Amination-reduction reaction as simple protocol for potential boronic molecular receptors. Insight in supramolecular structure directed by weak interactions

Article abstract of DOI:10.2478/s11532-010-0142-8

The synthesis of the potential molecular receptors in the amination-reduction reaction has been investigated within the model system comprising (2-formylphenyl)boronic acid and morpholine. The 3-amine substituted benzoxaborole was identified to be the intermediate of the synthesis and the unsubstituted benzoxaborole as the by-product resulting from reduction of the starting material. The insight into the reactivity of the starting materials as well as the intermediate benzoxaborole enabled significant rise in the yield of 2-(aminomethyl) phenylboronic acids synthesis. The solid state structure of 2-(piperidylmethyl)phenylboronic acid has been re-determined, and the description of the molecule and the crystal is given. The supramolecular layer structure directed by the weak C-H...O and C-H...π interactions was identified and scrutinized based on the geometry and Hirshfeld surface analyses. Versita Sp. z o.o.

Full text of DOI:10.2478/s11532-010-0142-8

Cent. Eur. J. Chem. • 9(2) • 2011 • 199-205
DOI: 10.2478/s11532-010-0142-8
Central European Journal of Chemistry
Amination-reduction reaction as simple
protocol for potential boronic molecular
receptors. Insight in supramolecular
structure directed by weak interactions
Invited Paper
Agnieszka Adamczyk-Woźniak*, Izabela Madura, Alicja Pawełko,
Andrzej Sporzyński, Anna Żubrowska, Jacek Żyła
Faculty of Chemistry, Warsaw University of Technology,
00-664 Warsaw, Poland
Received 15 September 2010; Accepted 24 November 2010
Abstract:
The synthesis of the potential molecular receptors in the amination-reduction reaction has been investigated within the model system
comprising (2-formylphenyl)boronic acid and morpholine. The 3-amine substituted benzoxaborole was identified to be the intermediate
of the synthesis and the unsubstituted benzoxaborole as the by-product resulting from reduction of the starting material. The insight into
the reactivity of the starting materials as well as the intermediate benzoxaborole enabled significant rise in the yield of 2-(aminomethyl)
phenylboronic acids synthesis. The solid state structure of 2-(piperidylmethyl)phenylboronic acid has been re-determined, and the
description of the molecule and the crystal is given. The supramolecular layer structure directed by the weak C–H…O and C–H…p
interactions was identified and scrutinized based on the geometry and Hirshfeld surface analyses
Keywords: Boronic acids • Benzoxaboroles • X-ray structure • Hirshfeld surface • Supramolecular structure
© Versita Sp. z o.o.
The amination-reduction reaction of commercially
1. Introduction
available (2-formylphenyl)boronic acid (1) with secondary
amines seems to be the most reasonable synthetic
strategy. According to the previously published reports
on the chemistry of boronic compounds, however,
various products could be expected under the amination-
reduction reaction conditions of (2-formylphenyl)boronic
acid with secondary amines [5-7]. Therefore, careful
investigation of the system was undertaken to assess
the real potential of the synthetic method and to optimize
reaction conditions.
Recent reports by Davis [8] imply that the receptor
properties of boron compounds result not only from the
boron-containing groups, but also from weak interactions
with other parts of the receptor. Hence, the investigations
of the supramolecular structure of substituted boronic
acids may be of significance.
2-(Aminomethyl)phenylboronic acids are known as
potent saccharide molecular receptors active at the
physiological pH level [1]. The continuous demand for
new and selective receptors, not only for sugars but also
for other hydroxyl compounds, makes their effective and
economical synthesis of crucial importance. Several
synthetic methods for 2-(aminomethyl)phenylboronic
acids have been reported up to now [2]. Unfortunately,
many of them are multi-step processes or suffer from
low selectivity and yields [3]. Some specific problems
with boronic acid purification e.g. irreversible binding
with silica-gel or formation of boroxins at elevated
temperatures make the issue of selectivity of their
synthesis even more important [4].
* E-mail: agnieszka@ch.pw.edu.pl
199

