Direct thionation and selenation of amides using elemental sulfur and selenium and hydrochlorosilanes in the presence of amines

Article abstract of DOI:10.1021/ol9010882

Reactions of amides with elemental sulfur in the presence of hydrochlorosilanes and amines give the corresponding thioamides in good to high yields. The process takes place via reduction of elemental sulfur by the hydrochlorosilane in the presence of a suitable amine. The methodology can be applied to the selenation of amides by using elemental selenium. Thlonation and selenation of an acetyl-protected sialic acid derivative are found to take place selectively at the amide group.

Full text of DOI:10.1021/ol9010882

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3064-3067
Direct Thionation and Selenation of
Amides Using Elemental Sulfur and
Selenium and Hydrochlorosilanes in the
Presence of Amines
Fumitoshi Shibahara,* Rie Sugiura, and Toshiaki Murai*
Department of Chemistry, Faculty of Engineering, Gifu UniVersity,
Yanagido, Gifu 501-1193, Japan
fshiba@gifu-u.ac.jp; mtoshi@gifu-u.ac.jp
Received May 18, 2009
ABSTRACT
Reactions of amides with elemental sulfur in the presence of hydrochlorosilanes and amines give the corresponding thioamides in good to
high yields. The process takes place via reduction of elemental sulfur by the hydrochlorosilane in the presence of a suitable amine. The
methodology can be applied to the selenation of amides by using elemental selenium. Thionation and selenation of an acetyl-protected sialic
acid derivative are found to take place selectively at the amide group.
The thiocarbonyl group plays an important role in organic
synthesis because of its unique chemical behavior and
specific reactivity profile.1-3 One method for the synthesis
of thiocarbonyl compounds4 is through thionation reactions
of carbonyl precursors by using a preformed S2- generating
species, such as hydrogen sulfide5a or its salts,5b silathianes,5c
and phosphorus sulfides.6 However, handling of these
reagents is particularly cumbersome because of odor, toxicity,
and stability issues, and/or the concurrent formation of
inseparable byproduct.6 In addition, pretreatment of the
carbonyl group is often required.4,5 As a consequence of these
(1) For recent examples as reactants, see: (a) Majumdar, K. C.; Pal,
A. K. Can. J. Chem. 2007, 86, 72. (b) Murai, T.; Asai, F. J. Am. Chem.
Soc. 2007, 129, 780. (c) Cheng, Y.; Liu, M.-F.; Fang, D.-C.; Lei, X.-M.
Chem.sEur. J. 2007, 13, 4282. (d) Downer-Riley, N. K.; Jackson, Y. A.
Tetrahedron 2007, 63, 10276. (e) Prokopcov, H.; Kappe, C. O. Org. Lett.
2007, 72, 4440. (f) Shibahara, F.; Suenami, A.; Yoshida, A.; Murai, T.
Chem. Commun. 2007, 2354. (g) Shibahara, F.; Yoshida, A.; Murai, T.
Chem. Lett. 2008, 37, 646. (h) Murai, T.; Asai, F. J. Org. Chem. 2008, 73,
9518. (i) Goossen, L. J.; Blanchot, M.; Salih, K. S. M.; Karch, R.; Rivas-
Nass, A. Org. Lett. 2008, 10, 4497. (j) Inamoto, K.; Hasegawa, C.; Hiroya,
(3) For recent examples as organocatalysts, see: (a) Doyle, A. G.;
Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (b) Geng, X.-L.; Li, G.-X.;
Chen, P.; Tian, S.-F.; Qu, J. J. Org. Chem. 2008, 73, 8558. (c) Ganesh,
M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464
.
(4) For reviews on the synthesis of thiocarbonyl compounds, see: (a)
Lebel, H. Sci. Synth. 2005, 22, 141. (b) Ishii, A.; Nakayama, J. In Topics
in Current Chemistry; Springer: Berlin/Heidelberg, 2005; Vol. 251, pp
181-225. (c) Murai, T. In Topics in Current Chemistry; Springer: Berlin/
Heidelberg, 2005; Vol. 251, pp 247-272. (d) Polshettiwar, V.; Kaushik,
K.; Doi, T. Org. Lett. 2008, 10, 5147
.
M. P. J. Sulfur. Chem. 2006, 27, 353, and references cited therein.
(2) For recent examples in total synthesis, see: (a) Maloney, D. J.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 7789. (b) Blanchet, J.;
Pouliquen, M.; Lasne, M.-C.; Rouden, J. Tetrahedron Lett. 2007, 48, 5727.
(c) England, D. B.; Padwa, A. J. Org. Chem. 2008, 73, 2792. (d) Schmidt,
A.; Lindner, A. S.; Shilabin, A. G.; Nieger, M. Tetrahedron 2008, 64, 2048.
(e) Zhao, Y.-M.; Gu, P.; Tu, Y.-Q.; Fan, C.-A.; Zhang, Q. Org. Lett. 2008,
10, 1763. (f) Amat, M.; Griera, R.; Fabregat, R.; Molins, E.; Bosch, J.
Angew, Chem. Int. Ed. 2008, 47, 3348. (g) Frankowski, K. J.; Golden, J. E.;
(5) (a) Charette, A. B.; Chua, P. Tetrahedron Lett. 1998, 39, 245. (b)
Charette, A. B.; Grenon, M. J. Org. Chem. 2003, 68, 5792. (c) Smith, D. C.;
Lee, S. W.; Fuchs, P. L. J. Org. Chem. 1994, 59, 348
.
(6) For reviews on thionation reactions using phosphorous sulfide
derivatives and Lawesson’s reagent, see: (a) Jesberger, M.; Davis, T. P.;
Barner, L. Synthesis 2003, 1929. (b) Ozturk, T.; Ertas, E.; Mert, O. Chem.
ReV. 2007, 107, 5210. Also see: (c) Curphey, T. J. J. Org. Chem. 2002, 67,
6461. (d) Pathak, U.; Pandey, L. K.; Tank, R. J. Org. Chem. 2008, 73,
Zeng, Y.; Lei, Y.; Aube´, J. J. Am. Chem. Soc. 2008, 130, 6018
.
2890.
10.1021/ol9010882 CCC: $40.75
Published on Web 06/17/2009
 2009 American Chemical Society

shortcomings, a new methodology for direct thionation of
carbonyl compounds, which relies on reaction of in situ
generated S2-, produced from easy-to-handle elemental sulfur
and an appropriate reducing agent, would be especially
attractive.7 The choice of a reducing agent that can selectively
reduce elemental sulfur in the presence of carbonyl com-
pounds is essential for the design of this new methodology.
Below, we describe the results of a study that has led to the
development of a direct carbonyl thionation process involving
in situ generation S2- by reaction of elemental sulfur with
hydrochlorosilanes in the presence of amines. Also, the
methodology has been extended to selenations of amides
using elemental selenium.8
Hydrosilanes are frequently used as reducing agents, but
they are observed to react only sluggishly with carbonyl
compounds in the absence of suitable additives.9 Owing to
this property, hydrosilanes were envisaged as likely reduc-
tants for elemental sulfur. Since the high oxophilicity of
silicon in chlorosilanes could potentially facilitate elimination
of oxygen from the carbonyl group, hydrochlorosilanes were
identified as ideal reducing agent in an elemental sulfur based
carbonyl thionation process (Figure 1).
lamine (3b) was generated as the sole product along with
recovered 1b. We hypothesized that, owing to their nucleo-
philicity and/or basicity, the amines formed by carbonyl
reduction might play an important role in the thionation
process. In fact, when DMAP (4-dimethylaminopyridine) is
employed as an additive in the HSiCl3/S8 promoted thionation
reaction of 1b, thioamide 2b is produced in a modestly high
yield. In addition, the yields for production of thioamides
2a and 2b from the respective amides 1a and 1b are
enhanced (88% and 93%, respectively) when a reduced
amount of S8 (1.1 equiv) is used and the reactions are run in
the presence of DMAP (1.1 equiv). Thionation of 1a with
Lawesson’s reagent (LR) also proceeded smoothly, but the
isolation of the product 2a by column chromatography
resulted in the contamination of the byproducts. Further
purification of the mixture gave 2a in a lower isolated yield.11
With the optimized conditions in hand, the scope of
thionation reactions of amides was explored (Scheme 2). The
Scheme 2.
Scope of Amidesa
Figure 1. An approach for direct thionation of carbonyl compounds
by elemental sulfur using hydrochlorosilane as a reductant.
To evaluate this proposal, reaction of N,N-dibenzylfor-
mamide (1a) with 2 equiv of S8 in the presence of 1.1 equiv
of HSiCl3 at 115 °C in toluene was carried out. Importantly,
the corresponding thioformamide 2a was generated in 78%
yield along with the byproduct dibenzylmethylamine (3a),
derived by reduction of 1a (Scheme 1).10 Under the HSiCl3/
Scheme 1. Optimization of Reaction Conditions
a Reaction conditions: mixtures of the amide or lactam (1 mmol), S8,
amine, and HSiCl3 (1.1 equiv each) in toluene in a sealed tube under air
were heated at 115 °C. b A major portion of the recovered material was the
starting amide. c The yield for a 20 mmol scale reaction for a 24 h period
was 80%.
observations made in this effort show that amines other than
DMAP (e.g., DABCO (1,4-diazabicyclo[2.2.2]octane) and
dibenzylamine) serve to promote efficient thionation reac-
tions. For example, the sterically hindered amides 1c-1e
do not undergo thionation reactions when DMAP is used.
S8 condition N,N-diphenylformamide (1b) does not react to
produce the thioamide product 2b. Rather, methyldipheny-
Org. Lett., Vol. 11, No. 14, 2009
3065

