)
174.9(2)
–6.0(4)
–174.9(2)
4.3(2)
2a
3
4
C2–C1–B1–O1
C2–C1–B1–O2
C6–C1–B1–O1
C6–C1–B1–O2
C7–O1–B1–O2
C7–O1–B1–C1
C10–O1–B1–O2
C10–O1–B1–C1
B1–O1–C7–N1
B1–O1–C7–C2
C1–C2–C7–O1
C3–C2–C7–O1
C8–N1–C7–O1
C9–N1–C7–O1
C8–N1–C7–C2
C9–N1–C7–C2
C7–N1–C8–C9x
C9–N1–C8–C9x
C7–N1–C9–C8x
C8–N1–C9–C8x
B1–C1–C2–C3
B1–C1–C2–C7
C6–C1–C2–C7
B1–C1–C6–C5
C3–C1–C2–C6
C2–C1–C6–C5
C1–C2–C3–C4
C4–C2–C3–C7
C2–C3–C4–C5
C3–C4–C5–C6
C4–C5–C6–C1
C1–C2–C7–N1
C3–C2–C7–N1
–25.6(2)
156.9(1)
153.0(1)
–24.5(2)
36.5(2)
23.2(2)
–143.6(1)
–147.1(1)
32.8(2)
–159.8(1)
–157.0(1)
20.1(2)
5.1(2)
–177.7(1)
–129.0(2)
–4.4(2)
2.8(2)
–175.8(2)
59.6(2)
–66.3(2)
–60.2(2)
174.0(2)
174.4(2)
–58.4(2)
–173.6(2)
58.7(2)
178.3(2)
–0.4(2)
–178.3(2)
–176.3(2)
0.4(3)
0.7(3)
–1.4(3)
177.1(2)
1.3(3)
–0.2(3)
–0.8(3)
127.2(2)
–51.5(3)
63.3(1)
–173.9(1)
–178.3(1)
58.4(1)
177.2(1)
–58.5(1)
179.5(1)
–3.0(2)
178.5(1)
–178.7(1)
1.0(2)
0.0(2)
–1.1(2)
–178.7(1)
0.3(2)
0.7(2)
–0.8(2)
60.9(2)
–121.5(1)
177.1(1)
–62.0(1)
178.9(1)
56.3(2)
–178.0(1)
–56.6(1)
172.8(1)
–6.0(2)
177.5(1)
–174.5(1)
–3.6(2)
2.1(2)
2.0(2)
–179.1(1)
1.3(2)
–2.8(2)
–171.3(1)
65.9(1)
179.0(1)
–57.1(2)
–179.9(1)
57.1(2)
179.5(1)
1.6(2)
–178.3(1)
179.0(1)
–0.4(2)
–1.1(2)
1.5(2)
179.5(1)
–1.1(2)
–0.3(2)
1.5(2)
–111.4(1)
70.6(2)
1.1(2)
–75.5(2)
105.7(1)
Symmetry operation (x) for (1) 1–x, 1–y, 2–z; (2,4) 2–x, 1–y, 1–z; (3) 2–x, 1–y, –z.
3

ACCEPTED MANUSCRIPT
Table S4. Hydrogen bonds geometry for compounds 1a, 2a, 3 and 4, Å,º.
D–H
H…A
D–H…A
D…A
1a
O2–H2…O3[–x+2,–y+1,–z+1]
0.815
1.897
178.73
2.712
2a
O1–H1…N1
O2–H2…O1[–x+1,–y,–z+1]
0.921
0.827
1.696
1.894
167.59
176.83
2.603
2.720
3
N1–H1A…O1
0.880
0.785
0.765
0.826
0.845
0.808
0.835
0.819
0.810
2.125
2.358
1.978
1.990
2.004
1.947
2.375
2.394
2.348
135.58
175.23
161.58
169.73
164.08
170.04
164.95
170.52
177.50
2.821
3.142
2.714
2.806
2.826
2.746
3.188
3.205
3.157
O1–H1…Cl1[x+1,–y+3/2,z–1/2]
O2–H2…O3[x,–y+3/2,z–1/2]
O3–H3A…O4[–x+1,–y+1,–z+1]
O3–H3B…O4
O4–H4A…O5
O4–H4B…Cl1
O5–H5A…Cl1[x,y,z–1]
O5–H5B…Cl1[x,–y+3/2,z–1/2]
4
O2–H2…Cl1[–x+1,y–1/2,–z+1/2]
N1–H1…Cl1[–x+1,–y+1,–z+1]
0.782
0.851
2.349
2.298
160.89
164.09
3.099
3.125
4