New reactions of selenocarboxylates

Article abstract of DOI:10.1021/ol047889z

(Chemical Equation Presented) By treatment with Woollins' reagent in toluene solution, carboxylic acids are converted to selenocarboxylic acids. The latter react in situ to provide new products of acid- or base-promoted substitution, addition, and amidation.

Full text of DOI:10.1021/ol047889z

ORGANIC
LETTERS
2005
Vol. 7, No. 2
203-206
New Reactions of Selenocarboxylates
Spencer Knapp* and Etzer Darout
Department of Chemistry & Chemical Biology, Rutgers, The State UniVersity of New
Jersey, Piscataway, New Jersey 08854-8087
knapp@rutchem.rutgers.edu
Received October 12, 2004
ABSTRACT
By treatment with Woollins’ reagent in toluene solution, carboxylic acids are converted to selenocarboxylic acids. The latter react in situ to
provide new products of acid- or base-promoted substitution, addition, and amidation.
Organoselenium compounds are important as reagents and
intermediates in organic synthesis,1-4 as heavy-atom versions
of oligonucleotides5,6 and proteins7 for crystallographic study,
as human metabolites,8 as cancer-preventative agents9,10 and
other medicinals,11,12 and as substrates for biomimetic
studies.13-15 Selenonucleophiles are even more reactive than
the corresponding thio reagents,16 and this is a property that
can be exploited for the introduction of the selenium atom
into organic structures. While hundreds of reactions of
nucleophilic selenolate reagents RSe- are known, far fewer
reactions of the selenocarboxylate anion RCOSe- have been
reported. These include Se-alkylation with simple alkyl
halides,17,18 Se-arsination with arylchloroarsines,19 and O-
silylation to give RC(dSe)OSiR′3.20 Undoubtedly, better
synthetic use could be made of selenocarboxylic acids if they
could be easily prepared under conditions where their ready
conversion to the nonnucleophilic diacyldiselenides RCOS-
eSeCOR could be suppressed. We find that a heterogeneous
suspension of Woollins’ reagent,21,22 [PhP(dSe)Se]2, in
toluene converts carboxylic acids to a solution of the
corresponding selenocarboxylic acid, which may be used
directly for a variety of new reactions of selenocarboxylates,
including acid- or base-promoted substitution, addition, and
amidation under mild conditions.
Woollins’ reagent (2, Scheme 1) is a selenium analogue
of Lawesson’s reagent, [ArP(dS)S]2 (Ar ) p-methoxy-
(1) Iwaoka, M.; Tomoda, S. Top. Curr. Chem. 2000, 208, 55-80.
(2) Wirth, T. Top. Curr. Chem. 2000, 208, 1-5.
(3) Back, T. G. Organoselenium ChemistrysA Practical Approach;
Oxford Press: New York, 2000.
Scheme 1. Synthesis of Selenocarboxylic Acids
(4) Paulmier, C. Selenium Reagents and Intermediates in Organic
Synthesis; Pergamon Press: Oxford, UK, 1986.
(5) Hobartner, C.; Micura, R. J. Am. Chem. Soc. 2004, 126, 1141-1149.
(6) Buzin, Y.; Carrasco, N.; Huang, Z. Org. Lett. 2004, 6, 1099-1102.
(7) Hatch, D. M.; Boles, J. O.; Li, Z. Z.; Silks, L. A. Curr. Org. Chem.
2004, 8, 47-64.
(8) Kobayashi, Y.; Ogra, Y.; Ishiwata, K.; Takayama, H.; Aimi, N.;
Suzuki, K. T. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15932-15936.
(9) El-Bayoumy, K.; Sinha, R. Mutat. Res. 2004, 551, 181-197.
(10) Whanger, P. D. Brit. J. Nutr. 2004, 91, 11-28.
(11) Soriano-Garcia, M. Curr. Med. Chem. 2004, 11, 1657-1669.
(12) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. ReV. 2001, 101,
2125-2179.
(13) Roy, G.; Nethaji, M.; Mugesh, G. J. Am. Chem. Soc. 2004, 126,
2712-2713.
phenyl); the latter has been used extensively for various
thionation reactions.23 The preparation of 2 entails treating
(14) Zhu, Y. T.; Gieselman, M. D.; Zhou, H.; Averin, O.; van der Donk,
W. A. Org. Biomol. Chem. 2003, 1, 3304-3315.
(15) Mugesh, G.; du Mont, W. W. Chem. Eur. J. 2001, 7, 1365-1370.
(16) Pearson, R. G.; Sobel, H. R.; Songstad, J. J. Am. Chem. Soc. 1968,
90, 319-326.
(17) Koketsu, M.; Asada, H.; Ishihara, H. Phosph. Sulf. Silicon Relat.
Elem. 2004, 179, 591-595 and references therein.
10.1021/ol047889z CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/18/2004

