Exploiting Coupling of Boronic Acids with Triols for a pH-Dependent click-Declick Chemistry

Article abstract of DOI:10.1021/acs.joc.8b01296

Click-like condensation of boronic acids with specifically designed triols (boronate-triol coupling) produces stable diamantane adducts in aqueous medium, which can be controllably cleaved to initial components under acidic conditions or by using boric acid as a chemical trigger. This novel click-declick strategy allows for the creation of temporary covalent connections between two or more modular units, which was demonstrated by the synthesis of new fluorophore-labeled natural molecules (peptides, steroids), supramolecular assemblies, modified polymers, boronic acid scavengers, solid-supported organocatalysts, biodegradable COF-like materials, and dynamic combinatorial libraries.

Full text of DOI:10.1021/acs.joc.8b01296

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Article
Exploiting coupling of boronic acids with triols
for a pH-dependent “click-declick” chemistry
Ivan S. Golovanov, Galina S. Mazeina, Yulia V. Nelyubina, Roman A. Novikov, Anton S.
Mazur, Sergey N. Britvin, Vladimir A. Tartakovsky, Sema L. Ioffe, and Alexey Yu. Sukhorukov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01296 • Publication Date (Web): 31 Jul 2018
Downloaded from http://pubs.acs.org on July 31, 2018
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Exploiting coupling of boronic acids with triols for a pHꢀdependent “clickꢀdeclick”
chemistry
a
a,b
c
a
Ivan S. Golovanov, Galina S. Mazeina, Yulia V. Nelyubina, Roman A. Novikov, Anton S.
1
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d
e
a
a
Mazur, Sergey N. Britvin, Vladimir A. Tartakovsky, Sema L. Ioffe, Alexey Yu.
,a
Sukhorukov*
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
1
19991, Leninsky prospect, 47, Moscow, Russia
Dmitry Mendeleev University of Chemical Technology of Russia
25047, Miusskaya sq. 9, Moscow, Russia
b
1
c
A. N. Nesmeyanov Institute of Organoelement Compounds 119991, Vavilov str. 28, Moscow,
Russia
d
Center for Magnetic Resonance, St. Petersburg State University
198504, University Av. 26, St. Petersburg, Russia
f
Department of Crystallography, St. Petersburg State University, Universitetskaya Nab. 7/9,
199034 St. Petersburg, Russia
*
Eꢀmail: sukhorukov@ioc.ac.ru
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ABSTRACT
Clickꢀlike condensation of boronic acids with specifically designed triols (boronateꢀtriol
coupling) produces stable diamantane adducts in aqueous medium, which can be controllably
cleaved to initial components under acidic conditions or by using boric acid as a chemical
trigger. This novel “clickꢀdeclick” strategy allows to create temporary covalent connections
between two or more modular units that was demonstrated by the synthesis of new fluorophoreꢀ
labeled natural molecules (peptides, steroids), supramolecular assemblies, modified polymers,
boronic acid scavengers, solidꢀsupported organocatalysts, biodegradable COFꢀlike materials and
dynamic combinatorial libraries.
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INTRODUCTION
The click chemistry concept since its introduction in 2001 has become the most eminent strategy
1
for a covalent linkage of two or more modular units to form a single structure. However, for
some certain tasks related to material science and biology it is important not only to connect the
functional units, but also to be able to disconnect those after the conjugate have served its role.
For this purpose, reversible click chemistry is needed. In this approach, functional units are
temporary connected to each other through a covalent linker, which can be cleaved (“declicked”)
under certain conditions (in a controllable manner) recovering the initial components. The
“
click/declick” strategy has a great potential for creating new drug delivery systems, dynamic
combinatorial libraries, biodegradable and adaptive (smart) polymeric materials, recoverable
2
chemical scavengers, etc.
The fundamental basis behind the reversible click chemistry is the phenomenon of a soꢀcalled
3
dynamic covalent bonding. In these reactions covalent bonds are readily formed and easily
broken in a reversible manner under physiological conditions. The most challenging task is to be
able to control the equilibrium making covalent adducts thermodynamically preferred under one
conditions and the initial reagents under another (for example, by changing pH or by adding a
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a
chemical trigger). Thus, not any reaction, which is reversible under normal conditions, can be
used for a reversible click process.
4
Probably, the most known dynamic covalent linkage is the boronꢀoxygen bond. Interaction of
1
boronic acids with alcohols occurs very easily (yet reversible) forming boronate esters RB(OR )
2
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c
(
Scheme 1). In particular, the boronateꢀdiol condensation have recently been used for the
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creation of various supramolecular assemblies and nanomaterials, covalent organic
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frameworks, selfꢀrepairing polymers, gels, molecular imprinting systems, biomolecular
10
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sensors, etc. However, a significant drawback of this chemistry is the low hydrolytic stability
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of boronate esters. Typically, either anhydrous conditions or addition of a chemical trigger
(
ligand L) are needed to shift the equilibrium to the desired boronate ester (or its complex). This
makes boronateꢀdiol adducts poor candidates for a controllable clickꢀdeclick chemistry in
aqueous phase.
Conventional approach:
HO
L
+
L
O
O
OH
OH
B
B
HO
boronate-diol
coupling
This work:
HO
HO
HO
base
O
O
O
OH
B
OH
B
boronate-triol
coupling
cat
- functional fragments
,
Scheme 1. Boronateꢀdiol and boronateꢀtriol couplings
Our approach to this problem is based on applying triols as partners for coupling with boronic
acids (Scheme 1). Here, we demonstrate, that the use of specifically designed functionalized
triols allows the preparation of very stable conjugates, which are resistant towards hydrolysis
under basic/neutral conditions, and readily decouple under acidic conditions regenerating the
initial triol and boronic acid. This new pHꢀcontrollable “clickꢀdeclick” reaction was used in
preparing analogs of known clickꢀadducts, dynamic combinatorial libraries, modified polymers,
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recoverable solidꢀsupported scavengers and biodegradable materials. It should be specially noted
that boronic acids are highly promising building blocks for click chemistry because of their high
availability, including macromolecular boronic acids, polymerꢀsupported boronic acids, as well
as boronic acidꢀlabeled biomolecules.
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RESULTS AND DISCUSSION
The scope of available triols is much more limited as compared to diols. Therefore, optimal
partners for the condensation with boronic acids are triols, which possess an additional
functional group used for prior derivatization by standard methods. N,N,NꢀTrihydroxyꢀ1,4,6,10ꢀ
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tetraazaadamantanes (TAAD, Scheme 2), which recently became available, bear three
hydroxyl groups together with a nucleophilic tertiary nitrogen atom and thus can be viewed as
promising bifunctional crosslinkers to couple boronic acids with appropriate electrophiles.
TAAD adducts with boronic acids should have stable zwitterionic diamantane structures 1,
1
4,15
which are expected to be water soluble.
Scheme 2. A general scheme of boronateꢀtriol coupling with TAAD as crosslinker
Initially, we explored the interaction of model Nꢀbenzyl salt NꢀBnꢀTAAD with phenylboronic
acid (Scheme 3). In this experiment, the formation of zwitterionic adduct 1а was detected, yet, a
considerable amount of unreacted starting materials was also present. Fortunately, addition of a
2 3
base (Na CO ) for interception of releasing HCl completely shifted the equilibrium to the desired
adduct 1a. According to a single crystal XꢀRay analysis (CCDC 1048294), this product has a
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diamantane structure with nearly ideal С3v symmetry. The size of diamantane measured as the
distance between the quaternary nitrogen and boron atoms is ca. 4.5 Å, which corresponds to the
length of rigid linker between phenyl and benzyl groups. Diamantane 1a is exceptionally
о
thermally stable (up to 260 С) and is moderately soluble in water (ca. 20 mg/mL).
1
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Na CO
2
3
CH OH, 48 h
3
Ph-B(OH)2
+
79%
HO N
O N
Ph
B
HO N
O N
O N
N
N
HO N
Ph
Ph
Cl
N-Bn-TAAD
HCl, H O
2
1a
4.5 Å
B
N
X-Ray of 1a
Scheme 3. Interaction of phenylboronic acid with model triol NꢀBnꢀTAAD
a
Figure 1. Hydrolysis of diamantane 1a in water. (A) pK dependence, 2 equiv. of acid. (B) pH
dependence, 2 equiv. of acid/base.
The need of a base in the synthesis of 1а indicates the pHꢀdependent character of boronateꢀtriol
linkage formation. This is clearly demonstrated by the studies of the hydrolytic stability of
diamantane 1а summarized in Figure 1. As can be seen from these data, diamantane 1а is stable
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in a broad range of pH from alkaline to moderately acidic. A noticeable cleavage of boronate
fragment to the initial components (NꢀBnꢀTAAD and PhB(OH)
yet complete hydrolysis required an excess of a strong acid with pK
change of pH from acidic to slightly alkaline (addition of NaHCO ) results in the reassembly of
2
) was observed at pH values <3,
a
<0 (at pH<1). Importantly,
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adduct 1а that confirms the reversible and pHꢀdependent character of boronateꢀtriol
condensation. Interestingly, an instantaneous change of pH from acidic to strongly alkaline by
addition of NaOH does lead to recombination of components into 1а. This is attributed to the fast
ꢀ
transformation of phenylboronic acid to the PhB(OH)
3
anion, which does not enter coupling
with triol NꢀBnꢀTAAD.
