Asymmetric benzaldehyde methylation with titanium TADDOLate complexes

Article abstract of DOI:10.1016/j.ica.2013.10.004

The Lewis acid catalyst derived from Ti(OⁱPr)₄ and (4R,5R)-(-)-2,2-dimethyl-α,α,α',α'-tetraphenyl-1, 3-dioxolane-4,5-dimethanol, (R,R)-TADDOL, [1], in the presence of Me ₂Zn, mediates the complete conversion of 4-chlorobenzaldehyde to (S)-1-(4-chlorophenyl)ethanol with 96% enantiomeric excess. With unsubstituted benzaldehyde, the maximum enantiomeric excess observed under the same conditions is 91%. Application of chlorinated (R,R)-TADDOL derivatives to the methylation of unsubstituted benzaldehyde reveals that addition of chloro substituents to the ligand also induces the result of increasing the enantioselectivity of the catalysis. The reaction of (-)-dimethyl 2,3-O-isopropylidene-l-tartrate with 3,4-dichlorophenyl magnesium bromide or 3,5-dichlorophenyl magnesium bromide yields the octachlorinated (R,R)-TADDOL derivatives (4R,5R)-(-)-2,2-dimethyl- α,α,α',α'-tetra-3,4-dichlorophenyl-1,3-dioxolane-4, 5-dimethanol, 3,4-[1] and (4R,5R)-(-)-2,2-dimethyl-α,α, α', α'-tetra-3,5-dichlorophenyl-1,3-dioxolane-4,5-dimethanol, 3,5-[1]. Catalysis screenings showed that 3,4-[1], in conjunction with Ti(O ⁱPr)₄ and Me₂Zn, forms a Lewis acid titanium TADDOLate catalyst capable of converting benzaldehyde to (S)-1-phenylethanol with >99% conversion and >96% enantiomeric excess.

Full text of DOI:10.1016/j.ica.2013.10.004

Inorganica Chimica Acta 409 (2014) 394–398
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Asymmetric benzaldehyde methylation with titanium TADDOLate
complexes
⇑
Mollie G. Baker-Salisbury, Brian S. Starkman, Gabrielle M. Frisenda, Leslie A. Roteta, Joseph M. Tanski
Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA
a r t i c l e i n f o
a b s t r a c t
The Lewis acid catalyst derived from Ti(OiPr)4 and (4R,5R)-(ꢀ)-2,2-dimethyl-
a
,
a
,
a0
,
a0-tetraphenyl-1,3-
Article history:
Received 18 August 2013
Received in revised form 2 October 2013
Accepted 3 October 2013
dioxolane-4,5-dimethanol, (R,R)-TADDOL, [1], in the presence of Me2Zn, mediates the complete conver-
sion of 4-chlorobenzaldehyde to (S)-1-(4-chlorophenyl)ethanol with 96% enantiomeric excess. With
unsubstituted benzaldehyde, the maximum enantiomeric excess observed under the same conditions
is 91%. Application of chlorinated (R,R)-TADDOL derivatives to the methylation of unsubstituted benzal-
dehyde reveals that addition of chloro substituents to the ligand also induces the result of increasing the
Available online 14 October 2013
Keywords:
Titanium(IV)
TADDOL
enantioselectivity of the catalysis. The reaction of (ꢀ)-dimethyl 2,3-O-isopropylidene-
dichlorophenyl magnesium bromide or 3,5-dichlorophenyl magnesium bromide yields the octachlori-
nated (R,R)-TADDOL derivatives (4R,5R)-(ꢀ)-2,2-dimethyl-
a0-tetra-3,4-dichlorophenyl-1,3-dioxo-
a0-tetra-3,5-dichlorophenyl-1,3-
L-tartrate with 3,4-
a,a, ,
a0
Asymmetric catalysis
lane-4,5-dimethanol, 3,4-[1] and (4R,5R)-(ꢀ)-2,2-dimethyl-
a,a, ,
a0
dioxolane-4,5-dimethanol, 3,5-[1]. Catalysis screenings showed that 3,4-[1], in conjunction with Ti(OiPr)4
and Me2Zn, forms a Lewis acid titanium TADDOLate catalyst capable of converting benzaldehyde to (S)-1-
phenylethanol with >99% conversion and >96% enantiomeric excess.
