Development of palladium-catalyzed decarboxylative allylation of electron-deficient sulfones and identification of unusual side products

Article abstract of DOI:10.1021/acs.joc.9b00068

The use of sulfones as electron-withdrawing groups in substrates for palladium-catalyzed decarboxylative allylation was explored. A previously published trifluoromethanesulfonyl-based substrate was highly reactive and selective under mild conditions, but the substrate scope was not readily expanded. Instead, 3,5-bis(trifluoromethyl)phenyl sulfones were employed, thereby simultaneously retaining most of the electron deficiency and providing facile synthetic access. Optimization of the catalytic conditions to maximize the product distribution to a synthetically useful level of the allylation product over the protonation side product proved extremely challenging, with inconsistent and irreproducible results afforded with Pd₂(dba)₃ as the palladium source. A variety of substrates were subjected to the optimized catalytic conditions of PdCp(1-cinnamyl) and Xantphos in tetrahydrofuran at 50 °C for 30 min. These conditions were applicable to all substrates with the exception of the α,α-dimethyl allyl ester, which required more forcing conditions and afforded four products: The allylation and protonation products, as expected, along with a cyclopropylation product and an unprecedented pseudodimeric product. The mechanism for the formation of these unusual side products is considered.

Full text of DOI:10.1021/acs.joc.9b00068

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Article
Development of Palladium-Catalyzed Decarboxylative Allylation of
Electron-Deficient Sulfones and Identification of Unusual Side Products
Monica A. Gill, and Jeffrey M. Manthorpe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00068 • Publication Date (Web): 09 Apr 2019
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Development of Palladium-Catalyzed Decarboxylative Allylation of Electron-Deficient
Sulfones and Identification of Unusual Side Products
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Monica A. Gill* and Jeffrey M. Manthorpe*
Carleton University
Department of Chemistry
1121 Colonel By Drive
203 Steacie Building
Ottawa, Ontario K1B 3Z8
Canada
monica.a.gill@gmail.com
jeff.manthorpe@carleton.ca
Typical Products
O O
S
O O
S
H
Ar
Ar
O
O O
S
PdCp(1-cinnamyl)
PPh3
53%
16%
F3C
O
O
O
O O
S
O O
S
THF, 65 °C
5 h
S
Ar
Ar
CF3
Ar
7%
24%
Atypical Products
Abstract: The use of sulfones as electron-withdrawing groups in substrates for palladium-
catalyzed decarboxylative allylation was explored. previously published
A
trifluoromethanesulfonyl-based substrate was highly reactive and selective under mild
conditions, but the substrate scope was not readily expanded. Instead, 3,5-
bis(trifluoromethyl)phenyl (BTMP) sulfones were employed, thereby simultaneously retaining
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most of the electron deficiency and providing facile synthetic access. Optimization of the
catalytic conditions to maximize the product distribution to a synthetically useful level of
allylation product over the protonation side product proved extremely challenging, with
inconsistent and irreproducible results afforded with Pd2(dba)3 as the palladium source. A
variety of substrates were subjected to the optimized catalytic conditions of PdCp(1-cinnamyl)
and XANTPHOS in THF at 50 °C for 30 minutes. These conditions were applicable to all
substrates with the exception of the α,α-dimethyl allyl ester, which required more forcing
conditions and afforded four products: the allylation and protonation products, as expected,
along with a cyclopropylation product and an unprecedented pseudodimeric product. The
mechanism for the formation of these unusual side products is considered.
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Introduction
The Tsuji-Trost allylic alkylation is a well-established method of metal-catalyzed C-C bond
construction.1–3 The intramolecular decarboxylative variant is a powerful subset of these
reactions.4 While palladium is the most commonly used metal, others, including iridium,5,6
rhodium, molybdenum and nickel,7 and ruthenium,8–11 have been used. The substrates for these
reactions are generally allylic β-keto esters; however, the use of other electron-withdrawing
O
EWG
O
ester, ketone,
nitro, nitrile,
etc.
R R
EWG =
EWG =
Pd(0)
SO2R
Existing
Work
Pd(0)
O O
S
EWG
R R
R
R R
R = Ph (work by Tunge et al.)
R = CF3, 3,5-bis(trifluoromethyl)phenyl
(this work)
Scheme 1. Pd-Catalyzed Decarboxylative Allylation
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groups (EWGs) has been reported (Scheme 1).12,13 We became interested in the possibility of
using allylic α-sulfonyl esters as substrates for a palladium-catalyzed decarboxylative allylation;
the use of a sulfur-based EWG would permit further manipulation of the homoallylic products
either by C-S bond cleavage or by use of the sulfone function.
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Initial efforts were directed towards using triflyl (-SO2CF3) as the EWG. Substrate 1 was
prepared via a one-pot triflation of sec-butyllithium with N-phenyltriflimide, followed by acylation
of the α-triflyl carbanion with allyl chloroacetate. We were pleased to observe that treatment of 1
with 5 mol% Pd2(dba)3 and 20 mol% PPh3 in THF gave homoallylic sulfone 2 in high yield (92%)
with short reaction times at room temperature (Figure 1).14,15 During the course of these studies,
Tunge and Weaver published a report describing Pd-catalyzed decarboxylative allylation on
similar phenyl sulfone systems such as 3;16 however, these substrates required noticeably more
forcing conditions. Notably, a 1:1 ratio of allylation 4 to protonation 5 products was produced
when PPh3 was employed as ligand; optimized conditions used BINAP and afforded products 4
and 5 in a ratio of 11.3:1. The analogous protonation side product was not observed with the
triflone substrate. Due to the high selectivity for the allylation product and the mild reaction
conditions, the allylation chemistry of strongly electron-withdrawing sulfones was further
explored.
O O
S
5 mol% Pd2(dba)3
20 mol% PPh3
O O
S
O
O O
S
Lead results
for this work
H
F3C
F3C
F3C
O
THF,
rt, 20 min
Allylation product
exclusively
2
not observed
1
92% yield
O
Optimized results
from Tunge et al.
O O
S
5 mol% Pd2(dba)3
10 mol% BINAP
O O
S
O O
S
H
Ph
O
Ph
Ph
+
Allylation to
protonation
side product ratio
11.3:1
toluene,
95 °C, 12-15 h
Ph Ph
Ph Ph
Ph Ph
3
4
5
84% yield
Figure 1. Pd-catalyzed decarboxylative allylation of triflones (top) & phenyl sulfones (bottom)
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Results and Discussion
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As we have described previously,15 exhaustive efforts were made to expand the substrate
scope of allylic α,α-dialkylated triflylacetates. The acylation of triflone anions, other than that
generated from sec-butyllithium and N-phenyltriflimide, was found to be quite challenging;
extensive efforts to elaborate the substrate scope using other secondary alkyllithiums were
fruitless. It was anticipated that 3,5-bis(trifluoromethyl)phenyl (BTMP) sulfones would provide a
reasonable compromise between the level of electron deficiency imparted by the triflones and
the requisite nucleophilicity of their corresponding anion to alkylate smoothly, thus allowing
much greater synthetic versatility and permitting preparation of a wide variety of substrates. The
utility of BTMP sulfones as an alternative to triflones had been demonstrated by Nájera and
coworkers.17–20
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It was envisioned that the desired substrates could be prepared from an esterification of 6,21
followed by a sulfide to sulfone oxidation, and alkylation (Figure 2). The esterification was more
challenging than anticipated, with most standard methods failing. Even in the presence of large
excess of allyl alcohol, the transesterification of the ethyl ester to the allyl ester failed to reach
(a)
1. PivCl, pyridine
DCM, MW, 80 °C
R2-X,
O
O
O
O O
S
R1
HO
K2CO3
S
X
Ar
OH
Ar
O
R1
Ar
O
R1
2. (NH4)6Mo7O24•4H2O
DMF, rt
R2 R2
6
7 X = S
8 X = SO2
H2O2, t-BuOH
9
F3C
= Ar
CF3
O
R3-X or NCS,
K2CO3
(b)
O
O O
O
O O
NaH, R2-X
O O
S
S
S
Ar
O
Ar
O
R1
R1
Ar
O
DMF, rt
R1
R2 R3
R2
10
DMF, 0 °C - rt
8
11
Figure 2. (a) Synthesis of α,α-dialkylated substrates; (b) Synthesis of differentially substituted substrates
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completion – a peculiar behavior of allylic esters that was discussed briefly in the original report
of Ti(OiPr)4 promoted transesterifiation.22 Conversion of 6 to the corresponding acyl chloride and
addition of allyl alcohol gave low yields of 7a, possibly resulting from undesired ketene
formation. Several mixed anhydride methods were attempted (ethyl chloroacetate, phenyl
chloroacetate and Boc2O) but were plagued by displacement of allyl alcohol by the
corresponding alcohol generated from the mixed anhydride (ethanol, phenol and tert-butanol,
respectively). Armed with the understanding of the strong tendency for the allylic ester products
to undergo transesterification, a new mixed anhydride esterification method was developed
specifically for this work.21 Use of a pivaloyl mixed anhydride suppressed transesterification and
provided synthetically useful amounts of the desired allylic esters; beneficially, this method
required only 1 equivalent of the allylic alcohol, which was quite useful when using more
precious allylic alcohols. Sulfides 7a-f were prepared in good to excellent yield (Table 1).
