A facile synthesis of N,3-disubstituted indoles and 3-hydroxyl indolines via an intramolecular SNAr of fluorinated amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2009.01.049

In this Letter, we describe a practical and highly versatile method for the preparation of N,3-disubstituted indoles and 3-hydroxyl indolines. This synthetic strategy relies on an epoxide-opening followed by an intramolecular S_NAr of the result

Full text of DOI:10.1016/j.tetlet.2009.01.049

Tetrahedron Letters 50 (2009) 1529–1532
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A facile synthesis of N,3-disubstituted indoles and 3-hydroxyl indolines via
an intramolecular SNAr of fluorinated amino alcohols
*
Cheng-yi Chen , Robert A. Reamer
Department of Process Research, Merck and Co., Inc., 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:
In this Letter, we describe a practical and highly versatile method for the preparation of N,3-disubstituted
indoles and 3-hydroxyl indolines. This synthetic strategy relies on an epoxide-opening followed by an
intramolecular SNAr of the resulting fluoroaryl amino alcohols. The reaction afforded 3-hydroxyl indo-
lines when carried out at lower temperature for the derivatives bearing multi-fluorine substituents at
the aromatic ring.
Received 17 December 2008
Revised 6 January 2009
Accepted 9 January 2009
Available online 15 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The indole and indoline scaffolds are prevalent substructures of
many natural products and biologically active compounds.1 The
need for efficient and practical syntheses of indoles and indolines
bearing a variety of substitution patterns provides a continual
challenge to organic chemists. Despite many diverse and creative
approaches that have been used to assemble these heterocycles,2
a general and efficient synthesis providing control over the regio-
selective introduction of substituents at C-2 and C-3 is of tanta-
alkoxide intermediates. The fact that a wide range of fluorinated
aromatic chloroketones are commercially available or these can
be readily prepared4 certainly enhances the synthetic potential of
the SNAr approach for the preparation of functionalized indoles
and hydroxylindolines. Furthermore, the planned indole synthesis
allows for the flexible, sequential introduction of R groups and var-
ious amines with potential extension to different substitution pat-
terns on the aromatic ring. In this Letter, we describe such a
practical and highly versatile method for the preparation of poly-
substituted indoles and 3-hydroxyl indolines.
The synthetic strategy that is outlined in Scheme 2 relies on an
epoxide opening followed by intramolecular SNAr5 of substituted
fluorobenzenes with various amines. A survey of the literature
showed that a single example based on this approach was on a
penta-F-substituted aromatic amino alkoxide.6 Apparently, the
generality of this transformation has not been well established,
especially in the case of mono-fluorinated derivatives of the type
6. Recently, Schirok reported the microwave-assisted syntheses
mount importance. We recently reported
a synthesis of 2-
substituted indoles 2 from readily accessible chloroacetophenones
of the type 1 and commercially available organometallic reagents
(Scheme 1).3a
Of particular significance is the regioselectivity and generality
attained under mild reaction conditions, making this method via-
ble for the preparation of many structurally diverse indoles. This
efficient synthesis of indoles relies on a unique [1,2]-aryl migration
mechanism and serves as a valuable tool for the modular synthesis
of C-2 substituted indoles.3b In an effort to develop a complimen-
tary method for the synthesis of C-3-substituted indoles and
indolines, we became interested in readily available chloroaceto-
phenones of the type 6 (Scheme 2).
As illustrated in Scheme 2, we envisioned that addition of orga-
nometallic agents to the ortho-F-substituted chloroketones would
afford carbinol, which could be further converted to epoxide in
situ. Epoxide opening via various amines would give amino alco-
hols bearing ortho-fluoroaryl groups. An intramolecular SNAr reac-
tion would in turn lead to the formation of either hydroxyl
indolines or indoles by in situ dehydration. The regioselective syn-
thesis of the C-3-substituted indole takes advantage of the unique
electronic properties of the fluorine substituent. The presence of a
fluorine substituent instead of an aniline moiety in the aromatic
ring was expected to prevent the facile [1,2] aryl migration of the
O
R
path a
O
Cl
R
NH
NH
O
3
4
Cl
R
N
net [1,2]-aryl migration
NH2
H
1
O
2
O
R
R
+
Cl
RM
NH
NH
path b
5
3
* Corresponding author.
