Pd(II)-Catalyzed Arylation and Intramolecular Amidation of γ-C(sp3)-H Bonds: En Route to Arylheteroarylmethane and Pyrrolidone Ring Annulated Furan/Thiophene Scaffolds

Article abstract of DOI:10.1021/acs.joc.7b00582

We report the Pd(II)-catalyzed, bidentate directing group (BDG)-assisted arylation and successive arylation/intramolecular amidation of γ-C(sp³)-H bonds. The Pd(II)-catalyzed BDG-assisted C-H activation and functionalization of the β-C(sp³)-H bonds of carboxylic acids are well documented, but only a few reports are available that deal with the BDG-directed functionalization of the γ-C(sp³)-H bonds. Various 3-methylthiophene/furan-2-carboxamides (1a-e) were derived from their corresponding carboxylic acids and bidentate directing groups. These compounds were then used as substrates to investigate the arylation and successive arylation/intramolecular amidation of the γ-C(sp³)-H bonds. The γ-C(sp³)-H arylation arose from the Pd(II)-catalyzed reactions of these compounds with aryl iodides with reaction periods of 4-24 h (except a few reactions which required 36 or 48 h). Notably, these reactions led to the construction of various unsymmetrical diarylmethane scaffolds, such as thiophene/furan-based arylheteroarylmethanes (3-6). Prolonging the reaction period to 48-70 h led to successive γ-C(sp³)-H arylation/intramolecular amidation and the construction of both C-C and C-N bonds. Accordingly, these reactions led to the construction of new classes of pyrrolidone-ring annulated thiophene/furan-based heterocyclic scaffolds (e.g., 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones (8), 4,5-dihydro-6H-furo[2,3-c]pyrrol-6-ones (10), and 1-phenyl-1,2-dihydro-3H-benzo[4,5]thieno[2,3-c]pyrrol-3-ones (12)), and notably, compounds 8, 10, and 12 resemble the skeletons of 3-phenylisoindolin-1-ones.

Full text of DOI:10.1021/acs.joc.7b00582

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Article
Pd(II)-Catalyzed Arylation and Intramolecular Amidation of #-
C(sp3)-H Bonds: En Route To Arylheteroarylmethane and
Pyrrolidone-Ring Annulated Furan/Thiophene Scaffolds
Ramarao Parella, and Srinivasarao Arulananda Babu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jun 2017
Downloaded from http://pubs.acs.org on June 8, 2017
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Pd(II)-Catalyzed Arylation and Intramolecular Amidation of γ-C(sp )-H Bonds: En Route
To Arylheteroarylmethane and Pyrrolidone-Ring Annulated Furan/Thiophene Scaffolds
Ramarao Parella and Srinivasarao Arulananda Babu*
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Department Chemical Sciences, Indian Institute of Science Education and Research (IISER)
Mohali, Knowledge City, Sector 81, SAS Nagar, Mohali, Manauli P.O., Punjab, 140306, India.
sababu@iisermohali.ac.in
ABSTRACT
We report the Pd(II)ꢀcatalyzed, bidentate directing group (BDG)ꢀassisted arylation and
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successive arylation/intramolecular amidation of γꢀC(sp )ꢀH bonds. The Pd(II)ꢀcatalyzed BDGꢀ
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assisted CꢀH activation and functionalization of the βꢀC(sp )ꢀH bonds of carboxylic acids are
well documented, but only a few reports are available which are dealing with the BDGꢀdirected
3
functionalization of the γꢀC(sp )ꢀH bonds. Various 3ꢀmethylthiophene/furanꢀ2ꢀcarboxamides
(1a-e) were derived from their corresponding carboxylic acids and bidentate directing groups.
These compounds were then used as substrates to investigate the arylation and successive
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arylation/intramolecular amidation of the γꢀC(sp )ꢀH bonds. The γꢀC(sp )ꢀH arylation arose from
the Pd(II)ꢀcatalyzed reactions of these compounds with aryl iodides with reaction periods of 4ꢀ24
h (except a few reactions which required 36 or 48 h). Notably, these reactions led to the
construction of various unsymmetrical diarylmethane scaffolds, such as thiophene/furanꢀbased
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arylheteroarylmethanes (3-6). Prolonging the reaction period to 48ꢀ70 h led to successive γꢀ
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C(sp )ꢀH arylation/intramolecular amidation and the construction of both CꢀC and CꢀN bonds.
Accordingly, these reactions led to the construction of new classes of pyrrolidoneꢀring annulated
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thiophene/furanꢀbased heterocyclic scaffolds (e.g., 4,5ꢀdihydroꢀ6Hꢀthieno[2,3ꢀc]pyrrolꢀ6ꢀones
(8),
4,5ꢀdihydroꢀ6Hꢀfuro[2,3ꢀc]pyrrolꢀ6ꢀones
(10)
and
1ꢀphenylꢀ1,2ꢀdihydroꢀ3Hꢀ
benzo[4,5]thieno[2,3ꢀc]pyrrolꢀ3ꢀones (12)) and notably, the compounds 8, 10, and 12 resemble
the skeletons of 3ꢀphenylisoindolinꢀ1ꢀones.
INTRODUCTION
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The transition metalꢀcatalyzed sp /sp CꢀH activation/functionalization process is a
powerful synthesis technique for constructing CꢀC and CꢀX bonds (where X can be O, S, N,
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ꢀ5
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etc.). The transition metalꢀcatalyzed functionalization of the sp /sp CꢀH bonds of organic
1ꢀ7
molecules can be performed with or without a directing group. There are numerous reports of
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synthesis methods dealing with the siteꢀselective functionalization of the C(sp )ꢀH bonds of
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a
different classes of arenes and heteroarenes. Since the work by Daugulis et al., special attention
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has been given to the siteꢀselective functionalization of the C(sp )ꢀH bonds of organic molecules,
such as alkyl chains and cyclic compounds. In 2005, Daugulis reported the Pd(II)ꢀcatalyzed
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direct arylation of βꢀC(sp )ꢀH bonds of carboxylic acids with the help a bidentate directing group
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(
BDG), such as 8ꢀaminoquinoline (DG-a) and 2ꢀ(methylthio)aniline) (DG-b). Yu’s group
exploited the monodentate directing group (e.g., 2,3,5,6ꢀtetrafluoroꢀ4ꢀ(trifluoromethyl)aniline,
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(
DG-c)) to accomplish the Pd(II)ꢀcatalyzed functionalization of the βꢀC(sp )ꢀH bonds of
carboxylic acids.
