Conjugate addition of aromatic amines to ethenetricarboxylates

Article abstract of DOI:10.1016/j.tet.2006.12.058

The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl₂

Full text of DOI:10.1016/j.tet.2006.12.058

Tetrahedron 63 (2007) 2320–2327
Conjugate addition of aromatic amines to ethenetricarboxylates
*
Shoko Yamazaki, Machiko Yamamoto and Akiko Sumi
Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528, Japan
Received 4 November 2006; revised 18 December 2006; accepted 19 December 2006
Available online 22 December 2006
Abstract—The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive
electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl2 and ZnBr2 at room
temperature gave amine adducts in high yields. The products were converted to a-amino acid, DL-aspartic acid derivatives. Using Lewis acids
such as Sc(OTf)3 and Zn(OTf)2 at higher temperature (40–80 ꢀC), the reaction of ethenetricarboxylates and N-methylaniline gave an aromatic
substitution product. A catalytic enantioselective conjugate addition using a chiral Lewis acid was also investigated. For example, the reaction
of 1,1-diethyl 2-tert-butyl ethenetricarboxylate with N-methylaniline in the presence of chiral bisoxazoline-Cu(II) complex in THF at ꢁ20 ꢀC
for 17 h gave an amine adduct in 91% yield and 78% ee. On the other hand, the reaction with aniline and primary aniline derivatives gave
adducts with almost no ee%.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
work-up gave amine adducts 3 in high yields (Eq. 1, Table 1).
The products from aniline 2a and N-methylaniline 2b are
stable to silica gel column chromatography. The amine
adducts from aliphatic amines such as benzylamine 2c, pyr-
rolidine, and N-methyl benzylamine are obtained quantita-
tively as well, however, they are unstable to silica gel
column chromatography and partially decomposed to start-
ing materials.5 The reaction of diethyl benzylidene malonate
(PhCH]C(CO2Et)2) with N-methylaniline 2b did not give
an adduct in dichloromethane at room temperature with
and without ZnCl2.
The conjugate addition of amines is considered to be a useful
reaction in synthetic organic chemistry.1 The reaction leads
to formation of carbon–nitrogen bonds and b-amino acid
derivatives.2 The conjugate addition reaction sometimes in-
volves reversibility arising from negative reaction entropy.3
The exploration of both kinetically and thermodynamically
favorable and synthetically useful systems is of high interest.
We are interested in exploring reactivity and utility of highly
electrophilic olefins, ethenetricarboxylates 1.4 The reaction
of 1 and aminesmay leadtoa-aminoacidderivatives. Nucleo-
philic reaction of aromatic amines also involves a selectivity
issue for nitrogen addition (C–N bond formation) or aromatic
substitution (C–C bond formation). In this work, the reaction
of ethenetricarboxylates with aromatic amines, transforma-
tion of the aza-Michael adducts to aspartic acid derivatives,
and chiral Lewis acid-catalyzed reaction were investigated.
Selective formation of a C–N or C–C bond in the presence
of Lewis acid has been also found in the reaction of 1 and
N-methylaniline.
r.t.
CH2Cl2
CO2R1
R1O2C
R2O2C
CO2R1
NR3R4
R1O2C
R2O2C
NHR3R4
+
2a: R3 = H, R4 = Ph
ð1Þ
1a: R1 = Et, R2 = tBu
3
2b: R3 = CH3, R4 = Ph
1b: R1 = Et, R2 = Et
2c: R3 = H, R4 = CH2Ph
1c: R1 = Et, R2 = CH2Ph
1d: R1 = CH2Ph, R2 = tBu
Table 1. Reaction of 1 and 2 without Lewis acid in CH2Cl2
2. Results and discussion
Entry Substrate R1
R2
Amine R3
R4
3 (Yield, %)a
tBu
tBu
Et
2a
2b
2a
2b
H
Ph
3a (98)
3b (91)
3c (88)
3d (100)
3e (94b)
3f (98)
3g (61)
The reaction of reactive electrophilic olefins, ethenetricar-
boxylates 1, and various amines with and without catalytic
Lewis acids was investigated. The reaction of ethenetri-
carboxylates 1a–d and aromatic amines 2a–c in dichloro-
methane at room temperature overnight and subsequent
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1d
1d
1d
Et
Et
Et
Et
Et
CH3 Ph
Ph
H
Et
CH3 Ph
CH3 Ph
H
CH3 Ph
CH2Ph 2b
CH2Ph tBu
CH2Ph tBu
CH2Ph tBu
2a
2b
2c
Ph
H
CH2Ph 3h (100)
Keywords: Ethenetricarboxylate; Aromatic amine; Conjugate addition;
Lewis acid.
* Corresponding author. E-mail: yamazaks@nara-edu.ac.jp
a
Isolated yield.
A small amount of unreacted 1c could not be removed.
b
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.058

S. Yamazaki et al. / Tetrahedron 63 (2007) 2320–2327
2321
1H NMR spectra of a mixture of 1a and aniline 2a in CDCl3
showed the immediate formation of adducts 3a. On the other
hand, the reaction of 1a and N-methylaniline 2b proceeds
slowly as shown in Figure 1. The reaction was not complete
after 18 h. The reaction might complete by concentration of
the solution, because the reaction without solvent proceeds
faster. Equilibrium in solution is assumed. DGꢀ differences
of 1b+2b/3d were calculated as positive values (less
stable), +16.0 and +15.4 kcal/mol by B3LYP/6-31G* in the
gas phase and SCRF¼dipole (solvent CH2Cl2), respec-
tively.6,7 The compound 3d was also calculated to have
a large dipole moment, m¼9.39 D. The observation that the
equilibrium is shifted to the right without solvent can be
understood by stabilization of dipole–dipole interactions
between molecules of the products 3.8
2b in the presence of ZnCl2, ZnBr2, and Sc(OTf)3 (0.2 equiv)
at room temperature gave 3b in high yields.9 Using Lewis
acids such as ZnCl2, Sc(OTf)3, and Zn(OTf)2 at higher tem-
perature (40–80 ꢀC), the reaction of 1 and N-methylaniline
2b gave an aromatic substitution product 4a as the major
product (Eq. 2, Table 2).10 In addition, the reaction of isolated
3b with Sc(OTf)3 (0.2 equiv) in CH2Cl2 at 40 ꢀC for 4 h gave
4b in 75% yield.11 The formation of a C–N bond must be
reversible and amine adducts 3 are transformed to the stable
C–C bond formation in the presence of the Lewis acid at
higher temperature. A small amount of compound 5 was iso-
lated from the reaction shown in entries 4 and 5. Compound 5
may be transiently formed during the formation of 4a and it
also shows the reversibility of C–N bond formation.
CO2R1
NHMe
R1O2C
The reaction of 1a and 2b in the presence of zinc chloride
(0.2 equiv) in CDCl3 at room temperature proceeded further
faster than without solvent to give 3b. The reaction of 1a and
+
Lewis Acid
R2O2C
1a: R1 = Et, R2 = tBu
1b: R1 = Et, R2 = Et
2b
100
1d: R1 = CH2Ph, R2 = tBu
ð2Þ
CDCl3(0.55M)
90
80
70
60
50
40
30
20
10
0
ZnCl2/CDCl3(0.55M)
CD2Cl2(0.55M)
neat
CO2R1
R1O2C
R2O2C
CO2R1
R1O2C
R2O2C
N
NHMe
3
4
The amine adducts 3 are considered as b- and a-amino acid
equivalents.12 Product elaboration was attempted. Thus, the
amine adducts 3f and 3h were converted to DL-aspartic acid
derivatives (Eq. 3). Dibenzyl esters 3f and 3h were trans-
formed to acetyl products 6a and 6b in order to decrease
the basicity of nitrogen and increase the stability toward
b-elimination of amine. Hydrogenolysis of 6a and 6b and
subsequent decarboxylation led to DL-aspartic acid deriva-
tives 7a and 7b smoothly.
