Enantiopure Ti(IV) amino triphenolate complexes as NMR chiral solvating agents

Article abstract of DOI:10.1002/chir.20994

Enantiopure Ti(IV) complexes bearing pseudo-C₃ amino triphenolate ligands have been synthesized and characterized. The complexes bearing ortho phenyl groups act as ¹H NMR chiral solvating agent (CSA) for the stereochemical analysis of a series of sulfoxides. The coordination of a Lewis base coligand (sulfoxide) and the presence of aromatic rings are the key structural factors for the efficiency of the CSA. Chirality, 2011. 2011 Wiley-Liss, Inc. Copyright

Full text of DOI:10.1002/chir.20994

CHIRALITY 23:796–800 (2011)
Enantiopure Ti(IV) Amino Triphenolate Complexes as NMR
Chiral Solvating Agents
1
1
1
1
2
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*
CRISTIANO ZONTA, ANDREJ KOLAROVIC, MIRIAM MBA, MARTA PONTINI, E. PETER KUNDIG, AND GIULIA LICINI
1Dipartimento di Scienze Chimiche, Universita` di Padova, via Marzolo 1, Padova 35131, Italy
2Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Anserment, 1211, Geneva 4, Switzerland
Contribution to the Carlo Rosini Special Issue
ABSTRACT
Enantiopure Ti(IV) complexes bearing pseudo-C3 amino triphenolate ligands
have been synthesized and characterized. The complexes bearing ortho phenyl groups act as 1H
NMR chiral solvating agent (CSA) for the stereochemical analysis of a series of sulfoxides. The
coordination of a Lewis base coligand (sulfoxide) and the presence of aromatic rings are the key
C
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structural factors for the efficiency of the CSA. Chirality 23:796–800, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: titanium complexes; triphenolamine; sulfoxides; chiral solvating agents
pounds 2c and 3c have been synthesized according to literature.12 If not
mentioned, all reactions were carried out under nitrogen, and the glass-
INTRODUCTION
Triphenolamines have recently emerged as an important
class of ligands, which form stable metal complexes able to
perform effectively in catalysis.1 In particular, d0 metal com-
plexes have shown to be effective catalysts in polymeriza-
tions,2,3 oxygen transfer processes,4–7 and Diels–Alder reac-
tions.8,9 Ti(IV) complexes, based on solution nuclear mag-
netic resonance (NMR) data and X-ray crystallography, form
as racemic mixtures of D and L species, resulting from a hel-
ical wrapping of the ligand around the metal ion, with racemi-
zation barriers of DG{ 5 65.7–74.4 kJ/mol. Control of the
handedness of the complex helicity can be obtained introduc-
ing a single, remote stereocenter at one of the benzylic posi-
tion. Recently, this approach has been used by Bull and
Davidson10,11 and by us [Fig. 1 (R)-1a].12 Enantiopure com-
plexes were obtained as single diastereoisomers in solution
and as well as in the crystal structure. Because of the high
catalytic performances of their racemic analogs, the proper-
ties of the enantiopure versions of these complexes have
been investigated, but modest stereoselections have been
observed.11 However, we have previously observed that
Ti(IV) complexes can coordinate an extra basic ligand, such
as sulfoxides;13,14 therefore, we decided to investigate the
ability of enantiopure Ti(IV) amino triphenolate complexes to
coordinate chiral sulfoxides and eventually discriminate the
two enantiomers, thus performing as chiral solvating agents
(CSAs). Although enantiopure sulfoxides are important class
of chiral molecules,15 a limited number of effective CSAs for
this class of molecules are available.16,17 Pirkle’s alcohol, (S)
or (R)-1-(9-anthryl)-2,2,2,-trifluoroethanol,18 and Kagan’s
CSA, (R)-(3,5-dinitrobenzoyl)-a-methyl benzyl amine,19 are
usually used, and they have been found to be effective also
with rather complex sulfinylic derivatives.20,21 Other systems
based on 2-arylpropionic acids and related structures have
been reported as well.22
˚
ware was oven-dried before use. Molecular sieves (3 and 4 A) were
heated (160 8C) under vacuum (0.4 mbar) for 16 h. Flash chromatogra-
phy: silica gel 60 (40 lm), P.H. Stehlin A. G. T.L.C.: Merck SIL G/
UV254; detection by UV/vis or by treatment with Ce–Mo-staining
reagent made from Ce(SO4)2 (4.0 g), H3PMo12040 (8.0 g), and H2SO4
(80.0 g) in 320 ml water. Optical rotations were measured on a Perki-
nElmer 241 polarimeter, c in g/100 ml. Infrared spectroscopy (IR) spec-
tra were recorded on a PerkinElmer fourier transform infrared spectros-
copy (FTIR) 1650. 1H and 13C{1H} NMR spectra (referenced to tetrame-
thylsilane or residual solvent peak) were recorded at 301 K on Bruker
AC-250, 300, and 400 MHz instruments. MS: electrospray ionization
mass spectrometry (ESI-MS) experiments were carried out in positive
mode on an Agilent Technologies LC/MSD Trap SL AGILENT instru-
ment, mobile phase acetonitrile/formic acid 0.1–1%. high resolution
mass spectrometry (HRMS) (electrospray ionization mass spectrometry-
time of flight detector (ESI-TOF)) were performed in an Applied Biosys-
tems ESI-TOF MarinerTM BiospectrometryTM Workstation, acetonitrile/
formic acid 0.1% as mobile phase with internal standards. In all cases,
isotope patterns were in agreement with the theoretical ones.
