Asymmetric Addition of Pyridyl Aluminum Reagents to Aldehydes Catalyzed by a Titanium(IV) Catalytic System of (R)-H8-BINOLate

Article abstract of DOI:10.1021/acs.joc.5b01410

The asymmetric addition of pyridyl aluminum reagents to aldehydes has been successfully developed by employing a titanium(IV) catalytic system of (R)-H₈-BINOLate, which affords a series of valuable optically active diarylmethanols containing various pyridyl groups in high yields with excellent enantioselectivities of up to 98% ee.

Full text of DOI:10.1021/acs.joc.5b01410

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The Journal of Organic Chemistry
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Asymmetric Addition of Pyridyl Aluminum Reagents to Aldehydes
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Catalyzed by a Titanium(IV) Catalytic System of (R)-H8-BINOLate
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Lijun Zhang,* Bing Tu, Min Ge, Yimei Li, Liangyu Chen, Wei Wang, and Shuangliu Zhou*
Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-
Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui
241000 China.
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E-mail: zljun@ahnu.edu.cn; slzhou@ahnu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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10 mol% (R)-H8-BINOL
3.0 equiv Ti(OiPr)4
OH
AlEt2(OEt2)
O
+
R'
R
R'
R
H
toluene, 0 oC, 12h
N
N
8
9
2.5 equiv
R = Ar, HeteroAr, Alkenyl, Alkyl
R' = H, CH3, OMe or Cl
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33 examples
up to 98% ee
Abstract: The asymmetric addition of pyridyl aluminum reagents to aldehydes has been successfully
developed by employing a titanium(IV) catalytic system of (R)-H8-BINOLate, which affords a series of
valuable optically active diarylmethanols containing various pyridyl groups in high yields with excellent
enantioselectivities of up to 98% ee.
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Introduction
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The catalytic asymmetric synthesis of chiral aryl alcohols has attracted extensive attention in the
past decade because they are very important precursors to many biologically active compounds.1 The
enantioselective addition of carbon-based nucleophiles to organic carbonyl compounds provides a
straightforward strategy for the construction of optically active alcohols.2 Arylboronic acids,3 arylzinc,4
arylaluminum,5 and aryltitanium reagents6 have demonstrated to be the excellent nucleophiles for the
asymmetric addition to carbonyl compounds. Additionally, aryl Grignard reagents7 and arylithiums8
after mixing with Ti(OiPr)4 have been used as aryl sources for the asymmetric addition to organic
carbonyl compounds, providing an alternative method for synthesizing diarylmethanols in high
enantioselectivity.
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Chiral diaryl alcohols bearing heteroaryl such as furyl, thienyl, pyridyl or indolyl groups are well-
known for their biological activity as well as key substructure in bioactive compounds and
pharmaceuticals.9 Usually, their syntheses were sporadically reported in a few papers via addition of
aryl nucleophiles to heteroaryl-substituted carbonyl compounds or reduction of diaryl ketones bearing
heteroaryl groups. The catalytic enantioselective addition of heteroaryl nucleophiles to organic carbonyl
compounds provided a systematical approach to synthesize chiral heteroaryl alcohols. Recently, the
optically active thienyl alcohols have been realized through the asymmetric additions of thienylboronic
acid10 or thienylaluminum reagents11 to organic carbonyl compounds in good yields and high
enantioselectivities. The optically active furyl alcohols were also reported through the asymmetric
addition of furylaluminum reagent12 or furyltitanium reagent13 to ketones in the presence of 10 mol%
(S)-BINOL. More recently, heteroaryl zinc14 and titanium reagents15 bearing thienyl, benzothienyl, furyl
and indolyl groups were also applied to asymmetric addition of aldehydes affording aryl heteroaryl- or
diheteroaryl methanol derivatives in high enantioselectivity. However, the more attractive asymmetric
addition of pyridyl nucleophiles to organic carbonyl compounds has not been reported up to now.
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Herein, we report the catalytic asymmetric addition of pyridyl aluminum reagents to aldehydes
catalyzed by a titanium(IV) catalyst of (R)-H8-BINOLate to provide a systematical synthesis of the
chiral diarylmethanols bearing various pyridyl groups.
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Results and Discussion
The pyridyl aluminum reagents were prepared through the reaction of AlEt2Cl with the
corresponding pyridyl lithium in situ produced from the halo-lithium exchange of pyridyl bromide with
nBuLi using the similar procedures with the previously reported.16 The resulting solution was filtered,
followed by an evaporation of the solvent under reduced pressures to afford the corresponding pyridyl
aluminum reagent (pyridyl)AlEt2(OEt2) in a quantative yield which was directly used in the next
asymmetric addition reactions. Asymmetric addition reactions of (3-pyridyl)AlEt2(OEt2) to 4-
methylbenzaldehyde (1b) were first screened using (S)-BINOL as chiral ligand, and the results are
summarized in Table 1. Different from addition reactions of AlPhEt2(THF) to aldehydes,5c the addition
of (3-pyridyl)AlEt2(OEt2) afforded the pyridyl addition product 7a exclusively, indicating that the
addition of pyridyl aluminum to aldehyde dominated in our current reaction system. The optimal
reaction conditions of 3.0 equiv. of Ti(OiPr)4 and 2.5 equiv. of (3-pyridyl)AlEt2(OEt2) in the presence of
10 mol% (S)-BINOL in toluene at 0°C were found to afford the corresponding product 3ba in 88% yield
with 81% ee (entry 2). Next, the different chiral ligands were tested for asymmetric addition reactions
(entries 8-11). Results showed that the modified (S)-BINOL derivatives afforded the addition product in
low enantioselectivity, and (R)-H8-BINOL was the most efficient one to afford 3ba in 91% yield with
excellent enantioselectivity of 90% ee (entry 11), which was consistent with the previous reported result
of asymmetric addition of aldehydes probably due to the smaller dihedral angle of H8-BINOL than
BINOL.17 Further optimization of the asymmetric addition of (3-pyridyl)AlEt2(OEt2) to 4-
methylbenzaldehyde employing (R)-H8-BINOL as chiral ligand (entries 11-21) showed that this reaction
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employing 3.0 equiv. of Ti(OiPr)4 and 2.5 equiv. of (3-pyridyl)AlEt2(OEt2) in toluene was still the best
one (entry 11). Lowered the temperature to -10 °C, the enantioselectivity of the asymmetric addition
product 3ba did not be improved (entry 21).
