A practical approach to non-natural or N-unsubstituted α-arylglycine derivatives: Hf(OTf)4-doped Me3SiCl system-catalyzed aminomethylation of electron-rich arenes with a new type of N,O-acetal

Article abstract of DOI:10.1016/j.tet.2008.07.052

The authors have demonstrated the Hf(OTf)₄-doped Me₃SiCl system-catalyzed aminomethylation of electron-rich aromatic compounds, such as indoles and anilines, with new types of N,O-acetals having a variety of functional groups, such a

Full text of DOI:10.1016/j.tet.2008.07.052

Tetrahedron 64 (2008) 9208–9215
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A practical approach to non-natural or N-unsubstituted a-arylglycine
derivatives: Hf(OTf)4-doped Me3SiCl system-catalyzed aminomethylation
of electron-rich arenes with a new type of N,O-acetal
*
Norio Sakai , Junichi Asano, Yuta Shimano, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2008
Received in revised form 15 July 2008
Accepted 15 July 2008
Available online 18 July 2008
The authors have demonstrated the Hf(OTf)4-doped Me3SiCl system-catalyzed aminomethylation of
electron-rich aromatic compounds, such as indoles and anilines, with new types of N,O-acetals having
a variety of functional groups, such as cyano, ester, bis(trimethylsilyl)amino, diallylamino, and cyclic
amino moieties, for the preparation of non-natural aromatic amino acid derivatives. Aminomethylation
using an N,O-acetal with a bis(trimethylsilyl)amino group was particularly successful in the direct
preparation of an N-unsubstituted
workup.
a
-indolylglycine derivative, which required only a standard aqueous
Keywords:
N,O-Acetal
Aminomethylation
Amino acid
Ó 2008 Elsevier Ltd. All rights reserved.
Hafnium triflate
1. Introduction
types of N,O-acetals as aminomethyl group equivalents, and found
that an Hf(OTf)4-doped Me3SiCl catalytic system highly and effec-
tively catalyzed the aminomethylation of electron-rich arenes,
Amino acids are among the most important and indispensable
materials for the maintenance of human life.1 Among these,
a
-
which led to the production of a
-aryl-amino acid precursors.11
arylglycine derivatives constitute the basic and central building
blocks necessary to build biologically active substances and natu-
rally occurring compounds, such as vancomycin and nocardicin.2,3
Thus, several practical approaches to construct these frameworks
and their derivatives have been developed by organic/medicinal
chemists.4 Friedel–Crafts-type reactions of electron-rich arenes
with a glycine cation equivalent are among the most useful tools in
Thus, our next effort focused on the development of an efficient and
direct preparation of N-underivatized amino acid derivatives using
a novel type of N,O-acetal. In conventional studies, the employed
imines and the imino esters typically contained a phenyl group and
an electron-withdrawing group on the nitrogen atom of the imine
to stabilize the structure. Use of these substituents, however, re-
quired severe deprotection conditions, which complicated the
otherwise facile synthesis of an N-unsubstituted amino acid
derivative.7c,12 To overcome this problem, we utilized an N,N-bis-
(trimethylsilyl)-N,O-acetal and an N,N-diallylamino-N,O-acetal as
glycine cation equivalents, since it is well-known that an N–Si bond
can readily be converted to an N–H bond via the usual aqueous
workup,13 and an allyl group on a nitrogen atom can also be
transformed to an N–H bond using the reductive cleavage.14 Here,
we first report the details of the Hf(OTf)4-doped Me3SiCl-catalyzed
aminomethylation of an electron-rich arene using an N,O-acetal
with a cyano group or an ester group, leading to the synthesis of an
achievement of the facile preparation of these a-aromatic amino
acid derivatives. However, most of the electrophilic sources
employed in the Friedel–Crafts reaction have been limited to im-
ines or imino esters.5,6 Moreover, the use of an N,O-acetal, which
functions as a glycine cation equivalent, has not been examined
extensively.7,8 Heaney and co-workers developed an effective
preparation of a-aryl-amino acid derivatives using an N,O-acetal, in
the presence of a typical silyl chloride, such as Me3SiCl; however,
most of the reactions required long reaction times to complete.9
Risch and co-workers demonstrated the aminoalkylation of arenes
with benzotriazolyl-substituted N,N-aminals in the presence of
stoichiometric amounts of AlCl3 and TiCl4, leading to the formation
a-arylglycine derivative. Second, we describe the Hf(OTf)4/Me3SiCl
catalytic system-catalyzed aminomethylation of indole with an
N,N-bis(trimethylsilyl)-N,O-acetal that directly produces an N-
of
a
-aryl-
a
-amino acid esters.10 In this context, we designed several
underivatized a-indolylglycine derivative without the deprotection
step. Third, we describe a two-step procedure that comprises
aminomethylation using an N,O-acetal with a diallylamino group
and the subsequent reductive deprotection of the allyl group with
* Corresponding author.
E-mail address: sakachem@rs.noda.tus.ac.jp (N. Sakai).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.052

N. Sakai et al. / Tetrahedron 64 (2008) 9208–9215
9209
Table 1
palladium to afford the corresponding N-unsubstituted
a-aryl-
Synthesis of a variety of amino acid precursors
amino acid derivatives in good yields.
X
N
X
Hf(OTf)4 (0.1 equiv)
Me3SiCl (1.2 equiv)
CH2Cl2, rt
2. Results and discussion
+
Ar
H
N
2.1. Preparation of N,O-acetals
Ar
CN
MeO
CN
3
5-22
Initially, a series of N,O-acetals 3 and 4 possessing a cyano group
or an ester group were prepared via the reaction of brominated
compound 1 with the corresponding cyclic secondary amine 2 in
the presence of a base, as shown in Scheme 1. A representative
reaction was as followed: 2-bromo-2-methoxyacetonitrile (1a) was
treated with piperidine (2a) in the presence of a 1.2 equiv of the
base, i-Pr2EtN, in THF at room temperature for 2 h, followed by non-
aqueous isolation and standard distillation (Kugelrohr), which gave
the desired methoxy(piperidino)acetonitrile (3a) in 84% yield.
Aqueous isolation and silica gel column purification of the acetal 3
resulted in decomposition of the N,O-acetals.
Run
Time (h)
Product
Yielda (%)
X
Y
X
1
2
3
4
5
0.1
0.3
0.5
5
CH2
CH2
CH2
CH2
O
H
94 (5)
85 (6)
89 (7)
78 (8)
86 (9)
N
MeO
CO2Me
Br
CN
Y
0.3
H
N
H
X
Y
N
6
7
8
0.1
0.5
0.5
CH2
O
NPh
d
d
d
92 (10)
79 (11)
85 (12)
Y
CN
Br
i-Pr2NEt (1.2 equiv)
+
N
THF, rt, 2h
MeO
X
N
H
MeO
X
N
Me
1a:X = CN
1b:X = CO2Me
2a-c
(1.2 equiv)
3a:X = CN, Y = CH2
3b:X = CN, Y = O
3c:X = CN, Y = NPh
9
0.3
0.2
0.5
1
1
1
CH2
CH2
CH2
O
O
NPh
NPh
H
82 (13)
74 (14)
66 (15)
85 (16)
82 (17)
82 (18)
94 (19)
84%
79%
85%
78%
64%
10
11
12
13
14
15
Me
Ph
H
Me
H
X
N
4a:X = CO2Me, Y = CH2
4b:X = CO2Me, Y = O
N
Y
CN
Scheme 1. Preparation of N,O-acetals 3 and 4.
1
Me
X
16
17
18
0.5
3
3
CH2
O
NPh
d
d
d
86 (20)
63 (21)
83 (22)
N
Me
2.2. Aminomethylation with N,O-acetals having a cyano
group and an ester group
O
CN
a
Isolated yield.
Based on our previous studies,11 the aminomethylation of a va-
riety of heterocycles with N,O-acetals 3, which possess a cyano
group, was then examined using an Hf(OTf)4/Me3SiCl catalytic
system. The results of these reactions are summarized in Table 1.
Most of the reactions involving substituted indoles, which had ei-
ther an electron-donating group or an electron-withdrawing group,
and N,O-acetals with a cyano group were completed within 0.5 h,
yielding the corresponding amino acid precursors in good to ex-
cellent yields (runs 1–4 and 6). In addition, the aminomethylation
successfully accommodated acetal substrates that had either an N-
phenyl-piperazine or a morpholine moiety (runs 5,7, and 8). Other
nucleophilic heterocycles, such as pyrrole and furan, were effi-
ciently aminomethylated in good yield (runs 9–18).
To produce a variety of aromatic glycine derivatives, amino-
methylation using N,O-acetals 4 with an ester group was performed
using the Hf(OTf)4/Me3SiCl catalytic system (Table 2). As a result,
most of the reactions that used an electron-rich heterocycle, such
as indoles, pyrroles, furans, and thiophenes, proceeded smoothly to
produce the corresponding amino acid derivatives 23–35 in good to
excellent yields. In particular, when aminomethylation of a sub-
strate consisting of both pyrrole and furan skeletons was con-
ducted, the aminomethyl group was selectively introduced onto the
pyrrole ring that showed a stronger nucleophilicity giving the
corresponding amino acid derivative 34 in a nearly quantitative
yield (run 12). Moreover, aminomethylation of acetal 4a with an
electron-rich arene, such as N,N-dimethylaniline, under optimized
conditions also yielded the aminomethylated product 35 in 91%
yield.
group. Generally, deprotection of an amino group that results in an
unsubstituted amino group is complicated and involves reductive
cleavage with a metal and hydration under acidic conditions. These
harsh experimental conditions may reduce the chemical yield.
