Three-component Fischer indole synthesis

Article abstract of DOI:10.1055/s-0030-1258037

Three-component coupling between acyl chlorides, diazonium salts, and alcohols or amines allows the formation of-hydrazono carboxylic acid derivatives which may be directly converted into indoles by a Fischer-type cylization. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258037

2296
LETTER
Three-Component Fischer Indole Synthesis
T
hree-Compone
a
nt Fischer
u
Indole
S
ynth
r
esis ent El Kaïm,* Laurence Grimaud,* Caroline Ronsseray
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, 75739 Paris Cedex 15, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: laurence.grimaud@ensta.fr
Received 24 June 2010
hydrazones could be directly transformed into indoles
Abstract: Three-component coupling between acyl chlorides, dia-
through a Fischer-type cyclization. Herein, we wish to
present our results on this study.
zonium salts, and alcohols or amines allows the formation of a-
hydrazono carboxylic acid derivatives which may be directly con-
verted into indoles by a Fischer-type cylization.
Before working on the Fischer cyclization, sets of alco-
Key words: indoles, Fischer, Japp–Klingeman, diazonium, hydra- hols and amines were evaluated as nucleophiles in the
zone, acid chloride, multicomponent reaction
three-component hydrazone formation. After addition of
an excess of pyridine to the acyl chloride in dichlo-
romethane, the diazonium salt was added at 0 °C and the
mixture stirred at room temperature for 2 hours. Then, the
resulting acyl pyridinium salt was transformed into an
ester or an amide by the addition of 1–1.2 equivalents of
an alcohol or an amine. Under these optimized conditions,
various hydrazones can be synthesized in moderate yields
(Scheme 1).
Indoles certainly represent one of the most important het-
erocyclic families.1 The search for new approaches to this
bicyclic core has constantly been triggered by the impres-
sive diversity of its biological activities.2 Among the nu-
merous methods available, the early Fischer indole
synthesis has always been the most relevant.3 More recent
trends in indole synthesis have focused on the use of orga-
nometallic processes4 as well as the disclosure of new
multicomponent synthetic pathways for high-throughput
screenings.5
Before trying to perform the direct conversion of these hy-
drazones into indoles from the crude mixture, the condi-
tions for the Fischer reaction had to be optimized working
with the pure hydrazones. Different sets of acidic condi-
tions were tested for this purpose: the addition of AlCl3,
BF3·OEt2 was attempted in refluxing dichloromethane but
failed to give any product. However, on heating the hydra-
zones in acetic acid as solvent, the expected indoles were
obtained quite efficiently. Optimum conditions involved
heating the hydrazones over 100 °C for several hours
(Scheme 2). It is worth noting that the reaction can be car-
ried out under microwave irradiation (100 W, 120 °C)
within 10 minutes for ester derivatives, but complex mix-
tures are obtained with amides under such conditions.
A few years ago, we reported a convenient access to a-
hydrazono carboxylic acid derivatives by addition of dia-
zonium salts to acyl chlorides (Scheme 1).6 The reaction
may be related to a Japp–Klingeman coupling7 as the dia-
zonium salt is trapped by the carbanion derived from the
deprotonation of the acylpyridinium. The resulting aza-
ketene intermediate rearranges, and finally a nucleophile
is added to trap the acyl moiety. The whole process might
be considered as a three-component coupling even if most
examples reported involved ethanol as the final nucleo-
phile. Therefore, we decided to benefit from this former
work to develop a new multicomponent access to indole
derivatives. Indeed, under acidic conditions, the resulting
Next, we decided to evaluate the three-component forma-
tion of indoles through sequential diazonium coupling and
Fischer cyclization wherein, after completion of the first
O
O
O
N
–
ArN2+ BF4
(3 equiv)
R1
N
R1
XR2
R1
Cl
–
then R2XH
CH2Cl2
N
NHAr
X = O, NR2
O
O
O
O
Ph
NAll2
Ph
OBn
NEt2
Ph
OEt
N
N
N
N
NH(4-ClC6H4)
60%
NH(4-FC6H4)
52%
NH(4-ClC6H4)
65%
NH(4-ClC6H4)
63%
Scheme 1 Hydrazone synthesis
SYNLETT 2010, No. 15, pp 2296–2298
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258037; Art ID: D16410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Three-Component Fischer Indole Synthesis
2297
Table 1 Synthesis of Various Functionalized Indoles (continued)
H
N
O
O
1.
