The synthesis of new oxazoline-containing bifunctional catalysts and their application in the addition of diethylzinc to aldehydes

Article abstract of DOI:10.1039/b822580j

The straightforward preparation of new modular oxazoline-containing bifunctional catalysts is reported employing a microwave-assisted Buchwald-Hartwig aryl amination as the key step. Covalent attachment of 2-(o-aminophenyl)oxazolines and pyridine derivati

Full text of DOI:10.1039/b822580j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The synthesis of new oxazoline-containing bifunctional catalysts and their
application in the addition of diethylzinc to aldehydes†
Vincent Coeffard, Helge Mu¨ller-Bunz and Patrick J. Guiry*
Received 16th December 2008, Accepted 9th February 2009
First published as an Advance Article on the web 12th March 2009
DOI: 10.1039/b822580j
The straightforward preparation of new modular oxazoline-containing bifunctional catalysts is
reported employing a microwave-assisted Buchwald–Hartwig aryl amination as the key step. Covalent
attachment of 2-(o-aminophenyl)oxazolines and pyridine derivatives generated in good-to-high yields a
series of ligands in two or three steps in which each part was altered independently to tune the activity
and the selectivity of the corresponding catalysts. These catalysts prepared in situ were subsequently
applied in the asymmetric addition of diethylzinc to various aldehydes, producing the corresponding
alcohols with enantioselectivities of up to 68%. A transition state model, based on relevant X-ray
crystal structures, has also been proposed to explain the observed stereoselectivities.
1–2 and proline-oxazoline ligands 3 from the readily available
Introduction
2-(o-aminophenyl)oxazoline scaffold 4 (Scheme 1).2 The ligands
Chiral oxazoline-containing ligands have attracted considerable
1–3 were applied to the enantioselective Nozaki–Hiyama–Kishi
attention in asymmetric catalysis due to their ready accessibility,
(NHK) allylation, crotylation and methallylation of a series of
modular nature and applicability in a wide range of metal-
aromatic and aliphatic aldehydes, providing the products in both
catalysed transformations.1 The majority of these ligands are easily
synthesised in a few high-yielding steps from commercially avail-
able chiral amino alcohols. The wide variety of enantiomerically
pure amino alcohols allows for the preparation of highly modular
asymmetric building blocks in the design of powerful and selective
catalysts. Thus, we have recently reported the straightforward
high yields and high enantioselectivities.2b,2c,3
In connection with this work, we became interested in the design
and synthesis of new oxazoline-containing ligands derived from
4 for applications in asymmetric bifunctional catalysis. Over the
past decade, this concept based on the synergistic activation of
electrophiles and nucleophiles has found numerous applications
in asymmetric catalysis.4,5 In particular, complexes containing
both a Lewis-acidic centre and a Lewis-basic moiety have re-
cently emerged as highly active and selective catalysts. Thus far,
many kinds of chiral bifunctional catalysts have been developed;
however, very few examples of oxazoline-containing bifunctional
catalysts have been reported for this purpose.6 So, we envisioned
that a novel range of oxazoline-containing ligands could be
readily made by covalent attachment of the chiral oxazoline
framework 4 to pyridine derivatives using a palladium-catalysed
synthesis
of
tridendate
bis(oxazoline)-based
ligands
Centre for Synthesis and Chemical Biology, Conway Institute of Biomolec-
ular Research, School of Chemistry and Chemical Biology, University
College Dublin, Belfield, Dublin 4, Ireland. E-mail: patrick.guiry@ucd.ie;
Fax: +353-1-7162501
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for compounds 4d, 5a–5e, 6–16 and ZnCl2·5e. CCDC reference
numbers 713716–713717. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b822580j
Scheme 1 The 2-(o-aminophenyl)oxazoline scaffold in previous ligand design.
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Scheme 2 Strategy for designing new bifunctional metal–ligand catalysts.
Buchwald–Hartwig amination (Scheme 2). Coordination of those
ligands to metals would produce metal–ligand complexes that
could have Lewis acid (metal)–Lewis base (pyridine) bifunctional
activity. Moreover, the vast variety of commercially available chiral
amino alcohol and pyridine derivatives should allow access to
highly modular bifunctional catalysts where each activation site
can be independently tuned by using the appropriate coupling
partners.
Herein we report the preparation of new modular bifunctional
catalysts and their application to an asymmetric benchmark
reaction, the addition of diethylzinc to aldehydes. A transition
state model, based on relevant X-ray crystal structures, is proposed
to explain the observed stereoselectivities.
in many cases over the last decade.9 Therefore, the Buchwald–
Hartwig reaction was carried out under microwave irradiation in
toluene using NaOt-Bu as the base, Pd2dba3 (5 mol% Pd) as the
palladium source and Xantphos (10 mol%) as the ligand (step
2). The bis(phosphine)-based Xantphos or BINAP ligands are
efficient ligands for amination reactions of halogenopyridines due
to their ability to prevent the formation of pyridine–palladium
complexes.10 After 1 h of reaction at 175 ◦C under microwave
heating, the ligands 5a–e were obtained in good yields (60–83%)
from amines 4a–e and 2-bromopyridine as coupling partners. It
has to be noted that this cross-coupling requires a one-hour reac-
tion time in order to ensure maximum conversions and to avoid
complex purifications of ligands 5a–e from the corresponding
amines 4a–e. At this stage, we were pleased to get crystals suitable
for X-ray analysis after slow evaporation at room temperature of
a saturated solution of 5e in a mixture of pentane/EtOAc (9/1).
From the crystallographic structure based on the distance of H1
and N1, we can assume hydrogen bonding takes place between
these two atoms (Fig. 1). This also implies that the geometry of
this ligand will allow the possible chelation of a metal between the
two nitrogens, N1 and N2, to form a six-membered ring.
Since the pioneering work of Oguni in 1984,11 there has been
extensive research into the diethylzinc addition to benzaldehyde,
and it is now regarded as one of the benchmark reactions for
understanding the catalytic potential of new ligands.12 However,
the ligand-specific nature of catalytic reactions ensures that
the search for new catalytic systems still attracts considerable
attention in asymmetric synthetic chemistry.13 In order to probe
the bifunctional activity of catalysts derived from ligands 5a–e,
the addition of Et2Zn to benzaldehyde was chosen as a model
reaction. The active bifunctional catalyst was formed in situ by
mixing the ligands 5a–e with 2.2 equivalents of Et2Zn for 30 min
at room temperature. Then, benzaldehyde was added dropwise at
-20 ◦C to the solution of bifunctional catalyst in toluene and the
Results and discussion
Our initial investigation concentrated on the study of the ef-
fect of the Lewis-acidic centre in the bifunctional activity of
the catalyst. For this purpose, we embarked upon the syn-
thesis of various ligands 5a–e composed of an oxazoline ring
linked by an N-phenylaniline unit to an unsubstituted pyri-
dine (Scheme 3). The synthesis started with the preparation of
2-(o-aminophenyl)oxazolines 4a–e from the commercially avail-
able 2-aminobenzonitrile by reaction with the appropriate chiral
amino alcohol in the presence of ZnCl2 (step 1).2b,2c,7 This is a
shorter and higher-yielding synthesis of 4a–e than our previous
approach based on the ring-opening of isatoic anhydride followed
by DAST-promoted cyclisation.2a
With the compounds 4a–e in hand, we envisaged the preparation
of ligands 5 through a C–N bond formation using a Buchwald–
Hartwig aryl amination (step 2).8 Conventionally, this reaction
requires high temperatures and long reaction times. Neverthe-
less, the use of microwave heating in palladium-catalysed aryl
amination has provided shorter reaction times and higher yields
Scheme 3 Preparation of pyridine-derived oxazoline ligands 5.
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Table 1 Asymmetric addition of diethylzinc to benzaldehyde using
ligands 5a–ea
Entry
Ligand
Yield (%)b
ee (%) (conf.)c
1
2
3
4
5
5a
5b
5c
5d
5e
81
88
78
79
89
11 (R)
6 (R)
28 (R)
27 (R)
58 (R)
a See experimental section. b After column chromatography. c The ee was
determined by HPLC using a Daicel Chiracel OD column. The absolute
configuration of the alcohol was assigned by comparison of the sign of the
specific rotation to the literature value (see experimental section).
Fig. 1 Crystal structure of ligand 5e, thermal ellipsoids are drawn on the
15% probability level.
been investigated: the influence of steric effects (ortho-pyridine
substitution) and the influence of electronic effects (ortho- and
para-pyridine substitutions). On the basis of the good results
obtained with the zinc complex of 5e (R = t-Bu), we synthesized
a set of new pyridine-derived ligands starting from 4e and
2-halogenopyridines (Table 2).
Using the optimized conditions described above for the
palladium-catalysed aryl amination under microwave heating, the
pyridine-substituted ligands 6–11 were synthesized in moderate-
to-excellent yields (59–92%) whatever the nature of substitution
(R1 and R2) and the leaving group (X = Cl or Br) of the pyridine
ring. It is worthwhile noting the reaction conducted on 4e with 2,6-
dibromopyridine as starting material afforded the desired ligand
11 in 59% yield along with bis(oxazoline)-disubstituted pyridine
12 (11/12, 70/30 on the basis of 1H NMR spectroscopy recorded
on the crude material, entry 6). The formation of this com-
pound prompted us to investigate the synthesis of bis(oxazoline)-
containing ligands 12–15 for application to asymmetric addition
of diethylzinc to aldehydes. Complexation of these ligands with
mixture was stirred for 24 hours. The results obtained are depicted
in Table 1.
Regardless of the ligands used for this reaction, 1-phenylpropan-
1-ol was obtained in good yields (78–89%) after 24 hours of
reaction. Whereas the use of 5a and 5b resulted in low enantiomeric
excess (11 and 6% respectively, entries 1 and 2), a significant
increase of the enantioselectivity was observed for the ligands
5c and 5d (28 and 27% respectively, entries 4 and 5). The more
hindered ligand 5e (R = t-Bu, entry 5) gave the best result by
producing the corresponding alcohol in 58% ee with a high yield
of 89%. Consequently, there is no influence of the oxazoline ring
substitution in terms of reactivity, however the R group does
influence the enantioselectivity by increasing the enantiomeric
excess when R is a bulky substituent.