(R)-1-(2-Benzyloxyphenyl)ethylamine Hydrochloride (4). (R)-2-(1-
Aminoethyl)phenol hydrochloride (100 mg, 0.73 mmol, 1.0 equiv) was
dissolved in N,N-Dimethylformamide (DMF) (3 ml), followed by Et3N
(103 ll, 0.73 mmol, 1.0 equiv) and Boc2O (175 mg, 0.80 mmol, 1.1
equiv). The mixture was stirred in N2 atmosphere overnight. The mix-
ture was then diluted with brine (10 ml) and CH2Cl2 (20 ml), and the
aqueous layer was extracted with CH2Cl2 (2 3 15 ml); the organic
phases reunited and dried over Na2SO4. Concentration in vacuo yielded
a red–brown oil which was dissolved in a mixture of MeOH/CHCl3 (1/2,
2 ml) and added to a previously stirred suspension of K2CO3 (444 mg,
3.2 mmol, 4.4 equiv) in MeOH/CHCl3 (1/2, 2 ml; N2-atmosphere). After
the addition of benzyl bromide (105 ll, 0.8 mmol, 1.2 equiv), the result-
ing suspension was refluxed for 24 h (N2-atmosphere). The mixture was
filtered and concentrated in vacuo. The residue was dissolved in CHCl3
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsors: University of Padova, Ministero dell’Istruzione, Uni-
versita` e Ricerca Scientifica (Prin 2008) and CARIPARO, Progetti Eccellenza
2009/10 (NANO-MODule), COST, Action D40 (Innovative Catalysis—New
Processes and Seletivities).
*Correspondence to: Giulia Licini, Dipartimento di Scienze Chimiche, Univer-
sita` di Padova, via Marzolo 1, Padova 35131, Italy. E-mail: giulia.licini@unipd.it
Received for publication 1 March 2011; Accepted 9 June 2011
DOI: 10.1002/chir.20994
EXPERIMENTAL
Materials and Methods
General remarks. Dry solvents were purchased from Fluka, where
‘‘degassed’’ solvents or solutions are noted. Degassing was carried out
by three freeze-pump-thaw cycles. Chemicals were purchased from
Aldrich, Fluka, or Acros and used without further purification. Com-
Published online 17 August 2011 in Wiley Online Library
(wileyonlinelibrary.com).
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2011 Wiley-Liss, Inc.

TI(IV) AMINO TRIPHENOLATE COMPLEXES AS CSA
797
124.5, 75.6, 35.6, 31.3, 29.6; elemental analysis %: experimental (calcu-
lated) C, 65.09 (64.87); H, 6.39 (6.35).
(R)-Bis-(2-hydroxy-3-methylbenzyl)-[1-(2-hydroxyphenyl)ethyl]amine
(5a). The starting bromide 3a (315 mg, 1.1 mmol, 2.2 equiv), amine
(R)-4 (130 mg, 0.5 mmol, 1.0 equiv) and K2CO3 (340 mg, 2.5 mmol, 5.0
equiv) were dissolved/suspended in dry MeCN (10 ml) and refluxed for
40 h (N2-atmosphere). The reaction was followed by thin-layer chroma-
tography (TLC) (EA/p.ether 5 1/9). The mixture was filtered, the filtra-
tion cake washed with additional ethyl acetate (EA), and the combined
solutions concentrated [0.37 g, 1H NMR (250 MHz, CDCl3): d 7.62–6.86
(m, 25H, ArH), 4.96 (s, 2H, CH2O), 4.63 (s, 4H, CH2O), 4.57 (q, 1H, J 5
7.2 Hz, CH), 3.84 (d, 2H, J 5 15.0 Hz, CH2N), 3.74 (d, 2H, J 5 15.0 Hz,
CH2N), 2.24 (s, 6H, ArCH3), 1.34 (d, 3H, J 5 7.0 Hz, CH3)]. The crude
protected triphenolamine was dissolved in EA (23 ml) and 10% Pd/C (32
mg) was added. After 2 h, the mixture was filtered through a pad of
celite and concentrated, resulting in isolation of a pale-yellow solid.
Precipitation from a mixture of CH2Cl2/hexane gave a pale-yellow solid
(90 mg, 48%).
[a]2D0: 299.0 (c 5 0.1 in CH2Cl2). M.p.: 132–135 8C. IR (KBr): 3398,
3046, 2973, 2921, 1594, 1472, 1387, 1227, 1199, 1083, 843, 749. 1H NMR
(250 MHz, CDCl3): d 9.22 (bs, 3H, OH), 7.28–6.68 (m, 10H, ArH), 4.63
(q, 1H, J 5 6.8 Hz, CH), 4.24 (d, 2H, J 5 12.8 Hz, CH2N), 3.52 (d, 2H,
J 5 12.8 Hz, CH2N), 2.35 (s, 6H, ArCH3), 1.52 (d, 3H, J 5 7.0 Hz, CH3);
13C NMR (75.5 MHz, CDCl3): d 156.5, 154.6, 131.2, 129.5, 128.6, 127.7,
125.7, 125.4, 121.3, 119.7, 119.1, 117.1, 53.1, 52.0, 16.3, 8.6 MS (ESI):
378.2 [M1H]1. Elemental analysis %: experimental (calculated) C, 75.99
(76.36); H, 7.20 (7.21); N, 3.74 (3.71).
