Synthesis of amines with pendant boronic esters by borrowing hydrogen catalysis

Article abstract of DOI:10.1021/ol402271a

Amine alkylation reactions of alcohols have been performed in the presence of boronic ester groups to provide products which are known to have use as molecular sensors. The boronic ester moiety could be present in either the alcohol or amine starting mate

Full text of DOI:10.1021/ol402271a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Amines with Pendant
Boronic Esters by Borrowing
Hydrogen Catalysis
Winson M. J. Ma, Tony D. James,* and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
t.d.james@bath.ac.uk; j.m.j.williams@bath.ac.uk
Received August 9, 2013
ABSTRACT
Amine alkylation reactions of alcohols have been performed in the presence of boronic ester groups to provide products which are known to have
use as molecular sensors. The boronic ester moiety could be present in either the alcohol or amine starting material and was not compromised in
the presence of a ruthenium catalyst.
In recent years a great deal of attention has been focused
on the alkylation reaction of amines, particularly the reac-
tion of an amine with an alkyl halide which is an electrophilic
alkylating agent.1 However, alkylation reactions can prove
difficult to control and the product is often over alkylated.2
There has been significant recent interest in the alkyla-
tion of amines with alcohols using hydrogen transfer
catalysts as an alternative to conventional alkylation
procedures.3,4
The hydrogen transfer catalysts operate by an activation
of the alcohol to an aldehyde in a process that we have
termed “Borrowing Hydrogen Methodology”.5
The borrowing hydrogen method typically uses ruthe-
nium or iridium as the catalyst and takes the hydrogen
from the alcohol 1 to form the aldehyde 2. This aldehyde
can react with an amine to form an imine 3, and the
hydrogen is then returned to give a CÀN bond in product
4 (Scheme 1).1e,5e,6
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r
10.1021/ol402271a
XXXX American Chemical Society