Figure 2. Boronic acid exchange in boronate adducts 1. (A) – boronic acids exchange at
different pH. (B) – kinetics of boronic acids exchange at pH 3.8.
For a further study of boronateꢀtriol equilibrium we conducted experiments on the exchange of
boronic acid residues between diamantane 1a and pꢀbromophenylboronic acid (Figure 2). Under
alkaline and neutral pH these compounds coꢀexist (“sleeping state”) indicating a large stability
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constant of complex 1a under these conditions (Figure 2, A). In contrast, in a slightly acidic
medium (AcOH in aqueous methanol) the equilibrium is established and two diamantane adducts
1а and 1b are detected in the reaction mixture (“dynamic exchange” area, Figure 2, A). Further
increase of acidity results in a complete cleavage of both adducts affording triol NꢀBnꢀTAAD
and two boronic acids (“hydrolysis” area, Figure 2, A). Thus, in this reaction a narrow area of
dynamic equilibrium exists at pH values 3.5−4.5, in which the exchange of boronate units can
occur without a significant hydrolysis of adducts 1. Kinetic measurements revealed that the
equilibrium between 1а and 1b is achieved within ca. 3 h under these conditions. Importantly,
this equilibrium can be “turned off” by raising the pH.
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The reversible exchange of boronate residues in adducts 1 can be exploited to recover boronic
acid from the complex with triol upon the action of B(OH) under mild pH conditions. Thus,
3
phenylboronic acid was almost quantitatively recovered from the aqueous solution of diamantane
3
1a and an excess of B(OH) with acetic acid additive (2 equivalents) using continuous extraction
with chloroform (see Experimental section).
We further explored substrate scope of the developed boronateꢀtriol condensation together with
the possibility of synthesis of adducts 1 bearing various substituents and functional fragments at
both ends of diamantane linker. In order to simplify the synthesis of target diamantanes 1, we
2
suggested a threeꢀcomponent procedure, in which quaternary salts NꢀR ꢀTAAD are generated
2
from readily available primary halides (or tosylates) R ꢀLG and trisꢀoxime TRISOXH
3
(Table
1). This oneꢀpot process involves intramolecular cyclotrimerization of oxime groups (see
Scheme 4), quaternization of tertiary nitrogen atom in TRISOXH and the boronateꢀtriol
3
coupling. The designed threeꢀcomponent condensation was found to be efficiently realized under
ambient temperature in methanol in the presence of alkali metal carbonates. Importantly, these
mild conditions are compatible with natural molecules (such as peptides) and other sensitive
substrates.
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Table 1. Substrate scope study of the threeꢀcomponent synthesis of diamantane adducts 1
HO
N
CH3OH, 24 h
then M2CO3
HO N
HO N
OH
OH
O N
OH
OH
R1
R1
R1
+
HO N
R2
+ LG
B
R2
B
N
B
N
R2
O N
O N
N
O
4
h, r.t.
HO N
N
HO
TRISOXH3
LG
1
M - Li (LG = Br), Na (LG = I, Cl)
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O
N
N
O
O
N
N
B
2
7
26
O
N
N
Li
N
O N
X
B
O
29
28
O
N
N
B
O
N
O
1
25
38
O
N
N
H
H
N
N
30
R
3
9
1
m, 79%
N
23 22
31
37
H
2
4
O
40
32
36
Ph
O
N
N
3
5
1
1
1
1
1
1
a R, X = H, 94% (LG = Br)
a R, X = H, 71% (LG = Cl)
a R, X = H, 64% (LG = OTs)
b R = H, X = Br, 90% (LG = Br)
c R = 3-CN, X = H, 77% (LG = Br)
33
34
1r, 80%
B
O
N
N
O
Ph
O
O N
B
O N
NHGlyGlyGlyOH
1n
,
84%
d R = 4-CO2CH3, X = H, 84% (LG = Br)
1e R = 2-Br-4-NO2, X = H, 99% (LG = Br)
O
N
N
O
N
H3C
B
O
N
N
O
N
1s
, 99%
Ph
O
N
N
B
1o, 99%
O
N
N
AlkFG
O
N O
O N
O
N
N
Ph
B
B
N
N
O
O
N
N
B
N O
O N
O
N
N
Ph
N
O
Ph
1
1
1
f Alk = CH3, 83% (LG = I)
1t, 87%
g Alk = nC4H9, 90% (LG = I)
1
p, 99%
h AlkFG = CH2CO2Et, 98% (LG = Br)
1i AlkFG = CH2C(O)Ph, 97% (LG = Br)
1j AlkFG = allyl, 85% (LG = Br)
O
N
O
N
N
N
O B
O
B
1
1
k AlkFG = propargyl, 89% (LG = Br)
N N
O
O
N
N
S
O
N
N
O
N
l AlkFG = CH2-1-Naphtyl, 91% (LG = Br)
Ph
B
N
O
1
u, 82%
1
q, 77%
This threeꢀcomponent procedure is applicable to a broad range of boronic acids as well as monoꢀ
diꢀhaloꢀsubstituted derivatives (both activated and nonꢀactivated) and tosylates. High isolated
/
yields of corresponding adducts 1 are generally observed. Isolation of products typically requires
separation from inorganic salts simply by trituration with water (for less water soluble products
1
) or acetone. Similar to 1a, other adducts 1 are highly thermally stable and hydrolytically
resistant (at pH > 7). Successful preparation of adducts 1r and 1s demonstrates the possibility of
16
synthesis of fluorescentꢀlabeled biomolecules using the developed boronateꢀtriol coupling
approach.
For the synthesis of trisꢀoxime TRISOXH a simple and green oneꢀpot protocol was developed
3
employing condensation of commercially available chloroacetone with ammonia and
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hydroxylamine in water (Scheme 4). Using this method, TRISOXH was prepared on a hundred
3
grams scale. If needed, the latter can be transformed into corresponding TAAD derivatives in a
13
single step according to our previously described procedures.
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Scheme 4. Green and scalable synthesis of TRISOXH3
Thus, high efficiency, controllable reversibility and broad scope of boronateꢀtriol condensation
make it a conceptually novel example of clickꢀprocess, in which adducts are not only easily
formed, but also can be cleaved (“declicked”) by changing pH or by using boric acid as a
chemical trigger. Here, we describe a few examples of application of this process in different
subfields of organic chemistry.
High efficiency of the threeꢀcomponent coupling demonstrated on model substrates suggests that
it can be used to construct more complicated molecular assemblies. In particular, we explored
the use of boronateꢀtriol coupling to prepare trifunctional triad molecules. To do so,
condensation of 1,3,5ꢀtris(bromomethyl)benzene
3
(tribromomesitylene) with several
functionalized boronic acids and TRISOXH was performed. As can be seen from Table 2, the
3
designed multiꢀcomponent condensation provides the desired triads 2 in a highly efficient
manner even with complex boronic acids. Unstable boronic acids (such as ferroceneboronic acid
2
FcB(OH) ) were used in a slight excess to prevent the formation of products of monoꢀ and bisꢀ
1
7
addition. Adducts 2 are analogs of known VanꢀderꢀWaals capsules (adducts 2d and 2f) and
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organocatalysts (2e), which were previously prepared by conventional clickꢀchemistry
approaches (CuAAC reactions or etherification).
Table 2. Substrate scope study of the multiꢀcomponent synthesis of triads 2
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The reversible character of boronateꢀtriol linkage in adducts 1 and 2 can be exploited to generate
1
9
dynamic combinatorial libraries (DCL’s), in which constituents are linked through a reversible
chemical reaction. DCL’s have a great potential utility for drug design and ultrafast in vitro
19ꢀ21
screening.
We demonstrated the possibility of creating a dynamic covalent system
comprising of eight adducts 2 from three different boronic building blocks and
tribromomesitylene as shown in Scheme 5.
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Scheme 5. Generation of dynamic combinatorial libraries employing reversible boronateꢀtriol
condensation
Thus, in the reaction of adduct 2а with pꢀbromophenylboronic acid in the presence of AcOH
redistribution of boronate fragments bounded to a tripodal matrix was observed. In the resulting
mixture, four possible combinatorial adducts were detected demonstrating the dynamic covalent
bond character of the boronateꢀtriol linkage under these conditions. Addition of 1ꢀpyreneboronic
acid to this mixture leads to further redistribution of boronate fragments and formation of a
dynamic combinatorial mixture of adducts 2 with almost all possible combinations of bounded
boronic acids. Product 2с ((Pyr,Pyr,Pyr)ꢀ2) was not observed by HRMS in this mixture
indicating some selectivity in competitive binding of boronic acids under thermodynamically
controlled conditions. It can be expected, that the dynamic equilibrium in combinatorial mixtures
of adducts 2 can be shifted to certain products upon the external stimuli, such as complexation
20
21
with metal ions or biomolecules. The number of species 2 generated in such a combinatorial
library may be increased by using a mixture of different trisꢀoximes, which are also readily
22
available.
