Efficient synthesis of racemic α-aryl-α-amino acid esters via aminoalkylation with in situ generated glycine cation equivalents

Article abstract of DOI:10.1055/s-1999-3497

Iminium salts generated in situ from ethyl glyoxylate, secondary amines and 1-H-benzotriazole are demonstrated to be excellent reagents for the regioselective mono-aminoalkylation of indoles, phenols, furans and pyrroles. This method provides a simple and

Full text of DOI:10.1055/s-1999-3497

PAPER
1027
Efficient Synthesis of Racemic a-Aryl-a-amino Acid Esters via
Aminoalkylation with in situ Generated Glycine Cation Equivalents
Hans-Joachim Grumbach, Beatrix Merla, Nikolaus Risch*
Universität-GH Paderborn, Fachbereich für Chemie und Chemietechnik, Warburger Straße 100, D-33098 Paderborn, Germany
Fax +49(5251)603245; E-mail: nr@chemie.uni-paderborn.de
Received 23 September 1998; revised 21 December 1998
derived from alkyl glyoxylates are the requirements for
the efficient aminoalkylation of aromatic compounds.
Abstract: Iminium salts generated in situ from ethyl glyoxylate,
secondary amines and 1-H-benzotriazole are demonstrated to be
excellent reagents for the regioselective mono-aminoalkylation of
indoles, phenols, furans and pyrroles. This method provides a sim-
ple and straightforward “one-pot” reaction sequence to a variety of
ethyl α-aryl-α-amino acid esters 5 and 8 in high yields.
Here we describe the in situ generation of the ternary imi-
nium salts 3a–d as glycine cation equivalents fromeasily
accessible substituted ethyl glyoxylate aminals2a–d. The
aminals are derived according to Katritzky14 from com-
Key words: a-aryl-a-amino acids, ternary iminium salt,
aminoalkylation, Mannich reaction, glycine cation equivalents
Nonproteinogenic a-aryl-a-amino acids are interesting
building blocks in the synthesis of natural products and, in
general, of biologically active compounds.1 The classical
Mannich procedure is only suitable for the formation of a
few a-aryl-a-amino acids derived from very electron-rich
aromatic compounds.2,3 Therefore, several synthetic
routes to this attractive class of substances have been de-
veloped.1a,1h,4 Numerous synthetic routes starting from
O’Donnell’s Schiff bases1f,5 or arylglyoxylates1g,6,7 are
convenient methods for the synthesis of arylglycines.
However, these methods in general require tedious multi-
step procedures. Furthermore, they are often restricted to
only few types of arenes or the yields are quite poor.8 The
method of Heaney9 for the preparation of a-aryl-a-amino
acids leads to good yields. However, long reaction times,
limitation to very electron-rich aromatic heterocycles and
the difficult preparation of the N,O-acetals10 are the main
restrictions of this strategy. Our motivation to use glycine
cation equivalents in the manner of reactive ternary imin-
ium salts for the aminoalkylation of numerous nucleo-
philic aromatic compounds is the consequence of the
latest developments in modern variants of the Mannich re-
action.11 Recently, we have disclosed that the amino-
alkylation of electron-rich aromatic compounds with ter-
nary iminium salts (containing alkyl and aryl groups) pro-
vides the corresponding Mannich products in good to
excellent yields.12 Our current goal is the development of
an efficient and inexpensive synthetic route using readily
available starting materials to yield aromatic a-amino ac-
ids in a simple “one-pot” reaction sequence.
Some preliminary studies of Groß13 and Katritzky14,15
have been very helpful for our purposes. Groß et al.13 have
described a facile method for the formation of aromatic a-
amino carboxylates. However, this method was not pur-
sued further, may be due to the difficult preparation10,16
and handling of the described iminium salt. A better prep-
aration and simple handling of the ternary iminium salts
Reagents and conditions: a) Bt-H/HNR2/Toluene, 65°C, 5 h; b) Lewis
acid/THF or CH2Cl2, 1 h; c) THF or CH2Cl2
Scheme 1
Synthesis 1999, No. 6, 1027–1033 ISSN 0039-7881 © Thieme Stuttgart · New York

1028
H.-J. Grumbach et al.