Having studied the Lewis-acidic moiety, our interest then
focused on the influence of the pyridine substitution in order to
gain more insight about the effect of the Lewis-basic moiety in
the bifunctional activity of these catalysts. Two parameters have
Table 2 Preparation of pyridine-derived oxazoline-containing ligands 6–11a
Entry
Ligand
X
R1
R2
Yield (%)b
1
2
3
4
5
6c
6
7
Cl
Br
Br
Br
Br
Br
NO2
NMe2
H
H
H
H
H
Me
CF3
MeO
Br
62
66
92
71
71
59
8
9
10
11
H
a See experimental section. b After column chromatography. c In this case, the reaction time was decreased (30 min) as well as the temperature (160 ◦C) in
order to minimize the amount of disubstituted pyridine 12 (ratio 11/12, 70/30 determined in the crude by 1H NMR spectroscopy).
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Scheme 4 Preparation of ligands 12–15.
metals would produce a bifunctional catalyst possessing two chiral
Lewis-acidic centres and one pyridine moiety acting as a Lewis
base. These ligands have been synthesized under similar conditions
by two different procedures depending on the symmetry of the
bis(oxazoline)-containing ligands desired (Scheme 4).
The reaction between the amine 4e and 2,6-dibromopyridine
produced the C2-symmetric ligand 12 in 70% yield without any
trace of compound 11. The non-C2-symmetric ligands 13–15
were synthesized in good yields (69–80%) from the corresponding
amines 4a–c and the mono-oxazoline containing ligand 11 by
microwave-assisted cross-coupling. This set of new ligands 6–15
was then applied to the asymmetric addition of diethylzinc to
benzaldehyde using the conditions described in Table 1. The results
obtained in this study are summarized in Table 3.
son with the result obtained using 5e (table 1, entry 5) para-
substituent effects have negligible impact on the selectivity of
the catalysts. Concerning the ligands bearing an ortho-substituent
on the pyridine ring, a substantial loss of catalytic activity and
enantioselectivity was observed regardless of the stereoelectronic
nature of the substituents (entries 3–6). With bis(oxazolines)-
containing ligands 12–15, active catalysts were formed which
produced the desired alcohol in 56–81% yield (entries 7–10).
Nevertheless, low enantiomeric excesses were obtained with a
reversal of the configuration of 1-phenylpropan-1-ol (in this case,
the formation of the (S)-enantiomer was favored). Hence, the
presence of an ortho-substituent on the pyridine ring leads to much
less selective bifunctional catalysts while the para-substituent did
not influence the enantioselective outcome of the reaction. So,
the bifunctional catalyst derived from 5e turned out to be the
best ligand in this series in terms of selectivity and activity for this
reaction. To evaluate the scope of 5e in the asymmetric addition of
diethylzinc, a diverse range of aldehydes was then tested (Table 4).
Similar levels of conversion and enantiomeric excess to those
found with benzaldehyde as substrate were obtained for aromatic
aldehydes except in the case of pentafluorobenzaldehyde, which
gave both lower yield and enantioselectivity (entries 1–5). On
the other hand, the reaction with a,b-unsaturated aldehydes gave
exclusively the 1,2-addition compounds in good yields (81–94%)
but with low enantiomeric excesses (entries 6 and 7). Unlike
a,b-unsaturated aldehydes, 3-phenylpropanal provided the corre-
sponding alcohol in good yield with enantioselectivity comparable
to the results obtained with benzaldehyde (entry 8). Surprisingly,
the addition of diethylzinc to heptanal gave higher enantiomeric
excess (ee = 54%) compared to the addition to the hindered
cyclohexylcarboxaldehyde (ee = 32%, entries 9 and 10). So far,
only Soai and co-workers have reported such a phenomenon in
the addition of diethylzinc to these aldehydes.14
The use of ligands 6 and 7 bearing a para-substituent on
the pyridine ring afforded 1-phenylpropan-1-ol in 60–78% yields
with good enantioselectivities (entries 1 and 2). By compari-
Table 3 Asymmetric addition of diethylzinc to benzaldehyde using
ligands 6–15a
Entry
Ligand
Yield (%)b
ee (%) (conf.)c
1
2
3
4
5
6
7
8
9
6
7
60
78
29
11
24
22
66
65
56
81
57 (R)
53 (R)
12 (R)
Racemic
32 (R)
14 (R)
7 (S)
8
9
10
11
12
13
14
15
8 (S)
15 (S)
9 (S)
10
a See experimental section. b After column chromatography. c The ee was
determined by HPLC using a Daicel Chiracel OD column. The absolute
configuration of the alcohol was assigned by comparison of the sign of the
specific rotation to the literature value (see experimental section).
Finally, we wished to probe the mechanism by which the
addition of diethylzinc to aldehydes occurred using these
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Table 4 Asymmetric addition of diethylzinc to various aldehydes using
5e as liganda
in excellent yield (99%) as a yellow solid. Moreover, crystals
suitable for X-ray analysis were obtained by slow evaporation
at room temperature of a saturated solution of this complex in
dichloromethane layered by hexane.
This crystallographic structure, Fig. 2, pointed out a chelation
of the zinc by the nitrogen of the oxazoline core N1 and N2 as
expected (vide supra). Furthermore, it is interesting to note that
the chelation of the ZnCl2 to N2 induces a shift of the proton to
the pyridyl nitrogen (N3) which behaves as a proton acceptor.15
Entry
R
Yield (%)b
ee (%) (conf.)c
1
2
3
4
5
6
7
8
9
p-ClC6H4
p-MeOC6H4
C6F5
2-Naphthyl
1-Naphthyl
∫
PhC C
(E)-PhCH CH
PhCH2CH2
Cyclohexyl
Hexyl
54
87
34
90
76
81
94
71
70
65
55 (R)
57 (R)
26 (R)
57 (R)
68 (R)
13 (R)
6 (R)
55 (R)
32 (R)
54 (R)
=
10
a See experimental section. b After column chromatography. c The ee was
determined by HPLC using a Daicel Chiracel OD column or a Daicel
Chiracel IA column (see experimental section). The absolute configuration
of the alcohol was assigned by comparison of the sign of the specific
rotation to the literature value (see experimental section).
oxazoline-containing bifunctional catalysts. In view of the results
obtained, we were interested to know whether the nitrogen of the
pyridine displayed an influence on the bifunctional activity of the
catalyst. For this purpose, we synthesized ligand 16 (an analogue
of 5e), where the pyridine ring was replaced by a phenyl ring
(Scheme 5).
Fig. 2 Crystal structure of ZnCl2·5e complex. Thermal ellipsoids are
drawn on the 15% probability level.
Based on the above results and X-ray crystal structures, a
plausible transition state in catalytic addition of diethylzinc to
aldehydes is shown in Fig. 3.
Scheme 5 Preparation of ligand 16.
Under microwave heating, the cross-coupling reaction of
iodobenzene and 4e produced the desired ligand 16 in 92%
yield. This ligand was then applied to the asymmetric addition
of diethylzinc to benzaldehyde using the conditions depicted in
Table 1. Under these conditions using 5 mol% of 16 as catalyst,
1-phenylpropan-1-ol was obtained in only 15% yield with very low
enantioselectivity (ee = 5% (R)) compared to the results obtained
with 5e (yield = 89%, ee = 58% (R), Table 1, entry 5). The lack of
asymmetric induction and catalytic activity attained by 16 suggest
that the Lewis acid alone in the Lewis base–Lewis acid bifunctional
catalyst derived from 5e is not sufficient to promote the reaction
with high levels of enantioselection.
Having established the crucial role of the Lewis-basic moiety
in the reactivity and the selectivity of these ligands, we then
examined the structure of the zinc–ligand complex. For this
purpose, we embarked upon the preparation of the ZnCl2.5e
complex which should reflect the structure of the bifunctional
catalyst EtZn(II)·5e formed in situ during the addition of Et2Zn to
aldehydes. Complexation of 5e with ZnCl2 in acetonitrile at room
temperature under an atmosphere of nitrogen gave rise to a yellow
solution of the desired zinc complex. After removal of the solvent
and washing with diethyl ether, the ZnCl2.5e complex was isolated
Fig. 3 Proposed transition state for diethylzinc addition to aldehydes.
The diethylzinc reagent would act as a Brønsted base by
deprotonating the ligand 5e to afford the N,N-chelated EtZn(II)
center as a Lewis acid.16 The aldehyde would approach the chiral
Lewis-acidic center via the opposite face of the bulky t-Bu group
and would chelate to this Lewis acid through an anti geometry
in order to minimize the steric interactions between the t-Bu and
the R group of the aldehyde. The pyridyl nitrogen would act as
a Lewis base by coordinating the diethylzinc reagent leading to a
six-membered chelation with the aldehyde. Therefore, the Re-face
attack should be favored through this transition state to furnish the
corresponding (R)-configured alcohol. It can be noted that the loss
of reactivity using ortho-substituted pyridines as ligand (Table 3,
entries 3–6) may be explained by a deleterious interaction between
the ortho-substituent and the diethylzinc. This interaction would
lessen the ability of the nitrogen to chelate diethylzinc in order to
promote the addition reaction onto the aldehyde.
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stirred at 60 ◦C for 15 min, at which point a 1M solution of ZnCl2
in Et2O (2.2 mL, 2.2 mmol) was added slowly. The mixture was
stirred under reflux for 4 days. The solvent was then removed under
reduced pressure and the product was purified by flash column
chromatography on silica gel.
