Enantioselective alkynylation of aromatic aldehydes catalyzed by readily available chiral amino alcohol-based ligands

Article abstract of DOI:10.1055/s-1999-3647

The asymmetric alkynylation reaction catalyzed by amino alcohol derived ligands (1R,2S)-3 or (1S,2R)-4 with dimethylzinc provides a simple and practical method to make chiral propargylic alcohols, and it is complementary to the asymmetric reduction method

Full text of DOI:10.1055/s-1999-3647

PAPER
1453
Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed by Readily
Available Chiral Amino Alcohol-Based Ligands
Zhen Li,* Veena Upadhyay, Ann E. DeCamp, Lisa DiMichele, Paul J. Reider
Department of Process Research, Merck Research Laboratories, Merck & Co. Inc., P. O. Box 2000, Rahway, New Jersey 07065, USA
Fax +1(732)5941499; E-mail: zhen_li@merck.com
Received 15 March 1999
for enantioselective alkynylation reactions are far from
Abstract: The asymmetric alkynylation reaction catalyzed by ami-
ideal.6–8 Some suffer from the use of substoichiometric to
no alcohol derived ligands (1R,2S)-3 or (1S,2R)-4 with dimethylz-
stoichiometric amounts of ligands or catalysts, others
from either moderate enantioselectivities or the formation
inc provides a simple and practical method to make chiral
propargylic alcohols, and it is complementary to the asymmetric re-
duction methods. In the presence of 10 mol% (1R,2S)-3 or (1S,2R)- of considerable amounts of byproducts (alkylated prod-
4, a variety of aromatic aldehydes were converted to the corre-
sponding chiral propargylic alcohols with very good enantioselec-
ucts).
Our research led us to the discovery of a practical and ef-
tivities and yields. This one-pot asymmetric reaction is carried out
ficient enantioselective method for the alkynylation of ar-
omatic aldehydes with both aromatic and aliphatic
acetylene substrates catalyzed by readily available chiral
ligands derived from commercially available amino alco-
hols. We have also devised the method to suppress the
alkyl addition to the aldehydes.
under mild reaction conditions. Neither strong base nor transmetal-
lation is required. It is an efficient reaction, greatly accelerated by
the added chiral ligand. Preliminary mechanistic and NMR studies
have also been carried out.
Key words: catalytic, asymmetric alkynylation, amino alcohol,
propargylic alcohols, dimethylzinc
O
ZnMe2, toluene/THF
HO
H
Chiral propargylic alcohols are useful building blocks for
the enantioselective synthesis of complex molecules.1 A
powerful approach to these compounds involves the
asymmetric reduction of a,b-ynones (approach A,
Scheme 1) via either the catalytic asymmetric
hydroboration2 or transition metal catalyzed transfer hy-
drogenation.3 While excellent yields and enantioselectiv-
ities are obtained for the alkyl substituted propargylic
alcohols (R1 = alkyl), there has been no report of reduction
of the corresponding aromatic a,b-ynones (R1 = Ar) by
these methods. A complementary approach to these com-
pounds involves the asymmetric addition of alkynes to ar-
omatic aldehydes (approach B, Scheme 1).
