Radical Perfluoroalkylation of Arenes via Carbanion Intermediates

Article abstract of DOI:10.1021/acs.joc.1c01296

The use of sodium dithionite with perfluoroalkyl iodides under basic conditions facilitates the direct perfluoroalkylation of arenes with pendant benzylic electron-withdrawing groups. This occurs via attack of the arene on the electrophilic perfluoroalkyl radical, through the donation of electron density from a benzylic anion. The substrate scope was expanded beyond benzylic nitriles with cyclic substrates bearing electron-withdrawing groups at the benzylic position - enforcing donation of electron density to the aromatic ring and enabling attack on the perfluoroalkyl radical.

Full text of DOI:10.1021/acs.joc.1c01296

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Radical Perfluoroalkylation of Arenes via Carbanion Intermediates
Lucas W. Hernandez, William P. Gallagher, Carlos A. Guerrero, Francisco Gonzalez-Bobes,
and John R. Coombs*
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ABSTRACT: The use of sodium dithionite with perfluoroalkyl iodides
under basic conditions facilitates the direct perfluoroalkylation of arenes
with pendant benzylic electron-withdrawing groups. This occurs via attack
of the arene on the electrophilic perfluoroalkyl radical, through the
donation of electron density from a benzylic anion. The substrate scope
was expanded beyond benzylic nitriles with cyclic substrates bearing
electron-withdrawing groups at the benzylic positionenforcing donation
of electron density to the aromatic ring and enabling attack on the
perfluoroalkyl radical.
Radical perfluoroalkylation reactions are reported to have a
broad substrate scope and employ inexpensive reagents and
initiators.1 Particularly, anilines (2) have been shown by
Onishi and co-workers to be competent substrates for the
installation of the HFP by employing heptafluoroisopropyl
iodide (3) to afford para-perfluoroalkylated anilines like 4
(Figure 2).9a However, the synthetic operations that would be
erfluoroalkyl-substituted arenes have received significant
Pinterest from the synthetic chemistry community over the
past few decades due to the prevalence of these moieties within
a large array of clinical drug candidates.1−12 One such clinical
candidate recently reported by Bristol Myers Squibb was the
heptafluoroisopropyl-substituted (HFP) 1, which is shown to
be a promising inverse agonist of RORγt (Figure 1).2
Figure 1. Recently reported inverse agonist of RORγt.
Although there are several reports utilizing transition metal
catalysis to install polyfluorinated alkyl groups, incorporation
of the HFP moiety has been limited and primarily achieved by
(a) stoichiometric reductive processes mediated by activated
copper,3f (b) copper-mediated processes requiring stoichio-
metric amounts of AgF,3d or (c) multistep sequences ending in
substitution of a tertiary hydroxyl group with fluoride from
DAST.2e Metal-catalyzed processes are scarce and often
limited by the few available precursors of the heptafluor-
oisopropyl unit and the instability of the corresponding
organometallic derivatives.13 On this basis, our initial work
toward compound 1 required several functional group
manipulations and an expensive starting material.2d,g Because
of these inefficiencies, we became interested in exploring other
options to install the HFP group and other perfluorinated
substituents. With the goal of improved simplicity and
synthetic efficiency, we turned our attention toward radical-
based processes.14
Figure 2. Previous reports from Onishi and Melchiorre that inspired
this work.
Received: June 3, 2021
Published: July 21, 2021
https://doi.org/10.1021/acs.joc.1c01296
J. Org. Chem. 2021, 86, 10903−10913
© 2021 American Chemical Society
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required to convert 4 to 1 would not be economical. Instead,
we were intrigued by the 2014 report by Melchiorre and co-
workers that directly introduced perfluoroalkyl groups through
photochemical activation of the electron donor−acceptor
(EDA) complex between perfluoroalkyl iodides and α-cyano
arylacetates (5) to afford 6.10a These substrates proceed
through an intermediary benzylic carbanion that donates
electron density to the aromatic ring, allowing for the
substitution of the electrophilic perfluoroalkyl radical.
Although the scope was limited to nitrile substituents and
did not include the HFP group installation, we hypothesized
that substrates that could form an intermediary benzylic
carbanion similar to the α-cyano arylacetates could be viable in
the reaction conditions developed by Onishi for anilines.10b
Therefore, we began to investigate these types of substrates in
the context of our ROR inverse agonist 1 and identified
sulfonyl tetralone 7 as a suitable substrate for the radical
perfluoroalkylation to furnish substituted 8. Importantly, we
were delighted to find that the newly developed process led to
a significant cost reduction, as 7 could be derived from
inexpensive β-tetralone in a single operation.14 Given the
limited examples of this type of transformation for the
installation of the HFP group, we decided to evaluate if the
method could be extended to other substrates and our efforts
are described herein.
chlorine gave 9b in 80% yield. Interestingly, the methane-
sulfonyl variant (9c) provided only 25 area percent (AP) of the
product by UHPLC-MS (UV),15 with some decomposition
observed. Attention was then turned to alternative perfluor-
oalkyl iodides. Contrary to the previous report,10a increased
chain length improved yields for perfluoroalkyl iodides (9d−
9f) and mixtures of constitutional isomers were not observed.
With the reaction in MTBE as solvent, significant quantities
of alkylated enol ethers derived from the solvent would form in
the perfluoroalkylation reaction.16 Fortunately, the undesired
byproduct could be hydrolyzed to the desired product with 6
N aqueous HCl. However, attempts to prepare α-cyano
arylacetate 10 from 5 revealed the formation of alkylated 11a,
which could not by hydrolyzed to give the desired product
(Scheme 1). Therefore, control of this alkylation side product
Scheme 1. Alkylation Byproducts in the Perfluoroalkylation
of 5 with MTBE as Solvent
The optimized conditions found for the functionalization of
7 employed sodium dithionite (1.45 equiv) as a radical
initiator, tetrabutylammonium hydrogensulfate (7.0 mol %) as
a phase transfer catalyst, 1 N aqueous sodium hydroxide (3.15
equiv) as base, and tert-butyl methyl ether (MTBE) as the
organic solvent, resulting in the formation of 8 in ∼80% yield
(Table 1). Investigation into alternative EWGs found that the
nature of the pendant functionality had a significant impact on
the reaction yield. Removal of the para-fluoro group led to a
diminished 59% yield of 9a, whereas replacing the fluorine with
was critical to expand the generality of this method. Of the
solvents evaluated, 2-propanol (IPA) and t-AmOH (2-methyl-
2-butanol) provided the product without any alkylation
observed.
Using IPA as solvent, we performed additional optimization
on cyanoacetate 5 and RFI 3. Initial conditions provided 10 in
57 AP (area percent by UHPLC-MS) of the product (Table 2,
entry 1). Minimal impact to the yield was observed when
increasing the equivalents of RFI 3 (entries 3−5). Portion-wise
addition of sodium dithionite provided a significant improve-
ment in product formation (74 AP, entry 6). Increasing
equivalents with portion-wise addition (entry 7) and the
addition of sodium dithionite and RFI 3 in portions (entry 8)
resulted in decreased conversion.
Table 1. Substrate Scope I: Initial Conditions Employing
a
MTBE as Solvent
As increasing the equivalents of initiator and RFI 3 did not
lead to improved yields, we hypothesized that the SO2
generated in the reaction could be inhibiting conversion.1f
Therefore, we reduced the Na2S2O4 equivalents (entry 9) and
observed a significant improvement in conversion to the
product. As we were now employing sub-stiochiometric
quantities of sodium dithionite and photochemical activation
of the EDG complex between the perfluoroalkyl iodide and α-
cyano arylacetates was known, light was excluded to ensure
reactivity could be attributed to Na2S2O4.10
Next, the equivalents of RFI 3 were varied (entries 10−12),
identifying 1.10 equiv as optimal (entry 12). Replacing IPA
with t-AmOH (entry 13) provided complete conversion and
87 AP of the product. No product was observed with sodium
bicarbonate as base (entry 14), implying that generation of the
benzyl carbanion was necessary for reactivity.18 Therefore, we
selected the conditions from entry 13 to continue our studies.
The substrate scope for this transformation was explored
with these optimized conditions (Scheme 2). While the yields
for 8 and 9b were diminished compared to the MTBE
conditions, an improvement was observed with 9a and 9c.
a
Unless otherwise noted, reactions were performed on a 1.5 mmol
scale relative to substrate, RFI (1.45 equiv), Na2S2O4 (1.45 equiv),
Bu4NHSO4 (7.0 mol %), 1 N NaOH (3.15 equiv), MTBE (7.0 mL/
g), rt, for 3 h. Conversion was monitored by UHPLC-MS. RFI =
perfluoroalkyl iodide. MTBE = tert-butyl methyl ether.
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was obtained in 90% isolated yield. Linear, alkyl chains (12b−
12d) resulted in p:o:p/o isomers, albeit in improved ratios
when compared to the previous literature report.10a,19 Primary
amides are also compatible with the reaction conditions, with
the formation of 12e in 84% yield.
Table 2. Optimization of the Aromatic Perfluoroalkylation
with Alcoholic Solvents
a
Considering Melchiorre’s substrate scope was limited to
benzylic nitriles, the impact on the EWG that can promote a
stabilized carbanion was then studied. Malononitrile 12j was
afforded in 79% yield, and a substituted naphthalene derivative
could provide 12k in 35% yield. By incorporating one of the
EWGs into the benzylic position of a bicyclic system,
perfluoroalkylation could occur without the need for nitrile
substitution, as in the case of indanone 12l and tetralone 12m.
This was further supported by isochormanones 12n and 12o
that were isolated in 69 and 77% yield, respectively.
Furthermore, without incorporating one of the EWGs into a
bicyclic system, it was found that a nitrile was necessary to
observe reactivity.17 Notably, acyclic malonates and sulfonyl
esters were not competent substrates in the reaction.
