Synthesis of α,β-unsaturated γ-amino esters with a quaternary center by ruthenium-catalyzed codimerization of N-acetyl α-arylenamines and acrylates

Article abstract of DOI:10.1039/c1ob06412f

Ruthenium-catalyzed highly selective codimerization of N-acetyl α-arylenamines with ethyl acrylates is reported. This codimerization reaction provides a new efficient method for the synthesis of α,β-unsaturated γ-amino esters with a quaternary center.

Full text of DOI:10.1039/c1ob06412f

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Synthesis of a,b-unsaturated c-amino esters with a quaternary center by
ruthenium-catalyzed codimerization of N-acetyl a-arylenamines and
acrylates†
Qiu-Shi Wang, Jian-Hua Xie, Lu-Chuan Guo and Qi-Lin Zhou*
Received 18th August 2011, Accepted 9th September 2011
DOI: 10.1039/c1ob06412f
Ruthenium-catalyzed highly selective codimerization of N-
acetyl a-arylenamines with ethyl acrylates is reported. This
codimerization reaction provides a new efficient method
for the synthesis of a,b-unsaturated c-amino esters with a
quaternary center.
insertion of a-diazoesters into vinyl halides and trapping with
amines,7 rhodium- and palladium-catalyzed ring opening of vinyl
epoxides with amines and azide,8 and Lewis acid-catalyzed N–H
insertions of methyl styryldiazoacetate with aniline.9 However, the
efficiencies of these methodologies, especially in the preparation
of the a,b-unsaturated g-amino esters with a quaternary center,
are unsatisfied. Therefore, the development of highly efficient
and atom-economic catalytic methods for the synthesis of a,b-
unsaturated g-amino esters is highly desired.
Transition metal-catalyzed selective codimerization of two
different alkenes, for example hydrovinylation, is a very im-
portant and highly atom-efficient olefin-forming reaction, and
has been the subject of extensive study.10 Recently, we stud-
ied codimerizations of a-substituted vinylarenes with ethylene
(hydrovinylation) and obtained olefin products with a quater-
nary center in high yields and high chemoselectivities11 This
result encouraged us to investigate the codimerization of N-
acetylenamines with functionalized alkenes to generate polyfunc-
tionalized alkenes. In this communication, we report the codimer-
ization of N-acetyl a-arylenamines with acrylates catalyzed
by a ruthenium complex RuHCl(CO)(PCy3)2, producing a,b-
unsaturated g-amino esters with a quaternary center in high yields
(Scheme 1).12
a,b-Unsaturated g-amino esters are very useful intermediates
and building blocks in organic synthesis.1 They can be found
in various bioactive natural products and drug molecules, such
as miraziridine A, a novel cysteine protease inhibitor from the
marine sponge Theonella aff. mirabilis,2 and AG7088, a rhinovirus
3
protease inhibitor for treatment of the common cold (Fig. 1).
More importantly, a,b-unsaturated g-amino esters can serve as
precursors for the preparation of g-amino acids, which are key
ingredients in pharmaceuticals.4 a,b-Unsaturated g-amino esters
are usually prepared from N-protected a-amino aldehydes by
Witting-type olefination reactions.5 Direct catalytic syntheses of
a,b-unsaturated g-amino esters are very limited. The reported cat-
alytic methods include the palladium-catalyzed rearrangement of
a-sulfonimidoyl b,g-unsaturated esters,6 the palladium-catalyzed
Scheme 1 The codimerization of N-acetyl a-arylenamines with acrylates.
The codimerization reaction was initially performed un-
der the standard conditions for the hydrovinylation of N-
acetylenamines.11d The reaction of N-(1-phenylvinyl)acetamide
(1a) with 2.0 equivalents of ethyl acrylate (2a) in the presence
of 5 mol% of catalyst RuHCl(CO)(PCy3)2 and 5 mol% of additive
AgOTf in DCE at 65 ◦C produced a,b-unsaturated g-amino ester
(E)-3a in 85% yield accompanied by a small amount (~5%) of
by-product formed from the dimerization of 1a (Table 1, entry
1). On increasing the amount of ethyl acrylate (2a) from 2.0 to
5.0 equivalents, the reaction became faster (reaction time changed
from 40 h to 3.5 h) and the yield of 3a increased to 96% (entry 2).
