Hypervalent iodine mediated para -selective fluorination of anilides

Article abstract of DOI:10.1021/jo302099d

A metal-free method for the direct regioselective fluorination of anilides has been developed. In the presence of bis(tert-butylcarbonyloxy)iodobenzene (PhI(OPiv)₂) and hydrogen fluoride-pyridine, the para-fluorination products of anilides were obtained in moderate to good yields. Because of its operational safety and the use of readily available reagents, this new procedure provides facile access to a variety of para-fluorinated anilides.

Full text of DOI:10.1021/jo302099d

Note
pubs.acs.org/joc
Hypervalent Iodine Mediated para-Selective Fluorination of Anilides
Tian Tian, Wen-He Zhong, Shuai Meng, Xiang-Bao Meng,* and Zhong-Jun Li*
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P
R China
S
* Supporting Information
ABSTRACT: A metal-free method for the direct regioselective fluorination of
anilides has been developed. In the presence of bis(tert-butylcarbonyloxy)-
iodobenzene (PhI(OPiv)2) and hydrogen fluoride-pyridine, the para-fluorina-
tion products of anilides were obtained in moderate to good yields. Because of
its operational safety and the use of readily available reagents, this new
procedure provides facile access to a variety of para-fluorinated anilides.
luorinated aromatic compounds are often prepared as
neur et al. developed a metal-free method for the oxidative
Fbioactive and pharmaceutical agents. Generally, molecular fluorination of phenols mediated by hypervalent iodine.14
1
Hypervalent iodine reagents have also attracted the attention of
our group.15 In continuation of our interest in hypervalent
iodine chemistry, herein we report a new method for the direct
fluorination of aromatic amines using hypervalent iodine
reagents.
The fluorination was conducted by treating a mixture of a
hypervalent iodine compound and fluorine sources with
anilides in dichloromethane. As shown in Table 1, evaluation
of different fluorine sources indicated that HF·Py afforded good
fluorine and electrophilic fluorinating reagents, such as XeF2,
AcOF, CF3OF, and CsSO4F, are used in the direct fluorination
of aromatic compounds, forming the C−F bond through
electrophilic fluorination. However, these unstable fluorinating
reagents are difficult to handle, and the electrophilic
fluorination usually provides low regioselectivity for electron-
rich aromatics; a mixture of o/p-isomers is obtained in most
cases.2 Other electrophilic fluorinating reagents such as
Selectfluor (F-TEDA-BF4), NFSi, and N-fluoro pyridinium
salts are commercially available, easy-to-handle, and stable.
Moreover, these reagents demonstrated high regioselectivity
and efficiency for fluorination. Nevertheless, they are
expensive.3 In order to prepare various fluorinated compounds,
great efforts have been dedicated to the formation of C−F
bond. More than 80 years ago, the Balz−Schiemann rection4
was discovered to convert diazonium tetrafluoroborate salts
into fluorinated arenes. In industry, the Halex process (halogen
exchange) is a common method for the synthesis of fluorinated
compounds by employing inexpensive inorganic fluoride
sources.5 Palladium-catalyzed nucleophilic fluorination achieves
C−F bond formation via reductive elimination.6 In addition,
Ag-mediated aryl stannane7 and arylboronic acids8 fluorinations
emerge as important methods for the preparation of a variety of
fluorinated compounds. However, facile methods with mild
conditions, high efficiency, and environmental protection are
still needed.
In recent years, hypervalent iodine reagents have been widely
used in oxidation synthesis, owing to their strong oxidizing
properties and availability.9 Recently, Kikugawa et al.10 and
Gu’s group11 reported the para-oxidation of anilides mediated
by hypervalent iodine reagents. In 2011, Kitamura’s group
developed a simple, practical, and convenient method for the
fluorination of 1,3-dicarbonyl compounds, achieved by direct
utilization of aqueous hydrofluoric acid and iodosylbenzene
(PhIO).12 At the same time, Mtiyamoto’s group reported the
hypervalent phenyl-λ3-iodane mediated para-selective aromatic
fluorination of 3-phenylpropyl ethers, via neighboring group
participation of alkoxy substituents.13 Very recently, Gouver-
a
Table 1. Optimization of the Reaction Conditions
b
hypervalent iodine
(equiv)
yield
(%)
entry substrates
additive
HF·Py
HF·Py
BF3·Et2O/H2O
AgF
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhIO (1.5)
56
66
2
c
3
nd
c
4
nd
c
5
MgF2
nd
c
6
K2HF
nd
c
7
LiF
nd
8
HF·Py
HF·Py
HF·Py
HF·Py
HF·Py
58
44
68
85
42
9
PhI(OCOCF3)2
PhI(OPiv)2 (1.5)
PhI(OPiv)2 (1.5)
PhI(OAc)2 (1.5)
10
11
12
a
Reaction conditions: 1a or 1b (0.5 mmol), additive (6 equiv),
b
c
CH2Cl2 (5 mL), rt, 12 h. Isolated yields. No desired product was
detected by NMR analysis.
