Asymmetric addition of diethylzinc to aldehydes catalyzed by new zinc-amides prepared by a rhodium-catalyzed asymmetric addition

Article abstract of DOI:10.1016/j.tetasy.2011.06.031

A new chiral zinc-amide 2s' was found to be an effective catalyst for the asymmetric addition of diethylzinc to aldehydes 3 through a screening method for asymmetric catalysts, in which two catalytic asymmetric reactions are connected. The chiral zinc cat

Full text of DOI:10.1016/j.tetasy.2011.06.031

Tetrahedron: Asymmetry 22 (2011) 1225–1230
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric addition of diethylzinc to aldehydes catalyzed by new
zinc-amides prepared by a rhodium-catalyzed asymmetric addition
⇑
⇑
Kazuhiro Yoshida , Naohisa Akashi, Akira Yanagisawa
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
A new chiral zinc-amide 2s0 was found to be an effective catalyst for the asymmetric addition of dieth-
ylzinc to aldehydes 3 through a screening method for asymmetric catalysts, in which two catalytic asym-
metric reactions are connected. The chiral zinc catalyst can be readily prepared catalytically from achiral
imine 1 by the chiral rhodium–diene complex mediated asymmetric addition of dimethylzinc.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 3 June 2011
Accepted 30 June 2011
Available online 6 August 2011
1. Introduction
[RhCl(C2H4)2]2 (3 mol % Rh)
Ts
H
MeZn
Ar
Ts
Ts
(R,R)-Ph-Bod* (6 mol %)
N
N
HN
Me2Zn (1.5 equiv.)
H2O
Catalytic asymmetric synthesis has attracted a great deal of
attention because small amounts of chiral catalysts can induce
the formation of large amounts of optically active compounds in
this system.1 If the chiral catalysts are prepared catalytically, an
enhanced amplification of the chirality can be expected due to
the multiplication of two catalytic asymmetric reactions.2 Herein
we report a new type of chiral zinc catalyst for the asymmetric
addition of diethylzinc to aldehydes, which was found by our
recent catalyst screening method,3 which connects two different
catalytic asymmetric reactions (Scheme 1).
Ar
Me
Ar
Me
dioxane, 50 °C
1
2'-ZnMe
2
94-98% ee
Ph
(R,R)-Ph-Bod* =
Ph
Scheme 2. Asymmetric addition of dimethylzinc to N-tosylarylimines 1 catalyzed
by an Rh/(R,R)-Ph-bod⁄ complex.
2. Results and discussion
Asymmetric Catalyst I*
A
B*
Åa
The catalyst screening8,9 was performed with the following one-
pot procedure. First, N-tosylarylimine 1 was reacted with dimeth-
ylzinc in the presence of Rh/(R,R)-Ph-bod⁄ catalyst at 50 °C for 3 h
to give chiral zinc-amide 20-ZnMe. Next, all of the volatile materials
were removed under reduced pressure from the reaction flask.
Benzaldehyde, diethylzinc, and hexane were then introduced into
the same flask and the mixture was stirred at 30 °C for 24 h. Final-
ly, the mixture was quenched by adding 1 M HCl aq and purified by
silica gel chromatography after extraction.
The results of the screening are shown in Table 1. When
N-tosyl-1-phenylimine 1a was employed as the substrate for the
first step of the reaction, the desired 1-phenyl-1-propanol 4a was
obtained in 79% yield as the final product (entry 1). In this case,
the enantiomeric excess (ee) of 4a was found to be 20%. The
screening for 1 with a substituent at the 4-position of the aromatic
ring also gave 4a in good yields, but unsatisfactory results were ob-
tained in terms of enantioselectivity (entries 2–12). On the other
hand, whereas similar results were observed in most of the screen-
ing for 1 with a substituent at the 2-position (entries 13–16),
remarkable enantioselectivity (73% ee) was observed with 1q,
Asymmetric Catalyst II*
D*
C
Scheme 1. Connection of two catalytic asymmetric reactions for catalyst screening.