Our results are in agreement with Melchiorre’s DFT
experiments, which hypothesized that alternative EWGs
would orient the intermediary anion perpendicular to the
arene.10b Therefore, the crucial donation of electron density to
the aromatic ring could not occur, preventing the attack on the
highly electrophilic perfluoroalkyl radical. Considering the new
scope of substrates, it can be concluded that incorporating one
of the EWGs in a bicyclic system with the arene enforces the
donation of electron density to the aromatic ring.
entry
RFI 3 equiv Na2S2O4 equiv
time
SM AP Prdt AP
1
2
3
4
5
1.45
1.45
2.00
2.50
3.00
1.45
2.00
2.00
1.45
1.10
2.00
2.50
1.10
1.10
1.45
1.45
1.45
1.45
1.45
1.45
2.00
2.00
0.30
0.30
0.30
0.30
0.30
0.30
4.5 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
45 min
45 min
45 min
45 min
45 min
45 min
31
29
29
28
31
10
11
27
12
12
9
57
51
59
62
61
75
76
63
73
75
71
67
87
0
b
6
b
7
8
c
d
9
d
10
d
11
d
12
9
0
100
d
,
,
e
f
13
14
d
a
Unless otherwise noted, reactions were performed on a 0.30 mmol
scale relative to substrate 5, RFI 3 (equiv), Na2S2O4 (equiv),
Bu4NHSO4 (7.0 mol %), 1 N NaOH (3.15 equiv), IPA (0.75M), rt,
for a specified time. Conversion was monitored by UHPLC-MS.
Na2S2O4 added in four portions. Na2S2O4 and RFI 3 added in two
portions. Reaction run in the dark. t-AmOH instead of IPA.
b
c
d
e
f
NaHCO3 instead of NaOH. RFI = perfluoroalkyl iodide.
Based on these observations, the body of literature
surrounding sodium dithionite in radical perfluoroalkylation
reactions,1f,8d and Melchiorre’s DFT studies,10b a plausible
mechanism for the described transformation is depicted in
Figure 3. Sodium dithionite under aqueous conditions is
known to decompose to the SO2 radical anion,1f which can
Installation of the electron-donating methoxy group dimin-
ished the yield, giving 12a in 27% yield. In the case of cyano
ester products derived from 7, alternative RFI reagents could be
employed such as 12b−12d. The HFP-containing product 10
a
Scheme 2. Substrate Scope II: Optimized Conditions for the Radical Aromatic Perfluoroalkylation
a
Unless otherwise noted, reactions were performed on a 1.5 mmol scale relative to substrate, RFI (1.10 equiv), Na2S2O4 (0.30 equiv), Bu4NHSO4
(7.0 mol %), 1 N NaOH (3.15 equiv), t-AmOH (0.75M), rt, for 45 min. Conversion was monitored by UHPLC-MS. RFI = perfluoroalkyl iodide.
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with Acquity Classic inlet. Data are reported in the form of m/z
(intensity relative to the base peak = 100). Infrared spectra were
measured neat on an Agilent Cary 630 FTIR spectrometer. Peaks are
reported in cm−1 with indicated relative intensities: s (strong, 0−33%
T); m (medium, 34−66% T), w (weak, 67−100% T), and br (broad).
UHPLC was performed on a Shimadzu Nexera X2 spectrometer with
monitoring at 220 nm using a gradient of 0 → 100% MeCN in H2O
with 0.1% TFA on an Ascentis Express C18 column.
Synthesis of Substrates. General Considerations. Substrates 5, S1
(12f precursor), S2 (12l precursor), and S3 (12e precursor) were
purchased from commercial suppliers. Aryl substrates S4 (12g
precursor) and S5 (12h precursor) were synthesized according to
the literature procedure,21 and all analytical data were in agreement
with the previous reports.22 Tetralone ester S6 (12m precursor) was
synthesized according to the literature procedure, and all analytical
data were in agreement.23 Substrate S7 (12j precursor) was
synthesized according to the literature procedure, and all analytical
data were in agreement.24
Figure 3. Proposed reaction mechanism.
General Procedure for the Synthesis of Sulfonyl Tetralone
Substrates. The following procedure was adapted from the
literature.25 To a round-bottom flask equipped with a stir bar under
a nitrogen atmosphere was added β-tetralone (1.00 equiv) followed
by MeOH (20 vol). Et3N (1.20 equiv) was then added followed by
the requisite sulfinic acid sodium salt (1.20 equiv). Then, I2 (1.00
equiv) was added as a single portion and the reaction was stirred at
ambient temperature overnight. Upon complete disappearance of
color and precipitation of the product, the reaction was filtered and
washed with IPA (2 × 8.0 vol). The resultant cake was dried under a
vacuum at 55 °C overnight to afford the sulfonylated product.
1-((4-Fluorophenyl)sulfonyl)-3,4-dihydronaphthalen-2(1H)-one
(7). Following the general procedure employing β-tetralone (100 g,
670 mmol) and sodium 4-fluorobenzenesulfinate (154 g, 803 mmol)
to afford the desired product as an off-white crystalline solid (108 g,
342 mmol, 51%). Rf = 0.28 (SiO2, Hex:EtOAc = 3:1); mp = 172−174
then transfer an electron to the perfluoroalkyl iodide,
generating the perfluoroalkyl radical. The enolate derived
from the substrate could be represented with two resonance
forms (I and II). The electron-rich aromatic ring could then
react with the electrophilic perfluoroalkyl radical, forming
radical anion III. Two modes of propagation could then
potentially be operative; (a) III could reduce a second
equivalent of perfluoroalkyl iodide, regenerating the radical, or
(b) III could be oxidized by SO2 in solution.20 Finally,
dearomatized intermediate IV could be deprotonated by the
hydroxide in solution, leading to the desired product V after
acidic workup.
In conclusion, we have developed conditions for the radical
perfluoroalkylation of arenes via enolate intermediates employ-
ing sodium dithionite as the radical initiator. The use of t-
AmOH as solvent enabled significant expansion of the
substrate scope. Additionally, by incorporating one of the
EWGs into a bicyclic system with the arene, the scope was
expanded beyond nitrile-containing substrates. The ability to
rapidly install HFP and other perfluoroalkyl groups will have a
tremendous impact on the types of scaffolds that can be
prepared for structure−activity relationship studies, as already
demonstrated with our work in a pharmaceutical candidate,11
as well as in other areas of research.12
1
°C; H NMR (500 MHz, chloroform-d) δ 7.76 (t, J = 6.4 Hz, 2H),
7.41−7.35 (m, 1H), 7.32−7.19 (m, 4H), 7.06 (d, J = 7.6 Hz, 1H),
4.82 (s, 1H), 3.64−3.56 (m, 1H), 3.01−2.90 (m, 2H), 2.58−2.48 (m,
1H); 13C{1H} NMR (126 MHz, chloroform-d) δ 201.0, 167.2, 165.1,
138.7, 133.6 (d, J = 3.6 Hz), 132.1, 132.1, 132.0, 129.8, 128.7, 127.0,
125.7, 116.5, 116.3, 77.5, 37.5, 27.0; 19F NMR (376 MHz,
chloroform-d) δ −102.08 to −102.19 (m); HRMS (CI-TOF, m/z)
calcd. For C16H13O3SF [M]+: calcd, 304.0569; found, 304.0564; IR
(ATR, neat, cm−1): 2933 (w), 1700 (m), 1588 (m), 1491 (m), 1323
(m), 1141 (s), 1077 (m), 839 (m).
1-((4-Chlorophenyl)sulfonyl)-3,4-dihydronaphthalen-2(1H)-one
(S8). Following the general procedure employing β-tetralone (3.00 g,
20.1 mmol) and sodium 4-chlorobenzenesulfinate (4.14 g, 20.2
mmol) to afford the desired product as a yellow solid (4.22 g, 12.7
mmol, 63%). Rf = 0.31 (SiO2, Hex:EtOAc = 3:1); mp = 173−175 °C;
1H NMR (500 MHz, chloroform-d) δ 7.70 (d, J = 8.5 Hz, 2H), 7.53
(d, J = 8.5 Hz, 2H), 7.43−7.37 (m, 1H), 7.36−7.31 (m, 1H), 7.30−
7.23 (m, 1H), 7.09 (d, J = 7.6 Hz, 1H), 4.83 (s, 1H), 3.68−3.55 (m,
1H), 3.06−2.89 (m, 2H), 2.60−2.48 (m, 1H); 13C{1H} NMR (126
MHz, chloroform-d) δ 200.9, 141.2, 138.7, 136.1, 132.1, 130.6, 129.8,
129.4, 128.7, 127.0, 125.5, 77.4, 37.5, 27.0; HRMS (CI-TOF, m/z)
calcd. For C16H13O3SCl [M]+: calcd, 320.0274; found, 320.0277; IR
(ATR, neat, cm−1): 3090 (w), 2937 (w), 1700 (m), 1569 (w), 1319
(s), 1141 (s), 1081 (s), 760 (s).
EXPERIMENTAL SECTION
■
General Experimental Methods. Unless otherwise noted, all
reactions were performed under ambient atmosphere at room
temperature. All reagents were purchased from commercial sources.
Standard benchtop techniques were employed for handling air-
sensitive reagents. Analytical thin-layer chromatography was per-
formed on Merck silica gel 60 F254 aluminum plates. Visualization
was accomplished with UV light and/or potassium permanganate
(KMnO4). The retention factor (Rf) values reported were measured
using a 5 × 2 cm2 TLC plate in a developing chamber containing the
solvent system described. Flash column chromatography was
performed using a Teledyne ISCO using appropriately sized
cartridges for the scale of the experiment. NMR spectra were
recorded on a 400 or 500 MHz spectrometer. Spectra are referenced
1-(Phenylsulfonyl)-3,4-dihydronaphthalen-2(1H)-one (S9). Fol-
lowing the general procedure employing β-tetralone (10.0 g, 67.0
mmol) and sodium benzenesulfinate (13.9 g, 80.4 mmol) to afford the
desired product as a yellow crystalline solid (11.4 g, 39.5 mmol, 59%).
