Pd-catalyzed synthesis of aryl and heteroaryl triflones from reactions of sodium triflinate with aryl (heteroaryl) triflates

Article abstract of DOI:10.1021/acs.joc.5b02523

A novel method for Pd-catalyzed triflination of aryl and heteroaryl triflates using NaSO₂CF₃ as the nucleophile is described. The combination of Pd₂(dba)₃ and RockPhos formed the most effective catalyst. A broad range of functional groups and heteroaromatic compounds were tolerated under the neutral reaction conditions. The order of reactivity ArOTf ≥ ArCl ≥ ArBr is consistent with transmetalation being a slow step of the reaction.

Full text of DOI:10.1021/acs.joc.5b02523

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Note
Pd-Catalyzed Synthesis of Aryl and Heteroaryl Triflones from Reactions
of Sodium Triflinate (NaSO2CF3) with Aryl(Heteroaryl) Triflates
Lynette A Smyth, Eric M Phillips, Vincent S Chan, Jose G Napolitano, Rodger Henry, and Shashank Shekhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02523 • Publication Date (Web): 06 Jan 2016
Downloaded from http://pubs.acs.org on January 11, 2016
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Pd-Catalyzed Synthesis of Aryl and Heteroaryl Triflones from
Reactions of Sodium Triflinate (NaSO2CF3) with
Aryl(Heteroaryl) Triflates
Lynette A. Smyth, † Eric M. Phillips, ‡ Vincent S. Chan, ‡ Jose G. Napolitano, § Rodger
Henry§and Shashank Shekhar‡, *
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†AbbVie Deutschland GmbH & Co. KG, Knollstraße, 67061 Ludwigshafen, Germany
‡AbbVie Inc., Process Research and Development, 1 North Waukegan Road, North Chicago, IL
60064, USA
§ AbbVie Inc., Discovery Chemistry and Technology, 1 North Waukegan Road, North Chicago,
IL 60064, USA
Email Address: Shashank.shekhar@abbvie.com
Abstract
A novel method for Pdꢀcatalyzed triflination of aryl and heteroaryl triflates using
NaSO2CF3 as the nucleophile is described. The combination of Pd2(dba)3 and RockPhos
formed the most effective catalyst. A broad range of functional groups and
heteroaromatic compounds were tolerated under the neutral reaction conditions. The
order of reactivity ArOTf ≥ ArCl ≥ ArBr is consistent with transmetallation being a slow
step of the reaction.
Compounds containing the triflone (SO2CF3) group exhibit unique chemical and
biological properties due to the strong electronꢀwithdrawing ability and high lipophilicity
of SO2CF3. Aryl and heteroaryl triflones (ArSO2CF3) are oftentimes present in new
molecular entities being explored for the potential treatment of cancer and immunological
diseases, among many others.1ꢀ5 This functionality forms building blocks of advanced
functional materials such as nonlinear optical chromophores,6,7and catalysts and
ligands.8,9
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The widespread application of traditional methods to prepare aryl(heteroaryl) triflones
such as FriedelꢀCrafts triflylations,10 aryl Grignard additions to (CF3SO2)2O,11 anionic
thiaꢀFries rerrangements,12ꢀ18 oxidation of aryltrifluoromethyl sulfides,19ꢀ23 nucleophilic
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trifluoromethylation
reactions24,25,26
cycloaddition
reactions,27ꢀ29
thermal
decomposition,30 etc. have been limited due to low yields, poor substrate scope, use of
expensive reagents, harsh reaction conditions, formation of isomeric products and
incompatibility of reaction conditions with common organic functional groups.31 New
synthetic approaches have been reported to complement the existing methods.32,33 We
reported a general method for Cu2O catalyzed reactions of NaSO2CF3 with
diaryliodonium salts to form aryltriflones under mild reaction conditions.34 More readily
accesible electrophiles, such as aryl halides and pseudohalides, did not react with
NaSO2CF3 under the reported conditions. In addition, one example of formation of a
heteroaryl triflone was reported.
Pdꢀ and Cuꢀcatalyzed reactions of aryl halides, pseudohalides, and boronic acids with
aryl and alkylsulfinate salts have been well documented;35,36,37,38,391,40ꢀ49 however, the use
of NaSO2CF3 as a nucleophilic coupling partner has never been reported. The strong
electronꢀwithdrawing character of the trifluoromethylsulfonyl group (σp = 0.96)50,51
substantially reduces the nucleophilicity of NaSO2CF3, rendering it a poor coupling
partner. Due to the poor nucleophilicity, the transmetalation of NaSO2CF3 with Pdꢀ or
Cuꢀcomplexes is likely to be challenging.52,53 Moreover, C–S reductive elimination from
putative Pd(II) and Cu(III) intermediates is expected to be difficult with such an electronꢀ
poor nucleophile.54 Development of stericallyꢀhindered phosphine ligands by Buchwald
and coꢀworkers have allowed other electronꢀpoor nucleophiles to couple successfully
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with aryl halides and pseudohalides in the presence of Pd catalysts.52,55,56,57,58,59,60ꢀ62
Given our interest in molecules containing aryl triflones,1 our success in synthesizing aryl
triflones from reactions of diaryl iodonium salts with NaSO2CF3,34 and recent examples
of Pdꢀcatalyzed couplings of electronꢀpoor nucleophiles, we were motivated to
investigate the Pdꢀcatalyzed formation of C(sp2)ꢀSO2CF3 bonds from reactions of
NaSO2CF3 and aryl (pseudo)halides. Herein, we describe a general method for the
synthesis of aryl and heteroaryl triflones from Pdꢀcatalyzed reactions of aryl and
heteroaryl triflates with NaSO2CF3 under neutral reaction conditions. A few examples of
Pdꢀcatalyzed reactions of aryl chlorides with NaSO2CF3 are also reported.
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The coupling of NaSO2CF3 with phenyl triflate (1a) was choosen for initial
optimization of the reaction conditions because we rationalized that transmetalation of
NaSO2CF3 with a Pd(II) aryl triflate complex obtained from oxidative addition of aryl
triflate to Pd(0) is expected to be more facile than transmetalation with the analogous
Pd(II) aryl halide intermediate.63 Since NaSO2CF3 is only sparingly soluble in common
organic solvents used in Pdꢀcatalyzed crossꢀcoupling reactions such as toluene, 1,4ꢀ
dioxane, tertꢀamyl alcohol, THF, DME, a phase transfer catalyst, tris(3,6ꢀ
dioxaheptyl)amine (TDA),52 that was reported to be the optimal phase transfer catalyst
for Pdꢀcatalyzed reaction of another poorly soluble nucleophile, NaNO2, was used to
further facilitate the reaction. Sterically bulky phosphine ligands that are known to be
effective for Pdꢀcatalyzed reactions of other electronꢀpoor nucleophiles were surveyed.
While formation of trace amounts of phenyl triflone (2a) was observed in the
presence of BrettPhos (I) (Table 1, entry 1), the use of the bulkier tertꢀbutylBrettPhos (II)
gave 2a in 23% yield (entry 2). Surprisingly, with RockPhos (III), which is similar in
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structure to II except for the substituents at the 6ꢀposition of the phosphine containing
aryl rings, 2a was formed in quantitative yield (entry 3). A similarly significant
difference in the reactivities of Pd catalysts based on ligands II and III was observed by
Buchwald and coꢀworkers in Pdꢀcatalyzed CꢀO bond forming reactions.64 The catalyst
based on adamantylꢀRockPhos (IV) formed 2a in 75% yield after 5 h (entry 4), whereas
only trace product formation was observed in the presence of cyclohexylꢀRockPhos (V)
(entry 5), demonstrating that substitutents bulkier than cyclohexyl groups on phosphorous
are essential for the catalytic activity. No product formation was observed in the presence
of other sterically bulky phosphine and carbene ligands that were evaluated in the
reaction (entries 6ꢀ8). Biarylphosphines containing electronꢀwithdrawing substitutents on
phosphorous are known to accelerate the reductive elimination step;65 however, no
product formation was observed in the presence of IX (entry 9). Although faster reaction
rate was observed in the presence of TDA than in its absence, the phase transfer catalyst
is not essential for the reaction (compare entries 3 and 12). Toluene was found to be the
optimal solvent (Table S1). While Pd2(dba)3 and [Pd(cinnamyl)Cl]2 were effective as Pdꢀ
precursors, negligible amount of product was formed when Pd(OAc)2 or Pd(MeCN)2Cl2
were used as the source of Pd (Table S1).
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The substitution of NaSO2CF3 with KSO2CF3 as the coupling partner for 1a
afforded 2a in a similar yield, however, the use of Baran’s reagent, Zn(SO2CF3)2, failed
to form 2a in any isolable yield. The coupled product 2a was observed in less than 5%
yield when either chlorobenzene (1a’) or bromobenzene (1a”) was used as the
electrophile instead of phenyl triflate (1a) under the reaction conditions shown in entry 3.
Increasing the reaction temperature to 100 °C formed 2a in 50% and 7% yield after 25 h
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when 1a’ and 1a” were respectively used as electrophiles (entries 10 and 11).66 The order
of reactivity, PhOTf >> PhCl >> PhBr, is consistent with transmetalation being a slow
step of the reaction.63,67
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Table 1. Evaluation of reaction parameters for Pdꢀcatalyzed formation of aryltriflone
Entry
X
L (mol%) Time (h) 2a (%)a
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2
3
4
5
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf VIII (5)
OTf
Cl
I (10)
II (6)
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2
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24
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23
>95
75
5
0
0
0
0
III (6)
IV (6)
V (10)
VI (6)
VII (5)
6
7b
8b
9
IX (10)
III (6)
III (6)
III (6)
10c
11c
12d
25
25
6
50
7
74
Br
OTf
All
experiments
were
conducted
with
phenyl
triflate/chlorobenzene/ bromobenzene (1 equiv), and
NaSO2CF3 (2 equiv) for the indicated time. (a) Assay yield
based on HPLC analysis at 210 nm. (b) No Pd2(dba)3 was
added. (c) Reaction at 100 °C. (d) No TDA was added.