The asymmetric addition4 of dimethylzinc to N-tosylarylimines
1 catalyzed by the Rh/(R,R)-Ph-bod⁄ complex,5 which was reported
by Hayashi et al. in 2006, was our choice of reaction for the prep-
aration and screening for new chiral zinc catalysts (Scheme 2). This
highly reliable reaction produces various 1-arylethylamines 2 with
high enantioselectivities; chiral zinc-amide intermediates 20-ZnMe
were assumed to be formed prior to work-up with H2O. Herein, we
attempted to use chiral zinc-amide 20 as a catalyst for the asym-
metric addition6,7 of diethylzinc to aldehydes 3.
⇑
Corresponding authors. Tel./fax: +81 43 290 2790 (K.Y.); tel./fax: +81 43 290
2789 (A.Y.).
E-mail addresses: kyoshida@faculty.chiba-u.jp (K. Yoshida), ayanagi@faculty.
chiba-u.jp (A. Yanagisawa).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.031

1226
K. Yoshida et al. / Tetrahedron: Asymmetry 22 (2011) 1225–1230
Table 1
Screening for asymmetric catalysts 20-ZnMe by connecting two reactionsa
[RhCl(C2H4)2]2 (3 mol % Rh)
Ts
H
MeZn
Ar
Ts
(R,R)-Ph-Bod* (6 mol %)
N
N
Me2Zn (1.5 equiv.)
Ar
Me
dioxane, 50 °C, 3 h
1
2'-ZnMe
OH
Et2Zn (40 equiv.)
hexane, 30 °C, 24 h
PhCHO
Ph
3a (20 equiv.)
(R)-4a
Entry
Ar
20-ZnMe
Yieldb of 4a (%)
eec,d of 4a (%)
1
2
3
4
5
6
7
8
Ph 1a
2a0
2b0
2c0
2d0
2e0
2f0
79
76
61
92
73
67
76
85
78
78
70
57
83
79
80
82
79
83
82
80
76
85
77
88
20
8
16
9
19
5
6
4-MeC6H4 1b
4-EtC6H4 1c
4-i-PrC6H4 1d
4-PhC6H4 1e
4-CF3C6H4 1f
4-FC6H4 1g
4-ClC6H4 1h
4-MeOC6H4 1i
4-EtOC6H4 1j
4-BuOC6H4 1k
4-BnOC6H4 1l
2-MeC6H4 1m
2-EtC6H4 1n
2-ClC6H4 1o
2-BrC6H4 1p
2-MeOC6H4 1q
2-EtOC6H4 1r
2g0
2h0
2i0
7
5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2j0
2k0
2l0
16
22
10
19
10
30
3
73
53
86
78
13
12
10
19
2m0
2n0
2o0
2p0
2q0
2r0
2s0
2t0
2,3-(MeO)2C6H3 1s
2,4-(MeO)2C6H3 1t
2,6-(MeO)2C6H3 1u
2,6-Me2C6H3 1v
1-Naphthyl 1w
2u0
2v0
2w0
2x0
2-Naphthyl 1x
a
Catalyst 20-ZnMe was prepared by the asymmetric addition of Me2Zn (1.5 equiv) to 1 in the presence of [RhCl(C2H4)2]2 (3 mol % Rh) and (R,R)-Ph-bod⁄ (6 mol %) in dioxane
at 50 °C for 3 h. After concentration of the mixture of 20-ZnMe, hexane, Et2Zn (40 equiv), and benzaldehyde 3a (20 equiv) were added to the residue. The resulting mixture was
stirred at 30 °C for 24 h.
b
Isolated yield.
