Synthesis of novel nitrogen-containing ligands for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(03)00356-2

New nitrogen-containing ligands derived from the (1R,2R)-trans-cyclohexanediamine chiral core unit have been synthesized and fully characterized. Their catalytic activity was tested in the asymmetric addition of diethylzinc to aldehydes leading to the res

Full text of DOI:10.1016/S0957-4166(03)00356-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1989–1994
Synthesis of novel nitrogen-containing ligands for the
enantioselective addition of diethylzinc to aldehydes
Mar´ıa Hechavarr´ıa Fonseca,a Ernst Eibler,a Manfred Zabelb and Burkhard Ko¨niga,*
aInstitut fu¨r Organische Chemie, Universita¨t Regensburg, D-93040 Regensburg, Germany
bZentrale Analytik, Universita¨t Regensburg, D-93040 Regensburg, Germany
Received 27 March 2003; revised 14 April 2003; accepted 24 April 2003
Abstract—New nitrogen-containing ligands derived from the (1R,2R)-trans-cyclohexanediamine chiral core unit have been
synthesized and fully characterized. Their catalytic activity was tested in the asymmetric addition of diethylzinc to aldehydes leading
to the respective secondary alcohols with enantioselectivities of up to 74% ee. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Synthesis of ligands
The search for new ligands for asymmetric catalysis is a
field of continuous interest. To facilitate practical appli-
cations new ligands should be easy to prepare from
simple and accessible starting materials.1 In this context
the use of nitrogen-containing ligands is growing.
Recent reports have shown that these compounds are
suitable for many types of catalysis including heteroge-
neous catalysis.2,3 High stability and good accessibility
from the chiral pool are particular advantages of nitro-
gen-containing ligands if compared with phosphines.
The synthesis shown in Scheme 1 yields sulfonamides
4a–f in three steps with yields higher than those previ-
ously reported by Katsuki et al. for the synthesis of a
similar achiral Schiff bases.7 The commercially avail-
able o-aminobenzyl alcohol 2 is used as starting mate-
rial.8 It is reacted with different sulfonyl chlorides in the
presence of pyridine to give the corresponding N-pro-
Bis(sulfonamide)-based ligands derived from (1R,2R)-
trans-cyclohexanediamine 1 have successfully been
applied as catalysts for many asymmetric transforma-
tions, such as the Simmons–Smith reaction4 and the
addition of organozinc reagents to carbonyl
compounds.5,6
We report here the synthesis of novel tetradentate
sulfonamide ligands, bearing the same homochiral core
and additional coordination sites. The tetraza ligands
were used as catalysts for the asymmetric alkylation of
aldehydes with diethylzinc.
* Corresponding
burkhard.koenig@chemie.uni-regensburg.de
author.
Fax:
+49-941-943-1717;
e-mail:
Scheme 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00356-2

1990
M. Hecha6arr´ıa Fonseca et al. / Tetrahedron: Asymmetry 14 (2003) 1989–1994
tected alcohols 3a–f in almost quantitative yields (Table
1). In the 1H NMR spectra of the six derivatives a
broad singlet at about l=8 is observed, corresponding
to the sulfonamide proton, which confirms the success-
ful substitution. By use of PCC9 the alcohols are oxi-
dized to the corresponding aldehydes 4a–f in very good
yields (Table 1). The Schiff bases 5a–f were obtained in
good yields from the condensation of chiral (1R,2R)-
trans-cyclohexanediamine and the respective aldehydes
in ethanol in a ratio of 1:2 (Table 1).
Dangel and Polt have proposed a mechanism for the
asymmetric addition of diethylzinc with tetraaza-lig-
ands, in which it was assumed that two Zn atoms are
involved in the alkyl transfer: the ‘inner’ Zn atom and
the ‘outer’ Zn atom.10 This mechanism could explain
the catalytic activity of our ligands. When diethylzinc
was added to the ligand a tetracoordinate sulfonamido
zinc complex is formed (Scheme 3). By coordination to
the Lewis acidic Zn atom the aldehyde is activated and
its electrophilicity is enhanced towards attack by the
diethylzinc.11 On the other hand, the ‘outer’ zinc atom
is coordinated (‘solvated’) by exchangeable oxygens.
This increases its nucleophilicity and favors the alkyl
transfer.
Table 1. Yields of substituted benzylalcohols 3, aldehydes
4 and Schiff bases 5
R
3 (%)
4 (%)
5 (%)
a: p-MeC6H4
b: C6H5
c: p-MeOC6H4
d: p-NO2C6H4
e: p-ClC6H4
f: 2,4,6-Cl3C6H2
98
95
100
100
100
100
74
61
90
95
99
90
85
74
78
91
69
71
2.2. Catalysis
The sulfonamide derivatives 5a–f (Scheme 1) were
screened in the asymmetric alkylation of benzaldehyde
6a with diethylzinc (Scheme 2).
