Synthesis of chiral 1,3-disubstituted tetrahydroisoquinolines and their use in the asymmetric addition of diethylzinc to aldehydes

Article abstract of DOI:10.3987/COM-09-S(S)123

The effects of modifications on three sites of 1-(1,2,3,4-tetrahydro- isoquinolin-1 -yl)-naphthalen-2-ol (THIQNOL) chiral ligands the asymmetric diethylzinc additions were examined. The studies showed that modifications at the nitrogen only reduce the eff

Full text of DOI:10.3987/COM-09-S(S)123

HETEROCYCLES, Vol. 80, No. 2, 2010
1319
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1319 - 1337. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd September, 2009, Accepted, 15th October, 2009, Published online, 16th October, 2009
DOI: 10.3987/COM-09-S(S)123
SYNTHESIS OF CHIRAL 1,3-DISUBSTITUTED
TETRAHYDROISOQUINOLINES AND THEIR USE IN THE
ASYMMETRIC ADDITION OF DIETHYLZINC TO ALDEHYDES
Patricia D. MacLeod, Amy M. Reckling, and Chao-Jun Li*
Department of Chemistry, McGill University, 801 Sherbrooke Street West,
Montreal, QC H3A 2K6, Canada
Abstract
–
The effects of modifications on three sites of
(THIQNOL) chiral
1-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-naphthalen-2-ol
ligands the asymmetric diethylzinc additions were examined. The studies
showed that modifications at the nitrogen only reduce the efficiency of these
types of ligands, whereas modifications at the 3-position of the
1,2,3,4-tetrahydroisoquinoline ring and the 3-position of the naphthol ring can
lead to chiral ligands which provide better enantioselectivities. In general, the use
of a simple phenyl group on the 1,2,3,4-tetrahydroisoquinoline ring and either a
phenyl or methoxyphenyl on the naphthol ring generates more effective chiral
ligands for the asymmetric addition of diethylzinc to aldehydes.
INTRODUCTION
The discovery of novel enantioselective reactions to generate optically active compounds plays a
fundamental role in pharmaceutical research and represents one of the most important developments in
modern organic chemistry.1 Many organic compounds of interest for pharmaceuticals and pesticides are
chiral and very often only one of the enantiomers is effective or desirable for biological purposes.
Because of this, the FDA now requires chiral drugs to be marketed in enantiomerically pure form.
Asymmetric catalysis, which uses chiral catalysts to generate chiral compounds, is at the forefront of
methodologies for achieving this challenge.2 Among the many chiral catalysts developed, BINAP-,3
QUINAP-4 and BINOL-based5 chiral complexes have been shown to be especially effective in
catalyzing asymmetric reactions.

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HETEROCYCLES, Vol. 80, No. 2, 2010
Of these types of reactions, the asymmetric addition of alkylzinc reagents to aldehydes in the presence of
catalytic amounts of chiral catalysts has garnered much attention in recent years.6 Different types of
ligands, including β-amino alcohols, amino thiols, amines and diols, have been employed to achieve
asymmetric inductions; however Betti-base type derivatives, aminoalkylnapthols first synthesized by
Betti in 1900,7 have also been shown to be effective chiral ligands.8 The Betti base and its derivatives
generally acquire their chirality from chiral centres on the molecule, whereas the more popular QUINAP-,
BINAP- and BINOL-based ligands possess a single chiral axis. Recently, we have synthesized a new
class of chiral compounds9 which have both a chiral centre and a chiral axis that exist in close proximity.
Such compounds can provide chiral match or mismatch effects, which can potentially enhance the
asymmetric inductions in catalysis. We use the asymmetric diethylzinc addition as a proof-of-concept
evaluation of such new chiral ligands. These compounds also have the potential to provide N,O; N,P
and N,S ligands and are easily synthesized by the direct aza-Friedel-Crafts addition. The subsequent
methylation and resolution of our lead-compound generated a representative chiral ligand
1-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-naphthalen-2-ol (THIQNOL), (S)-(-)-1a, which was used to
achieve 69% ee in the addition of diethylzinc to benzaldehyde (Scheme 1).9c In this report, we wish to
communicate the preparation of new chiral ligands based on our initial design and their activity towards
the asymmetric addition of diethylzinc to aldehydes.
O
OH
8 mol % (S)-1a
N
toluene
+
Et2Zn
H
OH
0 oC, 72 h
5a
6a
(S)-(-)-1a
Scheme 1
RESULTS AND DISCUSSION
While seeking out modifications to improve on the enantioselectivities we achieved using (S)-1a, we had
initially focused our modifications on the N-substituent. The methyl group was thus replaced by ethyl,
propyl, allyl or benzyl groups (1b-e). Using dibenzoyl L-tartaric acid (L-DBTA), we were then able to
resolve the ligands 1b-1d (Table 1). Unfortunately, we were unable to resolve ligand 1e; therefore, we
separated the enantiomers by chiral HPLC. With the optically pure ligands 1b-1e in hand, we then
examined their effectiveness in the asymmetric diethylzinc addition under the standard conditions. These
modifications however, only resulted in decreasing rather than increasing the ee for the addition of
diethylzinc to benzaldehyde (Table 2).

HETEROCYCLES, Vol. 80, No. 2, 2010
1321
Table 1: Synthesis and separation of 1b-e
NH
OH
N
N
N


enantiomeric
separation
R
R
R
RX, KHCO3
+
OH
OH
OH
(+)-1
(-)-1
2a
1
Yield 1 (%)
Separation
L-DBTAb
L-DBTA
L-DBTA
HPLCc
ee (-)-1 (%)d
ee (+)-1 (%)d
Entrya
RX
EtI
1
1
2
3
4
1b
1c
1d
1e
83
66
85
86
90
95
89 (99.5)
48
PrI
92
C3H5Br
BnCl
90
100
100
a See Experimental for detailed conditions b Dibenzoyl L-Tartaric acid c OD semi-prep column
d Determined by chiral HPLC
Table 2: Asymmetric diethylzinc addition to benzaldehyde using 1b-e
O
OH
8 mol % 1
toluene
+
Et2Zn
H
rt, 24 h
6a
5a
ee (%)a
42
Configb
1
Entry
(+)-1b
(-)-1c
(-)-1d
(-)-1e
1
2
3
4
S
R
R
R
38
38
39
a Determined by chiral HPLC b Configuration of
predominant enantiomer
With N-substitutions not giving us the increase in enantioselectivity that we desired, we decided to look at
alternative places to make modifications. We initially modified the 3-position of the
10
tetrahydroisoquinoline
ring;
firstly,
because
literature
has
shown
that
(R)-3-phenyl-3,4-dihydroisoquinoline
3
could be formed with high enantiopurity from
(±)-1,2-diphenylethylamine and secondly, because it is known that fixing that chiral centre will fix the

