Applications of N′-alkylated derivatives of TsDPEN in the asymmetric transfer hydrogenation of C=O and C=N bonds

Article abstract of DOI:10.1016/j.tetasy.2010.07.013

Arene/Ru(II) complexes of (R,R)-N-alkyl-TsDPEN ligands are effective in the asymmetric transfer hydrogenation of ketones and imines in formic acid/triethylamine solution. The complex derived from the N′-Bn derivative of TsDPEN reduces monocyclic imines in up to 60% ee, whilst the N′-Me derivative of TsDPEN forms a more active catalyst than the non-alkylated analogue and reduces ketones in up to 97% ee.

Full text of DOI:10.1016/j.tetasy.2010.07.013

Tetrahedron: Asymmetry 21 (2010) 2258–2264
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Applications of N0-alkylated derivatives of TsDPEN in the asymmetric
transfer hydrogenation of C@O and C@N bonds
*
José E. D. Martins, Miguel A. Contreras Redondo, Martin Wills
Department of Chemistry, Warwick University, Coventry CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Arene/Ru(II) complexes of (R,R)-N-alkyl-TsDPEN ligands are effective in the asymmetric transfer hydro-
genation of ketones and imines in formic acid/triethylamine solution. The complex derived from the
N0-Bn derivative of TsDPEN reduces monocyclic imines in up to 60% ee, whilst the N0-Me derivative of
TsDPEN forms a more active catalyst than the non-alkylated analogue and reduces ketones in up to
97% ee.
Received 5 July 2010
Accepted 6 July 2010
Available online 31 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
tional substituent on the non-tosylated nitrogen atom, that is, sec-
ondary amine derivatives.5 This is in contrast to the amino alcohols
The asymmetric transfer hydrogenation (ATH) of ketones and
imines represents an excellent method for the synthesis of enanti-
omerically pure alcohols and amines.1–4 Of the catalysts, which
have been reported for this application, complexes of enantiomeri-
cally pure N-tosylated-1,2-diphenylethane-1,2-diamine (TsDPEN)
1 exhibit an excellent combination of stability and versatility.
Complexes of TsDPEN with Ru(II), Rh(III), and Ir(III) 2–4, respec-
tively have been employed extensively in the synthesis of numer-
ous complex target molecules and chiral building blocks.1,4
commonly used in ATH reactions, which frequently bear secondary
alcohol groups.1,6 The N0-Me and N0-Et TsDPEN derivatives 5 and 6
have been used in the ATH of C@C bonds,5a whilst Ikariya has re-
ported on the reversible decarboxylation of formate using a Ru(II)
complex of 5.5b,c Also, N0-alkylated derivatives of N-tosyl-1,2-
diaminocyclohexane (TsDAC) have been used in ketone and imine
ATH.5d,5e Until recently, our own experience of ATH using a Ru(II)/
cymene complex formed in situ from N0-benzyl TsDPEN, that is, 7
indicated a poor level of catalytic activity.7 Switching to the iso-
lated catalysts 7–12, containing instead a benzene ring on the
Ru(II), however, gave much better results. Indeed the N0-Me com-
plex 7 exhibited a higher catalytic activity than the parent complex
2, for the ATH of both ketones and imines.8
2 (R=H, R1=Me, R2=iPr)
7 (R=Me, R1=H, R2=H)
8 (R=Et, R1=H, R2=H)
R2
Ph
NHTs
R1
Ru
9 (R=Pr, R1=H, R2=H)
NHR
1 (R=H)
Cl
R
Ph
TsN
10 (R=iBu, R1=H, R2=H)
11 (R=Bn, R1=H, R2=H)
12 (R=CH2CH2Ph, R1=H, R2=H)
N
5 (R=Me)
6 (R=Et)
2. Results and discussion
Ph
H
Ph
Encouraged by these results, we expanded upon our studies on
the ATH of ketones and imines using N0-substituted TsDPEN deriv-
atives. In the case of ketone reduction, we focused on the use of the
N0-Me derivative 7, which had previously demonstrated excellent
activity and selectivity.8 The reduction of a series of acetophenone
derivatives 13 to alcohols 14 was investigated (Scheme 1, Table 1).
The N0-methylated catalyst 7 was capable of the catalysis of the
asymmetric reduction of a range of acetophenones in high yields.
Rh
N
Ir
N
Cl
H
Cl
H
TsN
Ph
TsN
H
Ph
H
Ph
Ph
3
4
H
OH
O
1 mol% catalyst 7,
Despite the high level of interest in the complexes of TsDPEN cat-
alysts, that is, derived from the primary amine 1, very little has
been reported on the use of related complexes bearing an addi-
HCO2H, Et3N, 28oC
Y
Y
X
X
see Table 1
13
14
* Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652 4112.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
Scheme 1.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.013

J. E. D. Martins et al. / Tetrahedron: Asymmetry 21 (2010) 2258–2264
2259
Table 1
derivatives 18 and 19, containing 1,4-dimethyl and -diisopropyl
groups, respectively. In the event, 18 was prepared via the reaction
of the precursor 1,4-dimethyl-1,4-cyclohexadiene with RuCl3 fol-
lowed by the reaction with N0-benzyl-N-TsDPEN. Attempts to form
catalyst 19 by an analogous approach were unsuccessful at the
complexation step, possibly due to an unacceptably high level of
steric hindrance in the product. Complex 18 proved to be a poor
catalyst for acetophenone reduction [40% conversion in 7 days,
93% ee, (R)], however, it was slightly more effective than 15 in
the reduction of imine 16 (Table 2).
Reduction of ketones using catalyst 7 (Scheme 1)
Entry
X
Y
Time (h)
Conv (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
p-Cl
m-Cl
o-Cl
p-CH3
m-CH3
o-CH3
p-Br
m-Br
o-Br
p-CF3
m-CF3
H
CH3
H
H
H
H
H
H
H
H
H
H
H
10
10
3
3
4
7
6
23
3
3
99
99
100
100
99
99
97
96
100
100
100
100
100
96 (R)
93 (R)
90 (R)
90 (R)
67 (R)
97 (R)
94 (R)
81 (R)
90 (R)
89 (R)
64 (R)
88 (R)
89 (R)
Table 2
7
2
2
Reduction of imines using N-alkylated catalysts
Entry
Substrate
Catalyst
Time (d)
Conv (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
16
16
16
16
20
21
22
22
22
22
22
22
22
22
22
22
22
22
22
22
31
33
35
15 (in situ)
15 (preformed)
3
4
100
97
41 (S)
74 (S)
85 (S)
84 (S)
89 (S)
75 (S)
21 (R)
29 (R)
28 (R)
0
The lowest enantiomeric excesses were obtained with ketones
containing ortho-substituents, possibly due to an unfavorable ste-
ric interaction. This observation matches the previous observations
with this class of catalyst. More significantly, the reaction times re-
quired for the full reduction were shorter than those for the parent
complex 3; typically half the reaction time is required.8 In earlier
work on N0-alkylated catalysts 7–12, we found that it was essential
118
18
11
11
7
0.25
2
0.33
0.33
1
1
1
1
2
1
2
4
2
2
2
2
1.8
2
100
100
100
100
100
100
100
50
91
41
13
33
80
24
96
98
91
44
92
94
8
9
10
11
12
15
18
24
25
26
27
28
29
11
11
11
60 (R)
23 (R)
4 (R)
to employ benzene as the
g
6-arene ring in the complex in order to
obtain catalysts with reasonable activity.8 In this study, the reduc-
tion of acetophenone with the isolated p-cymene derivative 15, for
example, was found to be very slow, giving a product in only 27%
conversion after seven days [93% ee, (R)-configuration].