After optimizing the reaction conditions for coupling of 1a with Na2SO2CF3, the
reactivities of sterically and electronically diverse aryl triflates were explored (Scheme
1). Aryl triflones (2a-1) were isolated in synthetically useful yields from reactions of aryl
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triflates containing prevalent functional groups: dimethylamino, ether, acetal, carbamate,
thioether, acetate, ester, boronate ester, and acetyl. Aryl triflates containing substitutents
with a wide range of electronꢀdonating abilities (NMe2(σp = ꢀ0.83) to COCH3 (σp = 0.50))
formed the corresponding aryl triflones in high yields. Aryl triflates functionalized with
substitutents more electronꢀdeficient than acetyl were poor substrates for the reaction (1m
and 1n). Stericallyꢀhindered aryl triflates such as 1g and 1h were found to be suitable
substrates.
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Scheme 1. Scope of Pdꢀcatalyzed reaction of NaSO2CF3 with aryl triflates
Unless noted otherwise experiments were conducted with aryl triflate (1
equiv),NaSO2CF3 (1.5 equiv), for the indicated time. Assay yield based
on HPLC analysis at 210 nm. The isolated yield is reported within
parentheses. (a) Pd2(dba)3 (2.5 mol %), III (6 mol %) (b) Pd2(dba)3 (4
mol %), III (9.6 mol %) (c) Reaction at 100 °C. (d) Reaction at 90 °C.
(e) >25% of unreacted 1l was observed.
Heteroaryl triflates such as benzofuran (3a), benzothiophene (3b), indole (3c),
benzoxazole (3d), pyrrolopyridine (3e), quinoxaline (3f), quinoline (3g), and pyridine
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(3h) reacted with NaSO2CF3 under the standard reaction conditions to afford the
corresponding heteroaryl triflones in high yields (Scheme 2). While 6ꢀmethoxypyridinꢀ3ꢀ
yl triflate (3h) formed the coupled product 4h in quantitative yield, the unsubstituted, less
electronꢀrich pyridine, pyridinꢀ3ꢀyl triflate (3i), afforded the corresponding triflones 4i in
only 15% yield. Furthermore, pyridinꢀ2ꢀyl triflate (3j) failed to react.68
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Scheme 2. Scope of Pdꢀcatalyzed reaction of NaSO2CF3 with heteroaryl triflates
Unless noted otherwise experiments were conducted with heteroaryl triflate
(1 equiv),NaSO2CF3 (1.5 equiv) for the indicated time (a) Assay yield
based on HPLC analysis at 210 nm. The isolated yield is reported within
parentheses. (b) Reaction at 100 °C.
Aryl triflones could also be synthesized in moderate yields from reactions of electronꢀ
rich aryl chlorides with Na2SO2CF3 (Scheme 3). Electronꢀdeficient aryl chloride 4ꢀ
acetylphenyl chloride gave <20% yield of product before catalyst decomposition was
observed.
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Scheme 3. Pdꢀcatalyzed reaction of aryl chlorides with NaSO2CF3
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In general, lower catalyst loading, lower reaction temperature, and shorter reaction
times were required for the coupling of electronꢀrich aryl triflates with Na2SO2CF3 than
for coupling electronꢀpoor aryl triflates (Scheme 1). Comparison of the initial rates of
reaction of 1c, 1a, and 1l revealed that the electronꢀrich electrophile 1c reacts
approximately 50 times faster with NaSO2CF3 than the electronꢀpoor electrophile 1l
(Table 2). Although a similar dependence of the efficiency of Pdꢀcatalyzed reactions on
the electronꢀdonating ability of electrophiles was noted in C(sp2)ꢀNO2,52 and C(sp2)ꢀ
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SCF3 bondꢀforming reactions, the dependence appears to be more pronounced for the
formation of C(sp2)ꢀSO2CF3 bonds.
Table 2. Comparison of initial rates of reactions of electronically diverse aryl triflates
Entry
R
σp
initial rate (10ꢀ3 M/min)
1
2
3
OCH3 ꢀ0.27
21
4
0.4
H
0
COCH3 0.50
The superior reactivity of NaSO2CF3 with aryl triflates compared to aryl chlorides in
the presence of a Pd catalyst can indeed be attributed to the more facile transmetalation of
NaSO2CF3 with a cationic L.Pd(Ar)(OTf) intermediate than with a neutral L.Pd(Ar)(Cl)
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intermediate.63 However, it is not apparent if transmetalation is the rateꢀdeterming step
for the Pdꢀcatalyzed reactions of aryl triflates with NaSO2CF3. Insight into the most
challenging step of this novel transformation will help in further expanding the scope of
the methodology to include reactions of electronꢀpoor aryl and heteroaryl triflates.
The formation of aryl triflones from Pdꢀcatalyzed reactions of aryl triflates with
NaSO2CF3 is expected to proceed via the well established sequence of oxidative addition,
transmetalation, and reductive elimination steps. Oxidative addition as the rateꢀlimiting
step of the reaction can be ruled out because PdꢀRockPhos complex is known to react
with aryl triflates at room temperature,69 whereas, much higher temperatures (80ꢀ100 °C)
are needed for this catalytic reaction. This would suggest that either transmetalation or
reductive elimination could be the rateꢀlimiting step. In most Pdꢀcatalyzed C(sp2)ꢀX (X =
C(sp2), N, O, S) bondꢀforming reactions, both transmetalation70 and reductive
elimination54 steps are accelerated by electronꢀpoor electrophiles. One notable exception
is the more facile reductive elimination of aryl nitriles from arylpalladium(II) cyanide
complexes containing more electronꢀdonating electrophiles.71 Thus, the faster rates of
formation of aryl triflones from reactions of NaSO2CF3 with aryl triflates containing
electronꢀdonating substitutents is in contrast to the general reactivity trend observed in
most Pdꢀcatalyzed crossꢀcoupling reactions.
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The limited solubility of NaSO2CF3 in toluene made it difficult to determine the
dependence of rate of aryl(heteroaryl) triflone formation on the concentration of
NaSO2CF3. Nevertheless, we noticed that the reaction proceeds more effectively with
finely ground NaSO2CF3 than with coarse NaSO2CF3, which is also consistent with the
effect of the phase transfer catalyst. As expected for a heterogeneous reaction of this
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nature, efficient agitation of the reaction mixture was also found to be crucial. These
physical observations suggest that transmetalation is a challenging step, if not the rateꢀ
limiting step, in the Pdꢀcatalyzed reactions of aryl(heteroaryl) triflates with NaSO2CF3.
Stereoelectronic differences in substrate reactivities also offers some insight into the
reaction mechanism. The higher catalyst loading and reaction temperature required for 2ꢀ
methoxyphenyl triflate 1h (Table 2) compared to the coupling of the electronically
similar but less bulky 4ꢀmethoxyphenyl triflate 1c suggests that transmetalation is the
slowest step of the reaction. Since the PdꢀRockPhos complex is readily expected to
oxidatively insert into the more stericallyꢀhindered aryl triflate 1h,64 transmetalation of
NaSO2CF3 with Pd(II) is likely retarded due to the increased steric bulk introduced by the
orthoꢀmethoxy group. Furthermore, if reductive elimination was the rateꢀdetermining
step then it would be anticipated that 1h would react faster than 1c because the rate of
reductive elimination typically increases with greater steric bulk in the electrophile.54 We
tentatively suggest that transmetalation of NaSO2CF3 to (RockPhos).Pd(aryl)(triflate)
complex is the rateꢀlimiting step of the reaction. We also propose that the rate of
transmetalation increases with greater electronꢀdonating ability of the electrophile. Thus,
our future efforts will focus on identifying a soluble source of trifluoromethylsulfinate
that can more readily participate in the reaction than NaSO2CF3.
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In summary, a novel palladiumꢀcatalyzed method for the formation of aryl(heteroaryl)ꢀ
SO2CF3 bonds from the reactions of the corresponding triflates with NaSO2CF3 is
described. Given the ease of synthesis of aryl and heteroaryl triflates from phenols, low
cost and availability of NaSO2CF3, use of a commercially available catalyst, neutral
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reaction conditions which affords broad functional group tolerance, this transformation is
highly useful for rapidly accessing a wide variety of aryl and heteroaryl triflones.
