Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI) Fluoride Exchange Connections of Diverse Modules Launched From An SOF4 Hub

Article abstract of DOI:10.1002/anie.201611048

Sulfur(VI) fluoride exchange (SuFEx) is a new family of click chemistry based transformations that enable the synthesis of covalently linked modules via S^VI hubs. Here we report thionyl tetrafluoride (SOF₄) as the first multidimensional SuFEx connector. SOF₄ sits between the commercially mass-produced gases SF₆ and SO₂F₂, and like them, is readily synthesized on scale. Under SuFEx catalysis conditions, SOF₄ reliably seeks out primary amino groups [R-NH₂] and becomes permanently anchored via a tetrahedral iminosulfur(VI) link: R?N=(O=)S(F)₂. The pendant, prochiral difluoride groups R?N=(O=)SF₂, in turn, offer two further SuFExable handles, which can be sequentially exchanged to create 3-dimensional covalent departure vectors from the tetrahedral sulfur(VI) hub.

Full text of DOI:10.1002/anie.201611048

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Communications
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International Edition: DOI: 10.1002/anie.201611048
German Edition: DOI: 10.1002/ange.201611048
Click Chemistry Very Important Paper
Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI)
Fluoride Exchange Connections of Diverse Modules Launched From
An SOF4 Hub
Suhua Li, Peng Wu, John E. Moses, and K. Barry Sharpless*
give SVI N bonds. While the mechanistic details are yet to be
fully elucidated, these transactions are made possible by
a special co-action between the hydrogen-bonding environ-
ment of fluoride ion, and the kinetic and thermodynamic
properties of the bonds to sulfur(VI) and silicon centers. Key
to SuFEx activation is the requirement for fluoride to transit
from a strong covalent bond to a leaving group—a process
mediated by tertiary amine derived catalysts[8] and thought to
involve the bifluoride ion and related species.[7,9–13]
ꢀ
Abstract: Sulfur(VI) fluoride exchange (SuFEx) is a new
family of click chemistry based transformations that enable the
synthesis of covalently linked modules via SVI hubs. Here we
report thionyl tetrafluoride (SOF4) as the first multidimen-
sional SuFEx connector. SOF4 sits between the commercially
mass-produced gases SF6 and SO2F2, and like them, is readily
synthesized on scale. Under SuFEx catalysis conditions, SOF4
reliably seeks out primary amino groups [R-NH2] and
becomes permanently anchored via a tetrahedral iminosulfur-
ꢀ =
=
(VI) link: R N (O )S(F)2. The pendant, prochiral difluoride
Early in the development of SuFEx, we identified sulfuryl
fluoride (SO2F2)[7,14] as a sulfur(VI) hub for creating diaryl
sulfate links between molecules. Under SuFEx conditions, the
ꢀ =
=
groups R N (O )SF2, in turn, offer two further SuFExable
handles, which can be sequentially exchanged to create 3-
dimensional covalent departure vectors from the tetrahedral
sulfur(VI) hub.
latent reactivity of the otherwise stable SVI F bond is roused
ꢀ
to react with SuFExable substrates.[7,15]
While SuFEx is still an emerging technology it has already
found diverse applications including, for example: the syn-
thesis of tosylates[9] and sulfonyl azides;[10] application in
polymer chemistry[11] and post-polymerization modifica-
tion;[12,13] Suzuki coupling of aryl- and heteroaryl-fluorosul-
fates with boronic acids.[15] Of particular significance, how-
ever, is the potential for SuFEx in biochemical applications:
growing evidence supports the notion that proteins provide
molecular and dynamic electrostatic field environments that
sulfur(VI) fluoride linkages are adept at reading, and reacting
to.[16]
In a recent study with the Kelly group, we demonstrated
fluorosulfate-based probes as remarkable substrates capable
of selectively capturing protein side-chain groups, especially
the hydroxy group on tyrosine, in live human cells.[16a]
Seeking to expand the range of useful SuFEx connectors,
we considered other sulfur(VI) fluoride gases, including: SF6
(sulfur hexafluoride) and SOF4 (thionyl tetrafluoride) (Fig-
ure 1A). While SF6 is loaded with the most SuFEx potential,
it is also famously inert. SOF4, on the other hand, is a SVI hub
T
