Synthesis of thiazoline-oxazoline ligands and their application in asymmetric catalysis

Article abstract of DOI:10.1002/ejoc.201101335

A series of novel ligands incorporating oxazoline and thiazoline units were synthesized in high yield by employing a convergent route, in which the key step is a microwave-assisted palladium-catalyzed aryl amination. The new ligands were tested in the zin

Full text of DOI:10.1002/ejoc.201101335

FULL PAPER
DOI: 10.1002/ejoc.201101335
Synthesis of Thiazoline–Oxazoline Ligands and Their Application in
Asymmetric Catalysis
Seán C. McKeon,[a] Helge Müller-Bunz,[a] and Patrick J. Guiry*[a]
Keywords: Asymmetric catalysis / Ligand design / Alkylation / Allylation / N ligands
A series of novel ligands incorporating oxazoline and thiaz-
oline units were synthesized in high yield by employing a
convergent route, in which the key step is a microwave-as-
sisted palladium-catalyzed aryl amination. The new ligands
were tested in the zinc-catalyzed Friedel–Crafts alkylation of
Hiyama–Kishi (NHK) allylation of benzaldehyde, affording
enantiomeric excess values of up to 85%. A crystal structure
of the most successful ligand in this transformation bound to
iron(III) was obtained and demonstrated a tridentate binding
mode of the ligand. A transition state is proposed to account
indole with trans-β-nitrostyrene, inducing enantiomeric ex- for the preferential formation of the (R)-enantiomer in the
cess values of up to 69%. The complete series of these li-
gands was also applied to the chromium-catalyzed Nozaki–
NHK reaction.
Our previous work on tridentate [N,N,N]-bis(oxazoline)
ligands 1, which employed a Pd-catalyzed aryl amination as
Introduction
Since Brunner first applied a chiral oxazoline ring as a the key step in their synthesis, afforded us an opportunity
ligand in catalysis in 1986,[1] metal complexes of oxazoline- to study the analogous mixed thiazoline–oxazoline ligand
containing ligands have become one of the most successful, class 2 (Figure 1). We initiated this study as ligand class 1,
versatile, and commonly used classes of catalysts for asym- prepared first by us in 2002,[25] proved particularly success-
metric catalysis.[2–11] One of the main reasons for their pop- ful when applied in the asymmetric Cr-catalyzed allylation,
ularity is that the majority of these ligands are easily syn- crotylation, methallylation, and homoallenylation of alde-
thesized in a few high-yielding steps from commercially hydes.[26] The group of Du subsequently reported a different
available chiral amino alcohols. In contrast, thiazoline-con- synthetic approach to 1, which, unlike our approach that
taining ligands have not been used as abundantly in asym- could afford both C2- and non-C2-symmetric analogues,
metric catalysis since they were first investigated by gave only the C2-symmetric examples.[27] Du has signifi-
Helmchen in 1991.[12] Examples include bis(thiaz- cantly expanded the range of asymmetric transformations
oline)s,[13–19] phosphane–thiazolines,[15,16] pyridyl–thiaz- to which metal complexes of 1 have been applied, for exam-
olines,[15,17] hydroxyalkyl–thiazolines,[20] sulfanyl–thiaz- ple, the Henry reaction of α-keto esters,[28] the Friedel–
olines,[21,22] and tris-thiazolines.[23] Catalytic reactions Crafts alkylation of arenes with nitroalkenes,[29] and the
where both thiazolines and analogous oxazolines have been Michael reaction of nitroethane to nitroalkenes,[30] and Ni-
applied have shown that there is a distinct difference in re- shiyama also applied them to the asymmetric hydro-
activity between these two analogues.[24] This is not surpris- silylation of ketones and enones.[31]
ing considering the difference in atomic character between
oxygen and sulfur, such as, atomic radius, electronegativity,
bond length, and bond angle, and hence, the chelating be-
havior of such compounds towards metal ions. Therefore, a
ligand containing both of these structural motifs offers a
unique analogue of previous similar bis(oxazoline) or bis-
(thiazoline) ligands.
Recent modifications to the parent ligand structure in-
clude bis(thiazoline) 3[32] and bis(imidazoline) 4.[27] For
many of the transformations we studied, metal complexes
of the non-C2-symmetric ligands afforded higher enantio-
selectivities than the related C2-symmetric examples, and we
investigated this by preparing and testing bis(oxazoline) li-
gands 5 containing the N-thienylaniline unit.[33]
As a continuation of our study on unsymmetrical li-
gands, we have recently successfully applied six examples
(R1, R2 = iPr, tBu, Ph, Bn and two differentially substituted
analogues R1 = tBu, R2 = Bn and R1 = Bn, R2 = tBu) of
the mixed thiazoline–oxazoline ligand class 2 to the Frie-
del–Crafts alkylation of indole by using a range of nitro-
styrenes, obtaining enantiomeric excess values of up to 76%
(for R1 = tBu, R2 = Bn) in excellent yields.[34] In an attempt
[a] Centre for Synthesis and Chemical Biology,
School of Chemistry and Chemical Biology,
Conway Institute of Biomolecular and Biomedical Research,
University College Dublin
Belfield, Dublin 4, Ireland
Fax: +353-1-7162501
E-mail: p.guiry@ucd.ie
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101335.
Eur. J. Org. Chem. 2011, 7107–7115
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S. C. McKeon, H. Müller-Bunz, P. J. Guiry
FULL PAPER
side reaction, whereby the benzylic hydrogen on the thiaz-
oline ring of these ligands is abstracted by the base, re-
sulting in the generation of a series of side products in a
diastereomeric ratio of 6:1 or 3:1 arising from epimerization
of this chiral center. We had previously noted similar obser-
vations in the preparation of the ligand in which both the
thiazoline and oxazoline were derived from phenylglycin-
ol.[34]
Table 1. Synthesis of ligands 2 by Pd-catalyzed aryl amination.
Entry
Ligand
R1
R2
Yield [%]
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2f
iPr
iPr
iPr
tBu
tBu
Ph
Ph
Ph
Bn
Bn
tBu
Ph
Bn
iPr
Ph
iPr
tBu
Bn
iPr
Ph
70
70
59
68
79
31[a]
41[a]
29[a]
48
Figure 1. Tridentate oxazoline-, thiazoline-, and imidazoline-con-
taining ligands.
2g
2h
2i
2j
62
to enhance the enantioselectivity induced by these thiaz-
oline–oxazoline containing ligands in this reaction, the li-
gand series has now been expanded with the synthesis of 10
new analogues (i.e., 2a–j) and their application to the Frie-
del–Crafts alkylation of indole with trans-β-nitrostyrene.
The application of the complete series 2a–p to the chro-
mium-catalyzed Nozaki–Hiyama–Kishi (NHK) allylation
of benzaldehyde is also reported herein.
[a] Diastereomeric ratio 6:1.
Crystals of ligand 2e suitable for X-ray analysis were
grown by the slow evaporation at room temperature of a
saturated solution of 2e in a mixture of dichloromethane/n-
hexane (1:1). From the crystallographic structure we can see
that the three nitrogen atoms are in plane with one another,
forming a concave pocket for binding to a metal (Figure 2).
Results and Discussion
The key step in the convergent synthesis of tridentate
[N,N,N]-bis(oxazoline) ligands 2 is a microwave-assisted
Hartwig–Buchwald-type aryl amination.[35] The coupling of
2-(o-bromophenyl)thiazoline (6) and 2-(o-aminophenyl)ox-
azoline (7) allows a facile synthesis of a new range of steri-
cally and electronically diverse ligands in a few high-yield-
ing steps. The synthesis of these coupling partners can be
obtained in one and two steps, respectively, in very high
yields, and microwave-assisted coupling is preferred over
coupling under thermal conditions.[34]
Under the optimized reaction conditions in which tolu-
ene was used as a solvent, Pd2(dba)3 as the palladium
source, sodium tert-butoxide as base, and 1,1Ј-bis(diphenyl-
phosphanyl)ferrocene (DPPF) as the ligand, ligands 2a–j
were obtained in moderate to very high yields of 48–79%
(Table 1, Entries 1–5, 9–10), with the exception of phenyl-
glycinol-derived thiazoline-containing ligands 2f–i, which
were obtained in yields of 22–41% (Table 1, Entries 6–8).
