Direct asymmetric α-allylation of ketones with allylic alcohols Via Pd/enamine cooperative function

Article abstract of DOI:10.3987/COM-12-S(N)34

Direct asymmetric α-allylation of ketones with allylic alcohols is described. The combination of palladium with a new phosphine ligand bearing a chiral proline moiety promoted the reaction to afford the corresponding α-allylated ketones in moderate yield and enantioselectivity.

Full text of DOI:10.3987/COM-12-S(N)34

HETEROCYCLES, Vol. 86, No. 1, 2012
745
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 745 - 757. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 15th June, 2012, Accepted, 31st July, 2012, Published online, 8th August, 2012
DOI: 10.3987/COM-12-S(N)34
DIRECT ASYMMETRIC !-ALLYLATION OF KETONES WITH
ALLYLIC ALCOHOLS VIA Pd/ENAMINE COOPERATIVE FUNCTION
Shigeo Yasuda, Naoya Kumagai,* and Masakatsu Shibasaki*
Institute of Microbial Chemistry, Tokyo, Kamiosaki 3-14-23, Shinagawa-ku,
Tokyo,
141-0021,
Japan;
E-mail:
nkumagai@bikaken.or.jp;
mshibasa@bikaken.or.jp
This paper is dedicated to Professor Eiichi Negishi on the occasion of his 77th
birthday.
Abstract – Direct asymmetric !-allylation of ketones with allylic alcohols is
described. The combination of palladium with a new phosphine ligand bearing a
chiral proline moiety promoted the reaction to afford the corresponding
!-allylated ketones in moderate yield and enantioselectivity.
The palladium-catalyzed asymmetric Tsuji-Trost allylation is a highly attractive and powerful tool in
organic synthesis.1 Typically, preactivation of allylic alcohols as allylic acetates and carbonates is
required for the efficient formation of "-allyl electrophiles, and a stoichiometric amount of byproducts are
co-produced. In this regard, the direct use of allylic alcohols as substrates would be highly attractive
because the extra step required for the preparation of activated allylic alcohols is avoided, and the
byproduct is water.2,3 Recent advances in transition-metal catalyzed asymmetric Tsuji-Trost allylations
allow for the direct use of allylic alcohols as allylic electrophiles.4 The variety of compatible
nucleophiles, however, is limited to heteroatom nucleophiles,5 metal enolates,6 and indoles,7,8 some of
which require the combined use of a stoichiometric amount of Brønsted acid or Lewis acid to promote the
reaction, and simple carbonyl compounds have not been implemented in this class of reaction.
Therefore, the development of asymmetric allylations with allylic alcohols using simple carbonyl
compounds is highly desirable. Very recently, the direct catalytic asymmetric !-allylation of aldehydes
with allylic alcohols was reported by List and coworkers.9 For an analogous process using less reactive

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HETEROCYCLES, Vol. 86, No. 1, 2012
simple ketones as nucleophiles,10-12 there is only one example in a racemic system in which a
combination of amine organocatalysis and Pd catalysis is used, and the process has not been rendered
asymmetric.2i In that system, the enamine nucleophile generated in situ from the amine and ketone
undergoes nucleophilic attack on an in situ-generated !-allyl Pd complex.13 Inspired by this work, we
hypothesized that by covalently tethering a Pd complex and a chiral proline unit, dual activation of allylic
alcohol and ketone would act in close proximity to efficiently promote the reaction in an asymmetric
environment (Scheme 1). Herein we report the first example of a direct asymmetric "-allylation of
simple ketones with simple allylic alcohols using a tethered complex that harnesses the cooperative
function of !-allyl Pd activation and enamine activation.
dual
activation
O
Pd0
enamine
nucleophile
N
N
H
R
OH
PdII
[P]
[P]
R
[P] = phosphine unit
!-allyl Pd electrophile
Scheme 1. Strategy for Direct Asymmetric "-Allylation of Ketones with Allylic Alcohols
To realize the dual activation of allylic alcohol and ketone as delineated in Scheme 1, we designed a
chiral ligand 1a bearing a proline and 2-(diphenylphosphino)benzylamine, which are covalently tethered
by an amide linkage.14 Upon complexation with Pd0, the !-allyl Pd electrophile would be formed from
allylic alcohols close to the enamine nucleophile generated in situ from the pyrrolidino group in 1a and
the ketone substrate (Figure 1). As an analogous ligand, 1b and 1c bearing fluoro-substituted proline
units were also synthesized, and 1a–c were evaluated in an "-allylation of cyclohexanone (3a) with
3-phenyl-2-propen-1-ol (2a) (Table 1).
F
F
F
O
O
O
N
N
N
H
H
H
HN
Ph2P
1a
HN
Ph2P
1b
HN
Ph2P
1c
Figure 1. Phosphine ligands 1a–c bearing chiral proline ring through amide bond.

HETEROCYCLES, Vol. 86, No. 1, 2012
747
The reactions were conducted in the presence of [(!3-allyl)PdCl]2 and ligand 1 in a 1:3 ratio in DMSO at
room temperature.15 As expected, the reaction with ligand 1a proceeded to afford the desired product 4a
with moderate enantioselectivity, although the yield was only 10% (Table 1, Entry 1). Changing the
ratio of Pd/1a to 1:1 or 1:2 led to a significantly lower conversion. The yield increased slightly with a
higher loading of Pd and ligand 1a (Entry 2). Ligand 1b, bearing a 4-fluoro-substituted proline unit,
exhibited a higher reaction efficiency and afforded 4a in better yield, albeit with lower enantioselectivity
(Entry 3).
The best result was obtained with the reaction using ligand 1c bearing a
4,4-difluoro-substituted proline unit, which afforded the highest yield and modest enantioselectivity
(Entry 4). To examine the cooperative function of !-allyl Pd activation and enamine activation in close
proximity, the following control experiment was performed. The reaction with 1d, a ligand analogous to
1a lacking a phosphine moiety, and PPh3 hardly proceeded, and resulted in lower enantioselectivity
(Entry 5), suggesting that linkage of the phosphine unit and the chiral proline unit allows for dual
activation of the allylic alcohol and ketone in proximity. Decreasing the amount of Pd salt and ligand 1
led to a remarkable loss of conversion.
Table 1. Evaluation of Ligands 1 for Direct Asymmetric "-Allylation of 3a with 2a.
[(!3-allyl)PdCl]2 (x mol %Pd)
ligand 1 (3x mol %)
O
O
+
Ph
Ph
OH
DMSO, rt, 20 h
2a
4a
3a
(3.0 equiv)
O
Yield (%)a
Ligand
Abs. Config.
Entry
x
Ee (%)b
N
H
HN
1a
1a
1b
1c
1d
R
R
R
R
S
1
2
3
10
30
30
30
10
65
50
35
55
24
10
13
52
66
3
4
5c
1d
b
c
aIsolated yield. Determined by HPLC analysis using a DAICEL CHIRALCEL OD-H. with 20 mol % PPh3.
The scope of the present asymmetric "-allylation using the [(!3-allyl)PdCl]2/1c system is summarized in
Table 2. In addition to 2a, the present system was applicable to substituted cinnamyl alcohols 2b–e.
Although similar enantioselectivity was observed irrespective of the electronic nature of substituents, an
electron-donating substituent led to decreased reaction efficiency. The reaction of oxygen-containing
heterocyclic ketone 3b produced the corresponding product 4f, albeit with low yield and
enantioselectivity (Table 2, Entry 6).

