Organic Letters
Letter
by alkylation with 14C-MeI (Scheme 5). Using the standard
conditions (BnBr, t-BuOK, 23 °C) sulfinate 9 was generated as
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Scheme 5
Experimental procedure and data (PDF)
AUTHOR INFORMATION
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Corresponding Author
ORCID
a crystalline salt in 85% yield. Alkylation with MeI (1 equiv) in
DMF at 23 °C led to the formation of several products due to
competitive pyridine N-alkylation. The selectivity issue was
addressed by the addition of a phase transfer catalyst such as
tetrabutylammonium iodide (TBAI) to provide only the
sulfone product. This two-step, high-yielding route demon-
strates a remarkable improvement over the previously reported
[14C]MK-0663 synthesis.15
Odanacatib (MK-0822) 1, identified as a potent and selective
inhibitor of Cathepsin K,16 is in late stage clinical trials. A 14C-
labeled tracer was required for environmental risk assessment.17
Using a modified approach due to the sensitive functionality
present, we successfully generated sulfinate 10 in 25% yield
(Scheme 6). Although the yield of this key intermediate was
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We gratefully acknowledge E. Soli (Merck & Co., Inc.) for
performing 14C methylation of sulfinic acid 9; R. Marques, D.
Schenk, and R. Helmy (Merck & Co., Inc.) for their assistance
in 14C-tracer analysis; W. Pinto (Merck & Co., Inc.) for HRMS
data; J. Marra (Merck & Co., Inc.) for editing; and R. Reamer
(Reamer NMR Solutions, LLC) for NMR analysis.
Scheme 6
REFERENCES
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(1) Beaulieu, C.; Guay, D.; Wang, Z.; Evans, D. A. Tetrahedron Lett.
2004, 45, 3233.
(2) (a) Graham, S. L.; Scholz, T. H. Synthesis 1986, 1986, 1031.
(b) Chan, W. Y.; Berthelette, C. Tetrahedron Lett. 2002, 43, 4537.
(3) Treatment of methylsulfones with trialkylboranes has been
reported to produce sulfinic acids; however, the harsh conditions are
incompatible with functionalized substrates: Huang, H.-C.; Reinhard,
E. J.; Reitz, D. B. Tetrahedron Lett. 1994, 35, 7201.
(4) For a recent review on preparation and use of sulfinates in
synthesis, see: Aziz, J.; Messaoudi, S.; Alami, M.; Hamze, A. Org.
Biomol. Chem. 2014, 12, 9743.
(5) Baskin, J. M.; Wang, Z. Tetrahedron Lett. 2002, 43, 8479.
(6) The classic Julia olefination is obviously not a practical method
for preparation of arene sulfinic acids due to the harsh conditions and
numerous steps necessary to produce the arene sulfinate byproduct.
There have been several reported modifications to the Julia olefination
that use milder conditions and can be conducted in a single step;
however, they involve specific modifications to the aryl group that
would ultimately limit the generality of a sulfinic acid synthesis. See:
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(7) Baker-Glenn, C. A. G.; Barrett, A. G. M.; Gray, A. A.; Procopiou,
P. A.; Ruston, M. Tetrahedron Lett. 2005, 46, 7427.
(8) Zhao, F.; Luo, J.; Tan, Q.; Liao, Y.; Peng, S.; Deng, G.-J. Adv.
Synth. Catal. 2012, 354, 1914.
(9) Sturino, C. F.; O’Neill, G.; Lachance, N.; Boyd, M.; Berthelette,
C.; Labelle, M.; Li, L.; Roy, B.; Scheigetz, J.; Tsou, N.; Aubin, Y.;
Bateman, K. P.; Chauret, N.; Day, S. H.; Levesque, J.; Seto, C.; Silva, J.
́
H.; Trimble, L. A.; Carriere, M.; Denis, D.; Greig, G.; Kargman, S.;
Lamontagne, S.; Mathieu, M.; Sawyer, N.; Slipetz, D.; Abraham, W.
M.; Jones, T.; McAuliffe, M.; Piechuta, H.; Nicoll-Griffith, D. A.;
Wang, Z.; Zamboni, R.; Young, R. N.; Metters, K. M. J. Med. Chem.
2007, 50, 794.
(10) Chumachenko, N.; Sampson, P. Tetrahedron 2006, 62, 4540.
(11) Graham, S. L.; Scholz, T. H. Synthesis 1986, 1986, 1031.
(12) Umierski, N.; Manolikakes, G. Org. Lett. 2013, 15, 188.
(13) Examples of sulfinate protecting groups are not common in the
literature: (a) Castro Pineiro, J. L.; Cooper, L. C.; Gilligan, M.;
Humphries, A. C.; Hunt, P. A.; Ladduwahetty, T.; MacLeod, A. M.;
Merchant, K. J.; Van Niel, M. B.; Wilson, K. WO2006021805A1.
modest, it provided an efficient tactical approach, considering
an alternative would have required the design of a new
multistep synthesis possibly involving several radioactive
intermediates. Furthermore, as in the case of most clinical
drug candidates, bulk quantities of odanacatib were readily
available18 and only milligram quantities of radioactive 14C
compounds are typically required for routine tracer studies.
Subsequent alkylation of sulfinate 10 with 14C-MeI in MeCN
provided [14C]MK-0822.
In conclusion we have developed a one-step conversion of
methyl sulfones to sulfinates and have applied this chemistry to
a range of substrates to demonstrate its application in synthesis.
This late stage functionalization protocol affords a practical
point of diversity in targets of significant complexity and
provides a convenient method to incorporate 14C into bioactive
molecules containing a methyl sulfone.
C
Org. Lett. XXXX, XXX, XXX−XXX