Cyclic Alkenylsulfonyl Fluorides: Palladium-Catalyzed Synthesis and Functionalization of Compact Multifunctional Reagents

Article abstract of DOI:10.1002/anie.201910871

A series of low-molecular-weight, compact, and multifunctional cyclic alkenylsulfonyl fluorides were efficiently prepared from the corresponding alkenyl triflates. Palladium-catalyzed sulfur dioxide insertion using the surrogate reagent DABSO effects sulfinate formation, before trapping with an F electrophile delivers the sulfonyl fluorides. A broad range of functional groups are tolerated, and a correspondingly large collection of derivatization reactions are possible on the products, including substitution at sulfur, conjugate addition, and N-functionalization. Together, these attributes suggest that this method could find new applications in chemical biology.

Full text of DOI:10.1002/anie.201910871

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Cyclic Alkenylsulfonyl Fluorides: Palladium-Catalyzed Synthesis
and Functionalization of Compact Multi-functional Reagents
Authors: Terry Shing-Bong Lou, Scott W Bagley, and Michael C. Willis
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910871
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10.1002/anie.201910871
Angewandte Chemie International Edition
COMMUNICATION
Cyclic Alkenylsulfonyl Fluorides: Palladium-Catalyzed Synthesis
and Functionalization of Compact Multi-functional Reagents
Terry Shing-Bong Lou,[a] Scott W. Bagley[b] and Michael C. Willis*[a]
Abstract:
A
series of low molecular weight, compact and
fluorides, their synthesis involves multi-step routes and proceeds
via unstable sulfonyl chloride intermediates.[3e] We conceived of a
family of small, densely functionalized alkenylsulfonyl fluorides as
attractive reagents for possible applications in medical chemistry
and chemical biology (Scheme 1d). Such molecules would
contain multiple sp3-centres and numerous sites for further
functionalization, adding a valuable application to the SuFEx click
chemistry toolkit.[14] Importantly, the excellent functional group
tolerance achieved in Pd-catalyzed arylsulfonyl fluoride
syntheses suggested that these reactions could be engineered to
the preparation of alkenylsulfonyl fluorides from suitable alkenyl
(pseudo)halide precursors. In this Communication we report that
this is the case, and detail the efficient preparation of a broad
range of low molecular weight, functionalized alkenylsulfonyl
fluorides. We also demonstrate the diverse derivatization
reactions possible on these new reagents.
multifunctional cyclic alkenylsulfonyl fluorides are efficiently prepared
from the corresponding alkenyl triflates. Palladium catalyzed sulfur
dioxide insertion, using the surrogate reagent DABSO, achieves
sulfinate formation, before trapping with an F-electrophile delivers the
sulfonyl fluorides. A broad range of functional groups can be tolerated,
and a correspondingly large collection of derivatization reactions are
possible on the products, including substitution at sulfur, conjugate
addition, and N-functionalization. Together, these attributes suggest
new applications in chemical biology will be forthcoming.
The attractive balance of reactivity and stability that is harnessed
in sulfonyl fluorides has propelled these functional groups to the
vanguard of new applications in medicinal chemistry and
chemical biology.[1] While they also continue to be of interest as
intermediates in synthetic chemistry, it is their tolerance to
aqueous media and physiological conditions that is responsible
for their popularity in biological contexts.[2],[3],[2b, 2d, 4] Classically,
sulfonyl fluorides are prepared from the corresponding sulfonyl
chlorides by way of chloride-fluoride exchange, achieved using
potassium bifluoride (KHF2)[5] or the combination of KF with 18-
crown-6, which is inconvenient to handle due to hygroscopicity.[6]
The required sulfonyl chlorides, typically prepared via the
chlorosulfonation of arenes,[7] are moisture sensitive electrophiles
and as such are inherently limited by their stability and availability,
which is a particular concern in discovery chemistry (Scheme 1a).
