2,3-disubstituted indoles via palladium-catalyzed reaction of 2-alkynyltrifluoroacetanilides with arenediazonium tetrafluoroborates

Article abstract of DOI:10.1021/ol101321g

(Figure Presented) A novel palladium-catalyzed synthesis of free N-H 2,3-disubstituted indoles from arenediazonium tetrafluoroborates and 2-alkynyltrifluoroacetanilides is presented. The reaction tolerates a variety of useful substituents both in the starting alkyne and the arenediazonium salt, including bromo and chloro substituents, nitro, cyano, keto, ester, and ether groups, as well as ortho substituents such as methoxy and methyl groups.

Full text of DOI:10.1021/ol101321g

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3279-3281
2,3-Disubstituted Indoles via
Palladium-Catalyzed Reaction of
2-Alkynyltrifluoroacetanilides with
Arenediazonium Tetrafluoroborates
Sandro Cacchi,*,† Giancarlo Fabrizi,† Antonella Goggiamani,† Alcide Perboni,‡
Alessio Sferrazza,† and Paolo Stabile‡
Dipartimento di Chimica e Tecnologie del Farmaco, La Sapienza, UniVersita` di Roma,
P.le A. Moro 5, 00185 Rome, Italy, and Chemical DeVelopment Department,
GlaxoSmithKline, Via Fleming 4, 37135 Verona, Italy
sandro.cacchi@uniroma1.it
Received June 9, 2010
ABSTRACT
A novel palladium-catalyzed synthesis of free N-H 2,3-disubstituted indoles from arenediazonium tetrafluoroborates and 2-alkynyltrifluoro-
acetanilides is presented. The reaction tolerates a variety of useful substituents both in the starting alkyne and the arenediazonium salt,
including bromo and chloro substituents, nitro, cyano, keto, ester, and ether groups, as well as ortho substituents such as methoxy and
methyl groups.
We have recently found that the palladium-catalyzed reaction
of arenediazonium salts with alkynes in the presence of
Scheme 1
R3SiH gives hydroarylation products.1 This reaction, the first
application of alkyne-based palladium chemistry of arene-
diazonium salts,2 proceeds via carbopalladation intermediates
B, very likely preceded by π-alkyne-σ-arylpalladium com-
plexes A (Scheme 1).
As π-alkyne-σ-arylpalladium complexes containing a
proximate nitrogen nucleophile can undergo an intramolecu-
lar nucleophilic attack across the carbon-carbon triple bond
activated by coordination to palladium,3 we were attracted
by the idea of using 2-alkynyltrifluoroacetanilides as the
palladium-catalyzed synthesis of functionalized indoles 34
starting alkynes to involve arenediazonium salts in a new
via an aminopalladation/reductive elimination process (Scheme
† Universita` di Roma.
2).3 This approach might provide an exceedingly useful tool
‡ GlaxoSmithKline.
(1) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Persiani, D. Org. Lett. 2008,
for appending indole rings to aniline fragments. We show
here that such a transformation is possible and report the
first utilization of arenediazonium salts in the construction
of the functionalized pyrrole nucleus incorporated into indole
systems.
10, 1597.
(2) For a review on the palladium-catalyzed chemistry of arenediazonium
salts, see: Roglans, A.; Pla-Quintana, A.; Moreno-Man˜as, M. Chem. ReV.
2006, 106, 4622.
(3) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002,
2671.
10.1021/ol101321g  2010 American Chemical Society
Published on Web 06/22/2010