Amination-reduction reaction as simple protocol for potential
boronic molecular receptors. Insight in supramolecular
structure directed by weak interactions
2.4. Reduction of
3-morpholin-4-yl-2,1-
2. Experimental Procedure
benzoxaborol-1(3H)-ol (5)
To solution of 5 (0.150 g, 0.7 mmol) in methanol
(5 mL) at 25°C NaBH4 (0.038 g, 1 mmol) was added
and the mixture was stirred for 20 min. After this time
3 M HCl (10 mL) was added and left to stir for 10 min.
The resulting reaction mixture was extracted with diethyl
ether (3×20 mL), and the organic layer was evaporated
to afford 4 (0.030 g, 22% yield). The remaining aqueous
layer was neutralized to pH ca. 7-8 by adding 25%
aqueous ammonia solution. The reaction mixture was
extracted with diethyl ether (3×20 mL), and the organic
layer was evaporated to afford 0.124 g of the oily residue
containing 3 as the sole aromatic product contaminated
with small amounts of morpholine.
2.1. General
1H and 13C NMR spectra were recorded on a Varian
Mercury 400 spectrometer operating at frequency
400 and 100.1 MHz, respectively. 11B NMR spectra
were recorded on a Varian Unity Plus 200 operating at
64 MHz, chemical shifts were determined using inserts
with BF3•Et2O in benzene (δ = 0.0 ppm). Elemental
analyses for C, H and N were obtained using Perkin
Elmer CHNS/O II Model 240 analyzer.
(2-Formylphenyl)boronic
according to a known procedure, and its purity was
confirmed on the basis of H NMR; morpholine and
piperidine were purchased from Sigma-Aldrich and
solvents from POCH.
acid
was
obtained
1
2.5. Synthesis of [2-(piperidin-1-ylmethyl)
phenyl]boronic acid (3a)
A solution of piperidine (0.568 g, 6.7 mmol) in methanol
(30 mL) was prepared at -10ºC. 1 (1 g, 6.7 mmol) was
2.2. General synthetic
procedure
for
2-(morpholin-4-ylmethyl)phenyl] boronic
acid (3)
Morpholine and (2-formylphenyl)boronic acid were added, followed by addition of NaBH4 (0.57 g, 6.7 mmol)
dissolved in methanol in 1 : 1 ratio at the appropriate with vigorous stirring. After 20 min, HClaq (3 M, 10 mL)
temperature (Table 1). NaBH4 (1 molar ratio) was added was added (pH ca. 1) and mixed for another 10 min.
to the resulting clear solution while intense stirring. After Et2O (40 mL) was added to the post-reaction mixture
20 minutes, 10 mL of 3 M HCl solution was added (pH resulting in precipitation of the solid, which dissolved
ca. 1) and 4 was extracted with diethyl ether (4×20 mL). by addition of water. The aqueous phase was extracted
After separation of phases, the aqueous phase was with Et2O (2×30 mL) and then neutralized with NH3aq
neutralized with NH3aq until pH ca. 7. Product 3 was (pH ca. 7). 3a was extracted with Et2O (3×40 mL) from
isolated upon extraction of the neutral aqueous phase the resulting neutral aqueous phase. The combined
with diethyl ether (4×20 mL).
3. Cream crystals, yield 51-84%, the identity and evaporated under reduced pressure.
purity of the products was confirmed on the basis of 1H
3a. White crystals, yield 59%, 0.869 g, mp
NMR spectrum that were analogous to the previously 192-193ºC, H NMR (400 MHz , CDCl3) δH 2.91-1.25
organic phase was dried over anhydrous Na2SO4 and
1
reported [10].
(10H, m, br, 5CH2), 3.58 [2H, s, CH2], 7.16-7.14 [1H,
m, Ar], 7.32 [2H, m, Ar], 7.92 [m, 1H, Ar], 9.06 [s, br,
B(OH)2 lower intensity due to the exchange). H NMR
1
2.3. Reduction of (2-formylphenyl) boronic
acid, synthesis of 2,1-benzoxaborol-1
(400 MHz, CD3OD) δH 1,64 (2H, m, CH2), 1,78 (4H, br,
2CH2), 2,89 (4H, br, 2CH2), 4,13 (2H, s, CH2), 7,16-
3
(3H)-ol (4)
7.10 (2H, m, Ar), 7,24 (1H, m, Ar), 7,65 (1H, d, JHH
=
7.6 Hz, Ar). 13C NMR (100 MHz, CDCl3) δC 23.8, 25.1,
53.1, 64.5, 127.3, 129.8, 130.4, 136.2, 141.4. 11B NMR
(64 MHz, CDCl3) δB 30.9. 11B NMR (64 MHz, CD3OD)
δB 5.8, 18.5. Anal. Calcd for C12H18BNO2 (219.14): C,
65.79; H, 8.28; N, 6.39%, Found: C, 65.69; H, 8.21; N,
6.31%.
1 (0.147 g, 0.1 mmol) was dissolved in methanol (5 mL).
NaBH4 (0.040 g, 0.105mmol) was added to the resulting
clear solution and stirring was continued for the next
20 minutes at room temperature. HClaq (3 M, 10 mL)
was added to the resulting mixture. The aqueous phase
was extracted with Et2O (3×20 mL), the solution dried
over anhydrous Na2SO4 and solvent evaporated under
reduced pressure. Analogous reduction with NaBH3CN
resulted in 98% yield of pure 4.
2.6. Hirshfeld surface analysis
Molecular Hirshfeld surface in the crystal structure is
constructed basing on the electron distribution calculated
as the sum of spherical atom electron densities [18,19].
The surface enclosing a molecule is defined by points
4. White crystals, yield 97%, 0.128 g, mp 96-99°C (lit.
94-98°C) [22]. 1H NMR analogous to the one previously
reported [6].
200