Figure 2. Crystal structure of ligand 2e; thermal ellipsoids are
drawn at the 50% probability level, and all hydrogen atoms, except
for the NH group, have been omitted for clarity.
Catalytic Asymmetric Friedel–Crafts Alkylation
The Friedel–Crafts alkylation of arenes with electron-de-
The decrease in yields for these ligands is attributed to a ficient alkenes is one of the most important organic trans-
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Synthesis of Thiazoline–Oxazoline Ligands
formations to employ Lewis acid catalysts.[36,37] Recently, 7). The highest ee value obtained was for ligand 2c (R1 =
nitroalkenes have been used extensively as substrates in the iPr, R2 = Bn), which afforded product indole 7 in 69%ee
asymmetric Friedel–Crafts alkylation of indoles.[38,39] The (R) and 100% yield (Table 2, Entry 3). This is only slightly
nitro group is one of the strongest electron-withdrawing superior to the 67%ee obtained with the ligand when R1 =
groups known, so nitroalkenes have proven to be excellent R2 = iPr.[34]
Michael acceptors.[40] This, coupled with the fact the nitro
group is easily transformed into a range of different func-
tionalities, has resulted in their wide application in organic
Catalytic Asymmetric Nozaki–Hiyama–Kishi Allylation
synthesis.[41] Literature reports employing chiral Lewis acids
include the application of symmetrical examples of triden-
The NHK reaction has become an important and versa-
tate ligands 1 and 3 by Du who obtained ee values up to tile carbon–carbon bond-forming process, involving the nu-
83% (R) when ligand 1 (R1 and R2 = Ph) was employed.[29a] cleophilic addition of organochromium(III) reagents to car-
The application of our newly prepared ligands 2a–j in bonyl compounds. NHK reactions combine many unique
the zinc-catalyzed Friedel–Crafts alkylation of indole (8) and important features, including pronounced chemoselec-
with trans-β-nitrostyrene (9) afforded product 10 in excel- tivity of the organochromium(III) reagents for aldehydes,
lent yield and with a broad range of enantiomeric excess even in the presence of ketones; high levels of enantio-
values depending on the substitution of R1 and R2 selectivity; suitability of a wide range of substrates, includ-
(Table 2).
ing allyl, propargyl, alkenyl, alkynyl, and aryl halides, alk-
enyl triflates, and sulfonates and phosphates, as precursors
for the formation of organochromium intermediates and
compatibility with an array of functional groups in both
reaction partners.[42]
Table 2. The application of ligands 2a–j in the asymmetric zinc-
catalyzed Friedel–Crafts alkylation of indole.
To examine the versatility in asymmetric catalysis of this
novel class of ligands, ligands 2a–p were applied in the chro-
mium-catalyzed NHK allylation of benzaldehyde (Table 3).
In this study, we were pleased to find excellent conversions
were obtained for ligands 2a–p. As found in the application
of ligands 1 in this transformation,[26a] thiazoline–oxazoline
ligands 2k–m where R1 = R2 = iPr/tBu/Ph favored the for-
mation of the (S) enantiomer (Table 3, Entries 11–13). The
use of nondiasteromerically pure ligands 2f, 2g, 2i, and 2n
containing the phenylglycinol-derived thiazoline ring re-
sulted in poor enantiomeric excess regardless of the substi-
tution on the oxazoline (Table 3, Entries 6–8, 13). Benzyl-
substituted ligands were equally poor (Table 3, Entries 3, 9,
10, 14) with the exception of those that were combined with
a tert-butyl substituent (Table 3, Entries 15, 16).
Entry Ligand
R1
R2
Yield
[%][a]
ee
[%][b]
1
2
3
4
5
6
7
8
9
2a
iPr
iPr
iPr
tBu
tBu
Ph
Ph
Ph
Bn
Bn
tBu
Ph
Bn
iPr
Ph
iPr
tBu
Bn
iPr
Ph
100
100
100
100
99
100
100
99
19 (R)
56 (R)
69 (R)
8 (S)
67 (R)
rac
59 (R)
32 (R)
21 (R)
64 (R)
2b
2c
2d
2e
2f[c]
2g[c]
2h[c]
2i
100
94
10
2j
As in the application of bis(oxazolines) 1 in the allylation
of benzaldehyde,[26a] the Bn/tBu R group substitution pro-
vided the optimal enantioselectivities found for this reac-
tion. In this case, the results are even more contrasting to
those found for different substitutions, with poor to no en-
antiomeric excess being the result of any other combination
[a] Isolated yield. [b] Determined by chiral HPLC analysis of the
products by using a Daicel Chiralcel OD column (hexane/2-prop-
anol = 70:30, 0.9 mLmin–1); the absolute configurations of the
products were assigned by comparison of the chiral HPLC reten-
tion times with literature values.[38] [c] Diastereomeric ratio 6:1.
As in the application of previous tridentate [N,N,N]-bis- of R group (Table 3). A dramatic difference in selectivity
(oxazoline) and bis(thiazoline) ligands, the extended ligand depending on which ring the aromatic or alkyl group is situ-
series 2a–j showed a preference for the formation of the (R) ated is witnessed in this case. A 55%ee (R) was induced by
enantiomer in this transformation.[29a,34] Poor enantiomeric ligand 2p, where the benzyl group is on the thiazoline ring
excess values were obtained when both R1 and R2 were and the tert-butyl group is on the oxazoline (Table 3, En-
alkyl substituents (Table 2, Entries 1, 4). Enantiomeric ex- try 16). The best result was found in the application of li-
cess values were greatly improved with the use of aromatic gand 2o, 85%ee (R), which contained the bulky alkyl group
R groups, for both R1 and R2 (Table 2, Entries 8, 10), or in on the thiazoline and the aromatic group on the oxazoline
conjunction with an alkyl-substituted group (Table 2, En- ring (Table 3, Entry 15). This is slightly inferior to the
tries 2, 3, 5, 7, 9), except in the case of ligand 2f (R1 = Ph, 87%ee obtained in the allylation of benzaldehyde with tBu/
R2 = iPr; Table 2, Entry 6). In the cases where one R group Bn-substituted bis(oxazoline) ligand 1.[26a]
was aromatic and the other alkyl substituted, better enan-
After many attempts to synthesize chromium complexes
tiomeric excess values were obtained when the aromatic R of these ligands we were pleased to synthesize iron(III)
group was on the oxazoline ring and the alkyl substituent chloride complex 14, derived from our most successful li-
on the thiazoline ring (Table 2, Entry 2 vs. 6, 3 vs. 9, 5 vs. gand 2o and iron(II) chloride after oxidation in air, and
Eur. J. Org. Chem. 2011, 7107–7115
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S. C. McKeon, H. Müller-Bunz, P. J. Guiry
FULL PAPER
Table 3. The application of ligands 2a–p in the enantioselective No-
From this crystallographic evidence we can see the ligand
bound in a tridentate fashion to the metal ion in 14 through
the nitrogen bridging the phenyl groups and the nitrogen
atoms on the oxazoline and thiazoline rings. The σ bond
and two π bonds from the thiazoline and oxazoline enve-
lope the iron center in a concave pocket. If one assumes the
same coordination to chromium(II) in the NHK reaction,
this would leave the equatorial position for substrates to
bind to, and thus allow the reaction to proceed intramolec-
ularly.
zaki–Hiyama–Kishi allylation of benzaldehyde.
Entry Ligand
R1
R2
Conversion Yield
ee[c]
[%][a]
[%][b]
[%][d]
We propose the following catalytic cycle and key transi-
tion state to rationalize the preferential formation of the
(R) enantiomer of alcohol 13 with the use of ligand 2o
(Scheme 1).
