A direct and simple approach for the synthesis of indole-3-propanol and its acetates from dihydropyran

Article abstract of DOI:10.1007/s00706-008-0945-x

A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available phenylhydrazine hydrochlorides and dihydropyran. Synthesis of indole-3-propanol and its acetates was studied extensively for appropriate acetic acid and water mixture as the solvent.

Full text of DOI:10.1007/s00706-008-0945-x

Monatsh Chem 139, 1475–1478 (2008)
DOI 10.1007/s00706-008-0945-x
Printed in The Netherlands
A direct and simple approach for the synthesis of indole-3-propanol
and its acetates from dihydropyran
Aswathanarayana Srinivasa1, Kittappa M. Mahadevan1, Tholappanavara H. Sureshakumara1,
Vijaykumar Hulikal2
1
Department of Chemistry, Kuvempu University, Jnana Sahyadri, Shimoga, Karnataka, India
2
Bio Organics and Applied Materials Pvt. Ltd., Bangalore, India
Received 24 February 2008; Accepted 6 April 2008; Published online 9 June 2008
# Springer-Verlag 2008
Abstract A general method was developed for the
one-pot synthesis of highly functionalized indoles
from simple, commercially available phenylhydrazine
hydrochlorides and dihydropyran. Synthesis of indole-
3-propanol and its acetates was studied extensively
for appropriate acetic acid and water mixture as the
solvent.
an important industrial goal. Among the diverse and
creative approaches that have been discovered [2],
the Fischer indole reaction remains the bench-mark
to which other methods are compared [3]. Since its
discovery in the 1880s by Emil Fischer, various cat-
alysts have been used to effect the cyclization of aryl
hydrazones derived from ketones. Alternative cata-
lysts, including Brønsted acids (H2SO4, HCl, PPA,
AcOH) [4], Lewis acids (ZnCl2, TiCl4, PCl3) [5], and
solid acids (zeolite, montmorillonite clay) [6], have
been reported for the synthesis of the indole nucleus.
These conditions however often suffer from low yields
and involve two step processes (i.e. hydrazone forma-
tion and [3 þ 3] rearrangement) [7]. Although acetic
acid has not been employed for the synthesis of
indole-3-alkyl alcohols, but very recently Kevin et al.
[8] has attempted the synthesis of tryptophols in 4%
aqueous H2SO4 and obtained tryptophols in 50% yield
and the remaining 50% was the result of formation of
triol. To avoid the formation of the latter they used
acetonitrile as co-solvent. However, the use of sulfuric
acid is still a disadvantage due to its corrosive nature
and additional usage of co solvent is also required.
Hence, in continued substantial interest to develop
methods requiring mild reaction conditions, herein
we wish to report a convenient and efficient synthe-
sis one-pot synthesis of indole-3-propanol and its
acetates by the reaction of phenylhydrazine hy-
drochloride with cyclic enol ethers in presence of
Keywords Indole-3-propanol; Indole-3-propyl acetate;
Acetic acid; Phenylhydrazine hydrochloride; Dihydropyran.
Introduction
There is a considerable interest in efficient methods
to prepare indole derivatives, due to the methodolog-
ical challenges involved and the presence of these
heterocycles at the core of many bioactive structures,
both natural and synthetic [1]. Tryptophol homologs
represent an important class of powerful interme-
diates in organic synthesis. The important structural-
ly diverse pharmaceutical agents, which are derived
from tryptophol homologs include commercial
drugs: sumitriptan, indomethacin, tryptophanes, etc.
Indole-3-alkyl alcohols are fundamental building
blocks in organic synthesis and their preparation is
Correspondence: Kittappa M. Mahadevan, Department
of Chemistry, Kuvempu University, Jnana Sahyadri,
Shankaraghatta 577 451, Shimoga, Karnataka, India. E-mail:
mady_kmm@yahoo.co.uk

