Highly enantioselective 1,2-additions of various organolithium reagents to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2006.07.009

Several asymmetric 1,2-additions of various organolithium reagents (methyllithium, n-butyllithium, phenyllithium, lithioacetonitrile, lithium n-propylacetylide, lithium phenylacetylide) to aldehydes are shown to result in decent to excellent enantiomeric excesses (65-98%) when performed in the presence of a chiral lithium amido sulfide. The chiral lithium amido sulfides invariably exhibited higher levels of enantioselectivity in all the reactions tested, compared to the structurally similar chiral lithium amido ethers and the chiral lithium amide without a chelating group.

Full text of DOI:10.1016/j.tetasy.2006.07.009

Tetrahedron: Asymmetry 17 (2006) 2021–2027
Highly enantioselective 1,2-additions of various
organolithium reagents to aldehydes
Johan Granander, Jonas Eriksson and Goran Hilmersson*
¨
Department of Chemistry, Organic Chemistry, Go¨teborg University, SE-41296 Go¨teborg, Sweden
Received 8 June 2006; accepted 7 July 2006
Abstract—Several asymmetric 1,2-additions of various organolithium reagents (methyllithium, n-butyllithium, phenyllithium, lithio-
acetonitrile, lithium n-propylacetylide, lithium phenylacetylide) to aldehydes are shown to result in decent to excellent enantiomeric
excesses (65–98%) when performed in the presence of a chiral lithium amido sulfide. The chiral lithium amido sulfides invariably exhib-
ited higher levels of enantioselectivity in all the reactions tested, compared to the structurally similar chiral lithium amido ethers and the
chiral lithium amide without a chelating group.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
pounds can potentially be used as precursors in the synthe-
sis of novel chiral c-hydroxy amines and b-hydroxy
carboxylic acids. The success in the asymmetric 1,2-addi-
tion of lithium cyclopropylacetylide to a trifluoromethyl
ketone, yielding a precursor to efivarenz, shows that func-
tionalized organolithium reagents also can play a valuable
role in the development of enantiopure pharmaceuticals.
The asymmetric 1,2-addition of lithium cyclopropylacetyl-
ide has been studied in great detail and has resulted in
enantiomeric excesses of 99% and excellent conver-
sions.20–22
The asymmetric formation of new carbon–carbon bonds is
an area of organic synthesis currently experiencing intense
research. The nucleophilic 1,2-addition of an organometal-
lic reagent to a prochiral carbonyl substrate is frequently
used to create a new carbon–carbon bond and introduce
a new stereogenic centre.1–3 Organozinc reagents have pro-
ven particularly suited for this reaction due to their low
reactivity in the absence of a coordinating ligand and sev-
eral highly enantioselective and catalytic reactions have
been reported. However, the higher intrinsic reactivity of
organolithium reagents and the wider selection of reagents
available, directly and indirectly, make them an invaluable
alternative. The asymmetric 1,2-addition of alkyllithiums
to aldehydes produces optically active secondary alcohols
which can be used as chiral building blocks in further
asymmetric synthesis. Since the seminal work by Nozaki
in 1968, asymmetry has been induced in the 1,2-addition
reaction of alkyllithium reagents to aldehydes using chiral
amines,4–6 chiral lithium alkoxides7–9 and chiral lithium
amides.10–16 In contrast to the number of reports on asym-
metric 1,2-additions of alkyllithiums, only a handful of
studies have been devoted to the enantioselective 1,2-addi-
tion of functionalized organolithium reagents.17–19 The 1,2-
addition of lithiated nitriles to aldehydes, for example,
yields synthetically versatile b-hydroxy nitriles. These com-
Recently, we reported on the excellent enantioselectivity in
the 1,2-addition of n-butyllithium and methyllithium to
aldehydes induced by a novel chiral lithium amido sul-
fide.23 Herein, we report on the efficiency of the lithium
amido sulfide as a ligand in the asymmetric 1,2-addition
of alkyllithiums and functionalized organolithium reagents
(phenyllithium, lithioacetonitrile, lithium phenylacetylide
and lithium n-propylacetylide) to aldehydes. A comparison
of the enantioselectivity in the 1,2-addition reaction
between chiral lithium amides, formed from amines 1–6,
is also reported.
