Generation of ortho-SF5-Benzyne and Its Diels-Alder Reactions with Furans: Synthesis of 1-SF5-Naphthalene, Its Derivatives, and 1,6(1,7)-Bis-SF5-naphthalenes

Article abstract of DOI:10.1021/acs.joc.6b02276

Generation of ortho-SF₅-benzyne was achieved by a lithiation/elimination sequence starting from 2-fluoro-SF₅-benzene. The highly reactive ortho-SF₅-benzyne intermediate was trapped by furan or 2-methylfuran in situ, and th

Full text of DOI:10.1021/acs.joc.6b02276

Article
pubs.acs.org/joc
Generation of ortho-SF ‑Benzyne and Its Diels−Alder Reactions with
5
Furans: Synthesis of 1‑SF ‑Naphthalene, Its Derivatives, and 1,6(1,7)-
5
Bis-SF ‑naphthalenes
5
Oleksandr S. Kanishchev and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611, United States
*
S Supporting Information
ABSTRACT: Generation of ortho-SF -benzyne was achieved
5
by a lithiation/elimination sequence starting from 2-fluoro-
SF -benzene. The highly reactive ortho-SF -benzyne inter-
5
5
mediate was trapped by furan or 2-methylfuran in situ, and the
obtained stable Diels−Alder adducts were subjected to the
series of further chemical transformation, which led to the
formation of previously unknown 1-SF -naphthalene and its
5
derivatives with bromo, amino, hydroxy, and methyl
substituents, including bis-SF -substituted naphthalenes.
5
NMR spectroscopy experiments revealed characteristic
through-space coupling between the SF -group’s equatorial
5
fluorines and proton/carbon nuclei of −H, −CH , and −OH substituents in the peri-position to the SF -group of 1-SF -
3
5
5
naphthalenes.
INTRODUCTION
compounds with only a few examples of 2-SF -naphthalenes
5
■
6
appearing in the literature. The known approaches to 2-SF -
5
Small fluorinated substituents and fluorine itself continue to
play a vital role in life sciences research. Among fluorinated
substituents, the pentafluorosulfanyl (SF ) group is a relatively
new one, in which practical interest has emerged only recently.
When compared to the trifluoromethyl (CF ) group, the SF -
group is often described as its advanced analog, because of
7
1
naphthalene are based on the initial radical addition of SF Cl
SF Br) either to 1,4-dihydronaphthalene (Scheme 1a) or to
5
6a
(
5
5
2
Scheme 1. Known Synthetic Routes toward 2-SF -
5
3
5
6a−c
Naphthalenes
some unique and beneficial properties of the SF -group, which
5
include tetragonal bipyramidal shape, large steric volume, high
electronegativity and lipophilicity, and good chemical and
thermal stability. These features of the SF5 substituent
significantly influence the physicochemical properties of the
entire parent molecule. In relation to a biologically active
compound, this has a particular impact on its pharmacological
profile allowing fine-tuning of the important pharmacokinetic
parameters such as log D, pK , solubility, membrane
a
3
permeability, and metabolic stability. Recent studies revealed
that the SF -substituent should be considered as a bioisostere of
5
the CF -group and possibly of the tert-butyl substituent in drug
3
4
discovery programs. Although the application of SF building
5
blocks in medicinal chemistry is growing in magnitude, it is still
not a very common tool because of their limited commercial
availability and their challenging syntheses. That is why
6
b
benzobarralene (Scheme 1b). Both adducts were converted
into 2-SF -naphthalene via the series of further chemical
5
development of synthetic methods for new SF -containing
5
6a,b
transformations.
No examples of subsequent chemistry
building blocks remains an important field of endeavor for
fluorine chemists.
directed toward the preparation of substituted 2-SF5-
naphthalenes were provided, most likely because of the
availability of multiple reactive centers in such substrates,
The recent breakthrough in the chemistry of SF -arenes
5
5
achieved by Umemoto and co-workers which allowed large-
scale preparation of these compounds made a wide range of
simple SF -arene building blocks readily available. Despite this
Received: September 15, 2016
Published: October 27, 2016
5
fact, SF substituted naphthalenes are still quite a rare class of
5
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02276
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with the probable result of formation of a number of
regioisomers in typical SNAr/SEAr reactions. One example of
a substituted 2-SF -naphthalene, 2-SF -1-naphthol was recently
Table 1. Optimization of the Reaction Conditions for the
Preparation of 2
5
5
6c
described by Ponomarenko. Again, SF Cl was used as the
5
source of the SF -group in the radical addition to oxabenzo-
5
norbornadiene. The resulting adduct was then subjected to
dehydrochlorination and subsequent acid-catalyzed ring open-
ing to furnish 2-SF -1-naphthol (Scheme 1c).
5
a
Recognizing that new SF -containing building blocks might
entry
solvent
THF
Base
equiv of base
ratio 1/2
5
attract research interest from chemists involved in the design
and synthesis of biologically active compounds and new
1
2
3
4
5
6
7
8
9
nBuLi
1.1
1.1
1.1
1.1
1.1
1.1
1.5
2.0
2.2
100/0
80/20
50/50
50/50
100/0
100/0
25/75
0/100
0/100
Et O
2
nBuLi
materials, we turned our attention to SF -naphthalenes as an
Et O
2
secBuLi
tBuLi
5
underrepresented class of SF -substituted arenes.
Et O
2
5
Et O
2
LiHMDS
KHMDS
tBuLi
RESULTS AND DISCUSSION
Et O
2
■
Et O
2
With the aim to develop a strategy for the synthesis of SF -
naphthalenes and their derivatives without the need of using
toxic and not readily available gases (i.e., SF Cl and SF Br) and
5
Et O
2
tBuLi
Et O
2
tBuLi
5
5
aRatio determined from 19F NMR of organic phase after quenching
reaction mixture with sat. aq. NH Cl (entry 1) or with 10% aq. HCl
with a particular interest in the preparation of the yet unknown
-SF -substituted naphthalenes, we considered investigating the
1
4
5
(
entries 2−9).
“benzyne route” toward SF -naphthalenes. A similar approach
5
has previously been used by Schlosser and co-workers for the
8
preparation of various naphthalenes with a CF -group. For
NH
4
Cl (entry 1), the separated organic phase was analyzed by
3
19
example, in their synthesis of 1-CF -naphthalenes, lithiated 2-
F NMR. The remaining starting material 1 was easy to
3
chlorobenzotrifluoride eliminated LiCl and generated ortho-
differentiate from possible reaction products on the basis of the
characteristic pattern of the four equatorial fluorine atoms of its
CF -benzyne, which then underwent reaction with furan to give
3
the corresponding Diels−Alder adduct. Subsequent additional
SF -group, which appears as a doublet of doublets as a result of
5
chemical transformations led to 1-CF -naphthalene and a
the additional through-space fluorine−fluorine coupling of
3
8
number of derivatives (Scheme 2).
these equatorial fluorines with the ortho-fluorine substituent
TS
(
JF−F = 25 Hz). Thus, it was observed that no product and
8
Scheme 2. Schlosser’s Synthesis of 1-CF -Naphthalenes
mainly starting material 1 was detected when THF was used as
a solvent (entry 1), but ∼20% of some new product was
3
obtained when the reaction was carried out in Et O (entry 2).
2
This reaction product was isolated, and its structure was
1
19
13
confirmed to be 2 based on its H, F, C NMR and HRMS
9
19
data. With the exact F NMR shift of the desired product 2
known, it was then easy to further optimize the reaction
conditions. Screening of other bases revealed that sterically
hindered sec-BuLi and t-BuLi led to a higher conversion (∼50/
Considering a possible precursor for the ortho-SF -benzene
5
we took a close look at 2-fluoro-SF -benzene (1), the only
5
5
0) (entries 3 and 4), whereas reactions with LiHMDS or
ortho-substituted SF -benzene that can be directly prepared in
two steps from 2-fluorothiophenol using Umemoto’s method.