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HETEROCYCLES, Vol. 80, No. 2, 2010
chiral centre at position 1.11
Compound (S)-(R)-1f was isolated in moderate yield by direct addition of 2-naphthol to
(R)-3-phenyl-3,4-dihydroisoquinoline 3 using our methodology developed previously (Table 4, Entry 1).
To our delight, the application of this structure to the asymmetric addition of diethylzinc to benzaldehyde
yielded the product in 79% ee (Table 5, Entry 1). With this encouraging result in hand, we decided to
further modify the structure by installing a substituent at the 3-position of the naphthol ring. To this end,
we prepared various 3-substituted 2-naphthols according to the rhodium-catalyzed procedure of Oi and
co-workers (Table 3).12 We were then able to isolate the new chiral ligands in moderate yields through
the addition of the 3-substituted 2-naphthols to 3 (Table 4). To confirm the relative configurations of C-1
and C-3, we performed nOe measurements on (S)-(R)-1g.
Table 3: Addition of aryl bromides to 2-naphthol
2.5 mol % [Rh(cod)Cl]2
20 mol % HMPT
OH
Ar
OH
+
Ar-Br
K2CO3, Cs2CO3
toluene, 100 oC
5
4a
Entrya
4
Yield (%)b
36
Ar-Br
Product
OH
Br
1
OMe
OMe
5b
4b
OH
Br
2
43
OMe
5c
OMe
4c
OH
Br
3
4
20
48
4d
4e
5d
OH
Br
5e
a Conditions: naphthol (1 mmol), aryl bromide (2.4 mmol), K2CO3 (2 mmol), Cs2CO3
(2 mmol), [Rh(cod)Cl]2 (0.025 mmol), HMPT (0.2 mmol), toluene (2 mL).
b Isolated yield.

HETEROCYCLES, Vol. 80, No. 2, 2010
1323
Table 4: Addition of (R)-3-phenyl-3,4-dihydroisoquinoline to 2-naphthols
OH
H2O, 80 o
C
NH
+
N
R
OH
R
3
4
(S)-(R)-1
Entrya
4
Yield (%)b
Entrya
Yield (%)b
(S)-(R)-1
(S)-(R)-1
4
OH
OH
NH
OH
NH
1
52
OH
5
56
4a
(S)-(R)-1f
4e
OH
(S)-(R)-1j
NH
OH
2
48
4b
OH
NH
OH
6
54
(S)-(R)-1g
4f
OH
NH
OH
(S)-(R)-1k
69
3
OMe
4c
OMe
OH
OH
(S)-(R)-1h
NH
OH
OH
7
40
4g
OH
NH
OH
(S)-(R)-1l
4
48
OMe
4d
OMe
(S)-(R)-1i
a Reaction conditions: 3 (0.2 mmol) 4 (0.2 mmol) in 0.9 mL degassed water at 80 o
b Isolated yields
C
These new chiral ligands were then used to catalyze the diethylzinc addition to aldehydes (Table 5).
As mentioned previously, ligand (S)-(R)-1f yielded the diethylzinc addition product with better ee (79%)
than we had seen with our previous modifications at the N position (Table 5, Entry 1). The addition of a
moiety on the 3-position of the naphthol ring initially led to a further increase in ee, up to 92% for a
simple phenyl group (Table 5, Entry 2). This encouraging result led us to use ligand (S)-(R)-1g as the
chiral catalyst for the diethylzinc addition to a variety of aldehydes. In general, the ee’s for these
substrates were high, up to 97% for the 4-methylbenzaldehyde (Table 5, Entry 3). On the other hand, it
seems that there is a threshold for the amount of bulk on the added moiety that the system can sustain.

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HETEROCYCLES, Vol. 80, No. 2, 2010
Table 5: Asymmetric addition of diethylzinc to aldehydes using 1f-l
O
OH
Et2Zn / Heptane
R
H
R
8 mol % (S)-(R)-1
toluene, 0 oC, 72 h
5
6
(S)-(R)-1
5
product
yield (%)a
ee (%)b configc
entry
6a
6a
6b
6c
6d
6e
6f
1
5a: R=C6H5
5a: R=C6H5
85
79
77
72
77
94
70
84
57
93
68
79
57
65
65
79
92
97
94
95
96
93
93
87
95
95
90
7
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
(S)-(R)-1f
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1g
(S)-(R)-1h
(S)-(R)-1i
(S)-(R)-1j
(S)-(R)-1k
(S)-(R)-1l
2
3
5b: R=4-MeC6H5
4
5c: R=4-MeOC6H5
5d: R=3-MeOC6H5
5e: R=4-ClC6H5
5f: R=3-ClC6H5
5g: R=2-ClC6H5
5h: R=PhCH2CH2
5i: R=3-MeC6H5
5a: R=C6H5
5
6
7
6g
6h
6i
8
9
10
11
12
13
14
15
6a
6a
6a
6a
6a
5a: R=C6H5
5a: R=C6H5
5a: R=C6H5
68
40
5a: R=C6H5
a Isolated yields
b Determined by chiral HPLC
c Configuration of the predominant enantiomer of the product
This is exemplified by comparing the use of ligand (S)-(R)-1h and -1i. The use of the methoxy group in
the 3- or 4-position (Table 5, Entries 11 and 12) with these types of ligands keeps the enantioselectivity in
the same vicinity as the results given by (S)-(R)-1g (Table 5, Entry 2), though the 4-methoxy substituted
compound (S)-(R)-1h is slightly better. Once there is too much bulk added to the ligand, in this case, in
the form of the 3-naphthyl substituted naphthol (S)-(R)-1k and the 3-(3,5-di-tert-butyl phenyl)
3-substituted naphthol (S)-(R)-1j, the reaction is less effective and gives much lower enantioselectivities
(Table 5, Entries 13 and 14). Interestingly, when a third coordination site is added by replacing that same
aromatic ring by an aliphatic alcohol, (S)-(R)-1l, the enantioselectivity is once again reduced (Table 5,
Entry 15), showing that an extra coordination site is not beneficial to the reaction. This can be rationalized
by visualizing the molecule. As seen in Figure 1, the addition of the second hydroxyl group only gives the
zinc an opportunity to coordinate further away from the chiral atmosphere generated by the ligand.