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
iPr
iPr
iPr
tBu
tBu
Ph
tBu
Ph
Bn
iPr
Ph
iPr
tBu
Bn
iPr
Ph
iPr
tBu
Ph
98
100
99
100
100
89
100
100
100
100
94
100
100
85
77
78
81
84
88
80
90
87
85
87
78
87
81
67
84
75
19 (R)
35 (R)
13 (R)
3 (S)
11 (R)
5 (S)
12 (R)
11 (S)
5 (S)
2f[e]
2g[e]
2h[e]
2i
Ph
Ph
9
Bn
Bn
iPr
tBu
Ph
Bn
tBu
Bn
10
11
12
13
14
15
16
2j
9 (S)
2k
2l
39 (S)
10 (R)
31 (S)
6 (S)
85 (R)
55 (R)
2m[f]
2n
Bn
Bn
tBu
2o
2p
100
100
[a] Determined from the 300 MHz 1H NMR spectrum of the crude
silylated product. [b] Isolated yield of allylic alcohol 13. [c] Deter-
mined by chiral HPLC analysis of alcohol product 10 by using a
Daicel Chiralcel OD column. [d] Determined by comparison of the
chiral HPLC retention times with literature values.[26a] [e] Dia-
stereomeric ratio 6:1. [f] Diastereomeric ratio 9:1.[34]
Scheme 1. Proposed catalytic cycle and key intermediate for the
chromium-catalyzed allylation of benzaldehyde by using ligand 2o
(R1 = Bn; R2 = tBu).
crystallize it by slow evaporation of dichloromethane at
room temperature (Figure 3). Nishiyama previously re-
ported the iron(III) chloride complex of ligand 1 (R1 = R2
= iPr),[31b] and the structures are similar in that they are
both trigonal-bipyramidal coordination complexes, and the
thiazoline/oxazoline rings in 14, and the oxazoline rings in
their case, are situated at apical positions relative to each
other.
In this transition state the allyl moiety is proposed to
bind to the chromium in the equatorial position while the
aldehyde would coordinate at the apical position through
an anti geometry to minimize the steric interactions be-
tween the phenyl group of the benzaldehyde and the benzyl
group of the oxazoline. Therefore, attack from the Re face
should be favored through this transition state, thus form-
ing the (R) enantiomer preferentially. We believe the key
role of the tBu thiazoline substituent is to block coordina-
tion of benzaldehyde from the opposite apical site.
Conclusions
Our original tridentate thiazoline–oxazoline ligand series
has been expanded by the synthesis of 10 novel ligands,
incorporating a range of different functionalities as R
groups. These ligands were produced in moderate to excel-
lent yields by using a microwave-assisted Hartwig–Buch-
wald-type aryl amination as a key step in a convergent syn-
thesis, thus allowing the facile production of a diverse range
of analogues. This new series of ligands was then applied in
the zinc-catalyzed Friedel–Crafts reaction and the chro-
mium-catalyzed NHK reaction, in which they were success-
ful both in terms of catalytic activity and the induction of
Figure 3. Crystal structure of iron complex 14 derived from ligand
2p; thermal ellipsoids are drawn at the 50% probability level, and
all hydrogen atoms have been omitted for clarity.
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Synthesis of Thiazoline–Oxazoline Ligands
3J(H,H) = 7.9 Hz, 1 H, CH2O], 4.23 [dd, 3J(H,H) = 9.9 Hz,
2J(H,H) = 8.4 Hz, 1 H, CH2O], 4.39–4.42 (m, 1 H, CHN), 6.83–
6.86 (m, 1 H, Ar-HC), 6.96–6.99 (m, 1 H, Ar-HC), 7.25–7.29 (m,
enantioselectivity. The tridentate binding ability of these
versatile ligands has been proven by X-ray structural analy-
sis of an iron(II) ligand complex. On the basis of this crys-
tallographic evidence, a transition state has been proposed
to account for the excellent enantiomeric excess afforded by
ligand 20 (R1 = tBu, R2 = Bn) in the allylation of benzalde-
hyde [85% (R)]. These ligands are currently being applied
to a range of other asymmetric metal-catalyzed transforma-
tions, the results of which will be reported in due course.
3
4
3 H, Ar-HC), 7.38 [dd, J(H,H) = 8.3 Hz, J(H,H) = 0.7 Hz, 1 H,
3
4
Ar-HC], 7.68 [dd, J(H,H) = 7.9 Hz, J(H,H) = 1.5 Hz, 1 H, Ar-
HC], 7.80 [d, 3J(H,H) = 7.7 Hz, 1 H, Ar-HC], 10.73 (br. s, 1 H,
NH) ppm. 13C NMR (150 MHz, CDCl3, 25 °C, TMS): δ = 19.0
[CH(CH3)2], 19.8 [CH(CH3)2], 25.9 [C(CH3)3], 33.2 [C(CH3)3], 34.0
[CH(CH3)2], 34.7 (CH2S), 67.4 (CH2O), 76.5 (CHN), 84.0 (CHN),
114.7 [CAr(C=N)], 117.5, 119.0, 120.7, 121.2 [CAr(H)], 124.3
[CAr(C=N)], 130.2, 130.8, 131.4, 131.5 [CAr(H)], 141.7 [CAr(NH)],
144.3 [CAr(NH)], 162.7 (C=N), 165.0 (C=N) ppm. IR (KBr): ν =
˜
3209, 2957, 2869, 1643, 1578, 1518, 1453, 1213, 1026, 907,
750 cm–1. HRMS (ESI+): calcd for C25H31N3OS [M + H]+
422.2266; found 422.2274. C25H31N3OS (421.60): calcd. C 71.22,
H 7.41, N 9.97; found C 70.84, H 7.40, N 9.54.
Experimental Section
General Remarks: 1H NMR (300, 400, 500, and 600 MHz) and 13
C
NMR (75, 100, 125, and 150 MHz) spectra were recorded with
Varian Oxford 300, 400, 500, and 600 MHz spectrometers by using
tetramethylsilane as an internal standard. Elemental analysis was
performed in the School of Chemistry and Chemical Biology, Uni-
versity 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.
Routine electrospray mass spectrometric analysis was performed
with a Waters Micromass Quattro Ultima mass spectrometer.
High-resolution mass spectra were obtained by using a Micromass/
Waters LCT instrument. Infrared spectra were recorded with a Per-
kin–Elmer Infrared FT spectrometer. Optical rotation values were
measured at room temperature with a Perkin–Elmer 343 polarime-
ter. Melting points were determined in open capillary tubes with a
Gallenkamp melting point apparatus. Thin-layer chromatography
(TLC) was carried out on aluminum sheets precoated with silica
gel 60 F254 (Merck). Column chromatography separations were
performed by using Merck Kieselgel 60 (0.040–0.060 mm). Prepar-
ative layer chromatography was carried out on glass plates pre-
coated with silica gel 60 HF254+366 (Merck). All amination reac-
tions were conducted in a CEM Discover S-Class microwave reac-
tor. HPLC analyses were performed with LC 2010A machine
equipped with a UV/Vis detector employing a chiral OD column
from Daicel Chemical Industries. Solvents were dried immediately
before use by distillation from standard drying agents.