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
metric induction with
a
titanium(IV) complex of BINOL
(BINOL = 1,10-bi-2-naphthol), and the resolved chiral alkoxides,
Ti(OR-2Bu)4 or Ti(OS-2Bu)4 [34]. Whereas R- or S- BINOL in combina-
tion with achiral Ti(OiPr)4 results in ee of 1-phenylethanol in the
range of 50% [14], resolved BINOL in combination with chiral, re-
solved Ti(O2Bu)4 of the opposite configuration designation results
in ee’s of 1-phenylethanol in the range of 60% [34].
Chemical synthesis by asymmetric catalysis is an intensely
investigated field in modern chemical science and technology,
assisting with the preparation of enantioenriched compounds on
scales both small and large [1–3]. In the synthesis of enantiopure
secondary alcohols, the addition of organometallic reagents to
aldehydes, generally in the presence of an added titanium(IV) com-
pounds such as Ti(OiPr)4, exemplifies an active area of research.
These organometallic compounds include alkyl or aryl (i) lithium
[4,5], (ii) magnesium halide (Grignard) [6,7], (iii) aluminum [8–
10], (iv) titanium [11–16] and (v) zinc [11,14,17–31] reagents. Of
these, several of the zinc catalysts have been shown to mediate
Including BINOL [14,16,18,19,21,24,27], other catalytically use-
ful ligands for titanium mediated alkylation for aldehydes include
octahydroBINOL [15,16,21,23,24], amino alcohols [20,26,30,31],
bis(sulfonamides) [14,22,28], tetrahydrosalen [35], hydroxyamides
[29], and TADDOL [11–13,16,25]. Whereas the alkylation of alde-
hydes with diethyl zinc can be achieved with very good conversion
and high ee, dimethyl zinc typically results in much lower enantio-
meric excess in similar catalytic systems [13,14,34], with the
exception of a few notable examples. With (R,R)-TADDOL [1]
(Scheme 1), Seebach and co-workers have extensively investigated
the alkylation of aldehydes with dialkyl zinc compounds in the
presence of Ti(OiPr)4, achieving nearly 100% ee in ethylation with
diethyl zinc [11] and 94% ee in methylation with dimethyl zinc
[11,36]. With a stoichiometric amount of CH3Ti(OiPr)3 in the ab-
sence of dimethyl zinc at ꢀ25 °C, the selectivity can be increased
to 96% ee (S)-1-phenylethanol [11].
alkylation
without
added
titanium(IV)
compounds
[17,20,23,26,29,31]. Anchored catalysts [32] and porous materials
for heterogeneous catalysis, including a recyclable chiral material
[33], that mediate the addition of diethyl zinc to arylaldehydes in
the presence of titanium(IV) isopropoxide, have also been reported.
We have been investigating the methylation of benzaldehyde
with dimethyl zinc catalyzed by titanium complexes of resolved,
chiral diols. Our initial work showed that it is possible to modestly
increase the enantiomeric excess (ee) of 1-phenylethanol obtained
from the methylation of benzaldehyde by dichiral double asym-
More recently, reports of new derivatives of chiral ligands based
on TADDOL and amino alcohol frameworks have shown that it is
possible to observe high enantiomeric excess in the addition of di-
⇑
Corresponding author. Tel.: +1 845 437 5731.
E-mail address: jotanski@vassar.edu (J.M. Tanski).
0020-1693/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2013.10.004

M.G. Baker-Salisbury et al. / Inorganica Chimica Acta 409 (2014) 394–398
395
Scheme 1. Chiral diol (R,R)-TADDOL, [1], a perfluorobutyl derivative of the 1,3-dioxolane-4,5-dimethanol scaffold, and a ferrocenyl methylaziridin methanol amino alcohol.
methyl zinc to arylaldehydes. Ando and coworkers have shown
that perfluoroalkyl substituents on the 1,3-dioxolane-4,5-dimetha-
nol scaffold found in TADDOL can mediate the methylation of an
array of arylaldehydes in the presence of Ti(OiPr)4; in the case of
benzaldehyde, a perfluorobutyl derivative (Scheme 1) yielding
99% conversion and 95% ee (R)-1-phenylethanol [25]. Wang et al.
used the chiral ferrocene containing b-amino alcohol shown in
Scheme 1 to observe 96% conversion of benzaldehyde to (S)-1-
phenylethanol with 90% ee [26], remarkably in the absence of
any added titanium Lewis acid.