Received: September 27, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo302099d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
yields of fluorination products, while BF3·Et2O and other
villiaumites produced no fluorination product.
were obtained (entries 4 and 5). Furthermore, carbonate
protected aniline also formed a complex mixture, and no target
product was detected. We also tried some benzoyl-type
protecting groups, and the fluorination procedure usually
afforded products in moderate yields (entries 7−11). However,
the naphthoyl substrate furnished the product in only 13% yield
(entry 12).
Specifically, we first employed PIDA as the hypervalent
iodine reagent for its chemical stability and easy availability.
After 1a (1 mmol) was mixed with HF·Py (55%, 6 mmol) in
CH2Cl2 (5 mL), PhI(OAc)2 (1.2 mmol) was added, and the
mixture was stirred at room temperature for 12 h. After
purification by column chromatography, 2a was obtained in
56% yield; meanwhile, starting materials and some byproducts,
para-acetoxylation product 6a and N-iodophenylation product
6b, were detected10,11a (Scheme 1). The yield was increased to
To explore the scope of the fluorination reaction, several
aromatic amines were used. The results are summarized in
Table 3. We found that this reaction was tolerant to various
functional groups, such as alkyl, halogen, and ester groups. The
fluorination of pivaloanilide with a methyl group at the ortho-
position provided 4a in 80% yield (entry 1). Due to steric
effect, the reaction afforded 4b in 70% yield when the methyl
group was at the meta-position of pivaloanilide (entry 2).
Moreover, anilide with an o-ethyl group was fluorinated to give
4h in 64% yield (entry 8). In addition, reaction of disubstituted
anilides 3g and 3i proceeded smoothly to produce the para-
fluorinated products 4g and 4i in 78% and 72% yields,
respectively (entries 7 and 9). When the substrates contained
electron-withdrawing groups, such as halogen and ester groups,
moderate yields were obtained. The reaction mixture was more
complex and byproducts of para-pivaloylation and N-
iodophenylation were detected. These observations indicated
that the electronegativity of anilide substituent may have a great
impact on the reaction (entries 3−6 and 10). Furthermore, for
anilides with o-halogen substituents (entries 3 and 4),
prolonged reaction time was needed to finish the conversion.
We attempted the reaction with 3,4-dimethy-N-pivaloylanilines
3n; however, no desired products were detected.
Scheme 1. Reaction of Acetanilide with PhI(OAc)2
66% by using 1.5 mmol PhI(OAc)2 under the same condition.
When other hypervalent iodine reagents such as PhI-
(OCOCF3)2, PhI(OPiv)2 ,and PhIO (Table 1, entries 8−10)
were employed in this reaction, moderate yields were also
obtained. Gratifyingly, when 1b was subjected to the reaction in
the presence of PhI(OPiv)2, the side reactions were inhibited
and the product 2b was obtained in 85% yield (Table 1, entry
11).
In order to investigate the effect of protecting groups, a series
of aniline derivatives with different protecting groups were
subjected to the reaction. As summarized in Table 2, the results
showed that the pivaloyl substrate (1b) provided the highest
yield (entry 2). When trifluoroacetyl was used as the protecting
group, a 36% yield was obtained (entry 3). As for 1d and 1e
with the sulfonyl protecting groups, the reaction formed
complex mixtures, and only trace amounts of desired products
To further demonstrate the synthetic applicability of our new
fluorination method, deprotection of the pivaloyl group of 2b
was examined. After treatment with 6 N HCl in aqueous
solution under reflux, the product 4-fluoroaniline 5 was isolated
in 82% yield (Scheme 2).
