Modular synthesis of chiral β-diketiminato-type ligands containing 2-oxazoline moiety via palladium-catalyzed amination

Article abstract of DOI:10.1055/s-0030-1260124

A family of new chiral β-diketiminato-type ligands containing oxazoline moiety has been synthesized in moderate to high yields (typically 30-95%) via a Pd-catalyzed amination reaction of chiral oxazolines with primary amines and amides. Notably, (S)-tert-

Full text of DOI:10.1055/s-0030-1260124

PAPER
2609
Modular Synthesis of Chiral b-Diketiminato-Type Ligands Containing
2-Oxazoline Moiety via Palladium-Catalyzed Amination
Pascal I. Binda, Srinivas Abbina, Guodong Du*
Department of Chemistry, University of North Dakota, 151 Cornell Street Stop 9024, Grand Forks, ND 58202, USA
Fax +1(701)7772331; E-mail: gdu@chem.und.edu
Received 15 April 2011; revised 17 May 2011
may offer opportunity for electronic differentiation and
stereocontrol upon coordination.10 Given their extensive
applications, it is somewhat surprising that the chiral vari-
ants of b-diketiminato ligands are relatively less devel-
Abstract: A family of new chiral b-diketiminato-type ligands con-
taining oxazoline moiety has been synthesized in moderate to high
yields (typically 30–95%) via a Pd-catalyzed amination reaction of
chiral oxazolines with primary amines and amides. Notably, (S)-
tert-butylsulfinamide was successfully incorporated into the ligand oped in the literature,11,12 although these moieties are
framework as a coupling partner in amination. Due to the readily
often incorporated as subcomponents of multidentate or
macrocyclic ligands in chiral environments.13 In principle,
available pool of chiral building blocks, this represents a facile and
modular approach for synthesizing libraries of novel chiral b-
stereo-directing groups can be introduced into all the R1–
diketiminato-type ligands, with potential applications in asymmet-
R5 substituents. Of particular interest are ligands with
ric catalysis.
chiral substituents at the periphery (R1 and R5) that are in
Key words: chiral auxiliaries, ligands, chirality, nitrogen, amina-
close proximity with the open coordination site where ca-
tion, palladium
talysis is taking place. Among these, monoanionic, chiral
semicorrin14 and bisoxazoline ligands15 are some of the
successful examples, where chiral substituents are intro-
Because the reactivity and selectivity of metal catalysts
duced at the periphery (R1 and R5) positions. Another ap-
are largely determined by the auxiliary ligands, ligand de-
proach is to incorporate axial chirality at the backbone, as
sign has been a central theme in catalysis, particularly in
demonstrated in ligands derived from isoquinoline and 2-
asymmetric synthesis, which continues to be of great aca-
aminonaphthalene16 and in binaphthyl surrogates based
demic and industrial importance.1 One of the challenges is
on inner N–H–N hydrogen bonding.17 Variation of back-
to derive efficient chiral catalysts for asymmetric induc-
bone with stereogenic heteroatoms can also lead to axial
tion in different substrates with subtle variations. Since it
chirality.18
is not expected that a single catalyst will work for a wide
range of substrates, an efficient strategy towards new cat-
A
B
R3
alysts would be the design of a search pathway that pro-
vides access to a large number of structurally similar
ligands with tunable yet diverse substituents.2 Indeed,
many researchers have sought to develop asymmetric cat-
alysts by screening a large pool of chiral ligands.3 To this
end, a modular approach for the ligand library construc-
tion is highly desirable.4
R2
R4
R5
R4
R5
NH
N
NH
N
R1
R1
Figure 1 A: b-Diketiminato ligands where R1–R5 substituents can
be stereogenic. B: Anilinido-imino variations.
b-Diketiminato ligands (Figure 1A) have received great
attention in coordination chemistry due to the ease of fine
tuning of the steric and electronic properties.5 These
ligands are monoanionic upon deprotonation and form
strong bonds with metals, usually in a bidentate fashion.
Various b-diketiminato metal complexes have been em-
ployed in a number of catalytic reactions.6,7 In a broader
sense, the monoanionic, anilinido-imino ligands
(Figure 1B) can be included as a variation of the regular
b-diketiminato framework.8 One example is the ortho-ox-
azoline-substituted anilines, in which aniline nitrogens are
typically not further functionalized.9 Due to the presence
of an aromatic ring, the resonance in the backbone is at-
tenuated in comparison with the regular ligands and this
In our effort of constructing a chiral ligand framework, we
have envisioned a modular approach for the synthesis of a
library of chiral b-diketiminato type ligands based on the
direct coupling of two independent building blocks. The
synthetic target (see Scheme 1) is a type of anilinido-imi-
no ligands, with imine nitrogen from a chiral oxazoline
moiety and amine nitrogen from an aniline/amide moiety.
For the modular assembly, a choice of readily available
chiral building blocks is critical. The 2-oxazoline was
chosen as the imine nitrogen subunit because chiral ox-
azolines have widespread use as ligands and are readily
accessible from the chiral pool of amino alcohols.19 The
ability of varying both chiral and stereo-directing centers
independently allows the opportunity to explore the syn-
ergy between them. Herein we report the synthesis and
characterization of a library of new chiral b-diketiminato
type ligands via the Pd-catalyzed Buchwald–Hartwig
amination reaction (Scheme 1).
SYNTHESIS 2011, No. 16, pp 2609–2618
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260124; Art ID: M40611SS
© Georg Thieme Verlag Stuttgart · New York

2610
P. I. Binda et al.
PAPER
Pd(OAc)2
rac-BINAP
O
O
+
R'NH2
base, heating
NHR'
N
Br
N
*
*
R
R
R = Ph, i-Pr, i-Bu, s-Bu
NH2
NH2
NH2
O
S
NH2
O
:
R'NH2
NH2
NH2
Scheme 1 Synthesis of chiral b-diketiminato type ligands
We started out to synthesize a series of b-diketiminato Thus, heating a mixture of chiral oxazolines 1a–d and (R)-
type ligands containing one or two chiral substituents at a-methylbenzylamine in the presence of catalytic amount
the periphery, which are in close proximity with the open of Pd(OAc)2-BINAP under refluxing toluene afforded
coordination site where catalysis would take place. By in- compounds L1–L4 in moderate yields after purification
dependently varying two points of diversity, the oxazoline by column chromatography (see Table 1, entries 1–4).
fragment R and the amine component (R¢), a library of Compounds L1 and L3 were obtained as yellow solids
chiral b-diketiminato type ligands L1–L24 has been gen- while L2 and L4 are oily.
erated in a modular fashion (Scheme 1).
Table 1 Pd-Catalyzed Amination Reactions of Chiral Oxazolines
Chiral 2-(2¢-bromophenyl)oxazolines 1a–d were prepared
from readily available chiral amino alcohols in a single
step via two methods (Scheme 2).20,21 In our hands, the
second method seems to give better yields in shorter reac-
tion time and offers another possibility to modify the aryl
backbone. The resulting compounds 1a–d were utilized as
the coupling partners for the preparation of chiral b-
diketiminato type ligand variants (see below).
1a–d with Primary Alkyl- or Arylamines and Amidesa
Entry
R
R¢NH2
Ligand Time (h) Yield (%)b
NH2
1
2
3
4
Ph
L1
L2
L3
L4
68
37
40
37
35c
47
56
44
i-Pr
i-Bu
s-Bu
5
6
7
8
Ph
L5
L6
L7
L8
24
24
67
67
50c
73
30
36
NH2
method A
i-Pr
i-Bu
s-Bu
CN
R
Br
ZnCl2 (5 mol%), PhCl
130 °C, 44 h
OH
+
H2N
*
R
9
10
11
12
Ph
L9
48
48
48
48
84
77
74
83
NH2
*
i-Pr
i-Bu
s-Bu
L10
L11
L12
O
N
R = (R)-Ph (1a), (S)-i-Pr (1b),
(R)-i-Bu (1c), (S)-s-Bu (1d)
Br
method B
CHO
13
14
15
16
Ph
L13
L14
L15
L16
48
48
48
48
80
84
75
63
NH2
i-Pr
i-Bu
s-Bu
1. molecular sieves, r.t.