In this paper we report results on an application of the TADDOL
ligand framework, a highly useful framework for asymmetric syn-
thesis [37], in the asymmetric methylation of benzaldehydes with
dimethyl zinc. Specifically, octachlorinated (R,R)-TADDOL ligands
have been investigated as they may lead to even more Lewis acidic
titanium catalysts with even greater steric hindrance at the metal
active site, further activating and constraining the possible confor-
mations of the substrate bound to the catalyst leading to enhanced
enantiomeric selectivity.
theoretical values; this could be attributable to the fact that the
compounds do not crystallize analytically pure and are obtained
as powders. Infrared spectra were recorded as pressed KBr pellets
on a Thermo Nicolet Nexus 670 FT-IR spectrometer and are re-
ported in cmꢀ1. For mass spectrometry analysis, samples, dissolved
in CHCl3:CH3OH:NH4OH (800:195:5, v/v/v), were directly infused
using an Agilent 1100 HPLC system into an Agilent 6520 electro-
spray ionization quadrupole time-of-flight mass spectrometer
detecting in the negative ion mode. Mass spectra were obtained
using settings described previously [39]. Chiral GC analyses with
were carried out on an HP 6890 Series gas chromatograph using
50:1 split mode capillary injection (200 °C) with a flame ionization
detector (220 °C) and an Alltech Chirladex B-DM column (0.25 mm
ꢁ 30 m). Samples were injected as a diethyl ether solution, with an
initial oven temperature of 90 °C for 5 min, followed by ramping
0.5 °C per min to 95 °C and holding for 15 min at 95 °C. Retention
times for 1-phenylethanol 6.6 min (R), 7.0 min (S); for 1-(4-chloro-
phenyl)ethanol 22.5 min (R), 24.1 min (S).
2.2. General procedure for the asymmetric addition of Me2Zn to
benzaldehyde
2. Experimental section
Following a procedure derived from that of Chan [18] and Nakai
[19]: to a stirring solution of (R,R)-TADDOL ligand (0.21 mmol) in
CH2Cl2 (5 mL) was added Ti(OiPr)4 (1.4 mmol). After 1 h stirring,
the reaction mixture was cooled to 3 °C and 3 mL of dimethylzinc
solution (2.0 M in toluene, 6.0 mmol) was added. After stirring for
30 min, benzaldehyde was added (1.0 mmol) and the mixture was
stirred for 24 h. The reaction was quenched with 1 M HCl (20 mL)
and extracted with diethyl ether (3 ꢁ 20 mL). The combined organ-
ic layers were washed with brine, dried over anhydrous magne-
sium sulfate and concentrated. The remaining oil was analyzed
by 1H NMR and chiral GC (Alltech Chiraldex B-DM), to determine
the percent conversion to 1-phenylethanol and its enantiomeric
excess, respectively. An identical procedure was used for the meth-
ylation of 4-chlorobenzaldehyde.
2.1. General experimental
Unless otherwise stated, all manipulations were carried out at
room temperature in an inert atmosphere glove box or under a
nitrogen atmosphere using standard Schlenk techniques. All glass-
ware was oven dried at a temperature of 235 °C prior to use. Anhy-
drous solvents were purchased from Aldrich and stored under
nitrogen. Dimethyl zinc (2.0 M in toluene), titanium(IV) isopropox-
ide (97%), (ꢀ)-dimethyl-2,3-O-isopropylidene-
L-tartrate (97%),
benzaldehyde (99.5%), 4-chlorobenzaldehyde (97%), 1-phenyletha-
nol (98%), and (R)-(+)-1-(4-chlorophenyl)ethanol (95%) were pur-
chased from Aldrich. (R)-(+)-1-phenylethanol was obtained from
Fluka, and 1-(4-chlorophenyl)ethanol (97%) from Alfa-Aesar.