Based on our results and previous literature studies,10,11
a
possible mechanism for the para-fluorination of anilide is
shown in Scheme 3. The anilide first undergoes nucleophilic
attack by PhI(OPiv)2, forming the intermediate A. Cleavage of
the N−I bond releases PhI and generates nitrenium ion
intermediate B. As stabilized by the phenyl ring, the charge
delocalized intermediate C is preferred. Finally, the inter-
mediate C was trapped by HF to give the para-fluorination
product.
Table 2. para-Fluorination of Aniline with Different
a
Protecting Groups
In conclusion, we have developed a straightforward
regioselective metal-free method for the synthesis of para-
fluorinated anilides. By employing commercially available
PhI(OPiv)2 in the presence of HF·Py, the para-selective
fluorination of anilides was achieved. This convenient
procedure provides a new access to the construction of para-
fluorinated aromatic amines.
b
entry
substrates
R group
yield (%)
1
1a
1b
1c
1d
1e
1f
Ac-
68
85
36
2
Piv-
3
CF3CO-
c
4
Ts-
nd
c
5
Ms-
nd
EXPERIMENTAL SECTION
c
■
6
EtOCO-
nd
General Experimental Methods. All chemicals were purchased
as reagent grade and used without further purification, unless
otherwise noted. Dichloromethane was distilled over calcium hydride.
Analytical TLC was performed on silica gel60 F254 precoated on glass
plates, with detection by fluorescence and/or by staining with 5%
concentrated sulfuric acid in EtOH. Column chromatography was
7
1g
1h
1i
Bz-
53
54
53
52
50
13
8
4-Cl-C6H4CO-
4-C6H5-C6H4CO-
4-Br-C6H4CO-
4-NO2-C6H4CO-
2-naphthoyl-
9
10
11
12
1j
1k
1l
1
performed employing silica gel (230−400 mesh). H NMR spectra
were recorded on Advance spectrometers at 25 °C. Chemical shifts (in
ppm) were referenced with tetramethylsilane (δ = 0 ppm) in
deuterated chloroform and deuterated dimethyl sulfoxide (δ = 2.50
ppm). 13C NMR spectra were obtained by using the same NMR
a
Reaction conditions: 1a−l (0.5 mmol), PhI(OPiv)2 (1.5 equiv),
HF·Py (6 equiv), and CH2Cl2 (5 mL) at room temperature, 12 h.
Isolated yields. No desired product was detected by NMR analysis.
b
c
B
dx.doi.org/10.1021/jo302099d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 3. para-Fluorination of Anilides Using PhI(OPiv)2/HF·Py System
a
b
c
Reaction conditions: 3a−n (0.5 mmol), PhI(OPiv)2 (1.5 equiv), HF·Py (6 equiv), and CH2Cl2 (5 mL) at room temperature. Isolated yields. The
d
reaction was carried out for 24 h. No desired product was detected by NMR analysis.
a
Scheme 2. Deprotection of 4-Fluoro-N-pivaloylaniline
Scheme 3. Proposed Reaction Mechanism
a
Reaction conditions: 2b (0.5 mmol), HCl (6 M, 2.5 mL) at refluxing
temperature.
spectrometers and were calibrated with CDCl3 (δ = 77.00 ppm) and
DMSO (δ = 39.52 ppm). High-resolution mass spectrometry was
performed on FTICR mass spectrometer.
General Procedure A for Fluorination of Anilides. To a
solution of acetylaniline (0.5 mmol) and HF·Py (270 μL, 3 mmol) in
CH2Cl2 (2.0 mL) was added a solution of PhI(OPiv)2 (305 mg, 0.75
mmol) in CH2Cl2 (3.0 mL). The reaction mixture was stirred at room
temperature for 12 h followed by quenching with 0.2 equiv of Et3N.
After the solvent was removed under vacuum, the residue was purified
by flash column chromatography on aluminum oxide (pH 10) eluted
with EtOAc/hexane.
General Procedure B for Fluorination of Anilides (3j). To a
solution of 3j (0.5 mmol) and HF·Py (270 μL, 3 mmol) in CH2Cl2
(2.0 mL) was added a solution of PhI(OPiv)2 (305 mg, 0.75 mmol) in
CH2Cl2 (3.0 mL). The reaction mixture was stirred at room
temperature for 12 h. The reaction mixture was poured into CH2Cl2
(10 mL), neutralized with NaHCO3, and extracted with CH2Cl2 (6
mL × 3). The combined organic layer was washed with saturated salt
water and dried over anhydrous Na2SO4. The residue was purified by
flash column chromatography on aluminum oxide (pH 10) eluted with
EtOAc/hexane.
