One-pot, two-step, microwave-assisted palladium-catalyzed conversion of aryl alcohols to aryl fluorides via aryl nonaflates

Article abstract of DOI:10.1021/jo400255m

A convenient procedure for converting aryl alcohols to aryl fluorides via aryl nonafluorobutylsulfonates (ArONf) is presented. Moderate to good one-pot, two-step yields were achieved by this nonaflation and microwave-assisted, palladium-catalyzed fluorination sequence. The reductive elimination step was investigated by DFT calculations to compare fluorination with chlorination, proving a larger thermodynamic driving force for the aryl fluoride product. Finally, a key aryl fluoride intermediate for the synthesis of a potent HCV NS3 protease inhibitor was smoothly prepared with the novel protocol.

Full text of DOI:10.1021/jo400255m

Note
pubs.acs.org/joc
One-Pot, Two-Step, Microwave-Assisted Palladium-Catalyzed
Conversion of Aryl Alcohols to Aryl Fluorides via Aryl Nonaflates
‡
‡
‡
,‡
Johan Wannberg,†,‡ Charlotta Wallinder, Meltem Unlusoy, Christian Skold, and Mats Larhed*
̈
̈
̈
†KDev Exploratory AB, Nobels vag 3, SE-171 65 Solna, Sweden
‡Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23
Uppsala, Sweden
̈
S
* Supporting Information
ABSTRACT: A convenient procedure for converting aryl alcohols to aryl
fluorides via aryl nonafluorobutylsulfonates (ArONf) is presented. Moderate to
good one-pot, two-step yields were achieved by this nonaflation and microwave-
assisted, palladium-catalyzed fluorination sequence. The reductive elimination
step was investigated by DFT calculations to compare fluorination with
chlorination, proving a larger thermodynamic driving force for the aryl fluoride
product. Finally, a key aryl fluoride intermediate for the synthesis of a potent
HCV NS3 protease inhibitor was smoothly prepared with the novel protocol.
he introduction of fluorine atoms into aromatic rings of
Tpharmaceutically active compounds modifies their proper-
ties in various ways. Frequently, this is used as a means of
blocking metabolism (aromatic oxidation), modifying the pKa
of acidic or basic groups, to increase lipophilicity or improve
the affinity to a target protein.1−3 As a consequence,
fluoroaromatics are common among approved drugs as well
as in biocides.1−4 An additional area of importance for
fluorochemistry is the generation of synthetic intermediates.
The classical methods for the incorporation of a fluorine
atom to an aromatic scaffold (e.g., Halex− and Balz−
Schiemann reaction) require severe conditions with poor
functional group tolerance. However, in recent years, significant
progress has been made in this field. Electrophilic fluorinations
of Grignard5,6 and other Ar-M(X)Y reagents have been
presented.7 A number of transition-metal-mediated (catalytic
or stoichiometric) methods have been disclosed7−13 including
the palladium-catalyzed fluorinations of aryl triflates (Buchwald
fluorination)14 and aryl bromides.14,15 Recently a non-metal-
catalyzed method for direct deoxyfluorination of phenols was
published.16
Our interest in fluorine as a blocker of metabolism of
aromatic positions of drug compounds17 and generation of
essential building blocks in medicinal synthesis prompted us to
explore the palladium-catalyzed fluorination reaction. Some
issues with this reaction were identified, and solutions/
improvements were examined with the aims to (1) decrease
reaction times, (2) identify a one-pot, two-step protocol for
synthesis of aryl fluorides (2) from aryl alcohols (3), (3) avoid
the need for glovebox conditions, and (4) minimize side
product formation.
Phos18,19 as the ligand in dry toluene using 140 °C controlled
microwave heating.20−22 As expected, simply trying to work fast
and efficient while adding the highly hygroscopic cesium
fluoride (CsF) in an open atmosphere was not enough to
prevent water-induced formation of phenols (3) and diaryl
ethers under the fluorination conditions. Thus, various methods
of keeping the CsF away from the humid atmosphere was
explored. In our hands, the most effective and convenient
procedure of keeping the CsF dry was to weigh it in a reaction
vial (2−5 mL microwave vial) and then dry the vial (with
magnetic stirring bar) in a vacuum oven for at least 5 h. The vial
was then capped with a septum, nitrogen flushed by syringe
needles, and stored in dry atmosphere until used.
