Synthesis of α-(3-indolyl)glycine derivatives via spontaneous Friedel-Crafts reaction between indoles and glyoxylate imines

Article abstract of DOI:10.1055/s-2005-869978

Mannich-type Friedel-Crafts reaction between indoles and ethyl glyoxylate imines proceeded spontaneously in the absence of an acid catalyst. Ethyl α-(3-indolyl)glycinates were obtained in moderate to high yields. Reaction with (R)-α-methylbenzylamine deri

Full text of DOI:10.1055/s-2005-869978

2198
PAPER
Synthesis of a-(3-Indolyl)glycine Derivatives via Spontaneous Friedel–Crafts
Reaction between Indoles and Glyoxylate Imines
Synthesis of
a-(3
i
-
Indoly
a
l)glycine
D
o
erivative
s
via
S
pon
J
taneous
F
i
riedel–
a
Crafts Rea
n
c
tion g,* Zuo-Gang Huang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: jiangb@mail.sioc.ac.cn
Received 25 February 2005; revised 25 March 2005
Another method uses the direct coupling of indole deriva-
Abstract: Mannich-type Friedel–Crafts reaction between indoles
tives and glyoxylate imines/iminiums or glycine cation
and ethyl glyoxylate imines proceeded spontaneously in the ab-
sence of an acid catalyst. Ethyl a-(3-indolyl)glycinates were ob-
tained in moderate to high yields. Reaction with (R)-a-
equivalents (route f).5 It is worth mentioning that the first
total synthesis of bisindole alkaloid Dragmacidin B was
methylbenzylamine derived imine afforded chiral a-(3-indolyl)gly- achieved via the addition of indoles to cyclic a,a¢-dibro-
mo-N,N¢-dimethyl glycine anhydride.5c Stoichiometric
cinates with good diastereoselectivities (up to 96:4).
Lewis acid-promoted reaction between indoles and imin-
ium salts generated in situ from glyoxylate, secondary
amines, and 1H-benzotriazole constituted a straightfor-
ward one-pot stepwise preparation of (3-indolyl)glyci-
nates in high yields.6 The Cu(I)/Tol-BINAP-catalyzed
addition of indoles to N-tosylimino esters at –78 °C pro-
vided the chiral (3-indolyl)glycinates with high enantiose-
lectivity.7 The Pd(II)/BIPHEP catalyzed synthesis of the
racemates was also reported.8 Optically active ethyl (3-in-
dolyl)glycinates were obtained through the sequence of
Friedel–Crafts reaction catalyzed by Yb(OTf)3, hydroge-
nation and enzymatic resolution.9 Highly diastereoselec-
tive synthesis was achieved by means of TFA-promoted
Friedel–Crafts reaction between N-substituted indoles and
a chiral cyclic glyoxylate imine.10 Most of these Friedel–
Crafts reactions require a catalytic to stoichiometric
amount of Lewis acid or Brønsted acid (5 equiv of TFA
was employed in ref.10).11
Key words: Friedel–Crafts reaction, indolyl glycine, indole deriva-
tive, glyoxylate imine, spontaneous reaction
(3-Indolyl)glycine derivatives are important synthetic in-
termediates or building blocks for drug discovery1 and
marine bisindole alkaloid synthesis.2 There are several
methods to prepare this valuable non-proteinogenic ami-
no acid (Scheme 1). Hydrogenation of the hydroxyimino
(3-indolyl)gloxylates has been long used as a preparative
method (route a).1,2c Recently, (3-indolyl) glycine was
prepared by means of the Rh(III)-catalyzed reductive am-
ination of 3-indoleglyoxylic acid with ammonium for-
mate (route b).3 Oxidation of (3-indolyl) acetate induced
by FeCl3 and secondary amines was also reported (route
c).4 The synthesis of bisindole alkaloid Dragmacidins and
Hamacanthins involved a modified Strecker adduct as the
synthetic intermediate (route d)2b or arose from indolin-3-
ones (route e).2d,e
Previously, we reported a highly diastereoselective syn-
thesis of N-substituted (3-indolyl)glycines based on the
three-component Petasis reaction among (3-indolyl) bo-
ronic acid, glyoxylic acid hydrate and (R)-a-methyl ben-
zylamine.12 Herein, we disclose the observation of the
spontaneous Friedel–Crafts reaction between indoles and
ethyl glyoxylate imines without the use of an acid cata-
lyst.13,14
Me
N
HO
CO2R
a
HN
CN
d
N
H
N
H
R5
Br
R6
O
N
CO2R4
CO2H
b
O
e
R3
R2
OMe
N
H
N
N
MeO
NH
R1
PMP
H
CO2Et
catalyst ?
c
f
Ac
N
+
RO2C
N
H
CO2Et
R6
H
R5
N
H
R3
R2
N
+
N
R1
CO2R4
N
H
Scheme 2
Scheme 1
Initially, our intention was to examine the asymmetric in-
duction of chiral Brønsted acids in promoting this type of
aza-Friedel–Crafts reaction.15 Using CH2Cl2 as solvent, in
which PMPN=CHCO2Et (p-methoxyphenylimino glyox-
ylate) was generated by stirring the mixture of p-anisidine
and ethyl glyoxylate in the presence of MgSO4 at room
SYNTHESIS 2005, No. 13, pp 2198–2204
Advanced online publication: 24.06.2005
DOI: 10.1055/s-2005-869978; Art ID: F04105SS
x
x.