and iodide anions on the reaction outcome (Table 1). The
best result was obtained by increasing the TBAI:1a ratio to
2:1 (entry 3). Unsatisfactory results were obtained using
Pd(OAc)2 (entry 9) or Pd2(dba)3, with or without PPh3
(entries 10 and 11), as well as decreasing the reaction
temperature (entries 4 and 5). K2CO3 proved superior to
Cs2CO3 or K3PO4 (entry 3 vs entries 12 and 13, respectively).
However, we subsequently found that using Cs2CO3 affords
slightly higher or similar yields in some cases (Table 2,
entries 2 and 4 vs entries 3 and 5, respectively). Therefore,
it seems advisible that the effectiveness of the bases be
evaluated each time. Substituting NaI for TBAI produced
3a in low yield (entry 6), and the use of KI in the presence
of catalytic amounts (entry 7) or 1 equiv (entry 8) of TBAI
proved unsuccessful as well.
Scheme 2
We set out to use the reaction of 1a with 2a as a probe
for evaluating the feasibility of the reaction. First attempts,
however, met with failure. For example, complex mixtures
(which we did not further investigate) were obtained under
conditions commonly used with vinyl triflates,5 aryl iodides,5
bromides,6 and triflates6 [Pd(PPh3)4, K2CO3, MeCN], and no
indole formation was observed. We envisaged that 2,3-
disubstituted indoles might be accessible by reacting arene-
diazonium tetrafluoroborates with 2-alkynyltrifluoroaceta-
nilides in the presence of TBAI provided that a iododediazoni-
ation reaction7 generating “ArPdI” species could be achieved
under the reaction conditions.
The optimal reaction conditions were then employed when
the reaction was extended to other arenediazonium salts and
2-alkynyltrifluoroacetanilides (Table 2). The corresponding
indole derivatives were isolated in good to excellent yields
with a variety of neutral and electron-rich arenediazonium
salts. With electron-poor arenediazonium salts similar or
better results could be obtained when a TBAI:1 1.5:1 ratio
was used (entries 4 and 5 vs entry 6). The reaction tolerates
a variety of useful substituents both in the starting alkyne
and the arenediazonium salt component, including bromo
and chloro substituents, nitro, cyano, keto, ester, and ether
groups. The ability to incorporate bromo and chloro sub-
stituents makes this reaction particularly attractive for
increasing the molecular complexity, for example, via
transition metal-catalyzed coupling reactions. Arenediazo-
nium salts containing ortho substituents such as methoxy and
methyl groups also give the corresponding indole products
in good to high yields (entries 10, 12, and 30). Formation of
3-unsubstituted indoles 4 was in some cases observed.
To demonstrate this concept, we treated 2 equiv of 1a with
1 equiv of 2a in the presence of 5 mol % of Pd(PPh3)4 and
2 equiv of K2CO3 in MeCN at 60 °C for 2.5 h using a TBAI:
1a ratio of 1.2:1. Pleasingly, 3a was isolated in 40% yield
along with a 50% yield of 4-iodoanisole, very likely formed
via a iododiazoniation reaction (Table 1, entry 1).
Table 1. Optimization Studiesa
As to the mechanism, we believe that the reaction proceeds
through a domino process that starts with a iododediazonia-
tion step (Scheme 3, path a).8,9 The oxidative addition of
the resultant aryl iodide to Pd(0) affords a σ-arylpalladium
iodide that coordinates to the C-C triple bond to give a
π-alkyne-σ-arylpalladium complex C. A subsequent intramo-
lecular aminopalladation step generates a σ-indolylpalladium
intermediate D from which the desired free N-H indole is
formed via reductive elimination and hydrolysis (not neces-
sarily in this order).3
yield (%)b
temp time
entry
[Pd]
additive (equiv) (°C)
(h)
3a 4a 5ac
1
2
3
4
5
6
7
8
9
Pd(PPh3)4 TBAI (2.4)
Pd(PPh3)4 TBAI (3)
60
60
60
40
50
60
60
60
60
2.5
40
50
19
2.75 52d
Pd(PPh3)4 TBAI (4)
1
12
69
Pd(PPh3)4 TBAI (4)
e
Pd(PPh3)4 TBAI (4)
3.45 52f
45
Pd(PPh3)4 NaI (2.2)/I2 (0.2)
Pd(PPh3)4 KI (4)/ TBAI (0.2)
Pd(PPh3)4 KI (4)/ TBAI (1)
Pd(OAc)2 TBAI (4)
3.5
30 11 58
2.75 20 35 45
3.25 32 19 49
The intervention of an alternative mechanism involving
the formation of σ-arylpalladium iodides through the reaction
of σ-arylpalladium cations E with iodide anions (Scheme 3,
path b) appears less likely. This view is supported by the
observation that no indole formation was observed when 1a
and 2a were subjected to the best conditions found substitut-
ing TBACl for TBAI, even prolonging the reaction time to
6 h (2a was recovered in 76% yield). If σ-arylpalladium
chlorides were generated via trapping of E10 with chloride
anions, the known reluctance of aryl chlorides to undergo
oxidative addition reactions with palladium catalysts coor-
dinated to triphenylphosphine11 should be circumvented and
indoles should form to some extent.
5
13 42 27
Pd2(dba)3,
d
10
11
12
13
PPh3
TBAI (4)
60
60
60
60
3
38g 13 42
Pd2(dba)3 TBAI (4)
Pd(PPh3)4 TBAI (4)
Pd(PPh3)4 TBAI (4)
4.25 48
30
58h tr 30
50i
35
1
5
6
a Unless otherwise stated, reactions were carried out at 60 °C on a 0.35
mmol scale using 2 equiv of 1a, 1 equiv of 2a, 2 equiv of K2CO3, and 5
mol % of [Pd] in 3 mL of anhydrous MeCN in the presence of a iodide
source. b Yields are given for isolated products. c Calculated on 1a. d 1.5
equiv of 1a was used. e At 40 °C. f At 50 °C. g 4 equiv of PPh3. h In the
presence of 2 equiv of Cs2CO3. i In the presence of 2 equiv of K3PO4.
We then started an optimization study to explore the
influence of bases, temperature, the source of Pd(0) species,
3280
Org. Lett., Vol. 12, No. 14, 2010

