The p-toluenesulfonic acid-catalyzed transformation of polyfluorinated 2-alkynylanilines to 2-aminoarylketones and indoles

Article abstract of DOI:10.1016/j.tetlet.2015.07.078

The reactivity of a series of polyfluorinated 2-alkynylanilines with various alcohols using p-TSA has been studied. It was found that hydration of the triple bond gave rise to polyfluorinated 2-aminoarylketones and competed with an electrophilic heterocyc

Full text of DOI:10.1016/j.tetlet.2015.07.078

Accepted Manuscript
The p-toluenesulfonic acid-catalyzed transformation of polyfluorinated 2-alky-
nylanilines to 2-aminoarylketones and indoles
Larisa Politanskaya, Vitalij Shteingarts, Evgeny Tretyakov, Alexander Potapov
PII:
S0040-4039(15)01253-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.078
TETL 46567
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
9 June 2015
15 July 2015
29 July 2015
Please cite this article as: Politanskaya, L., Shteingarts, V., Tretyakov, E., Potapov, A., The p-toluenesulfonic acid-
catalyzed transformation of polyfluorinated 2-alkynylanilines to 2-aminoarylketones and indoles, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.07.078
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1
Tetrahedron Letters
The p-toluenesulfonic acid-catalyzed transformation of polyfluorinated 2-
alkynylanilines to 2-aminoarylketones and indoles
Larisa Politanskaya a,, Vitalij Shteingarts a,†, Evgeny Tretyakova,c and Alexander Potapovb,c
a N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Ak. Lavrentiev Avenue 9, 630090 Novosibirsk,
Russian Federation
b Boreskov Institute of Catalysis, Siberian Branch of Russian Academy of Sciences, Ak. Lavrentiev Avenue 5, 630090 Novosibirsk, Russian Federation
c Novosibirsk State University, Pirogova Street, 2, 630090 Novosibirsk, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reactivity of a series of polyfluorinated 2-alkynylanilines with various alcohols using p-TSA
has been studied. It was found that hydration of the triple bond gave rise to polyfluorinated 2-
aminoarylketones and competed with an electrophilic heterocyclization reaction leading to
polyfluorinated indoles. The dependence of the reaction pathways on the nature of the
alkynylaniline substituents has been examined.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
p-TSAcatalyzed hydration
Polyfluorinated 2-alkynylanilines
Polyfluorinated 2-aminoarylketones
Polyfluorinated indoles
The catalyzed addition of water to alkynes (hydration) is one
of the most convenient methods to construct a carbon-oxygen
bond and generate valuable carbonyl compounds with high atom
economy.1 There are several different synthetic protocols for
triple bond hydration. The mercury(II) assisted hydration of
alkynes, first described by Kucherov,2 has become one of the
classical synthetic procedures. In recent years, with increasing
demand for the use of less toxic metal catalysts, new methods for
alkyne hydration have been developed including those catalyzed
group on the o-position of the aromatic ring may compensate for
the effect of these acceptors. Finally, there is scarce evidence that
o-alkynylanilines undergo acid-catalysed cyclization to form
indoles.21 It has also been reported17 that, contrary to other
substrates, diarylalkynes containing a methoxy– or thiomethyl
substituent at the o-position in the presence of p-TSA do not
produce arylketones and instead undergo electrophilic cyclization
to produce benzofuran and benzothiophene derivatives.
Therefore, it is difficult to predict the result of the conversion of
polyfluorinated 2-alkynylanilines in an acidic medium.
by
Au–PPh2–PMO(Ph)
(PMO – periodic
mesoporous
organosilicas),3 cobalt(III) porphyrin complexes,4 Pd(II)–CuCl2–
O2,5 Sn/HCl(aq),6 and SnCl2.7 At the same time, alternative metal-
free protocols have been disclosed based on the use of Brønsted
acids such as HCl,8 H2SO4,9 HCO2H,10–12 MsOH,13 TfOH or
Tf2NH,14 and p-TSA.15 The use of p-TSA is perhaps the most
attractive, as it was reported16,17 that substituted alkynes in
aqueous or alcohol solvents underwent hydration to afford
carbonyl compounds in good to excellent yields. This procedure,
which afforded only Markovnikov adducts, is characterized by
the mildness of the acidic conditions and excellent regio– and
chemoselectivity. For these reasons, p-TSA was chosen for the
hydration of a previously obtained18 series of polyfluorinated 2-
alkynylanilines. This series was thought to be interesting,
because, on the one hand, accumulation of electron-withdrawing
fluorine atoms on the aromatic ring should prevent hydration,
especially in case of benzo-perfluorinated o-alkynylanilines. On
Thus, the aim of the present work was to examine the
reactivity of benzo-polyfluorinated 2-alkynylanilines in various
alcohols using p-TSA.
Previously reported polyfluorinated 2-iodoanilines 1(a–e)18
were cross-coupled with terminal alkynes 2(a–с) to give the
required polyfluorinated o-alkynylanilines 3(a–e)(a–с).18 The
crude products 3 were heated at reflux in various alcohols in the
presence of p-TSA (Scheme 1). To optimize the reaction
conditions, a large series of experiments were carried out in which
the solvent, catalyst loading and reaction time were sequentially
varied for each substrate. In each case, the reaction was terminated
after 19F NMR signals belonging to the starting compounds had
completely disappeared. The data on the optimized experimental
conditions and the yields of the products formed are summarized in
Table 1.
the other hand, the presence of the electron-donating amino
———
 Corresponding author. Tel.: +7-383-330-6859; fax: +7-383-330-9752; e-mail: plv@nioch.nsc.ru
†
Deceased