2-[(S)-4-Isopropyl-4,5-dihydrothiazol-2-yl]-N-{2-[(S)-4-phenyl-4,5-di-
hydrooxazol-2-yl]phenyl}benzenamine (2b): Yield: 70% (155 mg),
white semi-solid; Rf = 0.39 (cyclohexane/EtOAc, 8:1). [α]2D0
=
+179.3 (c = 1.3, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 0.83 [d, 3J(H,H) = 6.8 Hz, 3 H, CH(CH3)2], 0.86 [d,
3J(H,H) = 6.8 Hz, 3 H, CH(CH3)2], 1.86–1.95 [m, 1 H, CH-
(CH3)2], 2.92 [dd, 2J(H,H) = 10.7 Hz, 3J(H,H) = 9.4 Hz, 1 H,
CH2S], 3.09 [dd, 2J(H,H) = 10.7 Hz, 3J(H,H) = 8.8 Hz, 1 H, CH2S],
4.10–4.19 (m, 2 H, CHN, CH2O), 4.68 [dd, 2J(H,H) = 10.0 Hz,
3J(H,H) = 8.2 Hz, 1 H, CH2O], 5.42 [dd, 3J(H,H) = 10.0 Hz,
3J(H,H) = 8.3 Hz, 1 H, CHN], 6.88–6.95 (m, 2 H, Ar-HC), 7.24–
7.34 (m, 7 H, Ar-HC), 7.39–7.45 (m, 2 H, Ar-HC), 7.60 [dd,
3J(H,H) = 7.8 Hz, 4J(H,H) = 1.4 Hz, 1 H, Ar-HC], 7.89 [dd,
4
3J(H,H) = 7.8 Hz, J(H,H) = 1.4 Hz, 1 H, Ar-HC], 10.85 (br. s, 1
H, NH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = [18.2
CH(CH3)2], 19.8 [CH(CH3)2], 32.6 [CH(CH3)2], 34.0 (CH2S), 70.4
(CHN), 73.7 (CH2O), 84.0 (CHN), 115.0 [CAr(C=N)], 118.2, 119.4,
120.6 [CAr(H)], 123.3 [CAr(C=N)], 126.7, 127.4, 128.6, 130.4, 130.6,
131.3, 131.6 [CAr(H)], 141.6 (ipso-Ph), 142.7 [CAr(NH)], 143.9
[CAr(NH)], 164.2 (C=N), 165.0 (C=N) ppm. IR (NaCl): ν = 3197,
˜
3065, 2959, 1637, 1582, 1514, 1452, 1312, 1271, 1215, 1051, 949,
747, 700 cm–1. HRMS (ESI+): calcd. for C27H27N3OS [M + H]+
442.1953; found 442.1950. C27H27N3OS (441.59): calcd. C 73.44,
H 6.16, N 9.52, S 7.26; found C 73.36, H 6.26, N 9.22, S 7.31.
General Procedure for the Microwave-Assisted Aryl Amination: An
oven-dried tube was charged under an atmosphere of nitrogen with
2-(2-bromophenyl)thiazoline (0.500 mmol), sodium tert-butoxide
(0.0577 g, 0.6 mmol), DPPF (0.0225 g, 0.05 mmol), Pd2(dba)3
2-[(S)-4-Benzyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-isopropyl-4,5-di-
hydrothiazol-2-yl]phenyl}benzenamine (2c): Yield: 59% (134 mg),
white semi-solid; TLC: Rf = 0.22 (cyclohexane/EtOAc, 8:1). [α]2D0
=
+58.6 (c = 1.00, CHCl3). 1H NMR (500 MHz, CDCl3, 25 °C,
TMS): δ = 0.97 [d, 3J(H,H) = 6.8 Hz, 3 H, CH(CH3)2], 1.05 [d,
3J(H,H) = 6.8 Hz, 3 H, CH(CH3)2], 2.04–2.10 [m, 1 H, CH(CH3)2],
(0.0115 g,
0.0125 mmol),
and
2-(o-aminophenyl)oxazoline
(0.6 mmol). After the addition of dry, degassed toluene (2 mL) by
syringe, the tube was sealed under an atmosphere of nitrogen, and
the reaction mixture was placed in a microwave and heated at
180 °C for 1 h. The reaction mixture was then cooled to room tem-
perature before removing the seal and concentrated in vacuo to
3
2.71 [dd, 2J(H,H) = 13.7 Hz, J(H,H) = 8.3 Hz, 1 H, CH2Ph], 2.99
[app t, 2J(H,H) = 10.8 Hz, 1 H, CH2S], 3.13 [dd, 2J(H,H) =
13.7 Hz, 3J(H,H) = 5.4 Hz, 1 H, CH2Ph], 3.25 [dd, 2J(H,H) =
2
10.8 Hz, 3J(H,H) = 8.8 Hz, 1 H, CH2S], 4.02 [t, J(H,H) = 8.5 Hz,
yield
a brown oil. This was purified by preparative layer
1 H, CH2O], 4.25 [t, 2J(H,H) = 8.5 Hz, 1 H, CH2O], 4.34 [dt,
chromatography over silica gel (cyclohexane/EtOAc, 8:1) to yield
the pure product.
3
3J(H,H) = 8.8 Hz, J(H,H) = 5.9 Hz, 1 H, CHN], 4.54–4.60 (m, 1
H, CHN), 6.85–6.88 (m, 1 H, Ar-HC), 6.94–6.97 (m, 1 H, Ar-HC),
2-[(S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-isopropyl-
4,5-dihydrothiazol-2-yl]phenyl}benzenamine (2a): Yield: 70 %
(148 mg), white/yellow semi-solid; Rf = 0.35 (cyclohexane/EtOAc,
7.16–7.29 (m, 7 H, Ar-HC), 7.33 [d, 3J(H,H) = 7.8 Hz, 1 H, Ar-
3
HC], 7.40 [d, J(H,H) = 8.3 Hz, 1 H, Ar-HC], 7.65 [dd, 3J(H,H) =
7.8 Hz, 4J(H,H) = 1.5 Hz, 1 H, Ar-HC], 7.78 [dd, 3J(H,H) =
7.8 Hz, 4J(H,H) = 1.5 Hz, 1 H, Ar-HC], 10.76 (br. s, 1 H, NH)
ppm. 13C NMR (125 MHz, CDCl3, 25 °C, TMS): δ = 18.9
1
8:1). [α]2D0 = +3.5 (c = 0.50, CHCl3). H NMR (600 MHz, CDCl3,
25 °C, TMS): δ = 0.90 [s, 9 H, C(CH3)3], 0.97 [d, 3J(H,H) = 6.8 Hz,
3
3 H, CH(CH3)2], 1.05 [d, J(H,H) = 6.8 Hz, 3 H, CH(CH3)2], 2.04 [CH(CH3)2], 19.9 18.9 [CH(CH3)2], 33.1 [CH(CH3)2], 34.5 (CH2S),
[oct., 3J(H,H) = 6.8 Hz, 1 H, CH(CH3)2], 2.98 [dd, 2J(H,H) = 41.9 (CH2Ph), 68.2 (CHN), 70.6 (CH2O), 84.4 (CHN), 115.4
10.7 Hz, 3J(H,H) = 9.6 Hz, 1 H, CH2S], 3.26 [dd, 2J(H,H) =
10.7 Hz, 3J(H,H) = 8.7 Hz, 1 H, CH2S], 4.05 [dd, 3J(H,H) =
[CAr(C=N)], 118.4, 119.5, 119.6, 120.6 [CAr(H)], 123.1 [CAr(C=N)],
126.4, 128.4, 129.3, 130.3, 130.7, 131.4, 131.6 [CAr(H)], 138.1 (ipso-
Ph), 142.0 [CAr(NH)], 143.8 [CAr(NH)], 163.2 (C=N), 165.2 (C=N)
2
9.9 Hz, 3J(H,H) = 7.9 Hz, 1 H, CHN], 4.12 [dd, J(H,H) = 8.4 Hz,
Eur. J. Org. Chem. 2011, 7107–7115
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7111

S. C. McKeon, H. Müller-Bunz, P. J. Guiry
ppm. IR (NaCl): ν = 3021, 3066, 3025, 2957, 1639, 1581, 1514, 2393.1(4) Å3, T = 100 K, space group P212121 (no. 19), Z = 4,
FULL PAPER
˜
1451, 1313, 1269, 1214, 1048, 746, 700 cm–1. HRMS (ESI+): calcd.
for C28H29N3OS [M + H]+ 456.2110; found 456.2094. C28H29N3OS
(455.62): calcd. C 73.81, H 6.42, N 9.22, S 7.04; found C 73.51, H
6.49, N 8.92, S 6.74.
12367 reflections measured, 3801 unique (Rint = 0.0344), which
were used in all calculations. The final wR(F2) was 0.0809 (all
data).
2-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-phenyl-4,5-di-
hydrothiazol-2-yl]phenyl}benzenamine (2f): Yield: 31 % (68 mg),
white semi-solid; Rf = 0.35 (cyclohexane/EtOAc, 8:1). [α]2D0 = +93
(c = 0.70, CHCl3). 1H NMR (600 MHz, [D6]benzene, 25 °C, TMS):
2-[(S)-4-tert-Butyl-4,5-dihydrothiazol-2-yl]-N-{2-[(S)-4-isopropyl-
4,5-dihydrooxazol-2-yl]phenyl}benzenamine (2d): Yield: 68 %
(144 mg), white semi-solid; Rf = 0.33 (cyclohexane/EtOAc, 8:1).