R
*
1a–d
toluene, 24 h
Br
OH
+
H2N
2. NBS, K3PO4, 3 h
17
18
19
20
Ph
L17d
L18d
L19d
L20d
20
20
32
20
98
95
98
99
O
Scheme 2 Synthesis of chiral 2-oxazolines
i-Pr
i-Bu
s-Bu
NH2
The desired chiral b-diketiminato-type compounds L1–
L24 (Figure 1) were synthesized via a cross coupling
strategy, joining the chiral oxazoline and amine/amide
moieties in a modular fashion (Scheme 1). The Pd-cata-
lyzed Buchwald–Hartwig amination reaction was chosen
because it has been extensively studied and modified with
significant improvements for the cross coupling reaction
of aryl or alkyl halides with amines or amides.22,23 It has
been previously employed in the library synthesis, includ-
ing examples involving chiral oxazolines.24,25 In principle,
other cross coupling protocols such as Cu-catalyzed ami-
nation could be applied as well.
21
22
23
24
Ph
L21d
L22d
L23d
L24d
5 d
5 d
2 d
2 d
84
60
70
O
i-Pr
i-Bu
s-Bu
S
NH2
<10
a Reaction conditions: oxazoline 1a–d (1.0 equiv), amine (1.2 equiv),
t-BuONa (1.4 equiv), Pd(OAc)2 (5 mol%), rac-BINAP (5 mol%), tol-
uene, 120 °C.
b Isolated yields.
c Exists as a ~9:1 mixture of two stereoisomers.
d Reaction conditions: oxazoline 1a–d (1.0 equiv), benzamide or sul-
fonamide (4.0 equiv), Cs2CO3 (2 equiv), Pd(OAc)2 (10 mol%), rac-
BINAP (20 mol%), toluene, heating.
Synthesis 2011, No. 16, 2609–2618 © Thieme Stuttgart · New York

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Chiral b-Diketimine Ligands
2611
O
O
O
O
NH
N
NH
N
NH
N
NH
N
Ph
Ph
Ph
Ph
Ph
L1
L2
L3
L4
O
O
O
O
NH
N
NH
N
NH
N
NH
N
Naph
Naph
Naph
Naph
Ph
L5
L6
L7
L8
O
O
O
O
NH
N
NH
N
NH
N
NH
N
Ph
L9
L10
L11
L12
O
O
O
O
NH
N
NH
N
NH
N
NH
N
Ph
L13
L14
L15
L16
O
O
O
O
O
NH
N
O
NH
N
O
NH
N
O
NH
N
Ph
L17
L18
L19
L20
O
O
O
O
O
NH
N
O
NH
N
S
S
O
NH
N
O
NH
N
S
S
Ph
L21
L22
L23
L24
Figure 2 Structure of ligands L1–L24
In order to vary the amine terminal, the phenyl substituent er low. Attempts were made to improve the coupling reac-
R¢ in L1–L4 was replaced with naphthalene, a sterically tions without much success; yields of 30–73% were
bulkier substituent. Thus, ligands L5–L8 were similarly typically obtained for the series of alkylamines, in part,
synthesized from Pd-catalyzed amination of chiral oxazo- due to formation of several unidentified by-products and
lines 1a–d with (R)-1-(1-naphthyl)ethylamine in moder- subsequent difficulty in isolation. Use of state of the art
ate yields as oily compounds (Table 1, entries 5–8). It is phosphine ligands instead of BINAP, or other coupling
noted that the synthesis of L1, L7, and L8 required longer protocols such as Cu-catalyzed amination may improve
reaction times and the isolated yields were generally rath- the yields, and efforts along these lines are ongoing.
Synthesis 2011, No. 16, 2609–2618 © Thieme Stuttgart · New York

2612
P. I. Binda et al.
PAPER
We were interested in the effect of one stereogenic center 4-position.21 It should be noted that, in the isolated sam-
in conjunction with a bulky substituent on catalytic selec- ples, only one set of signals was detected for the remain-
tivity. In this context, ortho-substituted anilines were used ing ligands. Furthermore, the formulation of these
as the coupling partner. 2,6-Dimethylaniline and 2,6-di- compounds was confirmed with mass spectrometry (GC-
isopropylaniline were separately treated with chiral ox- MS and HRMS) and optical rotations, which are in agree-
azolines 1a–d under similar conditions as above to afford ment with the intended structures.
ligands L9–L16. Yields of this series were generally high-
In conclusion, a library of twenty four new chiral b-
er (63–84%; see Table 1), presumably due to the en-
diketiminato type ligands containing oxazoline moiety
hanced nucleophilicity upon deprotonation of arylamines
has been synthesized via the Pd-catalyzed Buchwald–
Hartwig amination reaction of chiral oxazolines and pri-
compared to alkylamines utilized in ligands L1–L8.
A primary amide as a coupling partner was also employed mary amines and amides. By independently varying two
to synthesize ligands L17–L20. Initial attempts under components (R and R¢), this modular synthetic approach
same conditions afforded minimal amount of the desired opens a pathway to obtain different combinations of
products, possibly because of the side reactions at high chirality (e.g., RR, RS, SS, and SR), allowing exploration
temperatures.8d In subsequent experiments, the reaction of the synergistic interactions between two chiral or ste-
temperature was reduced to 100 °C, the Pd and BINAP reo-directing centers in catalysis. It also offers the oppor-
loadings were increased to 10 mol% and 20 mol%, respec- tunity to introduce additional coordinating groups to
tively, and 4 equivalents of the amide (see Table 1) were stabilize the ligation. The ligand framework presented
employed. Under these conditions, compounds L17–L20 here should be widely applicable in a range of metal-
were obtained in very high yields (>95%) and in shorter based catalytic reactions. These compounds themselves
reaction times (see Table 1). This approach can be used to are also potential chiral proton sources,17 with the NH pro-
expand the library of chiral b-diketiminato type ligands to ton located in a chiral microenvironment. Considering the
incorporate chiral amide substituents when they are po- availability of large numbers of various chiral amines and
tentially beneficial, and a pool of chiral amides is avail- amides, this methodology will allow the synthesis of a
able as well.
large family of new chiral b-diketiminato-type ligands for
high throughput screening in asymmetric catalysis as well
as in other applications. Our ongoing efforts involve opti-
mizing and expanding the chiral b-diketiminato type
ligands and searching for applications in asymmetric ca-
talyses.
Under similar conditions, a chiral sulfinamide, (S)-tert-
butylsulfinamide,26 can be coupled to the oxazoline moi-
ety, resulting in compounds L21–L24. The reactions re-
quire longer reaction times, and the yields are generally
good (60–84%), except the one with sec-butyl substituent
(L24), despite the structural similarity and multiple at-
tempts. To the best of our knowledge, sulfinamides have
not previously been studied as coupling partners in the
Buchwald–Hartwig amination reaction.
All air- or moisture-sensitive reactions were carried out under a dry
N2 atmosphere, employing standard Schlenk line and dry box tech-
niques. Solvents were dried over Na/benzophenone and distilled un-
der N2. Deuterated solvents were purchased from Cambridge
Isotope Laboratory and used as received. 2-(2¢-Bromophenyl)ox-
azolines 1a–d were prepared and purified according to a modified
literature procedure. 2-Bromobenzonitrile, 2-bromobenzaldehyde,
(S)-tert-butylsulfinamide, (R)-2-phenylglycinol, (R)-a-methylben-
zylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (R)-leucinol, N-bro-
mosuccinimide, Cs2CO3, and K3PO4 were purchased from Aldrich
while L-Valinol and L-isoleucinol were purchased from Fluka and
used as received.
All 1H and 13C NMR spectra were recorded on a Bruker Avance-500
NMR spectrometer and referenced to the residual peaks in CDCl3 or
C6D6 at 298 K. Melting points were obtained on a Mel-Temp appa-
ratus and were uncorrected. Optical rotations were recorded on a
Rudolph Autopol III polarimeter with sodium D line (589 nm) at r.t.
GC/MS analyses were performed on an HP 5890 GC/HP 5971/B
MSD system with electron impact ionization (70 eV). High-resolu-
tion mass spectrometry (HRMS) was performed using high-resolu-
tion time of flight G1969A instrumentation (Agilent, Santa Clara,
CA, USA).
