Enantioselective addition of dimethylzinc to aldehydes catalyzed by a chiral perhydro-1,3-benzoxazine-based amino alcohol as ligand

Article abstract of DOI:10.1055/s-0031-1289742

Dimethylzinc undergoes efficient enantioselective addition to a wide variety of aromatic and aliphatic aldehydes in the presence of a catalytic amount of a chiral perhydro-1,3-benzoxazine-based amino alcohol. Methyl carbinols are obtained in good yields and in enantiomeric excesses of 99% or more in the absence of any metal other than zinc. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289742

PAPER
▌1343
paper
Enantioselective Addition of Dimethylzinc to Aldehydes Catalyzed by a Chiral
Perhydro-1,3-benzoxazine-Based Amino Alcohol as Ligand
Catalytic Enantioselective Addition of Dimethylzinc to Aldehydes
Rebeca Infante, Javier Nieto,* Celia Andrés*
IU CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid,
Spain
Fax +34983423013; E-mail: javiernr@qo.uva.es
Received: 07.12.2011; Accepted after revision: 02.03.2012
OH
Abstract: Dimethylzinc undergoes efficient enantioselective addi-
N
tion to a wide variety of aromatic and aliphatic aldehydes in the
Ph
H
O
presence of a catalytic amount of a chiral perhydro-1,3-benzoxa-
zine-based amino alcohol. Methyl carbinols are obtained in good
yields and in enantiomeric excesses of 99% or more in the absence
of any metal other than zinc.
1
Figure 1 Perhydro-1,3-benzoxazine ligand 1
Key words: asymmetric catalysis, zinc, aldehydes, chiral auxilia-
ries, amino alcohols
We initially examined the experimental conditions for the
reaction between two equivalents of dimethyl zinc (1.2
M) and 2-naphthaldehyde in the presence of 10 mol% of
ligand 1 in a 2:1 toluene–hexane mixture at various tem-
peratures. The results are listed in Table 1.
Among the asymmetric catalytic reactions that are avail-
able for C–C bond formation, the enantioselective addi-
tion of a diorganozinc reagent to an aldehyde in the
presence of a catalytic amount of a chiral ligand is a par-
ticularly convenient method for obtaining chiral second-
ary alcohols with high optical purity.1–4 In this respect, the
asymmetric addition of diethylzinc to aldehydes has at-
tracted a great deal of attention. However, although they
are more important than ethyl carbinols as building blocks
for the synthesis of bioactive compounds,5 chiral methyl
carbinols are usually prepared from ketones through enan-
tioselective reduction. This route is adopted mainly be-
cause of the low reactivity of dimethylzinc compared with
that of diethylzinc.6 Significant progress has recently been
made in the use of chiral chromium,7 titanium8,9 and
osmium10 complexes as catalysts for this reaction; howev-
er, these impressive methods depended on the presence of
others metals in addition to zinc. Only a few examples of
asymmetric methylation reactions of aldehydes, other
than benzaldehyde, that employ dimethylzinc and a cata-
lytic amount of chiral ligands in the absence of any addi-
tional metals have been reported that provide high yields
and high enantiomeric excesses.11–15 Therefore, the devel-
opment of a highly enantioselective methylation method
remains a challenge.
Table 1 Screening of Reaction Conditions for Asymmetric Methyl-
ation of 2-Naphthaldehyde Catalyzed by Ligand 1
O
OH
ZnMe2, 1 (10 mol%)
H
toluene–hexane (2:1)
2a
3a
Entrya
Yield (%)b ee (%)c
Temp (°C)
Time (h)
1
2
3
4
5
6
25
0
24
93
56
49
22
21
75
87
91
93
95
97
92
24
–10
–15
–20
–20 / r.t.
24
24
24
24/6
a Reactions were carried out with a Me2Zn/aldehyde/catalyst 1 molar
ratio of 2:1:0.1 in 2:1 toluene–hexane. All reactions were performed
in duplicate.
b Yields of pure compounds after column chromatography.
c The ee was determined by HPLC on a Chiralcel AS-H column. The
absolute configuration was assigned from the order of elution in
HPLC by comparison with literature data.
We have recently introduced the perhydro-1,3-benzoxa-
zine 1 (Figure 1) as an asymmetric ligand and have dem-
onstrated its use as a catalyst in asymmetric ethylation and
arylation reactions of a wide range of aldehydes.16
Under the optimized conditions for the addition of dieth-
ylzinc to aldehydes,16a carbinol 3a was obtained in good
yield but moderate enantioselectivity (87% ee; Table 1,
entry 1). Decreasing the temperature from room tempera-
ture to –20 °C increased the enantioselectivity from 87%
to 97% (entries 2–5). However, this was accompanied by
progressive loss in catalytic activity; the yield fell to 20%
at –20 °C with 68% recovery of the starting aldehyde 2a
(entry 5). Good catalytic performance in terms of both the
Here we report that perhydro-1,3-benzoxazine 1 also cat-
alyzes the asymmetric reaction of aldehydes with dimeth-
ylzinc.
