Enantioselective additions of aryltitanium tris(isopropoxide) to ketones: Structure of [(i-PrO)2Ti{μ-(S)-BINOLate}(μ-O-i-Pr)TiPh(O-i-Pr) 2], study of mechanistic and stereochemical insights

Article abstract of DOI:10.1002/adsc.201200672

Aryl addition reactions of ArTi(O-i-Pr)₃ to aromatic, heteroaromatic, or α,β-unsaturated ketones are described, producing tertiary alcohols in good to excellent enantioselectivities of up to 97% ee. The structure of the dititanium complex [(i-PrO)₂Ti{μ-(S)-BINOLate} (μ-O-i-Pr)TiPh(O-i-Pr)₂] [(S)-4] that simultaneously bears a chiral directing ligand and a nucleophile is reported. Complex (S)-4 possesses a pocket structure and has been illustrated as the key active species for addition reactions of both aldehydes and ketones. Mechanistic and stereochemical insights concerning addition reactions of organometallic reagents to organic carbonyls are rationalized based on the pocket structure and pocket size of (S)-4. Copyright

Full text of DOI:10.1002/adsc.201200672

UPDATES
DOI: 10.1002/adsc.201200672
Enantioselective Additions of Aryltitanium Tris(isopropoxide) to
Ketones: Structure of [(i-PrO)2Ti{m-(S)-BINOLate}
Pr)TiPh(O-i-Pr)2], Study of Mechanistic and Stereochemical
Insights
A
ACHTUNGTRENNUNG
Kuo-Hui Wu,a Yi-Yin Kuo,a Chien-An Chen,a Yi-Ling Huang,a
and Han-Mou Gaua,*
a
Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan, ROC
Fax : (+886)-4-2286-2547; e-mail: hmgau@dragon.nchu.edu.tw
Received: July 31, 2012; Revised: November 22, 2012; Published online: February 28, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200672.
Abstract: Aryl addition reactions of ArTiACTHNURGTNEUNG(O-i-Pr)3
to aromatic, heteroaromatic, or a,b-unsaturated ke-
tones are described, producing tertiary alcohols in
good to excellent enantioselectivities of up to 97%
ee. The structure of the dititanium complex [(i-
PrO)2Ti{m-(S)-BINOLate}ACTHNUTRGENN(UG m-O-i-Pr)TiPhACHTUNGTRNEN(UGN O-i-Pr)2]
[(S)-4] that simultaneously bears a chiral directing
ligand and a nucleophile is reported. Complex (S)-4
possesses a pocket structure and has been illustrat-
ed as the key active species for addition reactions
of both aldehydes and ketones. Mechanistic and ste-
reochemical insights concerning addition reactions
of organometallic reagents to organic carbonyls are
rationalized based on the pocket structure and
pocket size of (S)-4.
found that organoalanes[7] and organotitanium[2,8] re-
agents are excellent nucleophile sources for addition
reactions of aromatic or a,b-unsaturated ketones em-
ploying the titanium catalyst derived from BINOLs.
In addition, a few examples of addition reactions of
organoboron or organozinc compounds to ketones
have been reported.[9] Despite extensive studies on ti-
tanium-catalyzed addition reactions of aldehydes, the
reactivity and stereochemical insights have not been
Keywords: aryl addition; aryltitaniums; enantiose-
lectivity; ketones; titanium
Introduction
Titanium-catalyzed asymmetric addition reactions of well explored. Previous studies have suggested that
organometallic reagents to aldehydes have been es- the titanium-catalyzed addition reactions of aldehydes
tablished as one of the most powerful synthetic proto- involve a dititanium active species V containing only
cols for the synthesis of bioactive chiral secondary al- one bidentate chiral ligand and a nucleophile R’.[3b,10]
cohols, and a wide variety of ligands has been demon- In terms of stereochemistry, titanium catalysts of (R)-
strated to be highly enantioselective.[1,2] By contrast, BINOLate derivatives, such as (R)-BINOL,[11] 3-sub-
the construction of chiral tertiary alcohols via titani- stituted
(R)-BINOL,[12]
3,3’-disubstituted
(R)-
um-catalyzed addition reactions of ketones has been BINOL,[13] (R)-H4-BINOL[14] as well as (R)-H8-BI-
less reported. Only a few ligand types, such as cam-
NOL,[2,7e,10e,15] induce a Re-face addition to aldehydes,
ACHTUNGTRENNUNG
phorsulfonamide I,[3] camphordisulfonamide II,[4] and the catalysts of (S)-BINOLate derivatives direct
BINOL III[5] or sulfonamide alcohol IV,[6] have an Si-face addition.[11,16] By contrast, studies of titani-
proven to be effective when organozinc or organotin um-catalyzed organoalanes[7] or (3-furyl)Ti
ACTHNUTRGNEG(NU O-i-Pr)3
[8]
compounds are used as nucleophiles. Recently, we addition reactions of aromatic/heteroaromatic or a,b-
Adv. Synth. Catal. 2013, 355, 1001 – 1008
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Kuo-Hui Wu et al.