PAPER
mercially available ethyl glyoxylate (1),17 1-H-benzotria- pounds 4e–g, 4i and 4j. In comparison, this one-pot
zole (Bt-H)18 and a secondary amine (Scheme 1, Table 1). procedure requires mild reaction conditions.
The benzotriazol-2-yl isomers (2’) in the equilibrium mix-
When more powerful Lewis acids were used, such as
tures of both the benzotriazol-1-yl (2) and 2’ isomers19
Me3SiOTf (Tf = CF3SO2) and Me3SiB(OTf)4,24 a black,
have no detrimental influence on the aminoalkylation re-
semi-solid product resulted. The use of FeCl3, ZnCl2,
ZnBr2 or an excess of Lewis acid led to poorer yields. The
ethyl a-aryl-a-amino carboxylates 5 were isolated by
quenching the reaction mixture with aqueous NaHCO3
followed by the usual workup (2 N NaOH; extraction with
dichloromethane) and crystallization or purification by
chromatography on silica gel. The ethyl a-aryl-a-amino
action.1H NMR data of CDCl3 solutions of 2 exhibit, in all
cases, two singlets in the region 6.10 – 6.50 ppm, corre-
sponding to the NCHN proton, indicating the presence of
both 2 and 2’ isomers (ratio 2:2’ = 85:15 to 80:20).20
Changing the solvent resulted in different ratios of the
benzotriazol-1-yl and -2-yl isomers.21
The iminium salts 3 are generated in situ by an electro- carboxylates 5c, 5f–j, 5n and 5p (Table 2) can be used
philic attack of a Lewis acid on the aminals 2. The follow- without further purification.
ing nucleophilic attack of 4 on the iminium salt 3 yields
the ethyl a-aryl-a-amino carboxylates 5 (Scheme 1).
we observed a regioselective ortho-aminoalkylation of
In all experiments with phenols as aromatic substrates 4,
We started our studies using 2-naphthol (4a) and N-meth- these derivatives with respect to the hydroxy group. The
ylindole (4h) owing to the fact that these nucleophilic ar- results are summarized in Table 2. In contrast to
omatic compounds are standards in aminoalkylation Heaney’s25 earlier studies of Friedel–Crafts alkylation re-
reactions.12,22 With reference to O’Donnell5c and Gilchrist actions of electron-rich aromatic compounds, the ami-
et al.,23 the experiments were conducted to find the best noalkylation of N-methylindole (4h) always led to the
conditions in terms of Lewis acid, solvent, temperature expected 3-monoaminoalkylated products in high yields.
and stoichiometry. AlCl3 in THF (reflux; Method A) for The interaction of the iminium salts 3c or 3d with TiCl4
aminoalkylation of 4a–g and TiCl4 in dichloromethane at and 4h in dichloromethane (–40°C; 3–6 h) gave the di-in-
–78°C (Method B) for 4h–j gave the highest yields. These dolylacetate (6).25,26
procedures were also employed successfully for the ami-
noalkylation of considerably less active aromatic com-
The ethyl a-aryl-a-amino carboxylates 5 can be saponi-
