Catalytic enantioselective aryl transfer to aldehydes using chiral 2,2'-bispyrrolidine-based salan ligands

Article abstract of DOI:10.3390/molecules16042971

Chiral C₂-symmetric diamines have emerged as versatile auxiliaries or ligands in numerous asymmetric transformations. Chiral 2,2'-bispyrrolidine-based salan ligands were prepared and applied to the asymmetric aryl transfer to aldehydes with arylboronic acids as the source of transferable aryl groups. The corresponding diarylmethanols were obtained in high yields with moderate to good enantioselectivitives of up to 83% ee.

Full text of DOI:10.3390/molecules16042971

Molecules 2011, 16, 2971-2981; doi:10.3390/molecules16042971
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Catalytic Enantioselective Aryl Transfer to Aldehydes Using
Chiral 2,2’-Bispyrrolidine-Based Salan Ligands
Xuefeng Jia 1,2, Aijun Lin 1, Zhijie Mao 1, Chengjian Zhu 1,3,* and Yixiang Cheng 4,*
1
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry,
Nanjing University, Nanjing, 210093, China
2
School of Chemistry and Materials Science, Shanxi Normal University, Linfen, 041004, China
3
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai, 200032, China
4
School of Chemistry and Chemical Engineering, Key Laboratory of Mesoscopic Chemistry of
MOE, Nanjing University, Nanjing, 210093, China
* Authors to whom correspondence should be addressed; E-Mails: cjzhu@nju.edu.cn (C.Z.);
yxcheng@nju.edu.cn (Y.C.); Tel.: (+86)25-83594886; Fax: (+86)25-83594886.
Received: 24 December 2010; in revised form: 15 March 2011 / Accepted: 16 March 2011 /
Published: 6 April 2011
Abstract: Chiral C2-symmetric diamines have emerged as versatile auxiliaries or ligands
in numerous asymmetric transformations. Chiral 2,2’-bispyrrolidine-based salan ligands
were prepared and applied to the asymmetric aryl transfer to aldehydes with arylboronic
acids as the source of transferable aryl groups. The corresponding diarylmethanols were
obtained in high yields with moderate to good enantioselectivitives of up to 83% ee.
Keywords: 2,2’-bispyrrolidine; salan ligands; aryl transfer; arylboronic acid;
enantioselectivity
1. Introduction
Chiral diarylmethanols are important intermediates and precursors for the synthesis of
pharmacologically and biologically active compounds [1-8]. Therefore, the development of effective
catalyst systems for the synthesis of these compounds is of significant importance for organic
chemists. The scientifically important protocols for the synthesis of chiral diarylmethanols commonly

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involve two strategies: (1) the asymmetric reduction of prochiral diaryl ketones [9-13], (2) the
enantioselective aryl transfer to aromatic aldehydes [14-16]. The reduction method requires an ortho
substituent on one of the aryls or electronic different aryl groups for optimum results. The second
method seems easy to realize chiral induction due to the large steric and electronic differences between
an aryl group and a hydrogen atom on the aldehyde substrates with diphenylzinc. As reported
previously, many functionalized diarylzincs used as the transferring nucleophiles are unstable and
difficult to synthesize, so the method of the aryl transfer to aldehyde is greatly limited. Recently, an
elegant method that the arylzinc species prepared in situ by transmetalation between organoboron
[17-19] or organoboronic derivatives [20-26] and diethylzinc has been proposed as an alternative for
the synthesis of salt-free organozinc reagents. We have also successfully developed an efficient and
practical method for the synthesis of diarylmethanols by transmetalation using the arylboronic acid in
the presence of trimethylgallium [27]. These methods allow the exploitation of a broad range of
substituted aryl transfer reagents since numerous arylboronic acids are commercially available, and a
lot of excellent ligands were developed and applied to the asymmetric aryl transfer reaction with good
results [28-41]. For the future, the introduction of the new, effective and more easily available catalysts
is also a field of continuous interest for the catalytic aryl transfer reaction.
Chiral C2-symmetric diamines have emerged as versatile auxiliaries or ligands in numerous
asymmetric transformations [42-44]. (R,R)-2,2’-bispyrrolidine, initially developed by Hirama, was
synthesized by various routes [45-50], and its derivatives had been successfully employed as chiral
ligands or organocatalysts in many asymmetric reactions [51-59]. So far, the application of 2,2’-
bispyrrolidine-based salan ligands [60,61] in asymmetric catalysis has not been reported. We describe
herein our efforts toward the synthesis of optically active diarylmethanols through the asymmetric aryl
transfer to aldehydes under the catalysis of (R,R)-2,2’-bispyrrolidine-based salan ligands.
Figure 1. Structures of Ligands L1-L6.
2. Results and Discussion
A preliminary study was performed to test the catalytic property of the ligands L1-L6 (Figure 1) in
the asymmetric phenyl transfer reaction to 4-nitrobenzaldehyde at 0 °C. As is evident from Table 1, the
resulting products could be obtained in moderate yield, but low enantioselectivity when (1R,2R)-
cyclohexane-1,2-diamine-based ligands L1-L4 were tested (Table 1, entries 1-4). Gratifyingly, we
found that the ligands L5 and L6 were more effective in this reaction (Table 1, entries 5-6). The ee

