Enantioselective addition of dimethylzinc to aldehydes: Assessment of optimal N,N-substitution for 2-dialkylamino-1,1,2-triphenylethanol ligands

Article abstract of DOI:10.1016/j.tetasy.2004.05.026

A general methodology for the synthesis of 2-dialkylamino-1,1,2- triphenylethanol has been developed. Novel ligands 3, 4, and 5, bearing flexible alkyl chains on nitrogen have been synthesized by epoxide-ring opening of the encumbered (S)-triphenyloxirane. These ligands along with 2-piperidino-1,1,2- triphenyl ethanol 1 have been tested in the addition of dimethylzinc to aldehydes. This allowed for the assessment of the structural features that favor the catalytic activity and selectivity of the ligands with respect to nitrogen substitution.

Full text of DOI:10.1016/j.tetasy.2004.05.026

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2085–2090
Enantioselective addition of dimethylzinc to aldehydes: assessment
of optimal N,N-substitution for 2-dialkylamino-1,1,2-
triphenylethanol ligands
,
Noemı Garcıa-Delgado, Montserrat Fontes, Miquel A. Pericas, Antoni Riera and
*
ꢀ
ꢀ
ꢁ
Xavier Verdaguer*
Unitat de Recerca en Sꢀıntesi Asimꢁetrica (URSA-PCB), Parc Cientꢀıfic de Barcelona and Departament de Quꢀımica Orgꢁanica,
Universitat de Barcelona, c/Josep Samitier, 1-5, E-08028 Barcelona, Spain
Received 19 May 2004; accepted 25 May 2004
Available online 24 June 2004
Abstract—A general methodology for the synthesis of 2-dialkylamino-1,1,2-triphenylethanol has been developed. Novel ligands 3, 4,
and 5, bearing flexible alkyl chains on nitrogen have been synthesized by epoxide-ring opening of the encumbered (S)-triphenyl-
oxirane. These ligands along with 2-piperidino-1,1,2-triphenyl ethanol 1 have been tested in the addition of dimethylzinc to alde-
hydes. This allowed for the assessment of the structural features that favor the catalytic activity and selectivity of the ligands with
respect to nitrogen substitution.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
nature, which allows for the fast optimization of the
catalytic properties in any application.
Since its early reports, the catalytic enantioselective
addition of dialkylzinc species to aldehydes has been
studied extensively. A large variety of ligands have been
reported to yield the corresponding chiral secondary
alcohols in excellent enantiomeric excess.1 For the past
decade, our group has been working on the development
of synthetic chiral amino alcohol ligands derived from
epoxides that are readily accessible from the Sharpless
and Jacobsen epoxidation reactions (Fig. 1).2 The main
feature of these ligands is that they are modular in
Because of its decreased reactivity, asymmetric dimeth-
ylzinc addition has attracted much less attention than
the corresponding Et2Zn additions. However, the chiral
1-hydroxyethyl moiety resulting from the enantioselec-
tive addition of a methyl group to an aldehyde is
widespread in nature and makes this process highly
attractive from a synthetic point of view.3 Soai et al.
reported that N,N-dialkyl derivatives of norephedrine
work as efficient ligands for the asymmetric addition of
both Et2Zn and Me2Zn.4 In particular, N,N-di-n-butyl-
norephedrine (DBNE) bearing a conformationally flex-
ible N,N-dibutylamino fragment provided excellent
selectivities for the addition of dimethylzinc to aliphatic
aldehydes. Ligands of general structure II (Fig. 1) rep-
resent an excellent choice among other ligands reported
in the literature when performing asymmetric Et2Zn and
Ph2Zn additions.5 In particular, 2-piperidino-1,1,2-
triphenylethanol 1 provides excellent enantioselectivities
(up to 99% ee). In addition, the two enantiomers are
readily available in a two step reaction pathway starting
from triphenylethylene.6
NR2
NR2
NR2
Ph
Ph
OH
R'
Ph
Ph
Ar
OR'
Ph
OH
OH
I
II
III
Figure 1.