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
time (h)
Figure 1. Reaction of 1a and N-methylaniline 2b (25 ꢀC). Product percent-
age was estimated by NMR.
Table 2. Reaction of 1 and 2b in the presence of Lewis acid
Entry
Substrate
Lewis acid (equiv)
Solvent
Condition
3 (Yield, %)
4 (Yield, %)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1d
1d
1d
ZnCl2 (0.2)
ZnBr2 (0.2)
Sc(OTf)3 (0.2)
ZnCl2 (0.2)
ZnCl2 (0.2)
Zn(OTf)2 (0.2)
Sc(OTf)3 (0.2)
Sc(OTf)3 (0.2)
ZnCl2 (0.2)
Sc(OTf)3 (0.2)
Sc(OTf)3 (0.2)
ZnCl2 (0.2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
CH2Cl2
CH2Cl2
rt,a 16 h
3b (89)
3b (70)
3b (quant.)
3b (11)
rt,a 16 h
rt,a 16 h
40 ꢀC, 16 h
80 ꢀC, 2 h
80 ꢀC, 16 h
40 ꢀC, 16 h
80 ꢀC, 2 h
rt,a 16 h
4a (37)b
4a (52)c
4a (42)
4a (58)
4a (75)
9
3c (77)
3g (77)
10
11
12
13
14
40 ꢀC, 18 h
80 ꢀC, 17 h
rt, 16 h
40 ꢀC, 16 h
40 ꢀC, 16 h
4b (83)
4b (65)
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
Zn(OTf)3 (0.2)
Sc(OTf)3 (0.2)
4c (82)
4c (85)
a
rt refers to ca. 20–25 ꢀC.
Compound 5 (as a diastereomixture) was isolated in 23% yield.
Compound 5 was isolated in 8% yield.
b
c
CO2Et
EtO2C
tBuO2C
NMe
CO2Et
tBuO2C
CO2Et
5

2322
S. Yamazaki et al. / Tetrahedron 63 (2007) 2320–2327
17), whereas ligands 10 and 11 gave lower ee% (entries 9, 10,
CO2CH2Ph
CO2CH2Ph
AcCl
PhH2CO2C
tBuO2C
PhH2CO2C
tBuO2C
18, and 19). Reactions in dichloromethane have also been ex-
amined (entries 4, 5, 20, and 21). Use of CH2Cl2 gave similar
or lower yields and ee% compared to THF in the most cases.
The detailed solvent effects are under investigation. Aniline
2a as described above and primary aniline derivatives 2e–g
bearing para and ortho-substituents (4-CF3, 2-OCH3, and
2-Cl) gave almost no ee% (Eq. 5).
Et3N
CH2Cl2
NR4
O
NHR4
3f: R4 = Ph
6a: R4 = Ph (72%)
3h: R4 = CH2Ph
6b: R4 = CH2Ph (71%)
ð3Þ
CO2H
1) H2, Pd-C
MeOH
The obtained amine adducts in enantiomerically enriched
form did not give suitable crystals for X-ray analysis and
the absolute stereochemistry has not been determined yet.
2) H2O/EtOH
NR4
O
tBuO2C
7a: R4 = Ph (75%)
7b: R4 = CH2Ph (58%)
CO2R1
R1O2C
NHMe
+
8(or 9,10,11)-Cu(OTf)2
Catalytic enantioselective conjugate addition using a chiral
Lewis acid was also investigated. Chiral bisoxazolines
were first examined as chiral ligands of Lewis acid because
the Friedel–Crafts reaction of substrates 1 using the catalysts
has been proven to be effective.4d The reaction of 1,1-diethyl
2-tert-butyl ethenetricarboxylate 1a with aniline 2a in the
presence of a catalytic amount of chiral bisoxazoline
((S,S)-2,20-isopropylidene bis-(4-tert-butyl-2-oxazoline) 8)
R2O2C
THF
1a: R1 = Et, R2 = tBu
1b: R1 = Et, R2 = Et
X
2b: X = H
2d: X = Cl
1c: R1 = Et, R2 = CH2Ph
1d: R1 = CH2Ph, R2 = tBu
CO2R1
N
R1O2C
R2O2C
X
13
copper(II) complex, 8-Cu(OTf)2 (10%) in THF was first
examined, however, the reaction gave an adduct with almost
no ee%. The reaction of 1a with N-methylaniline 2b in the
presence of 8-Cu(OTf)2 (10%) in THF at room temperature
overnight gave an amine adduct 3b in 79% yield and 40%
ee (Eq. 4, Table 3). When the reaction temperature was de-
creased to ꢁ20 ꢀC, the reaction gave an amine adduct 3b in
91% yield and 78% ee. The reaction did not proceed at
ꢁ40 ꢀC. Reactions of substrates 1a–d and N-methylanilines
2b and 2d under various reaction conditions such as use of
chiral ligands 914 and 10 and other metal triflates were also
examined. Use of 8-Zn(OTf)2 also gave similar ee% at room
temperature and ꢁ20 ꢀC compared to use of 8-Cu(OTf)2
(entries 6 and 7). By use of 8-Mg(OTf)2 or 8-Sc(OTf)3 the re-
action proceeded with almost no ee%. Chiral ligands 9 gave
similar ee% at room temperature compared to 8 (entries 8 and
3b: X = H, R1 = Et, R2 = tBu
3i: X = Cl, R1 = Et, R2 = tBu
3d: X = H, R1 = Et, R2 = Et
3e: X = H, R1 = Et, R2 = CH2Ph
3g: R1 = CH2Ph, R2 = tBu
ð4Þ
H
O
O
O
O
N
N
N
N
tBu
iPr
tBu
iPr
8
9
O
O
O
O
N
N
N
N
Bn
Bn
10
11
Table 3. Reaction of 1 with 2 in the presence of chiral Lewis acid
Entry
Substrate
Amine
Lewis acid
Condition
3 (Yield, %)
ee (%)
[a]D (ꢀ)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2d
2d
2b
2b
2b
2b
2b
2b
2b
2b
2b
8-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
8-Zn(OTf)2
8-Zn(OTf)2
9-Cu(OTf)2
10-Cu(OTf)2
11-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
9-Cu(OTf)2
10-Cu(OTf)2
11-Cu(OTf)2
8-Cu(OTf)2
8-Cu(OTf)2
rt/THF
3b (79)
3b (91)
No reaction
3b (53)b
3b (86)b
3b (56)
3b (54)
3b (83)
3b (56)
3b (75)
3i (74)
40
78
ꢁ84
ꢁ20 ꢀC/THF
ꢁ40 ꢀC/THF
rt/CH2Cl2
ꢁ20 ꢀC/CH2Cl2
rt/THF
ꢁ163
69
77
49
61
49
39
0.9
75
87
41
43
71
41
58
22
18
23
24
ꢁ126
ꢁ146
ꢁ110
ꢁ115
ꢁ100
ꢁ64
ꢁ20 ꢀC/THF
rt/THF
rt/THF
9
10
11
12
13
14
15
16
17
18
19
20
21
rt/THF
rt/THF
ꢁ5.5
ꢁ110
ꢁ159
ꢁ103
ꢁ61
ꢁ20 ꢀC/THF
3i (87)
rta/THF
3d (78)
3e (75)
3g (58)
3g (79)
3g (68)
3g (61)
3g (78)
3g (48)
3g (69)
rta/THF
rt/THF
ꢁ80
ꢁ20 ꢀC/THF
ꢁ62
rt/THF
rt/THF
ꢁ81
ꢁ28
rt/THF
rt/CH2Cl2
ꢁ20 ꢀC/CH2Cl2
+25
ꢁ23
ꢁ29
a
The reaction at ꢁ20 ꢀC gave inferior yields and ee% to rt.
