Aminofluorination of 2-alkynylanilines: A Au-catalyzed entry to fluorinated indoles

Article abstract of DOI:10.3762/bjoc.10.42

The scope and limitations of gold-catalyzed tandem cycloisomerization/ fluorination reactions of unprotected 2-alkynylanilines to have access to 3,3-difluoro-2-aryl-3H-indoles and 3-fluoro-2-arylindoles are described. An unprecedented aminoauration/oxidation/ fluorination cascade reaction of 2-alkynylanilines bearing a linear alkyl group on the terminal triple bond is reported.

Full text of DOI:10.3762/bjoc.10.42

Aminofluorination of 2-alkynylanilines:
a Au-catalyzed entry to fluorinated indoles
Antonio Arcadi*1, Emanuela Pietropaolo1, Antonello Alvino2
and Véronique Michelet*3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 449–458.
1Dipartimento di Scienze Fisiche e Chimiche, Università di L’Aquila,
Via Vetoio- 67010 Coppito (AQ), Italy, 2Dipartimento di Chimica,
Sapienza, Università di Roma, P. le A. Moro 5, Roma, Italy and
3Institut de Recherche de Chimie Paris, UMR 8247, Ecole Nationale
Supérieure de Chimie de Paris, Chimie ParisTech, 11 rue P. et M.
Curie, F-75231 Paris Cedex 05, France
doi:10.3762/bjoc.10.42
Received: 05 October 2013
Accepted: 12 February 2014
Published: 20 February 2014
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
Email:
Antonio Arcadi* - arcadi@univaq.it; Véronique Michelet* -
veronique-michelet@chimie-paristech.fr
Guest Editor: F. D. Toste
* Corresponding author
© 2014 Arcadi et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
2-alkynylanilines; fluorination; gold catalysis; indoles; tandem
reactions
Abstract
The scope and limitations of gold-catalyzed tandem cycloisomerization/fluorination reactions of unprotected 2-alkynylanilines to
have access to 3,3-difluoro-2-aryl-3H-indoles and 3-fluoro-2-arylindoles are described. An unprecedented aminoauration/oxidation/
fluorination cascade reaction of 2-alkynylanilines bearing a linear alkyl group on the terminal triple bond is reported.
Introduction
Introducing fluorine atoms into organic molecules still faces lenging [4,5]. The variation of the indole structure has been a
challenges in organic synthesis [1]. Organofluorine compounds field of high interest for a long time, considering the impor-
found growing use in various areas including pharmaceuticals, tance of this skeleton as a ubiquitous skeleton of pharmaceut-
agrochemicals, and materials [2]. A significant proportion of icals and bioactive natural products [6-11]. The synthesis of
pharmaceuticals are fluorinated derivatives because the inclu- 3-substiuted 3-fluorooxindoles has been described in the pres-
sion of fluorine into organic compounds has been shown to ence of Selectfluor as a commercial source of F+, starting from
improve properties such as solubility, bioavailability and meta- 3-substituted indoles, in acetonitrile/water. These derivatives
bolic stability, which are of great importance for the develop- have been used as key adducts for the indole biosynthesis mech-
ment of a large number of viable drug candidates [3]. Finding anism as well as synthetic target for the development of novel
original methodologies for the selective preparation of fluori- medicinal agents [12]. Recently, 7-fluoroindole has been
nated heterocyclic compounds is therefore still highly chal- proposed as a potential candidate for the use in an antivirulence
449

