Synthesis of enantiopure o-hydroxybenzylamines by stereoselective reduction of 2-imidoylphenols: Application in the catalytic enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1002/(sici)1099-0690(199904)1999:4<805::aid-ejoc805>3.0.co;2-r

Enantiopure o-hydroxybenzylamines 2a-i were synthesized by diastereoselective reduction of the 2-imidoylphenols (R)-1a-i. Conformational analysis enabled the assignment of the absolute configurations of compounds 2a-i. The accessible o-hydroxybenzylamine (R,R)-2h serves as an effective catalyst precursor for highly enantioselective addition of diethylzinc to aliphatic and aromatic aldehydes. This pathway represents a practical and operationally very simple methodology for the enantioselective synthesis of both the enantiomers of secondary alcohols 7a-f.

Full text of DOI:10.1002/(sici)1099-0690(199904)1999:4<805::aid-ejoc805>3.0.co;2-r

FULL PAPER
Synthesis of Enantiopure o-Hydroxybenzylamines by Stereoselective Reduction
of 2-Imidoylphenols: Application in the Catalytic Enantioselective Addition of
Diethylzinc to Aldehydes
Gianni Palmieri[a]
Keywords: Aminophenols /Asymmetric synthesis / C–C coupling / Reductions / Conformation analysis
Enantiopure o-hydroxybenzylamines 2a–i were synthesized
by diastereoselective reduction of the 2-imidoylphenols (R)-
1a–i. Conformational analysis enabled the assignment of the
precursor for highly enantioselective addition of diethylzinc
to aliphatic and aromatic aldehydes. This pathway
represents
a practical and operationally very simple
absolute configurations of compounds 2a–i. The accessible o- methodology for the enantioselective synthesis of both the
hydroxybenzylamine (R,R)-2h serves as an effective catalyst enantiomers of secondary alcohols 7a–f.
Catalytic asymmetric synthesis is an important subject in transfer occur from the less hindered re face with formation
the field of organic synthesis. The development of efficient of the (S)-o-hydroxybenzylamine (S)-2i.
enantioselective catalysts applicable to a wide range of reac-
In Method B the optimal conditions were determined for
tions represents an important challenge in synthetic organic the stereoselective reduction of (R)-imidoylphenols 1a؊i
chemistry. Among these catalysts, β-amino alcohols have using sodium borohydride in methanol, in the presence of
been proved to be extremely efficient in catalytic reactions cerium trichloride (LucheЈs Reagent).[6] Cerium trichloride
such as the synthesis of optically active secondary alcohols enhances the acidity of methanol (through complexation)
by enantioselective addition of diorganozinc compounds and induces its reaction with NaBH4 giving
Ϫ
to aldehydes.[1]
BH(4Ϫn)(OCH3)n species. Alkoxy borohydrides are known
to be more reactive[7] than BH4Ϫ, and should be at least in
part responsible for the very high reduction rate. CeCl3
meanwhile can coordinate with the phenolic hydroxy group,
thus enhancing the reactivity of the imidoyl function
towards nucleophiles. The hypothesis of phenol/methanol
exchange with formation of an intermediate similar to 4
and a consequent intramolecular hydride transfer, as pro-
posed for the mechanism of Method A, must be rejected
for stereoelectronic reasons The proposed hypothetical
push-pull type mechanism of the reduction with electro-
philic assistance, probably provides the transition state for
the hydride transfer as shown in Figure 2.
The reduction rate and stereoselectivity both increase
with the amount of CeCl3 added. Reaction is very fast and
highly stereoselective in methanol at low temperature with
0.5 molar equiv. of CeCl3 · 7 H2O (with respect to 2-imido-
ylphenol, as shown in Figure 2). Generally the hydride
transfer occurs preferentially on the si face of the imidoyl
function with formation of o-hydroxybenzylamine (R,R)-2.
Only with bulky groups (R ϭ iPr, tBu), as in 1g, i, does the
transition structure assume a different conformation, with
a different orientation of the chiral group at the N atom (as
in 4i), inducing the hydride transfer to occur predominantly
from the less hindered re face of the imidoyl function with
formation of the o-hydroxybenzylamine (1S,1ЈR)-2g,i. In
the case of a bulky substrate, as in compound 1h, the reac-
tion is very slow with low conversion yield. Generally
method B leads to better yields and d.e., although method
A is sometimes preferable due to the different stereoselectiv-
ity and the convenience of the procedure and cheapness of
the reagent used.
In the course of developing the chemistry of 2-imidoyl-
phenols 1[2a] it has been found that they can be stereoselec-
tively reduced to (R,R)-o-hydroxybenzylamine 2. In ad-
dition, the presence of a catalytic amount of enantiopure
(R,R)-o-hydroxybenzylamine 2 significantly enhances the
rate of the reaction between diethylzinc and benzaldehyde
to give stereoselectively and nearly quantitatively (S)-1-
phenyl-1-propanol (7a) after hydrolysis. The o-
hydroxybenzylamines 2a؊i were obtained with good to
high d.e. and yields by two reductive methodologies applied
to the imidoylphenols 1a؊i, which are accessible starting
materials in both enantiomeric forms[2Ϫ4] (see Table 1).
Our methodology has been applied in Method A, and this
has already been used in the diastereoselective reduction of
the enamino esters.[5] The reaction of (R)-imidoylphenols
1a؊i with sodium borohydride in acetic acid/THF, occurs
through an intramolecular diastereoselective hydride trans-
fer in the aryloxyborohydride intermediate 4. The asymmet-
ric induction can be rationalized by examining the possible
transition-state geometries depicted in Figure 1 for 4a, i.