Chiral HPLC analysis.
c
d
Absolute configuration was determined by comparison of the sign of the specific rotation and the chiral HPLC retention time with data in the literature.
which has a methoxy group at the 2-position (entry 17). The
screening result for 1r with an ethoxy group was likewise notable,
but the selectivity was lower than that of 1q (entry 18). These re-
sults indicate that the coordination ability of the alkoxy group to
the zinc metal center is likely to be important for high enantiose-
lectivity. Moreover, the introduction of an additional methoxy
group at the 3- or 4-position of 1q was found to further improve
the enantioselectivity (entries 19 and 20). In particular, the highest
enantioselectivity (86% ee) was observed when N-tosyl-2,3-
dimethoxyphenylimine 1s was employed as the substrate for the
first step of the reaction (entry 19). Other substrates with substit-
uents at the 2,6-positions or a naphthyl moiety gave poor enanti-
oselectivity (entries 21–24).
was obtained with the 2s0-ZnEt catalyst, which was prepared
from 99% ee of 2s and diethylzinc (entry 2). Lowering the temper-
ature when using 2s0-ZnEt catalyst generally improved the
enantioselectivity (entries 3–5). At the end of the optimization,
it was found that 95% ee of 4a could be obtained by performing
the reaction at 0 °C in the presence of 3 mol % of 2s0-ZnEt catalyst
(entry 6).10 Under these conditions, the reaction of various
aldehydes 3 gave corresponding alcohols with high enantioselec-
tivities (entries 7–14). In particular, the ethylation of 2-naphthal-
dehyde 3i gave 4i with the highest enantioselectivity (96% ee)
(entry 14).
3. Conclusion
The generality of the ethylation of aldehydes 3 using organo-
zinc 2s0, which was found to be the best catalyst in the screening
in Table 1, was examined (Table 2). First, we prepared 99% ee of
2s by recrystallization of the enantiomerically enriched (95% ee)
2s obtained by the Rh-catalyzed asymmetric addition with H2O
quenching. Next, organozinc catalyst 2s0-ZnMe was prepared by
mixing 99% ee of 2s with dimethylzinc. When we applied this
catalyst (5 mol %) to the ethylation of benzaldehyde (3a) at
30 °C, 4a was produced with 83% ee (entry 1). A similar result
We have found a new chiral zinc catalyst for the asymmetric
addition of diethylzinc to aldehydes through a screening method
in which two catalytic asymmetric reactions were connected. Per-
formance of multiple asymmetric reactions consecutively is an
effective approach to amplify the asymmetric source. The fact that
chiral zinc catalyst 2s0 can be prepared from inexpensive reagents
by a Rh-catalyzed asymmetric addition underscores the advantage
of this catalyst over other catalysts.

K. Yoshida et al. / Tetrahedron: Asymmetry 22 (2011) 1225–1230
1227
Table 2
Asymmetric addition of diethylzinc to aldehydes 3 catalyzed by (S)-2s0
a
Ts
HN
Me
(S)-2s (99% ee, 3-5 mol %)
Et2Zn (2 equiv.)
OH
OMe
Ar'CHO
Ar'
OMe
(S)-2s
hexane, temp, 24 h
3
4
(R)-
Entry
3
(S)-2s (mol %)
Temp (°C)
Yieldb of 4 (%)
eec,d of 4 (%)
1e
2
3
4
5
6
7
8
9
10
11
12
13
14
Benzaldehyde 3a
5
5
5
5
5
3
3
3
3
3
3
3
3
3
30
30
20
0
73
73
84
77
48
74
68
60
70
72
77
69
79
90
83
85
88
94
95
95
94
90
91
91
75
80
89
96
ꢀ20
0
4-Methylbenzaldehyde 3b
4-Chlorobenzaldehyde 3c
4-Methoxybenzaldehyde 3d
2-Methylbenzaldehyde 3e
2-Chlorobenzaldehyde 3f
2-Methoxybenzaldehyde 3g
1-Naphthaldehyde 3h
0
0
0
0
0
0
0
0
2-Naphthaldehyde 3i
a
A mixture of (S)-2s (3–5 mol %) and diethylzinc (2 equiv) in hexane was stirred at room temperature for 1 h. Then, aldehyde 3 was added and the resulting mixture was
stirred for 24 h at the reaction temperature.
b
Isolated yield.