0
60 (R)
3 (R)
57 (R)
47 (R)
60 (R)
32 (R)
57 (R)
61 (R)
50 (R)
Further studies were also conducted on the application of N0-
alkylated Ru-based catalysts to asymmetric imine reductions. The
in situ formation of the p-cymene catalyst 15 gave poor results
for the reduction of imine 16 to amine 17; a product was formed
in only 41% ee after 3 days, although with 100% conversion
(Scheme 2, Table 2). The use of the isolated complex 15 gave an im-
proved ee of 74% after the same reaction time. In contrast, the ben-
zene-containing catalyst 11 gave a product of 85% ee after a
reaction time of just ca. 6 h (full conversion), again demonstrating
the importance of the structure of the arene component.
2
2
2
83
Entries 1–4 were run with MeCN as a cosolvent and entries 5–23 were run in
MeOH.9 Absolute configurations were obtained by comparison with the reported
data.10–15 except 34 and 36, which were assigned by analogy with 22 and 32.
These results suggest that some substitution on the aromatic li-
gand of Ru(II) complexes bearing N0-alkyl groups can be tolerated,
but the reactivity is sharply reduced by such substitution. Imines
20 and 21 were also reduced using 1 mol% of 11 in 100% conversion
after 8 h and in 89 and 75% ee (S), respectively. In these cases, and
from this point in these studies, imine reduction was conducted in
methanol following the dropwise method described by Black-
mond,9 as this was found to give better results during the initial
optimization studies for these particular substrates.
R2
24 (R=a, R1=H, R2=H)
15 (R=Bn, R1=Me, R2=iPr) 25 (R=b, R1=H, R2=H)
R1
18 (R=Bn, R1=Me, R2=Me)
19 (R=Bn, R1=iPr, R2=iPr)
26 (R=c, R1=H, R2=H)
27 (R=d, R1=H, R2=H)
28 (R=e, R1=H, R2=H)
29 (R=H, R1=H, R2=H)
Ru
Cl
R
TsN
N
Ph
H
Ph
d=
a=
b=
c=
OMe
e=
MeO
N
HN
H
OMe
N
MeO
The 1H NMR spectrum of 15 was complex and indicated that a mix-
ture of isomers may be present, possibly due to restricted rotation
of the g6-arene due to hindrance from the N0-benzyl group. If this
is the case then it may be that one isomer has a methyl group prox-
imal to the active site whilst another has the iPr group in this posi-
tion. Therefore, we thought that it would be worthwhile to prepare
R
X
X
20 R=Et
21 R=CH2Ph,
22 (X=H)
23 (X=H)
31 (X=OMe)
33 (X=Me)
35 (X=CF3)
32 (X=OMe)
34 (X=Me)
36 (X=CF3)
Whilst the asymmetric reduction of imines 16, 20, and 21 is rela-
tively well established,3 22 is a more challenging substrate for
which no effective ATH catalyst has yet been reported, although
other methods (e.g., hydrogenation) exist for their enantioselective
reduction.13 Several catalysts were tested in the asymmetric reduc-
tion of imine 22 to the amine 23 (Table 2). Of the N0-alkylated
series 7–12, following the optimization with respect to the concen-
tration and solvent, the N0-benzyl catalyst 11 gave the best result in
terms of ee; 60%, although catalysts 7–9 also reduced the substrate
MeO
MeO
1 mol% catalyst,
MeO
MeO
HCO2H, Et3N, 28oC
N
NH
Me
MeCN or MeOH
see Table 2
16
17
Me
H
Scheme 2.

2260
J. E. D. Martins et al. / Tetrahedron: Asymmetry 21 (2010) 2258–2264
in good yield. Catalysts containing arenes other than an
g
6-ben-
4. Experimental
zene (i.e., 15 and 18) proved to be poor catalysts, possibly due to
increased steric hindrance. In view of the promising results ob-
tained with N0-Bn catalyst 11, a further series of derivatives 24–
28, containing benzyl derivatives, were prepared and evaluated
in the reduction of 22. With the exception of 25, each of these gave
similar results to 11, although none gave better enantioselectivi-
ties. In order to establish whether the N0-benzyl group was provid-
ing an advantage, the unsubstituted complex 29 was prepared and
tested. This gave a product in only 44% conversion in 2 days and in
32% ee. Although the ees achieved with 11 and other N-benzylated
catalyst derivatives are modest, they are better than the level
achieved by alternative known, unsubstituted, catalysts. This indi-
cates that the N0-benzyl group may be interacting in a productive
manner with the substrate during the reduction transition state.
A series of derivatives 31, 33, and 35 were also reduced using 11
as a catalyst and gave products 32, 34, and 36 in similar conver-
sions and ees to those achieved with 22.
4.1. General procedure for the synthesis of ligands8
To a stirred solution of (R,R)-TsDPEN (0.30 g, 0.82 mmol) and
molecular sieves (1 g) in dried methanol (8 mL) was added the aro-
matic aldehyde (0.98 mmol) followed by three drops of glacial
acetic acid. The reaction was followed by TLC until the imine was
formed (3 h) and then sodium cyanoborohydride (0.15 g,
2.4 mmol) was added and the reaction mixture was left to stir
overnight at rt. The molecular sieves were filtered through filter
paper and the solution was concentrated under reduced pressure
to remove the methanol. The residue was dissolved in chloroform
(50 mL), washed with saturated NaHCO3 solution (30 mL), and
then dried over anhydrous MgSO4. The solvent was removed to
give the crude compound, which was purified by silica gel column
chromatography (0?30% v/v ethyl acetate/hexane) to afford the
product (80–98% yield).
Whilst it is difficult to be able to fully characterize the reduc-
tion transition state, it is interesting to note that the reduction of
22 and its derivatives gives products in an (R)-configuration
[(R,R)-configuration catalysts were used throughout]. This would
fit with a transition state similar to that shown in Figure 1,
although the low ee suggests that the selectivity for this partic-
ular approach is low, and that other modes of hydride transfer
conformation may be accessible at similar energy levels. The
presumption of imine protonation has been made on the basis
of the reported studies on this class of reaction,3h–k although it
is unclear whether or not a hydrogen bond exists between the
imine nitrogen atom and the N–H of the catalyst in the transition
state (as is the accepted mechanism for ketone reduction1e–i).
This mode of reduction is in contrast to that of 16, which gives
a product with an (S)-configuration. The control of this reaction
has been previously discussed.8
4.1.1. N0-(3-Methylbenzyl)-N-TsDPEN
80% yield. mp 102–105 °C; ½a D32
¼ ꢁ35 (c 0.6, CHCl3); mmax
ꢀ
(neat)/cmꢁ1 dH 3271, 3062, 3027, 1601, 1491, 1454, 1434, 1325,
1184, 915, 839, 790, 757, 697, 669; dH (300 MHz; CDCl3) 7.38–
6.90 (18H, m, Ar-H), 6.18 (1H, br s, NHTs), 4.30 (1H, d, J 7.5 Hz,
PhCHNHTs), 3.70 (1H, d, J 7.5 Hz, PhCHNbenzyl), 3.58 (1H, d, J
13.1 Hz, CHaHb), 3.37 (1H, d, J 13.1 Hz, CHaHb), 2.31 (6H, s,
2 ꢂ CH3), 1.54 (1H, br s, NHbenzyl); dC (75 MHz; CDCl3) 142.6,
138.0, 136.9, 129.0, 128.7, 128.6, 128.4, 128.3, 127.9, 127.6,
127.5, 127.4, 127.2, 127.0, 125.1, 125.0 66.7, 62.9, 50.7, 21.4. HRMS
calcd for C29H31N2SO2 [M+H]+ 471.2096, found 471.2083 (2.7 ppm
error).
