4,4′BOX based catalysts: Synthesis, structure and catalytic application

Article abstract of DOI:10.1016/j.catcom.2010.05.003

The synthesis of two new 4,4′ bisoxazoline ligands is described. The use of copper complexes of these and three other recently described related ligands as catalysts in a cyclopropanation reaction is discussed. The first structural data on one such chiral copper complex is reported herein.

Full text of DOI:10.1016/j.catcom.2010.05.003

Catalysis Communications 11 (2010) 1012–1016
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
4,4′BOX based catalysts: Synthesis, structure and catalytic application
Fiona Kirby a, David Frain a, Patrick McArdle b, Patrick O'Leary a,
⁎
a
National University of Ireland, Galway, School of Chemistry, SMAĊT (Synthetic Methods: Asymmetric Catalytic Transformations), Ireland
b
National University of Ireland, Galway, School of Chemistry, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of two new 4,4′ bisoxazoline ligands is described. The use of copper complexes of these and
three other recently described related ligands as catalysts in a cyclopropanation reaction is discussed. The
first structural data on one such chiral copper complex is reported herein.
Received 25 March 2010
Received in revised form 2 May 2010
Accepted 5 May 2010
© 2010 Elsevier B.V. All rights reserved.
Available online 13 May 2010
Keywords:
Bisoxazoline
Copper
Cyclopropanation
Ligand design
1. Introduction
2. Results and discussion
2,2′ Bisoxazolines are a highly useful ligand class in the area of
asymmetric synthesis [1]. They were first reported more than 20 years
ago [2,3] and complexes of these ligands with metals such as copper
[4], magnesium [5], zinc [5,6], iron [7], palladium [8] and many others
have found wide application in organic synthesis. The reactions to
which such complexes have been applied are amongst the most useful
in the synthetic chemists arsenal; Diels-Alder [9], cyclopropanations
[10,11], ene reactions [12], aldol reactions [13], alkylations [8] etc.
Though many variations of the BOX ligands have been reported in
general the degree of variation has been limited to the pendant groups
on the chiral centers or the substituents at the bridgehead. In this
paper we will present results in cyclopropanation chemistry. A
general review of this area has recently been published by Pellissier
[14].
We have for a number of years been working with BOX ligands
[15,16] and thus became interested in their design and ultimately
their redesign. We became interested in the prospect of preparing the
4,4′BOX ligands (Fig. 1) because the co-ordination complexes of these
ligands with metals would have the chiral centers internal to the
metallocycle thus introducing a twist into the ligand reminiscent of
the salen ligands. We have recently reported the synthesis of the first
members of this new class of ligands derived from Arabitol 1 and 2
and xylitol 3 (Fig. 2) [17].
Though Xylitol presents significant advantages over Arabitol in
terms of cost as a starting material it leads to a meso ligand and thus
will not function as an asymmetric ligand. Using our experience with
the XyliBOX ligand we have now prepared two new ligands 4 and 5
incorporating other chiral moieties into the XyliBOX structure giving
it potential for use in asymmetric synthesis. The additional chiral
elements in these ligands were derived from chiral butyric acids.
2.1. Synthesis
The new ligands were prepared from the TBDMS protected
diaminodialcohol 6 which is prepared from xylitol [17]. The amines
were reacted with chiral acid chlorides to form the amides. These
amides were isolated in good yield. The amides in turn were cyclised
in a tandem DARC reaction [17]. Tosyl fluoride was used to deprotect
the alcohols and activate them as the tosylates thus facilitating the
ring closure. The DBU facilitates the two steps. The new ligands were
isolated in exceptional yield (4 70%, 5, 80%) considering the tandem
DARC reactions involve 6 separate synthetic steps (Scheme 1).
2.2. Complex characterisation
The rational behind this work demanded that these 4,4′BOX ligands
would co-ordinate to metals such as copper in a similar manner to the
established 2,2′BOX ligands. Before applying complexes of these
ligands to the asymmetric cyclopropanation we decided to try to make
a copper complex, grow crystals and endeavour to confirm its
structure by X-Ray studies. The phenylAraBOX ligand was complexed
with copper(II)chloride and crystals grown from THF. The crystals
Abbreviations: BOX, bisoxazoline ligand; XyliBOX, 4,4′Bisoxazoline whose backbone
is derived from Xylitol; AraBOX, 4,4′Bisoxazoline whose backbone is derived from
Arabitol; DARC, deprotection, activation, ring closure.
