Sequential Xanthalation and O-Trifluoromethylation of Phenols: A Procedure for the Synthesis of Aryl Trifluoromethyl Ethers

Article abstract of DOI:10.1021/acs.joc.9b02717

Molecules containing trifluoromethoxyaryl groups are of interest in pharmaceutical, agrochemical, and materials science research, due to their unique physical and electronic properties. Many of the known methods to synthesize aryl trifluoromethyl ethers require harsh reagents and highly controlled reaction conditions and rarely occur when heteroaromatic units are present. The two-step O-trifluoromethylation of phenols via aryl xanthates is one such method that suffers from these drawbacks. Herein, we report a method for the synthesis of aryl trifluoromethyl ethers from phenols by the facile conversion of the phenol to the corresponding aryl and heteroaryl xanthates with newly synthesized imidazolium methylthiocarbonothioyl salts and conversion of these xanthates to the trifluoromethyl ethers under mild reaction conditions.

Full text of DOI:10.1021/acs.joc.9b02717

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Featured Article
Sequential Xanthalation and O-Trifluoromethylation of Phenols:
A Procedure for the Synthesis of Aryl-trifluoromethyl Ethers
Makoto Yoritate, Allyn Timothy Londregan, Yajing Lian, and John F. Hartwig
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02717 • Publication Date (Web): 18 Nov 2019
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The Journal of Organic Chemistry
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Sequential Xanthalation and O-Trifluoromethylation of Phenols: A
Procedure for the Synthesis of Aryl-trifluoromethyl Ethers
Makoto Yoritate,†,‡ Allyn T. Londregan,*,§ Yajing Lian,§ John F. Hartwig*,†
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†Department of Chemistry, University of California, Berkeley, CA 94720, United States
§Pfizer Inc., Medicine Design, Groton, CT 06340, United States.
ABSTRACT: Molecules containing trifluoromethoxyaryl groups are of interest in pharmaceutical, agrochemical, and materials sci-
ence research, due to their unique physical and electronic properties. Many of the known methods to synthesize trifluoromethoxy-
aryl ethers require harsh reagents, highly-controlled reaction conditions, and rarely occur when heteroaromatic units are present. The
two-step O-trifluoromethylation of phenols via aryl-xanthates is one such method that suffers from these drawbacks. Herein, we
report a facile synthesis of aryl trifluoromethyl ethers from phenols by the facile conversion of the phenol to the corresponding aryl
and heteroaryl xanthates with newly synthesized imidazolium methylthiocarbonothioyl salt and conversion of these xanthates to the
trifluoromethyl ethers under mild reaction conditions.
Introduction
using FluoLead in combination with antimony trichloride, but
the reported substrate scope for aryl-xanthates was limited to a
single unisolated example. Finally, to the best of our
knowledge, there have been few advancements on the synthesis
aryl xanthates. Most preparations use a two-step protocol con-
sisting of alcohol deprotonation with strong base followed by
condensation and alkylation with CS2, and MeI, respectively.
In our experience, this reaction is highly sensitive to the steric
and electronic properties of the phenol substrate (See Support-
ing Information).
Organic molecules containing fluorine are common in phar-
maceutical, agrochemical, and materials science, due to their
unique physical properties and bioactivities.1 New synthetic
methodologies to introduce fluorine into organic molecules,
therefore, has been studied extensively in recent years.2 The
OCF3 group is of particular interest to pharmaceutical research
owing to its high electronegativity (χ = 3.7), unique orthogonal
conformation relative to the aromatic ring,3 high lipophilicity4
and high metabolic stability. Although the OCF3 group posses-
ses an intriguing combination of properties, relatively few phar-
maceuticals exist that contain the moiety. The absence of such
strutures is due, in part, to the relatively harsh and toxic reaction
conditions needed for their synthesis and lack of existing me-
thods that tolerate heterocyclic diversity, both of which are im-
portant considerations in pharmaceutical research.
Scheme 1. Two-Step Trifluoromethoxylation of Phenol
Known methods to form aryl-trifluoromethyl ethers include
silver-mediated direct trifluoromethylation of phenols with the
Ruppert-Prakash reagent,5 silver-mediated trifluoromethoxyla-
tion of arylstannanes6a and aryldiazonium salts,6b C-H trifluoro-
methoxylation via redox-active catalysis or trifluoromethoxy
migration,7 and fluorodecarboxylation of aryloxydifluoro-ace-
tic acids.8 Other useful methods9-11 have been reported, but
many of them rely on harsh fluorinating reagents or are of nar-
row substrate scope.
Results and Discussion
We began our investigation by first developing a robust
method to form xanthates from aromatic and heteoraromatic al-
cohols. Under standard conditions with NaH, CS2, and MeI , 4-
dimethylaminocarboxy phenol 1a (Table 1) proceeded in low
conversion, likely due to the diminished nucleophilicity of 1a.
To improve this transformation, we evaluated several potential
reagents that could form xanthates. Reaction of 1a with com-
mercially available imidazole carbodithioate 4,12 which is re-
ported to be more reactive than CS2, did not proceed in appre-
ciable yield (entry 1). The same reaction with benzotriazole an-
alog 5 was much more effective and afforded 2a in 70% yield,
along with unreacted starting material (entry 2). Therefore, we
designed imidazolium and benzimidazolium analogs 6 and 7,13
which we expected to be more electrophilic than 5.14 After in-
vestigating the effects of added base, we found that the combi-
nation of imidazolium 6 and triethylamine formed xanthate 2a
in 99% yield (entry 3). The analogous reaction with benzimid-
azolium salt 7 afforded 2a in lower yield (entry 4, 2a: 79%), due
In this work, we focused our efforts on utilizing readily avail-
able aromatic and heteroaromatic alcohols as precursors for the
synthesis of aryl-trifluoromethyl ethers via aryl and heteroaryl
xanthates (Scheme 1). In his pioneering work on the subject,
Hiyama reported the conversion of phenols to trifluoromethoxy
arenes via methylxanthates.9c-e The trifluoromethylation reac-
tions, however, only proceeded with an exceptionally large ex-
cess of highly toxic HF-pyridine. Leroux and co-workers,9f in-
vestigated this transformation further and determined that hete-
rocyclic functionality, with the exception of 2-halo-azines, was
not tolerated (See Supporting Information). Some operational
improvements to this procedure were made by Umemoto,9g,
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to a side reaction, which was later determined to be thiocar- contrast, the yield of the trifluoromethyl aryl ether from reaction
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bonylation of the aromatic ring, owing to the stronger electro-
philicity of 7 than of 6. The conversion of phenol 1a to the cor-
responding xanthate with 6 in MeCN was as effective as in
DMF (entry 5 2a: 98%). The analogous reaction of the 4-
alkoxycarbonyl-substituted phenol 1b with 6 and 7 also formed
the xanthate in a high yield (91% and 99%, entries 6 and 7). The
reactions with these reagents to form aromatic xanthates are op-
erationally simple and convenient.
with trichloroisocyanuric acid (TCCA) was high (entry 6, 3a:
78%). The same reaction conducted in a glove box gave 2a in a
significantly lower 32% yield (entry 7). On the basis of the hy-
pothesis that water in the air facilitates the reaction, we found
that reactions with added water (1.0 equiv) were reproducible
and scalable (entry 8, 3a: 76%).17
Table 2. Development of Conditions for the Conversion of
Aryl Xanthates to Aryl Trifluoromethyl Ether
Table 1. Reactions of Phenols with a Series of Xanthalating
Reagents
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aStandard reaction conditions; 1 (0.5 mmol), xanthate-forming re-
agent (0.5 mmol), base (0.6 mmol), solvent (5 mL). bIsolated
yields. cYield was determined by 1H NMR using Me2SO2 as an in-
ternal standard instead of isolated yield. LG: Leaving Group.
aStandard conditions; 2 (50 mmol, 1.0 equiv.), XtalFluor-E (250
mmol, 5.0 equiv.), X+ source (50-150 mmol, 1-3 equiv.), additives,
(CH2Cl)2 (1 mL), 80 °C, 3 h. bYields were determined by 19F NMR
using PhCF3 as an internal standard. cThe reaction was conducted
Having established reliable conditions for the formation of
aromatic and heteroaromatic xanthates from phenols, we inves-
tigated the conversion of 4-dimethylaminocarbonyl phe-
noxyxanthate 2a to the corresponding aryl trifluoromethyl
ether. XtalFluor-E, a commercially available, free-flowing
solid, was chosen as a fluoride source due to its good stability
under air and low proclivity for thermal degradation.15 Control
investigations with other potential fluoride sources, including
PyFluor, HF/KF, HF/Pyr, DeoxoFluor, DAST, XtalFluor-M,
and XtalFluor-E with TCCA. These experiments showed that
the yield of the trifluoromethyl ether from xanthate 2a was the
highest with XtalFluor-E as the source of fluoride (see Support-
ing Information).
e
in a glove box. d0.5 mmol of 2 was used. 3.0 equivalent of
XtalFluor-E was used.
Reaction of the more electron-deficient 4-ethoxycarbonyl
phenoxyxanthate 2b occurred in high yield under slightly dif-
ferent conditions. We found that the reaction of 4-ethoxycar-
bonyl phenoxyxanthate 2b with XtalFluor-E and TCCA af-
forded a difluorochloromethyl ether (ArOCF2Cl; 18%) side
product, in addition to the desired trifluoromethyl ether (entry
9, 2b: 56%). In light of this result, fluoronium reagents, such as
N-fluorobenzenesulfoneiminde (NFSI) and Selectfluor, were
investigated as alternative halonium Lewis acid sources. Alt-
hough reactions were slower (24 h), treatment of 2b with 3
equiv of NFSI and XtalFluor-E afforded trifluoromethyl ether
3b in a high 75% yield (entry 10). Under these conditions with
XtalFluor-E, the yield of the reaction was the same with or with-
out with 1 equivalent of added water (entry 11, 2b: 70%). Re-
action of the more electron-rich 4-adamantyl phenoxyxanthate
2c was similar to that of 2b. The reaction of 2c with XtalFluor-
E and TCCA formed both the difluorochloromethyl ether and
the trifluoromethyl ether (Table 2; entry 12, 2c: 56%), whereas
the reaction of 2c with NFSI led to the desired 3c without the
chlorinated side product (Table 2; entry 13, 2c: 80%).
To optimize the formation of trifluoromethyl ether 3a from
xanthate 2a with XtalFluor-E, we tested a series of reactions
with various halonium oxidants as soft Lewis acids. Previous
computational studies by Keep,16 showed that halogen atoms
have a relatively high thiophilicity and are particularly useful
Lewis acids towards thiocarboyls. Hiyama,9c-e demonstrated
this principal when he utilized various sources of electrophilic
bromides (i.e. NBS or DBH) to accelerate the fluorination of
xanthates in the presence of HF-pyridine. Under our conditions,
the yields of the reactions with fluorinating, brominating, and
iodinating reagents as Lewis acid were low (entries 1-6); in
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The scope of the conversion of aromatic and heteroaromatic
alcohols to the corresponding trifluoromethyl aryl ethers under
the conditions discovered for the two-step trifluoromethoxyla-
tion of phenols is shown in Table 3. This operationally simple
method allowed for the facile formation of a broad range of xan-
thates from the corresponding phenols, using a minimal amount
of reagent 6 or 7 (1 equiv) and mild base (1.1 equiv) in MeCN.
Phenols 1a-1w were converted to the corresponding xanthates
2a–2w in over 90% yield with reagent 6, with a few exceptions.
The formation of xanthates from electron-poor phenols, such as
ethylbenzoate 2c, chromenone 2h, and hydroxypyrazole 2w,
proceeded in higher yield with the more electrophilic benzim-
idazole-derived reagent 7. Formation of the xanthate from 2,4-
di-t-butylphenol 1f with either reagents 6 or 7 resulted in poor
yield, because decomposition of the xanthalating reagents is
faster than desired xanthate formation (see Supporting Infor-
mation). Instead formation of 2f occurred quantitatively with
the less electrophilic benzotriazole 5.
Table 3. Substrate Scope of Two-Step Trifluoromethylation
2
3
of Phenol
4
5
6
7
8
9
condition A
XtalFluor-E (5.0 equiv.)
TCCA (1.0 equiv),
H2O (1.0 equiv)
SMe
(CH2Cl)2, 80 °C
6 (1.0 equiv)
Et3N (1.1 equiv)
OCF3
O
OH
Ar
Ar
Ar
condition B
S
MeCN, 0 °C to rt
XtalFluor-E (3.0 equiv.)
NFSI (3.0 equiv.)
(CH2Cl)2, 80 °C
3
1
2
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Trifluoromethoxylation of Arenesa,b,c,d
OCF3
OCF3
OCF3
Me2N
EtO
O
O
2a: 99%
(A) 3a: 56% (78%)
2b: 99%e
(B) 3b: 48% (76%)
2c: 94%
(B) 3c: 75% (80%)
OCF3
OCF3
O
O
OCF3
MeO2C
Ph
The conversion of the xanthates produced by this method
to the corresponding aryl trifluoromethyl ethers was performed
under one of two conditions: Condition A, with XtalFluor-E (5
equiv), TCCA (1 equiv), and H2O (1 equiv) in 1,2-dichloro-
ethane at 80 °C for 3–12 h, and Condition B, with XtalFluor-E
(3 equiv) and NFSI (3 equiv) in 1,2-dichloroethane at 80 °C for
12–48 h. All reactions were performed under atmospheric con-
ditions with no added controls. Generally, reactions with sub-
strates containing Lewis-basic functional groups, such as am-
ides, nitriles, or nitrogen-containing heteroaromatic rings, oc-
curred in higher yield under condition A than under condition
B. Reactions of substrates lacking Lewis basic functionality oc-
curred in higher yield under condition B than under condition
A.
O
2g: 97%
(B) 3g: 65% (83%)
2h: 97%
(B) 3h: 22% (36%)
2i: 93%
(B) 3i: 51% (70%)
OCF3
OCF3
OCF3
NC
t-Bu
t-Bu
2d: 84%
(A) 3d: 30% (62%)
2e: 92%
(B) 3e: (63%)
2f: 99%f
(B) 3f: 56% (81%)
OCF3
OCF3
OCF3
F3C
Br
I
2j: 94%
(B) 3j: (63%)
2k: 100%
(B) 3k: (66%)
2l: 97%
(B) 3l: (67%)
Trifluoromethoxylation of Arenes with Heteroarenesa,b,c,d
OCF3
OCF3
OCF3
Using condition A or B, we synthesized a variety of aryl tri-
fluoromethyl ethers from the corresponding xanthates in mod-
est to excellent yields. In several cases, the isolated yields were
lower than the yields determined by NMR spectroscopy be-
cause of the low boiling point of the product or the necessity for
preparative SFC or both. Both electron-poor and electron-rich
xanthates readily reacted to yield the desired aryl trifluorome-
thyl ethers. For certain substrates containing electron-rich aro-
matic rings, electrophilic chlorination reactions were observed
as side products from reaction with TCCA. This side product
could be avoided by utilizing condition B, with NFSI in place
of TCCA (for example: 3f, 56%; 3g: 65%). Trifluoromethoxy-
lation of more electron-neutral 4-bromophenol and 4-iodophe-
nol also proceeded smoothly to afford useful building blocks 3k
and 3l in 66% and 67% yield, respectively.
S
N
N
N
Cl
N
2o: 97%
(A) 3o: 50% (54%)
2m: 100%
2n: 91%
(A) 3m: 36% (46%)
(A) 3n: 64% (68%)
OCF3
OCF3
N
N
N
2p: 95%
2q: 85%
(B) 3p: 46% (60%)g
(B) 3q: 29%(46%)h
Trifluoromethoxylation of Heteroarenesa,b,c,d
OCF3
OCF3
OCF3
Me2N
N
Cl
N
N
O
2r: 87%
2s: 94%
2t: 84%
(A) 3r: 16% (22%)
(A) 3s: (36%)
(A) 3t: 11% (21%)
OCF3
OCF3
OCF3
N
N
2w: 99%e
N
N
Few examples of the conversion aromatic alcohols contain-
ing heterocyclic substituents or heteroaromatic alcohols to the
corresponding trifluoromethyl ethers have been reported.5,11 We
found that the conversion of xanthates derived from these clas-
ses of alcohols to the corresponding trifluoromethyl ether oc-
curred under both conditions A and B. The reactions of 2m-2q,
in which the aryl xanthate is substituted with a heteroaromatic
substituent afforded the corresponding trifluoromethyl ethers.
Likewise, xanthates derived from phenols substituted with six-
membered heteroarenes, such as 2o, 2p, and 2q, formed the cor-
responding heteroaryl trifluoromethyl ethers in good yield.
Cl
2u: 98%
(A) 3u: 39% (53%)
2v: 98%
(B) 3v: (16%)
(A) 3w: 30% (42%)
aStandard condition of xanthate formation; 1 (2.0 mmol), 6 (2.0
mmol), Et3N (2.0 mmol), MeCN (10 mL), 0 °C, 1 h. bCondition A;
2 (0.5 mmol), XtalFluor-E (2.5 mmol), TCCA (0.5 mmol), H2O
c
(0.5 mmol), and (CH2Cl)2 (10 mL), 80 °C. Condition B; 2 (0.5
mmol), XtalFluor-E (1.5 mmol), NFSI (1.5 mmol), and (CH2Cl)2
(10 mL), 80 °C. dNMR yields determined by 19F NMR using PhCF3
as an internal standard were reported in the parentheses. eReagent
f
7 was used instead of 6. Reagent 5 (1.5 equiv.), Cs2CO3 (2.0
equiv.), and DMF (0.1 M) were used instead of the standard condi-
tions. Selectfluor (0.5 mmol, 1.0 equiv.) was added. Selectfluor
(1.0 mmol, 2.0 equiv.) was added.
Heteroaromatic xanthates, in which the xanthyl group is con-
nected directly to a heteroaromatic ring, such as a pyridine or
quinoline, also formed the corresponding trifluoromethyl
ethers. Although yields were modest in most cases, these
g
h
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reactions enabled the conversions of heteroaromatic alcohols to Scheme 3. Control Experiment with Diethylamine
Page 4 of 13
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5
6
7
8
several previously unknown trifluoromethoxy heteroarenes (3r,
3u-3w). In certain instances, such as compound 3s, volatility
prevented complete isolation, even though the product was
formed in substantial yield, as determined by 1H and 19F NMR
spectroscopy. Perhaps most notable is example 3w. To the best
of our knowledge, this example represents the first known prep-
aration of a five-membered, nitrogen-containing heterocycle
containing an OCF3 group derived from the corresponding al-
cohol.
In summary, we have described an improved, two-step tri-
fluoromethoxylation of phenols via xanthate intermediates by
simple procedures and easy-handled reagents. In the first step,
phenols or heteroaryl alcohols react with imidazolium salt 6 or
benzimidazolium salt 7 to form xanthates in high yield. In the
second, XtalFluor-E reacts with the xanthate in the presence of
trichloroisocyanuric acid (TCCA) or N-fluorosulfonimide
(NFSI) to form a range of aryl and heteroaryl trifluoromethyl
ethers from common phenols and heteroaromatic alcohols. All
reactions were performed under atmospheric conditions with no
added controls. This methodology should be useful for pharma-
ceutical, agrochemical, and materials science research, in which
aromatic and heteroaromatic trifluoromethyl ethers are highly
sought
9
Observations made during the fluorination reactions of xan-
thates provided insight into a potential reaction mechanism. For
example, reactions under condition A gave Ar-OCF2Cl as by-
product in certain cases.18 In addition, under condition A, reac-
tions with one equivalent of water occurred in higher yields than
those lacking added water. These data suggest that the reactions
conducted under condition A and B proceed through slightly
different pathways (Scheme 2).
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The first step of the mechanism is likely coordination of the
thiocarbonyl group of the xanthates to TCCA or NFSI to form
activated species 9. Nucleophilic addition of fluoride then
would yield mono-fluoro intermediate 10. Two additional sub-
stitutions of fluoride would ultimately afford the desired trifluo-
romethyl ether 3. It is possible in the last step involving difluoro
intermediate 11 that homolytic cleavage of the C-S bond and
trapping with a source of Cl• occurs in competition with nucle-
ophilic substitution by fluoride. Consistent with the possibility
of these two parallel pathways for the final step, no byproduct
8 was observed in the presence of BHT
EXPERIMENTAL SECTION
General Remarks
All xanthate formations were conducted with N2-flushed round
bottom flask. All trifluoromethylation were conducted with 20
mL screw cap vial in air. All solvents for reactions were pur-
chased from Sigma Aldrich (anhydrous grade equipped sure
seal) and used as received. Unless otherwise stated, the reaction
temperatures above 23 °C refer to temperatures of an aluminum
heating block, which were controlled by an electronic tempera-
ture modulator. NMR spectra were recorded on Bruker AVQ-
400 and AV-600 instruments in UC Berkeley, and 500 MHz
Bruker Advanced with CryoProbe in Kyushu University.
Chemical shifts (δ) are reported in ppm, relative to the residual
solvent signal. Data from 1H NMR spectra are reported as fol-
lows: chemical shift (multiplicity, coupling constants, number
of hydrogens). Abbreviations are as follows: s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet), bs (broadening sin-
glet). All 13C NMR spectra were proton-decoupled. GC-MS
data were obtained on an Agilent 6890-N GC system containing
an Alltech EC-1 capillary column and an Agilent 5973 mass-
selective detector. High-resolution Electron Impact (EI) mass
spectral data were obtained from the University of California,
Berkeley Mass Spectrometry Laboratory. High-resolution Elec-
tron Spray Ionization (ESI) TOF-MS and Atmospheric Pressure
Chemical Ionization (APCI) TOF-MS were obtained from the
Lawrence-Berkeley National Laboratory Catalysis Center.
Scheme 2. Likely Mechanism for Conversion of Aryl Xan-
thate to Aryl Trifluoromethyl Ether
Further analysis of the reaction mixture with xanthate 2a re-
vealed the presence of carbamothioate byproduct 12a (Scheme
3). The formation of 12a can be attributed to liberation of di-
ethylamine from the degradation of XtalFluor-E, followed by a
Newman-Kwart-type rearrangement.19 Indeed, a control exper-
iment conducted with 2a, Et2NH, and TCCA produced the by-
product 12a, along with the hydrolyzed product 1a (Scheme
2B). From the water present in condition A, a small amount of
HF is likely generated, and this HF would protonate the diethyl-
amine to suppress this side reaction. It is uncertain why added
water does not have the same effect on reaction by path B, but
it is possible that the smaller amount of XtalFluor-E and lower
Lewis acidity of NFSI causes the competing Newman-Kwart-
type rearrangement to be slower.
A. Experimental Procedure
Synthesis of Phenols
1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 1q, 1s, 1t,
1u, and 1v were commercially available. The synthesis of 1o,
1p, 1r, and 1w are described below;
3-Hydroxy-6-dimethylaminocarbonyl pyridine (1r)
Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 2.11 g,
11.0 mmol, 1.1 equiv.) was added to a solution of 5-hydroxy-
picolinic acid (1.39 g, 10.0 mmol, 1.0 equiv.), dimethylamine
hydrochloride (897 mg, 11.0 mmol, 1.1 equiv.), 4-dimethyla-
minopyridine (DMAP, 1.22 g, 10.0 mmol, 1.0 equiv.) and diiso-
propylethylamine (3.8 mL, 22 mmol, 2.2 equiv.) in CH2Cl2 (20
mL) at room temperature. After stirring at room temperature for
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12 h, the solution was directly poured onto a silica gel column
11.67 (bs, 1H), 7.38–7.35 (m, 2H), 7.31 (d, J = 1.3 Hz, 1H),
7.25–7.22 (m, 2H), 4.87 (s, 2H); 13C NMR (151 MHz, CDCl3)
δ 189.2, 141.8, 132.6, 129.3, 125.7, 115.4, 45.2; HRMS (ESI),
calcd for C9H8Cl2N2ONa+ (M+Na)+ 252.9906, found 252.9900.
1
2
3
4
5
6
7
8
and purified (EtOAc/MeOH 100:0 to 80:20) to give 1.00 g of
1
1r (61%); white crystal; H NMR (600 MHz, CDCl3) δ 10.38
(bs, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.23
(dd, J = 8.4, 2.9 Hz, 1H), 3.00 (bs, 3H), 2.96 (bs, 3H); 13C NMR
(151 MHz, CDCl3) δ 167.9, 154.3, 145.1, 135.9, 124.7, 122.6,
Sodium hydroxide (1.00 g, 25.0 mmol, 3.2 equiv.) was
added to a solution of 21 (1.82 g, 7.88 mmol, 1.0 equiv.) and
MeOH (50 mL) at room temperature, causing the temperature
rise to approximately 40 °C. After stirring for 1 h at room tem-
perature, the mixture was concentrated and diluted with water
(10 mL). Insoluble material was removed by filtration. The so-
lution then was neutralized with conc. HCl. The resulting pre-
cipitate was filtered, washed with water, and dried under high
vacuum to give 1.51 g of 4-hydroxylpyrrazole 1w (99%); pale-
+
38.6, 35.2; HRMS (ESI), calcd for C8H11N2O2 (M+H)+
167.0815, found 167.0818.
4-(6-Chloropyridin-3-yl)phenol (1o)
9
Procedure A: To a 100 mL single neck round bottom flask, 4-
hydroxyphenylboronic acid (690 mg 6.00 mmol, 1.2 equiv.), 2-
chloro-5-bromopyridine (962 mg, 5.00 mmol, 1.0 equiv.), so-
dium carbonate (1.59 g, 15.0 mmol, 3.0 equiv.), 1,4-dioxane (19
mL), and H2O (6 mL) were added. The mixture was degassed
by bubbling with nitrogen for 30 min. [1,1’-Bis(diphe-
nylphosphino)ferrocene]dichloropalladium (PdCl2(dppf), 73.2
mg, 2 mol%) was added to the mixture at room temperature.
The mixture was warmed at 80 °C and stirred for 24 h, and then
cooled to room temperature. The resulting mixture was diluted
with water (20 mL), extracted with EtOAc (3 x 20 mL). The
combined organic extracts were washed with brine (30 mL),
dried over Na2SO4, filtered, and concentrated. The residue was
purified by silica gel column chromatography (EtOAc/Hexane
50:50 to 100:0) to give 905 mg of phenol 1o (88%); white crys-
tal; 1H NMR (500 MHz, (CD3)2SO) δ 9.76 (s, 1H), 8.64 (d, J =
2.5 Hz, 1H), 8.05 (dd, J = 8.2, 2.5 Hz, 1H), 7.58–7.54 (m, 2H),
7.52 (d, J = 8.2 Hz, 1H), 6.90–6.86 (m, 2H); 13C NMR (126
MHz, (CD3)2SO) δ 158.1, 148.1, 147.0, 136.9, 135.0, 128.1,
126.2, 124.2, 116.0; HRMS (ESI), calcd for C11H9ClNO+
(M+H)+ 206.0367, found 206.0368.
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14
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17
18
19
20
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23
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1
yellow powder; H NMR (600 MHz, CDCl3) δ 7.53 (s, 1H),
7.38–7.35 (m, 2H), 7.53–7.48 (m, 2H), 7.41 (s, 2H), 7.40–7.36
(m, 2H); 13C NMR (151 MHz, CDCl3) δ 143.1, 138.8, 131.9,
131.6, 129.7, 119.9, 114.0; HRMS (ESI), calcd for C9H8ClN2O+
(M+H)+ 195.0320, found 195.0319.
