Enantioselective desymmetrization of meso-epoxides with anilines catalyzed by polymeric and monomeric Ti(IV) salen complexes

Article abstract of DOI:10.1002/chir.20868

The active catalysts for the enantioselective ring opening (ARO) of meso-stilbene oxide, cis-butene oxide, cyclohexene oxide, cyclopentene oxide, and cyclooctene oxide with various substituted anilines were generated in situ by the reaction of Ti(O^i<

Full text of DOI:10.1002/chir.20868

CHIRALITY 23:76–83 (2011)
Enantioselective Desymmetrization of meso-Epoxides with
Anilines Catalyzed by Polymeric and Monomeric Ti(IV) Salen
Complexes
*
RUKHSANA I. KURESHY, MANISH KUMAR, SANTOSH AGRAWAL, NOOR-UL H. KHAN, BALCHAND DANGI,
SAYED H. R. ABDI, AND HARI C. BAJAJ
Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSMCRI),
Council of Scientific and Industrial Research (CSIR), G. B. Marg, Bhavnagar, Gujarat, India
ABSTRACT
The active catalysts for the enantioselective ring opening (ARO) of
meso-stilbene oxide, cis-butene oxide, cyclohexene oxide, cyclopentene oxide, and cyclo-
octene oxide with various substituted anilines were generated in situ by the reaction of
Ti(OiPr)4 with poly-[(R,R)-N,N0-bis-{3-(1,1-dimethylethyl)-5-methylene salicylidene}
cyclohexane-1,2-diamine]-1 and (1R,2R)-N,N0-bis[3,5-di(tert-butyl)salicylidene] cyclohex-
ane-1,2-diamine-2. These catalysts in the presence of nonracemic imine as an additive
provided b-amino alcohol in excellent yield (99%) and chiral purity (enantiomeric excess
(ee) up to 99%) for the ARO of meso-stilbene oxide with aniline. The same protocol was
less effective for the ARO of cyclic epoxides; however, when triphenylphosphine was
used as an additive, there was a significant improvement in catalyst performance for the
ARO of cyclohexene oxide (yield, 85–90%; ee, 63–67%). Both in situ generated polymeric
and monomeric catalysts performed in a similar manner except that the polymeric cata-
lyst Ti(IV)-1 was more active and recycled several times with retention of enantioselec-
tivity when compared with the monomeric catalyst Ti(IV)-2, which was nonrecyclable.
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VV
Chirality 23:76–83, 2011.
2010 Wiley-Liss, Inc.
KEY WORDS: enantioselective ring opening; meso-epoxides; chiral monomeric and
polymeric Ti(IV); salen; syn and anti-b-aminoalcohol
INTRODUCTION
tion of our ongoing interest in ARO reactions,15,19,20,35–37
we present here the application of in situ generated Ti
(IV) salen complexes 1 and 2 (derived from polymeric
and monomeric chiral salen ligands 1 and 2) as efficient
catalysts for the enantioselective ARO of meso-stilbene ox-
ide, cis-butene oxide, cyclohexene oxide, cyclopentene
oxide, and cyclooctene oxide with anilines as nucleophile
at RT in the presence of nonracemic imine and triphenyl
phosphine as additives. Both catalysts worked well to
give b-amino alcohols in high yield (ꢀ99%) and enantio-
meric excess (ee) (ꢀ99%) by the ARO of meso-stilbene
oxide with aniline in the presence of nonracemic imine
as an additive; however, only polymeric Ti(IV)-1 catalyst
was recyclable several times without loosing its effi-
ciency.
Enantiomerically pure b-amino alcohols are the key
structural units found in many biologically active com-
pounds, fine chemicals, and chiral auxiliaries. In recent
years, chiral amino alcohols have found a distinct role as
chiral ligands for various metal-catalyzed asymmetric or-
ganic transformations.1–8 To synthesize chiral b-amino
alcohols, several strategies, namely, aminohydroxylation
of olefins,9,10 addition of a-hydroxy ketones to imines,11–13
aminolytic kinetic resolution of racemic terminal/trans aro-
matic epoxides,14–18 and asymmetric ring opening (ARO)
of meso-epoxides,19–34 have been reported in the literature.
