Tris(2-Carboxyethyl)phosphine (TCEP) for the reduction of sulfoxides, sulfonylchlorides, N-oxides, and azides

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tris(2-Carboxyethyl)phosphine (TCEP) for the
Reduction of Sulfoxides, Sulfonylchlorides, N-Oxides,
and Azides
Anne-Marie Faucher a & Chantal Grand-Maître a
a Boehringer Ingelheim (Canada) Ltd., Research and Development , Laval (Québec), Canada
Published online: 15 Aug 2006.
To cite this article: Anne-Marie Faucher & Chantal Grand-Maître (2003) tris(2-Carboxyethyl)phosphine (TCEP) for the
Reduction of Sulfoxides, Sulfonylchlorides, N-Oxides, and Azides, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:20, 3503-3511, DOI: 10.1081/SCC-120024730
To link to this article: http://dx.doi.org/10.1081/SCC-120024730
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 20, pp. 3503–3511, 2003
tris(2-Carboxyethyl)phosphine (TCEP) for the
Reduction of Sulfoxides, Sulfonylchlorides,
N-Oxides, and Azides
*
Anne-Marie Faucher and Chantal Grand-Maıtre
ˆ
Boehringer Ingelheim (Canada) Ltd.,
Research and Development,
Laval (Quebec), Canada
´
INTRODUCTION
tris(2-Carboxyethyl)phosphine (TCEP), commercially available as a
hydrochloride complex, is an efficient reducing agent most commonly
used to reduce disulfide bonds. It is a good substitute for dithiothreitol
(DTT) to prevent the formation of intramolecular disulfide bridges in
protein, thus preserving their bioactive secondary structure.[1–3] Other
uses of TCEP seem to be limited to an analytical tool used for the
quantification of sulfides, disulfides, hypochlorous acid, hypochlorite
ions, iodine, and iodate ions.[4] In this article, we wish to report how
TCEP can be used as a convenient reducing agent in synthesis for the
reduction of several functional groups.
*Correspondence: Anne-Marie Faucher, Boehringer Ingelheim (Canada) Ltd.,
Research and Development, 2100 Cunard Street, Laval (Quebec), Canada, H7S
´
2G5; Fax: (450) 682-4189; E-mail: amfauche@lav.boehringer-ingelheim.com.
3503
DOI: 10.1081/SCC-120024730
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3504
There are several methods available for the reduction (de-oxygena-
tion) of sulfur- and nitrogen-containing molecules.[5–13] For sulfur-
containing molecules, one of the mildest reduction methods involves
the transfer of oxygen to a trivalent phosphorous atom. However,
many phosphorous reagents, and their corresponding oxides, present
handling challenges. When HMPT[8] is used for reduction, it produces
HMPA which is toxic. Trialkylphosphines are often flammable and have
unpleasant odors. As well, when trialkylphosphines are used as reducing
agents, a chromatographic separation is required to remove phosphine
oxide by-products from the desired material.[5,6,9,10] TCEP is an air
stable, odorless, crystalline phosphine. The three carboxyl groups
embedded in the structure contribute to the aqueous solubility of
TCEP and its corresponding oxide. These features give TCEP an
advantage over other phosphines in preparative reactions.
There are many reaction conditions described in the Lit.[5,6,8–10] for
the de-oxygenation of sulfur-containing molecules with trivalent phos-
phorous compounds. When the trivalent phosphorous compound is a
trialkylphosphine, it can be used alone or in the presence of a co-reactant
such as iodine, CCl4, acylating agents, etc. When used alone, the accepted
reaction mechanism involves a nucleophilic attack by phosphorous
according to Eq. (1). For less reactive sulfoxides, it may be advantageous
or even necessary to perform the reaction in the presence of a co-reactant
such as iodine. In this case, an iodophosphonium iodide complex
becomes the reactive species and the accepted reaction mechanism is
shown in Eq. (2).
ð1Þ
ð2Þ
RESULTS AND DISCUSSION
Sulfur-containing compounds with a high oxidation state were
selected to react with TCEP alone or in the presence of iodine.
Dibenzylsulfoxide was treated with TCEP (1.1 equiv.) in a mixture of
dioxane and water under reflux. The sulfoxide was converted to the
corresponding thioether in 18.5 h (Entry 1). Completion of the reaction