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Table 1. Optimization of Enantioselective 3-Pyridyl Addition to 4-Methylbenzaldehyde.a
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CF3
iPr
iPr
SiPh3
CF3
CF3
OH
O
Ligand (10 mol%)
Ti(OiPr)4
iPr
iPr
AlEt2(OEt2)
OH
OH
OH
OH
OH
OH
H
+
Solvent
N
N
1b
2a
3ba
SiPh3
iPr
iPr
C
B
A
CF3
Ti(OiPr)4
(equiv)b
2.5
temp
2a
entry
ligand
solvent
yield (%)
ee (%)c
(equiv) b
2.5
(°C)
0
1
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
A
toluene
toluene
toluene
toluene
THF
82
88
92
65
86
89
85
81
86
83
91
83
75
88
85
88
70
2
3.0
2.5
0
81
3
3.5
2.5
0
79
4
3.0
2.0
0
73
5
3.0
2.5
0
75
6
3.0
2.5
Et2O
0
66
7
3.0
2.5
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0
64
8
3.0
2.5
0
7 (-)
10
9
3.0
2.5
0
B
10
11
12
13
14
15
16
3.0
2.5
0
Rac
90 (-)
88 (-)
87 (-)
83 (-)
90 (-)
87 (-)
C
(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
3.0
2.5
0
3.0
2.0
0
3.0
1.5
0
3.5
2.5
0
2.5
2.5
0
3.0
2.5
0
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(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
3.0
3.0
3.0
3.0
3.0
2.5
2.5
2.5
2.5
2.5
n-hexane
Et2O
0
31
85
82
95
65
65 (-)
88 (-)
90 (-)
65 (-)
88 (-)
0
CH2Cl2
toluene
toluene
0
r.t
-10
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a4-methylbenzaldehyde (1.00 mmol), solvent (5.0 mL), time: 12 h. bEquivalents of Ti(OiPr)4 and 2a are
relative to 4-methylbenzaldehyde. cEnantioselectivities were determined by HPLC.
With the optimized conditions established, the asymmetric addition of 3-pyridyl aluminums to
various aromatic, heteroaromatic, α,β-unsaturated and aliphatic aldehydes were examined, and the
results were presented in Table 2. It was found that the substituent’s position of aromatic aldehydes had
an effect on the enantioselectivity of 3-pyridyl addition products (entries 1-16). For aromatic aldehydes
with either an electron-withdrawing or an electron-donating substituent at the para- or meta-position, 3-
pyridyl additions afforded the corresponding alcohols in high yields with excellent enantioselectivities
of 90% ee or greater, except for substrates of 3-chlorobenzaldehyde, 4-trifluoromethylbenzaldehyde and
4-fluorobenzaldehyde, which afforded the corresponding products 3ia (85% ee, entry 9), 3oa (82% ee,
entry 15) and 3pa (70% ee, entry 16), respectively. However, for aromatic aldehydes with either an
electron-withdrawing or an electron-donating substituent at the ortho-position, 3-pyridyl additions
afforded the corresponding products in low enantioselectivities (entries 6, 10 and 12), except for 2-
methylbenzaldehyde (90% ee, entry 3). Especially, for 2-nitrobenzaldehyde, the product 3na was
obtained in low enantioselectivity of 33% ee (entry 12). For ortho-substituted aromatic aldehydes, the
low enantioselectivities were obtained, probably because the chelate effect of the ortho-substitutent of
aromatic aldehydes made its coordination to the metal center small differentiation in terms of both Re-
face and Si-face reducing the enantioselectivity. The effect of chelate coordination was also found for
heteroaromatic aldehydes such as thiophene-2-carbaldehyde and furan-2-carbaldehyde, the diheteroaryl
methanols 3qa and 3ra were obtained in good yields with moderate enantioselectivities (entries 17 and
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18). For α,β-unsaturated aldehydes, the asymmetric addition afforded the corresponding 3-pyridyl
methanols 3sa-3ua in moderate to good enantioselectivities of 66-81% ee (entries 19-22). The aliphatic
aldehydes including the linear, branched, cyclic aldehydes were also examined, and the reactions
afforded the corresponding products 3va-3ya in high yields but with low to moderate
enantioselectivities of 48-75% ee (entries 19-22). To determine the absolute configuration of the 3-
pyridyl addition products, the 3-pyridyl methanol 3ka containing a heavy bromine atom was
characterized by an X-ray diffraction study, and the crystal data confirmed an S-configuration for 3ka
(see supporting information for details).
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Table 2. Enantioselective Addition of 3-Pyridyl Aluminum Reagent to Aldehydes Catalyzed by the
Titanium Catalyst of (R)-H8-BINOLate.a
(R)-H8-BINOL (10 mol%)
3.0 equiv. of Ti(OiPr)4
OH
O
AlEt2(OEt2)
R
+
R
H
toluene, 0 oC, 12 h
N
N
1
3
2a (2.5 equiv)
yield ee
entry RCHO
product
(%) (%)b
1
C6H5CHO (1a)
93
91
86
86
93
83
95
92
95
93
93
88
89
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
2
4-CH3C6H4CHO (1b)
2-CH3C6H4CHO (1c)
4-tBuC6H4CHO (1d)
4-(MeO)C6H4CHO (1e)
2-(MeO)C6H4CHO (1f)
3,4,5-(MeO)3C6H2CHO (1g)
4-ClC6H4CHO (1h)
3-ClC6H4CHO (1i)
90
3
90
4
97
5
90
6
57
7
96
8
90
9
85
10
11
12
2-ClC6H4CHO (1j)
66
3ja
3ka
3la
4-BrC6H4CHO (1k)
2-BrC6H4CHO (1l)
93 (S)c
66
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25d
4-(O2N)C6H4CHO (1m)
2-(O2N)C6H4CHO (1n)
4-(F3C)C6H4CHO (1o)
4-FC6H4CHO (1p)
2-thienylaldehyde (1q)
2-furylaldehyde (1r)
(E)-PhCH=CHCHO (1s)
(E)-2-(MeO)PhCH=CHCHO (1t)
(CH3)2C=CHCHO (1u)
nPrCHO (1v)
90
82
88
93
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93
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87
85
95
92
93
98
33
82
70
62
59
66
67
81
48
49
75
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3ma
3na
3oa
3pa
3qa
3ra
3sa
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3ta
3ua
3va
3wa
3xa
3ya
tBuCHO (1w)
iPrCHO (1x)
CyCHO (1y)
a (R)-H8-BINOL (0.10 mmol), Ti(OiPr)4 (3.00 mmol), 2a (2.50 mmol), aldehyde (1.00 mmol), toluene
(5.0 mL). Enantioselectivities were determined by HPLC. Absolute configuration was determined by
an X-ray diffraction, and other absolute configurations were assigned on the analogy of 3ka based on
the model A in Figure 1. d Cy: cyclohexyl group.