Fig. 1. Titanatranes 1a–d.
(15 ml), washed with saturated NH4Cl, dried over Na2SO4, and concen-
trated. The resulting pale-yellow oil was dissolved in 4 M HCl/dioxane
(12 ml), and the mixture was stirred for 10 min. This solution was con-
centrated, and the residue crystallized from toluene/p.e. yielding a light-
brown crystalline solid (180 mg, 94%).
M.p.: 195–198 8C. [a]2D0: 216.6 (c 5 0.5 in EtOH). 1H NMR (300 MHz,
CDCl3): d 7.50 (m, 1H, ArH), 7.43–7.23 (m, 6H, ArH), 6.93–6.87 (m, 2H,
ArH), 5.15 (‘‘d’’-AB system, 2H, J 5 2.3 Hz, CH2O), 4.81 (quintet, 1H,
J 5 6.0 Hz, CHCH3), 1.67 (d, 3H, J 5 6.8 Hz, CHCH3). 13C NMR (75.5
MHz, CDCl3): d 154.3, 135.5, 128.6, 127.4, 126.8, 126.1, 126.1, 124.9,
120.1, 110.9, 69.0, 45.5, 17.8 MS (ESI): 228.2 [M1H]1 (calcd. 228.3).
Elemental analysis %: experimental (calculated), C, 55.60 (55.34); H, 6.99
(6.97); N, 8.11 (8.07).
2-Benzyloxy-1-bromomethyl-3-methylbenzene (3a). NaBH4
(250 mg, 6.6 mmol, and 1.5 equiv) was added in one portion to a solution
of aldehyde 2a (1.00 g, 4.4 mmol) in 2-propanol (15 ml). The resulting
suspension was stirred at r.t. overnight. The mixture was then concen-
trated in vacuo and dissolved in a mixture of Et2O (40 ml) and 1 M NaOH
(30 ml). The aqueous phase was washed with Et2O (2 3 25 ml). The com-
bined organic phases were reunited and washed with brine (15 ml). The
solution, dried over Na2SO4 and concentrated in vacuo, yielded a pale-yel-
low oil, which was dissolved in dry toluene (20 ml) and placed on ice bath
for 5 min under N2-atmosphere. PBr3 (1.35 g, 469 ll, 4.8 mmol, and 1.1
equiv) was dissolved in a small amount of toluene (4 ml) and added drop
by drop to the solution. The resulting mixture was stirred on ice bath for
20 min and at room temperature for 30 min. The solution was diluted with
cold water (20 ml) and toluene (10 ml) and stirred vigorously. The or-
ganic phase was separated, washed with saturated aqueous NaHCO3 (10
ml), brine (10 ml), and dried over Na2SO4. The resulting solution was
concentrated in vacuo yielding a pale-yellow oil (1.07 g, 84%).
(R)-Bis-(2-hydroxy-3-tert-butylbenzyl)-[1-(2 hydroxyphenyl)ethyl]
amine (5b). The starting bromide 3b (0.9 g, 2.7 mmol, 2.2 equiv),
amine (R)-4 (324 mg, 1.2 mmol, 1.0 equiv) and K2CO3 (848 mg, 6.1
mmol, 5.0 equiv) were dissolved/suspended in dry MeCN (15 ml) and
refluxed for 48 h (N2-atmosphere). The reaction is followed by TLC
(EA/p.ether 5 1/19). The mixture was diluted with EA, filtered, and
concentrated. Light-brown oil; used directly in the next step [0.99 g, 1H
NMR (300 MHz, CDCl3): d 7.70 (m, 2H, ArH), 7.42–7.10 (m, 19H, ArH),
7.02 (m, 2H, ArH), 6.89–6.81 (m, 2H, ArH), 4.95 (d, 1H, J 5 12.3 Hz,
CH2O), 4.88 (d, 1H, J 5 12.3 Hz, CH2O), 4.70 (s, 4H, CH2O), 4.37 (q,
1H, J 5 6.9 Hz, CH), 3.81 (d, 2H, J 5 14.7 Hz, CH2N), 3.71 (d, 2H, J 5
14.7 Hz, CH2N), 1.36 (s, 18H, CH3C), 1.23 (d, 3H, J 5 6.9 Hz, CH3CH)].
The protected triphenolamine (2.7 mmol) was dissolved in EA (50 ml),
and 10% Pd/C (150 mg) was added. The mixture was stirred under H2-
atmosphere. After 2 h, the solution was filtered through a pad of celite
and concentrated, resulting in the isolation of a light-brown foam. Purifi-
cation by column chromatography (EA/p.ether 5 1/30, SilicaGel) led to
isolation of white foam (240 mg, 42%).