2. Results and discussion
Chiral amines, (S)-1, (R)-2, (S)-4 and (R)-6, were prepared
from (S)-phenylethylamine or (R)-phenylglycine according
to previously published methods.14,23–25 The novel chiral
*
Corresponding author. Tel.: +46 31 772904; fax: +46 31 7723840; e-mail:
hilmers@chem.gu.se
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.009

2022
J. Granander et al. / Tetrahedron: Asymmetry 17 (2006) 2021–2027
N
N
O
N
S
H
H
H
(S)-1
(R)-2
(R)-3
N
O
N
O
N
S
H
H
H
(R)-5
(R)-6
(S)-4
Table 1. Enantiomeric excesses and conversions of the 1,2-addition of
alkyl- and phenyllithium reagents (0.30 mmol) to aldehydes (0.05 mmol)
mediated by chiral amines (0.20 mmol) in Et2O/THF (2.0 mL) at ꢀ116 ꢁC
amino sulfide (R)-3 was synthesized in a fashion similar to
the preparation of (R)-6. The key step of the preparation of
(R)-5 was the copper(II)-catalyzed etherification of the cor-
responding tert-butoxycarbonyl amido alcohol using
potassium trifluorophenylborate according to the method
reported by Batey.26
Entry
Amine
R
R0
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
(S)-1
(R)-2
(R)-3
(S)-4
(R)-5
(R)-6
(S)-1
(R)-2
(R)-3
(S)-4
(R)-5
(R)-6
(S)-1
(R)-2
(R)-3
(S)-4
(R)-5
(R)-6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
CH3
CH3
CH3
CH3
CH3
CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
Ph
Ph
Ph
Ph
Ph
37
89
64
65
96
70
73
93
85
84
96
82
76
92
89
80
89
80
21 (S)a
79 (S)a
82 (S)a
75 (S)a
94 (S)a
96 (S)a
28 (S)b
80 (S)b
88 (S)b
79 (S)b
96 (S)b
98 (S)b
1 (R)c
The amines were lithiated and used as chiral inducers in the
1,2-addition of methyllithium, n-butyllithium and phenyl-
lithium to benzaldehyde and cyclohexanecarboxaldehyde,
respectively, in diethyl ether (Et2O)/tetrahydrofuran
(THF) mixtures at ꢀ116 ꢁC (Scheme 1). The product com-
positions were analyzed using chiral stationary phase gas
chromatography and the conversions and enantiomeric
excesses of the reactions are given in Table 1.
82 (R)c
95 (R)c
92 (R)c
80 (R)c
96 (R)c
O
HO
R
H
1. Li-amide (4.0 eq.), R'Li (2.0 eq.)
2. Methanol
R
H
R'
Scheme 1. Asymmetric 1,2-addition of alkyl- or phenyllithium to
aldehydes mediated by chiral lithium amides.
Ph
a Absolute configuration determined by comparison with authentic (S)-1-
phenyl-1-ethanol.23
Lithium amido sulfide Li-6 is the most efficient ligand,
yielding impressive enantiomeric excesses of 96%, 98%
and 96% in the additions of methyllithium, n-butyllithium
and phenyllithium, respectively. The chiral lithium amide
without an internal chelating group, Li-1, is evidently a
poor ligand in the reactions studied. The inability to form
a rigid chelate appears to have a very detrimental effect on
the enantioselectivity of the reaction. The conversions
using Li-1 are generally lower than when using the other
amides, possibly because the lesser steric bulk makes the
lithium amide able to add to the substrate aldehyde itself.
The lithium amido ethers, Li-2, Li-4 and Li-5 all produce
good selectivities with enantiomeric excesses ranging from
75% to 96%. Aryl ether Li-5 is the most effective of the lith-
ium amido ethers at inducing chirality in the addition of
alkyllithiums, while being the least effective ligand for
phenyllithium additions. When comparing the lithium ami-
do sulfides with the structurally analogues lithium amido
ethers, Li-3 versus Li-2 and Li-6 versus Li-5, it becomes
evident that the lithium amido sulfides are more efficient
at inducing asymmetry in the reaction.
b Absolute configuration determined by comparison of the specific rota-
tion with the literature values.27
c Absolute configuration determined by comparison of the specific rotation
with the literature values.28
The 1,2-addition of lithioacetonitrile to benzaldehyde
yields 3-hydroxy-3-phenylpropionitrile, a potential precur-
sor of fluoxetine. Previous studies of this reaction have re-
vealed a wide variety of different mixed complexes between
chiral lithium amides and lithioacetonitrile in solution.18,29
Asymmetric 1,2-addition reactions using chiral b-amino
ethers, have previously resulted in an enantiomeric excess
of 55%, when using Li-2 as the chiral inducer. Inspired
by the efficiency of Li-6 in the addition of alkyl- and
phenyllithium, the 1,2-addition of lithioacetonitrile to
benzaldehyde was re-examined using the new ligands. Lithio-
acetonitrile was generated in situ in the reaction vessel by
adding acetonitrile to a mixture of the chiral amine and
n-butyllithium at ꢀ78 ꢁC. The reaction was subsequently
cooled further to ꢀ116 ꢁC, and benzaldehyde was added

J. Granander et al. / Tetrahedron: Asymmetry 17 (2006) 2021–2027
2023
O
HO
H
N
1. Li-amide (4.0 eq.), LiCH2CN (2.0 eq.)
2. Methanol
H
Scheme 2. Asymmetric 1,2-addition of lithioacetonitrile to benzaldehyde yielding 3-hydroxy-3-phenylpropionitrile.
Table 3. Enantiomeric excesses and conversions of the 1,2-addition of
acetylenes (0.11 mmol) to aldehydes (0.05 mmol) mediated by chiral
amines (0.20 mmol) and n-butyllithium (0.30 mmol) in Et2O/THF
(2.0 mL) at ꢀ116 ꢁC
(Scheme 2). The products were analyzed using chiral sta-
tionary phase gas chromatography and the conversions
and enantiomeric excesses of the reactions are given in
Table 2.