b
c
To expand the substrate scope of this protocol, various substituted pyridyl aluminum reagents
were applied to the asymmetric addition of benzaldehyde (Table 3). For substituted 3-pyridyl aluminum
reagents with an electron-donating group, the reactions provided the corresponding 3-pyridyl methanols
3ab-3ae in good yields with moderate to good enantioselectivities of 42-85% ee. Reactions of
benzaldehyde with substituted 3-pyridyl aluminum reagents bearing a weak electron-withdrawing group
(Cl) afforded the corresponding products 3af and 3ag in moderated yields with the low
enantioselectivities. However, for 2-pyridyl or 3-pyridyl aluminum reagents bearing a strong electron-
withdrawing group such as cyano and nitro groups, the reaction efficiency was poor probably due to the
weak nucleophilicity. The catalytic system could also be suitable for 4-pyridyl aluminums to afford the
corresponding products 3ak and 3al in moderate yields with high enantioselectivities of 83% and 91%
ee, respectively.
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Table 3. Enantioselective Addition of Various Pyridyl Aluminum Reagents to Benzaldehyde.a,b
4
5
6
7
8
AlEt2(OEt2)
O
OH
10 mol% (R)-H8-BINOL
3.0 equiv Ti(OiPr)4
R'
H
+
R'
toluene, 0 oC, 12 h
N
N
2b-2n
2.5 equiv
1a
OH
3ab-3an
9
OH
OH
OH
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11
12
13
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OMe
N
OMe
N
N
N
3ae
90% yield; 42% ee
3ad
92% yield; 65% ee
3ac
85% yield; 85% ee
3ab
82% yield; 68% ee
OH
OH
OH
OH
Cl
3af
N
N
CN
N
NO2
N
Cl
3ag
3ai
trace
3ah
trace
76% yield; 30% ee 83% yield; 45% ee
OH
OH
OH
N
N
N
3ak
3al
3aj
trace
76% yield; 83% ee 85% yield; 91% ee
a (R)-H8-BINOL (0.10 mmol), Ti(OiPr)4 (3.00 mmol), pyridyl aluminum (2.50 mmol), aldehyde (1.00
mmol), toluene (5.0 mL). b Enantioselectivities were determined by HPLC.
In order to obtain the mechanistic insight, (3-pyridyl)AlEt2(OEt2) additions to 1a in the presence of
20, 40, 60, 80, or 100% ee of (R)-H8-BINOL were examined, which afforded 3aa in 24.4, 40.9, 41.1,
59.9, and 88.6% ee, respectively. A non linear effect of ee of 3aa vs. ee of (R)-H8-BINOL (Figure 1)
that was different from the asymmetric aryl addition system catalyzed by a titanium(IV) catalytic system
of (R)-H8-BINOLate,6b indicating that the more complex dimeric or polymeric titanium complex was
probably playing the role in the asymmetric addition of pyridyl nucleophiles to aldehydes, rather than
the dinuclear titanium complex [(R)-H8-BINOLate)Ti(OiPr)2]Ti(OiPr)4 involves only one H8-
BINOL.5a,18 Results showed that it was necessary to further explore the asymmetric addition of
heteroaryl nucleophiles to organic carbonyl compounds.
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Figure 1. Non Linear plot of ee of 3aa vs. ee of (R)-H8-BINOL.
Conclusion
In summary, the catalytic enantioselective heteroarylation of pyridyl aluminum nucleophiles
with aldehydes has been successfully developed employing the simple titanium catalyst of (R)-H8-
BINOLate to afford a series of chiral arylmethanols containing various pyridyl groups in high yields
with excellent enantioselectivities. The asymmetric addition of 3-pyridyl aluminum reagent to aromatic
aldehydes afforded the corresponding diarylmethanols containing 3-pyridyl group in high yields with
excellent enantioselectivities of up to 98% ee. The catalytic system could also be applied to substituted
3-pyridyl or 4-pyridyl aluminums bearing an electron-donating group to afford the corresponding
diarylmethanols containing substituted 3-pyridyl or 4-pyridyl groups in good yields with high
enantioselectivities of up to 91% ee. Results represent the first asymmetric addition of pyridyl
nucleophiles to organic carbonyl compounds. Further investigations of heteroaryl aluminum reagents in
asymmetric catalysis are currently underway.
Experimental Section
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General methods. All syntheses and manipulations of air- and moisture-sensitive materials were
performed under a dry argon atmosphere using standard Schlenk techniques or in a glovebox. Solvents
were refluxed and distilled over sodium/benzophenone under argon prior to use. (Pyridyl)AlEt2(OEt2)
was prepared according to previously reported procedures.16 The racemic alcohols bearing pyridyl
groups were prepared by the similar procedures for the preparation of the chiral alcohols employing
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BINOL instead of (R)-H8-BINOL. H and C NMR spectra in CDCl3 were recorded at 300 MHz/75
MHz (1H NMR/13C NMR) or 500 MHz/125 MHz (1H NMR/13C NMR) NMR spectrometer with
chemical shifts given in ppm from the internal TMS. High resolution mass spectral (HRMS) data were
obtained with an ionization mode of ESI and a TOF analyzer. Enantiomeric excesses were determined
by chiral HPLC with different chiral columns (AD-H column, OD-H column, AS-H column, and OJ-H
column) with n-hexane and iPrOH as solvents.
General Procedure for the Asymmetric Addition of Pyridyl Aluminum to Aldehydes. Under a
dry nitrogen atmosphere, (R)-H8-BINOL (0.0286 g, 0.10 mmol) and Ti(OiPr)4 (0.88 mL, 3.00 mmol)
were mixed in toluene (5 mL) at room temperature. After stirring for 30 min, (pyridyl)AlEt2(OEt2) (2.50
mmol) was added to the resulting solution at 0 °C. The mixture was stirred for another 10 min, and an
aldehyde (1.00 mmol) was added to the resulting solution at 0 °C. The mixture was allowed to react for
12 h at this temperature, and then quenched with H2O. The aqueous phase was extracted with ethyl
acetate (3 × 10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column
chromatography (silica gel), eluting with petroleum ether and ethyl acetate to give the product 3.
Enantiomeric excesses of products were determined by HPLC using suitable chiral columns from Daicel.
