A novel one-pot synthesis of highly diverse indole scaffolds by the Ugi/Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2006.04.127

A novel one-pot two-step multi component reaction of acrylic aldehydes, bromoanilines, acids and isocyanides yielding polysubstituted indoles is described. The reaction is based on the combination of an Ugi four-component reaction followed by an intramole

Full text of DOI:10.1016/j.tetlet.2006.04.127

Tetrahedron Letters 47 (2006) 4683–4686
A novel one-pot synthesis of highly diverse indole scaffolds by the
Ugi/Heck reaction
a,b,
a
a
a
a
*
´
Cedric Kalinski,
Michael Umkehrer, Jurgen Schmidt, Gunther Ross, Jurgen Kolb,
¨ ¨ ¨
Christoph Burdack,a Wolfgang Hillerb and Stephan D. Hoffmannb
aPriaton GmbH, Bahnhofstr. 9-15, D-82327 Tutzing, Germany
bTechnical University Munich, Lichtenbergstr. 4, D-85747 Garching, Germany
Received 21 March 2006; revised 18 April 2006; accepted 26 April 2006
Available online 19 May 2006
Abstract—A novel one-pot two-step multi component reaction of acrylic aldehydes, bromoanilines, acids and isocyanides yielding
polysubstituted indoles is described. The reaction is based on the combination of an Ugi four-component reaction followed by an
intramolecular Heck-reaction. The simultaneous use of formic acid and cinnamaldehydes affords in situ generation of 1H-indoles.
Convertible isocyanides can also be used with success in this Ugi/Heck strategy and enable synthesis of 1H-indole-2-carboxylic acid
building blocks.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Multi-component reactions (MCRs) are widely em-
ployed for the rapid assembly of compound arrays with
high molecular diversity. Coupled with a post-condensa-
tion modification, their utility is increased even further,
giving rise to numerous pharmacologically important
scaffolds.1–3
Gracias5 and Xiang6 is very wide and enables many
new applications.
Thus, we present herein the synthesis of new substituted
dihydro-indoles involving 2-bromoanilines 1a–b and
acrylic aldehydes 2a–b as starting materials in the
Ugi-reaction (Scheme 1).
In the course of our ongoing research on new post-con-
densation modifications, we recently reported that the
combination of the Ugi-four component reaction and
the Heck reaction yields highly substituted indol-2-ones
in a one-pot solution phase procedure.4 The potential of
the Ugi–Heck reaction developed at the same time by
The formation of the acyclic products (5) was originally
reported by Ugi et al. and the final ring-closing was per-
formed by a classical intramolecular Heck-reaction7–11
(Scheme 1). These two reaction steps were combined
in a new one-pot synthesis.
R2
R2
H
NH2
Br
CHO
N
R4
1a.U-4CR
1b.Heck
Br
N
R 4 NC
R3 COOH
+
+
+
R2
H
N
N
O
R1
R4
R1
3a-c
4a-c
R1
2a-b
R3
1a-b
O
O
O
R3
2a, R2:C6H5
2b, R2:CH3
3a, R3:CH3
3b, R3:C6H5
3c, R3:H
1a, R1:H
1b, R1:4-F
4a, R4:C(CH3)3
4b, R4:CH2C6H5
4c, R4:CH2CO2CH3
6a-f
5
Scheme 1. Ugi–Heck synthesis of substituted indoles.
Keywords: Ugi–reaction; Ugi–Heck reaction; Indole; Isocyanide-based multi-component reactions (IMCRs); Combinatorial chemistry.
*
Corresponding author. Tel.: +49815890400; fax: +498158904022; e-mail addresses: kalinski@priaton.de; umkehrer@priaton.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.127

4684
C. Kalinski et al. / Tetrahedron Letters 47 (2006) 4683–4686
The Ugi–Heck reaction was performed in a typical pro-
cedure,12 whereby the starting materials were mixed in
equimolar amounts and stirred for 24–48 h at room tem-
perature. Afterwards solvent was changed from polar
protic to polar aprotic and 10% of Pd-catalyst was
added. The reaction mixture was stirred for additional
24 h at 80 ꢁC. The expected compounds (6a–f) were iso-
lated as isomeric mixtures with moderate to good yields
(Table 1). They were characterized by 1H NMR,
13C NMR and HPLC-MS data. All the synthesized
compounds had purities >95%. The used bromoanilines,
acids, acrylic aldehydes and isocyanides could be varied
broadly, producing products with four potential points
of diversity.