H
R2
+
*
Ar
Ar
H
ligand, 10 mol%
-20°C
R2
1
2
N
OH
N
OH
Ph
Ph
Ph
Ph
(1R,2S)-3
(1S,2R)-4
Scheme 2
A typical procedure (Scheme 2) involves the addition of
dimethylzinc (1.1–1.2 equiv) in toluene to a solution of
the alkyne (1.2 equiv) in THF at –20 °C. The chiral ligand
(0.1 equiv) is added as a solid under nitrogen atmosphere
after 15 minutes, and after another 15 minutes, the arylal-
dehyde (1 equiv) is added. The reactions are generally
complete in 18–25 hours at –20 °C to –30 °C. An array of
aromatic aldehydes has been studied under these condi-
tions, and the representative results are summarized in Ta-
ble 1. As illustrated in Table 1, the corresponding chiral
propargylic alcohols 2 were formed in very good yields
and good enantioselectivities. Most of the substituted ar-
ylaldehydes underwent the addition reaction with higher
levels of enantioselectivity compared with the parent ben-
zaldehyde. Comparison of entries 1d and 1i suggests, that
for sterically similar substrates, electronic properties have
an effect on the enantioselectivity of the addition. The re-
sults from entries 1f, 1g demonstrate that this chemistry is
applicable to both aromatic and aliphatic acetylenes. Stud-
O
-
A
+
H
R1
HO
H
R2
*
R1
R1 = alkyl group only
R2
B
O
+
H
R2
R1
H
R1 =aromatic group
Scheme 1
However, unlike the catalytic enantioselective addition of
dialkyl-4 and alkenylzinc5 compounds to aldehydes where
considerable progress has been made, the current methods
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1454
Z. Li et al.
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ies have also been carried out with disubstituted alde- phenylacetylene at 0 ºC. Among them only the amino al-
hydes, such as 2,3-difluorobenzaldehyde (entry 1c), cohol derived bidentate ligands with tertiary substituted
which provided similar results with their corresponding amino groups6,11(e.g. 3–7) provided promising results as
mono-substituted aldehydes.
shown in Table 2. It is interesting to note that ligands with
a secondary amino group, such as ligand 8, were ineffec-
tive for the asymmetric alkynylation reaction, presumably
due to the strong chelation of the NH moiety with the zinc
reagent. Encouraging results were obtained with (1R,2S)-
N-pyrrolidinylnorephedrine (ligand 6). Further modifica-
tion of ligand 6 led to the development of ligands 312 and
4, which catalyzed the alkynylation reaction with the best
results in terms of both enantioselectivity and reactivity.
Ligands 3 and 4 can easily be prepared by the N-alkylation
of the commercially available chiral 2-amino-1,2-diphe-
nylethanol with the corresponding dibromo reagents.
Table 1 Asymmetric Alkynylation of Aldehydes Catalyzed by
(1R,2S)-3 and (1S,2R)-4 with Dimethylzinca
Entry Aldehyde
R2
Ligand
ee (%)b
Yield
(%)d
1a
1b
1c
Ph
Ph
Ph
(1R,2S)-3
(1S,2R)-4
(1S,2R)-4
68(–)(S)c 70
X
Y
82(–)
90
94
N
OH
Ph
N
OH
Ph
NH
H3C
H3C
H3C
Ph
Ph
81(+)
5. X = Y = nBu (1R,2S)
6. X, Y = -(CH2)4- (1R,2S)
(S)-7
(1R,2S)-8
1d
1e
1f
Ph
Ph
Ph
(1R,2S)-3
(1R,2S)-3
(1R,2S)-3
80(+)
80(+)
76(+)
85(+)
82(+)
62(+)
75(–)
77
77
81
67
74
65
87
Table 2 Ligand Study: Alkynylation of 2-Chlorobenzaldehyde with
Phenylacetylene in the Presence of Ligands 3–8a
1g
1h
1i
C3H7 (1R,2S)-3
Ligand
3
4
5
6
7
8
Ph
Ph
Ph
(1R,2S)-3
(1R,2S)-3
(1S,2R)-4
Ee (%)b
71
95
72
97
57
88
67
96
21
50
2
58
Conv. (%)c
a Reactions were carried out at 0 ºC with 10 mol % ligands following
the general procedure described in the experimental section.
b Determined by HPLC analysis of crude reaction mixture using
Chiral Cell OD-H column (10% IPA/hexane).
1j
c Determined by HPLC analysis of crude reaction mixture. In all cas-
es, no products other than the propargylic alcohols were detected.
a Reactions were carried out at -20 ºC to –30 °C with 10 mol % ligand
3 or 4 following the general procedure.
b The enantioselectivities were determined by HPLC analysis of crude
reaction mixture using chiral columns. The sign of rotation of the pre-
dominant enantiomer is indicated in parentheses.
A major challenge in the catalytic alkynylations with di-
alkylzinc reagents is to suppress or eliminate the undes-
ired transfer of the alkyl group, which was introduced by
the zinc reagent, to aldehydes. As reported in the litera-
ture,4 dialkylzincs are powerful regents for the transfer of
the alkyl groups to aldehydes. Indeed, alkylation of the al-
dehydes has been reported as a major side reaction in the
organozinc mediated enantioselective alkynylation reac-
tions in the literature.8b In our system, when the asymmet-
ric alkynylation reaction was carried out in toluene, the
corresponding a-methylaryl alcohol was obtained as a
byproduct in 5–12% yield. We were pleased to discover
that the use of 2.75/1 toluene/THF13 totally eliminated or
c The absolute configuration is based on measurement of the optical
rotation and comparison with the literature. See: 7b and Ramachan-
dran, P. V.; Teodorovic, A. V.; Rangaishenvi, M. V.; Brown, H. C. J.