However, changing the ruthenium catalyst to RuH2(CO)(PPh3)3 or
Fig. 1 Bioactive molecules containing the a,b-unsaturated g-amino
acid/ester moiety.
State Key Laboratory and Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin, 300071, China. E-mail: qlzhou@nankai.edu.cn;
Fax: +86 22 2350 6177; Tel: +86 22 2350 0011
† Electronic supplementary information (ESI) available: Detailed experi-
mental procedures, and the analysis data of new compounds. See DOI:
10.1039/c1ob06412f
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Table 1 Reaction conditions optimization for the codimerization of 1a and 2aa
Entry
Catalyst
Additive
Solvent
Temp./◦C
Time/h
Conv. (%)
Yield (%)b
1c
2
3
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuH2(CO)(PPh3)3
AgOTf
AgOTf
None
DCE
DCE
DCE
Toluene
Toluene
DCE
DCE
DCE
Toluene
DMF
Dioxane
DCE
DCE
DCE
65
65
65
140
140
65
45
25
65
65
65
65
65
65
65
65
40
3.5
20
20
20
20
19
72
20
20
20
20
20
20
20
40
> 97
100
27
41
25
13
100
92
76
8
51
100
63
100
82
86
85
96
None
None
None
None
90
4
RuH2(CO)(PPh3)3
None
5d
6
[Ru(p-cymene)Cl2]2/PPh3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
RuHCl(CO)(PCy3)2
NaHCO2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgBF4
AgPF6
AgSbF6
NaBArF
AgOTf
7
8
9
10
11
12
13
14
15
16e
86
33
0
47
86
60
91
77
DCE
DCE
80
a Reaction conditions: 0.01 mmol of [Ru] catalyst, 0.01 mmol of additive, 0.2 mmol of 1a, 1.0 mmol of 2a (5 eq.), 3 mL of solvent, 20 h. b Isolated yield.
c 2 equivalents of 2a. d 15 mol% of PPh3, 30 mol% of NaHCO2. e 2 mol% catalyst.
Table 2 Codimerization of N-acetyl a-arylenamines with acrylates cat-
[Ru(p-cymene)Cl2]2/PPh3, which are efficient for the addition
of olefinic C–H bonds of a,b-unsaturated ketones/esters to
olefins,12a–d led only to dimerization of 1a. The reaction tem-
perature strongly influenced reaction rate. Lowering the reaction
temperature to 45 ◦C and 25 ◦C decreased the reaction rate
and gave lower yields (entries 7 and 8 vs. entry 2). Solvent
screening experiments revealed that dichloroethane (DCE) was
the best reaction medium, and coordinating solvents such as
N,N-dimethylformamide (DMF) afforded no desired product.
Trifluoromethanesulfonic acid anion (OTf-) was demonstrated
to be the counteranion of choice for the catalyst, albeit that
the codimerization of 1a and 2a proceeded well with other
a
alyzed by RuHCl(CO)(PCy3)2
Entry Ar
R
Product Time/h Conv. (%) Yield (%)b
1
2
3
4
5
6
7
8
C6H5
4-MeC6H4
4-MeOC6H4 Et 3c
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
3-MeC6H4
2-MeC6H4
2-MeOC6H4 Et 3j
2-Naphthyl
C6H5
Et 3a
Et 3b
3.5
3.5
2.5
100
100
100
100
100
100
100
100
53
100
100
100
95
96
91
90
85
90
93
87
88
22
83
95
92
88
Et 3d
Et 3e
Et 3f
Et 3g
Et 3h
Et 3i
20
12
12
12
4
20
14
8
-
-
-
-
counteranions such as BF4 , PF6 , SbF6 , and BArF (entries
12–15). The reaction can be carried out at 2 mol% of catalyst
load, yielding codimerization product 3a in 80% yield with 86%
conversion (entry 16).
