Aromatic and benzylic C-H bond functionalization upon reaction between nitriles and perfluoroalkyl sulfoxides

Article abstract of DOI:10.1002/ejoc.200900873

We studied the thermal behavior of some intermediates formed by reaction of nitriles with perfluoroalkyl sulfoxides upon trifluoromethanesulfonic anhydride activation. Bistriflate ketal 3, precursor of sulfilimine 1, may undergo a rearrangement to sulfany

Full text of DOI:10.1002/ejoc.200900873

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900873
Aromatic and Benzylic C–H Bond Functionalization Upon Reaction between
Nitriles and Perfluoroalkyl Sulfoxides
Yohan Macé,[a] Céline Urban,[a] Charlotte Pradet,[b] Jean-Claude Blazejewski,[a] and
Emmanuel Magnier*[a]
Keywords: Rearrangement / C–H activation / Fluorine / Sulfur / Nitriles / Elimination
We studied the thermal behavior of some intermediates
formed by reaction of nitriles with perfluoroalkyl sulfoxides
upon trifluoromethanesulfonic anhydride activation. Bistrifl-
ate ketal 3, precursor of sulfilimine 1, may undergo a re-
arrangement to sulfanyl nitrile 5 after triflic acid elimination
under thermal conditions. With p-tolyl trifluoromethyl sulfox-
ide, remote triflic acid elimination from intermediate 4 leads
to benzamide 8 formation. These reactions involve, respec-
tively, selective functionalization of the aromatic ortho C–H
bond or the benzylic C–H bond para to the sulfoxide group.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The incorporation of perfluoroalkyl groups into mole-
cular structures is an intensive area of chemistry research
owing to the unusual properties these groups may confer.[1]
Among new reagents, perfluoroalkyl sulfoxides are em-
ployed as synthons,[2] fluorous tags, and scavengers.[3] They
are also used as precursors of reagents, or reagents them-
selves able to transfer perfluoroalkyl groups to various sub-
strates either by nucleophilic[4] or electrophilic[5] pathways.
In this context, we recently described easy and flexible
access to perfluoroalkylated acylsulfilimines 1 and derived
sulfoximines involving a Ritter-like reaction of perfluoro-
alkylated sulfoxides 2 with nitriles promoted by trifluoro-
methanesulfonic anhydride (Scheme 1).[6] This reaction was
shown to proceed via bistrifluoromethanesulfonic ketal in-
termediate 3, which, after hydrolysis, afforded acylsulfil-
imines 1, indicating the very high reactivity of activated spe-
cies 4.[7]
We thought that besides the hydrolytic pathway, ketal in-
termediate 3, which is also a triflate derivative, should be
amenable to further functionalization. In particular, alkyl
triflates are known to undergo easy thermal triflic acid eli-
mination when there is such a possibility (e.g., when R =
CH2RЈ in Scheme 1).[8] In our previous study all reactions
(and subsequent quenching with water) were performed at
Scheme 1. Sulfilimine formation.
–15 °C, leading effectively to the sole isolation, in good
yields, of the expected acetyl sulfilimines 1, thanks to the
stability of 3 under these conditions.
In this paper we investigated the behavior of intermediate
3 when the same reaction was performed at higher tempera-
ture (between 0 and 50 °C) with substrates possessing hy-
drogen atoms either at the α position or in a more remote
place susceptible to favor thermal triflic acid elimi-
nation.[8,9]
Results and Discussion
We first studied the reaction of trifluoromethylated sulf-
oxides with acetonitrile by mixing the reactants at room
temperature followed by heating at 50 °C for 5 h (Table 1,
Entries 1 and 4). Under these new conditions, instead of the
expected products resulting from a simple elimination of
triflic acid, we isolated, along with acylsulfilimines 1, re-
arranged (perfluoroalkylsulfanyl)phenyl acetonitrile deriva-
tives 5 in fair to good yields, depending on the substrate.[10]
This reaction proved to be applicable to other fluorinated
sulfoxides. Higher perfluoroalkyl groups were quite well tol-
erated (Table 1, Entries 3 and 5).
[a] Institut Lavoisier de Versailles, UMR CNRS 8180, Université
de Versailles, St Quentin en Yvelines,
45 avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-39254452
E-mail: magnier@chimie.uvsq.fr
[b] Synthetic Chemistry, GlaxoSmithKline,
Gunnels Wood Road, Stevenage SG1 2NY, England
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900873.
Eur. J. Org. Chem. 2009, 5313–5316
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5313