1
to residual chloroform (δ = 7.27 ppm, H; 77.16 ppm, 13C), residual
1
Rf = 0.21 (SiO2, Hex:EtOAc = 3:1); mp = 149−150 °C; H NMR
1
benzene (δ = 7.16 ppm, H; 128.06 ppm, 13C), and residual DMSO
(500 MHz, chloroform-d) δ 7.75 (d, J = 7.6 Hz, 2H), 7.72−7.66 (m,
1H), 7.57−7.51 (m, 2H), 7.40−7.33 (m, 1H), 7.33−7.28 (m, 1H),
7.22 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 3.62−
3.50 (m, 1H), 3.03−2.84 (m, 2H), 2.52 (ddd, J = 18.2, 11.4, 6.9 Hz,
1H); 13C{1H} NMR (126 MHz, chloroform-d) δ 201.0, 138.7, 137.6,
134.3, 132.0, 129.7, 129.2, 129.1, 128.6, 126.9, 125.9, 77.5, 37.4, 27.1;
HRMS (ESI-TOF, m/z) calcd. For C16H18NO3S [M + NH4]+: calcd,
1
(δ = 2.50 ppm, H; 39.52 ppm, 13C). Chemical shifts are reported in
parts per million (ppm). Data are presented as follows: chemical shift
(ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
br = broad), coupling constant J (Hz), and integration. Melting points
(°C) were measured on a Thomas-Hoover Unimelt and are
uncorrected. HRMS samples were run on the Thermo LTQ-Orbitrap
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Note
304.1002; found, 304.1006; IR (ATR, neat, cm−1): 2937 (w), 1707
(m), 1446 (m), 1491 (m), 1312 (m), 1141 (s), 1077 (m), 753 (m).
1-((4-Fluorophenyl)sulfonyl)-5-methoxy-3,4-dihydronaphtha-
len-2(1H)-one (S10). Following the general procedure employing 5-
OMe β-tetralone (5.00 g, 28.1 mmol) and sodium 4-fluorobenzene-
sulfinate (6.20 g, 34.0 mmol) to afford the desired product as an off-
white solid (4.60 g, 13.5 mmol, 48%). Rf = 0.26 (SiO2, Hex:EtOAc =
3:1); mp = 169−170 °C; 1H NMR (500 MHz, chloroform-d) δ 7.81−
7.74 (m, 2H), 7.24−7.17 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.66 (d, J
= 7.8 Hz, 1H), 4.81 (s, 1H), 3.88 (s, 3H), 3.36−3.24 (m, 1H), 3.24−
3.14 (m, 1H), 3.01 (ddd, J = 18.0, 6.5, 3.6 Hz, 1H), 2.47 (ddd, J =
18.0, 10.0, 7.5 Hz, 1H); 13C{1H} NMR (126 MHz, chloroform-d) δ
201.3, 167.2, 165.1, 156.7, 133.7 (d, J = 3.6 Hz), 132.1 (d, J = 10.0
Hz), 127.6, 127.3 (d, J = 42.7 Hz), 123.7, 116.4 (d, J = 22.7 Hz),
111.1, 77.3, 55.6, 36.9, 20.1; 19F NMR (376 MHz, chloroform-d) δ
−98.26 to −104.30 (m); HRMS (ESI-TOF, m/z) calcd. For
C17H19NFO4S [M + NH4]+: calcd, 352.1013; found, 352.1015; IR
(ATR, neat, cm−1): 2952 (w), 1711 (m), 1588 (m), 1465 (m), 1315
(m), 1141 (s), 1081 (m), 842 (m).
1-(Methylsulfonyl)-3,4-dihydronaphthalen-2(1H)-one (S11). Fol-
lowing the general procedure employing β-tetralone (10.0 g, 68.4
mmol) and sodium methanesulfinate (9.80 g, 82.0 mmol), the
material was purified by flash chromatography (80 g of SiO2 cartridge,
10 → 70% EtOAc in Hex over 30 min) to afford the desired product
as a red solid (8.00 g, 35.6 mmol, 52%). Rf = 0.14 (SiO2, Hex:EtOAc
= 3:1); mp = 86−88 °C; 1H NMR (500 MHz, chloroform-d) δ 7.43−
7.34 (m, 1H), 7.34−7.27 (m, 3H), 4.78 (s, 1H), 3.70−3.57 (m, 1H),
3.11 (s, 3H), 3.02−2.85 (m, 2H), 2.53 (ddd, J = 18.2, 12.1, 6.4 Hz,
1H); 13C{1H} NMR (126 MHz, chloroform-d) δ 202.8, 138.6, 132.2,
129.5, 128.5, 126.8, 124.4, 74.7, 40.7, 37.7, 26.6; HRMS (CI-TOF, m/
z) calcd. For C11H12O3S [M]+: calcd, 224.0507; found, 224.0510; IR
(ATR, neat, cm−1): 2933 (w), 1703 (m), 1308 (s), 1126 (s), 1323
(m), 962 (m), 764 (m), 734 (m).
(trifluoromethyl)benzene (1.09 g) to afford the desired product as
a yellow solid (1.24 g, 3.81 mmol, 95%). Chromatography = 24 g
SiO2 cartridge, 0 → 100% EtOAc in Hex over 20 min. Rf = 0.30
1
(SiO2, Hex:EtOAc = 3:1); mp = 102−104 °C; H NMR (500 MHz,
chloroform-d) δ 7.78−7.69 (m, 4H), 7.62−7.52 (m, 4H), 7.43 (s,
1H), 5.32 (s, 1H); 13C{1H} NMR (126 MHz, chloroform-d) δ 135.6,
133.7, 133.1, 131.3 (q, J = 32.7 Hz), 129.8, 129.7, 129.3, 127.42−
126.10 (m), 124.2, 122.1, 112.9, 62.3; 19F NMR (376 MHz,
chloroform-d) δ −62.92; HRMS (CI-TOF, m/z) calcd. For
C15H10NO2SF3 [M + H]+: calcd, 326.0463; found, 326.0475; IR
(ATR, neat, cm−1): 2937 (w), 1450 (w), 1323 (s), 1152 (s), 1129 (s),
1073 (s), 764 (m), 719 (m).
2-(Naphthalen-2-yl)-2-(phenylsulfonyl)acetonitrile (S14). Fol-
lowing the general procedure employing 2-bromonaphthalene (828
mg) to afford the desired product as a brown solid (1.05 g, 3.40
mmol, 85%). Product isolated as an inseparable mixture with
methylene starting material; all spectral peaks reported. Chromatog-
raphy = 24 g SiO2 cartridge, 0 → 100% EtOAc in Hex over 20 min. Rf
= 0.23 (SiO2, Hex:EtOAc = 3:1); mp = 165−167 °C; 1H NMR (500
MHz, chloroform-d) δ 8.05 (d, J = 7.8 Hz, 2H), 7.91−7.83 (m, 2H),
7.79 (br d, J = 7.2 Hz, 2H), 7.76−7.70 (m, 4H), 7.69−7.64 (m, 2H),
7.62−7.53 (m, 2H), 7.53−7.48 (m, 2H), 7.36 (dd, J = 8.5, 1.7 Hz,
1H), 5.43−5.11 (m, 1H), 5.32 (s, 1H), 4.08 (s, 2H); 13C{1H} NMR
(126 MHz, chloroform-d) δ 136.7, 135.4, 135.3, 134.2, 133.7, 132.7,
131.0, 130.1, 129.8, 129.7, 129.5, 129.2, 129.0, 128.9, 128.7, 128.3,
127.8, 127.1, 125.9, 122.6, 113.5, 110.3, 63.3, 45.7; HRMS (ESI-TOF,
m/z) calcd. For C18H17N2O2S [M + NH4]+: calcd, 325.1005; found,
325.1006; IR (ATR, neat, cm−1): 2926 (w), 1446 (w), 1334 (m),
1312 (m), 1151 (s), 1081 (m), 827 (m), 757 (m).
Ethyl 3-Oxoisochromane-4-carboxylate (S15). To a solution of
LHMDS (1.0 M, 10 mL, 10.0 mmol, 1.00 equiv) at −78 °C under an
inert atmosphere in a 40 mL vial equipped with an X-shaped stir bar
was added isochroman-3-one (1.48 g, 10.0 mmol, 1.00 equiv) in 2-
methyltetrahydrofuran (14 mL) slowly. The solution was stirred for
30 min at the same temperature before the addition of ethyl
chloroformate (2.4 mL, 12.5 mmol, 2.50 equiv). The reaction was left
in the dry ice bath and allowed to warm to ambient temperature
overnight. On completion by TLC, the reaction was quenched with
NH4Cl (20 mL) and diluted with EtOAc (20 mL). The phases were
separated, and the organic layer was dried over MgSO4, filtered,
concentrated over Celite under a vacuum, and purified by flash
chromatography (80 g SiO2 cartridge, 0 → 100% EtOAc in Hex over
20 min). The product was isolated as a colorless oil (1.01 g, 4.59
mmol, 46%). Chromatography = 24 g SiO2 cartridge, 0 → 100%
4-((4-Fluorophenyl)sulfonyl)isochroman-3-one (S12). Following
the general procedure employing isochroman-3-one (992 mg, 6.70
mmol) and sodium 4-fluorobenzenesulfinate (1.50 g, 8.15 mmol) to
afford the desired product as a white solid (1.10 g, 3.62 mmol, 54%).
1
Rf = 0.52 (SiO2, Hex:EtOAc = 2:1); mp = 173−174 °C; H NMR
(500 MHz, chloroform-d) δ 7.99−7.86 (m, 2H), 7.56−7.48 (m, 1H),
7.44 (t, J = 7.6 Hz, 1H), 7.33−7.25 (m, 4H), 5.92 (d, J = 14.2 Hz,
1H), 5.29 (d, J = 14.2 Hz, 1H), 5.09 (s, 1H); 13C{1H} NMR (126
MHz, chloroform-d) δ 167.6, 165.5, 162.5, 132.8 (d, J = 3.6 Hz),
132.7, 132.3 (d, J = 10.0 Hz), 130.6 (d, J = 80.8 Hz), 128.9, 125.0,
122.9, 116.8 (d, J = 22.7 Hz), 71.7, 71.1; 19F NMR (376 MHz,
chloroform-d) δ −99.42 to −102.21 (m); HRMS (ESI-TOF, m/z)
calcd. For C15H12FO4S [M + H]+: calcd, 307.0435; found, 307.0435;
IR (ATR, neat, cm−1): 2948 (w), 1729 (m), 1587 (m), 1490 (m),
1326 (m), 1144 (s), 1081 (m), 838 (m).
