Fluoro-substituted ketones from nitriles using acidic and basic reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2011.07.125

Fluoro-substituted aliphatic nitriles are shown to undergo the Houben-Hoesch reactions with arenes in CF₃SO₃H to give fluoro-substituted ketones in good yields. The fluorine substituents appear to enhance the reactivities of the nitriles (and the nitrilium ion intermediates) compared to similar aliphatic nitriles. Fluoro-substituted ketones are also shown to be accessible through the reactions of organometallic reagents and fluoro-substituted nitriles.

Full text of DOI:10.1016/j.tetlet.2011.07.125

Tetrahedron Letters 52 (2011) 5170–5172
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Tetrahedron Letters
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Fluoro-substituted ketones from nitriles using acidic and basic
reaction conditions
⇑
Erum K. Raja, Douglas A. Klumpp
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluoro-substituted aliphatic nitriles are shown to undergo the Houben–Hoesch reactions with arenes in
CF3SO3H to give fluoro-substituted ketones in good yields. The fluorine substituents appear to enhance
the reactivities of the nitriles (and the nitrilium ion intermediates) compared to similar aliphatic nitriles.
Fluoro-substituted ketones are also shown to be accessible through the reactions of organometallic
reagents and fluoro-substituted nitriles.
Received 27 May 2011
Revised 22 July 2011
Accepted 27 July 2011
Available online 3 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Houben–Hoesch reaction
Superacid
Nitrilium ion
Organofluorine
Introduction
Results and discussion
The Houben–Hoesch reaction is an acid-catalyzed reaction of
nitriles with aromatic compounds leading to aryl ketones.1 It has
previously been shown that nitriles having electron withdrawing
groups can form fairly reactive electrophiles in the Houben–
Hoesch reaction. This has been the basis for synthetic methodolo-
gies leading to halogen-substituted ketones,2 aminoketones,3
N-heterocyclic ketones,3 and other products.4 Likewise, Shudo
A variety of fluoro-substituted aliphatic nitriles are commer-
cially available and convenient synthetic methods can provide
ready access to these substrates.11 For example, fluoroacetonitrile
and difluoroacetonitrile were reacted with p-chloroanisole in the
presence of CF3SO3H and the respective ketones (1 and 2) were
formed in good yields (Fig. 1). A series of arenes were reacted with
mono-, di-, and trifluoroacetonitrile (Table 1). With fluoroacetonit-
and Ohwada have described
a
superacid-promoted Houben–
rile and benzene, a-fluorinated acetophenone (3) is prepared in
Hoesch reaction in which dicationic species are formed and these
superelectrophilic conversions are shown to give good yields of
aryl ketones.5
Although chlorinated alkylnitriles have been shown to provide
good yields of the corresponding chlorinated alkyl aryl ketones,6
similar conversions with fluorinated alkylnitriles have not been
extensively studied, the only example being the reaction of acti-
vated arenes with trifluoroacetonitrile (catalyzed by ZnCl2/HCl).7
89% isolated yield. This result indicates that the electrophilic
intermediate is fairly reactive, because a similar reaction with
acetonitrile produces only a moderate amount of acetophenone.
Electrophilic activation by fluorine is well known, as carbonyl
However,
a-fluorinated ketones are useful synthetic intermedi-
ates8 and a direct route to these compounds would have significant
value. Fluorine-substituted ketones are often prepared via electro-
philic fluorinations and by other routes.9,10 In the following Letter,
we describe a direct route to fluorinated ketones using the
Houben–Hoesch reaction and fluorinated nitriles. The superacid-
promoted chemistry is also shown to compliment synthetic reac-
tions of organometallic reagents and fluorinated nitriles.
⇑
Corresponding author. Tel.: +1 815 753 1959; fax: +1 815 753 4208.
E-mail address: dklumpp@niu.edu (D.A. Klumpp).
Figure 1. Superacid-promoted reactions of fluoro-substituted acetonitriles.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.125