Conclusion
In summary, we have designed and synthesized a series of novel
modular bifunctional oxazoline-containing ligands employing a
microwave-assisted Buchwald–Hartwig aryl amination as the key-
step. The bifunctional Zn(II) catalyst, which are easily prepared
in situ from the corresponding ligands, have been applied to the
asymmetric addition of diethylzinc to various aldehydes with
enantioselectivities up to 68%. From these results and X-ray
crystal structures, the bifunctional activity of these catalysts
has been proven and a transition state has been suggested to
explain the stereoselectivities observed. In the future, the modular
construction of these ligands should allow access to a wide variety
of new bifunctional catalysts by changing the oxazoline moiety,
the metal-containing backbone or the heterocycles (in this case,
only pyridine derivatives have been studied). Further applications
of these ligands to asymmetric transformations are ongoing in
these laboratories and the results of this work will be reported in
due course.
2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 4a. Amine
4a was obtained as
a white solid (1.86 g, 71%) from
L-phenylglycinol (1.51 g, 11 mmol) after purification by flash
chromatography (pentane/EtOAc, 3/1). All the physical and
spectroscopic data were in complete agreement with the reported
ones.2a
2-[(4S)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 4b. Amine
4b was obtained as
a white solid (1.80 g, 65%) from
L-phenylalaninol (1.66 g, 11 mmol) after purification by flash
chromatography (pentane/EtOAc, 3/1). All the physical and
spectroscopic data were in complete agreement with the reported
ones.2a
2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
4c.
Amine 4c was obtained as white solid (1.62 g, 72%) from L-valinol
(1.13 g, 11 mmol) after purification by flash chromatography
(pentane/EtOAc, 3/1). All the physical and spectroscopic data
were in complete agreement with the reported ones.2a
Experimental
1H NMR (300, 400 and 500 MHz) and 13C (75, 100 and
125 MHz) spectra were recorded with Varian Oxford 300, 400
or 500 MHz spectrometers using tetramethylsilane as an internal
standard. Chemical shifts (d) are given in parts per million and
coupling constants are given as absolute values expressed in Hertz.
Elemental analysis was performed in the School of Chemistry
and Chemical Biology, University College of Dublin. Crystal
data was collected with a Bruker SMART APEX CCD area
detector diffractometer in the School of Chemistry and Chemical
Biology, University College of Dublin. Mass spectra were obtained
using a Micromass Quattro micro instrument using electrospray
ionization. Infrared spectra were recorded with a Perkin-Elmer
Infrared FT spectrometer. Optical rotation values were measured
at room temperature with a Perkin-Elmer 343 polarimeter.
Melting points were determined in open capillary tubes with a
Gallenkamp melting point apparatus and are uncorrected. Thin-
layer chromatography (TLC) was carried out on aluminium sheets
precoated with silica gel 60 F254 or on plastic sheets precoated
with aluminium oxide 60 F254, neutral (Merck). Column chro-
matography separations were performed using Merck Kieselgel
60 (0.040–0.060 mm) or using aluminium oxide 90, standardized.
All amination reactions were conducted in a CEM Discover
S-Class microwave reactor. HPLC analyses were performed with
LC 2010A machine equipped with a UV/Vis detector employing
a chiral OD column from Daicel Chemical Industries or with LC
Agilent 1200 series machine equipped with a UV/Vis detector
employing a chiral IA column from Daicel Chemical Industries.
Solvents were dried immediately before use by distillation from
standard drying agents. Anhydrous chlorobenzene was purchased
from Sigma-Aldrich and used without further purification.
2-{(4S)-4-[(1S)-1-methylpropyl]-4,5-dihydro-1,3-yoxazol-2-yl}-
aniline 4d. Amine 4d was obtained as a colourless oil (1.44 g,
60%) from L-isoleucinol (1.29 g, 11 mmol) after purification by
flash chromatography (pentane/EtOAc, 95/5). TLC: Rf= 0.32
20
(pentane/EtOAc, 9/1); [a]D +5.1 (c 0.33 in CHCl3); found: C,
71.45; H, 8.3; N, 12.6. C13H18N2O requires C, 71.5; H, 8.3; N,
12.8%; umax(neat)/cm-1 3460, 3286, 2962, 2875, 1637, 1595, 1491,
1452, 1364, 1259, 1048 and 749; dH (400 MHz; CDCl3; Me4Si) 0.88
(3H, d, J 6.7, CH3CHEt), 0.96 (3H, t, J 7.3, CH3CH2), 1.27–1.38
(1H, m, CH3CH2), 1.59–1.72 (2H, m, CH3CH2 and CH3CHEt),
4.02 (1H, t, J 7.8, CH2O), 4.18–4.27 (1H, m, CHN), 4.31 (1H, dd,
J 9.6 and 7.8, CH2O), 6.20 (2H, br s, NH2), 6.65 (1H, app t, J 8.0,
Ph-C(4)H), 6.70 (1H, app d, J 7.6, Ph-C(6)H), 7.20 (1H, ddd, J 8.0,
7.6 and 1.5, Ph-C(5)H), 7.68 (1H, dd, J 7.9 and 1.5, Ph-C(3)H); dC
(100 MHz; CDCl3; Me4Si) 11.4 (CH3CH2), 14.7 (CH3CHEt), 26.1
(CH3CH2), 39.5 (CH3CHEt), 68.7 (CH2O), 71.3 (CHN), 109.0
(Ph-C2), 115.6 (Ph-C(6)H), 116.0 (Ph-C(4)H), 129.6 (Ph-C(3)H),
131.9 (Ph-C(5)H), 148.6 (Ph-C1), 163.6 (N=CO); m/z (ESI) 219.2
(MH+).
2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 4e.
Amine 4e was obtained as a white solid (1.85 g, 77%) from
L-tert-leucinol (1.29 g, 11 mmol) after purification by flash
chromatography (pentane/EtOAc, 3/1). All the physical and
spectroscopic data were in complete agreement with the reported
ones.2a
2) General procedure for the microwave-assisted palladium-
catalysed aryl amination
An oven-dried microwave vial was charged with Pd2dba3 (15.7 mg,
0017 mmol, 5 mol% Pd), Xantphos (39.7 mg, 0.069 mmol,
10 mol%), 2-(o-aminophenyl)oxazoline (0.69 mmol) and NaOt-
Bu (99.0 mg, 1.03 mmol) (2-halogenopyridine derivatives that
were solids at room temperature were added as solids following
the addition of NaOt-Bu). Then, the vial was capped and it
1) General procedure for the synthesis of 2-(o-aminophenyl)-
oxazolines 4a–4e
Anthranilonitrile (1.29 g, 11 mmol), the required amino alcohol
(11.0 mmol) and anhydrous chlorobenzene were added to a
Schlenk tube under an atmosphere of nitrogen. The solution was
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was evacuated and backfilled with nitrogen. This procedure was
repeated three times. Toluene (2.7 mL) and the 2-halogenopyridine
derivative (or iodobenzene) were added through the septum. Next,
the punctured cap ◦was replaced with a new cap and the mixture
was heated at 175 C in a CEM Discover microwave apparatus.
The initial power supplied was 300W. Once the temperature was
reached (IR measurement), the power dropped and fluctuated to
maintain the temperature at the desired value. The total heating
time of the reaction was 1h. The reaction vials were cooled to room
temperature using propelled air flow and the mixture was filtered
over silica and rinsed well with 75 mL of solvent (pentane/EtOAc,
1/1). The filtrate was subsequently evaporated under reduced
pressure and the residue purified by column chromatography.
C(3)H), 115.3 (Pyr-C(5)H), 117.3 (Ph-C(6)H), 118.7 (Ph-C(4)H),
126.3 (2C, Ph-CH2), 128.4 (1C, Ph-CH2), 129.2 (2C, Ph-CH2),
129.3 (Ph-C(3)H), 132.3 (Ph-C(5)H), 136.9 (Pyr-C(4)H), 138.3
(CIV, Ph-CH2), 142.8 (Ph-C1), 147.4 (Pyr-C(6)H), 155.3 (Pyr-C2),
164.1 (N=CO); m/z (ESI) 330.2 (MH+).
N-{2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
pyridin-2-amine 5c. Ligand 5c was obtained as a white solid
(161 mg, 83%) from amine 4c (141 mg, 0.69 mmol) and
2-bromopyridine (198 mL, 327 mg, 2.07 mmol) after purification by
flash chromatography on silica gel (pentane/EtOAc, 90/10). Mp:
74–77 ◦C; TLC: Rf= 0.30 (pentane/EtOAc, 95/5); [a]D +10.5
20
(c 0.56 in CHCl3); found: C, 72.7; H, 6.85; N, 14.4. C17H19N3O
requires C, 72.6; H, 6.8; N, 14.9%; umax(KBr)/cm-1 3436, 3023,
2956, 1633, 1562, 1540, 1418, 1349, 1148, 1047 and 748; dH
(500 MHz; CDCl3; Me4Si) 1.01 (3H, d, J 6.7, (CH3)2CH), 1.09
(3H, d, J 6.7, (CH3)2CH), 1.83 (1H, octuplet, J 6.7, (CH3)2CH),
4.05 (1H, app t, J 8.1, CH2O), 4.16 (1H, ddd, J 9.4, 8.1 and 6.7,
CHN), 4.39 (1H, dd, J 9.4 and 8.3, CH2O), 6.77 (1H, dd, J 7.8
and 4.9, Pyr-C(5)H), 6.83 (1H, d, J 8.3, Pyr-C(3)H), 6.89 (1H,
app t, J 7.5, Ph-C(4)H), 7.44 (1H, app td, J 8.2 and 1.5, Ph-
C(5)H), 7.52 (1H, app td, J 8.0 and 1.9, Pyr-C(4)H), 7.84 (1H,
dd, J 7.9 and 1.5, Ph-C(3)H), 8.29 (1H, dd, J 4.9 and 1.4, Pyr-
C(6)H), 8.83 (1H, d, J 8.6, Ph-C(6)H), 11.77 (1H, br s, NH); dC
(125 MHz; CDCl3; Me4Si) 18.9 (2C, (CH3)2CH), 33.4 ((CH3)2CH),
69.2 (CH2O), 72.9 (CHN), 111.5 (Ph-C2), 112.6 (Pyr-C(3)H),
115.3 (Pyr-C(5)H), 117.4 (Ph-C(6)H), 118.6 (Ph-C(4)H), 129.4
(Ph-C(3)H), 132.2 (Ph-C(5)H), 137.1 (Pyr-C(4)H), 142.9 (Ph-C1),
147.6 (Pyr-C(6)H), 155.5 (Pyr-C2), 163.8 (N=CO); m/z (ESI)
282.2 (MH+).
