ZrCl4-mediated regio- and chemoselective friedel-crafts acylation of indole

Article abstract of DOI:10.1021/jo200561f

An efficient method for regio- and chemoselective Friedel-Crafts acylation of indole using acyl chlorides in the presence of ZrCl₄ has been discovered. It minimizes/eliminates common competing reactions that occur due to high and multiatom-nucleophilic character of indole. In this method, a wide range of aroyl, heteroaroyl alkenoyl, and alkanoyl chlorides undergo smooth acylation with various indoles without NH protection and afford 3-acylindoles in good to high yields.

Full text of DOI:10.1021/jo200561f

NOTE
pubs.acs.org/joc
ZrCl4-Mediated Regio- and Chemoselective FriedelꢀCrafts
Acylation of Indole
Sankar K. Guchhait,* Maneesh Kashyap, and Harshad Kamble
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
S. A. S. Nagar (Mohali) - 160062, Punjab, India
S Supporting Information
b
ABSTRACT: An efficient method for regio- and chemoselective
FriedelꢀCrafts acylation of indole using acyl chlorides in the
presence of ZrCl4 has been discovered. It minimizes/eliminates
common competing reactions that occur due to high and multiatom-
nucleophilic character of indole. In this method, a wide range of
aroyl, heteroaroyl alkenoyl, and alkanoyl chlorides undergo smooth
acylation with various indoles without NH protection and afford 3-acylindoles in good to high yields.
cylindoles are versatile intermediates in the synthesis of
3-Aalkaloids, indole derivatives, and several heterocycles.1
They have been found to exhibit various pharmaceutical activities
like anticancer, antidiabetic, inhibitor of HIV-1 integrase, and
antinociceptive.2 Marketed drugs include pravodoline (analgesic)
and ramosetron (antiemetic). The synthesis of 3-acylindoles has
thus gained considerable attention. The common method for the
preparation of 3-acylindoles is FriedelꢀCrafts reaction.3ꢀ5 The
other significant approaches include VilsmeierꢀHaack reaction,6a
indole Grignard reaction,6b coupling of 3-indolylzinc chloride with
acyl chloride under Pd catalysis,6c and the reaction of indole with
N-(2-haloacyl)pyridinium salt.6d As indole is high and multiatom
nucleophilic in nature, under FriedelꢀCrafts acidic conditions it
suffers from competing side reactions such as 1-acylation and/or
1,3-diacylation, Mannich-type indole oligomerizations (di-, tri-,
and even tetra-), acylation of oligomerized products, and nucleo-
philic addition of indole to 3-acylindole forming bisindolylalkanol
or trisindolylalkane.3,4 To reduce/eliminate these side reactions,
NH-protected or electron-deactivated indoles were used in acyla-
tion processes.5 These methods require additional protec-
tionꢀdeprotection steps or limit the structural variation of
indole. Aluminum chloride, a Lewis acid (L.A.) traditionally used
in FriedelꢀCrafts reactions, results in oligomerizations of indole
because of its strong Lewis acidity.4a These challenges have incited
the development of alternative promoters/catalysts, for example,
alkylaluminium chloride,4a,b imidazolium chloroaluminate,3b and
SnCl4.4c However, these Lewis acids suffer from one or more
disadvantages such as commercial nonavailability, cost, toxicity,
and handling difficulty/hazards, nonfeasibility toward various
substituted/functionalized acylating reactants, and the inconveni-
ence of the procedure, especially extraction difficulty of the
reaction mixture. In the acylation of indole with acyl chlorides,
unavoidable liberation of HCl during the reaction mainly causes
the oligomerzations of indole (Scheme 1). The nature of the Lewis
acid has been found to be responsible for scavenging HCl or
preventing HCl-caused oligomerizations by forming an indoleꢀL.
