Nickel-Catalyzed Synthesis of Enamides and Enecarbamates via Isomerization of Allylamides and Allylcarbamates

Article abstract of DOI:10.1002/adsc.201500461

A single-component, air-stable nickel precatalyst can catalyze the isomerization of allylamides for the synthesis of enamides. The scope of the reaction encompasses various substituted allylamides and allylcarbamates as well as homoallylamides. The reaction can be performed on a multigram-scale without specialized glove-box equipment or Schlenk techniques.

Full text of DOI:10.1002/adsc.201500461

UPDATES
DOI: 10.1002/adsc.201500461
Nickel-Catalyzed Synthesis of Enamides and Enecarbamates via
Isomerization of Allylamides and Allylcarbamates
Juliette Halli,a Philipp Kramer,a Maren Bechthold,a and Georg Manolikakesa,*
a
Department of Biochemistry, Chemistry and Pharmacy, Institute for Organic Chemistry and Chemical Biology,
Goethe-University, Max-von-Laue Str. 7, 60438 Frankfurt am Main, Germany
E-mail: g.manolikakes@chemie.uni-frankfurt.de
Received: May 10, 2015; Revised: July 15, 2015; Published online: September 25, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500461.
Abstract: A single-component, air-stable nickel pre-
catalyst can catalyze the isomerization of allyl-
amides for the synthesis of enamides. The scope of
the reaction encompasses various substituted allyl-
amides and allylcarbamates as well as homoallyl-
amides. The reaction can be performed on a multi-
gram-scale without specialized glove-box equipment
or Schlenk techniques.
Furthermore, enamides and enecarbamates are val-
uable substrates for asymmetric hydrogenation reac-
tions.[3,4] Besides these applications, the enamide motif
is often found in natural products, for example, asper-
gillamides[5] and salicylihalamides[6].
Due to importance of these classes of compounds,
several protocols for their preparation have been re-
ported.[1–4] Classical procedures, such as the acylation
of imines or the condensation of amides and carbonyl
compounds require harsh reaction conditions and
lead to the formation of considerable amounts of by-
products.[7] An attractive alternative is the transition
metal-catalyzed[8–11] or base-mediated[12] isomerization
of readily available N-allylamides. Recently, Gooßen
and co-workers developed a stereoselective synthesis
Keywords: enamides; enecarbamates; homogeneous
catalysis; isomerization; nickel catalysis
Enamides and enecarbamates are very useful synthet- of enamides based on a ruthenium-catalyzed direct
ic intermediates for various transformations, such as addition of amides to terminal alkynes[13–15]
.
cycloadditions, cross-coupling reactions or asymmetric
C C bond formations (Scheme 1).
For one of our current research projects, we were
looking for an operationally simple, scalable and effi-
[1–4]
À
Scheme 1. Synthesis and applications of enamides.
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Juliette Halli et al.
pretreatment. Simple “argon sparging” of the cata-
lyst-solvent mixture before addition of the starting
material is sufficient for an effective isomerization.
Performing the reaction at higher or lower tempera-
tures did not affect the obtained E:Z-ratio (entry 5).
Performing the reaction in other, less polar aprotic
solvents, such as THF or CH2Cl2 afforded the enam-
ide in slightly lower yields (entries 6 and 7). When
NiCl2(PPh3)2, a stable nickel(II) complex, was used as
Scheme 2. Air-stable Ni(II)-aryl complexes.[18]
cient synthesis of aldehyde- and ketone-derived en- catalyst precursor, the allylamide 4a was recovered
amides and enecarbamates. From this point of view, almost quantitatively (entry 8).
the nickel(0)-catalyzed isomerization of N-allylamides
With the optimized reaction conditions in hand, we
reported by Lei[16] looked very promising. However, explored the scope of our method. As shown in
the employed Ni(0) catalyst, Ni(PPh3)4, is very air Scheme 3 various N-aryl and N-alkyl allylamides as
sensitive and necessitates the use of specialized equip- well as cyclic allylamides are suitable substrates and
ment for safe handling.[17] In the last years, easily ac- the desired enamides 5b–k could be obtained in mod-
cessible, air-stable Ni(II)-s-aryl complexes have been erate to excellent yields.
used as efficient precatalysts for various cross-cou-
The reaction of cinnamoylallylamide 4l proceeded
smoothly to afford enamide 5l in 64% yield. More-
pling reactions (Scheme 2).[18]
We envisioned, that these easy-to-handle Ni(II) over, highly functionalized allylamides, such as valine
complexes could be useful precatalysts for the
nickel(0)-catalyzed isomerization of N-allylamides.
To our delight, readily available Ni(II)-s-aryl com-
