Cu-catalyzed couplings of aryl iodonium salts with sodium trifluoromethanesulfinate

Article abstract of DOI:10.1021/jo401868x

A convenient method for the preparation of aryl trifluoromethylsulfones from the reactions of diaryliodonium salts with sodium trifluoromethanesulfinate in the presence of copper catalysts is described. Cuprous oxide in DMF was found to be the optimal catalyst for the reaction. The reaction conditions are tolerant of various functional groups as well as of various counteranions of the iodonium salt. The synthetic utility of the process is demonstrated by performing the reaction on a preparative scale (88 g).

Full text of DOI:10.1021/jo401868x

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Note
Cu-Catalyzed Couplings of Aryl Iodonium
salts with Sodium trifluoromethanesulfinate.
Steven C. Cullen, Shashank Shekhar, and Nandkishor K Nere
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 03 Nov 2013
Downloaded from http://pubs.acs.org on November 15, 2013
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Cu-Catalyzed Couplings of Aryl Iodonium Salts with Sodium
Trifluoromethanesulfinate
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Steven C. Cullen, Shashank Shekhar* and Nandkishor K. Nere
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Abbvie, Process Research and Development, 1 North Waukegan Road, North Chicago, ILꢀ60064
Email Address: Shashank.shekhar@abbvie.com
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Abstract
A convenient method for the preparation of aryl trifluoromethylsulfones from the reactions of diaryl
iodonium salts with sodium trifluoromethanesulfinate in the presence of copper catalysts is described.
Cuprous oxide in DMF was found to be the optimal catalyst for the reaction. The reaction conditions are
tolerant of various functional groups as well as of various counteranions of the iodonium salt. The synthetic
utility of the process is demonstrated by performing the reaction on a preparative scale (88 g).
Aryl sulfones (ArSO2R, R = alkyl, aryl) are common functional groups present in molecules of medicinal
interest. The traditional approaches to these compounds such as oxidation of the corresponding aryl sulfides
and sulfonylation of arenes are limited in scope due to limited availability of sulfides, incompatibility of
many functional groups with oxidative/acidicꢀreaction conditions as well as the formation of isomeric
products.1ꢀ3 Pdꢀ and Cuꢀcatalyzed methodologies that couple aryl halides, psuedohalides, and boronic acids
with sulfinic acid salts or sulfinic acid derivatives under mildly basic or neutral conditions have allowed for
the synthesis of a wide variety of aryl sulfones.4ꢀ16 Although numerous examples of the use of aryl and
alkyl sulfinic acid salts as nucleophiles have been reported, the use of a trifluoromethanesulfinic acid salt as
a nucleophile yielding aryltrifluoromethyl sulfones has never been reported (equation 1). Given the
increasing prevalance of aryltrifluoromethanesulfones in medicinally relevant compounds17ꢀ19 and the
significant challenges in introducing the trifluoromethylsulfonyl group on aryl rings,20ꢀ23 crossꢀcoupling
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methodologies that employ readily available and inexpensive trifluoromethanesulfinic acid salts such as
CF3SO2Na as a nucleophile will be of synthetic value.
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Several Pdꢀ and Cuꢀcatalyzed reactions based on the reported reaction conditions for the formation of
aryl sulfones were investigated to couple sodium trifluoromethanesulfinate (CF3SO2Na) with
2ꢀfluoroiodobenzene or 2ꢀfluorophenylboronic acid (equation 2);4ꢀ16,24,25 however, the coupled product,
2ꢀfluorophenyl trifluoromethanesulfone, was not observed in any isolable yield (data not shown). The poor
nucleophilicity of CF3SO2Na was hypothesized to be a likely cause for the lack of reactivity. We evaluated
diaryliodonium salts as coupling partners with CF3SO2Na because of the former are known to react with a
variety of nucleophiles, including poorly reactive nucleophiles such as fluoride.26ꢀ37
Recently, synthesis of diaryl sulfones from reactions of diaryliodonium salts with arylsulfinic acid salts
was reported.34 While arylsulfinic acid salts were competent as nucleophiles, the alkylsulfinic acid salt,
MeSO2Na, did not react.34 In a separate report, aryltrifluoromethyl sulfones were synthesized from the
reactions of arylsulfinate salts with an excess of electrophilic trifluoromethylating reagent in the presence
of copper (20 mol%), ligand (40 mol%), and Bu4NF (50 mol%) at elevated temperatures (130 °C).23
Herein, we report a mild Cuꢀcatalyzed method for coupling of diaryliodonium salts with CF3SO2Na to
generate aryltrifluoromethyl sulfones in high yields.17
Commercially available diphenyliodonium hexafluorophosphate (1a) was choosen as the coupling
partner for CF3SO2Na during the initial identification of reaction conditions (Table 1). No appreciable
amount of the coupled product (2a) was obtained when the reactants were heated upto 80 °C in solvents of
varying polarity (entries 1ꢀ5). The use of a catalytic amount of CuI (10 mol%) afforded 2a in 83% yield in
DMF (entry 6). In addition to the expected coupled product, the formation of small amounts of 2ꢀ
fluorophenol and 2,2’ꢀdifluorobiphenyl were also observed. Although 2a was formed in acceptable yield in
the presence of all the copper salts that were evaluated as catalysts (entries 6ꢀ9), the highest yields were
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obtained in the presence of Cu2O (entry 9). Equally high yields of 2a were also obtained in the presence of
only 2 mol% of Cu2O at a lower temperature of 50 °C in either DMF or THF (entries 10 & 11). While 1,4ꢀ
dioxane was also found to be an acceptable solvent for the reaction (entry 12), toluene and acetonitrile were
unsuitable as solvents (entries 13 and 14). Cupric oxide (CuO) was not as effective of a catalyst as cuprous
oxide (Cu2O) (entry 14), however, to our surprise, an excellent yield of 2a was obtained in the presence of
copper metal (entries 16 & 17). Although both Cu2O and copper metal proved to be highly effective
catalysts and are inexpensive sources of copper, Cu2O was chosen for further explorations.
