Synthesis of Ar-BINMOL ligands by [1,2]-wittig rearrangement to probe their catalytic activity in 1,2-addition reactions of aldehydes with Grignard reagents

Article abstract of DOI:10.1002/ejoc.201201301

We have demonstrated a highly diastereoselective synthesis of optically pure Ar-BINMOL-derived diols and their analogues. The present study demonstrates a unique cascade chirality transfer in a [1,2]-Wittig rearrangement that leads to chiral diols with three stereogenic centers, which include a chiral sp ³ center at the alcohol and C₂-axial chirality. Screening these ligands in the arylation of aromatic aldehydes with Grignard reagents shows that the naphthyl-substituted BINMOL promotes the aryl transfer reaction in good yields (70-92 %) and moderate-to-good enantioselectivities (up to 72 % ee), and a series of control experiments substantiates that the axial chirality and the chiral sp³ center at the alcohol of the Ar-BINMOLs are the pivotal enantioselectivity-controlling structure elements. In addition, this study demonstrated the importance of the chiral sp³ center at the alcohol on Ar-BINMOL for the aryl transfer reaction. Finally, we found that the chiral Ar-BINMOL ligand 2h mediated the titanium-promoted 1,2-addition of MeMgBr to aldehydes to give the desired products in good yields with excellent enantioselectivities (up to 92 % ee). Ar-BINMOL ligands: A new diastereoselective synthesis of optically pure Ar-BINMOL-derived diols and their analogues has been established through cascade chirality transfer of a [1,2]-Wittig rearrangement. The axial and sp³ central chirality of Ar-BINMOLs are the pivotal enantioselectivity-controlling structure elements in the 1,2-addition of aldehydes with Grignard reagents. Copyright

Full text of DOI:10.1002/ejoc.201201301

FULL PAPER
DOI: 10.1002/ejoc.201201301
Synthesis of Ar-BINMOL Ligands by [1,2]-Wittig Rearrangement to Probe
Their Catalytic Activity in 1,2-Addition Reactions of Aldehydes with Grignard
Reagents
Long-Sheng Zheng,[a] Ke-Zhi Jiang,[a] Yuan Deng,[a] Xing-Feng Bai,[a] Guang Gao,[a]
Feng-Lei Gu,[a] and Li-Wen Xu*[a,b]
Keywords: Asymmetric synthesis / Ligand design / Chiral ligands / Titanium / Grignard reaction
We have demonstrated a highly diastereoselective synthesis
of optically pure Ar-BINMOL-derived diols and their ana-
logues. The present study demonstrates a unique cascade
chirality transfer in a [1,2]-Wittig rearrangement that leads
to chiral diols with three stereogenic centers, which include
a chiral sp3 center at the alcohol and C2-axial chirality.
Screening these ligands in the arylation of aromatic alde-
hydes with Grignard reagents shows that the naphthyl-sub-
stituted BINMOL promotes the aryl transfer reaction in good
yields (70–92%) and moderate-to-good enantioselectivities
(up to 72% ee), and a series of control experiments substanti-
ates that the axial chirality and the chiral sp3 center at the
alcohol of the Ar-BINMOLs are the pivotal enantioselectivity-
controlling structure elements. In addition, this study demon-
strated the importance of the chiral sp3 center at the alcohol
on Ar-BINMOL for the aryl transfer reaction. Finally, we
found that the chiral Ar-BINMOL ligand 2h mediated the ti-
tanium-promoted 1,2-addition of MeMgBr to aldehydes to
give the desired products in good yields with excellent
enantioselectivities (up to 92% ee).
the addition of an aryl–metal reagent to aromatic alde-
hydes.[3,6] However, most enantioselective arylations of alde-
hydes rely on the use of expensive diphenylzinc reagents.[7]
A more practical and versatile methods would begin with
an aryl bromide or the corresponding Grignard reagent,
many of which are commercially available and inexpensive.
Although the addition of Grignard reagents to aldehydes is
an ideal and easy method to prepare the racemic secondary
alcohols, catalytic enantioselective Grignard reactions with
aldehydes have rarely been reported because of the high and
uncontrollable reactivity of Grignard reagents with aro-
matic aldehydes.[8] It is well known that the lack of suitable
catalyst systems has limited their further development dur-
ing recent decades.[9] Recently, Harada et al.[10] reported an
efficient method for the asymmetric Grignard addition of
aryl reagents to aldehydes in high enantioselectivities, which
was a significant improvement upon previous work. The
key to the success of this reaction was the use of 3-(3,5-
diphenylphenyl)-BINOL ligand (DPP-BINOL). For the in-
vestigation of a new catalyst system, the design and synthe-
sis of ligands is a key challenge to achieve enantioselective
arylation reaction of aldehydes.