4.1.2. N0-(4-Methylbenzyl)-N-TsDPEN
85% yield. mp 153–157 °C; ½a D32
¼ ꢁ42:7 (c 0.5, CHCl3); mmax
ꢀ
(neat)/cmꢁ1 3344, 3269, 3062, 3027, 2849, 1600, 1512, 1491,
1453, 1436, 1325, 1184, 1095, 915, 836, 799, 755, 698, 670; dH
(400 MHz; CDCl3) 7.38–6.89 (18H, m, Ar-H), 6.15 (1H, br s, NHTs),
4.30 (1H, d, J 7.7 Hz, PhCHNHTs), 3.67 (1H, d, J 7.7 Hz, PhCHNben-
zyl), 3.58 (1H, d, J 13.0 Hz, CHaHb), 3.36 (1H, d, J 13.0 Hz, CHaHb),
2.34 (3H, s, CH3), 2.32 (3H, s, CH3), 1.62 (1H, br s, NHbenzyl); dC
(100 MHz; CDCl3) 142.7, 138.9, 138.3, 137.0, 136.7, 136.3, 129.1,
128.4, 128.0, 127.9, 127.5, 127.2, 127.1, 66.7, 63.1, 50.6, 21.4,
X
21.1. HRMS calcd for
471.2101 (1.0 ppm error).
C
29H31N2SO2 [M+H]+ 471.2096, found
Ru
N
R
H
TsN
H
N
H
Ph
4.1.3. N0-(3,5-Dimethylbenzyl)-N-TsDPEN
88% yield. mp 127–129 °C; ½a D22
ꢀ
¼ ꢁ36:4 (c 0.48, CHCl3); mmax
Ph
(neat)/cmꢁ1: 3340, 3291, 3034, 2915, 2767, 1600, 1493, 1454,
1426, 1323, 1152, 1114, 1088, 1029, 915, 854, 802, 714, 697,
671; dH (300 MHz; CDCl3) 7.64–6.96 (17H, m, Ar-H), 6.42 (1H, br
s, NHTs), 4.56 (1H, d, J 7.2 Hz, PhCHNHTs), 3.95 (1H, d, J 7.3 Hz,
PhCHNbenzyl), 3.80 (1H, d, J 13.1 Hz, CHaHb), 3.59 (1H, d, J
13.1 Hz, CHaHb), 2.58 (3H, s, CH3), 2.54 (6H, s, 2CH3), 1.87 (1H, br
s, NHbenzyl); dC (75 MHz; CDCl3) 142.6, 139.2, 139.0, 138.4,
137.9, 136.9, 129.1, 128.7, 128.4, 127.9, 127.5, 127.4, 127.3,
127.0, 125.7, 66.8, 63.0, 50.8, 21.4, 21.2. HRMS calcd for
Figure 1. Proposed conformation of protonated imine relative to catalyst in hydride
transfer step.
3. Conclusion
In conclusion, we have demonstrated that Ru(II) complexes of
N0-alkylated, N-TsDPEN ligands are competent catalysts for the
asymmetric catalysis of the reduction of ketones and imines. In
the case of the N0-Me complex 7, the rates are faster than those
of the unmethylated parent complex. Imine reduction remains
challenging, and the mode of reduction by Ru/TsDPEN complexes
is less well understood, however, the N0-alkylated complexes in
some cases give reduction products of equal or improved ee, rela-
tive to the non-alkylated complexes in the reduction of certain cyc-
lic imines. Research continues into the synthesis and applications
of modified TsDPEN derivatives, particularly with respect to the
challenging field of imine reduction.
C
30H33N2SO2 [M+H]+ 485.2252, found 485.2259 (1.4 ppm error).
4.1.4. N0-(3,5-Dimethoxybenzyl)-N-TsDPEN
83% yield. mp 37–40 °C; ½a D23
¼ ꢁ39:1 (c 0.42, CHCl3); mmax
ꢀ
(neat)/cmꢁ1 3260, 3061, 3029, 2936, 2837, 1596, 1454, 1428,
1317, 1203, 1148, 1091, 1054, 920, 831, 812, 762, 698, 664; dH
(300 MHz; CDCl3) 7.37–6.88 (17H, m, Ar-H), 6.13 (1H, br s, NHTs),
4.31 (1H, d, J 7.7 Hz, PhCHNHTs), 3.77 (6H, s, 2 ꢂ OCH3), 3.66 (1H,
d, J 7.7 Hz, PhCHNbenzyl), 3.59 (1H, d, J 13.4 Hz, CHaHb), 3.34 (1H,

J. E. D. Martins et al. / Tetrahedron: Asymmetry 21 (2010) 2258–2264
2261
d, J 13.4 Hz, CHaHb), 2.32 (3H, s, CH3), 1.7 (1H, br s, NHbenzyl); dC
(75 MHz; CDCl3) 160.8, 142.7, 141.8, 138.8, 138.1, 136.9, 129.1,
128.4, 127.9, 127.6, 127.5, 127.3, 127.0, 105.7, 99.2, 66.5, 63.0,
55.3, 50.9, 21.4. HRMS calcd for C30H33N2SO4 [M + H]+ 517.2150,
found 517.2156 (1.1 ppm error).
1596, 1493, 1456, 1428, 1376, 1354, 1294, 1267, 1204, 1157,
1124, 1083, 1053, 1002, 939, 900, 829, 805, 756, 695, 678, 656;
dH (400 MHz; CDCl3) 7.35–6.30 (17H, m, ArH), 5.62 (6H, s, C6H6),
4.43 (1H, br m, NH), 4.30 (1H, br m, NCHNTs), 4.18 (1H, br m,
CHNHBenzyl), 4.10 (1H, d, J 10.4 Hz, CHaHb), 3.80 (7H, s, 2OCH3
and CHaHb), 2.24 (3H, s, CH3). dC (100 MHz; CDCl3) 161.1, 141.8,
139.4, 139.3, 138.5, 136.8, 129.0, 128.5, 127.9, 127.5, 126.8,
105.0, 99.9, 84.0, 81.4, 69.5, 60.1, 55.7, 21.2. HRMS calcd for
4.1.5. N0-(2,4,6-Trimethylbenzyl)-N-TsDPEN
98% yield. mp 175–177 °C; ½a D23
¼ ꢁ26:4 (c 0.36, CHCl3); mmax
ꢀ
C
36H37N2SO4Ru [MꢁCl]+ 695.1505, found 695.1521 (2.3 ppm
(neat)/cmꢁ1 3341, 3291, 2912, 1600, 1494, 1453, 1426, 1326,
1153, 1117, 1025, 912, 852, 808, 751, 697, 672; dH (300 MHz;
CDCl3) 7.32–6.76 (16H, m, Ar-H), 6.07 (1H, br s, NHTs), 4.27 (1H,
d, J 6.6 Hz, PhCHNHTs), 3.69 (1H, d, J 7.3 Hz, PhCHNbenzyl), 3.49
(1H, d, J 11.5 Hz, CHaHb), 3.32 (1H, d, J 11.5 Hz, CHaHb), 2.30 (3H,
s, CH3), 2.23 (3H, s, CH3), 2.05 (6H, s, 2 ꢂ CH3), 1.16 (1H, br s, NHb-
enzyl); dC (75 MHz; CDCl3) 142.6, 139.3, 138.4, 137.0, 136.8, 136.7,
132.6, 129.0, 128.9, 128.4, 128.0, 127.6, 127.3, 127.0, 68.2, 63.0,
error).
