Synthesis of secondary enamides by ruthenium-catalyzed selective addition of amides to terminal alkynes

Article abstract of DOI:10.1002/anie.200803068

(Chemical Equation Presented) Enamides made easy: A catalyst system generated in situ using bis(2-methallyl)-(cycloocta-1,5-diene)ruthenium(II), 1,4-bis(dicyclohexylphosphino)butane, and ytterbium triflate efficiently catalyzes the addition of primary amides to terminal alkynes, selectively forming the Z-anti-Markovnikov enamides. The E isomers are also accessible by combining the hydroamidation with an in situ double-bond isomerization reaction.

Full text of DOI:10.1002/anie.200803068

Communications
DOI: 10.1002/anie.200803068
Hydroamidation
Synthesis of Secondary Enamides by Ruthenium-Catalyzed Selective
Addition of Amides to Terminal Alkynes**
Lukas J. Gooßen,* Kifah S. M. Salih, and Mathieu Blanchot
Secondary enamides are abundant in functional materials[1]
and biologically active natural products, such as lansiumami-
de A,[2] TMC-95A-D,[3] crocacin,[4] alatamide,[5] aspergillami-
des A–B, chondriamide C, lobatamides A–F, and a range of
marine metabolites.[6] Furthermore, they are versatile syn-
thetic intermediates for the synthesis of heterocycles,[7] cross-
couplings,[8] and Heck reactions.[9] Traditional syntheses,
namely condensations of carbonyl derivatives with amides[10]
or acylations of imines,[11] require harsh reaction conditions
and are not stereoselective, leading to product mixtures with
the E isomer as the major product. This thermodynamically
favored isomer can also be synthesized by the isomerization
of N-allyl amides,[12] oxidative amidation of alkenes,[13] or
codimerization of N-vinyl amides with alkenes.[14] In contrast,
the thermodynamically disfavored Z-enamides are much
harder to obtain selectively. In stereospecific syntheses, such
as the Curtius rearrangement of a,b-unsaturated acyl
azides,[15] elimination of b-hydroxy-a-silylamides,[16] and cata-
lytic cross-couplings of amides with vinyl halides, pseudoha-
lides,[17] or alkenyltrifluoroborate salts,[18] the question of
selectivity is transferred to the preparation of the starting
materials.
As an alternative to these methods, we recently presented
a ruthenium-catalyzed anti-Markovnikov hydroamidation of
terminal alkynes.[19–22] In this atom-economic transformation,
the stereochemistry of the products is controlled by the choice
of ligands, so that both E- and Z-enamides can be synthesized
selectively from easily available starting materials. Unfortu-
nately, this procedure is strictly limited to secondary amides.
For the primary amide substrates, which would give access to
the more valuable secondary enamides, we have observed
either no conversion at all, or mostly double vinylation
products in traces and as mixtures of E/Z isomers and
rotamers. The lower reactivity of primary compared to
secondary amides is easily explained by their lower nucleo-
philicity, and underlines the magnitude of challenge presented
by this class of substrates. A highly developed catalyst system
is required that reaches new levels of activity and stereose-
lectivity for the anti-Markovnikov addition of primary amides
to alkynes. However, this catalyst must be designed such that
it does not allow further conversion of the more nucleophilic
and sterically only slightly more demanding monovinylated
products 3 or 4 (Scheme 1).
Scheme 1. Stereo- and chemoselectivity in hydroamidations.
To identify a catalyst system with such unique attributes,
we selected the reaction of benzamide with 1-hexyne as the
model system to examine the catalytic activity of various
ruthenium sources in combination with a range of ligands,
solvents, and additives (Table 1). As expected, a combination
of
bis(2-methallyl)(cycloocta-1,5-diene)ruthenium(II)
[(cod)Ru(met)2] with tri-n-butylphosphine and 4-(dimethyl-
amino)pyridine (DMAP), the most effective system for the
analogous reaction of secondary amides, led to only marginal
conversion and displayed no selectivity for the monoaddition
products (entry 1). Other ruthenium precursors were found to
be even less effective (entries 2, 3). Solvent screening
revealed that DMF was uniquely effective, resulting in an
increase in yield (entries 4–6). Based on the reasoning that the
coordination of a Lewis acid to the carbonyl oxygen would
acidify the amide protons, and therefore serve the same
purpose as an added base, we replaced DMAP by a Lewis
acid (entries 9, 10). We had previously found that DMAP
helps the deprotonation of the amide substrate and facilitates
its coordination to the ruthenium center. The replacement of
DMAP indeed led to a dramatic increase in catalyst activity,
and a 59% yield was achieved with ytterbium triflate
(Yb(OTf)3; entry 10).