The structures of the synthesized compounds L1–L24 are
shown in Figure 2, and they have been characterized by
1H and 13C NMR spectroscopy. Characteristic is the NH
signal in the downfield region of 9–10 ppm for L1–L16,
13.2–13.4 ppm for L17–L20, and 11–12 ppm for L21–
L24. The observation is consistent with the presence of an
intramolecular hydrogen bonding interaction between the
NH group and the imino nitrogen, which is typical for this
type of compounds. Also noteworthy is that the 1H NMR
(CDCl3) spectra of L1 and L5 showed two distinct N-H
peaks at d = 9.08 and 8.82 (minor) for L1; and at d = 9.21
and 8.88 (minor) for L5, respectively. Guiry and co-work-
ers have also observed the presence of two distinct NH
peaks in a similar ligand framework.27 At elevated tem-
perature (30 °C), these peaks coalesced to a single reso-
nance, which is attributed to the presence of rotamers
resulting from hindered rotation. When ligand L1 was
subjected to the VT-NMR experiment in the range of 0–
55 °C, however, no obvious shift or coalescence was ob-
served, suggesting the presence of a mixture of diastereo-
mers resulting from minor racemization. Preliminary
investigations suggested that the racemization occurred at
the oxazoline side, not the amine side; and this process is
rather specific to oxazolines with aryl substituents at the
Amination of Chiral Oxazolines with Primary Amines; General
Procedure
An oven dried Schlenk flask was charged with Pd(OAc)2 (5 mol%),
rac-BINAP (5 mol%), chiral aryl bromide 1a–d (1.2 mmol, 1.0
equiv), the appropriate primary amine (1.4 mmol, 1.2 equiv), t-
BuONa (1.7 mmol, 1.4 equiv), and anhyd degassed toluene (15
mL), and the mixture was refluxed under N2 flow at 120 °C until an
appropriate amount of the ligand was formed as judged by TLC
Synthesis 2011, No. 16, 2609–2618 © Thieme Stuttgart · New York

PAPER
Chiral b-Diketimine Ligands
2613
(hexane–EtOAc, 9:1) and 1H NMR spectroscopy. The crude prod-
uct was then purified by column chromatography on silica gel elut-
ing with a mixture of hexanes and EtOAc.
[NCH(R)CH2O], 108.9 (CHarom), 111.9 (CHarom), 114.6 (CHarom),
125.8 (CHarom), 126.0 (CHarom), 126.9 (CHarom), 128.8 (CHarom),
129.1 (CHarom), 129.8 (CHarom), 132.3 (CHarom), 145.7 (CHarom),
148.4 (CHarom), 164.0 (CHarom).
(4R)-4,5-Dihydro-2-{2¢-[(R)-a-methylbenzylamino]phenyl}-4-
phenyloxazole (L1)
Yield: 35%; mp 56–59 °C; [a]D –367.5 (c = 1.00, CHCl3).
GC/MS: m/z = 322 [M]+, 307, 207, 194, 129.
HRMS (ESI): m/z calcd for C21H27N2O [M + H]+: 323.21179;
found: 323.21277.
1H NMR (500.1 MHz, CDCl3): d = 1.54 [3 H, d, J = 5.0 Hz,
PhCH(CH3)N], 4.13 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.59 [1 H,
q, J = 5.0 Hz, PhCH(Me)N], 4.72 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 5.54 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 6.45 (1 H,
d, J = 10.0 Hz, ArH), 6.57 (1 H, t, J = 10.0 Hz, ArH), 7.13 (1 H, t,
J = 10.0 Hz, ArH), 7.18 (1 H, d, J = 10.0 Hz, ArH), 7.29 (1 H, t,
J = 10.0 Hz, ArH), 7.35 (2 H, m, ArH), 7.78 (2 H, d, J = 5.0 Hz,
ArH), 9.08 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 24.1 [PhCH(CH3)N], 59.4
[PhCH(Me)N], 69.0 [NCH(R)CH2O], 71.8 [NCH(R)CH2O], 107.3
(CHarom), 110.9 (CHarom), 113.5 (CHarom), 124.8 (CHarom), 125.4
(CHarom), 125.7 (CHarom), 126.4 (CHarom), 127.5 (CHarom), 127.6
(CHarom), 128.9 (CHarom), 131.5 (CHarom), 141.9 (CHarom), 144.4
(CHarom), 147.4 (CHarom), 164.7 (CHarom).
(4S)-4,5-Dihydro-2-{2¢-[(R)-a-methylbenzylamino]phenyl}-4-
sec-butyloxazole (L4)
Yield: 44%; [a]D –223.7 (c = 1.00, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.79 [1 H, m, MeCH2CH(Me)],
0.86 [3 H, d, J = 5.0 Hz, MeCH2CH(CH3)], 0.90 [3 H, t, J = 5.0 Hz,
CH3CH2CH(Me)], 1.25 [1 H, m, MeCH2CH(Me)], 1.51 [3 H, d,
J = 5.0 Hz, PhCH(CH3)N], 1.60 [1 H, m, MeCH2CH(Me)], 3.91 [1
H, t, J = 5.0 Hz, NCH(R)CH2O], 4.16 [1 H, m, NCH(R)CH2O], 4.26
[1 H, m, NCH(R)CH2O], 4.55 [1 H, q, J = 5.0 Hz, PhCH(Me)N],
6.40 (1 H, d, J = 10.0 Hz, ArH), 6.47 (1 H, t, J = 10.0 Hz, ArH),
7.04 (1 H, t, J = 10.0 Hz, ArH), 7.14 (1 H, t, J = 10.0 Hz, ArH), 7.19
(1 H, m, ArH), 7.25 (3 H, m, ArH), 7.63 (1 H, d, J = 5.0 Hz, ArH),
9.07 (1 H, s, ArNH).
GC/MS: m/z = 342 [M]+, 327, 207, 194, 129.
HRMS (ESI): m/z calcd for C23H23N2O [M + H]+: 343.18048;
13C{1H} NMR (125.8 MHz, CDCl3): d = 11.4 [MeCH(CH2CH3)],
15.4
[CH3CH(CH2Me)],
25.1
[MeCH(CH2Me)],
26.2
found: 343.18155.
[PhCH(CH3)N], 40.1 [MeCH(CH2Me)], 52.9 [PhCH(Me)N], 65.9
[NCH(R)CH2O], 71.8 [NCH(R)CH2O], 108.8 (CHarom), 111.8
(CHarom), 114.5 (CHarom), 126.0 (CHarom), 126.9 (CHarom), 128.8
(CHarom), 129.9 (CHarom), 132.3 (CHarom), 145.7 (CHarom), 148.4
(CHarom), 164.0 (CHarom).
(4S)-4,5-Dihydro-2-{2¢-[(R)-a-methylbenzylamino)phenyl}-4-
isopropyloxazole (L2)
Yield: 47%; [a]D –250.0 (c = 1.00, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.91 [3 H, d, J = 5.0 Hz,
(CH3)2CH], 0.98 [3 H, d, J = 5.0 Hz, (CH3)2CH], 1.51 [3 H, d,
J = 5.0 Hz, PhCH(CH3)N], 1.71 [1 H, m, (CH3)2CH], 3.92 [1 H, t,
J = 5.0 Hz, NCH(R)CH2O], 4.05 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 4.26 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.56 [1 H,
q, J = 5.0 Hz, PhCH(Me)N], 6.38 (1 H, d, J = 10.0 Hz, ArH), 6.46
(1 H, t, J = 10.0 Hz, ArH), 7.02 (1 H, t, J = 10.0 Hz, ArH), 7.13 (1
H, d, J = 10.0 Hz, ArH), 7.22 (1 H, m, ArH), 7.28 (3 H, m, ArH),
7.63 (1 H, d, J = 5.0 Hz, ArH), 9.09 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 19.0 [(CH3)2CH], 19.3
[(CH3)2CH], 25.2 [PhCH(CH3)N], 33.7 [(CH3)2CH], 52.9
[PhCH(Me)N], 69.1 [NCH(R)CH2O], 73.1 [NCH(R)CH2O], 108.8
(CHarom), 111.9 (CHarom), 114.5 (CHarom), 126.0 (CHarom), 126.9
(CHarom), 128.8 (CHarom), 129.9 (CHarom), 132.3 (CHarom), 145.7
(CHarom), 148.4 (CHarom), 164.1 (CHarom).
GC/MS: m/z = 322 [M]+, 307, 265, 207, 194, 129.
HRMS (ESI): m/z calcd for C21H27N2O [M + H]+: 323.21179;
found: 323.21346.
(4R)-4,5-Dihydro-2-{2¢-[(R)-1-(1-naphthyl)ethylamino]phe-
nyl}-4-phenyloxazole (L5)
Yield: 50%; [a]D –303.7 (c = 1.00, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 1.57 [3 H, d, J = 5.0 Hz,
ArCH(CH3)N], 4.05 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.62 [1 H,
t, J = 5.0 Hz, NCH(R)CH2O], 5.28 [1 H, q, J = 5.0 Hz,
ArCH(Me)N], 5.48 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 6.19 (1 H,
d, J = 5.0 Hz, ArH), 6.48 (1 H, t, J = 5.0 Hz, ArH), 6.94 (1 H, t,
J = 5.0 Hz, ArH), 7.22 (1 H, d, J = 5.0 Hz, ArH), 7.25 (1 H, m,
ArH), 7.30 (2H, m, ArH), 7.38–7.48 (5 H, m, ArH), 7.64 (1 H, d,
J = 5.0 Hz, ArH), 7.71 (1 H, d, J = 5.0 Hz, ArH), 7.81 (1 H, d,
J = 5.0 Hz, ArH), 8.10 (1 H, d, J = 5.0 Hz, ArH), 9.16 (1 H, s,
ArNH).
