Bisoxazolines with one and two sidearms: Stereodirecting ligands for copper-catalysed asymmetric allylic oxidations of alkenes

Article abstract of DOI:10.1039/b512570g

A series of sidearm functionalized bisoxazoline ligands has been synthesized by reaction of the monolithiated methyl{bis(oxazolinyl)methane with the appropriate electrophiles, and tested in the copper catalyzed asymmetric allylic oxidation of cyclohexene ("Kharasch-Sosnovski" reaction). The observed enantioselectivities were higher (up to 85% ee) than for the unfunctionalized bisoxazoline ("BOX") derivatives (ca. 60% ee). Regardless of the functional groups incorporated into the sidearm unit, the ee's obtained for the different derivatives were essentially indistinguishable. This implies that the sidearms do not interfere directly in this reaction and only play an indirect role by virtue of their steric demand. Three of the copper complexes have been characterized by X-ray diffraction, establishing a distorted octahedral coordination geometry around the copper atom in all three cases. In the elongated distorted CuN₂O₄ octahedra, the two nitrogen atoms of the oxazolines and one oxygen atom of each acetate ligand occupy the 'equatorial' positions whereas the sidearms do not interact with the metal centres. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b512570g

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/dalton | Dalton Transactions
Bisoxazolines with one and two sidearms: stereodirecting ligands for
copper-catalysed asymmetric allylic oxidations of alkenes
Markus Seitz,a Carmine Capacchione,a,c Ste´phane Bellemin-Laponnaz,b Hubert Wadepohl,a
Benjamin D. Warda and Lutz H. Gade*a
Received 7th September 2005, Accepted 26th October 2005
First published as an Advance Article on the web 14th November 2005
DOI: 10.1039/b512570g
A series of sidearm functionalized bisoxazoline ligands has been synthesized by reaction of the
monolithiated methyl{bis(oxazolinyl)}methane with the appropriate electrophiles, and tested in the
copper catalyzed asymmetric allylic oxidation of cyclohexene (“Kharasch–Sosnovski” reaction). The
observed enantioselectivities were higher (up to 85% ee) than for the unfunctionalized bisoxazoline
(“BOX”) derivatives (ca. 60% ee). Regardless of the functional groups incorporated into the
sidearm unit, the ee’s obtained for the different derivatives were essentially indistinguishable. This
implies that the sidearms do not interfere directly in this reaction and only play an indirect role by
virtue of their steric demand. Three of the copper complexes have been characterized by X-ray
diffraction, establishing a distorted octahedral coordination geometry around the copper atom in all
three cases. In the elongated distorted CuN2O4 octahedra, the two nitrogen atoms of the oxazolines and
one oxygen atom of each acetate ligand occupy the ‘equatorial’ positions whereas the sidearms do not
interact with the metal centres.
influence the activity and selectivity of the catalyst by nature of its
steric demand [case (c)] and thus be simply due to the reduction
of the active space available for the catalytic conversion.
Introduction
Bisoxazolines (“BOX”) have been established as a class of
“privileged” stereodirecting ligands in asymmetric catalysis.1 Their
transition metal complexes have been employed in a wide range
of catalytic transformations, in particular, in Lewis acid catalyzed
stereoselective reactions.2 They have provided the base for exten-
sive research efforts in the design of new chiral ligands and may be
combined with other ligating functions.3 A notable development
is the coupling of an additional “sidearm” to the bridging carbon
atoms of bisoxazolines.4 Tang and coworkers have found that such
potentially tricoordinating ligands may provide Cu-based Lewis
acid catalysts which display a significantly improved performance
in comparison to the BOX-reference system.4,5 However, the role
of the “sidearm” remains a matter of debate.
Fig. 1 Possible roles of ligand sidearms in bisoxazolines.
There are three conceivable ways in which a “sidearm”, which
is attached to the bridging carbon atom of the BOX-ligand may
interact with the active centre of a molecular catalyst (Fig. 1).
First, if it contains a ligating donor function (D) it may bind
directly to the metal centre, as represented for case (a) in Fig. 1.
This additional binding interaction is expected to stabilize the
complex and to change the electron density of the metal. If the
sidearm contains a substrate acceptor function (A), such as a
hydrogen bond donating functional group, as in case (b), then
an additional orientation of the catalytic substrate may be the
result. Finally, the addition of the sidearm may neither lead to a
direct interaction with the metal centre nor the substrate but may
The introduction of the additional ligating “arm” in the podand
structure of the bisoxazolines implies the loss of the twofold
rotational symmetry of the system, and therefore the reduction of
the number of diastereomeric intermediates and transition states
in a stereoselective transformation. This complication may be in
part offset by the “resymmetrization” of the system upon the
introduction of two identical ligand sidearms pointing in opposite
directions relative to the bisoxazoline unit. In such a system there
may be rapid exchange between the interaction of the two sidearms
with the metal centre or the substrate, as is exemplified in Fig. 2
for a bis(donor)-functionalized system. Here again, depending on
the catalyst and the type of reaction, the role of the sidearms may
also be purely steric.
aAnorganisch-Chemisches Institut, Universita¨t Heidelberg, Im Neuenheimer
Feld 270, 69120, Heidelberg, Germany. E-mail: lutz.gade@uni-hd.de
In our investigation into the catalytic utility of such additionally
functionalized stereodirecting bis(oxazoline) ligands6 we chose a
copper catalyzed reaction in which the copper does not primarily
play the role of a Lewis acid. A preparatively useful example
of a direct catalytic functionalization of hydrocarbons is the
bLaboratoire de Chimie Organome´tallique et de Catalyse, Universite´ Louis
Pasteur, 4 rue Blaise Pascal, 67000, Strasbourg, France
cDipartimento di Chimica, Universita` degli Studi di Salerno, via S. Allende
84081, Baronissi (SA), Italy
This journal is
The Royal Society of Chemistry 2006
Dalton Trans., 2006, 193–202 | 1 9 3
©

View Article Online
a sulfonylamido group in the side chain. For the synthesis of
the latter it proved important to use an excess of the lithiated
bisoxazoline in order to suppress the oligo- or polymerization of
the N-tosylaziridine. Compound 5 is characterized by the strong
m(RSO2N)-vibrational bands in the IR spectrum at 1326 cm−1 and
1158 cm−1. After recrystallization from n-hexane single crystals
of compound 5 were obtained which were suitable for an X-ray
structure analysis. Its molecular structure is depicted in Fig. 3
along with important bond lengths and angles.
Fig. 2 “Degenerate” interaction of the ligand sidearms in difunctionized
bisoxazolines.
copper-catalyzed Kharasch–Sosnovsky reaction, i.e. the allylic
acyloxylation of olefins.7,8 In the presence of chiral oxazoline-
based ligands it has been possible to render this reaction
enantioselective,9 although a truly efficient asymmetric catalyst
has not as yet been found. In this work we report a series of new
copper(II)-precatalysts for allylic oxidation and discuss the role
that ligand sidearms may play in it.
Results and discussion
Synthesis of the ligands
All sidearm functionalized bisoxazoline ligands employed in
this study were synthesized by reaction of the monolithi-
ated methyl{bis(oxazolinyl)}methane10 with the appropriate elec-
trophiles (Scheme 1). The lithiated starting material which was
generated in situ by deprotonation in the bridgehead position
˚
Fig. 3 Molecular structure of compound 5. Selected bond lengths (A)
and angles (◦): C5–N2, 1.263(3); C11–N3, 1.270(2); N1–S1, 1.6107(16);
O1–S1, 1.4376(15); O2–S1, 1.4338(15); C5–C3–C11, 106.21(14);
N2–C5–O3, 119.10(19); N2–C5–C3, 127.62(18); N3–C11–O4, 118.57(15);
N3–C11–C3, 127.36(16); O1–S1–O2, 120.15(8).
t
of the corresponding bisoxazoline with BuLi. Reaction of the
lithium salt with a range of aroyl and acyl chlorides gave the
ligands 1a–d and 2a, b while the corresponding transformation
with 2-chloromethyl pyridine yielded compounds 3a, b.
The two oxazoline rings in 5 are twisted relative to one another
with the two N-atoms, N2 and N3, adopting opposite orientations.