UPDATES
Table 1. Optimizations of titanium catalytic systems of addi-
unsaturated ketones reveal a reverse stereochemical
nature, such as a Re-face addition from a titanium cat-
alyst of (S)-BINOL. Furthermore, in terms of reactivi-
ty and enantioselectivity, the excellent titanium cata-
lyst of H8-BINOLate for addition reactions of alde-
hydes does not work well for ketones,[2] and the titani-
um/BINOL systems are not good catalysts for aliphat-
ic ketones.[7,8] Given the above observations, two
questions are raised. First, is the dititanium active
species V established for nucleophilic addition reac-
tions of aldehydes also an active species for addition
reactions of ketones? If the answer is yes, then the
second question is what would be the key structural
feature of the active species that causes the dramatic
changes in stereochemistry and reactivity toward al-
dehydes and ketones?
tion reactions of PhTiACTHNUTRGNEUNG
(O-i-Pr)3 to 2’-acetonaphthone.[a]
Entry L*
1a
(equiv.)
Ti
(equiv.)
(O-i-Pr)4 Conv.[b] ee[c]
ACHTUNGTRENNUNG
G
G
[%]
[%]
1
2
3
4
5
6
7
8
(S)-BINOL
(R)-BINOL
(R)-H8-BINOL 1.5
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
1.5
1.5
0
0
0
0
0
0
0.25
0.50
0.75
0.50
96
94
32
83
92
97
94
94
89
100
89
88
18
91
91
86
92
93
93
71
1.0
1.25
2.0
1.5
1.5
1.5
1.5
To explore the mechanistic and stereochemical in-
sights of titanium-catalyzed addition reactions of or-
ganic carbonyls, we here report asymmetric addition
[17]
reactions of ArTiACHTUNGTRENNUNG(O-i-Pr)3 (1) to ketones. The addi-
9
10[d]
tion reactions of aromatic or a,b-unsaturated ketones
afforded tertiary alcohols in good to excellent enan-
tioselectivities of up to 97% ee. Importantly, the struc-
ture of dititanium complex of [(i-PrO)2Ti{m-(S)-
[a]
2d, 0.50 mmol; toluene, 7 mL.
Conversions were calculated based on H NMR spectra
of the product.
The ee values were determined by HPLC using an appro-
priate chiral column.
[b]
[c]
[d]
1
BINOLate}ACHTUNGTRENNUNG(m-O-i-Pr)TiPhCAHTUNGTERNN(UGN O-i-Pr)2] [(S)-4] is report-
ed. The reverse stereochemical nature for addition re-
actions of ketones as compared to aldehydes and the
mechanistic insights are rationalized based on the
structure and stoichiometric reactions of (S)-4.
Room temperature.
has demonstrated that the titanium catalyst of
BINOL is an efficient system for nucleophilic addi-
tion reactions of aromatic/heteroaromatic or a,b-un-
saturated ketones in terms of reactivity and enantio-
Results and Discussion
The reaction was first optimized for the addition of selectivity, compared to systems demonstrated in pre-
PhTi
(O-i-Pr)3 (1a) to 2’-acetonaphthone (2d) [Table 1, vious studies.[3–6]
Eq. (1)] employing 10 mol% titanium complexes of The reaction scope of aryl additions of ArTiACHTUNGTRENNUNG(O-i-
ACHTUNGTRENNUNG
(R)-BINOL, (S)-BINOL or (R)-H8-BINOL, and the Pr)3 to representative ketones under the optimized
results are summarized in Table 1. When using conditions was then examined [Table 2, Eq. (2)], and
1.5 equivalents of PhTi
Ti(O-i-Pr)4, the catalysts of (S)- or (R)-BINOL pro- AlArxEt
duced addition product 3d in similar conversions of the titanium catalyst of (S)-BINOL worked well for
96 and 94% (entries 1 and 2) over a reaction time of ArTi(O-i-Pr)3 addition reactions of aromatic ketones,
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
12 h. Enantioselectivities of 3d were comparable for affording products 3 in excellent enantioselectivities
89 and 88% ee but have the opposite absolute struc- of ꢀ90% ee (entries 1–10) except for 2’-methylaceto-
tures. By contrast, the titanium catalyst of (R)-H8- phenone (2a). The addition of PhTiACTHNUGTRNEU(GN O-i-Pr)3 to the
BINOL was sluggish, furnishing 3d in a low conver- steric hindered substrate of 2a was rather slow, and
sion of 32% and a low enantioselectivity of 18% ee the reaction over 48 h furnished 3a in only a 50%
(entry 3). Reducing or increasing the amounts of yield with an enantioselectivity of 85% ee (entry 1). It
PhTiACHTUNGTRENNUNG(O-i-Pr)3 afforded 3d in somewhat lower conver- is a general feature that addition reactions of the ster-
sions or lower enantioselectivities (entries 4–6). The ically hindered ortho-substituted aromatic ketones,
effects of temperature and addition of 0.25, 0.50, or such as 3a, 3e or 1’-acetonaphthone (3c), require
0.75 equiv. of TiACHTNUTRGNEU(GN O-i-Pr)4 to the catalytic solution longer reaction times in order to achieve products in
were subsequently investigated (entries 7–10), and it satisfactory yields. In order to determine the stereo-
was found that the optimized reaction conditions chemistry of addition products, the phenyl addition to
were 1.5 equiv. PhTiACHTNUTRGENN(GU O-i-Pr)3, 0.50 equiv. TiAHCUTTGNREN(NUGN O-i-Pr)4, 2’-iodoacetophenone (2h) was conducted over 168 h
and a reaction temperature of 08C, producing 3d in to furnish 3h in a 45% yield but with an excellent
a 94% conversion and a 93% ee (entry 8). This study enantioselectivity of 94% ee (entry 8). The absolute
1002
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Enantioselective Additions of Aryltitanium Tris(isopropoxide) to Ketones
Table 2. Titanium-(S)-BINOLate-catalyzed addition reac-
Table 2. (Continued)
Entry 2
tions of ArTiACHTUNGTRENNUNG
(O-i-Pr)3 to ketones.[a]
Ar
Time 3
Yield[b] ee[c]
[h]
[%]
[%]
14
15
16
4-MeC6H4 16
3n 89
93
4-
Entry 2
Ar
Time 3
[h]
Yield[b] ee[c]
16
3b 91
3d 90
3f 81
93
94
86
MeOC6H4
[%]
[%]
2-naph-
16
1
2
Ph
Ph
48
24
3a 50
85
thyl
17
4-ClC6H4 48
3b 47
90
90
[a]
Ketone/(S)-BINOL/ArTiACHTNUTRGENN(UG O-i-Pr)3/TiACHTUNGTREN(NUGN O-i-Pr)4 =0.50/
0.050/0.75/0.25 mmol; toluene, 7 mL.