GC/MS: m/z = 308 [M]+, 293, 222, 207, 194, 152, 129.
HRMS (ESI): m/z calcd for C20H25N2O [M + H]+: 309.19614;
found: 309.19786.
13C{1H} NMR(125.8 MHz, CDCl3): d = 24.3 [ArCH(CH3)N], 49.8
[ArCH(Me)N], 70.5 [NCH(R)CH2O], 73.3 [NCH(R)CH2O], 108.8
(CHarom), 112.4 (CHarom), 115.0 (CHarom), 122.9 (CHarom), 125.8
(CHarom), 126.1 (CHarom), 126.4 (CHarom), 126.8 (CHarom), 127.7
(CHarom), 128.0 (CHarom), 129.2 (CHarom), 129.6 (CHarom), 130.3
(CHarom), 131.0 (CHarom), 133.0 (CHarom), 134.5 (CHarom), 140.7
(CHarom), 143.4 (CHarom), 148.7 (CHarom), 165.9 (CHarom).
Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C,
77.69; H, 7.99; N, 9.07.
(4R)-4,5-Dihydro-2-{2¢-[(R)-a-methylbenzylamino)phenyl}-4-
isobutyloxazole (L3)
Yield: 56%; mp 65–68 °C; [a]D –262.0 (c = 1.00, CHCl3).
GC/MS: m/z = 391, 281, 207, 193, 167, 149.
HRMS (ESI): m/z calcd for C27H25N2O [M + H]+: 393.19614;
found: 393.19700.
1H NMR (500.1 MHz, CDCl3): d = 0.89 [6 H, d, J = 5.0 Hz,
(CH3)2CH], 1.35 (1 H, m, i-PrCH2), 1.49 [3 H, d, J = 5.0 Hz,
PhCH(CH3)N], 1.56 (1 H, m, i-PrCH2), 1.84 [1 H, m, (CH3)2CH],
3.77 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.33 [2 H, m,
NCH(R)CH2O], 4.50 [1 H, q, J = 5.0 Hz, PhCH(Me)N], 6.33 (1 H,
d, J = 10.0 Hz, ArH), 6.46 (1 H, t, J = 10.0 Hz, ArH), 7.02 (1 H, t,
J = 10.0 Hz, ArH), 7.13 (1 H, m, ArH), 7.21 (1 H, m, ArH), 7.23 (3
H, m, ArH), 7.64 (1 H, d, J = 5.0 Hz, ArH), 9.02 (1 H, s, ArNH).
(4S)-4,5-Dihydro-2-{2¢-[(R)-1-(1-naphthyl)ethylamino]phenyl}-
4-isopropyloxazole (L6)
Yield: 73%; [a]D –359.4 (c = 1.00, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 1.06 [3 H, d, J = 5.0 Hz,
(CH3)2CH], 1.12 [3 H, d, J = 5.0 Hz, (CH3)2CH], 1.82 [3 H, d,
J = 5.0 Hz, ArCH(CH3)N], 1.87 [1 H, m, (CH3)2CH], 4.10 [1 H, t,
J = 5.0 Hz, NCH(R)CH2O], 4.25 [1 H, q, J = 5.0 Hz, ArCH(Me)N],
13C{1H} NMR (125.8 MHz, CDCl3): d = 22.6 [(CH3)2CH] , 23.4
[(CH3)2CH], 25.3 [(CH3)2CH], 26.1 [PhCH(CH3)N], 46.0 [i-
PrCH2], 53.2 [PhCH(Me)N], 65.4 [NCH(R)CH2O], 71.5
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2614
P. I. Binda et al.
PAPER
4.43 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 5.51 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 6.40 (1 H, d, J = 10.0 Hz, ArH), 6.60 (1 H, t,
J = 10.0 Hz, ArH), 7.08 (1 H, t, J = 10.0 Hz, ArH), 7.44 (1 H, t,
J = 10.0 Hz, ArH), 7.65–7.56 (3 H, m, ArH), 7.82–7.78 (2 H, m,
ArH), 7.98 (1 H, d, J = 10.0 Hz, ArH), 8.29 (1 H, d, J = 10.0 Hz,
ArH), 9.44 (1 H, br, ArNH).
HRMS (ESI): m/z calcd for C25H29N2O [M + H]+: 373.22744;
found: 373.22947.
(4R)-4,5-Dihydro-2-[2¢-(2,6-dimethylanilino)phenyl]-4-phenyl-
oxazole (L9)
Yield: 84%; mp 110–115 °C; [a]D –7.1 (c = 0.98, CHCl3).
13C{1H} NMR (125.8 MHz, CDCl3): d = 19.2 [(CH3)2CH], 19.6
[(CH3)2CH], 24.2 [ArCH(CH3)N], 34.0 [(CH3)2CH], 49.4
[ArCH(Me)N], 69.4 [NCH(R)CH2O], 73.4 [NCH(R)CH2O], 109.1
(CHarom), 112.2 (CHarom), 114.9 (CHarom), 122.8 (CHarom), 123.0
(CHarom), 125.9 (CHarom), 126.4 (CHarom), 127.8 (CHarom), 129.6
(CHarom), 130.1 (CHarom), 131.2 (CHarom), 132.6 (CHarom), 134.5
(CHarom), 140.9 (CHarom), 148.4 (CHarom), 164.4 (CHarom).
1H NMR (500.1 MHz, CDCl3): d = 2.12 (3 H, s, ArCH3), 2.16 (3 H,
s, ArCH3), 4.12 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.70 [1 H, t, J =
5.0 Hz, NCH(R)CH2O], 5.41 [1 H, t, J = 5.0 Hz, NCH(R)CH2O],
6.25 (1 H, d, J = 10.0 Hz, ArH), 6.60 (1 H, t, J = 10.0 Hz, ArH),
7.03 (3 H, m, ArH), 7.13 (1 H, t, J = 10.0 Hz, ArH), 7.25 (5 H, m,
ArH), 7.81 (1 H, d, J = 10.0 Hz, ArH), 9.91 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 20.1 (ArCH3), 32.1
(ArCH3), 70.1 [NCH(R)CH2O], 73.0 [NCH(R)CH2O], 108.1
(CHarom), 112.3 (CHarom), 116.5 (CHarom), 126.2 (CHarom), 126.6
(CHarom), 127.5 (CHarom), 127.7 (CHarom), 128.2 (CHarom), 128.4
(CHarom), 130.0 (CHarom), 133.8 (CHarom), 136.4 (CHarom), 137.1
(CHarom), 138.1 (CHarom), 140.4 (CHarom), 143.0 (CHarom), 147.6
(CHarom), 148.0 (CHarom), 165.2 (CHarom).
GC/MS: m/z = 358 [M]+, 355, 281, 221, 147.
HRMS (ESI): m/z calcd for C24H27N2O [M + H]+: 359.21179;
found: 359.21334.
(4R)-4,5-Dihydro-2-{2¢-(R)-1-(1-naphthyl)ethylamino]phenyl}-
4-isobutyloxazole (L7)
Yield: 30%; [a]D –318.3 (c = 1.00, CHCl3).
GC/MS: m/z = 342 [M]+, 222, 194, 120.
1H NMR (500.1 MHz, CDCl3): d = 1.07 [6 H, m, (CH3)2CH], 1.52
(1 H, m, i-PrCH2), 1.71 (1 H, m, i-PrCH2), 1.78 [3 H, d, J = 5.0 Hz,
ArCH(CH3)N], 2.01 [1 H, m, (CH3)2CH], 3.95 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 4.52 [2 H, m, NCH(R)CH2O], 5.43 [1 H, q, J = 5.0
Hz, ArCH(Me)N], 6.31 (1 H, d, J = 5.0 Hz, ArH), 6.58 (1 H, t,
J = 5.0 Hz, ArH), 7.04 (1 H, t, J = 5.0 Hz, ArH), 7.43 (1 H, t, J = 5.0
Hz, ArH), 7.66–7.55 (3 H, m, ArH), 7.80–7.77 (2 H, m, ArH), 7.97
(1 H, d, J = 10.0 Hz, ArH), 8.27 (1 H, d, J = 10.0 Hz, ArH), 9.32 (1
H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 22.9 [(CH3)2CH], 23.7
[(CH3)2CH], 24.2 [(CH3)2CH], 26.4 [ArCH(CH3)N], 46.3 (i-
PrCH2), 49.6 [ArCH(Me)N], 65.6 [NCH(R)CH2O], 71.8
[NCH(R)CH2O], 109.2 (CHarom), 112.3 (CHarom), 114.9 (CHarom),
122.8 (CHarom), 122.9 (CHarom), 125.8 (CHarom), 126.4 (CHarom),
127.7 (CHarom), 129.6 (CHarom), 130.1 (CHarom), 131.0 (CHarom),
132.6 (CHarom), 134.5 (CHarom), 140.8 (CHarom), 148.4 (CHarom),
164.3 (CHarom).