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Table 1: Evaluations of reaction parametersa
[Cu] (mol
%)
Temp Reaction
entry
Solvent
(°C) Time (h) 2a (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
NA
NA
NA
NA
NA
DMF
THF
toluene
80
80
80
24
24
24
24
24
17
17
17
15
10
16
16
16
16
16
16
16
<1
0
0
2
0
83
79
83
91
92
95
84
33
<2
24
98
72
1,4ꢀdioxane 80
MeCN
DMF
DMF
DMF
DMF
DMF
THF
80
80
80
80
80
50
50
CuI (10)
CuCl (10)
CuOAc (10)
Cu2O (10)
Cu2O (2)
Cu2O (2)
Cu2O (2) 1,4ꢀdioxane 50
Cu2O (2)
Cu2O (2)
CuO (2)
Cuc (2)
toluene
acetonitrile 50
50
DMF
DMF
THF
50
50
50
Cuc (2)
(a) All reactions were performed with 1a (1 equivalent), CF3SO2Na (1.1 equivalents) in solvent (0.21 M). (b) Assay yield
based on HPLC analysis at 210 nm. (c) Copper powder, complexometric purity ≥99.5%
The yield of the Cuꢀcatalyzed reaction of diphenyliodonium salts with CF3SO2Na was found to be
essentially independent of the nature of the counteranion (Table 2). This is an important observation and
bodes well for the generality of the reaction as the synthesis, yield and stability of diaryliodonium salts are
known to be dependent on the nature of the counteranion.26,38
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Table 2: Effect of counteranion on the yield of phenyltrifluoromethyl sulfonea
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6
7
8
9
Entry
Xꢀ
2a (%)b
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59
60
1
2
3
4
PF6
OTs
BF4
92
88
96
96
CF3SO3
(a) All reactions were performed with 1X (1 equivalent), CF3SO2Na (1.1 equivalents) in DMF (0.21 M). (b) Assay yield
based on HPLC analysis at 210 nm.
The substrate scope of the Cuꢀcatalyzed reactions of sodium trifluoromethanesulfinate with a variety of
diaryliodonium salts was explored (Table 3). The coupled product 2a was isolated in 86% yield (entry 1).
No effect on the efficiency of the reaction was observed when sterically hindered diꢀorthoꢀtolyliodonium
tetrafluoroborate was used as the electrophile (entry 2). However, a further increase in the steric bulk led to
a significantly lower yield of the coupled product (entry 3). The coupled product 2c was isolated in only
20% yield despite conducting the reaction with 20 mol% of Cu2O. Mesitol and mesitylene were observed
as side products. The reactions of electronꢀpoor (entries 4 and 5) as well as electronꢀrich (entry 6)
diaryliodonium salts afforded the corresponding coupled products in high yield. Functional groups such as
fluoride (entry 4), bromide (entry 7), ester (entry 8), and nitro (entry 11) were well tolerated under the
reaction conditions. The heterocyclic iodonium salt 1i was evaluated as coupling partner and was found to
form the desired product 2i in acceptable yield (entry 10).
Next, the reactivity and selectivity of unsymmetrical diaryliodonium salts were investigated.
Unsymmetrical iodonium salt 1j, containing sterically differentiated aryl groups, was found to be a suitable
substrate (entry 11). The coupled product 2d that arises from the reaction of the less sterically hindered aryl
group was observed in 60% yield while product 2c that could arise from the reaction of the more sterically
hindered aryl group was observed in less than 2% yield (30:1 ratio). The preferred reactivity of less
sterically hindered aryl groups with CF3SO2Na is consistent with reported Cuꢀcatalyzed reactions of
diaryliodonium salts with several other nucleophiles26,37,39 but is in contrast to the preferential reaction of
bulkier aryl group with phosphorous nucleophiles in the presence of copper chloride as catalyst.33 The
metalꢀcatalyzed reactions of unsymmetrical diaryliodonium salts containing an electronꢀrich and an
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electronꢀpoor aryl group generally shows significant preference for transfer of the more electronꢀrich aryl
group,26,40 but some exceptions have been observed.33,40 Interestingly, we observed only a modest
preference for transfer of the less electronꢀdonating aryl group in the reactions of unsymmetrical
diaryliodonium salts as reactions of 1k [(4ꢀNO2C6H4)I(C6H5)OTf], 1l [(3ꢀCF3C6H4)I(C6H5)OTf], and 1m
[(4ꢀNO2C6H4)I(4ꢀOMeC6H4)OTs] with CF3SO2Na in the presence of Cu2O as catalyst (entries 11ꢀ13) gave
1.5:1, 1.2:1, and 1.6:1 product ratios, respectively.
