Asymmetric synthesis of diarylmethylamines by diastereoselective addition of organometallic reagents to chiral N-tert-butanesulfinimines: Switchover of diastereofacial selectivity

Article abstract of DOI:10.1016/S0957-4166(02)00099-X

Diastereoselective addition of organometallic reagents to chiral N-tert-butanesulfinimines gave alkylated adducts in high yields and diastereoselectivities. Cleavage of the chiral auxiliary under mildly acidic conditions gave diarylmethylamines in high yi

Full text of DOI:10.1016/S0957-4166(02)00099-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 303–310
Asymmetric synthesis of diarylmethylamines by diastereoselective
addition of organometallic reagents to chiral
N-tert-butanesulfinimines: switchover of diastereofacial selectivity
Niklas Plobeck* and David Powell
Department of Chemistry, AstraZeneca R&D Montreal, 7171 Frederick-Banting Street, St-Laurent, Quebec, Canada H4S 1Z9
Received 8 February 2002; accepted 19 February 2002
Abstract—Diastereoselective addition of organometallic reagents to chiral N-tert-butanesulfinimines gave alkylated adducts in
high yields and diastereoselectivities. Cleavage of the chiral auxiliary under mildly acidic conditions gave diarylmethylamines in
high yield. A reversal in the diastereoselectivity was observed by using either phenylmagnesium bromide in toluene or
phenyllithium in THF. The use of the same chiral auxiliary thus allowed the synthesis of both enantiomers of a number of
diarylmethylamines. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Herein, we wish to report two sets of conditions for
nucleophilic additions to chiral N-tert-butanesulfinyl-
arylaldimines allowing the synthesis of both enan-
tiomers of chiral diarylmethylamines in high yield and
enantiomeric purity using the same chiral auxiliary
(Scheme 1). A switchover of diastereofacial selectivity
in the addition was observed depending on the reagent
and solvent used.
Diarylmethylamines are an important class of amines
present in many structures showing biological activity
and important as synthetic intermediates (Fig. 1).1–3
There are relatively few reports on asymmetric synthesis
of diarylmethylamines.4,5 Recently, the N-tert-butane-
sulfinyl group has been demonstrated to be a useful
readily available chiral auxiliary giving high asymmetric
induction for nucleophilic addition to imines.6 How-
ever, no examples of additions of aryl metal reagents to
N-tert-butanesulfinylarylaldimines have been reported.
Because of its favorable properties and the mild condi-
tions for cleavage, we wanted to apply this chiral
2. Results and discussion
2.1. Preparation of N-tert-butanesulfinyl aldimines
Chiral N-tert-butanesulfinyl aldimines 3 were prepared
in high yields by condensation of aldehydes with (R)-
tert-butanesulfinamide 1 (Table 1).7
auxiliary
diarylmethylamines.
to
the
asymmetric
synthesis
of
Figure 1.
* Corresponding author. Fax: +1 (514) 832 3232; e-mail: niklas.plobeck@astrazeneca.com
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00099-X

304
N. Plobeck, D. Powell / Tetrahedron: Asymmetry 13 (2002) 303–310
Scheme 1.
Table 1. Preparation of N-tert-butanesulfinyl aldimines 3a–g
Aldimine
R
Yield (%)
3a
3b
3c
3d
3e
3f
Phenyl
75
99
99
81
53
94
88
1-Naphthyl
4-Cl-Phenyl
4-Br-Phenyl
4-CF3-Phenyl
4-(CH3)2N-Phenyl
3-Furanyl
3g
2.2. Effects of solvent and organometallic reagent
based on the initial results in Table 2. Addition of
phenyllithium in THF at −78°C and phenylmagnesium
bromide in toluene at −45°C was compared for the
examples 3b–g. Most of the examples investigated gave
the corresponding N-tert-butanesulfinylamide 4 in high
yield and high diastereoselectivity. The switchover of
diastereofacial selectivity in the addition between
PhMgBr and PhLi was observed in all cases except 3f.
The substrate 3f containing a basic dimethylamino
group was an exception, giving no reaction with
PhMgBr and non-selective reaction with PhLi. The
diastereomeric mixture of sulfinylamides 4 could in
some cases be further purified by chromatography or
recrystallization. In the case of 4b, the diastereomeric
ratio was increased from 86:14 to >99:1 by two
recrystallizations.
The additions of PhLi and PhMgBr to the substrate 3c
were performed in different solvents (Table 2). The
additions were completed at −78°C and the reactions
were allowed to warm to 25°C over 4 h. The
diastereomeric ratios were determined after cleavage of
the chiral auxiliary by treatment with HCl in methanol.
Phenyllithium gave a fast reaction in THF, occurring
readily at −78°C to give a 27:73 diastereomeric ratio.
The reaction in toluene was slower and gave a lower
diastereomeric ratio. Addition of PhMgBr to 3c in
THF gave a very slow reaction (<5% conversion).