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Conditions for sulfide oxidation were then explored. The use of Oxone resulted in
23
24
decomposition, while use of FeCl3/H5IO6 or MnSO4/H2O2 resulted largely in sulfoxide
formation. However, chemoselective formation of sulfone was observed using catalytic
ammonium molybdate and aqueous H2O2 as reoxidant.25 Use of tert-butanol as solvent was
critical to suppress transesterification of the product, which was observed when i-PrOH and
MeOH were used. Sulfones 8a-f were prepared in generally excellent yield.
Table 1. Summary of results from preparation of α,α-dialkylated substrates
Entry
1
Sulfide 7
(Yield)
7a
Sulfone 8
(Yield)
8a
R2-X
BnBr
Prod
(Yield)
HO
R1
(89%)
(86%)
9a (98%)
2
MeI
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9b (95%)
9c (92%)
9d (90%)
3
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5
EtI
PrI
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n-hexylBr
9e (48%)
9f (27%)
9g (53%)
6
7
8
9h (89%)
9
7b (80%)
8b (99%)
BnBr
9i (90%)
9j (94%)
10
11
7c (75%)
7d (65%)
8c (85%)
8d (94%)
BnBr
BnBr
9k (89%)
9l (75%)
12
7e (76%)
8e (80%)
BnBr
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Similar to the findings of Tunge and Weaver16 in their studies of α,α-dialkylated phenyl
sulfones, optimal results for dialkylation of BTMP sulfones 8 were achieved using K2CO3 and dry
DMF. The crude reaction mixtures were typically quite clean and required column
chromatography only to remove any residual alkyl halide and DMF. The yields of 9a-l were good
to excellent, especially when activated electrophiles (such as benzyl bromide, methyl iodide,
and allyl bromide) were employed. For less activated electrophiles (such as 1-bromohexane 9e
and 1,6-dibromohexane 9f), the yields were substantially reduced despite longer reaction times
and the addition of tetrabutylammonium iodide. To access substrates that were differentially
substituted (Figure 2b), monoalkylated compounds were prepared by changing the base to
NaH, lowering the temperature and carefully controlling the stoichiometry of the alkyl halide.
Monoalkylated compounds 10a and 10b were prepared in moderate yield. The compounds
were then easily alkylated or chlorinated using K2CO3 in dry DMF to give differentially
substituted 11a-d (Table 2).
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Table 2. Summary of results from preparation of differentially substituted substrates
Entry
1
R2–X
BnBr
Monoalkylated 10
Electrophile
MeI
Product 11
(Yield)
(Yield)
10a (40%)
11a (69%)
11b (79%)
2
3
AllylBr
NCS
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11c (78%)
11d (94%)
4
EtI
MeI
10b (60%)
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The α,α-dibenzyl allyl ester 9a was chosen for optimization studies. Initial experiments
employed Pd2(dba)3 and PPh3 in THF, as was used with the triflone substrate 1. Difficulties were
encountered, however, with the reproducibility of results. The ratio of allylation to protonation
products was highly variable under apparently identical reaction conditions. Additionally, there
were experiments in which there was zero consumption of starting material, whereas the
previous iteration of the experiment had yielded promising results. The issue was eventually
traced to the quality of Pd2(dba)3; in particular, the presence or absence of palladium
nanoparticles. While studying the complex nature of Pd2(dba)3 in solution, Zalesskiy and
Ananikov26 found that commercial samples of the catalyst often contained up to 40% Pd
1
nanoparticles in a wide range of sizes (10-200 nm). They reported a simple H NMR assay to
determine the purity of Pd2(dba)3 (determined by the relative amount of free versus bound dba),
as well as a purification method. The assay of the commercial samples that had been used by
us revealed that even larger amounts of Pd nanoparticles than had been reported were present
(see SI for full details). Purification of Pd2(dba)3 according to that procedure was performed and
while the assay results were improved, the samples still contained substantial quantities of free
dba. (See Supporting Information for assays and photos.)
It was decided to use an alternate palladium precatalyst. We were pleased to observe
that the use of PdCp(1-cinnamyl), developed by Baird and coworkers,27 gave highly
reproducible results. Consistent reactivity was observed in side-by-side reactions as well as
reactions run on different days. Treatment of 9a with PdCp(1-cinnamyl) and PPh3 gave 12a in
reasonable yield; protonation product 13 was also observed. A solvent screen (Table 3, entries
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1-10) showed that ethereal solvents such as THF and diethyl ether promoted the formation of
allylation product 12a (entries 1 and 2), while also minimizing the formation of protonation
product 13. Ligand screening (Table 3, entries 11-24) was performed in THF at room
temperature to improve the allylation to protonation ratio. A range of mono- and bidentate
ligands was evaluated. The use of XANTPHOS (entry 24) yielded the most promising results,
but the ratio of allylation to protonation products was not yet synthetically useful. Finally,
increasing the reaction temperature to 50 °C using XANTPHOS as ligand resulted in 92:8 ratio
of allylation (12a) to protonation (13) products.
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Table 3: Optimization of solvent and ligand
PdCp(1-cinnamyl) (10 mol%)
Monodentate Ligand (20 mol%)
or Bidentate Ligand (10 mol%)
O
O O
S
O O
S
O O
S
H
Ar
O
Ar
Ar
+
solvent, rt
0.03 M, 18 h
Ph Ph
Ph Ph
12a
Ph Ph
9a
13
Entry
Solvent
THF
Liganda
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
%9ab %12ab %13b
1
2
0
81
81
0
19
19
0
Et2O
0
3
PhMe
DCM
100
0
4
33
0
67
0
5
1,4-Dioxane
DCE
100
100
100
100
100
0
6
0
0
7
MeCN
DMF
0
0
8
0
0
9
DME
0
0
10
MTBE
0
100
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THF
THF
THF
THF
THF
THF
THF
THF
THF
BINAP
MeO-BIPHEP
dppf
0
41
16
0
59
84
0
0
100
100
0
DPEphos
SEGPHOS
CyJohnPhos
P(2-furyl)3
dppb
0
0
10
11
12
13
14
15
16
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21
22
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16
0
84
0
100
100
100
0
0
0
0
0
0
100
PPh2
PPh2
PBu3∙HBF4
MeO
20
21
THF
THF
100
100
0
0
0
0
P
3
MeO
22
23
24
25
THF
THF
THF
THFc
DACH-phenyl
iPr-PHOX
XANTPHOS
XANTPHOS
100
100
0
0
0
0
0
84
92
16
8
0
aLigand structures shown in SI. Ratios determined by relative integration of H NMR
b
1
signals. cReaction was conducted at 50 °C.
