Incorporation of the pentafluorosulfanyl group through common synthetic transformations

Article abstract of DOI:10.1007/s00706-021-02760-4

The incorporation of –SF₅ group onto model amino acids has been achieved using commercially available synthons substituted with this group. This work investigates the influence of the –SF₅ group on a variety of common synthetic trans

Full text of DOI:10.1007/s00706-021-02760-4

Monatshefte für Chemie - Chemical Monthly (2021) 152:449–459
https://doi.org/10.1007/s00706-021-02760-4
ORIGINAL PAPER
Incorporation of the pentafuorosulfanyl group through common
synthetic transformations
Hugh G. Hiscocks1 · Dylan Lee Yit1 · Giancarlo Pascali2,3,4 · Alison T. Ung1
Received: 24 January 2021 / Accepted: 22 March 2021 / Published online: 31 March 2021
© Crown 2021
Abstract
The incorporation of –SF5 group onto model amino acids has been achieved using commercially available synthons substi-
tuted with this group. This work investigates the infuence of the –SF5 group on a variety of common synthetic transforma-
tions utilized in felds of bioconjugation and drug development, namely, amide coupling, reductive amination, diazo-coupling,
and CuAAC “click” reactions. The infuence of the novel substituent on the success of these common transformations is
presented, and alternative approaches for those which proved unsatisfactory are proposed herein.
Graphic abstract
Keywords Amines · Amino acids · Carboxylic acids · Michael addition · Drug research
Introduction
recent years, reports highlighting its unique physicochemical
profle have renewed interest in the substituent.
The –SF5 group has remained largely unexplored in the liter-
ature, since its frst reported synthesis by Silvey and Cady in
1950, likely due to concerns of the group’s stability and the
scarcity of –SF5 synthetic building blocks [1]. However, in
The –SF5 group demonstrates high chemical stability,
resistant to hydrolysis under both strong acidic and basic
conditions. Regarding steric demand, the –SF5 group occu-
pies a volume (49.2 cm3 mol−1), 1.5-fold that of the –CF3
group and only slightly smaller than that of the tert-butyl
group [2]. Much like the –CF3 group, the presence of the
multiple fuorine atoms renders it highly polar; for example,
phenyl sulfur pentafuoride exerts a dipole moment of 3.44
Debye [3]. This dipole moment provides the group with a
strong inductive electron-withdrawing efect. Despite this
polarity, the –SF5 group is also highly lipophilic with a
hydrophobicity constant of π = 1.51, relative to the –CF3
group with a hydrophobicity constant of π=1.09 [4].
The –SF5 groups’ unique physicochemical parameters
have resulted in its application within several felds, particu-
larly medicinal chemistry as a –CF3 alternative, afording
numerous –SF5 drug analogues with improved biological
* Alison T. Ung
Alison.Ung@uts.edu.au
1
School of Mathematical and Physical Sciences, Faculty
of Science, University of Technology Sydney, Broadway,
NSW 2007, Australia
2
Australian Nuclear Science and Technology Organisation,
Locked Bag 2001, Kirrawee DC, NSW 2232, Australia
3
School of Chemistry, University of New South Wales,
Kensington, NSW 2052, Australia
4
Prince of Wales Hospital, Nuclear Medicine and PET,
Randwick, NSW 2031, Australia
Vol.:(0123456789)
1 3

450
H. G. Hiscocks et al.
activities [5–9]. Furthermore, our group has recently discov-
ered that the –SF5 group, when incorporated on para- and
meta-substituted nitroarenes, is capable of undergoing [18F]\
[19F] radioisotopic exchange, suggesting its potential as a
stable [18F]F radiosynthon for application in Positron Emis-
sion Tomography [10].
as shown in Scheme 1 (method a). Amide coupling products
synthesized by this method were obtained as viscous yellow
oils in relatively low yield (15–26%) following purifcation
by column chromatography (Table 1).
Amide coupling reactions were monitored via TLC. Suc-
cessful syntheses were confrmed by 1H NMR spectra and
with HRMS. 19F NMR was used to ensure that the –SF5
group had been conserved under the reaction conditions
employed. A representative 19F NMR spectrum of compound
3a (Fig. 1) shows resonances at δ=85.03 and 63.40 ppm as
a quintuplet and doublet, respectively. The resonances are
indeed indicative of the –SF5 group’s presence [19].
The use of dimethylformamide (DMF) as a solvent was
necessary to completely solubilise each compound in the
reaction mixture, consequently, extensive washing of the
reaction mixture to partition DMF, EDCI.HCl, and the
N-acylurea by-product into the aqueous phase may have
resulted in minor product loss. Employing alternative water-
immiscible solvents such as dichloromethane could improve
product recovery. However, this may be detrimental to the
reaction itself [20].
A variety of reactions utilising both aryl and heterocy-
clic –SF5 derivatives have been investigated previously,
including traditional and vicarious nucleophilic aromatic
substitution [11, 12], azo-coupling, dediazoniation, click
chemistry, Sonogashira [13] and Negishi coupling [14], and
Diels–Alder additions [15–17].
Current knowledge surrounding the –SF5 group and its
potential application remains very much in its infancy, indi-
cating a signifcant gap in current literature. A more holistic
understanding of the –SF5 group infuences on various com-
monly used synthetic transformations would provide valu-
able information for future research endeavours concerning
the –SF5 group. In this work, the efect of the aryl –SF5
moiety on amide coupling, reductive amination, azo-cou-
pling, and CuAAC “click” reactions have been investigated,
to ascertain their feasibility as methods for incorporating
aryl–SF5 group into drugs and biomolecules.
The progress of each reaction was monitored by TLC,
which revealed the presence of unreacted amine precursor.