Hyatt,[8] Sharpless, and others, reported the use of ethenesulfonyl
fluoride (ESF) for incorporating sulfonyl fluoride groups through
conjugate addition or Pd-catalyzed Heck-type coupling reactions
using aryl iodides, boronic acids or diazonium salts (Scheme
1b).[9] These reactions work well, but are fundamentally limited to
the synthesis of sulfonyl fluorides with only ethyl or ethylene
linkers. The Willis laboratory reported the Pd-catalyzed synthesis
of (hetero)arylsulfonyl fluorides from the corresponding aryl
bromides, DABSO and NFSI,[10] and the Ball laboratory has also
reported a closely related protocol (Scheme 1c).[11] Unsurprisingly,
these latter two reports focus exclusively on planar arene and
hetero-arene substrates. A recent report has described the
electrochemical coupling of thiols and potassium fluoride as a
route to sulfonyl fluorides.[12]
Scheme 1. Common strategies for sulfonyl fluoride syntheses and the
approach and reagents reported here.
a) Classical sulfonyl fluoride synthesis
KF/18-crown-6
or KHF2
O
O
O
O
F
• highly reactive sulfonyl chlorides
• limited availability
S
S
R
Cl
R
b) Hyatt, Sharpless, Arvidsson and Qin
Base
Nuc
Ar
NucH
+
SO2F
SO2F
• use of highly toxic ESF
[Pd]
• limited to ethyl/ethylene linker
Ar
X
+
SO2F
SO2F
X = I, N2+BF4- or B(OH)2
c) Willis and Ball
[Pd]
Br/I
SO2F
DABSO
R
• limited to (hetero)aryl substrates
R
then "F+"
X
X
d) This work
Nu-
R
O
O
[Pd]
OTf
S
diverse
functionalization
DABSO
F
R
X
then NFSI
X
( )n
( )n
Nu-
E+
• compact molecular scaffold • orthogonal functionalities
• readily available starting materials • multiple reactive sites
There is an increasing demand for functionalized 3D-rich
molecules for use in medical chemistry and chemical biology
applications,[13] and while there are isolated reports of 3D-sulfonyl
Considering substrate availability we selected alkenyl
halides[10],[15] or pseudohalides as the starting materials, in
preference to alkenyl boronic acids[16] or preformed
organometallic reagents.[17] We employed cycloheptenyl iodide (1,
Table 1) as our test substrate and adopted our previously reported
protocol for the sulfination of aryl iodides,[15a] followed by
electrophilic fluorination using NFSI, as the initial reaction
conditions. Using these conditions only a low 17% yield of the
cycloheptenylsulfonyl fluoride 5a was obtained (entry 1). Reaction
monitoring established that alkenyl iodide 1 was fully consumed
and alkenylsulfinate 4a was formed in the first hour of reaction,
with the concentration of 4a decreasing over time. Prolonged
reaction time for the fluorination step was also found to diminish
the yield of alkenylsulfonyl fluoride 5a. We speculated that the
[a]
[b]
T. S.-B. Lou and Prof. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
S. W. Bagley.
Global Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT
06340, (USA)
Supporting Information for this article is given via a link at the end of
this document.
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10.1002/anie.201910871
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COMMUNICATION
excess base and alcoholic solvent in use was leading to the
decomposition of alkenylsulfinate 4 and alkenylsulfonyl fluoride 5
under these reaction conditions. By limiting the reaction time for
both steps to one hour, and performing a solvent switch to CH3CN
for the fluorination, the yield was improved to 56% (entries 2-3).
Substrates with different leaving groups were then examined, with
alkenyl bromide (2) and alkenyl triflate (3a) providing similar yields
when PdCl2(AmPhos)2 was used as catalyst (entry 4-6). Alkenyl
triflates were chosen for further investigation due to their ease of
preparation from the corresponding readily available ketones.
Finally, several solvents were evaluated for the fluorination step
(entry 6-8) with ethyl acetate providing the best yield (70%).
sulfonyl fluoride 5s, featuring a sulfonamide protected amine, is
shown, and illustrates the expected half-chair conformation
common to cyclohexenes as well as the relatively small C-SO2-F
bond-angle of 100.3°.[18],[19] Tetralone-derived alkenyl triflates
were converted into alkenylsulfonyl fluorides (5u-x) in moderate
to good yields. Interestingly, whilst substrate 3x bears both an
alkenyl and an aryl triflate, only the alkenyl triflate was converted
with the latter being preserved. It followed that aryl triflates are
inert to the present reaction conditions, with 96% recovery of the
biphenyl triflate and no formation of sulfonyl fluoride 5y occurring.