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Experimental Section
General methods. All palladiumꢀcatalyzed reactions were performed in a nitrogen glove
box. Aryl and hetroaryl triflates and nonaflates that were commercially unavailable were
synthesized using literature procedures. Anhydrous grade toluene, 1,4ꢀdioxane, tertꢀ
AmOH, and, DMF, were purchased is sureꢀseal bottles from commercial sources and
were sparged with nitrogen before use. Pd2(dba)3, phosphine ligands (I to VI and IX),
Pdꢀcarbene complexes (VII and VIII), phenyl triflate, 4ꢀmethoxylphenyl triflate, 4ꢀ
acetylphenyl triflate, 4ꢀnitrophenyl triflate, naphthaleneꢀ1ꢀtriflate, quinolinꢀ6ꢀtriflate,
chlorobenzene, bromobenzene, 4ꢀmethoxyphenyl chloride, 4ꢀdimethylaminophenyl
chloride, 4ꢀacetylphenyl chloride, various aryl and heteroaryl alcohols, triflic anhydride,
Nꢀ(5ꢀchloropyridinꢀ2ꢀyl)ꢀ1,1,1ꢀtrifluoroꢀNꢀ
((trifluoromethyl)sulfonyl)methanesulfonamide, NaSO2CF3, KSO2CF3, and Zn(SO2CF3)2
were purchased from commercial sources. NaSO2CF3 and KSO2CF3 were ground with a
mortar and pestle and dried overnight in a vacuum oven at 55ꢀ60 °C before use. The H,
1
13C, and 19F NMR spectra were recorded on a 400 or 600 or 700 MHz spectrometer, with
shifts reported in parts per million downfield from tetramethylsilane and referenced to
residual proton (1H) or deuterated solvent (13C). HPLC analyses were performed using
spectroscopic grades of acetonitrile and water with either 0.1 % H3PO4 or 0.1% HClO4 as
eluents. HRMS analyses were performed on a timeꢀofꢀflight mass spectrometer equipped
with an ESI source. Elemental analysis was performed using optimum combustion
analysis on an elemental analyzer.
General procedure for synthesis of aryl and heteroaryl triflates.
The aryl and heteroaryl triflates were synthesized either using procedure A or procedure
B.
Procedure A: A stirred solution of the phenol (1.0 equiv) in CH2Cl2 (0.2 M) was cooled
to ꢀ78 ˚C. DIPEA (1.25 equiv) was added followed by slow addition of 1 M triflic
anhydride in CH2Cl2 (1.3 equiv). The mixture was allowed to warm to 0 ˚C and the
reaction progress was monitored by TLC. When completed, CH2Cl2 was added, the
organic solution was washed with water followed by aqueous NaHCO3 and dried with
Na2SO4. Purification was carried out by flash column chromatography over silica gel
using an ethyl acetate/heptane gradient.
Procedure B: To a vial with magnetic stirring bar was charged phenol (1 equiv) and Nꢀ(5ꢀ
chloropyridinꢀ2ꢀyl)ꢀ1,1,1ꢀtrifluoroꢀNꢀ((trifluoromethyl)sulfonyl)methanesulfonamide (1.1
equiv). The solids were then suspended in CH2Cl2 (10 mL/g of phenol). To the reaction
i
was added Pr2EtN (4 equiv). The reaction was mixed at room temperature and the
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progress was monitored by HPLC. Upon completion of the reaction, the mixture was
concentrated and the resulting residue was purified by flash column chromatography on
silica gel using ethyl acetate/heptane gradient.
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4-(Dimethylamino)phenyl triflate (1b): Following the general procedure A, but without
allowing the reaction mixture to warm up to 0 °C (the reaction was complete within 30
min at ꢀ78 ˚C), 1.47 g of 4ꢀ(dimethylamino)phenol was converted to 1.78 g of 4ꢀ
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(dimethylamino)phenyl trifluoromethanesulfonate (62% yield, 96% purity). H NMR
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(500 MHz, CDCl3) δ 7.16 – 7.07 (m, 2H), 6.74 – 6.53 (m, 2H), 2.97 (s, 6H). C NMR
(126 MHz, CDCl3) δ 150.0 (C), 140.3 (C), 121.8 (CH), 118.8 (CF3, q, J = 320.3 Hz),
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112.5 (CH), 40.5 (CH3). F NMR (471 MHz, CDCl3) δ ꢀ72.8. The proton and carbon
data for this compound were consistent with literature report except for the CꢀF
coupling.72
Benzo[d][1,3]dioxol-5-yl trifate (1d). Following the general procedure A, 1.00 g of
benzo[d][1,3]dioxolꢀ5ꢀol was converted to 1.82 g of benzo[d][1,3]dioxolꢀ5ꢀyl
1
trifluoromethanesulfonate (93% yield). H NMR (500 MHz, CDCl3) δ 6.80 (d, J = 8.3
13
Hz, 1H), 6.78 – 6.73 (m, 2H), 6.05 (s, 2H). C NMR (126 MHz, CDCl3) δ 148.5 (C),
147.5 (C), 143.5 (C), 118.7 (CF3, q, J = 321.0 Hz), 114.4 (CH), 108.2 (CH), 103.4 (CH),
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102.5 (CH2). F NMR (471 MHz, CDCl3) δ ꢀ72.7. The proton data for this compound
was consistent with literature data.72
4-((tert-Butoxycarbonyl)amino)phenyl triflate (1e). Following the general procedure
A, 1.50 g of tertꢀbutyl (4ꢀhydroxyphenyl)carbamate was converted to 1.49 g of 4ꢀ((tertꢀ
1
butoxycarbonyl)amino)phenyl trifluoromethanesulfonate (61% yield). H NMR (500
MHz, CDCl3) δ 7.51 – 7.36 (m, 2H), 7.23 – 7.13 (m, 2H), 6.64 (br s, 1H), 1.52 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 152.4 (C), 144.5 (C), 138.5 (C), 121.9 (CH), 119.5 (CH),
118.8 (CF3, q, J = 320.3 Hz), 81.3 (C), 28.3 (CH3). 19F NMR (471 MHz, CDCl3) δ ꢀ72.8.
The proton and carbon data for this compound were consistent with literature data.73
4-(Methylthio)phenyl triflate (1f): Following the general procedure A, 1.50 g of 4ꢀ
(methylthio)phenol was converted to 1.68
g
of 4ꢀ(methylthio)phenyl
1
trifluoromethanesulfonate (92% yield). H NMR (500 MHz, CDCl3) δ 7.31 – 7.26 (m,
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2H), 7.22 – 7.15 (m, 2H), 2.49 (s, 3H). C NMR (126 MHz, CDCl3) δ 146.9 (C), 139.8
19
(C), 127.6 (CH), 121.7 (CH), 118.8 (CF3, q, J = 321.0 Hz), 15.8 (CH3). F NMR (471
MHz, CDCl3) δ ꢀ72.8. The proton, carbon and fluorine data for this compound were
consistent with literature data.59
2-Methoxyphenyl triflate (1h). Following the general procedure A, 1.00 g of 2ꢀ
methoxyphenol was converted to 1.73 g of 2ꢀmethoxyphenyl trifluoromethanesulfonate
1
(84% yield). H NMR (500 MHz, CDCl3) δ 7.36 – 7.29 (m, 1H), 7.22 (dd, J = 8.2, 1.6
13
Hz, 1H), 7.04 (dd, J = 8.3, 1.5 Hz, 1H), 6.98 (td, J = 7.8, 1.5 Hz, 1H), 3.92 (s, 3H). C
NMR (126 MHz, CDCl3) δ 151. 5 (C), 138.8 (C), 129.2 (CH), 122.5 (CH), 120.9 (CH),
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118.8 (CF3, q, J = 320.4 Hz), 113.2 (CH), 56.1 (CH3). F NMR (471 MHz, CDCl3) δ ꢀ
73.9. The proton and carbon data for this compound were consistent with literature data.74
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4-(((Trifluoromethyl)sulfonyl)oxy)phenyl acetate (1i): Following the general
procedure A, 1.50 g of 4ꢀhydroxyphenyl acetate was converted to 2.32 g of 4ꢀ
(((trifluoromethyl)sulfonyl)oxy)phenyl acetate. (83% yield). The compound was isolated
as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.26 (m, 2H), 7.23 – 7.15 (m, 2H),
2.31 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.9 (C), 150.1 (C), 146.7 (C), 123.4(CH),
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122.4 (CH), 118.8 (CF3, q, J = 320.6 Hz), 21.0. F NMR (471 MHz, CDCl3) δ ꢀ72.8.
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Anal. Calcd for C9H7F3O5S: C, 38.04; H, 2.48. Found: C, 38.36; H, 2.32.
Methyl 4-(((trifluoromethyl)sulfonyl)oxy)benzoate (1j): Following the general
procedure A, 1.50 g of methyl 4ꢀhydroxybenzoate was converted to 2.69 g of methyl 4ꢀ
1
(((trifluoromethyl)sulfonyl)oxy)benzoate (96% yield). H NMR (500 MHz, CDCl3) δ
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8.23 – 8.08 (m, 2H), 7.43 – 7.29 (m, 2H), 3.95 (s, 3H). C NMR (126 MHz, CDCl3) δ
165.5 (C), 152.5 (C), 131.9 (CH), 130.4 (C), 121.4 (CH), 118.8 (CF3, q, J = 321.0 Hz),
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52.6 (CH3). F NMR (471 MHz, CDCl3) δ ꢀ72.8. The proton and carbon data for this
compound were consistent with literature data.75
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl triflate (1k): Following the
general procedure B, 4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenol (767 mg, 3.5
mmol) was converted to 600 mg of benzo[d]oxazolꢀ5ꢀyl triflate (49% yield). The
1
compound was isolated as crystalline white solid. H NMR (600 MHz, CDCl3) 7.89 (d, J
13
= 8.6 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 1.35 (s, 12H); C NMR (150 MHz, CDCl3) δ
151.8 (C), 136.9 (CH), 120.6 (CH), 118.7 (CF3, q, J = 320.8 Hz), 84.3 (C), 24.9 (CH3);
19F NMR (564 MHz, CDCl3) δ ꢀ72.9. Anal. Calcd for C13H16BF3O5S: C, 44.34; H, 4.58.
Found: C, 43.75; H, 4.30. mp 104–106 °C.