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Reversible click chemistry can be efficiently exploited in materials science, in particular in the
design of functionallyꢀmodified polymeric materials. In this case, a functional unit (for example,
a chelator or catalyst) can be covalently immobilized on a solid polymeric matrix by means of
boronateꢀtriol linkage and after serving its role selectively removed regenerating the solid
support. To test this idea, we examined two variants employing a polymericꢀbound boronic acid
and a polymericꢀbound triol as solid supports.
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In the first variant, commercially available polystyreneꢀbound boronic acid (PSꢀB(OH)
used as a functionalized resin and a model quaternary salt Nꢀ(pꢀMeO CꢀBn)ꢀTAAD as a triol
component (Scheme 6). In our initial experiments, the TAAD salt was generated in situ from
methyl 4ꢀ(bromomethyl)benzoate 4 and TRISOXH . However, under these threeꢀcomponent
2
) was
2
3
conditions reaction was slow (15% and 50%ꢀloading after 24 and 96 h, respectively).
Furthermore, partial hydrolysis (and methanolysis) of bromide 4 was observed.
Scheme 6. Boronateꢀtriol condensation for postꢀmodification of polystyreneꢀbound boronic acid
The use of a preꢀsynthesized quaternary salt Nꢀ(pꢀMeO CꢀBn)ꢀTAAD in reaction with PSꢀ
2
B(OH)
2
proved to be more advantageous. After some optimization studies, we were delighted to
OHꢀH O mixture almost maximum polymer
find that at elevated temperature in a THFꢀCH
3
2
loading was achieved within 7 h (Scheme 6). The modified polystyrene prepared in such way
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was washed several times with THF, methanol and water to remove inorganic salts and the
remaining TAAD salt, which gave the desired material in 89% yield (with respect to initial PSꢀ
B(OH)
regeneration of the polymerꢀbound boronic acid (86% recovery, 8% loading) as well as the triol
salt Nꢀ(pꢀMeO CꢀBn)ꢀTAAD (Scheme 6).
2
). Treatment of this functionalized resin with HCl resulted in almost complete
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
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2
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0
2
The presence of boronateꢀtriol linkage and the methoxycarbonyl group in the polymer was
unambiguously proved by FTꢀIR spectroscopy. Characteristic BꢀOꢀN deformation band of the
B,O,Nꢀdiamantane unit was identified using FTꢀIR study and DFTꢀcalculations of specially
1
5
synthesized Nꢀisotopeꢀlabeled triol Nꢀ(pꢀMeO
diamantanes 1a,d (see Scheme 6 and Supporting Information for details).
We further examined the use of a triolꢀmodified polystyrene PSꢀCH ꢀTAAD as a solid support
2 2
CꢀBn)ꢀTAAD, its adduct with PSꢀB(OH) and
2
for immobilization of boronic acids (Scheme 7). Polymer PSꢀCH
reacting Merrifield resin (PSꢀCH Cl) with tetraazaadamantane TAAD. In the resulting polymer
almost 100% of chlorine atoms were substituted for TAADꢀgroups. Application of a less
nucleophilic TRISOXH (precursor of TAAD) resulted in much smaller loading of
2
ꢀTAAD was prepared by
2
3
tetraazaadamantane on Merrifield resin.
2
When a solution of phenylboronic acid or 3ꢀthienylboronic acid was exposed to PSꢀCH ꢀTAAD
2 3
resin in the presence of Li CO , nearly quantitative binding of both boronic acids to the solid
matrix was detected (92ꢀ95% loading). FTꢀIR spectroscopy study again revealed the presence of
the boronateꢀtriol linkage in the obtained polymers. Using this approach, we were able to prepare
a solidꢀsupported cinchona alkaloid by immobilizing cinchonineꢀderived boronic acid (Cinꢀ
2 2
B(OH) ) on PSꢀCH ꢀTAAD resin (Scheme 7). Polymerꢀsupported cinchona alkaloids are used
23
24
as recoverable heterogeneous organocatalysts for asymmetric alkylation, and aldol reactions.
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TAAD
or 15N-TAAD
1
R B(OH)
2
Cl
CH OH-THF, r.t.
3
PS
PS
PS
N
N
Cl
CH OH-THF
N
3
(15)
(15)
HCl
(15)
N
N
O
r.t., 144 h
(15)
N
N
PS-CH Cl
2
O
(
15)
OHOH
OH
PS-CH -TAAD
(
15)
N
O
B
R1
PS - polystyrene
1
2
PS-CH -TAAD-BR
2
(
83% yield, 96% loading)
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OH
(15)
B(OH)2
HO N
N
1
HO
R B(OH) :
2
B(OH)2
N
N(15)
N
Br
S
HO N
(
15)
Cin-B(OH)2
B(OH)2
9
5% yield
5% loading
88% yield
92% loading
88% yield
94% loading
TAAD
9
Scheme 7. Boronateꢀtriol condensation for postꢀmodification of Merrifield resin
As shown on the example of boronateꢀmodified resin PSꢀCH ꢀTAADꢀBꢀ3ꢀthienyl, the initial
2
solid support PSꢀCH
2
ꢀTAAD and 3ꢀthienylboronic acid are completely regenerated upon the
ꢀTAAD can be considered as a novel
action of hydrochloric acid (Scheme 7). Thus, PSꢀCH
2
selective and regeneratable covalent scavenger of boronic acids. As demonstrated in Scheme 8,
this scavenger can be used to remove the excess of boronic acid from the product in Suzukiꢀ
Miyaura coupling. A challenging synthesis of 4'ꢀtrifluoromethoxyꢀ1,1'ꢀbiphenol 5, which is an
25
important building block in medicinal chemistry, requires an excess of corresponding boronic
2
6
acid to ensure high conversion of nonꢀprotected 4ꢀbromophenol.
The residual 4ꢀ
trifluoromethoxyphenylboronic acid was recovered using the aboveꢀmentioned technique by
treatment of crude product with PSꢀCH ꢀTAAD resin followed by filtration of polymer and
2
hydrolysis. Apparently, PSꢀCH ꢀTAAD resin can be also used to functionalize boronic acids by
2
solidꢀphase synthesis.
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Scheme 8. PSꢀCH
2
ꢀTAAD resin as a covalent scavenger of boronic acids in SuzukiꢀMiyaura
coupling
Finally, we tested the developed boronateꢀtriol coupling for the preparation of biodegradable
COFꢀlike materials. Thus, condensation of trisꢀTAAD salt 6 with benzeneꢀ1,4ꢀdiboronic acid in
aqueous methanol in the presence of base (K
, route (1)). Same material was prepared by a parallel synthesis using condensation of
tribromomesitylene with dilithium salt 7 (Scheme 9, route (2)) as well as by a threeꢀcomponent
condensation of tribromomesitylene, trisꢀoxime TRISOXH , and benzeneꢀ1,4ꢀdiboronic acid
following the procedure shown in Table 2. Polymer Pꢀ1 was characterized by solid state H, B,
2 3
CO ) produced a polymeric material Pꢀ1 (Scheme
9
3
1
11
13
15
C and N NMR, FTꢀIR, thermal gravimetric analysis (TGA), differential scanning calorimetry
(DSC), BET, FEꢀSEM microscopy and elemental analysis. We were not able to determine the
molar mass distribution of Pꢀ1 due to its insolubility in water and organic solvents (yet, intensive
swelling was observed in methanol).
Solid state NMR and FTꢀIR revealed characteristic signals related to B,O,Nꢀdiamantane linkers
as well as to mesitylene and 1,4ꢀboroꢀsubstituted phenyl rings. Furthermore, terminal triol and ꢀ
2
B(OH) groups were identified from these studies. According to TGA and DSC, the polymer is
o
o
thermally stable up to 200 C and loses absorbed water (ca. 20% mass) at around 100ꢀ140 C.
SEM images the thermally treated Pꢀ1 showed a cracked surface morphology (Scheme 9). At
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high magnification, the specific growth structures resembling nanostructured flowers with large
surface areas were seen. Even cracked area consisted of these structures.
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Scheme 9. Synthesis of biodegradable COFꢀtype materials by boronateꢀtriol condensation
Upon acidic hydrolysis, Pꢀ1 underwent decomposition to initial TAAD salt 6 and benzeneꢀ1,4ꢀ
diboronic acid demonstrating a biodegradable character of this material. The ratio of these
monomers after hydrolysis was found to be ca. 1 : 2, respectively. Furthermore, the ratio of
terminal/nonꢀterminal benzeneꢀ1,4ꢀdiboronic residues determined as described in Supporting
information was found to be ca. 1 : 2. These data indicates that the polymer has a crossꢀlinked
rather than dendrimeric structure (in a dendrimer structure the ratio terminal/nonꢀterminal
benzeneꢀ1,4ꢀdiboronic residues should be ca. 2 : 1).