The 8ꢀaminoquinolineꢀtype BDGs (DG-a, DG-b and DG-c, etc., Scheme 1)
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,7,10ꢀ12
have
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been well exploited for the functionalization of the sp /sp CꢀH bonds of carboxylic acids, while
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picolinamide (PA)ꢀtype BDGs (DG-d, Dg-e, and DG-f, etc.) have been used for the
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functionalization of the sp /sp CꢀH bonds of amines. With regard to siteꢀselectivity, there are
numerous reports dealing with the PAꢀtype BDGꢀassisted functionalization of the γꢀCꢀH and
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1ꢀ7,13ꢀ20
remote δꢀ and εꢀCꢀH bonds of amines.
Notably, the 8ꢀaminoquinolineꢀtype BDGs have
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ꢀ7,10ꢀ12
favorably assisted the functionalization of the βꢀCꢀH bonds of carboxylic acids.
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While the functionalization of the remote γꢀ, δꢀ and εꢀC(sp /sp )ꢀH bonds of suitable
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amines has been well advanced using PAꢀtype BDGs,
however, similar work on suitable
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carboxylic acids is currently limited to the functionalization of the remote γꢀC(sp /sp )ꢀH bonds.
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Only a few reports deal with the BDGꢀassisted functionalization of the γꢀC(sp /sp )ꢀH bonds
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,7,23ꢀ27
(Schemes 1 and 2).
We assembled the 3ꢀmethylfuran/thiopheneꢀ2ꢀcarboxamides 1a-e from
their corresponding carboxylic acids and BDGs, such as 8ꢀaminoquinoline and 2ꢀ
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(
methylthio)aniline (Schemes 3ꢀ5). The γꢀC(sp )ꢀH bonds of compounds 1a-e can be subjected to
the Pd(II)ꢀcatalyzed arylation and successive arylation/intramolecular amidation to afford new
classes of furan/thiopheneꢀbased arylheteroarylmethane (unsymmetrical diarylmethane) scaffolds
and pyrrolidoneꢀring annulated furan/thiophene heterocycles (Schemes 3 and 4).
Apart from the CꢀH functionalization reactions comprising the intermolecular arylation,
alkylation, amination/amidation, acetoxylation, the BDGꢀassisted or directing groupꢀfree C–H
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functionalization technique was also well explored for performing the intramolecular sp /sp CꢀH
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ꢀ7,28ꢀ34
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amination/amidation reactions.
Notably, intramolecular sp /sp CꢀH amination/amidation
reactions have led to the assembly of various heterocyclic compounds and biologically active
molecules, including azetidines, pyrrolidines, piperidines, indolines, quinolones, isoindolinꢀ1ꢀ
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ꢀ7,28ꢀ33,35ꢀ39
one cores, and other cyclic amines.
In particular, Scheme 4 representative reports
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dealing with the functionalization/intramolecular amination/amidation of benzylic γꢀC(sp )ꢀH
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bonds of corresponding aromatic compounds affording the isoindolinꢀ1ꢀone cores and examples
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of bioꢀactive isoindolinꢀ1ꢀone cores.
Scheme 1. Bidentate directing group-assisted C-H functionalization.
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Scheme 2. Available examples of bidentate directing group-assisted sp / sp γ-C-H
functionalization.
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Scheme 3. Bio-active arylheteroarylmethanes and benzofurans/benzothiophenes. Synthesis
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of arylheteroarylmethanes via γ-C(sp )-H functionalization.
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Furan/thiopheneꢀbased molecules, arylheteroarylmethane and isoindolinꢀ1ꢀone scaffolds
independently have important roles in organic synthesis and pharmaceuticals. Functionalized
thiophenes/furans and benzothiophenes/benzofurans are important building blocks in organic
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synthesis, materials, and medicinal chemistry research.
Arylheteroarylmethane scaffolds
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5
which are a subclass of diarylmethanes, and isoindolinꢀ1ꢀone scaffolds both independently
have an important place in medicinal chemistry due to their wide range of pharmacological
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activities. Representative examples of bioꢀactive furan/thiopheneꢀbased molecules,
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arylheteroarylmethane (unsymmetrical diarylmethanes), and isoindolinꢀ1ꢀone scaffolds are
illustrated in Schemes 3 and 4.
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Scheme 4. Bio-Active isoindolinone scaffolds. Synthesis of isoindolinone scaffolds via the
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functionalization/intramolecular amidation of benzylic γ-C(sp )-H bonds.
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In continuation of our lab’s research programme on the CꢀH activation reactions, herein
we report our investigations on the Pd(II)ꢀcatalyzed BDGꢀassisted arylation and successive
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arylation/intramolecular amidation of γꢀC(sp )ꢀH bonds of 3ꢀmethylfuran/thiopheneꢀ2ꢀ
carboxamides and 3ꢀmethylbenzofuran/thiopheneꢀ2ꢀcarboxamides (Schemes 3 and 4). This work
reveals the construction of a wide range of new classes of furan/thiopheneꢀbased
arylheteroarylmethanes (3-7) and pyrrolidoneꢀring annulated furan/thiophene heterocyclic
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frameworks (e.g., 4,5ꢀdihydroꢀ6Hꢀthieno[2,3ꢀc]pyrrolꢀ6ꢀones (8), 4,5ꢀdihydroꢀ6Hꢀfuro[2,3ꢀ
c]pyrrolꢀ6ꢀones (10), and 4,5ꢀdihydroꢀ6Hꢀbenzothieno[2,3ꢀc]pyrrolꢀ6ꢀone (12)).
