Synthesis of a series of novel N,N-dialkyl-TsDPEN ligands and their application to enantioselective addition of dialkylzinc to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2008.04.020

A series of mono- and dialkylated derivatives of C2-symmetric N-tosyl-1,2-diphenylethylene diamines have been prepared and used as ligands for the enantiomeric control of the addition of diethylzinc to aldehydes. Addition products of up to 79% ee were formed.

Full text of DOI:10.1016/j.tetasy.2008.04.020

Tetrahedron: Asymmetry 19 (2008) 1250–1255
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Tetrahedron: Asymmetry
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Synthesis of a series of novel N,N-dialkyl-TsDPEN ligands and their
application to enantioselective addition of dialkylzinc to benzaldehyde
*
José E. D. Martins, Martin Wills
Department of Chemistry, The University of Warwick, 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:
A series of mono- and dialkylated derivatives of C2-symmetric N-tosyl-1,2-diphenylethylene diamines
have been prepared and used as ligands for the enantiomeric control of the addition of diethylzinc to
aldehydes. Addition products of up to 79% ee were formed.
Received 8 April 2008
Accepted 16 April 2008
Available online 26 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
Ph
HO
NMe2
OH
The addition of dialkylzincs to aldehydes (Scheme 1) is a well-
established synthetic reaction, which provides a means for the
preparation of secondary alcohols in high enantioselectivities.
Ligands (Fig. 1) which have been reported for this application
include homochiral 1,2-, 1,3- and 1,4-aminoalcohols such as 1–4,
and also diamines and disulfonylated compounds.1–3 The observa-
tion of non-linear chirality transfer effects when using DAIB 1 led
to the identification of a mechanism which involved the formation
of dimeric ligand/zinc intermediate. The high stability of the meso
dimer led to enrichment of the active catalytic reagent in situ.3a–c
Whilst it is possible to achieve high enantioselectivities in this
reaction through the use of a wide range of chiral amino alcohols,
disulfonylated derivatives are more frequently employed as tita-
nium(IV) complexes for optimum results.4
Me2N
OH
NMe2
2, up to 97% ee (R)2a
(-) DAIB 1, up to
95% ee (S)3
3, up to 94% ee (R)2b
SO2CF3
N
Ti(OiPr)2
OH
N
H
N
N
N
SO2CF3
6 up to 97% ee (S)4b
5, up to 80% ee (S)2d
4, up to 76% ee (S)2c
SO2CF3
Ph
Ph
N
NHSO2CF3
NHBoc
Ti(OiPr)2
N
NHSO2CF3
N
SO2CF3
O
9 up to 57% ee (R)5a
7
8 up to 79% ee (S)4h
O
Ligand
100% conversion
configuration depends
on ligand
HO
Ph
H
+ Et2Zn
Ph
Figure 1. Representative ligands used in diethylzinc addition reactions.
H
solvent, rt
Scheme 1. Asymmetric addition of diethylzinc to aldehydes.
second order effects have been reported, leading to methods for
asymmetric amplification.4g
The use of diamine 5 gave an addition product in 80% ee; other
derivatives of the diamine were more effective.2d,e The tita-
nium(IV) complex 6, of a C2-symmetric bistrifluoromethylsulfona-
mide 7, catalyzed the addition of alkylzincs to aldehydes in
excellent enantioselectivity, and was more efficient than the use
of the ligand alone.4b–d
Although the ditosylated diamine derivatives have been exten-
sively researched, the use of unsulfonylated diamines is less well
established, although there are a number of reports in the litera-
ture on the use of these as catalysts,1 including some recent exam-
ples.5a,b A paper by Rebolledo5a concluded that N,N-dialkylated-N0-
acylated (or carboxylated) derivatives of C2-symmetric diamines
such as 9 were effective catalysts for diethylzinc addition to benz-
aldehyde, although the best results were obtained using dimeric
derivatives of the ligands.4a
A large number of examples of N,N0-disulfonylated derivatives
of C2-symmetric diamines, including 1,2-diphenylethylene-1,2-
diamine 8,4h have now been tested in dialkylzinc additions,4 and
this area has been extensively reviewed.1,4b,c Detailed studies of
Despite the many diamines which have been tested in diethyl-
zinc addition reactions, we were not aware of any investigations on
derivatives which contained a combination of a monosulfonylated
amine and a basic amine, that is, which combine features of both
* Corresponding author. Tel.: +44 24 7642 3260; fax: +44 24 7652 4112.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.020

J. E. D. Martins, M. Wills / Tetrahedron: Asymmetry 19 (2008) 1250–1255
1251
sets of known ligands. In order to establish whether such deriva-
Ph
Ph
Ph
Ph
N
Ph
Ph
NH
Ph
tives might be effective, in this work we prepared a series of
candidate ligands from readily available N-tosyl-1,2-diphenyleth-
ylene-1,2-diamine (TsDPEN), a popular ligand for asymmetric
transfer hydrogenation, which is commercially available in either
enantiomeric form,6 and evaluated them as catalysts in the asym-
metric addition of diethylzinc to benzaldehyde.
O
O
TsHN HN
TsHN
TsHN
TsHN
N
(R,R)-22
Ph
(R,R)-20
(R,R)-21
(R,R)-16
With a diverse range of ligands in hand, we then examined the
use of each of them in the ethylation of benzaldehyde, which is
known to be a useful prototype reaction for comparison with other
catalysts (Scheme 3, Table 1). Each of the ligands proved to be
effective at promoting the addition reaction; however, the best
results in terms of both conversion and ee were obtained with
those containing a tertiary amine within a heterocyclic ring. The
highest ee (79%, R) was obtained using the azepan derivative 13,
in quantitative yield. Ligands containing acyclic substituents at
the basic amine did not give quantitative yields, although the less
hindered ligand 10 gave a product in higher conversion than 17.
