Structural influence of chiral tertiary aminonaphthol ligands on the asymmetric phenyl transfer to aromatic aldehydes

Article abstract of DOI:10.1002/chir.20903

A series of chiral tertiary aminonaphthol ligands were prepared from 2-naphthol, (S)-1-phenylethylamine, and aldehydes with diverse substituted groups. The results of asymmetric phenyl transfer to aromatic aldehydes catalyzed by these chiral ligands indicated that enantioselectivities were greatly influenced by the electronic and steric effects of the ligands. Copyright

Full text of DOI:10.1002/chir.20903

CHIRALITY 23:222–227 (2011)
Structural Influence of Chiral Tertiary Aminonaphthol Ligands on
the Asymmetric Phenyl Transfer to Aromatic Aldehydes
1
1
1,3
HUI WEI,1 LU YIN,1,2 HAIBIN LUO, XINGSHU LI, AND ALBERT S. C. CHAN
*
1School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
2School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China
3Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
ABSTRACT
A series of chiral tertiary aminonaphthol ligands were prepared from 2-naph-
thol, (S)-1-phenylethylamine, and aldehydes with diverse substituted groups. The results of
asymmetric phenyl transfer to aromatic aldehydes catalyzed by these chiral ligands indicated
that enantioselectivities were greatly influenced by the electronic and steric effects of the
C
VV
ligands. Chirality 23:222–227, 2011.
2010 Wiley-Liss, Inc.
KEY WORDS: aminonaphthol; asymmetric phenyl transfer; electronic and steric effects
INTRODUCTION
EXPERIMENTAL
General Methods
The asymmetric phenyl transfer to aromatic aldehydes or
their derivatives has attracted much attention in recent years
because the chiral diaryl alcohols or amines are key inter-
mediates for biologically active compounds, e.g., (R)-neobe-
nodine, (R)-orphenadrine, and (S)-cetirizine.1–19 Since Fu
and coworkers20 reported the first enantioselective catalytic
addition with diphenylzinc in 1997, many subsequent studies
seeking higher enantioselectivity of the transformation were
put in practice.21–42 Among them, Bolm and Mun˜iz21 made
significant contribution by introducing planar-chiral ferro-
cene-based hydroxy oxazolines, 2-aminocyclohexanol deriva-
tives,28 and b-hydroxysulfoximines30 as catalysts to this
reaction. Pu and coworkers32–34 used a series of binaphthol
derivatives as the catalyst for reaction of aromatic aldehydes
with diphenylzinc, gave the corresponding diaryl methanol
in good yields and high ees. Simultaneously, chiral amino
alcohols were also studied for the reaction by several groups
and good to excellent eanatioselectivities were obtained, Ha
and coworkers35 prepared chiral amino alcohols from (R)-
binaphthol, Wang and coworkers36 developed cyclopropane-
based chiral amino alcohols, Perica`s and coworkers37 made
a structural optimization of a family of amino alcohol ligands
with a common 2-amino-2-aryl-1,1-diphenylethanol skeleton.
On the other hand, some important arylzinc and other phe-
nyl transfer reagents for the asymmetric reaction were also
reported. Kim and Walsh38 developed a versatile method for
the asymmetric arylation of aldehydes beginning with aryl
bromides. Cote and Charette39 used the weak solubility of
magnesium methoxide for development a method to access
both functionalized dialkylzinc and diarylzinc reagents, Zhu
and coworkers40 reported the highly efficient and facile aryl
transfer to aldehydes using ArB(OH)2-Me3Ga systems.
The NMR spectra were recorded with TMS as the internal standard
on a Varian 400 spectrometer. Coupling constants were given in Hz.
Enantiomeric excess was determined by HPLC on a Chiralcel OB-H col-
umn. Optical rotations were determined on a Perkin Elmer 341 polarime-
ter. MS spectra were recorded on a Shimadzu LCMS-IT-TOF. All the
asymmetric phenyl transfer reactions were performed under an argon
atmosphere.
Preparation of 1-[(1S)-Phenyl{methyl[(10S)-
10-phenylethyl]-amino}methyl]-2-naphthol (3a)
A mixture of 2-naphthol (0.29 g, 2.0 mmol), benzaldehyde (0.26 g, 2.4
mmol), and (S)-(2)-1-phenylethylamine (0.26 g, 2.1 mmol) was stirred at
608C under nitrogen atmosphere. After stirring at reflux for 8 h (moni-
tored by TLC), EtOH (5 ml) was added to the reaction mixture at room
temperature. The white crystals were collected, washed with EtOH (3 3
3 ml), and purified by crystallization from EtOAc/hexane to give the
pure compound 1a. Colorless crystals, 93% yield. 1H NMR (400 MHz,
CDCl3) d 1.52 (d, J 5 6.9 Hz, 3H), 2.35 (brs, 1H), 3.92 (q, J 5 6.9 Hz,
1H), 5.47 (s, 1H), 7.15–7.83 (m, 16H), 13.70 (brs, 1H).