E-mail address: cheng_chen@merck.com (C. Chen).
Scheme 1. Synthesis of 2-substituted indoles via [1,2]-aryl migration.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.049

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C. Chen, R. A. Reamer / Tetrahedron Letters 50 (2009) 1529–1532
O
F
R
O
R
R
OH
K3PO4, DMAC
150 oC, 12 h
Cl
O
Cl
RM
Cl
RM R'NH2
X
X
X
N
R'
X
X
F
12
Ph
THF or toluene
F
F
13
6
R'NH2 or R'2NH
DMAc or neat
N
N
S
S
R
N
OM
R
R
OH
N
Me
N
F
OH
SNAr
X
H or R'
R'
X
X
F
N
13a
13b
13c
F
N
R'
N
R'
Ph
Ph
F
Ph
7
8
OH
N
Scheme 2. Synthesis of indole and indolines via intramolecular SNAr.
N
F
F
HN
F
F
13d
13e
14
of 7-azaindoles and N-alkylated indoles from mono-fluorinated
epoxides.7 However, further extensions to hydroxyl indolines have
not been disclosed.
Scheme 3. One-pot process for the synthesis of indoles.
Since the epoxide formation and the ring opening with amines
were well precedented in the literature,7,8 we decided to focus on
the study of the proposed intramolecular SNAr reaction. Instead of
using microwave irradiation as reported by Schirok and co-work-
ers, a method that was only shown to afford indoles,7 we chose
to investigate the SNAr reaction under conventional, thermal con-
ditions. Our investigation into an efficient intramolecular SNAr
reaction began with the ring opening of epoxide 97c with n-butyl-
amine as the nitrogen nucleophile in the presence of inorganic
bases. To find the optimal reaction conditions, a number of bases
and solvents were evaluated (Table 1). Reaction conditions were
initially screened using polar aprotic solvents such as N,N-dimeth-
ylacetamide (DMAc) and either K2CO3 or K3PO4 as the inorganic
bases at 100 °C for 12 h. Under these conditions, no SNAr occurred
to produce the desired indoles. We were pleased to find that sim-
ply increasing the reaction temperature to 150 °C allowed us to ob-
tain indole 11 in 78–85% assay yield. Apparently, the choice of
polar solvent was not critical as the reactions worked well in
DMAc, NMP, and DMSO. More conveniently, the reaction can be
run under neat conditions with excess n-butylamine serving both
as nucleophile for the epoxide opening and as acid scavenger in
the intramolecular SNAr displacement. We noted that the reaction
temperature is significantly lower than that in the microwave-as-
sisted conditions, where the internal temperature reaches 240
°C.7 We believe that using K3PO4 as base in DMAc or organic bases
under neat conditions at lower temperatures offers advantages in
terms of functional group tolerance. More importantly, running
the reactions at lower temperature (100 °C, vide infra) allows us
to synthesize a number of 3-hydroxylindolines.
With the optimal set of conditions for the epoxide opening-SNAr
sequence selected, we were then poised to test the one-pot process
and to evaluate the substrate scope of this reaction. Gratifyingly,
addition of organometallics (RM) to ketone 12 followed by aging
at ambient temperature afforded crude epoxide smoothly. The
epoxide was isolated by extraction and subjected to the ring-open-
ing intramolecular SNAr sequence.
To investigate the scope of the process, reactions using various
organometallics and amines (3–5 equiv) were carried out using
K3PO4 (1.5 equiv) in DMAc at 150 °C for 12 h to afford a wide
variety of N,3-disubstituted indoles ( 13a–e) as summarized in
Scheme 3. All reactions proceed in good yields using primary
amines such as n-butylamine, methylamine, and aminoethanol.