2
Tetrahedron Letters
Scheme 1. Synthesis of polyfluorinated 2-aminoarylketones 4 and indoles 5.
Table 1. The p-TSA–catalyzed transformation of 2-alkynylanilines 3 into 2-aminoarylketones 4 and indoles 5 in AlkOHa
p-TSA AlkOH,
Product
Ketone
Product
Indole
Entry
1
Substrate
Time (h)
Yieldb (%)
Yieldb (%)
(equiv)
Alk =
2
Et
7
60
12
2
3
2
2
2
Et
Et
Et
5
62
48
57
12
33
4
5
2
Bu
23
52
32
6
7
1
2
Et
Et
8
13
30
20
8
2
2
2
Me
Et
16
7
67
56
64
9
10
Bu
20
11
12
2
1
Et
6
25
62
Me
20
13
14
2
5
Et
Et
5
27
45
62
6
15
16
2
2
2
Me
Et
40
20
8
31
54
78
14
17
Bu

3
a Reaction conditions: 2-alkynylanilines 3 (2 mmol), p-TSA (2–10 mmol), AlkOH (25 mL), reflux.
b Isolated yield over 2 steps from iodoanilines 1(a–e).
not observed when the same reaction was carried out in MeOH
(Entry 15), however the yield of the corresponding ketone 4dd was
significantly reduced in comparison to the yield of ketone 4de
(Entry 16) due to thickening of the reaction mixture. Interestingly,
other tetrafluoro-substituted substrates 3d(a,b) gave only the
heterocyclisation products in good yields (Entries 4, 9). The
marked tendency of the highly deactivated substrates containing
the CH2OTHP-group (or rather the CH2OAlkgroup, formed in
situ) to form carbonyl compounds was most apparent in the case of
compound 3ec (Entry 17). This compound possessed low reactivity
and, therefore, remained unchanged at reflux in MeOH and EtOH
in presence of p-TSA. However, using more forcing conditions
(boiling BuOH) gave ketone 4ef in 78% yield. o-Alkynylaniline
3ea, bearing an alkyl substituent at the triple bond reacted
similarly, to form the corresponding ketone (Entry 5). However,
in the case of the related phenyl–substituted substrate 3eb, only
indole 5eb was formed in approximately the same yield (Entry
10).
Depending on the reaction conditions, arrangement and
number of fluorine atoms on the aromatic ring, the p-
TSAcatalyzed conversion of o-alkynylanilines 3 led to the
formation of 2-aminoarylketones 4, indoles 5 or a mixture of these
two compounds. The reaction of compounds 3a(ac), containing
two fluorine atoms in p-positions relative to the amino and
acetylene groups in EtOH, produced either a mixture of indoles
5a(a,b) and ketones 4a(a,b) which predominantly contained the
latter compound or solely the corresponding ketone 4ae (Entries 1,
6, 11). The reaction of 3ac was accompanied by a noticeable
thickening of the reaction mixture, and despite the fact that ketone
4ae was the only product, its yield was low (Entries 11).
Deprotection of the THPprotecting group is known to proceed
easily even at room temperature,19 and it is reasonable to assume
that in the case of 3ac (and all related compounds), hydration of the
triple bond was accompanied by alcoholysis of the CH2OTHP
fragment.
Thus, the main conclusion of our work was that the highly
deactivated polyfluorinated o-alkynylanilines could successfully
be involved in acidcatalyzed transformations. Particular sets of
fluorine substituents on the aromatic ring, regioselectively
provide the triple bond hydration products. Especially in this
regard, alkynes 3(a–e)с with R = СН2ОТНР stand out as they
appear to be more prone to the p-TSAcatalyzed hydration
reaction than other substrates. Generally, in the case of substrates
with R = Bu and Ph, the content of the ketone formed decreased or
vanished completely and only the corresponding indole was
formed. According to Table 1, taking into account the product ratio
of 4/5, it can be seen that the activating towards hydration effect
of R decreases in the series (СН2ОAlk > Bu  Ph) for a given set
of substituents on the aromatic ring.
The isomeric o-alkynylanilines 3b(ac), in which both fluorine
atoms were in a m-position relative to the acetylene group gave