The intramolecular hydride transfer occurs prevalently in
the less hindered si face of the immonium function in the
case of small R groups, as in 4a؊h, with formation of the
(R)-o-hydroxybenzylamines (R)-2a؊h. When R ϭ tBu the
more stable conformation for 4i is that depicted in Figure 1
and, therefore, only in this case does the consequent hydride
[a] Dipartimento di Scienze Chimiche,
v. S. Agostino 1, I-62032 Camerino, Italy
Fax: (internat.) ϩ39-737/637345
E-mail: palmieri@camserv.unicam.it
Eur. J. Org. Chem. 1999, 805Ϫ811
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0404Ϫ0805 $ 17.50ϩ.50/0
805

G. Palmieri
FULL PAPER
Table 1. Diastereoselective reduction of 2-imidoylphenols 1a؊i to o-hydroxybenzylamines 2a؊i
Method A: NaBH4/AcOH/THF, Ϫ70 to 20°C, 2 h; method B: NaBH4/CeCl3 · 7 H2O/MeOH, Ϫ90 to 20°C, 2 h.
[a]
Entry 1
R
2
∆δH
Method A
Method B
Yield (%)[b] d.e.[c]
config.[d]
Yield (%)[b] d.e.[c]
config.[d]
1
2
3
4
5
6
7
8
9
1a
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
0.37
0.49
0.48
0.48
0.50
0.44
0.55
0.16
0.59
34
56
56
49
54
53
65
81
44
83
77
71
78
72
82
83
68
20
R
R
R
R
R
R
R
R
S
88
87
93
89
78
93
65
86
84
92
91
71
93
42
27
95
R
R
R
R
R
R
S
1b
1c
1d
1e
1f
Et
Pr
(CH2)2CHϭCH2
iBu
(CH2)2Ph
iPr
1g
1h
1i
[e]
Ph
tBu
14
88
R
S
[a]
[c]
[b]
∆δH ϭ δH(S) Ϫ δH(R) of the benzylic proton introduced by the reduction. Ϫ
Yields of the pure isolated major diastereomer. Ϫ
[d]
1
The d.e. values were determined by H-NMR spectroscopy of the reaction mixture. Ϫ
Configuration of the new chiral center. Ϫ
[e] 71% of starting material was recovered.
The absolute configuration of the o-hydroxybenzylamine
(R,R)-2a was determined by chemical correlation with the
(R,R)-N-(1Ј-methylbenzyl)-3,4-dihydro-2H-1,3-benzoxazine
(R,R)-3a.[8] The absolute configuration of the o-hydroxy-
benzylamine (R,R)-2h was determined by analogy with
(R,R)-2a. In fact, the 13C-NMR spectra show γ effects[9] for
(R,R)-3a and (R,R)-3h between C-2 (δ ϭ 2.06 and 1.72) and
Me-4 or Ph-4 (δ ϭ 0.61 and 0.30, respectively). Moreover,
γ effects for (4S,1ЈR)-3a, between C-4 (δ ϭ 3.15) and
Me-1Ј (δ ϭ 1.51), and for (4S,1ЈR)-3h, between C-4 (δ ϭ
2.20) and C-1Ј (δ ϭ 1.13), are in agreement with the mini-
mized structures (R,R)-3a and (4S,1ЈR)-3a (see Figure 3),
obtained by conformational analysis.[10]
The conformations and the configurations of 3a, h were
1
confirmed by the H-NMR shielding effect induced from
the Ph-1Ј[11] on H-4eq, of 0.48 ppm for (R,R)-3a, h and the
shielding effect on H-2eq of 0.59 and 0.69 ppm for (4S,1ЈR)-
3a and (4S,1ЈR)-3h, respectively (see Figure 3). Analogous
conformations were assumed for o-hydroxybenzylamines
2a؊i, stabilized by the intramolecular hydrogen bond[10]
Figure 1. Method A: proposed mechanism and transition-state
model geometries for intramolecular diastereoselective hydride
(see Figure 4). The configuration of all the o-hydroxyben- transfer
806
Eur. J. Org. Chem. 1999, 805Ϫ811

Application in the Catalytic Enantioselective Addition of Diethylzinc to Aldehydes
FULL PAPER
zylamines (R,R)-2a؊i, were attributed on the basis of the
1H-NMR shielding effects ∆δH-1 ϭ 0.16Ϫ0.59 ppm (see
Table 1) caused by the Ph-1Ј[11] on the benzylic hydrogen
(H-1eq) introduced in the reduction.
