Conformational Analysis of Acyclic α-Fluoro Sulfur Motifs

Article abstract of DOI:10.1002/chem.202003361

Bioactive small molecules containing α-fluoro sulfur motifs [RS(O)_nCH₂F] are appearing with increasing frequency in the pharmaceutical and agrochemical sectors. Prominent examples include the anti-asthma drug Flovent and t

Full text of DOI:10.1002/chem.202003361

Accepted Article
Accepted Article
Title: Conformational Analysis of Acyclic α-Fluoro Sulfur Motifs
Authors: Nathalie Erdeljac, Christian Mück-Lichtenfeld, Constantin G.
Daniliuc, and Ryan Gilmour
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202003361
Link to VoR: https://doi.org/10.1002/chem.202003361
01/2020

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
Conformational Analysis of Acyclic α-Fluoro Sulfur Motifs
Nathalie Erdeljac, Christian Mück-Lichtenfeld, Constantin G. Daniliuc, and Ryan Gilmour*
[a]
Dr. N. Erdeljac, Dr. C. Mück-Lichtenfeld, Dr. C. G. Daniliuc, Prof. Dr. R. Gilmour
Organisch Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 36, 48149 Münster, Germany
E-mail: ryan.gilmour@uni-muenster.de
Supporting information for this article is given via a link at the end of the document.
Abstract: Bioactive small molecules containing α-fluoro sulfur motifs
[RS(O)nCH2F] are appearing with increasing frequency in the
pharmaceutical and agrochemical sectors. Prominent examples
include the anti-asthma drug Flovent® and the phenylpyrazole
insecticide pyrafluprole. Given the popularity of these structural units
in bioactive small molecule design, together with the varying oxidation
states of sulfur, a conformational analysis of α-fluoro sulfides,
sulfoxides and sulfones, would be instructive in order to delineate the
non-covalent interactions that manifest themselves in structure. A
combined crystallographic and computational analysis demonstrates
the importance of hyperconjugative donor-acceptor interactions in
achieving acyclic conformational control. The conformational disparity
in the syn- and anti-diastereoisomers of α-fluorosulfoxides is
particularly noteworthy.
generality of this effect is well established such that F-C-C-X motif
(X = electron-withdrawing group) prevails in the absence of
overriding steric factors.[1,2,9] Most recently, and pertinent to this
study, examples of sulfur (sulfoxides and sulfones) effects have
been disclosed.[10] To complement these investigations on the β-
fluoro-sulfur fragment, it was envisaged that a conformational
analysis of the α-fluoro-sulfur motif would be valuable given its
prominence in bioactive small molecules (Figure 1).
Introduction
Molecular editing with fluorine is an expansive strategy to
modulate the physicochemical contours of structure-function
interplay.[1] The strategic value of fluorination transcends classical
boundaries and continues to underpin innovation in the fields of
enantioselective catalysis,[2] agrochemistry[3] and medicinal
chemistry (Figure 1, top).[4] This translational impact is most
apparent in the context of bioisosterism, where direct- (C-H) or
deoxy-fluorination enables the local electronic environment to be
influenced with only nominal steric fluctuation.[5] Although subtle,
this process can elicit striking effects, including modulated
lipophilicity, intrinsic potency, metabolic stability and pKa
values.[6] In addition, the ionic character of the C-F(δ-) bond
facilitates stabilizing electrostatic interactions with proximal
electropositive groups, as is best represented by the diaxial
orientation of cis-3,5-difluoropiperidine.[7] Moreover, the low-lying
antibonding orbital (σC-F*) readily engages in stabilizing
stereoelectronic interactions with a plenum of donors (e.g. π-
systems, C-H bonds or O, N lone pairs).[1,2a,c] A prominent
example of this phenomenon is the stereoelectronic analysis of
the anomeric effect in fluoromethylamine reported by Dunitz and
co-workers.[8] Conformations in which donor-acceptor orbital
overlap (e.g. σ, π or nO/N → σC-F*) is optimal frequently dominate,
thus rendering judicious introduction of fluorine valuable in
enabling conformational control (Figure 1, center). A venerable
example of this phenomenon is the fluorine gauche effect, in
which stabilising donor (σC-H) → acceptor (σC-F*) interactions give
rise to the synclinal conformation of 1,2-difluoroethane.[9] The
Figure 1. Top: Examples of bioactive molecules containing the α-fluoro sulfur
motif. (A) Anti-inflammatory agent fluticasone propionate (Flovent®).[11] (B)
Insecticidal agent pyrafluprole.[12] (C) 5´-(monofluoromethylthio)adenosine
(MFMTA).[13] (D) LXR modulator.[14] (E) Striatal-enriched protein tyrosine
phosphatase (STEP) inhibitor.[15] Centre: Intramolecular interactions under
consideration. Bottom: The anomeric effect in fluoromethylamine and the
generic test series investigated.
1
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
Representative examples from the fields of agrochemistry and
pharmaceutical and agrochemistry are illustrated in Figure 1 (A-
E).[11-15] However, unlike β-fluoro sulfur motifs, interrogation of the
α-fluoro system must consider the related anomeric effect (Figure
1, center) inherent to systems that permit hyperconjugative nS →
σ* interactions.[16-18]
Similarly, the benzyl substituted analog 3b was prepared from 2-
mercaptobenzothiazole following a four-step literature protocol[22]
(full details are provided in the ESI). For the purposes of
comparison, the non-fluorinated sulfoxides 4a-c were prepared by
exposing 1a-c to standard m-CPBA-mediated oxidation
conditions. Finally, the α-fluorination of sulfides 1a-c was
achieved via a fluoro-Pummerer rearrangement sequence.
A recent computational study has established that it is feasible for
both the gauche and the anomeric effects to operate
synergistically in cyclic α-substituted sulfoxides.[19] To
complement this theoretical study, and expand upon our previous
Initial S-fluorination using Selectfluor®, α-deprotonation, and
subsequent attack of the liberated fluoride anion furnished the α-
fluorinated sulfides 5a-c. Regrettably, only α-fluoro sulfide 5b was
stable towards chromatographic purification and could be isolated
and fully characterised. Derivatives 5a/c were hydrolytically
unstable and thus were processed directly to the sulfoxide
analogs with m-CPBA. Whereas sulfoxides 6a/6b (anti/syn) and
8b (syn) were isolated, the anti diastereoisomer 8a proved to be
hydrolytically unstable towards column chromatography and
recalcitrant towards recrystallization.
investigations pertaining to the β-fluoro sulfur motif,
a
conformational analysis of acyclic F-Cα-S(O)n (n = 0, 1, 2) units is
disclosed.[20] To that end, a series of fluorinated and non-
fluorinated compounds were prepared and their conformational
behaviour interrogated by a combined crystallographic and
computational analysis (Figure 1, bottom).
Results and Discussion
X-Ray Crystallographic Structure Analysis: Single crystals
suitable for X-ray analysis were obtained for the α-fluorinated
sulfide 5b, sulfoxides 6a/b, 7a/b and 8a, and sulfones 3a-c.
Analyses of the fluorinated sulfide 5b and the non-fluorinated
equivalents 1b and 1c (Figure 2) confirmed the expected distal
alignment of the two largest substituents (Bn/Naph and BT),
thereby minimizing non-bonding interactions. In the case of α-
fluorosulfide 5b, the C-F bond is orientated anti to one of the non-
bonding electron pairs in a conformation that is fully consistent
with the anomeric effect [nS → σC-F*; dC-F = 1.394(3) Å].
Synthesis of Target Compounds: To facilitate direct
comparison between the test sets (Figure 1, bottom), a scaffold
based on the mercaptobenzothiazole core was conceived
(Scheme 1). To that end, sulfides 1a-c were prepared by direct
alkylation of 2-mercaptobenzothiazole with the respective alkyl
bromide. The resulting sulfides were then oxidized to the
corresponding sulfones 2a-c using ruthenium(III) chloride and
sodium periodate. Subsequently monofluorination by treatment
with NFSI in the presence of ZnCl2 and LiHMDS[21] furnished the
desired α-fluorinated sulfones 3a and 3c.
Figure 2. X-Ray crystallographic analyses of the α-fluoro-sulfide 5b (top, dC-F
1.394(3) Å) and its non-fluorinated analogs 1b (bottom left) and 1c (bottom
right).
=
Scheme 1. Synthesis of target compounds. (a) NaH, DMF, 0 °C to RT, o/n; (b)
NaIO4, RuCl3•xH2O, MeCN/CHCl3/H2O, RT, o/n; (c) NFSI, ZnCl2, LiHMDS, THF,
RT, 5 h; (d) m-CPBA, CH2Cl2, 0 °C to RT, 24 h; (e) i) Selectfluor®, 10 min., ii)
Et3N, 10 min, MeCN; (f) m-CPBA, CH2Cl2, RT, o/n.
2
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
Figure 3. Crystallographic analyses of the α-fluorinated sulfoxides 6a, 6b, 7a, 7b and their non-fluorinated analogs 4a and 4b.
state, whereas conformations I and III are observed for 7a and 7b,
respectively. Crystallographic analysis of the fluorinated
naphthalene substituted sulfoxide 8b is in line with the
conformational analysis for 7b (Figure 5) in which the C-F bond is
aligned antiperiplanar to the sulfur lone pair and gauche with
respect to the S=O bond. This illustrates the utility of this motif in
enabling acyclic conformational control.
In the case of the α-fluorinated sulfoxides, conformations that
manifest hyperconjugative effects are observed. In the X-ray
crystallographic structures of the fluorinated sulfoxides 6a/b and
7a/b (Figure 3), the carbon fluorine bonds are aligned gauche with
respect to the dihedral angle φF-C-S-O. In all cases except for 6a,
the carbon fluorine bonds are antiperiplanar to the non-bonding
electron lone pair on sulfur, in line with the anomeric effect. When
comparing the X-ray structure of the non-fluorinated phenyl
substituted derivative 4a with that of 6b, it appears as if H → F
substitution in this syn–diastereoisomer does not significantly
impact the solid-state conformation. The large aromatic
substituents are distal in both structures as expected. However,
in the anti-diastereoisomer (6a versus 6b/4a), a difference in the
solid-state conformational preference is observed. In 6a, the
Table 1. Selected crystallographic data for α-fluorinated sulfide 5b, sulfoxides
6a/b, 7a/b, 8a and sulfones 3a-c.
