Ready N-alkylation of enantiopure aminophenols: Synthesis of tertiary aminophenols

Article abstract of DOI:10.1016/S0040-4020(01)00589-0

A regioselective indirect alkylation of aminophenols to enantiopure tertiary aminophenols, which are useful chiral ligands for metal-catalysed asymmetric reactions, is reported. This very simple synthetic methodology, through reduction or alkylation of an intermediate benzoxazine, was performed in mild conditions, suitable for the conservation of the configuration of the stereogenic centres. Some crystalline aminophenols show the phenomenon of 'crystallization-induced asymmetric transformation'.

Full text of DOI:10.1016/S0040-4020(01)00589-0

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 6089±6096
Ready N-alkylation of enantiopure aminophenols:
synthesis of tertiary aminophenols
Cristina Cimarelli, Gianni Palmierip and Emanuela Volpini
Á
Dipartimento di Scienze Chimiche, Universita di Camerino, Via S. Agostino 1, I-62032 Camerino, Italy
Received 1 February 2001; revised 1 May 2001; accepted 24 May 2001
AbstractÐA regioselective indirect alkylation of aminophenols to enantiopure tertiary aminophenols, which are useful chiral ligands for
metal-catalysed asymmetric reactions, is reported. This very simple synthetic methodology, through reduction or alkylation of an inter-
mediate benzoxazine, was performed in mild conditions, suitable for the conservation of the con®guration of the stereogenic centres. Some
crystalline aminophenols show the phenomenon of `crystallization-induced asymmetric transformation'. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
In previous work, we have observed that a catalytic amount
of enantiopure aminophenol 1 and aminonaphthol 8 con-
siderably accelerate the addition of dialkylzincs to alde-
hydes, affording the corresponding alcohols in good
enantiomeric purity.1,4 The precatalyst aminophenol 1 is
an accessible compound generally obtained by stereoselec-
tive reduction of the corresponding 2-imidoylphenol 5.1±3
The aminoalkylation of electron-rich aromatic compounds
4the aromatic Mannich reaction) is a convenient route to
enantiopure aminonaphthol 8 that is obtained enantiopure
by a simple and straightforward condensation of 2-naphthol
with benzaldehyde and R-41)-1-phenylethylamine.4,5
Enantiopure aminophenols are important building blocks in
organic synthesis. Moreover they are used as ligands for the
preparation of chiral metal catalysts which are very useful in
stereoselective organic synthesis.1±5
The search for new metal-catalysed asymmetric reactions
has provided some fascinating insights into the effects
imposed on the metal catalysts by chiral ligands. A practical
consequence is the discovery of ligand-accelerated catalysis
4LAC).6 Thus, an existing catalysed process is improved by
the addition of a speci®c ligand, which leads to a faster
`ligand-accelerated' reaction. The concept is especially
valuable in reactions catalysed by early transition metals.7
Literature data showed that an increasing number of ali-
phatic substituents in the N atom of the ligand procures
Scheme 1.
Keywords: alkylation; aminophenols; benzoxazine.
Corresponding author. Tel.: 139-737-402241; fax: 139-737-637345; e-mail: palmieri@camserv.unicam.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00589-0

6090
C. Cimarelli et al. / Tetrahedron 57 *2001) 6089±6096
Table 1. Cyclization of aminophenols 1a±m to 3,4-dihydro-2H-1,3-benzoxazines 2a±m and their reduction to aminophenols 3a±m
Entry
1
R1
Rpc
R2
R3
2
Yielda 4%)
3
Yielda 4%)
drb
1
2
3
4
5
6
7
8
4R)-1a
H
Me
Et
H
H
H
H
H
H
H
H
H
H
H
OMe
H
4R)-2a
95
91
79
82
93
92
0
62
94
90
87
69
60
65
91
4R)-3a
85
84
60
72
76
63
±
4R,R)-1b
4R,R)-1c
4R,R)-1d
4R,R)-1e
4R,R)-1f
4R,R)-1g
41S,10R)-1g
4R,R)-1h
4R,R)-1i
41S,10R)-1i
4R,R)-1j
4^)-1k
Rpc
Rpc
Rpc
Rpc
Rpc
Rpc
Rpc
Rpc
Rpc
Rpc
Rpc
Me
iPr
4R,R)-2b1
4R,R)-2c
4R,R)-2d
4R,R)-2e
4R,R)-2f
4R,R)-2g
41S,10R)-2g
4R,R)-2h
4R,R)-2i1
41S,10R)-2i1
4R,R)-2j
4^)-2k
4R,R)-3b
4R,R)-3c
4R,R)-3d
4R,R)-3e
4R,R)-3f
96:4
98:2
98:2
99:1
99:1
4CH2)2Ph
Pr
iBu
tBu
tBu
41S,10R)-3g
4R,R)-3h
4R,R)-3i
41S,10R)-3i
4R,R)-3j
4^)-3k
0
75
±
9
4CH2)2CHvCH2
Ph
Ph
99:1
84:16
85:15
97:3
±
10
11
12
13
14
15
79d
60d
65
Me
Me
Me
Et
29
61
87
4^)-1l
4^)-1m
H
H
4^)-2l
4^)-2m
4^)-3l
4^)-3m
±
±
CH2Ph
a
Isolated yield.
4R,R)-3: 41S,10R)-3 dr was determined by 1H NMR spectroscopy of the crude reaction mixture.
RpNH2ˆ4R)-10-phenylethylamine.
b
c
d
Combined yields of the two diastereomers.
high ees in the alkylation of aldehydes.8±10 By reductive
amination of the acylphenol, secondary aminophenol 1
only can be prepared. Therefore, a careful and chemo-
selective alkylation of the amino group of aminophenol 1
should be required that can be performed by a multistep
procedure, but sometimes a complete loss of optical activity
was observed. An alternative way is offered by oxazines that
analogously to oxazolidines are useful substrates for nucleo-
philic additions as they act as acetal equivalents. Here we
report the results of our work in exploring the usefulness of
the reduction or alkylation of oxazine 2 to prepare enantio-
pure tertiary aminophenols.
The synthesis of benzoxazines 2 proceeds readily with good
yields and retention of con®guration at the chiral centres1,3±5
4see Table 1). Only in the case of aminophenol 4R,R)-1g any
trace of the corresponding oxazine was detected. Starting
from the aminophenols 1a±j, the benzoxazines were
obtained only with formaldehyde; more bulky aldehydes
such as acetaldehyde or phenylacetaldehyde failed.
The reduction with sodium borohydride of the intermediate
benzoxazines 2a±m to the N-methylaminophenols 3 occurs
readily and with good yields except in the case of the
t-butyloxazine 41S,10R)-2g. Under these mild reaction
conditions, the N-methylaminophenols 3 obtained retain
the con®guration of the chiral centre of the starting
oxazines.1,3±5 Only in the case of oxazines 4R,R)-2i and
41S,10R)-2i a partial epimerization to the C-1 chiral centre
was observed with the ®nal 4R,R)- and 41S,10R)-3i dr of 5.3
and 5.7, respectively 4see Table 1).
2. Results and discussion
Our strategy starts from cyclization of the aminophenols
1a±m to 1,3-benzoxazines 2a±m with formaldehyde
followed by reduction of the O±C2 bond with sodium boro-
hydride to N-methylaminophenol 3, or with the nucleophilic
addition of organometallic compounds as Grignard reagents
to prepare aminophenols 4 4Scheme 1). This strategy has
been occasionally applied to b-aminoalcohols or amino-
naphthols, through the intermediate oxazolidines11 or naph-
thoxazines8 but never has been applied to aminophenols
1a±m.
