General synthesis of mono-, di-, and tri-acetylated indoles from indolin-2-ones

Article abstract of DOI:10.1016/j.tet.2010.11.105

Having developed the one-pot triacetylation of indolin-3-ones, we have now devised a simple two-step reaction sequences to produce di- and mono-acetylated indoles from indolin-2-ones. The indolin-2-ones were first subjected to acetylation in the presence of acetic anhydride and a catalytic amount of N,N-dimethylaminopyridine to give 2-acetoxy-1,3-diacetylindoles. Subsequently, an enzyme-assisted deacetylation resulted in the chemoselective deprotection of the acetoxy group to produce 1,3-diacetyl-2-hydroxyindoles. However, a chemical deacetylation of 2-acetoxy-1,3-diacetylinoles under mild basic or acidic conditions resulted in the formation of 3-acetyl-2-hydroxyindoles.

Full text of DOI:10.1016/j.tet.2010.11.105

Tetrahedron 67 (2011) 982e989
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
General synthesis of mono-, di-, and tri-acetylated indoles from indolin-2-ones
*
Mukund Jha , Ting-Yi Chou, Brian Blunt
Department of Biology and Chemistry, Nipissing University, North Bay, ON, Canada P1B 8L7
a r t i c l e i n f o
a b s t r a c t
Article history:
Having developed the one-pot triacetylation of indolin-3-ones, we have now devised a simple two-step
reaction sequences to produce di- and mono-acetylated indoles from indolin-2-ones. The indolin-2-ones
were first subjected to acetylation in the presence of acetic anhydride and a catalytic amount of N,N-
dimethylaminopyridine to give 2-acetoxy-1,3-diacetylindoles. Subsequently, an enzyme-assisted
deacetylation resulted in the chemoselective deprotection of the acetoxy group to produce 1,3-diacetyl-
2-hydroxyindoles. However, a chemical deacetylation of 2-acetoxy-1,3-diacetylinoles under mild basic or
acidic conditions resulted in the formation of 3-acetyl-2-hydroxyindoles.
Received 30 September 2010
Received in revised form 28 November 2010
Accepted 30 November 2010
Available online 7 December 2010
Keywords:
Acetylation
Indole
Ó 2010 Elsevier Ltd. All rights reserved.
Indolin-2-one
Indoline-2-thione
3-Acetyl-2-hydroxyindole
3-Acetyl-2-hydroxyindoles
DMAP
Multiple acetylation
Enzyme-assisted reaction
Chemoselective
1. Introduction
deprotection of multiply acylated compounds can be employed.
Enzyme-catalyzed reactions have become very popular in organic
The indole nucleus is a basic skeletal framework for a large
number of biologically and industrially relevant molecules.1 The
importance of indole and its myriad derivatives is evident from the
growing volume of chemical literature found on them in the field of
pharmaceutical/medicinal chemistry,2 natural products,3 agro-
chemicals,4 and synthetic chemistry.5 Given the high significance of
indole-based molecules, there is a rising need for the development
of efficient and practical synthesis of substituted indoles. Our re-
search group is actively involved in exploring the chemistry of
substituted indoles to develop the synthesis of newer indole-based
heterocycles.6,7
Protection and deprotection steps are an integral part of organic
synthesis and are routinely applied in multistep synthetic trans-
formations.8 Some of the desirable criteria for designing synthetic
procedures for the introduction and removal of protecting groups are
selectivity, higher yields of the reaction, clean conversion, and their
easy manipulation.9 Among various protections, the acetyl group is
heavily used for the protection of heteroatoms (N, O, and S).8
In addition to chemical deprotection procedures, which may10 or
may not be selective, enzyme-assisted chemo- and regio-selective
synthesis11 and are often employed as a green and sometimes an
only alternative to achieve selectivity in the reaction outcomes.
Besides being highly selective in nature, the enzyme-catalyzed re-
actions are generally highyielding, clean, and use very mild reaction
conditions (room temperature). Candida antarctica lipase B (CALB),
commercially available in immobilized form (NovozymeÒ 435), is
a hydrolase enzyme known for its promiscuity and efficient catalysis
of transesterification reactions in organic solvents.12e15
The indolin-2-one moiety is a useful precursor for the synthesis
of indole derivatives.16 In our preliminary study,6 while pursuing
the acetyl protection of the N-1 position of indolin-2-one (1), we
disclosed an unprecedented multiple acetylation on the indolin-2-
one (1) framework in the presence of a catalytic amount of N,N-
dimethylaminopyridine (DMAP) in acetic anhydride. This resulted
in the synthesis of 2-acetoxy-1,3-diacetylindole (2) in excellent
yields where three nucleophilic sites, namely N-1, O at C-2 and C-3,
were acetylated in just one step.6 Earlier Beccalli et al. had reported
a triacylation of 3-(2-aryl-1-hydroxyethylidene)indol-2(3H)-one
moieties using ethyl formate.17 However, in their reaction multiple
acylation occurred only at the heteroatoms. Furthermore, the
acetylation of 1-alkylated indolin-2-ones in the presence of DMAP
resulted in the chemoselective synthesis of 3-acetyl-1-alkyl-2-
hydroxyindoles in one step.6 To make the easily obtainable per-
acetylated indole products synthetically more attractive, we
* Corresponding author. E-mail address: mukundj@nipissingu.ca (M. Jha).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.105

M. Jha et al. / Tetrahedron 67 (2011) 982e989
983
Table 2
envisioned selective as well as complete deprotection of relatively
labile acetyl groups on heteroatoms. Altogether, the strategy of
triacetylation of indolin-2-ones followed by selective as well as
complete deacetylation could give us an easy access to mono- and
di-acetyl substituted 2-hydroxyindoles.
Acetylation on 1-substituted indolin-2-ones (7e11) and indoline-2-thiones (12, 13)
Entry
Substrate
Product
Reaction
time (h)
Product
(% yield)
To systematically conclude our preliminary study6 on the acetyl-
ation of indolin-2-ones, we have examined the chemoselective
acetylation and deacetylation of variously substituted indolinones in
this report. The multi-acetyled products were subjected to deacety-
lation under enzyme-catalyzed transesterification and chemical
hydrolysis conditions to produce O-deacetylated and N,O-dideace-
tylated products, respectively. Herein, we wish to report a general
syntheses of 3-acetyl-2-hydroxyindoles, 1,3-diacetyl-2-hydroxyin-
doles, and 2-acetoxy-1,3-diacetylindoles from indolin-2-ones in ex-
cellent yields.
