A Synthesis of dual Warhead β-Aryl Ethenesulfonyl Fluorides and One-Pot Reaction to β-Sultams

Article abstract of DOI:10.1021/acs.orglett.6b03634

Herein, we report an operationally simple, ligand- and additive-free oxidative boron-Heck coupling that is compatible with the ethenesulfonyl fluoride functional group. The protocol proceeds at room temperature with chemoselectivity and E-isomer selectivity and offers facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl fluorides from commercial boronic acids. Furthermore, we demonstrate a one-pot click reaction to directly transform the products to aryl-substituted β-sultams.

Full text of DOI:10.1021/acs.orglett.6b03634

Letter
pubs.acs.org/OrgLett
A Synthesis of “Dual Warhead” β‑Aryl Ethenesulfonyl Fluorides and
One-Pot Reaction to β‑Sultams
Praveen K. Chinthakindi,§ Kimberleigh B. Govender,§,⊥ A. Sanjeeva Kumar,§,⊥ Hendrik G. Kruger,§
Thavendran Govender,§ Tricia Naicker,§ and Per I. Arvidsson*,§,†
§Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban, South Africa
†Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology,
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Herein, we report an operationally simple,
ligand- and additive-free oxidative boron-Heck coupling that
is compatible with the ethenesulfonyl fluoride functional group.
The protocol proceeds at room temperature with chemo-
selectivity and E-isomer selectivity and offers facile access to a
wide range of β-aryl/heteroaryl ethenesulfonyl fluorides from
commercial boronic acids. Furthermore, we demonstrate a
“one-pot click” reaction to directly transform the products to aryl-substituted β-sultams.
alladium catalyzed oxidative carbon−carbon bond for-
Pmation reactions are vital in the synthesis of complex
organic molecules. A variety of Pd catalyzed reactions have
been developed for the arylation of olefins such as Mizoroki−
Heck, Meerwein arylation, Heck−Matsuda, oxidative boron-
Heck, etc. Approaches using an oxidative boron-Heck coupling
Figure 1. Peptide vinyl sulfonyl fluoride proteasome inhibitor as
reported by Liskamp et al.11
are becoming increasingly attractive for modern organic
syntheses1 as they offer a wide range of advantages such as
efficiency, mild reaction conditions, good functional group
tolerance, and widespread applications.2 In particular, organo-
boronic acids used as nucleophiles offer many advantages, as
they are moisture and air stable, and have low toxicity, and a
large variety are commercially available.3 Recently our group
developed a Pd catalyzed cross-coupling method between
organoboronic acids and halo aryl sulfonyl fluorides.4 The
interest in the sulfonyl fluoride (SF) group was sparked by its
recent inclusion as a “click reagent” by the Sharpless laboratory5
as well as privileged “warheads” for covalent enzyme inhibition
by Lyn and co-workers.6 Moreover, Andrey et al. explored
sulfonyl fluorides as an alternative to sulfonyl chlorides7 and
Matthew et al. investigated SFs (PyFluor) as a selective deoxy
fluorination reagent.8 Also, one report has revealed the
usefulness of the SF functional group as a PET agent in radio
pharmaceuticals.9 Yet, despite these SFs having many
applications in material science,10 the full potential of SFs as
building blocks/intermediates in organic syntheses is yet to be
fully realized.
probes, as it is known to be a good connector,5,13 Michael
acceptor,14 and Diels−Alder dienophile.15
Albeit useful in a wide range of pharmaceutical and material
intermediates synthesis,12,16 the synthetic procedures to access
substituted ethenesulfonyl fluoride derivatives require multistep
syntheses (Scheme 1a, b) and suffer from disadvantages such as
the use of highly pyrophoric (n-BuLi),17 toxic and corrosive
reagents (SOCl2).18,16b Therefore, approaches that use simple
and commercial starting materials, such as ethenesulfonyl
fluoride and aryl boronic acids (cross-coupling), in a single step
would be highly advantageous. This method could be a valuable
addition to transition metal catalyzed late-stage functionaliza-
tion19 and bioorthogonal chemistry.20
Our earlier findings on palladium catalyzed cross-coupling
development4,21,4,6b inspired us to carry out Pd catalyzed
arylation of ESF. Herein we report the first and efficient ligand-
free oxidative boron-Heck coupling reaction to access diverse
aryl substituted ethenesulfonyl fluorides. The obtained
substituted ethenesulfonyl fluorides are handy building blocks
for consequent synthetic transformations.16a Until the final-
ization of this work, this was the first method where ESF was
used directly as a coupling partner in Pd catalyzed reactions.