Addition in CH2Cl2 as solvent has been reported to
give the best diastereoselectivity for addition of many
alkyl Grignard reagents,6 and addition of PhMgBr to
3c gave a good diastereomeric ratio (84:16) but was
slow (15% conversion). Toluene was found to give a
faster reaction and addition of PhMgBr occurred read-
ily at −45°C to give complete conversion in less than 4
h with good diastereofacial selectivity (d.r.=88:12). The
presence of AlMe3 as a Lewis acid additive to promote
the reaction gave a small improvement in diastereo-
selectivity but the reaction was much slower.
2.4. Effects of steric and electronic nature of reagent
The optimised reaction conditions were applied to dif-
ferent aryl Grignard reagents (Table 4). It was found
that aryl Grignard reagents with electron-withdrawing
or electron-donating groups could be added to aldimine
3a in high yield and high diastereomeric ratio giving the
same diastereomer in excess. 4-Fluorophenylmagnesium
bromide reacted more slowly and gave a lower yield,
whilst the sterically hindered mesityl Grignard reagent
gave a good yield but reacted with slightly lower
diastereoselectivity.
An interesting switchover in diastereoselectivity was
observed for the addition of PhMgBr compared to
PhLi.
2.3. Diastereoselective addition to N-tert-butane-
sulfinimines
2.5. Mechanism and stereochemistry
The most important results are shown in Table 3. Two
sets of conditions were used for the diastereoselective
addition of organometallic reagents to aldimines 3b–g
Switchover of diastereofacial selectivity in the addition
was observed between PhMgBr and PhLi in all cases
except 3f (Table 3). A similar switchover was observed

N. Plobeck, D. Powell / Tetrahedron: Asymmetry 13 (2002) 303–310
Table 2. Effect of solvent on diastereomeric ratio and % conversiona
305
M
Solvent
Temperature (°C)
3c to 4c % conversionb
D.r.c
Li
Li
MgBr
MgBr
MgBr
MgBr
THF
Toluene
THF
CH2Cl2
Toluene
Toluene+1.1 equiv. AlMe3
−78
85 (78)
75
B5
15
100 (86)
20
27:73
39:61
−78 to +25
−78 to +25
−78 to +25
−78 to −45
−78 to +25
84:16
88:12
91:9
a Addition of 1.8 M PhLi in cyclohexane/Et2O or 3 M PhMgBr in Et2O to 0.04 M 3c in solvent.
b As determined by 1H NMR, numbers in parenthesis indicate isolated yield after purification.
c Determined by chiral HPLC of the unpurified 5c HCl salt.
Table 3. Addition of organometallic reagents to N-tert-butanesulfinimines 3b–g
Aldimine 3
R
M
Sulfinylamide 4
Amine 5
Absolute config.
Yield (%)a
D.r.b
Yield (%)
b
c
d
e
f
1-Naphthyl
4-Cl-Phenyl
4-Br-Phenyl
4-CF3-Phenyl
4-Me2N-Phenyl
3-Furanyl
MgBr
Li
MgBr
Li
MgBr
Li
MgBr
Li
MgBr
Li
MgBr
Li
88 (62)c
84
86
78
89
85
85
92
N.r.
64
86:14 (99.5:0.5)c
Sd
Rd
Sd
Rd
Sd
Rd
Se
Re
–
94
94
97
94
80
88
71
75
–
8:92
88:12
27:73
85:15
13:87
80:20
8:92
–
:50:50f
97:3
–
–
81
74
g
76
64
Se
Re
29:71
a Yields represent isolated yields after purification.
b Determined by chiral HPLC of the unpurified amine·HCl.
c After two recrystallizations from EtOAc:hexanes.
d Determined by comparison of the sign of optical rotation with known lit. compounds.
e Determined by analogy with results in entry b, c and d.
f Based on isolated yield of diastereomers.
in the related addition of ester enolates to chiral
toluenesulfinimines8 and also in some cases for addition
to tert-butanesulfinimines.6 In those cases the stereo-
selectivity of addition was explained by proposing a
six-membered chelating transition state model in the
case of the magnesium reagent addition and a non-
chelation model for lithium reagent addition where
steric hindrance factors determine the selectivity. In the
three cases in our series where the absolute configura-
tions of the product diarylmethylamines are known
(5b–d), the observed stereoselectivity was the same as
predicted by these models. For example, addition of
phenyllithium and phenylmagnesium bromide to 3c
gave (R)-5c and (S)-5c, respectively (Scheme 2).

306
N. Plobeck, D. Powell / Tetrahedron: Asymmetry 13 (2002) 303–310
Table 4. Grignard additions to N-tert-butanesulfinyl aldimine 3a
Compound
R
Sulfinylamide 4
D.r.a
Amine 5
Yield (%)
Yield (%)
c
i
j
k
l
4-Cl
89
85
92
49
76
93:7
88:12
91:9
94
87
98
87
90
4-Me
4-MeO
4-F
92:8
2,4,6-Me
73:27b
a Determined by chiral HPLC of the unpurified amine·HCl.
b Determined by 1H NMR analysis of the (R)-MPA amide.
Scheme 2.