Among these, metal-catalyzed ARO of meso-epoxides with
amines is one of the most elegant, atom efficient, and
straightforward strategies for the synthesis of chiral
b-amino alcohols. Various chiral metal complexes of tita-
nium,19–21 vanadium,22 niobium,23,24 copper,25 lantha-
nides,4,6,8,26,27 chromium,14,15 scandium,7,28,29 indium,30,31
and bismuth32,33 have been used to catalyze this reaction
effectively. Recently, Zhou et al.34 also reported the use of
chiral Ti(IV) salen complex for ARO of meso epoxides with
dithiophosphorous acid as nucleophile, but catalyst recy-
cling was not attempted. As recycling of chiral catalysts is
an important criterion from commercial point of view,
therefore, it is highly desirable to develop recyclable cata-
Additional Supporting Information may be found in the online version of
this article.
Contract grant sponsor: DST
Contract grant sponsor: CSIR Network Project on Catalysis
*Correspondence to: Rukhsana I. Kureshy, Discipline of Inorganic Materials
and Catalysis, Central Salt and Marine Chemicals Research Institute
(CSMCRI), Council of Scientific and Industrial Research (CSIR), G. B. Marg,
Bhavnagar 364 002, Gujarat, India. E-mail: rukhsana93@yahoo.co.in
Received for publication 26 November 2009; Accepted 17 March 2010
DOI: 10.1002/chir.20868
Published online 17 May 2010 in Wiley Online Library
lysts for ARO of meso-epoxides with amines. In continua- (wileyonlinelibrary.com).
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VV
2010 Wiley-Liss, Inc.

ENANTIOSELECTIVE DESYMMETRIZATION OF meso-EPOXIDES
77
All products were characterized by appropriate spectro-
scopic techniques, microanalysis, LCMS, and optical rota-
tion, which were found to be in consonance with the
reported values.7,8,19,20
EXPERIMENTAL
Materials and Methods
Ti(OiPr)4, 1R,2R-(2)-1,2-diaminocyclohexane, (S)/(R)-1-
phenylethylamine, 2-methoxybenzaldehyde, 3-methoxy-
benzaldehyde, aniline (4), 2-methoxyaniline (5), 4-
methoxy aniline (6), 4-methylaniline (7), 4-chloroaniline
(8), 4-nitroaniline (9), meso-stilbene oxide (3), cis-butene
oxide (10), cyclohexene oxide (11), cyclopentene oxide
(12), and cyclooctene oxide (13) were purchased from
Aldrich Chemicals and were used as received. Racemic
(d, e) and nonracemic imines (f, g) were synthesized by
the condensation of appropriate arylaldehydes with a-
methylbenzylamine/(S)-1-phenylethylamine/(R)-1-phenyl-
ethylamine by the reported method.20 The synthesis and
characterization of ligands poly-[(R,R)-N,N0-bis-{3-(1,1-
dimethylethyl)-5-methylene salicylidene} cyclohexane-1,2-
diamine]-1 and (1R,2R)-N,N0-bis-[3,5-di(tert-butyl)salicyli-
dene] cyclohexane-1,2-diamine-2 and their precursors
were carried out as described earlier.15,35,36 The solvents
were dried by standard procedures, distilled, and stored
under nitrogen. NMR spectra were obtained with a Bruker
F113V spectrometer (500 and 125 MHz for 1H and 13C,
respectively) and were referenced internally with TMS.
FTIR spectra were recorded on Perkin Elmer Spectrum
GX spectrophotometer in KBr window. High-resolution
mass spectra were obtained with a LC-MS (Q-TOFF) LC
(Waters), MS (Micromass) instruments. For the product
purification, flash chromatography was performed using
silica gel 100–200 mesh (S.D. Fine-Chem, Mumbai, India).
Enantiomeric excesses of the products were determined
by HPLC (Shimadzu SCL-10AVP) using Daicel Chiralpak
AD, OD, and OJ chiral columns with 2-propanol/hexane
as an eluent. Optical rotations were measured with a Digi-
pol 781 Automatic Polarimeter Rudolph Instruments.
Recycling of the Catalyst
The recyclability of the polymeric Ti(IV)-1 catalyst was
assessed for ARO of meso-stilbene oxide (3) as a represen-
tative substrate with aniline (4) as a nucleophile. After the
catalytic run, the solvent was completely removed under
reduced pressure, and the residue was extracted with hex-
ane to isolate the product. The remaining solid was further
washed with hexane (10 ml), dried under reduced
pressure at 508C for 122 h, and was used as recovered
catalyst 1.
Characterization Data of Some Selected Compounds
(1S,2S)-1,2-Diphenyl-2-(phenylamino)-etha-
nol19,20
.
