Ruthenium-catalyzed stereoselective anti-markovnikov-addition of thioamides to alkynes

Article abstract of DOI:10.1021/ol801736h

(Chemical Equation Presented) A catalyst system generated in situ from bis(2-methallyl)-cycloocta-1,5-diene-ruthenium(ll) and a phosphine was found to efficiently catalyze the addition of thioamides to terminal alkynes with exclusive formation of the anti-Markovnikov thioenamide products. The stereoselectivity of the addition is usually high and controlled by the choice of the phosphine ligand, whereas the (E)-isomers are predominantly formed in the presence of tri(n-octyl)phosphine, the use of bis(dicyclohexylphosphino)methane preferentially leads to the formation of the (Z)-configured thioenamides.

Full text of DOI:10.1021/ol801736h

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4497-4499
Ruthenium-Catalyzed Stereoselective
anti-Markovnikov-Addition of Thioamides
to Alkynes
Lukas J. Goossen,*,† Mathieu Blanchot,† Kifah S. M. Salih,† Ralf Karch,‡ and
Andreas Rivas-Nass‡
Fachbereich Chemie, TU Kaiserslautern, Erwin-Schro¨dinger-Strasse, Building 54,
D-67663 Kaiserslautern, Germany, and UMICORE AG & CO. KG, Rodenbacher
Chaussee 4, D-63457 Hanau, Germany
goossen@chemie.uni-kl.de
Received July 29, 2008
ABSTRACT
A catalyst system generated in situ from bis(2-methallyl)-cycloocta-1,5-diene-ruthenium(II) and a phosphine was found to efficiently catalyze
the addition of thioamides to terminal alkynes with exclusive formation of the anti-Markovnikov thioenamide products. The stereoselectivity
of the addition is usually high and controlled by the choice of the phosphine ligand, whereas the (E)-isomers are predominantly formed in the
presence of tri(n-octyl)phosphine, the use of bis(dicyclohexylphosphino)methane preferentially leads to the formation of the (Z)-configured
thioenamides.
Enamides are abundant substructures in natural products and
bioactive molecules.1 As this moiety has been reported to
function as a pharmacophore, enamides are routinely in-
cluded in compound libraries used for lead discovery. In
sharp contrast, thioenamides, which should be of considerable
interest as structural variants of such subunits, with distinct
electronic and steric properties, are only scarcely found in
the chemical literature. Among the very few reactions
investigated starting from this compound class are the
photochemical preparation of isoquinolinethiones or thiazo-
lines from aromatic thioenamides.2 The remarkable neglect
of thioenamides in organic synthesis and drug discovery is
easily explained by the lack of a concise and generally
applicable synthetic entry to this substrate class: at present,
thioenamides are only accessible by treating the analogous
enamides, which themselves are not easily synthesized, with
Lawesson’s reagent2,3 or other similarly aggressive sulfur-
izing agents.4 This synthetic approach does not tolerate many
sensitive functionalities, and the required workup and
purification steps are rather complex and difficult. Thus, the
development of an expedient synthetic entry to the thioena-
mides substrate class remains a highly desirable target.
The practical synthesis of thioenamides via regio- and
stereoselective ruthenium-catalyzed anti-Markovnikov ad-
dition of thioamides to terminal alkynes disclosed herein (see
equation in Abstract) promises to meet this long-standing
synthetic challenge.5
† TU Kaiserslautern Chemie.
‡ UMICORE AG & CO. KG.
(3) Yde, B.; Yousif, N. M.; Pederson, U.; Thomsen, I.; Lawesson, S.-
(1) Yet, L. Chem. ReV. 2003, 103, 4283.
O. Tetrahedron 1984, 40, 2047.
(2) (a) Couture, A.; Dubiez, R.; Lablache-Combier, A. J. Chem. Soc.,
Chem. Commun. 1982, 842. (b) Couture, A.; Dubiez, R.; Lablache-Combier,
A. J. Org. Chem. 1984, 49, 714.
(4) (a) Couture, A.; Dubiez, R.; Lablache-Combier, A. Tetrahedron 1984,
40, 1835. (b) Yamamoto, K.; Yamazaki, S.; Murata, I. J. Org. Chem. 1988,
53, 5374.
10.1021/ol801736h CCC: $40.75
Published on Web 09/19/2008
2008 American Chemical Society