fied to a-aryl-a-amino acids 7 by treating them with 6 N
NaOH in the presence of some 1,4-dioxane (room temper-
Table 1 Ethyl Glyoxylate Aminals 2 Prepared
Prod-
ucta
mp (°C) or
Appearance
NR2
Yieldb
(%)
1H NMR (200 MHz, CDCl3/TMS)c
d, J (Hz)
IR (KBr or film)
n (cm–1)
2a
83–84d
1-piperidin-1-yl
86d
1.23 (t, 3 H, J = 7.1, CH2CH3), 1.32–1.42 [m, 2 H,
N(CH2)5], 1.59–1.69 [m, 4 H, N(CH2)5], 2.49–2.77
(m, 4 H, CH2NCH2), 4.28 (dq, 2 H, J = 7.1, 2.3,
CH2CH3), 6.17 (s, 1 H, NCHN), 7.34–7.53 (m, 2 H,
ArH), 7.69 (d, 1 H, J = 8.3, ArH), 8.09 (d, 1 H,
J = 8.2, ArH)
2939, 2930, 2814, 1763,
1449, 1235, 1191, 1181,
1125, 1081, 1027, 753,
744
2b
2c
yellow oil
yellow oil
1-morpholin-1-yl
(allyl)2N
86
96
1.21 (t, 3 H, J = 7.1, CH2CH3), 2.58–2.83 (m, 4 H,
CH2NCH2), 3.66–3.83 (m, 4 H, CH2OCH2), 4.27
(q, 2 H, J = 7.1, CH2CH3), 6.16 (s, 1 H, NCHN),
7.31–7.56 (m, 2 H, ArH), 7.73 (d, 1 H,
2969, 2857, 1749, 1451,
1265, 1218, 1177, 1123,
1069, 1029, 749
J = 8.3, ArH), 8.09 (d, 1 H, J = 7.9, ArH)
1.22 (t, 3 H, J = 7.1, CH2CH3), 3.05–3.19 [m, 2 H,
N(CH2CH=CH2)2], 3.61–3.73 [m, 2 H,
N(CH2CH=CH2)2], 4.27 (dq, 2 H, J = 7.1, 1.0,
CH2CH3), 5.16–5.32 [m, 4 H, N(CH2CH=CH2)2],
5.72–5.93 [m, 2 H, N(CH2CH=CH2)2], 6.35 (s, 1 H,
NCHN), 7.29–7.65 (m, 3 H, ArH), 8.09 (d, 1 H,
J = 8.2, ArH)
3092, 2981, 1751, 1450,
1370, 1277, 1260, 1215,
1179, 1132, 1108, 1060,
1029, 1002, 928, 747
2d
yellow oil
Bn2N
95
1.22 (t, 3 H, J = 7.1, CH2CH3), 3.41 (d, 2 H,
J = 13.9, NCH2Ph), 4.19–4.37 (m, 4 H, CH2CH3,
NCH2Ph), 6.20 (s, 1 H, NCHN), 7.14–7.50
(m, 13 H, ArH), 8.13 (d, 1 H, J = 8.6, ArH)
3082, 3030, 2982, 1752,
1494, 1452, 1370, 1217,
1154, 1075, 1060, 1027,
745, 699
a Satisfactory microanalyses obtained C ± 0.4, H ± 0.3, N ± 0.3.
b Yields of isolated products.
c
1H NMR data are given for the major benzotriazol-1-yl isomers 2a–d.
d Lit14 yield: 78%, mp 84–85°C.
Synthesis 1999, No. 6, 1027–1033 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Racemic a-Aryl-a-amino Acid Esters
1029
Table 2 Aminoalkylation of Aromatic Compounds 4 Using in situ Generated Ternary Iminium Salts 3
Prod- mp
NR2
Ar- (4)
Me-
thod
Yieldb
(%)
IR (KBr or film)
n (cm–1)
1H NMR (200 MHz, CDCl3/TMS)
d, J (Hz)
ucta (°C)
5a
72–73 1-piperidin-1-yl
A
87
1.12 (t, 3 H, J = 7.1, CH2CH3), 1.52–1.71 [m, 2954, 2938, 2818,
6 H, N(CH2)5], 2.38–2.42 (m, 4 H, CH2NCH2), 1742, 1622, 1600,
4.09 (dq, 2 H, J = 7.1, 1.6, CH2CH3), 4.83 (s, 1473, 1373, 1366,
1 H, ArCHN), 7.08 (d, 1 H, J = 8.9, ArH), 7.25– 1330, 1303, 1273,
7.33 (m, 1 H, ArH), 7.42–7.51 (m, 1 H, ArH), 1240, 1227, 1177,
7.66–7.75 (m, 2 H, ArH), 8.01 (d, 1 H, J = 8.6, 1159, 1144, 1110,
ArH), 12.01 (br s, 1 H, ArOH)
1018, 831, 750
5b
5c
5d
red oil 1-piperidin-1-yl
A
A
A
83c
1.24 (t, 3 H, J = 7.1, CH2CH3), 1.52–1.65 [m, 3358, 2935, 2854,