Other thiophenols, with any ortho-substituent bulkier than
fluorine, were observed to be substantially more sluggish
toward further oxidative chlorination/fluorination of the
5
KHMDS resulted in no product formation (entries 5 and 6).
Further increases of the amount of t-BuLi to 1.5, 2, and 2.2
equiv showed consistent improved conversion, but little
difference was noticed if 2 or 2.2 equiv of t-BuLi were used,
and in both cases all the starting material 1 was totally
consumed (entries 7−9). The reaction was scaled-up using 10 g
of 1 under the optimized conditions, with the addition product
5a
respective aryl-SF intermediates because of the high steric
3
demand of a six-coordinate sulfur substituent. The requisite
precursor 1 was prepared in 46% yield by the usual Umemoto
2
being isolated in 45% yield as a low melting solid (mp 48−49
5a
procedure starting from 2-fluorothiophenol (Scheme 3).
°
C) after SiO chromatography.
2
In our initial experiments (Table 1), a solution of 2-fluoro-
SF -benzene (1) in THF or Et O was treated with 1.1 equiv of
The obtained Diels−Alder adduct 2 was then subjected to
5
2
additional chemical transformations which led to preparation of
n-BuLi at −78 °C, and after 15−20 min at −78 °C an excess of
furan (10 equiv) was added in one portion. The cooling bath
was then removed, and the reaction mixture was stirred for 16
h. After quenching with 10% aq. HCl (entries 2−9) or sat. aq.
a series of 1-SF -substituted naphthalenes. Thus, deoxygenation
5
8
of epoxynaphthalene 2 using low-valent titanium species
resulted in the clean formation of the 1-SF -naphthalene 3
5
19
(
81% yield). The F NMR spectrum of 3 shows significant
deshielding of the SF -group fluorine atoms (δ : +69.4 (d),
5
F
Scheme 3. Synthesis of 2-Fluoro-SF -benzene (1)
5
+87.0 (m)) when compared with the chemical shifts reported
6b
for 2-SF -naphthalene (δ : +63.0 (d), +84.4 (m)) and SF -
5
F
5
1
0
benzene (δ : +62.2 (d), +84.2 (m)).
F
The acid-catalyzed opening of the epoxy bridge in 2 provided
8
-SF -1-naphthol 4a as a major reaction product, which can be
5
readily separated from the minor more polar 5-SF -1-naphthol
5
4
b by SiO chromatography (ratio of 4a/4b is 85:15 according
2
B
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Article
to 19F NMR of the reaction mixture) (Scheme 4). Both
naphthols were isolated as solids in 72% (4a) and 4% (4b)
yields.
spectra of the mixture also show characteristic through-space
coupling between the equatorial fluorine atoms of the SF -
5
TS
group and the protons ( JH−F = 3.3 Hz; δ
2.93 in CDCl
) and
3
H
TS
carbon ( J
of 6a.
= 10.6 Hz; δ 26.3 in CDCl ) of the CH -group
C−F
C
3
3
Scheme 4. Synthesis of 1-SF -Naphthalene (3) and 5(8)-SF -
5
5
Addition of bromine to the double bond of 2 (Br /CCl /
Naphthols (4a,b)
2
4
reflux) provided three stereoisomers 7a−c as major reaction
products in the 1:1:0.6 ratio (7a:7b:7c) as established on the
1
19
basis of the H and F NMR spectra of the crude product. All
three stereoisomers were isolated as individual compounds after
SiO chromatography. Structural assignment was based not
2
only on the obtained NMR data compared to the
8
When 2-Me-furan was used to intercept the benzyne
intermediate derived from 1, two regioisomeric adducts 5a
and 5b were formed in a 60/40 ratio (5a/5b). Both
corresponding CF -congeners described by Schlosser but
3
also on the structures of the dehydrobromination reaction
products, which were specific for each of the stereoisomers.
With the knowledge that exo-syn-elimination will be favored for
each of the isomers under the same dehydrobromination
regioisomers 5a and 5b have identical R values and were
f
isolated as a mixture after SiO chromatography in 42% yield.
2
1
1
1
However, their ratio can be easily determined from the H
conditions (t-BuOK/THF/rt), stereoisomer 7a formed
product 8a exclusively, stereoisomer 7c gave only product 8b,
and stereoisomer 7b reacted sluggishly affording the mixture of
products 8a and 8b in 40/60 ratio (8a/8b) (Scheme 6).
NMR spectrum of the mixture, where the CH -group of 5a
3
TS
appears as a pentuplet with JH−F = 2.8 Hz (δ 2.05 in CDCl )
H
3
and the CH -group of 5b as a singlet (δ 1.96 in CDCl ). In its
3
H
3
1
3
C NMR spectrum, through-space coupling between the CH3-
11
Alternatively, dehydrobromination (t-BuOK/THF; rt) per-
group and the equatorial fluorines of the SF -group of 5a is also
5
formed on the crude mixture of 7 provided regioisomers 8a and
8b (60/40 ratio) which were readily separable by SiO2
chromatography (R = 0.5 (8a), R = 0.2 (8b); PE/EA 9:1)
TS
observed ( J
= 5.6 Hz; δ 17.8 in CDCl ).
C−F
C 3
Deoxygenation of this regioisomeric mixture led to the
f
f
corresponding 1-Me-8-SF -naphthalene 6a and 1-Me-5-SF -
5
5
and were obtained in 39% (8a) and 36% (8b) yields,
respectively.
Deoxygenation of regioisomers 8a and 8b gave the
naphthalene 6b. Again very close R values did not allow one to
f
isolate 6a and 6b as individual compounds, and after SiO2
chromatography a mixture of regioisomers in 55/45 ratio (6a/
corresponding 2-bromo-8-SF -naphthalene 9b (55%) and 2-
1
13
5
6
b) was obtained in 61% yield (Scheme 5). H and C NMR
bromo-5-SF -naphthalene 9a (59%) as colorless solids (Scheme
5
6
). Structural elucidation of each of the regioisomers was done
Scheme 5. Synthesis of 1-Methyl-5(8)-SF -naphthalenes
1
5
on the basis of their NMR spectroscopy data. H NMR spectra
of 9a and 9b show a distinctive difference for the proton’s
(
6a,b)
signal in peri-position to the SF group. Thus, for 9a it appears
5
TS
as a well resolved doublet of pentuplets ( J
JH−H = 9.5 Hz), whereas, for 9b, it appears as an unresolved
multiplet due to the two similar coupling constants ( J
JH−H ≈ 2.6 Hz) plus due to additional peak broadening
imposed by quadrupolar relaxation of the neighboring bromine
atom.
= 2.9 Hz and
H−F
3
TS
≈
H−F
4
With the aim to further diversify 1-SF -substituted
5
naphthalene building blocks, bromonaphthalenes 9a and 9b
a
Scheme 6. Addition of Bromine to 2: Synthesis of 2-Bromo-5(8)-SF -naphthalenes and 2-Amino-5(8)-SF -naphthalenes
5
5
a
Reaction conditions: (a) Br , CCl , reflux, 30 min; (b) t-BuOK, THF, rt, 3 days; (c) Zn, TiCl , THF, reflux, 16 h; (d) trans-4-hydroxy-L-proline (40
2
4
4
mol %), CuI (20 mol %), K CO (3 equiv), 28% aq. NH OH, DMSO, 75 °C, 48 h.
2
3
4
C
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The Journal of Organic Chemistry
Article
a
Scheme 7. Addition of SF Cl to 2: Synthesis of 1,6(1,7)-Bis-SF -naphthalenes 13a,b
5
5
a
Reaction conditions: (a) SF Cl (2 equiv), Et B (10 mol %), CH Cl , −30 °C, 18 h then 25 °C, 6 h; (b) LiOH (5 equiv), DMSO, rt, 24 h; (c) Zn,
5
3
2
2
TiCl , THF, reflux, 16 h.