In contrast, these substances participate in efficient (79%,
90%, and 64%, respectively) thionation reactions that are
promoted by DABCO or dibenzylamine. DMF (1f) reacts
on a small scale in the presence of DMAP to yield the
thioamide 2f quantitatively and on a multigram scale without
a significant loss of efficiency (80% isolated yield). Thion-
ation reactions of secondary amides 1g-1l proceed smoothly
in the presence of either DMAP or DABCO to give
thioamides 2f-2l in high yields. The presence of electron-
donating and electron-withdrawing substituents on the aro-
matic rings of the benzamides 1k and 1l does not influence
the efficiency of the reaction. The piperidine and morpholine
derived amides 1m and 1n also react to generate thionated
products in good to excellent yields. In addition, the tertiary
lactam 1o is converted to the corresponding thiolactam 2o
in high efficiency under the thionation reaction conditions.
Importantly, amide 1p and lactam 1q, which contain remote
alkoxycarbonyl groups, undergo selective thionation reactions
at the amide groups, yielding 2p and 2q in respective yields
of 76% and 95% (Scheme 3). As a likely result of the
HSiPhCl2 and a lower reaction temperature (condition B)
enables efficient (83%) conversion of this substance to the
thiolactam 2r. The reaction of N-2-pyridylmethylformamide
(1s) under standard conditions (condition A) also gives a
complex mixture. In contrast, application of condition B to
1s also affords the thioamide 2s in 42% yield. The use of
LR for the thionation of 1s results in the formation of a
mixture of 2s and phosphorus-containing inseparable byprod-
ucts derived from LR.11
The procedure described above was applied to selenation
reactions of amides 1a, 1b, and 1h. Significantly, reaction
of amides with elemental selenium (1.1 equiv) in the presence
of HSiCl3 and DMAP (1.1 equiv each) at 115 °C affords
the corresponding selenoamides 4a, 4b, and 4h efficiently,
although the labile products partly decompose under the
workup conditions (Scheme 5).
Scheme 5. Direct Selenations of Carbonyl Compounds by
Elemental Selenium Using Hydrochlorosilane
Scheme 3. Chemoselectivity of Thionation
To demonstrate the preparative potential of the new
thionation and selenation reactions, the methodologies were
applied to the structurally and functionally more complex
acetyl protected sialic acid derivative 5. Interestingly, thion-
ation and selenation reactions of 5, a substrate that contains
a number of different carbonyl groups, take place selectively
at the amide moiety to give the corresponding products 6
and 7 in moderate yields (Scheme 6). Notably, the other
instability of the starting amide and product thioamide,
reaction of the secondary lactam 1r under the standard
Scheme 4
.
Thionations with the Other Hydrochlorosilane as a
Reductant
Scheme 6
.
Thionation and Selenation of Acetyl Protected Sialic
Acid Derivative
conditions gives rise to formation of a complex product
mixture (Scheme 4, condition A). In contrast, the use of
carbonyl functional groups in 5 remain intact under the
reaction conditions, and most of unreacted 5 is recovered
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Org. Lett., Vol. 11, No. 14, 2009

(some decomposition of the substrate and product are
observed to take place after prolonged reaction times).
In conclusion, the investigations described above have led
to the development of a new methodology for direct
thionation and selenation reactions of amides that employs
elemental sulfur and selenium, a hydrosilane, and an amine.
In the reaction pathways, elemental sulfur or selenium is
reduced in situ to generate S2- or Se2-, which then undergo
efficient thionation and selenation reactions with the amides.
In addition, the results of the effort show that the reaction
efficiency can be improved by simply changing the combina-
tion of readily available hydrosilane and amine used. Finally,
alkoxycarbonyl groups remain intact under the reaction
conditions used to transform amides to the corresponding
thioamides. The observations made in this effort suggest that
this methodology will have wide preparative applicability.
Acknowledgment. We acknowledge the generous dona-
tion of compound 5 from and helpful discussions with Dr.
Hiromune Ando (Gifu University, Japan). This research was
supported by a Grant-in-Aid for Scientific Research from
the MEXT and JSPS.
(7) For examples of reduction reactions of elemental sulfur, see: (a)
Gladysz, J. A.; Wong, V. K.; Jick, B. S. Tetrahedron 1979, 35, 2329. (b)
Horn, V. H.-G.; Hemeke, M. Chem. -Ztg. 1985, 109, 1.
(8) For a review on selenation, see: Hua, G.; Woollins, J. D. Angew.
Chem., Int. Ed. 2009, 48, 1368, and references therein.
(9) (a) Transition Metal for Organic Synthesis, 2nd ed.; Beller, M., Bolm,
C., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2004; Vol. 2. (b) Modern Reduction Methods; Andersson, P. G., Munslow,
I. J., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2008.
Supporting Information Available: Experimental details,
characterization data, and copies of 1H and 13C NMR for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Nagata, Y.; Dohmaru, T.; Tsurugi, J. Chem. Lett. 1972, 989.
(11) See Supporting Information for details.
(12) Dabdoub, M. J. Sci. Synth. 2004, 27, 215.
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