Palladium-Catalyzed Carbonylative Synthesis of 1,5-Dihydro-2H-pyrrol-2-ones from Propargyl Amines and Benzyl Chlorides

Article abstract of DOI:10.1002/adsc.202100001

A palladium-catalyzed double carbonylation of propargyl amines and benzyl chlorides employing benzene-1,3,5-triyl triformate (TFBen) as the CO source has been developed. By using this protocol, various 1,5-dihydro-2H-pyrrol-2-ones were produced in good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202100001

COMMUNICATIONS
DOI: 10.1002/adsc.202100001
Palladium-Catalyzed Carbonylative Synthesis of 1,5-Dihydro-2H-
pyrrol-2-ones from Propargyl Amines and Benzyl Chlorides
Zhengjie Le,+a Yiwen Zhu,+a Zhi-Peng Bao,a Jun Ying,a,* and Xiao-Feng Wub,*
a
Department of Chemistry,
Key Laboratory of Surface & Interface Science of Polymer Materials of Zhejiang Province,
Zhejiang Sci-Tech University, Hangzhou 310018,
E-mail: yingjun@zstu.edu.cn
Dalian National Laboratory for Clean Energy,
b
Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, 116023, Dalian, Liaoning, People’s Republic of China;
and
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straβe 29a, 18059 Rostock, Germany,
E-mail: xiao-feng.wu@catalysis.de
+
These authors contribute equally to this work.
Manuscript received: January 1, 2021; Revised manuscript received: January 28, 2021;
Version of record online: Februar 9, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100001
ylation of propargyl amines for the synthesis of 2,4- or
Abstract: A palladium-catalyzed double carbonyla-
tion of propargyl amines and benzyl chlorides
2,3-dienamides in the presence of Pd2(dba)3·CHCl3 and
DPPP under 40.8 atm CO pressure.[8] Ma’s group
employing benzene-1,3,5-triyl triformate (TFBen)
reported a facile and efficient method for the synthesis
as the CO source has been developed. By using this
of (E)-α-chloroalkylidene-β-lactams via a palladium-
protocol, various 1,5-dihydro-2H-pyrrol-2-ones
catalyzed cyclocarbonylation of propargyl amines with
were produced in good yields.
CuCl2 and benzoquinone under 20.4 atm of CO.[9]
Notably, the transformation features the trans-chlor-
ometalation of the triple bond of propargyl amines.
Keywords: double carbonylation; 1,5-dihydro-2H-
Recently, our group realized a palladium-catalyzed
pyrrol-2-ones; palladium catalysis; propargyl amines;
cyclocarbonylation of propargyl amines with TFBen
benzyl chlorides
(benzene-1,3,5-triyl triformate) to access 2-oxo-2,5-
dihydropyrroles.[10] In this reaction, TFBen[11] was
employed as the CO source and the key promoter as
1,5-Dihydro-2H-pyrrol-2-ones are recognized as a well. Herein, we now disclose a palladium-catalyzed
class of important moieties frequently found in double carbonylative cyclization of propargyl amines,
numerous natural products and pharmaceuticals with benzyl chlorides, and TFBen for the expedite con-
biological activities such as anti-diabetic (Ypaoamide struction of 1,5-dihydro-2H-pyrrol-2-one scaffolds.
B[1] and Glimepirid[2]), anti-tumor (Isomalyngamide
At the outset, the propargyl amine 1a was reacted
A[3]), anti-biotic (Althiomycin[4a]), and immunosuppres- with benzyl chloride 2a and TFBen in the presence of
sive property (Microcolin A[4b]). In order to establish Pd(OAc)2 as the catalyst and phosphine ligand at
°
these useful skeletons, many synthetic methods have 110 C in MeCN for 24 h (Table 1, entries 1–5).
been realized.[5] However, alternative procedures are Gratifyingly, the reaction with DPPF gave the highest
continuing under demand.