Synthesis of xanthate forming reagents
The reagent 4 is commercially available. N-(Methylthiothiocar-
bonyl)benzotriazole 5 were synthesized following a reported
procedure.20 The methods to synthesize imidazolium reagent 6
and benzimidazolium reagent 7 are described below;
Imidazolium salt (6)
A 250 mL single-neck-shield flask equipped with stir bar and
septum was purged with nitrogen. Methylthio(thiocarbonyl)im-
idazole 4 (7.09 g, 44.9 mmol, 1.0 equiv.)21 in benzene (120 mL)
was transferred to the flask via cannula. Iodomethane (28 mL,
450 mmol, 10 equiv.) was added to the mixture. The septum was
replaced with a screw cap quickly. The resulting mixture was
warmed to 80 °C with an oil bath. While stirring for 3 h, an
orange precipitate formed. The precipitate was filtered, washed
with anhydrous benzene (100 mL), and dried under high vac-
uum to give 6.44 g of imidazolium reagent 6 (48%); a bright
4-(Pyridin-3-yl)phenol (1p)
Procedure A was followed for the reaction of 3-bromopyridine
(790 mg, 5.00 mmol). The title compound 1p was obtained in
94% yield; white crystal; 1H NMR (500 MHz, (CD3)2SO) δ 9.69
(s, 1H), 8.81 (d, J = 1.9 Hz, 1H), 6.98 (dd, J = 4.7, 1.3 Hz, 1H),
7.97 (ddd, J = 7.9, 1.9, 1.3 Hz, 1H), 7.57–7.53 (m, 2H), 7.42
(dd, J = 7.9, 4.7 Hz, 1H), 6.90–6.86 (m, 2H); 13C NMR (126
MHz, (CD3)2SO) δ 157.6, 147.4, 147.0, 135.6, 133.1, 128.0,
127.7, 123.8, 115.9; HRMS (ESI), calcd for C11H10NO+ (M+H)+
172.0757, found 172.0756.
1
orange solid; mp. 89 °C; H NMR (600 MHz, (CD3)2SO), δ
10.14 (bs, 1H), 8.50 (dd, J = 2.2, 1.5 Hz, 1H), 7.97 (dd, J = 2.2,
1.5 Hz, 1H), 3.94 (s, 3H), 2.95 (s, 3H); 13C NMR (151 MHz,
(CD3)2SO) δ 197.6, 136.3, 125.1, 119.5, 36.7, 21.2; HRMS
(ESI), calcd for C6H9N2S2+ (M+H)+ 173.0202, found 173.0208.
1-(4-Chlorophenyl)-1H-pyrazol-4-ol (1j)
Benzimidazolium salt (7)
Ethyl-4-chloroacetoacetate (2.7 m
L, 20 mmol) was added
A 250 mL single-neck-shield flask equipped with a stir bar and
septum was purged with nitrogen. N-Methylthio(thiocarbonyl)-
benzimidazole (9.00 g, 43.2 mmol, 1.0 equiv.)22 in MeCN (90
mL) was transferred to the flask via cannula. Iodomethane (22
mL, 350 mmol, 8.0 equiv.) was added to the mixture. The sep-
tum was replaced with a screw cap quickly. The resulting mix-
ture was warmed to 80 °C with an oil bath. While stirring for
4.5 h, a bright orange precipitate was generated. The precipitate
was filtered, washed with EtOAc/Hexane 3:1 (100 mL), and
dried under high vacuum to give 10.9 g of benzimidazolium re-
agent 7 (72%) as a yellowish orange solid; mp. 1H NMR (500
MHz, CDCl3, rotamer was observed) δ 10.629 (bs, 1/2H),
10.627 (bs, 1/2H), 8.59–8.54 (m, 1H), 8.17–8.12 (m, 1H), 7.84–
to aqueous conc. HCl (5 mL) at room temperature. After stirring
at room temperature for 24 h, the solution was poured into ice
and extracted with EtOAc (3 x 20 mL). The combined organic
layer was dried over Na2SO4, filtered, and concentrated under
high vacuum at 0 °C to give 4-chloroacetoacetic acid, which
was diluted with 6 mL of water (solution A).
Sodium nitrite (1.38 g, 20.0 mmol, 1.0 equiv.) was added
dropwise to a solution of p-chloroaniline (2.52 g, 20.0 mmol,
1.0 equiv.), conc. HCl (5 mL), and H2O (20 mL) at 0 °C (solu-
tion B). After maintaining the solution B for 30 min at 0 °C, this
solution was transferred into solution A by pipet, and then
stirred for 10 min. An aqueous 6 M solution of sodium acetate
(10 mL) was added to the resulting solution dropwise
(CAUTION: CO2 bubbles violently). After stirring for 1 h, the
precipitate in the mixture was collected by filtration, washed
with H2O, and dried under high vacuum to give 2.02 g of (E)-
1-chloro-3-(2-(4-chlorophenyl)hydrazineylidene)propan-2-one
7.79 (m, 2H), 4.182 (s, 3/2H), 4.181 (s, 3/2H), 3.01 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ 198.0, 143.0, 132.7, 129.4, 128.5,
127.8, 116.0, 114.5, 34.0, 21.5; HRMS (ESI), calcd for
C10H11N2S2+ (M+H)+ 223.0358, found 223.0355.
1
(13) (58%); yellow powder; H NMR (600 MHz, CDCl3) δ
General Procedure B for the formation of xanthates.
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The Journal of Organic Chemistry
Page 6 of 13
Reagent 6 or 7 (2.00 mmol, 1.0 equiv.) was added to a solution
of the phenol 1a~1w (2.00 mmol, 1.0 equiv), triethylamine (330
µL, 2.2 mmol, 1.1 equiv.), and MeCN (10 mL) at 0 °C. After
stirring at 0 °C for 1 h, the mixture was quenched with saturated
aqueous NaHCO3 (20 mL) and extracted with EtOAc (2 x 20
mL). The combined organic extracts were dried over Na2SO4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography or recrystallization to give xanthates
2a~2w.
column chromatography (Hexane) to give the product as a pale-
yellow oil (676 mg, 92%). 2e: H NMR (600 MHz, CDCl3) δ
7.45–7.41 (m, 2H), 7.30 (tt, J = 7.7, 1.1 Hz, 1H), 7.13–7.09 (m,
2H), 2.68 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.9, 154.8,
129.7, 126.7, 122.2, 20.1; HRMS (EI), calcd for C8H8OS2+ (M)+
184.0017, found 184.0015.
1
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3
4
5
6
7
8
2,4-Di-t-butylphenoxy xanthate (2f)
Cesium carbonate (1.30 g, 4.00 mmol, 2.0 equiv.) was added to
a single-necked flask, dried by heat gun under vacuum, cooled,
and filled back with nitrogen. 2,4-di-t-butyl-phenol 1f (413 mg,
2.00 mmol, 1.0 equiv.) and DMF (20 mL) were added to the
flask. The resulting mixture was cooled to 0 °C, added benzotri-
azole reagent 5 (628 mg, 3.00 mmol, 1.5 equiv.). After stirring
for 3 h at 0 °C, the mixture was treated with saturated aqueous
NaHCO3, extracted with hexane (20 mL x 3). The combined or-
ganic extracts were dried over Na2SO4, filtered, and concen-
trated. The residue was purified by silica gel column chroma-
tography (EtOAc/Hexane 0:100) to give the product as a white
solid (587 mg, 99%). 2f: 1H NMR (600 MHz, CDCl3) δ 7.46–
7.44 (m, 1H), 7.26–7.23 (m, 1H), 7.01–6.98 (m, 1H), 2.70 (s,
3H), 1.38 (s, 9H), 1.35 (s, 9H); 13C NMR (151 MHz, CDCl3) δ
215.5, 151.0, 149.0, 140.4, 124.6, 123.69, 123.68, 34.91, 34.88,
31.6, 30.6, 20.1; HRMS (ESI), calcd for C16H24OS2Na+
(M+Na)+ 319.1161, found 319.1170.
9
4-Dimethylaminocarbonylphenoxy xanthate (2a)
General Procedure B was followed for the reaction of 4-dime-
thylaminocarbonyl phenol 1a (330 mg, 2.00 mmol) and imid-
azolium reagent 6 (600 mg, 2.00 mmol). The crude reaction
mixture was purified by silica gel column chromatography
(EtOAc/Hexane 1:1) to give the product as a white solid (510
mg, >99%).
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2a: 1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.13
(d, J = 8.4 Hz, 2H), 3.10 (bs, 3H), 3.01 (bs, 3H); 13C NMR (151
MHz, CDCl3) δ 215.4, 170.7, 155.3, 134.6, 128.8, 122.3, 39.8,
+
35.6, 20.2; HRMS (ESI), calcd for C11H14NO2S2 (M+H)+
256.0460, found 256.0464.
4-Ethoxycarbonylphenoxy xanthate (2b)
General Procedure B was followed for the reaction of 4-ethox-
ycarbonylphenol 1b (332 mg, 2.00 mmol) and benzimidazo-
lium reagent 7 (700 mg, 2.00 mmol). The crude reaction mix-
ture was purified by silica gel column chromatography
(EtOAc/Hexane 1:9) to give the product as a white solid (510
mg, 99%).
