Versatile indole synthesis by a 5-endo-dig cyclization mediated by potassium or cesium bases

Article abstract of DOI:10.1002/1521-3773(20000717)39:14<2488::AID-ANIE2488>3.0.CO;2-E

A mild route to indoles by cyclization of 2-(1-alkynyl)anilines is offered by the use of simple bases such as KOtBu, KH, or CsOtBu and N-methylpyrrolidinone (NMP) at room temperature. The reaction has a broad scope and allows the preparation of various functionalized indoles as well as new aza-or diazaindoles in excellent yields [see, for example, Eq. (1)].

Full text of DOI:10.1002/1521-3773(20000717)39:14<2488::AID-ANIE2488>3.0.CO;2-E

COMMUNICATIONS
[13] S. Bronco, G. Consiglio, S. Di Benedetto, E. Drent, E. Drent, H. J.
Heeres (Shell), GB-B 2 289 855, 1995.
[14] S. Bronco, G. Consiglio, S. Di Benedetto, M. Fehr, F. Spindler, A.
Togni, Helv. Chim. Acta 1995, 78, 883 ± 886.
[15] P. W. N. M. van Leeuwen, C. F. Roobeek, H. van der Heijden, J. Am.
Chem. Soc. 1994, 116, 12117± 12118.
[16] K. Nozaki, N. Sato, Y. Tonomura, M. Yasutomi, H. Takaya, T. Hijama,
T. Matsubara, N. Koga, J. Am. Chem. Soc. 1997, 119, 12779 ± 12795.
[17] A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Landert, A. Tijani, J.
Am. Chem. Soc. 1994, 116, 4062 ± 4066.
increase of reaction rate. Steric effects are also evident. When
the trifluoromethyl substituent is located in the ortho position
(1e) only low-molecular-weight oligomers are obtained in a
very low yield. Thus, placing the CF3 group in the phenyl meta
or para positions (1b ± d) does not drastically influence the
steric properties of the ligands and constitutes the modifica-
tion of choice for the formation of highly efficient systems for
the CO/propene copolymerization reaction.
Whereas electronic effects on the stereoselectivity of
several different catalytic asymmetric reactions have been
observed before,[21, 22, 27±29] a comparable influence on the
catalytic activity has been reported in particular for Rh-
catalyzed hydroformylation.[30±33] Because of the C1 symmetry
of the ligands, we believe that the isomeric intermediates
containing CO and/or the olefin coordinated to Pd display
significantly different reactivities. When the complex
[18] A. Togni, Angew. Chem. 1996, 108, 1581 ± 1583; Angew. Chem. Int. Ed.
Engl. 1996, 35, 1475 ± 1477.
[19] A. Togni, S. D. Pastor, Helv. Chim. Acta 1989, 72, 1038 ± 1042.
[20] A. Schnyder, L. Hintermann, A. Togni, Angew. Chem. 1995, 107, 996 ±
998; Angew. Chem. Int. Ed. Engl. 1995, 34, 931 ± 933.
[21] A. Schnyder, A. Togni, U. Wiesli, Organometallics 1997, 8, 255 ± 260.
[22] G. Pioda, A. Togni, Tetrahedron: Asymmetry 1998, 9, 3903 ± 3910.
[23] M. Sperrle, G. Consiglio, J. Am. Chem. Soc. 1995, 117, 12130 ± 12136.
[24] S. Bronco, G. Consiglio, Macromol. Chem. Phys. 1995, 197, 355 ± 365.
[25] S. Bronco, G. Consiglio, R. Hutter, A. Batistini, U. W. Suter, Macro-
molecules 1994, 27, 4436 ± 4440.
[26] K. Nozaki, M. Yasutomi, K. Nakamoto, T. Hiyama, Polyhedron 1998,
17, 1159 ± 1164.
[27] A. L. Casalnuovo, T. V. RajanBabu, T. A. Ayers, T. H. Warren, J. Am.
Chem. Soc. 1994, 116, 9869 ± 9882.
[28] T. V. RajanBabu, A. L. Casalnuovo, J. Am. Chem. Soc. 1996, 118,
6325 ± 6326.
[29] D. S. Clyne, Y. C. Mermet-Bouvier, N. Nomura, T. V. RajanBabu, J.