HRMS (ESI): m/z calcd for C23H23N2O [M + H]+: 343.18048;
found: 343.18171.
Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found: C,
80.09; H, 6.60; N, 8.10.
(4S)-4,5-Dihydro-2-[2¢-(2,6-dimethylanilino)phenyl]-4-isopro-
pyloxazole (L10)
Yield: 77%; [a]D –7.8 (c = 2.30, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.92 [3 H, d, J = 5.0 Hz,
(CH3)2CH], 0.98 [3 H, d, J = 5.0 Hz, (CH3)2CH], 1.81 [1 H, m,
(CH3)2CH], 2.19 (6 H, s, ArCH3), 4.03 [1 H, J = 5.0 Hz,
NCH(R)CH2O], 4.19 [1 H, J = 5.0 Hz, NCH(R)CH2O], 4.34 [1 H,
t, J = 5.0 Hz, NCH(R)CH2O], 6.21 (1 H, d, J = 10.0 Hz, ArH), 6.61
(1 H, t, J = 10.0 Hz, ArH), 7.12 (3 H, m, ArH), 7.27 (1 H, m, ArH)
7.78 (1 H, d, J = 10.0 Hz, ArH), 9.96 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 18.8 [(CH3)2CH]), 19.0
[(CH3)2CH]), 19.1 [(CH3)2CH]), 21.4 (ArCH3), 34.2 (ArCH3), 70.1
[NCH(R)CH2O], 73.2 [NCH(R)CH2O], 109.0 (CHarom), 112.1
(CHarom), 115.7 (CHarom), 126.6 (CHarom), 128.8 (CHarom), 128.9
(CHarom), 130.2 (CHarom), 132.5 (CHarom), 136.9 (CHarom) 137.3
(CHarom), 138.6 (CHarom), 148.1 (CHarom), 164.3 (CHarom).
GC/MS: m/z = 362, 341, 238, 217, 147.
HRMS (ESI): m/z calcd for C25H29N2O [M + H]+: 373.22744;
found: 373.22927.
(4S)-4,5-Dihydro-2-{2¢-[(R)-1-(1-naphthyl)ethylamino]phenyl}-
4-sec-butyloxazole (L8)
Yield: 36%; [a]D –303.1 (c = 1.00, CHCl3).
GC/MS: m/z = 308 [M]+, 265, 222, 194.
HRMS (ESI): m/z calcd for C20H26N2O [M + H]+: 309.19614;
found: 309.19726.
1H NMR (500.1 MHz, CDCl3):
d = 0.97 [6 H, m,
CH3CH2CH(CH3)], 1.03 [1 H, m, MeCH2CH(Me)], 1.59 [2 H, m,
MeCH2CH(Me)], 1.80 [3 H, d, J = 5.0 Hz, ArCH(CH3)N], 4.09 [1
H, t, J = 5.0 Hz, NCH(R)CH2O], 4.32 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 4.43 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 5.47 [1 H,
q, J = 5.0 Hz, ArCH(Me)N], 6.39 (1 H, d, J = 5.0 Hz, ArH), 6.58 (1
H, t, J = 5.0 Hz, ArH), 7.07 (1 H, t, J = 5.0 Hz, ArH), 7.44 (1 H, t,
J = 5.0 Hz, ArH), 7.63–7.55 (3 H, m, ArH), 7.79 (2 H, d, J = 10.0
Hz, ArH), 7.96 (1 H, d, J = 10.0 Hz, ArH), 8.27 (1 H, d, J = 10.0 Hz,
ArH), 9.39 (1 H, s, ArNH).
(4R)-4,5-Dihydro-2-[2¢-(2,6-dimethylanilino)phenyl]-4-isobutyl-
oxazole (L11)
Yield: 74%; [a]D +12.2 (c = 1.50, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.91 [6 H, d, J = 5.0 Hz,
(CH3)2CH], 1.18 [1 H, m, (CH3)2CH], 1.46 (1 H, m, i-PrCH2), 1.78
(1 H, m, i-PrCH2), 2.13 (6 H, s, ArCH3) 3.84 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 4.35 [2 H, m, NCH(R)CH2O], 6.10 (1 H, d,
J = 10.0 Hz, ArH), 6.56 (1 H, t, J = 10.0 Hz, ArH), 7.04 (4 H, m,
ArH), 7.71 (1 H, d, J = 10.0 Hz, ArH), 9.86 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 14.6 [(CH3)2CH], 18.8
[(CH3)2CH], 23.0 [(CH3)2CH], 24.1 (i-PrCH2), 26.1 (ArCH3), 46.3
(ArCH3), 65.6 [NCH2(R)CH2O] 71.8 [NCH2(R)CH2O] 108.9
(CHarom), 112.2 (CHarom), 115.3 (CHarom), 126.2 (CHarom), 128.4
(CHarom), 129.3 (CHarom), 130.1 (CHarom), 133.1 (CHarom), 136.7
(CHarom), 137.4 (CHarom), 138.6 (CHarom), 148.1 (CHarom), 164.2
(CHarom).
13C{1H} NMR (125.8 MHz, CDCl3): d = 11.7 [MeCH(CH2CH3)],
14.6
[CH3CH(CH2Me)],
25.7
[MeCH(CH2Me)],
35.1
[ArCH(CH3)N], 40.3 [MeCH(CH2Me)], 49.4 [ArCH(Me)N], 69.2
[NCH(R)CH2O], 72.0 [NCH(R)CH2O], 109.1 (CHarom), 112.1
(CHarom), 114.8 (CHarom), 122.8 (CHarom), 123.0 (CHarom), 125.8
(CHarom), 126.4 (CHarom), 127.7 (CHarom), 129.6 (CHarom), 130.1
(CHarom), 131.2 (CHarom), 132.6 (CHarom), 134.5 (CHarom), 140.9
(CHarom), 148.2 (CHarom), 164.3 (CHarom).
GC/MS: m/z = 322 [M]+, 194, 222, 180.
GC/MS: m/z = 372 [M]+, 357, 272, 257, 243, 155.
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Chiral b-Diketimine Ligands
2615
HRMS (ESI): m/z calcd for C21H26N2O [M + H]+ 323.21179; found:
323.21451.
13C{1H} NMR (125.8 MHz, CDCl3): d = 18.4 [(CH3)2CH], 18.5
[(CH3)2CH], 23.0 (CH3)2CH], 24.7 (CH3)2CH], 24.8 (CH3)2CH],
28.3 (CH3)2CH], 28.4 [(CH3)2CH], 30.7 [(CH3)2CH], 33.2
[(CH3)2CH], 68.8 [NCH(R)CH2O], 72.7 [NCH(R)CH2O], 108.6
(CHarom), 112.4 (CHarom), 115.2 (CHarom), 119.0 (CHarom), 122.9
(CHarom), 124.1 (CHarom), 127.5 (CHarom), 129.8 (CHarom), 132.6
(CHarom), 135.7 (CHarom), 140.8 (CHarom), 148.2 (CHarom), 150.0
(CHarom), 164.3 (CHarom).
Anal. Calcd for C21H26N2O: C, 78.22; H, 8.13; N, 8.69. Found: C,
77.83; H, 8.81; N, 8.65.
(4S)-4,5-Dihydro-2-[2¢-(2,6-dimethylanilino)phenyl]-4-sec-bu-
tyloxazole (L12)
Yield: 83%; [a]D +20.0 (c = 1.00, CHCl3).
GC/MS: m/z = 364 [M]+, 236, 162, 114.
HRMS (ESI): m/z calcd for C24H34N2O [M + H]+: 365.25874;
1H NMR (500.1 MHz, CDCl3):
d = 0.94 [6 H, m,
CH3CH2CH(CH3)], 1.38 [1 H, m, MeCH2CH(Me)] 1.60 [1 H, m,
MeCH2CH(Me)], 1.84 [1 H, m, MeCH2CH(Me)], 2.18 (6 H, s,
ArCH3), 3.88 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.42 [2 H, t,
J = 5.0 Hz, NCH(R)CH2O], 6.22 (1 H, d, J = 10.0 Hz, ArH), 6.62
(1 H, t, J = 10.0 Hz, ArH), 7.09 (3 H, m, ArH), 7.25 (1 H, m, ArH),
7.73 (1 H, d, J = 10.0 Hz, ArH), 9.91 (1 H, s, ArNH).
found: 365.26028.