SYNTHESIS 2012, 44, 1343–1348
Advanced online publication: 03.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289742; Art ID: SS-2011-T1133-OP
© Georg Thieme Verlag Stuttgart · New York

1344
R. Infante et al.
PAPER
yield and enantioselectivity was achieved when the mix- tate the determination of the enantiomeric excess by chiral
ture was stirred for 24 hours at –20 °C and then for six HPLC, alcohols 3n and 3o, obtained by addition of di-
hours at room temperature (75% yield, 92% ee; Entry 6). methylzinc to cyclohexanecarboxaldehyde and heptanal,
Figure 2 shows the evolution of the conversion and enan- respectively, were characterized as their benzoates (4n
tiomeric excess with reaction time under these conditions. and 4o, respectively).
Table 2 Asymmetric Addition of Dimethylzinc to Various Alde-
hydes Catalyzed by Ligand 1
O
OH
ZnMe2, 1 (10 mol%)
toluene–hexane (2:1)
R
H
R
2a–q
3a–q
Entrya Aldehyde
Product
Yield (%)b ee (%)c
OH
CHO
1
75
87
2a
3a
3b
Figure 2 Changes in conversion and enantiomeric excess with reac-
tion time at room temperature
OH
OH
CHO
2
3
4
96
91
91
94
Next, we evaluated the asymmetric catalysis by ligand 1
of addition reactions of dimethylzinc with a variety of al-
dehydes under the optimized conditions. The results are
shown in Table 2.
2b
CHO
58f
67 f
90
Optically active 1-arylethanols were obtained in good
yields and good-to-excellent enantioselectivities from
various aromatic aldehydes, including ortho-, meta- and
para-substituted benzaldehydes (Table 2, entries 1–11).
In general, there was little dependence on the electronic
character of the substituent in para-substituted benzalde-
hydes. 4-Tolualdehyde and 4-methoxybenzaldehyde,
which contain electron-donating groups, and 4-chloro-
and 4-(trifluoromethyl)benzaldehyde, which contain elec-
tron-withdrawing groups, behaved similarly in terms of
their enantioselectivities (entries 4, 6, 9, and 11), although
there were appreciable differnces in their reactivities.
2-Chloro- and 2-bromo-substituted benzaldehydes gave
slightly lower enantiomeric excesses than did other benz-
aldehydes substituted with donating groups in the ortho-
position (compare entries 7 and 10 with entries 3 and 5).
This is probably due to a combination of the electronic
and steric effects of the ortho-substituents. In the same
way, good enantioselectivity was achieved with the het-
erocyclic aldehyde 2-furaldehyde (83% ee; entry 12). The
best asymmetric inductions were found with 4-(trifluoro-
methyl)benzaldehyde (which contains a strongly electron-
withdrawing 4-trifluoromethyl group) and 3-chlorobenz-
aldehyde; these gave enantiomeric excesses of up to 97%
and 98%, respectively (entries 11 and 8).
2c
3c
OH
CHO
2d
3d
OH
CHO
OMe
5
93
92
86
OMe
2e
3e
OH
MeO
CHO
MeO
6d
72
70
2f
3f
OH
CHO
7
Cl
Cl
2g
3g
OH
CHO
8
70
97
74
98
98
95
80
97
Cl
Cl
2h
3h
OH
Cl
CHO
Cl
9d
2i
3i
Encouraged by these results, we focused our attention on
the asymmetric addition of dimethylzinc to several ali-
phatic aldehydes 2m–o in the presence of chiral ligand 1.
Extremely high enantioselective methylation was
achieved with 3-phenylpropanal, although the chemical
yield was moderate (entry 13). Cyclohexanecarboxalde-
hyde also showed a high enantiomeric excess of 88% (en-
try 14), whereas alkylation of the linear aldehyde heptanal
showed moderate enantioselectivity (entry 15). To facili-
OH
CHO
10
Br
Br
2j
3j
OH
F3C
CHO
F3
C
11
2k
3k
Synthesis 2012, 44, 1343–1348
© Georg Thieme Verlag Stuttgart · New York

PAPER
Catalytic Enantioselective Addition of Dimethylzinc to Aldehydes
1345
Table 2 Asymmetric Addition of Dimethylzinc to Various Alde-
hydes Catalyzed by Ligand 1 (continued)
hydro-1,3-benzoxazine skeleton and the aldehyde and
dimethylzinc and it minimizes nonbonded repulsion be-
tween the nonreactive Zn–CH3 group and the R substitu-
ent on the aldehyde.