4-Fluoroacetanilide (2a). Using general procedure A, compound
1
2a was isolated in 68% yield (52.0 mg, white solid); H NMR (400
MHz, CDCl3) δ 7.62 (s, 1H), 7.50−7.38 (m, 2H), 6.99 (t, J = 8.7 Hz,
2H), 2.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.5, 158.1,
C
dx.doi.org/10.1021/jo302099d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
133.8, 121.8, 115.6, 24.3; 19F NMR (376 MHz, CDCl3) δ −118.0.
These spectroscopic data correspond to previously reported data.16
4-Fluoro-N-pivaloylaniline (2b). Using general procedure A,
N-Pivaloyl-4-fluoro-2-methylaniline (4a). Using general proce-
dure A, compound 4a was isolated in 80% yield (83.7 mg, white solid);
mp 96.2−98.3 °C; H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 9.7,
1
1
5.4 Hz, 1H), 7.13 (s, 1H), 6.90 (d, J = 8.6 Hz, 2H), 2.23 (s, 3H), 1.34
(s, 9H), corresponding to previously reported data;22 13C NMR (101
MHz, CDCl3) δ 176.6, 158.7, 132.20, 131.6, 125.2, 117.0, 116.8, 113.3,
113.1, 39.6, 27.7, 17.8; 19F NMR (376 MHz, CDCl3) δ −117.6;
HRMS (ESI) m/z calcd for C12H17FNO [M + H]+: 210.1289, found
210.1290.
N-Pivaloyl-4-fluoro-3-methylaniline (4b). Using general proce-
dure A, compound 4b was isolated in 70% yield (73.2 mg, white
solid); mp 112.5−114.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (dd,
J = 6.6, 2.0 Hz, 1H), 7.30 (s, 1H), 7.23 (m, 1H), 6.93 (t, J = 9.0 Hz,
1H), 2.25 (s, 3H), 1.30 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
176.6, 159.1, 156.7, 133.6, 125.3, 125.1, 123.4, 123.3, 119.1, 119.0,
115.1, 114.9, 39.5, 27.6, 14.6, 14.6; 19F NMR (376 MHz, CDCl3) δ
−122.5; HRMS (ESI) m/z calcd for C12H17FNO [M + H]+: 210.1292,
found 210.1289.
compound 2b was isolated in 85% yield (83.0 mg, white solid); H
NMR (400 MHz, CDCl3) δ 7.48 (m, 2H), 7.28 (s, 1H), 7.02 (m, 2H),
1.32 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 121.8, 121.8, 115.6,
115.4, 27.6; 19F NMR (376 MHz, CDCl3) δ −118.3. These
spectroscopic data correspond to previously reported data.17
4-Fluorotrifluoroacetanilide (2c). Using general procedure A,
1
compound 2c was isolated in 36% yield (37.3 mg, white solid); H
NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.53 (ddd, J = 10.2, 5.1, 2.7
Hz, 2H), 7.08 (m, 2H), corresponding to previously reported data;18
13C NMR (101 MHz, CDCl3) δ 161.8, 159.3, 131.0, 122.6, 122.6,
116.3, 116.1, 114.3; 19F NMR (376 MHz, CDCl3) δ −75.7, −114.7,
corresponding to previously reported data.18
N-(4-Fluorophenyl)-benzamide (2g). Using general procedure
A, compound 2g was isolated in 53% yield (57.0 mg, colorless crystal);
1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.95 (m, 2H), 7.80
(m, 2H), 7.59 (dd, J = 5.0, 3.6 Hz, 1H), 7.53 (m, 2H), 7.20 (m, 2H);
13C NMR (101 MHz, DMSO-d6) δ 166.1, 160.1, 157.7, 136.2, 136.1,
135.4, 132.2, 129.0, 128.2, 122.8, 122.8, 115.9, 115.6, 40.7, 40.5, 40.3,
40.1, 39.9, 39.7, 39.5; 19F NMR (376 MHz, DMSO-d6) δ −118.9.