moderate to good yields. Following this new reaction
strategy, we synthesized different 1H-indoles (7a–h)
from substituted 2-bromoanilines 1a–b, cinnamaldehy-
des 2a,c and diverse isocyanides 4a–e (Table 2). The
resulting compounds were successfully isolated with
moderate to good yields and their assignments were
1
made on the basis of H NMR, 13C NMR and HPLC-
MS data. All the synthesized compounds had purities
>95%. Scheme 3 shows the result of the X-ray crystal
structure analysis of compound 7a which confirms the
spectroscopic results.15b
This versatile reaction offers many advantages. The use
of substituted 2-bromoanilines allows further derivatisa-
tion of the 1H-indole scaffold. Particularly, the reaction-
sequence tolerates the use of ‘convertible’ isocyanides
4d–e. These isocyanides originally reported by Arm-
strong et al.18,19 are cleavable under acidic conditions
and can generate a plethora of outgoing products via
To our delight, we also found a new access to the syn-
thesis of substituted 1H-indoles by involving cinamalde-
hydes 2a and 2c and formic acid 3c in our one-pot
procedure (Scheme 2). Under the conditions of the
Heck-reaction, the resulting formic group was partially
cleaved. Successive isomerisation led to 1H-indoles with
a munchnone mechanism. As illustrated, we cleaved
¨
the isocyanide moiety of compounds (7g–h) to synthe-
Table 1. Ugi–Heck synthesis of substituted indoles
Bromoanilines 1
Acrylic aldehydes 2
Carboxylic acids 3
Isocyanides 4
(%)
Product
1a
1a
1a
1a
1a
1b
2a
2a
2a
2a
2b
2b
3a
3a
3a
3b
3a
3c
4a
4b
4c
4a
4a
4a
43
27
25
33
19
48
6a13
6b
6c14
6d
6e
6f
R5
R5
NH2
R5
O
1a. U-4CR
R4 NC
Br
O
O
O
+
+
+
+
R1
OH
R3
R1
1b. Heck
R1
N
H
N
H
R4
N
N
H
R4
O
H
4a-e
3c, R3:H
1a-c
2a, 2c
7a-h
6g-n
4a, R4:C(CH3)3
2a, R5:H
2c, R5:4-OCH3
4b, R4:CH2C6H5
4c, R4:CH2CO2CH3
4d, R4:1-cyclohexen-1-yl
4e, R4:4-phenyl-1-cyclohexen-1-yl
Scheme 2. 1H-Indoles 7a–h synthesized from cinnamaldehydes and formic acid by the Ugi–Heck reaction.
Table 2. Synthesized 1H-indoles
Bromoanilines 1
Cinnamaldehydes 2
Isocyanides 4
(%)
Product
1a
1a
1a
1a
1c
1b
1a
1a
2a
2a
2a
2c
2a
2a
2a
2a
4b
4a
4c
4a
4b
4b
4d
4e
21
17
15
23
31
38
29
32
7a15a
7b
7c
7d
7e16
7f
7g17
7h

C. Kalinski et al. / Tetrahedron Letters 47 (2006) 4683–4686
4685
5. Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett.
2004, 45, 417.
6. Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.;
Chen, J.; Yang, Z. Org. Lett. 2004, 6, 3155.
7. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
8. Krause, N. Metallorganische Chemie, 1996; Spektrum
Akad. Verl.
9. Dounay, A. B.; Overmann, L. E. Chem. Rev. 2003, 103,
2945.
10. Terpko, M. O.; Heck, R. F. J. Am. Chem. Soc. 1979, 101,
5281.
11. Mori, M.; Ban, Y. Tetrahedron Lett. 1979, 20, 1133.
12. Typical Procedure: Aldehyde (3 mmol) and amine
(3 mmol) were stirred in 5 ml 2,2,2-trifluoroethanol for
1 h at room temperature. Then 3 mmol acid and 3 mmol
isocyanide were added. The reaction mixture was stirred
for 1–3 days at room temperature until the reaction was
completed (Indication by TLC). After the reaction was
completed, the solvent was evaporated and the resulting
residue was dissolved in 5 ml acetonitrile and 0.3 mmol
Pd(OAc)2 and 0.6 mmol PPh3 were added. The reaction
mixture was stirred for additional 16–24 h at 80 ꢁC.
Afterwards, the solvent was evaporated again, the result-
ing residue was dissolved in ethyl acetate and filtered
through a pad of silica. The resulting crude product was
purified by crystallisation from ethanol or by column
chromatography on silica gel (hexane/ethyl acetate).