The cyclohexane-derived ligand 16 gave a product in lower ee than
the analogous TsDPEN-derived diamine.
2. Results and discussion
A search of the literature revealed very little work on the
synthesis of monotosylated DPEN derivatives containing
a
tertiary basic amine group. Nagao et al. have reported the syn-
thesis of N-sulfonylated, N0,N0-dimethylated derivatives of homo-
chiral DPEN in enantioselective acyl transfer reactions; however,
this appears to be the major catalytic application of such
reagents to be reported to date.7 In contrast, several examples
of monotosylated DPENs containing secondary basic amines
have been reported.8 These include their use as ligands in Ru(II)
complexes for asymmetric catalysis of reduction reactions,8a–c
Fe-catalyzed epoxidation8d and silacycle-catalyzed Diels–Alder
reactions.8e
Ligands 10–15 and 17 were identified as a diverse range of
derivatives of the class of ligand we wished to investigate, that
is, TsDPEN derivatives containing a tertiary amine basic group. In
addition, the analogous 1,2-diaminocyclohexane derivative 16
and secondary amine derivatives 18 and 19 were also prepared
for purposes of comparison. Ligand 12 was prepared in both enan-
tiomerically pure forms from the precursor tosylated diamine. The
ligands were prepared following the methods illustrated in Scheme
2 and are, with the exception of 18,8c novel compounds.
O
H
OH
5 mol% ligand 10-19
See Table 1
+ Et2Zn
Ph
Ph
H
Toulene, 24h, rt
R
Scheme 3. Asymmetric addition of diethylzinc to benzaldehyde catalyzed by lig-
ands 10–19.
Table 1
Results of asymmetric benzaldehyde ethylation catalyzed by 10–19a
Ligand
Yield (%)
eea (%)
R/Sa
Ph
Ph
N
Ph
Ph
N
Ph
Ph
N
(R,R)-10
(R,R)-11
(R,R)-12
(S,S)-12
(R,R)-13
(R,R)-14
(R,R)-15
(R,R)-16
(R,R)-17
(R,R)-18
(R,R)-19
96
100
100
100
99
100
99
100
55
68
65
77
77
79
64
76
53
66
8
(R)
(R)
(R)
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
TsHN
TsHN
(R,R)-11
(ii)
TsHN
(R,R)-10
X
X=CH2,(R,R)-12
(i)
(iii)
(iv)
X=O, (R,R)-15
Ph
Ph
Ph
Ph
Ph
Ph
N
(viii)
TsHN HN
TsHN
NH2
TsHN
(R,R)-19
62
46
(R,R)-TsDPEN
(R,R)-13
13
(v)
(vii)
(vi)
a
Determined by GC analysis (Chrompac cyclodextrin-b-236M-19 50m),
T = 115 °C, P = 15 psi, benzaldehyde: 6.0 min; 1-phenylpropanol: tR (R) = 21.6 min,
tR (S) = 22.4 min.
Ph
Ph
Ph
Ph
Ph
Ph
N
TsHN
N
TsHN HN
TsHN
(R,R)-14
(R,R)-18
(R,R)-17
The ligands containing a secondary basic amine were inferior in
this application and delivered products in low yield and very low
ee (only 8–13% for the two examples tested). It therefore appears
that the presence of a tertiary basic amine is essential for optimum
results in this application, which mirrors the results obtained using
aminoalcohols as catalysts.
The results demonstrate that relatively simple dialkylated
derivatives of TsDPEN are effective for the catalysis of benzalde-
hyde alkylation with diethylzinc. As regards the mechanism
(Fig. 2), we anticipate that the active catalytic species is likely to
be zinc complex such as 23 (which may reversibly dimerize), con-
taining a 1:1 combination of Zn:ligand, and that this reacts with a
further molecule of diethylzinc through a transition state similar to
that depicted in 24.
Ph
Scheme 2. Synthesis of ligands. Reagents and conditions: (i) CH3CHO, AcOH, Na-
BH3CN, MeOH, 74%; (ii) 1,4-diiodobutane, K2CO3, MeOH, reflux, 63%; (iii) X = CH2,
1,5-diiodopentane, K2CO3, MeOH, reflux, 68%, X = O, di(2-iodoethyl)ether, K2CO3,
MeOH, reflux, 52%; (iv) 1,6-diiodohexane, K2CO3, MeOH, reflux, 65%; (v) phthaldi-
aldehyde, AcOH, NaBH3CN, MeOH, 53%; (vi) (a) PhCHO, NaBH3CN, MeOH, 88%; (b)
CH3COCl, Et3N, DCM, 93%; (c) LiAlH4, THF, reflux, 54%; (vii) (a) CH3COCl, Et3N, DCM,
quant; (b) LiAlH4, THF, reflux, 75%; (viii) trimethylacetaldehyde, AcOH NaBH3CN,
MeOH, 77%.
Ligands 11–13, 15 and 16 were efficiently prepared by substitu-
tion of the appropriate dielectrophile by the basic nitrogen of TsD-
PEN, whilst 10, 14 and 19 were formed by reductive amination
with aldehydes using sodium cyanoborohydride as the reducing
agent. Ligand 17 was prepared by a three-step process, via benzy-
lation to give 20, then acylation to 21 and finally reduction with
lithium aluminium hydride. Ligand 18 was formed via 22 followed
by reduction. In all cases, the ligands were formed in good to excel-
lent yields and were fully characterized.