Most recently, Liskamp et al. proposed peptide-derived
vinylic sulfonylfluorides as a new class of bielectrophilic
warheads for covalent drug discovery which selectively inhibited
the threonine residue in the proteasome active site, Figure 1.11
Based on this report, we became interested in the use of
ethenesulfonyl fluoride (ESF)12 as a starting material for such
Received: December 6, 2016
© XXXX American Chemical Society
A
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Letter
a
Scheme 1. Synthesis of β-Aryl Ethenesulfonyl Fluorides
Table 1. Optimization of Reaction Conditions
b
c
entry
oxidant
O2
base
solvent
yield (%) ratio (4a:5a)
1
2
LiOAc
DIPEA
TEA
DMF
DMF
DMF
DMF
DMF
CH3CN
THF
9.9
26.5
12
100:0
100:0
100:0
−
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
3
4
Cs2CO3
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
NR
58
5
95:5
6
28
92:8
7
77
100:0
59:41
31:69
27:73
8
DCE
16.8
9.5
trace
9
toluene
H2O
10
a
Reaction conditions: Boronic acid (1.0 equiv), ethenesulfonyl
fluoride (3.0 equiv), Pd(OAc)2 (10 mol %), base (1.2 equiv), oxidant
(2.0 equiv for Cu(OAc)2) under dry conditions in 4.0 mL of solvent.
Isolated yield of 4a. Percentages based on GC/MS analysis of the
crude reaction mixture (4a and 5a).
However, it is to be noted that while we awaited HRMS data of
our products, a report from the Sharpless group appeared that
describes the synthesis of β-aryl ethenesulfonyl fluoride
derivatives from arenediazonium tetrafluoroborates and ethe-
nesulfonyl fluoride using a palladium catalyzed Heck−Matsuda
cross-coupling reaction.16a Our work presents the synthesis of
β-aryl ethenesulfonyl fluoride derivatives from stable and
commercially available aryl boronic acids and demonstrates
the utility of the resulting β-aryl ethenesulfonyl fluoride as
starting materials for a mild one-pot synthesis of β-sultams that
are otherwise difficult to access.
To find a suitable catalytic system for the arylation of
ethenesulfonyl fluoride, a model reaction with phenyl boronic
acid and ethenesulfonyl fluoride was investigated using the
oxidative boron Heck conditions reported by Jung and co-
workers, i.e. Pd(OAc)2, O2, and Na2CO3 in DMF at 50 °C.22
However, under these conditions we observed the formation of
undesired homocoupling as the major product with only a trace
amount of the desired product (8%). Therefore, we attempted
to optimize the reaction conditions by evaluating various Pd
catalysts {i.e., Pd(PPh3)4, Pd2(dba)3, Pd(PPh3)2Cl2, and Pd−
C}; however, this did not improve the reaction yield. We then
shifted our focus to explore various oxidants {i.e., Cu(OAc)2,
DDQ, O2, and Air} and bases {NaOAc, Cs2CO3, DIPEA, TEA}
(Table 1). In the presence of DDQ as the oxidant no product
formation was observed (data not shown). Similarly, air
oxidation (data not shown) and O2 offered only low yields
(Table 1, entry 1). However, in the presence of a stoichiometric
amount of Cu(OAc)2, good improvement in yield was observed
(Table 1, entry 2); this is due to good synergy between Pd and
Cu in the catalytic cycle,23 which is known to enhance the rate
of the oxidation of Pd(0) to Pd (II).
Next, we investigated the influence of various bases on the
reaction yield. Using Cs2CO3 as a base there was no product
formation observed, which could be due to hydrolysis of the
sulfonyl fluoride, similar to our earlier findings on the cross-
coupling of halo aryl sulfonyl fluorides.4 The organic bases
(DIPEA, TEA) did not provide any further improvement in
yield (Table 1, entries 3 and 4). However, in the case of LiOAc
as a base there was an improved reaction yield. Interestingly,
reaction conditions using 10 mol % Pd(OAc)2, 2.0 equiv of
Cu(OAc)2, and 1.0 equiv of LiOAc in DMF at room
temperature exclusively gave the alkenyl product in 58% yield
(Table 1, entry 5) along with a minor amount of the conjugate
addition product. Conjugate addition has been reported by
b
c
several other research groups for various other α,β-unsaturated
cyclic/acyclic carbonyl systems.2,24
To avoid the undesired homocoupling and conjugate
addition, we slowly added the aryl boronic acid to the reaction
mixture over a period of ∼30 min; thereby, we were able to
avoid the homocoupling and observed a small improvement in
the yield. Still, a small amount of conjugate addition product
was observed under these conditions.