[a]2D0: 277.6 (c 5 0.1 in CH2Cl2). M.p.: 71–74 8C. IR (KBr): 3429,
2957, 2918, 2871, 1608, 1590, 1482, 1452, 1436, 1359, 1288, 1205, 1083,
846, 747. 1H NMR (300 MHz, CDCl3): d 7.27 (m, 2H, ArH), 6.96–6.66
(m, 8H, ArH), 4.29 (q, 1H, J 5 7.0 Hz, CH), 3.71 (d, 2H, J 5 13.2 Hz,
CH2N), 3.18 (d, 2H, J 5 13.2 Hz, CH2N), 1.55 (s, 18H, CH3C), 1.01 (d,
3H, J 5 7.2 Hz, CH3CH). 13C NMR (75.5 MHz, CDCl3): d 154.6, 154.5,
137.3, 129.5, 128.9, 128.4, 127.1, 122.6, 120.6, 119.8, 117.0, 52.5, 52.1,
34.8, 29.8, 9.0 (one signal overlapped). MS (ESI): 462.3 [M1H]1. Ele-
mental analysis %: experimental (calculated) C, 77.99 (78.05); H, 8.44
(8.52); N, 3.00 (3.03).
1H NMR (250 MHz, CDCl3): d 7.55–7.03 (m, 8H, ArH), 5.03 (s, 2H,
CH2O), 4.58 (s, 2H, CH2Br), 2.36 (s, 3H, CH3); 13C NMR (62.9 MHz,
CDCl3): d 155.6, 137.3, 132.2, 132.0, 131.5, 129.3, 128.7, 128.3, 128.0,
124.7, 74.8, 28.8, 16.5. Elemental analysis %: experimental (calculated) C,
61.31 (61.87); H, 5.21 (5.19).
2-Benzyloxy-1-bromomethyl-3-tert-butylbenzene (3b). Aldehyde
2b (10.0 g (85%), 37.3 mmol) was dissolved in 2-propanol (200 ml) and
NaBH4 (1.69 g, 44.7 mmol, 1.2 equiv) was added in one portion. The result-
ing suspension was stirred at r.t. overnight. The mixture was partially con-
centrated and dissolved in a mixture of Et2O (200 ml) and 10% KOH (100
ml). The aqueous phase was extracted with Et2O (100 ml), and the com-
bined organic phases were washed with brine (50 ml), dried over Na2SO4,
and concentrated. A pale-yellow liquid (9.9 g) was obtained, and it was used
directly in the next step. The oil was dissolved in dry toluene (170 ml) and
placed on ice bath for 10 min (N2-atmosphere). PBr3 (11.1 g (97%), 4 ml,
41.0 mmol, 1.1 equiv) was dissolved in toluene (35 ml) and added drop by
drop to the solution of alcohol. The mixture was stirred on ice bath for 20
min, and at room temperature for further 30 min. The solution was diluted
with cold water (50 ml) and stirred vigorously for 2 min. The organic phase
was separated and washed with saturated aqueous NaHCO3 (100 ml). The
aqueous layer was washed with additional toluene (50 ml), and the organic
phases were washed with water (70 ml), dried over Na2SO4, filtered
through a pad of celite, and concentrated yielding a pale-yellow oil (9.0 g,
85%).
(R)-Bis-(2-hydroxybiphenyl-3-ylmethyl)-[1-(2-hydroxyphenyl)ethyl]
amine (5c). The starting bromide 3c (440 mg, 1.25 mmol, and 2.2
equiv), amine (R)-4 (149 mg, 0.6 mmol, and 1.0 equiv), and K2CO3 (391
mg, 2.8 mmol, and 5.0 equiv) were dissolved/suspended in dry MeCN
(6 ml) and refluxed for 48 h (N2-atmosphere). The reaction was followed
by TLC (EA/p.ether 5 1/9; NMR). The mixture was concentrated, the
residue dissolved/suspended in CHCl3 (40 ml) and washed with diluted
brine (15 ml), the aqueous layer extracted with CHCl3 (15 ml), the or-
ganic phase dried over Na2SO4 and concentrated yielding a light-brown
viscous oil [510 mg, 1H NMR (250 MHz, CDCl3): d 7.76 (m, 2H, ArH),
7.56–6.90 (m, 33H, ArH), 4.98 (s, 2H, CH2O), 4.71 (q, 1H, J 5 7.0 Hz,
CH), 4.23 (s, 4H, CH2O), 3.91 (d, 2H, J 5 12.8 Hz, CH2N), 3.82 (d, 2H, J
5 12.8 Hz, CH2N), 1.43 (d, 3H, J 5 6.8 Hz, CH3)]. The crude protected
1H NMR (250 MHz, CDCl3): d 7.59–7.06 (m, 8H, ArH), 5.13 (s, 2H,
CH2O), 4.59 (s, 2H, CH2Br), 1.43 (s, 9H, CH3C); 13C NMR (75.5 MHz,
CDCl3): d 156.7, 143.7, 137.6, 132.1, 130.8, 128.7, 128.2, 128.0, 126.9,
Chirality DOI 10.1002/chir

798
ZONTA ET AL.
by i-PrOH (4.02 ppm); HR-MS (ESI): calcd for C25H28NO4Ti: 454.1495,
found 454.1484.
