New thiazoline-oxazoline ligands and their application in the asymmetric friedel-crafts reaction

Article abstract of DOI:10.1002/ejoc.200900683

Six members of a novel non-C₂-symmetric ligand class incorporating an oxazoline and. thiazoline unit have been prepared in a four-step, high-yielding and. convergent: synthesis, in which the key step is a microwave-assisted palladium-catalyzed

Full text of DOI:10.1002/ejoc.200900683

FULL PAPER
DOI: 10.1002/ejoc.200900683
New Thiazoline–Oxazoline Ligands and Their Application in the Asymmetric
Friedel–Crafts Reaction
Seán C. McKeon,[a] Helge Müller-Bunz,[a] and Patrick J. Guiry*[a]
Keywords: Asymmetric synthesis / Enantioselectivity / Synthetic methods / Tridentate ligands / Zinc
Six members of a novel non-C2-symmetric ligand class incor- meric excesses of up to 76% in the asymmetric Friedel–
porating an oxazoline and thiazoline unit have been pre-
pared in a four-step, high-yielding and convergent synthesis,
in which the key step is a microwave-assisted palladium-cat-
Crafts reaction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
alyzed aryl amination. The new ligands induced enantio- Germany, 2009)
and was prepared by a linear synthesis, which can only pro-
Introduction
duce C2-symmetric examples.[6] Here we disclose a facile,
microwave-enhanced, and convergent synthesis of the first
example of chiral tridentate ligands 4, which contain both
an oxazoline and a thiazoline moiety. Gaumont has re-
ported the only other ligand possessing an oxazoline and a
thiazoline, and this was a bidentate ligand (Figure 1).[7]
Compounds containing a chiral oxazoline ring are one
of the most successful, versatile, and commonly used classes
of ligands for asymmetric catalysis.[1] One of the main
reasons for their popularity is that the majority of these
ligands are easily synthesised in a few high-yielding steps
from commercially available chiral amino alcohols. In con-
trast to the widely applied oxazoline ligands, the thiazolines
have rarely been used in asymmetric catalysis since they
were first investigated by Helmchen in 1991.[2] Studies since
then have demonstrated that replacing an oxazoline with a
thiazoline infers quite different reactivity on the resulting
ligand when applied in asymmetric catalysis.[3] Therefore, a
ligand containing both of these structural motifs would of-
fer a unique analogue of previous similar bis(oxazoline) or
bis(thiazoline) ligands, which have proven successful in
asymmetric catalysis. It would also serve as a method of
individually tuning the steric and electronic properties of
both ring systems in order to maximise the ligand’s efficacy
and enantiodifferentiating ability.
We have previously synthesised the [N,N,N]-bis(oxaz-
oline) ligands 1 and 2, and found them to be successful in
the chromium-catalyzed Nozaki–Hiyama–Kishi reac-
tion.[4,5] The key step in their synthesis was a palladium-
catalyzed aryl amination which allowed us to prepare both
C2- and non-C2-symmetric analogues. These ligands were
synthesised by a Pd-catalyzed aryl amination. Ligand series
3, synthesised by Du, incorporates a bis(thiazoline) unit
Figure 1. Tridentate oxazoline and thiazoline ligands.
Results and Discussion
[a] Centre for Synthesis and Chemical Biology, Conway Institute
of Biomolecular Research, School of Chemistry and Chemical
Biology, University College Dublin,
Synthesis of New Thiazoline–Oxazoline Ligands 4a–f
Belfield, Dublin 4, Ireland
Fax: +353-1-7162501
E-mail: patrick.guiry@ucd.ie
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900683.
The synthesis of these new ligands began with the cou-
pling of the appropriate chiral α-amino alcohol with the
acyl chloride derived from 2-bromobenzoic acid, which af-
Eur. J. Org. Chem. 2009, 4833–4841
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4833

S. C. McKeon, H. Müller-Bunz, P. J. Guiry
FULL PAPER
forded the hydroxyamide intermediates 5a–d in excellent Table 1. Synthesis of ligands 4a–f by Pd-catalyzed aryl amination.
yields (Scheme 1). The carbonyl group was sulfinated by
using phosphorus pentasulfide[8] and the hydroxythioamide
subsequently cyclocondensed under reflux in pyridine to
form the thiazoline-containing bromo-coupling partners
6a–d in high overall yield. The amino-coupling partners 7a–
d were prepared in good yields in one step from commer-
cially available 2-aminobenzonitrile and the appropriate
chiral α-amino alcohol in the presence of ZnCl2.[9]
Entry
Ligand
R1
R2
Thermal[a]
(% yield)
26 (23)[c]
Microwave[b]
(% yield)
We then embarked on the investigation of the aryl amin-
ation towards the synthesis of ligands 4a–f (Table 1). As in
our synthesis of 1,[4,10] the optimised reaction conditions
determined were toluene as solvent, Pd2dba3 as the palla-
dium source, sodium tert-butoxide as base and DPPF as
the ligand.
The yields obtained were considerably lower than those
previously achieved in the synthesis of bis(oxazoline) ligand
1, which itself proved to be a slow reaction requiring 7 d to
achieve good yields. In the present study, poor yields were
observed even after 7 d of heating at 90 °C (Table 1, Ther-
mal). Yields were improved by the use of microwave assist-
ance, whereby heating the reaction mixture at 180 °C with
300 W for 1 h and by increasing the catalyst loading re-
sulted in the synthesis of ligands 4a–f in 25–85% yields. The
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
iPr
tBu
Ph
Bn
tBu
Bn
iPr
tBu
Ph
Bn
Bn
64 (45)[d]
83
28
6[e]
19
27
17
25[f]
64
72
61
tBu
[a] Used 2.5 mol-% Pd2dba3, 5 mol-% DPPF at 90 °C for 7 d. [b]
Used 5 mol-% Pd2dba3, 10 mol-% DPPF at 180 °C, 300 W for 1 h.
[c] Used 5 mol-% Pd2dba3, 10 mol-% DPPF at 90 °C for 7 d. [d]
Used 2.5 mol-% Pd2dba3, 5 mol-% DPPF. [e] Diastereomeric ratio
5:1. [f] Diastereomeric ratio 9:1. See Supporting Information for
details.
low yield of 25% (and 6% using thermal conditions) was epimerisation at (S)-4-phenyloxazolines are generally not
obtained for the preparation of the phenylglycinol-derived observed and has not been reported to date for 4-phenylthi-
ligand 4c. In addition, we noted that this ligand was enan- azolines. The diastereomeric ratio was increased by way of
tiomerically not pure, as we obtained a dr of 5:1 and 9:1, the microwave method (Table 1, Entry 3).
respectively. Initially, we had believed that the second set of
At this point crystals suitable for X-ray analysis were
1
peaks in the H NMR spectra were due to differences in grown by slow concentration at room temperature of a satu-
hydrogen bonding. However, we independently prepared rated solution of 4f in a mixture of dichloromethane/n-hex-
thiazoline (R)-6c and coupled it to oxazoline (S)-7c to yield ane (1:1). From the crystallographic structure we can see
the diastereomer of ligand 4c, whose peaks were identical that the three nitrogen atoms are in plane with one another
to those of the minor product previously observed. Such forming a concave pocket (Figure 2).
Scheme 1.
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Thiazoline–Oxazoline Ligands in Asymmetric Friedel–Crafts Reaction
Table 2. The application of ligands 4a–f in the asymmetric Friedel–
Crafts alkylation of indole.
Entry
Ligand
R1
R2
Yield[a] (%)
ee[b] (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
iPr
tBu
Ph
Bn
tBu
Bn
iPr
tBu
Ph
Bn
Bn
100
100
100
100
100
100
14 (R)
13 (R)
67 (R)
51 (R)
71 (R)
52 (R)
tBu
Figure 2. Crystal structure of ligand 4f, thermal ellipsoids are
drawn on the 50% probability level.
[a] Isolated yields by column chromatography. [b] Determined by
chiral HPLC analysis of the products using a Daicel Chiralcel OD
column (hexane/2-propanol, 70:30; 0.9 mL/min), the absolute con-
figurations of the products were assigned by comparison of the
chiral HPLC retention times with literature values.[13]
Friedel–Crafts Catalysis
The Friedel–Crafts alkylation of arenes with electron-de-
ficient alkenes is one of the most important organic trans-
Table 3. Asymmetric alkylation of indole with nitroalkenes cata-
formations to employ Lewis acid catalysts.[11,12] Recently, lyzed by 4e/Zn(OTf)2.
nitroalkenes have been used extensively as substrates in the
asymmetric Friedel–Crafts alkylation of indoles.[13,14] The
nitro group is one of the strongest electron-withdrawing
groups known, so nitroalkenes have proven excellent
Michael acceptors.[15] This, coupled with the fact that the
nitro group is easily transformed into a range of different
Entry
Ar
Product
Yield[a] (%)
ee[b] (%)
functionalities, has resulted in their wide application in or-
ganic synthesis.[16] The literature reports employing chiral
Lewis acids include the application of symmetrical exam-
ples of tridentate ligands 1 and 3 by Du who obtained ee
values up to 83% (R) when ligand 1 (R1 and R2 = Ph) was
employed.[17] The application of an analogue of ligand 1
which contained cis-phenyl substituents at both the 4- and
5-positions of the oxazoline rings was found to increase the
ee values in this transformation to 94% (R).[17] It was there-
fore of interest to investigate our novel thiazoline–oxazol-
ine-containing ligands in this process, the results of which
are given in Table 2.
1
2
3
4
5
6
7
8
9
Ph
10a
10b
10c
10d
10e
10f
10g
10h
10i
100
99
99
100
100
100
88
92
100
94
71 (R)
28
17
20
76
64
74
60
67
2-furylC6H4
2-MeOC6H4
2-ClC6H4
3-BrC6H4
3-ClC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
10
3,4-(MeO)2C6H3
10j
38
[a] Isolated yields by column chromatography. [b] Determined by
chiral HPLC analysis of the products using a Daicel Chiralcel OD
column (hexane/2-propanol, 70:30; 1.0 mL/min).