1
EtOAc in Hex over 20 min. Rf = 0.59 (SiO2, Hex:EtOAc = 2:1); H
NMR (500 MHz, chloroform-d) δ 7.38−7.30 (m, 3H), 7.26−7.21
(m, 1H), 5.68−5.59 (m, 1H), 5.30−5.17 (m, 1H), 4.75−4.64 (m,
1H), 4.30−4.09 (m, 2H), 1.36−1.17 (m, 3H); 13C{1H} NMR (126
MHz, chloroform-d) δ 166.6, 166.4, 131.0, 129.1, 128.9, 128.4, 127.8,
124.8, 70.2, 62.4, 53.2, 13.8; HRMS (ESI-TOF, m/z) calcd. For
C12H12O4Na [M + Na]+: calcd, 243.0628; found, 243.0639; IR (ATR,
neat, cm−1): 2981 (w), 1722 (s), 1461 (m), 1390 (m), 1286 (m),
1189 (m), 1021 (m), 753 (m).
Synthesis of Perfluoroalkylation Products. General Proce-
dure A: Perfluoroalkylation with MTBE. In a 20 mL scintillation vial
equipped with an X-shaped stir bar was added the substrate (1.50
mmol, 1.00 equiv) and Bu4NHSO4 (36.0 mg, 0.105 mmol, 7.00 mol
%). The solids were then dissolved in MTBE (7 vol), and stirring was
commenced. To the stirred solution was added NaOH (1.0 N, 4.73
mL, 4.73 mmol, 3.15 equiv), and the biphasic mixture was stirred at a
rate to ensure adequate mixing of the phases for 10 min. Na2S2O4
(379 mg, 2.18 mmol, 1.45 equiv) was then added in a single portion
followed by the requisite perfluoroalkyl iodide (2.18 mmol, 1.45
equiv), and the reaction was stirred for 3 h. A sample was then taken
for UHPLC analysis, and upon verification of complete conversion,
the stirring was stopped and the phases were allowed to separate. The
lower aqueous phase was removed, and the organic phase was washed
with NaCl (sat. aq., 7.0 vol). The phases were separated, HCl (6.0 N,
10 vol) was added, and stirring was commenced. The biphasic mixture
was stirred with monitoring by UHPLC to observe disappearance of
General Procedure for the Synthesis of Sulfonyl Acetonitrile
Substrates. The following procedure was adapted from the
literature.21 To a 40 mL scintillation vial equipped with an X-shaped
stir bar was added benzenesulfonylacetonitrile (962 mg, 5.20 mmol,
1.30 equiv), and the headspace was purged with nitrogen. DME (20
mL) was then added followed by NaH (60% in mineral oil, 480 mg,
12.0 mmol, 3.00 equiv) in portions under a stream of nitrogen. The
reaction was stirred until hydrogen evolution ceased. Then, PPh3 (126
mg, 0.48 mmol, 12 mol %) and Pd2(dba)3·CHCl3 (83.0 mg, 0.08
mmol, 2.0 mol %) were added and the solution was sparged with
nitrogen for 10 min. Then, the requisite halo-arene (4.00 mmol, 1.00
equiv) was added and the reaction was heated at 70 °C under a
positive pressure of nitrogen overnight. Upon completion by TLC,
the reaction was cooled to 0 °C with an ice bath and carefully
quenched with NaCl (sat. aq., 15 mL) and 5 drops of conc. HCl were
added. The phases were separated, and the aqueous phase was
extracted with EtOAc (3 × 5.0 mL). The combined organics were
dried over MgSO4, filtered, concentrated over Celite under a vacuum,
and purified by flash chromatography (24 g SiO2 cartridge, 0 → 60%
EtOAc in Hex over 20 min).
2-(Phenylsulfonyl)-2-(3-(trifluoromethyl)phenyl)acetonitrile
(S13). Following the general procedure employing 1-iodo-3-
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Note
the MTBE adduct (ca. 3 h). Upon complete hydrolysis, the stirring
was stopped and the phases were separated. The organic phase was
washed with NaCl (sat. aq., 7.0 vol), dried over MgSO4, filtered,
concentrated over Celite under reduced pressure, and purified by flash
chromatography.
472.0808; IR (ATR, neat, cm−1): 2948 (w), 1718 (m), 1446 (w),
1278 (m), 1208 (s), 1141 (s), 980 (s), 719 (s).
1-((4-Chlorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,4-dihy-
dronaphthalen-2(1H)-one (9b). Following general procedure A
employing S8 (481 mg, 1.50 mmol) and heptafluoroisopropyl iodide
(0.31 mL, 2.18 mmol) to obtain the desired product as a brown solid
(589 mg, 1.20 mmol, 80%).
General Procedure B: Perfluoroalkylation with t-AmOH. In a 20
mL scintillation vial equipped with an X-shaped stir bar was added the
substrate (1.50 mmol, 1.00 equiv) and Bu4NHSO4 (36.0 mg, 0.105
mmol, 7.00 mol %). The solids were then dissolved in t-AmOH (2.00
mL), and stirring was commenced. To the stirred solution was added
NaOH (1.0 N, 4.73 mL, 4.73 mmol, 3.15 equiv) and the biphasic
mixture was stirred at a rate to ensure adequate mixing of the phases
for 10 min. Na2S2O4 (78.0 mg, 0.45 mmol, 0.30 equiv) was then
added in a single portion followed by the requisite perfluoroalkyl
iodide (1.65 mmol, 1.10 equiv), and the reaction was stirred for 45
min. A sample was then taken for UHPLC analysis, and upon
verification of complete conversion, the reaction was quenched with
HCl (2.0 N, 3.00 mL, 6.00 mmol, 4.00 equiv) and the phases were
separated. The aqueous phase was extracted with EtOAc (3 × 5.00
mL), and the combined organics were dried over MgSO4, filtered,
concentrated over Celite under reduced pressure, and purified by flash
chromatography.
Characterization of Perfluoroalkylation Products. In many cases,
the products were isolated as a mixture of keto:enol tautomers. For
clarity, only the major tautomer spectral data is described. The major
tautomer is depicted in the manuscript.
1-((4-Fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,4-dihy-
dronaphthalen-2(1H)-one (8). Following general procedure A
employing 7 (457 mg, 1.50 mmol) and heptafluoroisopropyl iodide
(0.31 mL, 2.18 mmol) to obtain the desired product as a white solid
(567 mg, 1.20 mmol, 80%).
Following general procedure B employing S8 (481 mg, 1.50 mmol)
and heptafluoroisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the
desired product as a brown solid (490 mg, 1.00 mmol, 67%).
Chromatography = 12 g SiO2 cartridge, 0 → 60% EtOAc in Hex over
1
15 min. Rf = 0.29 (SiO2, Hex:EtOAc = 3:1); mp = 104−106 °C; H
NMR (500 MHz, chloroform-d) δ 7.60−7.54 (m, 2H), 7.46 (s, 1H),
7.42−7.35 (m, 3H), 7.15 (d, J = 8.1 Hz, 1H), 4.81 (s, 1H), 3.63−3.49
(m, 1H), 2.95−2.83 (m, 2H), 2.42 (ddd, J = 18.3, 11.6, 6.9 Hz, 1H);
13C{1H} NMR (126 MHz, chloroform-d) δ 199.7, 141.4, 139.6 (d, J =
1.8 Hz), 135.6, 132.7 (d, J = 1.8 Hz), 130.6, 129.6, 129.4, 129.2,
128.50−127.98 (m), 125.0 (br dd, J = 221.6, 10.9 Hz), 123.94−
116.66 (m), 91.1 (dquin, J = 202.9, 33.1 Hz), 76.5, 37.0, 27.1; 19F
NMR (376 MHz, chloroform-d) δ −73.61 to −77.33 (m), −182.42
(quin, J = 7.2 Hz); HRMS (ESI-TOF, m/z) calcd. For
C19H16NO3SF7Cl [M + NH4]+: calcd, 506.0422; found, 506.0416;
IR (ATR, neat, cm−1): 2960 (w), 1718 (m), 1580 (w), 1476 (w),
1305 (m), 1207 (s), 1141 (s), 980 (s).
1-(Methylsulfonyl)-6-(perfluoropropan-2-yl)-3,4-dihydronaph-
thalen-2(1H)-one (9c). Following general procedure B employing
S11 (337 mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL,
1.65 mmol) to obtain the desired product as an orange solid (249 mg,
0.63 mmol, 42%). Chromatography = 12 g SiO2 cartridge, 0 → 10%
MeOH in CH2Cl2 over 15 min. Rf = 0.18 (SiO2, Hex:EtOAc = 3:1);
mp = 125−127 °C; 1H NMR (500 MHz, chloroform-d) δ 7.61−7.55
(m, 2H), 7.48 (d, J = 8.1 Hz, 1H), 4.80 (s, 1H), 3.78−3.65 (m, 1H),
3.20 (s, 3H), 3.09−2.97 (m, 2H), 2.60 (ddd, J = 18.6, 12.1, 6.9 Hz,
1H); 13C{1H} NMR (126 MHz, chloroform-d) δ 201.8, 139.7 (d, J =
1.8 Hz), 133.1 (d, J = 1.8 Hz), 128.2 (d, J = 20.0 Hz), 127.8, 125.9
(br d, J = 10.9 Hz), 124.3 (br d, J = 10.9 Hz), 124.10−116.31 (m),
91.2 (dt, J = 202.5, 33.2 Hz), 74.4, 41.1, 37.5, 27.1; 19F NMR (376
MHz, chloroform-d) δ −75.42 (d, J = 8.2 Hz), −181.26 to −184.05
(m); HRMS (ESI-TOF, m/z) calcd. For C14H15NO3SF7 [M +
NH4]+: calcd, 410.0655; found, 410.0651; IR (ATR, neat, cm−1):
2941 (w), 1722 (m), 1305 (m), 1278 (m), 1211 (s), 1125 (s), 980
(m), 719 (m).