Org. Chem. 1999, 64, 7601 ± 7611.
[30] C. P. Casey, E. L. Paulsen, E. W. Beuttenmueller, B. R. Proft, L. M.
Petrovich, B. A. Matter, D. R. Powell, J. Am Chem. Soc. 1997, 119,
11817± 11825.
[31] L. A. van der Veen, M. D. K. Boele, F. R. Bregman, P. C. J. Kamer,
P. W. N. M. van Leeuwen, K. Goubitz, J. Fraanje, H. Schenk, C. Bo, J.
Am. Chem. Soc. 1998, 120, 11616 ± 11626.
[32] C. P. Casey, E. L. Paulsen, E. W. Beuttenmueller, B. R. Proft, B. A.
Matter, D. R. Powell, J. Am. Chem. Soc. 1999, 121, 63 ± 70.
[33] D. R. Palo, C. Erkey, Organometallics 2000, 19, 81 ± 86.
[34] M. Brookhart, M. I. Wagner, J. Am. Chem. Soc. 1996, 118, 7219 ± 7220.
‡
[(1d)PdMe] is placed under a CO atmosphere the product
‡
[(1d)Pd(CO)COMe] is formed through a highly regioselec-
tive coordination of the acyl moiety trans to the PAr2 group.[16]
The electrophilicity of the metal center, and hence that of the
coordinated substrates should be higher in the case of the
ligands bearing more electron-withdrawing PAr2 groups. This
also should coincide with a lower binding energy of the
substrate. In contrast to other catalytic systems,[34] in fact, the
kinetic order of the copolymerization with respect to carbon
monoxide is positive. The crucial assumption sustaining the
electronic effect on activity is that the configurational isomers
in which the monomers are coordinated trans to the PAr2
groups should be more reactive by virtue of their increased
electrophilicity in this position. Furthermore, it has to be
noted that in catalytic polyketone synthesis the electro-
philicity of the metal center needs to be carefully balanced in
order for olefins to compete with CO as ligands. Thus, for
ligands containing a basic PAr2 group, such as 1 f, CO is likely
to bind more strongly to the PdII center, leading to a drastic
decrease of the overall rate.
In conclusion, PdII systems combined with sterically very
similar chiral ferrocenyl ligands 1a ± g (except 1e) produce
almost completely isotactic copolymers from propene and CO
in a highly enantioselective fashion. Only small variations in
enantioface discrimination were observed, whereas drastic
changes in catalytic activity were noted by changing the
electronic properties of the PAr2 substituent.
Versatile Indole Synthesis by a 5-endo-dig
Cyclization Mediated by Potassium or Cesium
Bases**
Alain Louis Rodriguez, Christopher Koradin,
Wolfgang Dohle, and Paul Knochel*
The addition of heteroatomic nucleophiles to triple bonds is
an important reaction that often requires a high activation
energy.[1] Intramolecular additions proceed more readily and
a recent hydroamination of o-chlorostyrenes followed by
Received: March 10, 2000 [Z14831]
[1] F. Garbassi, CHEMTECH 1999, Oct, 48 ± 53.
[2] H. Seifert, Kunstoffe 1998, 88, 1154 ± 1157.
[3] A. Gray, Chem. Br. 1998, March, 44 ± 45.
[*] Prof. Dr. P. Knochel, Dr. A. L. Rodriguez, Dipl.-Chem. C. Koradin,
Dipl.-Chem. W. Dohle
[4] A. Sommazzi, F. Garbassi, Prog. Polym. Sci. 1997, 22, 1547± 1605.
[5] E. Drent, P. H. M. Budzelaar, Chem. Rev. 1996, 96, 663 ± 681.
[6] A. Wakker, H. G. Kormelink, P. Verbeke, J. C. M. Jordaan, Kunststoffe
1995, 85, 1056 ± 1064.
Department Chemie, Universität München
Butenandtstraûe 5 ± 13, 81377 München (Germany)
Fax : (‡49)89-2180-7680
[7] A. Sen, Acc. Chem. Res. 1993, 26, 303 ± 310.
E-mail: Paul.Knochel@cup.uni-muenchen.de
[8] A. Batistini, G. Consiglio, U. W. Suter, Angew. Chem. 1992, 104, 306 ±
3075; Angew. Chem. Int. Ed. Engl. 1992, 31, 303 ± 305.