only fluorinated indoles 5b(a,b,e) (Entries 2, 7, 13). Notably, in the
case of compound 3bc, the reactivity toward triple bond hydration
was altered by carrying out the reaction in MeOH (Entry 12)
leading to the selective formation of ketone 4bd in 62% yield. In
contrast, the reaction of 3ba in МеОН was very slow and only
10% of the corresponding carbonyl compound (which could not be
isolated) was observed in the reaction mixture after 15 h. When the
reaction of 3bb was conducted in МеОН, after 40 h the conversion
of the starting compound was approximately 50% and the reaction
product in this case was indole 5bb. Thus, in the cases of o-
alkynylanilines 3ba and 3bc, the rates of acidcatalyzed triple
bond hydration and heterocyclisation could be altered in favor of
preferential formation of the carbonyl compounds using MeOH
instead of EtOH.
Analysis of the influence of the location and number of fluorine
atoms on the product ratio of 4/5 revealed the following general
trends. The replacement of a p-hydrogen atom relative to the triple
bond on a fluorine atom increased the ability of the alkynylanilines
to undergo hydration (compare Entries 2 (4/5 = 0/62) and 1
(4/5 = 60/12), 13 (4/5 = 0/27) and 11 (4/5 = 25/0), 14 (4/5 = 6/45) and
16 (4/5 = 54/14)). This could be easily explained by the fluorine
atom being a -donating substituent. As for the other positions on
the aromatic ring, a cumulative effect of fluorine atoms was
present. The acceptor influence of the substituents on the
alkynylaniline increases as the number of fluorine atoms increases,
and this effect prevents the hydration reaction. In terms of the
influence of the number of fluorine atoms on the preference for the
formation of the carbonyl compounds, rather than the cyclization
products, the substrates can be arranged in the following order
(Figure 1).
However, for the trifluoro-substituted compounds 3c(ac)
containing a fluorine atom in the o-position relative to the
acetylene group, the reaction was always in favor of
heterocyclization, even when performing the reaction in MeOH
(Entries 3, 8, 14). Moreover, the accumulation of the deactivating
effect of the fluorine atoms was responsible for a significant
increase of the time required for reaction completion: 62 h in the
case 3cc even when using 2.5 times more catalyst.
The reaction time was significantly reduced by the introduction
of a fourth fluorine atom in the p-position relative to the acetylene
group (Entry 16) in spite of a lower amount of catalyst when
compared to Entry 14. It is noteworthy that the predominant
reaction product in this case was ketone 4de. Indole formation was
>
>


Figure 1. Relative reactivity of alkynylaniline to the p-TSAcatalyzed hydration reaction.
The proposed mechanism for the formation of 2-
aminoarylketones 4 and indoles 5 is shown in Scheme 2. Initially,
protonation of alkynylaniline 3 gives the intermediate cations A
and B. The relative stability of these carbocations is determined
by the ability of the substituents to help stabilize the positive
charge. When R is СН2ОAlk or an n-Bu–group, formation of A is
preferred since the vinyl cation intermediate can be stabilized by
the fluorinated aromatic ring. Subsequent addition of the alcohol
gives an enol, which tautomerizes to its more stabilized keto form
4. According to this, it can be seen that two alcohol molecules are
involved in the conversion of the triple bond into a keto–group.
One attacks the vinyl cation to form a substituted oxonium cation,
while the other reacts to give the enol. This reaction mechanism
helps to explain the fact that in MeOH, alkynylanilines 3 were
more prone to the formation of ketones compared to those
performed in EtOH. Moreover, the presented scheme helped