A. complex.4aꢀc In comparison to AlCl3, alkylaluminium chloride
(a milder Lewis acid and HCl scavenger) has been found to
minimize/eliminate the oligomerizations of indole and other side
reactions. To selectively favor the FriedelꢀCrafts acylation, Lewis
acid should also preferably activate the acylating agent to form an
acyl cation or a donorꢀacceptor complex of acylating agentꢀL.A.
Thus, the Lewis acid may play a crucial role for required selectivity
in FriedelꢀCrafts acylation of indole with acyl chlorides. As
alternative approach, N-acylbenzotriazoles inthe presence of TiCl4
that afford 3-acylation of indole without competing reactions7a and
a nucleophilic catalysis7b for acylation of NH-protected indole have
been documented. Here, we report ZrCl4-promoted regio- and
chemoselective FriedelꢀCrafts acylation of indole with acyl chlor-
ides. It minimizes/eliminates the common side reactions. A wide
range of aroyl, heteroaroyl, alkenoyl, and alkanoyl chlorides under-
go smooth acylation with various indoles without NH protection
and afford 3-acylindoles in good to high yields (Scheme 2).
Our investigation centered on Lewis acids with suitable hard/
soft acidity and charge density of the metal cation. Zr 4þ has a
higher charge-to-size ratio (Z2/r: 22.22 e2 mꢀ10) compared to
most of the main group elements and lighter and heavier
transition metal ions, such as Liþ, Bi3þ, In3þ, Sc3þ, Fe3þ, V3þ
,
and Al3þ (Z2/r: 1.35, 8.82, 11.39, 12.33, 13.85, 14.06, 16.98
e2 mꢀ10, respectively), and is relatively softer hard acid.8 This
inherent chemical feature of ZrCl4 has led it to be a promising
catalyst with strong Lewis acid behavior, operational simplicity,
and low toxicity (its LD50 for oral rat, 1688 mg kgꢀ1, is not
3
considered particularly poisonous).9 In addition, its relatively
high abundance and thus low cost offers attractive use in
catalysis.10,11 ZrCl4 as Lewis acid catalyst in FriedelꢀCrafts
acylation of benzene, toluene, and anthracene is also known.12
We speculated that ZrCl4 could play a required role and be
beneficial in selective acylation of indole. We investigated the
Received: March 18, 2011
Published: April 28, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1. FriedelꢀCrafts Acylation of Indoles and Its
Table 1. Screening of Lewis Acids and Conditions for
Common Competitive Side Reactions
FriedelꢀCrafts Acylation of Indolea
entry
Lewis acid
mol % neat/solvent time (h) yieldb (%)
reaction temperature: 30 °C
1
2
3
4
5
6
7
ZrCl4
50
50
50
50
50
50
50
neat
neat
neat
neat
neat
neat
neat
4
38
26
12
18
15
12
16
MoOCl2
VOCl3
Sc(OTf)3
FeCl3
6.5
6
5.5
7
Scheme 2. Our Procedure: ZrCl4-Promoted Regio- And
Chemo-Selective FriedelꢀCrafts Acylation of Indole
BiCl3
6
ZnCl2
6
addition at 0 °C, 0 f 30 °C, then continuation at 30 °C
8
ZrCl4
50
50
neat
4
54
34
15
57
52
60
55
36
48
64
72
68
64
0
9
MoOCl2
VOCl3
neat
7
10
11
12
13
14
15
16
17
50
neat
6.5
5
ZrCl4 þ LiClO4
MoOCl2 þ LiClO4 50, 100
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
50, 100
neat
neat
4.5
4
100
100
100
100
150
150
150
150
DCE
DCM
DMF
MeNO2
DCE
DCE
DCE
DCE
DCE
efficiency of ZrCl4 and other Lewis acids, additives, solvents, and
conditions for the FriedelꢀCrafts acylation of N-methylindole
with 2-bromobenzoyl chloride. The results are summarized in
Table 1. In most of the Lewis acids, competing side reactions such
as oligomerizations (a mixtureof dimerizationproducts asmajor),
subsequent acylation, and nucleophilic addition of indole to
acylated oligomerized products were found to take place, as
revealed by mass and NMR spectroscopic studies, and thus
resulted in formation of the desired acylated product in fewer
yields. These side reactions were found to be relatively less
successful in the presence of ZrCl4. Modification of conditions
such as switching the reaction temperature from 30 °C to 0 f
30 °C and neat to solution phase enhanced the desired acylation.