N-{2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}pyri-
din-2-amine 5a. Ligand 5a was obtained as a white solid (131 mg,
60%) from amine 4a (164 mg, 0.69 mmol) and 2-bromopyridine
(198 mL, 327 mg, 2.07 mmol) after purification by flash chro-
matography. Two purifications using column chromatography
were required to yield pure compound 5a. The first one was carried
out on silica gel (pentane/EtOAc, 90/10) and the second one on
alumina (pentane/EtOAc, 96/4). Mp: 88–89 ◦C; TLC: Rf = 0.28
(pentane/CH2Cl2, 55/45); [a]D20 +236.2 (c 1.0 in CHCl3); found: C,
76.1; H, 5.6; N, 13.0. C20H17N3O requires C, 76.2; H, 5.4; N, 13.3%;
u
max(KBr)/cm-1 3275, 3189, 2899, 1627, 1593, 1534, 1479, 1449,
1345, 1151, 1065 and 751; dH (300 MHz; CDCl3; Me4Si) 4.09 (1H, t,
J 8.3, CHN), 4.67 (1H, dd, J 10.0 and 8.3, CH2O), 5.46 (1H, dd, J
10.0 and 8.3, CH2O), 6.67–6.73 (2H, m, Pyr-C(5)H + Pyr-C(3)H),
6.86 (1H, app t, J 7.8, Ph-C(4)H), 7.20–7.34 (5H, m, Ph-CHN),
7.35–7.45 (2H, m, Pyr-C(4)H + Ph-C(5)H), 7.83 (1H, dd, J 7.9 and
1.6, Ph-C(3)H), 8.17–8.23 (1H, m, Pyr-C(6)H), 8.68 (1H, d, J 8.5,
Ph-C(6)H), 11.54 (1H, br s, NH); dC (75 MHz; CDCl3; Me4Si)
70.0 (CHN), 73.2 (CH2O), 110.0 (Ph-C2), 112.8 (Pyr-C(3)H or
Pyr-C(5)H), 115.3 (Pyr-C(5)H or Pyr-C(3)H), 117.6 (Ph-C(6)H),
119.1 (Ph-C(4)H), 126.1 (2C, Ph-CHN), 127.6 (1C, Ph-CHN),
128.8 (2C, Ph-CHN), 129.7 (Ph-C(3)H), 132.5 (Ph-C(5)H), 137.3
(Pyr-C(4)H), 142.3 (CIV, Ph-CHN), 142.9 (Ph-C1), 147.4 (Pyr-
C(6)H), 155.2 (Pyr-C2), 165.2 (N=CO); m/z (ESI) 316.2 (MH+).
N-(2-{(4S)-4-[(1S)-1-methylpropyl]-4,5-dihydro-1,3-oxazol-2-
yl}phenyl)pyridin-2-amine 5d. Ligand 5d was obtained as a white
solid (163 mg, 80%) from amine 4d (151 mg, 0.69 mmol) and
2-bromopyridine (198 mL, 327 mg, 2.07 mmol) after purification by
flash chromatography on silica gel (pentane/EtOAc, 95/5). Mp:
◦
20
43–45 C; TLC: Rf= 0.37 (pentane/EtOAc, 90/10); [a]D +55.2
(c 0.5 in CHCl3); found: C, 73.15; H, 7.2; N, 14.15. C18H21N3O
requires C, 73.2; H, 7.2; N, 14.2%; umax(KBr)/cm-1 3285, 3021,
2962, 2929, 1632, 1594, 1480, 1450, 1347, 1150, 1062 and 751; dH
(400 MHz; CDCl3; Me4Si) 0.94 (3H, d, J 6.7, CH3CHEt), 0.99
(3H, t, J 7.2, CH3CH2), 1.23–1.39 (1H, m, CH3CH2), 1.62–1.78
(2H, m, CH3CH2 and CH3CHEt), 4.06 (1H, t, J 7.9, CH2O), 4.23–
4.32 (1H, m, CHN), 4.37 (1H, dd, J 9.6 and 7.9, CH2O), 6.75–6.80
(1H, m, Pyr-C(5)H), 6.82 (1H, d, J 8.3, Pyr-C(3)H), 6.90 (1H, app
t, J 7.5, Ph-C(4)H), 7.45 (1H, ddd, J 8.4, 7.4 and 1.6, Ph-C(5)H),
7.53 (1H, ddd, J 8.3, 7.5 and 1.9, Pyr-C(4)H), 7.84 (1H, app dd,
J 7.8 and 1.6, Ph-C(3)H), 8.28 (1H, m, Pyr-C(6)H), 8.77 (1H, d,
J 8.4, Ph-C(6)H), 11.73 (1H, br s, NH); dC (100 MHz; CDCl3;
Me4Si) 11.2 (CH3CH2), 15.0 (CH3CHEt), 25.9 (CH3CH2), 39.5
(CH3CHEt), 68.8 (CH2O), 71.5 (CHN), 111.5 (Ph-C2), 112.5(Pyr-
C(3)H), 115.3 (Pyr-C(5)H), 117.5 (Ph-C(6)H), 119.0 (Ph-C(4)H),
129.4 (Ph-C(3)H), 132.2 (Ph-C(5)H), 137.3 (Pyr-C(4)H), 142.7
(Ph-C1), 147.3 (Pyr-C(6)H), 155.3 (Pyr-C2), 163.6 (N=CO); m/z
(ESI) 296.3 (MH+).
N-{2-[(4S)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}pyri-
din-2-amine 5b. Ligand 5b was obtained as a viscous oil (139 mg,
61%) from amine 4b (174 mg, 0.69 mmol) and 2-bromopyridine
(198 mL, 327 mg, 2.07 mmol) after purification by flash chro-
matography. Two purifications using column chromatography
were required to yield pure compound 5b. The first one was
carried out on silica gel (pentane/EtOAc, 90/10) and the sec-
ond one on alumina (pentane/EtOAc, 96/4). TLC: Rf= 0.30
20
(pentane/CH2Cl2, 55/45); [a]D +23.7 (c 0.5 in CHCl3); found:
C, 76.1; H, 5.9; N, 12.5. C21H19N3O requires C, 76.5; H, 5.9; N,
12.8%; umax(neat)/cm-1 3288, 3086, 3026, 1630, 1594, 1536, 1480,
1450, 1347, 1152, 1061 and 751; dH (300 MHz; CDCl3; Me4Si) 2.78
(1H, dd, J 13.6 and 6.6, PhCH2), 2.89 (1H, dd, J 13.6 and 7.9,
PhCH2), 3.93 (1H, app t, J 8.0, CH2O), 4.25 (1H, app t, J 8.5,
CH2O), 4.54 (1H, app qd, J 8.0 and 6.6, CHN), 6.41 (1H, app d, J
8.4, Pyr-C(3)H), 6.64 (1H, app dd, J 7.1 and 5.1, Pyr-C(5)H), 6.78
(1H, app t, J 7.5, Ph-C(4)H), 7.10–7.26 (5H, m, Ph-CH2), 7.28–
7.40 (2H, m, Pyr-C(4)H + Ph-C(5)H), 7.72 (1H, dd, J 7.9 and 1.3,
Ph-C(3)H), 8.17 (1H, app d, J 4.9, Pyr-C(6)H), 8.72 (1H, d, J 8.4,
Ph-C(6)H), 11.50 (1H, br s, NH); dC (75 MHz; CDCl3; Me4Si) 42.2
(PhCH2), 67.9 (CHN), 70.5 (CH2O), 111.2 (Ph-C2), 112.8 (Pyr-
N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
pyridin-2-amine 5e. Ligand 5e was obtained as a white solid
(161 mg, 79%) from amine 4e (151 mg, 0.69 mmol) and
2-bromopyridine (198 mL, 327 mg, 2.07 mmol) after purification by
This journal is
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Org. Biomol. Chem., 2009, 7, 1723–1734 | 1729
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flash chromatography on silica gel (pentane/EtOAc, 95/5). Mp:
129–132 ◦C; TLC: Rf= 0.23 (pentane/EtOAc, 95/5); [a]D20 +30.2
(c 1.0 in CHCl3); found: C, 73.4; H, 7.2; N, 13.6. C18H21N3O
requires C, 73.2; H, 7.2; N, 14.2%; umax(KBr)/cm-1 3436, 3288,
3025, 2966, 1633, 1594, 1482, 1451, 1419, 1149, 1073 and 751; dH
(500 MHz; CDCl3; Me4Si) 0.95 (9H, s, (CH3)3C), 4.08–4.17 (2H,
m, CH2O + CHN), 4.23–4.31 (1H, m, CH2O), 6.74–6.77 (1H, m,
Pyr-C(5)H), 6.76 (1H, d, J 8.0, Pyr-C(3)H), 6.88 (1H, app t, J
8.0, Ph-C(4)H), 7.43 (1H, td, J 8.0 and 1.5, Ph-C(5)H), 7.50 (1H,
app td, J 8.0 and 1.6, Pyr-C(4)H), 7.83 (1H, dd, J 7.9 and 1.5, Ph-
C(3)H), 8.30 (1H, app dd, J 4.8 and 1.6, Pyr-C(6)H), 8.84 (1H, d, J
8.0, Ph-C(6)H), 11.81 (1H, br s, NH); dC (125 MHz; CDCl3; Me4Si)
25.9 (3C, (CH3)3C), 33.9 ((CH3)3C), 67.1 (CH2O), 76.2 (CHN),
104.4 (Ph-C2), 112.6 (Pyr-C(3)H), 115.3 (Pyr-C(5)H), 117.4 (Ph-
C(6)H), 118.7 (Ph-C(4)H), 129.3 (Ph-C(3)H), 132.3 (Ph-C(5)H),
137.1 (Pyr-C(4)H), 142.9 (Ph-C1), 147.6 (Pyr-C(6)H), 155.6 (Pyr-
C2), 163.8 (N=CO); m/z (ESI) 296.2 (MH+).
