Synthesis of an 8-pentafluorosulfanyl analog of the antimalarial agent mefloquine

Article abstract of DOI:10.1016/j.tetlet.2010.07.113

The 8-SF₅ analog of mefloquine was synthesized in nine steps from commercially available starting materials and in five steps from a novel ortho-SF₅-substituted aniline intermediate.

Full text of DOI:10.1016/j.tetlet.2010.07.113

Tetrahedron Letters 51 (2010) 5137–5140
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of an 8-pentafluorosulfanyl analog of the antimalarial
agent mefloquine
Tingting Mo a,b, Xueling Mi a,b, Erin E. Milner c, Geoffrey S. Dow c, Peter Wipf a,b,
*
a Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
b Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA
c Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Av., Silver Spring, MD 20910, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The 8-SF5 analog of mefloquine was synthesized in nine steps from commercially available starting mate-
rials and in five steps from a novel ortho-SF5–substituted aniline intermediate.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 29 June 2010
Revised 20 July 2010
Accepted 20 July 2010
Available online 25 July 2010
The geographic extension of Plasmodium falciparum necessitates
the development of new antimalarial drugs that are active against
resistant parasite strains.1 Mefloquine (1) has been shown to have
high efficacy for both treatment and prophylaxis of chloroquine-
resistant malaria (Fig. 1).2 However, its present potential is limited
due to its adverse central nervous system (CNS) effects, including
anxiety, depression, hallucinations, and seizures.3 One explanation
for these undesirable neurological events may be the ability of
mefloquine to cross the blood–brain barrier, accumulate in the
brain, and interact with several CNS targets.4 However, despite
the relatively high incidence of these side effects, mefloquine con-
tinues to be used by virtue of its long half-life, relative safety in
pregnancy, activity against chloroquine-resistant strains, and the
absence of effective alternatives.
In order to ameliorate the neurotoxicity profile of mefloquine,
we set out to develop analogs that are less readily absorbed
through the blood–brain barrier but retain the antimalarial profile
of the quinoline methanol scaffold.5 By replacing the 8-trifluoro-
methyl (CF3) group in mefloquine with 6- and 7-pentafluorosulfa-
nyl (SF5) substituents, respectively, we previously prepared two
SF5-analogs that showed equivalent or improved activities com-
pared to the parent compound 1 (Fig. 1, compounds 2 and 3).5
Interestingly, 2 and 3 also exhibited better activity and selectivity
than their corresponding 6- and 7-CF3-congeners, 4 and 5. These
encouraging results demonstrate the effective biological mimicry
of the CF3–SF5 switch in quinoline containing antimalarial drugs
and prompted us to prepare the synthetically considerably
demanding 8-SF5-congener 6 of mefloquine.
ity, a substantially larger steric effect, and a slightly higher chem-
ical stability.7 However, due to the relative dearth of practical high-
yielding methods for introducing this highly fluorinated functional
group, to date there are still only a few SF5-containing building
blocks accessible.8 For pentafluorosulfanylbenzenes, oxidative
fluorination of aromatic disulfides is still the generally preferred
procedure, despite its origin dating back half a century ago.9 Most
of the recent routes involve the use of expensive silver(II) fluoride
or hazardous fluorine gas, and the yields are generally low
(<40%).10 Furthermore, the disulfide method is only applicable to
a few substituted benzenes.
In contrast to meta- and para-nitro-SF5-benzene, the corre-
sponding ortho-nitro product is not accessible by the disulfide
procedure, presumably because the steric hindrance from the
ortho-nitro group prevents further fluorination of the SF3 interme-
diate to give the SF5 moiety.11 To date, the only substrate contain-
ing an ortho-substituent known to be suitable for direct
fluorination is the bis-ortho-fluorodiphenyl disulfide.12 The ortho-
fluorine substituent can then be converted in moderate yield into
an amino group by nucleophilic aromatic substitution.
