Three-component Friedel-Crafts reaction of indoles, glyoxylate, and amine under solvent-free and catalyst-free conditions - Synthesis of (3-indolyl)glycine derivatives

Article abstract of DOI:10.1055/s-2005-922764

Solvent-free and catalyst-free three-component reactions of indoles, amines, and ethyl glyoxylate gave alkylation products in good to high yields (61-93%), providing a convenient synthesis of (3-indolyl)glycine derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922764

96
LETTER
Three-Component Friedel–Crafts Reaction of Indoles, Glyoxylate, and
Amine under Solvent-Free and Catalyst-Free Conditions – Synthesis of
(3-Indolyl)glycine Derivatives
S
ynthesis
u
of (3-Indolyl
n
)glycine De
r-
ivativesLing Zhao,a,b Li Liu,*a Hai-Bo Zhang,a,b Yan-Chao Wu,a,b Dong Wang,*a Yong-Jun Chen*a
a
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, P. R. of China
Fax +86(10)62554449; E-mail: yjchen@mail.iccas.ac.cn; E-mail: dwang210@mail.iccas.ac.cn
b
Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100080, P. R. of China
Received 21 September 2005
free asymmetric three-component aminoalkylation reac-
tion for the synthesis of aminoalkylnaphthols by heating
the reaction mixture at 60 °C. Herein, we would like to
report our initial results on the three component Friedel–
Crafts reaction of indoles, glyoxylate, and amines under
solvent- and catalyst-free conditions at ambient tempera-
ture for the convenient synthesis of (3-indolyl)glycine
derivatives.
Abstract: Solvent-free and catalyst-free three-component reactions
of indoles, amines, and ethyl glyoxylate gave alkylation products in
good to high yields (61–93%), providing a convenient synthesis of
(3-indolyl)glycine derivatives.
Key words: solvent-free, catalyst-free, indole, three-component
alkylation, amine
As reported by Jiang,4 the Friedel–Crafts alkylation reac-
tion between indoles and glyoxylate imines (which is pre-
pared by the reaction of glyoxylate with amine in CH2Cl2
in the presence of MgSO4 for one hour), was complete in
6–72 hours in organic solvents without using an acid cat-
alyst. Initially, we carried out the three-component reac-
tion of indole (1a), ethyl glyoxylate (2), and aniline (3a)
at ambient temperature without a catalyst under solvent-
free conditions (Scheme 1). It was found that the yield of
the reaction was dependent on the addition order of the
starting materials. Although mixing 2 and 3 in situ to
generate glyoxylate imine seemed to be reasonable, the
reaction of 2 and 3 proceeded very fast, forming a gel
too sticky to be stirred under solvent-free conditions.
However, the reaction proceeded smoothly if 1a was
mixed with 3 to form a liquid mixture, 2 was then added
with vigorous stirring. To our surprise, the reaction was
complete within one minute to give the products, ethyl 2-
(1H-indol-3-yl)-2-(phenylamino)acetate (4a) in 76% iso-
lated yield, and 5a in 19% yield (Figure 1) which resulted
from the reaction of glyoxylate with indole. Contrary to
the reaction of 1b with 2a, the effect of addition order on
Indolylglycines are an important class of non-proteino-
genic amino acids, which are very useful building blocks
for the synthesis of many biologically important com-
pounds such as dragmacidins,1 cephalosporin,2 and
pemedolac.3 Several methods for the synthesis of a range
of indolylglycine derivatives have appeared.4 We have
also reported a highly diastereoselective synthesis of in-
dolylglycines by a TFA-promoted Friedel–Crafts reaction
between N-substituted indoles and glyoxylate imines or
chiral cyclic glyoxylate imines.5 The Friedel–Crafts alkyl-
ation reaction is one of the most efficient methods for the
construction of carbon–carbon bonds to aromatics and
heteroaromatics.6 In general, the reaction requires a stoi-
chiometric amount or catalytic amount of Lewis acid,7
Brønsted acid,5 or organocatalyst,8 as well as organic sol-
vents. Recently, organic reactions under solvent-free con-
ditions have attracted considerable attention9 due to the
advantages in terms of green chemistry.10 Furthermore,
recently, the development of solvent-free and multicom-
ponent reactions is also of great concern. However, in
most cases, the solvent-free reaction requires microwave
or ultrasound irradiation.11 Palmieri12 reported a solvent-
R
R3
NH
O
R3
no catalyst
CO2Et
RNH2
+
+
N
R1
R2
solvent-free, r.t.