Scheme 3.
Screening the synthesized ligands revealed that only the
sulfonamide-derivatives 5a and 5b promote the asym-
metric alkylation of benzaldehyde with diethylzinc in
high yields and significant enantioselectivities.
In order to determine the optimal amount of the ligand
needed for the addition of diethylzinc to benzaldehyde
6a, experiments with variable quantities of ligand 5a
were carried out. Low yields and low enantiomeric
excesses of 7a were observed using 1 or 2.5 mol% of the
catalyst (48 h reaction time). However, quantitative
yield and good enantioselectivity were achieved when 5
mol% were used. Further increases to 7 or 10 mol% of
the catalyst did not improve the progress of the cataly-
sis. Thus, for all subsequent reactions 5 mol% of cata-
lyst were used.
Scheme 2.
Table 2 summarizes the yields and enantioselectivities
of (R)-1-phenylpropanol 7a reached with the sulfon-
amides (5 mol%) by addition of 2.5 equiv. of diethyl-
zinc and reaction in toluene at room temperature over
24 h. Quantitative yields of the secondary alcohol and
good asymmetric induction (70 and 74% ee, respec-
tively) were obtained with ligands 5a and 5b. A lower
yield, but still good enantioselectivity was obtained
with the p-methoxybenzene sulfonamide substituted lig-
and 5c. Ligands 5d–f gave less satisfactory results.
Encouraged by the results obtained with the sulfon-
amide derivatives 5a and 5b in the addition of diethyl-
zinc to benzaldehyde 6a the asymmetric alkylation was
extended to other aldehydes: p-chlorobenzaldehyde 6b,
p-methoxybenzaldehyde 6c (Scheme 2) and furfural 8
(Scheme 4) were selected as substrates. The reactions
were run under the same conditions described above
but at two different temperatures (0 and 25°C). The
results are summarized in Table 3. As expected, the
Table 2. Results obtained using the diimine-sulfonamide
ligands 5a–f in the asymmetric diethylzinc addition to benz-
aldehyde 6a
Entry
Catalyst
Yield (%)
ee (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
100
100
74
70 (R)
74 (R)
70 (R)
38 (R)
55 (R)
21 (R)
43
47
34a
a Yield determined by GC.
Scheme 4.

M. Hecha6arr´ıa Fonseca et al. / Tetrahedron: Asymmetry 14 (2003) 1989–1994
1991
Table 3. Addition of diethylzinc to p-substituted benzaldehydes 6b and 6c and heteroaromatic aldehyde 8 using the diimine-
sulfonamides 5a and 5b12
Entry
Aldehyde R
Ligand
Temp (°C)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
H
H
H
H
Cl
Cl
Cl
Cl
OMe
OMe
OMe
OMe
Furfural
Furfural
Furfural
Furfural
5a
5a
5b
5b
5a
5a
5b
5b
5a
5a
5b
5b
5a
5a
5b
5b
0
25
0
25
0
25
0
25
0
25
0
25
0
25
0
25
89
100
93
100
21
60
23
65
53
70
51
76
49
61
21
44
71 (R)
70 (R)
75 (R)
74 (R)
64 (R)
71 (R)
69 (R)
74 (R)
45 (R)
62 (R)
57 (R)
56 (R)
70 (R)
28 (R)
69 (R)
37 (R)
9
10
11
12
13
14
15
16
Table 4. Catalyzed addition of diethylzinc to benzaldehyde
yields obtained with both ligands and for all aldehydes
used were higher at room temperature (entries 6, 8, 10,
12, 14, and 16) than at 0°C (entries 5, 7, 9, 11, 13, 15),
but they were much lower than those obtained with
benzaldehyde (entries 1–4). The presence of an electron-
donor substituent (OMe) at the para-position of alde-
hyde 6c contributes to an increase in the yield of the
secondary alcohol 7c, while the electron-acceptor sub-
stituent (Cl, aldehyde 6b) in the same position causes
the opposite effect.
at increased temperatures.
Entry
Ligand
Temp (°C)
Yield (%)
ee (%)
1
2
3
4
5a
5a
5b
5b
50
25
50
25
100
100
100
100
62
70
67
74
Unexpectedly, the enantioselectivities achieved for both
para-substituted aromatic secondary alcohols 7b and 7c
were higher when the reactions were carried out at
room temperature (entries 6, 8, and 10). For the het-
eroaromatic aldehyde furfural 8 the opposite effect was
observed, i.e. at 0°C a better enantioselectivity (70 and
69% ee, entries 13 and 15) than at room temperature.