Therefore, we used a common aqueous workup that readily cleaves
N–Si bonds, leading to the formation of N–H bonds, and designed
a novel type of N,O-acetal with a bis(trimethylsilyl)amino group, as
follows. Treatment of methyl 2-bromo-2-methoxyacetate (1b) with
lithium bis(trimethylsilyl)amide in THF at room temperature was
followed by non-aqueous isolation and distillation under reduced
pressure to give N,O-acetal 36 in 47% yield (Scheme 2). Sub-
sequently, aminomethylation of indole with the N,O-acetal 3e was
examined using the Hf(OTf)4/Me3SiCl catalytic system. After stan-
dard isolation, the desired N-unsubstituted indolylglycine 37 was
obtained in 35% yield along with the byproduct, bis(indolyl)-
methane derivative 38, in 26% yield (Scheme 3). This result may be
due to a reduction in basicity of the amide anion by the inductive
effect of two silicon atoms.15 Namely, the amide group is a better
leaving group than the cyclic piperidino anion. When amino-
methylation was performed with 1 equiv of BF3$OEt2 instead of
Hf(OTf)4, the yield did not improve (47% of 37, 46% of 38).16 We
showed that the Hf(OTf)4/Me3SiCl-catalyzed aminomethylation of
an electron-rich heterocycle using the N,O-acetal with a bis-
(trimethylsilyl)amino group led to the direct synthesis of an N-
unsubstituted aromatic glycine derivative without the complicated
deprotection step.
Thus, to develop a useful method for the highly efficient prep-
aration of an N-underivatized aromatic glycine derivative, we pre-
pared an N,O-acetal with a diallylamino group. Diallylamino groups
2.3. Preparation of N-unsubstituted a-amino acids
can be easily converted to primary amino groups by use of the
14c
´
To illustrate the utility of this type of N,O-acetal, we then syn-
method described by Guibe and co-workers.
Treatment of
thesized an amino acid derivative with an underivatized amino
methyl 2-bromo-2-methoxyacetate with diallylamine in the

9210
N. Sakai et al. / Tetrahedron 64 (2008) 9208–9215
Table 2
Synthesis of a variety of
N(SiMe3)2
a
-arylglycine derivatives
+
N
H
MeO
CO2Me
X
X
Hf(OTf)4 (0.1 equiv)
Me3SiCl (1.2 equiv)
CH2Cl2, rt
36
+
Ar
H
1) 10% Hf(OTf)4/Me3SiCl
CH2Cl2, rt
N
N
Ar
CO2Me
2) H2O
MeO
CO2Me
23-35
4
MeO2C
NH2
CO2Me
Run
Time (h)
Product
Yielda (%)
+
X
Y
N
HN
NH
X
H
37:35%
38:26%
1
2
3
4
0.5
1
2
CH2
H
97 (23)
95 (24)
95 (25)
95 (26)
N
CO2Me
CO2Me
CH2
CH2
O
MeO
CO2Me
H
Scheme 3. Direct synthesis of N-unsubstituted indolylglycine 37 via a single-step
Y
reaction.
1
N
H
X
Br
Et3N
NH
N
+
N
2
THF, rt, 1h
MeO
CO2Me
5
6
1
1
CH2
O
H
H
99 (27)
89 (28)
MeO
CO2Me
(1.2 equiv)
Y
39:93%
N
Scheme 4. Preparation of N,O-acetal 39.
Me
X
Hf(OTf)4 (0.1 equiv)
NR2
7
8
1
3
CH2
O
d
d
98 (29)
86 (30)
N
NR2
Me3SiCl (1.2 equiv)
N
+
Ar
H
Me
CO2Me
MeO
CO2Me
CH2Cl2, rt
Ar
CO2Me
40-47
39: R= -CH2CH=CH2
X
N
9
10
11
4
4
4
CH2
O
O
O
O
S
94 (31)
96 (32)
78 (33)
R2N
R2N
Me
Y
CO2Me
Br
CO2Me
NR2
CO2Me
CO2Me
N
H
CO2Me
N
N
H
N
N
H
42: 100% (1 h)
12
1
CH2
d
d
99 (34)
91 (35)
40: 92% (1 h)
41: 100% (1 h)
O
X
X
NR2
NR2
CO2Me
NR2
Me
N
Me
N
Ph
O
CO2Me
43: 92% (1 h)
CO2Me
N
13
3
CH2
44: 86% (6 h)
45: 100% (1 h)
NR2
CO2Me
CO2Me
Me2N
NR2
a
Me
Isolated yield.
S
CO2Me
Me2N
presence of Et3N in THF at room temperature gave N,O-acetal 39 in
93% yield (Scheme 4).
46: 77% (3 h)
47: 55% (1 h)
a
-arylglycine derivatives with acetal 39. aIsolated
Scheme 5 shows the results of aminomethylation of various
heterocycles with N,O-acetal 39. In all cases, aminomethylation
with both heterocycles and electron-rich arenes proceeded
smoothly and efficiently to give the corresponding amino acid de-
rivatives 40–47 in good to excellent yields. Finally, deprotection of
the diallylamino group on the substituted product was performed
with 5% Pd(PPh3)4 and 6 equiv of 1,3-dimethylbarbituric acid in
CH2Cl2 at room temperature. The results of this reaction are
Scheme 5. Synthesis of a variety of
yield.
using N,O-acetal with a diallylamino group and deprotection of the
diallylamine group on the product successfully produced an N-
underivatized aromatic amino acid derivative.
summarized in Scheme 6. N-Substituted
underwent the reductive deprotection to give the desired
N-unsubstituted -arylglycine derivatives 37 and 48–51 in mod-
erate to good yields. Thus, we demonstrated that a sequential
procedure consisting of Hf(OTf)4-catalyzed aminomethylation
a-arylglycine derivatives
2.4. Plausible mechanism
a
A plausible mechanism for the aminomethylation of aromatic
compounds is shown in Scheme 7. First, coordination of hafnium
triflate to an oxygen atom of the starting acetal results in the for-
mation of an iminium complex.17 Then, Me3SiCl traps the in situ
generated methoxy ion, thus driving the equilibrium to completion
and promoting regeneration of the hafnium catalyst, because the
use of less than 1 equiv of Me3SiCl reduces the chemical yield.5g,18
Finally, the arene attacks the iminium intermediate to produce the
corresponding aminomethylated product. When the N,O-acetal
Br
N(SiMe3)2
CO2Me
n-BuLi
THF, rt, 1h
+
HN(SiMe3)2
(1.2 equiv)
MeO
CO2Me
MeO
36:47%
Scheme 2. Preparation of N,O-acetal 36.

N. Sakai et al. / Tetrahedron 64 (2008) 9208–9215
9211
5%Pd(PPh3)4
were recorded at 125 or 75 MHz using TMS or a center peak of
chloroform (77.0 ppm) as an internal standard. High-resolution
mass spectra were recorded using NBA (3-nitrobenzylalcohol) as
a matrix. Hf(OTf)4,19 2-bromo-2-methoxyacetonitrile (1a),20 and
methyl 2-bromo-2-methoxyacetate20 (1b) were prepared accord-
ing to the previously reported procedure.
1,3-dimethylbarbituric acid
(6 equiv)
N(allyl)2
CO2Me
NH2
Ar
Ar
CH2Cl2, rt
CO2Me
37, 48-51
H2N
CO2Me
NH2
NH2
Me
4.2. General procedure for the synthesis of N,O-acetals 3
N
O
Me
CO2Me
CO2Me
N
H
To a freshly distilled THF solution (100 mL), the corresponding
secondary amine 2 (24 mmol), diisopropylethylamine (4.1 mL,
24 mmol), and bromomethoxyacetonitrile (11.5 mL, 20.0 mmol)
were successively added, and the resulting solution was stirred for
2 h at room temperature. The mixture was then filtered without
any aqueous workup and the filtrate was directly distilled (Kugel-
rohr) to give the corresponding N,O-acetal 3.
48: 53% (1 h)
49: 48% (1 h)
37: 68% (0.1 h)
NH2
NH2
CO2Me
Me
S
CO2Me
Me2N
50: 63% (1 h)
51: 82% (1 h)
Scheme 6. Deprotection of diallylamino group. aIsolated yield.