Assuming that co-ordination of the diethylzinc molecule is to
the face of the metallocycle trans to the adjacent phenyl ring, to-
gether with p-stacking between the substrate arene and the further
phenyl ring, delivery of an ethyl group to the exposed face of the
aldehyde will deliver a product of correct configuration (R).

1252
J. E. D. Martins, M. Wills / Tetrahedron: Asymmetry 19 (2008) 1250–1255
1599, 1494, 1454, 1439, 1321, 1152, 1094, 1063, 936, 812, 762,
H
O
Ph
Ph
N
H
697, 662; dH (300 MHz; CDCl3)/ppm: 7.52–6.88 (15H, m, Ar-
H + NH), 4.60 (1H, d, J 10.6 PhCHNHTs), 3.81 (1H, d, J 10.6
PhCHNR2), 2.40–2.24 (7H, m, 2CH2 and CH3 singlet overlapping
at 2.33), 1.62 (4H, m, 2CH2). dC (75 MHz; CDCl3)/ppm: 142.2,
137.8, 136.5, 131.2, 129.4, 128.4, 127.6, 127.1, 127.0, 126.6, 126.4
(Ar-C), 68.7 (CH), 57.6 (CH), 46.7 (CH2), 22.0 (CH2), 20.8 (CH3).
HRMS calcd for C25H28N2O2S [M+H]+ 421.1940, found 421.1994
(12.0 ppm error).
Ph
Et
Et
Zn
TsN
OH
Zn
Et
N
ZnEt
(R)-configuration
Speculated
transition
state 24
Et
product.
N
(R,R)-23
Ph
Ts
Figure 2. Proposed mechanism for Et2Zn addition to benzaldehyde catalyzed by
TsDPEN derivatives.
4.3. N-(1,2-Diphenyl-2-piperidin-1-yl-ethyl)-4-methyl-
benzenesulfonamide (R,R)-12
3. Conclusions
In conclusion, we have investigated the synthesis of a series of
novel tertiary amine derivative of the popular TsDPEN chiral di-
amine and have found these to be effective in the control of the
addition reaction of diethylzinc to benzaldehyde. The results are
superior to those obtained using the secondary amine analogues.
The ligands described in this paper are likely to be of value in other
asymmetric catalytic applications, and studies of their applications
continues.
To a stirred solution of (1R,2R)-TsDPEN (0.2 g, 0.54 mmol) and
potassium carbonate (0.19 g, 1.4 mmol) in acetonitrile (3 mL) was
added 1,5-diiodobutane (0.09 mL, 0.62 mmol), and the reaction
mixture was left to stir overnight under reflux. The reaction mix-
ture was filtered in filter paper and the acetonitrile was evaporated
under reduced pressure. The residue was dissolved in chloroform
(30 mL), washed with water (25 mL) and then dried over anhy-
drous MgSO4. The solvent was removed to afford the product 12
as a white solid, which was purified by silica gel column chroma-
tography (0?30% v/v ethyl acetate/hexane) to afford the product
4. Experimental
as
a white solid (0.16 g, 0.37 mmol, 68%). Mp 108–110 °C;
20
4.1. N-(2-Diethylamino-1,2-diphenyl-ethyl)-4-methyl-
benzenesulfonamide (R,R)-10
½aꢀD ¼ þ3:3 (c 0.5, CHCl3); mmax (neat)/cmꢁ1: 3279, 3029, 2935,
2858, 2807, 1600, 1492, 1455, 1347, 1334, 1303, 1200, 1150,
1090, 1061, 932, 811, 793, 760, 697, 660; 7.52–6.88 (15H, m, Ar-
H + NH), 7.56–6.88 (14H, m, Ar-H), 4.61 (1H, d, J 11.0 PhCHNHTs),
3.52 (1H, d, J 11.0 PhCHNR2), 2.36 (3H, s, CH3), 2.23 (4H, m, 2CH2),
1.56 (4H, m, 2CH2), 1.28 (2H, m, CH2). dC (75 MHz; CDCl3)/ppm:
142.8, 138.5, 137.0, 132.1, 129.6, 129.0, 128.3, 127.6, 127.2, 127.0
(Ar-C), 74.6 (CH), 56.7 (CH), 26.4 (CH2), 24.1 (2CH2), 21.5 (CH3).
HRMS calcd for C26H31N2O2S [M+H]+ 435.2096, found 435.2130
(7.8 ppm error).