6 H, N(CH2)5], 2.54–2.57 (m, 4 H, CH2NCH2), 1742, 1626, 1601,
4.06 (s, 1 H, ArCHN), 4.18 (q, 2 H, J = 7.1,
CH2CH3), 6.30–6.42 (m, 2 H, ArH), 6.86 (d,
1 H, J = 8.2, ArH), 7.85 (br s, 1 H, ArOH)
1516, 1467, 1454,
1313, 1220, 1173,
1112, 1026, 976
yellow 1-piperidin-1-yl
oil
70
1.24 (t, 3 H, J = 7.1, CH2CH3), 1.51–1.72 [m, 2936, 2853, 1744,
6 H, N(CH2)5], 2.54–2.58 (m, 4 H, CH2NCH2), 1625, 1588, 1511,
3.76 (s, 3 H, OCH3), 4.07 (s, 1 H, ArCHN),
4.12–4.30 (m, 2 H, CH2CH3), 6.22–6.50 (m,
2 H, ArH), 6.91 (d, 1 H, J = 8.4, ArH)
1454, 1220, 1202,
1183, 1111, 1033
yellow 1-piperidin-1-yl
oil
76c
1.20 (t, 3 H, J = 7.1, CH2CH3), 1.40–1.68 [m, 2934, 1737, 1611,
6 H, N(CH2)5], 2.41–2.48 (m, 4 H, CH2NCH2), 1587, 1505, 1464,
3.79 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.01– 1454, 1296, 1257,
4.27 (m, 2 H, CH2CH3), 4.46 (s, 1 H, ArCHN), 1208, 1157, 1107,
6.38–6.54 (m, 2 H, ArH), 7.39 (d, 1 H, J = 8.3, 1034, 826
ArH)
5e
5f
yellow 1-piperidin-1-yl
oil
A
A
53c
1.26 (t, 3 H, J = 7.1, CH2CH3), 1.52–1.74 [m, 2935, 2854, 1744,
6 H, N(CH2)5], 2.30 (s, 3 H, ArCH3), 2.45–2.68 1628, 1581, 1453,
(m, 4 H, CH2NCH2), 4.12 (s, 1 H, ArCHN),
1369, 1266, 1220,
4.20 (q, 2 H, J = 7.1, CH2CH3), 6.60–6.70 (m, 1187, 1155, 1118,
2 H, ArH), 6.92 (d, 1 H, J = 7.7, ArH), 11.18 1028, 804
(br s, 1 H, ArOH)
yellow 1-piperidin-1-yl
oil
86
1.26 (t, 3 H, J = 7.1, CH2CH3), 1.36–1.48 [m, 3418, 2940, 2856,
2 H, N(CH2)5], 1.57–1.68 [m, 4 H, N(CH2)5], 2378, 2348, 1743,
2.28 (s, 3 H, ArCH3), 2.36–2.57 (m, 4 H,
CH2NCH2), 4.16–4.30 (m, 3 H, ArCHN,
1633, 1452, 1368,
1228, 1202, 1159,
CH2CH3), 5.91–5.93 (m, 1 H, ArH), 6.22-6.24 1116, 1026, 789,
(m, 1 H, ArH) 748
5g
5h
yellow 1-piperidin-1-yl
oil
Bd
98
89
1.22 (t, 3 H, J = 7.1, CH2CH3), 1.31–1.63 [m, 3419, 2932, 2852,
6 H, N(CH2)5], 2.38–2.60 (m, 4 H, CH2NCH2), 2359, 1731, 1633,
3.73 (s, 3 H, NCH3), 4.06–4.26 (m, 2 H,
CH2CH3), 4.36 (s, 1 H, ArCHN), 6.97–7.29 (m, 1152, 1118, 1032,
4 H, ArH), 7.80 (d, 1 H, J = 7.7, ArH) 741
1469, 1372, 1332,
yellow 1-piperidin-1-yl
oil
Bd
1.26 (t, 3 H, J = 7.1, CH2CH3), 1.35–1.63 [m, 2933, 2852, 2352,
6 H, N(CH2)5], 2.37–2.56 (m, 4 H, CH2NCH2), 2339, 1745, 1443,
3.70 (s, 3 H, N-CH3), 4.06–4.22 (m, 2 H,
1310, 1297, 1180,
CH2CH3), 4.26 (s, 1 H, ArCHN), 6.02–6.06 (m, 1155, 1118, 1030,
1 H, ArH), 6.09–6.19 (m, 1 H, ArH), 6.58–6.64 712
(m, 1 H, ArH)
5i
yellow 1-piperidin-1-yl
oil
Be
72
1.22 (t, 3 H, J = 7.1, CH2CH3), 1.42–1.46 (m, 2932, 2850, 2801,
2 H, N(CH2)5], 1.57–1.71 [m, 4 H, N(CH2)5], 1741, 1612, 1526,
2.29–2.48 (m, 4 H, CH2NCH2), 2.95 [s, 6 H,
1444, 1350, 1223,
N(CH3)2], 3.84 (s, 1 H, ArCHN), 4.02–4.29 (m, 1162, 1115, 1030,
2 H, CH2CH3), 6.69 (d, 1 H, J = 8.6, ArH), 7.30 946, 823
(d, 1 H, J = 8.6, ArH)
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1030
H.-J. Grumbach et al.