Isolated yield.
The ee values were determined by HPLC using appropri-
ate chiral columns.
3
Ph
48
3c 40
[b]
[c]
[d]
54% conversion.
4
5
6
Ph
Ph
Ph
16
16
16
3d 95
3e 43
3f 89
93
94
92
structure of 3h was confirmed as the R-configurati-
AHCTUNGTRENNUNG
on[7a,18] that is derived from a Re-face addition of the
phenyl nucleophile to the carbonyl carbon of 2h.
However, the same titanium catalyst of (S)-BINOL
induces an opposite Si-face addition of the nucleo-
philes to the aldehydes.[2]
This catalytic system also applied to addition reac-
tions of a,b-unsaturated (E)-1-phenyl-1-buten-3-one
or heterocyclic 2-acetylfuran, producing 3k or 3l in 84
and 82% ee (entries 11 and 12). However, the phenyl
addition to aliphatic ketone 2-methyl-3-butanone
(2m) produced addition product 3m in a low enantio-
7
8
9
Ph
Ph
Ph
16
3g 91
91
94
(R)
168 3h 45[d]
selectivity of 32% ee (entry 13). ArTiACTHNUTRGEN(UNG O-i-Pr)3 [Ar=
4-MeC6H4 (1b), 4-MeOC6H4 (1c), 2-naphthyl (1d), or
4-ClC6H4 (1e)] additions to aromatic ketones were
also studied to furnish diarylethanols in enantioselec-
tivities ranging from 86 to 94% ee (entries 14–17).
16
3i 90
97
To explore the mechanistic insights, PhTiACTHNURGTNEUNG(O-i-Pr)3
10
11
Ph
Ph
16
16
3j 90
3k 87
90
84
addition reactions of 2’-acetonaphthone in the pres-
ence of 0, 20, 40, 60, 80, or 100% ee (S)-BINOL af-
forded the product 3d in enantioselectivities of 1.7,
16.8, 37.8, 54.3, 75.5, and 91.5% ee, respectively. The
linear plot of ee values of the BINOL ligand vs. ee
values of 3d (Figure 1) suggests that the active metal-
lic species involves only one BINOLate ligand. The
12
13
Ph
Ph
48
16
3l 75
3m 70
82
32
linear effect was also observed for ArTiACTHNUTRGENUG(N O-i-Pr)3 addi-
tion reactions of aldehydes catalyzed by the titanium
derivative of (R)-H8-BINOL,[2a] indicating that addi-
tion reactions of both aldehydes and ketones might
involve the active species having a similar geometric
structure. However, the reverse stereochemistry of
Adv. Synth. Catal. 2013, 355, 1001 – 1008
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Kuo-Hui Wu et al.
UPDATES
1H and 13C NMR spectra are quite complicated, sug-
gesting an equilibrium process among (S)-4, [{(S)-
BINOLate}Ti
solution.[10b,d,19] Thus, we examined the 13C NMR spec-
tra of PhTi(O-i-Pr)3 (1a), [Ti{m-(S)-BINOLate}(O-i-
Pr)2]x, and (S)-4 in CD2Cl2 and CDCl3 solutions.
The phenyl reagent 1a has a dimeric structure of
2A
ACHTUNGTREN(GUN O-i-Pr)2]x, and PhTiACHTUNTGRNEN(UGN O-i-Pr)3 in CDCl3
A
ACHTUNGTRENNUNG
[PhTiACHTNGUTERN(NUGN O-i-Pr) CHUTNGTREN(NUNG m-O-i-Pr)]2 in CD2Cl2 at low tempera-
tures, showing two sets of 13C NMR signals for bridg-
ing and terminal O-i-Pr ligands. The phenyl character-
istic 13C NMR signal of 1a in CDCl3 at 208C appears
at d=187.5 ppm and a broad methine 13C NMR peak
is found at d=77.3 ppm [Figure 3 (a)]. Since the solid
state structures of both dimeric [Ti{m-(S)-BINOLate}-
Figure 1. The linear plot of ee values of 3d vs. ee values of
(S)-BINOL.
