Bicyclic phosphine-thiazole ligands for the asymmetric hydrogenation of olefins

Article abstract of DOI:10.1016/j.tetasy.2010.03.023

New bicyclic thiazole-based chiral N,P-chelating ligands were developed. High activities and enantioselectivities were achieved in the iridium-catalyzed asymmetric hydrogenation of olefins with the new ligands.

Full text of DOI:10.1016/j.tetasy.2010.03.023

Tetrahedron: Asymmetry 21 (2010) 1328–1333
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Bicyclic phosphine-thiazole ligands for the asymmetric hydrogenation of olefins
Jia-Qi Li a, Alexander Paptchikhine a, Thavendran Govender b, Pher G. Andersson a,
*
a Department of Biochemistry and Organic Chemistry, Uppsala University, Uppsala 75123, Sweden
b Department of Pharmacy, University of KwaZulu-Natal, Durban 4000, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
New bicyclic thiazole-based chiral N,P-chelating ligands were developed. High activities and enantiose-
Received 23 February 2010
Accepted 26 March 2010
Available online 11 May 2010
lectivities were achieved in the iridium-catalyzed asymmetric hydrogenation of olefins with the new
ligands.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1. Introduction
hydrogenation of olefins.12 Thus we chose to synthesize more
members of the set of bicyclic phosphine-thiazole ligands and
Chiral compounds and their preparation play an important role
in the production of fine chemicals, pharmaceuticals, and natural
products.1 As a result, various methods for creating stereogenic
centers have been developed. Due to its high efficiency, atom econ-
omy, and operational simplicity, the asymmetric hydrogenation
(the addition of H2 to a C@X (X = C, N or O) bond) has been widely
used in asymmetric synthesis.2 Early reports were dominated by
rhodium- and ruthenium-based catalysts.3 However the highly
stereoselective hydrogenation of olefins by rhodium- and ruthe-
nium-based catalysts usually requires a coordinating group close
to the carbon–carbon double bond.4 By contrast, iridium com-
plexes with chiral N,P-chelating ligands do not need a coordinating
group to achieve high enantioselectivity. They have therefore be-
come powerful tools for the hydrogenation of unfunctionalized
investigate their performance in the iridium-catalyzed asymmetric
hydrogenation.
PAr2
PAr2
N
PAr2
N
N
N
N
O
R1
R2
Ph
R
S
S
2
3
1
Figure 1. Bicyclic phosphine-oxazoline ligands 1, thiazole liangds 2, and bicyclic
phosphine-thiazole ligands 3.
2. Results and discussion
olefins, and useful complements to rhodium- and ruthenium-
based catalysts.
2.1. Synthesis of iridium complex 7
5
Since the success of Pfaltz’ PHOX catalysts,6
which are chiral analogues of Crabtree’s catalyst, a number of chi-
ral N,P-chelating ligands have been prepared and tested in the irid-
ium-catalyzed asymmetric hydrogenation of olefins.5a,b,d,e,7,8 The
bicyclic phosphine-oxazoline ligands 1 (Fig. 1) are among the most
successful types and give excellent results in the hydrogenation of
acyclic aromatic N-arylimines9a,b and enol phosphinates.9c,d Thia-
zole ligands 2 are also highly enantioselective in the hydrogenation
of a wide range of olefins.8b,d,k,j Encouraged by the excellent results
achieved with ligands 1 and 2, we developed the bicyclic phos-
phine-thiazole ligand 3c, which was effective in the hydrogenation
of vinyl boronates.10 The iridium-catalyzed asymmetric hydroge-
nation of unfunctionalized olefins is still highly substrate depen-
dent, and the development of new chiral ligands for this reaction
remains an important task.11 In known ligands, heteroaromatic
moieties have significantly affected enantioselectivities in the
As shown in Scheme 1, N-Boc-protected thioamide 4 was
cyclized with an a-bromoketone to yield the corresponding N-pro-
tected thiazole 5. The protecting group was readily removed under
acidic conditions to afford amine 6. Ligand 3 was obtained by treat-
ing 6 with a diarylphosphine chloride in the presence of di-iso-pro-
pylethylamine. Iridium complex 7 was prepared by refluxing 3 and
[Ir(COD)Cl]2 in CH2Cl2 followed by counterion exchange with Na-
BArFꢀ3H2O in a CH2Cl2/water mixture. Compound 7 was purified
by flash chromatography on silica gel. All complexes were isolated
as air stable solids. No decomposition of the complexes was
observed by 1H and 31P NMR after months in air.