Five-member alkenyl triflates (3j,t) were poor substrates, as was
an acyclic example (3z), with the latter undergoing decomposition
under the reactions conditions.
Table 1. Selected optimization studies.[a]
Table 2. Scope of the cyclic alkenyl sulfonyl fluorides.[a]
O
O
F
DABSO, Et3N
Pd(OAc)2, PAd2Bu
-
SO2
+NHEt3
X
S
NFSI
O
O
F
DABSO
PdCl2(AmPhos)2
i-PrOH, 75 °C, 16 h
solvent
rt, 1 h
OTf
-
S
SO2
NFSI
R
R
1, X = I; 2, X = Br
3a, X = OTf
4a
5a
X
EtOAc, rt
Et3N
i-PrOH, 75 °C
X
step 1
Variation in step 1
( )n
step 2
( )n
5
3
Entry
X
Solvent for step 2 Yield of 5a
SO2F
SO2F
SO2F
SO2F
SO2F
i-PrOH
i-PrOH
MeCN
MeCN
MeCN
MeCN
EtOAc
i-PrOH
1
2
3
4
5
6
7
8
as above
1 h
17%
37%
56%
52%
36%
56%
I
F
I
t-Bu
Ph
F
1 h
I
5a, 70%
5b, 71%
5c, 70%[b]
5d, 67%
PdCl2(AmPhos)2, 1 h
1 h
Br
OTf
OTf
OTf
OTf
SO2F
SO2F
BocHN
5g, 64%
SO2F
SO2F
PdCl2(AmPhos)2, 1 h
PdCl2(AmPhos)2, 1 h
PdCl2(AmPhos)2, 1 h
O
EtO
67% (70%)[b]
MeO
O
54%
O
5h, 74%
5e, 80%
5f, 57%
(gram-scale: 73%)
P(t-Bu)2
PhO2S
SO2Ph
N
N
N SO2
O2S
Me
SO2F
F
Me2N
O
DABSO
AmPhos
NFSI
N
Me
SO2F
Me
n
5l, 43%[c]
n=0 5j, trace
n=1 5k, 68%
[a] Reaction conditions: (step 1) Alkenyl (pseudo)halide (0.3 mmol, 1 equiv),
DABSO (0.6 equiv), Et3N (3 equiv), Pd(OAc)2 (5 mol%), PAd2(n-Bu) (7.5 mol%),
i-PrOH [0.25 M], 75 °C, 16 h; (step 2) NFSI (1.5 equiv), solvent [0.25 M], rt, 1 h.
Yields determined by 19F-NMR spectroscopy with internal standard. [b] Isolated
yield.
5i, 52%
SO2F
SO2F
SO2F
Boc
SO2F
N
N
O
O
S
X
O
Boc 5p, 82%
Cbz 5q, 65%
Bn 5r, 46% [c,d]
X =
5m, 49%
5n, 62%
5o, 69%
With alkenyl triflates selected as the substrates and optimized
conditions identified, we next examined the substrate scope for
the reaction (Table 2). While the parent cyclohexenylsulfonyl
fluoride proved to be too volatile for straight-forward isolation, a
broad range of cyclohexenyl triflate derivatives were examined in
this reaction. A variety of functional groups at 4-position were
tolerated, including phenyl (5b), tert-butyl (5c), geminal difluoro
(5d), ethyl ester (5e), methoxy ether (5f), Boc-protected amine
(5g) and spiro- dioxolane (5h). Viability for scale up was illustrated
by the gram-scale reaction to form sulfonyl fluoride 5h; one gram
of alkenyl triflate 3d (3.5 mmol) delivered 0.57 g (2.57 mmol) of
5h in 73% yield, which is comparable to the 74% yield obtained
for a 0.3 mmol scale reaction. Substrates with substituents at 3-
position were also converted into alkenylsulfonyl fluorides
efficiently, with electron-rich heteroaromatic 1-methylindole (5i)
and 2-methylfuran (5k) tolerated to give alkenylsulfonyl fluorides
in 52% and 68% yield, respectively. A substrate with a 6-methyl
substituent was slower to react and required heating to 95 °C for
the sulfination step, ultimately providing sulfonyl fluoride 5l in 43%
yield. Heterocyclic substrates were then explored, with sulfone
and dihydropyran containing products being efficiently obtained
(5m,n). Protected amines at both the 4- and 5-positions could also
be incorporated (5o-s). Of these, the substrates featuring
carbamate (5o-q) and sulfonamide (5s) groups were most
efficient, with the basic N-benzyl derivative requiring the addition
of Hünig's base in the fluorination step (5r). The X-ray structure of
SO2F
SO2F
N
n
TolO2S
n=0 5t, 0%
5s, 90%
SO2F
n=1 5u, 55% [e]
SO2F
SO2F
Ph
X
X = H, 5v, 63% [e]
5z, trace
5y, 0%[f]
OMe, 5w, 57% [e]
OTf, 5x, 59%[e]