Org. Chem. 1992, 57, 2379.
d Isolated yield of the corresponding propargylic alcohols.
The efficiency of the catalytic asymmetric alkynylation
reaction relies on the use of appropriate chiral ligands. A
series of chiral ligands, which included multidentate,9 tri-
dentate and bidentate ligands,10 was explored for the catal-
ysis of the alkynylation of 2-chlorobenzaldehyde with
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Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed
1455
greatly suppressed the methyl addition. In our optimized with an acetylene group became possible. Therefore, it is
conditions, the chiral propargylic acids were obtained as reasonable to postulate that there is no formation of the
the only product in all entries except in entry 1f where methyl (alkynyl) zinc species before the addition of the
2–3 % of the a-methylaryl alcohol was detected in the ligand. In the presence of the ligand, a complex involving
NMR of the crude reaction mixture.
zinc, the alkynyl group and the ligand is formed; this com-
plex is responsible for the transfer of the alkynyl group to
the aldehyde. Thus it is not surprising to find that the cat-
alytic asymmetric alkynylation reaction described above
is accelerated to a significant extent by the added ligand.
In the presence of 10 mol% ligand (1R,2S)-3, the dimeth-
ylzinc mediated addition of phenylacetylene to 2-chlo-
robenzenealdehyde was completed in 3 hours at 0ºC. By
comparison, in the absence of the chiral ligand, the reac-
tion proceeded to 30% conversion in 17 hours at 0ºC to
room temperature. Ligand acceleration is an important
phenomenon, and has been identified in several other
asymmetric catalytic reactions.15
A preliminary mechanistic study of the system was car-
ried out. Examination of the alkynylation reaction using
ligands of varying enantiomeric compositions provided
evidence that the intermediates involved are not mono-
meric.14 As demonstrated in the Figure, a nonlinear corre-
lation between ligand ee and product ee was observed
for the dimethylzinc mediated alkynylation of 2-fluoro-
benzaldehyde with phenylacetylene at –20 ºC catalyzed
by 10 mol% of ligand (1R,2S)-3.
The asymmetric alkynylation reaction catalyzed by amino
alcohol derived ligand (1R,2S)-3 or (1S,2R)-4 outlined
above provides a simple and practical method to make
chiral propargylic alcohols, and it is complementary to the
asymmetric reduction methods. This one-pot asymmetric
reaction is carried out under mild reaction conditions.
Neither strong base nor transmetallation is required. It is
also an efficient reaction, greatly accelerated by the added
catalytic amount of chiral ligand. Our NMR studies illus-
trate, for the first time, the ligand’s role in the formation
of chiral zinc-acetylide species. Applications of the cata-
lyst system to other enantioselective reactions are in
progress.
Reagents are used as received unless otherwise stated. 3Å molecu-
lar sieves were used to dry solvents for the alkynylation reaction.
Unless otherwise noted, all manipulations were carried out under an
inert atmosphere of N2. The glassware was oven dried prior to use
for the alkynylation reactions. Flash column chromatography was
performed using silica gel (EM Science, Silica gel 60, 230–400
mesh ASTM). Dimethylzinc was obtained from Aldrich as a 2M so-
lution in toluene, and was used as it was. 1H and 13C NMR chemical
shifts are reported in ppm; coupling constants are reported in Hz. 1H
and 13C NMR were recorded on Bruker 300 AM. IR spectra were
recorded on a Nicolet 510P FT-IR Spectrometer. Elemental analy-
ses were obtained from Quantitative Technologies Inc, Whitehouse,
NJ.
Figure Plot of ee of the propargylic alcohol as a function of ee of
ligand 3 in the dimethylzinc mediated enantioselective alkynylation
of 2-fluorobenzaldehyde with phenylacetylene in the presence of 10
mol% ligand 3 at –20 ºC. The enantioselectivities were determined by
HPLC analysis of crude reaction mixtures using Chiralcell OD-H co-
lumn (10% IPA in hexane).