Figure 2. Method B: transition state model geometry proposed for
the diastereoselective reduction of o-imidohylphenols 1a؊i with the
catalysis of CeCl3 · 7 H2O
Figure 4. Minimized most stable conformations[10] for the o-hydro-
xybenzylamines (R,R)-2a and (1S,1ЈR)-2a
Application of the o-Hydroxybenzylamines 2a؊i as
Catalyst Precursors in the Asymmetric Addition of
Diethylzinc to Aldehydes
In order to study the efficiency of the enantiopure o-
hydroxybenzylamines 2 as catalyst precursors, the asymmet-
ric addition of diethylzinc to aldehydes in toluene at 20°C
was selected as a test reaction, using a 1:1.2:0.06 molar ratio
for aldehydes/diethylzinc/catalyst precursor. The reaction is
one of the most important asymmetric reactions and was
used as model reaction.[1] The clean nucleophilic addition
of diethylzinc to aldehydes is stereoselective and accelerated
by the presence of optically active o-hydroxybenzylamines
(R,R)-2. The enantiomeric ratio of the alcohols 7, was de-
termined by GC analysis on a chiral capillary column
(DEX DMP).[12]
As reported in Table 2, the o-hydroxybenzylamines
(R,R)-2, generally obtained as major diastereomers from
the reduction of 2-imidoylphenols (R)-1, are the best cata-
lysts and lead to asymmetric inductions with better e.e. and
higher rates. In particular, the o-hydroxybenzylamine (R,R)-
2h leads to the best results in the asymmetric addition of
diethylzinc to benzaldehyde with formation of (S)-1-phenyl-
1-propanol (S)-7a. It is worth noting that the preparation
Figure 3. Minimized most stable conformations[10] for the 3,4-dihy-
dro-2H-1,3-benzoxazines (R,R)-3a and (4S,1ЈR)-3a
Eur. J. Org. Chem. 1999, 805Ϫ811
807

G. Palmieri
FULL PAPER
Table 2. Enantioselective addition of diethylzinc to aldehydes in the presence of catalytic amount of o-hydroxybenzylamines 2
[a]
2
R
7
(R1)Ar
reaction time [h]
Yield (%)[b]
e.e.[c]
config.[d]
(R,R)-2a
(R,R)-2b
(R,R)-2f
(R,R)-2g
(1S,αR)-2g
(R,R)-2h
(1S,αR)-2h
(R,R)-2i
(1S,αR)-2i
(R,R)-2h
(R,R)-2h
(R,R)-2h
(R,R)-2h
(R,R)-2h
Me
Et
7a
7a
Ph
4
96
93
97
92
89
93
84
94
88
92
93
92
86
82
55
57
45
35
10
89
60
62
8
94
86
72
98
97
S[13a]
S
Ph
4
(CH2)2Ph 7a
Ph
4
4
S
iPr
iPr
Ph
Ph
tBu
tBu
Ph
Ph
Ph
Ph
Ph
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
Ph
S
Ph
15
4
R
Ph
S
Ph
12
4
R
Ph
S
Ph
15
4
S
4-MeOPh
4-ClPh
Ph(CH2)2
iPr
S[13a]
S[13a]
S[13a]
S[13b]
S[13c]
5
4
4
Cyclohexyl
4
[a] Commercial (R)-(ϩ)-α-methylbenzylamine (99% e.e.) was used. Ϫ [b] GC yield on the mixture of the two enantiomers. Ϫ [c] Determined
by capillary chiral GC analysis using the chiral column MEGADEX DMP β.[12]
tation.
Ϫ
[d] Configuration determined by the sign of optical ro-
mass detector. Ϫ All melting points are uncorrected. Ϫ THF was
dried by refluxing over sodium wire until the blue color of benzo-
phenone ketyl persisted and then distilled into a dry receiver under
a nitrogen atmosphere. All reagents and solvents were distilled
prior to use or were of commercial quality from freshly opened
containers. Commercial methyllithium and butyllithium solutions
(Aldrich) were used under a dry atmosphere.
of the enantiomer (R)-1-phenyl-1-propanol (R)-7a is as
straightforward, by choosing the equally accessible (S)-
phenylethylamine for the preparation of the catalyst precur-
sor. The o-hydroxybenzylamine (R,R)-2h, which gave the
better stereoselectivity in the case of benzaldehyde, was
tested with different aromatic and aliphatic aldehydes. High
enantioselectivities were observed with electron donating
groups, such as in 4-methoxybenzaldehyde, or aliphatic al-
dehydes with branched alkyl chains (see Table 2).
Preparation of Starting 2-Imidoylphenols 1a؊i: The 2-imidoylphen-
ols 1a,b,h,i were prepared by direct condensation of the appropriate
o-acylphenol[3] and (R)-(ϩ)-α-methylbenzylamine (99% e.e.) ac-
cording to a previously reported procedure.[4] The 2-imidoylphen-
ols 1c؊g were prepared by alkylation of the 2-imidoylphenols
1a,b.[2] The data for the characterization of a number of unknown
2-imidoylphenols follows.
Conclusion
In summary, enantiopure o-hydroxybenzylamines 2a؊i
were synthesized by two simple new methodologies for dia-
stereoselective reduction of the 2-imidoylphenols (R)-1a؊i.
The accessible o-hydroxybenzylamine (R,R)-2h serves as an
effective catalyst precursor for the highly enantioselective
addition of diethylzinc to aliphatic and aromatic aldehydes.
This pathway represents a practical and operationally very
simple methodology for the enantioselective synthesis of
both enantiomers of the secondary alcohols 7a؊f. Further
studies on the mechanism of the asymmetric induction, the
modification of the ligand design and further applications
to other catalytic asymmetric reactions are now under
investigation.
2-[Phenyl{[(1ЈR)-1Ј-phenylethyl]imino}methyl]phenol [(R)-1h]: Mp
20
128Ϫ130°C (hexane). Ϫ [α]D ϭ Ϫ147.4 (c ϭ 3.1, CHCl3). Ϫ IR
1
(nujol): ν˜ ϭ 1595, 1440, 1290, 910 cmϪ1. Ϫ H NMR (300 MHz,
CDCl3): δ ϭ 1.53 (d, 3 H, J ϭ 6.6 Hz), 4.51 (q, 1 H, J ϭ 6.6 Hz),
6.60Ϫ7.82 (m, 14 H), 15.84 (br s, 1 H). Ϫ C21H19NO (301.4): calcd.
C 83.69, H 6.35, N 4.65; found C 83.82, H 6.31, N 4.83.
2-{2,2-Dimethyl[(1ЈR)-1Ј-phenylethyl]propanimidoyl}phenol [(R)-1i]:
20
Mp 168Ϫ170°C (hexane). Ϫ [α]D ϭ ϩ91.5 (c ϭ 2.2, CHCl3). Ϫ
IR (nujol): ν˜ ϭ 1622, 1290, 1230, 1113, cmϪ1. Ϫ 1H NMR (300
MHz, CDCl3): δ ϭ 1.19 (s, 9 H), 1.26 (d, 3 H, J ϭ 6.5 Hz), 4.25
(q, 1 H, J ϭ 6.5 Hz), 4.25 (br s, 1 H), 6.80Ϫ7.45 (m, 9 H). Ϫ
C19H23NO (281.4): calcd. C 81.10, H 8.24, N 4.98; found C 81.23,
H 8.33, N 5.18.
