Easy access to enamides: A mild nickel-catalysed alkene isomerization of allylamides

Article abstract of DOI:10.1039/c3cc43875a

The first Ni-catalysed alkene isomerization of allylamides for the synthesis of enamides was demonstrated. Various substituted N-allylamides were found to be suitable substrates for this isomerization. Isotopic labelling experiments showed that it is an i

Full text of DOI:10.1039/c3cc43875a

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Easy access to enamides: a mild nickel-catalysed alkene
isomerization of allylamides†
Cite this: DOI: 10.1039/c3cc43875a
a
a
Lu Wang,z Chao Liu,z Ruopeng Bai,a Yani Pana and Aiwen Lei*ab
Received 23rd May 2013,
Accepted 28th June 2013
DOI: 10.1039/c3cc43875a
www.rsc.org/chemcomm
The first Ni-catalysed alkene isomerization of allylamides for the
Many transition metal catalysts have been widely applied in
synthesis of enamides was demonstrated. Various substituted alkene isomerization.8 For the alkene isomerization of allylamides,
N-allylamides were found to be suitable substrates for this isomeriza- the noble transition metal catalysts, such as Rh,7c,9 Ru,7c,9,10 Os11
tion. Isotopic labelling experiments showed that it is an intramolecular and Ir,12 have mainly been used for the synthesis of enamides.
hydrogen transfer process.
However, only isolated examples have been reported with first-row
transition metals as the catalysts for this transformation, in which
Enamides have proven to be extremely fascinating synthons due to toxic Fe(CO)x7a,9a,13 or Cr(CO)x14 complexes were applied. To the best
their versatility for further synthetic transformations such as the of our knowledge, there has been no report on the use of nickel
Diels–Alder cycloaddition,1 enamide–olefin ring-closing meta- complexes as catalysts for the isomerization of allylamides to
thesis2 and synthesis of important heterocycles.3 Besides the above date. Herein, we report the first Ni-catalysed alkene isomeriza-
applications, this class of compounds has also been used in tion of allylamides for the synthesis of enamides by using simple
asymmetric hydrogenation reactions for the synthesis of enantio- Ni(PPh3)4 as the catalyst under mild conditions [eqn (1)].
selectively pure amides.4 Due to the importance of enamides, many
efforts have been focused on their synthesis. The classic method is
the direct acylation of imines with acyl chlorides or anhydrides.5
However, this method suffers from the unstable and corrosive
properties of the corresponding acylation reagents. Recently,
a stoichiometric TiCl4-promoted condensation of amides with
aldehydes (or ketones) has also been developed for the synthesis
(2)
Recently, our group has reported a nickel-catalysed Heck-
of enamides.6 For all of these transformations, by-products were type alkenylation of a-carbonyl alkyl bromides with olefins.15
generated in the reaction systems and stoichiometric amounts of When N-allyl-4-methylbenzamide (1a) was utilized as the sub-
bases were utilized. Consequently, developing novel processes for strate to react with ethyl 2-bromopropanoate, it was interesting
efficient and atom-economical assembling of enamides is highly to find that the alkene isomerization product 2a was obtained
desired. In this aspect, the direct alkene isomerization of allyl- in 36% yield [eqn (2)]. Following this initial discovery, we
amides is an atom-economic strategy to construct enamides.7
investigated a Ni-catalysed isomerization of allylamides for
the synthesis of enamides.
As shown in eqn (2), ethyl 2-bromopropanoate was not
involved in the alkene isomerization. Then, we tried to optimize
the reaction conditions for this alkene isomerization using
N-allyl-4-methylbenzamide (1a) as the model substrate. Inter-
estingly, when Ni(PPh3)4 was solely applied as the catalyst in
the absence of dppp (1,3-bis(diphenylphosphino)propane) and
K3PO4, the product enamide 2a was obtained in almost a
quantitative amount at 60 1C. Furthermore, the reaction tempera-
ture could be lowered to 30 1C and a 99% GC yield was obtained
(Table 1, entry 1). However, the reaction solution immediately
turned green and finally no product was observed when the
reaction mixture was exposed to oxygen or air (Table 1, entry 2).
