Organic Process Research & Development 2002, 6, 851−854
Large-Scale Preparation of [13C]Methyl Phenyl Sulfide from [13C]Methanol by a
One-Step Process
Rodolfo A. Martinez,*,† Marc A. Alvarez,† Stephen P. Velarde,†,§ Louis A. “Pete” Silks,† Philip L. Stotter,‡
Ju¨rgen G. Schmidt,† and Clifford J. Unkefer†
National Stable Isotope Resource, Szilard Resource, Bioscience DiVision, MS E529, Los Alamos National Laboratory,
Los Alamos, New Mexico 87545, and College of Sciences, UniVersity of Texas at San Antonio, San Antonio, Texas 78249,
U.S.A.
Abstract:
The most useful of the electrophilic one-carbon precursors,
methyl iodide and carbon dioxide, are difficult to store and
use efficiently because of their volatility.
We have developed a large-scale “one-pot” procedure for the
conversion of commercially available [13C]- or [2H3,13C]-
methanol to [13C]- or [2H3,13C]methyl phenyl sulfide. [13C]methyl
phenyl sulfide is a potentially versatile, chemically stable, and
nonvolatile labeling precursor. In addition, we report an
efficient method for the oxidation of [13C]methyl phenyl sulfide
to [13C]methyl phenyl sulfone. Finally, we have used [13C]methyl
phenyl sulfide to produce 13C-labeled methyl iodide, containing
exactly one or two deuterons.
Methyl phenyl sulfide has rich chemistry and if prepared
with carbon and deuterium labels in the methyl group would
be a potentially versatile labeled precursor (Scheme 1). For
example, methyl phenyl sulfide (1) can be used as a
nucleophilic synthon (2)10-16 and is easily converted into an
electrophilic synthon (3).17-24 In addition, methyl phenyl
sulfide would provide a chemically stable and nonvolatile
carrier for the valuable label.
Scheme 1
Introduction
Stable isotope-labeled amino acids and nucleotides are
required for structural and mechanistic studies of proteins
and oligonucleotides. In addition, isotopically labeled bio-
logically active compounds are required for many phases of
drug discovery and development including elucidation of
biosynthetic pathways, pharmacokinetics, and drug metabo-
lism. For many applications, site-specific 13C- or combined
13C,2H-labeling are required. Carbon-13 is enriched from its
lighter isotope by cryogenic distillation of carbon monoxide;
thus, all labeled carbons must be derived ultimately from
13CO. The highly efficient conversion of CO to useful
chemical precursors is a unique aspect of stable isotope-
labeling chemistry. Because inefficiencies in these first steps
add greatly to the expense of isotope labeling, considerable
effort was devoted to the preparation of useful synthetic
precursors giving rise to efficient large-scale methods for
the synthesis of methane,1 methanol,2,3 methyl iodide,3-7
sodium formate,8 potassium cyanide,9 and carbon dioxide.
Therefore, we would like to introduce a new very versatile
labeled one-carbon precursor [13C]methyl phenyl sulfide (4)
which can also be used to prepare [13C]methyl phenyl sulfone
(5).25-27 Choudhry and co-workers demonstrated the ap-
plication of [14C]methyl phenyl sulfone for the production
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* Corresponding author E-mail: rudy@lanl.gov. Telephone: (505) 667-1000.
Fax: (505) 665-5052.
† Los Alamos National Laboratory.
‡ University of Texas at San Antonio.
§ Present address: Thiokol Propulsion, Brigham City, UT 84302.
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10.1021/op025530p CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002
Vol. 6, No. 6, 2002 / Organic Process Research & Development
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