Remarkable enhancement effect of potassium tert-butoxide/THF solution in base-induced Sommelet-Hauser rearrangements

Article abstract of DOI:10.1016/j.tet.2010.09.105

A solution of potassium tert-butoxide in THF was shown to remarkably enhance the base-induced Sommelet-Hauser rearrangement of N-benzylic amino acid-derived ammonium ylides.

Full text of DOI:10.1016/j.tet.2010.09.105

Tetrahedron 66 (2010) 9389e9395
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Tetrahedron
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Remarkable enhancement effect of potassium tert-butoxide/THF solution in
base-induced SommeleteHauser rearrangements
*
Eiji Tayama , Keisuke Takedachi, Hajime Iwamoto, Eietsu Hasegawa
Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A solution of potassium tert-butoxide in THF was shown to remarkably enhance the base-induced
SommeleteHauser rearrangement of N-benzylic amino acid-derived ammonium ylides.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 September 2010
Received in revised form 28 September 2010
Accepted 28 September 2010
Available online 19 October 2010
Keywords:
Rearrangement
Pericyclic reaction
Ammonium salt
Ylide
Amino acid
1. Introduction
2. Results and discussion
The base-induced SommeleteHauser (SeH) rearrangement of
N-benzylic ammonium ylides is an interesting and useful trans-
formation in organic synthesis that can provide easy access to or-
tho-substituted aromatic compounds.1,2 However, the utility of this
rearrangement is severely limited by a competing [1,2] Stevens
rearrangement, resulting in a distribution of products, that is, de-
pendent on the reaction conditions and the substrate structures.3
For example, under common reaction conditions in the base-in-
duced rearrangement of N-benzylic amino acid-derived ammo-
nium ylides, the [1,2] Stevens rearrangement is known to be
First, we examined the rearrangement of the N-benzyl-N,N-
dimethylglycine tert-butyl ester-derived ammonium salt 1a, which
was promoted by common bases to afford N,N-dimethyl-o-tolyl-
glycine tert-butyl ester (2a) as the SeH product and N,N-dime-
thylphenylalanine tert-butyl ester (3a) as the [1,2] Stevens product
(Table 1). When the reaction was carried out by addition of solid
t-BuOK (1.1 equiv)5 to a THF solution of 1a at 0 ꢀC for 3 h under an
atmosphere of argon (entry 1), the [1,2] Stevens rearrangement
proceeded preferably to give 3a as the major product (43%). The
corresponding SeH rearrangement product 2a was obtained in
only 22% yield. The yield of 2a was slightly improved (40%) by ad-
dition of a THF solution of 1a to a suspension of solid t-BuOK in THF
(entry 2). Use of solid sodium tert-butoxide (t-BuONa), LDA, phe-
nyllithium, potassium hydroxide, and potassium carbonate did not
result in any improvement (entries 3e7). Interestingly, when the
reaction was carried out with a 1.0 M solution of t-BuOK in THF,6
the SeH rearrangement was dramatically accelerated to give 2a
in 80% yield along with the [1,2] Stevens product 3a in 8% yield
(entry 8). However, a t-BuOK/THF solution prepared from sublimed
grade (99% purity) solid t-BuOK (entry 9) or a solid t-BuOK obtained
by concentration of the commercially available t-BuOK/THF solu-
tion (entry 10) did not accelerate the SeH rearrangement. Analogue
bases, such as a solution of t-BuONa in THF (entry 11) or a solution
of potassium bis(trimethylsilyl)amide (KHMDS) in toluene (entry
12) did not show any enhancement effects in the SeH
rearrangement.
favored and produces a-benzylated amino acid derivatives as the
major reaction product. Recently, we reported that an electron-
withdrawing substituent on the aromatic ring of N-benzylic amino
acid-derived ammonium ylides enhances the SeH rearrangement.4
In the course of these investigations, we found that a solution of
potassium tert-butoxide (t-BuOK) in THF had a remarkable en-
hancement effect on the base-induced SeH rearrangement. Herein,
we wish to report that SeH rearrangements promoted by a solution
of t-BuOK in THF are shown to proceed under mild conditions with
minimal competition from the [1,2] Stevens rearrangement. This
enhancement effect was observed with a variety of N-benzylic
amino acid-derived ammonium ylides.
* Corresponding author. Tel.: þ81 25 262 7740; fax: þ81 25 262 7741; e-mail
address: tayama@chem.sc.niigata-u.ac.jp (E. Tayama).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.105

9390
E. Tayama et al. / Tetrahedron 66 (2010) 9389e9395
t-BuOK is not soluble in THF so much even if refluxing.9 (2) A
sublimed grade (99% purity) solid t-BuOK is more soluble in THF
than the reagent grade; however, the resulting mixture did not give
a clear solution. (3) Use of a solid t-BuOK obtained by concentration
of t-BuOK/THF solution afforded the similar result with the reagent
grade of solid t-BuOK. The reagent was not dissolved in THF com-
pletely after solidification. (4) When the reactions were carried out
using t-BuOK/THF solution in the presence of small amount
(0.2 equiv) of KOH or K2CO3, the yield of 3a was improved (2a: ca.
65%, 3a: ca. 20%). (5) 1H NMR analysis of t-BuOK/THF solution in
Table 1
Base-induced SeH rearrangement of 1a with various types of bases
Entry
Base (equiv)a
2a (%)b
3a (%)b
1
2
3
4
5
6
7
8
t-BuOK solid (1.1)
22
40
19
6
0
0
43
36
43
29
15
22
0
t-BuOK solid (1.1)c
THF-d8 showed a single peak of t-Bu substituent (d 1.01, s) without
any peaks of impurities.
t-BuONa solid (1.1)
LDA THF solution (1.1)
PhLi cyclohexaneeEt2O solution (1.1)
KOH powder (5)
To demonstrate the enhancement effect of t-BuOK/THF solution
in SeH rearrangements, we attempted the reaction of various types
of amino acid ester-derived ammonium salts 1bei with solid or
solution based t-BuOK (Table 2). In the reaction of benzyl ester-
derived ammonium salt 1b, the use of solid t-BuOK gave a mixture
of SeH and [1,2] rearrangement products (entry 1, 2b: 51%, 3b:
22%). However, the yield of 2b was improved with a t-BuOK/THF
solution (entry 2, 2b: 74%, 3b: 9%). This effect was also observed
using monosubstituted benzylammonium salts as substrates. In the
reaction of para-chlorobenzyl derivative 1c with a t-BuOK/THF
solution; the yield of SeH rearrangement product 2c was improved
to 87% (entry 4) from 60% (entry 3). The effect was clearly observed
using deactivated substrates, including electron-donating sub-
stituents,4,10 such as para-methyl (1d) and para-methoxy (1e) de-
rivatives. In both cases, the SeH rearrangement was accelerated
with the t-BuOK/THF solution. For example, the yield of 2d was
improved to 68% (entry 6) from 8% (entry 5), and the yield of 2e was
improved to 45% (entry 8) from 0% (entry 7). Similar results were
obtained in the reactions of meta- and ortho-substituted benzyl
derivatives 1fei (entries 9e16).
K2CO3 (1.2)
0
t-BuOK THF solution (1.1)d
t-BuOK THF solution (1.1)e
t-BuOK solid (1.1)f
80
18
15
36
15
8
9
42
43
35
34
10
11
12
t-BuONa THF solution (1.1)g
KHMDS toluene solution (1.1)h
a
Unless otherwise noted, the bases were added to a THF solution of 1a.
Isolated yield.
A THF solution of 1a was added to a suspension of t-BuOK in THF.
Commercially available from Aldrich or TCI.
Prepared from sublimed grade solid t-BuOK (not clear completely).