4
Tetrahedron Letters
elucidate the reasons behind the high propensity for hydration of
substituted oxonium cation and the hydroxyl group of the enol,
which should promote the hydration reaction (Scheme 3).
compounds bearing СН2ОAlk–groups. Presumably, these are
capable of forming an intramolecular hydrogen bond with the
Scheme 2. Proposed mechanism for the acid promoted formation of polyfluorinated 2-aminoarylketones 4 and indoles 5.
When R is a phenyl group, formation of B is preferred,
furnishing the five-membered indole. When the total effect of the
fluorine atoms and amino–group makes the substituted aniline a
stronger donor than the phenyl ring, protonation of the triple
bond leads to the formation of intermediate A and carbonyl
compounds (as was the case for 4ab). In all other cases, the
fluorine atoms led to the substituted aniline becoming less
efficient at stabilizing the positive charge than the phenyl ring
making formation of B preferred, giving rise to indoles 5(b–e)b.
The observed p-TSA–catalyzed heterocyclization of the
polyfluorinated 2-phenylethynyl-anilines can be considered as a
selective approach to benzo-polyfluorinated 2-phenylindoles. The
reaction yields are comparable to those obtained by the KOH–
promoted cyclization of polyfluorinated 2-alkynylanilines.19
Academy of Science. The authors thank the Russian Foundation
of Basic Research for financial support (grant 14-03-00108).
Supplementary Material: General methods and procedures,
assigned 1H, 19F 13C and NMR spectral data in table form, copies
of 1H, 19F and 13C NMR spectra. This material is available.
References and notes
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In summary, the purpose of this study was to expand the
applications of the p-TSA–catalyzed hydration of arylalkynes
using a range of polyfluorinated 2-(alkynyl)anilines prepared by
the Sonogashira cross-coupling of the corresponding 2-
iodanilines with terminal alkynes. We have demonstrated the
formation of polyfluorinated 2-aminoarylketones and / or benzo-
polyfluorinated indoles using this reaction.20 It was found that 2-
aminoarylketones were the predominant reaction product when
R = CH2OTHP, while in the cases of R = n-Bu and Ph, indoles
were obtained as the main products. The effect of the substituent
on the triple bond was a more important factor in determining the
path of the reaction, than the fluorine atoms on the aniline ring. A
related phenomenon was observed in the acid–catalyzed
transformation of 1-(2-(phenylethynyl)phenyl)-urea21 where in the
presence of trifluoromethanesulfonic acid, urea derivatives gave
indoles, while use of weaker TFA resulted in protonation of the
other carbon atom of the triple bond to ultimately give the six-
membered quinazolinone.
18. Politanskaya, L. V.; Chuikov, I. P.; Kolodina, E. A.; Shvartsberg,
M. S.; Shteingarts, V. D. J. Fluorine Chem. 2012, 135, 97–107.
19. Politanskaya, L. V.; Chuikov, I. P.; Shteingarts, V. D. Tetrahedron
2013, 69, 8477–8486.
Since the polyfluorinated indole nucleus is a structural
component in a large number of biologically active compounds,
as well as pharmaceuticals,22 the benzo-polyfluorinated indoles
prepared have potential application in terms of their bioactivity.
20. General procedure: Pd(PPh3)2Cl2 (56 mg, 0.08 mmol), CuI (34 mg,
0.18 mmol) and Et3N (3 mL) were added to a stirred solution of
aniline 1 (2 mmol) and alkyne 2 (3 mmol) in MeCN (12 mL) at
room temperature under an argon atmosphere. The reaction
mixture was stirred at 60 °C for 2 h and allowed to cool to room
temperature. Then the mixture was diluted with CH2Cl2 (10 mL),
poured into H2O (40 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were washed with H2O (30 mL) and
dried (MgSO4). Evaporation of the solvent in vacuo gave the crude
product 3 (the 1H and 19F NMR spectra closely agreed with the
Acknowledgments
Analytical and spectral measurements were performed by the
Collective Service Center of the Siberian Branch of the Russian

5
literature18) that was used further without purification. To a
solution of crude 3 in alcohol (25 mL), p-TSA was added, and the
mixture heated at reflux with stirring. The mixture was allowed to
cool to room temperature, diluted with CH2Cl2 (10 mL), poured
into H2O (40 mL) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with H2O (40 mL) and
dried (MgSO4). The solvent was evaporated in vacuo to give: a) a
mixture of products 4 and 5 that were separated and purified by
preparative TLC; b) compound 4 or 5 that was purified by
preparative TLC.
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L.; Tweedie, D. L.; Yeola, S.; Zhao, F.; Ranadive, S.; Robinson, B.

6
Tetrahedron
Highlights
 Synthesis of 9 polyfluorinated 2-aminoarylketones and 12 polyfluorinated indoles.
 The p-TSA–catalyzed reactions of polyfluorinated 2-alkynylanilines in alcohols.
 Hydration of the triple bond and/or an electrophilic heterocyclization reaction.

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The p-toluenesulfonic acid-catalyzed
transformation of polyfluorinated 2-
alkynylanilines to 2-aminoarylketones and
indoles
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Larisa Politanskaya, Vitalij Shteingarts, Evgeny Tretyakov and Alexander Potapov