he foundation of click chemistry as a framework for
creating functional molecular assemblies, was inspired by
examination of the central metabolism of life—a process
orchestrated by functional oligomers of a few dozen reactive
modules, all stitched together via heteroatom links and
reversible condensation processes.[1] Seeking to match the
efficiency of Natureꢀs near perfect synthesis machinery,
a stringent criterion was defined for a reaction to earn click
chemistry status.[1]
The discovery of the CuI-catalyzed azide–alkyne cyclo-
addition reaction (CuAAC) in 2002[2] had a profound influ-
ence on the evolution of click chemistry, demonstrating
immense versatility and application in fields as diverse as
materials science,[3] bioconjugation,[4] and drug discovery.[5,6]
In 2014, we reported a new embodiment of ideal click
chemistry: SuFEx (sulfur(VI) fluoride exchange)—a technol-
ogy for creating molecular connections with absolute reli-
ability and unprecedented efficiency through a sulfur(VI)
ꢀ
hub.[7] SuFEx reliably allows the flawless substitution of SVI
F
with aryl silyl ethers to give SVI O bonds, and with amines to
with a functional balance between reactivity and available S
ꢀ
ꢀ
F functionality.[17]
As with most of click chemistry, many of the essential
features of SOF4 were discovered long ago: first reported in
1902 by Moissan and Lebeau,[18] SOF4 is a trigonal bipyrami-
dal colorless gas with a boiling point of ꢀ498C (Fig-
ure 1A).[19,20] An improved synthesis of SOF4 (for labs with
no access to F2) was reported in 1960 by Smith and Engelhardt
at CRD DuPont. They found that in the presence of a catalytic
amount of NO2, the oxidation of SF4 by O2 gave enhanced
yields of SOF4 gas.[21]
[*] S. Li, J. E. Moses, K. B. Sharpless
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: sharples@scripps.edu
Homepage: http://www.scripps.edu/sharpless
P. Wu
Department of Chemical Physiology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
J. E. Moses
Despite being known for more than one hundred years,
the reactions of SOF4 have scarcely been studied, let alone
exploited. Cramer and Coffman (also at CRD DuPont)
reported the first detailed study of its chemistry in 1961. They
School of Chemistry, University of Nottingham
Nottingham, NG7 2RD (UK)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611048.
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or phenols (as their aryl silyl ethers under SuFEx catalysis[7]).
The final products, for up to three steps, arise in excellent
overall yield,[24] thereby allowing controlled projections to be
deliberately installed along 3 of the 4 tetrahedral axes
departing the SVI central hub.
Given the fidelity and scope of these three serial trans-
formations, we identify thionyl tetrafluoride (SOF4) as
another good connective hub for SuFEx click chemistry.
Our experience with SO2F2, a sister gas to SOF4 (Fig-
ure 1A), taught us about the benefits that tertiary amine
additives (e.g. TEA, DIPEA, DBU) can have on the speed
and yield of the desired reaction.[7] Similarly for SOF4, the
presence of a tertiary amine base significantly improved the
outcome of these transformations: exposing a solution of
primary amine (1) to 2 mol equiv of Et3N or DIPEA in
CH3CN, to SOF4 gas, resulted in excellent yields of the
tetrahedral iminosulfur oxydifluoride products (2) (Figure 2).
ꢀ
The selective decoration of NH2 moieties in biologically
significant building blocks was also readily accomplished,
=
giving the SuFExable steroid-N SOF2 cases (2-21 and 2-22)
=
and also the nucleotide-N SOF2 cases (2-23 and 2-24) all in
good yields. With the a-amino amide 1-25, intramolecular
displacement of the remaining fluoride, activated by amide
hydrogen bonding, gave the cyclic sulfamide 2-25 in moderate
yield (Figure 2). Generating the reactive amine in situ from
the corresponding azide under Staudinger conditions, did not
adversely affect the yield of the iminosulfur oxydifluoride
products (2-9, 2-22, 2-23).
Figure 1. A) Structure and boiling point of SF6, SOF4 and SO2F2.
B) Early examples of fluoride substitution reactions of SOF4. C) Com-
paring the trajectories of the click connections derived from: CuAAC-
triazole, SO2F2 and SOF4.