Use of LiClO4 as promoter along with catalyst is known to favor
FriedelꢀCrafts acylation. This modification enhanced the yield in
the presence of MoOCl2 (Table 1, entry 12) but could not
significantly increase the yield in case of ZrCl4 (Table 1, entry 11).
In screening of reaction solvents in the presence of ZrCl4, a low
dielectric solvent like DCE was found to be best to favor the
FriedelꢀCrafts acylation (Table 1, entries 13ꢀ16). IR studies of a
mixtureof CH3COCl andZrCl4 (1:1) in neat, DCE, DCM, DMF,
and MeNO2 at 0f30 °C were performed. They showed the
bathochromic shift of 182ꢀ216 cmꢀ1 from 1826 cmꢀ1 (for CdO
stretching in CH3COCl) without any peak of hypsochromic shift.
It indicates that ZrCl4 formed the donorꢀacceptor complex (not
the acyl cation) with acyl chloride in these solvents. The highest
bathochromic shift (216 cmꢀ1) observed in DCE solvent signifies
that the maximum activation of acyl chloride in donorꢀacceptor
complex occurred in this solvent. Among the Lewis acids
screened, ZrCl4 was found to be best for 3-acylation of indole
plausibly due to its suitable combination of higher charge-to-size
ratio and relatively softer hard acidity which favored the formation
of donorꢀacceptor complex. The presence of ZrCl4 is needed for
acylation, as the reaction did not proceed without it (Table 1,
entry 21). Changing the sequential addition of acyl chloride in
DCE followed by Lewis acid to indole in DCE resulted in
increased side reactions. In our optimized protocol, 1.5 equiv of
4
4.5
4.5
4
18c ZrCl4
19d ZrCl4
20e ZrCl4
4
4
4
21
no Lewis acid
48
a Indole/acyl chloride = 1:1. Anhydrous solvent used: 3 mL. b Isolated
yields. c Indole/acyl chloride = 1.3:1. d Indole/acyl chloride = 1.5:1.
e Indole/acyl chloride = 1:1.5.
ZrCl4 was found to be necessary. The variation in equivalence of
reactants (Table 1, entries 18ꢀ20) revealed that 1.3 equiv of
indole and 1 equiv of acyl chloride were optimal. The experi-
mental procedure is simple and straightforward.
With the optimized FriedelꢀCrafts acylation protocol in hand,
we next set out to explore its scope. To our delight, versatile
alkanoyl, alkenoyl, aroyl and heteroaroyl chlorides, and indoles
including NH-unprotected indole produced diverse 3-acylindoles
in good to high yields (Table 2). N-Acylation and 1,3-diacylation
of indole without NH-blocking are known in the literature. In
contrast, negligible N-acylated (1ꢀ3% yield) and no 1,3-diacy-
lated products were isolated by this method. Pivoloyl chloride,
which is known for its susceptibility toward decarbonylative
alkylation in the FriedelꢀCrafts acylation reaction, was found
to be a feasible acylating agent in ourdeveloped protocol affording
3-pivoloylindole in 75% yield (Table 2, entries 9 and 10). In place
of acid chloride, acid anhydride was also found to produce
3-acylindole in similar yields (Table 2, entries 7a and 7b). The
electron-rich indole such as 5-methoxyindole, which is known to
be more susceptible toward oligomerizations, was found to afford
aroylated product in good yield (Table 2, entry 20).