Interestingly, in a 1 : 1 reaction between trisꢀTAAD salt 6 and benzeneꢀ1,4ꢀdiboronic acid in the
2 3
presence of Li CO under highꢀdilute conditions (0.005 M) a dimeric structure 8 was formed
instead of polymer Pꢀ1 (Scheme 10). Furthermore, the interaction of salt 6 with an excess of
benzeneꢀ1,4ꢀdiboronic acid (12 equiv.) produced the trisꢀadduct 2g. Both compounds 2g and 8
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are likely to be intermediates in crossꢀcondensations leading to the polymer Pꢀ1 and were
observed in result of partial hydrolysis of Pꢀ1.
1
1
1
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1
1
1
1
2
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2
2
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Scheme 10. Oligomeric structures formed by boronateꢀtriol condensation of trisꢀTAAD salt 6
and benzeneꢀ1,4ꢀdiboronic acid
CONCLUSIONS
In this paper we have demonstrated that boronateꢀtriol condensation is a highly promising and
efficient strategy for linkage of two or more modular units in a single stable covalentꢀbonded
structure. Unlike traditional click approaches, the adducts formed by boronateꢀtriol condensation
can be declicked in controllable manner under the action of strong acids or a simple chemical
3
trigger (B(OH) ) allowing for creation a temporary connection between modular units. The
suggested click strategy was efficiently used in the design of fluorophoreꢀlabeled natural
molecules (peptides, steroids), supramolecular assemblies, modified polymers, boronic acid
scavengers, solidꢀsupported organocatalysts and biodegradable COFꢀlike materials. Furthermore,
a dynamic covalent character of B−O linkage in the boronateꢀtriol adducts under slightly acidic
conditions was successfully used to generate dynamic combinatorial libraries from available
boronic acids.
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EXPERIMENTAL SECTION
All reactions were carried out in ovenꢀdried (150 °C) glassware. THF was distilled over NaOH.
CH OH, EtOH, acetone, hexane, 1,2ꢀdimethoxyethane and ethyl acetate were distilled without
3
drying agents. Melting points were determined on a Kofler heating stage and were not corrected.
NMR spectra of solutions were recorded at room temperature (if not stated otherwise) with
0
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0
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3
4
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8
9
0
11
residual solvent peaks as internal standards. Chemical shifts in B are given relative to BF ·Et O
3
2
1
4
15
(
0 ppm). Chemical shifts in N and N are given relative to liquid NH
3
(0 ppm). Chemical shifts
19
in F are given relative to CFCl
3
(0 ppm). Multiplicities are indicated by s (singlet), d (doublet),
t (triplet), q (quartet), quint. (quintet), m (multiplet) and br. (broad). W values correspond to the
full width at halfꢀmaximum of signal in Hz. Solid state NMR were recorded on a 400 MHz
spectrometer with magnetic field of 9.4 T using a 4ꢀmm CP/MAS probe. Larmor frequency for
1
11
13
15
investigated nuclear H, B, C and N are 400.23, 128.41, 100.64 and 40.55 MHz
respectively. Samples were loaded into a zirconium oxide 4 mm rotor which was spun at 14 kHz.
TMS (0 ppm), H
(39.3 ppm relative to liquid NH
respectively. Single pulse NMR spectra for H, B and C respectively were acquired with 8,
3
BO
3
(19.8 ppm relative to BF
3 2 4
·Et O), and solid NH Cl at 2.5kHz spun rate
1
11
13
15
3
) were used as external references for H, B, C and
N
1
11
13
8
{
192 and 2048 scans; 3 ꢁs, 1.5 ꢁs and 3.2 ꢁs pulse length; 5 s, 0.2 s and 10 s relaxation delay.
1
13
1
15
H} C and { H} N CP/MAS NMR spectra respectively were acquired with 8192 and 32768
scans; 0.65 ms and 10 ms contact time; 5 s and 10 s relaxation delay. HRMS experiments were
performed on a massꢀspectrometer with electrospray ionization and a timeꢀofꢀflight (TOF)
–1
detector. Peaks in FTꢀIR spectra data are reported in cm with the following relative intensities:
s (strong), m (medium), w (weak), br (broad), sh (shoulder). Concentrations c in the optical
–
1
2
–1
rotation data are given in g/100 mL; [α]
D
values are given in 10 deg cm g . UV–Vis
ꢀ5
ꢀ1
absorption and fluorescence spectra were measured in a 1 cm cell for 5× 10 mol mL solutions
in MeOH at room temperature. Sorption/desorption isotherms of nitrogen in BET measurements
o
were measured at ꢀ196 C (77K). Micropore volumes (Vmicro) were determined using tꢀplot
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method. The total sorbed volumes (V ), including adsorption in the micropores and mesopores
tot
and on the external surface, were calculated from the amount of nitrogen adsorbed at relative
0
pressure p/p of 0.95, before the onset of interparticle condensation.
Fieldꢀemission scanning electron microscopy (FEꢀSEM) experiment was performed on Hitachi
SU8000. Targetꢀoriented approach was utilized for the optimization of the analytic
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
28
measurements. Before measurements the samples were mounted on a 25 mm aluminum
specimen stub and fixed by conductive graphite adhesive tape. Metal coating with a thin film (7
nm) of gold/palladium alloy (60/40) was performed using magnetron sputtering method as
29
described earlier. Images were acquired in secondary electron mode at 2 kV accelerating
voltage and at working distance 8ꢀ10 mm. Morphology of the samples was studied taking into
29
account possible influence of metal coating on the surface. TGA and DSC were measured in
o
flowing nitrogen with heating rate of 10 C/min. Xꢀray diffraction analysis was carried out using
graphite monochromated MoꢀKα radiation (λ = 0.71073 Å, ωꢀscans) at 120 K. The structure was
2
solved by direct method and refined by the fullꢀmatrix leastꢀsquares against F in anisotropic
approximation for nonꢀhydrogen atoms. The H(C) atom positions were calculated. All hydrogen
atoms were refined in isotropic approximation in riding model. Quantumꢀchemical calculations
were performed with the Gaussian 16 program. Analysis of vibrational frequencies was
performed for all optimized structures. All compounds were characterized by only real
vibrational frequencies.
+
ꢀ 13a
+
ꢀ 13c
+ ꢀ 13b
13с
TAAD salts [NꢀBnꢀTAAD] Br , [NꢀBnꢀTAAD] Cl , [NꢀMeꢀTAAD] I , and 6 were
prepared according to previously described protocols. All reagents were commercial grade and
used as received (if not stated otherwise).
3 3 2
Synthesis of TRISOXH . Water (3.28 mL) and NH solution 25 wt. % in H O (3.28 mL) were
14
15
added to hydroxylamine hydrochloride ( N or N) (574 mg, 8.14 mmol). Reaction mixture was
stirred until dissolved with cooling in a water bath, then chloroacetone (0.65 ml, 8.14 mmol) was
added. Then water bath was removed and reaction mixture was stirred for 1 hour at room
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temperature. The formed precipitate was filtered off, washed with water and then with Et O and
2
dried in vacuum at 0.1 Torr until constant weight to give 234 mg (yield 37%) of TRISOXH
3
or
1
5
1
NꢀTRISOXH as a white solid. H NMR spectrum of TRISOXH is in agreement with
3
3
1
3a
literature data. 100 Grams scale synthesis: To a solution of hydroxylamine hydrochloride (435
g, 6.3 mol) in water (5 L) was added ammonia aqueous solution (25 wt. %, 2 L, 26.7 mol)
through a dropping funnel with vigorous stirring within 20 minutes. Reaction mixture was stirred
until dissolved with iceꢀbath cooling, and then chloroacetone (500 ml, 6.3 mmol) was added
through a dropping funnel within ca. 10 minutes (temperature of the reaction mixture must not
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
exceed 45 C). After addition was complete, the reaction mixture was stirred for 1 hour. The
formed precipitate was filtered off and washed with 3 L of water and dried on air until constant
weight to give 147 g (yield 30%) of TRISOXH3.
15
15
3
Synthesis of NꢀTAAD. Prepared from NꢀTRISOXH according to a previously described
14
13a
1
15
method used for the synthesis of NꢀTAAD. White solid. H NMR spectrum of NꢀTAAD is
14
13a 15
in agreement with literature data for of NꢀTAAD.
N NMR: (50.68 MHz): σ = 170.0 (Nꢀ
OH,br). FTꢀIR (KBr): 3382 (s,br), 3228 (s,br), 2995 (m,br), 2942 (s), 2821 (s,br), 1736 (m), 1578
(
m,br), 1452(s, br), 1373 (s), 1322 (s), 1258 (w), 1234 (m), 1191 (s), 1074 (s), 1047 (w), 1011
s), 975 (w), 960 (w), 934 (w), 891 (w), 848 (w), 818 (s), 735 (s,br), 712 (w), 658 (w), 641 (w),
(
611(w), 586 (w,sh), 520 (m), 511 (m), 475 (m), 456 (w), 440 (w), 409 (w). ESIꢀHRMS m/z:
+
14 15
+
+
[
[
M+H] Calcd for [C
9
H
19 N N
3
O
3
]
234.1363; Found 234.1366; [M+Na] Calcd for
14
15
+
C H18 N N O Na] 256.1182; Found 256.1170.