[a] Reaction conditions: Alkenyl triflate 3 (0.3 mmol, 1 equiv), DABSO (0.6
equiv), Et3N (3 equiv), PdCl2(AmPhos)2 (5 mol%), i-PrOH [0.25 M], 75 °C, 0.5-
10 h; then NFSI (1.5 equiv), EtOAc [0.25 M], rt, 1 h. [b] step 1: 80 °C. [c] step 1:
μW, 95 °C. [d] step 2: DIPEA (3 equiv) was added after solvent switch and prior
to the addition of NFSI. [e] step 1: PdCl2(AmPhos)2 (5 mol%), DABSO (1 equiv),
Et3N (3 equiv), i-PrOH/1,4-dioxane (2:1) [0.25 M], 80 °C, 0.5-1.5 h. [f] 96%
recovery of biphenyl triflate.
With success in the preparation of a broad range of cyclic
functionalized alkenylsulfonyl fluorides achieved, we then
investigated derivatization reactions. As shown in Scheme 2,
nucleophilic substitution at sulfur was achieved by the reaction of
alkenylsulfonyl fluoride 5b with p-methoxyphenol to form
sulfonate ester 6 in 84% yield, and with pyrrolidine to form
sulfonamide 7 in 51% yield. With the aid of stoichiometric
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10.1002/anie.201910871
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Ca(NTf2)2 as Lewis acid,[3d] anilines could also be used as
nucleophiles to form alkenyl sulfonamides 8a and 8b in good
yields. Alternatively, softer sulfur nucleophiles such as thiols and
thiophenols underwent base-catalyzed conjugate addition to the
electron-poor alkene in quantitative yields (9a-c). Pd-catalyzed
hydrogenation of the alkene was also viable using balloon
pressure H2, forming the saturated sulfonyl fluoride 10 in 71%
yield, demonstrating an efficient method to access saturated
derivatives. Alkenylsulfonyl fluoride 5r, featuring a N-Bn group,
could undergo an efficient one-pot debenzylation/acylation using
propargyl chloroformate,[20] in quantitative yield. The resultant
alkynyl-bearing alkenylsulfonyl fluoride 11 could then perform the
“click” copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)
with benzyl azide, providing triazole 12. The Boc protecting group
of sulfonyl fluoride 5p could be cleaved using 20% (v/v)
trifluoroacetic acid (TFA) in dichloromethane, forming ammonium
salt 14, which could then be further derivatized upon removal of
the of the excess acid in vacuo. Alternatively, by treating the same
substrate with 4 N hydrochloric acid in dioxane, a hydrochloride
salt of the deprotected amine 13 was isolated in 92% yield as a
bench-stable white solid. The secondary ammonium salts 13 and
14 were able to react with various electrophiles; for example,
reaction with phenyl isocyanate formed urea 17 in 74% yield, and
reaction with phenyl isothiocyanate generated thiourea 18 in 84%
yield. Notably, using this strategy, a fluorophore could be attached
to the alkenylsulfonyl fluoride by the reaction with fluorescein
isothiocyanate (FITC) isomer I, giving 19 in 65% yield. Ammonium
salt 13 underwent reductive amination with nicotinaldehyde to
form tertiary amine 15 in 78% yield, illustrating the tolerance of
alkenylsulfonyl fluoride to such reductive conditions. In addition,
ammonium salt 14 could be combined with an amino acid using
T3P as coupling agent to form amide 20; biotin was conjugated to
ammonium 13 using HATU to form the biotinylated alkenylsulfonyl
fluoride 16. Together, the alkyne-, fluorophore- and biotin-
derivatized alkenylsulfonyl fluorides are examples of multi-
functional reagents primed for application to biological problems.