To a stirred solution of (1R,2R)-TsDPEN (0.20 g, 0.54 mmol) and
molecular sieves (1 g) in dried methanol (8 mL) was added acetal-
dehyde (0.06 mL, 1.2 mmol) followed by three drops of glacial ace-
tic acid. The reaction was followed by TLC until the imine was
formed (3 h) and then sodium cyanoborohydride (0.13 g, 2.2 mmol)
was added, and the reaction mixture was left to stir overnight at
room temperature. 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 a
crude solid, which was purified by silica gel column chromatogra-
phy (0?30% v/v ethyl acetate/hexane) to afford the product 10 as
4.4. N-(1,2-Diphenyl-2-piperidin-1-yl-ethyl)-4-methyl-
benzenesulfonamide (S,S)-12
To a stirred solution of (1S,2S)-TsDPEN (0.15 g, 0.4 mmol) and
potassium carbonate (0.14 g, 1.0 mmol) in acetonitrile (3 mL) was
added 1,5-diiodobutane (0.07 mL, 0.47 mmol), and the reaction
mixture was left to stir overnight under reflux. The reaction mix-
ture was filtered in filter paper and the acetonitrile was evaporated
under reduced pressure. The residue was dissolved in chloroform
(30 mL), washed with water (25 mL) and then dried over anhy-
drous MgSO4. The solvent was removed to afford the product as
a white solid, which was purified by silica gel column chromato-
graphy (0?30% v/v ethyl acetate/hexane) to afford the product
12 as a white solid (0.086 g, 0.19 mmol, 58%). Mp 108–110 °C;
20
a white solid (0.17 g, 0.40 mmol, 74%). Mp 79–82 °C; ½aꢀD ¼ þ11:4
(c 0.5, CHCl3); mmax (neat)/cmꢁ1: 3058, 3029, 2934, 2823, 1328,
1600, 1495, 1453, 1388, 1328, 1158, 1049, 937, 818, 725, 705; dH
(300 MHz; CDCl3)/ppm: 7.49–6.88 (15H, m, Ar-H + NH), 4.66 (1H,
d, J 10.9 PhCHNHTs), 3.75 (1H, d, J 10.9 PhCHNR2), 2.61 (2H, m,
CH2), 2.34 (3H, s, CH3), 2.05 (2H, m, CH2), 1.11 (6H, t, J 7.0 2CH3).
dC (75 MHz; CDCl3)/ppm: 142.7, 138.5, 137.2, 133.2, 129.6, 128.9,
128.3, 128.2, 127.8, 127.6, 127.2, 127.0 (Ar-C), 68.6 (CH), 57.2
(CH), 42.6 (2CH2), 21.4 (CH3), 13.8 (2CH3). HRMS calcd for
C25H31N2SO2 [M+H]+ 423.2096, found 423.2101 (1.1 ppm error).
25
½aꢀD ¼ ꢁ3:3 (c 0.5, CHCl3). mmax (neat)/cmꢁ1: 3279, 3031, 2933,
2853, 2807, 1598, 1494, 1453, 1349, 1334, 1303, 1202, 1151,
1090, 1056, 1028, 933, 812, 794, 759, 697, 657; dH (300 MHz;
CDCl3)/ppm: 7.52–6.88 (15H, m, Ar-H + NH), 4.61 (1H, d, J 11.0
PhCHNHTs), 3.52 (1H, d, J 11.0 PhCHNR2), 2.36 (3H, s, CH3), 2.23
(4H, m, 2CH2), 1.56 (4H, m, 2CH2), 1.28 (2H, m, CH2). dC (75 MHz;
CDCl3)/ppm: 142.8, 138.5, 137.0, 132.1, 129.6, 129.0, 128.3,
127.6, 127.2, 127.0 (Ar-C), 74.6 (CH), 56.7 (CH), 26.4 (CH2), 24.1
(2CH2), 21.5 (CH3). HRMS calcd for C30H30N2NaO3S [M+H]+
435.2096, found 435.2114 (4.1 ppm error).
4.2. N-(1,2-Diphenyl-2-pyrrolidin-1-yl-ethyl)-4-methyl-
benzenesulfonamide (R,R)-11
To a stirred solution of (1R,2R)-TsDPEN (0.1 g, 0.27 mmol) and
potassium carbonate (0.09 g, 0.7 mmol) in acetonitrile (2 mL) was
added 1,4-diiodobutane (0.04 mL, 0.31 mmol), and the reaction
mixture was left to stir overnight under reflux. The reaction mix-
ture was filtered in filter paper and the acetonitrile was evaporated
under reduced pressure. The residue was dissolved in chloroform
(20 mL), washed with water (20 mL) and then dried over anhy-
drous MgSO4. The solvent was removed to afford the product 11
as a white solid, which was purified by silica gel column chroma-
tography (0?30% v/v ethyl acetate/hexane) to afford the product
as a white solid (0.072 g, 0.17 mmol, 63%). Mp 116–119 °C;
4.5. N-(2-Azepan-1-yl-1,2-diphenyl-ethyl)-4-methyl-
benzenesulfonamide (R,R)-13
To a stirred solution of (1R,2R)-TsDPEN (0.2 g, 0.54 mmol) and
potassium carbonate (0.15 g, 1.1 mmol) in acetonitrile (3 mL) was
added 1,6-diiodohexane (0.10 mL, 0.65 mmol), and the reaction
20
½aꢀD ¼ ꢁ1:6 (c 0.5, CHCl3); mmax (neat)/cmꢁ1: 3286, 3029, 2905,

J. E. D. Martins, M. Wills / Tetrahedron: Asymmetry 19 (2008) 1250–1255
1253
mixture was left to stir overnight under reflux. The reaction mix-
ture was filtered in filter paper and the acetonitrile was evaporated
under reduced pressure. The residue was dissolved in chloroform
(25 mL), washed with water (20 mL) and then dried over anhy-
drous MgSO4. The solvent was removed to afford the crude prod-
uct, which was purified by silica gel column chromatography
(0?20% v/v ethyl acetate/hexane) to afford the product 13 as a
67.1 (4CH2), 56.5 (CH), 21.4 (CH3). HRMS calcd for C25H29N2O3S
[M+H]+ 437.1889, found 437.1894 (1.1 ppm error).