(4R,5R)-(ꢀ)-2,2-dimethyl-
a,a, ,
a0 a0-tetraphenyl-1,3-dioxolane-4,5-
dimethanol, (R,R)-TADDOL, was purchased from Strem. 3,4- and
3,5-dichlorophenyl magnesium bromide, 0.5 M in tetrahydrofuran,
97%, were purchased from Aldrich or Novel Chemical Solutions. All
reagents were used as received. TADDOL derivatives (4R,5R)-(ꢀ)-
2.3. Synthesis of (4R,5R)-(ꢀ)-2,2-dimethyl-
dichlorophenyl-1,3-dioxolane-4,5-dimethanol, 3,4-[1], and (4R,5R)-
(ꢀ)-2,2-dimethyl-
a0-tetra-3,5-dichlorophenyl-1,3-dioxolane-
4,5-dimethanol, 3,5-[1]
a,a, ,
a0 a0-tetra-3,4-
a,a, ,
a0
2,2-dimethyl-a,a, ,
a0 a0-tetra-3,4-dichlorophenyl-1,3-dioxolane-
4,5-dimethanol, 3,4-[1] and (4R,5R)-(ꢀ)-2,2-dimethyl-
a,a, , -
a0 a0
3,5-[1]
tetra-3,5-dichlorophenyl-1,3-dioxolane-4,5-dimethanol,
The octachlorinated TADDOL derivatives 3,4-[1] and 3,5-[1]
were prepared with Grignard reagents in a manner similar to that
previously reported for another chlorinated TADDOL [38]. (ꢀ)-Di-
were prepared in a manner similar to that previously reported
for another chlorinated TADDOL derivative [38].
1H NMR spectra were recorded at room temperature using a
Bruker Avance DPX 300 MHz spectrometer. Chemical shifts are re-
ported referenced to the solvent resonances of d 5.31 (1H) and d
53.84 (13C) ppm for dichloromethane-d2. Elemental analyses were
carried out by Columbia Analytical Services, Tucson, AZ, USA; sam-
ples were dried under vacuum at 105 °C for 2 h. prior to analysis.
The combustion analysis returns results that are higher than the
methyl-2,3-O-isopropylidene-L-tartrate (1.0 mL, 5.5 mmol) was
added dropwise to the Grignard reagent 3,4- or 3,5-dichlorophenyl
magnesium bromide (50 mL, 0.5 M in tetrahydrofuran, 25 mmol)
with stirring at 0 °C. After the reaction was allowed to reach room
temperature, it was refluxed at 70–80 °C under argon for 2 h. Once
cooled, approximately 20 mL of ammonium chloride was added
and the mixture was stirred for at least 1 h. The reaction was ex-

396
M.G. Baker-Salisbury et al. / Inorganica Chimica Acta 409 (2014) 394–398
tracted with ethyl acetate (2 ꢁ 50 mL). The combined organic lay-
ers were washed with brine, dried over anhydrous MgSO4, filtered,
concentrated, purified by column chromatography (ethyl acetate/
hexanes), concentrated again, dried on a vacuum line, triturated
multiple times with dry tetrahydrofuran to remove bulk water,
and finally dried with warming under vacuum. The resulting off-
white to yellow powders were obtained in variable yields depend-
ing on the success of the synthesis, purification and drying steps,
but could be obtained in up to 70% yield for 3,4-[1] and 60% for
3,5-[1].
126.79 (CarylH), 128.59 (CarylH), 128.82 (CarylH), 135.10 (Caryl),
135.33 (Caryl), 145.81 (Caryl), 147.22 (Caryl). Anal. Calc. for C31H22Cl8-
O4: C, 50.17; H 2.99; N, 0. Found: C, 52.49; H, 3.71; N, 0.12%. IR Data
(KBr pellet, cmꢀ1): 3543 (m, OH str), 3363 (s, br, OH str), 3086 (m,
CarylH str), 2987 (m, CH str), 2959 (m, CH str), 2929 (m, CH str),
2854 (m, CH str), 1728 (w), 1585 (vs), 1567 (vs), 1419 (vs), 1384
(s), 1337 (w), 1261 (m), 1238 (m), 1192 (m), 1169 (s), 1101 (s),
1070 (s), 969 (w), 862 (vs), 801 (vs), 733 (s), 713 (m), 510 (w),
435 (w). The m/z observed for the [MꢀH]ꢀ ion was 736.895 (calcu-
lated exact mass: 736.8954). This m/z matches the molecular for-
mula of the compound with 0.44 ppm error.