The title compound was isolated by column
chromatography (n-hexane/AcOEt: 90/10) as a white
solid. Melting point: 100–1028C.19 ee > 99% on HPLC
(Chiralpak OD column) mobile phase, 85/15 n-hexane/i-
PrOH; flow rate 1 ml/min, k 5 247 nm, tR (1S,2S) 5 15.91
min, tR (1R,2R) 5 20.60 min. LC-MS, m/z 290 [M 1 H]1,
1
272 (base peak) [M 2 OH]1, 312 [M 1 Na]1. H NMR
(500 MHz, CDCl3): d 5 2.38 (bs, OH), 4.40 (bs, NH), 4.51
(d, J 5 5.8 Hz, 1 H), 4.85 (d, J 5 5.8 Hz, 1 H), 6.50–6.53
(m, 2 H), 6.59–6.67 (m, 1 H), 7.01–7.09 (m, 2 H), 7.21–7.25
(m, 10 H) ppm. 13C NMR (125 MHz, CDCl3): 64.8, 78.1,
114.2, 117.9, 126.6, 127.3, 127.5, 128.2, 128.5, 129.0, 140.0,
140.6, 147.0 ppm. IR (KBr): 3546, 3407, 3027, 2880, 2849,
1600, 1502, 1451, 1429, 1320, 1033, 752, 695 cm21
.
(1S,2S)-1,2-Diphenyl-2-(2-methoxy-phenylamino)-
ethanol19,20
The title compound was isolated by col-
.
umn chromatography (n-hexane/AcOEt 90/10) as a white
solid. Melting point: 93–958C.19 ee 99% on HPLC (Chir-
alpak OJ column) mobile phase, 80/20 n-hexane/i-PrOH,
flow rate 0.5 ml/min, k 5 254 nm, tR (1S,2S) 5 35.5 min,
tR (1R,2R) 5 40.0 min. [a]2D7 5 248 (c 5 0.54, CH2Cl2).
LC-MS, m/z 661 [2M 1 Na]1, 320 [M 1 H]1, 302 (base
Typical Experimental Procedure for Ring
Opening of Epoxides
To a 5-ml round-bottom flask fitted with rubber septum
and equipped with a magnetic stirring bar, chiral poly-
meric 1/monomeric 2 salen ligand (0.02 mmol) was dis-
solved in dry toluene (0.8 ml). Ti(OiPr)4 (0.02 mmol) was
added to the above stirring solution at room temperature
(278C). After an interval of 1 h, an appropriate additive
(a–g) (0.02 mmol) was added to the resulting solution,
and the reaction mixture was further stirred for 20 min at
RT. An appropriate epoxide, namely, meso-stilbene oxide/
cyclohexene oxide/cyclooctene oxide/cis-butene oxide/
cyclopentene oxide (0.1 mmol), was then added to the
above stirring mixture. Subsequently after 20 min, an
appropriate aniline, namely, aniline (4), 2-methoxyaniline
1
peak) [M 2 OH]1, 342 [M 1 Na]1. H NMR (500 MHz,
CDCl3): d 5 2.73 (bs, OH), 3.79 (s, 3 H), 4.43 (d, J 5 6.2
Hz, 1 H), 4.79 (d, J 5 6.4 Hz, 1 H), 5.19 (bs, NH), 6.32
(dd, J 5 1.6 Hz, 7.2 Hz, 1 H), 6.51–6.70 (m, 3 H), 7.12–7.20
(m, 10 H) ppm. 13C NMR (125 MHz, CDCl3): 55.6, 64.9,
78.3, 109.6, 111.7, 117.1, 121.0, 126.7, 127.3, 127.7, 128.0,
128.3, 131.1, 140.2, 140.7, 140.6, 147.3 ppm. IR (in KBr):
3407, 3062, 3030, 2936, 2835, 1810, 1698, 1601, 1515, 1248,
1027, 846, 740, 700 cm21
.
