Benzene-1,3,5-triyl Triformate (TFBen)-Promoted Palladium-Catalyzed Carbonylative Synthesis of 2-Oxo-2,5-dihydropyrroles from Propargyl Amines

Article abstract of DOI:10.1021/acs.orglett.9b04147

In this letter, we developed a palladium-catalyzed procedure for the cyclocarbonylation of propargyl amines. Benzene-1,3,5-triyl triformate (TFBen) has been explored as the CO source and also as the key promotor. Various substituted 2-oxo-dihydropyrroles were produced in a facile manner in good yields (up to 90%).

Full text of DOI:10.1021/acs.orglett.9b04147

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Benzene-1,3,5-triyl Triformate (TFBen)-Promoted Palladium-
Catalyzed Carbonylative Synthesis of 2‑Oxo-2,5-dihydropyrroles
from Propargyl Amines
Jun Ying,†,§ Zhengjie Le,† and Xiao-Feng Wu*,†,‡
†Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
‡Leibniz-Institut fu
̈
r Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Straβe 29a, 18059 Rostock, Germany
̈
§Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and
Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, China, 200062
S
* Supporting Information
ABSTRACT: In this letter, we developed a palladium-
catalyzed procedure for the cyclocarbonylation of propargyl
amines. Benzene-1,3,5-triyl triformate (TFBen) has been
explored as the CO source and also as the key promotor.
Various substituted 2-oxo-dihydropyrroles were produced in a
facile manner in good yields (up to 90%).
2-Oxo-dihydropyrroles are frequently present as a momentous
scaffold in various natural products and also biologically active
compounds.1−4 For instance, ypaoamide B has been
considered as a candidate for the treatment of Type 2 diabetes
mellitus (T2DM).1 This antidiabetic molecular was isolated
from an Okeania sp. marine cyanobacterium. Althiomycin is a
sulfur-containing antibiotic isolated from Streptomyces althioti-
cus.2 Furthermore, Microcolin A is a new lipopeptide showing
potent immunosuppressive activity and was originally isolated
from Lyngbya majuscula (Scheme 1).3 Due to their recognized
potent applications, as we expected, many synthetic procedures
toward this scaffold have been developed.5
Alper’s research group reported a palladium-catalyzed selective
carbonylation of propargyl amines for the production of 2,4- or
2,3-dienamides under 41.4 bar pressure of CO (Scheme 2, eq
a).8 In 2005, Ma’s group realized a palladium-catalyzed
carbonylation of propargyl amines to produce (E)-α-
chloroalkylidene-β-lactams (Scheme 2, eq b).9 The reaction
was performed under 20.7 bar of CO with benzoquinone and
Scheme 2. Carbonylation of Propargyl Amines
On the other hand, transition-metal-catalyzed carbonylation
reactions have already been accepted as a straightforward tool
for the production of carbonyl-containing chemicals and can
prolong the carbon chain meanwhile.6,7 However, for the
carbonylation of propargyl amines to access amides or imides,
significantly less studies were reported.8−13 For example,
Scheme 1. Selected Natural Products Containing 2-Oxo-
dihydropyrrole
Received: November 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04147
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Organic Letters
Letter
CuCl2 as the reagents and oxidants. A rhodium-catalyzed
carbonylation of propargyl amines to give α-silylmethylene-β-
lactams was established by Matsuda, Nagashima and their co-
workers in 1991.10 Chiusoli’s research group discovered a
palladium-catalyzed carbonylation protocol for the synthesis of
α-[(alkoxycarbonyl)-methylene] β-lactams under oxidative
conditions as well.11 Herein, we developed a palladium-
catalyzed cyclocarbonylation of propargyl amines, producing a
series of 2-oxo-dihydropyrroles (Scheme 2, eq c). Remarkably,
TFBen, developed by our group,14 has been applied as a solid,
safe, and convenient CO source. Pholoroglucinol, as a product
from TFBen decomposition, can facilitate the cyclocarbonyla-
tion step.