Entry
Amine
R
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
(S)-1
(R)-2
(R)-3
(S)-4
(R)-5
(R)-6
(S)-1
(R)-2
(R)-3
(S)-4
(R)-5
(R)-6
(CH2)2CH3
(CH2)2CH3
(CH2)2CH3
(CH2)2CH3
(CH2)2CH3
(CH2)2CH3
Ph
Ph
Ph
Ph
Ph
48
66
40
47
79
34
31
91
67
78
92
42
66 (–)a
66 (–)a
69 (–)a
39 (–)a
57 (–)a
65 (–)a
84 (S)b
88 (S)b
90 (S)b
83 (S)b
82 (S)b
91 (S)b
Table 2. Enantiomeric excesses and conversions of the 1,2-addition of
acetonitrile (0.11 mmol) to benzaldehyde (0.05 mmol) mediated by chiral
amines (0.20 mmol) and n-butyllithium (0.30 mmol) in Et2O/THF
(2.0 mL) at ꢀ116 ꢁC
Entry
Amine
Conv. (%)
ee (%)a
1
2
3
4
5
6
(S)-1
(R)-2
(R)-3
(S)-4
(R)-5
(R)-6
81
97
60
82
90
88
12 (S)
55 (S)
31 (S)
15 (S)
5 (S)
10
11
12
75 (S)
Ph
a Absolute configuration determined by comparison with authentic (S)-3-
hydroxy-3-phenylpropionitrile.30
a Absolute configuration not determined.
b Absolute configuration determined by comparison of the specific rota-
tion with the literature values.32
The lithium amide without an internally chelating group,
Li-1, again only yielded a very low level of enantioselectiv-
ity but pleasingly the lithium amido sulfide Li-6 provided
the b-hydroxy nitrile product in an enantiomeric excess
of 75%. Though still far from being stereospecific it still
is a vast improvement compared to previous attempts.
Rather surprisingly the structurally analogues lithium
amido aryl ether, Li-5, yields an almost racemic product.
Li-1, actually offers an enantioselectivity of 66%, a value
similar to the usually more efficient amides with coordinat-
ing groups. Lithium amido sulfide Li-6 gave a similar
enantioselectivity of 65% while Li-3 offers a slightly higher
enantioselectivity of 69%. However, the conversions are
quite low for all additions (except for entries 2 and 5).
When lithium phenylacetylide was used as a nucleophile,
all lithium amides displayed similar enantioselectivities,
82–91%, while the chiral lithium amido sulfides Li-3 and
Li-6 were again the most efficient of the lithium amides
at inducing asymmetry in the reaction.
The chiral lithium amides were employed as chiral inducers
in the asymmetric 1,2-addition of lithium acetylides to
benzaldehyde. Extraordinary results were obtained in the
addition of lithium acetylides to trifluoromethyl ketones
using the lithium alkoxide of an ephedrine analogue.
Applying the same ligands in the addition of lithium acet-
ylides to aldehydes resulted in less satisfactory selectivities
unless exceptionally bulky lithium acetylides were used.22,31
The lithium acetylides were generated in situ through the
reaction between the acetylene and n-butyllithium at
ꢀ78 ꢁC. Benzaldehyde was added to the mixture at
ꢀ116 ꢁC yielding alkynyl alcohols (Scheme 3). The results
of the reactions are given in Table 3.
In order to test the efficiency of the reactions when per-
formed on a larger scale, a few experiments were conducted
with the amount of solvent, chiral amine and organo-
lithium reagent increased by a factor of 10 and the amount
of aldehyde increased by a factor of 20. The product
obtained was purified and isolated using flash chromato-
graphy and the chiral amine used, recovered through
an acid–base extraction (Scheme 4). The results of the
reactions are given in Table 4.
While the addition of lithium n-propylacetylide to benz-
aldehyde did not give any spectacular results, it should be
noted that the lithium amide without a chelating group,
The scaled up additions of n-butyllithium and lithioaceto-
nitrile to benzaldehyde offered the alcohol products in high
isolated yields and enantiomeric purities equal to or even
O
HO
H
1. Li-amide (4.0 eq.), LiC CR (2.0 eq.)
2. Methanol
H
R
Scheme 3. Asymmetric 1,2-addition of lithium acetylides to benzaldehyde mediated by chiral lithium amides.

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J. Granander et al. / Tetrahedron: Asymmetry 17 (2006) 2021–2027
O
positioned in a trans arrangement, based on DFT calcula-
tions, as shown in Figure 1.
HO
R
H
1. Li-2 (2.0 eq.), R'Li (1.0 eq.)
2. Methanol
R
H
R'
When the aldehyde substrates coordinate to the tricoordi-
nated lithium, it can approach from either the endo or
exo side of the mixed complex although the bulky substitu-
ent on the nitrogen makes the exo side considerably less
accessible than the endo side. The aldehyde has to orient it-
self so that the hydrogen is located within the cavity of the
mixed complex while the more sterically demanding substi-
tuent is pointing away from the complex before reaching
the transition state resulting in the product with the experi-
mentally observed configuration. The mixed complexes
between the chiral lithium amides and methyl-, n-butyl- and
phenyllithium are most likely similar but it is not certain
the lithium acetylides form the same kind of mixed dimers
in THF solution. The solution structures of the mixed com-
plexes between chiral lithium amides and lithioacetonitrile
are different, as lithioacetonitrile is predominantly N-lithi-
ated in THF,18,29 and possible transition state structures
for the 1,2-addition to aldehydes are more difficult to
predict.
