[1,2]-Aryl migration in the synthesis of substituted indoles: scope, mechanism, and high throughput experimentation

Article abstract of DOI:10.1016/j.tet.2008.11.026

A mild regioselective synthesis of substituted indoles from readily accessible 1-(2-aminophenyl)-2-chloroethanones is described. Addition of a range of carbon nucleophiles to α-chloro acetophenones 1 generates 2-substituted indoles 2 in moderate to excell

Full text of DOI:10.1016/j.tet.2008.11.026

Tetrahedron 65 (2009) 3285–3291
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
[1,2]-Aryl migration in the synthesis of substituted indoles: scope,
mechanism, and high throughput experimentation
*
Tao Pei , David M. Tellers, Eric C. Streckfuss, Cheng-yi Chen, Ian W. Davies
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild regioselective synthesis of substituted indoles from readily accessible 1-(2-aminophenyl)-2-
Received 26 September 2008
Received in revised form 6 November 2008
Accepted 7 November 2008
Available online 13 November 2008
chloroethanones is described. Addition of a range of carbon nucleophiles to a-chloro acetophenones 1
generates 2-substituted indoles 2 in moderate to excellent yields. A reaction mechanism involving
a [1,2]-aryl migration is proposed. This useful transformation is further examined using high throughput
experimentation.
Ó 2008 Elsevier Ltd. All rights reserved.
R2
1. Introduction
O
2
1
Cl
R2
1
RM
2
R
X
X
Indole is a common substructure of many natural products and
biologically active compounds.1 The need for efficient and practical
synthesis of indole bearing a variety of substitution patterns pro-
vides a continual challenge to organic chemists. The classic Fisher
synthesis converts aryl hydrazones to indoles at elevated temper-
ature (180–250 ꢀC) in the presence of Bronsted or Lewis acid.2–4 As
a result, the method suffers from poor regioselectivity when alkyl
ketones are used to make 2,3-disubstituted indole. The selectivity
problem also limits the more recently developed Pd-catalyzed in-
dole syntheses from o-haloanilines. In Larock’s method, a mixture
of isomers is obtained when a simple internal alkyne, such as 2-
pentyne, is used.5 A similar problem arises when an acyclic ketone
is used in Chen’s indole synthesis.6 Lu and co-workers recently
reported a one-pot, three-component, regioselective procedure to
synthesize 2,3-disubstituted indoles that was limited to aryl sub-
stituents.7 Despite these and many other creative approaches that
have been used to assemble the indoles,8 general and efficient
syntheses that control the introduction of substituents at C-2 and
C-3 are still lacking. The development of such general methods is of
contemporary significance.
N
THF or toluene
NH
R1
R1
1
2
Scheme 1.
5a as the sole product in 81% isolated yield (Scheme 2). We envi-
sioned that addition of a wide variety of organometallic reagents to
related a-chloro acetophenones would provide a direct access to 2-
substituted indoles with diverse functionalities. In this manuscript,
we continue to define the scope of the reaction.
O
nPrMgCl
Toluene
_10 to 22 °C
30 min
Cl
+
N
N
H
H
NH2
Cl
Cl
Cl
3
4, 0%
5a, 81%
Scheme 2.
We recently reported a highly efficient synthesis of substituted
indoles from readily accessible 1-(2-aminophenyl)-2-chloro-
ethanones9 and commercially available organometallic reagents
(Scheme 1).10 This new method is characterized by its high regio-
selectivity and good generality achieved under mild reaction con-
ditions making this transformation viable for the preparation of
structurally diverse indoles. For example, ketone 3 was treated with
2.5 equiv of nPrMgCl for 30 min and afforded 2-substituted indole
2. Results and discussion
Based on the observed regioselectivity in this transformation, we
propose the following reaction sequence (Fig. 1): nucleophilic ad-
dition of an organometallic reagent to the chloroketone 6a to form
tertiary alkoxide 8, followed by a facile [1,2]-aryl rearrangement11 to
form ketone 10, ring-closure and dehydration to form 2-substituted
indole 7. The aniline moiety serves as a key driver for the success
of the reaction, wherein the aniline nitrogen promotes the net
* Corresponding author. Fax: þ1 732 594 1499.
E-mail address: tao_pei@merck.com (T. Pei).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.026

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T. Pei et al. / Tetrahedron 65 (2009) 3285–3291
Table 1
O
R
Synthesis of 2-substituted indoles from ketone 3a
path a
O
Cl
O
R
Cl
NH
NH
R
O
RM
N
H
Cl
Toluene or THF
_10 to 22 °C
8
10
NH2
Cl
Cl
NH2
3
5
R
net [1,2]-aryl migration
6a
N
H
O
Entry
1f
RM
Product
Yieldg (%)
O
R
R
7
+
Cl
RM
N
H
89
NH
NH
MgBr
Cl
path b
9
8
5b
Figure 1. Proposed mechanism.
O
O
2e
86
45
76
N
H
O
O
MgBr
Cl
[1,2]-aryl rearrangement either through a conventional aryl migra-
tion or the formation of a bicyclic anion intermediate, such as 9, and
favors its migration.12,13 The aniline nitrogen could also serve as an
effective trap for the ketone in intermediate 10 and thus prevents
reaction of the ketone with an additional equivalent of the organo-
metallic reagent.
5c
3f
N
H
MgBr
Cl
5d
This net [1,2]-aryl migration mechanism is supported by two
simple experiments. When the dianion 1114 derived from N-2-
bromophenyl pivaloyl amide reacts with ketone 6a, the only
product observed, 13 results from migration of the unprotected
aniline group. Under the assumption that the intermediate 12
forms, there are two possible aniline derivatives, which could
participate in this [1,2]-aryl migration. The presence of the N-piv-
aloyl group disfavors its migration (Scheme 3).14 Another experi-
ment which supports the proposed rearrangement mechanism
4b,e
nHexLi
N
H
Cl
5e
5b,f
Me3SiCH2Li
PhMgCl
70
91
N
H
SiMe3
Cl
Cl
i
involves reaction of deuterium labeled alcohol 14 with PrMgCl in
5f
THF, which produces 2-D-7-chloroindole (15) in 69% yield (Scheme
4). An alternative reaction pathway involving epoxide formation
and subsequent rearrangement to form an aldehyde is ruled out
since it would lead to a 3-substituted indole after a [1,2]-hydride
shift.15
6e
N
H
5g
N
N
S
N
N
MgCl
7c,e
8c,e
9e
78
76
72
N
H
Cl
Cl
Li
5h
NHLi
LiO
Cl
N
H
NLi
6a
HN
N
H
O
NLi
O
MgCl
MgBr
O
5i
11 (2.0 equiv)
12
13 (65%)
Scheme 3.