We were now able to address the problem of selectivity,
and found that sterically demanding, electron-rich chelating
phosphines resulted in a major enhancement of the Z/E ratio
(entry 11–16). Using 1,4-bis-(dicyclohexylphosphino)butane,
the selectivity for the Z product 3 was increased to a 4:1 ratio
(entry 16). Moreover, owing to the high activity of the catalyst
system, the reaction temperature could be reduced to 608C
(entry 17). This led to substantially better yields of the
monoaddition products, largely because their hydrolysis by
[*] Prof. Dr. L. J. Gooßen, K. S. M. Salih, M. Blanchot
FB Chemie—Organische Chemie
TU Kaiserslautern
Erwin-Schrꢀdinger-Strasse Geb. 54
67663 Kaiserslautern (Germany)
Fax: (+49)631-205-3921
E-mail: goossen@chemie.uni-kl.de
Homepage: http://www.chemie.uni-kl.de/goossen
[**] We thank the DFG and Umicore AG for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803068.
8492
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Chemie
Table 1: Optimization of the catalyst and conditions.[a]
Ru source
Solv.
Ligand
Additive Yield [%] 3a:4a
1
2
3
[(cod)Ru{met}]2 PhMe nBu3P
DMAP
“
“
2
0
2
nd
nd
nd
Ru3CO12
[{(p-
“
“
”
”
cm)RuCl2}2]
4
5
6
7
8
[(cod)Ru(met)2] THF
“
”
”
“
“
“
“
”
“
“
3
3
17
16
17
nd
nd
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
MeCN
DMF
”
”
”
”
”
”
”
”
”
”
1:2
2:3
1:1
2:1
3:2
nd
1:1
nd
nd
2:1
4:1
12:1
18:1
18:1
2:5
1:4
Na2CO3
KI
Mg(OTf)2 45
Yb(OTf)3 59
“
“
“
“
“
“
9
10
11
12
13
14
15
16
17[b]
18[b]
19[b]
20
21
P(o-Fur)3
PPh3
0
10
0
johnphos
tBu3P
P(iPr)Ph2
dcypb
“
2
14
55
95
98
97[d]
98
89[f]
”
DMF[c]
DMF[c]
”
”
DMF[e] nBu3P
”
”
DMF dcypb
[a] 1.00 mmol benzamide, 2.00 mmol 1-hexyne, 5 mol% Ru source, 15
mol% phosphine (6 mol% for bidentate), 4 mol% additive, 3 mL
solvent, 1008C, 15 h. Yields determined by GC using n-tetradecane as
internal standard, selectivities determined by HPLC. [b] 608C. [c] Water
as co-solvent (108 mL). [d] 6 h reaction time. [e] 500 mg 3 ꢁ molecular
sieves as additive. [f] After complete reaction, triethylamine (200 mL) and
3 ꢁ molecular sieves (500 mg) were added, and the resulting mixture
was stirred at 1108C for 24 h. Abbreviations: p-cm=p-cymol, john-
phos=(2-biphenylyl)di-tert-butylphosphine, dcypb=1,4-bis-(dicyclohex-
ylphosphino)butane, Fur=furyl.