To an aminonaphthol 1a (2.0 mmol) solution in THF (3 ml), 35% aque-
ous formaldehyde (0.17 ml, 2.2 mmol) was added, and the mixture was
stirred for 15 h at room temperature. Solvent was removed, and the resi-
due was dried under reduced pressure to afford the crude oil, which was
purified by column chromatography on silica gel to give 2a as white
1
crystals. H NMR (400 MHz, CDCl3) d 1.58 (d, J 5 6.5 Hz, 3H), 4.13 (q,
J 5 6.5 Hz, 1H), 4.46 (dd, J 5 10.6, 2.0 Hz, 1H), 4.68 (d, J 5 10.6, 1H),
5.76 (s, 1H), 7.10–7.80 (m, 16H).
To a solution of naphthoxazine 2a (2.0 mmol) in THF (3.5 ml), NaBH4
(0.15 g, 4.0 mmol) was added at 08C in one pot. The solution was vigo-
rously stirred, and a solution of AcOH (2 ml) in THF (3 ml) was slowly
added. After the addition, the mixture was warmed up to room tempera-
ture until complete consumption of the starting naphthoxazine (moni-
tored by TLC) and then saturated Na2CO3 was added. When the emis-
sion of CO2 ceased, the organic layer was extracted with CH2Cl2, dried
For the advancement of the practical application of this use-
ful reaction, appropriate and affordable chiral ligands and phe-
nyl transfer reagents remain to be a challenge for scientists in
this field. In pursuit of more effective chiral ligands with the
opportunity for large-scale application, Chan and coworkers41
developed a new chiral tertiary aminonaphthol ligand for the
asymmetric catalytic phenyl transfer to aromatic aldehydes.
Herein, we expand the scope of the study and report a series
of new chiral tertiary aminonaphthol ligands and their struc-
tural influence on the phenyl transfer reaction.
Contract grant sponsor: Guangdong Province National Science Foundation of
China; Contract grant numbers: 20972198
*Correspondence to: Xingshu Li, School of Pharmaceutical Sciences, Sun
Yat-Sen University, Guangzhou, 510006, People’s Republic of China.
E-mail: xsli219@yahoo.com
Received for publication 19 February 2010; Accepted 22 June 2010
DOI: 10.1002/chir.20903
Published online 29 September 2010 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2010 Wiley-Liss, Inc.

CHIRAL TERTIARY AMINONAPHTHOL LIGANDS
223
(Na2SO4), filtered, and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel eluted with petro-
leum ether/AcOEt mixture to afford white crystals of 3a. M.p. 157–
1608C, [a]2D0 5 1270.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d
1.55 (d, J 5 6.6 Hz, 3H), 2.14 (s, 3H), 4.25 (brq, J 5 6.6 Hz, 1H), 5.37 (s,
1H), 7.10–8.00 (m, 16H), 14.00 (brs, 1H). 13C NMR (100 MHz, CDCl3) d
19.0, 33.2, 57.4, 68.6, 116.4, 120.2, 121.2, 122.6, 126.7, 127.9, 128.2, 128.4,
128.5, 128.8, 129.0, 129.1, 129.2, 129.3, 129.8, 132.3, 140.3, 156.1.
Similar procedures were used for the preparation of compounds 3b–
3l.
Intermediate 2e: white crystals, yield 92%. 1H NMR (400 MHz,
CDCl3) d 1.54 (d, J 5 6.8 Hz, 3H), 4.10 (q, J 5 6.8 Hz, 1H), 5.012 (d, J 5
11.2, 1H), 5.05 (dd, J 5 11.2, 1.6 Hz, 1H), 5.56 (s, 1H), 6.75–7.33 (m,
13H), 7.72–7.76 (m, 2H).