Introduction
Chiral arylmethanols are key structural elements of
many biologically active compounds and optoelectronic
molecules, which have found wide application as agrochem-
icals and pharmaceuticals.[1] Therefore, the synthesis of chi-
ral arylmethanols has attracted much attention in the past
decades. However, the enantioselective synthesis of diaryl-
methanols is not an easy task. Among the different ap-
proaches to diarylmethanols, there are two major protocols
for their enantioselective syntheses: the asymmetric re-
duction of unsymmetric diaryl ketones[2] and the enantiose-
lective addition of an aryl–metal reagent to aromatic alde-
hydes.[3] Aryl transfer to aldehydes represents a powerful
and widely used transformation and is a straightforward
route to enantiomerically enriched diarylmethanols.[4] Since
Seebach and Weber reported the first catalytic phenyl trans-
fer reaction of PhLi,[5] several groups have discovered enan-
tioselective catalysts based on amino alcohols and diols for
[a] Key Laboratory of Organosilicon Chemistry and Material
Technology of Ministry of Education, Hangzhou Normal
University,
Hangzhou 310012, P. R. China
Fax: +86-571-28865135
E-mail: liwenxu@hznu.edu.cn or licpxulw@yahoo.com
[b] State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences,
Very recently, we have developed a facile and practical
methodology for the preparation of new chiral diols, in
which the simple axial chiral monoalkylated BINOLs could
be converted into synthetically useful and enantiomerically
pure
1,1Ј-binaphthalene-2-α-arylmethanol-2Ј-ols
(Ar-
Lanzhou 730000, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201301.
BINMOLs) with axial and sp3-central chirality through the
axial-to-central chirality transfer of a [1,2]-Wittig re-
748
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Synthesis of Ar-BINMOL Ligands by [1,2]-Wittig Rearrangement
arrangement.[11] In this method, the chirality transfer pro- aldehdyes.[12a] These observations prompted us to investi-
cess showed very broad substrate scope in terms of ad- gate further syntheses of new Ar-BINMOLs and other diols
ditional aromatic ethers with excellent enantioselectivities by [1,2]-Wittig rearrangements and to explore the possibil-
and yields, and thus allows access to a broad range of chiral ity of enantioselective arylation of aromatic aldehydes with
Ar-BINMOLs. Over the past year, it has proved to be an Grignard reagents.
attractive and promising chiral ligand in several transfor-
mations.[12] Herein, we report the preparation of several
new chiral diol ligands endowed with axial and sp3-central
chirality and their application to the titanium-promoted
asymmetric 1,2-addition of aryl and methyl Grignard rea-
gents to aryl aldehydes to give diarylmethanols with good
enantioselectivities. More importantly, we report a new
Synthesis of New Ar-BINMOLs and Diol Ligands by [1,2]-
Wittig Rearrangement
Efforts to design the diol ligands focused on structural
strategy to prepare some Ar-BINMOL ligands by a double modifications that retained the sp3-central chirality of the
[1,2]-Wittig rearrangement, which provides versatile, op- alcohol and the C2-axial chirality and were performed with
tically pure compounds for organic synthesis (Scheme 1).
[1,2]-Wittig rearrangements. Therefore, we designed and
synthesized new chiral diols from BINOL (Scheme 2). As
benzyl ethers can lead to efficient [1,2]-Wittig rearrange-
ments, we turned our attention to the asymmetric [1,2]-Wit-
tig rearrangement of a BINOL-containing allylic ether. As
shown in Scheme 2, the rearrangement of the protected
mono-allylic ether 1j occurred in the presence of isobutyl-
lithium and yielded the corresponding chiral diol 2j in excel-
lent yield with perfect chirality transfer and enantio-
selectivity (Ͼ 99% ee). With the diol 2j in hand, we exam-
ined the cascade [1,2]-Wittig rearrangement to produce the
optically pure diol 4j. The absolute stereochemistry of 4j
was determined by X-ray analysis. The crystal structure of
(P)-(R,R)-4j (Figure 1) shows that the highly diastereoselec-
tive cascade chirality transfer through a [1,2]-Wittig re-
arrangement takes place with the aid of neighboring lithium
activation.
