Asymmetric addition of phenylzinc reagents to C-alkynyl nitrones. Enantiomeric enhancement by a product-like additive

Article abstract of DOI:10.1016/j.tetasy.2008.01.029

Asymmetric addition of diphenylzinc to C-alkynyl nitrones was achieved by utilizing di(t-butyl) (R,R)-tartrate as a chiral auxiliary to afford the corresponding optically active (S)-N-(1-phenyl-3-substituted prop-2-ynyl)hydroxylamines. By the addition of a product-like additive, enantiomeric enhancement was observed. A mixed zinc reagent, PhZnMe, improved the enantioselection to afford hydroxylamines in up to 92% ee.

Full text of DOI:10.1016/j.tetasy.2008.01.029

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 476–481
Asymmetric addition of phenylzinc reagents to C-alkynyl nitrones.
Enantiomeric enhancement by a product-like additive
Weilin Wei, Yoshihira Hamamoto, Yutaka Ukaji* and Katsuhiko Inomata*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa, Ishikawa 920-1192, Japan
Received 6 December 2007; accepted 17 January 2008
Abstract—Asymmetric addition of diphenylzinc to C-alkynyl nitrones was achieved by utilizing di(t-butyl) (R,R)-tartrate as a chiral aux-
iliary to afford the corresponding optically active (S)-N-(1-phenyl-3-substituted prop-2-ynyl)hydroxylamines. By the addition of a prod-
uct-like additive, enantiomeric enhancement was observed. A mixed zinc reagent, PhZnMe, improved the enantioselection to afford
hydroxylamines in up to 92% ee.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chiral amines are synthetically important target com-
pounds, since they can be found in natural products, phar-
maceuticals, and other bioactive molecules.1 For example,
chiral benzylic amines are found in such biologically active
compounds and their building blocks.2 One of the most
attractive approaches to the syntheses of benzylic amines
is the enantioselective addition of phenylmetal reagents to
imine derivatives.3,4 Although various methods for the
enantioselective synthesis of chiral benzylic amines are
known, including the reduction and alkylation of aromatic
imines, the direct asymmetric addition of phenyl reagents
to a C@N bond is still one of the more challenging prob-
lems, especially in terms of the availability of chiral auxil-
iaries. Very recently, we reported an enantioselective
nucleophilic addition of alkynylzinc reagents to nitrones
by utilizing a tartaric acid ester as a chiral auxiliary and
unprecedented enantiomeric enhancement by a racemic
product-like additive was realized.5 Herein, we report an
enantioselective addition of phenylzinc reagents to acyclic
nitrones bearing an alkynyl substituent on the carbon
by utilizing the tartaric acid ester as a chiral auxiliary to
produce N-(1-phenyl-3-substituted prop-2-ynyl)hydroxyl-
amines. The enantiomeric enhancement by the addition
of a product-like additive was again observed.
An asymmetric addition reaction of diphenylzinc to N-
benzyl C-alkynyl nitrone 2a was first examined (Table 1).
To a solution of 1.0 equiv of bis(methylzinc) salt of di(t-bu-
tyl) (R,R)-tartrate 1, prepared in situ from 1.0 equiv of di-
(t-butyl) (R,R)-tartrate [(R,R)-DTBT] and 2.0 equiv of
dimethylzinc in CH2Cl2, diphenylzinc (X = Ph) and nitrone
2a were successively added at 0 °C (Scheme 1, m = 1.0,
n = 0). After the usual workup, the corresponding N-
(propargylic)hydroxylamine 3a was obtained in 53% yield
and with an enantioselectivity of 70% ee (entry 1). The
addition predominantly occurred from the si-face of nit-
rone 2a, and the sense of the enantiofacial differentiation
was the same as that in our previous addition reactions
of alkynylzinc reagents to C-(phenyl-substituted) nitrones.5
When the reaction temperature was increased to 25 °C or
40 °C, the reaction proceeded smoothly to give the desired
product 3a with enantioselectivities of 76% ee and 79% ee,
respectively (entries 2 and 3). Previously, we observed
enantiomeric enhancement by a product-like additive in
the addition of alkynylzinc reagents.5 Thus, the effect of
the addition of a product-like additive 4, prepared in situ
from 0.2 equiv of racemic N-benzyl-N-[1-(4-methoxy-
phenyl)-3-phenylprop-2-ynyl]hydroxylamine and 0.2 equiv
of dimethylzinc, was also investigated in the present reac-
tion at 0 °C, 25 °C and 40 °C, respectively (Scheme 1,
m = 1.0, n = 0.2).5a To our delight, the enantioselectivity
was enhanced remarkably (entries 4–6). When the reaction
was carried out at 25 °C and 40 °C, 3a was obtained with
*
Corresponding authors. Tel.: +81 76 264 5700; fax: +81 76 264 5742
(K.I.); e-mail: inomata@cacheibm.s.kanazawa-u.ac.jp
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.029

W. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 476–481
Table 1. Asymmetric addition of phenylzinc reagents to nitrone 2a
477
Entry
m (equiv)
n (equiv)
X
Solvent
T (°C)
t (h)
Yield (%)
eea (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
0.2
1.0
1.0
0
0
0
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Meb
Meb
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Et2O
Toluene
Benzene
CHCl3
CHCl3
CH2Cl2
CHCl3
0
25
40
0
16
53
68
54
50
65
67
72
67
63
60
34
63
75
75
70
76
79
82
88
88
88
82
81
80
36
56
91
92
0.5
0.5
16
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0
25
40
25
25
25
25
25
25
25
25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0.2
0.2
0.2
1
a Enantiomer ratios were determined by HPLC analysis (Daicel Chiralcel OD-H).
