Use of triazole-ring formation to attach a Ru/TsDPEN complex for asymmetric transfer hydrogenation to a soluble polymer

Article abstract of DOI:10.1016/j.tetasy.2013.05.022

The cycloaddition of a chiral ligand containing a terminal alkyne to a soluble polymer containing an azide provides a convenient means for the attachment of an asymmetric transfer hydrogenation catalyst to a soluble polymer support. Using these ligands in complexes with Ru(II), gave good results in terms of conversion and enantioselectivity (up to 95% ee) in ketone reduction reactions.

Full text of DOI:10.1016/j.tetasy.2013.05.022

Tetrahedron: Asymmetry 24 (2013) 844–852
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Use of triazole-ring formation to attach a Ru/TsDPEN complex
for asymmetric transfer hydrogenation to a soluble polymer
⇑
Charlotte M. Zammit, Martin Wills
Department of Chemistry, Warwick University, Coventry CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2013
Accepted 29 May 2013
The cycloaddition of a chiral ligand containing a terminal alkyne to a soluble polymer containing an azide
provides a convenient means for the attachment of an asymmetric transfer hydrogenation catalyst to a
soluble polymer support. Using these ligands in complexes with Ru(II), gave good results in terms of con-
version and enantioselectivity (up to 95% ee) in ketone reduction reactions.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
O
Ru
Ru
N
Ru
N
A series of asymmetric transfer hydrogenation (ATH) catalysts
based on the ‘Ru(II)/TsDPEN’ system have been reported and suc-
cessfully applied to the enantioselective reduction of ketones to
alcohols.1 The first of this series was complex 1, reported in 1995
by Noyori et al.2 Since then, many applications have been
reported1–3and a number of related derivatives have been devel-
oped, including the tethered complexes 2 and 3.4
Cl
O
Cl
TsN
Ph
TsN
Ph
Cl
TsN
Ph
NH2
H
H
Ph
Ph
Ph
1
3
2
RO
Me
n
Significant efforts have been made towards the development of
‘supported’ versions of the Ru(II)/TsDPEN catalyst system. Popular
methods include immobilisation via a covalent attachment to a
support, or entrapment within a support (e.g., silica or polysty-
rene).5 In other cases the catalyst is converted into a form which
permits its ready removal from a reaction mixture e.g. as a surfac-
tant6 or as a derivative containing polyethylene glycol (PEG)
chains.7 In the majority of examples, the linkage (to silica or poly-
Ru
N
Ru
N
Cl
TsN
Cl
TsN
R= H or Me
H
H
PEG200-2000
Ph
Ph
Ph
Ph
4
5
2. Results and discussion
mer) is made to the sulfonyl group, the
g
6-arene ring or a side
To attach a Ru(II)/TsDPEN catalyst to a soluble polymer, we used
the well-established cycloaddition of an azide with an alkyne (a
‘click’ reaction),10 which has been used to attach biologically-active
groups to polymers.11 As it has been demonstrated that a proximal
triazole ring can itself become involved in co-ordination to the
ruthenium atom, and participate in catalysis,12 we investigated sys-
tems where this was distant from the TsDPEN unit. We first prepared
derivative 6 containing a terminal alkyne (Scheme 1). This was then
reacted in a copper-catalysed [3+2] cycloaddition reaction with
azide 7 (prepared from 2-benzyloxyethanol in two steps) to fur-
nish the triazole product 8, a model for the supported compound.
The same procedure was adopted for the synthesis of 1,4-disub-
stituted 1,2,3-triazole 9 by reacting 10 with benzyl azide 11
(formed in situ),13 5 mol % copper(II) sulfate pentahydrate and
10 mol % sodium ascorbate. The catalytic activity of each ligand
was investigated in the ATH of acetophenone (Table 1) by prepar-
ing catalysts in situ from the Ru(II)-pre-catalyst [RuCl2(benzene)]2.
Using formic acid/triethylamine (FA/TEA) as the hydrogen donor,
chain of the diamine unit, thereby leaving a primary amine group
to co-ordinate to the metal. Complex 4 represents an unusual
example whereby a soluble PEG chain is attached via the basic
nitrogen atom, without a significant reduction in the catalyst activ-
ity.7a This mirrors our own findings with N-alkylated TsDPEN
derivatives 5, in which a linear alkyl chain is tolerated by the
catalyst.8
In earlier studies, we employed copolymers of methyl methac-
rylate (MMA) and hydroxyethylmethacrylate (HEMA) as the basis
of soluble catalysts.9 Herein, we report a method for the attach-
ment of an ATH catalyst to a soluble methacrylate polymer using
a cycloaddition reaction.
⇑
Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652 4112.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.022

C. M. Zammit, M. Wills / Tetrahedron: Asymmetry 24 (2013) 844–852
845
Ph
Ph
A higher molecular weight HEMA/MMA copolymer 12c was
NHTs
X
prepared using half the amount of CoBF (Table 2). All the polymers
prepared exhibited monomodal distributions, and the Mn values
calculated by 1H NMR for the low molecular weight polymer 12b
correlated well with those calculated by GPC.
i)
HO
X
N
H
6 X = O 64%
10 X = CH2 39%
The HEMA:MMA copolymer ratio of 3:7 was calculated using the
integration of the methylene signals of the HEMA unit (OCH2-
CH2OH) at 4.12 and 3.85 ppm and the methoxy signal of the MMA
unit (OCH3) at 3.61 ppm. This ratio was utilised to calculate the hy-
droxyl group functionalisation value (fhydroxyl) as 2.77 mmol/g. The
molecular weight (Mn) of the copolymer was calculated from the 1H
NMR spectrum by integrating the vinyl protons of the end group
with respect to the methylene protons of the HEMA repeating unit
and the methyl protons of the MMA repeat unit (Scheme 2). Tosy-
lation of copolymer 12a–c using a known procedure9 furnished
13a–c. The O-tosyl group was subsequently substituted for an azide
upon reaction of 13a–c with 3 equiv of sodium azide to afford
copolymer 14a–c. The conversion of the HEMA/MMA copolymer
12a–c to the tosylated polymer 13a–c was confirmed by 1H NMR
spectroscopy through the appearance of the aromatic signals at
7.8 and 7.4 ppm together with the methyl signal at 2.5 ppm of the
O-tosyl (OTs) group. A change in chemical shift to higher frequency
was observed for the methylene group adjacent to the OTs func-
tionality (3.8–4.1 ppm) of the HEMA repeating unit, and indicated
quantitative conversion. The subsequent disappearance of the char-
acteristic signals belonging to the OTs group, in combination with a
chemical shift for the methylene group to a lower frequency value
of 3.5 ppm, gave strong evidence for the complete formation of the
azido derivatised copolymer 14a–c. The FTIR spectrum of the azido
derivatised copolymer 14a–c showed a strong absorption signal at
2104 cmꢀ1 which is characteristic of the azide group, and this was
used as a diagnostic tool to monitor the subsequent click reaction.
N3
ii)
R
R=CH2OCH2Ph 7
R=Ph, 11
Ph
Ph
NHTs
N
8 X=O, R=CH2OCH2Ph 60%
X=CH2, R=Ph 67%
R
N
9
N
X
N
H
Scheme 1. Preparation of triazole-functionalised TsDPEN derivatives. Reagents and
conditions: (i) 2,6-lutidine, (CF3SO2)2O, CH2Cl2, 0–22 °C, then Et3N, (R,R)-TsDPEN,
CH2Cl2, 0 °C to rt, o/n, 64% (X@O), 39% (X@CH2); (ii) for 8: CuSO4ꢁ5H2O, sodium
ascorbate, tBuOH:H2O, 30 °C, 5 h, 60%; (iii) for 9: C6H5CH2Br, NaN3, CuSO4ꢁ5H2O,
sodium ascorbate, tBuOH:H2O, 60 °C, 3 h, 67%.
at 28 °C each derivative demonstrated good catalytic activity (92–
99%) and enantioselectivity (93–95% ee).