H
CO2Et
N
R1
R2
3a, R = Ph
1a–i
2
4a–o
3b, R = PhCH2
3c, R = CH2=CHCH2
3d, R = (CH3)2CH
Scheme 1
SYNLETT 2006, No. 1, pp 0096–0100
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922764; Art ID: W11705ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (3-Indolyl)glycine Derivatives
97
catalyst-free reaction of 1a with 2 was also examined. A
reaction time of 30 minutes gave the product 5a in 57%
yield. Moreover, as soon as 2 was mixed with 3, the reac-
tion occurred and was complete immediately. For activat-
ed indole 1c, the three-component reaction provided
almost only aminoalkylation product 4c in 93% yield
(Table 1, entry 3). These results prove that the reaction of
2 with 3 is faster than that with 1a and that the product of
OH
CO2Et
N
H
5a
Figure 1
yield is not obvious. It is most probable that three reac- the Friedel–Crafts reaction of indole with in situ generated
tions occurred during the three-component reaction: in glyoxylate imine predominates in the solvent-free three-
situ formation of glyoxylate imine, reaction of indole with component reaction.
glyoxylate, and reaction of indole with the in situ-formed
glyoxylate imine. At the same time, the solvent- and
Table 1 Three-Component Friedel–Crafts Reaction of Indoles, Ethyl Glyoxylate (2), and Aminesa
Entry
1
Indole
Amine
Time (min)
1
Product
Yieldb (%)
76
NHPh
CO2Et
NH2
N
H
N
3a
3a
H
1a
4a
4b
2
1
85
NHPh
CO2Et
N
N
1b
3
4
5
6
7
8
3a
3a
3a
3a
1
1
93
85
63
65
80
82
NHPh
CO2Et
N
H
N
H
1c
4c
NHPh
CO2Et
MeO
MeO
N
H
N
H
1d
4d
1
NHPh
CO2Et
Br
Br
N
H
N
H
1e
4e
1
NC
NHPh
CO2Et
NC
N
H
N
H
1f
4f
1a
30
40
NHBn
CO2Et
NH2
3b
3b
N
H
4g
1b
NHBn
CO2Et
N
4h
Synlett 2006, No. 1, 96–100 © Thieme Stuttgart · New York

98
J.-L. Zhao et al.
LETTER
Table 1 Three-Component Friedel–Crafts Reaction of Indoles, Ethyl Glyoxylate (2), and Aminesa (continued)
Entry
9
Indole
Amine
Time (min)
30
Product
Yieldb (%)
1c
3b
73
72
77
63
75
NHBn
CO2Et
N
H
4i
10
11
12
13
1e
3b
3b
3b
3b
30
30
30
40
NHBn
CO2Et
Br
N
H
4j
1d
NHBn
CO2Et
MeO
N
H
4k
4l
NHBn
CO2Et
N
H
Ph
N
H
Ph
1g
1h
NHBn
CO2Et
N
H
N
H
4m
14
15
3b
3c
40
60
70
61
NHBn
CO2Et
N
H
N
H
1i
4n
4o
1a
NH2
NH
CO2Et
N
H
16
1a
4 h
49c
NH2
NH
CO2Et
3d
N
H
4p
a Solvent-free and catalyst-free conditions at r.t.
b Isolated yield.
c Derivative 5a also formed in 20% yield.
Based on the above results, various indoles 1a–f were em- Table 1, entries 5 and 6). N-Methylindole (1b) also
ployed in the reaction with 2 and 3a (Scheme 1) affording showed good reactivity leading to 4b in high yield (82%).
the corresponding products in 63–93% yield. 2-Methylin- When benzylamine (3b) was used in the three-component
dole (1c) showed the highest reactivity to give 4c in excel- reaction instead of aniline (3a), the reaction times in-
lent yield (93%). The electronic effect of the substituent creased to 30–40 minutes. With a bulky group at C-2 of
on C-5 of the indole ring has an effect on the yields: elec- the indole, such as isopropyl 1i, the reaction was complete
tron-donating groups (such as methoxy group) gave a high in 40 minutes (70% yield). Allylamine 3c exhibited lower
yield (85%, Table 1, entry 4), while electron-withdrawing reactivity but gave alkylated product 4o in 61% yield. The
groups (Br, CN) afford relatively low yields (63–65%, yield of the reaction with alkylamine 3d was low even
Synlett 2006, No. 1, 96–100 © Thieme Stuttgart · New York

LETTER
Synthesis of (3-Indolyl)glycine Derivatives
99
Khrisnamurti, R.; Surya Prakashi, G. K. Comprehensive
Organic Synthesis, Vol. 3; Trost, B. M., Ed.; Pergamon:
New York, 1991, 293. (c) For a review on the
after a longer reaction time (49%), and was accompanied
by 5a (20% yield). It is noteworthy that ethyl 2-(1H-indol-
3-yl)-2-(benzylamino)acetate (4g) was obtained in 80%
yield in the three-component solvent-free and catalyst-
free reaction of 1a, 2, and 3b within 30 minutes. The syn-
thesis of the same compound by the reaction of 1a with
benzylimino glyoxylate in toluene gave 4g in 61% yield
(48 h);4 the solvent-free and catalyst-free three-compo-
nent reaction represents a more convenient method.