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Table 2 (continued)
Prod- mp
NR2
Ar- (4)
Me-
thod
Yieldb
(%)
IR (KBr or film)
n (cm–1)
1H NMR (200 MHz, CDCl3/TMS)
d, J (Hz)
ucta (°C)
5j
yellow 1-morpholin-1-yl
oil
A
85
1.11 (t, 3 H, J = 7.1, CH2CH3), 2.56–2.79 (m, 2961, 2917, 2854,
4 H, CH2NCH2), 3.79–3.84 (m, 4 H, 2353, 2339, 1736,
CH2OCH2), 3.97–4.23 (m, 2 H, CH2CH3), 4.88 1622, 1600, 1469,
(s, 1 H, ArCHN), 7.06–7.11 (m, 1 H, ArH), 1455, 1370, 1266,
7.25–7.35 (m, 1 H, ArH), 7.41–7.54 (m, 1 H, 1186, 1121, 1030,
ArH), 7.69–7.77 (m, 2 H, ArH), 8.03 (d, 1 H, 748
J = 8.6, ArH), 11.28 (br s, 1 H, ArOH)
5k
red oil 1-morpholin-1-yl
A
77c
1.22 (t, 3 H, J = 7.1, CH2CH3), 2.48–2.70 (m, 3262, 2960, 2925,
4 H, CH2NCH2), 3.72–3.94 (m, 4 H,
2856, 1734, 1623,
CH2OCH2), 4.03 (s, 1 H, ArCHN), 4.09–4.30 1602, 1517, 1455,
(m, 2 H, CH2CH3), 6.29–6.56 (m, 2 H, ArH), 1384, 1313, 1267,
6.92 (d, 1 H, J = 8.3, ArH), 9.06 (br s, 2 H,
ArOH)
1195, 1174, 1158,
1119, 1070, 1030,
975, 748
5l
yellow 1-morpholin-1-yl
oil
A
A
40c
1.23 (t, 3 H, J = 7.1, CH2CH3), 2.24 (s, 3 H,
ArCH3), 2.57–2.68 (m, 4 H, CH2NCH2), 3.75– 2855, 2352, 2347,
3.80 (m, 4 H, CH2OCH2), 4.04 (s, 1 H,
ArCHN), 4.10–4.31 (m, 2 H, CH2CH3), 6.74
(d, 1 H, J = 8.2, ArH), 6.87 (s, 1 H, ArH), 6.98– 1185, 1148, 1118,
7.04 (m, 1 H, ArH), 9.76 (br s, 1 H, ArOH)
3389, 2959, 2920,
1737, 1633, 1500,
1454, 1384, 1267,
1030, 899, 749
5m
yellow 1-morpholin-1-yl
oil
43c
1.11 (t, 3 H, J = 7.1, CH2CH3), 2.16 (s, 3 H,
ArCH3), 2.46–2.52 (m, 4 H, CH2NCH2), 3.57– 2854, 1741, 1627,
3.69 (m, 4 H, CH2OCH2), 3.95 (s, 1 H, 1580, 1453, 1270,
3390, 2955, 2921,
ArCHN), 3.97–4.14 (m 2 H, CH2CH3), 6.50– 1194, 1157, 1117,
6.57 (m, 2 H, ArH), 6.84 (d, 1 H, J = 7.6, ArH), 1030, 891
9.77 (br s, 1 H, ArOH)
5n
5o
yellow 1-morpholin-1-yl
oil
Bd
93
1.23 (dt, 3 H, J = 7.1, 1.1, CH2CH3), 2.44–2.65 3448, 2958, 2855,
(m, 4 H, CH2NCH2), 3.58 –3.85 (m, 7 H, NCH3, 1737, 1473, 1372,
CH2OCH2), 4.04–4.28 (m, 2 H, CH2CH3), 4.37 1331, 1246, 1183,
(s, 1 H, ArCHN), 7.06–7.42 (m, 4 H, ArH), 7.84 1153, 1134, 1116,
(d, 1 H, J = 7.6, ArH)
1032, 735
yellow (allyl)2N