Phenyl(pyridin-3-yl)methanol (3aa).19 White solid. Yield (172 mg, 93%); ee = 89%; [α]25D = -3.64
(c 0.86, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-hexane/i-PrOH = 90:10,
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flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 16.61 min; tR(minor) = 19.98 min. H NMR (300
MHz, CDCl3) δ = 8.40 (s, 1 H), 8.26-8.24 (m, 1H), 7.68-7.66 (m, 1H),7.32-7.25 (m, 4H), 7.19-7.15 (m,
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1H), 5.78 (s, 1H), 4.84 (s, br, 1H) ppm. C{1H} NMR (75.0 MHz, CDCl3): δ = 147.9, 147.7, 143.3,
139.9, 134.5, 128.6, 127.7, 126.5, 123.5, 73.6 ppm.
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Pyridin-3-yl(p-tolyl)methanol (3ba).20 White solid. Yield (181 mg, 91%); ee = 90%; [α]25
=
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+13.33 (c 0.69, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column, n-hexane/i-PrOH =
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90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(minor) = 16.50 min; tR(major) = 17.47 min. H NMR
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(300 MHz, CDCl3): δ = 8.57-8.54 (s, 1H), 8.46-8.40 (m, 1H), 7.71-7.68 (s, 1H), 7.27-7.21 (m, 3H),
7.17-7.14 (m, 2H), 5.83 (d, J = 2.4 Hz, 1H), 2.34 (s, 3H) ppm. 13C{1H} NMR (125.0 MHz, CDCl3): δ =
148.2, 147.9, 140.3, 139.8, 137.6, 134.2, 129.3, 126.5, 123.4, 73.7, 20.9 ppm.
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Pyridin-3-yl(o-tolyl)methanol (3ca). White solid. M.p. 94-95 °C. Yield (171 mg, 86%). ee = 90%;
[α]25 = +24.46 (c 0.13, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column, n-
D
hexane/i-PrOH = 95:5, flow rate = 0.8 mL/min, λ = 254 nm). tR(minor) = 24.21 min; tR(major) = 25.42
min. 1H NMR (300 MHz, CDCl3): δ = 8.58 (s, 1H), 8.51-8.48 (m, 1H), 7.65-7.62 (s, 1H), 7.27-7.15 (m,
4H), 6.06 (s, 1H), 2.50 (s, 1H), 5.81 (s, 1 H), 2.27 (s, 3 H) ppm. 13C{1H} NMR (75.0 MHz, CDCl3): δ =
148.4, 148.1, 140.8, 138.8, 135.1, 134.9, 130.7, 127.8, 126.4, 126.3, 123.4, 70.8, 19.3 ppm. HRMS
(ESI) calcd for C13H14ON (M+H)+ 200.1070, found 200.1064.
(4-tert-Butylphenyl)(pyridin-3-yl)methanol (3da). White solid. M.p. 121-122 °C. Yield (207 mg,
86%). ee = 97%; [α]25D = -22.35 (c 0.51, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H
column, n-hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 9.21 min; tR(minor)
= 10.95 min. 1H NMR (300 MHz, CDCl3): δ = 8.57 (s, 1H), 8.43-8.41 (m, 1H), 7.74-7.71 (m, 1H), 7.39-
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7.36 (m, 2H), 7.29-7.32 (m, 2H), 5.84 (s, 1H), 3.20 (s, 1H), 1.30 (s, 9H) ppm. C{1H} NMR (125.0
MHz, CDCl3): δ = 150.9, 148.3, 148.1, 140.2, 139.6, 134.2, 126.3, 125.6, 123.4, 73.8, 34.5, 31.3 ppm.
HRMS (ESI) calcd for C16H20ON (M+H)+ 242.1539, found 242.1533.
(4-Methoxyphenyl)(pyridin-3-yl)methanol (3ea).20 White solid. Yield (200 mg, 93%). ee = 90%;
[α]25 = +10.25 (c 1.30, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column, n-
D
hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 37.20 min; tR(minor) = 45.12
min. 1H NMR (300 MHz, CDCl3): δ = 8.59 (s, 1 H), 8.48-8.46 (m, 1H), 7.72-7.68 (m, 1H),7.30-7.23 (m,
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3H), 6.91-6.87 (m, 1H), 5.84 (s, 1H), 3.80 (s, 3H), 2.66 (s, 1H) ppm. C{1H} NMR (125.0 MHz,
CDCl3): δ = 159.2, 148.2, 147.9, 140.0, 135.5, 134.2, 127.9, 123.3, 114.3, 73.5, 55.3 ppm.
(2-Methoxyphenyl)(pyridin-3-yl)methanol (3fa).20 White solid. Yield (178 mg, 83%). ee = 57%;
[α]25D = -7.31 (c 1.08, CH2Cl2). The ee was determined by HPLC (Chiralpak AD-H column, n-hexane/i-
PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 21.45 min; tR(minor) = 24.78 min. 1H
NMR (300 MHz, CDCl3): δ = 8.56 (s, 1H), 8.41-8.39 (m, 1H), 7.72-7.69 (m, 1H), 7.29-7.19 (m, 3H),
6.99-6.94 (m, 1H), 6.89-6.86 (m, 1H), 6.06 (s, 1H), 4.04-3.94 (m, 1H), 3.78 (s, 3H) ppm. 13C{1H} NMR
(75.0 MHz, CDCl3): δ = 156.3, 148.3, 148.1, 139.0, 134.2, 131.1, 129.0, 127.3, 123.2, 120.9, 110.6,
69.9, 55.3 ppm.
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Pyridin-3-yl(3,4,5-trimethoxyphenyl)methanol (3ga). Colorless oil. Yield (262 mg, 95%). ee =
96%; [α]25 = -1.29 (c 0.44, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column, n-
D
hexane/i-PrOH = 80:20, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 15.04 min; tR(minor) = 25.30
min. [α]25D = -1.29 (c 0.44, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 8.53-8.52 (m, 1H), 8.40-8.37 (m,
1H), 7.72-7.69 (m, 1H), 7.27-7.23 (m, 1H), 6.58 (s, 2H), 5.77 (s, 1H), 3.82 (s, 3H), 3.81 (s, 6H) ppm.
13C{1H} NMR (75.0 MHz, CDCl3): δ = 153.3, 148.4, 147.9, 139.5, 1389, 137.2, 134.3, 123.5, 103.3,
73.8, 60.8, 56.0 ppm. HRMS (ESI) calcd for C15H18O4N (M+H)+ 276.1230, found 276.1223.