Therefore the effect of Ti(OiPr)4 on the activity of
ligand 5a in the addition of diethylzinc to benzaldehyde
was investigated. A mixture of ligand (5 mol%) and
Ti(OiPr)4 (0.6 or 1.2 equiv.) dissolved in toluene was
stirred for 1 h under reflux to form the titanium com-
plex. After cooling to −30°C, diethylzinc (2.5 equiv.)
and benzaldehyde were added. The yield (36 and 48%
yield, respectively) and enantioselectivities (6 and 3%
ee, respectively, versus 70% ee without Lewis acid) of
1-phenylpropanol 7a decrease drastically under these
conditions. A likely rationale for this observation is the
formation of a complex of titanium and the chiral
sulfonamide 5a, analogous to the structurally character-
ized complex by Walsh.14 With the addition of
Ti(OiPr)4, sulfonamides are deprotonated and titanium
is coordinated by sulfonamido nitrogens and two sulfo-
nyl oxygens. This may lead to a less favorable catalyst
geometry.
The attempts to alkylate heptanal with diethylzinc in
the presence of the chiral sulfonamides 5a and 5b were
unsuccessful. No conversion could be detected after 4
days, neither at 0°C nor at room temperature.
To investigate the surprising increase in enantioselectiv-
ity with temperature in the reactions of 5a and 5b and
para-substituted benzaldehydes an additional set of
reactions was performed with both ligands13 at 50°C.
Using benzaldehyde 6a as substrate, quantitative yields
of 1-phenylpropanol 7a were achieved after 5 h. Enan-
tioselectivities decrease only slightly (by approx. 8%) in
comparison with the reaction at room temperature
(Table 4).
3. Conclusions
We have prepared six new tetradentate sulfonamide
ligands with (1R,2R)-trans-cyclohexane diamine as the
homochiral core. The ligands are available in three
simple synthetic steps in very good yields and large
amounts. All ligands were tested in the asymmetric
alkylation of benzaldehyde 6a with diethylzinc. Sulfon-
amides 5a–f showed catalytic activity in the asymmetric
reaction, reaching in case of 5a and 5b quantitative
yields of the chiral alcohol 7a in satisfying enantioselec-
2.2.1. Asymmetric alkylation using Ti(OiPr)4 as Lewis
acid. Ohno and Kobayashi reported that the asymmet-
ric alkylation using bidentate sulfonamide ligands 1 as
catalysts is rather slow even at room temperature and
yields chiral secondary alcohols in moderate yields and
enantioselectivities.5a But when this reaction was car-
ried out in the presence of Ti(OiPr)4, very good yields
and enantioselectivities were obtained.5b

1992
M. Hecha6arr´ıa Fonseca et al. / Tetrahedron: Asymmetry 14 (2003) 1989–1994
tivities 70 and 74% ee. A likely mechanism for the
catalysis with these ligands is suggested on the basis of
reported structures of tetraaza-complexes.
4.2.4. N-(2-Hydroxymethylphenyl)-4-nitrobenzenesulfon-
amide 3d. Obtained from o-aminobenzyl alcohol 2 (1 g,
8.1 mmol in 30 ml of CHCl3), pyridine (0.8 ml) and
4-nitrobenzenesulfonyl chloride (1.96 g, 8.8 mmol, in 9
ml of CHCl3) as a yellow solid (2.5 g, 8.1 mmol, 100%);
1H NMR (250 MHz, CDCl3): l=2.48 (bs, OH), 4.31 (s,
2H, CH2), 7.09 (m, 2H), 7.19–7.24 (m, 1H), 7.37 (d, 1H,
J=7.9 Hz), 7.89–7.94 (m, 2H), 8.21–8.26 (m, 2H), 8.8
(bs, 1H, NH).
4. Experimental
4.1. General remarks
The catalytic reactions were carried out in Schlenk
flasks under a nitrogen atmosphere and using dry tolu-
ene. The enantioselectivity of the products was deter-
mined by GC. To test the reproducibility of the results
obtained, each catalysis was performed at least twice
under exactly the same conditions.
4.2.5. N-(2-Hydroxymethylphenyl)-4-chlorobenzenesul-
fonamide 3e. Obtained from o-aminobenzyl alcohol 2 (1
g, 8.1 mmol in 30 ml of CHCl3), pyridine (0.8 ml) and
4-chlorobenzenesulfonyl chloride (1.87 g, 8.8 mmol in 9
ml of CHCl3) as a white solid (2.4 g, 8.1 mmol, 100%);
1H NMR (250 MHz, CDCl3): l=2.12 (s, OH), 4.34 (s,
2H, CH2), 7.06–7.1 (m, 2H), 7.18–7.25 (m, 1H), 7.35–
7.4 (m, 3H), 7.64–7.7 (m, 2H), 8.44 (bs, 1H, NH).
(1R,2R)-trans-Cyclohexanediamine15 was synthesized
according to the literature procedure. The optical
purity measured [h]2D5=−25 for the chiral diamine
matches the reported literature value16 [h]D25=−25.5 (c
5, HCl 1 M).
4.2.6.