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value of the product could be increased to 63% when the reaction was carried out at −25 °C (Table 1,
entry 7). Increasing catalyst loading had a positive impact on both the yield and enantioselectivity. The
best result was obtained in 88% yield with 83% ee while using 20 mol% of L6 (Table 1, entry 9).
Table 1. Asymmetric Phenyl Transfer to 4-nitrobenzaldehyde. a
Entry
Ligand
L1
L2
L3
L4
L5
L6
L6
L6
Mol%
10
10
10
10
10
10
10
15
T(°C)
0
0
0
0
0
0
-25
-25
-25
Yield(%)b
Ee(%)c
6
1
2
3
4
5
6
7
8
9
66
73
69
80
74
84
70
80
88
11
16
3
31
43
63
71
83(S) d
L6
20
a All the reactions were carried out on 0.2 mmol scale of substrates with 2 equiv of arylboronic acid
and 6 equiv of Et2Zn in toluene for 24 h. b Isolated yields. c Determined by HPLC with a Chiralcel
d
OB-H column. The absolute configuration of the products were determined by comparison with
literature values.
After having established the optimal protocol for the asymmetric phenyl transfer reaction, we
further extended the reaction to a series of aldehyde substrates (Table 2). The electronic properties of
the aromatic rings of the aldehydes have a significant influence on the enantioselectivity in this
reaction. The aldehydes with electron-withdrawing substituents provided better results than those with
electron-donating substituents in terms of ee values. 4-Nitrobenzaldehyde gave the corresponding
diarylmethanol with 83% ee, but 4-methoxybenzaldehyde only with 11% ee (Table 2, entries 1, 2 and
10). Similar results were obtained when 3-substituted-benzaldehydes (Table 2, entries 3 and 9) or 2-
substituted-benzaldehydes (Table 2, entries 5, 6 and 8) were tested. However, an exception was
observed for 2-nitrobenzaldehyde (Table 2, entry 4), presumably caused by the chelating effect of the
NO2 group with the lewis acids [62,63]. The enantioselectivity was also found to be influenced by the
steric effect with the same exception of 2-nitrobenzaldehyde. ortho-Substituted (-Cl or -Me)
benzaldehydes gave higher ee values (Table 2, entries 6 vs 2 or 8 vs 9). It should be noted that the
reaction of 2-naphthaldehyde proceeded well, giving 70% ee and good yield (Table 2, entry 11), and
α,β-unsaturated cinnamaldehyde gave the corresponding product with only moderate enantioselectivity
(Table 2, entry 12).
We also further investigated the asymmetric aryl transfer to aromatic aldehydes with substituted
phenylboronic acids. As shown in Table 3, when 4-chlorophenylboronic acid was chosen as the aryl
source and 4-nitrobenzaldehyde as the substrate, 71% ee was obtained (Table 3, entry 1). And 54% ee
was obtained when 4-methoxylphenylboronic acid was tested (Table 3, entry 3).