Ligand 3e: white crystals, 81% yield, m.p. 134.2–134.88C, [a]D20
5
1255.9 (c 1.11, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.59 (d, J 5 6.4
Hz, 3H), 2.21 (s, 3H), 4.27 (q, J 5 6.4 Hz, 1H), 5.98 (s, 1H), 6.86–8.00
(m, 15H), 14.09 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 18.0, 30.3,
54.8, 58.5, 113.9, 114.1, 114.3, 118.9, 118.9, 121.6, 123.9, 125.7, 125.8,
127.0, 127.1, 127.7, 127.8, 128.7, 128.8, 129.2, 131.1, 134.9, 154.5, 157.5,
160.0. HRMS m/z calcd for C26H24FNO (M11)1 386.1920, found:
386.1926.
Preparation of 1-[(1S)-(2-Methylphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3b)
Intermediate 1b: colorless crystals, 83% yield. 1H NMR (400 MHz,
CDCl3) d 1.50 (d, J 5 8.4 Hz, 3H), 1.91 (brs, 3H), 3.86 (q, J 5 8.4 Hz,
1H), 5.58 (s, 1H), 6.96–7.73 (m, 15H), 13.74 (brs, 1H).
Preparation of 1-[(1S)-(3-Furylphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3f)
Intermediate 1f: colorless crystals, 82% yield. 1H NMR (400 MHz,
CDCl3) d 1.52 (d, J 5 6.0 Hz, 3H), 2.28 (brs, 1H), 3.89 (q, J 5 6.0 Hz,
1H), 5.47 (s, 1H), 6.90–7.78 (m, 15H), 13.55 (brs, 1H).
Intermediate 2b: white crystals, 92% yield. 1H NMR (400 MHz,
CDCl3) d 1.59 (d, J 5 6.8 Hz, 3H), 2.03 (s, 3H), 4.07 (q, J 5 6.6 Hz, 1H),
5.00 (dd, J 5 10.8, 1.6 Hz, 1H), 5.07 (d, J 5 10.8 Hz, 1H), 5.43 (s, 1H),
6.75–7.30 (m, 13H), 7.74–7.77 (m, 2H).
Intermediate 2f: white crystals, 90% yield. 1H NMR (400 MHz, CDCl3)
d 1.54 (d, J 5 6.4 Hz, 3H), 3.96 (q, J 5 6.4 Hz, 1H), 4.90 (d, J 5 10.4,
1H), 5.13 (dd, J 5 10.4, 2.0 Hz, 1H), 5.16 (s, 1H), 6.78–7.35 (m, 13H),
7.73–7.74 (m, 2H).
Ligand 3b: white crystals, 86% yield, m.p. 152–1538C, [a]D20
5
1
1406.72 (c 0.922, CHCl3). H NMR (400 MHz, CDCl3) d 1.63 (d, J 5 7.2
Hz, 3H), 1.91 (s, 3H), 2.01 (s, 3H), 4.26 (q, J 5 7.2 Hz, 1H), 5.77 (s, 1H),
7.01–7.74 (m, 15H), 14.47 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 18.8,
19.6, 29.9, 59.7, 61.2, 116.2, 120.3, 120.7, 122.3, 126.5, 127.0, 127.7, 128.2,
128.2, 129.0, 129.4, 129.5, 130.0, 130.5, 132.6, 136.1, 136.3, 137.4, 157.8.
HRMS m/z calcd for C27H27NO (M11)1 382.2153, found: 382.2168.
Ligand 3f: white crystals, 78% yield, m.p. 162.6–163.88C, [a]D20
5
1246.0 (c 1.0.08, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.47 (d, J 5 7.0
Hz, 3H), 2.03 (s, 3H), 4.14 (q, J 5 7.0 Hz, 1H), 5.23 (s, 1H), 6.77–7.72
(m, 15H), 13.72 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 15.6, 31.8,
56.5, 66.7, 113.8, 114.0, 114.6, 114.8, 119.0, 119.7, 121.5, 123.6, 125.6,
126.8, 127.3, 127.8, 128.0, 128.8, 129.2, 130.9, 141.5, 141.6, 154.9, 160.6,
163.1. HRMS m/z calcd for C26H24FNO (M11)1 386.1920, found:
386.1923.
Preparation of 1-[(1S)-(3-Methylphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3c)
Intermediate 1c: colorless crystals; 80% yield. 1H NMR (400 MHz,
CDCl3) d 1.48 (d, J 5 9.2 Hz, 3H), 2.22 (brs, 3H), 3.87 (q, J 5 9.2 Hz,
1H), 5.41 (s, 1H), 6.96–7.72 (m, 15H), 13.72 (brs, 1H).