S
N
H
Cl
5j
O
HO
D
10d,e
11d,e
54
55
Cl
Cl
Me3Si
MgCl
MgCl
THF
D
NaBD4
dioxane
water
R
N
H
N
NH2
NH2
H
Cl
Cl
5k R = Sime3
5l
R = nBu
Cl
Cl
Bu
MgCl
3
14
15 (69%)
Scheme 4.
a
Reaction conditions: all reactions were carried out without optimization; ketone
3 (1.0 mmol) in either THF or toluene (2 mL) and nucleophile (2.5 mmol) were
stirred at ꢁ10 ꢀC for 15 min, then at room temperature for 15 min to 2 h.
To explore the generality of this transformation, the addition of
different organometallic reagents to 1-(2-amino-3-chlorophenyl)-
2-chloroethanone (3) was studied and the results are summarized
in Table 1. Similar to nPrMgCl, other primary alkyl Grignard reagents
reacted with 3 to give C-2 substituted indoles in excellent yields.
For example, 2-allyl-7-chloroindole (5b) and 7-chloro-2-[2-(1,3-
b
Addition of nucleophile at ꢁ40 ꢀC.
c
Nucleophile was generated in situ from corresponding aryl iodide and iPrMgCl.
d
Nucleophile was generated in situ from the corresponding alkynes and iPrMgCl.
e
Solvent¼THF.
f
Solvent¼toluene.
g
Yields refer to isolated product based on ketone 3.

T. Pei et al. / Tetrahedron 65 (2009) 3285–3291
3287
dioxan-2-yl)ethan-1-yl]indole (5c) were readily prepared from the
corresponding Grignard reagents in 89% and 86% yield, respectively
(Table 1, entries 1 and 2). Moreover, addition of organolithium
species such as n-hexyl lithium and trimethylsilylmethyl lithium
afforded 7-chloro-2-hexan-1-ylindole (5e) and 7-chloro-2-trime-
thylsilylmethylindole (5f) in 76% and 70% yield, respectively (Table
1, entries 4 and 5).
A number of aromatic and heteroaromatic functional groups
were readily introduced at the C-2 position of indoles by
addition of aryl and heteroaryl magnesium reagents to ketone 3.
For example, 2-phenyl-7-chloroindole (5g) was prepared in ex-
cellent yield (91%) using phenyl magnesium chloride (entry 6).
Heteroaryl nucleophiles, such as 2- and 3-pyridinylmagnesium
chloride, and 2-thienylmagnesium bromide gave the corre-
sponding 2-heteroaryl indoles (5h–j) in 78%, 76%, and 72% yield,
respectively (entries 7–9). Furthermore, 2-alkyn-1-ylindoles were
directly synthesized from alkynyl magnesium species (entries 10
and 11).
Having successfully employed various carbon nucleophiles for
the preparation of a range of 2-substituted indoles from ketone
3, we decided to extend our method to other substituted
ketones (Table 2). Not surprisingly, 1-(2-aminophenyl)-2-chloro-
ethanone (6a, X, R0¼H) worked well in the reaction, affording
2-thien-2-ylindole (7a) in 76% yield. The presence of either
electron-donating or electron-withdrawing substituents on the
phenyl ring had little impact on the transformation. 1-(2-Amino-
6-methoxyphenyl)-2-chloroethanone (6b, X¼6-MeO, R0¼H)
containing an electron-rich methoxy group was converted to 4-
methoxy-2-propylindole (7b) in 63% yield, while the substrate
The versatility of this method was further extended to the
preparation of 2,3-disubstituted indoles with excellent control of
regioselectivity, which would be difficult to prepare selectively
by other means. Hence, treatment of ketone 16 with 2.5 equiv of
nPrMgCl at ꢁ10 ꢀC to 22 ꢀC afforded 7-chloro-3-methyl-2-pro-
pylindole (17a) in 93% yield. Likewise, 7-chloro-3-methyl-2-
thien-2-ylindole (17b) was easily obtained in 80% yield
employing 2.0 equiv of 2-thienyllithium (Scheme 5). These par-
ticular examples clearly highlight the remarkable efficiency of
this method, which should be broadly applicable to other sub-
strates for the regioselective synthesis of 2,3-disubstituted
indoles.
O
Cl
Toluene or THF
_ 40 to 22 °C
R
RM
+
N
H
NH2
16
Cl
Cl
17a, 67% (in THF)
RM = nPrMgCl
93% (in toluene)
S
Li
Scheme 5.
RM =
17b, 80% (in toluene)
We next sought to apply this method to the synthesis of a li-
brary of indole derivatives16 with the goal of preparing milligram
quantities of interesting substrates for biological evaluation and
to help us refine our capabilities for throughput experimentation.
The selected ketone and Grignard reagents are illustrated in
containing
a trifluorosubstituted phenyl ring reacted with
nPrMgCl to form 4,5,6-trifluoro-2-propylindole (7c) in 68% yield.
7-Fluoro-5-methyl-2-phenylindole (7d) and 5,7-dimethyl-2-phe-
nylethynylindole (7e) were readily prepared by addition of either
phenyl or phenylethynyl magnesium chloride, respectively.
Under the same condition, phenyl bromide of aniline 6f (X=5-Br,
R0=H) was not reactive toward Mg–Br exchange, and 5-bromo-2-
phenylindole (7f) was prepared in 75% yield. N-Substitution was
also tolerated in this reaction as demonstrated in the reaction of
1-(N-methyl-2-aminophenyl)-2-chloroethanone (6g, X¼H, R0¼Me)
with nPrMgCl to form N-methyl-2-propylindole (7g) in very
high yield (91%).
