Highly efficient one-pot C-, N- and O-acylation of indolin-2-one analogs

Article abstract of DOI:10.1016/j.tetlet.2009.08.057

A highly efficient one-pot multiple acylation at chemically non-equivalent sites on indolin-2-one and related motifs using 4-(N,N-dimethylamino)pyridine as a catalyst is described. This procedure gives extremely facile entry to highly desired 3-acyl-2-hyd

Full text of DOI:10.1016/j.tetlet.2009.08.057

Tetrahedron Letters 50 (2009) 6044–6047
Contents lists available at ScienceDirect
Tetrahedron Letters
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Highly efficient one-pot C-, N- and O-acylation of indolin-2-one analogs
*
Mukund Jha , 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:
Received 4 July 2009
Revised 2 August 2009
Accepted 18 August 2009
Available online 21 August 2009
A highly efficient one-pot multiple acylation at chemically non-equivalent sites on indolin-2-one and
related motifs using 4-(N,N-dimethylamino)pyridine as a catalyst is described. This procedure gives
extremely facile entry to highly desired 3-acyl-2-hydroxy-indole synthons among other derivatives.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Acetylation
Indole
Indolin-2-one
Indoline-2-thione
3-Acetyl-2-hydroxyindole
DMAP
Multiple acylation
The indole core is a prevalent substructure in many natural
products and biologically active compounds.1 Owing to its biolog-
ical importance, indole-based compounds attract special attention
as building blocks for the development of therapeutic agents by
medicinal chemists.2,3 Furthermore, many indole-based alkaloids
also serve as naturally occurring plant protecting agents, such as
phytoalexins.4 The interesting and remarkable bioactivity sur-
rounding the indole moiety continues to be a vector in the devel-
opment of new methodologies to find useful compounds. Thus,
the need for the development of efficient and practical syntheses
of indoles bearing a variety of substitution patterns is of great sig-
nificance. The indolin-2-one (1) moiety serves as a useful starting
compound in the synthesis of many indole-based molecules.5,6
Our research group derives substantial capability in the chemistry
of indole-based naturally occurring and synthetic bioactive mole-
cules through previous experiences.6,7 Building on this evolving
expertise, our research team is actively involved in exploring the
reactivity of indolin-2-ones and its application in the synthesis of
biologically relevant compounds. Acetylation of indolin-2-one (1)
using acetic anhydride is well documented in the literature,8 how-
ever, a one-pot multiple acetylation on this framework is unprece-
dented. Herein, we wish to report a highly efficient one-pot
carbon-, nitrogen- and oxygen-acylation on indolin-2-one motifs.
Similar acetylation reactions on 1-alkylindolin-2-ones, indoline-
2-thione and 1-methylindoline-2-thione resulted in one-step
syntheses of multi-acetylated and/or chemoselectively mono-acet-
ylated products.
Our investigation led to a facile and efficient synthesis of 3-acet-
yl-1-alkyl-2-hydroxyindoles among other synthetically useful in-
dole derivatives. Several 3-acetyl-1-alkyl-2-hydroxyindoles have
been prepared previously in three steps using substituted anilines
as starting compounds.9,10 In these cases, the anilines were first
treated with a diketene to give intermediate 3-oxo-N-alkyl-N-aryl-
butanamides, which upon reacting with tosyl azide and a base re-
sulted in 2-diazo-3-oxo-N-alkyl-N-arylbutanamides (Scheme 1).
The 2-diazo-3-oxo-N-alkyl-N-arylbutanamides, in the presence of
5 mol % Rh2(OAc)4, in benzene produced 3-acetyl-1-alkyl-2-
hydroxyindoles. Furthermore, while working towards the synthe-
sis of (+)-yatakemycin, Boger and co-workers have reported
chemoselective S-acetylation of complex indoline-2-thione in
77% yield by using acetic anhydride;11 our investigation also re-
ports a similar observation (vide infra). In another synthetically
demanding endeavour, aromatic o-stannylmethylated isothiocya-
nates have been used to prepare S-acylated 2-mercaptoindoles.12
The use of acetic anhydride for heteroatom acetylation is quite
common but there are relatively few reports known that describe
its use in C-acetylation unaided by Lewis acids. For instance, the
preparation of 3-acetoxy-2-acetylbenzofuran from 2-(2H)-benzof-
uranone under acidic conditions was reported by Bergman and
Egestad.13 Simig and co-workers have demonstrated the use of
DMAP (1.1 equiv) and an acyl chloride for C-acylation step in the
synthesis of tenidap, an antirheumatic drug developed by Pfizer.14
As mentioned previously, indolin-2-ones have been converted to
thecorresponding N-acetylderivativesusing acetic anhydrideunder
* Corresponding author.
E-mail address: mukundj@nipissingu.ca (M. Jha).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.057