Data for 3,4-[1]: 1H NMR (300 MHz, CD2Cl2): d 1.22 (s, 6H, CH3),
4.17 (s, 2H, OH), 4.39 (s, 2H, CH), 7.1–7.6 (m, 12 H, Ar–CH). 13C NMR
(
13C–{1H}, 75.5 MHz, CD2Cl2): d 27.41 (CH3), 77.30 (COH), 81.41
3. Results and discussion
(CH), 110.81 (C(CH3)2), 127.23 (CarylH), 127.68 (CarylH), 129.79
(CarylH), 130.24 (CarylH), 130.53 (CarylH), 130.63 (CarylH), 132.43
(Caryl), 132.46 (Caryl), 132.53 (Caryl), 132.72 (Caryl), 142.70 (Caryl),
144.69 (Caryl). Anal. Calc. for C31H22Cl8O4: C, 50.17; H 2.99; N, 0.
Found: C, 51.68; H, 3.09; N, <0.05%. IR Data (KBr pellet, cmꢀ1):
3544 (m, OH str), 3351 (s, br, OH str), 2986 (m, CH str), 2933 (m,
CH str), 2888 (m, CH str), 1907 (w), 1769 (w), 1704 (w), 1590
(w), 1556 (w), 1470 (vs), 1437 (m), 1419 (m), 1382 (vs), 1337
(m), 1237 (s), 1169 (s), 1137 (s), 1098 (m), 1066 (s), 1031 (vs),
943 (w), 883 (s), 822 (s), 758 (s), 741 (s), 707 (w), 677 (s), 607
(w), 557 (w), 508 (w), 438 (w). The m/z observed for the [MꢀH]ꢀ
ion was 736.896 (calculated exact mass: 736.8954). This m/z
matches the molecular formula of the compound with 1.09 ppm
error.
3.1. Synthesis and characterization
The synthesis of two octachlorinated (R,R)-TADDOL derivatives
(Scheme 2) was accomplished via a Grignard reaction in a fashion
similar to that previously reported for the synthesis of TADDOL
derivatives [38]. The reaction of relatively inexpensive resolved,
chiral starting material (ꢀ)-dimethyl-2,3-O-isopropylidene-
L-tar-
trate with 3,4-dichlorophenyl magnesium bromide or 3,5-dichlo-
rophenyl magnesium bromide yields (4R,5R)-(ꢀ)-2,2-dimethyl-
a,a, ,
a0 a0-tetra-3,4-dichlorophenyl-1,3-dioxolane-4,5-dimethanol,
3,4-[1] and (4R,5R)-(ꢀ)-2,2-dimethyl-
a,a, ,
a0 a0-tetra-3,5-dichloro-
phenyl-1,3-dioxolane-4,5-dimethanol, 3,5-[1] (Scheme 3). Purifica-
tion of the ligands proved difficult, and off-white or slightly yellow
powders were obtained only after silica gel column chromatogra-
phy and repeated trituration with dry tetrahydrofuran to remove
water and the other solvents used in the synthesis and purification.
The ligands were characterized by NMR, IR, LC/MS and elemental
analysis. The NMR spectra show that there are two inequivalent
aryl groups in each compound. The 13C NMR of 3,5-[1], with sym-
metrically substituted 3,5-dichlorophenyl groups, contains eight
unique aryl carbon resonances, and that of 3,4-[1] with unsymmet-
rical 3,4-dichlorophenyl groups reveals all twelve unique aryl car-
bon resonances. Attempts were also made to synthesize the (R,R)-
TADDOL derivatives from 2,3- and 2,4-dichlorophenyl magnesium
bromide. These resulted in product mixtures containing only a low
yield of the desired product.
Data for 3,5-[1]: 1H NMR (300 MHz, CD2Cl2): d 1.26 (s, 6H, CH3),
4.06 (s, 2H, OH), 4.43 (s, 2H, CH), 7.20 (d, 4H, Ar–CH, J 1.85 Hz), 7.25
(t, 2H, Ar–CH, J 1.84 Hz), 7.35 (t, 2H, Ar–CH, J 1.87 Hz), 7.42 (d, 4H,
Ar–CH, J 1.88 Hz). 13C NMR (13C–{1H}, 75.5 MHz, CD2Cl2): d 27.49
(CH3), 77.48 (COH), 81.39 (CH), 111.30 (C(CH3)2), 126.17 (CarylH),
Scheme 2. Octachloro (R,R)-TADDOL derivatives 3,4-[1] and 3,5-[1].
Scheme 4. Conversion of benzaldehyde to 1-phenylethanol.
Scheme 3. Synthetic scheme for the preparation of (4R,5R)-(ꢀ)-2,2-dimethyl-a,a, ,
a0 a0-tetra-3,4-dichlorophenyl-1,3-dioxolane-4,5-dimethanol, 3,4-[1].