Using these optimized conditions, the substrate scope was evaluated (Table 4). It was
found that α,α-dialkylated allylic esters (entries 1-8) were converted to the desired allylation
products in good yields. Substitution in the 2-position of the allyl group resulted in a reduced
yield (entry 9) but was well tolerated in the 3-position (entry 10) in the crotyl-based substrate.
Likewise, the cinnamyl-based substrate (entry 12) resulted in a good yield. Substitution in the 1-
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position (entry 11) yielded the linear product. However, the yield was appreciably lower than for
the crotyl analogue (51% vs 77%). Protonation product 13 was also isolated (16%). The
corresponding branched product was not observed in any reactions. The differentially
substituted substrates (entries 13-16) gave excellent yields with one exception. Entry 16,
substituted with a methyl and an ethyl group, gave a substantially reduced yield in comparison
with the other substrates. It is interesting to compare this yield (57%) to that of the diethyl
substrate 9c (entry 2) (76%). This small structural change in the substrate resulted in a dramatic
drop in yield. In addition, the cycloheptyl substrate 9f (entry 7) can be viewed as similar to 9c,
though less sterically demanding because of the lack of rotational freedom of the a-substituents.
In light of this, the attenuated yield of 9f (65%) further establishes a relationship between steric
demand of the a-substituents and yield.
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Table 4. Substrate Scope
PdCp(1-cinnamyl) (10 mol%)
O
O O
S
O O
S
XANTPHOS (10 mol%)
R1
Ar
R1
Ar
O
R2 R3
THF, 50 °C, 30 min
R2 R3
9a-l; 11a-d
12a-l; 14a-d
Entry
1-8
Substrate
Product
% Yielda
a R2,R3 = CH2Ph, 79%
b R2,R3 = Me, 0%
O
O O
S
O
O
S
Ar
Ar
O
R2 R3
R2 R3
c R2,R3 = Et, 76%
12a-h
9a-h
d R2,R3 = n-Pr, 82%
e R2,R3 = hexyl, 86%
f R2,R3 = -(CH2)6-, 65%
g R2,R3 = allyl, 85%
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h R2,R3 = CH2CO2Et, 88%
5
6
7
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9
9
69%
O
O
S
O
O
S
O
Ar
Ar
O
Bn Bn
Bn Bn
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12i
9i
O
O
S
O
10
11
O
S
77%
O
Ar
Ar
O
Bn Bn
Bn Bn
12j
9j
O
S
O
51% (+16% 13)
O
O
S
O
Ar
Ar
O
Bn Bn
Bn Bn
12j
9k
O
O
O
S
12
13
76%
90%
O
O
S
Ar
O
Ph
Ar
Bn Bn
9l
Ph
12l
O
O
S
O
Ar
O
Ph
11a
14a
O
14
15
84%
90%
O
O
O
S
O
S
Ar
Ar
O
Ph
Ph
14b
11b
O
O
O
O
S
O
S
Ar
Ar
O
Cl
Cl
Ph
14c
Ph
11c
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16
O
S
57%
O
O
O
S
O
Ar
Ar
O
7
8
9
14d
a% Yield refers to purified, isolated material.
This difference in product distribution based on small structural changes was further
11d
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amplified by the α,α-dimethyl substrate 9b. Even after prolonged reaction times, the optimized
conditions only resulted in recovered starting material. It was noted, however, that the recovery
was never quantitative. We theorized that a catalytically inactive intermediate might be formed
with this substrate, thereby consuming the palladium early in the reaction. Analysis of the crude
1
mixtures by H NMR suggested that there was a small amount of allyl-containing material that
was neither starting material, nor expected products. All attempts at isolation of this material
were unsuccessful.
The complete consumption of dimethyl substrate 9b was achieved in 5 h by raising the
temperature to reflux; however, an interesting product distribution was obtained (Figure 3). In
addition to allylation 12b (53%) and protonation 15 (16%) products, two additional products
were observed. A cyclopropylation product 16 (7%), as well as a pseudodimeric product 17
(24%) were isolated and characterized. Dramatic changes in reactivity based on small structural
changes suggest a narrow kinetic window for different pathways leading to these products.
Lupton and coworkers invoked a similar argument to explain the unexpected side products
O O
S
O O
S
H
Ar
Ar
O
O O
S
PdCp(1-cinnamyl) (10 mol%)
PPh3 (20 mol%)
12b
F3C
15
O
THF, 65 °C
5 h
O O
S
O O
S
O O
S
CF3
Ar
Ar
Ar
9b
16
17
Figure 3. Product distribution from anomalous substrate 9b
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obtained from the decarboxylative allylation of propargyl carbazole allyl carbonates when subtle
protecting group changes were made.28
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9
There are a few examples of cyclopropyl products from allylation-type processes. Hegedus
reported in 1980 that ester enolates attacked the central carbon of a (π-allyl)palladium
complexes in THF/HMPA/Et3N to give excellent yields of cyclopropane products29 and Hoffmann
reported on the formation of cyclopropanes via attack on the central carbon of (π-allyl)palladium
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34
complexes by a variety of stabilized nucleophiles in the mid-1990s.30–33 Satake reported the
cyclopropylation of silyl ketene acetals by allyl acetate using an allylpalladium-pyridinylpyrazole
complex. The allylation product was competitive. Finally, Hou reported on amide enolates
attacking allylic carbonates in an enantioselective fashion using a Pd catalyst bearing a
specialized ferrocenyl-based phosphine ligand.35 We believe the work described in this Article
to be the first report of an intramolecular decarboxylative cyclopropylation.
The pseudodimeric product 17 appears to be unprecedented. Stoltz and coworkers have
shown that a Pd(II), 16-electron species with a σ-bound, η1-allyl ligand is the resting state in the
decarboxylative allylation of β-ketoesters.36 By invoking a similar intermediate (18), which would
originate from oxidation insertion of Pd(0) to 9b, one could envision a carboxylate-assisted C-H
O O
S
H
H
C
H
O O
S
Ar
Pd
O
Ar
O O
S
O
Pd
O
O O
S
O
O O
S
H
O
Ar
O O
S
Pd
12b
Ar
Ar
O
H
Ar
19
18
–CO2
O O
S
O O
S
O O
S
O O
Ar
Ar
+
Pd(0)
Ar
S
Pd
20
Ar
17
Figure 4. Possible mechanism for formation of side product 17
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activation of the allylation product 12b via a concerted metalation deprotonation (CMD)-type
mechanism (Figure 4).37 While this CMD step is theoretically reversible, it is also possible to
form a second carboxylate-bound intermediate 19; this step would be irreversible since
protonation of the allyl ligand would yield propene. Subsequent decarboxylation of 19 and
reductive elimination from intermediate 20 would result in the pseudodimer 17 and regenerate
Pd(0). It is currently unclear if the formation of these products offer insight into the mechanism
of decarboxylative allylation, or if this is unique to substrate 9b. The differences in reactivity and
product distributions for substrates with very small structural changes (9b vs 11d vs 9c)
suggests that the atypical products are accessible via narrow kinetic window controlled by the
steric and/or electronic nature of the substrate.