[9] K. Nozaki, T. Hiyama, J. Organomet. Chem. 1999, 576, 248 ± 253.
[10] A. Batistini, G. Consiglio, Organometallics 1992, 11, 1766 ± 1769.
[11] K. Nozaki, N. Sato, H. Takaya, J. Am. Chem. Soc. 1995, 117, 9911 ±
9912.
[**] We thank the DFG (Leibniz-Programm) and the Fonds der Chem-
ischen Industrie for generous financial support. A.L.R. and C. K.
thank the Humboldt-Foundation and the BASF AG, respectively, for
fellowships. W.D. was supported by the BMBF program (03 D 0056 2).
We thank Dr. J. Henkelmann (BASF AG) for helpful discussions and
the BASF AG for the generous gift of chemicals.
[12] Z. Jiang, A. Sen, J. Am. Chem. Soc. 1995, 117, 4455 ± 4467.
2488
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2488 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 14

COMMUNICATIONS
cyclization has provided an elegant access to indolines.[2] The
palladium-catalyzed synthesis of indoles starting from 2-alky-
nylanilines of type 1[3] or more frequently from their corre-
Table 2. Functionalized indoles 2a ± r obtained by the cyclization of the aniline
derivatives 1a ± r in the presence of KH (Method A) or KOtBu (Method B) at room
temperature.
Method[a] Yield [%][b]
sponding trifluoroacetamides has been well studied.[4]
A
Entry Aniline 1
Indole 2
molybdemum(0)-catalyzed cyclization of compounds 1 to
indoles 2 has been reported.[5] Recently,[6] we have reported
the high catalytic activity of CsOH ´ H2O[7] for promoting the
addition of anilines or alcohols to alkynes or styrenes. Herein,
we report a new mild synthesis of 2-substituted indoles of type
2 mediated by potassium or cesium bases in N-methylpyrro-
lidinone (NMP; Scheme 1).
1
2
3
4
5
6
7
8
9
1a: R ˆ Ph
1b: R ˆ Bu
2a: R ˆ Ph
2b: R ˆ Bu
A (B)
A (B)
A
B
A
B
A
A
A
72 (79)
76 (78)
67
62
61
81
70
61
75
1c: R ˆ 1-cyclohexenyl 2c: R ˆ 1-cyclohexenyl
1d: R ˆ H
2d: R ˆ H
1e: R ˆ (CH2)2OH
1 f: R ˆ CH(OEt)2
1g: R ˆ 2-thienyl
1h: R ˆ 2-thiazolyl
2e: R ˆ (CH2)2OH
2 f: R ˆ CH(OEt)2
2g: R ˆ 2-thienyl
2h: R ˆ 2-thiazolyl
1i: R ˆ 3-chloropropyl 2i: R ˆ cyclopropyl
1j: R ˆ 2-aminophenyl 2j: R ˆ 2-aminophenyl
10
A
82
Scheme 1. Base-mediated indole synthesis.
The scope of the reaction is broad and most of these ring
closures are complete within a few hours at room temper-
ature. Initial studies have shown that the strong base CsOH ´
H2O is an effective base for the cyclization of 2-(2-phenyl-
ethynyl)aniline (1a); however, a reaction temperature of
908C was required for the completion of the reaction
(Table 1). Similarly finely powdered KOH or NaOEt[8] led
11
1k
2k
A
80
12
13
14
1l
2l
B
7
7
7
7
2
4
Table 1. Na, K, Cs base-mediated cyclizations.
1m
2m
A
A
Base
T [8C]
t [h]
Yield [%][a]
NaH
60
80
25
25
90
25
8
15
4
5
5
< 5
66
79
72
68
71
NaOEt
KOtBu
KH
CsOH
CsOtBu
1n
2n
5
[a] Yield of isolated analytically pure 2a.
15
1o
2o
B
7
8
only to sluggish reactions below 808C. In strong contrast,
soluble potassium or cesium alkoxides such as KOtBu[9] or
CsOtBu[10] as well as KH[11] in NMP led to a fast reaction at
room temperature (3 ± 12 h). These mild reaction conditions
allow the presence of various functionalities in the starting (2-
alkynyl)anilines of type 1 and enables the preparation of a
range of polyfunctional indoles (Table 2).