[α]2D0 = +29.1 (c = 1.00, CHCl3). 1H NMR (500 MHz, CDCl3,
25 °C, TMS): δ = 0.89 [d, 3 J(H,H) = 6.8 Hz, 3 H, CH-
3
3
δ = {0.56* [d, J(H,H) = 6.7 Hz] and 0.60 [d, J(H,H) = 6.7 Hz]}
3
[1 H, CH(CH3)2, ratio 1:2], {0.73* [d, J(H,H) = 6.7 Hz] and 0.75
[d, J(H,H) = 6.7 Hz]} [1 H, CH(CH3)2, ratio 1:2], 1.30–1.36 [m, 1
3
3
(CH3)2], 0.96 [d, J(H,H) = 6.8 Hz, 3 H, CH(CH3)2], 1.01 [s, 9 H,
2
C(CH3)3], 1.75 [oct., 3J(H,H) = 6.8 Hz, 1 H, CH(CH3)2], 3.06 [app
t, 2J(H,H) = 10.8 Hz, 3J(H,H) = 10.8 Hz, 1 H, CH2S], 3.19 [dd,
2J(H,H) = 10.8 Hz, 3J(H,H) = 8.8 Hz, 1 H, CH2S], 3.99 [app t,
H, CH(CH3)2], {2.77 [app t, J(H,H) = 10.6 Hz] and 2.80* [app t,
2J(H,H) = 10.5 Hz]} (1 H, CH2S, ratio 2:1), {3.10* [dd, J(H,H) =
2
10.5 Hz, 3J(H,H) = 9.2 Hz] and 3.14 [dd, 2J(H,H) = 10.6 Hz,
3J(H,H) = 9.2 Hz]} (1 H, CH2S, ratio 1:2), 3.39–3.43 (m, 1 H,
CHN), 3.51 [app t, 3J(H,H) = 8.5 Hz, 2J(H,H) = 8.5 Hz CH2O],
{3.67 [dd, 3J(H,H) = 9.5 Hz, 2J(H,H) = 8.3 Hz] and 3.68–3.71*
3
2J(H,H) = 9.3 Hz, J(H,H) = 9.3 Hz, 1 H, CH2O], 4.03–4.08 (m, 1
H, CHN), 4.29 [dd, 2J(H,H) = 9.3 Hz, 3J(H,H) = 7.8 Hz, 1 H,
CH2O], 4.34 [dd, 3J(H,H) = 10.8 Hz, 3J(H,H) = 8.8 Hz, 1 H,
3
3
3
4
(m)} (1 H, CH2O, ratio 2:1), {5.44* [app t, J(H,H) = 9.8 Hz] and
CHN], 6.87 [ddd, J(H,H) = 8.0 Hz, J(H,H) = 6.1 Hz, J(H,H) =
2.2 Hz, 1 H, Ar-HC], 6.94–6.97 (m, 1 H, Ar-HC), 7.24–7.28 (m, 8
H, Ar-HC), 7.33 [d, 3J(H,H) = 8.3 Hz, 1 H, Ar-HC], 7.67 [dd,
3J(H,H) = 7.8 Hz, 4J(H,H) = 1.5 Hz, 1 H, Ar-HC], 7.82 [dd,
3J(H,H) = 8.3 Hz, 4J(H,H) = 1.0 Hz, 1 H, Ar-HC], 10.61 (br. s,
NH) ppm. 13C NMR (125 MHz, CDCl3, 25 °C, TMS): δ = 18.5
[CH(CH3)2], 18.9 [CH(CH3)2], 26.9 [C(CH3)3], 33.1 [CH(CH3)2],
33.3 (CH2S), 35.2 [C(CH3)3], 69.2 (CH2O), 72.8 (CHN), 87.9
(CHN), 115.4 [CAr(C=N)], 118.3, 119.4, 120.2, 120.9 [CAr(H)],
123.8 [CAr(C=N)], 130.3, 130.8, 131.4, 131.5 [CAr(H)], 142.1
[CAr(NH)], 144.1 [CAr(NH)], 162.7 (C=N), 165.2 (C=N) ppm. IR
5.48 [app t, 3J(H,H) = 9.8 Hz]} (1 H, CHN, ratio1:2), 6.67–6.74
(m, 2 H, Ar-HC), 6.91–7.08 (m, 5 H, Ar-HC), {7.18 [br. d, 3J(H,H)
3
= 7.0 Hz] and 7.21* [br. d, J(H,H) = 7.0 Hz]} (2 H, Ar-HC, ratio
2:1), {7.28* [br. d, 3J(H,H) = 8.1 Hz] and 7.34 [br. d, 3J(H,H) =
3
8.2 Hz]} (1 H, Ar-HC, ratio 1:2), {7.38* [br. d, J(H,H) = 8.1 Hz]
3
and 7.42 [br. d, J(H,H) = 8.2 Hz]} (1 H, Ar-HC, ratio 2:1), {7.87
3
4
3
[dd, J(H,H) = 7.8 Hz, J(H,H) = 1.2 Hz] and 7.92* [dd, J(H,H)
= 7.8 Hz, 4J(H,H) = 1.2 Hz]} (1 H, Ar-HC, ratio 2:1), 8.07–8.08
(m, 1 H, Ar-HC), [11.43* (br. s) and 11.59 (br. s)] (1 H, NH, ratio
1:2) ppm. 13C NMR (150 MHz, [D6]benzene, 25 °C, TMS): δ =
[17.7*, 17.9] [CH(CH3)2], [18.6, 18.7*] [CH(CH3)2], [32.5, 32.6*]
[CH(CH3)2], [40.1*, 40.4] (CH2S), [68.2*, 68.3] (CH2O), [72.7,
72.8*] (CHN), [81.2*, 81.3] (CHN), 114.6 [CAr(C=N)], [a, (118.8,
118.9*),(120.9, 121.0*),(120.9, 121.1*)] [CAr(H)], [124.0*, 124.0]
[CAr(C=N)], [(126.7, 126.7*), (127.0, 127.1*), (128.1, 128.2*),
(130.3, 130.4*), (130.8, 130.9*), (131.2, 131.3*), (131.6, 131.9*)]
[CAr(H)], [141.7, 141.9*] [CAr(NH)], [142.6, 142.7*] (ipso-Ph),
[144.4, 144.5*] [CAr(NH)], [162.2, 162.3*] (C=N), [166.7*, 166.9]
(NaCl, CHCl film): ν = 3220, 4082, 2957, 1584, 1454, 1317, 1274,
˜
3
1052, 939, 742 cm–1. HRMS (ESI+): calcd. for C25H31N3OS [M +
H]+ 422.2266; found 422.2245. C25H31N3OS (421.60): calcd. C
71.22, H 7.41, N 9.97, S 7.61; found C 71.18, H 7.53, N 9.63, S
7.39.
2-[(S)-4-tert-Butyl-4,5-dihydrothiazol-2-yl]-N-{2-[(S)-4-phenyl-4,5-di-
hydrooxazol-2-yl]phenyl}benzenamine (2e): Yield: 79% (180 mg),
white solid; m.p. 135–136 °C; Rf = 0.08 (cyclohexane/EtOAc, 8:1).
[α]2D0 = +171.0 (c = 1.01, CHCl3). 1H NMR (500 MHz, CDCl3,
25 °C, TMS): δ = 0.92 [s, 9 H, C(CH3)3], 2.98 [t, 2J(H,H) = 10.8 Hz,
(C=N) ppm. IR: ν = 3216, 2956, 2923, 2870, 2852, 1640, 1579,
˜
1515, 1451, 1047, 1027, 750, 698 cm–1. HRMS (ESI+): calcd. for
C27H27N3OS [M + H]+ 442.1953; found 442.1941.