Extension of the reaction to the poly-fluorinated aromatic ketones
provides access to fluorinated indoles. For example, running the
reaction with n-butylamine afforded the indoles 13d and 13e in
81% and 77% yield, respectively. Running the reactions with amino-
ethanol and 40% methylamine solution afforded indole 13b (70%)
and 13c (73%). Importantly, an N-cyclopropyl group can be readily
incorporated onto the indole using cyclopropyl amine as shown in
13a (65% yield). It should be noted that introduction of an N-cyclo-
F
F
F
F
F
F
F
O
O
N
R
19
N
R
F
F
15
20
Table 1
F
Optimization of the intramolecular SNAr
Ph
N
R
Ph
Ph
O
OH
intramolecular
SNAr
R = n-Bu
F
16
17
21
F
n-BuNH2
N
HN
F
F
F
F
:
O
9
10
11
N
R
F
Entrya
Base
Solvent
Temperature (°C)
Yieldb (%)
F
F
F
22
F
1
2
3
4
5
6
7
K2CO3
K3PO4
K2CO3
K3PO4
K3PO4
K3PO4
—
DMAc
DMAc
DMAc
DMAc
DMSO
NMP
100
100
150
150
150
150
150
NR
NR
78
85
83
81
84
F
F
F
F
F
O
N
R
F
N
R
F
n-BuNH2
F
18
23
24
a
All reactions were run in a sealed tube for 12 h.
Yield of indole (11) was assayed by HPLC.
b
Scheme 4. Competitive SNAr reactions in neat n-BuNH2.

C. Chen, R. A. Reamer / Tetrahedron Letters 50 (2009) 1529–1532
1531
propyl group to an indole is a difficult task, which calls for the cop-
per-mediated cyclopropanation using an excess amount of an
expensive cyclopropyl boronic acid or a bismuth derivative.9
The SNAr reaction failed for the para-F-substituted ketone such
that amino alcohol 14 was recovered completely (Scheme 3). Per-
plexed by the deactivating effect of para-F substitution, we decided
to perform some competition experiments to understand the ef-
fects of additional fluorine atom substitution. Four compounds
(15–18) were independently prepared using conventional meth-
ods,10 and were subjected to the SNAr reaction. As shown in
Scheme 4, substrate 15 afforded a 3:1 mixture of two compounds
19 and 20 in 67% yield, favoring substitution at less substituted
aromatic ring. This result clearly supports the fact that the para-F
N
N
S
HO
O
O
S
HN
N
N
F
O
O
a
F
F
F
25a
29
F
H
N
25 o
C
N
H
HO
N
S
N
S
OH
N
N
F
a
N
F
F
F
F
32
30
substituent disfavors the SNAr, presumably due to the
p-donor
capacity of fluorine.11 Conversely, for both substrates 16 and 17,
in which two regioisomers are possible, the SNAr reaction is com-
pletely regioselective, providing only indole 21 (70%) and 22
(73%), respectively. The SNAr reaction of 18 afforded a 3.3:1 mix-
ture of two readily separable compounds, 23 (53%) and 24 (16%),
favoring substitution at meta-substituted aromatic ring. These
competition experiments suggest that fluorine substitution acti-
vates the SNAr in the order: meta-F > ortho-F > H > para-F.
N
HO
N
O
HO
O
S
S
HN
F-
N
N
F
N+
31
a, b
F
F
F
33
a. Reactions were run in neat amines (10 eq) at 100 oC in a sealed tube for 12 h.
b. Crude product 30 was isolated and subjected to the reaction with morpholine.
Further, extending this methodology to a trisubstituted fluorok-
etone would allow the preparation of hydroxyl indolines and in-
doles in excellent yields with an even wider scope of the
substrates. We speculated that the additional fluorine substituents
would further accelerate the SNAr resulting in lower reaction tem-
perature. As highlighted in Scheme 5, ring opening of epoxide 25
and SNAr reaction using MeONH2, ethanolamine, and hydrazine
at 100 °C efficiently afforded the hydroxyl indolines (26a–c) in
89%, 92%, and 85% yield, respectively. Using dimethyl ethylene
diamine, structurally interesting indoles such as 27 and 28 were
obtained smoothly in 84% and 98% yield, respectively.12 In these
two cases, a second SNAr displacement occurred to form the six-
membered ring. In addition to the lower reaction temperatures,
we believed that the presence of additional fluorine atoms disfa-
vors dehydration to form the corresponding indoles due to the
inductive effect11 of the fluorine substituents. Scheme 6 These in-
doles (27 and 28) cannot be easily prepared via other means, but
are readily accessible using this strategy.
