A microwave-assisted, propylphosphonic anhydride (T3P) mediated one-pot Fischer indole synthesis

Article abstract of DOI:10.1016/j.tetlet.2011.06.053

A rapid, mild, and high yielding protocol for the Fischer indolization of arylhydrazines with T3P under microwave irradiation is described. Significant features of this method include short reaction times and preparative ease.

Full text of DOI:10.1016/j.tetlet.2011.06.053

Tetrahedron Letters 52 (2011) 4417–4420
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ò
A microwave-assisted, propylphosphonic anhydride (T3P ) mediated
one-pot Fischer indole synthesis
⇑
Matthieu Desroses, Krzysztof Wieckowski, Marc Stevens, Luke R. Odell
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
A rapid, mild, and high yielding protocol for the Fischer indolization of arylhydrazines with T3PÒ under
microwave irradiation is described. Significant features of this method include short reaction times and
preparative ease.
Article history:
Received 9 March 2011
Revised 23 May 2011
Accepted 13 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Fischer indole
Microwave
Propylphosphonic anhydride
Heterocycles
Ò
Propyl phosphonic acid cyclic anhydride (T3P , see Table 1) is
an efficient and mild amide coupling reagent and water scavenger,
morillonite clay) have been reported to catalyze the Fischer indole
1
8
synthesis. However, despite their common use, most reported
methods to prepare these heterocycles suffer from long reaction
times and often require the use of strongly acidic media and a large
excess of the acid catalyst. Consequently, new mild and expedient
protocols for this valuable and widely utilized reaction are of sig-
nificant importance.
1
which has attracted significant interest over the past few years.
This is due to its broad functional group tolerance, low toxicity,
and low epimerization tendency and easy work-up procedures.
Accordingly, a variety of new applications have been developed
for this reagent, including the direct conversion of carboxylic acids,
2
3
Ò
amides, and aldehydes into nitriles, the formation of isonitriles
from formamides, the synthesis of alkenes from alcohols, the
T3P has been identified as a mild water scavenger, but its syn-
3
a
4
thetic utility has not been investigated in the synthesis of indole
derivatives. Herein we report an efficient and operationally simple
one-pot synthesis of indole and tetrahydrocarbazole analogues
5
6
amidation of carboxylic acids, oxidation of alcohols, ester synthe-
sis, C–C coupling reactions,8 the formation of Weinreb amides,
7
9
10
11
Ò
the conversion of carboxylic acids into acid azides, the Lossen
and Beckmann rearrangements, and the preparation of several
using T3P .
1
2
The model reaction between phenylhydrazine (1a, 1.0 equiv)
substituted heterocycles.1
3–15
and cyclohexanone (2b, 1.0 equiv) in the presence of T3P (50%
Ò
The indole nucleus is a versatile heterocyclic system, occurring
in a variety of compounds with a broad spectrum of biological
solution in EtOAc) was used as a starting point for our investiga-
tion. The reaction mixture was heated at 70 °C under microwave
irradiation for 30 min with 1.25 equiv of T3PÒ (Table 1, entry
1). To our delight, this reaction provided full conversion of 1a into
the desired indole product 3a. With the aim of further reducing the
reaction time, optimization of the reaction conditions was per-
formed. Fine-tuning of the reaction conditions (time, temperature,
1
6
19
activities. Consequently, indole and its myriad of derivatives con-
tinue to capture the attention of organic and medicinal chemists
and a variety of well established methods are now available for
1
7
their production. Amongst these, the Fischer indole synthesis
from ketones and arylhydrazines is the most widely employed syn-
thetic procedure, especially for the large scale production of bio-
logically active compounds. This reaction involves an acid-
catalyzed 3,3-sigmatropic rearrangement of an N-arylhydrazone
intermediate followed by the elimination of ammonia. Several
Ò
and the amount of T3P ; see Table 1) led to a reliable protocol,
which furnished full conversion of 1a after only 5 min of micro-
wave irradiation at 100 °C. Moreover, the isolated yield from this
reaction was excellent (90%, Table 2, entry 1).
Ò
Brönsted acids (H
acids (ZnCl , TiCl
2
SO
, BiNO
4
, HCl, PPA, AcOH, TsOH, ionic liquids), Lewis
, Sc(OTf) ), and solid acids (zeolite, Mont-
To validate that the Fischer indolization was mediated by T3P
2
4
3
3
and not via a thermal process, a control experiment without the
addition of T3PÒ was performed. As expected, simply heating 1a
and 2a at 100 °C in ethyl acetate for 5 min showed no traces of ind-
⇑
Corresponding author. Tel.: +46 184714297; fax: +46 184714474.
E-mail address: luke.odell@orgfarm.uu.se (L.R. Odell).
Ò
olization (LC/MS analysis). Subsequent addition of T3P (1 equiv)
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.053

