Ipso-amidation of arylboronic acids: Xenon difluoride-nitriles as efficient reagent systems

Article abstract of DOI:10.1016/j.jfluchem.2009.05.015

The xenon difluoride-mediated, ipso-amidation of boronic acids has been achieved for the first time under mild conditions. This method provides a simple, one-pot procedure for the direct synthesis of a series of anilides from the corresponding arylboronic

Full text of DOI:10.1016/j.jfluchem.2009.05.015

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Journal of Fluorine Chemistry 130 (2009) 806–809
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Ipso-amidation of arylboronic acids: Xenon difluoride-nitriles as efficient
reagent systems§
*
*
G.K. Surya Prakash , Matthew D. Moran, Thomas Mathew, George A. Olah
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, 837 Bloom Walk, Los Angeles, CA 90089-1661, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
The xenon difluoride-mediated, ipso-amidation of boronic acids has been achieved for the first time
under mild conditions. This method provides a simple, one-pot procedure for the direct synthesis of a
series of anilides from the corresponding arylboronic acids and alkyl/aryl nitriles. Arylboronic acids
bearing electron donating groups gave anilides in high yields, while moderate yields were observed for
those bearing electron withdrawing groups. A plausible mechanism involving the formation of an aryl
radical cation through single electron transfer by xenon difluoride, followed by the nucleophilic addition
of the nitrile, is proposed.
Received 15 April 2009
Received in revised form 14 May 2009
Accepted 18 May 2009
Available online 27 May 2009
Keywords:
Xenon difluoride
Nitriles
ß 2009 Elsevier B.V. All rights reserved.
Anilide synthesis
Radical cation reaction
Amidation
1. Introduction
effective for the desilylative ipso-fluorination of trimethyl(phe-
nyl)silane to yield fluorobenzene [16]. It is also known to be a
The preparation of amides by various methods has been well
documented in the literature. Ritter et al. reported the direct
preparation of amides from nitriles and secondary/tertiary
alcohols [1,2] or olefins [3,4] in strong acid medium [5–7]. Since
the feasibility of the reaction is dependent on the stability of the
carbocation formed from the alcohol or olefin during the reaction,
application of this method for general practical purposes is limited,
although in our laboratory such reactions have been successfully
employed in preparing amides and trifluoromethylated amides in
good yields [8,9]. This reaction does not proceed with primary
alcohols, substituted phenols (to give anilides), or unsubstituted
olefins. More recently, Chan et al. have coupled arylboronic acids
with amides in the presence of copper(II) acetate to form anilides
[10], and the method has been further improved by Xie and co-
workers [11]. However, both methods require preformed amide,
reducing the synthetic utility of the reaction. Anilides are
important precursors for many dyes, drugs and pharmaceuticals.
For example, acetanilide, also known as Antifebrin, has been
widely used in analgesic and antipyretic drugs [12,13].
powerful oxidizing agent [15,17,18]. So far, no XeF2-mediated
amidation reactions have been reported. Herein, we report the
facile preparation of anilide derivatives from the reaction of
arylboronic acids with alkyl/aryl nitriles in the presence of XeF2.
2. Results and discussion
As a part of our attempt to expand the utility of XeF2 for ipso-
fluorination of substrates other than phenylsilanes, the reaction of
XeF2 with phenylboronic acid was carried out in acetonitrile.
Complete conversion of the starting materials was observed in a
short period of time (30 min for a 1 mmol scale reaction). Analysis
of the product obtained after the work-up of the reaction mixture
showed that ipso-amidation occurred at the boronic acid
functionality. The main product separated was acetanilide. In
order to ascertain that ipso-amidation occurred predominantly, the
reaction was repeated in an excess of benzonitrile. As expected,
benzanilide was separated as the major product. The general
application of this method has been investigated by conducting
this reaction with various substituted phenylboronic acids in
acetonitrile (Scheme 1). Reaction of the parent phenylboronic acid
with propiononitrile as well as benzonitrile yielded the corre-
sponding anilides in good yields. Ipso-amidation reactions were
found to be feasible in most of the cases, albeit with varying yields.
The reactions were found to occur under mild reaction
conditions (0 8C to room temperature), and required short reaction
times (0.5–2.5 h). In these reactions the nitrile is used as both the
Xenon difluoride, XeF2, has proven to be a versatile electrophilic
fluorinating agent in organic synthesis [14,15], and has been
§
Dedicated to Prof. Henry Selig on the occasion of receiving the 2009 American
Chemical Society Award for Creative Work in Fluorine Chemistry.
* Corresponding authors. Tel.: +1 213 740 5984.
E-mail address: gprakash@usc.edu (G.K. Surya Prakash).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.05.015