O
OH
ZnMe2, 1 (10 mol%)
toluene–hexane (2:1)
R
H
R
2a–q
3a–q
H
R
Entrya Aldehyde
Product
Yield (%)b ee (%)c
O
Zn
OH
Zn
O
CHO
N
51f
83
12
13
O
O
Ph
O
H
2l
3l
OH
CHO
40 f
Figure 3 Proposed transition state for the addition of dimethylzinc
to aldehydes catalyzed by ligand 1
>99
2m
3m
3n
3o
OH
OH
In conclusion, we have shown that chiral perhydro-1,3-
benzoxazine 1 is an efficient chiral ligand for the enan-
tioselective addition of dimethylzinc to a wide variety of
aldehydes under mild conditions and in the absence of ad-
ditional metals other than zinc. The enantioselectivity is
excellent for aromatic aldehydes and good for aliphatic or
α,β-unsaturated aldehydes. On the other hand, the yields
vary from moderate to high, depending on the starting al-
dehyde. These results compared favorably with the high-
est enantioselectivities reported for the asymmetric
addition of dimethylzinc to aldehydes.
CHO
64e
58e
14
15
88
74
2n
2o
OH
OH
16d
17
88
74
86
2p
3p
All reactions were carried out in anhyd solvents under argon in
47 f
1
dried glassware by means of Schlenk techniques. H NMR (300
MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3 by
using a Bruker AV-400 spectrometer. Chemical shifts for protons
are reported in ppm from TMS with the residual CHCl3 resonance
as the internal reference. Chemical shifts for carbons are reported in
ppm from TMS and are referenced to the carbon resonance of the
solvent. Specific rotations were measured by using a 5-mL cell with
a 1-dm path length and a Na lamp; the concentration is given in
grams per 100 mL. Flash chromatography was carried out using sil-
ica gel (230–240 mesh). Chemical yields refer to the pure isolated
substances. TLC analysis was performed on glass–backed plates
coated with silica gel 60 and an F254 indicator, and visualized by ei-
ther UV irradiation or by staining with I2 or phosphomolybdic acid
soln. Chiral HPLC analysis was performed using a Daicel Chiralcel
OD Column, Chiralpak AD-H, or Chiralpak AS–H. UV detection
was performed at 220 or 254 nm.
2q
3q
a Reactions were carried out with a Me2Zn/aldehyde/catalyst 1 molar
ratio of 2:1:0.1 in 2:1 toluene–hexane at –20 °C for 24 h and then for
6 h at r.t. unless otherwise indicated.
b Yields of pure compounds after column chromatography.
c The ee was determined by HPLC on a chiral column. The absolute
configuration was assigned by comparing the sign of the specific ro-
tation or the elution order in the HPLC analysis with literature data.
d At r.t. for 24 h.
e Yield of the benzoylated product.
f 22% of 2c, 12% of 2d, 20% of 2l, 38% of 2m, and 24% of 2q were
recovered.
The catalytic efficiency of ligand 1 for the addition of di-
methylzinc to α,β-unsaturated aldehydes was also exam-
ined. Allylic alcohol 3p was obtained in a good yield and
moderate enantioselectivity from trans-cinnamaldehyde
(entry 16), whereas methylation of α-methyl-trans-cin-
namaldehyde gave allylic alcohol 3q in a reasonably high
86% enantiomeric excess but with a moderate chemical
yield (entry 17).
Unless otherwise indicated, all compounds were purchased and
used as received. The ligand 1 was prepared according to reported
procedures.16a,18,19
Asymmetric Addition of Dimethylzinc to Aldehydes; General
Procedure
A 1.2 M soln of Me2Zn in toluene (0.83 mL, 1.0 mmol) was added
to an argon-purged flask containing ligand 1 (17.8 mg, 0.05 mmol)
and anhyd 1:2 toluene–hexane (0.2–0.5 mL) at r.t. The soln was
stirred for 10 min then cooled to –20 °C. The aldehyde (0.5 mmol)
was added and the mixture was kept at –20 °C for 24 h then warmed
to r.t. and stirred for 6 h. The reaction was quenched by dropwise
addition of aq NH4Cl. The organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layers were washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane–EtOAc). The ee values
were determined by HPLC on a chiral stationary phase.
In all of the cases, the reaction led to alcohols with the R-
configuration as a result of attack of the methyl group on
the Re face of the aldehyde carbonyl (Figure 3). The ste-
reochemical course of the reaction can be rationalized in
terms of an anti-5/4/4-fused tricyclic transition-state
structure, related to that proposed by Noyori.17 This tran-
sition structure prevents steric repulsion between the per-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1343–1348

1346
R. Infante et al.
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(1R)-1-(2-Naphthyl)ethanol (3a)
[EtOAc–hexane (1:30)] to give a colorless oil; yield: 74 mg (0.45
mmol, 90%), 93% ee; [α]D20 +26.8 (c 0.6, CHCl3).