4
were converted into the corresponding naphthylamines 10a
82% yield) and 10b (81% yield). This transformation was
performed under the coupling conditions developed by Ma and
substituted derivatives, including bis-SF -naphthalenes. One of
5
(
the remarkable features of 1-SF -naphthalenes is the through-
5
space coupling between proton (and carbon) nuclei of −H,
1
2
co-workers using the CuI/4-hydroxy-L-proline/NH OH
−CH , and −OH substituents in the peri-position to the SF
4
3
5
system in DMSO at 75 °C (Scheme 6).
group and its equatorial fluorines atoms, revealed by NMR
Low temperature radical addition of SF Cl to the double
spectroscopy.
5
7
bond of 2 was achieved using Et B in CH Cl while
3
2
2
maintaining the reaction mixture at −30 °C for 18 h. Similar
conditions were applied recently by Ponomarenko for the
EXPERIMENTAL SECTION
General Experimental Methods. NMR spectra were recorded in
■
1
13
addition of SF Cl to the unsubstituted analog of 2, 1,4-dihydro-
CDCl
3
at 25 °C at 300/500 MHz for H NMR; 125 MHz for
C
5
6c
19
NMR, and 282 MHz for F NMR. Chemical shifts (δ) are reported in
1,4-epoxynaphthalene. Predictably, two regioisomeric adducts
11a and 11b were formed in almost equal amounts (ratio 11a/
11b 52:48) and each regioisomer was formed as a single
ppm and are referenced to the solvent signal as an internal standard
1
13
(
CHCl at 7.26 ppm for H NMR, and CDCl at 77.16 ppm for C
3
3
19
NMR). F NMR spectra are referenced to CFCl as an internal
3
stereoisomer with trans disposition of exo-SF - and endo-Cl-
5
standard. Coupling constants (J) are reported in Hz. Multiplicities are
abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet),
p (pentuplet), m (multiplet or unresolved), and br (broad signal).
Reactions were monitored by TLC and/or 19F NMR. TLC was
performed on Sorbtech silica gel UV254 polyester backed 200 μm
thickness TLC plates and visualized with UV light. Chromatographic
purification was performed as flash chromatography using Sorbtech
silica gel 60A 40−63 μm (230−400 mesh) at positive nitrogen
pressure. HRMS spectra were obtained using a TOF mass analyzer in
positive or negative ESI or DART ionization modes. Melting points
were determined using a capillary melting point apparatus. Anhydrous
and regular solvents were used as received from commercial suppliers.
All other reagents were obtained from common vendors unless
6
c
substituents. Efficient separation of 11a/11b was not possible
using SiO chromatography, and a mixture of both regioisomers
2
was isolated in 73% yield (Scheme 7).
Dehydrochlorination (5 equiv of LiOH/DMSO; rt, 18 h)
13
performed on the mixture of 11a,b provided corresponding
compounds 12a and 12b in 59% total yield, which were readily
separable by SiO2 chromatography. 2,5-Bis-SF -substituted
5
oxabenzonorbornadiene 12a appeared as an oil (R = 0.55
f
(
PE/EA 9:1); 38% yield), while 2,8-bis-SF -substituted 12b was
5
isolated as a colorless solid (R = 0.1 (PE/EA 9:1); 21% yield)
f
TS
(Scheme 7). Interestingly, through-space coupling ( J = 6.7
F−F
Hz) between equatorial fluorine atoms of both SF -groups in
otherwise stated. SF Cl was supplied by Synquest Laboratories, Inc.
5
5
1
9
1
2b can be observed in its F NMR spectrum.
Note: The identities of compounds 2, 10, 12, and 13 were
1
13
19
Finally, deoxygenation of 12a and 12b under the previously
established on the basis of H, C, F NMR and HRMS data. For
compounds 3−9 and 11, relevant HRMS data were not able to be
established conditions (Zn/TiCl /THF; reflux, 16 h) gave the
4
1
obtained, and accordingly they are characterized on the basis of H,
corresponding 1,6-bis-SF -substituted naphthalene 13a (70%
5
13
19
C, F NMR and GC/MS (LC/MS), as well as from the logic of the
yield) and the 1,7-bis-SF -substituted naphthalene 13b (92%
5
synthetic sequences.
yield) as colorless solids (mp: 108−109 °C (13a); mp: 105−
Caution! Anhydrous hydrogen fluoride (bp 20 °C) is a very toxic
and extremely hazardous material. All of the experiments using
anhydrous hydrogen fluoride should be performed in an efficient fume
hood by personnel wearing proper protective clothing who are well
familiar with the precautions necessary for safe handling of anhydrous
1
06 °C (13b)). These constitute the first reported examples of
bis-SF -substituted naphthalenes (Scheme 7). Because of the
5
greater distance between SF -groups in planar naphthalene 13b
5
compared to 12b, through-space coupling was no longer
observed in its 19F NMR spectrum.
14
hydrogen fluoride!
5
a
2
-Fluorophenylsulfur Pentafluoride (1). Prepared according to
5a
the general literature procedure for making arylsulfur pentafluorides
from aromatic thiols. Thus, 2-fluorothiophenol (200 g; 1.56 mol) was
converted into 2-fluorophenylsulfur chlorotetrafluoride using KF/Cl2
CONCLUSIONS
■
5
a
In summary, we have developed convenient access to
previously unknown 1-SF -substituted naphthalenes starting
in CH CN: 320 g (86% yield) of the crude material were obtained,
3
5
which was then treated with a mixture of anhydrous HF (790 g; 39.5
from readily available 2-fluoro-SF -benzene. Our approach
5
mol; 29 equiv) and KHF (115 g; 1.5 mol; 1.1 equiv) in a sealed 2 L
2
relies on the lithiation of 2-fluoro-SF -benzene, resulting in
5
PTFE reactor. The reaction mixture was stirred at ambient
temperature for 65 h, and after the usual workup and distillation, 1
was isolated as a colorless liquid. Yield: 160 g (54%; 46% from 2-
ortho-SF -benzyne formation and subsequent trapping of this
5
highly reactive intermediate by furan in situ. Further simple
chemical transformations of the obtained oxabenzonorborna-
1
fluorothiophenol); bp 159−160 °C/760 mmHg. H NMR (300 MHz,
1
3
diene type of adduct led to 1-SF -naphthalene and a series of its
CDCl ): δ 7.76 (m, 1H), 7.52 (m, 1H), 7.23 (m, 1H). C NMR (125
5
3
D
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The Journal of Organic Chemistry
Article
1
= 260 Hz, 3J
126.3, 123.1, 118.1 (p, 4JC−F = 5.3 Hz), 108.9. 19F NMR (282 MHz,
MHz, CDCl ): δ 156.2 (dp, J
= 1.9 Hz), 140.2
C−F
3
C−F
2
2
3
2
(
(
dp, J
= 18.5 Hz, J
= 11.3 Hz), 133.9 (d, J
= 4.9 Hz), 124.2 (d, J
Hz). F NMR (282 MHz, CDCl ): δ 81.3 (m, 1F, SF ), 67.6 (ddm,
JF−F = 149.0 Hz, JF−F = 25 Hz, 4F, SF ), −108.8 (pm, JF−F = 25
= 9 Hz), 128.7
CDCl ): δ 87.1 (m, 1F, SF ), 69.3 (d, J = 149.0 Hz, 4F, SF ). LC/
C−F
C−F
C−F
3
5
F−F
5
3
4
2
−
p, J
= 3.7 Hz), 118.1 (d, J = 23.7
MS (-ESI): m/z 269 [M − H] ; RT 36.67 min.
C−F
C−F
C−F
1
9
1-Methyl-8-(pentafluorosulfanyl)-1,4-dihydro-1,4-epoxynaph-
thalene (5a) and 1-Methyl-5-(pentafluorosulfanyl)-1,4-dihydro-1,4-
epoxynaphthalene (5b). Prepared analogously to 2 from 1 (1 g; 4.5
mmol) and 2-methylfuran (3.7 g; 45 mmol; 10 equiv). Inseparable
3
5
2
TS
TS
5
Hz, 1F, C−F).