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HETEROCYCLES, Vol. 86, No. 1, 2012
Table 2. Scope of Direct Asymmetric "-Allylation of Ketones 3 with Allylic Alcohols 2 with Ligand
1c.
O
[(
!3-allyl)PdCl] (30 mol %Pd)
2
O
Y
1c (90 mol %)
+
OH
DMSO, rt, 20 h
Y
X
X
4
2
3
(3.0 equiv)
Ee (%)b
Entry
Yield (%)a
2
3
4
X
Y
1
2
3
4
5
6
66
55
39
39
14
25
2a
2b
2c
2d
2e
2a
C
C
C
C
C
O
3a
3a
3a
3a
3a
3b
H
CF3
F
OMe
NMe2
H
4a
4b
4c
4d
4e
4f
55
54
56
60
52
36
b
aIsolated yield. Determined by HPLC analysis. See experimental section for details.
The proposed mechanism for the present reaction is shown in Scheme 2. Initially, enamine intermediate
A is produced by reaction of the pyrrolidino group in ligand 1 with a ketone. Complexation of A and
[(!3-allyl)PdCl]2 through a phosphine moiety forms !-allyl PdII complex B’, and a subsequent
intramolecular nucleophilic attack of enamine to !-allyl PdII generates iminium cation C’, in which PdII is
reduced to Pd0. Hydrolysis of C’ leads to intermediate D, and the release of "-allyl ketone 4’16 and HCl.
There is another possible pathway from C’ to E, in which a ligand exchange of C’ with A occurs and
forms E, releasing iminium cation G. Pd0 complex D is responsible for the following catalytic cycle.
Coordination of allylic alcohol to E forms Pd0 olefin complex F and oxidative addition occurs with the
aid of HCl to generate !-allyl PdII complex B. Subsequent intramolecular nucleophilic attack of
enamine on !-allyl PdII and hydrolysis of iminium cation C to release product 4 proceed in a manner
similar to that of the initial cycle. We assume that the substituent on the proline unit slightly changes the
conformation of the ring, which affects the reactivity and enantioselectivity in this intramolecular attack
of enamine, and the most favorable conformation is attained with ligand 1c. Although the Pd/1 = 1:1
complex is shown in Scheme 2 for clarity, spectroscopic analysis of the Pd/1 mixture was unsuccessful
and therefore the structure of Pd/1 is not clear. Based on the fact that 3 equivalents of ligand 1 to Pd are
required for efficient conversion, an active Pd complex can be the Pd/1 complex in a ratio of 1:2 or 1:3.
We assume that another reason for the requirement of excessive amounts of ligand 1 to Pd (3 equiv to Pd,
0.9 equiv to allylic alcohol) is the reluctant hydrolysis of iminium cations (C, C’, G, and G’). If the
hydrolysis does not proceed easily, ligand 1 is arrested as an inactive form.
In summary, we demonstrated the allylation of simple ketones at the "-position with simple allylic
alcohols under a new system consisting of Pd and phosphine ligand bearing a chiral proline unit.

HETEROCYCLES, Vol. 86, No. 1, 2012
749
Linkage of a phosphine ligand and a chiral proline unit were essential for enantioinduction. There is still
room for improvement, however, with regard to the unsatisfactory yield, low enantioselectivity, and
requirement of high loading of Pd and ligand 1. Nevertheless, the reaction presented in this report is the
first example of the direct asymmetric "-allylation of simple ketones with simple allylic alcohols.
O
R'
R'
R'
R'
O
O
R' = H or F
[P] = PPh2
N
N
H
HN
HN
1
[P]
[P]
R'
A
H2O
[(!3-allyl)PdCl]2
R'
R'
R'
R'
R'
H2O
O
O
O
Cl–
G (R = Ar)
G' (R = H)
+
N
N
N
HN
HN
HN
Ar
Pd0
[P]
PdII
Cl
[P]
[P]
B (R = Ar)
B' (R = H)
R
OH
R
+H
Cl–
F
A
R'
R'
O
+
Cl–
N
HN
E
Pd0
Ar
OH
[P]
R
HCl
C (R = Ar)
C' (R = H)
H2O
R'
N
R'
R'
R'
O
O
N
H
HN
Pd0
HN
O
Pd0
4 (R = Ar)
4' (R = H)
R
O
[P]
[P]
H2O
HCl
E
D
Scheme 2. Postulated Reaction Mechanism
EXPERIMENTAL
General. Infrared (IR) spectra were recorded on a HORIBA FT210 Fourier transform infrared
spectrophotometer. NMR spectra were recorded on JEOL ECS-400 spectrometer. Chemical shifts for
proton are reported in parts per million downfield from tetramethylsilane and are referenced to residual
13
protonium in the NMR solvent (CDCl3: # 7.26 ppm). For C NMR, chemical shifts are reported in the
19
scale relative to NMR solvent (CDCl3: # 77.0 ppm). For F NMR, chemical shifts are reported in the