These spectroscopic data correspond to previously reported data.19
4-Chloro-N-(4-fluorophenyl)-benzamide (2h). Using general
procedure A, compound 2h was isolated in 54% yield (67.4 mg,
N-Pivaloyl-2,4-difluoroaniline (4c). Using general procedure A,
1
compound 4c was isolated in 40% yield (42.6 mg, yellow oil); H
NMR (400 MHz, CDCl3) δ 8.26 (td, J = 9.0, 6.0 Hz, 1H), 7.49 (s,
1H), 6.86 (m, 2H), 1.33 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
176.8, 159.8, 159.7, 157.4, 157.3, 154.1, 153.9, 151.5, 123.0, 123.0,
122.9, 122.9, 111.4, 111.4, 111.2, 111.2, 103.8, 103.5, 103.5, 103.3,
40.0, 27.7; 19F NMR (376 MHz, CDCl3) δ −115.5, −115.5, −127.2,
−127.2; HRMS (ESI) m/z calcd for C11H14F2NO [M + H]+:
214.1042, found 214.1038.
1
colorless crystal); H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H),
7.98 (m, 2H), 7.78 (m, 2H), 7.61 (m, 2H), 7.20 (t, J = 8.9 Hz, 2H);
13C NMR (101 MHz, DMSO-d6) δ 164.0, 136.1, 134.9, 133.1, 129.2,
128.1, 121.9, 121.8, 115.0, 114.7; 19F NMR (376 MHz, DMSO-d6) δ
−118.7. These spectroscopic data correspond to previously reported
data.20
N-Pivaloyl-2-chloro-4-fluoroaniline (4d). Using general proce-
dure A, compound 4d was isolated in 48% yield (55.0 mg, slight yellow
1
oil); H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 9.2, 5.7 Hz, 1H),
7.86 (s, 1H), 7.13 (dd, J = 8.0, 2.9 Hz, 1H), 7.00 (ddd, J = 9.1, 8.0, 2.9
Hz, 1H), 1.34 (s, 9H); 13C (101 MHz, CDCl3) δ 176.7, 159.6, 157.2,
131.4, 123.7, 122.9, 122.8, 116.4, 116.2, 114.9, 114.6, 40.2, 27.7; 19F
NMR (376 MHz, CDCl3) δ −116.7; HRMS (ESI) m/z calcd for
C11H14ClFNO [M + H]+: 230.0749, found 230.0742.
N-(4-fluorophenyl)-[1,1′-biphenyl]-4-carboxamide (2i). Using
general procedure A, compound 2i was isolated in 53% yield (77.2 mg,
1
colorless crystal); mp 232.0−234.5 °C; H NMR (400 MHz, DMSO-
d6) δ 10.35 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.82 (ddd, J = 7.1, 6.7,
4.2 Hz, 4H), 7.76 (m, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.43 (d, J = 7.2
Hz, 1H), 7.21 (dd, J = 12.2, 5.6 Hz, 2H); 13C NMR (101 MHz,
DMSO-d6) δ 165.7, 160.1, 157.7, 143.8, 139.7, 136.1, 134.2, 129.7,
129.0, 128.8, 127.5, 127.2, 122.9, 122.8, 115.9, 115.7; 19F NMR (376
MHz, DMSO-d6) δ −118.9. HRMS (ESI) m/z calcd for
C19H14FNNaO [M + Na]+: 314.0951, found 314.0952.
N-Pivaloyl-3-chloro-4-fluoroaniline (4e). Using general proce-
dure A, compound 4e was isolated in 55% yield (63 mg,slight yellow
solid); H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 6.4 Hz, 1H), 7.50
1
(s, 1H), 7.31 (dd, J = 6.8, 2.1 Hz, 1H), 7.04 (t, J = 8.7 Hz, 1H), 1.30
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 176.9, 155.9, 153.4, 134.6,
134.6, 122.6, 120.0, 119.9, 116.5, 116.2, 39.6, 27.5; 19F NMR (376
MHz, CDCl3) δ −116.6; HRMS (ESI) m/z calcd for C11H14ClFNO
[M + H]+: 230.0748, found 230.0742.