This leads to torsion angles N3–C11–C3–C2 120.3(2)◦ and C2–
C3–C5–N2 8.1(3)◦. This particular molecular arrangement is
thought to be due to the steric demand of the two isopropyl
substituents on the oxazoline rings and differs from that present
in the copper complex 10 (vide infra).
Tetradentate bis(oxazoline) ligands have received less attention
than their tridentate counterparts, with very few examples of
bisoxazolines incorporating two sidearms on the carbon bridge
having been synthesized to date. Their preparation can be easily ac-
complished by treating the bis(oxazolinyl)methane with an excess
of sodium hydride and subsequent treatment with the appropriate
electrophiles to give the gem-disubstituted bis(oxazoline) ligands
6–8 in good yields (Scheme 2).
Asymmetric allylic oxidation of cyclohexene catalyzed by copper
complexes containing BOX-derivatives with one and two sidearm(s)
Both the bisoxazoline ligand containing one sidearm as well
as those with two were systematically tested as stereodirecting
ligands, in combination with a variety of copper salts, in the
asymmetric allylic oxidation of cyclohexene which is generally
used as the substrate of reference. As the oxidizing agent we em-
ployed benzoyl(tert-butyl)peroxide. Previous studies have shown
that, using the bisoxazolines BOX or pybox as stereodirecting
Scheme 1 Synthesis of the bisoxazoline ligands 1–5 containing one
sidearm.
Using phenylisocyanate as the electrophilic agent gave bisox-
azoline 4, containing a carboxamido sidearm, whereas ring
opening of N-tosylaziridine gave rise to compound 5 possessing
1 9 4 | Dalton Trans., 2006, 193–202
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
Table 1 Asymmetric allylic oxidation of cyclohexene using PhCO3-t-Bu
as oxidant (isolated yields after reaction times of 5–7 days)
Entry Ligand Copper salt T/◦C Solvent
Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1b
1a
1a
1d
1c
2a
1e
2b
3a
3b
4
Cu(OTf)2
Cu(OTf)2
Cu(BF4)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OCl4)2
Cu(BF4)2
Cu(OTf)2
Cu(OCl4)2
Cu(BF4)2
Cu(OTf)2
Cu(OCl4)2
Cu(BF4)2
Cu(OTf)2
Cu(OCl4)2
Cu(BF4)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
49
52
47
53
41
44
55
45
44
54
45
72
70
72
72
55
60
54
60
50
51
60
51
61
68
65
60
60
60
60
68
70
70
71
71
71
80
77
79
77
55
72
4
5
5
5
5
Acetone 59
Acetone 67
Acetone 54
5
5
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
15
20
20
55
52
61
59
54
45
Scheme 2 Synthesis of the bisoxazoline ligands 6–8 containing two
sidearms.
5
0
0
5
6
20
20
20
0
20
20
7
8a
8a
8b
8c
ligands, enantioselectivities of ca. 60% ee (with yields of ca. 65%)
are obtained.
Since Andrus and coworkers have reported that it is possible
to induce high stereoselectivity (up to 96%, at low conversion) by
using the more electron-deficient tert-butyl p-nitroperbenzoate as
an oxidant,11 we also tested this reagent. The decreased reactivity
of the latter, however, limits the usefulness of the method since
only very low yields are obtained. The results obtained with the
new ligands 1–8 are summarized in Table 1.
Table 2 Asymmetric allylic oxidation of cyclohexene using p-
NO2PhCO3-t-Bu as oxidant (isolated yields after reaction times of 5–7
days)
The complexes which were tested catalyze the reaction with
a moderate degree of selectivity and reactivity at relatively low
catalyst loading (5 mol%). The type of copper salt employed
does not significantly affect the activity and selectivity, whilst
the variation of solvent appears to have an effect (with acetone
leading to higher selectivities but lower yields than the com-
monly used acetonitrile). This observation may be attributed
to the solvent dependence of cation–anion interaction in the
catalyst.
It is worth noting that the copper complexes of ligands 6 and
8a, both bearing two substituents on the carbon atom bridging
the two oxazoline units (6: benzyl; 8a: 2-pyridyl), display higher
selectivity. As previously observed, the use of p-NO2PhCO3-t-Bu
significantly enhances the selectivity of the conversion, albeit with
decreased reaction rate (Table 2).11 Compared to previous catalysts
tested for the Karasch–Sosnovski reaction, the ee values obtained
with the catalysts bearing ligands 6 and 8a are remarkably high
(up to 85%). Both ligands differ from one another in function-
ality and thus potential denticity, however, they are essentially
similar as far as the sterics of the bridgehead substituent are
concerned.
Entry
Ligand Copper salt
T/◦C
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
5
Cu(OTf)2
Cu(OCl4)2
Cu(BF4)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
20
20
20
87
63
73
19
52
42
60
47
49
77
77
72
79
85
84
82
85
65
5
5
5
−15
6
20
7
20
20
0
20
8a
8a
8b
This observation and that of the lower selectivity observed for
the catalysts bearing bisoxazoline ligands with only only sidearm
function may suggest that the steric demand of the sidearms
rather than binding interaction with the metal or the substrates is
responsible for the selectivity of the reaction.
This journal is
The Royal Society of Chemistry 2006
Dalton Trans., 2006, 193–202 | 1 9 5
©

View Article Online
Molecular structures of copper(II) complexes containing
BOX-derivatives with one and two sidearms
Reaction of copper(II) acetate monohydrate (2 molar equiv.) with
the ligands 3a, 5 and 8a (1 molar equiv.) gave the complexes
[(ligand)Cu(acetate)2] 9, 10 and 11, respectively (Scheme 3). Single
crystals were obtained from toluene solutions layered with n-
hexane which were subjected to slow diffusion.
˚
Fig. 4 Molecular structure of compound 9. Selected bond lengths (A)
and angles (◦): Cu1–N1, 1.946(6); Cu1–N2, 1.973(6); Cu1–O4, 1.954(5);
Cu1–O5, 1.977(5); Cu1–O3, 2.687(6); Cu1–O6, 2.540(5); N1–Cu1–N2,
90.1(3); O4–Cu1–N2, 93.9(3); N1–Cu1–O5, 92.4(3); N1–Cu1–O4,
158.2(2); N2–Cu1–O5, 154.1(2); O4–Cu1–O5, 93.2(2).
the unfunctionalized bisoxazoline (“BOX”) derivatives. Notably,
this effect was observed regardless of the functional groups
incorporated into the sidearm unit, the ee’s obtained for the
different derivatives being essentially indistinguishable. This leads
us to propose that the sidearms do not interfere directly in this
reaction, but most probably only play an indirect role by virtue of
their steric demand. In other words, we believe that in the case at
hand, we observe the third case (c) depicted in Fig. 1. This view
is supported by the absence of any interaction of the sidearms
with the metal centres or the other ligands established in the X-
ray structure analyses of compounds 9–11. Whether this situation
pertains for complexes with other transition metals is not clear
and under current investigation.
Scheme 3 Synthesis of the bisoxazoline–copper(II) complexes 9–11.
Experimental
The coordination geometry around the copper atoms is ap-
proximately octahedral in all three cases (Figs. 4–6). In the
elongated distorted CuN2O4 octahedra, the two nitrogen atoms
of the oxazolines and one oxygen atom of each acetate occupy
the ‘equatorial’ positions. Here, Cu–N and Cu–O distances range
General
All manipulations were performed under nitrogen. Solvents
were dried according to standard methods and saturated with
nitrogen. The deuterated solvents used for the NMR spectroscopic
measurements were degassed by three successive “freeze–pump–
˚
from 1.947(6)–1.991(4) A, respectively. The remaining two oxygen
˚
thaw” cycles and stored over 4-A molecular sieves. All other
atoms of the acetate ligands approach the ‘axial’ positions, with
˚
chemicals were used as received. Yields are given for isolated
products showing one spot on a TLC plate and no impurities were
detectable in the NMR spectrum. 2,2-Bis((S)-4-isopropyl-4,5-
dihydrooxazol-2-yl)-ethane,13 2,2-bis((S)-4-phenyl-4,5-dihydro-
oxazol-2-yl)-ethane,13 bis((S)-4-isopropyl-4,5-dihydrooxazol-2-
yl)-methane,10 2-(2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-
propyl)pyridine5 (3a), (4S)-2,2ꢀ-(1-phenylmethyl-2-phenylethyli-
dene)bis[4-(1-methylethyl)-4,5-dihydroxazole14 (6) and tert-butyl
p-nitrobenzoate11 were prepared according to literature proce-
much larger distances to copper (2.440(3)–2.750(4) A), and O–
Cu–O angles considerably less than 180◦ (140.8(2)–155.8(1)◦).