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tris(2-Carboxyethyl)phosphine (TCEP)
3505
was achieved more rapidly (2.5 h) when the concentration of the
reaction mixture was increased (Entry 2). Several experiments were per-
formed to determine if water as co-solvent and/or the molecule of
hydrogen chloride associated with commercially available TCEP had
a role in the reduction reaction. The reaction was conducted in the
absence of water (Entry 3) and resulted in a rapid consumption of
dibenzylsulfoxide but the reaction mixture contained only 40% of
desired thioether and two by-products. The product distribution did
not change with prolonged heating (17 h). These observations indicate
that the appearance of thioether reduction product is more rapid in
absence of water, but also suggest that the starting sulfoxide undergoes
side reactions, possibly through reaction with ‘‘naked’’ chloride ions.
The reaction was then performed in the presence of molecular sieve to
trap moisture and HCl (Entry 4). Under these conditions, the reaction
was inhibited. The addition of an equimolar amount of sodium hydro-
xide to the reaction mixture to neutralize HCl while maintaining water
present (Entry 5) also had an inhibitory effect. When solid TCEP was
preheated (in a different attempt to remove HCl from the reaction
mixture, Entry 6) the reaction proceeded to completion but had a
slower rate. Therefore, it was concluded that the presence of HCl in
the commercially available TCEP is beneficial to the reduction reaction
and that water may decrease the reaction rate but also prevents side
reactions. Adding a sub-stoichiometric amount of iodine to the reaction
mixture, but omitting water to preserve the iodophosphonium iodide
formed (Eq. (2)), improved the reaction rate (compare Entries 1 and 7).
The reaction did not require sodium iodide which is the case with other
trivalent phosphorous reagent.[8,9] A TCEP-iodine mixture was the
condition of choice for less reactive sulfoxides or sulfoxide bearing a
reactive functional group that did not withstand prolonged heating. The
reduction of benzylphenylsulfoxide with TCEP was too sluggish to be
useful (Entry 8), but with the addition of iodine, the conversion to
benzylphenylthioether was complete within 1 h (Entry 9). As well, the
reduction of methyl phenylsulfoxide with TCEP alone to its
corresponding thioether took 42 h (Entry 10), but only 1 h in the
presence of iodine (Entry 11). The reduction of methyl (phenylsulfinyl)-
acetate with TCEP did not give the desired product (Entry 12), but
when iodine was added, the desired thioether was obtained in 1 h
(Entry 13). Diphenylsulfoxide was completely converted in 2 h to
the desired thioether in the presence of iodine (Entry 14). Sulfones
were inert to the reaction conditions that involved the use of water
or iodine in presence of two equivalents of TCEP (Entries 15 to 18).
p-Toluenesulfonic acid and pyridinium p-toluenesulfonate were also