x
x
.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a-(3-Indolyl)glycine Derivatives via Spontaneous Friedel–Crafts Reaction
2199
temperature for one hour, upon subsequent addition of in- As shown in Table 2, a variety of 2-, 5-, 6-, or 7-substitut-
dole, it was found that the reaction proceeded spontane- ed indoles were used as nucleophiles to react with p-meth-
ously in the absence of an acid catalyst and moderate to oxyphenylimino glyoxylate. Using CH2Cl2 as solvent,
high yields (70–90%) of (3-indolyl)glycinate were ob- reaction of 5-bromo indole provided 85% yield of product
tained after an extension of several hours (Scheme 2).16
Comparable yields were obtained in toluene. Reaction in
ethereal solvent (THF, Et2O) was much slower. Only a
trace amount of product formed in DMSO. By lowering
Table 2 Reaction of Indoles with PMPN=CHCO2Et at Room Tem-
peraturea
the temperature to –20 °C, an appreciable amount (ca. Entry
Product
Time
48 h
Isolated yield
85%
50%) of product could be still isolated. It is noteworthy
that the ethyl glyoxylate used here was obtained from the
1
PMP NH
CO2Et
CO2Et
CO2Et
Br
50% solution in toluene and did not need redistillation or
heating to depolymerize.17
N
H
As shown in Table 1, imines generated from a variety of
7
amines were screened. Reaction with arylamine (p-anisi-
dine, aniline) derived imines proceeded smoothly in high
2
48 h
48 h
7 d
92%
69%
44%
PMP NH
yields (entries 1 and 2). Benzylic imines were less effec-
tive electrophiles (entries 3 and 4). Much lower yields
were obtained for aliphatic amine derived imines (entries
N
H
Br
8
5 and 6).
3
PMP NH
Table 1 Reaction of Indole with Imino Esters at Room Tempera-
O2N
turea
N
H
Entry
1
Product
Time
12 h
Isolated yield
89%
9
4 b
PMP NH
PMP NH
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
N
H
N
H
NO2
1
2
3
4
5
6
24 h
72 h
48 h
72 h
72 h
91%
46%
61%
33%
49%
10
Ph NH
5
6 h
72 h
12 h
48 h
94%
PMP NH
CO2Et
MeO
N
H
N
H
2
11
PMB NH
6 c
26%
PMP NH
CO2Et
MeO2C
N
H
N
H
3
12
Bn NH
7
> 99%
75%
PMP NH
CO2Et
Me
N
H
N
H
4
13
(CH3)2CH NH
CO2Et
8
PMP NH
CO2Et
Ph
N
H
N
H
5
14
a PMPN=CHCO2Et was obtained from the solution (20 mg/mL) in
CH2Cl2 (prepared as described above after removal of MgSO4 by fil-
tration and stored at r.t. for months without decomposition).
b Conditions: 40 °C, 36 h, < 5% yield based on 1H NMR analysis.
c Conditions: 0.4 M, 48 h, 53%; 0.4 M, 40 °C, 36 h, 67% isolated
yield.
6
a Imines were preformed in toluene in the presence of MgSO4.
Synthesis 2005, No. 13, 2198–2204 © Thieme Stuttgart · New York

2200
B. Jiang, Z.-G. Huang
PAPER
Table 3 Reaction of Indoles with the Chiral Imine at Room Tem-
(entry 1). The 6-bromo indole afforded 92% yield of 6-
bromo indol-3-yl glycinate, which is an important syn-
thetic intermediate for marine bisindole alkaloid synthesis
(entry 2).2 5-Nitro indol-3-yl glycinate was isolated in
69% yield, whereas only 44% yield of 7-nitro indol-3-yl
glycinate could be obtained after seven days of reaction
time (entries 3 and 4). The sluggish rate and low yield for
7-nitro indole might be caused by the possible intramolec-
ular hydrogen bond between the indole NH moiety and
the neighboring nitro group. Reaction of electron-donat-
ing 5-methoxy substituted indole proceeded more rapidly
giving 94% yield after six hours (entry 5). The 5-meth-
oxycarbonyl indole gave only 26% yield at room temper-
ature. Moderate yields were obtained at higher substrate
concentration and elevated temperature (entry 6). Reac-
tion of 2-methyl indole went smoothly with high yield,
whereas the 2-phenyl substitution slightly retarded the re-
action (entries 7 and 8). It should be noted that the addi-
tion of N-substituted indoles (N-TBDMS, N-Ts, etc) to
glyoxylate imines did not occur without acid catalysis.
The free indole NH moiety probably contributed to form-
ing a cyclic transition state, activating the imino group in
situ, and promoting the aza-Friedel–Crafts reaction in the
absence of an acid catalyst (Figure 1).18
peraturea
Entry Product
Time
48 h
Isolated drb and
20
yield
[a]D
1c
92%
92:8
NH
92°
(c = 0.92)
CO2Et
Ph
N
H
15
2
3
4
5
6
98 h
98 h
98 h
72 h
24 h
42%
62%
33%
79%
84%
90:10
57°
(c = 0.90)
NH
CO2Et
Ph
Br
N
H
16
87:13
70°
(c = 0.85)
NH
CO2Et
CO2Et
CO2Et
Ph
N
H
Br
17
67:33
33°
(c = 0.85)
NH
Ph
O2N
PMP
H
N
H
N
N
18
CO2Et
H
96:4
90°
(c = 0.85)
NH
Figure 1
Ph
MeO
Based on these results, the diastereoselectivity of this re-
action between indoles and chiral imines was then stud-
ied. As shown in Table 3, the aza-Friedel–Crafts reaction
of indole and the chiral (E)-2-(a-methylbenzyl imino)gly-
oxylate also proceeded smoothly in the absence of an acid
catalyst. The diastereoselectivities varied in different sol-
vents. The yield in CH2Cl2 was 58% with a disappointing
1:1 diastereoisomer ratio. Reaction in THF provided 52%
yield with 6:1 diastereoselectivity. The best result (92%
yield and 12:1 dr) was obtained in toluene (entry 1). Other
solvents (CHCl3, MeCN) gave moderate yields and ste-
reoselectivities. Reaction of 5-bromo indole provided
42% yield with 9:1 diastereoselectivity, while the yield
and isomer ratio for the 6-bromo (3-indolyl) glycinate
were 62% and 6.5:1, respectively (entries 2 and 3). How-
ever, 5-nitro indole gave rather poor result: 33% yield and
2:1 diastereoselectivity (entry 4). The best diastereoselec-
tivity (24:1) was obtained for the electron-donating 5-
methoxy substituted indole (entry 5). The fastest rate was
observed for 2-methyl indole (entry 6). Reactions of other
indoles (7-nitro-, 5-methoxycarbonyl-, 2-phenyl- etc.)