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Table 2. Asymmetric Phenyl Transfer to Aromatic Aldehydes. a
Entry
1
Ar
Product
Yield (%)b
Ee (%)c,d
83(S)
41(S)
75(S)
41(R)
80(R)
73(S)
26(S)
60(S)
52(S)
11(S)
70(S)
47(R)
4-NO2C6H4
4-ClC6H4
3-NO2C6H4
2-NO2C6H4
2-CF3C6H4
2-ClC6H4
3-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeOC6H4
2-C10H7
3a
3b
3c
3d
3e
3f
88
80
91
85
72
84
85
76
78
80
80
76
2
3
4
5
6
7
3g
3h
3i
8
9
10
11
12
3j
3k
3l
PhCH=CH
Table 3. Asymmetric Aryl Transfer to Aldehydes. a
Entry
Ar1
Ar2
Product
Yield (%)b Ee (%)c
1
2
3
4
5
4-Cl C6H4
4-Cl C6H4
4-MeOC6H4
4-MeOC6H4
3,5-diMeC6H3
4-NO2C6H4
3-BrC6H4
4-NO2C6H4
3-NO2C6H4
C6H5
4a
4b
4c
4d
4e
75
82
78
70
70
71
55
54(S)d
24
48
a All reactions were carried out on 0.15 mmol scale of substrates with 2 equiv of arylboronic acid
b
and 6 equiv of Et2Zn in toluene at −25 °C for 24 h in the presence of 20 mol% ligand; Isolated
c
yields; Enantiomeric excess was determined by HPLC with a Chiralcel OB-H, OD-H or AD-H
d
column; The absolute configuration of the products were determined by comparison with
literature values.
3. Experimental
3.1. General
All reactions were carried out under an argon atmosphere using standard Schlenk techniques.
Solvents were dried and distilled prior to use according to standard methods. Unless otherwise
indicated, all materials were obtained from commercial sources and liquid aldehydes were freshly
distilled before use. For thin-layer chromatography (TLC), compounds were visualized by irradiation
with UV light on GF 254 silica gel plates. 1H-NMR and 13C-NMR spectra were recorded in CDCl3 on
a Bruker ARX-300 spectrometer with chemical shifts being referenced to SiMe4 used as internal

Molecules 2011, 16
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standard. The coupling constants J are given in Hz. HPLC analysis were performed on a chiral column
(Daicel Chiralcel OB-H, OD-H or AD-H column) on a Chromatography Interface 600 Series Link
instrument and Series 200 pump), with Series 200 UV/VIS detection at 254 nm. The solvent system
used has hexane (A)-2-propanol (B) in the indicated proportions. Optical rotations were measured on
Rudolph Research Analytical Autopol III Automatic Polarimeter equipped with a 100 mm cell. Mass
spectra (EI-MS) were taken using a Shimadzu GCMS-QP2010 mass spectrometer. High Resolution
Mass Spectra (HRMS) were taken using a LTQ Orbitrap XL ThermoFisher unit.
3.2. Typical Procedure for the Asymmetric Aryl Transfer Reaction
In a 20 mL flame-dried Schlenk reaction tube, diethylzinc (0.9 mmol, 6 equiv, 1.5 M in toluene
solution) was added dropwise to a solution of phenylboronic acid (0.3 mmol, 2 equiv) in toluene
(3 mL) under an argon atmosphere. After stirring for 12 h at 60 °C, a toluene solution of L6 (20 mol%)
was introduced. The reaction was stirred for an additional 30 minutes and cooled to −25 °C followed
by the addition of aldehydes (0.15 mmol). After completion of the reaction (monitored by TLC), the
reaction solution was quenched with saturated aqueous NH4Cl (3 mL) and further extracted with ethyl
acetate (3 × 5 mL). The combined organic layer was dried over Na2SO4. Evaporation of the solvent
gave the crude product, which was further purified by preparative TLC to afford the corresponding
chiral diarylmethanols.
(S)-4-Nitrophenyl(phenyl)methanol (3a). 1H-NMR: δ 8.19 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 7.2 Hz,
2H), 7.37–7.33 (m, 5H), 5.92 (s, 1H), 2.25 (brs, 1H). 83% ee determined by HPLC with a Chiralcel
OB-H column (A/B = 70:30, 0.8 mL/min, uv 230 nm): tR = 21.05 min (minor), tR = 35.74 min (major).
[α]D23 = +31.6 (c = 0.50, EtOH).
(S)-4-Chlorophenyl(phenyl)methanol (3b). 1H-NMR: δ 7.38–7.33 (m, 4H), 7.31–7.27 (m, 5H), 5.80 (s,
1H), 2.20 (brs, 1H). 41% ee determined by HPLC with a Chiralcel OB-H column (A/B = 90:10,
23
1.0 mL/min, uv 230 nm): tR = 10.21 min (minor), tR = 18.33 min (major). [α]D = +5.9 (c = 0.64,
EtOH).
1
(S)-3-Nitrophenyl(phenyl)methanol (3c). H-NMR: δ 8.30 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.72 (d,
J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.40–7.29 (m, 5H), 5.92 (s, 1H), 2.13 (brs, 1H). 75% ee
determined by HPLC with a Chiralcel OB-H column (A/B = 80:20, 0.8 mL/min, uv 230 nm):
tR = 34.19 min (minor), tR = 47.40 min (major). [α]D23 = +42.5 (c = 0.40, EtOH).
1
(R)-2-Nitrophenyl(phenyl)methanol (3d). H-NMR: δ 7.94 (dd, J = 7.8, 1.5 Hz, 1H), 7.75 (dd, J = 7.8,
1.5 Hz, 1H), 7.64 (dt, J = 7.5, 1.2 Hz, 1H), 7.46 (t, J = 7.8, 1.5 Hz, 1H), 7.36–7.29 (m, 5H), 6.44 (s,
1H), 2.02 (brs, 1H). 41% ee determined by HPLC with a Chiralpark AD-H column (A/B = 90:10,
23
0.8 mL/min, uv 254 nm): tR = 13.57 min (major), tR = 14.62 min (minor); [α]D = 11.2 (c = 0.32,
EtOH).

