Selective Access to Heterocyclic Sulfonamides and Sulfonyl Fluorides via a Parallel Medicinal Chemistry Enabled Method

Article abstract of DOI:10.1021/acscombsci.5b00120

A sulfur-functionalized aminoacrolein derivative is used for the efficient and selective synthesis of heterocyclic sulfonyl chlorides, sulfonyl fluorides, and sulfonamides. The development of a 3-step parallel medicinal chemistry (PMC) protocol for the synthesis of pyrazole-4-sulfonamides effectively demonstrates the utility of this reagent. This reactivity was expanded to provide rapid access to other heterocyclic sulfonyl fluorides, including pyrimidines and pyridines, whose corresponding sulfonyl chlorides lack suitable chemical stability.

Full text of DOI:10.1021/acscombsci.5b00120

Technology Note
pubs.acs.org/acscombsci
Selective Access to Heterocyclic Sulfonamides and Sulfonyl Fluorides
via a Parallel Medicinal Chemistry Enabled Method
Joseph W. Tucker,* Lois Chenard, and Joseph M. Young
Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340,
United States
S
* Supporting Information
ABSTRACT: A sulfur-functionalized aminoacrolein derivative is used for the efficient and selective synthesis of heterocyclic
sulfonyl chlorides, sulfonyl fluorides, and sulfonamides. The development of a 3-step parallel medicinal chemistry (PMC)
protocol for the synthesis of pyrazole-4-sulfonamides effectively demonstrates the utility of this reagent. This reactivity was
expanded to provide rapid access to other heterocyclic sulfonyl fluorides, including pyrimidines and pyridines, whose
corresponding sulfonyl chlorides lack suitable chemical stability.
KEYWORDS: heterocyclic sulfonamides, sulfonyl fluorides, 3-step PMC protocol, rapid access
ulfonamides hold a privileged role in drug discovery efforts
Sdue in part to the unique electronic and conformational
properties they impart on compounds.1 Though various
conditions exist for the synthesis of sulfonamides,2 including
Pd-catalyzed coupling reactions3 and electrophilic amination
reactions of sulfinate salts,4 the vast majority of sulfonamide
syntheses are accomplished by the reaction of an amine with a
sulfonyl chloride. This strategic bond disconnection neces-
sitates robust methods for the synthesis of the requisite sulfonyl
halide. Therefore, we view the efficient and general access of
varied classes of sulfonyl chlorides as a valuable goal, applicable
to numerous drug discovery projects.
In particular, recent project work required a means to
generate 1-substituted pyrazole-4-sulfonyl chlorides (of type 5)
in order to rapidly assess the structure-activity-relationship
(SAR) around this particular sulfonamide motif. Initial attempts
at synthesizing this class of chlorides focused on direct Friedel−
Crafts sulfonylation of N-substituted pyrazoles by heating in
chlorosulfonic acid5 (Figure 1, A). Substrates bearing a variety
of N-substituents were examined to assess the generality of this
method for synthesizing sulfonyl chlorides with broad chemical
diversity. In exploring this chemistry, we often observed
formation of varying mixtures of regioisomeric sulfonyl
chlorides (eg., 2a and 2b) as a function of the N-substituent,
along with low overall yield. Isolation of the desired sulfonyl
chloride or the resulting sulfonamide was made more difficult
by the inability to distinguish the regioisomeric byproducts
during isolation by mass-triggered reverse phase HPLC
purification. Furthermore, we were limited to using preformed
N-substituted pyrazoles as starting materials, which were of
relatively limited supply in the corporate monomer store.
Figure 1. Synthesis of pyrazole-4-sulfonyl chlorides.