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807
reagent and the solvent, and no strong acid was required. These
features make this method very convenient and useful. The only
by-products of the reaction were xenon gas (evolved during the
reaction), the tetrafluoroborate anion (identified by its 19F NMR
boron-10 isotope shift of 0.669 ppm) as well as minor amounts
of B(OH)nF3ꢀn species and HF (all formed by successive fluorination
of the cleaved boronic acid functionality); the latter species was
neutralized with sodium bicarbonate solution, and all by-products
were removed by extraction. The source of characteristic orange-
chemical shift
d
, ꢀ147.97 ppm, and characteristic secondary
Table 1
Reactions of arylboronic acids with XeF2 in nitrile solution.
Arylboronic acid (1a–i)
Nitrile
Time (h)
Anilide (2a–e)
Yield (%)
CH3CN
0.5
0.5
0.5
84
58
70
CH3CH2CN
PhCN
CH3CN
CH3CN
1.0
1.5
95
33
CH3CN
1.5
2.5
58
40
CH3CN
CH3CN
1.5
2.0
41
13
CH3CN
CH3CN
C6F5CN
1.0
2.0
No identifiable products
No reaction
CH3CN
1.5
43

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808
G.K.S. Prakash et al. / Journal of Fluorine Chemistry 130 (2009) 806–809
Xie and co-workers in their copper(II) acetate-mediated N-
arylation reactions [11]. The reactivity observed for various
substituted arylboronic acids shown in Table 1 is in agreement
with a mechanism involving the formation of a radical cation, as
proposed by Lotian and Ramsden, for the reaction of XeF2 with
PhSiMe3 [16]. A plausible mechanism is shown in Scheme 2.
From the proposed mechanism the complete dominance of ipso-
amidation over ipso-fluorination is evident, as CH3CN is known
to be a better nucleophile than Fꢀ, and is in much higher
concentration in the reaction mixture. Similar reactions carried
out between phenylboronic acid and XeF2 in C6F6 and CH2Cl2
failed to give the corresponding fluoroarene.
Failure to achieve similar reactivity with the cyclic, phenyl-
boronic acid 1,3-propanediol ester and with potassium trifluor-
ophenylborate indicates that the OH groups on boron are crucial
for the reaction for the conversion of 5 to the enol 6, which
tautomerizes to the anilide 2. Further studies with other
electrophilic sources of fluorine, such as Selectfluor and N-
fluorobenzenesulfonimide (NFSI), showed no reaction, even at
80 8C, suggesting that generation of a radical cation intermediate
such as 3 is a key step in the anilide formation.
Scheme 1. Xenon difluoride-mediaited ipso-amidation of arylboronic acid.
brown color of the reaction mixture (which was retained on the
column during column chromatography) is presumably due to the
oligomerization of aromatic rings by a radical cation-induced chain
reaction (vide infra). Table 1 shows the scope of the reaction and
the yields of the products.
The synthetic role of xenon difluoride in this reaction was
determined by performing similar reactions of phenylboronic acid
in the presence of other chemical oxidants such as pyridinium
chlorochromate (PCC), cerium ammonium nitrate (CAN), manga-
nese dioxide (MnO2), potassium permanganate (KMnO4), and
sodium periodate (NaIO4). A blank reaction was also conducted in
the absence of XeF2 and other oxidants in an excess of acetonitrile
at elevated temperatures. In all of these cases no ipso-amidation,
and hence no anilide formation, was observed.
The chemical yields of the XeF2-mediated ipso-amidation
