Preparation, structure and catalytic activity of copper(II) complexes of novel 4,4′-BOX ligands

Article abstract of DOI:10.1016/j.tetlet.2010.05.135

This Letter details the synthesis of two new 4,4′-bisoxazoline (BOX) ligands. The copper(II) complex of one of the new ligands is structurally determined. The catalytic performance of the copper(II) complexes of the novel ligands, and that of our recently described phenyl AraBOX ligand in Diels-Alder reactions are reported. We have used the structural information to propose an explanation of a curious variation in the diastereoselectivity obtained in the case of one ligand complex.

Full text of DOI:10.1016/j.tetlet.2010.05.135

Tetrahedron Letters 51 (2010) 4103–4106
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation, structure and catalytic activity of copper(II) complexes of novel
4,40-BOX ligands
David Frain a, Fiona Kirby a, Patrick McArdle b, Patrick O’Leary a,
*
a
˙
National University of Ireland, Galway, School of Chemistry, SMACT (Synthetic Methods: Asymmetric Catalytic Transformations), Galway, Ireland
b National University of Ireland, Galway, School of Chemistry, Galway, Ireland
a r t i c l e i n f o
a b s t r a c t
This Letter details the synthesis of two new 4,40-bisoxazoline (BOX) ligands. The copper(II) complex of
one of the new ligands is structurally determined. The catalytic performance of the copper(II) complexes
of the novel ligands, and that of our recently described phenyl AraBOX ligand in Diels–Alder reactions are
reported. We have used the structural information to propose an explanation of a curious variation in the
diastereoselectivity obtained in the case of one ligand complex.
Article history:
Received 16 March 2010
Revised 17 May 2010
Accepted 28 May 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Bis(oxazoline)
Diels–Alder
Catalysis
Molecular modelling
AraBOX
XyliBOX
Metal complexes of oxazoline-based ligands have proved to be
very effective catalysts for asymmetric synthesis.1,2 Among these
ligands the bisoxazolines have been very successful since their
introduction in the early 1990s.3–5 Metal complexes of bisoxazo-
line ligands are both active and stereoselective catalysts in reac-
tions such as aldol condensations,6–8 cyclopropanations,9–11 ene
reactions12–14 and Diels–Alder cycloadditions,15–18 amongst many
others. In all the bisoxazolines reported to date the bulky groups
at the chiral centres exert their influence on the reaction outcome
from a position external to the metallocycle formed on complexa-
tion of the metals via the oxazoline nitrogens. We have prepared
ligands where the chiral centres are internal to the metallocycle
formed in the catalytic complex (Fig. 1). This arrangement is some-
what reminiscent of the Salen-type complexes.19 We also hope
that ultimately these ligands will address one problem which oc-
curs with standard BOX ligands. Regulating the electron density
of the oxazoline rings in standard BOX ligands is difficult because
of the potential for migration of the double bonds into conjugation.
This factor has traditionally limited the use of methylene-bridged
boxes and has led to the use of gem dimethyl-substituted bridges.
The so called AraBOX and XyliBOX ligands cannot undergo such a
migration. This concept will be developed in further publications.
Herein we report our initial catalytic results.
The closest related ligands to those reported here are probably
the spiroBOX of Sasai20 (synthesised as the racemate) and the so-
called BIOX ligands.21 These ligands differ quite radically in struc-
ture from the 2,20-BOX which has been so successful in stereoselec-
tive synthesis. These spiroBOX and BIOX ligands have, however, to
date found limited application in synthesis.
Recently we reported that arabitol could be used as a chiral
starting material in the synthesis of a novel C2-symmetric O-silyl
bis b-aminoalcohol 7, that could serve as a precursor for a new
class of bisoxazoline, and abbreviated to the ‘AraBOX’ ligand.22
* Corresponding author. Tel.: +353 91 492476; fax: +353 91 525700.
E-mail address: patrick.oleary@nuigalway.ie (P. O’Leary).
Figure 1. The 4,40-BOX ligands reported herein (left) and ‘traditional’ 2,20-BOX
ligands (right).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.135