Despite being the limiting reagent, unreacted aniline was
present beyond 18 h of reaction. This occurrence was attrib-
uted to the slow consumption of the remaining amino acid
Results and discussion
Pentafuorosulfanyl aniline in amide coupling
Table 1 Respective yields obtained of amide coupling products 3a–
3d
Amide coupling reactions have been applied extensively
for the synthesis and modifcation of peptides, and are the
most utilized transformation in the pharmaceutical indus-
try [18]. In this work, N-BOC-protected model amino acids
were used as carboxylic acid substrates for investigating the
nucleophilicity of 4-(pentafuorosulfanyl)aniline in the con-
text of amide coupling reactions. Amide coupling was frst
performed using HOBt and EDCI.HCl as coupling reagents,
3
Amino acid R1
Yield/%a
Yield/%b
a
b
c
d
Phe
Ala
Trp
Pro
19
15
26
21
44
36
38
41
aHOBt, EDCI.HCl, DMF, 18 h, r.t. bTMOS, PhMe, 36 h, 110 °C
Scheme 1
a) HOBt, EDCI.HCl, DMF, 18 h, r.t. b) TMOS, PhMe, 36 h, 110 °C.
1 3

Incorporation of the pentafuorosulfanyl group through common synthetic transformations
451
Fig. 1 19F NMR of compound 3a, showing resonances at δ=85.03 and 63.40 ppm as a quintuplet and doublet, respectively
precursor available for coupling through competitive side
reactions, namely the formation of the N-acylurea by-prod-
uct. In typical HOBt/EDCI coupling reactions, the amine
is sufciently nucleophilic to outcompete EDCI.HCl before
its rearrangement into the N-acylurea. However, it is not the
case for this reaction, as the electron-withdrawing efect of
the –SF5 group is likely to have hindered the reactivity of the
amine. The poor yields obtained by this method warranted
the investigation of alternative synthetic approaches towards
the desired products.
competitive hydrolysis. Yields obtained for amide cou-
pling products using the TMOS method were a substan-
tial improvement over the EDCI/HOBT coupling method
(36–44%) mentioned previously. Furthermore, unlike the
HOBt/EDCI case, the TMOS process does not generate by-
products such as the N-acylurea; therefore, reaction times
could be extended to 36 h without the occurrence of pre-
cursor-consuming side reactions. A 36 h reaction time was
necessary based on the poor nucleophilicity of 4-(pentafuor-
osulfanyl)aniline (2), and this parameter was used with all
the amino acid substrates. Longer reaction times were not
employed as TLC analysis of the crude mixtures started to
reveal the formation of other by-products, likely attributed
to either hydrolysis or thermal decomposition.
To further optimise the synthesis of compounds 3a–3d,
tetramethyl orthosilicate (TMOS) was investigated as a cou-
pling reagent as recently demonstrated by Braddock et al.
[21]. This method (method b) was attractive because of its
ability to facilitate amide coupling with electron-poor aniline
derivatives. To further maximise coupling efciency, reac-
tions were conducted in high concentrations using toluene as
a solvent and heated to refux in the presence of a 2.5 molar
equiv. of TMOS.
Pentafuorosulfanyl benzaldehyde in reductive
aminations
Similarly, to the previously described amide coupling reac-
tion, model amino acids were used as amine-bearing sub-
strates to investigate the reactivity of 4-(pentafuorosulfanyl)-
benzaldehyde in reductive amination reactions under typical
conditions. Reductive amination was achieved through the
condensation of 4-(pentafuorosulfanyl)benzaldehyde with
several C-protected amino acid esters. The subsequent imine
Completely anhydrous conditions were required to
avoid hydrolysis of the N-Boc group, particularly given the
reaction requirement for high temperatures and prolonged
reaction times. Refux of the reaction mixture at 110 °C,
with a large excess of TMOS and under a nitrogen atmos-
phere, proved efective for minimising the occurrence of
1 3

452
H. G. Hiscocks et al.
to form in situ as indicated by TLC. At that point, acetic
acid and sodium cyanoborohydride were added to the reac-
tion mixture in rapid succession to minimise the time that
the imine spends in its protonated state prior to reduction.
This ensured a maximal proportion of the iminium ion salt
underwent reduction rather than acid catalyzed cyclisation
through tryptophan’s imidazole ring.
Scheme 2
This side reaction is likely to have been promoted by the
high electrophilicity of the transient imine carbon result-
ing from the –SF5 groups electron-withdrawing efect. This
efect is evident from the work of Wang et al. [22], who
investigated the use of 1,1,1,3,3,3-trifuoroisopropyl alcohol
as a catalytic solvent for the synthesis of 1,2,3,4-tetrahydro-
ß-carbolines. From this research, it was observed that when
aromatic aldehydes bearing electron-withdrawing groups,
such as 4-nitro, underwent condensation with L-tryptophan
methyl ester, 1,2,3,4-tetrahydro-ß-carbolines were obtained
exclusively. On the other hand, aldehydes bearing donating
groups in the para position, such as 4-methoxybenzalde-
hyde, demonstrated exclusive favourability for the alterna-
tive imine product.
Table 2 Respective yields obtained of reductive amination products
6a–6f
6
Amino acid R1
R2
Yield/%
a
b
c
d
e
f
Gln
Tyr
Ser
Cys
Trp
Pro
t-Bu
Me
Bz
Et
Me
Bz
77
81
69
72
67
82
An alternative approach to amine functionalisation was
also investigated using pentafuorosulfanyl ethene, originally
believed to be capable of undergoing a Michael addition
owing to the electron-withdrawing efect of the –SF5 group.
However, this withdrawing efect occurs inductively rather
than through a resonance-based modality. Thus, ethene sul-
fanyl pentafuoride is incapable of forming the resonance
stabilised carbanion intermediate required for a Michael
addition to occur.
intermediates were reduced using NaB(CN)H3 under mildly
acidic conditions to yield the respective secondary amine
products, as shown in Scheme 2. Reductive amination reac-
tions aforded seven novel amino acid analogues in mod-
est-to-high yields (Table 2). Reductive amination products
were all obtained as viscous oils, except 6d which rapidly
dimerised upon exposure to air to form a light-yellow solid.
Products 6a, 6b formed white crystalline solids after pro-
longed storage.