General Procedure for the Stereoselective Reduction of 2-Imidoyl-
phenols 1a؊i to o-Hydroxybenzylamines 2a؊i. ؊ Method A: Re-
duction with NaBH(OAc)3/AcOH/THF: NaBH(OAc)3 was pre-
pared by adding NaBH4 (0.454 g, 12.0 mmol) to glacial acetic acid
(7.0 mL) and THF (18 mL) while keeping the internal temperature
between 10Ϫ20°C. After the evolution of H2 had ceased (0.5 h) the
mixture was cooled to Ϫ70°C. At this temperature the 2-imidoyl-
phenol 1a؊i (4.0 mmol) was added in one portion and the tempera-
Experimental Section
General Remarks: 1H- and 13C-NMR spectra were recorded with
a Varian VXR 300 instrument. Chemical shifts are given in ppm
downfield from Me4Si in CDCl3 solution. Coupling constants are
given in Hertz. Ϫ IR spectra were recorded with a PerkinϪElmer
257 spectrometer. Ϫ GC-MS analyses were performed with an HP
59970 workstation consisting of an HP-5890 gas chromatograph ture of the mixture allowed to rise slowly to room temperature (2
equipped with a methyl silicone capillary column and an HP-5970
808
h). Evaporation of acetic acid and THF in vacuo at 50°C, followed
Eur. J. Org. Chem. 1999, 805Ϫ811

Application in the Catalytic Enantioselective Addition of Diethylzinc to Aldehydes
FULL PAPER
by dissolution of the residue in CH2Cl2 and washing with Na2CO3
(sat. aqueous solution), provided the o-hydroxybenzylamines 2a؊i,
after evaporation of the solvent. The mixture was analysed by GC-
N 5.20; found C 80.41, H 8.48, N 5.03. Ϫ 2-[(1S)-1-{[(1ЈR)-1Ј-
Phenylethyl]amino}butyl]phenol [(1S,1ЈR)-2c]: H NMR (300 MHz,
1
CDCl3): δ ϭ 0.87 (t, 3 H, J ϭ 7.3 Hz), 1.00Ϫ1.35 (m, 2 H), 1.45
MS or 1H- and 13C-NMR spectroscopy for the determination of (d, 3 H, J ϭ 6.7 Hz), 1.54Ϫ1.74 (m, 2 H), 1.97 (br s, 1 H), 3.85 (q,
the d.e. and the yields of all the diastereoisomeric o-hydroxyben-
zylamines obtained. Purification and separation of diastereoiso-
mers separation was performed by flash chromatography or by pre-
parative HPLC on silica gel (10Ϫ20% ethyl acetate in hexane as
eluent). Yields are reported in Table 1.
1 H, J ϭ 6.4 Hz), 3.90 (t, 1 H, J ϭ 7.0 Hz), 6.70Ϫ7.40 (m, 9 H),
11.72 (br s, 1 H).
2-[(1R)-1-{[(1ЈR)-1Ј-Phenylethyl]amino}pent-4-enyl]phenol [(R,R)-
2d]: Colorless oil; [α]D20 ϭ ϩ33.8 (c ϭ 3.2, CHCl3). Ϫ IR (neat):
ν˜ ϭ 3420, 3300, 1585, 1485, 1250 cmϪ1. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.43 (d, 3 H, J ϭ 7.0 Hz), 1.62Ϫ2.10 (m, 5 H), 3.46
(t, 1 H, J ϭ 6.7 Hz), 3.70 (q, 1 H, J ϭ 6.7 Hz), 4.85Ϫ4.95 (m, 2
Method B: Reduction with NaBH4/CeCl3 · 7 H2O/MeOH: A mix-
ture of 2-imidoylphenol 1a؊i (4.0 mmol) and CeCl3 · 7 H2O (0.745
g, 2.0 mmol), dissolved in methanol (12 mL), was cooled to Ϫ90°C H), 5.59Ϫ5.73 (m, 1 H), 6.70Ϫ7.45 (m, 9 H), 11.70 (br s, 1 H). Ϫ
and NaBH4 (0.302 g, 8.0 mmol) was added in one portion with
13C NMR (75 MHz, CDCl3): δ ϭ 23.5, 30.3, 35.1, 55.2, 60.5, 115.2,
stirring. The temperature of the mixture was allowed to rise slowly 116.7, 118.9, 125.1, 126.3, 127.5, 128.4, 128.7, 129.1, 137.5, 143.3,
to room temperature (2 h). Dilution with CH2Cl2 (100 mL) was
followed by water hydrolysis (20 mL saturated aq. NH4Cl). The
organic layer was dried with Na2SO4, and provided the o-hydroxy-
157.7. Ϫ C19H23NO (281.4): calcd. C 81.10, H 8.24, N 4.98; found
80.94, 8.36, 4.81. 2-[(1S)-1-{[(1ЈR)-1Ј-Phenyl-
ethyl]amino}pent-4-enyl]phenol [(1S,1ЈR)-2d]: H NMR (300 MHz,
C
H
N
Ϫ
1
benzylamines 2a؊i after evaporation of the solvent. The mixture CDCl3): δ ϭ 1.47 (d, 3 H, J ϭ 6.4 Hz), 1.62Ϫ2.10 (m, 5 H), 3.86
was analysed by GC-MS or 1H- and 13C-NMR spectroscopy for
the determination of the yields of all the diastereoisomeric o-
hydroxybenzylamines and the d.e. obtained. Purification and sepa-
ration of diastereoisomers separation was performed by flash chro-
matography or by preparative HPLC on silica gel (10Ϫ20% ethyl
acetate in hexane as eluent). Yields are reported in Table 1.