Beilstein J. Org. Chem. 2014, 10, 449–458.
approach against persistent Pseudomonas aeruginosa infections Selectfluor under gold(I) catalysis [34-36] through a cascade
[13]. Fluorine introduction in the benzene moiety of respective cyclization/fluorination process [37]. Following our previous
indoles was accomplished through a variety of methods [14]. work on gold catalysts (Scheme 1) [38], we wish to report
4-Fluoroindole derivatives have been prepared through nucleo- herein a comprehensive study on gold-catalyzed tandem cycloi-
philic attack on intermediate 4-indolediazonium salts [15]. The somerization/fluorination reactions to access 3,3-difluoro-2-
regioselective fluorination of the benzene ring of indole to give aryl-3H-indoles and 3-fluoro-2-arylindoles, putting the stress on
the important neurochemicals 4-fluoroserotonin and 4-fluoro- the scope and limitations of such systems.
melatonin was accomplished by means of a lithiation/fluori-
Results and Discussion
nation sequence [16]. The validity of this latter strategy was
also demonstrated for the fluorination at the 2-position of Optimization of the catalytic system
N-protected indoles by electrophilic fluorinating agents. Our The substrate 2-{[4-(methoxy)phenyl]ethynyl}aniline (1a) was
literature search revealed that the access to C-3 fluorinated selected as a model substrate and was subjected to various
indole derivatives was less investigated. Fluorination of trialkyl- conditions in the presence of Selectfluor as the electrophilic
stannylindole derivatives with cesium fluoroxysulfate or Select- fluorine source. The results are compiled in Table 1. When the
fluor was investigated for the synthesis of the corresponding reaction of 1a was carried out at room temperature with an
3-fluoroindoles [17]. A borane–tetrahydrofuran complex has excess of Selectfluor and water in CH3CN in the absence of any
been used to study the reduction of 3,3-difluoro-2-oxindoles to catalyst (Table 1, entry 1), no desired fluorinated indole was
give the corresponding 3,3-difluoroindoines when electron- detected and degradation of the starting N-unprotected
withdrawing groups were present as substituents in the benzene 2-alkynylaniline 1a was observed, which excludes a fluoro-
nucleus. The 3,3-difluoro-2-oxindoles were prepared by the cyclization according to a direct electrophilic process [39].
reaction of appropriately substituted isatin derivatives with When the same reaction was performed in the presence of
DAST [18]. Anodic fluorination of various N-acetyl-3-substi- [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold
tuted indoles was successfully carried out to provide trans-2,3- (I) catalyst [40] (5 mol %), the formation of the difluorinated
difluoro-2,3-dihydroindoles which upon treatment with a base 3H-indole 2a was observed although in low overall yield
gave monofluoroindole derivatives or monofluoro-3H-indoles (Table 1, entry 2). No traces of C–C bond formation, a competi-
depending on the substituents at the 3-position [19]. More tive pathway in the presence of gold catalysts and Selectfluor
recently, the indole ring was difluorinated highly regioselec- [41-43] were observed. The yield of 2a was increased to 35%
tively at the C-3 carbon site with Selectfluor [20]. The C-3 when the reaction was carried out in the presence of 10 mol %
monofluorinated indole derivatives were supposed to serve as of the gold catalyst (Table 1, entry 3). Various other parameters
intermediates in the transformation and can be isolated under were modified to increase the reaction efficiency. The amount
suitable reaction conditions [21]. We envisaged that the amino- of water played a determinant role in CH3CN as the reaction
fluorination of the ready available o-alkynylaniline derivatives medium (Table 1, entries 3–5). The presence of water is consid-
should provide a viable alternative to the desired C-3 fluori- ered important both as a reagent and for helping the dissolution
nated indoles. Catalytic aminofluorination of alkenes and of Selectfluor in CH3CN. One of the most notable limitations
alkynes is receiving growing attention as efficient way to on the use of Selectfluor is indeed its relative insolubility in
construct fluorinated heterocycles [22,23]. In particular, commonly used organic solvents. Even in MeCN, the solvent of
Au-catalyzed fluorination strategies by using Selectfluor as an choice for many reactions with Selectfluor, its solubility is
electrophilic source of fluorine [24-31] can provide a powerful undesirably low and presents a limitation in its overall use as a
tool for building up nitrogen heterocycle derivatives. Fluori- fluorinating agent. The presence of a minimal amount of water
nated pyrrolidines [32] and fluorinated pyrazoles [33] have been has previously been reported to increase the yield of fluori-
synthesized from 1,ω-N-protected aminoalkynes and alkynyl nation in the 5-position of mono- and nonbrominated
phenylhydrazones, respectively. Propargyl amidines were 2-acylpyrroles with Selectfluor under microwave conditions
converted into 5-fluoromethylimidazoles in the presence of [44]. The presence of larger amounts of water may nevertheless
Scheme 1: Cycloisomerization/fluorination of functionalized indoles.
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Beilstein J. Org. Chem. 2014, 10, 449–458.
Table 1: Cycloisomerization/fluorination of 2-{[4-(methoxy)phenyl]ethynyl}aniline (1a).
Entry
[M] 10 mol %
Selectfluor (equiv)
solvent
t [h]
Yield [%]a
H2O (x equiv)
1
–
2.5
2.5
2.5
2.5
2.5
1
CH3CN (10)
CH3CN (10)
CH3CN (10)
CH3CN (50)
CH3CN (100)
CH3CN (100)
EtOH (0)
3
–
2
Ph3PAuNTf2b
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
AuCl
3
14
35
40
17
37
49
54
75
17
0
3
3
4
3
5
3
6
21
24
1.5
1.5
24
2
7
2.5
2
8
EtOH (100)
EtOH (100)
EtOH (50)
9
3
10
11
12
13
14
15
16
17
18
19
20
21
2
2
1,4-dioxane (100)
acetone (100)
EtOH (100)
EtOH (100)
EtOH (100)
EtOH (100)
EtOH (100)
EtOH (100)
EtOH (100)
EtOH (100)
EtOH (100)
3
2
0
3
2
56
38
45
53
0
AuCl3
3
2
NaAuCl4
3
0.25
2
KAuCl4
3
PdCl2
3
2
PtCl2
3
2
0
CuCl2·2H2O
RuCl3·2H2O
AgNTf2
3
2
0
3
2
0
3
2
0
aIsolated yield. b5 mol %.
speed up the protodeauration of the indolylgold species derived not give the desired difluorinated 3H-indole (Table 1, entries
from the gold-catalyzed aminoauration of 1a to give the 17–21). We selected the PPh3AuNTf2 catalyst as a highly effi-
2-substituted indole [39]. The reaction of 1a was also evaluated cient complex and the cheaper NaAuCl4·2H2O catalyst and
in various solvents and proceeded nicely in EtOH compared to decided to confront their reactivity to various substrates.
MeCN, 1,4-dioxane, and acetone (Table 1, entries 9, 11, and
12).
We selected some derivatives (1a–e, 1g, 1i and 4a,b) from
literature [38,39,45-51] and synthesized them together with new
In the presence of EtOH, we were pleased to find that the functionalized 2-alkynylanilines to evaluate the efficiency of the
desired adduct 2a was isolated in 75% yield (Table 1, entry 9). gold catalytic system.
The addition of NaHCO3 [20,33] as a base to the reaction mix-
ture failed to give 2a, whereas it was successful for the prepar- Scope and limitations of the catalytic system
ation of fluorinated pyrazole, via the gold(I)-catalyzed tandem The prepared 2-substituted anilines were then engaged in the
aminofluorination of 1-phenyl-2-(4-phenylbut-3-yn-2- cycloisomerization/fluorination process in the presence of the
ylidene)hydrazine. Other gold catalysts such as gold(III) species Au(I) cationic catalyst or the Au(III) catalyst (Table 2, condi-
presented interesting results for the reaction beside lower yield tions A and B). The anilines 1b–1f were subjected to condi-
than gold(I) catalyst (Table 1, entries 14–16 vs entries 9 and tions A and B at room temperature or refluxing ethanol. Under
13). Other transition metal catalysts such as PdCl2, PtCl2, conditions A, the NaAuCl4·2H2O catalyst operated smoothly
CuCl2·2H2O, RuCl3·2H2O, or AgNTf2 were also tested, but did and Selectfluor (3 equiv) was added when full conversion of the
451

