A practical mild, one-pot, regiospecific synthesis of 2,3-disubstituted indoles via consecutive Sonogashira and Cacchi reactions

Article abstract of DOI:10.1021/ol061136q

A practical one-pot, regiospecific three-component process for the synthesis of 2,3-disubstituted indoles was developed via consecutive Pd-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.

Full text of DOI:10.1021/ol061136q

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3271-3274
A Practical Mild, One-Pot, Regiospecific
Synthesis of 2,3-Disubstituted Indoles
via Consecutive Sonogashira and
Cacchi Reactions
Bruce Z. Lu,* Wenyi Zhao, Han-Xun Wei, Marine Dufour, Vittorio Farina,† and
Chris H. Senanayake†
Department of Chemical DeVelopment, Boehringer-Ingelheim Pharmaceuticals, Inc.,
Suite 205, East Leigh Street, Richmond, Virginia 23219
zlu@rdg.boehringer-ingelheim.com
Received May 9, 2006
ABSTRACT
A practical one-pot, regiospecific three-component process for the synthesis of 2,3-disubstituted indoles was developed via consecutive
Pd-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.
The indole nucleus is a prominent structural motif found in
numerous natural products and synthetic compounds with
vital medicinal value.1 The assembly of functionalized
indoles has captured the attention of synthetic chemists for
decades. Despite the fact that many methodologies have been
developed,2 regioselective formation of indoles with substitu-
tions at C2, C3, and at positions other than C5 remains
challenging by classical methods, such as the Fischer
indolization.3
tionalities, we have recently developed a novel Pd-catalyzed
regioselective indolization of 2-bromo- or 2-chloroanilines
with internal alkynes,4 based on Larock’s original protocol
(Scheme 1).5 Although this is an efficient process, one of
Scheme 1
Driven by the need to develop general and economical
processes for the synthesis of indoles with multiple func-
† Current address: Boehringer-Ingelheim Pharmaceuticals, Inc., 900
Ridgebury Road, Ridgefield, CT 06877.
(1) For a recent review of indole-containing natural products, see: (a)
Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155. (b) Lounasmaa, M.; Tolvanen,
A. Nat. Prod. Rep. 2000, 17, 175.
(2) For reviews on indole syntheses, see: (a) Indoles; Sundberg, R. J.,
Ed.; Academic: London, UK, 1996. (b) Sundberg, R. J. Pyrroles and their
Benzo Derivatives: Synthesis and Applications. In ComprehensiVe Het-
erocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
UK, 1984; Vol. 4, pp 313-376. (c) For a recent review on Fischer indole
synthesis, see: Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607.
the common problems is the removal of the minor regio-
isomer by nonchromatographic techniques. These consider-
(3) Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 6.
10.1021/ol061136q CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/22/2006