An NMR study of the reaction revealed some further
mechanistic insights. When dimethylzinc was added to
the solution of phenylacetylene in the absence of ligand,
1H and 13C NMR spectra of the mixture exhibited only the
independent signals of each compound. In particular, the
chemical shift of the triple bond in phenylacetylene still
remained at its original positions (79.1 and 84.4 ppm) in
the 13C NMR spectra. Thus, no interaction between dime-
thylzinc and phenylacetylene was observed at this point.
As the ligand (1R,2S)-3 was added to the mixture, the for-
(–)-1,3-Diphenylprop-2-yn-1-ol (2a)7a
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by elution with 8%
EtOAc/hexane. The enantiomeric excess was determined by HPLC
analysis of reaction mixtures on a Chiralcel OD-H column (20%
IPA/hexane).
IR (nujol gel): n = 3365, 3062, 3031, 2198, 1597, 1453, 1031, 756
cm–1;
mation of new species were observed in both 1H and 13C 1NMR (CDCl3, 300 MHz): d = 7.66 (m, 2 H, ArH), 7.52–7.48 (m, 2
H, ArH), 7.46–7.32 (m, 6 H, ArH), 5.71 (d, J = 6.1 Hz, 1 H), 2.50
(d, J = 6.2 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): d = 140.7, 131.8, 128.7, 128.6, 128.5,
128.4, 126.8, 122.5, 88.8, 86.7, 65.2.
NMR. A lowfield shift of the triple bond resonances from
79.1 and 84.4 ppm to 107.8 and 114.1 ppm respectively in
the 13C NMR spectrum indicated the zinc-acetylide for-
mation. The NMR study suggests that as the electronic
and steric properties around zinc were changed with the
addition of the ligand, substitution of the methyl group
Anal Calcd for C15H12O: C, 86.51; H, 5.81; O, 7.68. Found: C,
86.83; H, 5.82; O, 8.08.
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Z. Li et al.
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(–)-1-(2-Fluorophenyl)-3-phenylprop-2-yn-1-ol (2b)16
1H NMR (CDCl3, 300 MHz): d = 7.85 (d, J = 7.3 Hz, 1 H, ArH),
7.48 (m, 2 H, ArH), 7.43–7.27 (m, 6 H, ArH), 6.06 (s, 1 H), 2.70 (s,
1 H).
13C NMR (CDCl3, 75 MHz): d = 137.9, 132.9, 131.8, 129.8, 129.7,
128.7, 128.5, 128.4, 127.3, 122.3, 87.6, 86.7, 62.5.
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by gradient elution with
4% EtOAc/hexane (250 mL) and then 8% EtOAc/hexane (500 mL).
The enantiomeric excess was determined by HPLC analysis of re-
action mixtures on a Chiralcel OD-H column (10% IPA/hexane).
Anal Calcd for C15H11ClO: C, 74.23; H, 4.57; O, 6.59; Cl, 14.61.
Found: C, 73.96; H, 4.74; O, 6.96; Cl, 14.63.
IR (nujol gel): n = 3336, 2923, 2853, 2230, 1588, 1377, 1224, 754,
690 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.75 (td, J1 = 7.5 Hz, J2 = 1.7 Hz,
1 H, ArH), 7.50–7.47 (m, 2 H, ArH), 7.36–7.32 (m, 4 H, ArH),
7.23–7.18 (m, 1 H, ArH), 7.14–7.07 (m, 1 H, ArH), 5.98 (s, 1 H),
2.38 (s, 1 H).
13C NMR (CDCl3, 75 MHz): d = 160.3 (d, JCF = 248.5), 131.8, 131.1
(d, JCF = 8.3), 128.8, 128.5 (d, JCF = 3.3), 128.4, 127.9 (d, JCF = 13),
124.5 (d, JCF = 3.4), 122.3, 115.8 (d, JCF = 21.6), 87.6, 86.6, 59.6 (d,
JCF =4.7).
(+)-1-(2-Bromophenyl)-3-phenylprop-2-yn-1-ol (2e)17
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by elution with 10%
EtOAc/hexane. The enantiomeric excess was determined by HPLC
analysis of reaction mixtures on a Chiralcel OD-H column (5%
IPA/hexane).
