Silicon-Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope, Enantioselectivity, and Mechanism

Article abstract of DOI:10.1002/anie.201915519

SuFEx reactions, in which an S?F moiety reacts with a silyl-protected phenol, have been developed as powerful click reactions. In the current paper we open up the potential of SuFEx reactions as enantioselective reactions, analyze the role of Si and outline the mechanism of this reaction. As a result, fast, high-yielding, “Si-free” and enantiospecific SuFEx reactions of sulfonimidoyl fluorides have been developed, and their mechanism shown, by both experimental and theoretical methods, to yield chiral products.

Full text of DOI:10.1002/anie.201915519

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Chemie
International Edition: DOI: 10.1002/anie.201915519
German Edition: DOI: 10.1002/ange.201915519
Click Chemistry
Silicon-Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope,
Enantioselectivity, and Mechanism
Dong-Dong Liang+, Dieuwertje E. Streefkerk+, Daan Jordaan, Jorden Wagemakers,
Jacob Baggerman, and Han Zuilhof*
ꢀ1
ꢀ
ꢀ
Abstract: SuFEx reactions, in which an S F moiety reacts with
favorable Si F bond (BDE = 135 kcalmol ) results in highly
a silyl-protected phenol, have been developed as powerful click
reactions. In the current paper we open up the potential of
SuFEx reactions as enantioselective reactions, analyze the role
of Si and outline the mechanism of this reaction. As a result,
fast, high-yielding, “Si-free” and enantiospecific SuFEx reac-
tions of sulfonimidoyl fluorides have been developed, and their
mechanism shown, by both experimental and theoretical
methods, to yield chiral products.
reliable SuFEx reactions under metal-free conditions.
As a result, research into the SuFEx reaction has surged in
the last 5 years.[9] To expand the range of useful SuFEx
connectors, several SuFEx hubs and fluorosulfuryl transfer
reagents have been developed, such as ethenesulfonyl fluo-
ride,[10] SO2F2,[7] SOF4,[11] fluorosulfuryl imidazolium salt,[12]
and others.[13] Hereby, a wide variety of SuFEx-able substrates
with excellent functional group tolerance can be obtained,
affording almost quantitative yields and/or polymers with
high molecular weights and narrow polydispersity. For
example, SuFEx has been used in modifications of peptides
and proteins,[14] syntheses of functional polymers,[15] macro-
cycles,[16] MOFs[17] and functionalized surfaces,[18] prepara-
tions of ionic liquids,[19] and late-stage drug functionaliza-
tion.[20] In addition, SuFEx products have been used as
important substrates and key intermediates in various reac-
tions.[21]
Although the SuFEx reaction has become a very practical
click reaction, three key features are as of yet unclear: its
mechanism, an evaluation of the necessity and influence of Si-
based protection of the phenols, and the potential of the
SuFEx reaction as source of chiral molecules. To address all
three facets in one study, we here report on the investigation
of the SuFEx reaction of sulfonimidoyl fluorides. Sulfonimi-
doyl fluorides[22] bear a stable chiral sulfur-centered moiety,
and form an ideal platform for mechanistic and enantiose-
lectivity studies, whereby SN1 versus SN2 and addition/
elimination pathways can be identified via the chirality of
Introduction
Click chemistry[1] has been widely used to construct
functional molecular skeletons concisely and efficiently.[2]
A
variety of new click reactions has been developed, such as
CuI-catalyzed azide–alkyne cycloadditions (CuAAC)[3] as
well as metal-free click reactions[4] such as thiol–ene,[5a] oxime
ligation,[5b] (thio-)Michael,[5c] Diels–Alder,[5d] strain-promoted
cycloadditions between azide–alkyne (SPAAC),[5e] cyclo-oc-
tyne-o-quinone (SPOCQ),[5f,g] and cyclopropene-o-quinone[5h]
reactions. More recently, the pioneering work of Gembus[6]
and Sharpless[7] revived the sulfur(VI) fluoride exchange
(SuFEx) reaction from “old-school chemistry” to the latest
ꢀ
generation of click reactions. In this reaction, the S F bond is
typically stable enough to be unreactive in a wide variety of
reaction conditions, but in the presence of silyl-protected
phenols, fluorosulfates readily react to form sulfates requiring
ꢀ
only small amounts of catalyst (base or HF2 ). In this process,