The analogous addition of nucleophiles such as carboxy-
lates,6 amines,7 water,8 amides,9 and imides10 to alkynes
represents a particularly atom-economical entry to other
synthetically valuable substrate classes, provided that the
regio- and stereochemistry of the transformation can ef-
ficiently be controlled by the catalyst system. We have
previously developed several Ru(II)-catalysts that allow the
selective anti-Markovnikov addition of various nitrogen
nucleophiles, including amides, urethanes, carbamates, imi-
des, and ureas, to terminal alkynes.9,10 However, none of
these catalysts mediates the conversion of thioenamides. This
may be attributed to the substantially higher acidity of
thioamides compared to amides (pKa of 2-pyrrolidone, 24.2;
pyrrolidine-2-thione, 18.1),11 along with the fact that sulfur-
containing compounds are known catalyst poisons due to
their strong interaction with late transition metals. As an
added difficulty, thioamides are ambident nucleophiles and
can react at the nitrogen or sulfur terminus depending on
the electrophile used, following the HSAB concept. For
example, the reaction of pyrrolidine-2-thione with ethyl
bromoacetate affords the corresponding thioimino ester,12
whereas with benzoyl chloride, the thioenamide is formed.13
This additional chemoselectivity issue also had to be
controlled in our planned transition metal-catalyzed reaction.
Table 1. Optimization of the Catalyst and Conditionsa
yield/%
entry
Ru-precursor
ligand additive solvent (3a:4a)b
1
(cod)Ru(met)2
n-Bu3P DMAP PhMe 40 (6:1)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19c
20d
21
22
23e
”
”
”
”
”
”
”
”
”
”
K2CO3
LiCl
3 Å MS
”
”
”
”
”
”
”
”
”
”
”
”
”
84 (5:1)
87 (9:1)
93 (11:1)
72 (10:1)
80 (9:1)
0 (nd)
33 (8:1)
43 (5:1)
66 (2:1)
10 (nd)
96 (16:1)
80 (4:1)
15 (1:1)
[(p-cymene)RuCl2]2
(cod)RuCl2
Ru3(CO)12
RuCl3
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
(cod)Ru(met)2
PPh3
PFur3
t-Bu3P
n-Oct3P
dppm
dcypm
n-Oct3P
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
glyme 85 (12:1)
EtOH 55 (10:1)
DMF
mesit. 91 (13:1)
”
”
98 (6:1)
To identify an efficient catalyst for the desired hydrothioa-
midation, we selected the reaction of pyrrolidine-2-thione
(1a) with 1-hexyne (2a) as the model system and systemati-
cally examined the catalytic activity of various ruthenium
sources in combination with different ligands, solvents,
additives, and reaction conditions (Table 1). We initially
employed a combination of bis(2-methallyl)-cycloocta-1,5-
diene-ruthenium(II) [(cod)Ru(met)2] with tri(n-butyl)phos-
phine and 4-(dimethylamino)pyridine (DMAP) in toluene,
which was the most effective system for the analogous
addition of amides to alkynes. Under these conditions,
N-((E)-hex-1-enyl)pyrrolidine-2-thione (3a) was obtained in
rather low yield and unsatisfactory stereoselectivity along
with alkyne oligomerization products (entry 1). Substituting
DMAP with inorganic bases led to higher yields but no
improvements in selectivity (entry 2). Mild Lewis acids such
as lithium chloride or 3 Å molecular sieves improved both
yield and selectivity, with the added beneficial effect of the
latter that it removed water from the reaction mixture, thus
preserving the products from hydrolysis. As a result, 3a was
obtained in 93% yield and 11:1 stereoselectivity (entries 3,
4). Its identity was confirmed by comparison to a sample
that was prepared via a literature procedure.13 All alternative
Ru-precursors tested were less effective than the (cod)Ru-
(met)2 initially employed (entries 5-8). Furthermore, the use
of tri(n-alkyl)phosphines was crucial for achieving high
selectivities in favor of the (E)-products, best results having
been obtained with tri(n-octyl)phosphine (entries 9-14).
Nonpolar aromatic solvents such as toluene or mesitylene
were most effective, but other solvents can also be used
(entries 15-18). A temperature of 100 °C represents the best
82 (12:1)
87 (16:1)
dcypm K2CO3 PhMe 64 (1:1.5)
”
KOtBu
n-Oct3P 3 Å MS
”
”
76 (1:2)
84 (14:1)
a Conditions: 0.50 mmol pyrrolidine-2-thione, 1.00 mmol 1-hexyne, 0.01
mmol Ru-precursor, 0.03 mmol ligand (0.015 mmol for chelating phos-
phines), 0.02 mmol additive or 250 mg 3 Å MS, solvent (1.5 mL), 100 °C,
15 h; dppm ) bis(diphenylphosphino)methane, dcypm ) bis(dicyclohexyl-
phosphino)methane, mesit. ) mesitylene. b Yields and selectivities deter-
mined by GC using n-tetradecane as internal standard. c Temperature of 80
°C. d Temperature of 120 °C. e Pyrrolidine-2-thione (0.5 mmol), 1-hexyne
(0.5 mmol).
compromise between turnover rate and stereoselectivity
(entries 19, 20).
In an attempt to invert the stereoselectivity of the addition,
we combined the ligand with the lowest (E)-selectivity,
bis(dicyclohexylphosphino)methane (dcypm), with various
additives, and found that the (Z)-isomer can indeed be
obtained as the major product with 76% yield and 1:2
selectivity in the presence of potassium tert-butoxide (entries
21, 22). The alkyne is best used in excess to ensure complete
conversion of the thioamide, as some alkyne is consumed
by competing oligomerizations (entry 23).
Under optimized conditions (entries 12, 22), anti-Mark-
ovnikov-products are observed exclusively, and products
arising from reaction at the S- rather than the N-terminus of
the thioamide could never be detected. We believe that the
reaction follows a mechanism analogous to that proposed
for the addition of imides to alkynes:10 The alkyne first
coordinates to an Ru(II)-thioamide species generated from
the catalyst precursor, then a thioamide anion adds to the
C-C triple bond giving rise to a η1-Ru-vinyl complex.
(5) For a non-catalytic addition of thioamides to conjugated alkynes,
see: Nakhmanovich, A. S.; Glotova, T. E.; Komarova, T. N.; Skvortsova,
G. G.; Sigalov, M. B.; Modonov, V. B. Zh. Org. Khim. 1983, 19, 1428.
4498
Org. Lett., Vol. 10, No. 20, 2008