HETEROCYCLES, Vol. 80, No. 2, 2010
1325
Figure 1: Structure of (S)-(R)-1l minimized with Chem3D MM2
In summary, we have studied the effects of modifications on three sites of our reported THIQNOL chiral
ligands on the asymmetric diethylzinc additions. The studies show that modifications at the nitrogen
only reduce the efficiency of these types of ligands, whereas modifications at the 3-position of the
1,2,3,4-tetrahydroisoquinoline ring and the 3-position of the naphthol ring can lead to chiral ligands
which provide better enantioselectivities. However, it must be noted that there is a threshold for the
amount of bulk that can be added on the naphthol ring before the chiral ligand becomes less effective. In
general, the use of a simple phenyl group on the 1,2,3,4-tetrahydroisoquinoline ring and either a phenyl or
methoxyphenyl on the naphthol ring generates more effective chiral ligands for the asymmetric addition
of diethylzinc to aldehydes. With the knowledge gained from this study, we are provided the
opportunity to further investigate the synthesis of structurally similar molecules in an effort to generate
even more effective ligands. The application of these chiral ligands in other asymmetric reactions is
currently under investigation.

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HETEROCYCLES, Vol. 80, No. 2, 2010
EXPERIMENTAL
General
1H NMR spectra were recorded on Varian 300, 400 and 500 MHz spectrometers and the chemical shifts
were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3. The peak
patterns are indicated as follows: s, singlet; brs, broad singlet; d, doublet; t, triplet; dt, doublet of triplet;
dq, doublet of quartet; ddd, doublet of doublet of doublet; dtd, doublet of triplet of doublet; m, multiplet;
q, quartet; qn, quintet. The coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were
obtained at 75, 100, and 125 MHz spectrometers and referenced to the internal solvent signals (central
peak is 77.0 ppm in CDCl3). All reagents were purchased from Aldrich. All reagents were used without
further purification. 1-(1,2,3,4-Tetrahydro-isoquinolin-1-yl)-naphthalen-2-ol was prepared according to
9b,c
our previous work.
3-Phenyl-3,4-dihydroisoquinoline and 3-(hydroxymethyl)naphthalen-2-ol were
prepared according to literature methodology.10,13
N
OH
1b
1-(2-Ethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1b):
To
a
solution of
1-(1,2,3,4-tetrahydro-isoquinolin-1-yl)naphthalen-2-ol (0.550 g, 2.0 mmol) in DMF (17 mL), powdered
KHCO3 (0.204 g, 2.1 mmol) was added. The resulting slurry was stirred at room temperature for 10
minutes, then iodoethane (0.9 mL, 5.0 mmol) in DMF (12 mL) was added dropwise to the mixture. After
stirring for 22 h, CH2Cl2 was added to the reaction mixture and the solution was washed with water to
remove DMF. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure
to yield the crude product. Flash chromatography (hexanes/EtOAc = 10:1, 5:1) yielded a white powder
o
(0.503 g, 1.7 mmol, 83 %). mp 125-128 C; IR (solid): νmax 3022, 2952, 2869, 1620, 1597, 1462, 1412,
1
1268, 1234, 818, 742, 702; H NMR (CDCl3, 500MHz, ppm) δ 12.08 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H),
7.82 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.53 (dt, J = 8.4, 1.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H),
7.13-7.05 (m, 3H), 6.86 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.57 (s, 1H), 3.0 (ddd, J = 11.2, 5.6,
1.6 Hz, 1H), 3.39-3.31 (m, 1H), 2.74-2.84 (m, 2H), 2.71 (dt, J = 12.0, 3.6 Hz, 1H), 2.45 (m,1H), 1.11 (t, J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz, ppm) δ 155.6, 136.3, 134.1, 133.7, 129.4, 128.9, 128.4,
128.1, 127.5, 126.9, 126.4, 126.2, 122.4, 121.4, 119.9, 118.0, 61.8, 48.6, 48.2, 29.5, 11.4; HRMS (EI):
calculated for C21H21NO: [M+•] = 303.1623 m/z; found: [M+•] 303.1614 m/z.
Resolution: To a solution of 1 (1.847g, 6.1 mmol) in CH2Cl2 (8 mL), a solution of L-dibenzoyltartaric