Si-protection is useful, as Si and F form the strongest single
ꢀ
bond in nature, allowing the rapid formation of SO2 O bonds
the substrates and products. Although some examples of
from stable silyl ether precursors.[8] This synergy of the click
reaction with the formation of the thermodynamically
reactions of unprotected phenols with SO2F2
and R-
[7,20,23]
SO2F[24] have been reported, formation of Si F covalent
bonds (as in Figure 1c) has generally been considered to be a,
or even: the, main driving force for the reaction in aprotic
solvents,[7] but its role has remained under-investigated. Such
studies might not only lead to mechanistic insight, but may
also prevent an extra silanization step in cases where the
SuFEx reaction might not need it. This therefore inspired us
to explore silicon-free SuFEx reactions. Herein, we thus
report our detailed studies on the silicon-free SuFEx chemis-
try of sulfonimidoyl fluorides, exploring the scope, kinetics
and reaction mechanism by experimental and theoretical
(wB97XD/6-311+G(d,p) density functional theory) studies
(Figure 1d).
ꢀ
[*] Dr. D.-D. Liang,[+] D. E. Streefkerk,[+] D. Jordaan, J. Wagemakers,
Dr. J. Baggerman, Prof. Dr. H. Zuilhof
Laboratory of Organic Chemistry, Wageningen University
Stippeneng 4, 6708WE Wageningen (The Netherlands)
E-mail: Han.Zuilhof@wur.nl
Prof. Dr. H. Zuilhof
School of Pharmaceutical Science and Technology, Tianjin University
92 Weijin Road, Tianjin (China)
and
Department of Chemical and Materials Engineering, Faculty of
Engineering, King Abdulaziz University
Jeddah (Saudi Arabia)
[+] These authors contributed equally to this work.
While many sulfur-fluoride reagents with different valen-
cy have been studied (Figure 1a), sulfonimidoyl fluorides
have rarely been studied at all, let alone as SuFEx reagents,
although they have already been labelled as useful connectors
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201915519.
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In the presence of 1 equivalent 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), fluoride 1 reacted smoothly with
a variety of phenols 2 and 3-pyridinol to form the product
sulfoximine in good to excellent yields under ambient
conditions. Unlike in the normal SuFEx reaction, DBU acted
both as a catalyst and an acid scavenger due to the absence of
a silane group to stabilize the leaving fluoride anions in the Si-
free SuFEx. Most of the reactions actually reached comple-
tion within 10 min, providing one product, the sulfoximine, in
almost quantitative NMR yield without optimization of the
reaction conditions. The reaction exhibited an excellent
functional group tolerance, as phenol derivatives containing
alkyl (2b,c), ether (2d,g), pyridinyl (2e), amino (2 f), amide
(2h), carboxyl (2i), halogen (2m–q,v), ester (2s), hydrox-
ymethyl (2t), boronic acid (2u) and cyano (2y) functional
groups were successfully used as substrates. Similar to the
normal SuFEx reaction, alkyl alcohols, anilines and amides,
which are weaker nucleophiles compared to phenolates
generated from deprotonations by DBU, did not react in Si-
free SuFEx either. Moreover, screening revealed the Si-free
reaction was not very sensitive to steric hindrance although
reactions took longer, as target products were obtained
successfully for sterically hindered phenols, bearing bulky
ortho substituents, such as 2-bromophenol (2p-o), 2-(tert-
butyl)phenol (2r-o) and mesitol (2c). Unsurprisingly, meta-
substituted phenol derivatives (2b-m, 2m-m, 2p-m,) were
found to be excellent substrates. Di-substituted phenol
derivatives resorcinol (2k) and bisphenol A (BPA) (2l) also
partook in the reaction, albeit with 2 equivalents of the
sulfonimidoyl fluoride 1. Unfortunately, the resulting diaste-
reomers (3k,l) could not be separated by flash column
chromatography (see SI). Substrates containing strong elec-
tron-withdrawing substituents in the ortho- or para-position,
such as formyl (2w), cyano (2y), trifluoromethyl (2z) or nitro
(2ac, 2ad) or bearing two large groups (such as 2,6-di-tert-
butyl, 2aa) yielded hydrolysis by-products at a loss of the
target SuFEx products (see SI) at varying degree, and only
provide the SuFEx product very slowly under rigorously dry
conditions.