To approximately assess the by-product formation, reac-
tion mixtures were monitored by TLC, all of which indicated
an absence of aldehyde precursor after 2.5 h. Reaction times
were extended from 40 min to 3 h to maximise imine for-
mation. Additionally, 4 Å molecular sieve was employed to
remove water from the reaction mixture, thereby promoting
equilibriums favourability towards the desired imine prod-
uct. These synthetic modifcations also proved successful
in minimising the generation of benzyl alcohol by-product.
The L-tryptophan derivative was obtained with the
lowest yield among the reductive amination products, on
account of the imine intermediates participation in a Pic-
tet–Spengler side reaction through tryptophan’s imidazole
ring. The addition of acid to the reaction mixture is nec-
essary to ensure protonation of the imine and subsequent
hydride attack. However, in the case of L-tryptophan methyl
ester, the addition of acid has a catalytic efect promoting
a Pictet–Spengler side reaction (Scheme 3). To minimise
the occurrence of the 1,2,3,4-tetrahydro-ß-carboline by-
product, the reductive amination reactions were performed
in a step-wise procedure whereby the imine was frst allowed
Pentafuorosulfanyl phenylazide for CuAAC
The Cu-catalyzed Azide–Alkyne Cycloaddition (CuAAC)
has been used extensively as a bioconjugation method, on
account of its impressive selectivity and reaction rate. Addi-
tionally, the 1,4-triazole rings function as an amide bioisos-
tere, allowing for the biologically discrete modifcation of
peptides, thus warranting the investigation of 4-(pentafuoro-
sulfanyl)phenyl azide and the feasibility for its application in
CuAAC reactions. Ye et al. [23] have reported the CuAAC
reaction between gaseous 1-pentafuorosulfanyl acetylene
and phenyl azide, obtaining the subsequent 1,4-triazole
in 83% yield. In future, we would also like to investigate
4-(pentafuorosulfanyl)phenylacetylene and its participation
in CuAAC reactions with various azides.
In this work, the CuAAC reaction was performed between
methyl (2S)‐3‐phenyl‐2‐[(prop‐2‐yn‐1‐yl)amino]propanoate
(8) and 4-(pentafluorosulfanyl)phenyl azide (10) using
Cu(OAc)2 and sodium ascorbate as catalysts (Scheme 4).
Compound 8 was obtained by N-alkylation of l-phenylala-
nine methyl ester with propargyl bromide.
1 3

Incorporation of the pentafuorosulfanyl group through common synthetic transformations
453
Scheme 3
Initial attempts to synthesize the 4-(pentafuorosulfa-
nyl)phenyl azide entailed the reaction of the correspond-
ing aniline with a large excess of NaNO2 in HCl, with the
resulting diazonium chloride salt intermediate undergoing
in situ reaction with an excess of NaN3 to form the azide
product. However, these attempts proved unsuccessful as
the intermediate diazonium chloride lacked stability in the
aqueous reaction media, readily undergoing an undesired
nucleophilic substitution reaction to form the corresponding
phenolic by-product.
with trimethylsilyl azide (Scheme 4). Due to the explosive
nature of azide derivatives, the product 10 was stored in
solution as a safety precaution; the yield was assumed to
be quantitative.
The CuAAC click reaction was performed in a mixture of
water and acetonitrile (50:50) which was allowed to proceed
for 72 h at 60 °C before TLC fnally indicated the complete
consumption of the azide precursor. The subsequent click
product 11 was obtained as a brown viscous oil. The successful
synthesis of the desired product was advocated by the presence
of a characteristic singlet peak at 7.51 ppm, indicating the tria-
zole’s lone proton. Purifcation of the crude product by column
chromatography aforded the fnal product in a yield of 61%.
The slow reaction rate exhibited in the cycloaddition
was primarily attributed to the diminished reactivity of
4-(pentafuorosulfanyl)phenyl azide due to the reduced
electron density around the azide group provided by the
–SF5 groups inductive efect and delocalisation within the
aromatic ring. The detrimental infuence of these factors in
CuAAC reactions is supported by the work of Golas et al.
[24], who reported a clear negative correlation between
azide reactivity and both increased electron-withdrawing
To address this instability, 4‐(pentafluorosulfanyl)-
phenyl diazonium salt was prepared with a tetrafuorobo-
rate counter-cation from the corresponding amine using
the procedure described by Okazaki et al. [13], whereby
.
BF3 OEt2, tert-BuONO, and acetonitrile are utilized to serve
as a Lewis acid, N2 source, and solvent, respectively. Unlike
the chloride counter-cation, the tetrafuoroborate diazo-
nium salt could be easily isolated by fltration and stored
at room temperature for short periods without decompos-
ing. In this way, 4‐(pentafuorosulfanyl)phenyl diazonium
tetrafuoroborate (9) was obtained in a yield of 87% and
could be used to synthesize the azide product by reaction
1 3

454
H. G. Hiscocks et al.
Scheme 4
efect and steric hindrance of their substituents. Inversely,
alkynes substituted with electron-withdrawing groups
exhibit higher reactivity through the increased acidity of
the terminal Csp-H proton, thus encouraging its deproto-
nation before coordinating with the copper ligand, a rate-
determining step in the CuAAC mechanism [25]. Not-
withstanding this, Huang et al. [26] reported a successful
one-pot CuAAC reaction between aliphatic azides bearing
a terminal –SF5 group and a variety of alkyne functional-
ised compounds, achieving yields ranging between 57 and
91% after 18 h at 60 °C. The success of the CuAAC reac-
tions utilising aliphatic azides under similar conditions
further highlights the detrimental infuence of the elec-
tron-withdrawing aryl –SF5 moiety on the azide group and
its subsequent reactivity towards its alkyne click partner.