A
ACHTUNGTRENNUNG(O-i-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[10c]
BINOLate}
valent of PhTi
ACHTUNGTRENNUNG(O-i-Pr)2]x
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
solid. The molecular structure of (S)-4 (Figure 2) of (S)-4 is shown in Figure 3 (c). Close examination of
shows a dititanium species bearing one (S)-BINOLate the spectrum reveals that the solution contains [{(S)-
ligand, and is the first dititanium structure simultane- BINOLate}TiACHTNUTGRNEUNG(O-i-Pr)2]x, suggesting that (S)-4 partial-
ously containing a chiral ligand and a nucleophile. ly dissociates in solution to afford [{(S)-BINOLate}
Even though the solid state structure and elemental
ACHTUNGTRENNUNGTi-
analysis confirmed a dititanium species for (S)-4, the
Figure 2. The molecular structure of (S)-4. Hydrogens are
omitted for clarity.
Figure 3. 13C NMR spectra of (a) PhTi
BINOLate}Ti(O-i-Pr)2]x and (c) (S)-4 in CDCl3 at 208C.
ACHTUNGTRNE(NNUG O-i-Pr)3, (b) [{(S)-
ACHTUNGTRENNUNG
1004
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Adv. Synth. Catal. 2013, 355, 1001 – 1008

Enantioselective Additions of Aryltitanium Tris(isopropoxide) to Ketones
ACHTUNGTRENNUNG(O-i-Pr)2]x and [PhTiACHTUNRGTEGUN(NN O-i-Pr)2ACHTNUGTERNN(UGN m-O-i-Pr)]2. In addition does the (S)-4 structure direct opposite facial addi-
to the naphthyl 13C NMR signals, two characteristic tions toward aldehydes and aromatic ketones?
phenyl peaks at d=191.6 and 189.6 ppm and 4 me- Second, why does the (S)-4 not induce high enantiose-
thine 13C NMR peaks at d=80.9, 80.1, 79.0 and lectivities for addition reactions of aliphatic ketones?
78.5 ppm are observed for (S)-4, indicating the pres- Third, why is the titanium catalyst of (R)-H8-BINOL
ence of two phenyl-containing species in solution. The sluggish for addition reactions of ketones? To ration-
methine 13C NMR peak at d=80.9 ppm belongs to alize the above observations, we examined the pocket
the signal of [{(S)-BINOLate}Ti
the above mentioned phenyl and methine 13C NMR tures of [(i-PrO)2Ti{m-
characteristic signals do not match to signals of
(O-i-Pr)3][10c] [(rac)-5] and [(CyO)2Ti{m-(R)-H8-
[PhTi(O-i-Pr)2A(m-O-i-Pr)]2. One characteristic phenyl BINOLate}(m-OCy)Ti
(OCy)3][21] [(R)-6] (Cy=cyclo-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
R
G
N
ACHTUNGTRENNUNG
peak is attributed to the signal of (S)-4. The other hexyl) reported by Walsh et al. Since the naphthyl
phenyl resonance might be due to an unknown ring of the BINOLate ligand is planar, the closest
species or a species of trititanium complex contain- contacts of the pocket are from the alkoxide methine
ing one BINOLate ligand resulting from a further hydrogen to the naphthyl carbon atoms. They are
reaction of [PhTi
since the trititanium/BINOLate
(MeOCH2)2BINOLate}(m-O)(O-i-Pr)8] structure has shortest contact is from a methine hydrogen of one
been reported recently.[20]
cyclohexyl oxide ligand to the CH2 hydrogen atoms of
ACHUGTTERNNGU(O-i-Pr)2ACTHUNGTRE(NNUNG m-O-i-Pr)]2 with (S)-4 3.109 ꢁ in (S)-4 and 3.315 ꢁ in (rac)-5. For the ditita-
A
CHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Although the possibility of the trititanium species the puckered H4-naphthyl ring, and the distance is
(or unknown species) being the active catalyst is not only 2.545 ꢁ, which is about 0.6~0.8 ꢁ shorter than
ruled out based on the linear effect of the catalytic re- the distances in the BINOLate complexes. All of the
action, we propose, for two reasons, that the dititani- above questions can be reasonably rationalized in
um (S)-4 is the active catalyst. First, structures of diti- terms of the pocket sizes of the dititanium species.