This asymmetrical j2-acetate coordination is quite common in
copper acetate complexes.12 Most significantly, the additional
nitrogen donors (weakly nucleophilic sulfonamide NH in 10, more
strongly nucleophilic pyridine nitrogen atoms in 9 and 11) do not
coordinate to the respective copper centres, nor does there seem
to be any significant interaction with the acetato units.
1
dures. The H and 13C NMR spectra were recorded on Bruker
Conclusions
Avance DRX 200 or Varian Unity Plus 400 FT-NMR spectro-
meters at room temperature (295 K). The spectra were referenced
relative to tetramethylsilane using the residual protio-solvent (1H)
or the carbon (13C) resonance. IR spectra were recorded as thin
films between KBr plates using a FT-IR Merlin Excalibur FT3000
We have studied the influence of “sidearms” in bisoxazoline copper
complexes on their catalyst performance in the asymmetric allylic
alkylation of cyclohexene as substrate of reference. In general, the
observed enantioselectivities have been somewhat higher than for
1 9 6 | Dalton Trans., 2006, 193–202
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
Fig. 6 Molecular structure of compound 11. Selected bond lengths
◦
˚
(A) and angles ( ): Cu1–N1, 1.991(4); Cu1–N2, 1.976(4); Cu1–O4,
1.986(3); Cu1–O5, 1.948(3); N2–Cu1–N1, 89.72(15); N2–Cu1–O4,
92.80(15); O5–Cu1–N1, 95.75(14); O4–Cu1–N1, 156.45(14); O5–Cu1–N2,
153.24(16); O5–Cu1–O4, 92.48(14).
to warm to −50 ◦C and stirred for 1 h. This solution was then
cooled to −78 ◦C and a solution of benzoyl chloride (0.98 g,
0.70 mmol) in THF (5 mL) was slowly added with stirring.
◦
The reaction mixture was maintained at −78 C for 1 h, slowly
warmed to room temperature and then heated to reflux overnight.
An aqueous solution of KHCO3 (50 mL, 10%) was added, and
after removal of the organic phase the residue was extracted with
dichloromethane (3 × 50 mL). The organic layer was washed
with water and dried over anhydrous Na2SO4. Removal of solvent
gave a pale yellow oil which was purified by flash chromatography
(EtOAc–CH2Cl2, 20 : 80) affording 1a as a colourless oil (0.17 g,
1
3
75% yield). H NMR (300 MHz, CDCl3): d = 0.84 (d, JHH
=
3
5.3 Hz, 3H, H-1), 0.87 (d, JHH = 5.3 Hz, 3H, H-1), 0.91 (d,
3JHH = 6.9 Hz, 3H, H-1), 0.95 (d, JHH = 6.8 Hz, 3H, H-1),
3
1.62–1.86 (m, 2H, H-2), 1.88 (s, 3H, H-6), 3.86–4.10 (m, 4H,
H-3), 4.12–4.30 (m, 2H, H-4, H-4ꢀ), 7.30 (dd, 2H, H-11), 7.43 (t,
Fig. 5 a) Molecu◦lar structure of compound 10. Selected bond lengths
˚
3JHH = 7.3 Hz, 1H, H-12), 7.91 (d, JHH = 7.2 Hz, 2H, H-10).
3
(A) and angles ( ): Cu1–N1, 1.974(4); Cu1–N2, 1.975(4); Cu1–O6,
1.962(4); Cu1–O8, 1.966(4); N4–S1, 1.603(4); O4–S1, 1.434(4); O5–S1,
1.431(4); Cu1–O7, 2.501(3); Cu1–O9, 2.584(3); N1–Cu1–N2, 89.27(14);
O8–Cu1–N1, 91.93(16); O6–Cu1–N2, 92.77(16); O8–Cu1–N2, 157.79(14);
O6-Cu1–N1, 162.32(14); O6–Cu1–O8, 92.77(15). b) In-plane view of the
complex illustrating the orientation of the tosylamido sidearm (hydrogen
atoms omitted for clarity).
1
13
{ H} C NMR (75.5 MHz, CDCl3): d = 17.9–19.0 (C-1), 21.7
(C-6), 32.4 (C-2), 54.3 (C-7), 70.4–70.6 (C-7), 71.9–72.1 (C-3),
127.9 (C-12), 129.3 (C-10/C-11), 132.5 (C-10/C-11), 135.9 (C-9),
165.0 (C-5), 194.3 (C-8). MS (FAB+): C21H28N2O3 m/z (%) = 358
(23) [M + H]+, 341 (5) [M − CH3]+, 313 (5) [M − C3H7]+, 285 (4)
[M − C3H7 − CO]+, 253 (30), 251 (19) [M − COPh]+, 246 (4), 244
(5) [M − C6H10NO]+, 210 (5), 209 (33), 207 (4), 202 (4).
instrument. Mass spectra (EI or FAB) were recorded on Finnigan
MAT TSQ 700 or JEOL JMS-700 spectrometers, high resolution
mass spectra (HRMS) were recorded on the latter instrument.
Elemental analyses were performed by the microanalytical service
at the chemistry department of Heidelberg. Enantiomeric excesses
were determined by using a Finnigan SurveyerTM Modular HPLC
R
R
System equipped with a Chiralpakꢀ AS–H and/or Chiralcelꢀ
2,2-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-4,4-dimethyl-
pentan-3-one (1b). This compound was prepared as a colourless
oil from 2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-ethane
(0.50 g, 2.0 mmol), tert-BuLi in n-hexane (1.5 M, 1.5 mL,
2.2 mmol) and pivaloylchloride (0.48 g, 4.0 mmol) in THF
(50 mL) using the same procedure reported for 1a: yield 0.54 g
(81%). 1H NMR (200 MHz, CDCl3): d = 0.83–0.95 (m, 12H, H-1),
1.23 (s, 9H, H-10), 1.67–1.87 (m, 2H, H-2), 1.77 (s, 3H, H-6),
AD–H columns.
Preparation of the compounds
2,2-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-phenyl)-propan-
1-one (1a). A 1.70 M solution of tert-BuLi (0.16 g, 0.63 mmol)
in n-hexane was added dropwise to a solution of 2,2-bis((S)-4-
isopropyl-4,5-dihydrooxazol-2-yl)-ethane (0.16 g, 0.63 mmol) in
◦
1
13
THF (45 mL) with stirring at −78 C. The mixture was allowed
3.86–4.07 (m, 4H, H-3, H-4ꢀ), 4.21–4.33 (m, 2H, H-4). { H} C
This journal is
The Royal Society of Chemistry 2006
Dalton Trans., 2006, 193–202 | 1 9 7
©

View Article Online
NMR (50 MHz, CDCl3): d = 18.06 (C-1), 18.10 (C-1), 18.85 (C-1),
18.90 (C-1), 21.28 (C-6), 28.42 (C-10), 32.11 (C-2), 32.46 (C-2),
46.10 (C-9), 55.69 (C-7), 70.25 (C-4) 70.47 (C-4), 71.90 (C-3),
72.00 (C-3), 164.58 (C-5), 164.68 (C-5), 208.75 (C-8). IR (film)
[m/cm−1]: 2964 (s), 2907 (m), 2360 (w), 1704 (m), 1662 (s), 1520
(w), 1469 (m), 1335 (m), 1088 (m), 1039 (w), 978 (m). MS (FAB+):
(w), 2966 (s), 1728 (m), 1670 (s), 1610 (w), 1518 (m), 1466 (w),
1279 (w), 1188 (w), 1089 (m). MS (FAB+): C25H36N2O3 m/z
(%) = 413 (100.0) [M+ + H], 435 (1.9) [M+ + Na], 253 (21.1)
[bisoxazoline+ + H]. HRMS (FAB+): 413.2787 (C25H37N2O3
requires 413.2804). Calc. for C25H37N2O3·0.05CHCl3 (412.56): C
71.89, H 8.68, N 6.69. Found: C 71.84, H 8.86, N 6.41%.