To further demonstrate the scope of this reaction, several
natural phenolic derivatives were evaluated (Table 2). Euge-
nol (4a), vanillic acid (4b), raspberry ketone (4c), tyrosol
(4d) sesamol (4e), ferulic acid (4 f), and vic-thymol (4g),
salicyl aldehyde (4h), and vanillin (4i) all reacted smoothly
with fluoride 1 to form the corresponding sulfoximine in good
to excellent yields under ambient conditions.
After having established that the Si-free SuFEx reaction
proceeds smoothly and efficiently for a wide variety of phenol
substrates, we aimed for further insight, by studying other
catalysts and the reaction kinetics. Regarding the catalysts,
HF2 anion has been introduced as a superior rate-enhancing
agent.[29] Therefore we investigated the effects of this anion on
a range of reactions. When 1 was reacted with Si-protected
2b-p, then this quantitatively yielded product 3b-p at rt in 1 h
with one equivalent of catalyst. When using catalytic amounts
of HF2 anion (0.2 equiv), the same reaction reached com-
pletion, albeit at a much slower pace (30 h). When the
unprotected phenol was used with this catalyst (even with
1 equiv), then only trace amounts of product were observed.
Figure 1. a) Common fluoride substrates in SuFEx reaction; b) sulfox-
imines in anticancer drugs. c/d) Goal of present study: “Silicon-free”
SuFEx reactions.
from the start of recent SuFEx literature.[7] Despite this lack
of exploration, the SuFEx reactivity of sulfonimidoyl fluo-
rides has been shown to be comparable to sulfonyl fluorides,[7]
with further regulation possible by modification of substitu-
ents on the nitrogen atom, making them ideal tunable SuFEx
substrates. Further motive is provided by the usefulness of the
product, as the resulting sulfoximine group, and structural
variations thereof, can express significant medicinal activi-
ty.[25] For example, buthionine sulfoximine is a potential
adjunct with chemotherapy in the treatment of metastatic
melanoma,[26] while atuveciclib is the first potent and highly
selective PTEFb/CDK9 inhibitor to enter clinical trials for the
treatment of cancer (Figure 1b).[27]
As first part of our studies, the comparison between the
traditional and Si-free SuFEx reaction was investigated. By
mixing Si-protected (short for: tert-butyl-dimethylsilyl
(TBDMS)-protected) phenol with unprotected p-cresol and
performing the SuFEx reaction with N-benzoyl-4-methylben-
zenesulfonimidoyl fluoride 1 (ratios: 10:10:1, to obtain
pseudo first-order conditions), the relative reactivity of the
respective phenol derivative (free or Si-protected) can be
observed from the composition of the final product mixture.
This yielded a ratio for Ph-O-Si/CH3-Ph-OH of 5:95. The
analogous experiment with Si-protected cresol and unpro-
tected phenol yielded a ratio for CH3-Ph-O-Si/Ph-OH of 9:91
(ratios obtained from 1H NMR of products upon completion
of the reaction, typically < 2 min). This shows that a roughly
10:1 ratio was found for the reaction rate of unprotected
phenols and Si-protected phenols (see the Supporting In-
formation (SI) for details). During this reaction time,
exchange of the TBDMS-group from the cresol to the phenol
ꢀ
or vice versa was negligible. While the formation of the Si F
covalent bond can still be of relevance, it cannot be
characterized as the driving force behind the SuFEx reaction.
Since the unprotected phenol derivative was clearly more
reactive, we set out to outline the scope of Si-free SuFEx
reactions of 1, prepared according to literature,[28] via
a systematic variation of the nature of the phenol. The results
are displayed in Table 1.