1
4
4
4
81
78
80
2
3
2. Results and discussions
Acetylation of indolin-2-one (1) at N-1 using acetic anhydride is
well documented in the literature,18 however, a one-pot multiple
acetylation on this framework was unprecedented until our pre-
liminary report was published recently.6 DMAP is a general catalyst
well-known to catalyze acylation, alkylation, carbonylation, de-
hydration, esterification, nucleophilic substitution, etc. reactions
involving a variety of functional groups.19 The results of our pre-
liminary investigation are summarized here. A systematic in-
vestigation of this unique reaction revealed the triacetylated indole
derivative being the exclusive product in the case of acetic anhydride
(Table 1, entries 1 and 2). However, when higher anhydrides namely
propanoic and butyric anhydrides were used as acyl group donors,
4
5
4
4
94
90
Table 1
6
7
8
2
1
4
71
94
78
Multiple acylation on indolin-2-ones 1 and 2
O
R'
O
O
OX
R'
R'
O
R'
N
R
O
150 °C
DMAP
N
H
R
O
3 R = H, X = COR'
4
R = Cl, X = COR'
1 R = H
5 R = H, X = H
2
R = Cl
6
R = Cl, X = H
Entry
Substrate
Anhydride (R0)
Reaction time (h)
Product (% yield)
1
2
3
4
1
2
1
1
Me
Me
Et
4
1
4
4
3 (95)
4 (93)
5 (76)
6 (82)
of the reaction mixture led to the diacetylation at N and S producing
1-acetyl-1H-indol-2-yl ethanethioate (19, Table 2, entry 8). On the
contrary, the presence of an electron withdrawing acetyl group in 10
and 11 was detrimental to the chemoselectivity. In these cases the
triacetylated indole was isolated as a major product of the reaction
(Table 2, entries 4 and 5).
Previously, the syntheses of 3-acetyl-1-alkyl-2-hydroxyindoles
have been reported in three steps starting from substituted ani-
lines.22,23 Our one-step facile formation of 3-acetyl-1-alkyl-2-
hydroxyindoles (14e16) in good yields from easily available starting
materials represents a very simple and inexpensive alternative
procedure to access this framework.
To further widen the substrate scope of the triacetylation re-
action, we selected a range of variously substituted indolin-2-ones
(20e26) with variations in functional groups and the position of
their substitution on the indole ring. The indolin-2-ones 21, 22, 25,
and 26 were obtained from commercial sources, whereas 20, 23,
and 24 were synthesized from corresponding isatins using literature
Pr
the acylation occurred at only two positions, N and 3-C, in the major
product (Table 1, entries 3 and 4). A trace amount of (>5%) of tri-
acylated product was also isolated from the reaction mixture in these
cases. It is likely that the steric bulk imparted by longer chain acyl
groups might be slowing the formation of the triacylated products.
To exhibit the substrate variability, 1-alkylindolin-2-ones, indo-
line-2-thione, and 1-alkylindolin-2-thione, obtained using literature
procedures,20,21 were included in the preliminary study. Rather in-
teresting results were obtained with these substrates when subjected
to the acetic anhydride/DMAP reaction condition. 1-Alkylindolin-2-
one (7e9) and 1-methylindoline-2-thione (12) were chemo-
selectively monoacetylated to 3-acetyl-1-alkyl-2-hydroxyindoles
14e16 and 3-acetyl-1-alkyl-2-mercaptoindole (17), respectively
(Table 2). Whereas, in the case of indoline-2-thione (13) the acety-
lation first occurred at S (Table 2, entry 7), while a prolonged heating

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M. Jha et al. / Tetrahedron 67 (2011) 982e989
procedure. The indolin-2-ones were then subjected to acetic an-
hydride and 1 mol % DMAP at 150 ꢀC to obtain the 2-acetoxy-1,3-
diacetylindoles. As shown in Table 3, the reaction time for the
acetylation reaction of substituted indolin-2-one was generally
shorter than that for the unsubstituted analog 1. In most cases the
reaction was completed within 2 h, whereas indolin-2-one (1) re-
quired 4 h to undergo completion. The isolation of the desired
multi-acetylated products was straight forward. The reaction
Table 3
Multiple acylation on indolin-2-ones and indoline-2-thiones followed by CALB-catalyzed chemoselective O-deacetylation
Entry
1
Indolin-2-one
Product (% yield)
Reaction time (h)
Producta
Reaction time (h)
4
1
2
3
4
5
6
7
8
4
2
2
2
2
2
4
No reaction
1 Control (no enzyme)
1
1
1
1
1
4
9
1
2
1
3
10

M. Jha et al. / Tetrahedron 67 (2011) 982e989
985
Table 3 (continued )
Entry
Indolin-2-one
Product (% yield)
Reaction time (h)
1
Producta
Reaction time (h)
72
11
No reaction
12
4
No reaction
72
a
The products were obtained in quantitative yields in all the cases.
mixture was stripped off of the excess acetic anhydride under high
vacuum. The resulting residue was suspended in cold methanol and
the precipitate obtained was vacuum filtered followed by a wash
with hexanes. The triacetylation proceeded efficiently in almost all
cases (Table 3), except for 5-nitro indolin-2-one (25) where the
product yield was slightly lower (entry 8). The result obtained for
the acetylation of 7-chloroindolin-2-one (26) was anomalous with
respect to other indolinones. A diacetylated product 34 was
obtained in which the 3-C and the O at C-2 of 26 were acetylated but
the N-1 remained free from acetyl substitution (Table 3, entry 10).
This anomaly in the reactivity of 26 might be caused by the steric
hindrance imparted by the chloro group being present in close
proximity to the N-1. The thione analog 27 underwent diacetylation
analogous to indoline-2-thione (Table 3, entries 11 and 12). To ob-
tain an additional example of a multi-acetylated indole, acetylation
of compound 6 was attempted in the presence of acetic anhydride
and DMAP. Interestingly, the butanoyl group on N of 6 was
substituted with the acetyl group 6a under this reaction condition.
After having synthesized a number of 2-acetoxy-1,3-diac-
etylindoles, we set out to study selective deacetylations to produce
indole derivatives amenable to further chemical manipulations.
The acetyl group at heteroatoms (N, O, and S) are chemically labile
under hydrolytic conditions and can be deprotected simulta-
neously. To achieve selective deacetylation, we chose to employ the
commercially available immobilized enzyme CALB (NovozymeÒ
435) to carry out the desired transformations. The motivation of
using enzyme-assisted reactions in lieu of chemical conditions also
stems from their ‘green’ properties, such as clean and quantitative
conversion, mild conditions, catalyst recycling, and low waste
production. In a test reaction, a solution of 1,3-diacetyl-2-hydrox-
yindole (3) in THF was mixed with the enzyme CALB and 1-butanol
as acetyl acceptor. The enzyme was not introduced in the control
reaction mixture and only consisted of a solution of compound 3
and 1-butanol in THF. The reaction mixtures were shaken vigor-
ously at room temperature and the progress was monitored by thin
layer chromatography (TLC). After the reaction was completed (1 h)
the enzyme was filtered off, the solvent was evaporated under
vacuum and the product was analyzed by NMR. We were quite
pleased to observe that a chemoselective O-deacetylation took
place in quantitative yield to produce the desired product 36 (Table
3, entry 1). Under the control reaction conditions, the compound 3
did not undergo any transformation in 1 h and only the starting
material was isolated from the reaction mixture. After validating
the enzyme-assisted chemoselective O-deacetylation reaction,
eight 2-acetoxy-1,3-diacetylindoles and two thioesters were sub-
jected to the deacetylation reaction. As shown in Table 3, the en-
zymatic deacetylation proceeded in quantitative yields in all the
cases. There was a marked difference in the reactivity of 2-acetoxy-
1,3-diacetyl-5-nitroindole (33) and 2-acetoxy-1-acetyl-7-chlor-
oindole (34) where the reaction rate was found to be somewhat
slower toward the deacetylation reaction. The relatively high po-
larity of these compounds might be causing the slowdown in the
enzymatic transformation reaction. Furthermore, the thioesters 19
and 35 were not found to be the substrates for the enzyme studied.