Noteworthy is the observed chemoselective preference of
SOF4 for amines vs. other functional groups, which in the case
of catechol (1-16!2-16; Figure 2) contrasts with the reac-
tivity of the SO2F2 sister gas.[7,10] We were curious about the
outcomes of reacting aminophenols with both gases (SOF4
and SO2F2) simultaneously. When acetonitrile solutions of the
aminophenols 1-26–1-28 were exposed to a 1:1 ratio of SOF4:
SO2F2 in the presence of Et3N (3 equiv), the corresponding
SuFEx products 2-26–2-28 were formed in excellent yields,
respectively. This outcome is explained by the preferential
reaction pairing of SO2F2 with phenol and SOF4 with amine,
together with the decreasing opportunities for cross-over
reaction for each gas as the reaction proceeds and, at least in
found that SOF4 reacts with primary amines and anilines to
form the corresponding tetrahedral iminosulfur oxydifluoride
[22]
ꢀ =
(R N SOF2) products in moderate yields (Figure 1B).
Seppelt and Sundermeyer later reported (1971) an early
manifestation of silicon-mediated SuFEx: [(Me)3Si]3N upon
reaction with SOF4 gave the TMS-iminosulfur oxydifluoride
ꢀ =
((Me3Si)3N + SOF4!Me3Si N SOF2) in 85% yield (Fig-
ure 1B).[23] In the 50 years following these seminal reports, we
locate no practical applications of SOF4—perhaps not sur-
prising before SuFEx catalysis.
The opportunity for creating connections through the two
ꢀ
=
SuFExable S F handles of the SOF4-derived tetrahedral
the case of the F2OS N-Ar-OH, the enhanced acidity of the
iminosulfur oxydifluoride products did not escape our atten-
tion. Until now, the click “linkages” created via CuAAC-
derived triazoles and the SuFEx connective gas SO2F2, are
confined to trajectories in a plane. SOF4 is different; it is the
first polyvalent SuFEx connective gas that opens the door to
another dimension and trajectory (Figure 1C). This is impor-
tant because from biology to synthetic materials applications,
having access to the 3-dimensional world adds value to the
existing toolbox of click connections.
phenol group (Figure 3).
ꢀ =
Cramer and Coffman surveyed the reactivity of Ph N
SOF2 with a selection of amines and found that weakly basic
N-methylaniline gave no reaction. On the other hand, tert-
butylamine could substitute both fluorides, while piperidine
could substitute only one of them. The difluoride could also
react with sodium ethoxide to form the ethyl phenylsulfa-
mate.[22]
With our extensive range of iminosulfur oxydifluorides
=
Herein, we report our detailed studies on the SuFEx
chemistry of SOF4 and its iminosulfur oxydifluoride products.
We discovered that both the rates and yields for SOF4
transformations are much improved by the presence of
tertiary amine bases (e.g. Et3N and DIPEA). The initial
[F2SO( NR)], we revisited Cramer and Coffmanꢀs early work
with a wider selection of amine nucleophiles (Figure 4). The
reaction with secondary amines proceeded smoothly: when
2 mol equiv of the given amine were added to a solution of the
iminosulfur oxydifluorides (2) in acetonitrile at room temper-
ature, the mono-substituted products (3) were formed in
excellent yields, leaving a single unreacted fluoride in place.
These monosubstitution processes were near quantitative and
ꢀ
iminosulfur oxydifluoride products have two SuFExable S F
handles, and we demonstrate that these two fluorides can be
substituted in a serial manner by secondary alkyl amines and/
2
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Figure 2. The reactions of primary amines with SOF4 in the presence of Et3N. [a] The yield in parenthesis is for the reaction without Et3N. [b] The
amine was generated in situ by reducing the azide under Staudinger conditions with PMe3 and 1 to 3 equiv of H2O, see the Supporting
Information.
In the spirit of click chemistry (i.e. the goal of creating
stable and useful intermolecular linkages), we next inves-
tigated the reaction of a selection of iminosulfur oxydifluor-
ides (2) with aryl silyl ethers (5) under DBU or BEMP
activation (Figure 6). With DBU (10 mol%) and 1 mol equiv
of aryl silyl ether 5-1, the SuFEx reaction of iminosulfur
oxydifluoride 2-4 reached completion within just 5 minutes,
leading to the formation of the sulfurofluoridoimidate
product 6-1 in 96% yield. Lowering the catalyst loading of
DBU (2 mol%) required longer reaction times (1 h), but still
allowed gram scale SuFEx coupling of 2-5 with aryl silyl ether
5-2 in 93% yield (6-2). With BEMP (5 mol%) as the catalyst,
even the complex reactants: AZT derivative 2-23 and estrone
5-3 were readily connected to give 6-3 in 79% yield.
ꢀ
The exchange of just one S F bond under typical SuFEx
ꢀ
conditions revealed that the reactivity of the remaining S F
bond of the sulfurofluoridoimidate is significantly attenuated
Figure 3. The selectivity of SO2F2 and SOF4 towards aromatic hydroxy
and amino groups.
ꢀ
relative to the S F bonds of the iminosulfur oxydifluoride.
This is a welcome feature, particularly for instances when
sequential SuFEx based modification are desirable. To further
the products did not require purification.[25] Reactions of
iminosulfur oxydifluoride (2-4) with a selection of amino
acids proceeded equally well, albeit with concomitant hydro-
lytic loss of the second fluoride, giving the unsymmetrical
sulfamide products (4-1–4-3) in excellent yields (Figure 5).
ꢀ
calibrate the relative reactivity profiles of the various S F
environments, we performed a series of competition experi-
ꢀ
ments on substrates presenting two or more types of S F
functionality (Figure 7). When the para-disubstituted ben-
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Figure 6. Connecting amines with phenols.
Figure 4. The reaction of iminosulfur oxydifluorides with secondary
amines. [a] 1.2 equiv of proline methyl ester and 2 equiv of Et3N in
MeCN. [b] 1 equiv of amoxapine and 2 equiv of Et3N in DMSO.
Figure 7. Comparison of the reactivity of iminosulfur oxydifluoride with
sulfonyl fluoride and fluorosulfate.
Figure 5. The reaction of iminosulfur oxydifluorides with amino acids.
zene derivative 2-3, comprising both aryl sulfonyl fluoride
and related work,[7,15] we tentatively suggest the order of
ꢀ
ꢀ
ꢀ
(Ar SO2F) and aryl iminosulfur oxydifluoride groups (Ar
reactivity of SO2F2 and SOF4 derived S F bonds towards
=
ꢀ =
ꢀ
N SOF2), was treated with one equivalent of the aryl silyl
SuFEx reactions with aryl silyl ethers: N SOF2 > SO2F >
ꢀ
ꢀ =
ether 5-1 and DBU 10 mol% in acetonitrile, the SuFEx
reaction occurred exclusively at the iminosulfur oxydifluoride
center to give the corresponding product 6-5 in 95% yield.
The sulfonyl fluoride ( SO2F) group remained untouched
(Figure 7). Similarly, when the SuFEx reaction was performed
OSO2F > N S(O)(OAr)F.
From our earlier SuFEx studies with fluorosulfates
ꢀ
( OSO2F), we found that 2-tert-butylimino-2-diethylamino-
1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) was
the superior base for activating challenging substrates for
exchange.[7] BEMP was therefore the logical choice for
ꢀ
ꢀ
with the analogous fluorosulfate ( OSO2F) substrate 2-26
activating the remaining SVI F bond of the corresponding
ꢀ
under modified conditions (5 mol% DBU), the exchange
occurred exclusively at the iminosulfur oxydifluoride center
to give the corresponding product 6-6 in 94% yield. When the
sulfurofluoridoimidate 6-6 itself was exposed to the aryl silyl
ether (5-5) in the presence of DBU (10 mol%) over 16 h,
SuFEx catalysis achieved linkage exchange at the fluorosul-
fate group, yielding the mixed sulfate–sulfurofluoridoimidate
linked product 6-7 (Figure 7). From these few experiments,
sulfurofluoridoimidates (6). Indeed, the treatment of 6-2 with
the aryl silyl ether 5-1 in the presence of 10 mol% BEMP
(CH3CN, r.t., 1 h), gave the corresponding sulfurimidate 7-
1 in almost quantitative yield. BEMP proved equally efficient
at lower concentrations (5 mol%), and even two phenol
linkages could be installed in one pot without compromising
yield (7-2). Interestingly, secondary amines alone react
4
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sulfuryl derivatives in excellent yields (Figure 9). Of partic-
ular significance: the imino cyclic catecholate 9-1 is readily
ring-opened by piperidine and Boc- piperazine to give the
corresponding amino sulfonimidate products 10-1 and 10-2 in
excellent yields.