N-(2-Hydroxymethylphenyl)-2,4,6-trichloroben-
zenesulfonamide 3f. Obtained from o-aminobenzyl alco-
hol 2 (180 mg, 1.46 mmol in 8 ml of CHCl3), pyridine
(0.14 ml) and 2,4,6-trichlorobenzenesulfonyl chloride
(450 mg, 1.6 mmol in 8 ml of CHCl3). During the
reaction the color of the mixture changes from yellow
to red. Product 3f was obtained in quantitative yield
(536 mg, 1.46 mmol, 100%) and was directly used for
oxidation.
4.2. General procedure (GP1) for the synthesis of sub-
stituted amino alcohols 3
A solution of o-aminobenzyl alcohol 2 and pyridine in
dry CHCl3 was treated dropwise with a solution of the
appropriate sulfonyl chloride in CHCl3 at room tem-
perature. The reaction mixture was stirred for 3 h,
evaporated to dryness, the resulting residue was taken
up in ethyl acetate and saturated aqueous ammonium
chloride. The organic phase was separated, dried over
Na2SO4, filtered and evaporated to give the N-
sulfonamides.
4.3. General procedure (GP2) for the oxidation of sub-
stituted amino alcohols to aldehydes 4
To a stirred suspension of PCC in CH2Cl2 was added
dropwise a solution of the N-substituted amino alcohol
3 in the same solvent. The mixture was stirred for 3 h
at room temperature. The liquid was decanted from the
solid which was washed several times with Et2O. The
combined organic layer was passed through a short pad
of silica gel and evaporated to give the product. The
product was recrystallized from the specified solvent.
4.2.1. N-(2-Hydroxymethylphenyl)-4-methylbenzenesul-
fonamide 3a. Obtained from o-aminobenzyl alcohol 2 (2
g, 16.2 mmol) in 60 ml of CHCl3, pyridine (1.6 ml) and
4-toluenesulfonyl chloride (3.4 g, 18 mmol) in 17 ml of
1
CHCl3 as a white solid (4.4 g, 15.9 mmol, 98%); H
NMR (250 MHz, CDCl3): l=2.38 (s, 3H, CH3), 4.39
(s, 2H, CH2), 7.06–7.09 (m, 2H), 7.19–7.28 (m, 3H),
7.42 (d, 1H, J=7.9 Hz), 7.64 (dd, 2H, J=4.7, 1.8 Hz).
4.3.1. N-(2-Formylphenyl)-4-methylbenzenesulfonamide
4a. A suspension of PCC (5.13 g, 24 mmol) in CH2Cl2
(80 ml) and alcohol 3a (4.4 g, 15.9 mmol) in the same
solvent (160 ml) was reacted as described above. The
raw product was crystallized from CHCl3/EtOH (1:5,
24 ml) to yield 4a as white solid (3.2 g, 11.7 mmol,
4.2.2. N-(2-Hydroxymethylphenyl)benzenesulfonamide
3b. Obtained from o-aminobenzyl alcohol 2 (4 g, 33
mmol) benzenesulfonyl chloride (4.6 ml, 36 mmol) and
pyridine (3.12 ml) in CHCl3 (120+35 ml) as a white
solid (8.2 g, 31 mmol, 95%); 1H NMR (250 MHz,
CDCl3): l=4.3 (s, 2H, CH2), 7.06 (dd, 2H, J=5.4 Hz),
7.18–7.24 (m, 1H), 7.35–7.44 (m, 3H), 7.48–7.52 (m,
1H), 7.71–7.75 (m, 2H), 8.34 (bs, 1H, NH).
1
74%); H NMR (250 MHz, CDCl3): l=2.37 (s, 3H),
7.13–7.25 (m, 3H), 7.47–7.79 (m, 5H), 9.83 (s, 1H,
CHO), 10.79 (bs, 1H, NH).
4.3.2. N-(2-Formylphenyl)benzenesulfonamide 4b. A sus-
pension of PCC (5 g, 23.3 mmol) in CH2Cl2 (75 ml) and
the protected alcohol 3b (4.1 g, 15.5 mmol) in CH2Cl2
(155 ml) was reacted according to the GP2. After
crystallization from CHCl3/EtOH (1:5, 12 ml) a white
4.2.3. N-(2-Hydroxymethylphenyl)-4-methoxybenzene-
sulfonamide 3c. Obtained from o-aminobenzyl alcohol 2
(4 g, 33 mmol), 4-methoxybenzenesulfonyl chloride
(7.44 g, 36 mmol), pyridine (3.1 ml), and CHCl3 (120+
34 ml) as a light yellow solid (8.6 g, 31 mmol, 100%);
1H NMR (250 MHz, CDCl3): l=3.82 (s, 3H, OCH3),
4.40 (d, 2H, J=4.1 Hz, CH2), 6.86–6.89 (m, 2H),
7.07–7.1 (m, 2H), 7.19–7.28 (m, 1H), 7.41 (d, 1H,
J=7.9 Hz), 7.66–7.70 (m, 2H), 7.88 (bs, 1H, NH).