(1S,2S)-1,2-Diphenyl-2-(4-methoxy-phenylamino)-
(5), 4-methoxy aniline (6), 4-methyl aniline (7), 4-chloroa- ethanol19,20
. The title compound was isolated by col-
niline (8), and 4-nitroaniline (9) (0.1mmol), was added, umn chromatography (n-hexane/AcOEt 90/10) as a yel-
and the reaction mixture was further allowed to stir for the low solid. Melting point: 98–1028C.19 ee 95% on HPLC
specified time. The progress of the reaction was checked (Chiralpak OD column) mobile phase, 85/15 n-hexane/i-
on TLC using hexane/ethyl acetate (8/2) as mobile phase. PrOH; flow rate 1 ml/min, k 5 247 nm, tR (1S,2S) 5 18.68
After completion of the reaction, solvent was removed min, tR (1R,2R) 5 22.52 min. LC-MS, m/z 661 [2M 1
under vacuum, and the product was purified by column Na]1, 320 (base peak) [M 1 H]1, 342 [M 1 Na]1. 1H
chromatography using silica gel 100–200 mesh as station- NMR (500 MHz, CDCl3): d 5 3.64 (s, 3 H), 4.38 (d, J 5
ary phase and hexane/ethyl acetate (8:2) as mobile phase. 6.4 Hz, 1 H), 4.85 (d, J 5 6.4 Hz, 1 H), 6.47–6.51 (m, 2 H),
Chirality DOI 10.1002/chir

78
KURESHY ET AL.
6.62–6.66 (m, 2 H), 7.01–7.09 (m, 2 H), 7.15–7.22 (m, 10 0.97–1.15 (m, 1 H), 1.24–1.50 (m, 3 H), 1.68–1.78 (m, 2 H),
H) ppm. 13C NMR (125 MHz, CDCl3): 55.7, 66.2, 78.1, 2.04–2.16 (m, 2 H), 2.85 (bs, 1 H), 3.07–3.19 (m, 1 H),
114.7, 115.8, 126.7, 127.3, 127.8, 127.9, 128.5, 128.7, 140.3, 3.34–3.46 (m, 1 H), 3.83 (s, 3 H), 6.63–6.89 (m, 4 H) ppm;
140.7, 141.4, 152.6 ppm. IR (in KBr): 3483, 3393, 13C NMR (125 MHz, CDCl3): d 5 24.2, 25.0, 31.5, 33.0,
3026, 2964, 2833, 1807, 1510, 1453, 1254, 1024, 819, 753, 55.4, 55.6, 74.5, 109.7, 111.4, 117.2, 121.2, 137.5, 147.5
700 cm21
.
ppm. IR (in KBr): 3616, 3429, 3067, 2964, 1602, 1511, 1456,
1430, 1341, 1247, 1180, 1121, 1050, 1030, 977, 945 cm21
.
(1S,2S)-1,2-Diphenyl-2-(4-methyl-phenylamino)-
ethanol19,20
The title compound was isolated by col-
.
(1S,2S)-2-(4-Methoxyphenylamino)-cyclohexane-
1-ol19,20
The title compound was isolated by column
.
umn chromatography (n-hexane/AcOEt 90/10) as a white
solid. Melting point: 858C.19 ee > 99% on HPLC (Chiralpak
AD column,) mobile phase, 85/15 n-hexane/i-PrOH; flow
rate 1 ml/min, k 5 247 nm, tR (1R,2R) 5 20.60 min, tR
(1S,2S) 5 17.99 min. LC-MS, m/z 304 [M 1 H]1, 286
chromatography (n-hexane/AcOEt 85/15) as a white solid.
Melting point: 62–648C.19 ee 36% on HPLC (Chiralpak OD
column) mobile phase, 80/20 n-hexane/i-PrOH; flow rate
0.5 ml/min, k 5 247 nm, tR (1S,2S) 5 22.30 min, tR
1
(1R,2R): 27.48 min. [a]2D7 5 140.1 (c 5 3.2, CH2Cl2). H
(base peak) [M 2 OH]1. H NMR (500 MHz, CDCl3): d
1
NMR (500 MHz, CDCl3): d 5 0.85–1.10 (m, 1 H), 1.12–
1.40 (m, 3 H), 1.60–1.80 (m, 2 H), 2.0–2.18 (m, 2 H), 2.92–
3.04 (m, 1 H), 2.60 (bs, 1 H), 3.24–3.55 (m, 1 H), 3.73 (s, 3
H), 6.66 (d, J 5 8.8 Hz, 2 H), 6.76 (d, J 5 8.8 Hz, 2 H)
ppm; 13C NMR (125 MHz, CDCl3): d 5 24.2, 25.0, 31.4,
33.0, 55.6, 61.6, 74.3, 114.7, 116.3, 141.5, 152.8 ppm. IR (in
KBr): 3677, 3529, 3366, 3021, 3013, 2938, 2861, 2836, 1612,
1512, 1465, 1450, 1401, 1296, 1239, 1221, 1180, 1136, 1067,
5 2.15 (s, 3 H), 4.45 (d, J 5 6.2 Hz, 1 H), 4.81 (d, J 5 6.2
Hz, 1 H), 6.42–6.46 (m, 2 H), 6.84–6.88 (m, 2 H), 7.19–7.23
(m, 10 H) ppm. 13C NMR (125 MHz, CDCl3): 20.3, 65.2,
78.0, 114.4, 126.5, 127.2, 127.6, 128.1, 128.3, 129.5, 139.3,
139.5.4, 146.5 ppm. IR (in KBr): 3399, 3061, 3029,
2859, 2831, 1813, 1616, 1518, 1490, 1259, 1044, 815, 768,
700 cm21
.