M. Jha, B. Blunt / Tetrahedron Letters 50 (2009) 6044–6047
6045
Tosyl
azide,
Et3N
O
O
O
O
N2
Rh2OAc4
Benzene
R'
R'
R'
R'
OH
NHR
N
R
N
N
R
O
R
R = CH3 , Ph; R' = H, CH3 , OCH3
Scheme 1. Synthesis of 3-acetyl-2-hydroxyindoles9,10
reflux conditions.8 Reports in the literature and our own experience
suggest that this acetylation proceeds quite slowly. The reaction
generally requires 16–72 h for completion. In order to accelerate
the reaction rate we decided to use a catalyst (DMAP) for the acety-
lation reaction. DMAP is a general catalyst well known to catalyze
acylation, alkylation, carbonylation, dehydration, esterification,
nucleophilic substitution, etc. reactions involving a variety of func-
tionalgroups.15 Indeed, the useof 1 mol % of DMAPin the acetylation
reaction on indolin-2-one (1) increased the reaction rate signifi-
cantly.16 A thin layer chromatography (TLC) analysis revealed quan-
titative conversion to a single product in just 4 h. However, the
spectroscopic analysis of the isolated product indicated that more
than one acetylation had taken place on the indolin-2-one moiety.
In fact, three sites viz. –N, –O and 3-C of indolin-2-one (1) appeared
to have been acetylated in this single pot reaction.17 We decided to
systematically investigate the scope of this unique tri-acetylation
reaction in detail using indolin-2-one analogs and related com-
pounds with a variety of acyl anhydrides. The results summarized
in Table 1 indicate that the acetylation of 6-chloroindolin-2-one
(2) under similar reaction conditions also provided a tri-acetylated
product 4a in quantitative yield but the reaction time was reduced
to 1 h. The work-up16 for both the reactions (1 and 2) was relatively
straightforward; the excess of acetic anhydride was evaporated
under reduced pressure and the residues obtained were recrystal-
lized using methanol to give pure products. Furthermore, the
reactions of 1 with other anhydrides namely propionic and butyric
anhydrides (Table 1, entries 3 and 4) resulted in a mixture of
tri- (3b,c) and di- (5b,c) acylated products, the latter being the major
products. Because of high boiling nature of propionic and butyric
anhydrides, a work-up procedure similar to the one used for 1 and
2 was not easily amenable to remove the excess of anhydrides from
the reaction mixture. The reaction mixture was purified by partial
removal of acyl anhydride in vacuo and column chromatography
to obtain 1,3-diacyl-2-hydroxyindoles (5b,c) as major products
(Table 1). Isolation of the 5b and 5c as major products appears to
be a deviation from the exclusive triacylation witnessed in case of
acetylation reactions of compounds 1 and 2 (Table 1, entries 1 and