Table 1
Evaluation of (R,R)-TsDPEN and ligands 6, 8–10 in the ATH of acetophenone
O
OH
Ligands 6, 8-10
[RuCl2(benzene)]2
(
)
R
HCO2H:Et3N
S/C 100, 28°C
Entry
Ligand
ta (h)
Conv.b (%)
eeb (%)
1
2
3
4
5
(R,R)-TsDPEN
(R,R)-6
(R,R)-8
(R,R)-9
(R,R)-10
6
53
136
71
>99
92
99
97
97
95
93
95
95
95
45
a
CO2Me
i)
Number of hours necessary to observe a levelling-off in conversion.
Conversion and ee determined by GC analysis.
H
b
7
: 3
CO72Me
3
OH
O
OMe
O
O
HEMA
O
O
The ligands exhibited lower activities but similar enantioselec-
MMA
12a-c
tivities compared to (R,R)-TsDPEN and other N0-alkylated TsDPEN
ligands.2–4 Using the (R,R)-configured ligands in each case, the
alcohol was always formed with an (R)-configuration. The nitrogen
of the triazole moiety in 8 and 9 might coordinate to ruthenium in
a reversible manner,12 reducing the catalytic activity.
Investigations into the immobilisation of the chiral ligand onto a
polymer support were undertaken.14 The synthesis of copolymers
12 was achieved by catalytic chain transfer polymerisation (CCTP)
using methyl methacrylate (MMA) and 2-hydroxyethyl methacry-
late (HEMA) in a 70:30 mixture, in combination with 4,40-azo-
bis(4-cyanovaleric acid) and (CH3OH)2Co-(dmgBF2)2 (CoBF) as the
initiator and chain-transfer catalyst respectively (Scheme 2).14 The
first sample 12a was prepared without active CoBF, and this was
found to have a high molecular weight, as expected. We prepared
a sample of CoBF,15 and the FTIR spectrum of this sample matched
that of a standard.16 Similar molecular weights were obtained and
the dispersity (PDI) was approximately 2 for copolymer sample
12b (Table 2) was prepared with the fresh CoBF and the standard.16
ii)
OH
OTs
N3
13a-c
14a-c
Pol
iii)
Ph
NHTs
Pol
iv)
N
H
Ph
Ph
Ph
10
NHTs
N
N
Pol
N
N
H
15a-c
Scheme 2. Preparation of triazole-functionalised TsDPEN derivatives on soluble
polymer support. Reagents and conditions: (i) dioctylsulfosuccinate sodium salt, 4,40-
azobis(4-cyanovalericacid),CoBF,80 °C,4 h,seeTable2;(ii)TsCl,DMAP,Et3N,DCM,rt,
2 d; (iii) NaN3, DMF, 80 °C, 2.75 h then rt, 48 h; (iv) Et3N, CuBr, TBTA, DMSO, 20 °C,
24 h, 41% (polymer b), Et3N, CuBr, TBTA, DMSO, 25 °C, 24 h, then 50 °C, 72 h, 66%
(polymer c), CuSO4ꢁ5H2O, sodium ascorbate, tBuOH:H2O, 80 °C, 3 d, 98% (polymer a).
Table 2
Molecular weight (Mn) determination by 1H NMR and GPC analysis for the HEMA/MMA copolymers prepared using different samples of CoBF
Entry
Polymer
Ratioa
1H NMR g/mol
Mn
GPC g/mol
Mn
GPC g/mol
Mw
GPC g/mol
PDIb
1
2
3
4
12a
12b
12b
12c
Ac
A16
A
N/ad
1570
2430
N/ad
146 K
970
1080
2710
337 K
1790
2710
9210
2.30
1.84
2.50
3.40
B
a
b
c
[HEMA]:[MMA]:[CoBF] ratios: A = [0.42]:[1.0]:[4.27 ꢂ 10ꢀ5] and B = [0.42]:[1.0]:[2.14 ꢂ 10ꢀ5].
PDI (polydispersity index) = Mn/Mw
.
Inactive CoBF.
d
Polymer too large for Mn to be calculated accurately by 1H NMR.

846
C. M. Zammit, M. Wills / Tetrahedron: Asymmetry 24 (2013) 844–852
Copolymers 14a–c were reacted with ligand 10 to afford 15a–c
HO
H
HO
H
as indicated by the disappearance of the azide signal, and were iso-
lated by filtration in moderate to high yield (41–98%). The high
molecular weight polymer, 15a was too insoluble to be analysed
by solution phase techniques. The chemical modification of the
hydroxyl repeating unit in copolymers 12b and 12c required
slightly different work-up procedures due to their distinct solubil-
ity behaviours. In addition, the click protocol was modified with
the direct use of Cu(I) in combination with tris-[(1-benzyl-1H-
1,2,3-triazol-4-yl)methyl]amine (TBTA).17 Recent ligand screening
experiments11 have revealed the superior behaviour of this ligand
in the Cu(I)-catalysed alkyne-azide cycloaddition reaction for the
formation of glycopolymers.
O
17 92% ee
16 98% ee
The high molecular weight ligand (R,R)-15a displayed almost no
activity (1% conversion) in isopropanol/KOH after 24 h at 28 °C.
Compound (R,R)-15a was also evaluated in aqueous phase ATH
but gave alcohol in just 3% conversion and 59% ee. Treatment of
1 mol % ligand (R,R)-15b with 0.5 mol % [RuCl2(benzene)]2 in FA/
TEA at 28 °C afforded (R)-phenylethanol in high selectivity (95%
ee) and 90% conversion achieved in 6 days (Table 3: entry 7). The
use of 1 mol % of (R,R)-15c in combination with 0.5 mol %
[RuCl2(benzene)]2 in FA/TEA at 28 °C resulted in acetophenone
reduction with 100% conversion and 95% ee in 136 h (Table 3, entry
5).
The addition of water, in an attempt to recover the catalyst, pre-
cipitated the Ru(II)-15c complex. The FA/TEA mixture was then
carefully removed, following which the red solid catalyst was
washed with fresh portions of FA/TEA. The hydrogen donor and ke-
tone substrate were then recharged for the next cycle. Disappoint-
ingly, the recovered polymer-bound catalyst exhibited poor
reactivity with 15% conversion in 24 h and only 20% conversion
after 48 h (Table 3: entry 6). Sodium formate/water was also
unsuccessful with the alcohol being produced in only 7% conver-
sion after a 24 h reaction at 40 °C.
Due to the complexity of the 1H NMR spectra obtained for poly-
mer-immobilised ligands 15b and 15c, the vinyl end group protons
were not visible. A recent report by Haddleton et al.11 revealed
experimental evidence for the retention of the vinyl end group dur-
ing the CuAAc reaction between poly(propargyl methacrylate) and
cellobiose azide; this was assumed to be the case for the copoly-
mer-supported 1,2-diamine ligands.
The supported catalysts were tested by pre-mixing 0.5 mol % of
Ru(II) pre-catalyst, [RuCl2(benzene)]2 and 1 mol % of (R,R)-15a–c in
FA/TEA at 28 °C for 1 h, followed by the addition of acetophenone
(1.6 M). Ligand (R,R)-15a yielded (R)-phenylethanol with 98% con-
version and 94% ee (Table 3).
Table 3
Evaluation of the HEMA/MMA copolymer-supported ligands 15a–c in the ATH of
acetophenone
Supported
O
3. Conclusion
OH
15a-c
ligands
[RuCl2(benzene)]2
In conclusion, a series of TsDPEN ligands containing a triazole
unit have been prepared and tested in the ATH of ketones. The tri-
azole represents a convenient method for the attachment of the li-
gand to a soluble polymer support. The resulting supported ligand
is effective in the ATH of ketones.