the occurrence of the non-Pd(II) catalyzed nucleophilic
cyclization during, or immediately thereafter, the Sonogashira
coupling stage. Given that CuI could catalyze this cycliza-
tion,8 we chose to screen conditions without CuI.9
Scheme 2
Although several copper-free Sonogashira coupling pro-
tocols have been reported recently,10 the reaction rate without
copper as additive is usually slower.
We started our investigation of the three-component
reaction using 2-iodo-N-methanesulfonyl or trifluoroacetyl-
anilide (1a,b), phenylacetylene, followed, later, by bromo-
benzene (Scheme 3). Several important parameters were
Scheme 3
ations led us to investigate the Cacchi reaction (Scheme 2).6
This sequential process involves (a) the formation of the
o-alkynylaniline by Sonogashira coupling,7 (b) acylation with
trifluoroacetic anhydride, and (c) cyclization to form the
pyrrole ring by aminopalladation and reductive elimination.
The major advantage of this method is that the regioselec-
tivity follows from the sequence of events and is unambigu-
ous. The process conditions for each step should be mild,
which is desirable in view of the thermal lability of many
indole compounds. The drawbacks include the extensive use
of costly palladium catalyst, as well as the multistep nature
of the operation, which makes this sequence less succinct
than the Larock approach. It would help immensely if the
Sonogashira/protection/Cacchi domino protocol could be
done without isolating the intermediates. Herein we report
a practical one-pot process for the preparation of 2,3-
disubstituted indoles based on Cacchi’s protocol.
Mechanistically, it is possible but not trivial to conduct
the Sonogashira coupling and the aminopalladation under
the same conditions. To achieve the successful execution of
this catalytic process in one pot, it is essential to start with
N-protected aniline to allow the subsequent cyclization in
situ.6a However, one must be able to avoid the ready
cyclization of o-alkynylanilines to 2-substituted indoles, a
reaction that is likely to be competitive especially before the
RPdX species has been added. Therefore, one prerequisite
is to identify proper reaction conditions that would prevent
examined, including the base, solvent, temperature, and
ligand. The results are summarized in Table 1.
The effects of base and solvent were first evaluated. With
use of KOAc or K2CO3 in DMF, the Sonogashira coupling
of 1a and phenylacetylene was complete at 50 °C in 1 h.
However, conversion of 2a into 3 did not occur at the same
temperature after prolonged times (Table 1, entries 1 and
3). In contrast, in the presence of n-Bu4NOAc, conversion
of 2a into 3 proceeded at 50 °C, giving 3 and 4 in the ratio
of 68/32 (Table 1, entry 2). Using a combination of tetra-
methylguanidine (TMG) and n-Bu4NOAc as bases, 2 was
converted into 3 within 1 h at 100 °C, but the ratio of 3 vs
4 decreased (Table 1, entry 4). Similarly, with n-Bu4NOAc
as base, the Sonogashira coupling of 1b with phenylacetylene
was complete in 19 h at ambient temperature, while the
conversion of 2b into 3 took 7 h at 60 °C, affording 3 and
4 in a 70:30 ratio (Table 1, entry 5). Interestingly, it was
found that by using a combination of n-Bu4NOAc and
(8) (a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.
Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Pe´rez, M.; Garc´ıa-
Mart´ın, M. A.; Gonza´lez. M. J. Org. Chem. 1996, 61, 5804.
(9) Reaction with 5 mol % CuI, Pd(Ph3P)2Cl2, and TMG as base in DMF
gave the 2-monosubstituted indole as the major product. Extensive
dimerization of the alkyne was observed by using 5 mol % CuI, Pd(Ph3P)2-
Cl2, and K2CO3 as base in DMF.
(4) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina, V.;
Senanayake, C. H. Org. Lett. 2004, 6, 4129.
(5) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(6) (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33,
3915. (b) For a recent review, see: Battistuzzi, G.; Cacchi, S.; Fabrizi, G.
Eur. J. Org. Chem. 2002, 2671.
(7) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter
5. (b) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D. Application of
Transition Metal Catalysts in Organic Synthesis; Springer-Verlag: Berlin,
Germany, 1998; Chapter 10. (c) Rossi, R.; Carpita, A.; Bellina, F. Org.
Prep. Proced. Int. 1995, 27, 127. (d) Sonogashira, K. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 3,
Chapter 2.4.
(10) (a) Zhang, G. Synlett 2005, 619. (b) Liang, B.; Dai, M.; Chen, J.;
Yang, Z. J. Org. Chem. 2005, 70, 391. (c) Alami, M.; Ferri, F.; Linstrumelle,
G. Tetrahedron Lett. 1993, 34, 6403. (d) Nguefack, J.; Bolitt, V.; Sinou,
D. Tetrahedron Lett. 1996, 37, 5527. (e) Herrmann, W. A.; Bohm Volker,
P. W. Eur. J. Org. Chem. 2000, 22, 3679. (f) Fukuyama, T.; Shinmen, M.;
Nishitani, S.; Sato, M.; Ryu, I. Org. Lett. 2002, 4, 1691. (g) Pal, M.;
Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R. Synlett 2002, 12, 1976.
(h) Alonso, D.; Najera, C.; Pacheco, M. C. Tetrahedron Lett. 2002, 43,
9365. (i) Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P. Tetrahedron Lett.
2002, 43, 6673. (j) Uozumi, Y.; Kobayashi, Y. Heterocycles 2003, 59, 71.
(k) Ma, Y.; Song, C.; Jiang, W.; Wu, Q.; Wang, Y.; Liu, X.; Andrus, M.
B. Org. Lett. 2003, 5, 3317. (l) Soheili, A.; Albaneze-Walker, J.; Murry, J.
A.; Dormer, P. G.; Hughes, D. L. Org. Lett. 2003, 5, 4191.
3272
Org. Lett., Vol. 8, No. 15, 2006