No transformation was observed for 19 and 35 even after 72 h of
stirring (Table 3, entries 11 and 12).
Chemically, 2-acetoxy-1,3-diacetylindole (3) contains an ester and
an amide group. Owing to extra stability of the amide functionality, it
is possible to selectively perform chemical hydrolysis of the ester
group in the presence of an amide group.10 Thus, we attempted to
effect selective ester hydrolysis of 2-acetoxy-1,3-diacetylindole (3) to
ascertain if there is any merit in the use of the enzyme-assisted
deacetylation process described in this report. As shown in Table 4,
four hydrolytic conditions were chosen to carry out the desired
transformation. The reaction conditions were selected so as to rep-
resent mild and relatively harsh acidic and basic conditions for the
desired hydrolysis. The hydrolysis was found to be significantly
slower under acidic conditions relative to the basic conditions.
However, the reactions resulted in indiscriminate deacetylation
leading to 3-acetyl-2-hydroxyindole in all cases (Table 4). The best
result was obtained in 5% NaOH/THF (1:1) at room temperature fol-
lowed by acidification with dil HCl (Table 4, entry 3). Although the
chemical deacetylation did not afford the desired selective O-deace-
tylation, the double deacetylation of 2-acetoxy-1,3-diacetylindole (3)
represents a novel and mild method for the synthesis of 3-acetyl-2-
hydroxyindole (45) from indolin-2-one. The synthesis of 45 has been
reported previously starting from o-acetoacetochloroanilide in the
presence of potassium amide/ammonia in 67% yield.24 Another group
reported the synthesis of related 3-acetyl-6-bromooxindole from 6-
bromooxindole in three steps.25 In this synthesis the acetyl group was
indirectly installed at the 3 position by first acetylating 6-bromoox-
indole and treating 1-acetyl-6-bromooxindole with triethyl orthoa-
cetate followed by a basic cleavage of the resulting enol ether. Also, it
was interesting to note that the product of chemical deacetylation 45,
despite being a 1,3-diketone, is stable under harsh basic conditions
unlike normal 1,3-diketones.26 This stabilization is presumably due to
the aromatic effect of the indole nucleus.
Table 4
Chemical deacetylation of 2-acetoxy-1,3-diacetylindole 3
Entry
Reaction conditions
Reaction time (h)
% Yield
1
2
3
4
5% HCl/THF (1:1), rt
24
12
1
97
94
95
95
5% HCl/THF (1:1), 80 ꢀC
5% NaOH/THF (1:1), rt
5% NaOH/THF (1:1), 80 ꢀC
1
To further investigate and consolidate the results of double
deacetylation, under chemical conditions several 2-acetoxy-1,3-
diacetylindoles 4, 28e30, and 32 were subjected to the base-

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M. Jha et al. / Tetrahedron 67 (2011) 982e989
promoted hydrolysis. The results shown in Table 5 indicate that the
chemical hydrolysis went smoothly in all the cases in excellent
yields. No significant substitution effect was observed in the re-
action and the hydrolysis was complete within 1 h.
diacetylindoles to give 3-acetyl-2-hydroxyindoles in excellent
yields. The multiple acetylation followed by a chemical double
deacetylation reaction sequence represents a new, efficient and
general procedure for the synthesis 3-acetyl-2-hydroxyindoles.
4. Experimental
4.1. General
Table 5
Chemical deacetylation of 2-acetoxy-1,3-diacetylindoles 3, 4, 28e30, and 32
All reagents and solvents were used as supplied by commercial
sources without further purification. Melting points were mea-
sured using a MEL-TEMP II apparatus and are uncorrected. Pre-
coated fluorescent silica gel TLC plates were used to monitor the
progress of the reactions. IR spectra were recorded on a Nicolet
MAGNA-IR 560 Spectrophotometer. 1H and 13C NMR spectra were
obtained by a Bruker AV300 spectrometer. Chemical shifts of the 1H
NMR spectra are reported in parts per million (ppm) downfield
from tetramethylsilane. The GCeEIMS mass spectra were recorded
using Varian-450 GC instrument equipped with Varian 240-MS IT
mass spectrometer. HR-ESIMS spectra were obtained at the De-
partment of Chemistry, Dalhousie University, by Mr. Xiao Feng.
Entry
Triacetylated
indole
Product
Product
(% isolated yield)
1
3
45 (91)
46 (88)
47 (89)
48 (83)
2
3
4
28
29
30
4.2. General procedure for the synthesis of indolin-2-ones
from isatins
A mixture of substituted isatin (12.3 mmol), hydrazine hydrate
(368 mmol), potassium hydroxide (245 mmol), and ethylene glycol
(242 mmol) were heated at 100 ꢀC for 1 h. The reaction mixture was
cooled on ice bath and acidified using concd HCl (drop wise addi-
tion) along with vigorous stirring. The precipitated product was
vacuum filtered and washed with hexanes to give substituted
indolin-2-ones in 90e95% yield.
4.3. General procedure for DMAP-catalyzed acetylation of
indolin-2-ones and indoline-2-thiones
5
6
32
49 (85)
50 (88)
Appropriate indolin-2-one or indoline-2-thione (0.3 g) was
mixed with acetic anhydride (3 mL) and 4-dimethylaminopyridine
(DMAP, 1 mol %). The mixture was heated at 150 ꢀC in a round-
bottomed flask equipped with an air condenser and CaCl2 guard
tube. The reaction time for each reactant is provided in Tables 2 and
3. After the completion of the reaction excess acetic anhydride was
evaporated under reduced pressure. The solid residue obtained in
the case of the triacetylated products was suspended in cold
methanol and vacuum filtered. The product collected was thor-
oughly washed with hexane and dried. In the case of mono and
diacetylated products the solid residue was purified using flash
column chromatography (FCC) (silica gel, hexanes/ethyl acetate).
