Synthesis, structure and activity of sulfonamides derived from (+)-camphor in the enantioselective addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1016/j.molcata.2010.04.019

New chiral sulfonamides derived from (+)-camphor, with different substituents on camphor C2 and sulfonamide N, were synthesized. Their activity was tested in the reaction of Et₂Zn addition to benzaldehyde. The yield of the reaction was 44-96%, the enantiomeric excess was 1-69%. Sulfonamides possessing the 2-hydroxyl group gave an excess of 1-(S)-phenylpropanol, while catalysts containing other sulfonamides gave 1-(R)-phenylpropanol as a major product. The best catalytic efficacy was observed for sulfonamides with (R)-C2-OH group, while the use of thioketo- and mercaptosulfonamides resulted in low enantiomeric excess and yields not exceeding 60%. Crystal structures have been determined for sulfonamides with N-benzyl moiety and different substituents on the C2 atom. The structural analysis revealed the presence of intramolecular N?O(C2) and O_sulfo?O(C2) H-bonds, what confirms the ability of these molecules to adopt the conformation required for their bidentate coordination to Ti(IV) via the sulfonamide group and substituent at C2. The coordination mode for investigated sulfonamides was determined with the IR spectra for five obtained Ti(IV) complexes and crystal structure analysis of the ligands. The 3D structures of Ti(IV) complex catalysts containing investigated sulfonamides were postulated, which are consistent with the reported chirality of the addition product and observed % ee.

Full text of DOI:10.1016/j.molcata.2010.04.019

Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Synthesis, structure and activity of sulfonamides derived from (+)-camphor in
the enantioselective addition of diethylzinc to benzaldehyde
Anna Kozakiewicz, Małgorzata Ullrich, Mirosław Wełniak, Andrzej Wojtczak∗
Faculty of Chemistry, N. Copernicus University, Gagarina 7, 87-100 Torun´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New chiral sulfonamides derived from (+)-camphor, with different substituents on camphor C2 and sul-
fonamide N, were synthesized. Their activity was tested in the reaction of Et2Zn addition to benzaldehyde.
The yield of the reaction was 44–96%, the enantiomeric excess was 1–69%. Sulfonamides possessing the
2-hydroxyl group gave an excess of 1-(S)-phenylpropanol, while catalysts containing other sulfonamides
gave 1-(R)-phenylpropanol as a major product. The best catalytic efficacy was observed for sulfonamides
with (R)-C2–OH group, while the use of thioketo- and mercaptosulfonamides resulted in low enan-
tiomeric excess and yields not exceeding 60%. Crystal structures have been determined for sulfonamides
with N-benzyl moiety and different substituents on the C2 atom. The structural analysis revealed the pres-
ence of intramolecular N· · ·O(C2) and Osulfo· · ·O(C2) H-bonds, what confirms the ability of these molecules
to adopt the conformation required for their bidentate coordination to Ti(IV) via the sulfonamide group
and substituent at C2. The coordination mode for investigated sulfonamides was determined with the IR
spectra for five obtained Ti(IV) complexes and crystal structure analysis of the ligands. The 3D structures
of Ti(IV) complex catalysts containing investigated sulfonamides were postulated, which are consistent
with the reported chirality of the addition product and observed % ee.
Received 10 March 2010
Received in revised form 15 April 2010
Accepted 30 April 2010
Available online 11 May 2010
Keywords:
Sulfonamide
Camphor derivatives
Crystal structure
Catalytic activity
Diethylzinc addition
© 2010 Elsevier B.V. All rights reserved.
1. Introduction
asymmetric addition to acetophenone led to the tertiary (S)-alcohol
with 84% ee [3].
Catalytic synthesis is currently one of the most intensely devel-
oping fields in the organic chemistry. Currently, the asymmetric
addition of organometallic compounds to one of the heterotopic
sides of the carbonyl group is extensively investigated topic.
Numerous catalytic systems are currently tested for an addition
of organozinc compounds to aldehydes and ketones [1–5]. The
prototypic reaction of that kind is an addition of diethylzinc to ben-
zaldehyde (Scheme 1), which is usually used for testing the efficacy
of the developed catalysts. The addition is usually performed in a
presence of Ti(OiPr)4 which forms complexes with different organic
auxiliaries, such as 1,2-, 1,3- and 1,4-aminoalcohols, aminotiols,
diamines, diols and also sulfonamides, and subsequently activates
the substrate molecule [6,7]. Usually the excess of Ti(OiPr)4 is used,
what enhances the transfer of the alkyl group to aldehyde or ketone.
The use of monosulfonamide ligands derived from borneol in
the enantioselective Et2Zn addition to benzaldehyde was reported
for the first time by Ramón and Yus [8]. The highest catalytic effi-
ciency was obtained for the sulfonamide with N-benzyl moiety and
the (R)-C2–OH group in the camphor ring, with 71% ee for the syn-
thesis of (S)-1-phenylpropanol [8]. The use of the same ligand in the
Hui et al. [9] investigated the effects of substitution in the aro-
matic ring of monosulfonamides on the enantioselectivity of the
Et2Zn addition to different aldehydes. Results indicated that the
electron-withdrawing substituents make a reaction more difficult,
while the presence of electron-donating substituents enhances the
reaction and increases the reaction rate. It was found that the
para-substituted ligands gave higher enantioselectivity of addition
(66–72% ee) than those found for meta- and ortho- (37–68% ee) [9].
Authors also investigated the role of the solvent. The highest cat-
alytic efficiency was observed for the reaction conducted in toluene,
while the use of MeCN gave the worst results [9]. Authors suggested
that polar media enhanced the solvolysis and decomposition of
Et2Zn. The highest ee of 72% has been achieved in a synthesis of
(S)-1-phenylpropanol with the ligand possessing the para-phenyl
substituent. The use of the same ligand in the Et2Zn addition to
other aldehydes resulted in the enantiomeric excess 2–83% ee [9].
Architecture of Ti(IV) complexes with the auxiliary ligands
affects the catalytic efficacy. There are no reports on the struc-
ture of the catalyst molecules containing the ligands derived from
camphor. The structure of TiL2 complex with monosulfonamides
was investigated by Hamura et al. [10]. That structure revealed
the bidentate coordination of the ligand via O and N of the sul-
fonamide moiety, what resulted in positioning of the organic part
of sulfonamide distant from the expected position of the substrate
∗
Corresponding author. Tel.: +48 56 6114506; fax: +48 56 6542477.
E-mail address: awojt@chem.uni.torun.pl (A. Wojtczak).
1381-1169/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2010.04.019

A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
129
tigated to find the relation between the molecular architecture and
the observed catalytic properties of their Ti(IV) complexes.
2. Experimental
Melting points for 1–20 were determined using Boetius table.
Rotations were measured on a Lot-Oriel S-2 automatic polymeter.
The 1H and 13C NMR spectra were recorded on a Bruker Avance
300 MHz spectrometer using CDCl3 solutions. The IR spectra were
recorded on a Perkin Elmer Spectrum RX I spectrophotometer.
Elemental analyses were performed on ELEMENTARY Analysen-
systeme GmbH Vario MACRO CHN analyzer. GC analyses were
performed on a Perkin Elmer chromatograph using a Supelco ␤-Dex
325 column (30 m × 0.25 mm, isothermal conditions, T = 100 ◦C).
The crystals suitable for the diffraction experiments were
obtained by vapor diffusion method from the ethanol solution. X-
Ray diffraction data were measured using Oxford Sapphire CCD
diffractometer with Mo K␣ radiation, ꢁ = 0.71073 Å at 293(2) K. The
numerical absorption correction was applied, based on the crystal
shape [14]. The absolute structure was determined by the Flack
method [15]. Structures were solved and refined with the full-
matrix least-squares procedure using SHELX-97 program package
[16]. The structures 1, 9, 11 and 13 have been deposited with CCDC,
the deposition numbers are CCDC 767832 to 767835, respectively.
Scheme 1. Asymmetric addition of Et2Zn to benzaldehyde.
in the Ti(IV) coordination sphere. The research on Ti2L2 type com-
plexes has been conducted for several sulfonamide ligands with
the additional hydroxyl group in the amine moiety [11]. Structural
results revealed the ꢀ2 –NO coordination via the sulfonamide N
and the hydroxyl O atom, with that atom bridging two Ti centers
in a dimeric molecule. The Ti coordination sphere was a trigonal
bipyramid.
Wu and Gau investigated the catalytic activity of
Ti2(monosulfonamide)2 with similar ligands in the Et2Zn addition
to benzaldehyde, obtaining (R)-1-phenylpropanol with 92–100%
yields and 67–96% ee [12]. Their structural data showed different
coordination sphere of two Ti ions in the dimeric complex. One
Ti atom had the octahedral coordination sphere formed by N, O
atoms of sulfonamide, hydroxyl O and the OiPr groups, while for
the second Ti ion the sulfonamide oxygen does not participate
in the formation of trigonal bipyramidal sphere. The binuclear
complex Ti2L was also obtained with the single monosulfonamide
ligand coordinating via N, O atoms of sulfonamide and hydroxyl O,
which acted as a bridge [13]. The structural results on both types
of complexes indicated that the additional donor group of the
monosulfonamide ligand or the alkoxy ligand can act as the group
bridging two metal centers.
2.1. Preparation of ketosulfonamides 1–8
General procedure of synthesis of the investigated sulfonamides
is shown on Scheme 3. Initially, the (+)-10-camphorsulfonic acid
chloride was obtained from the respective sulfonic acid. The inves-
tigated ketosulfonamides were obtained as follows. The respective
amine (97.1 mmol) was added into CH2Cl2 (350 ml) and 65.2 mmol
of Et3N. A solution of (+)-10-camphorsulfonic acid chloride (15.00 g,
59.8 mmol) in CH2Cl2 (75 ml) was dropped into cooled (0 ◦C) solu-
tion of amines and the reaction mixture was stirred for 2.5 h.
Subsequently 600 ml AcOEt was added to precipitate triethylam-
monium hydrochloride. The reaction mixture was then quenched
by adding 200 ml water, 1 M aqueous HCl (200 ml) and brine
(200 ml). After drying over anhydrous Na2SO4 and filtering, the sol-
vent was evaporated under vacuum. The residue was dissolved in
CH2Cl2, a solid product was precipitated with EtOH.
The aim of the research reported here was to synthesize new lig-
ands derived from camphor, including those containing sulfur atom
at C2 position (Scheme 2). The catalytic efficacy of these chiral auxil-
iaries in the stereoselective addiction of Et2Zn to benzaldehyde was
also determined. Crystal structures of selected ligands were inves-
2.1.1.