Table 1. Synthesis of 2,3-Disustituted Indoles via the One-Pot,
Three-Component Reaction of 1a,b, Phenylacetylene, and
Bromobenzenea
Table 2. Synthesis of 2,3-Disustituted Indoles via the One-Pot,
Three-Component Sonogashira-Cacchi Domino Reactiona
T1/t1;
T2/t2
entry substr.
ligand
Ph3P
base
KOAc
solvent (°C/h)
2/3/4b
1
2
3
4
1a
1a
1a
1a
DMF
50/1;
50/17
50/1;
50/17
50/1;
50/17
50/1;
100/1
90/0/10
(3 equiv)
Ph3P
Ph3P
Ph3P
nBu4NOAc DMF
(3 equiv)
0/68/32
56/0/44
0/58/42
K2CO3
DMF
(3 equiv)
TMG
DMF
(2 equiv) +
nBu4NOAc
(1.5 equiv)
5
6
1b
1b
Ph3P
Ph3P
nBu4NOAc DMF
(4 equiv)
22/19
60/7
60/2;
60/19
0/70/30
0/94/6
nBu4NOAc ACN
(3 equiv) +
K2CO3
(3 equiv)
7
8
9
1b
1b
1b
Ph3P
Ph3P
Ph3P
K2CO3
ACN
DMF
50/18
trace
(3 equiv)
K2CO3
(t1 + t2)
60/4.5
0/98/2
(4 equiv)
K2CO3
(t1 + t2) (86)c
DMF- 60/0.5
0/97/3
(4 equiv)
H2O
(20/1)
DMF
(t1 + t2) (93)c
10d
11d
12d
13d
14d
1b
1b
1b
1b
1b
Ph3P
K2CO3
(4 equiv)
60/0.5
0/98/2
(t1 + t2) (91)c
(2-furyl)3P K2CO3
DMF
DMF
DMF
DMF
60/7
0/86/14
(4 equiv)
(t1 + t2)
60/3.3
(t1 + t2)
60/0.5
(p-F-Ph)3P K2CO3
(4 equiv)
(p-Tol)3P
complex
0/97/3
K2CO3
(4 equiv)
K2CO3
(t1 + t2) (89)c
(p-Me-
OPh)3P
60/23
0/100/0
(4 equiv)
(t1 + t2) (86)c
a All the reactions were run by mixing 5 mol % Pd(OAc)2, 20 mol %
phosphines, 1.2 equiv of the alkyne, and 1.0 equiv of 1a,b in DMF or ACN
(c ) 0.2 M). 1.2 equiv of bromobenzene was added once the iodoanilide
was consumed completely. b Measured by HPLC at a wavelength of 248
µm. c Solution yields (measured by HPLC). d The reaction was performed
under the same conditions except that bromobenzene was added at the
beginning.
K2CO3 as bases in acetonitrile, the conversion of 1b into
2b, and 2b into 3 at 60 °C was completed in 2 and 19 h,
respectively. In this case, 3 and 4 was obtained in the ratio
of 94:6 (Table 1, entry 6). With K2CO3 as the only base in
acetonitrile, 2b was not formed, probably due to the poor
solubility of K2CO3 in this solvent (Table 1, entry 7). Indeed,
replacing acetonitrile with DMF, the reaction proceeded
smoothly at 60 °C. Formation of 2b was complete in 1.5 h
while the conversion of 2b into 3 took 3 h, providing 3 and
4 in ratio of 98:2 (Table 1, entry 8). The advantage of using
the trifluoroacetyl as the protecting group is the ready
hydrolysis of the product in situ. Addition of small amounts
of H2O, ranging between 1 and 6 equiv, does not affect the
reaction rate or the product ratio (Table 1, entry 9) and effects
the desired hydrolysis.
a Method A: The reactions were run by mixing 5 mol % Pd(OAc)2, 20
mol % Ph3P, 1.2 equiv of the alkyne, 1.2 equiv of the aryl bromide, and
1.0 equiv of the anilide in DMF (c ) 0.2 M) at 60 °C. Method B: The
reactions were run by adding 1.2 equiv of arylbromide after the iodoanilide
was consumed completely. b Solution assays (HPLC).
On the basis of these initial results, it was concluded that
the optimal conditions for this one-pot process include the
following: (a) use of trifluoroacetyl as the protecting group
of the nitrogen, (b) use of K2CO3 as base and DMF as
solvent, and (c) reaction temperature of 60 °C. Alternatively,
the process can be performed in acetonitrile by using the
combination of n-Bu4NOAc and K2CO3 as bases.
To further simplify the procedure, bromobenzene was
added from the beginning, in a one-pot reaction, thus
eliminating the need to monitor the progress of the Sono-
gashira coupling before proceeding to the next step. Surpris-
Org. Lett., Vol. 8, No. 15, 2006
3273