RESULTS AND DISCUSSION
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To begin our investigations, we first assembled various 3ꢀmethylthiophene/furanꢀ2ꢀ
carboxamides for use as starting materials. Accordingly, the substrates 1a-g were assembled
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,8a,b
from their corresponding carboxylic acid chlorides and commonly used BDGs,
such as 8ꢀ
aminoquinoline and 2ꢀ(methylthio)aniline (Scheme 5). To examine the efficiency and role of the
BDGs, the substrates 1h-m were then assembled from their corresponding carboxylic acid
chlorides and amines (Scheme 5). After assembling the required starting materials, we attempted
to construct arylheteroarylmethane scaffold 3a via the Pd(II)ꢀcatalyzed, 8ꢀaminoquinolineꢀ
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assisted arylation of γꢀC(sp )ꢀH bonds of the thiopheneꢀ2ꢀcarboxamide system 1a. Table 1 shows
the optimized reaction conditions with various Pd catalysts, additives, and solvents.
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Scheme 5. Directing groups and substrates used to investigate the γ-C(sp )-H
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arylation/amidation reactions.
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a
Conditions: Substrate (0.125 mmol), 2a or ArI (0.75ꢀ1 mmol), Pd(OAc) (10ꢀ20 mol%),
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AgOAc (0.27 mmol), toluene (3 mL), 24ꢀ48 h, and 110 °C.
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The γꢀC(sp )ꢀH arylated derivative 3a (arylheteroarylmethane) was obtained in 14% yield
from the reaction of a mixture of substrate 1a (1 equiv), aryl iodide 2a (4 equiv), and Pd(OAc)2
o
catalyst without any additive in toluene at 110 C for 24 h (entry 1, Table 1). The reaction of 1a,
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a, and AgOAc additive without Pd(OAc) catalyst did not give any product (entry 2, Table 1).
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The arylation of 1a with 2ꢀ4 equiv of 2a using Pd(OAc) catalyst and AgOAc additive afforded
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the arylheteroarylmethane derivative 3a in low yields (32ꢀ45% yields, entries 3 and 4, Table 1).
Next, we performed the arylation of 1a with 6 equiv of 2a, Pd(OAc) catalyst, and AgOAc
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o
additive in toluene at 110 C for 4 h. This reaction afforded the arylheteroarylmethane derivative
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a with a maximum yield of 72% (entry 5 Table 1).
To improve the yield of 3a, we attempted the arylation of 1a with 2a using various Pd
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catalysts, additives, and solvents. The γꢀC(sp )ꢀH arylation of 1a with other palladium catalysts
such as PdCl , Pd(CH CN) Cl and Pd(TFA) afforded the arylheteroarylmethane derivative 3a
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3
2
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2
in 41ꢀ43% yield (entries 6ꢀ8, Table 1). We also tried the arylation of 1a with 2a with Pd(OAc)2
catalyst and various additives, such as KOAc, K CO , and Cs CO , which afforded 3a in 5ꢀ9%
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3
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yield (entries 9ꢀ11, Table 1). The arylation of 1a with 2a with Pd(OAc) catalyst and Ag CO as
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an additive afforded 3a in 41% yield (entry 12, Table 1). The arylation of 1a with 2a with
Pd(OAc) catalyst and AgOAc additive in solvents such as tBuOH and 1,2ꢀDCE afforded 3a in
2
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ꢀ15% yield (entries 13 and 14, Table 1). The arylation of 1a with 2a with Pd(OAc) catalyst and
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AgOAc additive in 1,4ꢀdioxane and tAmylOH afforded 3a in 45ꢀ49% yield (entries 15 and 16,
Table 1). 3a was not produced when using coupling partners such as aryl bromide 2b or aryl
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chloride 2c instead of aryl iodide 2a for the arylation of 1a with Pd(OAc) catalyst and AgOAc
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additive (entries 17 and 18, Table 1).
Next, to determine the role of the BDG 8ꢀaminoquinoline and to find other working
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directing groups in the arylation of γꢀC(sp )ꢀH bond, we performed the arylation of carboxamides
1g-m using the optimized reaction conditions (entry 5, Table 1). The Pd(II)ꢀcatalyzed arylation
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of the γꢀC(sp )ꢀH bond of the substrates 1g-m failed to afford the corresponding
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arylheteroarylmethane derivatives in characterizable amounts (Scheme 5). These reactions
indicated that the corresponding directing groups/amides did not effectively assist in the
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arylation of the γꢀC(sp )ꢀH bond of these substrates (Scheme 5). Additionally, while the 8ꢀ
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aminoquinolineꢀassisted γꢀC(sp )ꢀarylation of 1a was successful, the Pd(II)ꢀcatalyzed 8ꢀ
3
aminoquinolineꢀassisted γꢀC(sp )ꢀarylation of 1f did not afford the corresponding
arylheteroarylmethane derivative. The exact reaction for the failure of arylation of 1f is not clear
at this stage, but the presence of multiple coordinating N atoms in substrate 1f might have
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8a
hindered the CꢀH activation process, as suggested by Liu et al.