1
solid (2.5 g, 9.5 mmol, 61%) was obtained; H NMR
(250 MHz, CDCl3): l=7.17 (ddd, 1H, J=7.5, 6.7, 0.77
Hz), 7.42–7.59 (m, 5H), 7.66 (dd, 1H, J=1.6 Hz), 7.89
(dd, 2H, J=6.7, 1.6 Hz), 9.83 (s, 1H, CHO), 10.82 (bs,
1H, NH).

M. Hecha6arr´ıa Fonseca et al. / Tetrahedron: Asymmetry 14 (2003) 1989–1994
1993
4.3.3.
N-(2-Formylphenyl)-4-methoxybenzenesulfon-
J=8.2 Hz), 6.91 (ddd, 2H, J=7.7, 0.91 Hz), 7.16–7.27
(m, 4H), 7.43 (d, 4H, J=8.2 Hz), 7.48 (d, 2H, J=7.7
Hz), 8.46 (s, 2H, NꢀCH), 13.20 (s, 2H, NH); 13C NMR
(62.9 MHz, CDCl3): l=21.25, 24.29, 33.58, 73.44,
116.93, 120.39, 122.29, 127.08, 129.27, 131.27, 133.71,
136.45, 139.38, 143.1, 164.1; MS (ESI), m/z (%): 629.1
(100) [MH+]. Anal. calcd for C34H36N4O4S2: C, 64.95;
H, 5.78; N, 8.92. Found: C, 64.65; H, 5.79; N, 8.86.
amide 4c. The alcohol 3c (8.6 g, 29 mmol) in 320 ml of
CH2Cl2, PCC (10 g, 46.57 mmol) in 160 ml of CH2Cl2
gave aldehyde 4c as a white solid (7.7 g, 26.4 mmol,
1
90%); H NMR (250 MHz, CDCl3): l=3.81 (s, 3H),
6.88–6.91 (m, 2H), 7.16–7.19 (m, 1H), 7.47–7.85 (m,
5H), 9.82 (s, 1H, CHO), 10.75 (bs, 1H, NH).
4.3.4. N-(2-Formylphenyl)-4-nitrobenzenesulfonamide 4d.
To a suspension of PCC (2.8 g, 13 mmol) in 40 ml of
CH2Cl2 was added a solution of the protected alcohol
3d (2.7 g, 8.7 mmol in 80 ml of CH2Cl2) according to
GP2. After crystallization from CHCl3/EtOH (1:7, 16
ml) 4d as yellow solid (2.5 g, 8.3 mmol, 95%) was
4.4.2.
N,N%-Bis-(benzenesulfonamidphenyl-2-ylmethyl-
ene)cyclohexane-1R,2R-diamine 5b. The aldehyde
4b (997 mg, 3.8 mmol) and (1R,2R)-trans-cyclohexane-
diamine (218 mg, 1.9 mmol) were solved in dry EtOH
(7 ml), and the reaction mixture was refluxed for 1 h
under nitrogen. After work-up and recrystallization
from EtOH (5 ml), yellow crystals (850 mg, 1.41
mmol, 74%) were obtained; mp=185–186°C; IR
(KBr): w=3441, 3060, 2933, 2858, 1634, 1579, 1500,
1444, 1421, 1199, 1157, 1089, 931, 862, 752, 713 cm−1;
1H NMR (250 MHz, CDCl3): l=1.51–1.59 (m, 2H),
1.78–1.93 (m, 6H), 3.51–3.55 (m, 2H), 6.88–7.05 (m,
6H), 7.16–7.29 (m, 6H), 7.45 (d, 2H, J=8.0 Hz), 7.62
(dd, 4H, J=8.0 Hz), 8.44 (s, 2H, NꢀCH), 13.3 (s, 2H,
NH–SO2); 13C NMR (62.9 MHz, CDCl3): l=24.25,
33.46, 73.33, 116.99, 120.35, 122.43, 127.01, 128.75,
131.41, 132.52, 133.65, 139.24, 139.56, 164.12; MS
(ESI), m/z (%): 601.2 (100) [MH+]. Anal. calcd for
C32H32N4O4S2: C, 63.98; H, 5.37; N, 9.33; S, 10.67.
Found: C, 64.19; H, 5.65; N, 9.53; S, 10.66.
1
obtained; H NMR (250 MHz, DMSO-d6): l=7.08 (d,
1H, J=7.96 Hz), 7.39 (t, 1H, J=7.5 Hz), 7.58 (ddd,
1H, J=7.5, 1.6 Hz), 7.81 (dd, 1H, J=7.5, 1.6 Hz), 7.94
(ddd, 2H, J=6.9, 4.4, 2.4 Hz), 8.36 (ddd, 2H, J=6.9,
4.4, 2.4 Hz), 10.06 (s, 1H, CHO), 10.84 (bs, 1H, NH).