Table 2. Formation of Amines Containing a p-Boronic Ester
Groupa
Scheme 1. Borrowing Hydrogen Strategy in the Alkylation of
Amines with Alcohols
Table 1. Alkylation of Morpholine by Boronic Ester Alcohol 5aa
yield
entry
catalystb
mol %
ligand
none
mol %
(%)c
1
2
3
4
5
6
none
Ru
À
À
À
2
0
1
none
0
Ru
1
DPEphos
DPEphos
Dppf
40
84
16
62
Ru
2.5
1
5
Ru
2
Ru
2.5
Dppf
5
a The reaction was carried out with boronic ester alcohol (1.0 mmol)
with morpholine (1.0 mmol), catalyst (2.5 mol %), and base Na2CO3
(10 mol %) at 155 °C for 24 h. b Ru = [Ru(p-cymene)Cl2]2. c Isolated
yield by recrystallization.
Herein we report a simple one-pot reaction to generate
amines with pendant boronic acid derivatives, using either
an alcohol tethered to a boronic ester with an amine or
an amine tethered to a boronic ester with an alcohol. These
reactions are catalyzed by [Ru(p-cymene)Cl2]2 in the pre-
sence of a bidentate phosphine ligand to form secondary or
tertiary amines containing a boronic ester moiety.
In order to simplify handling and reaction workup
we protected boronic acid with pinacol using standard
methodology.7
We wanted to explore the use of Borrowing Hydrogen
Methodology for the preparation of boronic acid building
blocks which have been extensively used in the construc-
tion of sensors for saccharides and anions.8 We chose to
investigatethe couplingofboronic ester containingalcohol
5a with morpholine 6.
a The reaction was carried out with boronic ester alcohol (1.0 mmol)
with amine (1.0 mmol). b Boronic ester alcohol/amine (2:1), 5 mol %
catalyst, 10 mol % ligand, and 20 mol % base. c R = B-pinacolato.
d Isolated yield by recrystallization. e Percentage conversion since the
product could not be isolated cleanly.
(7) (a) D’Hooge, F.; Rogalle, D.; Thatcher, M. J.; Perera, S. P.; van
den Elsen, J. M. H.; Jenkins, A. T. A.; James, T. D.; Fossey, J. S. Polymer
2008, 49, 3362–3365. (b) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2008, 130, 14084.
(8) Bull, S. D.; Davidson, M. G.; Van den Elsen, J. M. H.; Fossey,
J. S.; Jenkins, A. T. A.; Jiang, Y.-B.; Kubo, Y.; Marken, F.; Sakurai, K.;
Zhao, J.; James, T. D. Acc. Chem. Res. 2013, 46, 312–326.
As shown in Table 1, the reaction was unsuccessful in the
absence of a catalyst or ligand (entries 1 and 2). However,
the use of either DPEphos or dppf led to good conversions
into the corresponding coupled product 7. We were parti-
cularly pleased that the boronic ester survived the reaction
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Formation of Amines Containing a m-Boronic Ester
Groupa
Table 4. Formation of p-Boronic Ester Amine by N-Alkylation
with Alcoholsa
a The reaction was carried out with boronic ester amine (1.0 mmol)
with alcohol (1.0 mmol). b R = B-pinacolato. c Isolated yield by recrys-
tallization.
Table 5. Formation of m-Boronic Ester Amine by N-Alkylation
with Alcoholsa
a The reaction was carried out with boronic ester amine (1.0 mmol)
with alcohol (1.0 mmol). b R = B-pinacolato. c Isolated yield by recrys-
tallization.
conditions, since boronic acid derivatives have well-estab-
lished chemistry with many transition metal catalysts.3c,9
Yet, more forcing reaction conditions were required than
those for substrates which do not contain boronic esters.
[Ru(p-cymene)Cl2]2 is a simple, commercially available
catalyst precursor, and we chose to use the [Ru(p-cymene)-
Cl2]2/DPEphos combination for the N-alkylation of other
alcohols.10 Table 2 contains the results obtained when the
para-substituted boronic ester substrate 5a was used. Table 3
contains the results obtained when the meta-substituted
boronic ester substrate 5b was used. The corresponding
a The reaction was carried out with boronic ester alcohol (1.0 mmol)
with amine (1.0 mmol). b Boronic ester alcohol/amine (2:1), 5 mol %
catalyst, 10 mol % ligand, and 20 mol % base. c R = B-pinacolato.
d Isolated yield by recrystallization. e Percentage conversion since the
product could not be isolated cleanly.
(9) (a) Guillena, G.; Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
2007, 46, 2358–2364. (b) Kranenburg, M.; Vanderburgt, Y. E. M.;
Kamer, P. C. J.; Vanleeuwen, P.; Goubitz, K.; Fraanje, J. Organome-
tallics 1995, 14, 3081–3089. (c) Lamb, G. W.; Williams, J. M. J. Chim.
Oggi. 2008, 26, 17–19.
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Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2004, 126, 5662–5663. (b)
Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J. Tetrahedron Lett.
2006, 47, 6787–6789.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Formation of an Unsymmetrical Bis-boronic Ester
Figure 1. Sensor 13.
reaction is probably due to the use of the less sterically
demanding methyl substituted secondary amine); the
unprotected sensor was prepared for comparison using
a standard reductive amination procedure in 54% yield.
Identical fluorescence behavior of the two sensors with
added saccharides was observed (the protecting group is
displaced under the measurement conditions)13 and clearly
demonstrates the validity of our new synthetic procedure
in the preparation of fluorescence sensors for saccharides
(Supporting Information). We are currently exploring the
use of our procedure in the preparation of novel imprinted
material based sensors.
In summary, the [Ru(p-cymene)Cl2]2/DPEphos/
Na2CO3 conditions were found to be effective for the
synthesis of amines with pendant boronic ester groups.
These compounds and their derivatives have impor-
tant applications as sensors.
ortho-substituted boronic ester did not undergo clean
amination under these reaction conditions.
We were pleased to find that alcohol 5a and 5b were
successfully aminated with a range of amines, with good
isolated yields being achieved in most cases. The use of
a sulfonamide (Table 2, entry 5) was an exception to this,
and this was also found to be the case in the amina-
tion of the corresponding m-substituted product (Table 3,
entry 5). Nevertheless, other amines, including anilines,
could be used in the reaction.
The general applicability of the reaction was further
confirmed by condensation of the para-boronic ester alco-
hol 10 and meta-boronic ester amine 11 (Tables 4 and 5) to
form bis-boronic ester 12 (Scheme 2).
Supporting Information Available. Experimental pro-
cedures and characterization of compounds are available
We also used the strategy to prepare a known saccharide
sensor 1312 in 84% yield (Figure 1; the success of this
1
with copies of H and 13C NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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(13) Xing, Z.; Wang, H.-C.; Cheng, Y.; Zhu, C.; James, T. D.; Zhao,
J. Eur. J. Org. Chem. 2012, 1223–1229.
(12) James, T. D.; Sandanayake, K. R. A. S.; Iguchi, R.; Shinkai, S.
J. Am. Chem. Soc. 1995, 117, 8982–8987.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX