NHC-catalyzed generation of difluorocarbene and its application to difluoromethylation of oxygen nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2011.09.012

Controlled generation of difluorocarbene was effected by an NHC catalyst under mild conditions starting from trimethylsilyl 2,2-difluoro-2- fluorosulfonylacetate (TFDA). Cyclohexenones and tetralones were treated with TFDA in the presence of catalytic amo

Full text of DOI:10.1016/j.jfluchem.2011.09.012

Journal of Fluorine Chemistry 133 (2012) 52–60
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
NHC-catalyzed generation of difluorocarbene and its application to
difluoromethylation of oxygen nucleophiles
*
Kohei Fuchibe, Yuta Koseki, Tatsuya Aono, Hisashi Sasagawa, Junji Ichikawa
Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba 305-8571, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Controlled generation of difluorocarbene was effected by an NHC catalyst under mild conditions starting
from trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate (TFDA). Cyclohexenones and tetralones were
treated with TFDA in the presence of catalytic amounts of N,N0-dimesitylimidazolium chloride and
sodium carbonate. The ketones were difluoromethylated with the generated difluorocarbene to afford
enol difluoromethyl ethers without difluorocyclopropanation. The ethers thus obtained were
dehydrogenated with DDQ to furnish aryl difluoromethyl ethers in high yield. Under similar conditions,
secondary amides underwent difluoromethylation selectively on the oxygen atom to give difluoromethyl
imidates, which allows the formation of 2-difluoromethoxypyridines.
Received 20 August 2011
Received in revised form 23 September 2011
Accepted 28 September 2011
Available online 6 October 2011
Keywords:
Difluorocarbene
NHC
ß 2011 Elsevier B.V. All rights reserved.
Difluoromethylation
Organocatalyst
Difluoromethyl ethers
Difluoromethyl imidates
1. Introduction
(trifluoromethyl)mercury [14,15] and trimethyl(trifluoromethyl)-
stannane [16] in combination with sodium iodide are reported to
Difluorocarbene is
a
synthetically useful species for the
release difluorocarbene. However, using a stoichiometric amount
of toxic reagents should be avoided in large-scale preparations.
As described above, the reported methods for generating
difluorocarbene have following drawbacks: (i) high reaction
temperatures, (ii) strongly basic conditions, (iii) use of hazardous
reagents, and in general, (iv) high loading of reagents. These
drawbacks need to be overcome [17].
Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) is
a practically useful reagent developed by Dolbier to generate
difluorocarbene under mild conditions in a catalytic manner [18].
This reagent releases difluorocarbene in the presence of a fluoride
ion (Fꢀ, 1–2 mol%), which is presumed to attack the Si atom of
TFDA to promote decomposition (Scheme 2). The generated
difluorocarbene is employed in difluorocyclopropanation of
alkenes [18,19], alkynes [20], and allenes [21,22].
introduction of a difluoromethylene group into organic molecules
[1]. Since CF2-containig compounds play crucial roles as pharma-
ceuticals, agrochemicals, and functional materials [1a,2], advance-
ment in the generation and the utilization of difluorocarbene is
desired in contemporary organic synthesis.
To date, three types of methods have been developed for the
generation of difluorocarbene (Scheme 1). Pyrolysis has been
studied in detail for decades and adopted to generate difluorocar-
bene (Scheme 1a). Sodium chlorodifluoroacetate (CClF2CO2Na),
which requires a high temperature (typically >120 8C), acts as a
representative reagent for this purpose [3–5]. Hexafluoropropyrene
oxide (HFPO, >150 8C) [6] and hexafluorocyclopropane (160–
170 8C) [7] also work as thermal precursors to difluorocarbene [8,9].
a
-Elimination of HCl and its analogous reactions are convenient
alternatives for the above-mentioned pyrolysis (Scheme 1b).
Chlorodifluoromethane (HCFC-22) is the reagent of choice to
release difluorocarbene at relatively low temperatures, although
Although useful, the rapid generation of difluorocarbene from
TFDA may cause an overreaction. When alkyl ketones were treated
by the TFDA/Fꢀ system, the formed enol difluoromethyl ethers
underwent further difluorocyclopropanation with the second
molecule of difluorocarbene [23].
To control the reaction, we focused on N-heterocyclic carbene
(NHC) as an activator of TFDA. NHC is a stable and nucleophilic
carbene [24], and acts as an organocatalyst in various synthetic
reactions [25]. Note that various NHC-catalyzed cyanosilylations
[26], aldol condensations [27], azidations [28], and trifluoro-
methylations [29] with Si-containing reagents have been reported
[30]. Because the reactivity of NHC can be tuned by altering the
strongly basic conditions are required [10]. Recently,
a-elimina-
tions triggered by nucleophilic substitutions on carbonyl group
[11] and sulfonyl group [12] are reported [13].
Decomposition of trifluoromethylmetal reagents provides
another route to difluorocarbene (Scheme 1c). Phenyl
* Corresponding author.
E-mail address: junji@chem.tsukuba.ac.jp (J. Ichikawa).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.09.012

K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
53
F–
O–SiMe3
F
F
O
O O
S
F
– CO2, – SO2
– Me3SiF
CClF2CO2Na,
(a)
, etc.
F–
:
CF2
+
F
CF3
HFPO
O
F
F
TFDA
Scheme 2. Generation of difluorocarbene by the TFDA/Fꢀ system.
Δ
:
CF2
(b)
O
(c)
Base
resulted in the formation of considerable amounts of difluorocy-
clopropane 3, making the reaction less selective (Entries 10–12).
The use of sodium carbonate with a ratio of 10:1 to IMesꢁHCl
was found to be suitable to achieve a high yield of 2a (Table 2).
When the loading of sodium carbonate was reduced to 2 mol%
(Na2CO3:IMesꢁHCl = 1:1), the yield of 2a decreased to 54% (Entry
1). On the other hand, the 100 mol% loading of sodium carbonate
(Na2CO3:IMesꢁHCl = 50:1) also reduced the yield of 2a, and the
undesired 3 was obtained in 32% yield (Entry 3). The use of larger
amounts of sodium carbonate also resulted in rapid formation of
difluorocarbene, leading to the undesired difluorocyclopropana-
tion reaction of 2a. Potassium carbonate, potassium tert-butoxide,
and DBU in place of sodium carbonate gave inferior results (Entries
4–6).