(R)
HCO2H:Et3N
S/C 100
Entry
Cata (run)
T (°C)
tb (h)
Conv.c (%)
eec (%)
1
2
3
4
5
6
7
15a (1)
15a (1)
15a (2)
15a (2)d
15c (1)
15c (2)
15b (1)
28
40
40
40
28
40
28
120
24
98
98
33
73
100
20
94 (R)
94 (R)
91 (R)
90 (R)
95 (R)
94 (R)
95 (R)
4. Experimental
4.1. General
28
46
136
48
144
90
Unless otherwise stated, all reactions were performed in flame
or oven-dried glassware under an atmosphere of nitrogen. Room
temperature refers to 20–22 °C, and ꢀ78 °C refers to a dry ice–ace-
tone bath. Commercially available reagents were used without
purification unless otherwise stated. Anhydrous solvents were
used as supplied. 1H and 13C NMR analyses were obtained on Bru-
ker DPX-300 (300 MHz), DPX-400 (400 MHz) and DPX-700
(700 MHz) spectrometers. All NMR chemical shift (d) values are re-
ported in parts per million (ppm) downfield from TMS (Me4Si) and
all coupling constants (J) are in Hertz (Hz). GPC measurements
were performed in N,N-dimethylformamide (0.03% w/v LiBr) at
50 °C and dichloromethane at 30 °C as appropriate; using Agilent
(Polymer Labs) 390-LC systems equipped with a PL-AT autosam-
a
Entry 1: 6.6 ꢂ 10ꢀ3 mmol [RuCl2(benzene)]2, 1.3 ꢂ 10ꢀ2 mmol ligand in HCO2-
H:Et3N; entry 2: 3.3 ꢂ 10ꢀ3 mmol [RuCl2(benzene)]2, 3.2 ꢂ 10ꢀ2 mmol ligand in
HCO2H:Et3N; entries 3 and 4: reuse in HCO2H:Et3N as in entry 1, [acetophe-
none] = 1.6 M. Entries
5
and 7: 4.6 ꢂ 10ꢀ3 mmol [RuCl2(benzene)]2, 9.2 ꢂ
10ꢀ3 mmol ligand in HCO2H:Et3N; entry 6: reuse from entry 5.
b
Number of hours necessary to observe a levelling-off in conversion.
Conversion and ee determined by GC analysis.
After addition of 0.5 mol % [RuCl2(benzene)]2.
c
d
The acetophenone reduction was repeated at 40 °C to furnish
alcohol in 98% conversion and with 94% ee (R) in 24 h (Table 3: en-
try 2). Upon completion of the reduction, the Ru(II)-15a catalyst
was recovered by filtration, washed with a 50:50 (v/v) mixture of
EtOAc/petroleum ether and neat DCM, and dried under vacuum.
The activity of the recovered Ru(II)-15a catalyst was assessed by
adding fresh portions of FA/TEA and ketone. In this case the ketone
was reduced to the alcohol in only 33% conversion although only a
slight erosion in ee was observed. Another portion of [RuCl2(ben-
zene)]2, was added to the reaction mixture and the conversion rose
to 43% after 1 h and to 73% after 46 h. Using 0.5 mol % [RuCl2(ben-
zene)]2 and 4.8 mol % (R,R)-15a ligand at 40 °C in FA/TEA, acetylfu-
ran was reduced to the (R)-enriched alcohol 16 in 99% conversion
and 98% ee in 24 h and with propiophenone to alcohol 17 in 70%
conversion and with 92% ee (R) after 24 h.
pler, a PL gel 5 lm bead-size guard column, two PL gel 5 lm Mixed
D columns (300 ꢂ 7.5 mm) and a refractive index detector; and the
data were analysed using Cirrus (V3.0) software. Polymethyl meth-
acrylate standards (200–467,400 g molꢀ1) were used to calibrate
the GPC. Low resolution mass spectrometry was run on a Bruker
Esquire 2000 electrospray mass spectrometer and high resolution
mass spectrometry was run on a Bruker MicrOTOF. Melting points
were obtained using a Stuart Scientific Melting Point SMP1 and are
uncorrected. Infrared spectra were recorded on a PerkinElmer
Spectrum 100 FTIR and a Nicolet Model Avatar 320 FTIR. Optical
rotations were measured using an Optical Activity Ltd. AA-1000

C. M. Zammit, M. Wills / Tetrahedron: Asymmetry 24 (2013) 844–852
847
Polarimeter and are recorded in 10ꢀ1 deg cm2 gꢀ1. GC analysis was
obtained using a Perkin Elmer 8500 chromatograph linked to a PC
running DataApex Clarity Software. HPLC measurements were ob-
tained using a Hewlett Packard 1050 HPLC system and the data
were analysed using DataApex Clarity Software. The following
compounds were prepared following literature methods;
bis(methanol)bis((difluoroboryl)dimethylglyoximato)cobalt(II)
(CoBF),15 benzyl azide,13 and tris–[(1-benzyl-1H-1,2,3-triazol-4-
yl)methyl]amine (TBTA).17
NaCl solution (10 cm3), dried (MgSO4) and concentrated under re-
duced pressure. The residue was then purified by flash column
chromatography using gradient elution from 10/90 to 12/88 v/v
EtOAc/petroleum ether to give the product (0.32 g, 1.04 mmol,
17.4%) as colourless oil; (found (EI): M++Na 329.0816. C16H18NaO4S
requires M 329.0818); m
max/cmꢀ1 (thin film) 2864 (CH2), 1353 and
1174 (SO2O), 1095 (C–O–C), 814 (p-substituted Ph), 722 and 698
(Ph); dH (300 MHz, CDCl3) 7.79 (2H, d, J 8.4, ArH), 7.36-7.24 (7H,
m, ArH), 4.48 (2H, s, OCH2Ph), 4.21–4.18 (2H, m, CH2OTs), 3.67–
.64 (2H, m, CH2OCH2Ph), 2.43 (3H, s, CH3 of OTs); dC (75 MHz,
CDCl3) 144.74 (C), 137.50 (C), 132.95 (C), 129.77 (2ꢂ CH), 128.38
(2 ꢂ CH), 127.94 (2 ꢂ CH), 127.77 (CH), 127.62 (2 ꢂ CH), 73.19
(CH2), 69.24 (CH2), 67.45 (CH2), 21.61 (CH3); ESI-MS m/z (CI) 329
(M++Na).
4.2. Synthesis of 2-(2-propynyloxy)ethanol18
To a stirred solution of ethylene glycol (16.70 g, 269.1 mmol)
under nitrogen was slowly added, portionwise, sodium hydride
(2.69 g, 67.3 mmol, 60% in mineral oil). Once effervescence
stopped, propargyl bromide (10.0 g, 67.3 mmol, 80% (w/w) in tolu-
ene) was added to the white suspension, heated to 45 °C and stir-
red at this temperature for 7.5 h. After cooling to rt, water (10 cm3)
was added and the mixture was extracted with chloroform
(3 ꢂ 10 cm3). The organic layers were combined, dried (MgSO4), fil-
tered and concentrated under reduced pressure. The residue was
purified by flash column chromatography using gradient elution
from 30/70 v/v diethyl ether/petroleum ether to 100% diethyl ether
to give the product (2.91 g, 29.1 mmol, 43.2%) as pale yellow oil;
(found (EI): M++Na, 123.0416. C5H8NaO2 requires M 123.0417);
4.5. Synthesis of [(2-azidoethoxy)methyl]benzene 721
To a stirred solution of 2-(phenylmethoxy)ethanol-1-(4-meth-
ylbenzenesulfonate) (0.10 g, 0.33 mmol) in N,N-dimethylformam-
ide (3 cm3) was added sodium azide (0.032 g, 0.49 mmol); the
reaction mixture was heated to 85–90 °C and stirred at this tem-
perature for 3.5 h. After cooling to rt, water (3 cm3) was added to
the pale yellow solution and extracted with diethyl ether
(3 ꢂ 3 cm3). The organic layers were combined, washed with water
(10 cm3) and saturated NaCl (10 cm3) successively, dried (Na2SO4),
m
max/cmꢀ1 (thin film) 3398 (OH), 3281 („CH), 2934 and 2870
filtered and concentrated under reduced pressure to give
(0.042 g, 0.24 mmol, 72.7%) as pale yellow oil; (found (EI):
M++Na, 200.0799. C9H11N3NaO requires M 200.0794); max/cmꢀ1
7
(CH2), 2116 (C„C), 1354, 1104 (C–O–C), 1065, 1027, 888; dH
(300 MHz, CDCl3) 4.22 (2 H, d, J 2.4, „CCH2), 3.80–3.75 (2H, m,
CH2O), 3.67–3.65 (2H, m, CH2O), 2.48 (1 H, t, J 2.4, „CH), 2.33
(1H, t, J 6.0, OH); dC (100 MHz, CDCl3) 79.42 („CH), 74.67 (C„CH),
71.16 (CH2), 61.63 (CH2), 58.36 (CH2); ESI-MS m/z (CI) 123
(M++Na).
m
(thin film) 2923 and 2861 (CH2), 2092 (N3), 1107 (C–O–C), 1092,
697 (Ph); dH (400 MHz, CDCl3) 7.38–7.27 (5H, m, ArH), 4.58 (2H,
s, OCH2Ph), 3.66 (2H, t, J 5.0, CH2CH2N3), 3.41 (2H, t, J 5.0,
CH2CH2N3); dC (100 MHz, CDCl3) 137.69 (C), 128.41 (2 ꢂ CH),
127.73 (CH), 127.58 (2 ꢂ CH), 73.23 (CH2), 68.81 (CH2), 50.77
(CH2); ESI-MS m/z (CI) 200 (M++Na).