When Ni(acac)2 was used as the catalyst precursor instead of
(1)
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072,
P. R. China. E-mail: aiwenlei@whu.edu.cn; Fax: +86-27-68754067;
Tel: +86-27-68754672
b Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen 518055, P. R. China
† Electronic supplementary information (ESI) available: Characterization of all
compounds and copies of 1H and 13C NMR spectra of isolated compounds. See
DOI: 10.1039/c3cc43875a
‡ These two authors contributed equally.
c
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Table 1 Impacts of reaction parameters on the Ni-catalysed isomerization of
N-ally-4-methylbenzamidea
Table 2 Substrate scope for the Ni-catalyzed isomerization of N-allylamidesa
Entry Substrate
Product
Yieldb (%) (E/Z)
1
2
3
4
5
6
7
8
9
1a: R = p-MeC6H4
2a: R = p-MeC6H4
2b: R = o-MeC6H4
2c: R = p-OMeC6H4
2d: R = p-CF3C6H4
2e: R = p-ClC6H4
2f: R = C6H5CH2
2g: R = Bu
2h: R = NPh2
2i: R = Boc
99 (56/44)
99 (60/40)
99 (53/47)
99 (47/53)
99 (77/23)
98 (61/39)
93 (96/4)
Entry
[M]
Solvent
Conversion
Yieldb (%)
1b: R = o-MeC6H4
1c: R = p-OMeC6H4
1d: R = p-CF3C6H4
1e: R = p-ClC6H4
1f: R = C6H5CH2
1
Ni(PPh3)4
Ni(PPh3)4
Ni(acac)2
Pd(PPh3)4
FeCl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
DME
EtOH
MeOH
100
—
—
—
—
—
37
50
100
100
99 (94d)
—
—
—
—
—
34
2c
3
4
5
6
7
8
9
10
t
t
1g: R = Bu
1h: R = NPh2
1i: R = Boc
91 (39/61)
CuCl2
94c (66/34)
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
48
99 (99d)
99
10
11
87 (100/0)
a
Unless otherwise noted, the reaction was carried out with 1a
(0.25 mmol), catalyst (0.025 mmol), solvent (2.0 mL), 30 1C, 9 h under
b
an argon atmosphere. Yield determined by GC analysis with biphenyl
as the internal standard. Under an air atmosphere. Isolated yields.
c
d
47d (100/0)
94 (—)
Ni(PPh3)4, substrate 1a was almost quantitatively recovered
(Table 1, entry 3), indicating that Ni(II) could not initiate the
reaction. To further evaluate the superiority of the Ni catalyst 12
for this allylamide isomerization, other transition metal
catalyst precursors were tested. Pd(PPh3)4, CuCl2 and FeCl2 all
a
Reaction conditions: 1 (0.25 mmol), Ni(PPh3)4 (0.025 mmol), ethanol
showed no reactivity for the isomerization under the same
conditions (Table 1, entries 4–6). Study of the solvent effects
showed that the isomerization product could be obtained in
THF or DME, but the yields decreased drastically (Table 1,
b
(2.0 mL) at 30 1C for 9 h under an argon atmosphere. Isolated yields.
c
d
Methanol as the solvent, 60 1C, 5d. Methanol as the solvent, 60 1C.
entries 7 and 8). When a polar protic solvent was utilized, such Isomerization of N,N-diallylamide could also generate N,N-di-
as ethanol or methanol, the desired isomerization product was (1-propenyl)amide (2l) in 94% yield (Table 2, entry 12).
obtained in 99% yield, respectively (Table 1, entries 9 and 10). It
To further explore the substrate applicability of the reaction,
was worth noting that the reaction could even be performed in N-allylamides with different allyl groups were also tested (Table 3).
