Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides

Article abstract of DOI:10.1021/acs.orglett.7b03950

The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C-H functionalization protocol.

Full text of DOI:10.1021/acs.orglett.7b03950

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis
of Sulfur(VI) Fluorides
Hua Zhou,† Paramita Mukherjee,‡ Rongqiang Liu,† Edelweiss Evrard,§ Dianpeng Wang,†
John M. Humphrey,‡ Todd W. Butler,‡ Lise R. Hoth,‡ Jeffrey B. Sperry,‡ Sylvie K. Sakata,∥
Christopher J. Helal,‡ and Christopher W. am Ende*,‡
†BioDuro, No. 233 North FuTe Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China
‡Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
§Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States
∥Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: The design, synthesis, and application of [4-
(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-
stable, crystalline reagent for the synthesis of sulfur(VI)
fluorides, is described. The utility of AISF is demonstrated in
the synthesis of a diverse array of aryl fluorosulfates and
sulfamoyl fluorides under mild conditions. Additionally, a
single-step preparation of AISF was developed that installed the
bis(fluorosulfonyl)imide group on acetanilide utilizing an
oxidative C−H functionalization protocol.
luorosulfates have been utilized in a myriad of applications,
1
2
Fextending from chemical biology to polymer chemistry.
The seminal report by Sharpless and co-workers which
describes the principles of sulfur(VI) fluoride exchange
(SuFEx) chemistry extols the virtues of the sulfur(VI) hub
and has established a foundation for numerous research
endeavors, further demonstrating the utility of fluorosulfates.2a
For example, a clickable aryl fluorosulfate chemical biology
probe was shown to selectively modify a conserved tyrosine
residue of the intracellular lipid binding protein (iLBP)
family.1c In cross-coupling applications, the aryl fluorosulfate
is an effective electrophile in a variety of transition-metal-
catalyzed transformations including Negishi,3 Suzuki,4 Sonoga-
shira,4c,5 Stille,3,6 Buchwald−Hartwig amination,7 and carbon-
ylation8 chemistries. Recently, the Sanford laboratory devel-
oped a deoxyfluorination procedure that utilizes the inter-
mediacy of a fluorosulfate to assemble aryl fluorides from
phenols.9 In addition, the corresponding nitrogen variant, the
sulfamoyl fluoride, is a particularly stable, yet effective, synthetic
precursor to substituted sulfamides.2a
Figure 1. (A) Synthesis of fluorosulfates and sulfamoyl fluorides using
sulfuryl fluoride gas. (B) Design and application of AISF, a solid
reagent for the synthesis sulfur(VI) fluorides.
The current state-of-the-art method to synthesize fluoro-
sulfates and sulfamoyl fluorides relies on the use of sulfuryl
fluoride gas (Figure 1A).10 However, the additional safety
precautions and specialized equipment required when working
with a toxic gas have impeded broad adoption of this reagent.
Alternatively, the use of 1,1′-sulfonyldiimidazole (SDI) as a
precursor to sulfuryl fluoride gas was recently reported.11 This
protocol relies on the ex situ generation of sulfuryl fluoride gas
and a specialized two-chamber reactor which pressurizes as
sulfuryl fluoride gas is generated. Therefore, an easily
manipulated, solid reagent that directly installs the −SO2F
group would facilitate the synthesis of these valuable functional
groups. Additionally, during the review process for this
manuscript, a new azolium triflate reagent to synthesize
sulfur(VI) fluorides was disclosed by Sharpless, Dong, and
co-workers; however, preparation of this reagent requires the
Received: December 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03950
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Letter
Figure 2. Substrate scope for the synthesis of fluorosulfates and sulfamoyl fluorides using AISF. Reaction conditions: phenol or amine (1 equiv),
AISF (1.2 equiv), DBU (2.2 equiv) in THF (0.2 M) at rt, 10 min. An average of two independent experiments was used to calculate the reported
yields. Key: (a) AISF (3.2 equiv), DBU (4.2 equiv); (b) AISF (1.2 equiv), Cs2CO3 (2.2 equiv), DMSO (0.2 M); (c) AISF (1.04 equiv), DBU (2.2
equiv) in THF (0.2 M) at 0 °C; (d) AISF (2.2 equiv), DBU (4.4 equiv), THF (0.2 M) at rt.