HETEROCYCLES, Vol. 80, No. 2, 2010
1327
acid (2.186 g, 6.1 mmol) in 100% EtOH (34 mL) was added dropwise. The resulting mixture was stirred
for 22 hours which led to the formation of a colorless salt. The solid was filtered, suspended in water and
treated with aqueous Na2CO3. After extraction with CH2Cl2, the organic phase was dried over MgSO4 and
the solvent was removed under reduced pressure to yield a light purple powder (0.813 g, 2.7 mmol, 44 %).
The enantiomeric purity was determined by chiral HPLC (Daicel Chiralcel OD-H, hexane/isopropanol =
97.5 2.5, flow rate 0.5 mL/min) to be 90 %. The mother liquor was evaporated under reduced pressure
and subjected to the same measures as above. A pale orange solid (0.100 g, 3.3 mmol, 54 %) was isolated
and its enantiomeric purity was determined to be 89 %. After one recrystallization from Et2O, a white
solid (0.138 g, 0.46 mmol, 7%) was collected and the enantiomeric purity was found to be 98 %, [α] 2D0
+315.0 (c 0.168, CH2Cl2). A second recrystallization was performed on the remaining solution and a
colorless, crystalline material (0.380 g, 1.3 mmol, 21 %) was isolated. The enantiomeric purity was
determined to be >99.5 %.
N
OH
1c
1-(2-Propyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol
(1c):
To
a
solution
of
1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1.651 g, 6.0 mmol) in DMF (30 mL), powdered
KHCO3 (0.661 g, 6.6 mmol) was added. The resulting slurry was stirred at room temperature for 10
minutes, then 1-iodopropane (2.4 mL, 30 mmol) in DMF (10 mL) was added dropwise to the mixture.
After stirring for 24 h, CH2Cl2 was added to the reaction mixture and the solution was washed with water
to remove DMF. The organic layer was dried over MgSO4 and the solvent removed under reduced
pressure to yield the crude product. Flash chromatography (hexanes/EtOAc = 10:1, 5:1) yielded a white
powder (1.252 g, 4.0 mmol, 66 %). mp 117-118 oC; IR (solid): νmax 2952, 2923, 2876, 1620, 1598, 1462,
1268, 814, 742, 702; 1H NMR (CDCl3, 400MHz, ppm) δ 12.01 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.77 (d,
J = 8.0 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.08-7.00 (m,
3H), 6.80 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 5.50 (s, 1H), 3.44 (dd, J = 11.2, 3.6 Hz, 1H),
3.34-3.27 (m, 1H), 2.85 (d, J = 16.4 Hz, 1H), 2.73-2.66 (m, 1H), 2.59 (t, J = 12.0 Hz, 1H), 2.33-2.26 (m,
1H), 1.55-1.51 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz, ppm) δ 155.4, 136.3, 134.1,
133.6, 129.3, 128.9, 128.4, 128.0, 127.4, 126.8, 126.3, 126.1, 122.4, 121.3, 119.8, 118.2, 62.4, 56.6, 48.7,
29.4, 19.5, 11.5; HRMS (EI): calculated for C22H23NO: [M+•] = 317.1780 m/z; found: [M+•] 317.1774
m/z.
Resolution: To a solution of 2 (0.317g, 1.0 mmol) in CH2Cl2 (1.3 mL), a solution of L-dibenzoyltartaric

1328
HETEROCYCLES, Vol. 80, No. 2, 2010
acid (0.358 g, 1.0 mmol) in 100% EtOH (6.0 mL) was added dropwise. The resulting mixture was stirred
for 20 h which led to the formation of a colorless salt. The solid was filtered, suspended in water and
treated with aqueous Na2CO3. After extraction with CH2Cl2, the organic phase was dried over MgSO4 and
the solvent was removed under reduced pressure to yield light purple powder (0.117 g, 0.4 mmol, 40 %).
The enantiomeric purity was determined by chiral HPLC (Daicel Chiralcel OD-H, hexane/isopropanol =
97.5 2.5, flow rate 0.5 mL/min) to be 95 %, with optical rotation [α] 2D0 -283.2 (c 0.175, CH2Cl2). The
mother liquor was evaporated under reduced pressure and subjected to the same measures as above. A
pale orange solid (0.197 g, 0.6 mmol, 60 %) was isolated and its enantiomeric purity was determined to
be 48 %.
N
OH
1d
1-(2-Allyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol
(1d):
To
a
solution
of
1-(1,2,3,4-tetrahydro-isoquinolin-1-yl)naphthalen-2-ol (1.376g, 5.0 mmol) in DMF (16 mL), powdered
KHCO3 (0.510 g, 5.1 mmol) was added. The resulting slurry was stirred at room temperature for 10 min,
then allyl bromide (0.43 mL, 5.0 mmol) was added dropwise to the mixture. After stirring for 23 h,
CH2Cl2 was added to the reaction mixture and water was used to wash off the DMF. The organic layer
was dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash chromatography
o
(hexanes/EtOAc = 3:1) yielded a fluffy white powder (1.334 g, 4.2 mmol, 85 %). mp 104-108 C; IR
(solid): νmax 2926, 2843, 1620, 1597, 1468, 1409, 1273, 1237, 935, 821, 746; 1H NMR (CDCl3, 500MHz,
ppm) δ 11.84 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.55-7.52 (m, 1H), 7.37-7.34 (m,
1H), 7.13-7.05 (m, 3H), 6.86 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.92-5.84 (m, 1H), 5.58 (s, 1H),
5.21 (dd, J = 10.0, 1.0 Hz, 1H), 5.12 (d, J = 17.0 Hz, 1H), 3.53-3.49 (m, 2H), 3.37-3.30 (m, 1H),
13
2.95-2.90 (m, 2H), 2.72-2.66 (m, 1H); C NMR (CDCl3, 125 MHz, ppm) δ 155.4, 136.1, 134.1, 133.7,
133.3, 129.6, 128.9, 128.5, 128.2, 127.6, 126.9, 126.5, 126.3, 122.5, 121.5, 119.8, 119.6, 117.7, 61.8, 57.6,
48.7, 29.4; HRMS (EI): calculated for C22H21NO: [M+•] = 315.1623 m/z; found: [M+•] 315.1616 m/z.
Resolution: To a solution of 13 (1.318 g, 4.2 mmol) in CH2Cl2 (5mL), a solution of di-benzoyl tartaric
acid (1.497 g, 4.2 mmol) in 100% EtOH (10 mL) was added dropwise. The resulting mixture was stirred
for 25 h with the formation of a colorless salt happening immediately after the addition of DBTA. The
solid was filtered, suspended in water and treated with aqueous Na2CO3. After extraction with CH2Cl2,
the organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to yield a
white powder (0.568 g, 1.8 mmol, 43 %). The enantiomeric purity was determined by chiral HPLC