HO
HO
N
H
N
H
R3
R2
N
CF3
N
CF3
Introduction of an SF5 group into an organic compound has
been of interest in the design of new materials, pharmaceuticals,
and agrochemicals.6 Compared to CF3, the symmetrical, octahedral
SF5 group demonstrates higher electronegativity and hydrophobic-
CF3
Mefloquine (1)
R1
2: R1 = H, R2 = H, R3 = SF5
3: R1 = H, R2 = SF5, R3 = H
4: R1 = H, R2 = H, R3 = CF3
5: R1 = H, R2 = CF3, R3 = H
6: R1 = SF5, R2 = H, R3 = H
* Corresponding author. Tel.: +1 4126248606; fax: +1 4126240787.
E-mail address: pwipf@pitt.edu (P. Wipf).
Figure 1. Mefloquine and its analogs, including the new analog 6.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.113

5138
T. Mo et al. / Tetrahedron Letters 51 (2010) 5137–5140
acetoacetate (11) in polyphosphoric acid, the somewhat difficult to
purify 8-pentafluorosulfanylquinoline intermediate 12 was ob-
tained in 70% yield and ca. 90% purity. The previously used chlori-
nation conditions with phosphorous oxychloride at 110 °C proved
to be too harsh for this quinoline,5 but the milder thionyl chloride
afforded the product in 86% yield. After nucleophilic aromatic sub-
stitution with 2-pyridylacetonitrile, oxidation of the carbon-nitrile
bond and Pt-catalyzed reduction of the ketone and pyridine moie-
ties in 13 proceeded in moderate to good yields to afford the target
molecule 6.15 This sequence was used to prepare 6 on 200 mg
scale.16–21
HO
N
H
NH2
SF5
N
CF3
SF5
6
ortho-SF5-aniline 7
Figure 2. Retrosynthetic strategy for preparation of 6.
In conclusion, we have developed an efficient synthetic route to
a novel 8-pentafluorosulfanyl analog of mefloquine that utilizes a
new preparation of ortho-SF5 aniline 7. Access to the latter com-
pound is of general utility since it can readily be converted into
other SF5-containing heterocyclic building blocks. The potency
and selectivity of 6 against P. falciparum strains as well as its CNS
effects are currently being evaluated and will be reported in due
course.
An important first objective of the present study was the prep-
aration of the novel ortho-SF5-aniline 7 from commercially avail-
able 3-SF5-phenol 8 en route to the 8-SF5 mefloquine analog 6
(Fig. 2).
We envisioned installing the ortho-amino group by the regiose-
lective nitration of a suitable pentafluorosulfanyl arene, followed
by reduction.13 Accordingly, we chose the commercially available
starting material 8 as the nitration substrate (Scheme 1). However,
the para-regioselectivity of the nitration of the phenol was poor,
since the hydroxyl group is a strong ortho-directing substituent.
To diminish the ortho-effect, 8 was converted into the trifluoro-
methyl sulfonate in 91% yield, and nitration now proceeded in
79% yield to give exclusively the desired product 9 with the NO2
group in the para-position to the TfO moiety. Subsequent Pd-cata-
lyzed reduction furnished the ortho-SF5-aniline 10 in 83% yield.
Removal of the triflate in 10 proved not to be trivial. Initial at-
tempts using Pd(II) salts and hydrogen transfer conditions led
either to the reductive cleavage of the SF5 group or to unspecific
decomposition. However, when a Pd(0) catalyst was employed in
the presence of formic acid and triethylamine,14 the desired prod-
uct 7 was formed. In our hands, the free base 7 was surprisingly
unstable in a neat (oily) form. However, we were able to obtain a
crystalline, stable storage form for 7 by converting it into its
corresponding hydrochloride salt. When aniline 7 was immedi-
ately subjected to a Conrad–Limpach reaction with 4,4,4-trifluoro-
Acknowledgments
We thank the Military Infectious Diseases Research Program
(MIDRP) and Medicines for Malaria Venture (MMV) for financial
support. This Letter was reviewed by the Walter Reed Army Insti-
tute of Research and the US Army Medical Research and Materiel
Command, and there is no objection to its publication or dissemi-
nation. The opinions expressed herein are those of the authors and
do not reflect the views or opinions of the Department of the Army
or the Department of Defense.