Compound
φFCSO [°]
dC-F [Å]
dS-C(F) [Å]
5b
6a
6b
7a
7b
8b
3a
3b
3c
-
1.394(3)
1.391(4)
1.373(6)
1.386(3)
1.385(2)
1.380(3)
1.367(4)
1.388(3)
1.366(7)
1.804(3)
1.867(4)
1.857(5)
1.850(3)
1.840(2)
1.869(2)
1.821(3)
1.812(2)
1.832(6)
-75.1(2)
-51.9(4)
-55.1(2)
53.8(1)
-52.9(2)
53.8(3)
59.1(2)
-58.5(4)
benzothiazole and phenyl moieties are aligned in
counterintuitive synclinal orientation, which may be
a
a
consequence of packing effects in the solid state. In addition, the
C-F bond is aligned between the non-bonding electron pair and
S=O bond of the sulfoxide. A longer C-F bond is observed in 6a
than in 6b (1.391(4) Å and 1.373(6) Å, respectively. See Table 1).
In the solid state, structure 6a also displays a weak C-H…F
interaction with a hydrogen atom on an adjacent benzothiazole
ring (C7-H7…F1 = 2.590 Å. Please see the extended crystal
packing in the ESI for full details). In contrast, the length of the
carbon fluorine bonds in the diastereomeric scaffolds 7a and 7b
(Bn versus Ph) are comparable in length (1.386(3) Å and 1.385(2)
Å, respectively). This may be a consequence of stabilising
hyperconjugative interactions of the type σ → σC-F* that are
conspicuously absent in 6b. No evidence of π → σC-F* interactions
was observed in this crystallographic analysis.
A direct
comparison of the benzyl substituted sulfoxides 4b (non-
fluorinated) with 7a/b (fluorinated) demonstrates that α-
fluorination has a notable impact on conformation. When
considering the conformational equilibrium in Figure 4 (I, II, III),
the non-fluorinated system adopts conformation II in the solid
Figure 4. Observed conformations of the non-fluorinated sulfoxide 4b (II) and
its α-fluorinated equivalents 7a and 7b in the solid state.
3
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
The influence of fluorine insertion is also evident from inspection
of the S(O)n-C(sp3) bond length in the fluorinated compounds, as
compared to the non-fluorinated analogs (Table 1). In general,
dS-C(F) > dS-C(H) which may be of note considering the
significance of fractional bonds in understanding the dependence
of small changes in ground state structure on reactivity.[23]
Computational Study of Conformers in Solution: To
complement the solid-state analysis, and compensate for the
absence of 3JHF coupling constants that would facilitate a detailed
NMR conformer population analysis,
a
computational
investigation was conducted. This would allow the dominant non-
covalent interactions that are operational in solution to be
delineated and allow a direct comparison with the crystallographic
analyses.
Figure 5. X-ray crystal structure of the α-fluorinated sulfoxide 8b.
Solid state analyses of the fluorinated and non-fluorinated
sulfones (Figure 6) indicate a preference for an antiperiplanar
alignment of the two aromatic substituents (Ph/Bn/Naph and BT),
with the exception of the non-fluorinated derivative 2a. Notably,
the C-F distances in 3a and 3c are similar (1.367(4) Å and
1.366(7) Å, respectively), but slightly longer in 3b (1.388(3) Å).
Furthermore, when comparing the mean lengths of the C-F bonds
(Table 1) between the three sulfur oxidation states the following
trend is observed: sulfide (1.390 Å) > sulfoxide (mean = 1.383 Å)
> sulfones (mean = 1.374 Å).
Initially, the sulfone series was evaluated at the DFT level of
theory (Figure 7). In general, this analysis revealed several
conformations within a very narrow free energy range (<1
kcal/mol). For all three fluorinated sulfones (3a-c), there was good
agreement between the calculated structure and the
crystallographic analysis. In all cases, preferred conformers were
identified in which the substituent (Ph, Bn and Naph) was anti to
the benzothiazole unit.
Figure 6. X-Ray crystallographic structures of α-fluorinated sulfones 3a-c (top) and their non-fluorinated equivalents 2a-c (bottom).
4
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
3a
6a
(anti)
3b
6b
(syn)
Figure 8. Sulfoxides 6a/b. DFT-optimized conformations (left) and overlay of
the conformer representing the solid-state structure with the experimental
structure (orange).
3c
Figure 7. Molecular structure of sulfones 3a-c. DFT-optimized conformations
(left) and overlay of the conformer representing the solid-state structure with the
experimental structure (orange).
7a
(anti)
In the sulfoxide series, divergence between the computed
solution conformation and the solid-state structure for several of
the diastereoisomers examined (6b, 7a and 8a, see Table 2).
Whereas the predicted conformation of the phenyl substituted
sulfoxide 6a is in line with the crystal structure analysis, the
computationally predicted structure of 6b adopts a conformation
in which the C-F and S=O bonds are aligned anti to one another
(Figure 8). This contrasts starkly with the crystallographic data, in
which a conformation that allows for a hyperconjugative nS → σC-
F* interaction manifests itself. (Figure 3). In the crystal structures
of 7a and 8a, a similar orientation of the carbon fluorine bond is
observed. In both cases the predicted conformer is preferred by
1.6 kcal/mol (see Table 2). The calculated structure of 7a (Figure
9) has the C-F bond partitioned between the sulfur lone pair and
the S=O bond, similar to the experimentally observed and
computationally predicted structure of its phenyl substituted
equivalent 6a (Figure 3). Whereas the predicted conformer of 8a
(Figure 10) is analogous to that calculated for 6b, in which the two
C-F and S=O dipoles are minimized by virtue of their anti-
alignment. Finally, the predicted structure of the syn substituted
phenyl derivative 7b matches the conformation determined by X-
ray analysis (Figure 9).
7b
(syn)
Figure 9. Structure of sulfoxides 7a/b. DFT-optimized conformations (left) and
overlay of the conformer representing the solid-state structure with the
experimental structure (orange).
5
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
8a
(syn)
Theory predicts at least six conformations of fluorinated sulfide 5b
with relative free energies <1kcal/mol. The X-ray structure only
correlates with one of these that is predicted to be +0.7 kcal/mol
high in energy than the most stable conformer (see Figure 11).
Figure 10. Molecular structure of 8a. DFT-optimized conformation (left) and
overlay of the conformer representing the solid-state structure with the
experimental structure (orange).
5b
Table 2. Selected crystallographic data for α-fluorinated sulfoxides 6a/b, 7a/b
and 8a and their predicted lowest energy conformers in CHCl3. ΔG = free energy
difference of the solid-state conformer (left) with respect to the predicted low
energy structure (right).
Figure 11. Structure of fluorinated sulfide 5b. DFT-optimized conformation (left)
and overlay of the conformer representing the solid-state structure with the
experimental structure (orange).
Compound
Experimental
(solid state)
Predicted
(solution)
ΔG (kcal/mol)
To further explore the acyclic conformational behaviour of α-fluoro
sulfoxides, a simplified model compound was conceived to
establish bond rotational profiles of the two diastereiosiosmers
(syn and anti) [diastereoisomers A (syn) and B (anti) of methyl-
(1-fluoroethyl)sulfoxide, Figure 12]. The O-S-C-F dihedral angle
(φ) energy profile was calculated at the TPSS-D3/def2-TZVP level
of theory, optimizing all other structural parameters on each point
of the profile. For each diastereoisomer, three energetic minima
were distinguished that mitigate unfavourable interactions
involving the polarised S=O and C-F bonds (Figure 12). The (syn)
diastereoisomer A has two low energy conformers in which either
destabilizing non-bonding interactions between the methyl
substituents are avoided (A-2, φ=69°) or in which the polar bonds
adopt an anti-orientation (A-3, φ=172°). For the anti-
diastereoisomer B, both of these conditions are satisfied in
conformer B-3 (φ=174°). Analysis of A-2 and B-2 reveals the
0
6a (anti)
6b (syn)
7a (anti)
7b (syn)
+0.7
+1.6
0
+1.6
presence of the suspected nS
interaction.[24]
→ σC-F* hyperconjugative
8a (syn)
Figure 12. Energy profile of S-C(F) bond rotation in the syn (A, left) and anti (B, right) diastereoisomers of methyl-(1-fluoroethyl)-sulfoxide.
6
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
of the Organic Chemistry department (WWU, Münster). Melting points
were assessed in oPentane capillaries on a Büchi B-540 apparatus. IR
spectra were measured on a Perkin Elmer 100 FT-IR (ATR) spectrometer.
The adsorption bands are reported in wavenumbers (cm-1) and intensities
are abbreviated and described as: w (weak), m (medium) or s (strong).
Although intuitive and didactically helpful in predicting the
conformation of α-fluoro sulfoxides, this interaction, does not
contribute significantly to the stabilisation of the molecule as
revealed by the second order perturbation theory energies (E2PT).
Although the hyperconjugative interaction nS → σ*C-F contributes
>3 kcal/mol to the total stabilisation, other interactions are more
dominant. Pertinent examples include the nO → σ*S-C(F) (E2PT ≈ 11
kcal/mol) and nF → σ*S-C(F) (E2PT ≈ 4 kcal/mol) interactions.
General Procedure 1: To a flame dried Schlenk flask containing 2-
mercaptobenzothiazole (1.00 eq.) and DMF (dried under 4Å MS) was
added NaH (60% in mineral oil, 1.30 eq.) at 0 °C. The mixture was stirred
at 0 °C for 30 min where after the brominated electrophile (1.10 eq.) was
added. The reaction mixture was stirred under an argon atmosphere at
room temperature overnight. The mixture was then diluted with water,
extracted with EtOAc (x 3) and the combined organic layers were dried
(Na2SO4) and concentrated in vacuo.