3-Cyanophenyl triflate (1m): Following the general procedure A, 1.50 g of 3ꢀ
hydroxybenzonitrile was converted to 1.48 g of 3ꢀcyanophenyl trifluoromethanesulfonate
(47% yield). 1H NMR (500 MHz, CDCl3) δ 7.72 (dt, J = 7.7, 1.3 Hz, 1H), 7.63 (t, J = 8.1
13
Hz, 1H), 7.61 – 7.58 (m, 1H), 7.56 (ddd, J = 8.3, 2.5, 1.2 Hz, 1H). C NMR (126 MHz,
CDCl3) δ 149.3 (C), 132.2 (CH), 131.4 (CH), 126.2 (CH), 125.1 (CH), 118.7 (CF3, q, J =
321.1 Hz), 116.7(C), 114.7 (C). 19F NMR (471 MHz, CDCl3) δ ꢀ72.5. The proton, carbon
and fluorine data for this compound were consistent with literature data.76
Benzofuran-5-yl triflate (3a): Following the general procedure B, benzofuranꢀ5ꢀol (500
mg, 3.7 mmol) was converted to benzofuranꢀ5ꢀyl trifluoromethanesulfonate (672 mg,
1
68% yield). The compound was isolated as colorless oil. H NMR (600 MHz, CDCl3) δ
7.73 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 9.0, 0.9 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.21
(dd, J = 8.9, 2.6 Hz, 1H), 6.83 (dd, J = 2.3, 0.9 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
153.5 (C), 147.5 (CH), 145.3 (C), 128.5 (C), 118.8 (CF3, q, J = 320.8 Hz), 117.5 (CH),
114.0 (CH), 112.6 (CH), 107.0 (CH); 19F NMR (564 MHz, CDCl3) δ ꢀ73.7; HRMS (m/z):
[MꢀH]ꢀ calcd for C9H5F3O4S 264.9788; found 264.9790.
Benzo[b]thiophen-5-yl triflate (3b): Following the general procedure B,
benzo[b]thiophenꢀ5ꢀol (800 mg, 5.3 mmol) was converted to 3b (1.1 g, 73% yield)
following flash column chromatography over silica gel using an ethyl acetate/heptanes
1
gradient. The compound was isolated as colorless oil. H NMR (700 MHz, CDCl3) δ
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7.92 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 5.4 Hz, 1H), 7.38 (d, J =
5.4 Hz, 1H), 7.26 (dd, J = 8.8, 2.1 Hz, 1H); C NMR (176 MHz, CDCl3) δ 147.0 (C),
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140.3 (C), 139.3(CO), 129.8 (CH), 124.0 (CH), 123.8 (CH), 118.8 (CF3, q, J = 320.8
Hz), 117.4 (CH), 115.9 (CH); 19F NMR (376 MHz, CDCl3) δ ꢀ72.8; Anal. Calcd for
C9H5F3O3S2: C, 38.30; H, 1.79. Found: C, 38.30; H, 1.52.
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1-(Triisopropylsilyl)-1H-indol-5-yl triflate (3c): To a solution of 5ꢀ(benzyloxy)ꢀ1Hꢀ
indole (2.50 g, 11.2 mmol) in DME (37 mL) at 0 ˚C was added NaH (50 wt% in mineral
oil, 1.08 g, 22.4 mmol, 2 equiv). After stirring at 0 ˚C for 20 min TIPSꢀCl (3.56 mL, 16.8
mmol, 1.5 equiv) was added and the mixture allowed to warm to room temperature and
stirred for a further 2 h. Brine was added,the product was extracted into EtOAc (x3) and
the combined organics dried (brine, Na2SO4). Purification was carried out by flash
column chromatography over silica gel using an ethyl acetate/heptane gradient to give
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4.25 g of 5ꢀ(benzyloxy)ꢀ1ꢀ(triisopropylsilyl)ꢀ1Hꢀindole (100% yield). H NMR (600
MHz, CDCl3) δ 7.50 – 7.47 (m, 2H), 7.41 – 7.37 (m, 3H), 7.34 – 7.29 (m, 1H), 7.23 (d, J
= 3.2 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.9, 2.6 Hz, 1H), 6.54 (dd, J = 3.2,
0.8 Hz, 1H), 5.10 (s, 2H), 1.67 (h, J = 7.6 Hz, 3H), 1.14 (d, J = 7.5 Hz, 18H).
To a solution of 5ꢀ(benzyloxy)ꢀ1ꢀ(triisopropylsilyl)ꢀ1Hꢀindole (4.25 g, 11.2 mmol) in
IPA:EtOAc:heptane (1:1:1, 93 mL) was added 10% Pd/C (298 mg,0.28 mmol, 0.025
equiv). This mixture was stirred at room temperature in an atmosphere of H2 for 4 h,
filtered through celite and the solvent removed to give a quantitative yield of 1ꢀ
(triisopropylsilyl)ꢀ1Hꢀindolꢀ5ꢀol, which was used directly in the next step.
Triflation was carried out using the general procedure A. From 2.00 g of 1ꢀ
(triisopropylsilyl)ꢀ1Hꢀindolꢀ5ꢀol, 1.64
g
of 1ꢀ(triisopropylsilyl)ꢀ1Hꢀindolꢀ5ꢀyl
trifluoromethanesulfonate was obtained (56% yield). The compound was isolated as
1
colorless oil. H NMR (600 MHz, CDCl3) δ 7.53 – 7.47 (m, 2H), 7.35 (d, J = 3.2 Hz,
1H), 7.03 (dd, J = 9.0, 2.6 Hz, 1H), 6.66 (dd, J = 3.1, 0.8 Hz, 1H), 1.68 (h, J = 7.6 Hz,
13
3H), 1.14 (d, J = 7.6 Hz, 18H). C NMR (151 MHz, CDCl3) δ 143.7 (C), 139.7 (C),
133.8 (CH), 131.8 (C), 118.9 (CF3, q, J = 320.9 Hz), 114.5 (CH), 114.3 (CH), 112.7
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(CH), 105.4 (CH), 18.0 (CH3), 12.8 (CH). F NMR (471 MHz, CDCl3) δ ꢀ72.87. Anal.
Calcd for C18H26F3NO3SSi: C, 51.29; H, 6.22. Found: C, 51.13; H, 6.35.
Benzo[d]oxazol-5-yl triflate (3d): Following the general procedure B, 1ꢀ
benzo[d]oxazolꢀ5ꢀol (400 mg, 3.0 mmol) was converted to benzo[d]oxazolꢀ5ꢀyl triflate
(600 mg, 76% yield). The compound was isolated as colorless oil. 1H NMR (400 MHz,
CDCl3) δ 8.21 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.35 (dd, J =
8.9, 2.5 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 157.7 (CH), 149.0 (C), 146.3 (C), 141.1
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(C), 119.3 (CH), 118.8 (CF3, q, J = 20.9 Hz), 114.1 (CH), 112.1 (CH); F NMR (376
MHz, CDCl3) δ ꢀ77.0; HRMS (m/z): [MꢀH]ꢀ calcd for C8H4F3NO4S 265.97397; found
265.97404.
1H-Pyrrolo[2,3-b]pyridin-5-yl trifluoromethanesulfonate (3e):
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Following the general procedure B, 1Hꢀpyrrolo[2,3ꢀb]pyridinꢀ5ꢀol (1 g, 7.5 mmol) was
converted to 1Hꢀpyrrolo[2,3ꢀb]pyridinꢀ5ꢀtriflate (1.6 g, 81% yield) following flash
column chromatography on SiO2 using an ethyl acetate/heptanes gradient. H NMR (400
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MHz, CDCl3) δ 9.52 (bs, 1H), 8.29 (d, J = 2.6 Hz, 1H), 7.89 (dd, J = 2.6, 0.7 Hz, 1H),
7.48 (dd, J = 3.3, 2.6 Hz, 1H), 6.60 (dd, J = 3.6, 2.0 Hz, 1H); C NMR (100 MHz,
CDCl3) δ 147.2 (C), 141.7 (C), 135.7 (CH), 128.1(CH), 121.6 (CH), 120.5 (C), 118.8
(CF3, q, J = 320.6 Hz), 101.9 (CH); HRMS (m/z): [M+H]+ calcd for C8H5F3N2O3S
267.0046; found 267.0049. mp 122.5ꢀ123.5 °C.
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A roundꢀbottom flask with magnetic stirring bar was charged with DMF (10 mL) under
N2 atmosphere. NaH (60 wt% in mineral oil, 180 mg, 1.2 equiv) was added and the
solution was cooled to 0 °C. 1HꢀPyrrolo[2,3ꢀb]pyridinꢀ5ꢀtriflate (1.0 g, 3.8 mmol) was
added. The reaction was warmed to room temperature and was mixed for 15 minutes.
TsCl (0.788 g, 1.1 equiv) was added in one portion and the reaction mixture was stirred
overnight. The reaction was slowly quenched with addition of water (5 mL). The mixture
was transferred to a separatory funnel and extracted with MTBE (20 mL). The aqueous
layer was back extracted with MTBE (10 mL). The combined organic layers were
washed with aqueous saturated NaCl (10 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The residue was dissolved in CHCl3 (2 mL) and
purified by flash column chromatography on a 120 g silica gel column with an
EtOAc/heptanes gradient. Compound 3e was isolated as crystalline white solid (1.2 g,
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76% yield). H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 2.6 Hz, 1 H), 8.10ꢀ8.05 (m, 2H),
7.87 (dd, J = 4.1, 0.4 Hz, 1H), 7.79 (d, J = 2.64 Hz, 1H), 7.32ꢀ7.30 (m, 2H), 6.64 (d, J =
4.0 Hz, 1H), 2.40 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 145.8 (C), 145.4 (C), 143.4 (C),
137.5 (CH), 134.8 (C), 129.9 (CH), 129.4 (CH), 128.3 (CH), 123.4 (C), 122.3 (CH),
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118.7 (CF3, q, J = 320.8 Hz), 104.9 (CH), 21.7 (CH3); F NMR (376 MHz, CDCl3) δ ꢀ
72.5; HRMS (m/z): [M+H]+ calcd for C15H11F3N2O5S2 421.0134; found 421.0132. mp
128ꢀ129 °C.