(4-Chlorophenyl)(pyridin-3-yl)methanol (3ha). White solid. M.p. 112-114 °C. Yield (202 mg,
92%). ee = 90%; [α]25 = -25.49 (c 1.02, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H
D
column, n-hexane/i-PrOH = 95:5, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 36.85 min; tR(minor)
= 43.61 min. 1H NMR (300 MHz, CDCl3): δ = 8.37 (s, 1H), 8.28-8.27 (d, J = 3.0 Hz, 1H), 7.67-7.63 (m,
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1H), 7.31-7.18 (m, 4H), 5.76 (s, 1H), 5.36 (s, br, 1H) ppm. C{1H} NMR (125.0 MHz, CDCl3): δ =
148.1, 147.6, 141.8, 139.6, 134.6, 133.5, 128.7, 127.8, 123.6, 72.9 ppm. HRMS (ESI) calcd for
C12H11ONCl (M+H)+ 220.0524, found 220.0519.
(3-Chlorophenyl)(pyridin-3-yl)methanol (3ia). White solid. M.p. 114-115 °C. Yield (208 mg, 95%).
ee = 85%; [α]25D = -25.43 (c 0.70, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column,
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n-hexane/i-PrOH = 95:5, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 15.71 min; tR(minor) =
20.61 min. 1H NMR (300 MHz, CDCl3): δ = 8.31 (s, 1H), 8.23-8.21 (m, 1H), 7.67-7.65 (m, 1H), 7.34 (s,
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1H), 7.23-7.17 (m, 4H), 6.21 (s, br, 1H), 5.73 (s, 1H) ppm. C{1H} NMR (125.0 MHz, CDCl3): δ =
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147.9, 147.4, 145.4, 139.7, 134.7, 134.4, 129.8, 127.7, 126.5, 124.6, 123.7, 72.8 ppm. HRMS (ESI)
calcd for C12H11ONCl (M+H)+ 220.0524, found 220.0519.
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(2-Chlorophenyl)(pyridin-3-yl)methanol (3ja). White solid. M.p. 134-135 °C. Yield (204 mg, 93%).
ee = 66%; [α]25D = +3.84 (c 1.46, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column,
n-hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 14.98 min; tR(minor) =
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17.91 min. H NMR (300 MHz, CDCl3): δ = 8.46 (s, 1H), 8.32-8.29 (m, 1H), 7.69-7.64 (m, 1H), 7.33-
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7.18 (m, 4H), 6.20 (s, 1H), 5.10 (s, br, 1H) ppm. C{1H} NMR (125.0 MHz, CDCl3): δ = 148.4, 148.2,
140.5, 138.5, 134.9, 132.2, 129.5, 129.0, 127.8, 127.3, 123.5, 70.1 ppm. HRMS (ESI) calcd for
C12H11ONCl (M+H)+ 220.0524, found 220.0519.
(4-Bromophenyl)(pyridin-3-yl)methanol (3ka). White solid. M.p. 123-124 °C. Yield (245 mg,
93%). ee = 93%; [α]25 = -9.39 (c 0.99, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H
D
column, n-hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 28.19 min;
tR(minor) = 31.85 min. 1H NMR (300 MHz, CDCl3): δ = 8.38 (s, 1H), 8.31-8.29 (m, 1H), 7.67-7.63 (m,
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1H), 7.47-7.43 (m, 2H), 7.27-7.19 (m, 3H), 5.76 (s, 1H), 5.02 (s, 1H) ppm. C{1H} NMR (75.0 MHz,
CDCl3): δ = 148.1, 147.6, 142.3, 139.6, 134.6, 131.7, 128.2, 123.6, 121.6, 73.0 ppm. HRMS (ESI) calcd
for C12H11ONBr (M+H)+ 264.0019, found 264.0013.
(2-Bromophenyl)(pyridin-3-yl)methanol (3la). White solid. M.p. 131-132 °C. Yield (232 mg, 88%).
ee = 66%; [α]25D = +10.50 (c 1.20, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column,
n-hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 13.20 min; tR(minor) =
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16.46 min. H NMR (300 MHz, CDCl3): δ = 8.54 (s, 1H), 8.38-8.36 (m, 1H), 7.70-7.62 (m, 2H), 7.54-
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7.51 (m, 1H), 7.39-7.33 (m, 1H), 7.26-7.14 (m, 2H), 6.19 (s, 1H), 4.40 (s, 1H) ppm. C{1H} NMR
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(75.0 MHz, CDCl3): δ = 148.7, 148.5, 142.0, 138.2, 134.8, 132.9, 129.4, 128.3, 127.9, 123.4, 122.5,
72.5 ppm. HRMS (ESI) calcd for C12H11ONBr (M+H)+ 264.0019, found 264.0014.
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(4-Nitrophenyl)(pyridin-3-yl)methanol (3ma). Yellow solid. M.p. 187-188 °C. Yield (207 mg,
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90%). ee = 98%; [α]25 = -24.09 (c 0.66, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H
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column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm). tR(major) = 37.54 min;
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tR(minor) = 59.95 min. H NMR (300 MHz, DMSO-d6): δ = 8.66-8.65 (m, 1 H), 8.47-8.45 (m, 1 H),
8.23-8.20 (m, 2H), 7.78-7.69 (m, 3H), 7.38-7.33 (m, 1H), 6.46-6.45 (m, 1H), 5.98-5.96 (m, 1 H) ppm.
13C{1H} NMR (75.0 MHz, DMSO-d6): δ = 152.9, 149.1, 148.5, 147.0, 140.3, 134.5, 127.75, 124.1, 71.9
ppm. HRMS (ESI) calcd for C12H11O3N2 (M+H)+ 231.0764, found 231.0759.
(2-Nitrophenyl)(pyridin-3-yl)methanol (3na). Yellow oil. Yield (188 mg, 82%). ee = 33%; [α]25
=
D
+9.84 (c 1.04, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-hexane/i-PrOH =
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90:10, flow rate = 1.0 mL/min, λ = 254 nm). tR(major) = 21.52 min; tR(minor) = 26.93 min. H NMR
(300 MHz, CDCl3): δ = 8.39 (s, 1H), 8.30-8.28 (m, 1H), 7.94-7.87 (m, 2H), 7.68-7.63 (m, 2H), 7.48-
7.42 (m, 1H), 7.23-7.18 (m, 1H), 6.44 (s, 1H), 5.29 (br, 1H) ppm. 13C{1H} NMR (75.0 MHz, CDCl3): δ
= 148.12, 148.06, 147.7, 138.3, 138.2, 135.2, 133.7, 129.0, 128.6, 124.6, 123.5, 68.7 ppm. HRMS (ESI)
calcd for C12H11O3N2 (M+H)+ 231.0764, found 231.0759.