C19H32N2O3 m/z (%) = 337 (100.0) [M+ + H], 459 (2.7) [M+
+
Na], 253 (9.6) [bisoxazoline+ + H]. HRMS (FAB+): 337.2520
(C19H33N2O3 requires 337.2520). Calc. for C19H32N2O3 (337.25):
C 67.82, H 9.59, N 8.33. Found: C 67.60, H 9.66, N 8.10%.
2,2-Bis((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-1-(4-nitrophenyl)-
propan-1-one (1e). This compound was prepared as a yellow
solid from 2,2-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)-ethane
(0.50 g, 1.6 mmol), tert-BuLi in n-hexane (1.5 M, 1.2 mL,
1.7 mmol) and p-nitrobenzylchloride (0.44 g, 2.4 mmol) in THF
(50 mL) using the same procedure reported for 1a: yield 0.51 g
(68%). 1H NMR (200 MHz, CDCl3): d = 2.26 (s, 3H, H-9),
4.00–4.28 (m, 2H, H-6), 4.60–4.72 (m, 2H, H-6ꢀ), 5.22–5.36 (m,
2,2-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-1-(4-nitrophenyl)-
propan-1-one (1c). This compound was prepared as a yellow
oil from 2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-ethane
(0.50 g, 2.0 mmol), tert-BuLi in n-hexane (1.5 M, 1.5 mL,
2.2 mmol) and p-nitrobenzoylchloride (0.41 g, 2.2 mmol) in THF
(50 mL) using the same procedure reported for 1a: yield 0.23 g
2H, H5), 7.29–7.34 (m, 10H, H-1, H-2, H-3), 8.13 (d, 2H, 3JHH
=
1
13
9.3 Hz, H-12), 8.19 (d, 2H, 3JHH = 9.3 Hz, H-13). { H} C NMR
(50 MHz, CDCl3): d = 21.11 (C-9), 54.39 (C-8), 69.42 (C-5), 69.63
(C-5), 75.11 (C-6), 75.38 (C-6), 123.06 (C-13), 126.60 (C-1/C-
2/C-3), 127.76 (C-1/C-2/C-3), 128.66 (C-1/C-2/C-3), 130.33
(C-12), 140.91 (C-4), 140.99 (C-4), 141.37 (C-11), 149.61 (C-14),
165.66 (C-7), 165.71 (C-7), 193.02 (C-10). IR (KBr) [m/cm−1]: 3062
(m), 3031 (m), 2962 (m), 1742 (m), 1659 (s), 1569 (s), 1525 (vs),
1454 (m), 1381 (m), 1343 (vs), 1268 (m), 1095 (s), 822 (m). MS
(FAB+): C27H23N3O5 m/z (%) = 470 (10.8) [M+ + H], 321 (100.0)
[bisoxazoline+ + H]. HRMS (FAB+): 470.1694 (C27H24N3O5
requires 470.1716). Calc. for C27H23N3O5·0.25CHCl3: C 65.55, H
4.69, N 8.42. Found: C 65.34, H 4.95, N 8.43%.
1
(29%). H NMR (200 MHz, CDCl3): d = 0.78–0.99 (m, 12H,
H-1), 1.60–1.81 (m, 2H, H-2), 1.82 (s, 3H, H-6), 3.80–4.06 (m,
3
4H, H-3, H-4ꢀ), 4.11–4.29 (m, 2H, H-4), 8.13 (d, JHH = 9.2 Hz,
3
1
13
2H, H-11), 8.19 (d, JHH = 9.2 Hz, 2H, H-10). { H} C NMR
(50 MHz, CDCl3): d = 17.92 (C-1), 18.06 (C-1), 18.56 (C-1), 18.82
(C-1), 21.11 (C-6), 32.31 (C-2), 32.43 (C-2), 54.03 (C-7), 70.45
(C-4), 70.73 (C-4), 71.99 (C-3), 72.11 (C-3), 122.82 (C-11), 130.35
(C-10), 141.20 (C-9), 149.56 (C-12), 164.29 (C-5), 164.31 (C-5),
193.87 (C-8). IR (film) [m/cm−1]: 3319 (m), 3070 (w), 2360 (w),
1730 (s), 1675 (s), 1530 (vs), 1466 (w), 1346 (m), 1273 (m), 1088
(m), 938 (m). MS (FAB+): C21H27N3O5 m/z (%) 402 (15.6) [M+
+ H], 253 (100.0) [bisoxazoline+ + H]. HRMS (FAB+): 402.2053
(C21H28N3O5 requires 402.2029).
2,2-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-1-(4-tert-butyl-
phenyl)-propan-1-one (1d). This compound was prepared as a
colourless oil from 2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-
2-yl)-ethane (0.50 g, 2.0 mmol), tert-BuLi in n-hexane (1.5 M,
1.5 mL, 2.2 mmol) and 4-tert-butylbenzoylchloride (0.80 g,
4.0 mmol) in THF (50 mL) using the same procedure reported
2,2-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-1-(quinolin-2-
yl)-propan-1-one (2a). This compound was prepared as a brown
oil from 2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-ethane
(0.70 g, 2.8 mmol), tert-BuLi in n-hexane (1.5 M, 2.1 mL,
3.1 mmol) and quinoline-2-carbonyl chloride (0.94 g, 4.9 mmol)
in THF (50 mL) using the same procedure reported for 1a: yield
1
1
for 1a: yield 0.48 g (59%). H NMR (200 MHz, CDCl3): d =
0.24 g (21%). H NMR (400 MHz, CDCl3): d = 0.86–0.94 (m,
0.83–0.97 (m, 12H, H-1), 1.31 (s, 9H, H-14), 1.69–1.84 (m, 2H,
H-2), 1.89 (s, 3H, H-6), 3.91–4.10 (m, 4H, H-3, H-4ꢀ), 4.19–4.22
12H, H-1), 1.73–1.87 (m, 2H, H-2), 2.20 (s, 3H, H-6), 3.96–4.09
(m, 4H, H-3, H-4ꢀ), 4.14–4.18 (m, 1H, H-4), 4.28–4.32 (m, 1H,
H-4), 7.62–7.66 (m, 1H, H-13), 7.74–7.78 (m, 1H,H-12), 7.87 (d,
3JHH = 8.1 Hz, 1H, H-14), 8.08 (d, 3JHH = 8.2 Hz, 1H, H-11), 8.16
(d, 3JHH = 8.6 Hz, 1H, H-17), 8.27 (d, 3JHH = 8.6 Hz, 1H, H-16).
(m, 2H, H-4), 7.37 (d, 3JHH = 8.6 Hz, 2H, H-11), 7.90 (d, 3JHH
=
1
13
8.6 Hz, 2H, H-10).{ H} C NMR (50 MHz, CDCl3): d = 17.86
(C-1), 17.91 (C-1), 18.74 (C-1), 18.97 (C-1), 21.74 (C-6), 31.03
(C-2), 31.13 (C-2), 32.29 (C-14), 35.00 (C-13), 54.31 (C-7), 70.34
(C-4) 70.49 (C-4), 71.85 (C-3), 71.94 (C-3), 124.91 (C-11), 125.22
(C-11), 129.24 (C-10), 129.75 (C-10), 132.97 (C-9), 156.20 (C-12),
165.08 (C-5), 165.15 (C-5), 193.87 (C-8). IR (film) [m/cm−1]: 3054
1
13
{ H} C NMR (100 MHz, CDCl3): d = 17.87 (C-1), 17.89 (C-1),
18.56 (C-1), 18.85 (C-1), 21.83 (C-6), 32.36 (C-2), 53.84 (C-7),
70.42 (C-4), 70.50 (C-4), 71.77 (C-3), 71.89 (C-3), 119.53 (C-17),
127.68 (C-14), 128.59 (C-13), 129.30 (C-15), 129.93 (C-12), 130.31
1 9 8 | Dalton Trans., 2006, 193–202
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
(C-11), 136.78 (C-16), 146.47 (C-10), 151.28 (C-9), 165.13 (C-5),
165.28 (C-5), 194.85 (C-8). IR (film) [m/cm−1]: 3057 (m), 2966 (s),
1743 (m), 1674 (s), 1603 (w), 1525 (m), 1464 (w), 1372 (m), 1275
(w), 1240 (w), 1168 (w). MS (FAB+): C24H29N3O3 m/z (%) 408
(44.2) [M+ + H], 253 (100.0) [bisoxazoline+ + H]. HRMS (FAB+):
408.2283 (C24H30N3O3 requires 408.2287).