References and notes
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NO2
2. HNO , H SO , 40 C, 79%
°
3
2
4
SF5
SF5
8
9
TfO
H2 (6 bar), Pd/C
Pd(PPh3)4, Et3N
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NH2
NH2
HCOOH, dioxane
reflux
AcOH, MeOH
83%
SF5
SF5
7
10
O
O
OH
F3C
OEt
1. SOCl2, DMF, 85°C, 86%
11
PPA, 150 °C
~70% over 2 steps
2. 2-pyridylacetonitrile
CF3
N
NaH, DMF, toluene, 80%
SF5
12
NC
N
HO
N
H
1. H2O2, AcOH, 75°C, 89%
2. H2, PtO2, HCl, EtOH, 47%
N
CF3
N
CF3
SF5
SF5
6 (dr > 20:1)
13
Scheme 1. Synthesis of 8-SF5 substituted mefloquine analog 6.

T. Mo et al. / Tetrahedron Letters 51 (2010) 5137–5140
5139
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addition of 40 g ice, neutralized to pH 5 by adding 5% NaOH solution and NaOH
pellets, extracted with EtOAc (two times), washed with brine, dried (MgSO4),
filtered, and concentrated. The crude brown residue was purified by
chromatography on SiO2 (25% EtOAc/hexanes) to yield 12 (0.980 g, 90%
purity, 70% over two steps) as a beige solid: 1H NMR (CDCl3) d 8.89 (br s,
1H), 8.65 (d, 1H, J = 7.8 Hz), 8.21 (dd, 1H, J = 1.5, 8.1 Hz), 7.54 (app t, 1H,
J = 8.1 Hz), 6.71 (d, 1H, J = 1.5 Hz); 19F NMR (CDCl3)
d 84.9 (quintet,
J = 155.1 Hz), 68.6 (d, J = 146.6 Hz), À68.7; EIMS m/z 339 (M+, 100), 211 (50),
183 (25); HRMS m/z calcd for C10H5F8NOS 338.9964, found 338.9954.
19. Experimental protocol and spectral data for 7ÁHCl: To a solution of crude 2-
(pentafluorosulfanyl)aniline 7 (8.7 mg, 0.040 mmol) in anhydrous diethyl ether
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(0.20 mL) was added 2 M HCl in diethyl ether (40 lL, 0.079 mmol) at room
temperature under N2. The reaction mixture was stirred for 30 min and
filtered. The filtrate was washed with diethyl ether (1 mL) and dried in vacuo
to provide 7ÁHCl (5.6 mg, 0.025 mmol, 64%) as a colorless solid: Mp 190.6 °C
(dec); IR (Neat) 2917, 2850, 1728, 1637, 1476, 1437, 1107, 1031, 843, 811,
721 cmÀ1 1H NMR (600 MHz, CD3OD) d 7.61 (dd, 1H, J = 8.4, 1.2 Hz), 7.30 (t,
;
1H, J = 8.4 Hz), 6.98 (d, 1H, J = 8.4 Hz), 6.80 (t, 1H, J = 8.4 Hz); 13C NMR
(125 MHz, CD3OD) d 153.9 (app quintet, J = 21.0 Hz), 139.0, 130.7, 126.3 (app
quintet, J = 5.4 Hz), 118.5, 115.7; 19F NMR (400 MHz, CD3OD) d 81.0 (quintet,
J = 159.2 Hz), 61.2 (d, J = 158.0 Hz); MS (EI) m/z 219 ([MÀHCl]+, 100), 111 (42),
92 (95); HRMS (EI) m/z calcd for C6H6NF5S (MÀHCl) 219.0141, found 219.0144.