9 3 3
Synthesis of (Nꢀ(pꢀCH O CꢀBn)ꢀTAAD. To a mixture of methyl 4ꢀ(bromomethyl)benzoate
3
2
(115 mg, 0.50 mmol) and TRISOXH
3
(115 mg, 0.50 mmol) was added 1 ml of methanol. The
o
reaction mixture was stirred for 91 hours at room temperature and then 5 hours at 40 C. The
resulting solution was evaporated and the residue was dried in vacuum at 0.1 Torr until constant
weight to give 249 mg (yield 99%) of Nꢀ(pꢀCH
3
O
2
CꢀBn)ꢀTAAD as a white solid. Mp = 231ꢀ
o
1
2
35 C (with dec.). H NMR (300 MHz, HSQC, DMSOꢀd ): σ = 1.23 (s, 9 H, 3 CH ), 3.42 (s, br,
6
3
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H, 3 CH ), 3.87 (s, 3 H, CO CH ), 4.77 (s, 2 H, CH C H ), 7.77 (d, J = 8.1 Hz, 2 H, 2 CH ),
2
2
3
2
6
4
Ar
1
3
8.05 (d, J = 8.0 Hz, 2 H, 2 CHAr), 8.30ꢀ8.90 (br, 3 H, 3 OH). C NMR (75 MHz, JMOD,
DEPT135, HSQC, DMSOꢀd ): σ = 20.6 (CH ), 52.4 (CH CO ), 54ꢀ57 (CH , br), 66.6
6
3
3
2
2
(
(
CH
2
C
6
H
4
), 75.6 (C, br), 129.6 (2 CHAr), 130.9 (CAr), 131.4 (CAr), 133.7 (2 CHAr), 165.7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
CO
2
Me). C NMR (75 MHz, DEPT135, HSQC, HMBC, DMSOꢀd
6
, 363K): σ = 20.1 (CH
3
),
5
1
2
1.8 (CH CO ), 54.2 (CH ), 66.8 (CH C H ), 75.2 (C), 129.1 (2 CH ), 130.4 (C ), 131.3 (C ),
3
2
2
2
6
4
Ar
Ar
Ar
33.1 (2 CHAr), 165.2 (CO
2
Me). FTꢀIR (KBr): 3484 (m,br), 3278 (s,br), 3039 (w), 2996 (m),
971 (w), 2953 (m), 2908 (w), 2828 (w), 2757 (w), 1961(w), 1838(w), 1724(s), 1679 (w),
1656(w), 1615(w), 1578 (w), 1512 (w), 1479 (m), 1446 (s), 1409 (s), 1372 (s), 1338 (w), 1320
m), 1285 (s,sh), 1229 (w), 1194 (s), 1117 (s), 1051 (w), 1025 (s), 1003 (s,sh), 954 (m), 934 (m),
(
8
5
71 (m), 846 (w), 831 (w), 811 (w), 794 (w), 770 (m), 749 (w), 709 (m), 670(w), 607 (m,br),
+
85 (m), 528(m), 466 (m,br), 430 (w), 413 (w). ESIꢀHRMS m/z: [MꢀBr] Calcd for
+
[
C H N O ] 379.1976; Found 379.1975. Anal. Calcd for C H BrN O •MeOH: C, 46.44; H,
1
8
27
4
5
18 27
4
5
6.36; N, 11.40. Found: C, 46.06; H, 6.20; N, 11.42.
1
5
3 2
Nꢀ(pꢀCH O CꢀBn)ꢀTAAD was prepared according to the procedure described above from 39
15
mg (0.1717 mmol) of methyl 4ꢀ(bromomethyl)benzoate, 115 mg (0.5 mmol) of N TRISOXH3
in MeOH (0.4 ml). 78 mg (Yield 99%). FTꢀIR (KBr): 3279 (s,br), 2996 (m,sh), 2952 (s,sh), 1725
(
s), 1639 (w), 1616 (w), 1578 (w), 1479 (m), 1440 (s), 1408 (m), 1372 (s), 1320 (m), 1285 (s,sh),
193 (s), 1114 (s), 1052 (s), 1025 (m), 1001 (m), 977 (m), 932 (m), 869 (m), 844 (w), 790 (w),
766 (m), 745 (w), 729 (w), 709 (m), 606 (m,sh), 583 (m), 526 (w), 490 (br,w),428 (w). ESIꢀ
1
+
14 15
27
+
HRMS m/z: [MꢀBr] Calcd for [C H N N O ] 382.1887; Found 382.1884.
1
8
3
5
Synthesis of EstꢀB(OH)
2
. To a stirred solution of estrone (135 mg, 0.5 mmol) in DMF (1.2 mL)
was added K CO (138 mg, 1.0 mmol) under argon atmosphere. After stirring for 1 hour at room
2
3
temperature, 3ꢀ(bromomethyl)phenylboronic acid (160 mg, 0.75 mmol) was added, and the
o
mixture was heated at 80 C for 3.5 hours with stirring. Then, the reaction mixture was
concentrated in vacuum, and the residue subjected to a column chromatography on silica gel.
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The column was eluated with hexaneꢀAcOEt mixtures (ratio 10 : 1 → 3 : 1) containing ca. 1% of
water and AcOH to remove unreacted estrone (50 mg, 37%). Eluation with hexaneꢀAcOEt 1 : 1
o
mixture provided 83 mg (41%) of target compound as white solid. Mp = 82ꢀ84 C (AcOEtꢀ
t
o
1
CH
3
O Bu). R
f
= 0.15 (hexaneꢀAcOEt, 1 : 1). [α]
D
= 83.3 (c = 0.75, AcOEt, 22 C). H NMR (300
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, DMSOꢀd ) δ 8.07 (s, 2H), 7.85 (s, 1H), 7.75 and 7.46 (2 d, J = 7.2 and 6.8 Hz, 1H and
6
1H), 7.36 (dd, J = 7.2, 6.8 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 6.74 (s,
1H), 5.05 (s, 2H), 2.82 (m, 2H), 2.42 (dd, J = 18.5, 8.4 Hz, 1H), 2.35, 2.19, 2.11 and 2.01ꢀ1.91(4
m, 1H, 1H, 1H and 2H), 1.77 (m, 1H), 1.58 – 1.46 and 1.44 – 1.33 (2 m, 3H and 3H), 0.84 (s,
1
3
3
H). C NMR (75 MHz, DEPT135, DMSOꢀd
6
) δ 219.6 (C), 156.3 (C), 137.4, 136.1 and 131.9
(
C), 133.9, 133.4, 129.3, 127.4 and 126.2 (CH), 114.6 (CH), 112.3 (CH), 69.3 (CH ), 49.6 (CH),
2
4
7.3 (CH
2
), 43.4 (CH), 37.8 (CH), 35.3 (CH
2
), 31.3 (CH
2
), 29.1 (CH
2
), 26.0 and 25.5 (CH
): σ = ꢀ0.5 (br, W = 534
] 405.2236; Found 405.2235.
To cinchonine (73.5 mg 0.25 mmol) and (3ꢀ
bromomethyl)phenyl)boronic acid (53.5 mg, 0.25 mmol) solvent mixture consisting of 0.5 ml of
DMF, 0.4 ml of EtOH and 0.15 ml of CHCl was added. Reaction mixture was stirred for 1 hour
2
),
11
21.1 (C), 13.5 (CH
3
) (CꢀB not observed). B NMR: (96 MHz, DMSOꢀd
6
+
+
Hz). ESIꢀHRMS m/z: [M+H] Calcd for [C25
H30BO
4
Synthesis of CinꢀB(OH)
2
.