Following general procedure B employing 7 (457 mg, 1.50 mmol)
and heptafluoroisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the
desired product as a white solid (482 mg, 1.02 mmol, 68%).
Chromatography = 12 g SiO2 cartridge, 0 → 60% EtOAc in Hex over
1
15 min. Rf = 0.29 (SiO2, Hex:EtOAc = 3:1); mp = 99−101 °C; H
NMR (500 MHz, chloroform-d) δ 7.72−7.66 (m, 2H), 7.48 (s, 1H),
7.42 (br d, J = 8.2 Hz, 1H), 7.20−7.11 (m, 3H), 4.78 (s, 1H), 3.64−
3.51 (m, 1H), 2.97−2.87 (m, 2H), 2.52−2.42 (m, 1H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 199.8, 167.4, 165.3, 139.6 (d, J =
2.7 Hz), 133.2 (d, J = 3.6 Hz), 132.7 (d, J = 1.8 Hz), 132.1 (d, J =
10.0 Hz), 129.2, 128.2 (d, J = 20.0 Hz), 125.1 (dd, J = 218.9, 10.9
Hz), 120.4 (dd, J = 287.0, 28.2 Hz), 116.6 (d, J = 22.7 Hz), 92.73−
89.58 (m), 76.8, 37.1, 27.2; 19F NMR (376 MHz, chloroform-d) δ
−75.48 (d, J = 6.8 Hz), −101.37 to −101.50 (m), −182.35 to
−182.42 (m); HRMS (CI-TOF, m/z) calcd. For C19H12O3SF8Na [M
+ Na]+: calcd, 495.0272; found, 495.0262; IR (ATR, neat, cm−1):
2948 (w), 1715 (m), 1592 (m), 1495 (m), 1290 (m), 1211 (s), 1141
(s), 980 (s).
1-((4-Fluorophenyl)sulfonyl)-6-(perfluoropropyl)-3,4-dihydro-
naphthalen-2(1H)-one (9d). Following general procedure A employ-
ing 7 (457 mg, 1.50 mmol) and perfluoropropyl iodide (0.31 mL, 2.18
mmol) to obtain the desired product as a yellow oil (269 mg, 0.57
mmol, 38%). Chromatography = 12 g SiO2 cartridge, 0 → 50%
1
EtOAc in Hex over 15 min. Rf = 0.33 (SiO2, Hex:EtOAc = 3:1); H
NMR (500 MHz, chloroform-d) δ 7.75−7.64 (m, 2H), 7.46 (s, 1H),
7.40 (d, J = 8.1 Hz, 1H), 7.20−7.12 (m, 3H), 4.79 (s, 1H), 3.64−3.53
(m, 1H), 2.99−2.87 (m, 2H), 2.55−2.38 (m, 1H); 13C{1H} NMR
(126 MHz, chloroform-d) δ 199.7, 167.4, 165.4, 139.5, 133.3 (d, J =
3.6 Hz), 132.5, 132.2 (d, J = 10.0 Hz), 130.1, 127.17−126.86 (m),
125.3 (t, J = 6.8 Hz), 123.3, 116.6 (d, J = 22.7 Hz), 108.6 (q, J = 39.1
Hz), 76.9, 37.0, 27.1; 19F NMR (376 MHz, chloroform-d) δ −79.84
to −79.98 (m), −79.93 (t, J = 10.2 Hz), −101.13 to −101.60 (m),
−111.89 (q, J = 9.5 Hz), −126.16; HRMS (CI-TOF, m/z) calcd. For
C19H16F8O3SN [M + NH4]+: calcd, 490.0718; found, 4490.0712; IR
(ATR, neat, cm−1): 2926 (w), 1722 (m), 1592 (m), 1495 (m), 1227
(m), 1144 (s), 1114 (s), 731 (s).
6-(Perfluoropropan-2-yl)-1-(phenylsulfonyl)-3,4-dihydronaph-
thalen-2(1H)-one (9a). Following general procedure A employing S9
(429 mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.31 mL, 2.18
mmol) to obtain the desired product as a yellow solid (400 mg, 0.88
mmol, 59%).
Following general procedure B employing S9 (429 mg, 1.50 mmol)
and heptafluoroisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the
desired product as a yellow solid (566 mg, 1.25 mmol, 83%).
Chromatography = 12 g SiO2 cartridge, 0 → 50% EtOAc in Hex over
1
15 min. Rf = 0.34 (SiO2, Hex:EtOAc = 3:1); mp = 105−108 °C; H
NMR (500 MHz, chloroform-d) δ 7.74 (dd, J = 8.2, 1.1 Hz, 2H),
7.71−7.67 (m, 1H), 7.58−7.51 (m, 3H), 7.46 (br d, J = 8.2 Hz, 1H),
7.22 (d, J = 8.2 Hz, 1H), 4.89 (s, 1H), 3.69−3.57 (m, 1H), 3.06−2.94
(m, 2H), 2.55 (ddd, J = 18.5, 11.5, 6.9 Hz, 1H); 13C{1H} NMR (126
MHz, chloroform-d) δ 199.7, 139.6 (d, J = 1.8 Hz), 137.1, 134.6,
132.6 (d, J = 1.8 Hz), 129.5, 129.3, 129.2, 128.1 (d, J = 20.9 Hz),
126.7, 126.05−116.57 (m), 105.2, 91.2 (ddt, J = 203.2, 66.3, 33.3
Hz), 76.8, 37.0, 27.2; 19F NMR (376 MHz, chloroform-d) δ −73.84
to −77.56 (m), −182.41 (quin, J = 7.2 Hz); HRMS (ESI-TOF, m/z)
calcd. For C19H17NO3SF7 [M + NH4]+: calcd, 472.0812; found,
1-((4-Fluorophenyl)sulfonyl)-6-(perfluorobutyl)-3,4-dihydro-
naphthalen-2(1H)-one (9e). Following general procedure A, and
scaling all reagents appropriately, employing 7 (500 mg, 1.64 mmol)
and perfluorobutyl iodide (0.41 mL, 2.38 mmol) to obtain the desired
product as a yellow solid (410 mg, 0.79 mmol, 48%). Chromatog-
raphy = 12 g SiO2 cartridge, 0 → 60% EtOAc in Hex over 15 min. Rf
1
= 0.28 (SiO2, Hex:EtOAc = 3:1); mp = 86−89 °C; H NMR (500
MHz, chloroform-d) δ 7.74−7.64 (m, 2H), 7.46 (s, 1H), 7.40 (d, J =
8.1 Hz, 1H), 7.21−7.11 (m, 3H), 4.79 (s, 1H), 3.64−3.51 (m, 1H),
3.00−2.88 (m, 2H), 2.51−2.40 (m, 1H); 13C{1H} NMR (126 MHz,
10908
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Note
chloroform-d) δ 199.7, 167.4, 165.4, 139.5, 133.2 (d, J = 2.7 Hz),
132.5, 132.2 (d, J = 10.0 Hz), 130.84−129.95 (m), 129.7, 127.1 (t, J =
6.4 Hz), 125.4 (br t, J = 6.4 Hz), 118.5 (t, J = 33.2 Hz), 117.33−
115.93 (m), 115.82−114.67 (m), 111.44−107.99 (m), 76.9, 37.0,
27.1; 19F NMR (376 MHz, chloroform-d) δ −79.42 to −82.45 (m),
−101.43 (tt, J = 8.5, 4.4 Hz), −111.15 (br t, J = 13.6 Hz), −122.54
(q, J = 9.5 Hz), −124.53 to −126.39 (m); HRMS (ESI-TOF, m/z)
calcd. For C20H16NO3SF10 [M + NH4]+: calcd, 540.0686; found,
540.0675; IR (ATR, neat, cm−1): 2956 (w), 1730 (w), 1588 (w),
1491 (w), 1234 (m), 1193 (w), 1129 (s), 831 (m).
1-((4-Fluorophenyl)sulfonyl)-6-(perfluorohexyl)-3,4-dihydro-
naphthalen-2(1H)-one (9f). Following general procedure A, and
scaling all reagents appropriately, employing 7 (500 mg, 1.64 mmol)
and perfluorohexyl iodide (0.52 mL, 2.38 mmol) to obtain the desired
product as a yellow solid (550 mg, 0.88 mmol, 54%). Chromatog-
raphy = 12 g SiO2 cartridge, 0 → 60% EtOAc in Hex over 15 min. Rf
= 0.26 (SiO2, Hex:EtOAc = 3:1); mp = 104−106 °C; 1H NMR (500
MHz, chloroform-d) δ 7.81−7.75 (m, 2H), 7.55 (s, 1H), 7.47 (d, J =
8.1 Hz, 1H), 7.32−7.17 (m, 3H), 4.90 (s, 1H), 3.73−3.61 (m, 1H),
3.08−3.02 (m, 1H), 3.02−2.97 (m, 1H), 2.60−2.49 (m, 1H);
13C{1H} NMR (126 MHz, chloroform-d) δ 199.7, 167.4, 165.4, 133.2
(d, J = 3.6 Hz), 132.5, 132.2 (d, J = 10.0 Hz), 130.2, 130.3 (br t, J =
24.5 Hz), 129.7 (d, J = 10.0 Hz), 127.1 (br t, J = 6.4 Hz), 125.3 (br t,
J = 5.9 Hz), 118.3 (br t, J = 33.2 Hz), 117.38−115.46 (m), 116.30−
114.86 (m), 114.26−112.02 (m), 111.48−109.69 (m), 109.49−
107.50 (m), 76.9, 37.0, 27.1; 19F NMR (376 MHz, chloroform-d) δ
−81.01 (br t, J = 10.2 Hz), −101.16 to −102.21 (m), −110.99 (br t, J
= 14.3 Hz), −121.51 (br s), −121.68 (br t, J = 13.6 Hz), −122.91 (br
d, J = 4.1 Hz), −126.27 (ddd, J = 23.5, 9.2, 4.1 Hz); HRMS (ESI-
TOF, m/z) calcd. For C22H16NO3SF14 [M + NH4]+: calcd, 640.0622;
found, 640.0604; IR (ATR, neat, cm−1): 2956 (w), 1729 (w), 1588
(w), 1491 (w), 1290 (m), 1189 (s), 1140 (s), 831 (m).
