Ru-catalyzed anti-Markovnikov addition of amides to alkynes: A regio- and stereoselective synthesis of enamides

Article abstract of DOI:10.1002/anie.200462844

(Chemical Equation Presented) The base-free anti-Markovnikov addition of secondary amides, anilides, lactams, ureas, bislactams, and carbamates to terminal alkynes is accomplished, for the first time, by a ruthenium-catalyzed reaction. Two complementary p

Full text of DOI:10.1002/anie.200462844

Communications
Homogeneous Catalysis
Ru-Catalyzed Anti-Markovnikov Addition of
Amides to Alkynes: A Regio- and Stereoselective
Synthesis of Enamides**
Lukas J. Gooßen,* Jan E. Rauhaus, and Guojun Deng
The enamide group is an important substructure that is often
found in natural products[1] and synthetic drugs that have,
amongst others, sedative,[2] cytotoxic,[3] or anti-inflamma-
tory[4] properties. Moreover, they are versatile synthetic
intermediates that can serve as substrates for polymeri-
zations,[5] [4+2] cycloadditions,[6,7] cross-coupling reactions,[8]
Heck olefinations,[9] halogenations,[8] enantioselective addi-
tions,[10] or asymmetric hydrogenations.[11] However, a regio-
and stereoselective construction of enamide substructures is
not at all trivial. Traditional syntheses—for example, from
carbonyl compounds and amides[12] or from hydroxylamines
and acetic anhydride[13]—require harsh conditions and yield
mixtures of E/Z products. Metal-catalyzed coupling reactions
of vinyl halides,[14] vinyl triflates,[15] or vinyl ethers[16] proceed
under milder conditions but suffer from the limited avail-
ability of these substrates.
In our opinion, a catalytic addition of amides to alkynes
would be an ideal synthetic entry to enamides, since it would
use readily available starting materials and be inherently
atom-economic (Scheme 1). Related addition reactions of
carboxylates,[17] water,[18] and amines[19] are well-estab-
lished.[20] However, to the best of our knowledge, there is
only one reported protocol in the literature for a catalytic
hydroamidation reaction of terminal alkynes:[21] Watanabe
et al. found that in the presence of Ru3CO12/trialkylphos-
phane catalysts, a very limited range of formanilides and
acetanilides can be added to 1-hexyne, albeit at extremely
high temperatures (1808C) and under pressure.[22] Clearly,
much more effective catalyst systems are required to allow an
application of this reaction in organic synthesis.
To identify a catalyst system for the desired hydroamida-
tion reaction, we chose the reaction of 1-hexyne (1a) with 2-
pyrrolidinone (2a) as a model system and investigated the
catalytic activity of several ruthenium complexes under
various conditions (Scheme 2, Table 1). As anticipated, no
[*] Dr. L. J. Gooßen,+ J. E. Rauhaus, G. Deng
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: goossen@oc.rwth-aachen.de
[+] New address:
Institut fꢀr Organische Chemie
Rheinisch-Westfꢁlische Technische Hochschule Aachen
Professor Pirlet Str. 1, 52074 Aachen (Germany)
Fax: (+49)241-80-93663
[**] We thank Prof. Dr. H.-J. Altenbach for helpful discussions, Martina
Eckardt for technical assistance, Prof. Dr. M. T. Reetz for generous
support and constant encouragement, and the DFG, the FCI, and
the BMBF for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200462844
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Angewandte
Chemie
Table 1: Optimization of reaction conditions for Scheme 2.[a]
Entry Ru source
Ligand
Additive Yield [%] 4a/
5a[b]
1
2
[Ru3(CO)12]
RuCl3·H2O
PnBu3
–
–
–
0
0
nd
nd
3
[Ru(acac)3]
–
–
0
nd
4
[Ru3(CO)12]
–
–
0
nd
5
6
7
8
[{RuCl2(p-cymene)}2]
RuCl3·H2O
[Ru(acac)3]
[{RuCl2(p-cymene)}2]
[RuCl2(cod)]
–
–
–
–
–
–
–
–
–
–
–
–
–
0
79
0
nd
1:1
nd
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PCy3
Cy2PCH2PCy2
P(1-Np)3
P(p-FC6H4)3
PPh3
95
92
67
25
30
0
85
62
66
0
1:1
1:1
11:1
3:1
1:2
nd
3:1
2:1
2:1
nd
9:1
5:2
5:1
19:1
28:1
nd
9
Scheme 1. Addition of amides to terminal alkynes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(PPh3)2]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
–
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
AgNO3
NaOtBu 52
NEt3
DABCO
pyridine 95
DMAP
61
50
93
<5
86
Cy2PCH2PCy2 DMAP
PnBu3
DMAP/
21:1
H2O[c]
Scheme 2. Addition of 2-pyrrolidinone to 1-hexyne.