4.2.1. 2-Methoxy-2-(piperidin-1-yl)acetonitrile21 (3a)
Colorless oil; 1H NMR (500 MHz, CDCl3)
d
1.50 (m, 2H), 1.58 (m,
4H), 2.66 (m, 4H), 3.43 (s, 3H), 4.56 (s, 1H); 13C NMR (125 MHz,
CDCl3) 24.1, 25.2, 48.4, 55.8, 87.1, 114.4.
with a bis(trimethylsilyl)amino group was used, aqueous workup of
the resulting mixture directly gave the corresponding N-unsub-
stituted amino acid.
d
4.2.2. 2-Methoxy-2-(morpholin-4-yl)acetonitrile21 (3b)
Colorless oil; 1H NMR (500 MHz, CDCl3)
2.67 (t, 4H, J¼5.0 Hz),
3.40 (s, 3H), 3.69 (m, 4H), 4.54 (s, 1H); 13C NMR (125 MHz, CDCl3)
47.4, 55.8, 66.3, 86.3, 113.9.
d
(TfO)4Hf(OMe)
R
R
E
R
R
N
N
Me3SiCl
Me3SiOMe
Cl
d
MeO
E
4.2.3. 2-Methoxy-2-(4-phenyl-piperazin-1-yl)acetonitrile21 (3c)
Yellow oil; 1H NMR (500 MHz, CDCl3)
Hf(OTf)4
Hf(OTf)4
d
2.88 (t, 4H, J¼5.0 Hz),
3.23 (m, 4H), 3.46 (s, 3H), 4.66 (s, 1H), 6.88 (t, 1H, J¼8.0 Hz), 6.92 (d,
(E = CN or CO2Me)
2H, J¼8.0 Hz), 7.27 (t, 2H, J¼8.0 Hz); 13C NMR (125 MHz, CDCl3)
d
47.3, 48.9, 55.9, 86.2, 114.0, 116.4, 120.1, 129.1, 151.0.
R
R
E
R
R
NH2
E
H2O
Ar
H
N
N
-HCl
Ar
Ar
E
4.3. General procedure for the synthesis of N,O-acetals 4
and 39
(R = Me3Si)
Scheme 7. Plausible mechanism for the Hf(OTf)4/Me3SiCl-catalyzed amino-
methylation.
To a freshly distilled THF solution (100 mL), the corresponding
secondary amine 2 (24 mmol), diisopropylethylamine (4.1 mL,
24 mmol), and methyl 2-bromo-2-methoxyacetate (11 mL,
20 mmol) were successively added, and the solution was stirred at
room temperature. After 2 h, the reaction was quenched by adding
a saturated aqueous solution (2 mL) of NaHCO3. The aqueous layer
was extracted with CHCl3, the organic phase was combined, dried
over anhydrous Na2CO3, filtered, and evaporated under reduced
pressure. The crude product was distilled (Kugelrohr) to give the
corresponding N,O-acetals.
3. Conclusion
In conclusion, we demonstrated that the Hf(OTf)4-doped
Me3SiCl system-catalyzed aminomethylation of aromatic com-
pounds, such as electron-rich heterocycles and arenes, using a new
class of an N,O-acetals with a cyano group or an ester group leads to
the production of a non-natural amino acid derivative. In addition,
we have found that for the Hf(OTf)4/Me3SiCl catalytic system, the
N,O-acetal with a bis(trimethylsilyl)amino group functions as an N-
unsubstituted glycine cation equivalent. Moreover, we have found
4.3.1. Methyl 2-methoxy-2-(piperidin-1-yl)acetate9a (4a)
Bp 71–72 ꢀC/5 mmHg (colorless oil); 1H NMR (300 MHz, CDCl3)
that
a sequential procedure consisting of Hf(OTf)4-catalyzed
aminomethylation of N,O-acetals with a diallylamino group and Pd-
catalyzed deprotection of the diallylamino group on the product
leads to the preparation of a variety of aromatic glycine derivatives.
d
1.3–1.4 (m, 2H), 1.5–1.6 (m, 4H), 2.5–2.8 (m, 4H), 3.39 (s, 3H), 3.77
(s, 3H), 4.23 (s,1H); 13C NMR (75 MHz, CDCl3)
55.5, 94.0, 168.7.
d 24.2, 25.8, 48.4, 51.4,
4. Experimental
4.3.2. Methyl 2-methoxy-2-(morpholin-4-yl)acetate9a (4b)
Bp 84–86 ꢀC/5 mmHg (colorless oil); 1H NMR (300 MHz, CDCl3)
4.1. General experimental
d
2.6–2.8 (m, 4H), 3.42 (s, 3H), 3.6–3.7 (m, 4H), 3.79 (s, 3H), 4.23 (s,
1H); 13C NMR (75 MHz, CDCl3)
d
47.6, 51.7, 55.8, 66.9, 93.4, 168.2.
Column chromatography was performed using silica gel. THF
was distilled from sodium/benzophenone and dried over 5 Å MS.
CH2Cl2 was distilled from P2O5 and dried over 4 Å MS. Secondary
amines 2a–c were commercially available and distilled prior to use.
All reactions were carried out under a N2 atmosphere, unless oth-
erwise noted. 1H NMR spectra were recorded at 500 or 300 MHz
using tetramethylsilane as an internal standard. 13C NMR spectra
4.3.3. Methyl 2-(diallylamino)-2-methoxyacetate (39)
Bp 69–70 ꢀC/5 mmHg (colorless oil); 1H NMR (300 MHz, CDCl3)
d
3.2–3.3 (m, 4H), 3.36 (s, 3H), 3.76 (s, 3H), 4.45 (s, 1H), 5.1–5.2 (m,
4H), 5.7–5.8 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 51.8, 52.1, 55.5,
89.8, 117.5, 135.7, 169.7; MS (ESI) 222 (MþþNa); HRMS (ESI) calcd
for C10H17NNaO3: 222.1106, found: 222.1095.

9212
N. Sakai et al. / Tetrahedron 64 (2008) 9208–9215
4.4. Preparation of N,O-acetal 36
8.37 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 24.1, 25.8, 50.7, 56.3,
109.4, 112.8, 113.3, 115.8, 122.6, 124.9, 125.8, 127.4, 135.4; MS (FAB)
318, 293, 291, 235, 233; HRMS (FAB) calcd for C15H17N3Br: 318.0606,
found: 318.0615 (MþþH).
To a freshly distilled THF solution (100 mL), hexamethyldisila-
zane (5.5 mL, 24 mmol), n-BuLi (15 mL, 24 mmol in 1.6 M hexane
solution), and the methyl 2-bromo-2-methoxyacetate (11 mL,
20 mmol) were successively added, and the resulting solution was
stirred at room temperature. After 1 h, the reaction was quenched by
adding a saturated aqueous solution (2 mL) of NaHCO3. The mixture
was poured into AcOEt (50 mL) and the organic layer was washed by
H2O (20 mLꢁ3). Then, the organic phase was dried over anhydrous
Na2CO3, filtered, and evaporated under reduced pressure. The crude
product was distilled to give the corresponding N,O-acetal 36.
4.5.5. 2-(1H-Indol-3-yl)-2-(morpholin-4-yl)acetonitrile (9)
Mp 148–149 ꢀC (a colorless crystal); 1H NMR (500 MHz, CDCl3)
d
2.62 (m, 4H), 3.72 (m, 4H), 5.05 (s, 1H), 7.16 (t, 1H, J¼7.5 Hz), 7.25
(t, 1H, J¼7.5 Hz), 7.35 (m, 2H), 7.80 (d, 1H, J¼7.5 Hz), 8.48 (br s, 1H);
13C NMR (125 MHz, CDCl3)
49.7, 55.7, 66.7, 108.2, 111.5, 115.7, 119.7,
d
120.2, 122.9, 124.3, 125.5, 136.7; MS (FAB) 241, 215, 86. Anal. Calcd
for C14H15N3O: C, 69.69; H, 6.27; N, 17.41. Found: C, 69.75; H, 6.67;
N, 17.41.
4.4.1. Methyl 2-(1,1,1,3,3,3-hexamethyldisilazan-2-yl)-2-
methoxyacetate (36)
4.5.6. 2-(1-Methyl-1H-indol-3-yl)-2-(piperidin-1-yl)acetonitrile (10)
Bp 74–75 ꢀC/3 mmHg (colorless oil); 1H NMR (300 MHz, CDCl3)
Mp 143–144 ꢀC (a colorless crystal); 1H NMR (500 MHz, CDCl3)
d
0.111 (s, 18H), 3.30 (s, 3H), 3.68 (s, 3H), 4.62 (s, 1H); 13C NMR
d 1.4–1.6 (m, 6H), 2.5–2.6 (m, 4H), 3.79 (s, 3H), 5.06 (s, 1H), 7.14
(75 MHz, CDCl3)
d
2.2, 52.1, 55.0, 87.7, 172.1; MS (ESI) 286 (MþþNa);
(t, 1H, J¼7.5 Hz), 7.26 (s, 1H), 7.27 (t, 1H, J¼7.5 Hz), 7.31 (d, 1H,
HRMS (ESI) calcd for C10H25NNaO3Si2: 286.1270, found: 286.1248.
J¼7.5 Hz), 7.82 (d, 1H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d
24.2, 25.9, 32.9, 50.7, 56.3, 107.9, 109.4, 116.3, 119.6, 120.1, 122.4,
4.5. General procedure for the Hf(OTf)4-catalyzed
aminomethylation of aromatics with an N,O-acetal
126.3, 128.5, 137.5; MS (FAB) 254, 227, 169. Anal. Calcd for
C16H19N3: C, 75.85; H, 7.56; N, 16.71. Found: C, 75.77; H, 7.37; N,
16.71.