This compound was obtained from 2-naphthaldehyde (78 mg, 0.5
mmol) and purified by flash chromatography [EtOAc–hexane
(1:30)] to give a colorless solid; yield: 64 mg (0.37 mmol, 75%),
92% ee.
HPLC [Chiralpak AD-H, hexane–i-PrOH (99:1), 1 mL/min,
λ = 254 nm]: tR = 33.3 min for enantiomer S, tR = 34.6 min for en-
antiomer R. The configuration was assigned by comparing the sign
of the optical rotation with the literature value: [α]D25 +28.4 (c 1.0,
CHCl3, R).23
1H NMR (300 MHz, CDCl3): δ = 1.51 (d, J = 6.4 Hz, 3 H), 2.90 (s,
1 H), 3.86 (s, 3 H), 5.11 (q, J = 6.4 Hz, 1 H), 6.89 (m, 1 H), 6.98 (m,
1 H), 7.26 (m, 1 H), 7.37 (m, 1 H).
HPLC [Chiralpak AS-H, hexane–i-PrOH (98:02), 1 mL/min,
λ = 254 nm]: tR = 19.1 min for enantiomer R, tR = 21.9 min for en-
antiomer S. The configuration was assigned by comparing the
HPLC elution order with literature data.20
1H NMR (300 MHz, CDCl3): δ = 1.58 (d, J = 6.5 Hz, 3 H), 2.50 (s,
1 H), 5.01 (q, J = 6.5 Hz, 1 H), 7.49–7.54 (m, 3 H), 7.79–7.87 (m, 4
13C NMR (75 MHz, CDCl3): δ = 22.8 (CH3), 55.1 (CH3), 66.2 (CH),
110.2 (CH), 120.6 (CH), 125.9 (CH), 128.1 (CH), 133.4 (C), 156.3
(C).
H).
13C NMR (75 MHz, CDCl3): δ = 25.0 (CH3), 70.3 (CH), 123.7 (CH),
123.8 (CH), 125.7 (CH), 126.0 (CH), 127.6 (CH), 127.9 (CH),
128.2 (CH), 132.8 (C), 133.2 (C), 143.1 (C).
(1R)-1-(4-Methoxyphenyl)ethanol (3f)
This compound was obtained from 4-methoxybenzaldehyde (68
mg, 61 μL, 0.5 mmol) and purified by flash chromatography
[EtOAc–hexane (1:20)] to give a colorless oil; yield: 59 mg (0.35
mmol, 72%), 92% ee.
(1R)-1-Phenylethanol (3b)
This compound was obtained from PhCHO (53 mg, 51 μL, 0.5
mmol) and purified by flash chromatography [EtOAc–hexane
(1:60)] to give a colorless liquid; yield: 58 mg (0.48 mmol, 96%),
91% ee.
HPLC [Chiralpak AS-H, hexane–i-PrOH (90:10), 1 mL/min,
λ = 254 nm]: tR = 12.2 min for enantiomer R, tR = 15.9 min for en-
antiomer S. The configuration was assigned by comparing the
HPLC elution order with literature data.24
1H NMR (300 MHz, CDCl3): δ = 1.44 (d, J = 6.6 Hz, 3 H), 2.89 (s,
1 H), 3.78 (s, 3 H), 4.78 (q, J = 6.4 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 2
H), 7.26 (d, J = 8.6 Hz, 2 H).
HPLC [Chiralcel OD, hexane–i-PrOH (95:05), 1 mL/min, λ = 220
nm]: tR = 9.5 min for enantiomer R, tR = 11.3 min for enantiomer S.
The configuration was assigned by comparing the HPLC elution or-
der with literature data.20
1H NMR (400 MHz, CDCl3): δ = 1.50 (d, J = 6.5 Hz, 3 H), 1.93 (br
s, 1 H), 4.90 (q, J = 6.5 Hz, 1 H), 7.28 (m, 1 H), 7.32–7.42 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 24.8 (CH3), 55.0 (CH3), 69.5 (CH),
113.6 (2 CH), 126.5 (2 CH), 138.0 (C), 158.6 (C).
13C NMR (100 MHz, CDCl3): δ = 24.8 (CH3), 69.6 (CH), 125.1 (2
CH), 126.9 (CH), 128.0 (2 CH), 145.7 (C).
(1R)-1-(2-chlorophenyl)ethanol (3g)
(1R)-1-(2-Methylphenyl)ethanol (3c)
This compound was obtained from 2-chlorobenzaldehyde (71 mg,
56 μL, 0.5 mmol) and purified by flash chromatography [EtOAc–
hexane (1:45)] to give a colorless oil; yield: 54 mg (0.35 mmol,
70%), 86% ee.