An alternative strategy was sought in which the de novo
synthesis of a pyrazole ring bearing appropriate functionality
would alleviate any potential regioselectivity issues and avoid
the harsh reaction conditions associated with pyrazole
Received: July 21, 2015
Revised: September 23, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acscombsci.5b00120
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ACS Combinatorial Science
Technology Note
functionalization. Herein, we present a realization of this
strategy by the identification of a bis-electrophilic reagent which
contains a low-valent sulfur functionality, allowing for the
synthesis of pyrazoles via a condensation reaction with readily
available hydrazines (Figure 1B).
for the standard reaction protocol. The isolated yields of final
targets for this library are presented in Table 1.
The three-step procedure was run without purification of
intermediates, and products were isolated by means of mass-
triggered semiautomated HPLC purification. It is important to
note that, unlike for the reactions run in Scheme 1, the
We identified the aminoacrolein derivative 36 as an
appropriate reagent for the formation of pyrazole-4-thioethers.
The use of 3 allows for incorporation of the required sulfur
substitution from the initial pyrazole synthesis.7 As a result, the
problems encountered with later-stage heterocycle functional-
ization are obviated. Furthermore, rich literature precedent
exists for the oxidative conversion of low-valent sulfur
precursors to sulfonyl chlorides under mild reaction con-
ditions.8 We identified the benzyl thioether9 as an appropriate
synthetic handle to allow for the generation of the desired
sulfonyl chloride (Scheme 1).
a
Table 1. PMC Synthesis of Pyrazole-4-sulfonamides
Scheme 1. Development of Selective Pyrazole-4-sulfonamide
Synthesis
Thioether 3 is a shelf stable and odorless solid, easily
accessible in multigram quantities by the reaction of N,N-
dimethylamino acrolein with benzyl sulfenyl bromide,
generated in situ from dibenzyl disulfide and bromine.
Demonstration of the desired reactivity began with con-
densation of p-tolylhydrazine·HCl with 3. Refluxing in ethanol
smoothly provided the functionalized pyrazole 6. It was found
that the oxidation of 6 was effected by treatment with a
preformed solution of N-chlorosuccinimide and HCl in
MeCN.10 Clean conversion to the sulfonyl chloride 7 was
observed after simple aqueous workup. The only byproducts
identifiable by 1H NMR analysis were the expected:
succinimide and benzyl chloride. Treatment of the crude
mixture with a representative amine in pyridine cleanly
provided the desired sulfonamide 8 in 83% yield over two
steps (Scheme 1).
The ability to rapidly probe the SAR of a particular chemical
series by means of library or parallel medicinal chemistry
(PMC) enabled synthesis is an important tool in drug
discovery.11 The high overall yield and the clean reaction
profiles of the transformations involved suggested this
procedure would translate well into a PMC mode. To
demonstrate this, a library using 13 structurally varied
hydrazines, each crossed with an alkyl and aryl amine template,
was run with conditions essentially identical to those developed
a
Isolated yield given after three steps. General conditions: Step 1, HCl
omitted when hydrazine was available as HCl salt, 0.20 M, 80 °C, 2 h;
step 2, 0.15 M, 0 °C to rt, 1.5 h; step 3, 0.1 M, rt, 12 h.
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ACS Combinatorial Science
Technology Note
operations involved with running these 26 reactions in parallel
are optimized with overall success rate, as opposed to individual
chemical yields, in mind. As a result, it is common that workup,
isolation, and purification processes lead to sub optimal isolated
yields, but provide sufficient quantities of final targets for
biological screening in drug discovery programs. This is typical
of PMC enabled chemical syntheses, which strive to make
numerous compounds quickly instead of fewer compounds in
maximal yield. This distinction is represented in the occasion-
ally low and variable yields observed for even structurally
related hydrazines in Table 1.
