One-pot N-alkylation/Heck approach to substituted indoles

Article abstract of DOI:10.1016/j.tetlet.2009.09.144

Here, we report the palladium-catalyzed one-pot N-alkylation/Heck cyclization of anilines to substituted indoles employing Pd(OAc)₂/XPhos. The scope and limitations of this methodology will be described.

Full text of DOI:10.1016/j.tetlet.2009.09.144

Tetrahedron Letters 50 (2009) 6968–6972
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Tetrahedron Letters
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One-pot N-alkylation/Heck approach to substituted indoles
*
Melissa L. Weinrich , Hilary P. Beck
Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2009
Revised 21 September 2009
Accepted 24 September 2009
Available online 29 September 2009
Here, we report the palladium-catalyzed one-pot N-alkylation/Heck cyclization of anilines to substituted
indoles employing Pd(OAc)2/XPhos. The scope and limitations of this methodology will be described.
Ó 2009 Elsevier Ltd. All rights reserved.
Due to the prevalence of indole functionality in several biologi-
cally active molecules, many research efforts are focused on devel-
oping novel general, mild, and efficient methods for the
regioselective preparation of substituted indoles from readily avail-
able starting materials.1 The intramolecular Heck reaction has been
widely used for the synthesis of substituted indoles.2 In addition, in-
doles have been prepared utilizing one-pot cascade reactions.3 For
example, the palladium-catalyzed one-pot cascade reactions of 2-
halo-anilines employing ketones4 and aldehydes5 have been re-
ported. Here, we report a mild, one-pot cascade reaction affording
substitutedindolesfromcommerciallyavailableanilinesandreadily
accessible Pd(OAc)2/XPhos.
(87%) along with debromination of the aniline (Table 1, entry 7).
At 50 °C, 23% conversion to the N-allylaniline 5 was observed (Ta-
ble 1, entry 8). The remaining material was unreacted starting
material and debrominated aniline. Using t-BuOH or DME as a sol-
vent for the cascade reaction with 2-chloroaniline 4 resulted in de-
sired indole 6 in 62% and 67% isolated yield, respectively (Table 1,
entries 13 and 14). Next, we examined different bases. For both 2-
bromo and 2-chloroanilines K3PO4, KOAc, and MeNCy2 resulted in
moderate conversion to N-allylanilines 5, but no Heck cyclization
product was detected (Table 1, entries 9, 10, 12, 15, 16, and 18).
K2CO3 resulted in high conversion of the 2-chloroaniline to the de-
sired indole 6; on the other hand, Cs2CO3 was found to be the best
base for 2-bromoaniline conversion to the indole 6 (Table 1, entry
14 vs entry 17 and entry 4 vs entry 11). In addition, both allyl bro-
mide and allyl chloride were excellent reagents for the cascade
reaction, while allyl methyl carbonate provided a moderate con-
version of the desired indole (Table 1, entries 19–21).
8
The palladium-catalyzed Heck reaction of 2-iodo- and 2-bro-
mo7-N-allylanilines has been reported. In addition, an intramolec-
ular Heck reaction employing palladium/imidazolium 3a catalyst
system with 2-chloro-N-allyl-anilines 1 afforded 3-substitued in-
doles 2 in moderate to high yields (Scheme 1).8 In our hands, N-
allylation of aniline 4 in the presence of K2CO3 resulted in low to
modest yields of the N-allylanilines 5.9 The major byproduct being
N,N-diallylanilines (X = Br, 14%; X = Cl 15%). The N-allylanilines 5
underwent an intramolecular Heck coupling reaction in the pres-
ence of XPhos and Pd(OAc)2 to give the desired substituted indole
6 in low yield (X = Br, 40%; X = Cl, 25%). A one-pot cascade reaction
involving Heck cyclization of 2-bromo- and 2-iodo-N-allyl-aniline
intermediates was recently disclosed.10 Thus, we sought a one-
pot cascade reaction to afford the desired substituted indole 6.
We turned our attention to the one-pot N-allylation/Heck cas-
cade of 2-bromo or 2-chloroanilines to access indoles. Several sol-
vents were examined for this transformation.11,12 For the 2-
bromoaniline 4, DME and t-BuOH gave 37% and 31% isolated yield
of indole 6, respectively (Table 1, entries 4 and 6). In addition a
reaction temperature of 80 °C is required for the cascade sequence.
A temperature of 25 °C resulted in recovered starting material
R1
R2
R1
R1
R2
Cl
Cl
Br
R2
ii
i
NH2
N
H
1
N
i-Pr
H
i-Pr
R1 = H, Me; R2 = H, Me, Ph
2
N
N
H
i-Pr
i-Pr
X
3a, X = Cl
3b, X = BF4
X
X
Br
iv
NH2
iii
N
N
H
H
4
5
6
Scheme 1. Reagents and conditions: (i) LDA, THF, À78 °C; (ii) 3a (1 mol %),
Pd2(dba)3 (1 mol %), Cs2CO3 (1.5 equiv), TBAB (1 equiv), DMA, 140 °C, 24–48 h,
21–70% (iii) K2CO3, 60 °C, MeCN, X = Br, 12 h, 40%; X = Cl, 4 d, 25%; (iv) XPhos
(10 mol %), Pd(OAc)2 (5 mol %), K3PO4 (3 equiv), n-BuOH, 2.5 h, 80 °C, X = Br, 35%;
X = Cl, 13%.
* Corresponding author. Tel.: +1 650 244 2190; fax: +1 650 837 9396.
E-mail address: hbeck@amgen.com (H.P. Beck).
Present address: Department of Chemistry, Reed College, 3203 S. E. Woodstock
Blvd., Portland, OR 97202, USA.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.144