2.2. Asymmetric hydrogenation of olefins
Complexes 7a–d were evaluated in the asymmetric hydrogena-
tions of various olefins (Table 1). Generally, complexes 7c and 7d
were more stereoselective than 7a and 7b. Complex 7b gave a
low conversion for most trisubstituted olefins. This is likely
* Corresponding author. Tel.: +46 18 471 3818; fax: +46 18 471 3816.
E-mail address: Pher.Andersson@biorg.uu.se (P.G. Andersson).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.023

J.-Q. Li et al. / Tetrahedron: Asymmetry 21 (2010) 1328–1333
1329
Ar Ar
BArF
Boc
Boc
H
S
PAr2
P
Ir
N
N
N
N
N
a
b
c
d
N
S
N
N
N
S
R
R
R
R
NH2
S
S
5a
6a
3a:R=Me, Ar=Ph
:R=Me
:R=Me
7a:R=Me, Ar=Ph
t
t
5b:R=tBu
5c:R=Ph
6b:R=tBu
6c:R=Ph
:R= Bu, Ar=Ph
:R=Ph, Ar=Ph
7b
3b
4
:R= Bu, Ar=Ph
3c
7c
:R=Ph, Ar=Ph
7d:R=Ph, Ar=o-Tol
3d:R=Ph, Ar=o-Tol
Scheme 1. Synthesis of iridium complexes 7. Reagents and conditions: (a) MeOH,
a
-bromo ketone, CaCO3, reflux, 4 h; (b) THF, 12 M HCl, 2 h; (c) Ar2PCl, iPr2NEt, THF, 0 °C then
4 °C overnight; (d) [Ir(COD)Cl]2, CH2Cl2, reflux 1 h then H2O, NaBArFꢀ3H2O, rt, 2 h.
because it bears a bulky tert-butyl group on the thiazole ring.
When the phosphine moiety was changed from diphenylphos-
phine to di-o-tolylphosphine, enantioselectivities were moderately
improved for most substrates (compare 7c vs 7d. Table 1, entries 2,
4, 5, 8, and 9). The difference was quite dramatic in the case of
polarimeter using a 1.0 dm cell and are reported as follows: con-
centration (c = g/dL) and solvent. Melting points were recorded as
their uncorrected values.
Enantiomeric excesses (ees) were determined by chiral HPLC or
GC. HPLC was performed with a DAD detector using Daicel Chir-
alpak OJ, OB-H, and AS-H columns. GC analysis was performed
using a Chiraldex b-DM column. Absolute configurations were
determined by comparing the retention times to those previously
reported.7g,8h
a-methyl trans-cinnamate 13.
Both the thiazole complex 7d and the analogous oxazoline com-
plex 8 gave excellent enantioselectivities in the asymmetric hydro-
genation of substrates 9 and 10 (Table 1, entries 1 and 2). Complex
7d out-performed 8 in the reduction of substrates 11, 12, 15, 16,
and 17 (entries 3, 4, 7, 8, and 9). Complex 7d also gave high yield
and excellent enantioselectivity in the hydrogenation of allylic alco-
hol 14, toward which 8 was inactive (entry 6). In general, the new
complexes provided good to excellent enantioselectivities for the
hydrogenationoftrisubstitutedolefins(entries1–6), butlowenanti-
oselectivities for 1,1-disubstituted olefins (entries 7, 8, and 9).
4.2. Literature preparations
Substrates 1,13 9,8b 11,8b 12,8b 13,8b 15,7g 16,7g 17,7g
etone,14 and -bromopinacolone15 were prepared according to the
literature procedures.
a-bromoac-
a
4.3. General procedure for the preparation of N-protected
thiazoles 5a–c
3. Conclusion
The N-Boc-protected thioamide 4 (5 mmol),
a-bromo ketone
We have developed a set of bicyclic thiazole-phosphine ligands
(5 mmol), and CaCO3 (25 mmol) were mixed in dry methanol
(25 mL). The reaction mixture was heated at reflux for 4 h. Once
TLC analysis indicated that the reaction was complete, the mixture
was filtered through a pad of Celite to remove CaCO3. The crude fil-
trate was purified by flash chromatography in EtOAc/pentane
(9:100) to afford 5 as white solids.
that were synthesized from readily available a-bromoketones. Irid-
ium complexes made from the new ligands were highly active and
enantioselective in the asymmetric hydrogenation of several ole-
fins. The best of these new iridium complexes, 7d, often gave better
results than its oxazoline analogue 8.