Beilstein J. Org. Chem. 2014, 10, 449–458.
Table 2: Cycloisomerization/fluorination reaction of 2-substituted anilines.
Entry
Aniline
t [h]
Cond.
T
Product
Yield [%]a
1
1
A
reflux
60
2b
1b
1b
2
3
0.75
B
A
reflux
74
83
2b
2c
24
rt
1c
4
1.5
B
rt
57
2c
1c
1d
1d
5
6
43
A
B
rt
76
85
2d
0.75
reflux
2d
2e
7
24
A
rt
67
1e
452

Beilstein J. Org. Chem. 2014, 10, 449–458.
Table 2: Cycloisomerization/fluorination reaction of 2-substituted anilines. (continued)
8
2
B
reflux
40
2e
1e
9
3
2
A
B
A
B
reflux
reflux
reflux
reflux
61
2f
1f
10
11
65
2f
1f
24
–
2g
1g
1g
12
1
–
2g
aIsolated yield.
gold(III)-catalyzed cyclization of 1 was observed. The use of occurred and the starting material was recovered. A complex
the cationic PPh3AuNTf2 complex allowed in situ addition of reaction mixture was obtained by reacting 1g in EtOH at reflux
Selectfluor. Both catalytic systems were efficient and depending for 1 h with an excess of Selectfluor (3 equiv) in the presence of
on the substrate higher yields were obtained either in the pres- Ph3PAuNTf2 catalyst (Table 2, entry 12).
ence of the Au(III) or Au(I) catalyst. The difluoro derivatives
2b–f were isolated in moderate to very good yields. In the case The case of aniline 1h was particularly interesting as it showed
of substrates 2b or 2d bearing an o-substituent group in the aryl that ethanol was not a fully inert solvent (Scheme 2, reaction 1).
moiety, better yields of these desired cyclized and functional- Indeed, when reacting aniline 1h substituted with electron-with-
ized derivatives were observed in ethanol at reflux (Table 2, drawing groups on both the aniline and the aryl moiety under
entries 1/2 and comparison of 5 vs 6). The reaction conditions Au(III) conditions, the desired product 2h was accompanied by
were compatible with a halogen substituent such as in 2e the hemiaminal difluoroadduct 3h, which was isolated in 56%
(Table 2, entries 7 and 8), which was obtained in up to 67% yield. The isolated 3h spontaneously decomposed to give
yield. Gratifyingly the presence of 4-substituted 1H-pyrazole quantitatively 2h. A similar trend was observed in the case of
allowed the clean formation of the corresponding difluoro- tosyl-protected aniline 4a (Scheme 2, reaction 2). The reaction
adduct 2f in good isolated yields (Table 2, entries 9 and 10). of the latter compound led to the formation of difluoro hemi-
One limitation was found when 2-substituted pyridylalkyne 1g aminal 5a in 42% yield. Interestingly a novel derivative 6a was
was subjected to conditions A (Table 2, entry 11). No reaction also isolated in 14% yield. We also tested the reactivity of
453