Quinoxalin-6-yl triflate (3f): Following the general procedure B, quinoxalinꢀ6ꢀol (937
mg, 6.4 mmol) was converted to quinoxalinꢀ6ꢀyl triflate (1.31 g, 73% yield). The
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compound was isolated as crystalline white solid. H NMR (400 MHz, CDCl3) δ 8.94 (s,
2H), 8.24 (dd, J = 9.2, 0.5 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.71 (dd, J = 9.2, 2.7 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 149.4 (C), 145.4 (CH), 145.1 (CH), 143.0 (C), 142.0
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(C), 132.1 (CH), 124.0 (CH), 121.3 (CH), 118.8 (CF3, q, J = 320.9 Hz); F NMR (376
MHz, CDCl3) δ ꢀ72.6; HRMS (m/z): [M+H]+ calcd for C9H5F3N2O3S 279.0046; found
279.0043. mp 76ꢀ77 °C.
6-Methoxypyridin-3-yl triflate (3h): Following general procedure A, using pyridine
(4.0 mL. 50.0 mmol) as the base, 6ꢀmethoxyꢀ3ꢀhydroxypyridine (2.5 g, 20.0 mmol) was
converted to 6ꢀmethoxypyridinꢀ3ꢀyl triflate (5.1 g, 92% yield). The compound was
isolated as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 3.2 Hz, 1H), 7.50 (dd,
J = 9.2, 2.8 Hz, 1H), 6.81 (dd, J = 9.2, 0.8 Hz, 1H), 3.96 (s, 3H). 13C NMR (100 MHz,
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CDCl3) δ 163.2 (C), 141.6 (C), 139.5 (CH), 132.0 (CH), 118.7 (CF3, q, J = 318 Hz) 112.2
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(CH), 54.2 (CH). F NMR (376 MHz, CDCl3) δ ꢀ72.5. HRMS (m/z): [MꢀH]ꢀ calcd for
C7H6F3NO4S 255.98969; found 255.99021.
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General procedure for Pd-catalyzed reactions of phenyl triflate with NaSO2CF3
(Table 1). Inside an inert atmosphere glove box, Pd2(dba)3 (0.02 g, 0.02 mmol) and
phosphine ligand (0.05 mmol) were charged to a 1ꢀdram vial equipped with a magnetic
stir bar and Teflon screw cap. Solvent (0.8 mL) was added, the vial was placed on a metal
heating block, temperature was raised to 80 °C and mixed for approximately 30 min.
Phenyl triflate (0.20 g, 0.88 mmol), and tris(3,6ꢀdioxaheptyl)amine (TDA) (0.014 g, 0.05
mmol) were charged to a separate 1ꢀdram vial. Toluene (0.8 mL) was added to obtain a
clear solution. The first 1ꢀdram vial was removed from the metal heating plate. The
solution of phenyl triflate and TDA was transferred to the 1ꢀdram vial containing the
catalyst with a syringe. NaSO2CF3 (0.28 g, 1.8 mmol) was charged, the 1ꢀdram vial was
returned to the heating block and the reaction mixture was vigorously stirred for the time
indicated in Table 1. The reaction mixture was removed from the heating block, cooled
to room temperature, brought outside the glove box, filtered through a Whatman 0.2 µm
PTFE filter, rinsed with dichloromethane (~15ꢀ20 mL) and was collected in a tared 25ꢀ
mL Erlenmeyer flask. The weight of filtered solution (Wtprod) was recorded. A portion (~
1.0ꢀ1.5 g) of the solution was weighed into a tared 25ꢀmL volumetric flask (Wtsample),
diluted to 25 mL with acetonitrile and was injected into an HPLC instrument. The area
corresponding to the product 2a was recorded (Aprod).
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Assay yield calculation: A known weight of the commercial sample of 2a was was
weighed into a 50ꢀmL volumetric flask (Wtstd), dissolved in 50 mL acetonitrile and
injected into a HPLC instrument. The area corresponding to the product was recorded
(Astd). The assay yield of 2a in entries 1ꢀ19, table 1 was determined by using the
following formula.
Aprod x Wtprod x Wtstd x 100
Assay yield (%)
=
Astd x Wtsample x theroretical yield (g)
General procedure for Pd-catalyzed reactions of aryl and heteroaryl triflates with
NaSO2CF3 (Table 2 and Table 3). Inside an inert atmosphere glove box, Pd2(dba)3 (1.5
mol %) and III (3.6 mol %) were charged to a 20ꢀmL vial equipped with a magnetic stir
bar, Teflon screw cap, and glass balls of 4 mm diameter (5ꢀ10).77 Toluene (1ꢀ1.5 mL)
was added, the vial was placed on a metal heating block, temperature was raised to 80 °C
and mixed for approximately 30 min. Aryl (heteroaryl) triflate (1 equiv), and TDA (5 mol
%) were charged to a separate 1ꢀdram vial. Additional toluene was added to obtain the
final concentration of 0.30 to 0.40 M. The 20ꢀmL vial was removed from the metal
heating plate. The solution of aryl (heteroaryl) triflate and TDA was transferred to the 20ꢀ
mL vial containing the catalyst with a syringe. NaSO2CF3 (1.5 equiv) was charged, the
20ꢀmL vial was returned to the heating block and the reaction mixture was heated for the
indicated time. The reaction mixture was removed from the heating block, cooled to
room temperature, brought outside the glove box, filtered through a Whatman 0.2 µm
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PTFE filter, rinsed with dichloromethane (~15ꢀ20 mL) and was collected in a tared 50ꢀ
mL Erlenmeyer flask. The weight of filtered solution (Wtprod) was recorded. A portion (~
0.2ꢀ0.5 g) of the solution was weighed into a tared 50ꢀmL volumetric flask (Wtsample),
diluted to 50 mL with acetonitrile and was injected into an HPLC instrument. The area
corresponding to the corresponding aryl (heteroaryl) triflones product was recorded
(Aprod). The filtrate was concentrated in vacuo. The crude product was isolated via flash
column chromatography. After the pure product was isolated, approximately 10ꢀ15 mg of
the pure product was weighed into a 50ꢀmL volumetric flask, dissolved in 50ꢀmL
acetonitrile and injected onto a HPLC instrument. The area corresponding to the product
was recorded (Astd). The yield of the product in the crude reaction mixture was calculated
using the formula shown above.
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(Trifluoromethylsulfonyl)benzene (2a): Following the general procedure, a mixture of
1a (0.25 g, 1.1 mmol), NaSO2CF3 (0.21 g, 1.3 mmol), Pd2(dba)3 (0.025 g, 0.028 mmol),
III (0.031 g, 0.066 mmol), and TDA (0.018 g, 0.055 mmol) were heated in toluene for 3
h. The desired product 2b (0.22 g, 96%) was calculated to be present in the crude reaction
mixture. The crude product was purified by flash column chromatography using 0ꢀ20%
EtOAc/heptanes as eluent to provide the title compound (0.20 g, 0.93 mmol, 84%) as
colorless oil. 1H NMR (700 MHz, CDCl3) δ 8.05 (d, J = 7 Hz, 2H), 7.86 (tt, J = 7, 1.4 Hz,
13
1H), 7.69 (m, 2H). C NMR (176 MHz, CDCl3) δ 136.6 (CH), 131.3 (q, J = 1.8. C),
19
130.8 (CH), 129.9 (CH), 119.8 (CF3, q, J = 334 Hz). F NMR (564 MHz, CDCl3) δ ꢀ
79.5. The proton, carbon and fluorine data for this compound were consistent with
literature data.34
1-Dimethylamino-4-(trifluoromethyl)sulfonyl)benzene (2b): Following the general
procedure, a mixture of 1b (0.50 g, 1.9 mmol), NaSO2CF3 (0.44 g, 2.8 mmol), Pd2(dba)3
(0.026 g, 0.028 mmol), III (0.031 g, 0.067 mmol), and TDA (0.030 g, 0.093 mmol) were
heated in toluene (5 mL) for 2 h. The desired product 2b (0.45 g, 98%) was calculated to
be present in the crude reaction mixture. The crude product was purified by flash column
chromatography using 0ꢀ10% EtOAc/heptanes as eluent to provide the title compound
1
(0.35 g, 1.4 mmol, 75%) as crystalline offꢀwhite solid. H NMR (600 MHz, CDCl3) δ
7.80 (d, J = 6 Hz, 2H), 6.76 (d, J = 6 Hz, 2H), 3.15 (s, 6H). 13C NMR (151 MHz, CDCl3)
δ 155.1 (C), 132.6 (CH), 123.04 (CF3, q, J = 326 Hz), 113.4 (C), 111.3 (CH), 40.1
(CH3). 19F NMR (564 MHz, CDCl3) δ ꢀ79.3; HRMS (m/z): [M+H]+ calcd for
C9H10F3NO2S 253.03843; found 253.03874. mp 139ꢀ140 °C.