Effects of temperature and solvent were examined (Table 3).
The reaction of indan-1-one 1a at 70 8C gave 2a in 39% yield (Entry
1). The yield of 2a was improved up to 70% at 80 8C (Entry 2),
whereas elevating the temperature to 90 8C showed no further
improvement (Entry 3). Thus, NHC is an efficient catalyst that acts
at 80 8C. 1,4-Dioxane and 1,1,2,2-tetrachloroethane were not
suitable solvents (Entries 4 and 5).
– MI
or Nu–
, etc.
Cl
H
F F
PhHgCF3
Me3SnCF3
+ NaI
Cl
,
Ph
, etc.
F F
Scheme 1. Conventional methods for difluorocarbene generation.
central heterocyclic core and the substituents on nitrogen, NHC is a
promising candidate for the activation of TFDA to regulate the
generation of difluorocarbene.
Based on the considerations described above, NHC-catalyzed
generation of difluorocarbene from TFDA were examined and
applied to difluoromethylation of oxygen nucleophiles. The details
of our investigations are described below.
2. Results and discussion
2.1. Reaction conditions
Indan-1-one 1a was selected as a model substrate for O-
difluoromethylation and treated with TFDA (2 equiv) in the
presence of 1–10 mol% of activators for TFDA. The yields of the
produced enol ether 2a and the undesired overreaction product
difluorocyclopropane 3 were determined by 19F NMR spectrosco-
py. The results of our examination on the activators are
summarized in Table 1.
NHC was conclusively found to be a suitable catalyst that can
control the rate of difluorocarbene generation from TFDA. By
optimizing the NHC catalyst and reaction conditions, indan-1-one
1a was successfully transformed into the corresponding enol
difluoromethyl ether 2a in a selective manner.
2.2. Mechanism of enol difluoromethyl ether formation
Fluoride ion, the activator originally adopted by Dolbier at 105–
120 8C [18b], gave only a 14% yield of 2a at 80 8C (Entry 1). Other
reagents such as DABCO and amine N-oxides, which can activate
Si-containing reagents [31], were found to be ineffective (Entries 2
and 3).
The difluorocarbene generation proceeded smoothly by using
an NHC catalyst. 1,3-Dimesitylimidazolylidene (IMes), generated
in situ from 1,3-dimesitylimidazolium chloride (IMesꢁHCl, 1 and
2 mol%) and sodium carbonate (10 and 20 mol%), gave 2a in 70%
and 74% yield, respectively (Entries 5 and 6). In these cases, only a
trace amount of 3 was observed. Note that the enol ether 2a was
stable enough upon standard silica gel chromatography and was
isolated in reasonable yield (Entry 6). Reducing the loadings of
TFDA from 2 to 1.2 equiv resulted in a diminished yield of 2a (61%,
Entry 7). IMesꢁHCl alone did not work well (4% of 2a, Entry 8),
which shows the effect of NHC.
Scheme 3 shows the proposed mechanism for the generation of
difluorocarbene and the formation of enol difluoromethyl ethers.
IMes, generated from IMesꢁHCl and sodium carbonate in situ,
attacks the Si atom of TFDA. Decomposition of TFDA provides the
key difluorocarbene, accompanied by formation of CO2, SO2, and
fluoride ion. The formed silylimidazolium salt A undergoes
desilylation with the released fluoride ion to regenerate free IMes.
The generated difluorocarbene reacts with 1a to afford 2a,
presumably via oxycarbenium intermediates [23b].
During the above experiments, tetrafluoroethylene was ob-
served in the 19F NMR spectra of the reaction mixtures (4 ppm vs.
C6F6) [32]. This suggests that difluorocarbene was actually formed
in the reaction medium.
2.3. Synthesis of aryl difluoromethyl ethers
It must be mentioned that isolated IMes gave a decreased yield
of 2a (52%) along with a 17% yield of 3 (Entry 9). The rapid
generation of difluorocarbene leads to undesired difluorocyclo-
propanation, even with the NHC catalyst. The use of imidazolinium
salt SIMesꢁHCl, triazolium salt 4ꢁHBr, and thiazolium salt 5ꢁHI also
2.3.1. Background and strategy
Aryl difluoromethyl ether units are often found in structures of
pharmaceuticals, agrochemicals, and their candidates. For exam-
ple, pantoprazole is a proton pump inhibitor and is used for a

54
K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
Table 1
NHC-catalyzed generation of difluorocarbene and formation of enol difluoromethyl ethers: effect of activator for TFDA.
Entry
Activator
Time (h)
2a (%)a
3 (%)a
1
2
3
4
5
6
NaF (1 mol%)
4
14
–
DABCO (2 mol%)
1
40
<1
–
Pyridine N-oxide (10 mol%)
NMO (10 mol%)
1
Trace
5
1
Trace
–
IMesꢁHCl (1 mol%), Na2CO3 (10 mol%)
IMesꢁHCl (2 mol%), Na2CO3 (20 mol%)
IMesꢁHCl (2 mol%), Na2CO3 (20 mol%)
IMesꢁHCl (1 mol%)
0.5
0.5
0.5
4
70
b
74, 72
61
Trace
7
c
7
8
4
–
9
IMesꢁ(1 mol%)
0.5
0.5
1
52
17
26
30
17
10
11
12
SIMesꢁHCl (2 mol%), Na2CO3 (20 mol%)
4ꢁHBr (2 mol%), Na2CO3 (20 mol%)
5ꢁHI (2 mol%), Na2CO3 (20 mol%)
54
46
1
34
DABCO = 1,4-diazabicyclo[2.2.2]octane; NMO = N-methylmorpholine N-oxide.
a
19F NMR yield based on (CF3)2C(p-Tol)2.
b
Isolated yield.
c
TFDA (1.2 equiv).
short-term treatment of erosion and ulceration of esophagus [33].
Zardaverine is a phosphodiesterase III/IV inhibitor and attracts
much attention as a potential therapeutic agent for asthma [34].
Brofluthrinate [35] is an insecticide that acts as a sodium channel
modulator [36] (Fig. 1).
above-mentioned selective formation of enol difluoromethyl
ethers (Scheme 4): six-membered ketones (cyclohexanone and
tetralone derivatives) would be transformed into the correspond-
ing enol difluoromethyl ethers with difluorocarbene, generated
by the NHC catalyst. The formed enol difluoromethyl ethers might
To date, aryl difluoromethyl ethers have been synthesized by an
electrophilic difluoromethylation of phenols with difluorocarbene
[37]. For instance, phenoxides are difluoromethylenated with
F–SiMe3
difluorocarbene, generated by
a-elimination of chlorodifluoro-
methane, to give aryl difluoromethyl ethers after protonation:
however, the preparation of the starting phenols is required [10a–
c,38,39].
Mes
+ F–
+ CO2
+ SO2
Mes
N
+
N
Me3Si
We envisaged developing
a new synthetic method for
N
N
aryl difluoromethyl ethers with substituents by utilizing the
Mes
Mes
A
IMes
Table 2
Effect of base.a
O
O
O
S
Entry
Base
Time (h)
2a (%)b
3 (%)b
OSiMe3
F
F
F
1
Na2CO3 (2 mol%)
Na2CO3 (20 mol%)
Na2CO3 (100 mol%)
K2CO3 (20 mol%)
t-BuOK (20 mol%)
DBU (2 mol%)
0.5
0.5
0.5
1
54
74
40
37
20
15
–
:
CF2
2c
3
Trace
32
2
O
OCHF2
CF2
O
4
5
0.5
0.5
–
6
–
1a
2a
DBU =1,8-diazabicyclo[5.4.0]undec-7-ene.
a
1a, TFDA (2 equiv), IMesꢁHCl (2 mol%), base, toluene, 80 8C.
19F NMR yield based on (CF3)2C(p-Tol)2.
Table 1, Entry 6.
Scheme 3. Proposed mechanism for CF2 generation and CHF2 ether formation.
b
c
OMe
N
OMe
OCF2H
OCF2H
N
MeO
S
O
Table 3
O
N
H
Effects of solvent and temperature.a
HN
N
Entry
Solvent
Temperature ( 8C)
Time (h)
2a (%)b
3 (%)b
Zardaverine
Pantoprazole
1
2c
3
Toluene
70
80
90
80
80
2
39
70
68
34
23
–
CN
O
Toluene
0.5
1
–
O
Toluene
Trace
Br
O
OCF2H
4
1,4-Dioxane
CHCl2CHCl2
1
–
–
5
1
a
Brofluthrinate
Fig. 1. Examples of bioactive aryl difluoromethyl ethers.
1a, TFDA (2 equiv), IMesꢁHCl (1 mol%), Na2CO3 (10 mol%).
19F NMR yield based on (CF3)2C(p-Tol)2.
Table 1, Entry 5.
b
c

K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
55
1 mol% IMes·HCl
TFDA (2.0 equiv)
O
OCHF2
OCHF2
O
OCF2H
:
CF2
– H2
R
R
R
10 mol% Na2CO3
O
Ph
O
Ph
Toluene, 80 °C, 1 h
1k
2k 50%
Scheme 4. Synthetic strategy for substituted aryl difluoromethyl ethers.
3 mol% SIMes·HCl
TFDA (2.0 equiv)
O
OCHF2
be readily dehydrogenated to construct a benzene ring, thus
targeting aryl difluoromethyl ethers [40]. Commercial and
synthetic availability of the cyclohexanone derivatives makes
this a practical approach for the synthesis of substituted aryl
difluoromethyl ethers.
30 mol% Na2CO3
Ph
1l
Ph
2l 57%
Toluene, 90 °C, 1 h
Scheme 5. Synthesis of cyclic and acyclic enol difluoromethyl ethers (19F NMR
yield).
2.3.2. One-pot synthesis of aryl difluoromethyl ethers
Various aryl difluoromethyl ethers were successfully synthe-
sized from cyclohexenones and tetralones via the expected
difluoromethylation–dehydrogenation sequence (Table 4). First,
3-phenylcylclohexenone 1b was transformed into the correspond-
ing enol difluoromethyl ether 2b (not shown) by the TFDA/NHC
system (Entry 1). The resulting mixture was treated with DDQ
(2 equiv) under reflux. Standard chromatographic separation of
the products gave biphenyl-3-yl difluoromethyl ether 6b in 78%
yield.
This method was successfully applied to tetralone deriva-
tives, which produced difluoromethyl naphthyl ethers. Not only
did parent 1c give 1-naphthyl ethers 6c in 81% yield, but also
bromo- and chlorotetralones 1d and 1e afforded the halogenat-
ed naphthyl ethers 6d and 6e in 75% and 77% yield, respectively
(Entries 2–4). Electron-rich tetralones appeared to be suitable
for this reaction: Methyl- and methoxy-substituted tetralones
1f–h afforded the corresponding naphthyl ethers 6f–h in 79–
the formation of the corresponding 2-naphthyl ether 6i in 90%
yield (Entry 8). A similar treatment of cyclohexanone 1j also
provided the corresponding biphenyl-4-yl difluoromethyl ether
6j (Entry 9).
Note that the TFDA/NHC system can be applied to the
synthesis of other enol difluoromethyl ethers (Scheme 5).
Flavanone 1k was transformed into the corresponding difluor-
omethoxychromene 2k in 50% yield. In addition, acetophenone 1l
afforded the corresponding enol ether 2l in 57% yield in the
presence of 3 mol% of SIMesꢁHCl catayst. It has been reported that
the treatment of 1l by the TFDA/Fꢀ system gives difluorocyclo-
propanated difluoromethyl ether in 27% yield at 120 8C [23a].
NHC was again found to be an efficient and selective catalyst for
the synthesis of enol difluoromethyl ethers. As described above,
NHC-catalyzed, controlled generation of difluorocarbene from
TFDA has realized a ketone-based one-pot synthesis of aryl
difluoromethyl ethers.
91% yield (Entries 5–7). The reaction of
b-tetralone 1i allowed
Table 4
One-pot synthesis of aryl difluoromethyl ethers.
2 mol% IMes·HCl
O
OCHF2
R
OCHF2
R
DDQ (2 equiv)
100 °C, 1–2 h
TFDA
R
20 mol% Na2CO3
Toluene, 80 °C, 1 h
1
2
6
.
Entry
1
1
6
TFDA (equiv)
2.0
Temp. (8C)
Yield (%)a
78
1b
6b
80
2
3
4
5
1c (R = H)
1d (R = Br)
1e (R = Cl)
1f
6c
6d
6e
6f
2.0
1.6
1.6
2.0
100
100
80
81
75
77
79
100
6
7
1g
1h
6g
6h
1.2
1.2
80
80
91
86
8b
9
1i
1j
6i
6j
1.6
1.6
100
100
90
63
DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone.
a
Yield in two steps.
b
The corresponding enol ether was obtained as a regioisomeric mixture (conjugated:nonconjugated = 88:12, 19F NMR).

56
K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
NR2
OCHF2
N
R2NH
OCF2
2NH
R2NH
:
CF2
R
R
R1
OCHF2
R1
R1
O
R1
O
C
Difluoromethyl
imidates
2-Difluoromethoxy-
pyridines
NR2
OCHF2
O-selective
H shift
Fig. 2.
R1
R2NH
O
R2N
CHClF2, NaOH
Scheme 7. Strategy for selective synthesis of difluoromethyl imidates.
Na
O
R1
R1
ambident anion B
5 mol%
NR2
R2NCHF2
NHC precursor
+
NPh
OCHF2
PhNH
Ph
7a
Ph
NCHF
TFDA (2.0 equiv)
OCHF2
O
2
then H3O+
R1
R1
+
20 mol% Na2CO3
Toluene, 80 °C
30 min
Ph
O
Ph
O
Scheme 6. Reported nonselective formation of difluoromethyl imidates under basic
8a
9
conditions.
–
–
–
–
0–53%
56%
80%
5%
IMes·HCl (20–30 min);
SIMes·HCl;
4·HBr;
2.4. Synthesis of difluoromethyl imidates
5·HI;
Scheme 8. Optimization of NHC precursors in difluoromethyl imidate formation
19F NMR yield).
2.4.1. Background and strategy
(
Difluoromethyl imidate is contained in the structure of 2-
difluoromethoxypyridine, which is a motif frequently found in
pharmaceuticals and bioactive molecules (Fig. 2) [41,42]. Difluor-
omethyl imidates have been synthesized by electrophilic O-
difluoromethylation of secondary amides with difluorocarbene
(Scheme 6). However, these difluoromethylations led to only a
partial success, which was due to affording a regioisomeric
mixture of O- and N-difluoromethylated products [43]. The poor
selectivity is presumably because the basic conditions, required for
the generation of difluorocarbene, cause deprotonation of the
amides. The resulting ambident anion B allows formation of not
only O- but also N-difluoromethylation products.
In general, (nondeprotonated) amides undergo alkylations on
the oxygen atom because the oxygen center is more nucleophilic
than the nitrogen center because of resonance (Scheme 7, C).
Having the NHC-catalyzed generation of difluorocarbene under
nearly neutral conditions in hand, we expected O-selective
difluoromethylation of amides to synthesize difluoromethyl
imidates [44].
the undesired tertiary amide 9 was not observed over all the NHC
precursors examined as a catalyst.
Various difluoromethyl imidates were efficiently synthesized
by the triazolium salt-based system (Table 5). Not only benzoic
acid-derived amides but also aliphatic acid-derived amides
afforded the corresponding imidates in high yield (Entries 1–4):
namely, amides 7a–d gave 8a–d in 66–81% yield. Electron-
donating and -withdrawing group on the N-aryl groups did not
affect the reaction (Entries 5–8). Although some amount of the
imidates decomposed during purification by column chromatog-
raphy, 19F NMR analysis suggested that substituted anilides 7e–h
gave 8e–h in 69–83% yield. It must be emphasized that the
undesired N-difluoromethylated products were not observed by
the 19F NMR analysis of the crude mixtures.
This method was successfully applied to the synthesis of 2-
difluoromethoxypyridines (Scheme 9). When pyridone 7i was
subjected to the TFDA/NHC system, the desired 8i was obtained in
60% yield, albeit accompanied by a 9% yield of N-difluoromethy-
lated product. The sequential difluoromethylation–dehydrogena-
tion process is also effective for six-membered lactams: 2-
difluoromethoxyquinoline 9 was synthesized from dihydroquio-
nolinone 7j in 92% yield in a one-pot operation.
2.4.2. Selective synthesis of difluoromethyl imidates
We optimized NHC precursors for difluoromethylation of
secondary amides (Scheme 8). It was revealed that IMesꢁHCl
was lacking in reproducibility and that triazolium salt 4ꢁHBr was a
suitable catalyst for this purpose [45]. Note that the formation of
5 mol% 4·HBr
O
OCHF2
N
O
TFDA (2.0 equiv)
+
NH
NCHF2
9%
20 mol% Na2CO3
Toluene, 80 °C, 0.3 h
7i
8i 60%
19F NMR yield)
(
H
N
N
OCHF2
N
OCHF2
As above
DDQ (1 equiv)
80 °C, 0.5 h
O
7j
8j
Scheme 9. Synthesis of 2-difluoromethoxypyridines.
9 92%

K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
57
Table 5
Selective synthesis of difluoromethyl imidates.
