One-pot synthesis of indoles from ketones and hydrazines under mild reaction conditions

Article abstract of DOI:10.1055/s-2001-16756

A facile one-pot method is presented for the synthesis of indoles via condensation of ketone with hydrazine followed by acylation and rearrangement. This convenient synthetic method provides an easy and simple access to indoles.

Full text of DOI:10.1055/s-2001-16756

PAPER
1635
One-Pot Synthesis of Indoles from Ketones and Hydrazines under Mild
Reaction Conditions
M
ild One-Pot Syn
k
thesis of Indo
i
les fro
k
m
Ketone
s
a
o
nd
H
ydrazines Miyata, Yasuo Kimura, Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Fax +81(78)4417556; E-mail: taknaito@kobepharma-u.ac.jp
Received 16 April 2001; revised 25 May 2001
ketone with the hydrazine (the first step); then 11 could be
subjected to acylation with TFAA to provide N-trifluoro-
acetylenehydrazine 12 (the second step). Subsequent
[3,3]-sigmatropic rearrangement of 12 could provide the
desired indole (the third step). Also, we felt that all these
three operations could be conveniently carried out in one-
pot without isolation of any compounds.
Abstract: A facile one-pot method is presented for the synthesis of
indoles via condensation of ketone with hydrazine followed by acy-
lation and rearrangement. This convenient synthetic method pro-
vides an easy and simple access to indoles.
Key words: N-trifluoroacetyl enehydrazine, ketone, indole, indo-
line, one-pot synthesis
Compounds involving the indole nucleus have gained
much attention due to their rich biological activity.1 Al-
though many synthetic routes to indoles have been devel-
oped,1–3 there is still a need for concise and practical
synthetic methods. Fischer indolization3 involving the
preparation of indoles from arylhydrazones has become
one of the most versatile and widely studied reactions in
organic chemistry. The requisite arylhydrazones are most
commonly prepared by the condensation of carbonyl
compounds with arylhydrazines. The development of
one-pot approaches to indoles is a new subject of consid-
erable interest because of their great significance in both
economical and ecological points of view. However, there
have only been a few reports4 on the one-pot synthesis of
indoles using Fischer indolization. Recently, we found a
useful method for synthesis of indoles 2 via thermal cy-
clization of N-trifluoroacetyl enehydrazines 1 which pro-
ceeds smoothly even under non-acidic conditions
(Scheme 1).5 Considering the proposed reaction pathway
involving several intermediates, we established a novel
one-pot procedure for the synthesis of indoles from ke-
tones and hydrazines under non-acidic reaction condi-
tions.
R2
∆
NH2
+
ketone
N
R1
solvent
MS 4Å
3: R1= Ph, R2=H
4: R1=R2= H
5: R1=H, R2=OMe
6: R1=H, R2= Me
7-10
condensation
R3
R3
R2
R4
R2
R4
TFAA
(Et3N)
N
N
NCOCF3
N
R1
0 °C
R1
11
12
acylation
rearrangement
∆
R3
R3
R2
R2
R4
+
R4
NHCOCF3
N
N
R1
R1
14
13
a: R1=Ph, R2=H, R3+R4=(CH2)3
b: R1=Ph, R2=H, R3+R4=(CH2)4
c: R1=Ph, R2=H, R3=(CH2)2-CHMe=R4
d: R1=Ph, R2=H, R3=Me, R4=Et
e: R1=R2=H, R3+R4=(CH2)3
f: R1=H, R2=OMe, R3+R4=(CH2)3
g: R1=H, R2=Me, R3+R4=(CH2)3
R1
R1
R2
∆
R2
NCOCF3
N
N
H
H
2
1
Scheme 1
Me
Me
Me
This one-pot synthesis of indoles consists of three steps as
shown in Scheme 2. We envisioned that we could first
prepare the required hydrazone 11 via condensation of the
O
O
O
O
7
8
9
10
Scheme 2
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,11,1635,1638,ftx,en;F03301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1636
O. Miyata et al.
PAPER
As a preliminary experiment, we first examined the prep- The present procedure was extended to one-pot synthesis
aration of indole from hydrazone 11a without isolation of of various types of indoles from ketones and hydrazines.