2). This deviation could have resulted from steric bulk imparted by
longer chain acyl groups. We plan to study this phenomenon in de-
tail in the near future.
The catalytic efficiency of DMAP for tri-acetylation can be ex-
plained as follows: the N of indole being the most nucleopilic8
likely gets acetylated first. Subsequently, the presence of elec-
tron-withdrawing acetyl group on N-1 position assists in the sec-
ond acetylation at C-3 of indole. The unique 1,3,5-tricarbonyl
system formed as a result, forces the acetylation of C-2 oxygen last
in this sequence of multiple acetylation.
After determining the generality of the reaction using a range of
acyl anhydrides we decided to restrict our study to acetic anhy-
dride and the use of various N-substituted indolin-2-ones (7–12)
which were synthesized following the previously published proce-
dures.8,18 Compounds 7–12 were subjected to acetylation reaction
in the presence of DMAP as described above. The catalytic acetyla-
tion of 1-alkylindolin-2-ones (7–10) resulted in the formation of
corresponding 3-acetyl-2-hydroxy derivatives (16–19) in good
yields (Table 2). It was interesting to note that C-monoacetylated
compounds, rather than expected O- and C-diacetylated products,
were exclusively formed. At this point, efforts were not made to
force O-acetylation by increasing the reaction time and/or applying
more heat. Formation of 3-acetyl-1-alkyl-2-hydroxyindoles (16–
19) in good yields from easily available starting materials and a
very simple and inexpensive reaction procedure is a significant
improvement to the previously reported three-step synthesis of
compounds of this type involving explosive diazo compounds
and expensive Rh catalyst.9,10 Mono-C-acetylation rather than di-
C- and O-acetylation in case of N-alkylated indolin-2-ones can be
explained, at least in part, due to the electron-donating nature of
N-alkyl groups which reduces the nucleophilicity of the chelated
enolic hydroxyl group. When electron-withdrawing N-acetyl
substituted indolin-2-ones 11 and 12 were reacted under similar
conditions, the tri-acetylated products 3a and 4a were obtained
in excellent yields (Table 2, entries 5 and 6).
To further expand the substrate scope of the reaction, synthet-
ically accessible indoline-2-thiones6 13 and 14 and commercially
Table 1
Reaction data for multiple acylation on indolin-2-ones 1 and 2
O
O
O
O
R'
OH
R'
R'
R'
R'
O
R'
+
O
O
N
150 ºC
DMAP
R
N
R'
N
H
R
R
O
O
O
5 R = H
6 R = Cl
1 R = H
2 R = Cl
3 R = H
4 R = Cl
Entry
Substrate
Anhydride (R’)
Reaction time (h)
Product 3/4 (% yield)
Product 5/6 (% yield)
1
2
3
4
1
2
1
1
Me
Me
Et
4
1
4
4
3a (95)
4a (93)
3b (<5)
3c (<5)
5a (<5)
6a (<5)
5b (76)
5c (82)
Pr