A. Adamczyk-Woźniak et al.
HO
B
OH
CHO
HO
OH
B
reduction
NR1R2
+
HNR1R2
2
3
1
dehydration
reduction
O
HO
B
HO
B
O
NR1R2
5
4
HNR1R2 = morpholine
Scheme 1. Reactivity of 1 under amination-reduction conditions.
where the contribution to the electron density from the yield (Scheme 1) [10]. In order to improve the synthetic
molecule of interest is equal to the contribution from all strategy for new potential boronic receptors, the
the other molecules. For each point on that isosurface reaction was investigated within the presented model
two distances are defined: de, the distance from the point system comprising (2-formylphenyl)boronic acid (1) and
to the nearest nucleus external to the surface, and di the morpholine (2).
distance to the nearest nucleus internal to the surface.
Reduction of 1 with both NaBH4 and NaBH3CN in
These distances can be normalized (dnorm) using atomic methanol at room temperature resulted in 4 almost
vdW radii [20]. The value of dnorm is negative/positive quantitatively. Extraction of the product with Et2O
when intermolecular contacts are shorter/longer than from the acidic aqueous phase results in much better
vdW separations. Because of the symmetry between de yields of 4 in comparison with the previously reported
and di in the expression for dnorm, where two Hirshfeld methodology (rise from 45% [6] to 97% in the present
surfaces touch, both will display a red spot identical in study).
color intensity as well as size and shape. Graphical plots
The 1H NMR spectrum of 1 and 2 mixture in
of the molecular Hirshfeld surfaces mapped with dnorm CD3OD revealed exclusively signals corresponding to 5
are displayed using a red–white–blue color scheme, immediately after preparation at room temperature. No
where red highlights shorter contacts, white is used traces of the previously postulated imine intermediate
for contacts around the vdW separation, and blue is [11] have been detected.
for longer contacts. Fig. 1 was generated using Crystal
Explorer 2.1 program [23].
Due to the above mentioned facts, formation of 4
and 5 under the amination-reduction reaction conditions
was expected. Several amination-reduction reactions
were carried out in methanol. Identification of the
structure and purity of the products was done by 1H NMR
of the post-reaction mixtures in CDCl3. The signals at
3.65 ppm (2H) in 3 and 5.10 ppm (2H) in 4 have been
taken into account. Formation of 5 was verified with
the 5.87 ppm (1H) signal, and conversion of 1 with the
presence of the formyl group signal at ca. 10 ppm (1H).
Surprisingly, none of the post-reaction mixtures
contained any traces of the expected benzoxaborole 5.
The reason of that lies in the reactivity of 5, which has
not been investigated so far. To explore the problem,
compound 5 was obtained according to the previously
described procedure [7,9], dissolved in MeOH and
3. Results and Discussion
The reactivity of (2-formylphenyl)boronic acid (1) in
the amination-reduction reaction with morpholine has
been investigated. According to our previously reported
results, simple reduction of 1 and subsequent cyclization
result in 2,1-benzoxaborol-1(3H)-ol (4) [6]. The other
possibility is the reaction of (2-formylphenyl)boronic
acid (1) with morpholine (2) resulting in 3-morpholin-
4-yl-2,1-benzoxaborol-1(3H)-ol (5) [7,9]. The desired
2-aminomethyl product (3) has previously been obtained
at amination-reduction conditions yet with moderate
201