Molecules 2011, 16
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1
(R)-2-Trifluoromethylphenyl(phenyl)methanol (3e). H-NMR: δ 7.66 (t, J = 7.8 Hz, 2H), 7.55 (t,
J = 7.8 Hz, 1H), 7.42–7.32 (m, 5H), 7.30–7.27 (m, 1H), 6.32 (s, 1H), 1.99 (brs, 1H). 80% ee
determined by HPLC with a Chiralcel OD-H column (A/B = 90:10, 0.5 mL/min, uv 254 nm):
tR = 9.33 min (major), tR = 11.79 min (minor). [α]D23 = −37.2 (c = 0.5, EtOH).
1
(S)-2-Chlorophenyl(phenyl)methanol (3f). H-NMR: δ 7.60 (d, J = 7.8 Hz, 1H), 7.42–7.39 (m, 2H),
7.36–7.28 (m, 5H), 7.25–7.22 (m, 1H), 6.24 (s, 1H), 2.05 (brs, 1H). 73% ee determined by HPLC with
a Chiralcel OB-H column (A/B = 90:10, 1.0 mL/min, uv 230 nm): tR = 8.97 min (minor),
tR = 10.00 min (major). [α]D23 = −20.6 (c = 0.64, EtOH).
1
(S)-3-Bromophenyl(phenyl)methanol (3g). H-NMR: δ 7.57 (s, 1H), 7.42–7.35 (m, 5H), 7.33–7.27 (m,
2H), 7.20 (t, J = 7.8 Hz, 1H), 5.78 (s, 1H), 2.33 (brs, 1H). 26% ee determined by HPLC with a
Chiralcel OB-H column (A/B = 90:10, 1.0 mL/min, uv 230 nm): tR = 15.17 min (minor),
tR = 27.81 min (major). [α]D23 = +11.4 (c = 0.76, EtOH).
1
(S)-2-Methylphenyl(phenyl)methanol (3h). H-NMR: δ 7.53 (d, J = 9.0 Hz, 1H), 7.34–7.21(m, 7H),
7.16 (t, J = 8.1 Hz, 1H), 6.02 (s, 1H), 2.26 (s, 3H), 1.95 (s, 1H). 60% ee determined by HPLC with a
Chiralcel OB-H column (A/B = 90:10, 1.0 mL/min, uv 230 nm): tR = 9.47 min (minor), tR = 10.6 min
(major). [α]D23 = −19.3 (c = 0.30, EtOH).
1
(S)-3-Methylphenyl(phenyl)methanol (3i). H-NMR: δ 7.41–7.34 (m, 4H), 7.30–7.27 (m, 2H),
7.24–7.16 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 5.81 (s, 1H), 2.35 (s, 3H), 2.02 (brs, 1H). 52% ee
determined by HPLC with a Chiralcel OB-H column (A/B = 90:10, 1.0 mL/min, uv 230 nm):
tR = 12.39 min (minor), tR = 21.34 min (major). [α]D23 = −15.8 (c = 0.34, EtOH).
1
(S)-4-Methoxylphenyl(phenyl)methanol (3j). H-NMR: δ 7.37–7.34 (m, 3H), 7.30–7.26 (m, 4H), 6.88
(d, J = 9.0 Hz, 2H), 5.81 (s, 1H), 3.78 (s, 3H), 2.23 (brs, 1H). 11% ee determined by HPLC with a
Chiralcel OB-H column (A/B = 90:10, 1.0 mL/min, uv 230 nm): tR = 21.79 min (minor),
tR = 24.03 min (major). [α]D23 = 8.1 (c = 0.42, EtOH).
1
(S)-2-Naphathyl(phenyl)methanol (3k). H-NMR: δ 7.90 (s, 1H), 7.86–7.79 (m, 3H), 7.50–7.42 (m,
5H), 7.38–7.28 (m, 3H), 6.01 (s, 1H), 2.06 (brs, 1H). 70% ee determined by HPLC with a Chiralcel
OD-H column (A/B = 85:15, 0.8 mL/min, uv 230 nm): tR = 12.71 min (major), tR = 15.08 min (minor).
[α]D23 = −18.4 (c = 0.46, EtOH).
1
(R)-1, 3-Diphenylprop-2-en-1-ol (3l). H-NMR: δ 7.47–7.33 (m, 5H), 7.32–7.27 (m, 3H), 7.29–7.24
(m, 2H), 6.70 (d, J = 15.6 Hz, 1H), 6.40 (dd, J = 6.3, 15.6 Hz, 1H), 5.40 (d, J = 6.6 Hz, 1H), 2.15 (brs,
1H). 47%ee determined by HPLC with a Chiralcel OD-H column (A/B = 80:20, 0.8 mL/min, uv
254 nm): tR = 9.31 min (minor), tR = 11.14 min (major). [α]D20 = +13.5 (c = 0.40, EtOH).
4-Chlorophenyl(4-nitrophenyl)methanol (4a). 1H-NMR: δ 8.20 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz,
2H), 7.36–7.27 (m, 4H), 5.90 (s, 1H), 2.04 (brs, H). 71% ee determined by HPLC with a Chiralcel OB-