5 mol% 4·HBr
R2NH
TFDA (2.0 equiv)
NR2
OCHF2
R2
R1
NCHF2
O
SMe
N
+
NMes Br–
20 mol% Na2CO3
Toluene, 80 °C
R1
MesN
R1
O
7
8
not observed
4·HBr
Entry
1
7
Time (h)
0.5
8
Yield (%)a
7a
8a
8b
8c
8d
8e
80
2
3
4
5
7b
7c
7d
7e
0.4
0.4
0.3
0.3
74
66
81
62, 83b
6
7
8
7f
7g
7h
0.3
0.4
0.3
8f
8g
8h
62, 69b
72, 83b
67, 77b
a
Imidates were obtained selectively.
19F NMR yield based on (CF3)2CTol2.
b
3. Conclusion
4.2. Synthesis of aryl difluoromethyl ethers
We have developed a versatile method for the controlled
generation of difluorocarbene from TFDA under mild conditions by
using NHC catalyst. Cyclohexenones and tetralones were trans-
formed into enol difluoromethyl ethers without difluorocyclopro-
panation. The enol ethers obtained were dehydrogenated with
DDQ to provide substituted aryl difluoromethyl ethers. Moreover,
secondary amides were similarly transformed into difluoromethyl
imidates via O-selective difluoromethylation, which allows the
formation of 2-difluoromethoxypyridines.
4.2.1. Typical procedure for synthesizing aryl difluoromethyl ethers
To
toluene solution (0.4 mL) of IMesꢁHCl (2.7 mg,
0.0079 mmol), sodium carbonate (8.5 mg, 0.080 mmol), and 6,7-
dimethyl- -tetralone 1g (70 mg, 0.40 mmol) was added TFDA
(100 L, 0.48 mmol) at room temperature. The reaction mixture
was stirred and heated at 80 8C for 1 h. After cooling the resulting
mixture to room temperature, DDQ (182 mg, 0.80 mmol) and
toluene (2 mL) was added and the mixture was heated at 100 8C for
2 h. Purification by column chromatography (SiO2, hexane) gave 6g
(82 mg, 91% yield).
a
a
m
4. Experimental
4.2.2. Spectra data of aryl difluoromethyl ethers
4.1. General information
4.2.2.1. 1-Difluoromethoxy-3-phenylbenzene
(6b). 1H
NMR
(500 MHz, CDCl3): = 7.56–7.59 (m, 2H), 7.41–7.48 (m, 4H),
d
IR spectra were recorded on Horiba FT-300S spectrometer.
NMR spectra were recorded on Bruker Avance 500, Bruker
AV600, or Bruker AV400 spectrometers in CDCl3, at 500, 600, or
400 MHz (1H NMR), at 126, 150, or 100 MHz (13C NMR), and at
470, 565, or 372 MHz (19F NMR). Chemical shift values were
7.38 (tt, J = 7.4, 2.1 Hz, 1H), 7.34 (s, 1H), 7.10 (dt, J = 2.4 Hz,
2
J = 6.7 Hz, 1H), 6.57 (t, JHF = 74.0 Hz, 1H). 13C NMR (126 MHz,
CDCl3):
d = 151.6, 143.3, 139.9, 130.1, 128.9, 127.9, 127.1, 124.2,
1
118.3, 118.1, 116.0 (t, JCF = 258 Hz). 19F NMR (470 MHz, CDCl3):
= 81.3 (d, 2JFH = 74 Hz, 2F). IR (neat):
n
˜ ¼ 1477, 1196, 1122, 912,
given in ppm relative to internal Me4Si (for 1H NMR:
CDCl3 (for 13C NMR: = 77.0), and C6F6 (for 19F NMR:
= 0.0) [32].
d
= 0.00),
d
741, 696 cm–1. HRMS (70 eV, EI): m/z calcd. for C13H10F2O ([M]+):
d
d
220.0700; found: 220.0689.
Mass spectra were taken with JMS-T100GCV spectrometer.
Elemental analyses were performed with a YANAKO MT-6
CHN Corder apparatus. TFDA was prepared according to the
procedure described by Dolbier [18b]. IMesꢁHCl and SIMesꢁHCl
were prepared according to the literature [46]. IMes, 4ꢁHBr, 5ꢁHI
were purchased and used without further purification. All the
reactions were conducted under argon. Column chromatography
and preparative thin-layer chromatography (PTLC) were per-
formed on silica gel.
4.2.2.2. 1-Difluoromethoxynaphthalene (6c). 1H NMR (500 MHz,
CDCl3):
d = 8.18–8.21 (m, 1H), 7.84–7.88 (m, 1H), 7.70 (d,
J = 8.3 Hz, 1H), 7.52–7.58 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.19 (d,
2
J = 7.5 Hz, 1H), 6.66 (t, JHF = 74.1 Hz, 1H). 13C NMR (126 MHz,
CDCl3):
121.6, 116.6 (t, JCF = 256 Hz), 113.7. 19F NMR (470 MHz, CDCl3):
= 81.9 (d, 2JFH = 74 Hz, 2F). IR (neat):
˜ ¼ 3059, 1373, 1120, 1051,
d = 147.4, 134.7, 127.7, 126.9, 126.6, 126.4, 125.4, 125.3,
1
d
n

58
K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
771 cmꢀ1. HRMS (70 eV, EI): m/z calcd. for C11H8F2O ([M]+):
194.0543; found: 194.0548.
7.36 (t, J = 6.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.55 (t, J = 74.0 Hz,
3
1H). 13C NMR (126 MHz, CDCl3):
d = 150.6 (t, JCF = 2.7 Hz), 140.1,
138.6, 128.8, 128.5, 127.4, 127.0, 119.8, 115.9 (t, 1JCF = 258 Hz). 19
F
4.2.2.3. 7-Bromo-1-difluoromethoxynaphthalene (6d). 1H NMR
NMR (470 MHz, CDCl3):
d
= 81.1 (d, JFH = 74 Hz, 2F). IR (neat):
2
(500 MHz, CDCl3):
d
= 8.34 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.67
n
˜ ¼ 3033, 1487, 1223, 1126, 764 cmꢀ1. HRMS (70 eV, EI): m/z calcd.