tanium complexes of [Ti2(m-BINOLate)(OR)6][10c] and The small pocket size of the titanium catalysts of H8-
[Ti2(m-H8-BINOLate)(OR)6][21] are well known in ad- BINOLate accommodates the small hydrogen atom
dition to the structure of (S)-4. Second, previous of the aldehydes, accounting for the excellent enantio-
mechanistic studies of titanium catalysts of BINOL- selectivities of the addition products. By contrast, the
ACHTUNGTRENNUNGate, diolate, and N-sulfonylated b-amino alcoholate aliphatic or aromatic groups of ketones are too large
suggested that the dititanium species containing one to fit in the small pocket size, resulting in the low re-
chiral ligand are involved in the catalytic addition re- activity and low enantioselectivity of the tertiary alco-
actions.[10]
hols. For titanium catalysts of BINOLate, the planar
To demonstrate that (S)-4 is the key active species aromatic, heteroaromatic, or a,b-unsaturated moiety
for addition reactions of both aldehydes and ketones, fits the pocket for inducing high enantioselectivities
a stoichiometric reaction of (S)-4 with 2-naphthylalde- of tertiary alcohols. Based on the observed reversal of
hyde produced the secondary (S)-2-naphthylphenyl- stereochemistry, the small hydrogen atom inserts into
methanol in an 80% ee, compared to the 77% ee ob- the pocket of (S)-4 predominantly for an Si-face addi-
tained from the catalytic reaction,[2a] and a reaction tion of the nucleophile [Figure 4 (a)]. Conversely, for
with 2’-acetonaphthone afforded tertiary diaryletha- addition reactions of ketones, the planar group of the
nol 3d in an 88% ee, compared to the 89% ee from aromatic, heteroaromatic, or a,b-unsaturated unit in-
the catalytic reaction (Table 1, entry 1). The above re-
sults support the argument that the (S)-4 complex is
the active species for aryl addition reactions of both
aldehydes and aromatic ketones. The structure of (S)-
4 that contains a chiral ligand is also consistent with
the observations of the linear effect of ee values of
BINOLate ligands vs. ee values of products in addi-
tion reactions of either aldehydes or aromatic ke-
tones. Stoichiometric reactions of (S)-4 with 2-naph-
thylaldehyde or 2’-acetonaphthone rule out the possi-
bility of pi-pi interactions for directing the reverse ste-
reochemistry since both substrates have a naphthalene
moiety for pi-pi interaction with the BINOLate
ligand.
To account for differences in reactivity and stereo-
chemistry toward aldehydes and ketones, the follow-
Figure 4. (a) The Si-face addition of the phenyl nucleophile
in (S)-4 to 2-naphthylaldehyde; (b) The Re-face addition of
ing issues need to be further elucidated. First, how Ph to 2’-acetonaphthone.
Adv. Synth. Catal. 2013, 355, 1001 – 1008
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1005

Kuo-Hui Wu et al.
UPDATES
a
Varian Mercury-400 (400 MHz) or an INOVA-600
serts into the pocket of (S)-4 for a Re-face addition
[Figure 4 (b)]. In addition, the pocket size of (S)-4 is
not large enough for aliphatic groups, and thus a low
yield and enantioselectivity were observed for the
product derived from the addition reaction of aliphat-
ic ketone (Table 2, entry 13).
(600 MHz) spectrometer, and 13C NMR spectra were record-
ed with the Varian Mercury-400 (100.70 MHz) or the
INOVA-600 (150 MHz). 1H and 13C chemical shifts were
measured relative to TMS (0.00 ppm) as the internal refer-
ence. Elemental analyses were performed using a Heraeus
CHN-O-RAPID instrument.
General Procedures for the Asymmetric ArTi
Pr)3 Addition Reaction of Ketone
ACHTUNGTNER(NUNG O-i-
Conclusions
Under a dry nitrogen atmosphere, (S)-BINOL (0.0143 g,
0.0500 mmol), PhTi(O-i-Pr)3 (0.227 g, 0.750 mmol), and
Ti(O-i-Pr)4 (0.075 mL, 0.25 mmol) were mixed in dry tolu-
ene (6 mL) at room temperature. The mixture was cooled to
08C and treated with a ketone (0.500 mmol) in 1 mL tolu-
ene. The mixture was allowed to react at 08C for a given
period and quenched with 2M aqueous NaOH (1 mL). The
aqueous phase was then extracted with ethyl acetate (3ꢂ
10 mL). The combined organic phase was dried over anhy-
drous MgSO4, filtered, and concentrated to dryness. The res-
In summary, a simple and highly enantioselective aryl
addition reaction of ArTiACHTNUTRGNENG(U O-i-Pr)3 to ketones is re-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ported. The titanium catalyst of BINOL is the best
performing system for aromatic/heteroaromatic or
a,b-unsaturated ketones. But the same system does
not work well for aliphatic ketones, and the titanium
system of H8-BINOL is sluggish for addition reactions
of ketones. The most important feature of this study
is a report of the first dititanium structure of (S)-4
that simultaneously bears the chiral directing BINOL- idue was purified by column chromatography to give the de-
sired product 3. Enantiomeric excesses of products were de-
termined by HPLC using suitable chiral columns.
ACHTUNGTRENNUNGate ligand and the phenyl nucleophile. Stoichiometric
reactions of (S)-4 with aromatic aldehyde or ketone
support the argument that (S)-4 is an active species in
the crucial and final step of the catalytic addition re-
action of organic carbonyl compounds. The pocket
structure and pocket sizes of the dititanium species
reasonably account for all reaction features of the ti-
tanium-catalyzed addition reactions, including the re-
verse stereochemistry of addition faces of nucleo-
philes to the aldehydes and to the aromatic ketones,
the sluggish reactions and low enantioselectivities of
the titanium catalysts of BINOLate toward the ali-
phatic ketones, and the poor reactivity and stereocon-
trol of the titanium catalysts of H8-BINOLate for ke-
tones. The mechanistic and stereochemical features
described in this study also apply to titanium catalysts
of C2-symmetric diols and C1-symmetric N-sulfonylat-
ed amino alcohols. Furthermore, the mechanistic in-
sights illustrated in this study may also apply to titani-
um-catalyzed nucleophilic addition reactions of or-
ganic carbonyls employing organometallic reagents of
organozinc, organoalanes, organolithium, Grignard,
and organotitanium reagents as well.