b PhZnMe was prepared in situ from 0.5 equiv of Ph2Zn and 0.5 equiv of Me2Zn.
the corresponding N-(propargylic)hydroxylamines 3 with
high enantioselectivities (Table 2). It was confirmed that
the addition of the product-like additive 4 was effective in
improving the enantioselectivity, as shown in the column
of n = 0.2 in Table 2. Not only in the case of C-(aryl-substi-
tuted alkynyl) nitrones 2a–c, but also in the case of C-(al-
kyl-substituted alkynyl) nitrone 2d, was the enantiomeric
excess remarkably enhanced in the presence of additive 4.
Furthermore, higher enantioselectivities were achieved by
the use of PhZnMe (entries 2 and 8).
Bn
Ar
OZnMe
N
1)
(n eq.)
4
t
Ph
MeZnO
MeZnO
CO2 Bu
Bn
Ph
OH
2) PhZnX (1.0 eq.)
N
t
Bn
O
CO2 Bu
N
3a
3)
(1.0 eq.)
1
Ph
(m + n eq.)
H
(Ar = 4-methoxyphenyl)
2a
Ph
Solvent, T oC, t h
It has now been confirmed that enantiomeric enhancement
occurs in the preparation of 3 by both the phenylation of
C-alkynyl nitrones and the alkynylation of C-aromatic nit-
rones.5 To scope such an intriguing enantiomeric enhance-
ment,7 asymmetric phenylation of a C-alkenyl nitrone 5
was examined next. The addition reaction proved sluggish
to afford the corresponding N-(allylic)hydroxylamine 6
with poor enantioselectivity, however, the enantioselectivi-
ty was also enhanced to 49% ee in the presence of the addi-
tive 4 (Scheme 3).8
Scheme 1.
high enantioselectivity of 88% ee. The effect of the solvent
was also investigated for further optimization at 25 °C. (en-
tries 5, 7–10). Although the enantioselectivity did not
remarkably change depending on the solvent used, higher
yields resulted in CHCl3. When 0.2 equiv of 1 was used,
the enantioselectivity was not satisfactory (entry 11). How-
ever, enantiomeric enhancement was still observed by the
addition of the product-like additive 4 to give 3a with im-
proved enantioselectivity (entry 12). Finally, it was found
that utilization of a mixed zinc species PhZnMe, prepared
in situ from Ph2Zn and Me2Zn,6 achieved the highest
enantioselectivity of 92% ee (entry 14).
3. Conclusion
As described above, the asymmetric addition of phenylzinc
reagents to C-alkynyl nitrones has been developed utilizing
tartaric acid esters as a chiral auxiliary. By the addition of a
product-like substrate, high enantioselectivities were
Asymmetric additions of phenylzinc reagents to several
other nitrones 2 were then performed (Scheme 2) to furnish
Bn
Ar
OZnMe
N
1)
(n eq.)
4
t
Ph
MeZnO
MeZnO
CO2 Bu
Bn
Ph
OH
2) PhZnX (1.0 eq.)
N
t
Bn
O
CO2 Bu
N
3
3)
(1.0 eq.)
R
1
R
(1.0 + n eq.)