4.8. 4-Methyl-N-(2-piperidin-1-yl-cyclohexyl)-
benzenesulfonamide (R,R)-16
To a stirred solution of (1R,2R)-(ꢁ)-N-p-tosyl-1,2-cyclohexane-
diamine (0.2 g, 0.74 mmol) and potassium carbonate (0.26 g,
2.0 mmol) in acetonitrile (3 mL) was added 1,5-diiodobutane
(0.13 mL, 0.86 mmol), and the reaction mixture was left to stir
overnight under reflux. The reaction mixture was filtered in filter
paper and the acetonitrile was evaporated under reduced pressure.
The residue was dissolved in chloroform (30 mL), washed with
water (25 mL) and then dried over anhydrous MgSO4. The solvent
was removed to afford the product 16 as a white solid, which was
purified by silica gel column chromatography (0?30% v/v ethyl
acetate/hexane) to afford the product as a white solid (0.15 g,
20
clear oil (0.16 g, 0.36 mmol, 65%). ½aꢀD ¼ þ39 (c 0.5, CHCl3); mmax
(neat)/cmꢁ1: 3030, 2923, 2853, 1599, 1495, 1453, 1312, 1151,
1091, 1077, 1056, 931, 810, 754, 696, 664; dH (300 MHz; CDCl3)/
ppm: 7.47–6.86 (15H, m, Ar-H + NH), 4.64 (1H, d,
J 10.9,
PhCHNHTs), 3.63 (1H, d, J 10.9, PhCHNR2), 2.54 (2H, m, CH2),
2.42 (2H, m, CH2), 2.33 (3H, s, CH3), 1.73–1.52 (8H, m, 4CH2). dC
(75 MHz; CDCl3)/ppm: 142.6, 138.1, 137.2, 133.6, 129.4, 128.9,
128.4, 127.7, 127.6, 127.2, 127.0 (Ar-C), 75.0 (CH), 57.5 (CH), 51.3
(2CH2), 29.0 (2CH2), 26.5 (2CH2), 21.4 (CH3). HRMS calcd for
C27H33N2O2S [M + H]+ 449.2252, found 449.2268 (3.5 ppm error).
20
0.44 mmol, 58%). Mp 82–84 °C; ½aꢀD ¼ ꢁ92 (c 1, CHCl3); mmax
4.6. N-[2-(1,3-Dihydro-isoindol-2-yl)-1,2-diphenyl-ethyl]-4-
methyl-benzenesulfonamide (R,R)-14
(neat)/cmꢁ1: 3195, 2919, 2854, 1598, 1493, 1401, 1345, 1319,
1163, 1066, 952, 904, 810, 768, 689; dH (300 MHz; CDCl3)/ppm:
7.76 (2H, d, J 8.2 Ar-H), 7.30 (2H, d, J 7.9 Ar-H), 2.62 (1H, m, CH),
2.09 (5H, m, NH + 2CH2), 1.72 (4H, m, 2CH2), 1.44–0.78 (10H,
5CH2). dC (75 MHz; CDCl3)/ppm: 143.1, 136.6, 129.4, 127.2 (Ar-C),
67.3 (CH), 53.3 (CH), 32.7 (CH2), 26.5 (CH2), 25.3 (CH2), 24.5
(CH2), 24.2 (CH2), 22.6 (CH2), 21.5 (CH3). HRMS calcd for
To a stirred solution of (1R,2R)-TsDPEN (0.20 g, 0.54 mmol) and
molecular sieves (1 g) in dried methanol (6 mL) was added phthal-
dialdehyde (0.08 g, 0.60 mmol) followed by 3 drops of glacial acetic
acid. The reaction was followed by TLC until the imine was formed
(4 h) and then sodium cyanoborohydride (0.13 g, 2.1 mmol) was
added, and the reaction mixture was left to stir overnight at room
temperature. The molecular sieves were filtered through filter pa-
per and the solution was concentrated under reduced pressure to
remove the methanol. The residue was dissolved in chloroform
(30 mL), washed with saturated NaHCO3 solution (20 mL) and then
dried over anhydrous MgSO4. The solvent was removed to give a
crude solid, which was purified by silica gel column chromatogra-
phy (0?30% v/v ethyl acetate/hexane) to afford the product 14 as a
light yellow solid (0.13 g, 0.27 mmol, 53%). Mp 69–72 °C;
C
18H29N2O2S [M+H]+ 337.1940, found 337.1952 (3.5 ppm error).
4.9. N-(2-Benzylamino-1,2-diphenyl-ethyl)-4-methyl-
benzenesulfonamide (R,R)-208d
To a stirred solution of (1R,2R)-TsDPEN (0.30 g, 0.82 mmol) and
molecular sieves (1 g) in dried methanol (8 mL) was added benzal-
dehyde (0.10 mL, 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 room temperature. The molecular sieves were filtered
through filter paper and the solution was concentrated under re-
duced 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 re-
moved to give a crude solid, which was purified by silica gel col-
umn chromatography (0?30% v/v ethyl acetate/hexane) to afford
the product 20 as a white solid (0.33 g, 0.72 mmol, 88%). Mp 136
23
½aꢀD ¼ þ16:5 (c 0.2, CHCl3); mmax (neat)/cmꢁ1: 3029, 2802, 1598,
1494, 1453, 1320, 1152, 1091, 932, 811, 743, 700, 663; dH
(300 MHz; CDCl3)/ppm: 7.50–6.94 (19H, m, Ar-H + NH), 4.77 (1H,
d, J 10.1, PhCHNHTs), 4.00 (1H, d, J 10.1, PhCHNR2), 3.91 (2H, d, J
10.5, NCHaHb), 3.75 (2H, d, J 10.5, NCHaHb), 2.35 (3H, s, CH3). dC
(75 MHz; CDCl3)/ppm: 142.2, 138.2, 137.5, 136.6, 132.0, 129.3,
128.5, 127.7, 127.5, 127.2, 127.1, 126.7, 126.6, 126.2, 121.6 (Ar-
C), 69.2 (CH), 57.6 (CH), 52.6 (2CH2), 20.9 (CH3). HRMS calcd for
C
29H29N2SO2 [M+H]+ 469.1940, found 469.1982 (8.9 ppm error).