4
3. Conclusions
The development of efficient and practical strategies to further
expand the diversity of indole-based heterocycles is highly desir-
able in organic synthesis. We have developed a simple synthesis of
N-substituted 3-acetyl-2-hyroxyindoles starting from indolin-2-
ones, which can be used as building blocks to access newer indole
heterocycles. N-Alkylated 3-acetyl-2-hydroxyindoles can be di-
rectly obtained upon treating N-alkylated indolin-2-one with acetic
anhydride in the presence of a catalytic amount of DMAP. The
strategy for the synthesis of N-acetylated 3-acetyl-2-hyroxyindoles
involves two steps starting from indolin-2-ones. First, the indolin-2-
one moieties are peracetylated in the presence of acetic anhydride
and DMAP leading to 2-acetoxy-1,3-diacetylindoles in excellent
yields. Subsequently, CALB enzyme-catalyzed chemoselective
deacetylation gave rise to 1,3-diacetyl-2-hydroxyindoles in overall
excellent yields. The use of an enzyme-catalyzed transformation
makes this step environmentally friendly. On the contrary, the
deacetylation under mild chemical conditions led to a non-selective
removal of the acetyl groups from N and O of 2-acetoxy-1,3-
4.3.1. 1,3-Diacetyl-1H-indol-2-yl acetate (3). Yield 95%. Mp: 137e
139 ꢀC (methanol). 1H NMR (300 MHz, CDCl3):
d
8.31 (d, J¼8 Hz, 1H),
7.61 (d, J¼7.5, 1H), 7.34 (dd, J¼8, 8 Hz, 1H), 7.21 (dd, J¼8, 8 Hz, 1H),
2.74 (s, 3H), 2.72 (s, 3H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
170.9, 167.8, 167.0, 161.8, 137.8, 129.1, 124.9, 122.9, 121.6, 116.3, 115.5,
27.0, 21.3, 19.0. FT-IR nmax (KBr): 3471, 1757, 1742, 1698, 1460,
748 cmꢁ1. GCeMS (EI): m/z (% relative abundance) 259 (Mþ, 5), 217
(40), 175(100), 150 (35), 129 (10). ESI-HRMS (amu): calcd
C14H13NNaO4 [MþNa]þ: 282.0742; found [MþNa]þ: 282.0745.
4.3.2. 3-Diacetyl-6-chloro-1H-indol-2-yl acetate (4). Yield 93%. Mp:
166e168 ꢀC (methanol). 1H NMR (300 MHz, CDCl3):
d
8.37 (s, 1H),
7.53 (d, J¼8 Hz, 1H), 7.19 (d, J¼8 Hz, 1H), 2.74 (s, 3H), 2.71 (s, 3H),
2.44 (s, 3H). 13C NMR (75 MHz, CDCl3):
170.7, 167.5, 166.8, 162.4,
d
138.4, 134.7, 125.0, 123.6, 120.1, 116.9, 114.7, 26.9, 21.3, 19.1. FT-IR
nmax (KBr): 3128, 1747, 1710, 1655, 1466, 742 cmꢁ1. GCeMS (EI): m/z
(% relative abundance) 293 (Mþ, 3), 253 (13) 251 (38), 211 (34), 209

M. Jha et al. / Tetrahedron 67 (2011) 982e989
987
(100), 162 (35), 129 (7). ESI-HRMS (amu): calcd C14H12ClNNaO4
100), 190 (100), 117 (14). ESI-HRMS (amu): calcd C11H12NOS
[MþNa]þ: 316.0353; found [MþNa]þ: 316.0353.
[MþH]þ: 206.0640; found [MþH]þ: 206.0629.
4.3.3. 1,10-(2-Hydroxy-1H-indole-1,3-diyl)dipropan-1-one (5). The
product was isolated using FCC (silica gel, hexanes/ethyl acetate) in
76% yield. Mp: 73e74 ꢀC (hexanes/ethyl acetate). 1H NMR
4.3.9. S-1H-Indol-2-yl ethanethioate (18). The product was isolated
using FCC (silica gel, hexanes/ethyl acetate) in 94% yield. Mp:
101e103 ꢀC (hexanes/ethyl acetate). 1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3):
2H), 7.24 (m, 2H), 3.18 (q, 2H), 2.82 (q, 2H), 1.34 (m, 6H). 13C NMR
(75 MHz, CDCl3): 180.2, 174.7, 172.3, 135.4, 125.6, 124.7, 122.6,
d
13.69 (s, 1H), 8.36 (d, J¼7.5 Hz, 1H), 7.35 (m,
d
8.66 (br s, 1H, D2O exchangeable), 7.64 (d, J¼8 Hz, 1H), 7.39 (d,
J¼8 Hz, 1H), 7.26 (dd, J¼8 Hz, 1H), 7.16 (dd, J¼7.5 Hz, 1H), 6.73 (s,
1H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3):
194.9, 137.8, 127.9,
d
d
119.2, 116.5, 100.6, 32.2, 27.6, 9.6, 8.4. FT-IR nmax (KBr): 2934, 1717,
1661, 1475, 738 cmꢁ1. GCeMS (EI): m/z (% relative abundance) 245
(Mþ, 28), 289 (100), 150 (75), 133 (15). ESI-HRMS (amu): calcd
C14H15NNaO3 [MþNa]þ: 268.0950; found [MþNa]þ: 268.0937.
123.4, 121.3, 120.8, 120.4, 111.1, 109.9, 30.1. FT-IR nmax (KBr): 3343,
1685, 1438, 1110, 743 cmꢁ1. GCeMS (EI): m/z (% relative abundance)
191 (Mþ, 100), 149 (37), 121 (10). ESI-HRMS (amu): calcd
C10H9NNaOS [MþNa]þ: 214.0303; found [MþNa]þ: 214.0290.
4.3.4. 1,10-(2-Hydroxy-1H-indole-1,3-diyl)dibutan-1-one (6). The
product was isolated using FCC (silica gel, hexanes/ethyl acetate) in
82% yield. Mp: 52e54 ꢀC (hexanes/ethyl acetate). 1H NMR (300 MHz,
4.3.10. S-1-Acetyl-1H-indol-2-yl ethanethioate (19). The product was
isolated using FCC (silica gel, hexanes/ethyl acetate) in 78% yield. Mp:
52e54 ꢀC (hexanes/ethyl acetate). 1H NMR (300 MHz, CDCl3):
d 8.21
CDCl3):
d
13.70 (s,1H), 8.35 (d, J¼8.5 Hz,1H), 7.36 (s,1H), 7.24 (m, 2H),
(d, J¼8.5 Hz, 1H), 7.60 (d, J¼7.5 Hz, 1H), 7.41 (dd, J¼7.5 Hz, 1H), 7.30
(dd, J¼7.5 Hz,1H), 7.03 (s,1H), 2.79 (s, 3H), 2.47 (s, 3H). D2O exchange
experiment did not result any change in 1H NMR spectrum. 13C NMR
3.16 (t, J¼7.5 Hz, 2H), 2.78(t, J¼7.5 Hz, 2H),1.85(m, 4H)1.12(m, 6H).13C
NMR (75 MHz, CDCl3): d 179.5, 173.9, 172.3, 135.5, 125.9, 124.7, 122.6,
119.2,116.6,101.1, 40.5,36.0,19.2,17.8,14.0,13.8. FT-IRnmax (KBr):2952,
1713, 1670, 1457, 743 cmꢁ1. GCeMS (EI): m/z (% relative abundance)
273 (Mþ, 15), 203 (100), 160 (48), 133 (22). ESI-HRMS (amu): calcd
C16H19NNaO3 [MþNa]þ: 296.1263; found [MþNa]þ: 296.1261.
(75 MHz, CDCl3): d 193.3, 170.0, 138.3, 128.6, 126.2, 123.6, 122.4, 122.1,
121.0, 116.0, 29.8, 27.1. FT-IR nmax (KBr): 3347, 3011, 1690, 1440,
749 cmꢁ1. GCeMS (EI): m/z (% relative abundance) 234 (Mþ,100),191
(20), 149 (47). ESI-HRMS (amu): calcd C12H11NNaO2S [MþNa]þ:
256.0408; found [MþNa]þ: 256.0410.