(5R)-1-Iso-propoxytitana-2,10,11-trioxa-6-aza-5-methyl-3,4-benzo-
8,9;12,13-bis(60-tert-butylbenzo)[4.4.4.01,6]tricyclotetradecane
(1b). 1H NMR (300 MHz, CDCl3): d 7.26–6.72 (m, 10H, ArH), 5.21
(septet, 1H, J 5 6.0 Hz, CHO), 3.70 (d, 1H, J 5 14.1 Hz, CH2N), 3.56 (d,
1H, J 5 13.2 Hz, CH2N), 3.21 (d, 2H, J 5 12.6 Hz, CH2N), 1.52 (d, 6H, J
5 5.7 Hz, CH3CHO), 1.46 (s, 9H, CH3C), 1.44 (s, 9H, CH3C); signal
CHN overlapped by i-PrOH (4.01 ppm), signal CH3CHN overlapped by
apical i-PrOH (1.52 ppm); 13C NMR (75.5 MHz, CDCl3): 163.7, 163.1,
162.7 (Ar-O), 136.5, 128.7, 128.4, 128.2, 127.9, 127.5, 126.3, 125.2, 125.1,
120.7, 120.4, 120.2, 116.5, 80.4, 77.5, 64.7, 54.0, 53.2, 51.2, 35.0, 29.8,
26.0, 25.6, 9.1. HR-MS (ESI): calcd for C31H40NO4Ti: 538.2435, found
538.2458.
(5R)-1-Iso-propoxytitana-2,10,11-trioxa-6-AZA-5-methyl-3,4-benzo-
8,9;12,13-bis(60-phenylbenzo)[4.4.4.01,6]tricyclotetradecane (1c).
1H NMR (300 MHz, CDCl3): d 7.67–7.63 (m, 4H, ArH), 7.42–7.06 (m,
12H, ArH), 6.95–6.87 (m, 3H, ArH), 6.77 (m, 1H, ArH), 4.78 (septet, 1H,
J 5 6.0 Hz, CHO), 4.14 (q, 1H, J 5 6.6 Hz, CHN), 3.89 (d, 1H, J 5 14.1
Hz, CH2N), 3.66 (d, 1H, J 5 13.2 Hz, CH2N), 3.36 (‘‘t’’, 2H, J 5 15.0 Hz,
CH2N), 1.59 (d, 3H, J 5 6.9 Hz, CH3CHN), 1.18 (d, 3H, J 5 6.0 Hz,
CH3CHO), 1.16 (d, 3H, J 5 6.3 Hz, CH3CHO); 13C NMR (75.5 MHz,
CDCl3): 159.4, 159.0, 158.6, 140.4, 140.1, 130.6, 130.4, 130.3, 130.0, 129.8,
128.9, 128.2, 127.9, 127.5, 125.34, 125.29, 125.0, 122.3, 115.4, 115.3, 112.7,
112.6, 112.5, 80.6, 64.7, 55.4, 25.6, 25.0, 24.8, 21.3, 21.0, 20.9. HR-MS
(ESI): calcd for C35H32NO4Ti: 578.1809, found 578.1833.
Scheme 1. Synthesis of enantiopure trifenolamines 5a–c and their titana-
trane complexes 1a–c.
triphenolamine (400 mg, 0.52 mmol) was dissolved in toluene (20 ml),
and 10% Pd/C (50 mg) was added. After 4 h, the reaction was filtered
through a pad of celite and concentrated, resulting in the isolation of yel-
low oil. The product was purified by column chromatography (EA/tolu-
ene 5 1/15; Silicagel) yielding a pale-yellow oil (120 mg, 40%).
[a]2D0: 119.4 (c 5 0.1 in CH2Cl2). M.p.: 145–148 8C. IR: 3422, 3056, 2972,
2926, 1608, 1590, 1497, 1460, 1431, 1382, 1290, 1222, 1082, 755, 699. 1H
NMR (250 MHz, CDCl3): d 7.40–7.06 (m, 16H, ArH), 6.87–6.77 (m, 4H,
ArH), 6.35 (bs, 3H, OH), 4.41 (q, 1H, J 5 6.8 Hz, CH), 3.86 (d, 2H, J 5 15.6
Hz, CH2N), 3.81 (d, 2H, J 5 15.6 Hz, CH2N), 1.58 (d, 3H, J 5 7.0 Hz, CH3).
13C NMR (75.5 MHz, CDCl3): d 156.0, 151.5, 136.9, 130.3, 129.6, 129.0,
128.7 (4 3 CH), 128.2, 127.3, 127.1, 123.3, 119.9, 119.2, 116.2, 54.9, 50.2,
9.1. MS (ESI): 502.2 [M1H]1. Elemental analysis %: experimental (calcu-
lated) C, 80.99 (81.41); H, 6.22 (6.23); N, 2.77 (2.79).
RESULTS AND DISCUSSION
Three new enantiopure ligands (R)-5a–c have been pre-
pared according to the protocol described recently for ligand
(S)-5d (Scheme 1).12 This strategy requires the synthesis of
the protected benzyl bromide 3a–c from the corresponding
aldehydes 2a–c. Two equivalents of benzylbromides 3a–c
react with the chiral amines (R)-423 furnishing the corre-
spondent tertiary amines. Hydrogenolysis using Pd/C as cat-
alyst afforded the desired ligand (R)-5a–c in satisfactory
yields. Triphenolamines (R)-5a–c cleanly react with Ti(Oi-
Pr)4 in dry CDCl3 yielding the corresponding mononuclear
complexes (R)-1a–c as single diastereomeric species, as con-
General Procedure for Preparation of Titanium Complexes
Ligands 5a–c were dissolved in deuterated chloroform in a 1-ml volu-
metric flask. In the same way, a stock solution of Ti(O-iPr)4 was pre-
pared (2-ml volumetric flask). Afterward, solutions corresponding to
equimolar amounts of reagents were mixed in a 1-ml volumetric flask
and more solvent was added up to 1 ml. The resulting solution was trans-
ferred to a screw-cap NMR tube and formation of the complex was moni-
tored via 1H NMR.