Scheme 4. Asymmetric 1,2-addition of organolithium reagents to alde-
hydes mediated by Li-2.
Table 4. Isolated yields, enantiomeric excesses and amounts of chiral
amine recovered of the 1,2-addition of organolithium reagents (1.0 mmol)
to aldehydes (1.0 mmol) mediated by (R)-2 (2.0 mmol) in Et2O/THF
(20.0 mL) at ꢀ116 ꢁC
Entry
R
R0
Isolated
ee (%) Amine recovered
yield (%)
(%)
1
2
3
4
Ph
(CH2)3CH3 80
85 (S) 97
81 (R) 98
55 (S) 98
80 (S) 95
c-C6H11 Ph
Ph
Ph
24
87
44
CH2CN
C„CPh
slightly greater than those obtained in the small scale reac-
tions showing that those two reactions easily can be scaled
up. The addition of lithium phenylacetylide offered only a
modest isolated yield of 44% of the alkynyl alcohol prod-
uct. It is possible that the 1:1 stoichiometry of the aldehyde
versus organolithium reagent in the reaction is not optimal
as we do not know what kind of mixed complexes are
formed between the lithium amide and lithium phenylacet-
ylide in solution. It has previously been reported that
2 equiv of lithium acetylide was required for full conversion
of a 1,2-addition of lithium cyclopropylacetylide to a
ketone.21 More disappointing was the low isolated yield
of the product obtained by the addition of phenyllithium
to cyclohexanecarboxaldehyde. Since phenyllithium is a
strong base, but a weak nucleophile, it is likely that it only
offers low yields in the 1,2-addition to enolizable aldehydes.
The chiral amine was recovered almost quantitatively after
each experiment.
3. Conclusion
Chiral lithium amido sulfide, Li-6, has been shown to be
superior to the other ligands tested in all reactions, yielding
enantioselectivities ranging from good to excellent. Li-6 ap-
pears to be a very versatile chiral inducer, able to induce
high levels of selectivity with various organolithium nucleo-
philes in the 1,2-addition reaction (Scheme 5). The chiral
lithium amido ethers offer decent selectivities in the addi-
tions of alkyllithiums, phenyllithium and lithium phenyl-
acetylide but are not as effective as the lithium amido
sulfide analogues. The lithium amido ether which forms a
six-membered chelate, Li-4, is generally equally or less able
than its shorter homologue, Li-2, at inducing asymmetry in
the 1,2-addition reactions. The chiral lithium amide with-
out a chelating group, Li-1, exhibits very low enantioselec-
tivities except when lithium acetylides were used as
nucleophiles.
Interestingly, the 1,2-addition of all organolithium reagents
in this study occur on the same side of the aldehyde
substrate indicating that similar reaction paths, including
transition state structures, are formed in the reactions.
Extensive low-temperature NMR-studies have shown that
the chiral lithium amido ethers and sulfides derived from
amino acids exclusively form mixed dimers with n-butyl-
lithium in THF.14,16,33,34 The lithiums of the mixed dimers
have been shown to be coordinated by one THF molecule,
each with one lithium also internally chelated by the coor-
dinating group of the lithium amide.35 The bulky substitu-
ents on the nitrogen and carbon backbone of the amide are
Investigations of the mixed complexes between chiral lith-
ium amides and the organolithium reagents phenyllithium
and lithium acetylides by spectroscopic and computational
methods are currently underway in order to increase the
understanding of these mixed complexes and how they
react.
O
HO
Ph
H
Ph
H
S
H
O
S
N
Bu
N
Bu
THF
Li
Li
THF
Li
Li
Ph
THF
Figure 1. The solution structure of a mixed dimer between Li-6 and n-butyllithium and a possible transition state structure rationalizing the experimentally
observed product configuration.

J. Granander et al. / Tetrahedron: Asymmetry 17 (2006) 2021–2027
2025
1.
R = Ph, R' = n-Bu
R = o-CH3Ph, R' = n-Bu
R = c-C6H11, R' = n-Bu
R = Ph, R' = Me
R = o-CH3Ph, R' = Me
R = Ph, R' = CH2CN
R = Ph, R' = C CPh
R = Ph, R' = C C(CH2)2CH3
R = c-C6H11, R' = Ph
98% ee
96% ee
93% ee
96% ee
87% ee
75% ee
91% ee
65% ee
96% ee
(4.0 eq.)
N
S
Li
O
HO
R
H
R'Li (2.0 eq.), Et2O/THF, −116 ºC
2. Methanol
R'
R
H
Scheme 5. Enantiomeric excesses obtained in a variety of asymmetric 1,2-additions using Li-6 as chiral ligand.
4. Experimental
cooled to ꢀ116 ꢁC using a Et2O/liquid nitrogen cooling
bath. After 15 min at this temperature a solution of benzal-
dehyde (1.0 M in hexane, 50 lL, 0.05 mmol, 1.0 equiv) was
added slowly, dropwise. The mixture was allowed to react
for 15 min before methanol (1.0 mL) was added to quench
the reaction. The mixture was allowed to warm up to room
temperature and HCl (10%, 1.0 mL) and Et2O (2.0 mL)
were added. A portion of the organic phase was dried over
Na2SO4 and analyzed using chiral stationary phase gas
chromatography.