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Conclusions
A palladium-catalyzed decarboxylative allylation of electron-deficient sulfones has been
developed. The presence of nanoparticles in commercial Pd2(dba)3 was found to be detrimental
to this chemistry. Use of an alternate palladium precatalyst, PdCp(1-cinnamyl), was critical for
reactivity and reproducibility. Solvent and ligand optimization were used to minimize the
formation of the undesired protonation side product. The reaction gives homoallylic products in
good to excellent yield at 50 °C with short reaction times. The major exception to this trend
occurs when both α-positions contain methyl groups. At room temperature, it is proposed that a
catalytically inactive species is formed, thus shutting down the catalytic cycle. The use of a
higher temperature and a longer reaction time permitted the consumption of the starting material
but gave a previously unobserved product distribution. Allylation, protonation, cyclopropylation
and pseudodimeric products were isolated and characterized. This work highlights that the
mechanism of palladium-catalyzed decarboxylative allylation is likely more complex than
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previously accepted and suggests that multiple competing pathways may be occurring
simultaneously.
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Experimental Section
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General Methods: All reagents were purchased from commercial sources and were used as
received, without further purification, unless otherwise noted. DCM, toluene and Et2O were
distilled from CaH2 immediately prior to use. DME, MTBE, MeCN and DMF were distilled from
CaH2 and stored over activated 4 Å molecular sieves under a nitrogen atmosphere. THF was
distilled from lithium aluminum hydride or sodium/benzophenone prior to use. All alkyl halides
were purified immediately prior to use by passage through a short column of activated basic
alumina in a Pasteur pipet fitted with a cotton plug. Reactions were monitored by thin-layer
chromatography (TLC) using glass-backed extra hard layer (60 Å) TLC plates from Silicycle and
visualized by fluorescence quenching under ultraviolet (UV) light and/or staining using
potassium permanganate or ceric ammonium nitrate. Microwave heating was performed in
glass vials (crimp-sealed with a septum liner and a metal fastener) in a Biotage Initiator 2.5
instrument with temperature monitored by an external surface sensor; the absorption level set to
normal. Flash column chromatographic (FCC) purification of products was performed either on
Silia-P Flash silica gel from Silicycle using a forced flow of eluent by the method of Still et al.38
or by automated chromatography on a Biotage Isolera One equipped with a UV detector.
Concentration in vacuo refers to rotary evaporation with a 40 °C water bath at the appropriate
pressure for the given solvent. Yields refer to purified and spectroscopically pure compounds
unless indicated as crude. NMR spectra were recorded on a Bruker Avance 300 MHz or Bruker
Avance III 400 MHz or JEOL ECZS 400 MHz spectrometer. Chemical shifts are reported in
parts per million (ppm). Spectra are referenced to the internal standard tetramethylsilane (TMS)
(0.00 ppm). 19F NMR spectra are referenced to trifluorotoluene (–63.7 ppm). Infrared (IR)
spectra were recorded on a Varian 1000 Scimitar Series or an ABB Bomem MB series
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spectrometer and absorptions are given in wavenumbers (cm-1). High resolution mass
spectrometry (HRMS) was performed on a Kratos Concept-11A mass spectrometer with an
electron beam of 70 eV at the Ottawa-Carleton Mass Spectrometry Center at University of
Ottawa, on a Bruker Maxis Impact Quadrupole-Time of Flight Mass Spectrometer in positive ESI
mode at the McGill Chemistry Mass Spectrometry Center, or a SciEx Qstar XL hybrid
quadrupole time-of-flight mass spectrometer in positive ESI mode at the Carleton Mass
Spectrometry Center. Compounds 1-2,15 3-5,16 6, 7a-c, and 7e21 were prepared and
characterized as previously reported.
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General Procedure for Esterification: A Biotage microwave vial was charged with a Teflon-
coated stirbar and carboxylic acid 6 (1.0 equiv). DCM (0.5 M relative to carboxylic acid) was
added to dissolve and the vial was sealed with a crimp top lid equipped with a septum. In
sequence, pivaloyl chloride (1.0 equiv), base (2.0 equiv) and alcohol (1.0 equiv) were added by
syringe through the septum. In the case of solid bases or alcohols, the final sealing of the tube
was delayed until addition was complete. The vial was heated for the indicated time at the
indicated temperature in the microwave reactor. The reaction mixture was then diluted with Et2O
(3× the volume of DCM), causing a white precipitate to form. This was washed with ice cold 0.1
M H2SO4 (equal to volume of DCM). The layers were separated and the aqueous phase was
extracted again with Et2O. The combined organic extracts were washed once with brine, then
dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was
purified via FCC using 5% EtOAc/hexanes.
But-3-en-2-yl-2-((3,5-bis(trifluoromethyl)phenyl)thio)acetate (7d): Reaction Time &
Temperature: 120 min, 80 °C. Base: Pyridine. Scale: 2.5 mmol. Yield: 579.0 mg, 65% (colorless
oil). 1H NMR (CDCl3, 400 MHz): δ 7.80 (s, 2H), 7.69 (s, 1H), 5.77 (ddd, J = 16.8, 10.4, 6.0 Hz,
1H), 5.37 (quintet, J = 6.4 Hz, 1H), 5.23 (d, J = 16.8 Hz, 1H, unresolved additional fine
coupling), 5.15 (d, J = 10.8 Hz, 1H, unresolved additional fine coupling), 3.73 (s, 2H), 1.30 (d, J
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= 6.4 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz): 167.9, 139.0, 136.6, 132.2 (q, J = 34 Hz), 128.5
(d, J = 3 Hz), 122.9 (q, J = 271 Hz), 120.1 (quintet, J = 4 Hz), 116.9, 73.1, 35.7, 19.6. 19F NMR
(376 MHz): δ -64.0. IR (film): 3091, 2988, 2937, 1735, 1648, 1618, 1457, 1414, 1355, 1287,
1187, 1044. HRMS (ESI-TOF): m/z [M+Na]+ Calcd for C14H12F6NaO2S: 381.0360; Found:
381.0367.
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General Procedure for Sulfide Oxidation: Volumes are based on 1 mmol scale. The sulfide
(1 equiv.) was dissolved in tert-butanol (0.4 M relative to sulfide), then ammonium molybdate
tetrahydrate (0.1 equiv.) was added. Hydrogen peroxide (35% in water, 4 equiv.) was added via
syringe, at which point the reaction mixture turned bright yellow. The reaction was stirred at
room temperature until completion, as shown by TLC. The solvent was evaporated in vacuo,
then the residue was partitioned in an equal volume of sat. NaHCO3(aq) (10 mL) and EtOAc (10
mL). The layers were separated, then the aqueous phase was extracted twice with EtOAc (10
mL each). The combined organic extracts were washed once with brine (15 mL), then dried over
anhydrous MgSO4, filtered and concentrated in vacuo to yield a colorless or light yellow oil. Most
substrates solidified to a waxy, off-white solid upon standing. Typically, the purity after this step
was excellent and the compounds were used without further purification.
Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)acetate (8a): Scale: 9.0 mmol. Yield: 2.93 g,
86% (white solid). 1H NMR (CDCl3, 400 MHz): δ 8.42 (s, 2H), 8.19 (s, 1H), 5.83 (ddt, J = 17.2,
10.4, 6.0 Hz, 1H), 5.31 (2 overlapping dd, 2H), 4.61 (d, J = 6.0 Hz, 2H – some unresolved fine
splitting observed), 4.24 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz): 161.5, 141.3, 133.1 (q, J = 34
Hz), 130.3, 129.4 (unresolved fine splitting), 128.0 (quintet, J = 3 Hz), 122.3 (q, J = 272 Hz),
120.4, 67.3, 60.6. 19F NMR (376.5 MHz): δ -63.9. IR (film): 3086, 2950, 1740, 1361, 1283, 1151.