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One hypothesis for the lack of strong chemoselectivity in the reactions of 1kꢀm is that two distinct
reaction pathways are occuring simultaneously, each having comparable rates but with opposite
chemoselectivities; for example, a catalytic reaction pathway favoring one product and a nonꢀcatalyzed
background pathway favoring the other.32 This possibility was ruled out when reactions of 1k and 1m with
CF3SO2Na was attempted in the absence of catalyst and produced less than 5% product. The modest
selectivity observed in the current work along with contrasting chemoselctivities reported for the reactions
of electronically differentiated unsymmetrical diaryliodonium salts in the presence of transition metal
catalysts point towards significantly different reaction pathways being operative under varying reaction
conditions.40
Table 3: Substrate scope of the reaction of iodonium salts with sodium trifluoromethanesulfinate.
Yield
entry
Diaryliodonium
Product
(%)
-
PF6
+
I
1
2
86
88
20
79
1a
1b
1c
1d
2a
2b
2c
2d
3a
4
5b
6
63
80
1e
1f
2e
2f
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Yield
(%)
entry
7
Diaryliodonium
Product
71
1g
2g
9
10
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8
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84
66
1h
1i
2h
2i
F
SO2CF3
10
60c
1j
2d
11
12
41d,e
81f,g
1k
1l
2k+2a
2l+2a
13
37+59h
1m
2f+2k
Unless noted otherwise, all experiments were performed with diaryliodonium salt (1 equivalent), CF3SO2Na
(1.1 equivalents), Cu2O (0.02 equivalents) in DMF (0.21 M) at 50 °C. (a) Cu2O (0.2 equivalents). (b) THF was
used as the reaction solvent. (c) Assay yield based on HPLC analysis. (d) 2k and 2a were observed in 1.5:1
ratio by HPLC. (e) Yield of 2k. (f) 2l and 2a were observed in a ratio of 1.2:1 by 1H NMR spectroscopy. (g)
Combined yield of 2l and 2a. We were unable to separate 2a and 2l by silica gel chromatography. (h) 2k and 2f
were observed in a ratio of 1.6:1.
Once a reasonable scope of the reaction was established in the presence of electronꢀwithdrawing,
electronꢀdonating, sterically hindered, and hetrocyclic functional groups (Table 3), a survey was conducted
to further assess the functional group tolerance under the standard reaction conditions. The Cuꢀcatalyzed
reaction of 1a with CF3SO2Na was conducted in the presence of a molar equivalent of additives containing
common functional groups (Table 4). The yield of the coupled product 2a was quantitavely determined
using high pressure liquid chromatography (HPLC). If the yield of 2a in the presence of an additive
containing a functional group is comparable to the reaction performed in the absence of any additives
(entry 1, Table 3), then it suggests that this particular functional group is well tolerated under the reaction
conditions and it is unlikely to inhibit the reaction when present in a complex molecular structure. This
rapid, complementary approach of understanding the functional group tolerance of a reaction was recently
discussed by Collins and Glorius41 and is likely to be very useful in studying new methodologies where the
starting materials are not commercially available and need to be synthesized. Since the functional groups
present in additives are distal to the reaction center, it is possible that in certain cases the impact of a
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functional group on the reaction when directly attached to the reaction center may contradict the
observations made in Table 4.
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Full consumption of 1a was observed in the presence of nitro, cyano, acetyl, dialkylamino, formyl,
boronic acid, terminal alkyne, phenol, amine and pyridine (Table 4, entries 1ꢀ8). The yields of the coupled
product 2a were comparable to that obtained in the absence of any additive (Table 1, entry 10).
Quantitative amounts of the additives were recovered at the end of the reaction demostrating that these
functional groups are unaffected by the reaction conditions. The inertness of boronic acid, terminal alkyne,
aniline and phenol is attributed to the neutral reaction conditions as the reactions of amines42, phenols31,
boronic acids43 and terminal alkynes44 with diaryliodonium salts in the presence of a base are known.
Although full consumption of 1a was observed in the presence of thioanisole, 2a was formed in only 55%
yield. Diphenyl sulfide (27%) was observed as the major side product in the reaction (Table 4, entry 9). The
formation of the diphenyl sulfide probably proceeds via the reaction of thioanisole with 1a in the presence
of copper to form diphenymethylsulfonium hexafluorophosphate and phenyl iodide.45
Diphenymethylsulfonium hexafluorophosphate then decomposes to dephenylsulfide under the reaction
conditions.
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Effect of additives that may bind the catalytically active copper species and inhibit catalysis was also
studied. While 2ꢀisobutyrlcyclohexanone had no impact on the reaction (entry 10), a lower yield of 2a was
observed in the presence of 7ꢀazaindole (entry 11). The presence of 1,10ꢀphenanthroline was found to
completely shut down the reaction (entry 12). The yield of the reaction was not affected by the presence of
a radical scavenger, TEMPO (entry 13).