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HETEROCYCLES, Vol. 86, No. 1, 2012
31
scale relative to CF3COOH (# –76.5 ppm) as an external reference. For P NMR, chemical shifts are
reported in the scale relative to H3PO4 (# 0.0 ppm in D2O) as an external reference. NMR data are
reported as follows: chemical shifts, multiplicity (s: singlet, d: doublet, dd: doublet of doublets, t: triplet,
q: quartet, m; multiplet, br: broad signal), coupling constant (Hz), and integration. Optical rotation was
measured using a 2 mL cell with a 1.0 dm path length on a JASCO polarimeter P-1030. High-resolution
mass spectra (ESI TOF (+)) were measured on ThermoFisher Scientific LTQ Orbitrap XL. HPLC
analysis was conducted on a JASCO HPLC system equipped with Daicel chiral-stationary-phase columns
(0.46 cm " x 25 cm). The absolute configuration of 4a was determined by comparing the sign of optical
rotation with the literature data reported by Koga et al.17 The absolute configuration of other products
was assigned by analogy.
Materials. Unless otherwise noted, materials were purchased from commercial suppliers and were used
without purification. THF and CH2Cl2 were purified by passing through a solvent purification system
(Glass Contour). Dry DMSO and CHCl3 were purchased from Kanto Chemical Co. Ltd. and used as
received. [(!3-allyl)PdCl]2 was purchased from Aldrich and used as received. Chiral proline
derivatives used for synthesis of ligands 1 were purchased from Aldrich and WATANABE CHEMICAL
Ind. Ltd. Allylic alcohol 2a was purchased from Kanto Chemical Co. Ltd. 2b was prepared by
following the literature procedure.18 Column chromatography was performed with Silica gel Merck 60
(230–400 mesh ASTM).
Preparation of Allylic Alcohols 2c–e. These compounds were synthesized by the following procedure.
(E)-3-(4-Methoxyphenyl)prop-2-en-1-ol (2d). To a 300 mL pear-shaped flask equipped with a
magnetic stirring bar, 4-methoxycinnamaldehyde (5.68 g, 35.0 mmol) and MeOH (140 mL) were added
at room temperature. The resulting solution was cooled to 0 °C and then NaBH4 (1.59 g, 42.0 mmol)
was added to the solution. After stirring for 30 min at 0 °C, sat. NaHCO3 aq. (200 mL) and CH2Cl2 (200
mL) were sequentially added to the reaction mixture. After stirring for 5 min at room temperature, the
organic layer and aqueous layer were separated. Aqueous layer was extracted with CH2Cl2 (3 x 100 mL)
and combined organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated. The
resulting residue was purified by silica gel column chromatography system (combiflash®:
1
n-hexane/EtOAc as eluent) to afford 2d (5.55 g, 97%) as a white solid; H NMR (CDCl3) # 7.32 (d, J =
8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 16.0 Hz, 1H), 6.23 (dt, J = 6.0, 16.0 Hz, 1H), 4.29 (d, J
= 6.0 Hz, 2H), 3.80 (s, 3H), 1.75 (brs, 1H); 13C NMR (CDCl3) # 159.2, 130.8, 129.4, 127.6, 126.2, 113.9,
63.8, 55.2.
1
(E)-3-(4-Fluorophenyl)prop-2-en-1-ol (2c): white solid; H NMR (CDCl3) # 7.33–7.30 (m, 2H),
7.01–6.97 (m, 2H), 6.55 (d, J = 16.0 Hz, 1H), 6.26 (dt, J = 5.7, 16.0 Hz, 1H), 4.29 (d, J = 5.7 Hz, 2H),
13
2.32 (brs, 1H); C NMR (CDCl3) # 162.3 (d, JC–F = 245.0 Hz), 132.8 (d, JC–F = 3.8 Hz), 129.8, 128.2 (d,

HETEROCYCLES, Vol. 86, No. 1, 2012
751
JC–F = 1.9 Hz), 127.9 (d, JC–F = 7.6 Hz), 115.4 (d, JC–F = 21.9 Hz), 63.4; 19F NMR (CDCl3) # –114.1.
1
(E)-3-(4-(N,N-Dimethylamino)phenyl)prop-2-en-1-ol (2e): yellow solid; H NMR (CDCl3) # 7.26 (d,
J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 15.8 Hz, 1H), 6.15 (dt, J = 6.0, 15.8 Hz, 1H), 4.23
13
(d, J = 6.0 Hz, 2H), 3.27 (brs, 1H), 2.92 (s, 6H); C NMR (CDCl3) # 149.7, 131.0, 127.2, 125.1, 124.0,
112.3, 63.5, 40.2.
NMR data of 2c,19 2d,20 and 2e20 are identical to literature data.
Preparation of Phosphine Ligands 1a–c. These compounds were synthesized over 4 steps starting
from commercially available 2-(diphenylphosphino)benzoic acid.
2-(Diphenylphosphino)benzamide (S1). To a 100 mL pear-shaped flask equipped with a magnetic
stirring bar, 2-(diphenylphosphino)benzoic acid (2.90 g, 10.0 mmol), and CHCl3 (40 mL) were added at
room temperature.
To the resulting suspension, (NH4)HCO3 (3.64 g, 46.0 mmol) and
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinone (3.46 g, 14.0 mmol) were added sequentially. After
stirring for 28 h at room temperature, the reaction mixture was diluted with CH2Cl2 (350 mL). The
mixture was washed with 1N HCl aq. (3 x 100 mL), 1N NaOH aq. (2 x 100 mL), and brine (100 mL), and
then dried over Na2SO4. After filtration, the filtrate was concentrated. The resulting residue was
purified by silica gel column chromatography (eluent: n-hexane/EtOAc = 1/1 to 1/2) to afford S1 (1.91 g,
1
62%) as a white solid; H NMR (CDCl3) # 7.55–7.52 (m, 1H), 7.27–7.16 (m, 12H), 6.91–6.88 (m, 1H),
13
6.07 (brs, 2H); C NMR (CDCl3) # 170.8, 139.8 (d, JC–P = 24.8 Hz), 137.1 (d, JC–P = 10.5 Hz), 136.6 (d,
J
C–P = 21.9 Hz), 134.2, 133.9, 133.7, 130.4, 128.6 (d, JC–P = 9.5 Hz), 128.5 (d, JC–P = 7.6 Hz), 127.9 (d, JC–P
= 3.8 Hz); 31P NMR (CDCl3) # –8.6.
NMR data are identical to literature data.21
(2-(Diphenylphosphino)phenyl)methylamine (S2). To a 300 mL pear-shaped flask equipped with a
magnetic stirring bar, S1 (1.59 g, 5.21 mmol), and THF (100 mL) were added at room temperature. The
resulting solution was cooled to 0 °C and then LiAlH4 (593 mg, 15.6 mmol) was added to the solution.
After stirring for 12 h at room temperature, the reaction mixture was cooled to 0 °C, and then H2O (15
mL), 8% NaOH aq. (30 mL), H2O (30 mL) were added sequentially. The resulting mixture was
extracted with CH2Cl2 (2 x 100 mL) and dried over Na2SO4. After filtration, the filtrate was
concentrated. The resulting residue was purified by silica gel column chromatography (eluent:
1
n-hexane/EtOAc = 1/2 to EtOAc only) to afford S2 (1.15 g, 76%) as a white solid; H NMR (CDCl3) #
7.46–7.43 (m, 1H), 7.37–7.25 (m, 11H), 7.16 (ddd, J = 1.2, 7.6, 8.7 Hz, 1H), 6.91–6.88 (m, 1H), 4.03 (d,
13
J = 1.6 Hz, 2H), 1.49 (brs, 2H); C NMR (CDCl3) # 147.3 (d, JC–P = 22.9 Hz), 136.3 (d, JC–P = 9.5 Hz),
135.0 (d, JC–P = 13.4 Hz), 133.8 (d, JC–P = 19.1 Hz), 133.4, 129.2, 128.7, 128.5 (d, JC–P = 19.1 Hz), 127.9
(d, JC–P = 4.8 Hz), 127.0, 45.1 (d, JC–P = 21.9 Hz); 31P NMR (CDCl3) # –15.3.
NMR data are identical to literature data.22