4. Experimental procedures
4.1. General
4.3.1. (1S,3R,4R)-tert-Butyl 3-(4-methylthiazol-2-yl)-2-azabicy-
clo[2.2.1]heptane-2-carboxylate 5a
Yield = 86%. Mp = 70.0–70.9 °C. (NMR spectra are reported for a
mixture of two rotamers.) 1H NMR (400 MHz, CDCl3): d 6.70–6.64
(m, 1H), 4.63–4.40 (m, 1H), 4.32–4.08 (m, 1H), 2.78–2.60 (m,
1H), 2.38–2.22 (m, 3H), 1.92–1.30 (m, 6H), 1.28–1.12 (m, 9H). 13C
NMR (100 MHz, CDCl3): d 173.3, 172.7, 155.0, 154.2, 152.5, 152.3,
112.7, 112.5, 79.8, 65.3, 64.9, 57.9, 56.8, 44.7, 43.9, 34.9, 34.1,
30.2, 29.6, 28.3, 28.1, 27.2, 27.0, 17.0. IR (neat, cmꢁ1): 1694,
1379, 1166, 1123, 1096. MS (EI) m/z (rel. intensity): 295 (M++1,
100%). HRMS (ESI) m/z = 295.1480, calcd for C15H23N2O2S [M+H]+:
259.1480.
a-Bromoacetophenone, trans-a-methylstilbene 10, and trans-2-
methyl-3-phenyl-2-propen-1-ol 14 were purchased from Sigma–
Aldrich Co. and used as received. Methanol was distilled from
Mg. Tetrahydrofuran was dried over and distilled from Na/benzo-
phenone ketyl under N2. CH2Cl2 and di-iso-propylethylamine were
distilled from CaH2. Flash chromatography was performed using
silica gel (Merck kieselgel 60 H 37–70 lm). Reactions were moni-
tored using TLC (Merck kieselgel 60 0.20 mm layer, UV254), and
the plates were visualized with UV light at 254 nm or stained with
ethanolic ninhydrin and then heated.
The 1H NMR, 13C NMR, and 31P NMR spectra were acquired in
CDCl3 or C6D6 on 400 or 300 MHz spectrometer. 1H NMR and 13C
NMR spectra were referenced to residual CHCl3 (7.26 ppm 1H;
77.16 ppm 13C) or C6H6 (7.16 ppm 1H; 128.62 ppm 13C). 31P NMR
spectra were referenced to external H3PO4. Chemical shifts are re-
ported in parts per million (ppm) and coupling constants, J, are re-
ported in hertz. Mass spectra were measured at 70 eV (EI). High
resolution mass spectrometric (HRMS) data were obtained using
a Bruker microTOF-Q II instrument operating at ambient tempera-
tures, using a sample concentration of approximately 1 ppm. Infra-
red (IR) spectra were recorded on a Perkin–Elmer 100 FT/IR
spectrometer. Optical rotations were measured on a thermostated
4.3.2. (1S,3R,4R)-tert-Butyl 3-(4-tert-butylthiazol-2-yl)-2-azabi-
cyclo[2.2.1]heptane-2-carboxylate 5b
Yield = 89%. Mp = 117.1–180.0 °C. (NMR spectra are reported for
a mixture of two rotamers.) 1H NMR (300 MHz, CDCl3): d 6.74–6.66
(m, 1H), 4.64–4.51 (m, 1H), 4.34–4.16 (m, 1H), 2.81–2.64 (m, 1H),
1.98–1.40 (m, 6H), 1.32–1.28 (m, 9H), 1.28–1.20 (m, 9H). 13C NMR
(75 MHz, CDCl3): d 173.0, 172.4, 166.7, 166.3, 155.2, 154.2, 109.4,
109.3, 79.7, 65.2, 64.9, 58.0, 56.6, 44.6, 43.9, 34.9, 34.6, 34.2,
30.2, 29.9, 29.7, 28.4, 28.1, 27.4, 27.0. IR (neat, cmꢁ1): 1703,
1362, 1156, 1128, 1094. MS (EI) m/z (rel. intensity): 337 (M++1,
100%). HRMS (ESI) m/z = 337.1944, calcd for
C18H29N2O2S
[M+H]+: 337.1950.