This compound was obtained from 2-tolualdehyde (60 mg, 60 μL,
0.5 mmol) and purified by flash chromatography [EtOAc–hexane
(1:60)] to give a colorless liquid; yield: 43 mg (0.29 mmol, 58%),
91% ee.
HPLC [Chiralcel OD, hexane–i-PrOH (99:1), 1 mL/min, λ = 220
nm]: tR = 24.7 min for enantiomer R, tR = 27.4 min for enantiomer
S. The configuration was assigned by comparing the HPLC elution
order with literature data.9
1H NMR (300 MHz, CDCl3): δ = 1.38 (d, J = 6.4 Hz, 3 H), 3.45 (s,
1 H), 5.19 (q, J = 6.3 Hz, 1 H), 7.17 (m, 1 H), 7.21–7.33 (m, 2 H),
7.50 (dd, J1 = 7.7 Hz, J2 = 1.7 Hz, 1 H).
HPLC [Chiralpak AD-H, hexane–i-PrOH (99:1), 1 mL/min,
λ = 220 nm]: tR = 18.4 min for enantiomer R, tR = 23.1 min for en-
antiomer S. The configuration was assigned by comparing the
HPLC elution order with literature data.21
1H NMR (300 MHz, CDCl3): δ = 1.46 (d, J = 6.4 Hz, 3 H), 2.36 (s,
3 H), 2.43 (br, 1 H), 5.12 (q, J = 6.4 Hz, 1 H), 7.13–7.28 (m, 3 H),
7.54 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 18.8 (CH3), 23.8 (CH3), 66.6 (CH),
124.4 (CH), 126.2 (CH), 127.0 (CH), 130.2 (CH), 134.0 (C), 143.8
(C).
13C NMR (75 MHz, CDCl3): δ = 22.4 (CH3), 66.6 (CH), 126.3 (CH),
127.0 (CH), 128.1 (CH), 129.1 (CH), 131.3 (C), 143.0 (C).
(1R)-1-(3-Chlorophenyl)ethanol (3h)
This compound was obtained from 3-chlorobenzaldehyde (71 mg,
58 μL, 0.5 mmol) and purified by flash chromatography [EtOAc–
hexane (1:30)] to give a colorless oil; yield: 54 mg (0.35 mmol,
70%), 98% ee; [α]D20 +40.1 (c 0.8, CHCl3).
(1R)-1-(4-Methylphenyl)ethanol (3d)
This compound was obtained from 4-tolualdehyde (60 mg, 56 μL,
0.5 mmol) and purified by flash chromatography [EtOAc–hexane
(1:60)] to give a colorless liquid; yield: 50 mg (0.33 mmol, 67%),
94% ee; [α]D20 +49.3 (c 0.5, CHCl3).
HPLC [Chiralpak AD-H, hexane–i-PrOH (99:1), 0.5 mL/min,
λ = 220 nm]: tR = 56.9 min for enantiomer R, tR = 67.6 min for en-
antiomer S. The configuration was assigned by comparing the sign
of the optical rotation with the literature value: [α]D25 +40.4 (c 1.0,
CHCl3, R).23
1H NMR (300 MHz, CDCl3): δ = 1.44 (d, J = 6.4 Hz, 3 H), 2.57 (br
s, 1 H), 4.82 (q, J = 6.4 Hz, 1 H), 7.13–7.29 (m, 3 H), 7.34 (s, 1 H).
HPLC [Chiralpak AS-H, hexane–i-PrOH (99:1), 1 mL/min, λ = 220
nm]: tR = 15.3 min for enantiomer R, tR = 18.2 min for enantiomer
S. The configuration was assigned by comparing the sign of the op-
tical rotation with the literature value: [α]D20 +53.2 (c 0.236, CHCl3,
R).22
1H NMR (300 MHz, CDCl3): δ = 1.49 (d, J = 6.4 Hz, 3 H), 2.39 (s,
3 H), 2.69 (br s, 1 H), 4.84 (q, J = 6.4 Hz, 1 H), 7.19 (d, J = 8.0 Hz,
2 H), 7.28 (d, J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 25.1 (CH3), 69.7 (CH), 123.5 (CH),
125.5 (CH), 127.4 (CH), 129.7 (CH), 134.2 (C), 147.8 (C).
13C NMR (75 MHz, CDCl3): δ = 20.9 (CH3), 24.9 (CH3), 69.9 (CH),
(1R)-1-(4-Chlorophenyl)ethanol (3i)
This compound was obtained from 4-chlorobenzaldehyde (71 mg,
0.5 mmol) and purified by flash chromatography [EtOAc–hexane
(1:30)] to give a colorless oil; yield: 75 mg (0.48 mmol, 97%), 95%
ee; [α]D20 +47.5 (c 0.7, CHCl3).