Scheme 1. Synthesis of Ar-BINMOLs by a asymmetric [1,2]-Wittig
rearrangement.[11,12a]
Results and Discussion
Chiral diols represent a very useful class of chiral ligands
that have been widely used as optically pure catalysts and
chiral auxiliaries; therefore, much effort has been dedicated
to practical procedures for their synthesis. Although the
[1,2]-Wittig rearrangement is recognized as a powerful
method for the synthesis of secondary alcohols by carbon–
oxygen cleavage and carbon–carbon bond forming reac-
tions and its mechanism and stereochemistry is well
studied, its utility in organic synthesis has been limited by
rather low yields, restricted substrate range, and the lack of
high diastereo- or stereoselectivity.[13] To prepare new chiral
BINOL-derived diol ligands, we have developed a strategy
with neighboring lithium activation for the asymmetric
Scheme 2. Synthesis of chiral allylic BINMOL derivative 4j by cas-
cade chirality transfer in a [1,2]-Wittig rearrangement.
To examine the cascade chirality transfer in the [1,2]-Wit-
[1,2]-Wittig rearrangement. This [1,2]-Wittig rearrangement tig rearrangement of BINMOL analogues, we synthesized
process showed very broad substrate scope with excellent the benzyl Ph-BINMOL 2k, in which the naphthol moiety
enantioselectivities (Ͼ 99% ee) and yields (84–96%). In a is protected but the alcohol is unbenzylated (Scheme 3). In
further study of the application of Ar-BINMOLs in asym- the next cascade rearrangement, we found the desired prod-
metric catalysis, we have found that the Ar-BINMOLs uct was obtained with perfect chirality transfer to give only
could successfully act as ligands to promote the asymmetric one diastereomer (Scheme 3). Although the yield is not
1,2-addition of diethylzinc to aldehydes and resulted in ex- ideal, it is a practical method for the preparation of di-
cellent yields and enantioselectivities (up to Ͼ 99.9% ee) in phenyl-substituted chiral secondary alcohols with axial and
the reactions of diethylzinc with a broad range of aromatic sp3-central chirality in excellent enantioselectivity (Ͼ 99%
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L.-W. Xu et al.
FULL PAPER
Scheme 4. Synthesis of chiral allylic BINMOL derivative 4l by cas-
cade chirality transfer in a [1,2]-Wittig rearrangement.
a large number of 1,1Ј-spirobiindan derivatives, including
chiral 1,1Ј-spirobiindan-7,7Ј-diol (SPINOL) and its P- or
N-containing spiro chiral ligands,[14] have been prepared
and their potential in asymmetric catalysis has been re-
vealed.[15] As an alternative to BINOL derivatives and Ar-
BINMOLs, we assume that 1,1Ј-spirobiindan-7,7Ј-diol can
be effectively modified by introducing a bulky phenyl group
and stereogenic secondary alcohol carbon-center to form a
new diol with axial and sp3-central chirality by axial-to-
central chirality transfer based on diastereoselective neigh-
boring lithium-assisted [1,2]-Wittig rearrangement.
As demonstrated in Scheme 5, the preparation of diol 7
(Ph-SPINMOL) commenced with 5. Benzylation of 5 fol-
lowed by a butyllithium-promoted [1,2]-Wittig rearrange-
ment at room temperature gave the desired diol 7 in moder-
ate yield with excellent chirality transfer (CT). As expected
and similarly to the axial-to-central chirality transfer of the
[1,2]-Wittig rearrangement of chiral monoalkylated BI-
NOLs, the Ph-SPINMOL was confirmed as an optically
pure chiral molecule (Ͼ 99% ee, see Supporting Infor-
mation).
Figure 1. The crystal structure of 4j.
ee). In analogy to a previous study on the axial-to-central
chirality transfer of [1,2]-Wittig rearrangement and to fur-
ther study the effect of a neighboring stereogenic alcohol,
we examined the cascade [1,2]-Wittig rearrangement of a
structurally divergent ether. Interestingly, the allyl- or
benzyl-substituted BINMOL (3l or 3m) led to the same chi-
ral product (P)-(R,R)-4l (Scheme 4). On the basis of this
finding, the absolute configuration of 4l from (S,R)-3l bear-
ing (R)-phenylmethanol and (S,R)-3m bearing (R)-allylic
alcohol was determined to be the (S, R,R) or (P)-(R,R) con-
former. This data also further reinforces the conclusion that
neighboring lithium activation is beneficial to the [1,2]-Wit-
tig rearrangement.