4.2.4. Compound 27
Isolated in 96% yield. Decomposition temperature 245–247 °C;
½
a 2D9
ꢀ
¼ ꢁ266:6 (c 0.01, CHCl3);
m
max(neat)/cmꢁ1 3206, 3061, 3028,
2858, 1494, 1456, 1436, 1375, 1271, 1205, 1127, 1084, 1054,
1026, 1002, 930, 899, 832, 822, 811, 797, 759, 696, 682, 655; dH
(400 MHz; CDCl3) 7.30–6.51 (18H, m, ArH), 5.58 (6H, s, C6H6),
4.53 (1H, br m, NH), 4.34–4.15 (2H, br m, CHNTs + CHNHBenzyl)),
4.12 (1H, d, J 11.0 Hz, CHaHb), 3.82 (1H, appt, J 11.5 Hz, CHaHb),
2.33 (3H, s, CH3), 2.24 (3H, s, CH3); dC (100 MHz; CDCl3) 142.1,
139.3, 139.2, 137.6, 137.1, 133.2, 129.5, 128.5, 128.1, 128.0,
127.4, 127.1, 126.8, 126.7, 84.0, 84.4, 69.6, 59.8, 21.2, 21.1. HRMS
45.5, 21.4, 20.9, 19.1. HRMS calcd for
499.2408, found 499.2419 (2.2 ppm error).
C
31H35N2SO2 [M+H]+
Catalysts 7–12 have previously been described and character-
ized.8 Catalyst 15 has been reported but not previously
characterized.7
calcd for
(0.1 ppm error).
C
35H35N2SO2Ru [MꢁCl]+ 649.1451, found 649.1450
4.2. General procedure for the synthesis of benzeneruthenium
N-alkyl catalysts8
4.2.5. Compound 28
A mixture of benzeneruthenium(II) chloride dimer (0.16 g,
0.33 mmol), ligand (0.44 mmol), and triethylamine (0.24 cm3,
1.7 mmol) in isopropanol (10 cm3) was heated at 80 °C for 1 h.
After cooling to rt, the solvent was removed under vacuum and
the residue was washed with isopropanol (20 cm3) and then water
(10 cm3). The residue was dried overnight under vacuum providing
a brown solid (41–96% yield). Purification by flash chromatography
on silica gel was required for catalysts 26, 18, and 15 (3:3:1 v/v/v
ethyl acetate/hexane/methanol).
Isolated in 96% yield. Decomposition temperature 224–226 °C;
½
a 3D1
ꢀ
¼ ꢁ276:5 (c 0.009, CHCl3);
m
max(neat)/cmꢁ1 3208, 3059,
3026, 2361, 1493, 1456, 1434, 1273, 1150, 1128, 1085, 1049,
1010, 939, 919, 830, 818, 696, 669, 655; dH (300 MHz; CDCl3)
7.30–6.52 (18H, m, ArH), 5.58 (6H, s, C6H6), 4.50 (1H, br m, NH),
4.35 (1H, br m, CHNTs), 4.18 (1H, dd, J 3.1, 13.0 Hz, CHNHBenzyl),
4.09 (1H, d, J 11.0 Hz, CHaHb), 3.83 (1H, t, J 11.4 Hz, CHaHb), 2.28
(3H, s, CH3), 2.21 (3H, s, CH3). dC (75 MHz; CDCl3) 142.0, 139.3,
138.4, 137.0, 136.3, 129.9, 129.0, 128.9, 128.7, 128.4, 128.2,
128.1, 128.0, 127.9, 127.6, 127.5, 127.4, 126.8, 126.6, 126.4,
126.2, 124.9, 124.3, 84.0, 81.2, 69.6, 60.2, 21.4, 21.2. HRMS calcd
for C35H35N2SO2Ru [MꢁCl]+ 649.1451, found 649.1466 (2.3 ppm
error).
4.2.1. Compound 24
Isolated in 92% yield. Decomposition temperature 238–240 °C;
½
a 3D1
ꢀ
¼ ꢁ200:9 (c 0.007, CHCl3);
m
max(neat)/cmꢁ1 3203, 3023,
1608, 1493, 1454, 1436, 1374, 1274, 1146, 1126, 1082, 916, 831,
804, 756, 697, 677, 655; dH (400 MHz; CDCl3) 7.32–6.52 (17H, m,
ArH), 5.61 (6H, s, C6H6), 4.50 (1H, br m, NH), 4.35 (1H, br m,
PhCHNTs), 4.18 (1H, br m, PhCHNbenzyl), 4.09 (1H, d, J 10.8 Hz,
CHaHb), 3.82 (1H, t, J 11.5 Hz, CHaHb), 2.24 (3H, s, CH3), 2.26 (6H,
s, 2 ꢂ CH3); dC (100 MHz; CDCl3) 141.8, 138.4, 137.0, 129.2,
129.0, 128.7, 127.9, 127.6, 126.8, 126.7, 126.3, 125.7, 125.0, 84.1,
83.4, 69.7, 60.3, 21.2. HRMS calcd for C36H37N2SO2Ru [MꢁCl]+
663.1644, found 663.1600 (6.6 ppm error).
4.2.6. Compound 18
A mixture of 1-4-dimethylbenzene ruthenium(II) chloride di-
mer (0.17 g, 0.30 mmol), N0-benzyl-N-TsDPEN (0.2 g, 0.44 mmol),
and triethylamine (0.24 cm3, 1.7 mmol) in isopropanol (10 cm3)
was heated at 80 °C for 1 h. After cooling to rt, the solvent was re-
moved under vacuum and the residue was dissolved in CHCl3
(20 cm3) and then washed with water (10 cm3) with vigorous stir-
ring for 3 min. The organic phase was separated, dried over anhy-
drous MgSO4, and evaporated providing a crude product which
was purified by column chromatography (3:3:1 v/v/v ethyl ace-
tate/hexane/methanol) providing 18 as a brown solid (0.095 g,
0.13 mmol, 31%). Decomposition temperature 166–168 °C;
4.2.2. Compound 25
Isolated in 41% yield. Decomposition temperature 199–200 °C;
½
a 3D0
ꢀ
¼ þ116 (c 0.01, CHCl3);
m
max(neat)/cmꢁ1 3225, 3067, 3029,
2916, 1598, 1492, 1453, 1431, 1269, 1124, 1080, 974, 940, 897,
827, 807, 695, 679, 655; dH (400 MHz; CDCl3) 7.37–6.50 (16H, m,
ArH), 5.40 (6H, s, C6H6), 4.57 (1H, d, J 11.1, PhCHNTs), 4.24 (1H,
dd, J 13.1, 11.5, PhCHNbenzyl), 3.99 (1H, br t, J 11.1, CHaHb), 3.50
(1H, d, J 12.7, CHaHb), 2.42 (3H, s, CH3), 2.28 (3H, s, CH3), 2.22
(3H, s, CH3), 1.65 (3H, s, CH3) (NH not observed); dC (125 MHz;
CDCl3) 142.6, 138.8, 137.4, 137.0, 132.0, 130.0, 129.8, 129.0,
128.9, 128.4, 128.3, 128.0, 127.5, 127.4, 127.0, 126.6, 126.3, 125.7,
83.4, 75.1, 71.5, 50.7, 21.4, 21.2, 20.9, 19.2. HRMS calcd for
½
a 2D1
ꢀ
¼ ꢁ208 (c 0.0036, CHCl3);
m
max(neat)/cmꢁ1 3026, 2919,
1598, 1493, 1453, 1376, 1272, 1129, 1082, 1011, 956, 901, 809,
742, 695, 654; dH (400 MHz; CDCl3) 7.45–6.50 (19H, m, ArH),
5.38 (2H, d, J 5.6 Hz, areneCHCH), 4.92 (2H, d, J 5.4 Hz, areneCHCH),
4.55 (1H, br m, NH), 4.24–4.08 (3H, br m, CHNTs + CHNHBen-
zyl + CHaHb), 3.47 (1H, t, J 7.0 Hz, CHaHb), 2.26 (6H, s, CH3), 2.24
(3H, s, CH3); dC (100 MHz; CDCl3) 142.5, 139.0, 138.7, 137.1,
136.5, 128.8, 128.6, 128.1, 127.8, 127.7, 127.2, 85.9, 81.4, 80.4,
70.0, 59.5, 18.9. HRMS calcd for
663.1607, found 663.1617 (1.5 ppm error).