A small amount of unreacted 1a could not be removed.
b

S. Yamazaki et al. / Tetrahedron 63 (2007) 2320–2327
2323
NH2
3. Experimental section
3.1. General methods
CO2Et
+
CO2Et
EtO2C
EtO2C
X
8-Cu(OTf)2
THF, r.t.
tBuO2C
tBuO2C
N
H
X
1a
3 with almost no ee%
Melting points are uncorrected. IR spectra were recorded in
the FT-mode. H NMR spectra were recorded at 400 MHz.
2a: X = H
1
2e: X = 4-CF3
2f: X = 2-OCH3
2g: X = 2-Cl
3a: X = H (94% yield)
13C NMR spectra were recorded at 100.6 MHz. 1H chemical
3j: X = 4-CF3 (90% yield)
3k: X = 2-OCH3 (45% yield)
3l: X = 2-Cl (91% yield)
shifts are reported in parts per million relative to Me4Si. 13
C
chemical shifts are reported in parts per million relative to
CDCl3 (77.1 ppm). 19F chemical shifts are reported in parts
per million relative to CFCl3. 13C multiplicities were deter-
mined by DEPT and HSQC. Mass spectra were recorded at
an ionizing voltage of 70 eV by EI or FAB. HPLC analysis
was performed with a UV detector (detection, 254 nm light)
and flow rate of 1.0 mL/min using a CHIRALPAK AS-H
(0.46 cmꢂ250 mm) column at 30 ꢀC. Optical rotations
were measured with a 1 cm i.d.ꢂ10 cm cell. All reactions
were carried out under a nitrogen atmosphere.
ð5Þ
Amine conjugate addition mechanisms in neutral conditions
have been studied.15,16 The studies suggest that the reaction
proceeds with trimeric or dimeric amines. In Lewis acid-
promoted amine conjugate addition, it may be also neces-
sary to take into account the trimeric or dimeric forms of
amine nucleophiles. Evans and co-workers have proposed
a mechanism for the catalytic asymmetric Mukaiyama–
Michael reaction of arylidene malonate.17 However, the
proposed facial selectivity is opposite to the Friedel–
Crafts/Michael reaction of arylidene malonate and ethene-
tricarboxylates 1 with indoles because the two faces of
the complex may not be simply differentiated.4d We have
explained the observed enantioselectivity by the secondary
orbital interaction on approach of indole to the less hindered
side of bisoxazoline-Cu(II)-coordinated complex of 1.4d
The facial selectivity in conjugate addition of amines with
bisoxazoline-Cu(II)-coordinated complex of 1 by steric
interaction is not straightforward. The diastereomeric inter-
action of the two faces with amine nucleophile will be
further investigated as well as the absolute stereochemistry
determination.
3.2. Typical experimental procedure (Table 2, entry 1)
To a solution of 1a (272 mg, 1.0 mmol) in dichloromethane
(1.8 mL) were added N-methylaniline 2b (107 mg, 0.11 mL,
1.0 mmol) and ZnCl2 (27 mg, 0.2 mmol) at 0 ꢀC. The mix-
ture was allowed to warm to room temperature and stirred
overnight (16 h). The reaction mixture was quenched by
water and then saturated aqueous NaHCO3. The mixture
was extracted with dichloromethane and the organic phase
was washed with water, dried (Na2SO4), and evaporated
in vacuo. The residue was purified by column chromato-
graphy over silica gel with hexane–ether as eluent to give
3b (338 mg, 89%).
One feature of the aromatic amine addition of 1 is that the
products are relatively stable at room temperature and to
silica gel column chromatography. In the reaction mecha-
nism of b-elimination of amine in neutral and acidic condi-
tions similar to the amine addition process, more molecules
of 3 or eliminated amine may participate in the proton
transfer step.15,16 The acidity of malonate hydrogen and ba-
sicity of the amino group facilitate the elimination process.
The introduction of an ester group at the 2-position of
methylene malonates for a decrease in basicity of the amino
group by electron-withdrawing effects and use of aromatic
amines seem to increase the stability of the amine adducts
toward silica gel column chromatography and room tem-
perature conditions to some degree.
3.2.1. Compound 3b. Rf ¼0.7 (hexane–ether¼1:1); pale
1
yellow oil; H NMR (400 MHz, CDCl3) d (ppm) 1.07 (t,
J¼7.1 Hz, 3H), 1.28 (t, J¼7.1 Hz, 3H), 1.35 (s, 9H), 2.79
(s, 3H), 3.94–4.09 (m, 2H), 4.16–4.27 (m, 2H), 4.17 (d,
J¼11.4 Hz, 1H), 5.06 (d, J¼11.4 Hz, 1H), 6.80 (tt, J¼7.2,
1.0 Hz, 1H), 6.93 (dd, J¼8.8, 0.9 Hz, 2H), 7.20–7.25 (m,
2H); 13C NMR (100.6 MHz, CDCl3) d (ppm) 13.91 (q), 14.08
(q), 27.99 (q), 33.64 (q), 52.56 (d), 61.76 (t), 61.83 (t), 63.76
(d), 82.18 (s), 115.28 (d), 119.02 (d), 128.91 (d), 150.03 (s),
167.06 (s), 167.36 (s), 168.67 (s); IR (neat) 2982, 1752, 1721,
1602, 1502, 1369, 1291, 1255, 1147, 1032 cmꢁ1; MS (EI)
m/z 379 (M+, 18), 278 (100), 160 (54%); HRMS M+
379.1996 (calcd for C20H29NO6 379.1995).
3.2.2. 1-tert-Butyl 2,2-diethyl 1-(phenylamino)ethane-
1,2,2-tricarboxylate (3a). Rf ¼0.6 (hexane–ether¼1:1);
In summary, we have shown the reaction of ethenetricarboxy-
lates with aromatic amines with and without catalytic
Lewis acids such as ZnCl2 and ZnBr2 gave amine adducts
in high yields. Transformation of the aza-Michael adducts
to aspartic acid derivatives was demonstrated. The reaction
of 1 and N-methylaniline 2b with Lewis acids such as
Sc(OTf)3 and Zn(OTf)2 at higher temperature (40–80 ꢀC)
gave an aromatic substitution product preferentially. Chiral
Lewis acid-catalyzed reaction of 1 and N-methylaniline 2b
gave an amine adduct enantioselectively. A new utility of
ethenetricarboxylates in organic synthesis has been demon-
strated in this study. Further elaboration of the products as
well as determination of the absolute stereochemistry of
the chiral products and elucidation of the origin of enantio-
selectivity is under investigation.
1
pale yellow oil; H NMR (400 MHz, CDCl3) d (ppm) 1.23
(t, J¼7.1 Hz, 3H), 1.31 (t, J¼7.1 Hz, 3H), 1.42 (s, 9H),
4.02 (d, J¼5.2 Hz, 1H), 4.12–4.28 (m, 4H), 4.64 (d,
J¼5.2 Hz, 1H), 6.69–6.72 (m, 2H), 6.76 (tt, J¼7.3, 1.0 Hz,
1H), 7.16–7.21 (m, 2H); 13C NMR (100.6 MHz, CDCl3)
d (ppm) 14.07 (q), 14.14 (q), 27.89 (q), 54.24 (d), 57.00
(d), 61.79 (t), 61.87 (t), 82.78 (s), 113.99 (d), 118.82 (d),
129.34 (d), 146.65 (s), 167.23 (s), 167.76 (s), 169.83 (s);
IR (neat) 3386, 2980, 1735, 1604, 1509, 1370, 1255,
1155 cmꢁ1; MS (EI) m/z 365 (M+, 23), 264 (100%);
HRMS M+ 365.1839 (calcd for C19H27NO6 365.1838).