M.G. Baker-Salisbury et al. / Inorganica Chimica Acta 409 (2014) 394–398
397
Table 1
Data for the addition of dimethyl zinc to benzaldehyde with Ti(OR)4 and (R,R)-TADDOL [1] and the octachloroTADDOL derivatives 3,4-[1] and 3,5-[1].a
b
Entry
Aldehyde
Ligand
mmol L
mmol Ti, OR
Time (hr)
%
eec
1
2
3
4
5
6
7
8
PhCHO
‘‘
‘‘
4-Cl–PhCHO
PhCHO
‘‘
‘‘
‘‘
‘‘
‘‘
‘‘
‘‘
‘‘
‘‘
‘‘
‘‘
[1]
‘‘
‘‘
‘‘
3,4-[1]
‘‘
‘‘
‘‘
0.21
0.21
0.21
0.21
1.4, OiPr
5.6, OiPr
0.5, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OiPr
1.4, OR-2Bu
1.4, OS-2Bu
24
24
24
24
24
96
120
24
24
24
72
120
24
24
24
24
>99
>99
45
91
92
61
96
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
0.21
96.5
90
93
90
87
95
90
94
88
83
85
89
0.105
0.0525
.105
0.0525
0.21
0.105
0.0525
.105
0.0525
0.21
9
‘‘
10
11
12
13
14
15
16
3,5-[1]
‘‘
‘‘
‘‘
‘‘
[1]
‘‘
0.21
a
b
c
Ti(OR)4 (in 5 mL CH2Cl2), 6.0 mmol Me2Zn/toluene, 1.0 mmol ArCHO, 3 °C.
As determined by 1H NMR.
Determined by chiral GC, Alltech Chiraldex B-DM.
3.2. Asymmetric methylation of benzaldehyde
an excess of (S)-1-phenylethanol or (S)-1-(4-chlorophenyl)ethanol,
as determined by GC analysis of authentic samples of 1-phenyleth-
anol, (R)-(+)-1-phenylethanol, 1-(4-chlorophenyl)ethanol and (R)-
(+)-1-(4-chlorophenyl)ethanol. This is consistent with what has
been reported by Seebach in investigation the alkylation of alde-
hydes with dialkyl zinc compounds in the presence of titanium
TADDOLates [11,12]. Remarkably, when the TADDOL aryl groups
are replaced with perfluoroalkyl substituents, the enantiomer pro-
duced in excess is reported to be (R)-1-phenylethanol [25].
Further, it is notable that in using achiral Ti(OiPr)4 and (R,R)-
TADDOL [1], (i) we have been able to observe higher enantiomeric
excesses in the methylation of benzaldehyde than with resolved
BINOL and the resolved chiral alkoxides, Ti(OR-2Bu)4 or Ti(OS-
2Bu)4, up to 91% from 60%, as expected based on previous observa-
tions for this system [11], and (ii) that the matched pair effect is
less prominent with TADDOL than it is with BINOL when Ti(OiPr)4
is substituted with the resolved chiral alkoxides, Ti(OR-2Bu)4 or
Ti(OS-2Bu)4. Comparison of entry 1 with 15 and 16 in Table 1 re-
veals a negligible matched pair effect, and in fact suggests that
the larger sec-butoxides impart less enantioselectivity to the catal-
ysis with (R,R)-TADDOL than does isopropoxide.
Catalysis screenings for the conversion of benzaldehyde to 1-
phenylethanol (Scheme 4) were conducted with (R,R)-TADDOL
[1] and the octachloro (R,R)-TADDOL ligands 3,4-[1] and 3,5-[1] un-
der varying conditions (Table 1). With unsubstituted (R,R)-TADDOL
ligand [1], entries 1–3 reveal that the maximum enantiomeric ex-
cess obtained under the conditions used is 91% (S)-1-phenyletha-
nol. Increasing the relative amount of Ti(OiPr)4 does not improve
the ee (entry 2), whereas decreasing the amount negatively
impacts both the conversion and ee (entry 3). When 4-chlorobenz-
aldehyde was employed as the substrate, the ee of (S)-1-(4-chloro-
phenyl)ethanol was observed to be 96% (entry 4). We reasoned
that the electron withdrawing ability of the chloride substituent
assisted in activating the carbonyl group for alkylation, and that
chlorination of the ligand would have a similar effect, in addition
to added steric hinderance from the dichlorophenyl groups versus
only phenyl substituents, and result in increased ee when unsub-
stituted benzaldehyde was used. This was observed to be the case.