HETEROCYCLES, Vol. 80, No. 2, 2010
1329
(Daicel Chiralcel AD hexane/isopropanol = 99:1, flow rate 1.0 mL/min) to be 92 %, with optical rotation
[α] 2D0 -260.3 (c 0.180, CH2Cl2). The mother liquor was evaporated under reduced pressure and subjected
to the same measures as above. A yellow solid was isolated and its enantiomeric purity was determined to
be 90%.
N
OH
1e
1-(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol
(1e):
To
a
solution
of
1-(1,2,3,4-tetrahydro-isoquinolin-1-yl)naphthalen-2-ol (1.158 g, 4.2 mmol) in MeCN (40 mL), powdered
KHCO3 (0.0.429 g, 4.3 mmol) was added. The resulting slurry was stirred at room temperature for 10 min,
then benzyl bromide (0.55 mL, 4.6 mmol) in MeCN (12 mL) was added dropwise to the mixture. After
stirring for 3 days, the solvent was removed under reduced pressure and flash chromatography was done
with hexanes/EtOAc (20:1, 10:1) to yield a pale yellow powder (1.313 g, 3.6 mmol, 86 %). mp 145-149
1
oC; IR (solid): νmax 2834, 1621, 1453, 1265, 814, 742, 699; H NMR (CDCl3, 400MHz, ppm) δ 11.86 (s,
1H), 8.10 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.52 (t, J = 6.8 Hz, 1H),
7.33 (t, J = 7.2 Hz, 1H), 7.28-7.21 (m, 5H), 7.14 (d, J = 8.8 Hz, 1H), 7.02 (m, 2H), 6.80-6.78 (m, 1H),
6.67 (d, J = 8.0 Hz, 1H), 5.57 (s, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.30 (dd, J = 10.8, 4.8 Hz, 1H),
3.23-3.11 (m, 2H), 2.74 (d, J = 16.8 Hz, 1H), 2.53 (dt, J = 11.6, 2.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz,
ppm) δ 155.1, 136.5, 135.9, 133.7, 129.64, 129.60 (2C), 129.0, 128.5, 128.4 (2C), 128.1, 127.5, 127.4,
127.0, 126.6, 126.2, 122.6, 121.5, 119.9, 118.1, 62.5, 59.5, 48.4, 29.2.
Resolution: Separation by chiral semi-prep HPLC (Daicel Chiralcel OD column, hexanes/isopropanol =
97.5:2.5, flow rate 3.0 mL/min) [α] 20 + 174.4 (c 0.219, CH2Cl2) (second peak).
D
General Procedure for Synthesis of 3-Substituted 2-Naphthols12:
Unless otherwise noted, [Rh(cod)Cl)2 (12.5 mg, 0.025 mmol), K2CO3 (276 mg, 2 mmol), Cs2CO3 (652
mg, 2 mmol) and 2-naphthol (144 mg, 1 mmol) were place in a sealable tube and placed under nitrogen
atmosphere. Dry toluene (2 mL) was then added, followed by HMPT (36 µL, 0.2 mmol) and aryl bromide
(2.4 mmol). The mixture was stirred vigorously at 100oC for 20 h. Upon cooling to room temperature, 10
mL conc HCl and 10 mL Et2O were added and the mixture stirred vigorously for 1 h. The mixture was
then extracted with Et2O three times and the organic extracts washed with brine. After drying over
MgSO4, the solvent was removed to yield the crude reaction mixture. Flash chromatography on silica gel
yielded the corresponding products.

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HETEROCYCLES, Vol. 80, No. 2, 2010
OH
4b
3-Phenylnaphthalen-2-ol (4b): Isolated by flash chromatography (hexanes/EtOAc = 9:1) to give a beige
1
powder (119 mg, 0.54 mmol, 54 %). H NMR (CDCl3, 400 MHz, ppm) δ 7.79-7.72 (m, 3H), 7.56-7.42
(m, 6H), 7.36-7.33 (m, 2H), 5.26 (brs, 1H). This is a known compound and the spectral data is consistent
with those reported in literature.14
OH
OMe
4c
3-(4-Methoxyphenyl)naphthalen-2-ol (4c): Isolated by flash chromatography (hexanes/EtOAc = 10:1)
to give a white powder (91 mg, 0.36 mmol, 36 %). 1H NMR (CDCl3, 500MHz, ppm) δ 7.76 (d, J = 8.0 Hz,
1H), 7.72-7.70 (m, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.34-7.31 (m, 2H), 7.05 (d, J =
9.0 Hz, 2H), 5.25 (s, 1H), 3.88 (s, 3H). This is a known compound and the spectral data is consistent with
those reported in literature.15
OH
OMe
4d
3-(3-Methoxyphenyl)naphthalen-2-ol (4d): Isolated by flash chromatography (hexanes/EtOAc
=
20:1) to give an orange oil (108 mg, 0.43 mmol, 43 %). IR (solid): νmax 3511, 3052, 3005, 2900, 2833,
1628, 1598, 1505, 1386, 1243, 1163, 1032, 811, 741; 1H NMR (CDCl3, 500MHz, ppm) δ 7.75 (d, J = 8.5
Hz, 1H), 7.72 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.43-7.39 (m, 2H), 7.33-7.30 (m, 2H), 7.12 (d, J = 8.0 Hz,
1H), 7.08 (s, 1H), 6.96 (dd, J = 8.5, 2.0 Hz, 1H), 5.49 (s, 1H), 3.83 (s, 3H); 13C NMR (CDCl3, 125 MHz,
ppm) δ 160.2, 150.8, 138.2, 134.3, 130.3, 130.3, 129.3, 128.8, 127.7, 126.5, 126.2, 123.8, 121.4, 114.8,
113.8, 110.2, 55.3.
OH
4e