Another problem identified was the formation of small
amounts of ArCl side products with the palladium salt
[(cinnamyl)PdCl]2 being the source of chloride. This
complicated the purifications due to the similar properties of
ArCl and the ArF products (2). Thus, a number of chloride-free
palladium catalysts were screened together with t-BuBrettPhos
as ligand, with Pd2(dba)3 proving to give an almost as active
catalytic system as [(cinnamyl)PdCl]2 but without the
undesired ArCl formation. Using 1-naphthyl triflate (1a) as a
model substrate in a 1.0 mmol reaction we were able to reach
full conversion of 1a to 1-fluoronaphthalene (2a) within 30 min
of microwave heating in a sealed reaction vial at 140 °C.
However, it was soon apparent that some less reactive
substrates 1 required longer times or higher temperatures for
full conversion. Since we wanted to keep the reaction times
short, we found that a higher temperature of 180 °C for 30 min
was suitable to provide a more robust generic reaction
procedure (Table 1). Despite the poor microwave absorbing
Initial efforts focused on running the Buchwald fluorination
protocol14 without employing a glovebox. Aryl triflates (1)
were used as arylating agents, CsF as the fluoride source,
[(cinnamyl)PdCl]2 as the palladium source, and t-BuBrett-
Received: February 7, 2013
Published: March 11, 2013
© 2013 American Chemical Society
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Note
properties of toluene,23 a reaction temperature of 180 °C was
reached within 1−2 min.
encouraging, although when using equimolar amounts or a
slight excess of nonaflyl fluoride in the first step, varying
amounts of diaryl ether could be observed after the fluorination
step. This was attributed to subquantitative conversion of 3 to 4
and/or hydrolysis of 4 to 3 by water and subsequent palladium-
catalyzed C−O coupling. Either way, increasing the excess
nonaflyl fluoride to 1.5 equiv eliminated this problem by
ensuring full conversion of the phenol 3 and/or by scavenging
any water present. Thus, full conversion of 1-naphthol (3a) to
1-fluoronaphthalene (2a) could be achieved in a one-pot
procedure with a GC yield of 83% (Table 2).
Table 1. Microwave-Heated Palladium-Catalyzed
Fluorination of Aryl Triflates
When other aryl alcohols 3 were explored, the time required
to obtain full conversion into ArONf 4 varied significantly, with
some very sluggish reactions. This was partly due to differences
in nucleophilicity of the aryl alcohols but also due to poor
solubility in toluene. The solubility could be improved by
adding a small volume of dry 1,4-dioxane. Importantly, this did
not seem to negatively affect the subsequent fluorination step in
those instances. By applying the general fluorination conditions
from the aryl triflates in Table 1 to the aryl nonaflate entries in
Table 2, all showed complete consumption of 4 (and 3) except
3b and 3c, which required 60 min of microwave heating to
reach full conversion in the second step.
a
b
GC yield. Isolated yield
Product 2a was initially isolated in surprisingly poor yield
despite the relatively high GC yield,24 while aryl fluorides 2b−d
were prepared in 63−80% isolated yields. Due to the volatility
of 2a and 2b, great care was required to prevent significant loss
of product during the purification and drying of these entries.
Aryl nonafluorobutansulfonates (aryl nonaflates, ArONf, 4)
can serve as cost-effective, convenient alternatives to aryl
triflates in transition-metal-catalyzed coupling reactions.25,26
The use of aryl nonaflates as substrates for fluorination
reactions has, as far as we can tell, not been previously
reported. By employing identical conditions as above (Table 1)
with 1-naphthyl nonaflate (4a) as the arylpalladium precursor,
full conversion to the corresponding fluoride (2a) was also
achieved (Scheme 1, I). The swift and straightforward synthesis
As previously observed by Buchwald,14 2,6-dimethyl
substitution (3d) did not seem to affect the reaction negatively,
but in this case rather the opposite. Tertiary aromatic amines
(3b), ethers (3c, 3k), nitriles (3d, 3h) ketones (3e, 3g) and
esters (3f) were also well tolerated. However, electron-rich 3 or
substrates containing protic functionalities proved unproductive
under these conditions. The discrepancies between GC yields
and isolated yields in Table 2 could mainly be explained by
losses due to ArF volatility and/or other purification problems.