Scheme 2. Proposed reaction mechanism.
precursor [(cod)Ru(met)2] by substitution of the labile 1,5-
cyclooctadiene ligand (COD) with phosphine ligands, and
replacement of the basic methallyl by amide groups acidified
1
with Yb(OTf)3. H NMR spectroscopic studies after catalyst
preformation show that the coordinated COD is liberated,
and 2-methylbutene is formed. In addition, 2,5-dimethylhex-
enes could not be detected by NMR spectroscopy or by GC-
MS. These observations rule out the possibility of the
ruthenium(0) species as the active catalyst because their
formation using [(cod)Ru(met)2] a would most likely involve
a reductive dimerization of the two methallyl ligands. In the
presence of an ytterbium salt with non-coordinating triflate
ligands, both ruthenium and ytterbium are likely to compete
for the coordinating amide ligands, so that neutral ruthenium
bisamide complexes c1 will be in equilibrium with cationic
solvent- and ligand-stabilized monoamide species c2.
The actual catalytic cycle (Scheme 2) is likely to start with
the coordination of an alkyne to a neutral or cationic
ruthenium(II) amide complex c to give p-complex d, followed
by the addition of an amide nucleophile to the h2-coordinated
alkyne, yielding h1-ruthenium vinyl complexes e or f. The E-
or the Z-configured amidoalkenyl ruthenium species will be
formed depending on whether the amide comes from inside
or outside the coordination sphere of ruthenium, respectively.
An intermediacy of ruthenium vinylidene complexes, as has
been proposed for the related catalytic addition of carboxylic
acids to alkynes,[23] can be ruled out on the basis of
deuteration studies. We have never observed the deuterium
traces of water was slowed. At this moderate temperature, the
presence of water was even found to enhance the selectivity
(entry 18) so that finally, near complete conversion and an
impressive 18:1 selectivity for the thermodynamically unfav-
orable and thus more interesting Z-enamide 3 was reached
within 6 h reaction time (entry 19).
We next tried to invert the selectivity of the reaction in
favor of the E-enamide 4 by modifying the catalyst system to
further improve the synthetic utility of the hydroamidation
process. The best result, obtained with nBu3P as the ligand
and 3 ꢀ molecular sieves as additives, was a 2.5:1 ratio of
E/Z isomer (entry 20), which was disappointing. A superior
strategy, however, proved to be the in-situ isomerization of
the double-bond isomers, after the reaction to form 3 is
complete, by adding triethylamine and heating the reaction
mixture to 1108C, and using molecular sieves to reduce the
hydrolytic cleavage to a minimum (entry 21). In this way an
E/Z ratio of 4:1 was achieved for the model system, and
E selectivities of up to 20:1 were reached for other substrates
(Table 2).
We believe that the catalytically active species in such
hydroamidations are phosphine-stabilized ruthenium(II)
amides, such as c (Scheme 2), generated from the catalyst
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Table 2: Scope of the hydroamidation protocols.[a]
Product
Yield [%] (Z/E)
Product
Yield [%] (Z/E)
Product
Yield [%] (Z/E)
A
B
94
89
(18:1)
(1:4)
A
B
97
92
(18:1)
(1:18)
A
B
91
79
(>40:1)
(1:20)
A
B
92
85
(17:1)
(1:4)
A
B
86
85
(23:1)
(1:4)
A
A
91
88
(31:1)
A
99
(20:1)
A
46
(30:1)
(10:1)
(14:1)
A
B
90
83
(19:1)
(1:17)
A
B
96
77
(22:1)
(1:20)
A
A
A
A
84
96
71
60
A
80
(20:1)
A
A
93
31
(19:1)
(18:1)
A
B
78
68
(35:1)[b]
(1:14)
(>40:1)
(19:1)[b]
(>40:1)
A
B
83
79
(19:1)
(1:18)
A
98
(20:1)
[a] Method A: 1.00 mmol benzamide, 2.00 mmol 1-hexyne, 5 mol% [(cod)Ru(met)2], 6 mol% dcypb, 4 mol% Yb(OTf)3, 3 mL DMF and 108 mL water
as co-solvent, 608C, 6 h. Yields reported are of isolated products, selectivities were determined by HPLC. Method B: After complete conversion
following method A, 3 ꢁ molecular sieves (500 mg) and triethylamine (200 mL) were added, and the mixture was heated to 1108C for 24 h. [b] The
reaction was performed without water to avoid hydrolysis of the sensitive products.