Scheme 3. Synthesis of Heterocyclic Sulfonyl Fluorides
The data presented in Table 1 do demonstrate a more critical
result for PMC syntheses: high monomer success rate, defined
as number of final targets isolated divided by the number of
monomers submitted to the library. Under these conditions,
the desired pyrazole-4-sulfonamides were recovered with high
overall success rates: 85% for the aryl amine and a 92% for the
alkyl amine template (Table 1).12 The protocol was effective for
electron-deficient (Table 1, entry 6) and electron-rich (Table 1,
entry 2) aryl hydrazines, as well as alkyl hydrazines (Table 1,
entries 1 and 3) including those with sterically hindered α-
branching (Table 1, entries 7, 9, 12, and 13). The high success
rate for both amine types along with the structural variety
accessible via the hydrazine monomers makes this PMC
protocol particularly valuable, allowing for variation in two
vectors from a central pyrazole core in only three chemical
steps.13 In addition, the relatively mild nature of the reaction
conditions make this protocol applicable to more heavily
functionalized and pharmaceutically relevant hydrazines and
amines which are stable to the acidic oxidation procedure.
We sought to demonstrate that the low yields observed for
some substrates were likely attributable to the working realities
of PMC synthesis discussed above. A poorly performing
example was selected from Table 1 and repeated using
techniques associated with typical batch-style synthetic
laboratory execution (Scheme 2). To this end, the 3-step
sulfonyl chlorides,15 we opted to investigate the oxidative
cleavage of these intermediates for the synthesis of the more
chemically stable sulfonyl fluorides.16,17 The solvent for the
oxidation was switched from MeCN to DCM due to decreased
solubility of these thioethers. Optimization then required
identification of a viable fluoride source. The use of KHF2 was
evaluated under various phase-transfer conditions, but provided
low yields of the desired sulfonyl fluoride. Ultimately the more
organic soluble benzyl trimethylammonium fluoride was found
to give the best conversion to the sulfonyl fluoride. Exposure of
a solution of thioether and fluoride source in DCM with a
minimal amount of water to a preformed mixture of oxidant
cleanly and rapidly afforded full conversion to the isolable
sulfonyl fluorides (14, 15).18,19
In conclusion, we have demonstrated the utility of 3 as a
valuable synthon for the selective generation of heterocycles
bearing appropriate functionality for facile conversion to
sulfonyl chlorides, sulfonyl fluorides and sulfonamides. The
power of this method is demonstrated by its use in a three-step
PMC protocol affording sulfonamide products of possible value
in drug discovery programs, with high success rates from readily
available and diverse hydrazine monomers. Furthermore, rapid
access to pyrimidyl and pyridyl sulfonyl fluorides promises
potential entry into chemical space not accessible via the
corresponding sulfonyl chlorides because of inherent instability
Scheme 2. Improvement of PMC Yield Using Standard
Synthetic Techniques
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.5b00120.
■
S
Full experimental, characterization data for all new
1
compounds, and copies of H and 13C NMR spectra
(PDF)
conversion of hydrazine 10{8} to sulfonamide 9{8,2} was
conducted without purification of any intermediates, and final
chromatographic isolation afforded 9{8,2} in 54% overall yield
after three steps. This clearly demonstrates that the 10% yield
observed in the library synthesis of 9{8,2} (Table 1, entry 8) is
not due to a lack of robustness or reproducibility of the
synthetic route.
Beyond the synthesis of pyrazoles, we recognized that 3 may
be suitable for the synthesis of a wide range of sulfur-
functionalized heterocycles. With this in mind, we explored the
condensation of bis-electrophile 3 with other bis-nucleophiles,
including amidines and amino-acrylates.14 We were delighted to
find that these reactions cleanly afforded functionalized
pyrimidine (12) and pyridine (13), respectively (Scheme 3).
Given the instability of many electron-deficient heterocyclic
AUTHOR INFORMATION
Corresponding Author
*Email: joseph.tucker@pfizer.com.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Drs. Christopher J. Helal, John Humphrey,
and Danica A. Rankic and Mr. Cory Stiff for helpful discussions,
■
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Technology Note
of KDR Kinase Inhibitors: Improvements in Physical Properties
Enhance Cellular Activity and Phamacokinetics. Bioorg. Med. Chem.
Lett. 2002, 12, 3537−3541.
Mr. Patrick Mullins for purification assistance, and Dr. Anabella
Villalobos for support.