OEt
O
O
Cl
OEt
AcOH
12 h
N
N
R1
XR2
R1
Cl
2. ArN2+BF4
3. R2XH
–
NHAr
Ar = 4-ClC6H4
N
NHAr
Ar = 4-ZC6H4
100 °C: 50%
110 °C: 90%
H
N
O
Scheme 2 Fischer synthesis
AcOH
reflux
XR2
Z
R1
step, the dichloromethane was evaporated, acetic acid was
added, and the mixture refluxed overnight. Following this
one-pot, two-step procedure, various functionalized in-
doles could be synthesized, starting from an aromatic or
an aliphatic acyl chloride and using either an alcohol or an
amine as the trapping agent. This method affords a
straightforward access to polysubstituted indoles in mod-
erate to good yields as outlined in Table 1.
X = O, NR3
Entry
5
R1
XR2
Z
F
Product, yield
H
N
O
Ph
Ph
Ph
Ph
Me
NHCy
OEt
NHCy
F
Ph
34%
Table 1 Synthesis of Various Functionalized Indoles
H
O
N
1.
6
7
8
9
Cl
Cl
Cl
Cl
O
O
OEt
Cl
N
Ph
R1
XR2
R1
Cl
2. ArN2+BF4
3. R2XH
–
47%
N
NHAr
Ar = 4-ZC6H4
H
O
N
OBn
NAll2
NEt2
H
N
OBn
O
Cl
AcOH
reflux
Ph
XR2
36%
Z
R1
H
O
N
X = O, NR3
R1
XR2
Z
F
Product, yield
NAll2
Entry
1
Cl
Ph
H
N
51%
O
H
N
O
Ph
OMe
OMe
OMe
F
Ph
NEt2
Cl
60%
H
N
48%
O
H
N
O
2
3
4
Me
F
F
F
OMe
F
10
Ph
NEt2
Cl
NEt2
Cl
63%
Ph
H
N
43%
O
O
F
The simplicity of the procedure compensates for the rela-
tively moderate overall yields of the isolated compounds,
which represent such important scaffolds. If proper di-
functional acyl chlorides and amines (or alcohols) are
chosen in the initial three-component coupling, further cy-
clizations involving the initial Fischer adducts may lead to
highly complex indole derivatives. Our research group is
currently working on such possibilities as well as oxida-
tive cyclizations onto indoles.
Ph
Ph
OCH2-cPr
Ph
39%
H
O
N
OBn
OBn
F
Ph
39%
To a CH2Cl2 solution of acid chloride (0.25 M) was added pyridine
(3 equiv). After 10 min, the mixture was cooled at 0 °C and the di-
azonium salt (1.1 equiv) added. The solution was stirred for 10 min
at 0 °C and then 2 h at r.t. The nucleophile was added (1.2 equiv),
Synlett 2010, No. 15, 2296–2298 © Thieme Stuttgart · New York

2298
L. El Kaïm et al.
LETTER
(2) (a) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22,
and the mixture was stirred at r.t. for a further 2 h. The CH2Cl2 was
evaporated in vacuo, the residue dissolved in AcOH (0.25 M) and
the solution heated at reflux temperature overnight. The solvent was
removed by evaporation, and the crude product purified by silica gel
flash column chromatography eluting with a mixture of PE–Et2O
(for amides) or CH2Cl2 (for esters)–Et3N (1%).
761. (b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21,
278.