3. Conclusion
tiomer of the stoichiometric chiral auxiliary to access
both enantiomers of the diarylmethylamine products
The practical and versatile asymmetric synthesis of
diarylmethylamines reported here utilizes N-tert-
butanesulfinimines 3, which are easily accessible in
large scale and high yield. Diastereoselective addition
of organomagnesium or organolithium reagents
to these N-tert-butanesulfinimines gives either
diastereomer of N-tert-butanesulfinamides 4 in excess
and in high yield by choice of reagent and solvent.
The diastereomeric N-tert-butanesulfinamides can in
some cases be further purified by chromatography or
recrystallization to give enantiomerically pure diaryl-
methylamines after cleavage of the chiral auxiliary.
The mild and rapid cleavage of the chiral auxiliary
allows the recovery of the diarylmethylamines in
high yield. The method thus requires only one enan-
5.
4. Experimental
4.1. Materials and methods
Purification by flash chromatography was carried out on
silica gel 60 (70–230 mesh), eluting with gradients of
EtOAc in hexane. Melting points were recorded on a
Bu¨chi 535 melting point apparatus and are uncorrected.
1Hand13CNMRspectrawererecordedonaVarianUnity
Plus 400 MHz spectrometer. Spectra were recorded in
CDCl3 or CD3OD and chemical shifts are given in ppm
relative to TMS. IR spectra were recorded on a Perkin–

N. Plobeck, D. Powell / Tetrahedron: Asymmetry 13 (2002) 303–310
307
Elmer Paragon 1000 FT-IR spectrometer. Dry solvents
with molecular sieves were obtained from Fluka.
4.3.4.
(R)-(−)-2-Methyl-N-[(1E)-[4-(trifluoromethyl)-
phenyl]methylene]-2-propanesulfinamide, 3e. Obtained in
53% yield as a yellow oil. IR (film)  2964, 1607, 1574,
1324, 1169, 1131, 1088 cm−1. 1H NMR (400 MHz,
CDCl3) l 8.64 (1H, s), 7.98 (2H, d, J=7.9 Hz), 7.74
(2H, d, J=7.9 Hz), 1.28 (9H, s). 13C NMR (100 MHz,
CDCl3) l 161.46, 136.83, 133.83, 133.52, 129.51, 125.95,
125.92, 124.97, 58.13, 22.59. HRMS calcd for
C12H15NSOF3 (M+H), 278.0826; found 278.0815 (4.0
ppm).
4.2. Accurate mass determination by time-of-flight mass
spectrometer
Time-of-flight mass spectrometer (LCT, Micromass
Inc. England) and HPLC (HP1100, Hewlett Packard)
were used for the accurate mass determination with
instrument parameters of: ion mode: electrospray; de-
solvation temp.: 350°C; source temp.: 130°C; sample
cone voltage: 30 V. Acquisition was carried out in the
mass range 100–1000 Da, one spectrum per second at
5000 resolution. The sample was introduced into LCT
mass spectrometer in loop injection mode with a HPLC
flow of 0.4 mL/min. The mobile phase consisted of 50%
water and 50% acetonitrile. Leucine-enkephalin (lock
mass 556.2771 Da) was used as the reference standard
(Sigma Ref. L-9133, 1 mg/mL in water). The sample
was prepared with the analyte compound and the refer-
ence standard in methanol each 0.5 mg/mL. One micro-
liter of the sample solution was injected into the LCT.
The mass calibration was performed with polyethylene
glycol (PEG) according to the LCT operator’s manual.
4.3.5.
(R)-(−)-N-[(1E)-[4-(Dimethylamino)phenyl]-
methylene]-2-methyl-2-propanesulfinamide, 3f. Obtained
in 94% yield as a light yellow solid, mp=81–83°C. IR
(KBr)  1610, 1583, 1548, 1362, 1179, 1083 cm−1. H
1
NMR (400 MHz, CDCl3) l 8.43 (1H, s), 7.72 (2H, d,
J=8.9 Hz), 6.69 (2H, d, J=8.9 Hz), 3.05 (6H, s), 1.24
(9H, s). 13C NMR (100 MHz, CDCl3) l 161.59, 152.96,
131.15, 122.31, 111.28, 57.25, 40.00, 22.43. HRMS
calcd for C13H21N2SO (M+H), 253.1374; found
253.1362 (4.7 ppm).
4.3.6. (R)-(−)-N-[(1E)-3-Furanylmethylene]-2-methyl-2-
propanesulfinamide, 3g. Obtained in 88% yield as a
white solid, mp=115–116°C. IR (KBr)  3111, 1609,
1147, 1070 cm−1. H NMR (400 MHz, CDCl3) l 8.55
1
4.3. Synthesis of N-tert-butanesulfinyl aldminines
(1H, s), 7.91 (1H, s), 7.49 (1H, s), 6.83 (1H, s), 1.24
(9H, s). 13C NMR (100 MHz, CDCl3) l 154.41, 147.65,
144.64, 124.26, 107.82, 57.43, 22.45. HRMS calcd for
C9H14NO2S (M+H), 200.0745; found 200.0737 (4.0
ppm).