5
9
-(Pentafluorosulfanyl)-1,4-dihydro-1,4-epoxynaphthalene (2).
t-BuLi (53 mL of 1.7 M solution in pentane; 5.75 g; 90 mmol; 2
equiv) was added dropwise at −78 °C to a solution of 1 (10 g; 45
mmol) in anhydrous Et O (80 mL) over 30 min. After addition, the
reaction mixture was stirred at −78 °C for more 30 min. Then furan
30 g; 0.45 mol; 20 equiv) was added fast in one portion, and the
cooling bath was removed. After 16 h of stirring, the reaction mixture
was poured into 10% HCl (100 mL). More Et O (50 mL) was added,
the organic layer was separated, and the aqueous layer was extracted
with Et O (80 mL). The combined organic phase was washed with
water (2 × 100 mL), dried with MgSO , and evaporated. The residue
was purified by column chromatography (PE/DCM (1:1); R = 0.5) to
give 2 as a yellowish solid. Yield: 5.5 g (45%); mp 48−49 °C. H NMR
300 MHz, CDCl ): δ 7.34 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.4 Hz,
H), 7.02−7.10 (m, 3H), 6.10 (m, 1H), 5.80 (s, 1H). C NMR (125
MHz, CDCl ): δ 151.9, 147.4 (p, J
Hz), 144.3, 142.2, 126.3, 122.8, 122.3 (p, J
JC−F = 3.3 Hz), 82.6. F NMR (282 MHz, CDCl ): δ 83.8 (m, 1F,
SF ), 64.1 (d, J = 149.0 Hz, 4F, SF ). HRMS (ESI+/DART): calcd
for [C H F OS] : 271.0211, found: 271.0218 [M + H] .
-Pentafluorosulfanylnaphthalene (3). To a suspension of Zn
powder (1.3 g; 20 mmol) in dry THF (10 mL), stirred and cooled in
an ice/water bath, was slowly added TiCl (1.9 g; 10 mmol). After
mixture of 5a and 5b (60:40) was obtained in 42% yield (0.54 g) after
1
column chromatography (PE/DCM 3:1; R = 0.2). 5a (major): H
f
NMR (500 MHz, CDCl ): δ 7.35 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 6.6
3
2
Hz, 1H), 7.06 (m, 1H), 7.03 (m, 1H), 6.77 (d, J = 5.4 Hz, 1H), 5.66
TS
13
(
(
=
8
8
2
d, J = 1.8 Hz, 1H), 2.05 (p, JH−F = 2.8 Hz, 3H, CH ). C NMR
3
(
3
2
125 MHz, CDCl ): δ 154.2, 147.9 (p, J
18 Hz), 145.6, 145.1, 126.1, 123.3 (p, J
1.0, 17.8 (p, JC−F = 5.6 Hz, CH ). F NMR (282 MHz, CDCl ): δ
= 2.5 Hz), 147.8 (p, J
C−F
= 5.6 Hz), 122.4, 93.3,
3
C−F
3
C−F
2
TS
19
3
3
2
3.8 (m, 1F, SF ), 66.4 (d, J = 149.0 Hz, 4F, SF ). GC-MS (m/z):
5
F−F
5
2
+
1
84 [M ]; RT 12.72 min. 5b (minor): H NMR (500 MHz, CDCl ):
3
4
δ 7.28 (d, J = 8.9 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.08 (m, 1H), 7.04
m, 1H), 6.81 (d, J = 5.4 Hz, 1H), 6.00 (m, 1H), 1.96 (s, 3H, CH ).
f
(
1
3
13
3
C NMR (125 MHz, CDCl ): δ 154.4, 148.1 (p, J
= 2.9 Hz),
3
C−F
(
3
2
3
13
147.0 (p, JC−F = 18 Hz), 146.7, 143.3, 126.2, 121.9 (p, JC−F = 4.8
Hz), 121.3, 89.8, 83.2 (p, JC−F = 3.1 Hz), 14.9. F NMR (282 MHz,
CDCl
MS (m/z): 284 [M ]; RT 12.2 min.
1
4
19
2
3
= 18 Hz), 146.8 (p, J
= 3
3
C−F
C−F
2
3
3
): δ 84.3 (m, 1F, SF ), 64.2 (d, JF−F = 149.0 Hz, 4F, SF ). GC-
5
5
= 4.8 Hz), 84.0 (p,
C−F
+
4
19
3
1
-Methyl-8-(pentafluorosulfanyl)naphthalene (6a) and 1-Meth-
2
5
F−F
5
yl-5-(pentafluorosulfanyl)naphthalene (6b). Prepared analogously to
3 from the mixture of 5a and 5b (0.4 g; 1.4 mmol). An inseparable
+
+
10
8 5
1
mixture of 6a and 6b (55:45) was obtained in 61% yield (0.23 g) after
1
column chromatography (pentane; R = 0.6). 6a (major): H NMR
f
4
(300 MHz, CDCl ): δ 8.28 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz,
3
addition, the cooling bath was removed and the green/yellow
suspension was heated under reflux for 15 min. The resulted black
suspension was cooled to ambient, and a solution of 2 (0.55 g; 2
mmol) in dry THF (5 mL) was added. The reaction mixture was
maintained at reflux for 16 h, then cooled, and poured into a mixture
1
H), 7.76 (d, J = 8.0 Hz, 1H), 7.58 (m, 1H), 7.42 (m, 2H), 2.93 (p,
TS
13
JH−F = 3.3 Hz, 3H, CH3). C NMR (125 MHz, CDCl ): δ 152.1 (p,
3
2J
3
= 15.4 Hz), 137.0, 134.8, 133.8, 129.5 (p, J
= 7.8 Hz), 129.1,
C−F
C−F
TS
19
1
28.9, 127.4, 126.0, 123.6, 26.3 (p, JC−F = 10.6 Hz, CH ). F NMR
3
2
(282 MHz, CDCl ): δ 87.3 (m, 1F, SF ), 72.7 (dp, J = 149.0 Hz,
3 5 F−F
of 10% HCl (50 mL) and Et O (30 mL), followed by stirring until the
TS
+
2
JF−H = 2.7 Hz, 4F, SF ). GC-MS (m/z): 268 [M ]; RT 8.84 min. 6b
5
remaining Zn dissolved. The Et O layer was separated, and the
1
2
(minor): H NMR (300 MHz, CDCl ): δ 8.37 (dp, J = 9.0 Hz, J = 3.0
3
aqueous layer was extracted with Et O (30 mL). The combined
2
Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.11 (dd, J = 7.9 Hz, J = 1.0 Hz,
organic phase was washed with water (2 × 30 mL), dried with MgSO4,
and evaporated. The residue after evaporation was purified by column
1
2
1
H), 7.55 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.45 (m, 1H),
.74 (s, 3H, CH3). C NMR (125 MHz, CDCl ): δ 152.5 (p, J
13
2
=
= 5.8
3
C−F
chromatography (pentane; R = 0.6) to give pure 3 as a colorless oil.
3
f
4.2 Hz), 135.7, 135.0, 134.2, 129.3, 127.9, 128.0, 127.4 (p, J
1
C−F
Yield: 0.42 g (81%). H NMR (500 MHz, CDCl ): δ 8.47 (dm, 1H,
4
19
3
Hz), 123.7 (p, J
CDCl ): δ 87.8(m, 1F, SF ), 69.8 (d, J = 149.0 Hz, 4F, SF ). GC-
MS (m/z): 268 [M ]; RT 8.84 min.
= 5.3 Hz), 123.1, 20.4. F NMR (282 MHz,
C−F
H-8), 8.09 (dd, J = 7.9 Hz, J = 0.9 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H),
2
3
5
F−F
5
7
1
.91 (d, J = 8.2 Hz, 1H), 7.66 (ddd, J = 9.1 Hz, J = 6.9 Hz, J = 1.4 Hz,
+
H), 7.57 (tm, J = 7.6 Hz, J = 0.7 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H).