The fluoroquinoline 2k had previously been imagined as an
intermediate in the synthesis of potent hepatitis C virus (HCV)
NS3 protease inhibitors, but all attempted methods to produce
2k failed at the time.27 Instead, the corresponding chloro
derivative had to be used for the subsequent nucleophilic
aromatic substitution with the 4-hydroxyphenylglycine deriva-
tive 5 resulting in a very sluggish reaction. With our new
methodology, 2k was synthesized in decent yield (Table 2),
and the reaction of 2k with 5 proceeded smoothly to furnish 6
in 6 h compared to several weeks for the chloro derivative
(Scheme 2).27
Scheme 1. Palladium-Catalyzed Fluorination of an Aryl
Nonaflate (4a) and Testing the Synthesis of 4a in Toluene
with CsF Present
As palladium-catalyzed chlorination and bromination of
ArOTf 1a (using KCl or KBr) has been reported using
[(cinnamyl)PdCl]2 and t-BuBrettPhos with KF as an additive,28
we wanted to compare the reactivity of different halide salts
under our conditions. A competitive experiment where 1 equiv
each of CsBr, CsCl, and CsF were present showed almost
exclusively the naphthyl fluoride product with <10% of ArCl 7a
and only traces of ArBr. Considering the ease of forming ArCl
side product when using [(cinnamyl)PdCl]2 as a Pd source, this
was somewhat surprising. A suspicion that ArCl or ArBr may
have formed and reacted further to ArF was disproved by
follow-up experiments using CsCl or CsBr alone, which
indicated practically no conversion to ArX.
In order to improve our understanding of the reaction, we
decided to perform a focused computational investigation by
means of density functional theory (DFT) calculations of
fluorination and chlorination. Phenyl was used as model aryl
moiety in the calculations. Of the parts in the proposed catalytic
cycle in Figure 1 only reductive elimination was investigated
because this reaction step is crucial for product formation and a
a
b
GC yield. Isolated yield.
of aryl nonaflates allowed us to envision a one-pot, two-step
strategy from phenols (3) to aryl fluorides (2). Stirring 1-
naphthol (3a) with nonafluoro-1-butansulfonylfluoride (non-
aflyl fluoride, NfF) in toluene without base did not result in any
reaction, even upon heating. However, after this reaction
mixture was added to a vial of dry CsF, the aryl nonaflate 4a
was immediately detected. By heating at 50 °C with CsF as
base, full conversion of 3a to 4a was reached within 1 h
(Scheme 1, II).
Initial attempts of applying the one-pot, two-step strategy,
whereby a slurry of Pd2(dba)3 and t-BuBrettPhos in toluene
was added by syringe to the nonaflation reaction, were
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Table 2. One-Pot, Two-Step Fluorination of ArOH via
ArONf
Scheme 2. Improved Synthesis of HCV NS3 Protease
Inhibitor intermediate 6
Figure 1. Proposed catalytic cycle for palladium-catalyzed aryl
halogenation.
reductive elimination because the bulky t-BuBrettPhos ligand
occupies two coordination sites, as seen in the X-ray structure
of similar complexes.30 From complex I reductive elimination is
calculated to proceed with fairly similar energy barriers to the
transition state for fluorination and chlorination, 95 and 101 kJ
mol−1, respectively. The structures including relevant bond
lengths in the optimized geometries of TS-a and TS-b can be
found in Supporting Information. Product formation giving 2l
shows that fluorination gives a significantly more thermody-
namically stable product (−23 kJ mol−1) compared to
chlorination (+48 kJ mol−1) providing 7l. Thus, fluorination
has a larger thermodynamic driving force in the reaction, and
this can be rationalized by a relatively more stable Ph−X bond
versus Pd−X bond for F in comparison to Cl.31 This result is in
accordance with the experimental result herein that fluorinated
product is the preferred outcome of the reaction in the
competitive experiments. However, the computational inves-
tigation does not explain the ease of forming the chlorinated
a
b
NfF (1.5 equiv), CsF (2.0 equiv), toluene, 50 °C. Pd2(dba)3 (2 mol
c
%), t-BuBrettPhos (6 mol%), MW, 180 °C, 30 min. 9:1 toluene:1,4-
dioxane. 1:1 toluene:1,4-dioxane. Isolated yields (>95% purity by H
NMR). nd = not determined.