[10c]
Synthesis of [{(S)-BINOLate}TiACHTNURTGENUNG(O-i-Pr)2]x
To a solution of (S)-BINOL (1.43 g, 5.00 mmol) in 50 mL
toluene, Ti(O-i-Pr)4 (1.50 mL, 5.00 mmol) was added at
room temperature under a dry nitrogen atmosphere. After
reacting for 2 h, the toluene was removed under reduced
pressures to give a quantitative yield of [{(S)-BINOLate}
AHCTUNGTERNGUN(N O-i-Pr)2]x as a dark red solid which was used directly with-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNGTi-
out further purification. 1H NMR (400 MHz, CDCl3): d=
7.87 (d, J=8.0 Hz, 2H), 7.51–7.47 (m, 2H), 7.38–7.34 (m,
2H), 7.18–7.14 (m, 4H), 6.78–6.71 (m, 2H), 4.51 (sept, J=
6.0 Hz, 2H), 1.10 (d, J=6.0 Hz, 6H), 1.04 (d, J=6.0 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3): d=158.9, 133.0,
130.0, 128.8, 128.0, 126.9, 125.4, 123.3, 121.1, 118.5, 80.9,
25.7, 25.4.
Synthesis of [(i-PrO)2Ti{m-(S)-BINOLate}
TiPh(O-i-Pr)2] [(S)-4]
ACHTUNGTRENUN(NG m-O-i-Pr)-
AHCTUNGTRENNUNG
To
10.0 mmol based on the formula of {(S)-BINOLate}Ti
Pr)2 in 30 mL hexane, PhTi(O-i-Pr)3 (4.53 g, 15.0 mmol) in
a solution of [{(S)-BINOLate}TiACHUTTGNENRNUG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
30 mL hexane was added at room temperature under a dry
nitrogen atmosphere. After reacting for 1 h, the solution
was concentrated to about 30 mL under reduced pressures.
The resulting concentrated solution was allowed to stand at
room temperature for 12 h to afford (S)-4 as an orange crys-
talline solid; yield: 5.51 g (73.2%). The 1H and 13C NMR
spectra of (S)-4 reveal complicated patterns. Anal. calcd. for
C41H52O7Ti2: C 65.43, H 6.96%; found: C 65.34, H 6.43%.
Experimental Section
General Remarks
[17]
ArTi
ACHTUNGTRENNUNG(O-i-Pr)3 was prepared according to literature proce-
dures. TiACHTUNGTRENNUNG(O-i-Pr)4 was freshly distilled prior to use. (R)-
BINOL, (S)-BINOL, and (R)-H8-BINOL were obtained
commercially. All syntheses and manipulations were carried
out under a dry nitrogen atmosphere using standard Schlenk
techniques or in a glovebox. Solvents were dried by reflux-
ing for at least 24 h over P2O5 (dichloromethane) or sodium/
benzophenone (THF, n-hexane or toluene) and were freshly
X-Ray Crystallography of (S)-4
The X-ray diffraction study of suitable crystals of (S)-4 was
performed on an Oxford Xcalibur Sapphire3 diffractometer
using graphite-monochromated Mo-Ka radiation (l=
0.71073 ꢁ), temperature 100(2) K, and f and w scan tech-
nique, and semi-empirical absorption was applied in the
1
distilled prior to use. H NMR spectra were obtained with
1006
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1001 – 1008

Enantioselective Additions of Aryltitanium Tris(isopropoxide) to Ketones
data corrections. The structure was solved by direct methods
(SHELXTL-97),[22] completed by subsequent difference
Fourier syntheses, and refined by full-matrix least squares
calculations based on F2 (SHELXTL-97). Crystal data:
C41H52O7Ti2, MM=752.63 gmolÀ1, orthorhombic, space
group P212121, a=9.9334(2) ꢁ, b=18.8692(3) ꢁ, c=
21.1612(4) ꢁ, V=3966.36(13) ꢁ3, Z=4, absorption coeffi-
cient=0.449 mmÀ1, total reflections collected 29237, unique
7790 (Rint =0.0486), goodness of fit indicator=1.034, R1 =
0.0458, wR2 =0.1188, absolute structure parameter=0.08(2).
CCDC 880452 contains the supplementary crystallographic
data for this paper [compound (S)-4]. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[2] a) K.-H. Wu, S.-L. Zhou, C.-A. Chen, M.-C. Yang, R.-
T. Chiang, C.-R. Chen, H.-M. Gau, Chem. Commun.
2011, 47, 11668; b) Q.-H. Li, H.-M. Gau, Chirality 2011,
23, 929.
[3] a) D. J. Ramꢃn, M. Yus, Tetrahedron Lett. 1998, 39,
1239; b) D. J. Ramꢃn, M. Yus, Tetrahedron 1998, 54,
5651.
[4] a) C. Garcꢄa, L. K. LaRochelle, P. J. Walsh, J. Am.