Pentafuorosulfanyl phenyl diazonium salt in azo
coupling
The azo-coupling reaction has been investigated extensively
as a method for the bioconjugation of prosthetic groups with
the phenolic side chains of tyrosine residues. The appealing
stability of the SF5-substituted tetrafuoroborate diazonium
salt 9 prompted its use in a diazo-coupling reaction with
N-acyl protected tyrosine methyl ester, whereby the model
amino acids’ phenolic side chain was used as a target for
chemo-selective bioconjugation (Scheme 5).
Diazo-coupling entailed the dropwise addition of the
diazonium salt in acetonitrile to a solution of the model
amino acid in a solution of acetonitrile and phosphate bufer
(1:1). The diazo-coupling product 13 precipitated from
Scheme 5
1 3

Incorporation of the pentafuorosulfanyl group through common synthetic transformations
455
solution immediately upon adding the solution containing
the diazonium salt. The –SF5 group was highly advanta-
geous in this case as it signifcantly promoted the electro-
philicity of the diazonium salt, allowing for reaction time as
short as 20 min. Furthermore, the lipophilic nature of the
phenyl –SF5 moiety allowed the product to precipitate from
the polar solvent mixture readily. N-Acyl protection of the
tyrosine derivative 12 was necessary to prevent the forma-
tion of the triazene by-product. The product was isolated by
fltration and washed with ethyl acetate to aford the pure
fnal product in a yield of 79%. The azo-coupling product
demonstrated an intense orange colour, a common charac-
teristic among azo-bridged compounds. The successful syn-
thesis was indicated by 1H NMR and confrmed by HRMS.
Reductive amination reactions proved efective, as the
–SF5 group’s electron-withdrawing efect rendered 4-(pen-
tafuorosulfanyl)benzaldehyde highly electrophilic, afording
the reductive amination products in moderate-to-high yields
(67–84%). Much like the reductive amination reaction, the
electronic efects imposed by the aryl–SF5 moiety proved
benefcial for increasing the electrophilicity and subsequent
reactivity of the diazonium salt in the azo-coupling reaction,
allowing for rapid introduction of the aryl–SF5 moiety via
the model tyrosine phenolic side chain.
Experimental
All chemical reagents and AR grade or analytical grade
solvents were acquired from commercial sources, such as
Sigma-Aldrich, Merck, and Fluorochem. All reactions were
monitored using TLC Silica gel 60 F254 with UV detection at
254 nm and stained with either iodine or ninhydrin reagent.
Automated column chromatography was performed using
LC-Prep. Solvents were removed under reduced pressure
using a Buchi Rotavapor rotary evaporator. High-resolution
mass spectra were obtained using an Agilent 6510 Q-TOF
Conclusions
From the results obtained, it is apparent that the electronic
efects of the –SF5 group have a substantial infuence on the
reactions investigated for introducing the group onto model
amino acids. 4-(Pentafurosulfanyl)aniline used in amide
coupling reactions lacked the nucleophilicity necessary for
efcient coupling to be achieved. The reaction rate of amide
coupling by the EDCI/HOBt method was hindered to such
an extent that amino acid precursor was consumed preferen-
tially to form the N-acylurea by-product. Tetramethyl ortho-
silicate (TMOS) was employed as an alternative coupling
reagent in an attempt to optimise the rate of amide coupling
reactions. Amide coupling by this method aforded modest
improvements in yield; however, prolonged reaction times
of up to 36 h were necessary even at elevated concentration
and temperature.
1
Mass Spectrometer (ESI). H NMR, 13CNMR, and 19F
NMR spectra were recorded on an Agilent 500 54 premium
1
shielded spectrometer 500 MHz (500 MHz H, 125 MHz
13C, 470.29 MHz 19F) in deuterated chloroform (CDCl3).
Synthesis of amide coupling products 3a–3d
General procedure A: To a solution of 110 mg 4-(pen-
tafuorosulfanyl)aniline (0.5 mmol) in 10 cm3 anhydrous
DMF was added N-Boc protected amino acid (0.505 mmol),
105 mg EDCI (0.55 mmol), and 65 mg HOBt (0.55 mmol) in
a closed vessel under nitrogen atmosphere. The reaction was
allowed to proceed overnight at room temperature with stir-
ring. The solution was quenched with 20 cm3 of water and
extracted with CHCl3 (3×20 cm3); the organic layers were
then combined and washed with water (2× 30 cm3). The
organic layer was dried with anhydrous MgSO4 and con-
centrated in vacuo to provide the crude product, which was
purifed by column chromatography using EtOAc:hexane
(30:70) as the eluent to aford the pure product.
Similarly, the CuAAC reaction performed in this work
also appears to have been hindered by the substantial elec-
tronic efects of the aryl–SF5 moiety, whereas present on
the azide counterpart. Future attempts using click chemis-
try to incorporate the –SF5 group onto biomolecules should
instead aim to utilise –SF5 functionalised terminal alkynes
for cycloaddition with azide-modifed biomolecules. In turn,
this strategy could exploit this electron-withdrawing efect
advantageously to facilitate a CuAAC reaction with the same
exemplary rate kinetics and selectivity as those reported in
the literature.
Scheme 6
1 3

456
H. G. Hiscocks et al.
General procedure B: To nitrogen fushed round-bottom
fask ftted with a refux condenser, and drying tube was
added 110 mg 4-(pentafuorosulfanyl)aniline (0.5 mmol) and
N-Boc protected amino acid (0.5 mmol) followed by 1 cm3
dry toluene and tetramethyl orthosilicate (250% mol), the
reaction mixture was then heated to 100 °C and allowed to
refux for 36 h. The reaction mixture was then quenched with
10 cm3 water and extracted with DCM (3 × 10 cm3). The
combined organic layers were washed with 30 cm3 1 N HCl,
followed by 30 cm3 saturated NaHCO3. The organic layer
was then dried with 30 cm3 saturated NaCl solution and
anhydrous MgSO4 and concentrated under reduced pressure
to provide the crude product, which was purifed by column
chromatography using EtOAc:hexane (30:70) as eluent to
aford the pure product.