C
36H37N2SO2Ru [MꢁCl]+
C
37H39N2SO2Ru [MꢁCl]+ 677.1775, found 677.1782 (1.1 ppm error).
4.2.3. Compound 26
4.2.7. Compound 15
Prepared as 18 using a mixture of p-cymeneruthenium(II) chlo-
ride dimer (0.20 g, 0.33 mmol), the N-benzyl ligand (0.2 g,
Isolated in 30% yield. Decomposition temperature 210–212 °C;
½
a 3D1
ꢀ
¼ ꢁ211:8 (c 0.005, CHCl3);
m
max(neat)/cmꢁ1 3212, 2968,

2262
J. E. D. Martins et al. / Tetrahedron: Asymmetry 21 (2010) 2258–2264
0.44 mmol), and triethylamine (0.24 cm3, 1.7 mmol) in isopropanol
(10 cm3). The product was purified by column chromatography
(3:3:1 v/v/v ethyl acetate/hexane/methanol) providing 15 as a
brown solid (0.16 g, 0.22 mmol, 51%) which appears to be a ca.
3:1 diastereoisomeric mixture. Decomposition temperature 119–
dC (100 MHz; CDCl3) 146.2, 146.1, 130.5, 126.3, 108.2 (Ar-C),
57.1 (CH), 54.9 (OMe), 54.7 (OMe), 40.2 (CH2), 28.6 (CH2), 28.0
(CH2), 9.5 (CH3).
4.3.3. Reduction product of 21 (R = Bn)
122 °C; ½a 2D5
ꢀ
¼ ꢁ404 (c 0.0023, CHCl3);
m
max(neat)/cmꢁ1: 3040,
Product was formed in 79% isolated yield. Enantiomeric excess
was determined by HPLC analysis (Chiracel IB hexane/isopropanol/
diethylamine = 80:20:0.1, flow rate 0.5 mL/min, 290 nm): ts =
2362, 2342, 1493, 1452, 1376, 1273, 1130, 1083, 1009, 955, 900,
858, 806, 792, 740, 695, 655; dH (400 MHz; CDCl3) 7.45–6.50
(19H, m, Ar-H), 5.68–5.28 (4H, m, Ar-H), 4.80–4.70 (1H, br s,
NH), 4.64 (1H, br s, CHNTs), 4.18 (3H, m, CHNTs + CHNHBen-
zyl + CHaHb), 3.63 (1H, t, J 11.7 Hz, CHaHb), 3.18 (0.75H, sept, J
7.0 Hz, CH), 3.02 (0.25H, sept, J 7.0 Hz, CH), 2.30 (0.75H, s, CH3),
2.26 (2.25H, s, CH3), 2.23 (3H, s, CH3), 1.40 (3H, d, J 6.6 Hz, CH3),
1.23 (3H, d, J 6.8 Hz, CH3); dC (150 MHz; CDCl3) 142.4, 139.0,
138.8, 137.1, 136.4, 129.1, 128.9, 128.1, 127.8, 127.7, 127.2,
126.8, 126.1, 80.2, 78.7, 69.9, 59.5, 30.4, 22.7, 21.1, 19.0. HRMS
20.4 min, tR = 27.5 min. ½a D30
¼ ꢁ8:3 (c 0.1, acetone) 75% ee (S) (cat-
ꢀ
alyst 11) (lit.12
[a]D = +15.0 (c 0.5–1.0, acetone) >98% ee (R) (cata-
lyst 5). dH (400 MHz; CDCl3) 7.35–7.22 (5H, m, Ar-H), 6.60 (2H, d,
J 8.7 Hz), 4.15 (1H, m, CH), 3.86 (3H, s, OCH3), 3.80 (3H, s, CH3),
3.20 (2H, m, CH2), 2.92 (2H, m, CH2), 2.73 (2H, m, CH2); dC
(100 MHz; CDCl3) 147.4, 146.9, 139.1, 130.4, 129.3, 128.6, 128.5,
127.2, 126.4 (Ar-C), 56.8 (OCH3), 55.8 (OCH3), 42.7 (CH2), 40.6
(CH2), 29.4 (CH3).
calcd for
(4.7 ppm error).
C
38H41N2SO2Ru [MꢁCl]+ 691.1919, found 691.1952
4.3.4. 2-Phenyl-piperidine 23
Product was formed in 84% isolated yield. Enantiomeric excess
was determined by GC analysis [Chrompac cyclodextrin-b-236M-
19 50 m, T = 145 °C, P = 15 psi, gas He, by use of the trifluoroaceta-
mide derivative, (R)-isomer 89.9 min, (S)-isomer 87.4 min];
4.3. Imine reduction by formic acid dropwise addition
method8,9
The catalyst (8.9 l
mol) and triethylamine (0.2 cm3, 1.4 mmol)
½
a 2D5
ꢀ
¼ þ14:7 (c 0.08, CH2Cl2) 60% ee (R) (lit.13a
½
a 2D2
ꢀ
¼ þ48:4 (c
were placed into a Schlenk tube and a solution of the imine
(0.14 g, 0.89 mmol) in methanol (3.56 cm3) was added. Formic acid
(0.14 cm3, 3.56 mmol) was added by a syringe pump over 30 min.
The reaction was monitored by GC until the specified conversion
was achieved. Work-up for 3,4-dihydro-6,7-dimethoxy-1-methyliso-
quinoline reduction products: The mixture was evaporated and the
residue was dissolved in CHCl3 (20 cm3), washed with saturated
NaHCO3 solution (10 cm3), and then the organic layer was sepa-
rated, dried over anhydrous MgSO4, and evaporated providing
the pure amine. Work-up for 2-phenyl-,3,4,5,6-tetrahydro-pyridine
reduction products: The mixture was evaporated and the residue
was dissolved in CHCl3 (2 cm3) and then a 1-M HCl solution
(15 cm3) was added and the system was stirred for 15 min. The
aqueous phase was separated and turned into basic (pH 12–14)
and extracted with DCM (3 ꢂ 15 mL). The organic layer was sepa-
rated, dried over anhydrous MgSO4, and evaporated providing the
pure amine.
0.31, CH2Cl2) 98% ee (R)); dH (300 MHz; CDCl3) 7.32–7.12 (5H, m,
ArH), 3.50 (1H, m, CH), 3.12 (1H, m, CHaHb), 2.72 (1H, m, CHaHb),
1.85–1.36 (6H, m, 3 ꢂ CH2); dC (75 MHz; CDCl3) 145.6, 128.3,
127.0, 126.6 (Ar-C), 62.3 (CH), 47.8 (CH2), 35.0 (CH2), 25.9 (CH2),
25.4 (CH2).