Chem. Soc. 2002, 124, 10970; b) M. Yus, D. J. Ramꢃn,
O. Prieto, Tetrahedron: Asymmetry 2002, 13, 2291;
c) M. Yus, D. J. Ramꢃn, O. Prieto, Eur. J. Org. Chem.
2003, 2745; d) S.-J. Jeon, P. J. Walsh, J. Am. Chem. Soc.
2003, 125, 9544; e) C. Garcꢄa, P. J. Walsh, Org. Lett.
2003, 5, 3641; f) D. J. Ramꢃn, M. Yus, Angew. Chem.
2004, 116, 286; Angew. Chem. Int. Ed. 2004, 43, 284;
g) H.-M. Li, P. J. Walsh, J. Am. Chem. Soc. 2004, 126,
6538; h) H.-M. Li, C. Garcꢄa, P. J. Walsh, Proc. Natl.
Acad. Sci. USA 2004, 101, 5425; i) H.-M. Li, P. J. Walsh,
J. Am. Chem. Soc. 2005, 127, 8355; j) S.-J. Jeon, H.-M.
Li, P. J. Walsh, J. Am. Chem. Soc. 2005, 127, 16416.
[5] a) S. Casolari, D. D’Addario, E. Tagliavini, Org. Lett.
1999, 1, 1061; b) H. Hanawa, S. Kii, K. Maruoka, Adv.
Synth. Catal. 2001, 343, 57; c) K. M. Waltz, J. Gaveno-
nis, P. J. Walsh, Angew. Chem. 2002, 114, 3849; Angew.
Chem. Int. Ed. 2002, 41, 3697; d) S. Kii, K. Maruoka,
Chirality 2003, 15, 68; e) P. G. Cozzi, S. Alesi, Chem.
Commun. 2004, 2448; f) J. G. Kim, K. M. Waltz, I. F.
Garcia, D. Kwiatkowski, P. J. Walsh, J. Am. Chem. Soc.
2004, 126, 12580; g) A. Cunningham, V. Mokal-Parekh,
C. Wilson, S. Woodward, Org. Biomol. Chem. 2004, 2,
741; h) Y.-F. Zhou, R. Wang, Z.-Q. Xu, W.-J. Yan, L.
Liu, Y.-F. Kang, Z.-J. Han, Org. Lett. 2004, 6, 4147.
[6] Y-F. Zhou, Z.-J. Han, L. Qiu, J.-Y. Liang, F.-B. Ren, R.
Wang, Chirality 2009, 21, 473.
Acknowledgements
Financial support from the National Science Council of
Taiwan under the grant number of NSC 99-2113M-005-005-
MY3 is appreciated.
References
[1] a) C. Bolm, J. P. Hilderbrand, K. MuÇiz, N. Hermanns,
Angew. Chem. 2001, 113, 3382; Angew. Chem. Int. Ed.
2001, 40, 3284; b) L. Pu, H.-B. Yu, Chem. Rev. 2001,
101, 757; c) D. J. Ramꢃn, M. Yus, Chem. Rev. 2006, 106,
2126; d) W. Brieden, R. Ostwald, P. Knochel, Angew.
Chem. 1993, 105, 629; Angew. Chem. Int. Ed. Engl.
1993, 32, 582; e) B. Weber, D. Seebach, Tetrahedron
1994, 50, 7473; f) J.-F. Lu, J.-S. You, H.-M. Gau, Tetra-
hedron: Asymmetry 2000, 11, 2531; g) X. Li, G. Lu,
W. H. Kwok, A. S. C. Chan, J. Am. Chem. Soc. 2002,
124, 12636; h) Z. Xu, R. Wang, J. Xu, C.-S. Da, W.-J.
Yan, C. Chen, Angew. Chem. 2003, 115, 5925; Angew.
Chem. Int. Ed. 2003, 42, 5747; i) G. Bringmann, R.-M.
Pfeifer, C. Rummey, K. Hartner, M. Breuning, J. Org.
Chem. 2003, 68, 6859; j) X.-P. Hui, C.-A. Chen, H.-M.
Gau, Chirality 2005, 17, 51; k) C.-D. Wu, A. Hu, L.
Zhang, W.-B. Lin, J. Am. Chem. Soc. 2005, 127, 8940;
l) T. Fang, D.-M. Du, S.-F. Lu, J. Xu, Org. Lett. 2005, 7,
2081; m) G. Gao, Q. Wang, X.-Q. Yu, R.-G. Xie, P. Lin,
Angew. Chem. 2006, 118, 128; Angew. Chem. Int. Ed.
2006, 45, 122; n) S.-H. Hsieh, H.-M. Gau, Chirality
2006, 18, 569; o) X.-P. Hui, C.-A. Chen, K.-H. Wu, H.-
M. Gau, Chirality 2007, 19, 10; p) F. Yang, P. Xi, L.
Yang, J. Lan, R.-G. Xie, J.-S. You, J. Org. Chem. 2007,
72, 5457; q) Y. S. Sokeirik, H. Mori, M. Omote, K.
Sato, A. Tarui, I. Kumadaki, A. Ando, Org. Lett. 2007,
9, 1927; r) F. Yang, S.-P. Wei, C.-A. Chen, P.-H. Xi, L.