2
,3-Dibromo-1,4-epoxy-1,2,3,4-tetrahydro-5-(pentafluoro-
1
3
2
C NMR (125 MHz, CDCl ): δ 151.8 (p, J
= 14 Hz), 134.9,
3
C−F
sulfanyl)naphthalenes (7a−c). A solution of 2 (5.15 g; 19 mmol) in
CCl (35 mL) was stirred at reflux while a solution of Br (4.8 g; 30
mmol) in CCl (15 mL) was added to it dropwise over 15 min. After
addition, the reaction mixture was maintained at reflux for more 30
3
1
33.7, 129.1, 128.5, 127.8, 127.7 (p, J
= 5.8 Hz), 126.4, 125.4 (p,
C−F
4
2
4
19
JC−F = 5.3 Hz), 123.8. F NMR (282 MHz, CDCl ): δ 87.0 (m, 1F,
3
4
2
+
SF ), 69.4 (d, J = 149.0 Hz, 4F, SF ). GC-MS (m/z): 254 [M ].
5
F−F
5
8
-Pentafluorosulfanyl-1-naphthol (4a) and 5-Pentafluoro-
min, then it was cooled, and evaporated to dryness. A part of the
sulfanyl-1-naphthol (4b). To a solution of 2 (0.55 g; 2 mmol) in
EtOH (15 mL) was added 38% HCl (3 mL), and the reaction mixture
was stirred under reflux for 72 h. Solvent was evaporated, DCM (50
mL) was added to the residue, and the organic phase was washed with
obtained residue was purified by SiO chromatography (PE/DCM
2
4:1), and analytically pure samples of each of the stereoisomers 7a−c
were obtained. Another part of the crude residue was directly
subjected to the further dehydrobromination step. Stereoisomer 7a: R
f
1
water (2 × 30 mL), dried with MgSO , and evaporated. The obtained
residue was purified by column chromatography (PE/EA (9:1)) to
give 4a as a light brown solid (R = 0.2) and 4b as a dark green solid
= 0.52 (PE/DCM 4:1); mp 82−85 °C. H NMR (300 MHz, CDCl ):
4
3
δ 7.64 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.44 (m, 1H), 5.81
(m, 1H), 5.49 (dd, J = 4.7 Hz, J = 0.9 Hz, 1H), 4.53 (dd, J = 4.7 Hz, J
f
1
13
(
R = 0.12). 4a: mp 70−72 °C. Yield: 0.42 g (72%). H NMR (500
= 2.7 Hz, 1H), 3.78 (d, J = 2.7 Hz, 1H). C NMR (125 MHz,
f
2
3
MHz, CDCl ): δ 8.16 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H),
CDCl
3
): δ 146.9 (p, JC−F = 19.1 Hz), 143.7, 138.3 (p, JC−F = 2.5 Hz),
3
3
4
7
.54 (dd, J = 8.1 Hz, J = 1.0 Hz, 1H), 7.44 (m, 2H), 7.18 (dd, J = 7.6
Hz, J = 1.3 Hz, 1H), 6.23 (p,
125 MHz, CDCl ): δ 150.4 (p, J
28.9 (p, J
128.7, 126.7, 125.7 (p, JC−F = 4.9 Hz), 88.4 (p, JC−F = 3.2 Hz), 83.4,
51.4, 50.2. F NMR (282 MHz, CDCl ): δ 82.7 (m, 1F, SF ), 64.3 (d,
3 5
TS
13
19
J
= 4.0 Hz, 1H, OH). C NMR
H−F
2
2
+
(
1
(
= 17 Hz), 150.0, 137.3, 134.8,
JF−F = 150.0 Hz, 4F, SF ). GC-MS (m/z): 348 [M − Br] ; RT 10.27
5
3
C−F
3
19
= 7.5 Hz), 127.1, 123.5, 123.2, 119.1, 117.0. F NMR
min. Stereoisomer 7b: R = 0.33 (PE/DCM 4:1); mp 128−130 °C.
C−F
f
2
1
282 MHz, CDCl ): δ 87.7 (m, 1F, SF ), 72.7 (d, J = 149.0 Hz, 4F,
H NMR (300 MHz, CDCl ): δ 7.61 (d, J = 8.2 Hz, 1H), 7.52 (d, J =
3
5
F−F
3
+
SF ). GC-MS (m/z): 271 [M ]; RT 9.22 min. 4b: yield: 22 mg (4%).
7.2 Hz, 1H), 7.40 (m, 1H), 5.84 (m, 1H), 5.59 (s, 1H), 4.23 (s, 2H).
5
1
13
2
H NMR (500 MHz, CDCl ): δ 8.52 (d, J = 8.4 Hz, 1H), 8.10 (dd, J =
C NMR (125 MHz, CDCl ): δ 147.3 (p, J
= 19.2 Hz), 144.9,
= 4.8 Hz), 123.9, 89.1
3
3
C−F
3
3
7
.9 Hz, J = 1.2 Hz, 1H), 8.03 (dp, J = 9.2 Hz, J = 3.0 Hz, 1H), 7.50 (m,
H), 7.45 (dd, J = 9.0 Hz, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H),
.59 (br s, 1H, OH). 13C NMR (125 MHz, CDCl ): δ 151.8 (p, J
139.4 (p, J
(p, J
= 2.5 Hz), 129.6, 125.7 (p, J
C−F
C−F
4
19
1
5
=
= 2.9 Hz), 87.9, 51.2, 50.4. F NMR (282 MHz, CDCl ): δ
C−F
3
2
2
82.4 (m, 1F, SF ), 64.3 (d, J = 150.0 Hz, 4F, SF ). GC-MS (m/z):
348 [M − Br] ; RT 11.32 min. Stereoisomer 7c: R = 0.45 (PE/
3
C−F
5
F−F
5
3
+
14.6 Hz), 151.7, 129.0, 128.4 (p, J
= 5.8 Hz), 128.3, 127.4,
C−F
f
E
DOI: 10.1021/acs.joc.6b02276
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
2
DCM 4:1); mp 137−139 °C. H NMR (300 MHz, CDCl ): δ 7.69 (d,
SF ), 69.3 (d, J
= 149.0 Hz, 4F, SF ). HRMS (ESI+): calcd for
3
5
F−F
5
+
J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.43 (m, 1H), 5.87 (m, 1H),
[C H F NS] : 270.0370, found: 270.0369.
10
9 5
5
1
1
1
.51 (s, 1H), 4.54 (dd, J = 4.7 Hz, J = 2.5 Hz, 1H), 3.94 (d, J = 2.5 Hz,
2-Amino-8-(pentafluorosulfanyl)naphthalene (10b). In a 5 mL
glass pressure tube to a solution of 9b (0.33 g; 1 mmol) in DMSO (2.5
mL) were added trans-4-hydroxy-L-proline (55 mg; 0.4 mmol), CuI
H). 13C NMR (125 MHz, CDCl ): δ 149.3 (p, J
2
= 18.2 Hz),
= 5.1 Hz),
= 2.2 Hz), 52.8, 49.2. F NMR (282 MHz,
3
C−F
3
3
43.8, 139.1 (p, J
= 2.5 Hz), 129.4, 125.7 (p, J
C−F
C−F
4
19
23.9, 86.8, 84.1 (p, J
(40 mg; 0.2 mmol), K CO (0.42 g; 3 mmol), and 28% aq. NH OH
2
3
4
C−F
2
CDCl ): δ 82.9 (m, 1F, SF ), 66.1 (d, J = 151.0 Hz, 4F, SF ). GC-
MS (m/z): 348 [M − Br] ; RT 10.70 min.