4.1. General
NMR spectra were recorded on a Varian 500 MHz or
400 MHz spectrometer using CDCl3 as solvent. Optical
rotations were measured using a Perkin–Elmer 341 LC
polarimeter. IR spectra were recorded on a Perkin–Elmer
1600 Series FTIR spectrometer. Melting points were deter-
mined using a Buchi Melting Point B-545. High-resolution
¨
mass spectroscopy was carried out on a Micromass LCT
spectrometer. GC analyses were performed using a Varian
Star 3400 CX gas chromatograph equipped with the chiral
stationary phase column CP-Chirasil-DEX CB (25 m,
0.32 mm) from Chrompack. Analyses were done using
He (1.5 mL minꢀ1) as carrier gas (injector 225 ꢁC, detector
250 ꢁC). The organolithium reagents were purchased from
Acros Organics and used as received. Dried solvents were
distilled from sodium/benzophenone.
4.4. General procedure for the scaled up addition of
organolithium reagents to aldehydes
Chiral amine (R)-2 (0.387 g, 2.0 mmol, 2.0 equiv) dissolved
in dry Et2O/THF 1:1 (20.0 mL) was lithiated and the
organolithium reagent (1.0 mmol, 1.0 equiv) was prepared
at ꢀ78 ꢁC under an N2-atmosphere as described above.
After 30 min at ꢀ78 ꢁC, the solution was cooled to
ꢀ116 ꢁC over a Et2O/liquid nitrogen cooling bath. After
15 min at this temperature, the aldehyde (1.0 mmol,
1.0 equiv) was added dropwise and the mixture allowed
to react for 30 min before being quenched with methanol
(10 mL). The mixture was allowed to reach room tempera-
ture and was washed with HCl (10%, 3 · 10 mL). The com-
bined aqueous phases were extracted with Et2O
(3 · 10 mL) and the combined organic phases dried over
Na2SO4 and the solvent removed under reduced pressure.
The resulting yellowish oil was purified using flash chroma-
tography (silica, ethyl acetate–hexane) yielding the product
as a clear colourless oil, which was analyzed using chiral
stationary phase gas chromatography. The combined aque-
ous phases were made strongly basic using NaOH (5 M,
40 mL) and extracted using CH2Cl2 (3 · 10 mL). The
combined organic phases were dried over Na2SO4 and
the solvent removed under reduced pressure yielding the
recovered (R)-2 as a pale yellow oil in close to quantitative
yield.
4.2. General procedure for the addition of alkyl- and
phenyllithium to aldehydes
The organolithium reagent (0.30 mmol, 6.0 equiv) was
added dropwise to a solution of the chiral amine
(0.20 mmol, 4.0 equiv) in dry Et2O/THF 1:1 (2.0 mL) at
ꢀ78 ꢁC under an N2-atmosphere. After 15 min, the solu-
tion was cooled to ꢀ116 ꢁC using a Et2O/liquid nitrogen
cooling bath and after a further 15 min at this temperature,
a solution of the aldehyde (1.0 M in hexane, 50 lL,
0.05 mmol, 1.0 equiv) was added slowly, dropwise. The
mixture was allowed to react for 15 min before methanol
(1.0 mL) was added to quench the reaction. The mixture
was allowed to warm up to room temperature and HCl
(10%, 1.0 mL) and Et2O (2.0 mL) were added. A portion
of the organic phase was dried over Na2SO4 and analyzed
using chiral stationary phase gas chromatography.
4.3. General procedure for the addition of lithioacetonitrile
and lithium acetylides to benzaldehyde
4.5. Synthesis of (R)-1-isopropylamino-1-phenyl-2-thio-
methylethane (R)-3
n-Butyllithium (2.5 M in hexanes, 125 lL, 0.30 mmol,
6.0 equiv) was added dropwise to a solution of the chiral
amine (0.20 mmol, 4.0 equiv) in dry Et2O/THF 1:1
(2.0 mL) at ꢀ78 ꢁC under an N2-atmosphere. After
15 min, a solution of acetonitrile or the acetylene (2.0 M
in toluene or hexane, 55 lL, 0.11 mmol, 2.2 equiv) was
added dropwise. After a further 15 min, the solution was
(R)-1-(tert-Butoxycarbonylamino)-2-methanesulfonyloxy-
1-phenylethane (20.12 g, 63.8 mmol, 1.0 equiv) dissolved in
THF (150 mL) was added slowly to a suspension of sodium
thiomethoxide (8.94 g, 127.6 mmol, 2.0 equiv) in dry THF
(150 mL) over 30 min while stirring. The mixture was then
allowed to react for 13 h. Water (100 mL) was added and

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J. Granander et al. / Tetrahedron: Asymmetry 17 (2006) 2021–2027
the solution concentrated under reduced pressure. The res-
idue was extracted with CH2Cl2 (3 · 100 mL), the com-
bined organic phases were washed with brine (100 mL)
and dried over Na2SO4. The solvent was removed under
reduced pressure yielding a slightly yellow powder (15.44 g,
97%). The crude product was purified with column chro-
(br, 1H, NH), 2.07 (s, 3H, SCH3), 2.65 (sept., 1H,
J = 6.3 Hz, CH(CH3)2), 2.68 (dd, 1H, J = 8.8, 13.2 Hz,
PhCH2CH), 2.78 (dd, 1H, J = 4.6, 13.2 Hz, PhCH2CH),
3.90 (dd, 1H, J = 4.6, 8.8 Hz, PhCH2CH), 7.18–7.38 (m,
5H, Ph);13C NMR (100 MHz, CDCl3): d 15.9 (CH3), 22.3
(NHCH(CH3)2), 24.6 (NHCH(CH3)2), 43.3 (PHCHCH2),
46.1 (NHCH(CH3)2), 58.7 (PhCHCH2), 127.4 (p-Ph),
128.4 (o-Ph), 128.7 (m-Ph), 143.8 (i-Ph); HRMS (ESI+):
found 210.1302. C12H20NS requires 210.1316.