20. Experimental protocol and spectral data for d-(2-pyridyl)-8-penta-
fluorosulfanyl-(2-trifluoromethyl)-4-quinolylaceto-nitrile (13). A solution of
12 (0.373 g, 0.990 mmol) in thionyl chloride (4.0 mL) was treated with a catalytic
amount of DMF (six drops). The reaction mixture was heated to 80 °C and kept at
reflux for 1 h. The mixture was cooled to 0 °C and quenched with 20 g of ice. The
suspension was extracted with diethyl ether (20 mL). The organic layer was
washed with sat. NaHCO3 (two times) and brine, dried (MgSO4), and
concentrated. The yellow residue was purified by chromatography on SiO2
(15%
EtOAc/hexanes)
to
provide
4-chloro-8-pentafluorosulfanyl-2-
16. Experimental protocol and spectral data for 4-nitro-3-(pentafluorosulfa-
(trifluoromethyl)quinoline (0.304 g, 86%) as a beige solid: mp 108.7–109.6 °C;
nyl)phenyl
trifluoromethane-sulfonate
(9).
A
solution
of
3-
IR (neat) 1336, 1263, 1185, 1141, 1114, 1021, 1075, 844, 818, 757, 721,
(pentafluorothio)phenol (8) (0.998 g, 4.40 mmol) in distilled pyridine
(5.0 mL) was treated dropwise at 0 °C with triflic anhydride (0.91 mL,
5.28 mmol). The reaction mixture was stirred for 10 min at 0 °C and at room
temperature for 1.5 h, diluted with diethyl ether (40 mL), and extracted with a
1 M solution of copper sulfate (three times). The organic layer was washed
with water and brine, dried (MgSO4), and concentrated. The residue was
purified by chromatography on SiO2 (10% diethyl ether/pentane) to yield 3-
667 cmÀ1 1H NMR (CDCl3) d 8.59 (dd, 1H, J = 1.2, 8.4 Hz), 8.46 (dd, 1H, J = 1.2,
;
7.8 Hz), 7.94 (s, 1H), 7.87 (dd, 1H, J = 8.1, 8.4 Hz); 13C NMR (CDCl3) d 151.8 (app
quintet, J = 15.0 Hz), 148.4 (q, J = 36.0 Hz), 145.4, 142.0, 133.1 (app t, J = 4.5 Hz),
129.4, 128.2, 128.2, 120.7 (q, J = 274.5 Hz), 118.3; 19F NMR (CDCl3) d 83.6
(quintet, J = 157.9 Hz), 71.7 (d, J = 177.7 Hz), À68.1; EIMS m/z 357 (M+, 100), 249
(25), 149 (55), 180 (60), 89 (20); HRMS (EI) m/z calcd for C10H4NF8SCl 356.9625,
found 356.9633.
(pentafluorosulfanyl)phenyl trifluoromethane-sulfonate (1.40 g, 91%) as
a
A cooled (0–5 °C) suspension of sodium hydride (38.8 mg, 1.54 mmol) in toluene
(6.0 mL) and DMF (3.0 mL) was treated for 10 min under argon gas with a
solution of 2-pyridylacetonitrile (0.18 mL, 1.66 mmol) in toluene (5.0 mL) and
DMF (1.5 mL). The resulting yellow-brown colored suspension was stirred for
1 h at the same temperature. A solution of 4-chloro-8-pentafluorosulfanyl-2-
(trifluoromethyl)quinoline (0.458 g, 1.28 mmol) in toluene (8.0 mL) and DMF
(3.0 mL) was added dropwise to the suspension over 5 min. After 0.5 h, the
reaction mixture was quenched with ice water (50 mL), extracted with EtOAc,
washed with water (three times) and brine, dried (MgSO4), and concentrated.