Obtained by concentration of t-BuOK THF solution prior to use.
Commercially available from Aldrich.
b
c
d
e
f
g
h
The reaction was carried out in THFetoluene (5:1).
The exact reason for this enhancement effect is unknown at
present, however, it is safe to say that a clear solution of t-BuOK in
THF might be disassociated efficiently7 to generate ammonium
ylide A (Scheme 1), which leads to 2a preferably by [2,3] carbanion
rearrangement (SeH rearrangement). Small amount of impurities
such as KOH and K2CO3 depending on exposure of solid t-BuOK to
air or moisture would be lowered the solubility in THF. The
resulting reagent might stabilize enolate form B8 or promote for-
mation of radical pair C, which leads to 3a by recombination ([1,2]
Stevens rearrangement). The following experimental results sup-
port these speculations: (1) A reagent grade (97% purity) solid
Table 2
Base-induced SeH rearrangement of amino acid ester-derived ammonium salts
1bei
Entry
R1
R2
R3
R4
t-BuOKa
2 (%)b
3 (%)b
1
2
3
4
5
6
7
8
CH2Ph
CH2Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
H
H
Cl
Cl
Me
Me
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Me
Me
b
b
c
c
d
d
e
e
f
Solid
THF solution
Solid
THF solution
Solid
THF solution
Solid
THF solution
Solid
THF solution
Solid
THF solution
Solid
THF solution
Solid
51
74
60
87
8
22
9
22
4
59
20
53
37
22
3
44
13
35
3
68
0
45
51
71
11
74
32
87
8
9
10
11
12
13
14
15
16
f
g
g
h
h
i
64
14
i
THF solution
73
a
Reagent grade of solid t-BuOK or commercially available THF solution of t-BuOK
were used.
b
Isolated yield.
The enhancement effect of the t-BuOK/THF solution on the SeH
rearrangement was also shown in the reaction of amino acid am-
ide-derived ammonium salts 4 (Scheme 2). A reaction of glycine
Scheme 1. Base-induced SeH versus [1,2] Stevens rearrangement.

E. Tayama et al. / Tetrahedron 66 (2010) 9389e9395
9391
diethylamide-derived ammonium salt 4a with solid t-BuOK affor-
ded the corresponding SeH rearrangement product 5a in 56% yield
along with the [1,2] Stevens product 6a in 15% yield. Similarly,
when the reaction was carried out with a solution of t-BuOK in THF,
5a was obtained in 83% yield without any detectable amount of 6a.
Finally, we examined the asymmetric SeH rearrangement of
the amino acid amide-derived ammonium salts 7a and 7b using
(R)-4-substituted-2,2-dimethyloxazolidine as
a chiral auxiliary
(Scheme 3)． Treatment of these compounds with a solution of
t-BuOK in THF afforded 8a or 8b, respectively, in good yields with
high diastereoselectivities (8a: 80%, 2S/2R¼89:11; 8b: 84%, 2S/
2R¼>98:2).11 Deacetonidation of 8 with 6 M hydrochloric acid gave
the corresponding peptide alcohols 9 in good yields (9a: 76%, 9b:
91%) without epimerization.
Scheme 2. t-BuOK-induced SꢁH rearrangement of amino acid amide-derived
ammonium salt 4a.
To further explore the scope and limitations of the t-BuOK/THF
solution-induced SeH rearrangement of amino acid amide-derived
ammonium salts 4, we prepared a series of substrates 4beh and
tested their reactivity under these reaction conditions (Table 3). A
reaction of cyclic tertiary amide 4b under the same conditions
proceeded slowly (entry 1). The product 5b was obtained in lower
yield (58%). By activating the substrates with an electron-with-
drawing substituent on the aromatic ring,4 such as para-tert-
butoxycarbonyl (4c: p-COt2Bu), the yield was improved to 92%
(entry 2). Next, we examined the reactions of secondary amide-
derived ammonium salts 4deg. Sterically hindered secondary
amides, such as tert-butyl amide derivative 4d, rearranged to 5d in
83% yield (entry 3); however, n-butyl and phenyl amide derivatives
4e and 4f resulted in lower yields (entry 4, 5e: 29%; entry 5, 5f:
20%). By adding an electron-withdrawing group, the SeH rear-
rangement proceeded smoothly to give 5g in 99% yield (entry 6).
These results imply that the intermolecular hydrogen bonds caused
by amide proton (NH) might inhibit the SeH rearrangement. tert-
Butyl amide derivative 4d would not form intermolecular hydrogen
bonds due to steric hindrance. Thus, we attempted the reaction
with the tertiary amide derivative 4h. The SeH rearrangement
proceeded smoothly without an electron-withdrawing group to
afford 5h in excellent yield (entry 7, 96%).
Scheme 3. Asymmetric SeH rearrangement of amino acid amide-derived ammonium
salts 7.
In conclusion, we have reported the enhancement effect of
a potassium tert-butoxide/THF solution in base-induced Somme-
leteHauser rearrangements. Under mild reaction conditions, the
rearrangements of N-benzylic amino acid esters and amide-derived
ammonium salts are shown to proceed with minimal competition
from the [1,2] Stevens rearrangement. The method provides effi-
cient access to
a-aryl amino acid derivatives and expands the
synthetic utility of the SeH rearrangement.
3. Experimental section
3.1. General
Infrared spectra were recorded on a PerkineElmer Spectrum
GX FT-IR spectrometer. 1H and 13C NMR spectra were measured
on a JEOL 270 MHz (1H: 270 MHz, 13C: 68 MHz), a Varian 400 MHz
(1H: 400 MHz, 13C: 100 MHz), and
a
Varian 500 MHz (1H:
500 MHz, 13C: 125 MHz) spectrometers. Splitting patterns are in-
dicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad peak. Specific rotations were recorded on
a JASCO Polarimeter Pe1010. High-resolution mass spectra were
measured on a Thermo Fisher Scientific LC/FT-MS spectrometer.
Elemental analyses were recorded on a Yanaco CHN Corder MT-3.
Reactions involving air- or moisture-sensitive compounds were
conducted in appropriate round-bottomed flask with a magnetic
stirring bar under an argon atmosphere. Tetrahydrofuran (THF)
was purchased from KANTO Chemical Co., Inc., Japan as an an-
hydrous solvent. A 1.0 M THF solution of potassium tert-butoxide
was purchased from Aldrich or Tokyo Chemical Industry Co., Ltd
(TCI). A reagent grade (97%) of potassium tert-butoxide was pur-
chased from KANTO Chemical Co., Inc., Japan. A sublimed grade
(99%) of potassium tert-butoxide was purchased from Aldrich. A
2.0 M THF solution of sodium tert-butoxide was purchased from
Aldrich. For thin layer chromatography (TLC) analysis throughout
this work, Merck TLC plates (silica gel 60 F254) were used. The
products were purified by preparative column chromatography on
silica gel (silica gel 60N, spherical neutral, KANTO Chemical Co.,
Inc., Japan).
Table 3
t-BuOK/THF solution-induced SeH rearrangement of amino acid amide-derived
ammonium salts 4beha
Entry
NR1
R2
5 (%)b
2
1
2
3
4
5
6
7
Pyrrolidin-1-yl
Pyrrolidin-1-yl
NHtBu
H
b
c
d
e
f
58
92
83
29
20
99
96
COt2Bu
H
H
H
NHnBu
NHPh
NHnBu
CO2 tBu
H
g
h
NMenBu
a
Commercially available THF solution of t-BuOK was used in the reactions.
Isolated yield.
b

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E. Tayama et al. / Tetrahedron 66 (2010) 9389e9395
3.2. Experimental
Calcd for C15H22ClNO2: C, 63.48; H, 7.81; N, 4.94. Found: C, 63.71; H,
7.95; N, 4.97.