3.2.3. Triethyl 1-(phenylamino)ethane-1,2,2-tricarboxy-
late (3c). Rf ¼0.5 (hexane–ether¼1:1); colorless oil;

2324
S. Yamazaki et al. / Tetrahedron 63 (2007) 2320–2327
1H NMR (400 MHz, CDCl3) d (ppm) 1.22 (t, J¼7.1 Hz, 3H),
1.23 (t, J¼7.1 Hz, 3H), 1.29 (t, J¼7.1 Hz, 3H), 4.05 (d, J¼
5.3 Hz, 1H), 4.11–4.28 (m, 6H), 4.74 (d, J¼5.3 Hz, 1H),
6.70–6.73 (m, 2H), 6.77 (tt, J¼7.4, 1.0 Hz, 1H), 7.16–7.21
(m, 2H); 13C NMR (100.6 MHz, CDCl3) d (ppm) 14.02
(q), 14.08 (q), 54.22 (d), 56.56 (d), 61.91 (t), 61.96 (t),
114.01 (d), 119.01 (d), 129.37 (d), 146.36 (s), 167.16 (s),
167.66 (s), 171.04 (s); IR (neat) 3387, 2983, 1734, 1604,
1510, 1371, 1255, 1178, 1030 cmꢁ1; MS (FAB) m/z 338
(M+H)+; HRMS (M+H)+ 338.1600 (calcd for C17H24NO6
338.1604).
1H NMR (400 MHz, CDCl3) d (ppm) 1.31 (s, 9H), 2.73 (s,
3H), 4.31 (d, J¼11.4 Hz, 1H), 4.87 (d, J¼12.2 Hz, 1H),
5.00 (d, J¼12.2 Hz, 1H), 5.07 (d, J¼11.4 Hz, 1H), 5.14 (d,
J¼12.4 Hz, 1H), 5.22 (d, J¼12.4 Hz, 1H), 6.81 (tt, J¼7.1,
0.9 Hz, 1H), 6.87 (dd, J¼8.8, 0.9 Hz, 2H), 7.07–7.09 (m,
2H), 7.17–7.34 (m, 10); 13C NMR (100.6 MHz, CDCl3)
d (ppm) 27.96 (q), 33.84 (q), 52.59 (d), 63.88 (d), 67.45
(t), 67.50 (t), 82.30 (s), 115.42 (d), 119.15 (d), 128.24 (d),
128.33 (d), 128.39 (d), 128.49 (d), 128.61 (d), 128.94 (d),
135.02 (s), 135.29 (s), 149.90 (s), 166.80 (s), 167.10 (s),
168.48 (s); IR (KBr) 2979, 1747, 1727, 1599, 1503, 1455,
1367, 1304, 1261, 1235, 1154 cmꢁ1; MS (EI) m/z 503
(M+, 1.4), 405 (51), 187 (63), 159 (76), 141 (89), 59
(100%); HRMS M+ 503.2309 (calcd for C30H33NO6
503.2308); Anal. Calcd for C30H33NO6: C, 71.55; H, 6.61;
N, 2.78. Found: C, 71.25; H, 6.67; N, 2.80.
3.2.4. Triethyl 1-(N-methyl-N-phenylamino)ethane-
1,2,2-tricarboxylate (3d). Rf ¼0.6 (hexane–ether¼1:1);
1
yellow oil; H NMR (400 MHz, CDCl3) d (ppm) 1.05 (t,
J¼7.1 Hz, 3H), 1.18 (t, J¼7.1 Hz, 3H), 1.27 (t, J¼7.1 Hz,
3H), 2.78 (s, 3H), 3.92–4.26 (m, 4H), 4.22 (d, J¼11.2 Hz,
1H), 5.17 (d, J¼11.2 Hz, 1H), 6.81 (tt, J¼7.3, 1.0 Hz, 1H),
6.92–6.94 (m, 2H), 7.21–7.26 (m, 2H); 13C NMR
(100.6 MHz, CDCl3) d (ppm) 13.80 (q), 13.99 (q), 14.22
(q), 33.50 (q), 52.47 (d), 61.37 (t), 61.75 (t), 61.83 (t),
62.63 (d), 114.93 (d), 119.04 (d), 128.96 (d), 149.59 (s),
166.76 (s), 167.26 (s), 169.68 (s); IR (neat) 2983, 1734,
1600, 1505, 1369, 1261, 1175, 1028 cmꢁ1; MS (EI) m/z
351 (M+, 42), 278 (100%); HRMS M+ 351.1689 (calcd for
C18H25NO6 351.1682).
3.2.8. 1-tert-Butyl 2,2-dibenzyl 1-(benzylamino)ethane-
1,2,2-tricarboxylate (3h). Rf ¼0.4 (hexane–ether¼1:2);
colorless oil; 1H NMR (400 MHz, CDCl3) d (ppm) 1.41 (s,
9H), 3.70 (d, J¼13.0 Hz, 1H), 3.84 (d, J¼7.1 Hz, 1H),
3.96 (d, J¼13.0 Hz, 1H), 3.97 (d, J¼7.1 Hz, 1H), 5.09–
5.30 (m, 2H), 7.20–7.35 (m, 15H); 13C NMR (100.6 MHz,
CDCl3) d (ppm) 27.97 (q), 52.28 (t), 55.45 (d), 60.26 (d),
67.25 (t), 67.30 (t), 82.20 (s), 127.11 (d), 128.27 (d),
128.33 (d), 128.35 (d), 128.57 (d), 135.28 (s), 135.34 (s),
139.72 (s), 167.26 (s), 167.45 (s), 171.19 (s); IR (neat)
3344, 3032, 2977, 1738, 1497, 1456, 1369, 1259,
1152 cmꢁ1; MS (EI) m/z 398 (M+ꢁNH2Ph, 16), 107
(H2NCH2Ph, 45), 91 (CH2Ph, 100%).
3.2.5. 1-Benzyl 2,2-diethyl 1-(N-methyl-N-phenylamino)-
ethane-1,2,2-tricarboxylate (3e). Rf ¼0.4 (hexane–
ether¼2:1); yellow oil; 1H NMR (400 MHz, CDCl3) d
(ppm) 1.06 (t, J¼7.1 Hz, 3H), 1.24 (t, J¼7.1 Hz, 3H), 2.69
(s, 3H), 3.93–4.09 (m, 2H), 4.13–4.25 (m, 2H), 4.23 (d,
J¼11.4 Hz, 1H), 5.05 (d, J¼12.5 Hz, 1H), 5.19 (d, J¼
12.5 Hz, 1H), 5.24 (d, J¼11.4 Hz, 1H), 6.82 (tt, J¼7.3,
0.9 Hz, 1H), 6.91 (d, J¼8.1 Hz, 2H), 7.15–7.17 (m, 2H),
7.20–7.29 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d (ppm)
13.86 (q), 13.99 (q), 33.48 (q), 52.48 (d), 61.82 (t), 61.91 (t),
62.84 (d), 66.87 (t), 115.22 (d), 119.26 (d), 128.02 (d), 128.20
(d), 128.44 (d), 129.03 (d), 135.47 (s), 149.63 (s), 166.71 (s),
167.20 (s), 169.50 (s); IR (neat) 2982, 1734, 1600, 1505,
1455, 1370, 1260, 1227, 1166, 1114, 1032 cmꢁ1; MS (EI)
m/z 413 (M+, 1.6), 351 (49), 278 (100%); HRMS M+
413.1842 (calcd for C23H27NO6 413.1838).