were sluggish. And hardly any product was formed in re-
action of N-substituted indoles and the chiral imine.
N
H
19
89:11
89°
(c = 1.40)
NH
CO2Et
Me
Ph
N
H
20
a The chiral imine was preformed in toluene in the presence of
MgSO4.
b The dr was determined by 1H NMR and the solvent for [a]D20 mea-
surement (mixture of diastereomers) was CHCl3.
c Conditions: 40 °C, 36 h; 80% isolated yield, 40:60 dr.
yields. Reaction of the chiral (E)-2-(a-methylben-
zylimino)glyoxylate afforded optically active (3-indolyl)
glycinate derivatives with moderate to high diastereose-
lectivities.19 N-Substituted indoles were ineffective in this
reaction without acid catalysis. The free indole NH moi-
ety probably contributed to activating the imino group by
intermolecular hydrogen bonding and promoting the aza-
Friedel–Crafts reaction in the absence of an acid catalyst.
In summary, the spontaneous Friedel–Crafts reaction be-
tween indoles and glyoxylate imines in the absence of an
acid catalyst was observed. A variety of substituted (3-in-
dolyl) glycinates were obtained in moderate to high
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were obtained
on a Varian Mercury 300 spectrometer using CDCl3 as solvent. IR
spectra (film of CDCl3 solution) were recorded on a Bio-Rad FTS-
185 spectrometer. EI–MS and HRMS were obtained on an Agilent
Synthesis 2005, No. 13, 2198–2204 © Thieme Stuttgart · New York

PAPER
Synthesis of a-(3-Indolyl)glycine Derivatives via Spontaneous Friedel–Crafts Reaction
2201
5973N MSD and an Ionspec 4.7 Tesla FTMS spectrometer. ESI MS
data were obtained on an APEXIII 7.0 Tesla FTMS spectrometer.
Ethyl 2-(1H-Indol-3-yl)-2-(isopropylamino)acetate (5)
Colorless oil.
IR: 3145, 2970, 1727, 1458, 1303, 1185, 1021, 738 cm–1.
General Procedure
1H NMR: d = 8.14 (s, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.36 (d, J =
7.8 Hz, 1 H), 7.24–7.12 (m, 3 H), 4.79 (s, 1 H), 4.26–4.09 (m, 2 H),
2.84 (sept, J = 6.6 Hz, 1 H), 1.23 (t, J = 6.9 Hz, 3 H), 1.12 (d, J =
6.6 Hz, 3 H), 1.11 (d, J = 6.6 Hz, 3 H).
13C NMR: d = 174.0, 136.3, 125.9, 122.7, 122.2, 119.7, 119.1,
113.2, 111.3, 61.0, 55.9, 46.5, 23.0, 22.6, 14.1.
MgSO4 (200 mg), ansidine (41 mg) and ethyl glyoxylate (70 mL,
50% solution in toluene) were mixed in CH2Cl2 or toluene (2 mL)
and stirred at r.t. for 1 h. Into the resulting iminoester solution, in-
dole (39 mg) was added and stirred for 12 h. Flash chromatography
of the reaction mixture on silica (hexane–EtOAc, 4:1) afforded the
product as a slightly yellow oil in 89% yield.
EI–MS: m/z (%) = 260 (0.2) [M+].
HRMS: m/z [M + Na]+ calcd for C15H20N2O2Na+: 283.1417; found:
Ethyl 2-(1H-Indol-3-yl)-2-(4-methoxyphenylamino)acetate (1)
Slightly yellow oil.
283.1421.
IR: 3405, 2984, 1734, 1513, 1239, 1043, 823, 746 cm–1.
1H NMR: d = 8.26 (s, 1 H), 7.83 (d, J = 7.5 Hz, 1 H), 7.33 (d, J =
7.8 Hz, 1 H), 7.23 (m, 1 H), 7.17 (m, 1 H), 6.75 (d, J = 9.0 Hz, 2 H),
6.62 (d, J = 9.0 Hz, 2 H), 5.33 (s, 1 H), 4.28–4.09 (m, 2 H), 3.72 (s,
3 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 172.8, 152.4, 140.7, 136.4, 125.8, 123.0, 122.4,
119.9, 119.5, 114.80, 114.77, 112.6, 111.4, 61.5, 55.7, 55.1, 14.1.
Ethyl 2-(1H-Indol-3-yl)-2-(pentylamino)acetate (6)
Colorless oil.
IR: 3408, 2931, 2859, 1734, 1458, 1186, 1024, 742 cm–1.