H
2
CHCl3, 25 oC, t h
(Ar = 4-methoxyphenyl)
Scheme 2.

478
W. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 476–481
Table 2. Asymmetric addition of phenylzinc reagents to nitrones 2 in the presence of a racemic product-like additive 4
Entry
2
X
t (h)
n = 0.2
n = 0
R
Ph
Yield (%)
ee (%)
Yield (%)
70
ee (%)
64a
1
2
3
4
5
6
7
8
a
b
c
Ph
0.5
1
1
1
1
1
1
1
72
75
75
66
64
70
67
67
88a
92a
87a
87a
90a
90a
82b
87b
Mec
Ph
pCH3C6H4
pBrC6H4
nC6H13
80
68
61
77a
53a
52b
Mec
Ph
Mec
Ph
d
Mec
a Enantiomeric ratio was determined by HPLC analysis (Daicel Chiralcel OD-H).
b Enantiomeric ratio was determined by HPLC analysis (Daicel Chiralcel OJ-H).
c PhZnMe was prepared in situ from 0.5 equiv of Ph2Zn and 0.5 equiv of Me2Zn.
Bn
Ar
OZnMe
N
1)
(n eq.)
4
t
Ph
Bn
OH
MeZnO
MeZnO
CO2 Bu
N
2) Ph2Zn (1.0 eq.)
t
Bn
O
Ph
Ph
CO2 Bu
N
6
3)
(1.0 eq.)
Ph
1
n = 0; 88%, 25% ee
n = 0.2; 76%, 49% ee
H
(1.0 + n eq.)
5
CH2Cl2, 25 oC, 24 h
(Ar = 4-methoxyphenyl)
Scheme 3.
realized. Furthermore, the enantiomeric enhancement by
the addition of N-(propargylic)hydroxylamine derivative
4 was also achieved in the case of C-alkenyl nitrones. Fur-
ther investigation on the present peculiar enantiomeric
enhancement by the product-like additive is currently in
progress in our laboratory.
Gel 60 (No. 9385-5B) and Merck’s Silica Gel 60 PF254 (Art.
107749), respectively.
4.2. Preparation of aldehydes
Phenylpropynal was prepared according to the procedure
described in Ref. 9. Other aldehydes were prepared in a
similar manner.
4. Experimental
4.1. General
4.2.1. Phenylpropynal.9 Obtained as an oil, IR (neat)
3297, 3061, 2856, 2189, 1660, 1489, 1444, 1388, 1261,
1
1174, 1027, 1002, 978, 758, 688 cmꢀ1; H NMR (CDCl3)
d 7.36–7.40 (m, 2H), 7.44–7.49 (m, 1H), 7.52–7.64 (m,
2H), 9.47 (s, 1H, CHO); HRMS (FAB+), found: m/z
131.04970. Calcd for C9H7O: (M++H), 131.05015.
All of the melting points were determined by a micro melt-
ing apparatus (Yamagimoto–Seisakusho) and are uncor-
rected. The 1H NMR spectra were recorded on JEOL
Lambda 400 and JEOL Lambda 300 spectrometers. The
chemical shifts were determined in the d-scale relative to
tetramethylsilane (d 0) as an internal standard. The IR
spectra were measured by JASCO FT/IR-230 spectrome-
ter. The specific optical rotations were recorded on JASCO
DIP-370 spectrometer. CHCl3 was treated with Merck’s
aluminum oxide 90 active basic (0.063–0.200 mm, activity
4.2.2. p-Tolylpropynal. Obtained as an oil, IR (neat) 3295,
3033, 2922, 2856, 2185, 1657, 1605, 1508, 1448, 1408, 1385,
1
1266, 1180, 1020, 982, 817, 711 cmꢀ1; H NMR (CDCl3) d
2.39 (s, 3H, CH3), 7.20 (d, J = 8.06 Hz, 2H), 7.49 (d,
J = 8.06 Hz, 2H), 9.41 (s, 1H, CHO); HRMS (FAB+),
found: m/z 145.06581. Calcd for C10H9O: (M++H),
145.06535.
˚
stage I, Art. 101076) and dried over MS 4 A just before
use. Et2O was freshly distilled from sodium diphenylketyl.