4.3.5. 1-(2-Hydroxy-1-methyl-1H-indol-3-yl)ethanone (14)22a. The
product was isolated using FCC (silica gel, hexanes/ethyl acetate) in
81% yield. Mp: 110e111 ꢀC (hexanes/ethyl acetate). 1H NMR
4.3.11. 1,3-Diacetyl-5-fluoro-1H-indol-2-yl acetate (28). Melting
point: 133e135 ꢀC (methanol). 1H NMR (CDCl3, 300 MHz):
d 8.29
(300 MHz, CDCl3):
J¼7.5 Hz,1H), 7.12 (dd, J¼8 Hz,1H), 6.95 (d, J¼8 Hz, 1H), 3.35 (s, 3H),
2.46 (s, 3H). 13C NMR (75 MHz, CDCl3):
172.9, 171.0, 138.9, 125.2,
122.2, 122.1, 119.7, 108.4, 101.7, 25.6, 20.3. FT-IR nmax (KBr): 3058,
2932, 1655, 1466, 748 cmꢁ1. GCeMS (EI): m/z (% relative abun-
dance) 189 (Mþ, 100), 174 (80), 147 (17), 91 (24). ESI-HRMS (amu):
calcd C11H11NNaO2 [MþNa]þ: 212.0687; found [MþNa]þ: 212.0683.
d
13.67 (br s, 1H), 7.37 (d, J¼7.5 Hz, 1H), 7.23 (d,
(dd, J¼9.0, 5.0 Hz, 1H), 7.30 (dd, J¼8.7, 2.7 Hz, 1H), 7.04 (ddd, J¼9.0,
9.0, 2.7 Hz, 1H), 2.73 (s, 6H), 2.45 (s, 3H). 13C NMR (CDCl3, 75 MHz):
d
d
172.1, 168.9, 168.2, 164.5, 161.2 (d, 1JCeF¼242 Hz), 135.0, 124.1 (d,
3JCeF¼9 Hz),118.7 (d, 3JCeF¼9 Hz),116.6 (d, 2JCeF¼24 Hz),116.0,111.2
(d, 2JCeF¼26 Hz), 27.4, 21.8, 19.6. FT-IR nmax (KBr): 3452, 3122, 1738,
1700, 1650, 1474, 1194, 815 cmꢁ1
. ESI-HRMS (amu): calcd
C14H12FNNaO4 [MþNa]þ: 300.0643; found [MþNa]þ: 300.0644.
4.3.6. 1-(5-Chloro-2-hydroxy-1-methyl-1H-indol-3-yl)ethanone
(15)22b. The product was isolated using FCC (silica gel, hexanes/
ethyl acetate) in 78% yield. Mp: 126e128 ꢀC (hexanes/ethyl ace-
4.3.12. 1,3-Diacetyl-5-chloro-1H-indol-2-yl acetate (29). Melting
point: 127e128 ꢀC (methanol). 1H NMR (CDCl3, 300 MHz):
d
8.25 (d,
J¼8.9 Hz,1H), 7.57 (s, 1H), 7.30 (d, J¼8.5 Hz,1H), 2.73 (s, 6H), 2.46 (s,
3H). 13C NMR (CDCl3, 75 MHz):
171.1, 167.6, 167.2, 163.7, 136.4,
130.5, 129.2, 123.4, 117.8, 114.9, 27.3, 21.7, 19.5. FT-IR nmax (KBr):
tate). 1H NMR (300 MHz, CDCl3)
d
: 13.56 (br s, 1H), 7.34 (s, 1H), 7.21
d
(d, J¼8.5 Hz, 1H), 6.88 (d, J¼8.5 Hz, 1H), 3.36 (s, 3H), 2.47 (s, 3H). 13C
NMR (75 MHz, CDCl3):
d
174.3, 170.9, 137.3, 127.6, 124.9, 123.7, 119.8,
3436, 1701, 1163, 1014, 882 cmꢁ1
. ESI-HRMS (amu): calcd
109.1, 101.2, 25.8, 20.4. FT-IR nmax (KBr): 3441, 1653, 1486, 708 cmꢁ1
.
C14H12ClNNaO4 [MþNa]þ: 316.0347; found [MþNa]þ: 316.0345.
GCeMS (EI): m/z (% relative abundance) 225 (33), 223 (Mþ, 100),
210 (30), 208 (85), 117 (33). ESI-HRMS (amu): calcd C11H10ClNNaO2
[MþNa]þ: 246.0298; found [MþNa]þ: 246.0294.
4.3.13. 1,3-Diacetyl-5-bromo-1H-indol-2-yl acetate (30). Melting
point: 121e123 ꢀC (methanol). 1H NMR (CDCl3, 300 MHz):
d
8.20 (d,
J¼8.4 Hz, 1H), 7.73 (s, 1H), 7.45 (d, J¼8.1 Hz, 1H), 2.73 (s, 6H), 2.46 (s,
3H).13C NMR (CDCl3, 75 MHz):
177.2,171.0,167.1,163.7,136.8,132.0,
4.3.7. 1-(1-Benzyl-5-chloro-2-hydroxy-1H-indol-3-yl)ethanone
(16). The product was isolated using FCC (silica gel, hexanes/ethyl
acetate) in 80% yield. Mp: 127e128 ꢀC (hexanes/ethyl acetate). 1H
d
129.0, 126.2, 123.8, 118.2, 115, 27.3, 21.7, 19.5. FT-IR nmax (KBr): 3442,
1699, 1670, 1618, 1456, 1370, 1164 cmꢁ1. ESI-HRMS (amu): calcd
C14H12BrNNaO4 [MþNa]þ: 359.9842; found [MþNa]þ: 359.9846.
NMR (300 MHz, CDCl3):
d 13.52 (br s, 1H), 7.32 (m, 6H), 7.09 (d,
J¼8.5 Hz, 1H), 6.77 (d, J¼8.5 Hz, 1H), 5.04 (s, 2H), 2.48 (s, 3H). 13C
NMR (75 MHz, CDCl3):
d
174.7, 170.9, 136.3, 135.7, 128.9, 127.8, 127.7,
4.3.14. 1,3-Diacetyl-5-iodo-1H-indol-2-yl acetate (31). Melting point:
93e95 ꢀC (methanol). 1H NMR (CDCl3, 300 MHz): 8.09 (d, J¼8.7, 1H),
7.94 (s, 1H), 7.63 (d, J¼8.5, 1H), 2.72 (s, 6H), 2.45 (s, 3H). 13C NMR
127.2, 124.9, 123.8, 119.8, 110.1, 101.1, 43.4, 20.5. FT-IR nmax (KBr):
3031,1660,1434, 750 cmꢁ1. GCeMS (EI): m/z (% relative abundance)
301 (17), 299 (Mþ, 54), 179 (7), 91 (100). ESI-HRMS (amu): calcd
C17H15ClNO2 [MþH]þ: 300.0791; found [MþH]þ: 300.0777.