In the present study we were pleased to find that quanti-
tative yields were observed for all ligands tested. However,
poor enantiomeric excesses were obtained when both R1,
R2 were alkyl substituents (Table 2, Entries 1 and 2). Good
Excellent yields were achieved for all substrates. In terms
enantiomeric excesses were obtained with the use of aro- of enantioselectivity certain trends became evident, particu-
matic R groups (Table 2, Entries 3 and 4). The combination larly in terms of the effect of the position of substitution
of a bulky tert-butyl group with a benzyl group also re- on the phenyl ring. Poor enantioselectivities were observed
sulted in good enantiomeric excess (Table 2, Entries 5 and for replacement of the phenyl substituent with an electron-
6). It was also of interest to note that a higher ee value was rich heterocycle and for substitution of the phenyl ring on
obtained with ligand 4e compared to 4f so that it is prefera- the ortho position regardless of the electronic nature of the
ble to have the benzyl substituent on the oxazoline rather substituent (Table 3, Entries 2–4). Good enantioselectivities
than the thiazoline.
were obtained when the ring was monosubstituted at the
On the basis of these results further investigations were meta or para position by either electron-donating or -with-
warranted to examine the compatibility of the optimal cata- drawing groups (Table 3, Entries 5–9). However, it was
lyst derived from ligand 4e with β-nitrostyrene substrates found that disubstitution by methoxy groups in the meta
possessing a range of steric and electronic variations and para positions resulted in a large decrease in ee
(Table 3).
(Table 3, Entry 7).
Eur. J. Org. Chem. 2009, 4833–4841
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4835

S. C. McKeon, H. Müller-Bunz, P. J. Guiry
FULL PAPER
7.0 mmol), and thionyl chloride (5 mL), was refluxed for 4 h. The
excess thionyl chloride was then removed in vacuo to leave the acyl
Conclusions
The first synthesis and application of chiral tridentate chloride as a white precipitate. This was dissolved in dichlorometh-
ane (70 mL) and added dropwise to a solution of the amino alcohol
(7.0 mmol) in triethylamine (2.45 mL, 17.5 mmol) and dichloro-
methane (20 mL) at 0 °C. The solution was then stirred at room
temperature for 24 h. The reaction mixture was then washed suc-
cessively with a saturated aqueous solution of ammonium chloride,
HCl (1 ), saturated aqueous solution of sodium hydrogen carbon-
ate and brine. The resulting organic layer was then dried with anhy-
drous sodium sulfate and concentrated in vacuo to yield pure prod-
uct.
ligands containing both a thiazoline and oxazoline is re-
ported. The key step in this convergent synthesis is a palla-
dium-catalyzed aryl amination allowing, in future, for a di-
verse analogue synthesis. This step was greatly enhanced by
the use of microwave conditions in comparison to conven-
tional heating. The six ligands synthesised were sub-
sequently applied in the zinc-catalyzed enantioselective
Friedel–Crafts alkylation of indole with a series of trans-β-
nitrostyrenes, yielding enantioselectivities up to 76%. Our
results highlight that, just as in our application of bis(ox-
azoline) ligands 1 and 2 in the Nozaki–Hiyama–Kishi reac-
(S)-2-Bromo-N-(1-hydroxy-3-methylbut-2-yl)benzamide (5a): Yield
91%, white solid. M.p. 109–111 °C (ref.[1] 113–115 °C). TLC: Rf =
0.38 (EtOAc). [α]2D0 = –19.2 (c = 1.00, CHCl3). 1H NMR (400 MHz,
tion, where non-C2-symmetric analogues proved optimal, CDCl3): δ = 0.98 [d, 3J = 2.8 Hz, 3 H, CH(CH3)2], 0.99 [d, 3J =
2.8 Hz, 3 H, CH(CH3)2], 1.99–2.07 [m, 1 H, CH(CH3)2], 2.71 (br.
s, 1 H, OH), 3.68–3.77 (m, 2 H, CH2O), 3.87–3.93 (m, 1 H, CHN),
the thiazoline–oxazoline ligands possessing different R
groups induced the highest levels of enantioselectivity.
However, they did not lead to an enhancement of enantio-
selectivity relative to the analogous C2-symmetric bis(oxaz-
olines). We are currently investigating the application of
non-C2-symmetric examples of ligand series 1 in this reac-
tion and the application of these novel thiazoline–oxazoline
ligands to a range of other catalytic asymmetric processes.
The results of these investigations will be reported in due
course.
3
3
3
6.26 (br. d, J = 7.9 Hz, 1 H, 1 H, NH), 7.22 (ddd, J = 8.0, J =
4
3
3
4
7.5, J = 1.8 Hz, 1 H, Ar-HC), 7.29 (ddd, J = 8.8, J = 7.6, J =
1.2 Hz, 1 H, Ar-HC), 7.47 (dd, 3J = 7.6, 4J = 1.8 Hz, 1 H, Ar-
HC), 7.53 (dd, 3J = 8.0, 4J = 1.2 Hz, 1 H, Ar-HC) ppm. 13C NMR
(100 MHz, CDCl3): δ = 18.9 [CH(CH3)2], 19.6 [CH(CH3)2], 29.1
[CH(CH3)2], 57.7 (CHN), 63.6 (CH2O), 119.1 [CAr(CO)], 127.6,
129.5, 131.2, 133.3 [CAr(H)], 137.9 [CAr(Br)], 168.4 (CON) ppm.
IR (NaCl, CHCl3 film): ν = 3404, 3278, 3067, 2962, 2878, 1642,
˜
1538, 1466, 1321, 1252, 1032, 752 cm–1. HRMS (ES+): calcd. for
C12H16BrNO2 [M + H]+ 286.0443; found 286.0456. C12H16BrNO2
(286.16): calcd. C 50.37, H 5.64, Br 27.92, N 4.89; found C 49.98,
H 5.48, Br 28.30, N 4.88.
Experimental Section
(S)-2-Bromo-N-(1-hydroxy-3,3-dimethylbut-2-yl)benzamide
(5b):
General Experimental: 1H NMR (300, 400, 500 and 600 MHz) and
13C (75, 100, 125 and 150 MHz) spectra were recorded with Varian
Oxford 300, 400, 500 or 600 MHz spectrometers by using tet-
ramethylsilane as an internal standard. Chemical shifts (δ) are given
in ppm and coupling constants (J) are given as absolute values in
Hz. 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. Routine electrospray mass spectro-
metric analysis was performed with a Waters Micromass Quattro
Ultima mass spectrometer. High-resolution mass spectra were ob-
tained by using a Micromass/Waters LCT instrument. Infrared
spectra were recorded with a Perkin–Elmer Infrared FT spectrome-
ter. Optical rotation values were measured at room temperature
with a Perkin–Elmer 343 polarimeter. Melting points were deter-
mined 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 (Merck). Column chromatography separations were per-
formed by using Merck Kieselgel 60 (0.040–0.060 mm). Preparative
layer chromatography was carried out on glass plates precoated
with silica gel 60 HF254+366 (Merck). All amination reactions were
conducted in a CEM Discover S-Class microwave reactor. HPLC
analyses were performed with an LC 2010A machine equipped with
a UV/Vis detector by employing a chiral OD column from Daicel
Chemical Industries. Solvents were dried immediately before use by
distillation from standard drying agents. Anhydrous pyridine and
chlorobenzene were purchased from Sigma–Aldrich and used with-
out further purification.
Yield 97%, white solid. M.p. 110–112 °C (ref.[2] 50.0–51.0 °C from
acetone/hexanes). TLC: Rf = 0.40 (EtOAc). [α]2D0 = –2.2 (c = 1.00,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.04 [s, 9 H, C(CH3)3],
3
2.40 (br. s, 1 H, OH), 3.68 (app. t, J = 8.0 Hz, 1 H, CH2O), 3.95
3
(br. d, J = 11.3 Hz, 1 H, CH2O), 4.06 (m, 1 H, CHN), 6.20 (br.
3
3
4
d, J = 8.2 Hz, 1 H, 1 H, NH), 7.28 (ddd, Ar-HC, J = 7.9, J =
3
3
4
1.7 Hz, 1 H, 9.2 Hz), 7.36 (ddd, J = 8.8, J = 7.4, J = 0.8 Hz, 1
H, Ar-HC), 7.56 (dd, 3J = 7.6, 4J = 1.6 Hz, 1 H, Ar-HC), 7.59 (br.
d, 3J = 8.0 Hz, 1 H, Ar-HC) ppm. 13C NMR (100 MHz, CDCl3): δ
= 27.3 [C(CH3)3], 34.0 [C(CH3)3], 60.5 (CHN), 63.3 (CH2O), 119.3
[CAr(CO)], 127.9, 130.0, 131.5, 133.6 [CAr(H)], 138.2 [CAr(Br)],
168.9 (CON) ppm. IR (NaCl, CHCl film): ν = 3243, 3067, 2961,
˜
3
1641, 1555, 1469, 1362, 1314, 1255, 1087, 1049, 750 cm–1. HRMS
(ES+): calcd. for C13H18BrNO2 [M
+
H]+ 300.0599; found
300.0606. C13H18BrNO2 (300.19): calcd. C 52.01, H 6.04, Br 26.62,
N 4.67; found C 51.96, H 6.03, Br 26.99, N 4.60.
(S)-2-Bromo-N-(2-hydroxy-1-phenylethyl)benzamide (5c): Yield
98%, white solid. M.p. 122–124 °C. TLC: Rf = 0.49 (EtOAc).