155.7 (Pyr-C4), 156.4 (Pyr-C2), 163.8 (N=CO); m/z (ESI) 339.3
(MH+).
N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
6-methylpyridin-2-amine 8. Ligand 8 was obtained as a white
solid (196 mg, 92%) from amine 4e (151 mg, 0.69 mmol) and
2-bromo-6-methylpyridine (236 mL, 357 mg, 2.07 mmol) after pu-
rification by flash chromatography on silica gel (pentane/EtOAc,
97/3). Mp: 49–51 ◦C; TLC: Rf= 0.32 (pentane/EtOAc, 97/3);
20
[a]D +22.7 (c 1.0 in CHCl3); found: C, 73.7; H, 7.4; N, 13.4.
C19H23N3O requires C, 73.8; H, 7.4; N, 13.6%; umax(KBr)/cm-1
3284, 3193, 2960, 1631, 1570, 1450, 1342, 1157, 1053, 783 and
752; dH (400 MHz; CDCl3; Me4Si) 0.99 (9H, s, (CH3)3C), 2.51
(3H, s, CH3-Pyr-C6), 4.10–4.22 (2H, m, CH2O + CHN), 4.24–
4.36 (1H, m, CH2O), 6.58–6.66 (1H, m, Pyr-C(3)H), 6.63 (1H,
d, J 7.4, Pyr-C(5)H), 6.88 (1H, app t, J 7.4, Ph-C(4)H), 7.38–
7.46 (2H, m, Ph-C(5)H and Pyr-C(4)H), 7.83 (1H, dd, J 7.8
and 1.9, Ph-C(3)H), 8.92 (1H, br s, Ph-C(6)H), 11.75 (1H, br s,
NH); dC (100 MHz; CDCl3; Me4Si) 25.9 (3C, (CH3)3C), 24.4
(CH3-Pyr-C6), 33.9 ((CH3)3C), 67.1 (CH2O), 76.2 (CHN), 109.2
(Pyr-C(3)H), 111.2 (Ph-C2), 114.3 (Pyr-C(5)H), 117.3 (Ph-C(6)H
or Ph-C(4)H), 118.6 (Ph-C(4)H or Ph-C(6)H),129.3 (Ph-C(3)H),
132.1 (Ph-C(5)H), 137.5 (Pyr-C(4)H), 143.1 (Ph-C1), 154.9 (Pyr-
C6), 156.5 (Pyr-C2), 163.7 (N=CO); m/z (ESI) 310.3 (MH+).
N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
4-nitropyridin-2-amine 6. Ligand 6 was obtained as a red solid
(143 mg, 62%) from amine 4e (151 mg, 0.69 mmol) and 2-chloro-
4-nitropyridine (328 mg, 2.07 mmol) after purification by flash
chromatography on silica gel (pentane/EtOAc, 96/4). Mp: 173–
175 ◦C; TLC: Rf= 0.36 (pentane/EtOAc, 96/4); [a]D20 +45.4 (c 1.0
in CHCl3); found: C, 63.4; H, 6.1; N, 16.2. C18H20N4O3 requires
C, 63.5; H, 5.9; N, 16.5%; umax(KBr)/cm-1 3448, 2962, 2868, 1639,
1523, 1483, 1454, 1352, 1057, 971, 753 and 745; dH (400 MHz;
CDCl3; Me4Si) 1.02 (9H, s, (CH3)3C), 4.17–4.27 (2H, m, CH2O +
CHN), 4.35 (1H, t, J 12.6, CH2O), 7.00 (1H, td, J 7.8 and 0.6,
Ph-C(4)H), 7.41 (1H, dd, J 5.5 and 1.7, Pyr-C(5)H), 7.45–7.52
(2H, m, Pyr-C(3)H + Ph-C(5)H), 7.88 (1H, dd, J 7.8 and 1.4,
Ph-C(3)H), 8.48 (1H, d, J 5.5, Pyr-C(6)H), 8.82 (1H, br d, J 8.5,
Ph-C(6)H), 12.43 (1H, br s, NH); dC (100 MHz; CDCl3; Me4Si)
25.9 (3C, (CH3)3C), 33.9 ((CH3)3C), 67.4 (CH2O), 76.0 (CHN),
105.2 (Pyr-C(3)H), 106.9 (Pyr-C(5)H), 112.3 (Ph-C2), 118.1 (Ph-
C(6)H), 120.4 (Ph-C(4)H), 129.5 (Ph-C(3)H), 132.3 (Ph-C(5)H),
141.7 (Ph-C1), 150.1 (Pyr-C(6)H), 154.9 (Pyr-C4), 156.9 (Pyr-C2),
163.9 (N=CO); m/z (ESI) 341.4 (MH+).
N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-6-
(trifluoromethyl)pyridin-2-amine 9. Ligand 9 was obtained as a
white solid (178 mg, 71%) from amine 4e (151 mg, 0.69 mmol)
and 2-bromo-6-trifluoromethylpyridine (468 mg, 2.07 mmol)
after careful purification by flash chromatography on silica gel
(pentane/EtOAc, 99/1). Mp: 59–62 ◦C; TLC: Rf= 0.10 (pen-
20
tane/EtOAc, 99/1); [a]D +24.1 (c 1.0 in CHCl3); found: C, 62.9;
H, 5.6; N, 11.4. C19H20F3N3O requires C, 62.8; H, 5.6; N, 11.6%;
u
max(KBr)/cm-1 3434, 3285, 2963, 2906, 1664, 1545, 1469, 1280,
1138, 804 and 753; dH (400 MHz; CDCl3; Me4Si) 0.99 (9H, s,
(CH3)3C), 4.18 (1H, dd, J 11.6 and 8.0, CHN), 4.19 (1H, dd, J
13.3 and 8.0, CH2O), 4.32 (1H, dd, J 13.3 and 11.6, CH2O), 6.89
(1H, d, J 8.4, Pyr-C(3)H), 6.96 (1H, td, J 8.3 and 1.1, Ph-C(4)H),
7.11 (1H, d, J 7.3, Pyr-C(5)H), 7.49 (1H, td, J 8.3 and 1.7, Ph-
C(5)H), 7.62 (1H, dd, J 8.4 and 7.3, Pyr-C(4)H), 7.88 (1H, dd, J
8.3 and 1.7, Ph-C(3)H), 8.98 (1H, dd, J 8.3 and 1.1, Ph-C(6)H),
12.26 (1H, br s, NH); dC (100 MHz; CDCl3; Me4Si) 25.9 (3C,
(CH3)3C), 33.9 ((CH3)3C), 67.2 (CH2O), 76.1 (CHN), 111.1 (q,
N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
4-dimethylaminopyridin-2-amine 7. Ligand 7 was obtained as a
brown solid (154 mg, 66%) from amine 4e (151 mg, 0.69 mmol)
and 2-bromo-4-dimethylaminopyridine17 (416 mg, 2.07 mmol)
after purification by flash chromatography on silica gel (pen-
tane/EtOAc, 65/35). Mp: 127–129 ◦C; TLC: Rf= 0.35 (pen-
tane/EtOAc, 65/35); [a]D20 +22.5 (c 1.0 in CHCl3); found: C, 70.7;
H, 7.7; N, 16.3. C20H26N4O requires C, 71.0; H, 7.7; N, 16.3%;
J3 3.1, Pyr-C(5)H), 111.7 (Ph-C2), 115.3 (Pyr-C(3)H), 118.0
C-F
(Ph-C(6)H), 119.7 (Ph-C(4)H), 121.7 (q, J1 274, CF3), 129.3
C-F
(Ph-C(3)H), 132.5 (Ph-C(5)H), 137.8 (Pyr-C(4)H), 142.1 (Ph-C1),
146.0 (q, J2 34, Pyr-C6), 155.4 (Pyr-C2), 164.0 (N=CO); m/z
C-F
(ESI) 364.2 (MH+).
u
max(KBr)/cm-1 3434, 3186, 2959, 1615, 1600, 1535, 1503, 1309,
1287, 1162, 1053, 810 and 752; dH (400 MHz; CDCl3; Me4Si)
0.99 (9H, s, (CH3)3C), 2.99 (6H, s, N(CH3)2), 4.10–4.34 (3H, m,
CH2O + CHN), 6.00 (1H, d, J 2.3, Pyr-C(3)H), 6.20 (1H, dd, J 6.1
and 2.3, Pyr-C(5)H), 6.83 (1H, app td, J 7.7 and 0.9, Ph-C(4)H),
7.40 (1H, ddd, J 8.5, 7.3 and 1.6, Ph-C(5)H), 7.80 (1H, dd, J 7.7
and 1.6, Ph-C(3)H), 8.00 (1H, d, J 6.1, Pyr-C(6)H), 8.74 (1H, app
d, J 8.5, Ph-C(6)H), 11.59 (1H, br s, NH); dC (100 MHz; CDCl3;
Me4Si) 25.9 (3C, (CH3)3C), 33.9 ((CH3)3C), 39.1 (2C, N(CH3)2),
67.0 (CH2O), 76.1 (CHN), 93.4 (Pyr-C(3)H), 101.6 (Pyr-C(5)H),
110.9 (Ph-C2), 117.4 (Ph-C(6)H), 118.0 (Ph-C(4)H), 129.2 (Ph-
C(3)H), 132.1 (Ph-C(5)H), 143.6 (Ph-C1), 147.6 (Pyr-C(6)H),
N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
6-methoxypyridin-2-amine 10. Ligand 10 was obtained as a white
powder (159 mg, 71%) from amine 4e (151 mg, 0.69 mmol) and
2-bromo-6-methoxypyridine(254 mL,389 mg,2.07 mmol)after pu-
rification by flash chromatography. Two careful purifications using
column chromatography were required to yield pure compound
10. The first one was carried out on silica gel (pentane/CH2Cl2,
85/15) and the second one on silica gel (pentane/EtOAc,
99/1). Mp: 60–63 ◦C; TLC: Rf= 0.10 (pentane/EtOAc, 99/1);
20
[a]D +14.8 (c 1.0 in CHCl3); found: C, 70.0; H, 7.05; N, 12.8.