Pyridin-3-yl(4-(trifluoromethyl)phenyl)methanol (3oa). White solid. M.p. 106-107 °C. Yield (223
mg, 88%). ee = 82%; [α]25D = -7.14 (c 1.33, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-
H column, n-hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 10.79 min;
tR(minor) = 13.32 min. 1H NMR (300 MHz, CDCl3): δ = 8.45 (s, 1H), 8.36 (s, 1H), 7.66-7.47 (m, 5H),
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7.26-7.23 (m, 1H), 5.88 (s, 1H), 4.78 (s, br, 1H) ppm. C{1H} NMR (125.0 MHz, CDCl3): δ = 148.4,
147.7, 147.2, 139.5, 134.7, 129.9 (q, J = 32.5 Hz), 126.7, 125.6 (q, J = 2.5 Hz), 124.0 (q, J = 270.0 Hz),
123.7, 73.1 ppm. HRMS (ESI) calcd for C13H11ONF3 (M+H)+ 254.0787, found 254.0782.
(4-Fluorophenyl)(pyridin-3-yl)methanol (3pa).20 White solid. Yield (189 mg, 93%). ee = 70%;
[α]25 = -21.38 (c 1.16, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-
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hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 16.26 min; tR(minor) = 18.93
min. 1H NMR (300 MHz, CDCl3): δ = 8.34 (s, 1H), 8.24-8.22 (m, 1H), 7.68-7.65 (m, 1H), 7.29-7.17 (m,
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3H), 7.01-6.95 (m, 2H), 5.75 (s, br, 2H) ppm. C{1H} NMR (125.0 MHz, CDCl3): δ = 162.1 (d, J =
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245.0 Hz), 147.7 (d, J = 42.5 Hz), 140.0, 139.2 (d, J = 2.5 Hz), 134.5, 128.2 (d, J = 8.8 Hz), 123.5,
115.5, 115.3, 72.8 ppm.
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Pyridin-3-yl(thiophen-2-yl)methanol (3qa). White solid. M.p. 79-80 °C. Yield (164 mg, 86%). ee =
62%; [α]25 = -58.62 (c 0.29, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-
D
hexane/i-PrOH = 90:10, flow rate = 0.7 mL/min, λ = 254 nm). tR(major) = 25.72 min; tR(minor) = 33.78
min. 1H NMR (300 MHz, CDCl3): δ = 8.55 (s, 1H), 8.43-8.41 (m, 1H), 7.80-7.78 (m, 1H), 7.29-7.25 (m,
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2H), 6.96-6.88 (m, 2H), 6.08 (s, 1H), 4.35 (s, br, 1H) ppm. C{1H} NMR (75.0MHz, CDCl3): δ =
148.7, 147.8, 147.4, 139.0, 134.2, 126.8, 125.7, 125.0, 123.5, 69.9 ppm. HRMS (ESI) calcd for
C10H10ONS (M+H)+ 192.0478, found 192.0473.
Furan-2-yl(pyridin-3-yl)methanol (3ra). Colorless oil. Yield (161 mg, 92%). ee = 59%; [α]25
=
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+47.56 (c 0.65, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column, n-hexane/i-PrOH =
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90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 17.02 min; tR(minor) = 19.14 min. H NMR
(300 MHz, CDCl3): δ = 8.62 (s, 1H), 8.53-8.51 (m, 1H), 7.83-7.80 (m, 1H), 7.41 (m, 1H), 7.33-7.29 (m,
1H), 6.35-6.33 (m, 1H), 6.16-6.14 (m, 1H), 5.88 (s, 1H) ppm. 13C{1H} NMR (125.0 MHz, CDCl3): δ =
155.0, 149.22, 148.3, 142.9, 136.5, 134.4, 123.4, 110.4, 107.8, 67.9 ppm. HRMS (ESI) calcd for
C10H10O2N (M+H)+ 176.0706, found 176.0701.
(E)-3-Phenyl-1-(pyridin-3-yl)prop-2-en-1-ol (3sa). Colorless oil. Yield (196 mg, 93%). ee = 66%;
[α]25 = +1.86 (c 0.45, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-
D
hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 18.77 min; tR(minor) = 24.17
min. 1H NMR (300 MHz, CDCl3): δ = 8.58 (s, 1H), 8.45-8.43 (m, 1H), 7.79-7.76 (m, 1H), 7.35-7.24 (m,
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6H), 6.70-6.66 (m, 1H), 6.37-6.29 (m, 1H), 5.41-5.39 (m, 1H), 3.94 (s, br, 1H) ppm. C{1H} NMR
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(75.0 MHz, CDCl3): δ = 148.6, 147.9, 138.6, 136.1, 134.3, 131.2, 130.8, 128.6, 128.0, 126.6, 123.6,
72.7 ppm. HRMS (ESI) calcd for C14H14ON (M+H)+ 212.1070, found 212.1075.
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(E)-3-(2-Methoxyphenyl)-1-(pyridin-3-yl)prop-2-en-1-ol (3ta). Colorless liquid. Yield (212 mg,
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88%). ee = 66%; [α]25 = +7.89 (c 0.48, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H
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column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm). tR(major) = 20.89 min;
tR(minor) = 30.01 min. 1H NMR (300 MHz, CDCl3): δ = 8.59 (s, 1H), 8.43-8.41 (m, 1H), 7.81-7.79 (m,
1H), 7.41-7.38 (m, 1H), 7.25-7.21 (m, 2H), 7.02-6.86 (m, 3H), 6.39-6.30 (m, 1H), 5.41-5.38 (m, 1H),
4.27 (s, br, 1H), 3.81 (m, 3H) ppm. 13C NMR{1H} (125.0 MHz, CDCl3): δ = 156.8, 148.3, 147.9, 138.9,
134.2, 131.5, 129.0, 127.1, 126.2, 125.1, 123.4, 120.5, 110.8, 73.1, 55.3 ppm. HRMS (ESI) calcd for
C15H16O2N (M+H)+ 242.1176, found 242.1177.
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3-Methyl-1-(pyridin-3-yl)but-2-en-1-ol (3ua). Colorless liquid. Yield (142 mg, 87%). ee = 80%;
[α]25 = +5.16 (c 2.19, CH2Cl2). The ee was determined by HPLC (Chiralpak OD-H column, n-
D
hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 16.64 min; tR(minor) = 21.81
min. 1H NMR (300 MHz, CDCl3): δ = 8.39 (s, 1H), 8.28-8.26 (m, 1H), 7.68-7.65 (m, 1H), 7.18-7.09 (m,
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1H), 5.41-5.38 (m, 1H), 5.29-5.27 (m, 1H), 4.48 (s, br, 1H), 1.68 (s, 3H), 1.66 (s, 3H) ppm. C{1H}
NMR (125.0 MHz, CDCl3): δ = 147.7, 147.3, 140.0, 135.3, 133.8, 127.2, 123.3, 67.8, 25.7, 18.2 ppm.