(CDCl3, 75 MHz): d 178.0, 171.1, 167.2, 163.4, 138.0, 135.1, 132.2, 128.2,
124.1, 118.5, 88.9, 27.3, 21.6, 19.5. FT-IR nmax (KBr): 3444, 1736, 1645,
1457, 1368, 1162 cmꢁ1
. ESI-HRMS (amu): calcd C14H12INNaO4
4.3.8. 1-(2-Mercapto-1-methyl-1H-indol-3-yl)ethanone (17). The
product was isolated using FCC (silica gel, hexanes/ethyl acetate) in
71% yield. Mp: 164e166 ꢀC (hexanes/ethyl acetate). 1H NMR
[MþNa]þ: 407.9703; found [MþNa]þ: 407.9683.
4.3.15. 1,3-Diacetyl-5-methyl-1H-indol-2-yl acetate (32). Melting
(300 MHz, CDCl3):
J¼7.5 Hz, 1H), 7.30 (m, 2H), 7.18 (d, J¼7.5, 1H), 3.73 (s, 3H), 2.66 (s,
3H). 13C NMR (75 MHz, CDCl3):
180.3, 177.6, 141.2, 125.6, 125.1,
d
15.66 (br s, 1H, D2O exchangeable), 7.52 (d,
point: 120e123 ꢀC (methanol). 1H NMR (CDCl3, 300 MHz):
d
8.15 (d,
J¼8.1 Hz, 1H), 7.37 (s, 1H), 7.12 (d, J¼8.2 Hz, 1H), 2.70 (s, 3H), 2.68 (s,
3H), 2.43 (s, 3H), 2.36 (s, 3H). 13C NMR (CDCl3, 75 MHz):
171.1,
d
d
123.2, 120.3, 112.1, 109.3, 29.3, 22.7. FT-IR nmax (KBr): 2935, 1595,
1443, 747 cmꢁ1. GCeMS (EI): m/z (% relative abundance) 205 (Mþ,
168.4, 167.4, 161.7, 136.0, 134.6, 130.3, 123.8, 121.9, 116.4, 116.0, 27.3,
21.8, 21.7, 19.4. FT-IR nmax (KBr): 3452, 2913, 1750, 1742, 1654, 1479,

988
M. Jha et al. / Tetrahedron 67 (2011) 982e989
2
1174, 818. ESI-HRMS (amu): calcd C15H15NNaO4 [MþNa]þ:
296.0893; found [MþNa]þ: 296.0889.
2JCeF¼24 Hz), 106.9 (d, JCeF¼26 Hz), 101.7, 27.2, 21.3. FT-IR nmax
(KBr): 3456, 3011, 1762, 1700, 1474, 1195, 815 cmꢁ1 ESI-HRMS (amu):
calcd C12H10FNNaO3 [MþNa]þ: 258.0537; found [MþNa]þ: 258.0531.
4.3.16. 1,3-Diacetyl-5-nitro-1H-indol-2-ylacetate(33). Melting point:
132e134 ꢀC (methanol).1H NMR (CDCl3, 300 MHz):
d
8.52(s,1H), 8.47
(d, J¼9.0 Hz, 1H), 8.26 (d, J¼7.8 Hz, 1H), 2.79 (s, 3H), 7.78 (s, 3H), 2.53
(s, 3H). 13C NMR (CDCl3, 75 MHz):
171.2, 167.3, 167.0, 165.8, 145.0,
4.4.3. 1,3-Diacetyl-5-chloro-2-hydroxyindole (38). Melting point:
145e147 ꢀC (THF). 1H NMR (CDCl3, 300 MHz):
d
13.41 (br s, 1H, D2O
exchangeable), 8.18 (s, 1H), 7.25e7.16 (m, 2H), 2.72 (s, 3H), 2.47 (s,
3H). 13C NMR (CDCl3, 75 MHz):
177.1, 171.9, 170.8, 133.8, 130.6,
126.0, 124.6, 119.5, 117.9, 101.2, 27.1, 21.4. FT-IR nmax (KBr): 3444,
d
142.3, 125.1, 122.7, 118.6, 116.7, 114.0, 27.3, 21.7, 19.7. FT-IR nmax (KBr):
3432,1773,1700,1653,1559,1347,1159 cmꢁ1. ESI-HRMS (amu): calcd
C14H12N2NaO6 [MþNa]þ: 327.0588; found [MþNa]þ: 327.0568.
d
1712, 1635, 1368, 1169, 810 cmꢁ1
. ESI-HRMS (amu): calcd
C12H9ClNO3 [MꢁH]ꢁ: 250.0276; found [MꢁH]ꢁ: 250.0275.
4.3.17. 3-Acetyl-7-chloro-1H-indol-2-yl acetate (34). Melting point:
179e180 ꢀC (methanol). 1H NMR (CDCl3, 300 MHz):
d
8.09 (br s, 1H,
4.4.4. 1,3-Diacetyl-5-bromo-2-hydroxyindole (39). Melting point:
D2O exchangeable), 7.39 (d, J¼7.7 Hz, 1H), 7.21 (d, J¼8.1 Hz, 1H),
140e144 ꢀC (THF). 1H NMR (CDCl3, 300 MHz):
d
13.49 (s, 1H, D2O ex-
changeable), 8.20 (d, J¼8.4 Hz,1H), 7.46 (s,1H), 7.36 (d, J¼8.4 Hz,1H,),
2.75 (s, 3H), 2.51 (s, 3H).13C NMR (CDCl3, 75 MHz):
177.2, 171.9, 170.8,
6.27 (dd, J¼8.0, 7.9 Hz, 1H), 2.72 (s, 3H), 2.42 (s, 3H). 13C NMR
(CDCl3, 75 MHz):
d
168.6, 167.4, 162.4, 136.8, 128.7, 123.3, 123.2,
d
122.2, 116.8, 115.3, 21.7, 18.7. FT-IR nmax (KBr): 3440, 2995, 1759,
1716, 1653, 1178, 794 cmꢁ1. ESI-HRMS (amu): calcd C12H10ClNNaO3
[MþNa]þ: 274.0241; found [MþNa]þ: 274.0023.
134.4,129.0,125.1,122.4,118.4,118.3,101.2, 27.2, 21.5. FT-IR nmax (KBr):
3425, 3068, 1699, 1624,1457, 1373,1289, 830 cmꢁ1. ESI-HRMS (amu):
calcd C12H9BrNO3 [MꢁH]ꢁ: 293.9771; found [MꢁH]ꢁ: 293.9773.
4.3.18. 1-Acetyl-6-chloro-1H-indol-2-yl ethanethioate (35). The
product was isolated using FCC (silica gel, hexanes/ethyl acetate) in
74% yield. Melting point: 70e72 ꢀC (hexanes/ethyl acetate). 1H NMR
4.4.5. 1,3-Diacetyl-5-iodo-2-hydroxyindole (40). Melting point:
129e131 ꢀC (THF). 1H NMR (CDCl3, 300 MHz):
d
13.42 (br s, 1H, D2O
exchangeable), 8.02 (d, J¼8.4, 1H), 7.58 (s, 1H), 7.54 (d, J¼8.4 Hz,
1H), 2.72 (s, 3H), 2.47 (s, 3H). 13C NMR (CDCl3, 75 MHz):
177.1,
171.3, 170.9, 135.1, 128.2, 125.4, 118.7, 100.9, 89.2, 27.3, 21.6. FT-IR
(CDCl3, 300 MHz):
d
8.31 (s, 1H), 7.47 (d, J¼8.3 Hz, 1H), 7.25 (d,
d
J¼8.4 Hz, 1H), 6.94 (s, 1H), 2.75 (s, 3H), 2.47 (s, 3H). 13C NMR (CDCl3,
75 MHz):
d
193.3, 170.3, 139.0, 132.8, 127.3, 124.7, 123.4, 122.2, 121.9,
nmax (KBr): 3445, 3125, 1750 cmꢁ1
. ESI-HRMS (amu): calcd
117.0, 30.2, 27.4. FT-IR nmax (KBr): 1705, 1412, 1310, 1210, 833,
C12H9INO3 [MꢁH]ꢁ: 341.9633; found [MꢁH]ꢁ: 341.9644.