Finally, to achieve the optimized reaction conditions we
explored various solvents {CH3CN, toluene, THF, DCE, and
H2O}. Polar aprotic solvents (CH3CN, THF) gave moderate to
good yields with minimum, or no, conjugate product formation
(Table 1, entries 6 and 7). This suggested that nitrogen- and
oxygen-containing solvents could act as ligands that stabilize
the palladium coordination complex25 and promote/switch the
oxidative addition over conjugate addition. The use of
chlorinated non-polar aprotic solvents such as DCE resulted
in an almost equal amount of the oxidative addition and
conjugate addition products (Table 1, entry 8). Again, this
could be due to the absence of coordinating heteroatoms (O
and N) in this solvent. This hypothesis was further supported
by observations of a nonpolar aprotic solvent, i.e. toluene,
where the conjugate addition product was observed as a major
product; lower yields were also seen in toluene due to poor
solubility of the starting materials (aryl boronic acid, LiOAc) in
this solvent (Table 1, entry 9). In contrast to our previous
report on cross-coupling reactions,4 water as a reaction solvent
drastically decreased the reaction yield (Table 1, entry 10).
Only a trace amount of product formation was observed with
some other byproducts, as well as small amounts of unreacted
starting material; most likely, the super Michael acceptor
ethenesulfonyl fluorides reacts with water under these
conditions.14
With the optimized conditions in hand (10 mol % Pd(OAc)2,
2.0 equiv of Cu(OAc)2, and 1.0 equiv of LiOAc in THF at
room temperature) we next investigated the substrate scope of
the reaction using various substituted arylboronic acids and
ethenesulfonyl fluoride as coupling partners (Figure 2).
Reaction with simple phenyl boronic acids proceeded smoothly
in an oxidative boron-Heck cross-coupling, without any
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Letter
Figure 2. Substrate scope for the synthesis of aryl substituted ethenesulfonyl fluorides using oxidative Heck coupling of boronic acids and
ethenesulfonyl fluoride (ESF).
conjugated addition, offering product 4a in 77% yield. The
electron-withdrawing groups (EWGs) (NO2 and Br) offered
products 4b, 4c, 4d, 4e, and 4f in moderate to good yields
without any conjugate addition product. However, substrates
with electron-donating groups (EDGs), i.e. yielding products
4g and 4h in 48% and 43% yield respectively, gave a small
amount of conjugate addition (<1%) byproduct. Steric effects
did not seem to significantly influence the reaction, as
substrates with 2-OMe, 2,6-di-OMe, and 2-OMe-5-chloro
groups offered the corresponding products in moderate yields.
Bicyclic (naphthalene; 4l and 4m in 55% and 55% yield) and
heterocyclic (thiophene 4n, 41% yield; indole 4o, 65%) boronic
acids gave only small amounts of conjugate addition product
along with an oxidative boron-Heck product. We also
attempted the same reaction conditions for heterocyclic
boronic acids (i.e., quinazoline and pyridine), but these
substrates did not offer any product, presumably due to
complexation of the palladium with the nitrogen atoms in these
substrates. Similarly, 2-NO2 phenyl boronic failed to give the
respective product. In summary, the reported methodology
offers acceptable yields of aryl ethenesulfonyl fluorides through
an operationally simple oxidative Heck reaction using widely
accessible boronic acids and ethenesulfonyl fluoride as reagents.
The limitation in yields was due to unwanted deboronation of
the aryl boronic acids, which was confirmed by GC-MS and
previously reported in the literature.26
isobutylamine and 4b. We observed an increased formation of
β-sultam 6a until a total of 2.5 equiv of amine had been added
to reach 100% conversion to the β-sultam over 20 min. A
separate experiment in which 4.0 equiv of the amine was
directly added to 4b led to 100% conversion to the β-sultam in
2 min.