IR (nujol gel): n = 3190, 2924, 2854, 1488, 1377, 1050, 1021, 753
cm–1.
1HNMR (CDCl3, 300 MHz): d = 7.86 (dd, J1 = 7.7 Hz, J2 = 1.6 Hz,
1 H, ArH), 7.60 (dd, J1 = 7.9 Hz, J2 = 1.0 Hz, 1 H, ArH), 7.50–7.47
(m, 2 H, ArH), 7.42–7.32 (m, 4 H, ArH), 7.26–7.19 (m, 1 H, ArH),
6.03 (d, 1 H, J = 5.2 Hz), 2.67 (d, 1 H, J = 5.2 Hz).
13C NMR (CDCl3, 75 MHz): d = 139.6, 133.1, 131.9, 130.0, 128.7,
128.4, 128.0, 122.9, 122.4, 87.9, 86.8, 64.7.
Anal. Calcd for C15H11FO: C, 79.63; H, 4.90; F, 8.40. Found: C,
79.67; H, 4.85; F, 8.19
Asymmetric Alkynylation Reactions. (+)-1-(2,3-Difluorophe-
nyl)-3-phenylprop-2-yn-1-ol (2c); Typical Procedure
Phenylacetylene (285.6 µL, 2.6 mmol) was added via a gas tight sy-
ringe to a 15 mL two-neck round bottom flask containing 0.4 mL
sieve-dried THF at r.t. under N2. The stirred mixture was then
cooled to –20 ºC for 5 minutes, followed by the addition of dimeth-
ylzinc in toluene 2M (1.2 mL, 2.4 mmol). The resulting solution
was stirred at –20 ºC for 15 min, and ligand (1S,2R)-4 (63.08 mg,
0.2 mmol) was added as a solid under N2. The homogenous solution
was stirred at –20 ºC for 15 min, and then 2,3-difluorobenzaldehyde
(1c) (284.2 mg, 2.0 mmol) was added via a syringe. The resulting
mixture was stirred at –20 ºC as reaction progress was monitored by
HPLC. When the reaction was complete (98% conversion, 18 h), it
was quenched by the addition of MeOH (1 mL) at –20 ºC, and as it
warmed to 0 ºC, sat. NH4Cl (2 mL) was added. EtOAc (50 mL) and
sat. NH4Cl (10 mL) were then added and the layers were separated.
The aqueous layer was extracted with EtOAc (2 x 20 mL). The com-
bined organic phase was washed with brine and dried (MgSO4). Af-
ter filtration, the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (silica gel,
10/1 hexane/EtOAc) to afford 460.8 mg (94% yield, 81% ee) pure
product. The enantiomeric excess was determined by HPLC analy-
sis of reaction mixtures on a Chiralcel OD-H column (5–10% IPA/
hexane).
Anal. Calcd for C15H11BrO: C, 62.74; H, 3.86; O, 5.57; Br, 27.83.
Found: C, 62.67; H, 4.05; O, 5.79; Br, 28.18.
(+)-1-(2-Nitrophenyl)-3-phenylprop-2-yn-1-ol (2f)
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by elution with 8%
EtOAc/hexane. The enantiomeric excess was determined by HPLC
analysis of reaction mixtures on a Chiralcel OD-H column (10%
IPA/hexane).
IR (nujol gel): n = 3180, 2923, 2854, 2220, 1522, 1376, 1033, 753
cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.03–7.98 (m, 2 H, ArH), 7.69 (td,
J1 = 7.61 Hz, J2 = 1.31 Hz, 1 H, ArH), 7.53 (td, J1 = 7.85 Hz, J2 =
1.42 Hz, 1 H, ArH), 7.48–7.41 (m, 2 H, ArH), 7.37–7.28 (m, 3 H,
ArH), 6.21 (s, 1 H), 3.28 (s, 1 H).
13C NMR (CDCl3, 75 MHz): d = 148.1, 135.5, 133.9, 131.9, 129.6,
129.4, 128.9, 128.4, 125.1, 121.9, 86.9, 86.6, 61.9.
Anal. Calcd for C15H11NO3: C, 71.14; H, 4.38; N, 5.53. Found: C,
70.80; H, 4.52; N, 5.37.