4.3.5. 2-(4-Methylphenyl)-piperidine 34
Product was formed in 75% isolated yield. Enantiomeric excess
was determined by GC analysis [Chrompac cyclodextrin-b-236M-
19 50 m, T = 145 °C, P = 15 psi, gas He, by use of the trifluoroaceta-
mide derivative, (R)-isomer 142.1 min, (S)-isomer 138.1 min];
½
a 3D1
ꢀ
¼ þ36:7 (c 0.4, CHCl3) 61% ee (R);
m
max(neat)/cmꢁ1 2929,
2850, 2784, 1636, 1514, 1441, 1370, 1324, 1308, 1262, 1205,
1180, 1109, 1018, 848, 814, 762; dH (300 MHz; CDCl3) 7.25 (2H,
m, Ar-H), 7.13 (2H, m, Ar-H), 3.55 (1H, m, CH), 3.18 (1H, m, CHaHb),
2.78 (1H, m, CHaHb), 2.32 (3H, s, CH3), 1.90–1.44 (6H, m, 3CH2); dC
(75 MHz; CDCl3) 142.6, 136.5, 129.0, 126.5 (Ar-C), 62.1 (CH), 47.8
(CH2), 35.0 (CH2), 25.9 (CH2), 25.4 (CH2), 21.0 (CH3). HRMS calcd
for C12H18N [M+H] 176.1434, found 176.1483 (27 ppm error).
4.3.1. (S)-Salsolidine 17
The reaction was monitored by NMR until complete. The prod-
uct was obtained in 72% isolated yield. Enantiomeric excess was
determined by GC analysis [Chrompac cyclodextrin-b-236M-19
50 m, T = 170 °C, P = 15 psi, gas He, imine 86.5 min, (S)-isomer
4.3.6. 2-(4-Methoxyphenyl)-piperidine 32
Product was formed in 70% isolated yield. Enantiomeric excess
was determined by NMR through derivatization with (5R)-
79.4 min, (R)-isomer 81.1 min]; ½a D28
¼ ꢁ32:9 (c 0.3, CHCl3) 84%
ꢀ
methyl-1-(chloromethyl)-2-pyrrolidinone.14
½
a 3D1
ꢀ
¼ þ11:7 (c 0.32,
ee (S) (catalyst 18) {lit.10
½
a 2D5
ꢀ
¼ þ56:5 (c 1.00, CHCl3) 91% ee (R)}.
CH3OH) 57% ee (R) {lit.15
½ ꢀ
a 2D2
¼ ꢁ21:1 (c 0.54, CH3OH) (S)} dH
dH (300 MHz; CDCl3) 6.61 (1H, s, Ar-H), 6.57 (1H, s, Ar-H), 4.14
(1H, q, J 6.6 Hz, CH), 3.85 (6H, s, 2xMeO), 3.36–3.24 (1H, m, CHaHb),
3.12–3.00 (1H, m, CHaHb), 2.94–2.79 (1H, m, CHaHb), 2.78–2.66
(1H, m, CHaHb), 1.50 (3H, d, J 6.6 Hz, CH3). dC (75 MHz; CDCl3)
147.5, 147.3, 130.7, 125.9, 111.5, 108.8 (Ar-C), 55.9, 55.7 (2
MeO), 50.9 (CH), 41.0 (CH2), 28.4 (CH2), 22.0 (CH3).
(400 MHz; CDCl3) 7.27 (2H, d, J 8.6 Hz, Ar-H), 6.84 (2H, d, J
8.7 Hz, Ar-H), 3.78 (3H, s, OCH3), 3.53 (1H, m, CH), 3.17 (1H, m,
CHaHb), 2.78 (1H, m, CHaHb), 2.32 (3H, s, CH3), 1.90–1.40 (6H, m,
3CH2); dC (100 MHz; CDCl3) 158.6, 137.8, 127.6, 113.7 (Ar-C),
61.7 (CH), 55.2 (OCH3), 47.9 (CH2), 35.0 (CH2), 25.9 (CH2), 25.5
(CH2).
4.3.2. Reduction product of 20 (R = Et)
4.3.7. 2-(4-Trifluoromethylphenyl)-piperidine 36
Product was formed in 94% isolated yield. Enantiomeric excess
was determined by HPLC analysis (Chiracel IB hexane/isopropa-
nol/diethylamine = 90:10:0.1, flow rate 0.5 mL/min, 290 nm): ts =
Product was formed in 70% isolated yield. Enantiomeric excess
was determined by GC analysis [Chrompac cyclodextrin-b-236M-
19 50 m, T = 145 °C, P = 15 psi, gas He, by use of the trifluoroaceta-
mide derivative,14 (R)-isomer 107.4 min, (S)-isomer 102.7 min];
25.3 min, tR = 34.0 min. ½a D26
¼ ꢁ50:3 (c 0.1, CH2Cl2) 89% ee (S)
ꢀ
(catalyst 11) (lit.11
½
a 2D0
ꢀ
¼ ꢁ51:9 (c 2.1, CH2Cl2) 83% ee (S)). dH
½
a 3D3
ꢀ
¼ þ14:4 (c 0.17, CHCl3) 50% ee (R);
m
max(neat)/cmꢁ1 2938,
(400 MHz; CDCl3) 6.60 (1H, s, Ar-H), 6.57 (1H, s, Ar-H), 3.85
(6H, s, 2xMeO), 3.82 (1H, br s, CH), 3.23 (1H, m, CHaHb), 2.96
(1H, m, CHaHb), 2.70 (2H, m, CH2), 1.90 (1H, m, CHaHb), 1.70
(1H, m, CHaHb), 1.60 (1H, br s, NH), 1.01 (3H, t, J 7.3 Hz, CH3).
2855, 1619, 1560, 1416, 1321, 1162, 1111, 1066, 1015, 837, 661;
dH (300 MHz; CDCl3) 7.55 (2H, d, J 8.1 Hz, Ar-H), 7.48 (2H, d, J
8.1 Hz, Ar-H), 3.61–3.68 (1H, m, NHCH), 3.27–3.32 (1H, m, NHCH-
aCHb), 2.76–2.84 (1H, m, NHCHaCHb), 1.95–1.42 (7H, m,

J. E. D. Martins et al. / Tetrahedron: Asymmetry 21 (2010) 2258–2264
2263
NHCH2CH2CH2); dC (75.5 MHz, CDCl3) 149.9 (Cq), 129.6 (Cq, q, J
32 Hz), 127.3 (CH), 125.7 (CH), 124.6 (Cq, q, J 272), 62.3 (Cq),
47.9 (CH2), 35.44 (CH2), 26.1 (CH2), 25.6 (CH2); HRMS calcd for
(1H, br s, OH), 1.86–1.68 (2H, m, CH2), 0.90 (3H, t, J 7.4 Hz, CH3);
dC (100.6 MHz; CDCl3) 144.6, 128.4, 127.5, 126.0 (Ar-C), 76.0
(CH), 31.9 (CH2), 10.2 (CH3).
C12H15NF3 [M+H] 230.1156, found 230.1151 (2.1 ppm error).
4.4.6. (R)-1-(3-Methylphenyl)ethanol
4.4. Ketone ATH by using N-methyl-TsDPEN-Ru(II) catalyst 7
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 125 °C, P = 15 psi, ketone 26.1 min, (R)-isomer 37.7 min, (S)-iso-
In a Schlenk tube were placed catalyst 7 (0.0059 g, 0.01 mmol)
and formic acid/triethylamine 5:2 complex (1 cm3). The system
was stirred for 30 min at 28 °C and then the ketone was added
(1 mmol). The reaction was monitored by GC until the specified
conversion was achieved. The mixture was filtered on a small silica
gel column (4:1 Hex/EtOAc) and then evaporated providing the
pure alcohol.
mer 38.8 min]; ½a D22
ꢀ
¼ þ54:2 (c 0.66, CHCl3) 94% ee (R) {lit.18
½
a 2D6
ꢀ
¼ ꢁ42:6 (c 0.62, CHCl3) for 84% ee (S)}. dH (300 MHz; CDCl3)
7.26–7.4 (4H, m, Ar-H), 4.80 (1H, q, J 6.4 Hz, PHCHOH), 2.34 (3H,
s, CH3), 1.44 (3H, d, J 6.4 Hz, CH3). dC (75 MHz; CDCl3) 145.8,
138.1, 128.4, 128.2, 126.1, 122.4 (Ar-C), 70.3 (CH), 25.1 (CH3),
21.4 (CH3).