Scheme 2. Functionalization of alkenylsulfonyl fluorides.
OMe
O
O
R
1,2-addition on S
O
O
O
O
S
N
S
S
PG = Boc. R = Me 8a, 76%
PG = Ts, R = H 8b, 55%
O
N
H
Ph
N
Ph
PG
6, 84%
7, 51%
a
b
c
1,4-addition on C
R
Hydrogenation
SO2F
S
SO2F
O
O
e
d
n
S
O
F
PG = Boc. n = 0, R = F 9a
PG = Ts, n = 0, R = F 9b
99% d.r. 3.5:1
99% d.r. 2.2:1
N
X
O
5
PG
PG = Ts, n = 1, R = OMe 9c 98% d.r. 2.9:1
10, 71%
f
h
g
SO2F
SO2F
N-debenzylation/
acylation/CuAAC
N-deprotection
i
SO2F
SO2F
N
O
N
O
Ph
N
N
N
HCl •HN
13, 92%
O
O
N
• TFA
14
H
H
11, 98%
12, 99%
j
k
l
m
n
O
S
O
O
OH
N
SO2F
SO2F
Ph
SO2F
HN
H
NH
H
N
PhHN
N
N
BocHN
HOOC
Y
O
15, 78%
Reductive amination
20, 75%
Y = O 17, 74%
Y = S 18, 84%
SO2F
SO2F
Amide coupling
HN
N
N
Urea/thiourea formation
16, 40%
Biotinylation
19, 65%
FITC labelling
S
O
N-functionalisation
Reaction conditions: Unless specified, 1 equiv of alkenylsulfonyl fluoride 5 was used. [a] X = CHPh; phenol (1.1 equiv), Cs2CO3 (2 equiv), CH3CN [0.2 M], rt, air,
1 h. [b] X = CHPh; pyrrolidine (5 equiv), CH3CN [0.1 M], 70 °C, air, 3 h. [c] X = NPG; aniline (2.2 equiv), Ca(NTf2)2 (1.1-2.0 equiv), t-amyl-OH [0.2 M], 60 °C, 16 h.
[d] X = NPG; thiol (1.1 equiv), DBU (10 mol%), DCM [0.2 M], air, rt, 1-2 h. [e] X = C(OCH2CH2O); Pd/C (30 mol%), EtOAc [0.2 M], H2 (balloon), 40 °C, 24 h. [f] X =
NBoc; HCl (4 N in dioxane) (10 equiv), 1,4-dioxane [0.2 M], rt, 16 h. [g] X = NBoc; 20% (v/v) TFA in DCM [0.1 M], rt, 30 min. [h] X = NBn; propargyl chloroformate
(1.8 equiv), CHCl3 [0.33 M], –20 °C to 60 °C, 2 h. [i] Benzyl azide (1.1 equiv), CuSO4×5H2O (5 mol%), sodium ascorbate (10 mol%), t-BuOH/H2O (1:1) [0.23 M], air,
16 h. [j] Aldehyde (3 equiv), Et3N (1 equiv), NaBH(OAc)3 (3 equiv), DCM [0.2 M], rt, 16 h. [k] 13 (1.1 equiv), Biotin (1.0 equiv), HATU (1.05 equiv), Et3N (2.5 equiv),
DMF [0.08 M], N2, rt, 16 h. [l] Et3N (1 equiv), PhNCO or PhNCS (1 equiv), THF [0.2 M], rt, 16 h. [m] Et3N (1 equiv), FITC isomer I (1 equiv), THF [0.2 M], rt, 16 h. [n]
Boc-Phe-OH (1 equiv), Et3N (3 equiv), T3P (50% in EtOAc) (2 equiv), DMF [0.1 M], 0 °C, 16 h.
This article is protected by copyright. All rights reserved.

10.1002/anie.201910871
Angewandte Chemie International Edition
COMMUNICATION
[15] a) E. J. Emmett, B. R. Hayter, M. C. Willis, Angew. Chem. Int. Ed. 2014,
53, 10204-10208; b) B. Nguyen, E. J. Emmett, M. C. Willis, J. Am.
Chem. Soc. 2010, 132, 16372-16373.
[16] a) Y. Chen, P. R. D. Murray, A. T. Davies, M. C. Willis, J. Am. Chem.