The precursors 1 were prepared by the Sonogashira cross-
coupling[12] of the corresponding (2-iodo- or 2-bromoanilines
3 with 1-alkynes in satisfactory to excellent yields. Various
2-substituted indoles are conveniently prepared either by
using KH (1.3 ± 2.1 equiv; Method A) or KOtBu (1.3 ± 1.7
equiv; Method B). An excess of base is necessary in these
cyclizations since the final product is an unreactive potassium
salt of indoles 2. It is not basic enough to deprotonate a
further molecule of starting material 1. Several functional
16
17
1p
2p
B
B
61[c]
1q
2q
80[d]
18
1r
2r
B
90[d]
[a] Method A: KH (1.3 ± 1.7equiv), NMP, room temperature, 3 ± 12 h. Method B:
KOtBu (1.3 ± 2.1 equiv), NMP, room temperature, 3 ± 12 h. [b] Yields of isolated
groups such as a hydroxy (entry 5; Table 2), an acetal (entry 6; analytically pure products. [c] Tˆ 608C, t ˆ 5 h. [d] Tˆ 808C, t ˆ 6 h.
Angew. Chem. Int. Ed. 2000, 39, No. 14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2489 $ 17.50+.50/0
2489

COMMUNICATIONS
was stirred for 4 h at room temperature. After the same workup procedure
as described for method A, the product 2a (76 mg, 0.39 mmol) was
obtained in 79% yield.
Table 2), an additional amino group (entry 10; Table 2), an
alkyne (entry 11; Table 2), or a nitro group (entry 12; Table 2)
are tolerated. When the alkyne bears a 3-chloropropyl
substituent (entry 9; Table 2), a cyclopropanation occurs after
cyclization providing 2-cyclopropylindole (2i) in 75% yield.
Remarkably, this cyclization reaction can be extended to
various heterocyclic precusors such as the aminopyridines 1m
and 1n (entries 15 and 16; Table 2). In all cases, a smooth
cyclization occurs under similar reaction conditions (Meth-
od A or MethodB) providing new types of heterocycles of
interest for pharmaceutical applications. It was also possible
to perform this ring closure on solid phase. Thus, 4-iodobenz-
amide attached to a Rink ± MBHA resin 4 undergoes a
smooth Sonogashira reaction[13] with (trimethylsilyl)acetyle-
ne. After desilylation a second cross-coupling with 2-iodo-
aniline provides the expected precursor for cyclization. Treat-
ment with KOtBu (15 equiv) in NMP (258C, 24 h) affords the
indole 5 in 81% purity after cleavage from the resin. Similarly,
the Rink ± MBHA resin attached 2-bromoaniline derivative 6
was converted to the 2-phenyl-substituted indole 7 (88%
purity after cleavage from the resin) using an analogeous
reaction sequence (Scheme 2).
Received: December 23, 1999 [Z14460]
[1] a) T. E. Müller, M. Beller, Chem. Rev. 1998, 98, 675; b) M. Beller,
T. H. Riermeier in Transition Metals for Organic Synthesis (Eds.: M.
Beller, C. Bolm), Wiley-VCH, 1998; c) J. H. Teles, S. Brode, M.
Chabanas, Angew. Chem. 1998, 110, 1475; Angew. Chem. Int. Ed. 1998,
37, 1415; d) B. F. Kukharev, V. K. Stankevich, G. R. Klimenko, Russ. J.
Org. Chem. 1993, 29, 2005.
[2] M. Beller, C. Breindl, T. H. Riermeier, M. Eichberger, H. Trauthwein,
Angew. Chem. 1998, 110, 3571; Angew. Chem. Int. Ed. 1998, 37, 3389;
b) see also M. Beller, M. Eichberger, H. Trauthwein, Angew. Chem.
1997, 109, 2306; Angew. Chem. Int. Ed. Engl. 1997, 36, 2225; c) M.
Beller, O. R. Thiel, H. Trauthwein, Synlett 1999, 243.