Preparation of 1-[(1S)-(4-Furylphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3g)
Intermediate 1g: colorless crystals, 83% yield. 1H NMR (400 MHz,
CDCl3) d 1.50 (d, J 5 6.8 Hz, 3H), 2.21 (brs, 1H), 3.87 (q, J 5 6.8 Hz,
1H), 5.43 (s, 1H), 6.88–7.75 (m, 15H), 13.63 (brs, 1H).
Intermediate 2c: white crystals, 93% yield. 1H NMR (400 MHz,
CDCl3) d 1.54 (d, J 5 6.4 Hz, 3H), 2.22 (s, 3H), 3.96 (q, J 5 6.4Hz, 1H),
4.97 (d, J 5 10.4 Hz, 1H), 5.12 (dd, J 5 10.4, 1.6 Hz, 1H), 5.16 (s, 1H),
6.79–7.40 (m, 13H), 7.73–7.77 (m, 2H).
Ligand 3c: white crystals, 79% yield, m.p. 175.7–176.88C, [a]D20
5
1259.5 (c 0.504, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.52 (d, J 5 7.2
Hz, 3H), 2.10 (s, 3H), 2.26 (s, 3H), 4.21 (q, J 5 7.0 Hz, 1H), 5.29 (s, 1H),
6.97–7.84 (m, 15H), 14.01 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 20.5,
21.7, 31.9, 56.4, 67.3, 115.2, 118.9, 120.0, 121.3, 125.1, 125.4, 125.7, 126.4,
126.6, 127.2, 127.5, 127.7, 127.8, 127.9, 128.2, 128.5, 131.1, 137.4, 138.9,
Intermediate 2g: white crystals, 94% yield. 1H NMR (400 MHz,
CDCl3) d 1.54 (d, J 5 6.4 Hz, 3H), 3.96 (q, J 5 6.4 Hz, 1H), 5.13 (dd, J 5
11.2, 1.6 Hz, 1H), 5.15 (d, J 5 11.2 Hz, 1H), 6.76–7.38 (m, 13H), 7.73–
7.77 (m, 2H).
Ligand 3g: white crystals, 80% yield, m.p. 167.1–168.38C, [a]D20
5
154.9. HRMS m/z calcd for
C
27H27NO (M11)1 382.2153, found:
1254.3 (c 0.97, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.50 (d, J 5 7.2
Hz, 3H), 2.08 (s, 3H), 4.33 (q, J 5 7.2 Hz, 1H), 5.31 (s, 1H), 6.91–7.90
(m, 15H), 13.91 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 19.2, 32.9,
57.7, 67.5, 115.7, 116.1, 120.0, 120.7, 122.5, 126.6, 127.8, 128.3, 128.8,
129.1, 129.7, 129.9, 130.6, 131.9, 135.9, 135.9, 155.8, 161.0, 163.5. HRMS
m/z calcd for C26H24FNO (M11)1 386.1920, found: 386.1924.
382.2171.
Preparation of 1-[(1S)-(4-Methylphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3d)
Intermediate 1d: colorless crystals, 50% yield. 1H NMR (400 MHz,
CDCl3) d 1.55 (d, J 5 9.2 Hz, 3H), 2.31 (s, 3H), 2.35 (b, 1H), 3.95 (b, J 5
9.2 Hz, 1H), 5.51 (s, 1H), 7.07–7.80 (m, 15H), 13.86 (b, 1H).
Intermediate 2d: white crystals. 1H NMR (400 MHz, CDCl3) d 1.59
(d, J 5 6.6 Hz, 3H), 2.32 (s, 3H), 4.02 (q, J 5 6.6 Hz, 1H), 5.01 (d, J 5
10.3 Hz, 1H), 5.19 (dd, J 5 10.3, 1.8 Hz, 1H), 5.21 (s, 1H), 6.90–7.50 (m,
13H), 7.80–7.90 (m, 2H).
Ligand (3d): white crystals, m.p. 155–1608C, [a]2D0 5 1238.5 (c 1.08,
CHCl3). 1H NMR (400 MHz, CDCl3) d 1.54 (d, J 5 7.0 Hz, 3H), 2.14 (s,
3H), 2.26 (s, 3H), 4.24 (q, J 5 7.0 Hz, 1H), 5.34 (s, 1H), 7.00–8.00 (m,
15H), 14.10 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 19.0, 21.2, 33.1,
57.2, 68.3, 116.6, 120.1, 121.2, 122.6, 123.0, 126.6, 127.8, 128.5, 128.6,
129.0, 129.2, 129.3, 129.6, 131.4, 132.3, 137.2, 137.8, 156.0.