20
ꢁ138 °C (lit.8d 139 °C); ½aꢀD ¼ ꢁ33 (c 0.5, CHCl3); mmax (neat)/
4.7. 4-Methyl-N-(2-morpholin-4-yl-1,2-diphenyl-ethyl)-
benzenesulfonamide (R,R)-15
cmꢁ1: 3247, 3027, 2847, 1601, 1493, 1454, 1438, 1332, 1275,
1261, 1159, 916, 840, 807, 763, 697, 671; dH (300 MHz; CDCl3)/
ppm: 7.40–6.88 (10H, m, Ar-H), 6.19 (1H, br s, NH), 4.31 (1H, d, J
7.8, PhCHNHTs), 3.68 (1H, d, J 7.8 PhCHNHBn), 3.61 (1H, d, J 13.2,
CHaHb), 3.40 (1H, d, J 13.2, CHaHb), 2.30 (3H, s, CH3), 1.80 (1H, br
s, NH). dC (75 MHz; CDCl3)/ppm: 142.7, 139.6, 138.8, 138.2,
136.9, 129.1, 128.5, 128.4, 128.0, 127.9, 127.6, 127.5, 127.3,
127.2, 127.1 (Ar-C), 66.8 (CH), 63.1 (CH), 50.8 (CH2), 21.4 (CH3).
HRMS calcd for C28H29N2O2S [M+H]+ 457.1940, found 457.1944
(0.8 ppm error).
To a stirred solution of (1R,2R)-TsDPEN (0.2 g, 0.54 mmol) and
potassium carbonate (0.15 g, 1.1 mmol) in acetonitrile (3 mL) was
added 2-iodoethylether (0.09 mL, 0.65 mmol), and the reaction
mixture was left to stir overnight under reflux. The reaction mix-
ture was filtered in filter paper and the acetonitrile was evaporated
under reduced pressure. The residue was dissolved in chloroform
(25 mL), washed with water (20 mL) and then dried over anhy-
drous MgSO4. The solvent was removed to afford the crude product
15, which was purified by silica gel column chromatography
(0?30% v/v ethyl acetate/hexane) to afford the product as a light
yellow solid (0.12 g, 0.28 mmol, 52%). Mp 147–149 °C;
4.10. N-Benzyl-N-[1,2-diphenyl-2-(toluene-4-sulfonylamino)-
ethyl]-acetamide (R,R)-21
20
½aꢀD ¼ þ12:7 (c 0.5, CHCl3); mmax (neat)/cmꢁ1: 3196, 3032, 2918,
(R,R)-20 (0.12 g, 0.26 mmol) was dissolved in dichloromethane
(4 mL) and then acetylchloride (0.022 mL, 0.3 mmol) and triethyl-
amine (0.037 mL, 0.26 mmol) were added, and the reaction mix-
ture was left to stir overnight at room temperature. The mixture
was washed with water (10 mL), extracted with chloroform
(3 ꢂ 15 mL) and then dried over anhydrous MgSO4. The solvent
was removed to afford the product as a yellow oil, which was puri-
2852, 1598, 1495, 1454, 1390, 1325, 1151, 1114, 1092, 999, 931,
867, 800, 750, 697, 661; dH (300 MHz; CDCl3)/ppm: 7.53–6.88
(15H, m, Ar-H + NH), 4.69 (1H, d, J 11.0, PhCHNHTs), 3.65 (4H, m,
2CH2), 3.54 (1H, d, J 11.0, PhCHNR2), 2.34 (3H, s, CH3), 2.28 (4H,
m, 2CH2). dC (75 MHz; CDCl3)/ppm: 143.0, 138.0, 137.0, 131.3,
129.6, 129.1, 128.3, 128.0, 127.9, 127.7, 127.2 (Ar-C), 74.1 (CH),

1254
J. E. D. Martins, M. Wills / Tetrahedron: Asymmetry 19 (2008) 1250–1255
fied by silica gel column chromatography (0?40% v/v ethyl ace-
tate/hexane) to afford the product 21 as yellow oil (0.122 g,
followed by 0.39 g (1.4 mmol) of Rochelle salt (Na/K tartarate) was
added and the reaction mixture was stirred for additional 2 h. The
product was extracted with chloroform (3 ꢂ 30 mL) and the com-
bined organic fractions were washed with brine (2 ꢂ 20 mL), dried
over MgSO4, filtered and concentrated under reduced pressure to
afford the crude product, which was purified by silica gel column
chromatography (0?20% v/v ethyl acetate/hexane) to afford the
product 18 as a white solid (0.18 g, 0.46 mmol, 75%). Mp 116–
25
0.24 mmol, 93% yield). Mp 42–44 °C; ½aꢀD ¼ ꢁ46 (c 1.0, CHCl3);
mmax (neat)/cmꢁ1: 3030, 2924, 1733, 1619, 1495, 1454, 1416,
1327, 1157, 1092, 1061, 951, 930, 858, 809, 758, 728, 696, 666.