use of sulfuryl fluoride gas and the reagent is reported to be
hygroscopic, requiring storage at 4 °C or in a desiccator to
minimize reagent decomposition.12 Toward this end, we report
the invention of AISF ([4-(Acetylamino)phenyl]-
ImidodiSulfuryl diFluoride), a convenient, shelf-stable, crystal-
line reagent for the synthesis of fluorosulfates and sulfamoyl
fluorides (Figure 1B and Figure 2).
Scheme 1. Synthesis of AISF through an Oxidative C−H
Functionalization of Acetanilide (22)
In designing a solid reagent to install the −SO2F group, we
required three key attributes: (1) the reagent must demonstrate
comparable or improved reactivity to sulfuryl fluoride gas; (2) it
must be a crystalline, shelf-stable and easily manipulated solid;
and (3) it must be readily accessible on decagram scale from
commercially available starting materials. We were inspired by
the solid alternatives of triflic anhydride (e.g., N-phenyl-
triflimide,13 Comin’s reagent,14 trifluoromethanesulfonic imida-
zolide,15 and 4-nitrophenyltriflate)16 and explored multiple
structural variations of these reagents for the potential to
transfer an −SO2F group. Ultimately, the stable, crystalline
solid AISF was identified as a reagent that fulfilled the
aforementioned criteria.
A synthesis of AISF was developed that directly installed the
bis(fluorosulfonyl)imide through an iodine(III)-promoted
oxidative C−H functionalization of acetanilide (22, Scheme
1).17 AISF was isolated as a white, crystalline, free-flowing solid
(yield = 77%, >400 g prepared, mp 141.0−143.1 °C, dec), with
X-ray crystallography providing unambiguous structural con-
firmation (Figure 1B). The reagent is easily manipulated in an
open atmosphere and is stable at ambient temperature either as
a solid or in solution (THF-d6), with no measurable
decomposition over a prolonged period of time (>1 month,
Supplementary Figure S3). Differential scanning calorimetry
(DSC) indicated low thermal potential (319 J/g, Supplemen-
tary Figure S5) for the decomposition of AISF, which occurs
subsequent to the reagent’s melt at approximately 140 °C and
is consistent with the lack of high energy functional groups
within the molecule. Further evaluation through differential
accelerating rate calorimetry (DARC) revealed an accompany-
ing pressure increase associated with the exotherm (Supple-
mentary Figure S6), and therefore, to prevent reagent
decomposition, it is recommended to avoid heating AISF
beyond approximately 140 °C. To facilitate the scale-up of
AISF, a chromatography-free protocol was also developed and
showcased on decagram scale (see the Supporting Informa-
tion).
We found that reaction of phenols with AISF occurs rapidly
in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
to produce the desired fluorosulfates in high yield (Figure
2A).18 The reaction is unaffected by the presence of electron-
withdrawing or -donating substituents on the phenol and is
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tolerant of heterocycles as well as sterically encumbered
substrates. AISF can also be used in the presence of reactive
functional groups (i.e., aniline, carboxylic acid, 1° and 2°
alcohols), generating the desired fluorosulfates (12−14) in
good yields. Careful control of stoichiometry is also easily
accomplished with the solid reagent. This is exemplified by the
monofunctionalization of 2-hydroxycarbazole to generate
fluorosulfate 15 when 1 equiv of AISF is employed (structure
confirmed by X-ray crystallography, Figure 2A). Alternatively,
the addition of greater than 2 equiv of AISF in the reaction
affords the corresponding bis-functionalized product 16.
strated in the preparation of diaryl sulfate 292a and in the aryne
chemistry to access triazole 32,20 further demonstrating the
broad utility of AISF (Figure 3B).