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a
Table 1. Optimization of reaction conditions. γ-C(sp )-H arylation of substrate 1a
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entry PdL (10 mol%) 2a (mmol) additive solvent
T ( C) t (h) 3a: yield (%)
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5
6
7
8
9
1
1
1
Pd(OAc)2
ꢀ
0.5
ꢀ
toluene
110
110
110
110
110
110
110
110
110
110
110
110
85
24 14
0.5
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
24
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
0.25
0.5
32
45
72
41
43
42
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
Pd(MeCN) Cl
2
2
Pd(TFA)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(OAc)2
KOAc
K CO
toluene
toluene
0
1
2
5
2
3
Cs CO toluene
6
2
3
Ag CO toluene
41
6
2
3
13
AgOAc tBuOH
1
4
5
AgOAc 1,2ꢀDCE
80
15
49
45
0
1
AgOAc 1,4ꢀdioxane 100
16
AgOAc tAmylOH 110
b
c
1
7
8
AgOAc toluene
AgOAc toluene
110
110
1
0
a
b
c
All the reactions were performed using 2a. 2b was used instead of 2a. 2c was used instead of
2
a.
1
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Scheme 6. γ-C(sp )-H arylation of 1a,b. Construction of thiophene/furan-based
arylheteroarylmethanes 3/4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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52
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60
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
b
1
.0 mmol of the corresponding aryl iodide was used in this reaction. 20 mol% catalyst was
c
used. 1.0 mmol of the corresponding aryl iodide was used in this reaction.
We next explored the generality and substrate scope of this protocol using substrates 1a-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
d. Scheme 6 shows the Pd(OAc) ꢀcatalyzed, AgOAcꢀpromoted, 8ꢀaminoquinolineꢀassisted
2
3
arylation of the γꢀC(sp )ꢀH bond of 1a and 1b with a variety of aryl iodides under the optimized
reaction conditions (entry 5, Table 1). The arylation of 1a with aryl iodides containing a
substituent at the para position (e.g., Ac, COOMe, Et, NO , and Br) and PhI afforded the
2
corresponding arylheteroarylmethane derivatives 3b-g in 53ꢀ72% yield (Scheme 6). We then
3
performed the Pd(II)ꢀcatalyzed γꢀC(sp )ꢀH arylation of 1a with a disubstituted aryl iodide and a
variety of heteroaryl iodides, which afforded the corresponding arylheteroarylmethane derivative
3h and thediheteroarylmethane derivatives 3i-n in 46ꢀ96% yield (Scheme 6).
We next performed the Pd(II)ꢀcatalyzed arylation using the furanꢀ2ꢀcarboxamide
derivative 1b. The arylation of substrate 1b with aryl iodides containing a substituent at the para
or meta position (e.g., Ac, COOR, OMe, alkyl, NO , CN, and Cl) afforded the corresponding
2
arylheteroarylmethane derivatives 4a-k in 55ꢀ93% yield (Scheme 6). We also performed the
arylation of 1b with a disubstituted aryl iodide and heteroaryl iodides, which afforded the
corresponding arylheteroarylmethane derivative 4l and diheteroarylmethane derivatives 4m-o in
5
5ꢀ82% yield (Scheme 6).
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Scheme 7. γ-C(sp )-H arylation of 1c,d. Construction of benzo-thiophene/furan-based
arylheteroarylmethanes 5/6.
3
-
C(sp )-H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AQ
N
Ar
H
Pd(OAc) (10 mol%)
AgOAc (0.27 mmol)
2
H
H
N
N
AQ
+
Ar I
X
X
O
toluene (3 mL)
O
2
o
5a-h; X = S
a-f; X = O
1
c; X = S, 1d; X= O
4-24 h, 110 C
(0.75 mmol)
6
(0.125 mmol)
arylheteroarylmethanes
R
R
5d; R = OMe; 56% (24 h)a
5e; R = COOEt; 41% (12 h)
5a; R = COCH ; 60% (8 h)
5b; R = OMe; 52% (7 h)
3
5
f; R = NO ; 49% (12 h)
2
H
N
5
c; R = COOMe; 46% (10 h)
H
AQ
S
N
AQ
O
S
O
Br
F
N
N
5
g; 76% (15 h)a
h; 71% (24 h)a
5
H
H
N
N
AQ
S
AQ
S
O
O
R
R
b
6
c; R = OMe; 31% (6 h)
6d; R = Et; 59% (6 h)
6
6
a; R = COCH ; (61%) (36%) (5 h)
3
b
b; R = COOCH ; (66%) (44%) (4 h)
3
H
H
N
N
AQ
O
AQ
O
O
O
Br
O
O
O
N
6e; 45% (10 h)
f; 57% (24 h)a
AQ
6
H
H
N
N
AQ
O
O
O
a
b
1.0 mmol of the corresponding aryl iodide was used in this reaction. 0.5 mmol of the
corresponding aryl iodide was used in this reaction.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
Scheme 8. MTA-directed γ-C(sp )-H arylation of 1e. Construction of thiophene-based
arylheteroarylmethanes 7.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
0
.75 mmol of the corresponding aryl iodide was used in this reaction.
We next expanded the scope of this protocol by performing the γꢀC(sp )ꢀH arylation of 1c
and 1d (Scheme 7) with a variety of aryl iodides under the optimized reaction conditions (entry
, Table 1). The arylation of 1c with aryl iodides containing a substituent at the para or meta
3
5
position (e.g., Ac, COOR, OMe, and NO ) afforded the corresponding arylheteroarylmethane
2
derivatives 5a-f in 41ꢀ60% yield (Scheme 7). The arylation of 1c with heteroaryl iodides also
afforded the corresponding diheteroarylmethane derivatives 5g and 5h in 71ꢀ76% yield (Scheme
3
7
). Then, the Pd(OAc) ꢀcatalyzed γꢀC(sp )ꢀH arylation of 1d with aryl iodides containing a
2
substituent at the para position (e.g., Ac, COOMe, OMe, and Et) afforded the corresponding
arylheteroarylmethane derivatives 6a-d in 31ꢀ66% yield (Scheme 7). The arylation of 1d with a
1
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disubstituted aryl iodide and a heteroaryl iodide also afforded the corresponding
arylheteroarylmethane derivative 6e and diheteroarylmethane derivative 6f in 45ꢀ57% yield
(Scheme 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
We next examined the γꢀC(sp )ꢀH arylation using the BDG 2ꢀ(methylthio)aniline.