1-Methoxy-4-(trifluoromethyl)sulfonyl)benzene (2c): Following the general procedure,
a mixture of 1c (0.50 g, 2.0 mmol), NaSO2CF3 (0.46 g, 2.9 mmol), Pd2(dba)3 (0.027 g,
0.029 mmol), III (0.033 g, 0.070 mmol), and TDA (0.032 g, 0.098 mmol) were heated in
toluene (5 mL) for 2 h. The desired product 2c (0.46 g, 98%) was calculated to be present
in the crude reaction mixture. The crude product was purified by flash column
chromatography using 0ꢀ10% EtOAc/heptanes as eluent to provide the title compound
1
(0.40 g, 1. mmol, 85%) as crystalline white solid. H NMR (700 MHz, CDCl3) δ 7.96,
13
7.96, (d appt, J = 8.4, 3.5 Hz, 2H), 7.11 (d appt, J = 9.1, 2.8 Hz, 2H), 3.94 (S, 3H). C
NMR (176 MHz, CDCl3) δ 166.2 (C), 133.3 (CH), 122.0 (C), 119.0 (CF3, q, J = 326 Hz),
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115.3 (CH), 56.0 (CH3).19F NMR (376 MHz, CDCl3) δ ꢀ82.8. The proton, carbon and
fluorine data for this compound were consistent with literature data.34
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5-((Trifluoromethyl)sulfonyl)benzo[d][1,3]dioxole (2d): Following the general
procedure, a mixture of 1d (0.50 g, 1.9 mmol), NaSO2CF3 (0.43 g, 2.8 mmol), Pd2(dba)3
(0.026 g, 0.028 mmol), III (0.031 g, 0.067 mmol), and TDA (0.030 g, 0.093 mmol) were
heated in toluene (5 mL) for 2 h. The desired product 2d (0.41 g, 87%) was calculated to
be present in the crude reaction mixture. The crude product was purified by flash column
chromatography using 0ꢀ10% EtOAc/heptanes as eluent to provide benzo[d][1,3]dioxolꢀ
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5ꢀyl triflone (0.37 g, 1.5 mmol, 79%) as crystalline white solid. H NMR (700 MHz,
CDCl3) δ 7.63 (dd, J = 8.4, 2.1 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.03 (d, J = 8.4 Hz,
13
1H), 6.18 (s, 2H). C NMR (176 MHz, CDCl3) δ 154.9 (C), 148.9 (C), 128.0 (CH),
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123.7 (C), 119.5 (CF3, q, J = 324 Hz), 109.9 (CH), 109.2 (CH), 103.1 (CH2). F NMR
(376 MHz, CDCl3) δ ꢀ78.6 Anal. Calcd for C8H5F3O4S: C, 37.80; H, 1.98. Found: C,
38.10; H, 1.83. mp 98ꢀ100 °C.
tert-Butyl(4-((trifluoromethyl)sulfonyl)phenyl)carbamate (2e): Following the general
procedure, a mixture of 1e (0.50 g, 1.5 mmol), NaSO2CF3 (0.34 g, 2.2 mmol), Pd2(dba)3
(0.020 g, 0.022 mmol), III (0.025 g, 0.053 mmol), and TDA (0.024 g, 0.073 mmol) were
heated in toluene (4.5 mL) for 5.5 h. The desired product 2e (0.44 g, 92%) was calculated
to be present in the crude reaction mixture. The crude product was purified by flash
column chromatography using 0ꢀ10% EtOAc/heptanes as eluent to provide the title
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compound (0.38 g, 1.2 mmol, 80%) as crystalline white solid. H NMR (700 MHz,
CDCl3) δ 7.94 (d appt, J = 7.0, 2.1 Hz, 2H), 7.66 (d appt, J = 9.1, 2.1 Hz, 2H), 6.90 (s,
13
1H), 1.15 (s, 9H). C NMR (176 MHz, CDCl3) δ 151.7 (C), 146.3 (C), 132.5 (CH),
123.6 (C), 119.9 (CF3, q, J = 326 Hz), 118.2 (CH), 82.4 (C), 28.2 (CH3). 19F NMR (376
MHz, CDCl3) δ ꢀ78.7. HRMS (m/z): [M+H]+ calcd for C12H14F3NO4S 325.05956; found
325.05979. mp 105ꢀ107 °C.
Methyl(4-((trifluoromethyl)sulfonyl)phenyl)sulfane (2f): Following the general
procedure, a mixture of 1f (0.50 g, 1.8 mmol), NaSO2CF3 (0.43 g, 2.8 mmol), Pd2(dba)3
(0.025 g, 0.028 mmol), III (0.031 g, 0.066 mmol), and TDA (0.030 g, 0.092 mmol) were
heated in toluene (5 mL) for 12 h. The desired product 2f (0.44 g, 92%) was calculated to
be present in the crude reaction mixture. The crude product was purified by flash column
chromatography using 0ꢀ5% EtOAc/heptanes as eluent to provide the title compound
1
(0.34 g, 1.3 mmol, 72%) as amorphous white solid. H NMR (700 MHz, CDCl3) δ 7.89
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(d appt, J = 8.4, 2.8 Hz, 2H), 7.43 (d appt, J = 7.7, 2.1 Hz, 2H), 2.58 (s, 3H). C NMR
(151 MHz, CDCl3) δ 151.9 (C), 130.8 (CH), 125.9 (C), 125.5 (CH), 119.8 (CF3, q, J =
329 Hz), 14.5 (CH3). 19F NMR (564 MHz, CDCl3) δ ꢀ78.6. Anal. Calcd for C8H5F3O2S2:
C, 37.49; H, 2.75. Found: C, 37.52; H, 2.78.
1-((Trifluoromethyl)sulfonyl)naphthalene (2g): Following the general procedure, a
mixture of 1g (0.50 g, 1.8 mmol), NaSO2CF3 (0.42 g, 2.7 mmol), Pd2(dba)3 (0.041 g,
0.045 mmol), III (0.051 g, 0.11 mmol), and TDA (0.029 g, 0.091 mmol) were heated in
toluene (5 mL) for 4.5 h. The desired product 2g (0.43 g, 92%) was calculated to be
present in the crude reaction mixture. The crude product was purified by flash column
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chromatography using 0ꢀ8% EtOAc/heptanes as eluent to provide the title compound
(0.39 g, 1.5 mmol, 83%) as crystalline white solid. H NMR (400 MHz, CDCl3) δ 8.82
1
(d, J = 8.8 Hz, 1H), 8.47 (dd, J = 7.6, 1.2 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.01 (d, J =
13
8.4 Hz, 1H), 7.78 (m, 1H), 7.68 (m, 2H). C NMR (176 MHz, CDCl3) δ 138.5 (CH),
135.2 (CH), 134.3 (C), 130.2 (C), 129.7 (CH), 129.3 (CH), 127.8 (CH), 126.9 (C), 124.5
(CH), 124.4 (CH), 120.3 (CF3, q, J = 326 Hz).19F NMR (376 MHz, CDCl3) δ ꢀ77.8. Anal.
Calcd for C11H7F3O2S: C, 50.77; H, 2.71. Found: C, 50.92; H, 2.29. mp 56ꢀ58 °C.
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1-Methoxy-2-((trifluoromethyl)sulfonyl)benzene (2h): Following the general
procedure, a mixture of 1h (0.50 g, 1.9 mmol), NaSO2CF3 (0.61 g, 3.9 mmol), Pd2(dba)3
(0.071 g, 0.078 mmol), III (0.088 g, 0.19 mmol), and TDA (0.032 g, 0.10 mmol) were
heated in toluene (5.5 mL) for 20 h. The desired product 2h (0.42 g, 89%) was calculated
to be present in the crude reaction mixture. The crude product was purified by flash
column chromatography using 0ꢀ8% EtOAc/heptanes as eluent to provide the title
compound (0.30 g, 1.2 mmol, 64%) as white solid in approximately 90% purity by
HPLC. 1H NMR (700 MHz, CDCl3) δ 8.00 (dd, J = 8.4, 2.1 Hz, 1H), 7.75 (m, 1H), 7.16
(t, J = 7.7 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H). 13C NMR (176 MHz, CDCl3) δ
159.9 (C), 138.5 (CH), 133.5 (CH), 121.0 (CH), 119.9 (CF3, J = 354 Hz), 119.8 (C),
113.0 (CH), 56.5 (CH3). 19F NMR (376 MHz, CDCl3) δ ꢀ76.9.
4-((Trifluoromethyl)sulfonyl)phenyl acetate (2i): Following the general procedure, a
mixture of 1i (0.50 g, 1.8 mmol), NaSO2CF3 (0.41 g, 2.6 mmol), Pd2(dba)3 (0.024 g,
0.026 mmol), III (0.030 g, 0.063 mmol), and TDA (0.028 g, 0.088 mmol) were heated in
toluene (5 mL) for 20 h. The desired product 2i (0.40 g, 84%) was calculated to be
present in the crude reaction mixture. The crude product was purified by flash column
chromatography using 0ꢀ8% EtOAc/heptanes as eluent to provide the title compound
(0.36 g, 1.3 mmol, 75%) as clear oil. 1H NMR (600 MHz, CDCl3) δ 8.09 (d aapt, J = 6.6,
3.0 Hz, 2H), 7.46 (d appt, J = 7.2, 3.0 Hz, 2H), 2.39 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 168.1 (C), 157.1 (C), 132.6 (CH), 128.1 (C), 123.2 (CH), 119.7 (CF3, J = 326
19
Hz), 21.1 (CH3). F NMR (564 MHz, CDCl3) δ ꢀ78.4. Anal. Calcd for C9H7F3O4S: C,
40.30; H, 2.63. Found: C, 40.37; H, 2.49.