stereoselective Friedel–Crafts alkylation reaction, see:
Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem.
Int. Ed. 2004, 43, 550. (d) Review on alkylation of indoles,
see: Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi,
A. Synlett 2005, 1199.
(7) (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552.
(b) Chen, Y. J.; Ge, C.-S.; Wang, D. Synlett 2000, 1429.
(c) Jørgensen, K. A. Synthesis 2003, 1117. (d) Shirakawa,
S.; Berger, R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127,
2858.
(8) (a) Dessole, G.; Herrera, R. P.; Ricci, A. Synlett 2004, 2374.
(b) Török, B.; Abid, M.; London, G.; Esquibel, J.; Török,
M.; Mhadgut, S. C.; Yan, P.; Surya Prakash, G. K. Angew.
Chem. Int. Ed. 2005, 44, 3086.
The three-component reaction of 1a, 2, and 3b was also
carried out on a gram scale affording the product 4g in
78% yield14 (smaller scale, 80% yield). Although during
the scale-up reaction under solvent-free conditions an
exothermic phenomenon was observed, this did not in-
fluence the yield.
(9) (a) Tanaka, T. Solvent-free Organic Synthesis; Wiley-VCH:
Weinheim, 2003. (b) For a review, see: Cave, G. W. V.;
Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159.
(10) Anastas, P. T.; Warner, J. C. Green Chemistry—Theory and
Practice; Oxford University Press: New York, 1998.
(11) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Varma, R. S. Pure Appl. Chem. 2001, 73, 193.
(c) Gholap, A. R.; Venkatesan, K.; Daniel, T. Green Chem.
2004, 6, 147.
In conclusion, the solvent-free and catalyst-free three-
component Friedel–Crafts alkylation of indoles, amine,
and glyoxylate was developed for the convenient synthe-
sis of (3-indolyl)glycine derivatives.
The acceleration effect in the solvent-free reaction was at-
tributed to the concentration effect. Further mechanistic
investigations are underway in this respect.
(12) Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org.
Chem. 2001, 66, 4759.
(13) 4b: colorless oil. IR: 3399, 3051, 2981, 1732, 1602, 1547,
1504, 1239, 1185, 1023 cm–1. 1H NMR: d = 7.88 (d, J = 7.8
Hz, 1 H), 7.37–7.16 (m, 6 H), 6.77 (t, J = 7.3 Hz, 1 H), 6.70
(d, J = 8.6 Hz, 2 H), 5.44 (s, 1 H), 4.35–4.15 (m, 2 H), 3.75
(s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H). 13C NMR: d = 172.7, 146.7,
137.4, 129.3, 127.7, 126.4, 122.1, 119.7, 119.6, 118.1,
113.4, 111.0, 109.6, 61.6, 54.3, 32.9, 14.2. HRMS: m/z calcd
for C19H20N2O2 (M+): 308.1525, found: 308.1521.
4c: colorless oil. IR: 3400, 2958, 2870, 1729, 1602, 1503,
1460, 1306, 1200, 1020 cm–1. 1H NMR: d = 7.97 (s, 1 H),
7.83–7.81 (m, 1 H), 7.26–7.10 (m, 5 H), 6.74 (t, J = 7.2 Hz,
1 H), 6.65 (d, J = 7.8 Hz, 2 H), 5.30 (s, 1 H), 4.32–4.07 (m,
2 H), 2.43 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H). 13C NMR: d =
172.5, 146.7, 135.2, 133.4, 129.3, 126.8, 121.4, 119.9,
118.8, 118.0, 113.2, 110.6, 107.5, 61.5, 54.1, 14.2, 12.1.
HRMS: m/z calcd for C19H20N2O3 (M+): 308.1525, found:
308.1528.