Table 1
Asymmetric hydrogenations catalyzed by the iridium complexes 7a–d and 8a
o-Tol
Ph Ph
BArF
Ph Ph
P
Ph Ph
P
Ph Ph
P
o-Tol
BArF
BArF
BArF
BArF
P
P
Ir
Ir
Ir
Ir
Ir
N
N
N
N
N
Entry
Substrate
N
N
N
N
S
N
Ph
Ph
Me
tBu
Ph
Ph
7a
7b
7c
7d
8
S
S
S
O
Conv.b (%)
eec (%)
Conv.b (%)
eec (%)
Conv.b (%)
eec (%)
Conv.b (%)
eec (%)
Conv.b (%)
eec (%)
1
99
82 (R)
99
22 (R)
99
97 (R)
99
97 (R)
99
99 (R)
MeO
9
Ph
2
3
83
99
97 (R)
32 (S)
0
45
97
97 (R)
83 (S)
99
99
99 (R)
76 (S)
99
36
98 (R)
38 (S)
Ph
10
28
47 (S)
11
CO2Et
4
5
6
98
58
99
85 (R)
54 (R)
45 (R)
0
0
0
66
82
99
92 (R)
15 (R)
93 (R)
99
99
95
98 (R)
84 (R)
93 (R)
99
99
0
69 (R)
90 (R)
Ph
Ph
12
CO2Et
13
OH
Ph
14
7
8
9
99
99
99
49 (S)
15 (S)
2 (S)
96
99
99
20 (R)
3 (S)
99
99
99
86 (S)
44 (S)
2 (S)
99
99
99
83 (S)
50 (S)
17 (S)
99
99
99
81 (S)
28 (S)
3 (S)
15
16
17
3 (S)
a
b
c
Conditions: 0.25 M substrate in CH2Cl2, 0.5 mol % catalyst, 50 bar H2, rt, overnight.
Determined by 1H NMR spectroscopy.
Determined by chiral GC or HPLC compared to the literature.7g,8h

J.-Q. Li et al. / Tetrahedron: Asymmetry 21 (2010) 1328–1333
1331
4.3.3. (1S,3R,4R)-tert-Butyl 3-(4-phenylthiazol-2-yl)-2-azabicy-
clo[2.2.1]heptane-2-carboxylate 5c
tilled di-iso-propylethylamine (3 mmol) was added and the solu-
tion was cooled to 0 °C in an ice-bath. Freshly distilled Ar2PCl
(1.2 mmol) was added dropwise and the reaction mixture was kept
in fridge (4 °C) overnight. The solution was allowed to warm to rt
and was then washed with saturated NaHCO3 (20 mL). The aque-
ous phase was extracted with CH2Cl2 (3 ꢂ 15 mL) and the com-
bined organic layers were dried over Na2SO4. The crude product
was purified by flash chromatography on silica gel (deactivated
with 5% Et3N) with Et3N/CH2Cl2/pentane (0.5:20:80) as the eluent
to afford 3 as white foams.
Yield = 80%. Mp = 170.9–171.3 °C. (NMR spectra are reported for
a mixture of two rotamers.) 1H NMR (400 MHz, CDCl3): d 7.92–7.83
(m, 2H), 7.46–7.28 (m, 4H), 4.78–4.60 (m, 1H), 4.42–4.21 (m, 1H),
2.97–2.83 (m, 1H), 2.02–1.62 (m, 5H), 1.56–1.26 (m, 9H), 0.93–0.77
(m, 1H). 13C NMR (75 MHz, CDCl3): d 174.0, 173.4, 155.5, 155.2,
154.3, 134.8, 134.5, 128.6, 128.5, 127.8, 127.7, 126.2, 126.1,
112.4, 112.1, 80.0, 79.9, 65.3, 64.9, 58.0, 56.9, 44.7, 43.8, 35.0,
34.2, 30.2, 29.6, 28.3, 28.1, 27.2, 26.9. IR (neat, cmꢁ1): 1683,
1384, 1155, 1122, 1103. MS (EI) m/z (rel. intensity): 357 (M++1,
45%), 300 (100), 227 (92). HRMS (ESI) m/z = 357.1620, calcd for
4.5.1. Ligand 3a
C
20H25N2O2S [M+H]+: 357.1637.
Yield = quant. ½a D23
ꢃ
¼ ꢁ2:9 (c 1, C6D6). 1H NMR (300 MHz, C6D6):
d 7.66–7.58 (m, 2H), 7.56–7.48 (m, 2H), 7.28–7.21 (m, 2H), 7.18–
7.01 (m, 5H), 6.25 (q, J = 1.1 Hz, 1H), 4.58 (d, J = 7.1 Hz, 1H), 3.80
(s, 1H), 2.66 (m, 1H), 2.28 (d, J = 1.0 Hz, 3H), 2.10 (dp, J = 9.6, 2.0,
1H), 1.04–1.24 (m, 2H), 0.93 (m, 1H), 0.83 (m, 1H), 0.69 (m, 1H).