(4R)-4,5-Dihydro-2-[2¢-(2,6-diisopropylanilino)phenyl]-4-
isobutyloxazole (L15)
Yield: 75%; mp 65–68 °C; [a]D +2.8 (c = 1.00, CHCl3).
13C{1H} NMR (125.8 MHz, CDCl3): d = 11.7 [MeCH(CH2CH3)],
14.7 [CH3MeCH(CH2Me)], 15.1 [MeCH(CH2Me)], 18.8
[MeCH(CH2Me)], 26.2 (ArCH3), 39.9 (ArCH3), 68.6
[NCH(R)CH2O], 71.6 [NCH(R)CH2O], 108.9 (CHarom), 112.1
(CHarom), 115.7 (CHarom), 126.5 (CHarom), 128.7 (CHarom), 130.1
(CHarom), 131.9 (CHarom), 137.0 (CHarom), 137.1 (CHarom), 138.5
(CHarom), 148.0 (CHarom), 164.6 (CHarom).
1H NMR (500.1 MHz, CDCl3): d = 0.90 [6 H, d, J = 5.0 Hz,
(CH3)2CH], 1.11–1.05 [12 H, m, (CH3)2CH], 1.34 (1 H, m, i-
PrCH2), 1.57 (1 H, m, i-PrCH2), 1.82 [1 H, m, (CH3)2CH], 3.10 [2
H, m, 2 × (CH3)2CH], 3.84 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.35
[2 H, m, NCH(R)CH2O], 6.16 (1 H, d, J = 10.0 Hz, ArH), 6.55 (1
H, t, J = 10.0 Hz, ArH), 7.04 (1 H, t, J = 10.0 Hz, ArH), 7.20 (3 H,
m, ArH), 7.74 (1 H, d, J = 10.0 Hz, ArH), 9.88 (1 H, s, ArNH).
GC/MS: m/z = 322 [M]+, 222, 194, 208.
HRMS (ESI): m/z calcd for C21H28N2O [M + H]+: 323.21179;
13C{1H} NMR(125.8 MHz, CDCl3): d = 22.4 [(CH3)2CHCH2], 22.6
[(CH3)2CHCH2], 23.0 (i-PrCH2), 23.2 [(CH3)2CH], 24.9
[(CH3)2CH], 25.0 [(CH3)2CH], 25.7 [(CH3)2CH], 28.5
[(CH3)2CHCH2], 28.9 [(CH3)2CH], 46.3 [(CH3)2CH], 65.2
[NCH(R)CH2O], 71.8 [NCH(R)CH2O], 108.1 (CHarom), 112.1
(CHarom), 114.8 (CHarom), 118.7 (CHarom), 122.8 (CHarom), 124.1
(CHarom), 127.6 (CHarom), 129.8 (CHarom), 132.2 (CHarom), 135.4
(CHarom), 147.8 (CHarom), 149.2 (CHarom), 164.1 (CHarom).
found: 323.21403.
(4R)-4,5-Dihydro-2-[2¢-(2,6-diisopropylanilino)phenyl]-4-phe-
nyloxazole (L13)
Yield: 80%; mp 80–85 °C; [a]D +53.3 (c = 1.00, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.98 (3 H, d, J = 5.0 Hz,
(CH3)2CH], 1.01 [3 H, d, J = 5.0 Hz, (CH3)2CH], 1.09 [6 H, d,
J = 5.0 Hz, (CH3)2CH], 3.00 [2 H, m, 2 × (CH3)2CH], 4.13 (1 H, t,
GC/MS: m/z = 378 [M]+ 236, 128, 162.
HRMS (ESI): m/z calcd for C25H36N2O [M + H]+: 379.27439;
J = 5.0 Hz, NCH(R)CH2O], 4.67 [1 H, t,
J
=
5.0 Hz,
found: 379.27593.
NCH(R)CH2O], 5.44 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 6.22 (1H,
d, J = 10 Hz, ArH), 6.60 (1 H, t, J = 10.0 Hz, ArH), 6.77 (1 H, t,
J = 10.0 Hz, ArH), 7.03 (3 H, d, J = 10.0 Hz, ArH), 7.43–7.28 (5 H,
m, ArH), 8.06 (1 H, d, J = 10.0 Hz, ArH), 9.89 (1 H, s, ArNH).
(4S)-4,5-Dihydro-2-[2¢-(2,6-diisopropylanilino)phenyl]-4-sec-
butyloxazole (L16)
Yield: 63%; mp 58–62 °C; [a]D +18.7 (c = 1.00, CHCl3).
13C{1H} NMR (125.8 MHz, CDCl3): d = 22.4 [(CH3)2CH], 23.0
[(CH3)2CH], 24.4 [CH3)2CH], 24.9 [(CH3)2CH], 28.1 [(CH3)2CH],
28.6 [(CH3)2CH], 70.1 [NCH(R)CH2O], 73.2 [NCH(R)CH2O],
107.7 (CHarom), 112.2 (CHarom), 115.1 (CHarom), 118.7 (CHarom),
122.9 (CHarom), 124.0 (CHarom), 126.6 (CHarom), 127.7 (CHarom),
128.9 (CHarom), 130.0 (CHarom), 133.7 (CHarom), 136.1 (CHarom),
140.5 (CHarom), 143.0 (CHarom), 148.9 (CHarom), 149.7 (CHarom),
165.5 (CHarom).
1H NMR (500.1 MHz, CDCl3): d = 0.82 [3 H, d, J = 5.0 Hz,
MeCH2CH(CH3)], 0.89 [3 H, t, J = 5.0 Hz, CH3CH2CH(Me)],
1.11–1.04 [12 H, m, 2 × (CH3)2CH], 1.22 [2 H, m,
MeCH2CH(Me)], 1.57 [1 H, m, MeCH2CH(Me)], 3.08 [2 H, m,
2 × (CH3)2CH], 3.95 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.22 [1 H,
t, J = 5.0 Hz, NCH(R)CH2O], 4.35 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 6.12 (1 H, d, J = 10.0 Hz, ArH), 6.56 (1 H, t,
J = 10.0 Hz, ArH), 7.04 (1 H, t, J = 10.0 Hz, ArH), 7.21 (2 H, m,
ArH), 7.25 (1 H, t, J = 10.0 Hz, ArH) 7.69 (1 H, d, J = 10.0 Hz,
ArH), 9.93 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 11.7 [CH3CH(CH2CH3)],
14.7 [MeCH(CH2Me)], 14.8 [CH3CH(CH2CH3)], 22.5 [(CH3)2CH],
23.3 [(CH3)2CH], 25.2 [(CH3)2CH], 26.3 [(CH3)2CH], 28.5
[MeCH(CH2Me)], 28.5 [(CH3)2CH], 39.7 [(CH3)2CH], 68.6
[NCH(R)CH2O], 71.8 [NCH(R)CH2O], 108.2 (CHarom), 112.0
(CHarom), 115.2 (CHarom), 118.8 (CHarom), 123.0 (CHarom), 123.9
(CHarom), 127.5 (CHarom), 129.7 (CHarom), 132.4 (CHarom), 135.5
(CHarom), 147.8 (CHarom), 149.7 (CHarom), 164.1 (CHarom).
GC/MS: m/z = 398 [M]+, 236, 220, 193.
HRMS (ESI): m/z calcd for C27H32N2O [M + H]+ 399.24309; found:
399.24452
(4S)-4,5-Dihydro-2-[2¢-(2,6-diisopropylanilino)phenyl]-4-iso-
propyloxazole (L14)
Yield: 84%; [a]D +6.9 (c = 1.00, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.88 [3 H, d, J = 5.0 Hz,
(CH3)2CH], 0.94 [3 H, d, J = 5.0 Hz, (CH3)2CH], 1.03 [3 H, d,
J = 5.0 Hz, (CH3)2CH], 1.16 [6 H, m, (CH3)2CH], 1.24 [3 H, d,
J = 5.0 Hz, (CH3)2CH], 1.76 [1 H, m, (CH3)2CH], 3.01 [2 H, m,
2 × (CH3)2CH], 4.01 [1 H, t, J = 5.0 Hz, NCH(R)CH2O], 4.14 [1 H,
t, J = 5.0 Hz, NCH(R)CH2O], 4.31 [1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 6.14 (1 H, d, J = 10.0 Hz, ArH), 6.51 (1 H, t,
J = 10.0 Hz, ArH), 7.04 (1 H, t, J = 10.0 Hz, ArH), 7.21 (2 H, m,
ArH), 7.26 (1 H, t, J = 10.0 Hz, ArH) 7.71 (1 H, d, J = 10.0 Hz,
ArH), 9.81 (1 H, s, ArNH).