Table 4: Functional group tolerance of Cuꢀcatalyzed reaction of sodium trifluorosulfinate with
diaryliodonium salt
Remaining
additive (%)
Entry
1
Additive
2a (%)a
91
100
CN
N
O2N
O
2
93
90
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Remaining
additive (%)
Entry
3
Additive
2a (%)a
90
100
7
8
9
4
5
6
90
92
98
100
96
BF4K
10
11
12
13
14
15
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98
7
8
89
78
93
95
9
55b
93
77.6
83.5
SMe
10
11
12
45c,d
0f
>95e
>95e
13
92
87
All reactions were performed with 1a (1 equivalent), CF3SO2Na (1.1 equivalents), and additive (1.0 equivalent)
in DMF (0.2 M). (a) Assay yield based on HPLC analysis at 210 nm.(b) PhSPh (27%) was observed. (c)
Unreacted 1a (16%) was observed. (d) Formation of trace amounts of Nꢀphenylated 7ꢀazaindole was observed.
(e) Trace amounts of DMF may overlap with the peak of additive on the HPLC spectrum, (f) Unreacted 1a
(90%) was observed.
With regard to the mechanism of the reaction, the observation of complete consumption of 1a along with
almost quantitative yield of 2a in the presence of a radical scavenger, TEMPO, suggests that the Cuꢀ
catalyzed reactions of diaryliodonium salts with CF3SO2Na may proceed via a nonꢀradical pathway.
Reaction pathways that involves Cu(I)ꢀCu(III) intermediates have been proposed for the Cuꢀcatalyzed
reactions of diaryliodonium sallts.23,37,46 The lower yield obtained in the presence of Cu(II) catalyst (Table
1, entry 15) supports Cu(I) as catalytically active species. It is unclear how the reaction proceeds in the
presence of metallic copper. Perhaps a layer of Cu2O typically present on the surface of metallic copper
catalyzes the reaction.47
Although a stoichiometric amount of aryl iodide is generated as a coꢀproduct in the reaction, separation
of the aryl iodide from aryl trifluoromethylsulfone by silica gel column chromatography was trivial in most
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cases. While silica gel column chromatography is a convenient method of separating compounds on small
scale, it can be difficult to scale up as well as be cost prohibitive to perform on a large scale. Distillation is
the preferred method to separate a mixture of compounds with different boiling points on scale. To
demonstrate the utility of a distillation protocol on preparetively relevant scale, the reaction of 1d with
CF3SO2Na was performed at 88 g scale (Scheme 1). The expected products 2d and 2’d were observed in
the reaction mixture. A packed distillation column with a height equivalent to theoretical plates (HETP) of
19 with gradual variation of reflux ratio (ratio of liquid that is returned to the distillation column to the
liquid drawn out as a collected fraction) from 4:1 to 6:1 under receiver pressure of around 15 mmHg was
found to be sufficient to effect the desired separation. Analytically pure 2d and 2’d were isolated in 83.7%
and 78.6% yield, respectively, after distillation of the reaction mixture (Scheme 1).
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An aryl iodide and a sodium salt of the counteranion on the diaryliodonium salt are the coꢀproducts of
the reported reaction. The recovered aryl iodide is a starting material for the synthesis of diaryliodonium
salts used in the reaction and, therefore, does not represent a waste stream if it is recovered and recycled.
Scheme 1
-
BF4
F
F
F
F
+
SO2CF3
I
I
Cu2O (2 mol%)
DMF, 50 °C
CF3SO2Na
+
+
1d(88 g)
2d
2'd
F
F
SO2CF3
I
Distillation
36 g (83.7%)
33 g (78.6%)
In summary, a convenient method for the preparation of aryl trifluoromethylsulfones from the
reactions of corresponding diaryliodonium salt and sodium trifluormethansulfinate has been developed.
Both electronꢀrich and electronꢀpoor aromatic diaryliodonium salts provided the coupled products in good
yields. The reaction was tolerant of varying the counteranion of diaryliodonium salts. Tolerance of several
common organic functional groups (nitro, cyano, acetyl, dialkylamino, formyl, boronic acid, terminal
alkyne, unprotected amine, alcohol and pyridine) under the standard reaction conditions was rapidly
demonstrated by performing reactions of diphenyliodonium hexafluorophosphate with sodium
trifluormethansulfinate in the presence of additives containing these functional groups. Low yields of IIa
observed in the presence of heterocyclic compounds such as 2ꢀazaindole and 1,10ꢀphenanthroline that may
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bind the copper catalyst is a major limitation of the current methodology. The synthetic utility of the
methodology was demonstrated by performing a reaction at 88 g. Fractional distillation of the reaction
mixture allowed for the efficient recovery of the desired product as well as of the aryl iodide side product.
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General methods. All copperꢀcatalyzed reactions were performed in a nitrogen filled glove box or using
Schlenk techniques under a N2 or Ar atmosphere. Anhydrous grade DMF, THF, toluene, 1,4ꢀdioxane,
acetonitrile, THF, aryl iodides, sodium trifluoromethanesulfinate and copper salts were purchased from
commercial sources and were used without further purification. Diaryliodonium salts were either purchased
from commercial sources or were synthesized by following literature procedures.26,32,48 Column
1
chromatography was performed using silica gel. H NMR, 19F NMR and 13C NMR spectra were recorded
on a 400 or 600 or 700 MHz spectrometer, with chemical shifts reported in parts per million downfield
from tetramethylsilane and referenced to residual proton (1H) or deuterated solvent (13C). HPLC analyses
were performed by gradient elution with acetonitrile and either 0.1% aq H3PO4 or 0.1% aq HClO4.