The tolerance of functionalities such as chloro, bromo, nitro,
and methoxy in this protocol provides the opportunity for their
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NOTE
Table 2. FriedelꢀCrafts 3-Acylation of Various Indoles with Versatile Aroyl, Heteroaroyl, Alkenoyl, And Alkanoyl
Chloridesa
a Indole/acyl chloride/ZrCl4 = 1.3: 1: 1.5. b Isolated yields.
various further chemical manipulations in 3-acylindole deriva-
tives. Several moieties, which are present in drugs, therapeutic
agents, or their precursors, could be incorporated easily by this
acylation methodology into 3-acylindole products in good to high
yields. These groups are trimethoxyphenyl (anticancer agent),
adamantyl (antimalarial agent), isoquinoline (antitubercular
agent), 2-(4-isobutylphenyl)propanoyl (ibuprofen, anti-inflam-
matory drug), and cinnamoyl (anticancer agent). Since the indole
scaffold is omnipresent in natural products and bioactive com-
pounds, the method enabling the incorporation of therapeutically
important versatile moieties into 3-acylindoles is much more
useful in the medicinal chemistry research.
minimization/elimination of competing side reactions which are
common in Lewis/Br€onsted acid conditions. In this method, a
wide range of aroyl, heteroaroyl, alkenoyl, and alkanoyl chlorides
undergo smooth acylation with various indoles without NH
protection. This protocol offers several advantages including
use of economical, low toxic, and easy-handling Lewis acid, a
simple procedure, good to high yields of products, generality, and
feasibility for incorporation of therapeutically important motifs,
which render its potential application.
’ EXPERIMENTAL SECTION
In conclusion, we have developed ZrCl4-mediated regio-
General considerations: The starting materials and solvents were used
and chemoselective FriedelꢀCrafts 3-acylation of indole with
as received from commercial suppliers without further purification. The
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NOTE
1H and 13C spectra were recorded in CDCl3/DMSO-d6/CD3OD
solvents on a 400 MHz spectrometer using TMS as internal standard.
Melting points determined are uncorrected.
33.6; HRMS (ESI) calcd for C16H13ClNO [M þ H]þ 270.0686, found
m/z 270.0685, calcd for C16H12ClNNaO [M þ Na]þ 292.0505, found
m/z 292.0508.
Representative Experimental Procedure for the Synthesis
of 3-Benzoylindole (Table 2, Entry 1). To a solution of indole (153
mg, 1.3 mmol) in anhyd DCE (1.5 mL) taken in a round-bottom flask at
0 °C under nitrogen was added benzoyl chloride (140 mg, 1 mmol) in
anhyd DCE (1.5 mL) by a syring under nitrogen. Zirconium tetrachloride
(349.5 mg, 1.5 mmol) was added under a flow of nitrogen. The reaction
temperature was then gradually increased to 30 °C, and the reaction was
continued at 30 °C. After completion of the reaction as indicated by TLC
(4 h), the resultant mixture was quenched with water (5 mL) and
extracted with EtOAc (2 ꢁ 30 mL). The combined organic layer was
washed with water (10 mL), dried with anhyd Na2SO4, and concentrated
under vacuum. The column chromatographic purification of crude mass
on silica gel eluting with EtOAcꢀpetroleum ether provided 3-benzoylin-
dole (157 mg, 71% yield).
1H-Indol-3-yl(4-methoxyphenyl)methanone (Table 2, en-
try 5):4b. light yellow solid; mp 88ꢀ89 °C; IR (KBr) νmax 3442, 2934,
1624 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 8.23 (d, J = 7.0 Hz,
1H), 7.94 (s, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.1 Hz, 1H),
7.23ꢀ7.21 (m, 2H), 7.05 (d, J = 7.8 Hz, 2H), 3.83 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ = 188.8, 161.6, 136.5, 134.8, 132.8, 130.5,
126.3, 122.9, 121.6, 121.4, 115.0, 113.6, 112.1, 55.3; MS (APCI) m/z
252 (MHþ).