GC/MS: m/z = 378 [M]+, 236, 128, 162.
HRMS (ESI): m/z calcd for C25H36N2O [M + H]+: 379.27439;
found: 379.27582.
Amination of Chiral Oxazolines with Amides; General Proce-
dure
An oven-dried Schlenk flask was charged with Pd(OAc)2 (10
mol%), rac-BINAP (20 mol%), chiral aryl bromide 1a–d (0.6
Synthesis 2011, No. 16, 2609–2618 © Thieme Stuttgart · New York

2616
P. I. Binda et al.
PAPER
mmol, 1.0 equiv), benzamide or sulfinamide (2.4 mmol, 4.0 equiv),
Cs2CO3 (1.2 mmol, 2.0 equiv), and anhyd degassed toluene (15
mL). The mixture was heated under N2 flow until an appropriate
amount of the ligand was formed as judged by TLC (hexane–
EtOAc, 8:2) and H NMR spectroscopy. The crude product was
then purified by column chromatography.
(CHarom), 128.8 (CHarom), 129.7 (CHarom), 132.3 (CHarom), 133.9
(CHarom), 141.3 (CHarom), 164.0 (CHarom), 165.9 (CHarom).
GC/MS: m/z = 322 [M]+, 265, 245, 224, 146.
HRMS (ESI): m/z calcd for C20H23N2O2 [M + H]+: 323.17540;
found: 323.17817.
1
(4S)-4,5-Dihydro-2-[2¢-(benzamido)phenyl]-4-sec-butyloxazole
(4R)-4,5-Dihydro-2-[2¢-(benzamido)phenyl]-4-phenyloxazole
(L17)
Yield: 98%; mp 118–122 °C; [a]D –132.2 (c = 1.00, CHCl3).
(L20)
Yield: 99%; [a]D +99.0 (c = 1.00, CHCl3).
1H NMR (500.1 MHz, C6D6): d = 0.73 [3 H, d, J = 5.0 Hz,
MeCH2CH(CH3)], 0.83 [3 H, t, J = 5.0 Hz, CH3MeCH2CH(Me)],
1.11 [1 H, m, MeCH2CH(Me)], 1.38 [1 H, m, MeCH2CH(Me)],
1.50 [1 H, m, MeCH2CH(Me)], 3.70 (1 H, t, J = 5.0 Hz,
NCH(R)CH2O], 3.93 (1 H, m, NCH(R)CH2O], 4.02 (1 H, m,
NCH(R)CH2O], 6.95 (1 H, t, J = 10.0 Hz, ArH), 7.33 (3 H, m, ArH),
7.40 (1 H, t, J = 10.0 Hz, ArH), 7.98 (1 H, d, J = 5.0 Hz, ArH), 8.29
(2 H, m, ArH), 9.49 (1 H, d, J = 10.0 Hz, ArH), 13.19 (1 H, s,
ArNH).
1H NMR (500.1 MHz, C6D6): d = 3.81 [1 H, t, J = 10.0 Hz,
NCH(R)CH2O], 4.20 [1 H, t, J = 10.0 Hz, NCH(R)CH2O], 5.08 [1
H, t, J = 10.0 Hz, NCH(R)CH2O], 6.96 (1 H, t, J = 10.0 Hz, ArH),
7.07 (2 H, t, J = 10.0 Hz, ArH), 7.11–7.28 (6 H, m, ArH), 7.38 (1 H,
t, J = 10.0 Hz, ArH), 8.06 (1 H, d, J = 5.0 Hz, ArH), 8.24 (2 H, d,
J = 5.0 Hz, ArH), 9.65 (1 H, d, J = 5.0 Hz, ArH), 13.37 (1 H, s,
ArNH).
13C{1H} NMR (125.8 MHz, C6D6): d = 70.3 [NCH(R)CH2O], 73.3
[NCH(R)CH2O], 113.7 (CHarom), 120.5 (CHarom), 122.6 (CHarom),
127.2 (CHarom), 128.0 (CHarom), 128.2 (CHarom), 128.4 (CHarom),
128.7 (CHarom), 129.2 (CHarom), 129.8 (CHarom), 131.7 (CHarom),
133.5 (CHarom), 136.0 (CHarom), 141.7 (CHarom), 142.0 (CHarom),
165.3 (CHarom), 166.0 (CHarom).
13C{1H} NMR (125.8 MHz, C6D6): d = 11.9 [MeCH(CH2CH3)],
15.3
[CH3CH(CH2Me)],
26.0
[MeCH(CH2Me)],
39.8
[MeCH(CH2Me)], 63.4 [NCH(R)CH2O], 71.9 [NCH(R)CH2O],
114.0 (CHarom), 120.3 (CHarom), 122.5 (CHarom), 127.5 (CHarom),
128.2 (CHarom), 129.1 (CHarom), 131.9 (CHarom), 132.3 (CHarom),
132.4 (CHarom), 132.9 (CHarom), 136.2 (CHarom), 141.3 (CHarom),
164.0 (CHarom), 166.0 (CHarom).
GC/MS: m/z = 342 [M]+, 341, 325, 251, 207, 147.
HRMS (ESI): m/z calcd for C22H19N2O2 [M + H]+: 343.1441; found:
343.14494.
GC/MS: m/z = 322 [M]+, 265, 245, 146.
HRMS (ESI): m/z calcd for C20H23N2O2 [M + H]+: 323.17540;
found: 323.17860.
(4S)-4,5-Dihydro-2-[2¢-(benzamido)phenyl]-4-isopropylox-
azole (L18)
Yield: 95%; [a]D +83.0 (c = 1.00, CHCl3).
(4R)-4,5-Dihydro-2-{2¢-[(S)-tert-butylsulfinamido]phenyl}-4-
phenyloxazole (L21)
Yield: 84%; mp 120–122 °C; [a]D –113.2 (c = 1.0, CHCl3).
1H NMR (500.1 MHz, C6D6): d = 0.78 [3 H, d, J = 5.0 Hz,
(CH3)2CH], 0.88 [3 H, d, J = 5.0 Hz, (CH3)2CH], 1.52 [1 H, m,
(CH3)2CH], 3.68 [1 H, t, J = 10.0 Hz, NCH(R)CH2O], 3.81 [1 H, t,
J = 10.0 Hz, NCH(R)CH2O], 4.02 [1 H, t, J = 10.0 Hz,
NCH(R)CH2O], 6.94 (1 H, d, J = 10.0 Hz, ArH), 7.31 (3 H, m,
ArH), 7.39 (1 H, t, J = 10.0 Hz, ArH), 7.97 (1 H, d, J = 10.0 Hz,
ArH), 8.34 (2 H, m, ArH), 9.53 (1 H, d, J = 10.0 Hz, ArH), 13.29 (1
H, s, ArNH).
13C{1H} NMR (125.8 MHz, C6D6): d = 19.0 [(CH3)2CH], 19.2
[(CH3)2CH], 33.4 [(CH3)2CH], 69.6 [NCH(R)CH2O], 73.2
[NCH(R)CH2O], 113.9 (CHarom), 120.3 (CHarom), 122.5 (CHarom),
127.6 (CHarom), 128.0 (CHarom), 128.2 (CHarom), 128.8 (CHarom),
129.8 (CHarom), 131.9 (CHarom), 133.0 (CHarom), 136.2 (CHarom),
141.4 (CHarom), 164.2 (CHarom), 165.9 (CHarom).
1H NMR (500.1 MHz, C6D6): d = 1.27 (9 H, s, t-C4H9), 3.81 [1 H, t,
J = 10.0 Hz, ArC(N)CHCH2O], 4.21 [1 H, t, J = 10.0 Hz,
ArC(N)CHCH2O], 5.13 [1 H, t, J = 10.0 Hz, ArC(N)CHCH2O],
6.86 (1 H, t, J = 10.0 Hz, ArH), 7.15–7.28 (6 H, br, ArH), 7.68 (1 H,
d, J = 10.0 Hz, ArH), 8.02 (1 H, d, J = 10.0 Hz, ArH), 11.43 (1 H,
s, ArNH).