IR (nujol gel): n = 3270, 2923, 2853, 2270, 1376, 1272, 755 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.53–7.46 (m, 3 H, ArH), 7.45–
7.29 (m, 3 H, ArH), 7.22–7.10 (m, 2 H, ArH), 5.98 (s, 1 H), 2.30 (s,
1 H).
(+)-1-(2-Nitrophenyl)hex-2-yn-1-ol (2g)
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by elution with 10%
EtOAc/hexane. The enantiomeric excess was determined by HPLC
analysis of reaction mixtures on a Chiralpak AS column (5% IPA/
hexane).
13C NMR (CDCl3, 75 MHz): d = 150.5 (dd, J1CF = 261.2 Hz, J2CF
=
12.7 Hz), 148.4 (dd, J1CF = 250.5 Hz, J2CF = 12.7 Hz), 131.8, 130.3
(d, JCF = 10.1 Hz), 128.9, 128.4, 124.4 (dd, J1CF = 6.5 Hz, J2CF = 4.9
Hz), 123.1 (t, JCF = 2.8 Hz), 122.1, 117.4 (d, JCF = 17.1), 87.0 (d, JCF
= 20.9 Hz), 59.2 (dd, J1CF = 5.1 Hz, J2CF = 3.0 Hz).
IR (nujol gel): n = 3385, 2964, 2934, 2872, 2220, 1608, 1350, 1034,
725 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.96 (t, J = 1.93 Hz, 1 H, ArH),
7.93 (dd, J1 = 2.39 Hz, J2 = 1.5 Hz, 1 H, ArH), 7.66 (td, J1 = 7.59
Hz, J2 = 1.15 Hz, 1 H, ArH), 7.49 (td, J1 = 7.69 Hz, J2 = 1.44 Hz, 1
H, ArH), 5.97 (t, J1 = 1.97 Hz, 1 H), 2.22 (td, J1 = 7.13 Hz, J2 = 2.06
Hz, 2 H), 2.17 (s, 1H), 1.60–1.49 (m, 2H), 0.97 (t, J = 7.33 Hz, 3H).
13C NMR (CDCl3, 75 MHz): d = 148.2, 136.0, 133.7, 129.4, 129.1,
124.9, 88.0, 78.0, 61.5, 21.9, 20.7, 13.5.
Anal Calcd for C15H10F2O: C, 73.76; H, 4.13; F, 15.56. Found: C,
73.77; H, 4.04; F, 15.46.
(+)-1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol (2d)
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by elution with 9%
EtOAc/hexane. The enantiomeric excess was determined by HPLC
analysis of reaction mixtures on a Chiralcel OD-H column (10%
IPA/hexane).
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39; O, 21.89.
Found: C, 65.83; H, 5.99; N, 6.43; O, 21.53.
IR (nujol gel): n = 3180, 2923, 2854, 2270, 1488, 1376, 1023, 746
cm–1.
Synthesis 1999, No. SI, 1453–1458 ISSN 0039-7881 © Thieme Stuttgart · New York

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Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed
1457
(+)-1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (2h)
crude product was purified by crystallization from hexane to give
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by gradient elution with
5% EtOAc/hexane (350 mL) and 11% EtOAc/hexane (600 mL).
The enantiomeric excess was determined by HPLC analysis of re-
action mixtures on a Chiralcel OD column (10% IPA/hexane).
4.5 g (85% yield) of pure (1R,2S)-3 as a white solid.
IR (nujol gel): n = 3450, 2922, 2853, 1376, 1335, 1193, 773 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.15–7.07 (m, 5 H, ArH), 6.99–
6.92 (m, 5 H, ArH), 5.26 (d, J = 3.58 Hz,, 1 H), 3.72 (s, 1 H), 3.31
(d, J = 3.47 Hz, 1 H), 2.77–2.72 (m, 2 H), 2.64–2.57 (m, 2H), 1.87–
1.83 (m, 4H).
IR (nujol gel): n = 3397, 2924, 2854, 2240, 1489, 1247, 1028, 763
cm–1.
13C NMR (CDCl3, 75 MHz): d = 140.7, 137.5, 129.3, 127.5, 127.3,
127.1, 126.8, 126.2, 76.9, 74.1, 53.0, 23.6.