Table 3
96-Well plate indole synthesis
O
O
O
F
O
Cl
Cl
Cl
Cl
F
F
Cl
NH2
NH2
NH2
6a
NH2
O
F
6c
6d
6e
O
O
O
Cl
F
Cl
+
Cl
NH2
NH2
NH2
N
H
Cl
6h
6i
6g
3
Table 2
Synthesis of 2-substituted indoles from ketone 6
O
Cl
Cl
MgBr
18b
BrMg
RM
MgBr
18c
X
R
X
MgBr
THF or toluene
_ 40 to 22 °C
N
NHR'
6, R' = H, Me
18a
18d
R'
MgBr
7
S
MgBr
OMe
F
MgBr
18e
S
F
F
Ph
MgBr
BrMg
18f
18h
18g
N
H
CF3
O
N
H
N
H
N
MgBr
F
H
MgBr
7a, 76%a,d
7b, 63%b,c
7c, 68%a,c
7d, 66%b,c
BrMg
Br
MgBr
Ph
18j
18l
18i
18k
Ph
N
H
N
H
N
1) THF/toluene (50/50), _ 40 °C
7e, 52%b,c
7f, 75%b,c
7g, 91%b,c
2) add RMgX via multichannel pipetter
2) warm to RT, NH4Cl quench
3) MTBE extraction
96-well plate
All reactions were carried out without optimization. Yields refer to isolated material
based on ketone 6.
a
4) Mass Directed HPLC
Solvent¼toluene.
b
Solvent¼THF.
c
RM¼Grignard reagent.
Indole Library
d
RM¼organolithium reagent.

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T. Pei et al. / Tetrahedron 65 (2009) 3285–3291
Table 3. The library synthesis was performed in a 96-well plate
using 160 mol (w30 mg) of ketone and 300 L of solvent per
for future optimization. Reaction set-up, execution, and work-up
took approximately 0.5 day while compound isolation and purifi-
cation was completed in approximately two days in a completely
automated manner.
m
m
well.17 The ketones were dispensed across rows and the
Grignard reagents were dispensed across columns. For example,
ketone 6a was dispensed in positions A1–A12 and Grignard 18a
was dispensed in positions A1, B1, C1, etc. through H1. All
manipulations were performed inside an inert atmosphere
glovebox in order to simplify handling of the Grignard reagents.
The temperature and solvent mixture (THF/toluene) chosen
were viewed as the most general thereby offering the greatest
opportunity to synthesize a diverse array of substrates.
3. Summary
We have discovered a new and practical method for the ef-
ficient and regioselective synthesis of substituted indoles from
1-(2-aminophenyl)-2-chloroethanones. The reaction proceeds via
a [1,2]-aryl rearrangement followed by intramolecular conden-
sation to form the indole. The method introduces substituents at
the C-2 position of the indole and tolerates different substitution
Following Grignard addition, aqueous ammonium chloride
quench, and extraction into MTBE, the reaction mixture was
analyzed by HPLC and high resolution mass spectrometry to
determine conversion and confirm product identity. Complete
details regarding synthesis, yield, and purification can be found
patterns on the
a-chloro ketone. We believe that this method
can serve as a valuable tool for the modular synthesis of indole-
containing medicinal agents, and with some refinement a useful
platform for reaction optimization is achievable. In summary,
this simple procedure, which proceeds under mild reaction
conditions with inexpensive starting materials renders this
method a valuable addition to those that have already been
popularized.
in Section
4 and Supplementary data. Moderate to good
conversions were obtained in nearly all cases. Automated mass-
directed chromatography was used to purify each sample directly
from the work-up mixture.18 After separation, the solvent in each
sample was lyophilized and the samples were re-analyzed by
HPLC to assess for purity. A total of 62 indoles were isolated in
greater than >90 HPLC area percent purity. The remaining
indoles from the 96-well library were either isolated in un-
acceptable yields (<0.5 mg) or contained an unacceptable level of
impurities attributed to decomposition.19 A selection of the in-
doles prepared with this technique are shown in Table 4 and
serve to highlight the diversity of substrates acceptable via use of
this methodology. These compounds were not prepared in the
serial manner and have therefore allowed us to define the scope
of accessible derivatives. It should be noted that for Grignard 18l,
a mixture of monomer 7n and dimer 7o (80/20) was obtained,
which were characterized and separated based on their molec-
ular weights.
4. Experimental
4.1. General methods
Reagents and solvents obtained from commercial suppliers
were used without purification or drying unless otherwise noted.
All reactions were conducted in standard RB-flasks under a nitro-
gen atmosphere. NMR spectra were obtained on Burker DPX-400
and DPX-500 spectrometer. Flash column chromatography was
performed employing 200–400 mesh silica gel (Aldrich) eluting
with mixtures of hexanes and ethyl acetate. HPLC was performed
on an Agilent 1100 series machine using a Agilent ZORBAX (Eclipse
While the recoveries are moderate to poor compared to those
obtained via sequential compound synthesis (Tables 1 and 2), the
application of this methodology to high throughput parallel syn-
thesis allows rapid access to a large number of indole structures
with yields that are suitable for biological activity screening. It
should be stressed that the main focus was to expand our capa-
bilities in high throughput experimentation and build a platform
Plus C18) column (4.6ꢂ50 mm, 1.8
mm, 600 bar), 1.50 mL/min
flowrate, 215 nm detection, 28 ꢀC column temperature; mobile
phase MeCN/0.1 wt % aqueous H3PO4 10/90 ramp to 95/5 over
9 min and stay for 1 min.
4.2. General procedure for the acylation of anilines
A modified procedure of Sugasawa reaction was used to react
anilines with nitriles.9
Aniline (100 mmol, 1.0 equiv) and chloroacetonitrile (250 mmol,
2.5 equiv) were added sequentially to a mixture of AlCl3 pellets
(120 mmol, 1.2 equiv) and BCl3 solution (1.0 M in dichloromethane,
120 mmol, 1.2 equiv) with extra 60 mL dichloromethane cooled in
ice bath. The cloudy solution was stirred for 0.5 h at room tem-
perature before being heated at reflux for 12 h. The reaction mix-
ture was then cooled in ice bath, quenched with 2 N HCl 150 mL,
heated at reflux for 20 min, cooled, and extracted with dichloro-
methane (2ꢂ100 mL). The combined organic layers were dried over
MgSO4, concentrated, and chromatographed to afford corre-
sponding 2-chloroethanone.
