Pd(II)-Catalyzed Bidentate Directing Group-Aided Chemoselective Acetoxylation of Remote ε-C(sp2)-H Bonds in Heteroaryl-Aryl-Based Biaryl Systems

Article abstract of DOI:10.1021/acs.joc.6b01933

In this Article, we report our successful attempt on the Pd(II)-catalyzed, bidentate directing group-aided, chemoselective acetoxylation/substitution of remote ε-C(sp²)-H bonds using heteroaryl-aryl-based biaryl systems. While the bidentate dir

Full text of DOI:10.1021/acs.joc.6b01933

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Article
Pd(II)-Catalyzed Bidentate Directing Group-Aided
Chemoselective Acetoxylation of Remote Epsilon-
C(sp2)-H Bonds in Heteroaryl-Aryl-Based Biaryl Systems
Naveen, Vadla Rajkumar, Srinivasarao Arulananda Babu, and Bojan Gopalakrishnan
*
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01933 • Publication Date (Web): 18 Nov 2016
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Pd(II)-Catalyzed Bidentate Directing Group-Aided Chemoselective Acetoxylation of
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Remote ε-C(sp )-H Bonds in Heteroaryl-Aryl-Based Biaryl Systems
Naveen, Vadla Rajkumar, Srinivasarao Arulananda Babu* and Bojan Gopalakrishnan
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
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ABSTRACT
In this paper, we report our successful attempt on the Pd(II)-catalyzed, bidentate directing
2
group-aided, chemoselective acetoxylation/substitution of remote ε-C(sp )-H bonds using
heteroaryl-aryl-based biaryl systems. While the bidentate directing group (BDG)-aided, C-H
activation and functionalization/acetoxylation of the β-, γ- and δ-C-H bonds of appropriate
carboxamide systems were well documented, there exist only rare reports dealing on the C-H
activation and functionalization of remote ε-C-H bonds of appropriate substrates. Especially, the
2
BDG-aided chemoselective acetoxylation of remote ε-C(sp )-H bond over cyclization has not
been explored well. Accordingly, in this work the treatment of various picolinamides /
oxalylamides / pyrazine-2-carboxamides 4/7/9/11, which were derived from the corresponding
C-3 arylated furfurylamines or thiophen-2-ylmethanamines with PhI(OAc) in the presence of
2
the Pd(OAc) catalyst successfully afforded the corresponding ε-C-H acetoxylated products. The
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chemoselective acetoxylation of the ε-C-H bond was possible and facilitated by the biaryl
substrate 4/7/9/11 and not by the biaryl substrate 2a.
INTRODUCTION
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Transition metal-catalyzed sp /sp C-H activation/functionalization is one of the
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-4
remarkable synthetic transformations in organic synthesis. While the directing group-free C-H
activation/functionalization is well documented, the directing group-aided C-H
activation/functionalization has become a powerful synthetic strategy for accomplishing the site-
1
selectivity. Especially, the use of the bidentate directing groups (BDGs) has offered a new zeal
-4
for achieving the site-selective C-H functionalization (e.g., arylation, alkylation and
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-8
acetoxylation) of organic molecules.
The 8-aminoquinoline (8AQ)-type BDGs have
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3
preferentially assisted the functionalization of sp /sp β-C-H bonds of carboxylic acid
5-8
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3
substrates. The picolinamide (PA)-type BDGs have assisted the functionalization of sp /sp γ-
5
-8
2
3
and δ-C-H bonds of amine systems. The BDG-aided functionalization of sp /sp β- and γ-C-H
5
-8
bonds of appropriate carboxamide systems were well documented; and there also have been
2
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some outstanding efforts on the BDG-aided functionalization of remote sp /sp δ- and ε-C-H
5
,8-10
bonds of appropriate carboxamide systems.
In particular, to the best of our knowledge, there
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exist only rare reports dealing on the BDG-aided functionalization of remote sp /sp ε-C-H
1
1
bonds.
While the Pd(II)-catalyzed C-H activation strategy has been well explored for the
construction
of
C-C
bonds;
the
Pd(II)-catalyzed,
PhI(OAc) -promoted
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C-H
acetoxylation/oxygenation tactic comprising the conversion of a C-H bond in to a C-O bond has
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,12-18
2
In particular, the acetoxylation of sp C-H bonds of
also received substantial attention.