4.3. Synthesis of 2-(benzyloxy)ethanol19
To a stirred solution of ethylene glycol (11.13 g, 179.3 mmol) in
a N,N-dimethylformamide:methanol solution (1:1 v/v, 10 cm3) was
added sodium hydride (1.04 g, 26.0 mmol, 60% in mineral oil) por-
tionwise over a period of 20–25 min. The resulting solution was
stirred at 20–22 °C for 17 h, followed by the dropwise addition of
benzyl bromide (3.07 g, 18.0 mmol). The reaction mixture was stir-
red at 20–22 °C for 24 h, quenched with 10% (v/v) HCl solution
(11 cm3) and extracted with ethyl acetate (3 ꢂ 20 cm3). The organ-
ic layers were combined, washed with saturated NaCl solution
(60 cm3), dried (Na2SO4), filtered and concentrated under reduced
pressure to give the product (1.09 g, 7.16 mmol, 39.9%) as colour-
less oil. This was used directly without further purification in the
next step; (found (EI): M++Na 175.0732. C9H12NaO2 requires M
4.6. Synthesis of N-[(R,R)-2-(prop-2-ynyloxyethylamino)-1,2-
diphenylethyl]-4-methyl benzenesulfonamide 6
To
a stirred solution of 2-(2-propynyloxy)ethanol (0.25 g,
2.5 mmol) and 2,6-lutidine (0.35 g, 3.3 mmol) in dichloromethane
(5 cm3) was added dropwise trifluoromethanesulfonic anhydride
(0.70 g, 2.5 mmol) at 0–5 °C. The solution was then stirred at 5–
10 °C for 45 min, heated to 22 °C and stirred at this temperature
for 1.5 h. In
a separate round-bottomed flask, triethylamine
(0.37 g, 3.7 mmol) was added to a solution of (R,R)-TsDPEN
(0.57 g, 1.6 mmol) in dichloromethane (3 cm3) at 5 °C. The triflate
solution was then added dropwise to this TsDPEN solution whilst
maintaining the temperature between 0–5 °C. The reaction mix-
ture was warmed to rt and left to stir overnight. The solution
was then diluted with saturated NaHCO3 (20 cm3) and extracted
with dichloromethane (10 cm3). The organic layer was washed fur-
ther with saturated NaHCO3 (2 ꢂ 20 cm3), water (20 cm3), satu-
rated NaCl (20 cm3), dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (20/80 v/v EtOAc/petroleum ether) to give 6 (0.45 g,
1.0 mmol, yield 64.3%) as a colourless oil; (found (EI): M++H,
175.0730);
m
max/cmꢀ1 (thin film) 3394 (OH), 2927 and 2865
(CH2), 1719, 1453, 1115 (C–O–C), 1068, 1028, 892, 739 and 698
(Ph); dH (400 MHz, CDCl3) 7.38–7.27 (5H, m, ArH), 4.56 (2H, s,
OCH2Ph), 3.75 (2H, t, J 4.5, CH2O), 3.59 (2H, t, J 4.5, CH2OH), 2.25
(1H, br s, OH); dC (100 MHz, CDCl3) 137.90 (C), 128.42 (2ꢂ CH),
127.76 (overlapping CH and 2ꢂ CH), 73.25 (CH2), 71.34 (CH2),
61.83 (CH2); ESI-MS m/z (CI) 175 (M++Na). The spectroscopic data
were in agreement with the literature values.
449.1896. C26H29N2O3S requires M, 449.1893); ½a D30
¼ þ5:6 (c
ꢃ
4.4. Synthesis of 2-(phenylmethoxy)ethanol-1-(4-4.4 methyl-
benzenesulfonate)20
0.22, CHCl3); m
max/cmꢀ1 (thin film) 3273 („CH), 2919 and 2856
(CH2), 2100 (C„C), 1598, 1323 and 1154 (SO2), 1090 (C–O–C),
812 (Ph), 762 and 698 (Ph), 665; dH (400 MHz, CDCl3) 7.38 (2 H,
d, J 8.4, ArH), 7.13–6.89 (12H, m, ArH), 6.31 (1H, br s, NHTs), 4.23
(1 H, d, J 8.0, PhCHNHTs), 4.06 (2H, t, J 1.8, CH2C„CH), 3.65 (2 H,
d, J 8.0, PhCHNHCH2), 3.60–3.55 (1H, m, NHCHaHb), 3.52–3.47
(1H, m, NHCHaHb), 2.67–2.61 (1H, m, CH2CHaHbO), 2.51–2.46
(1H, m, CH2CHaCHbO), 2.44 (1H, t, J 2.4, „CH), 2.34 (3H, s, CH3 of
NTs), 1.72 (1H, br s, NH); dC (100 MHz, CDCl3) 142.68 (C), 139.10
To a stirred solution of 2-(benzyloxy)ethanol (0.92 g, 6.0 mmol)
in pyridine (9 cm3) at 0 °C was added p-toluenesulfonyl chloride
(1.15 g, 6.05 mmol). The reaction mixture was stirred overnight
at room temperature, diluted with water (20 cm3) and extracted
with diethyl ether (3 ꢂ 7 cm3). The organic layers were combined,
washed with saturated NaHCO3 solution (10 cm3) and saturated

848
C. M. Zammit, M. Wills / Tetrahedron: Asymmetry 24 (2013) 844–852
(C), 138.27 (C), 137.08 (C), 129.10 (2 ꢂ CH), 128.32 (2 ꢂ CH),
127.89 (2 ꢂ CH), 127.63 (2 ꢂ CH), 127.50 (CH), 127.45 (2 ꢂ CH),
127.26 (CH), 127.17 (2 ꢂ CH), 79.64 („CH), 74.62 (C„CH), 69.18
(CH2), 67.78 (CH), 63.13 (CH), 58.17 (CH2), 46.46 (CH2), 21.45
(CH3); ESI-MS m/z (CI) 449 (M++H), 471 (M++Na).
ourless oil; ½a 3D0
ꢃ
¼ þ4:7 (c 0.315, CHCl3); (found (EI): M++H,
580.2758. C34H38N5O2S requires M 580.2741);
m
max/cmꢀ1 (thin
film) 3254 (NH), 2926 and 2858 (CH2), 1600, 1454, 1320 and
1153 (SO2), 811 (p-substituted Ph), 760 and 698 (Ph), 666; dH
(700 MHz, CDCl3) 7.38–7.33 (5H, m, ArH), 7.28–7.26 (2H, m,
ArH), 7.21 (1H, s, CH of triazole), 7.11–7.10 (3H, m, ArH), 7.04–
6.98 (5H, m, ArH), 6.91–6.87 (4H, m, ArH), 6.35 (1H, br s, NH),
5.50 (2H, s, CH2Ph), 4.23 (1H, d, J 9.1, PhCHNHTs), 3.59 (1H, d, J
9.1, PhCHNHCH2), 2.64 (2H, t, J 8.8, CH2C(C)N), 2.43–2.39 (1H, m,
NHCHaHbCH2), 2.32 (3H, s, CH3 of NHTs), 2.32–2.27 (1H, m,
NHCHaHbCH2), 1.66–1.55 (2H, m, NHCH2CH2CH2), 1.48–1.37 (2H,
m, NHCH2CH2CH2); dC (176 MHz, CDCl3) 148.33 (C), 142.65 (C),
139.17 (C), 138.18 (C), 136.97 (C), 134.95 (C), 129.02 (4 ꢂ CH),
128.56 (CH), 128.23 (2 ꢂ CH), 127.98 (2 ꢂ CH), 127.80 (2 ꢂ CH),
127.54 (2 ꢂ CH), 127.40 (CH), 127.36 (2 ꢂ CH), 127.16 (CH),
127.06 (2 ꢂ CH), 120.65 (CH of triazole), 67.69 (CH), 63.04 (CH),
53.96 (CH2), 46.64 (CH2), 29.30 (CH2), 26.78 (CH2), 25.36 (CH2),
21.38 (CH3). ESI-MS m/z (CI) 580 (M++H), 602 (M++Na).