dH (300 MHz; CDCl3)/ppm: 7.42–6.66 (20H, m, Ar-H + NH), 5.16
(1H, dd, J 9.0, 10.0, PhCHNHTs), 4.72 (2H, AB system, J 18.0,
PhCH2NR), 2.25 (3H, s, CH3), 2.10 (3H, s, CH3), 1.25 (2H, s, CH2).
dC (75 MHz; CDCl3)/ppm: 173.8 (C@O), 141.6, 137.8, 137.6, 136.5,
134.6, 129.0, 128.3, 127.8, 127.6, 127.4, 127.2, 126.5, 126.1,
126.0, 125.3 (Ar-C), 60.7 (CH), 58.0 (CH), 47.9 (CH2), 22.0 (CH3),
20.7 (CH3). HRMS calcd for C30H30N2NaO3S [M+Na]+ 521.1864,
found 521.1870 (1.1 ppm error).
20
118 °C; ½aꢀD ¼ ꢁ11:5 (c 0.5, CHCl3); mmax (neat)/cmꢁ1: 3228, 3064,
2972, 2858, 1598, 1493, 1437, 1454, 1324, 1148, 1081, 1039,
925, 908, 847, 810, 770, 752, 695, 667; dH (300 MHz; CDCl3)/
ppm: 7.41–6.87 (15H, m, Ar-H + NH), 4.23 (1H, d, J 8.0 PhCHNHTs),
3.61 (1H, d, J 8.0 PhCHNHR), 2.50–2.28 (5H, m, CH2 and CH3 singlet
overlapping at 2.34), 1.0 (3H, t, J 7.1 CH3). dC (75 MHz; CDCl3)/ppm:
142.7, 139.3, 138.3, 137.0, 129.0, 128.2, 127.8, 127.6, 127.4, 127.2,
127.1 (Ar-C), 67.6 (CH), 63.0 (CH), 41.4 (CH2), 21.4 (CH3), 15.2
(CH3). HRMS calcd for C23H27N2O2S [M+H]+ 395.1784, found
395.1797 (3.2 ppm error).
4.11. N-[2-(Benzyl-ethyl-amino)-1,2-diphenyl-ethyl]-4-methyl-
benzenesulfonamide (R,R)-17
To a stirred solution of (R,R)-21 (0.1 g, 0.2 mmol) in dry THF
(7 mL), a 2 M solution of LiAlH4 (0.4 mL, 0.8 mmol) was added drop-
wise. The system was refluxed for 4 h and then 1 mL of water fol-
lowed by 0.12 g (0.44 mmol) of Rochelle salt (Na/K tartarate) was
added, and the reaction mixture was stirred for additional 2 h.
The product was extracted with chloroform (3 ꢂ 15 mL) and the
combined organic fractions were washed with brine (2 ꢂ 10 mL),
dried over MgSO4, filtered and concentrated under reduced pres-
sure to afford the crude product, which was purified by silica gel
column chromatography (0?20% v/v ethyl acetate/hexane) to af-
ford the product 17 as a white solid (0.05 g, 0.1 mmol, 54%). Mp
4.14. N-[2-(2,2-Dimethyl-propylamino)-1,2-diphenyl-ethyl]-4-
methyl-benzenesulfonamide (R,R)-19
To a stirred solution of (1R,2R)-TsDPEN (0.30 g, 0.82 mmol) and
molecular sieves (1 g) in dried methanol (8 mL) was added tri-
methylacetaldehyde (0.1 mL, 0.90 mmol) followed by three drops
of glacial acetic acid. The reaction was followed by TLC until the
imine was formed (4 h) and then sodium cyanoborohydride
(0.15 g, 2.4 mmol) was added, and the reaction mixture was left
to stir overnight at room temperature. The molecular sieves were
filtered through filter paper and the solution was concentrated un-
der reduced pressure to remove the methanol. The residue was dis-
solved in chloroform (50 mL), washed with saturated NaHCO3
solution (30 mL) and then dried over anhydrous MgSO4. The sol-
vent was removed to give a crude solid, which was purified by sil-
ica gel column chromatography (0?30% v/v ethyl acetate/hexane)
to afford the product 19 as a white solid (0.28 g, 0.66 mmol, 77%).
20
115–117 °C; ½aꢀD ¼ ꢁ33 (c 0.5, CHCl3); mmax (neat)/cmꢁ1: 3236,
3062, 3031, 2972, 2926, 2829, 1598, 1494, 1455, 1377, 1347,
1150, 1075, 1089, 1052, 933, 814, 761, 699, 666. dH (300 MHz;
CDCl3)/ppm: 7.45–6.78 (20H, m, Ar-H + NH), 4.74 (1H, d, J 10.9,
PhCHNHTs), 3.86 (1H, d, J 13.6, CHaHb), 3.73 (1H, d, J 10.9, PhCHNR2),
2.99 (1H, d, J 13.6, CHaHb), 2.53 (1H, m, CHaHb), 2.30 (3H, s, CH3),
2.20 (1H, m, CHaHb), 1.19 (3H, t 7.0, CH3). dC (75 MHz; CDCl3)/
ppm: 142.6, 138.5, 138.2, 137.1, 132.6, 129.9, 128.8, 128.7, 128.3,
127.9, 127.7, 127.6, 127.2, 127.0 (Ar-C), 67.6 (CH), 57.2 (CH), 53.2
(CH2), 42.6 (CH2), 21.4 (CH3), 13.8 (CH3). HRMS calcd for
20
Mp 97–99 °C; ½aꢀD ¼ ꢁ37 (c 0.5, CHCl3); mmax (neat)/cmꢁ1: 3180,
2954, 1600, 1495, 1470, 1456, 1373, 1319, 1148, 1092, 945, 931,
811, 784, 751, 699, 660; dH (300 MHz; CDCl3)/ppm: 7.43–6.83
(15H, m, Ar-H + NH), 4.22 (1H, d, J 8.0 PhCHNHTs), 3.53 (1H, d, J
8.0 PhCHNHR), 2.34 (3H, s, CH3), 2.14 (1H, d, J 11.3 CHaHb), 1.95
(1H, d, J 11.3 CHaHb), 0.84 (9H, s, 3CH3). dC (75 MHz; CDCl3)/
ppm: 142.7, 139.4, 138.4, 136.9, 129.1, 128.3, 127.9, 127.5, 127.4,
127.2, 127.1 (Ar-C), 68.5 (CH), 63.4 (CH), 59.4 (CH2), 31.5 (C),
27.6 (CH3), 21.4 (3CH3). HRMS calcd for C26H33N2O2S [M+H]+
437.2252, found 437.2260 (1.8 ppm error).