(1S,4S)-(N-benzyl)-(2-keto-7,7-dimethylbicyclo[2.2.1]hept-1-yl)
methanesulfonamide (1)
Colorless solid (90.0%), mp 52–53 ◦C, [␣]D20 = 7.7 [c = 1.70
(CHCl3)]. 1H NMR (200 MHz, CDCl3) ı (ppm): 7.43–7.22 (m, 5H, CH),
5.75 (t, J = 5.8 Hz, 1H, NH), 4.36 (d, J = 5.8 Hz, 2H, CH2(Bn)), 3.13, 2.86
(2d, J = 15.0 Hz, 2H, CH2S), 2.41–2.25, 2.18–1.90, 1.50–1.35 (3m, 1,
5, 1H, CH2CH(CH2)2), 0.94, 0.74 (2s, 6H, 2 × CH3). 13C NMR (50 MHz,
CDCl3) ı (ppm): 216.65 (C O), 136.89(C), 128.52 (2 × CH), 128.15
(2 × CH), 127.60 (CH), 59.03 (C), 50.37 (CH2), 48.48 (C), 47.20 (CH2),
42.70 (CH2), 42.52 (CH), 26.79 (CH2), 26.53 (CH2), 19.57 (CH3), 19.21
(CH3). IR(KBr): 3246 (NH), 1728 (C O), 1496 (HC C), 1329, 1150
(SO2N) cm−1. Anal. Calcd (%) for C17H23N1O3S1: C, 63.52; H, 7.21;
N, 4.36. Found (%): C, 63.31; H, 7.11; N, 4.49.
2.1.2. (1S,4S)-N-(4-methylphenyl)-(2-keto-7,7-
dimethylbicyclo[2.2.1]hept-1-yl) methanesulfonamide
(2)
Colorless solid (90.2%), mp 144–145 ◦C, [␣]D20 = 67.1 [c = 1.75
(CHCl3)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 7.67 (s, 1H, NH),
7.21–7.10 (m, 4H, 4 × CH), 3.36, 2.83 (2d, J = 15.3 Hz, 2H, CH2S),
2.32 (s, 3H, CH3), 2.49–2.41, 2.23–1.96, 1.55–1.42 (3m, 1, 5, 1H,
CH2CH(CH2)2), 0.95, 0.86 (2s, 6H, 2 × CH3). 13C NMR (75 MHz,
CDCl3) ı (ppm): 217.34 (C O), 135.39(C), 134.92 (C), 129.91
Scheme 2. Ligands 1–20 investigated in the enantioselective addition of Et2Zn to
benzaldehyde.

130
A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
Scheme 3. Scheme of the synthesis of sulfonamide ligands derived from camphor.
(2 × CH), 122.55 (2 × CH), 59.67 (C), 49.04 (C), 48.61 (CH2), 43.04
(CH2), 42.77 (CH), 27.57 (CH2), 27.02 (CH2), 20.81 (CH3), 19.83
(CH3), 19.31 (CH3). IR(KBr): 3305(NH), 1739 (C O), 1442 (HC C),
1334, 1162 (SO2N) cm−1. Anal. Calcd (%) for C17H23N1O3S1: C,
63.52; H, 7.21; N, 4.36. Found (%): C, 63.58; H, 7.19; N, 4.36.
2.19–1.94, 1.55–1.43 (3m, 1, 5, 1H, CH2CH(CH2)2), 0.95, 0.87 (2s, 6H,
2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm): 217.26 (C O), 137.74
(C), 135.13 (C), 134.06 (C), 130.32 (CH), 123.87 (CH), 119.87 (CH),
59.65 (C), 49.01 (C), 48.54 (CH2), 43.03 (CH2), 42.77 (CH), 27.56
(CH2), 27.01 (CH2), 19.81 (CH3), 19.78 (CH3), 19.31 (CH3), 19.12
(CH3). IR(KBr): 3221 (NH), 1735 (C O), 1484 (HC C), 1324, 1150
(SO2N) cm−1. Anal. Calcd (%) for C18H25N1O3S1: C, 64.45; H, 7.51;
N, 4.18. Found (%): C, 64.33; H, 7.40; N, 4.30.
2.1.3. (1S,4S)-N-(2-methylphenyl)-(2-keto-7,7-dimethylbicyclo
[2.2.1]hept-1-yl) methanesulfonamide (3)
Colorless solid (85.3%), mp 116–118 ◦C, [␣]D20 = 56.0 [c = 1.85
(CHCl3)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 7.44 (d, J = 7.8 Hz,
1H, CH), 7.33 (s, 1H, NH), 7.25–7.08 (m, 3H, 3 × CH), 3.55, 2.99
(2d, J = 15.3 Hz, J = 15.0 Hz, 2H, CH2S), 2.37 (s, 3H, CH3), 2.50–2.39,
2.29–1.93, 1.53–1.43 (3m, 1, 5, 1H, CH2CH(CH2)2), 1.03, 0.91 (2s,
6H, 2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm): 216.73 (C O),
135.47(C), 131.41 (C), 131.19 (CH), 126.86 (CH), 125.66 (CH), 122.66
(CH), 59.48 (C), 50.23 (CH2), 48.70 (C), 42.84 (CH2), 42.79 (CH), 26.98
(CH2), 26.93 (CH2), 19.85 (CH3), 19.47 (CH3), 18.23 (CH3). IR(KBr):
2.1.6. (1S,4S)-N-methyl-N-phenyl-(2-keto-7,7-dimethylbicyclo
[2.2.1]hept-1-yl) methanesulfonamide (6)
Colorless solid (65.0%), mp 104–105 ◦C, [␣]D20 = 27.6 [c = 1.65
(CHCl3)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 7.44–7.34 (m, 4H,
4 × CH), 7.31–7.24 (m, 1H, CH), 3.48, 2.86 (2d, J = 14.7 Hz, 2H, CH2S),
3.38 (s, 3H, CH3N), 2.55–2.44, 2.42–2.31, 2.09–1.86, 1.61–1.49 (4m,
1, 1, 3, 2H, CH2CH(CH2)2), 1.10, 0.84 (1s, 6H, 2 × CH3). 13C NMR
(75 MHz, CDCl3) ı (ppm): 215.16 (C O), 141.50 (C), 129.16 (2 × CH),
127.03 (CH), 126.14 (2 × CH), 58.26 (C), 47.70 (C), 45.12 (CH2), 42.83
(CH), 42.48 (CH2), 38.29 (CH3N), 26.77 (CH2), 25.15 (CH2), 20.02
(CH3), 19.66 (CH3). IR(KBr): 1729 (C O), 1457 (HC C), 1325, 1152
(SO2N) cm−1. Anal. Calcd (%) for C17H23N1O3S1: C, 63.52; H, 7.21;
N, 4.36. Found (%): C, 64.02; H, 7.15; N, 4.35.
3291 (NH), 1734 (C O), 1458 (HC C), 1319, 1146 (SO2N) cm−1
Anal. Calcd (%) for C17 23N1O3S1: C, 63.52; H, 7.21; N, 4.36. Found
.
H
(%): C, 63.50; H, 7.24; N, 4.41.
2.1.4.
(1S,4S)-N-(2,4-dimethylphenyl)-(2-keto-7,7-dimethylbicyclo
[2.2.1]hept-1-yl) methanesulfonamide (4)
2.1.7. (1S,4S)-N,N-di-iso-butyl-(2-keto-7,7-dimethylbicyclo
[2.2.1]hept-1-yl) methanesulfonamide (7)
Colorless solid (55.6%), mp 100–102 ◦C, [␣]D20 = 39.8 [c = 1.55
(CHCl3)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 7.28–7.22 (m, 1H,
CH), 7.23 (s, 1H, NH), 7.05–6.96 (m, 2H, 2 × CH), 3.53, 2.96 (2d,
J = 15.3 Hz, 2H, CH2S), 2.34 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.49–2.39,
2.24–1.94, 1.52–1.42 (3m, 1, 5, 1H, CH2CH(CH2)2), 1.02, 0.92 (2s,
6H, 2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm): 216.72 (C O),
135.75(C), 132.70(C), 132.34 (C), 131.88 (CH), 127.33 (CH), 123.67
(CH), 59.46 (C), 49.91 (CH2), 48.64 (C), 42.82 (CH2), 42.76 (CH), 26.96
(CH2), 26.90 (CH2), 20.72 (CH3), 19.82 (CH3), 19.46 (CH3), 18.22
(CH3). IR(KBr): 3249 (NH), 1739 (C O), 1418 (HC C), 1333, 1150
(SO2N) cm−1. Anal. Calcd (%) for C18H25N1O3S1: C, 64.45; H, 7.51;
N, 4.18. Found (%): C, 63.50; H, 7.46; N, 4.11.
Colorless solid (60.1%), mp 104–106 ◦C, [␣]D20 = 26.4 [c = 4.95
(CHCl3)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 3.31, 2.77 (2d,
J = 14.4 Hz, 2H, CH2S), 2.99 (ddd, J = 24.0 Hz, J = 13.8 Hz, J = 7.5 Hz,
4H, 2 × CH2), 2.59–2.49, 2.42–2.31, 2.10–1.84 (3m, 1, 1, 5H,
CH2CH(CH2)2), 1.68–1.56 (m, 1H, CH), 1.44–1.34 (m, 1H, CH), 1.15,
0.88 (2s, 6H, 2 × CH3), 0.94 (dd, J = 6.9 Hz, 12H, 4 × CH3). 13C NMR
(75 MHz, CDCl3) ı (ppm): 215.49 (C O), 58.40(C), 56.83 (2 × CH2),
47.67 (C), 46.45 (CH2), 42.92 (CH), 42.57 (CH2), 27.42 (2 × CH),
26.84 (CH2), 25.31 (CH2), 20.16(4 × CH3), 20.13 (CH3), 19.78 (CH3).
IR(KBr): 1734 (C O), 1458 (HC C), 1319, 1146 (SO2N) cm−1. Anal.
Calcd (%) for C18H33N1O3S1: C, 62.94; H, 9.68; N, 4.08. Found (%): C,
63.50; H, 9.52; N, 4.55.
2.1.5.