C19H23N3O2 requires C, 70.1; H, 7.1; N, 12.9%; umax(KBr)/cm-1
1730 | Org. Biomol. Chem., 2009, 7, 1723–1734
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©

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3287, 3192, 2962, 2868, 1633, 1590, 1577, 1446, 1281, 1259, 1147,
1051, 786 and 750; dH (500 MHz; C6D6; 65 ◦C; Me4Si) 0.79 (9H, s,
(CH3)3C), 3.74–3.88 (3H, m, CH2O + CHN), 3.81 (3H, s, CH3O-
Pyr-C6), 6.26 (1H, d, J 7.8, Pyr-C(3)H or Pyr-C(5)H), 6.44 (1H,
d, J 7.8, Pyr-C(5)H or Pyr-C(3)H), 6.79 (1H, app td, J 7.5 and 1.0,
Ph-C(4)H), 7.11 (1H, t, J 7.8, Pyr-C(4)H), 7.29 (1H, ddd, J 8.7, 7.2
and 1.6, Ph-C(5)H), 8.05 (1H, dd, J 7.8 and 1.6, Ph-C(3)H), 8.93
(1H, app d, J 8.7, Ph-C(6)H), 12.06 (1H, br s, NH); dC (125 MHz;
C6D6; 65 ◦C; Me4Si) 25.5 (3C, (CH3)3C), 33.4 ((CH3)3C), 52.8
(CH3O-Pyr-C6), 66.6 (CH2O), 76.1 (CHN), 100.8 (Pyr-C(3)H
or Pyr-C(5)H), 102.9 (Pyr-C(5)H or Pyr-C(3)H), 111.7 (Ph-C2),
117.9 (Ph-C(6)H), 118.5 (Ph-C(4)H), 129.4 (Ph-C(3)H), 131.8
(Ph-C(5)H), 139.5 (Pyr-C(4)H), 143.5 (Ph-C1), 154.1 (Pyr-C2),
163.7 (Pyr-C6), 164.0 (N=CO); m/z (ESI) 326.4 (MH+).
C(5)H), 7.43 (1H, t, J 7.9, Pyr-C(4)H), 7.84 (2H, dd, J 7.8 and
1.7, Ph-C(3)H), 8.72 (2H, app d, J 8.7, Ph-C(6)H), 11.68 (2H, br s,
NH); dC (100 MHz; CDCl3; Me4Si) 25.9 (6C, (CH3)3C), 33.9 (2C,
(CH3)3C), 67.1 (2C, CH2O), 76.3 (2C, CHN), 103.0 (Pyr-C(3)H
and Pyr-C(5)H), 111.5 (2C, Ph-C2), 118.4 (2C, Ph-C(6)H), 118.6
(2C, Ph-C(4)H), 129.3 (2C, Ph-C(3)H), 131.8 (Pyr-C(4)H), 138.5
(2C, Ph-C(5)H), 142.9 (2C, Ph-C1), 153.9 (2C, Pyr-C2), 163.7 (2C,
N=CO); m/z (ESI) 512.2 (MH+).
N2 -{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
N6-(2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl)pyridine-
2,6-diamine 13. Ligand 13 was prepared from amine 4a (159 mg,
0.69 mmol), 6-bromopyridine 11 (217 mg, 0.58 mmol), NaOt-Bu
(66.3 mg, 0.69 mmol), Xantphos (33.6 mg, 0.058 mmol), Pd2dba3
(13.3 mg, 0.015 mmol, 5 mol% Pd) in 2.3 mL of toluene. The
mixture was heated at 165 ◦C for 1h in a microwave apparatus with
the initial power supplied being 300W. Compound 13 was obtained
as a white powder (213 mg, 69%) after purification by flash
chro◦matography on silica gel (pentane/CH2Cl2, 70/30). Mp: 138–
6-bromo-N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]-
phenyl}pyridin-2-amine 11. Ligand 11 was prepared from
amine 4e (151 mg, 0.69 mmol), 2,6-dibromopyridine (136 mg,
0.58 mmol), NaOt-Bu (66.3 mg, 0.69 mmol), Xantphos (33.6 mg,
0.058 mmol), Pd2dba3 (13.3 mg, 0.015 mmol, 5 mol% Pd) in
2.3 mL of toluene. The mixture was heated at 160 ◦C for
30 min in a microwave apparatus with an initial power supplied
being 300W. The compound 11 was obtained as a white powder
(128 mg, 59%) after purification by flash chromatography on silica
gel (pentane/CH2Cl2, 80/20). Mp: 68–71 ◦C; TLC: Rf = 0.26
20
140 C; TLC: Rf= 0.35 (pentane/CH2Cl2, 70/30); [a]D +185.1
(c 1.0 in CHCl3); found: C, 73.9; H, 6.5; N, 12.6. C33H33N5O2
requires C, 74.6; H, 6.3; N, 13.2%; umax(KBr)/cm-1 3398, 3267,
3030, 2918, 2849, 1629, 1567, 1436, 1268, 1155, 1064, 749 and
697; dH (400 MHz; CDCl3; Me4Si) 0.99 (9H, s, (CH3)3C), 4.12–
4.21 (3H, m, tBu-CHCH2O + tBu-CHN + Ph-CHCH2O), 4.26–
4.33 (1H, m, tBu-CHCH2O), 4.78 (1H, dd, J 10.0 and 8.5, Ph-
CHCH2O), 5.54 (1H, dd, J 9.0 and 8.5, Ph-CHN), 6.30 (1H, d, J
7.8, Pyr-C(5)H or Pyr-C(3)H), 6.36 (1H, d, J 7.8, Pyr-C(3)H or
Pyr-C(5)H), 6.86 (1H, app td, J 8.0 and 1.0, Ph-C(4)H), 6.91
(1H, app td, J 8.0 and 1.0, Ph-C(4)H), 7.27–7.45 (8H, m, 2 ¥
Ph-C(5)H + Pyr-C(4)H + Ph-CHN), 7.82 (1H, dd, J 7.9 and 1.6,
Ph-C(3)H), 7.91 (1H, dd, J 7.9 and 1.6, Ph-C(3)H), 8.68 (1H, app
d, J 7.8, Ph-C(6)H), 8.72 (1H, app d, J 7.8, Ph-C(6)H), 11.52 (1H,
br s, NH), 11.85 (1H, br s, NH); dC (100 MHz; CDCl3; Me4Si)
26.0 (3C, (CH3)3C), 33.9 ((CH3)3C), 67.1 (tBu-CHCH2O), 70.0
(Ph-CHN), 73.1 (Ph-CHCH2O), 76.1 (tBu-CHN), 103.2 + 103.3
(Pyr-C(3)H + (Pyr-C(5)H), 111.3 + 111.5 (2 ¥ Ph-C2), 118.3–
118.6 (4C, 2 ¥ Ph-C(6)H) + 2 ¥ (Ph-C(4)H)), 126.4 (2C, Ph-CHN),
127.5 (1C, Ph-CHN), 128.7 (2C, Ph-CHN), 129.2 + 129.5 (2 ¥ Ph-
C(3)H), 131.8 + 132.1 (2 ¥ Ph-C(5)H), 138.5 (Pyr-C(4)H), 142.3
(CIV, PhCHN), 142.9 + 143.1 (2 ¥ Ph-C1), 153.8 (2C, 2 ¥ Pyr-C2),
163.7 + 165.2 (2 ¥ N=CO); m/z (ESI) 532.4.2 (MH+).
20
(pentane/CH2Cl2, 80/20); [a]D +16.0 (c 1.0 in CHCl3); found:
C, 58.1; H, 5.4; N, 10.9. C18H20BrN3O requires C, 57.8; H, 5.4;
N, 11.2%; umax(KBr)/cm-1 3274, 3047, 2962, 2904, 1633, 1586,
1523, 1449, 1357, 1281, 1159, 1054, 777 and 752; dH (300 MHz;
CDCl3; Me4Si) 1.55 (9H, s, (CH3)3C), 4.12–4.22 (2H, m, CH2O +
CHN), 4.3 (1H, dd, J 13.1 and 11.7, CH2O), 6.66 (1H, d, J 8.1,
Pyr-C(3)H), 6.83–6.98 (2H, m, Pyr-C(5)H and Ph-C(4)H), 7.34
(1H, app t, J 7.8, Pyr-C(4)H), 7.48 (1H, app td, J 8.5 and 1.3, Ph-
C(5)H), 7.81 (1H, dd, J 7.8 and 1.3, Ph-C(3)H), 8.81 (1H, d, J 8.5,
Ph-C(6)H), 12.10 (1H, br s, NH); dC (75 MHz; CDCl3; Me4Si) 25.9
(3C, (CH3)3C), 34.1 ((CH3)3C), 67.2 (CH2O), 76.1 (CHN), 110.6
(Pyr-C(3)H), 111.6 (Ph-C2), 117.5 (Ph-C(6)H), 118.2 (Pyr-C(5)H
or Ph-C(4)H), 119.6 (Ph-C(4)H or Pyr-C(5)H), 129.3 (Ph-C(3)H),
132.4 (Ph-C(5)H), 139.0 (Pyr-C(4)H), 139.4 (Pyr-C6), 142.0 (Ph-
C1), 155.1 (Pyr-C2), 163.8 (N=CO); m/z (ESI) 374.1/376.1 in a
ratio 1/1 (MH+).
N2 -{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
N6 -(2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl)-
pyridine-2,6-diamine 12. Ligand 12 was prepared from amine 4e
(141 mg, 0.69 mmol), 2,6-dibromopyridine (68 mg, 0.29 mmol),
NaOt-Bu (66.3 mg, 0.69 mmol), Xantphos (16.8 mg, 0.029 mmol),
Pd2dba3 (6.6 mg, 0.007 mmol, 5 mol% Pd) in 1.1 mL of toluene.