4.3.5. N-(2-Formylphenyl)-4-chlorobenzenesulfonamide
4e. To a stirred suspension of PCC (2.8 g, 12.9 mmol)
in 40 ml of CH2Cl2 was added a solution of alcohol 3e
(2.6 g, 8.6 mmol) in 80 ml of CH2Cl2 following the
described procedure. After work-up aldehyde 4e (2.5 g,
1
8.5 mmol, 99%) was obtained; H NMR (250 MHz,
CDCl3): l=7.17–7.24 (m, 1H), 7.42 (dt, 2H, J=6.7, 4.4
Hz), 7.50–7.70 (m, 3H), 7.82 (dt, 2H, J=6.7, 4.4 Hz),
9.83 (s, 1H, CHO), 10.82 (bs, 1H, NH).
4.3.6. N-(2-Formylphenyl)-2,4,6-trichlorobenzenesulfon-
amide 4f. Alcohol 3f (536 mg, 1.5 mmol in CH2Cl2 (70
ml) was added to a suspension of PCC (472 mg, 2.2
mmol) in 50 ml of CH2Cl2 according to GP2. After
work-up the product was obtained as a yellow solid
(480 mg, 1.3 mmol, 90%); 1H NMR (250 MHz, CDCl3):
l=7.20 (ddd, 1H, J=7.5, 6.4 Hz), 7.44 (s, 2H), 7.55
(ddd, 1H, J=7.5, 6.4, 1.5 Hz), 7.64–7.69 (m, 2H), 9.89
(s, 1H, CHO), 11.56 (bs, 1H, NH).
4.4.3. N,N%-Bis-(4-methoxybenzenesulfonamidphenyl-2-
ylmethylene)cyclohexane-(1R,2R)-diamine 5c. Aldehyde
4c (2 g, 6.87 mmol) and (1R,2R)-trans-cyclohexanedi-
amine (0.39 g, 3.43 mmol) in EtOH (25 ml) reacted for
1 h as described by GP3. A yellow powder (3.5 g, 5.4
mmol, 78%) was obtained after crystallization from
EtOH (16 ml); mp=200–202°C; IR (KBr): w=3574,
2929, 2856, 2360, 2341, 1627, 1595, 1577, 1497, 1338,
1261, 1154, 1093, 925 cm−1; 1H NMR (400 MHz,
CDCl3): l=1.53–1.64 (m, 2H), 1.78–1.96 (m, 6H), 3.48
(s, 6H), 3.62–3.64 (m, 2H), 6.19 (dd, 4H, J=7.0, 2.0
Hz), 6.97 (dd, 2H, J=7.5, 6.7 Hz), 7.22–7.3 (m, 2H),
7.33 (dd, 2H, J=7.5 Hz), 7.43 (dd, 4H, J=6.7, 2.0 Hz),
7.52 (d, 2H, J=8.2 Hz), 8.55 (s, 2H, NꢀCH), 13.22 (s,
2H, NH–SO2); 13C NMR (101 MHz, CDCl3): l=24.26,
33.67, 55.24, 73.43, 113.68, 116.75, 120.3, 122.2, 129.22,
130.61, 131.22, 133.7, 139.4, 162.48, 163.92; MS (ESI),
m/z (%): 661.2 (100) [MH+]. Anal. calcd for
C34H36N4O6S2: C, 61.80; H, 5.49; N, 8.48. Found: C,
61.73; H, 5.45; N, 8.43.
4.4. General procedure (GP3) for the synthesis of
imines 5
(1R,2R)-trans-Cyclohexane diamine and the corre-
sponding aldehyde 4 were dissolved in dry EtOH in a
molar ratio of 1:2, respectively. The resulting mixture
was refluxed under nitrogen atmosphere for the time
stated and the solvent was evaporated in vacuum. The
crude Schiff base was recrystallized in the indicated
solvent.
4.4.1.
N,N%-Bis-(4-methylbenzenesulfonamidphenyl-2-
4.4.4.
N,N%-Bis-(4-nitrobenzenesulfonamidphenyl-2-
ylmethylene)cyclohexane-1R,2R-diamine 5a. Aldehyde
4a (1.6 g (5.7 mmol) and (1R,2R)-trans-cyclohexanedi-
amine (326 mg, 2.86 mmol) were solved in 15 ml of dry
EtOH. The reaction mixture was refluxed for 1 h.