Moreover, the oxazines 4R,R)-2b,i,j undergo nucleophilic
additions of Grignard reagents with the formation of tertiary
aminophenols 4R,R)-4 4Table 2). The reactions take place
readily at 2708C with good yields and retention of con-
®guration at the chiral centres.1,3±5 At higher temperature,
there is a considerable epimerization at the C-1 chiral
centre, because of the elevated basicity of the reaction
medium. Even at the low temperature used for the alkyl-
ation, the aminophenols 4R,R)-4ia±ic, in the same way as
4R,R)-3i, with R2ˆphenyl, were obtained with moderate
drˆ80:20±86:14.
Table 2. Alkylation of the benzoxazines 2b,i,j to aminophenols 4
Entry
2a
R2
R3
R4
4a
Yieldb 4%)
drc
1
2
3
4
5
6
7
8
9
4R,R)-2b Me
4R,R)-2b Me
4R,R)-2b Me
4R,R)-2i Ph
4R,R)-2i Ph
4R,R)-2i Ph
4R,R)-2j Me OMe Me 4R,R)-4ja
4R,R)-2j Me OMe Bn 4R,R)-4jb
4R,R)-2j Me OMe Ph
H
Me 4R,R)-4ba 83
Bn 4R,R)-4bb 85
92:8
99:1
99:1
80:20
71:29
81:19
96:48
93:7
H
H
H
H
H
The epimerization observed for these aminophenols 3 and 4
can occur easily by the elimination of the chiral amine
through the formation of the intermediate 6 stabilized by
the phenyl group 4Scheme 2a). This hypothesis is supported
by the following experimental evidence. When the amino-
phenol 4R,R)-4ia was treated with benzylamine, exchange
of the amines occurs in two days at room temperature 4see
Scheme 2b).
Ph
4R,R)-4bc
91
Me 4R,R)-4ia 64d
Bn 4R,R)-4ib 88d
Ph
4R,R)-4ic
85d
86
71
63
4R,R)-4jc
87:3
a
R1NH2ˆ4R)-10-phenylethylamine.
4R,R)-3: 41S,10R)-3 dr was determined by H NMR spectroscopy of the
crude reaction mixture.
Combined yields of the two diastereomers.
b
c
Isolated yield.
1
In addition, the solid and crystalline 41S,10R)-4ia, dissolved
20
d
in CHCl3, shows an initial optical activity [a]D ˆ151.0 4c

C. Cimarelli et al. / Tetrahedron 57 *2001) 6089±6096
6091
Scheme 2.
1.7) which decreases in the time to a ®nal value of
The aminonaphthol 8, very similar to aminophenols 1,
shows useful application in stereoselective catalysis and is
a very accessible product by a straightforward and stereo-
selective synthesis.4,5 This aminonaphthol can be cyclized
with formaldehyde to the respective naphthoxazine 9, but
differently from benzoxazines 2, it is inert when treated with
sodium borohydride or Grignard reagents 4see Scheme 3).
20
[a]D ˆ269.6 after 43 h at room temperature. This muta-
rotation phenomenon was also observed for the amino-
20
phenol 41S,10R)-4ib: from an initial [a]D ˆ165.2 4c 2.1,
20
CHCl3) to a ®nal value of [a]D ˆ288.0 after 44 h at room
temperature 4see Fig. 1a).
The epimerization of these aminophenols was con®rmed by
1H NMR spectroscopy in CDCl3 solution; in Fig. 1b, de
variation vs time has been reported. The 4R,R)-4ia and
4R,R)-4ib are the ®nal major diastereomers in CHCl3
solution with dr of 80:20 and 71:19, respectively. Allowing
the CHCl3 solution of the 4R,R)-4ia,ib diastereomers to
evaporate slowly, the starting crystalline 41S,10R)-4ia,ib
were newly obtained. They again show the epimerization
in CHCl3 solution and these cycles can be repeated several
times. This is a typical situation of `asymmetric transfor-
mation of second kind' induced by the preferential crystal-
lization of a diastereomer.12±16 It is noteworthy that the two
secondary diastereomers aminophenols 41S,10R)- and
4R,R)-1i are stable and do not epimerize in CHCl3 solution.
This may be due to a minor steric tension in the compounds
respect to the corresponding tertiary aminonaphthols 4ia,ib.
3. Stereochemistry
The con®guration of the unknown aminophenols 3 and 4 has
been attributed on the basis of the general trend observed in
1
the H NMR spectroscopic chemical shift: the H-1, at the
stereogenic centre C-1, of the 4R,R)-3 and 4R,R)-4 absorb at
Ddˆ0.07±0.26 ppm up®eld compared to the distereomers
41S,10R)-3 and 41S,10R)-4. This trend can be explained
considering the more stable conformations of the possible
two diastereoisomers, obtained with PM3 semiempirical
minimisation.17 The phenyl group of the auxiliary amine
exercises a shielding magnetic anisotropy18 on the proton
H-1 in the 4R,R) diastereoisomer. Similar shielding effect
can be observed on vicinal groups as the N-methyl group in
Figure 1. Trend of the variation of the optical activity and de observed for the aminophenols 4R,R)- and 41S,10R)-4ia,ib when dissolved in CHCl3 or CDCl3.

6092
C. Cimarelli et al. / Tetrahedron 57 *2001) 6089±6096
Scheme 3.
the case of 4R,R)-3i, for which two equally stable confor-
mations are obtained from conformational analysis.
3028, 2970, 1610, 1581, 1500, 1283 cm21 1H NMR
;
4300 MHz, CDCl3): d 1.64 4d, 3H, Jˆ6.6 Hz), 2.32 4s,
3H), 3.78 4s, 3H), 4.94 4q, 1H, Jˆ6.6 Hz), 6.90±7.40 4m,
8H), 16.80 4brs, 1H); 13C NMR 475 MHz, CDCl3): d 14.8,
25.3, 56.1, 58.8, 112.8, 119.0, 119.2, 125.7, 126.3, 126.8,
127.1, 128.8, 144.3, 157.8, 169.8. Anal. calcd for
C17H19NO2 4269.3): C, 75.81; H, 7.11; N, 5.20%. Found:
C, 75.62; H, 7.18; N, 5.42%.
4. Conclusions
In summary, a regioselective indirect alkylation of amino-
phenols 1a±m to enantiopure tertiary aminophenol 3 and 4,
which are useful chiral ligand for metal-catalysed asym-
metric reactions, is reported. This very simple synthetic
methodology, through reduction or alkylation of the inter-
mediate benzoxazines 2 was performed in mild conditions,
suitable for the conservation of the con®guration of the
chiral centres. Some crystalline aminophenols show the
phenomenon of crystallization-induced asymmetric trans-
formation.
5.1.2. 4-Methoxy-2-..1R)-1-{[.1R)-1-phenylethyl]amino}-
20
ethyl)phenol [.R,R)-1j]. Yield 74%; oil; [a]D ˆ158.9 4c
2.9, CHCl3); IR 4liquid ®lm): 3303, 1497, 1253, 763 cm21
;
1H NMR 4300 MHz, CDCl3): d 1.34 4d, 3H, Jˆ6.8 Hz), 1.41
4d, 3H, Jˆ6.8 Hz), 1.86 4brs, 1H), 3.59 4q, 1H, Jˆ6.8 Hz),
3.65 4q, 1H, Jˆ6.8 Hz), 3.73 4s, 3H), 6.30±6.40 4m, 1H),
6.65±6.85 4m, 2H), 7.10±7.40 4m, 5H), 11.25 4brs, 1H); 13C
NMR 475 MHz, CDCl3): d 22.8, 23.5, 55.4, 55.7, 56.3,
112.9, 114.2, 117.0, 126.3, 127.2, 127.5, 128.8, 143.6,
151.3, 152.5. Anal. calcd for C17H21NO2 4271.4): C,
75.25; H, 7.80; N, 5.16%. Found: C, 75.13; H, 7.73; N,
5.28%.