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C13H10F6NaO4S 399.0102; Found 399.0091.
2-Methylallyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)acetate (8b): Scale: 1.4 mmol.
Yield: 539 mg, 99% (white solid). 1H NMR (CDCl3, 400 MHz): δ 8.42 (s, 2H), 8.18 (s, 1H), 4.96
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(m, 1H), 4.95 (m, 1H), 4.53 (s, 2H), 4.25 (s, 2H), 1.71 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): δ
161.5, 141.3, 138.3, 133.2 (q, J = 35 Hz), 129.4 (d, J = 4 Hz), 128.0 (unresolved fine splitting),
122.3 (q, J = 272 Hz), 114.9, 70.0, 60.6, 19.3. 19F NMR (376.5 MHz): δ -63.9. IR (film): 3088,
2949, 1731, 1362, 1189, 1152, 1129, 1101. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C14H12F6NaO4S 413.0258; Found 413.0238.
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But-2-en-1-yl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)acetate (8c): Scale: 1.1 mmol.
Yield: 364.3 mg, 85% (white solid). 1H NMR (CDCl3, 400 MHz): δ 8.42 (s, 2H), 8.19 (s, 1H), 5.81
(m, 1H), 5.49 (dtq, J = 15.2, 6.8, 1.6 Hz, 1H), 4.68 (d, J = 7.2 Hz, 2H, cis isomer, 6%), 4.56 (d, J
= 6.8 Hz, 2H trans isomer, 94%), 4.21 (s, 2H), 1.72 (dm, J = 6.4 Hz, unresolved fine coupling,
3H, trans isomer), 1.68 (m, 3H, cis isomer). 13C{1H} NMR (CDCl3, 100 MHz): δ 161.5, 141.3,
133.1 (q, J = 34 Hz), 129.4 (d, J = 3 Hz), 127.8 (unresolved fine splitting), 122.3 (q, J = 272 Hz),
123.2, 67.5, 60.6, 17.7. 19F NMR (376.5 MHz): δ -63.9. IR (film): 3088, 3012, 2951, 1731, 1396,
1363, 1285, 1285, 1153, 1127, 1101. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C14H12F6NaO4S
413.0258; Found 413.0246.
But-3-en-2-yl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)acetate (8d): Scale: 1.3 mmol.
Yield: 477.0 mg, 94% (white solid). 1H NMR (CDCl3, 400 MHz): δ 8.41 (s, 2H), 8.18 (s, 1H), 5.73
(ddq, J = 17.2, 10.4, 6.4 Hz, 1H), 5.33 (dt, J = 6.4, 6.4 Hz, 1H), 5.24 (d, J = 17.2 Hz, 1H), 5.18
(d, J = 10.4 Hz, 1H), 4.21 (s, 2H), 1.29 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz):
161.0, 141.3, 135.9, 133.1 (q, J = 34 Hz), 129.4 (d, J = 4 Hz), 127.9 (quintet, J = 4 Hz), 122.3
(q, J = 272 Hz), 117.7, 74.3, 60.9, 19.5. 19F NMR (376 MHz): δ -63.9. IR (film): 3083, 3012,
2952, 1729, 1363, 1283, 1151, 1135, 1100. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C14H12F6NaO4S 413.0258; Found 413.0248.
Cinnamyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)acetate (8e): Scale: 1.5 mmol. Yield:
546.4 mg, 80% (white solid). 1H NMR (CDCl3, 400 MHz): δ 8.43 (s, 2H), 8.15 (s, 1H), 7.29-7.38
(mult, 5H), 6.64 (d, J = 16.0 Hz, some broadening of peaks, 1H), 6.16 (dt, J = 16.0, 6.8 Hz, 1H),
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4.77 (dd, J = 6.4, 0.8 Hz, 2H), 4.25 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 161.6, 141.3,
136.2, 135.5, 133.6 (q, J = 34 Hz), 129.4 (d, J = 4 Hz), 128.7, 128.6, 127.9 (unresolved fine
splitting), 126.7, 122.3 (q, J = 272 Hz), 120.8, 67.3, 60.5. 19F NMR (376 MHz): δ -63.9. IR (film):
3088, 3029, 2996, 2940, 1738, 1364, 1337, 1315, 1279, 1156, 1137, 1102. HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C19H14F6NaO4S 475.0415; Found 475.0406.
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General Procedure for α,α-Dialkylation of Sulfones: Volumes are based on 1 mmol scale.
An oven-dried round-bottom flask was charged with the appropriate sulfone (1 equiv). Under an
inert atmosphere, dry DMF (10 mL) (0.1 M relative to sulfone) was added via syringe. Finely
powdered anhydrous K2CO3 (5 equiv) was added to the reaction mixture in a single portion. The
reaction mixture was allowed to stir for 15 minutes at room temperature. Typically, the reaction
mixture turned yellow in color during this time. Purified alkyl halide (5 equiv, if volatile; 2.3 equiv,
if not) was added via syringe to flask. The reaction mixture stirred at room temperature until
deemed complete by TLC. The reaction mixture was diluted with water (50 mL) (5x volume of
DMF), then extracted five times with EtOAc (10 mL each). The combined organic extracts were
washed once with water, once with brine, then dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The material was purified by FCC (typically 5% EtOAc/hexane) to give
the desired product.
Allyl 2-benzyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-phenylpropanoate (9a): Scale:
6.64 mmol. Yield: 3.66 g, 98% (colorless oil, may solidify upon standing). 1H NMR (CDCl3, 400
MHz): δ 8.16 (s, 2H), 8.02 (s, 1H), 7.21 – 7.22 (m, 10H), 5.81 (ddt, J = 17.2, 10.8, 6.0 Hz, 1H),
5.34 (br s, 1H), 5.28 – 5.30 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 3.52 (d, J = 14.0 Hz, 2H), 3.44 (d,
J = 14.0 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz): 167.1, 141.4, 133.7, 132.1 (q, J = 34 Hz),
131.04 (d, J = 4 Hz), 130.95, 130.0, 122.4 (q, J = 271 Hz), 120.7, 79.4, 67.2, 39.6. 19F NMR
(376.5 MHz): δ –63.6. IR (film): 3091, 3070, 3035, 2936, 1738, 1650, 1625, 1603, 1497, 1456,
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1427, 1357, 1334, 1280, 1186, 1145, 1098, 1032. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C27H22F6NaO4S 579.1041; Found 579.1054.
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Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-2-methylpropanoate (9b): Scale: 0.66
mmol. Yield: 252.9 mg, 95% (colorless oil, may solidify). 1H NMR (CDCl3, 400 MHz): δ 8.32 (s,
2H), 8.18 (s, 1H), 5.86 (ddt, J = 16.3, 10.5, 5.9 Hz, 1H), 5.39 – 5.26 (m, 2H), 4.62 (dt, J = 5.9,
1.3 Hz, 2H), 1.69 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz): 168.0, 138.7, 132.5 (q, J = 35 Hz),
130.9 (d, J = 3 Hz), 130.4, 127.7 (quintet, J = 3 Hz), 122.4 (q, J = 272 Hz), 119.9, 69.9, 67.1,
20.0. 19F NMR (376.5 MHz): δ –63.8. IR (film): 3090, 2995, 2950, 1745, 1651, 1626, 1606,
1470, 1393, 1360, 1334, 1316, 1281, 1181, 1137, 1097. HRMS (ESI/Q-TOF) m/z: [M+Na]+
Calcd for C15H14F6NaO4S 427.0415; Found 427.0418.
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Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-2-ethylbutanoate (9c): Scale: 0.66 mmol.