d
1
successful outcome of the reaction.29 Accordingly, the starting
point for the DFT calculations was the prereductive elimination
complex I in Figure 2, which might be generated from either a
phenyl triflate (1l) or the corresponding phenyl nonaflate (4l).
In this complex the phenyl moiety and halide already have the
cis configuration that provides proximity of the moieties for
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was then immediately capped with a septum and evacuated and
backfilled with N2 three times via a syringe needle. While cooling, the
vial was put in a desiccator for storage until used. The highly
hygroscopic CsF showed a 5% weight loss on drying at 120 °C under
reduced pressure (<10 mbar) overnight. Consequently, this was
compensated for when weighing in the “wet” CsF before drying.
General Procedure A: Fluorination of Aryl Triflates. Aryl
triflate32 (1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (18
mg, 0.020 mmol), and t-BuBrettPhos (29 mg, 0.060 mmol) (Pd:L =
1:1.5) in 4 mL of dry toluene were stirred in a dried glass vial for about
5 min at room temperature. The mixture was then added by syringe to
a capped vial with CsF (2.0 mmol), and the resulting reaction mixture
was microwave heated at 180 °C for 30 min. After being cooled to
room temperature, the reaction mixture was purified by silica flash
chromatography using the conditions indicated below.
General Procedure B: One-Pot, Two-Step Conversion of Aryl
Alcohols to Aryl Fluorides. Nonaflation Step. Aryl alcohol (1.0
mmol) and perfluoro-1-butanesulfonyl fluoride (453 mg, 1.5 mmol)
dissolved in 2 mL of dry toluene was added by syringe to a capped vial
with CsF (320 mg, 2.0 mmol). (For aryl alcohols poorly soluble in
toluene, the reaction vial was quickly uncapped and the alcohol added
as dry material before recapping and flushing with N2.) The reaction
was stirred at 50 °C for the times indicated in Table 2.
Figure 2. Free energy profile of reductive eliminations from fluoride
containing Ia and chloride containing Ib.
product when using [(cinnamyl)PdCl]2 as Pd source. Possibly
an explanation could be revealed from a thorough investigation
of the catalyst activation if chloride would enter the initial
catalytic cycle.
Fluorination Step. Tris(dibenzylideneacetone)dipalladium(0) (18
mg, 0.020 mmol) and t-BuBrettPhos (29 mg, 0.060 mmol) (Pd:L =
1:1.5) in 2 mL of dry toluene was stirred in a dried glass vial for about
5 min at room temperature. The mixture was then added by syringe to
the previous reaction mixture through the septum, and the resulting
reaction mixture was microwave heated at 180 °C for 30 min. After
being cooled to room temperature, the reaction mixture was purified
by silica flash chromatography and isolated using the conditions
indicated below.
An operationally convenient one-pot, two-step procedure for
the conversion of aryl alcohols to aryl fluorides in isolated yields
of 41−85% has been developed. Aryl alcohols were first in situ
converted to aryl nonaflates using CsF as base. Next, Pd2(dba)3
and t-BuBrettPhos were added to catalyze the microwave-
heated fluorination. A radiation time of 30−60 min and a
reaction temperature of 180 °C furnished full conversion.
Competitive experiments showed that fluorination was
favored over both chlorination and bromination under the
present reaction conditions and DFT calculations showed that
fluorination was preferred over the corresponding chlorination
in the reductive elimination step.