* Corresponding authors: Tel.: +34-977920-211; fax: +34-977920-224
(M.A.P.); tel.: +34-934037093; fax: +34-934037095 (X.V.); e-mail
addresses: mapericas@iciq.es; xverdaguer@pcb.ub.es
We have previously reported the synthesis of several
ligands of general structure II bearing cyclic alkyl
groups on nitrogen. Here we report on the synthesis of
Present address: Institute of Chemical Research of Catalonia, Avgda.
€
Paısos Catalans s/n, E-43007 Tarragona, Spain.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.026

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N. Garcıa-Delgado et al. / Tetrahedron: Asymmetry 15 (2004) 2085–2090
2086
new ligands of general structure II with distinct flexible
alkyl groups on nitrogen. This would allow for the
correct assessment of the structural features that favor
the catalytic activity of type II ligands with respect to
nitrogen substitution. In a second stage, the novel
ligands were tested in the enantioselective addition of
dimethylzinc to benzaldehyde and heptanal along with
(R)-2-piperidino-1,1,2-triphenylethanol 1.
examined. Soai et al. reported the dialkylation of nor-
ephedrine with several primary alkyl halides under
K2CO3/MeOH conditions.4 Under the same conditions,
reaction with (R)-2-amino-1,1,2-triphenylethanol with
EtBr provided exclusively monoalkylation compounds.
This reaction is very sensitive to steric hindrance around
the amino group, since a similar behavior has been
reported with the regioisomeric 2-amino-1,2,2-triphe-
2e
nylethanol.
On the other hand, it is known that
reductive amination (RCHO/Pt/H2) of structurally re-
lated 2-amino-1,2-diphenylethanol affords again mono-
alkylation products. The double alkylation has been
accomplished, albeit with low yields, by using stoichio-
metric amounts of aluminum trichloride as activator
during the reductive amination process.11
R
R
N
N
Ph
Ph
OH
Ph
Ph
OH
Ph
Ph
1
2, R = Me
3, R = Et
To find a reliable process for the synthesis of ligands 3–
5, route B was next examined. The nucleophilic ring
opening of (S)-triphenyloxirane under Crotti conditions
(amine/LiClO4/82 °C, acetonitrile)12 with cyclic second-
ary amines led to the convenient synthesis of a number
of b-amino alcohols. However, initial experiments with
straight chain di-n-butylamine in refluxing acetonitrile
did not provide any of the desired epoxide ring-opening
product, probably because of its increased steric hin-
drance with respect to cyclic amines. To check whether
the ring opening with di-n-butylamine was feasible, the
reaction temperature was raised to 155 °C in the absence
of solvent (Table 1). Under these conditions 5 was de-
tected as a minor product in the reaction mixture.
Further efforts to optimize the reaction temperature and
the equivalents of lithium perchlorate to increase the
yield of amino alcohol 5 is summarized in Table 1.
4, R = n-Pr
5, R = n-Bu
2. Synthesis of the ligands
The presence of a trisubstituted amine in the 1,2-amino
alcohol ligand is crucial to attain good catalytic activi-
ties in the enantioselective alkylation of aldehydes.7
With this in mind, we planned the synthesis of ligands 2–
5, which bear a straight chain N,N-dialkylamino groups
of increasing length. Ligand 2 was synthesized from the
commercially available (R)-2-amino-1,1,2-triphenyleth-
anol by means of reductive amination with formalde-
hyde and sodium cyanoborohydride8 (Scheme 1).
Attempts to prepare 2, by means of an Eschweiler–Clark
reaction (CH2O, HCO2H)9 as previously reported in the
literature,10 led to the isolation of the corresponding N-
methyl cyclic aminal. Alternatively, alkylation of the
corresponding primary amine with MeI in K2CO3/
MeOH produced the desired compound in a 58% yield.
However, reproducibility of this procedure was poor,
probably because of the partial formation of the qua-
ternary amine.
Table 1. Ring opening of (S)-triphenyloxirane with di-n-butylamine
HO
Ph
N
O
LiClO4
Ph
Ph
Ph
10 eq.HNBu 2
Bu
Ph
Ph
Bu
5
T (°C)
Time
Equiv. LiClO4
Yield (%)a
155
140
140
140
120
120
8.5 h
8 h
2
2
2
2
4
4
Minor
36
Me Me
NH2
N
(CH2O)n
12 h
Minor
Minor
17
Ph
Ph
OH
Ph
Ph
OH
Ph
2.5 days
2 days
1.5 days
NaBH3CN
MeOH
87%
Ph
2
45b
a Yields refer to isolated crystalline compounds of >95% purity as
determined by elemental analysis.
b Yield estimated by 1H NMR analysis of the final reaction mixture
was 70%.
