Benzylic substitution of gramines with boronic acids and rhodium or iridium catalysts

Article abstract of DOI:10.1021/ol063042m

(Chemical Equation Presented) Gramine-Mel salts were useful starting materials for the synthesis of 3-benzyl- and 3-allylindoles by the 1,4-addition of boronic acids to the C=C-C=N linkages generated in situ under Rh(I)-catalysis. On the other hand, under Ir(I) catalysis, the reaction of gramines with indoles was used to produce nonsymmetrical diindolylmethanes.

Full text of DOI:10.1021/ol063042m

ORGANIC
LETTERS
2007
Vol. 9, No. 6
961-964
Benzylic Substitution of Gramines with
Boronic Acids and Rhodium or Iridium
Catalysts†
Gabriela de la Herra´n, Amaya Segura, and Aurelio G. Csa´ky2*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad Complutense,
28040-Madrid, Spain
csaky@quim.ucm.es
Received December 16, 2006
ABSTRACT
Gramine−MeI salts were useful starting materials for the synthesis of 3-benzyl- and 3-allylindoles by the 1,4-addition of boronic acids to the
CdC−CdN linkages generated in situ under Rh(I)-catalysis. On the other hand, under Ir(I) catalysis, the reaction of gramines with indoles was
used to produce nonsymmetrical diindolylmethanes.
The indole scaffold is one of the most medicinally relevant
cores. Substituted indoles have been referred to as priVileged
structures since they are capable of binding to many receptors
with high affinity. Therefore, the synthesis and selective
functionalization of indoles have been the focus of active
research over the years.1 Currently, the implementation of
new mild, selective procedures with ample functional group
tolerance for the preparation of indoles is of high interest.
Methods which use readily available starting materials and
make use of aqueous media are particularly welcome to
design new manufacturing processes.
Gramines (3-aminomethylindoles) are readily prepared by
the Mannich reaction2 and constitute valuable intermediates
in the synthesis of complex indole-containing molecules
(Figure 1).
† Dedicated to Prof. Miguel Yus in honor of his 60th birthday.
(1) (a) Sundberg, R. J. In Best Synthetic Methods, Indoles; Academic
Press: New York, 1996; p 7. (b) Sundberg, R. J. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Ress, C. W., Scriven, E. F.
V.; Bird, C. W., Eds.; Pergamon Press: Oxford, 1996; Vol. 2, p 119. (c)
Gribble, G. W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Ress, C. W., Scriven, E. F. V., Bird, C. W., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, p 207. (d) Joule, J. A. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; Thomas, E. J., Ed.;
George Thieme Verlag: Stuttgart, Germany, 2000; Category 2, Vol. 10,
Chapter 10.13. (e) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001,
2491. (f) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893. (g) Tois, J.; Franze´n, R.; Koskinen, A. Tetrahedron 2003, 59,
5345. (h) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int.
Ed. 2004, 43, 550. (i) Cacchi, S.; Fabrici, G. Chem. ReV. 2005, 105, 2873.
(j) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005,
1199. (k) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875.
Figure 1. Gramines as versatile starting materials for the func-
tionalization of indoles.
Gramines can be used to assist functionalization at C-4
of the indole ring by directed ortho-metalation3 and of C-3
by retro-Mannich sequences.4 In addition, the amino func-
(2) Houlihan, W. J. Indoles Part 2. In The Chemistry of Heterocyclic
Compounds; Weissberger,A., Taylor, E. C., Eds.; Wiley-Interscience: New
York, 1972.
10.1021/ol063042m CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/17/2007