An N,O-acetal (0.60 mmol), an aromatic compound (0.50 mmol),
and freshly distilled trimethylchlorosilane (0.60 mmol) were suc-
cessively mixed together in CH2Cl2 (2 mL) at room temperature
with stirring. After 1 min, Hf(OTf)4 (0.050 mmol) was added and
the resulting thick suspension was stirred until the reaction
reached completion, as shown by TLC (SiO2: hexane/AcOEt¼2:1).
The reaction was quenched with a saturated aqueous solution
(2 mL) of NaHCO3. The combined organic layer was dried over so-
dium carbonate and evaporated under reduced pressure. The crude
product was purified by silica gel column chromatography (hexane/
AcOEt) to afford indolylglycine derivatives.
4.5.7. 2-(1-Methyl-1H-indol-3-yl)-2-(morpholin-4-yl)-
acetonitrile (11)
Mp 161–162 ꢀC (a colorless crystal); 1H NMR (500 MHz, DMSO)
d
2.53 (m, 4H), 3.62 (m, 4H), 3.82 (s, 3H), 5.51 (s, 1H), 7.12 (t, 1H,
J¼7.5 Hz), 7.23 (t, 1H, J¼7.5 Hz), 7.50 (m, 2H), 7.75 (d, 1H, J¼7.5 Hz);
13C NMR (125 MHz, DMSO)
32.4, 49.4, 54.0, 66.0, 105.9, 110.1,
d
116.4, 119.3, 119.4, 121.9, 125.8, 129.3, 137.0; MS (FAB) 256, 229, 169.
Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C,
70.28; H, 7.06; N, 16.33.
4.5.8. 2-(1-Methyl-1H-indol-3-yl)-2-(4-phenyl-piperazin-1-yl)-
acetonitrile (12)
4.5.1. 2-(1H-Indol-3-yl)-2-(piperidin-1-yl)acetonitrile (5)
Mp 139–140 ꢀC (colorless crystal); 1H NMR (300 MHz, CDCl3)
Mp 153–154 ꢀC (a colorless crystal); 1H NMR (500 MHz, CDCl3)
d
1.4–1.6 (m, 6H), 2.4–2.6 (m, 4H), 5.07 (s, 1H), 7.12 (t, 1H, J¼7.0 Hz),
d 2.75 (m, 4H), 3.20 (m, 4H), 3.78 (s, 3H), 5.13 (s, 1H), 6.85 (t, 1H,
7.22 (t, 1H, J¼7.0 Hz), 7.35 (s, 1H), 7.37 (d, 1H, J¼7.0 Hz), 7.83 (d, 1H,
J¼7.5 Hz), 6.89 (d, 2H, J¼7.5 Hz), 7.14 (t, 1H, J¼8.5 Hz), 7.22–7.34 (m,
J¼7.0 Hz), 8.24 (br s,1H); 13C NMR (75 MHz, CDCl3)
d
24.1, 25.9, 50.7,
5H), 7.81 (d, 1H, J¼8.5 Hz); 13C NMR (125 MHz, CDCl3)
d 32.9, 49.2,
56.4, 109.6, 111.3, 116.1, 120.1, 122.8, 123.9, 125.7, 136.7; MS (FAB)
240, 215, 84. Anal. Calcd for C15H17N3: C, 75.28; H, 7.16; N, 17.56.
Found: C, 75.17; H, 7.31; N, 17.71.
49.4, 55.4, 107.1, 109.6, 115.8, 116.2, 119.8, 119.9, 120.0, 122.5, 126.1,
128.8, 129.4, 137.6, 151.1; MS (FAB) 330, 304, 169. Anal. Calcd for
C21H22N4: C, 76.33; H, 6.71; N, 16.96. Found: C, 76.16; H, 6.70; N,
16.82.
4.5.2. 2-(5-Methoxy-1H-indol-3-yl)-2-(piperidin-1-yl)-
acetonitrile (6)
4.5.9. 2-(Piperidin-1-yl)-(1H-pyrrol-2-yl)acetonitrile (13)
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.4–1.5 (m, 2H),1.5–1.6
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.4–1.5 (m, 2H),1.6–1.7
(m, 4H), 2.5–2.6 (m, 4H), 4.81 (s, 1H), 6.15 (s, 1H), 6.35 (s, 1H), 6.79
(s, 1H), 8.52 (br s, 1H); 13C NMR (125 MHz, CDCl3)
23.9, 25.8, 50.9,
(m, 4H), 2.4–2.6 (m, 4H), 3.85 (s, 3H), 5.02 (s, 1H), 6.87 (d, 1H,
J¼8.5 Hz), 7.23 (d, 1H, J¼8.5 Hz), 7.30 (m, 2H), 8.26 (br s, 1H); 13C
d
NMR (75 MHz, CDCl3)
d
24.2, 25.9, 50.6, 55.8, 56.4, 101.9, 111.9,
57.2, 108.5, 108.7, 118.9, 123.7; MS (FAB) 189, 163, 84; HRMS (FAB)
calcd for C11H15N3: 189.1266, found: 189.1263 (Mþ).
112.9, 116.1, 124.6, 126.2, 131.8, 154.1; MS (FAB) 269, 244, 185, 84;
HRMS (FAB) calcd for C16H19N3O: 269.1528, found: 269.1526.
4.5.10. 2-(1-Methyl-1H-pyrrol-2-yl)-2-(piperidin-1-yl)-
acetonitrile (14)
4.5.3. Methyl 3-(cyano(piperidin-1-yl)methyl)-1H-indole-
carboxylate (7)
Mp 127–128 ꢀC (a colorless crystal); 1H NMR (500 MHz, CDCl3)
Mp 153–155 ꢀC (white powder); 1H NMR (500 MHz, CDCl3)
d 1.4–1.6 (m, 6H), 2.4–2.5 (m, 4H), 3.61 (s, 3H), 4.71 (s, 1H), 6.04 (t,
d
1.4–1.5 (m, 2H), 1.5–1.6 (m, 4H), 2.5–2.6 (m, 4H), 3.95 (s, 3H), 5.10
(s, 1H), 7.39 (d, 1H, J¼7.0 Hz), 7.44 (s, 1H), 7.94 (d, 1H, J¼7.0 Hz), 8.51
(br s, 1H), 8.60 (s, 1H); 13C NMR (125 MHz, CDCl3)
24.1, 25.8, 51.9,
1H, J¼3.5 Hz), 6.33 (d,1H, J¼3.5 Hz), 6.62 (d, 1H, J¼3.5 Hz); 13C NMR
(125 MHz, CDCl3)
d 24.1, 25.8, 33.9, 50.3, 56.4, 106.6, 110.8, 114.8,
d
123.7, 124.4; MS (FAB) 203, 177, 119. Anal. Calcd for C12H17N3: C,
70.90; H, 8.43; N, 20.67. Found: C, 71.12; H, 8.16; N, 20.91.
56.2, 111.1, 111.3, 115.8, 122.3, 123.1, 124.2, 125.2, 125.4, 139.3, 168.0;
MS (FAB) 298, 271, 213. Anal. Calcd for C17H19N3O2: C, 68.67; H,
6.44; N, 14.13. Found: C, 68.38; H, 6.28; N, 14.16.
4.5.11. 2-(1-Phenyl-1H-pyrrol-2-yl)-2-(piperidin-1-yl)-
acetonitrile (15)
4.5.4. 2-(5-Bromo-1H-indol-3-yl)-2-(piperidin-1-yl)acetonitrile (8)
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.3–1.5 (m, 6H), 2.33
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.4–1.5 (m, 2H),1.5–1.6
(m, 2H), 2.59 (m, 2H), 4.52 (s, 1H), 6.25 (t, 1H, J¼3.5 Hz), 6.51 (d, 1H,
(m, 4H), 2.4–2.6 (m, 4H), 5.00 (s, 1H), 7.2–7.4 (m, 3H), 7.97 (s, 1H),
J¼3.5 Hz), 6.87 (d, 1H, J¼3.5 Hz), 7.3–7.5 (m, 5H); 13C NMR (75 MHz,

N. Sakai et al. / Tetrahedron 64 (2008) 9208–9215
9213
CDCl3)
d
23.9, 25.7, 49.7, 55.3, 108.1, 112.1, 115.1, 123.7, 124.1, 124.9,
4.5.19. Methyl 2-(1H-indol-3-yl)-2-(piperidin-1-yl)acetate (23)
Colorless oil; 1H NMR (300 MHz, CDCl3)
1.3–1.4 (m, 2H),1.5–1.6
125.9, 127.5, 128.9, 129.6, 139.4; MS (FAB) 265, 240, 181; HRMS
(FAB) calcd for C17H19N3: 265.1579, found: 265.1587 (Mþ).
d
(m, 4H), 2.5–2.6 (m, 4H), 3.64 (s, 3H), 4.38 (s, 1H), 7.10 (t, 1H,
J¼7.5 Hz), 7.14 (t, 1H, J¼7.5 Hz), 7.16 (s, 1H), 7.25 (d, 1H, J¼7.5 Hz),
7.76 (d, 1H, J¼7.5 Hz), 8.96 (br s, 1H); 13C NMR (75 MHz, CDCl3)
4.5.12. 2-(Morpholin-4-yl)-(1H-pyrrol-2-yl)acetonitrile (16)
Mp 129–131 ꢀC (a colorless crystal); 1H NMR (300 MHz, CDCl3)
d 24.2, 25.6, 51.7, 52.2, 66.3, 109.9, 111.3, 119.2, 119.5, 121.9, 124.4,
d
2.57 (m, 4H), 3.73 (m, 4H), 4.82 (s, 1H), 6.17 (d, 1H, J¼5.0 Hz), 6.38
127.2, 135.9, 172.9; MS (FAB) 273, 212, 188; HRMS (FAB) calcd for
C16H21N2O2: 273.1603, found: 273.1596.