Incorporation of the fluorosulfate group into a peptide or
protein imparts a reactive handle for further modification or to
assist in the investigation of binding events such as protein−
ligand or protein−protein interactions (PPIs). Therefore, to
evaluate the capacity of AISF to chemoselectively label a
tyrosine residue under biologically relevant conditions, we
explored the modification of the peptidic macrocycle
desmopressin in an aqueous environment (Figure 4). Thus,
Synthesis of sulfamoyl fluorides was also achieved using AISF
(Figure 2B). Subjecting amines to the same reaction conditions
identified for the synthesis of fluorosulfates from phenols
(DBU, THF, 10 min) produced the corresponding sulfamoyl
fluorides (17−21) in good yield. It is noteworthy that these
reactions do not require the addition of the activating agents
DMAP or DABCO, as reported with sulfuryl fluoride gas2a and
similar to what was observed with the azolium triflate reagent.12
We next evaluated the single-flask cross-coupling of phenols
via the intermediacy of the AISF-derived fluorosulfate (Figure
3A). Subjecting phenol 23 to modified Buchwald−Hartwig
Figure 4. Selective modification of the tyrosine residue on the peptidic
macrocycle desmopressin with AISF in pH 8.6, 0.1 M Tris buffer/
KF:DMSO (1:1) followed by treatment with DTT (5 mM). Reduced,
fluorosulfate-modified desmopressin (deamino-Cys-Tyr-Phe-Gln-Asn-
Cys-Pro-dArg-Gly-NH2, 33) was analyzed by LC−MS/MS.
addition of AISF to a pH 8.6 Tris buffer/DMSO solution (1:1)
containing potassium fluoride and desmopressin resulted in the
successful labeling of the peptide with a single −SO2F group,
despite the presence of multiple potentially reactive amino
acids and functional groups (i.e., Tyr, Arg, Gln, Asn, disulfide
bond). The site of modification was established by reduction of
the disulfide with dithiothreitol (DTT) and then analysis by
liquid chromatography (LC)−mass spectrometry (MS) utiliz-
ing a LTQ Orbitrap XL spectrometer. In the tandem mass
spectrum, detection of the −SO2F-modified b3 ion, in
combination with the lack of modification of the y7 ion, is
consistent with selective conversion of the tyrosine residue to
the corresponding aryl fluorosulfate. It is noteworthy that at pH
8.6, potassium fluoride (KF) additive was necessary for
conversion of the tyrosine residue to the fluorosulfate. This is
attributed to an alternative reaction pathway in which KF reacts
with AISF to generate sulfuryl fluoride in situ as the reactive
species (see Supplementary Figure S12 for 19F NMR
experiments). Alternatively, at pH 10, and presumably with
the tyrosine phenol deprotonated in solution, KF is not
required and the tyrosine residue is modified through reaction
with AISF without generating sulfuryl fluoride (Supplementary
Figure S10). The capacity of AISF to possess dual reactivity
modes, namely through direct functionalization of phenols and
Figure 3. Single-flask reactions of phenols via the intermediacy of
AISF-generated fluorosulfates.
amination conditions7b in the presence of AISF afforded the
corresponding aniline product 24 in excellent yield (94%).
Similar results were also observed with both modified Suzuki4b
and Sonogashira5 cross-couplings generating biaryl 25 and
alkyne 26, respectively. These reactions highlight the chemo-
selectivity of AISF, as the reagent was inert to the catalyst,
ligand and nucleophiles present in the reaction mixtures.19
Additional single-vessel phenol transformations were demon-
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N. C.; Dong, J.; Noodleman, L.; Sharpless, K. B.; Wilson, I. A.;
Encalada, S. E.; Kelly, J. W. J. Am. Chem. Soc. 2015, 137, 7404.
(c) Chen, W.; Dong, J.; Plate, L.; Mortenson, D. E.; Brighty, G. J.; Li,
S.; Liu, Y.; Galmozzi, A.; Lee, P. S.; Hulce, J. J.; Cravatt, B. F.; Saez, E.;
Powers, E. T.; Wilson, I. A.; Sharpless, K. B.; Kelly, J. W. J. Am. Chem.