tionality can be made to depart as the leaving group to furnish
stabilized benzylic-type cations (indolium ions) which can
be trapped by heteronucleophiles and by stabilized car-
bon nucleophiles.5,6 However, their reaction with nonstabi-
lized carbon nucleophiles has been scarcely considered7 and
has found limited success only in the case of N-protected
indoles.
We observed that 4 was also produced in the absence of
PhB(OH)2, but no reaction took place without a Rh(I)
complex or a base. Therefore, it was reasonable to assume
that coordination of the exocyclic nitrogen with the Rh(I)
complexes will be slowing down transmetalation from boron
to rhodium, thus preventing the formation of enough con-
centration of the [Ph-RhI] species required for the addition
of Ph.11,12 At the same time, this type of coordination will
be assisting the formation of intermediate I. Under these
circumstances, another gramine molecule will act as a
nucleophile to generate compound II. Retro-Mannich reac-
tion on intermediate II and final protonation will explain
the formation of 4 as the major reaction product.
The transition-metal-catalyzed conjugate addition of or-
ganometallic reagents to electron-deficient olefins is one of
the most reliable methods for selective C-C bond formation.8
In particular, the Rh(I)-catalyzed conjugate addition of aryl-
and alkenylboronic acids can be carried out in water-tolerant
solvents and is compatible with the presence of unprotected
OH and NH groups.9 This method of C-C bond formation
has been applied to a variety of substrates including R,â-
unsaturated ketones, esters, amides, aldehydes, alkenylphos-
phonates, nitroalkenes, and alkenyl sulfones. However, the
conjugate addition to CdC-CdN systems has not been
reported. Recently, Ir(I) complexes have also been shown
to catalyze conjugate addition reactions of boronic acids.10
We report herein a new approach to the benzylic func-
tionalization of indoles by the conjugate addition to the
CdC-CdN linkages generated in situ under Rh(I) or Ir(I)
catalysis, without the need of protection of the indole
nitrogen.
On this basis, we devised a new method13,14 for the syn-
thesis of nonsymmetrical diindolylmethanes 6 (Scheme 2).
Scheme 2. Synthesis of Nonsymmetrical Diindolylmethanes
Scheme 1 depicts the attempted benzylic substitution of
the Me2N group of gramine (1a) with Ph when treated with
Reaction of gramines 1 with 5-bromoindole15 (7) and
K3PO4 under Rh(I) or Ir(I) catalysis (complexes 3) led to
compounds 6 (Table 1). In addition to Rh(I) catalysis (3a,
3b), Ir(I) catalysis was found to promote this transformation,
Scheme 1. Attempted Benzylic Substitution of 1a with
PhB(OH)2 under Rh(I) Catalysis
(3) First report on DoM-functionalization of gramines at C-4: (a) Iwao,
A. Heterocycles 1993, 36, 29. See also: (b) Fukuda, T.; Akashima, H.;
Iwao, M. Tetrahedron 2005, 61, 6886.
(4) For the functionalization at C-3 by a halonium-induced retro-Mannich
reaction, see: Chauder, B.; Larkin, A.; Snieckus, V. Org. Lett. 2002, 4,
815 and references cited therein.
(5) (a) Howe, E. E.; Zambito, A. J.; Snyder, H. R.; Tishler, M. J. Am.
Chem. Soc. 1945, 67, 38. (b) Thesing, J.; Schu¨lde, F. Chem. Ber. 1952, 85,
324. (c) Brewster, J. H.; Eliel, E. L. Org. React. 1953, 7, 99. (d) Allbright,
J. D.; Snyder, H. R. J. Am. Chem. Soc. 1959, 81, 2239. (e) Baciocchi, E.;
Schiroli, A. J. Chem. Soc. B 1968, 401. (f) Somei, M.; Karasawa, Y.;
Kaneko, C. Heterocycles 1981, 16, 941. (g) Iwao, M.; Motoi, O. Tetrahedron
Lett. 1995, 36, 5929.
(6) For examples of combined applications of benzylic, C-3 and C-4
functionalizations of gramines in the synthesis of complex indoles, see:
(a) Shinohara, H.; Fukuda, T.; Iwao, M. Tetrahedron 1999, 55, 10989. (b)
Hurt, C. R.; Lin, R.; Rapoport, H. J. Org. Chem. 1999, 64, 225. (c) Smith,
A. B.; Kanoh, N.; Ishiyama, H; Hartz, R. A. J. Am. Chem. Soc. 2000, 122,
11254.
(7) (a) Snyder, H. R.; Eliel, E. L.; Carnahan, R. E. J. Am. Chem. Soc.
1951, 53, 970. (b) Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8, 4939.
(c) Murahashi, S.-I.; Yano, T. J. Am. Chem. Soc. 1980, 102, 2456.
(8) For recent reviews, see: (a) Tomioka, K.; Nagaoka, Y. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 3, Chapter 31.1. (b) Kanai, M.; Shibasaki,
M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New
York, 2000; p 569. (c) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033. (d) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (e) Lipshutz,
B. H. In Organometallics in Organic Synthesis. A Manual, 2nd ed.;
Schlosser, M., Ed.; Wiley: Chichester, 2002; p 665.
(9) For reviews, see: (a) Hayashi, T. Synlett 2001, 879. (b) Bolm, C.;
Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001,
40, 3284. (c) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (d)
Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (e) Hayashi, T.
Bull. Chem. Soc. Jpn. 2004, 77, 13.
PhB(OH)2 (2a) and the Rh(I) complexes 3a or 3b in the
presence of K3PO4 as the base. Under these reaction
conditions, diindolymethane (4) was isolated (75%) together
with minor amounts (10%) of the expected product 5a.
962
Org. Lett., Vol. 9, No. 6, 2007