1-Fluoronaphthalene (2a).33 Synthesized from 1-naphthyl
triflate according to general procedure A and from 3a according to
general procedure B. The reaction mixtures were purified using
pentane as eluent to give 2a as colorless oils. Procedure A: 77.2 mg,
1
53% yield. Procedure B: 75.1 mg, 51% yield. H NMR (400 MHz,
CDCl3): δ 8.17−8.12 (m, 1H), 7.91−7.85 (m, 1H), 7.65 (d, J = 8.3
Hz, 1H), 7.60−7.49 (m, 2H), 7.42 (td, J = 8.0, 8.0, 5.4 Hz, 1H), 7.17
(ddd, J = 10.7, 7.7, 1.0 Hz, 1H). 13C NMR (100.5 MHz, CDCl3): δ
158.9 (d, JCF = 252 Hz), 135.0 (d, JCF = 3 Hz), 127.7 (d, JCF = 3 Hz),
126.9 (d, JCF = 1 Hz), 126.3 (d, JCF = 2 Hz), 125.7 (d, JCF = 8 Hz),
123.8 (d, JCF = 4 Hz), 123.9 (d, JCF = 16 Hz), 120.7 (d, JCF = 5 Hz),
109.5 (d, JCF = 20 Hz).
EXPERIMENTAL SECTION
■
General Information. The microwave reactions were performed
in a single-mode microwave reactor producing controlled irradiation at
2450 MHz with a power of 0−400 W. The reaction temperature was
determined using the built-in online IR-sensor. GC−MS analyses were
performed with a CP-SIL 8 CB Low Bleed (30 m × 0.25 mm) or a
Factor Four VF 5 ms (30 m × 0.25 mm) capillary column using a 70−
300 °C temperature gradient and EI ionization at 70 eV. Analytical
UHPLC−MS was performed with an ion-trap mass spectrometer and
UV-DAD detection using a C18 column (50 × 3 mm). Acetonitrile in
0.05% aqueous formic acid was used as mobile phase at a flow rate of
1.5 mL/min. Silica gel (Merck 60, 40−63 μm) was used for flash
chromatography. Analytical thin-layer chromatography was done using
aluminum sheets precoated with silica gel (Merck, F254); detection was
by UV (254 nm). Nuclear magnetic resonance (NMR) spectra were
recorded at 400 MHz for 1H, at 100.5 MHz for 13C, and at 376 MHz
Ethyl 4-Fluorobenzoate (2b).34 Synthesized from ethyl 4-
(((trifluoromethyl)sulfonyl)oxy)benzoate according to general proce-
dure A and from 3f according to general procedure B. The reaction
mixtures were purified using 0−50% diethyl ether in pentanes to give
2b as colorless oils. Procedure A: 107 mg, 63% yield. Procedure B: 119
1
mg, 71% yield. H NMR (400 MHz, CDCl3): 8.12−7.97 (m, 2H),
7.16−7.01 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).
13C NMR (100.5 MHz, CDCl3): δ 165.64 (d, JCF = 252 Hz), 165.61,
132.01 (d, JCF = 10 Hz), 126.71 (d, JCF = 3 Hz), 115.39 (d, JCF = 22
Hz), 61.04, 14.27.
(4-Fluorophenyl)(phenyl)methanone (2c).35 Synthesized from
4-benzoylphenyl trifluoromethanesulfonate according to general
procedure A and from 3g according to general procedure B. The
reaction mixtures were purified using 0−10% ethyl acetate in
isohexane as eluent to give 2c as colorless oils. Procedure A: 160
mg, 80% yield. Procedure B: 132 mg, 66% yield. 1H NMR (400 MHz,
CDCl3): δ 7.87−7.83 (m, 2H), 7.79−7.75 (m, 2H), 7.62−7.57 (m,
1H), 7.52−7.47 (m, 2H), 7.19−7.13 (m, 2H) 13C NMR (100.5 MHz,
CDCl3): δ 195.40, 165.54 (d, JCF = 254 Hz), 137.65, 133.96 (d, JCF = 3
1
for 19F. H and 13C NMR chemical shifts were reported as δ (ppm)
and referenced using the residual solvent signal (1H, CDCl3 at 7.26
ppm; 13C, CDCl3 at 77.16 ppm). 19F NMR chemical shifts were
reported as δ (ppm) and verified with a reference sample containing a
sealed capillary with CFCl3 giving a reference signal at 0 ppm. All
reagents were purchased from commercial suppliers and used without
further purification. Compounds 2a−g, j are known compounds; 2k is
a new compound. Compounds 2h and 2i are known, but there are no
NMR data reported in the literature. All final compounds were ≥95%
pure as determined by NMR.