Table 4
A selection of indoles prepared in library synthesisa
F
F
F
N
H
N
H
F
N
H
S
7j, 2 mg, 5% yield
7h, 3 mg, 8% yield
7i, 9 mg, 27% yield
OCF3
F
S
4.2.1. 1-(2-Amino-3-chlorophenyl)-2-chloroethanone (3)
Bright yellow solid, mp 104–106 ꢀC. 1H NMR (500 MHz, CDCl3):
Cl
N
N
H
d
7.61 (dd, J¼8.2,1.2 Hz,1H), 7.46 (dd, J¼7.8,1.2 Hz,1H), 6.85 (br s, 2H),
N
H
6.63 (m, 1H), 4.68 (s, 2H). 13C {1H} NMR (125 MHz, CDCl3):
d
192.3,
7m, 13 mg, 40%
7k, 3 mg, 6% yield
7l, 2 mg, 4% yield
147.2,134.8,129.5,121.0,116.0,115.5, 46.5. Anal. Calcd for C8H7Cl2NO:
C, 47.09; H, 3.46; N, 6.86. Found: C, 46.95; H, 3.29; N, 6.78.
H
N
NH
N
H
4.2.2. 1-(2-Amino-4,5,6-trifluorophenyl)-2-chloroethanone (6c)
White solid, mp 105–106 ꢀC. 1H NMR (500 MHz, CDCl3):
d
6.39
(br s, 2H), 6.28 (ddd, J¼11.6, 6.0, 2.3 Hz, 1H), 4.68 (d, J¼4.7 Hz, 2H).
13C {1H} NMR (125 MHz, CDCl3):
190.1 (m), 156.5 (dd, J¼11.1,
7n, 5 mg, 14% yield
7o, 1.5 mg, 3% yield
a
Isolated quantity of product and yields are shown.
d

T. Pei et al. / Tetrahedron 65 (2009) 3285–3291
3289
6.8 Hz), 154.5 (dd, J¼11.1, 3.2 Hz), 153.8 (dd, J¼10.8, 6.5 Hz), 151.8
(dd, J¼11.8, 6.5 Hz), 148.0 (dd, J¼7.4, 12.9 Hz), 132.4 (m), 130.5 (dd,
J¼17.2, 16.0 Hz), 103.0 (dt, J¼14.2, 2.5 Hz), 99.4 (ddd, J¼20.3, 3.1,
1.2 Hz), 50.6 (d, J¼18.4 Hz). 19F {1H} NMR (470 MHz, CDCl3):
13C {1H} NMR (100 MHz, CDCl3):
118.2, 115.5, 98.6, 8.7, 7.4. Anal. Calcd for C11H10ClN: C, 68.93; H,
5.26; N, 7.31. Found: C, 68.77; H, 5.24; N, 7.14.
d
142.5, 132.9, 130.0, 120.4, 120.3,
d
ꢁ124.7 (dd, J¼22.9, 13.7 Hz), ꢁ128.9 (dd, J¼22.9, 15.3 Hz), ꢁ175.6
4.3.5. 7-Chloro-2-hexan-1-ylindole (5e)
(m). Anal. Calcd for C8H5ClF3NO: C, 42.98; H, 2.25; N, 6.26. Found: C,
42.64; H, 2.09; N, 6.20.
Pale yellow oil. 1H NMR (400 MHz, CDCl3):
d 8.06 (br s), 7.44 (m,
1H), 7.12 (m, 1H), 7.01 (m, 1H), 6.30 (m, 1H), 2.79 (t, J¼7.7 Hz, 2H),
1.74 (m, 2H), 1.38 (m, 6H), 0.93 (m, 3H). 13C {1H} NMR (125 MHz,
4.2.3. 1-(2-Amino-3-fluoro-5-methylphenyl)-2-chloroethanone (6d)
CDCl3): d 140.9, 133.1, 130.3, 120.4, 120.3, 118.3, 115.8, 100.5, 31.6,
Yellow solid, mp 98–91 ꢀC. 1H NMR (500 MHz, CDCl3):
d
7.21 (s,
1H), 7.01 (dd, J¼11.9, 1.9 Hz, 1H), 5.99 (br s, 2H), 4.67 (s, 2H), 2.27 (s,
3H). 13C {1H} NMR (100 MHz, CDCl3):
29.1, 29.0, 28.3, 22.7, 14.1. HRMS calcd for C14H19ClN (MþH)þ:
236.1206; found: 236.1198.
d
192.2 (d, J¼2.4 Hz), 152.4,
150.5, 138.2 (d, J¼14.2 Hz), 125.2 (d, J¼3.0 Hz), 124.3 (d, J¼6.7 Hz),
4.3.6. 2-Trimethylsilylmethylindole (5f)
120.5 (d, J¼17.8 Hz), 116.7 (d, J¼4.3 Hz), 46.6, 20.5 (d, J¼1.8 Hz). 19F
Pale yellow oil. 1H NMR (400 MHz, CDCl3):
d
7.85 (br s, 1H), 7.37
(m, 1H), 7.06 (m, 1H), 6.98 (m, 1H), 6.11 (m, 1H), 2.21 (s, 2H), 0.11 (s,
9H). 13C {1H} NMR (125 MHz, CDCl3):
138.8, 132.9, 131.0, 120.3,
{1H} NMR (470 MHz, CDCl3):
d
ꢁ136.4. Anal. Calcd for C9H9ClFNO:
C, 53.61; H, 4.50; N, 6.95. Found: C, 53.80; H, 4.37; N, 6.83.
d
119.6, 117.6, 115.4, 99.7, 19.1, ꢁ1.8. HRMS calcd for C12H18ClNSi
4.2.4. 1-(2-Amino-3-chlorophenyl)-2-chloropropanone (16)
(MþH)þ: 238.0819; found: 238.0823.