raphy = 12 g SiO2 cartridge, 0 → 50% EtOAc in Hex over 15 min. Rf
= 0.30 (SiO2, Hex:EtOAc = 3:1); mp = 78−80 °C; H NMR (500
1
MHz, chloroform-d) δ 7.85−7.73 (m, 2H), 7.48 (d, J = 8.2 Hz, 1H),
7.25 (t, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 1H), 4.85 (s, 1H), 3.86
(s, 3H), 3.52−3.36 (m, 1H), 3.29 (ddd, J = 16.0, 6.9, 2.0 Hz, 1H),
3.05−2.94 (m, 1H), 2.44 (ddd, J = 18.6, 11.9, 6.9 Hz, 1H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 199.8, 167.4, 165.4, 156.8 (br s),
133.9, 133.4 (d, J = 2.7 Hz), 132.1 (d, J = 10.0 Hz), 131.5, 127.7 (d, J
= 2.7 Hz), 126.6 (br d, J = 15.4 Hz), 122.69−118.22 (m), 116.6 (d, J
= 22.7 Hz), 92.6 (dt, J = 238.9, 34.1 Hz), 76.8, 62.1 (br s), 37.0, 21.2;
19F NMR (376 MHz, chloroform-d) δ −73.50 to −74.24 (m), −74.88
(quin, J = 7.8 Hz), −100.97 to −101.87 (m); HRMS (CI-TOF, m/z)
calcd. For C20H14O4SF7 [M]+: calcd, 502.0485; found, 502.0480; IR
(ATR, neat, cm−1): 2941 (w), 1718 (w), 1588 (w), 1495 (w), 1237
(s), 1211 (s), 1141 (s), 976 (s).
Ethyl 2-Cyano-2-(4-(perfluoropropyl)phenyl)acetate (12b). Fol-
lowing general procedure B employing 5 (0.26 mL, 1.50 mmol) and
perfluoropropyl iodide (0.24 mL, 1.65 mmol) to obtain the desired
product as an orange oil (129 mg, 0.36 mmol, 24%). Careful analysis
1
of the crude reaction mixture by H NMR revealed a 14:4:1 ratio of
para:ortho:para/ortho substitution. The isolated yield corresponds to
the major para-product. Chromatography = 12 g SiO2 cartridge, 0 →
40% MTBE in Hex over 15 min. Rf = 0.49 (SiO2, Hex:EtOAc = 3:1);
1H NMR (500 MHz, chloroform-d) δ 7.70−7.62 (m, 4H), 4.82 (s,
1H), 4.28 (qd, J = 7.1, 1.0 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 164.2, 134.0, 129.9 (t, J = 24.5
Hz), 128.4, 127.8 (t, J = 6.4 Hz), 116.8 (td, J = 32.7, 13.6 Hz),
119.48−114.46 (m), 114.9, 108.6 (q, J = 38.1 Hz), 63.8, 43.5, 13.8;
19F NMR (376 MHz, chloroform-d) δ −80.03 (t, J = 10.2 Hz),
−112.01 (br d, J = 9.5 Hz), −126.35 (s); HRMS (CI-TOF, m/z)
calcd. For C14H11NO2F7 [M + H]+: calcd, 358.0678; found,
358.0670; IR (ATR, neat, cm−1): 2989 (w), 1748 (m), 1349 (m),
1200 (s), 1178 (s), 1114 (s), 895 (m), 734 (m).
Ethyl 2-Cyano-2-(4-(perfluoropropan-2-yl)phenyl)acetate (10).
Following general procedure B employing 5 (0.26 mL, 1.50 mmol)
and heptafluoroisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the
desired product as a yellow oil (481 mg, 1.35 mmol, 90%).
Chromatography = 12 g SiO2 cartridge, 0 → 30% EtOAc in Hex
Ethyl 2-Cyano-2-(4-(perfluorobutyl)phenyl)acetate (12c). Fol-
lowing general procedure B employing 5 (0.26 mL, 1.50 mmol)
and perfluorobutyl iodide (0.28 mL, 1.65 mmol) to obtain the desired
product as an orange oil (220 mg, 0.54 mmol, 36%). Careful analysis
1
1
over 15 min. Rf = 0.49 (SiO2, Hex:EtOAc = 3:1); H NMR (500
of the crude reaction mixture by H NMR revealed a 13:3:1 ratio of
MHz, chloroform-d) δ 7.63−7.58 (m, 2H), 7.58−7.53 (m, 2H), 4.75
(s, 1H), 4.18 (q, J = 6.2 Hz, 2H), 1.20 (br t, J = 7.0 Hz, 3H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 164.2, 133.2, 128.6 (d, J = 2.7 Hz),
127.9 (d, J = 20.9 Hz), 126.7 (br d, J = 10.9 Hz), 120.4 (qd, J = 286.0,
27.7 Hz), 114.9, 91.2 (dquin, J = 202.8, 33.1 Hz), 63.6, 43.2, 13.7; 19F
NMR (376 MHz, chloroform-d) δ −75.77 (d, J = 8.2 Hz), −182.64
(t, J = 6.8 Hz); HRMS (CI-TOF, m/z) calcd. For C14H11NO2F7 [M +
H]+: calcd, 358.0678; found, 358.0675; IR (ATR, neat, cm−1): 1748
(m), 1279 (m), 1203 (s), 1167 (m), 1099 (m), 984 (m), 954 (m),
708 (m).
Ethyl 3-(tert-Butoxy)-2-cyano-2-(4-(perfluoropropan-2-yl)-
phenyl)propanoate (11a). Following general procedure A employing
5 (0.26 mL, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL,
1.65 mmol) to obtain the desired product as a yellow oil (160 mg,
0.361 mmol, 24%). 10 was also isolated (180 mg, 0.510 mmol, 34%).
Due to the nature of the alkylated compound as an undesired
byproduct, only the minimum analytical data required for
identification was acquired. Chromatography = 12 g SiO2 cartridge,
0 → 30% EtOAc in Hex over 15 min. 1H NMR (500 MHz,
chloroform-d) δ 7.76 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H),
4.44−4.20 (m, 2H), 4.13 (d, J = 8.4 Hz, 1H), 3.73 (d, J = 8.4 Hz,
1H), 1.31 (t, J = 7.1 Hz, 3H), 1.19 (s, 9H); 13C{1H} NMR (126
MHz, chloroform-d) δ 166.2, 135.4, 127.9 (d, J = 20.9 Hz), 127.5 (d,
J = 2.7 Hz), 126.6 (br d, J = 10.9 Hz), 117.5, 124.69−116.63 (m),
92.99−89.10 (m), 74.8, 67.1, 63.6, 55.6, 27.3, 14.0; 19F NMR (376
MHz, chloroform-d) δ −75.64 (d, J = 6.8 Hz), −182.63 (dt, J = 14.7,
7.0 Hz).
para:ortho:para/ortho substitution. The isolated yield corresponds to
the major para-product. All characterization data were in agreement
with the previous report.10a
Ethyl 2-Cyano-2-(4-(perfluorohexyl)phenyl)acetate (12d). Fol-
lowing general procedure B employing 5 (0.26 mL, 1.50 mmol) and
perfluorohexyl iodide (0.36 mL, 1.65 mmol) to obtain the desired
product as an orange solid (297 mg, 0.59 mmol, 39%). Careful
1
analysis of the crude reaction mixture by H NMR revealed a 14:3:1
ratio of para:ortho:para/ortho substitution. The isolated yield
corresponds to the major para-product. All characterization data
were in agreement with the previous report.10a
2-Cyano-2-(4-(perfluoropropan-2-yl)phenyl)acetamide (12e).
Following general procedure B employing S3 (240 mg, 1.50 mmol)
and heptafluoroisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the
desired product as an off-white solid (413 mg, 1.26 mmol, 84%).
Chromatography = 12 g SiO2 cartridge, 0 → 10% MeOH in CH2Cl2
over 15 min. Rf = 0.24 (SiO2, CH2Cl2:MeOH = 95:5); mp = 153−
1
155 °C; H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.84−7.75
(m, 2H), 7.75−7.70 (m, 2H), 7.66 (s, 1H), 5.26 (s, 1H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 165.5, 136.7, 129.4 (d, J = 1.8 Hz),
126.7 (br d, J = 10.9 Hz), 125.7 (d, J = 20.0 Hz), 117.9, 120.6 (qd, J =
286.9, 27.7 Hz), 93.65−89.27 (m), 43.6; 19F NMR (376 MHz,
DMSO-d6) δ −75.22 (d, J = 8.2 Hz), −180.56 to −183.58 (m);
HRMS (CI-TOF, m/z) calcd. For C12H7N2OF7 [M + H]+: calcd,
329.0525; found, 329.0522; IR (ATR, neat, cm−1): 3384 (w), 3187
(w), 2262 (w), 1715 (s), 1278 (m), 1211 (s), 1103 (m), 984 (s).
2-(4-(Perfluoropropan-2-yl)phenyl)-2-(phenylsulfonyl)-
acetonitrile (12f). Following general procedure B employing S1 (386
mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL, 1.65
mmol) to obtain the desired product as a yellow solid (620 mg, 1.46
mmol, 97%). Chromatography = 12 g SiO2 cartridge, 0 → 40%
EtOAc in Hex over 15 min. Rf = 0.40 (SiO2, Hex:EtOAc = 3:1); mp =
1-((4-Fluorophenyl)sulfonyl)-5-methoxy-6-(perfluoropropan-2-
yl)-3,4-dihydronaphthalen-2(1H)-one (12a). Following general
procedure B employing S10 (502 mg, 1.50 mmol) and heptafluor-
oisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the desired
product as a brown solid (206 mg, 0.41 mmol, 27%). Chromatog-
10909
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Note
93−95 °C; 1H NMR (500 MHz, chloroform-d) δ 7.75−7.68 (m, 3H),
7.63 (d, J = 8.2 Hz, 2H), 7.55−7.45 (m, 4H), 5.34 (s, 1H); 13C{1H}
NMR (126 MHz, chloroform-d) δ 135.5, 134.0, 130.2 (d, J = 1.8 Hz),
129.9, 129.3, 129.0 (d, J = 20.9 Hz), 128.8, 126.4 (br d, J = 10.0 Hz),
120.2 (qd, J = 286.7, 28.2 Hz), 112.9, 91.1 (ddt, J = 203.7, 66.8, 33.3
Hz), 62.3; 19F NMR (376 MHz, chloroform-d) δ −75.69 (dq, J = 9.9,
5.3 Hz), −182.66 (dt, J = 14.6, 7.0 Hz); HRMS (CI-TOF, m/z) calcd.
For C17H10NO2SF7 [M + H]+: calcd, 425.0399; found, 426.0393; IR
(ATR, neat, cm−1): 2930 (w), 1282 (m), 1203 (s), 1151 (s), 1103
(m), 1085 (m), 984 (m), 950 (s).