1476
A. Srinivasa et al.
Scheme 1
glacial acetic acid as medium and catalyst as well.
Acetic acid promoted synthesis of 3-substituted
indoles from phenylhydrazine hydrochloride and cy-
clic enol ethers has thus proven to be a highly attrac-
tive and powerful alternative.
By adopting the optimized condition and in order
to widen the scope of this approach towards the syn-
thesis of indole-3-alkyl acetate we explored the one-
pot reaction between a wide variety of functionalized
phenylhydrazine hydrochlorides with dihydropyran
by using 80% aqueous acetic acid. The results are
shown in the Table 1.
Results and discussions
Since our initial aim was to obtain indole-3-alkyl
alcohol, we altered the reaction conditions. During
our study, we suspected that 4a–4f were produced
due to the high concentration of acetic acid in the
reaction. Hence to avoid the formation of acetates,
we thought of increasing the concentration of water
in the reaction medium. It was observed that addi-
tion of water to the reaction significantly improved
the reaction profile, producing less than 3% of 4a.
In 50% aqueous acetic acid, the reaction proceeded
smoothly to afford the indole-3-propanol 3a in 92%
yield. Furthermore the reaction was carried out in
When dihydropyran (2) was added to a solution of
phenylhydrazine hydrochloride (1a) in acetic acid
at reflux temperature (Scheme 2), indole 3a was
obtained in 4% isolated yield. The major product
of the reaction was the ester 4a, resulting from fur-
ther reaction of 3a with acetic acid and formation of
side products were observed. After considerable study
on the formation of 4a, it was observed that in 80%
aqueous acetic acid at 100ꢀC, the formation of side
product was reduced considerably and the isolated
yield of 4a was increased significantly (75%).
Scheme 2

Synthesis of indole-3-propanol and its acetates
1477
means of IR, NMR, and mass spectra. Herein we describe
spectral data for 4a–4f, which could not be found in literature.
Table 1 Synthesis of indole-3-propyl acetate
Products
R
Time=min
Yields=%a
General procedure for the Fischer indole reaction
3a
3b
3c
3d
3e
3f
H
140
120
120
170
180
150
75
70
68
70
65
55
for the synthesis of 3
Me
OMe
F
Cl
Br
To a solution of 0.144g phenylhydrazine ꢁ HCl (1.0mmol) in
2 cm3 50% aqueous acetic acid was added 0.084 g dihydro-
pyran (1.0mmol) drop-wise over 2 min at room temperature.
The reaction was stirred at 50ꢀC for 10min and refluxed for
the appropriate time (Table 1). After completion of the reac-
tion as indicated by TLC, the reaction mixture was quenched
with 20cm3 saturated aqueous NaHCO3 solution and ex-
tracted with 2ꢂ15cm3 ethyl acetate. The combined organic
layers were dried (NaSO4), concentrated, and the crude prod-
uct was purified by column chromatography on silica gel
(60–120 mesh, ethyl acetate:petroleum ether, 3:7).
a isolated yields
Table 2 Synthesis of indole-3-propanol
Products
R
Time=min
Yields=%a
4a
4b
4c
4d
4e
4f
H
55
45
50
70
75
75
92
96
92
88
84
84
General procedure for the Fischer indole reaction
Me
OMe
F
Cl
Br
for the synthesis of 4
To a solution of 0.144g phenylhydrazine ꢁ HCl (1.0mmol) in
80% aqueous acetic acid was added 0.092 g dihydropyran
(1.1mmol) drop-wise over 2 min at room temperature. The re-