Preparation of 1-[(1S)-(3,5-Dimethylphenyl){methyl[(10S)-
10-phenylethyl]amino}methyl]-2-naphthol (3h)
Intermediate 1h: colorless crystals, 94% yield. 1H NMR (400 MHz,
CDCl3) d 1.45 (d, J 5 6.8 Hz, 3H), 2.17 (s, 6H), 3.85 (q, J 5 6.8 Hz, 1H),
5.36 (s, 1H), 6.78–7.71 (m, 14H), 13.77 (brs, 1H).
Intermediate 2h: white crystals, 95% yield. 1H NMR (400 MHz, CDCl3) d
1.52 (d, J 5 6.6 Hz, 3H), 2.17 (s, 6H), 3.95 (q, J 5 6.8 Hz, 1H), 5.01 (d, J 5
10.4 Hz, 1H), 5.12 (s, 1H), 5.14 (dd, J 5 10.4, 2.0 Hz, 1H), 6.62–7.40 (m,
13H), 7.73–7.76 (m, 2H).
Ligand 3h: white crystals, 87% yield, m.p. 185.7–198.38C, [a]D20
5
1232.6 (c 1.01, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.50 (d, J 5 6.8
Hz, 3H), 2.10 (s, 3H), 2.21 (s, 6H), 4.21 (q, J 5 6.8 Hz, 1H), 5.23 (s, 1H),
6.78–7.85 (m, 14H), 14.02 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 21.4,
21.7, 57.4, 59.2, 74.4, 112.4, 118.5, 122.8, 123.1, 126.5, 127.0, 127.5, 128.0,
128.5, 128.6, 128.9, 129.0, 129.1, 133.0, 137.5, 143.3, 145.5, 152.8. HRMS
m/z calcd for C28H29NO (M11)1 396.2327, found: 396.2315.
Preparation of 1-[(1S)-(2-Furylphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3e)
Intermediate 1e: colorless crystals, 85% yield. 1H NMR (400 MHz,
CDCl3) d 1.50 (d, J 5 6.8 Hz, 3H), 2.33 (brs, 1H), 3.93 (q, J 5 6.8 Hz,
1H), 5.84 (s, 1H), 6.92–7.78 (m, 15H), 13.55 (brs, 1H).
Chirality DOI 10.1002/chir

224
WEI ET AL.
Fig. 1. The preparation of chiral aminonaphthol ligands.
Preparation of 1-[(1S)-(2-Chlorophenyl){methyl[(10S)-10-
126.4, 127.7, 128.3, 128.7, 128.8, 129.0, 129.6, 129.8, 130.3, 132.1, 141.6,
155.9, 159.8. HRMS m/z calcd for C27H27NO2 (M11)1 398.2120, found:
phenylethyl]amino}methyl]-2-naphthol (3i)
398.2103.
Intermediate 1i: colorless crystals, 82% yield. 1H NMR (400 MHz,
CDCl3) d 1.50 (d, J 5 6.8 Hz, 3H), 2.18 (brs, 1H), 3.98 (q, J 5 6.8 Hz,
1H), 5.93 (s, 1H), 7.05–7.78 (m, 15H), 13.63 (brs, 1H).
Preparation of 1-[(1S)-(4-Methoxyphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3l)
Intermediate 1l: colorless crystals, 82% yield. 1H NMR (400 MHz,
CDCl3) d 1.47 (d, J 5 7.2 Hz, 3H), 2.25 (q, J 5 7.2 Hz, 1H), 3.67 (s, 3H),
3.86 (d, J 5 7.2 Hz, 1H), 5.40 (s, 1H), 6.72–7.72 (m, 15H), 13.75 (brs,
1H).
Intermediate 2i: white crystals, 91% yield. 1H NMR (400 MHz,
CDCl3) d 1.52 (d, J 5 6.8 Hz, 3H), 4.45 (q, J 5 6.8 Hz, 1H), 4.80 (dd, J
5 10.8, 2.0 Hz, 1H), 4.90 (d, J 5 10.8 Hz, 1H), 5.76 (s, 1H), 6.85–7.44
(m, 13H), 7.72–7.76 (m, 2H).