Replacement of the S=O unit by N-F as shown in Figure 13,
reinstates the anomeric effect as a defining conformational factor
in these closely related systems, due to the less diffuse character
of nitrogen electron pairs. Herein, hyperconjugative stabilisation
of E2PT = 11.2 kcal/mol for the nN → σ*C-F interaction is calculated.
This final comparison serves to underscore the modular nature of
hyperconjugative interactions in enabling acyclic conformational
control. This is fully consistent with the stereoelectronic analysis
of the anomeric effect in fluoromethylamine delineated by
Dunitz.[8]
General Procedure 2: To a solution of the designated thioether (1.00 eq.)
in DCM was added m-chloroperoxybenzoic acid (1.00 eq.) at 0 °C. The
resulting mixture was stirred at room temperature for 24-26 h where after
the solvent was removed under reduced pressure to afford the crude
product.
General Procedure 3: The designated thioether (1.00 eq.) was dissolved
in a mixture of CHCl3 / MeCN / H2O (1 : 1 : 2.6) and NaIO4 (4.00 eq.) and
ruthenium (III) chloride hydrate (2 mg) was added. The mixture was stirred
at room temperature overnight and then filtered over Celite®. The organic
solvents were removed in vacuo and the residue was extracted with DCM
(x 3). The combined organic layers were washed (brine), dried (MgSO4)
and concentrated under reduced pressure to obtain the crude product.
General Procedure 4: A flame dried Schlenk flask was charged with
Selectfluor® (1.25 eq.) and ACN. The designated thioether (1.00 eq. in
ACN) was then added dropwise to the suspension and the mixture was
stirred under argon at room temperature for 10 min where after Et3N (1.25
eq.) was added. The reaction mixture was stirred for another 10 min at
room temperature before it was poured into water, extracted with DCM (x
3), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved
in DCM and m-chloroperoxybenzoic acid (1.00 eq.) was added at 0 °C.
The reaction mixture was then stirred at room temperature for 17-45 h
where after a saturated aq. solution of Na2SO3 was added and the mixture
was stirred at room temperature for another 2 h. The organic layer was
then washed with saturated aq. NaHCO3, dried (Na2SO4), filtered and
concentrated under reduced pressure.
Figure 13. Model compound used for comparing the nS
hyperconjugation with an nN → σ*C-F interaction.
→
σ*C-F
Conclusion
General Procedure 5: Based on a modified literature procedure.[21] ZnCl2
(3.50 eq.) was flame dried in a Schlenk flask and dry THF was added.
LiHMDS (2.20 eq.) was then added and the mixture was stirred at room
temperature for 5 min where after the designated sulfone (1.00 eq.) was
added. After stirring for 30 min NFSI (2.00 eq.) was added and the resulting
reaction mixture was then stirred at room temperature for 6-7 h. The
reaction was set-up and stirred under an argon atmosphere. A solution of
aq. HCl (1 M) was then added and the mixture was extracted with EtOAc
(x 3). The combined organic layers were dried (MgSO4) and concentrated
in vacuo to obtain the crude mixture.
Motivated by the increasing popularity of the RS(O)nCHFR motif
in bioactive small molecule discovery, a combined experimental
and computational analysis of α-fluoro-sulfides, -sulfoxides and -
sulfones is disclosed. Conformations that are intuitively preferred
by stereoelectronic theory generally prevail as demonstrated
through the inclusion of several X-ray analyses. Given the
prevalence of S=O and C-F based interactions that are
independently prevalent in small molecule drug discovery,[25,26] it
is envisaged that this analysis of the RS(O)nCHFR motif will find
application in focused molecular design.
2-(Benzylthio)benzo[d]thiazole (1a). The product was synthesized from
benzyl bromide (0.77 mL, 6.50 mmol, 1.10 eq.) according to General
Procedure 1. The product was purified via flash chromatography (CyH :
EtOAc / 50 : 1) and was afforded as a light yellow solid (1.522 g, 99%).
M.p.: 35 °C; Rf 0.33 (CyH : EtOAc / 20 : 1); HRMS m/z (ESI): Calcd. for
C14H11NS2Na+ 280.0225, found 280.0229; 1H NMR (600 MHz, Methylene
chloride-d2, 298 K) δ 7.89 (ddd, 3JHH = 8.2 Hz, 4JHH = 1.2 Hz, 5JHH = 0.6
Experimental Section
3
4
5
Hz, 1H, HC4), 7.79 (ddd, JHH = 8.0 Hz, JHH = 1.2 Hz, JHH = 0.6 Hz,
1H, HC7), 7.50 – 7.47 (m, 2H, HC10), 7.46 – 7.43 (m, 1H, HC5), 7.36 –
7.28 (m, 4H, HC6,11,12), 4.62 (s, 2H, H2C8); 13C{1H} NMR (151 MHz,
Methylene chloride-d2, 298 K) δ 166.9 (C1), 153.8 (C3), 137.2 (C9), 136.0
(C2), 129.7 (C10), 129.2 (C11), 128.2 (C12), 126.6 (C5), 124.8 (C6), 122.0
(C4), 121.6 (C7), 38.1 (C8); IR (cm-1): 3059 (w), 3030 (w), 1495 (m), 1454
(s), 1424 (s), 1310 (m), 1275 (m), 1239 (m), 1192 (m), 1124 (m), 1071 (m),
1019 (m), 996 (s), 934 (m), 916 (m), 860 (m), 814 (m), 768 (m), 748 (s),
725 (s), 709 (s), 691 (s), 675 (s).
General Information: All commercially available chemicals were purchased
as reagent grade and were used directly as received. Solvents used for
extractions and flash chromatography were of technical grade and distilled
prior to use. Where indicated, dry solvents were dried through a Grubbs
purification system. Pre-coated silica gel 60 F254 aluminium plates from
Merck were used for thin layer chromatography (TLC) and were visualized
under UV-light and/or stained with a solution of KMnO4. Fluka silica gel
(230-400 mesh) was employed for purification with flash chromatography.
NMR measurements were performed by the NMR service of the Organic
Chemistry institute (WWU, Münster) on a Bruker AV300, AV400 or an
Agilent DD2 600 at the indicated temperature. Additional 1D and 2D NMR
experiments (e.g., 1H{19F}, 19F{1H}, DEPT, COSY, HMBC and HSQC)
were used to assign the resonances of previously unreported compounds.
Chemical shifts (δ, ppm) are referenced to esidual solvent signals and the
coupling constants (J) are given in Hz. The resonance multiplicities are
declared as: s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet).
High resolution mass spectra (HR-ESI) were recorded by the MS service
2-(Phenethylthio)benzo[d]thiazole (1b). The product was synthesized
from (2-bromoethyl)benzene (450 µL, 3.29 mmol, 1.10 eq.) according to
General Procedure 1. The product was purified by flash chromatography
(CyH : EtOAc / 30 : 1) and was obtained as a colourless oil (789 mg, 97%).
Rf 0.21 (CyH : EtOAc / 30 : 1); HRMS m/z (ESI): Calcd. for C15H13NS2Na+
294.0387, found 294.0384; 1H NMR (600 MHz, Methylene chloride-d2, 298
3
4
K) δ 7.88 (ddt, JHH = 8.1 Hz, JHH = 1.2 Hz, 5JHH = 0.6 Hz, 1H, HC4),
7.80 (ddt, 3JHH = 8.0 Hz, 4JHH = 1.2 Hz, 5JHH = 0.6 Hz, 1H, HC7), 7.44
(m, 1H, HC5), 7.36 – 7.29 (m, 5H, HC6,11,12), 7.26 (m, 1H, HC13), 3.61
7
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
(m, 2H, H2C8), 3.15 (m, 2H, H2C9); 13C{1H} NMR (151 MHz, Methylene
chloride-d2, 298 K) δ 167.2 (C1), 154.0 (C3), 140.4 (C10), 135.9 (C2),
129.2 (C11), 129.1 (C12), 127.2 (C13), 126.6 (C5), 124.7 (C6), 122.0 (C4),
121.6 (C7), 36.1 (C9), 35.3 (C8); IR (cm-1): 3060 (w), 3026 (w), 2923 (w),
2853 (w), 1603 (w), 1560 (w), 1496 (w), 1455 (m), 1425 (s), 1309 (m), 1274
(w), 1238 (m), 1177 (w), 1157 (w), 1126 (w), 1075 (w), 1018 (m), 992 (s),
934 (w), 880 (w), 851 (w), 826 (w), 752 (s), 724 (m), 712 (m), 695 (s),
668 (m).
3JHH = 8.4 HZ, 4JHH = 1.9 Hz, 1H, HC10), 4.92 (s, 2H, H2C8); 13C{1H}
NMR (101 MHz, Methylene chloride-d2, 298 K) δ 165.9 (C1), 153.3 (C3),
137.6 (C2), 133.8 (C12), 133.7 (C13), 131.7 (C14), 129.1 (C11), 128.6
(C6), 128.5 (C18), 128.4 (C10), 128.3 (C5), 128.2 (C15), 127.5 (C16),
127.2 (C17), 125.9 (C4), 124.6 (C9), 123.0 (C7), 61.7 (C8); IR (cm-1): 2925
(w), 1598 (w), 1507 (w), 1473 (m), 1457 (w), 1425 (w), 1406 (w), 1364 (w),
1314 (s), 1276 (m), 1254 (w), 1233 (m), 1210 (w), 1162 (w), 1140 (s), 1124
(m), 1086 (w), 1023 (m), 969 (w), 957 (w), 949 (w), 922 (w), 902 (m), 872
(w), 864 (w), 851 (m), 828 (m), 764 (s), 753 (s), 725 (s), 707 (m), 683 (w).