Amination-reduction reaction as simple protocol for potential
boronic molecular receptors. Insight in supramolecular
structure directed by weak interactions
treated with NaBH4, resulting in 3 (56% yield). The result the general procedure. Decreasing reaction temperature
clearly indicates that 5, formed instantly after mixing of resulted in an increase of the yield of 3 and simultaneous
1 and 2 in the amination reaction, gives the desired drop in the amount of 4 formed (Table 1), which strongly
product (3) upon reduction, so 5 can be treated as an supports the hypothesis.
intermediate for the synthesis of 3. Unexpectedly, the
In the case of many investigated amination-
other isolated product of the reaction was 4 (22% yield). reduction reactions of 1 with morpholine, mixtures of
The most probable explanation of this observation is a 3 and 4 have been obtained. Due to this fact, it was
fast equilibrium in solution (Scheme 2).
important to develop an efficient purification method.
The equilibrium must be strongly right-shifted, as the The separation of the products was possible due to the
solution of 5 in CD3OD displays no traces of the signal hydrophilic character of 3 hydrochloride formed after
corresponding to the CHO group. The fast reduction of the acidification of the reaction with HClaq. The selective
1, however, shifts the equilibrium to the left resulting in extraction of 4 with diethyl ether was possible under
4 in a reasonable yield. Due to instant and quantitative these conditions. The extraction of hydrophobic 3 with
formation of 5 in the reaction of 1 and morpholine, the diethyl ether was possible at neutral pH after addition of
limiting factor of the synthesis is not the expected [11] NH3aq. The basification should be carried out carefully,
low reactivity of the amine, rather a fast rate of the as both 3 and 4 transform into hydrophilic species at
reduction of 1 resulting in a stable 4. Therefore, limiting basic pH (Scheme 3).
the reduction rate of 1 should result in higher yields of
3.
Following the developed procedure, [2-(piperidin-1-
ylmethyl)phenyl]boronic acid (3a, HNR1R2 = piperidine)
The influence of temperature on yields of 3 and 4 has has been obtained in reasonable yield (59%) and fully
been investigated within the model system according to characterized. The cyclic anhydride of 3a has been
previously obtained by Wulff and co-workers [12] by the
Table 1. Isolated yields of 3 a nd 4 depending on temperature of
aminationoftheanhydrideofthecorrespondingbromide.
The characteristic signals of the benzyl protons in the 1H
NMR spectra of 3a and its boroxin in CDCl3 are 3.58
and 3.90 ppm [12], respectively. 3a has been previously
investigated as potential receptor of hydroxyacids and
diols [13]. Following the contribution of Collins and co-
workers [14], the structure of 3a in methanol solution
was investigated by 11B NMR spectroscopy. The
presence of the methyl ester with the N-B dative bond
(major signal at 18 ppm) and the fully solvated form with
proton transfer (minor signal at ca. 6 ppm) was identified.
Surprisingly, crystallization of the sample from methanol
solution resulted in the crystals of 3a, containing free
B(OH)2 group and no built up methanol molecules. Its
X-ray structure has been previously determined [15], yet
only the formation of a molecular dimer was indicated.
Hence, we present here a detailed molecular and crystal
structure of 3a.
the reaction.
Temp. (ºC)
Yield of 3 (%)
Yield of 4 (%)
65
25
0
51
35
67
74
84
22
20
11
-10
HO
OH
HO
B
1
B
O
CHO
NR1R2
HNR1R2
+
5
4
3
Molecules of 3a crystallize in the P21/n space
group symmetry of the monoclinic system. The crystal
data are summarized in Supplemental Table 1 of the
Scheme 2. Formation of 3 and 4 under the amination-reduction
reaction conditions.
OH
HO
HO
OH
HO
OH
B
B
B
OH
Cl
NHR1R2 NH3aq
OH
NR1R2
NR1R2
hydrophilic
hydrophobic
hydrophilic
3
Scheme 3. Various forms of 3 depending on pH.
202