HETEROCYCLES, Vol. 80, No. 2, 2010
1331
3-(3,5-Di-tert-butylphenyl)naphthalen-2-ol (4e): Isolated by flash chromatography (hexanes/EtOAc =
9:1) to yield an orange oil (33 mg, 0.1 mmol, 20 %). 1H NMR (CDCl3, 500MHz, ppm) δ 7.78 (d, J = 8.0
Hz, 1H), 7.74-7.72 (m, 2H), 7.52-7.52 (m, 1H), 7.44-7.41 (m, 1H), 7.37-7.31 (m, 4H), 5.40 (s, 1H), 1.38
13
(s, 16H); C NMR (CDCl3, 125 MHz, ppm) δ 152.1, 150.9, 135.8, 134.3, 131.4, 129.2, 128.9, 127.7,
126.3, 126.3, 123.8, 123.4, 122.4, 110.0, 35.1, 31.5.
OH
4f
3-(Naphthalen-2-yl)naphthalen-2-ol (4f): Isolated by flash chromatography (hexanes/EtOAc = 9:1) to
give a white powder (129 mg, 0.48 mmol, 48 %). mp 116-118 oC; IR (solid): νmax 3518, 3050, 2922, 1628,
1595, 1515, 1357, 1160, 826, 741; 1H NMR (CDCl3, 500MHz, ppm) δ 8.04 (s, 1H), 8.00 (d, J = 8.0 Hz,
1H), 7.93-7.90 (m, 2H), 7.84 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 8.0,
13
1.5 Hz, 1H), 7.47-7.54 (m, 2H), 7.47-7.44 (m, 1H), 7.37-7.34 (m, 1H), 7.25 (s, 1H), 5.36 (s, 1H); C
NMR (CDCl3, 125 MHz, ppm) δ 150.9, 134.4, 134.3, 133.6, 132.9, 130.4, 129.8, 129.0, 129.0, 128.2,
128.1, 127.8, 127.8, 127.2, 126.7, 126.6, 126.3, 123.9, 110.3; HRMS (EI): calculated for C20H14O: [M+•]
= 270.1044 m/z; found: [M+•] 270.1037 m/z.
General Procedure for Addition of 3-Substituted 2-Naphthols to 3-Phenyl-3,4-dihydroisoquinoline:
Unless otherwise noted, 3-phenyl-3,4-dihydroisoquinoline (0.2 mmol) and the corresponding naphthol
(0.2 mmol) were placed under nitrogen atmosphere and degassed water (0.4 mL) was added to the capped
vessel. The reaction mixture was heated to 80 oC and stirred overnight. After extraction with CH2Cl2, the
solvent was removed and the crude mixture purified by flash chromatography on silica gel.
NH
OH
1f
1-((1S,3R)-3-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1f): Addition of 2-naphthol
(1 mmol) to 3-phenyl-3,4-dihydroisoquinoline (1 mmol). Filtering and washing with Et2O yields a beige
powder (0.264 g, 0.75 mmol, 75 %). mp 150-152 oC; IR (solid): νmax 3280, 3022, 2926, 1622, 1598, 1453,
1343, 1266, 1235, 1010, 812, 739, 700; 1H NMR (CDCl3, 500MHz, ppm) δ 11.80 (s, 1H), 8.04 (d, J = 8.5
Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 7.0 Hz,
2H), 7.38-7.29 (m, 4H), 7.11-7.09 (m, 3H), 6.91-6.89 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 4.28

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HETEROCYCLES, Vol. 80, No. 2, 2010
13
(dd, J = 11.0, 3.0 Hz, 1H), 3.31-3.25 (m, 2H), 3.09 (dd, J = 16.5, 3.0 Hz, 1H); C NMR (CDCl3, 125
MHz, ppm) δ 155.8, 142.7, 135.7, 134.1, 133.5, 123.0, 128.97 (2C), 128.64, 128.6, 128.5, 128.2, 127.1,
127.0, 126.9, 126.6 (2C), 122.7, 121.5, 120.2, 118.2, 59.4, 56.8, 38.5; HRMS (EI): calculated for
C25H21NO: [M+•] = 351.1623 m/z; found: [M+•] 351.1616 m/z.
NH
OH
1g
3-Phenyl-1-((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1g): Addition of
3-phenyl-2-naphthol (1.2 mmol) to 3-phenyl-3,4-dihydroisoquinoline (1.2 mmol). Filtering and washing
o
with cold Et2O, then drying for 3 h in a 60 C oven yields a white powder (0.242 g, 0.56 mmol, 48 %).
o
1
mp 129-132 C; IR (solid): νmax 3279, 3057, 3029, 2920, 1602, 1492, 1453, 1423, 1012, 745, 698; H
NMR (CDCl3, 500MHz, ppm) δ 12.10 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.80 (s,
1H), 7.62 (d, J = 7.0 Hz, 2H), 7.53 (t, J = 7.0 Hz, 1H), 7.49 (d, J = 7.0 Hz, 2H), 7.43-7.31 (m, 7H),
7.17-7.13 (m, 2H), 6.98-6.95 (m, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.37 (s, 1H), 4.36 (dd, J = 11.5, 3.5 Hz,
1H), 3.37-3.32 (m, 2H), 3.13 (dd, J = 16.5, 3.5 Hz, 1H), 2.84 (s, 1H); 13C NMR (CDCl3, 125 MHz, ppm)
δ 153.8, 142.5, 128.4, 135.7, 134.2, 133.0, 132.6, 130.2, 129.7 (2C), 129.0, 128.9 (2C), 128.6, 128.2,
128.1, 128.0 (2C), 127.2, 127.0, 126.94, 126.88, 126.6 (2C), 126.5, 123.0, 121.2, 118.4, 59.6, 57.1, 38.3.
NH
OH
OMe
1h
3-(4-Methoxyphenyl)-1-((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1h):
Flash chromatography (CH2Cl2/hexanes = 3:1) yields a white powder (72 mg, 0.16 mmol, 69 %). mp
146-150 oC; IR (solid): νmax 3279, 2853, 1600, 1509, 1451, 1418, 1241, 1166, 1153, 1011, 840, 756, 745,
701; 1H NMR (CDCl3, 500MHz, ppm) δ 12.13 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),
7.74 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.0 Hz, 2H), 7.35-7.27 (m, 4H),
7.12-7.07 (m, 2H), 6.93-6.91 (m, 3H), 6.73 (d, J = 8.0 Hz, 1H), 6.29 (s, 1H), 4.28 (dd, J = 11.5, 3.5 Hz,

HETEROCYCLES, Vol. 80, No. 2, 2010
1333
1H), 3.80 (s, 3H), 3.31-3.26 (m, 1H), 3.07 (dd, J = 16.5, 3.5 Hz, 1H), 2.73 (s, 1H); 13C NMR (CDCl3, 125
MHz, ppm) δ 158.8, 153.9, 142.5, 135.7, 134.1, 132.7, 132.1, 130.75 (2C), 130.71, 129.6, 128.9 (2C),
128.8, 128.5, 128.2, 128.1, 126.9, 126.8, 126.7, 126.6 (2C), 126.4, 122.9, 121.1, 118.4, 113.5 (2C), 59.4,
57.0, 55.2, 38.3; HRMS (EI): calculated for C32H27NO2: [M+•] = 457.2042 m/z; found: [M+•] 457.2047
m/z.
NH
OH
OMe
1i
3-(3-Methoxyphenyl)-1-((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1i):
Flash chromatography (CH2Cl2/hexanes = 3:1) yields a white powder (46 mg, 0.10 mmol, 48 %). Mp
134-139 oC; IR (solid): νmax 3282, 3027, 2924, 2832, 1599, 1489, 1453, 1417, 1262, 1043, 1012, 744, 726,
699; 1H NMR (CDCl3, 500MHz, ppm) δ 12.1 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H),
7.78 (s, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.37-7.28 (m, 5H), 7.22-7.09 (m, 4H), 6.93
(t, J = 8.0 Hz, 1H), 6.87 (dd, J = 8.5, 2.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.32 (s, 1H), 4.31 (dd, J =
11.5, 3.5 Hz, 1H), 3.81 (s, 3H), 3.33-3.27 (m, 1H), 3.08 (dd, J = 16.5, 3.0 Hz, 1H), 2.77 (s, 1H); 13C NMR
(CDCl3, 125 MHz, ppm) δ 159.2, 153.8, 142.4, 139.7, 135.7, 134.1, 133.0, 132.4, 130.1 (2C), 129.0,
128.9 (2C), 128.5, 128.11, 128.07, 127.0, 126.9, 126.8, 126.6 (2C), 126.5, 122.9, 122.2, 121.2, 118.4,
115.5, 112.6, 59.5, 57.1, 55.3, 38.3; HRMS (EI): calculated for C32H27NO2: [M+•] = 457.2042 m/z; found:
[M+•] 457.2030 m/z.
NH
OH
1j
3-(3,5-Di-tert-butylphenyl)-1-((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol
(1j):
Addition
of
3-(3,5-di-tert-butylphenyl)naphthalen-2-ol
(0.1
mmol)
to

