method for the preperation of ynamides from amides and alkynyl
bromides in the presence of an iron catalyst. This is the first
example of iron-catalyzed formation of C(sp)-N bonds.
Initially, we optimized the reaction conditions using phenyl-
ethynyl bromide and (S)-4-methyloxazolidin-2-one as model
substrate, and the selected results are listed in Table 1. No
reaction took place in the absence of catalyst. FeCl3, FeCl2, and
FeCl3 ·6H2O showed high catalytic activity, while Fe2O3 was
almost inactive (Table 1, entries 1-4). A variety of bases were
evaluated, and K2CO3 showed the best efficiency (Table 1,
entries 1 and 5-8). Among the solvents tested, toluene was
found to be superior to DMF, DMSO, and 1,4-dioxane (Table
1, entries 1 and 9-11). Ligands had a pronounced impact on
the coupling reaction (Table 1, entries 1 and 12-16). Ligands
that are routinely used for copper coupling reactions such as
1,10-phenanthroline, N,N,N′,N′-tetramethylethane-1,2-diamine
(TMEDA), and L-proline exerted a poor effect on the reaction
(Table 1, entries 13-15), and only a trace of the product was
observed without the use of ligand (Table 1, entry 12). The use
of N,N′-dimethylethane-1,2-diamine (DMEDA) substantially
accelerated the reaction, and a 96% isolated yield was obtained
(Table 1, entry 1). The dioxygenated ligands such as acetateac-
etone did not lead to efficient catalysis (Table 1, entry 16). The
reaction could be scaled up to 10 mmol with the combination
of 5 mol % of FeCl3 ·6H2O and 10 mol % of DMEDA to give
an 85% yield (Table 1, entry 18).
We next examined the scope and generality of the coupling
reaction with various nitrogen nucleophiles under the optimized
conditions (Table 1, entry 1). Notably, both oxazolidinones and
sulfonamides underwent N-alkynylation in good yields (Table 2).
We noticed that oxazolidinones bearing different substituents such
as CH3-, Ph-, Bn-, and i-Pr- worked well and afforded the
corresponding ynamides in good to high yields (Table 2, entries
1-5). Acyclic carbamates were almost inactive under the reaction
conditions. Both alkylsulfonamides and arylsulfonamides were
compatible with the reaction conditions (Table 2, entries 6-17).
In the cases of arylsulfonamides, the electronic properties of the
substituents in the aryl ring presented little impact to the reactions
and high yields were obtained (Table 2, entries 6-8). Methylsu-
fonamide readily coupled with phenylethynyl bromide to give a
96% yield (Table 2, entry 9). N-Benzyl and N-alkyl-substituted
sulfonamides afforded the desired products in high yields (Table
2, entries 6-14). However, the reactivity of N-phenyl-substituted
sulfonamides was slightly decreased (Table 2, entry 14). It should
be noted that the free hydroxy group tolerated the reaction
conditions (Table 2, entry 15). As mentioned, with significant
pharmaceutical indole cycles, a 70% yield was obtained after the
coupling with indole-5-carbonitrile (Table 2, entry 16). At the same
time, pyrrolidin-2-one was transferred to its corresponding ynamide
in 57% yield (Table 2, entry 17).
The reaction scope was also studied with respect to alkynyl
bromides, and the results are summarized in Table 3. The
catalytic system enabled a variety of alkynyl bromides to couple
with the N-nucleophiles smoothly to give the desired ynamides.
In the case of arylalkynyl bromides, either electron-donating
or electron-withdrawing groups in the aryl ring tolerated the
reaction to give the corresponding ynamides in high yields
(Table 3, entries 1-12). The alkyl alkynyl bromides were also
coupled smoothly with oxazolidinones and sulfonamides to give
good yields under the reaction conditions (Table 3, entries
13-16). The reaction was able to be performed by using (3-
bromoprop-2-ynyl)triisopropylsilane (TIPS) and 3-bromoprop-
2-yn-1-ol as the substrates but with relatively lower yields (Table
3, entries 17-20).
The reusability of iron catalyst was tested in the coupling reaction
of phenylethynyl bromide and (S)-4-methyloxazolidin-2-one using
10 mol % of FeCl3 ·6H2O. The product was isolated by filtration.
The residue was washed with diethyl ether (3 × 15 mL) and
subjected to the second run by charging with the same substrate,
0.2 mmol DMEDA, 1 mmol K2CO3, and 5 mL of toluene. The
catalytic system showed high efficiency of reusability and could
be recycled nine times only with a small decrease in activities
without the need for addition of catalyst (Scheme 2).
SCHEME 2
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In conclusion, we have developed an efficient and convenient
method for the preparation of ynamides by FeCl3 ·6H2O-
catalyzed coupling reaction of alkynyl bromides and N-
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directly by using inexpensive, easy-to-handle, and environmen-
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provided a practical and straightforward approach toward
ynamides.
Experimental Section
Alkynyl bromides (1.2 mmol) and DMEDA (0.2 mmol) were added
to a stirred solution of N-nucleophiles (1 mmol), K2CO3 (2.0 mmol),
FeCl3 ·6H2O (0.1 mmol), and toluene (5 mL) under air, and the
resulting mixture was stirred at 90 °C for 12 h. The suspension was
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3529. (c) Correa, A.; Bolm, C. AdV. Synth. Catal. 2008, 350, 391–394. (d) Correa,
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4632 J. Org. Chem. Vol. 74, No. 12, 2009