Scheme 6. Synthesis of hydroxylindolines from cyclic amines.
uct. This structurally distinct indole bearing an amine containing
side chain clearly incorporated 2 equiv of pyrrolidine. Apparently,
the SNAr reaction occurs to from cyclic ammonium species such as
31 which upon reacting with excess amine resulted in ring opening
to form indoline 32. Similar process was observed using morpholine
to afford indoline 29 in 74% yield. More interestingly, combination of
pyrrolidine and morpholine allowed for the preparation of hydroxy-
lindoline 33 in 71% yield. These examples clearly indicate that a wide
variety of N-substituents can be introduced by judicious combina-
tion of amines. The isolation of the indolines rather than the indoles
further supports our hypothesis that additional fluorine substitution
on the aromatic ring in combination with milder conditions (100 °C)
prevents the dehydration process.
In summary, we have developed a highly versatile protocol for
the preparation of a wide variety of indole and hydroxylindolines
from commercially available chloroketones, organometallics, and
amines. The success of the transformation relies on the facile intra-
molecular SNAr reaction. The method constitutes a practical and
modular strategy to access both indoles and hydroxylindolines,
which are useful motifs in a variety of interesting, biologically ac-
tive compounds. We believe that such strategy will find wide
applications in the synthesis of indole and hydroxylindolines.
Realizing that a secondary amine such as dimethyl ethylene dia-
mine can be applied to the SNAr reaction as shown in cases 27 and 28,
we next explored the reaction using cyclic amine such as pyrrolidine
and morpholine. Surprisingly, reaction of epoxide 25a with excess
pyrrolidine gave hydroxylindoline 32 in 79% yield as the sole prod-
N
S
N
HO
100 oC, 12 h
S
+
References and notes
RNH2
O
F
N
F
1. For recent reviews on indole alkaloids and references to the biological activities
of compounds containing the indole substructure: (a) Kawasaki, T.; Higuchi, K.
Nat. Prod. Rep. 2007, 24, 843. and references cited therein; (b) Saxton, J. E.. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1998; Vol. 51, (c)
Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559; (d) Brancale, A.; Silvestri, R. Med. Res.
Rev. 2007, 27, 209; (e) Harper, S.; Avolio, S.; Carfi, A.; Giuliano, C.; Padron, J.;
Bonelli, F.; Migliaccio, G.; De Francesco, R.; Laufer, R.; Rowley, M.; Narjes, F. J.
Med. Chem. 2005, 48, 4547; For references to the biological activity of
compounds containing the 3-hydroxyl indoline substructure, see: (f) Engel,
S.; Skoumbourdis, A. P.; Childress, J.; Neumann, S.; Deschamps, J. R.; Thomas, C.
J.; Colson, A.-O.; Costanzi, S. G.; Marvin, C. J. Am. Chem. Soc. 2008, 130, 5115; (g)
Estrada, E.; Pena, A. Bioorg. Med. Chem. 2000, 8, 2755.
2. For recent reviews and selected examples on indole/indoline synthesis, see: (a)
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (b) Cacchi, S.; Fabrizi,
G. Chem. Rev. 2005, 105, 2873; (c) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285; (d) Joule, J.. In Science of Synthesis; Thomas, E. J., Ed.; Thieme: Stuttgart,
2000; Vol. 10, p 361; (e) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491;
(f) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045; (g) Sunderberg, R. J.
Indoles; Academic Press: San Diego, 1996; For a review and selected examples
on indoline synthesis, see: (h) Kihara, M.; Iwai, Y.; Nagao, Y. Heterocycles 1995,
F
F
R
F
25a
26
F
F
N
N
N
HO
HO
HO
S
S
S
N
N
N
N
F
F
OH
OMe
S
NH2
F
F
26a
26b
26c
S
X
S
25b: X = C
25a: X = N
O
F
F
N
N
F
F
25a, b
F
N
N
+
MeHN
27
28
NHMe
Scheme 5. Synthesis of indoles and hydroxylindolines at 100 °C.