Scheme 1.
The synthesis of ligands 3–5 was attempted following
synthetic routes A and B (Scheme 2). With the (R)-2-
amino-1,1,2-triphenylethanol in hand route A was first
Optimal conditions required 2–4 equiv of LiClO4 and
120 °C. Increasing the amount of the Lewis acid pro-
moter and the temperature resulted in a faster reaction.
However, higher temperatures and addition of an excess
of LiClO4 (over 4 equiv) produced the undesired lithium
epoxide rearrangement that generates a ketone by-
product (Scheme 3) with the consequent decrease in
yield.13 The use of other Lewis acid salts [CaCl2,
Mg(ClO4)] did not produce any of the desired ring-
opening product.
R
R
A
NH2
B
N
O
Ph
Ph
OH
Ph
Ph
OH
3-5
Ph
Ph
Ph
Ph
Ph
Scheme 2.

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N. Garcıa-Delgado et al. / Tetrahedron: Asymmetry 15 (2004) 2085–2090
2087
substrate. In this set of experiments the active catalysts
were prepared by mixing 2 equiv of Me2Zn and 10 mol %
of the corresponding amino alcohol in hexane or toluene
at room temperature. After 30 min the reaction was
cooled to the desired temperature and the aldehyde was
then added. The reactions were analyzed by GC, the
results are summarized in Table 3.
Li
O
O
H
O
LiClO4
Ph
Ph
shift
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Scheme 3.
Preparation of novel ligands 3, 4, and 5 was accom-
plished in practical yields by running the reactions with
10 equiv of the corresponding amine without solvent at
120 °C (Table 2). Reactions with low-boiling amines
were conducted in a pressure tube. Conveniently, all the
new isolated ligands were crystalline solids. The enan-
tiomeric excess of the final compounds isolated was
>95% ee by 19F NMR analysis of the corresponding
diastereomeric Mosher’s acid salts.
Ligands 1–2 were clearly superior to 3–5 in terms of
conversion and enantioselectivity. Thus, using 10 mol %
of 1 the resulting 1-phenylethanol was obtained in
greater than 90% ee. When the reaction temperature was
reduced to 0 °C (Table 3, entry 1) the best enantiomeric
excess was obtained (94% ee), but with slightly lower
conversion numbers in comparison with the reaction
performed at room temperature. With respect to sol-
vents, hexane behaved slightly better than toluene when
1 or 5 were used (Table 3, entries 1–2 and 11–12). As a
general trend, open chain N-alkyl substituents (in
ligands 2–5) had a deleterious effect on enantioselectivity
and conversion. While the N,N-dimethyl substituted
amino alcohol 2 showed only slightly decreased enantio-
selectivity (85% ee), a sharp decrease was observed
when the homologous N,N-diethylamino derivative 3
was used (21% ee). From this point on, an increase in
the chain length of the substituents on nitrogen
had practically no effect on either selectivity or conver-
sion.
Table 2. Synthesis of amino alcohols 3–5 from (S)-triphenyloxirane
HO
Ph
O
LiClO4, 120 ºC
10 eq.HNR 2
Ph
Ph
Ph
N R
Ph
Ph
R
R
Equiv.
LiClO4
Time
(days)
Product
Yield
(%)a
Rotation
Et
Pr
Bu
2
4
4
5 days
2 days
1.5 days
3
4
5
40
57
45
())
())
())
The catalytic efficiency of ligands 1–5 for the addition of
Me2Zn to aliphatic substrates was also examined.
Heptanal was chosen as a standard straight chain
aldehyde. Reactions were run using 2 equiv of Me2Zn
and 10 mol % of the corresponding b-amino alcohol li-
gand. Again, 2-piperidino-1,1,2-triphenylethanol 1 was
a superior catalyst and provided 2-octanol in 69% ee
(Table 4). Solvent had an important influence in the
enantiomeric excess of the product alcohol, again
hexane provided better selectivities than toluene
(Table 4, entries 1–4). On the other hand, the reaction
a Yields refer to isolated crystalline compounds of >95% purity as
determined by elemental analysis.