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HETEROCYCLES, Vol. 86, No. 1, 2012
tert-Butyl (S)-2-((2-(diphenylphosphino)phenyl)methylcarbamoyl)pyrrolidine-1-carboxylate (S3).
To a 50 mL pear-shaped flask equipped with a magnetic stirring bar, N-(tert-butoxycarbonyl)-L-proline
(513 mg, 2.38 mmol), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinone (607 mg, 2.45 mmol), and CH2Cl2
(6.0 mL) were added at room temperature. The resulting solution was cooled to 0 °C, and then S2 (715
mg, 2.45 mmol) in CH2Cl2 (6.0 mL) was added. After stirring for 12 h at room temperature, the reaction
mixture was washed with 1N HCl aq. (3 x 50 mL), sat. NaHCO3 aq. (2 x 50 mL), H2O (50 mL), and brine
(2 x 50 mL), and then dried over Na2SO4. After filtration, the filtrate was concentrated. The resulting
residue was purified by silica gel column chromatography (eluent: n-hexane/EtOAc = 2/1) to afford S3
(929 mg, 80%) as a white solid.
(S)-N-(2-(Diphenylphosphino)phenyl)methylpyrrolidine-2-carboxyamide (1a).
To a 100 mL
pear-shaped flask equipped with a magnetic stirring bar, S3 (1.03 g, 2.12 mmol) and CH2Cl2 (2.5 mL)
were added at room temperature. The resulting solution was cooled to 0 °C, and then 4N HCl/CPME
(2.12 mL, 8.48 mmol) was added. After stirring for 14 h at room temperature, sat. NaHCO3 aq. (60 mL)
was added to the reaction mixture. After stirring for additional 20 min, the resulting mixture was
extracted with CH2Cl2 (3 x 60 mL). The combined organic layer was dried over Na2SO4. After
filtration, the filtrate was concentrated. The resulting residue was purified by silica gel column
chromatography (eluent: CHCl3 only to CHCl3/MeOH = 20/1) to afford 1a (750 mg, 92%) as a colorless
1
viscous oil; IR (neat) 3326, 3054, 2970, 2871, 1661, 1513, 1478, 1434, 1092, 747, 697, 665 cm–1; H
NMR (CDCl3) # 7.80 (brs, 1H), 7.42 (dd, J = 4.4, 6.8 Hz, 1H), 7.35–7.32 (m, 7H), 7.29–7.23 (m, 4H),
7.19 (dd, J = 7.6, 7.6 Hz, 1H), 6.91 (dd, J = 4.4, 7.6 Hz, 1H), 4.73 (dd, J = 6.2, 14.7 Hz, 1H), 4.60 (dd, J
= 5.7, 14.7 Hz, 1H), 3.54 (dd, J = 5.2, 8.9 Hz, 1H), 2.85 (ddd, J = 6.6, 6.9, 10.1 Hz, 1H), 2.71 (ddd, J =
6.2, 6.2, 10.1 Hz, 1H), 2.10–2.01 (m, 1H), 1.87–1.79 (m, 2H), 1.64–1.57 (m, 2H); 13C NMR (CDCl3) #
174.7, 142.8 (d, JC–P = 24.8 Hz), 136.2 (d, JC–P = 9.5 Hz), 135.5 (d, JC–P = 14.3 Hz), 133.8 (d, JC–P = 7.6
Hz), 133.6 (d, JC–P = 6.7 Hz), 129.2, 129.0 (d, JC–P = 5.7 Hz), 128.7 (d, JC–P = 4.8 Hz), 128.5 (d, JC–P = 1.9
31
Hz), 128.4 (d, JC–P = 2.9 Hz), 127.5, 60.3, 46.9, 41.6 (d, JC–P = 22.9 Hz), 30.5, 25.9; P NMR (CDCl3) #
21
–15.4; HRMS (ESI) calcd. for C24H26N2OP m/z 389.1777 [M+H]+, found 389.1780; ["]D –18.0 (c 2.0,
CHCl3).
1b and 1c were synthesized by the above procedure using commercially available
N-(tert-butoxycarbonyl)-cis-4-fluoro-L-proline and N-(tert-butoxycarbonyl)-4,4-difluoro-L-proline23,
respectively, instead of N-(tert-butoxycarbonyl)-L-proline.
N-(2-(Diphenylphosphino)phenyl)methyl-(4S)-fluoropyrrolidine-(2S)-carboxyamide (1b): colorless
viscous oil; IR (neat) 3336, 3005, 1660, 1520, 1478, 1434, 1271, 1217, 1112, 956, 747, 698, 666 cm–1;
1H NMR (CDCl3) # 7.75 (brs, 1H), 7.44–7.41 (m, 1H), 7.33–7.20 (m, 11H), 7.15 (dd, J = 7.6, 7.6 Hz, 1H),
6.88 (dd, J = 4.6, 7.6 Hz, 1H), 5.07 (ddd, J = 3.7, 3.9, 53.2 Hz, 1H), 4.72 (dd, J = 6.2, 14.9 Hz, 1H), 4.58