601 cmꢁ1
.
ESI-HRMS (amu): calcd C12H10ClNNaO2S [MþNa]þ:
290.0013; found [MþNa]þ: 290.0003.
4.4.6. 1,3-Diacetyl-5-methyl-2-hydroxyindole (41). Melting point:
109e112 ꢀC (THF). 1H NMR (CDCl3, 300 MHz):
d 13.40 (br s, 1H, D2O
4.3.19. 1-(1-Acetyl-2-hydroxy-1H-indol-3-yl)butan-1-one (6a). The
product was isolated using FCC (silica gel, hexanes/ethyl acetate) in
81% yield (methanol). Melting point: 95e97.5 ꢀC. 1H NMR (CDCl3,
exchangeable), 8.16 (d, J¼7.6 Hz, 1H), 7.13 (s, 1H), 7.04 (d, J¼8.0 Hz,
1H), 2.73 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H). 13C NMR (CDCl3, 75 MHz):
d
175.5,172.5,170.9,134.7,133.5,127.0,123.1,120.2,116.1,102.0, 27.2,
300 MHz):
d
13.52 (br s, 1H, D2O exchangeable), 8.35 (d, J¼7.0 Hz,
21.8, 21.3. FT-IR nmax (KBr): 3444, 1700, 1653, 1559, 1177, 810 cmꢁ1
.
1H), 7.40 (d, J¼7.0 Hz, 1H), 7.28e7.26 (m, 2H), 3.17 (t, J¼7.3 Hz, 2H),
ESI-HRMS (amu): calcd C13H13NNaO3 [MþNa]þ: 254.0771; found
2.53 (s, 3H), 1.83 (m, 2H), 1.09 (t, J¼7.4 Hz, 3H). 13C NMR (CDCl3,
[MþNa]þ: 254.0771.
75 MHz):
d 175.7, 174.1, 172.2, 135.8, 126.3, 125.0, 123.1, 119.5, 116.9,
101.9, 40.9, 21.3, 18.1, 14.1. FT-IR nmax (KBr): 3441, 2962, 1629, 1459,
4.4.7. 1,3-Diacetyl-5-nitro-2-hydroxyindole (42). Melting point:
1192, 718 cmꢁ1
.
ESI-HRMS (amu): calcd C14H14NO3 [MꢁH]ꢁ:
149e150 ꢀC (THF). 1H NMR (CDCl3, 300 MHz):
d
13.43 (br s, 1H, D2O
exchangeable), 8.45 (d, 1H, J¼8.8 Hz), 8.21e8.15 (m, 2H), 2.80 (s,
3H), 2.63 (s, 3H). 13C NMR (CDCl3, 75 MHz):
178.8, 172.0, 171.0,
244.0979; found [MꢁH]ꢁ: 244.0972.
d
4.4. General procedure for CALB-catalyzed O-deacetylation of
2-acetoxy-1,3-diacetylindoles
145.2, 139.6, 124.1, 122.2, 116.8, 114.5, 100.8, 27.2, 21.7. FT-IR nmax
(KBr): 3440, 1717, 1653, 1558, 1506, 1170 cmꢁ1. ESI-HRMS (amu):
calcd C12H9N2O5 [MꢁH]ꢁ: 261.0517; found [MꢁH]ꢁ: 261.0503.
Appropriate 2-acetoxy-1,3-diacetylindole (0.2 g) was mixed
with CALB enzyme (0.2 g) and 1-butanol (1 equiv) in THF (6 mL).
The mixture was shaken vigorously (180 rpm) at ambient temper-
ature. The reaction time for each reactant is provided in Table 3.
After the completion of reaction the enzyme was filtered off and the
filtrate was rotary evaporated to obtain 1,3-diacetyl-2-hydrox-
yindoles in quantitative yields.
4.4.8. 1,3-Diacetyl-6-chloro-2-hydroxyindole (43). Melting point:
134e136 ꢀC (THF). 1H NMR (CDCl3, 300 MHz):
d
13.37 (s, 1H, D2O
exchangeable), 8.39 (s, 1H), 7.30e7.21(m, 2H), 2.77 (s, 3H), 2.51 (s,
3H). 13C NMR (CDCl3, 75 MHz):
176.2, 172.1, 170.8, 137.6, 136.1,
d
132.0, 125.2, 120.1, 117.5, 101.4, 27.2, 21.5. FT-IR nmax (KBr): 3444,
3125,1706,1310, 817, 620 cmꢁ1. ESI-HRMS (amu): calcd C12H9ClNO3
[MꢁH]ꢁ: 250.0276; found [MꢁH]ꢁ: 250.0265.
4.4.1. 1,3-Diacetyl-2-hydroxyindole (36). Melting point: 98e99 ꢀC
(THF). 1H NMR (CDCl3, 300 MHz):
d
13.45 (s, 1H, D2O exchangeable),
8.33 (d, J¼8.0 Hz, 1H), 7.38 (d, J¼6.7 Hz, 1H,), 7.28e7.25 (m, 2H), 2.78
(s, 3H), 2.52 (s, 3H). 13C NMR (CDCl3, 75 MHz):
175.9, 172.4, 171.0,
4.4.9. 3-Acetyl-7-chloro-2-hydroxyindole (44). Melting point: 117 ꢀC
(THF). 1H NMR (CDCl3, 300 MHz):
d 8.46 (br s,1H, D2O exchangeable)
d
7.35e7.05 (m, 3H), 2.5 (s, 3H). 13C NMR (CDCl3, 75 MHz): 175.9, 172.2,
133.7, 125.3, 124.7, 123.4, 118.6, 116.5, 102.6, 20.9. FT-IR nmax (KBr):
3444, 2962, 1744, 1559, 1540,772 cmꢁ1. ESI-HRMS (amu): calcd
C10H9ClNO2 [MþH]þ: 210.0316; found [MþH]þ: 210.0321.
135.7, 126.4, 125.1, 123.1, 119.6, 116.9, 102.0, 27.3, 21.3. FT-IR nmax
(KBr): 3452, 3125,1718,1670,1375,1175, 780 cmꢁ1. ESI-HRMS (amu):
calcd C12H11NNaO3 [MþNa]þ: 240.0631; found [MþNa]þ: 240.0626.