(1S,4S)-N-(3,4-dimethylphenyl)-(2-keto-7,7-dimethylbicyclo
[2.2.1]hept-1-yl) methanesulfonamide (5)
2.1.8. (1S,4S)-(2-keto-7,7-dimethylbicyclo
[2.2.1]hept-1-yl)morpholinesulfonmethane (8)
Colorless solid (92.2%), mp 139–141 ◦C, [␣]D20 = 60.9 [c = 1.60
(CHCl3)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 7.61 (s, 1H, NH),
7.10–7.05 (m, 2H, 2 × CH), 7.03–6.97 (m, 1H, CH), 3.38, 2.83 (2d,
J = 15.3 Hz, 2H, CH2S), 2.24 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.51–2.41,
Colorless solid (91.9%), mp 144–147 ◦C, [␣]D20 = 32.3 [c = 4.40
(CHCl3)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 3.74 (t, J = 6.0 Hz,
4H, 2 × CH2), 3.30–3.26 (m, 4H, 2 × CH2), 3.32, 2.72 (2d, J = 14.7 Hz,
J = 11.1 Hz, 2H, CH2S), 2.56–2.32, 2.12–1.90, 1.68–1.57, 1.46–1.37

A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
131
(4m, 2, 3, 1, 1H, CH2CH(CH2)2), 1.11, 0.86 (2s, 6H, 2 × CH3). 13C NMR
(75 MHz, CDCl3) ı (ppm): 215.08 (C O), 66.47 (2 × CH2), 58.07 (C),
47.88 (C), 45.71 (2 × CH2), 44.40 (CH2), 42.71 (CH), 42.50 (CH2),
26.83 (CH2), 25.06 (CH2), 19.90 (CH3), 19.69 (CH3). IR(KBr): 1734
(C O), 1319, 1146 (SO2N) cm−1. Anal. Calcd (%) for C14H23N1O4S1:
C, 55.79; H, 7.69; N, 4.65. Found (%): C, 55.50; H, 7.61; N, 4.55.
Na2SO4. After the removal of Et2O, a crude product was crystallized
from EtOH to obtain 11 (0.089 g, 89% yield).
2.3.1. (1S,2R,4S)-(N-benzyl)-(7,7-dimethylbicyclo[2.2.1]hept-1-
yl-2-thiol) methanesulfonamide
(11)
Colorless solid (89%), mp 134–136 ◦C, 1H NMR (300 MHz, CDCl3)
ı (ppm): 7.42–7.28 (m, 5H, 5 × CH), 4.58 (t, J = 6.0 Hz, 1H, NH), 4.35
(ddd, J = 21.6 Hz, J = 14.1 Hz, J = 6.3 Hz, 2H, CH2(Bn)), 3.88, 2.82 (2d,
J = 13.8 Hz, 2H, CH2S), 3.49–3.36 (m, 1H, CHS), 2.52 (d, J = 7.5 Hz,
1H, SH), 2.20–1.90, 1.75–1.69, 1.63–1.49, 1.33–1.19 (4m, 2, 3, 1,
1H, CH2CH(CH2)2), 0.93, 0.79 (2s, 6H, 2 × CH3). 13C NMR (75 MHz,
CDCl3) ı (ppm): 136.84(C), 128.89 (2 × CH), 128.10 (CH), 128.05
(2 × CH), 53.43 (CH2), 49.80 (C), 49.52 (C), 47.32 (CH2), 45.13 (CH),
43.78 (CH), 39.94 (CH2), 33.02 (CH2), 27.26 (CH2), 20.86 (CH3), 19.88
(CH3). IR(KBr): 3269 (NH), 2567 (SH), 1460 (HC C), 1317, 1147
(SO2N) cm−1. Anal. Calcd (%) for C17H25N1O2S2: C, 60.14; H, 7.42;
N, 4.13. Found (%): C, 60.19; H, 7, 35; N, 4.19.
2.2. Preparation of thioketosulfonamides 9–10
The ketosulfonamide 1 (5.00 g, 15.55 mmol), Na2SO4 (5.00 g)
and Lawesson reagent (11.78 g, 29.12 mmol) were dissolved in
250 ml of toluene and molecular sieves 4A (3.00 g) added. The
reaction mixture was heated under reflux for 50 h. After cooling,
the resulted crystals were separated by suction. Then silica gel
(70–100 mesh) deactivated with Et3N was added to a filtrate. The
product was deposited on silica by evaporation of toluene with
a rotary evaporator. A residue was placed on a chromatographic
column with silica gel and eluted with toluene (I CC). The orange
product was repeatedly purified using chromatography (eluent
CH2Cl2-petroleum ether 1:1, II CC) (eluent CH2Cl2-petroleum ether
1:4, III CC) and (eluent EtOAc:petroleum ether 1:20, IV CC) and addi-
tional crystallization from petroleum ether (acetone bath) giving
2.58 g (44% yield) of the pure thioketosulfonamide 9. TLC: eluent:
CH2Cl2 Rf = 0.56, eluent: toluene Rf = 0.18, eluent: petroleum ether-
EtOAc Rf = 0.56 orange spot, vanillin as a developer.
2.3.2. (1S,2R,4S)-(7,7-dimethylbicyclo[2.2.1]hept-1-yl-2-
thiol)morpholinesulfonmethane
(12)
Colorless solid (97.5%), mp 149–150 ◦C, 1H NMR (300 MHz,
CDCl3) ı (ppm): 3.64 (t, J = 6.2 Hz, 4H, 2 × CH2), 3.32–3.21 (m, 4H,
2 × CH2), 3.35, 2.70 (2d, J = 13.8 Hz, J = 11.1 Hz, 2H, CH2S), 3.45–3.38
(m, 1H, CHS), 2.53 (d, J = 7.5 Hz, 1H, SH), 2.46–2.32, 2.12–1.90,
1.68–1.57, 1.46–1.37 (4m, 2, 3, 1, 1H, CH2CH(CH2)2), 1.10, 0.83 (2s,
6H, 2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm): 66.43 (2 × CH2),
58.01 (C), 47.82 (C), 45.68 (2 × CH2), 44.39 (CH2), 43.70 (CH), 42.71
(CH), 42.50 (CH2), 26.83 (CH2), 25.06 (CH2), 19.90 (CH3), 19.69
(CH3). IR(KBr): 2561 (SH), 1319, 1146 (SO2N) cm−1. Anal. Calcd (%)
for C14H25N1O3S2: C, 52.63; H, 7.89; N, 4.38. Found (%): C, 52.50; H,
7.81; N, 4.45.
2.2.1. (1S,4S)-(N-benzyl)-(7,7-dimethylbicyclo[2.2.1]hept-1-yl-2-
thione) methanesulfonamide
(9)
Orange solid (44%), mp 91–95 ◦C, [␣]D20 = 156.7 [c = 2.00
(CHCl3)]. 1H NMR (200 MHz, CDCl3) ı (ppm): 7.42–7.26 (m,
5H, 5 × CH), 4.57 (t, J = 5.6 Hz, 1H, NH), 4.37 (d, J = 6.2 Hz, 2H,
CH2(Bn)), 3.99, 3.00 (2d, J = 15.0 Hz, 2H, CH2S), 2.90–2.40, 2.20–1.98,
1.70–1.99 (3m, 3, 2, 2H, CH2CH(CH2)2), 1.16, 0.80 (2s, 6H, 2 × CH3).
13C NMR (50 MHz, CDCl3) ı (ppm): 265.08 (C S), 136.84(C), 128.70
(2 × CH), 128.02 (2 × CH), 127.85 (CH), 69.65 (C), 54.98 (CH2), 52.67
(CH2), 50.49 (C), 47.43 (CH2), 44.88 (CH), 29.27 (CH2), 27.18 (CH2),
20.29 (CH3), 19.69 (CH3). IR(KBr): 3316 (NH), 1454 (HC C), 1325,
1136 (SO2N), 1249 (C S) cm−1. Anal. Calcd (%) for C17H23N1O2S2:
C, 60.50; H, 6.87; N, 4.15. Found (%): C, 60.39; H, 6.73; N, 4.29.
2.4. Preparation of hydroxysulfonamides 13–20
The general procedure of reduction of 1–8 to obtain 13–20
is as follows. The solution of ketosulfonamide (1.5 mmol) in THF
(10 ml) was cooled to −50 ◦C under argon atmosphere. l-Selectride
(12 mmol, 1 M solution in THF) was then slowly added. The mix-
ture was stirred at this temperature for 1 h, allowed to warm up to
the room temperature, and stirred for 4 days. Then reaction mix-
ture was cooled to 0 ◦C, quenched by addition of water (1 ml), EtOH
(8 ml), 3 M NaOH (10 ml) and 30% H2O2 (8 ml). The solution was
saturated with K2CO3 and extracted with CH2Cl2 (3 × 20 ml). Com-
bined organic phase was washed with water, brine and dried over
MgSO4. The drying agent was filtered out, solvent was evaporated in
vacuo. The obtained precipitate was re-crystallized from methanol
(13, 14, 16–20) or ethanol (15).
2.2.2. (1S,4S)-(2-methylphenyl)-(7,7-dimethylbicyclo[2.2.1]hept-
1-yl-2-thione) methanesulfonamide
(10)
Orange solid (24%), mp 112.5–114 ◦C, [␣]D20 = 123.7 [c = 2.00
(CHCl3)]. 1H NMR (200 MHz, CDCl3) ı (ppm): 7.55 (d, J = 8.0 Hz, 1H,
CH), 7.26–7.11 (m, 3H, 3 × CH), 6.64 (s, 1H, NH), 4.17, 3.19 (2d,
J = 14.8 Hz, 2H, CH2S), 2.75–2.41, 2.17–1.98, 1.70–1.37 (3m, 3, 2,
2H, CH2CH(CH2)2), 2.35 (s, 3H, CH3), 1.20, 0.83 (2s, 6H, 2 × CH3).
13C NMR (50 MHz, CDCl3) ı (ppm): 265.10 (C S), 135.16(C), 131.12
(CH), 129.86 (C), 127.17 (CH), 125.54 (CH), 122.20 (CH), 69.61 (C),
54.81 (CH2), 52.32 (CH2), 50.22 (C), 44.99 (CH), 29.42 (CH2), 27.06
(CH2), 20.38 (CH3), 19.70 (CH3), 18.17 (CH3). IR(KBr): 3412 (NH),
1444 (HC C), 1316, 1125 (SO2N), 1252 (C S) cm−1. Anal. Calcd (%)
for C17H23N1O2S2: C, 60.50; H, 6.87; N, 4.15. Found (%): C, 60.32; H,
6.78; N, 4.21.
