Copper-Catalyzed Three-Component Cascade Michael Addition/Heck-Type Alkylation/Annulation: Accessing Fully Substituted 1,3-Dihydro-2 H-pyrrol-2-ones

Article abstract of DOI:10.1021/acs.orglett.9b03189

We report a highly efficient copper-catalyzed three-component reaction of alkylamines, acetylenedicarboxylates, and α-bromocarbonyls for the assembly of fully substituted 1,3-dihydro-2H-pyrrol-2-ones. A variety of alkylamines and ammonium salt are functionalized with acetylenedicarboxylates and α-bromocarbonyls. N-aryl enaminoesters are also successfully alkylated with α-bromocarbonyls. This protocol is understood to proceed through radical Heck-type coupling of in-situ-generated bulky trisubstituted alkenes with bulky tertiary alkyl bromides, which is realized for the first time.

Full text of DOI:10.1021/acs.orglett.9b03189

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Three-Component Cascade Michael Addition/
Heck-Type Alkylation/Annulation: Accessing Fully Substituted 1,3-
Dihydro‑2H‑pyrrol-2-ones
Dan Ba, Yanhui Chen, Weiwei Lv, Si Wen, and Guolin Cheng*
College of Materials Science & Engineering, Huaqiao University, Xiamen 361021, China
S
* Supporting Information
ABSTRACT: We report a highly efficient copper-catalyzed
three-component reaction of alkylamines, acetylenedicarbox-
ylates, and α-bromocarbonyls for the assembly of fully
substituted 1,3-dihydro-2H-pyrrol-2-ones. A variety of alkyl-
amines and ammonium salt are functionalized with
acetylenedicarboxylates and α-bromocarbonyls. N-aryl enam-
inoesters are also successfully alkylated with α-bromocarbon-
yls. This protocol is understood to proceed through radical
Heck-type coupling of in-situ-generated bulky trisubstituted
alkenes with bulky tertiary alkyl bromides, which is realized for
the first time.
he Mizoroki−Heck (M−H) reaction is one of the most
powerful C−C-bond-forming methods in synthetic
presence of Fe,4 Co,5 Ni,6 Cu,7 Pd,8 Au,9 or Ir;10 such highly
active alkyl radical species were subsequently captured by
terminal alkenes (see Scheme 1b). However, internal alkenes
have had limited application in radical Heck-type reactions,
with only isolated examples available for 1,2-disubstituted
alkenes.7d,10 Trisubstituted alkenes are almost unstudied; to
the best of our knowledge, only one example using 1,1-
diphenylpropene and primary alkyl bromides has been
reported to give a 32% yield.9 The utilization of trisubstituted
alkenes and tertiary alkyl halides as coupling partners remains a
major challenge in this area, probably because of the steric
hindrance between the substrates. As our ongoing interest in
enaminone and enaminoester chemistry,11 we report herein a
copper-catalyzed alkylation of enaminoesters with tertiary alkyl
bromides12 and the subsequent annulation for the synthesis of
fully substituted 1,3-dihydro-2H-pyrrol-2-ones (see Scheme
1c).
T
organic chemistry.1 Major efforts have been devoted toward
the use of aryl, alkenyl, or benzyl halides2 as coupling partners
for the synthesis of functionalized alkenes (see Scheme 1a). In
Scheme 1. Radical Heck-Type Coupling
1,3-Dihydro-2H-pyrrol-2-one represents one of the most
important classes of heterocycles and constitutes the structural
core of a variety of synthetic bioactive compounds13a−c and
natural products.13d As a result, chemists are interested in
developing many new synthetic methods to obtain a wide
spectrum of 1,3-dihydro-2H-pyrrol-2-one derivatives.14
We discovered that refluxing a DCE solution of benzyl
amine (1a), dimethyl acetylenedicarboxylate (DMAD, 2a),
and ethyl 2-bromo-2-methylpropanoate (3a) under a N2
atmosphere at 100 °C for 24 h in the presence of Cu(OTf)2
(10 mol %), 2,2′-bipyridine (bpy, 10 mol %), and K3PO4 (1
equiv) results in the formation of the desired product (4a) in
10% yield (Table 1, entry 1). Different solvents were screened,
contrast, alkyl halides, including tertiary alkyl halides, are less
successful in the field of M−H reaction, because of the sluggish
oxidative addition of low-valent metal catalysts to C(sp3)−X
bonds, especially tertiary C(sp3)−X bonds, and the facile β-
hydride elimination of alkyl metal species.3 To address this
long-standing challenge, a radical Heck-type coupling was
assumed to be a promising choice for the alkylation of alkenes.