Chiral HPLC analysis.
c
d
Absolute configuration was determined by the comparison of the sign of the specific rotation and the chiral HPLC retention time with the data in the literature.
The catalyst was prepared from (S)-2s and dimethylzinc.
e
to room temperature, the mixture was quenched with 1 N NaOH
aq and extracted with EtOAc three times. The combined organic
layers were washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The crude product was then recrys-
tallized (EtOAc/hexane) to give N-tosylarylimines 1.
4. Experimental
4.1. General
All anaerobic and moisture-sensitive manipulations were car-
ried out using standard Schlenk techniques or glove box tech-
niques under argon. NMR spectra were recorded on a JEOL JNM
ECA-500 spectrometer (500 MHz for 1H and 125 MHz for 13C)
and ECS-400 spectrometer (400 MHz for 1H and 100 MHz for 13C)
at Chemical Analysis Center, Chiba University. Chemical shifts are
reported in d ppm referenced to an internal SiMe4 standard for
1H NMR and chloroform-d (d 77.0) for 13C NMR. High-resolution
mass spectra were recorded on Thermo Fisher Scientific Exactive
Orbitrap mass spectrometers at Chemical Analysis Center, Chiba
University. Optical rotations were measured with a JASCO P-1020
polarimeter.
4.3.2. N-Phenylmethylidene-4-methylbenzenesulfonamide 1a
Yield, 95%. 1H NMR (CDCl3) d 2.44 (s, 3H), 7.35 (d, J = 7.9 Hz, 2H),
7.46–7.52 (m, 2H), 7.59–7.64 (m, 1H), 7.87–7.95 (m, 4H), 9.03 (s,
1H).
4.3.3. N-(4-Methylphenyl)methylidene-4-methylbenzenesulfon-
amide 1b
Yield, 77%. 1H NMR (CDCl3) d 2.43 (s, 3H), 2.44 (s, 3H), 7.26–7.29
(m, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.87–7.90
(m, 2H), 8.99 (s, 1H).
4.3.4. N-(4-Ethylphenyl)methylidene-4-methylbenzenesulfon-
4.2. Materials
amide 1c
Yield, 63%. 1H NMR (CDCl3) d 1.25 (t, J = 7.6 Hz, 3H), 2.43 (s, 3H),
2.71 (q, J = 7.6 Hz, 2H), 7.30–7.34 (m, 4H), 7.80–7.89 (m, 4H), 8.99
(s, 1H).
Toluene and 1,4-dioxane were distilled from sodium benzophe-
none-ketyl under argon and stored in a glass flask with a Teflon
stopcock. [RhCl(C2H4)2]2 was prepared according to the reported
procedures.11 Hexane, p-toluenesulfonamide, boron trifluoride
diethyl ether complex, dimethylzinc (1 M solution in hexane),
diethylzinc (1 M solution in hexane), and (1R,4R)-2,5-dibenzylbicy-
clo[2.2.2]octa-2,5-diene [(R,R)-Ph-bod⁄] were used as received.
4.3.5. N-(4-Isopropylphenyl)methylidene-4-methylbenzenesulfon-
amide 1d
Yield, 56%. 1H NMR (CDCl3) d 1.26 (d, J = 7.1 Hz, 6H), 2.44 (s, 3H),
2.93–3.01 (m, 1H), 7.31–7.35 (m, 4H), 7.81–7.88 (m, 4H), 8.99 (s,
1H).
4.3. Procedures for the preparation of N-tosylarylimines 112
4.3.6. N-(4-Phenylphenyl)methylidene-4-methylbenzenesulfon-
amide 1e
4.3.1. General procedure A
To a mixture of p-toluenesulfonamide (10.0 mmol) and alde-
hyde (10.0 mmol) in toluene (20 mL) was slowly added boron tri-
fluoride diethyl ether complex (0.80 mmol, 0.098 mL) at reflux
under argon and the mixture was stirred for 12 h. After cooling
Yield, 44%. 1H NMR (CDCl3) d 2.45 (s, 3H), 7.35 (d, J = 8.2 Hz, 2H),
7.40–7.49 (m, 3H), 7.62 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H),
7.90 (d, J = 8.2 Hz, 2H), 8.00 (d, J = 8.7 Hz, 2H), 9.00 (s, 1H).