M. L. Weinrich, H. P. Beck / Tetrahedron Letters 50 (2009) 6968–6972
6969
Table 1
One-pot N-allylation/Heck reaction conditions
X
X
H
N
NH2
N
H
4
6
5
Entry
X
Reagent
Base (3 equiv)
Solvent
Temperature (°C)
Time (h)
Conversion to 6a,b (%)
Conversion to 5b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl methyl carbonate
Allyl chloride
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KOAc
Cs2CO3
MeNCy2
K2CO3
K2CO3
K3PO4
KOAc
Toluene
DCE
Dioxane
DME
NMP
t-BuOH
DME
DME
DME
DME
DME
DME
t-BuOH
DME
DME
DME
DME
DME
DME
DME
80
80
80
80
80
80
50
25
80
80
80
80
80
80
80
80
80
80
80
80
80
20
20
20
20
20
18
24
24
24
24
24
24
24
24
24
24
24
24
48
48
48
5c
9c
6c
37c
8c
31c
0
0
0
0
23
0
50
84
50
38
50
0
62c
67c
0
14c
50
64
0
38
0
0
10
0
>95
43
>95
Cs2CO3
MeNCy2
K2CO3
K2CO3
K2CO3
23
0
DME
a
b
c
Reactions were carried out at 1 mmol substrate with reagent (1 equiv), XPhos (10 mol %), Pd(OAc)2 (5 mol %), base (3 equiv), in 5 mL of solvent.
Conversion was determined using 1H NMR.
Isolated yield.
Table 2
Catalyst system requirements
Next, we sought to establish that both XPhos and Pd(OAc)2 are
required for the catalytic system (Table 2). Reaction with only
Pd(OAc)2 resulted in 50% conversion to N-allylaniline 8 and unre-
acted starting material 7. Similarly, reaction with only XPhos pro-
vided unreacted 7 and 40% conversion to N-allylaniline 8. However,
in the presence of both XPhos and Pd(OAc)2 the desired indole 6
was obtained in 67% isolated yield. Thus, XPhos and Pd(OAc)2 are
required for the Heck cyclization step of the one-pot cascade
sequence.
Cl
Cl
H
Br
NH2
N
N
H
7
6
8
Entry XPhos
Pd(OAc)2
(mol %)
Conversion to 6a,b Conversion to 8b
(mol %)
(%)
(%)
Next, we examined the palladium/imidazolium 3 catalyst sys-
tem in order to determine whether it could also facilitate this
one-pot transformation. Treatment of 2-chloroaniline 7 with allyl
bromide, 1 mol % NHC-ligand 3b, and 1 mol % Pd2(dba)3 resulted
in 77% conversion to N-allylaniline 8 with <10% conversion to the
desired indole 6 (Scheme 2).
1
2
3
10
0
10
5
5
0
67c
0
0
14c
50
40
a
Reactions were carried out at 1 mmol substrate in 5 mL DME with allylbromide
(1 equiv), K2CO3 (3 equiv), at 80 °C for 24 h.
Conversion was determined using 1H NMR.
Isolated yield.
b
c
It has been reported that the reaction rate of intramolecular
Heck cyclization can be accelerated under microwave heating
conditions.13 Thus, we examined microwave heating conditions
in order to increase the reaction rate and reduce the reaction time.
Heating the reaction under microwave conditions for 10 min at
80 °C provided only unreacted starting material 7 (Scheme 2, con-
ditions (ii)). Continued heating for an additional 20 min at 150 °C
resulted in N-allylaniline 8 formation with the rest of the material
being unreacted starting material 7 (22% conversion). Additional
heating under microwave conditions for 20 min at 200 °C in-
creased the production of 8 (50% conversion). None of the desired
indole 6 was observed under these microwave heating conditions.
Next, we turned our attention to extending this one-pot cascade
reaction to other 2-halo substituted anilines (Table 3). 2-Fluoro-4-
methylaniline underwent N-allylation under the reaction condi-
tions, but no indole product was formed (Table 3, entry 1). In a sim-
ilar manner, 2-fluoroaniline also provided the N-allyl-analog, but
none of the desired indole was observed (Table 3, entry 2). In con-
trast, 2-chloro-4-methylaniline and 2-choloraniline afforded the
Cl
Cl
H
Br
NH2
N
N
i or ii
H
7
6
8
Scheme 2. Reagents and conditions: (i) 3b (1 mol %), Pd2(dba)3 (1 mol %), Cs2CO3
(1.5 equiv), TBAB (1 equiv), DMA, 140 °C, 20 h. (ii) XPhos (10 mol %), Pd(OAc)2
(5 mol %), K2CO3 (3 equiv), DME, lW.
respective indoles in 67% and 68% isolated yield (Table 2, entry 1
and Table 3, entry 3). When 2-iodo-4-trifluoromethylaniline was
treated under the reaction conditions only the N-allylaniline was
isolated (Table 3, entry 4). On the other hand, reaction with 2-
chloro-4-trifluoromethylaniline provided the desired indole in
67% yield (Table 3, entry 5). Thus, 2-fluoro and 2-iodoanilines do