δ=85.17 (m, J=149.5 Hz, 1F), 63.43 (d, J=149.5 Hz, 4F)
ppm.
tert‐Butyl 2‐[[4‐(pentafluoro‐λ6‐sulfanyl)phenyl]carba-
moyl]pyrrolidine‐1‐carboxylate (3d, C16H21F5N2O3S) Com-
pound 3d was synthesized using procedure B, as a yellow
oil (46 mg, 0.205 mmol, 41%). Rf = 0.32 in EtOAc:hexane
(3:7); HPLC: tR = 6 min 35 s; HRMS (EI): m/z calcd for
1
C16H22F5N2O3S [M + H]+ 417.1266, found 417.1268; H
NMR (CDCl3): δ=7.59 (m, 2H), 7.55 (m, 2H), 4.54–4.48
(m, 1H), 3.52–3.43 (m, 1H), 3.42–3.32 (m, 1H), 2.52–2.40
(m, 1H) 2.06–1.88 (m, 3H), 1.50 (s, 9H) ppm; 13C NMR
(CDCl3): δ = 24.61, 27.35, 28.41, 47.34, 60.53, 62.93,
81.25, 118.69, 126.79, 141.13, 163.27, 170.44 ppm; 19F
NMR (CDCl3): δ = 85.45 (m, J = 149.5 Hz, 1F), 63.42 (d,
J=149.5 Hz, 4F) ppm.
tert‐Butyl N‐[(1S)‐1‐[[4‐(pentafluoro‐λ6‐sulfanyl)-
phenyl]carbamoyl]‐ 2‐ phenylethyl]carbamate (3a,
Synthesis of reductive amination products 6a–6f
C
20H25F5N2O3S) Compound 3a was synthesized using
procedure B, as a yellow oil (98 mg, 0.22 mmol, 44%).
Rf = 0.22 in EtOAc:hexane (3:7); HRMS (EI): m/z calcd
for C20H24F5N2O3S [M–H]− 465.1271, found 465.1301;
1H NMR (CDCl3): δ = 7.60 (d, J = 8.5 Hz, 2H), 7.43 (d,
J=8.5 Hz, 2H) 7.29–7.18 (m, 5H), 4.83–4.80 (m, 1H), 3.02
(m, 2H), 1.63 (s, 9H) ppm; 13C NMR (CDCl3): δ = 28.26,
37.91, 118.94, 126.85, 127.24, 128.90, 129.18, 129.28,
136.19, 140.08, 170.18 ppm; 19F NMR (CDCl3): δ=85.03
(m, J=150 Hz, 1F), 63.40 (d, J=150 Hz, 4F) ppm.
To a nitrogen fushed reaction vessel was added C-protected
amino acid methyl ester hydrochloride (1.1 mmol) dissolved
in 15 cm3 anhydrous DCM. NEt3 (1.1 mmol, 153 mm3) was
added dropwise to the vessel, and the reaction was allowed
to stir for 20 min. After 20 min, 232 mg 4-(pentafuorosul-
fanyl)benzaldehyde (1 mmol) was added dropwise to the
reaction vessel followed by 440 mg NaB(CN)H3 (7 mmol)
and a few drops of glacial acetic acid. The reaction was
allowed to proceed overnight at room temperature with stir-
ring. Upon confrmation of reaction completion via TLC, the
reaction was quenched with 20 cm3 saturated NaHCO3 and
then extracted with CHCl3 (3 × 10 cm3), dried with anhy-
drous MgSO4, and concentrated under reduced pressure. The
crude product was purifed by column chromatography using
EtOAc:hexane (1:1) as eluent to aford the fnal product.
tert‐Butyl N‐[(1S)-1-[[4‐(pentafuoro‐λ6‐sulfanyl)phenyl]car-
bamoyl]ethyl]carbamate (3b, C14H19F5N2O3S) Compound 3b
was synthesized using procedure B, as a yellow oil (38 mg,
0.18 mmol, 36%). Rf =0.16 in EtOAc:hexane (1:1); HPLC:
tR =6 min 27 s; HRMS (EI): m/z calcd for C14H18F5N2O3S
1
[M–H]− 389.0958, found 389.0948; H NMR (CDCl3):
δ=7.64 (d, J=10 Hz, 2H), 7.56 (d, J=10 Hz, 2H), 4.84–
4.82 (m, 1H), 1.48 (s, 9H), 1.44 (d, J = 7 Hz, 3H) ppm;
13C NMR (CDCl3): δ = 28.30, 118.80, 126.87, 126.91,
171.17 ppm; 19F NMR (CDCl3): δ=85.16 (m, J=150 Hz,
1F), 63.40 (d, J=150 Hz, 4F) ppm.
tert‐Butyl (2S)-4-carbamoyl-2-[[[4-(pentafuoro-λ6-sulfanyl)-
phenyl]methyl]amino]butanoate (6a, C16H23F5N2O3S) Com-
pound 6a was obtained as a white solid (324.2 mg,
0.77 mmol, 77%). Rf =0.26 in EtOAc:hexane (1:1); HPLC:
tR =6 min 34 s; HRMS (EI): m/z calcd for C16H24F5N2O3S
1
[M + H]+ 419.1428, found 419.1415; H NMR (CDCl3):
tert‐Butyl N‐[(1S)‐2‐(1H‐indol‐3‐yl)‐1‐[[4‐(pentafluoro‐
λ6‐sulfanyl)phenyl]carbamoyl]ethyl]carbamate (3c,
C22H24F5N3O3S) Compound 3c was synthesized using
procedure B, as a white solid (96 mg, 0.19 mmol, 38%).