Scheme 3. Synthesis of chiral allylic BINMOL derivative 4k by cas-
cade chirality transfer in a [1,2]-Wittig rearrangement.
Scheme 5. The synthesis of a new SPINOL-derived diol (Ph-
SPINMOL) by [1,2]-Wittig rearrangement.
These promising results encouraged us to extend the
scope of the [1,2]-Wittig rearrangement to 1,1Ј-spirobi-
indan-7,7Ј-diol (5). 1,1Ј-Spirobiindan-7,7Ј-diol belongs to
To illustrate the synthetic potential and structural char-
the family of C2-symmetric ligands. The structure of 1,1Ј- acteristics of these chiral Ar-BINMOLs and analogous
spirobiindan offers a promising combination of chemical compounds in asymmetric catalysis, we also prepared some
robustness and conformational rigidity. In the past decade, diols without chiral sp3 carbon atoms derived from Ar-
750
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Synthesis of Ar-BINMOL Ligands by [1,2]-Wittig Rearrangement
BINMOLs (Scheme 6) and used them to check the crucial aldehydes with Grignard reagents and gave good yields in
role of the alcoholic sp3 chiral center in subsequent aryl- the presence of Ph-BINMOL 2a, the enantioselectivities
ations of aromatic aldehydes with Grignard reagents. The were low (35–39% ee). The solvent effects were evaluated
Ar-BINMOLs 8a–c were treated with trimethylsilyl chloride with the ligand 2a and dichloromethane (DCM) was found
(TMSCl)/NaI[16] to give the corresponding deoxygenated to be the best solvent that gave promising results in term
products 9a–c in high yields.
of enantioselectivity (46% ee). Ar-BINMOLs with either
electron-withdrawing or electron-donating substituents (2b–
2f) as well as a phenyl-substituted chiral diol (2g) were ap-
plied to promote the arylation of aldehyde. When using chi-
ral Ar-BINMOLs 2b–d, the desired product 12a was ob-
tained in 36–56% ee. Interestingly, o-methyl-substituted 2e
and naphthyl-substituted 2h gave the same level of enantio-
selectivity (65 or 66% ee) in this reaction, and the use of
BINOL or BINOL-linked Ar-BINMOL 2i resulted in de-
creased enantioselectivities (38 and 57% ee, respectively).
However, there were almost no difference in the enantio-
selectivity when either 2e or 2h was used. The slight differ-
ence in the catalytic activity of 2e and 2h in the model 1,2-
addition reaction of benzaldehyde and (4-fluorophenyl)-
magnesium bromide propelled us to conduct further ligand
screening in the model arylation of 2-methoxybenzaldehyde
(10b) with phenylmagnesium bromide (11b).
Scheme 6. Synthesis of deoxygenated phenol ligands 9a–c. Condi-
tion A for 8a: TMSCl/NaI (6 equiv.) in CH3CN, room temperature.
Condition B for 8b–c: TMSCl/NaI (10 equiv.) in CH3CN, reflux.
Ar-BINMOL/Chiral Diol Ligands in the Titanium-
Promoted 1,2-Additon of Aldehydes with Grignard Reagents
Table 1. Preliminary screening of chiral Ar-BINMOL ligands for
the asymmetric 1,2-addition of (4-fluorophenyl)magnesium brom-
ide to benzaldehyde.[a]
With the Ar-BINMOLs and analogous compounds in
hand, we immediately sought to establish the catalytic po-
tential of these diols in asymmetric reactions. In our pre-
vious report, we have shown that excellent results were
achieved with Ar-BINMOLs in the asymmetric 1,2-ad-
dition of diethylzinc to aldehydes (Scheme 7).[12] Therefore,
we had a great interest to test our ligands for the arylation
of aldehydes with Grignard reagents.
Entry
Ligand
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
2a
THF
Et2O
64
74
54
59
54
59
54
64
59
50
35
39
46
47
56
49
66
65
57
38
2a
2a
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
2b
2c
2d
2e
2h
2i
10
(S)-BINOL
[a] 1 equiv. of Grignard reagent was treated with 2 equiv. of
Ti(OiPr)4 at 0 °C for 1–2 h, and then the mixture of Grignard rea-
gent and titanium was added to the solution of benzaldehdye
(1 equiv.), Ar-BINMOL or BINOL ligand (10 mol-%), and
Ti(OiPr)4 (2 equiv.). The reaction was carried out at 0 °C for 15 h.