matography (silica, CH2Cl2) yielding white crystals.
20
Mp = 98.8 ꢁC; ½aꢁD ¼ ꢀ36:4 (c 1.01, CH2Cl2); IR (KBr)
mmax 3384, 2975, 2905, 1679, 1523, 1363, 1268, 1176 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.43 (s, 9H, C(CH3)3),
2.01 (s, 3H, SCH3), 2.90 (d, J = 6.3 Hz, 2H, PhCHCH2),
4.86 (br, 1H, PhCHCH2), 5.15 (br, 1H, NH), 7.25–7.37
(m, 5H, Ph); 13C NMR (100 MHz, CDCl3): d 16.2 (CH3),
28.6 (C(CH3)3), 41.2 (PhCHCH2), 53.9 (PHCHCH2), 80.0
(C(CH3)3), 126.5 (p ꢀ Ph), 127.8 (o-Ph), 128.9 (m-PH),
141.6 (i-Ph), 155.4 (CO); HRMS (ESI+): found 268.1378.
C14H22NO2S requires 268.1371.
4.6. Synthesis of (R)-1-isopropylamino-1-phenyl-2-phen-
oxyethane (R)-5
A suspension of potassium trifluorophenylborate (2.32 g,
12.6 mmol, 2.0 equiv), copper(II)acetate monohydrate
(1.40 g, 7.0 mmol, 1.1 equiv), DMAP (0.16 g, 1.3 mmol,
˚
0.2 equiv) and 4 A molecular sieves (6.0 g) in CH2Cl2
(75 mL) under an oxygen atmosphere was stirred for
5 min before (R)-2-(tert-butoxycarbonylamino)-2-phenyl-
propanol (1.50 g, 6.3 mmol, 1.0 equiv) was added. The
resulting mixture was stirred at room temperature over-
night before being decanted into a separatory funnel. The
reaction flask and molecular sieves were rinsed with
CH2Cl2 (15 mL) and water (100 mL) was added to the
funnel and the phases separated. The aqueous phase was
extracted with CH2Cl2 (3 · 25 mL). The combined organic
extracts were washed with brine (75 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was puri-
fied through flash chromatography (silica, ethyl acetate–
hexane 1:6) yielding (R)-1-(tert-butoxycarbonylamino)-1-
phenyl-2-phenoxyethane as a clear colourless oil (0.44 g,
(R)-1-(tert-Butoxycarbonylamino)-1-phenyl-2-thiomethyl
ethane (7.36 g, 29.5 mmol, 1.0 equiv) was dissolved in
CH2Cl2 (50 mL).
Trifluoroacetic
acid
(13.5 mL,
177.1 mmol, 6.0 equiv) was added and the solution stirred
overnight. Water (100 mL) was added, the water phase
then separated and the organic phase was extracted with
aqueous hydrochloric acid (10%, 3 · 50 mL). The com-
bined water phases were basified with aqueous sodium
hydroxide (5 M, 800 mL). The milky mixture was extracted
with CH2Cl2 (4 · 100 mL). The combined organic phases
were washed with brine (100 mL) and dried over Na2SO4.
The solvent was evaporated under reduced pressure, which
afforded a pale yellow oil (2.87 g, 58%). The crude product
was purified with column chromatography (silica, CH2Cl2–
22% yield) that slowly crystallized upon standing.
20
20
MeOH–Et3N 97:2:1) yielding a yellow oil. ½aꢁD ¼ ꢀ36:9 (c
Mp = 83.2 ꢁC; ½aꢁD ¼ ꢀ15:0 (c 1.00, CH2Cl2); IR (neat)
1.01, CH2Cl2); IR (neat) mmax 3366, 3022, 2907, 2838, 2355,
mmax 3384, 2976, 2925, 1686, 1598, 1521, 1366, 1245 cmꢀ1
;