(d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.8, 1.9 Hz, 1H), 7.44 (t, J = 8.0 Hz,
for C13H10F2O ([M]+): 220.0700; found: 220.0699.
2
1H), 7.23 (d, J = 8.0 Hz, 1H), 6.68 (t, JHF = 73.6 Hz, 1H). 13C NMR
(126 MHz, CDCl3):
d
= 146.3, 133.0, 130.4, 129.4, 127.4, 125.8,
4.2.2.10. 4-Difluoromethoxy-2-phenylchromene
(2k). 1H
NMR
1
125.1, 124.1, 120.9, 116.2 (t, JCF = 256 Hz), 114.5. 19F NMR
(500 MHz, CDCl3): d = 7.44–7.47 (m, 2H), 7.33–7.42 (m, 4H),
2
(470 MHz, CDCl3):
d
= 81.5 (d, JFH = 74 Hz, 2F). IR (neat):
7.21 (dt, J = 5.0, 1.5 Hz, 1H), 6.94 (dt, J = 7.5, 1.0 Hz, 1H), 6.83 (dd,
2
n
˜ ¼ 3062, 1589, 1124, 1049, 823, 742 cmꢀ1. HRMS (70 eV, EI):
J = 8.0, 1.0 Hz, 1H), 6.55 (t, JHF = 74.0 Hz, 1H), 6.02 (d, J = 3.5 Hz,
m/z calcd. for C11H779BrF2O ([M]+): 271.9648; found: 271.9644.
1H), 5.29 (d, J = 3.5 Hz, 1H). 13C NMR (126 MHz, CDCl3):
d = 154.1,
143.8, 140.2, 131.0, 128.71, 128.67, 126.9, 122.0, 121.2, 117.5,
1
4.2.2.4. 7-Chloro-1-difluoromethoxynaphthalene (6e). 1H NMR
116.1, 115.3 (t, JCF = 260 Hz), 103.7, 77.1. 19F NMR (470 MHz,
2
(500 MHz, CDCl3):
d
= 8.16 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.68
CDCl3):
d
= 80.0 (d, JFH = 74 Hz, 2F). IR (neat):
n
˜ ¼ 3033, 1655,
(d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.8, 2.1 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1
1454, 1122, 756 cmꢀ1. HRMS (70 eV, EI): m/z calcd. for C16H12F2O2
H), 7.23 (d, J = 7.9 Hz, 1H), 6.68 (t, JHF = 73.7 Hz, 1H). 13C NMR
([M]+): 274.0805; found: 274.0811.
2
(126 MHz, CDCl3):
d = 146.4, 132.8, 132.7, 129.4, 127.9, 127.1,
1
125.6, 125.1, 120.8, 116.2 (t, JCF = 259 Hz), 114.5. 19F NMR
4.2.2.11. 1-Difluoromethoxystyrene (2l). 1H NMR (500 MHz,
CDCl3): d = 7.59–7.61 (m, 2H), 7.36–7.39 (m, 3H), 6.53 (t,
2
(470 MHz, CDCl3):
d
= 81.5 (d, JFH = 74 Hz, 2F). IR (neat):
n
˜ ¼ 2918, 1593, 1358, 1119, 1032, 822 cmꢀ1. HRMS (70 eV, EI):
J = 74.0 Hz, 1H), 5.13 (d, J = 3.4 Hz, 1H), 4.74 (d, J = 3.4 Hz, 1H).
m/z calcd. for C11H735ClF2O ([M]+): 228.0154; found: 228.0145
13C NMR (126 MHz, CDCl3):
d
= 154.3, 133.6, 129.4, 128.5, 125.3,
1
115.8 (t, JCF = 258 Hz), 93.0. 19F NMR (470 MHz, CDCl3):
d = 80.3
4.2.2.5. 1-Difluoromethoxy-7-methylnaphthalene (6f). 1H NMR
(500 MHz, CDCl3):
(d, JFH = 74 Hz, 2F). IR (neat):
n
˜ ¼ 2927, 1635, 1126, 1047,
2
d
= 7.94 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.66
771 cmꢀ1. HRMS (70 eV, EI): m/z calcd. for C9H8F2O ([M]+):
(d, J = 8.3 Hz, 1H), 7.38 (dd, J = 8.4, 1.6 Hz, 1H), 7.34 (t, J = 7.9 Hz,
1H), 7.16 (d, J = 7.9 Hz, 1H), 6.65 (t, 2JH–F = 74.2 Hz, 1H), 2.55 (s, 3H).
170.0543; found: 170.0542.
13C NMR (126 MHz, CDCl3):
d
= 147.0, 136.5, 133.0, 129.2, 127.6,
4.3. Synthesis of difluoromethyl imidates
1
126.6, 125.1, 124.3, 120.4, 116.6 (t, JCF = 257 Hz), 113.8, 22.0. 19F
2
NMR (470 MHz, CDCl3):
d
= 82.0 (d, JFH = 74 Hz, 2F). IR (neat):
˜ ¼ 3062, 1365, 1115, 1032, 822 cmꢀ1. HRMS (70 eV, EI): m/z calcd.
4.3.1. Typical procedure for synthesizing difluoromethyl imidates
To a toluene solution (1.5 mL) of 4ꢁHBr (3.4 mg, 0.0098 mmol),
sodium carbonate (4.2 mg, 0.040 mmol), and N-phenylcyclohex-
n
for C12H10F2O ([M]+): 208.0700; found: 208.0699.
anecarboxamide 7d (39 mg, 0.19 mmol) was added TFDA (75
mL,
4.2.2.6. 1-Difluoromethoxy-6,7-dimethylnaphthalene (6g). 1H NMR
0.38 mmol) at room temperature. The reaction mixture was stirred
and heated at 80 8C for 20 min. After cooling the resulting mixture
to room temperature, aquaus NaOH was added to quench the
reaction. Extraction with dichloromethane and purification by
column chromatography (SiO2, hexane:AcOEt = 50:1, 0 8C) gave 8d
(39 mg, 81% yield).