Yellow crystals of the Schiff base 5a (1.54 g, 2.45 mmol,
85%) were obtained after recrystallization from EtOH
(10 ml); mp=273–274°C; IR (KBr): w=3649, 3443,
2925, 2860, 2361, 1630, 1599, 1578, 1497, 1449, 1411,
ylmethylene)cyclohexane-(1R,2R)-diamine 5d. (1R,2R)-
trans-Cyclohexanediamine (415 mg, 3.64 mmol) and
the aldehyde 4d (2.23 g, 7.28 mmol) in dry EtOH (20
ml) were refluxed for 3 h following GP3. The product
was obtained as a yellow solid (2.3 g, 3.3 mmol, 91%);
mp=118–120°C; IR (KBr): w=3576, 3448, 3103, 2933,
2861, 1630, 1606, 1578, 1531, 1499, 1347, 1311, 1088,
1043, 760, 733 cm−1; 1H NMR (250 MHz, CDCl3):
l=1.53–1.98 (m, 8H), 3.57–3.61 (m, 2H), 7.01 (dt, 2H,
J=8.0, 1.1 Hz), 7.29–7.34 (m, 4H), 7.50 (d, 2H, J=8.0
Hz), 7.72 (s, 8H), 8.5 (s, 2H, NꢀCH), 13.62 (s, 2H,
1338, 1288, 1157, 1089, 928, 811, 757 cm−1; H NMR
(250 MHz, CDCl3): l=1.48–1.59 (m, 2H), 1.72–1.96
(m, 6H), 2.06 (s, 6H), 3.54–3.58 (m, 2H), 6.62 (d, 4H,
1

1994
M. Hecha6arr´ıa Fonseca et al. / Tetrahedron: Asymmetry 14 (2003) 1989–1994
NH–SO2); 13C NMR (101 MHz, CDCl3): l=24.17,
33.58, 73.15, 116.96, 120.21, 123.22, 123.88, 128.17,
132.07, 133.82, 138.75, 145.22, 149.68, 164.33; MS
(ESI), m/z (%): 691.2 (100) [MH+].
enantiomeric excess was determined by chiral GC
(Column Restek Rt bDEX). The absolute configuration
was determined by polarometric measurements and
compared with the literature values.17–19
4.4.5.
N,N%-Bis-(4-chlorobenzenesulfonamidphenyl-2-
References
ylmethylene)cyclohexane-(1R,2R)-diamine 5e. A mixture
of (1R,2R)-trans-cyclohexanediamine (260 mg, 2.28
mmol) and the aldehyde 4e (1.35 g, 4.57 mmol) in
EtOH (14 ml) was stirred at reflux for 1 h. A yellow
powder (1 g, 1.6 mmol, 69%) was obtained after recrys-
tallization from EtOH (12 ml); mp=177–178°C; IR
(KBr): w=3466, 2939, 2860, 1630, 1579, 1500, 1475,
1427, 1394, 1337, 1282, 1201, 1157, 1089, 933, 831, 767,
1. Adria´n, F.; Burguete, M. I.; Fraile, J. M.; Garc´ıa, J. I.;
Garc´ıa, J.; Garc´ıa-Espan˜a, E.; Luis, S. V.; Mayoral, J. A.;
Royo, A. J.; Sa´nchez, M. C. Eur. J. Inorg. Chem. 1999,
00, 2347–2354.
2. Blaser, H. U.; Jalett, H. P.; Wiehl, J. J. Mol. Catal. 1991,
68, 215–222.
613 cm−1; H NMR (250 MHz, CDCl3): l=1.55–1.60
1
3. Fache, F.; Dunjic, B.; Gamez, P.; Lemaire, M. Top.
Catal. 1997, 4, 201–209.
(m, 2H), 1.76–1.94 (m, 6H), 3.55–3.59 (m, 2H), 6.77 (dt,
4H, J=6.6, 4.4 Hz), 6.97 (ddd, 2H, J=7.5, 6.6, 0.9 Hz),
7.23–7.31 (m, 4H), 7.41–7.5 (m, 6H), 8.48 (s, 2H,
NꢀCH), 13.33 (s, 2H, NH–SO2–); 13C NMR (101 MHz,
CDCl3): l=24.21, 33.56, 73.29, 116.84, 120.25, 122.7,
128.37, 128.92, 131.61, 133.72, 137.76, 138.94, 138.97,
164.11; MS (ESI, -pESI), m/z (%): 667.3 (100) [M−H+]−.
Anal. calcd for C32H30Cl2N4O4S2: C, 57.40; H, 4.52; N,
8.37. Found: C, 57.45; H, 4.41; N, 8.35.
4. (a) Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno,
M.; Imai, N.; Kobayashi, S. Tetrahedron 1995, 51, 1203;
(b) Denmark, S. E.; Christenson, B. L.; Coe, D. M.;
O‘Connor, S. P. Tetrahedron Lett. 1995, 36, 2215.
5. (a) Takahashi, H.; Kawakita, T.; Yoshioka, M.;
Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30,
7095–7098; (b) Takahashi, H.; Kawakita, T.; Ohno, M.;
Yoshioka, M.; Kobayashi, S. Tetrahedron 1992, 48,
5691–5700; (c) Yoshioka, M.; Kawakita, T.; Ohno, M.
Tetrahedron Lett. 1989, 30, 1657–1660.
6. (a) Knochel, P. Chemtr. Org. Chem. 1995, 8, 205–221; (b)
Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.