3.2.1. Representative procedure for base-induced SommeleteHauser
rearrangement of N-benzyl glycine tert-butyl ester-derived ammo-
nium salt 1a. A 1.0 M THF solution of potassium tert-butoxide
(0.36 mL, 0.36 mmol) was added to a solution of 1a (109 mg,
0.33 mmol) in THF (3.0 mL) at 0 ꢀC. The mixture was stirred for 3 h
at the same temperature under an argon atmosphere. The resulting
mixture was quenched with saturated aqueous ammonium chlo-
ride and extracted with ethyl acetate. The combined extracts were
washed with saturated aqueous sodium hydrogen carbonate and
brine. The solution was dried over sodium sulfate and concentrated.
Purification of the residue by chromatography on silica gel (hexane/
ethyl acetate¼8:1 to 2:1 as eluent) gave 2a (65.6 mg, 80% yield) as
a pale yellow oil and 3a (6.8 mg, 8% yield) as a colorless oil.
3.2.7. tert-Butyl 3-(4-chlorophenyl)-2-(dimethylamino)propanoate
(3c). Colorless oil. IR (film) 2977, 2936, 2869, 2832, 2788, 1726,
1492, 1454, 1392, 1367, 1255, 1222, 1148, 1094, 1046, 1017, 982, 953,
879, 845, 816, 773 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.23 (2H, ddd,
J¼8.6, 2.2, 2.2 Hz, ArH), 7.14 (2H, ddd, J¼8.6, 2.2, 2.2 Hz, ArH), 3.27
(1H, dd, J¼9.4, 5.8 Hz, NCHCO), 2.98 (1H, dd, J¼13.4, 9.4 Hz, CH2Ph),
2.83 (1H, dd, J¼13.4, 5.8 Hz, CH2Ph), 2.40 (6H, s, N(CH3)2), 1.36 (9H,
s, t-Bu); 13C NMR (100 MHz, CDCl3)
d 170.4,136.9,132.1,130.6,128.3,
81.1, 69.7, 41.7, 35.6, 28.2. Anal. Calcd for C15H22ClNO2: C, 63.48; H,
7.81; N, 4.94. Found: C, 63.24; H, 7.92; N, 4.88.
3.2.8. tert-Butyl (dimethylamino)(2,5-dimethylphenyl)acetate (2d).
Pale yellow oil. IR (film) 2977, 2930, 2866, 2819, 2770, 1741, 1502,
1457, 1391, 1367, 1257, 1214, 1144, 1103, 1047, 958, 900, 845, 810,
3.2.2. tert-Butyl (dimethylamino)(2-methylphenyl)acetate (2a). Pale
yellow oil. IR (film) 2978, 2866, 2819, 2771, 1741, 1461, 1392, 1367,
1278, 1256, 1220, 1143, 1103, 1046, 945, 901, 879, 837, 814,
787 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.38 (1H, d, J¼1.6 Hz, ArH),
7.02 (1H, d, J¼8.0 Hz, ArH), 6.97 (1H, dd, J¼8.0, 1.6 Hz, ArH), 3.97
753 cmꢁ1
;
1H NMR (270 MHz, CDCl3)
d
7.59e7.51 (1H, m, ArH),
(1H, s, NCHCO), 2.36 (3H, s, ArCH3), 2.29 (3H, s, ArCH3), 2.26 (6H, s,
7.23e7.11 (3H, m, ArH), 4.03 (1H, s, NCHCO), 2.42 (3H, s, ArCH3),
N(CH3)2),1.38 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d 171.1,135.5,
2.27 (6H, s, N(CH3)2), 1.38 (9H, s, t-Bu); 13C NMR (68 MHz, CDCl3)
135.4, 133.7, 130.1, 128.5, 128.2, 80.9, 71.3, 43.3, 27.9, 20.9, 19.3. Anal.
Calcd for C16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found: C, 72.86; H,
9.65; N, 5.37.
d
171.1, 136.9, 135.7, 130.3, 128.0, 127.5, 126.1, 81.0, 71.2, 43.2, 27.9,
19.7. Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found: C,
72.34; H, 9.46; N, 5.52.
3.2.9. tert-Butyl 2-(dimethylamino)-3-(4-methylphenyl)propanoate
(3d). Pale yellow oil. IR (film) 2976, 2934, 2867, 2831, 2787, 1723,
1516, 1453, 1391, 1367, 1256, 1222, 1147, 1100, 1073, 1045, 1027, 990,
3.2.3. tert-Butyl 2-(dimethylamino)-3-phenylpropanoate (3a). Colorless
oil. IR (film) 2977, 2936, 2867, 2831, 2787, 1723, 1454, 1391, 1367, 1256,
1221, 1147, 1064, 1030, 980, 951, 874, 845, 739, 699 cmꢁ1
;
1H NMR
974, 878, 845, 807, 774 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.09 (2H,
(270 MHz, CDCl3)
d
7.31e7.15 (5H, m, Ph), 3.31 (1H, dd, J¼9.8, 5.7 Hz,
d, J¼8.4 Hz, ArH), 7.06 (2H, d, J¼8.4 Hz, ArH), 3.29 (1H, dd, J¼9.6,
5.6 Hz, NCHCO), 2.98 (1H, dd, J¼13.2, 9.6 Hz, CH2Ar), 2.84 (1H, dd,
J¼13.2, 5.6 Hz, CH2Ar), 2.40 (6H, s, N(CH3)2), 2.30 (3H, s, ArCH3),
NCHCO), 3.02 (1H, dd, J¼13.1, 9.8 Hz, CH2Ph), 2.88 (1H, dd, J¼13.1,
5.7 Hz, CH2Ph), 2.41 (6H, s, N(CH3)2), 1.34 (9H, s, t-Bu); 13C NMR
(68 MHz, CDCl3)
d
170.7, 138.3, 129.2, 128.2, 126.3, 80.9, 70.0, 41.8, 36.3,
1.36 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d 170.7, 135.7, 135.2,
28.1. Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found: C,
71.97; H, 9.43; N, 5.46.
129.0, 128.9, 80.8, 70.0, 41.8, 35.9, 28.2, 21.0. Anal. Calcd for
C16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found: C, 72.74; H, 9.60; N,
5.26.
3.2.4. Benzyl (dimethylamino)(2-methylphenyl)acetate (2b). Col-
orless oil. IR (film) 3065, 3032, 2953, 2866, 2821, 2774, 1744, 1488,
1458, 1377, 1344, 1258, 1197, 1145, 1102, 1046, 968, 891, 746,
3.2.10. tert-Butyl (dimethylamino)(5-methoxy-2-methylphenyl)ace-
tate (2e). Colorless oil. IR (film) 2977, 2867, 2832, 2772, 1739, 1611,
1580, 1501, 1464, 1392, 1367, 1349, 1283, 1248, 1215, 1145, 1109,
1043, 959, 899, 844, 815, 788, 701 cmꢁ1; 1H NMR (400 MHz, CDCl3)
697 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.54e7.50 (1H, m, ArH),
7.30e7.25 (3H, m, ArH), 7.22e7.13 (5H, m, ArH), 5.16 (1H, d,
J¼12.4 Hz, CH2Ph), 5.08 (1H, d, J¼12.4 Hz, CH2Ph), 4.23 (1H, s,
NCHCO), 2.41 (3H, s, ArCH3), 2.27 (6H, s, N(CH3)2); 13C NMR
d
7.14 (1H, d, J¼3.0 Hz, ArH), 7.05 (1H, d, J¼8.4 Hz, ArH), 6.74 (1H,
dd, J¼8.4, 3.0 Hz, ArH), 3.97 (1H, s, NCHCO), 3.78 (3H, s, OCH3), 2.34
(100 MHz, CDCl3)
d 171.7, 137.1, 135.8, 134.9, 130.5, 128.4, 128.3,
(3H, s, ArCH3), 2.26 (6H, s, N(CH3)2), 1.38 (9H, s, t-Bu); 13C NMR
128.0, 127.87, 127.86, 126.2, 70.5, 66.3, 43.2, 19.7. Anal. Calcd for
C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.55; H, 7.55; N,
5.01.