5. Experimental
5.1. General methods
1H and 13C NMR spectra were recorded at 200 or 300 MHz
and at 50 or 75 MHz, respectively. Chemical shifts are given
in ppm down®eld from Me4Si in CDCl3 solution. Coupling
constants are given in Hz. IR spectra were recorded using
FTIR apparatus. GC±MS analyses were performed with a
gas chromatograph equipped with a methyl silicone
capillary column and obtained by EI methods. Optical rota-
tions were measured in a 1 dm cell at 208C. All melting
points are uncorrected. All reagents and solvents were
distilled prior to use or were of commercial quality from
freshly opened containers.
5.2. General procedure for the preparation of the
3,4-dihydro-2H-1,3-benzoxazines 2a±m
To a solution of aminonaphthol 1 42 mmol) in THF 43 mL)
was added 35% aqueous formaldehyde 42.2 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 puri®ed by ®ltration through a SiO2
pad eluting with CH2Cl2.
5.2.1. 3-[.1R)-1-Phenylethyl]-3,4-dihydro-2H-1,3-benz-
20
oxazine [.R)-2a]. Oil, [a]D ˆ131.9 4c 6.2, CHCl3); IR
The 2-imidoyl phenols 5 were prepared by direct condensa-
tion of the appropriate o-acylphenol and 4R)-41)-1-methyl-
benzylamine 499%) according to described procedure.19±21
The aminophenols 1a±m were prepared by reduction of the
corresponding 2-imidoyl phenols 5.1,3,4 The characterization
of the newly prepared imidoylphenol 4R)-5j and amino-
phenol 4R,R)-1j follows.
4®lm): 2960, 2925, 1850, 1481, 1228, 751 cm21; H NMR
1
4300 MHz, CDCl3): d 1.47 4d, 3H, Jˆ6.6 Hz), 3.77 4d, 1H,
Jˆ16.6 Hz), 3.99 4q, 1H, Jˆ6.6 Hz), 4.13 4d, 1H, Jˆ
16.6 Hz), 4.87 4d, 1H, Jˆ10.3 Hz), 5.10 4dd, 1H, Jˆ10.3,
1.7 Hz), 6.80±7.40 4m, 9H); 13C NMR 475 MHz, CDCl3): d
21.6, 48.7, 57.6, 80.1, 116.2, 120.5, 127.2, 127.3, 127.4,
127.5, 127.6, 128.5, 144.6, 154.8. Anal. calcd for
C16H17NO 4239.3): C, 80.30; H, 7.16; N, 5.85. Found: C,
80.15; H, 7.32; N, 5.98.
5.1.1. 4-Methoxy-2-{[.1R)-1-phenylethyl]ethanimidoyl}-
phenol [.R)-5j]. Yield 87%; yellow oil; IR 4liquid ®lm):

C. Cimarelli et al. / Tetrahedron 57 *2001) 6089±6096
6093
5.2.2. .4R)-4-Ethyl-3-[.1R)-1-phenylethyl]-3,4-dihydro-
Jˆ6.6 Hz), 4.55 4dd, 1H, Jˆ11.0, 2.0 Hz), 5.04 4d, 1H,
Jˆ11.0 Hz), 6.80±7.40 4m, 9H); 13C NMR 475 MHz,
CDCl3): d 22.3, 29.9, 37.4, 60.1, 61.9, 76.9, 116.8, 119.5,
121.9, 127.6, 128.0, 128.3, 128.9, 130.3, 145.1, 155.0. Anal.
calcd for C20H25NO 4295.4): C, 81.31; H, 8.53; N, 4.74.
Found: C, 81.16; H, 8.67; N, 4.95.
20
2H-1,3-benzoxazine [.R,R)-2c]. Oil; [a]D ˆ212.9 4c
2.8, CHCl3); IR 4liquid ®lm): 2972, 2930, 1852, 1489,
1453, 1228, 1078, 754 cm21
;
1H NMR 4300 MHz,
CDCl3): d 0.85 4t, 3H, Jˆ7.4 Hz), 1.48 4d, 3H, Jˆ6.6 Hz),
1.54±1.90 4m, 2H), 3.28±3.38 4m, 1H), 3.85 4q, 1H,
Jˆ6.6 Hz), 5.00 4d, 1H, Jˆ11.0 Hz), 5.14 4dd, 1H, Jˆ
11.0, 1.7 Hz), 6.75±7.45 4m, 9H); 13C NMR 475 MHz,
CDCl3): d 11.1, 21.7, 31.1, 57.8, 59.0, 74.2, 116.3, 120.0,
125.1, 127.1, 127.3, 127.7, 128.2, 128.8, 145.2, 154.4. Anal.
calcd for C18H21NO 4267.4): C, 80.86; H, 7.92; N, 5.24.
Found: C, 80.75; H, 8.01; N, 5.09. .4S)-4-Ethyl-3-[.1R)-
1-phenylethyl]-3,4-dihydro-2H-1,3-benzoxazine [.S,R)-
2c]: 1H NMR 4300 MHz, CDCl3): d 1.08 4t, 3H,
Jˆ7.2 Hz), 1.39 4d, 3H, Jˆ6.6 Hz), 1.50±1.90 4m, 2H),
3.30±3.40 4m, 1H), 4.03 4q, 1H, Jˆ6.6 Hz), 4.51 4dd, 1H,
Jˆ1.8, 10.8 Hz), 4.80 4d, 1H, Jˆ10.8 Hz), 6.75±7.45 4m,
9H).
5.2.7. .4R)-4-But-3-enyl-3-[.1R)-1-phenylethyl]-3,4-di-
20
hydro-2H-1,3-benzoxazine [.R,R)-2h]. Oil; [a]D
258.3 4c 4.4, CHCl3); IR 4liquid ®lm): 2951, 2907, 1869,
ˆ
1480, 756 cm21; H NMR 4300 MHz, CDCl3): d 1.50 4d,
1
3H, Jˆ6.6 Hz), 1.60±2.00 4m, 3H), 2.20±2.40 4m, 1H),
3.44±3.54 4m, 1H), 3.86 4q, 1H, Jˆ6.6 Hz), 4.80±4.96
4m, 2H), 5.03 4d, 1H, Jˆ11.0 Hz), 5.16 4dd, 1H, Jˆ11.0,
1.7 Hz), 5.58±5.80 4m, 1H), 6.80±7.40 4m, 9H); 13C NMR
475 MHz, CDCl3): d 21.5, 26.9, 30.3, 37.6, 55.8, 59.1, 74.2,
114.5, 116.4, 120.2, 127.2, 127.4, 127.7, 128.3, 128.7,
138.5, 145.0, 154.4. Anal. calcd for C20H23NO 4293.4): C,
81.87; H, 7.90; N, 4.77. Found: C, 81.98; H, 7.75; N, 4.96.
5.2.3. .4R)-4-Phenylethyl-3-[.1R)-1-phenylethyl]-3,4-di-
20
hydro-2H-1,3-benzoxazine [.R,R)-2d]. Oil; [a]D
262.1 4c 5.1, CHCl3); IR 4liquid ®lm): 2954, 2927, 1477,
ˆ
5.2.8. .4R)-6-Methoxy-4-methyl-3-[.1R)-1-phenylethyl]-
3,4-dihydro-2H-1,3-benzoxazine [.R,R)-2j]. Crystals; mp
1231, 754 cm21; H NMR 4300 MHz, CDCl3): d 1.53 4d,
110±1138C 4hexane); [a]D ˆ252.35 4c 1.4, CHCl3); IR
1
20
1
3H, Jˆ6.6 Hz), 1.81±2.19 4m, 2H), 2.25±2.42 4m, 1H),
2.80±2.89 4m, 1H), 3.50±3.60 4m, 1H), 3.89 4q, 1H,
Jˆ6.6 Hz), 5.09 4d, 1H, Jˆ11.0 Hz), 5.21 4dd, 1H, Jˆ
11.0, 1.6 Hz), 6.85±7.40 4m, 14H); 13C NMR 475 MHz,
CDCl3): d 21.6, 32.7, 40.3, 56.2, 59.2, 74.2, 116.4, 120.2,
124.8, 125.7, 127.3, 127.4, 127.8, 128.3, 128.4, 128.5,
128.7, 142.4, 145.1, 154.4. Anal. calcd for C24H25NO
4343.5): C, 83.93; H, 7.34; N, 4.08. Found: C, 84.16; H,
7.28; N, 4.23.