2.4.1. (1S,2R,4S)-(N-benzyl)-(2-hydroxy-7,7-
dimethylbicyclo[2.2.1]hept-1-yl) methanesulfonamide
(13)
Colorless solid (92.4%), mp 98–101 ◦C, [␣]D20 = −40.00 [c = 0.1
(CHCl3)]. 1H, NMR, CDCl3, ı (ppm): 7.42–7.29 (m, 5H, 5 × CH), 4.78
(t, J = 5.7 Hz, 1H, NH), 4.33 (d, J = 5.1 Hz, 2H, CH2), 4.07 (dt, J = 6.9 Hz,
J = 3.3 Hz, 1H, CHOH), 3.17 (d, J = 3.3 Hz, 1H, OH), 3.31, 2.72 (2d,
J = 13.8 Hz, 2H, CH2S), 1.79–1.56, 1.53–1.40, 1.15–1.05 (3m, 5, 1, 1H,
CH2CH(CH2)2), 0.98, 0.72 (2s, 2 × 3H, 2 × CH3). 13C NMR (75 MHz,
CDCl3) ı (ppm): 136.64 (C), 128.92 (2 × CH), 128.19 (2 × CH), 128.10
(CH), 76.37 (CHOH), 53.18 (CH2), 50.35 (C), 48.66 (C), 47.39 (CH2),
44.32 (CH), 38.95 (CH2); 30.43 (CH2); 27.33 (CH2); 20.44 (CH3),
19.77 (CH3). IR(Nujol): 3529 (OH), 3303 (NH), 1453 (HC C), 1308,
1132 (SO2N), 1086 (CO) cm−1. Anal. Calcd (%) for C17H25N1O3S1: C,
63.13; H, 7.79; N, 4.33. Found (%): C, 63.15; H, 7.84; N, 4.39.
2.3. Preparation of mercaptosulfonamides 11 and 12
A solution of thioketosulfonamide 9 (0.10 g, 2.37 mmol) in
Et2O (5 ml) was quickly added to a suspension of LiAlH4 (0.10 g,
2.63 mmol) in Et2O at room temperature. The reaction was con-
ducted for 5 min and carefully quenched with water (5 ml). The
organic layer was separated, whereas an aqueous one was extracted
with Et2O (3 × 10 ml). The combined organic layers were rinsed
with water (5 ml), brine (2 × 5 ml) and then dried over anhydrous

132
A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
2.4.2. (1S,2R,4S)-N-(4-methylphenyl)-(2-hydroxy-7,7-
dimethylbicyclo[2.2.1]hept-1-yl) methanesulfonamide
(14)
C, 64.06; H, 8.06; N, 4.15. Found (%): C, 64.04; H, 8.11;
N, 4.19.
Colorless solid (95.8%), mp 102–104 ◦C, [␣]D20 = −44.00 [c = 0.1
(CHCl3)]. 1H, NMR, CDCl3, ı (ppm): 7.18–7.10 (m, 4H, 4 × CH),
6.9–6.8 (bs, 1H, NH), 4.17–4.07 (bs, 1H, CHOH), 3.23–3.14 (bs, 1H,
OH), 3.60, 2.94 (2d, J = 13.8, 2H, CH2S), 2.33 (s, 3H, CH3), 1.83–1.63,
1.60–1.47, 1.16–1.04 (3m, 5, 1, 1H, CH2CH(CH2)2), 1.00, 0.75 (2s,
2 × 3H, 2 × CH3). 13C, NMR, CDCl3, ı (ppm): 135.36 (C), 133.98 (C),
130.24 (2 × CH), 121.23 (2 × CH), 76.42 (CHOH), 51.23 (CH2), 50.34
(C), 48.82 (C), 44.37 (CH), 39.09 (CH2), 30.47 (CH2), 27.29 (CH2),
20.81 (CH3), 20.47 (CH3), 19.83 (CH3). IR(Nujol): 3562 (OH), 3277
(NH), 1511 (HC C), 1332, 1140 (SO2N), 1087 (CO) cm−1. Anal. Calcd
(%) for C17H25N1O3S1: C, 63.13; H, 7.79; N, 4.33. Found (%): C, 63.18;
H, 7.86; N, 4.45.
2.4.6. (1S,2R,4S)-N-methyl-N-phenyl-(2-hydroxy-7,7-
dimethylbicyclo[2.2.1]hept-1-yl) methanesulfonamide
(18)
Colorless solid (88.2%), mp 105–108 ◦C, [␣]D20 = −33.00 [c = 0.1
(CHCl3)]. 1H, NMR, CDCl3, ı (ppm): 7.44–7.39 (m, 4H, 4 × CH),
7.37–7.28 (m, 1H, CH), 4.08 (dt, J = 7.8 Hz, J = 3.9 Hz, 1H, CHOH), 3.36
(s, 3H, CH3), 3.07 (d, J = 3.9 Hz, 1H, OH), 3.37, 2.79 (2d, J = 13.2 Hz, 2H,
CH2S), 1.82–1.61, 1.59–1.46, 1.19–1.05 (3m, 5, 1, 1H, CH2CH(CH2)2),
1.03, 0.77 (2s, 2 × 3H, 2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm):
141.33 (C), 129.37 (2 × CH), 127.42 (CH), 126.28 (2 × CH), 76.38
(CHOH), 50.04 (C), 48.76 (C), 47.29 (CH2), 44.44 (CH), 38.91 (CH2),
38.37 (CH3), 30.56 (CH2), 27.28 (CH2), 20.57 (CH3), 19.89 (CH3).
IR (Nujol): 3516 (OH), 1454 (HC C), 1330, 1142 (SO2N), 1087
(CO) cm−1. Anal. Calcd (%) for C17H25N1O3S1: C, 63.13; H, 7.79; N,
4.33. Found (%): C, 63.21; H, 7.84; N, 4.50.
2.4.3. (1S,2R,4S)-N-(2-methylphenyl)-(2-hydroxy-7,7-
dimethylbicyclo[2.2.1]hept-1-yl) methanesulfonamide
(15)
Colorless solid (87.5%), mp 88–90 ◦C, [␣]D20 = −43.00 [c = 0.1
(CHCl3)]. 1H, NMR, CDCl3, ı (ppm): 7.47–7.40 (m, 1H, CH), 7.29–7.21
(m, 2H, 2 × CH), 7.18–7.10 (m, 1H, CH), 6.35 (s, 1H, NH), 4.12
(dt, J = 7.8 Hz, J = 3.9 Hz, 1H, CHOH), 3.13 (d, J = 3.9 Hz, 1H, OH),
3.55, 3.00 (2d, J = 13.5 Hz, 2H, CH2S), 2.34 (s, 3H, CH3), 1.81–1.63,
1.60–1.50, 1.18–1.10 (3m, 5, 1, 1H, CH2CH(CH2)2), 1.03, 0.78 (2s,
2 × 3H, 2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm): 134.75 (C),
131.24 (CH), 129.93 (C), 127.40 (CH), 125.89 (CH), 122.06 (CH),
76.38 (CHOH), 52.23 (CH2), 50.48 (C), 48.80 (C), 44.35 (CH), 39.04
(CH2), 30.42 (CH2), 27.30 (CH2), 20.52 (CH3), 19.85 (CH3), 18.05
(CH3). IR (Nujol): 3542 (OH), 3275 (NH), 1497 (HC C), 1325, 1139
(SO2N), 1086 (CO) cm−1. Anal. Calcd (%) for C17H25N1O3S1: C, 63.13;
H, 7.79; N, 4.33. Found (%): C, 63.19; H, 7.82; N, 4.48.
2.4.7. (1S,2R,4S)-N,N-di-iso-butyl-(2-hydroxy-7,7-
dimethylbicyclo[2.2.1]hept-1-yl) methanesulfonamide (19)
Colorless solid (86.5%), mp 82–85 ◦C, [␣]D20 = −36.00 [c = 0.1
(CHCl3)]. 1H, NMR, CDCl3, ı (ppm): 7.44–7.39 (m, 4H, 4 × CH),
7.37–7.28 (m, 1H, CH), 4.08 (dt, J = 7.8 Hz, J = 3.9 Hz, 1H, CHOH),
3.36 (s, 3H, CH3), 3.07 (d, J = 3.9 Hz, 1H, OH), 3.37, 2.79 (2d,
J = 13.2 Hz, 2H, CH2S), 1.82–1.61, 1.59–1.46, 1.19–1.05 (3m, 5, 1, 1H,
CH2CH(CH2)2), 1.03, 0.77 (2s, 2 × 3H, 2 × CH3). 13C NMR (75 MHz,
CDCl3) ı (ppm): 76.49 (CHOH), 56.46 (2 × CH2), 50.23 (C), 49.36
(CH2), 48.63 (C), 44.46 (CH), 38.87 (CH2), 30.78 (CH2), 27.31 (CH2),
27.26 (2 × CH), 20.58 (CH3), 20.12 (4 × CH3), 19.92 (CH3). IR(Nujol):
3521 (OH), 1326, 1139 (SO2N), 1087 (CO) cm−1. Anal. Calcd (%) for
C18H35N1O3S1: C, 62.57; H, 10.21; N, 4.05. Found (%): C, 62.60; H,
10.32; N, 4.41.
2.4.4. (1S,2R,4S)-N-(2,4-dimethylphenyl)-(2-hydroxy-7,7-
dimethylbicyclo[2.2.1]hept-1-yl) methanesulfonamide
2.4.8. (1S,2R,4S)-(2-hydroxy-7,7-dimethylbicyclo[2.2.1]
(16)
hept-1-yl) morpholinesulfonmethane (20)
Colorless solid (94.9%), mp 120–123 ◦C, [␣]D20 = −24.00 [c = 0.1
(CHCl3)]. 1H, NMR, CDCl3, ı (ppm): 7.31–7.23 (m, 1H, CH), 7.08–7.00
(m, 2H, 2 × CH), 6.19 (s, 1H, NH), 4.11 (dt, J = 7.8 Hz, J = 3.9 Hz, 1H,
CHOH), 3.12 (d, J = 3.9 Hz, 1H, OH), 3.51, 2.97 (2d, J = 13.5 Hz, 2H,
CH2S), 2.31 (s, 3H, CH3), 1.85–1.62, 1.60–1.48, 1.17–1.07 (3m, 5,
1, 1H, CH2CH(CH2)2), 1.02, 0.78 (2s, 2 × 3H, 2 × CH3). 13C NMR
(75 MHz, CDCl3) ı (ppm): 136.23 (C), 131.93 (CH), 131.89 (C), 131.04
(C), 127.90 (CH), 123.41 (CH), 76.38 (CHOH), 52.10 (CH2), 50.46 (C),
48.77 (C), 44.37 (CH), 39.00 (CH2), 30.43 (CH2), 27.30 (CH2), 20.87
(CH3), 20.54 (CH3), 19.86 (CH3), 18.07 (CH3). IR(Nujol): 3616 (OH),
3247 (NH), 1498 (HC C), 1334, 1158 (SO2N), 1084 (CO) cm−1. Anal.