[b] Isolated yields. [c] Determined by HPLC with a Daicel CHI-
RALCEL OB-H column.
Scheme 7. Enantioselective addition of diethylzinc to aldehydes
using BINMOL 2i.
Our study began with a preliminary screening of BINOL
and several of the Ar-BINMOLs shown in Scheme 1. By
using benzaldehyde (10a), and (4-fluorophenyl)magnesium
Further optimization studies with chiral Ar-BINMOLs
bromide (11a) as a probing substrate, the reaction was per- 2a–2i and various Ar-BINMOL-derived ligands (4–9) un-
formed with Ti(OiPr)4 at 0 °C, and the results are summa- der different conditions are summarized in Table 2. Com-
rized in Table 1. Although both tetrahydrofuran (THF) and pounds 2e and 2h exhibited promising enantioselectivities
diethyl ether (Et2O) were good solvents for the arylation of (65–66% ee) in the reaction of benzaldehyde (10a) and (4-
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FULL PAPER
fluorophenyl)magnesium bromide (11a), and we found that and the absolute configuration is opposite to that of 2e or
2h is superior to 2e in the arylation of 2-methoxybenzalde- 2h, which can clearly be explained by the cooperative effect
hyde (10b) with phenylmagnesium bromide (11b). There- of the chiral sp3 center of the alcohol and the neighboring
fore, we continued to examine the enantioselective induc- MeO group on the titanium complex. Moreover, the intro-
tion of new Ar-BINMOLs (2f–j) and their derivatives (4 duction of a phenyl ring at the ortho-position of Ph-
and 9) as well as SPINOL-derived diol 7 as ligands in this BINMOL (for example, 2g) did not improve the enantio-
reaction. These ligands were screened for the arylation un- selectivity in comparison to that of o-methyl-substituted
der modified conditions (Table 2, Entries 3–15). The highest Ar-BINMOL 2e. When using the allylic BINMOL 2j as li-
efficiency and enantioselectivity for the reaction was still gand, almost no enantioselectivity was observed in this re-
observed with Ar-BINMOL 2h. Interestingly, although 2f action, which confirmed the importance of the CH(OH)-
resulted in low enantioselectivity (36% ee), the o-methoxy linked aromatic ring on the Ar-BINMOL ligands.
group on this ligand changed the stereochemical outcome
Unfortunately, with 4j–l prepared from cascade dia-
stereoselective [1,2]-Wittig rearrangement as ligand, the
enantioselectivity decreased to only 3–6% ee (Table 2, En-
tries 7 and 8). In addition, although chiral 1,1Ј-spirobi-
indan-7,7Ј-diol (SPINOL) could also promote this reaction
smoothly, the enantioselectivity was rather poor (Table 2,
Entry 10). More interestingly, when using diol 7 prepared
from SPINOL, the product 12b obtained was racemic.
To support the hypothesis that a chiral sp3 alcohol or
secondary alcohol moiety (CH–OH) is crucial to the tita-
nium-promoted arylation of aldehyde (Figure 2), we evalu-
ated the catalytic activity of 9 with or without a phenolic
group (Table 2, Entries 12–14). The beneficial effects of a
secondary alcohol moiety on Ar-BINMOLs were con-
firmed in this reaction, in which both 9a without an ad-
ditional alcohol or phenol moiety and 9c with a long-dis-
tance meso-position phenol moiety resulted in racemic
product. These illustrations clearly demonstrate that the Ar-
BINMOL analogues without an alcoholic moiety (CH–
OH) lead to the formation of inactive titanium catalysts
(Figure 2, II and III)[17] in enantioselective induction. Fur-
ther evidence is that 9b with a capable neighboring phenol
gives 12b in comparable enantioselectivity (43% ee).
Table 2. Optimization of reaction conditions with chiral Ar-
BINMOL ligands.[a]
Entry
Ligand Solvent
Temp. [°C] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
2h
2e
2f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Et2O
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
30
71
72
70
76
77
75
82
79
77
72
87
35
87
86
81
98
55
65
65
47
71
63
–36
–51
61
–2
3
6
4
–21
0
0
2g[d]
2i
2j[d]
4j
4k
4l
5
7
9a
9b
9c
2h
2h
2h
2h
2h
2h
9
10
11
12
14
15
16
17
18
19
20
21
–43
0
41
55
42
63
65
61
The solvent effects were also evaluated with the ligand
2h for the arylation of 2-methoxybenzaldehyde (10b) with
phenylmagnesium bromide (11b). These results continued
to confirm that DCM was the best solvent in terms of
enantioselectivity (Table 2, Entries 16 and 17). Efforts to
improve the enantioselectivity by adjusting the reaction
temperature (Table 2, Entries 18–21) and the amount of
Ti(OiPr)4 were unsuccessful.