1758, 1597, 1493 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d
1H NMR (500 MHz, CDCl3): d 1.44 (s, 9H, C(CH3)3),
4.16 (s (br), 1H, CH2O), 4.25 (dd, J = 4.4, 9.6 Hz, 1H,
CH2O), 5.07 (s (br), 1H, PhCH), 5.33 (s (br), 1H, NH),
6.89–6.96 (m, 3H, Ph), 7.25–7.49 (m, 7H, Ph); 13C NMR
(125 MHz, CDCl3): d 28.6 (CH3), 54.1 (PhCH), 70.7
((CH3)3C), 80.0 (CH2O), 114.2 (o-OPh), 121.4 (p-OPh),
127.0 (Ar), 127.8 (Ar), 128.7 (Ar), 129.7 (Ar), 140.0
(i-Ph), 155.5 (CO), 158.5 (i-OPh); HRMS (ESI+): found
214.1227. C14H16NO requires 214.1232.
1.78 (br, 2H, NH2), 2.10 (s, 3H, CH3), 2.68 (dd, 1H,
J = 9.2, 13.5 Hz, PhCHCH2), 2.83 (dd, 1H, J = 4.2,
13.5 Hz, PhCHCH2), 4.12 (dd, 1H, J = 4.2, 9.2 Hz,
PhCHCH2), 7.27–7.40 (m, 5H, Ph); 13C NMR (100 MHz,
CDCl3): d 16.1 (CH3), 44.6 (PhCHCH2), 54.7 (PhCHCH2),
126.6 (p-Ph), 127.6 (o-Ph), 128.7 (m-Ph), 144.8 (i-Ph);
HRMS (ESI+): found 168.0846. C9H14NS requires
168.0847.
(R)-1-Amino-1-phenyl-2-thiomethylethane (4.60 g, 27.5
mmol, 1.0 equiv) was dissolved in THF (40 mL) and
DMPU (40 mL). Sodium carbonate (5.83 g, 55.0 mmol,
2.0 equiv) and isopropyl iodide (9.10 g, 5.2 mL, 55.0 mmol,
2.0 equiv) were added and the solution was refluxed. After
16 h of reflux, water (100 mL) was added and the mixture
was allowed to reach room temperature. The mixture was
concentrated under reduced pressure and extracted with
Et2O (3 · 100 mL). The combined organic extracts were
washed with water (3 · 100 mL) and the solvent removed
under reduced pressure. The crude product was purified
with column chromatography (silica, CH2Cl2–Et3N 99:1)
(R)-1-(tert-Butoxycarbonylamino)-1-phenyl-2-phenoxy-
ethane (0.44 g, 1.4 mmol, 1.0 equiv) and trifluoroacetic acid
(0.96 g, 0.63 mL, 8.4 mmol, 6.0 equiv) were dissolved in
CH2Cl2 (10 mL) and the resulting solution stirred at room
temperature overnight. NaOH (5 M, 20 mL) was added
and the aqueous phase extracted with CH2Cl2
(2 · 10 mL). The combined organic extracts were washed
with brine (15 mL), dried over Na2SO4 and concentrated
in vacuo. The resulting oil was purified through flash chro-
matography (silica, ethyl acetate–hexane–Et3N 20:80:1)
yielding (R)-1-phenyl-2-phenoxyethaneamine as a clear
20
colourless oil (0.30 g, 100% yield). ½aꢁD ¼ ꢀ39:6 (c 1.04,
followed by Kugelrohr distillation, yielding (R)-3 as a
CH2Cl2); IR (neat) mmax 3379, 3032, 2925, 1595, 1495,
¨
1
colourless oil (4.22 g, 73%). Bp = 138 ꢁC, 0.09 mbar;
1241 cmꢀ1; H NMR (500 MHz, CDCl3): d 2.40 (s (br),
20
½aꢁD ¼ ꢀ61:0 (c 1.05, CH2Cl2); IR (neat) mmax = 3290,
2H, NH2), 3.95 (dd, J = 9.0, 9.3 Hz, 1H, CH2O), 4.11
(dd, J = 3.6, 9.3 Hz, 1H, CH2O), 4.44 (dd, J = 3.6,
9.0 Hz, 1H, PhCH), 6.89–6.99 (m, 3H, Ph), 7.24–7.35 (m,
3H, Ph), 7.39 (m, 2H, Ph), 7.47 (m, 2H, Ph); 13C NMR
1
3023, 2926, 2854, 1946, 1707, 1451, 1365, 1167 cmꢀ1; H
NMR (400 MHz, CDCl3): d 1.02 (d, 3H, J = 6.3 Hz,
CH(CH3)2), 1.07 (d, 3H, J = 6.3 Hz, CH(CH3)2), 1.71

J. Granander et al. / Tetrahedron: Asymmetry 17 (2006) 2021–2027
2027
6. Seebach, D.; Crass, G.; Wilka, E.-M.; Hilvert, D.; Brunner,
E. Helv. Chim. Acta 1979, 62, 2695–2698.
7. Mukaiyama, T.; Suzuki, K.; Kobayashi, S. Chem. Lett. 1978,
219–222.
8. Ye, M.; Logaraj, S.; Jackman, L. M.; Hillegass, K.; Hirsh, K.
A.; Bollinger, A. M.; Grosz, A. L.; Mani, V. Tetrahedron
1994, 50, 6109–6116.
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5187–5190.