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D. Frain et al. / Tetrahedron Letters 51 (2010) 4103–4106
This methodology has now been expanded to the first synthesis
of the tert-butyl-substituted AraBOX ligand 2 (Scheme 1). The pre-
viously reported intermediate diamine was treated with the tert-
butyl-substituted acid chloride giving the diamide 9 in 79% yield.23
Using a one-pot tandem DARC reaction, the tert-butyl-substituted
AraBOX ligand 2 was isolated in 71% yield.24 The DARC reaction in-
volves the use of tosyl fluoride to both deprotect the silyl-protected
alcohols and activate them as the tosylates. DBU also plays a dual
role by acting as a catalyst for the deprotection step and as a base
in the in situ ring closure.
We have also expanded this methodology to synthesise the
meso phenyl XyliBOX ligand 3 which, using a similar synthesis, is
derived from xylitol.
Having synthesised the three ligands, our attention now turned
to the metal complexes of the ligands and their catalytic activity
and selectivity. Complexation of the phenyl XyliBOX ligand 3 with
copper(II) chloride followed by careful crystallisation resulted in
the isolation of crystals of the Cu(PhXyliBOX)Cl2 complex which
were suitable for X-ray crystal structure determination (Fig. 2).25
The X-ray structure shows complexation through the nitrogens
and the non-planarity of the BOX due to the chirality of the centres
within the metallocycle. The geometry around the copper centre
was found to be square planar.
We decided to use the Diels–Alder cycloaddition reaction as the
first test of the catalytic performance of complexes derived from
our ligands. Copper(II) complexes of both phenyl AraBOX and
tert-butyl AraBOX were tested as catalysts in the Diels–Alder
cycloaddition of cyclopentadiene with 7-crotonoyl-2-oxazolidi-
none (Table 1).26 The results where the 2,20-BOX ligands 4, 5 and
6 were used under similar conditions, as reported by Takacs
et al.,27 are included for comparison.
Scheme 1. Synthetic routes for the preparation of AraBOX and XyliBOX Ligands.
We also showed that, via an efficient one-pot tandem deprotec-
tion/activation/ring-closure (DARC) reaction, phenyl AraBOX 1
could be prepared from benzyl amide.
Figure 2. Two comparative views of the X-ray crystal structure of the Cu(PhXyliBOX)Cl2 complex.