All acylation reactions (Table 2) were carried out following this
representative procedure.
1H-Indol-3-yl-phenylmethanone (Table 2, entry 1):4b,13a
.
white solid; mp 243ꢀ245 °C; yield 71% ; IR (KBr) νmax 3144, 2935,
1598 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (d, J = 7.2 Hz,
1H), 7.93 (s, 1H), 7.79 (d, J = 7.4 Hz, 2H), 7.60 (d, J = 6.8 Hz, 1H), 7.55
(t, J = 7.6 Hz, 3H), 7.29ꢀ7.24 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ = 190.5, 140.9, 137.1, 136.3, 131.5, 128.9, 128.8, 126.6, 123.6,
122.4, 121.9, 115.4, 112.7; MS (APCI) m/z 222 (MHþ).
2-Bromophenyl(1-methyl-1H-indol-3-yl)methanone (Table 2,
entry 6): white solid; mp 150ꢀ152 °C; IR (KBr) νmax 3352, 2970, 1738,
1606 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ = 8.38ꢀ8.36 (m, 1H), 7.67
(d, J = 7.8 Hz, 1H), 7.44ꢀ7.31 (m, 7H), 3.82 (s, 3H); 13C NMR (100
MHz, CDCl3) δ = 189.3, 142.3, 138.8, 137.8, 133.2, 130.4, 128.6, 127.0,
126.4, 123.8, 123.0, 122.7, 119.5, 116.1, 109.8, 33.6; HRMS (ESI) calcd
for C16H12BrNNaO [M þ Na]þ 336.0000, found m/z 335.9999.
1-Methyl-1H-indol-3-yl-phenylmethanone (Table 2, entry
2):7b. white solid; mp 116ꢀ118 °C; IR (KBr) νmax 3150, 2926,
1
1596 cmꢀ1; H NMR (400 MHz, CDCl3) δ = 8.43ꢀ8.41 (m, 1H),
7.77 (d, J = 7.1 Hz, 2H), 7.52ꢀ7.48 (m, 1H), 7.45ꢀ7.41 (m, 3H),
7.32ꢀ7.29 (m, 3H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
190.8, 140.9, 138.0, 137.5, 131.1, 128.6, 128.3, 127.0, 123.7, 122.7, 122.6,
115.4, 109.7, 33.5; MS (APCI) m/z 236 (MHþ).
1-(1H-Indol-3-yl)ethanone (Table 2, entries 7a and 7b):13a
.
white solid; mp 189ꢀ190 °C; IR (KBr) νmax 3155, 2920, 1612 cmꢀ1; 1H
NMR (400 MHz, CD3OD) δ = 8.22 (d, J = 7.2 Hz, 1H), 8.13 (s, 1H),
7.45 (d, J = 7.2 Hz, 1H), 7.23ꢀ7.20 (m, 2H), 2.52 (s, 3H); 13C NMR
(100 MHz, CD3OD) δ = 196.8, 138.4, 135.6, 126.7, 124.3, 123.2, 122.8,
118.4, 112.9, 27.2; MS (APCI) m/z 160 (MHþ).
4-Chlorophenyl(1H-indol-3-yl)methanone (Table 2, entry
3):4b. yellowish white solid; mp 241ꢀ242 °C; IR (KBr) νmax 3297, 3006,
1737, 1591 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 8.24 (d, J = 7.2
Hz, 1H), 7.96 (s, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H),
7.54 (d, J = 7.2 Hz, 1H), 7.33ꢀ7.23 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ = 189.2, 139.5, 137.1, 136.5, 136.3, 130.7, 128.9, 126.5,
123.7, 122.5, 121.8, 115.2, 112.7; MS (APCI) m/z 256 (MHþ).