Yang, J.-B. Lan, H.-M. Gau, J.-S. You, Chem. Eur. J.
2008, 14, 2223; s) T. Ukon, T. Harada, Eur. J. Org.
Chem. 2008, 4405; t) C.-A. Chen, K.-H. Wu, H.-M.
Gau, Polymer 2008, 49, 1512; u) J. Wang, W.-T. Wang,
W. Li, X.-L. Hu, K. Shen, C. Tan, X.-H. Liu, X.-M.
Feng, Chem. Eur. J. 2009, 15, 11642; v) C.-S. Da, J.-R.
Wang, X.-G. Yin, X.-Y. Fan, Y Liu, S.-L. Yu, Org. Lett.
2009, 11, 5578.
[7] a) C.-A. Chen, K.-H. Wu, H-M. Gau, Angew. Chem.
2007, 119, 5469; Angew. Chem. Int. Ed. 2007, 46, 5373;
b) C.-A. Chen, K.-H. Wu, H.-M. Gau, Adv. Synth.
Catal. 2008, 350, 1626; c) K.-H. Wu, D.-W. Chuang, C.-
A. Chen, H.-M. Gau, Chem. Commun. 2008, 2343;
d) D. B. Biradar, H.-M. Gau, Org. Lett. 2009, 11, 499;
e) S.-L. Zhou, K.-H. Wu, C.-A. Chen, H.-M. Gau, J.
Org. Chem. 2009, 74, 3500; f) D. B. Biradar, S.-L. Zhou,
H.-M. Gau, Org. Lett. 2009, 11, 3386.
[8] S.-L. Zhou, C.-R. Chen, H.-M. Gau, Org. Lett. 2010,
12, 48.
[9] a) R. Shintani, M. Inoue, T. Hayashi, Angew. Chem.
2006, 118, 3431; Angew. Chem. Int. Ed. 2006, 45, 3353;
b) A. Iuliano, S. Facchetti, T. Funaioli, Chem.
Commun. 2009, 457; c) H.-S. Lai, Z.-Y. Huang, Q. Wu,
Y. Qin, J. Org. Chem. 2009, 74, 283; d) M. Hantano, T.
Miyamoto, K. Ishihara, Org. Lett. 2007, 9, 4535.
[10] a) M. Mori, T. Nakai, Tetrahedron Lett. 1997, 38, 6233;
b) J.-S. You, M.-Y. Shao, H-M. Gau, Organometallics
2000, 19, 3368; c) J. Balsells, T. J. Davis, P. Carroll, P. J.
Walsh, J. Am. Chem. Soc. 2002, 124, 10336; d) K.-H.
Wu, H.-M. Gau, Organometallics 2004, 23, 580; e) K.-
H. Wu, H.-M. Gau, J. Am. Chem. Soc. 2006, 128,
14808.
[11] A. S. C. Chan, F.-Y. Zhang, C.-W. Yip, J. Am. Chem.
Soc. 1997, 119, 4080.
[12] a) T. Harada, K. Kanda, Org. Lett. 2006, 8, 3817; b) Y.
Muramatsu, T. Harada, Angew. Chem. 2008, 120, 1104;
Adv. Synth. Catal. 2013, 355, 1001 – 1008
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1007

Kuo-Hui Wu et al.
UPDATES
Angew. Chem. Int. Ed. 2008, 47, 1088; c) Y. Muramat-
su, T. Harada, Chem. Eur. J. 2008, 14, 10560.
[13] Q. S. Guo, B. Liu, Y. N. Lu, J. S. Li, Tetrahedron: Asym-
X. G. Yin, X. Y. Fan, Y. Liu, S. L. Yu, Org. Lett. 2009,
11, 5578.
[17] H.-T. Yang, S.-L. Zhou, F.-S. Chang, C.-R. Chen, H.-M.
Gau, Organometallics 2009, 28, 5715.
metry 2005, 16, 3667.
[14] X. Shen, H. Guo, K. Ding, Tetrahedron: Asymmetry
2000, 11, 4321.
[15] a) G. Liu, X. Li, W. L. Chan, A. S. C. Chan, Chem.
Commun. 2002, 172; b) Y. Nakagawa, Y. Muramatsu,
T. Harada, Eur. J. Org. Chem. 2010, 6535.
[18] G. A. Rabah, G. F. Koser, Tetrahedron Lett. 1996, 37,
6453.
[19] K.-H. Wu, H.-M. Gau, Organometallics 2003, 22, 5193.
[20] Q.-S. Guo, H.-B. Song, J.-S. Li, Z. Anorg. Allg. Chem.
2006, 632, 721.
[16] a) F. Y. Zhang, C. W. Yip, A. S. C. Chan, Tetrahedron:
Asymmetry 1997, 8, 585; b) F. Y. Zhang, A. S. C. Chan,
Tetrahedron: Asymmetry 1997, 8, 3651; c) D. Moore, L.
Pu, Org. Lett. 2002, 4, 1855; d) C. S. Da, J. R. Wang,
[21] K. M. Waltz, P. J. Carroll, P. J. Walsh, Organometallics
2004, 23, 127.
[22] G. M. Sheldrick, SHELXTL, Version 5.10; Bruker An-
alytical X-ray Systems, Inc., Madison, WI, 1997.
1008
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1001 – 1008