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HETEROCYCLES, Vol. 80, No. 2, 2010
3-phenyl-3,4-dihydroisoquinoline (0.1 mmol). Flash chromatography (CH2Cl2/hexanes = 1:1) yields a
white powder (30 mg, 0.56 mmol, 56 %). mp 149-152 oC; IR (solid): νmax 3284, 2960, 2923, 2861, 1592,
1454, 1414, 1362, 1247, 878, 741, 700; 1H NMR (CDCl3, 500MHz, ppm) δ 12.01 (s, 1H), 8.08 (d, J = 9.0
Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.53-7.46 (m, 5H), 7.41-7.33 (m, 5H), 7.16-7.13 (m, 2H),
6.99-6.95 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.38 (s, 1H), 4.37 (dd, J = 11.5, 3.5 Hz, 1H), 3.37-3.32 (m,
13
1H), 3.12 (dd, J = 16.5, 3.0 Hz, 1H), 2.84 (s, 1H), 1.36 (s, 16H); C NMR (CDCl3, 125 MHz, ppm) δ
154.1, 150.0, 142.6, 137.4, 135.8, 134.2, 133.7, 132.9, 130.2, 129.0, 128.9 (2C), 128.6, 128.2, 128.1,
127.1, 126.8, 126.7 (2C), 126.5, 124.2 (2C), 122.8, 121.4, 121.2, 118.1, 59.6, 57.2, 38.4, 34.9, 31.6.
NH
OH
1k
3-(Naphthalen-2-yl)-1-((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol
(1k):
Flash chromatography (CH2Cl2/hexanes = 1:2) yields a white powder (52 mg, 0.11 mmol, 54 %). mp
o
1
151-154 C; IR (solid): νmax 3280, 2922, 2880, 1621, 1600, 1450, 1415, 1260, 1014, 819, 746, 700; H
NMR (CDCl3, 500MHz, ppm) δ 12.21 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 8.04 (s, 1H), 7.88-7.80 (m, 5H),
7.76 (dd, J = 8.5, 2.0 Hz, 1H), 7.53 (td, J = 7.0, 1.0 Hz, 1H), 7.54-7.43 (m, 4H), 7.39-7.27 (m, 4H),
7.15-7.10 (m, 2H), 6.96 (t, J = 7.0 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.34 (s, 1H), 4.30 (dd, J = 11.5, 3.5
13
Hz, 1H), 3.34-3.28 (m, 1H), 3.09 (dd, J = 16.5, 3.0 Hz, 1H), 2.78 (s, 1H); C NMR (CDCl3, 125 MHz,
ppm) δ 154.0, 142.4, 136.1, 135.7, 134.1, 133.4, 133.0, 132.6, 132.5, 130.4, 129.0, 128.9, 128.6, 128.3,
128.2, 128.1, 127.5, 127.2, 127.0, 126.9, 126.95, 126.87, 126.5, 125.8, 123.0, 121.2, 118.5, 59.5, 57.1,
38.3; HRMS (EI): calculated for C35H27NO: [M+•] = 477.2093 m/z; found: [M+•] 477.2101 m/z.
NH
OH
OH
1l
3-(Hydroxymethyl)-1-((3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol
(1l):
Preparative TLC (CHCl3/ethyl acetate = 17:1) yields a white powder (36 mg, 0.8 mmol, 40 %). mp
o
142-146 C; IR (solid): νmax 3595, 3292, 3057, 2922, 2891, 2853, 1627, 1452, 1406, 1261, 1198, 1055,