toluene
DCM
DCM
DCM
DCM
0
–10
–40
[a] 1 equiv. of Grignard reagent was treated with 2 equiv. of
Ti(OiPr)4 at 0 °C for 1–2 h, and then the mixture of Grignard rea-
gent and titanium was added to the solution of benzaldehdye
(1 equiv.), ligand (10 mol-%), and Ti(OiPr)4 (2 equiv.). The reaction
was carried out at –40 to 30 °C for 10 h. [b] Isolated yields. [c]
Determined by HPLC with a Daicel CHIRALCEL OJ-H column.
[d] (R,S) conformer derived from (R)-BINOL.
Based on the experimental validation of the stereocon-
trolling ability of the Ar-BINMOL 2h, we further examined
Figure 2. Possible titanium complex derived from Ar-BINMOL – the importance of the alcohol (CH–OH).
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Synthesis of Ar-BINMOL Ligands by [1,2]-Wittig Rearrangement
the generality of the present arylation of aromatic aldehydes methanols 13a–i with good enantioselectivities (85–92%
with Grignard reagents and representative results are sum- ee). Therefore, an enantioselectivity enhancement with 2h
marized in Table 3. With several Grignard reagents in hand, in comparison to the previous method[12b] is observed in
a wide range of aromatic aldehydes with different substitu- the reaction, in which unprecedented yields and enantio-
ents on aromatic rings, including methyl, methoxy, and hal- selectivities are achieved in the asymmetric methylation of
ide substituents, could be used as electrophiles, and good to aldehydes.
excellent yields were uniformly obtained. As shown in
Table 3, although moderate-to-good enantioselectivities
were obtained in the arylation of aldehydes, variation of
the electronic and steric nature of the Grignard reagents or
aromatic aldehyde appeared to have little influence on the
asymmetric induction in the presence of ligand 2h. These
results clearly demonstrate that Ar-BINMOL 2h as a chiral
ligand can give promising and acceptable enantioselectivi-
ties in the direct arylation of aldehydes with Grignard rea-
gents. In addition, it shows that the development of new
chiral diols or analogues by modification of the backbone
of chiral Ar-BINMOLs would be attractive.
Table 3. Synthesis of chiral diarylmethanols through arylation of
aldehydes with Grignard reagents.[a]
Entry
R
RЈ
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
o-CH3
m-OCH3
m-F
m-Br
p-CH3
p-Br
p-OCH3
naphthyl
o-CH3
o-OCH3
m-Br
m-F
o-CH3
o-Br
H
H
H
H
H
H
H
H
F
F
F
F
p-MeO
p-MeO
p-MeO
p-MeO
p-MeO
12b: 84
12d: 91
12e: 91
12f: 92
12g: 85
12h: 76
12i: 70
12j: 77
12k: 74
12l: 83
12m: 76
12n: 82
12o: 77
12p: 85
12q: 72
12r: 89
12s: 70
70
55
54
50
50
55
61
54
65
69
56
54
72
55
66
69
71
9
10
11
12
13
14
15
16
17
Scheme 8. Asymmetric 1,2-addition of MeMgBr to aromatic alde-
hydes.
o-Cl
H
m-Br
Conclusions
We have demonstrated a highly diastereoselective synthe-
sis of optically pure Ar-BINMOL-derived diols and their
analogues by an enantioselective [1,2]-Wittig rearrangement
with the aid of the directing effect of functional group/
neighboring lithium atom. The present study demonstrates
unique cascade or relay chirality transfer in a [1,2]-Wittig
[a] In a typical procedure, 1 equiv. of Grignard reagent was treated
with 2 equiv. of Ti(OiPr)4 at –78 °C for 1–2 h, and then the mixture
of Grignard reagent (1.0 equiv.) and titanium was added to the
solution of aromatic aldehyde (1 equiv.), Ar-BINMOL ligand 2h
(10 mol-%), and Ti(OiPr)4 (2 equiv.). The reaction was carried out
at –20 °C for 10 h. [b] Isolated yields. [c] Determined by HPLC.