yield (82%) of the desired product 3aa (Table 1,
In the construction of carbonyl-containing scaffolds entry 4), while other phosphine ligands gave much
in organic synthesis, transition-metal-catalyzed carbon- inferior results. Then, a few palladium catalysts were
ylative reactions have become one of the most efficient examined and lower yields of 3aa were obtained
and straightforward approaches.[6,7] However, only a (Table 1, entries 6–8). Moreover, employing other
few studies have been reported on the carbonylation of solvents such as DMSO, DMF, toluene, and DCM
propargyl amines to access amides or lactams. In 1996, gave reduced yields (Table 1, entries 9–12). It was
Alper and coworkers developed a selective carbon- shown that the reaction yield was decreased to 76%
Adv. Synth. Catal. 2021, 363, 1878–1881
1878
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
Table 1. Optimization of Reaction Conditions.[a]
Entry
Catalyst
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(acac)2
Pd(TFA)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PCy3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
toluene
DCM
MeCN
MeCN
MeCN
MeCN
10
12
20
82
0
70
67
0
28
27
74
0
76
43
64
38
DPPP
DPPF
Xantphos
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
9
10
11
12
13[b]
14[c]
15[d]
16[e]
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.2 equiv.), TFBen
(3.0 equiv.), catalyst (10 mol%), ligand (20 mol%), Et3N
°
(2.0 equiv.), solvent (2.0 mL), 110 C, 24 h, isolated yield.
[b] Catalyst (5 mol%), ligand (10 mol%).
[c] TFBen (2.0 equiv.).
[d]
°
120 C.
[e]
°
100 C. DPPP: 1,3-bis(diphenylphosphino)propane. DPPF:
1,1’-bis(diphenylphosphino)ferrocene. Xantphos: 4,5-bis(di-
phenylphosphino)-9,9-dimethylxanthene.
when the catalyst loading was reduced (Table 1,
entry 13). The reaction efficiency dropped as well
when the loading of phosphine ligand was decreased.
Additionally, when the amount of TFBen was de-
creased, only 43% yield of 3aa was achieved (Table 1,
entry 14). Finally, raising or reducing the temperature
hampered the reaction (Table 1, entries 15–16). In the
Scheme 1. Scope of propargyl amines. Reaction conditions: 1
(0.5 mmol), 2a (1.2 equiv.), TFBen (3.0 equiv.), Pd(OAc)2
(10 mol%), DPPF (20 mol%), Et3N (2.0 equiv.), MeCN
°
(2.0 mL), 110 C, 24 h, isolated yield.
case of shorten the reaction time to 18 hours, large was noteworthy that the propargyl amine 1o with a
amount of non-cyclized intermediate could be detected thiophene ring was smoothly converted to the target
and lead to the decreased yield of the final product.
product 3oa in 78% yield. Unfortunately, alkyl-
Then, the scope of propargyl amines 1 was substituted compounds failed to give the desired
investigated under the optimal reaction conditions products 3pa-qa. It is also important to mention that
(Scheme 1). For compounds bearing electron-donating no reaction occurred when mono-substituted (1r) and
or withdrawing groups, the reaction afforded the non-substituted propargyl amine (1s) were tested.
corresponding products 3ba–la in good to excellent These results suggest that the need of R2 and R3 is
yields (72–92%). It was found that substrates with an mainly due to steric effect to promote the cyclization
o-Me or m-Me group gave lower yields than one with step. The need of aromatic group for R1 is to maintain
a p-Me group, which could be due to the steric the activity of the triple bond and ready for the
hindrance in the cyclocarbonylation step. Furthermore, following addition reaction. A substrate with R2 and R3
compounds containing biphenyl and naphthyl units as ethyl group was tested, but very low yield (<5%) of
were successfully transformed to the expected products the corresponding product was obtained.
3ma and 3na in 82% and 74% yield, respectively. It
Adv. Synth. Catal. 2021, 363, 1878–1881
1879
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
Next, a variety of benzyl chlorides 2 were studied the corresponding products 3ab–aj in good yields (70–
in the reaction with the propargyl amine 1a as shown 87%). It was shown that compounds with an o-Me or
in Scheme 2. The reaction of compounds with elec- m-Me substituent gave lower yields than one with a p-
tron-donating or withdrawing substituents furnished Me substituent, suggesting that the steric hindrance
might have an effect on the first carbonylation step.