Ligand 3i: white crystals, 83% yield, m.p. 135–136.38C, [a]2D0 5 1407.8
(c 1.06, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.62 (d, J 5 6.8 Hz, 3H),
2.07 (s, 3H), 4.27 (q, J 5 6.8Hz, 1H), 6.07 (s, 1H), 7.06–8.20 (m, 15H),
14.10 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 19.0, 30.5, 59.9, 61.6,
115.8, 120.2, 121.2, 122.6, 126.9, 127.8, 128.2, 128.3, 128.6, 128.8, 128.9,
129.2, 129.5, 129.8, 131.5, 132.6, 134.4, 137.2, 142.3, 155.7, 157.6. HRMS
m/z calcd for C26H24ClNO (M11)1 402.1625, found: 402.1593.
Intermediate 2l: white crystals, 93% yield. 1H NMR (400 MHz, CDCl3)
d 1.54 (d, J 5 6.8 Hz, 3H), 3.72 (s, 3H), 3.96 (q, J 5 6.8 Hz, 1H), 4.95 (d,
J 5 10.0 Hz, 1H), 5.12 (dd, J 5 10.0, 2.0 Hz, 1H), 5.14 (s, 1H), 6.71–7.38
(m, 13H), 7.72–7.76 (m, 2H).
Ligand 3l: white crystals, 83% yield, m.p.178.3–182.58C, [a]D20
5
1215.3 (c 1.06, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.54 (d, J 5 6.0
Hz, 3H), 2.09 (s, 3H), 3.69 (s, 3H), 4.20 (q, J 5 6.0 Hz, 1H), 5.29 (s, 1H),
6.77–7.82 (m, 15H), 14.04 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 18.5,
32.9, 55.0, 57.5, 67.6, 114.1, 116.5, 120.0, 121.0, 122.4, 126.4, 126.6, 127.6,
128.3, 128.8, 129.0, 129.1, 129.9, 130.1, 132.0, 132.1, 155.7, 159.1. HRMS
m/z calcd for C27H27NO2 (M11)1 398.2120, found: 398.2100.
Preparation of 1-[(1S)-(4-Chlorophenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3j)
Intermediate 1j: colorless crystals, 85% yield. 1H NMR (400 MHz,
CDCl3) d 1.48 (d, J 5 6.8 Hz, 3H), 2.13 (brs, 1H), 3.95 (q, J 5 6.8 Hz,
1H), 5.47 (s, 1H), 7.08–7.73 (m, 15H), 13.58 (brs, 1H).
Typical Procedure for the Phenyl Transfer Reaction
Intermediate 2j: white crystals, 90% yield. 1H NMR (400 MHz, CDCl3)
d 1.53 (d, J 5 6.4Hz, 3H), 3.95 (q, J 5 6.4 Hz, 1H), 4.85 (d, J 5 10.8 Hz,
1H), 5.11 (dd, J 5 10.8, 1.8 Hz, 1H), 5.14 (s, 1H), 6.94–7.35 (m, 13H),
7.71–7.74 (m, 2H).
A solution of phenyl boronic acid (122 mg, 1.0 mmol) and diethylzinc
(3.0 mmol, 1M in hexane) in toluene was added to a dry flask under an
argon atmosphere at 08C, then with constant stirring at 608C for 12 h to
prepare a transfer reagent. After cooling to 2108C, ligand (16 mmol %)
and DiMPEG (10 mol %) were added. The resulting mixture was stirred
for 0.5 h at 2108C, then p-chlorobenzaldehyde (70 mg, 0.5 mmol) in tolu-
ene was subsequently added dropwise via a syringe. After being stirred
for 15 h at 2108C, the reaction was quenched with 1M HCl, extracted
with ethyl acetate, and concentrated in vacuo. The extracts were applied
directly onto a silica gel column (1:20 ethylacetate/petroleumether as
eluent) to give the desired diarylmethanol. The enantiomeric excess was
determined by chiral HPLC, using a Chiralcel OB-H column with 10%
isopropanol in hexane as eluent.
Ligand 3j: white crystals, 82% yield, m.p. 198–199.48C, [a]D20
5
1219.9 (c 1.06, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.53 (d, J 5 7.0
Hz, 3H), 2.09 (s, 3H), 4.21 (q, J 5 7.0 Hz, 1H), 5.29 (s, 1H), 7.16–7.74
(m, 15H), 13.87 (brs, 1H). 13C NMR (100 MHz, CDCl3) d 21.0, 32.9,
57.1, 67.5, 115.8, 120.0, 120.7, 122.6, 124.4, 126.6, 127.8, 128.3, 128.8,
129.0, 129.1, 129.8, 130.3, 131.9, 133.7, 137.0, 138.7, 155.8. HRMS m/z
calcd for C26H24ClNO (M11)1 402.1625, found: 402.1595.