Scheme 8 shows the arylation of the substrate 1e with a variety of aryl iodides under the
optimized reaction conditions (entry 5, Table 1). The arylation of 1e with aryl iodides containing
a substituent at the para or meta position (e.g., OMe, Ac, COOMe, Et, and NO ) afforded the
2
corresponding arylheteroarylmethane derivatives 7a-e in 50ꢀ58% yield (Scheme 8). The
arylation of 1e with disubstituted aryl iodides and heteroaryl iodides also afforded the
corresponding arylheteroarylmethane derivatives 7f and 7g and the diheteroarylmethane
derivatives 7h and 7i in 53ꢀ61% yield (Scheme 8). Notably, the yields of 7 (Scheme 8) obtained
using the BDG 2ꢀ(methylthio)aniline were comparable with those of 3 obtained using the 8ꢀ
aminoquinoline BDG (Scheme 6). We also attempted the removal of the BDG 8ꢀaminoquinoline
3
after the Pd(II)ꢀcatalyzed γꢀC(sp )ꢀHꢀarylation of 1a. The NaOHꢀmediated amide hydrolysis of a
representative arylheteroarylmethane derivative 3a afforded the carboxylic acid 3aa in 64% yield
(Scheme 9). Additionally, the treatment of the 3a with MeOH in BF ˖OEt afforded the methyl
3
2
ester derivative 3ab in 85% yield (Scheme 9).
The γꢀCꢀH arylations of the methyl group in compounds 1a-e resulted in the
corresponding arylheteroarylmethanes and diheteroarylmethanes 3-7 containing the methylene γꢀ
3
CꢀH bonds. Thus, under the experimental conditions used for the γꢀC(sp )ꢀH arylation of the
compounds 1a-e, we expected that it would also possible to accomplish the intramolecular CꢀH
amidation through the methylene γꢀCꢀH bonds in the compounds 3-7. We therefore explored the
3
possibility of successive arylation/intramolecular amidation of the remote γꢀC(sp )ꢀH bonds of
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
substrates 1a-e employing the Pd(OAc) catalyst and AgOAc additive. The successive arylation
2
and intramolecular amidation of the substrates e.g., 1a-c are expected to afford the corresponding
new classes of pyrrolidoneꢀring annulated furan/thiopheneꢀbased heterocycles 8, 10, and 12
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 10).
Scheme 9. Representative trials to remove the directing group.
3
Scheme 10. Proposed successive arylation and intramolecular amidation of γ-C(sp )-H
bonds towards pyrrolidone-ring annulated thiophene/furan-based heterocycles.
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Table
2.
Optimization
of
reaction
conditions.
Successive
γ-C(sp )-H
a
arylation/intramolecular amidation of 1a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
Entry PdL (x mol%) 2a
Additive Solvent
T ( C) t (h) Yield (%)
2
(mmol)
3a
8a 9a
b
1
2
3
4
5
6
7
Pd(OAc) (10)
0.75
0.5
1
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
110
110
110
110
110
110
110
4
72
ꢀ
ꢀ
2
Pd(OAc) (10)
24 40 20 <5
48 <5 59 12
48 <5 64 10
48 <5 71 12
48 49 39 <5
48 32 45 <5
2
Pd(OAc) (10)
2
Pd(OAc) (20)
1
2
Pd(OAc) (20) 1.25
2
PdCl (20)
1.25
1.25
2
Pd(MeCN) Cl
2
2
(20)
8
9
Pd(TFA) (20)
1.25
1.25
1.25
1.25
1.25
1.25
1.25
AgOAc toluene
110
110
110
110
110
80
48 36 21 16
48 64 <5 <5
2
Pd(OAc) (20)
KOAc
K CO
toluene
toluene
2
10
Pd(OAc) (20)
48 49
48 43
0
0
2
2
3
11
12
13
14
Pd(OAc) (20)
Cs CO toluene
0
0
2
2
3
Pd(OAc) (20)
Ag CO toluene
48
0
43
9
6
2
2
3
Pd(OAc) (20)
AgOAc 1,2ꢀDCE
48 30
<5
2
Pd(OAc) (20)
AgOAc 1,4ꢀdioxane 100
48 34 21 <5
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
1
1
5
6
7
8
Pd(OAc) (20)
1.25
1.25
1.25
1.25
0.5
AgOAc tAmylOH 110
48 17 15 <5
48 58 <5 <5
2
Pd(OAc) (20)
AgOAc tBuOH
AgOAc toluene
AgOAc toluene
AgOAc toluene
AgOAc toluene
85
2
c
d
d
e
f
Pd(OAc) (20)
110
110
110
110
110
48
48
0
0
0
0
0
0
0
0
0
0
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd(OAc) (20)
2
19
Pd(OAc) (20)
24 33
24 19
2
20
Pd(OAc) (20)
0.5
2
21
Pd(OAc) (20)
0.5
AgOAc toluene
24 20 <5 <5
2
a
b
c
All the reactions were performed using 2a. Result of entry 5, Table 1. 2b was used instead
d
d
e
of 2a. 2c was used instead of 2a. Quinoline (40 mol%) was added as an additive. 2ꢀMethyl
f
quinoline (40 mol%) was added as an additive. 2ꢀHydroxyꢀ4ꢀmethylquinoline (40 mol%) was
added as an additive.