Table 1. Synthesis of Nonsymmetrical Diindolylmethanesa
Table 2. Synthesis of 3-Benzyl- and 3-Allylindoles from
Methiodides 8a
no.
1
3b
6 (%)c
no.
8
2
5, 9 (%)b
1
2
3
4
5
1a, R1) H, R2 ) H
1a, R1) H, R2 ) H
1a, R1) H, R2 ) H
1b, R1) CH3O, R2 ) H
1c, R1) H, R2 ) CH3O
3a
3b
3c
3c
3c
6a (62)
6a (73)
6a (81)
6b (79)
6c (74)
1
2
3
4
5
6
7
8
9
8a, R1) H, R2 ) H
8a, R1) H, R2 ) H
8a, R1) H, R2 ) H
8a, R1) H, R2 ) H
8a, R1) H, R2 ) H
2a, Ar ) Ph
2a, Ar ) Ph
2b, Ar ) 4-MeOC6H4 5b (77)d
2c, Ar ) 2-MeOC6H4
2d, Ar ) 4-CF3C6H4
5a (65)c
5a (85)d
5c (75)d
5d (82)d
5e (80)d
5f (76)d
5g (85)d
9a (82)d
9b (78)d
9c (65)d
9d (80)d
9e (75)d
a Reaction conditions: 1 (0.2 mol %), 3 (0.01 mol %), 7 (0.25 mol %),
K3PO4 (0.2 mol %), dioxane-H2O 10:1 (1.0 mL), 50 °C. b 3a, [(cod)RhCl]2;
3b, [(cod)2Rh]BF4; 3c, [(cod)IrCl]2. c Yield of the isolated product after
column chromatography on silica gel.
8b, R1) CH3O, R2 ) H 2d, Ar ) 4-CF3C6H4
8c, R1) H, R2 ) CH3O 2d, Ar ) 4-CF3C6H4
8a, R1) H, R2 ) H
8a, R1) H, R2 ) H
2e, Ar ) 2-BrC6H4
2f, R3 ) Ph
2g, R3 ) 4-CF3C6H4
2h, R3 ) 4-ClC6H4
10 8a, R1) H, R2 ) H
11 8a, R1) H, R2 ) H
12 8b, R1) CH3O, R2 ) H 2f, R3 ) Ph
13 8c, R1) H, R2 ) CH3O 2f, R3 ) Ph
and in fact, the Ir(I) complex 3c was found to be superior to
the Rh(I) compounds 3a or 3b.
Benzylic substitution of gramines 1 with boronic acids was
made possible when quaternizing the amino group in the
form of methiodides 8. The Me3N+ group in 8 is not able to
coordinate Rh(I), thus allowing for successful formation of
[R-RhI] species by transmetalation from boron to rhodium
(Scheme 3, Table 2). Reaction of compounds 8 with
a Reaction conditions: 1 (0.2 mol %), 2 (0.4 mol %), 3 (0.01 mol %),
K3PO4 (0.2 mol %), dioxane-H2O 8:2 (1.0 mL), 65 °C. b Yield of the isolated
product after column chromatography on silica gel. c Catalyst 3a, [(co-
d)RhCl]2. d Catalyst 3b, [(cod)2Rh]BF4.
the chloride dimer 3a (Table 2, entries 1 and 2). The reaction
was general for electron-rich, electron-deficient, or sterically
hindered ortho-substituted arylboronic acids (entries 2-8).
Similarly, the reaction with alkenylboronic acids 2f-h
produced the allylindoles 9 (entries 9-13).
Scheme 3. Rh(I)-Catalyzed Benzylic Substitution of
Methiodides 8 with Boronic Acids 2
This method for the synthesis of C-3 benzyl and allyl-
indoles is devoid from competition with the regiose-
lectivity problems usually found in some other synthetic
procedures.16
In conclusion, this paper demonstrates that under Rh(I)
catalysis, RB(OH)2 compounds are able to afford conju-
gate addition products with the CdC-CdN linkages gener-
ated in situ from the readily available gramine-MeI salts
used as starting materials, leading to C-3 benzyl and allyl
indole derivatives. Additionally, a new method for the
synthesis of nonsymmetrical diindolylmethanes has been
described, making use of gramines as starting materials in
combination with Ir(I) catalysis. All of these transformations
are carried out in a water-containing solvent, which can be
of interest from environmental and manufacturing stand-
points.
arylboronic acids 2a-e in the presence of K3PO4 under Rh-