3. Catalysis
3.1. Results
As the starting point to examine the efficiency of these
ligands 1–5 in catalysis, benzaldehyde was chosen as
Table 3. Enantioselective addition of Me2Zn to benzaldehyde catalyzed by ligands 1–5
O
OH
Me
10% mol ligand
Ph
Ph
H
2 eq. Me2Zn
8
9
Entry
Ligand
Solvent
T (°C)
Time (h)
Conversion (%)a
Ee (%)b
1
1
1
1
1
2
2
3
3
4
4
5
5
Hexane
Toluene
Hexane
Toluene
Hexane
Toluene
Hexane
Toluene
Hexane
Toluene
Hexane
Toluene
0
24
48
24
27
24
24
24
24
24
24
24
24
87
65
98
95
38
55
6121
63
67
66
60
26
94
93
91
90
85
81
2
0
3
rt
rt
0
4
5
6
rt
0
7
8
rt
0
13
30
22
25
18
9
10
11
12
rt
0
rt
a Conversion was determined by GC.
b Enantiomeric excess was determined by GC on a b-DEX 120 column.

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N. Garcıa-Delgado et al. / Tetrahedron: Asymmetry 15 (2004) 2085–2090
2088
Table 4. Catalytic enantioselective addition of Me2Zn to heptanal mediated by ligands 1, 2, and 5
O
OH
Me
9
10% mol ligand
2 eq.Me 2Zn
C6H13
H
C6H13
8
Entry
Ligand
Solvent
T (°C)
Time (h)
Conversion (%)a
Ee (%)b
1
2
3
4
5
6
1
1
1
1
2
5
Toluene
Hexane
Toluene
Hexane
Hexane
Hexane
22
22
0
36
36
22
22
24
24
85
83
67
80
56
60
57
69
35
69
42
9
0
0
0
a Conversion was determined by GC.
b Determined by GC upon analysis of the corresponding acetate on a b-DEX 120 column.
temperature had only a limited effect on the reaction
enantioselectivity (Table 4, entries 2 and 4). As in the
reaction with benzaldehyde, switching the piperidino
group for a noncyclic N,N-dialkylamino group resulted
in a sharp decrease in enantiomeric excess, down to 9%
ee in the case of 5 (Table 4, entry 6).
It is interesting to note that the same model may serve to
explain why ligands with an ephedrine backbone exhibit
differential behavior. There are several examples in the
literature of highly effective ephedrine derived ligands
containing a N,N-di-n-butyl moiety (DBNE, and g6-
arene-chromium complex of DBNE).3;4 In the case of
ephedrine (model structure V) a much smaller hydrogen
atom replaces the axial –Ph group in IV. In this sce-
nario, there is room enough to accommodate a larger n-
Bu group on nitrogen with no energy penalization for
the corresponding transition states.
3.2. Discussion
In a similar fashion to Et2Zn, addition of Me2Zn
catalyzed by 1–5 provides the product alcohols with S
configuration in agreement with the Noyori rule.14
Theoretical calculations show that the stereochemical
outcome of the dialkylzinc addition to aldehydes can
be predicted on the basis of four diastereomeric transi-
tion state structures [anti-(S), anti-(R), syn-(S), syn-
(R)].15 In the case of Et2Zn addition to benzaldehyde
catalyzed by 1, the anti-(S) TS was calculated to
have the lowest energy barrier by means of a quan-
tum mechanics/molecular mechanics (IMOMM) proce-
dure.16 A model structure of the anti-(S) TS for
2-dialkylamino-1,1,2-triphenylethanol ligand IV and for
N,N-dialkylephedrine derivatives V is depicted in Figure
2. According to this model, bulky alkyl groups on
nitrogen may produce the destabilization of IV because
of an unfavorable steric interaction with the gem-
diphenyl moiety, as would occur for ligands 3–5.
Conversely, smaller dialkyl groups on nitrogen (ligands
1–2) lead to tolerable interactions in the transition state.
In this case, the corresponding TS’s are not perturbed
and better conversions and selectivities could be
recorded.