4.7. Synthesis of N-[(R,R)-2-(hex-5-ynylamino)-1,2-diphenyl-
ethyl]-4-methyl benzenesulfonamide 10
To a stirred solution of hexyn-1-ol (1.04 g, 10.6 mmol) and 2,6-
lutidine (2.38 g, 22.2 mmol) in dichloromethane (21 cm3) was
added dropwise trifluoromethanesulfonic anhydride (4.78 g,
16.95 mmol) at 0–5 °C. The solution was then stirred at 5–10 °C
for 1 h, heated to 22 °C and stirred at this temperature for 1.5 h.
In
a separate round-bottomed flask, triethylamine (1.61 g,
15.9 mmol) was added to a solution of (R,R)-TsDPEN (2.32 g,
6.33 mmol) in dichloromethane (10 cm3) at 5 °C. The triflate solu-
tion was then added dropwise to this TsDPEN solution whilst
maintaining the temperature between 0–5 °C. The reaction mix-
ture was warmed to rt and left to stir overnight. The solution
was then diluted with saturated NaHCO3 (50 cm3) and extracted
with dichloromethane (24 cm3). The organic layer was washed fur-
ther with saturated NaHCO3 (3 ꢂ 20 cm3), water (2 ꢂ 50 cm3), sat-
urated NaCl (50 cm3), dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (16/84 v/v EtOAc/petroleum ether) to give 10
(1.11 g, 2.49 mmol, 39.3%) as a white solid; Mp 95–97 °C; (found
4.9. Synthesis of N-[(R,R)-2-(1-phenoxymethyl-1H-1,2,3-triazol-
4-yl)methoxy ethylamino)-1,2-diphenylethyl]-4-methylbenzene-
sulfonamide 8
To a stirred solution of [(2-azidoethoxy)methyl]benzene 7
(0.030 g, 0.17 mmol) in tert-butanol:water (8:2 v/v, 1.3 cm3) was
added
N-[(R,R)-2-(prop-2-ynyloxyethylamino)-1,2-diphenyl-
ethyl]-4-methylbenzene sulfonamide 6 (0.076 g, 0.17 mmol). So-
dium ascorbate (3.3 ꢂ 10ꢀ3 g, 0.017 mmol) and copper(II) sulfate
pentahydrate (0.021 g, 0.08 mmol) were added sequentially and
the reaction mixture was stirred at 30 °C for 5 h whilst monitoring
by TLC (Rf product = 0.48, Rf starting alkyne = 0.85; eluent:
EtOAc = 100%; potassium permanganate stain). The pale blue solu-
tion was concentrated under reduced pressure and the oily residue
was dissolved in a mixture of water (2.5 cm3) and ethyl acetate
(3 cm3). The water layer was re-extracted with EtOAc (3 cm3)
and the organic layers combined, washed with 6% (w/v) NaCl solu-
tion, dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash column chromatography using gradi-
ent elution from 70/30 to 75/25 v/v EtOAc/petroleum ether to give
(EI): M++H, 447.2105. C27H31N2O2S requires
¼ ꢀ26:6 (c 0.38, CHCl3);
max/cmꢀ1 (solid) 3281 („CH),
M 447.2101);
½
a 2D4
ꢃ
m
2932 and 2859 (CH2), 2324 (C„C), 1601, 1326 and 1159 (SO2),
1086 (C–O–C), 816 (Ph), 762 and 699 (Ph), 669; dH (400 MHz,
CDCl3) 7.38 (2H, d, J 8.4, ArH), 7.14–6.89 (12H, m, ArH), 6.25 (1H,
br s, NHTs), 4.25 (1H, d, J 8.0, PhCHNHTs), 3.61 (2H, d, J 8.0,
PhCHNHCH2), 2.44–2.37 (1H, m, NHCHaHbCH2), 2.33 (3H, s, CH3
of NTs), 2.33–2.26 (1H, m, NHCHaHbCH2), 2.15–2.12 (2H, m,
CH2C„CH), 1.93 (1H, t,
J 2.6, „CH), 1.56–1.41 (4H, m,
NHCH2CH2CH2), 1.23 (1H, br s, NH); dC (100 MHz, CDCl3) 142.63
(C), 139.19 (C), 138.25 (C), 136.97 (C), 129.01 (2 ꢂ CH), 128.21
(2 ꢂ CH), 127.81 (2 ꢂ CH), 127.48 (2 ꢂ CH), 127.37 (CH), 127.32
(2 ꢂ CH), 127.16 (CH), 127.04 (2 ꢂ CH), 84.12 („CH), 68.47
(C„CH), 67.74 (CH), 63.01 (CH), 46.49 (CH2), 28.95 (CH2), 25.87
(CH2), 21.35 (CH3), 18.14 (CH2). ESI-MS m/z (CI) 447 (M++H), 469
(M++Na).
8 (0.064 g, 0.10 mmol, 60.5%) as a colourless oil; ½a D32
¼ þ6:7 (c
ꢃ
0.115, CHCl3); (found (EI): M++H, 626.2801. C35H40N5O4S requires
M, 626.2796); m
max/cmꢀ1 (thin film) 3272 (NH), 2919 and 2866
(CH2), 1720, 1600, 1453, 1319 and 1154 (SO2), 1093, 932, 813 (p-
substituted Ph), 768 and 699 (Ph), 667; dH (400 MHz, CDCl3) 7.71
(1H, s, CH of triazole), 7.37–7.25 (7H, m, ArH), 7.10–7.09 (3H, m,
ArH), 7.01–6.95 (5H, m, ArH), 6.92–6.86 (4H, m, ArH), 4.59 (over-
lapping 2H, s, CH2C(C)N and 2H, t, J 5.2, PhCH2OCH2), 4.52 (2H, s,
PhCH2OCH2), 4.25 (1H, d, J 8.2, PhCHNHTs), 3.87 (2H, t, J 5.2,
PhCH2OCH2CH2), 3.67 (1H, d, J 8.2, PhCHNHCH2), 3.61–3.56 (1H,
qd, NHCH2CHaHbO), 3.51–3.47 (1H, m, NHCH2CHaHbO), 2.68–2.63
(1H, m, NHCHaHbCH2O), 2.52–2.46 (1H, m, NHCHaHbCH2O), 2.31
(3H, s, CH3 of NHTs); dC (100 MHz, CDCl3) 144.88 (C), 142.58 (C),
139.18 (C), 138.21 (C), 137.12 (C), 129.01 (2 ꢂ CH), 128.49
(2 ꢂ CH), 128.21 (2 ꢂ CH), 127.91 (CH), 127.78 (2 ꢂ CH), 127.68
(2 ꢂ CH), 127.54 (overlapping CH and 2 ꢂ CH), 127.53 (2 ꢂ CH),
127.40 (CH), 127.08 (2 ꢂ CH), 123.71 (CH of triazole), 73.25
(CH2), 69.29 (CH2), 68.28 (CH2), 67.55 (CH), 64.32 (CH2), 63.28
(CH), 50.33 (CH2), 46.44 (CH2), 21.38 (CH3); ESI-MS m/z (CI) 626
(M++H), 648 (M++Na).