(PhP)5 with 10 equiv of selenium powder in refluxing
toluene. The resulting red solid is collected by filtration and
stored in a desiccator at 23 °C. Reaction of 2 with amides
to give selenoamides has been reported.24,25 We observe that
carboxylic acids 1 react with 2 in hot toluene solution over
the course of several hours. During this period, 2 is
consumed, as evidenced by the disappearance of the red solid
and the appearance of a white solid coating the inside of the
flask, presumably the byproduct 2,4,6-triphenyl-1,3,5-trioxa-
2,4,6-triphosphinane-2,4,6-trioxide 4.24 The resulting yellow-
orange toluene solution contains the selenocarboxylic acid
3. The odor and toxicity issues normally associated with
organophosphorus and organoselenium compounds are easily
minimized by the standard precautions of working with
gloves and in a good fume hood, and no special handling
techniques are required.
Selenolesters such as 8 show diagnostic Se-CdO resonances
at ∼200 ppm.18 The yield of 8 was increased to quantitative
by using excess 6. The acidity of 6 is predicted to be greater
than that of the corresponding carboxylic and thiocarboxylic
acids;26,27 hence, the reaction of 6 with 7 can be thought of
as an acid-promoted conjugate addition of the seleno-
carboxylate, PhCH2COSe-. This is to our knowledge the first
example of addition of a selenocarboxylate to an alkene.
The efficiency of the selenocarboxylate addition to 7
prompted us to examine a more electron-rich alkene, tri-O-
benzyl-D-glucal 10 (Scheme 2). Selenylation of propionic
acid as for 5 led to a toluene solution of the presumed
selenopropionic acid 9, which was cooled to -40 °C and
then treated with 10. Completion of the reaction occurred
over 16 h at -5 °C and led cleanly to a single adduct, the
2-deoxy-1-seleno-R-D-glucopyranose derivative 11 (H-1 at
6.31 ppm, dd, J ) 4.6 and 1.2 Hz). This reaction is
noteworthy for the stereoselectivity of the addition, which
required no additional catalyst. Also notable is the nonin-
terference by a Ferrier rearrangement,28 which might have
competed with glycal addition29 under these conditions.
Another electron-rich alkene, R-methylstyrene (12) was
smoothly converted to selenolester 13 by simply stirring with
6. Very few methods exist for the synthesis of tertiary
selenols,30 and reduction or hydrolysis of alkene adducts such
as 13 ought to provide a straightforward route.
Efficient reaction of 3 with various substrates can be
effected by simply adding them to the toluene solution and
then monitoring their disappearance by TLC. Treatment of
phenylacetic acid 5 with 2 (Scheme 2) and then addition of
Scheme 2. Addition of Selenocarboxylates to Alkenes
The pronounced acidity of selenocarboxylates was ex-
ploited in two acid-promoted heterocyclic ring-opening
addition reactions (Scheme 3). Cyclo-uridine diacetate 15
Scheme 3. Heterocyclic Ring-Opening Reactions
1 equiv of cyclohexenone 7 to the presumed selenocarboxylic
acid 6 gave the product of Michael addition, selenolester 8.
(18) Koketsu, M.; Nada, F.; Hiramatsu, S.; Ishihara, H. J. Chem. Soc.,
Perkin Trans. 1 2002, 737-740.
reacted31 with the selenocarboxylic acid (14) prepared from
acetic acid to give the 2′-seleno ribonucleoside 16. Although
(19) Kanda, T.; Mizoguchi, K.; Koike, T.; Murai, T.; Kato, S. Synthesis
1994, 282-286.
(20) Kato, S.; Kageyama, H.; Kawahara, Y.; Murai, T.; Ishihara, H.
Chem. Ber. 1992, 125, 417-422.
(26) Kageyama, H.; Murai, T.; Kanda, T.; Kato, S. J. Am. Chem. Soc.
1994, 116, 2195-2196.
(27) Remko, M.; Rode, B. M. J. Phys. Chem. 1999, 103, 431-435.
(28) Dunkerton, L. V.; Adair, N. K.; Euske, J. M.; Brady, K. T.;
Robinson, P. D. J. Org. Chem. 1988, 53, 845-850.
(29) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem.
1990, 55, 5812-5813.
(30) Stoll, S. S.; Bott, S. G.; Barron, A. R. J. Chem. Soc., Dalton Trans.
1997, 1315-1322.
(31) Le Hir de Fallois, L.; De´cout, J.-L.; Fontecave, M. J. Chem. Soc.,
Perkin Trans. 1 1997, 2587-2596.
(21) Fitzmaurice, J. C.; Williams, D. J.; Wood, P. T.; Woollins, J. D. J.
Chem. Soc., Chem. Commun. 1988, 741-743.
(22) Grossmann, G.; Ohms, G.; Kru¨ger, K.; Karaghiosoff, K.; Eskstein,
K.; Hahn, J.; Hopp, A.; Malkina, O. L.; Hrobarik, P. Zeitschr. Anorg. Allg.
Chem. 2001, 627, 1269-1278.
(23) Jesberger, M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929-1958.
(24) Bethke, J.; Karaghiosoff, K.; Wessjohann, L. A. Tetrahedron Lett.
2003, 44, 6911-6913.
(25) Bhattacharyya, P.; Woollins, J. D. Tetrahedron Lett. 2001, 42,
5949-5951.
204
Org. Lett., Vol. 7, No. 2, 2005