(2S,3S)-2-N-Phenylamino-3-butanol20,24
.
The title
1038 cm21
.
compound was isolated by column chromatography (n-
hexane/AcOEt 90/10) as an oil. ee 19% on HPLC (Chir-
alpak OD column) mobile phase, 97.5/2.5 n-hexane/i-
PrOH; flow rate 1 ml/min, k 5 247 nm, tR (2S,3S) 5 35.63
min, tR (2R,3R) 5 38.57 min. LC-MS, m/z 166 [M 1 H]1,
1H NMR (500 MHz, CDCl3): d 5 1.14 (d, J 5 6.8 Hz, 1H),
1.25 (d, J 5 6.8 Hz, 3H), 2.61 (brs, 1H), 3.31 (m, 1H), 3.62
(m, 2H), 6.66–6.74 (m, 3H), 7.15–7.18 (m, 2H) ppm. 13C
NMR (125 MHz, CDCl3): d 5 17.3, 19.5, 56.1, 71.4, 114.3,
118.2, 129.3, 147.7 ppm. IR (KBr) 3398, 3053, 2974, 2926,
1922, 1602, 1505, 1439, 1376, 1318, 1254, 1005, 902, 751,
(1S,2S)-2-(4-Methylphenylamino)-cyclohexane-
1-ol19,20
The title compound was isolated by column
.
chromatography (n-hexane/AcOEt 90/10) as a brownish
liquid. ee 38% on HPLC (Chiralpak OD column) mobile
phase, 90/10 n-hexane/i-PrOH; flow rate 0.8 ml/min, k 5
247 nm, tR (1S,2S):17.99 min, tR (1R,2R): 20.60 min. 1H
NMR (500 MHz, CDCl3); d 5 1.01–1.05 (m, 2H), 1.23–1.40
(m, 5 H), 1.70–1.75 (m, 2 H), 2.24 (s, 3 H), 3.062–3.10 (m,
1 H), 6.64 (d, 2 H, J 5 8 Hz), 7.00 (d, 2 H, J 5 8 Hz) ppm;
13C NMR (125 MHz, CDCl3): d 5 20.40, 24.31, 25.11,
31.60, 33.10, 60.73, 74.55, 114.81, 129.88 ppm. IR (in KBr):
3665, 3390, 3105, 3019, 2928, 2860, 2734, 1866, 1617, 1519,
692 cm21
(1S,2S)-2-(Phenylamino)-cyclohexane-1-ol19,20
.
.
The 1451, 1451, 1405, 1300, 1252, 1182, 1128, 1066, 936 cm21
.
title compound was isolated by column chromatography
(n-hexane/AcOEt 90/10) as a white solid. Melting point:
58–608C.19 ee 67% on HPLC (Chiralpak OJ column) mobile
phase, 95/5 n-hexane/i-PrOH; flow rate 0.4 ml/min, k 5
247 nm, tR (1S,2S) 5 13.73 min, tR (1R,2R) 5 15.38 min.
LC-MS, m/z 192 [M 1 H]1, 214 [M 1 Na]1. 1H NMR
(500 MHz, CDCl3): d 5 1.03–1.41 (m, 4 H), 1.71–1.77 (m,
2 H), 2.09–2.15 (m, 2 H), 2.89 (m, 2 H), 3.13 (ddd, J 5 3.9
Hz, J 5 10.0 Hz, J 5 10.1 Hz, 1 H), 3.33 (ddd, J 5 4.2 Hz, J
5 10.4 Hz, J 5 10.5 Hz, 1 H), 6.7–7.2 (m, 2 H), 7.21–7.25
(m, 5 H); 13C NMR (125 MHz, CDCl3): d 5 24.2, 24.9,
31.5, 33.1, 60.1, 74.4, 114.3, 118.3, 129.3, 147.8. IR
(in KBr): 3354, 2931, 2858, 1602, 1501, 1448, 1320, 1067,
(1S,2S)-2-(Phenylamino)-cyclooctane-1-ol4,20
.