N-trifluoroacetyl enehydrazine 12a (Scheme 3). The hy- The results are summarized in Table 1 (Scheme 2). We
drazone 11a, prepared from cyclopentanone (7) and first chose a combination of commercially available cy-
diphenylhydrazine (3) was treated with TFAA in THF at clopentanone (7) and diphenylhydrazine (3). Condensa-
0 °C and subsequently, the reaction mixture containing tion of 7 with 3 proceeded smoothly in the presence of
the N-trifluoroacetyl enehydrazine 12a was stirred under molecular sieves 4 Å (MS 4 Å) in THF under reflux to
reflux for rearrangement to give the indole 13a and indo- give hydrazone 11a. After the starting material had been
line 14a in 69% and 30% yield, respectively. In order to consumed (TLC), TFAA was added to the same reaction
trap TFA formed, the acylation was carried out in the vessel at 0 °C, and the reaction mixture was stirred under
presence of Et3N to give a 1:2.5 mixture of 13a and 14a in reflux whilst monitoring by TLC. This one-pot procedure
99% combined yield, of which the latter was readily con- afforded a 1:1 mixture of indole 13a and indoline 14a in
verted into indole 13a by either treatment with 1 equiva- 92% combined yield (entry 1). When benzene was used as
lent of TFA at 65 °C or by heating in xylene at 140 °C. solvent, the indole 13a was obtained in 81% yield as a sole
These results suggested that this method was suitable for product (entry 2). In the absence of MS 4 Å, a prolonged
the synthesis of indoles.
reaction time was required for the preparation of hydra-
zone 11a. Therefore, the presence of MS 4 Å is indispens-
able in the condensation step. The reaction of
cyclohexanone (8) with 3 in benzene gave the indole 13b
as a sole product in 81% yield (entry 4). Under the same
conditions, the substrate 9 having a substituent in the cy-
clopentanone ring was exclusively converted into the cor-
responding indole 13c in 77% yield (entry 5). On the other
hand, the reaction of 9 in the presence of triethylamine
gave a mixture of 13c and 14c (entry 6). To demonstrate
the generality, we next investigated the one-pot reaction
of acyclic ketone 10 with diphenylhydrazine 3. The indole
13d was obtained in 86% yield (entry 7). The one-pot re-
action of ketone 7 and N-monophenylhydrazine 4 gave the
indole 13e6 in 25% yield accompanied by some unidenti-
N
NCOCF3
N
N
N
Ph
Ph
Ph
12a
13a
11a
N
NHCOCF3
Ph
14a
Scheme 3
Table 1 One-Pot Synthesis of Indoles and Indolines
Reaction Time (h)a
Yield (%)
Entry
1
Hydrazine Ketone
Solvent
THF
Et3N
–
i)
ii)
2
iii)
9
Product
13a+14a
13a
13+14
13
47
81
58
81
77
19
86
25
31
45
23
33
39
14
45
–
3
3
3
3
3
3
3
4
4
4
5
5
6
7
7
9
92
81
58
81
77
90
86
25
35
45
47
33
39
2
benzene
THF
–
6
3
3
3
8
–
6
1.5
1
1
13b
–
4
8
benzene
benzene
benzene
benzene
benzene
benzene
toluene
THF
–
1.5
15
16
20
1
3
13b
–
5
9
–
4
5
13c
–
6
9
+
4
5
13c+14c
13d
71
–
7
10
7
+
1
3.5
8
–
1
2.5
12.5
16
5
13e
–
9
7
+
0.5
1
0.5
1
13e+14e
13e
4
10
11
12
13
7
+
–
7
+
2
1
13f+14f
13f
24
–
7
benzene
benzene
+
4
2
5
7
+
4
2
7
13g
–
a i) Reaction time for condensation reaction (first Step); ii) Reaction time for acylation reaction (second Step); iii) Reaction time for rearrange-
ment reaction (third Step).