D. Frain et al. / Tetrahedron Letters 51 (2010) 4103–4106
4105
Table 1
As expected the Cu(II)(PhAraBOX) energy profiles showed a
lower activation energy for the reaction leading to the endo prod-
uct as compared with the exo product (difference in activation
energies ꢀ30 kJ molꢁ1). This is consistent with the endo product
being the kinetically favoured product. In the same study,
Cu(II)(PhXyliBOX) energy profiles showed effectively the same
activation energy for reactions to give both endo and exo products
confirming a decrease in importance of kinetic factors in this case
increasing the amount of thermodynamically favoured exo
product.
In summary, we have successfully synthesised the first three
members of the 4,40-BOX family. The copper(II) chloride complex
of the XyliBOX ligand was characterised. We have employed the
copper(II) complexes of the new ligands in Diels–Alder cycloaddi-
tions reaction obtaining reasonable enantioselectivities. A curious
variation in the diastereoselectivity obtained in the case of the
XyliBOX-based catalyst can be explained by reference to the likely
structure of an intermediate complex and secondary orbital
interactions.
Cu(II)AraBOX complex catalysed Diels–Alder reaction
Ligand
Metal source
Conversion %
Endo/exo
ee endo
1 (R)
1 (R)
1 (R)
1 (R)
1 (R)
2 (R)
2 (R)
3
Cu(OTf)2
60
4
90
52
99
60
70/30
—
70/30
70/30
80/20
77/23
44 (S)
—
53 (S)
—
7 (S)
12 (S)
Cu(ClO4)ꢃ6H2Oa
Cu(ClO4)ꢃ6H2O
Cu(SbF6)2
Cu(SbF6)2 (40 h)
Cu(OTf)2
Cu(ClO4)ꢃ6H2O
Cu(OTf)2
96
99
90
90
59/41
90/10
85/15
87/13
a
4 (R)
5 (S)
6 (S)
Cu(OTf)2
22 (R)27
8 (S)27
a
Cu(OTf)2
Cu(OTf)2
76 (S)27
a
a
No molecular sieves used.
Acknowledgement
In the case of the phenyl AraBOX ligand 1, copper(II) complexes
This material is based upon work supported by the Science
Foundation Ireland under Grant No. 05/RF/CHO39.
with the triflate or perchlorate anion gave encouraging results,
with 44% and 53% ee, respectively. The conversion was better when
the perchlorate salt was used.
References and notes
Encouragingly, the first application of these ligands in a cata-
lytic context gave a higher enantioselectivity (with the triflate salt)
than those reported with 4 and 5, which are the two established
BOX ligands. The enantioselectivity reported with BOX 6, possibly
the best known and most widely used BOX ligand, is somewhat
better, but considering these as first generation ligands, the results
certainly indicate promise.
In the case of the tert-butyl AraBOX ligand 2 the triflate-based
complex showed reduced selectivity giving only 12% ee. Though
it is disappointing, this does compare with the performance of
the BOX 5 under similar conditions.
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Asymmetry 2009, 20, 1272–1278.
Interestingly, we see in the case of both ligands 1 and 2 that the
complex derived from the R ligand gives the S product whereas the
complexes derived from the 2,20-BOX ligands 3, 4 and 5 give the
same enantiomer of the product as the ligand was employed.
The results with meso 3 were interesting in terms of the diaste-
reoselectivity of the reaction. The selectivity in this case is atypical
in the large amount of the exo product produced. The copper(II)
complexes of AraBOX ligands give diastereoselectivities more typ-
ical of those seen with BOX ligands. We propose that the increase
in exo product formation is due to secondary orbital interactions
between the carbonyl of the co-ordinated dienophile and the Xyli-
BOX ligand.28 This interaction in effect turns off secondary orbital
interactions between the same carbonyl and the incoming cyclo-
pentadiene which are, in general, responsible for favouring the
kinetically favoured endo product over the thermodynamically fa-
voured exo product. Apparently such interactions are not present
in the AraBOX case possibly due to a change in geometry about
the metal. We have tested this hypothesis by calculating the acti-
vation energy barrier to the Diels–Alder reaction (semi-empirical
PM-3). This was accomplished by modelling the endo and exo prod-
ucts co-ordinated to the copper(II) ligand (both XyliBOX and Ara-
BOX). The Cu(II)(PhXyliBOX) product complex is closely related
to the crystal structure mentioned above with the geometry about
the copper being square planar. The Cu(II)(PhAraBOX) product
complex shows geometry at the copper intermediate between
square planar and tetrahedral. We generated an energy profile as
the C–C bonds formed, in the Diels–Alder reaction, lengthened
allowing us to estimate the activation energy barrier for the for-
ward reaction.
10. Fraile, J. M.; García, J. I.; Gissibl, A.; Mayoral, J. A.; Pires, E.; Reiser, O.; Roldán,
M.; Villalba, I. Chem. Eur. J. 2007, 13, 8830–8839.
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17, 1568–1572.
12. McDonagh, C.; O’Leary, P. Tetrahedron Lett. 2009, 50, 979–982.
13. Qian, C. T.; Wang, L. C. Tetrahedron: Asymmetry 2000, 11, 2347–2357.
14. Kolodziuk, R.; Goux-Henry, C.; Sinou, D. Tetrahedron: Asymmetry 2007, 18,
2782–2786.
15. Phomkeona, K.; Takemoto, T.; Ishima, Y.; Shibatomi, K.; Iwasa, S.; Nishiyama,
H. Tetrahedron 2008, 64, 1813–1822.
16. Barroso, S.; Blay, G.; Al-Midfa, L.; Munoz, M. C.; Pedro, J. R. J. Org. Chem. 2008,
73, 6389–6392.
17. O’Leary, P.; Krosveld, N. P.; De Jong, K. P.; van Koten, G.; Gebbink, R. Tetrahedron
Lett. 2004, 45, 3177–3180.
18. Matsumoto, K.; Jitsukawa, K.; Masuda, H. Tetrahedron Lett. 2005, 46, 5687–
5690.
19. McGarrigle, E. M.; Gilheany, D. G. Chem. Rev. 2005, 105, 1563–1602.
20. Kato, T.; Marubayashi, K.; Takizawa, S.; Sasai, H. Tetrahedron: Asymmetry 2004,
15, 3693–3697.
21. Kanemasa, S.; Adachi, K.; Yamamoto, H.; Wada, E. Bull. Chem. Soc. Jpn. 2000, 73,
681.
22. Frain, D.; Kirby, F.; McArdle, P.; O’Leary, P. Synlett 2009, 1261–1264.
23. To a stirring solution of 7 (270 mg, 0.74 mmol) and triethylamine (400
2.8 mmol) in CH2Cl2 (5 mL) was added a solution of trimethylacetyl chloride
(300 L, 2.5 mmol) in CH2Cl2 (2 mL) via syringe pump over 6 h. The reaction
lL,
l
was quenched by addition of satd aq NaHCO3. The layers were separated and
the aqueous phase was extracted with CH2Cl2 (3 ꢂ 5 mL. The combined organic
phase was dried over MgSO4, filtered, concentrated in vacuo and purified by
column chromatography on SiO2 (pet. ether/EtOAc; 75:25) to yield 9 (310 mg,
79%).
24. Procedure for the tandem deprotection/activation/ring closure reaction: 4,40-
methylenebis[(4R)-2-tert-butyl-2-oxazoline] 2: To a solution of 9 (300 mg,
0.525 mmol) and p-toluenesulfonyl fluoride (200 mg, 1.155 mmol) in dry
MeCN (8 mL) was added DBU (185 lL, 1.115 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; 75:25) to yield the desired
AraBOX 2 (99 mg, 71%); 1H NMR (400 MHz, CDCl3) d = 1.74 (2H, t, J = 6.9 Hz),