The
title compound was isolated by column chromatography
(n-hexane/AcOEt 90/10) as a white solid. Melting point
55–568C.20 ee 46% on HPLC (Chiralpak OD column) mo-
bile phase, 95/5 n-hexane/i-PrOH; flow rate 0.8 ml/min, k
5 247 nm, tR (1S,2S) 5 27.12 min, tR (1R,2R) 5 29.34 min.
1
LC-MS, m/z 218 [M 1 H]1; H NMR (500 MHz, CDCl3):
1.05–1.45 (m, 4H), 1.50–2.15 (m, 8H), 3.40–3.50 (m, 1H),
3.60–3.70 (m, 1H), 4.50 (br, 1H), 6.70–7.20 (m, 6H) ppm.
IR (KBr): 3315, 3107, 3054, 3027, 2941, 1923, 1690, 1604,
1498, 1465, 1306, 1256 cm21
.
748 cm21
.
RESULTS AND DISCUSSION
(1S,2S)-2-(2-Methoxyphenylamino)-cyclohexane-
The active catalysts for the asymmetric epoxide ring-
. The title compound was isolated by column opening reaction with anilines as nucleophile were gener-
1-ol19,20
chromatography (n-hexane/AcOEt 90/10) as a white solid. ated in situ by the reaction of poly-[(R,R)-N,N0-bis-{3-(1,1-
Melting point: 68–708C.19 ee 29% on HPLC (Chiralpak OJ dimethylethyl)-5-methylene salicylidene} cyclohexane-1,2-
column) mobile phase, 80/20 n-hexane/i-PrOH; flow rate diamine]-1/(1R,2R)-N,N0-bis[3,5-di(tert-butyl)salicyliden]
0.5 ml/min, k 5 247 nm, tR (1S,2S) 5 20.54 min, tR cyclohexane-1,2-diamine-2 with Ti(OiPr)4 (Fig. 1). To
(1R,2R) 5 22.05 min. [a]2D7 5 149.6 (c 5 3.0, CH2Cl2, 63% begin with we have carried out ring opening of meso-stil-
1
ee).1H NMR (500 MHz, CDCl3): H NMR (CDCl3): d 5 bene oxide (3) taken as model substrate with aniline (4)
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE DESYMMETRIZATION OF meso-EPOXIDES
79
carried out present ring-opening reaction at 10 and 08C as
well and found out that there was only a marginal increase
in the enantioselectivity (entries 7–10) by lowering the
reaction temperature from RT. The advantage of this little
increase in the enantioselectivity was however outweighed
by the increase in the reaction time and low product
yields. Hence, our next effort to increase the reactivity and
enantioselectivity of ARO reaction was on application of
various achiral (a–c) and racemic (d,e)/nonracemic addi-
tives (f,g) with the above optimized process. The efficacy
of these additives has been previously reported by us on
the enantioselective epoxide ring-opening reaction to form
chiral b-amino alcohols.19,20 Among the various additives
(Fig. 2) used, the use of single enantiomer of additive (f)
with 20 mol % catalyst loading at RT for the ARO of meso-
stilbene oxide (3) produced chiral b-amino alcohol (40) in
high yield (99%) and ee (>99%) within 9–12 h (entries
21,22). Noticeably, the use of (g), which is opposite enan-
tiomer of (f), caused decrease in yield and ee of the
Fig. 1. Structure of chiral polymeric and monomeric salen ligands 1
and 2.
using variable loadings of the above in situ generated com-
plexes as catalyst in toluene at RT (Table 1, entries 1–6).
The results showed that 20 mol % of both the catalysts is
optimum (entries 3, 4) in terms of yield and ee of the prod-
uct b-aminoalcohol 40 at RT. Further, in view of well-
known impact of temperature on enantioselectivity and
product yield in an asymmetric organic transformation; we
TABLE 1. Optimization of reaction condition for meso-stilbene oxide (3) with aniline (4) using in situ generated chiral
Ti(IV) polymeric and monomeric complexes 1 and 2
b-Aminoalcohol 40
Entry
Catalyst (mol %)
Additive
Temperature (8C)
Solvent
Time (h)
Yield (%)a
ee (%)b
1(2)c
3(4)
5(6)
7(8)
10
20
40
20
20
20
20
20
20
20
20
20
20
20
–
–
–
–
–
a
b
c
d
e
f
RT
RT
RT
108C
08C
RT
RT
RT
RT
RT
RT
RT
RT
RT
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
18 (25)
12 (18)
10 (15)
13 (20)
24 (36)
10 (14)
10 (14)
10 (16)
10 (14)
10 (16)
9 (12)
65 (60)
75 (72)
76 (74)
67 (60)
63 (51)
85 (79)
83 (80)
55 (40)
75 (70)
61 (50)
99 (99)
95 (90)
88 (85)
75 (70)
22 (20)
43 (42)
44 (42)
46 (44)
52 (49)
55 (50)
48 (35)
46 (40)
54 (50)
69 (67)
>99 (99)
75 (72)
87 (84)
62 (54)
9(10)
11(12)
13(14)
15(16)
17(18)
19(20)
21(22)
23(24)d
25(26)
27(28)
g
f
f
9 (12)
9 (14)
9 (16)
THF
aIsolated yield.