Chromatography = 12 g SiO2 cartridge, 0 → 50% EtOAc in Hex
over 15 min. Rf = 0.23 (SiO2, Hex:EtOAc = 3:1); H NMR (500
1
MHz, chloroform-d) δ 7.79 (br d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz,
2H), 5.23 (s, 1H); 13C{1H} NMR (126 MHz, chloroform-d) δ 129.5,
129.3 (d, J = 20.9 Hz), 127.9 (d, J = 1.8 Hz), 127.5 (br d, J = 10.9
Hz), 124.35−116.00 (m), 111.2, 91.1 (ddt, J = 203.5, 66.5, 33.5 Hz),
27.7; 19F NMR (376 MHz, chloroform-d) δ −75.72 (d, J = 6.8 Hz),
−180.56 to −184.28 (m); HRMS (CI-TOF, m/z) calcd. For
C12H5N2F7 [M + H]+: calcd, 311.0419; found, 311.0411; IR (ATR,
neat, cm−1): 2889 (w), 1278 (m), 1203 (s), 1167 (m), 1103 (m), 984
(m), 954 (m), 708 (m).
2-(3-Methyl-4-(perfluoropropan-2-yl)phenyl)-2-(phenylsulfonyl)-
acetonitrile (12g). Following general procedure B employing S4 (407
mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL, 1.65
mmol) to obtain the desired product as a white solid (540 mg, 1.23
mmol, 82%). Chromatography = 12 g SiO2 cartridge, 0 → 40%
EtOAc in Hex over 15 min. Rf = 0.40 (SiO2, Hex:EtOAc = 3:1); mp =
2-(1-(Perfluoropropan-2-yl)naphthalen-2-yl)-2-(phenylsulfonyl)-
acetonitrile (12k). Following general procedure B employing S14
(461 mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL, 1.65
mmol) to obtain the desired product as a brown solid (248 mg, 0.52
mmol, 35%). Chromatography = 12 g SiO2 cartridge, 0 → 60%
EtOAc in Hex over 15 min. Rf = 0.27 (SiO2, Hex:EtOAc = 3:1); mp =
1
101−104 °C; H NMR (500 MHz, chloroform-d) δ 7.79−7.68 (m,
1
3H), 7.58−7.51 (m, 2H), 7.48 (br d, J = 7.9 Hz, 1H), 7.25−7.19 (m,
2H), 5.21 (s, 1H), 2.49 (d, J = 9.0 Hz, 3H); 13C{1H} NMR (126
MHz, chloroform-d) δ 140.0, 135.5, 134.7, 134.1, 129.9, 129.2, 128.2,
127.2, 127.1, 126.7 (br d, J = 19.1 Hz), 120.7 (qd, J = 287.5, 27.7 Hz),
112.9, 94.1 (ddt, J = 207.4, 64.6, 30.7 Hz), 62.2, 21.7 (br d, J = 16.3
Hz); 19F NMR (376 MHz, chloroform-d) δ −74.75 (dt, J = 10.2, 5.8
Hz), −178.94 (br d, J = 4.1 Hz); HRMS (CI-TOF, m/z) calcd. For
C18H12NO2SF7 [M + H]+: calcd, 440.0555; found, 440.0555; IR
(ATR, neat, cm−1): 2907 (w), 1271 (m), 1226 (s), 1207 (s), 1136
(s), 1103 (m), 1084 (m), 961 (m).
136−139 °C; H NMR (500 MHz, chloroform-d) δ 8.21−8.13 (m,
2H), 8.10−8.05 (m, 1H), 8.02−7.94 (m, 3H), 7.82−7.74 (m, 1H),
7.69−7.62 (m, 4H), 6.14 (d, J = 10.2 Hz, 1H); 13C{1H} NMR (126
MHz, chloroform-d) δ 136.5, 135.4, 134.3, 133.4, 130.8 (d, J = 6.4
Hz, 1C), 129.7, 129.6, 129.3, 128.1, 127.9, 126.8, 126.69−126.23
(m), 125.02−124.55 (m), 124.4 (d, J = 18.2 Hz), 120.9 (ddd, J =
289.1, 29.3, 10.4 Hz), 114.0 (d, J = 2.7 Hz), 99.63−96.46 (m), 60.8
(d, J = 32.7 Hz); 19F NMR (376 MHz, chloroform-d) δ −65.71 to
−68.50 (m), −73.09 (quin, J = 6.1 Hz), −157.56 (br d, J = 8.2 Hz);
HRMS (ESI-TOF, m/z) calcd. For C21H16N2O2SF7 [M + NH4]+:
calcd, 493.0815; found, 493.0813; IR (ATR, neat, cm−1): 3034 (w),
1346 (m), 1223 (s), 1155 (s), 1107 (m), 1058 (m), 969 (m), 924
(m).
2-(3-Chloro-4-(perfluoropropan-2-yl)phenyl)-2-(phenylsulfonyl)-
acetonitrile (12h). Following general procedure B employing S5 (438
mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL, 1.65
mmol) to obtain the desired product as a white solid (578 mg, 1.26
mmol, 84%). Chromatography = 12 g SiO2 cartridge, 0 → 40%
EtOAc in Hex over 15 min. Rf = 0.40 (SiO2, Hex:EtOAc = 3:1); mp =
Methyl 2-Hydroxy-6-(perfluoropropan-2-yl)-1H-indene-3-car-
boxylate (12l). Following general procedure B employing S2 (285
mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL, 1.65
mmol) to obtain the desired product as a white solid (463 mg, 1.29
mmol, 86%). Chromatography = 12 g SiO2 cartridge, 0 → 60%
EtOAc in Hex over 15 min. Rf = 0.28 (SiO2, Hex:EtOAc = 3:1); mp =
134−136 °C; 1H NMR (500 MHz, chloroform-d) δ 11.11 (br s, 1H),
7.67 (br d, J = 7.8 Hz, 1H), 7.59−7.45 (m, 2H), 3.97 (s, 3H), 3.60 (s,
2H); 13C{1H} NMR (126 MHz, chloroform-d) δ 182.0, 168.9, 142.5,
133.7 (d, J = 2.7 Hz), 124.8 (br d, J = 10.9 Hz), 121.86−121.64 (m),
120.7 (br d, J = 11.8 Hz), 120.2 (d, J = 1.8 Hz), 124.41−117.09 (m),
104.8, 98.58−86.09 (m), 51.6, 37.7; 19F NMR (376 MHz,
chloroform-d) δ −75.83 (d, J = 8.2 Hz), −181.60 (t, J = 6.8 Hz);
HRMS (CI-TOF, m/z) calcd. For C14H9O3SF7 [M]+: calcd,
358.0440; found, 358.0456; IR (ATR, neat, cm−1): 2963 (w), 1159
(m), 1588 (m), 1274 (m), 1211 (s), 1185 (s), 1159 (s), 977 (s).
Methyl 6-(1-((Difluoro-λ3-methyl)-λ2-fluoraneyl)-1,2,2,2-tetra-
fluoroethyl)-2-hydroxy-3,4-dihydronaphthalene-1-carboxylate
(12m). Following general procedure B employing S6 (261 mg, 1.50
mmol) and heptafluoroisopropyl iodide (0.23 mL, 1.65 mmol) to
obtain the desired product as an orange solid (409 mg, 1.10 mmol,
73%). Chromatography = 12 g SiO2 cartridge, 0 → 30% EtOAc in
Hex over 15 min. Rf = 0.68 (SiO2, Hex:EtOAc = 3:1); mp = 77−79
°C; 1H NMR (500 MHz, chloroform-d) δ 13.41 (s, 1H), 7.72 (d, J =
8.5 Hz, 1H), 7.32 (br d, J = 8.5 Hz, 1H), 3.84 (s, 3H), 2.77 (t, J = 7.6
Hz, 2H), 2.49 (t, J = 7.6 Hz, 2H), 1.10 (s, 1H); 13C{1H} NMR (126
MHz, chloroform-d) δ 179.8, 172.1, 134.4, 133.84−133.54 (m),
126.20−125.80 (m), 124.47−123.56 (m), 123.12−122.56 (m),
122.09−119.32 (m), 99.3, 91.5 (dquin, J = 201.1, 32.8 Hz), 51.9,
29.2, 27.7, 26.9; 19F NMR (376 MHz, chloroform-d) δ −75.75 (s),
−75.77 (s), −182.51 to −182.65 (m); HRMS (CI-TOF, m/z) calcd.
For C15H11F7O3 [M]+: calcd, 372.0596; found, 372.0600; IR (ATR,
neat, cm−1): 2960 (w), 1625 (w), 1588 (w), 1450 (w), 1274 (m),
1211 (s), 1182 (s), 977 (s).