[α]2D0 = +10.5 (c = 1.00, CHCl3). 1H NMR (500 MHz, CDCl3): δ =
2.55 (br. s, 1 H, OH), 3.97 (br. s, 2 H, CH2O), 5.24–5.29 (m, 1 H,
3
CHN), 6.81 (br. d, J = 6.4 Hz, 1 H, NH), 7.25–7.39 [m, 7 H, Ar-
HC, Ar-HC(Ph)], 7.55 (dd, 3J = 7.8, 4J = 1.5 Hz, 1 H, Ar-HC), 7.58
(dd, 3J = 7.8, 4J = 1.0 Hz, 1 H, Ar-HC) ppm. 13C NMR (125 MHz,
CDCl3): δ = 56.4 (CHN), 66.3 (CH2O), 119.3 [CAr(CO)], 126.9,
127.6, 128.0, 128.9, 129.8, 131.4, 133.4, 137.4 [CAr(H)], 138.5
[CAr(Br)], 167.7 (CON) ppm. IR (NaCl, CHCl3 film): ν = 3297,
˜
3062, 2938, 2874, 1643, 1532, 1462, 1311, 1033, 750, 698 cm–1.
HRMS (ES+): calcd. for C15H14BrNO2 [M + H]+ 320.0286; found
320.0300. C15H14BrNO2 (320.18): calcd. C 56.27, H 4.41, Br 24.96,
N 4.37; found C 56.06, H 4.40, Br 24.79, N 4.23.
General Procedure for the Synthesis of 2-(o-Bromophenyl)hydroxy-
(S)-2-Bromo-N-(1-hydroxy-3-phenylprop-2-yl)benzamide (5d): Yield
amides 5a–e:
A
solution of 2-bromobenzoic acid (1.407 g,
96%, white solid. M.p. 97–98 °C. TLC: Rf = 0.44 (EtOAc). [α]2D0
=
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Thiazoline–Oxazoline Ligands in Asymmetric Friedel–Crafts Reaction
3
3
–22.2 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.57 Ar-HC), 7.32 (app. t, J = 7.5 Hz, 1 H, Ar-HC), 7.50 (br. d, J =
2
3
(br. s, 1 H, OH), 3.00 (d, 3J = 7.4 Hz, 2 H, CH2Ph), 3.69 (dd, J =
7.6 Hz, 1 H, Ar-HC), 7.61 (br. d, J = 8.0 Hz, 1 H, Ar-HC) ppm.
3
2
3
11.1, J = 4.7 Hz, 1 H, CH2O), 3.79 (dd, J = 11.1, J = 3.6 Hz, 1
13C NMR (100 MHz, CDCl3): δ = 27.0 [C(CH3)3], 35.4 [C(CH3)3,
CH2S], 88.3 (CHN), 121.1 [CAr(C=N)], 127.2, 130.4, 130.8, 133.7
3
H, CH2O), 4.38–4.44 (m, 1 H, CHN), 6.29 (br. d, J = 7.4 Hz, 1
H, NH), 7.22–7.33 [m, 7 H, Ar-HC(Ph), Ar-HC], 7.38 (dd, 3J = [CAr(H)], 135.5 [CAr(Br)], 165.0 (C=N) ppm. IR (NaCl, CHCl3
4
3
4
7.6, J = 1.8 Hz, 1 H, Ar-HC), 7.54 (dd, J = 7.9, J = 1.0 Hz, 1 film): ν = 2956, 2838, 1618, 1466, 1366, 1272, 1221, 1118, 1055,
˜
H, Ar-HC) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.9 (CH2Ph),
53.3 (CHN), 63.7 (CH2O), 119.2 [CAr(CO)], 126.7, 127.5, 128.7,
1028, 932, 761 cm–1. HRMS (ES+): calcd. for C13H16BrNS [M +
H]+ 298.0265; found 298.0269. C13H16BrNS (298.24): calcd. C
129.3, 129.4, 131.3, 133.3, 137.5, [CAr(H)], 137.7 [CAr(Br)],168.0 52.35, H 5.41, Br 26.79, N 4.70, S 10.75; found C 52.55, H 5.39,
(CON) ppm. IR (NaCl, CHCl film): ν = 3391, 3276, 3064, 2931, Br 26.85, N 4.59, S 10.55.
˜
3
1641, 1536, 1461, 1333, 1095, 1035, 748, 698 cm–1. HRMS (ES+):
(S)-2-(2-Bromophenyl)-4-phenyl-4,5-dihydrothiazole (6c): Yield 80%
calcd. for C16H16BrNO2 [M + H]+ 334.0443; found 334.0437.
C16H16BrNO2 (334.21): calcd. C 57.50, H 4.83, Br 23.91, N 4.19;
found C 57.11, H 4.73, Br 23.91, N 4.11.
(2.291 g), colourless oil. TLC: Rf = 0.57 (pentane/EtOAc, 3:1).
[α]2D0 = +50.3 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
2
3
2
3.43 (dd, J = 10.9, J = 10.1 Hz, 1 H, CH2S), 3.89 (dd, J = 10.9,
3J = 8.9 Hz, 1 H, CH2S), 5.75 (app. t, 3J = 9.5 Hz, 1 H, CHN),
7.26–7.42 [m, 5 H, Ar-HC(Ph)], 7.46–7.49 (m, 2 H, Ar-HC), 7.61
(R)-2-Bromo-N-(2-hydroxy-1-phenylethyl)benzamide (5e): Yield
93%, white solid. M.p. 122–124 °C. TLC: Rf = 0.49 (EtOAc).
1
3
4
3
4
[α]2D0 = –12.2 (c = 1.15, CHCl3). H NMR (400 MHz, CDCl3): δ =
(dd, J = 7.7, J = 1.7 Hz, 1 H, Ar-HC), 7.66 (dd, J = 8.0, J =
1.2 Hz, 1 H, Ar-HC) ppm. 13C NMR (100 MHz, CDCl3): δ = 42.6
(CH2S), 81.2 (CHN), 121.5 [CAr(C=N)], 127.0, 127.5, 128.0, 129.0,
130.7, 131.4, 133.9 [CAr(H)], 135.5 [CAr(4°)], 142.0 [CAr(4°)], 167.9
3
2.51 (br. s, 1 H, OH), 3.99 (app. t, J = 4.7 Hz, 2 H, CH2O), 5.25–
5.29 (m, 1 H, CHN), 6.80 (br. d, 3J = 6.4 Hz, 1 H, NH), 7.25–7.40
4
[m, 7 H, Ar-HC, Ar-HC(Ph)], 7.55 (dd, 3J = 7.8, J = 1.5 Hz, 1 H,
Ar-HC), 7.58 (dd, 3J = 7.8, 4J = 1.0 Hz, 1 H, Ar-HC) ppm. 13C (C=N) ppm. IR (KBr): ν = 3061, 3028, 2927, 2851, 1617, 1467,
˜
NMR (125 MHz, CDCl3): δ = 56.4 (CHN), 66.3 (CH2O), 119.3 1434, 1028, 940, 759, 698 cm–1. HRMS (ES+): calcd. for
[CAr(CO)], 126.9, 127.6, 128.0, 128.9, 129.8, 131.4, 133.4, 137.3 C15H12BrNS [M + H]+ 317.9952; found 317.9959. C15H12BrNS
[CAr(H)], 138.5 [CAr(Br)], 167.7 (CON) ppm. IR (KBr): ν = 3300,
(318.23): calcd. C 56.61, H 3.80, Br 25.11, N 4.40, S 10.08; found
C 56.64, H 3.79, Br 24.68, N 4.34, S 9.80.
˜
3074, 2950, 2885, 1635, 1542, 1464, 1318, 1036, 752, 699 cm–1. MS
(ESI): m/z = 320.2/322.2 (1:1). C15H14BrNO2 (320.18): calcd. C
56.27, H 4.41, Br 24.96, N 4.37; found C 56.07, H 4.28, Br 24.67,
N 4.33.
(S)-4-Benzyl-2-(2-bromophenyl)-4,5-dihydrothiazole (6d): Yield 80%
(2.392 g), colourless oil. TLC: Rf = 0.55 (pentane/EtOAc, 3:1).
[α]2D0 = –34.0 (c = 1.05, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
2
3
General Procedure for the Synthesis of 2-(o-Bromophenyl)thiazolines
6a–e: To a solution of 2-(o-bromophenyl)hydroxyamide (9.0 mmol)
in dry pyridine (40 mL), was added phosphorus pentasulfide
(8.00 g, 17.9 mmol), and the mixture was refluxed for 22 h. The
reaction mixture was cooled, and 20% potassium hydroxide solu-
tion (aq.) (35 mL) was added. The resulting aqueous phase was
then extracted with dichloromethane (3ϫ 15 mL). The organic
phases were combined, washed with 2  HCl, dried with anhydrous
sodium sulfate and concentrated in vacuo to yield the crude prod-
uct. This was purified by column chromatography on silica gel
(pentane/EtOAc, 1:1), to yield pure product.
2.91 (dd, J = 13.7, J = 9.1 Hz, 1 H, CH2Ph), 3.20 (dd, 2J = 11.1,
3J = 6.8 Hz, 1 H, CH2S), 3.34 (dd, 2J = 13.7, 3J = 5.1 Hz, 1 H,
CH2Ph), 3.41 (dd, J = 11.1, J = 8.4 Hz, 1 H, 1 H, CH2S), 4.93–
5.03 (m, 1 H, CHN), 7.22–7.36 [m, 7 H, Ar-HC(Ph), Ar-HC], 7.51
(dd, J = 7.6, J = 1.7 Hz, 1 H, Ar-HC), 7.63 (dd, J = 7.9, J =
1.0 Hz, 1 H, Ar-HC) ppm. 13C NMR (75 MHz, CDCl3): δ = 38.7
(CH2Ph), 40.1 (CH2S), 79.1 (CHN), 121.4 [CAr(C=N)], 126.8,
127.5, 128.8, 129.6, 130.6, 131.2, 133.8 [CAr(H)], 135.5 [CAr(4°)],
2
3
3
4
3
4
138.6 [CAr(4°)], 166.6 (C=N) ppm. IR (KBr): ν = 3060, 2926, 1617,
˜
1464, 1268, 1049, 937, 756 cm–1. HRMS (ES+): calcd. for
C16H14BrNS [M + H]+ 332.0109; found 332.0100. C16H14BrNS
(332.26): calcd. C 57.84, H 4.25, Br 24.05, N 4.22, S 9.65; found C
57.60, H 4.21, Br 23.69, N 4.12, S 9.71.