bThe ee was determined using chiral OD column.
cData in parenthesis given for complex 2.
dReaction conducted in the presence of (R)-N-(2-methoxybenzylidene)-1-phenylethanamine as additive.
Chirality DOI 10.1002/chir

80
KURESHY ET AL.
Fig. 2. Structure of additives.
TABLE 2. Asymmetric ring opening of meso-stilbene oxide
(3) with various amines (4–9) using in situ generated chiral
polymeric and monomeric Ti(IV) salen complexes 1 and 2
in the presence of nonracemic imine (f) as additivea
desired product (Table 1, entries 23, 24). These results
suggest the existence of synergy between the catalyst and
the additive during the transfer of chirality during the
epoxide ring-opening reaction in the catalytic cycle. Such
an observation had also been reported previously for chi-
ral BINOL and Schiff base systems.38,20 Furthermore, we
also checked the solvent dependence of this catalytic ARO
protocol and found that dichloromethane and THF
(entries 25–28) are not as good as toluene (entries 21, 22).
Next, to see the efficacy of this protocol, we further
explored the use of various nucleophiles, namely 2-
methoxyaniline (5), 4-methoxyaniline (6), 4-methylaniline
(7), 4-chloroaniline (8), and 4-nitroaniline (9), in the ring
opening of meso-stilbene oxide (3) with in situ generated
polymeric/monomeric complexes 1 and 2 in combination
with nonracemic imine (f) as an additive at RT. The results
summarized in Table 2 have shown that the substituents
present on aniline have profound affect on its nucleophilic-
ity. The electron-donating substituents like OMe and Me
increase the nucleophilicity of the aniline making the
epoxide ring-opening reaction more facile (entries 3–8),
thus resulting in high yield (85–92%) of b-amino alcohols
and high chiral induction (ee; up to 99%) (entry 3),
whereas substituents like NO2 and Cl drastically reduced
the availability of lone pair of electrons on the nitrogen of
the aniline, thereby making these nucleophiles ineffective
to open the epoxide ring (entries 9–12). Overall, both the
in situ generated complexes 1 and 2 gave comparable
yields and enantioselectivities of b-aminoalcohols; how-
ever, reaction took longer time with monomeric complex
2 as catalyst against polymeric complex 1. The enhanced
reactivity in the case of polymeric complex 1 may be
attributed to the increase reactive sites, which may be
Chirality DOI 10.1002/chir
b-Aminoalcohol 40-90
Entry
Amine
Time (h)
Yield (%)b
ee (%)c
1(2)d
3(4)
5(6)
7(8)
9(10)
11(12)
4
5
6
7
8
9
9(12)
10 (14)
10 (16)
10 (16)
24 (24)
24 (24)
99 (99)
92 (91)
90 (89)
92 (85)
–
>99 (99)
99 (95)
95 (95)
77 (63)
–
–
–
aAll reactions were carried out at room temperature using 0.1 mmol epox-
ide, amine 0.1 mmol, complexes 1 and 2 0.02 mmol in the presence of
0.02 mmol additive.
bIsolated yield.
cThe ee was determined using chiral OD, OJ, AD column.
dData in parenthesis given for complex 2.

ENANTIOSELECTIVE DESYMMETRIZATION OF meso-EPOXIDES
81
TABLE 3. Asymmetric ring opening of epoxides (10–13)
with aniline (4) in the presence of different additives using
in situ generated chiral polymeric and monomeric Ti(IV)
salen complexes 1 and 2a
Further, on conducting the ARO of cyclohexene oxide
(11) with electron-rich substituted anilines (4–7) using in
situ generated complexes 1 and 2 as catalysts and triphe-
nylphosphine (a) as an additive, only moderate product
yield with low ee for respective aminoalcohols was
achieved (Table 4, entries 3–8). On the other hand, elec-
tron-deficient anilines (8,9) failed to react with cyclohex-
ene oxide (11) under this condition (Table 4). In all the
catalytic runs, (S) enantiomer of the product chiral b-
amino alcohols (110, 140–180) formed in excess with the
(R)-form of in situ generated Ti (IV) salen complexes 1
and 2.