(
3
at room temperature, then heated in oil bath at 50 °C for 3 hours and after that kept for 12 hours
at room temperature. Then, the reaction mixture was heated in oil bath at 90 °C for 1 hour (it is
important to monitor temperature at this stage) and was concentrated in vacuum. The residual
orange oil was and triturated with Et
2
O (2×2 ml) and water (3×1 ml). The resulting beige colored
0
solid was dried in a vacuum (0.1 Torr, 100 °C for 4 h). Yield: 88 mg (69%). Mp = 238ꢀ242 C
o
1
(with dec.). [α]
.4 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.30 (s, 2H), 8.17 – 8.09, 7.99, 7.91 – 7.69 (m, d, J = 6.7
Hz and m, 1H, 1H and 5H), 7.57 (t, J = 7.6 Hz, 1H), 6.86 (s, 1H), 6.56 (s, 1H), 6.11 – 5.97 (m,
D 6
= 50.6 (c = 1.00, MeOH, 25 C). H NMR (300 MHz, DMSOꢀd ) δ 9.02 (d, J =
4
1H), 5.40ꢀ5.15 (m, 2H), 5.14 (d, J = 12.1 Hz, 1H), 4.94 (d, J = 12.1 Hz, 1H), 4.24 (m, 1H), 3.98
–
3.88 (m, 2H), 3.51 (m, 1H), 2.96 (m, 1H), 2.69 (m, 1H), 2.30 (m, 1H), 1.98 – 1.72 (m, 3H),
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3
1
.07 (m, 1H). C NMR (75 MHz, JMOD135, DMSOꢀd ) δ 150.1 (CH), 147.6 and 145.0 (C),
6
139.4, 137.1, 135.6 and 135.3 (CH), 129.7, 129.3, 128.0 and 127.1 (CH), 126.9 and 124.3 (C),
123.8 and 120.0 (CH), 117.0 (CH ), 67.0 and 64.7 (CH), 62.5 (CH ), 56.0 and 53.7 (CH ), 36.6
) (CꢀB not observed). B NMR: (96 MHz, DMSOꢀd ): σ =
.7 (br, W = 1181 Hz). FTꢀIR: 3384 (s,br), 3228 (s,br), 2956 (s,br), 2375 (w), 2346 (w), 1943
2
2
2
11
(
CH), 26.4 (CH), 22.9 and 20.6 (CH
2
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
(
w), 1870 (w), 1846 (w), 1794 (w), 1751 (w), 1718 (m,sh), 1686 (w), 1638 (m), 1617 (m), 1591
s), 1572 (m), 1542 (w), 1509 (s), 1438 (s,sh), 1342 (s,sh), 1262 (s), 1208 (s), 1153 (m), 1129 (s),
(
1
090 (s), 1064 (s), 1033 (s), 1001 (s), 934 (s), 871 (s), 798 (s), 776 (s), 764 (s), 720 (s), 669 (w),
+
634 (m), 615 (w), 553 (s,sh), 492 (w), 459 (m), 444 (w), 423 (m). ESIꢀHRMS m/z: [MꢀBr]
+
Calcd for [C26
H
30BN
2
O
3
] 429.2349; Found 429.2352.
+
ꢀ
Synthesis of adduct 1a from [NꢀBnꢀTAAD] Cl . To a stirred solution of phenylboronic acid
+
ꢀ
(
61 mg, 0.5 mmol) in 3.8 mL of CH
3
OH was added [NꢀBnꢀTAAD] Cl (178 mg, 0.5 mmol).
After 24 h at room temperature, Na CO
2
3
(26.5 mg, 0.25 mmol) was added and the mixture was
kept for additional 24 h with occasional shaking. The reaction mixture was evaporated in
vacuum and the product was separated from sodium chloride by extraction with EtOAc/EtOH (1
:
1) mixture. Combined extracts were evaporated in vacuum, the residue was triturated with
o
AcOEt/CH
3
OH (1 : 10) mixture and dried in vacuum (0.1 Torr and 100 C) until constant weight
1
to give 160 mg (79%) of adduct 1a as a white solid. Mp above 260 °C. H NMR (300 MHz,
HSQC, DMSOꢀd
(m, 3 H, mꢀ and pꢀC
NMR (75 MHz, HSQC DMSOꢀd
26.0 and 131.1 (o, m, pꢀC ), 126.2 (iꢀC
CꢀB not observed). B NMR: (96 MHz, DMSOꢀd
432 (s,br), 3067 (w,sh), 3042 (w), 2993 (w) 2946 (w), 1654 (m,sh), 1497 (w), 1483 (w), 1458
6
): σ = 1.54 (s, 9 H, 3CH
), 7.31 (d, J = 6.8 Hz, 2 H, oꢀ C
): σ = 21.5 (CH ), 63.4 (CH
CH ), 129.0, 130.4 and 132.9 (o, m, pꢀC
): σ = 2.0 (br, W = 960 Hz). FTꢀIR (KBr):
3
), 3.47 (s, 6 H, 3CH
), 7.48−7.57 (m, 5 H, CH
), 65.7 (C CH
2
), 4.62 (s, 2 H, CH
2
C
6
H
5
), 7.03
1
3
6
H
5
6
H
5
2
C
6
H
5
). C
6
3
2
6
H
5
2
) 71.8 (C), 125.4,
2
CH )
1
6
H
5
6
H
5
2
6
H
5
11
(
6
3
(w), 1433 (w), 1416 (w), 1369 (s), 1322 (w), 1258 (s), 1226 (s), 1202 (m), 1057 (m), 1038 (w),
1005 (s,sh), 976 (m), 940 (m), 925 (m,sh), 886 (s), 869 (w), 827 (w), 772 (s), 743 (s), 702 (s),
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2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
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5
5
5
5
5
5
5
5
5
6
+
6
69 (m), 647 (m), 612 (m), 567 (s), 512 (m), 458 (w), 433 (m). ESIꢀHRMS m/z: [M+H] Calcd
+
for [C22
H28BN
4
O
3
] 407.2253; Found 407.2255. Anal. Calcd for C22
H27BN
4
O
3
: C, 65.04; H,
6.70; N, 13.79. Found: C, 64.96; H, 6.61; N, 13.87. For XꢀRay diffraction analysis the sample
was crystallized from MeOH:H O (1:1) to give single crystals of 1a•4H O (CCDC 1048294).
2
2
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hydrolysis of adduct 1a (procedure for Figure 1). To a solution of 1a (10 mg, 0.025 mmol) in
D O (0.5 mL) a reagent (acid or base, see Supporting information, 0.05 mmol) was added and
2
reaction mixture was stirred at room temperature for 5 hours. Then, the solution was transferred
1
into NMR tube and H NMR spectrum was recorded and concentrations of 1a and N-BnꢀTAAD
were measured. For measurements of pH values same experiments were conducted in H
instead of D O (for primary data see Supporting information).
2
O
2
Exchange of boronic acid residues in diamantanes 1. To a solution of (4ꢀ
bromophenyl)boronic acid (5 mg, 0.025 mmol) and diamantane 1a (10 mg, 0.025 mmol) in
3 2
CD ODꢀD O mixture (0.25 mL/0.25 mL) was added reagent (acid or base, see Supporting
information, 0.05 mmol). The reaction mixture was stirred at room temperature for 2 hours, then
1
transferred into NMR tube and H NMR spectrum was recorded. The amount of PhB(OH)
2
and
NꢀBnꢀTAAD salt was measured. For measurements of pH values same experiments were
conducted in CH OHꢀH O instead of D O (for primary data see Supporting information).
Kinetics of boronic acid residue exchange. A mixture of (4ꢀbromophenyl)boronic acid (5 mg,
3
2
2
0
3 2
.025 mmol) and diamantane 1a (10 mg, 0.025 mmol) was dissolved in CD ODꢀD O (0.25
1
mL/0.25 mL) and kept for 96 hours at room temperature. H NMR revealed that almost no
exchange of boronic acid residues took place (less than 5 % of PhB(OH) ). Then, AcOH solution
2
1
in D
2
O (25 µL, prepared by mixing 5.6 µL of AcOH in 50 µL D
2
O) was added and H NMR
spectra were recorded with 10ꢀ20 minutes intervals (for primary data see Supporting
information).
3 3
Cleavage of diamantane 1a with B(OH) . B(OH) (2.5 mmol, 155 mg) and AcOH (29 µL, 0.5
mmol) were added to a solution of 1a (100 mg, 0.25 mmol) in 10 ml of H O. Continuous liquidꢀ
2
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liquid extraction with hot CHCl (30 ml) was performed for 5 hours. Then organic layer was
3
collected and concentrated in vacuum. The residue was dried in vacuum until constant weight to
give 27 mg (90%) of PhB(OH)
2
as a white solid.
2
General procedure for threeꢀcomponent coupling of boronic acids, alkylating agents R LG
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and TRISOXH
3
3
to give adducts 1. To boronic acid (0.5 mmol) and TRISOXH (115 mg, 0.5
2
mmol) were added methanol (1 mL) and alkylating agent R LG (0.5 mmol if not stated
otherwise) and the mixture was stirred for 20 hours at rt. Base (0.25 mmol) was added, and
stirring was continued for additional 4 hours. Then, the reaction mixture was concentrated in
vacuum and triturated with acetone (if not stated otherwise) to remove inorganic salts. Crude
product was dried in a vacuum at 0.1 Torr until constant weight.