Yellow solid, mp 54–55 ꢀC. 1H NMR (500 MHz, CDCl3):
d 7.75
(dd, J¼8.2, 1.2 Hz, 1H), 7.47 (dd, J¼7.7, 1.3 Hz, 1H), 6.89 (br s, 2H),
4.3.7. 7-Chloro-2-pyridin-2-ylindole (5h)
6.65 (m, 1H), 5.30 (q, J¼6.6 Hz, 1H), 1.74 (d, J¼6.6 Hz, 3H). 13C {1H}
Pale yellow solid, mp 118–120 ꢀC. 1H NMR (400 MHz, CDCl3):
NMR (125 MHz, CDCl3):
d
195.0, 147.7, 134.6, 129.8, 121.0, 115.7,
d
9.68 (br s, 1H), 8.62 (m, 1H), 7.79 (m, 1H), 7.73 (td, J¼7.3, 1.7 Hz,
115.3, 53.0, 20.3. Anal. Calcd for C9H9Cl2NO: C, 49.57; H, 4.16; N,
6.42. Found: C, 49.35; H, 4.07; N, 6.35.
1H), 7.55 (d, J¼7.9 Hz, 1H), 7.21 (m, 2H), 7.06 (t, J¼7.8 Hz, 1H), 7.04
(d, J¼2.3 Hz, 1H). 13C {1H} NMR (100 MHz, CDCl3):
d 149.7, 149.2,
137.3, 136.5, 133.8, 130.4, 122.4, 122.3, 120.8, 119.8, 119.6, 116.8,
101.1. HRMS calcd for C13H10ClN2 (MþH)þ: 229.0533; found:
229.0539.
4.3. General procedure for the preparation of indoles
To a solution of a-chloro acetophenone (1.00 mmol) in 2.0 mL
either toluene or THF at ꢁ10 ꢀC was added dropwise a solution of
RMgX or RLi (2.50 mmol). The reaction was kept <10 ꢀC during
addition and stirred in cold bath for 15 min before removal of the
bath. After 15 min to 2 h at room temperature, the mixture was
quenched with diluted aqueous NH4Cl, extracted with MTBE,
washed with brine, and dried over MgSO4. After concentration,
the crude residue was chromatographed to afford the desired
indole.
4.3.8. 7-Chloro-2-pyridin-3-ylindole (5i)
White solid, mp 207–209 ꢀC. 1H NMR (400 MHz, CDCl3 and
CD3COD):
d
8.93 (dd, J¼2.3, 0.7 Hz, 1H), 8.40 (dd, J¼5.0, 1.5 Hz, 1H),
8.13 (dt, J¼8.0, 2.0 Hz, 1H), 7.43 (m, 1H), 7.40 (m, 1H), 7.10 (dd, J¼7.6,
1.0 Hz, 1H), 6.95 (t, J¼7.7 Hz, 1H), 6.84 (s, 1H). 13C {1H} NMR
(100 MHz, CDCl3 and CD3COD):
d 146.7, 145.3, 135.1, 135.0, 134.8,
130.5, 129.6, 124.7, 122.6, 121.1, 119.5, 117.0, 102.4. HRMS calcd for
C13H10ClN2 (MþH)þ: 229.0533; found: 223.0528.
4.3.1. 7-Chloro-2-propylindole (5a)
4.3.9. 7-Chloro-2-thien-2-ylindole (5j)
Yellow oil. 1H NMR (500 MHz, CDCl3):
d
8.08 (br s, 1H), 7.45 (d,
Pale yellow solid, mp 86–88 ꢀC. 1H NMR (500 MHz, CDCl3):
J¼7.9 Hz,1H), 7.14 (d, J¼7.6 Hz,1H), 7.03 (m,1H), 6.31 (s, 1H), 2.78 (t,
d
8.38 (br s, 1H), 7.52 (d, J¼7.9 Hz, 1H), 7.34 (m, 2H), 7.22 (dd, J¼7.6,
J¼7.5 Hz, 2H), 1.80 (m, 2H), 1.05 (t, J¼7.4 Hz, 3H). 13C {1H} NMR
0.6 Hz,1H), 7.12 (dd, J¼5.0, 3.7 Hz,1H), 7.07 (t, J¼7.8 Hz,1H), 6.77 (d,
(125 MHz, CDCl3):
d
140.7, 133.1, 130.3, 120.4, 120.3, 118.4, 115.8,
J¼2.3 Hz, 1H). 13C {1H} NMR (125 MHz, CDCl3):
d 134.9, 133.8, 133.1,
100.7, 30.3, 22.4, 13.9. HRMS calcd for C11H13ClN (MþH)þ:
130.5, 128.0, 125.2, 123.6, 121.8, 121.2, 119.1, 116.2, 101.2. Anal. Calcd
for C12H8ClNS: C, 61.67; H, 3.45; N, 5.99. Found: C, 61.34; H, 3.39; N,
5.81.
194.0737; found: 194.0726.
4.3.2. 2-Allyl-7-chloroindole (5b)
Pale yellow oil. 1H NMR (500 MHz, CDCl3):
d
8.13 (br s, 1H), 7.49
4.3.10. 7-Chloro-2-(2-trimethylsilylacetyn-1-yl)indole (5k)
(d, J¼7.7 Hz, 1H), 7.18 (dd, J¼7.6, 0.8 Hz, 1H), 7.06 (t, J¼7.8 Hz, 1H),
White solid, mp 62–64 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.39 (br
6.37 (m, 1H), 6.06 (ddt, J¼17.0, 10.1, 6.7 Hz, 1H), 5.28 (m, 2H), 3.58
s, 1H), 7.48 (dd, J¼8.0, 0.5 Hz, 1H), 7.24 (d, J¼7.6 Hz, 1H), 7.06 (t,
(m, 2H). 13C {1H} NMR (125 MHz, CDCl3):
d 137.9, 134.4, 133.4, 130.3,
J¼7.9 Hz, 1H), 6.81 (d, J¼2.2 Hz, 1H), 0.31 (s, 9H). 13C {1H} NMR
120.7, 120.5, 118.6, 117.7, 116.0, 101.4, 32.8. HRMS calcd for C11H11ClN
(100 MHz, CDCl3): d 133.1, 128.7, 122.7, 121.1, 119.4, 119.3, 116.1,
(MþH)þ: 192.0580; found: 192.0573.