1
firmed by the H NMR spectra. Titanatrane (S)-1d has been
prepared as previously reported.12
Chiral complexes 1a–d have been tested as catalysts in the
stereoselective sulfoxidation of p-tolyl methyl sulfide furnish-
ing high yields in the sulfoxide but low ees, results in line
with what was recently reported by Bull and Davidson for a
similar complex (see Supporting Information). However, even
if the results, in term of stereoselections, are not appealing,
interestingly in the reaction mixture obtained using (R)-1c
(5R)-1-Iso-propoxytitana-2,10,11-trioxa-6-AZA-5-methyl-3,4-
benzo-8,9;12,13-bis(60-methylbenzo)[4.4.4.01,6]tricyclotetra-
decane (1a). 1H NMR (300 MHz, CDCl3): d 7.24–6.69 (m, 10H,
ArH), 5.20 (septet, 1H, J 5 6.0 Hz, CHO), 3.76 (d, 1H, J 5 13.5 Hz,
CH2N), 3.57 (d, 1H, J 5 13.5 Hz, CH2N), 3.25 (d, 1H, J 5 13.5 Hz,
CH2N), 3.21 (d, 1H, J 5 13.5 Hz, CH2N), 2.29 (s, 3H, CH3Ar), 2.26 (s,
3H, CH3Ar), 1.55 (d, 3H, J 5 6.0 Hz, CH3CHO), 1.54 (d, 3H, J 5 6.3 Hz,
CH3CHO), 1.51 (d, 3H, J 5 6.9 Hz, CH3CHN); signal CHN overlapped
1
and (S)-1d as catalysts, we notice that the H NMR signals
corresponding to the methyl group of sulfoxides 7 appeared
splitted (Fig. 2). A possible explanation could be that the
Ti(IV) complex was acting both as catalyst for sulfoxide forma-
Fig. 2. 1H NMR of the reaction mixture for pTolSMe 6a oxidation catalyzed by (R)-1c.
Chirality DOI 10.1002/chir

TI(IV) AMINO TRIPHENOLATE COMPLEXES AS CSA
799
tion and as CSA for the newly formed sulfoxide. A separation
of about 0.1 ppm was observed in a 0.08 M solution of sulfox-
ide 7a with 10% of complex (R)-1c (Fig. 2).
Addition of commercially available (1)-(R)-7a resulted
1
into an increasing of the more shielded H NMR signal (2.68
ppm) and allowed the assignment, the resonances for the
two diastereomeric complexes (R)-1cꢀ(S)-7a and (R)-1cꢀ(R)-
7a, respectively. These preliminary results lead us to investi-
gate more in detail this phenomenon. In fact, not only among
the large range of CSA used only few are reported for the
enantiomeric excess determination of chiral sulfoxides, but
also a very limited number of CSA are based on early transi-
tion.17,24 The behavior of the three Ti(IV) complexes (R)-1a–
c in the presence of increasing amount of (6)-methyl phenyl
sulfoxide 7b in CDCl3 has been investigated more in detail
and only in the case of complex (R)-1c a splitting of the
methyl signal could be observed. The CSA capability of (R)-
1c has been experimentally evaluated with a series of sulfox-
ides and other molecules containing a basic donor function.
A shift of proton resonances were observed in all the cases
but only with aryl methyl sulfoxides a significative splitting
on at least one signal was obtained. To gain more detailed in-
formation on the process, the binding constants (KR and KS)
for aryl-methyl sulfoxides with different electronic demand
(phenyl, p-dimethylamino, and p-nitro benzene) (6)-7b–d in
deuterochloroform were determined via 1H NMR titrations
[Table 1; On purpose written routine using Scientist (Micro-
Math Scientific Software) were used to fit signals for a 1:1
complex].
Titration experiments highlight that the efficient separa-
tion originates from two cooperative phenomena: (i) a signifi-
cant difference in the two coordination constants (the more
favorable coordination of complex (R)-1c with the R enan-
tiomers) and (ii) a difference in the chemical shifts induced
by complexation (Dd). Noteworthy, R sulfoxides bound twice
stronger than the corresponding S enantiomers in all cases.
This effect combines with larger chemical shift changes
observed for the diasteromeric (R)-1cꢁ(R)-7b–d complexes.
Moreover, in the set of molecules under study, Ka values
follow Hammet r parameter for the substitution of the aro-
Fig. 3. Minimized structures of diasteromeric complexes (R)-1c with
(R)-7b (left) and (S)-7b (right). [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
matic ring suggesting an interaction in which the oxygen of
the sulfoxide is directly coordinated to the Ti(IV) metal
(coordination ability parallels the Lewis basicity of the sulfox-
ides 7d > 7b > 7c). Indeed, several d0 metals, such as
Ti(IV), V(V), Mo(VI), and Re(VII) have shown the capability
to expand their coordination sphere in the presence of an
extra ligand.13,25,26 A confirmation of the mode of binding of
the sulfoxide comes from theoretical calculations. The struc-
ture of the metal complex (R)-1c have been optimized using
density functional (B3LYP) calculations at the LANL2DZ
level (see Supporting Information).27 Complex (R)-1c dis-
plays a bipyramidal geometry in agreement with the crystal-
lographic data reported by Bull and Davidson.10 The coordi-
nation with the two enantiomers of sulfoxide 7b give rise to
the formation of two diasteroisomers in which the oxygen is
coordinated to the metal.