[3] a) K. Iritani, S. Matsubara, K. Utimoto, Tetrahedron Lett. 1988, 29,
1799. For other recent indole synthesis, see: b) B. Witulski, T. Stengel,
Angew. Chem. 1999, 111, 2521; Angew. Chem. Int. Ed. 1999, 38, 2426;
c) M. T. Baumgartner, M. A. Nazareno, M. C. Murguia, A. B. Pierini,
R. A. Rossi, Synthesis 1999, 2053; d) Y. Kondo, S. Kojima, T.
Sakamoto, J. Org. Chem. 1997, 62, 6507.
[4] a) A. Arcadi, S. Cacchi, F. Marinelli, Tetrahedron Lett. 1992, 33, 3915;
b) S. Cacchi, G. Fabrizi, F. Marinelli, L. Moro, P. Pace, Synlett 1997,
1363; c) A. Arcadi, S. Cacchi, V. Carnicelli, F. Marinelli, Tetrahedron
1994, 50, 437.
[5] a) F. E. Mc Donald, A. K. Chatterjee, Tetrahedron Lett. 1997, 38, 7687;
b) F. E. Mc Donald, Chem. Eur. J. 1999, 5, 3103.
[6] a) D. Tzalis, P. Knochel, Angew. Chem. 1999, 111, 1547; Angew. Chem.
Int. Ed. 1999, 38, 1463; b) D. Tzalis, C. Koradin, P. Knochel,
Tetrahedron Lett. 1999, 40, 6193.
[7] a) E. E. Dueno, F. Chu, S.-I. Kim, K. W. Jung, Tetrahedron Lett. 1999,
40, 1843; b) F. Chu, E. E. Dueno, K. W. Jung, Tetrahedron Lett. 1999,
40, 1847; c) J. Busch-Peterson, Y. Bo, E. J. Corey, Tetrahedron Lett.
1999, 40, 2065.
[8] The treatment of 1a with NaOEt in boiling ethanol does not lead to
the corresponding indole 2a, showing that the use of NMP is essential
for the direct cyclization of 1a to 2a; see also: T. Sakamoto, Y. Kondo,
H. Yamanaka, Heterocycles 1986, 24, 31.
[9] KOtBu has exceptional basic properties: a) M. Schlosser, Pure Appl.
Chem. 1988, 60, 1627; b) M. Schlosser, J. Hartmann, J. Am. Chem. Soc.
1976, 98, 4674; c) M. Schlosser, G. Rauchschwalbe, J. Am. Chem. Soc.
1978, 100, 3258.
[10] Cesium tert-butoxide is conveniently prepared by the addition of
tBuOH to cesium in toluene at 08C (15 min).
Scheme 2. Solid-phase synthesis of indoles.
[11] The suspension of KH in NMP may generate the soluble potassium
enolate of N-methylpyrrolidinone. Reaction products derived from
this enolate have been isolated in related cyclization reactions.
[12] a) S. Takahashi, Y. Kuroyama, K. Sonogashira, N. Hagihara, Synthesis
1980, 627; b) T. Sakamoto, M. Shiraiwa, Y. Kondo, H. Yamanaka,
Synthesis 1983, 312; c) A. F. Littke, G. C. Fu, Angew. Chem. 1999, 111,
2568; Angew. Chem. Int. Ed. 1999, 38, 2411.
In summary, the combination of KOtBu, KH, or CsOtBu
with the polar solvent NMP allows a smooth preparation of
various indoles and azaindoles by a 5-endo-dig cycliza-
tion.[14, 15]
[13] M. D. Collini, J. W. Ellingboe, Tetrahedron Lett. 1997, 38, 7963.
[14] J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 738.
[15] A patent application with the BASF AG has been filed.
ExperimentalSection
Typical procedure for the preparation of 2-phenylindole (2a): Method A:
To a stirred solution of potassium hydride (42 mg, 1.05 mmol) in NMP
(4 mL) was added under argon (2-phenylethynyl)aniline (1a) (97mg,
0.50 mmol) in NMP (1 mL). The reaction mixture was vigorously stirred for
5 h at room temperature. Water (1 mL) and dichloromethane (50 mL) were
added, and the resulting solution was washed with a saturated NaCl
solution, dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, dichloromethane/
pentane 7/3) to give 2-phenylindole (2a) (73 mg, 0.36 mmol, 72% yield;
m.p. 171 ± 1758C).
Method B: The reaction was carried out as above using potassium tert-
butoxide (73 mg, 0.65 mmol) instead of potassium hydride. The reaction
2490
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2490 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 14