3.2.9. 1-tert-Butyl 2,2-diethyl 1-(N-(4-chlorophenyl)-N-
methylamino)ethane-1,2,2-tricarboxylate (3i). Rf ¼0.4
1
(hexane–ether¼2:1); pale yellow oil; H NMR (400 MHz,
CDCl3) d (ppm) 1.09 (t, J¼7.1 Hz, 3H), 1.28 (t, J¼7.1 Hz,
3H), 1.36 (s, 9H), 2.76 (s, 3H), 3.97–4.11 (m, 2H), 4.15 (d,
J¼11.4 Hz, 1H), 4.17–4.29 (m, 2H), 4.99 (d, J¼11.4 Hz,
1H), 6.83–6.87 (m, 2H), 7.16–7.20 (m, 2H); 13C NMR
(100.6 MHz, CDCl3) d (ppm) 13.98 (q), 14.07 (q), 28.01
(q), 33.79 (q), 52.47 (d), 61.84 (t), 61.93 (t), 63.72 (d),
82.47 (s), 116.32 (d), 123.87 (s), 128.78 (d), 148.62 (s),
166.95 (s), 167.20 (s), 168.34 (s); IR (neat) 2981, 1732,
1597, 1498, 1369, 1258, 1154, 1034 cmꢁ1; MS (EI) m/z
415 (M+, 12), 413 (M+, 34), 314 (83), 312 (100), 194
(78%); HRMS M+ 413.1602 (calcd for C20H2835ClNO6
413.1605), 415.1598 (calcd for C20H2837ClNO6 415.1576).
3.2.6. 1-tert-Butyl 2,2-dibenzyl 1-(phenylamino)ethane-
1,2,2-tricarboxylate (3f). Rf ¼0.6 (hexane–ether¼1:1);
1
pale yellow oil; H NMR (400 MHz, CDCl3) d (ppm) 1.36
(s, 9H), 4.15 (d, J¼5.1 Hz, 1H), 4.67 (d, J¼5.1 Hz, 1H),
5.10 (d, J¼12.3 Hz, 1H), 5.16 (d, J¼12.3 Hz, 2H), 5.23 (d,
J¼12.4 Hz, 1H), 6.66 (d-like, J¼7.5 Hz, 2H), 6.76 (t-like,
J¼7.3 Hz, 1H), 7.14–7.18 (m, 2H), 7.23–7.34 (m, 10H);
13C NMR (100.6 MHz, CDCl3) d (ppm) 27.85 (q), 54.28
(d), 57.06 (d), 67.53 (t), 67.62 (t), 82.91 (s), 114.07 (d),
118.93 (d), 128.28 (d), 128.39 (d), 128.45 (d), 128.52 (d),
128.59 (d), 128.68 (d), 129.34 (d), 135.04 (s), 135.16 (s),
146.49 (s), 166.99 (s), 167.47 (s), 169.65 (s); IR (neat)
3388, 3033, 2988, 1739, 1603, 1506, 1456, 1370, 1256,
1152 cmꢁ1; MS (FAB) m/z 490 (M+H)+; HRMS (M+H)+
490.2237 (calcd for C29H32NO6 490.2230).
3.2.10. 1-tert-Butyl 2,2-diethyl 1-(4-(trifluoromethyl)-
phenylamino)ethane-1,2,2-tricarboxylate (3j). Rf ¼0.4
(hexane–ether¼1:1); colorless oil; 1H NMR (400 MHz,
CDCl3) d (ppm) 1.22 (t, J¼7.1 Hz, 3H), 1.31 (t, J¼7.1 Hz,
3H), 1.42 (s, 9H), 4.04 (d, J¼4.9 Hz, 1H), 4.12–4.24 (m,
2H), 4.26 (q, J¼7.1 Hz, 2H), 4.68 (d, J¼4.9 Hz, 1H), 6.72
(d, J¼8.4 Hz, 2H), 7.42 (dq, J¼8.4, 0.6 Hz, 2H); 13C
NMR (100.6 MHz, CDCl3) d (ppm) 14.05 (CH3), 14.12
(CH3), 27.88 (CH3), 53.80 (CH), 56.24 (CH), 61.99 (CH2),
62.07 (CH2), 83.25 (C), 113.02 (CH), 120.39 (q, JCF¼33 Hz,
C), 124.84 (q, JCF¼270 Hz, C), 126.73 (q, JCF¼3.8 Hz, CH),
149.31 (C), 167.00 (C), 167.74 (C), 169.24 (C); 19F NMR
(376 MHz, CDCl3) ꢁ61.71; IR (neat) 3383, 2983, 1739,
1618, 1535, 1371, 1330, 1156, 1113, 1067 cmꢁ1; MS (EI)
m/z 433 (M+, 12), 332 (100%); HRMS M+ 433.1720 (calcd
for C20H26F3NO6 433.1712).
3.2.7. 1-tert-Butyl 2,2-dibenzyl 1-(N-methyl-N-phenyl-
amino)ethane-1,2,2-tricarboxylate (3g). Rf ¼0.6 (hex-
ane–ether¼2:1); pale yellow crystals; mp 82–84 ꢀC;

S. Yamazaki et al. / Tetrahedron 63 (2007) 2320–2327
2325
3.2.11. 1-tert-Butyl 2,2-diethyl 1-(2-methoxyphenyl-
amino)ethane-1,2,2-tricarboxylate (3k). Rf ¼0.5 (hex-
J¼7.1 Hz, 3H), 1.27 (t, J¼7.1 Hz, 3H), 1.37 (s, 9H), 2.80
(s, 3H), 3.94 (q, J¼7.1 Hz, 2H), 4.07 (s, 2H), 4.19–4.24
(m, 2H), 6.52 (d-like, J¼8.7 Hz, 2H), 7.08 (d-like,
J¼8.7 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) d (ppm)
13.89 (q), 14.09 (q), 27.86 (q), 30.74 (q), 50.96 (d), 55.71
(d), 61.31 (t), 61.73 (t), 81.11 (s), 112.53 (d), 123.75 (s),
129.12 (d), 148.83 (s), 167.57 (s), 168.23 (s), 171.46 (s);
IR (neat) 3419, 2980, 1732, 1616, 1524, 1369, 1300,
1149 cmꢁ1; MS (EI) m/z 379 (M+, 77), 305 (53), 278
(100%); HRMS M+ 379.1997 (calcd for C20H29NO6
379.1995).
1
ane–ether¼1:1); yellow oil; H NMR (400 MHz, CDCl3)
d (ppm) 1.24 (t, J¼7.4 Hz, 3H), 1.30 (t, J¼7.1 Hz, 3H),
1.41 (s, 9H), 3.83 (s, 3H), 4.03 (d, J¼5.7 Hz, 1H), 4.12–
4.28 (m, 4H), 4.65 (d, J¼5.7 Hz, 1H), 6.69–6.73 (m, 2H),
6.78 (dd, J¼6.8, 1.6 Hz, 1H), 6.83–6.88 (m, 1H); 13C NMR
(100.6 MHz, CDCl3) d (ppm) 14.07 (q), 14.11 (q), 27.87
(q), 54.38 (d), 55.59 (q), 56.69 (d), 61.75 (t), 61.78 (t),
82.57 (s), 110.01 (d), 110.74 (d), 117.94 (d), 121.10 (d),
136.49 (s), 147.47 (s), 167.19 (s), 167.59 (s), 169.74 (s); IR
(neat) 3392, 2980, 1739, 1603, 1516, 1459, 1370, 1253, 1155,
1030 cmꢁ1; MS (EI) m/z 395 (M+, 54), 339 (36), 294 (100%);
HRMS M+ 395.1944 (calcd for C20H29NO7 395.1944).