(100 MHz, CDCl3) d 171.0, 158.0, 136.6, 131.1, 128.9, 114.1, 112.4, 81.0,
71.5, 55.4, 43.4, 27.9, 18.9. Anal. Calcd for C16H25NO3: C, 68.79; H,
9.02; N, 5.01. Found: C, 68.78; H, 9.10; N, 4.97.
3.2.5. Benzyl 2-(dimethylamino)-3-phenylpropanoate (3b). Colorless
oil. IR (film) 3064, 3031, 2939, 2867, 2831, 2787, 1730, 1496, 1454,
1377, 1349, 1265, 1210, 1160, 1150, 1081, 1065, 1029, 978, 911, 748,
3.2.11. tert-Butyl 2-(dimethylamino)-3-(4-methoxyphenyl)propanoate
(3e). Colorless oil. IR (film) 2976, 2936, 2867, 2833, 2787, 1722, 1613,
1513, 1456, 1391, 1367, 1299, 1248, 1147, 1105, 1072, 1037, 981, 952,
698 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.32e7.14 (10H, m, ArH), 5.04
878, 844, 823, 775, 750 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.12 (2H,
(2H, s, OCH2Ph), 3.49 (1H, dd, J¼9.6, 5.6 Hz, NCHCO), 3.07 (1H, dd,
ddd, J¼8.4, 2.4, 2.4 Hz, ArH), 6.80 (2H, ddd, J¼8.4, 2.4, 2.4 Hz, ArH),
3.78 (3H, s, OCH3), 3.26 (1H, dd, J¼9.8, 5.6 Hz, NCHCO), 2.96 (1H, dd,
J¼13.5, 9.8 Hz, CH2Ar), 2.82 (1H, dd, J¼13.5, 5.6 Hz, CH2Ar), 2.40 (6H,
J¼13.4, 9.6 Hz, CH2Ph), 2.94 (1H, dd, J¼13.4, 5.6 Hz, CH2Ph), 2.39 (6H,
s, N(CH3)2); 13C NMR (100 MHz, CDCl3)
d 171.3, 138.0, 135.7, 129.1,
128.41, 128.37,128.3, 128.1,126.4, 69.5, 65.9, 41.9, 36.2. Anal. Calcd for
C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.49; H, 7.58; N, 5.07.
s, N(CH3)2), 1.35 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d 170.7,
158.1, 130.3, 130.2, 113.6, 80.8, 70.2, 55.2, 41.8, 35.5, 28.2. Anal. Calcd
for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.66; H, 9.17; N,
5.22.
3.2.6. tert-Butyl (5-chloro-2-methylphenyl)(dimethylamino)acetate
(2c). Colorless oil. IR (film) 2979, 2868, 2822, 2775, 1740, 1483,
1457, 1393, 1368, 1349, 1256, 1220, 1145, 1085, 1046, 998, 958, 910,
3.2.12. tert-Butyl (4-chloro-2-methylphenyl)(dimethylamino)acetate
(2f). Colorless oil. IR (film) 2979, 2868, 2821, 2774, 1741, 1596, 1482,
1455, 1392, 1368, 1256, 1222, 1143, 1046, 947, 882, 859, 836, 789,
841, 811, 786 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.59 (1H, d,
J¼2.0 Hz, ArH), 7.14 (1H, dd, J¼8.4, 2.0 Hz, ArH), 7.07 (1H, d,
J¼8.4 Hz, ArH), 3.96 (1H, s, NCHCO), 2.37 (3H, s, ArCH3), 2.27 (6H, s,
736, 701 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.51 (1H, d, J¼8.0 Hz,
N(CH3)2), 1.39 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d
170.4,
ArH), 7.19e7.14 (2H, m, ArH), 3.96 (1H, s, NCHCO), 2.39 (3H, s,
137.5, 135.2, 131.9, 131.5, 128.1, 127.6, 81.4, 71.2, 43.2, 27.9, 19.2. Anal.
ArCH3), 2.25 (6H, s, N(CH3)2), 1.38 (9H, s, t-Bu); 13C NMR (100 MHz,

E. Tayama et al. / Tetrahedron 66 (2010) 9389e9395
9393
CDCl3)
d
170.6, 138.8, 134.3, 133.1, 130.1, 129.5, 126.2, 81.3, 70.8, 43.1,
27.9, 20.9, 15.0; HRMSeESI (m/z): [MþH]þ calcd for C16H26NO2:
27.9, 19.5; HRMSeESI (m/z): [MþH]þ calcd for C15H23ClNO2:
264.1958. Found: 264.1951.
284.1412. Found: 284.1408.
3.2.19. tert-Butyl 2-(dimethylamino)-3-(2-methylphenyl)propanoate
(3i). Colorless oil. IR (film) 2977, 2936, 2868, 2831, 2786, 1725,
1493, 1454, 1391, 1367, 1257, 1219, 1147, 1069, 1047, 979, 881, 846,
3.2.13. tert-Butyl 3-(3-chlorophenyl)-2-(dimethylamino)propanoate
(3f). Pale yellow oil. IR (film) 2977, 2936, 2868, 2832, 2788, 1721,
1598, 1573, 1477, 1452, 1391, 1367, 1256, 1221, 1146, 1079, 1046, 983,
743 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.16e7.05 (4H, m, ArH), 3.29
952, 845, 780, 698, 686 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
(1H, dd, J¼10.0, 5.2 Hz, NCHCO), 3.03 (1H, dd, J¼13.6, 10.0 Hz,
CH2Ar), 2.89 (1H, dd, J¼13.6, 5.2 Hz, CH2Ar), 2.43 (6H, s, N(CH3)2),
2.34 (3H, s, ArCH3), 1.32 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d
7.22e7.15 (3H, m, ArH), 7.11e7.07 (1H, m, ArH), 3.28 (1H, dd, J¼9.6,
5.6 Hz, NCHCO), 2.99 (1H, dd, J¼13.6, 9.6 Hz, CH2Ar), 2.85 (1H, dd,
J¼13.6, 5.6 Hz, CH2Ar), 2.40 (6H, s, N(CH3)2), 1.37 (9H, s, t-Bu); 13C
d
170.8, 136.4, 136.3, 130.2, 129.8, 126.4, 125.7, 80.8, 68.6, 41.9, 33.5,
NMR (100 MHz, CDCl3)
d
170.4, 140.4, 133.9, 129.45, 129.36, 127.4,
28.1, 19.5; HRMSeESI (m/z): [MþH]þ calcd for C16H26NO2:
126.5, 81.2, 69.7, 41.7, 35.9, 28.1; HRMSeESI (m/z): [MþH]þ calcd for
264.1958. Found: 264.1956.
C15H23ClNO2: 284.1412. Found: 284.1409.
3.2.20. N,N-Diethyl-2-dimethylamino-2-(2-methylphenyl)acetamide
(5a). White solid. IR (film) 2972, 2931, 2875, 2829, 2784, 1646,
1450, 1427, 1379, 1361, 1270, 1252, 1220, 1192, 1134, 1096, 1045, 949,
3.2.14. tert-Butyl (dimethylamino)(2,4-dimethylphenyl)acetate (2g).