HETEROCYCLES, Vol. 80, No. 2, 2010
1335
1
1016, 896, 745, 701; H NMR (CDCl3, 500MHz, ppm) δ 8.03 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz,
1H), 7.69 (s, 1H), 7.53-7.47 (m, 3H), 7.41 (t, J = 7.5 Hz, 2H), 7.37-7.33 (m, 2H), 7.14-7.13 (m, 2H),
6.94-6.91 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 4.81 (d, J = 13.0 Hz, 1H), 4.75 (d, J = 13.0 Hz,
1H), 4.32 (dd, J = 11.5, 3.5 Hz, 1H), 3.36-3.31 (m,1 H), 3.13 (dd, J = 16.5, 3.5 Hz, 1H); 13C NMR
(CDCl3, 125 MHz, ppm) δ 154.5, 142.3, 135.4, 133.9, 133.0, 130.8, 129.03, 128.98, 128.6, 128.3, 128.1,
127.9, 127.40, 127.00, 127.6.69, 126.63, 126.57, 123.1, 121.3, 118.1, 62.9, 59.4, 56.9, 38.2; HRMS (EI):
calculated for C26H23NO2: [M+•] = 381.1729 m/z; found: [M+•] 381.1719 m/z.
General Procedure for Diethylzinc Additions to Aldehydes
Under nitrogen atmosphere, 0.5 mL of diethylzinc (1M in heptane) was introduced. To it, was added 0.5
mL of toluene, ligand (0.02 mmol in 0.5 mL toluene) and the corresponding aldehyde (0.25 mmol). The
o
mixture was stirred at 0 C for 72 h then quenched with 3 mL of 2M HCl. The mixture was washed
three times with 5 mL of Et2O, once with brine, dried over MgSO4 and filtered. The solvent was
removed and the product, an oil, was isolated by flash chromatography (hexanes/EtOAc = 9:1). All of the
below compounds are known compounds and the spectral data are identical to those reported in the
literature.10
(R)-1-Phenylpropan-1-ol (6a): Isolated by thin layer chromatography (hexane/EtOAc = 3:1, Rf = 0.4).
HPLC (Daicel Chiralcel OD-H, hexane/isopropanol = 97.5:2.5, flow rate = 0.5 mL/min) tR = 22.7 min, tR
= 26.4 min, ee = 69 %; 1H NMR (CDCl3, 300 MHz, ppm) δ 7.34-7.20 (m, 5H), 4.54 (t, J = 6.0 Hz, 1H),
2.54 (brs, 1H), 1.86-1.64 (m, 2H), 0.88 (t, J = 6.0 Hz, 3H).
(R)-1-p-Tolylpropan-1-ol (6b): Isolated by thin layer chromatography (hexane/ EtOAc = 3:1, Rf = 0.4).
HPLC (Daicel Chiralcel AD-H, hexane/isopropanol = 97.5:2.5, flow rate = 1.0 mL/min) tR = 11.2 min, tR
= 12.7 min, ee = 53 %; 1H NMR (CDCl3, 200 MHz, ppm) δ 7.29-7.14 (m, 4H), 4.57 (t, J = 6.6 Hz, 1H),
2.43 (s, 1H), 2.35 (s, 3H), 1.84-1.69 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).
(R)-1-(4-Methoxyphenyl)propan-1-ol (6c): Isolated by thin layer chromatography (hexane/ EtOAc = 3:1,
Rf = 0.5). HPLC (Daicel Chiralcel OD-H, hexane/isopropanol = 95:5, flow rate = 1.0 mL/min) tR = 11.8
min, tR = 13.6 min, ee = 38 %; 1H NMR (CDCl3, 300 MHz, ppm) δ 7.24 (d, J = 11.4 Hz, 2H), 6.87 (d, J =
9Hz, 2H), 4.52 (t, J = 6.6 Hz, 1H), 3.791 (s, 3H), 2.11 (s, 1H), 1.86-1.65 (m, 2H), 0.87=8 (t, J = 7.5 Hz,
3H).
(R)-1-(3-Methoxyphenyl)propan-1-ol (6d): Isolated by thin layer chromatography (hexane/EtOAc = 3:1,
Rf = 0.5). HPLC (Daicel Chiralcel OJ-H, hexane/isopropanol = 98:2, flow rate = 0.8 mL/min) tR = 31.5, tR
= 33.7 min, ee = 62 %; 1H NMR (CDCl3, 200 MHz, ppm) δ 7.30-7.22 (m, 1H), 6.93-6.79 (m, 3H), 4.57 (t,
J = 6.6 Hz, 1H), 3.81 (s, 3H), 1.94 (s, 1H), 1.89-1.69 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).
(R)-1-(4-Chlorophenyl)propan-1-ol (6e): Isolated by thin layer chromatography (hexane/EtOAc = 3:1,
Rf = 0.6). HPLC (Daicel Chiralcel OD-H, hexane/isopropanol = 98:2, flow rate = 1 mL/min) tR = 13.3

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HETEROCYCLES, Vol. 80, No. 2, 2010
min, tR = 14.2 min, ee = 70 %; 1H NMR (CDCl3, 400 MHz, ppm) δ 7.32-7.25 (m, 4H), 4.57 (t, J = 6.8 Hz,
1H), 1.96 (s, 1H), 1.82-1.67 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).
(R)-1-m-Tolylpropan-1-ol (6f): HPLC (Daicel Chiralcel OB-H, hexane/isopropanol = 95:5, flow rate =
0.5 mL/min) tR = 13.0 min, tR = 15.4 min, ee = 95 %; 1H NMR (CDCl3, 400 MHz, ppm) δ 7.24-7.21 (m,
1H), 7.15-7.07 (m, 3H), 4.53 (t, J = 7.2 Hz, 1H), 2.35 (s, 3H), 1.84-1.69 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).
(R)-1-(3-Chlorophenyl)propan-1-ol (6g): HPLC (Daicel Chiralcel OD-H, hexane/isopropanol = 96:4,
1
flow rate = 0.5 mL/min) tR = 16.7 min, tR = 17.9 min, ee = 93 %; H NMR (CDCl3, 300 MHz, ppm) δ
7.34 (s, 1H), 7.30-7.19 (m, 3H), 4.58 (t, J = 6.8 Hz, 1H), 1.98 (brs, 1H), 1.83-1.71 (m, 2H), 0.91 (t, J =
7.6 Hz, 3H).
(R)-1-(2-Chlorophenyl)propan-1-ol (6h): HPLC (Daicel Chiralcel OB-H, hexane/isopropanol =
1
97.5:2.5, flow rate = 0.5 mL/min) tR = 15.1 min, tR = 18.4 min, ee = 93 %; H NMR (CDCl3, 300 MHz,
ppm) δ 7.53 (d, J = 8.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.21-7.17 (m, 1H), 5.06 (brs, 1H), 2.10 (s, 1H),
1.86-1.67 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).
(R,E)-1-Phenylpent-1-en-3-ol (6i): HPLC (Daicel Chiralcel OD-H, hexane/isopropanol = 95:5, flow rate
= 1.0 mL/min) tR = 12.9 min, tR = 21.6 min, ee = 87 %; 1H NMR (CDCl3, 300 MHz, ppm) δ 7.38 (d, J =
7.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.25 (d, J = 6.8 Hz, 1H), 6.57 (d, J = 16.4 Hz, 1H), 6.21 (dd, J =
15.6, 6.4 Hz, 1H), 4.21 (td, J = 6.4, 6.4 Hz, 1H), 1.73-1.62 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).
ACKNOWLEDGEMENTS
We are grateful to the Canada Research Chair (Tier I) foundation (to CJL), the CFI, NSERC and ACS-GCI
Pharmaceutical Roundtable for support of our research. AR thanks NSERC for a Summer Research
Fellowship.
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