2-((Naphthalen-2-ylmethyl)thio)benzo[d]thiazole (1c). The compound
was prepared from 2-(bromomethyl)naphthalene (3.62 g, 16.4 mmol, 1.10
eq.) according to General Procedure 1. The crude mixture was adsorbed
on silica and purified by flash chromatography (CyH : EtOAc / 60 : 1), which
afforded the product as a white solid (3.16 g, 69%). M.p.: 78 °C; Rf 0.30
(CyH : EtOAc / 19 : 1); HRMS m/z (ESI): Calcd. for C18H13NS2Na+
330.0387, found 330.0386; 1H NMR (500 MHz, Methylene chloride-d2, 298
K) δ 7.94 (dh, 4JHH = 2.0 Hz, 5JHH = 0.7 Hz, 1H, HC14), 7.90 (ddd, 3JHH
2-((Fluoro(phenyl)methyl)sulfonyl)benzo[d]thiazole (3a). The product
was synthesized from 2a (243 mg, 0.84 mmol, 1.00 eq.) following General
Procedure 5 (reaction time: 7 h). The crude product was adsorbed to silica
and purified by flash chromatography (CyH : EtOAc / 10 : 1), which
afforded the product as a white solid (188 mg, 73%). M.p.: 141 °C; Rf 0.30
(CyH : EtOAc / 8 : 1); HRMS m/z (ESI): Calcd. for C14H10FNO2S2Na+
330.0035, found 330.0034; 1H NMR (600 MHz, Methylene chloride-d2, 298
K) δ 8.29 (ddd, 3JHH = 8.3 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC4),
8.08 (ddd, 3JHH = 8.1 Hz, 4JHH = 1.4 Hz, 5JHH = 0.8 Hz, 1H, HC7), 7.70
(ddd, 3JHH = 8.3, 7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.66 (ddd, 3JHH = 8.3,
7.2 Hz, 4JHH = 1.3 Hz, 1H, HC6), 7.61 (m, 2H, HC10), 7.57 (m, 1H, HC12),
7.51 (m, 2H, HC11), 6.65 (d, 2JFH = 45.7 Hz, 1H, HC8); 13C{1H} NMR (151
MHz, Methylene chloride-d2, 298 K) δ 162.6 (C1), 152.9 (C3), 137.5 (C2),
131.6 (d, 5JFC = 1.5 Hz, C12), 128.8 (C11), 128.4 (C6), 128.3 (d, 3JFC =
6.3 Hz, C10), 127.9 (C5), 126.5 (d, 2JFC = 19.4 Hz, C9), 125.6 (C4), 122.4
(C7), 102.0 (d, 1JFC = 222.5 Hz, C8); 19F NMR (564 MHz, Methylene
chloride-d2, 298 K) δ -173.1 (d, 2JFH = 45.7 Hz, 1F, FC8); IR (cm-1): 2968
(w), 1494 (w), 1460 (m), 1413 (w), 1347 (s), 1316 (m), 1294 (w), 1236 (w),
1197 (w), 1156 (m), 1083 (m), 1040 (m), 1021 (m), 984 (w), 854 (w), 791
(w), 760 (s), 734 (m), 709 (w), 696 (s).
4
5
= 8.2 Hz, JHH = 1.2 Hz, JHH = 0.6 Hz, 1H, HC4), 7.85 – 7.81 (m, 3H,
4
HC11,15,18), 7.78 (ddd, 3JHH = 8.0 Hz, JHH = 1.3 Hz, 5JHH = 0.6 Hz,
3
4
1H, HC7), 7.59 (dd, JHH = 8.5 Hz, JHH = 1.8 Hz, 1H, HC10), 7.48 (m,
3
4
2H, HC16,17), 7.44 (ddd, JHH = 8.2, 7.3 Hz, JHH = 1.3 Hz, 1H, HC5),
7.31 (ddd, 3JHH = 8.0, 7.3 Hz, 4JHH = 1.2 Hz, 1H, HC6), 4.78 (s, 2H,
H2C8); 13C{1H} NMR (126 MHz, Methylene chloride-d2, 298 K) δ 166.8 (C1),
153.8 (C3), 136.0 (C2), 134.6 (C9), 133.9 (C13), 133.4 (C12), 129.0 (C11),
128.5 (C14), 128.3 (C18), 128.2 (C15), 127.5 (C10), [126.9,
126.7](C16,17), 126.6 (C5), 124.9 (C6), 122.0 (C4), 121.7 (C7), 38.4 (C8);
IR (cm-1): 3051 (w), 2926 (w), 1597 (w), 1508 (w), 1454 (m), 1424 (s), 1361
(w), 1310 (m), 1275 (w), 1240 (w), 1203 (w), 1122 (m), 1074 (m), 1017 (m),
1000 (m), 963 (m), 950 (m), 935 (m), 898 (m), 874 (w), 854 (m), 817 (m),
772 (w), 748 (s), 725 (s), 703 (m), 668 (m).
2-(Benzylsulfonyl)benzo[d]thiazole (2a). The product was synthesized
from 1a (200 mg, 0.78 mmol, 1.00 eq.) according to General Procedure 3.
The product was purified by recrystallization of the crude mixture (DCM :
CyH) and was afforded as a white solid (156 mg, 69%). M.p.: 108 °C; Rf
0.22 (CyH : EtOAc / 4 : 1); HRMS m/z (ESI): Calcd. for C14H11NO2S2Na+
312.0129, found 312.0123; 1H NMR (400 MHz, Methylene chloride-d2, 298
K) δ 10.20 (ddd, 3JHH = 8.3 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC4),
9.93 (ddd, 3JHH = 8.0 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC7), 9.62
(ddd, 3JHH = 8.3, 7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 9.55 (ddd, 3JHH = 8.3,
7.2 Hz, 4JHH = 1.3 Hz, 1H, HC6), 9.32 – 9.19 (m, 5H, HC10,11,12), 6.69
(s, 2H, H2C8); 13C{1H} NMR (101 MHz, Methylene chloride-d2, 298 K) δ
165.8 (C1), 153.3 (C3), 137.6 (C2), 131.7 (C10), 129.7 (C12), 129.4 (C11),
128.6 (C6), 128.2 (C5), 127.2 (C9), 125.9 (C4), 122.9 (C7), 61.5 (C8); IR
(cm-1): 2978 (w), 2920 (w), 1554 (w), 1496 (w), 1478 (w), 1456 (w), 1421
(w), 1405 (w), 1333 (m), 1315 (w), 1276 (w), 1252 (w), 1198 (w), 1150 (m),
1128 (m), 1081 (w), 1073 (w), 1024 (w), 940 (w), 927 (w), 882 (w), 851 (w),
779 (m), 760 (m), 730 (m), 697 (m), 687 (m).
2-((1-Fluoro-2-phenylethyl)sulfonyl)benzo[d]thiazole
(3b).
Synthesized according to following literature procedure.22 1H NMR (600
3
4
MHz, Methylene chloride-d2, 298 K) δ 8.26 (ddd, JHH = 8.2 Hz, JHH =
5
3
4
1.5 Hz, JHH = 0.7 Hz, 1H, HC4), 8.08 (ddd, JHH = 7.9 Hz, JHH = 1.5
Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.67 (m, 2H, HC5,6), 7.35 (m, 2H, HC12),
7.33 – 7.29 (m, 3H, HC11,13), 5.83 (ddd, 2JFH = 48.2 Hz, JHH = 10.3,
3
2.5 Hz, 1H, HC8), [3.63 (ddd, 3JFH = 38.9 Hz, 2JHH = 15.0 Hz, 3JHH = 2.5
Hz, 1H), 3.39 (ddd, 3JFH = 16.3 Hz, 2JHH = 15.0 Hz, 3JHH = 10.4 Hz,
1H)](H2C9); 13C{1H} NMR (151 MHz, Methylene chloride-d2, 298 K) δ
162.8 (C1), 153.5 (C3), 138.1 (C2), 133.7 (C10), 130.1 (C11), 129.5 (C12),
129.1 (C6), 128.5 (C5), 128.3 (C13), 126.2 (C4), 123.0 (C7), 102.9 (d,
1JFC = 223.7 Hz, C8), 33.9 (d, 2JFC = 19.4 Hz, C9); 19F NMR (564 MHz,
Methylene chloride-d2, 298 K) δ -177.7 (ddd, 2JFH = 48.2 Hz, 3JFH = 39.0,
16.4 Hz, 1F, FC8).
2-((Fluoro(naphthalen-2-yl)methyl)sulfonyl)benzo[d]thiazole
(3c).
The compound was synthesized from 2c (80 mg, 0.24 mmol, 1.00 eq.)
according to General Procedure 5 (reaction time: 6 h). The product was
purified by flash chromatography (CyH : EtOAc / 14 : 1) and was obtained
as a light yellow solid (29 mg, 35%). M.p.: 166 °C; Rf 0.28 (CyH : EtOAc /
5 : 1); HRMS m/z (ESI): Calcd. for C18H12NO2S2FNa+ 380.0186, found
380.0196; 1H NMR (600 MHz, Methylene chloride-d2, 298 K) δ 8.31 (ddd,
3JHH = 8.2 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC4), 8.13 (s, 1H,
HC14), 8.08 (ddd, 3JHH = 8.1 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC7),
7.98 (d, 3JHH = 8.5 Hz, 1H, HC11), 7.93 (m, 2H, HC15,18), 7.71 (ddd,
3JHH = 8.3, 7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.66 (m, 2H, HC6,10), 7.62
2-(Phenethylsulfonyl)benzo[d]thiazole (2b). The compound was
synthesized from 1b (200 mg, 0.74 mmol, 1.00 eq.) according to General
Procedure 3. The product was purified by flash chromatography (DCM)
and was afforded as a white solid (118 mg, 53%). M.p.: 84 °C; Rf 0.63
(DCM); HRMS m/z (ESI): Calcd. for C15H13NO2S2Na+ 326.0280, found
326.0288; 1H NMR (600 MHz, Methylene chloride-d2, 298 K) δ 8.22 (ddd,
3JHH = 8.3 Hz, 4JHH = 1.3 Hz, 5JHH = 0.7 Hz, 1H, HC4), 8.05 (ddd, 3JHH
= 8.1 Hz, 4JHH = 1.3 Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.67 (ddd, 3JHH = 8.3,
7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.62 (ddd, 3JHH = 8.3, 7.2 Hz, 4JHH =
1.3 Hz, 1H, HC6), 7.28 – 7.23 (m, 2H, HC12), 7.20 – 7.17 (m, 3H,
HC11,13), 3.80 (m, 2H, H2C8), 3.19 (m, 2H, H2C9); 13C{1H} NMR (151 MHz,
Methylene chloride-d2, 298 K) δ 166.3 (C1), 153.4 (C3), 137.7 (C10), 137.4
(C2), 129.3 (C12), 129.0 (C11), 128.6 (C6), 128.2 (C5), 127.5 (C13), 125.9
(C4), 123.0 (C7), 56.4 (C8), 29.1 (C9); IR (cm-1): 2930 (w), 1601 (w), 1552
(w), 1496 (w), 1469 (m), 1455 (m), 1422 (w), 1403 (w), 1327 (m), 1312 (m),
1260 (w), 1236 (w), 1203 (w), 1165 (w), 1146 (s), 1127 (m), 1084 (m), 1072
(w), 1025 (m), 1005 (m), 965 (w), 907 (w), 852 (m), 773 (m), 762 (s),
741 (m), 728 (m), 696 (s).