(S)-2-(2-Bromophenyl)-4-isopropyl-4,5-dihydrothiazole (6a): Yield
85% (2.174 g), colourless oil. TLC: Rf = 0.31 (pentane/EtOAc, 3:1).
1
[α]2D0 = –71.4 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
(R)-2-(2-Bromophenyl)-4-phenyl-4,5-dihydrothiazole (6e): Yield 75%
3
3
1.07 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.12 [d, J = 6.8 Hz, 3 H,
(2.148 g), colourless oil. TLC: Rf = 0.57 (pentane/EtOAc, 3:1).
CH(CH3)2], 2.17 [oct, J = 6.8 Hz, 1 H, CH(CH3)2], 3.23 (dd, 2J = [α]2D0 = –47.2 (c = 1.25, CHCl3). H NMR (400 MHz, CDCl3): δ =
3
1
3
2
3
2
3
2
10.8, J = 9.6 Hz, 1 H, CH2S), 3.46 (dd, J = 10.8, J = 9.0 Hz, 1
3.40 (dd, J = 11.0, J = 10.1 Hz, 1 H, CH2S), 3.87 (dd, J = 11.0,
H, CH2S), 4.47–4.53 (m, 1 H, CHN), 7.23 (ddd, 3J = 7.9, J = 7.5, 3J = 8.9 Hz, 1 H, CH2S), 5.73 (app. t, 3J = 9.5 Hz, 1 H, CHN),
3
4J = 1.8 Hz, 1 H, Ar-HC), 7.32 (ddd, J = 7.9, J = 7.6 H, 1.2 Hz, 7.24–7.39 [m, 5 H, Ar-HC(Ph)], 7.44–7.47 (m, 2 H, Ar-HC), 7.60
3
3
Ar-HC), 7.49 (dd, 3J = 7.7, J = 1.8 Hz, 1 H, Ar-HC), 7.60 (dd, 3J
(dd, J = 7.6, J = 1.7 Hz, 1 H, Ar-HC), 7.64 (dd, J = 8.0, J =
1.1 Hz, 1 H, Ar-HC) ppm. 13C NMR (100 MHz, CDCl3): δ = 42.4
(CH2S), 80.9 (CHN), 121.4 [CAr(C=N)], 126.8, 127.3, 127.7, 128.7,
130.5, 131.1, 133.7 [CAr(H)], 135.2 [CAr(4°)], 141.8 [CAr(4°)], 167.6
4
3
4
3
4
= 8.0, 4J = 1.2 Hz, 1 H, Ar-HC) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.3 [C(CH3)2], 19.9 [C(CH3)2], 33.2 [C(CH3)2], 36.8
(CH2S), 84.5 (CHN), 121.4 [CAr(C=N)], 127.4, 130.6, 131.1, 133.1
[CAr(H)], 135.7 [CAr(Br)], 165.5 (C=N) ppm. IR (NaCl, CHCl3 (C=N) ppm. IR (KBr, CHCl3 film): ν = 3053, 2927, 2859, 1614,
˜
film): ν = 2959, 2873, 1624, 1465, 1228, 1021, 935, 759 cm–1.
1451, 1281, 1229, 1021, 939, 753, 701 cm–1. MS (ESI): m/z = 318.2/
˜
HRMS (ES+): calcd. for C12H14BrNS [M + H]+ 284.0109; found 320.2 (1:1). C15H12BrNS (318.23): calcd. C 56.61, H 3.80, Br 25.11,
284.0113. C12H14BrNS (284.22): calcd. C 50.71, H 4.96, Br 28.11,
N 4.93, S 11.28; found C 50.73, H 4.89, Br 27.67, N 4.82, S 11.50.
N 4.40, S 10.08; found C 56.63, H 3.78, Br 24.95, N 4.35, S 9.99.
General Procedure for the Screening of Conditions for Palladium-
(S)-2-(2-Bromophenyl)-4-tert-butyl-4,5-dihydrothiazole (6b): Yield Catalysed Aryl Aminations: To an oven-dried Radleys® tube was
91% (2.443 g), cream crystals. M.p. 97–98 °C. TLC: Rf = 0.48 (pen-
added the amino- (0.60 mmol) and bromo-coupling partners
(0.50 mmol), base (0.60 mmol), ligand (0.05 mmol) and palladium
precursor (0.025 mmol Pd). Dry degassed solvent (1.5 mL) was
tane/EtOAc, 3:1). [α]2D0 = –87.5 (c = 1.00, CHCl3). 1H NMR
3
(400 MHz, CDCl3): δ = 1.10 [s, 9 H, C(CH3)3], 3.30 (app. t, J =
3
10.8 Hz, 1 H, CH2S), 3.40 (app. t, J = 10.0 Hz, 1 H, CH2S), 4.41 added via syringe and the reaction mixture stirred under nitrogen
3
3
(app. t, J = 10.0 Hz, 1 H, CHN), 7.23 (app. t, J = 7.9 Hz, 1 H, at the required temperature for 7 d. The reaction mixture was co-
Eur. J. Org. Chem. 2009, 4833–4841
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4837

S. C. McKeon, H. Müller-Bunz, P. J. Guiry
FULL PAPER
oled to room temperature. The solvent was removed in vacuo, and
a 1H NMR spectrum was obtained to determine if any of the aryl-
amine product had formed.
3
3
3
4
= 10.3, J = 8.8 Hz, 1 H, CHN), 6.86 (ddd, J = 8.2, J = 6.5, J
= 1.8 Hz, 1 H, Ar-HC), 6.95–6.99 (m, 1 H, Ar-HC), 7.22–7.28 (m,
3 H, Ar-HC), 7.34 (d, 3J = 8.3 Hz, 1 H, Ar-HC), 7.70 (dd, 3J =
4
3
4
7.8, J = 1.5 Hz, Ar-HC), 7.82 (dd, J = 8.3, J = 1.5 Hz, Ar-HC),
10.66 (br. s, NH) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.9
[C(CH3)3], 26.9 [C(CH3)3], 33.3 (CH2S), 34.0 [C(CH3)3], 35.2
[C(CH3)3], 67.4 (CH2O), 76.3 (CHN), 87.7 (CHN), 114.9
[CAr(C=N)], 117.9, 119.2, 120.5, 121.2 [CAr(H)], 124.3 [CAr(C=N)],
130.3, 130.8, 131.4, 131.5 [CAr(H)], 141.9 [CAr(NH)], 144.3
[CAr(NH)], 162.7 (C=N), 165.0 (C=N) ppm. IR (NaCl, CHCl3
Thermal Procedure for the Synthesis of Ligands 4a–g (Method A):
An oven-dried Schlenk tube was charged with 2-(2-bromophenyl)-
thiazoline (1.00 mmol), sodium tert-butoxide (0.115 g, 1.2 mmol),
1,1Ј-bis(diphenylphosphanyl)ferrocene (DPPF) (0.055 g, 0.10
mmol), Pd2dba3 (0.023 g, 0.025 mmol), and 2-(o-aminophenyl)-
oxazoline (1.2 mmol). After the addition of dry, degassed toluene
(8 mL) via syringe, the Schlenk tube was capped under nitrogen
and the reaction mixture (brown suspension) was heated at 90 °C
for 7 d. The reaction mixture was then cooled to room temperature
and concentrated in vacuo to give a brown oil. This was purified
by preparative layer chromatography on silica gel (cyclohexane/
EtOAc, 8:1) to yield pure product.
film): ν = 3220, 3083, 2955, 1641, 1582, 1516, 1453, 1317, 1213,
˜
1051, 750 cm–1. HRMS (ES+): calcd. for C26H33N3OS [M + H]+
436.2423; found 436.2402. C26H33N3OS (435.62): calcd. C 71.69,
H 7.64, N 9.65; found C 71.60, H 7.51, N 9.35.
2-[(S)-4-Phenyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-phenyl-4,5-di-
hydrothiazol-2-yl]phenyl}benzenamine (4c): Yield 6 % (28 mg;
Method A), 25% (60 mg; Method B), white semi-solid. TLC: Rf =
0.32 (cyclohexane/EtOAc, 8:1). [α]2D0 = +307.4 (c = 1.00, CHCl3).
Microwave Procedure for the Synthesis of Ligands 4a–g (Method B):
An oven-dried tube was charged under nitrogen with 2-(2-bro-
mophenyl)thiazoline (0.500 mmol), sodium tert-butoxide (0.0577 g,
2
3
1H NMR (600 MHz, [D6]benzene): δ = [2.70* (dd, J = 10.8, J =
0.6 mmol),
1,1Ј-bis(diphenylphosphanyl)ferrocene
(DPPF)
2
3
9.1) and 2.71 (dd, J = 10.8, J = 9.1 Hz)] (1:7, 1 H, CH2S), [3.03*
(dd, 2J = 10.8, 3J = 9.1 Hz) and 3.03 (dd, 2J = 10.8 Hz, 3J =
9.0 Hz)] (1:7, 1 H, CH2S), [3.58* (app. t, 3J = 8.2 Hz) and 3.59
(0.0225 g, 0.05 mmol), Pd2dba3 (0.0115 g, 0.0125 mmol), and 2-(o-
aminophenyl)oxazoline (0.6 mmol). After the addition of dry, de-
gassed toluene (2 mL) via syringe, the tube was sealed under nitro-
gen, and the reaction mixture was placed in a microwave oven and
heated at 180 °C for 1 h. The reaction mixture was then cooled to
room temperature before removing the seal and concentrated in
vacuo to yield a brown oil. This was purified by preparative layer
chromatography on silica gel (cyclohexane/EtOAc, 8:1) to yield
pure product.