The orange residue was purified by chromatography on SiO2 (25% EtOAc/
hexanes) to provide 13 (0.450 g, 80%) as a light orange solid: Mp 146.2 °C (dec);
colorless oil that was used immediately for the next reaction. A solution of
this sulfonate (1.40 g, 4.00 mmol) in conc. sulfuric acid (13 mL) was slowly
treated with fuming nitric acid (11 mL) at 0 °C. The reaction mixture was
stirred for 7.5 h at 40 °C, quenched with ice (40 g), extracted with diethyl ether
(40 mL), washed with sat. NaHCO3 (2 Â 30 mL) and brine, dried (MgSO4), and
concentrated. The yellow residue was purified by chromatography on SiO2
(10%AcOEt/hexanes) to provide 9 (1.25 g, 79%) as a colorless solid: Mp 70.2–
71.8 °C; IR (Neat) 3105, 1549, 1431, 1366, 1250, 1211, 1131, 822, 781,
749 cmÀ1
; d 8.48 (d, 1H, J = 2.4 Hz), 8.26 (d, 1H,
1H NMR (acetone-d6)
J = 9.0 Hz), 8.20 (dd, 1H, J = 2.1, 9.0 Hz); 13C NMR (acetone-d6) d 150.5, 146.7,
144.8 (app quintet, J = 22.5 Hz), 129.3, 128.6, 124.4 (app quintet, J = 5.3 Hz),
119.7 (q, J = 318.0 Hz); 19F NMR (acetone-d6) d 76.4 (quintet, J = 155.1 Hz), 68.7
(d, J = 152.3 Hz), À72.2; EIMS m/z 397 (M+, 4), 84 (75), 69 (99), 57 (100); HRMS
(EI) m/z calcd for C7H3NO5F8S2 396.9325, found 396.9311.
IR (Neat) 2876, 1368, 1275, 1179, 1144, 1122, 846, 833, 793, 654 cmÀ1 1H NMR
;
(CDCl3) d 8.61 (ddd, 1H, J = 0.9, 1.8, 5.1 Hz), 8.47 (d, 1H, J = 8.7 Hz), 8.41 (dd, 1H,
J = 0.9, 8.1 Hz), 8.10 (s, 1H), 7.79 (dd, 1H, J = 8.1, 8.4 Hz), 7.78 (ddd, 1H, J = 2.1, 7.8,
7.8 Hz), 7.46 (d, 1H, J = 8.1 Hz), 7.33 (ddd, 1H, J = 0.9, 5.1, 7.5 Hz), 6.07 (s, 1H); 13
C
17. Experimental
protocol
and
spectral
data
for
4-amino-3-
NMR (CDCl3) d 153.0, 152.4 (app quintet, J = 15.8 Hz), 150.6, 148.7 (q,
(pentafluorosulfanyl)phenyl trifluoromethane-sulfonate (10). A solution of 9
(126 mg, 0.317 mmol) in acetic acid (1.0 mL) and methanol (1.0 mL) was
treated with 10% Pd on carbon (33.8 mg, 0.0317 mmol). The reaction mixture
was hydrogenated under 6 bar H2 pressure in a Parr apparatus for 4 h and
filtered through Celite. The filtrate was concentrated, extracted with diethyl
ether, washed with sat. NaHCO3, water and brine, dried (MgSO4), and
concentrated. The residue was purified by chromatography on SiO2 (10%
diethyl ether/pentane) to provide 10 (96.7 mg, 83%) as a colorless solid: mp
66.4–66.7 °C; IR (Neat) 3547, 3431, 1634, 1502, 1407, 1247, 1215, 1133, 850,
J = 36.0 Hz), 143.2, 141.9, 138.4, 132.6 (app t, J = 5.3 Hz), 128.6, 128.2, 127.3,
124.3, 122.6, 120.9 (q, J = 273.8 Hz), 117.5, 117.4, 43.4; 19F NMR (CDCl3) d 83.7
(quintet, J = 157.9 Hz), 71.6 (d, J = 169.2 Hz), À68.1; EIMS m/z 439 (M+, 60), 428
(25), 273 (25), 89 (30), 78 (100); HRMS (EI) m/z calcd for C17H9N3F8S 439.0389,
found 439.0388.