4nujol): 1497, 1283, 1046, 704 cm21; H NMR 4300 MHz,
CDCl3): d 1.36 4d, 3H, Jˆ7.0 Hz), 1.43 4d, 3H, Jˆ6.6 Hz),
3.59 4q, 1H, Jˆ7.0 Hz), 3.71 4s, 3H), 3.88 4q, 1H, Jˆ
6.6 Hz), 4.96 4d, 1H, Jˆ11.1 Hz), 5.12 4dd, 1H, Jˆ11.1,
1.6 Hz), 6.40±6.80 4m, 3H), 7.10±7.40 4m, 5H); 13C NMR
475 MHz, CDCl3): d 21.2, 24.6, 52.8, 56.1, 59.2, 74.6,
113.6, 117.5, 126.7, 127.5, 127.6, 128.8, 129.0, 146.3,
148.8, 153.7. Anal. calcd for C18H21NO2 4283.4): C,
76.29; H, 7.47; N, 4.94. Found: C, 76.07; H, 7.28; N, 4.75.
5.2.4. .4R)-3-[.1R)-1-Phenylethyl]-4-propyl-3,4-dihydro-
5.2.9. 3,4-Dimethyl-3,4-dihydro-2H-1,3-benzoxazine [2k].
Oil; IR 4liquid ®lm): 2973, 1487, 1446, 1273, 1248, 1214,
20
2H-1,3-benzoxazine [.R,R)-2e]. Oil; [a]D ˆ225.9 4c 5.8,
CHCl3); IR 4liquid ®lm): 2941, 2905, 1857, 1481, 753 cm21
;
928 cm21; H NMR 4300 MHz, CDCl3): d 1.48 4d, 3H,
1
1H NMR 4300 MHz, CDCl3): d 0.73 4t, 3H, Jˆ7.1 Hz),
1.00±2.30 4m, 4H), 1.49 4d, 3H, Jˆ6.6 Hz), 3.40±3.50
4m, 1H), 3.84 4q, 1H, Jˆ6.6 Hz), 5.02 4d, 1H, Jˆ11.0 Hz),
5.15 4dd, 1H, Jˆ11.0, 1.7 Hz), 6.80±7.40 4m, 9H); 13C
NMR 475 MHz, CDCl3): d 13.9, 19.3, 21.6, 40.7, 56.0,
59.0, 74.2, 116.3, 120.1, 125.2, 127.1, 127.2, 127.7, 128.3,
128.7, 145.2, 154.4. Anal. calcd for C19H23NO 4281.4): C,
81.10; H, 8.24; N, 4.98. Found: C, 80.98; H, 8.19; N, 5.07.
Jˆ7.0 Hz), 2.57 4s, 3H), 3.75 4q, 1H, Jˆ7.0 Hz), 4.71 4d,
1H, Jˆ10.1 Hz), 4.95 4d, 1H, Jˆ10.1 Hz), 6.80±7.35 4m,
4H; 13C NMR 475 MHz, CDCl3): d 23.7, 40.2, 55.4, 79.9,
117.0, 120.9, 125.4, 128.1, 128.6, 153.6. Anal. calcd for
C10H13NO 4163.2): C, 73.59; H, 8.03; N, 8.58. Found: C,
75.69; H, 7.86; N, 8.69.
5.2.10. 3-Isopropyl-4-methyl-3,4-dihydro-2H-1,3-benz-
oxazine [2l]. Oil; IR 4liquid ®lm): 2970, 1582, 1447,
1
5.2.5. .4R)-4-Isobutyl-3-[.1R)-1-phenylethyl]-3,4-dihydro-
1238, 1032, 924 cm21; H NMR 4300 MHz, CDCl3): d
20
2H-1,3-benzoxazine [.R,R)-2f]. Oil; [a]D ˆ240.3 4c 3.7,
1.10 4d, 3H, Jˆ6.6 Hz), 1.17 4d, 3H, Jˆ6.6 Hz), 1.48 4d,
3H, Jˆ7.0 Hz), 3.07 4hept, 1H, Jˆ6.6 Hz), 3.92 4q, 1H,
Jˆ7.0 Hz), 4.95 4s, 2H), 6.70±7.15 4m, 4H); 13C NMR
475 MHz, CDCl3): d 22.0, 22.4, 25.2, 50.3, 52.6, 76.5,
117.2, 120.6, 127.5, 127.7, 128.4, 155.2. Anal. calcd for
C12H17NO 4191.3): C, 75.35; H, 8.96; N, 7.32. Found: C,
75.21; H, 8.82; N, 7.51.
CHCl3); IR 4liquid ®lm): 2925, 1853, 1491, 1226, 750 cm21
;
1H NMR 4300 MHz, CDCl3): d 0.44 4d, 3H, Jˆ6.4 Hz), 0.85
4d, 3H, Jˆ6.6 Hz), 1.20±1.37 4m, 1H), 1.51 4d, 3H,
Jˆ6.6 Hz), 1.66±1.90 4m, 2H), 3.49±3.58 4m, 1H), 3.84
4q, 1H, Jˆ6.6 Hz), 5.04 4d, 1H, Jˆ11.0 Hz), 5.16 4dd, 1H,
Jˆ11.0, 1.6 Hz), 6.80±7.40 4m, 9H); 13C NMR 475 MHz,
CDCl3): d 21.3, 21.4, 23.8, 26.9, 48.3, 54.2, 59.1, 74.2,
116.3, 120.2, 125.5, 127.1, 127.2, 127.8, 128.3, 128.7,
145.1, 154.5. Anal. calcd for C20H25NO 4295.4): C, 81.31;
H, 8.53; N, 4.74. Found: C, 81.45; H, 8.65; N, 4.59.
5.2.11. 3-Benzyl-4-ethyl-3,4-dihydro-2H-1,3-benzoxazine
[2m]. Oil; IR 4liquid ®lm): 3063, 2962, 1582, 1486, 1220,
1
754 cm21; H NMR 4300 MHz, CDCl3): d 0.99 4t, 3H,
Jˆ7.3 Hz), 1.68±1.85 4m, 2H), 3.41 4t, 1H, Jˆ7.3 Hz),
3.73 4d, 1H, Jˆ13.4 Hz), 4.04 4d, 1H, Jˆ13.4 Hz), 4.71
4dd, 1H, Jˆ10.4, 1.5 Hz), 4.97 4d, 1H, Jˆ10.4 Hz), 6.80±
7.40 4m, 9H); 13C NMR 475 MHz, CDCl3): d 11.2, 30.9,
56.7, 58.9, 77.3, 116.5, 120.2, 124.6, 127.2, 127.5, 128.2,
128.7, 129.2, 138.6, 153.6. Anal. calcd for C17H19NO
5.2.6. .4S)-4-.tert-Butyl)-3-[.1R)-1-phenylethyl]-3,4-di-
20
hydro-2H-1,3-benzoxazine [.S,R)-2g]. Oil; [a]D
1165.3 4c 2.13, CHCl3); IR 4liquid ®lm): 2945, 1857,
ˆ
1282, 749 cm21; H NMR 4300 MHz, CDCl3): d 1.10 4s,
1
9H), 1.36 4d, 3H, Jˆ6.6 Hz), 3.76 4s, 1H), 3.90 4q, 1H,

6094
C. Cimarelli et al. / Tetrahedron 57 *2001) 6089±6096
4253.3): C, 80.60; H, 7.56; N, 5.53. Found: C, 80.45; H,
7.68; N, 5.36.