1H NMR: d = 8.70 (s, 1 H), 7.76 (d, J = 7.2 Hz, 1 H), 7.30 (d, J =
7.2 Hz, 1 H), 7.21–7.10 (m, 2 H), 7.07 (d, J = 2.4 Hz, 1 H), 4.69 (s,
1 H), 4.25–4.09 (m, 2 H), 2.70–2.59 (m, 2 H), 1.55 (m, 2 H), 1.32
(m, 4 H), 1.21 (t, J = 7.2 Hz, 3 H), 0.88 (t, J = 6.6 Hz, 3 H).
EI–MS: m/z (%) = 324 (27) [M+].
+
HRMS: m/z [M + H]+ calcd for C19H21N2O3 : 325.1547; found:
13C NMR: d = 173.7, 136.2, 125.9, 122.8, 122.1, 119.6, 119.2,
112.9, 111.3, 61.0, 58.5, 48.0, 29.6, 29.4, 22.5, 14.1, 14.0.
325.1529.
EI–MS: m/z (%) = 289 (6) [M + H]+, 6%).
HRMS: m/z [M + Na]+ calcd for C17H24N2O2Na+: 311.1730; found:
Ethyl 2-(1H-Indol-3-yl)-2-(phenylamino)acetate (2)
Slightly yellow oil.
311.1729.
IR: 3409, 2983, 1730, 1603, 1505, 1313, 1194, 1018, 747 cm–1.
1H NMR: d = 8.15 (s, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 7.38 (d, J =
7.8 Hz, 1 H), 7.26–7.12 (m, 5 H), 6.72 (m, 1 H), 6.64 (d, J = 8.1 Hz,
2 H), 5.40 (s, 1 H), 4.77 (br, 1 H), 4.30–4.10 (m, 2 H), 1.22 (t, J =
6.9 Hz, 3 H).
13C NMR: d = 172.7, 146.4, 136.3, 129.2, 125.6, 123.2, 122.3,
119.8, 119.3, 118.0, 113.3, 111.9, 111.4, 61.5, 54.1, 14.0.
EI–MS: m/z (%) = 294 (16) [M+].
HRMS: m/z [M + Na]+ calcd for C18H18N2O2Na+: 317.1260; found:
Ethyl 2-(5-Bromo-1H-indol-3-yl)-2-(4-methoxyphenylami-
no)acetate (7)
Yellow oil.
IR: 3396, 2984, 1731, 1513, 1462, 1239, 1035, 822 cm–1.
1H NMR: d = 8.34 (s, 1 H), 7.97 (s, 1 H), 7.28 (m, 1 H), 7.19 (d, J =
8.7 Hz, 2 H), 6.75 (d, J = 8.7 Hz, 2 H), 6.61 (d, J = 8.7 Hz, 2 H),
5.26 (s, 1 H), 4.29–4.11 (m, 2 H), 3.72 (s, 3 H), 1.23 (t, J = 7.2 Hz,
3 H).
13C NMR: d = 172.5, 152.6, 140.5, 135.1, 127.4, 125.3, 124.2,
317.1262.
122.1, 114.9, 114.8, 113.2, 112.8, 112.3, 61.7, 55.7, 55.0, 14.1.
EI–MS: m/z (%) = 402 (15.4) [M+], 404 (12.6) [M + 2]+.
HRMS: m/z [M + Na]+ calcd for C19H19N2O3BrNa+: 425.0471;
found: 425.0484.
Ethyl 2-(1H-Indol-3-yl)-2-(4-methoxybenzylamino)acetate (3)
Slightly yellow oil.
IR: 3406, 2929, 1732, 1612, 1513, 1458, 1249, 1180, 1107, 1032,
818, 744 cm–1.
1H NMR: d = 8.16 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.36 (d, J =
7.8 Hz, 1 H), 7.28–7.18 (m, 4 H), 7.12 (t, J = 7.2 Hz, 1 H), 6.86 (d,
J = 8.4 Hz, 2 H), 4.69 (s, 1 H), 4.26–4.10 (m, 2 H), 3.81 (s, 3 H),
3.76 (d, J = 2.4 Hz, 2 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 173.5, 158.6, 136.3, 131.6, 129.6, 125.9, 123.0,
122.1, 119.7, 119.3, 113.7, 112.8, 111.3, 61.0, 57.2, 55.2, 50.1,
14.1.
Ethyl 2-(6-Bromo-1H-indol-3-yl)-2-(4-methoxyphenylami-
no)acetate (8)
Slightly yellow oil.
IR: 3393, 2835, 1730, 1513, 1239, 1035, 821 cm–1.
1H NMR: d = 8.27 (s, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.43 (s, 1 H),
7.22 (m, 1 H), 7.11 (d, J = 2.4 Hz, 1 H), 6.71 (d, J = 7.5 Hz, 2 H),
6.55 (d, J = 7.5 Hz, 2 H), 5.24 (s, 1 H), 4.21–4.07 (m, 2 H), 3.68 (s,
3 H), 1.16 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 172.5, 152.6, 140.5, 137.2, 124.7, 123.6, 123.3,
120.8, 116.0, 114.9, 114.8, 114.3, 113.0, 61.7, 55.7, 55.0, 14.1.
EI–MS: m/z (%) = 339 (2) [M + H]+.
HR–MS: m/z [M + Na]+ calcd for C20H22N2O3Na+: 361.1523;
found: 361.1523.
EI–MS: m/z (%) = 402 (3.5) [M+], 404 (2.7) [M + 2]+.