3.3.2. Triethyl 1-(4-(methylamino)phenyl)ethane-1,2,2-
tricarboxylate (4b). Rf ¼0.5 (hexane–ether¼1:2); pale yel-
low oil; 1H NMR (400 MHz, CDCl3) d (ppm) 1.01 (t,
J¼7.1 Hz, 3H), 1.19 (t, J¼7.1 Hz, 3H), 1.26 (t, J¼7.1 Hz,
3H), 2.79 (s, 3H), 3.95 (q, J¼7.1 Hz, 2H), 4.00–4.08 (m,
1H), 4.13–4.25 (m, 3H), 4.16 (br s, 2H), 6.52 (d-like,
J¼8.7 Hz, 2H), 7.09 (d-like, J¼8.7 Hz, 2H); 13C NMR
(100.6 MHz, CDCl3) d (ppm) 13.81 (q), 13.98 (q), 30.57
(q), 49.92 (d), 55.55 (d), 61.14 (t), 61.33 (t), 61.77 (t),
112.41 (d), 122.82 (s), 129.16 (d), 149.05 (s), 167.32 (s),
168.14 (s), 172.47 (s); IR (neat) 3419, 2982, 1733, 1616,
1525, 1369, 1300, 1158, 1030 cmꢁ1; MS (EI) m/z 351
(M+, 58), 305 (48), 277 (100%); HRMS M+ 351.1699 (calcd
for C18H25NO6 351.1682); Anal. Calcd for C18H25NO6: C,
61.52; H, 7.17; N, 3.99. Found: C, 61.37; H, 7.26; N, 3.96.
3.2.12. 1-tert-Butyl 2,2-diethyl 1-(2-chlorophenylamino)-
ethane-1,2,2-tricarboxylate (3l). Rf ¼0.5 (hexane–
ether¼2:1); yellow oil; 1H NMR (400 MHz, CDCl3)
d (ppm) 1.23 (t, J¼7.1 Hz, 3H), 1.32 (t, J¼7.1 Hz, 3H),
1.42 (s, 9H), 4.05 (d, J¼5.3 Hz, 1H), 4.13–4.31 (m, 4H),
4.69 (br d, J¼5.3 Hz, 1H), 5.42 (br s, 1H), 6.67–6.71 (m,
1H), 6.78 (d-like, J¼8.1 Hz, 1H), 7.12–7.16 (m, 1H), 7.26
(dd, J¼7.8, 1.6 Hz, 1H); 13C NMR (100.6 MHz, CDCl3)
d (ppm) 14.02 (q), 14.10 (q), 27.81 (q), 54.02 (d), 56.68
(d), 61.91 (t), 61.96 (t), 82.92 (s), 112.23 (d), 118.71 (d),
120.40 (s), 127.42 (d), 129.47 (d), 142.77 (s), 166.95 (s),
167.54 (s), 169.25 (s); IR (neat) 3388, 2981, 1739, 1598,
1514, 1370, 1257, 1156, 1035 cmꢁ1; MS (EI) m/z 401
(M+, 3.0) 399 (M+, 8.4), 298 (45), 100 (30), 57 (100%);
HRMS M+ 399.1453 (calcd for C19H2635ClNO6 399.1449),
401.1446 (calcd for C19H2637ClNO6 401.1419).
3.3.3. 1-tert-Butyl 2,2-dibenzyl 1-(4-(methylamino)-
phenyl)ethane-1,2,2-tricarboxylate (4c). Rf ¼0.4 (hexane–
ether¼1:1); pale yellow oil; 1H NMR (400 MHz, CDCl3) d
(ppm) 1.32 (s, 9H), 2.80 (s, 3H), 4.09 (d, J¼11.9 Hz, 1H),
4.22 (d, J¼11.9 Hz, 1H), 4.87 (s, 2H), 5.17 (s, 2H), 6.47
(d-like, J¼8.6 Hz, 2H), 6.98–7.04 (m, 2H), 7.04 (d-like,
J¼8.6 Hz, 2H), 7.20–7.37 (m, 8H); 13C NMR (100.6 MHz,
CDCl3) d (ppm) 27.79 (q), 30.65 (q), 50.94 (d), 55.72 (d),
67.03 (t), 67.31 (t), 81.22 (s), 112.55 (d), 123.40 (s),
128.07 (d), 128.08 (d), 128.12 (d), 128.27 (d), 128.38 (d),
128.54 (d), 129.08 (d), 135.13 (s), 135.38 (s), 148.84 (s),
167.30 (s), 167.92 (s), 171.26 (s); IR (neat) 3422, 2979,
1733, 1615, 1524, 1456, 1369, 1294, 1147 cmꢁ1; MS (EI)
m/z 503 (M+, 38), 402 (19), 338 (25), 91 (100%); HRMS
M+ 503.2309 (calcd for C30H33NO6 503.2308).
3.2.13. 1-tert-Butyl 2,2-diethyl 1-(N-benzyl-N-phenyl-
amino)ethane-1,2,2-tricarboxylate (3m). Rf ¼0.7 (hex-
ane–ether¼1:1); colorless oil; 1H NMR (400 MHz, CDCl3)
d (ppm) 1.02 (t, J¼7.1 Hz, 3H), 1.26 (t, J¼7.1 Hz, 3H),
1.35 (s, 9H), 3.89–3.96 (m, 2H), 4.16–4.25 (m, 2H), 4.20
(d, J¼11.2 Hz, 1H), 4.46 (d, J¼16.7 Hz, 1H), 4.53 (d,
J¼16.7 Hz, 1H), 5.21 (d, J¼11.2 Hz, 1H), 6.76 (t-like,
J¼7.1 Hz, 1H), 6.90 (d-like, J¼8.1 Hz, 2H), 7.11–7.16 (m,
3H), 7.20–7.22 (m, 4H); 13C NMR (100.6 MHz, CDCl3)
d (ppm) 13.71 (q), 14.05 (q), 27.93 (q), 51.02 (t), 52.85
(d), 61.83 (t), 61.88 (t), 64.51 (d), 82.50 (s), 117.01 (d),
119.60 (d), 126.73 (d), 127.06 (d), 128.27 (d), 128.79 (d),
138.13 (s), 147.86 (s), 167.21 (s), 167.32 (s), 169.05 (s);
IR (neat) 2980, 1758, 1733, 1600, 1505, 1369, 1301, 1244,
1152 cmꢁ1; MS (EI) m/z 455 (M+, 14) 354 (100%);
HRMS M+ 455.2300 (calcd for C26H33NO6 455.2308).
3.3.4. Compound 5 (assumed to be ca. 1:1 diastereomix-
ture). Rf ¼0.4 (hexane–ether¼1:2); yellow oil; 1H NMR
(400 MHz, CDCl3) d (ppm) 1.01 (m, 6H), 1.28 (t, J¼
7.1 Hz, 6H), 1.33 (s, 9H), 1.36 (s, 9H), 2.75 (s, 3H), 3.91–
4.27 (m, 11H), 5.02 (d, J¼11.4 Hz, 1H), 6.84 (d, J¼8.4 Hz,
2H), 7.13 (dd, J¼8.4, 1.5 Hz, 2H); 13C NMR (100.6 MHz,
CDCl3) d (ppm) 13.89 (q), 14.04 (q), 14.08 (q), 27.81 (q),
27.95 (q), 33.69 (q), 50.85 (d), 52.45 (d), 52.48 (d), 55.56
(d), 61.27 (t), 61.68 (t), 61.76 (t), 61.82 (t), 63.47 (d), 63.59
(d), 81.11 (s), 82.16 (s), 115.07 (d), 115.13 (d), 125.47 (s),
128.78 (d), 149.45 (s), 149.49 (s), 166.92 (s), 166.96 (s),
167.26 (s), 167.36 (s), 168.14 (s), 168.48 (s), 171.26 (s); IR
(neat) 2980, 1732, 1612, 1519, 1369, 1301, 1152,
1035 cmꢁ1; MS (EI) m/z 651 (M+, 30), 550 (100%);
HRMS M+ 651.3257 (calcd for C33H49NO12 651.3255).