4-(Methoxycarbonylethyl)phenoxy xanthate (2g)
General Procedure B was followed for the reaction of methyl 3-
(4-hydroxyphenyl)propanoate 1g (360 mg, 2.00 mmol) and im-
idazolium reagent 6 (600 mg, 2.00 mmol). The crude reaction
mixture was purified by silica gel column chromatography
(EtOAc/Hexane 1:9) to give the product as a white solid (524
mg, 97%). 2g: 1H NMR (600 MHz, CDCl3) δ 7.26–7.23 (m, 2H),
7.04–7.00 (m, 2H), 3.67 (s, 3H) , 2.97 (t, J = 7.7 Hz, 2H), 2.66
(s, 3H), 2.65 (t, J = 7.7 Hz, 2H); 13C NMR (151 MHz, CDCl3)
δ 216.0, 173.2, 153.2, 139.0, 129.5, 122.1, 51.8, 35.6, 34.88,
31.6, 30.6, 20.1; HRMS (ESI), calcd for C12H14O3S2Na+
(M+Na)+ 293.0277, found 293.0278.
1
2b: H NMR (600 MHz, CDCl3) δ 8.14–8.10 (m, 2H), 7.19–
7.15 (m, 2H), 4.39 (q, J = 6.9, 2H), 2.68 (s, 3H), 1.39 (t, J = 6.9,
3H); 13C NMR (151 MHz, CDCl3) δ 215.3, 165.8, 158.0, 131.3,
128.9, 122.4, 61.3, 20.2, 14.5; HRMS (ESI), calcd for
C11H12O3S2Na+ (M+Na)+ 279.0120, found 279.0115.
4-Adamantylphenoxy xanthate (2c)
General Procedure B was followed for the reaction of 4-ada-
mantylphenol 1c (456 mg, 2.00 mmol) and imidazolium reagent
6 (600 mg, 2.00 mmol). The crude reaction mixture was purified
by silica gel column chromatography (EtOAc/Hexane 0:1 to
1:100) to give the product as a white solid (598 mg, 94%).
2c: 1H NMR (600 MHz, CDCl3) δ 7.41–7.38 (m, 2H), 7.05–7.02
(m, 2H), 2.67 (s, 3H), 2.12–2.08 (m, 3H), 1.92 (d, J = 2.2 Hz,
6H), 1.82–1.72 (m, 6H); 13C NMR (151 MHz, CDCl3) δ 216.0,
152.5, 149.8, 126.2, 121.4, 43.4, 36.9, 36.3, 29.1, 20.1; HRMS
(ESI), calcd for C18H23OS2+ (M+H)+ 319.1185, found 319.1186.
O-Methylthiocarbonyl-7-hydroxycoumarin (2h)
General Procedure B was followed for the reaction of 7-hy-
droxycoumarin (umbelliferone) 1h (324 mg, 2.00 mmol) and
imidazolium reagent 6 (600 mg, 2.00 mmol). The crude reaction
mixture was purified by silica gel column chromatography
(EtOAc/Hexane 1:9 to 1:3) to give the product as a white solid
(490 mg, 97%). 2h: 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J =
9.5 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H),
7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.43 (d, J = 9.5 Hz, 1H); 13C
NMR (151 MHz, CDCl3) δ 215.1, 160.3, 156.8, 154.9, 142.9,
128.8, 119.2, 117.4, 116.6, 111.4, 20.3; HRMS (ESI), calcd for
C11H9O3S2+ (M+H)+ 252.9988, found 252.9982.
4-Cyanophenoxy xanthate (2d)
General Procedure B was followed for the reaction of 4-cyano-
phenol 1d (238 mg, 2.00 mmol) and imidazolium reagent 6 (600
mg, 2.00 mmol). The crude reaction mixture was purified by
silica gel column chromatography (EtOAc/Hexane 1:1) to give
the product as a white solid (351 mg, 84%).
4-Benzoylphenoxy xanthate (2i)
General Procedure B was followed for the reaction of 4-benzo-
ylphenol 1i (396 mg, 2.00 mmol) and imidazolium reagent 6
(600 mg, 2.00 mmol). The crude reaction mixture was purified
by silica gel column chromatography (EtOAc/Hexane 1:3 to
1:2) to give the product as a white solid (538 mg, 93%). 2i: 1H
NMR (600 MHz, CDCl3) δ 7.91–7.88 (m, 2H), 7.81 (dd, J = 8.4,
1.4 Hz, 2H), 7.60 (tt, J = 7.4, 1.4 Hz, 1H), 7.49 (dd, J = 8.4, 7.4
Hz, 1H), 7.24–7.21 (m, 2H), 2.69 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 215.2, 195.5, 157.7, 137.5, 135.7, 132.6, 131.8, 130.0,
128.5, 122.3, 20.2; HRMS (ESI), calcd for C15H12O2S2Na+
1
2d: H NMR (600 MHz, CDCl3) δ 7.75–7.71 (m, 2H), 7.25–
7.22 (m, 2H), 2.68 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 214.9,
157.6, 133.9, 123.7, 118.2, 110.7, 20.3; HRMS (ESI), calcd for
C9H7NOS2Na+ (M+Na)+ 231.9861, found 231.9854.
Phenoxy xanthate (2e)
General Procedure B was followed for the reaction of phenol 1e
(376 mg, 4.00 mmol) and imidazolium reagent 6 (1.20 g, 4.00
mmol). The crude reaction mixture was purified by silica gel
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The Journal of Organic Chemistry
HRMS (ESI), calcd for C15H12NOS3+ (M+H)+ 318.0076, found
(M+Na)+ 311.0171, found 311.0168.
1
318.0081.
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5
6
7
8
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4-Trifluoromethylphenoxy xanthate (2j)
General Procedure B was followed for the reaction of 4-trifluo-
romethylphenol 1j (324 mg, 2.00 mmol) and imidazolium rea-
gent 6 (600 mg, 2.00 mmol). The crude reaction mixture was
purified by silica gel column chromatography (Hexane) to give
4-(6-Chloropyridine-3-yl)phenoxy xanthate (2o)
General Procedure B was followed for the reaction of 4-(6-chlo-
ropyridine-3-yl)phenol 1o (411 mg, 2.00 mmol) and imidazo-
lium reagent 6 (600 mg, 2.00 mmol). The crude reaction mix-
ture was purified by silica gel column chromatography
(EtOAc/Hexane 1:1 to 1:2) to give the product as a white solid
(575 mg, 97%).
1
the product as a pale-yellow oil (475 mg, 94%). 2j: H NMR
(500 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2
Hz, 2H), 2.69 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 215.3,
156.9, 128.9 (q, J = 33 Hz, C), 127.1 (q, J = 3.6 Hz, CH), 123.9
(q, J = 272 Hz, CF3), 123.0 20.2; 19F NMR (470 MHz, CDCl3)
δ 62.3 (s); HRMS (EI), calcd for C9H7F3OS2 251.9890, found
251.9894.
2o: 1H NMR (600 MHz, CDCl3) δ 8.61 (dd, J = 2.6, 0.7 Hz, 1H),
7.84 (dd, J = 8.4, 2.6 Hz, 1H), 7.61–7.58 (m, 2H), 7.41 (dd, J =
8.4, 0.7 Hz, 1H), 7.24–7.21 (m, 2H), 2.70 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 215.9, 155.0, 150.8, 148.1, 137.3, 135.0,
134.8, 128.4, 124.4, 123.2, 20.2; HRMS (ESI), calcd for
C13H11ClNOS2+ (M+H)+ 295.9965, found 295.9961.
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4-Bromophenoxy xanthate (2k)
General Procedure B was followed for the reaction of 4-bromo-
phenol 1k (346 mg, 2.00 mmol) and imidazolium reagent 6 (600
mg, 2.00 mmol). The crude reaction mixture was purified by
silica gel column chromatography (Hexane) to give the product
as a pale-yellow oil (525 mg, >99%).
4-(Pyridine-3-yl)phenoxy xanthate (2p)
General Procedure B was followed for the reaction of 4-(pyri-
dine-3-yl)phenol 1p (342 mg, 2.00 mmol) and imidazolium re-
agent 6 (600 mg, 2.00 mmol). The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
1:1 to 1:2) to give the product as a yellow oil (499 mg, 95%).
2p: 1H NMR (600 MHz, CDCl3) δ 8.85 (d, J = 2.2 Hz, 1H), 8.61
(dd, J = 4.8, 1.5 Hz, 1H), 7.88 (ddd, J = 7.7, 2.2, 1.8 Hz, 1H),
7.65–7.61 (m, 2H), 7.38 (dd, J = 7.7, 4.8 Hz, 1H), 7.24–7.21 (m,
2H), 2.69 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.9, 154.8,
148.7, 148.3, 136.3, 135.8, 134.6, 128.4, 123.8, 123.0, 20.2;
HRMS (ESI), calcd for C13H12NOS2+ (M+H)+ 262.0355, found
262.0361.
1
2k: H NMR (600 MHz, CDCl3) δ 7.55–7.52 (m, 2H), 7.01–
6.97 (m, 2H), 2.67 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.6,
153.7, 132.8, 124.1, 120.0, 20.2; HRMS (EI), calcd for
C8H7BrOS2 261.9122, found 261.9124.