Colorless oil. IR (film) 2978, 2866, 2818, 2770,1742,1501,1457,1392,
1367, 1276, 1255, 1219, 1143, 1047, 953, 896, 876, 837, 788 cmꢁ1; 1H
914, 891, 859, 829, 752 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.41 (1H,
NMR (400 MHz, CDCl3)
d
7.42 (1H, d, J¼8.0 Hz, ArH), 6.99 (1H, d,
d, J¼7.2 Hz, ArH), 7.25e7.13 (3H, m, ArH), 4.45 (1H, s, NCHCO), 3.52
(1H, dq, J¼13.6, 7.2 Hz, CH2CH3), 3.20 (1H, dq, J¼13.6, 7.2 Hz,
CH2CH3), 3.14 (1H, dq, J¼15.0, 7.2 Hz, CH2CH3), 2.95 (1H, dq, J¼15.0,
7.2 Hz, CH2CH3), 2.43 (3H, s, ArCH3), 2.39 (6H, s, N(CH3)2), 1.09 (3H,
t, J¼7.2 Hz, CH2CH3), 0.97 (3H, t, J¼7.2 Hz, CH2CH3); 13C NMR
J¼8.0 Hz, ArH), 6.96 (1H, s, ArH), 3.98 (1H, s, NCHCO), 2.38 (3H, s,
ArCH3), 2.29 (3H, s, ArCH3), 2.25 (6H, s, N(CH3)2), 1.38 (9H, s, t-Bu);
13C NMR (100 MHz, CDCl3)
d 171.2, 137.0, 136.6, 132.6, 131.0, 127.9,
126.8, 80.8, 71.0, 43.2, 27.9, 21.0, 19.6; HRMSeESI (m/z): [MþH]þ
calcd for C16H26NO2: 264.1958. Found: 264.1953.
(100 MHz, CDCl3) d 170.9,137.0, 135.2,130.6, 128.9, 127.7, 126.0, 66.1,
42.2, 41.0, 40.1, 19.3, 14.0, 12.7. Anal. Calcd for C15H24N2O: C, 72.54;
H, 9.74; N, 11.28. Found: C, 72.31; H, 9.81; N, 11.23.
3.2.15. tert-Butyl 2-(dimethylamino)-3-(3-methylphenyl)propanoate
(3g). Pale yellow oil. IR (film) 2977, 2935, 2868, 2831, 2787, 1726,
1609, 1453, 1391, 1367, 1254, 1219, 1145, 1095, 1072, 1044, 979, 871,
3.2.21. N,N-Diethyl-2-dimethylamino-3-phenylpropanamide
(6a). White solid. IR (film) 2972, 2934, 2869, 2827, 2784, 1637, 1456,
1379, 1360, 1264, 1220, 1138, 1076, 1040, 974, 938, 881, 789, 736,
845, 779, 740, 700 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.15 (1H, dd,
J¼7.8, 7.8 Hz, ArH), 7.03e6.98 (3H, m, ArH), 3.30 (1H, dd, J¼9.8,
5.4 Hz, NCHCO), 2.98 (1H, dd, J¼13.4, 9.8 Hz, CH2Ar), 2.85 (1H, dd,
J¼13.4, 5.4 Hz, CH2Ar), 2.41 (6H, s, N(CH3)2), 2.30 (3H, s, ArCH3),
701 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 7.25e7.13 (5H, m, Ph), 3.53
(1H, dd, J¼10.5, 3.5 Hz, NCHCO), 3.33 (1H, dq, J¼13.5, 7.0 Hz,
CH2CH3), 3.26e3.16 (3H, m, CH2Ph and CH2CH3), 2.95 (1H, dq, J¼14.8,
7.5 Hz, CH2CH3), 2.84 (1H, dd, J¼12.5, 3.5 Hz, CH2Ph), 2.41 (6H, s, N
(CH3)2),1.04 (3H, t, J¼7.0 Hz, CH2CH3), 0.80 (3H, t, J¼7.5 Hz, CH2CH3);
1.34 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d 170.7, 138.1, 137.6,
130.0, 128.1, 127.0, 126.2, 80.8, 70.0, 41.8, 36.2, 28.1, 21.3;
HRMSeESI (m/z): [MþH]þ calcd for C16H26NO2: 264.1958. Found:
264.1953.
13C NMR (100 MHz, CDCl3)
d 170.1, 139.4, 129.4, 128.2, 126.0, 65.8,
41.62, 41.60, 40.4, 32.6,14.2,12.9. Anal. Calcd for C15H24N2O: C, 72.54;
H, 9.74; N, 11.28. Found: C, 72.36; H, 9.78; N, 11.17.
3.2.16. tert-Butyl (3-chloro-2-methylphenyl)(dimethylamino)acetate
(2h). Colorless oil. IR (film) 2979, 2869, 2822, 2775,1730,1638,1572,
1453,1392,1368,1256,1216,1145,1050,1012, 949, 901, 873, 837, 777,
3.2.22. N,N-Dimethyl-1-(2-methylphenyl)-2-oxo-2-(pyrrolidin-1-yl)
ethanamine (5b). Colorless oil. IR (film) 2951, 2873, 2781,1646,1418,
1342,1308,1259,1226,1190,1096,1048, 985, 958, 916, 864, 828, 754,
713 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.47 (1H, dd, J¼8.0, 1.2 Hz,
ArH), 7.30 (1H, dd, J¼8.0, 1.2 Hz, ArH), 7.12 (1H, dd, J¼8.0, 8.0 Hz,
ArH), 4.09 (1H, s, NCHCO), 2.47 (3H, s, ArCH3), 2.27 (6H, s, N(CH3)2),
729 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.52e7.48 (1H, m, ArH),
1.39 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d
170.6, 137.8, 135.1,
7.23e7.14 (3H, m, ArH), 4.31 (1H, s, NCHCO), 3.59e3.52 (1H, m,
NCH2CH2), 3.47e3.39 (2H, m, NCH2CH2), 3.01e2.94 (1H, m,
NCH2CH2), 2.44 (3H, s, ArCH3), 2.37 (6H, s, N(CH3)2),1.94e1.66 (4H, m,
134.9,128.6,126.8,126.6, 81.3, 71.5, 43.0, 27.9,15.9; HRMSeESI(m/z):
[MþH]þ calcd for C15H23ClNO2: 284.1412. Found: 284.1411.
NCH2CH2); 13C NMR (100 MHz, CDCl3)
d 170.4, 137.3, 134.8, 130.4,
3.2.17. tert-Butyl 3-(2-chlorophenyl)-2-(dimethylamino)propanoate
(3h). Pale yellow oil. IR (film) 2978, 2938, 2868, 2832, 2787, 1731,
1472, 1455, 1393, 1368, 1257, 1222, 1148, 1052, 978, 953, 884, 845,
129.0,127.7,126.2, 68.0, 45.9, 45.6, 42.6, 26.2, 23.8,19.5. Anal. Calcd for
C15H22N2O:C, 73.13;H, 9.00;N,11.37. Found:C, 72.85;H, 8.99;N,11.07.
752, 683 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.35e7.31 (1H, m,
3.2.23. 1-(5-tert-Butoxycarbonyl-2-methylphenyl)-N,N-dimethyl-2-
oxo-2-(pyrrolidin-1-yl)ethanamine (5c). Pale yellow oil. IR (film)
3052, 2977, 2876, 2777, 1710, 1645, 1423, 1368, 1303, 1255, 1185,
ArH), 7.26e7.22 (1H, m, ArH), 7.17e7.12 (2H, m, ArH), 3.44 (1H, dd,
J¼8.0, 6.8 Hz, NCHCO), 3.11e3.06 (2H, m, CH2Ar), 2.43 (6H, s, N
(CH3)2), 1.35 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d
170.6,
1130, 1037, 1001, 987, 944, 850, 763, 736, 702 cmꢁ1 1H NMR
;
136.0, 134.3, 131.6, 129.4, 127.8, 126.5, 81.0, 67.6, 41.8, 33.6, 28.1;
HRMSeESI (m/z): [MþH]þ calcd for C15H23ClNO2: 284.1412.