Methyl 4-((trifluoromethyl)sulfonyl)benzoate (2j): Following the general procedure, a
mixture of 1j (0.50 g, 1.8 mmol), NaSO2CF3 (0.41 g, 2.6 mmol), Pd2(dba)3 (0.040 g,
0.044 mmol), III (0.049 g, 0.11 mmol), and TDA (0.028 g, 0.088 mmol) were heated in
toluene (5 mL) at 90 °C for 18 h. The crude product was purified by flash column
chromatography using 0ꢀ8% EtOAc/heptanes as eluent to provide the title compound
(0.36 g, 1.3 mmol, 75%) as crystalline white solid. 1H NMR (700 MHz, CDCl3) δ 8.32 (d
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aapt, J = 8.4, 2.1 Hz, 2H), 8.12 (d, J = 8.4 Hz, 2H), 4.0 (s, 3H). C NMR (176 MHz,
CDCl3) δ 164.9 (C), 137.4 (C), 135.2 (C), 130.9 (CH), 130.8 (CH), 119.7 (CF3, J = 327
19
Hz), 53.1 (CH3). F NMR (376 MHz, CDCl3) δ ꢀ78.0. Anal. Calcd for C9H7F3O4S: C,
40.30; H, 2.63. Found: C, 40.25; H, 2.38. mp 56ꢀ58 °C.
4,4,5,5-Tetramethyl-2-(4-((trifluoromethyl)sulfonyl)phenyl)-1,3,2-dioxaborolane
(2k): Following the general procedure, a mixture of 1k (0.25 g, 0.71 mmol), NaSO2CF3
(0.17 g, 1.1 mmol), Pd2(dba)3 (0.016 g, 0.018 mmol), III (0.020 g, 0.043 mmol), and
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TDA (0.029 g, 0.089 mmol) were heated in toluene (2.2 mL) at 90 °C for 23 h. The
desired product 2k (0.21 g, 88%) was calculated to be present in the crude reaction
mixture. The crude product was purified by flash column chromatography using 0ꢀ8%
EtOAc/heptanes as eluent to provide the title compound (0.15 g, 0.43 mmol, 61%) as
crystalline white solid. 1H NMR (700 MHz, CDCl3) δ 8.08 (d, J = 7.7 Hz, 2H), 8.02 (d, J
13
= 7.7 Hz, 2H), 1.37 (s, 12H). C NMR (176 MHz, CDCl3) δ 135.8 (CH), 133.3 (C),
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129.6 (CH), 119.8 (CF3, J = 326 Hz), 84.9 (C), 24.9 (CH3). 19F NMR (376 MHz, CDCl3)
δ ꢀ78.4. Anal. Calcd for C13H16BF3O4S: C, 46.45; H, 4.80. Found: C, 47.08; H, 4.89. mp
87ꢀ88 °C.
1-(4-(Trifluoromethyl)sulfonyl)phenyl)ethanone (2l): Following the general procedure,
a mixture of 1l (0.50 g, 1.9 mmol), NaSO2CF3 (0.44 g, 2.8 mmol), Pd2(dba)3 (0.051 g,
0.056 mmol), III (0.063 g, 0.13 mmol), and TDA (0.030, 0.093 mmol) were heated in
toluene (5 mL) at 90 °C for 32 h. The desired product 2l (0.34 g, 72%) was calculated to
be present in the crude reaction mixture. The crude product was purified by flash column
chromatography using 0ꢀ8% EtOAc/heptanes as eluent to provide the title compound
(0.28 g, 1.1 mmol, 60%) as crystalline white solid. 1H NMR (400 MHz, CDCl3) δ 8.21 (d
13
aapt, J = 8.8, 1.6 Hz, 2H), 8.16 (m, 2H), 2.74 (s, 3H). C NMR (176 MHz, CDCl3) δ
196.9 (C), 142.9 (C), 135.1 (C), 131.3 (CH), 129.4 (CH), 119.7 (CF3, J = 326 Hz), 27.0
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(CH3). F NMR (376 MHz, CDCl3) δ ꢀ78.0. Anal. Calcd for C9H7F3O3S: C, 42.86; H,
2.80. Found: C, 43.15; H, 2.58. mp 58ꢀ60 °C.
3-((Trifluoromethyl)sulfonyl)benzonitrile (2m): Following the general procedure, a
mixture of 1m (0.50 g, 2.0 mmol), NaSO2CF3 (0.47 g, 3.0 mmol), Pd2(dba)3 (0.046 g,
0.050 mmol), III (0.056 g, 0.12 mmol), and TDA (0.032 g, 0.10 mmol) were heated in
toluene (5.5 mL) at 100 °C for 20 h. The desired product 2m (0.19 g, 41%) was
calculated to be present in the crude reaction mixture. The crude product was purified by
flash column chromatography using 0ꢀ8% EtOAc/heptanes as eluent to provide the title
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compound (0.05 g, 0.21 mmol, 11%) as amorphous white solid. H NMR (600 MHz,
CDCl3) δ 8.35 (s, 1H), 8.30 (d, J = 7.0 Hz, 1H), 8.14 (d aapt, J = 6.6, 1.2 Hz, 1H), 7.88
(t, J = 7.8 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 139.4 (CH), 134.5 (CH), 134.2 (CH),
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133.4 (C), 133.1 (CH), 119.5 (CF3, J = 326 Hz), 116.1 (C), 115.0 (C). F NMR (376
MHz, CDCl3) δ ꢀ78.0. Anal. Calcd for C9H7F3O3S: C, 42.86; H, 2.80. Found: C, 43.15;
H, 2.58.
5-((Trifluoromethyl)sulfonyl)benzofuran (4a): Following the general procedure, a
mixture of 3a (0.20 g, 0.75 mmol), NaSO2CF3 (0.18 g, 3.0 mmol), Pd2(dba)3 (0.017 g,
0.019 mmol), III (0.021 g, 0.045 mmol), and TDA (0.012 g, 0.038 mmol) were heated in
toluene (2.1 mL) at 80 °C for 9 h. The desired product 4a (0.18 g, 96%) was calculated to
be present in the crude reaction mixture. The crude product was purified by flash column
chromatography using dichloromethane as eluent to provide the title compound (0.16 g,
1
0.65 mmol, 86%) as crystalline white solid. H NMR (600 MHz, CDCl3) δ 8.37 (d, J =
1.8 Hz, 1H), 7.98 (dd, J = 9.0, 1.8 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 9.0 Hz,
13
1H), 6.98 (d, J = 2.4 Hz, 1H). C NMR (151 MHz, CDCl3) δ 158.8 (C), 148.1 (CH),
128.7 (C), 126.6 (CH), 125.8 (CH), 125.6 (C), 119.9 (CF3, J = 326 Hz), 113.1 (CH),
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107.2 (CH). 19F NMR (564 MHz, CDCl3) δ ꢀ78.5. Anal. Calcd for C9H5F3O3S: C, 43.29;
H, 2.01. Found: C, 43.27; H, 1.86. mp 80ꢀ81 °C.
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5-((Trifluoromethyl)sulfonyl)benzo[b]thiophene (4b): Following the general
procedure, a mixture of 3b (0.50 g, 1.8 mmol), NaSO2CF3 (0.42 g, 2.7 mmol), Pd2(dba)3
(0.041 g, 0.04 mmol), III (0.050 g, 0.11 mmol), and TDA (0.029 g, 0.089 mmol) were
heated in toluene (5.5 mL) at 80 °C for 5 h. The desired product 4b (0.46 g, 97%) was
calculated to be present in the crude reaction mixture. The crude product was purified by
flash column chromatography using dichloromethane as eluent to provide the title
compound (0.40 g, 1.5 mmol, 85%) as crystalline white solid.
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1H NMR (700 MHz, CDCl3) δ 8.54 (d, J = 1.4 Hz, 1H), 8.15 (d appt, J = 8.4, 0.7 Hz,
1H), 7.92 (dd, J = 7.4, 2.1 Hz 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 5.6, 0.7 Hz,
1H). 13C NMR (176 MHz, CDCl3) δ 147.86 (C), 139.6 (C), 130.27 (CH), 127.3 (CH),
127.0 (C), 124.4 (CH), 124.0 (CH), 119.7 (CF3, J = 326 Hz). 19F NMR (376 MHz,
CDCl3) δ ꢀ78.4. Anal. Calcd for C9H5F3O2S2: C, 40.60; H, 1.89. Found: C, 40.52; H,
1.59. mp 100ꢀ102 °C.
5-((Trifluoromethyl)sulfonyl)-1-(triisopropylsilyl)-1H-indole (4c): Following the
general procedure, a mixture of 3c (0.50 g, 1.2 mmol), NaSO2CF3 (0.28 g, 1.8 mmol),
Pd2(dba)3 (0.027 g, 0.030 mmol), III (0.33 g, 0.071 mmol), and TDA (0.019 g, 0.050
mmol) were heated in toluene (3.8 mL) at 80 °C for 2 h. The desired product 4c (0.42 g,
88%) was calculated to be present in the crude reaction mixture. The crude product was
purified by flash column chromatography using dichloromethane as eluent to provide the
title compound (0.40 g, 0.99 mmol, 83%) as crystalline white solid. 1H NMR (700 MHz,
CDCl3) δ 8.36 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.4, 2.1 Hz, 1H), 7.68 (d, J = 9.1 Hz 1H),
7.45 (d, J = 3.5 Hz, 1H), 6.83 (d, J = 9.1 Hz, 1H), 1.72 (sept, J = 6.3 Hz, 3H), 1.15 (d, J =
7.7 Hz, 18 H). 13C NMR (176 MHz, CDCl3) δ 145.1 (C), 134.5 (CH), 131.5 (C), 125.4
(CH), 122.6 (CH), 121.2 (C), 120.1 (CF3, J = 326 Hz), 114.7 (CH), 106.5 (CH), 17.9
(CH3), 12.7 (CH). 19F NMR (376 MHz, CDCl3) δ ꢀ83.5. Anal. Calcd for
C18H26F3NO2SSi: C, 53.31; H, 6.46; N, 3.45. Found: C, 53.26; H, 6.53; N, 3.34. mp 124ꢀ
126 °C.