A. Adamczyk-Woźniak et al.
Supplementary materials. Supplemental Tables 2 and
3 list the selected geometrical parameters and the
geometry of hydrogen bonds, respectively. The B(OH)2
fragment in 3a is twisted with respect to the phenyl
ring by 27.9(6)º. The similar twist was observed in the
previously described morpholine and thiomorpholine
analogs [10]. The piperidyl substituent in 3a has a chair
conformation and is oriented in a way that enables the
formation of an intramolecular O–H…N hydrogen bond.
It should be noted that these are the only interactions
that involve the nitrogen atom. Both the intramolecular
O–H…N and the intermolecular O–H…O hydrogen
bonds that form a centrosymmetric dimer in 3a are also
found in the above-mentioned analogs. The dimer is
described by the R22(8) graph set [16,17] and it can be
regarded as a primary supramolecular motif.
To rate the weaker interactions that are present
in the crystals of 3a we used the Hirshfeld surface
analysis [18] that is a useful tool for depicting types and
directionality of weak intermolecular interactions [19].
The graphical plot of the molecular Hirshfeld surface of
Figure 1. Hirshfeld surface of O–H…O bonded 3a dimer mapped
with dnorm. The O–H…O and O–H…N hydrogen bonds
within the surface are shown as a dashed lined. The red
spots on the surface indicate the presence of weaker
intermolecular interactions.
Figure 2.
The square-grid layer structure of 3a directed by C–H…O hydrogen bonds and enhanced by weak C–H…p interactions. View towards
the (–101) plane. H-bonds are presented as dashed lines and labeled from 1 to 4 in order: N–H…O (intramolecular), O–H…O, C–H…O
and C–H…p (intermolecular).
203

Amination-reduction reaction as simple protocol for potential
boronic molecular receptors. Insight in supramolecular
structure directed by weak interactions
3a dimer mapped with dnorm [20] is presented in Fig. 1. temperature and use of an appropriate purification
The red depressions on the surface (distances shorter method. The role of weak intermolecular interactions in
than sum of the vdW radii) indicate the regions of the crystals of 2-(aminomethyl)phenylboronic acids was
significant interactions, highlighting both acceptors and shown, and the resulting supramolecular structure was
donors. The most intense spots occur above the oxygen described.
atom and the methylene group hydrogen atoms. They
correspond to two C–H…O interactions of which the
shortest has a C…O bond distance equal to 3.585(1) Å
(labeled 3 in Fig. 2). These H-bonds join the dimers of
Supplementary materials
3a into a square grid layer structure on the (–101) plane
(Fig. 2).
Crystal data for 3a, details of solution and refinement
are given in supplementary file and summarized in
Supplemental Table 1. Supplemental Figure 1 presents a
dimer of 3a with thermal ellipsoids and atoms numbering
scheme. Supplemental Tables 2 and 3 list the selected
geometrical parameters and geometry of the hydrogen
bonds, respectively. CCDC 784187 contains the
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html, or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (+44) 1223-336033; e-mail: deposit@ccdc.cam.
Each mesh of the grid is additionally enhanced by
weak C–H…π interactions (labeled 4 in Fig. 2). They
appear on the Hirshfeld surface as small spots above
the phenyl ring, which is acting as a π-acceptor. The
donors are the protons from the piperidyl substituent.
Therefore, the second level of molecular arrangement
in 3a is a 2-D assembly with the symmetry of p21/b layer
group [21]. These layers are further zipped into a 3-D
structure by rather weak C–H…O interactions between
H-donors form the phenyl ring and the oxygen atom
(small red spots in Fig.1).
1
uk. Copies of H, 13C and 11B spectra of 3a are also
provided.
4. Conclusions
Acknowledgement
The amination-reduction reaction can act as simple and
efficacious protocol for 2-(aminomethyl)phenylboronic
acids. In case of the investigated amines, the amination
reaction resulting in amine substituted benzoxaborole
intermediate turned out to be fast and efficient, yet
reversible. The reversibility of its formation together with
the fast reduction of the starting aldehyde were the main
obstaclesthatwerecircumventedbyloweringthereaction
This
work
has
been
supported
by
the
European Union in the framework of European
SocialFundthroughtheWarsawUniversityofTechnology
Development Programme by a scholarship awarded
by the Center of Advanced Studies for Agnieszka
Adamczyk-Woźniak.
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