HRMS: m/z [M + H]+ calcd for C19H20N2O3Br+: 403.0652; found:
Ethyl 2-(Benzylamino)-2-(1H-indol-3-yl)acetate (4)9
Colorless oil.
403.0658.
1H NMR: d = 8.19 (s, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.37–7.13 (m,
8 H), 4.71 (s, 1 H), 4.23–4.11 (m, 2 H), 3.82 (s, 2 H), 1.22 (t, J = 7.2
Hz, 3 H).
13C NMR: d = 173.5, 139.4, 136.3, 128.38, 128.37, 127.1, 125.9,
123.1, 122.1, 119.7, 119.2, 112.6, 111.4, 61.0, 57.4, 51.5, 14.1.
Ethyl 2-(4-Methoxyphenylamino)-2-(5-nitro-1H-indol-3-yl)ace-
tate (9)
Yellow oil.
IR: 3363, 2934, 1731, 1610, 1514, 1333, 1242, 822, 740 cm–1.
Synthesis 2005, No. 13, 2198–2204 © Thieme Stuttgart · New York

2202
B. Jiang, Z.-G. Huang
PAPER
1H NMR: d = 8.94 (s, 1 H), 8.84 (s, 1 H), 8.11 (d, J = 9.0 Hz, 1 H),
7.37 (m, 2 H), 6.75 (d, J = 8.7 Hz, 2 H), 6.62 (d, J = 8.7 Hz, 2 H),
5.36 (s, 1 H), 4.30–4.13 (m, 2 H), 3.72 (s, 3 H), 1.24 (t, J = 7.2 Hz,
3 H).
1H NMR: d = 7.90 (s, 1 H), 7.79 (m, 1 H), 7.27 (m, 2 H), 7.12 (m, 2
H), 6.73 (d, J = 6.9 Hz, 2 H), 6.58 (d, J = 6.9 Hz, 2 H), 5.22 (s, 1 H),
4.26–4.04 (m, 2 H), 3.71 (s, 3 H), 2.49 (s, 3 H), 1.17 (t, J = 7.2 Hz,
3 H).
13C NMR: d = 172.0, 152.7, 141.8, 140.2, 139.6, 126.3, 125.2,
118.0, 117.1, 115.4, 115.0, 114.8, 111.5, 62.0, 55.7, 54.9, 14.0.
EI–MS: m/z (%) = 369 (48) [M+].
13C NMR: d = 172.6, 152.2, 140.6, 135.0, 133.4, 126.6, 121.2,
119.7, 118.6, 114.7, 114.5, 110.5, 107.3, 61.3, 55.6, 54.8, 14.0,
11.8.
EI–MS: m/z (%) = 338 (32) [M+].
HRMS: m/z [M + Na]+ calcd for C20H22N2O3Na+: 361.1523; found:
+
HRMS: m/z [M + H]+ calcd for C19H20N3O5 : 370.1397; found:
370.1413.
361.1531.
Ethyl 2-(4-Methoxyphenylamino)-2-(7-nitro-1H-indol-3-yl)ace-
tate (10)
Yellow oil.
Ethyl 2-(4-Methoxyphenylamino)-2-(2-phenyl-1H-indol-3-
yl)acetate (14)
Slightly yellow oil.
IR: 3005, 1716, 1421, 1363, 1223, 1093, 904 cm–1.
IR: 3392, 2917, 1733, 1515, 1327, 1235, 1099, 1035, 823, 738 cm–1.
1H NMR: d = 9.93 (s, 1 H), 8.19 (t, J = 8.7 Hz, 2 H), 7.43 (s, 1 H),
7.26 (t, J = 8.1 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 2 H), 6.61 (d, J = 8.7
Hz, 2 H), 5.35 (s, 1 H), 4.29–4.12 (m, 2 H), 3.71 (s, 3 H), 1.21 (t,
J = 7.2 Hz, 3 H).
13C NMR: d = 172.0, 152.7, 140.2, 133.0, 129.9, 129.6, 128.0,
125.5, 119.7, 119.4, 114.9, 114.8, 114.6, 61.8, 55.6, 54.9, 14.1.
1H NMR: d = 8.32 (s, 1 H), 7.91 (d, J = 7.5 Hz, 1 H), 7.65 (d, J =
7.5 Hz, 2 H), 7.48–7.41 (m, 3 H), 7.38–7.07 (m, 4 H), 6.61 (d, J =
8.4 Hz, 2 H), 6.38 (d, J = 8.7 Hz, 2 H), 5.38 (s, 1 H), 4.30–4.06 (m,
2 H), 3.64 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 172.7, 152.2, 140.5, 137.4, 135.8, 132.0, 128.9,
128.8, 128.5, 126.5, 122.5, 120.3, 120.1, 114.60, 114.58, 111.0,
108.5, 61.5, 55.6, 55.6, 54.7, 14.0.
EI–MS: m/z (%) = 369 (15) [M+].
+
HRMS: m/z [M + H]+ calcd for C19H20N3O5 : 370.1397; found:
EI–MS: m/z (%) = 400 (3.3) [M+].
HRMS: m/z [M + Na]+ calcd for C25H24N2O3Na+: 423.1679; found:
370.1412.
Ethyl 2-(5-Methoxy-1H-indol-3-yl)-2-(4-methoxyphenylami-
no)acetate (11)
423.1673.
Colorless oil.
IR: 3402, 2833, 1731, 1513, 1239, 1031, 824 cm–1.