1H NMR (CDCl3, 300 MHz): d = 7.66 (dd, J1 = 7.52 Hz, J2 = 1.72
Hz, 1 H, ArH), 7.52–7.46 (m, 2 H, ArH), 7.37–7.29 (m, 4 H, ArH),
7.02 (td, J1 = 7.43 Hz, J2 = 0.94 Hz, 1 H, ArH), 6.96–6.93 (m, 1 H,
ArH), 5.94 (d, J = 5.65 Hz, 1 H), 3.93 (s, 3 H), 3.10 (d, J = 5.90 Hz,
1H).
Anal Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24; O, 5.98.
Found: C, 80.79; H, 8.07; N, 5.07; O, 5.84.
(1S,2R)-2-(1,3-dihydroisoindol-2-yl)-1,2-diphenylethanol (4)18
Sodium carbonate (7.4 g, 70 mmol) was added as a solid to a stirred
solution of a,a’-dibromo-o-xylene (3.96 g, 15 mmol) in CH3CN (30
mL) in a 3-neck round bottom flask. After the addition, the mixture
was stirred at r.t. for 5 min, and then (1S,2R)-2-amino-1,2-diphe-
nylethanol (2.13 g, 10 mmol) was added. The resulting mixture was
stirred vigorously and heated to reflux for 12 h, after which time it
was cooled down to r.t. and H2O (30 mL) was added. The layers
were separated, and the aqueous layer was extracted with TBME (3
x 150 mL). The combined organic layers were washed with brine
(150 mL), dried (MgSO4), filtered and concentrated. The crude
product was purified by column chromatography (silica gel, 10:1
hexane: EtOAc). It was then dissolved in hexane, and filtered to get
rid of the insoluble reddish solid. The filtrate was then concentrated
to provide the pure product (70% yield) as a light colored solid.
13C NMR (CDCl3, 75 MHz): d = 156.9, 131.8, 129.8, 128.9, 128.5,
128.3, 128.1, 122.8, 120.1, 111.0, 88.6, 86.1, 61.6, 55.7.
Anal. Calcd for C16H14O2: C, 80.65; H, 5.92; O, 13.43. Found: C,
80.35; H, 5.87; O, 13.34.
(+)-1-(2-Methylphenyl)-3-phenylprop-2-yn-1-ol (2i)
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by elution with 10%
EtOAc/hexane. The enantiomeric excess was determined by HPLC
analysis of reaction mixtures on a Chiralcel OD-H column (10%
IPA/hexane).
IR (nujol gel): n = 3246, 2923, 2853, 2220, 1376, 753 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.74 (m, 1 H, ArH), 7.48 (m, 2 H,
ArH), 7.45–7.20 (m, 6 H, ArH), 5.85 (s, 1 H), 2.51 (s, 3 H).
IR (nujol gel): n = 3200, 2923, 2853, 2283, 1376, 750 cm–1.
13C NMR (CDCl3, 75 MHz): d = 138.4, 136.1, 131.8, 130.9, 128.6,
128.5, 128.4, 126.7, 126.3, 122.6, 88.6, 86.5, 62.9, 19.1.
1H NMR (CDCl3, 300 MHz): d = 7.26–7.18 (m, 5 H, ArH), 7.16–
7.13 (m, 5 H, ArH), 7.06–6.95 (m, 4 H, ArH), 5.34 (d, J = 3.35 Hz,
1 H), 4.10 (dd, J1 = 23.24 Hz, J2 = 11.74 Hz, 4 H), 3.76 (d, J = 3.34
Hz, 1 H).
Anal Calcd for C16H14O: C, 86.45, H, 6.35; O, 7.20. Found: C,
86.32; H, 6.31; O, 7.21.
13C NMR (CDCl3, 75 MHz): d = 140.3, 139.2, 136.5, 129.5, 127.6,
(–)-1-(2-naphthyl)-3-phenylprop-2-yn-1-ol (2j)
The typical procedure for 2c was followed. The compound was pu-
rified by flash chromatography (silica gel) by elution with 10%
EtOAc/hexane. The enantiomeric excess was determined by HPLC
analysis of reaction mixtures on a Whelk-O column (4% IPA/hex-
ane).