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arenes considered as a direct and efficient method for synthesizing phenolic compounds, which
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are important substances in industry and academic research.
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Scheme 1. Functionalization of Remote δ- and ε-C(sp )-H Bonds.
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The BDG-aided acetoxylation of sp /sp β- and γ-C-H bonds of appropriate carboxamide
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8,16,17
systems were well documented.
A literature survey
revealed that the attempts on the
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Pd(II)-catalyzed, BDG-aided functionalization of remote δ- or ε-C(sp )-H bonds with PhI(OAc)2
generally gave the cyclized products (e.g., 1b, 1f, 1h and 1i). The BDG-aided chemoselective
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1-5,8
acetoxylation of remote ε-C(sp )-H bond over cyclization has not explored well.
Accordingly,
obtaining control on the acetoxylation/substitution over cyclization and chemoselectivity in the
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BDG-aided functionalization of remote δ- or ε-C-H bond of a suitable substrate considered to be
a challenging task. With regard to the available reports dealing on the Pd(II)-catalyzed,
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PhI(OAc) -promoted activation/functionalization of remote ε-C(sp )-H bond; Daugulis,
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Chen and Zhao groups have independently revealed that the reactions of the compounds 1g
and 1e exclusively gave the corresponding cyclized products (Scheme 1).
In general, the C-H functionalization processes are substrate specific; however, it is
possible to achieve the chemoselective acetoxylation/substitution or cyclization using suitably
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modified substrates or directing groups or changing the reaction conditions. In this regard,
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Chen reported the alkoxylation of remote δ-C(sp )-H bond using alcohol as a co-solvent. Shi
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reported the chemoselective acetoxylation/substitution or cyclization of remote δ-C(sp )-H
bonds using substrate 1a, which was installed with different DGs. The chemoselective
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acetoxylation of remote δ-C(sp )-H bond was achieved using TA-Py as the directing group and
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the cyclization involving the δ-C(sp )-H bond was achieved using TAA as the directing group
1
Scheme 1). It is also worth to mention here that Yu reported the NHTf-group directed Pd(II)-
8
(
catalyzed δ-C-H (ortho C-H) acetoxylation of triflate protected phenethylamine and
phenylpropylamine systems with tert-butyl peroxyacetate as an oxidant in the presence of either
18a
DMF or CH CN as the promoter. Furthermore, Yu has reported an example of NHTf-group
3
directed ε-C-H acetoxylation of triflate protected phenylpropylamine system with tert-butyl
peroxyacetate as an oxidant in the presence of CH CN, which afforded the corresponding ε-C-H
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18a
acetoxylated product in 33% yield.
Taking an impetus from the enduring developments on the site-selective acetoxylation of
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C-H bonds,
we envisaged to study the prevailing subject comprising dominant cyclization
over acetoxylation/substitution in the Pd(II)-catalyzed, bidentate ligand picolinamide (PA)-aided
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functionalization of ε-C(sp )-H bond using an appropriate substrate. Accordingly, herein, we
report our successful attempt on the Pd(II)-catalyzed, bidentate directing group-aided
2
chemoselective acetoxylation of remote ε-C(sp )-H bond using the heteroaryl-aryl-based biaryl
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system 1m (Scheme 2).
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Scheme 2. Selective Acetoxylation of γ-, δ- and ε-C(sp )-H Bonds.
RESULTS AND DISCUSSION
Typically, the suitable systems for attempting the Pd(II)-catalyzed, BDG-aided
2
acetoxylation of remote ε-C(sp )-H bond are either the 3-phenylpropan-1-amine-type system 1e
or the biaryl-type system 1g (Scheme 1). However, the Pd(II)-catalyzed, bidentate directing
group-aided reactions of 1g and 1e with PhI(OAc) were reported to give the corresponding
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cyclized products (Scheme 1). Hence, we envisaged to attempt the chemoselective
1
2
acetoxylation of remote ε-C(sp )-H bonds using biaryl systems having a combination of
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heteroaryl-aryl rings, e.g., thiophene-phenyl system 2a and furan-phenyl system 4a (Scheme
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3).
