Metallation of N-vinylpyrroles and -Indoles with Hg(OAc)2: N-vinyl vs. pyrrole nucleophilic sites

Article abstract of DOI:10.1039/c2dt12393b

N-Vinylpyrroles and -indoles bearing electron-withdrawing substituents at the pyrrole ring are mercurated, with 1 equivalent of Hg(OAc)₂ in dry MeCN (20-80 °C), regioselectively at the vinyl group (yields are almost quantitative), while their congeners without electron-withdrawing functions are mercurated both at the N-vinyl group and the pyrrole ring.

Full text of DOI:10.1039/c2dt12393b

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PAPER
Metallation of N-vinylpyrroles and -indoles with Hg(OAc)2: N-vinyl vs.
pyrrole nucleophilic sites†
Boris A. Trofimov,* Andrey V. Ivanov, Igor A. Ushakov, Elena Yu. Schmidt, Lyubov N. Sobenina,
Alexander M. Vasil’tsov and Albina I. Mikhaleva
Received 12th December 2011, Accepted 15th February 2012
DOI: 10.1039/c2dt12393b
N-Vinylpyrroles and -indoles bearing electron-withdrawing substituents at the pyrrole ring are mercurated,
with 1 equivalent of Hg(OAc)2 in dry MeCN (20–80 °C), regioselectively at the vinyl group (yields are
almost quantitative), while their congeners without electron-withdrawing functions are mercurated both at
the N-vinyl group and the pyrrole ring.
media10), of certain interest are the cross-coupling reactions of
1
Introduction
the N-protected mercurated pyrroles (e.g., pyrrolyl mercuric
acetate) with functional olefins to afford the corresponding func-
tionalized C-vinylpyrroles.13 Since recently, N-vinylpyrroles and
-indoles with diverse substituents have become readily available
via the direct reactions of ketones (in the form of their ketox-
imes) with acetylene in the superbasic KOH/DMSO suspensions
(Trofimov reaction).14 This new large group of reactive pyrroles
and indoles proved to be rewarding building blocks and mono-
mers for the design of optoelectronic materials15 and
pharmaceuticals.16
This paper deals with the mercuration of N-vinylpyrroles and
-indoles by Hg(OAc)2 with the aim to (i) evaluate the relative
activity of the two nucleophilic sites: the N-vinyl group and
pyrrole nucleus and (ii) to synthesise a new family of metalated
pyrroles and indoles which are applicable as potent synthetic
starting materials, particularly for the above-mentioned cross-
coupling reactions.17
Pyrrole and indole derivatives play a multifold role in the func-
tionalities of living matter, from solar energy natural converters
(chlorophylls) and oxygen transfer in mammals to fine regulators
of human being activities (hormones).1 In turn, organomercury
compounds are widely used in organic synthesis,2 biochemical
research,3 medicine4 and agriculture.5 In the last three decades,
organomercury compounds have received considerable attention
in the search for versatile reagents in controlled transmetallation
reactions.6 Organomercury(II) derivatives have been successfully
employed to prepare the organometallic compounds of transition
metals as well as main group metals, which are otherwise in-
accessible by classical Grignard and/or lithiation reactions.7
Although the toxicity of mercury compounds should always be
considered, there are recognized benefits, e.g. the possibility to
prepare functionalized organomercury derivatives and achieve
high selectivities of transmetallation reactions.8 Organomercury
haptens were conjugated to chicken immunoglobulin G to give
anti-mercury antibodies exhibiting high activity.9
The combination of pyrrole or indole nuclei with organomer-
cury moieties in a single molecule may lead to the compounds
exhibiting the beneficial properties of both these structural enti-
ties. Meanwhile, the chemistry of mercurated pyrrole and indole
compounds is until now just sporadically explored, causing it to
remain challenging and intriguing. It is well known that the
pyrrole ring is sensitive towards electrophilic attack by mercury
cations,10 although in most cases the structures of the substi-
tution products were not determined exactly.11 It was assumed
that they may be true substitution products or complexes.12 In
light of the easy mercuration of pyrroles (even in aqueous
Among the N-vinyl derivatives of compounds with a pyrrole
nucleus, only N-vinylcarbazole was known to add mercury(II)
acetate across the double bond.18 Later, acetoxymercuration of
the N-vinyl group in aqueous MeCN was developed as the
deprotection (devinylation) procedure of N-vinylpyrroles.19
2
Results and discussion
Herein, the following N-vinylpyrrole and -indole derivatives
have been employed for the investigation of their
acetoxymercuration:
The reaction was carried out in dry MeCN at ambient temp-
erature to 80 °C. The experimental results have shown that the
reactivity of pyrroles 1–8 and the direction of acetoxymercura-
tion dramatically varies depending on their structure and the
reaction conditions.
Most of the functionalized pyrroles and indoles (2, 4, 6–8)
reacted with Hg(OAc)2 at an equimolar ratio to selectively give