4.8. Synthesis of N-[(R,R)-2-(1-benzyl-1H-1,2,3-triazol-4-yl)butyl-
amino)-1,2-diphenylethyl]-4-methylbenzene-sulfonamide 9
To a stirred solution of benzyl bromide (0.083 g, 0.48 mmol) in
tert-butanol:water (1:1 v/v, 1.2 cm3) were added N-[(R,R)-2-(hex-
5-ynylamino)-1,2-diphenylethyl]-4-methylbenzene-sulfonamide
10 (0.22 g, 0.49 mmol) and sodium azide (0.033 g, 0.51 mmol). So-
dium ascorbate (9.6 ꢂ 10ꢀ3 g, 0.048 mmol) and copper(II) sulfate
pentahydrate (6.0 ꢂ 10ꢀ3 g, 0.024 mmol) were then added sequen-
tially to this solution the reaction mixture was stirred at 60 °C for
3 h (whilst monitoring by TLC and mass spectrometry). The resul-
tant brown solution was quenched with cold water (1.8 cm3) and
10% aqueous ammonia solution (0.4 cm3); the mixture was then
stirred for 15 min. The mixture was concentrated under reduced
pressure to remove tert-butanol and the residue was dissolved in
a solution of water (5 cm3) and EtOAc (6 cm3). The water layer
was re-extracted with ethyl acetate (5 cm3) and the organic layers
combined, washed with water (10 cm3), dried (MgSO4) and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography using gradient elution from 70/30
to 80/20 v/v EtOAc/petroleum ether (silica column pre-treated
with 1% triethylamine) to give 9 (0.19 g, 0.33 mmol, 66.6%) as a col-
4.10. Synthesis of HEMA/MMA copolymers 12a–c
The synthesis of polymer 12b is provided as a representative
procedure for the polymerisation of HEMA and MMA with 4,40-azo-
bis(4-cyanovaleric acid) as the initiator and CoBF as the catalyst.
MMA and HEMA were purified by being passed through basic alu-

C. M. Zammit, M. Wills / Tetrahedron: Asymmetry 24 (2013) 844–852
849
mina to remove inhibitors and acidic impurities, and degassed by
bubbling nitrogen gas for 30 min. The water was also degassed
by bubbling nitrogen gas for 30 min prior to use. All three polymers
were prepared using a [HEMA]:[MMA] molar ratio of [30]:[70]. The
[HEMA]/[MMA]/[CoBF] ratios for 12a/b and 12c were [0.42]/[1.0]/
[4.27 ꢂ 10ꢀ5] and [0.42]/[1.0]/[2.14 ꢂ 10ꢀ5] respectively. Function-
alisation of hydroxyl groups fhydroxyl = 2.77 mmol/g, was calculated
from the 1H NMR analysis. The spectroscopic data were in agree-
ment with the literature values.9
using petroleum ether and the pale red solid was filtered and
washed with petroleum ether (400 cm3). The polymer was then
ground using a pestle and mortar and dried under reduced pres-
sure to give the tosylated HEMA/MMA copolymer 13b (4.70 g,
9.07 mmol HEMA units, 65.5%) as pale yellow oil; m
max/cmꢀ1 (thin
film) 2991 and 2951, 1724 (C@O), 1481, 1448, 1360 (SO2), 1242,
1173 (SO2), 1147, 920, 815, 749 (Ph); dH (300 MHz, CDCl3) 7.81
(2H, br s, CH o to SO2 on OTs), 7.38 (2H, br s, CH o to CH3 on
OTs), 6.21–6.17 (m, CH), 5.55–5.48 (m, CH), 4.22 (2H of HEMA, br
s, CH2CH2OTs), 4.14 (2H of HEMA, br s, CH2CH2OTs), 3.60 (3H of
MMA, br s, OCH3), 2.5 (3H of HEMA, br s, CH3 of OTs), 2.07–1.82
(2H of polymer, br m, CH2), 1.10–0.83 (3H of polymer, br m,
CCH3); dC (75 MHz, CDCl3) 177.63 (C@O), 176.64 (C@O), 144.95
(C o to SO2 on OTs), 132.46 (C o to CH3 on OTs), 129.85 (CH o to
SO2 on OTs), 127.72 (CH o to CH3 on OTs), 67.19 (CH2CH2OTs),
61.92 (CH2CH2OTs), 54.16 (CH2), 52.67 (C), 51.60 (OCH3), 44.63
(CH2), 44.27 (CH2), 21.47 (CH3 of OTs), 18.51 (CH3), 16.23 (CH3);
m/z (GPC) Mn = 1773, Mw = 2817, PDI = 1.59; Mn was also deter-
mined to be 1617 g/mol by the integration of the multiplets at
6.2 ppm (0.11H) and 5.5 ppm (0.10H); the two CH2 signals at
4.2 ppm and 4.1 ppm (1.82H combined); and the CH3 signal at
3.6 ppm (3H) in the 1H NMR spectrum.
4.11. Synthesis of HEMA/MMA copolymer 12b
Dioctylsulfosuccinate sodium salt (0.29 g, 0.67 mmol) was
added to deoxygenated water (65 cm3) in a 150 mL 3-necked
round-bottomed flask under nitrogen. The aqueous mixture was
further degassed by two freeze-pump-thaw cycles before being
heated to 80 °C. The monomer/catalyst feed was then prepared in
a Schlenk tube, whereby deoxygenated and inhibitor-free MMA
(18.72 g, 187.0 mmol) and HEMA (10.34 g, 79.46 mmol) were
added; the tube was then pump-filled with nitrogen three times.
The catalytic chain transfer agent, CoBF (3.6 ꢂ 10ꢀ3 g,
8.0 ꢂ 10ꢀ3 mmol) was then added, and the mixture was left to stir
for 10 min until all of the CoBF dissolved to give an orange solution.
Immediately prior to the transfer of the monomer/catalyst feed,
4,40-azobis(4-cyanovaleric acid) (0.29 g, 1.0 mmol) was added to
the aqueous solution at 80 °C. The monomer/catalyst feed was then
transferred to the aqueous solution via syringe at a rate of
3 mL minꢀ1 during which the aqueous solution turned opaque.
Once the addition was complete the mixture was left to stir at
80 °C for 4 h. The water was then removed from the polymer by
concentrating the mixture at 90 °C under reduced pressure to give
the HEMA/MMA copolymer as a pale yellow paste. This was tritu-
rated with petroleum ether, filtered, dried under reduced pressure
and ground using a pestle and mortar to give the HEMA/MMA (3:7
ratio) copolymer 12b (28.4 g, 98.1% based on mass) as a white so-
4.14. Synthesis of azido derivatised HEMA/MMA copolymers
14a–c
The synthesis of azido derivatised HEMA/MMA copolymer 14b
is a representative procedure for the functionalisation of tosylated
HEMA/MMA copolymers 13a–c. Functionalisation of azido groups
fazido = 2.58 mmol/g, was calculated from the 1H NMR analysis. This
compound is novel.