Calcd (%) for C18H27N1O3S1: C, 64.06; H, 8.06; N, 4.15. Found (%): C,
64.02; H, 8.10; N, 4.21.
Colorless solid (90.4%), mp 174–176 ◦C, [␣]D20 = −39.00 [c = 0.1
(CH3Ph)]. 1H NMR (300 MHz, CDCl3) ı (ppm): 4.09 (q, J = 4.2, 1H,
CHOH), 3.82–3.76 (m, 4H, 2 × CH2), 3.31–3.25 (m, 4H, 2 × CH2),
3.24, 2.66 (2d, J = 14.1 Hz, J = 13.2 Hz, 2H, CH2S), 3.17 (d, J = 3.9 Hz,
1H, OH), 1.87–1.48, 1.17–1.09 (2m, 6, 1H, CH2CH(CH2)2), 1.07, 0.83
(2s, 6H, 2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm): 76.39 (CHOH),
66.45 (2 × CH2), 49.97 (C), 48.81 (C), 46.41 (CH2), 45.86 (2 × CH2),
44.43 (CH), 38.94 (CH2), 30.73 (CH2), 27.31 (CH2), 20.57 (CH3), 19.90
(CH3). IR(Nujol): 3520 (OH), 1334, 1128 (SO2N) 1072(CO) cm−1
Anal. Calcd (%) for C14H25N1O4S1: C, 55.42; H, 8.30; N, 4.62. Found
(%): C, 55.40; H, 8.22; N, 4.58.
.
2.5. Enantioselective addition of diethylzinc to benzaldehyde
2.4.5. (1S,2R,4S)-N-(3,4-dimethylphenyl)-(2-hydroxy-7,7-
dimethylbicyclo[2.2.1]hept-1-yl)methanesulfonamide
(17)
The reaction of Et2Zn addition was performed according to
Scheme 1, under dry argon. Titanium tetraisopropoxide (0.42 ml,
1.4 mmol) was added to the appropriate ligand (1–20) (0.2 mmol)
dissolved in methylene chloride (5 ml). The mixture was stirred
for 1 h at room temperature, cooled to −50 ◦C, and diethylz-
inc was added (3 ml of 1 M hexane solution, 3 mmol). Stirring
was continued at this temperature, and benzaldehyde (0.1 ml,
1 mmol) was added. The mixture was allowed to warm up to
the room temperature and stirred for the period of time indi-
cated in Table 1. The reaction was quenched with 1 M HCl (10 ml),
then precipitate was filtered out. The organic layer was sepa-
rated and the aqueous layer was extracted three times with 5 ml
of ethyl acetate. Combined organic extracts were washed with
brine, dried over MgSO4 and purified by column chromatography
(hexane/ethyl acetate 5:1) to give 1-phenylpropanol. The enan-
Colorless solid (94.1%), mp 135–138 ◦C, [␣]D20 = −45.00 [c = 0.1
(CHCl3)]. 1H, NMR, CDCl3, ı (ppm): 7.12–7.07 (m, 1H, CH), 7.05–6.91
(m, 2H, 2 × CH), 6.51 (s, 1H, NH), 4.13 (dt, J = 7.5 Hz, J = 4.2 Hz,
1H, CHOH), 3.14 (d, J = 4.2 Hz, 1H, OH), 3.49, 2.95 (2d, J = 13.8 Hz,
2H, CH2S), 2.24 (d, J = 5.7 Hz, 6H, 2 × CH3), 1.87–1.61, 1.59–1.47,
1.18–1.08 (3m, 5, 1, 1H, CH2CH(CH2)2), 1.01, 0.76 (2s, 2 × 3H,
2 × CH3). 13C NMR (75 MHz, CDCl3) ı (ppm): 138.19 (C), 134.16
(C), 134.10 (C), 130.67 (CH), 122.58 (CH), 118.54 (CH), 76.41
(CHOH), 51.27 (CH2), 50.39 (C), 48.83 (C), 44.37 (CH), 39.05 (CH2),
30.49 (CH2), 27.31 (CH2), 20.51 (CH3), 19.91 (CH3), 19.84 (CH3),
19.16 (CH3). IR(Nujol): 3464 (OH), 3126 (NH), 1499 (HC C), 1323,
1137 (SO2N), 1086 (CO) cm−1. Anal. Calcd (%) for C18H27N1O3S1:

A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
133
Table 1
Addition of Et2Zn to benzaldehyde in a presence of sulfonamides 1–20.
R3
R1
R2
Sequence of
additives
Field [%]
ee% (configuration)a
1
2
3
4
5
6
7
8
O
H
H
H
H
Bn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
87
64
64
48
52
51
50
53
16(R)
12(R)
7.6(R)
5.5(R)
5.9(R)
5.6(R)
1.9(R)
1.1(R)
O
O
O
O
O
O
O
4-C6H4Me
2-C6H4Me
2,4-C6H3Me2
3,4-C6H3Me2
Ph
H
Me
iBu
iBu
Morpholine
13
14
15
16
17
18
19
20
–OH
–OH
–OH
–OH
–OH
–OH
–OH
–OH
H
H
H
H
Bn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
98
95
92
92
92
50
52
45
53(S)
36(S)
38(S)
35(S)
51(S)
1.3(S)
0.6(S)
1.1(S)
4-C6H4Me
2-C6H4Me
2,4-C6H3Me2
3,4-C6H3Me2
Ph
H
Me
iBu
iBu
Morpholine
13
14
15
16
17
18
19
20
–OH
–OH
–OH
–OH
–OH
–OH
–OH
–OH
H
H
H
H
Bn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
Ti/Zn
97
96
94
95
97
52
54
54
69(S)b,c
65(S)b,d
65(S)b,d
36(S)b
4-C6H4Me
2-C6H4Me
2,4-C6H3Me2
3,4-C6H3Me2
Ph
H
64(S)b
Me
0.2(S)b
2.1(S)b
2.0(S)b
iBu
iBu
Morpholine
9
10
S
S
H
H
Bn
2-C6H4Me
Ti/Zn
Ti/Zn
47
49
9.2(R)
3.7(R)
9
10
S
S
H
H
Bn
2-C6H4Me
Zn/Ti
Zn/Ti
59
56
5(R)
1(R)
9
10
S
S
H
H
Bn
2-C6H4Me
Zn
Zn
57
52
10(R)e
2(R)e
11
12
–SH
–SH
H
Bn
Ti/Zn
Ti/Zn
46
44
2.3(R)
1.7(R)
Morpholine
11
12
–SH
–SH
H
Bn
Zn/Ti
Zn/Ti
52
59
1(R)
0.6(R)
Morpholine
Reaction conditions:
a
1.4 mmol Ti(OiPr)4 added to the appropriate ligand (1 to 20) (0.2 mmol) dissolved in CH2Cl2.
b
1.4 mmol Ti(OiPr)4 added to the appropriate ligand (1 to 20) (0.2 mmol) dissolved in toluene. The mixture stirred for 1 h at room temperature, cooled to −50 ◦C, then
diethylzinc (3 mmol) and benzaldehyde (1 mmol) were added. The reaction quenched with 1 M HCl (10 ml). The enantiomeric excess determined by GC using a ␤-Dex column.
c
Literature data previously published for 13 by Ramón et al. [8]: 71% ee of (S)-1-phenylpropanol by Hui et al. [9]: 71% ee of (S)-1-phenylpropanol.
Literature data previously published for 14 and 15 by Hui et al. [9]: 48% ee of (S)-1-phenylpropanol.
The activity of mercapto- and thioketosulfonamide auxiliaries was determined for the Ti/Zn and Zn/Ti sequence of metal compound dosage, results of addition performed
d
e
with the use of 9 and 10 ligands in an absence of Ti(OiPr)4.
(cm−1): 1747 (C O), 1332, 1142 (SO2N). Complex 23 (ligand 13),
orange, IR (Nujol) (cm−1): 1312, 1140 (SO2N), 662 (Ti–O). Complex
24 (ligand 19), orange, IR (Nujol) (cm−1): 1325, 1139 (SO2N), 665
(Ti–O). Complex 26 (ligand 25 [17]) orange, IR (Nujol) (cm−1): 3501
(OH), 3256 (NH), 1315, 1142 (SO2N), 665 (Ti–O).
tiomeric excess was determined by GC analysis using a ␤-Dex
column.
2.6. Synthesis of Ti-sulfonamide complexes 21–24 and 26
The Ti(IV) complexes 21–24 and 26 obtained from sulfonamides
1, 7, 13, 19 and 25 [17] respectively, were synthesized using the
following procedure. The sample of ketosulfonamide 1 (0.719 g,
2.238 mmol) was dissolved in 20 ml dry toluene, then Ti(NMe2)4
was added (0.3 ml, 1.119 mmol), and the reaction mixture was
stirred under argon for 2.5 h at ambient temperature. The color
change from yellow to dark red confirmed the formation of the
complex 21. The mixture was concentrated using vacuum pump.
The addition of dry hexane (20 ml) resulted in the formation of red
sediment, which was dried under vacuum. The IR spectra of the
formed complexes were recorded. However, attempts to obtain
monocrystals suitable for the structural analysis had failed. Due
to the instability of the complexes, we have not been able to obtain
the NMR spectra.
3. Results and discussion
Ketosulfonamide ligands 1–8 were synthesized from amines
and (+)-10-camphorsulfonic acid chloride. Hydroxy ligands 13–20
were obtained by the reduction of the carbonyl group in ligands
1–8 with l-Selectride (Scheme 3). Selected thioketo- or mercap-
tosulfonamides differing significantly by the bulk of the N-bound
group have also been synthesized to explore the effect of such sub-
stituents. Thioketosulfonamides 9 and 10 were synthesized from
ketosulfonamides 1 and 3 with the use of the Lawesson reagent.
Reduction of respective thioketosulfonamides with LiAlH4 gave
mercaptosulfonamides 11–12 (Scheme 3). Crystal structures of the
sulfonamides with the N-benzyl moiety were determined with the
X-ray diffraction method. The sulfonamide ligands were applied
in the asymmetric addition of diethylzinc to benzaldehyde in the
presence of titanium tetraisopropoxide (Scheme 1).
The IR results for the obtained complexes are as follows. Com-
plex 21 (ligand 1), dark red, IR (Nujol) (cm−1): 3290 (NH), 1739
(C O), 1323, 1144 (SO2N). Complex 22 (ligand 7), orange, IR (Nujol)

134
A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
Table 2
Crystallographic data for sulfonamide ligands: 1, 9, 11 and 13.