action was refluxed for the appropriate time (Table 1). After
completion of the reaction as indicated by TLC, the reaction
mixture was quenched with 20 cm3 saturated aqueous NaHCO3
solution and extracted with 2ꢂ15 cm3 ethyl acetate. The com-
bined organic layers were dried (NaSO4), concentrated and
the crude product was purified by column chromatography on
silica gel (60–120 mesh, ethyl acetate:petroleum ether, 3:7).
a isolated yields
water to know the effect of acetic acid in the reac-
tion, but only formation of aryl hydrazones was ob-
served. The results obtained with other substituents
are given in Table 2. Alternatively, indole-3-propa-
nols were also obtained from the corresponding acet-
ates on treatment with KOH in ethanol at room
temperature.
In conclusion, we demonstrated that phenylhy-
drazine hydrochloride and dihydropyran can be
transformed into functionally diversified indole-3-
propanols and acetates in a direct and simple pro-
cedure. The resulting products are of considerable
interest as building blocks, since their functional
group should allow a variety of subsequent synthesis
modifications.
3-(1H-Indol-3-yl)propyl acetate (4a, C13H15NO2)
Pale yellow viscous oil; IR (KBr): ꢀꢀ¼ 3522, 3401, 1742,
1
1426, 1241cmꢃ1; H NMR (400MHz, CDCl3): ꢁ ¼ 8.01 (br
s, 1H), 7.59 (dt, 1H, J ¼ 7.8, 1.1Hz), 7.32 (dt, 1H, J ¼ 8.0,
0.8 Hz), 7.19 (ddd, 1H, J ¼ 8.0, 7.1, 1.3 Hz), 7.13 (dd, 1H,
J ¼ 8.2, 1.2 Hz), 7.01(d, 1H, J ¼ 0.9 Hz), 4.15 (t, 2H, J ¼
6.3 Hz), 2.85 (dt, 2H, J ¼ 7.6, 0.8 Hz), 2.08 (m, 5H) ppm;
13C NMR (100MHz, CDCl3): ꢁ ¼ 181.3, 136.5, 127.1,
121.5, 121.1, 119.0, 118.8, 115.8, 109.5, 62.9, 32.9, 21.5,
17.3ppm; MS: m=z ¼ 218 (Mþ 1).
3-(5-Methyl-1H-indol-3-yl)propyl acetate (4b, C14H17NO2)
Pale yellow viscous oil; IR (KBr): ꢀꢀ¼ 3458, 3428, 1748,
1451, 1245, 1028cmꢃ1
;
1H NMR (400MHz, CDCl3):
ꢁ ¼ 7.98 (br s, 1H), 7.44 (s, 1H), 7.28 (d, 1H, J ¼ 8.2 Hz),
7.10 (dd, 1H, J ¼ 8.3, 1.1 Hz), 6.88 (d, 1H, J ¼ 0.98 Hz),
4.13 (t, 2H, J ¼ 6.3 Hz), 2.80 (dt, 2H, J ¼ 7.5, 0.9Hz), 2.53
(s, 3H), 2.08 (m, 5H) ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼
171.2, 136.4, 127.3, 122.9, 121.2, 120.3, 119.1, 117.1, 116.6,
62.9, 33.3, 21.2, 17.5, 16.6ppm; MS: m=z ¼ 231 (Mþ).
Experimental
All the melting points were recorded in open capillaries. The
purity of the compounds was checked by TLC on silica gel
and they were purified by column chromatography. H NMR
1
and 13C NMR spectra were recorded on a Bruker-400MHz
spectrometer using TMS as an internal standard. IR spectra
were obtained using a FTS-135 spectrometer instrument. Mass
spectra were recorded on a JEOL SX 102=DA-6000 (10 kV)
FAB mass spectrometer. Elemental analyses (C, H, N, O) were
conducted using the Elementar Vario EL III; their results were
in favorable agreement with the calculated values. The com-
pounds 3a–3f, are known and their identities were proven by
3-(5-Methoxy-1H-indol-3-yl)propyl acetate (4c, C14H17NO3)
Pale yellow viscous oil; IR (KBr): ꢀ ¼ 3358, 3257, 1748,
ꢀ
1
1678, 1499, 1245, 1011 cmꢃ1; H NMR (400 MHz, CDCl3):
ꢁ ¼ 7.96 (br s, 1H), 7.28 (d, J ¼ 8.6, 1H), 7.13 (m, 2H), 6.88 (t,
1H, J ¼ 7.4 Hz), 4.01 (t, 2H, J ¼ 6.5 Hz), 3.78 (s, 3H), 2.81 (dt,
2H, J ¼ 6.9, 0.7 Hz), 2.10 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3): ꢁ ¼ 174.1, 152.8, 132.0, 127.9, 122.4, 120.5, 117.1,