Elemental analysis was performed using optimum combustion analysis on an elemental analyzer.
Procedure for Cu-catalyzed reaction of diphenyliodonium hexafluorophosphate (1a) with sodium
trifluoromethanesulfinate (Table 1).
A 40ꢀmL reaction vial equipped with a magnetic stir bar and fitted with a teflonꢀcoated septum screw cap
was charged with diphenyliodonium hexafluorophosphate (1a) (0.464 g, 1.09 mmol), sodium
trifluoromethanesulfinate (0.176 g, 1.20 mmol) and copper salts/Cu (0.11 – 0.02 mmol) (except entries 1ꢀ5)
inside an inert atmosphere glove box. Appropriate amount of solvent was added with a syringe to achieve
the reaction concentration of 0.22ꢀ0.24 M. The reaction vial was heated to 50ꢀ80 °C, as appropriate, by
placing the reaction vial inside a metal heating block and the reaction mixture was stirred for 14ꢀ18 h. Upon
reaction completion, the reaction mixture was cooled to the room temperature and was brought outside of
the glove box. In order to determine the amount of product formed, the reaction mixture was filtered
through a filter funnel that was preꢀpacked with celite, the celite was rinsed with solvent (~8ꢀ10 mL) and
was collected in a tared 25ꢀmL Erlenmeyer flask. The weight of filtered solution (Wtprod) was recorded.
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Next, the amount of the product present in the filtered solution was determined by HPLC analysis as
follows. A small portion of the filtered solution (~0.6ꢀ1.1 g) was weighed into a tared 50ꢀmL volumetric
flask (Wtsample). Acetonitrile was added to achieve a total volume of 50 mL; a small portion (1ꢀ1.5 mL) of
this solution was then injected into an HPLC instrument. The area response corresponding to the product
IIa was recorded (Aprod).
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Assay yield calculation: The commercially available product IIa was weighed into a 50ꢀmL volumetric
flask (Wtstd), dissolved in 50 mL acetonitrile and was analysed by an HPLC instrument. The area
corresponding to the product was recorded (Astd). The assay yield of 2a in entries 1ꢀ17, 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)
Procedure for Cu-catalyzed reaction of diphenyliodonium salts (1X) with sodium
trifluoromethanesulfinate (Table 2).
A 40ꢀmL reaction vial equipped with a magnetic stir bar and fitted with a teflonꢀcoated screw cap septum
ꢀ
ꢀ
ꢀ
was charged with diphenyliodonium salt (1X, X = PF6 , OTsꢀ, BF4 , CF3SO3 ) (1 equiv), sodium
trifluoromethanesulfinate (1.2 equiv) and Cu2O (0.02 equiv) inside an inert atmosphere glove box.
Appropriate amount of DMF was added with a syringe to achieve the reaction concentration of 0.22ꢀ0.24
M. The reaction mixture was heated to 50 °C by placing the reaction vial inside a metal heating block and
the reaction mixture was stirred for 14ꢀ18 h. Upon completion, the reaction mixture was cooled to the room
temperature, brought outside the glove box. In order to determine the amount of the product formed, the
reaction mixture was filtered through a filter funnel that was preꢀpacked with celite, the celite was rinsed
with solvent (~8ꢀ10 mL), and was collected in a tared 25ꢀmL Erlenmeyer flask. The assay yield of 2a in
entries 1ꢀ17, Table 1 was determined as described above.
General procedure for Cu-catalyzed reaction of diaryl iodonium salts with sodium
trifluoromethanesulfinate (Table 3).
A 40ꢀmL reaction vial equipped with a magnetic stir bar and fitted with a Teflonꢀcoated screw cap was
charged with the diaryl iodonium salt 1a-l (1 equiv), sodium trifluoromethanesulfinate (1.1 equiv) and
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copper(I) oxide (0.02 equiv). The vial was purged with N2 for not less than 1 hour. DMF was purged with
N2 for not less than 60 minutes after which time the appropriate amount was added to the reaction vial to
achieve a final concentration of 0.22ꢀ0.24 M. The vial was kept under N2 and heated to an internal
temperature of 50 ºC and stirred overnight (18 h). The reaction mixture was diluted with 12 mL of a 3:1
heptanes:ethyl acetate solution and was washed with 12 mL of 5% K2CO3 solution. The organic layer was
filtered through a pad of celite and was then concentrated in vacuo to an oil. The product was isolated by
silica gel column chromatography.
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(Trifluoromethylsulfonyl)benzene (2a).23,49 Following the general procedure, 1a (0.368 g, 0.863 mmol)
was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from the
reaction mixture by silica gel column chromatography using 0ꢀ10% ethyl acetate in heptanes as the eluent.