Found: 284.1404.
(500 MHz, CDCl3)
d
8.01 (1H, d, J¼2.0 Hz, ArH), 7.80 (1H, dd, J¼8.0,
2.0 Hz, ArH), 7.23 (1H, d, J¼8.0 Hz, ArH), 4.33 (1H, s, NCHCO),
3.57e3.51 (1H, m, NCH2CH2), 3.51e3.43 (1H, m, NCH2CH2),
3.40e3.34 (1H, m, NCH2CH2), 3.07e3.00 (1H, m, NCH2CH2), 2.49
(3H, s, ArCH3), 2.37 (6H, s, N(CH3)2), 1.93e1.69 (4H, m, NCH2CH2),
3.2.18. tert-Butyl (dimethylamino)(2,3-dimethylphenyl)acetate (2i).
Colorless oil. IR (film) 2978, 2933, 2867, 2819, 2771, 1730, 1463,
1391,1367,1277,1251,1215,1143,1098,1045, 949, 901, 877, 841, 814,
1.58 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3)
d 169.6, 165.8, 142.7,
135.1, 130.6, 130.1,130.0, 128.6, 80.8, 68.9, 46.0, 45.7, 42.5, 28.2, 26.3,
23.8, 19.8. Anal. Calcd for C20H30N2O3: C, 69.33; H, 8.73; N, 8.09.
Found: C, 69.48; H, 8.98; N, 7.79.
776, 721 cmꢁ1; 1H NMR (400 MHz, acetone-d6)
2.0 Hz, ArH), 7.09 (1H, dd, J¼7.6, 2.0 Hz, ArH), 7.06 (1H, dd, J¼7.6,
7.2 Hz, ArH), 4.19 (1H, s, NCHCO), 2.31 (3H, s, ArCH3), 2.28 (3H, s,
ArCH3), 2.25 (6H, s, N(CH3)2), 1.39 (9H, s, t-Bu); 13C NMR (100 MHz,
d
7.32 (1H, dd, J¼7.2,
3.2.24. N-tert-Butyl-2-(dimethylamino)-2-(2-methylphenyl)acet-
CDCl3)
d
171.3,136.7,135.6,135.5, 129.2, 126.0, 125.3, 80.9, 71.2, 43.0,
amide (5d). White solid. IR (film) 3339, 3064, 2962, 2870, 2826,

9394
E. Tayama et al. / Tetrahedron 66 (2010) 9389e9395
2781, 1681, 1512, 1456, 1391, 1363, 1252, 1228, 1174, 1097, 1040, 916,
888, 759, 738 cmꢁ1; 1H NMR (270 MHz, CDCl3)
7.36e7.29 (1H, m,
2878, 2786, 1651, 1452, 1403, 1376, 1363, 1347, 1265, 1208, 1190,
1141, 1047, 961, 895, 845, 804, 744, 703 cmꢁ1 1H NMR (400 MHz,
CDCl3) 7.35e7.30 (3H, m, ArH), 7.28e7.23 (1H, m, ArH), 7.23e7.12
(5H, m, ArH), 4.43 (1H, s, NCHCO), 3.64 (1H, d, J¼9.2 Hz, NCHCH2O),
3.51 (1H, ddd, J¼10.0, 4.8, 4.8 Hz, NCHCH2O), 3.40 (1H, ddd, J¼9.2,
4.8, 1.2 Hz, NCHCH2O), 3.05 (1H, dd, J¼13.6, 4.8 Hz, CH2Ph), 2.93
(1H, dd, J¼13.6, 10.0 Hz, CH2Ph), 2.45 (3H, s, ArCH3), 2.39 (6H, s, N
(CH3)2), 1.82 (3H, s, C(CH3)2), 1.58 (3H, s, C(CH3)2); 13C NMR
d
;
ArH), 7.22e7.10 (3H, m, ArH), 6.92 (1H, br, NH), 3.90 (1H, s, NCHCO),
d
2.46 (3H, s, ArCH3), 2.21 (6H, s, N(CH3)2), 1.34 (9H, s, t-Bu); 13C NMR
(68 MHz, CDCl3) d 171.3, 137.3, 136.2, 130.8, 127.3, 126.9, 126.0, 72.7,
50.5, 43.9, 28.6, 20.5. Anal. Calcd for C15H24N2O: C, 72.54; H, 9.74; N,
11.28. Found: C, 72.42; H, 9.89; N, 11.00.
3.2.25. N-n-Butyl-2-(dimethylamino)-2-(2-methylphenyl)acetamide
(5e). Colorless oil. IR (film) 3313, 3063, 3023, 2956, 2868, 2823,
2776, 1660, 1521, 1463, 1376, 1239, 1176, 1155, 1083, 1041, 982, 895,
(100 MHz, CDCl3) d 169.5, 137.7, 137.3, 134.8, 130.9, 129.2, 128.9,
128.3, 128.1, 127.0, 125.9, 95.6, 67.2, 66.4, 57.6, 41.5, 40.7, 27.5, 22.3,
19.3. Anal. Calcd for C23H30N2O2: C, 75.37; H, 8.25; N, 7.64. Found: C,
75.38; H, 8.39; N, 7.55.
743 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
7.35 (1H, d, J¼6.5 Hz, ArH),
7.19e7.11 (3H, m, ArH), 6.96 (1H, br, NH), 4.01 (1H, s, NCHCO),
3.31e3.18 (2H, m, CH2CH2CH2CH3), 2.47 (3H, s, ArCH3), 2.23 (6H, s,
N(CH3)2), 1.54e1.43 (2H, m, CH2CH2CH2CH3), 1.37e1.27 (2H, m,
CH2CH2CH2CH3), 0.90 (3H, t, J¼7.0 Hz, CH2CH2CH2CH3); 13C NMR
3.2.30. (2R,40R)-2-(40-Benzyl-20,20-dimethyl-10,30-oxazolidin-30-yl)-
N,N-dimethyl-1-(2-methylphenyl)-2-oxo-ethanamine
[(2R)-8a].
589 þ20.1 (c 0.50, EtOH); IR (film) 3060, 3028, 2980,
2933, 2872, 2783, 1647, 1452, 1404, 1375, 1342, 1308, 1265, 1242,
1207, 1187, 1142, 1077, 1045, 962, 913, 845, 806, 748, 701 cmꢁ1 1H
NMR (400 MHz, CDCl3) 7.60e7.55 (1H, m, ArH), 7.37e7.14 (6H, m,
26
Colorless oil. [a]
(100 MHz, CDCl3) d 172.0, 137.3, 136.0, 130.8, 127.4, 127.1, 126.0, 72.3,
44.0, 38.7, 31.6, 20.4, 20.1, 13.7. Anal. Calcd for C15H24N2O: C, 72.54;
H, 9.74; N, 11.28. Found: C, 72.65; H, 9.85; N, 11.00.