(I) catalysis afforded the benzylic substitution products 5.
In this reaction, Rh(I) catalysis was superior to Ir(I) catalysis,
as in the latter case, only 4 was isolated. We also observed
better performance of the cationic Rh(I) complex 3b over
(15) 5-Bromoindole (7) was chosen as model example for the synthesis
of non-symmetrical diindolylmethanes. Further applications derived from
halogen-metal exchange or transition-metal-catalyzed couplings can be
foreseen for compounds 6.
(10) Nishimura, T.; Yasuhara, Y.; Hayashi, T. Angew. Chem., Int. Ed.
2006, 45, 5164.
(11) For the binding of aliphatic amines to Rh(I), see: (a) Lautens, M.;
Fagnou, K. J. Am. Chem.Soc. 2001, 123, 7170. (b) Lautens, M.; Fagnou,
K.; Yang, D. J. Am. Chem. Soc. 2003, 125, 14884. (c) Cho, Y.; Zunic, V.;
Senboku, H.; Olsen, M.; Lautens, M. J. Am. Chem. Soc. 2006, 128, 6837
and references cited therein. The yield in 5a was not improved when the
reaction was carried out in the presence of Bu4NI (1.1 mol).
(12) For a related coordination of the CH2NMe2 group of 1a with Pd(II)
salts leading to cyclometalation to the 2-position of the indole moiety, see:
Tollari, S.; Demartin, F.; Cenini, S.; Palmisano, G.; Raimondi, P. J.
Organomet. Chem. 1997, 527, 93.
(13) For a review on the synthesis and medicinal relevance of diindoly-
lalkanes, see: Chakrabarty, M.; Basak, R.; Harigaya, Y. Heterocycles 2001,
55, 2431.
(14) To the best of our knowledge, there is only one previously reported
synthesis of nonsymmetrical diindolylmethanes. See: Chalaye-Mauger, H.;
Denis, J.-N.; Averbuch-Pouchot, M.-T.; Valle´e, Y. Tetrahedron 2000, 56,
791.
(16) For other recent syntheses of 3-benzylindoles and 3-allylindoles,
see: (a) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001. (b)
Tokuyama, H.; Watanabe, M.; Hayashi, Y.; Kurokawa, T.; Peng, G.;
Fukuyama, T. Synlett 2001, 1403. (c) Zhu, X.; Ganesan, A. J. Org. Chem.
2002, 67, 2705. (d) Sefkow, M.; Buchs, J. Org. Lett. 2003, 5, 193. (e)
Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org. Lett. 2003,
5, 2497. (f) Mahadevan, A.; Sard, H.; Gonzalez, M.; McKewb, J. C.
Tetrahedron Lett. 2003, 44, 4589. (g) Campbell, J. A.; Bordunov, V.; Broka,
C. A.; Dankwardt, J.; Hendricks, R. T.; Kress, J. M.; Walker, K. A. M.;
Wang, J.-H. Tetrahedron Lett. 2004, 45, 3793. (h) Bandini, M.; Melloni,
A.; Umani-Ronchi, A. Org. Lett. 2004, 6, 3199. (i) Kimura, M.; Futamata,
M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592. (j) Jia, Y.;
Zhu, J. J. Org. Chem. 2006, 71, 7826. (k) Westermaier, M.; Mayr, H. Org.
Lett. 2006, 8, 4791. (l) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem.,
Int. Ed. 2006, 45, 793. (m) Kofink, C. C.; Knochel, P. Org. Lett. 2006, 8,
4121.
Org. Lett., Vol. 9, No. 6, 2007
963

Acknowledgment. We thank Prof. Joaqu´ın Plumet (De-
partamento de Qu´ımica Orga´nica, UCM) for his continuous
help. UCM-CAM Regional Plan Proyect PR45/05-14157 and
Repsol-YPF are gratefully acknowledged for financial sup-
port.
Supporting Information Available: Experimental pro-
cedures and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL063042M
964
Org. Lett., Vol. 9, No. 6, 2007