HETEROCYCLES, Vol. 86, No. 1, 2012
753
(dd, J = 6.0, 14.9 Hz, 1H), 3.59 (dd, J = 3.0, 10.3 Hz, 1H), 3.15 (dd, J = 12.1, 21.5 Hz, 1H), 3.01 (ddd, J
13
= 3.7, 12.1, 35.7 Hz, 1H), 2.41–2.32 (m, 1H), 2.26–2.09 (m, 1H), 1.85 (brs, 1H); C NMR (CDCl3) #
173.6, 142.6 (d, JC–P = 24.8 Hz), 136.2 (d, JC–P = 9.5 Hz), 136.1 (d, JC–P = 9.5 Hz), 135.2 (d, JC–P = 14.3
Hz), 133.9, 133.7 (d, JC–P = 9.5 Hz), 133.5 (d, JC–P = 10.5 Hz), 129.1, 128.6 (d, JC–P = 2.9 Hz), 128.5 (d,
JC–P = 1.9 Hz), 128.4 (d, JC–P = 2.9 Hz), 127.4, 93.4 (d, JC–F = 175.4 Hz), 58.9, 53.0 (d, JC–F = 21.9 Hz),
41.6 (d, JC–P = 23.8 Hz), 37.3 (d, JC–F = 21.9 Hz); 19F NMR (CDCl3) # –173.4–173.9 (m); P NMR
31
21
(CDCl3) # –15.3; HRMS (ESI) calcd. for C24H25FN2OP m/z 407.1683 [M+H]+, found 407.1685; ["]D
–13.5 (c 1.0, CHCl3).
(S)-N-(2-(Diphenylphosphino)phenyl)methyl-4,4-difluoropyrrolidine-2-carboxyamide
(1c):
colorless viscous oil; IR (neat) 3330, 3055, 3004, 1667, 1519, 1478, 1434, 1358, 1249, 1157, 1093, 746,
698 cm–1; 1H NMR (CDCl3) # 7.59 (brs, 1H), 7.45 (dd, J = 4.6, 7.3 Hz, 1H), 7.38–7.36 (m, 7H), 7.30–7.22
(m, 5H), 6.95 (ddd, J = 0.9, 4.6, 7.6 Hz, 1H), 4.77 (dd, J = 6.4, 14.4 Hz, 1H), 4.64 (dd, J = 5.5, 14.4 Hz,
1H), 3.66 (dd, J = 7.1, 9.2 Hz, 1H), 3.14–3.06 (m, 1H) 2.92–2.82 (m, 1H), 2.59–2.48 (m, 1H), 2.37–2.24
13
(m, 1H), 1.90 (brs, 1H); C NMR (CDCl3) # 171.7, 142.3 (d, JC–P = 25.7 Hz), 136.3 (d, JC–P = 1.9 Hz),
136.2 (d, JC–P = 1.9 Hz), 135.7 (d, JC–P = 14.3 Hz), 134.0, 133.9 (d, JC–P = 7.6 Hz), 133.7 (d, JC–P = 6.7 Hz),
130.1 (dd, JC–F = 246.0, 251.7 Hz), 129.6 (d, JC–P = 4.8 Hz), 129.4, 128.8 (d, JC–P = 3.8 Hz), 128.6 (d, JC–P
= 2.9 Hz), 128.5 (d, JC–P = 3.8 Hz) 127.9, 58.5–58.4 (m), 52.9 (dd, JC–F = 28.6, 28.6 Hz), 42.2 (d, JC–P
=
19
31
21.0 Hz), 38.1 (dd, JC–F = 24.8, 25.8 Hz); F NMR (CDCl3) # –99.1–99.9 (m), –104.9–105.6 (m); P
NMR (CDCl3) # –15.6; HRMS (ESI) calcd. for C24H24F2N2OP m/z 425.1589 [M+H]+, found 425.1590;
["]D21 –8.3 (c 1.0, CHCl3).
(S)-N-Benzylpyrrolidine-2-carboxyamide (1d). This compound was synthesized by the same
procedure as for S3 and 1a starting from commercially available N-(tert-butoxycarbonyl)-L-proline and
benzylamine; colorless viscous oil; IR (neat) 3316, 3062, 3030, 2966, 2871, 1655, 1522, 1454, 1360,
1
1249, 1104, 733, 699 cm–1; H NMR (CDCl3) # 7.93 (brs, 1H), 7.25–7.21 (m, 2H), 7.18–7.15 (m, 3H),
4.33 (d, J = 6.0 Hz, 2H), 3.68 (dd, J = 5.3, 9.2 Hz, 1H), 2.89 (ddd, J = 6.6, 6.9, 10.3 Hz, 1H), 2.77 (ddd, J
13
= 6.2, 6.4, 10.3 Hz, 1H), 2.12 (brs, 1H), 2.10–2.01 (m, 1H), 1.89–1.81 (m, 1H), 1.66–1.55 (m, 2H); C
NMR (CDCl3) # 175.0, 138.5, 128.4, 127.3, 127.0, 60.4, 47.0, 42.6, 30.6, 26.0; HRMS (ESI) calcd. for
C12H17N2O m/z 205.1335 [M+H]+, found 205.1337; ["]D21 –45.7 (c 1.0, CHCl3).
NMR data are identical to literature data.24
Typical Procedure for the Direct Asymmetric "-Allylation of Ketones 3 with Allylic Alcohols 2.
(R)-2-((E)-3-Phenylprop-2-en-1-yl)cyclohexanone (4a). To a flame dried test tube equipped with a
stirring bar and 3-way glass stopcock, [(!3-allyl)PdCl]2 (8.2 mg, 0.023 mmol), 3-phenyl-prop-2-en-1-ol
(2a, 20 mg, 0.15 mmol) in DMSO (0.60 mL), cyclohexanone (44 mg, 0.45 mmol), and DMSO solution of
ligand 1c (1.35 mL, 0.135 mmol, 0.10 M) were added sequentially at room temperature. After stirring