Alkyl radical could be generated from alkyl halides in the
Received: September 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03189
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Alkylamines, α-Bromocarbonyls, and
Acetylenedicarboxylates
a
b
entry
catalyst
solvent
base
ligand
yield (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
CuBr
DCE
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
KOAc
KOtBu
KOH
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
−
10
28
20
32
15
5
20
15
50
57
trace
0
toluene
MeCN
MTBE
THF
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
CuI
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
11
12
13
14
15
16
17
−
0
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
56
45
43
0
67
69
72
c
18
19
20
L1
L1
L1
cd
,
cde
, ,
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), 3a (0.2 mmol),
solvent (1 mL), base (1 equiv), Cu salt (10 mol %), and ligand (10
b
mol %) under a nitrogen atmosphere at 100 °C for 24 h. The yields
1
were determined by H NMR analysis of the crude products using
c
d
CH2Br2 as the internal standard. MTBE (0.5 mL). KOAc (2 equiv).
e
At 120 °C. DCE = 1,2-dichloroethane. MTBE = Methyl tertiary
butyl ether.
including toluene, MeCN, MTBE, and THF; MTBE provided
the highest yield (Table 1, entries 2−5). The three-component
annulation proved most effective with Cu(OTf)2 as the
optimal catalyst, while alternative copper catalysts used in
this annulation were ineffective (Table 1, entries 6−8). A
subsequent investigation of bases showed that a weak base
(KOAc) was slightly more suitable for this transformation
(Table 1, entry 10),12i and no desired product was formed in
the presence of strong bases or without a base (Table 1, entries
11−13). Further optimization revealed that ligands were
crucial to the reactivity. All substituted 2,2′-bipyridine ligands
could deliver (4a) in moderate yields, and the reaction was
shut down in the absence of a ligand (see Table 1, entries 14−
17). Delightfully, a 67% yield was obtained when 0.5 mL of
MTBE was used (Table 1, entry 18). A slight higher yield
could be achieved by evaluation of the loading of base and
reaction temperature (Table 1, entry 20).
Under the optimized reaction conditions, we next
investigated the substrate scope of this three-component
reaction (see Scheme 2). Benzylamines with both electron-
donating and electron-withdrawing groups were all suitable
substrates in this cascade reaction, giving the corresponding
1,3-dihydro-2H-pyrrol-2-ones (4a−4p) in moderate to good
yields. Various functional groups, such as Me, OMe, F, Cl, and
a
Reaction conditions: 1 (0.1 mmol), 2 (1 equiv), 3 (2 equiv), MTBE
(0.5 mL), KOAc (2 equiv), Cu(OTf)2 (10 mol %), and bpy (10
mol %) under nitrogen atmosphere at 120 °C for 24 h. Reaction
performed with 1 mmol scale of 1q or 1y.
b
Br on the phenyl rings of benzylamines were all tolerated.
Furan-2-ylmethanamine and thiophen-2-ylmethanamine were
found to be capable substrates under the optimized conditions,
providing the corresponding products (4q and 4r) in 43% and
94% yields, respectively. It was noted that 2,2,2-trifluoroethan-
1-amine was also tolerable and afforded (4s) in 50% yield. This
protocol was not sensitive to the steric hindrance. Cyclohexyl-
amine, cyclopropylamine, and tert-butylamine all could deliver
the 1,3-dihydro-2H-pyrrol-2-ones (4v−4x) in good yields.