1-(1-Methyl-1H-indol-3-yl)ethanone (Table 2, entry 8):13b
.
white solid; mp 106ꢀ107 °C; IR (KBr) νmax 3468, 3106, 1642,
1
1529 cmꢀ1; H NMR (400 MHz, CDCl3) δ = 8.37ꢀ8.32 (m, 1H),
7.62 (s, 1H), 7.30ꢀ7.28 (m, 3H), 3.76 (s, 3H), 2.47 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ = 192.9, 137.4, 135.8, 126.2, 123.2, 122.5, 122.4,
116.8, 109.6, 33.5, 27.5; MS (APCI) m/z 174 (MHþ).
4-Chlorophenyl(1-methyl-1H-indol-3-yl)methanone (Table 2,
entry 4): off-white solid; mp 144ꢀ145 °C; IR (KBr) νmax 3367, 2946,
1699 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ = 8.39ꢀ8.36 (m, 1H), 7.73
(d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.35ꢀ7.32 (m,
3H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 189.4, 139.1,
137.7, 137.5, 137.2, 130.0, 128.5, 127.0, 123.8, 122.8, 122.6, 115.3, 109.7,
1-(1H-Indol-3-yl)-2,2-dimethylpropan-1-one (Table 2, en-
try 9):4b. white solid; mp 160ꢀ162 °C; IR (KBr) νmax 3275, 2969, 1609,
1260 cmꢀ1; 1H NMR (400 MHz,CD3OD) δ = 8.32 (d, J = 7.5 Hz, 1H),
8.20 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.22ꢀ7.15 (m, 2H), 1.41 (s, 9H);
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NOTE
13C NMR (100 MHz, CD3OD) δ = 205, 137.4, 133.6, 128.7, 124.0, 123.5,
123.0, 114.4, 112.5, 45.0, 29.4; MS (APCI) m/z 202 (MHþ).
1606 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 12.2 (s, 1H), 9.24 (s,
1H), 8.84 (s, 1H), 8.33 (d, J = 5.9 Hz, 1H), 8.19 (s, 2H), 8.14 (d, J = 8.3
Hz, 1H), 7.90 (t, J = 7.0, 1H), 7.73 (t, J = 7.1 Hz, 1H), 7.58 (d, J = 6.0 Hz,
1H), 7.30 (d, J = 3.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ =
188.0, 149.5, 148.3, 136.7 (2CH), 136.5, 132.8, 131.1, 129.4, 128.6,
127.2, 126.6, 126.0, 123.4, 122.2, 121.4, 115.2, 112.3; HRMS (ESI) calcd
for C18H12N2NaO [M þ Na]þ 295.0847, found m/z 295.0850.
2,2-Dimethyl-1-(1-methyl-1H-indol-3-yl)propan-1-one (Table 2,
entry 10):13c. white solid; mp 139ꢀ140 °C; IR (KBr) νmax 3680, 2967,
1631 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ = 8.52ꢀ8.50 (m, 1H), 7.78
(s, 1H), 7.30ꢀ7.28 (m, 3H), 3.82 (s, 3H), 1.41 (s, 9H); 13C NMR (100
MHz, CDCl3) δ = 202.0, 136.4, 134.3, 128.2, 123.4, 123.2, 122.4, 112.7,
109.2, 44.0, 33.5, 28.9; MS (APCI) m/z 216 (MHþ).
Bis(1H-indol-3-yl)methanone (Table 2, entry 15):13f. reddish
brown solid; mp 287ꢀ289 °C; IR (KBr) νmax 3180, 2920, 1736,
1584 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 8.28 (d, J = 7.1 Hz,
2H), 8.17 (s, 2H), 7.51 (d, J = 7.3 Hz, 2H), 7.21 (t, J = 7.7, 4H), 13C
NMR (100 MHz, DMSO-d6) δ = 184.6, 136.4, 131.9, 126.5, 122.5,
121.4, 121.0, 116.8, 111.9; MS (APCI) m/z 261 (MHþ).