All other solvents were distilled and stored over drying
agents. Flash column chromatography and thin-layer chro-
matography (TLC) were performed on Cica-Merck’s Silica
4.2.3. (4-Bromophenyl)propynal. Mp 95–97 °C (from hex-
ane/AcOEt; unstable on storage); IR (KBr) 3283, 3087,
2922, 2890, 2191, 1654, 1581, 1475, 1392, 1264, 1067,

W. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 476–481
479
1
1009, 988, 822, 764 cmꢀ1; H NMR (CDCl3) d 7.46 (d,
J = 8.61 Hz, 2H), 7.56 (d, J = 8.61 Hz, 2H), 9.41 (s, 1H,
CHO); HRMS (FAB+), found: m/z 208.96006. Calcd for
C9H6OBr: (M++H), 208.96020.
1654, 1496, 1455, 1353, 1078, 1028, 754, 698 cmꢀ1
;
1H
NMR (CDCl3) d 0.89 (t, J = 7.14 Hz, 3H, CH3), 1.35 (m,
4H, (CH2)2), 1.43 (quin, J = 7.14 Hz, 2H, CH2), 1.59 (quin,
J = 7.14 Hz, 2H, CH2), 2.50 (t, J = 7.14 Hz, 2H,
C„CCH2), 5.21 (s, 2H, CH2Ph), 6.89 (s, 1H, ArHC@N),
7.30–7.39 (m, 3H), 7.40–7.56 (m, 2H); HRMS (FAB+),
found: m/z 244.16954. Calcd for C16H22NO: (M++H),
244.17014.
4.2.4. Non-2-ynal. Obtained as an oil, IR (neat) 2931,
2859, 2201, 1671, 1457, 1387, 1226, 1137, 824, 790,
726 cmꢀ1; H NMR (CDCl3) d 0.88 (t, J = 7.14 Hz, 3H,
1
CH3), 1.31 (m, 4H, (CH2)2), 1.39 (quin, J = 7.14 Hz, 2H,
CH2), 1.60 (quin, J = 7.14 Hz, 2H, CH2), 2.41 (t,
J = 7.14 Hz, 2H, C„CCH2), 9.17 (s, 1H, CHO); HRMS
(FAB+), found: m/z 139.11263. Calcd for C9H15O:
(M++H), 139.11230.
4.3.5. (Z)-1-Phenyl-N-[(E)-3-phenylallylidene]methanamine
oxide 5. To a solution of cinnamaldehyde (925 mg,
7.0 mmol) in CH2Cl2 (4.5 ml) was added a CH2Cl2
(4.5 ml) solution of N-(benzyl)hydroxylamine (865 mg,
7.0 mmol) at 25 °C under an argon atmosphere. The reac-
tion mixture was stirred at 0 °C overnight. The solvent was
removed in vacuo and the residue was recrystallized from
hexane/AcOEt to give nitrone 5 (1.229 g) in 74% yield.
Mp 124–125 °C (from hexane/AcOEt); IR (KBr) 3051,
1545, 1494, 1457, 1424, 1347, 1319, 1291, 1199, 1177,
1122, 1072, 1026, 961, 941, 915, 861, 821, 764, 747,
4.3. Preparation of nitrones
4.3.1. (Z)-1-Phenyl-N-(3-phenylprop-2-ynylidene)methan-
amine oxide 2a. To
a solution of phenylpropynal
˚
(262 mg, 2.0 mmol) in CH2Cl2 (3 ml) with MS 3 A
(342 mg) was added a CH2Cl2 (3 ml) solution of N-(benzyl)
hydroxylamine (246 mg, 2.0 mmol) at 0 °C under an argon
atmosphere. The reaction mixture was stirred at 0 °C over-
1
700 cmꢀ1; H NMR (CDCl3) d 4.96 (s, 2H, CH2Ph), 6.94
(d, J = 16.34 Hz, 1H), 7.21 (d, J = 9.76 Hz, 1H), 7.28–
7.36 (m, 3H), 7.38–7.50 (m, 8H). Calcd for C16H15NO:
C, 80.98; H, 6.37; N, 5.90. Found: C, 81.00; H, 6.37; N,
5.90.
˚
night. After filtration to remove the MS 3A, the solvent
was removed in vacuo and the residue was partitioned be-
tween ethyl acetate and water. The organic extract was
washed successively with water, brine, and dried over so-
dium sulfate. After evaporation of the solvent, the residue
was separated by silica gel [treated with 10% (w/w) water in
advance to deactivate] column chromatography (eluted
with CHCl3) to afford 2a (170 mg) in 36% yield. The nit-
rone was so labile that it was partially decomposed during
purification even by treatment with deactivated silica gel.