(8) For selected examples of oxidations of other low-valent sulfur
precursors, see: (a) Wright, S. W.; Hallstrom, K. N. A Convenient
Preparation of Heteroaryl Sulfonamides and Sulfonyl Fluorides from
Heteroaryl Thiols. J. Org. Chem. 2006, 71, 1080−1084. (b) Woolven,
ABBREVIATIONS
■
PMC, parallel medicinal chemistry; SAR, structure−activity-
relationship; HPLC, high pressure liquid chromatography;
MeCN, acetonitrile; DCM, dichloromethane
́
H.; Gonzalez-Rodriguez, C.; Marco, I.; Thompson, A. L.; Willis, M. C.
DABCO-Bis(sulfur dioxide), DABSO, as a Convenient Source of
Sulfur Dioxide for Organic Synthesis: Utility in Sulfonamide and
Sulfamide Preparation. Org. Lett. 2011, 13, 4876−4878. (c) Johnson,
M. W.; Bagley, S. W.; Mankad, N. P.; Bergman, R. G.; Masciti, V.;
Toste, F. D. Application of Fundamental Organometallic Chemistry to
the Development of a Gold-Catalyzed Synthesis of Sulfinate
Derivatives. Angew. Chem., Int. Ed. 2014, 53, 4404−4407.
REFERENCES
■
(1) (a) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. Small
Molecule Conformational Preferences Derived from Crystal Structure
Data. A Medicinal Chemistry Focused Analysis. J. Chem. Inf. Model.
2008, 48, 1−24. (b) Chang, C.-P.; Wu, C.-H.; Song, J.-S.; Chou, M.-
C.; Wong, Y.-C.; Lin, Y.; Yeh, Y.-K.; Sadani, A. A.; Ou, M.-H.; Chen,
K.-H.; Chen, P.-H.; Kuo, P.-C.; Tseng, C.-T.; Chang, K.-H.; Tseng, S.-
L.; Chao, Y.-S.; Hung, M.-S.; Shia, K.-S. Discovery of 1-(2,4-
Dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)-
methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-
1H-pyrazole-3-carboxamide as a Novel Peripherally Restricted
Cannabinoid-1 Receptor Antagonist with Significant Weight-Loss
Efficacy in Diet-Induced Obese Mice. J. Med. Chem. 2013, 56, 9920−
9933.
(2) (a) Caddick, S.; Wilden, J. D.; Bush, H. D.; Wadman, S. N.; Judd,
D. B. A New Route to Sulfonamides via Intermolecular Radical
Addition to Pentafluorophenyl Vinylsulfonate and Subsequent
Aminolysis. Org. Lett. 2002, 4, 2549−2551. (b) Caddick, S.; Wilden,
J. D.; Judd, D. B. Direct Synthesis of Sulfonamides and Activated
Sulfonate Esters from Sulfonic Acids. J. Am. Chem. Soc. 2004, 126,
1024−1025. (c) Ruano, J. L. C.; Parra, A.; Yuste, F.; Mastranzo, V. M.
Mild and General Method for the Synthesis of Sulfonamides. Synthesis
2008, 2008, 311−319. (d) Moon, S.-Y.; Nam, J.; Rathwell, K.; Kim,
W.-S. Copper-Catalyzed Chan-Lam Coupling between Sulfonyl Azides
and Boronic Acids at Room Temperature. Org. Lett. 2014, 16, 338−
341.
(3) (a) Rosen, B. R.; Ruble, J. C.; Beauchamp, T. J.; Navarro, A. Mild
Pd-Catalyzed N-Arylation of Methanesulfonamide and Related
Nucleophiles: Avoiding Potentially Genotoxic Reagens and By-
products. Org. Lett. 2011, 13, 2564−2567.
(4) (a) Baskin, J. M.; Wang, Z. A Mild, Convenient Synthesis of
Sulfinic Acid Salts and Sulfonamides from Alkyl and Aryl Halides.