E. K. Raja, Douglas A. Klumpp / Tetrahedron Letters 52 (2011) 5170–5172
5171
Table 1
Besides fluoro-substituted acetonitriles, several other types of
nitriles gave ketone products in fair to good yields. The fluoro-
substituted benzyl cyanide leads to ketone 16 (Eq 1). Although
benzylic fluoro-substituents are known to form carbocations in
superacid,3a there is no evidence for such chemistry in this system.
The dinitrile (17) provides the 1,6-diketone from reaction with
benzene in superacid (Eq 2). Houben–Hoesch
Products and yields from the reactions of fluoro-substituted acetonitriles
Products from CH2FCN, CF3SO3H, arene:
ð1Þ
ð2Þ
Products from CHF2CN, CF3SO3H, arene:
reactions of aliphatic dinitriles (without fluoro-subsitituents) have
been studied previously and reaction at both nitrile groups has been
somewhat rare.14 Likewise, a perfluorinated ketone (19) is formed
from the perfluorooctanenitrile (Eq 3). This conversion is considered
representative for these Houben–Hoesch reactions. Since superacid
is necessary for these reactions with arenes, it suggests either par-
tial or complete protonation of the nitrile group (Eq 4). There is evi-
dence for diprotonated, superelectrophilic nitriles being involved in
some Houben–Hoesch reactions,5 however, such intermediates are
unlikely in the present case. It is expected that the fluoro-substitu-
ents reduce that basicity of the nitrile, so diprotonation would be
extremely difficult.
Products from CF3CN, CF3SO3H, arene:
ð3Þ
ð4Þ
groups and carboxonium ions show greater electrophilic reactivi-
ties when substituted by fluorine atom(s).12 Reactions with aryl
ethers, a dialkyl-substituted benzene, and a phenol also provide
the products (4–6) from the Houben–Hoesch reaction. Unexpect-
edly, the yields for these conversions are lower than that with ben-
zene, despite the use of activated arenes (i.e., stronger
nucleophiles). This may be the result of partial protonation of the
activated arenes, as phenols and aryl ethers are known to be pro-
tonated in superacid.13
Similar reactions utilizing difluoroacetonitrile also provide the
Houben–Hoesch products (7–10) in good yields. In general, the
product yields were higher than those obtained with fluoroaceto-
nitrile. This is likely due to enhanced electrophilic activation from
the second fluorine substituent. We also examined the reactions of
trifluoroacetonitrile. At room temperature, this substance is a gas
so it was condensed at ꢀ78 °C and dissolved in CH2Cl2. The result-
ing solution was reacted with arenes (dissolved in CH2Cl2) and
CF3SO3H at 0 °C and allowed to warm to room temperature. The
conversions using trifluoroacetonitrile were generally good,
producing the trifluoromethyl ketones in high yields. Although
1,4-dimethoxybenzene does provide the expected ketone product
(observed in solution by GC–MS), isolation of the product leads
to massive decomposition or polymerization. With the good con-
Although these Houben–Hoesch reactions have not been
optimized, good yields have been obtained of the fluorine-
substituted ketones. In a typical procedure, the nitrile (1 mmol)
is dissolved in 1 mL of the arene nucleophile to which is added
0.5 mL of triflic acid (5.6 mmol). For solid arenes, CHCl3 may be
used as a co-solvent. The solution is stirred at 50 °C overnight
and it is then poured over ice. The products are extracted into
chloroform and isolated using standard methods. Other acids
systems (H2SO4, CF3CO2H, and sulfated zirconia) were also exam-
ined in the reaction of fluoroacetonitrile with benzene, but only
superacidic CF3SO3H provided a useful yield of the
a-fluoroaceto-
phenone. In Whalley’s report of the Houben–Hoesch reaction
with trifluoroacetonitrile, highly activated arenes (resorcinol
and alkylated derivatives) gave the corresponding ketones from
reactions with ZnCl2 and HCl.7 This suggests that weaker acids
systems can effectively promote the Houben–Hoesch reaction
with fluoro-substituted nitriles, but it is only effective with acti-
vated aromatic compounds. Also noteworthy, several previous
studies have utilized CF3SO3H as an acid catalyst to give Hou-
ben–Hoesch products from activated arenes and nonfluorinated
aliphatic nitriles.15
The superacid-promoted Houben–Hoesch reactions provide a
complimentary set of products to those from organometallic
reactions. For example, phenyllithium and 3-fluorophenyl-magne-
version to
a,a,a-trifluoroacetophenone (11), it is again clear that
trifluoroacetonitrile forms a highly electrophilic intermediate with
CF3SO3H. Interestingly, acetonitriles are known for their tendencies
to form triazines in strong acid, but no triazines are formed with
the fluoro-substituted acetonitriles.
sium bromide provide the
a-fluoroacetophenones (3 and 20). Prod-
uct 20 is notable because it possesses meta-oriented

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E. K. Raja, Douglas A. Klumpp / Tetrahedron Letters 52 (2011) 5170–5172
References and notes
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Conclusion
Fluoro-substituted aliphatic nitriles have been shown to react
with arenes in superacid-promoted Houben–Hoesch reactions.
The reaction provides a convenient route to mono-, di-, and trifluo-
romethyl ketones. Two important factors appear to be involved:
the superacidic CF3SO3H more readily forms the required nitrilium
ions and the fluoro-substituents enhance the electrophilic reactiv-
ities of the nitrilium ions. The fluoro-substituted aliphatic nitriles
also react efficiently with organometallic reagents to afford the flu-
oro-substituted ketones.17
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Acknowledgments
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within.
17. Some fluorinated compounds are known to be highly toxic, so work with these
compounds should only be done by properly trained personnel.
We gratefully acknowledge the support of the National Science
Foundation (CHE-0749907) and the NIH-National Institute of
General Medical Sciences (GM085736-01A1).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.125.