Yield: 261.8 mg, 92% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.29 (s, 2H), 8.15 (s, 1H),
5.83 (ddt, J = 17.2, 10.8, 6.0 Hz, 1H), 5.31 (d, J = 17.2 Hz, 1H), 5.28 (d, J = 10.4 Hz, 1H), 4.58
(d, J = 6.0 Hz), 2.27 (dq, J = 14.8, 7.6 Hz, 2H), 2.01 (dq, J = 14.8, 7.2 Hz, 2H), 1.09 (t, J = 7.2
Hz). 13C{1H} NMR (CDCl3, 100 MHz): 167.2, 139.9, 132.4 (q, J = 34 Hz), 130.8 (d, J = 3 Hz),
130.4, 127.4 (quintet, J = 3 Hz), 122.4 (q, J = 272 Hz), 119.9, 77.8, 66.9, 23.5, 8.7. 19F NMR
(376.5 MHz): δ -63.8. IR (film): 3089, 2983, 2950, 2892, 1743, 1729, 1453, 1359, 1332, 1315,
1281, 1228, 1186, 1145, 1096. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C17H18F6NaO4S
455.0728; Found 455.0726.
Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-2-propylpentanoate (9d): Scale: 1.3 mmol.
Yield: 538.2 mg, 90% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 5.83 (ddt, J = 16.4, 10.4, 6.0
Hz, 1H), 5.27 – 5.33 (m, 2H), 4.56 (d, J = 6.0 Hz, 2H), 2.11 (m, 2H), 1.90 (m,, 2H), 1.67 – 1.56
(m, 2H), 1.40 – 1.29 (m, 2H), 0.95 (t, J = 7.3 Hz, 6H). 13C{1H} NMR (CDCl3, 100 MHz): 167.4,
139.7, 132.3 (q, J = 35 Hz), 130.8 (d, J = 3 Hz), 130.5, 127.4 (quintet, J = 3 Hz), 122.4 (q, J =
272 Hz), 119.8, 66.8, 32.7, 17.5, 14.3. 19F NMR (376.5 MHz): δ –63.8. IR (film): 3089, 2970,
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2939, 2879, 1745, 1731, 1651, 1626, 1605, 1467, 1359, 1334, 1315, 1281, 1187, 1149, 1098.
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H22F6NaO4S 483.1041; Found 483.1032.
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Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-2-hexyloctanoate (9e): Scale: 0.53 mmol.
Yield: 139.5 mg, 48% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 2H), 8.14 (s, 1H),
5.83 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.27 – 5.33 (m, 2H), 4.56 (d, J = 6.0 Hz, 2H), 2.08 – 2.15
(m, 2H), 1.89 - 1.95 (m, 2H), 1.20 – 1.37 (m, 16H), 0.86 – 0.88 (m, 6H). 13C{1H} NMR (CDCl3,
100 MHz): 167.5, 139.7, 132.4 (q, J = 43 Hz), 130.8 (unresolved fine splitting), 130.5, 127.5,
122.4 (q, J = 280 Hz), 120.0, 76.7, 66.9, 31.3, 30.6, 29.6, 23.9, 22.5, 14.0. 19F NMR (376.5
MHz): δ –63.8. IR (film): 2959, 2926, 1732,1359, 1280, 1186, 1146, 1101. HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C25H34F6NaO4S 567.1980; Found 567.1992.
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Allyl 1-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)cycloheptanecarboxylate (9f): Scale: 0.40
mmol. Yield: 50.0 mg, 27% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.25 (s, 2H), 8.14 (s,
1H), 5.85 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.32 (d, J = 17.6 Hz + additional unresolved fine
coupling, 1H), 5.29 (d, J = 10.0 Hz + additional unresolved fine coupling, 1H), 4.61 (d, J = 6.0
Hz, 2H), 2.25 – 2.40 (m, 4H), 1.81 – 1.87 (m, 2H), 1.43 – 1.64 (m, 6H). 13C{1H} NMR (CDCl3,
100 MHz): 167.9, 139.1, 132.4 (q, J = 35 Hz), 130.8 (unresolved fine coupling), 130.5, 127.5
(app t, J = 4 Hz), 122.4 (q, J = 272 Hz), 119.9, 77.6, 67.1, 30.9, 29.2, 23.4. 19F NMR (376.5
MHz): δ –63.8. IR (film): 3086, 2934, 2863, 1743, 1732, 1464, 1359, 1334, 1315, 1280, 1181,
1142, 1102. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H20F6NaO4S 481.0884; Found
481.0883.
2-allyl 1,3-diethyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)propane-1,2,3-tricarboxylate
(9g): Scale: 0.80 mmol. Yield: 233.0 mg, 53% (white solid). 1H NMR (CDCl3, 400 MHz): δ 8.33
(s, 2H), 8.20 (s, 1H), 5.83 (ddt, J = 17.2, 10.8, 6.0 Hz, 1H), 5.31 (overlapping doublets, 2H),
4.61 (d, J = 6.0 Hz, 2H), 4.22 – 4.17 (m, 4H), 3.44 (AB, J = 16.8 Hz, 2H), 3.36 (AB, J = 16.8 Hz,
2H), 1.31 (t, J = 7.2 Hz, 6H). 13C{1H} NMR (CDCl3, 100 MHz): 168.9, 165.7, 137.3, 132.8 (q, J =
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35 Hz), 131.1 (unresolved fine coupling), 130.2, 128.3, 122.3 (q, J = 272 Hz), 120.0, 72.6, 67.7,
61.5, 33.3, 13.9. 19F NMR (376.5 MHz): δ –63.9. IR (film): 3088, 2987, 2945, 2910, 1741, 1650,
1626, 1606, 1449, 1416, 1397, 1359, 1344, 1282, 1186, 1149, 1106, 1062, 1029. HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C21H22F6NaO8S 571.0837; Found 571.0845.
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Allyl 2-allyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)pent-4-enoate (9h): Scale: 1.3 mmol.
Yield: 527.3 mg, 89% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.30 (s, 2H), 8.16 (s, 1H),
5.89 – 5.78 (m, 3H), 5.35 – 5.18 (m, 6H), 4.59 (d, J = 6.0 Hz, 2H), 2.93 (dd AB, J = 14.4, 6.8 Hz,
2H), 2.80 (dd AB, J = 14.4, 6.8 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz): 166.5, 139.4, 132.5
(q, J = 34 Hz), 130.9 (d, J = 3 Hz), 130.3, 127.7 (quintet, J = 3 Hz), 122.4 (q, J = 271 Hz), 120.9,
76.0, 67.2, 35.0. 19F NMR (376.5 MHz): δ –63.8. IR (film): 3087, 3026, 2987, 2954, 1859, 1733,
1641, 1626, 1605, 1439, 1359, 1339, 1316, 1281, 1214, 1188, 1147, 1100. HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C19H18F6NaO4S 479.0728; Found 479.0730.
2-Methylallyl 2-benzyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-phenylpropanoate
(9i): Scale: 0.51 mmol. Yield: 261.6 mg, 90% (white solid). 1H NMR (CDCl3, 400 MHz): δ 8.14
(s, 2H), 8.01 (s, 1H), 4.97 (s, 2H), 4.54 (s, 2H), 3.54 (d, J = 14.0 Hz, 2H), 3.46 (d, J = 14.0 Hz,
2H), 1.62 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): 167.2, 141.4, 138.0, 133.7, 132.2 (q, J = 35
Hz), 130.9, 128.3, 127.7, 127.2 (app t, J = 3 Hz), 122.4 (q, J = 272 Hz), 115.3, 79.4, 69.9, 39.5,
19.5. 19F NMR (376.5 MHz): δ –63.6. IR (film): 3090, 3035, 2935, 1736, 1660, 1625, 1603,
1497, 1455, 1357, 1335, 1315, 1280, 1187, 1147, 1098, 1033. HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C28H24F6NaO4S 593.1197; Found 593.1184.