Molecules 2011, 16
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H column (A/B = 80:20, 0.8 mL/min, uv 230 nm): tR = 22.92 min (minor), tR = 25.07 min (major).
[α]D23 = −19.5 (c = 0.64, EtOH).
1
4-Chlorophenyl(3-bromophenyl)methanol (4b). H-NMR: δ 7.53 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H),
7.39–7.28 (m, 4H), 7.25–7.24 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 5.77 (s, 1H), 2.04 (brs, 2H). 55% ee
determined by HPLC with a Chiralcel OD-H column (A/B = 85:15, 0.8 mL/min, uv 230 nm):
tR = 7.80 min (major), tR = 8.58 min (minor). [α]D23 = +22.8 (c = 0.60, EtOH).
1
(S)-4-Methoxylphenyl(4-nitrophenyl)methanol (4c). H-NMR: δ 8.19 (d, J = 8.7 Hz, 2H), 7.57 (d,
J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.88 (s, 1H), 3.80 (s, 3H), 2.20 (s,
1H). 54%ee determined by HPLC with a Chiralpark AD-H column (A/B = 85:15, 0.8 mL/min, uv 254
nm): tR = 15.60 min (minor), tR = 19.25 min (major). [α]D23 = +27.9 (c = 0.44, EtOH).
1
4-Methoxylphenyl(3-nitrophenyl)methanol (4d). H-NMR: δ 8.28 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H),
7.71 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 6.6 Hz, 2H), 6.89 (d, J = 6.9 Hz, 2H),
5.88 (s, 1H), 3.80 (s, 3H), 2.28 (brs, 1H). 24% ee determined by HPLC with a Chiralcel OD-H column
(A/B = 85:15, 0.8 mL/min, uv 230 nm): tR =15.08 min (major), tR =16.23 min (minor). [α]D23 = +23.8
(c = 0.50, EtOH).
1
3, 5-Dimethylphenyl(phenyl)methanol (4e). H-NMR: δ 7.42–7.28 (m, 5H), 7.01 (s, 2H), 6.93 (s, 1H),
5.77 (s, 1H), 2.31 (s, 6H), 2.18 (brs, 1H). 48% ee determined by HPLC with a Chiralcel OD-H column
(A/B = 90:10, 0.8 mL/min, uv 254 nm): tR = 8.67 min (minor), tR = 9.58 min (major). [α]D23 = +20.4 (c
= 0.65, EtOH).
4. Conclusions
In summary, we haved reported the asymmetric aryl transfer to aldehydes with arylboronic acids as
aryl sources in the presence of the chiral 2,2’-bispyrrolidine-based ligand L6. The corresponding
diarylmethanols could be obtained in high yields with moderate to good enantioselectivities. Further
work on the asymmetric addition mechanism and the broad application of chiral 2,2’-bispyrrolidine-
based ligands in other asymmetric catalytic reactions are now in progress in our laboratory.
Acknowledgements
We gratefully acknowledge the National Natural Science Foundation of China (20832001,
20972065, 21074054) and the National Basic Research Program of China (2007CB925103,
2010CB923303) for their financial support. The Major Scientific and Technological Special Project
(2009ZX09103-081) is also acknowledged.
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Sample Availability: Samples of the compounds are available from the authors.
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