13C NMR (75 MHz, C6D6): d 176.0, 153.5, 140.7, 140.4, 140.3,
140.3, 134.5 (d, J = 24.1), 131.7 (d, J = 16.8), 129.6, 128.6, 128.5,
128.3, 127.8, 113.2, 69.1 (d, J = 30.2), 58.8 (d, J = 7.5), 46.8 (d,
J = 6.1), 36.8, 29.7, 28.3, 17.4. 31P NMR (121 MHz, C6D6): d 40.68.
IR (neat, cmꢁ1): 2965, 2871, 1478, 1430, 729, 699. MS (EI) m/z
(rel. intensity): 378 (M+, 8%), 301 (9), 166 (15), 162 (10), 136
(13), 84 (100). HRMS (ESI) m/z = 379.1387, calcd for C22H24N2PS
[M+H]+: 379.1398.
4.4. General procedure for preparation of thiazoles 6a–c
N-Protected thiazole 5 (3 mmol) was dissolved in THF (15 mL).
Then 12 M HCl (15 mL) was added slowly and the reaction mixture
was stirred at rt for 2 h. THF was then removed under vacuum. The
reaction mixture was slowly poured into aqueous saturated NaHCO3
solutionandthemixturewasextractedwithCH2Cl2 (3 ꢂ 30 mL).The
combined organic layer was dried over MgSO4. After concentration
under vacuum, the residue was purified by flash chromatography
on silica gel (deactivated with 5% Et3N) with Et3N/EtOAc/pentane
(5:8:100) as the eluent to afford 6 as white solids.
4.4.1. 2-((1S,3R,4R)-2-Azabicyclo[2.2.1]heptan-3-yl)-4-methylthi
4.5.2. Ligand 3b
azole 6a
Yield = quant. ½a D23
ꢃ
¼ ꢁ5:0 (c 1, C6D6) 1H NMR (300 MHz, C6D6):
Yield = 87%. ½a 2D3
ꢃ
¼ þ48:5 (c 1, CHCl3). Mp = 81.3–81.9 °C. 1H
d 7.71–7.63 (m, 2H), 7.57–7.48 (m, 2H), 7.32–7.24 (m, 2H), 7.22–
7.15 (m, 2H), 7.14–7.03 (m, 2H), 6.43 (s, 1H), 4.58 (d, J = 7.4 Hz,
1H), 4.30 (s, 1H), 3.83 (s, 1H), 2.64 (m, 1H), 2.18 (dp, J = 9.6, 2.0,
1H), 1.39 (s, 9H), 1.28–1.05 (m, 2H), 0.97 (m, 1H), 0.89 (m, 1H),
0.77 (m, 1H). 13C NMR (75 MHz, C6D6): d 175.7, 167.1, 140.8,
140.5, 140.4, 140.3, 134.3 (d, J = 23.6), 131.8 (d, J = 17.7), 129.5,
128.6, 128.5, 128.3, 127.8, 110.1, 69.0 (d, J = 29.6), 58.9 (d,
J = 6.6), 46.9 (d, J = 6.4), 36.9, 35.1, 30.3, 29.9, 28.4. 31P NMR
(121 MHz, C6D6): d 40.83. IR (neat, cmꢁ1): 2958, 2867, 1586,
1511, 1479, 1458, 1433, 1058, 740, 695. MS (EI) m/z (rel. intensity):
421 (M+, 41%), 420 (100), 391 (17), 343 (29), 325 (35), 266 (70),
253 (37), 235 (29), 220 (23), 185 (31), 183 (69), 84 (24). HRMS
(ESI) m/z = 421.1860, calcd for C25H30N2PS [M+H]+: 421.1867.
NMR (400 MHz, CDCl3): d 6.73 (s, 1H), 4.10–4.08 (m, 1H), 3.60–
3.58 (m, 1H), 2.69–2.66 (m, 1H), 2.35 (s, 3H), 1.95 (br s, 1H),
1.75–1.54 (m, 4H), 1.47–1.41 (m, 1H), 1.19–1.15 (m, 1H). 13C
NMR (100 MHz, CDCl3): d 178.8, 153.1, 113.3, 62.4, 56.0, 44.3,
33.8, 33.2, 28.4, 17.2. IR (neat, cmꢁ1): 3298, 2957, 1526 1194,
727. MS (EI) m/z (rel. intensity): 195 (M++1, 100%), 194 (34), 165
(46). HRMS (ESI) m/z = 195.0959, calcd for C10H15N2S [M+H]+:
195.0956.