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Scheme 3. Chemoselective Cyclization and Acetoxylation of Remote ε-C(sp )-H Bonds.
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To begin with our studies on the Pd(II)-catalyzed directing group-aided chemoselective
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acetoxylation of remote ε-C(sp )-H bond in the heteroaryl-aryl-based biaryl system, initially we
assembled the picolinamide substrates 2a and 4a (Scheme 3). Then, we attempted the Pd(II)-
catalyzed, functionalization of the ε-C-H bond present in the thiophene ring of substrate 2a with
PhI(OAc) as an oxidant. This reaction gave the cyclized product 3a in 50% yield instead of the
2
ε-C-H acetoxylated product 3b (Scheme 3). Next, we attempted the Pd(II)-catalyzed
functionalization of the ε-C-H bond present in the phenyl ring of substrate 4a with PhI(OAc)2.
Fortunately, our endeavor for accomplishing the ε-C-H acetoxylation went right and this reaction
selectively gave the ε-C-H acetoxylated products 5a (mono OAc) and 6a (di OAc). These
reactions indicated that the substrate 4a was found to be an appropriate design for accomplishing
the ε-C-H acetoxylation, while 2a was not a suitable design.
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Table 1. Picolinamide-Aided ε-C-H Acetoxylation of 4b
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Encouraged by the successful attempt on the ε-C-H acetoxylation reaction using the
heteroaryl-aryl-based biaryl system 4a (Scheme 3); we next performed the optimization of
reaction conditions. Table 1 shows the results of the ε-C-H acetoxylation reaction of the
picolinamide substrate 4b in the presence of various oxidants/additives and palladium catalysts.
Amongst the optimization reactions performed, the reaction of 4b with 2 equiv of PhI(OAc) and
2
o
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0 mol% of the Pd(OAc) catalyst in toluene at 110 C for 24 h found to afford the ε-C-H
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acetoxylated product 5b in a maximum yield of 80% (entry 4, Table 1).
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Noticeably, in the substrate 4b the ε-C-H bond was selectively acetoxylated over the ε-
m
C-H bond to afford the mono acetoxylated product 5b and the corresponding bis acetoxylated
product 6b was not obtained in characterizable amounts. This is because, in the substrate 4b the
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methyl substituent present at the ortho-position with respect to the ε-C-H bond perhaps hinders
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the acetoxylation of the ε-C-H bond. It is to be noted that the preliminary acetoxylation reaction
m/n
of substrate 4a without any substituent at the ortho-position with respect to the ε-C-H bond
gave the products 5a (mono OAc) and 6a (di OAc, Scheme 3). Thus, in continuation of the
optimization of reactions, we desired to reexamine the scope of the preliminary reaction of
substrate 4a using different equiv of PhI(OAc) to selectively obtain either the product 5a (mono
2
OAc) or the product 6a (di OAc). Accordingly, the reaction of 4a with 1.1 equiv of PhI(OAc)2
gave only traces of the products 5a and 6a (entry 1, Table 2). The reaction of 4a with 2 equiv of
PhI(OAc) gave the products 5a and 6a in 45 and 16% yields, respectively (entry 2, Table 2). The
2
reaction of 4a with 3 equiv of PhI(OAc) afforded only the product 6a (di OAc) in 45% yield
2
(
entry 3, Table 2). This reaction indicated that it is possible to selectively obtain the bis
acetoxylated product 6a (di OAc) using excess amounts of PhI(OAc) . Subsequently, the Pd(II)-
2
catalyzed acetoxylation of 4a was also performed in a gram scale, which gave the products 5a
and 6a in 42 and 14% yields, respectively (Table 2).
Next, to elaborate the substrate scope, we assembled substrates 4c-i containing different
m/n
substituents at the meta-position with respect to the ε-C-H bond. Then, we performed the
Pd(II)-catalyzed, ε-C-H acetoxylation of substrates 4c-i with PhI(OAc) (Table 2). Except for one
2
case (entry 6, Table 2), irrespective of the substituents in the aryl rings of 4c-i, the acetoxylation
reactions furnished the corresponding products 5c-i (mono OAc) and 6c-i (di OAc) in 52-72%
yields (combined yields of 5 and 6).