3
3
2
(app. t, J = 8.2 Hz)] (1:7, 1 H, CH2O), [3.92 (dd, J = 10.1 Hz, J
= 8.2 Hz) and 3.95* (dd, 3J = 10.1 Hz, 2J = 8.2 Hz)] (7:1, 1 H,
3
3
3
CH2O), [4.70 (dd, J = 10.0 Hz, J = 8.2 Hz) and 4.90* (dd, J =
10.1 Hz, J = 8.2 Hz)] (9:1, 1 H, CHN), [5.25 (app. t, J = 9.0 Hz)
and 5.33* (app. t, J = 9.1 Hz)] (13:1, 1 H, CHN), 6.69–6.72 (m, 2
3
3
3
H, Ar-HC), 6.92–6.95 (m, 1 H, Ar-HC), 6.96–7.02 (m, 9 H, Ar-
HC), 7.06–7.08 (m, 1 H, Ar-HC), 7.13–7.14 (m, 1 H, Ar-HC),
3
4
3
4
2-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-isopropyl-4,5-
dihydrothiazol-2-yl]phenyl}benzenamine (4a): Yield 26 % (106 mg;
Method A), 64% (130 mg; Method B), clear oil. TLC: Rf = 0.28
(cyclohexane/EtOAc, 8:1). [α]2D0 = +20.0 (c = 0.6, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.90 [d, 3J = 6.7 Hz, 3 H, CH(CH3)2], 0.97
[d, 3J = 6.7 Hz, 3 H, CH(CH3)2], 0.98 [d, 3J = 6.7 Hz, 3 H,
[7.34* (dd, J = 7.8 Hz, J = 0.7 Hz) and 7.41 (dd, J = 7.8 Hz, J
3
4
= 0.5 Hz)] (1:9, 1 H, Ar-HC), [7.42* (dd, J = 7.3 Hz, J = 0.7 Hz)
3
4
and 7.46 (dd, J = 8.3 Hz, J = 0.7 Hz)] (1:9, 1 H, Ar-HC), [7.83
(dd, 3J = 7.7 Hz, 4J = 1.5 Hz) and 7.91* (dd, 3J = 7.8 Hz, 4J =
1.4 Hz)] (9:1, 1 H, Ar-HC), [8.07 (dd, 3J = 7.8 Hz, 4J = 1.6 Hz)
and 8.08* (dd, 3J = 7.8 Hz, 4J = 1.6 Hz)] (9:1, 1 H, Ar-HC), [11.64*
(br. s) and 11.80 (br. s)] (1:9, 1 H, NH) ppm. 13C NMR (150 MHz,
[D6]benzene): δ [39.8*, 40.2] (CH2S), [70.0, 70.1*] (CHN), [72.8*,
73.0] (CH2O), [80.9, 81.0*] (CHN), [114.6, 114.7*] [CAr(C=N)],
[{117.0, 117.5*}, {119.0, 119.2*},{120.0, 120.2*},{120.7, 120.8*}]
(CAr(H)), [123.2*, 123.6] [CAr(C=N)], [{126.5*, 126.5}, {126.6*,
126.6}] (o-Ph, m-Ph), [{126.8*, 126.9}] (p-Ph), 126.9 (p-Ph),
[{128.1, 128.2*}, {128.3, 128.3*}] (o-Ph, m-Ph), [{130.4, 130.6*},
{130.8, 130.9*}, 131.5, {131.6, 132.2*}] [CAr(H)], [141.7, 142.1*]
[CAr(NH)], [142.6*, 142.6] (i-Ph), [142.9, 142.9*] (i-Ph), [144.3,
144.4*] [CAr(NH)], [163.6, 163.7*] (C=N), [166.8*, 166.8] (C=N).
HRMS (ES+): calcd. for C30H25N3OS [M + H]+ 476.1797; found
3
3
CH(CH3)2], 1.06 [d, J = 6.7 Hz, 3 H, CH(CH3)2], 1.77 [oct, J =
3
6.7 Hz, 1 H, CH(CH3)2], 2.07 [oct, J = 6.7 Hz, 1 H, CH(CH3)2],
2
3
2
3.00 (dd, J = 10.7, J = 9.8 Hz, 1 H, CH2S), 3.27 (dd, J = 10.7,
3J = 8.7 Hz, 1 H, CH2S), 3.99–4.11 (m, 2 H, CH2O, CHN), 4.31
(dd, 2J = 9.1, J = 7.8 Hz, 1 H, CH2O), 4.40–4.46 (m, 1 H, CHN),
3
3
3
4
6.86 (ddd, J = 8.1, J = 6.7, J = 1.6 Hz, 1 H, Ar-HC), 6.94–6.98
(m, 1 H, Ar-HC), 7.23–7.30 (m, 3 H, Ar-HC), 7.39 (d, 3J = 8.2 Hz,
3
4
1 H, Ar-HC), 7.66 (dd, J = 7.8, J = 1.4 Hz, 1 H, Ar-HC), 7.80
(dd, 3J = 7.6, 4J = 1.1 Hz, 1 H, Ar-HC), 10.73 (br. s, 1 H, NH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4 [CH(CH3)2], 18.8
[CH(CH3)2], 19.0 [CH(CH3)2], 19.9 [CH(CH3)2], 33.1 [CH(CH3)2],
33.2 [CH(CH3)2], 34.6 (CH2S), 69.1 (CH2O), 72.9 (CHN), 84.2
(CHN), 115.1 [CAr(C=N)], 117.8, 119.2, 120.2, 120.9 [CAr(H)],
123.7 [CAr(C=N)], 130.2, 130.7, 131.3, 131.5 [CAr(H)], 141.8
[CAr(NH)], 144.0 [CAr(NH)], 162.7 (C=N), 165.1 (C=N) ppm. IR
476.1789. IR (NaCl, CHCl film): ν = 3198, 3063, 3027, 2964, 2922,
˜
3
2851, 1636, 1579, 1515, 1451, 1271, 751, 699 cm–1. C30H25N3OS
(475.60): calcd. C 75.76, H 5.30, N 8.84; found C 75.17, H 5.44, N
8.49.
(NaCl): ν = 3204, 3081, 2958, 1583, 1453, 1314, 1049, 974,
˜
2-[(S)-4-Benzyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-benzyl-4,5-di-
hydrothiazol-2-yl]phenyl}benzenamine (4d): Yield 19 % (96 mg;
Method A), 64% (160 mg; Method B), white oil. TLC: Rf = 0.28
(cyclohexane/EtOAc, 8:1). [α]2D0 = +74.9 (c = 1.03, CHCl3). 1H
749 cm–1. HRMS (ES+): calcd. for C24H29N3OS [M + H]+
408.2110; found 408.2098. C24H29N3OS (407.57): calcd. C 70.73,
H 7.17, N 10.31; found C 70.45, H 7.04, N 10.63.
2
3
2-[(S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-tert-butyl- NMR (600 MHz, CDCl3): δ = 2.73 (dd, J = 13.8, J = 8.2 Hz, 1
4,5-dihydrothiazol-2-yl]phenyl}benzenamine (4b): Yield 28% (61 mg;
H, CH2Ph), 2.80 (dd, 2J = 13.8, 3J = 8.8 Hz, 1 H, CH2S), 3.00 (dd,
Method A), 83 % (180 mg; Method B), white solid. M.p. 130– 2J = 10.9, 3J = 7.1 Hz, 1 H, CH2Ph), 3.15 (dd, 2J = 13.8, 3J =
132 °C. TLC: Rf = 0.35 (cyclohexane/EtOAc, 8:1). [α]2D0 = +13.3 (c
= 0.75, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.89 [s, 9 H,
C(CH3)3], 1.01 [s, 9 H, C(CH3)3], 3.05 (app. t, J = 10.8 Hz, 1 H,
5.9 Hz, 1 H, CH2Ph), 3.19 (dd, 2J = 10.9, 3J = 8.2 Hz, 1 H,
2
3
CH2Ph), 3.24 (dd, J = 13.8, J = 5.3 Hz, 1 H, CH2S), 4.00 (app.
3
2
3
t, J = 7.9 Hz, 1 H, CH2O), 4.24 (dd, J = 8.2, J = 9.1 Hz, 1 H,
CH2O), 4.49–4.54 (m, 1 H, CHN), 4.78–4.83 (m, 1 H, CHN), 6.86–
6.89 (m, 1 H, Ar-HC), 6.95–6.98 (m, 1 H, Ar-HC), 7.15–7.21 (m,
2
3
3
CH2S), 3.18 (dd, J = 10.8, J = 8.8 Hz, 1 H, CH2S), 4.03 (dd, J
= 9.8, 3J = 7.3 Hz, 1 H, CHN), 4.11 (app. t, J = 8.3 Hz, 1 H,
3
2
3
3
4
CH2O), 4.28 (dd, J = 9.8, J = 8.3 Hz, 1 H, CH2O), 4.33 (dd, J
10 H, Ar-HC), 7.26–7.31 (m, 2 H, Ar-HC), 7.37 (dd, J = 8.5, J
4838
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4833–4841

Thiazoline–Oxazoline Ligands in Asymmetric Friedel–Crafts Reaction
3
4
= 0.9 Hz, 1 H, Ar-HC), 7.46 (dd, J = 8.2, J = 0.9 Hz, 1 H, Ar-
Method B), colourless oil. M.p. 54–57 °C (turned into an oil). TLC:
Rf = 0.27 (8:1, cyclohexane/EtOAc). [α]2D0 = +7.0 (c = 1.00, CHCl3).