6970
M. L. Weinrich, H. P. Beck / Tetrahedron Letters 50 (2009) 6968–6972
Table 3
Substitution scope of the cascade reaction
X
X
H
N
Br
NH2
R1
R1
N
H
9
10
11
Entry
Aniline
Time (h)
Conversion to 10a,b (%)
Conversion to 11b (%)
F
1
48
0
65c
NH2
F
2
3
48
48
48
28
24
48
48
20
48
0
49c
38c
77
NH2
Cl
68c
NH2
F3C
F3C
I
4
0
NH2
Cl
5
67c
14
57c
46c
0
NH2
Cl
6
NH2
Cl
7
NH2
Cl
NH2
8
Cl
9
99
NH2
Cl
10
67c
NH2
a
b
c
Reactions were carried out at 1 mmol substrate in 5 mL DME with allylbromide (1 equiv), XPhos (10 mol %), Pd(OAc)2 (5 mol %), K2CO3 (3 equiv), at 80 °C.
Conversion was determined using 1H NMR.
Isolated yield.
not provide access to indoles under these cascade reaction
conditions.
conditions. Toward this end, we first examined the effect of methyl
substitution on the reaction. 4-, 5-, and 6-Methyl groups were all
well tolerated under the reaction conditions providing the indole
derivatives in 46–67% yield (Table 1 entry 14, Table 3, entries 7
and 8). Allowing the reaction to proceed for 48 h provided higher
yields of the desired indoles (Table 3, entry 6 vs entry 7 and entry
9 vs entry 10).
Having established the optimal reaction conditions, we exam-
ined the scope of this cascade reaction. Since 2-chloroanilines are
generally more readily available and less expensive than the corre-
sponding 2-bromoanilines we sought to examine whether substi-
tution on 2-chloroanilines was tolerated under the reaction

M. L. Weinrich, H. P. Beck / Tetrahedron Letters 50 (2009) 6968–6972
6971
Next, we examined whether other functional groups would be
tolerated under these reaction conditions. Electron-donating
3-methoxy and 5-methoxy groups were tolerated providing the
4-methoxy and 6-methoxy substituted indoles in moderate yields
(Table 4, entries 1 and 2). In addition, the 5-carboxamide group is
tolerated providing 50% conversion to the desired indole (Table 4,
Table 4
Effect of substitution on cascade reaction
Cl
Cl
H
Br
NH2
N
R1
R1
N
R1
H
12
10
13
Entry
Aniline
Time (h)
Conversion to 10a,b (%)
Conversion to 13b (%)
OMe
Cl
1
48
56c
23
NH2
Cl
NH2
Cl
NH2
2
3
24
28
48
48
48
42
22
48
22
48
50
20
56
MeO
O
50
NH2
MeO2C
Cl
NH2
4
15
Cl
NH2
5
64c
15
F3C
NC
Cl
6
56
28
NH2
Cl
7
32c
61c
17c
16
NC
NH2
O2N
Cl
8
NH2
Cl
9
49c
16
42
O2N
NH2
Cl
10
11
NH2
NO2
Cl
20c
N
H
a
b
c
Reactions were carried out at 1 mmol substrate in 5 mL DME with allylbromide (1 equiv), XPhos (10 mol %), Pd(OAc)2 (5 mol %), K2CO3 (3 equiv) at 80 °C.
Conversion was determined using 1H NMR.
Isolated yield.