109.8, 99.2, 96.1, ꢁ0.3. Anal. Calcd for C13H14ClNSi: C, 63.01; H, 5.69;
N, 5.65. Found: C, 63.20; H, 5.88; N, 5.44.
4.3.3. 7-Chloro-2-(2-[1,3]-dioxan-2-ylethyl)indole (5c)
Pale yellow oil. 1H NMR (400 MHz, CDCl3):
d
8.72 (br s, 1H), 7.42
4.3.11. 7-Chloro-2-hexyn-1-ylindole (5l)
(d, J¼7.7 Hz,1H), 7.11 (d, J¼7.5 Hz, 1H), 6.99 (t, J¼7.7 Hz,1H), 6.27 (d,
J¼1.8 Hz, 1H), 4.66 (t, J¼4.8 Hz, 1H), 4.20 (m, 2H), 3.82 (m, 2H), 2.95
(t, J¼7.1 Hz, 2H), 2.20 (m, 1H), 2.05 (m, 2H), 1.41 (m, 1H). 13C {1H}
Pale yellow oil. 1H NMR (500 MHz, CDCl3):
d 8.33 (br s, 1H), 7.48
(dd, J¼8.0, 0.4 Hz, 1H), 7.22 (dd, J¼7.6, 0.7 Hz, 1H), 7.06 (td, J¼7.9,
1.1 Hz, 1H), 6.71 (m, 1H), 2.50 (t, J¼7.1 Hz, 2H), 1.65 (m, 2H), 1.43 (m,
NMR (100 MHz, CDCl3):
d
140.1, 133.2, 130.2, 120.2, 120.2, 118.4,
2H), 1.00 (t, J¼7.3 Hz, 3H). 13C {1H} NMR (125 MHz, CDCl3):
d 133.0,
115.9, 100.2, 100.5, 67.0, 34.1, 25.7, 22.2. HRMS calcd for
129.2, 122.2, 121.0, 120.5, 119.2, 116.0, 108.2, 94.7, 72.5, 30.6, 22.1,
19.3, 13.6. HRMS calcd for C14H15ClN (MþH)þ: 232.0893; found:
232.0900.
C14H17ClNO2 (MþH)þ: 266.0948; found: 266.0954.
4.3.4. 7-Chloro-2-cyclopropylindole (5d)
Pale yellow oil. 1H NMR (400 MHz, CDCl3):
d
8.16 (br s, 1H), 7.41
4.3.12. 4,5,6-Trifluoro-2-propylindole (7c)
(d, J¼7.8 Hz, 1H), 7.12 (d, J¼7.4 Hz, 1H), 7.01 (t, J¼7.9 Hz, 1H), 6.20 (d,
Light brown oil. 1H NMR (400 MHz, CDCl3):
d
7.91 (br s, 1H),
J¼2.3 Hz, 1H), 2.00 (tt, J¼5.1, 3.3 Hz, 1H), 1.02 (m, 2H), 0.82 (m, 2H).
6.88 (m, 1H), 6.31 (m, 1H), 2.71 (t, J¼7.5 Hz, 2H), 1.75 (m, 2H),

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T. Pei et al. / Tetrahedron 65 (2009) 3285–3291
1.02 (t, J¼7.4 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3):
d
148.9
1H), 3.74 (d, J¼11.3 Hz, 1H). 13C {1H} NMR (125 MHz, CDCl3):
(dd, J¼12.8, 2.4 Hz), 146.5 (dd, J¼12.8, 2.4 Hz), 144.2 (dd,
J¼11.2, 2.8 Hz), 141.7 (dd, J¼11.2, 5.6 Hz), 141.2 (d, J¼3.2 Hz),
136.0 (dd, J¼17.6, 14.4 Hz), 133.6 (dd, J¼17.6, 14.4 Hz), 130.6 (t,
J¼12.8 Hz), 114.2 (d, J¼18.4 Hz), 95.7 (d, J¼4.8 Hz), 93.6 (dd,
J¼21.7, 4.0 Hz), 30.0, 22.1, 13.6. 19F {1H} NMR (376 MHz,
d
142.0, 129.6, 126.8, 123.6, 120.9, 118.1, 74.6 (t, J¼22.5 Hz), 47.8.
HRMS calcd for C8H9DCl2NO (MþH)þ: 207.0202; found:
207.0201.
CDCl3):
d
ꢁ144.3 (d, J¼20.7 Hz), ꢁ146.3 (d, J¼20.7 Hz), ꢁ174.1
4.6. 7-Chloro-2-D-indole (15)
(m). HRMS calcd for C11H11F3N (MþH)þ: 214.0844; found:
214.0837.
To a solution of 1-(2-amino-3-chlorophenyl)-2-chloro-1-D-
ethan-1-ol (14, 207 mg, 1.0 mmol) in THF (2.0 mL) cooled at ꢁ10 ꢀC
i
4.3.13. 5,7-Dimethyl-2-phenylethynylindole (7e)
was added PrMgCl (2.0 M in THF, 1.25 mL, 2.5 mmol), warmed to
Light brown oil. 1H NMR (500 MHz, CDCl3):
d
8.15 (br s, 1H), 7.62
(m, 2H), 7.43 (m, 3H), 7.30 (s, 1H), 6.94 (s, 1H), 6.84 (d, J¼2.0 Hz,1H),
2.49 (s, 3H), 2.48 (s, 3H). 13C {1H} NMR (125 MHz, CDCl3):
134.3,
room temperature for 1 h, quenched with saturated NH4Cl,
extracted with MTBE, washed with brine, and dried over MgSO4.
After concentration, the crude residue was chromatographed to
give indole 15 (105 mg, 69%) as a white solid. Mp 52–54 ꢀC. 1H NMR
d
131.5, 130.1, 128.6, 128.5, 127.7, 125.9, 122.8, 119.7, 118.5, 118.1, 109.0,
92.4, 82.3, 21.4, 16.6. HRMS calcd for C18H16N (MþH)þ: 246.1283;
found: 246.1278.