shifting from the terminal to the 2-position in hydroamida-
tions of 1-[D]-alkynes. By using an N,N-deuterated amide, the
deuterium was exclusively found in the 2-position of the
enamide products, which is in agreement with the mechanistic
steps detailed below.
ides 3a–g,t in high yields and good to excellent Z/E selectiv-
ities. On the other hand, a range of primary amides, among
them sensitive, highly functionalized derivatives, were added
to phenylacetylene (3h–s). Common functional groups, such
as ester, ether, alkene, nitrile, nitro, and halide groups are
tolerated, and even fragile acrylic, oxalic, malonic or a-
cyanoacetic amides were efficiently converted. Arguably, the
unprecedented outcome was the synthesis of the enamide 3k,
in which a primary amide functionality was selectively
vinylated in the presence of a secondary amide group.
The one-pot addition/isomerization sequence (Table 2,
method B) was successfully applied to the synthesis of a
representative selection of E enamides (4a–e,j,k,p,t). This
sequence proved to be highly efficient and extremely general
in its application. The E selectivities were usually high and
functional groups were well-tolerated. As a result, terminal
alkynes and amides can now also be successfully utilized as
starting materials for the synthesis of E-enamides.
In the E selective pathway, a coordination site made
vacant at the ruthenium center is filled as necessary by
another amide, which also provides the proton required for
protonolytic release of the enamide product and regeneration
of the initial ruthenium(II) species c. In the competing
Z selective pathway, the proton is also formally provided by
the amide, but the protons are expected to move easily and
relatively fast between the free and the coordinated amide or
the triflate species. This proton activity is enhanced by the
Lewis acid ytterbium(III), which has a tendency to coordinate
to the amides, thereby weakening their affinity to both
ruthenium and the protons. As a result, the protonolysis and
ligand exchange steps are facilitated. Thus, at any stage of the
catalytic cycles, salt metathesis of the ruthenium(II) and
ytterbium(III) species can occur, bridging the neutral and the
cationic pathways.
Enamides thus accessible in only one step from easily
available materials include the natural products lansiumami-
de A (3s)[2] and alatamide (4t),[5] the previously published
syntheses of which involved three to four steps and lower
product yields. This also applies to compound 3u, which is a
key intermediate in Castedoꢁs total synthesis of aristolac-
tam.[7]
Table 2 illustrates the wide scope and synthetic utility of
the Z selective anti-Markovnikov hydroamidation. Benz-
amide was reacted with various alkynes, such as aliphatic,
alicyclic, haloalkyl, and aromatic derivatives, yielding enam-
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access to a fast synthetic route to the structural motif that is
present in many natural products and is hard to access by
other synthetic means.
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Experimental Section
3a: An oven-dried flask was charged with bis(2-methallyl)(cycloocta-
1,5-diene)ruthenium(II) (16.0 mg, 0.05 mmol), benzamide (1a,
121.1 mg,
1.00 mmol),
1,4-bis(dicyclohexylphosphino)butane
(27.0 mg, 0.06 mmol), and ytterbium triflate (24.8 mg, 0.04 mmol)
and flushed with nitrogen. Dry DMF (3.0 mL), 1-hexyne (2a, 229 mL,
2.00 mmol) and water (108 mL, 6.00 mmol) were then added with a
syringe. The resulting solution was stirred for 6 h at 608C, then poured
into an aqueous sodium bicarbonate solution (30 mL) and extracted
repeatedly with 20 mL portions of ethyl acetate. The combined
organic layers were washed with water and brine, dried over
magnesium sulfate, filtered, and the volatiles were removed in
vacuo. The residue was purified by column chromatography (silica
gel, ethyl acetate/hexane 1:9) to obtain 3a as a pale-yellow oil
(191.1 mg, 94%).
For explicit experimental data, including spectroscopic data, see
the Supporting Information.
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Received: June 25, 2008
Published online: September 29, 2008
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Keywords: alkynes · amides · enamides · hydroamidation ·
.
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