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K. Yoshida et al. / Tetrahedron: Asymmetry 22 (2011) 1225–1230
4.3.7. N-(4-Trifluoromethylphenyl)methylidene-4-methylbenz-
enesulfonamide 1f
4.3.18. N-(2-Methoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1q
Yield, 81%. 1H NMR (CDCl3) d 2.45 (s, 3H), 7.37 (d, J = 7.9 Hz, 2H),
7.75 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.2 Hz,
2H), 9.08 (s, 1H).
Yield, 73%. 1H NMR (CDCl3) d 2.43 (s, 3H), 3.93 (s, 3H), 6.94–7.00
(m, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.52–7.59 (m, 1H), 7.89 (d,
J = 8.4 Hz, 2H), 8.06–8.07 (m, 1H), 9.54 (s, 1H).
4.3.8. N-(4-Fluorophenyl)methylidene-4-methylbenzenesulfon-
amide 1g
4.3.19. N-(2-Ethoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1r
Yield, 70%. 1H NMR (CDCl3) d 2.44 (s, 3H), 7.15–7.19 (m, 2H),
7.35 (d, J = 7.9 Hz, 2H), 7.87–7.89 (m, 2H), 7.93–7.97 (m, 2H),
9.00 (s, 1H).
Yield, 60%. 1H NMR (CDCl3) d 1.47 (t, J = 7.3 Hz, 3H), 2.43 (s, 3H),
4.14 (q, J = 7.3 Hz, 2H), 6.92–7.01 (m, 2H), 7.33 (d, J = 7.8 Hz, 2H),
7.50–7.55 (m, 1H), 7.89 (d, J = 7.8 Hz, 2H), 8.04–8.07 (m, 1H),
9.53 (s, 1H).
4.3.9. N-(4-Chlorophenyl)methylidene-4-methylbenzenesulfon-
amide (1h)
4.3.20. N-(2,3-Dimethoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1s
Yield, 91%. 1H NMR (CDCl3) d 2.44 (s, 3H), 7.35 (d, J = 8.3 Hz, 2H),
7.45 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.3 Hz,
2H), 8.99 (s, 1H).
Yield, 60%. 1H NMR (CDCl3) d 2.43 (s, 3H), 3.89 (s, 3H), 3.96 (s,
3H), 7.06–7.16 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.61–7.64 (m,
1H), 7.89 (d, J = 8.0 Hz, 2H), 9.44 (s, 1H).
4.3.10. N-(4-Methoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1i
4.3.21. N-(2,4-Dimethoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1t
70% yield. 1H NMR (CDCl3) d 2.43 (s, 3H), 3.88 (s, 3H), 6.95–6.99
(m, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.86–7.90 (m, 4H), 8.94 (s, 1H).
Yield, 68%. 1H NMR (CDCl3) d 2.42 (s, 3H), 3.87 (s, 3H), 3.89 (s,
3H), 6.40 (s, 1H), 6.51 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H),
7.87 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H), 9.41 (s, 1H).
4.3.11. N-(4-Ethoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1j
Yield, 38%. 1H NMR (CDCl3) d 1.44 (t, J = 6.9 Hz, 3H), 2.43 (s, 3H),
4.11 (q, J = 7.3 Hz, 2H), 6.93 (d, J = 4.6 Hz, 2H), 7.32 (d, J = 7.8 Hz,
2H), 7.87 (d, J = 7.8 Hz, 4H), 8.93 (s, 1H).
4.3.22. N-(2,6-Dimethoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1u
Yield, 75%. 1H NMR (CDCl3) d 2.42 (s, 3H), 3.88 (s, 6H), 6.54 (d,
J = 8.7 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.46 (t, J = 8.2 Hz, 1H), 7.89
(d, J = 8.0 Hz, 2H), 9.55 (s, 1H).