In summary, SOF4 gas is the first multidimensional
connector that reacts efficiently with primary amines to
form reactive iminosulfur oxydifluoride derivatives. Tuning
the SuFEx catalyst conditions allows the sequential activation
ꢀ
and exchange of these SuFExable S F bonds, which project
outward along roughly tetrahedral vectors from the central
SVI hub. This study complements our earlier work with SO2F2,
by expanding the SuFEx universe of available connectors.
The additional SuFExable SVI F bonds enrich the scope of
ꢀ
this valuable click chemistry linker by allowing the extra
departure links into the 3-dimensional tetrahedral world.
Acknowledgements
We thank the NIH (P50 GM103368, R01 GM117145) for
financial support for this project. S.L. was partially supported
by the Skaggs Institute for Chemical Biology.
Figure 8. The connections of primary amines with two phenols or one
Conflict of interest
phenol and one secondary amine.
The authors declare no conflict of interest.
directly with 6-2, producing 7-3, 7-4 in excellent yields
(Figure 8).
Keywords: amines · click chemistry · phenols · SuFEx reaction ·
Another manifestation of the 3rd dimension of SuFEx
plugin reactions from SOF4-derived hubs is the direct reaction
of phenyliminosulfur oxydifluorides (2–4) with TMS-pro-
tected catechols (Figure 9). The entrained inter- and intra-
molecular SuFEx reactions proceeded smoothly with DBU
(5 mol%) to form the four (9-1–9-4) iminooxy cyclic catechol
thionyl tetrafluoride
[1] a) K. B. Sharpless, H. C. Kolb, Book of Abstracts, 217th ACS
National Meeting, Anaheim, CA, March 21 – 25 1999, ORGA-
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[2] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
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Polym. Sci. Part A 2007, 45, 5182; c) D. D. Dꢁaz, S. Punna, P.
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Finn, J. Polym. Sci. Part A 2004, 42, 4392; d) P. Wu, A. K.
Feldman, A. K. Nugent, C. J. Hawker, A. Scheel, B. Voit, J.
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Int. Ed. 2014, 53, 9430; Angew. Chem. 2014, 126, 9584.
Figure 9. The reaction of iminosulfur oxydifluorides with catechols and
the activity of the product towards amines.
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[8] The catalysis is exceedingly facile.
[9] V. Gembus, F. Marsais, V. Levacher, Synlett 2008, 1463.
[10] A. S. Barrow, J. E. Moses, Synlett 2016, 1840.
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[16] a) Notable for its highly selective in vivo SuFEx result, the lipid
binding protein CRAPB2, in human MC7 breast cancer cells was
adducted at Tyr134 via a specifically catalyzed SuFEx reaction
with a small biarylfluorosulfate molecule. Moreover, this capture
event on Tyr134, was also shown to suppress the transcription of
the expected, rar-linked, downstream proteins, see: W. Chen, J.
Dong, L. Plate, D. E. Mortenson, G. J. Brighty, S. Li, Y. Liu, A.
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[24] Including the initial anchoring step, introducing the imido ligand
and leaving two fluorides.
[25] Although they are all stable to silica gel chromatography and
TLC analysis.
Manuscript received: November 11, 2016
Final Article published: && &&, &&&&
6
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Communications
Click Chemistry
Multidimensional clicking: SOF4 gas is
reported as the first multidimensional
sulfur(VI) hub for SuFEx click chemistry.
Reliably seeking out primary amino
groups, the trigonal bipyramidal SOF4 (A)
becomes permanently anchored via a tet-
rahedral iminosulfur(VI) (B) link (see
S. Li, P. Wu, J. E. Moses,
K. B. Sharpless*
&&&& — &&&&
Multidimensional SuFEx Click Chemistry:
Sequential Sulfur(VI) Fluoride Exchange
Connections of Diverse Modules
Launched From An SOF4 Hub
ꢀ =
scheme). The difluoride groups in R N
=
(O )SF2, in turn, offer two further
ꢀ
SuFExable and prochiral S F bonds,
which can be sequentially exchanged to
project 3-dimensional covalent vectors.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!