;
d
ArH), 6.97 (2H, d, J¼7.2 Hz, ArH), 4.84 (1H, s, NCHCO), 4.27e4.19
(1H, m, NCHCH2O), 3.84e3.74 (2H, m, NCHCH2O), 2.55e2.43 (1H,
m, CH2Ph), 2.51 (3H, s, ArCH3), 2.44 (6H, s, N(CH3)2), 2.27 (1H, dd,
J¼14.0, 2.6 Hz, CH2Ph), 1.76 (3H, s, C(CH3)2), 1.66 (3H, s, C(CH3)2);
3.2.26. 2-(Dimethylamino)-2-(2-methylphenyl)-N-phenylacetamide
(5f). Colorless oil. IR (film) 3320, 3055, 2984, 2956, 2873, 2832,
2787, 1688, 1599,1519,1441,1311,1266,1169, 1153,1098,1079, 1040,
962, 898, 744, 703 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
9.00 (1H, br,
13C NMR (100 MHz, CDCl3)
d 168.8, 137.8, 137.6, 134.7, 131.0, 129.4,
NH), 7.57 (2H, ddd, J¼8.0, 1.2, 1.2H, ArH), 7.42e7.38 (1H, m, ArH),
7.31 (2H, ddd, J¼8.0, 1.2, 1.2 Hz, ArH), 7.22e7.13 (3H, m, ArH), 7.09
(1H, tt, J¼7.4, 1.2 Hz, ArH), 4.17 (1H, s, NCHCO), 2.51 (3H, s, ArCH3),
129.0, 128.7, 128.0, 126.7, 125.8, 96.1, 66.4, 66.0, 59.3, 41.2, 39.7, 26.7,
23.5, 19.5; HRMSeESI (m/z): [MþH]þ calcd for C23H31N2O2:
367.2380. Found: 367.2367.
2.31 (6H, s, N(CH3)2); 13C NMR (100 MHz, CDCl3)
d 170.2, 137.8,
137.5, 135.2, 131.0, 129.0, 127.8, 127.3, 126.3, 124.0, 119.4, 72.6, 44.0,
20.5. Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51; N,10.44. Found: C,
76.07; H, 7.64; N, 10.29.
3.2.31. (2S,40R)-N,N-Dimethyl-2-(20,20-dimethyl-40-phenyl-10,30-ox-
azolidin-30-yl)-1-(2-methylphenyl)-2-oxo-ethanamine
[(2S)-8b].
24
Pale yellow oil. [
a
]
ꢁ33.6 (c 1.00, EtOH); IR (film) 2982, 2930,
589
2873, 2787, 1651, 1604, 1478, 1451, 1397, 1346, 1306, 1246, 1200,
1169, 1140, 1069, 962, 928, 844, 821, 750, 702 cmꢁ1 1H NMR
(400 MHz, CDCl3) 7.43e7.31 (4H, m, ArH), 7.27e7.16 (5H, m, ArH),
3.2.27. 2-(5-tert-Butoxycarbonyl-2-methylphenyl)-N-n-butyl-2-(di-
methylamino)acetamide (5g). Pale yellow oil. IR (film) 3339, 3054,
2961, 2872, 2829, 2783, 1711, 1675, 1518, 1460, 1368, 1303, 1263,
;
d
4.30 (1H, dd, J¼6.4, 2.0 Hz, NCHPh), 4.10 (1H, s, NCHCO), 4.03 (1H,
dd, J¼8.8, 6.4 Hz, CH2O), 3.72 (1H, dd, J¼8.8, 2.0 Hz, CH2O), 2.23
(6H, s, N(CH3)2), 2.10 (3H, s, ArCH3), 1.96 (3H, s, C(CH3)2), 1.64 (3H, s,
1165, 1129, 1039, 947, 891, 849, 737, 703 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
7.99 (1H, d, J¼2.0 Hz, ArH), 7.75 (1H, dd, J¼8.0, 2.0 Hz, ArH),
7.20 (1H, d, J¼8.0 Hz, ArH), 7.07 (1H, br, NH), 4.02 (1H, s, NCHCO),
3.26 (2H, dt, J¼6.8, 6.8 Hz, CH2CH2CH2CH3), 2.52 (3H, s, ArCH3), 2.23
(6H, s, N(CH3)2), 1.58 (9H, s, t-Bu), 1.54e1.43 (2H, m,
CH2CH2CH2CH3), 1.39e1.27 (2H, m, CH2CH2CH2CH3), 0.89 (3H, t,
C(CH3)2); 13C NMR (100 MHz, CDCl3)
d 170.6, 141.7, 138.5, 134.5,
130.8, 128.9, 128.2, 128.0, 127.9, 126.0, 125.7, 96.4, 71.3, 67.0, 60.0,
41.2, 25.9, 22.3, 18.8. Anal. Calcd for C22H28N2O2: C, 74.97; H, 8.01;
N, 7.95. Found: C, 74.96; H, 8.19; N, 7.72.
J¼7.2 Hz, CH2CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
d 171.7,165.6,
142.3, 136.3, 130.7, 130.0, 128.4, 128.3, 80.7, 72.1, 44.0, 38.7, 31.6,
28.2, 20.7, 20.1,13.7. Anal. Calcd for C20H32N2O3: C, 68.93; H, 9.26; N,
8.04. Found: C, 68.78; H, 9.37; N, 7.82.
3.2.32. (2S,10R)-N-(10-Benzyl-20-hydroxyethyl)-2-(dimethylamino)-
26
2-(2-methylphenyl)acetamide (9a). White solid. [
a
]
þ83.3 (c
589
1.00, EtOH); IR (film) 3363, 3054, 2985, 2954, 2872, 2830, 2785,
1659, 1513, 1462, 1337, 1266, 1174, 1155, 1097, 1042, 959, 896, 741,
3.2.28. N-n-Butyl-2-(dimethylamino)-N-methyl-2-(2-methylphenyl)
acetamide (5h). Pale yellow oil. 6:4 mixture of rotamers. IR (film)
2957, 2929, 2871, 2784, 1650, 1463, 1403, 1293, 1255, 1190, 1137,
703 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.33e7.19 (7H, m, ArH),
7.17e7.13 (3H, m, ArH and NH), 4.20e4.10 (1H, m, NCHCH2O), 3.93
(1H, s, NCHCO), 3.64 (1H, dd, J¼11.0, 3.6 Hz, NCHCH2O), 3.55 (1H,
dd, J¼11.0, 5.2 Hz, NCHCH2O), 3.04e2.50 (1H, br, OH), 2.99 (1H, dd,
J¼14.0, 6.4 Hz, CH2Ph), 2.82 (1H, dd, J¼14.0, 9.0 Hz, CH2Ph), 2.42
(3H, s, ArCH3), 2.01 (6H, s, N(CH3)2); 13C NMR (100 MHz, CDCl3)
1090, 1042, 957, 932, 892, 863, 846, 794, 752 cmꢁ1 1H NMR
;
(270 MHz, CDCl3) d 7.43e7.34 (1H, m, ArH), 7.23e7.11 (3H, m, ArH),
4.47 (1H, s, NCHCO), 3.41 (0.6H, dd, J¼13.5, 7.3 Hz, CH2CH2CH2CH3),
3.30 (0.6H, dd, J¼13.5, 7.3 Hz, CH2CH2CH2CH3), 3.20e3.04 (0.4H, m,
CH2CH2CH2CH3), 2.95e2.77 (0.4H, m, CH2CH2CH2CH3), 2.90 (1.2H,
s, NCH3), 2.73 (1.8H, s, NCH3), 2.44 (3H, s, ArCH3), 2.39 (6H, s, N
(CH3)2), 1.54e1.08 (4H, m, CH2CH2CH2CH3), 0.91 (1.8H, t, J¼7.3 Hz,
CH2CH2CH2CH3), 0.84 (1.2H, t, J¼6.9 Hz, CH2CH2CH2CH3); 13C NMR
d
173.3, 137.6, 137.3, 135.8, 130.9, 129.1, 128.6, 127.6, 127.1, 126.7,
126.2, 71.9, 65.0, 53.0, 43.8, 36.9, 20.4. Anal. Calcd for C20H26N2O2:
C, 73.59; H, 8.03; N, 8.58. Found: C, 73.34; H, 8.08; N, 8.47.