The preparation of compounds 3a and 3g is described
in a published procedure. Compounds 3b–f were pre-
pared analogously.7
4.4. General procedure for the addition of Grignard
4.3.1. (R)-(−)-2-Methyl-N-[(1E)-1-naphthalenylmethyl-
ene]-2-propanesulfinamide, 3b. Obtained in 99% yield as
a yellow solid, mp=52–54°C. IR (KBr)  3054, 2965,
1579, 1512, 1364, 1178, 1073 cm−1. 1H NMR (400
MHz, CDCl3) l 9.16 (1H, s), 9.02 (1H, d, J=8.4 Hz),
8.04 (1H, d, J=6.5 Hz), 8.00 (1H, d, J=8.4 Hz), 7.91
(1H, d, J=7.4 Hz), 7.66–7.55 (3H, m), 1.33 (9H, s). 13C
NMR (100 MHz, CDCl3) l 162.44, 133.83, 133.24,
131.95, 131.16, 129.33, 128.79, 127.98, 126.44, 125.18,
124.31, 57.62, 22.58. HRMS calcd for C15H18NSO (M+
H), 260.1109; found 260.1101 (3.1 ppm).
reagents to N-tert-butanesulfinyl aldimines
A solution of the N-tert-butanesulfinyl aldimine 3 (0.2
mmol) in dry toluene (5 mL) at −45°C was treated with
dropwise addition of Grignard reagent (0.4 mmol). The
reaction mixture was stirred at −45°C for 4 h then
quenched with sat. aq. NH4Cl. Aqueous workup and
concentration followed by column chromatography
through silica gel gave the purified compound. The
diastereomeric ratio was determined by HPLC analysis
of the unpurified amine·HCl formed after cleavage of
the sulfinyl group (Chiracel AD column, 97:3:0.1 hex-
anes/EtOH/DEA; 1.0 mL/min; 254 nm).
4.3.2.
(R)-(−)-N-[(1E)-(4-Chlorophenyl)methylene]-2-
methyl-2-propanesulfinamide, 3c. Obtained in 99% yield
as a white solid, mp=41–42°C. IR (KBr)  2957, 1592,
1566, 1488, 1404, 1363, 1090 cm−1. 1H NMR (400
MHz, CDCl3) l 8.55 (1H, s), 7.79 (2H, d, J=8.9 Hz),
7.45 (2H, d, J=8.9 Hz), 1.27 (9H, s). 13C NMR (100
MHz, CDCl3) l 161.42, 138.57, 132.46, 130.47, 129.28,
57.85, 22.56. HRMS calcd for C11H15NSOCl (M+H),
244.0563; found 244.0553 (4.1 ppm).
Compounds in Table 3.
4.4.1.
(R)-2-Methyl-N-[(S)-1-naphthalenylphenyl-
methyl]-2-propanesulfinamide, 4b. This reaction was car-
ried out on a 2 mmol scale. Obtained in 88% yield as a
white solid, mp=134–135°C. Recrystallization from
EtOAc:hexanes
provided
the
product
in
a
diastereomeric ratio of 98:2 with 74% yield. A second
recrystallization gave a d.r. of >99.5:0.5 and 62% yield.
The diastereomeric ratio as determined by chiral HPLC
was in agreement with that obtained by 1H NMR
analysis of the crude reaction mixture. IR (KBr)  3208,
4.3.3.
(R)-(−)-N-[(1E)-(4-Bromophenyl)methylene]-2-
methyl-2-propanesulfinamide, 3d. Obtained in 82% yield
as a yellow oil. IR (film)  3455, 1608, 1587, 1364, 1085
cm−1. H NMR (400 MHz, CDCl3) l 8.53 (1H, s), 7.72
1
1
2959, 1598, 1493, 1454, 1061, 923 cm−1. H NMR (400
(2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz), 1.25 (9H,
s). 13C NMR (100 MHz, CDCl3) l 161.59, 132.87,
132.26, 130.62, 127.20, 57.89, 22.58. HRMS calcd for
C11H15NSOBr (M+H), 288.0057; found 288.0051 (2.1
ppm).
MHz, CDCl3) l 8.00–7.22 (12H, m), 6.45 (1H, d,
J=2.8 Hz), 3.78 (1H, d, J=2.8 Hz), 1.26 (9H, s). 13C
NMR (100 MHz, CDCl3) l 141.98, 136.59, 133.90,
130.97, 128.82, 128.77, 127.88, 127.80, 126.20, 125.60,

308
N. Plobeck, D. Powell / Tetrahedron: Asymmetry 13 (2002) 303–310
125.11, 123.62, 58.90, 55.99, 22.69. HRMS calcd for
C21H24NSO (M+H), 338.1578; found, 338.1584 (−1.8
ppm).
MHz, CDCl3) l 7.41–7.10 (9H, m), 5.61 (1H, d, J=2.8
Hz), 3.68 (1H, d, J=2.8 Hz), 2.30 (3H, s), 1.25 (9H, s).
13C NMR (100 MHz, CDCl3) l 141.39, 139.75, 137.51,
129.47, 128.49, 127.79, 127.52, 127.11, 61.84, 55.77,
22.64, 21.00. HRMS calcd for C18H24NSO (M+H),
302.1578; found 302.1575 (1.0 ppm).
4.4.2.
