Synthesis of 2-substituted indoles via a palladium-catalyzed domino Heck reaction and dealkylation

Article abstract of DOI:10.1016/j.tetlet.2010.01.113

A palladium-catalyzed domino Heck reaction and dealkylation for the preparation of 2-substituted indoles is described. This novel transformation is based on an intramolecular Heck reaction followed by dealkylation.

Full text of DOI:10.1016/j.tetlet.2010.01.113

Tetrahedron Letters 51 (2010) 1844–1846
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Tetrahedron Letters
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Synthesis of 2-substituted indoles via a palladium-catalyzed domino Heck
reaction and dealkylation
*
Hui Mao, Jie-Ping Wan, Yuanjiang Pan, Cuirong Sun
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed domino Heck reaction and dealkylation for the preparation of 2-substituted
indoles is described. This novel transformation is based on an intramolecular Heck reaction followed
by dealkylation.
Received 9 November 2009
Revised 22 January 2010
Accepted 29 January 2010
Available online 4 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The indole skeleton is prevalent in numerous biologically active
natural products and pharmaceuticals.1 For example, indolodiox-
ane (U86192A) is found to be active in anti-hypertension.2 The
MDL 103371 is a kind of glycine receptor antagonist for the poten-
tial treatment of stroke.3 Tryptophan derivatives are proved to pos-
sess inhibitory activity against the IDO enzyme.4
12 h, in the presence of Pd(OAc)2, PPh3, and KOBu-t in DMF at
120 °C, the product was isolated as indole 3c as mentioned above.
The interesting transformation resulted from a Heck/dealkylation
domino process triggered us to further explore the potential reac-
tion parameters affecting the result. Briefly, the solvent and tem-
perature, as well as different palladium sources including
Pd(OAc)2, PdCl2, and Pd(PPh3)2Cl2 were tested in this reaction
and Pd(OAc)2 was found to be the most effective palladium catalyst
(Table 1, entries 1–3). Compared with DMF and toluene, DMSO was
the best solvent as reaction medium (Table 1, entries 1, 4, and 5).
Finally, both the reactions carried out at 110 °C and 130 °C gave
During the past 100 years, considerable attention had been direc-
ted toward the synthesis and functionalization of compounds con-
taining the indole unit. Classical methods used for indole synthesis
include the Fisher indole synthesis,5 the Bischler indole synthesis,6
and the Madelung cyclization of N-acyl-o-toluidines.7 Recently,
transition metal-catalyzed reactions especially the palladium-cata-
lyzed transformations have been widely applied to the synthesis and
functionalization of indoles.8 In particular, the cyclization of o-halo-
N-allylanilines9 and o-haloanilinoenamines10 basedontheintramo-
lecular Heck reaction to form the indole ring has been extensively
investigated. Based on these literature results, we envisioned that
the compound 1 readily prepared from chalcone may undergo sim-
ilar transformation to provide novel indole derivatives 2. Unexpect-
edly, the further transformed product 3 instead of 2 was formed in
our study. To the best of our knowledge, this kind of cascade trans-
formation has not been previously reported. Therefore, systematic
study on the new reaction was carried out, and herein we wish to re-
port our results on the unprecedented synthesis of 2-substituted in-
doles (Scheme 1).
(b) This Work
(a) Privious Report
2
R
Cyclization of o-halo-N-allylanilines:
1
2
2
R
2
R
R
R
N
I
I
Pd
Pd
2
3
1
N
R
N
R
N
R
1
1
1
R
1
N
H
Cyclization of o-haloanilino enamines:
2
R
2
I
R
Pd
N
R
N
R
1
1
In order to explore the potential reaction, we prepared the o-
iodo-N-allylimines 1 in two steps from benzaldehyde (Scheme 2).
Firstly, the cross condensation between benzaldehyde and differ-
ent aromatic ketones afforded chalcones.11 Secondly, the conden-
sation of chalcone with 2-iodobenzenamine was carried out by
TiCl4/Et3N catalyst system as described by Saito et al.12
Scheme 1. Palladium-catalyzed cyclization for the synthesis of indoles based on
the intramolecular Heck reaction.
I
Ph
O
I
CHO
+
NH
NaOH
To investigate the proposed reaction for indole synthesis, we
firstly selected the o-iodo-N-allylimine 1c as model reaction. After
O
2
Ph
Ar
TiCl , Et N
4
3
N
1
Ar
EtOH, H O, rt
2
Ar
4
CH Cl , 0
2
2
* Corresponding author. Tel.: +86 0571 8795 1264; fax: +86 0571 8795 1629.
E-mail address: suncuirong@zju.edu.cn (C. Sun).
Scheme 2. Preparation of o-iodo-N-allylimines from benzaldehyde and different
aromatic ketones.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.113