(500 MHz, CDCl3):
d
8.35, 7.61 (d, J¼7.9 Hz, 1H), 7.27 (dd, J¼7.6,
0.9 Hz, 1H), 7.12 (t, J¼7.8 Hz, 1H), 6.65 (d, J¼2.2 Hz, 1H). 13C {1H}
NMR (125 MHz, CDCl3):
d
133.2, 129.4, 124.6 (t, J¼28.0 Hz), 121.4,
4.3.14. 7-Fluoro-5-methyl-2-phenylindole (7d)
120.7, 119.4, 116.7, 103.6. HRMS calcd for C8H6DClN (MþH)þ:
White solid, mp 145–147 ꢀC. 1H NMR (500 MHz, CDCl3):
d
8.37
153.0330; found: 153.0325.
(br s, 1H), 7.68 (d, J¼7.2 Hz, 2H), 7.47 (t, J¼7.7 Hz, 2H), 7.37 (t,
J¼7.4 Hz, 1H), 7.21 (s, 1H), 6.79 (m, 2H), 2.47 (s, 3H). 13C {1H} NMR
(125 MHz, CDCl3):
d
149.0 (d, J¼243.0 Hz), 138.8, 132.9
4.7. High throughput indole library synthesis
(d, J¼4.9 Hz), 132.0, 130.5 (d, J¼5.6 Hz), 129.1, 128.0, 125.2, 123.3 (d,
J¼12.9 Hz), 115.9 (d, J¼3.1 Hz), 108.7 (d, J¼16.0 Hz), 100.1 (d,
4.7.1. Procedure for preparation of indole library
A THF stock solution of each ketone was prepared in THF
(0.3 M) and 530 mL (160 mmol ketone) was transferred via mul-
tichannel pipetter to 1 mL vials containing micro-stirbars in the
appropriate row of an aluminum 96-well plate. The THF was
removed via evaporation in a GenevacÒ Centrifuge Evaporator.
The 96-well plate was brought into an inert atmosphere glove-
box, placed on a tumble stirrer equipped to a circulating cooler,
J¼2.4 Hz), 21.5. 19F {1H} NMR (470 MHz, CDCl3):
d
ꢁ136.5. Anal.
Calcd for C15H12FN: C, 79.98; H, 5.37; N, 6.22. Found: C, 79.71; H,
5.32; N, 6.06.
4.3.15. 7-Chloro-3-methyl-2-propylindole (17a)
Pale yellow oil. 1H NMR (500 MHz, CDCl3):
d 7.95 (br s, 1H), 7.46
(d, J¼7.9 Hz, 1H), 7.20 (dd, J¼7.5, 0.6 Hz, 1H), 7.10 (t, J¼7.7 Hz, 1H),
2.77 (t, J¼7.5 Hz, 2H), 2.31 (s, 3H),1.77 (m, 2H),1.06 (t, J¼7.4 Hz, 3H).
and THF/toluene (1:1, 150 mL total) was added to each well. The
13C {1H} NMR (125 MHz, CDCl3):
d
136.1, 132.4, 131.0, 120.4, 119.8,
plate was cooled to ꢁ40 ꢀC and Grignard reagent (2.5 equiv) was
added in four portions via a multichannel pipetter over the
course of 45 min. After addition, the reactions were warmed to
20 ꢀC over 1 h. Upon completion of an additional 1 h age, the
solutions were cooled to 5 ꢀC and diluted aqueous ammonium
116.8, 115.8, 108.2, 28.2, 23.0, 13.9, 8.7. HRMS calcd for C12H15ClN
(MþH)þ: 208.0893; found: 208.0889.
4.3.16. 7-Chloro-3-methyl-2-thien-2-ylindole (17b)
Off-white solid; mp 111–112 ꢀC. 1H NMR (400 MHz, CDCl3):
chloride (200 mL) and MTBE (300 mL) were added to each vial.
d
8.17 (br s,1H), 7.48 (d, J¼7.9 Hz,1H), 7.40 (m, 1H), 7.30 (m,1H), 7.18
After warming to room temperature, the 96-well plate was re-
moved from the glovebox and the organic layer was separated
and washed with brine using a 12-channel pipetter to introduce
and remove liquids. To assess conversion, purity, and identity,
(m, 2H), 7.08 (m, 1H), 2.49 (s, 3H). 13C {1H} NMR (125 MHz, CDCl3):
d
134.6, 133.0, 131.3, 129.2, 127.7, 125.4, 124.7, 121.9, 120.5, 117.6,
116.0, 110.4, 10.0. HRMS calcd for C13H11ClNS (MþH)þ: 248.0301;
found: 248.0292.
a portion of each solution (20 mL) was sampled, diluted, and
analyzed by HPLC. The remaining solution was concentrated
under reduced pressure and re-dissolved in DMSO for preparative
mass-directed HPLC purification. Supplementary data contains
the product indole structures, reaction conversions, and yields of
each compound.
4.4. 2-(N-Trimethylacetyl-2-aminophenyl)indole (13)14
Pale brown oil. 1H NMR (500 MHz, CDCl3):
d 8.44 (br s, 1H),
8.39 (d, J¼7.9 Hz, 1H), 8.22 (br s, 1H), 7.68 (d, J¼7.9 Hz, 1H), 7.45
(m, 2H), 7.39 (m, 1H), 7.26 (m, 1H), 7.20 (m, 2H), 6.65 (s, 1H), 1.22
(s, 9H). 13C {1H} NMR (125 MHz, CDCl3):
d
177.2, 136.6, 135.8, 134.2,
4.7.2. Chromatography and mass spectrometry
129.3, 128.7, 124.3, 123.7, 122.8, 121.7, 120.7, 120.6, 120.5, 111.1,
102.6, 39.9, 27.5. HRMS calcd for C19H21N2O (MþH)þ: 293.1654;
found: 293.1660.