6046
M. Jha, B. Blunt / Tetrahedron Letters 50 (2009) 6044–6047
Table 2
Reaction data for acetylation on 1-substituted indolin-2-ones (7–12), indoline-2-thiones (13,14) and benzofuran-3-one (15)
Entry
Substrate
Product
Reaction time (h)
Product (% yield)
Ac
O
O
OH
1
4
81
N
N
Me
Me
7
16
Ac
OH
2
3
1
4
4
4
4
1
4
2
1
75
78
80
94
90
94
78
71
90
N
Bn
N
Bn
8
17
Ac
Cl
Cl
Cl
O
O
OH
OH
N
N
Me
Me
9
18
Ac
Cl
4
N
N
Bn
Bn
10
19
Ac
O
OAc
5
N
N
Ac
Ac
11
3a
Ac
O
OAc
6
N
Cl
N
Ac
Cl
Ac
12
4a
SAc
S
S
S
7
N
H
N
H
13
20
SAc
8
N
H
13
N
Ac
21
Ac
SH
Ac
9
N
N
Me
Me
14
22
O
OAc
10
O
O
15
23

M. Jha, B. Blunt / Tetrahedron Letters 50 (2009) 6044–6047
6047
available benzofuran-3-one (15) were treated with acetic anhy-
References and notes
dride in the presence of 1 mol % DMAP. The reactivity of thione
13 was found to be somewhat different than indolin-2-ones (1,2).
The TLC analysis revealed that the thione 13 was completely con-
sumed within one hour of the reaction. However, the spectroscopic
analysis of the product indicated that only S-acetylation had taken
place and compound 20 (S-acetylated 2-mercaptoindole) was iso-
lated in excellent yield (Table 2, entry 8). Heating for an additional
3 h resulted in the formation N,S-diacetylated product 21 in good
yield (Table 2, entry 9) but no C-acetylated product was isolated
from the reaction mixture. While the absence of C-acetylation in
this case initially appeared surprising but upon close inspection
it was discerned that the higher nucleophilicity of the S atom is
responsible for this. Subsequent acetylation occurred at N- which
is next in the order of nucleophilicity. After the N- and S-diacetyla-
tion, the nucleophilicity of the 3-C was lost and therefore no fur-
ther acetylation occurred under the applied reaction conditions.
On the contrary, the N-methyl substituted thione 14 reacted with
acetic anhydride in fashion similar to N-alkylindolin-2-ones
(7–10), giving rise to the 3-acetyl-2-mercapto product 22 in 71%
yield. This observation is consistent with the effect of electron-
donating N-alkyl group on the nucleophilicity of S/O on the neigh-
bouring C-2 carbon (vide supra). The reaction results indicate that
the electron-donating ability of N-methyl group becomes detri-
mental to the nucleophilicity of S at C-2. With the thione S unacet-
ylated, the C-3 carbon remains nucleophilic enough to undergo
acetylation. We will continue to investigate this aspect.
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Acetylation occurred at both C-2 and C-3 O-positions in the case
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In conclusion, we have described first one-pot multiple acyla-
tion of indolin-2-ones, indoline-2-thiones and benzofuran-3-one
using catalytic amount of DMAP and acyl anhydrides. Indolin-2-
ones devoid of N-alkyl substitution resulted in triacetylation at
N-1, C-2 O and C-3 carbon. N-Methylindolin-2-ones, under identi-
cal conditions, furnished N-methyl-3-acetyl-2-hydroxyindoles as
the major product. Indoline-2-thiones devoid of N-alkyl substitu-
tion underwent chemoselective monoacetylation on S after 1 h of
reaction time; prolonged reaction time led to the formation of
N- and S-diacetyl derivative. On the other hand, N-methylindo-
line-2-thione resulted in chemoselective monoacetylation at the
C-3 position. The variance in chemistry witnessed here by subtle
change in reactivity is quite interesting and warrants further inves-
tigation. The products obtained through this acylation study with
unprecedented results are extremely valuable in preparing a large
number of unexplored heterocyclic systems.
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16. In a typical procedure, indolin-2-ones (0.5 g, 3.76 mmol), acetic anhydride
(3.8 g, 37.5 mmol) and 4-dimethylaminopyridine (DMAP, 1 mol %) were heated
at 150 °C for 4 h in a round-bottomed flask equipped with air condenser and
CaCl2 guard tube. After the completion of reaction (as evident from TLC), the
excess of acyl anhydride was evaporated under reduced pressure and residue
was recrystallized using methanol to give 3a as white solid (0.93 g, 95% yield).
Mp: 137–139 °C (methanol). 1H NMR (300 MHz, CDCl3): d 8.31 (d, J = 8 Hz, 1H),
7.61 (d, J = 7.5, 1H), 7.34 (dd, J = 8, 8 Hz, 1H), 2.21 (dd, J = 8, 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. FTIR mmax
(KBr): 3471, 1757, 1742, 1698, 1460, 748 cmÀ1. GC–MS (EI): m/z (% relative
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 for granting ac-
cess to its analytical facility.
abundance) 259 (M+, 5), 217 (40), 175(100), 150 (35), 129 (10).
16
17. Spectroscopic data are given in Ref.
.
18. Crestini, C.; Saladino, R. Synth. Commun. 1994, 24, 2835–2841.