3
4
3
(ddd, JHH = 8.4, 6.9 Hz, JHH = 1.5 Hz, 1H, HC16), 7.59 (ddd, JHH =
7.9, 6.8 Hz, 4JHH = 1.4 Hz, 1H, HC17), 6.81 (d, 2JFH = 45.6 Hz, 1H, HC8);
13C{1H} NMR (151 MHz, Methylene chloride-d2, 298 K) δ 163.3 (C1), 153.5
(C3), 138.2 (C2), 135.2 (d, 5JFC = 1.1 Hz, C12), 133.2 (C13), 129.8 (d,
3JFC = 7.1 Hz, C14), 129.3 (C11), 129.1 (C18), 129.0 (C6), 128.6 (C16),
128.5 (C5), 128.5 (C15), 127.6 (C17), 126.2 (C4), 124.6 (d, 3JFC = 5.5 Hz,
2
1
C10), 124.4 (d, JFC = 19.4 Hz, C9), 123.0 (C7), 102.9 (d, JFC = 222.8
Hz, C8); 19F NMR (564 MHz, Methylene chloride-d2, 298 K) δ -172.3 (d,
2JFH = 45.6 Hz, 1F, FC8); IR (cm-1): 2923 (w), 2852 (w), 1600 (w), 1550
(w), 1507 (w), 1466 (m), 1420 (w), 1367 (w), 1345 (s), 1317 (m), 1276 (m),
1260 (w), 1240 (w), 1222 (m), 1212 (w), 1151 (s), 1123 (m), 1084 (m),
1043 (m), 1020 (m), 968 (m), 954 (m), 910 (m), 885 (w), 867 (m), 852 (m),
830 (m), 776 (m), 764 (s), 741 (m), 732 (s), 694 (m), 654 (s).
2-((Naphthalen-2-ylmethyl)sulfonyl)benzo[d]thiazole
(2c).
The
compound was prepared from 1c (140 mg, 0.46 mmol, 1.00 eq.) following
General Procedure 3. The crude mixture was purified by flash
chromatography (CyH : EtOAc / 12 : 1) which afforded the product as a
light yellow solid (110 mg, 71%). M.p.: 132 °C; Rf 0.28 (CyH : EtOAc / 6 :
1); HRMS m/z (ESI): Calcd. for C18H13NO2S2Na+ 362.0285, found
362.0280; 1H NMR (400 MHz, Methylene chloride-d2, 298 K) δ 8.28 (ddd,
3JHH = 8.3 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC4), 7.95 (ddd, 3JHH
2-(Benzylsulfinyl)benzo[d]thiazole
(4a).
The
compound
was
synthesized from 1a (1.00 g, 3.89 mmol, 1.00 eq.) following General
Procedure 2 (reaction time: 26 h). The product was purified by flash
chromatography (DCM) and was afforded as a white solid (701 mg, 66%).
M.p.: 121 °C; Rf 0.09 (DCM); HRMS m/z (ESI): Calcd. for C14H11NOS2Na+
296.0174, found 296.0181; 1H NMR (600 MHz, Methylene chloride-d2, 298
K) δ 8.10 (ddd, 3JHH = 8.3 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC4),
7.97 (ddd, 3JHH = 8.1 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.59
(ddd, 3JHH = 8.3, 7.2 Hz, 4JHH = 1.2 Hz, 1H, HC5), 7.50 (ddd, 3JHH = 8.3,
5
= 8.1 Hz, 4JHH = 1.3 Hz, JHH = 0.7 Hz, 1H, HC7), 7.82 (m, 1H, HC15),
7.78 (d, 3JHH = 8.4 Hz, 1H, HC11), 7.77 (s, 1H, HC14), 7.73 (m, 1H, HC18),
7.68 (ddd, 3JHH = 8.3, 7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.59 (ddd, 3JHH
= 8.3, 7.2 Hz, 4JHH = 1.2 Hz, 1H, HC6), 7.49 (m, 2H, HC16,17), 7.36 (dd,
8
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
4
7.2 Hz, JHH = 1.2 Hz, 1H, HC6), 7.34 – 7.26 (m, 3H, HC11,12), 7.19 –
2-((Fluoro(phenyl)methyl)sulfinyl)benzo[d]thiazole
(6a/b).
The
2
2
7.16 (m, 2H, HC10), [4.52 (d, JHH = 13.2 Hz, 1H), 4.34 (d, JHH = 13.1
Hz, 1H)](H2C8); 13C{1H} NMR (151 MHz, Methylene chloride-d2, 298 K) δ
177.8 (C1), 154.4 (C3), 136.6 (C2), 131.1 (C10), 129.3 (C9), 129.2 (C12),
129.1 (C11), 127.4 (C5), 126.7 (C6), 124.4 (C4), 122.8 (C7), 63.3 (C8); IR
(cm-1): 2960 (w), 2907 (w), 1493 (w), 1467 (w), 1455 (w), 1417 (w), 1314
(w), 1275 (w), 1233 (w), 1160 (w), 1134 (w), 1124 (w), 1086 (w), 1074 (w),
1048 (m), 1032 (w), 1004 (w), 1016 (w), 977 (w), 945 (w), 920 (w), 886 (w),
856 (w), 847 (w), 811 (w), 766 (w), 756 (m), 732 (m), 697 (m), 684 (m).
compounds were synthesized from 1a (700 mg, 2.72 mmol, 1.00 eq.)
according to General Procedure 4 (reaction time: 17 h). The crude product
was adsorbed on silica and purified via flash chromatography (n-Pentane :
Et2O / 15 : 1) which afforded the products as white solids (6a: 78 mg, 9%
and 6b: 41 mg, 5%). 6a (anti): M.p.: 136 °C; Rf 0.27 (n-Pentane : Et2O / 4 :
1); HRMS m/z (ESI): Calcd. for C14H10FNOS2Na+ 314.0086, found
314.0092; 1H NMR (600 MHz, Methylene chloride-d2, 298 K) δ 8.14 (ddd,
3JHH = 8.3 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC4), 7.95 (ddd, 3JHH
= 8.2 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.61 (ddd, 3JHH = 8.3,
3
2-(Phenethylsulfinyl)benzo[d]thiazole (4b). The compound was
synthesized from 1b (300 mg, 1.11 mmol, 1.00 eq.) following General
Procedure 2 (reaction time: 24 h). The product was purified via flash
chromatography (DCM) and was obtained as a white solid (185 mg, 58%).
M.p.: 84 °C; Rf 0.10 (DCM); HRMS m/z (ESI): Calcd. for C15H13NS2ONa+
310.0331, found 310.0338; 1H NMR (600 MHz, Methylene chloride-d2, 298
K) δ 8.07 (ddd, 3JHH = 8.2 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 2H, HC4),
8.04 (ddd, 3JHH = 8.1 Hz, 4JHH = 1.3 Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.58
(ddd, 3JHH = 8.3, 7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.51 (ddd, 3JHH = 8.1,
7.2 Hz, 4JHH = 1.2 Hz, 1H, HC6), 7.29 (m, 2H, HC11), 7.25 – 7.20 (m, 3H,
HC12,13), [3.52 (ddd, 2JHH = 13.3 Hz, 3JHH = 10.2, 6.3 Hz, 1H), 3.45 (ddd,
2JHH = 13.3 Hz, 3JHH = 10.0, 5.5 Hz, 1H)](H2C8), [3.25 (ddd, 2JHH =
14.1 Hz, 3JHH = 10.0, 6.3 Hz, 1H), 2.98 (ddd, 2JHH = 14.1 Hz, 3JHH = 10.2,
5.5 Hz, 1H)]( H2C9); 13C{1H} NMR (151 MHz, Methylene chloride-d2, 298
K) δ 178.2 (C1), 154.7 (C3), 139.0 (C10), 136.7 (C2), 129.3 (C12), 129.2
(C11), 127.5 (C5), 127.3 (C13), 126.7 (C6), 124.4 (C4), 122.9 (C7),
58.0 (C8), 28.1 (C9); IR (cm-1): 2920 (w), 1601 (w), 1557 (w), 1497 (m),
1471 (m), 1455 (m), 1428 (m), 1401 (m), 1312 (m), 1279 (w), 1259 (w),
1233 (m), 1219 (m), 1202 (w), 1180 (w), 1157 (w), 1129 (w), 1078 (m),
1047 (s), 1020 (m), 999 (m), 969 (w), 946 (m), 919 (w), 863 (w), 843 (m),
832 (w), 759 (s), 747 (s), 731 (s), 700 (s), 683 (m), 666 (m).