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Table 2. Picolinamide-Aided ε-C-H Acetoxylation of 4a and 4c-i
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a
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.3 mmol of 4a/4h was used. 1.1 Equiv of PhI(OAc) was used. 2 Equiv of PhI(OAc) was
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We observed an interesting trend in entries 4-6 (Table 2), which revealed that the
selectivity with regard to the mono/bis acetoxylation reaction was found to be dependent on the
m/n
nature of the alkyl substituents present at the meta-position with respect to the ε-C-H bond in
the corresponding substrates 4c-e. Substrate 4c containing a methyl group in the aryl ring
afforded the products 5c (mono OAc, 47%) and 6c (di OAc, 25%). Substrate 4d with an ethyl
group in the aryl ring afforded the products 4d (mono OAc, 24%) and 6d (di OAc, 44%).
However, substrate 4e with an isopropyl group in the aryl ring selectively afforded 6e (di OAc,
55%) and the product 5e (mono OAc) was not obtained in characterizable amounts. These
observations indicated that yield of the bis acetoxylation product gradually increased when the
alkyl substituent was changed from Me to Et and then to isopropyl. While an exact reason for
this trend is not clear at this stage, however, an inductive effect might be operational in the
substrates 4c-e. Apart from this observation, substrates 4f-i containing other substituents in the
aryl ring (e.g., OMe, Ac, Cl and Br) afforded the corresponding mono acetoxylation products
(
e.g., 5f, 5h and 5i) as the predominant compounds over the corresponding bis acetoxylation
products (e.g., 6f, 6h and 6i, Table 2).
Recently, Yu et al. and other research groups have reported an interesting approach for
23
achieving meta selective C−H functionalization using norbornene as the transient mediator. We
were interested to use norbornene in the Pd(II)-catalyzed ε-C-H acetoxylation of substrates 4c
and 4d to improve the mono/bis acetoxylation selectivity. Table 3 shows the results of the Pd(II)-
catalyzed ε-C-H acetoxylation of substrates 4c and 4d with PhI(OAc) in the presence of
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norbornene. The reaction of 4c with 1 equiv of PhI(OAc) and without norbornene showed the
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formation of mono/bis acetoxylated products 5c/6c in 12% yield with a ratio of 98:2 (entry 1,
Table 3). The reaction of 4c with 2 equiv of PhI(OAc) and without norbornene showed the
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formation of mono/bis acetoxylated products 5c/6c in 44% yield with a ratio of 75:25 (entry 2,
Table 3). The reaction of 4c with 3 equiv of PhI(OAc) and without norbornene showed the
2
formation of mono/bis acetoxylated products 5c/6c in 61% yield with a ratio of 5:95 (entry 3,
Table 3). This reaction indicated that it is possible to selectively obtain the bis acetoxylated
product 6c (di OAc) using excess amounts of PhI(OAc) . These observed results (entries 1-3,
2
Table 3) with regard to the ratios of mono/bis acetoxylated products were comparable to the
results obtained for substrate 4a (entries 1-3, Table 2). Next, we performed the acetoxylation of
4c with 1-4 equiv of PhI(OAc) and norbornene (1 equiv). While we expected the formation of
2
products 5c/6c with an improved mono/bis chemoselectivity, however, these reactions showed
the formation of products 5c/6c in low yields (19-28% yields, entries 4-7, Table 3). Further, the
observed trend with regard to the ratio of products 5c/6c obtained using norbornene (entries 4-7,
Table 3) was comparable to the reactions carried out without norbornene (entries 1-3, Table 3).
Notably, the chemoselectivity was found to shift gradually from mono OAc to bis OAc while
increasing the equiv of PhI(OAc) . Then, we also performed the reaction of substrate 4d with 2
2
equiv of PhI(OAc) and without norbornene, which showed the formation of mono/bis
2
acetoxylated products 5d/6d in 56% yield with a ratio of 41:59 (entry 8, Table 3). The reaction of
4d with 2 equiv of PhI(OAc) and norbornene (0.5 equiv) showed the formation of mono/bis
2
acetoxylated 5d/6d in 41% yield with a ratio of 41:59 (entry 9, Table 3). The same reaction with
excess of norbornene (6 equiv) showed the formation of mono/bis acetoxylated 5d/6d in 36%
yield with a ratio of 57:43 (entry 10, Table 3). The use of norbornene as a mediator in the Pd(II)-
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8
9
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
catalyzed ε-C-H acetoxylation of substrates 4c and 4d were not fruitful and apparently, the
corresponding acetoxylated products were obtained in low yields when compared to the reactions
carried out without norbornene.