13C{1H} NMR (125.8 MHz, C6D6): d = 22.8 [(CH3)3C], 56.8
[CMe3], 70.1 [PhCH(N)CH2O], 73.4 (PhCH(N)CH2O], 112.5
(CHarom), 115.4 (CHarom), 120.3 (CHarom), 127.1 (CHarom), 128.0
(CHarom), 128.3 (CHarom), 128.5 (CHarom), 129.1 (CHarom), 130.4
(CHarom), 133.3 (CHarom), 142.7 (CHarom), 146.1 (CHarom), 165.2
(CHarom).
GC/MS: m/z = 308 [M]+, 250, 207, 178, 146.
HRMS (ESI): m/z calcd for C19H21N2O2 [M + H]+: 309.15975;
GC/MS (EI): m/z = 238, 207, 180, 131,118.
GC/MS (CI): m/z = 342 (M+).
HRMS (ESI): m/z calcd for C19H22N2O2S [M + H]+: 343.14747;
found: 309.16149.
(4R)-4,5-Dihydro-2-[2¢-(benzamido)phenyl]-4-isobutyloxazole
(L19)
Yield: 98%; mp 86–89 °C; [a]D –16.6 (c = 1.00, CHCl3).
found: 343.15012.
Anal. Calcd for C19H22N2O2S: C, 66.64; H, 6.48; N, 8.18. Found: C,
66.67; H, 6.52; N, 8.09.
1H NMR (500.1 MHz, C6D6): d = 0.85 [3 H, d, J = 5.0 Hz,
(CH3)2CH], 0.94 [3 H, d, J = 5.0 Hz, (CH3)2CH], 1.03 (2 H, m, i-
PrCH2), 1.40 [(CH3)2CH], 3.50 [1 H, t, J = 5.0 Hz, NCH(R)CH2O],
4.03 [2 H, m, NCH(R)CH2O], 6.95 (1 H, t, J = 10.0 Hz, ArH), 7.32
(3 H, m, ArH), 7.38 (1 H, t, J = 10.0 Hz, ArH), 7.99 (1 H, d, J = 10.0
Hz, ArH), 8.32 (2 H, m, ArH), 9.55 (1 H, d, J = 10.0 Hz, ArH),
13.21 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, C6D6): d = 20.8 [(CH3)2CH], 22.1
[(CH3)2CH], 25.4 [(CH3)2CH], 45.8 [i-PrCH2], 65.0
[NCH(R)CH2O], 71.9 [NCH(R)CH2O], 114.1 (CHarom), 120.4
(CHarom), 122.0 (CHarom), 122.5 (CHarom), 124.2 (CHarom), 127.7
(4S)-4,5-Dihydro-2-{2¢-[(S)-tert-butylsulfinamido]phenyl}-4-
isopropyloxazole (L22)
Yield: 60%; [a]D +66.5 (c = 0.75, CHCl3).
1H NMR (500.1 MHz, C6D6): d = 0.82 [3 H, d, J = 10.0 Hz,
(CH3)2CH], 0.97 [3 H, d, J = 10.0 Hz, [(CH3)2CH], 1.37 [9 H, s, t-
C4H9], 1.52 [1 H, m, J = 5.0 Hz, [(CH3)2CH], 3.68 [1 H, t, J = 10.0
Hz, ArC(N)CHCH2O], 3.82 [1 H, t, J = 10.0 Hz, ArC(N)CHCH2O],
4.02 [1 H, t, J = 10.0 Hz, ArC(N)CHCH2O], 6.83 (1 H, t, J = 10.0
Hz, ArH), 7.19 (1 H, t, J = 10.0 Hz, ArH), 7.59 (1 H, d, J = 10.0 Hz,
ArH), 8.02 (1 H, d, J = 10.0 Hz, ArH), 11.29 (1 H, s, ArNH).
Synthesis 2011, No. 16, 2609–2618 © Thieme Stuttgart · New York

PAPER
Chiral b-Diketimine Ligands
2617
13C{1H} NMR (125.8 MHz, C6D6): d = 18.8 [(CH3)2CH], 19.0
[(CH3)2CH], 22.9 [(CH3)3C], 33.4 [(CH3)2CH], 56.4 (CMe3), 69.4
[ArC(N)CHCH2O], 73.2 [ArC(N)CHCH2O], 113.1 (CHarom), 116.0
(CHarom), 120.3 (CHarom), 130.2 (CHarom), 132.9 (CHarom), 146.2
(CHarom), 164.2 (CHarom).
References
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GC/MS: m/z = 204, 161, 133, 119, 106.
HRMS (ESI): m/z calcd for C16H25N2O2S [M + H]+: 309.16422;
found: 309.16874.
(4R)-4,5-Dihydro-2-{2¢-[(S)-tert-butylsulfonamido]phenyl}-4-
isobutyloxazole (L23)
Yield: 70%; [a]D +85.4 (c = 0.57, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.94 [6 H, m, [(CH3)2CH], 1.25
[9 H, s, t-C4H9], 1.63 [2 H, m, (i-PrCH2], 1.83 [1 H, m, (CH3)2CH],
3.87 [1 H, t, J = 6.32 Hz, ArC(N)CHCH2O], 4.11 [1 H, t, J = 7.55
Hz, ArC(N)CHCH2O], 4.40 [1 H, t, J = 6.95 Hz, ArC(N)CHCH2O],
6.90 (1 H, t, J = 8.48 Hz, ArH), 7.35 (1 H, t, J = 7.95 Hz, ArH), 7.41
(1 H, d, J = 8.03 Hz, ArH), 7.71 (1 H, d, J = 8.48 Hz, ArH), 11.04
(1 H, s, ArNH).
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13C{1H} NMR (125.8 MHz, CDCl3): d = 22.3 [(CH3)2CH], 22.8
[(CH3)3C], 23.1 [(CH3)2CH], 45.7 [i-PrCH2], 56.7 (CMe3), 64.8
[ArC(N)CHCH2O], 71.7 [ArC(N)CHCH2O], 112.6 (CHarom), 115.1
(CHarom), 120.1 (CHarom), 129.1 (CHarom), 132.6 (CHarom), 144.9
(CHarom), 163.6 (CHarom).
GC/MS: m/z = 264, 216, 161, 145, 120.
HRMS (ESI): m/z calcd for C17H27N2O2S [M + H]+: 323.17987;
found: 323.18379.
(4S)-4,5-Dihydro-2-{2¢-[(S)-tert-butylsulfonamido]phenyl}-4-
sec-butyloxazole (L24)
Yield: <10%; [a]D +64.1 (c = 0.85, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 0.75 [3 H, m, MeCH2CH(CH3)],
0.89 [1 H, m, MeCH2CH(Me)], 0.91 [3 H, m, CH3CH2CH(Me)],
0.94 [1 H, m, MeCH2CH(Me)], 1.28 [1 H, m, MeCH2CH(Me)],
1.38 [9 H, s, t-C4H9], 4.13 [1 H, t, J = 8.48 Hz, ArC(N)CHCH2O],
4.26 [1 H, t, J = 8.08 Hz, ArC(N)CHCH2O], 4.36 [1 H, t, J = 8.90
Hz, ArC(N)CHCH2O], 6.93 (1 H, t, J = 7.64 Hz, ArH), 7.37 (1 H, t,
J = 8.33 Hz, ArH), 7.46 (1 H, d, J = 8.52 Hz, ArH), 7.77 (1 H, d, J =
7.22 Hz, ArH), 11.06 (1 H, s, ArNH).
13C{1H} NMR (125.8 MHz, CDCl3): d = 11.3 [MeCH(CH2CH3)],
15.0 [CH3CH(CH2Me)], 23.0 [(CH3)3C], 25.9 [MeCH(CH2Me)],
39.5 [MeCH(CH2Me)], 56.9 (CMe3), 69.0 [ArC(N)CHCH2O), 71.6
[ArC(N)CHCH2O], 112.6 (CHarom), 115.2 (CHarom), 123.8 (CHarom),
132.3 (CHarom), 132.8 (CHarom), 145.0 (CHarom), 163.7 (CHarom).
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GC/MS: m/z = 218, 178, 161, 133.
HRMS (ESI): m/z calcd for C17H27N2O2S [M + H]+: 323.17987;
found: 323.18127.
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Acknowledgment
Financial support from ND EPSCoR through NSF grant #EPS-
0814442 and the University of North Dakota is greatly appreciated.
We are very grateful to Dr. Alena Kubatova and her group at the
University of North Dakota for assistance with TOF MS.
Synthesis 2011, No. 16, 2609–2618 © Thieme Stuttgart · New York

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P. I. Binda et al.
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Synthesis 2011, No. 16, 2609–2618 © Thieme Stuttgart · New York