4.4.2. 2-((1S,3R,4R)-2-Azabicyclo[2.2.1]heptan-3-yl)-4-tert-butyl
thiazole 6b
Yield = 87%. ½a 2D3
ꢃ
¼ þ42:2 (c 1, CHCl3). Mp = 102.9–103.4 °C. 1H
NMR (400 MHz, CDCl3): d 6.76 (s, 1H), 4.13–4.11 (m, 1H), 3.61–
3.58 (m, 1H), 2.67–2.64 (m, 1H), 2.03 (br s, 1H), 1.75–1.57 (m,
4H), 1.49–1.42 (m, 1H), 1.32 (s, 9H), 1.20–1.15 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 177.8, 167.0, 109.9, 62.5, 56.0, 44.4, 34.8,
33.9, 33.0, 30.1, 28.4. IR (neat, cmꢁ1): 3330, 2965, 1513, 1199,
754. MS (EI) m/z (rel. intensity): 237 (M++1, 100%), 236 (27), 207
(70). HRMS (ESI) m/z = 237.1421, calcd for C13H21N2S [M+H]+:
237.1425.
4.5.3. Ligand 3c
Yield = quant. ½a D23
ꢃ
¼ þ3:1 (c 1, C6D6). 1H NMR (300 MHz, C6D6):
d 8.03–7.98 (m, 2H), 7.67–7.61 (m, 2H), 7.58–7.50 (m, 2H), 7.31–
7.20 (m, 4H), 7.19–7.02 (m, 5H), 6.87 (s, 1H), 4.62 (d, J = 7.6, 1H),
3.83 (s, 1H), 2.67 (s, 1H), 2.09 (m, 1H), 1.27–1.07 (m, 2H), 0.95
(m, 1H), 0.86 (m, 1H), 0.73 (m, 1H). 13C NMR (75 MHz, C6D6): d
176.8, 156.3, 140.6, 140.3, 140.2, 140.2, 135.6, 134.5 (d, J = 23.6),
131.7 (d, J = 17.7), 129.7, 128.9, 128.7, 128.6, 127.9, 126.8, 112.7,
69.1 (d, J = 28.4), 58.9 (d, J = 7.9), 46.9 (d, J = 6.4), 36.8, 29.8, 28.4.
31P NMR (121 MHz, C6D6): d 40.84. IR (neat, cmꢁ1): 2971, 2868,
1479, 1432, 1050, 735, 692. MS (EI) m/z (rel. intensity): 441 (M,
6%), 440 (11), 363 (10), 266 (14), 166 (24), 136 (11), 129 (19),
114 (11), 84 (100). HRMS (ESI) m/z = 441.1547, calcd for
4.4.3. 2-((1S,3R,4R)-2-Azabicyclo[2.2.1]heptan-3-yl)-4-phenyl-
thiazole 6c
Yield = 97%. ½a 2D3
ꢃ
¼ þ58:6 (c 1, CHCl3). Mp = 100.2–100.6 °C. 1H
NMR (400 MHz, CDCl3): d 7.96–7.82 (m, 2H), 7.43–7.40 (m, 2H), 7.35
(s, 1H), 7.34–7.26 (m, 1H), 4.20–4.14 (m, 1H), 3.64–3.59 (m, 1H),
2.81–2.77 (m, 1H), 2.01 (br s, 1H), 1.78–1.67 (m, 3H), 1.66–1.57
(m, 1H), 1.51–1.41 (m, 1H), 1.23–1.16 (m, 1H). 13C NMR (100 MHz,
CDCl3): d 179.7, 156.0, 135.1, 128.6, 127.7, 126.2, 112.9, 62.4, 56.0,
44.3, 33.8, 33.3, 28.3. IR (neat, cmꢁ1): 3312, 2947, 1492, 1177, 743. MS
(EI) m/z (rel. intensity): 257 (M++1, 100%), 256 (62), 227 (90). HRMS
(ESI) m/z = 257.1108, calcd for C15H17N2S [M+H]+: 257.1112.
C
27H26N2PS [M+H]+: 441.1554.