4. Conclusions
In summary, a general methodology for the synthesis of
2-dialkylamino-1,1,2-triphenylethanol has been devel-
oped. The ring opening of the sterically hindered (S)-
triphenyloxirane with 2–4 equiv of LiClO4 and a straight
chain dialkyl amine in the absence of solvent allows the
synthesis of novel ligands 3, 4, and 5 in one step. The
nucleophilic ring opening shown proceeds in a stereo-
specific manner. The effectiveness of 1–5 ligands toward
dimethylzinc addition to both aromatic and aliphatic
aldehydes has been examined. Up to 94% and 69% ee
has been achieved in the asymmetric addition to benz-
aldehyde and heptanal, respectively, when using 2-pip-
eridino-1,1,2-triphenyl ethanol 1. Comparison of the
results obtained for the series of piperidino, dimethyl,
diethyl, di-n-propyl and di-n-butyl ligands has allowed
us to ascertain that small alkyl groups on the chelating
nitrogen provide far better enantiocontrol for type II
catalysts. This finding stresses once again the impor-
tance and advantages of a modular ligand design for the
optimization of ligand architecture.
Ph
Me
H
5. Experimental
H
Ph
Me
Ph
O
Me
5.1. Instruments and materials
O
Zn NR
Ph
Zn NR
Zn
H
H
Zn
Me
H
Dimethylzinc reactions were carried out on a Radley’s
Metz Syn-10 Reaction Station under argon. Hexane was
distilled under nitrogen and stored over sodium. Tolu-
ene was distilled over sodium prior to use. Aldehydes
were distilled and stored under argon. All reactions were
performed under argon. Enantiomerically pure (S)-
R
O
R
O
Me
IV
V
Figure 2.

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N. Garcıa-Delgado et al. / Tetrahedron: Asymmetry 15 (2004) 2085–2090
2089
triphenyloxirane was prepared as described by Jacobsen
et al., followed by recrystallization on hexane. Optical
rotations were measured at room temperature on a
Perkin–Elmer 241MC polarimeter. Melting points were
determined by differential scanning calorimetry (DSC)
using a Mettler Toledo DSC. Infrared spectra were
recorded on a Fourier Thermo Nicolet Nexus FT-IR
using NaCl film or KBr pellet techniques. NMR spectra
were acquired on a Varian Unity-300 or a Mercury 400
instrument. 1H chemical shifts are quoted relative to
TMS and 13C, 19F shifts relative to solvent signals.
Carbon multiplicities have been assigned by distortion-
less enhancement polarization transfer (DEPT) experi-
ments. Mass spectra (MS) were measured by the
Servei d’Espectrometria de Masses of the Universitat
de Barcelona and elemental analysis (EA) by the
1.92 mL (18.4 mmol) of diethylamine were used. The
reaction mixture was heated for 5 days. The product was
filtered on silica using hexane/EtOAc 10% to remove the
excess amine. The product was recrystallized from a 2-
propanol/H2O mixture to obtain 3 as a white crystalline
1
solid (254 mg, overall yield 40%). Mp ¼ 104–105 °C. H
NMR (CDCl3): d 7.64 (d, J ¼ 7 Hz, 2H), 7.30–6.90 (m,
13H), 4.76 (s, 1H), 2.45 (m, 2H), 2.24 (m, 2H), 1.54 (s,
1H, OH), 0.89 (t, J ¼ 7 Hz, 6H). 13C NMR (CDCl3): d
149.2 (Cq), 145.9 (Cq), 137.6 (Cq), 131.5 (CH), 127.8
(CH), 127.4 (CH), 127.1 (CH), 126.9 (CH), 126.8 (CH),
126.2 (CH), 125.8 (CH), 125.7 (CH), 78.2 (Cq), 73.8
(CH), 44.9 (CH2), 12.5 (CH3). IR (KBr): mmax 2967,
1493, 1165, 1078, 702 cmÀ1. MS (CI, NH3): m=z 345
(Mþ, 100%). EA (calculated for C24H27NO, found): C
(83.44, 83.27),
H
(7.88, 7.74),
N
(4.05, 3.94).
ꢀ
Servicios Xerais de Apoio a Investigacion of the Uni-
versidade de A Coruna. Gas chromatography (GC)
ꢀ
½aŠ ¼ À121:2 (c 1.01, CHCl3).