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HETEROCYCLES, Vol. 86, No. 1, 2012
for 20 h at room temperature, EtOAc (5 mL) and H2O (5 mL) were added to the reaction mixture. After
separation of organic layer and aqueous layer, aqueous layer was extracted with EtOAc (3 x 5 mL). The
combined organic layer was filtered through a short pad of silica gel with EtOAc as eluent, and the filtrate
was concentrated. The resulting residue was purified by silica gel column chromatography (eluent:
1
n-hexane/EtOAc = 40/1 to 20/1) to afford 4a (21.1 mg, 66%) as a colorless oil; H NMR (CDCl3) #
7.37–7.27 (m, 4H), 7.19 (t, J = 7.1 Hz, 1H), 6.40 (d, J = 15.8 Hz, 1H), 6.20 (ddd, J = 6.6, 8.0, 15.8 Hz,
1H), 2.71–2.64 (m, 1H), 2.47–2.39 (m, 2H), 2.36–2.29 (m, 1H), 2.22–2.12 (m, 2H), 2.09–2.04 (m, 1H),
13
1.90–1.85 (m, 1H), 1.74–1.61 (m, 2H), 1.46–1.36 (m, 1H); C NMR (CDCl3) # 212.5, 137.5, 131.6,
21
128.4, 128.3, 127.0, 126.0, 50.7, 42.1, 33.5, 33.0, 27.9, 25.0; ["]D 16.3 (c 1.1, CHCl3, 55% ee); HPLC
[DAICEL CHIRALCEL OD-H, detection at 254 nm, 9:1 n-hexane/iPrOH, flow rate = 1.0 mL/min, tR =
5.7 min (minor), 6.5 min (major)].
NMR data are identical to literature data.2i
(R)-2-((E)-3-(4-Trifluoromethylphenyl)prop-2-en-1-yl)cyclohexanone (4b): colorless oil; IR (neat)
1
2936, 2863, 1711, 1614, 1449, 1414, 1326, 1164, 1122, 1067, 1016, 971, 858 cm–1; H NMR (CDCl3) #
7.52 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 6.41 (d, J = 16.0 Hz, 1H), 6.35–6.27 (m, 1H),
2.71–2.65 (m, 1H), 2.48–2.40 (m, 2H), 2.36–2.28 (m, 1H), 2.21–2.13 (m, 2H), 2.10–2.02 (m, 1H),
13
1.90–1.83 (m, 1H), 1.75–1.61 (m, 2H), 1.46–1.36 (m, 1H); C NMR (CDCl3) # 212.2, 140.9, 131.3,
130.3, 128.7 (q, JC–F = 32.4 Hz), 126.1, 125.3 (q, JC–F = 3.8 Hz), 124.2 (q, JC–F = 269.8 Hz), 50.5, 42.1,
19
33.7, 33.0, 27.9, 25.0; F NMR (CDCl3) # –62.2; HRMS (ESI) calcd. for C16H18F3O m/z 283.1304
21
[M+H]+, found 283.1304; ["]D 11.8 (c 1.1, CHCl3, 54% ee); HPLC [DAICEL CHIRALCEL OJ-3,
detection at 254 nm, 99:1 n-hexane/iPrOH, flow rate = 1.0 mL/min, tR = 14.6 min (minor), 15.6 min
(major)].
(R)-2-((E)-3-(4-Fluorophenyl)prop-2-en-1-yl)cyclohexanone (4c): colorless oil; IR (neat) 3036, 2935,
1
2861, 1709, 1601, 1508, 1448, 1430, 1227, 1158, 1129, 970, 852, 823 cm–1; H NMR (CDCl3) #
7.60–7.56 (m, 2H), 7.26 (dd, J = 8.7, 8.9 Hz, 2H), 6.64 (d, J = 15.8 Hz, 1H), 6.40 (ddd, J = 6.6, 7.8, 15.8
Hz, 1H), 2.98–2.91 (m, 1H), 2.75–2.67 (m, 2H), 2.65–2.58 (m, 1H), 2.49–2.34 (m, 3H), 2.18–2.15 (m,
1H), 2.03–1.91 (m, 2H), 1.75–1.65 (m, 1H); 13C NMR (CDCl3) # 212.5, 161.9 (d, JC–F = 244.1 Hz), 133.7
(d, JC–F = 3.8 Hz), 130.4, 128.1 (d, JC–F = 1.9 Hz), 127.4 (d, JC–F = 7.6 Hz), 115.3 (d, JC–F = 21.0 Hz), 50.7,
42.1, 33.6, 33.0, 27.9, 25.0; 19F NMR (CDCl3) # –115.3; HRMS (ESI) calcd. for C15H18FO m/z 233.1336
21
[M+H]+, found 233.1337; ["]D 15.5 (c 0.7, CHCl3, 56% ee); HPLC [DAICEL CHIRALPAK AY-3,
detection at 254 nm, 9:1 n-hexane/iPrOH, flow rate = 1.0 mL/min, tR = 8.0 min (minor), 9.5 min (major)].
(R)-2-((E)-3-(4-Methoxyphenyl)prop-2-en-1-yl)cyclohexanone (4d): colorless oil; IR (neat) 3583,
2934, 2860, 1708, 1607, 1510, 1464, 1446, 1290, 1248, 1175, 1128, 1035, 969 cm–1; 1H NMR (CDCl3) #
7.26 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.33 (d, J = 15.8 Hz, 1H), 6.05 (ddd, J = 6.6, 8.0, 15.8