(q, 1 H, J ϭ 6.7 Hz), 3.94 (t, 1 H, J ϭ 6.7 Hz), 4.97Ϫ5.10 (m, 2
H), 5.73Ϫ5.85 (m, 1 H), 6.70Ϫ7.45 (m, 9 H), 11.70 (br s, 1 H).
2-[(1R)-3-Methyl-1-{[(1ЈR)-1Ј-Phenylethyl]amino}butyl]phenol
[(R,R)-2e]: Colorless oil, [α]D20 ϭ ϩ64.3 (c ϭ 2.7, CHCl3). Ϫ 1H
NMR (300 MHz, CDCl3): δ ϭ 0.62 (d, 3 H, J ϭ 6.0 Hz), 0.82 (d,
3 H, J ϭ 6.1 Hz), 1.43 (d, 3 H, J ϭ 6.9 Hz), 1.35Ϫ1.70 (m, 3 H),
1.95 (br s, 1 H), 3.50 (dd, 1 H, J ϭ 7.9, 5.9 Hz), 3.70 (q, 1 H, J ϭ
2-[(1R)-1-{[(1ЈR)-1Ј-Phenylethyl]amino}ethyl]phenol [(R,R)-2a]: Mp
56Ϫ57°C (AcOEt/hexane). Ϫ [α]D20 ϭ ϩ142.1 (c ϭ 1.66, CHCl3 ). 6.9 Hz), 6.70Ϫ7.45 (m, 9 H), 11.75 (br s, 1 H). Ϫ 13C NMR (75
Ϫ IR (nujol): ν˜ ϭ 3300, 2960, 1580, 1470, 1250 cmϪ1. Ϫ 1H NMR MHz, CDCl3): δ ϭ 22.2, 23.5, 23.9, 25.1, 45.7, 55.7, 59.1, 117.2,
(300 MHz, CDCl3): δ ϭ 1.34 (d, 3 H, J ϭ 6.8 Hz), 1.42 (d, 3 H, 119.5, 126.5, 126.8, 128.0, 128.7, 129.1, 129.2, 143.8, 158.2. Ϫ
J ϭ 6.8 Hz), 2.10 (br s, 1 H), 3.64 (q, 1 H, J ϭ 6.8 Hz), 3.70 (q, 1
C19H25NO (283.4): calcd. C 80.52, H 8.89, N 4.94; found C 80.33,
8.74, 5.18. 2-[(1S)-3-Methyl-1-{[(1ЈR)-1Ј-phenylethyl]-
H, J ϭ 6.8 Hz), 6.60Ϫ7.33 (m, 9 H), 12.30 (br s, 1 H). Ϫ 13C NMR
H
N
Ϫ
(75 MHz, CDCl3): δ ϭ 23.5, 24.0, 55.9, 56.6, 117.3, 119.7, 126.8, amino}butyl]phenol [(1S,1ЈR)-2e]: 1H NMR (300 MHz, CDCl3):
127.0, 128.0, 128.1, 128.8, 129.3, 144.0, 158.1. Ϫ MS; m/z (%): 241 δ ϭ 0.88 (d, 3 H, J ϭ 6.4 Hz), 0.93 (d, 3 H, J ϭ 6.4 Hz), 1.40Ϫ1.60
[Mϩ] (58), 226 (100), 122 (98), 105 (100), 77 (88). Ϫ C16H19NO (m, 1 H), 1.49 (d, 3 H, J ϭ 6.6 Hz), 1.64 (t, 2 H, J ϭ 7.0 Hz), 2.00
(241.3): calcd. C 79.63, H 7.94, N 5.80; found C 79.76, H 7.91, N (br s, 1 H), 3.85 (q, 1 H, J ϭ 6.6 Hz), 4.00 (t, 1 H, J ϭ 7.1 Hz),
5.62. Ϫ 2-[(1S)-1-{[(1ЈR)-1Ј-Phenylethyl]amino}ethyl]phenol [(1S,
1ЈR)-2a]: H NMR (300 MHz, CDCl3): δ ϭ 1.44 (d, 3 H, J ϭ 6.7
Hz), 1.48 (d, 3 H, J ϭ 6.7 Hz), 1.90 (br s, 1 H), 3.92 (q, 1 H, J ϭ
6.7 Hz), 4.01 (q, 1 H, J ϭ 6.7 Hz), 6.75Ϫ7.42 (m, 9 H), 11.77 (br
s, 1 H).
6.70Ϫ7.40 (m, 9 H), 11.75 (br s, 1 H).
1
2-[(1R)-3-Phenyl-1-{[(1ЈR)-1Ј-phenylethyl]amino}propyl]phenol
20
[(R,R)-2f]: Mp 101Ϫ102°C (CH2Cl2-hexane). Ϫ [α]D ϭ Ϫ5.97
1
(c ϭ 1.4, CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.42 (d, 3
H, J ϭ 6.7 Hz), 1.90Ϫ2.20 (m, 3 H), 2.35Ϫ2.60 (m, 2 H), 3.50 (t,
1 H, J ϭ 6.9 Hz), 3.70 (br q, 1 H, J ϭ 6.7 Hz), 6.70Ϫ7.40 (m, 14
H), 11.65 (br s, 1H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 23.4,
32.4, 37.5, 55.2, 60.7, 116.8, 119.0, 125.1, 125.9, 126.3, 127.5, 128.2,
2-[(1R)-1-{[(1ЈR)-1Ј-Phenylethyl]amino}propyl]phenol
[(R,R)-2b]:
Mp 124Ϫ125°C (AcOEt/hexane). Ϫ [α]D20 ϭ ϩ80.0 (c ϭ 3.85,
CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.77 (t, 3 H, J ϭ 7.5
Hz), 1.43 (d, 3 H, J ϭ 6.9 Hz), 1.50Ϫ1.90 (m, 2 H), 2.10 (br s, 1 128.3, 128.4, 128.8, 129.1, 141.1, 143.3, 157.7. Ϫ C23H25NO
H), 3.34 (t, 1 H, J ϭ 7.1 Hz), 3.72 (q, 1 H, J ϭ 6.9 Hz), 6.70Ϫ7.42 (331.4): calcd. C 83.34, H 7.60, N 4.23; found C 83.26, H 7.74, N
(m, 9 H), 11.70 (br s, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 4.04.