5-((Trifluoromethyl)sulfonyl)benzo[d]oxazole (4d): Following the general procedure, a
mixture of 3d (0.20 g, 0.75 mmol), NaSO2CF3 (0.18 g, 1.1 mmol), Pd2(dba)3 (0.017 g,
0.019 mmol), III (0.021 g, 0.045 mmol), and TDA (0.012 g, 0.037 mmol) were heated in
toluene (2.1 mL) at 80 °C for 9.5 h. The desired product 4d (0.18 g, 94%) was calculated
to be present in the crude reaction mixture. The crude product was purified by flash
column chromatography using EtOAc/heptanes (0ꢀ12%) as eluent to provide the title
1
compound (0.15 g, 0.61 mmol, 81%) as crystalline white solid. H NMR (600 MHz,
CDCl3) δ 8.54 (d, J = 1.8 Hz, 1H), 7.33 (s, 1H), 8.12 (dd, J = 9.0, 1.8 Hz 1H), 7.89 (d, J =
13
8.4 Hz, 1H). C NMR (151 MHz, CDCl3) δ 155.1 (CH), 154.8 (C), 141.1 (C), 128.3
(CH), 128.0 (C), 124.9 (CH), 119.8 (CF3, J = 326 Hz), 112.8 (CH).19F NMR (564 MHz,
CDCl3) δ ꢀ78.2. HRMS (m/z): [M+H]+ calcd for C8H4F3NO3S 250.98668; found
250.98640. mp 88ꢀ89 °C.
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1-Tosyl-5-((trifluoromethyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4e): Following the
general procedure, a mixture of 3e (0.20 g, 0.48 mmol), NaSO2CF3 (0.11 g, 0.71 mmol),
Pd2(dba)3 (0.011 g, 0.012 mmol), III (0.013 g, 0.029 mmol), and TDA (0.008 g, 0.024
mmol) were heated in toluene (2.1 mL) at 80 °C for 8 h. The desired product 4e (0.17 g,
88%) was calculated to be present in the crude reaction mixture. The crude product was
purified by flash column chromatography using dichloromethane as eluent to provide the
title compound (0.16 g, 0.39 mmol, 82%) as crystalline white solid. 1H NMR (700 MHz,
CDCl3) δ 9.00 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 2.8 Hz, 1H), 8.18 (d appt, J = 8.4, 2.1 Hz
2H), 8.05 (d, J = 3.5 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 3.5 Hz, 1 H), 2.47 (S
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= 3 H). C NMR (176 MHz, CDCl3) δ 149.6 (C), 146.5 (C), 146.1 (CH), 134.3 (C),
132.8 (CH), 130.0 (CH), 129.9 (CH), 128.6 (CH), 122.8 (C), 122.6 (C), 119.7 (CF3, J =
19
324 Hz), 105.3 (CH), 21.8 (CH3). F NMR (376 MHz, CDCl3) δ ꢀ78.4 HRMS (m/z):
[M+H]+ calcd for C15H11F3N2O4S2 405.01851; found 405.01856. mp 151ꢀ152 °C.
6-((Trifluoromethyl)sulfonyl)quinoxaline (4f): Following the general procedure, a
mixture of 3f (0.40 g, 1.4 mmol), NaSO2CF3 (0.34 g, 2.2 mmol), Pd2(dba)3 (0.033 g,
0.036 mmol), III (0.040 g, 0.086 mmol), and TDA (0.023 g, 0.072 mmol) were heated in
toluene (4 mL) at 80 °C for 12 h. The desired product 4f (0.31 g, 81%) was calculated to
be present in the crude reaction mixture. The crude product was purified by flash column
chromatography using ethyl acetate/heptanes (0ꢀ15%) as eluent to provide the title
1
compound (0.28 g, 1.1 mmol, 74%) as crystalline white solid. H NMR (600 MHz,
CDCl3) δ 9.11 (d, J = 8.4 Hz, 2H), 8.97 (s, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.31 (dd, J =
8.4, 2.4 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 148.7 (CH), 147.4 (C), 146.1 (C), 141.9
(C), 135.5 (CH), 132.9 (C), 132.5 (CH), 128.2 (CH), 119.8 (CF3, J = 328 Hz). 19F NMR
(564 MHz, CDCl3) δ ꢀ77.7 HRMS (m/z): [M+H]+ calcd for C9H5F3N2O2S 263.00966;
found 263.01071. mp 89ꢀ90 °C.
6-((Trifluoromethyl)sulfonyl)quinoline (4g): Following the general procedure, a
mixture of 3g (0.30 g, 1.1 mmol), NaSO2CF3 (0.37 g, 2.2 mmol), Pd2(dba)3 (0.025 g,
0.027 mmol), III (0.030 g, 0.065 mmol), and TDA (0.018 g, 0.054 mmol) were heated in
toluene (4 mL) at 80 °C for 27.5 h. The crude product was purified by flash column
chromatography using ethyl acetate/heptanes (0ꢀ15%) as eluent to provide the title
1
compound (0.23 g, 0.89 mmol, 82%) as crystalline white solid. H NMR (700 MHz,
CDCl3) δ 9.23 (dd, J = 4.2, 1.4 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.45 (dd, J = 9.1, 1.4
Hz, 1H), 8.43 (d, J =9.1 Hz, 1H), 8.26 (dd, J = 8.8, 2.1 Hz, 1H), 7.70 (dd, J = 8.4, 4.2 Hz,
13
1H). C NMR (176 MHz, CDCl3) δ 155.0 (CH), 150.9 (C), 137.7 (CH), 134.2 (CH),
19
132.1 (CH), 129.1 (C), 127.6 (CH), 127.4 (C), 123.3 (CH), 119.9 (CF3, J = 326 Hz). F
NMR (376 MHz, CDCl3) δ ꢀ78.1. HRMS (m/z): [M+H]+ calcd for C10H6F3NO2S
262.01450; found 262.01456. mp 70ꢀ71 °C.
2-Methoxy-5-((trifluoromethyl)sulfonyl)pyridine (4h): Following the general
procedure, a mixture of 3h (0.50 g, 1.9 mmol), NaSO2CF3 (0.46 g, 2.9 mmol), Pd2(dba)3
(0.045 g, 0.049 mmol), III (0.055 g, 0.12 mmol), and TDA (0.031 g, 0.097 mmol) were
heated in toluene (5 mL) at 100 °C for 21 h. The desired product 4h (0.47 g, >99%) was
calculated to be present in the crude reaction mixture. The crude product was purified by
flash column chromatography using ethyl acetate/heptanes (0ꢀ15%) as eluent to provide
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the title compound (0.36 g, 1.5 mmol, 77%) as crystallinewhite solid. H NMR (400
MHz, CDCl3) δ 8.81 (d, J = 2.4 Hz, 1H), 8.08 (ddq, J = 8.8, 2.4, 0.8 Hz, 1H), 6.96 (dd, J
13
= 8.8, 0.8 Hz, 1H), 4.09 (s, 3H). C NMR (100 MHz, CDCl3) δ 168.9 (C), 152.1 (CH),
19
139.8 (CH), 120.3 (C), 119.7 (CF3, J = 323 Hz), 112.4 (CH), 55.0 (CH3). F NMR (376
MHz, CDCl3) δ ꢀ78.9. Anal. Calcd for C7H6F3NO3S: C, 34.86; H, 2.51; N, 5.81. Found:
C, 35.27; H, 2.39; N, 5.67. mp 41ꢀ3 °C.
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3-((Trifluoromethyl)sulfonyl)pyridine (4i): Following the general procedure, a mixture
of 3i (0.50 g, 2.2 mmol), NaSO2CF3 (0.52 g, 3.3 mmol), Pd2(dba)3 (0.050 g, 0.055
mmol), III (0.062 g, 0.13 mmol), and TDA (0.036 g, 0.11 mmol) were heated in toluene
(5 mL) at 100 °C for 21 h. The desired product 4i (0.071 g, 15%) was calculated to be
present in the crude reaction mixture. By normal phase SiO2 chromatography, triflate 3i
and product 4i were found to coꢀelute. To purify 4i, the unreacted triflate was hydrolyzed
using Cs2CO3,78 then the crude product was purified by flash column chromatography
using dichloromethane as eluent to provide the title compound (0.026 g, 0.12 mmol, 6%)
as amorphous white solid. 1H NMR (400 MHz, CDCl3) δ 9.24 (d, J = 2.4 Hz, 1H), 9.06
(dd, J = 4.8, 1.6 Hz, 1H), 8.34 (m, 1H), 7.66 (m, 1H). 13C NMR (100 MHz, CDCl3) δ
156.7 (CH), 151.3 (CH), 138.3 (CH), 128.5 (C), 124.3 (CH), 119.5 (CF3, J = 324 Hz). 19F
NMR (376 MHz, CDCl3) δ ꢀ78.3. LRMS (m/z): [M+H]+ calcd for C6H5F3NO2S 212.0;
found 212.0.
Acknowledgments: The design, study conducted, analysis and financial support of the
study were provided by AbbVie. Lynette A. Smyth, Eric M. Phillips, Vincent S. Chan,
Jose G. Napolitano, Rodger Henry and Shashank Shekhar are AbbVie employees.
Supporting Information Available: 1H, 19F and 13C NMR spectra of
aryl(heteroaryl)triflones.
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