6972
M. L. Weinrich, H. P. Beck / Tetrahedron Letters 50 (2009) 6968–6972
Fujii, N.; Ohno, H. Org. Lett. 2009, 11, 1979–1982; (c) Isono, N.; Lautens, M. Org.
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Macchia, M. J. Med. Chem. 2003, 46, 4032–4042. For conditions using LDA as
base see 6c, 8.
10. For 2-bromo see: (a) Jensen, T.; Pedersen, H.; Bang-Anderson, B.; Madsen, R.;
Jorgensen, M. Angew. Chem., Int. Ed. 2008, 47, 888–890; For 2-iodo see: (b) El
Kaim, L.; Gizzi, M.; Grimaud, L. Org. Lett. 2008, 10, 3417–3419; (c) Yokoyama,
Y.; Takagi, N.; Hikawa, H.; Kaneko, S.; Tsubaki, N.; Okuno, H. Adv. Synth. Catal.
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entry 3). However, the 4-methyl carboxylate provided the desired
indole in only 15% conversion with the corresponding N-allylani-
line as the major observed product (Table 4, entry 4). 4- and 5-Tri-
fluoromethyl substitution provided the corresponding 5- and 6-
trifluoromethyl-3-methyl indoles in excellent yield (Table 3, entry
5 and Table 4, entry 5). In contrast, the 4-cyano group afforded low
conversion while the 5-cyano functionality provided 3-methyl-5-
cyano indole in 32% isolated yield (Table 4, entries 6 and 7). 4-Nitro
and 5-nitro-anilines undergo conversion to 5- and 6-nitro-3-meth-
ylindole in moderate yield (Table 4, entries 8 and 9). By contrast, 6-
nitro aniline provided the corresponding indole in low yield (16%
conversion) with 16% conversion to the N-allylaniline observed
(Table 4, entry 10). N-Alkyl substitution on 2-chloroaniline does
not seem to be tolerated under the reaction conditions. For exam-
ple, 2-chloro-N-methyl aniline provided 1,3-dimethylindole in 20%
isolated yield with the corresponding N-allylaniline being the ma-
jor product (Table 4, entry 11).
We have developed a one-pot N-alkylation/Heck cascade of 2-
chloroanilines to access substituted indoles. The reaction is general
and mild, tolerating several functional groups. The reaction em-
ploys simple and easily accessible and air stable starting materials
and reagents. Several steric and electronic substituents are toler-
ated. Extending the reaction to substituted bromoanilines and
other heterocycles is currently underway.14 In addition, experi-
ments to understand the solvent effect and reaction mechanism,
including mechanistic rationale for the preference of aryl chlorides
over aryl bromides, are planned.
11. All reagents were purchased from commercial sources and were used without
purification. Reagents were weighed out on the bench top and the reactions
were carried out under normal atmosphere conditions. No special precautions
to remove oxygen were taken.
12. Typical procedure: To substituted 2-chloro or 2-bromoaniline (1 mmol),
potassium carbonate (3 mmol), XPhos (10 mol %), and allyl bromide
(1 mmol) in a screw cap vial with stir bar was added 5 mL DME at room
temperature followed by palladium acetate (5 mol %). The reaction vial was
capped and heated to 80 °C with stirring for 24–48 h. The reaction was cooled
to room temperature and concentrated under reduced pressure. The desired
indole was separated and purified using flash chromatography (0–10% EtOAc
in hexanes) giving an colorless oil. One example: Table 4, entry 8 1H NMR
(400 MHz, CDCl3, d ppm 8.56–8.60 (1H, m), 8.10–8.15 (1H, m), 7.35–7.40 (1H,
m), 7.11–7.16 (1H, m), 2.39 (3H, d, J = 1.2 Hz).
Acknowledgment
Financial support provided by the Amgen Summer Internship
program is gratefully acknowledged.
13. Kaukoranta, P.; Källström, K.; Andersson, P. G. Adv. Synth. Catal. 2007, 349,
2595–2602.
14. Nitrogen substitution on the aniline ring affording pyrrolopyridines was
examined under the reaction conditions. Unfortunately, 3-chloropyrazin-2-
amine did not produce the desired pyrrolopyrazine and limited conversion to
the N-allyl derivative was observed (10% conversion determined from 1H
NMR). Both 3-chloro and 4-chloro pyridines analogs also failed to produce the
corresponding pyrrolopyridines. On the other hand, 2-chloropyridin-3-amine
afforded 13% conversion to the desired 3-methylpyrrolopyridine, but the
corresponding N-allyl derivative was the major product. Prolonged heating for
48 h under the reaction conditions resulted in dechlorination of the substrate.
References and notes
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