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Table 1: Scope of Si-free SuFEx reactions of sulfonimidoyl fluoride 1 with phenolic derivatives.[a]
[a] Conversion was determined by 1H NMR measurements. Isolated yield in brackets. Reaction conditions for 1H NMR conversion: 1 (0.05 mmol),
phenolic derivative 2 (1.05 equiv) and DBU (1.0 equiv) in CD3CN (0.55 mL), rt. For isolated yield: Fluoride 1 (0.5 mmol), phenolic derivatives 2
(0.5 mmol), DBU (1.5 mmol) in anhydrous CH3CN (1 mL), rt. [b] Hydrolysis by-product was formed (see SI). [c] 2 equiv of DBU were used. [d] 2 equiv
of 1 were used.
The likely role the HF2 anion plays in these reactions is
clarified if it is added to Si-protected 2b-p in the absence of
any 1. Within 10 min, full deprotection of the TBDMS group
is then achieved. Therefore, when used in a standard SuFEx
reaction, HF2 anion might act as follows: it effects the rapid
deprotection of Si-protected phenols. In aprotic solvents, this
then yields a highly reactive phenolate, which—upon reac-
tion—frees up a fluoride anion, allowing the reformation of
HF2 anion, or fluoride by itself might affect the deprotection
of a subsequent Si-protected phenol. The high rate of both the
deprotection and of the SuFEx reaction of the phenolate
would then allow the use of only small amounts of catalysts, as
has been observed experimentally. In line with this, for
unprotected phenols HF2ꢀ is a poor catalyst: since fluoride is
only a poor base, it will—unlike DBU—not induce the
formation of the reactive phenolates; as a result, nothing
happens.
As a start of our kinetics study, we compared the reaction
rate of the Si-free SuFEx reaction of the sterically hindered 2-
(tert-butyl)phenol (2r-o,) with a traditional SuFEx reaction
with the Si-protected 2-(tert-butyl)phenol analogue 5. At
room temperature, both these reactions were finished in
under two minutes; therefore the kinetics were studied in
CD3CN using low-temperature NMR. Under pseudo first-
order conditions, the second-order rate constant found for 2r-
o at ꢀ308C was (3.0 ꢁ 0.1) ꢀ 10ꢀ3 mꢀ1 sꢀ1. For 5 the kinetics
were clearly slower, but interestingly showed an activation
phase, with a clear S-shape appearance of the product over
time (see SI). To test whether this could be due to the
appearance of unprotected phenol 2r-o upon a rate-deter-
mining desilylation of 5, we studied this desilylation under
these reaction conditions (ꢀ308C) with equimolar concen-
tration of 5 and (CH3)4NF (both 0.12m). This yielded a full
desilylation within 2 min, suggesting that for silylated phenols
the reaction is initiated by freeing up some Fꢀ anion, which
can deprotect a Si-protected phenol, which can subsequently
react and free up another Fꢀ, etc. Here DBU can play
a double role, as it has been reported to catalyze the
desilylation,[30] while as a base, of course, it also increases
the nucleophilicity of the phenol.
Further mechanism investigations were made possible by
utilizing the chirality of sulfur atom in the sulfonimidoyl
fluoride 1 and its SuFEx products. Previous mechanism-
oriented reports have typically focused on substitution
reactions on disulfides, yielding addition–elimination and
SN2 as the most widely accepted mechanisms, with the
detailed mechanism being sensitive to the strain,[31a] counter
cations,[31b] leaving groups,[31c] substituents on sulfur atom,[31d]
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Table 2: Scope of Si-free SuFEx reactions of sulfonimidoyl fluoride 1 with
Table 3: Enantioselective silicon-free SuFEx reactions.[a]
naturally occurring phenols.[a]
Enantiomer[b]
Phenol
ee[c]
enantiomer-1
2b-p
2ac
6
73% (95[d])
<2%
>99%
7
>99%
enantiomer-2
2b-p
2ac
6
71% (95[d])
<2%
>99%
7
>99%
[a] Reaction conditions: enantiomer-1/enantiomer-2 (1 mL, 3.6 mm in
CH3CN), phenolic derivative (1 equiv), DBU (1 equiv), rt. When
phenolate 6 or 7 was adopted as the substrate, DBU was not added.