To realize the Pd(II)ꢀcatalyzed BDGꢀdirected successive arylation/intramolecular
3
amidation of the remote γꢀC(sp )ꢀH bond, we first attempted the successive
arylation/intramolecular amidation reaction using the thiopheneꢀ2ꢀcarboxamide system 1a. Table
2
shows the optimization of the reaction conditions using various Pd catalysts, additives, and
o
solvents. The Pd(II)ꢀcatalyzed arylation of 1a with 4ꢀ6 equiv of 2a in toluene at 110 C for 4 h
afforded the arylheteroarylmethane derivative 3a in 72% yield (entry 1, Table 2). We then
prolonged the reaction period to accomplish the successive arylation/intramolecular amidation of
3
γꢀC(sp )ꢀH bond of substrate 1a. The Pd(II)ꢀcatalyzed reaction of a mixture containing 1a (1
o
equiv) and aryl iodide 2a (4 equiv) was carried out in toluene at 110 C for 24 h. This reaction
afforded 3a in 40% yield and the expected pyrrolidoneꢀring annulated thiophene heterocycle 8a
in 20% yield via the intramolecular CꢀH amidation (entry 2, Table 2). To improve the yield of
this process, we next performed the reaction of 1a (1 equiv) and aryl iodide 2a (8ꢀ10 equiv) in
1
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toluene at 110 C for 48 h with 10ꢀ20 mol% of the Pd(OAc) catalyst. These reactions afforded
2
8
a in improved yields (59ꢀ71%, entries 3ꢀ5, Table 2).. In these reactions, 3a was obtained in
5% yield along with the arylheteroarylketone 9a in 10ꢀ12% yield. It is obvious that the product
a was formed from the CꢀH arylated product 3a via the intramolecular CꢀH amidation process.
It is assumed that the ketone product 9a was formed from the Pd(II)ꢀcatalyzed oxidation of
<
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
4
5
methylene group of 3a with adventitious oxygen in the reaction system.
Next, to improve the yield of 8a further, we attempted the arylation of 1a with 2a using
various Pd catalysts, additives, and solvents. The reactions of 1a with 2a with other palladium
catalysts PdCl , Pd(CH CN) Cl , and Pd(TFA) afforded both 3a and 8a without any
2
3
2
2
2
improvement in the yield for 8a (entries 6ꢀ8, Table 2). We also tried the Pd(II)ꢀcatalyzed reaction
of 1a with 2a with various additives, such as, KOAc, K CO , and Cs CO , which were not
2
3
2
3
fruitful, and the yield of 8a did not improve (entries 9ꢀ11, Table 2). The reaction of 1a with 2a
with Pd(OAc) catalyst and Ag CO additive gave 8a in 43% yield (entry 12, Table 2). We also
2
2
3
tried the reaction of 1a with 2a with Pd(OAc) catalyst and AgOAc additive in other solvents,
2
such as 1,2ꢀDCE, 1,4ꢀdioxane, tAmylOH, and tBuOH. These trails were also not fruitful, and the
yield of the product 8a did not improve (entries 13ꢀ16, Table 2). The Pd(II)ꢀcatalyzed reactions
of 1a with coupling partners such as aryl bromide 2b or aryl chloride 2c instead of aryl iodide 2a
were ineffective (entries 17 and 18, Table 2). Additionally, to find out whether we can use lesser
amounts of aryl iodide 2a and to improve the yield of 8a further, we attempted the Pd(II)ꢀ
catalyzed arylation of 1a with 2a (4 equiv) using various additives/ligands such as quinoline, 2ꢀ
methyl quinoline and 2ꢀhydroxyꢀ4ꢀmethylquinoline. These trails were also not fruitful, and the
product 8a was not formed (entries 19ꢀ21, Table 2).
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
Scheme 11. Successive arylation/intramolecular amidation of the γ-C(sp )-H bond of 1a.
a,b
Synthesis of pyrrolidone-ring annulated thiophene scaffolds 8b-z and 8aa.
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a
All reactions were performed using 1a (0.125 mmol), ArI (1.25 mmol), Pd(OAc) (20 mol%),
2
AgOAc (0.27 mmol) in toluene (2ꢀ3 mL).
b
The corresponding ketone products 9g-p and 9aa (minor products) were isolated in pure forms.
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In rest of the cases, the corresponding ketone products 9 (minor products) were not obtained in
characterizable amounts.
c
1
.5 mmol of ArI was used.
We then explored the generality and substrate scope of this arylation/intramolecular
3
amidation protocol using substrates 1a-c. Scheme 11 shows amidation of the γꢀC(sp )ꢀH bond of
1a with a variety of aryl iodides under the optimized reaction conditions (entry 5, Table 2). The
3
Pd(II)ꢀcatalyzed successive γꢀC(sp )ꢀH arylation/intramolecular amidation of 1a with aryl
iodides containing a substituent at the para position (e.g., F, Cl, Br, I, Ac, COOMe, and alkyl)
and PhI afforded the corresponding pyrrolidoneꢀring annulated thiopheneꢀbased heterocyclic
scaffolds 8b-n in 44ꢀ71% yield (Scheme 11). In some cases, the corresponding arylheteroaryl
ketones 9g-n were also obtained in 7ꢀ28% yield, as observed in the optimization reactions (Table
45
2).
Next, we performed the arylation/intramolecular amidation of 1a with aryl iodides
containing a substituent at the meta position (e.g., OMe, COOEt, NO , Cl, F, Br, I, Me, and CF ).
2
3
These reactions afforded the corresponding pyrrolidoneꢀring annulated thiopheneꢀbased
heterocyclic scaffolds 8o-w in 51ꢀ66% yield (Scheme 11). In some cases, the corresponding
arylheteroarylketones 9o and p were also obtained in 20ꢀ27% yield, as observed in the
4
5
optimization reactions (Table 2). Furthermore, the amidation of 1a with various disubstituted
aryl iodides afforded the corresponding pyrrolidoneꢀring annulated thiopheneꢀbased heterocyclic
scaffolds 8x, 8y and 8z and 8aa in 54ꢀ82% yield (Scheme 11). In one of the reactions, the
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corresponding arylheteroarylketone 9aa was also obtained in 12% yield as observed in the
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optimization reactions (Table 2).
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Scheme 12. Successive arylation/intramolecular amidation of the γ-C(sp )-H bond of 1b.