Preparation of 1-[(1S)-(3-Methoxyphenyl){methyl[(10S)-10-
phenylethyl]amino}methyl]-2-naphthol (3k)
Intermediate 1k: colorless crystals, 84% yield. 1H NMR (400 MHz,
CDCl3) d 1.47 (d, 3H), 2.28 (brs, J 5 6.8 Hz, 1H), 3.65 (d, 3H), 3.87 (q, J
5 6.8 Hz, 1H), 5.41 (d, 1H), 6.69–7.72 (m, 15H), 13.68 (brs, 1H).
Intermediate 2k: white crystals, 92% yield. 1H NMR (400 MHz,
CDCl3) d 1.54 (d, J 5 6.8 Hz, 3H), 3.69 (s, 3H), 3.96 (q, J 5 6.8 Hz, 1H),
4.96 (d, J 5 11.2 Hz, 1H), 5.13 (dd, J 5 11.2, 1.6 Hz, 1H), 5.16 (s, 1H),
6.56–7.41 (m, 13H), 7.72–7.76 (m, 2H).
RESULTS AND DISCUSSION
The aminonaphthol ligands were first used in the asym-
metric addition of dialkylzincs to aldehydes by Palmieri
et al.42,43 They found that a catalytic amount of enantiopure
aminophenol or aminonaphthol considerably accelerated the
addition of dialkylzincs to aldehydes, affording the corre-
sponding alcohols in good enantioselectivity. Wang and co-
workers44 reported the effective enantioselective ethylation
of aryl aldehydes at room temperature by a chiral amino-
naphthol, which was obtained by condensation of 2-naphthol,
Ligand 3k: white crystals, 81% yield, m.p. 147.3–148.68C, [a]D20
5
1239.8 (c 0.226, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.51 (d, J 5 5.6
Hz, 3H), 2.11 (s, 3H), 3.709 (s, 3H), 4.22 (q, J 5 5.6 Hz, 1H), 5.30 (s,
1H), 6.69–7.85 (m, 15H), 13.95 (brs, 1H). 13C NMR (100 MHz, CDCl3) d
19.9, 32.9, 55.1, 57.2, 68.4, 112.9, 114.9, 116.1, 119.9, 121.0, 121.3, 122.4,
Chirality DOI 10.1002/chir

CHIRAL TERTIARY AMINONAPHTHOL LIGANDS
225
Fig. 2. The asymmetric phenyl transfer reaction using various chiral aminonaphthol ligands.
benzaldehyde, and (S)-methylbenzylamine followed by N-
TABLE 1. The asymmetric phenyl transfer to other aromatic
aldehydes
methylation. Expanding on our study of the asymmetric phe-
nyl transfer to aromatic aldehydes catalyzed with tertiary
aminonaphthol,41 we synthesized a number of aminonaph-
thol ligands from 2-naphthol, (S)-1-phenylethylamine and a
variety of aldehydes to investigate the structural influence of
the aminonaphthol ligands on the enantioselectivity of the
phenyl transfer reaction. Initially, the reaction of 2-naphthol
with (S)-1-phenylethylamine and aromatic aldehydes gave 1-
aminoalkylation compound 1 in high yields and diastereo-
meric ratio under mild conditions,42,43 The reaction of com-
pound 1 with formaldehyde in THF gave intermediates 2,
which were reduced with sodium boronhydride to afford the
target products in moderate to good yields (Fig. 1).
To study the relationship between enantioselectivities and
ligand structures for the asymmetric phenyl transfer reac-
tions, we chose 3a as a model ligand and used the optimal
conditions previously established (i.e., carrying out the reac-
tion at 2108C in toluene in the presence of 16 mol % of ligand,
6.0 equiv. of Et2Zn, 2.0 equiv. of PhB(OH)2 and 10 mol % of
DiMPEG for 15 h41). In the presence of 3a and a polyether
(DiMPEG), the reaction of p-chlorobenzaldehyde with phe-
nyl transfer reagent (prepared by mixing PhB(OH)2 and 6.0
equiv. of ZnEt2 afforded the (4-chlorophenyl)(phenyl)metha-
Entry
R
Yield (%)a,b
ee (%)c,d
1
2
3
4
5
6
7
8
o-Me-phenyl
m-Me-phenyl
p-Me-phenyl
o-Cl-phenyl
o-F-phenyl
63
67
52
46
45
43
55
65
76
58
34
95
93
80
94
95
92
70
97
87
73
62
p-F-phenyl
p-MeO-phenyl
1-Naphthyl
2-Furyl
9
10
11
t-Bu
n-Bu
aAll reactions were performed on a 0.5 mmol scale using 16 mol % of 3b, 6
equiv. of Et2Zn, 2.0 equiv. of PhB(OH)2, 10 mol % of DiMPEG in toluene
(first at 608C for 12 h, then at 2158C for 15 h).