[b] enantiomer-1 and enantiomer-2 refer to two enantiomers with
retention times of 16.8 and 18.8 min with chiral HPLC, respectively. [c] ee
[a] Conversion was determined by 1H NMR measurements. Reaction
conditions for 1H NMR yield: 1 (0.05 mmol) phenolic derivative 2
(1.05 equiv) and DBU (1.0 equiv) in CD3CN (0.55 mL), rt. [b] Hydrolysis
by-product was formed (see SI). [c] 2 equiv of DBU were used.
determined using chiral HPLC and calculated by
majority ꢀ minority
ee=
ꢃ 100%, [d] 10 equiv 2b-p used.
majority þ minority
provided important mechanistic information, as it shows that
SuFEx proceeds through SN2 or addition-elimination chan-
nels rather than via an SN1 mechanism when a good
nucleophile was used. The racemization or SN1 mechanism
was a possible reason of low stereoselectivity when a poor
nucleophile (4-methyl-2-nitrophenol) was used. If the SN2 or
addition-elimination is a competitive reaction with the
racemization, we reasoned that the racemization could be
inhibited when a large excess of a good nucleophile (10 equiv
p-cresol) was used. In fact, the experimental results showed
that under such conditions the %ee was significantly im-
proved (95% ee). However, the key finding was avoiding
DBU altogether, and using sodium phenolate 6 and sodium 4-
methyl-2-nitrophenolate 7 as nucleophiles. In this case
stereospecific products were obtained, and no racemization
of the reactants was observed, even for 7, which takes
overnight to get to 80% conversion. This further demon-
strated that the silicon-free SuFEx reaction mechanism
proceeds via an SN2 or addition-elimination mechanism.
To further distinguish concerted SN2 and addition-elimi-
nation reaction paths, quantum chemical calculations were
performed at the wb97xd/6-311+G(d,p) level of theory, using
the SMD solvent model to represent CH3CN as implemented
in Gaussian 16.[33] We computed the potential energy surfaces
(PES) for the SuFEx reaction between fluoride 1 and
phenolate 6 (Scheme 1; to slightly simplify the calculation,
we replaced the 4-methylbenzenesulfonimidoyl with a benze-
nesulfonimidoyl group). Because of the strong S-F covalent
bond ( ꢂ 90 kcalmolꢀ1), fluoride 1 is very stable, and the
leaving of fluoride is generally considered to be one of the
rate-limiting steps. However, for the reaction under study, this
does not seem to be the case. Compound 1 undergoes the
Figure 2. Possible mechanisms of SuFEx reactions.
nucleophiles,[31e] solvents,[31e–g] and so on (see for an over-
view[32]). Analogously, we considered as the three most likely
mechanisms those summarized in Figure 2.
If one enantiomer of 1 is used as the substrate in SuFEx
reactions, the SN1 reaction pathway will provide the race-
mized products. Conversely, stereospecific products will be
obtained through the SN2 or addition-elimination pathway.
Firstly, enantiomers of sulfonimidoyl fluoride 1 were shown to
be very stable in solution without DBU, but readily racemize
when DBU was present. The rate of this racemization
reaction, with excess DBU under pseudo first-order condi-
tions, is (1.9 ꢁ 0.1) ꢀ 10ꢀ3 mꢀ1 sꢀ1 at ꢀ308C, showing its facile
occurrence and competitive character (see SI). Since this
would reduce the usefulness of the reaction, further studies
were performed.
To this aim, a good and a poor nucleophile—p-cresol and
4-methyl-2-nitrophenol, respectively—were adopted in Su-
FEx reactions. With the good nucleophile a good stereose-
lectivity (ca. 70% ee) was achieved, whereas with the poor
nucleophile only < 2% ee was obtained (Table 3). This
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Scheme 1. Potential energy surface for SuFEx reaction with phenolate.
nucleophilic attack by 6 via TS1, with a rate-limiting enthalpic Conclusion
barrier of only 2.74 kcalmolꢀ1. This confirms the experimen-
tally observed high reaction rate. However, in TS1 the S-F
bond was still largely unchanged (length increase from 1.64 to
1.72 ꢁ; Wiberg bond order decrease from 0.520 to 0.496),
likely due to a relatively early TS (r(O···S) = 2.33 ꢁ; B.O. =
0.151).