But-2-en-1-yl 2-benzyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-phenylpropanoate
(9j): Scale: 0.31 mmol. Yield: 166.3 mg, 94% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.16
(s, 2H), 8.02 (s, 1H), 7.21 (br s, 10H), 5.77 – 5.85 (m, 1H – mixture of cis/trans), 5.44 – 5.52 (m,
1H – mixture of cis/trans), 4.70 (d, J = 6.8 Hz, 2H, minor cis isomer – 5 %), 4.56 (d, J = 6.8 Hz,
2H, major trans isomer – 95%), 3.51 (d, J = 14.0 Hz, 2H), 3.42 (d, J = 14.0 Hz, 2H), 1.72 (d, J =
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6.4 Hz, 3H, major trans isomer), 1.68 (d, J = 7.6 Hz, 3H, minor cis isomer) . 13C{1H} NMR
(CDCl3, 100 MHz): 167.1, 141.5, 133.8, 133.7, 132.0 (q, J = 34 Hz), 130.9 (broadened shoulder;
overlapping peak likely), 128.2, 127.6, 127.1 (app t, J = 4 Hz), 122.3 (q, J = 272 Hz), 123.1,
79.2, 67.3 (major isomer), 61.9 (minor isomer), 39.5, 17.6 (major isomer), 13.0 (minor isomer).
19F NMR (376.5 MHz): δ -63.6. IR (film): 3091, 3066, 3034, 2943, 1733, 1497, 1456, 1357,
1335, 1315, 1280, 1186, 1145, 1098. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C28H24F6NaO4S
593.1197; Found 593.1195.
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But-3-en-2-yl 2-benzyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-phenylpropanoate
(9k): Scale: 0.49 mmol. Yield: 249.6 mg, 89% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.19
(s, 2H), 8.03 (s, 1H), 5.71 (ddd, J = 17.2, 10.4, 6.4 Hz, 1H), 5.39 (dq, J = 6.4, 6.4 Hz, 1H), 5.23
(d, J = 17.6 Hz, 1H), 5.18 (d, J = 10.8 Hz, 1H), 3.42 – 3.55 (m, 4H), 1.27 (d, J = 6.4 Hz, 3H).
13C{1H} NMR (CDCl3, 100 MHz): 166.9, 141.3, 135.7, 133.74, 133.69, 132.0 (q, J = 5 Hz), 131.0
(d, J = 3 Hz), 130.9, 128.1, 127.59, 127.55, 127.1 (app t, J = 3 Hz), 122.4 (q, J = 271 Hz),
117.9, 79.1, 74.7, 39.5, 39.3, 19.3. 19F NMR (376 MHz): δ - 63.6. IR (film): 3091, 3067, 3035,
2987, 2936, 1726, 1625, 1603, 1497, 1456, 1358, 1336, 1315, 1280, 1187, 1145, 1099, 1034.
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C28H24F6NaO4S 593.1197; Found 593.1201.
Cinnamyl 2-benzyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-phenylpropanoate (9l):
Scale: 0.19 mmol. Yield: 89.6 mg, 75% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.18 (s,
2H), 8.00 (s, 1H), 7.34 – 7.35 (m, 5H), 7.19 – 7.22 (m, 10H), 6.62 (d, J = 16.0 Hz, 1H), 6.13 (dt,
J = 16.0, 6.8 Hz, 1H), 4.78 (d, J = 6.4 Hz, 2H), 3.53 (d, J = 14.0 Hz, 2H), 3.45 (d, J = 14.0 Hz,
2H). 13C{1H} NMR (75 MHz): 167.3, 141.4, 136.5, 135.6, 133.7, 132.1 (q, J = 35 Hz), 131.1 (d, J
= 3 Hz), 131.0, 128.7, 128.6, 128.3, 127.8, 127.2 (quintet, J = 4 Hz), 126.8, 122.4 (q, J = 273
Hz), 120.6, 79.3, 67.2, 39.7.19F NMR (376.5 MHz): δ –63.6. IR (film): 3089, 3030, 2957, 1731,
1357, 1279, 1185, 1144, 1096, 1096. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C33H26F6NaO4S
655.1354; Found 655.1363.
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General Procedure for Monoalkylation of Sulfones: Volumes are based on 1 mmol scale.
A dry round-bottom flask was charged with the appropriate sulfone (1.0 mmol, 1 equiv). Under
an inert atmosphere, dry DMF (10 mL) (0.1 M relative to sulfone) was added via syringe.
Sodium hydride (dry) was added (1.1 equiv) to this solution in 2-3 portions. The reaction mixture
was allowed to stir for 30 minutes at room temperature. Typically, the reaction mixture turned
yellow in color during this time. All alkyl halides were purified immediately prior to use by
passage over a short column of activated basic alumina in a Pasteur pipet fitted with a cotton
plug. Purified alkyl halide (1.2 equiv. for BnBr; 1.3 equiv. for EtI) was added via syringe to the
reaction flask. The reaction mixture was stirred at room temperature until deemed complete by
TLC. The reaction mixture was quenched with saturated NH4Cl(aq) (2 mL), then diluted with water
(50 mL) (5x volume of DMF), then extracted five times with EtOAc (10 mL each). The combined
organic extracts were washed once with water, once with brine, then dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The material was purified by FCC (typically 5%
EtOAc/hexane) to afford the desired product.
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Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-phenylpropanoate (10a): Scale: 0.53
mmol. Yield: 99.7 mg, 40% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.33 (s, 2H), 8.18 (s,
1H), 7.22 – 7.29 (m, 3H), 7.13 – 7.15 (m, 2H), 5.61 (ddt, J = 17.2, 10.8, 6.0 Hz, 1H), 5.15 (d, J =
10.8 Hz, 1H), 5.11 (dd, J = 17.2, 1.2 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.31 (dd, J = 11.2, 3.6
Hz, 1H), 3.50 (dd, J = 13.6, 3.6 Hz, 1H), 3.18 (dd, J = 11.6, 13.2 Hz, 1H). 13C{1H} NMR (CDCl3,
100 MHz): δ 164.5, 139.8, 134.5, 133.0 (q, J = 34 Hz), 130.9, 129.9 (d, J = 4 Hz), 129.0, 128.9,
128.0 (app t, J = 3 Hz), 127.7, 122.3 (q, J = 272 Hz), 119.8, 72.2, 67.0, 32.6. 19F NMR (376
MHz): δ –63.8. IR (film): 3092, 3038, 2949, 1742, 1360, 1342, 1318, 1281, 1189, 1145, 1104.
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H16F6NaO4S 489.0571; Found 489.0570.
Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)butanoate (10b): Scale: 0.53 mmol. Yield:
128.4 mg, 60% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.32 (s, 2H), 8.17 (s, 1H), 5.80 (ddt,
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J = 17.2, 10.4, 6.4 Hz, 1H), 5.31 (d, J = 17.2 Hz, 1H), 5.27 (d, J = 10.8 Hz, 1H), 4.60 (d, J = 6.0
Hz, 2H), 3.98 (dd, J = 11.2, 3.6 Hz, 1H), 2.13 – 2.23 (m, 1H), 1.86 – 1.98 (m, 1H), 1.04 (t, J =7.2
Hz). 13C{1H} NMR (CDCl3, 100 MHz): δ 165.0, 139.8, 132.9 (q, J = 35 Hz), 130.4, 130.0
(unresolved fine coupling), 127.8 (unresolved fine coupling), 122.3 (q, J = 272 Hz), 120.2, 72.3,
67.1, 20.7, 11.4. 19F NMR (376 MHz): δ –63.9. IR (film): 3092, 2981, 2941, 2886, 1744, 1462,
1361, 1339, 1281, 1184, 1144, 1104. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H14F6NaO4S
427.0415; Found 427.0405.