Hz), 132.81 (d, JCF = 9 Hz), 132.61, 130.02, 128.50, 115.59 (d, JCF
=
22 Hz).
1-(Benzyloxy)-3-fluorobenzene (2d).36 Synthesized from 3-
(benzyloxy)phenyl trifluoromethanesulfonate according to general
procedure A and from 3c according to general procedure B. The
reaction mixtures were purified using 5% dichloromethane in
isohexane as eluent to give 2d as colorless oils. Procedure A: 128
General Procedure for Drying of CsF. CsF (320 mg, 2.0 mmol)
was added as quickly as possible to a 2−5 mL microwave vial and then
dried in a vacuum oven (120 °C, <10 mbar, minimum 5 h). The vial
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Note
mg, 63% yield. Procedure B: 112 mg, 56% yield. 1H NMR (400 MHz,
2.5 Hz, 1H). 13C NMR (100.5 MHz, CDCl3): δ 166.2 (d, JCF = 265
Hz), 161.9, 159.7 (d, JCF = 8 Hz), 152.5 (d, JCF = 5 Hz), 139.2 (d, JCF
= 4 Hz), 129.8, 129.0, 127.5, 121.6 (d, JCF = 5 Hz), 119.9 (d, JCF = 2
Hz), 113.3 (d, JCF = 13 Hz), 107.6 (d, JCF = 4 Hz), 101.8 (d, JCF = 17
Hz), 55.7. 19F NMR (376 MHz, CDCl3) δ: −113.1. HRMS (ESI):
calcd for C16H13FNO (M + H)+ 254.0981, found: 254.0986.
CDCl3): δ 7.50−7.34 (m, 5H), 7.34−7.19 (m, 1H), 6.84−6.64 (m,
3H), 5.07 (s, 2H). 13C NMR (100.5 MHz, CDCl3): δ 163.66 (d, JCF
=
244 Hz), 160.15 (d, JCF = 11 Hz), 136.51, 130.25 (d, JCF = 10 Hz),
128.67, 128.15, 127.51, 110.68 (d, JCF = 3 Hz), 107.77 (d, JCF = 21
Hz), 102.64 (d, JCF = 25 Hz), 70.25.