Soc. 2016, 138, 7353. (d) Chen, W.; Dong, J.; Li, S.; Liu, Y.; Wang, Y.;
Yoon, L.; Wu, P.; Sharpless, K. B.; Kelly, J. W. Angew. Chem., Int. Ed.
2016, 55, 1835. (e) Ren, G.; Zheng, Q.; Wang, H. Org. Lett. 2017, 19,
1582.
(2) (a) Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2014, 53, 9430. (b) Dong, J.; Sharpless, K. B.; Kwisnek,
L.; Oakdale, J. S.; Fokin, V. V. Angew. Chem., Int. Ed. 2014, 53, 9466.
(c) Gao, B.; Zhang, L.; Zheng, Q.; Zhou, F.; Klivansky, L. M.; Lu, J.;
Liu, Y.; Dong, J.; Wu, P.; Sharpless, K. B. Nat. Chem. 2017, 9, 1083.
(d) Li, S.; Cohen-Karni, D.; Beringer, L. T.; Wu, C.; Kallick, E.;
Edington, H.; Passineau, M. J.; Averick, S. Polymer 2016, 99, 7.
(e) Oakdale, J. S.; Kwisnek, L.; Fokin, V. V. Macromolecules 2016, 49,
4473.
(3) Roth, G. P.; Fuller, C. E. J. Org. Chem. 1991, 56, 3493.
(4) (a) Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.;
Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H. J. Am.
Chem. Soc. 1998, 120, 4550. (b) Hanley, P. S.; Ober, M. S.; Krasovskiy,
A. L.; Whiteker, G. T.; Kruper, W. J. ACS Catal. 2015, 5, 5041.
(c) Liang, Q.; Xing, P.; Huang, Z.; Dong, J.; Sharpless, K. B.; Li, X.;
Jiang, B. Org. Lett. 2015, 17, 1942. (d) Zhang, E.; Tang, J.; Li, S.; Wu,
P.; Moses, J. E.; Sharpless, K. B. Chem. - Eur. J. 2016, 22, 5692.
(e) Pridgen, L. N.; Huang, G. K. Tetrahedron Lett. 1998, 39, 8421.
(5) Hanley, P. S.; Jansma, M. J.; Krasovskiy, A. L. PCT Int. Appl. WO
2017030971 A1, 2017.
(6) Roth, G. P.; Sapino, C. Tetrahedron Lett. 1991, 32, 4073.
(7) (a) Lim, T.; Byun, S.; Kim, B. M. Asian J. Org. Chem. 2017, 6,
1222. (b) Hanley, P. S.; Clark, T. P.; Krasovskiy, A. L.; Ober, M. S.;
O’Brien, J. P.; Staton, T. S. ACS Catal. 2016, 6, 3515.
(8) (a) Roth, G. P.; Thomas, J. A. Tetrahedron Lett. 1992, 33, 1959.
(b) McGuire, M. A.; Sorenson, E.; Owings, F. W.; Resnick, T. M.; Fox,
M.; Baine, N. H. J. Org. Chem. 1994, 59, 6683. (c) Fang, W.-Y.; Leng,
J.; Qin, H.-L. Chem. - Asian J. 2017, 12, 2323.
(9) Schimler, S. D.; Cismesia, M. A.; Hanley, P. S.; Froese, R. D. J.;
Jansma, M. J.; Bland, D. C.; Sanford, M. S. J. Am. Chem. Soc. 2017, 139,
1452.
(10) Alternative preparations of fluorosulfates that do not use sulfuryl
fluoride gas include: (a) Cramer, R.; Coffman, D. J. Org. Chem. 1961,
26, 4164. (b) Boudakian, M. M.; Hyde, G. A.; Kongpricha, S. J. Org.
Chem. 1971, 36, 940. (c) Padma, D. K.; Bhat, V. S.; Murthy, A. R. V. J.
Fluorine Chem. 1982, 20, 425.
amines, or to serve as an in situ precursor to sulfuryl fluoride,
expands the utility of the AISF reagent.