4.15. Synthesis of azido derivatised HEMA/MMA copolymer 14b
The tosylated HEMA/MMA copolymer 13b (2.43 g, 4.69 mmol),
sodium azide (0.93 g, 14.3 mmol) and anhydrous N,N-dimethyl-
formamide (61 cm3) were reacted according to the general proce-
dure for 2 days. Dichloromethane (200 cm3) and water (100 cm3)
were then added to the reaction mixture and the organic layer sep-
arated, re-extracted with water (4 ꢂ 100 cm3) and saturated NaCl
solution (100 cm3), dried (MgSO4), filtered and concentrated under
reduced pressure. The residue was triturated with petroleum ether,
and the resultant solid was filtered and washed with water
(100 cm3) and petroleum ether (100 cm3). The polymer was then
dried under reduced pressure at 90 °C and ground using a pestle
and mortar to give 14b (0.45 g, 1.2 mmol, 25.6%) as a pale yellow
lid;
m
max/cmꢀ1 (solid) 3502 (OH), 2992 and 2952, 1721 (C@O),
1480, 1448, 1387, 1240, 1147, 1075, 987, 965; dH (300 MHz, CDCl3)
6.26–6.20 (m, CH), 5.62–5.48 (m, CH), 4.12 (2 H of HEMA, br s,
CH2CH2OH), 3.84 (2H of HEMA, br s, CH2CH2OH), 3.61 (3H of
MMA, br s, OCH3), 2.18–1.83 (2H of polymer, br m, CH2), 1.27–
0.84 (3H of polymer, br m, CCH3); dC (100 MHz, CDCl3) 178.01
(C@O), 176.73 (C@O), 66.67 (CH2CH2OH), 60.27 (CH2CH2OH),
54.27 (CH2), 52.89 (C), 51.71 (OCH3), 44.84 (CH2), 44.43 (CH2),
18.64 (CH3), 16.85 (CH3); GPC m/z Mn = 973, Mw = 1789,
PDI = 1.84; ESI-MS m/z (CI); Mn was also determined to be
1570 g/mol by the integration of the multiplets at 6.2 ppm
(0.11H) and 5.6 ppm (0.11H); the two CH2 signals at 4.1 ppm
(0.95H) and 3.8 ppm (0.95H); and the CH3 signal at 3.6 ppm (3H)
in the 1H NMR spectrum.
solid; m
max/cmꢀ1 (solid) 2993 and 2951, 2104 (N3), 1722 (C@O),
1479, 1446, 1388, 1270, 1239, 1143, 989, 965, 842; dH (400 MHz,
CDCl3) 6.30–6.20 (m, CH), 5.60–5.47 (m, CH), 4.12 (2 H of HEMA,
br s CH2CH2N3), 3.60 (3H of MMA, br s, OCH3), 3.50 (2H of HEMA,
br s, CH2CH2N3), 2.07–1.82 (2H of polymer, br m, CH2), 1.26–0.84
(3H of polymer, br m, CCH3); dC (100 MHz, CDCl3) 178.33 (C@O),
177.06 (C@O), 63.74 (CH2CH2N3), 54.33 (CH2), 52.87 (C), 51.78
(OCH3), 49.47 (CH2CH2N3), 44.86 (CH2), 44.49 (CH2), 18.72 (CH3),
16.44 (CH3); m/z (GPC) Mn = 2451, Mw = 7110, PDI = 2.90; Mn was
also determined to be 2878 g/mol by the integration of the multi-
plets at 6.3 ppm (0.05H) and 5.5 ppm (0.06H); the two CH2 signals
at 4.1 ppm (0.81H) and 3.5 ppm (0.81H); and the CH3 signal at
3.6 ppm (3H) in the 1H NMR spectrum.
4.12. Synthesis of tosylated HEMA/MMA copolymers 13a–c
The synthesis of tosylated HEMA/MMA copolymer 13b is a rep-
resentative procedure for the functionalisation of copolymers 12a–
c. Functionalisation of the tosyl groups ftosyl = 1.93 mmol/g, was
calculated from 1H NMR analysis. This compound has been re-
ported and fully characterised; and the spectroscopic data were
in agreement with the literature values.9
4.13. Synthesis of tosylated HEMA/MMA copolymer 13b
4.16. Synthesis of N-[(R,2R)-2-(1-ethoxy-1H-1,2,3-triazol-4-yl)-
butylamino)-1,2-diphenylethyl]-4-methylbenzenesulfonamide
derivatised HEMA/MMA Copolymers 15a–c
At first, HEMA/MMA copolymer 12b (5.00 g, 13.9 mmol HEMA
units), dichloromethane (35 cm3), p-toluenesulfonyl chloride
(4.90 g, 25.7 mmol), DMAP (0.25 g, 2.1 mmol) and triethylamine
(2.46 g, 24.3 mmol) were reacted according to the general proce-
dure to give the crude product as a red gum. This was triturated
The monotosylated 1,2-diamine derivatised HEMA/MMA
copolymer 15a was synthesised from the azido derivatised

850
C. M. Zammit, M. Wills / Tetrahedron: Asymmetry 24 (2013) 844–852
HEMA/MMA copolymer 14a using a Cu(II)/sodium ascorbate mix-
ture. Polymers 15b–c were synthesised using the Cu(I)/TBTA sys-
tem. Functionalisation of the monotosylated 1,2-diamine
fdiamine = 1.20 mmol/g, was calculated from the HEMA:MMA (3:7)
ratio of the previous polymers 12–14. This compound is novel.
azeotropic mixture (1.0 cm3) was stirred at 28 °C for 1 h, after
which the substrate (1.6 mmol) was added. The reaction mixture
was then stirred at 28 °C for the amount of time recorded. At inter-
vals, a small aliquot of the reaction mixture was passed through a
short column of silica gel in a Pasteur pipette and eluted with ethyl
acetate. This solution was analysed by chiral GC to determine the
conversion and enantiomeric excess. Once the specified conversion
was achieved, the solution was passed through a column of silica
gel, eluted with ethyl acetate, concentrated under reduced pres-
sure and purified by flash column chromatography to afford the
alcohol product.
Method B: A solution of ruthenium dimer (0.008 mmol) and dia-
mine ligand (0.016 mmol) in anhydrous isopropanol (0.32 cm3)
was stirred at 80 °C for 25 min. After cooling to 28 °C, a 0.1 M
potassium hydroxide solution (0.284 cm3, 0.04 mmol) was added
followed by a solution of substrate (1.6 mmol) in isopropanol
(13 cm3); and the reaction mixture was then stirred at 28 °C for
the amount of time recorded. At intervals, a small aliquot of the
reaction mixture was passed through a short column of silica gel
packed in a Pasteur pipette and eluted with ethyl acetate. The solu-
tion was analysed by chiral GC to determine the conversion and
enantiomeric excess.
4.17. Synthesis of N-[(R,2R)-2-(1-ethoxy-1H-1,2,3-triazol-4-yl)-
butylamino)-1,2-diphenylethyl]-4-methylbenzenesulfonamide
derivatised HEMA/MMA copolymer 15a
To a stirred mixture of azido derivatised HEMA/MMA copoly-
mer 14a (0.24 g, 0.62 mmol) and N-[(R,R)-2-(hex-5-ynylamino)-
1,2-diphenylethyl]-4-methyl benzenesulfonamide 10 (0.20 g,
0.44 mmol) in tert-butanol:water (1:1 v/v, 17 cm3) were added
sequentially sodium ascorbate (0.0009 g, 4 ꢂ 10ꢀ6 mmol) and cop-
per(II) sulfate (0.0055 g, 2.2 ꢂ 10ꢀ5 mmol). The suspension was
heated to 80 °C and stirred at this temperature for 3 days, follow-
ing which the solid was filtered and washed with dichloromethane.
The filtered polymer was suspended in dichloromethane (100 cm3)
and stirred at 40 °C for 30 min, cooled to room temperature, fil-
tered, washed with dichloromethane and dried under vacuum to
give 15a (0.36 g, 0.43 mmol, 97.7%) as a blue solid; m
max/cmꢀ1 (so-
lid) 2991 and 2949, 1725 (C@O), 1599, 1452, 1387, 1266, 1241,
1146, 985, 966, 914, 812, 757 and 699 (Ph), 665. Spectroscopic
and GPC data could not be obtained due to the insolubility of the
functionalised polymer in a range of solvents, namely acetone,
chloroform, dichloromethane, N,N-dimethylformamide, dimethyl-
sulfoxide, methanol, tetrahydrofuran, 1,2-dichloroethane, benzene,
pyridine, acetonitrile and water. Attempts at dissolving the poly-
mer at higher temperatures were not successful.
Method C: A solution of ruthenium dimer (6.6 ꢂ 10ꢀ3 mmol)
and diamine ligand (13.2 ꢂ 10ꢀ3 mmol) in water (3 cm3) was stir-
red at 60 °C for 1 h. Sodium formate (6.6 mmol) was added to the
solution followed by the substrate (0.6 mmol), and the reaction
mixture was stirred at 60 °C for the amount of time recorded. At
intervals, a small aliquot of the reaction mixture was cooled to
room temperature and the product extracted with ethyl acetate.