Ϫ
2-[(1S)-3-Phenyl-1-{[(1ЈR)-1Ј-phenylethyl]amino}propyl]-
1
10.7, 23.6, 29.0, 55.2, 62.5, 116.6, 118.8, 125.0, 126.3, 127.4, 128.3,
128.8, 129.3, 143.4, 157.7. Ϫ C17H21NO (255.3): calcd. C 79.96, H
8.29, N 5.49; found C 79.77, H 8.13, N 5.62. Ϫ 2-[(1S)-1-{[(1ЈR)-
1Ј-Phenylethyl]amino}propyl]phenol [(1S,1ЈR)-2b]: 1H NMR (300
MHz, CDCl3): δ ϭ 0.85 (t, 3 H, J ϭ 7.3 Hz), 1.50 (d, 3 H, J ϭ 6.6
Hz), 1.57Ϫ1.92 (m, 2 H), 2.10 (br s, 1 H), 3.83 (t, 1 H, J ϭ 7.0
Hz), 3.88 (q, 1 H, J ϭ 6.9 Hz), 6.70Ϫ7.42 (m, 9 H), 11.70 (br s,
1 H).
phenol [(1S,1ЈR)-2f]: H NMR (300 MHz, CDCl3): δ ϭ 1.42 (d, 3
H, J ϭ 6.7 Hz), 1.90Ϫ2.20 (m, 3 H), 2.35Ϫ2.60 (m, 2 H), 3.84 (q,
1 H, J ϭ 6.7 Hz), 3.94 (t, 1 H, J ϭ 6.9 Hz), 6.70Ϫ7.40 (m, 14 H),
11.65 (br s, 1H);
2-[(1R)-2-Methyl-1-{[(1ЈR)-1Ј-phenylethyl]amino}propyl]phenol
[(R,R)-2g]: Mp 119Ϫ121°C (AcOEt-hexane). Ϫ [α]D20 ϭ ϩ92.1
(c ϭ 1.6, CHCl3). Ϫ IR (nujol) ν˜ ϭ 3305, 2750, 1590, 1255 cmϪ1
.
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.71 (d, 3 H, J ϭ 7.0 Hz),
[(1R)-1-{[(1ЈR)-1Ј-Phenylethyl]amino}butyl]phenol [(R,R)-2c]: Mp 0.90 (d, 3 H, J ϭ 6.7 Hz), 1.42 (d, 3 H, J ϭ 6.7 Hz), 1.94 (octet, 1
64Ϫ65°C (AcOEt/hexane). Ϫ [α]D20 ϭ ϩ63.1 (c ϭ 1.3, CHCl3). Ϫ
IR (nujol): ν˜ ϭ 3300, 1585, 1255, 1100 cmϪ1. Ϫ 1H NMR (300
H, J ϭ 6.7 Hz), 2.10 (br d, 1 H, J ϭ 11.6 Hz), 3.12 (d, 1 H, J ϭ
7.0), 3.67 (dq, 1 H, J ϭ 11.6, 7.0 Hz), 6.67Ϫ7.39 (m, 9 H), 11.80
MHz, CDCl3): δ ϭ 0.77 (t, 3 H, J ϭ 7.2 Hz), 1.05Ϫ1.32 (m, 2 H), (br s, 1 H). Ϫ 13C NMR (300 MHz, CDCl3): δ ϭ 19.2, 19.8, 23.6,
1.41 (d, 3 H, J ϭ 7.0 Hz), 1.55Ϫ1.74 (m, 2 H), 1.97 (br s, 1 H),
3.42 (t, 1 H, J ϭ 7.2 Hz), 3.68 (m, 1 H), 6.70Ϫ7.40 (m, 9 H), 11.72
(br s, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 14.2, 19.8, 24.1,
33.1, 55.3, 67.1, 116.5, 118.5, 123.9, 126.3, 127.4, 128.2, 128.7,
130.1, 143.4, 158.0. Ϫ C18H23NO (269.4): calcd. C 80.26, H 8.61,
N 5.20; found: C 80.12, H 8.69, N 5.13. Ϫ 2-[(1S)-2-Methyl-1-
38.8, 55.7, 61.2, 117.1, 119.3, 126.0, 126.8, 128.0, 128.7, 129.2, {[(1ЈR)-1Ј-phenylethyl]amino}propyl]phenol [(1S,1ЈR)-2g]: Colorless
129.5, 143.9, 158.2. Ϫ C18H23NO (269.4): calcd. C 80.26, H 8.61, oil. Ϫ [α]D20 ϭ ϩ54.1 (c ϭ 1.2, CHCl3). Ϫ H NMR (300 MHz,
1
Eur. J. Org. Chem. 1999, 805Ϫ811
809

G. Palmieri
FULL PAPER
CDCl3): δ ϭ 0.83 (d, 3 H, J ϭ 6.8 Hz), 1.01 (d, 3 H, J ϭ 6.7 Hz), (hexane). Ϫ [α]D20 ϭ Ϫ36.1 (c ϭ 1.6, CHCl3). Ϫ IR (nujol): ν˜ ϭ
1
1.47 (d, 3 H, J ϭ 6.7 Hz), 2.02 (octet, 1 H, J ϭ 6.8 Hz), 3.67 (d, 1
1608, 1491, 1227, 940 cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ
H, J ϭ 7.0 Hz), 3.80 (q, 1 H, J ϭ 6.6 Hz), 6.68Ϫ7.43 (m, 9 H), 1.53 (d, 3 H, J ϭ 6.6 Hz), 3.98 (q, 1 H, J ϭ 6.6 Hz), 4.72 (br s, 1
11.60 (br s, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 20.0, 20.1, H), 4.83 (d, 1 H, J ϭ 10.9 Hz), 5.07 (dd, 1 H, J ϭ 10.9, 2.0 Hz),
20.4, 33.4, 54.7, 68.0, 117.3, 118.9, 124.4, 127.0, 127.8, 128.7, 129.1,
130.5, 144.4, 158.2.