oil
A
74f
1.10 (t, 3 H, J = 7.1, CH2CH3), 3.24–3.49 [m, 2980, 1737, 1622,
4 H, N(CH2CH=CH2)2], 3.94–4.27 (m, 2 H, 1601, 1468, 1454,
CH2CH3), 5.09 (s, 1 H, ArCHN), 5.17–5.28 [m, 1368, 1270, 1246,
4 H, N(CH2CH=CH2)2], 5.81–6.07 [m, 2 H, 1235, 1184, 1161,
N(CH2CH=CH2)2], 7.10 (d, 2 H, J = 8.9, ArH), 1143, 1111, 1027,
7.24–7.32 (m, 1 H, ArH), 7.42–7.51 (m, 1 H, 997, 929, 825, 747
ArH), 7.67–7.75 (m, 2 H, ArH), 8.00 (d, 1 H,
J = 8.6, ArH), 11.50 (br s, 1 H, ArOH)
5p
yellow (allyl)2N
oil
Bg
96
1.25 (t, 3 H, J = 7.1, CH2CH3), 3.16–3.40 [m, 2977, 2956, 2926,
4 H, N(CH2CH=CH2)2], 3.70 (s, 3 H, NCH3), 1742, 1468, 1445,
4.04–4.33 (m, 2 H, CH2CH3), 4.92 (s, 1 H,
ArCHN), 5.06–5.21 [m, 4 H,
N(CH2CH=CH2)2], 5.74–6.03 [m, 2 H,
N(CH2CH=CH2)2], 6.95–7.29 (m, 4 H, ArH),
7.10–7.85 (m, 1 H, ArH)
1373, 1332, 1179,
1153, 1120, 919,
746
5q
5r
92
Bn2N
Bh
84i
1.31 (t, 3 H, J = 7.1, CH2CH3), 3.55–3.79 (m, 3069, 3029, 2974,
5 H, NCH3, N(CH2Ph)), 3.84–3.97 (m, 2 H, 2937, 2833, 2815,
N(CH2Ph)), 4.08–4.43 (m, 2 H, CH2CH3), 4.88 1724, 1495, 1474,
(s, 1 H, ArCHN), 6.97–7.41 (m, 14 H, ArH),
7.49–7.60 (m, 1 H, ArH)
1453, 1336, 1173,
1153, 1138, 1033,
999, 751, 697
yellow Bn2N
oil
A
79j
1.24 (t, 3 H, J = 7.1 , CH2CH3), 3.63–3.91 [m, 2935, 2837, 1732,
10 H, 2 OCH3, N(CH2Ph)2], 4.06–4.32 (m, 2 H, 1612, 1586, 1505,
CH2CH3), 4.74 (s, 1 H, ArCHN), 6.34–6.57 (m, 1454, 1296, 1218,
2 H, ArH), 7.03–7.49 (m, 11 H, ArH)
1159, 1133, 1031,
835, 747, 699
Synthesis 1999, No. 6, 1027–1033 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Racemic a-Aryl-a-amino Acid Esters
1031
Table 2 (continued)
Prod- mp
NR2
Ar- (4)
Me-
thod
Yieldb
(%)
IR (KBr or film)
1H NMR (200 MHz, CDCl3/TMS)
d, J (Hz)
ucta (°C)
n (cm–1)
5s
yellow Bn2N
oil
A
81i
1.13 (t, 3 H, J = 7.1, CH2CH3), 3.86 [s, 4 H,
3062, 3030, 2353,
N(CH2Ph)2], 3.96–4.24 (m, 2 H, CH2CH3), 5.28 2346, 1801, 1623,
(s, 1 H, ArCHN), 7.21–7.61 (m, 13 H, ArH), 1601, 1583, 1455,
7.80–7.87 (m, 2 H, ArH), 8.00 (d, 1 H, J = 8.5, 1435, 1382, 1247,
ArH), 11.93 (br s, 1 H, ArOH)
1208, 1108, 963,
749, 703
a Satisfactory microanalyses obtained C ± 0.4, H ± 0.3, N ± 0.3.