1
9
11
13
Formula sum
Formula weight
Color
Crystal system
Space group
C17H23N1O3S1
321.42
Colorless
Monoclinic
P21
C17H23N1O2S2
337.48
Orange
Orthorhombic
P212121
C17H25N1O2S2
339.50
Colorless
Orthorhombic
P212121
C17H25N1O3S1
323.44
Colorless
Orthorhombic
P212121
Unit cell dimensions
a (Å)
b (Å)
c (Å)
ˇ (◦)
V (Å3)
Z
11.0662(9)
9.3451(7)
15.913(1)
92.639(7)
1643.9(2)
4
6.7784(7)
14.822(1)
17.305(1)
6.8777(4)
9.7499(5)
26.297(1)
8.391(2)
10.882(2)
37.009(7)
1738.7(3)
4
1763.4(2)
4
3379.3(12)
8
Density (calculated) (Mg/m3)
Absorption coefficient (mm−1
F(0 0 0)
1.299
0.209
688
1.289
0.313
720
1.279
0.308
728
1.271
0.204
1392
)
Crystal size (mm)
ꢂ range for data collection(deg)
0.16 × 0.16 × 0.08
0.29 × 0.16 × 0.11
0.26 × 0.24 × 0.22
0.40 × 0.25 × 0.05
2.29–25.99
2.73–31.49
2.60–31.45
2.17–24.00
Index ranges
−13 ≤ h ≤ 13
−11 ≤ k ≤ 10
−15 ≤ l ≤ 19
−9 ≤ h ≤ 7
−8 ≤ h ≤ 10
−13 ≤ k ≤ 13
−36 ≤ l ≤ 38
−7 ≤ h ≤ 9
−21 ≤ k ≤ 20
−25 ≤ l ≤ 24
−12 ≤ k ≤ 12
−42 ≤ l ≤ 42
Reflections collected
Independent reflections
Transmission max/min
Parameters
12158
17370
17532
21119
6208[Rint = 0.1132]
0.9826/0.9669
401
5334[Rint = 0.1534]
0.9668/0.9158
201
5390[Rint = 0.0483]
0.9552/0.9241
201
5319 [Rint = 0.1618]
0.9899/0.9230
437
Goodness-of-fit on F2
Final R indices [I > 2ꢃ(I)]
R indices (all data)
0.988
1.057
1.035
1.125
R1 = 0.0973, wR2 = 0.1428
R1 = 0.1730, wR2 = 0.1730
−0.06(18)
R1 = 0.0968, wR2 = 0.1692
R1 = 0.1978, wR2 = 0.2144
−0.47(17)
R1 = 0.0521, wR2 = 0.1125
R1 = 0.0776, wR2 = 0.1248
0.08(8)
0.327 and −0.276
R1 = 0.1372, wR2 = 0.3310
R1 = 0.1780, wR2 = 0.3662
0.1(3)
0.429 and −0.318
Flack (x)
Largest diff. peak and hole (e Å−3
)
0.238 and −0.275
0.357 and −0.263
ꢀ
ꢀ
ꢀ
ꢀ
2
2
R1
=
||F0| − |Fc||/
|F0|, wR2 = [
w(F0 − Fc2)2/
(w|F0| )2]1/2
The catalytic activity was determined for Ti(IV) complexes with
cess is important for that group of ligands. In the research reported
here we have investigated the effect of the sequence of metal
addition (Ti/Zn or Zn/Ti) for the group of mercapto- and thioke-
tosulfonamides, but the effect was negligible (Table 1). The use of
Et2Zn alone was tested for thioketosulfonamides and gave the same
results as observed with the use of Ti(OiPr)4 and subsequent addi-
tion of Et2Zn (Table 1). That clearly indicates that C2 S is involved
in the interactions with Zn atom and the initial formation of Ti-
sulfonamide complex is not necessary for the activity of that group
of ligands.
Our data indicate that the substituent at N atom also affects the
catalytic properties of the investigated sulfonamides. The highest
catalytic efficacy in each group is obtained for N-benzyl sulfon-
amides (1, 9, 11, 13). The replacement of benzyl moiety with the
methylphenyl or dimethylphenyl group caused significant reduc-
tion in the yield and % ee (Table 1). The small effect observed for
thioketo- or mercaptosulfonamides is caused by the small effi-
ciency of these ligands (1–9% ee). The difference is even more
pronounced for use of Et2Zn alone (Table 1). These results suggest
the importance of the bulk of substituents on the sulfonamide N
atom. The CH2 group of the benzyl moiety plays a role of a spacer
decreasing the steric hindrance on N and allowing the easy forma-
tion of the catalytically active species by N coordination to the metal
center. The increasing bulk of substituents results in the decrease of
the yield of the Et2Zn addition to benzaldehyde. The lowest yields
and % ee are found for the sulfonamides derived from the sec-
ondary amines (di-iso-butyl, morpholine). That is consistent with
data published by Ramón and Yus [8], although the authors have
not formulated such conclusion.
four groups of ligands differing by the substituent bound to C2 atom
of the bornyl moiety. The addition was performed in CH2Cl2. The
lowest % ee was obtained for sulfonamides with the S atom bound
to bornyl C2 (1–9% ee), while 2-hydroxysulfonamides revealed the
highest activity among the investigated ligands, reaching 53% ee
for 13 and the yield up to 98% (Table 1). Our data on the catalytic
activity of 13–15 are consistent with those published previously by
other authors [8,9] and are the reference data for the whole proce-
dure. Additionally, for the group of most active ligands, the addition
was also performed in toluene. For some ligands (14, 15), the use
of toluene increased the % ee values by the factor of 2. The best val-
ues, obtained also for ligand 13, were 69% ee and yield 97%. Results
for 13 are in good accordance with those published by Ramón et
al. [8]. Data obtained for addition performed in CH2Cl2 and toluene
reported here are also consistent with the suggested importance of
the low dipole moment of the solvent molecule for the efficiency
of addition [9].
The use of 2-hydroxysulfonamides as chiral auxiliaries in the
Et2Zn addition resulted in (S)-1-phenylpropanol as a main product.
For all other groups of investigated ligands the main product was
(R)-1-phenylpropanol. That indicates the different spatial arrange-
ment of the complex catalyst, in particular the position of bulky
bornyl moiety as a factor responsible for the stereoselectivity.
Previous reports on the use of bis(sulfonamides) with the O
atom at bornyl C2 indicated that the sequence of adding the metal
compounds has no significant effect on the yield and enantiomeric
excess obtained in the Et2Zn addition to benzaldehyde [17–18].
In our previous research for bis(sulfonamide) auxiliaries [17], the
product of the Et2Zn addition was not detected, when the reaction
was conducted in an absence of Ti(OiPr)4. For monosulfonamides
with hydroxy- and keto-groups reported here, no addition prod-
uct was also obtained in an absence of Ti(OiPr)4. It suggests that
the formation of Ti-sulfonamide complex prior to the addition pro-
3.1. Crystal structure determination
To assess the configuration of the chiral centers, conformation
of molecules and intramolecular interactions, the crystal structure

A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
135
Table 3
Hydrogen bonds and intramolecular C–H· · ·X interactions involving heteroatoms of the sulfonamide group or substituent at C2 in crystal structures of 1, 9, 11 and 13.
D–H· · ·A
d(D–H)
0.900
d(H· · ·A)
2.458
<DHA
d(D· · ·A)
1
9
N2–H2B· · ·O1[x + 1, y, z]
N1–H1B· · ·O1[x − 1/2, −y + 3/2, −z]
116.37
147.86
2.969(8)
0.900
2.086
2.888(6)
O1–H1A· · ·O3
O1–H1A· · ·S1
O1–H1A· · ·O2B
N2–H2N· · ·O3B
N2–H2N· · ·O2
O4–H4B· · ·O5
O4–H4B· · ·S2
0.820
0.820
0.820
1.059
1.059
0.820
0.820
1.776
2.642
2.563
2.000
2.325
2.091
2.923
149.87
127.82
145.96
162.85
149.16
148.07
128.88
2.519(2)
3.211(2)
3.275(3)
3.028(2)
3.280(2)
2.820(1)
3.497(2)
13
C–H· · ·X
d(D–H)
d(H· · ·X)
<CHX
d(C· · ·X)
C8–H8A· · ·O3
0.96
0.93
0.97
0.97
2.48
2.60
2.50
2.57
140
101
149
100
3.272(10)
2.925(12)
3.369(10)
2.897(11)
C17–H17A· · ·N1
1
C25–H25B· · ·O6[1 − x, 1/2 + y, 1 − z]
C30–H30B· · ·O4
C6–H6A· · ·O1
0.97
0.97
0.93
2.59
2.57
2.58
129
120
166
3.285(7)
3.171(5)
3.486(7)
C10–H10B· · ·S1
9
C17–H17A· · ·O2[1 + x, y, z]
C9–H9B· · ·S1
0.96
0.97
0.97
2.66
2.79
2.57
131
109
105
3.368(3)
3.236(2)
2.972(4)
C10–H10B· · ·S1
C11–H11B· · ·O2
11
13
C4–H4A· · ·O4[1 − x, 1/2 + y, 1/2 − z]
C8–H8B· · ·O1
0.98
0.96
0.96
2.56
2.36
2.30
152
120
136
3.455(18)
2.962(19)
3.072(22)
C29–H29A· · ·O4
was determined for sulfonamides 1, 9, 11, 13 with N-benzyl moi-
ety, that revealed the highest catalytic efficacy in four groups of
ligands. The details of the data collection and structure refinement
are presented in Table 2. Details of the H-bonds and intramolecu-
lar C–H· · ·X interactions involving heteroatoms of the sulfonamide
group or substituent at C2 are presented in Table 3. The valence
geometry of the investigated compounds is typical for the bornyl
and sulfonamide moieties. The details of the crystal structures can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data request/cif.
3.3. Crystal structure of (1S,4S)-(N-benzyl)-(7,7-
dimetylobicyclo[2.2.1]hept-1-yl-2-tion)methanesulfonamide
(9)
The asymmetric part of the structure contains one molecule
of sulfonamide 9 (Fig. 2). Determination of the absolute structure
with the Flack method was inconclusive, since the Flack parameter
was x = −0.47(17). Therefore the absolute structure was assigned
based on the known chirality of C1 and C4 centers in the (+)-
camphor substrate used for the synthesis. The sulfonamide SO2
3.2. Crystal structure of (1S,4S)-(N-benzyl)-(2-keto-7,7-
dimethylobicyclo[2.2.1]hept-1-yl)methane sulfonamide
(1)
The asymmetric part of the structure contains two molecules
of sulfonamide 1 (Fig. 1). The absolute configuration was deter-
mined using the Flack method [15] and is consistent with the
chirality of (+)-camphor substrate used for the synthesis. Con-
formation of the sulfonamide fragments of two molecules is
different, the C2–C1–C10–S1 and C1–C10–S1–N1 torsion angles
being 75.3(8)/−170.0(6) and −95.4(8)/166.7(6)◦ for molecules I and
II, respectively. Despite that difference, position of the benzyl moi-
ety relative to the bornyl ring system is similar in both molecules.