with dichloromethane (3 × 50 mL). The organic layer was
washed with water and dried over anhydrous Na2SO4. Removal
of the solvent gave a pale yellow oil which was purified by flash
chromatography (EtOAc) affording 3b as a white solid (0.51 g,
1
78%). H NMR (400 MHz, CDCl3): d = 1.73 (s, 3H, H-9), 3.66
2
2
(d, JHH = 13.5 Hz, 1H, H-10), 3.69 (d, JHH = 13.5 Hz, 1H,
H-10), 4.16–4.23 (m, 2H, H-6), 4.70–4.76 (m, 2H, H-6ꢀ), 5.19–5.30
(m, 2H, H5), 7.16–7.37 (m, 12H, H-1, H-2, H-3, H-13, H-15),
1
13
7.56–7.60 (m, 1H, H-14), 8.59–8.60 (m, 1H, H-12). { H} C
NMR (100 MHz, CDCl3): d = 21.64 (C-9), 43.32 (C-10), 44.18
(C-8), 69.51 (C-5), 69.65 (C-5), 75.46 (C-6), 75.51 (C-6), 121.80
(C-13/C-15), 124.96 (C-13/C-15), 126.73 (C-1/C-2/C-3), 126.85
(C-1/C-2/C-3), 127.51 (C-1/C-2/C-3), 127.59 (C-1/C-2/C-3),
128.60 (C-1/C-2/C-3), 128.70 (C-1/C-2/C-3), 136.09 (C-14),
142.25 (C-4), 142.34 (C-4), 149.25 (C-12), 157.30 (C-11), 169.14
(C-7), 169.19 (C-7). IR (KBr) [m/cm−1]: 3062 (w), 3026 (w),
2945 (w), 2889 (w), 1657 (vs), 1241 (w), 1176 (m), 1096 (s),
972 (s), 921 (w), 764 (s), 701 (m). MS (FAB+): C26H25N3O2
m/z (%) = 412 (100.0) [M+ + H]. HRMS (FAB+): 412.2041
(C26H26N3O2 requires 412.2024). Calc. for C26H25N3O2·0.3CHCl3:
2,2-Bis((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-1-(quinolin-2-yl)-
propan-1-one (2b). This compound was prepared as a white solid
from 2,2-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)-ethane (0.32 g,
1.0 mmol), tert-BuLi in n-hexane (1.5 M, 0.8 mL, 1.1 mmol) and
quinoline-2-carbonyl chloride (0.29 g, 1.5 mmol) in THF (50 mL)
using the same procedure reported for 1a: yield 0.40 g (84%). 1H
NMR (400 MHz, CDCl3): d = 2.33 (s, 3H, H-9), 4.13–4.24 (m, 2H,
H-6), 4.56–4.80 (m, 2H, H-6ꢀ), 5.26–5.35 (m, 2H, H5), 7.20–7.33
C
74.95,
H 6.05, N 10.07. Found: C 74.73, H 6.05,
N 10.00%.
(m, 10H, H-1, H-2, H-3), 7.56–7.65 (m, 1H, H-15), 7.77 (m, 1H,
3
H-14), 7.88 (m, 1H, H-16), 8.10 (m, 1H, H-13), 8.20 (d, JHH
=
3
1
13
8.5 Hz, 1H, H-19), 8.29 (d, JHH = 8.5 Hz, 1H, H-18). { H} C
NMR (100 MHz, CDCl3): d = 21.91 (C-9), 54.02 (C-8), 69.52
(C-5), 69.55 (C-5), 75.51 (C-6), 75.70 (C-6), 119.61 (C-19), 126.84
(C-1/C-2/C-3/C-15/C-16), 127.37 (C-1/C-2/C-3/C-15/C-16),
127.71 (C-1/C-2/C-3/C-15/C-16), 128.51 (C-1/C-2/C-3/C-
15/C-16), 128.73 (C-1/C-2/C-3/C-15/C-16), 129.41 (C-17),
130.03 (C-14), 130.39 (C-13), 137.00 (C-18), 142.17 (C-4), 142.23
(C-4), 146.49 (C-12), 151.05 (C-11), 166.82 (C-7), 194.46 (C-10).
IR (KBr) [m/cm−1]: 3058 (m), 3002 (w), 2933 (w), 1716 (m),
1664 (vs), 1564 (m), 1352 (w), 1307 (w), 1129 (m), 1083 (w), 981
(m), 930 (m), 845 (w). MS (FAB+): C30H25N3O3 m/z (%) = 476
(100.0) [M+ + H], 498 (3.0) [M+ + Na]. HRMS (FAB+): 476.1950
(C30H26N3O3 requires 476.1974). Calc. for C26H26N3O3·0.3CHCl3:
C 71.17, H 4.99, N 8.22. Found: C 71.40, H 5.17, N 8.26%.
N-Phenyl-2,2-bis[(4S)-4-isopropyl-1,3-oxazolin-2-yl]propiona-
mide (4). This compound was prepared as a colourless oil from
2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-ethane (0.16 g,
0.63 mmol), tert-BuLi in n-hexane (1.7 M, 0.4 mL, 0.68 mmol)
and phenyl isocyanate (0.76 mL, 0.70 mmol) in THF (50 mL)
using the same procedure reported for 3b. Purification by flash
chromatography (EtOAc–CH2Cl2, 20 : 80) gave the desired
product 4 (0.15 g, 64% yield) as a colourless oil. 1H NMR
(300 MHz, CDCl3): d = 1.01–0.91 (m, 12H, H-1), 1.83 (sept,
3JHH = 6.8 Hz, 2H, H-3), 1.88 (1, 3H, H-6), 4.05 (m, 2H, H-3),
3
4.30 (m, 4H, H-4, H4ꢀ), 7.10 (t, JHH = 7.4 Hz, 1H, H-13), 7.31
3
(m, 2H, H-12), 7.60 (d, JHH = 8.6 Hz, 2H, H-11), 11.85 (s, 1H,
1
13
9-H). { H} C NMR (75.5 MHz, CDCl3) d = 18.1 (C-1), 18.6
(C-1), 22.4 (C-6), 32.5 (C-2), 49.8 (C-7), 70.7 (C-4), 71.9 (C-3),
120.0 (C-13), 129 (C-11/C-12), 129.4 (C-11/C-12), 138.2 (C-10),
165.4 (C-5), 166.0 (C-8). MS (EI): C21H29N3O3 m/z (%) 371.4
[M]+ (0.1), 252.3 [M − PhCONH]+ (10), 209.3 [M − (PhCONH +
CH(CH3)2)]+ (100). Calcd. for C21H29N3O3: C, 67.8; H, 7.9; N,
11.3. Found: C, 67.3; H, 7.9; N, 11.2%.
2-(2,2-Bis((R)-4-phenyl-4,5-dihydrooxazol-2-yl)propyl)pyridine
(3b). A solution of 1.5 M tert-BuLi in n-hexane (1.2 mL,
1.7 mmol) was added dropwise to a solution of 2-bis((R)-4-
phenyl-4,5-dihydrooxazol-2-yl)-ethane (0.50 g, 1.6 mmol) in THF
(45 mL) with stirring at −78 ◦C. The mixture was allowed to
warm to −50 ◦C and stirred for 1 h. This solution was then
cooled to −78 ◦C and a solution of 2-(chloromethyl)-pyridine
(0.60 g, 4.7 mmol) in THF (5 mL) was slowly added with stirring.
◦
The reaction mixture was maintained at −78 C for 1 h, slowly
warmed to room temperature and then heated to reflux overnight.