b Yields of isolated products.
c After column chromatography (silica gel, t-BuOMe/acetone = 90 : 10).
d Reaction time: 2 h.
e Reaction time: 4 h.
f After column chromatography (silica gel, petroleum ether (bp 50–70°C)/Et2O = 1 : 1).
g Reaction time: 2.5 h.
h Reaction time: 3 h.
i After column chromatography (silica gel, EtOAc/hexane = 1 : 1).
j After column chromatography (silica gel, t-BuOMe/acetone = 99 : 1).
Scheme 2
ature, 2 h), and then adjusting the pH of the solution to the
isoelectric point with 1 N HCl.
In summary, the aminoalkylation of phenols and aromatic
N- and O-heteroaromatics with 3 provides a simple and
straightforward route to a variety of ethyl a-aryl-a-amino
carboxylates in good yields. Our method only utilizes in-
expensive, readily available starting materials. The range
of reactions using in situ generated iminium salts 3 will be
extended by adding other nucleophiles, such as allyl-
silanes or organometallic compounds.
The debenzylation of 5q,r by heterogenous catalyzed hy-
drogenolysis offered the ethyl a-aryl-a-amino carboxy-
lates 8 with a free amino functionality (Scheme 2, Table
3). N-debenzylation of 5q,r was achieved with Pearl-
man’s catalyst [20% Pd(OH)2/C].27,28
Furthermore, there are many notable prospects. Based on
our results in the formation of racemic a-aryl-a-amino ac-
ids, we also expect our method to be suitable for dia-
stereoselective syntheses.
Table 3 Ethyl a-Aryl a-amino Carboxylates 8 with a Free Amino Group
Sub-
strate
Prod-
ucta
Appearance
Yieldb
(%)
1H NMR (200 MHz, CDCl3/TMS)
d, J (Hz)
IR (film)
n (cm–1)
5q
5r
8a
8b
yellow oil
97c
1.21 (t, 3 H, J = 7.2, CH2CH3), 2.02 (br s, 2 H, NH2),
3.74 (s, 3 H, NCH3), 4.03–4.31 (m, 2 H, CH2CH3),
4.88 (s, 1 H, ArCHN), 7.03–7.36 (m, 4 H, ArH), 7.71
(d, 1 H, J = 7.8, ArH)
2980, 2935, 2359, 1728, 1611,
1550, 1474, 1445, 1425, 1371,
1335, 1245, 1182, 1156, 1025,
742
yellow oil
93c,d
1.22 (t, 3 H, J = 7.1, CH2CH3), 2.59 (br s, 2 H, NH2),
5.67 (s, 6 H, 2 OCH3), 4.07 – 4.27 (m, 2 H, CH2CH3),
4.68 (s, 1 H, ArCHN), 6.47–6.51 (m, 2 H, ArH),
7.15–7.26 (m, 1 H, ArH)
2978, 2939, 1733, 1612, 1588,
1508, 1465, 1296, 1264, 1211,
1158, 1117, 1032, 834
a Satisfactory microanalyses obtained C ± 0.4, H ± 0.3, N ± 0.3. For the structure of substituent Ar, see Table 2 under 5q, r.
b Yields of isolated products.
c After column chromatography (silica gel, CH2Cl2/MeOH = 95 : 5).
d Compound 8b is mentioned in Lit5c without further characterization.
