Selective functionalization in positions 2 and 3 of indole via an iodine - Copper exchange reaction

Article abstract of DOI:10.1021/ol049498q

Two selectively successive I/Cu exchange reactions performed with (Nphyl)CuLi allow the functionalization of indoles in positions 2 and 3. The 2,3-diketones prepared by this method can readily be converted to tricyclic heterocycles by standard methods.

Full text of DOI:10.1021/ol049498q

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1665-1667
Selective Functionalization in Positions
2 and 3 of Indole via an Iodine−Copper
Exchange Reaction
Xiaoyin Yang, Andreas Althammer, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received March 17, 2004
ABSTRACT
Two selectively successive I/Cu exchange reactions performed with (Nphyl)CuLi allow the functionalization of indoles in positions 2 and 3.
The 2,3-diketones prepared by this method can readily be converted to tricyclic heterocycles by standard methods.
The indole system occurs in numerous natural products as
well as in many therapeutic agents.1 The preparation of
polyfunctional indoles is therefore an important research
field, and numerous methods have been developed.2 The
direct lithiation of indoles in positions 2 and 3 has been
described;3 however, the resulting lithiated indoles are
compatible with only weakly electrophilic functional groups
at the indole ring.4 Recently, we have shown that mild
conditions are required for performing an iodine-copper
exchange. The excellent functional group tolerance of
organocopper compounds allows the preparation of new
polyfunctional arylcopper species bearing even an aldehyde
group.5 Herein, we wish to report an application of the
iodine-copper exchange reaction for performing a selective
metalation of the 2,3-diiodoindole derivative 1.6 Thus, the
treatment of 1 with the lithium cuprate (PhMe2CCH2)2CuLi
((Nphyl)2CuLi (2); 25 °C, 0.5 h) in a mixture of THF and
diethyl ether (THF/Et2O ) 3:1) provides the cuprate 3. Its
treatment with various electrophiles (E1) furnishes polyfunc-
tional indoles of type 4. The reactions of the 3-iodoindoles
4 with (Nphyl)2CuLi in a 3:1 THF/Et2O mixture at -78 °C
for 30 min lead to the highly functionalized copper species
of type 5, which react with electrophiles (E2) leading to the
indole derivatives of type 6 (Scheme 1, Tables 1 and 2).
(1) Joule, J. A. Sci. Synth. 2001, 10, 361-652.
(2) For some recent methods, see: (a) Gribble, G. W. J. Chem. Soc.,
Perkin Trans 1. 2000, 1045-1048. (b) Battistuzzi, G.; Cacchi, S.; Fabrizi,
G. Eur. J. Org. Chem. 2002, 2671-2681. (c) Battistuzzi, G.; Cacchi, S.;
Fabrizi, G. Marinelli, F.; Parisi, L. M. Org. Lett. 2002, 4, 1355-1358. (d)
Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675-704. (e) Beller, M.;
Breinde, C.; Riermeier, T. H.; Eichberger, M; Tranlhwein, H Angew. Chem.,
Int. Ed. 1998, 37, 3389-3391. (f) Witulski, B.; Stengel, T. Angew. Chem.,
Int. Ed. 1999, 38, 2426-2430. (g) Kondo, Y.; Kojima, S.; Sakamoto, T. J.
Org. Chem. 1997, 62, 6507-6511. (h) Coleman, R. S.; Chen, W. Org. Lett.
2001, 3, 1141-1144. (i) Watanabe, M.; Yamamoto, T.; Nishiyama, M.
Angew. Chem., Int. Ed. 2000, 39, 2501-2504. (j) Takeda, A.; Kamijo, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662-5663. (k) Wagaw, S.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251-10263.
(l) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571-1578. (m) Ko¨hling, P.; Schmidt, A. M.;
Eilbracht, P. Org. Lett. 2003, 5, 3213-3216. (n) Knepper, K.; Bra¨se, S.
Org. Lett. 2003, 5, 2829-2832. (o) Barluenga, J. Pure Appl. Chem. 2002,
74, 1317-1326.
(4) (a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5615-
5616. (b) Knodo, Y.; Matsudaira, T.; Salo, J.; Musata, N.; Sakamolo, T.
Angew. Chem., Int. Ed. Engl. 1996, 35, 736-738.
(3) (a) Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 26,
5935-5938. (b) Matsuzono, M.; Fukuda, T.; Iwao, M. Tetrahedron Lett.
2001, 42, 7621-7623. (c) Saulnier, M. G.; Gribble, G. W. J. Org. Chem.
1982, 47, 757-761. (d) Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2000,
41, 8717-8721.
(5) (a) Piazza, C.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 3263-
3265. (b) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org. Lett. 2003, 5,
1229-1231. (c) Yang, X.; Knochel, P. Synlett 2004, 1, 81-84.
(6) Witulski, B.; Buschmann, N.; Bergstra¨âer, U. Tetrahedron 2000, 56,
8473-8480. See also ref 3c.
10.1021/ol049498q CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/09/2004