1H-Indol-3-yl(3,4,5-trimethoxyphenyl)methanone (Table2,
entry 11):13d. white solid; mp 132ꢀ134 °C; IR (KBr) νmax 3193, 2938,
1575 cmꢀ1; 1H NMR (400 MHz DMSO-d6) δ = 8.27ꢀ8.25 (m, 1H), 8.1
(d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.29ꢀ7.23 (m, 2H), 7.11 (d,
J = 2.5 Hz, 2H), 3.86 (s, 6H), 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ = 189.4, 153.0, 140.4, 137.1, 136.2, 136.1, 126.8, 123.5, 122.3, 121.8,
115.2, 112.6, 106.4, 60.5, 56.3; MS (APCI) m/z 312 (MHþ).
1-1H-Indol-3-yl-2-(4-isobutylphenyl)propan-1-one (Table 2,
entry 16): white solid; mp 157ꢀ160 °C; IR (KBr) νmax 3261, 2955,
1620, 1436 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H),
8.20 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 7.3 Hz, 2H),
7.21ꢀ7.14 (m, 2H), 7.05 (d, J = 7.3 Hz, 2H), 4.68ꢀ4.67 (m, 1H), 2.35
(d, J = 6.7 Hz, 2H), 1.78ꢀ1.72 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 0.81 (d,
J = 6.2 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ = 195.7, 140.0,
139.1, 136.6, 134.0, 128.9, 127.2, 125.7, 122.8, 121.7, 121.3, 115.4,
112.0, 46.7, 44.1, 29.5, 22.1, 18.8; HRMS (ESI) calcd for C21H23NNaO
[M þ Na]þ, 328.1677, found m/z 328.1674.
1-Methyl-1H-indol-3-yl(3,4,5-trimethoxyphenyl)methanone
(Table 2, entry 12):13e. white solid; mp 167ꢀ170 °C; IR (KBr) νmax
3338, 2937, 1618, 1580 cmꢀ1;1H NMR (400 MHz, CDCl3) δ=8.36ꢀ8.34
(m, 1H), 7.56 (s, 1H), 7.32ꢀ7.29 (m, 3H), 7.06 (s, 2H), 3.91 (s, 3H), 3.86
(s, 6H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 189.8, 152.9,
140.7, 137.5, 137.4, 136.2, 127.2, 123.6, 122.6, 122.5, 115.3, 109.7, 106.3,
60.9, 56.3, 33.5; MS (APCI) m/z 326 (MHþ).
1-(1H-Indol-3-yl)-3-phenylprop-2-en-1-one (Table 2, entry
17):13g. yellowish white solid; mp 225ꢀ230 °C; IR (KBr) νmax 2924,
1640, 1559 cmꢀ1; 1H NMR(400MHz, DMSO-d6) δ = 8.75 (s, 1H), 8.35
(d, J = 7.1 Hz, 1H), 7.87ꢀ7.83 (m, 3H), 7.65 (d, J = 15.5 Hz, 1H),
7.52ꢀ7.44 (m, 4H), 7.28ꢀ7.21 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ = 183.5, 139.5, 136.8, 135.1, 134.7, 129.7, 128.8, 128.3, 125.8, 124.5,
123.1, 121.8, 121.7, 117.6, 112.1; MS (APCI) m/z 248 (MHþ).
1H-Indol-3-yl(tricyclo[3.3.1.13,7]dec-1-yl)methanone (Table 2,
entry 13): off-white solid; mp 192ꢀ196 °C; IR (KBr) νmax 3218, 2923,
1
1622, 1605 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ = 8.45 (s,1H),
8.26 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.18ꢀ7.10 (m, 2H),
2.03 (s, 9H), 1.81ꢀ1.71 (m, 6H); 13C NMR (100 MHz, DMSO-d6) δ =
200.9, 135.4, 132.1, 127.2, 122.4, 122.1, 121.4, 112.2, 111.6, 45.9, 36.2,
27.9; HRMS (ESI) calcd for C19H21NNaO [M þ Na]þ, 302.1521,
found m/z 302.1515.