Obtained as an oil, IR (neat) 3062, 3030, 2923, 2215,
1654, 1578, 1541, 1495, 1451, 1238, 1178, 1072, 1027,
4.4. Preparation of N-benzyl-N-[1-(4-methoxyphenyl)-3-
phenylprop-2-ynyl]hydroxylamine
To a toluene (9 ml) solution of phenyl acetylene (337 mg,
3.3 mmol) was added dimethylzinc (3.3 ml of 1.0 M solu-
tion in hexane, 3.3 mmol) at 0 °C under an argon atmo-
sphere, and the mixture was stirred for 30 min. To the
solution, a toluene (9 ml) solution of N-(4-methoxybenzyl-
idene)-1-phenylmethanamine oxide (732 mg, 3.0 mmol)
was added. The resulting solution was stirred at 0 °C for
14 h and quenched by the addition of a saturated aq NaH-
CO3 solution. After filtration of the precipitate, the filtrate
was extracted with AcOEt. The combined extracts were
washed with brine, dried over Na2SO4, and condensed un-
der reduced pressure. The residue was separated by TLC
on SiO2 to isolate the corresponding hydroxylamine (hex-
ane/AcOEt = 3:1) in 97% yield (1.00 g). Mp 116–117 °C
(from hexane/AcOEt), IR (KBr) 3235, 2924, 1608, 1509,
1489, 1456, 1333, 1303, 1246, 1172, 1077, 1033, 801, 753,
1
754, 697 cmꢀ1; H NMR (CDCl3) d 5.37 (s, 2H, CH2Ph),
7.10 (s, 1H, ArHC@N), 7.29–7.39 (m, 6H), 7.47–7.55 (m,
4H); HRMS (FAB+), found: m/z 236.10799. Calcd for
C16H14NO: (M++H), 236.10754.
In a similar manner, nitrones 2b–2d were prepared from the
corresponding aldehydes and N-(benzyl)hydroxylamine.
4.3.2. (Z)-1-Phenyl-N-(3-p-tolylprop-2-ynylidene)methan-
amine oxide 2b. Obtained as an oil, IR (neat) 3029,
2921, 2188, 1655, 1606, 1541, 1507, 1454, 1240, 1178,
816, 753, 698 cmꢀ1
;
1H NMR (CDCl3) d 2.39 (s, 3H,
699, 690 cmꢀ1; H NMR (CDCl3) d 3.81 (s, 3H, OCH3),
1
CH3), 5.31 (s, 2H, CH2Ph), 7.11 (s, 1H, ArHC@N), 7.20
(d, J = 8.01 Hz, 2H), 7.38 (d, J = 8.01 Hz, 2H), 7.30–7.38
(m, 3H), 7.53–7.40 (m, 2H); HRMS (FAB+), found: m/z
250.12306. Calcd for C17H16NO: (M++H), 250.12319.
3.97 (d, J = 13.06 Hz, 1H, CH2Ph), 4.06 (d, J = 13.06 Hz,
1H, CH2Ph), 4.90 (s, 1H, OH), 4.97 (s, 1H, ArCHNBn),
6.91 (d, J = 8.61 Hz, 2H) 7.28–7.41 (m, 8H), 7.54–7.58
(m, 4H); HRMS (FAB+), found: m/z 344.1650. Calcd for
C23H22NO: (M++H), 344.1652.
4.3.3.
(Z)-1-Phenyl-N-[3-(4-bromophenyl)prop-2-ynylid-
ene]methanamine oxide 2c. Mp 90–91 °C (from hexane/
AcOEt), IR (KBr) 3060, 3029, 2922, 2186, 1640, 1584,
1536, 1485, 1452, 1395, 1355, 1290, 1241, 1173, 1071,
4.5. Asymmetric phenylation
4.5.1. Representative procedure for asymmetric phenylation
of N-benzyl C-alkynyl nitrone 2a (Table 2, entry 2). To a
CHCl3 (3 ml) solution of (R,R)-DTBT (157 mg, 0.6 mmol)