25[d] [Ru(methallyl)2(cod)]
26[e] [Ru(methallyl)2(cod)]
27
28
PnBu3
PnBu3
DMAP
DMAP
88
84
75
98
28:1
33:1
1:5
[Ru(methallyl)2(cod)]
[Ru(methallyl)2(cod)]
Cy2PCH2PCy2 H2O[c]
Cy2PCH2PCy2 H2O[f]
enamide products were observed in the presence of the
literature systems[21c,22] at ambient pressure and a temperature
of only 1008C (entries 1 and 2). In contrast, several other
ruthenium sources, although inactive themselves (entries 2–
5), displayed noticeable catalytic activity when combined with
tri-n-butylphosphane (entries 6–10). In all cases, the anti-
Markovnikov products 4a and 5a were formed regioselec-
tively. However, a significant stereoselectivity (E/Z > 10:1)
was observed only for 1,5-cyclooctadienebis(2-methallyl)ru-
thenium [Ru(methallyl)2(cod)]; with all other ruthenium
sources, 4a and 5a were formed in almost equal amounts.
The reaction of [Ru(methallyl)2(cod)] with monodentate
phosphanes leads to the formation of isolable bis(2-meth-
allyl)bis(phosphane)ruthenium(ii) complexes, which show the
same reactivity as the mixtures prepared in situ (entry 16).
Among all the ligands investigated, tri-n-butylphosphane
1:5
[a] Conditions: pyrrolidinone (1.0 mmol), 1-hexyne (2.0 mmol), ruthe-
nium source (0.02 mmol), ligand (0.06 mmol; or 0.03 mmol for chelat-
ing ligands), additive (0.04 mmol), toluene (3 mL), 1008C, 15 h. The
yields and selectivities were determined by GC using n-tetradecane as
the internal standard. Abbreviations: acac=acetylacetonate; Np=
naphthyl; DABCO=1,4-diazabicyclo[2.2.2]octane. [b] nd=not deter-
mined. [c] 0.5 mmol H2O; [d] The reaction vessel was briefly purged
with air. [e] 1.2 mmol 1-hexyne. [f] 8-mmol H2O.
the presence of air and moisture had only a minor influence
on the yields and selectivities of this optimized reaction
protocol (entries 22, 24, and 25).
Since Z enamides are of similar synthetic importance but
particularly hard to synthesize,[23] we next set out to identify a
complementary Z-selective hydroamidation catalyst. Starting
with the [Ru(methallyl)2(cod)]/Cy2PCH2PCy2 system, which
had already shown some Z selectivity (entry 12), we again
studied the influence of additives. Interestingly, this catalyst
was completely inhibited by the addition of DMAP
(entry 23), while other bases and additives had only a minor
influence on the reaction outcome. Only the addition of small
quantities of water increased both its activity and Z selectiv-
ity, such that 5a also became accessible in excellent yield
(99%, Z/E = 5:1; entries 27 and 28).
To make up for losses due to oligomerization and
evaporation, the alkyne is best used in a slight excess of at
least 1.2 equivalents (entries 22 and 26).
Currently, we can only speculate about the exact reaction
mechanism; more in-depth investigations are underway. The
Z-selective protocol is likely to follow the mechanism
gave the highest
E selectivity in combination with
[Ru(methallyl)2(cod)] (entries 10–15). Triarylphosphanes
were less effective, and use of the chelating phosphane
bis(dicyclohexylphosphanyl)methane (Cy2PCH2PCy2) even
led to a reversal of the stereoselectivity in favor of the Z
product (entry 12).
As in our recently disclosed protocol for the anti-
Markovnikov addition of carboxylic acids to alkynes,[17c] the
addition of pyridine derivatives (2 equiv with respect to
ruthenium) strongly enhanced the catalyst performance;
other additives had no beneficial effects (entries 17–22). 4-
(N,N-Dimethylamino)pyridine (DMAP), in particular, led to
a significant increase in both the activity and the stereo-
selectivity of the [Ru(methallyl)2(cod)]/PnBu3 catalyst
system, and allowed the synthesis of 4a in almost quantitative
yield with an E/Z selectivity of 28:1 (entry 22). Gratifyingly,
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proposed for the addition of carboxylic acids to alkynes,[17] but
it is difficult to pinpoint the origin of the reversal of selectivity
when adding monodentate phosphanes and DMAP. A con-
ceivable mechanism for the E-selective protocol might
À
involve oxidative addition of the N H bond to the ruthenium,
followed by insertion of the alkyne into the resultant metal–
nitrogen bond, and reductive elimination of the enamide
product. On the other hand, the two mechanisms may mainly
differ in concerted against stepwise addition of the nucleo-
phile and the proton.[17a,b]
À
Scheme 3. Addition of N H compounds to terminal alkynes.
To investigate the scope of this new hydroamidation
protocol, we applied it to the addition of a broad variety of
nitrogen nucleophiles to several terminal alkynes (Scheme 3).
Table 2 demonstrates the impressive scope of the E-
selective reaction. Various alkynes were successfully con-
verted into enamides, among them phenylacetylene, acetyle-
necarboxylic esters, trimethylsilylacetylene, and even conju-
gated enynes. The trimethylsilyl-enamides obtained should be
attractive substrates for further coupling reactions, and the
dienamides for hetero-Diels–Alder reactions.