(125 MHz, CDCl3): d 55.4 (PhCH), 73.9 (CH2O), 114.8
(o-OPh), 121.2 (p-OPh), 127.2 (o-Ph), 128.0 (p-Ph), 128.8
(m-Ph), 129.7 (m-OPh), 141.7 (i-Ph), 158.8 (i-OPh); HRMS
(ESI+): found 214.1227. C14H16NO requires 214.1232.
(R)-1-Phenyl-2-phenoxyethaneamine (0.30 g, 1.4 mmol,
1.0 equiv) and acetone (0.33 g, 0.41 mL, 5.6 mmol, 4 equiv)
were dissolved in benzene (25 mL) and the solution re-
fluxed with a Dean–Stark trap overnight. The mixture
was cooled to room temperature and the solvent and excess
acetone removed in vacuo. The residue was dissolved in dry
ethanol (15 mL), and NaBH4 (0.11 g, 2.8 mmol, 2.0 equiv)
was added. The resulting mixture was stirred at room tem-
perature for 4 h before water (15 mL) was added. The eth-
anol was removed under reduced pressure and the aqueous
phase extracted with CH2Cl2 (3 · 10 mL). The combined
organic extracts were washed with brine (15 mL), dried
over Na2SO4 and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography (silica, ethyl ace-
11. Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P.
Tetrahedron: Asymmetry 1997, 8, 1519–1523.
12. Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. J.
Org. Chem. 1998, 63, 8266–8275.
´
13. Corruble, A.; Davoust, D.; Desjardins, S.; Fressigne, C.;
´
Giessner-Prettre, C.; Harrison-Marchand, A.; Houte, H.;
Lasne, M.-C.; Maddaluno, J.; Oulyadi, H.; Valnot, J.-Y.
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14. Arvidsson, P. I.; Hilmersson, G.; Davidsson, O. Chem. Eur. J.
¨
1999, 5, 2348–2355.
15. Arvidsson, P. I.; Davidsson, O.; Hilmersson, G. Tetrahedron:
¨
tate–hexane–Et3N 10:90:1) yielding (R)-5 as a clear viscous
20
Asymmetry 1999, 10, 527–534.
16. Granander, J.; Sott, R.; Hilmersson, G. Tetrahedron 2002, 58,
4717–4725.
17. Soai, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1979, 52,
3371–3376.
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colourless oil (0.33 g, 92% yield). ½aꢁD ¼ ꢀ51:5 (c 1.06,
in CH2Cl2); IR (neat) mmax 3330, 3063, 2962, 2866, 1949,
1596, 1494, 1458, 1239 cmꢀ1
;
1H NMR (500 MHz,
CDCl3): d 1.06 (d, J = 6.3 Hz, 3H, CH3), 1.10 (d,
J = 6.3 Hz, 3H, CH3), 2.75 (sept, J = 6.3 Hz, 1H,
(CH3)2CH), 4.01 (t, J = 8.7 Hz, 1H, CH2O), 4.07 (dd,
J = 4.0, 9.4 Hz, 1H, CH2O), 4.25 (dd, J = 4.0, 8.3 Hz,
1H, PhCH), 6.90–6.99 (m, 3H, Ph), 7.24–7.33 (m, 3H,
Ph), 7.38 (m, 2H, Ph), 7.47 (m, 2H, Ph); 13C NMR
(125 MHz, CDCl3): d 22.3 (CH3), 24.5 (CH3), 46.3
((CH3)2CH), 59.9 (PhCH), 73.1 (CH2O), 115.0 (o-OPh),
121.2 (p-OPh), 127.8 (p-Ph), 127.9 (o-Ph), 128.7 (m-Ph),
129.6 (m-OPh)141.3 (i-Ph), 158.9 (i-OPh); HRMS (ESI+):
found 256.1699. C17H22NO requires 256.1701.
19. Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett.
1979, 447–448.
20. Thompson, A. S.; Corley, E. G.; Huntington, M. F.;
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21. Thompson, A. S.; Corley, E. G.; Huntington, M. F.;
Grabowski, E. J. J.; Remenar, J. F.; Collum, D. B. J. Am.
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22. Jiang, B.; Feng, Y. Tetrahedron Lett. 2002, 43, 2975–2977.
23. Granander, J.; Sott, R.; Hilmersson, G. Tetrahedron: Asym-
metry 2003, 14, 439–447.
24. Juaristi, E.; Murer, P.; Seebach, D. Synthesis 1993, 1243–
1246.
Acknowledgements
25. Sott, R.; Granander, J.; Williamson, C.; Hilmersson, G.
Chem. Eur. J. 2005, 11, 4785–4792.
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J. Am. Chem. Soc. 1979, 101, 1455–1460.
Financial support from The Swedish Research Council and
the Knut and Alice Wallenberg Foundation is gratefully
acknowledged. We thank Docent O. Davidsson and Dr.
¨
´
A. Dahlen at AstraZeneca Research and Development,
`
`
28. Fontes, M.; Verdaguer, X.; Sola, L.; Pericas, M. A.; Riera, A.
J. Org. Chem. 2003, 69, 2532–2543.
Mo¨lndal (Sweden), for the high-resolution mass spectro-
metry analyses.
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2004, 126, 6798–6805.
30. Koenig, T. M.; Mitchell, D. Tetrahedron Lett. 1994, 35, 1339–
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