Synthesis 2001, No. 11, 1635–1638 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Mild One-Pot Synthesis of Indoles from Ketones and Hydrazines
1637
fied compounds (entry 8). The acylation of intermediary useful method for construction of various types of indoles
hydrazone 11e with TFAA in the presence of triethy- and indolines.
lamine improved the yield of indole 13e (31%), along
with the indoline 14e and the corresponding enehydrazine
(entry 9). Furthermore, the one-pot reaction in boiling tol-
uene gave the corresponding indole 13e in 45% yield (en-
try 10). The one-pot reaction of 7 with hydrazine 5 having
the p-methoxy group in benzene ring afforded indole 13f7
and indoline 14f (entries 11, 12). Similarly, the one-pot re-
action of 7 with hydrazine 6 having the p-methyl group in
benzene ring gave indole 13g8 (entry 13).
1H NMR spectra were recorded at 200 MHz, 300 MHz, or 500
MHz. IR spectra were recorded using FTIR apparatus. Mass spectra
were obtained by EI method. Medium-pressure column chromatog-
raphy (MCC) was performed using Lobar Größe B (E. Merck 310-
25, Lichroprep Si60).
Conversion of Hydrazone 11a into Indole 13a and Indoline 14a
(i) In the absence of Et3N
To a solution of the hydrazone 11a (250 mg, 1 mmol) in THF (3
mL) was added TFAA (210 mg, 1 mmol) under a N2 atm at 0 °C.
After stirring at this temperature for 1 h, the reaction mixture was
refluxed for 5 h, monitoring the reaction by TLC. The reaction mix-
ture was concentrated under reduced pressure. Purification of the
residue by MCC (hexane–EtOAc, 9:1) afforded indole 13a (161
mg, 69%) and indoline 14a (104 mg, 30%).
We compared the yields of indoles and indolines in one-
pot synthesis with those in stepwise synthesis (isolations
of both hydrazones and N-trifluoroacetyl enehydrazines
(intermediates) in each step). Indoline 14a was obtained
from hydrazine 3 in total 87% yield in the stepwise pro-
cess, while 13a and 14a were obtained in 92% combined
yield by the one-pot process. Furthermore, 13b and 13d
(ii) In the presence of Et3N
were obtained in 44% and 11% total yields, respectively, To a solution of the hydrazone 11a (250 mg, 1 mmol) in THF (3
mL) was added Et3N (303 mg, 3 mmol) and TFAA (210 mg, 1
via the stepwise process, compared to 81% and 86%
mmol) under a N2 atm at 0 °C. After stirring at this temperature for
yields, respectively, via the above one-pot process. There-
1 h, the reaction mixture was refluxed for 5 h, monitoring the reac-
tion by TLC. The reaction mixture was concentrated under reduced
pressure. Purification of the residue by MCC (hexane–EtOAc, 9:1)
fore, the one-pot synthesis is generally preferable to the
stepwise process for the preparation of indoles.
afforded indole 13a (65 mg, 28%) and indoline 14a (247 mg, 71%).
The advantages of this one-pot procedure are as follows:
(i) the tedious isolation of the intermediates 11 and 12 is
unnecessary; (ii) the crucial rearrangement proceeds un-
der mild conditions to give indoles and indolines in mod-
One-Pot Reaction; General Procedure
To a solution of the hydrazine (1 mmol) in THF (15 mL) was added
the ketone (5 mmol) and MS 4 Å (4 g) under a N2 atm at r.t., and the
erate to excellent yield; (iii) furthermore, in boiling
reaction mixture was refluxed for 0.5–20 h, monitoring the reaction
benzene or toluene, indoles were obtained as a sole prod-
uct.