Soc. 2018, 140, 8781-8787; b) Y. Chen, M. C. Willis, Chem. Sci. 2017,
8, 3249-3253; c) A. S. Deeming, C. J. Russell, M. C. Willis, Angew.
Chem. Int. Ed. 2016, 55, 747-750; d) V. Vedovato, E. P. A. Talbot, M.
C. Willis, Org. Lett. 2018, 20, 5493-5496.
[17] a) A. S. Deeming, C. J. Russell, A. J. Hennessy, M. C. Willis, Org. Lett.
2014, 16, 150-153; b) A. S. Deeming, C. J. Russell, M. C. Willis,
Angew. Chem. Int. Ed. 2015, 54, 1168-1171; c) E. J. Emmett, B. R.
Hayter, M. C. Willis, Angew. Chem. Int. Ed. 2013, 52, 12679-12683; d)
D. C. Lenstra, V. Vedovato, E. Ferrer Flegeau, J. Maydom, M. C. Willis,
Org. Lett. 2016, 18, 2086-2089.
[18] For an example of an arylsulfonyl fluouride X-ray structure, see: D.
Jantke, A. N. Marziale, T. Reiner, F. Kraus, E. Herdtweck, A. Raba, J.
Eppinger, J. Organomet. Chem. 2013, 744, 82-91.
In conclusion, we have reported an efficient and general
synthesis of multifunctional alkenylsulfonyl fluorides. These Pd-
catalyzed reactions proceed from alkenyl triflates readily formed
from commonly available ketones, and display good functional
group tolerance. We have shown that templates in this new class
of sulfonyl fluoride are able to undergo a variety of orthogonal
derivatization processes, including nucleophilic substitution at
sulfur, conjugate addition to the alkene, Pd-catalyzed
hydrogenation of the olefin, N-functionalization, and a CuAAC
click reaction. We anticipate that these attributes will result in
these compact, low molecular weight and densely functionalized
reagents being exploited in a variety of chemical biology, synthetic
and medicinal chemistry applications.
[19] Deposition Number 1944829 contains the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
Acknowledgements
We are grateful to the Croucher Foundation (to T.S.-B.L.), and
the EPSRC for their support of this study. S.W.B. thanks Ed Conn,
John Curto and Alyn Davies (all Pfizer) for helpful discussions and
Ivan Samadjiev (Pfizer) for assistance with X-ray crystallographic
studies.
[20] R. G. Bhat, Y. Ghosh, S. Chandrasekaran, Tetrahedron Lett. 2004, 45,
7983-7985.
Keywords: sulfur • fluoride • catalysis • synthetic methods •
multifunctional
References
[1]
[2]
a) C. G. Swain, C. B. Scott, J. Am. Chem. Soc. 1953, 75, 246-248; b)
M. E. Aberlin, C. A. Bunton, J. Org. Chem. 1970, 35, 1825-1828.
a) M. P. Kamps, S. S. Taylor, B. M. Sefton, Nature 1984, 310, 589-592;
b) D. A. Shannon, C. Gu, C. J. McLaughlin, M. Kaiser, R. A. van der
Hoorn, E. Weerapana, Chembiochem 2012, 13, 2327-2330; c) E. C.
Hett, H. Xu, K. F. Geoghegan, A. Gopalsamy, R. E. Kyne, C. A.
Menard, A. Narayanan, M. D. Parikh, S. Liu, L. Roberts, R. P.
Robinson, M. A. Tones, L. H. Jones, ACS Chem. Biol. 2015, 10, 1094-
1098; d) A. Narayanan, L. H. Jones, Chem. Sci. 2015, 6, 2650-2659.
a) T. Ikawa, T. Nishiyama, T. Nosaki, A. Takagi, S. Akai, Org. Lett.
2011, 13, 1730-1733; b) A. V. Bogolubsky, Y. S. Moroz, P. K.
Mykhailiuk, S. E. Pipko, A. I. Konovets, I. V. Sadkova, A. Tolmachev,
ACS Comb. Sci. 2014, 16, 192-197; c) M. K. Nielsen, C. R. Ugaz, W. Li,
A. G. Doyle, J. Am. Chem. Soc. 2015, 137, 9571-9574; d) P.
Mukherjee, C. P. Woroch, L. Cleary, M. Rusznak, R. W. Franzese, M.