Entries 5 and 10 show that TADDOLs 3,4-[1] and 3,5-[1] lead to
96.5% and 95% (S)-1-phenylethanol, respectively. These are compa-
rable with results achieved recently by Ando [25] and Wang [26]
with different catalytic ligands, and by Seebach with TADDOL
and stoichiometric CH3Ti(OiPr)3 in the absence of dimethyl zinc
[11]. Catalysts screening were then performed with reduced
amounts of the octachloro (R,R)-TADDOL ligands. From these
experiments, we were able to determine that for both octachloro
(R,R)-TADDOL derivatives, less ligand could be used in the catalysis
without compromising the percent conversion and with only a
minor decrease in the ee, however, the later requiring increased
reaction times. Entries 8, 9, 13, and 14 indicated that decreasing
the relative amount of the ligand results in a decrease in the ob-
served ee at a reaction time of 24 h, whereas entries 6, 7, 11, and
12 show that decreasing the relative amount of ligand while
increasing the reaction time leads to observed ee’s that are closer
to those that employed the larger amount of ligand. For example,
in the case of 3,4-[1], comparison of entries 5 and 7 reveals a de-
crease in the ee of 1-phenylethanol from 96.5% to 93% when the
amount of ligand used is reduced by a factor of four while the reac-
tion time is increased by a factor of five. Similarly, in the case of
3,5-[1], comparison of entries 10 and 12 reveals a decrease in the
ee of 1-phenylethanol from 95% to 94% when the amount of ligand
used is reduced by a factor of four while the reaction time is in-
creased by a factor of five. In every case, (R,R)-TADDOL results in
4. Conclusions
In the alkylation of arylaldehydes with dialkyl zinc and titanium
(IV) alkoxides, we have found that (R,R)-TADDOL can mediate the
methylation of 4-chlorobenzaldehyde with dimethyl zinc in the
presence of titanium(IV) isopropoxide with >99% conversion and
96% enantiomeric excess, greater than the selectivity observed
for unsubstituted benzaldehyde under the same conditions, >99%
conversion and 91% enantiomeric excess. Likewise, addition of
chloro substituents to the ligand also induces the result of increas-
ing the enantioselectivity of the catalysis. The octachlorinated
(R,R)-TADDOL ligands described lead to enhanced enantiomeric
selectivity, resulting >99% conversion and >96% enantiomeric ex-
cess (S)-1-phenylethanol.
Acknowledgements
This material is based upon work supported by a National Sci-
ence Foundation Research in Undergraduate Institutions grant
(No. 0911324, J.M.T. P.I.), and the Office of the Dean of the Faculty
at Vassar College, to whom we are grateful for support. Many

398
M.G. Baker-Salisbury et al. / Inorganica Chimica Acta 409 (2014) 394–398
[19] M. Mori, T. Nakai, Tetrahedron Lett. 38 (1997) 6233.
[20] T. Hayase, T. Sugiyama, M. Suzuki, T. Shibata, K. Soai, J. Fluorine Chem. 84
(1997) 1.
[21] K.M. Waltz, P.J. Carroll, P.J. Walsh, Organometallics 23 (2004) 127.
[22] A.M. Costa, C. García, P.J. Carroll, P.J. Walsh, Tetrahedron 61 (2005) 6442.
[23] Y.-C. Qin, L. Pu, Angew. Chem., Int. Ed. 45 (2006) 273.
[24] T. Harada, T. Ukon, Tetrahedron Asymmetry 18 (2007) 2499.
[25] Y.S. Sokeirik, A. Hoshina, M. Omote, K. Sato, A. Tarui, I. Kumadaki, A. Ando
Chem, Asian J. 3 (2008) 1850.
thanks to Dr. Teresa Garrett for assistance with the mass spectrom-
etry, performed using instrumentation supported by a National
Science Foundation Major Research Instrumentation grant (No.
1039659, Teresa A. Garrett P.I.).
References
[1] I. Ojima (Ed.), Catalytic Asymmetric Synthesis, second ed., Wiley, New York,
2000.
[26] M.-C. Wang, Q.-J. Zhang, G.-W. Li, Z.-K. Liu, Tetrahedron Asymmetry 20 (2009)
288.