4-Iodophenoxy xanthate (2l)
General Procedure B was followed for the reaction of 4-iodo-
phenol 1l (440 mg, 2.00 mmol) and imidazolium reagent 6 (600
mg, 2.00 mmol). The crude reaction mixture was purified by
silica gel column chromatography (Hexane) to give the product
as a white solid (602 mg, 97%).
4-(Pyrimidine-5-yl)phenoxy xanthate (2q)
2l:1H NMR (600 MHz, CDCl3) δ 7.75–7.71 (m, 2H), 6.89–6.85
(m, 2H), 2.67 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.5,
154.5, 138.8, 124.5, 91.0, 20.2; HRMS (EI), calcd for C8H7IOS2
309.8983, found 309.8988.
General Procedure B was followed for the reaction of 4-(pyrim-
idine-5-yl)phenol 1q (344 mg, 2.00 mmol) and imidazolium re-
agent 6 (600 mg, 2.00 mmol). The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
1:2 to 1:4) to give the product as a white solid (445 mg, 85%).
1
4-(1H-Imidazol-1-yl)phenoxy xanthate (2m)
2q: H NMR (600 MHz, CDCl3) δ 9.22 (s, 1H), 8.97 (s, 2H),
General Procedure B was followed for the reaction of 4-(1H-
imidazol-1-yl)phenol 1m (320 mg, 2.00 mmol) and imidazo-
lium reagent 6 (600 mg, 2.00 mmol). The crude reaction mix-
ture was purified by silica gel column chromatography
(EtOAc/Hexane 1:2 to 1:1) to give the product as a white solid
(500 mg, >99%).
7.66–7.62 (m, 2H), 7.29–7.25 (m, 2H), 2.70 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 215.8, 157.7, 155.4, 155.0, 133.6, 132.7,
+
128.4, 123.5, 20.2; HRMS (ESI), calcd for C12H11N2OS2
(M+H)+ 263.0307, found 263.0308.
O-(6-(dimethylcarbamoyl)pyridin-3-yl) S-methyl car-
bonodithioate (2r)
2m: 1H NMR (600 MHz, CDCl3), δ 7.86 (dd, J = 1.2, 1.2 Hz,
1H), 7.47–7.42 (m, 2H), 7.28 (dd, J = 1.2, 1.2 Hz, 1H), 7.25–
7.21 (m, 3H), 2.69 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.8,
153.4, 135.7, 135.6, 130.7, 123.8, 122.7, 118.4, 20.2; HRMS
General Procedure B was followed for the reaction of 6-carbox-
yamide-3-hydroxypyridine 1r (332 mg, 2.00 mmol) and imid-
azolium reagent 6 (600 mg, 2.00 mmol). The crude reaction
mixture was purified by silica gel column chromatography
(EtOAc/Hexane 1:2 to 1:4) to give the product as a white solid
(445 mg, 87%).
+
(ESI), calcd for C11H11N2OS2 (M+H)+ 251.0307, found
251.0304.
4-(Benzothiazole-2-yl)phenoxy xanthate (2n)
2r: 1H NMR (600 MHz, CDCl3) δ 8.37 (d, J = 2.6 Hz, 1H), 7.75
(d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.4, 2.6 Hz, 1H), 3.14 (s, 3H),
3.12 (s, 3H), 2.70 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.2,
168.1, 152.2, 151.4, 142.4, 131.1, 124.9, 39.3, 36.1, 20.2;
General Procedure B was followed for the reaction of 4-(ben-
zothiazole-2-yl)phenol 1n (422 mg, 2.00 mmol) and imidazo-
lium reagent 6 (600 mg, 2.00 mmol). The crude reaction mix-
ture was purified by silica gel column chromatography
(EtOAc/Hexane 1:20 to 1:10) to give the product as a white
solid (549 mg, 91%).
+
HRMS (ESI), calcd for C10H13N2O2S2 (M+H)+ 257.0413,
found 257.0410.
2n: 1H NMR (600 MHz, CDCl3) δ 8.18–8.15 (m, 2H), 8.08 (d,
J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 8.1, 7.3
Hz, 1H), 7.40 (dd, J = 8.1, 7.3 Hz, 1H), 7.27–7.23 (m, 2H), 2.70
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.5, 166.8, 156.6,
154.2, 135.3, 129.0, 126.6, 125.5, 123.5, 123.1, 121.8, 20.2;
O-(6-chloropyridin-3-yl) S-methyl carbonodithioate (2s)
General Procedure B was followed for the reaction of 6-chloro-
3-hydroxypyridine 1s (220 mg, 2.00 mmol) and imidazolium
reagent 6 (600 mg, 2.00 mmol). The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
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1:3) to give the product as a pale-yellow solid (352 mg, 94%).
aryltrifluoromethylethers (ArOCF3) 3a~3w
General Procedure C (Reaction conditions with TCCA):
2s: 1H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 2.9 Hz, 1H), 7.44
(dd, J = 8.4, 2.9 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H); 13C NMR
(151 MHz, CDCl3) δ 215.4, 150.2, 148.7, 143.8, 133.2, 124.9,
20.4; HRMS (ESI), calcd for C7H7ClNOS2+ (M+H)+ 219.9652,
found 219.9648.
1
2
3
4
5
6
7
8
A 20 mL vial was charged with xanthate 2 (0.5 mmol, 1.0
equiv.), TCCA (116 mg, 0.5 mmol, 1.0 equiv.), and XtalFluor-
E (573 mg, 2.5 mmol, 5.0 equiv.) in air. Then, anhydrous di-
chloroethane (5 or 10 mL) and water (9.0 mg, 0.5 mmol, 1.0
equiv.) were added to the vial. (*One equivalent of water was
weighed into a pipet, and the water was transferred to the flask
by forced air.) The resulting mixture was stirred at 80 °C for the
reported reaction time. After cooling to room temperature, the
mixture was quenched with saturated aqueous NaHCO3 (5 mL),
stirred for 30 min, and filtered through a pad of Celite. The fil-
trate was extracted with EtOAc (2 x 10 mL). Activated charcoal
powder (ca. 1 g) and silica gel (ca. 1 g) were added to the com-
bined organic layer (Note: Charcoal helps to remoce brown by-
products derived from XtalFluor-E). After stirring for 1 min, the
mixture was filtered with Celite and washed with EtOAc. The
filtrate was concentrated and purified by silica gel column chro-
matography to give ArOCF3 (3).
O-(Quinoline-3-yl) S-methyl carbonodithioate (2t)
General Procedure B was followed for the reaction of 3-hy-
droxyquinoline 1t (290 mg, 2.00 mmol) and imidazolium rea-
gent 6 (600 mg, 2.00 mmol). The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
0:1 to 1:9) to give the product as a brown oil (395 mg, 84%).
2t: 1H NMR (600 MHz, CDCl3) δ 8.74 (d, J = 1.8 Hz, 1H), 8.14
(d, J = 8.4 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.1 Hz,
1H), 7.72 (dd, J = 8.4, 7.3 Hz, 1H), 7.57 (dd, J = 8.1, 7.3 Hz,
1H), 2.70 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.8, 148.0,
146.3, 146.1, 129.6, 129.5, 128.2, 127.8, 127.5, 127.1, 20.3;
HRMS (ESI), calcd for C11H10NOS2+ (M+H)+ 236.0198, found
236.0196.
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17
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19
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23
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General Procedure D (Reaction conditions with NFSI):
A 20 mL vial was charged with xanthates 2 (0.5 mmol, 1.0
equiv.), NFSI (473 mg, 1.5 mmol, 3.0 equiv.), and XtalFluor-E
(343 mg, 1.5 mmol, 3.0 equiv.) under air. Then, anhydrous di-
chloroethane (2 or 5 mL) was added to the vial. The resulting
mixture was stirred at 80 °C for desired reaction time. After
cooling to room temperature, the mixture was quenched with
saturated aqueous NaHCO3 (5 mL), stirred for 30 min, and fil-
tered through a pad of Celite. The filtrate was extracted with
EtOAc (2 x 10 mL). Activated carbon powder (ca. 1 g) and sil-
ica gel (ca. 1 g) were added to the combined organic layer. After
stirring for 1 min, the mixture was filtered with Celite and
washed with EtOAc. The filtrate was concentrated and purified
by silica gel column chromatography to give ArOCF3 (3).
O-(Quinoline-7-yl) S-methyl carbonodithioate (2u)
General Procedure B was followed for the reaction of 3-hy-
droxyquinoline 1u (290 mg, 2.00 mmol) and benzimidazolium
reagent 6 (600 mg, 2.00 mmol). The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
1:9) to give the product as a white solid (459 mg, 98%).
2u: 1H NMR (600 MHz, CDCl3) δ 8.93 (dd, J = 4.4, 1.5 Hz, 1H),
8.16 (d, J = 9.2 Hz, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 7.54 (d,
J = 2.6 Hz, 1H), 7.50 (dd, J = 9.2, 2.6 Hz, 1H), 7.43 (dd, J = 8.4,
4.4 Hz, 1H), 2.71 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 215.6,
152.4, 150.7, 146.7, 136.1, 131.3, 128.7, 125.2, 121.8, 119.2,
+
20.4; HRMS (ESI), calcd for C11H10NOS2 (M+H)+ 236.0198,
found 236.0195.