4.4.2. 1,3-Diacetyl-5-fluoro-2-hydroxyindole (37). Melting point:
4.5. General procedure for chemical deacetylation of
2-acetoxy-1,3-diacetylindoles
140e142 ꢀC (THF). 1H NMR (CDCl3, 300 MHz):
d 13.63 (br s, 1H, D2O
exchangeable), 8.31 (dd, J¼9.0, 5.0 Hz, 1H), 7.08 (dd, J¼8.9, 2.6 Hz,
1H), 6.96 (ddd, J¼9.0, 9.0, 2.6 Hz, 1H), 2.77 (s, 3H), 2.52 (s, 3H). 13C
Appropriate 2-acetoxy-1,3-diacetylindoles (0.2 g) was mixed with
5% NaOH and THF (1:1 v/v, 4 mL). The mixture was stirred at room
temperature for 1 h. The THF was evaporated under reduced pressure
NMR (CDCl3, 75 MHz):
d
176.9, 172.3, 170.8, 160.4 (d, 1JCeF¼242 Hz),
3
3
131.6, 124.7 (d, JCeF¼9.5 Hz), 118.1 (d, JCeF¼9 Hz), 112.7 (d,

M. Jha et al. / Tetrahedron 67 (2011) 982e989
989
and the residue was acidified using 1 M HCl to pH 2. The precipitated
Supplementary data
product was filtered off and washed with hexanes (Table 5).
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.11.105.
4.5.1. 3-Acetyl-2-hydroxyindole (45). Melting point: 195e197 ꢀC. 1H
NMR (CDCl3, 300 MHz):
(br s, 1H, D2O exchangeable), 7.38 (s, 1H), 7.18e7.04 (m, 3H), 2.50 (s,
3H). 13C NMR (CDCl3, 75 MHz):
174.3, 173.0, 136.5, 125.7, 123.1,
d 13.47 (br s, 1H, D2O exchangeable), 8.81
References and notes
d
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic: New York, NY, 1970; (b)
Sundberg, R. J. Pyrroles and Their Benzoderivatives: Synthesis and Applications
In. Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, UK, 1984; Vol. 4, pp 313e376; (c) Sundberg, R. J. In Best
Synthetic Methods, Indoles; Academic: New York, NY, 1996; pp 7e11; (d) Joule, J.
A. In Indole and its Derivatives. Science of Synthesis: HoubeneWeyl Methods of
Molecular Transformations; Thomas, E. J., Ed.; George Thieme: Stuttgart, Ger-
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122.5, 120.3, 110.7, 102.5, 20.8. FT-IR nmax (KBr): 3448, 3166, 3027,
1675, 1464, 1290, 744 cmꢁ1. ESI-HRMS (amu): calcd C10H8NO2
[MꢁH]ꢁ: 174.0561; found [MꢁH]ꢁ: 174.0549.
4.5.2. 3-Acetyl-5-fluoro-2-hydroxyindole (46). Melting point: 218e
222 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 8.09 (br s, 1H, D2O ex-
changeable), 8.31 (dd, J¼8.9, 2 Hz, 1H), 6.92e6.89 (m, 2H), 2.47 (s,
3H). 13C NMR (CDCl3, 75 MHz):
d 175.6, 172.9, 159.10 (d,
3
2
1JCeF¼238 Hz), 132.1, 124.3 (d, JCeF¼9 Hz), 112.1 (d, JCeF¼24 Hz),
3
2
110.9 (d, JCeF¼9 Hz), 107.8 (d, JCeF¼26 Hz), 101.6, 20.8. FT-IR nmax
(KBr): 3423, 3161, 1666, 1473, 1285, 899 cmꢁ1. ESI-HRMS (amu):
calcd C10H9FNO2 [MþH]þ: 194.0612; found [MþH]þ: 194.0613.
4.5.3. 3-Acetyl-5-chloro-2-hydroxyindole (47). Melting point: 239e
240 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 8.37 (s, 1H), 7.32 (s, 1H), 7.15 (d,
J¼6.5 Hz,1H), 6.93 (d, J¼8.4 Hz, 1H), 2.48 (s, H), 2.20 (s, 3H). 13C NMR
(CDCl3, 125 MHz):
d 175.6, 172.4, 134.4, 127.8, 125.3, 124.5, 120.2,
111.2, 101.7, 20.8. FT-IR nmax (KBr): 3445, 3169, 1667, 1445, 1292,
814 cmꢁ1. GCeMS (EI): m/z (% relative abundance) 209 (Mþ,100),191
(50), 163(27), 138 (22). ESI-HRMS (amu): calcd C10H9ClNO2 [MþH]þ:
210.0322; found [MþH]þ: 210.0308.
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M. Eur. J. Org. Chem. 2003, 2209e2219.
4.5.4. 3-Acetyl-5-bromo-2-hydroxyindole (48). Melting point: 201e
202 ꢀC. 1H NMR (CDCl3, 300 MHz):
d
13.50 (s, 1H), 8.20 (d, 1H,
J¼8.7 Hz), 7.47 (s, 1H), 7.36 (d, 1H, J¼8.7 Hz), 2.75 (s, 3H), 2.51 (s,
3H). 13C NMR (CDCl3, 125 MHz):
175.9, 172.5, 135.1, 128.3, 125.2,
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199e250.
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d
123.3, 115.5, 111.9, 101.2, 21.1. FT-IR nmax (KBr): 3419, 1704, 1622,
1288 cmꢁ1. GCeMS (EI): m/z (% relative abundance) 253 (Mþ, 70),
209 (75), 191 (72), 97 (75). ESI-HRMS (amu): calcd C10H7BrNO2
[MꢁH]ꢁ: 251.9660; found [MꢁH]ꢁ: 251.9670.
4.5.5. 3-Acetyl-5-methyl-2-hydroxyindole (49). Melting point: 214e
215 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 8.50 (s, 1H), 7.18 (s, 1H), 6.99 (d,
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1H, J¼8.0 Hz), 6.90 (d, 1H, J¼8.0 Hz), 2.48 (s, 3H), 2.40 (s, 3H). 13C
NMR (CDCl3, 75 MHz): d 174.0,173.0,134.2, 131.9,126.3, 123.2, 121.0,
110.3, 101.8, 21.8, 20.8. FT-IR nmax (KBr): 3455, 3172, 1669, 1614,
1287, 860 cmꢁ1. GCeMS (EI): m/z (% relative abundance) 189 (Mþ,
100), 143 (10). ESI-HRMS (amu): calcd C11H11NNaO2 [MþNa]þ:
212.0687; found [MþNa]þ: 212.0685.
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4.5.6. 3-Acetyl-6-chloro-2-hydroxyindole (50). Melting point: 228e
230 ꢀC.1H NMR (CDCl3, 300 MHz):
d 7.90 (br s,1H, D2O exchangeable),
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7.26 (s, 1H), 7.08 (dd, J¼8.2, 2 Hz, 1H), 7.01 (s, 1H), 2.47 (s, 3H). FT-IR
nmax (KBr): 3452, 3219, 1682, 1247 cmꢁ1. ESI-HRMS (amu): calcd
C10H7ClN2 [MꢁH]ꢁ: 208.0171; found [MꢁH]ꢁ: 208.0167.
Acknowledgements
Financial support from Nipissing University (M.J.) and Ontario
Work Study Program Nipwork (B.B.) is gratefully acknowledged. We
would also like to thank Laurentian University and Acadia Univer-
sity for granting access to their analytical facility.