The title compound 2a was obtained as a colorless oil. (0.155 g, 86%). 1H NMR (700 MHz, CDCl3) δ 7.95
(d, J = 14 Hz, 2H), 7.76 (app t, J = 7.0 Hz, 1H), 7.59 (app t, J = 7.0 Hz, 2H). 13C NMR (176 MHz, CDCl3)
δ 136.8 (s), 131.3 (s), 130.8 (s), 130.1 (s), 119.9 (q, J = 325.6 Hz). 19F (564 MHz, CDCl3) δ ꢀ78.45. Anal.
Calcd for C7H5F3O2S: C, 40.00; H, 2.40. Found: C, 40.01; H, 2.31.
1-Methyl-2-(trfluoromethylsulfonyl)benzene (2b).23 Following the general procedure, 1b (1.15 g, 2.90
mmol) was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from
the reaction mixture by silica gel column chromatography using 0ꢀ8% ethyl acetate in heptanes as the
eluent. The title compound 2b was obtained as a colorless oil (0.57 g, 88%). 1H NMR (600 MHz, CDCl3) δ
8.08 (dd, J = 8.0, 0.9 Hz, 1H), 7.68 (td, J = 7.6, 1.4, Hz, 1H), 7.48ꢀ7.43 (m, 2H), 2.73 (s, 3H). 13C NMR
(151 MHz, CDCl3) 142.2 (s), 136.3 (s), 135.5 (s), 133.3 (s), 129.8 (s), 127.2 (s), 120.1 (q, J = 327.7 Hz),
20.6 (s). 19F (564 MHz, CDCl3) δ ꢀ78.34. Anal. Calcd for C8H7F3O2S: C, 42.86; H, 3.15%. Found C, 42.89;
H, 2.91%.
1,3,5-Trimethyl-2-(trifluoromethylsulfonyl)benzene (2c). Following the general procedure, 1c (2.0 g, 3.9
mmol) was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from
the reaction mixture by silica gel column chromatography using 0ꢀ8% ethyl acetate in heptanes as the
1
eluent. The title compound 2c was obtained as a colorless oil (0.2 g, 20%). H NMR (600 MHz, CDCl3) δ
6.91 (s, 2H), 2.29 (s, 9H). 13C NMR (151 MHz, CDCl3) 146.7 (s), 136.9 (s), 131.1 (s), 130.0 (s), 123.0 (q, J
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= 336.7 Hz), 20.7 (s), 16.9 (s). 19F (564 MHz, CDCl3) δ ꢀ78.90. Anal. Calcd for C10H11F3O2S: C, 47.61%;
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H, 4.40. Found: C, 47.99; H, 3.99.
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1-Fluoro-2-(trifluoromethylsulfonyl)benzene (2d). Following the general procedure, 1d (1.0 g, 2.2
mmol) of bis(2ꢀfluoromethylphenyl) tetrafluoroborate was reacted with sodium trifluoromethanesulfinate.
The analytically pure product was isolated from the reaction mixture by silica gel column chromatography
using 0ꢀ30% ethyl acetate in heptanes as the eluent. The title compound 2d was obtained as a colorless oil
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(0.40 g, 79%). H NMR (600 MHz, CDCl3) δ 8.07ꢀ7.97 (m, 1H), 7.91ꢀ7.79 (m, 1H), 7.46 (td, J = 7.9, 1.0
Hz, 1H), 7.39ꢀ7.34 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 161.2 (d, J = 265.8 Hz), 139.3 (d, J = 9 Hz),
133.3 (s), 125.3 (d, J = 3.0 Hz), 119.7 (d, J = 12 Hz), 119.65 (q, J = 326.2 Hz), 118.1 (d, J = 19.6 Hz). 19F
(564 MHz,CDCl3) δ ꢀ78.3 (d, J = 9.4 Hz), ꢀ103.8 (m).22
1-(Trifluoromethyl)-4-(trifluoromethylsulfonyl)benzene (2e). A 40ꢀmL reaction vial equipped with a
magnetic stir bar and fitted with a teflonꢀcoated screw cap was charged with the diaryl iodonium salt 1e
(0.680 g, 1.35 mmol), sodium trifluoromethanesulfinate (0.232 g, 1.484 mmol) and copper(I) oxide (3.86
mg, 0.027 mmol). The vial was purged with N2 for not less than1 hour. THF was purged with N2 for not
less than 30 minutes after which 6 mL was added to the reaction vial. The vial was kept under N2 and
heated to an internal temperature of 50 ºC and stirred overnight (6 h). The reaction mixture was filtered
through a pad of celite and was washed with diethyl ether (10 mL). Celite (3 g) was added to the filtered
solution and was concentrated in vacuo. The product adsorbed on celite was purified by silica gel column
chromatography, eluting with 0ꢀ30% diethyl ether in pentane. The title compound 2e was obtained as a
1
white solid (0.238 g, 63%). H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 8.2 Hz, 2H), 7.96(d, J = 7.9 Hz,
2H). 13C NMR (151 MHz, CDCl3) δ 138.0 (q, J = 33 Hz), 135.1 (s), 131.4 (s) 127.0 (q, J = 3 Hz), 119.6 (q,
J = 326.2 Hz) 112.7 (q, J = 282.4 Hz). 19F (564 MHz, CDCl3) δ ꢀ78.04, ꢀ63.74. Anal. Calcd for C8H4F6O2S:
C, 34.54; H, 1.45. Found: C, 34.34; H, 1.25. mp 38ꢀ39 °C.