⁎
Corresponding author. Tel.: +353 91 492476; fax: +353 91 525700.
E-mail address: patrick.oleary@nuigalway.ie (P. O'Leary).
1566-7367/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.05.003

F. Kirby et al. / Catalysis Communications 11 (2010) 1012–1016
1013
Fig. 1. Views of the metal complexes of standard 2,2′ BOX ligands and those of the 4,4′ BOX ligands which are the subject of this study.
were analysed and the structure solved [18]. Two views A and B of the
structure are shown in Fig. 3 and key data from the crystal structure are
outlined in Table 1. It confirms that the co-ordination chemistry of the
ligand is as expected and the copper is bound to the two nitrogens. The
bond lengths of the co-ordination at 2.0 are slightly longer than those
reported by Evans for the 2,2′BOX ligand (1.9 ).[19] The N–Cu–N angle
is ∼90° which is slightly less than the same angle in the 2,2′BOX
complex (94°). The geometry around the copper is a distorted
tetrahedron which is not unexpected given the geometry of similar
2,2′BOX complexes vary between mainly square planar right through
to mainly tetrahedral depending on the functionality present. The
twist in the complex is also evident showing the effect of having the
chiral centers contained within the metallocycle. The twist can be
quantified by the torsion angle between the C=N in each planar
oxazoline ring. This value of 52° represents a large deviation from the
planarity of the 2,2′BOX systems. The unit cell contained six molecules
arranged in a spiral the formation of which is probably aided by π
stacking. Views of the unit cell C and D are also shown in Fig. 3.
[20,21] and generally is thought to be due to a change in conformation
in co-ordination to the metal center [22]. Reversals of this type are
seen for Diels-Alder reactions but are much rarer in cyclopropanation
reactions [23]. The ee's achieved are undoubtedly modest, particularly
when viewed in tandem with entries 7 and 8 in the table which show
reported results for the same reaction using the copper complexes of
the 2,2′BOX ligands 9 and 10 [24,25]. In these cases superior
enantioselectivity was obtained though the diastereoselectivity is
far from ideal. It is important to note that this is the first generation of
these ligands and they do provide a basis on which to develop
structure activity relationships and design the next generation of such
catalysts. For instance it is evident from the XyliBOX ligands that
chirality on the pendant arms of the ligands does have an effect on the
selectivity of the catalysts. A logical step would be the inclusion of
such a sidearm on the already chiral AraBOX framework to enhance
selectivity. Such a study is in train in our laboratory.
3. Conclusion
We have completed the synthesis of two new 4,4′BOX ligands. In
addition we have confirmed the structure of the copper complex of
one such ligand by X-ray analysis. We have applied copper complexes
of all five reported 4,4′BOX ligands to the asymmetric catalysis of a
cyclopropanation. In the case of two ligands we have observed an
unusual reversal of selectivity in the cyclopropanation reaction. The
ee's achieved in both cases though modest are encouraging for the
development of this catalyst class. The two new ligands reported in
this communication are synthesised from the cheap and widely
available xylitol or ‘wood alcohol’ and chirality is introduced late on in
the synthetic scheme which is a significant development economi-
cally on our previous arabitol based ligands. We continue to develop
these and related ligands and applications of the ligands already
reported and we will report these shortly.
2.3. Application of copper complexes to the catalysis of the
cyclopropanation reaction
The copper complexes of ligands 1–5 were utilised as catalysts in
the cyclopropanation of styrene using ethyl diazoacetate (Scheme 2).
The results obtained are presented in Table 2. The catalyst loading
used was 1% relative to the limiting reagent, ethyl diazoacetate.