Tetrahedron Lett. 2002, 43, 8479−8483. (b) Deeming, A. S.; Russell,
C. J.; Willis, M. C. Combining Organometallic Reagents, the Sulfur
Dioxide Surrogate DABSO, and Amines: A One-Pot Preparation of
Sulfonamides, Amenable to Array Synthesis. Angew. Chem., Int. Ed.
2015, 54, 1168−1171. (c) Johnson, M. G.; Gribble, M. W., Jr.; Houze,
J. B.; Paras, N. A. Convenient Route to Secondary Sulfinates:
Application to the Stereospecific Synthesis of α-C-Chiral Sulfona-
mides. Org. Lett. 2014, 16, 6248−6251.
(5) Markwalder, J. A.; Arnone, M. R.; Benfield, P. A.; Boisclair, M.;
Burton, C. R.; Chang, C.-H.; Cox, S. S.; Czerniak, P. M.; Dean, C. L.;
Deleniak, D.; Grafstrom, R.; Harrison, B. A.; Kaltenbach, R. F., III;
Nugiel, D. A.; Rossi, K. A.; Sherk, S. R.; Sisk, L. M.; Stouten, P.;
Trainor, G. L.; Worland, P.; Seitz, S. P. Synthesis and Biological
Evaluation of 1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one
Inhibitors of Cyclin-Dependent Kinases. J. Med. Chem. 2004, 47,
5894−5911.
(6) For the synthesis of 3 and its use as a precursor for vinamidinium
salts, see: Matthews, D. P. Synthesis of N-[3-(dimethylamino)-2-
(substituted thio)-2-propenylidene]-N-methylmethanaminium salts
via 2-(alkylthio)- and 2-(arylthio)-3-(dimethylamino)acroleins. J. Org.
Chem. 1984, 49, 2823−2824.
(7) The use of 2-bromo-3-(dimethylamino)acrolein was also
considered to synthesize the 4-Br-pyrazole followed by a thio-coupling
reaction. This route was not pursued due to the increased step count,
see: Fraley, M. E.; Rubino, R. S.; Hoffman, W. F.; Hambaugh, S. R.;
Arrington, K. L.; Hungate, R. W.; Bilodeau, M. T.; Tebben, A. J.;
Rutledge, R. Z.; Kendall, R. L.; McFall, R. C.; Huckle, W. R.; Coll, K.
E.; Thomas, K. A. Optimization of a Pyrazole[1,5-a]pyrimidine Class
(9) For a selective example of the oxidative cleavage of benzyl
thioethers, see: Wang, M.; Gao, M.; Miller, K. D.; Sledge, G. W.;
Zheng, Q.-H. [11C]GSK2126458 and [18F]GSK2126458, The First
Radiosynthesis of New Potential PET Agents for Imaging of PI3K and
mTOR in Cancers. Bioorg. Med. Chem. Lett. 2012, 22, 1569−1574.
(10) We found that treatment of a solution of HCl in MeCN with
NCS rapidly formed a homogenous yellow solution, presumably
because of the formation of Cl2, see: Mahajan, T.; Kuman, L.; Dwivedi,
K.; Agarwal, D. D. Efficient and Facile Chlorination of Industrially-
Important Aromatic Compounds using NaCl/p-TsOH/NCS in
Aqueous Media. Ind. Eng. Chem. Res. 2012, 51, 3881−3886.
(11) For an example of strategic use of parallel medicinal chemistry
in a drug discovery program, see: Claffey, M. M.; Helal, C. J.; Verhoest,
P. R.; Kang, Z.; Fors, K. S.; Jung, S.; Zhong, J.; Bundesmann, M. W.;
Hou, X.; Liu, S.; Kleiman, R. J.; Vanase-Frawley, M.; Schmidt, A. W.;
Menniti, F.; Schmidt, C. J.; Hoffman, W. E.; Hajos, M.; McDowell, L.;
O’Connor, R. E.; MacDougall-Murphy, M.; Fonseca, K. R.; Becker, S.