1532
C. Chen, R. A. Reamer / Tetrahedron Letters 50 (2009) 1529–1532
41, 2279; (i) Bastos, M. M.; Mayer, L. M. U.; Figueira, E. C. S.; Soares, M.; Kover,
W. B.; Boechat, N. J. Heterocycl. Chem. 2008, 45, 969; (j) Wipf, P.; Maciejewski, J.
Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabe, F. J. Am. Chem. Soc.
2007, 129, 44.
P. Org. Lett. 2008, 10, 4383.
10. Compounds 15–17 were prepared by addition of 2-fluorophenyl lithium to the
3. (a) Tao, P.; Chen, C.; Dormer, P. G.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47,
corresponding di-fluorinated
a-chloroketones, whereas 18 was prepared from
4231;
b
Tao, P.; Tellers, D. M.; Streckfuss, E. C.; Chen, C.; Davies, I. W.
2,3-difluorophenyl lithium and the 2’,4’-difluoro a
-chloroacetophenone. These
Tetrahedron, in press.
crude epoxides were directly subjected to the SNAr reaction in neat n-butyl
amine at 150 °C for 12 h.
11. (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3; (b) Taft, R. W.; Topson, R. D. Prog.
Phys. Org. Chem. 1987, 16, 1.
4. Rosen, J.; Steinhuebel, D.; Palucki, M.; Davies, I. W. Org. Lett. 2007, 9, 667.
5. For selected examples on the intramolecular SNAr reaction; see: (a) Kogan, K.;
Biali, S. E. Org. Lett. 2007, 9, 2393; (b) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J.
H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 10004; (c)
Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L.
Angew. Chem., Int. Ed. 1998, 37, 2700; (d) Janetka, J. W.; Rich, D. H. J. Am. Chem.
Soc. 1997, 119, 6488; (e) Zhu, J. Synlett 1997, 133.
6. For the first example of the SNAr on a pentafluorinated benzene derivative, see:
Petrov, V. P.; Barkhash, V. A. Khim Geterotsikl Soedin 1970, 73. 385 and 622.
7. (a) Schirok, H. J. Org. Chem. 2006, 71, 5538; (b) Schirok, H. Synlett 2005, 1255;
(c) Schirok, H. Synthesis 2008, 9, 1404.
12. Procedure for the preparation of indole 28 follows: A mixture of 25a (0.13 g, 0.5
mmol) and N,N-dimethylethylene diamine (0.44 g, 5 mmol, 10 equiv) was
heated in a sealed tube at 100 °C for 12 h. The mixture was cooled to ambient
temperature, concentrated and partitioned between 5 mL of MTBE and 5 mL of
water. Separation of the organic layer followed by concentration in vacuo
afforded indole 28 (0.13 g, 98% yield) as an oil: 1H NMR (CDCl3, 500 MHz): d
7.79 (d, 1H, J = 3.3 Hz), 7.67 (s, 1H), 7.48 (dd, 1H, J = 7.7, 3.6 Hz), 7.20 (d, 1H,
J = 3.3 Hz), 6.97 (dd, 1H, J = 13.8, 8.7 Hz), 4.28 (m, 2H), 3.45 (m, 2H), 3.21 (d, 3H,
J = 2.8 Hz 13C NMR (CDCl3, 125 MHz): d 163.5, 146.5 (d, J = 234.1 Hz), 142.7,
128.2 (d, J = 9.2 Hz), 125.2 (d, J = 2.5 Hz), 121.9 (d, J = 11.7 Hz), 120.4, 115.8,
112.7 (d, J = 24.7 Hz), 112.2, 111.3 (d, J = 9.0 Hz), 51.1, 43.9, 41.6 (d, J = 9.8 Hz).
19F NMR (CDCl3, 470.5 MHz): d À139.07.
8. For epoxide opening with amines to form amino alcohols; see: Shivani; Pujala,
B.; Chakraborti, A. K. J. Org. Chem. 2007, 72, 3713. and references cited therein.
9. For N-cyclopropylation of indoles; see: (a) Tsuritani, T.; Strotman, N. A.;
Yamamoto, Y.; Kawasaki, M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653; (b)