industrial ethanol (95% of purity) to afford 2a in an equivalent Substitutions at the allylic position could slow down the reaction
yield. Therefore, ethanol was chosen as the solvent. We have rate of this isomerization. Therefore, prolonged reaction time
also tried 5 mol% and 1 mol% catalyst loadings, and the and higher temperature were required to obtain excellent yields
desired product 2a was obtained in 99% and 78%, respectively, (Table 3, entries 1 and 2). A 1,1-disubstituted allylic system
at 30 1C after 9 h. However, low catalyst loading sometimes has such as 4-methyl-N-(3-methylbut-2-enyl)benzamide worked well
problematic generality and reproducibility for other substrates, to afford the desired product 4c in a moderate yield in 45 h
therefore, catalyst with 10 mol% loading was applied as the at 60 1C (Table 3, entry 3).
general condition. The standard reaction conditions were
determined to be: [Ni(PPh3)4] (10 mol%), ethanol, 30 1C, 9 h.
It is noteworthy that the ‘long-distance’ migration of double
bonds could be successfully achieved to generate the corres-
With the optimized conditions in hand, the isomerization ponding enimides. Homoallylamides, such as N-(but-3-enyl)-4-
reactions of a range of N-allylamides were tested (Table 2). First methylbenzamide 5a afforded the isomerization product 6a in
of all, feasibility of the N-protected groups was investigated. 91% yield when the reaction time was prolonged to one week
With both electron-donating and electron-withdrawing substi- [Scheme 1, eqn (3)]. Isomerization of N-allylamide over 5 positions
tuents on the aromatic rings, reactions proceeded smoothly to could also be realized [Scheme 1, eqn (4)], although a considerable
afford the desired products in excellent yields (Table 2, entries amount of side-product resulting from the ‘incomplete’ double
1–4). Halide substituents could be well tolerated, which pro- bond shift was obtained.
vided high potential for additional product functionalization
As this alkene isomerization could be conducted smoothly
(Table 2, entry 5). Moreover, N-alkyl protected allylamides such in a protonic solvent, we expected to know whether the solvent
as N-phenylacetyl, N-pivaloyl and cyclic allylamide could also be has participated in the transformation. Thus, deuteration experi-
well transformed into the corresponding isomerization pro- ments were performed as shown in Scheme 2. With CD3OD as the
ducts (Table 2, entries 6, 7 and 10). Notably, urea, carbamate reaction solvent, no deuterated product was obtained [Scheme 2,
and imide derivatives also afforded the isomerization product eqn (5)], while for the deuterated substances 1a-d with the normal
in moderate to excellent yields (Table 2, entries 8, 9 and 11). CH3OH as the solvent, deuteration occurred wholly kept in the
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Table 3 Substrate scope for the Ni-catalyzed isomerization of N-allylamidesa
such a nickel-catalysed isomerization reaction underwent an
intramolecular hydrogen transfer.
In conclusion, we have developed an inexpensive and con-
venient nickel-catalysed isomerization reaction of N-allylamides
under mild conditions for the synthesis of enamides which were
widely used in organic synthesis. Various substituted N-allyl-
amides were found to be suitable substrates for this isomeriza-
tion, and this method could also realise the ‘long-distance’
migration of double bonds. The reaction was performed well
in industry grade alcohol. Studies on the scope of the reaction
and mechanistic studies are underway.
Entry Substrate
1
Product
Yieldb (%) (E/Z)
91c (100/0)
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21025206 and
21272180), the China Postdoctoral Science Foundation funded
project (2012M521458) and the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1030).
2
99d
3
50e (100/0)
Notes and references
a
Reaction conditions: 3 (0.25 mmol), Ni(PPh3)4 (0.025 mmol), ethanol
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product molecules, and only the intramolecular hydrogen trans-
fer product 2aa and 2ab were detected using GC-MS and NMR
with a 1 : 1 ratio [Scheme 2, eqn (6)]. These results indicated that
c
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