Position of the sulfonamide oxygen atoms relative to the gem-
dimethyl moiety is also different, since they are located on the
same side of the C4–S1 line in molecule I and on the opposite side
in molecule II. The sulfonamide NH and the C O group form the
intermolecular H-bond N2–H2B· · ·O1 [x + 1, y, z] with N2· · ·O1 dis-
tance being 2.969(8) Å. The differences in the conformation of two
molecules result in their different interactions in the crystal lat-
tice. Molecule I forms the intramolecular interactions C8–H8A· · ·O3
3.272 Å and C17–H17A· · ·N1 2.925 Å. For molecule II, the spatial
proximity of camphor C30 and the carbonyl oxygen results in
the intramolecular contact C30–H30B· · ·O4 of 2.897 Å. Molecule II
also participates in the intermolecular interaction C25· · ·O6[1 − x,
1/2 + y, 1 − z], the distance being 3.369 Å (Table 3).
Fig. 1. Asymetric part of the crystal structure of 1.

136
A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
Fig. 2. Asymmetric part of the crystal structure of 9.
and bornyl gem-dimethyl groups are positioned on the same side
of the C4–C7–C1–C10–S2 axis of the molecule. Conformation of
the molecule can be described as twisted with the torsion angles
C2–C1–C10–S2 and C1–C10–S2–N1 of −132.8(4) and 62.7(5)◦,
respectively. The twist around C10–S2 bond, describing the posi-
tion of C10 methylene group relative to the sulfonic oxygens,
reflects the steric hindrance around C10. In that orientation, the
C10 methylene is involved in the intramolecular interactions with
S1 substituent of the bornyl moiety, the C10· · ·S1 distance being
3.170 Å. Analysis of the crystal packing of 9 revealed the presence of
the intermolecular hydrogen bonds N2–H1B· · ·O1[x − 1/2, −y + 3/2,
−z], the N· · ·O distance is 2.888(6) Å. Also the sulfonamide oxygen
atoms are involved in the C–H· · ·O interactions, the intermolecular
C6–H6A· · ·O1 of 3.285 Å and intramolecular C17–H17A· · ·O2[1 + x,
y, z] of 3.486 Å (Table 3).
interactions between C8 methyl group and the aromatic ring of
the adjacent molecule, the distance between C–H and the cen-
ter of gravity of the aromatic ring C8–H8C· · ·␲[−1/2 + x, 1/2 − y,
−z] being 3.585 Å. Also the intramolecular interaction C11· · ·O2
2.972 Å is formed between the aromatic ring and the sulfonamide
group.
3.5. Crystal structure of (1S,2R,4S)-(N-benzyl)-(2-hydroxy-7,7-
dimethylobicyclo[2.2.1]hept-1-yl) methanesulfonamide
(13)
The asymmetric part of the unit cell contains two molecules
of hydroxysulfonamide (Fig. 4). The configuration of the C2 atom
was determined as R using the Flack method [15]. The observed
anisotropy of the atomic displacement parameters indicate the
rotational disorder of the bornane and sulfonamide moieties. How-
ever, it was impossible to define the discrete model of that disorder.
The crystal structure reveals the conformational disorder of the
sulfonamide group in molecule I with major population 60%. The
C2–C1–C10–S1 torsion angle is similar for molecule I in the minor
population and molecule II (−58.2(15)◦ and −55.6(13)◦) while
for molecule I in a major population it is −32.8(14)◦. However,
the statistically significant differences in C1–C10–S1–N1 torsion
angle are found between the two molecules, the values being
163.4(9)/−153.8(12)◦ and −56.9(10)◦ for molecule I and II, respec-
tively. That results in different relative position of benzyl groups.
Analysis of crystal packing revealed that benzyl groups form
the interactions C31· · ·␲1[−1/2 + x, 1/2 − y, −z] being 3.752 Å and
N1B· · ·␲2[1/2 + x, 1/2 − y, −z] of 3.239 Å, where ␲1 and ␲2 denote
for the gravity centers of the aromatic ring in molecule I and
II, respectively. The relative orientation of the sulfonamide SO2
and gem-dimethyl groups is found trans in molecule I, while in
3.4. Crystal structure of (1S,2R,4S)-(N-benzyl)-(1,7,7-
dimetylobicyclo[2.2.1]hept-1-yl-2-tiol) methanesulfonamide
(11)
Single molecule of mercaptosulfonamide 11 constitutes the
asymmetric part of the crystal structure (Fig. 3). The configura-
tion of the C2 atom was determined as R using the Flack method
[15]. The bornyl gem-dimethyl and sulfonic groups are positioned
anticlinal relative to each other. The respective torsion angles are
C2–C1–C10–S2 −70.7(2)◦ and C1–C10–S2–N1 166.6(2)◦. The C10
methylene hydrogen atoms and sulfonamide oxygen atoms are
positioned trans relative to the C10–S2 axis. The C10 group par-
ticipates in the intramolecular interaction with the –SH group,
the C10–H10B· · ·S1 distance being 3.236 Å. The 2R configuration
results in the formation of the intramolecular C9· · ·S1 interac-
tion of 3.368 Å. The packing analysis revealed the intermolecular
Fig. 3. Asymmetric part of the crystal structure of 11.

A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
137
Fig. 4. Asymmetric part of the crystal structure of 13.
molecule II it is gauche (Fig. 4). The hydrogen atoms of C10 methy-
lene are positioned gauche relative to the SO2 oxygens in molecule
II, while in molecule I they occupy the opposite positions relative to
the C10–S1 axis. The described conformation results in the inter-
molecular H-bonds involving atoms of the sulfonamide moieties
(N2· · ·O3, N2· · ·O2A) and the intramolecular H-bonds involving
the bornyl OH and sulfonamide O and S atoms (Table 3). The
hydroxyl groups of both molecules participate in the intramolec-
ular interactions with the methyl groups of the bornane moiety
(C8–H8B· · ·O1 2.962 Å and C29–H29A· · ·O4 3.072 Å). Also there is
an intermolecular C–H· · ·O interaction C4–H4A· · ·O4[1 − x, 1/2 + y,
1/2 − z] of 3.455 Å.
the sulfonamide group and the substituent at C2, forming the 7-
membered chelate ring.
The experimental confirmation of the coordination mode for
complexes was difficult due to their instability in a presence of
water traces. However, some information can be obtained from the
IR spectra by analysis of frequencies for Ti-ligand bands or those
characteristic for the sulfonamide ligands. The IR spectra for the
obtained Ti-sulfonamide complexes 21–24 and 26 have been com-
pared with those for the respective sulfonamides 1, 7, 13, 19 and
25 (Table 4; Fig. 5a and b).
For the ketosulfonamide 1 derived from the primary amine, the
changes in the frequencies of bands attributed to the stretching
N–H vibrations 3241 cm−1 (1) to 3290 cm−1 (21) and C O from
1724 cm−1 (1) to 1739 cm−1 (21) suggest that these groups are
involved in the Ti(IV) binding. The lack of shifts for the bands
attributed to the stretching vibrations of SO2N group (Table 4) sug-
gests that its O atoms are not involved in the metal coordination.
However, no shifts have been detected between IR spectra of sul-
fonamide 7 and its Ti complex 22. That might suggest that either
3.6. Model of the catalyst architecture
Literature reports revealed that the most frequent mode of
sulfonamide coordination to Ti(IV) is ꢀ2 –NO or ꢀ2 –OO via the
sulfonamide group [10,19–21]. The sulfonamides reported here are
derived from camphor and have an additional substituent at bornyl
C2, which also might participate in the ligand binding to the metal
center [11–13]. So far, there are no structural reports on the Ti(IV)
complexes of such sulfonamides. However, their ability to adopt
the conformation required for the bidentate coordination involving
C2-bound group might be estimated based the known structures of
sulfonamides. Analysis of camphor-derived sulfonamide structures
in the CSD database revealed the presence of the intramolecular
N· · ·O(C2) hydrogen bonds, the N· · ·O distance ranging from 2.774
to 3.052 Å. The structures of sulfonamides 1, 9, 11, 13 reported
here do not have such interaction. Analysis revealed that the
reported hydroxysulfonamide 13 or similar molecules deposited
with CCDC can form the intramolecular H-bond (C2)O· · ·Osulfo, with
the distance ranging from 2.813 to 2.980 Å, resembling the distance
between the donor groups in the Ti coordination sphere. Also, anal-
ysis of the intramolecular interactions indicates lack of steric factors
restricting the conformation of the investigated molecules. There-
fore, we might conclude that molecules belonging to the reported
groups of ligands could coordinate bidentately to Ti(IV) center via
Table 4
Selected bands in the IR spectra of complexes 21–24, 26 and sulfonamide ligands 1,
7, 13, 19 and 25 [cm−1].
ꢄ(NH)
ꢄ(OH)
ꢄ(C O)
ꢄ(SO2N)
ꢄ(Ti–O)
1
21
3241
3290
–
–
1724
1739
1325
1323
1145
1144
–
–
7
22
–
–
–
–
1747
1747
1331
1332
1140
1142
–
–
13
23
3529
–
3302
–
–
–
1308
1312
1132
1140
–
662
a
a
19
24
3521
–
–
–
–
–
1326
1325
1139
1139
–
665
a
25 [15]
26
3245
3256
3516
3501
–
–
1309
1315
1130
1142
–
665
a
Bands masked by the stretching vibrations attributed to water molecule.

138
A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
Fig. 5. Comparison of the IR spectra for (a) ketosulfonamide 1 and its complex 21. (b) hydroxysulfonamide 25 and its complex 26.
complex was not formed, unstable or too labile to be detected. In
the IR spectra for that group of complexes, the bands for Ti–O or
Ti–N cannot be assigned with no doubt, since the vibrations of the
ligand groups occur in the same range as those for the Ti–NMe2
moieties originated from substrate.