Y. Macé, C. Urban, C. Pradet, J.-C. Blazejewski, E. Magnier
SHORT COMMUNICATION
Table 1. Temperature effect on the reaction between nitriles and
sulfoxides.[a,b]
In the particular case of cyclopropyl carbonitrile, the re-
arrangement reaction was accompanied by the ring opening
of the cyclopropyl cycle (Table 1, Entries 10 and 11).[13] We
thus isolated chlorinated product 5g, presumably arising by
the mechanism shown in Scheme 3.
En-
try
R
RF
RЈ
RЈЈ
1, Yield
5, Yield [%]
[c]
[%][c]
1
H
H
H
Br
Br
H
H
H
H
H
H
Me
CF3
CF3
C4F9
CF3
C4F9
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
1a, 32
1a, 11
1b, 0
5a, 68 (51)
5a, 64 (56)
5b, 100 (63)
5c, 94 (92)
5d, 100 (63)
5e, 26 (23)
5e, 85 (70)
5f, 16 (6)
2[d]
3
4
5
1c, 6
H
1d, 0
6
Et
Et
Ph
Ph
1e, 16
1e, 15
1f, 54
1f, 11
1g, 4
7[d]
8
9[d]
10
11[d]
12
5f, 10 (10)
5g, 88 (45)[e]
5g, 23 (18)[e]
–CH2CH2–
–CH2CH2–
H
H
H
H
Scheme 3. Reaction of phenyltrifluoromethyl sulfoxide with cy-
clopropyl carbonitrile.
1g, 53
H
H
Ph
Ph
1h, 16 (12) 5h, 33 (4)[f]
1h, 17 (13) 5h, 0
13[d] Me
Preferential ring opening of intermediate 3g leading to
intermediate 7 occurs. Further “usual” rearrangement of 7
followed by workup with saturated sodium chloride solu-
tion exchanging the alkyl triflate group for chlorine then
gives rise to observed chloride 5g.
Another notable exception concerning p-tolyl trifluoro-
methyl sulfoxide (Table 1, Entries 12–15) was that disap-
pointingly low yields, or no trace amount, of rearranged
products 5 were isolated because of extensive charring of
the reaction mixture. We suspected that in this particular
case another reaction pathway was operative, possibly in-
volving the benzylic hydrogen atoms of the aromatic methyl
group.
To discriminate between thermal vicinal triflic acid elimi-
nation leading to the preceding rearrangement and remote
elimination from the methyl group, the reaction of p-tolyl
trifluoromethyl sulfoxide with aromatic nitriles was studied.
With such nitriles, a new type of compound was formed
and shown to have benzamide structure 8 (Table 2).[14]
These amides were isolated in modest to fair yields after
hydrolytic workup, along with expected sulfilimines 1; the
optimal temperature for this process was between 0 and
5 °C in most cases. Table 2 shows that the yield of amides
8 increases at the expense of 1 with the less nucleophilic
nitriles (Table 2, Entries 7–10). Conversely, lower yields of
amides 8 were achieved with the more nucleophilic nitriles
(Table 2, Entries 1–6), suggesting a competitive mechanism
14
Me
1i, 10 (10) 5i, 0
1i, 13 (6)
15[d] Me
5i, 0
[a] Experimental conditions: r.t. to 50 °C, 5 h, unless otherwise
noted. [b] Compounds 1a–h were previously described, see ref.[6]
[c] 19F NMR spectroscopic yields, isolated yields in brackets.
[d] Experimental conditions: 0 °C to r.t., 10 h. [e] A ring-opened
chlorinated product was formed, see text and Scheme 3. [f] This
product was not isolated in pure form.
In the case of higher nitriles, it was found that starting
the reaction at 0 °C followed by 10 h at room temperature
was beneficial to the yield of 5 (Table 1, Entry 6 vs. 7). A
minor improvement was observed for the benzylacetonitrile
derivative (Table 1, Entries 8 and 9). To rationalize our ex-
perimental findings, we propose that when the substituent
of the nitrile component bears at least one α-hydrogen
atom, there is the possibility, under thermal conditions, of
triflic acid elimination from intermediates 3, leading first to
the expected sulfilimino keteneacetals 6 (Scheme 2).
Scheme 2. Thermal rearrangement reaction of sulfilimines 3.
The latter intermediates 6 proved to be surprisingly for the formation of the two types of compounds.
prone to undergo an electrocyclic ring closure followed by We thus suggest that benzamides 8 and sulfilimines 1 are
a further hetero-ring-opening/rearomatization process en formed concurrently via a common early intermediate. Ac-
route to isolated α-perfluoroalkylthio nitriles 5. The overall tivated form 4 of sulfoxide 2 could be the candidate of
result is net transfer of the alkylated nitrile moiety from choice, as shown by the following mechanistic proposal
sulfur to carbon at the ortho position of the newly formed (Scheme 4). This reaction is noteworthy in that it occurs by
perfluoroalkylsulfanyl group. This process achieves thus the an intermolecular process at the para position of the sulfox-
same task as a selective ortho C–H aromatic bond acti- ide functionality (aromatic Pummerer).[9]
vation followed by carbon–carbon bond formation, but
without the need for a transition-metal catalyst[11] (C–H enough by reaction at the sulfur center with the nitrile com-
bond functionalization sensu Fokin and Schreiner).[12]
ponent, it may suffer a competitive deprotonation to give
When activated sulfoxide 4 is not captured rapidly
5314
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Eur. J. Org. Chem. 2009, 5313–5316

