Synthesis of indole-3-carboxylic acid derivatives by Pd(0)-catalyzed intramolecular α-arylation of β-(2-iodoanilino) esters

Article abstract of DOI:10.1021/jo800034m

(Chemical Equation Presented) β-(2-Iodoanilino) esters undergo intramolecular α-arylation in the presence of Pd(PPh₃) ₄ and potassium phenoxide. The reaction is a useful methodology for the preparation of indole-3-carboxylic acid ester derivatives.

Full text of DOI:10.1021/jo800034m

for the construction of complex polycyclic compounds, have
remained less explored. Among them, the most extensive study
has been done on the intramolecular R-arylation of ketones10-16
and amides,17-22 while few examples of the use of dicarbonyl
compounds,23-25 aldehydes and nitro derivatives,26 or esters27
have been reported.
Synthesis of Indole-3-carboxylic Acid Derivatives
by Pd(0)-Catalyzed Intramolecular r-Arylation of
â-(2-Iodoanilino) Esters
Daniel Sole´* and Olga Serrano
As part of our ongoing program on the synthesis of nitrogen
heterocycles, we have been studying the palladium-catalyzed
intramolecular coupling of amino-tethered vinyl28 or aryl
halides12 with enolates.29 During this work, we have also
reported the palladium-catalyzed intramolecular acylation of
â-(2-iodoanilino) esters to give 2,3-dihydroquinolin-4-ones.30
This reaction appears to involve the formation of a four-
membered azapalladacyclic transient intermediate, which strongly
modifies the interaction of the metal center with the carbonyl
group forcing the otherwise unfavorable nucleophilic attack. We
realized that if we significantly increased the enolization of the
ester we could overcome the nucleophilic attack at the alkoxy-
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, and
Institut de Biomedicina (IBUB), UniVersitat de Barcelona,
08028-Barcelona, Spain
dsole@ub.edu
ReceiVed January 7, 2008
(7) Intermolecular R-arylation of nitriles: (a) Culkin, D. A.; Hartwig, J.
F. J. Am. Chem. Soc. 2002, 124, 9330. (b) You, J.; Verkade, J. G. Angew.
Chem. Int. Ed. 2003, 42, 5051. (c) Wu, L.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 15824.
(8) Intermolecular R-arylation of aldehydes: (a) Terao, Y.; Fukuoka, Y.;
Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2002, 43, 101. (b)
Mart´ın, R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2007, 46, 7236.
(9) Selected references on the intermolecular R-arylation of 1,3-dicarbonyl
compounds: (a) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
(b) Kashin, A. N.; Mitin, A. V.; Beletskaya, I. P.; Wife, R. Tetrahedron
Lett. 2002, 43, 2539. (c) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68,
8003.
(10) (a) Muratake, H.; Hayakawa, A.; Natsume, M. Tetrahedron Lett.
1997, 38, 7577. (b) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997,
38, 7581. (c) Muratake, H.; Natsume, M.; Nakai, H. Tetrahedron 2004,
60, 11783.
(11) Khan, F. A.; Czerwonka, R.; Reissig, H.-U. Eur. J. Org. Chem.
2000, 3607.
(12) (a) Sole´, D.; Vallverdu´, L.; Bonjoch, J. AdV. Synth. Catal. 2001,
343, 439. (b) Sole´, D.; Vallverdu´, L.; Peidro´, E.; Bonjoch, J. Chem. Commun.
2001, 1888. (c) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia, M.;
Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1578.
(13) Shao, Z.; Chen, J.; Huang, R.; Wang, C.; Li, L.; Zhang, H. Synlett
2003, 2228.
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(15) Tietze, L. F.; Braun, H.; Steck, P. L.; El Bialy, S. A. A.; To¨lle, N.;
Du¨fert, A. Tetrahedron 2007, 63, 6437.
(16) Khartulyari, A. S.; Maier, M. E. Eur. J. Org. Chem. 2007, 317.
(17) (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546. (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(18) Freund, R.; Mederski, W. W. K. R. HelV. Chim. Acta 2000, 83,
1247.