4.5.4. Ligand 3d
Yield = 67%. ½a 2D3
ꢃ
¼ ꢁ81:1 (c 1, C6D6). 1H NMR (300 MHz, C6D6):
d 8.07 (m, 1H), 7.96 (m, 1H), 7.46 (m, 1H), 7.27–7.06 (m, 5H), 7.04–
6.94 (m, 2H), 6.82 (m, 1H), 6.76 (s, 1H), 4.76 (d, J = 6.1, 1H), 3.86 (s,
1H), 2.72 (s, 1H), 2.65 (s, 3H), 2.30 (s, 1H), 2.11 (d, J = 9.9), 1.98 (d,
J = 1.8, 3H), 1.31–1.24 (m, 2H), 0.88–0.67 (m, 2H). 13C NMR
(75 MHz, C6D6): d 177.2, 156.2, 143.1, 142.7, 140.1, 139.8, 139.1,
139.0, 137.8, 137.6, 135.6, 132.5, 131.8, 130.9, 130.4, 130.3,
129.5, 128.9, 126.8, 126.4, 125.8, 112.8, 70.4 (d, J = 34.2), 59.2 (d,
4.5. General procedure for preparation of ligands 3a–d
Compound 6 (1 mmol) was co-evaporated with dry toluene
(3 ꢂ 20 mL) and dissolved in dry THF (6 mL) under N2. Freshly dis-

1332
J.-Q. Li et al. / Tetrahedron: Asymmetry 21 (2010) 1328–1333
J = 9.5), 47.2 (d, J = 7.1), 36.6, 29.8, 28.7, 21.9 (d, J = 24.0), 20.8 (d,
J = 20.3). 31P NMR (121 MHz, C6D6): d 23.35. IR (neat, cmꢁ1):
2971, 2869, 1488, 1466, 1445, 1052, 748, 691. MS (EI) m/z (rel.
intensity): 469 (M, 31%), 468 (64), 453 (18), 377 (17), 370 (15),
257 (20), 256 (30), 255 (100), 179 (21), 165 (21), 84 (19). HRMS
(ESI) m/z = 469.1859, calcd for C29H30N2PS [M+H]+: 469.1867.
4.6.4. Complex 7d
Yield = 75%. ½a 2D3
ꢃ
¼ þ14:5 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.86–7.70 (m, 9H), 7.62–6.89 (m, 16H), 6.70 (s, 1H),
5.11–5.01 (m, 1H), 4.85–4.78 (m, 1H), 4.77–4.68 (m, 1H),
3.75–3.57 (m, 2H), 3.30 (s, 3H), 3.22–3.10 (m, 1H), 2.87–2.75 (m,
1H), 2.38–2.14 (m, 5H), 2.10–2.05 (m, 1H), 1.99–1.88 (m, 1H),
1.82–1.62 (m, 5H), 1.52–0.98 (m, 5H). 13C NMR (100 MHz, CDCl3):
d 171.8 (d, J = 2.8), 161.8 (q, J = 51.4), 157.8, 141.8 (d, J = 14.4),
139.5 (q, J = 16.0), 134.8 (m), 132.9, 132.6–132.3 (m), 132.0,
131.2, 130.2, 130.0–128.3 (m), 127.4 (d, J = 7.2), 126.9, 126.5,
126.4, 125.3, 124.5, 122.8, 119.2, 117.5, 116.4, 89.9 (d, J = 6.9),
77.9, 75.6, 67.0 (d, J = 20.9), 64.9, 60.0, 42.4, 38.8, 36.3, 34.6, 29.8,
29.0, 27.8, 24.4 (d, J = 6.5), 24.1, 21.6 (d, J = 7.1). 31P NMR
(121 MHz, CDCl3): d 50.5. IR (neat, cmꢁ1): 1353, 1273, 1161,
1121, 1095. HRMS (ESI) m/z = 769.2343, calcd for C37H41IrN2PS
[MꢁBArF]+: 769.2357.
4.6. General procedure for the preparation of iridium complexes
7a–d
Compound 3 (0.5 mmol) was dissolved in CH2Cl2 (20 mL) and
[Ir(COD)Cl]2 (0.25 mmol) was added. The atmosphere in the flask
was evacuated and replenished with N2 three times. The mixture
was heated at reflux for 1 h. After the solution was cooled to rt, dis-
tilled H2O was added. Under vigorous stirring, NaBArFꢀ3H2O was
added to the biphasic solution in one portion. The mixture was stir-
red vigorously for 1 h and extracted with CH2Cl2 (3 ꢂ 10 mL). Com-
bined organic phase was dried over Na2SO4. After concentration in
vacuum, the residue was purified on silica gel with CH2Cl2/pentane
(1:1) as the eluent to afford 7 as an orange solid.
4.7. General procedure for iridium-catalyzed asymmetric hydro
genation of olefins
A vial was charged with substrate (0.25 mmol) and an Ir com-
plex (0.5 mol %). Dry CH2Cl2 was added and the vial was placed
in a high-pressure hydrogenation apparatus, which was then
purged with H2 three times before H2 pressure was adjusted to
50 bar. The mixture was stirred at rt overnight. After the pressure
was released, solvent was removed under vacuum. Conversion was
determined by 1H NMR of the crude product. The residue was fil-
tered through a short plug of silica gel with pentane/diethyl ether
(1:1) as the eluent. After the solvent was removed under vacuum,
enantiomeric excesses were determined by chiral HPLC or GC.