3.2.33. (2S,10R)-2-(Dimethylamino)-N-(20-hydroxy-10-phenylethyl)-
25
(68 MHz, CDCl3)
d
171.8, 171.6, 137.2, 136.8, 135.2, 134.9, 130.6, 130.5,
2-(2-methylphenyl)acetamide (9b). White solid. [
a
]
589 þ5.9 (c 1.00,
129.0, 128.8, 127.82, 127.75, 126.1, 126.0, 66.4, 66.2, 48.9, 47.8, 42.3,
42.1, 34.6, 33.4, 30.3, 29.1, 20.0, 19.3, 13.82, 13.79. Anal. Calcd for
C16H26N2O: C, 73.24; H, 9.99; N, 10.68. Found: C, 73.12; H, 10.10; N,
10.43.
EtOH); IR (film) 3348, 3245, 3055, 2987, 2956, 2870, 2830, 2783,
1669, 1507, 1463, 1335, 1265, 1177, 1155, 1070, 1043, 983, 896, 850,
747, 705 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.68 (1H, d, J¼6.8 Hz,
NH), 7.43 (1H, dt, J¼8.4, 2.0 Hz, ArH), 7.40e7.34 (2H, m, ArH),
7.34e7.28 (3H, m, ArH), 7.24e7.15 (3H, m, ArH), 5.00 (1H, ddd,
J¼6.8, 6.0, 4.6 Hz, NCHPh), 4.08 (1H, s, NCHCO), 3.83 (1H, dd, J¼11.2,
6.0 Hz, CH2O), 3.79 (1H, dd, J¼11.2, 4.6 Hz, CH2O), 3.00e2.50 (1H,
br, OH), 2.48 (3H, s, ArCH3), 2.21 (6H, s, N(CH3)2); 13C NMR
3.2.29. (2S,40R)-2-(40-Benzyl-20,20-dimethyl-10,30-oxazolidin-30-yl)-
N,N-dimethyl-1-(2-methylphenyl)-2-oxo-ethanamine
[(2S)-8a].
25
White solid. [a]
589 þ72.1 (c 1.00, EtOH); IR (film) 3055, 2984, 2935,

E. Tayama et al. / Tetrahedron 66 (2010) 9389e9395
9395
Soc. 1964, 86, 1108e1110; (i) Puterbaugh, W. H.; Hauser, C. R. J. Am. Chem. Soc.
1964, 86, 1105e1107; (j) Jones, G. C.; Beard, W. Q.; Hauser, C. R. J. Org. Chem.
1963, 28, 199e203; (k) Beard, W. Q., Jr.; Hauser, C. R. J. Org. Chem. 1961, 26,
371e375; (l) Beard, W. Q., Jr.; Hauser, C. R. J. Org. Chem. 1960, 25, 334e343; (m)
Lednicer, D.; Hauser, C. R. J. Am. Chem. Soc. 1957, 79, 4449e4451; (n) Brasen, W.
R.; Hauser, C. R. Org. Synth. 1954, 34, 61e63; (o) Kantor, S. W.; Hauser, C. R. J. Am.
Chem. Soc. 1951, 73, 4122e4131; (p) Wittig, G.; Tenhaeff, H.; Schoch, W.; Koenig,
G. Liebigs Ann. Chem. 1951, 572, 1e22; (q) Sommelet, M. C.R. Hebd. Sceances.
Acad. Sci. 1937, 205, 56e58.
(100 MHz, CDCl3)
d 173.0, 139.0, 137.4, 135.6, 131.0, 128.9, 127.9,
127.7, 127.3, 126.8, 126.2, 72.0, 66.6, 56.0, 44.0, 20.4. Anal. Calcd for
C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C, 73.06; H, 7.83; N,
8.71.
Acknowledgements
3. Studies about competition between base-induced [1,2] Stevens and SeH re-
This work was supported by The Union Tool Scholarship Foun-
dation, The Foundation for Japanese Chemical Research, and The
Uchida Energy Science Promotion Foundation.
ꢀ
arrangements: (a) Jonczyk, A.; Lipiak, D. J. Org. Chem. 1991, 56, 6933e6937; (b)
ꢀ
Jonczyk, A.; Lipiak, D.; Sienkiewicz, K. Synlett 1991, 493e496.
4. (a) Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem. 2008, 6, 3673e3680;
(b) Tayama, E.; Kimura, H. Angew. Chem., Int. Ed. 2007, 46, 8869e8871.
5. The purity of solid t-BuOK did not affect the results. Both the reagent grade
(97% purity) and the sublimed grade (99% purity) afforded practically identical
results.
Supplementary data
6. Commercially available from Aldrich or TCI. Both the reagents afforded prac-
tically identical results.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.09.105. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
7. Previously, it was reported that both the solid and THF-based solution of
t-BuOK form tetramers. See: (a) Schmidt, P.; Lochmann, L.; Schneider, B. J. Mol.
ꢁ
Struct. 1971, 9, 403e411; (b) Halaska, V.; Lochmann, L.; Lim, D. Collect. Czech.
Chem. Commun. 1968, 33, 3245e3253. However, our experimental results
showed different activities.
8. We attempted the reactions of amino ketone-derived ammonium salts (tert-
butyl and phenyl ketones) using t-BuOK/THF solution instead of ester 1a and
amide 4a. However, the corresponding SeH products were not obtained. Sta-
bilization of enolate form B would inhibit SeH rearrangement.
9. Solubility of sublimed solid t-BuOK in THF (25 g/100 g) was reported. See: (a)
Feuer, H.; Shepherd, J. W.; Savides, C. J. Am. Chem. Soc. 1956, 78, 4364e4367.
10. Studies about substituent effects on the benzyl group in fluoride-induced SeH
rearrangement were reported. See: (a) Tanaka, T.; Shirai, N.; Sato, Y. Chem.
Pharm. Bull. 1992, 40, 518e520; (b) Nakano, M.; Sato, Y. J. Org. Chem. 1987, 52,
1844e1847.
11. The stereochemistry of 8b was determined after deacetonization to 9b. The 2S-
configuration of 9b was determined by 1H NMR comparison with the (S)-au-
thentic sample. The configuration of 8a and 9a were determined by the analogy
with 8b and 9b. For experimental details, see Supplementary data.
References and notes
ꢀ
1. For reviews: (a) Marko, I. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.;Pergamon:Oxford,1991;Vol. 3, Chapter3.10;(b)Nitrogen,Oxygen,
and Sulfur Ylide Chemistry; Clark, J. S., Ed.; Oxford University: Oxford, 2002.
2. Examples of base-induced SeH rearrangements of ammonium ylides: (a) Ha-
nessian, S.; Talbot, C.; Saravanan, P. Synthesis 2006, 723e734; (b) Klunder, J. M.
J. Heterocycl. Chem. 1995, 32, 1687e1691; (c) Weinreb, S. M.; Basha, F. Z.; Hibino,
S.; Khatri, N. A.; Kim, D.; Pye, W. E.; Wu, T.-T. J. Am. Chem. Soc. 1982, 104,
536e544; (d) Bumgardner, C. L.; Hsu, H.-B.; Afghahi, F.; Roberts, W. L.; Pur-
rington, S. T. J. Org. Chem. 1979, 44, 2348e2353; (e) Sanders, E. B.; Secor, H. V.;
Seeman, J. I. J. Org. Chem. 1978, 43, 324e330; (f) Mander, L. N.; Turner, J. V. J. Org.
Chem. 1972, 38, 2915e2916; (g) Klein, K. P.; Van Eenam, D. N.; Hauser, C. R. J.
Org. Chem. 1967, 32, 1155e1160; (h) Puterbaugh, W. H.; Hauser, C. R. J. Am. Chem.