Preparation of highly substituted (β-acylamino)acrylates via iron-catalyzed alkoxycarbonylation of N-vinylacetamides with carbazates

Article abstract of DOI:10.1039/c4cc05338a

An efficient iron(ii)-catalyzed alkoxycarbonylation reaction between N-vinylacetamides and carbazates is reported. The corresponding useful highly substituted (β-acylamino)acrylates could be obtained in reasonable to good yields and stereoselectivity under mild reaction conditions. This journal is

Full text of DOI:10.1039/c4cc05338a

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Preparation of highly substituted
(b-acylamino)acrylates via iron-catalyzed
alkoxycarbonylation of N-vinylacetamides
with carbazates†
Cite this: Chem. Commun., 2014,
50, 11661
Received 11th July 2014,
Accepted 6th August 2014
Ran Ding,a Qiu-Chi Zhang,a Yun-He Xu*a and Teck-Peng Loh*ab
DOI: 10.1039/c4cc05338a
www.rsc.org/chemcomm
An efficient iron(II)-catalyzed alkoxycarbonylation reaction between
Initially, our attempt involved the search for optimized reac-
N-vinylacetamides and carbazates is reported. The corresponding useful tion conditions by carrying out the reaction of N-vinylacetamide
highly substituted (b-acylamino)acrylates could be obtained in reason- 1a with carbazate 2a. The observed results are shown in Table 1.
able to good yields and stereoselectivity under mild reaction conditions. Using 20 mol% [Fe(Pc)] (iron(II)phthalocyanine) as a catalyst, the
desired product (Z)-methyl 3-acetamido-3-phenylacrylate 3a
(b-Acylamino)acrylate derivatives are useful building blocks in could be obtained only in low yields when PIDA (phenyliodine
organic synthesis which have been used widely for the asymmetric diacetate), BQ (benzoquinone), TBPB (tert-butyl benzoperoxoate)
synthesis of b-amino acids and chiral amines.1 Accordingly, the DTBP (di-tert-butyl peroxide) or DCP (dicumyl peroxide) was used
synthesis of this class of compounds has attracted much attention.2 as an oxidant in acetonitrile at 80 1C (Table 1, entries 1–5). To our
Common methods to access this class of compounds include delight, the desired product could be obtained in 68% yield
the condensation of b-ketoester with an amine source3 and the when TBHP (tert-butyl hydroperoxide) was used as the oxidant
Pd-catalyzed a-arylation of b-amido-acrylate.4 However, these with Cs2CO3 as the additive. Furthermore, after reducing the catalyst
methods suffer from a limited substrate scope and difficulties loading to 10 mol% and the base amount to one equivalent, the
in controlling the E/Z selectivity of the product. Therefore, a more yield of the desired product only decreased slightly at 60 1C (Table 1,
efficient and general method to access (b-acylamino)acrylate entry 11). However, other tested bases (Table 1, entries 12–16), iron
derivatives is highly desirable. We envisage that the direct C–H catalysts (Table 1, entries 17–19) or used solvents (Table 1, entries
alkoxycarbonylation of N-vinylacetamides will provide one of 20–22) did not favour the transformation to the desired product. It
the most direct entries to this class of compounds. However, was found that increasing TBHP loading and increasing the reaction
the Pd-catalyzed C–H carbonylation of N-vinylacetamides with concentration could not improve the product yield significantly.
carbon monoxide led to the formation of 1,3-oxazin-6-ones.5 Control experiments were also carried out and the iron catalyst was
An attractive strategy is to use carbazate, a very useful source of found to be necessary to afford the product (Table 1, entry 26).
ester groups discovered by Taniguchi and coworkers, as the Finally, the optimized conditions were established to be: [Fe(Pc)]
carbonylation reagent.6 During the past few years, carbazates (10 mol%), Cs2CO3 (1 equiv.), and TBHP (2.0–2.4 equiv.) at 60 1C
have been widely used by many groups including those of Tian,7 in CH3CN for 2 hours.