On the basis of the above findings, further studies on the rearrangement that leads to chiral diols with three stereo-
synthetic application of Ar-BINMOL 2h in the asymmetric genic centers, including a chiral secondary alcohol and
1,2-addition of MeMgBr to aldehydes were carried out un- C2-axial chirality. In addition, we report the first synthesis
der the modified conditions similar to those of a previous of a SPINOL-derived diol (Ph-SPINMOL) prepared from
report.[12b] The results from scope studies for the enantiose- chiral 1,1Ј-spirobiindan-7,7Ј-diol through a highly dia-
lective 1,2-addition of MeMgBr to aldehydes with Ar- stereoselective [1,2]-Wittig rearrangement, which further
BINMOL ligand 2h are shown in Scheme 8. Reactions with disclosed the potential of [1,2]-Wittig rearrangements for
substituted aromatic aldehydes were highly effective in con- the enantioselective synthesis of chiral diols. To probe the
versions and enantioselectivities. Halide as well as methyl enantioselective induction activity of these chiral diols pre-
substituents on the aromatic ring of the aldehydes are also pared through [1,2]-Wittig rearrangements, the synthesis of
well tolerated in this reaction, which leads to the chiral aryl- chiral diarylmethanols by arylation of aromatic aldehydes
Eur. J. Org. Chem. 2013, 748–755
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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753

L.-W. Xu et al.
FULL PAPER
the mixture was stirred at room temperature for one hour. After
the reaction was completed, it was quenched with water and ex-
tracted with EtOAc. The combined organic layers were dried with
Na2SO4 and concentrated in vacuo. The crude products were puri-
fied by column chromatography (silica gel, petroleum ether/EtOAc
= 4:1) to afford the pure Ar-BINMOL 2. Except for 2g, the Ar-
BINMOL products 2a–2f and 2h are known compounds and have
been reported in our previous paper.[11,12a] The syntheses of other
chiral diols are presented in the Supporting Information.
with Grignard reagents was selected as a model. The ligand
screening results show that the naphthyl-substituted
BINMOL 2h promotes this aryl transfer reaction in good
yields and moderate-to-good enantioselectivities, and a
series of control experiments substantiate that both the ax-
ial and sp3 central chirality of the Ar-BINMOLs are the
pivotal enantioselectivity-controlling structure elements in
the catalytic arylation of aldehydes with aryl Grignard rea-
gents. In addition, this study demonstrated the importance
of the sp3 chiral center at the alcohol on Ar-BINMOL for
the aryl transfer reaction. Although the arylation reaction
of aldehydes with Grignard reagents is not a good model
for the evaluation of the catalytic activity of Ar-BINMOLs
and chiral diol analogues owing to moderate enantio-
selectivity, the present work and new [1,2]-Wittig rearrange-
ment chemistry provides the basis for further synthetic ap-
plications involving Ar-BINMOLs as efficient chiral ligands
to produce excellent chirality transfer in metal-catalyzed or-
ganic transformations. Finally, we found the chiral Ar-
BINMOL ligand 2h mediated titanium-promoted 1,2-ad-
dition of MeMgBr to aldehydes to give the desired products
in good yields with excellent enantioselectivities (up to 92%
ee). Further studies in our laboratory aimed at the applica-
tion of the chiral Ar-BINMOL ligands described herein in
chiral synthesis and asymmetric catalysis are currently un-
derway.
(R)-2Ј-[(S)-(1,1Ј-Biphenyl-2-yl)(hydroxy)methyl]-[1,1Ј-binaphthalen]-
1
2-ol (2g): H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.8 Hz, 1
H), 7.97 (d, J = 8.0 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.82–7.77
(m, 2 H), 7.50 (t, J = 7.2 Hz, 1 H), 7.38–7.34 (m, 1 H), 7.25–7.15
(m, 5 H), 7.08 (t, J = 8.0 Hz, 2 H), 7.02 (d, J = 8.8 Hz, 2 H), 6.91–
6.89 (m, 1 H), 6.83–6.79 (m, 1 H), 6.58 (d, J = 6.8 Hz, 2 H), 6.24
(d, J = 8.4 Hz, 1 H), 5.99 (s, 1 H), 5.84 (s, 1 H), 3.10 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 150.7, 141.9, 141.1, 140.0, 138.9,
133.5, 133.4, 130.2, 130.0, 129.1, 128.9, 128.8, 128.2, 128.1, 127.8,
127.5, 127.3, 126.8, 126.7, 126.3, 126.2, 126.1, 125.2, 125.0, 123.1,
117.8, 117.0, 70.7 ppm. IR (KBr): ν = 3540, 3057, 2922, 1620, 1595,
˜
1512, 1478, 1452, 1341, 1278, 1195, 1144, 1004, 940, 840, 760, 741,
704, 635 cm–1. MS (ESI–): m/z = 902 [2M – 2H]+. HRMS (EI):
calcd. for C33H24O2 [M – 1]+ 451.1701; found 451.1776. [α]2D6
+34.26 (c = 0.33, CHCl3).