Derivative 1a. Prepared according to general procedure from 61 mg (0.5 mmol) of
phenylboronic acid, 115 mg (0.5 mmol) of TRISOXH
in MeOH (1 ml). Li CO (18.5 mg, 0.25 mmol) was used as a base. 191 mg (yield 94%). Yield
of 1a prepared from benzyl chloride: 71%; from benzyl tosylate: 64%. Nꢀ1a was prepared
3
and 58 µl (0.5 mmol) of benzyl bromide
2
3
1
5
1
5
according to general procedure from NꢀTRISOXH
3
and benzyl bromide. FTꢀIR: 3409 (s,br),
3
068 (w,sh), 2985 (w,sh) 2940 (w), 1703 (m), 1653 (m,sh), 1497 (w), 1477 (w), 1458 (w), 1434
(m), 1419 (w), 1372 (s), 1330 (w), 1264 (m,sh), 1226 (s), 1197 (m), 1056 (m), 1036 (w), 1002
(s,sh), 973 (m), 937 (m), 883 (m), 826 (w), 773 (m), 742 (s), 703 (s), 668 (m), 646 (m), 610 (m),
+
563 (s), 511 (w), 458 (w), 433 (m). ESIꢀHRMS m/z: [M+H]
Calcd for
1
4
15
+
+
[
C
22
H
28B N N
3
O
3
] 410.2165;
Found
Found
410.2170;
416.2255;
[M+Li]
Calcd
Calcd
for
for
14
15
+
+
[C H B N N O Li] 416.2247;
[M+Na]
2
2
27
3
3
14
15
+
[C22
H
28B N N
3
O
3
Na] 432.1985; Found 432.1993.
Derivative 1b. Prepared according to general procedure from 100.5 mg (0.5 mmol) of (4ꢀ
bromophenyl)boronic acid, 115 mg (0.5 mmol) of TRISOXH and 58 µl (0.5 mmol) of benzyl
(18.5 mg, 0.25 mmol) was used as a base. 218 mg (yield 90%).
3
bromide in MeOH (1 ml). Li
2
CO
3
1
White solid. Mp above 260 °C. H NMR (300 MHz, DMSOꢀd
6
): σ = 1.52 (s, 9 H), 3.45 (s, 6 H),
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
4
.52 (s, 2 H), 7.23 (m, 4 H), 7.54 (m, 5 H). C NMR (75 MHz, JMOD, DMSOꢀd ): σ = 21.5
6
(CH
3 2 2
), 63.4 (CH ), 66.1 (CH ) 71.9 (C), 119,1 (C), 126.1 (C), 128.9 and 132.9 (CH), 129.1,
11
130.5 and 133.4 (CH), 139.2 (C). B NMR: (96 MHz, DMSOꢀd
6
): σ = 2.39 (br, W = 288 Hz).
+
+
+
ESIꢀHRMS m/z: [M+H] Calcd for [C22
H
27BBrN
4
O
3
] 485.1358; Found 485.1349. [M+Na]
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
Calcd for [C22
H26BBrN
4
O
3
Na] 507.1177; Found 507.1173. [M+K]
Calcd for
+
[
C H BBrN O K] 523.0917; Found 523.0909. Anal. Calcd for C H BBrN O : C, 54.46; H,
2
2
26
4
3
22 26
4
3
5
.40; N, 11.55. Found: C, 54.42; H, 5.41; N, 11.48.
Derivative 1c. Prepared according to general procedure from 61 mg (0.5 mmol) of
phenylboronic acid, 115 mg (0.5 mmol) of TRISOXH and 97.5 mg (0.5 mmol) of 3ꢀ
3
(
bromomethyl)benzonitrile in MeOH (1 ml). Li
2
CO
3
(18.5 mg, 0.25 mmol) was used as a base.
1
1
70 mg (yield 77%). White solid. Mp above 260 °C. H NMR (300 MHz, DMSOꢀd
6
): σ = 1.54
(
s, 9 H), 3.48 (s, 6 H), 4.55 (s, 2 H), 7.04 (m, 3 H), 7.30 (d, J = 6.6 Hz, 2 H), 7.72 (dd, J = 7.6
1
3
Hz, J = 7.8 Hz 1 H) 7.85 (d, J = 7.8 Hz, 1 H), 8.02 (s, 1H), 8.06 (d, J = 7.6 Hz, 1 H). C NMR
(75 MHz, DEPT 135, DMSOꢀd ): σ = 21.9 (CH ), 64.0 (CH ), 65.2 (CH ) 72.4 (C), 112.8(C),
118.8(C), 125.9, 126.5 and 131.6 (CH), 128.1 (C), 130.7, 134.6, 137.0 and 138,2 (CH), (CꢀB not
6
3
2
2
11
observed). B NMR: (96 MHz, DMSOꢀd ): σ = 3.69 (br, W = 1350 Hz). ESIꢀHRMS m/z:
6
+
+
[
M+H] Calcd for [C23
H
27BN
5
3
O ]
432.2206; Found 432.2198. Anal. Calcd for
C H BN O •H O: C, 61.48; H, 6.28; N, 15.59. Found: C, 61.84; H, 6.45; N, 15.16.
23
26
5
3
2
Derivative 1d. Prepared according to general procedure from 61 mg (0.5 mmol) of
phenylboronic acid, 115 mg (0.5 mmol) of TRISOXH and 114,5 mg (0.5 mmol) of methyl 4ꢀ
3
(bromomethyl)benzoate in MeOH (1 ml). Li
2
CO
3
(18.5 mg, 0.25 mmol) of was used as a base.
1
1
89 mg (yield 84%) White solid. Mp = 231ꢀ235 °C (with dec.). H NMR (300 MHz, DMSOꢀd ):
6
σ = 1.53 (s, 9 H), 3.48 (s, 6 H), 3.89 (s, 3 H), 4.60 (s, 2 H), 7.04 (m, 3 H), 7.28 (d, J = 6.0 Hz, 2
1
3
H), 7.67 (d, J = 7.7 Hz, 2 H), 8.06 (d, J = 7.7 Hz, 2 H). C NMR (75 MHz, DEPT 135, DMSOꢀ
d ): σ = 21.5 (CH ), 52.4 (CH ), 63.6 (CH ), 65.2 (CH ) 71.9 (C), 125.4, 126.1 and 131.2 (CH),
6
3
3
2
2
11
1
6
29.6, 133.4 (CH), 131,0 (C), 131,3 (C),148.2 (C), 165.7 (C). B NMR: (96 MHz, DMSOꢀd ): σ
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=
2.03 (br, W = 1178 Hz). FTꢀIR (KBr): 3417 (m,br), 3005 (m,sh), 2941 (m), 1722 (s), 1639 (w),
1616 (w), 1578 (w), 1510 (w), 1476 (m), 1436 (s), 1421 (w), 1368 (s), 1319 (m), 1287 (s), 1256
(s), 1223 (s), 1188 (s), 1114 (s), 1058 (m), 1037 (w), 1005 (s), 994 (s), 978 (m), 944 (s), 890 (s),
871(m), 843 (w), 814 (w) , 775 (m), 762 (m), 745 (s), 728 (w), 702 (s), 665 (w), 646 (w), 581
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
4 5
(m), 564 (m), 529 (br,s), 486 (br,s),421 (m). ESIꢀHRMS m/z: [M+H] Calcd for [C24H30BN O ]
+
+
465.2308; Found 465.2300. [M+Na] Calcd for [C H BN O Na] 487.2127; Found 487.2123
24 29 4 5
Anal. Calcd for C24
10.78.
H29BN
4
O
5
2
•2H O: C, 57.61; H, 6.65; N, 11.20. Found: C, 57.35; H, 6.13; N,
Derivative 1e. Prepared according to general procedure from 61 mg (0.5 mmol) of
phenylboronic acid, 115 mg (0.5 mmol) of TRISOXH and 177 mg (0.6 mmol) of 2ꢀbromoꢀ1ꢀ
bromomethyl)ꢀ4ꢀnitrobenzene in MeOH (1 ml). Li CO (18.5 mg, 0.25 mmol) was used as a
3
(
2
3
base. Reaction mixture was triturated with Et
2
O:EtOH (10:1) to remove LiBr. 269 mg (Yield
1
99%). White solid. Mp = 221ꢀ223 °C (with dec.). H NMR (300 MHz, DMSOꢀd ): σ = 1.56 (s, 9
6
H), 3.65 (s, 6 H), 4.79 (s, 2 H), 7.05 (m, 3 H), 7.29 (d, J = 6.4 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 1 H),
13
8.32 (d, J = 8.3 Hz, 1 H), 8.55 (s, 1 H). C NMR (75 MHz, DEPT 135, DMSOꢀd ): σ = 21.5
6
(
CH
3
2 2
), 64.15(CH ), 64.32 (CH ) 72.0 (C), 122.9 (CH), 125.4, 126.0 and 131.2 (CH), 127,4 (С),
1
1
1
28.5 (CH), 133.1 (C) 136.9 (CH), 149.1 (C). B NMR: (96 MHz, DMSOꢀd
6
): σ = 2.34 (br, W =
] 530.1209; Found 530.1205.
Na] 552.1028; Found 552.1029. Anal. Calcd for
O: C, 49.01; H, 4.86; N, 12.99. Found: C, 49.02; H, 4.98; N, 12.95.