Y.; Knochel, P. J. Org. Chem. 1996, 61, 8229–8243; (c)
Lutz, C.; Knochel, P. J. Org. Chem. 1997, 62, 7895–7898;
(d) Nowotny, S.; Vettel, S.; Knochel, P. Tetrahedron Lett.
1994, 35, 4539–4540; (e) Ostwald, R.; Chavant, P. Y.;
Stadtmuller, H.; Knochel, P. J. Org. Chem. 1994, 59,
4143–4153.
4.4.6. N,N%-Bis-(2,4,6-trichlorobenzenesulfonamidphenyl-
2-ylmethylene)cyclohexane-(1R,2R)-diamine 5f. Accord-
ing to GP3
a
mixture of (1R,2R)-trans-
cyclohexanediamine (29 mg, 0.25 mmol) and aldehyde
4f (186 mg, 0.51 mmol) in EtOH (5 ml) was refluxed for
1 h. Yellow crystals of 5f (147 mg, 0.18 mmol, 71%)
were obtained after recrystallization from EtOH (4 ml);
mp=132–134°C; IR (KBr): w=3446, 3067, 2931, 2858,
1633, 1562, 1537, 1498, 1412, 1367, 1290, 1177, 1140,
1040, 934, 864, 834, 797, 756, 661, 617, 574 cm−1; H
1
7. Irie, R.; Ito, Y.; Katsuki, T. Tetrahedron Lett. 1991, 32,
6891–6894.
NMR (250 MHz, CDCl3): l=1.43–1.97 (m, 8H), 3.41–
3.48 (m, 2H), 6.96–7.02 (dt, 2H, J=7.6 Hz), 7.19–7.25
(dt, 2H, J=7.6 Hz), 7.33–7.40 (m, 8H), 8.42 (s, 2H,
NꢀCH), 14.15 (s, 2H, NH–SO2); 13C NMR (101 MHz,
CDCl3): l=24.17, 33.05, 73.16, 115.55, 119.71, 122.29,
131.27, 131.83, 133.88, 133.93, 136.32, 138.3, 139.04,
164.18; MS (ESI), m/z (%): 807.1 (100) [MH]+. Anal.
calcd for C32H26Cl6N4O4S2: C, 47.60; H, 3.25; N, 6.94.
Found: C, 47.32; H, 3.41; N, 6.78.
8. Consonni, R.; Dalla Croce, P.; Ferraccioli, R.; La Rosa,
C. J. Chem. Soc., Perkin Trans. 1 1996, 1809–1814.
9. Hewson, A. T.; Hughes, K.; Richardson, SK.; Sharpe, D.
A.; Wadsworth, A. H. J. Chem. Soc., Perkin Trans. 1
1991, 1565–1569.
10. Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003–3006.
11. Kim, T.-J.; Lee, H.-Y.; Ryu, E.-S.; Park, D.-K.; Cho, C.
S.; Shim, S. C.; Jeong, J. H. J. Organomet. Chem. 2002,
649, 258–267.
12. 5 mol% of the chiral ligands 4a and 4b were used in the
catalytic reactions. The reaction time was 48 h in all
cases.
4.5. General procedure for the addition of diethylzinc
to aldehydes
13. The procedure of the reaction was as described before.
After complexation of the ligand with diethylzinc the
temperature of the mixture was increased to 50°C, subse-
quently the remaining amount of diethylzinc and the
benzaldehyde were added and the reaction was stirred for
5 h.
14. Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P.
J. J. Am. Chem. Soc. 1998, 120, 6423–6424.
15. Galsbøl, F.; Steenbøl, P.; Sørensen, B. S. Acta Chem.
Scand. 1972, 26, 3605–3611.
16. Smith, L. I.; Opie, J. W. Org. Synth. Collect. 1955, 3,
56–58.
17. Oriyama, T. Chem. Lett. 1984, 12, 2071–2074.
18. Soai, K. J. Org. Chem. 1988, 53, 927–928.
19. Hayashi, M. J. Chem. Soc., Perkin Trans. 1 1991, 25–28.
The ligand (5 mol%) was dissolved in dry toluene (6 ml)
under nitrogen, diethylzinc (1.1 M solution in toluene,
0.1 ml, 0.11 mmol) was added, and the mixture was
allowed to stir for 1 h at room temperature, then cooled
to 0°C or maintained at room temperature. Additional
diethylzinc (2.17 ml, 2.39 mmol) was added slowly and
after five minutes the aldehyde (1 mmol) was added.
The reaction was stirred until TLC showed complete
conversion of the aldehyde, quenched with 2 M HCl (6
ml), the phases were separated and the aqueous phase
was extracted with Et2O (3×10 ml). The combined
organic extracts were dried over Na2SO4, filtered and
concentrated under reduced pressure. The product was
purified by short path distillation or by flash chro-
matography to give the alcohol as colorless oil. The