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Faucher and Grand-Maıtre
3506
inert to the reaction conditions with and without iodine (Entries 19 to
21). These later results contrast with what has been reported for other
trialkylphosphines.[10a] However, an alternative to the generation of
thiols from sulfonates involved the use of sulfonyl chlorides which
were rapidly and cleanly converted to the corresponding thiols
(Entries 22 and 23) using four equivalents of TCEP in a refluxing
dioxane-water mixture.
The de-oxygenation procedures could also be applied to N-oxides.
4-Phenylpyridine-N-oxide was deoxygenated using TCEP (1.1 equiv.) in
dioxane at reflux in 25 h (Entry 24). The use of water or iodine had no
apparent effect on the reaction rate (Entries 24 and 25). TCEP also
deoxygenated collidine-N-oxide with no significant difference in reaction
rate compared to 4-phenylpyridine-N-oxide (Entries 26 and 27).
Competition experiments involving equimolar amounts of TCEP, colli-
dine-N-oxide, and 4-phenylpyridine-N-oxide, with water or with iodine,
produced collidine and phenylpyridine as a 1:1.2 mixture. Nicotine-N-
oxide and N,N-dimethylbenzylamine-N-oxide were completely reduced
by TCEP within 1 h in a refluxing mixture of dioxane and water
(Entries 28 and 29).
Azides are known to react with tertiary phosphines to produce
phosphinimines.[14] The phosphinimines are then converted to their
corresponding primary amines and phosphine oxides in the presence of
water.[15] P-Azidobenzoic acid in the presence of TCEP and water was
converted to p-aminobenzoic acid within 15 min at ambient temperature
with a slight exotherm (Entry 30). The reaction was complete when gas
evolution had ceased. Thus, the transformation of azides to primary
amines is rapid, clean, and efficient with TCEP.
EXPERIMENTAL
All substrates used in this study and their respective reaction
products are known and most are commercially available. The reaction
products were characterized by 1H NMR, HPLC, and MS and the
collected data was compared with that of the literature. Commercially
available solvents and reagents, including TCEP (Sigma), were used as
received without purification. The reactions were monitored by reverse
phase HPLC (water-acetonitrile, 0.1% trifluoroacetic acid) on an YMC
Combiscreen ODS-AQ column. NMR spectra were acquired on a
Brucker 400 MHz spectrometer using DMSO-d6 and MS spectra were
obtained from a Micromass LCZ instrument in electrospray mode. We

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tris(2-Carboxyethyl)phosphine (TCEP)
3507
also performed LCMS analyses on a Waters-Micromas ZQ platform in
electrospray mode.
General Procedure for the Reduction of Sulfoxides, Sulfonyl
Chlorides, and N-Oxides with TCEP and Water
To a solution of substrate in a mixture of dioxane and water was
added TCEP (see ‘‘Table of Results’’ for amounts). The resulting solution
was heated to reflux under an atmosphere of nitrogen and the reaction
was monitored by HPLC. Upon completion, the reaction mixture was
diluted with water (1N NaOH when an amine was the reaction product)
and extracted with dichloromethane. The resulting organic solution was
dried with anhydrous MgSO4 and concentrated under reduced pressure
affording in most cases a crude isolate with greater than 90% homoge-
neity (HPLC) which could be purified further by flash chromatography
on a short column of silica using mixtures of hexane and ethyl acetate as
eluent.
General Procedure for the Reduction of Sulfoxides, Sulfonyl
Chlorides, and N-Oxides with TCEP and Iodine
Same as above but water was omitted and iodine was added. Upon
completion, the crude reaction mixture was diluted with dichloromethane
and washed with aqueous 30% NaHSO3 and water, then treated with
anhydrous MgSO4 and concentrated under reduced pressure to afford a
crude isolate with greater than 90% homogeneity (HPLC).
General Procedure for the Reduction of p-Azidobenzoic Acid
with TCEP and Water
Same as above for sulfoxides, sulfonyl chlorides, and N-oxides
except that the reaction was performed at ambient temperature. Upon
completion, the reaction mixture was diluted with 1N NaH2PO4 (pH
4.5) and extracted with ethyl acetate. The organic phase was then
treated with anhydrous MgSO4 and concentrated under reduced
pressure to afford a crude isolate with greater than 99% homogeneity
(HPLC).

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ˆ
Faucher and Grand-Maıtre
3508

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tris(2-Carboxyethyl)phosphine (TCEP)
3509

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ˆ
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3510
CONCLUSION
tris(2-carboxyethyl)phosphine (TCEP) has been shown to efficiently
reduce sulfoxides, sulfonylchlorides, N-oxides, and azides with significant
practical value. TCEP is particularly attractive compared to other tri-
alkylphosphines because it is an air stable and odorless solid. Also, this
phosphine and its corresponding oxide are water soluble thus facilitating
a clean isolation of the desired end-product using simple aqueous/organic
extraction procedures.
ACKNOWLEDGMENTS
The authors thank Kimberley Thompson and Pierre Lavalle
´
e for
useful advice.
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Received in the USA April 17, 2003

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