O-(Pyridine-3-yl) S-methyl carbonodithioate (2v)
General Procedure B was followed for the reaction of 4-ethox-
ycarbonyl phenol 1v (185 mg, 2.00 mmol) and benzimidazo-
lium reagent 6 (600 mg, 2.00 mmol). The crude reaction mix-
ture was purified by silica gel column chromatography
(EtOAc/Hexane 1:1 to 3:1) to give the product as a yellow oil
(353 mg, 98%)
4-(Dimethylaminocarbonyl)trifluoromethoxybenzene (3a)
General Procedure C was followed for the reaction of xanthate
2a (128 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (10 mL) for 3 h. The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
1:3 to 1:1) to give a mixture of 3a (65.0 mg, 56%) and
ArOCF2Cl byproduct (1.9 mg, 1.5%). 3a: a pale-yellow solid;
1H NMR (600 MHz, CDCl3) δ 7.48–7.44 (m, 2H), 7.26–7.22 (m,
2H), 3.11 (s, 3H), 2.98 (s, 3H); 13C NMR (151 MHz, CDCl3) δ
170.4, 149.9, 134.9, 129.0, 120.8, 120.4 (q, J = 258.7, CF3),
39.6, 35.5; 19F (376 MHz, CDCl3) δ –59.0 (s); HRMS (ESI),
calcd for C10H11F3NO2+ (M+H)+ 234.0736, found 234.0742.
1
2v: H NMR (600 MHz, CDCl3): δ 8.53 (dd, J = 4.8, 1.1 Hz,
1H), 8.42 (d, J = 2.6 Hz, 1H), 7.46 (ddd, J = 8.4, 2.6, 1.1 Hz,
1H), 7.37 (dd, J = 8.4, 4.8 Hz, 1H), 2.68 (s, 3H); 13C NMR (151
MHz, CDCl3) δ 215.6, 151.3, 147.6, 144.1, 136.1, 131.3, 128.7,
+
125.2, 121.8, 119.2, 20.4; HRMS (ESI), calcd for C11H10NOS2
(M+H)+ 236.0198, found 236.0195.
4-(Ethoxycarbonyl)trifluoromethoxybenzene (3b)
O-(1-(4-Chlorophenyl)-1H-pyrazol-4-yl) S-methyl car-
bonodithioate (2w)
General Procedure D was followed for the reaction of xanthate
2b (128 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (2 mL) for 24 h. The crude reaction mixture was
purified by silica gel column chromatography (Hexane) to give
the product as a pale-yellow oil (56.0 mg, 48%). 3b: 1H NMR
(600 MHz, CDCl3) δ 7.48–7.44 (m, 2H), 7.26–7.22 (m, 2H),
3.11 (s, 3H), 2.98 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 170.4,
149.9, 134.9, 129.0, 120.8, 120.4 (q, J = 258.7, CF3), 39.6, 35.5;
19F (376 MHz, CDCl3) δ –59.0 (s); HRMS (EI), calcd for
C10H9F3O3+ (M)+ 234.0504, found 234.0507.
General Procedure B was followed for the reaction of 4-hydrox-
ypyrazole 1w (389 mg, 2.00 mmol) and benzimidazolium rea-
gent 7 (700 mg, 2.00 mmol). The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
1:9) to give the product as a white solid (563 mg, 99%).
1
2w: H NMR (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.68 (s, 1H),
7.62–7.59 (m, 2H), 7.44–7.41 (m, 2H), 2.68 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 214.5, 140.1, 138.7 134.2, 132.5, 129.7,
+
120.2, 118.9, 20.4; HRMS (ESI), calcd for C11H9ClN2OS2
(M+Na)+ 306.9737, found 306.9740.
4-(Adamantyl)trifluoromethoxybenzene (3c)
General Procedure D was followed for the reaction of xanthate
2c (159 mg, 0.50 mmol). The reaction was conducted with
General
procedures
for
the
synthesis
of
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The Journal of Organic Chemistry
dichloroethane (2 mL) for 24 h. The crude reaction mixture was
C14H9O2F3+ (M)+ 266.0555, found 266.0558.
1
2
3
4
5
6
7
8
purified by silica gel column chromatography (Hexane) to give
the product as a white solid (118 mg, 80%). 3c: 1H NMR (600
MHz, CDCl3) δ 7.39–7.35 (m, 2H), 7.17–7.13 (m, 2H), 2.13–
2.09 (m, 3H), 1.90 (d, J = 2.2, 6H), 1.82–1.72 (m, 6H); 13C
NMR (151 MHz, CDCl3) δ 150.1, 147.2, 126.4, 120.7 (q, J =
257, CF3), 120.6, 43.4, 36.8, 36.2, 29.1; 19F NMR (376 MHz,
CDCl3) δ –59.1 (s), HRMS (EI), calcd for C17H19F3O+ (M)+
296.1388, found 296.1392.
4-(1H-Imidazol-1-yl)trifluoromethoxybenzene (3m)
General Procedure C was followed for the reaction of xanthate
2m (125 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (10 mL) for 12 h. The crude reaction mixture was
filtered through a pad of silica gel (EtOAc) and then purified by
preparative SFC to remove byproducts derived from XtalFluor-
E (85% CO2 : 15% MeOH (0.2% 7 M NH3 in MeOH), Flow:3.0
mL/min, Princeton PPU 250mm x 10.0mm 5mm) to give the
product as a white solid (41.0 mg, 36%). 3q: 1H NMR (CDCl3,
400 MHz) δ 7.69 (s, 1H), 7.30–7.26 (m, 2H), 7.22–7.18 (m, 2H),
7.11–7.07 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 157.8, 154.9,
9
2,4-(Di-t-butyl)trifluoromethoxybenzene (3f)
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11
12
13
14
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16
17
18
19
20
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22
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General Procedure D was followed for the reaction of xanthate
2f (148 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (2 mL) for 24 h. The crude reaction mixture was
purified by silica gel column chromatography (Hexane) to give
the product as a colorless oil (77.1 mg, 56%). 3f: 1H NMR (600
MHz, CDCl3) δ 7.42 (d, J = 2.6 Hz, 1H), 7.22 (dd, J = 8.4, 2.6
Hz, 2H), 7.18–7.14 (m, 1H), 1.41 (s, 9H), 1.33 (s, 9H); 13C
NMR (151 MHz, CDCl3) δ 148.5, 146.6, 139.9, 124.9, 124.1,
120.9 (q, J = 258, CF3), 118.4, 35.1, 34.8, 31.6, 30.4; 19F NMR
(376 MHz, CDCl3) δ –55.8 (s), HRMS (EI), calcd for
C15H21F3O+ (M)+ 274.1544, found 274.1549.
149.9, 133.9, 133.2, 128.6, 121.9, 120.5 (q, J = 258, CF3); 19
F
NMR (376 MHz, CDCl3) δ –58.0 (s); HRMS (APCI) calcd for
C11H8F3N2O+ (M+H)+ 241.0583; Found 241.0586.
4-(Benzothiazole-2-yl)trifluoromethoxybenzene (3n)
General Procedure C was followed for the reaction of xanthate
2n (151 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (10 mL) for 3 h. The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
0:1 to 1:100) to give a mixture of 3n (53.6 mg, 38%), ArOCF2Cl
byproduct (5.9 mg, 3.8%), and ArOCFCl2 byproduct (3.6 mg,
4-(Methoxycarbonylethyl)trifluoromethoxybenzene (3g)
General Procedure D was followed for the reaction of xanthate
2g (135 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (2 mL) for 24 h. The crude reaction mixture was
purified by silica gel column chromatography (Hexane) to give
the product as a pale-yellow oil (81.1 mg, 65%). 3g: 1H NMR
(600 MHz, CDCl3) δ 7.23–7.20 (m, 2H), 7.15–7.11 (m, 2H),
3.67 (s, 3H), 2.95 (t, J = 7.7 Hz, 2H), 2.95 (t, J = 7.7 Hz, 2H);
13C NMR (151 MHz, CDCl3) δ 173.1, 147.8, 139.4, 129.7,
121.2, 120.6 (q, J = 258, CF3), 51.8, 35.6, 30.3; 19F NMR (376
1
2.2%).23 3n: pale-yellow solid; H NMR (600 MHz, CDCl3) δ
8.16–8.12 (m, 2H), 8.08 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz,
1H), 7.52 (dd, J = 8.1, 7.3 Hz, 1H), 7.41 (dd, J = 8.1, 7.3 Hz,
1H), 7.34 (d, J = 8.4 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ
166.3, 154.2, 151.2, 135.3, 132.3, 129.2, 126.7, 125.6, 123.5,
121.8, 121.3, 120.5 (q, J = 259, CF3); 19F NMR (376 MHz,
CDCl3) δ –58.1 (s); HRMS (ESI), calcd for C14H9F3NOS+
(M+H)+ 296.0351, found 296.0347.
+
MHz, CDCl3) δ –57.9 (s), HRMS (EI), calcd for C11H11F3O3
4-(6-Chloropyridine-3-yl)trifluoromethoxybenzene (3o)
General Procedure C was followed for the reaction of xanthate
2o (148 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (5 mL) for 12 h. The crude reaction mixture was
purified by silica gel column chromatography (EtOAc/Hexane
9:1 to 3:1) to give a mixture of 3o (68.5 mg, 50%), ArOCF2Cl
byproduct (2.7 mg, 1.9%), and ArOCFCl2 byproduct (2.5 mg,
(M)+ 248.0660, found 248.0662.