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a,b
Synthesis of pyrrolidone-ring annulated furan scaffolds 10a-c.
a
All reactions were performed using 1b (0.125 mmol), ArI (1.5 mmol), Pd(OAc) (20ꢀ30 mol%),
2
AgOAc (0.27 mmol) in toluene (2ꢀ3 mL).
b
The corresponding ketone products 11a (minor product) was isolated in pure form. In rest of
the cases, the corresponding ketone products 11 (minor products) were not obtained in
characterizable amounts.
We next investigated the arylation and intramolecular amidation process using substrate
1b. Scheme 12 shows the Pd(II)ꢀcatalyzed arylation and intramolecular amidation of 1b with aryl
iodides containing a substituent at the para or meta position under the optimized reaction
conditions (entry 5, Table 2). These reactions afforded the corresponding pyrrolidoneꢀring
annulated furanꢀbased heterocyclic scaffolds 10a-c in 33ꢀ56% yield (Scheme 12). In one of the
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reactions, the corresponding arylheteroaryl ketone system 11a was also obtained in 23% yield, as
observed in the optimization reactions (Table 2). We next expanded the substrate scope of this
protocol by performing arylation and intramolecular amidation reaction using benzothiopheneꢀ
based substrate 1c. Scheme 13 shows the Pd(II)ꢀcatalyzed arylation and intramolecular amidation
of 1c with aryl iodides containing a substituent at the para position and disubstituted aryl iodides
under the optimized reaction conditions (entry 5, Table 2). These reactions afforded the
corresponding pyrrolidoneꢀring annulated benzothiopheneꢀbased heterocyclic scaffolds 12a-d in
37ꢀ53% yield (Scheme 13).
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3
Scheme 13. Successive arylation/intramolecular amidation of the γ-C(sp )-H bond of 1c.
a,b
Synthesis of pyrrolidone-ring annulated benzothiophene scaffolds 12a-f.
a
All reactions were performed using 1c (0.125 mmol), ArI (1.5 mmol), Pd(OAc) (20 mol%),
2
AgOAc (0.27 mmol) in toluene (2ꢀ3 mL) for 48ꢀ70 h.
b
The corresponding ketone products 13 (minor products) were not obtained in characterizable
amounts.
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Scheme 14. Control experiments to explain the proposed mechanism of the successive
arylation/intramolecular amidation affording the pyrrolidone-ring annulated scaffolds.
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This reaction was performed without Pd(OAc) . 10 mol% of 2a was used. 0.125 mmol of 2a
2
d
was used. The reaction was performed in aerobic condition.
Overall, arylheteroarylmethane and diheteroarylmethane scaffolds 3-7 were obtained in
3
good to high yield from the Pd(II)ꢀcatalyzed γꢀC(sp )ꢀH arylation of 1a-e. The pyrrolidoneꢀring
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annulated thiophene/furanꢀbased heterocyclic scaffolds 8a-z, 8aa, 10a-c, and 12a-d were
3
obtained in low to good yield from the Pd(II)ꢀcatalyzed successive γꢀC(sp )ꢀH
arylation/intramolecular amidation of substrates 1a-c. Some of the Pd(II)ꢀcatalyzed successive γꢀ
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3
C(sp )ꢀH arylation/intramolecular amidation reactions of substrates 1a-c afforded the
corresponding pyrrolidoneꢀring annulated thiophene/furanꢀbased heterocyclic scaffolds in low to
satisfactory yield. The exact reason for the low yield of some of the pyrrolidoneꢀring annulated
thiophene/furanꢀbased products is not clear at this stage, although some of the possible reasons
are as follows. Firstly, these processes are two step reactions, and the pyrrolidoneꢀring annulated
thiophene/furanꢀbased heterocyclic scaffolds 8a-z, 8aa, 10a-c, and 12a-d were formed after the
formation of the corresponding CꢀH arylated products 3-5. Next, in some of the cases, the
corresponding ketone products 9 and 11 were formed as the byproducts from the Pd(II)ꢀ
catalyzed oxidation of the methylene groups of 3 and 4.
We also performed some control experiments shown in Scheme 14 to determine a
plausible mechanism for the formation of scaffolds 8a-z, 8aa, 10a-c, and 12a-d from the
arylation and intramolecular amidation of substrates 1a-c. We first performed the reaction of 1a
with the Pd(OAc) catalyst and AgOAc additive without using any aryl iodide. Without any aryl
2
iodide, we expected that this reaction would afford the product 14 via the Pd(II)ꢀcatalyzed
intramolecular CꢀH amidation (eq 1, Scheme 14), but it did not.
Next, we treated 3a with excess amounts of 2a, the Pd(OAc) catalyst, and AgOAc
2
additive. This reaction successfully afforded the expected scaffold 8a (54%, eq 2, Scheme 14)
along with the arylheteroaryl ketone derivative 9a (10%), as obtained in the optimization
reactions (Table 2). Notably, the reactions using 10 mol% or 1 equiv of 2a afforded the expected
product 8a in 12ꢀ27% yield and the byꢀproduct 9a in 18ꢀ20% yield (eq 2, Scheme 14). Since we
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have used the same aryl iodide 2a, which was used to assemble 3a in the reaction shown in
Scheme 14 (eq 2), we then treated 3a with a different aryl iodide to check whether the amidation
is occurring or not. Accordingly, we treated 3a with 1ꢀchloroꢀ4ꢀiodobenzene, Pd(OAc) catalyst,
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and AgOAc additive. Similar to the outcome of reaction of 3a with 2a, the reaction of 3a with 1ꢀ
chloroꢀ4ꢀiodobenzene also afforded the expected scaffold 8a in 51% yield along with 9a in 10%
yield (eq 3, Scheme 14). We then performed the reaction of 3a with the Pd(OAc) catalyst and
2
AgOAc additive without using any aryl iodide. We expected that this reaction would afford 8a
via the Pd(II)ꢀcatalyzed CꢀH amidation (eq 4, Scheme 14). However, it did not afford 8a, and the
starting material 3a was recovered (40% recovery). The reaction did afford the arylheteroaryl
ketone derivative 9a as a byꢀproduct in 15% yield (eq 4, Scheme 14). Then, to check whether the
product 9a was formed in the above reactions due to adventitious moisture, we performed the
reaction of 3a with 2a, Pd(OAc) catalyst and AgOAc additive and water. This reaction afforded
2
the product 8a in 11ꢀ20% yields and 9a in only 7ꢀ8% yields (eq 5, Scheme 14). While we
expected that this reaction will afford only the product 9a as the major isomer, however, we
obtained both the products 8a and 9a (eq 5, Scheme 14) similar to the reactions shown in eq 2
(Scheme 14). It is assumed that the ketone 9a was formed from the Pd(II)ꢀcatalyzed oxidation of
4
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the methylene group of 3a with adventitious oxygen in the reaction system.