5-Bromo-1H-indol-3-ylphenylmethanone (Table 2, entry
18):13a. off-white solid; mp 265ꢀ267 °C; IR (KBr) νmax 3155, 2936,
1589 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 2 Hz, 1H),
8.03 (s, 1H), 7.81ꢀ7.79 (m, 2H), 7.63ꢀ7.61 (m, 1H), 7.57ꢀ7.50 (m,
3H), 7.41 (dd, J = 8.6, J = 2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
1H-Indol-3-yl(quinolin-3-yl)methanone (Table 2, entry
14): yellowish brown solid; mp 235ꢀ239 °C; IR (KBr) νmax 2925,
4757
dx.doi.org/10.1021/jo200561f |J. Org. Chem. 2011, 76, 4753–4758

The Journal of Organic Chemistry
NOTE
δ = 189.8, 139.9, 136.8, 135.4, 131.3, 128.4, 128.3, 128.0, 125.7, 123.5,
114.7, 114.4, 114.3; MS (APCI) m/z 300 (MHþ).
(c) Barreca, M. L.; Ferro, S.; Rao, A.; De Luca, L.; Zappalꢀa, M.;
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2005, 48, 7084–7088.
(3) (a) Sundberg, R. J. Indoles; Academic Press: New York, 1996;
Chapter 11, pp 105ꢀ118 and references cited therein. (b) For Mannich-
type indole dimerization induced by protic acids/Lewis acids, see:
Yeung, K.-S.; Farkas, M. E.; Qiu, Z.; Yang, Z. Tetrahedron Lett. 2002,
43, 5793–5795 and references cited therein.
(4) (a) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.;
Yoshino, H. Org. Lett. 2000, 2, 1485–1487. (b) Wynne, J. H.; Lloyd,
C. T.; Jensen, S. D.; Boson, S.; Stalick, W. M. Synthesis 2004, 2277–2282.
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1-Methyl-1H-indol-3-yl(4-nitrophenyl)methanone (Table 2,
entry 19):7a. yellowish white solid; mp 183ꢀ184 °C; IR (KBr) νmax
3430, 2972, 1637 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ = 8.41ꢀ8.39
(m, 1H), 8.33 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H) 7.49 (s, 1H),
7.41ꢀ7.36 (m, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
188.4, 149.1, 146.3, 138.1, 137.0, 129.3, 126.8, 124.2, 123.6, 123.3, 122.6,
115.2, 109.8, 33.7; MS (APCI) m/z 281(MHþ).
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5-Methoxy-1H-indol-3-yl(4-methoxyphenyl)methanone
(Table 2, entry 20):13f. off white solid; 161ꢀ164 °C; IR (KBr) νmax
3133, 2926, 1603 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ = 7.89 (s,
1H), 7.78 (t, J=7.6 Hz, 3H), 7.41 (d, J = 8.7 Hz, 1H), 7.08 (d, J=7.6 Hz,
2H), 6.89 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ = 188.7, 161.6, 155.3, 135.0, 132.9, 131.5, 130.4,
127.1, 114.7, 113.6, 112.8, 103, 55.3, 55.2 MS (APCI) m/z 282 (MHþ).
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’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dure; H, 13C, IR, and MS for known compounds; H, 13C,
HRMS, IR, and melting points for unknown compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
1
1
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 91 (0)172 2214683. Fax: 91 (0)172 2214692. E-mail:
skguchhait@niper.ac.in.
’ ACKNOWLEDGMENT
We gratefully acknowledge financial support from CSIR,
New Delhi, for this investigation.
’ REFERENCES
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(2) For a few representative examples, see: (a) Wu, Y. S.; Coumar,
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(b) Nicolaou, I.; Demopoulos, V. J. J. Med. Chem. 2003, 46, 417–426.
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