HETEROCYCLES, Vol. 86, No. 1, 2012
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Hz, 1H), 3.79 (s, 3H), 2.68–2.61 (m, 1H), 2.44–2.28 (m, 3H), 2.20–2.03 (m, 3H), 1.89–1.85 (m, 1H),
13
1.74–1.60 (m, 2H), 1.46–1.35 (m, 1H); C NMR (CDCl3) # 212.7, 158.7, 130.9, 130.3, 127.0, 126.1,
113.9, 55.3, 50.8, 42.1, 33.5, 33.0, 27.9, 25.0; HRMS (ESI) calcd. for C16H20NaO2 m/z 267.1356 [M+Na]+,
21
found 267.1356; ["]D 18.5 (c 0.7, CHCl3, 60% ee); HPLC [DAICEL CHIRALCEL OD-H, detection at
254 nm, 9:1 n-hexane/iPrOH, flow rate = 1.0 mL/min, tR = 6.6 min (minor), 7.1 min (major)].
(R)-2-((E)-3-(4-(N,N-Dimethylamino)phenyl)prop-2-en-1-yl)cyclohexanone (4e):
yellow oil; IR
(neat) 2932, 2859, 2801, 1708, 1610, 1521, 1445, 1352, 1223, 1188, 1165, 1127, 966, 814 cm–1; 1H NMR
(CDCl3) # 7.23 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.9 Hz, 2H), 6.30 (d, J = 15.6 Hz, 1H), 5.98 (ddd, J = 6.6,
8.0, 15.6 Hz, 1H), 2.94 (s, 6H), 2.68–2.61 (m, 1H), 2.44–2.28 (m, 3H), 2.21–2.00 (m, 3H), 1.88–1.85 (m,
1H), 1.74–1.59 (m, 2H), 1.46–1.35 (m, 1H); 13C NMR (CDCl3) # 212.8, 149.7, 131.3, 126.8, 126.2, 123.9,
112.5, 51.0, 42.1, 40.6, 33.4, 33.0, 27.9, 25.0; HRMS (ESI) calcd. for C17H24NO m/z 258.1852 [M+H]+,
21
found 258.1855; ["]D 24.0 (c 0.1, CHCl3, 52% ee); HPLC [DAICEL CHIRALPAK AY-H, detection at
254 nm, 9:1 n-hexane/iPrOH, flow rate = 1.0 mL/min, tR = 19.1 min (minor), 21.7 min (major)].
(R)-3-((E)-3-Phenylprop-2-en-1-yl)-4H-pyran-4-one (4f): colorless oil; 1H NMR (CDCl3) # 7.33–7.27
(m, 4H), 7.22–7.18 (m, 1H), 6.41 (d, J = 15.6 Hz, 1H), 6.15 (ddd, J = 6.2, 8.0, 15.6 Hz, 1H), 4.22–4.16
(m, 2H), 3.76 (ddd, J = 3.4, 10.8, 14.4 Hz, 1H), 3.47 (dd, J = 9.2, 11.4 Hz, 1H), 2.72–2.58 (m, 3H), 2.44
13
(dt, J = 3.4, 14.4 Hz, 1H), 2.24–2.16 (m, 1H); C NMR (CDCl3) # 207.6, 137.1, 132.2, 128.5, 127.2,
21
126.6, 126.0, 72.2, 68.6, 51.2, 42.4, 29.3; ["]D 15.0 (c 0.4, CHCl3, 36% ee); HPLC [DAICEL
CHIRALCEL OD-H, detection at 254 nm, 9:1 n-hexane/iPrOH, flow rate = 1.0 mL/min, tR = 11.0 min
(minor), 13.2 min (major)].
NMR data are identical to literature data.2i
ACKNOWLEDGEMENTS
This work was financially supported by KAKENHI (No. 20229001 and 23590038). N. K. thanks the
Japan Prize Foundation for supporting this research by their grants in 2012.
REFERENCES AND NOTES
1. For recent reviews, see: (a) B. M. Trost, M. R. Machacek, and A. Aponick, Acc. Chem. Res., 2006,
39, 747; (b) J. T. Mohr and B. M. Stoltz, Chem. Asian J., 2007, 2, 1476; (c) Z. Lu and S. Ma, Angew.
Chem. Int. Ed., 2008, 47, 258; (d) M. Diéguez and O. Pàmies, Acc. Chem. Res., 2010, 43, 312.
2. For recent reviews on Pd catalyzed allylic alkylations with allylic alcohols, see: (a) J. Muzart, Eur. J.
Org. Chem., 2007, 3077; (b) M. Kimura and Y. Tamaru, Mini-Rev. Org. Chem., 2009, 6, 392. For
selected examples of related studies, see: (c) F. Ozawa, H. Okamoto, S. Kawagishi, S. Yamamoto, T.
Minami, and M. Yoshifuji, J. Am. Chem. Soc., 2002, 124, 10968; (d) K. Manabe and S. Kobayashi,