D
~
analyses were carried out on a Agilent 6890N chroma-
tograph.
5.3.2. (R)-2-Dipropylamino-1,1,2-triphenylethanol 4.
Following the general procedure, 50 mg (0.18 mmol) of
(S)-triphenyloxirane, 78 mg (0.73 mmol) of LiClO4, and
0.25 mL (1.83 mmol) of di-n-propylamine were used.
The reaction mixture was heated for 2 days. The
product was extracted and filtered on silica using
hexane/EtOAc 10% to remove the excess amine. The
crude product was solved in CH2Cl2 and was sub-
mitted to acid-basic extraction to yield 4 as a white
solid in 56% yield (38 mg). Mp ¼ 74.6 °C. 1H NMR
(CDCl3): d 7.62 (d, J ¼ 7 Hz, 2H), 7.35–6.95 (m, 13H),
6.00 (br s, 1H), 4.72 (s, 1H), 2.32 (m, 2H), 2.13 (m,
2H), 1.35 (m, 4H), 0.68 (t, J ¼ 7 Hz, 6H). 13C NMR
(CDCl3): d 149.0 (Cq), 145.8 (Cq), 137.4 (Cq), 131.6
(CH), 127.8 (CH), 127.4 (CH), 127.1 (CH), 126.9
(CH), 126.2 (CH), 125.9 (CH), 125.8 (CH), 78.4 (Cq),
74.5 (CH), 53.9 (CH2), 20.7 (CH2), 11.5 (CH3). IR
(KBr): mmax 2957, 1449, 704 cmÀ1. MS (CI, NH3): m=z
373 (Mþ, 100%). EA (calculated for C26H31NO,
found): C (83.60, 83.82), H (8.37, 8.05), N (3.75, 3.52).
5.2. Synthesis of (R)-2-dimethylamino-1,1,2-triphenyl-
ethanol 210
To a stirred solution of 0.1g (0.35 mmol) of ( R)-2-ami-
no-1,1,2-triphenylethanol in 1 mL of methanol, para-
formaldehyde (62 mg, 0.11 mmol) and a 20% HCl
solution in ethanol (26 lL) were added. Next, 43 mg
(0.69 mmol) of NaBH3CN in 1mL of methanol was
added via canulae. The reaction mixture was stirred at
room temperature for 3.5 days. The crude reaction was
quenched with 1mL of water and filtered over Celite.
The organic solvents were removed under vacuum and
the aqueous solution was acidified with a HCl (1M),
washed with Et2O. NaOH (1M) solution was then
added to the resulting aqueous solution until a white
solid formed. The aqueous solution was then extracted
with CH2Cl2. The organic layer was dried (MgSO4) and
removed under vacuum. The desired product (95 mg)
was obtained as a white solid in 87% yield.
½aŠ ¼ À118:2 (c 0.6, CHCl3).
D
1H NMR: d (CDCl3) 7.63 (m, 2H), 7.15–6.95 (m, 13H),
5.11 (d, J ¼ 2 Hz, 1H), 4.18 (d, J ¼ 2 Hz, 1H), 4.15 (s,
1H), 2.12 (s, 3H).
5.3.3. (R)-2-Dibutylamino-1,1,2-triphenylethanol 5. Fol-
lowing the general procedure, 0.50 g (1.84 mmol) of
(S)-triphenyloxirane, 0.78 g (7.34 mmol) of LiClO4, and
3.1mL (18.4 mmol) of di- n-butylamine were used.
The reaction was heated for 1.5 days. Next, the
product was filtered on SiO2 using hexane/EtOAc
5% to eliminate the excess amine, the yellow solid
was recrystallized in methanol. Compound 5 was
5.3. Preparation of (R)-2-dialkylamino-1,1,2-triphenyl-
ethanols
General procedure. (S)-Triphenyloxirane, LiClO4, and
the appropriate dialkylamine were placed in a pressure
tube. The mixture was heated at 120 °C until the reac-
tion was completed (TLC). The crude reaction mixture
was then poured over a H2O/CH2Cl2 biphasic mixture.