5.3.5.
butyl)phenol [.R,R)-3e]. Oil; [a]D ˆ29.7 4c 1.0,
CHCl3); IR 4liquid ®lm): 2959, 1587, 1454, 1256 cm21
2-..1R)-1-{Methyl[.1R)-1-phenylethyl]amino}-
20
;
1H NMR 4300 MHz, CDCl3): d 0.87 4t, 3H, Jˆ7.2 Hz),
1.05±1.30 4m, 2H), 1.48 4d, 3H, Jˆ7.0 Hz), 1.71±1.88
4m, 2H), 2.09 4s, 3H), 3.60±3.70 4m, 1H), 4.21 4q, 1H,
Jˆ7.0 Hz), 6.70±7.40 4m, 9H), 11.70 4brs, 1H); 13C NMR
475 MHz, CDCl3): d 14.3, 15.8, 20.1, 25.3, 32.5, 57.3,
65.9, 116.4, 118.7, 125.7, 127.1, 127.4, 128.2, 128.3,
129.0, 139.8, 157.6. Anal. calcd for C19H25NO 4283.4): C,
80.52; H, 8.89; N, 4.94%. Found: C, 80.63; H, 8.73; N,
4.97%.
5.3. General procedure for the reduction of the
benzoxazines 2a±m to aminophenols 3a±m
A solution of benzoxazine 41.0 mmol) in ethanol 45 mL)
was treated with an excess of NaBH4 43.0 mmol, 0.113 g)
and stirred at room temperature for 2 h. The reaction
mixture, diluted with CH2Cl2 450 mL), was treated with a
saturated aqueous solution of ammonium chloride 410 mL).
The organic layer was dried and evaporated. The residue,
puri®ed by ¯ash chromatography 4cyclohexane/ethyl
acetate: 95/5 as eluent), gave the aminophenols 3a±m.
5.3.6. 2-..1R)-3-Methyl-1-{methyl[.1R)-1-phenylethyl]-
amino}butyl)phenol [.R,R)-3f]. Crystals; mp 53±558C
20
4hexane); [a]D ˆ227.3 4c 1.6, CHCl3); IR 4nujol): 2924,
5.3.1.
2-.{Methyl[.1R)-1-phenylethyl]amino}methyl)-
2854, 1446,1400, 1377, 1258, 1158 cm21 1H NMR
;
20
phenol [.R)-3a]. Oil; [a]D ˆ19.1 4c 4.85, CHCl3); IR
4300 MHz, CDCl3): d 0.87 4d, 3H, Jˆ6.5 Hz), 0.93 4d,
3H, Jˆ6.3 Hz), 1.40±1.50 4m, 1H), 1.48 4d, 3H, Jˆ
6.6 Hz), 1.55±1.93 4m, 2H), 2.02 4s, 3H), 3.81 4dd, 1H,
Jˆ11.1, 3.6 Hz), 4.20 4q, 1H, Jˆ6.6 Hz), 6.80±7.40 4m,
9H), 11.75 4brs, 1H); 13C NMR 475 MHz, CDCl3): d 14.0,
21.8, 24.3, 25.5, 32.8, 38.0, 57.3, 63.4, 116.6, 118.7, 126.1,
127.4, 128.1, 128.3, 128.4, 128.5, 128.6, 157.6. Anal. calcd
for C20H27NO 4297.4): C, 80.76; H, 9.15; N, 4.71%. Found:
C, 80.64; H, 9.28; N, 4.58%.
4liquid ®lm): 2975, 1589, 1491, 1475, 1452, 1376,
1257 cm21; H NMR 4300 MHz, CDCl3): d 1.51 4d, 3H,
1
Jˆ6.9 Hz), 2.21 4s, 3H), 3.63 4d, 1H, Jˆ13.9 Hz), 3.78 4d,
1H, Jˆ13.9 Hz), 3.80 4q, 1H, Jˆ6.9 Hz), 6.70±7.45 4m,
9H), 11.75 4brs, 1H); 13C NMR 475 MHz, CDCl3): d 17.7,
37.7, 58.5, 63.0, 116.4, 119.5, 122.5, 128.1, 128.5, 128.6,
128.9, 129.0, 141.0, 158.5. Anal. calcd for C16H19NO
4241.3): C, 79.63; H, 7.94; N, 5.80%. Found: C, 79.85; H,
7.82; N, 5.96%.
5.3.7. 2-..1R)-1-{Methyl[.1R)-1-phenylethyl]amino}pent-
20
5.3.2. 2-..1R)-1-{Methyl[.1R)-1-phenylethyl]amino}ethyl)-
4-enyl)phenol [.R,R)-3h]. Oil; [a]D ˆ29.3 4c 2.9,
20
phenol [.R,R)-3b]. Oil; [a]D ˆ110.9 4c 2.2, CHCl3); IR
CHCl3); IR 4liquid ®lm): 2975, 1588, 1491, 1472, 1257,
4liquid ®lm): 2974, 1492, 1453, 1374, 1257, 754 cm21; H
913, 755 cm21; H NMR 4300 MHz, CDCl3): d 1.47 4d,
1
1
NMR 4300 MHz, CDCl3): d 1.44 4d, 3H, Jˆ6.7 Hz), 1.52 4d,
3H, Jˆ6.8 Hz), 2.02 4s, 3H), 4.04 4q, 1H, Jˆ6.8 Hz), 4.17
4q, 1H, Jˆ6.7 Hz), 6.73±7.48 4m, 9H), 11.80 4brs, 1H); 13C
NMR 475 MHz, CDCl3): d 14.0, 17.5, 23.0, 32.6, 58.9,
116.3, 119.1, 127.3, 127.4, 127.8, 128.4, 128.5, 129.3,
141.2, 158.6. Anal. calcd for C17H21NO 4255.3): C, 79.96;
H, 8.29; N, 5.49%. Found: C, 80.13; H, 8.41; N, 5.31%.
3H, Jˆ7.0 Hz), 1.85±1.95 4m, 4H), 2.09 4s, 3H), 3.60±
3.72 4m, 1H), 4.21 4q, 1H, Jˆ7.0 Hz), 4.90±5.05 4m, 2H),
5.65±5.85 4m, 1H), 6.80±7.40 4m, 9H), 11.70 4brs, 1H); 13C
NMR 475 MHz, CDCl3): d 16.3, 29.9, 31.4, 33.0, 57.9, 65.9,
115.5, 117.1, 119.3, 125.8, 128.0, 128.7, 128.8, 128.9,
129.4, 129.5, 138.5, 158.1. Anal. calcd for C20H25NO
4295.4): C, 81.31; H, 8.53; N, 4.74%. Found: C, 81.16; H,
8.68; N, 4.90%.
5.3.3. 2-..1R)-1-{Methyl[.1R)-1-phenylethyl]amino}pro-
20
pyl)phenol [.R,R)-3c]. Oil; [a]D ˆ112.7 4c 10.2,
5.3.8. 2-[.S)-{Methyl[.1R)-1-phenylethyl]amino}.phenyl)-
methyl]phenol [.1S,10R)-3i]. Oil; IR 4liquid ®lm): 2976,
CHCl3); IR 4liquid ®lm): 3029, 1255, 1587, 1491,
754 cm21; H NMR 4300 MHz, CDCl3): d 0.82 4t, 3H,
1586, 1472, 1255, 755 cm21 1H NMR 4300 MHz,
;
1
Jˆ7.3 Hz), 1.49 4d, 3H, Jˆ6.6 Hz), 1.75±2.00 4m, 2H),
2.12 4s, 3H), 3.58 4dd, 1H, Jˆ8.9, 4.5 Hz), 4.25 4q, 1H,
Jˆ6.6 Hz), 6.80±7.50 4m, 9H), 11.70 4brs, 1H); 13C NMR
475 MHz, CDCl3): d 11.7, 16.2, 23.8, 32.9, 57.8, 68.0,
116.9, 119.2, 125.8, 128.0, 128.8, 128.9, 129.8, 129.9,
140.2, 158.2. Anal. calcd for C18H23NO 4269.4): C, 80.26;
H, 8.61; N, 5.20%. Found: C, 80.39; H, 8.54; N, 5.38%.