The conversion was in general N90% except in the case of the
MePrXyliBOX where it dropped to 79%. The use of Cu(OTf)2 did not
alter the result in this regard. The trans:cis ratio typically was around
60:40 with only the PhXyliBOX 3 and MePrXyliBOX 4 (entries 3 and 4)
showing little or no selectivity. The asymmetric catalysts did give
modest enantioselectivities in both the cis and trans isomers. The
highest ee being achieved in the cis diasteromer with the PhAraBOX
ligand (entry 1) at 32%ee. In the trans case the highest ee achieved was
with the MePrXyliBOX ligand (entry 5) at 26%ee.
4. Experimental
It is interesting to note that ligands (R)-PhAraBOX 1 and (S)-
tBuAraBOX 2 which have opposite configuration at the chiral centers
selectively form the same stereoisomers of product. This so-called
reversal in selectivity is not unknown in oxazoline ligand chemistry
All chemicals were purchased from Aldrich Chemical Company
and generally used without further purification. Melting points were
measured on a Stuart Scientific SMP3 apparatus. IR spectra were
Fig. 2. Previously reported 4,4′ BOX ligands 1–3 which are used in this study.

1014
F. Kirby et al. / Catalysis Communications 11 (2010) 1012–1016
Scheme 1. Previously reported 4,4′BOX ligands and the synthesis of the two new ligands 4 and 5.
measured on a Perkin Elmer Spectrum 1000 FT-IR, or a Perkin Elmer
Spectrum One FT-IR. Optical rotations were measured on The
polarimeter is a UniPOL L1000 polarimeter at 589 nm (Na) in a
10 cm cell. Thin layer chromatography (TLC) was carried out on
precoated silica gel plates (Merck 60 F254); column chromatography
was conducted using Merck silica gel 60 or Apollo Scientific silica gel
40–63 µ. 1H NMR (400 MHz), 13C NMR (100 MHz), were recorded on
a JEOL ECX-400 NMR spectrometer. All spectra were recorded at probe
temperatures (∼20 °C) using tetramethylsilane as internal standard.
All chiral liquid–liquid chromatography (HPLC) was carried out on a
Varian instrument, with an UV/Vis detector at the specified wave-
length, with a Daicel CHIRALCEL OD 0.46 cm_×25 cm column, under
conditions described for each experiment. All chiral GC analysis was
carried out on a Varian 3900 instrument, using helium as the mobile
phase and a FID (Flame Ionisation Detector), with a CYCLODEX-β
0.25 mmΦ×30 m column under conditions described for each
experiment. Acid chlorides were prepared with reference to a
previous report [26].
stirred at room temperature overnight, concentrated in vacuo and
purified by column chromatography on SiO2 (Pet. Ether-EtOAc; 80:20)
to yield 7 (800 mg, 78%) as a white solid. [α]D −12.3 (c 0.007, MeCN,
23 °C); 1H NMR (400 MHz, CDCl3) δ=6.13–6.07 (2H, m, 2×NH), 3.92–
3.89 (2H, m, 2×CHN), 3.72–3.66 (2H, m, one of CH2OSi), 3.57–3.53
(2H, dd, J=10.0, 4.5 Hz, one of CH2OSi), 2.17–2.09 (2H, m, 2×CHCH3),
1.9–1.83 (1H, m, one of CHCH2CH), 1.71–1.6 (3H, m, one of CHCH2CH,
CH2CH3), 1.49–1.38 (2H, m, CH2CH3), 1.15–1.13 (6H, dd, J=6.9, 1.6 Hz,
2×CH3CH), 0.94–0.88 (24H, m, 2×t bu, 2×CH3CH2), 0.07–0.05 [12H,
m, 2×Si(CH3)2]; 13C NMR (100 MHz, CDCl3) δ=176.4,64.4, 64.0, 47.8,
43.3, 32.9, 27.4, 25.9, 18.3, 17.6, 12.0, −5.3; IR 3292, 2959, 2930, 2858,
1638 cm−1. ESI-HRMS calcd for C27H58N2O4Si2 529.3857, found m/z
529.3897 (M–H)−
.