To evaluate the recycle ability of the in situ generated
chiral polymeric and monomeric Ti(IV) salen complexes 1
and 2, we conducted catalytic runs using meso-stilbene ox-
ide (3) as a model substrate with aniline (4) in presence
of nonracemic imine (f) as an additive at RT. The in situ
generated polymeric complex 1 was precipitated out after
the first catalytic run by the addition of excess amount of
n-hexane to the reaction mixture, and the resulting cata-
lyst was collected by filtration. The recovered catalyst 1
was thoroughly washed with hexane and dried under vac-
uum at RT. The recovered catalyst was characterized by
b-Aminoalcohol
100-130
Entry
Oxide
Additive
Time (h)
Yield (%)b
ee (%)c
1(2)d
3(4)
5(6)
7(8)
10
f
10
12
12
10
24
12
15
12
12
10
15
15
15
12
15
15
80 (76)
85 (80)d
75 (70)
67 (65)
57 (50)
90 (85)
75 (70)
77 (70)
81 (75)
80 (75)
70 (65)
75 (70)
33 (30)
46 (40)
54 (50)
47 (40)
19 (15)
Racemic
Racemic
Racemic
28 (22)
a
b
c
f
a
b
c
f
a
b
c
f
a
b
c
9(10)
11
12
13
11(12)
13(14)
15(16)
17(18)
19(20)
21(22)
23(24)
25(26)
27(28)
29(30)
31(32)
67 (63)
30 (25)
TABLE 4. Asymmetric ring opening of cyclohexene oxide
(11) with various amines (4-9) using in situ generated chiral
polymeric and monomeric Ti(IV) salen complexes 1 and 2
in presence of triphenylphosphine a as additivea
Racemic
Racemic
37 (32)
Racemic
Racemic
Racemic
46 (38)
33 (30)
Racemic
aAll reactions were carried out at room temperature using 0.1 mmol epox-
ide, amine 0.1 mmol, complexes 1 and 2 0.02 mmol in the presence of
0.02 mmol additive.
bIsolated yield.
cThe ee was determined using chiral AD, OD, OJ column.
dData in parenthesis given for complex 2.
working in cooperation.39 Recyclability of polymeric cata-
lyst 1 was another advantage over monomeric catalyst 2,
which was nonrecyclable.
The scope of this protocol for the ring-opening reaction
was further extended to cis-butene oxide (10), cyclohex-
ene oxide (11), cyclopentene oxide (12), and cyclooctene
oxide (13) with aniline (4) as nucleophile and nonracemic
(f) as an additive for the synthesis of respective b-amino
alcohols (Table 3 entries 1, 2, 9, 10, 17, 18, 25, and 26). In
most of the cases, although the product yield was good to
excellent, the reaction took racemic pathway. These
results led us to explore the use of nonchiral additives
with these epoxides without changing other reaction pa-
rameters. The triethylamine (c) as an additive failed to
show any enantioselectivity (entries 7, 8, 15, 16, 23, 24, 31,
and 32), whereas triphenylphosphine (a) performed bet-
ter. The best results with this additive (a) using catalysts
1 and 2 were obtained in the case of ring opening of cyclo-
hexene oxide (11) with aniline (4) (yield, 90 and 85%; ee,
67 and 63% entries 11, 12).
b-Aminoalcohol 110,
140-180
Entry
Amine
Time(h)
Yield (%)b
ee (%)c
1(2)d
3(4)
5(6)
7(8)
9(10)
11(12)
4
5
6
7
8
9
12
13
15
17
24
24
90 (85)
70 (64)
72 (68)
75 (71)
–
67 (63)
29 (25)
36 (33)
37 (32)
–
–
–
aAll reactions were carried out at room temperature using 0.1 mmol epox-
ide, 0.1 mmol amine, complexes 1 and 2 0.02 mmol in the presence of
0.02 mmol additive.
bIsolated yield.
cThe ee was determined using chiral OD, OJ, column.
dData in parenthesis given for complex 2.
Chirality DOI 10.1002/chir

82
KURESHY ET AL.
TABLE 5. Data for the asymmetric ring opening of meso-
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