4106
D. Frain et al. / Tetrahedron Letters 51 (2010) 4103–4106
3.89 (2H, app. t, J = 7.8 Hz), 4.17–4.13 (2H, m), 4.34 (2H, app. t, J = 8.7 Hz); 13C
stirring catalyst was added 1-(trans-crotonoyl)-2-oxazolidinone (51 mg,
0.33 mmol) and freshly distilled cyclopentadiene (0.10 mL, 1.21 mmol). The
reaction proceeded for 16 h. A mixture of endo and exo products was isolated as
an oil. The reaction resulted in 60% conversion with an endo/exo ratio of 70:30.
The crude mixture was then purified by column chromatography (pet./EtOAc,
3:2) affording a mixture of endo and exo products as a colourless oil, from
which the enantiomeric excess (ee) of the endo diastereomer was found to be
44% (S), as measured on the purified product using chiral HPLC (CHIRACEL OD,
254 nm, hexane/iso-propyl alcohol, 98:2, 1.0 mL/min), t(S) 22.5, t(R) 28.5.
27. Takacs, J. M.; Quincy, D. A.; Shay, W.; Jones, B. E.; Ross, C. R. Tetrahedron:
Asymmetry 1997, 8, 3079–3087.
NMR (100 MHz, CDCl3) d = 27.9, 33.2, 43.3, 64.9, 73.5, 174.2; IR 2924, 1720,
1642, 1080, 779 cmꢁ1; Anal. Calcd for C15H26N2O2: C, 67.63; H, 9.84; N, 10.52.
Found: C, 66.79; H, 10.11; N, 9.92; [a] +24.1 (c 0.7, MeCN, 23 °C).
D
25. Crystallographic data (excluding structure factors) for the structure reported in
this Letter have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 758186. Copies of the data can
be obtained free of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: (internat.) +44 1223/336-033; e-mail: deposit@ccdc.cam.
ac.uk].
26. Typical procedure for the Diels–Alder reaction: To a flame-dried N2 filled
Schlenk tube was added Cu(OTf)2 (0.033 mmol, 10 mol %), phenyl AraBOX
ligand 1 (0.033 mmol, 10 mol %), 4 Å powdered molecular sieves (20 mg) and
CH2Cl2 (2 mL). This mixture was stirred under N2 for 90 min at rt. To this
28. Maruoka, K.; Imoto, H.; Yamamoto, H. J. Am. Chem. Soc. 2002, 116, 12115–
12116.