An aqueous solution of NH4Cl (50 mL, 10%) was added, and
after removal of the organic phase the residue was extracted
N -(3,3-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)butyl)-4-
methylbenzolsulfonamide (5). This compound was prepared as
This journal is
The Royal Society of Chemistry 2006
Dalton Trans., 2006, 193–202 | 1 9 9
©

View Article Online
a white solid from 2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-
2-yl)-ethane (1.10 g, 4.4 mmol), tert-BuLi in n-hexane (1.5 M,
3.2 mL, 4.8 mmol) and tosylaziridine (0.65 g, 3.3 mmol) in THF
(50 mL) using the same procedure reported for 3b: yield 0.49 g
(25%). 1H NMR (400 MHz, CDCl3): d = 0.87–0.89 (m, 6H, H-1),
0.93–0.96 (m, 6H, H-1), 1.44 (s, 3H, H-6), 1.71–1.81 (m, 2H,
H-2), 2.05–2.09 (m, 2H, H-8), 2.45 (s, 3H, H-15), 3.07–3.11 (m,
2H, H-9), 3.91–3.99 (m, 4H, H-3, H-4ꢀ), 4.19–4.25 (m, 2H, H-4),
2-(2,2-Bis((S)-4,5-dihydro-4-isopropyloxazol-2-yl)-3-(pyridin-2-
yl)propyl)pyridine (8a). This compound was prepared as a white
solid from bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-methane
(0.6 g, 2.5 mmol), NaH (0.30 g, 12.5 mmol) and 2-(chlormethyl)-
pyridine (1.9 g, 15 mmol) in THF (50 mL) using the same
3
7.20–7.22 (m, 1H, H-10), 7.32 (d, JHH = 8.4 Hz, 2H, H-13),
3
1
13
7.76 (d, JHH = 8.3 Hz, 2H, H-12). { H} C NMR (100 MHz,
CDCl3): d = 17.85 (C-1), 17.91 (C-1), 18.56 (C-1), 18.60 (C-1),
21.47 (C-6), 22.42 (C-15), 32.26 (C-2), 32.42 (C-2), 36.45 (C-8),
39.25 (C-7), 42.29 (C-9), 70.07 (C-4), 70.40 (C-4), 71.53 (C-3),
71.63 (C-3), 127.09 (C-12), 129.46 (C-13), 137.39 (C-11), 142.77
(C-14), 167.91 (C-5), 168.00 (C-5). IR (KBr) [m/cm−1]: 3081
(m), 2959 (s), 2908 (m), 2866 (m), 1651 (vs), 1474 (m), 1326
(s), 1158 (vs), 1095 (s), 977 (m), 927 (w), 659 (s), 569 (s). MS
(FAB+): C23H35N3O4S m/z (%) = 450 (100.0) [M+ + H], 253
(13.2) [bisoxazolin+ + H]. [M+ + H]. HRMS (FAB+): 450.2437
(C23H37N3O4S requires 450.2427). Calc. for C23H36N3O4S: C
61.44, H 7.85, N 9.35, S 7.13. Found: C 61.16, H 8.12, N 9.51, S
7.09%.
1
procedure reported for 7: 0.73 g (69%). H NMR (200 MHz,
3
3
CDCl3): d = 0.78 (d, 6H, JHH = 6.8 Hz, H-1), 0.82 (d, JHH
=
2
6.8 Hz, 6H, H-1), 1.67 (m, 2H, H-2), 3.45 (d, JHH = 13.6 Hz,
2
2H, H-7), 3.58 (d, JHH = 13.6 Hz, 2H, H-7), 3.73–3.85 (m, 4H,
4-H), 4.06–4.26 (m, 2H, 3-H), 7.06–7.13 (m, 2H, H-11), 7.44–7.64
1
13
(m, 4H, H-10/H-12) 8.55–8.51 (m 2H, H-11). { H} C NMR
(50 MHz, CDCl3): d = 17.7 (C-1), 18.9 (C-1), 32.2 (C-2), 39.8
(C-7), 47.2 (C-6), 69.8 (C-4), 71.8 (C-3), 121.4 (C-10/C-12),
125.4 (C-10/C-12), 135.6 (C-11), 148.9 (C-9), 158.0 (C-8), 166.1
(C-5). MS (FAB+): C25H32N4O2 m/z (%) = 421 (100.0). Calc. for
C25H32N4O2: C 71.40, H 7.67, N 13.32. Found: C 71.12, H 7.58,
N 13.19%.
3-(2,2-Bis((S)-4,5-dihydro-4-isopropyloxazol-2-yl)-3-(pyridin-3-
yl)propyl)pyridine (8b). This compound was prepared as a pale
yellow solid from (4S)-bis-[(1-methylethyl)-4,5-dihydrooxazole]
(0.5 g, 2.1 mmol), NaH (0.25 g, 10.5 mmol) and 3-(chlormethyl)-
pyridine (1.6 g, 12.5 mmol) in THF (50 mL) using the same
procedure reported for 7: yield 0.30 g (34%). 1H NMR (200 MHz,
(S)-2-(2-((S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl)-1,3-di(naph-
thalen-2-yl)propan-2-yl)-4-isopropyl-4,5-dihydrooxazole (7).
A
solution of bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-methane
(0.6 g, 2.5 mmol), in 10 mL of THF was added dropwise to a
stirred suspension of NaH (0.30 g, 12.5 mmol) in THF (30 mL)
◦
at room temperature. The mixture was then cooled to 0 C and
3
3
CDCl3): d = 0.82 (d, JHH = 6.7 Hz, 6H, H-1), 0.89 (d, JHH
=
a solution of 2-(bromomethyl)naphthalene (3.3 g, 12.5 mmol)
in THF (10 mL) was slowly added with stirring. The reaction
mixture was slowly warmed to room temperature and then heated
to reflux overnight. An aqueous solution of NH4Cl (50 mL,
10%) was carefully added, and after removal of the organic
phase the residue was extracted with dichloromethane (3 ×
50 mL). The organic layer was washed with water and dried
over anhydrous Na2SO4. Removal of solvent gave a colourless oil
which was purified by flash chromatography (hexane–EtOAc, 90 :
2
6.7 Hz, 6H, H-1), 1.59 (m, 2H, H-2), 3.14 (d, JHH = 14.0 Hz,
2
2H, H-7), 3.39 (d, JHH = 14.0 Hz, 2H, H-7), 3.78–3.95 (m, 4H,
4-H), 4.09–4.22 (m, 2H, 3-H), 7.15–7.21 (m, 2H, H-11), 7.64–7.58
1
13
(m, 2H, H-12), 8.47–8.43 (m 4H, H-9/H-10).). { H} C NMR
(50 MHz, CDCl3): d = 18.1 (C-1), 18.7 (C-1), 32.6 (C-2), 37.9
(C-7), 48.1 (C-6), 70.2 (C-4), 72.0 (C-3), 122.8 (C-11), 132.3
(C-12), 137.8 (C-9/C-10), 148.2 (C-8), 151.4 (C-9/C-10), 165.2
(C-5). MS (EI): C25H32N4O2 m/z (%): 421.3 [M]+ (20), 328.2
[M − PyCH2]+ (100), 92.0 [CH2Py]+ (40). Calcd. for C25H32N4O2:
C, 71.40; H, 7.67; N, 13.32; Found C, 70.16; H, 7.78; N,
12.67%.
1
10) affording a colourless sticky solid. (0.72 g, 55%). H NMR
3
(200 MHz, CDCl3): d = 0.81 (d, J = 6.7 Hz, 6H, H-1), 0.92 (d,
2
3J = 6.7 Hz, 6H, H-1), 1.69 (m, 2H, H-2), 3.49 (d, J = 14 Hz,
2H, H-7), 3.67 (d, 2J = 14 Hz, 2H, H-7), 3.98–3.83 (m, 4H, H-4),
4.24–4.12 (m, 2H, H-3), 7.48–7.38 (m, 6H, Ar–H), 7.84–7.75 (m
8H, Ar–H). 13C NMR (50 MHz, CDCl3): d = 18.0 (C-3), 18.9
(C-3), 32.6 (C-2), 40.0 (C-7), 48.6 (C-6), 70.0 (C-4), 72.0 (C-3),
125.4 (Ar), 125.8 (Ar), 127.3 (Ar), 127.3 (Ar), 127.5 (Ar), 127.6
(Ar), 128.8 (Ar), 129.3 (Ar), 132.4 (Ar), 133.3 (Ar), 134.6 (Ar),
166.2 (C-5). MS (FAB+): C35H38N2O2 m/z (%) = 519.5 (100.0)
[M+ + H], 577.4 (50) [M − CH2Naph+]. HRMS (FAB+): 519.3008
(C35H39N2O2 requires 519.3011).