2
3
1 H, CH2S], 3.04 [dd, J(H,H) = 10.8 Hz, J(H,H) = 9.3 Hz, 1 H,
CH2S], 4.06 [dd, 3J(H,H) = 10.8 Hz, 3J(H,H) = 8.8 Hz, 1 H, CHN],
4.11 [app t, 2J(H,H) = 8.3 Hz, 3J(H,H) = 8.3 Hz, 1 H, CH2O], 4.67
2-[(S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-phenyl-4,5-di-
hydrothiazol-2-yl]phenyl}benzenamine (2 g): Yield: 41% (94 mg),
colorless oil; Rf = 0.38 (cyclohexane/EtOAc, 8:1). [α]2D0 = +98.0 (c
= 1.00, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
2
3
[dd, J(H,H) = 8.3 Hz, J(H,H) = 10.2 Hz, 1 H, CH2O], 5.37 [dd,
3J(H,H) = 8.3 Hz, J(H,H) = 10.2 Hz, 1 H, CHN], 6.89–6.96 (m,
2 H, Ar-HC), 7.23–7.34 (m, 8 H, Ar-HC), 7.37 [br. d, J(H,H) =
3
2
[0.70* (s), 0.73 (s)] [9 H, C(CH3)3, ratio 8:1], 3.08 [dd, J(H,H) =
3
10.7 Hz, 3J(H,H) = 10.0 Hz, 1 H, CH2S], 3.56–3.64 (m, 2 H, CHN,
CH2S), 3.82 [app t, 2J(H,H) = 8.2 Hz, 3J(H,H) = 8.2 Hz 1 H,
CH2O], 3.91 [dd, 3J(H,H) = 9.9 Hz, 2J(H,H) = 8.2 Hz, 1 H, CH2O],
8.3 Hz, 1 H, Ar-HC], 7.61 [dd, 3J(H,H) = 7.8 Hz, 4J(H,H) =
1.5 Hz, 1 H, Ar-HC], 7.90 [dd, 3J(H,H) = 7.8 Hz, 4J(H,H) =
1.5 Hz, 1 H, Ar-HC], 10.64 (br. s, 1 H, NH) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C, TMS): δ = 26.8 [C(CH3)3], 33.3 (CH2S),
35.0 [C(CH3)3], 70.2 (CHN), 73.7 (CHN), 73.7 (CH2O), 87.8
(CHN), 115.2 [CAr(C=N)], 118.5, 119.6, 119.7, 120.8 [CAr(H)],
123.8 [CAr(C=N)], 126.8, 127.4, 128.6, 130.5, 130.7, 131.3, 131.7
[CAr(H)], 141.8 [CAr(4°)], 142.6 [CAr(4°)], 144.1 [CAr(4°)], 164.3
3
5.61 [app t, J(H,H) = 9.2 Hz, 1 H, CHN], 6.75–6.79 (m, 1 H, Ar-
HC), 6.92–6.96 (m, 1 H, Ar-HC), 7.16–7.30 [m, 8 H, Ar-HC(Ph),
Ar-HC], 7.41 [d, 3J(H,H) = 8.21 Hz, 1 H, Ar-HC], 7.69 [dd,
4
3
3J(H,H) = 7.9 Hz, J = 1.3 Hz, 1 H, Ar-HC], 7.72 [dd, J(H,H) =
4
7.9 Hz, J(H,H) = 1.1 Hz, 1 H, Ar-HC], [10.66* (br. s), 10.86 (br.
s)] (1 H, NH, ratio 1:6) ppm. 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ = 24.8 [C(CH3)3], 32.7 [C(CH3)3], 39.7 (CH2S), 66.3
(CH2O), 75.0 (CHN), 79.7 (CHN), 113.4 [CAr(C=N)], 115.5, 117.7,
120.1, 120.3 [CAr(H)], 123.2 [CAr(C=N)], 125.8, 126.4, 127.4 (m-
Ph, p-Ph, o-Ph), 129.2, 130.0, 130.3, 130.4 [CAr(H)], 140.5
[CAr(NH)], 141.3 (ipso-Ph), 143.1 [CAr(NH)], 161.6 (C=N), 166.4
(C=N) ppm. HRMS (ESI+): calcd. for C28H29N3OS [M + H]+
(C=N), 165.2 (C=N) ppm. IR (NaCl, CHCl film): ν = 3219, 3070,
˜
3
3027, 2954, 1588, 1512, 1452, 1307, 1276, 1214, 1048, 750,
689 cm–1. HRMS (ESI+): calcd. for C28H29N3OS [M + H]+
456.2110; found 456.2118. C28H29N3OS (455.62): calcd. C 73.81,
H 6.42, N 9.22, S 7.04; found C 73.48, H 6.32, N 9.01, S 6.64.
Single-Crystal Structure Analysis of Ligand 2e: Crystals suitable for
X-ray analysis were grown by the slow evaporation at room tem-
perature of a saturated solution of ligand 2e from dichloromethane/
456.2110; found 456.2090. IR (NaCl, CHCl film): ν = 3195, 3026,
˜
3
2956, 2903, 2867, 1643, 1609, 1580, 1517, 1451, 1027, 750,
n-hexane (1:1). C28H29N3OS, M = 455.60, orthorhombic, a = 699 cm–1. C28H29N3OS (455.62): calcd. C 73.81, H 6.42, N 9.22, S
9.6913(9) Å, b = 13.6777(13) Å, c = 18.0533(17) Å, U =
7.04; found C 73.67, H 6.49, N 9.06, S 6.87.
7112
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7107–7115

Synthesis of Thiazoline–Oxazoline Ligands
2-[(S)-4-Benzyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-phenyl-4,5-dihy-
drothiazol-2-yl]phenyl}benzenamine (2h): Yield: 29% (70 mg), white
semi-solid; Rf = 0.29 (cyclohexane/EtOAc, 8:1). [α]2D0 = +52.8 (c =
1.10, CHCl3). 1H NMR (600 MHz, [D6]benzene, 25 °C, TMS): δ =
{2.18* [dd, 2J(H,H) = 13.8 Hz, 3J(H,H) = 8.4 Hz] and 2.24 [dd,
126.4, 128.4, 129.3, 130.2, 130.8, 131.3, 131.4 [CAr(H)], 138.7 (ipso-
Ph), 141.6 [CAr(NH)], 144.1 [CAr(NH)], 162.7 (C=N), 165.9 (C=N)
ppm. IR (KBr): ν = 3192, 3026, 2957, 2927, 1641, 1578, 1517, 1452,
˜
1315, 1273, 1214, 1053, 908, 739, 701 cm–1. HRMS (ESI+): calcd.
for C28H29N3OS [M + H]+ 456.2110; found 456.2118. C28H29N3OS
2J(H,H) = 13.7 Hz, 3J(H,H) = 8.2 Hz]} (1 H, CH2Ph, ratio 2:3), (455.62): calcd. C 73.81, H 6.42, N 9.22; found C 73.58, H 6.45, N
{2.66 [dd, 2J(H,H) = 13.7 Hz, 3J(H,H) = 5.2 Hz] and 2.73* [dd,
2J(H,H) = 13.8 Hz, 3J(H,H) = 8.4 Hz]} (1 H, CH2Ph, ratio 3:1),
{2.76 [dd, 2J(H,H) = 10.7 Hz, 3J(H,H) = 9.7 Hz] and 2.77* [dd,
2J(H,H) = 10.7 Hz, 3J(H,H) = 9.6 Hz]} (1 H, CH2S, ratio 3:1),
{3.08* [dd, 2J(H,H) = 10.7 Hz, 3J(H,H) = (H,H) = 8.5 Hz] and
3.12 [dd, 2J(H,H) = 10.7 Hz, 3J(H,H) = 8.7 Hz]} (1 H, CH2S, ratio
1:2), 3.51–3.61 (m, 2 H, CH2O), [3.91–3.96 (m) and 4.10–4.15* (m)]
8.89.
2-[(S)-4-Benzyl-4,5-dihydrothiazol-2-yl]-N-{2-[(S)-4-phenyl-4,5-di-
hydrooxazol-2-yl]phenyl}benzenamine (2j): Yield: 62% (151 mg),
white solid, Mp: 70–72 °C; Rf = 0.26 (cyclohexane/EtOAc, 8:1).