(R)-N-[(S)-(4-Chlorophenyl)phenylmethyl]-2-
methyl-2-propanesulfinamide, 4c. Obtained in 86% yield
as an off-white solid, mp=136–139°C. IR (KBr) 
3443, 3212, 1601, 1490, 1454, 1364, 1059 cm−1. 1H
NMR (400 MHz, CDCl3) l 7.37–7.26 (9H, m), 5.61
(1H, d, J=2.8 Hz), 3.71 (1H, d, J=2.8 Hz), 1.26 (9H,
s). 13C NMR (100 MHz, CDCl3) l 142.13, 129.75,
133.46, 129.23, 128.97, 128.77, 128.03, 127.10, 61.39,
55.89, 22.64. HRMS calcd for C17H21NSOCl (M+H),
321.1032; found 322.1019 (4.0 ppm).
4.4.8.
(R)-N-[(R)-(4-Methoxyphenyl)phenylmethyl]-2-
methyl-2-propanesulfinamide, 4j. The diastereomeric
ratio as determined by chiral HPLC was in agreement
with that obtained from 1H NMR analysis of the
(R)-a-methoxyphenylacetic amide.9 Obtained in 92%
yield as a slight yellow oil. IR (film)  3444, 2958, 1511,
1
1455, 1252, 1057 cm−1. H NMR (400 MHz, CDCl3) l
7.41–7.27 (7H, m), 6.84 (2H, d, J=8.4 Hz), 5.60 (1H,
s), 3.76 (3H, s), 3.65 (1H, s), 1.25 (9H, s). 13C NMR
(100 MHz, CDCl3) l 159.06, 141.51, 134.85, 128.47,
127.51, 114.13, 61.57, 55.79, 55.21, 22.66. HRMS calcd
for C18H24NSO2 (M+H), 318.1528; found 318.1515 (4.1
ppm).
4.4.3.
(R)-N-[(S)-(4-Bromophenyl)phenylmethyl]-2-
methyl-2-propanesulfinamide, 4d. Obtained in 89% yield
as a white crystalline solid, mp=136–137°C. IR (KBr)
 3305, 3081, 2955, 1485, 1455, 1400, 1068, 1008 cm−1.
1H NMR (400 MHz, CDCl3) l 7.50–7.27 (9H, m), 5.60
(1H, d, J=2.8 Hz), 3.73 (1H, bs), 1.25 (9H, s). 13C
NMR (100 MHz, CDCl3) l 143.14, 141.40, 132.81,
130.68, 130.08, 129.14, 128.19, 122.70, 62.54, 57.00,
23.74.
4.4.9.
(R)-N-[(R)-(4-Fluorophenyl)phenylmethyl]-2-
methyl-2-propanesulfinamide, 4k. Obtained in 49% yield
as an off-white solid, mp=64–65°C. IR (KBr)  3448,
3202, 2960, 1603, 1509, 1455, 1223, 1059 cm−1. 1H
NMR (400 MHz, CDCl3) l 7.40–7.26 (5H, m), 7.03–
6.98 (2H, m), 5.63 (1H, d, J=2.8 Hz), 3.67 (1H, d,
J=2.8 Hz), 1.26 (9H, s). 13C NMR (100 MHz, CDCl3)
l 163.39, 160.95, 141.05, 138.44, 129.01, 128.93, 128.64,
127.74, 115.82, 115.61, 61.56, 55.90, 22.64. HRMS
calcd for C17H21NSOF (M+H), 306.1328; found
206.1319 (2.9 ppm).
4.4.4. (R)-2-Methyl-N-[(S)-phenyl[4-(trifluoromethyl)-
phenyl]methyl]-2-propanesulfinamide, 4e. Obtained in
85% yield as a yellow oil. IR (neat)  3192, 2961, 1619,
1455, 1418, 1326, 1125, 1068 cm−1. 1H NMR (400
MHz, CDCl3) l 7.60–7.55 (4H, m), 7.36–7.25 (5H, m),
5.70 (1H, s), 3.76 (1H, s), 1.26 (9H, s). 13C NMR (100
MHz, CDCl3) l 145.29, 141.74, 129.08, 128.80, 128.23,
128.16, 127.82, 127.64, 127.18, 125.56, 61.62, 56.03,
22.63.
4.4.5. (R)-2-N-[(S)-(3-Furanyl)phenylmethyl]-2-methyl-
2-propanesulfinamide, 4g. Obtained in 76% yield as a
light yellow oil. IR (neat)  3196, 2978, 1503, 1474,
1455, 1364, 1157, 1058 cm−1. 1H NMR (400 MHz,
CDCl3) l 7.40–7.28 (7H, m), 6.33 (1H, d, J=1.8 Hz),
5.56 (1H, d, J=2.8 Hz), 3.66 (1H, d, J=2.8 Hz), 1.24
(9H, s). 13C NMR (100 MHz, CDCl3) l 143.46, 141.80,
140.51, 128.77, 127.95, 127.15, 126.34, 109.64, 55.72,
54.61, 22.58. HRMS calcd for C15H20NO2S (M+H),
278.1215; found 278.1216 (−0.4 ppm).
4.4.10.