Derivative 1f. Prepared according to general procedure from 122 mg (1.0 mmol) of
phenylboronic acid, 230 mg (1.0 mmol) of TRISOXH and 63 µl (1.0 mmol) of CH I in MeOH
+
+
5 5
709 Hz). ESIꢀHRMS m/z: [M+H] Calcd for [C22H26BBrN O
+
+
[M+Na] Calcd for [C22
5 5
H25BBrN O
C
22
H
25BBrN •0.5H
5
O
5
2
3
3
(2 ml). Na
2
0
CO
3
(53 mg, 0.5 mmol) of was used as a base. 287 mg (Yield 83%). White solid. Mp
1
=
232ꢀ240 C (with dec.). H NMR (300 MHz, DMSOꢀd
6
): σ = 1.55 (s, 9 H), 3.00 (s, 3 H), 3.53
13
(s, 6 H), 7.06 (m, 3 H), 7.31 (d, J = 6.0 Hz, 2 H). C NMR (75 MHz, JMOD, DMSOꢀd6): σ =
21.4 (CH ), 50.6 (CH ), 65.8 (CH ), 71.9 (C), 125.4, 126.0 and 131.2 (CH), (CꢀB not
3
3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
+
observed). B NMR: (96 MHz, DMSOꢀd ): σ = 2.15 (br, W = 455 Hz). ESIꢀHRMS m/z: [M+H]
6
+
+
Calcd
for
[C16
H24BN
4
O
3
] 331.1939;
Found
331.1940.
[M+Na]
Calcd
for
+
[C H BN O Na] 353.1758; Found 353.1761. Anal. Calcd for C H BN O •H O: C, 55.19; H,
1
6
23
4
3
16 23
4
3
2
7
.24; N, 16.09. Found: C, 54.96; H, 6.86; N, 15.64.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Derivative 1g. nꢀBuI (56 µl, 1.5 mmol) was added to a mixture of 61 mg (0.5 mmol) of
phenylboronic acid and 115 mg (0.5 mmol) of TRISOXH in MeOH (1 ml). Reaction mixture
3
2 3
was stirred for 24 hours and then Na CO (26.5 mg, 0.25 mmol) was added. After 48 hours
additional 115 µl (1.0 mmol) of nꢀBuI were added to ensure full conversion. The mixture was
stirred for additional 24 hours, concentrated in vacuum and triturated with acetone to remove
LiBr. Crude product was dried in vacuum at 0.1 Torr until constant weight. 176 mg (Yield 90%).
1
White solid. Mp above 260 °C. H NMR (300 MHz, DMSOꢀd
6
): σ = 0.91 (t, J = 7.2 Hz 3 H),
1
.26ꢀ1.32 (m, 2 H), 1.58 (s, 9 H), 1.63 (m, 2 H), 3.17ꢀ3.27 (br, 2 H), 3.48 (s, 6 H), 7.05 (m, 3 H),
13
6 3 2
7.32 (d, J = 6.4 Hz, 2 H). C NMR (75 MHz, JMOD, DMSOꢀd ): σ = 13.3 (CH ), 19.1 (CH )
21.4 (CH
3
), 22.2 (CH
2
), 62.8 (CH
2
), 63.7 (CH
2
), 71.9 (C), 125.3, 126.0 and 131.2 (CH), (CꢀB not
1
1
+
observed). B NMR: (96 MHz, DMSOꢀd ): σ = 2.60 (br, W = 381 Hz). ESIꢀHRMS m/z: [M+H]
6
+
+
Calcd
for
[C19
H30BN
4
O
3
] 373.2409;
Found
373.2406.
[M+Na]
Calcd
for
+
[
C H BN O Na] 395.2228; Found 395.2225. Anal. Calcd for C H BN O •H O: C, 58.47; H,
1
9
29
4
3
19 29
4
3
2
8.01; N, 14.36. Found: C, 58.77; H, 7.68; N, 14.35.
Derivative 1h. Prepared according to general procedure from 61 mg (0.5 mmol) of
phenylboronic acid, 115 mg (0.5 mmol) of TRISOXH and 56 µl (0.5 mmol) of ethyl 2ꢀ
3
bromoacetate in EtOH (1 ml). Li
mixture was triturated with Et
2 3
CO (18.5 mg, 0.25 mmol) was used as a base. Reaction
2
O:MeOH (10:1) to remove LiBr. 228 mg (yield 98%). White
1
solid. Mp = 196 °C (with dec.). H NMR (300 MHz, DMSOꢀd
6
): σ = 1.21 (t, J = 6.8 Hz, 3 H),
1.53 (s, 9 H), 3.73 (s, 6 H), 4.19 (br, 2 H), 4.54 (s, 2 H), 7.06 (m, 3 H), 7.29 (d, J = 6.1 Hz, 2 H).
1
3
C NMR (75 MHz, JMOD, DMSOꢀd
6 3 3 2 2
): σ = 13.7 (CH ), 21.5 (CH ), 59.8 (CH ), 62.1 (CH ),
11
6
4.3 (CH ) 71.9 (C), 125.5, 126.1 and 131.1 (CH), 127.2 (C), 164.1 (C), (CꢀB not observed). B
2
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9
+
NMR: (96 MHz, DMSOꢀd ): σ = 2.2 (br, W = 857 Hz). ESIꢀHRMS m/z: [M+H] Calcd for
6
+
+
+
[C19
H28BN
4
O
5
] 403.2151; Found 403.2140, [M+Na] Calcd for [C19
H
27BN
4
O
5
Na] 425.1970;
] 401.2006; Found 401.1997. Anal. Calcd for
C H BN O •3.5H O: C, 49.04; H, 7.37; N, 12.04. Found: C, 48.60; H, 6.84; N, 11.90.
ꢀ
ꢀ
4 5
Found 425.1959, [MꢀH] Calcd for [C19H26BN O
19
27
4
5
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Derivative 1i. Prepared according to general procedure from 61 mg (0.5 mmol) of
phenylboronic acid, 115 mg (0.5 mmol) of TRISOXH and 99 mg (0.5 mmol) of 2ꢀ
3
bromoacetophenone in MeOH (1 ml). Li
2
CO
3
(18.5 mg, 0.25 mmol) was used as a base. 227 mg
1
(yield 97%). White solid. Mp = 200ꢀ204 °C (with dec.) H NMR (300 MHz, DMSOꢀd ): σ =
6
1
7
.58 (s, 9 H), 3.84 (s, 6 H), 5.25 (s, 2 H), 7.07 (m, 3 H), 7.31 (d, J = 6.6 Hz, 2 H), 7.59 (dd, J =
13
.3 Hz, J = 7.7 Hz, 2 H), 7.74 (t, J = 7.3 Hz 1 H), 7.90 (d, J = 7.7 Hz, 2 H). C NMR (75 MHz,
DEPT 135, DMSOꢀd
6
): σ = 21.6 (CH
3 2 2
), 64.57 (CH ), 64.68 (CH ) 72.1 (C), 125.5, 126.2 and
1
1
1
31.2 (CH), 127.9, 129.1 and 134.9 (CH), 134.2 (C), 148.1 (C), 190.8 (C). B NMR: (96 MHz,
+
+
6 4 4
DMSOꢀd ): σ = 4.3 (br, W = 1314 Hz). ESIꢀHRMS m/z: [M+H] Calcd for [C23H28BN O ]
+
+
435.2202; Found 435.2194, [M+Na] Calcd for [C23
H
27BN
O
4 4
Na] 457.2022; Found 457.2014,
+
+
ꢀ
[
[
M+K] Calcd for [C H BN O K] 473.1761; Found 473.1754, [MꢀH] Calcd for
23
27
4
4
ꢀ
C
23
H
26BN
4
O
4
] 433.2057; Found 433.2048. Anal. Calcd for C23
.64; N, 11.91. Found: C, 58.41; H, 6.05; N, 11.57.
Derivative 1j. Prepared according to general procedure from 61 mg (0.5 mmol) of
phenylboronic acid, 115 mg (0.5 mmol) of TRISOXH and 43 µl (0.5 mmol) of allyl bromide in
MeOH (1 ml). Li CO (18.5 mg, 0.25 mmol) was used as a base. 158 mg (yield 85%). White
H
27BN
O
4 4
•2H
2
O: C, 58.74; H,
6
3
2
3
1
solid. Mp above 260 °C. H NMR (300 MHz, DMSOꢀd
d, J = 7.0 Hz, 2 H), 5.58 (m, 2 H), 6.01 (m, 1 H), 7.05 (m, 3 H), 7.30 (d, J = 5.9 Hz, 2 H). C
NMR (75 MHz, JMOD, D O): σ = 21.5 (CH ), 63.7 (CH ), 66.8 (CH ), 72.3 (C), 122.2 (CH),
127.8, 128.0 and 131.1 (CH), 131.2 (CH ), (CꢀB not observed). B NMR: (96 MHz, DMSOꢀd ):
6
): σ = 1.56 (s, 9 H), 3.46 (s, 6 H), 3.91
1
3
(
2
3
2
2
11
2
6
+
+
4 3
σ = 3.09 (br, W =960 Hz). ESIꢀHRMS m/z: [M+H] Calcd for [C18H26BN O ] 357.2096; Found
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