4-(3-Fluorophenyl)morpholine (2e).37 Synthesized from 3b
according to general procedure B. The reaction mixture was purified
using 25−50% dichloromethane in pentane as eluent to give 2e as a
(2S)-2-(3-Bromo-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)-
phenyl)-2-((tert-butoxycarbonyl)amino)acetic acid (6).27
A
mixture of 5 (346 mg, 1.00 mmol) and potassium tert-butoxide (224
mg, 2.00 mmol) in dry DMSO (3 mL) was stirred at room
temperature. After 10 min, 2k (127 mg, 0.500 mmol) was added and
the reaction stirred under nitrogen at 64 °C for 6 h. The reaction
mixture was partitioned between water (60 mL) and diethyl ether (60
mL). The aqueous layer was acidified with 1 M HCl (aq) to pH 5 and
extracted with dichloromethane (2 × 60 mL). The combined
dichloromethane layers were dried (MgSO4) and evaporated. The
residue was purified by reversed-phase (C18) silica chromatography
using a 10−90% gradient of acetonitrile in water with 0.05% formic
acid. Product fractions were pooled and evaporated, and the product
dried under vacuum overnight to give 107 mg (37%) of 6 as a light
1
colorless oil: 74.5 mg, 41% yield. H NMR (400 MHz, CDCl3): δ
7.24−7.17 (m, 1H), 6.68−6.64 (m, 1H), 6.61−6.52 (m, 2H), 3.88−
3.82 (m, 4H), 3.18−3.22 (m, 4H). 13C NMR (100.5 MHz, CDCl3): δ
164.02 (d, JCF = 243 Hz), 153.12 (d, JCF = 10 Hz), 130.34 (d, JCF = 10
Hz), 110.94 (d, JCF = 2 Hz), 106.39 (d, JCF = 22 Hz), 102.58 (d, JCF
=
25 Hz), 66.88, 49.00.
4-Fluoro-3,5-dimethylbenzonitrile (2f).38 Synthesized from 3d
according to general procedure B. The reaction mixture was purified
using 0−50% diethyl ether in pentanes as eluent to give 2f as a white
1
solid: 120 mg, 80% yield. H NMR (400 MHz, CDCl3): δ 7.36−7.29
(m, 2H), 2.26 (d, J = 2.3 Hz, 6H). 13C NMR (100.5 MHz, CDCl3): δ
162.45 (d, JCF = 253 Hz), 132.93 (d, JCF = 6 Hz), 126.27 (d, JCF = 20
Hz), 118.45, 107.44 (d, JCF = 5 Hz), 14.38 (d, JCF = 4 Hz).
1
brown semisolid. H NMR (400 MHz, CDCl3): δ 8.98 (br s, 1H),
8.20, (d, J = 9.3 Hz, 1H), 7.72−7.60 (m, 4H), 7.35 (d, J = 8.6 Hz, 1H),
7.27−7.15 (m, 4H), 7.05 (d, J = 8.6 Hz, 1H), 6.60 (s, 1H), 5.93 (br d,
J = 6.9 Hz, 1H), 5.07(br d, J = 6.9 Hz, 1H), 3.87 (s, 3H), 1.34 (s, 9H).
13C NMR (100.5 MHz, CDCl3): δ 173.0, 163.3, 163.3, 158.5, 155.1,
149.6, 148.1, 140.1, 135.9, 132.9, 130.8, 129.0, 128.4, 128.3, 123.5,
122.6, 120.4, 115.8, 114.5, 104.3, 101.2, 80.0, 57.9, 56.1, 28.5.
Computational Details. The DFT calculations were performed
using Jaguar version 7.640 employing the B3LYP hybrid func-
tional41−43 with the LACVP*+ basis set, which uses an effective
core potential44 for Pd and 6-31+G* for all other atoms. All
geometries were optimized in the gas phase with a subsequent single-
point energy calculation in the solution phase, utilizing the PBF
solvation model45,46 with parameters suitable for toluene (dielectric
constant, epsout = 2.38 and probe radius, radprb = 2.7620911).
Vibrational analysis was performed for the optimized geometries in the
gas phase, and the free energies for the geometries were calculated by
adding the thermodynamic contribution, including zero-point energy,
at 453.15 K to the solution-phase energy. Dispersion correction was
calculated for the gas phase geometries using the DFT-D3 program47
(version 2.0, rev 1) and was added to obtain the final energies. The
TSs were verified to have exactly one negative frequency in the
vibrational analysis and the ground states were verified to have no
negative frequencies.
1-(4-Fluorophenyl)ethanone (2g).39 Synthesized from 3e
according to general procedure B, using 1,4-dioxane/toluene 1:9 as
solvent. The reaction mixture was purified using a gradient of 0−20%
diethyl ether in pentanes as eluent to give 2g as a colorless oil: 89.1
1
mg, 65% yield. H NMR (400 MHz, CDCl3): δ 8.01−7.87 (m, 2H),
7.16−6.99 (m, 2H), 2.54 (s, 3H). 13C NMR (100.5 MHz, CDCl3): δ
196.35, 165.75 (d, JCF = 254 Hz), 133.54 (d, JCF = 3 Hz), 130.87 (d,
JCF = 10 Hz), 115.55 (d, JCF = 22 Hz), 26.43.