(R)-2-Methyl-N-[(R)-phenyl(2,4,6-trimethyl-
phenyl)methyl]-2-propanesulfinamide 4l. The diastereo-
1
meric ratio was determined by H NMR analysis of the
(R)-a-methoxyphenylacetamide derivative. Obtained in
76% yield as a slight yellow solid, mp=60–63°C. IR
(KBr)  3252, 2958, 1611, 1493, 1450, 1363, 1074 cm−1.
1H NMR (400 MHz, CDCl3) l 7.35–7.18 (5H, m), 6.84
(2H, s), 6.09 (1H, d, J=5.1 Hz), 3.69 (1H, d, J=5.1
Hz), 2.25 (9H, s), 1.32 (9H, s). 13C NMR (100 MHz,
CDCl3) l 142.23, 137.33, 136.41, 136.21, 130.24, 128.15,
126.47, 126.28, 56.54, 22.82, 20.95. HRMS calcd for
C20H28NSO (M+H), 330.1891; found 330.1881 (3.0
ppm).
Compounds in Table 4.
4.4.6.
(R)-N-[(R)-(4-Chlorophenyl)phenylmethyl]-2-
methyl-2-propanesulfinamide, 4c. Obtained in 89% yield
as an off-white solid, mp=65–68°C. IR (KBr)  3446,
3194, 2959, 1490, 1455, 1364, 1089, 1060 cm−1. 1H
NMR (400 MHz, CDCl3) l 7.38–7.26 (9H, m), 5.61
(1H, d, J=2.8 Hz), 3.69 (1H, d, J=2.8 Hz), 1.25 (9H,
s). 13C NMR (100 MHz, CDCl3) l 141.10, 140.78,
133.60, 128.98, 128.67, 128.64, 127.85, 127.74, 61.61,
55.94, 22.61. HRMS calcd for C17H21NSOCl (M+H),
321.1032; found 322.1020 (3.7 ppm).
4.5. General procedure for the addition of lithium
reagents to N-tert-butanesulfinyl aldimines
A solution of the N-tert-butanesulfinyl aldimine 3 (0.2
mmol) in dry THF (5 mL) at −78°C was treated with
dropwise addition of the organolithium reagent (0.4
mmol). The reaction mixture was stirred at −78°C for 4
h then quenched with sat. aq. NH4Cl. Aqueous workup
and concentration followed by column chromatography
through silica gel gave the purified compound. The
diastereomeric ratio was determined by HPLC analysis
of the unpurified amine hydrochloride formed after
cleavage of the sulfinyl group (Chiracel AD column,
97:3:0.1 hexanes/EtOH/DEA; 1.0 mL/min; 215 nm).
4.4.7.
(R)-2-Methyl-N-[(R)-(4-methylphenyl)phenyl-
methyl]-2-propanesulfinamide, 4i. Obtained in 85% yield
as a off-white solid, mp=59–61°C. IR (KBr)  3442,
2958, 1636, 1513, 1364, 1179, 1060 cm−1. H NMR (400
1

N. Plobeck, D. Powell / Tetrahedron: Asymmetry 13 (2002) 303–310
309
4.5.1.
(R)-2-Methyl-N-[(R)-1-naphthalenylphenyl-
room temperature for 1 h. The mixture was concen-
trated to dryness and precipitated with diethyl ether.
The precipitate was collected by filtration and washed
with diethyl ether to give the amine hydrochloride of
sufficient purity such that no other purification was
required.
methyl]-2-propanesulfinamide, 4b. Obtained in 84% yield
as a light yellow oil. IR (film)  3441, 3205, 2959, 1510,
1474, 1455, 1364, 1058 cm−1. 1H NMR (400 MHz,
CDCl3) l 8.32 (1H, d, J=8.4 Hz), 7.85 (1H, d, J=7.4
Hz), 7.79 (1H, dd, J=6.5 Hz, 2.8 Hz), 7.58–7.24 (9H, m),
6.45 (1H, d, J=2.8 Hz), 3.91 (1H, d, J=2.8 Hz), 1.23
(9H, s). 13C NMR (100 MHz, CDCl3) l 140.62, 137.57,
133.93, 130.49, 128.87, 128.65, 128.62, 128.47, 126.83,
125.87, 125.60, 125.23, 123.15, 57.61, 55.87, 22.61.
4.6.1. (a1S)-a-Phenyl-1-naphthalenemethanamine, 5b.
Obtained in 94% yield as a white solid, mp=245–250°C
(dec.). IR (KBr)  3384, 2854, 2361, 1600, 1510, 1452
1
cm−1. H NMR (400 MHz, CD3OD) l 8.00–7.96 (3H,
m), 7.70–7.64 (2H, m), 7.52–7.41 (7H, m), 6.45 (1H, s),
4.90 (5H, bs). 13C NMR (100 MHz, CD3OD) l 138.32,
135.54, 133.55, 131.37, 130.72, 130.34, 130.11, 129.19,
128.10, 127.44, 126.16, 124.42, 124.13, 56.00. [h]2D3=
+0.22 (c 0.9, MeOH). The amine hydrochloride was
converted to the free amine by treatment with sodium
carbonate. [h]D23=−17.8 (c 0.6, CHCl3). (lit.10 [h]D23=
+43.6 (c 1.0, CHCl3 for (R)).