Scheme 3. Scope of Dimethyl-Substituted Propargyl
Amines
a
At the beginning, propargyl amine 1a was chosen as the
model substrate for the cyclocarbonylation (Table 1). The
a
Table 1. Screening of the Reaction Conditions with 1a
entry
[Pd]
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
DMF
DMF
DMF
DMF
25
20
34
40
48
37
50
43
40
85
70
62
85
85
70
XPhos
DPPP
DPPB
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DMF
CH3CN
DMSO
THF
toluene
DCM
DCM
DCM
DCM
DCM
DCM
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (5 mol %), DPPF (10
mol %), TFBen (3.0 equiv), DCM (2.0 mL), 90 °C, 24 h, isolated
yield.
9
10
11
12
13
14
15
bearing an o-Me or a m-Me group on the benzene ring might
be due to the steric hindrance effect. Additionally, substrates
containing electron-withdrawing groups can be transformed
into the corresponding products 2h−l in high yields as well.
Furthermore, biphenyl and naphthyl substituted propargyl
amines can also be converted into the target products 2m and
2n in 83% and 88% yield, respectively. Notably, a 72% yield of
product 2o was obtained when the propargyl amine with a
thiophene ring was tested.
Then, various types of propargyl amines were synthesized
and tested under our optimal reaction conditions (Table 1,
entry 13) as shown in Scheme 4. The reaction with propargyl
amines with no substituents at the α-position (R2, R3 = H)
could also give the desired products 2aa−ae in 52−65% yields.
Furthermore, products 2af−ah were obtained in high yields
from the corresponding substrates with mono substituents (R2
= alkyl, R3 = H). It was noted that an 86% yield of product 2ai
was achieved when the disubstituted propargyl amine (R2, R3 =
alkyl) was examined. Additionally, the reaction with the alkyl-
substituted compound gave trace product 2aj. Finally, the
desired cyclocarbonylated products 2ak−as can still be
produced from compounds bearing the N-substituents (R4 ≠
H), albeit in moderate yields. However, no reaction occurred
when the nitrogen substituted with an isopropyl or amide
group (2an, 2at, 2au).
b
b c
,
b d
,
a
Reaction condition: 1a (0.5 mmol), Pd catalyst (5 mol %), ligand
(10 mol %), TFBen (3.0 equiv), Et3N (1.0 equiv), solvent (2.0 mL),
b
c
90 °C, 24 h, isolated yield. Without Et3N. DPPF (20 mol %).
d
DPPF (5 mol %).
reaction of 1a with TFBen (3.0 equiv) catalyzed by Pd(OAc)2
(5 mol %) and PPh3 (10 mol %) under the assistance of Et3N
(1.0 equiv) at 90 °C for 24 h afforded the target product 2a in
25% isolated yield (Table 1, entry 1). Then, a couple of
phosphine ligands such as XPhos, DPPP, DPPB, and DPPF
were tested (Table 1, entries 2−5). It was shown that DPPF
gave the highest yield of 48% (Table 1, entry 5). In addition,
various solvents were examined (Table 1, entries 6−10).
Fortunately, the reaction with DCM improved the yield of 2a
to 85% (Table 1, entry 10). Moreover, lower yields were
obtained when other Pd catalysts were employed (Table 1,
entries 11−12). Remarkably, we found the yield of product 2a
maintained even in the absence of Et3N (Table 1, entry 13).
Finally, increasing or decreasing the amount of ligand did not
promote this transformation (Table 1, entries 14−15).
Subsequently, under our optimal reaction conditions (Table
1, entry 13), a series of dimethyl-substituted propargyl amines
1 were tested (Scheme 3). The reaction with electron-donating
substituents afforded the expected products 2a−g in good to
excellent yields. The difference in yields between substrates
Control experiments were performed as well to gain some
insights into the reaction mechanism (Scheme 5). First, the
reaction with the propargyl amine 1aa gave the desired product
2aa in 58% yield under the standard conditions (Scheme 5, eq
B
DOI: 10.1021/acs.orglett.9b04147
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Letter
a
Scheme 4. Scope of Various Types of Propargyl Amines
Scheme 5. Control Experiments
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (5 mol %), DPPF (10
mol %), TFBen (3.0 equiv), DCM (2.0 mL), 90 °C, 24 h, isolated
yield.