N-Pivaloyl-5-chloro-4-fluoro-2-methylaniline (4f). Using gen-
eral procedure A, compound 4f was isolated in 43% yield (52.2 mg,
slight yellow solid); mp 107.2−109.4 °C; 1H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 7.2 Hz, 1H), 7.18 (s, 1H), 6.95 (d, J = 9.4 Hz,
1H), 2.20 (s, 3H), 1.32 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
176.6, 156.2, 153.8, 132.2, 130.0, 130.0, 125.2, 117.8, 117.6, 39.6, 27.6,
17.3; 19F NMR (376 MHz, CDCl3) δ −120.4; HRMS (ESI) m/z calcd
for C12H16ClFNO [M + H]+: 244.0904, found 244.0899.
4-Bromo-N-(4-fluorophenyl)-benzamide (2j). Using general
procedure A, compound 2j was isolated in 52% yield (76.5 mg,
1
colorless crystal); H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H),
7.90 (d, J = 8.6 Hz, 2H), 7.77 (ddd, J = 15.6, 9.4, 5.1 Hz, 4H), 7.19 (t,
J = 8.8 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 165.1, 160.2,
157.8, 135.9, 134.4, 132.0, 130.4, 126.0, 122.9, 122.8, 115.9, 115.7,
40.8, 40.5, 40.3, 40.1, 39.9, 39.7, 39.5; 19F NMR (376 MHz, DMSO-
d6) δ −118.6. HRMS (ESI) m/z calcd for C13H10BrFNO [M + Na]+:
293.9925, found 293.9924.
4-Nitro-N-(4-fluorophenyl)-benzamide (2k). Using general
procedure A, compound 2k was isolated in 50% yield (65.1 mg,
colorless crystal); H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H),
N-Pivaloyl-4-fluoro-2,5-dimethylaniline (4g). Using general
procedure A, compound 4g was isolated in 78% yield (87.0 mg,
1
1
white solid); mp 116.5−117.8 °C; H NMR (400 MHz, CDCl3) δ
8.37 (m, 2H), 8.19 (m, 2H), 7.80 (m, 2H), 7.22 (dd, J = 12.2, 5.6 Hz,
2H); 13C NMR (101 MHz, DMSO-d6) δ 164.4, 160.4, 158.0, 149.8,
141.0, 135.6, 129.8, 124.2, 123.0, 123.0, 116.0, 115.8, 40.8, 40.6, 40.3,
40.1, 39.9, 39.7, 39.5; 19F NMR (376 MHz, DMSO-d6) δ −118.2.
These spectroscopic data correspond to previously reported data.20
N-(4-Fluorophenyl)-2-naphthalenecarboxamide (2l). Using
general procedure A, compound 2l was isolated in 13% yield (17.2
7.46 (d, J = 7.5 Hz, 1H), 7.21 (s, 1H), 6.79 (d, J = 10.0 Hz, 1H), 2.20
(s, 3H), 2.14 (s, 3H), 1.30 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
176.7, 159.6, 157.1, 131.1, 129.7, 129.6, 126.9, 126.8, 122.5, 122.3,
116.4, 116.2, 39.4, 27.5, 17.2, 14.1, 14.1; 19F NMR (376 MHz, CDCl3)
δ −121.9; HRMS (ESI) m/z calcd for C13H19FNO [M + H]+:
224.1445, found 224.1446.
N-Pivaloyl-2-ethyl-4-fluoroaniline (4h). Using general proce-
dure A, compound 4h was isolated in 64% yield (71.7 mg,slight yellow
solid); mp 103.5−104.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.58 (dd,
J = 8.6, 5.5 Hz, 1H), 7.28 (d, J = 6.8 Hz, 1H), 6.87 (m, 2H), 2.53 (q, J
= 7.5 Hz, 2H), 1.30 (s, 9H), 1.20 (t, J = 7.5 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 176.8, 161.5, 159.1, 138.5, 138.4, 131.0, 130.9, 126.2,
126.1, 114.9, 114.7, 113.0, 112.8, 77.3, 77.0, 76.7, 39.4, 27.5, 24.2, 13.4;
19F NMR (376 MHz, CDCl3) δ −117.0; HRMS (ESI) m/z calcd for
C13H19FNO [M + H]+: 224.1445, found 224.1445.
1
mg, colorless crystal); H NMR (400 MHz, DMSO-d6) δ 10.63 (s,
1H), 8.19 (m, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.02 (m, 1H), 7.85 (dd, J
= 8.7, 5.0 Hz, 2H), 7.76 (d, J = 7.0 Hz, 1H), 7.60 (m, 3H), 7.23 (t, J =
8.8 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 167.8, 160.1, 157.7,
136.3, 135.2, 133.8, 130.8, 130.2, 129.0, 127.6, 127.0, 126.1, 125.7,
125.6, 122.3, 122.2, 116.0, 115.8, 40.8, 40.5, 40.3, 40.1, 39.9, 39.7, 39.5.