1-Methoxy-4-(trifluoromethylsulfonyl)benzene (2f).23 Following the general procedure, 1f (0.750 g, 1.75
mmol) was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from
the reaction mixture by silica gel column chromatography using 0ꢀ25% ethyl acetate in heptanes as the
eluent. The title compound 2f was obtained as a colourless oil (0.335 g, 80%). 1H NMR (600 MHz, CDCl3)
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δ 8.11 (d, J = 9.0 Hz, 2H), 7.33ꢀ7.15 (m, 2H), 4.09 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 166.1 (s), 131.2
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7
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(s), 120.9 (s). 119.9 (q, J = 324.6 Hz) 115.2 (s), 55.9 (s). 19F (564 MHz, CDCl3) δ ꢀ83.65. Anal. Calcd for
C8H7F3O3S: C, 40.00; H, 2.94. Found: C, 40.23; H, 2.49.
9
1-Bromo-4-(trifluoromethylsulfonyl)benzene (2g). Following the general procedure, 1g (0.80 g, 1.5
mmol) was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from
the reaction mixture by silica gel column chromatography using 0ꢀ8% ethyl acetate in heptanes as the
eluent. The title compound 2g was obtained as a white solid (0.311 mg, 71%). 1H NMR (600 MHz, CDCl3)
δ 7.90 (d, J = 7.9 Hz, 2H), 7.85ꢀ7.83 (m, 2H), 13C NMR (151 MHz, CDCl3) δ. 133.4 (s), 132.8 (s), 132.0
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(s), 130.3 (s), 119.6 (q, J = 326.0 Hz). 19F (564 MHz, CDCl3) δ ꢀ78.3. Anal. Calcd for C7H4BrF3O2S: C,
29.08; H, 1.39. Found: C, 29.21; H, 1.31. mp 63ꢀ64 °C.
1-Carboethoxy-4-(trifluoromethylsulfonyl)benzene (2h). Following the general procedure, 1h (1.0 g, 1.9
mmol) was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from
the reaction mixture by silica gel column chromatography using 0ꢀ8% ethyl acetate in heptanes as the
1
eluent. The title compound 2h was obtained as a white solid (0.551 g, 84%). H NMR (600 MHz, CDCl3)
δ 8.37ꢀ8.27 (m, 2H), 8.13 (d, J = 8.4 Hz, 2H), 4.46 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 164.3 (s), 137.7 (s), 134.9 (s), 130.8 (s), 130.7 (s), 119.6 (q, J = 326.2 Hz), 62.3 (s),
14.3 (s). 19F (564 MHz, CDCl3) δ ꢀ82.8. Anal. Calcd for C10H9F3O4S: C, 42.56; H, 3.21. Found: C, 42.67;
H, 3.09. mp 45ꢀ47 °C.
2-((Trifluoromethyl)sulfonyl)thiophene (2i).50 Following the general procedure, 2i (0.40 g, 0.86 mmol)
was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from the
reaction mixture by silica gel chromatography using 0ꢀ30% diethyl ether in hexanes as the eluent. The title
compound 2i was obtained as a white solid (0.122 g, 66%). 1H NMR (700 MHz, CDCl3) δ 7.97 (d, J = 4.9
Hz, 1H), 7.90 (d, J = 3.8 Hz, 1H), 7.25 (appt, J = 4.4 Hz, 1H). 13C NMR (176 MHz, CDCl3) δ 139.7 (s),
139.6 (s), 130.6 (d, J = 1.7 Hz), 129.3 (s), 119.8 (q, J = 314.6 Hz). 19F (376 MHz, CDCl3) δ ꢀ78.7. Anal.
Calcd for C5H3F3O2S2: C, 27.78; H, 1.40. Found: C, 27.24; H, 1.24.
1-nitro-4-(trifluoromethylsulfonyl)benzene (2k).20 Following the general procedure, 1i (0.50 g, 1.0
mmol) was reacted with sodium trifluoromethanesulfinate. The analytically pure product was isolated from
the reaction mixture by silica gel column chromatography using 0ꢀ8% ethyl acetate in heptanes as the
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eluent. The title compound 2i was obtained as a white solid (109 mg, 41%). 1H NMR (600 MHz, CDCl3) δ
8.57ꢀ8.50 (m, 2H), 8.34ꢀ8.26 (m, 2H).13C NMR (151 MHz, CDCl3) δ 152.4 (s), 137.1 (s), 132.3 (s), 124.9
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(s), 119.6 (q, J = 339.7 Hz). 19F (564 MHz, CDCl3) δ ꢀ75.5. Anal. Calcd for C7H4F3NO4S: C, 32.95; H,
1.58; N, 5.49 Found: C, 32.78; H, 1.37; N, 5.30. mp 80ꢀ82 °C.
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Table 3, entry 12: Following the general procedure, 1l (0.50 g, 1.0 mmol) was reacted with sodium
trifluoromethanesulfinate. A mixture of 2l and 2a was isolated from the reaction mixture by silica gel
column chromatography using 0ꢀ15% ethyl acetate in heptanes as the eluent. The mixture of 2l and 2a was
obtained as a white solid (199 mg, 81%) in a ratio of 1.2:1.0 as determined by 1H NMR spectroscopy.