Besides lactams, various secondary amides, anilides, ureas,
bislactams, carbamates, and even chiral auxiliaries for sub-
sequent cycloaddition reactions[7] can be used as the N H-
À
Table 2: Substrate scope of the hydroamidation reaction (Scheme 3).[a]
Product
Yield [%]
Product
Yield [%]
Product
Yield [%]
(ratio 4/5)
(ratio 4/5)
(ratio 4/5)
95 (28:1)
99 (1:5)[b]
97 (30:1)
92 (1:8)[b]
99 (30:1)
93 (8:1)
4a
4d
4b
4e
4c
4 f
81 (30:1)
98 (24:1)
99 (30:1)
99 (30:1)
99 (30:1)
4g
4h
4i
69 (3:1)
70 (2:1)
94 (30:1)
84 (3:1)
4j
4k
4n
4l
86 (30:1)
83 (30:1)
4m
4o
12 (1:2)
33 (30:1)
99 (30:1)
94 (30:1)
99 (23:1)
4p
4s
4v
4q
4t
4r
4u
4x
38 (30:1)
96 (6:1)
97 (30:1)
84 (24:1)
4w
[a] Conditions: amide (1.0 mmol), alkyne (2.0 mmol), [Ru(methallyl)2(cod)] (0.02 mmol), PnBu3 (0.06 mmol), DMAP (0.04 mmol), toluene (3 mL),
1008C, 15 h; yields refer to isomeric mixtures of isolated products. [b] Complementary conditions: amide (1.0 mmol), alkyne (2.0 mmol),
[Ru(methallyl)2(cod)] (0.02 mmol), Cy2PCH2PCy2 (0.03 mmol), water (8.0 mmol), toluene (3.0 mL), 1008C, 15 h.
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[4] D. Davyt, W. Entz, R. Fernandez, R. Mariezcurrena, A. W.
coupling partner. The reaction proceeds smoothly even in the
presence of sensitive functional groups such as esters, ethers,
ketones, halides, or silanes. For most substrates, the E
products were obtained in an isomeric ratio greater than
20:1, and only imides gave only moderate yields and
selectivities; primary amides could not be converted.
The Z-selective protocol was also successfully applied to
selected substrates (Table 2, first row). Although this protocol
does not yet reach the selectivity of its E-selective counter-
part, the examples 5a and 5b demonstrate that the stereo-
selectivity of the reaction can indeed be inverted by modify-
ing the ligand system.
In summary, a ruthenium-catalyzed reaction has been
developed that allows, for the first time, the anti-Markovni-
kov addition of secondary amides, anilides, lactams, ureas,
bislactams, and carbamates to terminal alkynes. Two comple-
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new transformation is well-suited for applications in synthetic
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Experimental Section
4a: An oven-dried flask was charged with [Ru(methallyl)2(cod)]
(6.4 mg, 0.02 mmol) and DMAP (4.99 mg, 0.04 mmol), and flushed
with argon. Subsequently, PnBu3 (15 mL, 0.06 mmol), 2-pyrrolidinone
(2a; 85.1 mg, 1 mmol), 1-hexyne (1a; 229 mL, 2.0 mmol), and dry
toluene (3.0 mL) were added with a syringe. The resulting green
solution was stirred for 15 h at 1008C, then poured into an aqueous
NaHCO3 solution (30 mL). The resulting mixture was extracted
repeatedly with 20 mL portions of ethyl acetate, the combined
organic layers were washed with water and brine, dried with MgSO4,
and filtered, and the volatiles were removed in vacuo. The residue was
purified by column chromatography (SiO2, ethyl acetate/hexanes 3:1)
to yield 4a (158.9 mg, 95% yield, 97% isomeric purity) as a colorless
oil.
1H NMR (300.1 MHz, CDCl3): d = 6.86 (d, 3J = 14.7 Hz, 1H), 4.92
3
3
3
(dt, J = 14.7 Hz, 7.2 Hz, 1H), 3.48 (t, J = 7.2 Hz, 2H), 2.46 (t, J =
3
8.1 Hz, 2H), 2.01–2.14 (m, 4H), 1.24–1.39 (m, 4H), 0.88 ppm (t, J =
7.2 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d = 172.2, 123.6, 112.5,
45.3, 32.3, 31.3, 29.7, 22.1, 17.4, 13.9 ppm; MS (EI, 70 eV): m/z (%):
167 (20), 124 (100) [M]+, 86 (23), 69 (12), 41 (21); HRMS (EI): calcd
for C10H17NO: 167.131014; found: 167.130871.
The experiments in Table 2 were carried out analogously. All
products were purified by column chromatography and characterized
by NMR spectroscopy and standard/high-resolution mass spectrom-
etry.
Received: December 7, 2004
Revised: March 24, 2005
Published online: May 27, 2005
Keywords: alkynes · amides · enamides ·
.
homogeneous catalysis · hydroamidation · ruthenium
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