L.; Nelson, F. R.; Liras, S. Application of Structure-Based Drug Design
and Parallel Chemistry ot Identify Selective, Brain Penetrant, In Vivo
Active Phosphodiesterase 9A Inhibitors. J. Med. Chem. 2012, 55,
9055−9068.
(12) No quality controls were run on the purity of the hydrazines
that were ordered from the internal chemical file prior to library
execution. However, for those hydrazines that failed to afford products
for both amines used, samples were ordered retrospectively and they
were found to have decomposed during storage. These false-negative
results are neither reported in the table nor calculated into the library
success rate.
(13) For selected examples of pyrazole syntheses in parallel, see:
(a) Vickerstaffe, E.; Warrington, B. H.; Ladlow, M.; Ley, S. V. Fully
Automated Polymer-Assisted Synthesis of 1,5-Biaryl Pyrazoles. J.
Comb. Chem. 2004, 6, 332−339. (b) Sidique, S.; Ardecky, R.; Su, Y.;
́
Narisawa, S.; Brown, B.; Millan, J. L.; Sergienko, E.; Cosford, N. D. P.
Design and Synthesis of Pyrazole Derivatives as Potent and Selective
Inhibitors of Tissue-Nonspecific Alkaline Phophatase (TNAP). Bioorg.
Med. Chem. Lett. 2009, 19, 222−225. (c) Ma, W.; Peterson, B.; Kelson,
A.; Laborde, E. Efficient Synthesis of Trisubstituted Pyrazoles and
Isoxazoles Using a Traceless “Catch and Release” Solid-Phase Strategy.
J. Comb. Chem. 2009, 11, 697−703. (d) Pendri, A.; Dodd, D. S.; Chen,
J.; Cvijic, M. E.; Kang, L.; Baska, R. A.; Carlson, K. E.; Burford, N. T.;
Sun, C.; Ewing, W. R.; Gerritz, S. W. Solid Phase Synthesis of 1,5-
Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1
Receptor. ACS Comb. Sci. 2012, 14, 197−204.
(14) An insightful reviewer asked for the same reaction sequence to
be demonstrated using hydroxylamine to generate isoxazole-4-sulfonyl
fluoride. Despite condensation of 3 with hydroxylamine hydrochloride
proceeding smoothing to afford the thioether, no desired sulfonyl
1
fluoride could be isolated after oxidation. Crude H NMR analysis
indicated successful oxidative cleavage; however, multiple attempts at
purification and isolation failed.
(15) Johnson, T. B.; Sprague, J. M. A New Method for the
Preparation of Alkyl Sulfonyl Chlorides. J. Am. Chem. Soc. 1936, 58,
1348−1352.
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Technology Note
(16) For a review on the stability and reactivity of sulfonyl fluorides,
see: Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Sulfur(VI)
Fluoride Exchange (SuFEx): Another Good Reaction for Click
Chemistry. Angew. Chem., Int. Ed. 2014, 36, 9430−9448.
(17) For the use of sulfonyl fluorides in the parallel synthesis of
sulfonamides, see: Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.;
Pipko, S. E.; Konovets, A. I.; Sadkova, I. V.; Tolmachev, A. Sulfonyl
Fluorides as Alternative to Sulfonyl Chlorides in Parallel Synthesis of
Aliphatic Sulfonamides. ACS Comb. Sci. 2014, 16, 192−197.
(18) For a selected example of the synthesis of pyridine-3-sulfonyl
chlorides, see: Hogan, P. J.; Cox, B. G. Aqueous Process Chemistry:
The Preparation of Aryl Sulfonyl Chlorides. Org. Process Res. Dev.
2009, 13, 875−879.
(19) For a selected example of the preparation and use of a pyrimidyl
sulfonyl chloride, see: Gerard, G.; Rojas de la Parra, V.; Lauwers, A.
Phenyl- and benzylthiazolypiperazine derivatives for the treatment of
neurodegenerative diseases and their preparation. WO 2009/019295
A2, Feb 12, 2009.
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