In conclusion, we have designed and synthesized a novel,
crystalline, and bench-stable reagent for the installation of the
−SO2F group. AISF boasts exceptional reactivity with a wide
array of phenol and amine nucleophiles, as demonstrated by the
rapid conversion to fluorosulfates and sulfamoyl fluorides under
mild reaction conditions. Furthermore, AISF is compatible with
other potentially reactive functional groups and reagents as
exemplified in several one-flask transformations of phenols and
the selective functionalization of a tyrosine residue on a
peptidic macrocycle under aqueous conditions. We anticipate
the user-friendliness, broad applicability, and ease of prepara-
tion of AISF will facilitate further exploration into the value of
fluorosulfates and sulfamoyl fluorides by others.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03950.
1
Full experimental details and procedures; H, 13C, and
19F NMR spectra; supporting figures and data (PDF)
Accession Codes
CCDC 1812516−1812519 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: christopher.amende@pfizer.com.
ORCID
John M. Humphrey: 0000-0001-8753-9479
Christopher J. Helal: 0000-0002-9091-2091
Christopher W. am Ende: 0000-0001-8832-9641
Notes
(11) Veryser, C.; Demaerel, J.; Bieliunas, V.; Gilles, P.; De
̅
Borggraeve, W. M. Org. Lett. 2017, 19, 5244.
(12) Guo, T.; Meng, G.; Zhan, X.; Yang, Q.; Ma, T.; Xu, L.;
Sharpless, K. B.; Dong, D. Angew. Chem., Int. Ed. 2017, DOI: 10.1002/
anie.201712429.
This work was performed as a collaboration between BioDuro
and Pfizer.
The authors declare the following competing financial
interest(s): H.Z., R.L., and D.W. are employees at BioDuro.
P.M., E.E., J.M.H., T.W.B., L.R.H., J.B.S., S.K.S., C.J.H., and
C.W.A. are employees at Pfizer, Inc.
(13) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14,
4607.
(14) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(15) Effenberger, F.; Mack, K. E. Tetrahedron Lett. 1970, 11, 3947.
(16) Zhu, J.; Bigot, A.; Elise, M.; Tran Huu, D. Tetrahedron Lett.
1997, 38, 1181.
ACKNOWLEDGMENTS
■
We thank J. Bellenger (HPLC purification, Pfizer), I.
Samardjiev and B. Samas (X-ray crystallography, Pfizer), K.
Farley (NMR support, Pfizer), C. Li (hydrolytic stability,
Pfizer), R. Duzguner (DSC, Pfizer), P. Mullins (Pfizer), G.
West (Pfizer), and J. Du Bois (Stanford University) for
insightful discussions and T. Deng (BioDuro) and C. Mirsaidi
(BioDuro) for leadership and support.
(17) Pialat, A.; Berges
Taillefer, M. Chem. - Eur. J. 2015, 21, 10014.
̀ ́
, J.; Sabourin, A.; Vinck, R.; Liegault, B.;
(18) Additional base and solvent combinations were also effective in
converting phenols to fluorosulfates and amines to sulfamoyl fluorides
in the presence of AISF. Refer to the Supporting Information for
selected examples.
(19) For the Suzuki coupling, water was added after generation of the
fluorosulfate.
(20) Chen, Q.; Yu, H.; Xu, Z.; Lin, L.; Jiang, X.; Wang, R. J. Org.
Chem. 2015, 80, 6890.
REFERENCES
■
(1) (a) Fadeyi, O. O.; Hoth, L. R.; Choi, C.; Feng, X.; Gopalsamy, A.;
Hett, E. C.; Kyne, R. E.; Robinson, R. P.; Jones, L. H. ACS Chem. Biol.
2017, 12, 2015. (b) Baranczak, A.; Liu, Y.; Connelly, S.; Du, W.-G. H.;
Greiner, E. R.; Genereux, J. C.; Wiseman, R. L.; Eisele, Y. S.; Bradbury,
D
DOI: 10.1021/acs.orglett.7b03950
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