H. Mao et al. / Tetrahedron Letters 51 (2010) 1844–1846
1845
Table 1
Table 2 (continued)
Optimization of the reaction conditionsa
Entry
Product
Yieldb (%)
Ph
I
S
Pd, PPh3, T
KOBu-t, Solvent
PMB
N
N
N
PMB
H
H
9
40
71
1c
3c
Temperature (°C)
3i
Entry
Pd salt
Solvent
Yieldb (%)
1
2
3
4
5
6
7
Pd(OAc)2
PdCl2
DMF
DMF
DMF
DMSO
Toluene
DMSO
DMSO
120
120
120
120
120
110
130
46
Trace
40
70
30
N
H
10
P(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
3j
a
Conditions: 1 (0.5 mmol), Pd(OAc)2 (0.025 mmol), PPh3 (0.05 mmol), KOBu-t
(1 mmol), DMSO (3 ml), 12–16 h.
45
35
b
Isolated yield.
a
Conditions: 1c (0.5 mmol), Pd (0.025 mmol), PPh3 (0.05 mmol), KOBu-t
(1 mmol), solvent (3 ml), 12 h.
b
Isolated yield.
Ph
R
Pd(OAc)
L
2
I
Table 2
Synthesis of 2-substituted indoles from o-iodo-N-allyliminesa
I
N
Ph
KOBu-t
Pd
L
Ph
1
t-BuO
Pd(OAc) , PPh , 120ºC
I
2
3
R
N
H
KOBu-t, DMSO
N
R
Ph
L
Ph
PdI
L
PdI
1
3
L
PdI
Entry
1
Product
Yieldb (%)
Ph
H
N
5
R
favor
+
H
R
R
N
N
H
N
H
63
unfavor (β-H elimination)
3
6
Ph
3a
R
+
HPd(L)I
N
N
H
2
3
67
70
7
3b
Scheme 3. A plausible mechanism for this novel domino Heck reaction and
dealkylation.
OMe
Br
N
H
sharply decreased yield (Table 1, entries 4, 6, and 7). According to
these results, the optimal reaction conditions for this reaction were
determined as Pd(OAc)2 (0.05 equiv)/PPh3 (0.10 equiv) in the pres-
ence of KOBu-t (2 equiv) by using DMSO as solvent at 120 °C.13
Under the established conditions, we then investigated the appli-
cation scope of the novel transformation by using different imine
substrates 1 derived from the corresponding chalcones. As shown
in Table 2, a wide range of functionalized imines 1 had been found
to smoothly lead to corresponding indoles, including aromatic, het-
eroaromatic, and hydrogen substitutions. Notably, the R groups with
electron-donating substituent were favored and gave relatively
higheryields (Table 2, entries2 and 3). On theother hand, the indoles
obtained from electron-withdrawing groups were in lower yields
(Table 2, entries 4–8). In addition, heteroaromatic-substituted entry
gave the product in moderate yield (Table 2, entry 9). Finally, the
imine directly prepared from cinnamaldehyde afforded unsubstan-
tiated indole in good yield under standard reaction conditions (Table
2, entry 10).
Accordingto the reaction resultsand related Heck reaction mech-
anistic study,14 we proposed the catalytic mechanism for this novel
transformation. As shown in Scheme 3, the palladium–ligand com-
plexgeneratedfromthereductionof Pd(OAc)2, firstlyundergoesoxi-
dative addition to the carbon–iodine bond of o-iodo-N-allylimine 1
to produce intermediate 5. Followed by the intramolecular Heck
insertion, the secondary alkylpalladium species 6 is formed. Finally,
to aromatize this five-membered ring, the dealkylation rather than
3c
3d
3e
3f
N
4
5
6
7
8
59
57
55
52
51
H
Cl
N
H
F
N
H
CF
3
N
H
3g
NO
2
N
H
3h