(19) Honda, T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631.
(20) (a) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193. (b)
Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363.
(21) Kim, G.; Kim, J. H.; Lee, K. Y. J. Org. Chem. 2006, 71, 2185.
(22) Arao, T. K.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47,
1417.
(23) (a) Ciufolini, M. A.; Browne, M. E. Tetrahedron Lett. 1987, 28,
171. (b) Ciufolini, M. A.; Qi, H.-B.; Browne, M. E. J. Org. Chem. 1988,
53, 4149.
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2004, 6, 2357.
(26) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355.
(27) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465.
(28) (a) Sole´, D.; Peidro´, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225. (b)
Sole´, D.; Diaba, F.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746. (c) Sole´,
D.; Urbaneja, X.; Bonjoch, J. AdV. Synth. Catal. 2004, 346, 1646.
(29) For the Pd-catalyzed coupling with â,γ-unsaturated nitronates, see:
Sole´, D.; Urbaneja, X.; Bonjoch, J. Tetrahedron Lett. 2004, 45, 3131.
(30) Sole´, D.; Serrano, O. Angew. Chem. Int. Ed. 2007, 46, 7270.
â-(2-Iodoanilino) esters undergo intramolecular R-arylation
in the presence of Pd(PPh3)4 and potassium phenoxide. The
reaction is a useful methodology for the preparation of
indole-3-carboxylic acid ester derivatives.
The indole nucleus is a ubiquitous motif in bioactive natural
products as well as synthetic pharmaceuticals.1 Accordingly,
after 100 years of intensive research, a variety of well-
established methods for elaborating and functionalizing indoles
are available. In particular, recent advances in the area of
palladium-catalyzed transformations have led to the development
of several reliable methods for the synthesis of indoles from
simple starting materials.2
During the last years, the palladium-catalyzed arylation of
enolate-type nucleophiles has received a great deal of attention.3
The intermolecular versions of the reaction have been thoroughly
explored, and it is now possible to introduce an aromatic moiety
to a broad range of enolate-type nucleophiles.4-9 In contrast,
the intramolecular processes, which offer promising procedures
(1) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996. (b) Joule,
J. A. In Science of Synthesis; George Thieme Verlag: Stuttgart 2000; Vol.
10. (c) Kazuhiro, H.; Kawassaki, T. Nat. Prod. Rep. 2007, 24, 843 and
previous reviews in these series.
(2) For recent reviews on palladium-catalyzed synthesis of indoles, see:
(a) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (b) Humphrey, G.
R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875.
(3) For a recent review, see: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234.
(4) Selected references on the intermolecular R-arylation of ketones: (a)
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473. (b) Fox,
J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 1360. (c) Hamada, T.; Chieffi, A.; A¨ hman, J.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 1261.
(5) Selected references on the intermolecular R-arylation of esters: (a)
Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996. (b)
Jorgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 12557. (c) Liu, X.; Hartwig, J. F. J. Am. Chem.
Soc. 2004, 126, 5182.
(6) Selected references on the intermolecular R-arylation of amides: (a)
de Filippis, A.; Gomez Pardo, D.; Cossy, J. Tetrahedron 2004, 60, 9757.
(b) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
4976.
10.1021/jo800034m CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/20/2008
2476
J. Org. Chem. 2008, 73, 2476-2479

SCHEME 1
to give a reaction mixture in which indoline 2 was the only
detected product (entry 1). The amount of the catalyst could be
reduced to 2.5% mol without any effect on the cyclization
reaction (entry 2). However, after column chromatography of
the reaction mixtures, considerable amounts of indole 3,
produced by air oxidation of the cyclization product,28,31 were
isolated together with indoline 2. It should be noted that, in
contrast to the synthesis of indoles, the synthesis of indolines
has received little attention, and apart from the intensively
studied reduction of indoles,32 only a few efficient methods have
been reported.33
The use of LiO-t-Bu, a stronger base than PhOK, in
combination with a biaryl-based phosphine27 resulted in the
formation of indole 3 as the main product (entry 3). On the
other hand, the use of a weak base such as K3PO4 in the presence
of a catalytic quantity of phenol34 resulted in low reaction rates
when using either THF (entry 4) or toluene as the solvent (entry
5), while the more polar solvent DMF directly afforded indole
3 (entries 6 and 7). Interestingly, the use of K3PO4 in DMF
without phenol led to the formation of a complex reaction
mixture from which indole 3 was isolated together with major
amounts of anilines 4 and 530,35 (entry 8).