4-(2,2-Bis((S)-4,5-dihydro-4-isopropyloxazol-2-yl)-3-(pyridin-4-
yl)propyl)pyridine (8c). This compound was prepared as a
2 0 0 | Dalton Trans., 2006, 193–202
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
pale yellow oil from bis((S)-4-isopropyl-4,5-dihydrooxazol-2-
yl)-methane2 (0.4 g, 1.7 mmol), NaH (0.20 g, 8.3 mmol) and
4-(chlormethyl)-pyridine (1.3 g, 10.0 mmol) in THF (50 mL) using
the same procedure reported for 8a: yield 0.34 g (48%). 1H NMR
(200 MHz, CDCl3): d = 0.83 (d, 3 JHH = 6.7 Hz, 6H, 1-H), 0.90 (d, 3
JHH = 6.7 Hz, 6H, 1-H), 1.64 (m, 2H, 2-H), 3.20 (d, 2 JHH = 14 Hz,
2H, H-7), 3.40 (d, 2 JHH = 14 Hz, 2H, H-7), 3.94–3.79 (m, 4H, H-
4), 4.20–4.14 (m, 2H, H-3), 7.14 (d, 3 JHH = 6 Hz, 2H, H-9/H-10),
{N-(3,3-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)butyl)-4-
methylbenzolsulfonamide}copper(II) acetate (10). This com-
pound was prepared as blue crystals from ligand 5 (50 mg,
0.11 mmol) and copper(II) acetate monohydrate (50 mg,
0.22 mmol) using the same procedure reported for 9: yield 25 mg
(36%). IR (KBr) [m/cm−1]: 3106 (w), 2960 (m), 2872 (m), 1662 (s),
1595 (m), 1563 (m), 1400 (s), 1329 (m), 1158 (s), 1105 (s), 926 (w),
821 (m). MS (FAB): C27H41CuN3O8S m/z (%) = 571 (37.8) [M+ −
OAc], 512 (100.0) [M+ − 2 OAc]. Calcd. for C27H41CuN3O8S: C,
51.37; H, 6.55; N, 6.66, S 5.08; Found C, 51.19; H, 6.51; N, 6.48,
S 5.37%.
2
8.48 (d, JHH = 6 Hz, 2H, H-9/H-10). 13C NMR (50 MHz,
CDCl3): d = 18.0 (C-1), 18.7 (C-1), 32.6 (C-2), 37.5 (C-7), 47.2
(C-6), 70.2 (C-4), 72.1 (C-3), 125.5 (C-9), 145.6 (C-8), 149.5
(C-10), 165.1 (C-5). MS (FAB+): C25H32N4O2 m/z (%) = 421.5
(100.0) [M+ + H]. HRMS (FAB+): 421.2635 (requires 421.2604).
{2-(2,2-Bis((S)-4,5-dihydro-4-isopropyloxazol-2-yl)-3-(pyridin-
2-yl)propyl)pyridine}copper(II) acetate monohydrate (11). This
compound was prepared as blue crystals from ligand 8a
(50 mg, 0.12 mmol) and copper(II) acetate monohydrate (56 mg,
0.28 mmol) using the same procedure reported for 9: yield 14 mg
(20%). MS (FAB): C29H38CuN4O6 m/z (%) = 542 (19) [M+
−
OAc], 483 (100.0) [M+ − 2OAc]. Calcd. for C29H38CuN4O6: C,
57.84; H, 6.36; N, 9.30; Found C, 57.93; H, 6.55; N, 9.13%.
General procedure for the asymmetric allylic oxidation catalyzed
by Cu(II) complexes
{2-(2,2-Bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)propyl)pyri-
dine}copper(II) acetate monohydrate (9·H2O). To a stirred
solution of ligand 3a (50 mg, 0.14 mmol) in methanol (2 mL) a
solution of copper(II) acetate monohydrate (56 mg, 0.28 mmol) in
methanol (3 mL) was added. After 12 h the solvent was removed
in vacuo, the residue extracted with toluene (5 mL) and filtered
through a Celite pad. Layering of the resulting solution of 9
with n-hexane gave blue crystals: Yield 10 mg (14%). IR (KBr)
[m/cm−1]: 2963 (m), 2930 (w), 2873 (w), 1671 (s), 1589 (s), 1400
(m), 1333 (m), 1240 (m), 1104 (m), 1040 (w), 777 (w), 678 (w).
A solution of the suitable ligand (0.05 mmol) and Cu salt
(0.04 mmol) in distilled acetonitrile (3.0 mL) was stirred a rt
for 1 h to ensure the formation of the copper complex. The
solution was then cooled to the desired temperature and the
cyclohexene (5 mmol) was added. To the stirred mixture a solution
of peroxyester (0.85 mmol) in acetonitrile (2 mL) was added
dropwise. After the reaction was judged to be complete (TLC
disappearance of the peroxyester), which generally was the case
after 5–7 days, the solvent was removed in vacuo, and the residue
was dissolved in CH2Cl2 (20 mL), washed successively with an
aqueous KHCO3 solution (10%), brine, and water and dried
MS (FAB): C24H35CuN3O6·H2O m/z (%) = 465 (80.5) [M+
−
OAc], 406 (100.0) [M+ − 2OAc]. Calcd. for C24H35CuN3O6·H2O:
C, 53.08; H, 6.87; N, 7.74; Found C, 53.20; H, 6.81; N, 8.07%.
Table 3 X-Ray data for 5, 9·H2O, 10 and 11
5
9·H2O
10
11
Empirical formula
Formula weight
Crystal size/mm
Crystal system
Space group
C23H35N3O4S
449.60
0.30 × 0.25 × 0.13
Monoclinic
P21
6.5200(4)
19.3181(11)
9.6743(6)
90
106.0890(10
90
C24H37CuN3O7
543.11
C27H41CuN3O8S
631.22
0.25 × 0.25 × 0.10
Monoclinic
P21
9.3203(6)
10.7524(8)
16.0394(11)
90
104.198(2
90
C29H38CuN4O6
602.17
0.22 × 0.06 × 0.02
0.30 × 0.25 × 0.15
Orthorhombic
Orthorhombic
P212121
9.3854(12)
14.6399(18)
19.322(2)
90
90
90
2654.9(6)
P212121
9.1940(10)
16.122(2)
19.152(6)
90
90
90
2838.8(10)
4
1.409
0.819
˚
a/A
˚
b/A
˚
c/A
a/◦
b/◦
c /◦
3
˚
V/A
1170.79(12)
2
1.275
1558.30(19)
2
1.345
Z
4
Dc/Mg m−3
l/mm−1
1.359
0.869
0.172
0.817
T/K
100(2)
484
18426
6926 [0.035]
6926/1/302
1.042
R1 = 0.045, wR2 = 0.106
R1 = 0.060, wR2 = 0.116
0.69 and −0.36
100(2)
1148
29150
4693 [0.137]
4693/0/323
1.054
R1 = 0.074, wR2 = 0.191
R1 = 0.092, wR2 = 0.203
0.93 and −0.74
100(2)
666
13654
6927 [0.053]
6927/1/367
1.057
R1 = 0.053, wR2 = 0.129
R1 = 0.072, wR2 = 0.138
1.47 and −0.88
193(2)
1268
10824
4819 [0.061]
4819/0/367
1.095
R = 0.047, wR2 = 0.089
R = 0.069, wR2 = 0.108
0.38 and −0.48
F(000)
Refl. collected
Refl. indep. [Rint
Data/rest./par.
]
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
Largest residual peak and
hole/e A
−3
˚
This journal is
The Royal Society of Chemistry 2006
Dalton Trans., 2006, 193–202 | 2 0 1
©

View Article Online
over Na2SO4. Concentration and chromatography on a silica gel
column with a hexane–ethyl acetate mixture (50 : 1) afforded pure
allylic benzoate. The yields and ee’s are given in Tables 1 and 2. In
general, slightly higher yields were obtained upon increasing the
reaction times without loss of enantioselectivity
2 Selected examples: (a) D. A. Evans, D. Seidel, M. Rueping, H. W. Lam,
J. T. Shaw and C. W. Downey, J. Am. Chem. Soc., 2003, 125, 12692;
(b) D. A. Evans, K. A. Scheidt, J. N. Johnston and M. C. Willis, J. Am.
Chem. Soc., 2001, 123, 4480; (c) J. Cong-Dung Le and B. Pagenkopf,
Org. Lett., 2004, 6, 4097; (d) J. Thorhauge, M. Johannsen and K. A.