(500 MHz, CDCl3):
d = 7.91 (s, 1H), 7.61 (s, 1H), 7.59 (d, J = 7.8 Hz,
1H), 7.31 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.65 (t,
2JHF = 74.4 Hz, 1H), 2.47 (s, 3H), 2.44 (s, 3H). 13C NMR (126 MHz,
CDCl3):
d = 146.9, 136.8, 136.6, 133.7, 127.3, 125.1, 124.4 (2C),
120.9, 116.7 (t, 1JCF = 250 Hz), 112.8, 20.4, 20.2. 19F NMR (470 MHz,
2
CDCl3):
d
= 82.2 (d, JFH = 74 Hz, 2F). IR (neat):
n
˜ ¼ 2920, 1606,
1379, 1122, 1045 cmꢀ1. HRMS (70 eV, EI): m/z calcd. for C13H12F2O
4.3.2. Spectra data of difluoromethyl imidates
([M]+): 222.0856; found: 222.0865.
4.3.2.1. Difluoromethyl N-phenyl-1-phenylmethanimidate (8a). 1H
d
= 7.48 (t, 2JHF = 72.8 Hz, 1H, broad), 7.38
4.2.2.7. 1-Difluoromethoxy-6-methoxynaphthalene (6h). 1H NMR
NMR (500 MHz, CDCl3):
(t, J = 7.5 Hz, 2H), 7.22–7.29 (m, 5H), 7.05 (t, J = 7.5 Hz, 1H), 6.78 (d,
(500 MHz, CDCl3):
d = 8.09 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 8.4 Hz,
J = 7.5 Hz, 2H). 13C NMR (126 MHz, CDCl3):
d = 153.4 (broad), 146.0,
1 H), 7.38 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 9.2, 2.6 Hz, 1H), 7.15 (d,
131.2, 129.5, 129.2, 128.2, 123.9, 120.9, 113.6 (t, 1JCF = 255 Hz). 19
F
2
J = 2.6 Hz, 1H), 7.03 (dd, J = 7.7, 1.0 Hz, 1H), 6.65 (t, JHF = 74.2 Hz,
2
1H), 3.93 (s, 3H). 13C NMR (126 MHz, CDCl3):
d = 158.4, 147.6,
NMR (470 MHz, CDCl3):
n
d
= 70.8 (d, JFH = 73 Hz, 2F). IR (neat):
˜ ¼ 2929, 1687, 1267, 1113, 912, 744 cmꢀ1. HRMS (70 eV, EI): m/z
1
136.2, 126.1, 124.1, 123.3, 121.6, 119.3, 116.5 (t, JCF = 257 Hz),
111.2, 105.7, 55.3. 19F NMR (470 MHz, CDCl3):
= 82.0 (d,
calcd. for C14H11F2NO ([M]+): 247.0809; Found: 247.0812.
d
2JFH = 74 Hz, 2F). IR (neat):
n
˜ ¼ 1635, 1516, 1255, 1171,
4.3.2.2. Difluoromethyl N-phenylethan-1-imidate (8b). 1H NMR
1132 cmꢀ1. HRMS (70 eV, EI): m/z calcd. for C12H10F2O2 ([M]+):
2
(500 MHz, CDCl3):
d
= 7.37 (t, JHF = 72.1 Hz, 1H), 7.32 (t,
224.0649; found: 224.0656.
J = 7.6 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 2H),
1.94 (s, 3H). 13C NMR (126 MHz, CDCl3):
d = 157.3, 146.3, 129.2,
4.2.2.8. 2-Difluoromethoxynaphthalene (6i). 1H NMR (600 MHz,
1
124.1, 120.5, 113.0 (t, JCF = 255 Hz), 15.6. 19F NMR (470 MHz,
CDCl3):
d = 7.85 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.80
2
CDCl3):
d
= 71.0 (d, JFH = 72 Hz, 2F). IR (neat):
n˜ ¼ 1701, 1238,
(d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.52 (t, J = 9.0 Hz, 1H), 7.45–7.49 (t,
1105, 1086, 912 cmꢀ1. HRMS (70 eV, EI): m/z calcd. for C9H9F2NO
([M]+): 185.0652; found: 185.0653.
2
J = 9.0 Hz, 1H), 7.28 (dd, J = 9.0, 2.4 Hz, 1H), 6.63 (t, JHF = 73.9 Hz,
1H). 13C NMR (100 MHz, CDCl3):
d = 149.0, 133.8, 131.0, 130.1,
127.8, 127.5, 126.9, 125.7, 119.7, 116.1 (t, 1JCF = 256 Hz), 115.4. 19
F
4.3.2.3. Difluoromethyl N-phenyl-2-methylpropan-1-imidate (8c). 1H
2
NMR (565 MHz, CDCl3):
d
= 81.2 (d, JFH = 74 Hz, 2F). IR (neat):
2
n
˜ ¼ 2927, 1255, 1171, 912, 742 cmꢀ1. HRMS (70 eV, EI): m/z calcd.
NMR (500 MHz, CDCl3):
d
= 7.33 (t, JHF = 72.6 Hz, 1H), 7.31 (t,
for C11H8F2O ([M]+): 194.0543; found: 194.0540.
J = 8.0 Hz, 2H), 7.09 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 2H), 2.72
(septet, J = 6.5 Hz, 1H), 1.14 (d, J = 6.5 Hz, 6H). 13C NMR (126 MHz,
d
= 163.0, 146.2, 129.2, 123.8, 120.3, 113.4 (t, 1JCF = 254 Hz),
4.2.2.9. 1-Difluoromethoxy-4-phenylbenzene
(6j). 1H
NMR
CDCl3):
28.6, 19.2. 19F NMR (470 MHz, CDCl3):
d
= 70.3 (d, 2JFH = 73 Hz, 2F).
(400 MHz, CDCl3): = 7.53–7.60 (m, 4H), 7.44 (t, J = 6.8 Hz, 2H),
d

K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
59
IR (neat):
n
˜ ¼ 2978, 1695, 1244, 1109, 912 cmꢀ1. HRMS (70 eV, EI):
n
˜ ¼ 1604, 1311, 1232, 1065, 912 cmꢀ1. HRMS (70 eV, EI): m/z calcd.
m/z calcd. for C11H13F2NO ([M]+): 213.0965; Found: 213.0968.
for C10H7F2NO ([M]+): 195.0496; found: 195.0496.