The next stationary point, however, was not the set of
products, but a five-coordinated sulfur intermediate, INT1,
which was found to be lower in energy than the reactant pair.
This intermediate is characterized by an r(O···S) = 1.78 ꢁ,
and a r(S···F) = 1.93 ꢁ, indicating bonding of the O to S
(B.O. = 0.544), but also no loss of F yet (B.O. = 0.315).
In conclusion, we have demonstrated that Si-free SuFEx
reactions with phenolate anions can be readily performed in
a stereoselective manner with excellent functional group
tolerance and good to quantitative yields in minutes at room
temperature. The Si-free SuFEx is faster than the traditional
one, and detailed kinetics of the latter might point to a more
complex reaction scheme there. A combination of these
experiments with theoretical calculations show that the Si-
free SuFEx reaction is a fast, bimolecular, enantiospecific and
slightly exothermic click reaction, making it amenable for
a wide range of substrates. These studies contribute to
a clearer understanding and continuing development of
SuFEx reactions, as well as providing a practical approach
for the construction of optically pure sulfoximines.
=
Interestingly, the S O bond does not elongate significantly
during the reaction (1.44–1.45 ꢁ, with the bond length of
a typical S O bond = 1.64 ꢁ[34]), nor does the charge on this O
ꢀ
atom vary a lot during the reaction.
This intermediate readily loses fluoride via TS2 (DH° of
this step is only 0.53 kcalmolꢀ1), giving rise to the products.
Acknowledgements
ꢀ
Activation of S F loss by the base has been one of the most
widely accepted mechanism models to date.[6,11,35] This might
be the case for much poorer nucleophiles, including the Si-
protected phenols, but such activation is apparently not
needed for phenolate SuFEx reactions. In summary, these
DFT calculations thus suggest that SuFEx with a phenolate
nucleophile attacking a sulfonimidoyl fluoride takes places
with bimolecular kinetics via an addition–elimination mech-
anism, although a concerted SN2 reaction under experimental
conditions cannot be excluded given the very low barrier
observed for loss of Fꢀ.
The authors thanks Tjerk Sminia for synthetic support and
Barend van Lagen for technical support. Financial support of
the National Science Foundation of China (grant #21871208)
and Wageningen University is greatly acknowledged.
Conflict of interest
The authors declare no conflict of interest.
This SuFEx reaction has a reaction enthalpy of about
ꢀ5 kcalmolꢀ1, which is nice to drive a reaction quietly to
completion, and better than many other click reactions that
are simply too exothermic.[36]
Keywords: enantioselectivity · kinetics · reaction mechanisms ·
SuFEx
We also aimed to characterize the nucleophilic attack by
DBU. However, no TS could be found, and the energy simply
increases upon decreasing the r(N···S) distance (to > 19 kcal
molꢀ1 for r(N···S) = 1.7 ꢁ. Apparently, the steric bulk of DBU
makes this a really non-nucleophilic base in this reaction.
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Manuscript received: December 5, 2019
Revised manuscript received: January 30, 2020
Version of record online: && &&
,
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Research Articles
Click Chemistry
D.-D. Liang, D. E. Streefkerk, D. Jordaan,
J. Wagemakers, J. Baggerman,
H. Zuilhof*
&&&& — &&&&
Silicon-Free SuFEx Reactions of
Sulfonimidoyl Fluorides: Scope,
Enantioselectivity, and Mechanism
The SuFEx reaction is shown to proceed
quantitatively and fast with wide scope
without silyl protection of the phenol.
Mechanistic studies reveal a stereospecif-
ic bimolecular nucleophilic substitution.
Angew. Chem. Int. Ed. 2020, 59, 2 – 9
ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!