4.1.2. Synthesis of bisamide 8
To a stirring solution of 6 (670 mg, 1.85 mmol) and triethylamine
(566 μL, 4.07 mmol) in CH2Cl2 (20 mL) at 0 °C was added (S)-(+)-2-
phenylbutyric acid chloride (743 μL, 4.07 mmol). The mixture was
stirred at room temperature over night, concentrated in vacuo and
purified by column chromatography on SiO2 (Pet. Ether-EtOAc; 80:20)
to yield 8 (840 mg, 69%) as a white solid.[α]D −21.7 (c 0.002, MeCN,
23 °C); 1H NMR (400 MHz, CDCl3) δ=7.3–7.18 (10H, m, 10×ArH),
6.23 (1H, t, J=8.6 Hz, NH), 6.08–6.07 (1H, m, NH), 3.87–3.32 (6H, m,
2×CH2OSi, 2×CHN), 3.27–3.21 (2H, m, 2×CHAr), 2.21–2.11 (2H, m,
one of CH2CH3), 1.85–1.72 (2H, m, one of CH2CH3), 1.7–1.59 (1H, m,
4.1. Synthesis of bis amides 7 and 8
4.1.1. Synthesis of bis amide 7
To a stirring solution of 6 (700 mg, 1.93 mmol) and triethylamine
(593 μL, 4.25 mmol) in CH2Cl2 (20 mL) at 0 °C was added (S)-(+)-2-
methylbutyric acid chloride (513 μL, 4.25 mmol). The mixture was

F. Kirby et al. / Catalysis Communications 11 (2010) 1012–1016
1015
Fig. 3. The X-Ray crystal structure of the PhenylAraBOXCuCl2 complex.
one of CHCH2CH), 1.56–1.46 (1H, m, one of CHCH2CH), 0.91–0.84 (6H,
m, 2×CH3CH2), 0.81, 0.79, 0.78, 0.76 (18H, series of singlets due to
rotamers, 2×t-bu), −0.01–0.17 (12H, series of singlets due to
rotamers, 2×Si(CH3)2);13C NMR (100 MHz, CDCl3) δ=173.5, 140.2,
140.0, 128.8, 128.7, 128.1, 64.1, 63.9, 63.7, 55.4, 48.2, 47.9, 32.4, 26.4,
26.2, 25.9, 18.2, 12.5, 12.4, -5.5, −5.6; IR 3305, 2955. 2928, 2857,
1649 cm−1. ESI-HRMS calcd for C37H62N2O4Si2 655.4326 found m/z
(oxazoline) 4 (105 mg, 70%) as a yellow oil. [α]D −25.6 (c 0.01, MeCN,
23 °C); 1H NMR (400 MHz, CDCl3) δ=4.3 (2H, m, J=8.8, one of
CH2O), 4.12–4.23 (2H, m, 2×CHN), 3.94 (2H, t, J=7.6, one of CH2O),
2.34–2.4 (2H, m, 2×CHCH3), 1.91–1.98 (1H, m, one of CHCH2CH), 1.6–
1.68 (3H, m, one of CH2CH3, one of CHCH2CH), 1.41–1.52 (2H, m, one
of CH2CH3), 1.14 (6H, d, J=6.9, 2×CHCH3), 0.90 (6H, t, J=7.5,
2×CH3CH2); 13C NMR (100 MHz, CDCl3) δ=171.4, 72.3, 62.9, 42.2,
35.1, 27.3, 17.4, 11.7; IR 2966, 1663, 976 cm−1. ESI-HRMS calcd for
655.4290 (M+H)+
.
C15H26N2O2 267.2072, found m/z 267.1971 (M+H)+
.