1478
A. Srinivasa et al.
115.9, 112.6, 103, 62.9, 33.5, 22.1, 17.2ppm; MS: m=z ¼ 247
(Mþ).
University, Shankaraghatta, for providing laboratory facilities.
The authors are also thankful to RSIC, Indian Institute of
Science, Bangalore.
3-(5-Fluoro-1H-indol-3-yl)propyl acetate (4d, C13H14FNO2)
Pale yellow semi solid; IR (KBr): ꢀꢀ¼ 3423, 2956, 1581, 1449,
1370, 1241, 1048 cmꢃ1
;
1H NMR (400MHz, CDCl3): ꢁ ¼
References
8.18 (br s, 1H), 7.24 (dd, 1H, J ¼ 7.4, 2.2Hz), 7.21 (m, 1H),
6.97 (s, 1H), 6.91 (dt, 1H, J ¼ 9.0, 2.4 Hz), 4.12 (t, 2H,
J ¼ 6.4 Hz), 2.81 (dt, 2H, J ¼ 7.5, 0.9 Hz), 2.09 (s, 3H), 1.99
(m, 3H) ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼ 171.1,
158.5, 156.1, 132.9, 127.5, 127.4, 123.0, 116.2, 115.9, 111.5,
110.3, 110.0, 103.6, 103.5, 62.8, 32.7, 21.2, 17.6ppm; MS:
m=z ¼ 235 (Mþ).
1. a) Ihara M, Fukumoto K (1995) Nat Prod Rep 12:277;
b) Saxton JE (1994) Nat Prod Rep 11:493; (c) Saxton JE
(1983) Indoles. Wiley-Interscience, New York
2. Gribble GW (2000) J Chem Soc Perkin, Trans 1:1045
3. a) Gribble GW (1994) Contemp Org Synth 1:1; b) Hughes
DL (1993) Org Prep Proc Int 25:607; c) Robinson B (1982)
Wiley-Interscience, New York
4. a) Miyata O, Kimura Y, Muroya K, Hiramatsu H, Naito
T (1999) Tetrahedron Lett 40:3601; b) Kissman HM,
Farnsworth DW, Witkop B (1952) J Am Chem Soc
74:3948; c) Hegde V, Madhukar P, Madura JD, Thummel
RP (1990) J Am Chem Soc 112:4549; d) Hillier MC,
Marcoux JF, Zhao D, Grabowski EJJ, Mckeon AE, Tillyer
RD (2005) J Org Chem 70:8385
5. a) Nakazaki M, Yamamoto K (1976) J Org Chem 41:1877;
b) Ackermann L, Born R (2004) Tetrahedron Lett 45:9541;
c) Baccolini G, Todesco PE (1981) J Chem Soc Chem
Commun:563
3-(5-Chloro-1H-indol-3-yl)propyl acetate (4e, C13H14ClNO2)
Pale yellow oil; IR (KBr): ꢀꢀ¼ 3572, 3427, 2925, 2854, 1688,
1
1462, 1227, 1099, 1056cmꢃ1; H NMR (400 MHz, CDCl3):
ꢁ ¼ 8.05 (br s, 1H), 7.65 (d, 1H, J ¼ 2.1Hz), 7.31 (d, 1H, J ¼
2.3 Hz), 7.13 (m, 3H), 3.84 (t, 2H, J ¼ 6.1 Hz), 2.83 (dt, 2H,
J ¼ 7.8, 1.0Hz), 2.04 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3): ꢁ ¼ 172.3, 134.3, 128.1, 125.4,122.9, 122.2, 118.3,
114.7, 112.0, 62.3, 32.8, 21.2, 17.4ppm; MS: m=z ¼ 252
(Mþ 1).
3-(5-Bromo-1H-indol-3-yl)propyl acetate (4f, C13H14BrNO2)
Pale yellow oil; IR (KBr): ꢀꢀ¼ 3498, 3375, 2978, 2891, 1734,
1458, 1022 cmꢃ1; 1H NMR (400 MHz, CDCl3): ꢁ ¼ 7.99 (br s,
1H), 7.63 (d, 1H, J ¼ 1.6 Hz), 7.10 (m, 2H), 6.89 (s, 1H), 3.98
(t, 2H, J ¼ 6.4 Hz), 2.77 (dt, 2H, J ¼ 7.9, 0.8 Hz), 2.03 (s, 3H),
1.85 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 171.8,
134.8, 129.5, 124.6, 122.8, 121.4, 115.7, 112.0, 111.8, 62.6,
32.2, 21.3, 17.3ppm; MS: m=z ¼ 296 (Mþ 1).
6. a) Mhaske SB, Argade NP (2004) Tetrahedron 60:3417;
´
b) Lipinska T, Guibe-Jampel E, Petit A, Loupy A (1999)
Synth Commun 29:1349; c) Dhakshinamoorthy A,
Pitchumani K (2005) Appl Catal 292:305; d) Zhu HP,
Yang F, Tang J, He MY (2003) Green Chem 5:38
7. a) Zepeda LG, Morales-Rios MS, Joseph-Nathan P
(1992) Synth Commun 22:3243; b) Shono T, Matsumura
Y, Tsubata K (1984) J Org Chem 49:3711; c) Fischer GW
(1995) J Heterocycl Chem 32:1557; d) Pete B, Bitter I,
Szantay CJ, Schon I, Toke L (1998) Heterocycles
48:1139
Acknowledgements
We are grateful to Department of Post Graduate Studies and
Research in Chemistry and Industrial Chemistry, Kuvempu
8. Campos KR, Woo JCS, Lee S, Tillyer RD (2004) Org Lett
6:79