21. Experimental
protocol
and
spectral
data
for
d-(2-piperidyl)-8-
(6).
pentafluorosulfanyl-(2-trifluoromethyl)-4-quinoline-methanol
A
suspension of 13 (197 mg, 0.448 mmol) in acetic acid (2.6 mL) was treated
dropwise at room temperature with H2O2 (0.35 mL, 4.48 mmol). The reaction
mixture was placed in a preheated (75 °C) oil bath until it turned into light
yellow. The mixture was quenched with ice water (10 mL), extracted with
diethyl ether (10 mL), washed with sat. NaHCO3 solution and brine, dried
(MgSO4), and concentrated. The yellow residue was purified by
chromatography on SiO2 (16% EtOAc/hexanes) to provide 2-pyridyl-8-
pentafluorosulfanyl-(2-trifluoromethyl)-4-quinolylketone (171 mg, 89%) as a
colorless solid: Mp 98.9–99.7 °C; IR (neat) 1687, 1271, 1245, 1211, 1182, 1137,
801 cmÀ1 1H NMR (CDCl3) d 7.51 (d, 1H, J = 2.7 Hz), 7.20 (dd, 1H, J = 2.7,
;
9.0 Hz), 6.79 (d, 1H, J = 9.0 Hz), 4.64 (br s, 2H); 13C NMR (CDCl3) d 141.9, 138.9,
138.3 (app quintet, J = 17.2 Hz), 126.0, 122.0 (app quintet, J = 5.3 Hz), 120.2,
118.9 (q, J = 318.8 Hz); 19F NMR (CDCl3) d 85.6 (quintet, J = 152.3 Hz), 64.4 (d,
J = 149.5 Hz), À72.6; EIMS m/z 367 (M+, 10), 234 (55), 106 (60), 84 (100); HRMS
(EI) m/z calcd for C7H5NO3F8S2 366.9583, found 366.9571.
18. Experimental protocol and spectral data for 4-hydroxy-8-pentafluorosulfanyl-
2-(trifluoromethyl)quinoline (12). To a solution of 10 (1.46 g, 3.98 mmol) in
anhydrous degassed dioxane (65 mL) at room temperature were added
1114, 844, 829, 759, 731 cmÀ1 1H NMR (CDCl3) d 8.62 (ddd, 1H, J = 0.9, 1.8,
;
4.5 Hz), 8.42 (dd, 1H, J = 1.2, 7.8 Hz), 8.38 (ddd, 1H, J = 0.9, 0.9, 8.1 Hz), 8.12 (dd,
1H, J = 1.2, 8.4 Hz), 8.04 (ddd, 1H, J = 1.8, 7.8, 7.8 Hz), 7.90 (s, 1H), 7.72 (app t,
1H, J = 8.1 Hz), 7.60 (ddd, 1H, J = 1.2, 4.5, 7.5 Hz); 13C NMR (CDCl3) d 194.4,
152.9, 151.8 (app t, J = 15.0 Hz), 149.8, 147.8 (q, J = 35.3 Hz), 147.2, 141.6,
137.8, 132.4 (app t, J = 5.3 Hz), 130.6, 128.5, 127.8, 127.1, 124.4, 121.1 (q,
J = 273.8 Hz), 117.2; 19F NMR (CDCl3) d 84.1 (quintet, J = 157.9 Hz), 71.7 (d,
J = 149.5 Hz), À68.0; EIMS m/z 428 (M+, 65), 399 (100), 273 (95), 272 (30);
HRMS (EI) m/z calcd for C16H8N2OF8S 428.0230, found 439.0215.
tetrakis(triphenylphosphine)
palladium(0)
(0.209 g,
0.199 mmol),
triethylamine (2.0 mL, 14.3 mmol), and formic acid (0.54 mL, 14.3 mmol).