Analytical HPLC–MS to assess purity and area percent con-
version were obtained on a Waters Acquity UPLC with PDA UV
Detector and on a Waters Acquity SQD (single quad) using
Electrospray ionization equipped with a Waters Acquity BEH
4.5. 1-(2-Amino-3-chlorophenyl)-2-chloro-1-D-ethan-1-ol (14)
column (2.1ꢂ50 mm, 1.7
mm particles). Mass-directed HPLC pu-
rification was performed on a Waters Auto purification system
in conjunction with a Waters 3100 SQ Detector with Electro-
spray positive ionization equipped with a Waters Xbridge Prep
To
a
solution of 1-(2-amino-3-chlorophenyl)-2-chloro-
ethanone (3, 1.02 g, 5.0 mmol) in 1,4-dioxane (9.0 mL) and
water (1.0 mL) was added NaBD4 (256 mg, 6.0 mmol) at room
temperature, aged for 1 h, quenched with saturated NH4Cl,
extracted with MTBE, washed with brine, and dried over
MgSO4. After concentration, the crude residue was chromato-
graphed to give alcohol 14 (0.78 g, 75%) as a white solid. Mp
C18 column (30 mm (id)ꢂ75 mm,
5 mm particles). The in-
strument was set to trigger collection by MþH or MþNa.
Fractions were collected into pre-tared high recovery 20 mL
vials. Selected fractions were evaporated to dryness in a Gene-
vac HT-24 and the vials were reweighed to calculate yields/
recovery. The following gradient was employed for all the
indoles:
61–63 ꢀC. 1H NMR (500 MHz, CDCl3):
1H), 6.97 (dd, J¼7.7, 1.4 Hz, 1H), 6.66 (m, 1H), 4.01 (d, J¼11.3 Hz,
d
7.24 (dd, J¼7.9, 1.5 Hz,

T. Pei et al. / Tetrahedron 65 (2009) 3285–3291
3291
Miyata, O.; Kimura, Y.; Muroya, K.; Hiramatsu, H.; Naito, T. Tetrahedron Lett.
1999, 40, 3601.
4. Leading references to current application of Fisher indole synthesis: (a) Hughes,
D. L. Org. Prep. Proced. Int.1993, 25, 609; (b) Wagaw, S.; Yang, B. Y.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 10251.
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Chem. 1997, 62, 2676.
Mobile phase: A¼waterþ0.1% formic acid, B¼acetonitrileþ0.1%
formic acid
Flow rate: 70 mL/min
Run time: 8.0 min
7. Lu, B. Z.; Zhao, W.; Wei, H. X.; Dufour, M.; Farina, V.; Senanayake, C. H. Org. Lett.
2006, 8, 3271.
Time
Gradient (for most samples)
%A
%B
8. Recent reviews on indole synthesis: (a) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (c)
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Diego, CA, 1996.
9. These compounds can be easily prepared via Friedel–Crafts acylation from
corresponding anilines and nitriles; see: Sugasawa, T.; Toyoda, T.; Adachi, M.;
Sasakura, K. J. Am. Chem. Soc. 1978, 100, 4842.
0.0
1.0
5
5.2
7.5
7.7
65
65
5
5
5
35
35
95
95
95
35
65
10. Pei, T.; Chen, C.; Dormer, P. G.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4231.
11. Huang, R. L. J. Org. Chem. 1954, 19, 1363.
12. (a) Cram, D. J. J. Am. Chem. Soc. 1949, 71, 3863; (b) Winstein, S.; Baird, R. J. Am.
Chem. Soc. 1957, 79, 756.
Acknowledgements
13. The chlorohydrin was isolated in high yield in the reaction of 2-chloro-
acetophenone with Grignard reagent even after prolonged aging; see: Bar-
luenga, J.; Florez, J.; Yus, M. J. Chem. Soc., Perkin Trans. 1 1983, 3019.
14. The dilithium reagent generated from N-2-bromophenyl pivaloyl amide reacted
We would like to thank Robert A. Reamer, Peter G. Dormer, Tom
J. Novak, Chris J. Welch, and Xiaoyi Gong for assistance with the
NMR, HRMS, and chromatographic analysis.
with
a-chloroketone to form the 3-substituted indole; see: Wender, P. A.;
White, A. W. Tetrahedron 1983, 39, 3767.
15. (a) Geissman, T. A.; Akawie, R. I. J. Am. Chem. Soc. 1951, 73, 1993; (b) Crombie, L.;
Hardy, R.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1985, 1373.
16. Recent publications on parallel synthesis of indole library: (a) Lindquist, C.;
Ersoy, O.; Somfai, P. Tetrahedron 2006, 62, 3439; (b) Fokas, D.; Yu, L.;
Baldino, C. M. Mol. Diversity 2005, 9, 81; (c) Smart, B. P.; Pan, Y. H.; Weeks,
A. K.; Bollinger, J. G.; Bahnson, B. J.; Gelb, M. H. Bioorg. Med. Chem. 2004,
12, 1737.
17. For examples of applying this technique to reaction screening, see: (a) Maligres,
P. E.; Krska, S. W.; Humphrey, G. R. Org. Lett. 2004, 6, 3147; (b) Shultz, C. S.;
Dreher, S. D.; Ikemoto, N.; Williams, J. M.; Grabowski, E. J. J.; Krska, S. W.; Sun,
Y.; Dormer, P. G.; DiMichele, L. Org. Lett. 2005, 7, 3405; (c) Tellers, D. M.; Bio, M.;
Song, Z. J.; McWilliams, J. C.; Sun, Y. Tetrahedron: Asymmetry 2006, 17, 550; (d)
Tellers, D. M.; McWilliams, J. C.; Humphrey, G.; Journet, M.; DiMichele, L.;
Hinksmon, J.; McKeown, A. E.; Rosner, T.; Sun, Y.; Tillyer, R. D. J. Am. Chem. Soc.
2006, 128, 17063.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.026.
References and notes
1. Recent reviews on indole alkaloids and references to the biological activity of
compounds containing the indole substructure: (a) Kawasaki, T.; Higuchi, K.
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978.
19. The decomposition is attributed to the prolonged solution exposure necessi-
tated during the chromatography. In our hands, these 2-substituted indoles
should be stored below ambient temperature in the solid state.
2. A review of Fisher indole synthesis: Robinson, B. Chem. Rev. 1963, 63, 373.
3. An improved synthesis was developed to allow the conversion happen under
milder condition using N-trifluoroacetyl enehydrazines as substrates; see: