Catalytic nucleophilic addition of olefinic C-H bond to α,β-unsaturated-γ-lactams

Article abstract of DOI:10.1016/j.tetlet.2015.08.036

A novel catalytic nucleophilic addition of olefins to α,β-unsaturated-γ-lactams has been developed with a cyclic N-acyliminium ion as a key intermediate. It provides an efficient approach to 5-alkenyl-2-pyrrolidinones from simple and readily available starting materials and the desired products could be obtained in moderate to good yields (23-85%).

Full text of DOI:10.1016/j.tetlet.2015.08.036

Tetrahedron Letters 56 (2015) 5533–5536
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic nucleophilic addition of olefinic CAH bond to
a,b-unsaturated-c-lactams
⇑
Maorong Wang, Bao Gao, Hanmin Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel catalytic nucleophilic addition of olefins to a,b-unsaturated-c-lactams has been developed with a
Received 24 June 2015
Revised 10 August 2015
Accepted 14 August 2015
Available online 20 August 2015
cyclic N-acyliminium ion as a key intermediate. It provides an efficient approach to 5-alkenyl-2-pyrrolidi-
nones from simple and readily available starting materials and the desired products could be obtained in
moderate to good yields (23–85%).
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
CAH addition
N-Acyliminium ion
Pyrrolidin-2-ones
Lewis acid
Brønsted acid
Introduction
employed to construct the 5-alkenyl-2-pyrrolidinones (Scheme 1,
path C). However, the required Grignard reagents were normally
5
As an important class of five-membered heterocycles, pyrro-
lidin-2-ones represent a structural motif frequently found in
numerous natural products, bioactive molecules, and polymers.
synthesized beforehand. All of the above three methods require
multi-steps and generate by-products, therefore it is still a chal-
lenge for developing an efficient and general strategy to update
these old processes. Recently, Bao and co-workers reported a TBHP
assisted coupling method for the synthesis of allylamines with
1
Among various pyrrolidin-2-ones derivatives, 5-alkenyl-2-pyrro-
lidinones have gained considerable attention, as the substructure
is not only widely prevalent in several potential therapeutic com-
6
alkynes and N-methyl-2-pyrrolidone. Mao and co-workers
2
e
pounds, such as the EP4-selective agonist AS701666 (1), and the
EP4 receptor agonism L-902688 (2),2 but also present in many
natural products, including Berberidaceae alkaloid isonuevamine
reported copper-catalyzed decarboxylation coupling reaction
toward 5-alkenyl-2-pyrrolidinones starting from cinnamic acids
d
7
and N-methyl-2-pyrrolidone. However, super stoichiometric
2
b
2g
(3)
and hasubanan alkaloid aknadilactam (4)
(Fig. 1).
amount of oxidant (TBHP) was required in both of the above pro-
tocols. Herein, we describe a novel catalytic nucleophilic addition
Consequently, intense efforts have been devoted to the synthesis
of these compounds.
of olefinic CAH bond to
a,b-unsaturated-c-lactams to acquire
One of the earliest methods employed for constructing 5-alke-
5-alkenyl-2-pyrrolidinones with a cyclic N-acyliminium ion as
key intermediate under mild conditions (Scheme 1).8 To the best
of our knowledge, this is an atom-economic synthesis of
5-alkenyl-2-pyrrolidinones through nucleophilic addition reaction
nyl-2-pyrrolidinones involved the cyclization of
c-aminocarba-
mate (Scheme 1, path A).3 However, this strategy often suffered
from harsh conditions such as high reaction temperature
(
180 °C). In order to solve these problems, more efficient methods
of olefinic CAH bond to a,b-unsaturated-c-lactams.
conducted under milder reaction conditions were developed. One
of the most popular strategies currently being used for the
construction of these compounds involves the elimination of
b-alkoxypyrrolidinones (Scheme 1, path B),4 which often formed
large amounts of by-products due to the utilization of strong bases
and the multistep reaction processes. Besides, the reaction of
N-alkyl succinamides and alkenyl Grignard reagents was also
The cyclic N-acyliminium ions are highly reactive electrophiles,
which have been extensively utilized for the construction of nitro-
gen-containing ring systems via CAC bond formation reactions.6
In this strategy, the research groups of Jacobsen and Dixon have
successfully installed pyrrolidinone moieties at C2- and C3-posi-
,9
1
0
tions of the indole ring, respectively. Our group has been working
for the study of N-acyliminium ion intermediates as well. In 2011,
we successfully developed
a novel and efficient Brønsted
acid catalyzed intermolecular enantioselective N-alkylation of
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2015.08.036
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

5
534
M. Wang et al. / Tetrahedron Letters 56 (2015) 5533–5536
CO
2
H
previous work
O
OH
O
P
O
N
O
OH
N
F
O
N
O
O
HO
F
N
H
Bn
N
N
∗
O
P
O
N
NBn
CH
3
N
(1)
(2)
∗
N
HO
H
BnN
C-N formation
O
O
3
1
2
AS701666
L-902688
present work
R2
CH
3
O
R2
O
O
XnM
TsO
N
N
O
R1
OCH
O
TsOH
MXn
2
R
1
NBn
BnN
O
N
H
3
CO
H CO
C-C formation
O
OCH3
Bn
1
A
3
3
H CO
OH
O
3
3
4
Scheme 2. Proposed protocol for the synthesis of functionalized pyrrolidin-2-one
Isonuevamine
Aknadilactam
derivatives.
Figure 1. Pharmaceutical and bioactive 5-alkenyl-2-pyrrolidinone derivatives.
Table 1
a
indoles with N-benzyl-
(
a
,b-unsaturated-
Scheme 2, Eq. 1). In connection with our previous work, we
envisioned that a cooperative catalysis consisting of Lewis acid
and Brønsted acid may promote the reaction of ,b-unsaturated-
-lactams and olefins. As shown in Scheme 2, N-acyliminium ion
c
-lactam as electrophiles
Optimization of reaction conditions
1
1
8
O
Ph
Ph
Lewis acid, BrØnsted acid
NBn
+
Ph
a
o
O
Ph
Solvent, T C, 6 h
N
Bn
c
1
2a
3a
intermediates would be generated in the presence of Brønsted acid.
Then, a Prins-type reaction of A and olefin 2 might occur and
enable the generation of 5-alkenyl-2-pyrrolidinones in the cat-
alytic system of Lewis acids and Brønsted acids.
Entry
Lewis acid
Fe(OTs)
Y(OTf)
Brønsted acid
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
3
TsOH
TsOH
TsOH
TsOH
TsOH
PivOH
TTCEc
TTCE
TTCE
TTCE
TTCE
TTCE
TTCE
TTCE
50
50
50
50
50
50
50
50
50
50
50
50
50
60
40
50
50
50
17
59
46
57
42
13
55
43
20
Trace
18
28
Trace
59
3
ÁxH
2
O
O
Eu(OTf)
Zn(OTf)
3
ÁxH
2
Results and discussion
2
Yb(OTf)
3
ÁxH
2
O
O
O
O
c
Y(OTf)
Y(OTf)
Y(OTf)
3
ÁxH
3
ÁxH
3
ÁxH
2
2
2
To validate our hypothesis, we began our study on synthesis of
c
HOTf
5
-alkenyl-2-pyrrolidinones by examining the reaction between
N-benzyl- ,b-unsaturated- -lactam 1 and 1,1-diphenylethylene
a in the presence of a catalytic amount of Lewis acid and Brønsted
acid. To our delight, the employment of Fe(OTs) as the Lewis acid
NH
2
SO
3
H
a
c
Y(OTf) ÁxH O
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
None
None
CH Cl2
3
3
3
3
3
3
3
2
2
2
2
2
2
2
2
2
10
Y(OTf)
Y(OTf)
Y(OTf)
Y(OTf)
Y(OTf)
Y(OTf)
None
ÁxH
ÁxH
ÁxH
ÁxH
ÁxH
ÁxH
O
O
O
O
O
O
CCl
4
c
11
12
13
14
DCE
CH NO
3
3
2
and TsOH as the Brønsted acid resulted in the formation of the
desired product 3a in 17% yield at 50 °C in TTCE. Encouraged by
this result, we investigated the reaction conditions in detail, and
the results are summarized in Table 1. The effect of Lewis acids
was first evaluated. The reaction efficiency was dramatically
improved and product 3a was obtained in 59% yield (Table1, entry
Toluene
TTCE
TTCE
TTCE
TTCE
15
42
1
1
1
6
7
8
Trace
Trace
NR
Y(OTf)
None
3
ÁxH
2
O
TTCE
a
Reaction conditions:
Brønsted acid (15 mol %) in solvent (1 mL) under N
1 (0.2 mmol), 2a (0.4 mmol), Lewis acid (5 mol %),
2
) when a catalytic amount of Y(OTf)
catalytic system. An extensive screening of Lewis acids demon-
strated that other Lewis acids such as Eu(OTf) O, Zn(OTf)
ÁxH
and Yb(OTf) O could also catalyze this transformation, but
ÁxH
none of these catalysts could improve the yield (Table 1, entries
–5). Next, Brønsted acids were examined and the results revealed
3
ÁxH
2
O was introduced to the
2
at T °C for 6 h.
b
Isolated yield.
3
2
2
,
c
PivOH = 2,2-Dimethylpropanoate, HOTf = Trifluoromethanesulfonic acid, TTCE =
1,1,2,2-Tetrachloroethane, DCE = 1,2-Dichloroethane.
3
2
3
proceed more efficiently in polar solvents than in non-polar ones,
and TTCE was found to be the best choice. In addition, with either
an increase or decrease in the temperature, inferior results were
observed. Furthermore, the control reactions demonstrated that
the product 3a was rarely formed in the absence of either Lewis
acid or Brønsted acid. These results declared that Lewis acid and
Brønsted acid were essential for promoting the reactivity of the
transformation.
With the optimized reaction conditions in hand, we subse-
quently evaluated the scope of olefins. Initially, a series of 1,1-disub-
stitutedethylenes were subjected to the present reaction, and the
corresponding products 3a–3e were obtained in moderate to good
yields (Table 2, entries 1–5). The reactions were significantly
affected by electronic properties of the alkenes. In general, the alke-
nes with electron-donating group exhibited higher reactivities to
give the corresponding products. For example, 1-methoxy-4-(1-
phenylvinyl)benzene 2c, bearing electron-donating group in the
phenyl ring, gave the desired products 3c in 84% yield (Table 2, entry
that TsOH was the best choice, while other Brønsted acids gave
lower yields (Table 1, entries 6–11). To achieve better results, the
effect of solvent was also studied. The reaction was found to
O
R2
R1
180 C
o
OR
R
1
Path A
Path B
O
R2
NHR3
N
R
3
R2
R2
X
R1
1
) PBr
3
R1
O
N
R
2) t-BuOK
O
N
R
3
3
O
R2
R1
+
1) NaBH4
2) HCl
NR3
MgCl
R1
O
Path C
R2
N
R
O
3
O
R2
R2
NR3
+
R
1
This work
O
R1
N
R
3
). 1-Methoxy-4-(prop-1-en-2-yl)benzene 2e showed highest
3
activity to give the corresponding product 3e in 85% yield (Table 2,
Scheme 1. Synthetic methods of 5-alkenyl-2-pyrrolidinones.
entry 5). For the 1,1-disubstituted alkenes substituted with

M. Wang et al. / Tetrahedron Letters 56 (2015) 5533–5536
5535
Table 2
and Brønsted acid was most likely involved in the present reaction.
The cyclic N-acyliminium ion intermediate A was generated by the
Substrate scope of olefinsa
reaction of N-benzyl-
amount of TsOH. Subsequently, Y(OTf)
a
,b-unsaturated-
c
-lactam 1 with the catalytic
O
R2
R2
3 2
Y(OTf) ·xH O (5 mol%)
TsOH (15 mol%)
TTCE, 50 oC, 6 h
12
3
coordinates with O atom
R1
NBn
+
R1
O
of the N-acyliminium ion to form B, which could enhance the elec-
trophilicity of the species. The nucleophilic addition of alkene 2 to
the N-acyliminium ion B takes place to yield species C. Deprotona-
tion of C affords the final product 3 together with regeneration of
the corresponding Lewis acid and Brønsted acid to the next cat-
alytic cycle. The nucleophilic addition of alkene to the intermediate
B would be the rate-limiting step as witnessed by the higher
reactivity observed by the electron-rich alkenes. Therefore, 1,1-
disubstituted aryl-alkenes showed higher activity than styrenes.
N
Bn
1
2
3
R1
R2
Yieldb (%)
Entry
Product
E/Z
1
2
3
4
5
Ph
4-MeC
4-MeOC
Ph
Ph
Ph
Ph
Me
H
3a
3b
3c
3d
3e
3f
59
76
84
54
85
42
23
32
64
33
65
62
56
30
54
—
6
H
4
1.1:1
1.3:1
1.1:1
12:1
6
H
4
2-Naphthyl
4-MeOC
Ph
2-MeC
3-MeC
4-MeC
6
H
4
c
6
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
7
8
9
6
H
6
H
6
H
4
4
4
H
H
H
3g
3h
3i
Conclusions
1
1
1
1
1
1
0
1
2
3
4
5
2,5-Me
4-t-BuC
2
C
H
6 4
H
3j
In summary, we have developed a novel nucleophilic addition
6
H
4
H
H
3k
3l
4-MeOC
4-EtOC
4-FC
2-Naphthyl
6
H
4
reaction of olefinic CAH bond to N-benzyl-
lactam for the synthesis of 5-alkenyl-2-pyrrolidinones. With
Y(OTf) O and TsOH as catalysts, the reaction could proceed
a,b-unsaturated-c-
6
H
4
H
H
H
3m
3n
3o
c
6
H
4
3
ÁxH
2
smoothly and give corresponding products in moderate to good
yields under mild conditions. Further studies on the synthesis of
chiral 5-alkenyl-2-pyrrolidinones promoted by chiral catalyst are
ongoing in our group.
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Y(OTf)
15 mol %) in TTCE (2.5 mL) under N
Isolated yield.
.5 mmol of 2 was used for 12 h.
3
ÁxH
2
O (5 mol %), TsOH
(
2
at 50 °C for 6 h.
b
c
2
Acknowledgments
different aryl groups, lower E/Z ratio was observed. Styrenes were
also suitable substrates, and moderate yields were achieved with
high stereoselectivity. However, an obvious steric hindrance effect
on the reactivity was observed, which was demonstrated by the
reactivities of ortho-methyl and para-methyl substituted styrenes
This work was supported by the Chinese Academy of Sciences
and the National Natural Science Foundation of China (21222203,
2
1133011 and 21372231).
2
3
2
g and 2i. 4-Methylstyrene smoothly furnished the desired product
i in 64% yield (Table 2, entry 9), but the sterically hindered
-methylstyrene formed the product 3g only in 23% yield under
Supplementary data
Supplementary data (experimental procedures and full charac-
the same reaction conditions (Table 2, entry 7). An effect of elec-
tronic properties of the substituents on the reactivity was observed
as well. 2,5-Dimethylstyrene acquired the desired product 3j in 33%
yield, while relative electron deficiency rendered the 2-methyl-
styrene to gain the product 3g in 23% yield (Table 2, entries 7 and
1
13
terization of all products including H, C NMR and HRMS spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.08.036.
References and notes
1
0). The reaction of 2-vinylnaphthalene proceeded smoothly and
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the reaction with 2.5 mmole of olefins for 12 h. Simple aliphatic
alkenes have been subjected to the standard reaction conditions
and only trace amounts of product could be detected.
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