(3) (a) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16,
2241. (b) Fischer, E.; Hess, O. Ber. Dtsch. Chem. Ges. 1884,
17, 559. (c) Robinson, B. The Fischer Indole Synthesis; John
Wiley and Sons: Chichester, 1982. (d) Hughes, D. L. Org.
Prep. Proced. Int. 1993, 25, 607.
Representative Analytical Data
Methyl 5-Fluoro-3-phenyl-1H-indole-2-carboxylate
1H NMR (400 MHz, CDCl3): d = 9.05 (s, 1 H), 7.55 (d, J = 7.8 Hz,
2 H), 7.49 (dd, J = 7.8, 7.3 Hz, 2 H), 7.44–7.41 (m, 1 H), 7.40 (dd,
J = 9.0 Hz, JH–F = 4.8 Hz, 1 H), 7.30 (dd, JH–F = 8.8 Hz, J = 2.5 Hz,
1 H), 7.15 (ddd, J = 9.0 Hz, JH–F = 8.8 Hz, J = 2.8 Hz, 1 H), 3.85 (s,
(4) For recent reviews, see: (a) Patil, S.; Buolamwini, J. K.
Curr. Org. Synth. 2006, 3, 477. (b) Cacchi, S.; Fabrizi, G.
Chem. Rev. 2005, 105, 2873. For selected recent examples,
see: (c) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826.
(d) Zhao, J.; Larock, R. J. Org. Chem. 2006, 71, 5340.
(5) For a review, see: (a) Campo, J.; Garcia-Valverde, M.;
Marcaccini, S.; Rojo, M. J.; Torroba, T. Org. Biomol. Chem.
2006, 4, 757. For recent examples, see: (b) Kalinski, C.;
Umkehrer, M.; Schmidt, J.; Ross, G.; Kolb, J.; Burdack, C.;
Hiller, W.; Hoffmann, S. D. Tetrahedron Lett. 2006, 47,
4683. (c) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F.
Org. Lett. 2007, 9, 4223. (d) Ohno, H.; Ohta, Y.; Oishi, S.;
Fujii, N. Angew. Chem. Int. Ed. 2007, 46, 2295.
(e) Barluenga, J.; Jimenez-Aquino, A.; Valdes, C.; Aznar, F.
Angew. Chem. Int. Ed. 2007, 46, 1529. (f) Leogane, O.;
Lebel, H. Angew. Chem. Int. Ed. 2008, 47, 350; and
references cited herein.
3 H). 13C NMR (100.6 MHz, CDCl3): d = 162.5, 158.9 (d, JC–F
=
234.9 Hz), 133.4, 132.7, 130.7, 128.6 (d, JC–F = 10.2 Hz), 128.4,
127.9, 124.6 (d, JC–F = 5.1 Hz), 124.3, 115.5 (d, JC–F = 27.1 Hz),
113.1 (d, JC–F = 10.3 Hz), 106.5 (d, JC–F = 24.2 Hz), 52.3. IR (thin
film): 1685, 1537, 1497, 1458, 1344 cm–1. HRMS: m/z calcd:
269.0852; found: 269.0855.
Acknowledgment
C.R. thanks the Ecole Polytechnique for a fellowship. Financial
support was provided by the ENSTA.
(6) Atlan, V.; El Kaim, L.; Supiot, C. Chem. Commun. 2000, 15,
1385.
References
(7) (a) Phillips, R. R. Org. React. 1959, 60, 144. For selected
examples of Japp–Klingemann/Fisher indole syntheses,
see: (b) Chen, Y.; Shibata, M.; Rajeswaran, M.; Srikrishnan,
T.; Dugare, S.; Pandey, R. K. Tetrahedron Lett. 2007, 48,
2353. (c) Pete, B. Tetrahedron Lett. 2008, 49, 2835.
(d) Heinrich, T.; Böttcher, H. Bioorg. Med. Chem. Lett.
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(1) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045. (b) Sundberg, R. J. The Chemistry of Indoles;
Academic Press: New York, 1970. (c) Sundberg, R. J.
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