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
Table 3. Trials to Improve the Chemoselectivity in the Pd(II)-Catalyzed Directed ε-C-H
a
Acetoxylation of 4a and 4d Using Norbornene Additive
entry
R
PhI(OAc)2 norbornene
(x equiv)
combined yield of
5 and 6 (%)
12
mono/bis ratio
5:6
98:2
(y equiv)
0
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Et
1
2
3
1
2
3
4
2
2
2
0
44
61
27
15
28
25
56
41
36
75:25
5:95
0
1
75:25
84:16
51:49
5:95
1
1
1
0
41:59
41:59
57:43
Et
0.5
6
10
Et
a
Yields and mono/bis ratio of 5/6 were determined from the crude NMR spectra of the
corresponding reaction mixtures.
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7
8
9
Then, to extend the substrate scope and generality of this work, we assembled substrates
4
j-m and 7a-c (Table 4), which have different substituents at the para-position with respect to
n
m
the ε-C-H bond (or substituents at the ortho-position with respect to the ε-C-H bond). Initially,
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
we performed the Pd(II)-catalyzed, ε-C-H acetoxylation of substrates 4j-m with PhI(OAc) to
2
afford the products 5j-m in 32-60% yields, respectively (Table 4). Then, we performed the
Pd(II)-catalyzed, ε-C-H acetoxylation of substrates 7a-c with PhI(OAc) to afford the
2
corresponding products 8a-c in 32-53% yields, respectively (Table 4). It is to be noted that in the
n
m
substrates 4j-m and 7a-c the ε-C-H bonds were selectively acetoxylated over the ε-C-H bonds.
This is because, in the substrates 4j-m, the corresponding substituents present at the ortho-
m
m
positions with respect to the ε-C-H bonds perhaps hinder the acetoxylation of the ε-C-H
n
bonds. Hence, the corresponding ε-C-H acetoxylated products 5j-m and 8a-c were selectively
obtained. The low yields of the products 5k-m may be due to the corresponding electron-
n
withdrawing groups (e.g., Cl, Br, NO ) present at the para-position with respect to the ε-C-H
2
bond in the substrates 4k-m. Subsequently, inspired by the successful attempts of the Pd(II)-
catalyzed acetoxylation of ε-C-H bond using substrates 4 and 7, we also attempted the Pd(II)-
catalyzed acetoxylation of ζ-C-H bond using substrate 4n. However, the reaction of substrate 4n
with PhI(OAc) failed to give any acetoxylated product (Table 4).
2
After accomplishing the Pd(II)-catalyzed chemoselective ε-C-H acetoxylation using the
bidentate directing group picolinamide (PA), we wished to test the ε-C-H acetoxylation using
6h
other bidentate directing groups, such as, pyrazine-2-carboxamide (PyrA) and oxalylamide
11c
OA). In this regard, we initially performed the Pd(II)-catalyzed acetoxylation of the pyrazine-
(
2-carboxamide substrates 9a-d with PhI(OAc) , which gave the products 10a-d in 44-57%
2
yields, respectively (Scheme 4). Similar to the PA-directed acetoxylation of substrate 4a which
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1
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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
gave both the corresponding mono and bis acetoxylation products 5a and 6a; the PyrA-directed
acetoxylation of substrate 9a also gave both the corresponding mono and bis acetoxylation
products 10a and 10aA. Further, the yields obtained for the PA-directed acetoxylation of
substrates 4b,j,l (46-80%, Table 4) were slightly higher than the yields obtained for the PyrA-
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
2
4
directed acetoxylation of substrates 9b-d (44-57%, Scheme 4). Recently, Yu et al. stated that in
the directing group-based C-H activation, strongly coordinating N / S/ P heteroatoms often
outcompete the directing groups for catalyst binding, thus preventing the C-H
activation/functionalization process. In the present case, it seems that the presence of an extra
nitrogen atom in the PyrA-BDG did not interfere much with the acetoxylation process. Thus, the
efficiency of the pyrazine-2-carboxamide (PyrA) bidentate directing group was comparable to
the picolinamide (PA) bidentate directing group.