products were also found to vary with the electronic nature of
the aromatic substituent in arylboronic acids. The presence of an
electron donating group (EDG; i.e., OMe) increased the yield
relative to phenylboronic acid, while the presence of an electron
withdrawing group (EWG) decreased the yield. In order to
prepare perfluorobenzanilide, perfluorophenylboronic acid was
treated with perfluorobenzonitrile under similar conditions. No
reaction was observed due to extremely low reactivity of the
substrates. It was interesting to note the behavior of 2-
ethoxyphenylboronic acid and 2,4,6-trimethylphenylboronic
acid, both electron rich substrates, towards this reaction; 2-
ethoxyphenylboronic acid gave 2-ethoxyacetanilide with only
33% isolated yield, while no reaction was observed in the case of
2,4,6-trimethylphenylboronic acid. In both cases the steric effect
appears to predominate over the electronic effect because of the
possible significant hindrance by the ortho substituent during
ipso-substitution. This phenomenon has also been observed by
It is interesting to note that the reaction of 1,4-phenylenedi-
boronic acid with XeF2 in CH3CN failed to yield the bis-ipso-
amidated product, but instead gave 4-fluoroacetanilide in mod-
erate yield (43%, last entry in Table 1). The analogous reaction,
however, between 4-acetamidobenzeneboronic acid and XeF2
failed to yield any isolable products. These results suggest that
ipso-fluorination occurs prior to ipso-amidation, but the reasons for
ipso-fluorination in this case remain unclear.
3. Conclusions
Direct preparation of anilides by ipso-amidation of arylboronic
acids from the corresponding alkyl and arylnitriles has been
achieved for the first time using xenon difluoride. Failure of other
various oxidants in the ipso-amidation of arylboronic acids using
nitriles clearly demonstrates the potential of the XeF2–nitrile
system for ipso-amidation. Observation of partial ipso-fluorination
in 1,4-phenylenediboronic acid unveils a probable XeF2-mediated
ipso-fluorination strategy for the conversion of arylboronic acids to
the corresponding fluoroarenes.
4. Experimental
4.1. General
Acetonitrile (DriSolv, >99.8%, EMD Chemicals Inc.), benzonitrile
(99%, Aldrich) and pentafluorobenzonitrile (99%, Aldrich) were
used as received. Xenon difluoride (>99.5%, Synquest Laboratories
Inc.) was stored in the glove box and used as received.
Phenylboronic acid, 4-nitrophenylboronic acid (both from Alfa
Aesar), 4-fluorophenylboronic acid, 1,4-phenylenebisboronic acid,
pentafluorophenylboronic acid, 4-methoxyphenylboronic acid, 2-
ethoxyphenylboronic acid (all from Aldrich), t-butyl-phenylboro-
nic acid, and 2,4,6-trimethylphenylboronic acid (both from Oak-
wood Products) were used as received. Proton, 13C, and 19F NMR
were spectra were recorded on a Varian AS 400 Inova NMR
spectrometer. Proton and 13C NMR chemical shifts were deter-
mined relative to the 1H and 13C chemical shifts of the solvent,
CDCl3 (residual proton resonance,
d d
7.26 ppm for 1H and
77.16 ppm for 13C). Fluorine-19 chemical shifts were referenced to
that of CFCl3 added in the solvent (CDCl3). GC/MS data were
acquired on a Hewlett Packard 5890 Series II Gas Chromatograph
coupled with 5971 Series Mass Selective Detector. All products
were identified by comparing their spectra with those of the
authentic samples.
Scheme 2. Mechanism of ipso-amidation of arylboronic acid using the XeF2–nitrile
system.