The mixture was heated at 175 ◦C for 45 min in a microwave appa-
ratus with an initial power supplied being 300W. The compound
12 was obtained as a white powder (104 mg, 70%) after purification
by flash chromatography on silica gel (pentane/CH2Cl2, 55/45).
N2 -{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
N6-(2-[(4S)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl)pyridine-
2,6-diamine 14. Ligand 14 was prepared from amine 4b (174 mg,
0.69 mmol), 6-bromopyridine 11 (217 mg, 0.58 mmol), NaOt-Bu
(66.3 mg, 0.69 mmol), Xantphos (33.6 mg, 0.058 mmol), Pd2dba3
(13.3 mg, 0.015 mmol, 5 mol% Pd) in 2.3 mL of toluene. The
mixture was heated at 165 ◦C for 1h in a microwave apparatus
with the initial power supplied being 300W. Compound 14 was
obtained as a white powder (253 mg, 80%) after purification by
flash chromatography on silica gel (pentane/CH2Cl2, 80/20). Mp:
Mp: 140–142 ◦C; TLC: Rf= 0.37 (pentane/CH2Cl2, 55/45); [a]D
20
◦
20
-3.7 (c 1.0 in CHCl3); found: C, 72.4; H, 7.2; N, 13.4. C31H37N5O2
requires C, 72.8; H, 7.3; N, 13.7%; umax(KBr)/cm-1 3428, 3100,
2958, 2919, 1634, 1567, 1434, 1357, 1283, 1255, 1154, 1054 and
749; dH (400 MHz; CDCl3; Me4Si) 1.01 (18H, s, (CH3)3C), 4.14–
4.22 (4H, m, CH2O + CHN), 4.27–4.33 (2H, m, CH2O), 6.39
(2H, d, J 7.9, Pyr-C(5)H and Pyr-C(3)H), 6.89 (2H, app td, J
7.8 and 1.1, Ph-C(4)H), 7.39 (2H, ddd, J 8.7, 7.5 and 1.7, Ph-
84–86 C; TLC: Rf= 0.47 (pentane/CH2Cl2, 80/20); [a]D -7.2
(c 1.0 in CHCl3); found: C, 74.6; H, 6.7; N, 12.6. C34H35N5O2
requires C, 74.8; H, 6.5; N, 12.8%; umax(KBr)/cm-1 3189, 3099,
2963, 2902, 1634, 1567, 1436, 1358, 1279, 1256, 1155, 1056 and
750; dH (300 MHz; CDCl3; Me4Si) 1.00 (9H, s, (CH3)3C), 2.88 (1H,
dd, J 13.6 and 7.6, PhCH2), 3.04 (1H, dd, J 13.6 and 7.6, PhCH2),
4.01–4.04 (5H, m, tBu-CHCH2O + tBu-CHN + Bn-CHCH2O),
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4.67 (1H, quint, J 7.6, Bn-CH), 6.15 (1H, d, J 7.9, Pyr-C(5)H or
Pyr-C(3)H), 6.38 (1H, d, J 7.9, Pyr-C(3)H or Pyr-C(5)H), 6.87
(2H, app t, J 7.5, 2 ¥ Ph-C(4)H), 7.20–7.43 (8H, m, 2 ¥ Ph-
C(5)H + Pyr-C(4)H + PhCH2), 7.83 (2H, d, J 7.9, 2 ¥ Ph-C(3)H),
8.68 (1H, d, J 8.5, Ph-C(6)H), 8.73 (1H, d, J 8.5, Ph-C(6)H),
11.48 (1H, br s, NH), 11.65 (1H, br s, NH); dC (75 MHz; CDCl3;
Me4Si) 25.9 (3C, (CH3)3C), 33.9 ((CH3)3C), 42.4 (1C, PhCH2),
67.1 (tBu-CHCH2O), 68.1 (Bn-CHN), 70.5 (Bn-CHCH2O), 76.3
(tBu-CHN), 103.0 + 103.6 (Pyr-C(3)H + (Pyr-C(5)H), 111.3 +
111.5 (2 ¥ Ph-C2), 118.4–118.6 (4C, 2 ¥ Ph-C(6)H) + 2 ¥ Ph-
C(4)H)), 126.4 (1C, PhCHN), 128.6 (2C, PhCHN), 129.3 (4C,
PhCHN + 2 ¥ Ph-C(3)H), 131.7 + 131.9 (2 ¥ Ph-C(5)H), 138.4
(2C, Pyr-C(4)H + CIV PhCH2), 142.9 (2 ¥ Ph-C1), 153.8 + 153.9
(2C, 2 ¥ Pyr-C2), 163.7 + 164.2 (2 ¥ N=CO); m/z (ESI) 546.4
(MH+).
Ph-C(6)H), 7.78 (1H, dd, J 7.9 and 1.5, Ph-C(3)H), 10.67 (1H,
br s, NH); dC (100 MHz; CDCl3; Me4Si) 25.9 (3C, (CH3)3C), 33.9
((CH3)3C), 67.0 (CH2O), 76.3 (CHN), 110.4 (Ph-C2), 113.1 (Ph-
C(6)H), 116.9 (Ph-C(4)H), 121.2 (2C, 2 ¥ Ph-NH), 122.5 (Ph-NH),
129.2 (2C, 2 ¥ Ph-NH), 129.9 (Ph-C(3)H), 131.8 (Ph-C(5)H), 141.6
(Ph-C1), 145.6 (CIV, Ph-NH), 163.6 (N=CO); m/z (ESI) 219.2
(MH+); m/z (ESI) 295.3 (MH+).
3) General procedure for addition of diethylzinc to aldehydes
A solution of ligand (0.025 mmol) in toluene (0.5 mL) was cooled
to 0 ◦C. A 1.1M solution of diethylzinc in toluene (1 mL, 1.1 mmol)
was added over a period of 5 min. The yellow solution was stirred
at room temperature for 30 minutes, cooled at -20 ◦C and the
aldehyde was added (0.5 mmol) dropwise. Then the mixture was
stirred at -20 ◦C for 24 hours. The reaction mixture was quenched
with 10% H2SO4 aqueous solution (2 mL) and extracted with
diethyl ether. The organic layer was washed with 10% H2SO4
aqueous solution (3 mL), saturated aqueous NaHCO3 (5 mL)
solution and dried over MgSO4. The solvent was evaporated and
the residue was purified by flash chromatography.
N2 -{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
N6 -(2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl)pyri-
dine-2,6-diamine 15. Ligand 15 was prepared from amine 4c
(141 mg, 0.69 mmol), 6-bromopyridine 11 (217 mg, 0.58 mmol),
NaOt-Bu (66.3 mg, 0.69 mmol), Xantphos (33.6 mg, 0.058 mmol),
Pd2dba3 (13.3 mg, 0.015 mmol, 5 mol% Pd) in 2.3 mL of toluene.
The mixture was heated at 165 ◦C for 1h in a microwave apparatus
with the initial power supplied being 300W. Compound 15 was
obtained as a white powder (208 mg, 72%) after purification by
flash chromatography on silica gel (pentane/CH2Cl2, 70/30). Mp:
1-Phenylpropan-1-ol. The alcohol was obtained as a colourless
oil after purification by flash chromatography (pentane/EtOAc,
20
90/10). Yield : 89% (in the case of 5e as ligand). [a]D +19.8 (c
1.0 in CHCl3). {Lit.18 [a]D +40.3 (c 1.21 in CHCl3) for 96% ee
20
105–108 ◦C; TLC: Rf= 0.23 (pentane/CH2Cl2, 70/30); [a]D -9.1
20
(R)}. 58% ee (R, in the case of 5e as ligand) by HPLC analysis
(hexane/2-propanol, 98/2; 0.8 mL/min), tr = 13.2 min for (R)
and tr = 15.9 min for (S).
(c 1.0 in CHCl3); found: C, 72.1; H, 7.1; N, 13.7. C30H35N5O2
requires C, 72.4; H, 7.1; N, 13.7%; umax(KBr)/cm-1 3190, 3100,
2960, 2900, 1643, 1567, 1437, 1357, 1283, 1154, 1061, 784 and 749;
dH (400 MHz; CDCl3; Me4Si) 1.02 (9H, s, (CH3)3C), 1.12 (6H, d, J
6.7, (CH3)2CH), 1.83 (1H, octuplet, J 6.7, (CH3)2CH), 4.05 (1H,
t, J 8.1, iPr-CHCH2O), 4.14–4.23 (3H, m, tBu-CHCH2O + iPr-
CHN + tBu-CHN), 4.30–4.33 (1H, m, tBu-CHCH2O), 4.40 (1H,
dd, J 9.4 and 8.1, iPr-CHCH2O), 6.39 (2H, d, J 7.9, Pyr-C(5)H
and Pyr-C(3)H), 6.89 (2H, app td, J 8.0 and 1.0, 2 ¥ Ph-C(4)H),
7.39 (2H, ddd, J 8.7, 7.7 and 1.6, 2 ¥ Ph-C(5)H), 7.44 (1H, t, J 7.9,
Pyr-C(4)H), 7.85 (2H, dd, J 8.0 and 1.6, 2 ¥ Ph-C(3)H), 8.70–8.76
(2H, m, 2 ¥ Ph-C(6)H), 11.65 (1H, br s, NH), 11.68 (1H, br s, NH);
dC (100 MHz; CDCl3; Me4Si) 19.0 ((CH3)2CH), 19.5 ((CH3)2CH),
25.9 (3C, (CH3)3C), 33.5 ((CH3)2CH), 33.9 ((CH3)3C), 67.1 (tBu-
CHCH2O), 69.2 (iPr-CHCH2O), 73.0 (iPr-CHCH2O), 76.3 (tBu-
CHN), 103.0 + 103.1 (Pyr-C(3)H + Pyr-C(5)H), 111.5 + 111.6 (2 ¥
Ph-C2), 118.4–118.6 (4C, 2 ¥ Ph-C(6)H) + 2 ¥ (Ph-C(4)H)), 129.3
(2C, 2 ¥ Ph-C(3)H), 131.8 (2C, 2 ¥ Ph-C(5)H), 138.5 (Pyr-C(4)H),
142.9 + 143.0 (2 ¥ Ph-C1), 154.0 (2C, 2 ¥ Pyr-C(2)), 163.7 (2C, 2 ¥
N=CO); m/z (ESI) 498.5 (MH+).