Moreover, 1-(chloromethyl)-4-vinylbenzene 2k and 1-
(chloromethyl)naphthalene 2l worked well to give the
desired products 3ak and 3al in high yields. Notably,
72% yield of the product 3am was obtained when 3-
(chloromethyl)thiophene 2m was subjected to the
reaction system.
In order to better understanding of the reaction
pathway, a set of control experiments were conducted
(Scheme 3). When TEMPO (2.0 equiv.) was added to
the reaction system under standard conditions, the
target product 3aa was achieved in 80% yield,
indicating that a radical process could be ruled out
here (Scheme 3, eq 1). Reducing the reaction temper-
°
ature to 90 C led to 15% of the final product 3aa and
70% of the mono-carbonylated product 4 (Scheme 3,
eq 2). Subsequently, 4 could be converted to the
desired product 3aa in 98% yield under standard
conditions (Scheme 3, eq 3). These findings suggested
that the mono-carbonylated product 4 was a key
intermediate in the double carbonylation of propargyl
amines and benzyl chlorides. Notably, under our
standard conditions, when TFBen was replaced with
Mo(CO)6 (3 equiv.) or acetic formic anhydride
(3 equiv.), only non-cyclized intermediate 4 could be
detected.
On the basis of previous reports[10–12] and above
control experiments, a plausible mechanism for the
palladium-catalyzed double carbonylation of propargyl
(1.2 equiv.), TFBen (3.0 equiv.), Pd(OAc)2 amines and benzyl chlorides has been proposed
Scheme 2. Scope of benzyl chlorides. Reaction conditions: 1a
(0.5 mmol),
(10 mol%), DPPF (20 mol%), Et3N (2.0 equiv.), MeCN
2
(Scheme 4). Initially, the active Pd(0) catalyst, formed
from Pd(II) and DPPF, can react with benzyl chloride
2a to give the Pd(II) intermediate A via oxidative
addition. Subsequently, CO is released from TFBen
and is inserted to A, providing the acyl Pd(II) complex
°
(2.0 mL), 110 C, 24 h, isolated yield.
Scheme 3. Control experiments.
Scheme 4. Plausible mechanism.
Adv. Synth. Catal. 2021, 363, 1878–1881
1880
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
A. Yamano, K. Ozaki, S. Sumimoto, A. Iwasaki, K.
B. The nucleophilic addition of the propargyl amine
1a to B leads to the Pd(II) species C, which can
undergo reductive elimination to form the mono-
carbonylated product 4. Then, the reaction of 4 and
Pd(0) generates the Pd(II) complex D. In this step, a
PdIIH complex should be generated in advance and
then followed by insertion into the triple bond to give
complex D. The key Pd(II) intermediate E can be
formed via the second CO insertion of D. Finally,
reductive elimination of E affords the target product
3aa and regenerates the active Pd(0) catalyst for the
next catalytic cycle.
In conclusion, we have developed a new approach
to access 1,5-dihydro-2H-pyrrol-2-one skeletons via a
palladium-catalyzed double carbonylation of propargyl
amines and benzyl chlorides. Using TFBen as the CO
source, the reaction affords various 1,5-dihydro-2H-
pyrrol-2-ones in good yields.
Suenaga, T. Teruya, J. Nat. Prod. 2018, 81, 1103–1107.
[2] M. K. Gurjar, R. A. Joshi, S. R. Chaudhuri, S. V. Joshi,
A. R. Barde, L. K. Gediya, P. V. Ranade, S. M. Kadam,
S. J. Naik, Tetrahedron Lett. 2003, 44, 4853–4855.
[3] Y. Kan, B. Sakamoto, T. Fujita, H. Nagai, J. Nat. Prod.
2000, 63, 1599–1602.
[4] a) H. Nakamura, Y. Iitaka, H. Sakakibara, H. Umezawa,
J. Antibiot. 1974, 27, 894–896; b) F. E. Koehn, R. E.
Longley, J. K. Reed, J. Nat. Prod. 1992, 55, 613–619.
[5] a) Y. Gao, M. Shirai, F. Sato, Tetrahedron Lett. 1997, 39,
6849–6852; b) E. T. Pelkey, S. J. Pelkey, J. G. Greger,
Adv. Heterocycl. Chem. 2015, 115, 151–285.