HRMS (ESI) calcd for C10H14ON (M+H)+ 164.1070, found 164.1075.
1-(Pyridin-3-yl)butan-1-ol (3va). Colorless liquid. Yield (128 mg, 85%). ee = 48%; [α]25D = -4.60 (c
0.41, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-hexane/i-PrOH = 90:10,
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flow rate = 0.5 mL/min, λ = 254 nm). tR(major) = 14.50 min; tR(minor) = 17.06 min. H NMR (300
MHz, CDCl3): δ = 8.53-8.49 (m, 2H), 7.73-7.70 (m, 1H), 7.31-7.26 (m, 1H), 4.74 (t, J = 6.5 Hz, 1H),
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2.21 (s, br, 1H), 1.80-1.68 (m, 2H), 1.36-1.26 (m, 2H), 0.97-0.87 (m, 3H) ppm. C{1H} NMR (125.0
MHz, CDCl3): δ = 148.7, 147.8, 140.2, 133.6, 123.5, 72.0, 41.2, 18.8, 13.9 ppm. HRMS (ESI) calcd for
C9H14ON (M+H)+ 152.1070, found 152.1065.
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2,2-Dimethyl-1-(pyridin-3-yl)propan-1-ol (3wa). White solid. M.p. 91-92 °C. Yield (157 mg, 95%).
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ee = 49%; [α]25D = -21.84 (c 1.90, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column,
n-hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 8.31 min; tR(minor) = 9.65
min. 1H NMR (300 MHz, CDCl3): δ = 8.38-8.36 (m, 2H), 7.69-7.66 (m, 1H), 7.25-7.20 (m, 1H), 4.39 (s,
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1H), 3.64 (s, br, 1H), 0.91 (s, 9 H) ppm. C{1H} NMR(75.0 MHz, CDCl3): δ = 148.8, 148.1, 137.9,
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135.3, 122.7, 79.7, 35.7, 25.7 ppm. HRMS (ESI) calcd for C10H16ON (M+H)+ 166.1226, found
166.1221.
2-Methyl-1-(pyridin-3-yl)propan-1-ol (3xa). Colorless liquid. Yield (139 mg, 92%). ee = 75%;
[α]25D = -2.10 (c 0.39, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column, n-hexane/i-
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PrOH = 95:5, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 10.49 min; tR(minor) = 13.28 min. H
NMR (500 MHz, CDCl3): δ = 8.28 (s, 2H), 7.69-7.67 (m, 1H), 7.29-7.24 (m, 1H), 4.41-4.38 (m, 1H),
1.97-1.92 (m, 1H), 0.98-0.96 (m, 3H), 0.81-0.79 (m, 3H) ppm. 13C{1H} NMR (125.0 MHz, CDCl3): δ =
148.0, 139.4, 134.4, 123.2, 35.2, 18.6, 17.9 ppm. HRMS (ESI) calcd for C9H14ON (M+H)+ 152.1070,
found 152.1065.
Cyclohexyl(pyridin-3-yl)methanol (3ya). White solid. M.p. 70-72 °C. Yield (179 mg, 93%). ee =
64%; [α]25 = -9.72 (c 0.71, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-
D
hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 9.81 min; tR(minor) = 11.47
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min. H NMR (500 MHz, CDCl3): δ = 8.38-8.37 (m, 2H), 7.67-7.65 (m, 1H), 7.27-7.22 (m, 1H), 4.39
(d, J = 5.0 Hz, 1H), 3.77 (s, br, 1H), 1.62-0.91 (m, 11H) ppm. 13C{1H} NMR (125.0 MHz, CDCl3): δ =
148.1, 139.3, 134. 5, 123.2, 76.5, 44.9, 29.0, 28.5, 26.3, 25.93, 25.86 ppm. HRMS (ESI) calcd for
C12H18ON (M+H)+ 192.1383, found 192.1378.
(2-Methylpyridin-3-yl)(phenyl)methanol (3ab). Colorless liquid. Yield (163 mg, 82%). ee = 68%;
[α]25D = +3.81 (c 0.65, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column, n-hexane/i-
PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm). tR(major) = 16.16 min; tR(minor) = 23.70 min. 1H
NMR (300 MHz, CDCl3): δ = 8.24-8.22 (m, 1H), 7.89-7.86 (m, 1H), 7.29-7.24 (m, 5H), 7.16-7.11 (m,
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1H), 5.92 (s, 1H), 4.04 (s, br, 1H), 2.36 (s, 3H) ppm. C{1H} NMR (75.0 MHz, CDCl3): δ = 155.5,
147.4, 142.2, 137.3, 134.3, 128.6, 127.9, 127.1, 121.4, 72.4, 22.1 ppm. HRMS (ESI) calcd for
C13H14ON (M+H)+ 200.1070, found 200.1072.
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(6-Methylpyridin-3-yl)(phenyl)methanol (3ac). Colorless liquid. Yield (169 mg, 85%). ee = 85%;
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[α]25 = +6.26 (c 1.82, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-
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hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 13.93 min; tR(minor) = 23.09
min. 1H NMR (300 MHz, CDCl3): δ = 8.42-8.41 (m, 1H), 7.58-7.54 (m, 1H), 7.35-7.27 (m, 5H), 7.10-
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7.08 (m, 1H), 5.82 (s, 1H), 2.93 (s, br, 1H), 2.50 (s, 3H) ppm. C{1H} NMR (75.0 MHz, CDCl3): δ =
157.0, 147.1, 143.5, 137.0, 134.9, 128.5, 127.5, 126.4, 123.1, 73.5, 23.6 ppm. HRMS (ESI) calcd for
C13H14ON (M+H)+ 200.1070, found 200.1077.
(5-Methoxypyridin-3-yl)(phenyl)methanol (3ad). White solid. M.p. 73-74 °C.Yield (198 mg, 92%).
ee = 65%; [α]25D = +5.63 (c 0.96, CH2Cl2). The ee was determined by HPLC (Chiralpak OJ-H column,
n-hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 24.59 min; tR(minor) =
30.56 min. 1H NMR (500 MHz, CDCl3): δ = 8.04-7.92 (m, 2H), 7.31-7.22 (m, 6H), 5.79-5.75 (m, 1H),
3.75-3.72 (m, 3H) ppm. 13C{1H} NMR (75.0 MHz, CDCl3): δ = 155.7, 143.3, 140.8, 140.0, 135.9, 128.6,
127.8, 126.5, 118.7, 73.4, 54.5 ppm. HRMS (ESI) calcd for C13H14O2N (M+H)+ 216.1019, found
216.1025.