7-Trifluoromethoxy coumarin (3h)
General Procedure D was followed for the reaction of xanthate
2g (126 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (2 mL) for 6 h. The crude reaction mixture was
filtered through a pad of silica gel (EtOAc/Hexane 3:1) and then
purified by preparative SFC to remove (PhSO2)2NH as a main
contaminant (95%-40% CO2 : MeOH, Flow:3.0 mL/min,
Princeton PPU 250mm x 10.0mm 5mm) to give the product as
a white solid (25.0 mg, 22%). 3h: 1H NMR (CDCl3, 400 MHz)
δ 7.71 (d, J = 9.8 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.22 (s, 1H),
7.16 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 9.4 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 159.9, 154.8, 151.3, 142.4, 129.1, 120.3
(q, J = 256, CF3), 117.3, 116.9, 116.9, 109.3; 19F NMR (376
MHz, CDCl3) δ –57.9 (s); HRMS (APCI) Calculated for
C10H6F3O3+ (M+H)+ 231.0260; Found 231.0261.
1
1.6%).23 3o: pale-yellow solid; H NMR (CDCl3, 600 MHz) δ
8.58 (d, J = 2.6 Hz, 1H), 7.81 (dd, J = 8.4, 2.6 Hz, 1H), 7.58–
7.55 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H);
13C NMR (151 MHz, CDCl3) δ 150.9, 149.6, 147.9, 137.2,
135.3, 134.4, 128.6, 124.5, 121.7, 120.5 (q, J = 257, CF3); 19
F
NMR (376 MHz, CDCl3) δ –59.0 (s); HRMS (APCI) calcd for
C12H8ClF3NO+ (M+H)+ 274.0241; Found 274.0240.
4-(Pyridine-3-yl)trifluoromethoxybenzene (3p)
General Procedure D was followed for the reaction of xanthate
2p (131 mg, 0.50 mmol) with the exception adding selectfluor
(117 mg, 0.50 mmol, 1.0 equiv.). The reaction was conducted
with dichloroethane (2 mL) for 12 h. The crude reaction mixture
was filtered through a pad of silica gel (EtOAc/Hexane 3:1) and
then purified by preparative SFC to remove (PhSO2)2NH as a
main contaminant (95% CO2 : 5% MeOH (0.2% 7 M NH3 in
MeOH), Flow:3.0 mL/min, Princeton PPU 250mm x 10.0mm
5mm) to give the product as a colorless oil (55.0 mg, 46%). 3p:
1H NMR (CDCl3, 400 MHz) δ 8.90–8.79 (m, 1H), 8.63 (d, J =
4.8 Hz, 1H), 7.87 (t, J = 5.6 Hz, 1H), 7.66–7.57 (m, 2H), 7.43–
7.32 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 149.3, 148.8,
148.1, 136.5, 136.0, 134.5, 128.6, 123.7, 121.6, 120.5 (q, J =
258, CF3); 19F NMR (376 MHz, CDCl3) δ –57.8 (s); HRMS
4-(Benzoyl)trifluoromethoxybenzene (3i)
General Procedure D was followed for the reaction of xanthate
2i (144 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (2 mL) for 24 h. The crude reaction mixture was
purified by silica gel column chromatography (Hexane) to give
the product as a colorless oil (68.3 mg, 51%). 3i: 1H NMR (600
MHz, CDCl3) δ 7.89–7.85 (m, 2H), 7.79 (d, J = 7.7 Hz, 2H),
7.61 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.34–7.30 (m,
2H); 13C NMR (151 MHz, CDCl3) δ 195.2, 152.2, 137.2, 136.0,
132.8, 132.1, 130.0, 128.5, 120.5 (q, J = 259, CF3), 120.3; 19
NMR (376 MHz, CDCl3) δ –58.8 (s); HRMS (EI), calcd for
F
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(APCI) calcd for C12H9F3NO+ (M+H)+ 240.0631; Found
240.0624.
General Procedure C was followed for the reaction of xanthate
1
2
3
4
5
6
7
8
2w (142 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (5 mL) for 3 h. The crude reaction mixture was
purified by silica gel column chromatography to give a mixture
of 3w (39.4 mg, 30%) andArOCF2Cl byproduct (1.8 mg, 1.3%).
3w: brown oil; 1H NMR (CDCl3, 600 MHz) δ 7.89 (s, 1H), 7.66
(s, 1H), 7.61–7.58 (m, 2H), 7.45–7.42 (m, 2H); 13C NMR (151
MHz, CDCl3) δ 138.5, 135.6, 133.3, 132.9, 129.8, 129.3, 120.6
(q, J = 258 Hz, CF3), 118.6; 19F NMR (376 MHz, CDCl3) δ –
60.7 (s); HRMS (EI) calcd for C10H6ClF3N2O+ (M)+ 262.0121;
Found 262.0125.
4-(Pyrimidine-3-yl)trifluoromethoxybenzene (3q)
General Procedure D was followed for the reaction of xanthate
2q (131 mg, 0.50 mmol) with the exception adding selectfluor
(354 mg, 1.00 mmol, 2.0 equiv.). The reaction was conducted
with dichloroethane (2 mL) for 12 h. The crude reaction mixture
was filtered through a pad of silica gel (EtOAc/Hexane 1:1) and
then purified by preparative SFC to remove (PhSO2)2NH as a
main contaminant (95% CO2 : 5% MeOH (0.2% 7 M NH3 in
MeOH), Flow:3.0 mL/min, Princeton PPU 250mm x 10.0mm
5mm) to give the product as a white solid (35.0 mg, 29%). 3q:
1H NMR (CDCl3, 400 MHz) δ 9.25 (s, 1H), 8.95 (s, 2H), 7.63
(d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 157.8, 154.9, 149.9, 133.9, 133.2, 128.6, 121.9,
120.5 (q, J = 258, CF3); 19F NMR (376 MHz, CDCl3) δ –58.0
(s); HRMS (APCI) calcd for C11H8F3N2O+ (M+H)+ 241.0583;
Found 241.0586.
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20
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34
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ASSOCIATED CONTENT
Supporting Information
Additional experimental procedures and original spectral data
(PDF)
The Supporting Information is available free of charge on the ACS
Publications website.
5-Dimethylaminocarbonyl-3-trifluoromethoxypyridine (3r)
General Procedure C was followed for the reaction of xanthate
2r (128 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (5 mL) for 24 h. The crude reaction mixture was
purified by silica gel column chromatography to give a mixture
of 3q (19.2 mg, 16%), ArOCF2Cl (0.6 mg, 0.5%), and
ArOCFCl2 (0.6 mg, 0.4%). 3q: brown oil; 1H NMR (CDCl3, 600
MHz) δ 8.49 (d, J = 2.6 Hz 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.65
(dd, J = 8.8, 2.6 Hz, 1H), 3.14 (s, 3H), 3.11 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 167.7, 152.9, 146.3, 141.0, 129.1, 125.2,
120.4 (q, J = 260 Hz, CF3), 39.2, 36.1; 19F NMR (376 MHz,
AUTHOR INFORMATION
Corresponding Author
*Email: jhartwig@berkeley.edu
allyn.t.londregan@pfizer.com
ORCID
John F. Hartwig: 0000-0002-4157-468X
Makoto Yoritate: 0000-0003-2182-3914
Allyn T. Londregan: 0000-0001-8832-340X
+
CDCl3) δ –58.0 (s); HRMS (APCI) calcd for C9H10F3N2O2
Present Addresses
‡Graduate School of Pharmaceutical Science, Kyushu University,
Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
(M+H)+ 235.0689; Found 235.0691.
3-Trifluoromethoxyquinoline (3t)
General Procedure C was followed for the reaction of xanthate
2t (118 mg, 0.50 mmol). The reaction was conducted with di-
chloroethane (5 mL) for 24 h. The crude reaction mixture was
purified by silica gel column chromatography to give a mixture
of 3q (11.7 mg, 11%) and ArOCF2Cl byproduct (0.3 mg, 0.3%).
3q: 1H NMR (CDCl3, 600 MHz) δ 8.84 (d, J = 2.6 Hz, 1H), 8.17
(d, J = 8.4 Hz, 1H), 7.88–7.86 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H),
7.77 (ddd, J = 8.4, 6.6, 1.1 Hz, 1H), 7.64 (ddd, J = 8.1, 6.6, 1.1
Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 146.0, 144.6, 142.9,
130.3, 129.3, 128.3, 128.0, 127.9, 126.2, 120.7 (q, J = 260,
CF3); 19F NMR (376 MHz, CDCl3) δ –58.1 (s); HRMS (EI)
calcd for C10H6F3NO+ (M)+ 213.0401; Found 213.0404.
ACKNOWLEDGMENT
We are thankful for support from the Pfizer and the NIH
(1R35GM130387). We also thank Dr. Vincent Mascitti for his
helpful insight into this research.
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2u (118 mg, 0.50 mmol). The reaction was conducted with di-
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1
uct as a brown oil (41.6 mg, 39%). 3u: H NMR (CDCl3, 600
MHz) δ 8.95 (dd, J = 4.0, 1.8 Hz, 1H), 8.18–8.15 (m, 2H), 7.65
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1-(4-Chlorophenyl)-4-(trifluoromethoxy)-1H-pyrazole (3w)
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the byproducts.
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