6.80Ϫ7.50 (m, 14 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 21.5,
58.8, 59.3, 74.4, 116.5, 120.1, 120.3, 127.1, 127.5, 127.7, 128.0,
128.2, 128.6, 128.9, 130.2, 143.8, 145.2, 155.0. Ϫ C22H21NO
(315.4): calcd. C 83.78, H 6.71, N 4.44; found C 83.92, H 6.81, N
4.27. Ϫ (4S)-4-Phenyl-3-[(1ЈR)-1Ј-phenylethyl]-3,4-dihydro-2H-1,3-
benzoxazine [(4S,1ЈR)-3h]: Yield 87%, colorless crystals, mp
117Ϫ119°C (hexane). Ϫ [α]D20 ϭ ϩ63.1 (c ϭ 1.9, CHCl3). Ϫ IR
2-[(R)-Phenyl-{[(1ЈR)-1Ј-phenylethyl]amino}methyl]phenol [(R,R)-
2h]: Colorless oil; [α]D20 ϭ Ϫ120.8 (c ϭ 1.96, CHCl3); IR (neat):
ν˜ ϭ 3300, 1585, 1480, 1250, 1095 cmϪ1. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.47 (d, 3 H, J ϭ 6.7 Hz), 2.26 (br s, 1 H), 3.83 (br
q, 1 H, J ϭ 6.7 Hz), 4.65 (s, 1 H), 6.42Ϫ7.45 (m, 14 H), 12.20 (br
s, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 23.7, 56.4, 65.3, 117.6,
119.9, 124.5, 127.0, 127.8, 128.2, 128.3, 129.3, 129.4, 129.5, 129.8,
142.6, 143.7, 158.6. Ϫ C21H21NO (303.4): calcd. C 83.13, H 6.98,
N 4.62; found: C 83.38, H 7.13, N 4.46. Ϫ 2-[(S)-Phenyl-{[(1ЈR)-
1Ј-phenylethyl]amino}methyl[phenol [(1S,1ЈR)-2h]: 1H NMR (300
MHz, CDCl3): δ ϭ 1.44 (d, 3 H, J ϭ 6.7 Hz), 2.26 (br s, 1 H), 3.70
(br q, 1 H, J ϭ 6.7 Hz), 4.81 (s, 1 H), 6.42Ϫ7.45 (m, 14 H), 12.20
(br s, 1 H).
1
(nujol): ν˜ ϭ 1608, 1230, 1128, 935 cmϪ1. Ϫ H NMR (300 MHz,
CDCl3): δ ϭ 1.58 (d, 3 H, J ϭ 6.6 Hz), 4.12 (q, 1 H, J ϭ 6.6 Hz),
4.38 (dd, 1 H, J ϭ 10.5, 2.0 Hz), 4.58 (d, 1 H, J ϭ 10.5 Hz), 5.21
(br s, 1 H), 6.80Ϫ7.50 (m, 14 H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 21.7, 57.1, 57.9, 76.1, 116.8, 120.0, 120.4, 127.0, 127.4, 127.8,
128.1, 128.3, 128.5, 128.9, 129.8, 143.8, 144.1, 154.8. Ϫ C22H21NO
(315.4): calcd. C 83.78, H 6.71, N 4.44; found C 83.97, H 6.65,
N 4.36.
General Procedure for the Enantioselective Addition of Diethylzinc
to Benzaldehyde by Using Catalytic o-Hydroxybenzylamines: Under
a nitrogen atmosphere, a toluene solution of Et2Zn (6.0 mmol, 1.1
) was added to a mixture of benzaldehyde (5.0 mmol) and o-
hydroxybenzylamine 2 (0.30 mmol) at 0°C and the mixture was
stirred at room temperature for 5Ϫ15 h. The progress of the reac-
tion was monitored by GC analysis of an aliquot of the reaction
mixture, before quenching. Aqueous hydrochloric acid (2 ) was
added to quench the reaction under cooling with ice-water. The
resulting mixture was extracted with CH2Cl2, and the extract was
dried and evaporated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel (hexane/AcOEt) fol-
lowed by bulb-to-bulb distillation. The product was identified by
spectroscopic methods and the optical rotation was measured. Op-
tical purities (% e.e.) were determined by GC analyses of the re-
sulting alcohols on a chiral capillary column MEGADEX DMP β
(30% dimethylpentyl-β-cyclodextrin on OV1701, 25 m, 0.25 mm
ID, 0.25 µm film).[12]
2-[(1R)-2,2-Dimethyl-1-{[(1ЈR)-1Ј-phenylethyl]amino-
[propyl}phenol [(R,R)-2i]: Mp 110Ϫ112°C (hexane). Ϫ [α]D20 ϭ
ϩ104.3 (c ϭ 2.2, CHCl3). Ϫ IR (nujol): ν˜ ϭ 3400, 1713, 1461, 1377
1
cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.87 (s, 9 H), 1.47 (d,
3 H, J ϭ 6.8 Hz), 2.43 (br s, 1 H), 3.11 (s, 1 H), 3.59 (q, 1 H, J ϭ
6.8 Hz), 6.65Ϫ7.40 (m, 9 H), 12.20 (br s, 1 H). Ϫ 13C NMR (75
MHz, CDCl3): δ ϭ 23.67, 27.29, 35.92, 55.64, 70.48, 116.92,
118.18, 122.01, 126.68, 127.69, 128.48, 128.85, 131.80, 143.34,
158.79. Ϫ C19H25NO (283.4): calcd. C 80.52, H 8.89, N 4.94; found
C 80.39, H 8.97, N 4.71. Ϫ 2-[(1S)-2,2-Dimethyl-1-{[(1ЈR)-1Ј-
phenylethyl]amino}propyl]phenol [(1S,1ЈR)-2i]: Mp 76Ϫ78°C (hex-
ane). Ϫ [α]D20 ϭ ϩ73.2 (c ϭ 1.8, CHCl3). Ϫ IR (nujol): ν˜ ϭ 3430,
1
1587, 1463, 1257 cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.00
(s, 9 H), 1.47 (d, 3 H, J ϭ 6.6 Hz), 1.90 (br s, 1 H), 3.70 (s, 1 H),
3.79 (q, 1 H, J ϭ 6.6 Hz), 6.65Ϫ7.40 (m, 9 H), 11.70 (br s, 1 H).