(1.5 mL). The tube was sealed with a closure and vigorously stirred at
75 °C for 48 h. The cold reaction mixture was then partitioned
between water (25 mL) and EtOAc (25 mL). After separation of the
EtOAc layer, the water phase was extracted with more EtOAc (25
mL), and the organic phase was combined, washed with brine, dried
3
5
F−F
5
+
2
-Bromo-5-(pentafluorosulfanyl)-1,4-dihydro-1,4-epoxynaph-
thalene (8a) and 2-Bromo-8-(pentafluorosulfanyl)-1,4-dihydro-1,4-
epoxynaphthalene (8b). To a solution of crude 7 (4.3 g; 10 mmol) in
anhydrous THF (50 mL) was added tBuOK (1.15 g; 10 mmol), and
the reaction mixture was stirred for 72 h. Solvent was evaporated, and
the residue was partitioned between Et O (75 mL) and water (75
mL). After separation of the Et O layer, the water phase was extracted
with MgSO , and evaporated. The obtained residue was purified by
4
SiO chromatography (R = 0.3; PE/CH Cl 1:1) to give 10b: mp 80−
2
f
2
2
1
81 °C (beige solid). Yield: 0.22 g (81%). H NMR (300 MHz,
CDCl
2
): δ 7.97 (dd, J = 8.0 Hz, J = 1.1 Hz, 1H), 7.83 (d, J = 8.0 Hz,
2
3
with more Et O (2 × 50 mL), and the combined organic phase was
1H), 7.69 (d, J = 8.8 Hz, 1H), 7.52 (m, 1H), 7.21 (m, 1H), 6.99 (dd, J
2
13
washed with water, dried with MgSO , and evaporated. The obtained
= 8.8 Hz, J = 2.2 Hz, 1H), 4.08 (br s, 2H, NH
2
). C NMR (125 MHz,
): δ 150.0 (p, JC−F = 14.0 Hz), 146.4, 133.3, 130.6, 129.6,
3
4
2
residue was purified by column chromatography (PE/EA (9:1)) to
CDCl
129.4, 128.3 (p, JC−F = 5.8 Hz), 119.9, 118.5, 105.7 (p, JC−F = 4.9
3
4
give 8a as a light brown oil (R = 0.5) and 8b as a light brown solid (Rf
f
Hz). 19F NMR (282 MHz, CDCl
= 149.0 Hz, 4F, SF ). HRMS (ESI+): calcd for [C10
70.0370, found: 270.0381.
): δ 88.3 (m, 1F, SF ), 68.5 (d, JF−F
2
=
0.2) in 75% total yield. (Alternatively when a pure sample of each of the
3
5
+
stereoisomers 7a−c was subjected to the above-mentioned dehydrobromi-
nation conditions, stereoisomer 7a formed product 8a exclusively,
stereoisomer 7c gave product 8b only, and stereoisomer 7b afforded
5
H F NS] :
9 5
2
endo-2-Chloro-exo-3,8-bis(pentafluorosulfanyl)-1,2,3,4-tetra-
hydro-1,4-epoxynaphthalene (11a) and endo-2-Chloro-exo-3,5-
bis(pentafluorosulfanyl)-1,2,3,4-tetrahydro-1,4-epoxynaphthalene
1
9
products 8a and 8b in a 40/60 ratio (8a/8b) as was determined by
F
1
NMR of their reaction mixtures). 8a: Yield: 1.35 g (39%). H NMR
(
11b). In 100 mL glass pressure tube containing a solution of 2 (2.03
(
300 MHz, CDCl ): δ 7.48 (d, J = 7.1 Hz, 1H), 7.38 (d, J = 8.4 Hz,
3
g; 7.5 mmol) in anhydrous CH Cl (20 mL) at −50 °C, SF Cl (2.45 g;
1
2
2
5
1
1
1
H), 7.14 (m, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.11 (m, 1H), 5.54 (d, J =
5 mmol) was condensed under the solvent surface. Then 1.5 mL of 1
.0 Hz, 1H). 13C NMR (125 MHz, CDCl ): δ 149.8, 147.2 (p, J
2
=
3
C−F
M hexane solution of Et B (0.15 g; 1.5 mmol) was added. The tube
3
3
8.6 Hz), 145.2 (p, J
= 3.1 Hz), 138.7, 137.9, 126.7, 123.4, 123.2
C−F
was sealed with a PTFE closure, and the reaction mixture was stirred at
3
4
19
(
p, J
= 4.8 Hz), 87.2, 85.9 (p, J
= 3.3 Hz). F NMR (282
C−F
C−F
−
30 °C (cryostat) for 18 h and then at 25 °C for 6 h. It was diluted
2
MHz, CDCl ): δ 83.4 (m, 1F, SF ), 64.2 (d, J = 150.0 Hz, 4F,
SF ). GC-MS (m/z): 347 [M ]; RT 8.87 min. 8b: mp 67−69 °C.
Yield: 1.25 g (36%). H NMR (500 MHz, CDCl ): δ 7.37 (d, J = 6.8
3
5
F−F
with CH Cl (30 mL), washed with brine, and dried with MgSO and
+
2
2
4
5
evaporated. The obtained residue was purified by column chromatog-
1
3
raphy (PE/EA (9:1)) to give 2.36 g (73%) of 11a and 11b (ratio 11a/
Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.17 (m, 1H), 7.06 (d, J = 2.1 Hz,
1
1
1b (60:40)) as a white solid (R = 0.25; PE/EA (95:5)). 11a: H
f
1
3
1
H), 5.90 (m, 1H), 5.79 (dd, J = 2.1 Hz, J = 1.1 Hz, 1H). C NMR
NMR (300 MHz, CDCl ): δ 7.71 (d, J = 6.6 Hz, 1H), 7.58 (d, J = 7.0
3
2
(
125 MHz, CDCl ): δ 150.1, 147.6 (p, J
= 18.6 Hz), 144.9 (p,
3
C−F
Hz, 1H), 7.47 (m, 1H), 5.94 (s, 1H), 5.90 (m, 1H), 5.07 (tm, J = 4.2
3
3
JC−F = 3.1 Hz), 141.1, 136.0, 127.3, 122.8, 122.7 (p, J
= 4.8 Hz),
13
C−F
Hz, 1H), 3.96 (m, 1H). C NMR (125 MHz, CDCl ): δ 149.6 (p,
3
7.9 (p, 4J
= 2.5 Hz), 84.4 (C-4). F NMR (282 MHz, CDCl ): δ
19
2
3
8
8
3
C
−
F
3
JC−F = 19.2 Hz), 143.9, 138.6 (p, J
JC−F = 5.1 Hz), 123.6, 93.0 (p, J
= 2.5 Hz), 129.8, 126.2 (p,
C−F
2
3.0 (m, 1F, SF ), 65.2 (d, J = 150.0 Hz, 4F, SF ). GC-MS (m/z):
3
2
5
F−F
5
= 11.7 Hz), 83.4 (m), 83.1 (p,
C−F
+
47 [M ]; RT 10.94 min.