thione added smoothly to various alkynes, among them alkyl-
and aryl-substituted alkynes, trimethylsilylacetylene, and
conjugated enynes. On the other hand, phenylacetylene
reacted with a range of secondary thioamides bearing
aromatic or aliphatic substitutents, as well as with an example
for a thiocarbamate. In most cases, the products were
obtained in good yields and high selectivities for the (E)-
configured anti-Markovnikov-thioenamides. These represen-
tative examples illustrate that this protocol is likely to be
generally applicable to the synthesis of functionalized (E)-
thioenamides. Primary thioamides and internal alkynes were
not converted.
Table 2. Substrate Scope of the Thioenamide Synthesisa
The scope of the complementary (Z)-selective hydrothioa-
midation was also tested on a number of examples. The
protocol and appears to be as high-yielding, but so far, the
level of stereoselectivity never exceeded a moderate 1:8 ratio.
Further work is aimed at extending the synthetic utility of
this complementary protocol by improving the (Z)-selectivity
with the help of customized ligands.
In summary, a Ru-based catalyst system has been devel-
oped that efficiently mediates the addition of thioamides to
terminal alkynes, giving rise to (E)-configured anti-Mark-
ovnikov products. Various thioenamides can thus be obtained
in high regio- and stereoselectivities, among them substrates
attractive for further derivatization, for example, trimethyl-
silyl-thioenamides for cross-couplings, and thiodienamides
for hetero-Diels-Alder reactions. A reversal of the stereo-
selectivity in favor of the (Z)-products was also achieved
by modifying the phosphine ligand and base.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft for financial support and the Deutscher Aka-
demischer Austauschdienst for a scholarship for K.S.M.S.
Supporting Information Available: Complete experi-
mental procedures including analytical data for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL801736H
a Conditions: 1.00 mmol thioamide, 2.00 mmol alkyne, 0.02 mmol
(cod)Ru(met)2, 0.06 mmol n-Oct3P, 500 mg 3 Å MS, 3 mL toluene, 100
°C, 15 h. b Isolated yields, in brackets the stereoisomeric ratio as determined
by GC. c (cod)Ru(met)2 (0.05 mmol), 0.06 mmol dcypm, 0.04 mmol KOtBu.
d (cod)Ru(met)2 (0.05 mmol), 0.15 mmol n-Oct3P. e Stereoisomeric ratio
(6) (a) Mitsudo, T.-A.; Hori, Y.; Watanabe, Y. J. Org. Chem. 1985, 50,
1566. (b) Doucet, H.; Derrien, N.; Kabouche, Z.; Bruneau, C.; Dixneuf,
P. H. J. Organomet. Chem. 1997, 551, 151. (c) Goossen, L. J.; Paetzold,
J.; Koley, D. Chem. Commun. 2003, 706.
1
as determined by H NMR.
(7) (a) Pholki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104. (b) Beller,
M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368.
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A.; Wakatsuki, Y. J. Am. Chem. Soc. 2001, 123, 11917. (b) Suzuki, T.;
Tokunaga, M.; Wakatsuki, Y. Org. Lett. 2001, 3, 735. (c) Hintermann, L.;
Labonne, A. Synthesis 2007, 8, 1121.
Depending on whether the attack occurs from inside or
outside the coordination sphere of the ruthenium, the metal
will end up in (E)- or (Z)-position to the thioamide group.
The product is liberated by protonolysis, regenerating the
initial Ru(II)-species and completing the catalytic cycle.
To investigate the scope of the (E)-selective hydrothioa-
midation protocol, we applied it to the addition of a broad
variety of thioamides to several terminal alkynes (Table 2).
We were pleased to find that on one hand, pyrrolidine-2-
(9) (a) Goossen, L. J.; Rauhaus, J. E.; Deng, G. Angew. Chem., Int. Ed.
2005, 44, 4042. (b) Yudha S., S.; Kuninobu, Y.; Takai, K. Org. Lett. 2007,
9, 5609.
(10) Goossen, L. J.; Blanchot, M.; Brinkmann, C.; Goossen, K.; Karch,
R.; Rivas-Nass, A. J. Org. Chem. 2006, 71, 9506.
(11) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
(12) Bahaji, E. H.; Bastide, P.; Bastide, J.; Rubat, C.; Tronche, P. Eur.
J. Med. Chem. 1988, 23, 193.
(13) Lacroix, S.; Rixhon, V.; Marchand-Brynaert, J. Synthesis 2006, 14,
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