756
HETEROCYCLES, Vol. 86, No. 1, 2012
Org. Lett., 2003, 5, 3241; (e) Y. Kayaki, T. Koda, and T. Ikariya, J. Org. Chem., 2004, 69, 2595;
(f) H. Kinoshita, H. Shinokubo, and K. Oshima, Org. Lett., 2004, 6, 4085; (g) M. Kimura, M.
Futamata, R. Mukai, and Y. Tamaru, J. Am. Chem. Soc., 2005, 127, 4592; (h) I. Usui, S. Schmidt, M.
Keller, and B. Breit, Org. Lett., 2008, 10, 1207; (i) I. Usui, S. Schmidt, and B. Breit, Org. Lett., 2009,
11, 1453; (j) R. Matsubara, K. Masuda, J. Nakano, and S. Kobayashi, Chem. Commun., 2010, 46,
8662; (k) G. Jiang and B. List, Adv. Synth. Catal., 2011, 353, 1667; (l) H. Hikawa and Y. Yokoyama,
J. Org. Chem., 2011, 76, 8433; (m) R. Ghosh and A. Sarkar, J. Org. Chem., 2011, 76, 8508; (n) Y.
Tao, B. Wang, J. Zhao, Y. Song, L. Qu, and J. Qu, J. Org. Chem., 2012, 77, 2942.
3. For recent examples of allylic alkylations with allylic alcohols using other transition-metal catalysis,
see: (a) M. Utsunomiya, Y. Miyamoto, J. Ipposhi, T. Ohshima, and K. Mashima, Org. Lett., 2007, 9,
3371; (b) A. B. Zaitsev, S. Gruber, and P. S. Pregosin, Chem. Commun., 2007, 4692; (c) A. B.
Zaitsev, S. Gruber, P. A. Plüss, P. S. Pregosin, L. F. Veiros, and M. Wörle, J. Am. Chem. Soc., 2008,
130, 11604; (d) T. Ohshima, Y. Miyamoto, J. Ipposhi, Y. Nakahara, M. Utsunomiya, and K.
Mashima, J. Am. Chem. Soc., 2009, 131, 14317; (e) T. Ohshima, Y. Nakahara, J. Ipposhi, Y.
Miyamoto, and K. Mashima, Chem. Commun., 2011, 47, 8322.
4. For reviews, see: (a) M. Bandini, Angew. Chem. Int. Ed., 2011, 50, 994; (b) M. Bandini, G. Cera,
and M. Chiarucci, Synthesis, 2012, 504.
5. (a) Y. Yamashita, A. Gopalarathnam, and J. F. Hartwig, J. Am. Chem. Soc., 2007, 129, 7508; (b) C.
Defieber, M. A. Ariger, P. Moriel, and E. M. Carreira, Angew. Chem. Int. Ed., 2007, 46, 3139; (c) M.
Roggen and E. M. Carreira, Angew. Chem. Int. Ed., 2011, 50, 5568; (d) M. Lafrance, M. Roggen,
and E. M. Carreira, Angew. Chem. Int. Ed., 2012, 51, 3470.
6. C. García-Yebra, J. P. Janssen, F. Rominger, and G. Helmchen, Organometallics, 2004, 23, 5459.
7. B. M. Trost and J. Quancard, J. Am. Chem. Soc., 2006, 128, 6314.
8. For intramolecular asymmetric allylations with allylic alcohols, see: (a) S. Tanaka, T. Seki, and M.
Kitamura, Angew. Chem. Int. Ed., 2009, 48, 8948; (b) M. Bandini and A. Eichholzer, Angew. Chem.
Int. Ed., 2009, 48, 9533; (c) H. Yamamoto, E. Ho, K. Namba, H. Imagawa, and M. Nishizawa, Chem.
Eur. J., 2010, 16, 11271; (d) M. Bandini, M. Monari, A. Romaniello, and M. Tragni, Chem. Eur. J.,
2010, 16, 14272; (e) K. Miyata, H. Kutsuna, S. Kawakami, and M. Kitamura, Angew. Chem. Int. Ed.,
2011, 50, 4649; (f) P. Mukherjee and R. A. Widenhoefer, Angew. Chem. Int. Ed., 2012, 51, 1405.
9. G. Jiang and B. List, Angew. Chem. Int. Ed., 2011, 50, 9471.
10. For the direct use of ketones in Pd catalyzed asymmetric allylic alkylations with other allylic
electrophiles, see: (a) X. Zhao, D. Liu, F. Xie, Y. Liu, and W. Zhang, Org. Biomol. Chem., 2011, 9,
1871; (b) X. Zhao, D. Liu, H. Guo, Y. Liu, and W. Zhang, J. Am. Chem. Soc., 2011, 133, 19354.
11. For catalytic asymmetric allylic alkylations with ketone enamines, see: (a) D. J. Weix and J. F.

HETEROCYCLES, Vol. 86, No. 1, 2012
757
Hartwig, J. Am. Chem. Soc., 2007, 129, 7720; (b) X. Zhao, D. Liu, F. Xie, and W. Zhang,
Tetrahedron, 2009, 65, 512.
12. For reviews on catalytic asymmetric allylic alkylations with ketone enolates, see: (a) M. Braun and T.
Meier, Synlett, 2006, 661; (b) M. Braun and T. Meier, Angew. Chem. Int. Ed., 2006, 45, 6952.
13. For reviews on the combination of transition-metal catalysis and amine organocatalysis, see: (a) Z.
Shao and H. Zhang, Chem. Soc. Rev., 2009, 38, 2745; (b) A. E. Allen and D. W. C. MacMillan,
Chem. Sci., 2012, 3, 633.
14. Our group has reported various catalytic asymmetric reactions utilizing amide-based ligand, see:
(a) A. Nojiri, N. Kumagai, and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 3779; (b) T. Nitabaru, A.
Nojiri, M. Kobayashi, N. Kumagai, and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 13860; (c) T.
Mashiko, N. Kumagai, and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 14990; (d) A. Matsuzawa, T.
Mashiko, N. Kumagai, and M. Shibasaki, Angew. Chem. Int. Ed., 2011, 50, 7616.
15. The reactions using other Pd salts, Pd(OAc)2, Pd2(dba)3·CHCl3, Pd(PPh3)4, did not proceed at all.
16. 4’ was detected by 1H NMR analysis, while quantity of 4’ could not be estimated due to its volatility.
17. M. Murakata, M. Nakajima, and K. Koga, J. Chem. Soc., Chem. Commun., 1990, 1657.
18. Z. Wu, G. S. Minhas, D. Wen, H. Jiang, K. Chen, P. Zimniak, and J. Zheng, J. Med. Chem., 2004, 47,
3282.
19. D. Craig and N. K. Slavov, Chem. Commun., 2008, 6054.
20. A. Bouziane, M. Hélou, B. Carboni, F. Carreaux, B. Demerseman, C. Bruneau, and J.-L. Renaud,
Chem. Eur. J., 2008, 14, 5630.
21. H. Y. Kwon, S. Y. Lee, B. Y. Lee, D. M. Shin, and Y. K. Chung, Dalton Trans., 2004, 921.
22. (a) M. Hingst, M. Tepper, and O. Stelzer, Eur. J. Inorg. Chem., 1998, 73; (b) J. P. Cahill, F. M.
Bohnen, R. Goddard, C. Krüger, and P. J. Guiry, Tetrahedron: Asymmetry, 1998, 9, 3831.
23. These proline derivatives can be prepared following the literature procedure from an inexpensive
compound, see: J. Chiba, G. Takayama, T. Takashi, M. Yokoyama, A. Nakayama, J. J. Baldwin, E.
McDonald, K. J. Moriarty, C. R. Sarko, K. W. Saionz, R. Swanson, Z. Hussain, A. Wong, and N.
Machinaga, Bioorg. Med. Chem., 2006, 14, 2725.
24. I. Held, E. Larionov, C. Bozler, F. Wagner, and H. Zipse, Synthesis, 2009, 2267.