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809
4.2. Typical ipso-amidation procedure for the direct preparation of
anilides from arylboronic acids
4.3.5. 2-Ethoxyacetanilide (2c)
1H NMR (CDCl3): 8.38 (m, 1H), 7.78 (bs, 1H, N–H), 7.00 (m, 1H),
6.93 (m, 1H), 6.84 (m, 1H), 4.10 (q, 2H, OCH2CH3), 2.18 (s, 3H,
COCH3), 1.45 (t, 3H, OCH2CH3). 13C NMR (CDCl3): 168.25, 147.00,
127.85, 123.55, 121.04, 119.83, 110.87, 64.21, 25.09, 14.97. GC/MS
CAUTION! Combining solid arylboronic acids with XeF2 leads to
spontaneous combustion, even in an inert (argon) atmosphere. Only
solutions of the two reagents should be combined.
(m/z): 179 (M+, 32), 136 (M+ꢀCOCH3, 33), 103 (M++1ꢀCOCH3
&
A 50-mL round bottom flask, fitted with a gas inlet tube (with
Teflon stopcock), was equipped with a magnetic stirrer (Teflon) and
a rubber septum. A small, positive flow of argon was maintained
through the gas inlet by means of a tygon tube connection through a
Schlenk line. The arylboronic acid (1 mmol) was then weighed into
the flask. Inside the drybox, xenon difluoride (1.5 mmol, 3 mmol in
the caseof1,4-phenylenediboronicacid)was weighed into atapered
round bottom flask fitted with a rubber septum. In the fumehood,
nitrile was syringed under argon into the flask containing the
arylboronic acid (3 mL) and into the flask with the XeF2 (4 mL). The
XeF2–nitrile mixture was then sonicated until the XeF2 had fully
dissolved, and was then syringed into the mixture of partially
dissolved arylboronic acid–nitrile mixture at 0 8C. The reaction
mixture was stirred for 0.5–2.5 h depending on the boronic acid
substrate taken. As the reaction proceeded, the solution became
homogenous and orange-brown in color.
CH2CH3, 100).
4.3.6. 4-t-Butylacetanilide (2d)
1H NMR (CDCl3): 7.41 (m, 2H), 7.37 (m, 2H), 7.18 (bs, 1H, N–H),
2.16 (s, 3H, CH3), 1.30 (s, 9H, t-butyl). 13C NMR (CDCl3): 168.21,
147.31, 135.18, 125.82, 119.77, 34.36, 31.34, 24.54. GC/MS (m/z):
191 (M+, 27), 134 (M+ꢀC(CH3)3, 100), 91 (M+ꢀC(CH3)3 & COCH3,
21).
4.3.7. 4-Fluoroacetanilide (2e)
1H NMR (CDCl3): 7.44 (m, 2H), 7.40 (bs, 1H, N–H), 6.99 (m, 2H),
2.16 (s, 3H, CH3). 13C NMR (CDCl3): 168.50, 159.49 (d, JC–F
,
1
243 Hz), 133.95 (d, 4JC–F, 3.0 Hz), 121.92 (d, 3JC–F, 7.5 Hz), 115.73 (d,
2JC–F, 23.2 Hz), 24.52). 19F NMR (376 MHz, CDCl3): ꢀ118.03 (m).
GC/MS (m/z): 152 (M+ꢀ1, 17), 110 (M+ꢀCOCH3, 100).
The resulting mixture was extracted with CH2Cl2 (3ꢁ 10 mL),
washed with 10% NaHCO3 solution (10 mL) and water (2ꢁ 10 mL)
followed by brine (10 mL), and dried over sodium sulfate. The
solvent was removed by rotary evaporation and the crude product
was purified by column chromatography (60–200 mesh silica,
hexane/ethyl acetate as the eluent). The products were identified
by spectral analysis (1H, 13C, 19F NMR, and GC/MS) and the
structures were confirmed by comparing their spectral data with
those of the authentic samples. Purity was found to exceed 95% for
all compounds as determined by GC/MS.
4.3.8. 4-Chloroacetanilide (2f)
1H NMR (CDCl3): 7.44 (m, 2H), 7.27 (m, 2H), 7.20 (bs, 1H, N–H),
2.17 (s, 3H, CH3). 13C NMR (CDCl3): 168.38, 136.50, 129.42, 129.15,
121.16, 24.73. GC/MS (m/z): 169 (M+, 18), 127 (100), 126
(M+ꢀCOCH3, 98).
4.3.9. 4-Nitroacetanilide (2g)
1H NMR (CDCl3): 10.33 (bs, 1H, N–H), 8.76 (m, 2H), 8.21 (m, 2H),
2.15 (m, 3H, CH3). 13C NMR (CDCl3): 169.25, 136.14, 125.87,
123.40, 122.33, 20.12. GC/MS (m/z): 180 (M+, 18), 137 (M+ꢀCOCH3,
100), 91 (M+ꢀCOCH3 & NO2, 46).
4.3. Spectral data of products
Acknowledgment
4.3.1. Acetanilide (2a)
1H NMR (400 MHz, CDCl3):
d
7.61 (bs, 1H, N–H), 7.48 (m, 2H),
Financial support of our work by the Loker Hydrocarbon
Research Institute is gratefully acknowledged.
7.30 (m, 2H), 7.09 (m, 1H), 2.18 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): 168.42, 137.98, 129.13, 124.46, 119.98, 24.63. GC/MS (m/
z): 135 (M+, 26), 92 (M+ꢀCOCH3, 100).
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1H NMR (CDCl3): 7.51 (m, 2H), 7.31 (m, 2H), 7.16 (bs, 1H, N–H),
7.10 (m, 1H), 2.39 (q, 2H, CH2), 1.25 (t, 3H, CH3). 13C NMR (CDCl3):
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