Aromatic and Benzylic C–H Bonds Functionalization
Table 2. Reaction of p-tolyltrifluoromethyl sulfoxide with aromatic sulfonic anhydride activation enables chemical diversity
nitriles.[a]
(perfluoroalkylated sulfilimines, perfluoroalkyl sulfanyl ace-
tonitriles, as well as benzamides) through aromatic or (re-
mote) benzylic carbon–hydrogen bond functionalization.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and copies of the NMR spectra for
all new compounds.
Acknowledgments
Entry
R
1, Yield [%][b] 8, Yield [%][b]
Y. M. thanks GlaxoSmithKline and the Centre National de la Re-
cherche Scientifique (CNRS) for financial support (BDI grant),
and C. U. thanks the French Ministry of Research for a PhD grant.
1
H
H
H
p-Me
p-Me
p-Me
p-Br
o-Br
p-NO2
m-NO2
1j, 56
1j, 68
1j, 4
8a, 2
2[c]
3[d]
4
8a, 2
8a, 12
8b, trace
8b, 0
1k, 57
1k, 61
1k, 16
1l, 12
1m, 4
1n, 0
5[c]
6[d]
7
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8b, 0
8c, 15
8d, 41
8e, 19
8f, 29
8
9
10
1o, 0
[a] Experimental conditions: 0–5 °C, 5 h, unless otherwise noted.
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mediate 9.[9] Further efficient reaction of 9 with nitrile
(either stepwise or concerted as shown in Scheme 4 for con-
venience), may then give rise, after hydrolysis, to observed
benzamides 8, involving the functionalization of a remote
benzylic carbon–hydrogen bond in a coupled Pummerer/
Ritter cascade.
According to this mechanism, more deactivated nitrile
groups should give benzamides 8 in better yields and this
was observed in our experiments (Table 2, Entries 7–10). In
fact, activated intermediate 4 being not immediately cap-
tured at the sulfur center by the nitrile enjoys ample time
to be converted into highly reactive species 9.
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literature by another method: R. Lantzsch, A. Marhold, W.
Behrenz, I. Hammann U. S. Patent 4438275, 1984; b) com-
pound 5a is commercially available but we were unable to track
down its origin in the literature (CAS registry number: 237424–
20–3).
Conclusions
In summary, fine-tuning of the experimental conditions
and substrate choice during the reaction of perfluoroalk-
ylated sulfoxides with nitriles under trifluoromethane-
Eur. J. Org. Chem. 2009, 5313–5316
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Y. Macé, C. Urban, C. Pradet, J.-C. Blazejewski, E. Magnier
[11] a) G. Dyker, Angew. Chem. Int. Ed. 1999, 38, 1698–1712; b) [14] Another preparation of benzamide 8a was described in the
SHORT COMMUNICATION
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Published Online: September 22, 2009
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