-Bromo-5-(pentafluorosulfanyl)naphthalene (9a). Prepared
analogously to 3 from 8a (1.19 g; 3.4 mmol). R = 0.55 (PE); mp
6−78 °C (colorless solid). Yield: 0.67 g (59%). H NMR (300 MHz,
CDCl ): δ 8.32 (dp, J = 9.5 Hz, J = 2.9 Hz, 1H), 8.09 (d, J = 7.9 Hz,
4J
3
19
= 4.8 Hz), 55.1 (p, J
= 4.2 Hz). F NMR (282 MHz,
C−F
C−F
2
2
CDCl ): δ 82.4 (m, 1F, SF ), 82.3 (m, 1F, SF ), 65.8 (d, J = 150.0
3
5
5
F−F
2
3
f
Hz, 4F, SF ), 61.6 (dd, J = 146.0 Hz, J
= 6.0 Hz, 4F, SF ). GC-
1
5
F−F
F−H
5
7
+
1
MS (m/z): 304 [M − SF ] ; RT 9.33 min. 11b: H NMR (300 MHz,
5
3
CDCl ): δ 7.69 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.46 (m,
3
1
9
H), 8.07 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.72 (dd, J =
1
H), 6.27 (s, 1H), 5.53 (d, J = 4.9 Hz, 1H), 5.04 (tm, J = 4.5 Hz, 1H),
13
.5 Hz, J = 2.2 Hz, 1H), 7.54 (m, 1H). C NMR (125 MHz, CDCl ):
13
2
3
3.84 (m, 1H). C NMR (125 MHz, CDCl ): δ 146.7 (p, J
= 19.6
3
C−F
2
3
δ 151.9 (p, J = 15.4 Hz), 135.9, 132.6, 131.7, 130.9, 127.9 (p, J
=
3
C−F
C−F
Hz), 143.6, 138.2 (m), 129.3, 126.8, 126.1 (p, J = 4.8 Hz), 92.2 (p,
C−F
4
19
5.7 Hz), 127.2 (p, J
= 5.2 Hz), 126.2, 125.0, 120.8. F NMR
2
3
19
C−F
JC−F = 12.0 Hz), 84.7 (m), 82.5, 55.4 (p, J
= 4.1 Hz). F NMR
C−F
2
(
282 MHz, CDCl ): δ 86.3 (m, 1F, SF ), 69.3 (d, J = 149.0 Hz, 4F,
3 5 F−F
(
282 MHz, CDCl ): δ 82.2 (m, 1F, SF ), 82.0 (m, 1F, SF ), 64.2 (d,
+
3
5
5
SF ). GC-MS (m/z): 334 [M ]; RT 9.58 min.
2
2
3
5
JF−F = 149.0 Hz, 4F, SF ), 62.3 (dd, J = 146.0 Hz, J
4
= 4.8 Hz,
5
F−F
F−H
2
-Bromo-8-(pentafluorosulfanyl)naphthalene (9b). Prepared
+
F, SF ). GC-MS (m/z): 304 [M − SF ] ; RT 9.21 min.
5
5
analogously to 3 from 8b (1.05 g; 3 mmol). R = 0.5 (PE); mp 74−
f
2
,5-Bis(pentafluorosulfanyl)-1,4-dihydro-1,4-epoxynaphthalene
1
7
1
7
(
1
6 °C. Yield: 0.55 g (55%). H NMR (300 MHz, CDCl ): δ 8.63 (m,
3
(12a) and 2,8-bis(pentafluorosulfanyl)-1,4-dihydro-1,4-epoxynaph-
thalene (12b). A mixture of regioisomers 11a and 11b (ca. 60:40)
(1.75 g; 4 mmol) was dissolved in anhydrous DMSO (25 mL), and
LiOH (0.49 g; 20 mmol) was added. The reaction mixture was stirred
for 24 h, then diluted with water (200 mL) and saturated aq. NaHCO3
solution, and extracted with EA (4 × 50 mL). The combined organic
H), 8.10 (dd, J = 7.9 Hz, J = 1.0 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H),
.78 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.8 Hz, J = 1.7 Hz, 1H), 7.54
m, 1H). 13C NMR (125 MHz, CDCl ): δ 150.8 (p, J
2
= 14.5 Hz),
3
C−F
3
33.5, 133.2, 130.5, 130.0, 128.6 (p, J
= 5.6 Hz), 128.5, 127.7 (p,
C−F
4
19
JC−F = 5.3 Hz), 124.3, 123.3. F NMR (282 MHz, CDCl ): δ 86.2
3
2
(
m, 1F, SF ), 69.2 (d, J = 149.0 Hz, 4F, SF ). GC-MS (m/z): 334
phase was washed with brine (2 × 50 mL), dried with MgSO , and
5
F−F
5
4
+
[
M ]; RT 9.59 min.
-Amino-5-(pentafluorosulfanyl)naphthalene (10a). Prepared
evaporated. The obtained residue was purified by column chromatog-
2
raphy (PE/EA (9:1)) to give 12a as an oil (R
white solid (R = 0.1) in 59% total yield. 12a: yield: 0.61 g (38%). H
NMR (500 MHz, CDCl ): δ 7.51 (d, J = 7.1 Hz, 1H), 7.43 (d, J = 8.4
Hz, 1H), 7.34 (m, 1H), 7.22 (m, 1H), 6.24 (m, 1H), 5.96 (d, J = 1.0
f
= 0.55) and 12b as a
1
analogously to 10b from 9a (0.24 g; 0.72 mmol). R = 0.3 (PE/
f
f
1
CH Cl 1:1); light brown oil. Yield: 0.16 g (82%). H NMR (300
3
2
2
MHz, CDCl ): δ 8.26 (dp, J = 9.4 Hz, J = 3.0 Hz, 1H), 7.79 (d, J = 7.8
3
1
3
2
Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.36 (m, 1H), 7.09 (dd, J = 9.5 Hz, J
Hz, 1H). C NMR (125 MHz, CDCl
3
): δ 170.4 (dp, JC−F = 20.8 Hz,
1
3
6
2
=
2.5 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 3.96 (br s, 2H, NH ).
C
JC−F = 1.5 Hz), 149.4, 148.1 (p, JC−F = 18.9 Hz), 143.8, 142.8 (p,
2
2
3JC−F = 6.1 Hz), 127.7, 124.1, 123.6 (p, JC−F = 4.8 Hz), 84.6 (p, JC−F
3
4
NMR (125 MHz, CDCl ): δ 152.0 (p, J
= 13.7 Hz), 144.4, 136.8,
3
C−F
3
4
3
19
131.3, 126.7 (p, J
= 5.1 Hz), 124.2, 124.0 (p, J
= 5.8 Hz),
= 3.3 Hz), 83.7 (p, J
82.9 (m, 1F, SF ), 80.2 (m, 1F, SF ), 65.5 (d, J
= 3.8 Hz). F NMR (282 MHz, CDCl ): δ
C−F
C−F
C
−
F
3
21.5, 120.4, 109.0. 1 F NMR (282 MHz, CDCl ): δ 87.6 (m, 1F,
9
2
= 153.0 Hz, 4F,
F−F
1
3
5
5
F
DOI: 10.1021/acs.joc.6b02276
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2
SF ), 64.1 (d, J = 150.0 Hz, 4F, SF ). HRMS (nESI/DART): calcd
M. D.; Donnelly, D. J.; Meanwell, N. A. J. J. Med. Chem. 2015, 58,
5
F−F
5
−
−
for [C H F OS ] : 394.9628, found: 394.9634 [M − H] . 12b: mp
8315. (d) Welch, J. T. Application of SF Substitution in Life Sciences
10
5
10
2
5
1
7
9−80 °C. Yield: 0.33 g (21%). H NMR (500 MHz, CDCl ): δ 7.53
Research (Chapter 6 in ref 1b).
(4) (a) Joliton, A.; Plancher, J.-M.; Carreira, E. M. Angew. Chem., Int.
3
(
5
m, 1H), 7.47 (2 × d, overlapped, 2H), 7.24 (m, 1H), 6.30 (m, 1H),
1
3
2
.88 (m, 1H). C NMR (125 MHz, CDCl ): δ 169.3 (dp, J = 21.3
̈
Ed. 2016, 55, 2113−2117. (b) Westphal, M. V.; Wolfstadter, B. T.;
3
C−F
5
2
3
Hz, J
=
5
= 1.7 Hz), 148.8, 148.1 (p, J
6.8 Hz), 143.6 (p, J
.1 Hz), 84.8 (p, J
δ 82.0 (m, 1F, SF ), 79.9 (m, 1F, SF ), 66.1 (dm, J = 152.0 Hz, 4F,
SF ), 64.6 (dp, J
ESI-): calcd for [C H ClF OS ] : 430.9394, found: 430.9398 [M +
= 19.4 Hz), 145.3 (p, J
= 2.9 Hz), 127.8, 124.04, 123.99 (p, J
= 3.3 Hz), 83.0. F NMR (282 MHz, CDCl ):
C−F 3
Plancher, J.-M.; Gatfield, J.; Carreira, E. M. ChemMedChem 2015, 10,
461−469. (c) Altomonte, S.; Baillie, G. L.; Ross, R. A.; Riley, J.; Zanda,
M. RSC Adv. 2014, 4, 20164−20176.
C−F
C−F
C−F
=
3
3
C−F
C−F
4
19
2
5
5
F−F
(5) (a) Umemoto, T.; Garrick, L. M.; Saito, N. Beilstein J. Org. Chem.