4.3.12. N-(4-Butoxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1k
Yield, 38%. 1H NMR (CDCl3) d 0.97 (t, J = 7.3 Hz, 3H),1.44–1.54
(m, 2H), 1.75–1.82 (m, 2H), 2.43 (s, 3H), 4.03 (t, J = 6.4 Hz, 2H),
6.95 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.85–7.88 (m, 4H),
8.93 (s, 1H).
4.3.23. N-(2,6-Dimethylphenyl)methylidene-4-methylbenzenesulfon-
amide 1v
Yield, 68%. 1H NMR (CDCl3) d 2.44 (s, 3H), 2.56 (s, 6H), 7.10 (d,
J = 7.8 Hz, 2H), 7.27–7.35 (m, 3H), 7.89 (d, J = 7.8 Hz, 2H), 9.50 (s,
1H).
4.3.13. N-(4-Benzyloxyphenyl)methylidene-4-methylbenzenesulfon-
amide 1l
4.3.24. N-(1-Naphthyl)methylidene-4-methylbenzenesulfon-
amide 1w
Yield, 42%. 1H NMR (CDCl3) d 2.43 (s, 3H), 5.14 (s, 2H), 7.04 (d,
J = 5.0 Hz, 2H), 7.22–7.42 (m, 7H), 7.86–7.90 (m, 4H), 8.94 (s, 1H).
Yield, 90%. 1H NMR (CDCl3) d 2.43 (s, 3H), 7.35 (d, J = 8.4 Hz, 2H),
7.57 (t, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H),
7.91 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.2 Hz,
1H), 8.15 (d, J = 7.2 Hz, 1H), 8.98 (d, J = 8.2 Hz, 1H), 9.61 (s, 1H).
4.3.14. N-(2-Methylphenyl)methylidene-4-methylbenzenesulfon-
amide 1m
Yield, 55%. 1H NMR (CDCl3) d 2.43 (s, 3H), 2.60 (s, 3H), 7.25–7.31
(m, 2H), 7.33–7.36 (m, 2H), 7.45–7.49 (m, 2H), 8.00 (d, J = 7.8 Hz,
2H), 9.34 (s, 1H).
4.3.25. N-(2-Naphthyl)methylidene-4-methylbenzenesulfon-
amide 1x
Yield, 34%. 1H NMR (CDCl3) d 2.44 (s, 3H), 7.33–7.39 (m, 2H),
7.55–7.60 (m, 1H), 7.60–7.66 (m, 1H), 7.85–7.90 (m, 2H), 7.90–
7.98 (m, 3H), 8.00–8.06 (m, 1H), 8.33 (s, 1H), 9.07 (s, 1H).
4.3.15. N-(2-Ethylphenyl)methylidene-4-methylbenzenesulfon-
amide 1n
Yield, 77%. 1H NMR (CDCl3) d 1.24 (t, J = 7.6 Hz, 3H), 2.44 (s, 3H),
2.97 (q, J = 7.7 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 7.49–7.53 (m, 1H), 7.89 (d, J = 8.4 Hz, 2H), 8.04–8.06 (m,
1H), 9.35 (s, 1H).