[α]2D0 = +187.6 (c = 1.00, CHCl3). 1H NMR (500 MHz, CDCl3,
25 °C, TMS): δ = {2.54* [dd, 2J(H,H) = 13.7 Hz, 3J(H,H) = 9.3 Hz]
2
3
and 2.61 [dd, J(H,H) = 13.7 Hz, J(H,H) = 9.3 Hz]} (1 H, CH2O,
3
(1 H, CHN, ratio 2:1), {5.40 [qt, J(H,H) = 9.1 Hz] and 5.49* [qt,
2
3
ratio 1:7), {2.87* [dd, J(H,H) = 11.3 Hz, J(H,H) = 6.9 Hz] and
2.90 [dd, 2J(H,H) = 11.3 Hz, 3J(H,H) = 6.9 Hz]} (1 H, CH2Ph,
ratio 1:9), 3.01–3.10 (m, 2 H, CH2Ph, CH2O), 4.11 [t, 3J(H,H) =
8.3 Hz, 1 H, CH2S], [4.60–4.69 (m) and 4.70–4.76* (m)] (1 H, CHN,
ratio 6:1), 4.67 [dd, 3J(H,H) = 9.8 Hz, 2J(H,H) = 8.3 Hz, 1 H,
CH2S], 5.43 [dd, 3J(H,H) = 9.8 Hz, 3J(H,H) = 8.3 Hz, 1 H, CHN],
6.90–7.03 (m, 4 H, Ar-HC), 7.14–7.34 (m, 10 H, Ar-HC), {7.44*
3J(H,H) = 9.1 Hz]} (1 H, CHN, ratio 3:1), 6.65–6.68 (m, 1 H, Ar-
HC), 6.72–6.76 (m, 1 H, Ar-HC), 6.86–6.88 (m, 1 H, Ar-HC), 6.93–
7.06 (m, 8 H, Ar-HC), 7.16–7.18 (m, 1 H, Ar-HC), {7.34* [dd,
3J(H,H) = 8.4 Hz, 4J(H,H) = 0.7 Hz] and 7.37 [dd, 3J(H,H) =
7.8 Hz, 4J(H,H) = 0.6 Hz]} (1 H, Ar-HC, ratio 1:2), {7.45* [dd,
3J(H,H) = 8.4 Hz, 4J(H,H) = 0.9 Hz] and 7.47 [dd, 3J(H,H) =
8.2 Hz, 4J(H,H) = 0.6 Hz]} (1 H, Ar-HC, ratio 1:2), {7.90 [dd,
3J(H,H) = 7.8 Hz, 4J(H,H) = 1.5 Hz] and 7.94* [dd, 3J(H,H) =
7.8 Hz, 4J(H,H) = 1.5 Hz]} (1 H, Ar-HC, ratio 2:1), {7.99* [dd,
3J(H,H) = 7.8 Hz, 4J(H,H) = 1.6 Hz] and 8.00 [dd, 3J(H,H) =
[br. d, 3J(H,H) = 7.3 Hz] and 7.45 [br. d, J(H,H) = 8.3 Hz]} (1 H,
3
Ar-HC, ratio 1:4), {7.48* [br. d, 3J(H,H) = 6.8 Hz] and 7.50 [br. d,
3J(H,H) = 8.3 Hz]} (1 H, Ar-HC, ratio 1:6), {7.60 [dd, J(H,H) =
3
7.8 Hz, 4J(H,H) = 1.5 Hz] and 7.62* [dd, 3J(H,H) = 7.8 Hz,
4
7.8 Hz, J(H,H) = 1.6 Hz]} (1 H, Ar-HC, ratio 2:3), [11.60* (br. s)
4J(H,H) = 1.5 Hz]} (1 H, Ar-HC, ratio 6:1), {7.89 [dd, J(H,H) =
3
and 11.70 (br. s)] (1 H, NH, ratio 2:3) ppm. 13C NMR (150 MHz,
[D6]benzene, 25 °C, TMS): δ = [40.0*, 40.2] (CH2S), [41.2*, 41.4]
(CH2Ph), [67.9*, 68.0] (CHN), [69.8*, 69.9] (CH2O), [81.2, 81.3*]
(CHN), 114.9 [CAr(C=N)], [(117.2, 117.2*), (119.0, 119.1*), (120.2,
120.3*), (120.7, 120.7*)] [CAr(H)], [123.4*, 123.5] [CAr(C=N)],
[(126.1, 126.1*), (126.7, 126.7*), (127.1*, 127.1), (128.1, 128.1*),
(128.2, 128.3*), (129.3*, 129.3), (130.3, 130.4*), (130.8*, 130.9),
(131.3, 131.3*), (131.8, 132.0*)] [CAr(H)], [138.2*, 138.3] (ipso-Ph),
[142.0, 142.1*] [CAr(NH)], [142.7, 142.7*] (ipso-Ph), [144.2, 144.2*]
[CAr(NH)], [162.6, 162.6*] (C=N), [166.8*, 166.9] (C=N) ppm. IR
7.8 Hz, 4J(H,H) = 1.5 Hz] and 7.91* [dd, 3J(H,H) = 7.8 Hz,
4J(H,H) = 1.5 Hz]} (1 H, Ar-HC, ratio 7:1), [11.02* (br. s) and
11.09 (br. s)] (1 H, NH, ratio 1:6) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C, TMS): δ = [36.3*, 36.3] (CH2Ph), [39.9*, 40.0]
(CH2O), [70.5, 70.5*] (CHN), 73.5 (CH2S), [78.7, 78.7*] (CHN),
115.1 [CAr(C=N)], [118.0, (119.2*, 119.3), 119.5, (120.5*, 120.6)]
[CAr(H)], 122.9 [CAr(C=N)], [126.2, (126.7, 126.8*), 127.5, 128.3,
(128.6*, 128.7), 129.3, 130.4, 130.8, 131.5, 131.6] [CAr(H)], 138.6
(ipso-Ph), 141.7 (ipso-Ph), 142.7 [CAr(NH)], 143.8 [CAr(NH)],
[164.1*, 164.1] (C=N), 166.0 (C=N) ppm. IR (NaCl): ν = 3170,
˜
(NaCl, CHCl film): ν = 3203, 3062, 3026, 2962, 2923, 2851, 1638,
˜
3
3062, 3026, 2923, 1638, 1577, 1515, 1451, 1313, 1270, 1214, 1162,
941, 749, 699 cm–1. HRMS (ESI+): calcd. for C31H27N3OS [M +
H]+ 490.1953; found 490.1953. C31H27N3OS: C 76.04, H 5.56, N
8.58 found C 75.74, H 5.56, N 8.38.
1608, 1579, 1517, 1452, 1053, 1029, 752, 699 cm–1. HRMS (ESI+):
calcd. for C31H27N3OS [M + H]+ 490.1953; found 490.1940.
C31H27N3OS (489.63): calcd. C 76.04, H 5.56, N 8.58; found C
75.88, H 5.60, N 8.55.
General Procedure for the Catalytic Enantioselective Friedel–Crafts
2-[(S)-4-Benzyl-4,5-dihydrothiazol-2-yl]-N-{2-[(S)-4-isopropyl-4,5-di- Reaction: To a dried Schlenk tube was added Zn(OTf)2 (9.3 mg,
hydrooxazol-2-yl]phenyl}benzenamine (2i): Yield: 48 % (110 mg),
0.025 mmol) and the ligand (0.025 mmol) under an atmosphere of
nitrogen followed by the addition of toluene (2 mL). The solution
white semi-solid; Rf = 0.37 (cyclohexane/EtOAc, 8:1). [α]2D0 = +36.8
1
(c = 0.50, CHCl3). H NMR (600 MHz, CDCl3, 25 °C, TMS): δ = was stirred at room temperature for 30 min, and trans-β-nitro-
0.92 [d, 3J(H,H) = 6.8 Hz, 3 H, CH(CH3)2], 1.01 [d, 3J(H,H) = styrene 9 (74.5 mg, 0.5 mmol) was added. The mixture was stirred
6.8 Hz, 3 H, CH(CH3)2], 1.80 [oct., 3J(H,H) = 6.8 Hz, 1 H,
for 10 min and cooled to –20 °C before indole (8; 57 mg, 0.5 mmol)
was added. After stirring for 15 h at –20 °C, the solvent was re-
2
3
CH(CH3)2], 2.81 [dd, J(H,H) = 13.6 Hz, J(H,H) = 9.0 Hz, 1 H,
CH2Ph], 3.01 [dd, 2J(H,H) = 10.9 Hz, 3J(H,H) = 6.8 Hz, 1 H, moved under vacuum. Purification by column chromatography on
CH2S], 3.21 [dd, 2J(H,H) = 10.9 Hz, 3J(H,H) = 8.2 Hz, 1 H, CH2S],
silica gel (pentane/EtOAc, 5:1) afforded desired product 3-(2-nitro-
1-phenylethyl)-1H-indole (10). Rf = 0.20 (pentane/EtOAc, 5:1).