General Procedure
To a stirred mixture of indole (1a, 35 mg, 0.3 mmol) and aniline (3a,
42 mL, 0.45 mmol) ethyl glyoxylate 2 (freshly distilled; 50 mg, 0.45
mmol) was added at ambient temperature. The reaction mixture was
stirred for 1 min. The crude product was purified by flash chroma-
tography on silica gel (petroleum ether–EtOAc, 4:1) to give ethyl 2-
(1H-indol-3-yl)-2-(phenylamino)acetate 4a4 as a colorless oil (66
mg, 75%) and ethyl 2-(1H-indol-3-yl)-2-hydroxyacetate (5a, 12
mg, 19%). (3-Indolyl)glycine derivatives were characterized by 1H,
13C NMR, and IR spectroscopy and HRMS or elemental analysis.13
Acknowledgment
We thank the National Natural Science Foundation of China
and Chinese Academy of Sciences for financial support.
4d: light yellow oil. IR: 3407, 2983, 2832, 1729, 1603, 1503,
1487, 1309, 1211, 1024 cm–1. 1H NMR: d = 8.24 (s, 1 H),
7.28–7.12 (m, 5 H), 6.89 (dd, J = 8.8, 2.4 Hz, 1 H), 6.76 (t,
J = 7.3 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 2 H), 5.37 (s, 1 H),
4.32–4.17 (m, 2 H), 3.88 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR: d = 172.8, 154.3, 146.7, 131.6, 129.4, 126.2,
123.9, 118.2, 113.5, 112.9, 112.0, 101.1, 61.6, 55.9, 54.4,
21.1, 14.2. HRMS: m/z calcd for C19H20N2O3 (M+):
324.1474, found: 324.1476.
4e: white solid; mp 123–125 °C. IR: 3409, 3381, 2985,
1710, 1602, 1506, 1455, 1314, 1270, 1021 cm–1. 1H NMR:
d = 8.27 (s, 1 H), 7.95 (d, J = 1.8 Hz, 1 H), 7.24 (dd, J = 8.6,
1.8 Hz, 1 H), 7.16–7.04 (m, 4 H), 6.72 (m, 1 H), 6.60 (dd,
J = 8.6, 1.0 Hz, 2 H), 5.29 (s, 1 H), 4.26–4.08 (m, 2 H), 1.20
(t, J = 7.1 Hz, 3 H). 13C NMR: d = 172.5, 146.4, 135.2,
129.4, 127.5, 125.4, 124.5, 122.2, 118.4, 115.3, 113.6,
113.3, 113.0, 112.1, 61.9, 54.2, 14.1. HRMS: m/z calcd for
C18H17N2O2 (M+): 372.0473, found: 372.0477.
References and Notes
(1) (a) Kawasaki, T.; Ohno, K.; Enoki, H.; Umemoto, Y.;
Sakamoto, M. Tetrahedron Lett. 2002, 43, 4245.
(b) Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.;
Inagawa, M.; Sakamoto, M. Org. Lett. 2000, 2, 3027.
(c) Yang, C. G.; Wang, J.; Tang, X. X.; Jiang, B.
Tetrahedron: Asymmetry 2002, 13, 383.
(2) Blaszczak, L. C.; Turner, J. US Patent, 4492694, 1985.
(3) Katz, A. H.; Demerson, C. A.; Shaw, C. C.; Asselin, A. A.;
Humber, L. G.; Conway, K. M.; Gavin, G.; Guinosso, C.;
Jensen, N. P.; Mobilio, D.; Noureldin, R.; Schmid, J.; Shah,
U.; Van Engen, D.; Chau, T. T.; Weichman, B. M. J. Med.
Chem. 1988, 31, 1244.
(4) Jiang, B.; Huang, Z.-G. Synthesis 2005, 2198; and references
cited therein.
(5) (a) Lei, F.; Chen, Y.-J.; Sui, Y.; Liu, L.; Wang, D. Synlett
2003, 1160. (b) Chen, Y. J.; Lei, F.; Liu, L.; Wang, D.
Tetrahedron 2003, 59, 7609.
4f: light yellow oil. IR: 3381, 2982, 2221, 1730, 1604, 1506,
1471, 1230, 1195, 1099 cm–1. 1H NMR: d = 8.65 (s, 1 H),
8.22 (s, 1 H), 7.44–7.43 (m, 2 H), 7.36 (d, J = 2.0 Hz,
(6) (a) Olah, G. A. Friedel–Crafts and Related Reactions, Vol.
III, Part 1; Interscience: New York, 1964. (b) Olah, G. A.;
Synlett 2006, No. 1, 96–100 © Thieme Stuttgart · New York

100
J.-L. Zhao et al.