prolonged heating at 70 °C was required, 14 survived without
significant side reactions to give the adduct in good yield.
GlcNAc-oxazoline 17, which is known to open under acidic
conditions,32 reacted in one pot with 2 and propionic acid to
provide directly the 2-acetamido-2-deoxy-1-seleno-â-D-glu-
copyranose derivative 18. The selenoacid 9 is thus formed
in situ and then reacts with 17, which is otherwise stable to
2 and to the starting carboxylic acid. Selenolesters such as
11, 16, and 18 might serve as precursors, by way of
derivatization on Se, to various carbohydrate seleno-
conjugates.33-35
Given the demonstrated nucleophilicity of anionic thio-
carboxylates, the SN2 reaction of selenocarboxylates ought
to be an excellent way to introduce selenium into carbo-
hydrate, peptidyl, and other frameworks. Indeed, the partially
protected R-D-glucopyranoside 2-triflate36 19 reacted with 6
in the presence of diisopropylethylamine to give the 2-seleno-
R-D-mannopyranoside derivative 20 (Scheme 4). Clean SN2
of the displacement conditions. Anomeric SN2 displacements
by other selenium nucleophiles have been previously re-
ported.33,35
Mitsunobu reactions with thiocarboxylates as the nucleo-
phile have been known for some time and are among the
most dependable ways to introduce the protected thiol
group,37 and yet no selenocarboxylate example has appeared.
Notably, however, N-tert-butoxycarbonylserine benzyl ester
(23) underwent successful conversion to the selenocysteine
derivative 24 in the presence of 6 (Scheme 4). To avoid
addition of 6 to the diisopropyl azodicarboxylate, the
complex of triphenylphosphine and DIAD was preformed
in THF solution at -40 °C. The solution was cooled to -78
°C; the substrate 23 was added, and then the toluene solution
of 6 was added by cannula at the same temperature.
The Williams amidation reaction of thiocarboxylic acids
with azides provides amides under mildly basic conditions.38
It is particularly useful in situations where the corresponding
amine is configurationally or solvolytically unstable. Sele-
nocarboxylic acids ought to undergo an analogous amidation;
this was evaluated with the 2-acetamido-2-deoxy-â-D-glu-
copyranosyl azide39 25 as the substrate (Scheme 5). Genera-
Scheme 4. Alkylation of Selenocarboxylate Anions
Scheme 5. Williams Amidations with Selenocarboxylates
reaction has occurred under mild conditions, significantly
milder, in fact, than those required by the anion of thioacetic
acid in the same displacement reaction.36 The 3-hydroxy
becomes acylated under the reaction conditions, possibly by
way of base-promoted intramolecular Se-to-O acyl migration,
followed by intermolecular Se-acylation by additional 6.
Acetobromo-R-D-glucose 21 reacted with selenocarboxy-
late 6 in the presence of 2,6-lutidine to give the product of
SN2 reaction at the anomeric center, 1-seleno-â-D-gluco-
pyranose derivative 22 (Scheme 4). The absence of both
eliminated product and the R-anomer attests to the mildness
tion of selenocarboxylic acid 6 as before, and then addition
of 25 and 1.7 equiv of 2,6-lutidine, led to an amidation
reaction at room temperature, and the N-glucopyranosyl
amide product 26 was isolated in high yield following
chromatography. Related N-glycosylamides have been shown
to inhibit rabbit muscle glycogen phosphorylase b.40 Inas-
much as the corresponding reaction of thiocarboxylates with
glucopyranosyl azides requires heating at 60 °C,41 the
selenocarboxylate is probably more reactive in Williams
amidation. A parallel observation of the greater reactivity
(32) Grant, L.; Liu, Y.; Walsh, K. E.; Walter, D. S.; Gallagher, T. Org.
Lett. 2002, 4, 4623-4625.
(37) Park, J. D.; Kim, D. H. J. Med. Chem. 2002, 45, 911-918.
(38) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J.
Am. Chem. Soc. 2003, 125, 7754-7755.
(33) Czernecki, S.; Randraimandimby, D. J. Carbohydr. Chem. 1996,
15, 183-190.
(34) Witczak, Z.; Czernecki, S. AdV. Carbohydr. Chem. Biochem. 1998,
53, 143-199.
(39) Wittmann, V.; Lennartz, D. Eur. J. Org. Chem. 2002, 1363-1367.
(40) Gyo¨rgydea´k, Z.; Hadady, Z.; Felfo¨ldi, N.; Krakomperger, A.; Nagy,
V.; To´th, M.; Brunya´nszki, A.; Dosca, T.; Gergely, P.; Somsa´k, L. Bioorg.
Med. Chem. 2004, 12, 4861-4870.
(35) Benhaddou, R.; Czernecki, S.; Randriamandimby, D. Synlett 1992,
967-968.
(36) Knapp, S.; Naughton, A. B. J.; Jaramillo, C.; Pipik, B. J. Org. Chem.
1992, 57, 7328-7334.
(41) For a catalyzed variant, see: Fazio, F.; Wong, C.-H. Tetrahedron
Lett. 2003, 44, 9083-9085.
Org. Lett., Vol. 7, No. 2, 2005
205