4
418
M. Desroses et al. / Tetrahedron Letters 52 (2011) 4417–4420
Table 1
Table 2 (continued)
Screening of reaction conditions
O
Entry Ketone/
aldehyde
Product
T (°C)
Time
(min)
Yield
(%)
H
T3P®
N
NH2
+
EtOAc, MW
Pr
N
H
3a
O
P
1
a
2a
1 equiv
1
equiv
O
P
Pr
O
P
T3P =
Pr
O
O
O
N
H
Entry
T3PÒ (equiv)
Time (min)
T (°C)
Conversiona (%)
3
h
1
2
3
4
5
6
7
8
9
1.25
0.5
1
1
1
30
30
5
5
5
5
8
5
70
70
70
90
100
100
100
100
100
100
90
50
95
100
90
O
85c
9
1
110
110
15
15
N
H
3i
2
i
0.8
0.8
O
92
b
c
0
0
0
75c
0
2j
b
c
0
then 1
2 ꢀ 5
then 95
N
H
a
b
c
3j
Determined by LC/MS analysis.
Reaction in the absence of T3P .
Only the intermediate hydrazone was observed.
Ò
O
1
1
1
2
N
H
3k
110
130
15
15
96c
2
k
O
Table 2
2
CO Me
CO
2
Me
Synthesis of indole derivatives from 1a and various ketones and aldehydes
90c
N
R2
2l
H
H
N
O
3l
T3P (1-1.25 equiv)
EtOAc, MW
R2
R1
NH
2
+
R
1
O
N
H
1
a
2a-m
1 equiv
0.55 mmol
3a-m
2m
82c
1
3
140
10
1
0
equiv
.55 mmol
N
H
3
m
Entry Ketone/
aldehyde
Product
T (°C)
Time
(min)
Yield
(%)
a
b
c
1 equiv of T3PÒ employed.
Reaction conducted on a 5 mmol scale.
.25 of equiv of T3P employed.
O
Ò
1
9
98
0a
1
100
5
b
N
H
2
a
3
a
O
to the reaction mixture and heating for an additional 5 min, affor-
ded the indole product (Table 1, entry 9) confirming the crucial role
of T3PÒ in promoting this reaction.
Encouraged by these results, this procedure was then further
evaluated for its scope and general applicability. To this end, a vari-
ety of ketone and aldehyde substrates were examined and the re-
sults are presented in Table 2. Although the reaction proceeded
well with 4-tert-butylcyclohexanone (2b) a longer reaction time
was needed (10 min) to achieve full conversion (entry 2). The use
of other cyclic and branched ketone substrates also required a
slight adjustment of the conditions. Linear ketones such as pen-
tan-3-one (2c) and methyl ethyl ketone (2d) gave the correspond-
ing indoles in good yields (entries 3 and 4) after heating at 110 °C
for 15 min. Cyclopentanone (2e) and propiophenone (2f) both per-
formed well, affording 76% and 75% yields of the desired products
2
100
10
95a
N
H
3
2
b
b
O
2
0
2
c
82c
3
4
5
110
110
130
15
15
15
N
H
3c
O
2
d
76c
76c
75c
N
H
3d
O
N
H
2
e
3e
3g
O
3
e and f, respectively (entries 5 and 6). The reaction with the
branched substrate, isobutyl methyl ketone (2g) was carried out
in two steps. Firstly, the intermediate hydrazone derivative was
formed by heating at 100 °C for 5 min followed by cyclization at
6
7
N
H
130
15
2
f
3f
O
1
50 °C for 10 min. This procedure furnished the desired product
1
1
00 then
50
5 then
10
86c
77c
in an excellent yield (86%, entry 7), while attempts to conduct
the reaction in one step resulted in either insufficient conversion
or product degradation. Interestingly, 3d and g were produced as
single regioisomers via cyclization of the most substituted ene-
hydrazine. This is consistent with T3P acting as a mild acid cat-
alyst for the Fischer cyclization.
2
g
N
H
O
2
1
Ò
8
110
15
18n
Both indanone isomers 2i and j
and -tetralone (2k) were successfully cyclized to give good yields
of the fused ring systems 3i–k (entries 9–11). The functionalized
a
2
h
indole 3l was prepared in excellent yield (90%, entry 12) from

M. Desroses et al. / Tetrahedron Letters 52 (2011) 4417–4420
4419
Table 3
Synthesis of indole derivatives from 2a and various arylhydrazines
O
P
Pr
O
P
Pr
O
P
Pr
O
HO
O
O
OH
H
N
T3P® (1 equiv)
EtOAc, MW
NH2
R
+
R
N
H
0
00
Figure 1. The structure of P,P ,P -tripropyl triphosphonic acid.
1
1
0
b-i
equiv
.55 mmol
2a
3n-u
1 equiv
0.55 mmol
In summary, we have developed a rapid, mild, and high yielding
Ò
protocol for the indolization of arylhydrazines with T3P under
Entry
1
Hydrazine
R=
Product
T (°C)
Time (min)
Yield (%)
82
microwave irradiation. One significant feature of this procedure
is the ease of product purification. Pure products could generally
be obtained after evaporation and filtration through a plug of silica.
This method provides a valuable alternative to the strongly acidic
or toxic reagents commonly employed for this transformation. Fur-
ther studies investigating the use of T3PÒ in the synthesis of other
heterocycles are currently underway in our laboratory.
MeO
4-OMe
110
10
N
H
1b
3
n
Me
4-Me
2
110
10
84
N
1c
H
Acknowledgment
3
o
Br
We gratefully acknowledge the financial support from the Knut
and Alice Wallenberg’s Foundation.
4
-Br
3
4
5
110
110
130
10
10
10
98
94
86
N
1d
H
3
p
Supplementary data
F
4-F
1
N
Supplementary data (experimental details and H NMR spectra
1e
H
for compounds 3a–u) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.053.
3
q
F3C
4-CF
3
N
H
References and notes
1f
3
r
1
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1
1
1
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2
4
(
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well tolerated affording good to excellent yields of the correspond-
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2
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acting as a water scavenger and driving the initial equilibrium to-
ward formation of the phenylhydrazone intermediate. This process
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in a microwave vial. The reaction volume was then made up to 0.5 mL with
EtOAc and the vessel was sealed under air. The mixture was heated under
microwave irradiation (Biotage Initiator) at 100–150 °C for 5–15 min. The
solvent was evaporated under reduced pressure and the oily residue was
purified by filtration through a plug of silica gel (eluent: isohexane/EtOAc, 8:2)
to yield the desired indole or tetrahydrocarbazole.
2
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