4.4. Procedure for the screening for the asymmetric catalysts 20
by connecting two reactions
4.4.1. General procedure B
4.3.16. N-(2-Chlorophenyl)methylidene-4-methylbenzenesulfon-
amide 1o
A mixture of [RhCl(C2H4)2]2 (0.400 mg, 0.00100 mmol, 3 mol %
Rh) and (R,R)-Ph-bod⁄ (1.00 mg, 0.00400 mmol, 2 equiv to Rh) in
1,4-dioxane (0.30 mL) was placed in a 20 mL Schlenk tube and stir-
red for 5 min at room temperature. To this solution were added N-
tosylarylimine 1 (0.0660 mmol), additional 1,4-dioxane (0.40 mL),
and Me2Zn (0.10 mL, 0.10 mmol; 1.02 M solution in hexane). The
mixture was stirred for 3 h at 50 °C. After cooling to room temper-
ature, the mixture was thoroughly concentrated under reduced
pressure. To the mixture were added hexane (2.0 mL), diethylzinc
(2.70 mL 2.70 mmol; 1.05 M solution in hexane), and benzalde-
hyde 3a (0.134 mL, 1.32 mmol). After stirring for 24 h at 30 °C,
Yield, 75%. 1H NMR (CDCl3) d 2.45 (s, 3H), 7.34–7.37 (m, 3H),
7.46–7.52 (m, 2H), 7.90 (d, J = 8.5 Hz, 2H), 8.14–8.17 (m, 1H),
9.50 (s, 1H).
4.3.17. N-(2-Bromophenyl)methylidene-4-methylbenzenesulfon-
amide 1p
Yield, 23%. 1H NMR (CDCl3) d 2.45 (s, 3H), 7.36–7.46 (m, 4H),
7.66 (d, J = 6.4 Hz, 1H), 7.91 (d, J = 6.4 Hz, 2H), 8.15 (d, J = 6.4 Hz,
1H), 9.43 (s, 1H).

K. Yoshida et al. / Tetrahedron: Asymmetry 22 (2011) 1225–1230
1229
the mixture was quenched by 1 M HCl aq and extracted with EtOAc
three times. The combined organic layers were washed with brine
and dried over Na2SO4. The crude product was purified by PTLC on
silica gel (EtOAc/hexane = 1:4) to give 4a.
4.6.4. (R)-1-(4-Chlorophenyl)-1-propanol 4c
This product was characterized by the comparison of the spec-
troscopic data with those reported previously13; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OB-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 22.0 min [(S)-enantiomer], 24.4 min [(R)-enan-
tiomer] or Daicel Chiralcel OD-H, hexane/2-propanol = 98:2,
flow = 0.5 mL/min, retention times = 8.9 min [(S)-enantiomer],
10.5 min [(R)-enantiomer].16
4.5. Procedure for the asymmetric addition of dimethylzinc to
N-tosylarylimines 1 catalyzed by a rhodium–diene complex4
4.5.1. General procedure C
A mixture of [RhCl(C2H4)2]2 (1.20 mg 0.00300 mmol, 3 mol %
Rh) and (R,R)-Ph-bod⁄ (3.10 mg, 0.0120 mmol, 2 equiv to Rh) in
1,4-dioxane (0.30 ml) was placed in a 20 mL Schlenk tube and stir-
red for 5 min at room temperature. To this solution were added
successively N-tosylarylimine 1 (0.200 mmol), additional 1,4-diox-
ane (0.40 mL), and Me2Zn (0.30 mL, 0.30 mmol; 1.02 M solution in
hexane). After stirring for 3 h at 50 °C, the resulting mixture was
quenched with 7% NH3 aq and extracted with Et2O. The combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated on a rotary evaporator. The residue was purified
by PTLC (EtOAc/hexane = 1:2) to give 2.