1). Surprisingly, no product 2aa could be observed if we
perform the reaction under a CO gas atmosphere (2 bar)
(Scheme 5, eq 2). Then, the formamide 3 was prepared and
subjected to the standard conditions. It was shown that 80% of
2aa was obtained, which indicated 3 might be a possible
intermediate in this reaction (Scheme 5, eq 3). Second, no
reaction occurred in the absence of Pd(OAc)2 suggested that
the palladium catalyst was crucial for this carbonylative
transformation (Scheme 5, eq 4). Subsequently, a trace
amount of the key intermediate 4 was observed if we perform
the reaction of 3 under a CO gas atmosphere (2 bar) (Scheme
5, eq 5). It was noteworthy that when phloroglucinol was
added to the reaction of 3 under 2 bar CO atmosphere, a 35%
yield of the amide 4 was achieved and a 20% yield of 3 was
recovered (Scheme 5, eq 6). These results imply that
phloroglucinol might facilitate the cyclocarbonylation step to
produce the amide 4. Additionally, treatment of the amide 4
under the standard conditions produced the product 2aa in
92% yield (Scheme 5, eq 7). Noteworthy, no reaction occurred
under our standard conditions when N-methyl-N-(3-phenyl-
prop-2-yn-1-yl)formamide was applied (Scheme 5, eq 8).
Finally, no reaction occurred when other formates were
applied as the CO source, which supports TFBen playing
multiple important roles in this reaction for the synthesis of 2-
oxo-dihydropyrroles (Scheme 5, eq 9). As N-formyl saccharin
has been proven as a promising CO surrogate,14 it is been
tested in the current system as well (Scheme 5, eq 10).
However, no target product could be detected in the presence
of N-formyl saccharin (3 equiv) with or without phloroglucinol
C
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Letter
(3 equiv). This might be due to the release of CO from N-
formyl saccharin needing the assistance of base which is not
present in the current reaction system.
chromatography on silica gel to afford the corresponding
products. (PDF)
On the basis of our previous experiences15 and control
experiments, a plausible mechanism for the cyclocarbonylation
of propargyl amines is proposed and shown in Scheme 6. First,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiao-feng.wu@catalysis.de.
ORCID
Scheme 6. Plausible Mechanism
Xiao-Feng Wu: 0000-0001-6622-3328
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial supports National Natural Science
Foundation of China (21772177).
REFERENCES
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DPPF, which will give Pd−H species after reaction with
TFBen. The formamide 3 is formed via the reaction of the
propargyl amine 1aa with TFBen. Subsequently, addition of
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catalyst. Finally, the expected 2-oxo-dihydropyrroles 2aa can
be achieved through the reaction of 4 with TFBen.
In conclusion, a facile and straightforward procedure for the
synthesis of 2-oxo-dihydropyrroles via palladium-catalyzed
cyclocarbonylation of propargyl amines has been developed.
In this reaction, TFBen plays multiple important roles: (1) CO
source; (2) phloroglucinol source which promotes the
cyclocarbonylation step.
ASSOCIATED CONTENT
* Supporting Information
■
S
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04147.
General comments, procedure for substrates prepara-
tion, general reaction procedures, analytic data for
substrates and products, NMR spectra for substrates
and products. To a solution of a propargyl amine 1 (0.5
mmol, 1.0 equiv) in DCM (2.0 mL) were added
Pd(OAc)2 (5.6 mg, 5 mol %), DPPF (27.7 mg, 10 mol
%), and TFBen (315 mg, 1.5 mmol, 3.0 equiv) in a 15
mL tube which was filled with nitrogen. Then, the vial
was sealed and placed in an oil bath that was preheated
to 90 °C. After a time period of 24 h, the reaction vial
was allowed cooled to rt. The reaction mixture was
filtered and washed with EtOAc and then concentrated
in vacuo. The crude mixture was purified by column
D
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E
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