the addition products 10, 12, 14–16 across the vinyl group in
almost quantitative yields (Table 1), thus demonstrating a higher
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the
Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian
Federation. E-mail: boris_trofimov@irioch.irk.ru
†Electronic supplementary information (ESI) available: These might
include comments relevant to but not central to the matter under discus-
sion, limited experimental and spectral data, and crystallographic data.
See DOI: 10.1039/c2dt12393b
5512 | Dalton Trans., 2012, 41, 5512–5516
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nucleophilicity of the β-carbon of the vinyl group. This is likely
to be due to the electron-withdrawing effect of the functional
groups which decreases the nucleophilicity of the pyrrole
carbons to a higher degree as compared to the more remote vinyl
group.
In the case of 1-(5-(4-bromophenyl)-N-vinylpyrrol-2-yl)-
2,2,2-trifluoroethanone 4 with a 3-fold excess of Hg(OAc)2,
along with the electrophilic addition of mercury acetate to the
double bond, substitution of the pyrrole position 4 by the
HgOAc residue selectively took place, whereas the pyrrole pos-
ition 3 was unreactive arguably due to the stronger electron-with-
drawing effect of the substituent relative to the contiguous C-3
atom:
both the pyrrole cycle and the diazo fragment occurred, which
delivered N-vinylpyrrolomercurodiazolinium acetate 11 with the
N-vinyl group remaining intact, yield 89%:
The reaction is assumed to be preceded by the mercuration of
the azo group to form the intermediate cation A. This is then fol-
lowed by intramolecular electrophilic substitution of the pyrrole
proton in position 3 by the mercury cation:
Noteworthy, the N-vinyl group of compound 3 appeared to be
completely inert even with 3 equivalents of Hg(OAc)2, which is
in agreement with the cationic nature of the 1 : 1 addition
product 11.
For N-vinyl-4,5,6,7-tetrahydroindole 5, the regioselectivity of
the reaction was not observed. At a 5 : Hg(OAc)2 = 1 : 1 molar
ratio (rt, 2–3 h), the mercuration of the pyrrole ring took place.
Among pyrroles and indoles with electron-withdrawing substi-
1
tuents,
2,3-dimethyl-5-(phenyldiazenyl)-N-vinylpyrrole
3
In this case, in the H NMR spectrum of the reaction mixture,
behaved (rt, 2–2.5 h) in quite a different way: instead of electro-
philic addition to the double bond, simultaneous mercuration of
along with the starting indole 5 (∼60%), the signals of other N-
vinyl groups belonging to the species with the mercurated
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Table 1 Mercuration of pyrroles 2, 4, 6–8: conditions and products
Conditionsa
Pyrrole
Temperature, °C
80
Time, h
8
Product
Yield, %
98
2
4
6
60
60
3
4
87b
99
7
35
2
99
8
35
2
99
a Here, optimal reaction temperatures and times, found by variation of the experimental conditions, are given. b According to 1H NMR data,
conversion is 73%.
pyrrole ring, as well as signals of the addition product across the
vinyl groups, were discernible. With 2 equivalents of Hg(OAc)2,
about 40% of the starting indole 5 remained in solution, thus
indicating that after mercuration of one position of the pyrrole
ring, the latter, as having a higher anionic character, became
much more reactive. The reactivity of indole 5 (actually, a 2,3-
dialkylsubstituted pyrrole) was much higher as compared to pyr-
roles and indoles with electron-withdrawing substituents.
However, indole 5 with 3 equivalents of Hg(OAc)2, under the
same mild conditions (room temperature), underwent exhaustive
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mercuration at all possible nucleophilic sites to give the corres-
ponding trimercuric acetate 13 in 90% yield:
Pyrrole 1 behaved similarly but under harsher conditions: with
4 equivalents of Hg(OAc)2 the exhaustively mercurated product
9 (yield 93%) was obtained:
A peculiar feature of the mercuration products 10, 14 and 17
is that under the action of NaBH4 (aqueous MeCN, room temp-
erature, 0.5 h) they release the initial N-vinyl derivatives, for pro-
ducts 10 and 17 simultaneous reduction of the carbonyl group
was being observed:
to the formation of exhaustively mercurated species) occurs.
These new families of the mercurated pyrrole and indole deriva-
tives are potent synthetic intermediates, and are particularly
promising precursors for diverse cross-coupling and transmetal-
lation reactions. Taking into account the important role of
pyrrole and indole compounds in biochemical processes, the
reaction found may be helpful in the medicinal research.
Acknowledgements
We are grateful to the Presidium of RAS (project nos. 7.5, 93
and 5.9.1) for financial support. This work was also carried out
under financial support of the leading scientific schools by the
President of the Russian Federation (grant NSh-3230.2010.3).
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This journal is © The Royal Society of Chemistry 2012