We also probed the influence of DBU to see if this changed
the reactivity toward the S−F bond or catalyzed the Michael
reaction; addition of 1.0 equiv of isobutylamine to 4b in the
presence of 0.1−0.5 equiv of DBU led to slow formation of the
β-sultam. With these results in hand, we investigated the scope
of the β-sultam formation using excess methylamine in THF
(see Supporting Information for details). The transformation
worked well for a range of aryl ethenesulfonyl fluorides
containing both electron-donating and -withdrawing groups, i.e.
producing β-sultams 6b−6d (Scheme 2). It is anticipated that
Scheme 2. Synthesis of β-Sultams
In order to prove the synthetic potential of the disclosed
methodology and explore the dual warhead concept of the β-
aryl ethenesulfonyl fluorides, the addition of primary amines
was investigated. The concurrent manuscript by Sharpless et al.,
describes the selective conjugate addition of secondary amines
to the β-aryl ethenesulfonyl fluoride products without affecting
the S−F bond, while Liskamp and co-workers described an
unexpected β-sultam formation in the presence of excess of
primary amines for their β-aliphatic ethenesulfonyl fluoride
reagents. We initiated our investigation using NMR spectros-
copy experiments by the addition of only 1.0 eq. of
isobutylamine to 4b; under these conditions, no reaction
occurred after 5 min. Keeping the reaction mixture overnight
led to 50% conversion to the corresponding β-sultam 6a;
notably, no trace of the corresponding Michael addition
product could be detected in the sample. In the next
experiment, we added aliquots (0.1 equiv) of the amine
sequentially to the NMR tube already containing 1.0 eq. of
the β-sultam forms via a Michael addition that in a concerted
reaction expels F− and forms a sulfene intermediate, to which
the amine adds intramolecularly; substrates with an EWG
appears to react faster than those with EDG substituents.
Finally, we developed this method as a one-pot procedure.
After completion of the oxidative boron-Heck reaction between
the boronic acid and ethenesulfonyl fluoride, we directly added
excess methylamine to the reaction mixture followed by stirring
for another 5 min. This gave the corresponding β-sultam in
high yield after column chromatography (Scheme 3).
In summary, we have developed a facile synthetic method to
access substituted β-aryl ethenesulfonyl fluorides using an
oxidative boron-Heck cross-coupling reaction that proceeds
C
DOI: 10.1021/acs.orglett.6b03634
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Scheme 3. One Pot-Click Synthesis of β-Sultams
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The reported method is complementary to previously reported
procedures and utilizes boronic acids, a class of starting material
that has widespread commercial availability. The obtained aryl
substituted ethenesulfonyl fluorides represent a “dual warhead”
with two electrophilic sites that has found use as covalent
enzyme inhibitors and as synthetic reagents. We also
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03634.
Experimental procedures and full characterization data
(1H, 19F, 13C, and GC-MS) with copies of spectra for all
the compounds (PDF)
(18) Reddy, M. V. R.; Mallireddigari, M. R.; Pallela, V. R.; Cosenza, S.
C.; Billa, V. K.; Akula, B.; Subbaiah, D. R. C. V.; Bharathi, E. V.;
Padgaonkar, A.; Lv, H.; Gallo, J. M.; Reddy, E. P. J. Med. Chem. 2013,
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: per.arvidsson@scilifelab.se.
ORCID
(19) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S.
W. Chem. Soc. Rev. 2016, 45, 546−576.
Per I. Arvidsson: 0000-0002-9453-6812
Author Contributions
⊥K.B.G. and A.S.K. contributed equally.
Notes
(20) (a) Ourailidou, M. E.; van der Meer, J.-Y.; Baas, B.-J.;
Jeronimus-Stratingh, M.; Gottumukkala, A. L.; Poelarends, G. J.;
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(b) Yang, M.; Li, J.; Chen, P. R. Chem. Soc. Rev. 2014, 43, 6511−6526.
(21) (a) Wakchaure, P. B.; Borhade, S. R.; Sandstrom, A.; Arvidsson,
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P. I. Eur. J. Org. Chem. 2015, 2015, 213−219. (b) Nandi, G. C.; Kota,
S. R.; Wakchaure, P. B.; Chinthakindi, P. K.; Govender, T.; Kruger, H.
G.; Naicker, T.; Arvidsson, P. I. RSC Adv. 2015, 5, 62084−62090.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(c) Borhade, S. R.; Sandstrom, A.; Arvidsson, P. I. Org. Lett. 2013, 15,
̈
This work is based on the research supported in part by the
National Research Foundation of South Africa for the Grant
87706. We are also grateful to the Claude Leon Foundation for
postdoctoral fellowship to P.K.C., UKZN postdoctoral fellow-
ship to S.K.A., master fellowship to K.B.G., and to Dr. Lisa D.
Haigh at Imperial College London for assistance with HRMS.
1056−1059.
(22) Jung, Y. C.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org. Lett.
2003, 5, 2231−2234.
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M. Org. Lett. 2001, 3, 3313−3316.
(24) (a) Shockley, S. E.; Holder, J. C.; Stoltz, B. M. Org. Process Res.
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C.; Yang, G.; Gridnev, I. D.; Zhang, W. Org. Lett. 2015, 17, 2250−
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