3
4
3
HC), 7.65 (dd, J = 7.6, J = 1.5 Hz, 1 H, Ar-HC), 7.79 (dd, J =
7.6, 4J = 1.5 Hz, 1 H, Ar-HC), 10.97 (br. s, 1 H, NH) ppm. 13C 1H NMR (600 MHz, [D6]benzene): δ = [2.70 (dd, J = 10.7, J =
2
3
NMR (150 MHz, CDCl3): δ = 36.6 (CH2Ph), 40.5 (CH2S), 42.0 9.6 Hz) and 2.71* (dd, 2J = 10.7 Hz, 3J = 9.2 Hz)] (3:1, 1 H, CH2S),
2
3
2
3
(CH2Ph), 68.3 (CHN), 70.6 (CH2 O), 79.0 (CHN), 115.1
[CAr(C=N)], 117.7, 119.4, 119.7, 120.7 [CAr(H)], 122.9 [CAr(C=N)],
126.3, 126.4, 128.4, 129.3, 130.3, 130.9, 131.4, 131.6 [CAr(H)], 138.1
[3.02 (dd, J = 10.7, J = 8.7 Hz) and 3.03* (dd, J = 10.8 Hz, J
3
= 8.8 Hz)] (3:1, 1 H, CH2S), [3.58 (app. t, J = 8.2 Hz) and 3.59*
(app. t, J = 8.2 Hz)] (3:1, 1 H, CH2O), [3.92* (dd, J = 10.1, J =
3
3
2
(i-Ph), 138.6 (i-Ph), 141.8 [CAr(NH)], 143.8 [CAr(NH)], 163.1 8.1 Hz) and 3.95 (dd, 3J = 10.1 Hz, 2J = 8.1 Hz)] (1:3, 1 H, CH2O),
3
3
3
3
(C=N), 166.0 (C=N) ppm. IR (KBr): ν = 3166, 3025, 2918, 2850,
[4.70* (dd, J = 9.8, J = 8.5 Hz) and 4.90 (dd, J = 10.0 Hz, J =
˜
1638, 1578, 1515, 1452, 1052, 1031, 739, 699 cm–1. HRMS (ES+):
8.4 Hz)] (1:3, 1 H, CHN), [5.25* (app. t, 3J = 9.0 Hz) and 5.33
calcd. for C32H29N3OS [M + H]+ 504.2110; found 504.2101. (app. t, 3J = 9.1 Hz)] (1:3, 1 H, CHN), 6.69–6.73 (m, 2 H, Ar-HC),
C32H29N3OS (503.66): calcd. C 76.31, H 5.80, N 8.34; found C
76.11, H 5.80, N 8.16.
6.92–6.95 (m, 1 H, Ar-HC), 6.96–7.02 (m, 9 H, Ar-HC), 7.06–7.08
3
(m, 1 H, Ar-HC), 7.12–7.14 (m, 1 H, Ar-HC), [7.35 (dd, J = 8.4,
4J = 0.6 Hz) and 7.41* (dd, 3J = 8.4 Hz, 4J = 0.6 Hz)] (3:1, 1 H, Ar-
HC), [7.43 (dd, 3J = 8.1, 4J = 0.7 Hz) and 7.47* (dd, 3J = 8.3 Hz, 4J
= 0.6 Hz)] (3:1, 1 H, Ar-HC), [7.83* (dd, 3J = 7.8, 4J = 1.5 Hz)
2-[(S)-4-Benzyl-4,5-dihydrooxazol-2-yl]-N-{2-[(S)-4-tert-butyl-4,5-di-
hydrothiazol-2-yl]phenyl}benzenamine (4e): Yield 27 % (63 mg;
Method A), 72 % (170 mg; Method B), white solid. M.p. 124–
126 °C. TLC: Rf = 0.28 (cyclohexane/EtOAc, 8:1). [α]2D0 = +56.3 (c
= 1.10, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.00 [s, 9 H,
C(CH3)3], 2.70 (dd, 2J = 13.9, 3J = 7.8 Hz, 1 H, CH2Ph), 3.03–3.10
(m, 2 H, CH2Ph, CH2S), 3.17 (dd, 2J = 11.0, 3J = 9.0 Hz, 1 H,
3
4
and 7.91 (dd, J = 7.9 Hz, J = 1.5 Hz)] (1:3, 1 H, Ar-HC), [8.07*
4
3
4
(dd, 3J = 7.8, J = 1.6 Hz) and 8.08 (dd, J = 7.8 Hz, J = 1.6 Hz)]
(1:3, 1 H, Ar-HC), [11.64 (br. s) and 11.80* (br. s)] (3:1, 1 H, NH)
ppm. 13C NMR (150 MHz, [D6]benzene): δ = [39.8, 40.2*] (CH2S),
[70.0*, 70.1] (CHN), [72.8, 73.0*] (CH2O), [80.8*, 81.0] (CHN),
[114.6*, 114.7] [CA r (C=N)], [{117.0*, 117.5}, {119.0*,
119.1},{120.0*, 120.2},{120.7*, 120.8}] (CAr(H)), [123.2, 123.6*]
[CAr(C=N)], [{126.5, 126.5*}, {126.6, 126.6*}] (o-Ph, m-Ph),
[{126.8*, 126.9}] (p-Ph), [{128.1*, 128.2}, {128.3*, 128.3}] (o-Ph,
m-Ph), [{130.4*, 130.6}, {130.7*, 131.0}, {131.5*, 131.6}, 132.2]
[CAr(H)], [141.7*, 142.1] [CAr(NH)], [142.6, 142.6*] (i-Ph), [142.9*,
143.0] (i-Ph), [144.3*, 144.4] [CAr(NH)], [163.6*, 163.7] (C=N),
2
3
CH2S), 4.00 (t, J = 7.8, J = 7.8 Hz, 1 H, CH2O), 4.21–4.27 (m,
2 H, CHN, CH2O), 4.51–4.57 (m, 1 H, CHN), 6.88 (ddd, 3J = 8.2,
3J = 6.5, J = 1.9 Hz, 1 H, Ar-HC), 6.95 (app. t, J = 7.8 Hz, 1 H,
Ar-HC), 7.15–7.22 (m, 5 H, Ar-HC), 7.24–7.30 (m, 3 H, Ar-HC),
7.34 (br. d, 3J = 7.8 Hz, 1 H, Ar-HC), 7.67 (dd, 3J = 7.8, 4J =
1.2 Hz, 1 H, Ar-HC), 7.79 (dd, 3J = 7.8, 4J = 1.2 Hz, 1 H, Ar-HC),
10.61 (br. s, NH) ppm. 13C NMR (125 MHz, CDCl3): δ = 26.9
[C(CH3)3], 33.2 (CH2S), 35.1 [C(CH3)3], 41.9 (CH2Ph), 68.1
(CHN), 70.7 (CH2O), 88.2 (CHN), 115.7 [CAr(C=N)], 119.0, 119.7,
120.6 [CAr(H)], 123.1 [CAr(C=N)], 126.4, 128.4, 129.4, 130.4, 130.8,
131.4, 131.7 [CAr(H)], 138.1 [CAr(4°)], 142.3 [CAr(4°)], 143.9
[CAr(4°)], 163.1 (C=N), 165.2 (C=N) ppm. IR (NaCl, CHCl3 film):
4
3
[166.7, 166.8*] (C=N) ppm. IR (NaCl, CHCl3 film): ν = 3206,
˜
3066, 3030, 2922, 1629, 1585, 1513, 1451, 1307, 1276, 1307, 750,
694 cm–1. HRMS (ES+): calcd. for C30H25N3OS [M + H]+
476.1797; found 476.1811.
ν = 3219, 3068, 3030, 2950, 1593, 1510, 1455, 1308, 1273, 1219, General Procedure for the Catalytic Enantioselective Friedel–Crafts
˜
1048, 988, 942, 745, 698 cm– 1 . HRMS (ES+ ): calcd. for Reaction: Zn(OTf)2 (9.3 mg, 0.025 mmol) and ligand 4
C29H31N3OS [M + H]+ 470.2266; found 470.2268. C29H31N3OS (0.025 mmol) were placed in a dried Schlenk tube under nitrogen
(469.64): calcd. C 74.17, H 6.65, N 8.95; found C 73.98, H 6.66, N
8.61.
followed by the addition of dry degassed toluene (2 mL). This solu-
tion was stirred at room temperature for 30 min before the nitroal-
kene 11 (0.5 mmol) was added. The resulting mixture was stirred
at room temperature for 10 min and then cooled to –20 °C before
adding indole 8 (57 mg, 0.5 mmol). After stirring at –20 °C for
15 h, the solvent was removed in vacuo, and the crude mixture was
purified by column chromatography on silica gel (pentane/EtOAc,
5:1) to yield the desired pure product. The enantioselectivity was
determined by HPLC using a Chiralcel® OD column.