13. Compound 6a was isolated in 43% yield as a beige solid.
1H (DMSO, 250.13 MHz): 0.89 (s, 9H, C–(CH3)3, 2.20 (s,
3H, CH3–C@O), 5.75 (s, 1H, CH–C@O), 6.08 (s, 1H,
C@CH–C6H5), 7.05–7.45 (m, 7H, ar), 7.62–7.65 (m, 2H,
ar). 13C (DMSO, 62.89 MHz): 23.87 (CH3–C@O), 27.38
(C–(CH3)3), 50.30 (C–(CH3)3), 65.38 (CH), 116.32
(C@CH–C6H5), 119.20, 119.94, 123.38, 127.23, 128.46,
128.54, 129.32, 130.48, 134.79, 135.94, 144.87 (ar), 165.00
(CH3–C@O), 168.37 (CONH). MS (ESI): m/z = 349
[M+H]+, 371 [M+Na]+. Mp: 194.6 ꢁC.
Scheme 3. Result of the X-ray analysis of compound 7a.
5 eq AcCl
7g
O
O
MeOH, 50 °C
8
N
H
HCl aq.
THF, r.t.
OH
7h
9
N
O
H
Scheme 4. Synthesis of 1H-indole building blocks by the use of
convertible isocyanides.
14. Compound 6c was isolated in 19% yield as a brown solid.
1H (DMSO, 250.13 MHz): 2.36 (s, 3H, CH3–C@O), 3.54
3
(s, 3H, COOCH3), 3.64 (d, 2H, J = 5.53 Hz, NH–CH2–
size the corresponding carboxylic acid20 9 and ester 8
(Scheme 4).
COOCH3), 5.72 (s, 1H, CH–C@O), 6.10 (s, 1H, C@CH–
C6H5), 7.09–7.42 (m, 9H, ar), 8.28 (t, 1H, 3J = 5.53 Hz,
NH–CH2–COOCH3). MS (ESI): m/z = 365 [M+H]+, 387
[M+Na]+.
The resulting 1H-indole-2-carboxylic acid derivatives
constitute pharmacologically relevant building blocks
due to their diverse expansion potential by alkylation
or amide formation.
15. (a) Compound 7a was isolated in 21% yield as a white
solid. 1H (CDCl3, 250.13 MHz): 4.33 (s, 2H, Ph–CH2–
C@C), 4.48 (d, 2H, 3J = 5.37 Hz, NH–CH2–C6H5), 6.12
(s, 1H, NH–CH2–C6H5), 7.04–7.09 (m, 4H, ar–H), 7.14–
7.16 (m, 4H, ar–H), 7.19–7.35 (m, 4H, ar–H); 7.43 (d, 1H,
3J = 8.22 Hz, ar–H), 7.65 (d, 1H, 3J = 8.06 Hz, ar–H),
9.29 (s, 1H, NH). 13C (CDCl3, 62.89 MHz): 30.21 (C6H5–
CH2–C@C), 43.95 (NH–CH2–C6H5), 111.85, 114.65,
119.98, 120.36, 124.80, 126.78, 127.52, 127.76, 127.99,
128.04, 128.70, 129.01, 129.06, 135.16, 137.49, 139.22 (ar),
161.84 (C@O). MS (ESI): m/z = 341 [M+H]+, 364
[M+Na]+. Mp: 171.6 ꢁC. (b) A colourless needle of 7a,
1.00 · 0.05 · 0.05 mm, was analyzed with a Oxford-Dif-
fractions Excalibur3 diffractometer with Mo-Ka source
In summary, a novel one-pot two-step solution phase
procedure based on the combination of the Ugi- and
the Heck-reaction for the preparation of highly substi-
tuted dihydro-indoles, 1H-indoles and 1H-indole-2-car-
boxylic acid building blocks has been reported.
Current efforts are now focused on the development of
new pharmacological scaffolds based on the combina-
tion of combinatorial and classical chemistry.
˚
(0.71073 A). p- and x-scans with Dp/Dx = 1ꢁ with a
2hmax = 40.5ꢁ were used. The data collection was per-
formed at 120 2 K. Compound 5a crystallizes in the
monoclinic space group C2/c. The unit cell parameters are:
References and notes
˚
a = 28.419(2), b = 4.8960(3), c = 27.529(2) A, b =
3
˚
1. Do¨mling, A. Combinat. Chem. High Throughput Screening
1998, 1, 1.
2. Do¨mling, A.; Ugi, I. Angew. Chem. Int. Ed. 2004, 39, 3168.
3. Do¨mling, A. Chem. Rev. 2006, 106, 17.
4. Umkehrer, M.; Kalinski, C.; Kolb, J.; Burdack, C.
Tetrahedron Lett. 2006, 47, 2391.