The reaction mixture was heated at reflux for 1 h under a nitrogen atmosphere,
cooled to room temperature, and filtered through Celite. The filtrate was
concentrated and extracted with CH2Cl2, washed with water (three times) and
brine, dried (MgSO4), and concentrated. The brown residue was purified by
chromatography on SiO2 (1% triethylamine and 10% diethyl ether in pentane)
to provide crude 2-aminophenylsulfur pentafluoride 7 (0.700 g, 3.19 mmol) as
a colorless liquid. A solution of this crude material (0.700 g, 3.19 mmol) in
polyphosphoric acid (10 mL) at 110 °C was treated with ethyl 4,4,4-
trifluoroacetoacetate (4.3 mL, 29.4 mmol) and heated at reflux at 150 °C for
1 h. The reaction mixture was cooled to room temperature, quenched by
A
solution
of
2-pyridyl-8-pentafluorosulfanyl-(2-trifluoro-methyl)-4-
quinolylketone (83.2 mg, 0.194 mmol) in conc. hydrochloric acid (79 mL,
0.971 mmol) and abs EtOH (2.0 mL) was treated with platinum oxide
(4.4 mg, 0.0194 mmol). The flask was purged with hydrogen twice and
hydrogenated under balloon pressure of H2. After 2 h, no alcohol

5140
T. Mo et al. / Tetrahedron Letters 51 (2010) 5137–5140
846, 826, 785, 721, 652 cmÀ1
intermediate appeared on TLC (50% EtOAc/hexanes to check for the alcohol
;
1H NMR (acetone-d6, 600 MHz) d 8.75 (d, 1H,
intermediate by UV, followed by 75% dichloromethane/EtOH to check for the
final product by UV and ninhydrin staining) anymore. The mixture was filtered
through a pad of florisil, concentrated, extracted with diethyl ether (20 mL),
washed with sat. NaHCO3 and NaOH aqueous solution (pH 13) and brine, dried
(MgSO4), and concentrated. The yellow residue was purified by
chromatography on SiO2 (5% triethylamine in EtOAc, then 5% triethylamine
and 5% MeOH in EtOAc). The crude product (65.0 mg) was crystallized from
MeOH to obtain 6 (40.0 mg, 47%) as a colorless solid in a dr >20:1: Mp 182.0 °C
(dec); IR (Neat) 3088, 2937, 2600 (br), 1422, 1366, 1267, 1224, 1183, 1113,
J = 8.4 Hz), 8.58 (d, 1H, J = 7.8 Hz), 8.19 (s, 1H), 7.97 (dd, 1H, J = 7.8, 8.4 Hz), 5.58
(d, 1H, J = 3.6 Hz), 3.03 (ddd, 1H, J = 3.0, 4.8, 10.8 Hz), 2.98 (app d, 1H,
J = 12.0 Hz), 2.56 (dt, 1H, J = 3.0, 12.0 Hz), 1.72 (app d, 1H, J = 12.6 Hz), 1.47
(app d, 1H, J = 12.6 Hz), 1.42 (app d, 1H, J = 12.6 Hz), 1.39–1.22 (m, 2H), 1.57
(tq, 1H, J = 3.6, 13.2 Hz); 13C NMR (acetone-d6, 600 MHz) d 154.5, 152.1 (app
quintet, J = 13.5 Hz), 148.4 (q, J = 34.5 Hz), 141.7, 133.1 (app t, J = 4.5 Hz), 131.0,
129.1, 127.9, 122.5 (q, J = 273.0 Hz), 116.5, 73.5, 62.3, 47.6, 27.3, 27.0, 25.1; 19
F
NMR (acetone-d6) d 86.6 (quintet, J = 150.2 Hz), 72.8 (d, J = 144.7 Hz), À67.1;
HRMS (ESI) m/z calcd for C16H17N2OF8S (M+H) 437.0934, found 437.0923.