The organic layer was dried (MgSO4) and removed
under vacuum. The excess amine was removed by fil-
tration on SiO2 to yield the crude amino alcohol.
obtained as
a white crystalline solid in 45%
yield (0.33 g). Mp ¼ 97.8 °C. 1H NMR (CDCl3): d 7.62
(dd, J ¼ 8 Hz, J0 ¼ 1Hz, 2H), 7.35–6.95 (m, 13H),
6.05 (br s, 1H), 4.73 (s, 1H), 2.36 (m, 2H), 2.14 (m,
2H), 1.31 (m, 4H), 1.06 (m, 4H), 0.78 (t, J ¼ 7 Hz,
6H). 13C NMR: (CDCl3) d 149.2 (Cq), 145.9 (Cq),
137.4 (Cq), 131.6 (CH), 127.8 (CH), 127.3 (CH),
127.1 (Cq), 127.0 (CH), 126.9 (CH), 126.2 (CH),
125.9 (CH), 125.7 (CH), 74.5 (CH), 51.7 (CH2), 29.7
(CH2), 20.3 (CH2), 13.9 (CH3). IR (KBr): mmax 2927,
1597, 1449, 1161, 1030, 696 cmÀ1. MS (CI, NH3): m=z
5.3.1. (R)-2-Diethylamino-1,1,2-triphenylethanol 3. Fol-
lowing the general procedure, 0.50 g (1.84 mmol) of (S)-
triphenyloxirane, 0.39 g (3.67 mmol) of LiClO4, and
400 (Mþ, 1 00%). EA (calculated for CH34NO,
28

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N. Garcıa-Delgado et al. / Tetrahedron: Asymmetry 15 (2004) 2085–2090
2090
found): C (83.74, 83.65), H (8.78, 9.06), N (3.49,
Acknowledgements
3.46). ½aŠ ¼ À115:5 (c 1.08, CHCl3). Enantiomeric
D
excess was determined by 19F NMR upon mixing a
stoichiometric amount of Mosher’s acid. Enantio-
meric excess was determined to be >95%. 19F NMR
(CDCl3): d ðMosher RÞ ¼ À70:915, d ðMosher SÞ ¼
À71:084.
We thank the DGI-MYCT (BQU2002-02459) and
DURSI (2001SGR50) for financial support. X.V.
ꢀ
ꢀ
thanks the DURSI for ‘Distincio per a la Promocio de la
Recerca Universitaria’. N.G.D. thanks the DURSI and
Universitat de Barcelona for a fellowship.
5.4. Enantioselective amino alcohol-catalyzed addition of
dimethylzinc to aldehydes
References and notes
General procedure. In a reaction tube flushed with argon
and equipped with a magnetic stirring bar, a solution of
the chiral catalyst (10 mol %) in 2 mL of anhydrous
solvent was added. 2 M dimethylzinc (0.5 mL, 1mmol)
in toluene was added via syringe and the reaction
mixture was stirred at room temperature for 30 min.
The reaction was then cooled to the desired tempera-
ture and the aldehyde (0.5 mmol) was added dropwise.
The reacting mixture was stirred for the designated
time.
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5.4.1. Addition of dimethylzinc to benzaldehyde. Work-up
and analysis conditions: The reaction was quenched by
the addition of a saturated NH4Cl solution (1mL). The
solution was then extracted with Et2O and the combined
organic extracts were washed with a 1M HCl solution,
followed by saturated NaHCO3 solution. Conversion
and enantiomeric purity of the resulting alcohols were
determined by GC analysis.
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GC analysis: Supelco b-DEX 120 column, 30 m length,
130 °C isotherm, tR aldehyde 6.0 min, tR R isomer
12.7 min, tR S isomer 13.1 min.
ꢁ
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analysis conditions: A reaction aliquot was quenched by
the addition of a saturated NH4Cl solution (1mL). The
solution was then extracted with Et2O and the combined
organic extracts were washed with a 1M HCl solution
followed by saturated NaHCO3 solution. Conversion to
the resulting alcohols was determined from the crude
mixture by GC analysis of the organic extract.
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15.9 min.
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€
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room temperature. The mixture was extracted with Et2O
and the organic layers were washed with 1M NaCl
solution. Enantiomeric purity of the resulting alcohols
was determined from the organic extract by GC analy-
sis.
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GC analysis: Supelco b-DEX 120 column, 30 m length,
100 °C isotherm, tR S isomer 18.4 min, tR R isomer
20.9 min.
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