C
30H33N2O2S [M+H]+ 485.2252, found 485.2259 (1.4 ppm error).
4.12. N-[1,2-Diphenyl-2-(toluene-4-sulfonylamino)-ethyl]-
acetamide (R,R)-22
(1R,2R)-TsDPEN (0.5 g, 1.3 mmol) was dissolved in dichloro-
methane (10 mL) and then acetylchloride (0.1 mL, 1.5 mmol) and
triethylamine (0.2 mL, 1.3 mmol) were added, and the reaction mix-
ture was left to stir overnight at room temperature. The mixture was
washed with water (20 mL), extracted with chloroform (3 ꢂ 30 mL)
and then dried over anhydrous MgSO4. The solvent was removed to
afford the product 22 as a white solid (0.55 g, 1.3 mmol, quantita-
4.15. General procedure for enantioselective addition of
diethylzinc to benzaldehyde2c
20
tive yield). Mp 222–224 °C; ½aꢀD ¼ þ7 (c 1.0, CHCl3); mmax (neat)/
A solution of ligand (R,R)-13 (0.022 mmol) in dry toluene (1 mL)
was stirred under N2 in a flame-dried schlenk tube at 25 °C for
10 min. The system was cooled to ꢁ78 °C and then diethylzinc
1 M solution was added (1.1 mmol). The system was stirred at that
temperature for 1 h and then the cooling bath was removed, and the
system was stirred for another 1 h at room temperature when benz-
aldehyde was added (0.44 mmol). The system was stirred at room
temperature and monitored by GC. The reaction was quenched with
aqueous HCl (10%, 5 mL) and extracted with Et2O, dried over MgSO4,
filtered and concentrated in vacuum to give the crude reaction
cmꢁ1: 3304, 3033, 1651, 1539, 1319, 1154, 1058, 1087, 922, 808,
696, 670; dH (300 MHz; CDCl3)/ppm: 7.48–6.84 (15H, m, Ar-
H + NH), 5.30 (1H, dd, J 8.0, 9.0, PhCHNHTs), 4.62 (1H, dd, J 9.0,
8.5, PhCHNHR), 2.27 (3H, s, CH3), 2.07 (3H, s, CH3). dC (75 MHz;
CDCl3)/ppm: 170.8 (C@O), 142.0, 138.3, 137.3, 137.2, 128.5, 127.7,
127.4, 127.0, 126.8, 126.9, 126.7, 126.1 (Ar-C), 62.4 (CH), 58.3
(CH), 22.6 (CH3), 20.7 (CH3). HRMS calcd for C23H24N2NaO3S
[M+Na]+ 431.1396, found 431.1405 (2.0 ppm error).
24
4.13. N-(2-Ethylamino-1,2-diphenyl-ethyl)-4-methyl-
benzenesulfonamide (R,R)-188c
mixture, which was analyzed by GC. ½aꢀD ¼ þ36 (c 0.72, CHCl3)
20
79% ee (R) (lit.6a ½aꢀD ¼ þ47:0 (c 1.4, CHCl3) 95% ee (R)); dH
(400 MHz; CDCl3)/ppm: 7.36–7.24 (5H, m, Ar-H), 4.57 (1H, t, J
6.5,PhCH(OH)CH2), 2.00 (1H, br s, OH), 1.86-1.68 (2H, m, CH2),
0.90 (3H, t, J 7.4, CH3); dC (100.6 MHz; CDCl3)/ppm: 144.6, 128.4,
127.5, 126.0 (Ar-C), 76.0 (CH), 31.9 (CH2), 10.2 (CH3).
To a stirred solution of (R,R)-22 (0.25 g, 0.6 mmol) in dry THF
(15 mL), a 2 M solution of LiAlH4 (0.6 mL, 1.2 mmol) was added
dropwise. The system was refluxed for 4 h and then 2 mL of water

J. E. D. Martins, M. Wills / Tetrahedron: Asymmetry 19 (2008) 1250–1255
1255
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Acknowledgments
We thank Coordenacßão de Aperfeicßoamento de Pessoal de Ens-
inol Superior (CAPES) for the scholarship to J.E.D.M. We thank the
EPSRC Mass Spectrometry Service (Swansea) for analysis of certain
ligands and intermediates and the use of the EPSRC Chemical Data-
base Service at Daresbury.9
6. (a) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005, 127,
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