Scheme 1. Selective Functionalization in Positions 2 and 3 of
Indole via Iodine-Copper Exchange
Table 1. 3-Iodoindole of Type 4 Obtained by the Reaction of
the Cuprate 3 with Electrophiles
According to this sequence, the diiodoindole 1 is a
synthetic equivalent of 1,2-bianionic synthon 7. Thus, the
allylation of the cuprate 3 with allyl bromide leads to the
3-iodo-2-allylindole derivative 4a in 92% yield (entry 1 of
Table 1). The acylation of the indolyl cuprate 3 is catalyzed
by 4-(dimethylamino)pyridine (DMAP) (10 mol %).7 Under
these conditions, aliphatic acid chlorides (entries 2 and 3)
as well as aromatic acid chlorides (entries 4 and 5) provide
the iodoketones 4b-e in 78-84% yields. The sensitive
acryloyl chloride reacts as expected, furnishing the unsatur-
ated ketone 4f in 67% yield. The acylation with ethyl oxaloyl
chloride leads to the iodoketoester 4g in 75% yield (entry
7). Finally, the reaction with 3-iodo-2-cyclohexen-1-one
provides the addition-elimination product 4h in 66% yield
(entry 8). The selectivity for an I/Cu exchange in position 2
rather than in position 3 is best explained by considering
the higher electronegativity of C(2) compared to C(3).8
For the second exchange reaction, we have treated the
3-iodoindole 4a, 4c, 4d, and 4h with (Nphyl)2CuLi (1.2
equiv) in a 3:1 mixture of THF and Et2O at -78 °C followed
by the addition of a second electrophile. Thus, the copper
reagent 5a is readily allylated with allyl bromide giving the
bis-allylated product 6a in 88% yield (entry 1 of Table 2).
For performing the acylation reactions, we found that the
use of N-methylpyrrolidinone (NMP) as a cosolvent and
DMAP (10 mol %) as a catalyst was advantageous.
a Isolated yield of analytically pure product. b Reaction was performed
in the presence of DMAP (10 mol %).
(7) (a) Heinrich, M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse, H.
Angew. Chem., Int. Ed. 2003, 42, 4826-4828. (b) Steglich, W.; Ho¨fle, G.
Angew. Chem., Int. Ed. Engl. 1969, 8, 981-983. (c) Ho¨fle, G.; Steglich,
W.; Vorbru¨ggen, A. Angew. Chem., Int. Ed. Engl. 1978, 17, 569-583.
(8) Typical Procedure for Synthesis of the 3-Iodoindole (4c). A dry
and argon-flushed 25 mL flask, equipped with a magnetic stirrer and a
septum, was charged with CuCN (216 mg, 2.4 mmol) and dry THF (8 mL).
A solution of neophyllithium in Et2O (1.1 M, 4.4 mL, 4.8 mmol) was added
at -78 °C. The resulting solution was warmed to room temperature for 10
min and then cannulated into a solution of 1-benzenesulfonyl-2,3-diiodo-
1H-indole (1) (1.02 g, 2.0 mmol) in dry THF (4 mL) at -78 °C. The reaction
was stirred at room temperature for 30 min. DMAP (24 mg, 0.2 mmol)
and cyclopentane carbonyl chloride (840 mg, 6.0 mmol) were added
successively at room temperature. The resulting solution was stirred at room
temperature for 1 h, quenched with saturated aqueous NH4Cl solution, and
poured into water (40 mL). The aqueous phase was extracted with diethyl
ether (3 × 30 mL). The combined organic fractions were washed with brine
(30 mL), dried over Na2SO4, and concentrated in vacuo. Purification by
flash chromatography yielded 824 mg (86%) of 4c as a white solid, mp
153 °C.
Thus, the reaction of 5a with pivaloyl chloride furnished
the desired indolyl ketone 6b in 68% yield (entry 2). The
keto-substituted indolylcuprates 5b and 5c can be readily
prepared by the I/Cu exchange reaction. Good yields of the
corresponding 1,2-diketones 6c-h can therefore be obtained
(entries 3-8). Remarkably, even the R,â-unsaturated keto-
substituted indolylcuprate 5d can be readily prepared in this
way. After acylation with propionyl chloride and ethyl oxalyl
chloride, the desired products 6i and 6j were obtained in 80
and 72% yields (entries 9 and 10).
This method provides functionalized organocopper inter-
mediates and gives a simple access to diketones otherwise
difficult to prepare. These diketones can be converted to more
complex heterocycles. Thus, treating the diketone 6h with
1666
Org. Lett., Vol. 6, No. 10, 2004