125.2 (2 CH), 128.9 (2 CH), 136.8 (C), 142.8 (C).
(1R)-1-(2-Methoxyphenyl)ethanol (3e)
This compound was obtained from 2-methoxybenzaldehyde (68
mg, 62 μL, 0.5 mmol) and purified by flash chromatography
Synthesis 2012, 44, 1343–1348
© Georg Thieme Verlag Stuttgart · New York

PAPER
Catalytic Enantioselective Addition of Dimethylzinc to Aldehydes
1347
HPLC [Chiralcel OD, hexane–i-PrOH (95:5), 1 mL/min, λ = 220
nm]: tR = 9.2 min for enantiomer S, tR = 10.0 min for enantiomer R.
The configuration was assigned by comparing HPLC elution order
with literature data25 and the sign of the optical rotation with the lit-
erature value: [α]D25 +46.1 (c 1.0, CHCl3, R).23
1H NMR (300 MHz, CDCl3): δ = 1.38 (d, J = 6.5 Hz, 3 H), 2.49 (s,
1 H), 4.74 (q, J = 6.5 Hz, 1 H), 7.19–7.29 (m, 4 H).
HPLC [Chiralcel OD, hexane–i-PrOH (95:05), 1 mL/min, λ = 220
nm]: tR = 12.7 min for enantiomer R, tR = 20.4 min for enantiomer
S. The configuration was assigned by comparing the HPLC elution
order with literature data.20
1H NMR (300 MHz, CDCl3): δ = 1.27 (d, J = 6.3 Hz, 3 H), 1.72–
1.90 (m, 2 H), 2.23 (br s, 1 H), 2.66–2.85 (m, 2 H), 3.85 (sext,
J = 6.3 Hz, 1 H), 7.21–7.26 (m, 3 H), 7.31–7.36 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 25.0 (CH3), 69.3 (CH), 126.7 (2
CH), 128.3 (2 CH), 132.7 (C), 144.1 (C).
13C NMR (75 MHz, CDCl3): δ = 24.0 (CH3), 32.0 (CH2), 40.7
(CH2), 67.2 (CH), 125.7 (CH), 128.3 (4 CH), 142.0 (C).
(1R)-1-(2-Bromophenyl)ethanol (3j)
(2R,3E)-4-Phenylbut-3-en-2-ol (3p)
This compound was obtained from 2-bromobenzaldehyde (93 mg,
0.5 mmol) and purified by flash chromatography [EtOAc–hexane
(1:45)] to give a colorless oil; yield: 74 mg (0.37 mmol, 74%), 80%
ee.
This compound was obtained from trans-cinnamaldehyde (59 mg,
64 μL, 0.5 mmol) and purified by flash chromatography [EtOAc–
hexane (1:30)] to give a yellow oil; yield: 65 mg (0.44 mmol, 88%),
74% ee.
HPLC [Chiralcel OD, hexane–i-PrOH (98:2), 1 mL/min, λ = 220
nm]: tR = 14.7 min for enantiomer R, tR = 16.5 min for enantiomer
S. The configuration was assigned by comparing the HPLC elution
order with literature data.26
HPLC [Chiralcel OD, hexane–i-PrOH (90:10), 1 mL/min, λ = 254
nm]: tR = 10.1 min for enantiomer R, tR = 15.0 min for enantiomer
S. The configuration was assigned by comparing the HPLC elution
order with literature data.9
1H NMR (300 MHz, CDCl3): δ = 1.46 (d, J = 6.4 Hz, 3 H), 2.42 (br
s, 1 H), 5.21 (q, J = 6.4 Hz, 1 H), 7.12 (m, 1 H), 7.31 (m, 1 H), 7.50
(dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1 H), 7.57 (dd, J1 = 7.8 Hz, J2 = 1.7
Hz, 1 H).
1H NMR (300 MHz, CDCl3): δ = 1.39 (d, J = 6.4 Hz, 3 H), 2.70 (s,
1 H), 4.50 (quint, J = 6.4 Hz, 1 H), 6.28 (dd, J1 = 15.9 Hz, J2 = 6.4
Hz, 1 H), 6.57 (d, J = 15.9 Hz, 1 H), 7.24–7.42 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 23.2 (CH3), 68.6 (CH), 126.3 (2
CH), 127.4 (CH), 128.4 (2 CH), 129.1 (CH), 133.5 (CH), 136.6 (C).
13C NMR (75 MHz, CDCl3): δ = 23.5 (CH3), 69.1 (CH), 121.6 (C),
126.6 (CH), 127.8 (CH), 128.7 (CH), 132.6 (CH), 144.5 (C).