Jørgensen, Angew. Chem., Int. Ed., 1998, 37, 2404; (e) D. A. Evans and
J. M. Janey, Org. Lett., 2001, 3, 2125; (f) C. Christensen, K. Juhl and
K. A. Jørgensen, Chem. Commun., 2001, 2222; (g) D. A. Evans, J. S.
Johnson and E. J. Olhava, J. Am. Chem. Soc., 2000, 122, 1635; (h) F.
Glorius and A. Pfaltz, Org. Lett., 1999, 1, 141.
3 Reviews: (a) F. Fache, E. Schulz, M. Lorraine Tommasino and M.
Lemaire, Chem. Rev., 2000, 100, 2159; (b) A. K. Ghosh, P. Mathivanan
and J. Cappiello, Tetrahedron: Asymmetry, 1998, 9, 1; (c) H. A.
McManus and P. J. Guiry, Chem. Rev., 2004, 104, 4151.
4 (a) J. Zhou and Y. Tang, J. Am. Chem. Soc., 2002, 124, 9030; (b) J. Zhou,
M.-C. Ye, Z.-Z. Huang and Y. Tang, J. Org. Chem., 2004, 69, 1309; (c) J.
Zhou and Y. Tang, Chem. Commun., 2004, 432; (d) M.-C. Ye, B. Li, J.
Zhou, X.-L. Sun and Y. Tang, J. Org. Chem., 2005, 70, ASAP.
5 Y. Tang, M. C. Ye and J. Zhou, J. Comb. Chem., 2004, 6, 301.
6 (a) S. Bellemin-Laponnaz and L. H. Gade, Chem. Commun., 2002,
1286; (b) C. Dro, S. Bellemin-Laponnaz, R. Welter and L. H. Gade,
Angew. Chem., Int. Ed., 2004, 43, 4479; (c) B. D. Ward, S. Bellemin-
Laponnaz and L. H. Gade, Angew. Chem., Int. Ed., 2005, 44, 1668;
(d) C. Foltz, B. Stecker, G. Marconi, S. Bellemin-Laponnaz, H.
Wadepohl and L. H. Gade, Chem. Commun., 2005, 5115.
The enantiopurity of the products was determined by chiral
HPLC using the following conditions:
2-Cyclohexenyl-1-benzoate. AS–H column [hexane; flow rate
0.5 ml min−1; tr = 18.3 min (R), 19.3 min (S)].
2-Cyclohexenyl-1-nitrobenzoate. AD–H column [hexane–2-
propanol 99.5 : 0.5; flow rate 0.5 ml min−1; tr = 30.8 min (R),
34.9 min (S)].
Crystal structure determinations
Suitable crystals of the protioligand 5 and the complexes 9·H2O,
10 and 11 were obtained by layering concentrated solutions in
dichloromethane with pentane or diethyl ether and allowing slow
diffusion at room temperature. Intensity data were collected at
low temperature on a Bruker AXS Smart 1000 CCD (5, 9, 10)
and a Nonius Kappa CCD (11) diffractometer. A semi-empirical
absorption correction was applied. The structures were solved
with heavy atom and/or direct methods and refined by full
matrix least squares. Hydrogen atoms were input at calculated
positions and refined with the riding model, except the amide
hydrogens, which were taken from difference Fourier synthesis
and refined. In complex 10, the distance d(N4–H4) was restrained
7 M. S. Kharasch and G. Sosnovsky, J. Am. Chem. Soc., 1958, 80, 756.
8 (a) M. S. Kharasch and G. Sosnovsky, J. Am. Chem. Soc., 1959, 81,
5819; (b) A. L. Beckwith and A. A. Zavistas, J. Am. Chem. Soc., 1986,
108, 8230.
9 (a) A. S. Gokhale, A. B. E. Minindis and A. Pfaltz, Tetrahedron
Lett., 1995, 36, 1831; (b) M. B. Andrus, A. B. Agrade, X. Chen and
M. G. Pamment, Tetrahedron Lett., 1995, 36, 2945; (c) K. Kawasaki,
S. Tsumura and T. Katsuki, Synlett, 1995, 1245; (d) A. Levina and
J. Muzart, Tetrahedron: Asymmetry, 1995, 6, 147. For reviews, see:
(e) M. B. Andrus and J. C. Lashley, Tetrahedron, 2002, 58, 845 (f) J.
Eames and M. Watkinson, Angew. Chem., Int. Ed., 2001, 40, 3567.
10 S. E. Denmark and C. M. Stiff, J. Org. Chem., 2000, 98, 5875.
11 M. B. Andrus and Z. Zhou, J. Am. Chem. Soc., 2002, 124, 8806.
12 (a) J. Ratilainen, K. Airola, R. Fro¨hlich, M. Nieger and K. Rissanen,
Polyhedron, 1999, 18, 2265; (b) A. S. Antsyshkina, M. A. Porai-Koshits,
V. N. Ostrikova, M. Pilkington and H. Stoeckli-Evans, Eur. J. Inorg.
Chem., 2002, 1985; (c) C. P. Raptopoulou, S. Paschalidou, A. A.
Pantazaki, A. Terzis, S. P. Perlepes, T. Lialiaris, E. G. Bakalbassis,
J. Mrozinski and D. A. Kyriakidis, J. Inorg. Biochem., 1998, 71, 15;
(d) P. Molenveld, J. F. J. Engbersen, H. Kooijman, A. L. Spek and
D. N. Reinhoudt, J. Am. Chem. Soc., 1998, 120, 6726; (e) S. Youngme,
C. Pakawatchai, H.-K. Fun and K. Chinnakali, Acta Crystallogr.,
Sect. C: Cryst. Struct. Commun., 1998, 54, 1586; (f) B. Kozlevcar,
A. Murn, K. Podlipnik, N. Lah, I. Leban and P. Segedin, Croat.
Chem. Acta, 2004, 77, 613; (g) R. Grobelny, T. Glowiak, J. Mrozinski,
L. Brzozka, W. Baran and P. Tomasik, Pol. J. Chem., 1995, 69,
559; (h) M. B. Meder and L. H. Gade, Eur. J. Inorg. Chem., 2004,
2716.
˚
to 0.93(2) A. The positions of the hydrogen atoms of the water
of crystallization in 9·H2O were inferred by relatively short
intermolecular O · · · O vectors. The calculations were performed
using the programs DIRDIF,15 SHELXS-8616 and SHELXL-
97.17 Graphical representations were drawn with PLATON.18
Anisotropic displacement elipsoids are scaled to 40% probability.
Crystal and experimental data are given in Table 3.
CCDC reference numbers 283311–283314.
For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b512570g
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft for support
of this work, the Alexander-von-Humboldt Foundation for a
fellowship (C.C.) and Matthieu Eckert for experimental help.
Support by BASF (Ludwigshafen) and Degussa (Hanau) is
gratefully acknowledged.
13 S. Bellemin-Laponnaz and L. H. Gade, Angew. Chem., Int. Ed., 2002,
41, 3473.
14 M. Honma, T. Sawada, Y. Fujisawa, M. Utsugi, H. Watanabe, A.
Umino, T. Matsamura, T. Hagihara, M. Takano and M. Nakada, J. Am.
Chem. Soc., 2003, 125, 2860.
15 P. T. Beurskens, G. Beurskens, R. de Gelder, S. G. Granda, R. O. Gould,
R. Israel and J. M. M. Smits, DIRDIF-99, University of Nijmegen, The
Netherlands, 1999.
References
16 G. M. Sheldrick, SHELXS-86, University of Go¨ttingen, Germany,
1 (a) R. E. Lowenthal, A. Abiko and S. Masamune, Tetrahedron Lett.,
1990, 31, 6005; (b) D. A. Evans, K. A. Woerpel, M. M. Hinman and
M. M. Faul, J. Am. Chem. Soc., 1991, 113, 726; (c) E. J. Corey, N. Imai
and H. Y. Zhang, J. Am. Chem. Soc., 1991, 113, 728; (d) D. Mu¨ller, G.
Umbricht, B. Weber and A. Pfaltz, Helv. Chim. Acta, 1991, 74, 232.
1986.
17 G. M. Sheldrick, SHELXL-97, University of Go¨ttingen, Germany,
1997.
18 A. L. Spek, J. Appl. Crystallogr., 2003, 36, 7.
2 0 2 | Dalton Trans., 2006, 193–202
This journal is
The Royal Society of Chemistry 2006
©