6-Fluoro-2-naphthonitrile (2h). Synthesized from 3h according
to general procedure B, using 1,4-dioxane/toluene 1:9 as solvent. The
reaction mixture was purified using a gradient of 5−15% ethyl acetate
in isohexane as eluent to give 2h as a white solid: 110 mg, 64% yield,
mp 125−127 °C. 1H NMR (400 MHz, CDCl3): δ 8.23−8.20 (m, 1H),
7.95−7.85 (m, 2H), 7.66−7.62 (m, 1H), 7.50 (dd, J = 9.4, 2.5 Hz,
1H), 7.42−7.32 (m, 1H). 13C NMR (100.5 MHz, CDCl3): δ 162.5 (d,
JCF = 251 Hz), 135.8 (d, JCF = 10 Hz), 134.0 (d, JCF = 1 Hz), 131.1 (d,
JCF = 9 Hz), 129.3 (d, JCF = 2 Hz), 128.5 (d, JCF = 6 Hz), 127.4, 118.9,
118.3, 111.5 (d, JCF = 21 Hz), 108.8 (d, JCF = 3 Hz). 19F NMR (376
MHz, CDCl3) δ: −108.8. HRMS (ESI): calcd for C11H7FN (M + H)+
172.0563, found 172.0560.
2-(4-Fluorophenyl)-6-methyl-4H-chromen-4-one (2i). Synthe-
sized from 3i according to general procedure B. The reaction mixture
was purified using first 0−10% ethyl acetate in isohexane, then
dichloromethane as eluent to give 2i as a white solid: 169 mg, 69%
ASSOCIATED CONTENT
■
1
yield, mp 150−153 °C. H NMR (400 MHz, CDCl3): δ 8.01−7.98
S
* Supporting Information
1HNMR and 13CNMR spectra of all isolated compounds.
Structures of the optimized TS geometries. Energies and atomic
coordinates for all optimized geometries. This material is
available free of charge via the Internet at http://pubs.acs.org.
(m, 1H), 7.93−7.87 (m, 2H), 7.49 (dd, J = 8.6, 2.2 Hz, 1H), 7.43 (d, J
= 8.6 Hz, 1H), 7.23−7.15 (m, 2H), 6.73 (s, 1H), 2.45 (s, 3H). 13C
NMR (100.5 MHz, CDCl3): δ 178.5, 164.8 (d, JCF = 253 Hz), 162.4,
154.6, 135.4, 135.2, 128.6 (d, JCF = 9 Hz), 128.2 (d, JCF = 3 Hz), 125.2,
123.6, 117.9, 116.4 (d, JCF = 22 Hz), 107.3, 21.1. 19F NMR (376 MHz,
CDCl3) δ: −107.7. HRMS (ESI): calcd for C16H12FO2 (M + H)+
255.0821, found 255.0818.
AUTHOR INFORMATION
Corresponding Author
*Tel: +46-18-4714667. Fax: +46-18-4714474. E-mail: mats.
larhed@orgfarm.uu.se.
■
4-Fluoro-6-methyl-2-(trifluoromethyl)quinoline (2j).14 Syn-
thesized from 3j according to general procedure B. The reaction
mixture was purified using 0−10% ethyl acetate in isohexane as eluent
1
to give 2j as a white solid: 195 mg, 85% yield. H NMR (400 MHz,
Notes
CDCl3): δ 8.12 (dd, J = 8.8, 1.8, 1H), 7.90−7.88 (m, 1H), 7.69 (dd, J
= 8.7, 2.0 Hz, 1H), 7.39 (d, J = 9.6 Hz, 1H), 2.60 (s, 3H). 13C NMR
(100.5 MHz, CDCl3): δ 165.9 (d, JCF = 270 Hz), 148.3 (dq, JCF = 35, 8
Hz), 148.3 (d, JCF = 6 Hz), 139.6 (d, JCF = 2 Hz), 134.4, 129.7 (d, JCF
= 4 Hz), 121.0 (dq, JCF = 275, 5 Hz), 119.9 (d, JCF = 13 Hz), 119.26
(d, JCF = 5 Hz), 102.3 (dq, JCF = 19, 2 Hz), 22.06.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from
VINNOVA and thank Prof. Per-Ola Norrby for stimulating
discussions.
4-Fluoro-7-methoxy-2-phenylquinoline (2k). Synthesized from
3k according to general procedure B, using 1,4-dioxane/toluene 1:1 as
solvent. The reaction mixture was purified using 0−10% ethyl acetate
in isohexane as eluent to give 2k as a white solid; 186 mg, 73% yield,
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■
1
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