carbonyl group and favor the R-arylation (Scheme 1). The lower
reactivity of esters and the relative instability of the â-amino
ester moiety under basic conditions would make enolization a
more challenging task. However, it should be noted that we
have recently reported the Pd(0)-catalyzed intramolecular
coupling of amino-tethered vinyl halides with esters using
potassium phenoxide as the base.28c
Bromide 1b was less efficient than iodide 1a in the R-ary-
lation reactions and afforded lower yields of the cyclization
products (entries 9 and 10).
The scope of the R-arylation reaction was examined with
respect to a range of differently substituted â-(2-iodoanilino)
esters (Table 2). The results of optimization studies carried out
with 1a led us to use two general procedures for their cyclization
reactions: method A, which is based on the use of PhOK (2.25
equiv) as the base, and method B, in which K3PO4 is used
together with a catalytic amount of phenol.
We herein report our studies on the Pd(0)-catalyzed intramo-
lecular R-arylation of â-(2-haloanilino) esters, which constitutes
a useful methodology for the synthesis of functionalized indole-
3-carboxylic acid ester derivatives.
Our efforts were initially focused on the reaction of esters
1a,b. The most representative results of these studies are
summarized in Table 1. We were pleased to find that, in the
presence of 5% mol of Pd(PPh3)4 and 2.25 equiv of PhOK in
refluxing THF, aryl iodide 1a underwent the desired cyclization
As shown in Table 2, the reaction is applicable to iodoanilines
with different electronic properties on the aromatic ring. It was
TABLE 1. Pd(0)-Catalyzed r-Arylation of 1a and 1b
entry
1
X
catalyst (%)
additives (equiv)
solvent
THF
T (°C)/time (h)
NMR yielda (%)
isolated yield (%)
I
Pd(PPh3)4 (5)
KOtBu (2.25)
phenol (2.75)
KOtBu (2.25)
phenol (2.75)
LiOtBu (2)
reflux/7.5
2 (87)
2 (50), 3 (17)
2
3
4
5
6
7
I
I
I
I
I
I
Pd(PPh3)4 (2.5)
THF
reflux/7.5
90 °C/24
reflux/24
90 °C/48
90 °C/24
90 °C/24
2 (95)
2 (56), 3 (5)
2 (5), 3 (47)d
Pd2(dba)3 (5)
Lb (5.5)
Pd(PPh3)4 (10)
dioxanec
THF
K3PO4 (3)
Phenol (0.3)
K3PO4 (3)
Phenol (0.3)
K3PO4 (3)
phenol (0.3)
K3PO4 (3)
1a (70), 2 (28)
1a (15), 2 (75)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Toluenec
DMFc
DMFc
1a (14), 2 (38), 3 (14)
3 (66)
3 (55)
phenol (0.3)
K3PO4 (3)
8
9
I
Br
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
DMFc
THF
110 °C/48
reflux/24
3 (16), 4 (27), 5 (28)
KOtBu (2.25)
phenol (2.75)
K3PO4 (3)
2 (73)
10
Br
Pd(PPh3)4 (10)
DMFc
90 °C/24
2 (17), 3 (30)
phenol (0.3)
a Yield determined by 1H NMR. b L: 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl. c The reaction was carried out in a sealed tube. d tert-Butyl
1,5-dimethylindole-3-carboxylate, which could not be separated from 2, was also produced in 8% yield.