R. Reese, J. W. Tucker, J. M. Humphrey, S. M. Etuk, S. C. Kwan, C. W.
Am Ende, N. D. Ball, Org. Lett. 2018, 20, 3943-3947; e) S. A. Zhersh,
O. P. Blahun, I. V. Sadkova, A. A. Tolmachev, Y. S. Moroz, P. K.
Mykhailiuk, Chem. Eur. J. 2018, 24, 8343-8349.
[3]
[4]
[5]
D. E. Fahrney, A. M. Gold, J. Am. Chem. Soc. 1963, 85, 997-1000.
a) J. Dong, L. Krasnova, M. G. Finn, K. B. Sharpless, Angew. Chem.
Int. Ed. 2014, 53, 9430-9448; b) Q. Zheng, J. Dong, K. B. Sharpless, J.
Org. Chem. 2016, 81, 11360-11362.
[6]
[7]
T. A. Bianchi, L. A. Cate, J. Org. Chem. 1977, 42, 2031-2032.
a) O. Lindner, L. Rodefeld, in Ullmann's Encyclopedia of Industrial
Chemistry, 2000; b) J. P. Bassin, R. J. Cremlyn, F. J. Swinbourne,
Phosphorus, Sulfur, and Silicon and the Related Elements 1991, 56,
245-275.
[8]
[9]
J. J. Krutak, R. D. Burpitt, W. H. Moore, J. A. Hyatt, J. Org. Chem.
1979, 44, 3847-3858.
a) H.-L. Qin, Q. Zheng, G. A. L. Bare, P. Wu, K. B. Sharpless, Angew.
Chem. Int. Ed. 2016, 55, 14155-14158; b) G. F. Zha, Q. Zheng, J. Leng,
P. Wu, H. L. Qin, K. B. Sharpless, Angew. Chem. Int. Ed. 2017, 56,
4849-4852; c) P. K. Chinthakindi, K. B. Govender, A. S. Kumar, H. G.
Kruger, T. Govender, T. Naicker, P. I. Arvidsson, Org. Lett. 2017, 19,
480-483.
[10] A. T. Davies, J. M. Curto, S. W. Bagley, M. C. Willis, Chem. Sci. 2017,
8, 1233-1237.
[11] A. L. Tribby, I. Rodriguez, S. Shariffudin, N. D. Ball, J. Org. Chem.
2017, 82, 2294-2299.
[12] G. Laudadio, A. A. Bartolomeu, L. Verwijlen, Y. Cao, K. T. de Oliveira,
T. Noel, J. Am. Chem. Soc. 2019, 141, 11832-11836.
[13] a) P. A. Clemons, N. E. Bodycombe, H. A. Carrinski, J. A. Wilson, A. F.
Shamji, B. K. Wagner, A. N. Koehler, S. L. Schreiber, Proc. Natl. Acad.
Sci. U S A 2010, 107, 18787-18792; b) F. Lovering, J. Bikker, C.
Humblet, J. Med. Chem. 2009, 52, 6752-6756; c) T. J. Ritchie, S. J.
Macdonald, Drug Discov. Today 2009, 14, 1011-1020.
[14] A. S. Barrow, C. J. Smedley, Q. Zheng, S. Li, J. Dong, J. E. Moses,
Chem. Soc. Rev. 2019, 48, 4731-4758.
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10.1002/anie.201910871
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
T. S.-B. Lou, S. W. Bagley, and M. C.
Willis* __________ Page – Page
conjugate
addition
SF warhead for
molecular probes
OTf
SO2F
Pd, DABSO
O
O
F
Cyclic Alkenylsulfonyl Fluorides:
Palladium-Catalyzed Synthesis and
Functionalization of Compact Multi-
functional Reagents
R
R
hydrogenation
S
then NFSI
X
X
( )n
( )n
N
nucleophilic
substitution
X
• Readily available starting materials
• Compact molecular scaffold
• Multiple reactive sites
N-deprotection
other orthogonal
reactions
A family of compact low molecular weight cyclic alkenylsulfonyl fluorides are readily
prepared from the corresponding alkenyl triflates using palladium catalysis. These
densely functionalized reagents undergo a diverse range of derivatization reactions,
including substitution at sulfur, conjugate addition, and N-functionalization.
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