(6-Methoxypyridin-3-yl)(phenyl)methanol (3ae). Colorless liquid. Yield (193 mg, 90%). ee = 42%;
[α]25 = +0.86 (c 2.32, CH2Cl2). The ee was determined by HPLC (Chiralpak OD-H column, n-
D
hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 15.30 min; tR(minor) = 16.41
min. 1H NMR (300 MHz, CDCl3): δ = 8.11 (s, 1H), 7.54-7.51 (m, 1H), 7.34-7.25 (m, 5H), 6.70-6.65 (m,
1H), 5.78-5.76 (m, 1H), 3.92-3.90(m, 3H), 2.56 (s, br, 1H) ppm. 13C{1H} NMR(75.0 MHz, CDCl3): δ =
163.7, 145.1, 143.2, 137.4, 132.2, 128.6, 127.7, 126.3, 110.9, 73.7, 53.5 ppm. HRMS (ESI) calcd for
C13H14O2N (M+H)+ 216.1019, found 216.1023.
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(2-Chloropyridin-3-yl)(phenyl)methanol (3af). Colorless liquid. Yield (167 mg, 76%). ee = 30%;
[α]25D = -1.53 (c 0.45, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-hexane/i-
PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 19.59 min; tR(minor) = 22.71 min. 1H
NMR (300 MHz, CDCl3): δ = 8.18 (s, 1H), 8.02-8.00 (m, 1H), 7.34-7.27 (m, 6H), 6.10 (s, 1H), 3.47 (s,
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1H) ppm. C{1H} NMR (125.0 MHz, CDCl3): δ = 149.3, 148.2, 141.4, 138.0, 136.9, 128.6, 128.1,
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126.9, 122.8, 72.0 ppm. HRMS (ESI) calcd for C12H11ClON (M+H)+ 220.0524, found 220.0525.
(6-Chloropyridin-3-yl)(phenyl)methanol (3ag). Colorless liquid. Yield (182 mg, 83%). ee = 45%;
[α]25 = +2.20 (c 0.54, CH2Cl2). The ee was determined by HPLC (Chiralpak AS-H column, n-
D
hexane/i-PrOH = 90:10, flow rate = 0.8 mL/min, λ = 254 nm). tR(major) = 15.05 min; tR(minor) = 18.75
min. 1H NMR (300 MHz, CDCl3): δ = 8.28-8.26 (m, 1H), 7.64-7.61 (m, 1H), 7.33-7.22 (m, 6H), 5.80 (s,
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1H), 3.50 (s, 1H) ppm. C NMR(75.0 MHz, CDCl3): δ = 150.1, 147.8, 142.6, 138.4, 137.2, 128.8,
128.1, 126.4, 124.0, 73.3 ppm. HRMS (ESI) calcd for C12H11ClON (M+H)+ 220.0524, found 220.0526.
Phenyl(pyridin-4-yl)methanol (3ak). White solid. M.p. 135.5-140.2 °C Yield (135mg, 73%). ee =
83%; [α]25 = +36.25 (c 0.16, CH2Cl2). The ee was determined by HPLC (Chiralpak OD column, n-
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hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm). tR(major) = 34.88 min; tR(minor) = 36.57
min. 1H NMR (300 MHz, CDCl3): δ = 8.46-8.44 (m, 2H), 7.36-7.27 (m, 7H), 5.79 (s, 1H) ppm. 13C{1H}
NMR(125.0 MHz, CDCl3): δ = 152.8, 149.5, 142.7, 128.8, 128.3, 126.8, 121.3, 74.9. ppm. HRMS (ESI)
calcd for C12H11ON (M+H)+ 186.0913, found 186.0915.
(2-Methylpyridin-4-yl)(phenyl)methanol (3al). White solid. M.p. 83-84 °C Yield (175 mg, 88%).
ee = 91%; [α]25D = +10.19 (c 0.52, CH2Cl2). The ee was determined by HPLC (Chiralpak OD-H column,
n-hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm). tR(major) = 18.02 min; tR(minor) =
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23.16 min. H NMR (300 MHz, CDCl3): δ = 8.18-8.16 (m, 1H), 7.32-7.23 (m, 5H), 7.18 (s, 1H), 7.08-
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7.07 (m, 1H), 5.71 (s, 1H), 4.71 (s, br, 1H), 2.43 (s, 3H) ppm. C{1H} NMR(75.0 MHz, CDCl3): δ =
158.1, 153.5, 148.5, 143.1, 128.6, 127.9, 126.7, 120.8, 118.6, 74.7, 24.0 ppm. HRMS (ESI) calcd for
C13H14ON (M+H)+ 200.1070, found 200.1071.
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X-ray Crystallography. The X-ray diffractions of suitable crystals of compounds (S)-3ka were
performed on a Burker SMART CCD area detector diffractometer using graphite-monochromated Mo-
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Kα radiation (λ = 0.71073 Å); temperature 273(2) K; ϕ and ω scan technique; SADABS effects and
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empirical absorption were applied in the data corrections. All structures were solved by direct methods
(SHELXTL-97), completed by subsequent difference Fourier syntheses, and refined by full-matrix least
squares calculations based on F2 (SHELXTL-97).21 All hydrogen atoms were refined using a riding
model. Crystal data for (S)-3ka: C12H10BrNO, M = 264.12, Orthorhombic, space group P 212121, T =
293(2) K, a = 5.8390(11) Å, b = 7.5480(14) Å, c = 24.921(5) Å, V = 1098.3(4) Å3, Z = 4, absorption
coefficient = 3.713 mm-1, total reflections collected 9269, unique 2514 (Rint = 0.0401), Goodness of Fit
Indicator = 1.032, R1 = 0.0404, wR2 = 0.0990. Absolute structure parameter = 0.033(16).
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Acknowledgment. The authors thank the National Natural Science Foundation of China (21172003,
21172004, 21372009) and Special and Excellent Research Fund of Anhui Normal University for the
financial support.
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Supporting Information Available: Copies of HPLC analytic data, and H and 13C NMR spectra of
the compounds 3 and CIF file of (S)-3ka. This material is available free of charge via the Internet at
http://pubs.acs.org.
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