4.6.5. (R)-1-(4-Methoxyphenyl)-1-propanol 4d
This product was characterized by the comparison of the spec-
troscopic data with those reported previously13; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OD-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 36.0 min [(R)-enantiomer], 41.7 min [(S)-
enantiomer].16
4.6.6. (R)-1-(2-Methylphenyl)-1-propanol 4e
This product was characterized by the comparison of the spec-
troscopic data with those reported previously17; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OB-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 15.9 min [(S)-enantiomer], 21.9 min [(R)-
enantiomer].18
4.5.2. N-[(1S)-1-(2,3-Dimethoxyphenyl)ethyl]-4-
methylbenzenesulfonamide (S)-2s
Yield, 41%, 95% ee. The ee was determined by HPLC analysis
with a stationary phase column Chiralcel OD-H column (hexane/
2-propanol = 4:1, flow = 0.3 mL/min, wavelength = 254 nm, reten-
tion times = 25.0 min [(R)-enantiomer], 28.9 min [(S)-enantio-
mer]). 1H NMR (CDCl3) d 1.43 (d, J = 7.1 Hz, 3H), 2.33 (s, 3H), 3.79
(s, 3H), 3.80 (s, 3H), 4.55–4.62 (m, 1H), 5.34 (d, J = 8.7 Hz, 1H),
6.56–6.58 (m, 1H), 6.70–6.73 (m, 1H), 6.82–6.86 (m, 1H), 7.10 (d,
J = 8.0 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3) d 21.5,
23.8, 51.2, 55.8, 60.8, 111.7, 119.6, 124.0, 127.0, 129.2, 135.5,
137.6, 142.8, 146.0, 152.5; HRMS (ESI) calcd for C17H21O4NNaS
([M+Na]+) 358.1084, found 358.1078. Crystallization in EtOAc/hex-
4.6.7. (R)-1-(2-Chlorophenyl)-1-propanol 4f
This product was characterized by the comparison of the spec-
troscopic data with those reported previously16; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OB-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 14.0 min [(S)-enantiomer], 17.6 min [(R)-
enantiomer].14
ane (1:2) increased the ee to >99% ee; ½a D20
¼ ꢀ20:8 (c 0.300,
ꢁ
CHCl3); mp 131–136 °C.
4.6.8. (R)-1-(2-Methoxyphenyl)-1-propanol 4g
This product was characterized by the comparison of the spec-
troscopic data with those reported previously13; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OD-H, hexane/2-propanol = 500:1, flow = 0.5 mL/min,
retention times = 122.5 min [(R)-enantiomer], 152.8 min [(S)-
enantiomer].17
4.6. Procedures for the asymmetric addition of diethylzinc to
aldehydes 3 catalyzed by 2s0
4.6.1. General procedure D
A
mixture of 2s (0.0060 mmol) and diethylzinc (0.40 mL,
0.40 mmol; 1.05 M solution in hexane) in hexane (1.00 mL) was
stirred at room temperature for 1 h. Then the mixture was cooled
to appropriate temperature, added aldehyde 3 (0.200 mmol), and
stirred for 24 h. The mixture was then quenched by NH4Cl aq
and extracted with EtOAc three times. The combined organic layers
were washed with brine and dried over Na2SO4. The crude product
was purified by PTLC on silica gel (EtOAc/hexane = 1:4) to give 4.
4.6.9. (R)-1-(1-Naphthyl)-1-propanol 4h
This product was characterized by the comparison of the spec-
troscopic data with those reported previously16; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OD-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 38.8 min [(S)-enantiomer], 54.9 min [(R)-
enantiomer].16
4.6.2. (R)-1-Phenylpropanol 4a
This product was characterized by the comparison of the spec-
troscopic data with those reported previously13; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OD-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 26.0 min [(R)-enantiomer]], 30.8 min [(S)-
enantiomer].14
4.6.10. (R)-1-(2-Naphthyl)-1-propanol 4i
This product was characterized by the comparison of the spec-
troscopic data with those reported previously19; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OD-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 55.8 min [(S)-enantiomer], 64.5 min [(R)-
enantiomer].14
4.6.3. (R)-1-(4-Methylphenyl)-1-propanol 4b
This product was characterized by the comparison of the spec-
troscopic data with those reported previously13; the ee value was
determined by HPLC analysis with a stationary phase column Dai-
cel Chiralcel OB-H, hexane/2-propanol = 98:2, flow = 0.5 mL/min,
retention times = 21.8 min [(S)-enantiomer], 26.5 min [(R)-
enantiomer].15
Acknowledgments
We thank Dr. Takeharu Toyoshima for some initial experiments.
We appreciate the financial support from JGC-S Scholarship Foun-
dation (No. 2208) to K.Y.

1230
K. Yoshida et al. / Tetrahedron: Asymmetry 22 (2011) 1225–1230
9. For examples of screening strategies where chiral ligands are rapidly prepared
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