These spectroscopic data correspond to previously reported data.21 19F
NMR (376 MHz, DMSO-d6) δ −118.8.
D
dx.doi.org/10.1021/jo302099d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
N-Pivaloyl-4-fluoro-2,6-dimethylaniline (4i). Using general
procedure A, compound 4i was isolated in 72% yield (80.7 mg,
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1
white solid); mp 124.5 −126.0 °C; H NMR (400 MHz, CDCl3) δ
7.03 (s, 1H), 6.72 (d, J = 9.1 Hz, 2H), 2.11 (s, 6H), 1.30 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 176.1, 161.4, 159.0, 137.0, 136.9, 129.2,
113.7, 113.5, 76.5, 76.2, 75.9, 38.3, 26.8, 17.5, 17.5; 19F NMR (376
MHz, CDCl3) δ −116.5; HRMS (ESI) m/z calcd for C13H19FNO [M
+ H]+: 224.1449, found 224.1445.
6-Fluoro-3-[(2,2-dimethyl-1-oxopropyl)amino]-benzoic Acid
Ethyl Ester (4j). Using general procedure B, compound 4j was
isolated in 51% yield (68.4 mg, slight yellow oil); 1H NMR (400 MHz,
CDCl3) δ 7.88 (m, 2H), 7.50 (s, 1H), 7.08 (dd, J = 10.7, 8.4 Hz, 2H),
4.37 (t, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.32 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 177.0, 164.2, 159.7, 157.1, 134.2, 134.1,
126.6, 126.5, 123.3, 117.6, 117.4, 77.5, 77.2, 76.9, 61.6, 39.7, 27.7, 14.4;
19F NMR (376 MHz, CDCl3) δ −115.0; HRMS (ESI) m/z calcd for
C14H19FNO3 [M + H]+: 268.1344, found 268.1344.
4-Fluoroaniline (5). The 4-fluoro-N-pivaloylaniline 2b (97.6 mg,
0.5 mmol) was suspended in 6 N HCl(2 mL) and stirred overnight at
100 °C. The yellow solution was cooled to room temperature and
diluted with water (2.5 mL), and then concentrated sodium hydroxide
was added dropwise until the pH was alkaline. The reaction mixture
was extracted with CH2Cl2 (6 mL × 3). The combined organic layer
was washed with brine and dried over anhydrous Na2SO4. The residue
was purified by silica gel column chromatography eluted with EtOAc/
hexane. Compound 5 was isolated in 82% yield (45.6 mg, yellow
́
(d) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66,
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1
liquid); H NMR (400 MHz, CDCl3) δ 6.84 (m, 2H), 6.60 (m, 2H),
3.50 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 157.51, 155.17, 142.35,
116.02, 115.94, 115.71, 115.48, 77.32, 77.00, 76.68; 19F NMR (376
MHz, CDCl3) δ −126.85 (m). These spectroscopic data correspond
to previously reported data.23
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ASSOCIATED CONTENT
* Supporting Information
■
S
All experimental procedures and data for compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xbmeng@bjmu.edu.cn; zjli@bjmu.edu.cn.
■
Notes
(19) Xiao, F.; Liu, Y.; Tang, C.; Deng, G. J. Org. Lett. 2012, 14, 984.
(20) Waisser, K.; Kunes, J.; Roman, M.; Budesínsky, M.; Exner, O.
̌ ̌ ̌
́
The authors declare no competing financial interest.
Phosphorus, Sulfur Silicon Relat. Elem. 1994, 97, 71.
(21) Gonec, T.; Bobal, P.; Sujan, J.; Pavlacka, L.; Vesely, L.;
Kreckova, E.; Kos, J.; Jampilek, J.; Pesko, M.; Guo, J.; Coffey, A.;
Kralova, K.; Kollar, P.; Imramovsky, A.; Placek, L. Molecules 2012, 17,
613.
ACKNOWLEDGMENTS
■
This work was financially supported by grants from the
National Basic Research Program of China (Grant No.
2012CB822100) and the National Natural Science Foundation
of China (Grant No. 20972012).
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