4.4.1. (R)-1-Phenylethanol
4.4.7. (R)-1-(4-Chlorophenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, T = 115 °C,
P = 15 psi, gas He, ketone 22.7 min, (R)-isomer 35.5 min, (S)-isomer
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 130 °C, P = 15 psi, ketone 34.6 min, (R)-isomer 64.8 min, (S)-iso-
38.9 min]; ½a 2D2
ꢀ
¼ þ54:7 (c 0.68, CHCl3) 96% ee (R) {lit.7 ½a D22
ꢀ
¼ þ49
mer 71.4 min].
½
a 3D1
ꢀ
¼ þ51:1 (c 0.8, Et2O) 90% ee (R) {lit.19
(c 1.00, CHCl3) 98% ee (R)}; dH (400 MHz; CDCl3) 7.38–7.24 (5H, m,
Ar-H), 4.87 (1H, q, J 6.5 Hz, PhCHCH3), 2.07 (1H, br s, OH), 1.48 (3H,
d, J 6.5 Hz, CH3); dC (100.6 MHz; CDCl3) 145.6, 128.5, 127.5, 125.4
(Ar-C), 70.4 (CH), 25.2 (CH3).
½
a 2D7
ꢀ
¼ þ44:2 (c 1, Et2O) 92% ee (R)}; dH (400 MHz; CDCl3) 7.29
(4H, dd, J 5.3 and 3.0 Hz, Ar-H), 4.85 (1H, q, J 6.5 Hz, CH), 2.11
(1H, br s, OH), 1.45 (3H, d, J 6.5 Hz, CH3); dC (100.6 MHz; CDCl3)
144.3, 133.1, 128.6, 126.8, 69.7, 25.3.
4.4.2. (R)-1-(20-Chlorophenyl)ethanol
4.4.8. (R)-1-(3-Chlorophenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 150 °C, P = 15 psi, ketone 13.7 min, (R)-isomer 20.7 min, (S)-iso-
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, T = 140 °C,
P = 15 psi, gas He, ketone 22.7 min, (R)-isomer 41.3 min, (S)-isomer
mer 22.4 min];
½
a 2D4
ꢀ
¼ þ44 (c 0.4, CHCl3) 67% ee (R) {lit.16
44.1 min]; ½a 2D4
ꢀ
¼ þ39 (c 1, CHCl3) 90% ee (R) {lit.20
½
a 2D5
ꢀ
¼ ꢁ43:5
½
a 2D0
ꢀ
¼ þ41 (c 1.0, CHCl3) 67% ee (R)}; dH (400 MHz; CDCl3) 7.56
(c 1.08, CHCl3) 99% ee (S)}; dH (400 MHz; CDCl3) 7.36 (1H, br s,
ArH), 7.30–7.20 (3H, m, ArH), 4.85 (1H, q, J 6.4 Hz, PhCHCH3),
2.15 (1H, br s, OH), 1.46 (3H, d, J 6.4 Hz, CH3); dC (100.6 MHz;
CDCl3) 147.9, 134.4, 129.8, 127.5, 125.6, 123.6 (Ar-C), 69.8 (CH),
25.2 (CH3).
(1H, dd, J 7.8 and 1.8 Hz, Ar-H), 7.32–7.25 (2H, m, Ar-H), 7.18
(1H, td, J 7.7 and 1.8 Hz, Ar-H), 5.26 (1H, dq, J 6.3 and 2.8 Hz,
PhCHCH3), 2.33 (1H, br d, J 3.0 Hz, OH), 1.46 (3H, d, J 6.5 Hz,
CH3); dC (100.6 MHz; CDCl3) 143.1, 131.6, 129.4, 128.4, 127.2,
126.4 (Ar-C), 66.9 (CH), 23.5 (CH3).
4.4.9. (R)-1-(3-Bromophenyl)ethanol
4.4.3. (R)-1-(20-Bromophenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, T = 115 °C,
P = 15 psi, gas He, ketone 25.6 min, (R)-isomer 43.8 min, (S)-isomer
Enantiomeric excess and conversion were determined by GC
analysis through its acetate derivative [Chrompac cyclodextrin-b-
236M-19 50 m, gas He, T = 160 °C, P = 15 psi, ketone 15.4 min,
45.9 min];
½
a 2D4
ꢀ
¼ þ31:7 (c 0.7, CHCl3) 89% ee (R) {lit.21
(R)-isomer 21.8 min, (S)-isomer 23.6 min]; ½a D24
ꢀ
¼ þ32:7 (c 0.8,
½
a 2D0
ꢀ
¼ ꢁ30:3 (c 0.96, CHCl3) 92% ee (S)}. dH (400 MHz; CDCl3)
CHCl3) 64% ee (R) {lit.17
dH (300 MHz; CDCl3) 7.59–7.06 (4H, m, Ar-H), 5.20 (1H, q, J
½
a 2D0
ꢀ
¼ ꢁ39:5 (c 0.96, CHCl3) 81% ee (S)};
7.53–7.18 (4H, m, ArH), 4.84 (1H, q, J 6.4 Hz, CH), 2.10 (1H, br,
OH), 1.47 (3H, d, J 6.4 Hz, CH3). dC (100 MHz; CDCl3) 148.1, 130.4,
130.1, 128.5, 124.0, 122.6 (Ar-C), 69.7 (CH), 25.2 (CH3).
6.3 Hz, CH -OH), 1.44 (3H, d, J 6.3 Hz, CH3). dC (75 MHz; CDCl3)
a
144.0, 132.0, 128.1, 127.2, 126.0, 121.0 (Ar-C), 68.5 (CH), 22.9
(CH3).
4.4.10. (R)-1-(4-Trifluoromethylphenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 120 °C, P = 15 psi, ketone 12.7 min, R isomer 24.2 min, (S)-iso-
4.4.4. (R)-1-(4-Methylphenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 125 °C, P = 15 psi, ketone 28.3 min, (R)-isomer 35.2 min, (S)-iso-
mer 26.1 min]; ½a D22
ꢀ
¼ þ27 (c 0.4 in CH3OH) 88% ee (R) (lit.20
½
a 2D2
ꢀ
¼ ꢁ28:1 (c 1.13 in CH3OH) >99% ee (S)); dH (400 MHz; CDCl3)
mer 38.1 min]; ½a D22
ꢀ
¼ þ56:1 (c 0.6, CHCl3) 97% ee (R) {lit.18
7.60 (2H, d, J 8.3 Hz, ArH), 7.48 (2H, d, J 8.3 Hz, ArH), 4.95 (1H, q, J
6.4 Hz, PhCHCH3), 2.07–2.02 (1H, m, OH), 1.50 (3H, d, J 6.4 Hz,
CH3); dC (100.6 MHz; CDCl3) 149.7 (F3C),125.7, 125.5, 125.4 (Ar-
C), 69.8 (CH), 25.4 (CH3).
½
a 2D2
ꢀ
¼ ꢁ53:0 (c 0.55, CHCl3) for 92% ee (S)}. dH (300 MHz; CDCl3)
7.22–7.15 (2H, m, Ar-H), 7.12–7.06 (2H, m, Ar-H), 4.73 (1H, q, J
6.4 Hz, PHCHOH), 2.30 (3H, s, CH3), 1.38 (3H, d, J 6.4 Hz, CH3). dC
(75 MHz; CDCl3) 143.0, 136.9, 129.1, 125.4 (Ar-C), 70.0 (CH), 25.1
(CH3), 21.1 (CH3).