Rf = 0.38 in EtOAc:hexane (3:7); HRMS (EI): m/z calcd
for C22H25F5N3O3S [M + H]+ 506.1531, found 506.1545;
1H NMR (CDCl3): δ = 7.66 (d, J = 8 Hz, 1H), 7.61 (d,
J=8.5 Hz, 2H), 7.38 (m, 3H), 7.22 (t, J=7.5 Hz, 1H), 7.13
(t, J = 7.5 Hz, 1H), 3.38 (dd, J= 5, 14 Hz, 1H), 3.26 (dd,
J=7.5, 14 Hz, 1H), 1.43 (s, 9H) ppm; 13C NMR (CDCl3):
δ=28.42, 109.21, 111.50, 118.85, 119.10, 120.25, 122.75,
123.41, 126.99, 150.45, 170.58 ppm; 19F NMR (CDCl3):
δ = 7.69 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8 Hz, 2H), 3.88
(d, J = 14 Hz, 1H), 3.65 (d, J= 14 Hz, 1H), 3.11 (m, 2H),
3.07–2.31 (m, 2H), 1.48 (s, 9H) ppm; 13C NMR (CDCl3):
δ=23.12, 28.04, 29.48, 45.11, 60.01, 82.01, 126.54, 128.83,
175.49 ppm; 19F NMR (CDCl3): δ=84.83 (m, J=150 Hz,
1F), 63.02 (d, J=149.5 Hz, 4F) ppm.
Methyl (2S)-3-(4-hydroxyphenyl)-2-[[[4-(pentafluoro-
λ6-sulfanyl)phenyl]methyl]amino]propanoate (6b,
C17H18F5NO3S) Compound 6b was obtained as a white solid
(333.7 mg, 0.81 mmol, 81%). Rf = 0.32 in EtOAc:hexane
(3:7); HPLC: tR = 5 min 3 s; HRMS (EI): m/z calcd for
1 3

Incorporation of the pentafuorosulfanyl group through common synthetic transformations
457
C17H19F5NO3S [M + H]+ 412.1000, found 412.0999; H
NMR (CDCl3): δ=7.64 (d, J=8.5 Hz, 2H), 7.30 (d, J=8 Hz,
2H), 7.01 (d, J=8 Hz, 2H), 6.74 (d, J=8 Hz, 2H), 3.87 (d,
J=14 Hz, 1H), 3.68 (s, 3H), 3.65 (d, J=14 Hz, 1H), 3.44
(t, J=6.5 Hz, 1H), 2.92 (dd, J=6, 13.5 Hz, 1H), 2.86 (dd,
J = 7.5, 13.5 Hz, 1H) ppm; 13C NMR (CDCl3): δ = 38.84,
51.06, 51.84, 62.09, 115.32, 125.89, 125.93, 125.96, 128.16,
129.05, 130.41, 143.65, 154.54, 174.98 ppm; 19F NMR
(CDCl3): δ=84.95 (m, J=150 Hz, 1F), 63.02 (d, J=150 Hz,
4F) ppm.
67.10, 73.19, 74.86, 124.91, 124.94, 124.98, 126.03, 126.06,
126.10, 127.89, 128.33, 128.84, 128.89, 135.33, 142.84,
143.54, 175.01 ppm; 19F NMR (CDCl3): δ = 84.99 (m,
J=149.5 Hz, 1F), 63.03 (d, J=149.5 Hz, 4F) ppm.
1
Benzyl (2S)‐1‐[[4‐(pentafuoro‐λ6‐sulfanyl)phenyl]methyl]-
pyrrolidine‐2‐carboxylate (6f, C19H20F5NO2S) Compound 6f
was obtained as a yellow oil (345.57 mg, 0.82 mmol, 82%
yield). Rf =0.68 in EtOAc:hexane (3:7); HPLC: tR =8 min
0 s; HRMS (EI): m/z calcd for C19H21F5NO2S [M + H]+
1
422.1208, found 422.1209; H NMR (CDCl3): δ = 7.69
Benzyl (2S)-3-hydroxy-2-[[[4-(pentafuoro-λ6-sulfanyl)phe-
nyl]methyl]amino]propanoate (6c, C17H18F5NO3S) Com-
pound 6c was obtained as a yellow oil (284.3 mg, 0.69 mmol,
69%). Rf = 0.60 in EtOAc:hexane (3:7); HPLC: tR =5 min
23 s; HRMS (EI): m/z calcd for C17H19F5NO3S [M + H]+
412.1000, found 412.0994; 1H NMR (CDCl3): δ=7.69 (d,
J=8.5 Hz, 2H), 7.4 (d, J=8.5 Hz, 2H), 7.38–7.34 (m, 5H),
5.19 (s, 2H), 3.95 (d, J=14 Hz, 1H), 3.82 (dd, J=4.5, 11 Hz,
1H), 3.76 (d, J=13.5 Hz, 3H), 3.68 (dd, J=6, 10.5 Hz, 1H),
3.45 (t, J=5.5 Hz, 1H) ppm; 13C NMR (CDCl3): δ=51.10,
61.94, 62.64, 67.04, 126.04, 126.06, 126.1, 128.18, 128.23,
128.52, 128.63 128.52, 135.25, 143.22, 172.66 ppm; 19F
NMR (CDCl3): δ = 84.65 (m, J = 150 Hz, 1F), 63.02 (d,
J=149.5 Hz, 4F) ppm.
(d, J = 9 Hz, 2H), 7.51–5.08 (m, 5.39–5.08 (m, 2H), 4.06
(d, J = 14.5 Hz, 1H), 3.98 (d, J = 13.5 Hz, 1H), 3.57 (d,
J = 13.5 Hz, 1H), 3.44 (d, J = 13.5 Hz, 1H), 3.00–1.68
(m, 6H) ppm; 13C NMR (CDCl3): δ=27.81, 50.96, 61.34,
61.81, 126.00, 126.04, 128.29, 143.63, 174.99 ppm; 19F
NMR (CDCl3): δ = 84.70 (m, J = 149.5 Hz, 1F), 63.03 (d,
J=149.5 Hz, 4F) ppm.