of selenophenolate (compared with thiophenolate) toward
azides was recorded in 1990.42
proved to be entirely unreactive toward an excess of
thioacetic acid, it was effectively converted to the acetamide
30 by selenoacetic acid 12 at 70 °C.
A more stringent test of amidation uses the electron-poor
carboxylic acid N-Cbz-glycine (27, Scheme 5). Conversion
of 27 to its ammonium salt with Hu¨nig’s base, followed by
selenylation with 2, gave a toluene solution of the presumed
selenocarboxylic acid. Heating with 25 (0.2 equiv based on
27) in the presence of CHCl3 and additional Hu¨nig’s base
produced N-glycosyl-glycine derivative 28.43 The selenylation
method is selective for the carboxylate in the presence of
the carbamate protecting group and gives as an intermediate
the first example of a protected R-amino selenocarboxylic
acid.
In summary, selenocarboxylates generated in situ are
versatile reagents for the introduction of selenium into
organic structures and for amidation. They also ought to
prove useful for applications where the nucleophilicity of
the corresponding thiocarboxylic acid is insufficient.
Acknowledgment. We are grateful to NIH (AI055760)
for financial support, UNCF-Merck for a graduate fellowship
to E.D., and Prof. L. J. Williams for stimulating discussions.
Another challenge to amidation is provided by the hindered
2-azidopiperidine derivative 29 (Scheme 5), an intermediate
in a projected synthesis of XylNAc-isofagamine. While 29
Supporting Information Available: Experimental de-
tails, spectral characterization, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(42) Bartra, M.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetrahedron 1990,
46, 587-594.
(43) Saha, U.; Roy, R. Tetrahedron Lett. 1995, 36, 3635-3638.
OL047889Z
206
Org. Lett., Vol. 7, No. 2, 2005