was added dimethylzinc (1.55 ml of 1.0 M solution in
hexane, 1.55 mmol) at 0 °C under an argon atmosphere,
and the mixture was stirred for 10 min. To the solution,
1
1008, 952, 824, 771, 736, 697 cmꢀ1; H NMR (CDCl3) d
5.31 (s, 2H, CH2Ph), 6.19 (s, 1H, ArHC@N), 7.32–7.41
(m, 4H), 7.50–7.54 (m, 5H); HRMS (FAB+), found: m/z
314.01786. Calcd for C16H13NOBr: (M++H), 314.01805.
4.3.4. (Z)-1-Phenyl-N-(non-2-ynylidene)methanamine oxide
2d. Obtained as an oil, IR (neat) 3030, 2928, 2857, 2232,
a
CHCl3 (3 ml) solution of racemic N-benzyl-N-
[1-(4-methoxyphenyl)-3-phenylprop-2-ynyl]hydroxylamine

480
W. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 476–481
(34 mg, 0.1 mmol) was added. After stirring for 10 min,
diphenylzinc (1.95 ml of 0.128 M solution in toluene,
0.25 mmol) was added to the solution. The reaction mix-
ture was warmed to 25 °C and stirred for 1 h, then a CHCl3
(3 ml) solution of nitrone 2a (117 mg, 0.5 mmol) was
added. The resulting solution was stirred at 25 °C for 1 h
and quenched by the addition of a saturated aq NH4Cl
solution. After filtration of the precipitate, the filtrate was
extracted with AcOEt. The combined extracts were washed
with brine, dried over Na2SO4, and condensed under re-
duced pressure. The residue was separated by TLC on
SiO2 to isolate 3a (hexane/AcOEt = 3:1) in 75% yield
(117 mg).
7.14–7.39 (m, 8H), 7.52–7.58 (m, 2H); HRMS (FAB+),
found: m/z 322.21737. Calcd for C22H28NO: (M++H),
322.21709. The enantiomer ratio was determined by HPLC
analysis (Daicel Chiralcel OD-H, hexane/EtOH = 75:1, de-
tected at 254 nm).
4.5.6. Asymmetric phenylation of (Z)-1-phenyl-N-[(E)-3-
phenylallylidene]methanamine oxide 5 (Scheme 3). To a
CH2Cl2 (1.8 ml) solution of (R,R)-DTBT (95 mg,
0.36 mmol) was added dimethylzinc (0.78 ml of 1.0 M solu-
tion in hexane, 0.78 mmol) at 0 °C under an argon
atmosphere, and the mixture was stirred for 10 min. To
the solution, a CH2Cl2 (1.8 ml) solution of racemic
N-benzyl-N-[1-(4-methoxyphenyl)-3-phenylprop-2-ynyl]-
hydroxylamine (21 mg, 0.06 mmol) was added. After stir-
ring for 10 min, diphenylzinc (2.3 ml of 0.129 M solution
in toluene, 0.30 mmol) was added to the solution. Then a
CH2Cl2 (1.8 ml) solution of nitrone 5 (72 mg, 0.30 mmol)
was added. The resulting solution was stirred at 25 °C for
24 h and then quenched by the addition of a saturated aq
NaHCO3 solution. After filtration of the precipitate, the fil-
trate was extracted with AcOEt. The combined extracts
were washed with brine, dried over Na2SO4, and condensed
under reduced pressure. The residue was separated by TLC
on SiO2 to isolate 6 (hexane/AcOEt = 10:1) in 76% yield
(73 mg).
4.5.2. (S)-N-Benzyl-N-(1,3-diphenylprop-2-ynyl)hydroxyl-
25
amine 3a.10 Mp 133–134 °C (from EtOH); ½aꢁD ¼ ꢀ42
(c 1.23, EtOH, 92% ee); IR (KBr) 3239, 3029, 2905, 1597,
1488, 1452, 1331, 1298, 1179, 1070, 1026, 1003, 988, 916,
1
826, 812, 757, 729, 690 cmꢀ1; H NMR (CDCl3): d 3.89
(d, J = 12.69 Hz, 1H, CH2Ph), 3.99 (d, J = 12.69 Hz, 1H,
CH2Ph), 4.87 (s, 1H, ArCHNBn), 5.69 (s, 1H, OH),
7.28–7.37 (m, 10H), 7.59–7.61 (m, 5H). Calcd for
C22H19NO: C, 84.31; H, 6.11; N, 4.47. Found: C, 84.31;
H, 6.15; N, 4.43. The enantiomer ratio was determined
by HPLC analysis (Daicel Chiralcel OD-H, hex-
ane/iPrOH = 45:1, detected at 254 nm).