1-(4-Chlorophenyl)propan-1-ol. The alcohol was obtained as
a colourless oil after purification by flash chromatography (pen-
20
tane/EtOAc, 90/10). Yield : 54%. [a]D +18.2 (c 2.4 in CHCl3).
{Lit.19 [a]D20 +27.3 (c 2.4 in CHCl3)}. 55% ee (R) by HPLC analysis
(hexane/2-propanol, 99/1; 1.0 mL/min) using an OD column, tr =
18.7 min for (S) and tr = 20.1 min for (R).
1-(4-Methoxyphenyl)propan-1-ol. The alcohol was obtained
as a colourless oil after purification by flash chromatography
20
(pentane/EtOAc, 90/10). Yield : 87%. [a]D +14.4 (c 1.25 in
CHCl3). {Lit.18 [a]D20 +38.9 (c 1.23 in CHCl3) for 96% ee (R)}. 57%
ee (R) by HPLC analysis (hexane/2-propanol, 95/5; 0.5 mL/min)
using an OD column, tr = 19.1 min for (R) and tr = 21.5 min for
(S).
1-Pentafluoropropan-1-ol. The alcohol was obtained as a
colourless oil after purification by flash chromatography (pen-
20
tane/EtOAc, 90/10). Yield : 34%. [a]D -1.4 (c 2.1 in pentane).
{Lit.20 [a]D +3.0 (c 2.01 in pentane) for 96% ee (S)}. 26% ee (R)
20
by HPLC analysis (heptane/EtOH, 99.5/0.5; 0.5 mL/min) using
2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]-N-phenylani-
line 16. Ligand 16 was obtained as a clear yellow oil (187 mg,
92%) from amine 4e (151 mg, 0.69 mmol) and iodobenzene
(220 mL, 422 mg, 2.07 mmol) after purification by flash chro-
matography on silica gel (pentane/Et2O, 98/2). TLC: Rf = 0.48
an IA column, tr = 40.1 min for (S) and tr = 41.6 min for (R).
1-(2-Naphthyl)propan-1-ol. The alcohol was obtained as a
colourless oil after purification by flash chromatography (pen-
20
tane/EtOAc, 85/15). Yield : 90%. [a]D +21.7 (c 1.2 in benzene).
20
(pentane/Et2O, 95/5); [a]D +47.3 (c 1.0 in CHCl3); found: C,
20
{Lit.21 [a]D +29.8 (c 4.7 in benzene) for 99% ee (R)}. 57% ee (R)
77.1; H, 7.5; N, 9.1. C19H22N2O requires C, 77.5; H, 7.5; N, 9.5%;
by HPLC analysis (hexane/2-propanol, 98/2; 1.0 mL/min) using
u
max(KBr)/cm-1 3172, 3029, 2960, 1634, 1593, 1457, 1325, 1287,
an OD column, tr = 26.7 min for (S) and tr = 29.8 min for (R).
1-(1-Naphthyl)propan-1-ol. The alcohol was obtained as a
1135, 1052 969, 747 and 697; dH (400 MHz; CDCl3; Me4Si) 0.95
(9H, s, (CH3)3C), 4.08–4.17 (2H, m, CHN + CH2O), 4.24–4.31
(1H, m, CH2O), 6.74 (1H, app t, J 8.0 and 1.0, Ph-C(4)H), 7.02
(1H, t, J 7.2, Ph-NH), 7.22–7.39 (6H, m, Ph-NH + Ph-C(5)H +
white solid after purification by flash chromatography (pen-
20
tane/EtOAc, 90/10). Yield : 76%. [a]D +43.8 (c 1.2 in CHCl3).
1732 | Org. Biomol. Chem., 2009, 7, 1723–1734
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{Lit.18 [a]D +60.3 (c 1.11 in CDCl3) for 97% ee (R)}. 68% ee
20
X-ray structure determination of 5e and ZnCl2.5e
(R) by HPLC analysis (hexane/2-propanol, 90/10; 1.0 mL/min)
using an OD column, tr = 5.3 min for (S) and tr = 8.5 min for (R).
Single-crystal structure of 5e. Crystals suitable for X-ray anal-
ysis were grown in pentane/EtOAc (9/1) solution at room temper-
1-Phenylpent-1-yn-3-ol. The alcohol was obtained as
a
ature. C18H21N3O, M = 295.38, orthorhombic, a = 6.1265(4), b =
3
˚
˚
colourless oil after purification by flash chromatography (pen-
13.8082(9), c = 19.2305(13) A, U = 1626.82(19) A , T = 293 K,
space group P212121 (no.19), Z = 4, 8732 reflections measured,
2067 unique (Rint = 0.0205) which were used in all calculations.
The final wR(F2) was 0.1009 (all data).
20
tane/EtOAc, 90/10). Yield : 81%. [a]D +7.5 (c 1.25 in Et2O).
20
{Lit.22 [a]D +21.97 (c 1.27 in Et2O) for 90% ee (R)}. 13% ee (R)
by HPLC analysis (hexane/2-propanol, 90/10; 1.0 mL/min) using
an OD column, tr = 5.9 min for (R) and tr = 12.0 min for (S).
(E)-1-Phenylpent-1-en-3-ol. The alcohol was obtained as a
Single-crystal structure of ZnCl2·5e. Crystals suitable for
X-ray analysis were grown in a solution of dichloromethane
layered by hexane at room temperature. C18H21N3OCl2 Zn, M =
colourless oil after purification by flash chromatography (pen-
20
tane/EtOAc, 90/10). Yield : 94%. [a]D +1.8 (c 1.0 in CHCl3).
431.65, orthorhombic, a = 10.4417(6), b = 11.1428(6), c =
{Lit.18 [a]D20 +18.4 (c 0.61 in CHCl3) for 75% ee (R)}. 6% ee (R) by
HPLC analysis (hexane/2-propanol, 90/10; 1.0 mL/min) using
an OD column, tr = 7.4 min for (R) and tr = 10.8 min for (S).
3
˚
˚
17.0180(9) A, U = 1980.04(19) A , T = 293 K, space group P212121
(no.19), Z = 4, 13618 reflections measured, 4783 unique (Rint
=
0.0194) which were used in all calculations. The final wR(F2) was
0.0759 (all data).
1-Phenylpentan-3-ol. The alcohol was obtained as a colourless
oil after purification by flash chromatography (pentane/EtOAc,
90/10). Yield : 71%. [a]D -12.2 (c 2.45 in CHCl3). {Lit.23 [a]D
20
20
Acknowledgements
-23.5 (c 2.45 in CHCl3) for 97% ee (R)}. 55% ee (R) by HPLC
analysis (hexane/2-propanol, 95/5; 1.0 mL/min) using an OD
column, tr = 8.8 min for (R) and tr = 12.3 min for (S).
1-Cyclohexypropan-1-ol. The alcohol was obtained as a
colourless oil after purification by flash chromatography (pen-
We thank Science Foundation Ireland for the award of a
Postdoctoral scholarship (054/RFP4/CHE/0075) to VC. We
acknowledge financial support from the Centre for Synthesis
and Chemical Biology (CSCB), which was funded by the Higher
Education Authority’s Programme for Research in Third-level
Institutions (PRTLI).
20
tane/EtOAc, 90/10). Yield : 70%. [a]D +1.8 (c 1.0 in CHCl3).
20
{Lit.18 [a]D +5.4 (c 0.61 in CHCl3) for 93% ee (R)}. 32% ee (R)
by HPLC analysis of the 3,5-dinitrobenzoate (hexane/2-propanol,
98/2; 1.0 mL/min) using an OD column, tr = 8.8 min for (S) and
tr = 12.3 min for (R).
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20
20
Preparation of the ZnCl2.complex 5e
To an oven-dried Schlenk tube was added ligand 5e (50 mg,
0.17 mmol) and dry acetonitrile (2.5 mL) under an atmosphere
of nitrogen. A 1M solution of ZnCl2 in Et2O (170 mL, 0.17 mmol)
was added and the solution was stirred at room temperature for
3 hours. The solvents were then removed under vacuum to leave
a solid residue. This solid was washed three times with Et2O and
dried under vacuum to leave a yellow solid (72 mg, 99%). Mp:
200–205 ◦C (decomposition); found: H, 4.5; N, 9.3. C18H21N3O
requires H, 4.9; N, 9.7%; dH (400 MHz; CDCl3; Me4Si) 1.07 (9H, s,
(CH3)3C), 4.33 (1H, dd, J 10.0 and 6.4, CHN), 4.49 (1H, dd, J
10.0 and 9.3, CH2O), 4.56 (1H, dd, J 9.3 and 6.4, CH2O), 6.41
(1H, t, J 6.4, Pyr-C(5)H), 6.90 (1H, d, J 9.4, Pyr-C(3)H), 7.17 (1H,
t, J 7.9, Ph-C(4)H), 7.34–7.53 (4H, m, Ph-C(5)H + Ph-C(6)H +
Pyr-C(4)H + Pyr-C(6)H), 7.74 (1H, d, J 7.9, Ph-C(3)H), 11.97
(1H, br s, NH); dC (100 MHz; CDCl3; Me4Si) 25.8 (3C, (CH3)3C),
34.5 ((CH3)3C), 70.0 (CH2O), 74.0 (CHN), 109.0 (Pyr-C(5)H),
113.4 (Pyr-C(3)H), 119.1 (Ph-C2), 124.1 (Ph-C(4)H), 124.9 (Ph-
C(6)H), 130.4 (Ph-C(3)H), 133.4 (Ph-C(5)H), 134.9 (Pyr-C(4)H
or Pyr-C(6)H), 141.2 (Pyr-C(6)H or Pyr-C(4)H), 146.4 (Ph-C1),
156.3 (Pyr-C2), 167.9 (N=CO).
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