(2R,3E)-3-Methyl-4-phenylbut-3-en-2-ol (3q)
This compound was obtained from α-methyl-trans-cinnamaldehyde
(66 mg, 73 μL, 0.5 mmol) and purified by flash chromatography
[EtOAc–hexane (1:20)] to give a colorless oil; yield: 38 mg (0.23
mmol, 47%), 86% ee.
(1R)-1-[4-(Trifluoromethyl)phenyl]ethanol (3k)
This compound was obtained from 4-(trifluoromethyl)benzalde-
hyde (87 mg, 69 μL, 0.5 mmol) and purified by flash chromatogra-
phy [EtOAc–hexane (1:30)] to give a colorless oil; yield: 93 mg
(0.49 mmol, 98%), 97% ee; [α]D20 +26.1 (c 0.9, CHCl3).
HPLC [Chiralcel OD, hexane–i-PrOH (95:05), 1 mL/min, λ = 254
nm]: tR = 9.8 min for enantiomer R, tR = 11.0 min for enantiomer S.
The configuration was assigned by comparing the HPLC elution or-
der with literature data.27
1H NMR (300 MHz, CDCl3): δ = 1.41 (d, J = 6.5 Hz, 3 H), 1.93 (s,
3 H), 2.85 (br s, 1 H), 4.41 (q, J = 6.5 Hz, 1 H), 6.56 (s, 1 H), 7.23–
7.41 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 13.2 (CH3), 21.6 (CH3), 73.3 (CH),
124.1 (CH), 126.2 (CH), 127.9 (2 CH), 128.8 (2 CH), 137.5 (C),
141.5 (C).
HPLC [Chiralpak AS-H, hexane–i-PrOH (99:01), 0.5 mL/min,
λ = 220 nm]: tR = 32.1 min for enantiomer R, tR = 34.2 min for en-
antiomer S. The configuration was assigned by comparing the sign
of the optical rotation with the literature value: [α]D = +24.14 (c
1.41, CHCl3, R).9
1H NMR (300 MHz, CDCl3): δ = 1.43 (d, J = 6.5 Hz, 3 H), 3.38 (s,
1 H), 4.86 (q, J = 6.5 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.57 (d,
J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 25.1 (CH3), 69.6 (CH), 124.1 (q,
J
C-F = 271.6 Hz, 1C), 125.3 (2 CH), 125.6 (2 CH), 129.5 (q, JC-CF =
Benzoates 4n and 4o; General Procedure
32.1 Hz, 1C), 149.6 (C).
BzCl (77 mg, 64 μL, 0.55 mmol) was added under N2 at r.t. to a soln
of 1-cyclohexylethanol (3n) or octan-2-ol (3o) (0.5 mmol) obtained
by adding Me2Zn to CyCHO or heptanal, respectively, in anhyd
pyridine (1.5 mL). The mixture was stirred until the starting materi-
al disappeared (TLC) and then the reaction was quenched with sat.
aq NaHCO3 (10 mL). The mixture was extracted with CH2Cl2 (3 ×
15 mL), washed with brine, dried (MgSO4), and concentrated. The
residue was purified by column chromatography (silica gel, hex-
ane).
19F NMR (282 MHz, CDCl3): δ = –63.08 (3 F).
(1R)-1-(2-Furyl)ethanol (3l)
This compound was obtained from 2-furaldehyde (48 mg, 42 μL,
0.5 mmol) and purified by flash chromatography [EtOAc–hexane
(1:20)] to give a colorless oil; yield: 28 mg (0.25 mmol, 51%), 83%
ee.
HPLC [Chiralcel OD, hexane–i-PrOH (99:1), 1 mL/min, λ = 220
nm]: tR = 28.6 min for enantiomer R, tR = 30.8 min for enantiomer
S. The configuration was assigned by comparing the HPLC elution
order with literature data.9
1H NMR (300 MHz, CDCl3): δ = 1.51 (d, J = 6.5 Hz, 3 H), 2.56 (br
s, 1 H), 4.84 (q, J = 6.5 Hz, 1 H), 6.21 (d, J = 3.2 Hz, 1 H), 6.31 (d,
J = 3.2 Hz, 1 H), 7.35 (s, 1 H).
(1R)-1-Cyclohexylethyl Benzoate (4n)28
This compound was obtainedfrom aldehyde 2n (66 mg, 0.5 mmol)
in two steps: methyl addition and esterification of the intermediate
alcohol 3n. The product was purified by flash chromatography
(hexane) to give a colorless oil; yield: 74 mg (0.32 mmol, 64% over-
all), 88% ee.