2012, 8, 461−471. (b) Umemoto, T. Patent WO2008/118787.
(c) Umemoto, T. Patent US 2009/7592491. (d) Umemoto, T. Patent
US2010/7820864. (e) Umemoto, T. Patent US2010/7851646.
(f) Umemoto, T. Patent US2010/0130790. (g) Umemoto, T. Patent
WO2010/033930.
2
TS
= 149.0 Hz, JF−F = 6.7 Hz, 4F, SF ). HRMS
5
F−F
5
−
(
1
0
6
10
2
−
Cl] .
,6-Bis-pentafluorosulfanylnaphthalene (13a). Prepared analo-
gously to 3 from 12a (0.61 g; 1.54 mmol). R = 0.4 (PE), mp 108−109
1
f
1
°
C (colorless solid). Yield: 0.41 g (70%). H NMR (300 MHz,
(6) (a) Lal, G. S.; Minnich, K. E. Patent US 2006/0069285 A1.
(b) Dolbier, W. R., Jr.; Mitani, A.; Warren, R. D. Tetrahedron Lett.
CDCl ): δ 8.55 (dm, J = 9.6 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.24
dd, J = 7.9 Hz, J = 1.1 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.97 (dd, J =
.8 Hz, J = 2.5 Hz, 1H), 7.68 (m, 1H). C NMR (125 MHz, CDCl ):
3
(
9
2
007, 48, 1325−1326. (c) Ponomarenko, M. V.; Lummer, K.; Fokin,
A. A.; Serguchev, Y. A.; Bassil, B. S.; Roschenthaler, G.-V. Org. Biomol.
Chem. 2013, 11, 8103−8112.
1
3
3
̈
2
2
δ 151.6 (p, J
= 15.3 Hz), 151.3 (p, J
= 18.4 Hz), 134.8, 133.7,
C−F
C−F
3
3
1
30.2 (p, J
= 5.6 Hz), 128.5, 127.3 (p, J
= 4.9 Hz), 126.7 (p,
C−F
C−F
(7) Aït-Mohand, S.; Dolbier, W. R., Jr. Org. Lett. 2002, 4, 3013−3015.
(8) Bailly, F.; Cottet, F.; Schlosser, M. Synthesis 2005, 2005, 791−
797.
3
3
19
JC−F = 5.1 Hz), 125.8, 124.7 (p, J = 4.2 Hz). F NMR (282 MHz,
CDCl ): δ 85.5 (m, 1F, SF ), 82.7 (m, 1F, SF ), 69.2 (d, J = 149.0
Hz, 4F, SF ), 62.6 (d, J = 150.0 Hz, 4F, SF ). HRMS (ESI-): calcd
C−F
2
3
5
5
F−F
2
5
F−F
5
(9) During the preparation of our manuscript, the work describing
access to various substituted benzynes starting from aryl(mesityl)-
iodonium tosylates has been published, which also included examples
−
−
for [C H ClF S ] : 414.9440, found: 414.9456 [M + Cl] .
10
6
10 2
1
,7-Bis-pentafluorosulfanylnaphthalene (13b). Prepared analo-
gously to 3 from 12b (0.33 g; 0.85 mmol). R = 0.4 (PE), mp 105−106
C (colorless solid). Yield: 0.29 g (92%). H NMR (300 MHz,
CDCl ): δ 8.95 (m, 1H), 8.20 (dd, J = 7.9 Hz, J = 1.0 Hz, 1H), 8.08
d, J = 8.2 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.90 (dd, J = 9.0 Hz, J =
.0 Hz, 1H), 7.68 (m, 1H). C NMR (125 MHz, CDCl ): δ 153.3 (p,
= 17.7 Hz), 152.6 (p, J = 15.4 Hz), 135.1, 133.2, 129.8, 129.3
C−F
= 5.6 Hz), 126.7, 126.5, 124.4 (m), 123.2 (p, J
F NMR (282 MHz, CDCl ): δ 85.4 (m, 1F, SF ), 82.8 (m, 1F, SF ),
9.5 (d, J = 149.0 Hz, 4F, SF ), 62.3 (d, J = 150.0 Hz, 4F, SF5).
HRMS (ESI-): calcd for [C H ClF S ] : 414.9440, found: 414.9461
f
of SF -benzynes and their adducts with furan, i.e. compound 2 and its
5
1
°
regioisomer. However, no further conversion into naphthalenes was
reported: Sundalam, S. K.; Nilova, A.; Seidl, T. L.; Stuart, D. R. Angew.
Chem., Int. Ed. 2016, 55, 8431−8434.
(10) Dolbier, W. R., Jr.; Sergeeva, T. A. Org. Lett. 2004, 6, 2417−
2419.
3
(
1
3
2
3
2
2
J
C−F
p, J
3
3
(
= 4.2 Hz).
(11) Altundas, A.; Dastan, A.; McKee, M. M.; Balci, M. Tetrahedron
2000, 56, 6115−6120.
C−F
C−F
1
9
3
5
5
2
2
6
(12) Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009,
74, 4542−4546.
F−F
5
F−F
−
10
6
10 2
−
[
M + Cl] .
(13) Dolbier, W. R., Jr.; Aït-Mohand, S.; Schertz, T. D.; Sergeeva, T.
A.; Cradlebaugh, J. A.; Mitani, A.; Gard, G. L.; Winter, R. W.;
Thrasher, J. S. J. Fluorine Chem. 2006, 127, 1302−1310.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02276.
■
(14) For example, see: Miethchen, R.; Peters, D. General Instructions
*
S
for the Handling of Hydrogen Fluoride in Houben-Weyl Methods of
Organic Chemistry, Vol. E 10a; Organo-Fluorine Compounds; Georg
Thieme Verlag: Stuttgart, Germany, 2000; pp 95−100.
1
13
19
Copies of H, C, and F NMR spectra for compounds
−13 (PDF)
1
AUTHOR INFORMATION
Corresponding Author
E-mail: wrd@chem.ufl.edu.
■
*
Notes
The authors declare no competing financial interest.
REFERENCES
■
(
1) (a) Ojima, I. Fluorine in medicinal chemistry and chemical biology;
Wiley-Blackwell: Chichester, U.K., 2009. (b) Gouverneur, V.; Muller,
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Biophysical Aspects to Clinical Applications. Molecular Medicine and
Medicinal Chemistry, Vol. 6; Imperial College Press: London, U.K.,
2
012. (c) Kirsch, P. Modern Fluoroorganic Chemistry. Synthesis,
Reactivity, Applications, 2nd ed.; Wiley-VCH: Weinheim, Germany,
013.
2) General reviews on SF -substituent chemistry: (a) Savoie, P. R.;
2
(
5
Welch, J. T. Chem. Rev. 2015, 115, 1130. (2015). (b) von Hahmann,
C. N.; Savoie, P. R.; Welch, J. T. Curr. Org. Chem. 2015, 19, 1592.
(
c) Altomonte, S.; Zanda, M. J. J. Fluorine Chem. 2012, 143, 57.
3) Reviews covering application of the SF -substituent in medicinal
(
5
chemistry: (a) Barnes-Seeman, D.; Beck, J.; Springer, C. Curr. Top.
Med. Chem. 2014, 14, 855. (b) Bassetto, M.; Ferla, S.; Pertusati, F.
Future Med. Chem. 2015, 7, 527. (c) Gillis, E. P.; Eastman, K. J.; Hill,
G
DOI: 10.1021/acs.joc.6b02276
J. Org. Chem. XXXX, XXX, XXX−XXX