[6] a) S. Sumino, A. Fusano, T. Fukuyama, I. Ryu, Acc.
Chem. Res. 2014, 47, 1563–1574; b) A. Brennführer, H.
Neumann, M. Beller, Angew. Chem. Int. Ed. 2009, 48,
4114–4133; Angew. Chem. 2009, 121, 4176–4196; c) Q.
Liu, H. Zhang, A. Lei, Angew. Chem. Int. Ed. 2011, 50,
10788–10799; Angew. Chem. 2011, 123, 10978–10989;
d) S. Zhao, N. P. Mankad, Catal. Sci. Technol. 2019, 9,
3603–3613.
Experimental Section
[7] a) P. Gautam, B. M. Bhanage, Catal. Sci. Technol. 2015,
5, 4663–4702; b) S. D. Friis, A. T. Lindhardt, T.
Skrydstrup, Acc. Chem. Res. 2016, 49, 594–605; c) L. R.
Odell, F. Russo, M. Larhed, Synlett, 2012, 23, 685–698;
d) H. Konishi, K. Manabe, Synlett, 2014, 25, 1971–1986;
e) T. Morimoto, K. Kakiuchi, Angew. Chem. Int. Ed.
2004, 43, 5580–5588; Angew. Chem. 2004, 116, 5698–
5706.
General Procedure
Propargyl amines 1 ( 0.5 mmol, 1.0 equiv.), Pd(OAc)2 (11.2 mg,
10 mol%), DPPF (55.4 mg, 20 mol%), and a 2.5 mL vial
containing TFBen (315 mg, 1.5 mmol, 3.0 equiv.) were added
to an oven-dried In-Ex tube[13] (15 mL) which was then placed
under vacuum and refilled with nitrogen three times. Et3N
(140 μL, 1.0 mmol, 2.0 equiv.), benzyl chlorides 2 (0.6 mmol,
1.2 equiv.) and MeCN (2.0 mL) were added into the tube via
[8] Y. Imada, H. Alper, J. Org. Chem. 1996, 61, 6766–6767.
[9] S. Ma, B. Wu, X. Jiang, J. Org. Chem. 2005, 70, 2588–
2593.
°
syringe. The tube was sealed and stirred at 110 C for 24 h.
Upon the reaction was completed, the resulting mixture was
filtered through a pad of tripolite and washed with EtOAc. The
filtrate was concentrated under vacuum and purified by silica
gel column using chromatography (PE/EA) to obtain the
corresponding products 3.
[10] J. Ying, Z. Le, X.-F. Wu, Org. Lett. 2020, 22, 194–198.
[11] a) Z. Le, J. Ying, X.-F. Wu, Org. Chem. Front. 2019, 6,
3158–3161; b) J. Ying, L.-Y. Fu, G. Zhong, X.-F. Wu,
Org. Lett. 2019, 21, 5694–5698; c) L.-Y. Fu, J. Ying, X.-
F. Wu, J. Org. Chem. 2019, 84, 12648–12655; d) J. Ying,
Q. Gao, X.-F. Wu, J. Org. Chem. 2019, 84, 14297–
14305; e) L.-Y. Fu, J. Ying, X. Qi, J.-B. Peng, X.-F. Wu,
J. Org. Chem. 2019, 84, 1421–1429.
[12] a) X.-F. Wu, J. Schranck, H. Neumann, M. Beller,
ChemCatChem 2012, 4, 69–71; b) L. Troisi, C. Granito,
F. Rosato, V. Videtta, Tetrahedron 2010, 51, 371–373.
[13] Z. Yin, X. F. Wu, Org. Process Res. Dev. 2017, 21,
1869–1871.
Acknowledgements
We acknowledge financial supports from the Joint Funds of
Zhejiang Natural Science Foundation and Taizhou
(LTY21B020001).
References
[1] a) D. G. Nagle, V. J. Paul, M. A. Roberts, Tetrahedron
Lett. 1996, 37, 6263–6266; b) K. Sueyoshi, M. Yamada,
Adv. Synth. Catal. 2021, 363, 1878–1881
1881
© 2021 Wiley-VCH GmbH