Li,8 Du,9 Zhu,10 etc. Inspired by these seminal studies and due to
The optimized reaction conditions were then applied to
our interest in developing direct C–H bond functionalization of various acyclic N-vinylacetamides (Table 2). It was found that
N-vinylacetamides,11 herein, we report a new and simple method the substituents on the phenyl ring of the N-vinylacetamide did
to prepare highly substituted (b-acylamino)acrylates using not affect the yields of the reaction of 1 with 2a. Different halide
N-vinylacetamides and carbazates catalyzed by cheap and low substituents were tolerated in the final products which permit
toxicity iron catalysts.
their further functionalization in subsequent steps. However,
the substituents at the ortho-position could lead to a slightly
decreased Z/E selectivity of the products. In addition, different
heteroaryls such as benzofurans, furans and thiophene substituted
N-vinylacetamides were also applied as substrates in this reaction,
the corresponding products could be isolated in reasonable yields
and with high stereoselectivities. Furthermore, N-vinylacetamide 1p
with a cyclohexyl group could also be used well and afforded the
desired product 3p in 63% yield and in a 92/8 ratio of Z/E selectivity.
a Hefei National Laboratory for Physical Sciences at the Microscale and Department
of Chemistry, University of Science and Technology of China, Hefei, 230026,
China. E-mail: xyh0709@ustc.edu.cn
b Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore, 637371,
Singapore. E-mail: teckpeng@ntu.edu.sg
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc05338a
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Table 1 Optimization of the reaction conditions of alkoxycarbonylation
of acyclic N-vinylacetamide with carbazate 2aa,b
Table 2 Iron-catalyzed direct alkoxycarbonylation of 1 with different
carbazatesa,b,c
Catalyst
Entry (mol%)
Base
Yieldc
Solvent t (h) (%)
Oxidantb T (1C) (equiv.)
1
2
3
4
5
6
7
8
[Fe(Pc)] (20) PIDA
[Fe(Pc)] (20) BQ
80
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
30
37
35
Trace
Trace
41
68
68
68
66
68
47
51
62
58
65
Trace
22
26
47
47
56
68
68
68
80
80
80
80
80
80
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
[Fe(Pc)] (20) TBPB
[Fe(Pc)] (20) DTBP
[Fe(Pc)] (20) DCP
[Fe(Pc)] (20) TBHP
[Fe(Pc)] (20) TBHP
[Fe(Pc)] (20) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (5) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (10) TBHP
FeCl3 (20) TBHP
FeCl2 (20) TBHP
FeBr2 (20) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (10) TBHP
[Fe(Pc)] (10) TBHP
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (1.0)
Na2CO3 (1.0)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
CH3COOK (2.0) CH3CN
LiOH (2.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
KHCO3 (2.0)
K3PO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Toluene 3
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
3
3
3
2
2
23d [Fe(Pc)] (10) TBHP
24e [Fe(Pc)] (10) TBHP
25e, f [Fe(Pc)] (10) TBHP
26
TBHP
Trace
a
Reaction conditions: the mixture of 1a (0.2 mmol), 2a (0.8 mmol),
b
oxidant (2.0 equiv.) and base in solvent (1.5 mL). TBHP was used with
c
d
2.0–2.4 equiv. (5–6 M in decane). Isolated yields. Solvent (1.0 mL).
e
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), TBHP (2.0–2.4 equiv.,
f
80 mL, 5–6 M in decane), solvent (1.0 mL). A 94:6 Z/E ratio was determined
from 1H NMR spectra of the crude product.
Finally, ethyl hydrazinecarboxylate and benzohydrazide were
used as carbonyl sources in the current reaction,12 products 3q
and 3r were efficiently formed in 62% and 60% yields, respec-
tively. After establishing the current simple and efficient method
for preparation of highly substituted (b-acylamino)acrylates, a
gram-scale reaction between 1a and 2a was tested. To our
delight, the product 3a could also be obtained in a steady 61%
yield (please see the details in the ESI†).
a
Reaction conditions: the mixture of 1a (0.3 mmol), 2a (0.6 mmol),
TBHP (2.0–2.4 equiv., 120 mL, 5–6 M in decane), Cs2CO3 (1.0 equiv.)
and [Fe(Pc)] in 1.5 mL of CH3CN was heated at 60 1C for 2 hours.
b
c
Isolated yields. The ratios of Z/E shown in parentheses were deter-
mined from the crude 1H NMR spectra of the corresponding reactions.