9
10
11
12
13
Et 3k
Me 3l
tBu 3m
A variety of N-acetyl a-arylenamines 1 was studied under the
optimal reaction conditions. The electronic property of the a-
arylenamine substrate has a strong effect on the reaction rate and
the yield of a,b-unsaturated g-amino ester product. Substrates
containing an electron-donating group at the para- or meta-
position of the phenyl ring of the a-arylenamine showed high
reaction rates and high yields (Table 2, entries 2, 3 and 8).
Substrates having an electron-withdrawing group exhibited slow
reaction rates, however the yields of the codimerizations are still
high (entries 4–7). The reaction was also sensitive to the steric
effect of the substituents on the substrates. ortho-Substitution on
the ring of the a-arylenamine substrate led to a slower reaction
and a lower yield, especially N-acetyl-a-(2-methylphenyl)enamine
gave only 22% yield and 53% conversion (entry 9). Substrate a-(2-
naphthyl)enamine also gave the desired codimerization product
in high yield. The R group of the acrylate has little impact on
3
20
C6H5
a The reaction conditions were the same as those in Table 1, entry 2. For
details of operation and analysis, see ESI. b Isolated yield.
The codimerization reaction of N-vinylacetamide (4) with ethyl
acrylate (2a) was also studied (Scheme 2). When the reaction was
performed with 5 mol% catalyst codimerization products 5 and
6 were obtained in 46% and 38% yield, respectively. By adding
another 5 mol% catalyst to the reaction mixture, compound 5
was converted to compound 6. If 10 mol% catalyst was directly
used in the beginning, the reaction gave only compound 6.
These results showed that the reaction may produce compound
5 first, which is isomerized to the more stable compound 6 in the
presence of catalyst RuHCl(CO)(PCy3)2/AgOTf. The reaction of
N-vinylacetamide with ethyl acrylate produced b,g-unsaturated b-
amino ester 5, instead of the expected a,b-unsaturated g-amino
t
the reaction except in the case of the very bulky Bu (2c), which
resulted in a low reaction rate, although the yield of the reaction
was kept at 88%.
44 | Org. Biomol. Chem., 2012, 10, 43–45
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(2010CB833300), and the “111” project (B06005) of the Ministry
of Education of China for financial support.
Notes and references
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Scheme 2 Codimerization of N-vinylacetamide (4) and ethyl acrylate
(2a).
ester, indicating that the reaction might proceed via a different
mechanism.11d
To demonstrate the utility of the codimerization products,
a,b-unsaturated g-amino esters, as key intermediates in organic
synthesis, we converted 3a to tricyclic compound 10, which
is the structural motif in natural products of the Erythrina
alkaloids group.13 The a,b-unsaturated g-amino ester 3a was
hydrogenated over Pd/C catalyst to give saturated g-amino ester
7 in quantitative yield. Treatment of the g-amino ester 7 with
LHMDS, followed by reaction with ethyl 2-bromoacetate, gave
the substituted 2-pyrrolidinone 8 in 81% yield. Cyclization of
8 under acidic conditions, followed by a reduction with Pd/C
under hydrogen, afforded the tricyclic compound 10 (Scheme 3).
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pyrroloisoquinoline-type tricyclic compounds with a quaternary
center.
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Scheme 3 Synthesis of tricyclic compound 10.
In conclusion, we have developed an efficient ruthenium-
catalyzed codimerization of N-acetyl a-arylenamines with acry-
lates. The new reaction provides convenient access to a,b-
unsaturated g-amino esters with a quaternary center. Further
studies on this reaction, especially in searching for efficient chiral
ligands to accomplish chiral induction, are in progress in our
laboratory.
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Acknowledgements
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China (973 Program)
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 43–45 | 45
©