[2] P.J. Walsh, M.C. Kowzlowski, Fundamentals of Asymmetric Catalysis, University
Science Books, 2008.
[27] A.R. Abreu, M. Lourenço, D. Peral, M.T.S. Rosado, M.E.S. Eusébio, Ò. Palacios, J.C.
Bayón, M.M. Pereira, J. Mol. Catal. A Chem. 325 (2010) 91.
[28] A. Venegas, L. Rivas, G. Huelgas, C.A. de Parrodi, D. Madrigal, G. Aguirre, M.
Parra-Hake, D. Chávez, R. Somanathan, Tetrahedron Asymmetry 21 (2010)
2944.
[29] P. Geoghegan, P. O’Leary, ACS Catal. 2 (2012) 573.
[30] C.M. Jones, H. Li, A.J. Hickman, L.D. Hughs, S.J. Sobelman, A.R. Johnson,
Tetrahedron Asymmetry 23 (2012) 501.
[3] H.-U. Blaser, S. Elke (Eds.), Asymmetric Catalysis on Industrial Scale:
Challenges, Approaches and Solutions, Wiley, New York, 2004.
[4] Y. Nakagawa, Y. Muramatsu, T. Harada, Eur. J. Org. Chem. (2010) 6535.
[5] E. Fernández-Mateos, B. Maciá, M. Yus, Eur. J. Org. Chem. (2012) 3732.
[6] Y. Muramatsu, T. Harada, Angew. Chem., Int. Ed. 47 (2008) 1088.
[7] Y. Muramatsu, T. Harada, Chem. Eur. J. 14 (2008) 10560.
[8] A.S.C. Chan, F.-Y. Zhang, C.-W. Yip, J. Am. Chem. Soc. 119 (1997) 4080.
[9] B.L. Pagenkopf, E.M. Carreira, Tetrahedron Lett. 39 (1998) 9593.
[10] S. Zhou, D.-W. Chuang, S.-J. Chang, H.-M. Gau, Tetrahedron Asymmetry 20
(2009) 1407.
[31] M. Rachwalski, S. Jarzynski, M. Jasinski, S. Lenniak, Tetrahedron Asymmetry 24
(2013) 689.
´
´
´
[32] X. Yang, W. Su, D. Liu, H. Wang, J. Shen, C. Da, R. Wang, A.S.C. Chan,
Tetrahedron 56 (2000) 3511.
[11] D. Seebach, D.A. Plattner, A.K. Beck, Y.M. Wang, D. Hunziker, Helv. Chim. Acta
75 (1992) 2171.
[12] B. Weber, D. Seebach, Tetrahedron 50 (1994) 7473.
[13] M. Ueki, Y. Matsumoto, J.J. Jodry, K. Mikami, Synlett (2001) 1889.
[14] P.J. Walsh, Acc. Chem. Res. 36 (2003) 739.
[33] L. Ma, M.M. Wanderley, W. Lin, ACS Catal. 1 (2011) 691.
[34] S.N. MacMillan, K.T. Ludford, J.M. Tanski, Tetrahedron Asymmetry 19 (2008)
543.
[35] S.N. MacMillan, C.F. Jung, T. Shalumova, J.M. Tanski, Inorg. Chim. Acta 362
(2009) 3134.
[15] Q. Li, H.-M. Gau, Chirality 23 (2011) 929.
[16] K.-H. Wu, S. Zhou, C.-A. Chen, M.-C. Yang, R.-T. Chiang, C.-R. Chen, H.-M. Gau,
Chem. Commun. 47 (2011) 11668.
[17] M.J. Jin, S.J. Ahn, K.S. Lee, Tetrahedron Lett. 37 (1996) 8767. and important
earlier references therein.
[36] D. Seebach, L. Behrendt, D. Felix, Angew. Chem., Int. Ed. 30 (1991) 1008.
[37] H. Pellissier, Tetrahedron 64 (2008) 10279.
[38] E. Weber, N. Dörpinghaus, C. Wimmer, Z. Stein, H. Krupitsky, I. Goldberg, J. Org.
Chem. 57 (1992) 6825.
[39] E. Bulat, T.A. Garrett, J. Biol. Chem. 286 (2011) 33819.
[18] F. Zhang, C. Yip, R. Cao, A.S.C. Chan, Tetrahedron Asymmetry 8 (1997) 585.