7.2 Hz, 4JHH = 1.2 Hz, 1H, HC5), 7.51 (ddd, JHH = 8.2, 7.1 Hz, 4JHH =
1.2 Hz, 1H, HC6), 7.42 (tq, 3JHH = 7.3 Hz, 4JHH = 1.2 Hz, 1H, HC12), 7.30
(tt, 3JHH = 7.5 Hz, 4JHH = 1.0 Hz, 2H, HC11), 7.15 – 7.08 (m, 2H, HC10),
6.54 (d, 2JFH = 45.6 Hz, 1H, HC8); 1H NMR (600 MHz, Methylene
3
3
Chloride-d2, 193 K) δ 8.12 (d, JHH = 8.2 Hz, 1H, HC4), 7.93 (d, JHH =
8.1 Hz, 1H, HC7), 7.61 (ddd, 3JHH = 8.3, 7.1 Hz, 4JHH = 1.3 Hz, 1H, HC5),
7.50 (td, 3JHH = 7.6, 6.8 Hz, 4JHH = 1.3 Hz, 1H, HC6), 7.39 (t, 3JHH = 7.4
Hz, 1H, HC12), 7.25 (t, 3JHH = 7.6 Hz, 2H, HC11), 6.95 (d, 3JHH = 7.5 Hz,
2
2H, HC10), 6.62 (d, JFH = 44.5 Hz, 1H, HC8); 13C{1H} NMR (151 MHz,
Methylene chloride-d2, 298 K) δ 174.3 (d, 3JFC = 10.3 Hz, C1), 154.4 (C3),
136.5 (C2), 131.3 (d, 5JFC = 1.6 Hz, C12), 128.8 (d, 2JFC = 19.6 Hz, C9),
128.8 (C11), 128.1 (d, 3JFC = 6.2 Hz, C10), 127.6 (C5), 127.0 (C6), 124.7
(C4), 122.8 (C7), 109.7 (d, 1JFC = 218.7 Hz, C8); 13C{1H} NMR (151 MHz,
Methylene Chloride-d2, 193 K)δ 173.0 (d, 3JFC = 11.7 Hz, C1), 153.4 (C3),
135.1 (C2), 130.6 (C12), 128.0 (C11), 127.1 (d, 3JFC = 5.9 Hz, C10), 126.9
2
(C5), 126.9 (d, JFC = 19.7 Hz, C9), 126.2 (C6), 123.7 (C4), 122.3 (C7),
109.0 (d, 1JFC = 215.6 Hz, C8); 19F NMR (564 MHz, Methylene chloride-
d2, 298 K) δ -171.5 (d, 2JFH = 45.6 Hz, 1F, FC8); 19F NMR (564 MHz,
2
Methylene Chloride-d2, 193 K) δ -171.6 (d, JFH = 44.5 Hz, 1F, FC8); IR
(cm-1):3031 (w), 2959 (w), 2924 (w), 1556 (w), 1495 (w), 1470 (m), 1456
(m), 1429 (m), 1353 (w), 1331 (w), 1312 (m), 1292 (w), 1261 (w), 1228 (m),
1191 (w), 1144 (m), 1126 (w), 1090 (m), 1070 (s), 1048 (m), 1031 (m),
1012 (m), 997 (s), 957 (m), 918 (m), 875 (w), 842 (m), 762 (s), 733 (m),
693 (s), 671 (s). 6b (syn): M.p.: 125 °C; Rf 0.19 (n-Pentane : Et2O / 4 : 1);
HRMS m/z (ESI): Calcd. for C14H10FNOS2Na+ 314.0086, found 314.0091;
1H NMR (600 MHz, Methylene chloride-d2, 298 K) δ 8.07 (ddd, 3JHH =
2-((Naphthalen-2-ylmethyl)sulfinyl)benzo[d]thiazole (4c). The product
was synthesized from 1c (140 mg, 0.46 mmol, 1.00 eq.) following General
Procedure 2 (reaction time: 24 h). The desired product was purified by
flash chromatography (DCM) and was obtained as a white solid (81 mg,
54%). M.p.: 152 °C; Rf 0.23 (DCM); HRMS m/z (ESI): Calcd. for
C18H13NOS2Na+ 346.0331, found 346.0328; 1H NMR (400 MHz,
Methylene chloride-d2, 298 K) δ 8.12 (d, 3JHH = 8.3 Hz, 1H, HC4), 7.94 (d,
3JHH = 8.1 Hz, 1H, HC7), 7.85 – 7.79 (m, 1H, HC15), 7.74 (d, 3JHH = 8.4
Hz, 2H, HC11,18), 7.69 (s, 1H, HC14), 7.60 (ddd, 3JHH = 8.5, 7.2 Hz, 4JHH
= 1.3 Hz, 1H, HC5), 7.55 – 7.44 (m, 3H, HC6,16,17), 7.24 (dd, 3JHH = 8.4
Hz, 4JHH = 1.8 Hz, 1H, HC10), [4.69 (d, 2JHH = 13.1 Hz, 1H), 4.51 (d,
2JHH = 13.0 Hz, 1H)](H2C8); 13C{1H} NMR (101 MHz, Methylene chloride-
d2, 298 K) δ 177.8 (C1), 154.5 (C3), 136.6 (C2), [133.7, 133.6](C12,13),
130.7 (C14), 128.8 (C11), 128.4 (C18), 128.2 (C10,15), 127.4 (C5), 127.1
(C16), 127.0 (C17), 126.8 (C9), 126.7 (C6), 124.4 (C4), 122.8 (C7), 63.6
(C8); IR (cm-1): 2919 (w), 1696 (w), 1596 (w), 1575 (w), 1556 (w), 1508
(w), 1473 (m), 1455 (w), 1425 (m), 1367 (w), 1313 (m), 1274 (w), 1261 (m),
1240 (w), 1206 (w), 1145 (w), 1120 (m), 1085 (m), 1075 (m), 1048 (s),
1015 (m), 999 (m), 969 (w), 955 (m), 943 (m), 902 (m), 874 (m), 846 (w),
823 (m), 776 (w), 756 (m), 743 (s), 728 (s), 676 (m), 667 (m).
4
5
3
8.2 Hz, JHH = 1.2 Hz, JHH = 0.7 Hz, 1H, HC4), 8.01 (ddd, JHH = 8.0
Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.59 (ddd, 3JHH = 8.3, 7.2
Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.53 (ddd, JHH = 8.1, 7.2 Hz, 4JHH = 1.2
3
Hz, 1H, HC6), 7.47 (m, 1H, HC12), 7.39 (m, 4H, HC10,11), 6.46 (d, 2JFH
= 46.1 Hz, 1H, HC8); 1H NMR (600 MHz, Methylene chloride-d2, 193 K) δ
8.06 (d, 3JHH = 8.1 Hz, 1H, HC4), 8.04 (d, JHH = 8.2 Hz, HC7), 7.59 (t,
3
3JHH = 7.6 Hz, 1H, HC5), 7.53 (t, 3JHH = 7.5 Hz, 1H, HC6), 7.48 (t, 3JHH
= 7.3 Hz, 1H, HC12), 7.43 (t, 3JHH = 7.4 Hz, 2H, HC11), 7.38 (d, 3JHH =
7.6 Hz, 2H, HC10), 6.56 (d, 2JHH = 45.1 Hz, 1H, HC8); 13C{1H} NMR (151
MHz, Methylene chloride-d2, 298 K) δ 173.3 (d, 3JFC = 5.8 Hz, C1), 154.3
(C3), 136.7 (C2), 131.4 (d, 5JFC = 1.5 Hz, C12), 130.4 (d, 2JFC = 19.6 Hz,
3
C9), 129.4 (C11), 127.6 (C5), 127.3 (d, JFC = 6.4 Hz, C10), 127.1 (C6),
124.7 (C4), 122.9 (C7), 108.1 (d, 1JFC = 231.7 Hz, C8); 13C{1H} NMR (151
MHz, Methylene chloride-d2, 193 K) δ 172.4 (d, 3JFC = 5.5 Hz, C1), 153.2
(C3), 135.4 (C2), 130.7 (C12), 129.1 (d, 2JFC = 19.9 Hz, C9), 128.7 (C11),
3
126.9 (C5), 126.3 (C6), 126.2 (d, JFC = 6.5 Hz, C10), 123.6 (C6), 122.3
(C4), 106.1 (d, 1JFC = 233.8 Hz, C8); 19F NMR (564 MHz, Methylene
chloride-d2, 298 K) δ -179.0 (d, 2JFH = 46.1 Hz, 1F, FC8); 19F NMR (564
MHz, Methylene chloride-d2, 193 K) δ -182.7 (d, 2JFH = 42.9 Hz, 1F, FC8);
IR (cm-1): 3068 (w), 2947 (w), 2922 (w), 2851 (w), 1585 (w), 1556 (w), 1495
(w), 1476 (w), 1463 (m), 1456 (m), 1421 (m), 1352 (w), 1315 (m), 1275 (w),
1225 (m), 1188 (w), 1162 (w), 1124 (w), 1089 (m), 1069 (m), 1038 (m),
1017 (m), 945 (m), 930 (w), 861 (w), 846 (w), 836 (w), 775 (m), 756 (s),
732 (m), 697 (s), 685 (m), 663 (s).
2-((1-Fluoro-2-phenylethyl)thio)benzo[d]thiazole (5b). A flame dried
Schlenk flask was charged with Selectfluor® (160 mg, 0.46 mmol, 1.25 eq.)
and ACN (2 mL). Thioether 1b (100 mg, 0.36 mmol, 1.00 eq.) in ACN (2
mL) was then added dropwise to the suspension and the mixture was
stirred under argon at room temperature for 15 min where after Et3N (62
µL, 0.46 mmol, 1.25 eq.) was added. The reaction mixture was stirred for
another 15 min at room temperature before it was poured into water,
extracted with DCM (x 3), dried (Na2SO4) and concentrated in vacuo. The
product was purified through flash chromatography (CyH : EtOAc / 15 : 1
→ 5 : 1) followed by preparative TLC (CyH : EtOAc / 10 : 1 x 1 and 5 : 1 x
2) and was obtained as a colorless oil (19 mg, 21%). Rf 0.48 (CyH : EtOAc
/ 5 : 1); HRMS m/z (ESI): Calcd. for C15H12NS2FNa 312.0287, found
312.0284; 1H NMR (600 MHz, Methylene chloride-d2, 298 K) δ 7.93 (ddd,
3JHH = 8.2 Hz, 4JHH = 1.2 Hz, 5JHH = 0.6 Hz, 1H, HC4), 7.83 (ddd, 3JHH
= 8.0 Hz, 4JHH = 1.3 Hz, 5JHH = 0.6 Hz, 1H, HC7), 7.47 (ddd, 3JHH = 8.3,
7.2 Hz, 4JHH = 1.2 Hz, 1H, HC5), 7.39 – 7.30 (m, 6H, HC6,11,12,13), 6.82
(dt, 2JFH = 53.1 Hz, 3JHH = 6.1 Hz, 1H, HC8), 3.42 (dd, 3JFH = 19.4 Hz,
3JHH = 6.0 Hz, 2H, H2C9); 13C{1H} NMR (151 MHz, Methylene chloride-d2,
2-((1-Fluoro-2-phenylethyl)sulfinyl)benzo[d]thiazole
(7a/b).