4.5.2.
(R)-N-[(R)-(4-Chlorophenyl)phenylmethyl]-2-
methyl-2-propanesulfinamide, 4c. Obtained in 78% yield
as an off-white solid, mp=77–80°C.
4.5.3.
(R)-N-[(R)-(4-Bromophenyl)phenylmethyl]-2-
methyl-2-propanesulfinamide, 4d. Obtained in 85% yield
as a white solid, mp=96–98°C. IR (KBr)  3442, 2959,
1634, 1486, 1403, 1364, 1058 cm−1. 1H NMR (400
MHz, CDCl3) l 7.45–7.24 (9H, m), 5.59 (1H, d, J=2.8
Hz), 3.71 (1H, d, J=2.8 Hz), 1.25 (9H, s). 13C NMR
(100 MHz, CDCl3) l 141.60, 140.69, 131.90, 128.95,
128.65, 127.83, 127.72, 121.72, 61.64, 55.92, 22.59.
4.6.2. (a1R)-a-Phenyl-1-naphthalenemethanamine, 5b.
Obtained in 94% yield as a white solid. [h]2D3=−0.20 (c
1.1, MeOH).
4.6.3. (a1R)-4-Chloro-a-phenyl-benzenemethanamine, 5c.
Obtained in 94% yield as a white solid, mp=267–
4.5.4. (R)-2-Methyl-N-[(R)-phenyl[4-(trifluoromethyl)-
phenyl]methyl]-2-propanesulfinamide, 4e. Obtained in
92% yield as a yellow oil. IR (neat)  3191, 1619, 1474,
1455, 1325, 1165, 1068 cm−1. 1H NMR (400 MHz,
CDCl3) l 7.59–7.28 (9H, m), 5.69 (1H, s), 3.79 (1H, s),
1.26 (9H, s). 13C NMR (100 MHz, CDCl3) l 146.42,
140.39, 130.11, 129.80, 129.47, 128.77, 128.02, 127.79,
127.61, 125.79, 125.23, 61.90, 56.02, 22.58.
1
270°C. H NMR (400 MHz, CD3OD) l 7.48–7.41 (9H,
m), 5.87 (1H, s), 4.89 (3H, bs). 13C NMR (100 MHz,
CD3OD) l 138.13, 137.34, 136.01, 130.16, 128.32,
58.67. [h]2D3=−0.33 (c 1.0, MeOH). The amine hydro-
chloride was converted to the free amine by treatment
with sodium carbonate. [h]2D3=−1.0 (c 1.0, EtOH). (lit.5
[h]2D3=+10.8 (c 2.18, EtOH for (S)).
4.5.5. (R)-N-[[4-(Dimethylamino)phenyl]phenylmethyl]-2-
methyl-2-propanesulfinamide, 4f. First diastereomer:
4.6.4. (a1S)-4-Chloro-a-phenyl-benzenemethanamine, 5c.
Obtained in 97% yield as a white solid. [h]2D3=+0.30 (c
1.0, MeOH).
1
obtained in 30% yield as a yellow solid. H NMR (400
MHz, CDCl3) l 7.39–7.22 (7H, m), 6.68 (2H, d, J=9.3
Hz), 5.55 (1H, d, J=2.8 Hz), 3.69 (1H, d, J=2.8 Hz),
2.93 (6H, s), 1.25 (9H, s). Second diastereomer:
obtained in 34% yield as a yellow solid. IR (KBr) 
3215, 2956, 1614, 1522, 1060 cm−1. 1H NMR (400
MHz, CDCl3) l 7.43–7.19 (7H, m), 6.65 (2H, d, J=8.4
Hz), 5.57 (1H, d, J=2.8 Hz), 3.63 (1H, d, J=2.8 Hz),
2.90 (6H, s), 1.25 (9H, s). 13C NMR (100 MHz, CDCl3)
l 150.01, 141.87, 130.42, 128.39, 128.20, 127.75, 127.29,
112.51, 61.54, 55.71, 40.44, 22.69.
4.6.5. (a1S)-4-Bromo-a-phenyl-benzenemethanamine, 5d.
1
Obtained in 80% yield as a white solid. H NMR (400
MHz, CD3OD) l 7.63–7.61 (2H, m), 7.47–7.36 (7H, m),
5.68 (1H, s), 4.90 (3H, bs). [h]2D3=+1.2 (c 1.0, MeOH).
(lit.4 [h]2D3=+2.3 (c 1.0, MeOH for (S)).
4.6.6. (a1R)-4-Bromo-a-phenyl-benzenemethanamine, 5d.
Obtained in 88% yield as a white solid. [h]2D3=−1.3 (c
1.0, MeOH). (lit.4 [h]D23=+2.3 (c 1.0, MeOH for (S)).