Synthesis 1999, No. 6, 1027–1033 ISSN 0039-7881 © Thieme Stuttgart · New York

1032
H.-J. Grumbach et al.
PAPER
Anhyd THF was freshly distilled from potassium under argon. Col-
umn chromatography on silica gel was performed with Merck Kie-
selgel 60 (0.040-0.063 mm). 1H and 13C NMR spectra were
recorded on a Bruker ARX 200 spectrometer, using TMS as internal
standard. IR spectra were recorded on a Nicolet 510 P FT-IR spec-
trometer. GC/MS data were obtained from a Finnigan MAT Mag-
num System 240. Melting points were determined on a Mettler
FP61 apparatus and are uncorrected. Elemental analyses were per-
formed on a Perkin Elmer Elemental Analyser. Satisfactory mi-
croanalyses were obtained for the new compounds 2, 5 and 8: C ±
0.4, H ± 0.3, N ± 0.3.
References
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Ethyl Glyoxylate Aminals 2; General Procedure
A solution of ethyl glyoxylate (1; 9.4 mL, 0.05 mol, 50% in toluene,
Fluka) in toluene (30 mL) was stirred at 65°C for 1 h. First 1H-ben-
zotriazol (6.0 g, 0.05 mol; Fluka) and then the secondary amine
(0.05 mol) were added. The mixture was stirred for 4 h at this tem-
perature. Afterwards, MgSO4 was added to remove the water, the
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Ethyl a-Aryl-a-amino Carboxylates 5a–f, j–m, o, r, s; General
Procedure
Method A: All reactions were conducted under argon. To generate
the iminium salt, a solution of ethyl glyoxylate aminal 2 (2.5 mmol)
in anhyd THF (20 mL) was cooled to 0°C. AlCl3 (0.33 g, 2.5 mmol
+ 0.33 g, 2.5 mmol for each oxygen in the side chains of the aromat-
ic compound 4)29 was added in one portion under stirring. After a
reaction time of 1 h at this temperature, the aromatic compound 4
(2.5 mmol) was added and the solution heated under reflux (5a, d–
f, j–m, o, r, and s: 4 h; 5b and c: 5 h.) The mixture was quenched
with aq sat. NaHCO3 solution (50 mL) at 0°C, basified by the addi-
tion of NaOH (2 N, 20 mL) to pH 10 – 12 and extracted with CH2Cl2
(3 î 50 mL). The combined organic layers were washed neutral and
dried (MgSO4). The solvent was removed in vacuo and the residue
crystallized from MeOH, purified by column chromatography on
silica gel or used without further purification.
(2) Biekert, E.; Funck, T. Chem. Ber. 1960, 93, 626.
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Ethyl a-Aryl-a-amino Carboxylates 5g–i, n, p, q; General
Procedure
Method B: All reactions were conducted under argon. To generate
the iminium salt, a solution of ethyl glyoxylate aminal 2 (2.5 mmol)
in anhyd CH2Cl2 (30 mL) was cooled to –78°C. TiCl4 (0.28 mL, 2.5
mmol) was added in one portion under stirring. After a reaction time
of 0.5 h at this temperature, the aromatic compound 4 was added.
The temperature was then allowed to rise to –60°C (typically 2 h).
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A solution of 5q or 5r (0.5 mmol) in anhyd EtOH (10 mL) was
stirred at r.t. in the presence of 20% Pd(OH)2/C (0.02 g) and H2 was
bubbled through the mixture until the debenzylation was completed
(TLC control). After removal of the catalyst by filtration through
Celite, the filtrate was evaporated to yield 8a or 8b.
Acknowledgement
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Int. Ed. Engl. 1997, 36, 1700.
We would like to thank the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft for supporting this research.
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Synthesis 1999, No. 6, 1027–1033 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Racemic a-Aryl-a-amino Acid Esters
1033
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Article Identifier:
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Synthesis 1999, No. 6, 1027–1033 ISSN 0039-7881 © Thieme Stuttgart · New York