The
products were synthesized from 1b (700 mg, 2.58 mmol, 1.00 eq.)
according to General Procedure 4 (reaction time: 45 h). The crude was
adsorbed on silica and purified by flash chromatography (CyH : EtOAc /
100 : 1 → 50 : 1) which afforded the products as white solids (7a: 46 mg,
6% and 7b: 26 mg, 3%). 7a (anti): M.p.: 114 °C; Rf 0.20 (CyH : EtOAc / 6 :
1); HRMS m/z (ESI): Calcd. for C15H12NOS2FNa+ 328.0237, found
328.0243; 1H NMR (600 MHz, Methylene chloride-d2, 298 K) δ 8.12 (ddd,
3JHH = 8.3 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC4), 8.05 (ddd, 3JHH
= 8.1 Hz, 4JHH = 1.2 Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.61 (ddd, 3JHH = 8.3,
3
3
298 K) δ 162.7 (d, JFC = 2.8 Hz, C1), 153.6 (C3), 136.4 (C2), 135.4 (d,
7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.54 (ddd, JHH = 8.1, 7.2 Hz, 4JHH =
3JFC = 3.2 Hz, C10), 130.23 (C11), 129.21 (C12), 128.08 (C13), 126.90
1.2 Hz, 1H, HC6), 7.28 – 7.24 (m, 2H, HC12), 7.23 – 7.18 (m, 3H,
HC11,13), 5.83 (ddd, 2JFH = 48.2 Hz, 3JHH = 8.9, 3.6 Hz, 1H, HC8), [3.42
(ddd, 3JFH = 16.9 Hz, 2JHH = 15.1 Hz, 3JHH = 8.9 Hz, 1H), 3.18 (ddd,
3JFH = 34.1 Hz, 2JHH = 15.2 Hz, 3JHH = 3.6 Hz, 1H)](H2C9);1H NMR (600
MHz, Methylene chloride-d2, 193 K) δ 8.11 (d, 3JHH = 8.2 Hz, 1H, HC4),
8.08 (d, 3JHH = 8.1 Hz, 1H, HC7), 7.61 (t, 3JHH = 7.7 Hz, 1H, HC5), 7.55
(t, 3JHH = 7.7 Hz, 1H, HC6), 7.27 (m, 2H, HC12), 7.25 – 7.20 (m, 1H,
HC13), 7.16 (d, 3JHH = 7.4 Hz, 2H, HC11), 5.80 (dd, 2JFH = 48.1 Hz, 3JHH
1
(C5), 125.52 (C6), 122.72 (C4), 121.75 (C7), 99.91 (d, JFC = 225.3 Hz,
C8), 41.79 (d, 2JFC = 22.1 Hz, C9); 19F NMR (564 MHz, Methylene
chloride-d2, 298 K) δ -148.0 (dt, 2JFH = 53.1 Hz, 3JFH = 19.5 Hz, 1F, FC8);
IR (cm-1): 1495 (w), 1455 (m), 1425 (m), 1310 (m), 1275 (w), 1237 (w),
1203 (w), 1183 (w), 1158 (w), 1126 (w), 1078 (w), 1053 (w), 1018 (w), 980
(s), 849 (m), 822 (m), 753 (s), 725 (s), 696 (s), 667 (m).
9
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
2
= 9.0 Hz, 1H, HC8), 3.38 (td, JHH = 14.6 Hz, 3JHH = 9.5 Hz, 1H, HC9),
Keywords: conformational analysis • crystallography • fluorine •
gauche effect • stereoelectronics
2.89 (dd, 3JFH = 39.0 Hz, 2JHH = 14.8 Hz, 1H, H2C9); 13C{1H} NMR (151
MHz, Methylene chloride-d2, 298 K) δ 173.8 (d, 3JFC = 10.8 Hz, C1), 154.6
(C3), 136.7 (C2), 134.3 (d, 3JFC = 2.5 Hz, C10), 130.2 (C11), 129.2 (C12),
127.9 (C13), 127.7 (C5), 127.1 (C6), 124.8 (C4), 122.9 (C7), 109.6 (d,
1JFC = 222.5 Hz, C8), 33.8 (d, 2JFC = 19.7 Hz, C9); 13C{1H} NMR (151
MHz, Methylene chloride-d2, 193 K) δ 172.5 (d, 3JFC = 11.7 Hz, C1), 153.6
(C3), 135.5 (C2), 133.1 (C10), 129.5 (C11), 128.5 (C12), 127.2 (C13),
127.0 (C5), 126.3 (C6), 123.8 (C4), 122.3 (C7), 108.3 (d, 1JFC = 220.8 Hz,
C8), 31.8 (d, 2JFC = 20.0 Hz, C9); 19F NMR (564 MHz, Methylene chloride-
d2, 298 K) δ -177.3 (ddd, 2JFH = 48.1 Hz, 3JFH = 34.1, 16.9 Hz, 1F, FC8);
19F NMR (564 MHz, Methylene chloride-d2, 193 K) δ -179.7 (m, 1F, FC8);
IR (cm-1): 1602 (w), 1557 (w), 1495 (w), 1470 (m), 1454 (m), 1425 (m),
1342 (w), 1315 (m), 1302 (w), 1232 (m), 1188 (w), 1151 (w), 1124 (w),
1082 (m), 1071 (m), 1051 (s), 996 (m), 945 (m), 918 (w), 854 (m), 760 (s),
729 (s), 717 (m), 695 (s), 681 (m). 7b (syn): M.p.: 128 °C; Rf 0.16 (CyH :
EtOAc / 6 : 1); HRMS m/z (ESI): Calcd. for C15H12NOS2FNa+ 328.0237,
found 328.0242; 1H NMR (600 MHz, Methylene chloride-d2, 298 K) δ 8.07
(ddd, 3JHH = 8.3 Hz, 4JHH = 1.2 Hz, 3JHH = 0.7 Hz, 1H, HC4), 8.05 (ddd,
3JHH = 8.0 Hz, 4JHH = 1.3 Hz, 5JHH = 0.7 Hz, 1H, HC7), 7.59 (ddd, 3JHH
= 8.3, 7.2 Hz, 4JHH = 1.3 Hz, 1H, HC5), 7.53 (ddd, 3JHH = 8.1, 7.2 Hz,
4JHH = 1.2 Hz, 1H, HC6), 7.40 – 7.30 (m, 5H, HC11,12,13), 5.69 (ddd,
2JFH = 47.5 Hz, 3JHH = 8.1, 5.9 Hz, 1H, HC8), [3.53 (ddd, 3JFH = 26.8 Hz,
[1]
[2]
D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308-319.
a) L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem. Int. E. 2011, 50,
11860-11871; b) D. Cahard, V. Bizet, Chem. Soc. Rev. 2014, 43,
135−147. c) M. Aufiero, R. Gilmour, Acc. Chem. Res. 2018, 51, 1701-
1710.
[3]
[4]
T. Fujiwara, D. O’Hagan, J. Fluorine Chem. 2014, 167, 16−29.
a) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Müller, U.
Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637-643; b) K. Müller, C.
Faeh, F. Diederich, Science 2007, 317, 1881-1886; c) S. Purser, P. R.
Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330;
d) D. O'Hagan, J. Fluorine Chem. 2010, 131, 1071–1081; e) E. P. Gillis,
K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem.
2015, 58, 8315-8359; e) N. A. Meanwell, J. Med. Chem. 2018, 61, 5822-
5880.
[5]
[6]
T. Liang, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214-8264.
a) B. E. Smart, J. Fluorine Chem. 2001, 109, 3-11; b) Q. A. Huchet, B.
Kuhn, B. Wagner, H. Fischer, M. Kansy, D. Zimmerli, E. M. Carreira, K.
Müller, J. Fluorine Chem. 2013, 152, 119-128; c) K. Müller, Chimia 2014,
68, 356-362; d) Q. A. Huchet, B. Kuhn, B. Wagner, N. A. Kratochwil, H.
Fischer, M. Kansy, D. Zimmerli, E. M. Carreira, K. Müller, J. Med. Chem.
2015, 58, 9041-9060; e) B. Linclau, Z. Wang, G. Compain, V. Paumelle,
C. Q. Fontenelle, N. Wells, A. Weymouth-Wilson Angew. Chem. Int. Ed.
2016, 55, 674-678; f) N. Erdeljac, G. Kehr, M. Ahlqvist, L. Knerr, R.
Gilmour, Chem. Commun. 2018, 54, 12002-12005; g) M. Salwiczek, E.
K. Nyakatura, U. I. M. Gerling, S. Ye, B. Koksch, Chem. Soc. Rev. 2012,
41, 2135-2171.