1H NMR: d = 8.12 (s, 1 H), 7.23 (m, 3 H), 6.88 (d, J = 8.7 Hz, 1 H),
6.76 (d, J = 9.0 Hz, 2 H), 6.62 (d, J = 9.0 Hz, 2 H), 5.28 (s, 1 H),
4.26–4.11 (m, 2 H), 3.86 (s, 3 H), 3.73 (s, 3 H), 1.23 (t, J = 7.2 Hz,
3 H).
Ethyl 2-(1H-Indol-3-yl)-2-[(R)-1-phenylethylamino]acetate (15)
Colorless oil.
IR: 3409, 2979, 1733, 1457, 1186, 1025, 744 cm–1.
1H NMR: d = 8.19 (s, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.37–7.06 (m,
9 H), 4.53 (s, 1 H), 4.14–3.98 (m, 2 H), 3.71 (q, J = 6.6 Hz, 1 H),
1.34 (d, J = 6.6 Hz, 3 H), 1.12 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 172.8, 154.2, 152.4, 140.7, 131.5, 126.1, 123.7,
114.78, 114.75, 112.8, 112.12, 112.10, 100.9, 61.4, 55.8, 55.6, 55.2,
14.1.
13C NMR: d = 173.4, 144.7, 136.3, 128.4, 127.0, 126.9, 125.9,
123.5, 122.1, 119.6, 119.4, 112.6, 111.3, 61.0, 55.9, 55.1, 24.1,
13.9.
EI–MS: m/z (%) = 354 (6) [M+].
EI–MS: m/z (%) = 322 (0.2) [M+].
HRMS: m/z [M + Na]+ calcd for C20H22N2O4Na+: 377.1472; found:
HRMS: m/z [M + H]+ calcd for C20H23N2O2 : 323.1754; found:
+
377.1495.
323.1752.
Ethyl 2-(5-Methoxycarbonyl-1H-indol-3-yl)-2-(4-methoxyphe-
nylamino)acetate (12)
Ethyl 2-(5-Bromo-1H-indol-3-yl)-2-[(R)-1-phenylethylami-
no]acetate (16)
Slightly yellow oil.
Slightly yellow oil.
IR: 3315, 2952, 1722, 1686, 1620, 1516, 1438, 1242, 1016, 823,
769 cm–1.
1H NMR: d = 8.61 (s, 1 H), 8.47 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H),
7.37 (d, J = 8.4 Hz, 1 H), 7.27 (m, 1 H), 6.74 (d, J = 8.4 Hz, 2 H),
6.61 (d, J = 8.4 Hz, 2 H), 5.37 (s, 1 H), 4.28–4.11 (m, 2 H), 3.94 (s,
3 H), 3.72 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 172.5, 168.0, 152.5, 140.5, 139.1, 125.5, 124.3,
123.9, 122.6, 122.1, 114.9, 114.8, 114.4, 111.1, 61.7, 55.7, 54.9,
51.9, 14.0.
IR: 3329, 2979, 1736, 1450, 1184, 1024, 886, 702 cm–1.
1H NMR: d = 8.34 (s, 1 H), 7.80 (d, J = 1.8 Hz, 1 H), 7.41–7.20 (m,
8 H), 7.09 (d, J = 2.7 Hz, 1 H), 4.49 (s, 1 H), 4.18–4.01 (m, 2 H),
3.70 (q, J = 6.6 Hz, 1 H), 1.37 (d, J = 6.6 Hz, 3 H), 1.16 (t, J = 7.2
Hz, 3 H).
13C NMR: d = 173.1, 144.6, 135.0, 128.5, 127.8, 127.2, 126.9,
125.2, 124.4, 122.2, 113.1, 113.0, 112.7, 61.2, 55.7, 55.2, 24.1,
14.0.
EI–MS: m/z (%) = 401 (0.68) [M + H]+, 403 (0.63).
HRMS: m/z [M + H]+ calcd for C20H22N2O2Br+: 401.0859; found:
EI–MS: m/z (%) = 382 (19) [M+].
HRMS: m/z [M + Na]+ calcd for C21H22N2O5Na+: 405.1421; found:
401.0853.
405.1411.
Ethyl 2-(6-Bromo-1H-indol-3-yl)-2-[(R)-1-phenylethylami-
no]acetate (17)
Slightly yellow oil.
Ethyl 2-(4-Methoxyphenylamino)-2-(2-methyl-1H-indol-3-
yl)acetate (13)
Slightly yellow oil.
IR: 3340, 2927, 1730, 1454, 1186, 803, 701 cm–1.
IR: 3383, 2837, 1730, 1575, 1513, 1460, 1240, 1176, 1039, 752
cm–1.
Synthesis 2005, No. 13, 2198–2204 © Thieme Stuttgart · New York

PAPER
Synthesis of a-(3-Indolyl)glycine Derivatives via Spontaneous Friedel–Crafts Reaction
2203
1H NMR: d = 8.44 (s, 1 H), 7.56 (s, 1 H), 7.38–7.20 (m, 8 H), 7.07
(d, J = 2.4 Hz, 1 H), 4.49 (s, 1 H), 4.12–3.97 (m, 2 H), 3.67 (q, J =
6.6 Hz, 1 H), 1.34 (d, J = 6.6 Hz, 3 H), 1.10 (t, J = 6.9 Hz, 3 H).
13C NMR: d = 173.2, 144.5, 137.2, 128.5, 127.1, 126.9, 124.9,
123.9, 123.0, 120.8, 115.8, 114.2, 113.2, 61.2, 55.7, 55.1, 24.1,
14.0.
Ethyl 2-Amino-2-(1H-indol-3-yl)acetate (21)
[a]20D = +90 (c = 1.10, CHCl3); [Lit.: –88 (antipode in ref.9)].