4.4.11. (R)-1-(2-Methylphenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 150 °C, P = 15 psi, ketone 12.3 min, (R)-isomer 18.5 min, (S)-iso-
4.4.5. (R)-1-Phenylpropan-1-ol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 115 °C, P = 15 psi, ketone 29.3 min, (R)-isomer 45.8 min, (S)-iso-
mer 19.8 min]; ½a D24
ꢀ
¼ þ64:7 (c 0.4, CHCl3) 81% ee (R) {lit.18
½
a 2D9
ꢀ
¼ ꢁ72:1 (c 0.53, CHCl3) for 91% ee (S)}; dH (300 MHz; CDCl3)
mer 47.9 min];
½
a 2D2
ꢀ
¼ þ51:5 (c 1, CHCl3) 93% ee (R) {lit.7
7.49–7.06 (4H, m, ArH), 5.05 (1H, q, J 6.4 Hz, CH), 2.30 (3H, s,
CH3), 1.41 (3H, d, J 6.4 Hz, CH3). dC (75 MHz; CDCl3) 143.9, 134.2,
130.3, 127.1, 126.3, 124.5, 66.7, 23.9, 18.9.
½
a 2D0
ꢀ
¼ þ47:0 (c 1.4, CHCl3) 95% ee (R)}; dH (400 MHz; CDCl3)
7.36–7.24 (5H, m, Ar-H), 4.57 (1H, t, J 6.5 Hz, PhCH(OH)CH2), 2.00

2264
J. E. D. Martins et al. / Tetrahedron: Asymmetry 21 (2010) 2258–2264
Buitrago, E.; Ryberg, P.; Adolfsson, H. Chem. Eur. J. 2009, 15, 5709–5718; (n) Wu,
X.; Xiao, J. Chem. Commun. 2007, 2449–2466; (o) Wu, X.; Li, X.; King, F.; Xiao, J.
Angew. Chem., Int. Ed. 2005, 44, 3407–3411; (p) Šterk, D.; Stephan, M. S.; Mohar,
B. Tetrahedron: Asymmetry 2002, 13, 2605–2608.
4.4.12. (R)-1-(3-Trifluoromethylphenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis [Chrompac cyclodextrin-b-236M-19 50 m, gas He,
T = 120 °C, P = 15 psi, ketone 16.7 min, (R)-isomer 39.8 min, (S)-iso-
3. (a) Wills, M. In Modern Reduction Methods; Andersson, P. G., Munslow, I. J., Eds.;
Wiley-VCH: Weinheim, 2008; pp 271–296. Chapter 11; (b) Uematsu, N.; Fujii,
A.; Hasjiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917;
(c) Williams, G. D.; Wade, C. E.; Wills, M. Chem. Commun. 2005, 4735–4737; (d)
Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841–843; (e) Blacker, J.; Martin, J. Scale up
studies in Asymmetric Transfer Hydrogenation. In Asymmetric Catalysis on an
Industrial Scale: Challenges, Approaches and Solutions; Blaser, H. U., Schmidt, E.,
Eds.; Wiley, 2004; pp 201–216; (f) Sun, X.; Manos, G.; Blacker, J.; Martin, J.;
Gavriilidis, A. Org. Proc. Res. Dev. 2004, 8, 909–914; (g) Guijarro, D.; Pablo, O.;
Yus, M. Tetrahedron Lett. 2009, 50, 5386–5388; (h) Åberg, J. B.; Samec, J. S. M.;
Bäckvall, J.-E. Chem. Commun. 2006, 2771–2773; (i) Casey, C. P.; Clark, T. B.;
Guzei, I. A. J. Am. Chem. Soc. 2007, 129, 11821–11827; (j) Samec, J. S. M.; Éll, A.
H.; Åberg, J. B.; Primalov, T.; Eriksson, L.; Bäckvall, J.-E. J. Am. Chem. Soc. 2006,
128, 14293–14305; (k) Casey, C. P.; Johnson, J. B. J. Am. Chem. Soc. 2005, 127,
1883–1894.
4. (a) Takamura, H.; Ando, J.; Abe, T.; Murata, T.; Kadota, I.; Uemura, D.
Tetrahedron Lett. 2008, 49, 4626–4629; (b) Fu, R.; Chen, J.; Guo, L.-C.; Ye, J.-L.;
Ruan, Y.-P.; Huang, P.-Q. Org. Lett. 2009, 11, 5242–5245; (c) Kumarasway, G.;
Ramakrishna, G.; Naresh, P.; Jagadeesh, B.; Sridhar, B. J. Org. Chem. 2009, 74,
8468–8471; (d) Zhang, B.; Xu, M.-H.; Lin, G.-Q. Org. Chem. 2009, 11, 4712–4715.
5. (a) Xue, D.; Chen, Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G. J. Org. Chem.
2005, 70, 3584–3591; (b) Koike, T.; Ikariya, T. Adv. Synth. Catal. 2004, 346, 37–
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N. A.; Rodriguez-Apodaca, R.; Aguirre, G.; Parra-Hake, M.; Cole, T.; Somanathan,
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ARKIVOC 2005, 6, 162–171.
mer 43.7 min]; ½a D21
ꢀ
¼ þ27:6 (c 0.7, CH3OH) 89% ee (R) {lit.22
½
a 2D2
ꢀ
¼ ꢁ27:9 (c 1.64, CH3OH) >99% ee (S)}; dH (400 MHz; CDCl3)
7.64 (1H, s, ArH), 7.56–7.43 (3H, m, ArH), 4.95 (1H, q, J 6.5 Hz,
PhCHCH3), 2.10 (1H, br s, OH), 1.50 (3H, d, J 6.5 Hz, CH3); dC
(100.6 MHz; CDCl3) 146.7 (F3C), 128.9, 128.8, 124.3, 124.2, 122.2,
122.2 (Ar-C), 69.8 (CH), 25.4 (CH3).
4.4.13. (R)-1-(40-Bromophenyl)ethanol
Enantiomeric excess and conversion were determined by GC
analysis through its acetate derivative [Chrompac cyclodextrin-b-
236M-19 50 m, gas He, T = 150 °C, P = 15 psi, ketone 28.5 min,
(R)-isomer 45.6 min, (S)-isomer 48.5 min]; ½a D24
¼ þ38:6 (c 1.2,
ꢀ
CHCl3) 90% ee (R) {lit.23
½
a 2D6
ꢀ
¼ þ32:8 (c 1.6 CHCl3) 80% ee (R)};
dH (400 MHz; CDCl3) 7.48–7.44 (2H, m, ArH), 7.25–7.21 (2H, m,
ArH), 4.84 (1H, q, J 6.4 Hz, CH(OH)CH3), 2.03 (1H, br s, OH), 1.45
(3H, d, J 6.5 Hz, CH3); dC (100.6 MHz; CDCl3) 144.8 (ArC-Br),
131.6, 127.2, 121.2 (Ar-C), 69.8 (CH), 25.3 (CH3).
Acknowledgments
6. (a) Schlatter, A.; Kunda, M. K.; Woggon, W.-D. Angew. Chem., Int. Ed. 2004, 43,
6731–6734; (b) Vriamont, N.; Govaerts, B.; Grenouillet, P.; de Bellefon, C.;
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Mortreux, A.; Carpentier, J.-F. Tetrahedron Lett. 2001, 42, 1899–1901; (d) Watts,
C. C.; Thoniyot, P.; Cappuccio, F.; Verhagen, J.; Gallagher, B.; Singaram, B.
Tetrahedron: Asymmetry 2006, 17, 1301–1307.
We thank the EPSRC (Project Grant No. EP/F019424/1) for gener-
ous financial support of this project. Dr. B. Stein and colleagues of
the EPSRC National Mass Spectroscopic service (Swansea) are
thanked for HRMS analysis of certain compounds. We acknowledge
the use of the EPSRC Chemical Database Service at Daresbury.24
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