The coordination results in a variation to an octahedrical
geometry (Fig. 3). Because of the pseudo-C3 symmetry of
the complex, the coordination of the sulfoxides to each of the
three different equatorial sectors affords three different dia-
stereomeric complexes. The geometries of the six diaster-
eomers have been minimized and, in agreement with the ex-
perimental results, the diasteromeric complexes formed by
(R)-1c and sulfoxide (R)-7 are more stable (average energy
difference 5 1 kJ/mol, see Supporting Information). This is
probably due by additive aromatic stabilizing interactions
between the phenyl moieties present on the upper rim of the
complex and the aromatic ring of the sulfoxide (Fig. 3, struc-
ture on the left). The methyl group is forced to the center of
the aromatic shielding region of complex (R)-1c explaining
the higher variation in chemical shifts observed.28 The key
role of p–p interactions is confirmed when an aliphatic sulf-
oxide was used. In the case of racemic n-octyl methyl sulfox-
ide, large variations of chemical shifts were observed
(around 0.6 ppm) without any significant signal splitting.
TABLE 1. Binding constants (KR/KS) and Dd (ppm) of S-CH3
resonances for sulfoxides 7b–d/(R)-1c in CDCl3 at 300 K
CONCLUSIONS
In summary, we developed an efficient methodology for
the synthesis of enantiopure amino triphenolate ligands. The
corresponding Ti(IV) complexes form as single diastereom-
ers in solution, and they are effective, even if not stereoselec-
tive, catalyst for sulfoxidations. Furthermore, they act as
CSA for the definition of the stereochemistry and enantiopur-
ity of methyl aryl sulfoxides. Binding constant values and
theoretical calculations confirm the high tendency of d0
metal complexes to expand their coordination sphere for the
accommodation of an extra ligand. Moreover, this example
Entries
Sulfoxide
Ka (M21
)
Dd (ppm)a
1
2
3
4
5
6
(R)-7b
(S)-7b
(R)-7c
(S)-7c
(R)-7d
(S)-7d
483
213
299
162
675
337
20.12
20.10
20.12
20.09
2012
20.09
aChemical shifts variation of the S-CH3 of 7b–d.
Chirality DOI 10.1002/chir

800
ZONTA ET AL.
17. Uccello-Barretta G, Balzano F, Salvadori P. Enantiodiscrimination by
NMR spectroscopy. Curr Pharm Des 2006;12:4023–4045.
reinforces the idea the C3 receptors are able to perform as
enantiodiscriminating agents.29–31
18. Pirkle WH, Sikkenga DL, Pavlin SM. Nuclear magnetic resonance deter-
mination of enantiomeric composition and absolute configuration of
gamma-lactones using chiral 2,2,2-trifluoro-1-(9-anthryl)ethanol. J Org
Chem 1977;42:384–387.
ACKNOWLEDGMENTS
The authors thank Dr. Julien Andries for preliminary
experiments.
19. Deshmukh ME, Dun˜ach SJ, Kagan HB. A convenient family of chiral
shift reagents for measurement of enantiomeric excesses of sulfoxides.
Tetrahedron Lett 1984;25:3467–3470.
LITERATURE CITED
20. Bendazzoli P, Di Furia F, Licini G, Modena G. Enantioselective oxodation
of thioethers—an easy route to enantiopure C2 symmetrical bis-methyl-
sulfinylbenzenes. Tetrahedron Lett 1993;34:2975–2978.
1. Licini G, Mba M, Zonta C. Amine triphenolate complexes: synthesis,
structure and catalytic activity. Dalton Trans 2009;27:5265–5277.
2. Chmura AJ, Chuck CJ, Davidson MG, Jones MD, Lunn MD, Bull SD
Mahon MF. A germanium alkoxide supported by a C-3-symmetric ligand
for the stereoselective synthesis of highly heterotactic polylactide under
solvent-free conditions. Angew Chem Int Ed 2007;46:2280–2283.
21. Corich M, Di Furia F, Licini G, Modena G. Enantioselective oxidation of
thioethers—synthesis of tyrans-N,N-dialkylacetamide-1,3-dithiolanes-S-ox-
ide and their use in asymmetric aldol-type reactions. Tetrahedron Lett
1992;34:3043–3044.
3. Chmura AJ, Davidson MG, Frankis CJ, Jones MD, Lunn MD. Highly
active and stereoselective zirconium and hafnium alkoxide initiators for
solvent-free ring-opening polymerization of rac-lactide. Chem Commun
2008;11:1293–1295.
22. Fauconnot L, Nugier-Chauvin C, Noiret N, Patin H. Enantiomeric excess
determination of some chiral sulfoxides by NMR: use of (S)-ibuprofen1
and (S)-naproxen1 as shift reagents. Tetrahedron Lett 1997;38:7875–
7878, and references therein.
4. Mba M, Prins LJ, Licini G. C-3-Symmetric Ti(IV) triphenolate amino com-
plexes as sulfoxidation catalysts with aqueous hydrogen peroxide. Org
Lett 2007;9:21–24.
23. Ku¨ndig E P, Botuha C, Lemercier G, Romanens P, Saudan L, Thibault S.
Asymmetric syntheses of 2-(1-aminoethyl)phenols. Helv Chim Acta
2004;87:561–579.