1846
H. Mao et al. / Tetrahedron Letters 51 (2010) 1844–1846
4. Van Esseveldt, B. C. J.; van Delft, F. L.; Smits, J. M. M.; de Gelder, R.; Schoemaker,
H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2004, 346, 823.
5. (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241; (b) Robinson, B. Chem. Rev. 1969,
69, 227.
6. Verkade, P. E. Recl. Trav. Chem. 1946, 65, 912.
7. Madelung, W. Ber. 1912, 45, 1128.
b-hydrogen elimination of intermediate 6 provides indole derivative
3 after neutralization.
In summary, we have developed a palladium-catalyzed Heck
reaction/dealkylation domino process for the synthesis of 2-substi-
tuted indoles. Throughthe reaction of 2-iodobenzenamineand read-
ily available chalcones, the o-iodo-N-allylimine 1 could be facilely
prepared and undergo this novel transformation under palladium
catalysis. The results from our study demonstrated an unprece-
dented reaction pattern compared with classical Heck reaction. This
study therefore provided useful considerations for new reaction de-
sign of palladium catalysis. Further investigations into the mecha-
nism are undergoing in our laboratory.
8. For recent reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
9. For cyclization of o-halo-N-allylanilines, see: (a) Mori, M.; Chiba, K.; Ban, Y.
Tetrahedron Lett. 1977, 1037; (b) Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S.
J. Org. Chem. 1980, 45, 2709; (c) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28,
5291; (d) Carrol, M. A.; Holmes, A. B. Chem. Commun. 1998, 1395; (e) Yun, W.;
Mohan, R. Tetrahedron Lett. 1996, 37, 7189; (f) Macor, J. E.; Ogilvie, R. J.; Wythes,
M. J. Tetrahedron Lett. 1996, 37, 4289.
10. For cyclization of o-haloanilino enamines, see: (a) Iida, H.; Yuasa, Y.; Kibayashi,
C. J. Org. Chem. 1980, 45, 2938; (b) Michael, J. P.; Chang, S.-F.; Wilson, C.
Tetrahedron Lett. 1993, 34, 8365; (c) Edmonson, S. D.; Mastracchio, A.; Parmee,
E. R. Org. Lett. 2000, 2, 1109; (d) Akermark, B.; Oslob, J. D.; Heuschert, U.
Tetrahedron Lett. 1995, 36, 1325.
Acknowledgment
11. Basnet, A.; Thapa, P.; Karki, R. Bioorg. Med. Chem. 2007, 15, 4351.
12. Saito, T.; Kobayashi, S.; Ohgaki, M. Tetrahedron Lett. 2002, 43, 2627.
13. Typical procedure: KOBu-t (1 mmol) was added to a solution of o-iodo-N-
allylimine (0.5 mmol), Pd(OAc)2 (0.025 mmol), and PPh3 (0.05 mmol) in DMSO
(3 mL) under nitrogen atmosphere. The mixture was stirred at room
temperature for 1 h and then heated at 120 °C for 12 h. Then it was cooled,
the reaction was quenched with hydrochloric acid (5%), and the mixture was
extracted with ethyl acetate (30 ml). The organic layer was washed with
sodium carbonate (5%), brine, dried over Na2SO4, and concentrated. The
residue was purified by flash column chromatography to give the product. One
example (3c): White solid, yield 70%, 1H NMR (DMSO, 500 MHz): d 11.39 (1H, s,
NH), 7.78–7.79 (2H, d, J = 8.7 Hz), 7.46–7.49 (1H, d, J = 7.75 Hz), 7.36–7.37 (1H,
d, J = 6.95 Hz), 7.02–7.07 (3H, m), 6.95–6.98 (1H, m), 6.75 (1H, s), 3.80 (1H, s,
COMe). 13C NMR (DMSO, 125 MHz): d 158.5, 138.9, 138.0, 129.0, 127.0, 125.0,
122.2, 120.8, 120.3, 115.0, 112.2, 98.2, 55.3. Mass (ESI, m/z): 246.1 (M+Na)+.
HRMS (ESI, m/z): calcd for C15H13NONa: 246.0895; found: 246.0892.
14. (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009; (b) Amatore,
C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
Financial support from the National Natural Science Foundation
of China (No. 20772109) is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.113.
References and notes
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970; (b)
Sundberg, R. J. Indoles; Academic Press: London, 1996; (c) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045.
2. Chae, J. B.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336.
3. Watson, T. J. N.; Horgan, S. W. Org. Process Res. Dev. 2000, 4, 477.