4.3.2.4. Difluoromethyl
N-pheny-1-cyclohexylmethanimidate
Acknowledgments
2
(8d). 1H NMR (500 MHz, CDCl3):
d
= 7.31 (t, JHF = 72.6 Hz, 1H),
7.31 (t, J = 8.0 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 2H),
2.37–2.42 (m, 1H), 1.68–1.74 (m, 4H), 1.57–1.65 (m, 3H), 1.15–1.23
This research was partly supported by Grant-in-Aid for
Exploratory Research from MEXT, Japan, and the Naito Foundation.
We acknowledge generous gift of methyl 2,2-difluoro-2-fluor-
osulfonylacetate from Kanto Denka Kogyo Co., Ltd.
(m, 1H), 1.07–1.13 (m, 2H). 13C NMR (126 MHz, CDCl3):
d = 162.2,
146.1, 129.2, 123.7, 120.4, 113.4 (t, 1JCF = 254 Hz), 38.4, 29.0, 25.4,
2
25.2. 19F NMR (470 MHz, CDCl3):
d
= 70.5 (d, JFH = 73 Hz, 2F). IR
(neat):
n
˜ ¼ 2935, 1697, 1238, 1124, 912 cmꢀ1. HRMS (70 eV, EI):
m/z calcd. for C14H17F2NO ([M]+): 253.1278; found: 253.1282.
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(500 MHz, CDCl3):
d
= 7.36 (t, JHF = 72.3 Hz, 1H), 7.12 (d,
J = 7.8 Hz, 2H), 6.68 (d, J = 7.8 Hz, 2H), 2.32 (s, 3H), 1.94 (s, 3H).
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N-(p-methoxyphenyl)ethan-1-imidate
2
(8f). 1H NMR (500 MHz, CDCl3):
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3H). 13C NMR (126 MHz, CDCl3):
d = 157.4, 156.4, 139.5, 121.6,
1
114.4, 113.0 (t, JCF = 255 Hz), 55.4, 15.5. 19F NMR (470 MHz,
2
CDCl3):
d
= 70.6 (d, JFH = 72 Hz, 2F). IR (neat):
n
˜ ¼ 2956, 1699,
HRMS (70 eV, EI): m/z calcd. for
10H11F2NO2 ([M]+): 215.0758; Found: 215.0760.
1506, 1230, 1103 cmꢀ1
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2
NMR (500 MHz, CDCl3):
d
= 7.34 (t, JHF = 72.1 Hz, 1H), 7.02 (dd,
3JHF = J = 8.5 Hz, 2H), 6.74 (dd, 4JHF = 4.0 Hz, J = 8.5 Hz, 2H), 1.95 (s,
3H). 13C NMR (126 MHz, CDCl3):
d
= 159.7 (d, 1JCF = 242 Hz), 157.9,
3
2
142.4 (d, JCF = 3 Hz), 121.9, 115.4 (d, JCF = 23 Hz), 112.9 (t,
1JCF = 255 Hz), 15.6. 19F NMR (470 MHz, CDCl3):
d = 70.5 (d,
2JFH = 72 Hz, 2F), 42.0 (tt, 3JFH = 8.5 Hz, 4JFH = 4.0 Hz, 1F). IR (neat):
n
˜ ¼ 1705, 1506, 1240, 1109, 914 cmꢀ1. HRMS (70 eV, EI): m/z calcd.
for C9H8F3NO ([M]+): 203.0558; found: 203.0553.
4.3.2.8. Difluoromethyl N-(p-chlorophenyl)ethanimidate (8h). 1H
2
NMR (500 MHz, CDCl3):
d
= 7.33 (t, JHF = 72.0 Hz, 1H), 7.29 (d,
J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 1.95 (s, 3H). 13C NMR
(126 MHz, CDCl3): = 157.8, 144.9, 129.6, 129.3, 121.9, 112.9 (t,
1JCF = 256 Hz), 15.6. 19F NMR (470 MHz, CDCl3):
= 70.4 (d,
d
d
2JFH = 72 Hz, 2F). IR (neat):
n
˜ ¼ 1703, 1240, 1136, 1088,
914 cmꢀ1. HRMS (70 eV, EI): m/z calcd. for C9H835ClF2NO ([M]+):
219.0262; found: 219.0260.
4.3.2.9. 2-Difluoromethoxypyridine (8i). 1H NMR (500 MHz, CDCl3):
d
= 8.20 (dd, J = 5.0, 1.5 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.48 (t,
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2JHF = 73.5 Hz, 1H), 7.10 (ddd, J = 7.5, 5.0, 1.0 Hz, 1H), 6.90 (d,
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120.0, 114.0 (t, JCF = 255 Hz), 111.5. 19F NMR (470 MHz, CDCl3):
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d
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CDCl3):
d = 8.13 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.77
(dd, J = 7.7, 3.0 Hz, 1H), 7.74 (t, 2JHF = 72.7 Hz, 1H), 7.68 (ddd, J = 7.7,
7.7, 3.0 Hz, 1H), 7.48 (ddd, J = 7.7, 7.7, 3.0 Hz, 1H), 7.00 (d,
J = 8.8 Hz, 1H). 13C NMR (126 MHz, CDCl3):
130.3, 127.8, 127.6, 126.1, 125.7, 113.9 (t, 1JCF = 255 Hz), 111.8. 19
d = 157.3, 145.5, 140.5,
(b) W.R. Dolbier Jr., F. Tian, J.-X. Duan, A.-R. Li, S. Ait-Mohand, O. Bautista, S.
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F
2
NMR (470 MHz, CDCl3):
d
= 72.1 (d, JFH = 73 Hz, 2F). IR (neat):

60
K. Fuchibe et al. / Journal of Fluorine Chemistry 133 (2012) 52–60
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