1H NMR: d = 8.73 (s, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.31 (d, J =
8.4 Hz, 1 H), 7.26–7.09 (m, 3 H), 4.91 (s, 1 H), 4.28–4.06 (m, 2 H),
2.42 (s, 2 H), 1.20 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 174.4, 136.4, 125.3, 122.4, 122.2, 119.7, 119.1,
114.8, 111.4, 61.3, 51.7, 14.1.
EI–MS: m/z (%) = 327 (29) [M – CO2Et]+, 329 (27).
HRMS: m/z [M + Na]+ calcd for C20H21N2O2BrNa+: 423.0679;
found: 423.0669.
Acknowledgment
Ethyl 2-(5-Nitro-1H-indol-3-yl)-2-[(R)-1-phenylethyl-
amino]acetate (18)
Yellow oil.
We thank National Natural Science Foundation of China and
Shanghai Municipal Committee of Science and Technology for fi-
nancial support.
IR: 3116, 2979, 1725, 1520, 1476, 1335, 1234, 1112, 817, 739 cm–1.
1H NMR (major isomer): d = 8.86 (s, 1 H), 8.67 (d, J = 2.1 Hz, 1 H),
8.11 (m, 1 H), 7.43–7.26 (m, 7 H), 4.59 (s, 1 H), 4.30–4.03 (m, 2 H),
3.72 (q, J = 6.6 Hz, 1 H), 1.40 (d, J = 6.6 Hz, 3 H), 1.17 (t, J = 6.9
Hz, 3 H).
1H NMR (minor isomer): d = 8.80 (s, 1 H), 8.55 (d, J = 2.1 Hz, 1 H),
8.08 (m, 1 H), 7.40–7.30 (m, 7 H), 4.48 (s, 1 H), 4.35–4.10 (m, 2 H),
3.88 (q, J = 6.6 Hz, 1 H), 1.43 (d, J = 6.6 Hz, 3 H), 1.28 (t, J = 6.9
Hz, 3 H).
References
(1) (a) Shen, T.-Y. US Patent, 3316260, 1967; Chem. Abstr.
1968, 86, P49447u. (b) Blaszczak, L. C.; Turner, J. R. EP
122157, 1984; Chem. Abstr. 1985, 102, 131813.
(2) (a) Yang, C.-G.; Huang, H.; Jiang, B. Curr. Org. Chem.
2004, 8, 1691. (b) Jiang, B.; Smallheer, J. M.; Amaral-Ly,
C.; Wuonola, M. A. J. Org. Chem. 1994, 59, 6823.
(c) Jiang, B.; Gu, X.-H. Heterocycles 2000, 53, 1559.
(d) Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.;
Inagawa, M.; Sakamoto, M. Org. Lett. 2000, 2, 3027.
(e) Kawasaki, T.; Kouko, T.; Totsuka, H.; Hiramatsu, K.
Tetrahedron Lett. 2003, 44, 8849.
(3) Bergman, J.; Bergman, S.; Lindstroem, J.-O. Tetrahedron
Lett. 1989, 30, 5337.
(4) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura,
M. J. Org. Chem. 2002, 67, 8685.
(5) (a) O’Donnell, M. J.; Bennett, W. D. Tetrahedron 1988, 44,
5389. (b) Clark, B. P.; Harris, J. R. Synth. Commun. 1997,
27, 4223. (c) Whitlock, C. R.; Cava, M. P. Tetrahedron Lett.
1994, 35, 371.
(6) Grumbach, H.-J.; Merla, B.; Risch, N. Synthesis 1999, 1027.
(7) Johannsen, M. Chem. Commun. 1999, 2233.
(8) Hao, J.; Taktak, S.; Aikawa, K.; Yusa, Y.; Hatano, M.;
Mikami, K. Synlett 2001, 1443.
13C NMR: d = 172.9, 114.3, 141.7, 138.4, 128.7, 127.5, 127.2,
126.3, 125.5, 117.9, 117.1, 116.0, 111.4, 61.5, 56.9, 55.6, 23.9,
14.0.
EI–MS: m/z (%) = 368 (0.8) [M + H]+.
HRMS: m/z [M + H]+ calcd for C20H22N3O4 : 368.1605; found:
+
368.1605.
Ethyl 2-(5-Methoxy-1H-indol-3-yl)-2-[(R)-1-phenylethylami-
no]acetate (19)
Colorless oil.
IR: 3407, 2930, 1733, 1488, 1456, 1456, 1214, 1176, 1027, 703
cm–1.
1H NMR: d = 8.32 (s, 1 H), 7.35–7.19 (m, 7 H), 7.08 (d, J = 2.4 Hz,
1 H), 7.02 (d, J = 2.7 Hz, 1 H), 6.84 (dd, J = 9.0, 2.4 Hz, 1 H), 4.51
(s, 1 H), 4.15–4.98 (m, 2 H), 3.81 (s, 3 H), 3.73 (q, J = 6.6 Hz, 1 H),
1.33 (d, J = 6.6 Hz, 3 H), 1.13 (t, J = 6.9 Hz, 3 H).
13C NMR: d = 173.4, 154.0, 144.8, 131.4, 128.4, 127.02, 126.96,
126.5, 123.9, 112.64, 112.60, 112.0, 100.9, 61.0, 55.76, 55.72, 55.0,
24.3, 14.0.
(9) Janczuk, A.; Zhang, W.; Xie, W.; Lou, S.; Cheng, J.; Wang,
P. G. Tetrahedron Lett. 2002, 43, 4271.
(10) Lei, F.; Chen, Y.-J.; Sui, Y.; Liu, L.; Wang, D. Synlett 2003,
1160.