2JHH = 14.6 Hz, 3JHH = 5.9 Hz, 1H), 3.45 (ddd, JHH = 14.6 Hz, 2JFH =
2
14.2 Hz, 3JHH = 8.1 Hz, H2C9); 1H NMR (600 MHz, Methylene chloride-d2,
3
3
193 K) δ 8.05 (d, JHH = 8.2 Hz, 1H, HC4), 8.00 (d, JHH = 8.1 Hz, 1H,
HC7), 7.56 (t, 3JHH = 7.5 Hz, 1H, HC5), 7.50 (t, 3JHH = 7.6 Hz, 1H, HC6),
7.39 – 7.27 (m, 5H, HC11,12,13), 5.72 (dt, 2JFH = 46.8 Hz, 3JHH = 7.6 Hz,
1H, HC8), 3.54
–
3.43 (m, 2H, H2C9); 13C{1H} NMR (151 MHz,
Methylene chloride-d2, 298 K) δ 174.1 (d, 3JFC = 6.5 Hz, C1), 154.5 (C3),
136.7 (C2), 133.9 (d, 3JFC = 5.3 Hz, C10), 130.3 (C11), 129.5 (C12), 128.3
(C13), 127.6 (C5), 127.0 (C6), 124.5 (C4), 122.9 (C7), 107.6 (d, 1JFC =
238.8 Hz, C8), 36.2 (d, 2JFC = 20.5 Hz, C9); 13C{1H} NMR (151 MHz,
Methylene chloride-d2, 193 K) 173.1 (d, 3JFC = 6.4 Hz, C1), 153.4 (C3),
135.4 (C2), 132.6 (d, 3JFC = 6.3 Hz, C10), 129.6 (C11), 128.8 (C12), 127.6
(C13), 126.9 (C5), 126.1 (C6), 123.3 (C4), 122.3 (C7), 106.5 (d, 1JFC =
240.3 Hz, C8), 35.2 (d, 2JFC = 20.5 Hz, C9); 19F NMR (564 MHz,
Methylene chloride-d2, 298 K) δ -181.7 (ddd, 2JFH = 47.4 Hz, 3JFH = 26.8,
14.2 Hz, 1F, FC8); 19F NMR (564 MHz, Methylene chloride-d2, 193 K) δ -
183.4 (m, 1F, FC8); IR (cm-1): 3062 (w), 2942 (w), 1557 (w), 1497 (w),
1474 (m), 1456 (m), 1429 (m), 1346 (w), 1314 (m), 1261 (m), 1237 (w),
1201 (w), 1187 (w), 1163 (w), 1132 (w), 1086 (m), 1064 (s), 1049 (s), 1019
(s), 1003 (m), 945 (m), 930 (m), 907 (m), 864 (m), 847 (w), 819 (m), 750
(s), 730 (s), 700 (s), 687 (s).
[7]
a) J. P. Snyder, N. S. Chandrakumar, H. Sato, D. C. Lankin, J. Am. Chem.
Soc. 2000, 122, 544-545; b) C. Sparr, H. M. Senn, R. Gilmour, Angew.
Chem. Int. Ed. 2009, 48, 3065-3068.
[8]
[9]
J. J. Irwin, T.-K. Ha, J. D. Dunitz, Helv. Chim. Acta 1990, 73, 1805-
1817.
a) Y. P. Rey, C. Thiehoff, R. Gilmour, Isr. J. Chem. 2017, 57, 92-100; b)
I. G. Molnꢀr, M. C. Holland, M. C.; Daniliuc, K. N. Houk, R. Gilmour,
Synlett 2016, 27, 1051-1055.
[10] a) C. Thiehoff, M. C. Holland, C. G. Daniliuc, K. N. Houk, R. Gilmour,
Chem. Sci. 2015, 6, 3565-3571; b) C. Thiehoff, L. Schifferer, C. G.
Daniliuc, N. Santschi, R. Gilmour, J. Fluorine Chem. 2016, 182, 121-
126.; c) N. Santschi, C. Thiehoff, M. C. Holland, C. G. Daniliuc, K. N.
Houk, R. Gilmour, Organometallics 2016, 35, 3040–3044.
2-((Fluoro(naphthalen-2-yl)methyl)sulfinyl)benzo[d]thiazole (8b). The
compound was prepared from 1c (700 mg, 2.28 mmol, 1.00 eq.) following
General Procedure 4 (reaction time: 40 h). The crude mixture was
adsorbed on silica and purified via flash chromatography (n-Pentane : Et2O
/ 15 : 1 → 10 : 1) which afforded the product as a light yellow solid (48 mg,
6%). M.p.: 135 °C; Rf 0.22 (CyH : EtOAc / 6 : 1); HRMS m/z (ESI): Calcd.
for C18H12NOS2FNa+ 364.0240, found 364.0240; 1H NMR (600 MHz,
Methylene chloride-d2, 298 K) δ 8.04 (ddd, 3JHH = 8.2 Hz, 4JHH = 1.2 Hz,
5JHH = 0.6 Hz, 1H, HC4), 7.99 (ddd, 3JHH = 8.1 Hz, 4JHH = 1.2 Hz, 5JHH
= 0.6 Hz, 1H, HC7), 7.90 (s, 1H, HC14), 7.88 (m, 2H, HC11,15), 7.83 (m,
1H, HC18), 7.60 – 7.50 (m, 4H, HC5,6,16,17), 7.43 (dd, 3JHH = 8.5 Hz,
4JHH = 1.8 Hz, 1H, HC10), 6.63 (d, 2JFH = 46.0 Hz, 1H, HC8); 13C{1H}
NMR (151 MHz, Methylene chloride-d2, 298 K) δ 173.4 (d, 3JFC = 5.9 Hz,
C1), 154.3 (C3), 136.7 (C2), 134.8 (C12), 133.3 (C13), 129.3 (C11), 128.9
(C18), 128.4 (C15), 128.1 (C16), 127.8 (d, 3JFC = 7.2 Hz, C14), 127.6 (C5),
127.5 (C11), 127.1 (C6), 124.7 (C4), 123.5 (d, 3JFC = 5.8 Hz, C10), 122.8
(C7), 108.4 (d, 1JFC = 232.2 Hz, C8); 19F NMR (564 MHz, Methylene
chloride-d2, 298 K) δ -178.6 (d, 2JFH = 46.1 Hz, 1F, FC8); IR (cm-1): 3063
(w), 2920 (w), 2851 (w), 1680 (w), 1600 (w), 1558 (w), 1508 (w), 1474 (m),
1457 (m), 1427 (m), 1363 (m), 1316 (m), 1271 (m), 1238 (m), 1186 (m),
1152 (m), 1124 (m), 1090 (m), 1041 (m), 1019 (m), 1002 (m), 909 (m), 868
(m), 826 (m), 757 (s), 726 (s), 689 (m), 677 (m).
[11] J. Zhou, C. Jin, W. Su, Org. Process Res. Dev. 2014, 18, 928-933.
[12] Y. Guo, X. Wang, L. Qu, S. Xu, Y. Zhao, R. Xie, RSC Adv. 2017, 7,
11796-11802.
[13] M. Gatel, M. Muzard, D. Guillerm, G. Guillerm, J. Med. Chem. 1996, 31,
37-41.
[14] H. Ratni, D. Blum-Kaelin, H. Dehmlow, P. Hartman, P. Jablonski, R.
Masciadri, C. Maugeais, A. Patiny-Adam, N. Panday, M. Wright,
Bioorganic Med. Chem. Lett. 2009, 19, 1654-1657.
[15] M. R. Witten, L. Wissler, M. Snow, S. Geschwindner, J. A. Read, N. J.
Brandon, A. C. Nairn, P. J. Lombroso, H. Käck, J. A. Ellman, J. Med.
Chem. 2017, 60, 9299-9319.
[16] R. U. Lemieux, N. J. Chu, Abstracts of Papers; 133rd National Meeting
of the American Chemical Society; San Francisco, CA, April 1958;
American Chemical Society: Washington, DC, p 31N.
[17] a) V. K. Aggarwal, J. M. Worrall, H. Adams, R. Alexander, B. F. Taylor,
J. Chem. Soc., Perkin Trans. 1 1997, 21-24; b) M. L. Trapp, J. K. Watts,
N. Weinberg, M. P. Pinto, Can. J. Chem. 2006, 84, 692-701.
[18] a) A. E. Reed, P. von Ragué Schleyer, Inorg. Chem. 1988, 27, 3969-
3987; b) J. J. Urban, J. Phys. Org. Chem. 2005, 18, 1061-1071.
[19] M. P. Freitas, J. Org. Chem. 2012, 77, 7607-7611.
Acknowledgements
We acknowledge generous financial supported from the WWU
Münster (doctoral fellowship to NE), and the German Research
Council DFG (Excellence Cluster “Cells in Motion” and SFB 858).
We thank Prof. Dr. Jack D. Dunitz FRS (ETH Zürich) for
stimulating discussions.
[20] For additional examples of this motif in bioactive small molecules, see a)
K. Biggadike, R. K. Bledsoe, A. M. Hassell, B. E. Kirk, I. M. McLay, L. M.
Shewchuk, E. L. Stewart, J. Med. Chem. 2008, 51, 3349-3352; b) J. R.
Sufrin, A. J. Spiess, D. L. Kramer, P. R. Libby, C. W. Porter, J. Med.
Chem. 1989, 32, 997-1001.
[21] F. Jiang, Y. Zhao, J. Hu, Org. Chem. Front. 2014, 1, 625-629.
10
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
[22] a) E. Pfund, C. Lebargy, J. Rouden, T. Lequeux, J. Org. Chem. 2007, 72,
7871-7877; b) F. Larnaud, E. Pfund, B. Linclau, T. Lequeux, J. Fluor.
Chem. 2012, 134, 128-135.
[23] H.-B. Bürgi, J. D. Dunitz, J. Am. Soc. 1987, 109, 2924-2926.
[24] A. E. Reed, R. B. Weinstock, F. Weinhold, J. Chem. Phys. 1985, 83,
735–746.
[25] C. Bissantz, B. Kuhn, M. A. Stahl, J. Med. Chem. 2010, 53, 5061-5084.
[26] B. Kuhn, E. Gilberg, R. Taylor, J. Cole, O. Korb, J. Med. Chem. 2019, 66,
10441-10455.
11
This article is protected by copyright. All rights reserved.

10.1002/chem.202003361
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
Insert graphic for Table of Contents here.
Given the importance of α-fluoro sulfur motifs in bioactive small molecules, together with the varying oxidation states of sulfur, a
conformational analysis of α-fluoro sulfides, sulfoxides and sulfones is disclosed in order to delineate the non-covalent interactions that
manifest themselves in structure. A combined crystallographic and computational analysis demonstrates the importance of
hyperconjugative donor-acceptor interactions in achieving acyclic conformational control.
Institute and/or researcher Twitter usernames: @GilmourLab @WWU_Muenster
12
This article is protected by copyright. All rights reserved.