Table 3, entry 13: Following the general procedure, 1m (0.60 g, 1.1 mmol) was reacted with sodium
trifluoromethanesulfinate. 2k (0.17 g) was isolated from the reaction mixture by silica gel column
chromatography using 8% ethyl acetate in heptane and 2f (0.10 g) was isolated using 15% ethyl acetate in
heptanes as the eluent.
Fractional distillation procedure for the separation of 2d and 2’d.
A distillation apparatus consisting of the three stacked vacuum insulated cylindrical columns of 2.54 cm
internal diameter and 45 cm length each was setꢀup (Figure 1). One of the columns was packed with
stainless steel wireꢀmesh while the other two were packed with stainless steel random packing. The
columns were not characterized for the number of theoretical stages but were approximated to have around
19 stages based on assumed HETP (height equivalent to theoretical plate) of 5 cm. A vacuum insulated
cylindrical section equipped with a solenoid valve was used to connect a condenser and a column with
random packing to control the liquid returned to the packed column and fraction withdrawal.
A reaction solution (111.73 g) containing a mixture of 2d, 2’d (70.94 g, rest of the weight was DMF) was
charged to a 500ꢀmL fourꢀneck roundꢀbottom flask and was heated with a heating mantle equipped with the
temperature and heating rate control. The solution was diluted with additional 84 g of DMF to establish
vaporꢀliquid contact through better wetting of the packing and to preꢀheat the column packing during initial
total reflux. Furthermore, a magnetic stirrer was placed in the batch still to avoid ‘liquid bumping’ so as to
avoid any solution carryover into the packed column. The vacuum was applied at the top condenser and
controlled at around 15 mmHg throughout the operation. Both the vapor and the internal batch still
temperatures were monitored using thermocouples. The top condenser jacket temperature was maintained
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at 5 °C while the side condenser temperature was maintained at ꢀ10 °C using two different recirculating
chillers. The cold trap and the receiver were kept in a dry ice/acetone bath to minimize vapor loss to
vacuum lines. The column was run at total reflux at the batch still temperature of 60 °C. Slowly the batch
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still temperature was increased to 90 °C and the fraction containing predominantly 2’d was collected at the
reflux ratio of 4:1 until no liquid fraction was observed in the receiver. The first receiver was replaced with
a new receiver, the batch still temperature was increased to 135 °C and the fraction containing 2d was
collected. The recovery of 2’d was 93.4% while the recovery of 2d was 100%. Please note that the
recovery percentages are for the distillation only and are different than the yields reported in the text
(Scheme 1), which represent the overall process yield.
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Procedure for Cu-catalyzed reaction of diphenyliodonium hexafluorophosphate (2a) with sodium
trifluoromethanesulfinate in the presence of additives (Table 4).
A 40ꢀmL reaction vial equipped with a magnetic stir bar and fitted with a teflonꢀcoated screw cap septum
was charged with 1a (0.20 g, 0.47 mmol), sodium trifluoromethanesulfinate (0.081 g, 0.52 mmol), additive
(0.47 mmol) and Cu2O (1.34 mg, 9.39 ꢁmol) inside an inert atmosphere glove box. DMF (2 mL) was added
with a syringe. The reaction mixture was heated to 50 °C by placing the reaction vial inside a metal heating
block and the reaction mixture was stirred for 14ꢀ18 h. Upon completion, the reaction mixture was removed
from the heating block and was brought outside of the glove box. In order to determine the amount of
product formed and the amount of unreacted additive remaining, the reaction mixture was filtered through a
filter funnel that was preꢀpacked with celite, the celite was rinsed with THF (~4ꢀ6 mL), and was collected
in a tared 25ꢀmL Erlenmeyer flask. The assay yield of 2a in entries 1ꢀ13, Table 4 was determined as
described above for the general procedure for the reactions reported in Table 1. To determine the amounts
of the additive remaining after the reaction, the commercially available additive was weighed into a 50ꢀmL
volumetric flask (Wtstd), acetonitrile was added to achieve a total volume of 50 mL and a small portion (1ꢀ
1.5 ml) of this solution was injected into an HPLC instrument. The area corresponding to the additive was
recorded (Astd). The amount of the additive remaining after the reaction was determined by using the
formula described for the reactions reported in Table 1.
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Figure 1: Distillation apparatus set up
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Acknowledgments: The design, study conduct, analysis and financial support of the
study were provided by AbbVie. Steven C. Cullen, Shashank Shekhar and Nandkishor
Nere are AbbVie employee.
Supporting Information Available: 1H, 19F and 13C NMR spectra of aryl
trifluoromethyl sulfones.This material is available free of charge via the Internet at
http://pubs.acs.org.
(1)
Rappoport, Z., Stirling, C. J. M., Eds.; Wiley: New York, 1988.
(2) Truce, W. E.; Klinger, T. C.; Beand, W. W. Organic Chemistry of Sulfur;
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Schank, K. In The Chemistry of Sulfones and Sulfoxides; Patai, S.,
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Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M.; Bernini, R. J. Org.
Chem. 2004, 69, 5608.
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Beaulieu, C.; Guay, D.; Wang, Z.; Evans, D. A. Tetrahedron Lett. 2004,
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Journal 2011, 17, 5652.
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