bIsolated yield.
cDetermined by HPLC analysis.
dThe absolute configuration was determined by comparison of the HPLC elu-
tion order with the literature data.1
Chirality DOI 10.1002/chir

226
WEI ET AL.
seemed to decrease the energy difference between the R-
transition state and the S-transition state, which resulted in
lower enantioselectivities. On the other hand, the ortho-
groups led to an increase in energy difference between two
transition states.
CONCLUSION
In conclusion, we have synthesized a series of new amino-
naphthol ligands from 2-naphthol, (S)-1-phenylethylamine,
and various aromatic aldehydes. Results of asymmetric phe-
nyl transfer reactions with these chiral aminonaphthol
ligands showed that the enantioselectivities were greatly
influenced by the structures of the aminonaphthol ligands
with a marked ortho-effect of the ligands.
Fig. 3. The proposal transition states of asymmetric phenyl transfer to
aldehydes.
nol in 89% yield with 90% ee (Fig. 2). Ligand 3b, which was
derived from 2-naphthol, o-methylbenzaldehyde, and (S)-1-
phenylethylamine, gave better enantioselectivity (91% yield
with 94% ee). On the other hand, ligands 3c and 3d, derived
from m-methylbenzaldehyde and p-methylbenzaldehyde,
afforded lower enantioselectivities (78% yield with 70% ee for
3c and 86% yield with 67% ee for 3d, respectively) under the
same reaction conditions. These results implied that either
the steric effect of the ligands played an important role for
the reaction, or rather the ortho- electron-donating substituents
on the aldehyde moiety of the ligands promoted high enantio-
selectivities. In contrast, strong electron-drawing groups were
unfavorable to the ees. Chiral ligands 3e, 3f, and 3g, with a flu-
oro atom on ortho-, meta-, and para-position of the aldehyde
part of the ligand, gave 69%, 79%, and 81% ee, respectively. It
was also observed that ligand 3h, which was derived from 3,5-
dimethylbenzaldehyde, gave only 39% ee under the same con-
ditions. The ortho effect was also supported by the results of
ligands 3i and 3j. With o-Cl on the aldehyde moiety of the
ligand, 3i gave 69% yield with 93% ee, while 3j, which pos-
sessed p-Cl on the aldehyde moiety, afforded 88% ee. The enan-
tioselectivities of ligands with meta- or para-substituents were
quite similar. Chiral ligands 3k and 3l, with a methoxy group
on the meta- or para-position, afforded 87% and 89% ee, respec-
tively. Similar enantioselectivities were also found for ligands
3c vs 3d (70% and 67% ee) and 3f vs 3g (79% and 81% ee).
The asymmetric phenyl transfer to other aldehydes cata-
lyzed by ligand 3b was investigated in Table 1. The results
indicated that enantioselectivity was also influenced by the
steric effect of the substrates. o-Methylbenzaldehyde and m-
methylbenzaldehyde gave 95% and 93% ee, respectively, but p-
methylbenzaldehyde provided only 83% ee under the same
reaction conditions (Table 1, entry 1–3). When p-methoxyben-
zaldehyde was used as the substrate, only 70% ee was
obtained. On the other hand, a small substituted group on the
ortho- or para-position of the aldehydes seemed to have little
effect on the enantioselectivity (Table 1, entry 5 and 6), which
was consistent with our expectation. On the other hand, ali-
phatic aldehydes were also tested with 3b as the chiral ligand.
Unlike aromatic aldehydes which provided good results, ali-
phatic aldehydes only gave moderated chemical yields and
ees at the same reaction conditions (Table 1, entry 10 and 11).
In contrast to the enantioselective addition of dialkyl com-
pounds to aldehydes of which the mechanism has been con-
siderably studied, relatively less is known about the reaction
of phenylation of aldehydes. According to reported mecha-
nism45–49 of the Ph2Zn addition to aldehydes in the presence
of a mixed Ph2Zn/Et2Zn species and amino alcohols, the pro-
posed transition state of the reaction with aminonaphthol as
the ligand is shown in Figure 3. The substituted groups on
meta- and para-position of the aldehyde moiety of the ligands
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