3.3. Typical experimental procedure (Table 2, entry 8)
To a solution of 1a (136 mg, 0.5 mmol) in 1,2-dichloro-
ethane (0.9 mL) were added N-methylaniline 2b (54 mg,
54 mL, 0.5 mmol) and Sc(OTf)3 (49 mg, 0.1 mmol). The
mixture was heated to 80 ꢀC for 2 h. The reaction mixture
was cooled to room temperature and quenched by water
and then saturated aqueous NaHCO3. The mixture was
extracted with dichloromethane and the organic phase was
washed with water, dried (Na2SO4), and evaporated invacuo.
The residue was purified as above to give 4a (143 mg, 75%).
3.3.5. 1-tert-Butyl 2,2-dibenzyl 1-(N-phenylacetamido)-
ethane-1,2,2-tricarboxylate (6a). To a solution of 3f
(490 mg, 1.0 mmol) in dichloromethane (0.8 mL) were
3.3.1. Compound 4a. Rf ¼0.3 (hexane–ether¼2:1); pale
1
yellow oil; H NMR (400 MHz, CDCl3) d (ppm) 1.01 (t,

2326
S. Yamazaki et al. / Tetrahedron 63 (2007) 2320–2327
added triethylamine (202 mg, 0.28 mL, 2.0 mmol) and ace-
tyl chloride (157 mg, 0.14 mL, 2.0 mmol) at 0 ꢀC. The mix-
ture was allowed to warm to room temperature and stirred
overnight (16 h). The reaction mixture was cooled to 0 ꢀC
and water was added to the mixture. The mixture was
extracted with dichloromethane and the organic phase was
washed with 1 N HCl and saturated NaCl solution, dried
(Na2SO4), and evaporated in vacuo. The residue was purified
by column chromatography over silica gel with hexane–
ether as eluent to give 6a (385 mg, 72%).
(s), 175.84 (s); IR (neat) 2979, 1738, 1626, 1594, 1495,
1394, 1370, 1258, 1156 cmꢁ1; MS (EI) m/z 307 (M+, 5.4),
206 (32), 164 (100%); HRMS M+ 307.1419 (calcd for
C16H21NO5 307.1420).
3.3.8. 3-(tert-Butoxycarbonyl)-3-(N-benzylacetamido)-
propanoic acid (7b). Rf ¼0.3 (ether); pale yellow crystals;
1
mp 89–90 ꢀC; H NMR (400 MHz, CDCl3) d (ppm) 1.40
(s, 9H), 2.15 (s, 3H), 2.62 (dd, J¼16.9, 6.0 Hz, 1H), 3.29
(dd, J¼16.9, 7.4 Hz, 1H), 4.35 (dd, J¼7.4, 6.0 Hz, 1H),
4.59 (d, J¼16.8 Hz, 1H), 4.64 (d, J¼16.8 Hz, 1H), 7.19–
7.38 (m, 5H), 9.22 (br s, 1H); 13C NMR (100.6 MHz,
CDCl3) d (ppm) 21.74 (q), 27.85 (q), 34.89 (t), 53.88 (t),
58.03 (d), 82.28 (s), 127.32 (d), 127.96 (d), 128.85 (d),
136.03 (s), 168.41 (s), 171.81 (s), 175.88 (s); IR (KBr)
2980, 1735, 1701, 1607, 1487, 1449, 1420, 1365, 1290,
1180, 1159 cmꢁ1; MS (EI) m/z 321 (M+, 1.4), 265 (54),
222 (49), 178 (100%); HRMS M+ 321.1576 (calcd for
C17H23NO5 321.1576); Anal. Calcd for C17H23NO5: C,
63.54; H, 7.21; N, 4.36. Found: C, 63.32; H, 7.21; N, 4.32.
Rf ¼0.4 (hexane–ether¼1:2); colorless oil; 1H NMR
(400 MHz, CDCl3) d (ppm) 1.42 (s, 9H), 1.69 (s, 3H), 4.64
(d, J¼10.6 Hz, 1H), 5.01 (d, J¼10.6 Hz, 1H), 5.01 (d,
J¼12.3 Hz, 1H), 5.07 (d, J¼12.3 Hz, 1H), 5.16 (d,
J¼12.3 Hz, 1H), 5.23 (d, J¼12.3 Hz, 1H), 7.18–7.34 (m,
15H); 13C NMR (100.6 MHz, CDCl3) d (ppm) 22.67 (q),
27.90 (q), 52.47 (d), 62.81 (d), 67.42 (t), 83.00 (s), 128.15
(d), 128.25 (d), 128.27 (d), 128.30 (d), 128.33 (d), 128.44
(d), 128.55 (d), 128.61 (d), 129.54 (d), 135.23 (s), 135.28
(s), 143.18 (s), 166.98 (s), 167.10 (s), 167.69 (s), 171.37
(s); IR (neat) 2978, 1737, 1673, 1596, 1495, 1370, 1260,
1154 cmꢁ1; MS (EI) m/z 531 (M+, 5.4), 489 (17), 430
(23), 388 (44), 91 (100%); HRMS M+ 531.2258 (calcd for
C31H33NO7 531.2257).
3.4. Typical procedure for Table 3 (entry 2)
A powdered mixture of Cu(OTf)2 (18 mg, 0.05 mmol) and 8
(16 mg, 0.054 mmol) was dried under vacuum for 1 h. THF
(1 mL) was added under N2 and the solution stirred for 1 h.
The mixture was cooled to ꢁ20 ꢀC and compound 1a
(0.136 g, 0.5 mmol) in THF (0.4 mL) was added to the mix-
ture and stirred for 15 min, followed by addition of 2b
(54 mg, 0.05 mL, 0.5 mmol). After 17 h the reaction mixture
was filtered through a plug of silica gel, washed with Et2O,
dried (MgSO4), and the solvent removed. The residue was
purified by column chromatography over silica gel eluting
with hexane–ether to give 3b (173 mg, 91%). 3b; HPLC
(hexane–iPrOH¼49:1) minor peak tR1¼4.7 min, major
peak tR2¼6.6 min, 78% ee; [a]2D7 ꢁ163 (c 1.06, CHCl3).
Compound 3i (Table 3, entry 12); HPLC (hexane–iPrOH¼
49:1) minor peak tR1¼4.7 min, major peak tR2¼6.5 min,
87% ee; [a]2D7 ꢁ159 (c 1.63, CHCl3).
Compound 3d (Table 3, entry 13); HPLC (hexane–iPrOH¼
49:1) minor peak tR1¼6.1 min, major peak tR2¼8.2 min,
41% ee; [a]2D4 ꢁ103 (c 1.30, CHCl3).