(s, 1H), 6.82 (s, 1H), 8.47 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d
49.8,
56.6, 66.6, 108.7, 109.5, 114.4, 119.4, 122.5; MS (FAB) 191, 86. Anal.
Calcd for C10H13N3O: C, 62.81; H, 6.85; N, 21.97. Found: C, 62.84; H,
6.69; N, 22.31.
4.5.20. Methyl 2-(5-methoxy-1H-indol-3-yl)-2-(piperidin-1-yl)-
acetate (24)
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.3–1.4 (m, 2H),1.5–1.6
4.5.13. 2-(1-Methyl-1H-pyrrol-2-yl)-2-(morpholine-4-yl)-
acetonitrile (17)
(m, 4H), 2.5–2.6 (m, 4H), 3.69 (s, 3H), 3.84 (s, 3H), 4.34 (s, 1H), 6.82
(d, 1H, J¼7.5 Hz), 7.20 (d, 1H, J¼7.5 Hz), 7.22 (s, 1H), 7.26 (s, 1H), 8.49
Mp 107–108 ꢀC (a colorless crystal); 1H NMR (300 MHz, CDCl3)
(br s, 1H); 13C NMR (75 MHz, CDCl3)
d 24.4, 25.8, 51.7, 52.1, 55.8,
d
2.57 (m, 4H), 3.66 (s, 3H), 3.70 (m, 4H), 4.75 (s, 1H), 6.07 (s, 1H),
66.6, 101.4, 110.3, 111.8, 112.4, 124.8, 127.7, 131.1, 154.1, 172.7; MS
(FAB) 303, 245, 218; HRMS (FAB) calcd for C17H23N2O3: 303.1709,
found: 303.1720.
6.38 (s, 1H), 6.66 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
33.9, 49.4,
55.6, 66.6, 106.7, 111.3, 114.3, 114.3, 122.4, 124.7; MS (FAB) 205, 179,
119; HRMS (FAB) calcd for C11H15N3O: 205.1215, found: 205.1214
(Mþ).
4.5.21. Methyl 3-(2-methoxy-2-oxo-1-(piperidin-1-yl)ethyl)-1H-
indole-5-carboxylate (25)
4.5.14. 2-(4-Phenyl-piperazin-1-yl)-2-(1H-pyrrol-2-yl)-
acetonitrile (18)
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.3–1.4 (m, 2H),1.5–1.6
(m, 4H), 2.5–2.6 (m, 4H), 3.69 (s, 3H), 3.91 (s, 3H), 4.46 (s, 1H), 7.27
Mp 123–125 ꢀC (a colorless crystal); 1H NMR (500 MHz, CDCl3)
(s, 1H), 7.34 (d, 1H, J¼7.5 Hz), 7.86 (d, 1H, J¼7.5 Hz), 8.55 (s, 1H), 9.70
d
2.71 (m, 4H), 3.20 (m, 4H), 4.91 (s, 1H), 6.19 (s, 1H), 6.41 (s, 1H),
(br s, 1H); 13C NMR (75 MHz, CDCl3)
d 24.1, 25.6, 51.8, 52.1, 65.9,
6.83 (s, 1H), 6.88 (t, 1H, J¼8.5 Hz), 6.91 (d, 2H, J¼8.5 Hz), 7.27 (t, 2H,
111.1, 111.6, 121.6, 122.2, 123.3, 125.7, 126.9, 138.6, 168.2, 172.6; MS
(FAB) 331, 271, 246; HRMS (FAB) calcd for C18H23N2O4: 331.1658,
found: 331.1658.
J¼8.5 Hz), 8.43 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 49.1, 49.6,
56.3, 108.7, 109.3, 114.5, 116.3, 119.4, 120.1, 122.9, 129.2, 150.9; MS
(FAB) 266, 240,161; HRMS (FAB) calcd for C16H18N4: 266.1531,
found: 266.1533 (Mþ).
4.5.22. Methyl 2-(1H-indol-3-yl)-2-(morpholin-4-yl)acetate (26)
Colorless oil; 1H NMR (500 MHz, CDCl3)
d 2.4–2.5 (m, 4H), 3.5–
4.5.15. 2-(1-Methyl-1H-pyrrol-2-yl)-2-(4-phenyl-piperazin-1-yl)-
acetonitrile (19)
3.7 (m, 4H), 3.59 (s, 3H), 4.32 (s, 1H), 7.05 (t, 1H, J¼7.5 Hz), 7.10 (t,
1H, J¼7.5 Hz), 7.14 (s, 1H), 7.22 (d, 1H, J¼7.5 Hz), 7.75 (d, 1H,
Mp 135–137 ꢀC (a colorless crystal); 1H NMR (300 MHz, CDCl3)
J¼7.5 Hz), 8.75 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 51.2, 51.7,
d
2.70 (m, 4H), 3.16 (m, 4H), 3.64 (s, 3H), 4.80 (s, 1H), 6.07 (s, 1H),
6.38 (s, 1H), 6.65 (s, 1H), 6.85–6.90 (m, 3H), 7.22 (t, 2H, J¼7.0 Hz);
13C NMR (75 MHz, CDCl3)
34.1, 40.4, 49.1, 55.5, 106.8, 111.4, 114.4,
66.1, 66.8, 109.5, 111.2, 119.5, 119.8, 122.2, 124.3, 126.8, 136.1, 172.1;
MS (FAB) 275, 215, 188; HRMS (FAB) calcd for C15H18N2O3:
275.1396, found: 275.1369.
d
116.3, 120.0, 122.9, 124.8, 129.1, 151.0; MS (FAB) 280, 254, 161. Anal.
Calcd for C17H20N4: C, 72.83; H, 7.19; N, 19.98. Found: C, 72.82; H,
7.33; N, 20.00.
4.5.23. Methyl 2-(1-methyl-1H-indol-3-yl)-2-(piperidin-1-yl)-
acetate (27)
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.3–1.4 (m, 2H),1.5–1.6
4.5.16. 2-(5-Methylfuran-2-yl)-2-(piperidin-1-yl)acetonitrile (20)
(m, 4H), 2.5–2.6 (m, 4H), 3.67 (s, 3H), 3.70 (s, 3H), 4.38 (s, 1H), 7.11
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.4–1.5 (m, 2H),1.6–1.7
(t, 1H, J¼7.5 Hz), 7.14 (s, 1H), 7.20 (d, 1H, J¼7.5 Hz), 7.24 (t, 1H,
(m, 4H), 2.30 (s, 3H), 2.5–2.6 (m, 4H), 4.78 (s, 1H), 5.95 (d, 1H,
J¼7.5 Hz), 7.76 (d, 1H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 24.2,
J¼3.5 Hz), 6.39 (d, 1H, J¼3.5 Hz); 13C NMR (75 MHz, CDCl3)
d
13.7,
25.7, 32.6, 51.5, 52.0, 66.2, 108.8, 109.1, 119.2, 119.6, 121.6, 127.7,
128.5, 136.6, 172.6; MS (FAB) 287, 227, 202; HRMS (FAB) calcd for
23.8, 25.5, 50.8, 56.9, 106.4, 111.4, 114.2, 144.3, 153.7; MS (FAB) 204,
178, 147, 84; HRMS (FAB) calcd for C12H16N2O: 204.1263, found:
204.1255 (Mþ).
C17H23N2O2: 287.1760, found: 287.1746.
4.5.24. Methyl 2-(1-methyl-1H-indol-3-yl)-2-(morpholin-4-yl)-
4.5.17. 2-(5-Methylfuran-2-yl)-2-(morpholine-4-yl)-
acetate (28)
acetonitrile (21)
Colorless oil; 1H NMR (500 MHz, CDCl3)
d 2.4–2.5 (m, 4H), 3.6–
Yellow oil; 1H NMR (500 MHz, CDCl3)
d
2.23 (s, 3H), 2.53 (m, 4H),
3.7 (m, 4H), 3.64 (s, 3H), 3.68 (s, 3H), 4.31 (s, 1H), 7.06 (t, 1H,
3.69 (m, 4H), 4.72 (s, 1H), 5.90 (d, 1H, J¼3.0 Hz), 6.35 (d, 1H,
J¼7.5 Hz), 7.08 (s, 1H), 7.16 (t, 1H, J¼7.5 Hz), 7.21 (d, 1H, J¼7.5 Hz),
J¼3.0 Hz); 13C NMR (125 MHz, CDCl3)
d
13.6, 49.7, 56.1, 66.4, 106.5,
7.73 (t, 1H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d 32.8, 51.2, 51.8,
111.9, 113.8, 143.2, 154.0; MS (FAB) 206, 177, 84; HRMS (FAB) calcd
for C11H14N2O2: 205.0977, found: 205.0983 (Mþ).