5. Zonta C, Cazzola E, Mba M, Licini G. C-3-Symmetric titanium(IV) tripheno-
late amino complexes for a fast and effective oxidation of secondary amines
to nitrones with hydrogen peroxide. Adv Synth Catal 2008; 350:2503–2506.
24. For another Ti(IV) based CSA see:Potvin PG. A microscale NMR method
of determining absolute stereochemistries in beta-amino alcohols by
enantioselective complexation and the mode of action of their oxidative
resolution. J Org Chem 1992;57:3272–3274.
6. Mba M, Pontini M, Lovat S, Zonta C, Bernardinelli G, Ku¨ndig EP, Licini
G. C-3 vanadium(V) amine triphenolate complexes: vanadium haloperoxi-
dase structural and functional models. Inorg Chem 2008;47:8616–8918.
25. Ku†hn FE, Santos AM, Roesky PW, Herdtweck E, Schere W, Gisdakis P,
Yudanov IV, Di Valentin C, Ro†sch N. Trigonal-bipyramidal Lewis base
adducts of methyltrioxorhenium (VII) and their bisperoxo congeners:
characterization, application in catalytic epoxidation, and density func-
tional mechanistic study. Chem Eur J 1999;5:3603–3615.
7. Romano F, Linden A, Mba M, Zonta C, Licini G. Molybdenum(VI) amino
triphenolate complexes as catalysts for sulfoxidation, epoxidation and hal-
operoxidation. Adv Synth Catal 2010;352:2937–2942.
8. Bull SD, Davidson MG, Johnson AL, Robinson DEJE, Mahon MF. Synthe-
sis, structure and catalytic activity of an air-stable titanium triflate, supported
by an amine tris(phenolate) ligand. Chem Commun 2003;1750–1751.
26. Lovat S, Mba M, Abbenhuis HCL, Vogt D, Zonta C, Licini G. Role of
intermolecular interactions in oxygen transfer catalyzed by silsesquiox-
ane trisilanolate vanadium(V). Inorg Chem 2009;48:4724–4728.
9. Bull SD, Davidson MG, Johnson AL, Mahon MF, Robinson DEJE. An air
stable moisture resistant titanium triflate complex as a Lewis acid catalyst
for CꢂꢂC bond forming reactions. Chem Asian J 2010;5:612–620.
27. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheese-
man JR, Montgomery JA Jr., Vreven T, Kudin KN, Burant JC, Millam JM,
Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G,
Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K,
Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai
H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo
C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi
R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador
P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC,
Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz
JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Lia-
shenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham
MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B,
Chen W, Wong MW, Gonzalez C, Pople JA. Gaussian 03, Revision D.02.
Wallingford, CT: Gaussian, Inc.; 2004.
10. Axe P, Bull SD, Davidson MG, Gilfillan CJ, Jones MD, Robinson DEJE,
Turner LE, Mitchell WL. Enantiopure pseudo-C-3-symmetric titanium alk-
oxide with propeller-like chirality. Org Lett 2007;9:223–226.
11. Axe P, Bull SD, Davidson MG, Jones MD, Robinson DEJE, Mitchell WL,
Warren JE. An enantiopure pseudo-C-3-symmetric titanium triflate with
propeller-like chirality as a catalyst for asymmetric sulfoxidation reac-
tions. Dalton Trans 2009;46:10169–10171.
12. Bernardinelli G, Seidel TM, Ku¨ndig EP, Prins LJ, Kolarovic A, Mba M, Pon-
tini M, Licini G. Stereoselective dimerization of racemic C-3-symmetric
Ti(IV) amine triphenolate complexes.
2007;16:1573–1576.
J Chem Soc Dalton Trans
13. Bonchio M, Calloni S, Di Furia F, Licini G, Modena G, Moro S, Nugent
WA. Titanium(IV)-(R,R,R)-tris(2-phenylethoxy)amine-alkylperoxo com-
plex mediated oxidations: the biphilic nature of the oxygen transfer to or-
ganic sulfur compounds. J Am Chem Soc 1997;119:6935–6936.
28. Hunter CA, Packer MJ, Zonta C. From structure to chemical shift and
vice-versa. Prog Magn Reson 2005;47:27–39.
29. Pinte´r A, Haberhauer, G. Synthesis of chiral threefold and sixfold func-
tionalized macrocyclic imidazole peptides. Tetrahedron 2009;65:2217–
2225.
14. Bonchio M, Bortolini O, Licini G, Moro S, Nugent WA. On the mecha-
nism of the oxygen transfer to sulfoxides by Ti(IV)/trialkanolamine/oer-
oxo complexes, evidence for a metal template process. Eur J Org Chem
2003;4:507–511.
30. Gibson SE, Castaldi MP. Applications of chiral C3-symmetric molecules.
Chem Commun 2006:3045–3062, and references therein.
15. Wojaczynska E, Wojaczynski J. Enantioselective synthesis of sulfoxides:
2000–2009. Chem Rev 2010;110:4303–4356.
31. Santoni G, Mba M, Bonchio M, Nugent WA, Zonta C, Licini G. Stereose-
lective control by face-to-face versus edge-to-face aromatic interactions:
the case of C3-Ti(IV) amino trialkolate sulfoxidation catalysts. Chem Eur
J 2010;16:645–654.
16. Seco JM, Quin˜oa´ E, Riguer R. The assignment of absolute configuration
by NMR. Chem Rev 2004;104:17–117.
Chirality DOI 10.1002/chir