CDCl3): d 1.42 4d, 3H, Jˆ6.6 Hz), 2.34 4s, 3H), 3.85 4q,
1H, Jˆ6.6 Hz), 4.95 4s, 1H), 6.80±7.60 4m, 14H), 12.75
4brs, 1H); 13C NMR 475 MHz, CDCl3): d 18.7, 33.4, 57.1,
73.2, 117.0, 119.4, 127.5, 127.9, 128.0, 128.1, 128.3, 128.4,
128.5, 128.6, 128.7, 129.0, 129.1, 129.7. Anal. calcd for
C22H23NO 4317.4): C, 83.24; H, 7.30; N, 4.41%. Found:
C, 83.41; H, 7.42; N, 4.24%. 4R,R)-3i.4
5.3.4. 2-..1R)-1-{Methyl[.1R)-1-phenylethyl]amino}-3-
5.3.9. 4-Methoxy-2-..1R)-1-{methyl[.1R)-1-phenylethyl]-
amino}ethyl)phenol [.R,R)-3j]. Crystals; mp 65±688C
20
phenylpropyl)phenol [.R,R)-3d]. Oil; [a]D ˆ222.5 4c
20
3.8, CHCl3); IR 4liquid ®lm): 2973, 1588, 1493, 1471,
4hexane); [a]D ˆ17.3 4c 1.1, CHCl3); IR 4nujol): 2924,
1
1
1453, 1256 cm21; H NMR 4300 MHz, CDCl3): d 1.42 4d,
2854, 2361, 1459, 1377, 1287 cm21; H NMR 4300 MHz,
3H, Jˆ6.6 Hz), 2.09 4s, 3H), 2.12±2.24 4m, 2H), 2.40±2.54
4m, 2H), 3.76 4t, 1H, Jˆ6.6 Hz), 4.20 4q, 1H, Jˆ6.6 Hz),
6.85±7.40 4m, 14H), 11.75 4brs, 1H); 13C NMR 475 MHz,
CDCl3): d 26.9, 31.9, 32.6, 33.1, 57.6, 65.4, 116.7, 118.9,
125.3, 125.9, 127.1, 127.5, 128.2, 128.3, 128.4, 128.5,
128.6, 129.0, 147.8, 157.7. Anal. calcd for C24H27NO
4345.5): C, 83.44; H, 7.88; N, 4.05%. Found: C, 83.59; H,
7.64; N, 3.84%.
CDCl3): d 1.43 4d, 3H, Jˆ6.7 Hz), 1.51 4d, 3H, Jˆ6.9 Hz),
2.00 4s, 3H), 3.78 4s, 3H), 4.02 4q, 1H, Jˆ6.7 Hz), 4.10 4q,
1H, Jˆ6.9 Hz), 6.60±6.80 4m, 2H), 7.20±7.40 4m, 6H),
12.50 4brs, 1H); 13C NMR 475 MHz, CDCl3): d 14.4,
17.2, 26.9, 32.6, 55.8, 59.1, 112.5, 113.9, 116.5, 118.5,
127.5, 127.8, 128.3, 128.5, 141.2, 152.6. Anal. calcd for
C18H23NO2 4285.4): C, 75.76; H, 8.12; N, 4.91%. Found:
C, 75.93; H, 8.19; N, 4.78%.

C. Cimarelli et al. / Tetrahedron 57 *2001) 6089±6096
6095
5.3.10. 2-[1-.Dimethylamino)ethyl]phenol [.^)-3k]. Oil;
5.4.2. 2-..1R)-1-{Phenethyl[.1R)-1-phenylethyl]amino}-
ethyl)phenol [.R,R)-4bb]. Crystals; mp 84±878C 4hexane);
1
IR 4liquid ®lm): 2979, 1586, 1401, 1257 cm21; H NMR
20
4300 MHz, CDCl3): d 1.39 4d, 3H, Jˆ6.8 Hz), 2.32 4s,
6H), 3.58 4q, 1H, Jˆ6.8 Hz), 6.70±7.40 4m, 4H), 12.50
4brs, 1H); 13C NMR 475 MHz, CDCl3): d 16.2, 42.2, 65.2,
116.8, 119.4, 127.7, 128.1, 128.8, 157.9. Anal. calcd for
C10H15NO 4165.2): C, 72.69; H, 9.15; N, 8.48%. Found:
C, 72.86; H, 9.33; N, 8.29%.
[a]D ˆ131.6 4c 2.5, CHCl3); IR 4nujol): 3021, 1455, 1251,
1376, 1107, 748 cm21; 1H NMR 4300 MHz, CDCl3): d 1.52
4d, 3H, Jˆ6.6 Hz), 1.55 4d, 3H, Jˆ6.8 Hz), 2.00±2.28 4m,
2H), 2.62 4t, 2H, Jˆ8.5 Hz), 4.08 4q, 1H, Jˆ6.8 Hz), 4.39
4q, 1H, Jˆ6.6 Hz), 6.60±7.40 4m, 14H), 11.62 4brs, 1H); 13C
NMR 475 MHz, CDCl3): d 14.5, 19.2, 37.6, 51.1, 58.8, 60.1,
116.9, 119.9, 126.4, 127.5, 128.3, 128.5, 128.6, 128.7,
128.9, 129.1, 129.2, 140.3, 142.8, 158.0. Anal. calcd for
C24H27NO 4345.5): C, 83.44; H, 7.88; N, 4.05. Found: C,
83.65; H, 7.75; N, 4.19.
5.3.11. 2-{1-[Isopropyl.methyl)amino]ethyl}phenol [.^)-
3l]. Oil; IR 4liquid ®lm): 2973, 2874, 1589, 1479, 1463,
1
1259, 754 cm21; H NMR 4300 MHz, CDCl3): d 1.08 4t, 6
H, Jˆ6.6 Hz), 1.40 4d, 3H, Jˆ6.7 Hz), 2.20 4s, 3H), 3.17
4hept, 1H, Jˆ6.6 Hz), 3.85 4q, 1H, Jˆ6.7 Hz), 6.70±7.25
4m, 4H), 12.70 4brs, 1H); 13C NMR 475 MHz, CDCl3): d
18.1, 18.6, 31.4, 49.4, 62.0, 116.9, 119.3, 127.9, 128.6,
128.7, 157.9. Anal. calcd for C12H19NO 4193.3): C, 74.57;
H, 9.91; N, 7.25%. Found: C, 74.32; H, 9.85; N, 7.37%.
5.4.3. 2-..1R)-1-{Benzyl[.1R)-1-phenylethyl]amino}ethyl)-
20
phenol [.R,R)-4bc]. Oil; [a]D ˆ15.79 4c 2.64, CHCl3); IR
1
4liquid ®lm): 3029, 1490, 1453, 1289, 1255, 753 cm21; H
NMR 4300 MHz, CDCl3): d 1.36 4d, 3H, Jˆ7.0 Hz), 1.62 4d,
3H, Jˆ7.0 Hz), 3.48 4d, 1H, Jˆ14.7 Hz), 4.01 4d, 1H,
Jˆ14.7 Hz), 4.12 4q, 1H, Jˆ7.0 Hz), 4.22 4q, 1H, Jˆ
7.0 Hz), 6.80±7.40 4m, 14H), 11.05 4brs, 1H); 13C NMR
475 MHz, CDCl3): d 17.6, 18.4, 50.9, 57.9, 60.1, 116.5,
119.5, 126.9, 127.4, 127.5, 127.6, 128.2, 128.3, 128.4,
128.5, 128.6, 128.7, 140.1, 157.1. Anal. calcd for
C23H25NO 4331.4): C, 83.34; H, 7.60; N, 4.23%. Found:
C, 83.53; H, 7.45; N, 4.08%.