Scheme 2. Synthesis of Triazafluorene of Type 8
Table 2. 2,3-Disubstituted Indoles Obtained by the Reaction of
the Copper Reagents 5a-d with Electrophiles
By performing a metathesis reaction of the diallylated
product 6a with Grubbs catalyst (5 mol %) in refluxing CH2-
Cl2, we have obtained the carbazole 9 in nearly quantitative
yield (Scheme 3).10
Scheme 3. Formation of Carbazole 9 via RCM Reaction
In conclusion, we have shown that the 2,3-diiodoindole
derivative 1 can selectively undergo two successive iodine-
copper exchange reactions and react with two different
electrophiles. This method gives an easy access to 2,3-
diketoindoles, which can be readily converted to new
heterocycles. Further extension of this method is currently
underway in our laboratory.11
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank Chemetall GmbH,
Degussa AG, BASF AG, and Wacker-Chemie for gifts of
chemicals.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL049498Q
(9) Haddadin, M. J.; Agha, B. J.; Tabri, R. F. J. Org. Chem. 1979, 44,
494-497.
(10) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (b)
Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372-374. (c)
Grobelny, Z.; Stolarzewicz, A.; Adamus, G.; Buika, G.; Grazulevicius, J.
V. J. Organomet. Chem. 2000, 595, 66-69.
(11) Typical Procedure for Synthesis of the 2,3-Diketone (6c). A dry
and argon-flushed 25 mL flask, equipped with a magnetic stirrer and a
septum, was charged with CuCN (54 mg, 0.6 mmol) and dry THF (2 mL).
A solution of neophyllithium in Et2O (1.1 M, 1.1 mL, 1.2 mmol) was added
at -78 °C. The resulting solution was warmed to room temperature for 10
min and then cannulated into a solution of 4c (239 mg, 0.5 mmol) in dry
THF (2 mL) at -78 °C. The reaction mixture was stirred at room
temperature for 30 min. Then, DMAP (6 mg, 0.05 mmol) and NMP (0.2
mL) were added successively at -78 °C and the resulting mixture was
kept stirring for 15 min at this temperature. Benzoyl chloride (420 mg, 1.5
mmol) was added, and the resulting solution was stirred at room temperature
for 2 h. It was quenched with saturated aqueous NH4Cl solution and poured
into water (15 mL). The aqueous phase was extracted with diethyl ether (3
× 15 mL). The organic fractions were washed with brine (15 mL), dried
over Na2SO4, and concentrated in vacuo. Purification by flash chromatog-
raphy yielded 167 mg (73%) of 6c as a white solid, mp 122 °C.
a Isolated yield of analytically pure product. b Reaction was performed
using NMP as a cosolvent and DMAP (10 mol %) as a catalyst.
NH2NH2‚H2O (2 equiv) in refluxing ethanol for 12 h affords
the tricyclic heterocycle 8. The phenylsulfonyl group is also
removed during the heterocycle synthesis (Scheme 2).9
Org. Lett., Vol. 6, No. 10, 2004
1667