The model obtained for the catalysts formed with the keto-
sulfonamide auxiliaries 1–5 with the –NHR group (Fig. 6) is
consistent with the results of the catalytic Et2Zn addition to ben-
zaldehyde (Table 1). The observed enantiomeric excess for the
(R)-1-phenylpropanol product was small (5–16% ee). The model
reveals that, despite the coordination via the carbonyl oxygen, the
gem-dimethyl group is distant from the catalytic center and causes
only small steric hindrance, which is not a discriminating factor for
the substrate positioning. Therefore, the addition to Re and Si sides
of the aldehyde is almost equally probable. The obtained yields vary
from 48% to 87% (Table 1). Such difference might result from the
difficulties in forming a Ti–N coordination bond by ligands with
bulky substituents on the sulfonamide N atom.
Ketosulfonamides 6–8 derived from the secondary amines bind
to Ti(IV) via atoms of the sulfonamide group. The model of such
architecture was proposed in our previous paper [17]. Such archi-
tecture of the active complex explains the observed enantiomeric
excesses and yields (Table 1). Low yields (50–53%) obtained with
auxiliaries 6–8 might result from the presence of two substituents
at N atom, which restrict the access to the free electron pair of
nitrogen. The coordination via the keto group results in a relatively
For complexes 23 and 24 the broad bands from water had
masked any bands that could be attributed to the ligand NH
or OH bands. Therefore, no direct conclusions could be derived
for these complexes. However, comparison of the IR spectra
for the synthesized Ti complex 26 and for previously reported
bis(hydroxysulfonamide) 25 [15] revealed shifts for the NH and OH
bands (Table 4), what confirms an involvement of these groups in
the coordination to Ti. In the IR spectrum of complex 23 the shift
of the bands related to stretching of the sulfonamide group were
detected relative to the spectrum of the pure ligand 13, also indi-
cating that the sulfonamide group is coordinated to Ti. No such
shift was found between the spectra of complex 24 and the respec-
tive ligand 19. That difference suggests that sulfonamides derived
from the secondary amines (e.g. 19) do not bind to the metal cen-
ter via their sulfonamide group, contrary to those derived from
the primary amines, such as 13. The additional bands at 664 cm−1
observed in the IR spectra of 23, 24 and 26 can be attributed to the
stretching Ti–O vibrations [22]. The lack of shifts observed for the
bands of sulfonamide group for 24 and the presence of identical
band at 664 cm−1 suggests the involvement of the ligand hydroxyl
group in coordination.
The structural data and IR spectra allow to conclude that the
hydroxy- and ketosulfonamides derived from primary amines
coordinate bidentately via the sulfonamide group and the sub-
stituent at C2 of the bornyl moiety. The ketosulfonamides obtained
from the secondary amines coordinate to Ti only via the sul-
fonamide group (ꢀ2 –NO or ꢀ2 –OO). The IR data reveal that
hydroxysulfonamides obtained from the secondary amines coordi-
nate to Ti via the hydroxyl group, but do not reveal their bidentate
coordination involving the sulfonamide group. Such difference
in the coordination mode between hydroxysulfonamides derived
from primary and secondary amines is consistent with the observed
differences in their catalytic activity (Table 1).
The possible architecture of the Ti-sulfonamide complexes, in
particular the position of groups that might determine the orien-
tation of substrate in the complex, was analyzed using program
Mercury [23]. The obtained models were optimized with Molecu-
lar Mechanics method as implemented in Arguslab program [24]
using UFF forcefield.
Fig. 6. Model of the active complex formed with 1 keto- (gray) and 13 hydroxysul-
fonamide (black) with the preferred orientation of the substrate as obtained with
Arguslab MM calculations [24]. The preferred Si and Re faces are exposed for Et2Zn
addition for hydroxy- and keto-auxiliaries, respectively.

A. Kozakiewicz et al. / Journal of Molecular Catalysis A: Chemical 326 (2010) 128–140
139
large distance of the terpene group compared to that calculated for
hydroxysulfonamide, what decreases significantly the steric con-
trol of the substrate positioning. That conclusion derived from the
model is consistent with the observed low % ee of 1.1–5.6% (Table 1).
Hydroxysulfonamides 13–17 coordinate to Ti via the hydroxyl O
and one of the atoms of the sulfonamide group. The presence of exo
hydroxyl group results in a position of gem-dimethyl group close to
the reaction center. Such arrangement causes the steric restrictions
for the substrate on one side of the coordination plane and conse-
quently the increased control of enantioselectivity of addition. That
explains the observed increase of enatioselectivity with the use of
hydroxysulfonamides comparing to the effect of ketosulfonamide
auxiliaries. The change from the keto- to hydroxysulfonamides also
causes the reversion of the configuration of the newly formed chi-
ral center in the dominant product from R to S. The MM calculation
for the model with hydroxysulfonamides clearly indicated the pre-
ferred orientation of the substrate corresponding to the addition to
the Si face, consistent with the activity data presented in Table 1.
The crystal structure analysis for 1, 9, 11 and 13 revealed the
importance of the intramolecular interactions of C10–H or bornane
CH groups with the sulfonamide moiety or substituent at C2 for the
conformation of the sulfonamide molecule (Table 3). For the sul-
fonamide coordination via the substituent at C2, the gem-dimethyl
group should be a major steric factor influencing the orientation of
the substrate molecule in the reaction center.
Differences in the position of gem-dimethyl group in keto- and
hydroxysulfonamides relative to the reaction center are displayed
on Fig. 6. For ligands with the sp2 character of bornyl C2 (C O), the
substituent at C2 is positioned in the plane defined by C1, C2, C3 and
C4 atoms, while for (2R)-hydroxysulfonamides that group is posi-
tioned above the plane. Therefore, in all hydroxysulfonamides of
the known structure, the gem-dimethyl group C8–C7–C9 is signifi-
cantly closer to substituent at C2 than in ketosulfonamides (Fig. 6),
with the average distance between the center of mass of the gem-
dimethyl and C2-bound oxygen being 3.512(11) Å for hydroxy- and
3.904(10) Å for keto-compounds.
The obtained models for the auxiliaries with the benzyl group
suggest the explanation for their highest activity among the inves-
tigated compounds. The CH2 group of benzyl allows the aromatic
ring positioning approximately 3.7 Å from the plane of the ring of
benzaldehyde substrate (Fig. 6). That indicates the importance of
the stacking interactions between the substrate and the ligand. The
lack of the CH2 group in the aniline derivatives does not permit such
positioning of both rings and would decrease the stabilizing effect
in the active complex.
The ligands with the sulfur atom bound to C2 gave the low-
est yields and % ee among four investigated groups. These results
suggest that the formation of catalytically active complex involves
the substituent containing an oxygen atom, while the presence of
S atom prevents the coordination. One might assume that lack of
coordination via the sulfur atom results in an increased distance
between the bulky bornyl moiety and the center of reaction, what
decreases the steric control of the enantioselectivity of the addition.
The observation made during the procedure of assessing the activ-
ity was that the addition of thioketo- or mercaptosulfonamides to
the Ti(OiPr)4 solution had caused no color change. That is an indi-
cator for the lack of coordination of these ligands to Ti. However,
the presence of S C or HS–C donors could result in the formation of
a complex between the ligand and Et2Zn. Such a process competes
with a formation of the Ti-ligand complex. The experiments per-
formed with Et2Zn added to the reaction mixture containing these
ligands prior to the addition of Ti(OiPr)4 resulted in the increase of
the yield but decrease in the enantiomeric excess, when compared
to the Et2Zn addition performed with hypothetical formation of
the Ti-sulfonamide catalyst before injection of Et2Zn. That seems
to confirm that in a presence of the sulfur-containing ligands the
direct non-stereospecific addition of Et2Zn to benzaldehyde is a
significant process in the system.
The structural analysis revealed that sulfonamides 9–12, with
sulfur-containing substituent at C2, might bidentately coordinate
to Ti(IV) either via two atoms of the sulfonamide group or via sub-
stituent at the bornyl C2 and the sulfonamide group. The active
complex with such ligands might have an architecture analo-
gous to that of the corresponding oxygen ligands. Data in Table 1
revealed that the difference in activity of thioketo- and mer-
captosulfonamides are much smaller than those found for keto-
and hydroxy-compounds. That does not exclude the possibility
of coordination of the sulfur compounds via substituent at C2.
The presence of S atom bound to C2 causes much larger distance
between S and the center of mass of the gem-dimethyl [4.320(25) Å
for C2 S and 3.903(10) Å for C2–SH], compared to the oxygen lig-
ands. In both cases the gem-dimethyl is distant from the reaction
center due to the distance of S to C2 much longer than that to oxy-
gen. The assumed bidentate coordination ꢀ2 –NO or ꢀ2 –NS(C2)
is in good agreement with the low % ee (1.7–9.2%) observed for
(R)-1-phenylpropanol. The research revealed that the formation
of Ti-sulfonamide complex with auxiliaries containing the C2-
oxygen group is necessary for the Et2Zn addition to benzaldehyde.
However, the addition performed with the sulfur-containing lig-
ands resulted in the formation of 1-phenylpropanol (Table 1) even
without addition of Ti(OiPr)4. That leads to the conclusion, that
mercapto- and thioketosulfonamides can form a homodimeric cat-
alyst with the Zn-sulfonamide moiety, what is consistent with the
paper by Kitamura et al. [25].
4. Conclusions
The structural data and IR spectra allow to conclude that the
hydroxy- and ketosulfonamides derived from primary amines
coordinate bidentately via the sulfonamide group and the sub-
stituent at C2 of the bornyl moiety. The ketosulfonamides obtained
from the secondary amines coordinate to Ti only via the sul-
fonamide group (ꢀ2 –NO or ꢀ2 –OO). The hydroxysulfonamides
obtained from the secondary amines coordinate monodentately to
Ti via the hydroxyl group, but there is no IR data indicating if they
coordinate bidentately via other group. The crystal structure analy-
sis for 1, 9, 11 and 13 revealed the importance of the intramolecular
interactions of C10–H or bornane CHn groups with the sulfonamide
moiety of substituent at C2 for the conformation of the sulfon-
amide molecule. Both the structural data and molecular modeling
indicate that for sulfonamides coordinating via the substituent at
C2, the gem-dimethyl group is a major steric factor determining
the orientation of the substrate molecule in the reaction center
and consequently the chirality of the product. Data for the sulfur-
containing auxiliaries indicate that the non-stereospecific addition
conducted with the Et2Zn-sulfonamide active complex is a sig-
nificant process in the investigated system. In all groups of the
investigated auxiliaries the presence of bulky substituents on the
sulfonamide N results in a decrease of the catalytic efficacy, while
the best results are obtained for N-benzyl sulfonamides. That is
consistent with the modeling results suggesting the importance of
the ␲–␲ interactions between the benzyl ring and the substrate.
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