66.0, 66.9, 108.1, 109.3, 119.5, 119.7, 121.9, 127.4, 128.8, 136.9, 172.0;
MS (FAB) 287, 229, 202; HRMS (FAB) calcd for C16H21N2O3:
289.1552, found: 289.1568.
4.5.18. 2-(5-Methylfuran-2-yl)-2-(4-phenyl-piperazin-1-yl)-
acetonitrile (22)
4.5.25. Methyl 2-(1-methyl-1H-pyrrol-2-yl)-2-(piperidin-1-yl)-
Mp 112–113 ꢀC (a colorless crystal); 1H NMR (500 MHz, CDCl3)
acetate (29)
d
2.32 (s, 3H), 2.78 (m, 4H), 3.26 (m, 4H), 4.87 (s, 1H), 5.99 (d, 1H,
Brown oil; 1H NMR (500 MHz, CDCl3)
d 1.4–1.5 (m, 2H), 1.5–1.6
J¼5.0 Hz), 6.46 (d, 1H, J¼5.0 Hz), 6.87 (t, 1H, J¼7.5 Hz), 6.91 (d, 2H,
(m, 4H), 2.4–2.5 (m, 4H), 3.69 (s, 3H), 3.70 (s, 3H), 4.26 (s, 1H), 6.03
J¼7.5 Hz), 7.27 (t, 2H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d
13.7,
(t, 1H, J¼3.5 Hz), 6.09 (d, 1H, J¼3.5 Hz), 6.59 (d, 1H, J¼3.5 Hz); 13C
48.9, 49.5, 55.9, 106.5, 111.9, 113.9, 116.3, 120.1, 129.1, 143.6, 151.0,
154.0; MS (FAB) 281, 255, 161. Anal. Calcd for C17H19N3 O: C, 72.57;
H, 6.81; N, 14.94. Found: C, 72.35; H, 6.91; N, 14.94.
NMR (125 MHz, CDCl3) d 24.4, 26.1, 34.1, 50.7, 51.3, 66.2,106.4,109.7,
123.4, 126.2, 171.0; MS (FAB) 237, 177, 152; HRMS (FAB) calcd for
13H21N2O2: 237.1603, found: 237.1611.
C

9214
N. Sakai et al. / Tetrahedron 64 (2008) 9208–9215
4.5.26. Methyl 2-(1-methyl-1H-pyrrol-2-yl)-2-(morpholin-4-yl)-
2H, J¼7.5 Hz), 7.58 (d, 2H, J¼7.5 Hz), 7.95 (br s, 2H); 13C NMR
acetate (30)
(75 MHz, CDCl3) d 40.3, 52.2, 111.2, 113.3, 119.1, 119.5, 122.0, 123.3,
Brown oil; 1H NMR (500 MHz, CDCl3)
d
2.4–2.6 (m, 4H), 3.5–3.6
126.5, 136.2, 174.0; MS (FAB) 304, 245.
(m, 4H), 3.70 (s, 3H), 3.71 (s, 3H), 4.28 (s, 1H), 6.03 (t, 1H, J¼3.5 Hz),
6.11 (d, 1H, J¼3.5 Hz), 6.60 (d, 1H, J¼3.5 Hz); 13C NMR (125 MHz,
4.5.34. Methyl 2-(diallylamino)-2-(1H-indol-3-yl)acetate (40)
CDCl3)
d
34.1, 50.1, 51.5, 65.7, 67.0,106.7,110.3,123.7,125.1,170.4; MS
Colorless oil; 1H NMR (500 MHz, CDCl3)
d 3.2–3.4 (m, 4H), 3.70 (s,
(FAB) 239, 179, 152; HRMS (FAB) calcd for C12H19N2O3: 239.1396,
found: 239.1407.
3H), 4.95 (s, 1H), 5.0–5.2 (m, 4H), 5.8–5.9 (m, 2H), 7.10 (t, 1H,
J¼7.5 Hz), 7.13 (s,1H), 7.18 (t,1H, J¼7.5 Hz), 7.30 (d,1H, J¼7.5 Hz), 7.76
(d, 1H, J¼7.5 Hz), 8.34 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 51.4,
4.5.27. Methyl 2-(5-methylfuran-2-yl)-2-(piperidin-1-yl)-
53.3, 60.2, 111.0, 111.1, 117.3, 119.7, 119.8, 122.2, 124.1, 126.9, 136.1,
136.2, 172.9; MS (FAB) 285 (MþH, 33%), 225 (MꢂCO2Me, 100%);
HRMS (FAB) calcd for C17H21 N2O2: 285.1603, found: 285.1606.
acetate (31)
Colorless oil; 1H NMR (500 MHz, CDCl3)
d 1.4–1.5 (m, 2H),1.5–1.6
(m, 4H), 2.28 (s, 3H), 2.4–2.5 (m, 4H), 3.73 (s, 3H), 4.17 (s, 1H), 5.91
(d, 1H, J¼3.0 Hz), 6.22 (d, 1H, J¼3.5 Hz); 13C NMR (125 MHz, CDCl3)
4.5.35. Methyl 2-(5-bromo-1H-indol-3-yl)-2-(diallylamino)-
d
13.5, 24.0, 25.6, 51.7, 51.9, 67.4, 106.1, 110.6, 146.8, 152.5, 170.1; MS
acetate (41)
(FAB) 238, 178, 153; HRMS (FAB) calcd for C13H20NO3: 238.1443,
found: 238.1446.
Colorless oil; 1H NMR (500 MHz, CDCl3)
d 3.1–3.3 (m, 4H), 3.73
(s, 3H), 4.87 (s, 1H), 5.1–5.3 (m, 4H), 5.8–5.9 (m, 2H), 7.16 (d, 1H,
J¼7.5 Hz), 7.20 (d, 1H, J¼7.5 Hz), 7.25 (s, 1H), 7.91 (s, 1H), 8.40 (br s,
4.5.28. Methyl 2-(5-methylfuran-2-yl)-2-(morpholin-4-yl)-
1H); 13C NMR (125 MHz, CDCl3)
d 51.5, 53.3, 60.1, 111.1, 112.6, 113.0,
acetate (32)
117.5, 122.5, 125.1, 125.2, 128.6, 134.8, 135.8, 172.6; MS (FAB) 363
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
2.14 (s, 3H), 2.3–2.5 (m,
(MþH, 22%), 303 (MꢂCO2Me, 100%) 268; HRMS (FAB) calcd for
4H), 3.5–3.7 (m, 4H), 3.61 (s, 3H), 4.05 (s, 1H), 5.79 (d, 1H, J¼3.5 Hz),
C17H20N2O2Br: 363.0708, found: 363.0691.
6.11 (d, 1H, J¼3.5 Hz); 13C NMR (75 MHz, CDCl3)
d 13.4, 50.8, 52.0,
66.5, 66.7, 106.2, 111.2, 145.7, 152.8, 169.4; MS (FAB) 240, 180, 158;
HRMS (FAB) calcd for C12H18NO4: 240.1236, found: 240.1235.
4.5.36. Methyl 2-(diallylamino)-2-(1H-pyrrol-2-yl)acetate (42)
Yellow oil; 1H NMR (500 MHz, CDCl3)
3.1–3.3 (m, 4H), 3.73 (s,
d
3H), 4.60 (s, 1H), 5.1–5.2 (m, 4H), 5.7–5.8 (m, 2H), 6.11 (t, 1H,
4.5.29. Methyl 2-(5-methylthiophen-2-yl)-2-(morpholin-4-yl)-
J¼3.0 Hz), 6.14 (d, 1H, J¼3.0 Hz), 6.76 (d, 1H, J¼3.0 Hz), 8.74 (br s,
acetate (33)
1H); 13C NMR (125 MHz, CDCl3)
d 51.7, 53.2, 61.3, 108.0, 108.7, 117.6,
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
2.45 (s, 3H), 2.4–2.6
118.1, 125.7, 135.2, 171.9; MS (FAB) 235 (MþH, 19%), 175 (MꢂCO2Me,
(m, 4H), 3.7–3.8 (m, 4H), 3.74 (s, 3H), 4.24 (s, 1H), 6.60 (d, 1H,
100%); HRMS (FAB) calcd for
235.1453.
C13H19N2O2: 235.1447, found:
J¼3.5 Hz), 6.83 (d, 1H, J¼3.5 Hz); 13C NMR (75 MHz, CDCl3)
d 15.3,
51.1, 52.1, 66.7, 69.3, 124.5, 127.6, 135.0, 141.3, 170.7; MS (FAB) 256,
196, 169; HRMS (FAB) calcd for C12H18NO3S: 256.1007, found:
256.0995.