In addition to the previously reported5 multi-step synthe-
sis of indoles and indolines via thermal cyclization of N-
trifluoroacetyl enehydrazines, the newly found one-pot
procedure disclosed a broader aspect of the potentiality of
thermal cyclization of N-trifluoroacetyl enehydrazine,
thus establishing the one-pot synthesis as a simple and
by TLC. After cooling to 0 °C, TFAA (2 mmol)9 was added to the
reaction mixture. [In the case of entries 6, 7, 9–13 (Table 1), TFAA
(2 mmol) and Et3N (3 mmol) were added.] After stirring at the same
temperature for 0.5–4 h, the reaction mixture was refluxed for 1–16
h, monitoring the reaction by TLC. The reaction mixture was then
filtered to remove MS 4 Å, and the filtrate was concentrated under
reduced pressure. Purification of the residue by MCC afforded the
indole and indoline as shown in Table 1. Analytical data for the in-
doles and indolines are summarized in Table 2.
Table 2 Spectral Data for Indoles 13 and Indolines 14
Product
13a
Mp
1H NMR (300 MHz, CDCl3 / TMS)
(ppm), J (Hz)
IR
(cm–1)
Molecular For- HRMS (m/z)
mula
(°C)a
–
2.55 (br quint, 2H, J = 7.0), 2.91 (pseudo-t, 4H, J = 7.0),
7.10–7.52 (m, 9H)
3010, 1599, 1501 C17H15N
1450, 1209
233.1177
346.1277
14a
137–140
1.58 (m, 1H), 1.81–1.90 (m, 2H), 2.18 (m, 1H), 2.26–2.47
3425, 3024, 1725, C19H17F3N2O
(m, 2H), 3.95 (dd, 1H, J = 10.0, 3.0,), 6.58 (br d, 1H, J = 8.0), 1593, 1498
6.77 (br s, 1H), 6.83 (br t, 1H, J = 8.0), 7.08 (br t, 1H, J =
8.0), 7.16 (br d, 1H, J = 8.0), 7.24–7.31 (m, 3H), 7.42–7.47
(m, 2H)
13b
13c
–
–
1.89 (br quint, 4H, J = 3.0), 2.60 (m, 2H), 2.80 (m, 2H),
7.02–7.54 (m, 9H)
2939, 1599, 1502, C18H17N
1459
247.1357
247.1360
0.92 (d, 3H, J = 6.5), 2.10 (m, 1H), 2.86 (m, 3H), 3.46 (m, 2961, 2861, 1598, C18H17N
1H), 7.11 (m, 2H), 7.35 (m, 2H), 7.44–7.50 (m, 5H) 1502, 1450, 1377
Synthesis 2001, No. 11, 1635–1638 ISSN 0039-7881 © Thieme Stuttgart · New York

1638
O. Miyata et al.
PAPER
Table 2 Spectral Data for Indoles 13 and Indolines 14 (continued)
Product
Mp
1H NMR (300 MHz, CDCl3 / TMS)
(ppm), J (Hz)
IR
(cm–1)
Molecular For- HRMS (m/z)
mula
(°C)a
14c
92–94
0.95 (d, 3H, J = 7.5), 1.58–1.73 (m, 2H), 1.95 (m, 1H), 2.35– 3442, 3024, 1740, C20H19F3N2O
360.1445
2.57 (m, 2H), 4.12 (dd, 1H, J = 8.0, 2.0), 6.39 (d, 1H, J =
8.0), 6.71 (br s, 1H), 6.78 (td, 1H, J = 8.0, 1.0), 7.02 (br t,
1H, J = 8.0), 7.14 (br d, 1H, J = 8.0), 7.24 (m, 3H), 7.41 (m,
2H)
1593, 1497
13d
13e6
14e
–
–
–
0.98 (t, 3H, J = 8.0), 2.34 (s, 3H), 2.68 (q, 2H, J = 8.0), 7.07 3009, 1598, 1500, C17H17N
(m, 3H), 7.32 (m, 2H), 7.49 (m, 4H) 1206
235.1374
157.0891
270.0962
2.52 (br quint, 2H, J = 8.0), 2.84 (pseudo-t, 4H, J = 8.0), 7.07 3477, 1666, 1611, C11H11N
(m, 2H), 7.28 (m, 1H), 7.42 (m, 1H), 7.76 (br s, 1H)
1468, 1228
1.66 (m, 1H), 1.74–1.88 (m, 2H), 2.20 (m, 1H), 2.31–2.42
3424, 2963, 1720, C13H13F3N2O
(m, 2H), 3.69 (dd, 1H, J = 8.5, 2.0, 1H), 4.67 (br s, 1H), 6.57 1611, 1486