Methyl (2S)‐3‐phenyl‐2‐[(prop‐2‐yn‐1‐yl)amino]pro-
panoate (8, C13H15NO2) To a nitrogen fushed vessel was
added 1.116 g l-phenylalanine methyl ester hydrochloride
(5.18 mmol) in 20 cm3 anhydrous CH3CN followed by
1.79 g K2CO3 (13 mmol). In a separate fask, 615 mg pro-
pargyl bromide (392 mm3, 5.18 mmol) was dissolved in 10
cm3 anhydrous CH3CN. The propargyl bromide solution was
added dropwise to the reaction vessel and the reaction was
allowed to proceed for 12 h at room temperature. After 12 h,
the reaction was checked with TLC and quenched with 60
cm3 of water, the aqueous layer was extracted with CHCl3
(3×20 cm3), and the organic layers combined, dried with
anhydrous MgSO4. The solvent was removed in vacuo to
give compound 8 as a yellow oil (923 mg, 4.25 mol, 82%).
The product was used in the next reaction step without fur-
ther purifcation. Rf =0.55 in EtOAc:hexane (1:1); HRMS
(EI): m/z calcd for C13H16NO2 [M + H]+ 218.1176, found
218.1151; 1H NMR (CDCl3): δ=7.31–7.19 (m, 5H), 3.68
(s, 3H), 3.43 (d, J = 17 Hz, 2H), 3.37 (d, J = 17 Hz, 1H),
3.11–2.84 (m, 2H), 2.19 (t, J=2.5 Hz, 1H) ppm; 13C NMR
(CDCl3): δ = 36.81, 39.43, 51.81, 61.12, 71.79, 81.17,
126.86, 128.50, 129.17, 136.84, 174.28 ppm.
Ethyl (2S)-2-[[[4-(pentafuoro-λ6-sulfanyl)phenyl]methyl]-
amino]-3-sulfanylpropanoate (6d, C12H18F5NO2S2) Com-
pound 6d was obtained as a yellow oil (263.08 mg,
0.72 mmol, 72%). Rf =0.71 in EtOAc:hexane (3:7); HPLC:
tR =4 min 55 s; HRMS (EI): m/z calcd for C12H17F5NO2S2
1
[M + H]+ 366.0610, found 366.0608; H NMR (CDCl3):
δ=7.71 (d, J=9 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 4.27–4.19
(m, 2H), 3.95 (d, J= 14 Hz, 1H), 3.76 (d, J= 14 Hz, 1H),
3.43 (t, J=5.5 Hz, 1H), 3.16 (dd, J=11 Hz, 1H), 3.13 (dd,
J=11 Hz, 1H), 1.37–1.25 (m, 3H) ppm; 13C NMR (CDCl3):
δ = 51.10, 61.93, 63.63, 67.04, 126.04, 126.10, 128.18,
128.23, 128.51, 128.63, 135.24, 143.22, 172.58 ppm; 19F
NMR (CDCl3): δ = 84.79 (m, J = 149.5 Hz, 1F), 63.01 (d,
J=149.5 Hz, 4F) ppm.
Methyl (2S)-3-(1H-indol-3-yl)-2-[[[4-(pentafluoro-
λ6-sulfanyl)phenyl]methyl]amino]propanoate (6e,
C20H19F5N2O2S) Compound 6e was obtained as a colourless
oil (291 mg, 0.67 mmol, 67%). Rf =0.635 in EtOAc:hexane
(1:1); HPLC: tR = 5 min 27 s; HRMS (EI): m/z calcd for
C20H20F5N2O2S [M + H]+ 447.1165, found 447.1168;
1H NMR (CDCl3): δ = 7.58 (d, J = 8.5 Hz, 2H), 7.55 (d,
J = 8 Hz, 2H), 7.36 (d, J = 8 Hz, 1H), 7.27 (d, J = 8. Hz,
1H), 7.20 (t, J=7 Hz, 1H), 7.10 (t, J =7 Hz, 1H), 7.03 (s,
1H), 3.87 (d, J=14 Hz, 1H), 3.66 (s, 3H), 3.60 (d, J=13 Hz,
1H), 3.22 (dd, J=5.5, 14.5 Hz, 1H), 3.12 (dd, J=7, 14.5 Hz,
1H) ppm; 13C NMR (CDCl3): δ=22.72, 30.99, 52.61, 53.78,
4‐(Pentafuorosulfanyl)phenyldiazonium tetrafuoroborate
(9) To a solution of 480 mg 4-(pentafuorosulfanyl)aniline
(2.2 mmol) in 10 cm3 DCM cooled over an ice bath was
.
added 470 mg BF3 OEt2 (410 mm3, 3.3 mmol) dropwise,
followed by the dropwise addition of 390 mm3 t-BuONO
(3.3 mmol). The reaction was allowed to proceed at 0 °C
for 20 min, while being covered from excessive light. The
resulting precipitate was isolated via vacuum fltration,
washed with Et2O (2 × 10 cm3), and allowed to air dry to
aford the fnal product as a white solid (607 mg, 1.9 mmol,
87%). IR (ATR): v =2924, 2852, 2309, 1574, 1418, 1304,
1 3

458
H. G. Hiscocks et al.
1053, 858 (S-F), 768 cm−1. IR spectrum is consistent with
those reported in the literature.
dissolved in 5 cm3 MeCN was then added dropwise to the
reaction mixture. The reaction was allowed to proceed for a
further 20 min at which point the precipitate that formed was
isolated via vacuum fltration, washed with cold deionised
water (2 × 10 cm3), and allowed to air dry. Compound 13
was obtained as a bright orange solid (368 mg, 0.79 mmol,
79%). Rf = 0.35 in EtOAc:hexane (40:60); HRMS (EI):
m/z calcd for C18H17F5N3O4S [M–H]− 466.0865, found
466.0864; 1H NMR (CDCl3): δ=7.93 (m, 4H), 7.26 (s, 1H),
7.15 (d J = 8.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 5.99 (d,
J=7.5 Hz, 1H), 4.93 (d, J=8 Hz, 1H), 3.77 (1H), 3.23 (dd,
J = 6, 14.5 Hz, 1H) 3.14 (dd, J = 6, 14.5 Hz, 1H), 2.06 (s,
3H) ppm; 13C NMR (CDCl3): δ=23.23, 36.96, 52.52, 53.22,
118.64, 122.24, 127.39, 127.39, 134.11, 135.49, 137.27,
151.89, 169.61, 171.99 ppm; 19F NMR (CDCl3): δ=83.45
(m, J=149.5 Hz, 1F), 63.01 (d, J=149.5 Hz, 4F) ppm.