1
120−121 °C; H NMR (500 MHz, chloroform-d) δ 7.81−7.72 (m,
3H), 7.62−7.52 (m, 3H), 7.46 (s, 1H), 7.38 (br s, 1H), 5.19 (s, 1H);
13C{1H} NMR (126 MHz, chloroform-d) δ 135.9, 135.53−135.01
(m), 134.4 (br s), 133.9, 130.0, 129.5, 129.2 (br d, J = 10.9 Hz), 127.8
(br s), 126.60−125.39 (m), 123.9 (br d, J = 25.4 Hz), 121.6 (br d, J =
28.2 Hz), 119.3 (br d, J = 28.2 Hz), 117.29−116.56 (m), 112.4, 92.7
(dquin, J = 211.4, 33.7 Hz), 61.7; 19F NMR (376 MHz, chloroform-
d) δ −71.13 to −72.62 (m), −74.01 (br s), −168.26 (br s), −179.68
(br s); HRMS (CI-TOF, m/z) calcd. For C17H10NO2SF7Cl [M +
H]+: calcd, 460.0009; found, 460.0006; IR (ATR, neat, cm−1): 2911
(w), 1267 (m), 1230 (s), 1211 (s), 1174 (s), 1137 (s), 976 (m), 954
(s).
2-(4-(Perfluoropropan-2-yl)-3-(trifluoromethyl)phenyl)-2-
(phenylsulfonyl)acetonitrile (12i). Following general procedure B
employing S13 (488 mg, 1.50 mmol) and heptafluoroisopropyl iodide
(0.23 mL, 1.65 mmol) to obtain the desired product as a brown solid
(167 mg, 0.34 mmol, 23%). After isolation, it was found that this
product was in a 7:1 ratio with its constitutional isomer as an
inseparable mixture. Characterization data described for the major
constitutional isomer for clarity. Chromatography = 12 g SiO2
cartridge, 0 → 75% CH2Cl2 in Hex over 30 min. Rf = 0.35 (SiO2,
Hex:EtOAc = 3:1); mp = 102−104 °C; 1H NMR (500 MHz,
benzene-d6) δ 7.37 (s, 1H), 7.30 (d, J = 7.6 Hz, 2H), 7.20−7.17 (m,
1H), 6.95 (br d, J = 8.5 Hz, 1H), 6.87−6.80 (m, 1H), 6.66 (t, J = 7.8
Hz, 2H), 4.12 (s, 1H); 13C{1H} NMR (126 MHz, benzene-d6) δ
134.9, 133.6, 132.3, 130.3, 129.9 (quin, J = 5.7 Hz), 129.6, 128.7,
128.41−128.03 (m), 128.0 (br s), 126.5 (br s), 123.5, 121.75−118.95
(m), 112.5, 92.2 (dt, J = 211.4, 32.8 Hz), 61.5; 19F NMR (376 MHz,
benzene-d6) δ −57.56 (br d, J = 51.8 Hz), −74.72 (br dd, J = 24.5, 6.8
Hz), −179.48 to −184.06 (m); HRMS (CI-TOF, m/z) calcd. For
C18H9NO2SF10 [M + H]+: calcd, 494.0273; found, 494.0279; IR
(ATR, neat, cm−1): 2915 (w), 1259 (m), 1215 (s), 1174 (s), 1137
(s), 1114 (s), 972 (m), 954 (m).
Ethyl 7-(1-((Difluoro-λ3-methyl)-λ2-fluoraneyl)-1,2,2,2-tetrafluor-
oethyl)-3-oxoisochromane-4-carboxylate (12n). Following general
procedure B employing S15 (330 mg, 1.50 mmol) and heptafluor-
oisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the desired
product as a colorless oil (404 mg, 1.03 mmol, 69%). Analysis of the
mixture showed the product as an 8:1 mixture of keto:enol tautomers.
2-(4-(Perfluoropropan-2-yl)phenyl)malononitrile (12j). Following
general procedure B employing S7 (213 mg, 1.50 mmol) and
heptafluoroisopropyl iodide (0.23 mL, 1.65 mmol) to obtain the
desired product as a yellow oil (368 mg, 1.19 mmol, 79%).
10910
https://doi.org/10.1021/acs.joc.1c01296
J. Org. Chem. 2021, 86, 10903−10913

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
For clarity, only the analytical data for the major isomer is reported.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01296
Chromatography = 24 g SiO2 cartridge, 0 → 100% EtOAc in Hex
1
over 20 min. Rf = 0.70 (SiO2, Hex:EtOAc = 2:1); H NMR (500
MHz, chloroform-d) δ 7.65 (br d, J = 8.2 Hz, 1H), 7.55−7.46 (m,
2H), 5.70 (d, J = 14.2 Hz, 1H), 5.33 (d, J = 14.2 Hz, 1H), 4.78 (s,
1H), 4.31−4.17 (m, 2H), 4.17−4.09 (m, 1H), 1.32−1.25 (m, 3H);
13C{1H} NMR (126 MHz, chloroform-d) δ 165.8, 165.6, 132.7, 132.3
(d, J = 1.8 Hz), 128.7 (d, J = 2.7 Hz), 127.4 (d, J = 20.9 Hz), 126.4
(br d, J = 10.0 Hz), 122.6 (br d, J = 11.8 Hz), 120.4 (qd, J = 286.7,
26.3 Hz), 91.2 (dquin, J = 203.2, 33.2 Hz), 69.9, 63.0, 53.0, 13.9; 19F
NMR (376 MHz, chloroform-d) δ −74.86 to −76.17 (m), −181.32 to
−183.13 (m); HRMS (ESI-TOF, m/z) calcd. For C15H12F7O4 [M +
H]+: calcd, 389.0618; found, 389.0606; IR (ATR, neat, cm−1): 2986
(w), 1733 (m), 1303 (m), 1278 (m), 1204 (s), 1167 (s), 1103 (m),
980 (s).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to David (Sloan) Ayers, Jonathan Marshall,
and Michael Peddicord of Bristol Myers Squibb for their help
with characterizing compounds. The authors are grateful to
Eric Simmons of Bristol Myers Squibb for useful discussions
during the course of this work. Matthew Winston (now at
Merck & Co., Inc.) is acknowledged for preliminary
mechanistic experiments and useful discussions.
4-((4-Fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-
isochroman-3-one (12o). Following general procedure B employing
S12 (459 mg, 1.50 mmol) and heptafluoroisopropyl iodide (0.23 mL,
1.65 mmol) to obtain the desired product as a white solid (550 mg,
1.16 mmol, 77%). Chromatography = 24 g SiO2 cartridge, 0 → 100%
EtOAc in Hex over 20 min. Rf = 0.70 (SiO2, Hex:EtOAc = 2:1); mp =
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1
140−142 °C; H NMR (500 MHz, chloroform-d) δ 7.99−7.89 (m,
2H), 7.70 (br d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.51 (d, J = 8.2 Hz,
1H), 7.33−7.24 (m, 2H), 5.98 (d, J = 14.5 Hz, 1H), 5.36 (d, J = 14.5
Hz, 1H), 5.13 (s, 1H); 13C{1H} NMR (126 MHz, chloroform-d) δ
167.8, 165.7, 161.7, 133.7 (d, J = 2.7 Hz), 132.4 (d, J = 10.0 Hz),
131.7 (d, J = 2.7 Hz), 129.0 (d, J = 20.9 Hz), 126.4, 126.2 (br d, J =
10.0 Hz), 122.6 (br d, J = 10.9 Hz), 120.3 (dd, J = 287.0, 27.2 Hz),
116.9 (d, J = 23.6 Hz), 92.88−89.66 (m), 71.2, 70.4; 19F NMR (376
MHz, chloroform-d) δ −75.39 (br dd, J = 9.5, 6.8 Hz), −100.28 (t, J
= 8.2 Hz), −182.19 (quin, J = 7.2 Hz); HRMS (ESI-TOF, m/z) calcd.
For C18H11F8O4S [M + H]+: calcd, 475.0245; found, 475.0229; IR
(ATR, neat, cm−1): 2956 (w), 1737 (m), 1588 (w), 1495 (w), 1278
(m), 1211 (s), 1148 (s), 984 (s).
ASSOCIATED CONTENT
■
sı
* Supporting Information
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D. Discovery of Annulating Reagents Enabling the One-Step and
Highly Stereoselective Synthesis of Cyclopentyl and Cyclohexyl
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Synthesis of (3aR, 9bR)-8-Fluoro-7-(perfluoropropan-2-yl)9b-(phe-
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Joe, C. L.; Coombs, J. R.; Gallagher, W. P.; Kopp, N.; Gonzalez-
Bobes, F.; Eastgate, M. D.; Vaidyanathan, R. Development of a
Scalable Synthetic Route to BMS-986251, Part I: Synthesis of the
Cyclohexane Dicarboxylate Fragment. Org. Process Res. Dev. 2021, 25,
1547. (g) Kalidindi, S.; Gangu, A. S.; Kuppusamy, S.; Sathasivam, S.;
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01296.
Additional optimization of reaction conditions, table of
unsuccessful substrates, and NMR spectra of new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
John R. Coombs − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States; orcid.org/0000-0003-1473-2651;
Email: john.coombs@bms.com
Authors
Lucas W. Hernandez − Chemical Process Development,
Bristol Myers Squibb, New Brunswick, New Jersey 08903,
United States; orcid.org/0000-0001-9530-0927
William P. Gallagher − Chemical Process Development,
Bristol Myers Squibb, New Brunswick, New Jersey 08903,
United States
Carlos A. Guerrero − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States; Present Address: Janssen Research &
Development, LLC, 1400 McKean Road, Spring House,
Pennsylvania, 19477, United States
Francisco Gonzalez-Bobes − Chemical Process Development,
Bristol Myers Squibb, New Brunswick, New Jersey 08903,
United States; orcid.org/0000-0001-7876-7154
10911
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J. Org. Chem. 2021, 86, 10903−10913

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Development of a Scalable Synthetic Route to BMS-986251, Part 2:
Synthesis of the Tricylcic Core and the API. Org. Process Res. Dev.
2021, 25, 1556.
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(15) In keeping with standard industrial practice for optimization,
in-process yields are assessed using “area percentage” (AP) yields. AP
values are uncorrected for the difference in LC response factor for the
starting material versus the desired product. These data, while
approximate, give insight into general trends, aid in determining
optimal conditions for lead reactions, and help approximate reaction
conversion.
(16)
Proposed structure for the MTBE alkylation byproduct, based
on UHPLC-MS and the fact that it hydrolyzes to 8.
(17) See the Supporting Information for details.
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and bicarbonate is too great to facilitate deprotonation of the
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improved, with the major product being the desired para isomer.
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