Significantly, ammonium acetate underwent this annulation
successfully, providing (4y) in reasonable yield. Other
functionalized alkyl bromides were also competent coupling
partners for this transformation (4aa−4ac). Not surprisingly,
4ad could be isolated in 66% yield when diethyl
acetylenedicarboxylate was subjected to the reaction con-
ditions.
B
DOI: 10.1021/acs.orglett.9b03189
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We then explored the scope of arylamines of this
transformation (see Scheme 3). Utilizing the same conditions,
several functionalized bromides can be used in addition to 3a,
providing moderate yields of the products (6r−6t).
To further display the synthetic utility of this protocol, the
gram scale experiment was conducted, delivering (4a) in 64%
yield (eq 1). N-cyclohexyl enaminoester (5u) was also
Scheme 3. Scope of N-aryl Enaminoesters and α-
a
Bromocarbonyls
synthesized and resubmitted to the reaction conditions, the
desired product (4v) was isolated in 82% yield (eq 2). In the
context of our mechanistic hypothesis, a radical pathway may
be involved, which was consistent with the fact that the
reaction was inhibited completely by adding 1 equiv of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) (eq 3). When 1 equiv
of radical scavenger 1,1-diphenylethylene (DPE) was added to
the reaction system, trisubstituted alkene (7) was obtained in
80% yield, along with (4a) in 10% yield (eq 4).
We propose a mechanism of this reaction, as shown in
Scheme 4.7d,e After the generation of tertiary alkyl radical
Scheme 4. Proposed Reaction Pathway
a
Reaction conditions: 5 (0.1 mmol), 3 (2 equiv), MTBE (0.5 mL),
KOAc (2 equiv), Cu(OTf)2 (10 mol %), and bpy (10 mol %) under a
b
nitrogen atmosphere at 120 °C for 24 h. Anilines (0.1 mol), 2a (1
equiv), 3 (2 equiv), MTBE (0.5 mL), KOAc (2 equiv), Cu(OTf)2 (10
mol %), and bpy (10 mol %) under a nitrogen atmosphere at 120 °C
c
for 24 h. Reaction performed with 1 mmol scale of 5q.
unfortunately, low yields of the desired products (6) were
produced, along with a substantial amount of DMAD and
anilines. As this transformation was proposed to involve
Michael addition of DMAD and amines, the lower
nucleophilicity of arylamines may retard the productivity. A
range of Michael addition adducts (5a−5q) then were
synthesized.15 The adducts (5a−5q) and α-bromocarbonyls
(3a−3d) were subjected to the standard conditions to give
products (6a−6t) in high yields. Substrates with substituents at
the para- (6b−6e), meta- (6f−6j), or ortho- positon (6k−6n)
on arylamine moieties all reacted to give the corresponding
products in high yields. The compatibility of an iodo- group
provided possibilities for further synthetic manipulations (6i).
Especially noteworthy is that the highly electron-deficient 3,5-
bis(trifluoromethyl) and 2,3,4,5,6-pentafluoro substrates could
also have good reactivity (6o and 6p). We also found that
species (A) from the reaction of α-bromocarbonyls (3) and a
Cu(II) catalyst, the addition of A to Michael addition adducts
(5) occurs, generating the radical intermediates (B).
Subsequently, intermediates B react with the Cu(III) species
to give intermediates C with regeneration of a Cu(II) catalyst.
Then, the base-mediated elimination of intermediates C occurs
to finish the Heck-type intermediates (D), which could
undergo intramolecular annulation to form the final products
4 and 6.
C
DOI: 10.1021/acs.orglett.9b03189
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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pyrrol-2-ones from amines, acetylenedicarboxylates, and α-
bromocarbonyls. The challenging Heck-type coupling of a
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03189.
■
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General experimental procedures, characterization data,
1
and H and 13C NMR spectra of new compounds
(PDF)
Accession Codes
CCDC 1907553 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: glcheng@hqu.edu.cn.
ORCID
Guolin Cheng: 0000-0003-1013-2456
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSF of China (No.
21672075) and the Instrumental Analysis Center of Huaqiao
University.
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DOI: 10.1021/acs.orglett.9b03189
Org. Lett. XXXX, XXX, XXX−XXX