112.32(1)ꢁ, V = 3543.4(4) A , Z = 8, qcalc = 1.276 g cmÀ3
,
F(000) = 1440. The data were collected in the h k l range
À27 to 27, À4 to 4, À26 to 26; 1727 reflections with
I > 2r(I) were measured. Non-hydrogen atoms were
refined anisotropically by full-matrix least-squares meth-
ods on F2. The positions of the hydrogen atoms were

4686
C. Kalinski et al. / Tetrahedron Letters 47 (2006) 4683–4686
determined geometrically and refined using the riding
cyclohexyl), 4.39 (s, 2H, CH2–C6H5), 5.25 (t, 1H,
3J = 4.03 Hz, C@CH cyclohexenyl), 6.68 (s, 1H, C(O)–
NH), 7.09–7.31 (m, 7H, ar), 7.44 (d, 1H, 3J = 8.22 Hz, ar),
7.62 (d, 1H, 3J = 8.06 Hz, ar), 9.68 (s, 1H, NH). 13C
(CDCl3, 62.89 MHz): 21.88, 22.42, 24.01, 27.65 (CH2
cyclohexenyl), 30.07 (CH2–C6H5), 111.99, 113.32, 113.74
(Cq), 119.90, 120.29, 124.72, 127.04, 128.23, 128.91 (Cq),
129.10 (Cq), 129.13, 132.42 (Cq), 135.46 (Cq), 139.13 (Cq)
(ar), 160.12 (C@O). MS (ESI): m/z = 331 [M+H]+, 353
[M+Na]+.
model. One phenyl group is disordered and was refined
using a split model for the atomic positions (C19, C20
C22, C23). Final R = 0.066, Rw = 0.141 for all observed
reflections. Crystallographic data (excluding structure
factors) have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication No.
CCDC 600942. Further details on the crystal structure
investigation may be obtained from the Cambridge
Crystallographic Data Centre free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB12EZ, UK
(fax: (+44) 1223 336 033; e-mail: deposit@ccdc.cam.
ac.uk), quoting the depository number.
18. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996,
118, 2574.
19. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995,
117, 7842.
16. Compound 7e was isolated in 31% yield as a white solid.
1H (CDCl3, 215.13 MHz): 2.44 (s, 3H, C6H5–CH3), 4.30
(s, 2H, C6H5–CH2–C@C), 4.48 (d, 2H, 3J = 5.52 Hz, NH–
CH2–C6H5), 6.11 (s, 1H, NH–CH2–C6H5), 7.04–7.08 (m,
4H, ar–H), 7.12–7.16 (m, 4H, ar–H), 7.25–7.33 (m, 4H, ar–
H), 7.42 (s, 1H, ar–H), 9.36 (s, 1H, NH). 13C (CDCl3,
62.89 MHz): 21.58 (CH3–C6H5), 30.19 (C6H5–CH2–
C@C), 43.95 (NH–CH2–C6H5), 111.61, 114.17, 119.26,
126.71, 126.74, 127.50, 127.75, 128.06, 128.70, 129.00,
129.27, 129.66, 133.66, 137.57, 139.36 (ar), 162.00 (C@O).
MS (ESI): m/z = 355 [M+H]+, 377 [M+Na]+. Mp:
196.1 ꢁC.
20. Compound 9 was prepared as follows: 60 mg (0.15 mmol)
of 7h were dissolved in 4 mL of a solution of THF/water
9/1. The mixture was stirred over night at room temper-
ature. Then, 15 mL methylene chloride were added and
the resulting organic layer was washed with brine and
dried over magnesium sulfate. The crude product was
washed with cold chloroform to yield 9 (29 mg, 77%) as a
1
white solid. H (DMSO, 250.13 MHz): 4.45 (s, 2H, CH2–
C6H5), 6.98 (dt, 1H, 3J = 7.18, 4J = 0.63 Hz, ar), 7.09–7.40
3
(m, 7H, ar), 7.55 (d, 1H, J = 8.05 Hz, ar), 11.22 (s, 1H,
NH). 13C (DMSO, 62.89 MHz): 24.52 (CH2–C6H5),
106.93, 113.31 (Cq), 114.26, 115.08, 118.81, 120.51,
122.22 (Cq), 122.41 (Cq), 123.05, 123.29, 130.30 (Cq),
136.72 (Cq), 158.59 (C@O). MS (ESI): m/z = 250 [MÀH].
17. Compound 7g was isolated in 29% yield as a white solid.
1H (CDCl3, 215.13 MHz): 1.49–1.64 (m, 4H, cyclohex-
enyl), 1.77–1.79 (m, 2H, cyclohexenyl), 2.06–2.09 (m, 2H,