(11) (a) Friedel-Crafts and Related Reactions, Vol. 1; Olah, G.
A., Ed.; Interscience: New York, 1963. (b) A most recent
example using 1.2 equivalents of a strained chiral silane
reagent as Lewis acid: Shirakawa, S.; Berger, R.; Leighton,
J. L. J. Am. Chem. Soc. 2005, 127, 2858.
EI-MS: m/z (%) = 352 (1.3) [M+].
+
HRMS: m/z [M + H]+ calcd for C21H25N2O3 : 353.1860; found:
353.1869.
(12) (a) Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett.
2001, 42, 2545. (b) Petasis, N. A.; Zavialov, I. A. J. Am.
Chem. Soc. 1997, 119, 445. (c) Petasis, N. A.; Goodman,
A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.
(13) For other examples for indole as nucleophile in Friedel–
Crafts reactions, see: (a) Bandini, M.; Melloni, A.; Umani-
Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550. (b) Gong,
Y.; Kato, K.; Kimoto, H. Bull. Chem. Soc. Jpn. 2002, 75,
2637. (c) Gong, Y.; Kato, K. Tetrahedron: Asymmetry 2001,
12, 2121. (d) Gong, Y.; Kato, K.; Kimoto, H. Synlett 2000,
1058. (e) Gong, Y.; Kato, K. J. Fluorine Chem. 2001, 108,
83. (f) Decker, M.; Faust, R.; Wedig, M.; Nieger, M.;
Holzgrabe, U.; Lehmann, J. Heterocycles 2001, 55, 1455.
(g) Dubois, L.; Dorey, G.; Potier, P.; Dodd, R. H.
Tetrahedron: Asymmetry 1995, 6, 455. (h) Onys’ko, P. P.;
Rassukanaya, Y. V.; Sinitsa, A. D. Zh. Obshch. Khim. 2002,
72, 1802. (i) Levkovskaya, G. G.; Rudyakova, E. V.;
Rozentsveig, I. B.; Mirskova, A. N.; Albanov, A. I. Zh. Org.
Khim. 2000, 36, 1378.
Ethyl 2-(2-Methyl-1H-indol-3-yl)-2-[(R)-1-phenylethylami-
no]acetate (20)
Slightly yellow oil.
IR: 3398, 2978, 1730, 1461, 1193, 1024, 744 cm–1.
1H NMR: d = 7.83 (s, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.36–7.23 (m,
7 H), 7.08 (m, 2 H), 4.42 (s, 1 H), 4.24–3.99 (m, 2 H), 3.91 (q, J =
6.3 Hz, 1 H), 2.25 (s, 3 H), 1.39 (d, J = 6.3 Hz, 3 H), 1.16 (t, J = 7.2
Hz, 3 H).
13C NMR: d = 173.2, 144.9, 135.1, 134.0, 128.3, 126.85, 126.83,
126.82, 121.0, 119.5, 118.8, 110.4, 107.5, 60.9, 55.0, 54.2, 24.8,
14.0, 11.4.
EI–MS: m/z (%) = 336 (1.2) [M+].
+
HRMS: m/z [M + H]+ calcd for C21H25N2O2 : 337.1910; found:
337.1909.
Synthesis 2005, No. 13, 2198–2204 © Thieme Stuttgart · New York

2204
B. Jiang, Z.-G. Huang
PAPER
(14) Reviews for Mannich-type reaction involving glyoxylate
imines, see: (a) Taggi, A. E.; Hafez, A. M.; Leckta, T. Acc.
Chem. Res. 2003, 36, 10. (b) Jørgensen, K. A. Synthesis
2003, 1117. (c) Cordova, A. Acc. Chem. Res. 2004, 37, 102.
(15) For examples for chiral Brønsted acid catalysis in Mannich
type or aza-Friedel–Crafts reactions, see: (a) Akiyama, T.;
Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed.
2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 5356. (c) Uraguchi, D.; Sorimachi, K.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 11804.
(16) Using pulverized 4 Å MS as a dehydrating agent or
removing of MgSO4 by filtration before addition of indoles,
comparable results were obtained and the possibility of
MgSO4 as a weak Lewis acid catalyst was excluded:
(a) Kisanga, P.; McLeod, D.; D’Sa, B.; Verkade, J. J. Org.
Chem. 1999, 64, 3090. (b) Kisanga, P. B.; Verkade, J. G. J.
Org. Chem. 1999, 64, 4298.
(17) Commercially available reagent: Fluke #50705, Lancaster
#19207 and TCI #G0264. Control experiments gave similar
results using ethyl glyoxylate (or its hydrate) prepared
according to the literature: (a) Bailey, P. D.; Smith, P. D.;
Pederson, F.; Clegg, W.; Rosair, G. M.; Teat, S. J.
Tetrahedron Lett. 2002, 43, 1067. (b) Viirre, R. D.; Hudson,
R. H. E. J. Org. Chem. 2002, 68, 1630.
(18) Although this reaction could be accelerated by a catalytic to
stoichiometric amount of acid (CF3CO2H, MsOH, etc.), the
yields were not improved and the diastereoselectivities were
deteriorated in the following study.
(19) Hydrogenation of N-[(R)-a-methylbenzyl]indolyl glycinate:
10% Pd(OH)2 (20% on carbon), H2 (5 atm), EtOH, r.t., 24 h,
41% yield of (+)-ethyl (3-indolyl)glycinate (21).
Synthesis 2005, No. 13, 2198–2204 © Thieme Stuttgart · New York