13C NMR (75 MHz, CDCl3): δ = 21.1 (CH3), 63.4 (CH), 105.0 (CH),
110.0 (CH), 141.8 (CH), 157.5 (C).
HPLC [Chiralpak AS-H, hexane, 1 mL/min, λ = 254 nm]: tR = 6.4
min for enantiomer R, tR = 7.5 min for enantiomer S. The configu-
ration was assigned by assuming an analogous reaction mechanism
for the methyl addition stage.
1H NMR (400 MHz, CDCl3): δ = 0.95–1.25 (m, 5 H), 1.27 (d,
J = 6.4 Hz, 3 H), 1.45–1.90 (m, 6 H), 4.99 (quint, J = 6.4 Hz, 1 H),
7.35–7.41 (m, 2 H), 7.48 (m, 1 H), 8.03–8.07 (m, 2 H).
(2R)-4-Phenylbutan-2-ol (3m)
This compound was obtained from 3-phenylpropanal (67 mg, 66
μL, 0.5 mmol) and purified by flash chromatography [EtOAc–hex-
ane (1:60)] to give a colorless liquid; yield: 30 mg (0.20 mmol,
40%), >99% ee.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1343–1348

1348
R. Infante et al.
PAPER
(8) Blay, G.; Fernández, I.; Hernández-Olmos, V.; Marco-
13C NMR (100 MHz, CDCl3): δ = 16.8 (CH3), 25.8 (2 CH2), 26.2
(CH2), 28.2 (CH2), 28.4 (CH2), 42.5 (CH), 74.8 (CH), 128.0 (2 CH),
129.2 (2 CH), 130.7 (C), 132.3 (CH), 165.7 (C).
Aleixandre, A.; Pedro, J. R. Tetrahedron: Asymmetry 2005,
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Ding, X.; Jing, T.-T.; Song, M.-P. J. Org. Chem. 2008, 73,
168.
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(1R)-1-Methylheptyl Benzoate (4o)
This compound was obtained from aldehyde 2o (64 mg, 0.5 mmol)
in two steps: methyl addition and esterification of the intermediate
alcohol 3o. The product was purified by flash chromatography
(hexane) to give a colorless oil; yield: 68 mg (0.28 mmol, 58% over-
all), 74% ee; [α]D20 –29.1 (c 0.8, MeOH).
HPLC [Chiralpak AD-H, hexane, 0.5 mL/min, λ = 220 nm]:
tR = 10.7 min for enantiomer S, tR = 11.7 min for enantiomer R. The
configuration was assigned by comparing the sign of the optical ro-
tation with the literature value: [α]D20 –40.6 (c 1.06, MeOH, R).29
1H NMR (400 MHz, CDCl3): δ = 0.85–0.90 (m, 3 H), 1.28–1.42 (m,
8 H), 1.34 (d, J = 6.3 Hz, 3 H), 1.59 (m, 1 H), 1.73 (m, 1 H), 5.17
(sext, J = 6.3 Hz, 1 H), 7.39–7.44 (m, 2 H), 7.53 (m, 1 H), 8.04–8.08
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3), 19.9 (CH3), 22.5
(CH2), 25.3 (CH2), 29.0 (CH2), 31.6 (CH2), 35.9 (CH2), 71.5 (CH),
128.1 (2 CH), 129.4 (2 CH) 130.8 (C), 132.5 (CH), 166.0 (C).
(16) (a) Andrés, C.; Infante, R.; Nieto, J. Tetrahedron:
Asymmetry 2010, 21, 2230. (b) Infante, R.; Nieto, J.; Andrés,
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Acknowledgment
We acknowledge financial support from the Spanish Ministerio de
Ciencia e Innovación (project CTQ2008-03960/BQU) and from
Junta de Castilla y León (GR168). R.I. also thanks Junta de Castilla
y León for a predoctoral fellowship.
(18) Pedrosa, R.; Andrés, C.; Rosón, C. D.; Vicente, M. J. Org.
Chem. 2003, 68, 1852.
(19) Andrés, C.; González, I.; Nieto, J.; Rosón, C. D.
Tetrahedron 2009, 65, 9728.
(20) Xiao, J.; Wong, Z. Z.; Lu, Y. P.; Loh, T. P. Adv. Synth. Catal.
2010, 352, 1107.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinIfatgnonmSorti
i
npfurotIangSiuptor
(21) Li, D. R.; He, A.; Falck, J. R. Org. Lett. 2010, 12, 1756.
(22) Xu, Y.; Alcock, N. W.; Clarkson, G. J.; Docherty, G.;
Woodward, G.; Wills, M. Org. Lett. 2004, 6, 4105.
(23) Inagaki, T.; Phong, L. T.; Furuta, A.; Ito, J.-I.; Nishiyama, H.
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© Georg Thieme Verlag Stuttgart · New York