Scheme 3
Table 2. Synthesis of Free N-H 2,3-Disubstituted Indoles 3 via
Palladium-Catalyzed Reaction of Arenediazonium
Tetrafluoroborates 1 with 2-Alkynyltrifluoroacetanilides 2a
ides has been developed. The new method tolerates a variety
of useful functional groups both in the alkyne and in the
arenediazonium salt component, including bromo and chloro
substituents, nitro, cyano, keto, ester, and ether groups, as
well as ortho substituents.
Acknowledgment. We gratefully acknowledge MURST
and the University “La Sapienza” for financial support.
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101321G
(4) For recent reviews on the palladium chemistry of indoles, see: (a)
Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (b)
Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (c) Cacchi, S.; Fabrizi,
G. Chem. ReV. 2005, 105, 2873. (d) Humphrey, G. R.; Kuethe, J. T. Chem.
ReV. 2006, 106, 2875. (e) Patil, S.; Buolamwini, J. K. Curr. Org. Synth.
2006, 3, 477. (f) Ackermann, L. Synlett 2007, 507. (g) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (h) Kru¨ger, K.; Tillack,
A.; Beller, M. AdV. Synth. Catal. 2008, 350, 2153. (i) Joucla, L.; Djakovitch,
L. AdV. Synth. Catal. 2009, 351, 673.
(5) (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33,
3915. (b) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett
1997, 1363.
(6) Cacchi, S.; Fabrizi, G.; Lamba, D.; Marinelli, F.; Parisi, L. M.
Synthesis 2003, 728.
(7) (a) Barbero, M.; Degani, I.; Dughera, S.; Fochi, R. J. Org. Chem.
1999, 64, 3448. (b) Hubbard, A.; Okazaki, T.; Laali, K. K. J. Org. Chem.
2008, 73, 316.
a Unless otherwise stated, reactions were carried out at 60 °C in 1-5.5
h on a 0.35 mmol scale using 2 equiv (Procedure A) or 1.5 equiv (Procedure
B) of 1, 1 equiv of 2, 2 equiv of K2CO3, 5 mol % of Pd(PPh3)4, 4 equiv
(Procedure A) or 3 equiv (Procedure B) of TBAI in 3 mL of anhydrous
MeCN. b Yields are given for isolated products. c In the presence of Cs2CO3.
d 4r was isolated in 21% yield. e 4t was isolated in 29% yield. f 4z was
isolated in 12% yield.
(8) Fabrizi, G.; Goggiamani, A.; Sferrazza, A.; Cacchi, S. Angew. Chem.,
Int. Ed. 2010, 49, 4067.
(9) Control experiments revealed that arenediazonium salts are quickly
converted into the corresponding aryl iodides in the presence of TBAI. For
example, 4-methoxybenzene tetrafluoroborate is converted to 4-iodoanisole
in 73% yield after 5 min at 60 °C.
(10) Yamashita, R.; Kikukawa, K.; Wada, F.; Matsuda, T. J. Organomet.
Chem. 1980, 201, 463.
(11) Aryl chlorides did not give indole derivatives upon treatment with
2-alkynyltrifluoroacetanilides using Pd(PPh3)4 and Cs2CO3 or K2CO3 in
MeCN even at temperatures as high as 120 °C. Cacchi, S.; Fabrizi, G.;
Goggiamani, A. AdV. Synth. Catal. 2006, 348, 1301.
In conclusion, an efficient approach providing free N-H
2,3-disubstituted indoles in good to high yields from arene-
diazonium tetrafluoroborates and 2-alkynyltrifluoroacetanil-
Org. Lett., Vol. 12, No. 14, 2010
3281