4.5.37. Methyl 2-(diallylamino)-2-(1-methyl-1H-pyrrol-2-yl)-
acetate (43)
Brown oil; 1H NMR (500 MHz, CDCl3)
d 3.0–3.2 (m, 2H), 3.4–3.6
4.5.30. Methyl 2-(1-(furan-2-ylmethyl)-1H-pyrrol-2-yl)-2-
(m, 2H), 3.61 (s, 3H), 3.72 (s, 3H), 4.71 (s, 1H), 5.0–5.2 (m, 4H), 5.6–
(piperidin-1-yl)acetate (34)
5.8 (m, 2H), 6.00 (t, 1H, J¼2.0 Hz), 6.02 (d, 1H, J¼2.0 Hz), 6.59 (d, 1H,
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.4–1.6 (m, 6H), 2.4–
J¼2.0 Hz); 13C NMR (125 MHz, CDCl3)
d 33.9, 51.2, 52.9, 60.0, 106.5,
2.5 (m, 4H), 3.68 (s, 3H), 4.37 (s, 1H), 5.12 (d, 1H, J¼16.0 Hz), 5.44 (d,
1H, J¼16.0 Hz), 6.06 (m, 2H), 6.17 (d, 1H, J¼3.5 Hz), 6.30 (d, 1H,
J¼3.5 Hz), 6.67 (t, 1H, J¼3.5 Hz), 7.34 (t, 1H, J¼3.5 Hz); 13C NMR
109.8,117.0,123.4,126.7, 136.3,171.7; MS (FAB) 248 (MþH, 39%), 189
(MꢂCO2Me, 100%); HRMS (FAB) calcd for C14H21N2O2: 249.1603,
found: 249.1608.
(75 MHz, CDCl3) d 24.4, 26.1, 43.4, 50.5, 51.3, 66.2, 107.1, 107.7, 110.0,
110.2, 122.6, 125.9, 142.2, 151.2, 170.7; MS (FAB) 303, 244, 218;
HRMS (FAB) calcd for C17H23N2O3: 303.1709, found: 303.1716.
4.5.38. Methyl 2-(diallylamino)-2-(1-phenyl-1H-pyrrol-2-yl)-
acetate (44)
Yellow oil; 1H NMR (500 MHz, CDCl3)
d 3.0–3.1 (m, 2H), 3.3–3.4
4.5.31. Methyl 2-(4-(dimethylamino)phenyl)-2-(piperidin-1-yl)-
(m, 2H), 3.66 (s, 3H), 4.61 (s, 1H), 4.9–5.0 (m, 4H), 5.4–5.5 (m, 2H),
acetate (35)
6.20 (t, 1H, J¼3.0 Hz), 6.28 (d, 1H, J¼3.0 Hz), 6.82 (d, 1H, J¼3.0 Hz),
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.3–1.4 (m, 2H),1.5–1.6
7.2–7.5 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 51.2, 52.9, 58.9, 107.9,
(m, 4H), 2.3–2.4 (m, 4H), 2.87 (s, 6H), 3.60 (s, 3H), 3.78 (s, 1H), 6.59
111.2, 116.6, 123.6, 126.5, 127.3, 127.6, 128.8, 136.4, 139.8, 171.9; MS
(d, 2H, J¼10 Hz), 7.20 (d, 2H, J¼10 Hz); 13C NMR (75 MHz, CDCl3)
(FAB) 311 (MþH, 28%), 251 (MꢂCO2Me,100%); HRMS (FAB) calcd for
d
24.3, 25.6, 40.3, 51.6, 52.4, 112.0, 123.4, 129.5, 150.2, 172.8; MS
C19H23N2O2: 311.1760, found: 311.1754.
(FAB) 277, 218, 192; HRMS (FAB) calcd for C16H25N2O2: 277.1916,
found: 277.1900.
4.5.39. Methyl 2-(diallylamino)-2-(5-methylfuran-2-yl)acetate (45)
Colorless oil; 1H NMR (500 MHz, CDCl3)
2.27 (s, 3H), 3.1–3.2 (m,
d
4.5.32. Methyl 2-amino-2-(1H-indol-3-yl)acetate (37)
2H), 3.3–3.4 (m, 2H), 3.73 (s, 3H), 4.66 (s,1H), 5.1–5.2 (m, 4H), 5.8–5.9
Brown oil; 1H NMR (500 MHz, CDCl3)
d
2.00 (br s, 2H), 3.70 (s,
(m, 2H), 5.92 (d, 1H, J¼3.5 Hz), 6.17 (d, 1H, J¼3.5 Hz); 13C NMR
3H), 4.92 (s, 1H), 7.12 (t, 1H, J¼7.5 Hz), 7.15 (s, 1H), 7.18 (t, 1H,
(125 MHz, CDCl3) d 13.6, 51.8, 53.8, 60.8, 106.1, 110.5, 117.6, 135.7,
J¼7.5 Hz), 7.32 (d, 1H, J¼7.5 Hz), 7.70 (d, 1H, J¼7.5 Hz), 8.39 (br s,
147.4, 152.3, 170.6; MS (FAB) 250 (MþH, 23%) 190 (MꢂCO2Me, 100%)
1H); 13C NMR (125 MHz, CDCl3)
d
51.8, 52.2, 111.3, 115.3, 119.1, 119.9,
153; HRMS (FAB) calcd for C14H20NO3: 250.1443, found: 250.1455.
122.2, 122.4, 125.4, 136.4, 174.9; MS (FAB) 205 (MþH, 45%), 188
(MþꢂNH2, 100%), 145 (MþꢂCO2Me, 96%); HRMS (FAB) calcd for
4.5.40. Methyl 2-(diallylamino)-2-(5-methylthiophen-2-yl)-
C
11H13N2O2: 205.0977, found: 205.0976.
acetate (46)
Colorless oil; 1H NMR (500 MHz, CDCl3)
d 2.45 (s, 3H), 3.2–3.3
4.5.33. Methyl 2,2-bis(1H-indol-3-yl)acetate22 (38)
White solid; 1H NMR (300 MHz, CDCl3)
3.72 (s, 3H), 5.49 (s,
1H), 6.95 (s, 2H), 7.05 (t, 2H, J¼7.5 Hz), 7.13 (d, 2H, J¼7.5 Hz), 7.25 (t,
(m, 4H), 3.75 (s, 3H), 4.77 (s, 1H), 5.1–5.2 (m, 4H), 5.8–5.9 (m, 2H),
d
6.59 (d, 1H, J¼3.5 Hz), 6.72 (d, 1H, J¼3.5 Hz); 13C NMR (125 MHz,
CDCl3)
d 15.3, 51.7, 53.2, 62.6, 117.5, 124.4, 126.6, 135.8, 137.0, 140.3,

N. Sakai et al. / Tetrahedron 64 (2008) 9208–9215
9215
816; (d) Williams, R. M. Synthesis of Optically Active
Oxford, 1989; Vol. 7.
2. Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889.
a
-Amino Acids; Pergamon:
171.5; MS (FAB) 266 (MþH,15%), 206 (MꢂCO2Me,100%),169; HRMS
(FAB) calcd for C14H20NO2S: 266.1215, found: 266.1223.
3. Salituro, G. M.; Townsend, C. A. J. Am. Chem. Soc. 1990, 112, 760.
4. (a) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222; (b) Soloshonok,
V. A.; Cai, C.; Hruby, V. J. Tetrahedron Lett. 2000, 41, 135; (c) O’Donnell, M. J.,
Ed. a-Amino acid synthesis (Tetrahedron Symposia in Print). Tetrahedron 1988,
44, 5253.
4.5.41. Methyl 2-(diallylamino)-2-(4-(dimethylamino)-
phenyl)acetate (47)
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 2.93 (s, 6H), 3.1–3.2
5. For selected papers and reviews on the preparation of
a-aryl amino acid
(m, 4H), 3.67 (s, 3H), 4.46 (s, 1H), 5.0–5.2 (m, 4H), 5.8–5.9 (m, 2H),
6.65 (d, 2H, J¼8.5 Hz), 7.20 (d, 2H, J¼8.5 Hz); 13C NMR (75 MHz,
derivatives, see: (a) Soueidan, M.; Collin, J.; Gil, R. Tetrahedron Lett. 2006, 47,
5467; (b) Jiang, B.; Huang, Z.-G. Synthesis 2005, 2198; (c) Lei, F.; Chen, Y.-J.;
Sui, Y.; Liu, L.; Wang, D. Synlett 2003, 1160; (d) Janczuk, A.; Zhang, W.; Xie,
W.; Lou, S.; Cheng, J.; Wang, P. G. Tetrahedron Lett. 2002, 43, 4271; (e) Bur,
S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221; (f) Speckamp, W. N.; Moole-
naar, M. J. Tetrahedron 2000, 56, 3817; (g) Huang, T.; Li, C.-J. Tetrahedron Lett.
2000, 41, 6715; (h) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2000, 39, 4114; (i) Johannsen, M. Chem. Commun. 1999,
2233; (j) Ben-Ishai, D.; Sataty, I.; Peled, N.; Goldshare, R. Tetrahedron 1987,
43, 439.
CDCl3)
d 40.3, 51.4, 53.1, 67.3, 112.1, 117.4, 123.6, 129.5, 135.6, 150.1,
173.1; MS (FAB) 289, 229; HRMS (FAB) calcd for C17H25N2O2:
289.1916, found: 289.1926.
4.6. General procedure for deallylation
A diallylated compound (0.5 mmol), 1,3-dimethylbarbituric acid
(458 mg, 3.00 mmol), and Pd(PPh3)4 (28.9 mg, 0.0250 mmol) were
successively mixed together in CH2Cl2 (3 mL) at room temperature
with stirring. After 1 h, the reaction was quenched with 1 N HCl
(3 mL) and the reaction mixture was washed with CHCl3 (5 mLꢁ3).
Then, to neutralize the resulting mixture, a saturated aqueous so-
lution (10 mL) of NaHCO3 was then added. The organic layer was
dried over Na2CO3 and evaporated under reduced pressure to afford
the corresponding product.