The ethyl acetate layer was passed through a short column of silica
gel in a Pasteur pipette and analysed by chiral GC to determine the
conversion and enantiomeric excess.
4.18. Synthesis of N-[(R,R)-2-(1-ethoxy-1H-1,2,3-triazol-4-yl)-
butylamino)-1,2-di phenylethyl]-4-methylbenzene-sulfon-
amide derivatised HEMA/MMA copolymer 15b
4.20. Procedure for ketone reductions using the polymer-
supported diamine ligand
To a stirred solution of azido derivatised HEMA/MMA copoly-
mer 14b (0.024 g, 0.062 mmol), triethylamine (2 ll, 1.45 mg,
Ruthenium dimer (6.6 ꢂ 10ꢀ3 mmol), polymer-supported dia-
mine ligand (0.013 mmol or 0.063 mmol: equivalent to 1 mol %
and 4.8 mol %, respectively), substrate (1.3 mmol) and formic
acid/triethylamine (5:2) azeotrope (0.8 cm3) were reacted accord-
ing to method A. After completion of the reaction, the polymeric li-
gand was removed from the mixture by filtration for the recycle
experiment, washed with an appropriate solvent and dried under
reduced pressure. The ligand was then added to a clean Schlenk
tube and subjected to fresh portions of formic acid/triethylamine
(5:2) azeotrope (0.8 cm3) and substrate (1.3 mmol); the reduction
was monitored by GC analysis.
1.40 ꢂ 10ꢀ2 mmol) and DMSO-d6 (1.0 cm3) was added N-[(R,R)-2-
(hex-5-ynylamino)-1,2-diphenylethyl]-4-methylbenzene sulfon-
amide 10 (0.022 g, 0.049 mmol); the mixture was then degassed
by two freeze-pump-thaw cycles before being placed under nitro-
gen. Next, TBTA (0.008 g, 0.015 mmol) and copper(I) bromide
(0.002 g, 0.014 mmol) were then added to the solution, and the
reaction was quickly placed under vacuum and then nitrogen.
The reaction mixture was stirred at 20 °C for 24 h, following which
the solution was analysed by 1H NMR to determine the extent of
the reaction. Once the presence of the azido derivatised HEMA/
MMA copolymer could not be detected; water (20 cm3) was added
to the solution and the precipitated solid was filtered, washed with
water (50 cm3) and petroleum ether (50 cm3) and dried under re-
duced pressure to give 15b (0.017 g, 0.02 mmol, 40.8%) as a blue
4.21. NMR monitoring experiments
In a NMR tube equipped with a magnetic stirrer were added
ruthenium dimer (0.005 mmol), diamine ligand (0.01 mmol) and
d6-benzene (0.05 cm3) in the formic acid/triethylamine (5:2) azeo-
tropic mixture (0.7 cm3). The NMR tube was shaken gently and a
NMR cap with holes was then fitted. The catalytic mixture was stir-
red at 28 °C for 1 h, after which acetophenone (1.1 mmol) was
added using a syringe. The NMR tube was again shaken gently using
a cap without holes and then left to stir at 28 °C for the amount of
time recorded. The reduction was monitored in two ways: (1) an
NMR tube was placed in the NMR spectrometer, and the reaction
monitored using a pre-set programme which records chromato-
grams at regular intervals at 28 °C; and (2) at intervals the NMR
sample was removed from the oil bath set at 28 °C and analysed
using the NMR spectrometer. Data analysis was performed using
the MestreC software. The conversion of acetophenone to 1-phen-
solid; m
max/cmꢀ1 (solid) 2989 and 2949, 1726 (C@O), 1600, 1455,
1267, 1137, 966, 911, 812, 758 and 670 (Ph), 665; dH (400 MHz,
CDCl3) 7.70 (1H, s, CH of triazole), 7.35–6.85 (14H of diamine, m,
ArH), 5.45 (2H of HEMA, s, CH2), 4.65 (2H of HEMA, br s, CH2),
4.35 (2H of polymer, br s, CH2), 3.70 (1H of diamine, s, CH-1,2-dia-
mine), 3.55 (br s, overlapping 3H, OCH3 and CH2-1,2-diamine), 2.48
(3H of diamine, br s, CH3 of NTs), 2.10–1.40 (2H of polymer, br m,
CH2), 1.67–1.47 (2H of diamine, br m, CH2-1,2-diamine), 1.25–0.78
(3H of polymer, br m, CCH3).
4.19. Representative procedures for ketone reductions
Method A: A solution of ruthenium dimer (0.008 mmol) and dia-
mine ligand (0.016 mmol) in the formic acid/triethylamine (5:2)

C. M. Zammit, M. Wills / Tetrahedron: Asymmetry 24 (2013) 844–852
851
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ton CHOH in the product alcohol (4.9 ppm) with the integration
of the 3 protons CH3 in acetophenone (2.5 ppm).
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4.22. 1-Phenylethanol4
½
a 2D8
ꢃ
¼ þ52:2 (c 1.0 CHCl3) 95% ee (R) {lit.4½a D22
¼ þ49:0 (c 1.0,
ꢃ
CHCl3) 98% ee (R)}; dH (400 MHz; CDCl3) 7.38–7.24 (5H, m, ArH),
4.88 (1H, q, J 6.4, PhCH(OH)), 1.98 (1H, br s, OH), 1.49 (3H, d, J
6.4, CH3); dC (75 MHz; CDCl3) 145.8 (C), 128.5 (2 ꢂ CH), 127.4
(CH), 125.4 (2 ꢂ CH), 70.4 (CH), 25.1 (CH3); Enantiomeric excess
and conversion determined by GC analysis [Chrompac cyclodex-
trin-b-236 M-19 50 m, T = 115 °C, P = 15 psi, gas H2, ketone
10.0 min, (R)-isomer 15.4 min, (S)-isomer 16.7 min]. The spectro-
scopic data were in agreement with the literature values. The prod-
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authentic, commercial reference sample.
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4.23. 2-Furylethanol 16
dH (400 MHz; CDCl3) 7.28 (1H, d, J 2.0, ArH
J 3.4 and 2.0, ArH b to O and b to CH(OH)CH3), 6.14 (1H, d, J 3.4, ArH
to CH(OH)CH3), 4.78 (1H, q, J 6.4, CHOH), 2.32 (1H, br s, OH), 1.44
a to O), 6.24 (1H, dd,
a
(3H, d, J 6.4, CH3); dC (100 MHz; CDCl3) 157.58 (C), 141.78 (CH),
110.03 (CH), 105.00 (CH), 63.48 (CH), 21.17 (CH3); Enantiomeric
excess and conversion determined by GC analysis [Chrompac
cyclodextrin-b-236 M-19 50 m, T = 85 °C, P = 15 psi, gas H2, ketone
11.2 min, (R)-isomer 17.2 min, (S)-isomer 18.3 min]. The spectro-
scopic data were in agreement with the literature values.22
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4.24. 1-Phenylpropan-1-ol 17
dH (300 MHz; CDCl3) 7.38–7.24 (5H, m, ArH), 4.59 (1H, td, J 6.6
and 3.3, PhCH(OH)), 1.90–1.68 (overlapping 1H, d, J 3.3, OH and 2H,
m, CH2), 0.92 (3H, t, J 7.5, CH3); dC (75 MHz; CDCl3) 144.56 (C),
128.38 (2 ꢂ CH), 127.48 (CH), 125.94 (2 ꢂ CH), 76.01 (CH), 31.86
(CH2), 10.13 (CH3); Enantiomeric excess and conversion were
determined by GC analysis (Chrompac cyclodextrin-b-236 M-19
50 m, T = 115 °C, P = 15 psi, gas H2, ketone 13.6 min, R isomer
20.8 min, S isomer 21.9 min). The spectroscopic data were in agree-
ment with the literature values.23
Acknowledgments
The authors would like to thank the EU (ESF) for a STEPS Post-
graduate Award (C.M.Z.). We thank Professor D. M. Haddleton and
his group for the provision of a standard sample of CoBF for com-
parison with our own material.
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