5.3.12. 2-{1-[Benzyl.methyl)amino]propyl}phenol [.^)-
3m]. Oil; IR 4liquid ®lm): 2973, 2794, 1586, 1490, 1454,
1254, 754 cm21; 1H NMR 4300 MHz, CDCl3): d 0.83 4t, 3H,
Jˆ7.4 Hz), 1.75±2.10 4m, 2H), 2.21 4s, 3H), 3.41 4dd, 1H,
Jˆ9.57, 3.75 Hz), 3.50 4d, 1H, Jˆ13.0 Hz), 3.73 4d, 1H,
Jˆ13.0 Hz), 6.80±7.40 4m, 9H), 11.90 4brs, 1H); 13C
NMR 475 MHz, CDCl3): d 11.8, 23.7, 38.6, 59.9, 71.5,
117.1, 119.2, 126.0, 127.9, 128.9, 129.0, 129.6, 129.9,
137.9, 157.5. Anal. calcd for C17H21NO 4255.4): C, 79.96;
H, 8.29; N, 5.49%. Found: C, 79.79; H, 8.36; N, 5.37%.
5.4.4. 2-[.S)-{Ethyl[.1R)-1-phenylethyl]amino}.phenyl)-
methyl]phenol [.S,R)-4ia]. Crystals; mp 130±1328C
20
4hexane); [a]D ˆ151.0 4c 1.7, CHCl3); IR 4nujol): 3028,
1
2930, 1482, 1378, 1251, 751 cm21; H NMR 4300 MHz,
CDCl3): d 0.84 4t, 3H, Jˆ7.0 Hz), 1.47 4d, 3H, Jˆ6.9 Hz),
2.70±3.00 4m, 2H), 4.05 4q, 1H, Jˆ6.9 Hz), 5.03 4s, 1H),
6.60±7.40 4m, 14H), 12.10 4brs, 1H); 13C NMR 475 MHz,
CDCl3): d 16.6, 18.3, 42.7, 60.3, 70.9, 117.1, 119.5, 127.9,
128.3, 128.5, 128.8, 129.0, 129.3, 129.4, 129.5, 130.1,
139.3, 143.2, 157.6. Anal. calcd for C23H25NO 4331.4): C,
83.34; H, 7.60; N, 4.23%. Found: C, 83.45; H, 7.52; N,
4.31%. 2-[.R)-{Ethyl[.1R)-1-phenylethyl]amino}.phenyl)-
5.4. General procedure for the alkylation of
benzoxazines .R,R)-2b,i,j with Grignard reagents
To a solution of benzoxazines 4R,R)-2b,i,j 41.0 mmol) in
anhydrous THF 43.0 mL) under inert atmosphere, cooled
to 2608C, was added dropwise the Grignard reagent
41.5 mmol, 1 M in THF) with stirring. The reaction mixture
was stirred for 4 h with the temperature allowed to rise
slowly to 2108C, and then was quenced with NH4Cl
saturated solution 45 mL) and extracted with CH2Cl2
42£30 mL). The solution was dried with anhydrous
Na2SO4 then ®ltered and the solvent evaporated under
reduced pressure. Chromotographic separation of the
crude oil obtained, with cyclohexane/ethyl acetateˆ90:10
as eluent afforded the alkylated aminophenols 4R,R)-4;
yields 63±94%.
20
methyl]phenol [.R,R)-4ia]: Oil; [a]D ˆ269.6 4c 1.7,
1
CHCl3, drˆ4.0); H NMR 4300 MHz, CDCl3): d 0.73 4t,
3H, Jˆ7.2 Hz), 1.45 4d, 3H, Jˆ7.0 Hz), 2.55±2.75 4m,
2H), 4.21 4q, 1H, Jˆ7.0 Hz), 4.90 4s, 1H), 6.60±7.60 4m,
14H), 12.50 4brs, 1H); 13C NMR 475 MHz, CDCl3): d
15.7, 18.3, 42.1, 57.8, 72.2, 117.4, 119.8, 127.9, 128.4,
128.5, 128.7, 128.9, 129.1, 129.3, 129.5, 130.1, 141.3,
141.6, 157.7.
5.4.5. 2-[.S)-{Phenethyl[.1R)-1-phenylethyl]amino}-
.phenyl)methyl]phenol [.S,R)-4ib]. Crystals; mp 112±
5.4.1. 2-..1R)-1-{Ethyl[.1R)-1-phenylethyl]amino}ethyl)-
20
phenol [.R,R)-4ba]. Oil; [a]D ˆ212.04 4c 3.5, CHCl3); IR
20
1148C 4hexane); [a]D ˆ165.2 4c 2.5, CHCl3); IR 4nujol):
4liquid ®lm): 3030, 2933, 1601, 1491, 1378, 1255, 1078,
1
3085, 3027, 2928, 1586, 1254, 992, 753 cm21; H NMR
1
753 cm21; H NMR 4300 MHz, CDCl3): d 0.70 4t, 3H,
4300 MHz, CDCl3): d 1.52 4d, 3H, Jˆ6.8 Hz), 1.98±2.10
4m, 1H), 2.23±2.37 4m, 1H), 2.80±2.90 4m, 2H), 4.24 4q,
1H, Jˆ6.8 Hz), 5.05 4s, 1H), 6.50±7.60 4m, 19H), 11.85 4s,
1H); 13C NMR 475 MHz, CDCl3): d 14.9, 38.1, 50.2, 58.8,
72.5, 117.5, 120.2, 126.4, 126.5, 127.5, 128.2, 128.3, 128.6,
128.7, 128.8, 129.0, 129.1, 129.3, 129.7, 130.0, 140.2,
141.0, 157.7. Anal. calcd for C29H29NO 4407.5): C, 85.47;
H, 7.17; N, 3.44. Found: C, 85.32; H, 7.28; N, 3.21. 2-[.R)-
{Phenethyl[.1R)-1-phenylethyl]amino}.phenyl)methyl]-
Jˆ7.2 Hz), 1.49 4d, 3H, Jˆ6.8 Hz), 1.55 4d, 3H,
Jˆ6.8 Hz), 2.42±2.78 4m, 2H), 4.08 4q, 1H, Jˆ6.8 Hz),
4.32 4q, 1H, Jˆ6.8 Hz), 6.80±7.25 4m, 9H), 12.10 4brs,
1H); 13C NMR 475 MHz, CDCl3): d 12.5, 14.7, 15.4, 18.9,
41.5, 58.1, 116.3, 119.2, 126.5, 126.9, 127.5, 127.9, 128.4,
128.5, 142.3, 157.7. Anal. calcd for C18H23NO 4269.4): C,
80.26; H, 8.61; N, 5.20. Found: C, 80.43; H, 8.54; N, 5.38.
2-..1S)-1-{Ethyl[.1R)-1-phenylethyl]amino}ethyl)phenol
1
[.S,R)-4ba]: H NMR 4300 MHz, CDCl3): d 1.06 4t, 3H,
20
phenol [.R,R)-4ib]: Oil; [a]D ˆ288.0 4c 2.5, CHCl3
Jˆ7.1 Hz), 1.37 4d, 3H, Jˆ6.8 Hz), 1.45 4d, 3H, Jˆ
6.8 Hz), 2.40±2.70 4m, 2H), 4.01 4s, 1H, Jˆ6.8 Hz), 4.15
4s, 1H, Jˆ6.8 Hz), 6.80±7.25 4m, 9H), 12.10 4brs, 1H).
drˆ2.4); 1H NMR 4300 MHz, CDCl3): d 1.55 4d, 3H,
Jˆ7.0 Hz), 2.08±2.42 4m, 2H), 2.60±2.78 4m, 1H),

6096
C. Cimarelli et al. / Tetrahedron 57 *2001) 6089±6096
2.94±3.12 4m, 1H), 4.26 4q, 1H, Jˆ7.0 Hz), 4.93 4s, 1H),
6.60±7.60 4m, 19H), 12.20 4brs, 1H).
129.5, 140.5, 151.3. Anal. calcd for C24H27NO2 4361.5):
C, 79.74; H, 7.53; N, 3.87. Found: C, 79.58; H, 7.68; N,
3.73.