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General Procedure for Differentially Substituted α,α-Dialkylated Sulfones: Volumes are
based on 1 mmol scale. A dry round-bottom flask was charged with the appropriate
monoalkylated sulfone 10a or 10b (1.0 mmol, 1 equiv). Under an inert atmosphere, dry DMF (10
mL) (0.1 M relative to sulfone) was added via syringe. Finely powdered anhydrous K2CO3 (5
equiv) was added to the reaction mixture in a single portion. The reaction mixture was allowed
to stir for 15 minutes at room temperature. Typically, the reaction mixture turned yellow in color
during this time. All alkyl halides were purified immediately prior to use by passage over a short
column of activated basic alumina in a Pasteur pipet fitted with a cotton plug. Purified alkyl
halide (5 equiv. for MeI and allyl bromide; 2.3 equiv. for BnBr) was added via syringe to flask.
The reaction mixture stirred at room temperature until deemed complete by TLC. The reaction
mixture was diluted with water (50 mL) (5x volume of DMF), then extracted five times with
EtOAc (10 mL each). The combined organic extracts were washed once with water, once with
brine, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was
purified by FCC (typically 5% EtOAc/hexane) to yield the product.
Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-2-methyl-3-phenylpropanoate (11a):
Scale: 0.21 mmol. Yield: 69.7 mg, 69% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.34 (s,
2H), 8.19 (s, 1H), 7.21 – 7.27 (m, 3H), 7.05 – 7.08 (m, 2H), 5.80 (ddt, J = 17.6, 10.0, 6.0 Hz,
1H), 5.26 – 5.30 (m, 2H), 4.57 – 4.59 (m, 2H), 3.46 (d, J = 12.8 Hz, 1H), 3.12 (d, J = 12.8 Hz,
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1H), 1.58 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 167.1, 138.7, 133.1, 132.6 (q, J = 34 Hz),
131.1 (d, J = 3 Hz), 130.3, 130.2, 128.7, 127.8, 122.4 (q, J = 272 Hz), 120.0, 74.6, 67.2, 39.0,
15.4. 19F NMR (CDCl3, 282 MHz): –63.9. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C21H18F6NaO4S 503.0728; Found 503.0722 .
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Allyl 2-benzyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)pent-4-enoate (11b): Scale: 0.30
mmol. Yield: 120.0 mg, 79% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.35 (s, 2H), 8.15 (s,
1H), 5.93 – 6.03 (m, 1H), 5.82 (ddt, J = 16.8, 10.4, 6.4 Hz, 1H), 5.27 – 5.33 (m, 2H), 5.14 – 5.20
(m, 2H), 3.39 (d, J = 13.2 Hz, 2H), 3.34 (d, J = 13.2 Hz, 2H), 2.88 (dd, J = 16.0, 6.0 Hz, 1H),
2.77 (dd, J = 15.6, 7.6 Hz, 1H). 13C{1H} NMR (CDCl3, 100 MHz) 166.7, 140.0, 133.1, 132.4 (q, J
= 35 Hz), 131.4, 131.3 (d, J = 4 Hz), 130.9, 130.2, 128.6, 127.9, 127.6 (quintet, J = 4 Hz), 122.4
(q, J = 272 Hz), 120.3, 120.0, 77.6, 67.2, 38.4, 35.4. 19F NMR (376 MHz): δ –63.8. IR (film):
3086, 2945, 1731, 1359, 1280, 1187, 1147, 1099. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C23H20F6NaO4S 529.0884; Found 529.0859.
Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-2-chloro-3-phenylpropanoate (11c) The
monobenzylated sulfone 11a (138 mg, 0.30 mmol, 1 equiv) was dissolved in THF (3 mL, 0.1 M
relative to sulfone). Finely powdered K2CO3 (207 mg, 1.50 mmol, 5 equiv) was added, and the
flask contents were stirred for 15 min at room temperature. N-Chlorosuccinimide (40 mg, 0.30
mmol, 1 equiv) was then added in a single portion. The reaction mixture was stirred overnight,
then the solvent was removed in vacuo. The crude product was purified via FCC (5%
EtOAc/hexane) to give 116 mg (78%) chlorinated product 11c as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ 8.39 (s, 2H), 8.20 (s, 1H), 5.77 (ddt, J = 17.6, 10.8, 6.0 Hz, 1H), 5.26
(overlapping dd, 2H), 4.63 (dd, J = 12.8, 6.0 Hz, 1H), 4.55 (dd, J = 12.8, 6.0 Hz, 1H), 4.13 (d, J
= 13.6 Hz, 1H), 3.52 (d, J = 13.6 Hz, 1H). 13C{1H} NMR (CDCl3, 100 MHz) 162.6, 137.1, 132.8
(q, J = 35 Hz), 131.5 (d, J = 3 Hz), 131.4, 129.6, 128.5, 128.3, 122.3 (q, J = 272 Hz), 88.6, 68.6,
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The Journal of Organic Chemistry
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39.2. 19F NMR (376 MHz): δ –63.8. IR (film): 3094, 3040, 2949, 1748, 1358, 1358, 1281, 1189,
1155, 1104. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H15ClF6NaO4S 523.0181; Found
523.0181.
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Allyl 2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-2-methylbutanoate (11d): Scale: 0.29
mmol. Yield: 128.6 mg, 94% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 5.85 (ddt, J = 17.2,
11.6, 5.6 Hz, 1H), 5.35 - 5.28 (m, 2H), 4.56 – 4.66 (m, 2H), 2.10 (dq, J = 13.2, 7.6 Hz, 1H), 1.94
(dq, J = 13.2, 7.2 Hz, 1H), 1.67 (s, 3H), 0.94 (t, J = 7.2 Hz). 13C{1H} NMR (CDCl3, 100 MHz): δ
167.3, 138.8, 132.5 (q, J = 35 Hz), 130.9 (unresolved), 130.5, 127.6 (septet, J = 4 Hz), 122.4 (q,
J = 271 Hz), 120.0, 74.4, 67.1, 26.7, 15.2, 8.6. 19F NMR (376 MHz): δ –63.8. IR (film): 3092,
2992, 2949, 2886, 1748, 1735, 1360, 1334, 1314, 1281, 1179, 1148, 1093. HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C16H16F6NaO4S 441.0571; Found 441.0570.
General Procedure for Pd-Catalyzed Decarboxylative Allylation: Volumes are based on
0.14 mmol scale. A flame-dried Schlenk flask was charged with η5-cyclopentadienyl-η3-1-
phenylallylpalladium (10 mol %) and XANTPHOS (10 mol%), then the flask was purged and
backfilled three times with argon. Freshly distilled THF (5 mL) (0.028 M relative to substrate)
was added via syringe. The flask was immersed in a preheated 50 °C oil bath for 60 minutes to
form the active catalyst. The substrate (1 equiv) was dissolved in 1 mL of dry THF and added
dropwise to the catalyst solution via syringe. The reaction was stirred at 50 ˚C and was
monitored by TLC until starting material was completely consumed (approx. 30 mins). The
reaction was then quenched with brine (5 mL), then extracted three times with EtOAc (10 mL
each). The combined organic extracts were washed once with brine (10 mL), then dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by FCC
(2.5% - 10% EtOAc/hexanes).
(2-allyl-2-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)propane-1,3-diyl)dibenzene (12a):
Scale: 0.14 mmol. Yield: 58.0 mg, 79% (colorless oil). 1H NMR (CDCl3, 400 MHz): δ 8.04 (s,
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