LETTER
136.0, 128.4, 128.4, 127.1, 125.7, 122.9, 122.7, 120.4,
1 H),7.16–7.12 (m, 2 H), 6.75 (t, J = 7.3 Hz, 1 H), 6.63 (d,
J = 8.1 Hz, 2 H), 5.37 (s, 1 H), 4.30–4.11 (m, 2 H), 1.22 (t,
J = 7.1 Hz, 3 H). 13C NMR: d = 171.8, 146.0, 129.3, 125.7,
125.6, 125.5, 125.4, 120.5, 118.6, 113.8, 113.6, 112.4,
103.3, 62.1, 54.1, 14.1. HRMS: m/z calcd for C19H17N3O2
(M+): 319.1321, found: 319.1326.
120.1, 117.2, 113.8, 61.1, 57.6, 51.5, 16.6, 14.2. HRMS:
m/z calcd for C20H22N2O2 (M+): 322.1681, found: 322.1677.
4n: white solid; mp 98–99 °C. IR: 3403, 3182, 2960, 2858,
1729, 1495, 1460, 1301, 1221, 1183 cm–1. 1H NMR: d = 7.97
(s, 1 H), 7.74 (d, J = 7.3 Hz, 1 H), 7.30–7.22 (m, 6 H), 7.13–
7.07 (m, 2 H), 4.67 (s, 1 H), 4.23–4.00 (m, 2 H), 3.78 (d,
J = 13.2 Hz, 1 H), 3.72 (d, J = 13.2 Hz, 1 H), 3.24–3.13 (m,
1 H), 2.20 (s, 1 H), 1.29–1.26 (m, 6 H), 1.14 (t, J = 7.1 Hz, 3
H). 13C NMR: d = 173.2, 143.2, 140.0, 135.2, 128.3, 127.0,
126.8, 121.3, 119.8, 119.5, 110.5, 106.5, 60.9, 56.5, 51.0,
25.4, 23.2, 22.1, 14.1. HRMS: m/z calcd for C22H26N2O2
(M+): 350.1994, found: 350.1999.
4j: white solid; mp 117–119 °C. IR: 3311, 3280, 2978, 2835,
1732, 1565, 1452, 1230, 1196, 1099 cm–1. 1H NMR: d = 8.70
(s, 1 H), 7.82 (d, J = 1.8 Hz, 1 H), 7.35–7.22 (m, 6 H), 7.11–
7.07 (m, 2 H), 4.66 (s, 1 H), 4.26–4.11 (m, 2 H), 3.86 (d,
J = 13.0 Hz, 1 H), 3.81 (d, J = 13.0 Hz, 1 H), 2.60 (br s, 1 H),
1.23 (t, J = 7.1 Hz, 3 H). 13C NMR: d = 173.2, 139.1, 135.0,
128.6, 128.5, 127.7, 127.4, 125.2, 124.3, 122.1, 113.2,
112.9, 112.5, 61.4, 57.2, 51.7, 14.2. HRMS: m/z calcd for
C19H20N2O2Br (M + H): 387.0702, found: 387.0708.
4m: light yellow oil. IR: 3409, 2979, 2932, 1729, 1592,
1495, 1450, 1187, 1025, 747 cm–1. 1H NMR: d = 8.09 (s, 1
H), 7.56 (d, J = 7.6 Hz, 1 H), 7.36–7.22 (m, 6 H), 7.08–7.00
(m, 2 H), 4.70 (s, 1 H), 4.25–4.09 (m, 2 H), 3.84 (d, J = 13.0
Hz, 1 H), 3.79 (d, J = 13.0 Hz, 1 H), 2.46 (s, 3 H), 1.94 (s, 1
H), 1.21 (t, J = 7.1 Hz, 3 H). 13C NMR: d = 173.5, 139.7,
(14) The scale-up experiment was performed on a gram scale: To
a stirred mixture of 1a (1.0 g, 8.5 mmol) and benzylamine
(3b; 1.43 mL, 1.4 g, 12.8 mmol), 2 (1.3 g, 12.8 mmol) was
added at ambient temperature. The reaction mixture was
stirred for 40 min. The crude product was purified by flash
chromatography on silica gel (petroleum ether–EtOAc, 4:1)
to give ethyl 2-(1H-indol-3-yl)-2-(benzylamino)acetate
(4g,4 2.06 g, 78%).
Synlett 2006, No. 1, 96–100 © Thieme Stuttgart · New York