3.3.6. 1-tert-Butyl 2,2-dibenzyl 1-(N-benzylacetamido)-
ethane-1,2,2-tricarboxylate (6b). Rf ¼0.3 (hexane–
ether¼1:2); colorless oil; 1H NMR (400 MHz, CDCl3)
d (ppm) 1.33 (s, 9H), 1.79 (s, 3H), 4.18 (d, J¼17.0 Hz,
1H), 4.21 (d, J¼17.0 Hz, 1H), 4.60 (br s, 2H), 5.03 (d,
J¼12.1 Hz, 1H), 5.10 (d, J¼12.0 Hz, 1H), 5.20 (d,
J¼12.3 Hz, 1H), 5.23 (d, J¼12.1 Hz, 1H), 7.10–7.34 (m,
15H); 13C NMR (100.6 MHz, CDCl3) d (ppm) 21.57 (q),
27.82 (q), 51.84 (d), 54.42 (t), 60.93 (d), 67.40 (t), 67.53
(t), 82.67 (s), 127.43 (d), 127.69 (d), 128.22 (d), 128.30
(d), 128.43 (d), 128.53 (d), 128.62 (d), 128.72 (d), 128.94
(d), 135.28 (s), 135.38 (s), 136.26 (s), 167.27 (s), 171.66
(s); IR (neat) 2978, 1733, 1661, 1497, 1456, 1369, 1278,
1154 cmꢁ1; MS (EI) m/z 545 (M+, 7.2), 489 (26), 446
(72), 91 (100%); HRMS M+ 545.2433 (calcd for
C32H35NO7 545.2414).
3.3.7. 3-(tert-Butoxycarbonyl)-3-(N-phenylacetamido)-
propanoic acid (7a).
A mixture of 6a (320 mg,
0.602 mmol) and 10% Pd–C (64 mg, 10 mol%) in methanol
(6.0 mL) was stirred in a hydrogen atmosphere for 17 h at
room temperature. The catalyst was removed by filtration
(Celite) and washed with methanol. The filtrate was concen-
trated to give a crude residue. To the residue was added
water–ethanol (1:1, 0.6 mL) and the mixture was refluxed
for 3 h. The reaction mixture was concentrated in vacuo
and extracted with dichloromethane. The organic phase was
dried (Na2SO4) and evaporated in vacuo. The residue was
purified by column chromatography over silica gel with
hexane–ether as eluent to give 7a (139 mg, 75%).
Compound 3e (Table 3, entry 14); HPLC (hexane–iPrOH¼
49:1) minor peak tR1¼7.6 min, major peak tR2¼12.1 min,
43% ee; [a]2D3 ꢁ61 (c 1.57, CHCl3).
Compound 3g (Table 3, entry 15); HPLC (hexane–iPrOH¼
49:1) minor peak tR1¼6.5 min, major peak tR2¼8.1 min,
71% ee; [a]2D6 ꢁ80 (c 0.69, CHCl3).
3.5. 1H NMR measurements for reactions shown in
Figure 1
(a) CDCl3 or CD2Cl2 solution: a NMR sample was prepared
by addition of N-methylaniline 2b (36 mg, 37 mL,
0.33 mmol) (and ZnCl2 (9 mg, 0.067 mmol)) to a solution
of 1a (90 mg, 0.33 mmol) in CDCl3 or CD2Cl2 (0.6 mL) in
a NMR tube. The tube was set into an NMR probe and peri-
odically measured at 25 ꢀC. (b) Neat reaction: N-methyl-
aniline 2b (107 mg, 0.11 mL, 1.0 mmol) was added to 1a
Rf ¼0.1 (ether); pale yellow oil; 1H NMR (400 MHz, CDCl3)
d (ppm) 1.48 (s, 9H), 1.85 (s, 3H), 2.79 (dd, J¼16.8, 7.1 Hz,
1H), 3.26 (dd, J¼16.8, 7.1 Hz, 1H), 4.82 (t, J¼7.1 Hz, 1H),
7.28–7.44 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d (ppm)
22.70 (q), 27.95 (q), 35.01 (t), 59.88 (d), 82.51 (s), 128.37
(d), 128.62 (d), 129.81 (d), 142.38 (s), 168.63 (s), 171.39

S. Yamazaki et al. / Tetrahedron 63 (2007) 2320–2327
2327
(272 mg, 1.0 mmol) in a flask and stirred at 25 ꢀC. A portion
was periodically taken from the mixture and diluted with
CDCl3. The 1H NMR spectrum was measured immediately.
The product percentage was calculated by peak area ratios.
6. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski,
J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,
R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision C.02; Gaussian: Wallingford, CT, 2004.
7. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1998, 37, 785.
Acknowledgements
This work was supported by the Ministry of Education,
Culture, Sports, Science, and Technology of the Japanese
Government. We are grateful to Professor K. Kakiuchi
(Nara Institute of Science and Technology) and Professor
S. Umetani (Kyoto University) for mass spectra and elemen-
tal analysis. We thank Ms. K. Ohmitsu, Ms. S. Masaki, Ms.
M. Tsukada, and Ms. Y. Iwata for experimental help.
Supplementary data
Computational data (the Cartesian coordinate of the opti-
mized geometry of 3d). Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2006.12.058.
8. McQuarrie, D. A.; Simon, J. Physical Chemistry: A Molecular
Approach; University Science Books: California, CA, 1997,
Chapter 16.
References and notes
9. The reaction of 1a with benzylphenylamine gave C–N adduct
3m only in 39% yield along with starting materials. This is prob-
ably because of the steric hindrance of the amine nucleophile.
1. (a) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633; (b)
Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833.
2. (a) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem.
Commun. 2001, 1240; (b) Palomo, C.; Oiarbide, M.; Halder,
CO2Et
N
EtO2C
tBuO2C
ꢀ
R.; Kelso, M.; Gomez-Bengoa, E.; Garcia, J. M. J. Am.
Chem. Soc. 2004, 126, 9188; (c) Hamashima, Y.; Somei, H.;
Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6,
1861; (d) Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org.
Chem. 2006, 71, 4706; (e) Li, K.; Hii, K. K. Chem. Commun.
2003, 1132; (f) Nakama, K.; Seki, S.; Kanemasa, S.
Tetrahedron Lett. 2002, 43, 829; (g) Sibi, M. P.; Shay, J. J.;
Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615.
3. (a) M€uller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675; (b)
Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C. G.;
Seayad, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett
2002, 1579.
3m
10. Using various Lewis acid such as ZnCl2, AlCl3, and SnCl4 at
higher temperature and longer reaction time, the product yields
decreased or the reaction mixture decomposed.
11. The reaction of the isolated 3b with ZnCl2 (0.2 equiv) in
CH2Cl2 at room temperature for 17 h and work-up gave the
mixture of 3b, 1a, and 2b (ca. 6:1:1). This result also shows
the reversibility of C–N bond.
4. (a) Yamazaki, S.; Kumagai, H.; Takada, T.; Yamabe, S. J. Org.
Chem. 1997, 62, 2968; (b) Yamazaki, S.; Yamada, K.; Yamabe,
S.; Yamamoto, K. J. Org. Chem. 2002, 67, 2889; (c) Yamazaki,
S.; Morikawa, S.; Iwata, Y.; Yamamoto, M.; Kuramoto, K. Org.
Biomol. Chem. 2004, 2, 3134; (d) Yamazaki, S.; Iwata, Y.
J. Org. Chem. 2006, 71, 739.
12. For other examples, see: Reboule, I.; Gil, R.; Collin, J.
Tetrahedron: Asymmetry 2005, 16, 3881.
13. (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325;
(b) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.;
Thorhauge, J. Acc. Chem. Res. 1999, 32, 605; (c) Jørgensen,
K. A. Angew. Chem., Int. Ed. 2000, 39, 3558.
5. (a) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.;
Massaccesi, M.; Torregiani, E. J. Org. Chem. 2005, 70, 169;
(b) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052; (c)
Graunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25; (d) Toda,
F.; Takumi, H.; Nagami, M.; Tanaka, K. Heterocycles 1998,
47, 469.
14. Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030.
15. (a) Okumoto, S.; Yamabe, S. J. Org. Chem. 2000, 65, 1544; (b)
Pardo, L.; Osman, R.; Weinstein, H.; Rabinowits, J. R. J. Am.
Chem. Soc. 1993, 115, 8263.
16. Menger, F. M.; Smith, J. H. J. Am. Chem. Soc. 1969, 91, 4211.
17. Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, W.;
Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134.