ingly, the overall reaction rate is significantly enhanced
(Table 1, entry 10) and Sonogashira reaction of the bro-
mobenzene is not a problem. The mechanism for this
accelerating effect is not yet understood. Several other lig-
ands were briefly evaluated for comparison (Table 1, entries
11-14). Electron-deficient ligands appear to slow the
formation of the desired product, mainly due to inefficient
Cacchi cyclization. The reaction can be extended to a variety
of aryl halides. In the coupling with aryl bromides containing
electron-withdrawing fuctionalities, the sequential procedure
was applied, to avoid competing oxidative addition of the
latter. To evaluate the scope of this one-pot process, a variety
of indoles were synthesized. The results are summarized in
Table 2. In all cases examined, excellent yields were
obtained. The reaction times described in the table reflect
closely the reaction rate in each case since all the reactions
were carefully monitored.
p-tolylacetylene, the Sonogashira coupling was very sluggish
under the same conditions and resulted in the formation of
unidentified side products. In this case, by using Cs2CO3 as
base in place of K2CO3, the reaction proceeded cleanly in
3.5 h, and in 83% yield (entry 4, Table 2). With an electron-
withdrawing group at the para position of the iodide, the
Sonogashira coupling, as well as the whole reaction, took
longer (entries 5 and 6, Table 2).
In addition, when a nitrile group was present at the para
position of the amide, the cyclization became extremely
sluggish due to the decreased nucleophilicity of the nitrogen
toward Pd(II) (entries 8-10, Table 2).
In summary, we have developed a practical and economi-
cal one-pot process for synthesis of 2,3-disubstituted indoles
based on Cacchi’s original protocol. This Pd-catalyzed
domino indolization procedure allows rapid access to a
variety of 2,3-disubstituted indoles regiospecifically under
fairly mild conditions.
Substitutions on all three components have an effect on
the reaction rate. The one-pot coupling of the 2-iodoanilide
1b with phenylacetylene and 4-bromoanisole is complete
within 1 h to give 5 in 60% solution yield, while the same
reaction with methyl (4-bromo)benzoate is complete in 2.5
h, affording 6 in 85% yield (entries 2 and 3, Table 2). With
Supporting Information Available: Experimental pro-
cedures and physical data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061136Q
3274
Org. Lett., Vol. 8, No. 15, 2006