4-(Pentafluorosulfanyl)phenyl azide (10) In a two-neck
round-bottom fask containing 317 mg 4‐(pentafuorosulfa-
nyl)phenyl diazonium tetrafuoroborate (1 mmol) was added
10 cm3 anhydrous MeCN, and the solution was cooled to
0 °C with an ice bath under a nitrogen atmosphere. TMSN3
(146 mm3, 1.1 mmol) was then added dropwise to the solu-
tion over 5 min. The reaction mixture was then heated at
60 °C for approximately 1 h. Excess TMSN3 was then
removed by rotary evaporation, and the product was stored
dissolved in the original 10 cm3 of MeCN as an orange
solution. The yield was assumed to be quantitative and the
product was used without further purifcation. Rf =0.95 in
EtOAc:hexane (1:1).
Methyl (2S)-2-[[[1-[4-(pentafuorosulfanyl)phenyl]-1,2,3-tri-
azol-4-yl]methyl]amino]-3-phenylpropanoate (11,
C19H19F5N4O2S) To a solution of 4-(pentafuorosulfanyl)phe-
nyl azide (10, approx. 1 mmol) and 217 mg methyl (2S)‐3‐
phenyl‐2‐[(prop‐2‐yn‐1‐yl)amino]propanoate (1 mmol)
in 10 cm3 MeCN was added 18 mg Cu(OAc)2 (0.1 mmol)
dissolved in 5 cm3 H2O shortly followed by 40 mg sodium
ascorbate (0.2 mmol) dissolved in 5 cm3 H2O to aford a
homogenous green solution. The reaction temperature was
brought to 60 °C and allowed to proceed for 3 days and
monitored via TLC. The reaction mixture was concentrated
by rotary evaporation to remove MeCN and then extracted
with CHCl3 (2×10 cm3). The organic layers were combined,
washed with saturated NaCl solution, and dried with anhy-
drous MgSO4. The organic layer was then concentrated in
vacuo. The crude product was then purifed via column chro-
matography to aford the pure product as a golden yellow
oil (283 mg, 0.61 mmol, 61%). Rf =0.19 in EtOAc:hexane
(40:60); HRMS (EI): m/z calcd. for C19H20F5N4O2S
Attempted use of ethenesulfanyl pentafuoride
as a Michael acceptor
The high volatility of ethene sulfanyl pentafuoride (14)
(Scheme 6) required the use of a closed system, pressur-
ised with nitrogen and ice bath in order to minimise the
evaporative loss of precursor. Partly unsurprisingly, TLC
of the reaction mixture indicated that product formation did
not occur, despite the strong electron-withdrawing efect of
the –SF5 group.
In a further attempt to obtain the Michael-type product,
a microfuidic platform was utilized to perform test reac-
tions across a temperature range of 20–100 °C, using DMSO
as the solvent. The closed environment of the microfuidic
system is advantageous as it ensures that no volatile rea-
gents are lost and provides a high surface/volume ratio
that typically allows for more efcient and homogeneous
heating. However, also in these conditions, no conjugation
product was detected. These results indicate that the –SF5
group’s inductive efect is not sufcient by itself to provide
a Michael-type addition product.
1
[M + H]+ 463.1222, found 463.1229; H NMR (CDCl3):
δ=7.91 (d, J=11.5 Hz, 2H), 7.76 (d, J=8.5, 2H), 7.53 (s,
1H), 7.31–7.19 (m, 5H), 5.30 (s, 2H), 4.05 (d, J=14.5 Hz,
1H), 3.88 (d, J=14.5 Hz, 1H), 3.71 (s, 3H), 3.55 (dd, J=5.5,
8 Hz, 1H), 3.05 (dd, J=5.5, 13.5 Hz, 1H), 2.87 (dd, J=8.5,
13.5 Hz, 1H) ppm; 13C NMR (CDCl3): δ = 39.72, 43.23,
51.99, 62.21, 119.61, 119.89, 126.78, 127.76, 128.45,
137.62, 148.48, 174.73 ppm; 19F NMR (CDCl3): δ=83.22
(m, J=149.5 Hz, 1F) 63.13 (d, J=149.5 Hz, 4F) ppm.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s00706-021-02760-4.
Acknowledgements We would like to thank the University of Tech-
nology of Sydney for supporting this study. HH gratefully acknowl-
edges the Australian Government and the University of Technology
Sydney for providing the Research Training Program Stipend. HH
gratefully acknowledges the Australian Institute of Nuclear Science
and Engineering for providing the Residential Student Scholarship. GP
acknowledges the Australian National Imaging Facility. The authors
also acknowledge Glen Surjadinata and Luke Hunter for useful discus-
sion and assistance with MS data.
Methyl (2S)-2-acetamido-3-[4-hydroxy-3-[(1E)-2-[4-(pen-
tafluorosulfanyl)phenyl]diazen-1-yl]phenyl]propanoate
(13, C18H18F5N3O4S) In a two-neck round-bottom flask
237 mg N-acyl l-tyrosine methyl ester (1 mmol) was sus-
pended in 5 cm3 0.1 M Na2HPO4 followed by 5 cm3 MeCN
and stirred until completely dissolved. 4-(Pentafuorosulfa-
nyl)phenyl diazonium tetrafuoroborate (317 mg, 1 mmol)
1 3

Incorporation of the pentafuorosulfanyl group through common synthetic transformations
459
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Declarations
Conflict of interest The authors declare no competing fnancial inter-
est.
14. Grigolato L, Brittain WDG, Hudson AS, Czyzewska MM, Cobb
SL (2018) J Fluor Chem 212:166
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1 3