These control reactions indicated that (a) the process comprising the formation of
pyrrolidoneꢀring annulated thiophene/furanꢀbased heterocyclic scaffold (e.g., 8a-z, 8aa, 10a-c,
and 12a-d) involves two steps: CꢀH arylation and intramolecular CꢀH amidation; (b) the
pyrrolidoneꢀring annulated thiophene/furanꢀbased heterocyclic scaffolds were formed only after
the formation of the corresponding CꢀH arylated products (e.g., arylheteroarylmethanes 3-5); and
(c) aryl iodide seems to be an important component in the intramolecular amidation step, which
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affords the pyrrolidoneꢀring annulated thiophene/furanꢀbased heterocyclic scaffolds from the Cꢀ
H arylated products (e.g., arylheteroarylmethanes/diheteroarylmethanes 3-5).
The Pd(II)ꢀcatalyzed reactions of compounds 1a-d with aryl iodides with reaction periods
of 4ꢀ24 h (except a few reactions which required 36 or 48 h) afforded the corresponding
diarylmethanes 3-6 (mono arylated products) in satisfactory to high yields (Table 1 and Schemes
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6,7). In these reactions the column chromatographic purification of the corresponding crude
reaction mixtures did not afford any other corresponding byꢀproducts, such as, bisꢀarylated
products or intramolecular CꢀH amidation products (e.g., 8, 10, and 12) in characterizable
amounts, and in most of the reactions the corresponding starting materials (1a-c) were also
recovered. On the other hand, the Pd(II)ꢀcatalyzed reactions of compounds 1a-c with aryl iodides
3
with reaction periods of 48ꢀ70 h led to the corresponding successive γꢀC(sp )ꢀH
arylation/intramolecular amidation products 8, 10, and 12 (Table 2, Schemes 11ꢀ13) in
satisfactory to high yields. While some of the reactions gave the corresponding ketones 9, and 11
as the byꢀproducts, the column chromatographic purification of the corresponding crude reaction
mixtures also did not afford any other corresponding bisꢀarylated products in characterizable
amounts. At this stage, an exact reason for the selective formation 8, 10, and 12 via the mono
arylation followed by intramolecular CꢀH amidation over the bis arylation is not clear to us. It is
proposed that the formation of five memberedꢀring during the reductive elimination step
(Scheme 15) might be the driving force to afford the corresponding cyclized products 8, 10, and
12 over the bis arylation.
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Scheme 15. Proposed mechanism for the Pd(II)-catalyzed γ-C(sp )-H arylation of 1a-d and
successive arylation/intramolecular amidation of 1a-c.
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On basis of the results from the control reactions (Scheme 14) and the observed products
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-5, and 8/10/12, the γꢀC(sp )ꢀH arylation and successive arylation/intramolecular amidation can
be plausibly explained via a chelationꢀ and BDGꢀassisted mechanism in concurrence with the
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proposed Pd ꢀPd catalytic cycle mechanism (Scheme 15). It is well documented that
Pd(OAc) functions as a catalyst and the AgOAc additive regenerates the Pd(OAc) catalyst in
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the catalytic process. An initial coordination of 1a with Pd(OAc) followed by the γꢀC(sp )ꢀH
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activation generates the Pd(II) species 15, which undergoes an oxidative addition with ArI to
afford the Pd(IV) species 16. Species 16 then undergoes reductive elimination to afford the
species 17. Species 17 then undergoes a ligand exchange followed by protonation with AcOH to
3
afford the γꢀC(sp )ꢀH arylated product 3a and the Pd(OAc) catalyst (Scheme 15).
2
Subsequently, 3a reacts with the palladium(II) catalyst to afford the Pd(II) species 18,
which undergoes an oxidative addition with ArI to afford the Pd(IV) species 19. Species 19 then
undergoes reductive elimination to afford the pyrrolidoneꢀring annulated thiopheneꢀbased
heterocycle 8 and the palladium(II) species 20 (Scheme 15). Plausibly, species 20 then generates
biaryl 21 and palladium(II) catalyst involving reductive elimination, ligand exchange and
4
8
protonation processes, respectively. Given that depending on the reaction conditions used, the
Pd(II)ꢀcatalyzed arylation of 1a selectively afforded either mono arylated product 3a or the
cyclized products 8, hence, it is believed that the formation of bisꢀarylated product 22 seems to
be a less favoured process than the formation of a five memberedꢀring in the reductive
elimination step involving the species 19.
The arylheteroarylmethane and diheteroarylmethane scaffolds 3-7 were characterized by
NMR and HRMS analysis. A representative diheteroarylmethane derivative 3l was also
characterized by Xꢀray structure analysis (see the SI for the Xꢀray structure). Characteristically,
the corresponding benzylic signals of 3-7 appeared as singlet peaks around δ 4.4ꢀ4.8 ppm in the
proton NMR spectra. Similarly, the pyrrolidoneꢀring annulated thiophene/furanꢀbased
heterocyclic scaffolds 8a-z, 8aa, 10a-c, and 12a-d were characterized by NMR and HRMS
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