4.2. Synthesis of ligands 4 and 5
4.2.2. Synthesis of PhPrXyliBOX 5
To a solution of 8 (800 mg, 1.22 mmol) and p-toluenesulfonyl
fluoride (469 mg, 2.68 mmol) in dry acetonitrile (30 mL) was added
DBU (400 µL, 2.68 mmol). The mixture was stirred at reflux overnight,
cooled and concentrated in vacuo. The residue was purified by flash
chromatography on SiO2 (Pet. Ether-EtOAc; 70:30) to yield desired bis
(oxazoline) 5 (380 mg, 80%) as a colourless oil. [α]D −76.2 (c 0.008,
MeCN, 23 °C); 1H NMR (400 MHz, CDCl3) δ=7.29(10H, m, 10×ArH ),
4.25 (4H, m, 2×CH2O),3.93 (2H, m, 2×CHN), 3.44 (2H, m, 2×CHAr)
2.05–2.08 (1.91-2.0, 2H, m, one of CH3CH2), (1H, m, one of CHCH2CH),
1.82–1.84(2H, m, one of CH3CH2), 1.61–1.7 (1H, m, one of CHCH2CH),
0.89 (6H, t, J=7.3 Hz, 2×CH3CH2); 13C NMR (100 MHz, CDCl3)
δ=168.9, 140.2, 128.6, 128, 127.1, 72.5, 62.9, 47.35, 41.8, 27.1, 12.3; IR
2963, 2931, 1658 cm−1. ESI-HRMS calcd for C25H30N2O2 389.2229,
4.2.1. Synthesis of MePrXyliBOX 4
To a solution of 7 (300 mg, 0.56 mmol) and p-toluenesulfonyl
fluoride (217 mg, 1.24 mmol) in dry acetonitrile (15 mL) was added
DBU (186 µL, 1.24 mmol). The mixture was stirred at reflux overnight,
cooled and concentrated in vacuo. The residue was purified by flash
chromatography on SiO2 (Pet. Ether-EtOAc; 70:30) to yield desired bis
Table 1
Key bond lengths and angles for PhenylAraBOXCuCl2 complex.
Atoms
Bond lengths,
N–Cu
Cl–Cu
2.004, 2.011
2.21, 2.22
found m/z 389.2218 (M–H)−
.
Atoms
Bond angle,°
4.3. Cyclopropanation reaction: general procedure
N–Cu–N
Cl–Cu–Cl
89.72
99.68
4.3.1. General procedure for asymmetric cyclopropanation catalyzed by
ligand–Cu(I) complexes
A solution of ligand (0.013 mmol) and [Cu(OTf)]2·C6H6 (3 mg,
0.006 mmol) in CH2Cl2 (1 mL) was stirred under a nitrogen atmosphere
at room temperature for 90 min and transferred through a cotton plug
Atoms
Torsion angles,°
N–Cu–N–Cl
C5=N1 N2=C3
143.50, 98.56
52.35 (representing the deviation of the
two oxazolines from the one plane)

1016
F. Kirby et al. / Catalysis Communications 11 (2010) 1012–1016
Scheme 2. Copper catalyzed cyclopropanation of styrene using ethyl diazoacetate.
Table 2
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Results for the cyclopropanation of styrene.
Ligand
Metal salt Conv % Trans: cis % ee (cis)
% ee (trans)
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1
2
3
4
5
6
(R)Ph-AraBOX 1 Cu(OTf)
(S)tBu-AraBOX 2 Cu(OTf)
99
99
91
79
60:40
62:38
48:52
53:47
62:38
59:41
70:30
77:23
32 (1R, 2 S) 16 (1R, 2R)
14 (1R, 2 S) 7 (1R, 2R)
PhXyliBOX 3
Cu(OTf)
Cu(OTf)
–
–
MePrXyliBOX 4
MePrXyliBOX 4
PhPrXyliBOX 5
24 (1 S, 2R) 24 (1 S, 2 S)
31 (1 S, 2R) 26 (1 S, 2 S)
Cu(OTf)2 80
Cu(OTf)
Cu(OTf)
99
98
77
6 (1 S, 2R)
4 (1 S, 2 S)
724 Ph-2,2′BOX 9
54
99
66
99
825 t-Bu-2,2′BOX 10 Cu(OTf)
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added. A solution of ethyldiazoacetate (137 µL, 1.2 mmol) in dry CH2Cl2
was added over ca. 6 h via a syringe pump. After the addition was
complete, the reaction was stirred for an additional 12 h. The reaction
was then concentrated in vacuo to afford the crude product. Conversion
and trans/cis ratio were determined by 1H NMR. Flash chromatography
of the residue (Petrol-EtOAc; 25:1) provided a mixture of trans/cis
isomers. The enantiomeric excess of each isomer was determined by
chiral GC (Cyclodex-B 30 m×0.252 mm×0.25 µm).
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Acknowledgment
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This publication has emanated from research conducted with the
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