plexes 1 and 2 catalyze the isomerization of allyl-
amide 4a very efficiently even at room temperature
(Table 1, entries 1 and 2).
The desired enamide could be obtained in 95% iso-
lated yield and an E:Z-ratio of 77:23 and, respective-
ly, 76:24. The Ni(II) precatalyst 3, bearing a bidentate
phosphine ligand, displayed a significantly reduced ac-
tivity (entry 3). Lowering the catalyst loading to
2 mol% did not affect the yield or E:Z-ratio (entry 4).
Strikingly, the use of specialized glove-box equipment
or Schlenk techniques is not required for this nickel-
catalyzed isomerization. The reaction can be carried
out in commercially available MeOH without any
Table 1. Optimization of the reaction conditions.
No. Solvent Conditions Catalyst
Yield of 5a[a]
(E:Z)
1
2
3
4
5
6
7
8
MeOH r.t./24 h
MeOH r.t./24 h
MeOH r.t./5 d
MeOH r.t./24 h
5 mol% 1
5 mol% 2
5 mol% 3
2 mol% 1
95% (77:23)
95% (76:24)
28% (46:56)
95% (75:25)
95% (76:24)
81% (76:33)
87% (67:33)
0%
MeOH 508C/24 h 2 mol% 1
THF
r.t./24 h
2 mol% 1
2 mol% 1
5 mol%
CH2Cl2 r.t./24 h
MeOH r.t./24 h
NiCl2(PPh)3
[a]
Isolated yield after column chromatography, E:Z ratio
determined by NMR.
Scheme 3. Reaction scope for the Ni-catalyzed isomeriza-
tion. Phth=phthaloyl.
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Nickel-Catalyzed Synthesis of Enamides and Enecarbamates
duced pressure. Purification of the crude residue by column
chromatography (n-hexane:EtOAc+0.2 vol% NEt3) afford-
ed the analytically pure product. For most enamides and
enecarbamates the E- and Z-isomers could be readily sepa-
rated by column chromatography. In some cases partial pu-
rification of one isomer was possible. In other cases E- and
Z-isomers could not be separated with simple column chro-
matography.
Scheme 4. Reaction scope for the Ni-catalyzed isomeriza-
tion. Phth=phthaloyl.
Detailed experimental procedures, NMR spectra, HR-MS
data and IR analyses are available in the Supporting Infor-
mation.
allylamide 4m or the ibuprofen-derived allylamide 4n,
were converted to the corresponding isomerization
products 5m and 5n in 88% and 91% yields. Urea,
imide and carbamate derivatives could be trans-
formed efficiently into the N-protected enamines 5o–t
in 48–95% yields. However, a higher catalyst loading,
higher temperatures and prolonged reaction times
were required for these substrates. It is worth men-
tioning that the isomerization of allylamide 4a was
performed routinely on a 15-g scale. Although a slight
decrease in the yield was observed, the desired enam-
ide 5a was isolated in satisfactory yield of 82%.
Acknowledgements
This work was financially supported by the Fonds der Chem-
ischen Industrie (Liebig Fellowship to G. M.) and the Evonik
Foundation (Ph.D. Fellowship to J. H.). We would like to
thank Rockwood Lithium (Frankfurt), BASF (Ludwigsha-
fen) and Evonik Industries (Darmstadt) for the generous
gifts of chemicals.
This nickel-catalyzed isomerization is not limited to
allylamides. Also homoallylamides 4u and 4v under-
went the isomerization to the corresponding enamides
5u and 5v in 91% and 69% yield via a “long-distance”
migration of the double bond (Scheme 4). However,
prolonged reaction times are necessary for these
“long-distance” isomerizations.
In summary, we have developed a practical synthe-
sis of enamides starting from the corresponding, read-
ily accessible N-allylamides. We have shown that
single-component, air-stable Ni(II)-s-aryl complexes
can catalyze this isomerization very efficiently. The
scope of the reaction is broad and encompasses vari-
ous substituted allylamides, -ureas, -imides and -car-
bamates as well as homoallylic substrates. The reac-
tion can be performed on a multigram-scale in com-
mercially available MeOH without specialized glove-
box equipment or Schlenk techniques.
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Experimental Section
Typical Procedure for the Ni-Catalyzed Isomerization
of Allylamides
A 10-mL reaction tube was charged with [Ni(PPh3)2(1-naph-
thyl)Br] (5–10 mol%) and methanol (0.4 mLmmolÀ1 allyl-
amide/-carbamate) and capped with a rubber septum. The
resulting suspension was degassed by slowly bubbling argon
through the mixture for 15 min with simultaneous sonication
in an ultrasound bath. The N-allylamide or, respectively,
-carbamate was added at room temperature under vigorous
stirring. The reaction mixture was stirred at the specified
temperature for the specified time, afterwards diluted with
EtOAc+0.2 vol% NEt3 and filtered through a short plug of
celite and silica gel. The plug was rinsed with additional
EtOAc. The combined filtrates were concentrated under re-
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