J. Org. Chem, Vol. 73, No. 6, 2008 2477

TABLE 2. Synthesis of Indoles and Indolines by Pd(0)-Catalyzed r-Arylation of â-(2-Iodoanilino) Esters
a Method A: 5% mol of Pd(PPh3)4, phenol (2.75 equiv), and KO-t-Bu (2.25 equiv) in THF at reflux. Method B: 10% mol of Pd(PPh3)4, K3PO4 (3 equiv),
and phenol (0.3 equiv) in DMF at 90 °C in a sealed tube. b Yields refer to pure products isolated by flash chromatography. c 1H NMR analysis of the crude
reaction mixture gave 72% yield of 7a and 13% yield of 8a. d 1H NMR analysis of the crude reaction mixture gave 80% yield of 7b. e 10% mol of Pd(PPh3)4.
f Methyl 4-(methylamino)benzoate was also isolated. g 1H NMR analysis of the crude reaction mixture gave 83% yield of 10. h 1H NMR analysis of the
crude reaction mixture gave 80% yield of 13a and 15% yield of 14a. i N-methyl-p-toluidine was also isolated (6%). j Methyl 2-methyl-3-[N-methyl-N-(4-
methylphenyl)amino]propionate was also isolated (11%). k 20% mol of Pd(PPh3)4.
found, however, that substrates with electron-withdrawing
groups (Cl, F, and CO2Me) at the arene ring underwent the
R-arylation reaction in lower yields than those obtained from
iodoanilines with electron-neutral (H and Me) or electron-
donating groups (OMe). The low yields of the arylation reactions
(32) (a) Robinson, B. Chem. ReV. 1969, 69, 785. (b) Gribble, G. W. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 8, p 612.
(31) Chou, S.-S. P.; Yuan, T.-M. Synthesis 1991, 171.
2478 J. Org. Chem., Vol. 73, No. 6, 2008

of ester 1a (75 mg, 0.23 mmol) in THF (5 mL) were added under
argon phenol (59 mg, 0.63 mmol), KO-t-Bu (0.5 mmol, 0.5 mL of
1 M solution in tert-butyl alcohol), and Pd(PPh3)4 (7 mg, 0.006
mmol). The solution was heated at reflux for 7.5 h. After being
cooled at room temperature, the mixture was diluted with CH2Cl2
and washed with saturated aqueous NaHCO3 and 1 N aqueous
NaOH. The organic layer was dried and concentrated. The residue
was purified by flash chromatography (Al2O3, from hexanes to
hexanes-EtOAc 6%) to give indoline 2 (27 mg, 56%) and indole
3 (3 mg, 5%).
Representative Procedure for the Pd(0)-Catalyzed R-Aryla-
tion Using K3PO4 as the Base (Table 1, Entry 6). A mixture of
ester 1a (75 mg, 0.23 mmol), K3PO4 (143 mg, 0.68 mmol), phenol
(6 mg, 0.068 mmol), and Pd(PPh3)4 (26 mg, 0.022 mmol) in DMF
(3 mL) was stirred at 90 °C in a sealed tube for 48 h. The reaction
mixture was poured into water and extracted with Et2O. The organic
extracts were washed with brine and with 1 N NaOH solution, dried,
and concentrated. The residue was purified by flash chromatography
(SiO2, from hexanes to hexanes-EtOAc 10%) to give indole 3 (31
mg, 66%).
Methyl 1,5-dimethyl-2,3-dihydro-1H-indole-3-carboxylate (2):
1H NMR (CDCl3, 300 MHz) δ 2.26 (s, 3H), 2.76 (s, 3H), 3.49 (t,
J ) 9 Hz, 1H), 3.61 (dd, J ) 9 and 7.8 Hz, 1H), 3.77 (s, 3H), 4.08
(broad t, J ) 8.4 Hz, 1H), 6.45 (d, J ) 8.1 Hz, 1H), 6.96 (dm, J
) 8.1 Hz, 1H), 7.09 (s, 1H); 13C NMR (CDCl3, 100.5 MHz) δ
20.7 (CH3), 36.6 (CH3), 46.0 (CH), 52.3 (CH3), 58.1 (CH2), 107.9
(CH), 125.5 (CH), 126.9 (C), 127.5 (C), 129.1 (CH), 150.7 (C),
172.5 (C). Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82.