127.5, 127.1, 127.0, 126.2, 122.4, 76.6, 76.6, 74.0, 58.3.
Anal Calcd for C22H21NO: C, 83.78; H, 6.71; N, 4.44. Found: C,
83.59; H, 6.66; N, 4.33.
References and Notes
IR (nujol gel): n = 3267, 2924, 2854, 2220, 1597, 1376, 1169, 754
cm–1.
(1) Nicolaou, K. C.; Webber, S. E. J. Am. Chem. Soc. 1984, 106,
5734.
1H NMR (CDCl3, 300 MHz): d = 8.06 (s, 1 H, ArH), 7.90–7.86 (m,
3 H, ArH), 7.75 (dd, J1 = 8.64 Hz, J2 = 1.18 Hz, 1 H, ArH), 7.55–
7.52 (m, 4 H, ArH), 7.37–7.34 (m, 3 H, ArH), 5.88 (d, J =1.63 Hz,
1H), 2.94 (s, 1 H).
13C NMR (CDCl3, 75 MHz): d = 138.1, 133.4, 133.3, 131.9,128.7,
128.7, 128.4, 128.3, 127.8, 126.4, 125.6, 124.8, 122.5, 88.9, 86.9,
65.3.
Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.;
Hamada, Y. Tetrahedron Lett. 1986, 27, 2199.
Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116,
6457.
Vourloumis, D.; Kim, K. D.; Petersen, J. L.; Magriotis, P. A.
J. Org. Chem. 1996, 61, 4848.
(2) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153.
Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc.
1996, 118, 10938.
Anal. Calcd for C19H14O: C, 88.34; H, 5.46; O, 6.19. Found: C,
87.94; H, 5.09; O, 6.25.
Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214.
Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1997, 38, 7511.
Midland, M. M.; Kazubski, A. J. Org. Chem. 1982, 47, 2814.
(3) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738
(4) a) For a review of asymmetric alkylation reactions, see:
Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49.
b) Williams, D. R.; Fromhold, M. G. Synlett 1997, 523.
(5) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170.
Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115,
1593.
(6) For a review of the addition of organozinc reagents to
aldehydes, see: Soai, K., Niwa, S. Chem. Rev. 1992, 92, 833.
(1R,2S)- 1,2-diphenyl-2-pyrrolidin-1-ylethanol (3)12
Sodium carbonate (8.48 g, 80 mmol) was added as a solid to a
stirred solution of 1,4-dibromobutane (2.87 mL, 24 mmol) in
CH3CN (80 mL) in a 3-neck round bottom flask. After the addition,
the mixture was stirred at r.t. for 5 min, and then (1R,2S)-2-amino-
1,2-diphenylethanol (4.27 g, 20 mmol) was added. The resulting
mixture was stirred vigorously and heated to reflux for 12 h, after
which time it was cooled down to r.t. and H2O (100 mL) was added.
The layers were separated, and the aqueous layer was extracted with
TBME (3 x 250 mL). The combined organic layers were washed
with brine (250 mL), dried (MgSO4), filtered and concentrated. The
Synthesis 1999, No. SI, 1453–1458 ISSN 0039-7881 © Thieme Stuttgart · New York

1458
Z. Li et al.
PAPER
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3151.
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b) Ramos Tombo, G. M.; Didier, E.; Loubinoux, B. Synlett
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(10) Bidentate ligands such as diimine, binaphthol, (–)-DAIB,
pyrrolidine methanol and its derivatives, and amino alcohol
and its derivatives were studied in the reaction.
(11) Thompson, A. S.; Corley, E. G.; Huntington, M. F.;
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Thompson, A. S.; Corley, E. G.; Huntington, M. F.;
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(18) The chiral compound is not known. For the reference on the
racemic form see:
Patent; Heidenbluth, K.; Franke, J.; Faltus, H.; Tönjes, H.;
Schmidt, J. VEB
Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120,
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ARZNEIMITTELWERK DRESDEN; FR 1578569; 1968.
Patent; Heidenbluth, K.; Franke, J.; Faltus, H.; Tönjes, H.;
Schmidt, J. DD 69802; 1969.
Article Identifier:
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Synthesis 1999, No. SI, 1453–1458 ISSN 0039-7881 © Thieme Stuttgart · New York