(dd, 1H, J = 7.0, 1.0), 6.78 (td, 1H, J = 7.0, 1.0), 6.79 (br s,
1H), 7.07 (m, 2H)
13f7
14f
–
–
–
2.52 (br quint, 2H, J = 7.0), 2.82 (pseudo-t, 4H, J = 7.5), 3.84 3478, 2956, 1667, C12H13NO
(s, 3H), 6.74 (dd, 1H, J = 8.5, 2.0), 6.91 (d, 1H, J = 2.0), 7.17 1603, 1585, 1466
187.1007
300.1095
171.1048
(br d, 1H, J = 8.5), 7.71 (br s, 1H)
1296, 1228
1.66 (m, 1H), 1.82 (m, 2H), 2.08 (m, 1H), 2.40 (m, 2H), 3.72 3478, 1750, 1601, C14H15F3N2O2
(br d, 1H, J = 8.0), 3.75 (s, 3H), 4.31 (br s, 1H), 6.52 (br d, 1466, 1296, 1204
1H, J = 8.0), 6.65 (dd, 1H, J = 8.0, 2.0), 6.67 (d, 1H, J = 2.0)
13g8
2.43 (s, 3H), 2.52 (br quint, 2H, J = 7.0), 2.80 (pseudo-t, 4H, 3478, 1516, 1190, C12H13N
J = 7.0), 6.91 (br dd, 1H, J = 8.0, 1.0), 7.17 (br d, 1H, J =
8.0), 7.22 (br d, 1H, J = 1.0), 7.71 (br s, 1H)
804, 591
a Mps are not given for oily products.
(3) Reviews of Fischer indole synthesis: (a) Robinson, B.
Chem. Rev. 1963, 63, 373. (b) Robinson, B. Chem. Rev.
1969, 69, 227. (c) Ishii, H. Acc. Chem. Res. 1981, 14, 275.
(d) Robinson, B. The Fischer Indole Synthesis; Wiley: New
York, 1982. (e) Hughes, D. L. Org. Prep. Proced. Int. 1993,
25, 609. (f) Murakami, Y. Yakugaku Zasshi 1999, 119, 35.
(g) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 10251.
(4) One-pot synthesis of indole from aldehyde and hydrazine
has been carried out under acidic conditions using 4%
H2SO4: Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R.
D.; Verhaeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59,
3738.
(5) (a) Miyata, O.; Kimura, Y.; Muroya, K.; Hiramatsu, H.;
Naito, T. Tetrahedron Lett. 1999, 40, 3601. (b) Miyata, O.;
Kimura, Y.; Naito, T. Chem. Commun. 1999, 2429.
(6) Wender, P. A.; Cooper, C. B. Tetrahedron 1986, 42, 2985.
(7) Kempter, G.; Schwalba, M.; Stoss, W.; Walter, K. J. Prakt.
Chem. 1962, 18, 39.
Acknowledgement
This work was supported in part by Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports and Culture,
Japan and a research grant from the Science Research Promotion
Fund of the Japan Private School Promotion Foundation.
References and Notes
(1) For recent reviews: (a) Saxton, J. E. Monoterpenoid Indole
Alkaloids Supplement to Part 4; Wiley: Chichester, 1994.
(b) Saxton, J. E. Nat. Prod. Rep. 1996, 13, 327. (c) Ihara,
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(d) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 15, 327.
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(b) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551.
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Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791.
(d) Rainier, J. D.; Kennedy, A. R.; Chase, E. Tetrahedron
Lett. 1999, 40, 6325.
(8) Kelly, A. H.; McLead, D. H.; Parrick, J. Can. J. Chem. 1965,
43, 296.
(9) The acylation using 1 equiv of TFAA was not completed.
Synthesis 2001, No. 11, 1635–1638 ISSN 0039-7881 © Thieme Stuttgart · New York