=
General Procedure for the Catalytic Asymmetric Addition of Grig-
nard Reagents to Aldehydes: In a flame dried Schlenk tube, (S,R)-
2h (21.3 mg, 0.05 mmol) and Ti(OiPr)4 (0.295 mL, 1.0 mmol) were
mixed in DCM (0.5 mL) at room temperature. After the resulting
mixture was stirred for 5 min, 2-MeOC6H4CHO (0.5 mmol) in
DCM (0.5 mL) was added. After 30 min, the mixture was cool to
–20 °C. A mixture of PhMgBr (1 mL, 1 m in THF) and Ti(OiPr)4
(0.295 mL, 1.0 mmol) in DCM (3 mL) stirred for 30 min at room
temperature was added dropwise to the mixture over a period of
5–10 min. The reaction was stirred at –20 °C for 10 h. After the
reaction was completed as monitored by TLC, the reaction mixture
was quenched with 1 n aqueous HCl and extracted with DCM
(3ϫ10 mL). The combined organic layers were washed with brine,
dried with Na2SO4, filtered, and the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 10:1)
to give the pure product (76.0 mg, 71% yield, 71% ee).
Experimental Section
General: Flash column chromatography was performed over silica
(200–300 mesh). 1H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively, with an Advance (Bruker) 400 MHz
NMR Spectrometer and were referenced to the internal solvent sig-
nals. Thin layer chromatography was performed with silica gel
F254 TLC plates and visualized with ultraviolet light. HPLC was
carried out with a Waters 2695 Millennium system equipped with
a photodiode array detector. EI and CI mass spectra were per-
formed with a Trace DSQ GC/MS spectrometer. Data are reported
in the form of (m/z). The substrates including isobutyllithium were
commercial available and used directly. Diarylmethanols and some
of the [1,2]-Wittig rearrangement products were known and con-
firmed by the usual spectroscopic methods (1H NMR, 13C NMR,
IR). The ESI-MS analysis of the samples was performed with an
LCQ advantage mass spectrometer (ThermoFisher Company,
USA), equipped with an ESI ion source in the positive ionization
mode, and data was acquired with the Xcalibur software (Version
1.4). DCM was dried and distilled from CaH2. THF and Et2O
were distilled from sodium benzophenone. Aldehydes and titanium
tetraisopropoxide were used after distillation. X-ray diffraction:
data sets were collected with Bruker APEX DUO and Bruker
APEX-II CCD diffractometers. Programs used: data collection
Bruker APEX2,[18a] data reduction Bruker SAINT, absorption cor-
rection for multi-scan, structure solution SHELX-97,[18b] structure
refinement SHELXL-97,[18b] graphics Bruker SHELXTL.[18b]
CCDC-893055 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): General remarks, NMR and IR spectroscopic data for the
products.
Acknowledgments
This work was supported by the National Natural Science Founder
of China (NSFC) (grant numbers 21173064 and 21205025), the
Zhejiang Provincial Natural Science Foundation of China
(Y4100020 and Q12B020037), and the Program for Excellent
Young Teachers in Hangzhou Normal University (HNUEYT,
JTAS 2011-01-014). X. L. W. is greatly indebted to Prof. Shibasaki
Masakatsu, Graduate School of Pharmaceutical Sciences, The Uni-
versity of Tokyo and Prof. Chun-Gu Xia, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences for their help.
General Procedure for the Synthesis of Chiral Ar-BINMOL Deriva-
tives 2a–2h by [1,2]-Wittig Rearrangement: The [1,2]-Wittig re-
arrangements were performed by stirring a solution of compound
1 (5 mmol) in anhydrous THF (30 mL) at –78 °C, followed by the
addition of a solution of iBuLi in hexane (1.23 m, 2.5 equiv.) under
N2. The mixture was warmed slowly to room temperature, and then
754
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Eur. J. Org. Chem. 2013, 748–755

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Published Online: December 5, 2012
Eur. J. Org. Chem. 2013, 748–755
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