[α]2D0 = –17.2 [c = 1.00, CH2Cl2, 71%ee (R)] {ref.[38] [α]2D0 = +25.3
[c = 0.9, CH2Cl2, 84%ee (S)]}. 1H NMR (500 MHz, CDCl3, 25 °C,
TMS): δ = 4.93 [dd, 2J(H,H) = 12.5 Hz, 3J(H,H) = 8.3 Hz, 1 H,
3.25 [dd, 2J(H,H) = 13.6 Hz, J(H,H) = 5.2 Hz, 1 H, CH2Ph], 3.99
3
[app t, 2J(H,H) = 8.0 Hz, 3J(H,H) = 8.0 Hz, 1 H, CH2O], 4.03–
4.07 (m, 1 H, CHN), 4.29 [dd, 2J(H,H) = 9.4 Hz, 3J(H,H) = 8.0 Hz,
1 H, CH2O], 4.92–4.96 (m, 1 H, CHN), 6.86 [ddd, 3J(H,H) =
3
4
8.0 Hz, J(H,H) = 7.3 Hz, J(H,H) = 1.0 Hz, 1 H, Ar-HC], 6.96–
CH2NO2], 5.05 [dd, 2J(H,H) = 12.5 Hz, 3J(H,H) = 7.6 Hz, 1 H,
3
6.99 (m, 1 H, Ar-HC), 7.18–7.31 (m, 7 H, Ar-HC), 7.33 [dd, CH2NO2], 5.18 [app. t, J(H,H) = 8.0 Hz, 1 H, CHCH2NO2], 7.02
3J(H,H) = 8.3 Hz, 4J(H,H) = 0.8 Hz, 1 H, Ar-HC], 7.46 [dd, [d, 3J(H,H) = 2.2 Hz, 1 H, Ar-HC], 7.07 [app. t, J(H,H) = 7.8 Hz,
3
3J(H,H) = 8.3 Hz, 4J(H,H) = 0.8 Hz, 1 H, Ar-HC], 7.66 [dd, 1 H, Ar-HC], 7.19 [app. t, J(H,H) = 7.8 Hz, 1 H, Ar-HC], 7.23–
3
3J(H,H) = 7.8 Hz, 4J(H,H) = 1.5 Hz, 1 H, Ar-HC], 7.83 [dd, 7.26 (m, 1 H, Ar-HC), 7.30–7.35 (m, 5 H, Ar-HC), 7.44 (d, 3J =
4
3J(H,H) = 7.9 Hz, J(H,H) = 1.6 Hz, 1 H, Ar-HC), 10.90 (br. s, 1 7.8 Hz, 1 H, Ar-HC), 8.06 (br. s, 1 H, NH) ppm. 13C NMR
H, NH) ppm. 13C NMR (150 MHz, CDCl3, 25 °C, TMS): δ = 18.5
(125 MHz, CDCl3, 25 °C, TMS): δ = 41.6 (CHCH2NO2), 79.5
[CH(CH3)2], 19.1 [CH(CH3)2], 33.1 [CH(CH3)2], 36.7 (CH2Ph), (CH2NO2), 111.4 [CAr(H)], 114.5 [CAr(4°)], 118.9, 120.0, 121.6,
40.3 (CH2S), 69.0 (CH2O), 73.2 (CHN), 78.9 (CHN), 114.8 122.7 [CAr(H)], 126.1 [CAr(4°)], 127.6 (p-Ph), 127.8 (m-Ph), 128.9
[CAr(C=N)], 117.2, 119.1, 120.5, 121.0 [CAr(H)], 123.7 [CAr(C=N)],
(o-Ph), 136.5, 139.2 [CAr(4°)] ppm. HPLC (Chiracel OD, hexane/2-
Eur. J. Org. Chem. 2011, 7107–7115
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7113

S. C. McKeon, H. Müller-Bunz, P. J. Guiry
FULL PAPER
propanol
(major) min.
=
70:30, 0.9 mLmin–1): tR
=
23.0 (minor), 27.5
b = 14.6870(7) Å, c = 17.2000(9) Å, U = 2801.4(2) Å3, T = 100 K,
space group P212121 (no. 19), Z = 4, 28526 reflections measured,
6949 unique (Rint = 0.0360) which were used in all calculations.
The final wR(F2) was 0.0728 (all data).
General Procedure for the Nozaki–Hiyama–Kishi Allylation of Benz-
aldehyde: Anhydrous chromium(III) chloride (4.0 mg, 25.3 μmol)
was flamed in an oven-dried Schlenk tube under vacuum and was
then allowed to cool under an atmosphere of nitrogen. Manganese
(41.7 mg, 0.76 mmol) was added under an atmosphere of nitrogen,
followed by the addition of dry THF (1 mL) and dry acetonitrile
(150 μL) by syringe. The resulting grey suspension was allowed to
stand at room temperature for approximately 20 min and then
stirred vigorously under an atmosphere of nitrogen for 1 h. DIPEA
(13 μL, 75.9 μmol) freshly distilled prior to use was added followed
by ligand 2a–p (30.4 μmol) dissolved in THF (100 μL). This was
stirred at room temperature for 1 h prior to the addition of allyl
bromide (44 μL, 0.51 mmol) with the resulting chromium(III) allyl
solution being stirred for a further 1 h. The reaction was initiated
by the addition of benzaldehyde (26 μL, 0.25 mmol) and chlorotri-
methylsilane (64 μL, 0.51 mmol) and stirred under an atmosphere
of nitrogen at room temperature for 16 h. The allyl bromide and
benzaldehyde were both distilled by Kügelrohr and the chlorotri-
methylsilane was flushed through a short pad of alumina to remove
any HCl before they were used. The resulting green/brown suspen-
sion was quenched with saturated aqueous NaHCO3 (1 mL), and
this mixture was then filtered through a short pad of silica gel by
using Et2O as the eluent to remove the catalyst. The filtrate was
then extracted with Et2O and dried by using Na2SO4. The com-
bined organic extracts were concentrated in vacuo to yield a yellow
oil. The % conversion of the reaction was then determined at this
CCDC-835634 (for 2e) and -835635 (for 14) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR spectra for 2a–j; HPLC chromato-
grams for catalysis products 10 and 13.
Acknowledgments
S. McK. is grateful to the Science Foundation Ireland (05/RFP/
CHE0075)for financial support. We acknowledge facilities pro-
vided by the Centre for Synthesis and Chemical Biology (CSCB),
funded by the Programme for Research in Third-Level Institutions
(PRTLI) of the Higher Education Authority. We would also like to
thank Dr. Jimmy Muldoon and Dr. Dilip Rai of the CSCB for
NMR and mass spectra, respectively, and Mrs. Geraldine Fitzpa-
trick and Dr. Yannick Ortin of the UCD School of Chemistry and
Chemical Biology for NMR spectra.
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2.58 (m, 2 H, CH2HC=CH2), 4.71 [app t, J(H,H) = 6.5 Hz, 1 H,
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www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7107–7115

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Received: September 13, 2011
Published Online: October 18, 2011
Eur. J. Org. Chem. 2011, 7107–7115
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