4.6.1. Complex 7a
Yield = 84%. ½a 2D3
ꢃ
¼ ꢁ35:5 (c 1, CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.76–7.68 (m, 9H), 7.55–7.27 (m, 13H), 6.87 (s, 1H),
5.00–4.93 (m, 1H), 4.92–4.88 (m, 1H), 4.55–4.44 (m, 1H),
3.95–3.87 (m, 2H), 3.17–3.06 (m, 1H), 3.04–2.98 (m, 1H), 2.52
(s, 3H), 2.49–2.28 (m, 4H), 2.10–1.75 (m, 5H), 1.71–1.46 (m, 5H).
13C NMR (75 MHz, CDCl3): d 170.8 (d, J = 10.6), 161.7 (q, J = 49.6),
152.6, 134.8–134.5 (m), 133.8, 132.2–131.9 (m), 132.1, 130.0,
129.6–128.3 (m), 126.9, 126.3, 126.0, 122.8, 119.1, 117.5 (m),
116.8, 96.7 (d, J = 10.9), 87.8 (d, J = 15.0), 67.5 (d, J = 8.4), 66.1,
65.7, 60.5 (d, J = 6.1), 42.3 (d, J = 5.2), 37.5, 36.7, 33.9, 32.3, 28.3,
27.4, 25.6, 18.3. 31P NMR (121 MHz, CDCl3): d 57.7. IR (neat,
cmꢁ1): 1353, 1272, 1166, 1123, 1103. HRMS (ESI) m/z =
679.1899, calcd for C30H35IrN2PS [MꢁBArF]+: 679.1888.
Acknowledgments
This work was supported by the Swedish Research Council (VR;
Contract 2009-3101) and the Knut and Alice Wallenberg Founda-
tion, Sweden. J.-Q.L. thanks the China Scholarship Council for a fel-
lowship. The authors are grateful to Mr. B. Peters for HRMS and Dr.
T. L. Church and Mr. J. Verendel for carefully reading the manuscript.
4.6.2. Complex 7b
Yield = 69%. ½a 2D3
ꢃ
¼ þ54:3 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.78–7.68 (m, 10H), 7.63–7.36 (m, 10H), 7.11 (s, 1H),
7.04–6.93 (m, 2H), 5.05–5.00 (m, 1H), 4.69–4.62 (m, 1H), 4.61–
4.53 (m, 1H), 3.75–3.66 (m, 2H), 3.54–3.43 (m, 1H), 3.08–3.02
(m, 1H), 2.51–2.28 (m, 2H), 2.22–1.66 (m, 5H), 1.60–1.27 (m,
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d 7.82–7.71 (m, 8H), 7.70–7.62 (m, 2H), 7.60–7.40 (m, 12H), 7.35–
7.21 (m, 4H), 7.12–7.08 (m, 2H), 5.06–4.98 (m, 1H), 4.75–4.61 (m,
1H), 4.20–4.07 (m, 1H), 3.84–3.73 (m, 1H), 3.55–3.43 (m, 1H),
3.21–3.05 (m, 2H), 2.41–2.26 (m, 1H), 2.22–2.00 (m, 5H), 1.97–
1.85 (m, 2H), 1.84–1.73 (m, 1H), 1.68–1.59 (m, 1H), 1.44–1.08
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J = 50.2), 157.9, 134.8, 132.8, 132.5, 132.4, 123.2, 132.1, 130.4,
130.0–129.4 (m), 129.3–128.5 (m), 128.4–128.2 (m), 127.7, 126.4,
126.2, 125.3, 122.8, 119.1, 117.5, 116.5, 95.3 (d, J = 11.0), 89.0 (d,
J = 15.3), 68.1 (d, J = 12.6), 66.1, 64.9, 59.8, 42.6 (d, J = 5.46), 38.3,
36.5, 33.9, 30.6, 28.1, 27.5, 25.0. 31P NMR (121 MHz, CDCl3): d
50.3. IR (neat, cmꢁ1): 1353, 1274, 1158, 1119, 1067. HRMS (ESI)
m/z = 741.2042, calcd for C35H37IrN2PS [MꢁBArF]+: 741.2044.

J.-Q. Li et al. / Tetrahedron: Asymmetry 21 (2010) 1328–1333
1333
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