When the optimized reaction conditions were employed for The selected protecting group on the nitrogen atom is impor-
the alkoxycarbonylation reaction of cyclic N-vinylacetamide 4a, tant for the product yield; as more bulky protecting groups will
unfortunately, only very poor yield (o10%) of the product was decrease the yield. Moreover, it was noticed that the electronic
obtained accompanied by the decomposed starting material. effect from the substituents on the phenyl ring of the cyclic
After careful investigation (Table 3), we found that the choice of N-vinylacetamides on the product yield is quite different from
base was crucial for the product yield. Next, different bases that observed in acyclic N-vinylacetamides. For example, with
were further examined in the reaction and finally one equiva- the halide or ester substituent, only moderate yields of the
lent of K2CO3 was found to be suitable for affording product 5a products could be realized. It seems that the steric effect from
in an acceptable yield at room temperature. Other bases such as the substituted methyl group at the 3-position is not sensitive
LiOH, KOH or K3PO4 were found to be less effective in affording for the generation of the product, 61% yield of 5j could be
the desired product.
observed. Variation on the ring size was also studied; the sub-
With the further optimized reaction conditions in hand, strates with a six- or seven-membered ring could also be smoothly
various cyclic N-vinylacetamides were tested for the preparation transferred into the target products in 50% and 62% yields,
of tetra-substituted (b-acylamino)acrylate derivatives (Table 4). respectively (Table 4, entries 5k and 5l).
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Table 3 Optimization of the reaction conditions of alkoxycarbonylation
of cyclic N-vinylacetamide with carbazate 2aa,b
Entry
Catalyst (mol%)
Base (equiv.)
t (h)
Yield (%)
1
2
3
4
5
6
7
8
9
[Fe(Pc)] (10)
[Fe(Pc)] (10)
[Fe(Pc)] (10)
[Fe(Pc)] (10)
[Fe(Pc)] (10)
[Fe(Pc)] (10)
[Fe(Pc)] (10)
[Fe(Pc)] (20)
[Fe(Pc)] (20)
LiOH (1)
1
1
1
1
1
1
0.5
0.5
1
42
50
34
Trace
57
Trace
54
60
LiOHÁH2O (1)
K3PO4 (1)
KOH (1)
K2CO3 (1)
Cs2CO3 (1)
K2CO3 (1)
K2CO3 (1)
37
Scheme 1 Proposed possible mechanism for the alkoxycarbonylation of
N-vinylacetamide with carbazate.
a
Reaction conditions: the solution of 4a (0.2 mmol), 2a (0.4 mmol),
TBHP (2.0–2.4 equiv., 80 mL, 5–6 M in decane), base (1.0 equiv.)
and [Fe(Pc)] in 1.0 mL of CH3CN was run at room temperature for 1 hour.
b
Isolated yields.
In conclusion, we have developed an iron-catalyzed alkoxy-
carbonylation reaction of N-vinylacetamides with carbazates
under simple and mild reaction conditions. Various acyclic
and cyclic N-vinylacetamides as starting materials were found
to be tolerated in the titled reaction. The observed good
stereoselectivities and reasonable yields of the products make
this method a general tool for the synthesis of highly substituted
(b-acylamino)acrylate derivatives via direct functionalization of
N-vinylacetamides.
Table 4 Iron-catalyzed direct alkoxycarbonylation of 4 with carbazate 2aa,b
We gratefully acknowledge the funding support of the
National Science Foundation for Young Scientists of China
(21202156), the National Natural Science Foundation of China
(21372210), and the Fundamental Research Funds for the Central
Universities (WK2060190023) and the Natural Science Foundation
of Anhui Province (1308085QB37). The authors also thank Nanyang
Technology University for financial support of this research. The
authors are grateful to Mr Koh Peng Fei Jackson for his careful
proofreading of the final manuscript.
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