4.5.3. (S)-N-Benzyl-N-(1-phenyl-3-p-tolylprop-2-ynyl)hydr-
25
4.5.7. (R,E)-N-Benzyl-N-(1,3-diphenylallyl)hydroxylamine
oxylamine 3b. Mp 135–136 °C (from EtOH); ½aꢁD ¼ ꢀ45
25
6. Obtained as an oil, ½aꢁD ¼ þ7 (c 0.73, EtOH, 49%
(c 1.23, EtOH, 87% ee); IR (KBr) 3236, 3028, 2918, 1600,
1542, 1508, 1495, 1453, 1353, 1289, 1075, 1029, 1020,
985, 913, 861, 815, 757, 738, 696 cmꢀ1; 1H NMR (CDCl3):
d 2.37 (s, 3H, CH3), 3.99 (s, 2H, CH2Ph), 4.93 (s, 1H,
ArCHNBn), 5.25 (s, 1H, OH), 6.87–7.86 (m, 14H). Calcd
for C23H21NO: C, 84.37; H, 6.47; N, 4.28. Found: C,
84.09; H, 6.50; N, 4.34. The enantiomer ratio was deter-
mined by HPLC analysis (Daicel Chiralcel OD-H, hex-
ane/iPrOH = 60:1, detected at 254 nm).
ee); IR (neat) 3529, 3082, 3059, 3027, 2923, 2850, 1599,
1494, 1452, 1246, 1072, 1028, 966, 744, 697 cmꢀ1 1H
;
NMR (CDCl3): d 3.81 (d, J = 13.42 Hz, 1H, CH2Ph),
3.95 (d, J = 13.42 Hz, 1H, CH2Ph), 4.44 (d, J = 8.04 Hz,
1H), 4.75 (s, 1H, OH), 6.54 (m, 1H), 6.65 (d,
J = 11.20 Hz, 1H), 7.27–7.58 (m, 15H); HRMS (FAB+),
found: m/z 316.16955. Calcd for C22H22NO: (M++H),
316.17014. The enantiomeric ratio was determined by
HPLC analysis (Daicel Chiralcel OD-H, hex-
ane/iPrOH = 20:1, detected at 254 nm).
4.5.4. (S)-N-Benzyl-N-[3-(4-bromophenyl)-1-phenylprop-2-
ynyl]hydroxylamine 3c. Mp 166–167 °C (from EtOH);
25
½aꢁD ¼ ꢀ69 (c 0.50, EtOH, 90% ee); IR (KBr) 3339, 3063,
Acknowledgments
3030, 2971, 2894, 1602, 1485, 1453, 1393, 1297, 1272,
1070, 1049, 1011, 880, 824, 736, 699 cmꢀ1 1H NMR
;
The present work was financially supported in part by
Grant-in-Aid for Scientific Research on Priority Areas
‘‘Advanced Molecular Transformations of Carbon Re-
sources” from The Ministry of Education, Culture, Sports,
Science and Technology (MEXT) and NOVARTIS Foun-
dation (Japan) for the Promotion of Science.
(CDCl3): d 3.98 (d, J = 13.17 Hz, 1H, CH2Ph), 4.06 (d,
J = 13.17 Hz, 1H, CH2Ph), 4.98 (s, 1H, ArCHNBn), 5.05
(s, 1H, OH), 7.28–7.49 (m, 12H), 7.57–7.63 (m, 2H). Calcd
for C22H18NOBr: C, 67.35; H, 4.60; N, 3.57. Found: C,
67.51; H, 4.70; N, 3.52. The enantiomer ratio was deter-
mined by HPLC analysis (Daicel Chiralcel OD-H, hex-
ane/iPrOH = 45:1, detected at 254 nm).
References
4.5.5. (S)-N-Benzyl-N-(1-phenylnon-2-ynyl)hydroxylamine
25
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1603, 1585, 1558, 1494, 1454, 1330, 1180, 1074, 1050,
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was too small to be compared, the major peaks in HPLC
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identical to each other.
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˜
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Bn
Ph
OH
Bn
Ph
OH
N
N
H2, cat. Pd(OH)2/C
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EtOH, rt, 2 h
48%
R
R
Ph
Ph
Ph
6
7
6. It was previously reported that a mixed zinc reagent PhZnEt
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Bn
Ph
OH
Bn
Ph
OH
N
N
H2, cat. Pd(OH)2/C
EtOH, rt, 2 h
59%
S
R
Ph
3a
7
`
`
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