Beilstein J. Org. Chem. 2014, 10, 449–458.
Scheme 2: Synthesis of hemiaminal derivatives.
trifluoroacetyl-protected aniline 4b, but no cyclization occurred Supporting Information File 1), in 39% yield. Pleasingly, the
and the starting material was recovered. In the case of the tolyl- monofluoro derivative 8i was isolated in 25% yield by conduct-
substituted alkyne 4c, the difluorinated product 5c was the only ing the same reaction at 50 °C and in the presence of a lower
isolated derivative in moderate 54% yield (Scheme 2, reaction amount of Selectfluor.
3).
The mechanism for the formation of 7 (Scheme 4) may imply
We also envisaged evaluating the influence of the alkynyl amino-auration of the alkyne 1i to generate the indolyl–Au
substituent of the aniline moiety. For this purpose, the Au(III)- complex I according to the results observed in the tandem
catalyzed cycloisomerization/fluorination process was tested on aminopalladation/oxidation process of azidoalkynes [52]. Then
n-alkyl-substituted derivative 1i (Scheme 3). The reaction the C–Au bond is oxidized by Selectfluor [53-57] and would
conducted at room temperature led to the (E)-2-(1-fluorohexyl- give the 2-hexyl-3H-indol-3-one (9). The formation of this
idene)indolin-3-one (7), whose structure and stereochemistry latter derivative by the oxidation of 2-hexyl-1H-indole [58-62]
was confirmed by 1H NMR and NOESY experiments (see or 3-fluoro-2-hexyl-1H-indole (8i) [63] cannot be ruled out. The
Scheme 3: Reaction on n-hexyl-substituted derivative 1i.
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Beilstein J. Org. Chem. 2014, 10, 449–458.
Scheme 4: Mechanism rationale for the formation of 7.
following fluorination [64-67] of 9 led to 2-(1-fluorohexyl)-3H- indoles. We found that the cyclization of various unprotected
indol-3-one (10), which tautomerizes to accomplish the stereo- anilines in acetonitrile followed by one-pot addition of Select-
selective formation of 7.
fluor in DMSO allowed the clean formation of monofluori-
nated derivatives and results are collected in Table 3.
Considering the reactivity of anilines 1a–1i in the presence of
NaAuCl4·H2O complex in ethanol and the formation of 8 in the With the optimal reaction conditions in hand, the substrate
presence of 1 equivalent of Selectfluor, we decided to modify scope was examined. In the presence of the electron-rich
our initial procedure to selectively prepare 3-fluoro-2-aryl- aromatic groups on the terminal triple bond the desired prod-
Table 3: Cycloisomerization/fluorination reaction of 2-alkynyl-substituted anilines.
Entry
Aniline
t [h] step a/b
Product
Yield [%]a
1
1.5/1
41
8a
1a
1b
2
3
0.2/3
37
55
8b
8c
1/1
1c
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Beilstein J. Org. Chem. 2014, 10, 449–458.
Table 3: Cycloisomerization/fluorination reaction of 2-alkynyl-substituted anilines. (continued)
4
0.3/1
20b
8f
1f
1i
5
6
3/4
40
8i
1.5/6
85
8j
1j
aIsolated yield. b40% of 2f was also isolated.
ucts were isolated in moderate yields (Table 3, entries 1–3). In
the presence of the 1H-pyrazolyl moiety the difluorination
prevailed over the monofluorination process (Table 3, entry 4).
With the 2-alkynylanilines bearing a linear alkyl group on the
terminal triple bond, better results were observed in the pres-
ence of electron withdrawing groups in the aromatic ring of the
aniline framework (Table 3, compare entry 5 with entry 6). It’s
noteworthy that the preparation of 3-fluoroindoles is quite chal-
lenging. Because of overoxidation, the isolation of 3-fluoroin-
doles from 2-alkynylanilines has been reported to fail to occur
[52] using previously developed silver catalysts [68]. In our
cases, the fluorination reactions were conducted at 0 °C to avoid
overoxidation processes.
Supporting Information
Supporting Information File 1
Experimental.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-42-S1.pdf]
Acknowledgements
This work was supported by Università dell'Aquila, the
Ministère de l’Education et de la Recherche and the Centre
National de la Recherche Scientifique (CNRS). Johnson
Matthey Inc. is acknowledged for a generous loan of AuCl3,
PdCl2 and PtCl2.
Conclusion
References
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2-alkynylanilines.
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