6. For selected reviews and papers for the reaction of carbon nucleophiles with
N,O- and N,N-acetals, leading to the amino acid derivatives, see: (a) Taggi, A. E.;
Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10; (b) Arend, M.; Westermann,
B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044; (c) Katritzky, A. R.; Rachwal,
S.; Hitchings, G. J. Tetrahedron 1991, 47, 2683; (d) Katritzky, A. R.; Kirichenko, N.;
Rogovoy, B. V.; He, H. Y. J. Org. Chem. 2003, 68, 9088; (e) Lebouvier, N.; Laroche,
C.; Huguenot, F.; Brigaud, T. Tetrahedron Lett. 2002, 43, 2827; (f) Sugiura, M.;
Kobayashi, S. Org. Lett. 2001, 3, 477; (g) Ferraris, D.; Young, B.; Dudding, T.;
Drury, W. J., III; Lectka, T. Tetrahedron 1999, 55, 8869; (h) Ferraris, D.; Dudding,
T.; Young, B.; Drury, W. J., III; Lectka, T. J. Org. Chem. 1999, 64, 2168; (i) Ko-
bayashi, S.; Ishitani, H.; Komiyama, S.; Oniciu, D. C.; Katritzky, A. R. Tetrahedron
Lett. 1996, 37, 3731; (j) Tsukamoto, T.; Kitazume, T. Chem. Lett. 1992, 21, 1377; (k)
Yamamoto, Y.; Nakada, T.; Nemoto, H. J. Am. Chem. Soc. 1992, 114, 121; (l) Ka-
tritzky, A. R.; Shobana, N.; Harris, P. A. Tetrahedron Lett. 1990, 31, 3999.
7. (a) Ge, C.-S.; Chen, Y.-J.; Wang, D. Synlett 2002, 37; (b) DeNinno, M. P.; Eller, C.;
Etienne, J. B. J. Org. Chem. 2001, 66, 6988; (c) O’Donnell, M. J.; Falmagne, J.-B.
Tetrahedron Lett. 1985, 26, 699.
4.6.1. Methyl 2-amino-2-(1-methyl-1H-pyrrol-2-yl)acetate (48)
Brown oil; 1H NMR (500 MHz, CDCl3)
d 1.88 (br s, 2H), 3.67 (s,
3H), 3.74 (s, 3H), 4.65 (s, 1H), 6.01 (t, 1H, J¼3.5 Hz), 6.05 (d, 1H,
J¼3.5 Hz), 6.57 (d, 1H, J¼3.5 Hz); 13C NMR (125 MHz, CDCl3)
d 33.9,
8. For papers on the reaction of boronic acids with a-hydroxyglycine, see: Sugiura,
M.; Mori, C.; Hirano, K.; Kobayashi, S. Can. J. Chem. 2005, 83, 937.
9. (a) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron 1997, 53, 2941 and
references cited therein; (b) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. J. Chem.
Soc., Chem. Commun. 1988, 1161.
10. (a) Piper, S.; Risch, N. Synlett 2004, 1489; (b) Grumbach, H.-J.; Merla, B.; Risch,
N. Synthesis 1999, 1027.
11. For detailed examinations of Lewis acids for aminomethylation of electron-rich
arenes with N,O-acetals, see our preliminary papers: (a) Sakai, N.; Asano, J.;
Shimano, Y.; Konakahara, T. Synlett 2007, 2675; (b) Sakai, N.; Hirasawa, M.;
Hamajima, T.; Konakahara, T. J. Org. Chem. 2003, 68, 483; (c) Sakai, N.; Hama-
jima, T.; Konakahara, T. Tetrahedron Lett. 2002, 43, 4821.
51.6, 52.3,106.6,106.8,123.1,130.6,173.9; MS (FAB): 169,152; HRMS
(FAB) calcd for C8H13N2O2: 169.0977, found: 169.0979.
4.6.2. Methyl 2-amino-2-(5-methylfuran-2-yl)acetate23 (49)
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.99 (br s, 2H), 2.27 (s,
3H), 3.75 (s, 3H), 4.43 (s, 1H), 5.90 (d, 1H, J¼3.5 Hz), 6.15 (d, 1H,
J¼3.5 Hz); 13C NMR (75 MHz, CDCl3)
d 13.5, 51.5, 58.2, 106.2, 108.9,
116.9, 135.7, 171.5; MS (FAB): 170, 153.
12. Gong, Y.; Kato, K.; Kimoto, H. Synlett 2000, 1058.
4.6.3. Methyl 2-amino-2-(5-methylthiophen-2-yl)acetate (50)
Colorless oil; 1H NMR (500 MHz, CDCl3)
2.01 (br s, 2H), 2.44 (s,
13. (a) Gong, Y.; Kato, K. J. Fluorine Chem. 2001, 108, 83; (b) Colvin, E. W.; McGarry,
D.; Nugent, M. J. Tetrahedron 1988, 44, 4157; (c) Okano, K.; Morimoto, T.; Sekiya,
M. Chem. Pharm. Bull. 1985, 33, 2228; (d) Bestmann, H. J.; Wo¨lfel, G. Angew.
Chem., Int. Ed. Engl. 1984, 23, 53; (e) Hirao, A.; Hattori, I.; Yamaguchi, K.; Na-
kahama, S.; Yamazaki, N. Synthesis 1982, 461.
d
3H), 3.75 (s, 3H), 4.78 (s, 1H), 6.60 (d, 1H, J¼3.5 Hz), 6.80 (d, 1H,
J¼3.5 Hz); 13C NMR (125 MHz, CDCl3)
d 15.2, 52.5, 54.6, 124.6, 124.8,
139.7, 140.9, 173.4; MS (FAB): 186, 169; HRMS (FAB) calcd for
C8H12NO2S: 186.0589, found: 186.0607.
14. (a) Hirner, S.; Panknin, O.; Edefuhr, M.; Somfai, P. Angew. Chem., Int. Ed. 2008,
47, 1907; (b) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002,
´
41, 2535; (c) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58,
6109.
15. (a) Arnett, E. M.; Moe, K. D. J. Am. Chem. Soc. 1991, 113, 7068; (b) Grimm, D. T.;
Bartmess, J. E. J. Am. Chem. Soc. 1992, 114, 1227.
16. The aminomethylation of N,O-acetal 36 with other electron-rich arenes, such as
pyrrole, furan, and aniline derivative, did not produce the corresponding amino
acid derivatives.
17. For mechanistic work on an intermediate in the alkylation of acyclic acetals,
see: Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915.
18. When the reaction was carried out in the presence of 0.5 equiv of Me3SiCl, the
yield of the aminomethylated product was less than 50%. For selected papers
on reactions enhanced by a coexistence of Lewis acid and Me3SiCl, see: (a)
Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015; (b) Mukaiyama, T.;
Wariishi, K.; Saito, Y.; Hayashi, M.; Kobayashi, S. Chem. Lett. 1988, 1101; (c)
Yamanaka, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 159; (d) Lee, P. H.;
Lee, K.; Sung, S.-Y.; Chang, S. J. Org. Chem. 2001, 66, 8646; (e) Tsuji, R.;
Yamanaka, M.; Nishida, A.; Nakagawa, M. Chem. Lett. 2002, 428; (f) Yang, L.;
Xu, L.-W.; Xia, C.-G. Tetrahedron Lett. 2007, 48, 1599.
19. Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett. 1995, 36, 409.
20. Dinzo, S. E.; Freeksen, R. W.; Pabst, W. E.; Watt, D. S. J. Org. Chem. 1976, 41, 2846.
21. Kantlehner, W.; Haug, E. Synthesis 1982, 146.
22. Earle, M. J.; Fairhurst, R. A.; Heaney, H. Tetrahedron Lett. 1991, 32, 6171.
23. Mueller, U.; Connell, R.; Goldmann, S.; Mohrs, K.H.; Angerbauer, R.; Matthias,
M.G.; Niewoehner, U.; Gruetzmann, R.; Beuck, M. Ger. Offen. 1996, 156; Chem.
Abstr. 1996, 125, 142561.
4.6.4. Methyl 2-amino-2-(4-(dimethylamino)phenyl)acetate (51)
Yellow oil; 1H NMR (500 MHz, CDCl3)
d 1.80 (br s, 2H), 2.93 (s,
6H), 3.68 (s, 3H), 4.52 (s, 1H), 6.68 (d, 2H, J¼8.5 Hz), 7.21 (d, 2H,
J¼8.5 Hz); 13C NMR (75 MHz, CDCl3)
d 40.4, 52.1, 58.1, 112.5, 127.4,
133.9, 150.2, 174.9; MS (FAB) 210, 192; HRMS (FAB) calcd for
C
11H17N2O2: 209.1290, found: 209.1287.
Acknowledgements
This work was partially supported by a grant for the ‘High-Tech
Research Center’ Project for Private Universities: a matching fund
subsidy from MEXT, 2000–2004, and 2005–2007. N.S. acknowl-
edges the TORAY Award in Synthetic Organic Chemistry, Japan.
References and notes
1. (a) Na´jera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584; (b) Ohfune, Y. Acc. Chem.
Res. 1992, 25, 360; (c) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl. 1983, 22,