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 19.14, 27.29, 36.08, 54.37,
70.69, 116.99, 117.88, 121.86, 126.57, 127.33, 128.38, 128.59,
131.46, 143.91, 158.34. Ϫ C19H25NO (283.4): calcd. C 80.52, H
8.89, N 4.94; found C 80.42, H 8.91, N 5.13.
General Procedure for the Preparation of 3,4-Dihydro-2H-1,3-
Benzoxazines 3a, h: To a solution of 2 (2 mmol) in THF (3 mL)
was added 35% aqueous formaldehyde (2.2 mmol). The solution
was stirred for 15 h at room temperature. Solvent was removed and
the residue dried under reduced pressure. The crude material was
purified by filtration through an SiO2 pad eluting with CH2Cl2.[9]
Acknowledgments
`
Financial support from Ministero dellЈUniversita e della Ricerca
Scientifica e Tecnologica, Rome, and the University of Camerino
(National Project “Stereoselezione in Sintesi Organica. Metodolo-
gie ed applicazioni”) is gratefully acknowledged.
(4R)-4-Methyl-3-[(1ЈR)-1Ј-phenylethyl]-3,4-dihydro-2H-1,3-
1
benzoxazine [(R,R)-3a]: Yield 86%, colorless oil. Ϫ H NMR (300
MHz, CDCl3): δ ϭ 1.38 (d, 3 H, J ϭ 7.0 Hz), 1.46 (d, 3 H, J ϭ
6.4 Hz), 3.63 (q, 1 H, J ϭ 6.9 Hz), 3.91 (q, 1 H, J ϭ 6.6 Hz), 5.03
(d, 1 H, J ϭ 11.1 Hz), 5.18 (dd, 1 H, J ϭ 11.1, 2.1 Hz), 6.80Ϫ7.45
(m, 9 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 22.8, 24.6, 52.6,
59.4, 74.7, 117.0, 120.8, 126.2, 127.5, 127.8, 128.8, 129.0, 129.1,
146.3, 155.0. Ϫ C17H19NO (253.3): calcd. C 80.60, H 7.56, N 5.53;
found C 80.81, H 7.74, N 5.32. (4S)-4-Methyl-3-[(1ЈR)-1Ј-phenyl-
ethyl]-3,4-dihydro-2H-1,3-benzoxazine [(4S,1ЈR)-3a]: Yield 83%,
colorless oil. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.42 (d, 3 H,
J ϭ 6.5 Hz), 1.50 (d, 3 H, J ϭ 7.0 Hz), 4.06 (q, 1 H, J ϭ 6.6 Hz),
4.11 (q, 1 H, J ϭ 6.7 Hz), 4.58 (dd, 1 H, J ϭ 10.7, 1.7 Hz), 4.91
(d, 1 H, J ϭ 10.7 Hz), 6.80Ϫ7.45 (m, 9 H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 21.2, 25.2, 49.4, 59.2, 76.7, 117.2, 120.7, 126.6, 127.7,
127.9, 128.2, 128.5, 128.9, 144.5, 154.9.
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Asymmetric Catalysis in Organic Synthesis, John Wiley: New
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G. Bartoli, M. Bosco, C. Cimarelli, R. Dalpozzo, G. De
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[2b]
1651Ϫ1665. Ϫ
C. Cimarelli, G. Palmieri, Tetrahedron 1998,
54, 15711Ϫ15720.
[3]
The o-pivaloylphenol, which is not commercially available, was
prepared as described in: J. A. Miller, J. Org. Chem. 1987, 52,
322Ϫ323.
(4R)-4-Phenyl-3-[(1ЈR)-1Ј-phenylethyl]-3,4-dihydro-2H-1,3-benz
oxazine [(R,R)-3h]: Yield 91%, colorless crystals, mp 98Ϫ100°C
810
Eur. J. Org. Chem. 1999, 805Ϫ811

Application in the Catalytic Enantioselective Addition of Diethylzinc to Aldehydes
FULL PAPER
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Synthesis 1983, 902Ϫ903.
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[4c]
P. G. Baraldi, D. Simoni, S. Manfredini,
Semiempirical PM3 calculations were performed with the Spar-
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[5d]
[12]
D. Xu, K. Prasad, O. Repic, T. J. Blacklock, Tetrahedron:
Optical purities (% e.e.) were determined by GC analyses of
the resulting alcohols on a chiral capillary column MEGADEX
DMP β (30% dimethylpentyl-β-cyclodextrin on OV1701, 25 m,
0.25 mm ID, 0.25 µm film).
Asymmetry 1997, 8, 1445Ϫ1451.
[6]
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811