2-[(S)-4-Benzyl-4,5-dihydrothiazol-2-yl]-N-{2-[(S)-4-tert-butyl-4,5-di-
hydrooxazol-2-yl]phenyl}benzenamine (4f): Yield 17 % (80 mg;
Method A), 60% (142 mg; Method B), white semi-solid. TLC: Rf
= 0.37 (cyclohexane/EtOAc, 8:1). [α]2D0 = +35.0 (c = 1.25, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 0.93 [s, 9 H, C(CH3)3], 2.80 (dd,
2J = 13.6, 3J = 8.8 Hz, 1 H, CH2S), 3.00 (dd, 2J = 10.9, 3J = 6.9 Hz,
1 H, CH2Ph), 3.20–3.24 (m, 2 H, CH2Ph, CH2S), 4.02 (dd, 3J =
9.9, 3J = 8.1 Hz, 1 H, CH2O), 4.10 (app. t, 3J = 9.1 Hz, 1 H,
3-(2-Nitro-1-phenylethyl)-1H-indole (10a): TLC: Rf = 0.20 (pentane/
CH2O), 4.22 (dd, 3J = 9.9, 2J = 8.4 Hz, 1 H, CH2O), 4.89–4.94 (m, EtOAc, 5:1). [α]2D0 = –17.2 [c = 1.0, CH2Cl2, 71% ee (R)]. 1H NMR
3
1 H, CHN), 6.84–6.87 (m, 1 H, Ar-HC), 6.98 (app. t, J = 7.5 Hz, (500 MHz, CDCl3): δ = 4.93 (dd, 2J = 12.5, 3J = 8.3 Hz, 1 H,
3
2
3
1 H, Ar-HC), 7.17–7.31 (m, 8 H, Ar-HC), 7.43 (d, J = 8.2 Hz, 1 CH2NO2), 5.05 (dd, J = 12.5, J = 7.6 Hz, 1 H, CH2NO2), 5.18
H, Ar-HC), 7.66 (dd, 3J = 7.8, 4J = 1.4 Hz, 1 H, Ar-HC), 7.80 (dd,
(app. t, J = 8.0 Hz, 1 H, CHCH2NO2), 7.02 (d, J = 2.2 Hz, 1 H,
3
3
4
3
3
3J = 7.8, J = 1.3 Hz, 1 H, Ar-HC), 10.86 (br. s, 1 H, NH) ppm.
Ar-HC), 7.07 (app. t, J = 7.8 Hz, 1 H, Ar-HC), 7.19 (app. t, J =
13C NMR (150 MHz, CDCl3): δ = 26.0 [C(CH3)3], 30.9 [C(CH3)3], 7.8 Hz, 1 H, Ar-HC), 7.23–7.26 (m, 1 H, Ar-HC), 7.30–7.35 (m, 5
36.7 (CH2Ph), 40.3 (CH2S), 67.3 (CH2O), 76.7 (CHN), 78.7 H, Ar-HC), 7.44 (d, 3J = 7.8 Hz, 1 H, Ar-HC), 8.06 (br. s, 1 H,
(CHN), 114.5 [CAr(C=N)], 116.9, 118.9, 121.0, 121.2 [CAr(H)], NH) ppm. 13C NMR (125 MHz, CDCl3): δ = 41.6 (CHCH2NO2),
124.2 [CAr(C=N)], 126.3, 128.4, 129.4, 130.2, 130.8, 131.3, 131.4 79.5 (CH2NO2), 111.4 [CAr(H)], 114.5 [CAr(4°)], 118.9, 120.0, 121.6,
[CAr(H)], 138.7 (ipso-Ph), 141.5 [CAr(NH)], 144.3 [CAr(NH)], 162.6 122.7 [CAr(H)], 126.1 [CAr(4°)], 127.6 (p-Ph), 127.8 (m-Ph), 128.9
(C=N), 165.8 (C=N) ppm. IR (KBr): ν = 3196, 2953, 2903, 2867,
(o-Ph), 136.5, 139.2 [CAr(4°)] ppm. Enantiomeric excess determined
by HPLC: Chiracel® OD, hexane/2-propanol (70:30), 0.9 mL/min,
retention times: tminor = 22.8 min, tmajor = 26.5 min.
˜
1643, 1578, 1515, 1452, 1315, 1213, 1050, 1027, 749 cm–1. HRMS
(ES+): calcd. for C29H31N3OS [M + H]+ 470.2266; found 470.2255.
C29H31N3OS (469.64): calcd. C 74.17, H 6.65, N 8.95; found C
73.80, H 6.69, N 8.88.
3-[1-(Furan-2-yl)-2-nitroethyl]-1H-indole (10b): TLC: Rf = 0.11
(pentane/EtOAc, 5:1). [α]2D0 = +14.0 (c = 1.12, CHCl3, 28% ee). 1H
2
3
2-[(S)-4-Phenyl-4,5-dihydrooxazol-2-yl]-N-{2-[(R)-4-phenyl-4,5-di-
hydrothiazol-2-yl]phenyl}benzenamine (4g): Yield 22 % (53 mg;
NMR (400 MHz, CDCl3): δ = 4.90 (dd, J = 12.5, J = 7.4 Hz, 1
H, CH2NO2), 5.05 (dd, 2J = 12.5, 3J = 8.1 Hz, 1 H, CH2NO2), 5.25
Eur. J. Org. Chem. 2009, 4833–4841
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4839

S. C. McKeon, H. Müller-Bunz, P. J. Guiry
FULL PAPER
3
3
(app. t, 3J = 7.8 Hz, 1 H, CHCH2NO2), 6.15–6.16 (m, 1 H, Ar- (app. t, J = 8.0 Hz, 1 H, CHCH2NO2), 7.01 (br. d, J = 2.4 Hz, 1
3
3
3
HC), 6.30 (dd, J = 3.3, J = 1.9 Hz, 1 H, Ar-HC), 7.10 (d, J =
H, Ar-HC), 7.08 (ddd, 3J = 7.9, 3J = 7.3, 4J = 0.8 Hz, 1 H, Ar-
HC), 7.18–7.24 (m, 4 H, Ar-HC), 7.30 (br. s, 1 H, Ar-HC), 7.35
(br. d, 3J = 8.2 Hz, 1 H, Ar-HC), 7.41 (br. d, 3J = 8.0 Hz, 1 H, Ar-
HC), 8.15 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 41.2 (CHCH2NO2), 79.2 (CH2NO2), 111.5 [CAr(H)], 113.6
[CAr(4°)], 118.7, 120.1, 121.6, 122.9 [CAr(H)], 125.9 [CAr(4°)] 126.0,
3
3
4
2.5 Hz, 1 H, Ar-HC), 7.13 (ddd, J = 8.0, J = 7.1, J = 1.0 Hz, 1
H, Ar-HC), 7.21 (ddd, 3J = 8.1, 3J = 7.1, 4J = 1.0 Hz, 1 H, Ar-
3
4
HC), 7.34–7.38 (m, 2 H, Ar-HC), 7.55 (dd, J = 7.9, J = 0.8 Hz,
1 H, Ar-HC), 8.10 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 35.8 (CHCH2NO2), 77.9 (CH2NO2), 107.4, 110.5,
111.5 [CAr(H)], 111.7 [CAr(4°)], 118.7, 120.0, 122.7, 122.7 [CAr(H)], 127.9, 128.0, 130.2 [CAr(H)], 134.8, 136.5, 141.3 [CAr(4°)] ppm. En-
125.7, 136.3 [CAr(4°)], 142.3 [CAr(H)], 152.2 [CAr(4°)] ppm. Enan-
tiomeric excess determined by HPLC: Chiracel® OD, hexane/2-pro-
panol (70:30), 0.9 mL/min, retention times: tmajor = 14.3 min, tminor
= 20.3 min.
antiomeric excess determined by HPLC: Chiracel® OD, hexane/2-
propanol (70:30), 0.9 mL/min, retention times: tminor = 24.4 min,
tmajor = 32.7 min.
3-[1-(4-Methoxyphenyl)-2-nitroethyl]-1H-indole (10g): TLC: Rf =
0.10 (pentane/EtOAc, 5:1). [α]2D0 = –4.0 (c = 1.15, CHCl3, 74% ee).
3-[1-(2-Methoxyphenyl)-2-nitroethyl]-1H-indole (10c): TLC: Rf =
0.12 (pentane/EtOAc, 5:1). [α]2D0 = –6.3 (c = 1.12, CHCl3, 17% ee).
2
1H NMR (400 MHz, CDCl3): δ = 3.76 (s, 3 H, OCH3) 4.89 (dd, J
1H NMR (400 MHz, CDCl3): δ = 3.88 (s, 3 H, OCH3) 4.96 (dd, 2J = 12.3, 3J = 8.4 Hz, 1 H, CH2NO2), 5.04 (dd, 2J = 12.3, 3J =
= 12.5, 3J = 9.0 Hz, 1 H, CH2NO2), 5.02 (dd, 2J = 12.5, 3J =
7.5 Hz, 1 H, CH2 NO2 ), 5.13 (app. t, 3 J = 8.0 Hz, 1 H,
6.8 Hz, 1 H, CH2NO2), 5.59 (dd, 3J = 9.0, 3J = 6.8 Hz, 1 H,
CHCH2NO2), 6.82–6.86 (m, 2 H, Ar-HC), 7.00 (br. d, 3J = 1.9 Hz,
3
3
4
3
3
4
CHCH2NO2), 6.81 (ddd, J = 8.5, J = 7.5, J = 1.0 Hz, 1 H, Ar-
1 H, Ar-HC), 7.07 (ddd, J = 8.0, J = 7.2, J = 0.9 Hz, 1 H, Ar-
HC), 7.19 (ddd, 3J = 8.1, 3J = 7.1, 4J = 1.0 Hz, 1 H, Ar-HC), 7.22–
3
4
HC), 6.90 (dd, J = 8.2, J = 0.7 Hz, 1 H, Ar-HC), 7.03–7.09 (m,
3
3
4
3
3 H, Ar-HC), 7.16 (ddd, J = 8.1, J = 7.0, J = 1.1 Hz, 1 H, Ar-
7.25 (m, 2 H, Ar-HC), 7.34 (br. d, J = 8.2 Hz, 1 H, Ar-HC), 7.43
3
3
4
3
HC), 7.21 (ddd, J = 9.1, J = 8.2, J = 1.7 Hz, 1 H, Ar-HC), 7.30
(br. d, J = 8.0 Hz, 1 H, Ar-HC), 8.07 (br. s, 1 H, NH) ppm. 13C
3
3
4
(br. d, J = 8.2 Hz, 1 H, Ar-HC), 7.46 (dd, J = 7.9, J = 0.5 Hz,
NMR (100 MHz, CDCl3): δ = 40.9 (CHCH2NO2), 55.2 (OCH3),
79.8 (CH2NO2), 111.3 [CAr(H)], 114.3 [2ϫ CAr(H)], 114.8 [CAr(4°)],
1 H, Ar-HC), 8.02 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 34.5 (CHCH2NO2), 54.5 (OCH3), 77.1 (CH2NO2), 119.0, 119.9, 121.4, 122.7 [CAr(H)], 126.1 [CAr(4°)], 128.8 [2ϫ
109.8, 110.2 [CAr(H)], 112.9 [CAr(4°)], 118.0, 118.7, 119.7, 120.9, CAr(H)], 131.2, 136.5, 158.9 [CAr(4°)] ppm. Enantiomeric excess de-
121.4 [CAr(H)], 125.5, 126.2 [CAr(4°)], 127.6, 127.9 [CAr(H)], 135.3, termined by HPLC: Chiracel® OD, hexane/2-propanol (70:30),
155.8 [CAr(4°)] ppm. Enantiomeric excess determined by HPLC:
Chiracel® OD, hexane/2-propanol (70:30), 0.9 mL/min, retention
times: tminor = 12.2 min, tmajor = 14.2 min.