5.4.6. 2-[.R)-{Benzyl[.1R)-1-phenylethyl]amino}.phenyl)-
20
methyl]phenol [.R,R)-4ic]. Oil; [a]D ˆ249.8 4c 4.7,
753 cm21; H NMR 4300 MHz, CDCl3): d 1.54 4d, 3H,
Acknowledgements
CHCl3, drˆ4.1); IR 4liquid ®lm): 3025, 1465, 1257, 1372,
1
Á
Financial support from Ministero dell'Universita e della
Jˆ7.2 Hz), 3.40 4d, 1H, Jˆ14.6 Hz), 4.08 4d, 1H, Jˆ
14.6 Hz), 4.39 4q, 1H, Jˆ7.2 Hz), 4.85 4s, 1H), 6.70±7.60
4m, 19H), 12.20 4s, 1H); 13C NMR 475 MHz, CDCl3): d
17.6, 51.1, 58.1, 72.2, 117.0, 119.6, 126.3, 127.5, 127.7,
127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6, 128.9,
129.4, 129.9, 138.5, 140.6, 156.9. Anal. calcd for
C28H27NO 4393.5): C, 85.46; H, 6.92; N, 3.56. Found: C,
85.61; H, 6.84; N, 3.77%. 2-[.S)-{Benzyl[.1R)-1-phenyl-
Ricerca Scienti®ca e Tecnologica, Rome, and the University
of Camerino 4National Project `Stereoselezione in Sintesi
Organica. Metodologie ed applicazioni') is gratefully
acknowledged.
References
1
ethyl]amino}.phenyl)methyl] phenol [.S,R)-4ic]: Oil; H
1. Palmieri, G. Eur. J. Org. Chem. 1999, 805±811.
2. Cimarelli, C.; Palmieri, G. Tetrahedron 1998, 54, 15711±
15720.
NMR 4300 MHz, CDCl3): d 1.48 4d, 3H, Jˆ6.9 Hz), 3.64 4d,
1H, Jˆ14.4 Hz), 3.91 4d, 1H, Jˆ14.4 Hz), 4.31 4q, 1H,
Jˆ6.9 Hz), 5.11 4s, 1H), 6.70±7.60 4m, 19H), 12.00 4s, 1H).
3. Cimarelli, C.; Palmieri, G. Tetrahedron: Asymmetry 2000, 11,
2555±2563.
5.4.7. 2-..1R)-1-{Ethyl[.1R)-1-phenylethyl]amino}ethyl)-
4. Palmieri, G. Tetrahedron: Asymmetry 2000, 11, 3361±3373.
5. Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org.
Chem. 2001, 66, 000.
20
4-methoxyphenol [.R,R)-4ja]. Oil; [a]D ˆ27.65 4c 2.2,
CHCl3, drˆ28); IR 4liquid ®lm): 2928, 1492, 1453, 1378,
1
1286, 1215 cm21; H NMR 4300 MHz, CDCl3): d 0.67 4t,
6. Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1059±1070.
7. Brunner, H. Synthesis 1988, 645±654.
3H, Jˆ7.2 Hz), 1.46 4d, 3H, Jˆ6.9 Hz), 1.52 4d, 3H,
Jˆ6.9 Hz), 2.42±2.72 4m, 2H), 3.77 4s, 3H), 4.04 4q, 1H,
Jˆ6.9 Hz), 4.26 4q, 1H, Jˆ6.9 Hz), 6.60±7.40 4m, 8 H),
11.50 4brs, 1H); 13C NMR 475 MHz, CDCl3): d 14.6,
15.4, 18.8, 41.5, 55.7, 58.1, 59.0, 112.4, 113.7, 116.4,
127.5, 127.9, 128.4, 128.7, 128.9, 142.4, 152.6. Anal.
calcd for C19H25NO2 4299.4): C, 76.22; H, 8.42; N, 4.68.
Found: C, 76.39; H, 8.49; N, 4.47.
8. Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna, F.;
Tortorella, P. Tetrahedron 1999, 55, 14685±14692.
9. Cardellicchio, C.; Ciccarella, G.; Naso, F.; Schingaro, E.;
Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667±3675.
10. Delair, P.; Einhorn, C. Tetrahedron 1995, 51, 165±172.
11. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835±875.
5.4.8. 2-..1R)-1-{Phenethyl[.1R)-1-phenylethyl]amino}-
12. Harris, M. M. The study of optically labile compounds. Prog.
Stereochem. 1958, 2, 157.
20
ethyl)-4-methoxyphenol [.R,R)-4jb]. Oil; [a]D ˆ23.22
4c 2.1, CHCl3, drˆ14); IR 4liquid ®lm): 3021, 1489, 1264,
13. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates
and Resolutions, Wiley: New York, 1981 p 374.
14. Buchanan, C.; Graham, S. H. J. Chem. Soc. 1950, 500±507.
15. Eliel, E. Stereochemistry of Carbon Compounds, McGraw-
Hill: New York, 1962 p 63.
1
1341, 758 cm21; H NMR 4300 MHz, CDCl3): d 1.50 4d,
3H, Jˆ6.8 Hz), 1.53 4d, 3H, Jˆ6.8 Hz), 1.98±2.24 4m, 2H),
2.62 4t, 2H, Jˆ8.1 Hz), 3.80 4s, 3H), 4.06 4q, 1H, Jˆ6.8 Hz),
4.33 4q, 1H, Jˆ6.8 Hz), 6.60±7.50 4m, 13H), 11.10 4brs,
1H); 13C NMR 475 MHz, CDCl3): d 13.8, 17.7, 26.9, 37.1,
50.6, 55.9, 60.0, 112.8, 113.8, 116.6, 126.0, 127.6, 127.7,
128.0, 128.1, 128.2, 128.6, 135.5, 139.8, 151.2, 152.7. Anal.
calcd for C25H29NO2 4375.5): C, 79.96; H, 7.78; N, 3.73%.
Found: C, 80.12; H, 7.63; N, 3.81%.
16. Mason, S. F. Molecular Optical Activity and the Chiral
Discriminations, Cambridge University Press: Cambridge,
UK, 1982, p 208.
17. Semiempirical PM3 calculations were performed with the
Spartan 5.0.3, Wavefunction Inc., 18401 Von Karmen Ave.,
#370, Irvine, CA 92715.
5.4.9. 2-..1R)-1-{Benzyl[.1R)-1-phenylethyl]amino}ethyl)-
20
18. Harada, N.; Watanabe, M.; Kuwahara, S.; Sugio, A.; Kasai,
Y.; Ichikawa, A. Tetrahedron: Asymmetry 2000, 11, 1249±
1253.
4-methoxyphenol [.R,R)-4jc]. Oil; [a]D ˆ119.48 4c 2.3,
CHCl3, drˆ7.0); IR 4liquid ®lm): 3031, 1492, 1287,
1
764 cm21; H NMR 4300 MHz, CDCl3): d 1.35 4d, 3H,
19. Boatman, S.; Hauser, C. R. J. Org. Chem. 1966, 31, 1785±
1789.
Jˆ6.8 Hz), 1.60 4d, 3H, Jˆ7.0 Hz), 3.48 4d, 1H, Jˆ
14.6 Hz), 3.76 4s, 3H), 3.97 4d, 1H, Jˆ14.6 Hz), 4.08 4q,
1H, Jˆ6.8 Hz), 4.19 4q, 1H, Jˆ7.0 Hz), 6.70±7.50 4m,
13H), 10.40 4brs, 1H); 13C NMR 475 MHz, CDCl3): d
17.6, 18.8, 51.4, 56.3, 58.5, 60.3, 113.1, 114.6, 117.2,
127.3, 128.1, 128.7, 128.8, 128.9, 129.0, 129.1, 129.2,
20. Singh, R. V.; Tandon, J. P. J. Prakt. Chem. 1979, 321, 151.
21. Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983,
902±903.