Found: C, 69.79; H, 7.37; N, 6.57.
Methyl 1,5-dimethylindole-3-carboxylate (3): 1H NMR (CDCl3,
300 MHz) δ 2.49 (s, 3H), 3.80 (s, 3H), 3.90 (s, 3H), 7.12 (dd, J )
8.4 and 1.5 Hz, 1H), 7.23 (d, J ) 8.4 Hz, 1H), 7.73 (s, 1H), 7.96
(m, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 21.5 (CH3), 33.4 (CH3),
50.9 (CH3), 106.3 (C), 109.4 (CH), 121.2 (CH), 124.3 (CH), 126.8
(C), 131.4 (C), 135.1 (CH), 135.5 (C), 165.5 (C). Anal. Calcd for
C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.02; H, 6.43;
N, 6.72.
of 6c are due in part to the formation of dechlorinated products.
In general, the indolines could not be obtained in the 3-mono-
substituted series, the corresponding indoles being formed
directly. In the few cases in which the indolines were formed,
their rapid oxidation to the indoles was again observed. On the
contrary, the reaction could be successfully applied to the
preparation of 2,3- and 3,3-disubstituted and 2,3,3-trisubstituted
indolines (entries 19-24). Benzyl and ethyl esters can also be
used as substrates in this reaction.
The effectiveness of PhOK in the aforementioned Pd(0)-
catalyzed intramolecular arylation reactions is somewhat sur-
prising since the pKa of phenol is considerably lower than that
of esters.36 It should be noted that no competition was observed
between the desired R-arylation and the nucleophilic attack at
the alkoxycarbonyl group in any of the cyclization reactions
reported in this work. Interestingly, although we previously
reported that treatment of 1a with Pd(PPh3)4 and K3PO4 in either
THF or toluene resulted in a nucleophilic attack at the
carbonyl,30 the addition of a catalytic amount of phenol to the
same reaction conditions promoted the R-arylation (Table 1,
entries 4 and 5). In these reactions, the phenoxide anion might
be playing an additional role to that of the base; it could also
be acting as a ligand by displacing the iodide at the metal center.
Thus, the formation of a transient palladium phenoxide
complex would stabilize the otherwise unstable palladium
intermediate, preventing the nucleophilic attack at the carbonyl.
Moreover, the intramolecular reaction of the phenoxide ligand
with the coordinated carbonyl group would facilitate the
enolization.34
In summary, we have developed a new methodology for the
synthesis of indole-3-carboxylic acid esters based on the Pd-
(0)-catalyzed intramolecular R-arylation of â-(2-iodoanilino)
esters. Further studies to expand the methodology and provide
deeper insight into the role of phenoxide in these processes are
underway and will be published in due course.
Acknowledgment. This research was supported by MEC
(Spain)-FEDER (Project No. CTQ2007-60573/BQU) and DURSI-
Catalonia (Grant No. 2005SGR-00442). D.S. thanks the DURSI
for “Distincio´ per a la promocio´ de la Recerca Universita`ria”.
Experimental Section
Representative Procedure for the Pd(0)-Catalyzed R-Aryla-
tion Using PhOK as the Base (Table 1, Entry 2). To a solution
(33) For recent examples, see: (a) Beller, M.; Breindl, Cl.; Riermeier,
T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403. (b) Moutrille, C.; Zard, S.
Z. Tetrahedron Lett. 2004, 45, 4631. (c) Ganton, M. D.; Kerr, M. A. Org.
Lett. 2005, 7, 4777.
(34) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 15168.
Supporting Information Available: Characterization data for
all new compounds and experimental procedures for preparation
of starting materials. 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
(35) The formation of products from hydrodehalogenation and dealky-
lation of the starting material has been reported; see ref 12a.
(36) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
JO800034M
J. Org. Chem, Vol. 73, No. 6, 2008 2479