0.9 mL/min, retention times: tminor = 23.0 min, tmajor = 26.4 min.
3-[1-(4-Bromophenyl)-2-nitroethyl]-1H-indole (10h): TLC: Rf = 0.1
(pentane/EtOAc, 5:1). [α]2D0 = +7.5 (c = 1.1, CHCl3, 60% ee). 1H
2
3
3-[1-(2-Chlorophenyl)-2-nitroethyl]-1H-indole (10d): TLC: Rf = 0.12
(pentane/EtOAc, 5:1). [α]2D0 = +20.8 (c = 1.10, CHCl3, 20% ee). 1H
NMR (400 MHz, CDCl3): δ = 4.91–5.01 (m, 2 H, CH2NO2), 5.73
NMR (400 MHz, CDCl3): δ = 4.90 (dd, J = 12.5, J = 8.6 Hz, 1
H, CH2NO2), 5.04 (dd, 2J = 12.5, 3J = 7.3 Hz, 1 H, CH2NO2), 5.14
(t, 3J = 7.9 Hz, 1 H, CHCH2NO2), 7.00 (dd, 3J = 2.5, J = 0.6 Hz,
4
(app. t, 3J = 8.0 Hz, 1 H, CHCH2NO2), 7.04–7.20 (m, 6 H, Ar- 1 H, Ar-HC), 7.08 (ddd, J = 8.0, J = 7.2, J = 1.0 Hz, 1 H, Ar-
3
3
4
HC), 7.31 (d, 1 H, Ar-HC), 7.40–7.43 (m, 2 H, Ar-HC), 8.11 (br.
HC), 7.18–7.22 (m, 2 H, Ar-HC), 7.35–7.45 (m, 4 H, Ar-HC), 8.11
s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 38.0 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 41.0
(CHCH2NO2), 77.7 (CH2NO2), 111.4 [CAr(H)], 113.2 [CAr(4°)], (CHCH2NO2), 79.2 (CH2NO2), 111.5 [CAr(H)], 113.9 [CAr(4°)],
118.9, 120.0, 122.0, 122.8, [CAr (H)], 126.2 [CAr(4°)], 127.3, 128.9, 118.8, 120.1, 121.5 [CAr(H)], 122.9 [CAr(4°)], 125.9, 129.5, 132.1
129.0, 130.1 [CAr(H)], 133.8, 136.4, 136.5 [CAr(4°)] ppm. Enantio-
[CAr(H)] ppm. Enantiomeric excess determined by HPLC: Chira-
cel® OD, hexane/2-propanol (70:30), 0.9 mL/min, retention times:
tminor = 27.5 min, tmajor = 34.5 min.
meric excess determined by HPLC: Chiracel® OD, hexane/2-propa-
nol (70:30), 0.9 mL/min, retention times: tminor = 16.5 min, tmajor
=
25.2 min.
3-[1-(4-Chlorophenyl)-2-nitroethyl]-1H-indole (10i): TLC: Rf = 0.07
3-[1-(3-Bromophenyl)-2-nitroethyl]-1H-indole (10e): TLC: Rf = 0.14 (pentane/EtOAc, 5:1). [α]2D0 = +3.3 (c = 1.05, CHCl3, 67% ee). H
1
1
2
3
(pentane/EtOAc, 5:1). [α]2D0 = –2.0 (c = 1.00, CHCl3, 76% ee). H
NMR (400 MHz, CDCl3): δ = 4.89 (dd, J = 12.5, J = 8.6 Hz, 1
H, CH2NO2), 5.04 (dd, 2J = 12.5, 3J = 7.3 Hz, 1 H, CH2NO2), 5.15
(app. t, 3J = 8.0 Hz, 1 H, CHCH2NO2), 6.99 (dd, 3J = 2.5, 4J =
2
3
NMR (400 MHz, CDCl3): δ = 4.89 (dd, J = 12.6, J = 8.4 Hz, 1
H, CH2NO2), 5.02 (dd, 2J = 12.6, 3J = 7.5 Hz, 1 H, CH2NO2), 5.14
(app. t, 3J = 8.0 Hz, 1 H, CHCH2NO2), 7.00 (dd, 3J = 2.5, 4J =
3
3
4
0.4 Hz, 1 H, Ar-HC), 7.07 (ddd, J = 8.0, J = 7.2, J = 1.0 Hz, 1
H, Ar-HC), 7.20 (ddd, 3J = 8.1, 3J = 7.1, 4J = 1.0 Hz, 1 H, Ar-
HC), 7.24–7.29 (m, 4 H, Ar-HC), 7.34 (d, 3J = 8.2 Hz, 1 H, Ar-
HC), 7.39 (d, 3J = 7.9 Hz, 1 H, Ar-HC), 8.11 (br. s, 1 H, NH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 40.9 (CHCH2NO2), 79.3
(CH2NO2), 111.5 [CAr(H)], 113.9 [CAr(4°)], 118.9, 120.1, 121.5,
122.9 [CAr(H)], 125.9 [CAr(4°)], 129.1, 129.1 (m-Ph, o-Ph), 133.4,
3
3
4
2.0 Hz, 1 H, Ar-HC), 7.08 (ddd, J = 8.0, J = 7.2, J = 0.9 Hz, 1
H, Ar-HC), 7.17 (t, 3J = 7.8 Hz, 1 H, Ar-HC), 7.20 (ddd, 3J = 8.1,
3J = 7.1, J = 1.0 Hz, 1 H, Ar-HC), 7.26 (br. d, J = 7.8 Hz, 1 H,
4
3
Ar-HC), 7.34 (br. d, 3J = 8.2 Hz, 1 H, Ar-HC), 7.36–7.39 (m, 1 H,
3
4
Ar-HC), 7.41 (br. d, J = 8.0 Hz, 1 H, Ar-HC), 7.45 (app. t, J =
1.8 Hz, 1 H, Ar-HC), 8.12 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 41.1 (CHCH2NO2), 79.2 (CH2NO2), 111.5 136.5, 137.7 [CAr(4°)] ppm. Enantiomeric excess determined by
[CAr(H)], 113.6 [CAr(4°)], 118.7, 120.1, 121.6, 122.9 [CAr(H)], 123.0, HPLC: Chiracel® OD, hexane/2-propanol (70:30), 0.9 mL/min, re-
125.9 [CAr(4°)], 126.5, 130.5, 130.8, 130.9 [CAr(H)], 136.5, 141.6
[CAr(4°)] ppm. Enantiomeric excess determined by HPLC: Chira-
cel® OD, hexane/2-propanol (70:30), 0.9 mL/min, retention times:
tminor = 25.0 min, tmajor = 33.8 min.
tention times: tminor = 25.9 min, tmajor = 31.9 min.
3-[1-(3,4-Dimethoxyphenyl)-2-nitroethyl]-1H-indole (10j): TLC: Rf =
0.05 (pentane/EtOAc, 5:1). [α]2D0 = –6.2 (c = 1.02, CHCl3, 38% ee).
1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H, OCH3) 3.83 (s, 3
3-[1-(3-Chlorophenyl)-2-nitroethyl]-1H-indole (10f): TLC: Rf = 0.20 H, OCH3) 4.91 (dd, J = 12.3, 3J = 8.5 Hz, 1 H, CH2NO2), 5.04
2
(pentane/EtOAc, 5:1). [α]2D0 = –3.0 (c = 1.2, CHCl3, 64% ee). 1H
(dd, 2J = 12.3, 3J = 7.4 Hz, 1 H, CH2NO2), 5.13 (app. t, 3J =
8.0 Hz, 1 H, CHCH2NO2), 6.79–6.83 (m, 2 H, Ar-HC), 6.89 (dd,
2
3
NMR (400 MHz, CDCl3): δ = 4.90 (dd, J = 12.6, J = 8.4 Hz, 1
H, CH2NO2), 5.03 (dd, 2J = 12.6, 3J = 7.5 Hz, 1 H, CH2NO2), 5.15
3J = 8.2, J = 2.0 Hz, 1 H, Ar-HC), 6.99 (d, J = 2.0 Hz, 1 H, Ar-
4
3
4840
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Eur. J. Org. Chem. 2009, 4833–4841

Thiazoline–Oxazoline Ligands in Asymmetric Friedel–Crafts Reaction
3
3
4
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S. C. McK. is grateful to Science Foundation Ireland for its finan-
cial support (05/RFP/CHE0075). We acknowledge facilities pro-
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funded by the Higher Education Authority’s Programme for Re-
search in Third-Level Institutions (PRTLI). We would also like to
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Received: June 19, 2009
Published Online: August 26, 2009
Eur. J. Org. Chem. 2009, 4833–4841
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4841