4.6.7. (a1R)-a-Phenyl-4-(trifluoromethyl)-benzenemethan-
4.5.6. (R)-2-N-[(R)-(3-Furanyl)phenylmethyl]-2-methyl-
2-propanesulfinamide, 4g. Obtained in 64% yield as a
light yellow oil. IR (neat)  3201, 2959, 1501, 1455,
1
amine, 5e. Obtained in 71% yield as a white solid. H
NMR (400 MHz, CD3OD) l 7.77 (2H, d, J=7.9 Hz),
7.65 (2H, d, J=7.9 Hz), 7.48–7.44 (5H, m), 5.81 (1H,
s), 4.90 (3H, bs). [h]2D3=+0.81 (c 1.0, MeOH).
1
1364, 1158, 1060 cm−1. H NMR (400 MHz, CDCl3) l
7.41–7.26 (7H, m), 6.39 (1H, s), 5.45 (1H, d, J=3.2
Hz), 3.65 (1H, d, J=3.2 Hz), 1.23 (9H, s). 13C NMR
(100 MHz, CDCl3) l 143.64, 140.87, 140.08, 128.51,
127.79, 127.60, 127.18, 109.52, 55.03, 54.64, 22.53.
HRMS calcd for C15H20NO2S (M+H), 278.1215; found
278.1203 (4.3 ppm).
4.6.8. (a1R)-a-Phenyl-4-(trifluoromethyl)-benzenemethan-
amine, 5e. Obtained in 75% yield as a white solid.
[h]2D3=−0.65 (c 1.1, MeOH).
4.6.9. (a3R)-a-Phenyl-3-furanmethanamine, 5g. Obtained
1
4.6. General procedure for the cleavage of the sulfinyl
chiral auxiliary
in 81% yield as a white solid. H NMR (400 MHz,
CD3OD) l 7.59–7.43 (7H, m), 6.52 (1H, s), 5.59 (1H, s),
4.90 (3H, bs). 13C NMR (100 MHz, CD3OD) l 145.82,
142.47, 137.90, 130.33, 128.37, 124.23, 110.19, 52.23.
[h]2D3=−0.42 (c 2.0, MeOH).
Compound 4 (0.12 mmol) was treated with a 1:1 mix-
ture of MeOH and 4.0 M HCl in dioxane (2 mL) at

310
N. Plobeck, D. Powell / Tetrahedron: Asymmetry 13 (2002) 303–310
4.6.10.
(a3R)-a-Phenyl-3-furanmethanamine,
5g.
Acknowledgements
Obtained in 74% yield as a white solid. [h]2D3=+0.17 (c
1.3, MeOH).
We thank Dr. William Brown and Dr. Christopher
Walpole for valuable discussions and support and Mr.
Edward Zhou for accurate mass determinations.
4.6.11. (a1R)-4-Methyl-a-phenyl-benzenemethanamine,
5i. Obtained in 87% yield as a white solid, mp=256–
259°C (dec.). H NMR (400 MHz, CD3OD) l 7.47–
7.39 (5H, m), 7.31–7.25 (4H, m), 5.60 (1H, s), 4.88 (3H,
bs), 2.35 (3H, s). 13C NMR (100 MHz, CD3OD) l
140.21, 138.72, 135.59, 130.83, 130.24, 129.95, 128.32,
59.20, 21.10. [h]2D3=−0.16 (c 1.0, EtOH).
1
References
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4.6.12. (a1R)-4-Methoxy-a-phenyl-benzenemethanamine,
5j. Obtained in 98% yield as a white solid, mp=214–
215°C (dec.). H NMR (400 MHz, CD3OD) l 7.47–
7.40 (5H, m), 7.33 (2H, d, J=9.3 Hz), 6.99 (2H, d,
J=9.3 Hz), 5.60 (1H, s), 4.88 (3H, s), 3.80 (3H, bs). 13C
NMR (100 MHz, CD3OD) l 161.62, 138.80, 130.42,
130.23, 129.90, 128.14, 115.55, 58.95, 55.85. [h]2D3=
+0.28 (c 1.5, MeOH).
1
4.6.13.
(a1R)-4-Fluoro-a-phenyl-benzenemethanamine,
1
5k. Obtained in 87% yield as a white solid. H NMR
(400 MHz, CD3OD) l 7.48–7.42 (7H, m), 7.22–7.18
(2H, m), 5.69 (1H, s), 4.89 (3H, bs). 13C NMR (100
MHz, CD3OD) l 165.52, 163.06, 138.37, 134.70,
130.78, 130.70, 130.37, 130.11, 128.23, 117.19, 116.97,
58.66. [h]2D3=+0.1 (c 0.8, MeOH).
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8883–8904 and references cited therein.
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J. A. J. Org. Chem. 1999, 64, 1278–1284.
4.6.14. (a1R)-2,4,6-Trimethyl-a-phenyl-benzenemethan-
amine, 5l. Obtained in 90% yield as a white solid. H
NMR (400 MHz, CD3OD) l 7.42–7.37 (3H, m), 7.20
(2H, d, J=7.4 Hz), 7.00 (2H, s), 6.06 (1H, s), 4.89 (3H,
bs). 13C NMR (100 MHz, CD3OD) l 140.54, 138.54,
137.80, 131.73, 131.34, 130.18, 129.28, 126.82, 54.08,
20.97, 20.87. [h]2D3=+0.41 (c 1.5, MeOH).
1
8. Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron
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