Successively, we attempted the ε-C-H acetoxylation using substrates 11a and 11b
containing the oxalylamide (OA) directing group (Scheme 4). The Pd(II)-catalyzed acetoxylation
of the oxalylamide substrate 11a with PhI(OAc) afforded the expected ε-C-H acetoxylated
2
products 12 (mono OAc) and 13 (bis OAc) in 35 and <15% yields (Scheme 4). Similar to the
acetoxylation reaction of substrate 4c, the acetoxylation of 11a also afforded the corresponding
mono and bis ε-C-H acetoxylated products 12 and 13 were obtained. Finally, the Pd(II)-catalyzed
acetoxylation of the oxalylamide substrate 11b with PhI(OAc) afforded the expected product 14
2
in 48% yield. Similar to the acetoxylation reaction of substrate 4b, in the substrate 11b the ε-C-
n
m
H bond was selectively acetoxylated over the ε-C-H bond to afford the mono acetoxylated
product 14 (Scheme 4).
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Table 4. Picolinamide-Aided ε-C-H Acetoxylation of 4/7
1
R
R1
R2
R2
Hn
Pd(OAc)2 (10 mol%)
mH
OAc
PhI(OAc)2 (2 equiv)
NHPA
mH
X = S, O; R1 = H, Me;
R2 = Me, Cl, Br, NO2
toluene (2-8 mL),
NHPA
b, 5j-m / 8a-c
X
1
10 oC, 15-24 h
X
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
4 / 7
0.1-1 mmol)
5
PA = picolinamide
(
entry
biaryl system (4)
t (h)
product (5)
5 / 8: yield (%)
Me
Me
1a
Hn
4b
24
5b; 80
OAc
NHPA
mH
mH
NHPA
S
S
S
Me
Me
Me
Me
Hn
OAc
NHPA
2b
4j
18
5j; 60
mH
mH
NHPA
S
Cl
Cl
Hn
OAc
NHPA
mH
mH
3c
NHPA 4k
16
15
5k; 40
5l; 46
S
S
S
Br
Br
Hn
OAc
NHPA
mH
mH
4c
4l
NHPA
S
O2N
O2N
mH
Hn
OAc
NHPA
5c
6b
7d
mH
4m
24
5m; 32
NHPA
NHPA
NHPA
S
S
Me
mH
Me
mH
Hn
OAc
NHPA
7a
7b
18
24
8a; 53
8b; 32
O
O
Br
mH
Br
Hn
OAc
NHPA
mH
O
O
Me
Me
Me
Me
Hn
OAc
mH
mH
8e
7c
16
8c; 35
NHPA
NHPA
O
O
H3C
trial on the
H3C
-C-H bond
H
remote -C-H
acetoxylation
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
OAc
H
NHPA
NHPA
toluene (2 mL)
110 oC, 24 h
S
S
5n; 0%
4n (0.1 mmol)
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2
2
2
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2
2
3
3
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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
mmol of 4b was used. 0.18 mmol of 4j/7a was used. 0.12 mmol of 4k/4l/4m was used.
c
d
1
e
.15 mmol of 7b was used. 0.2 mmol of 7c was used.
0
Scheme 4. Pyrazine-2-Carboxamide and Oxalylamide-Aided ε-C-H Acetoxylation
Reactions.
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
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7
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9
a
b
.13 mmol of 9a/9d was used. 0.15 mmol of 9b was used. 0.17 mmol of 9c was used.
c
0
We faced some difficulty to isolate the corresponding acetoxylated products in pure form
from the column chromatography purification process with regard to acetoxylation of the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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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
oxalylamide substrates 11a and 11b. The acetoxylation reaction need to be performed using 5-
7.5 mol% of the Pd(OAc) catalyst in <4 h period. The purity of the mono C-H acetoxylated
2
products 12 and 14 is >95%. The NMR spectra of these products revealed the presence of traces
of grease and some impurity. The, purity of the bis C-H acetoxylated product 13 is about 85%.
Our repetitive efforts to get these compounds in completely pure form were not fruitful. When
the acetoxylation of the oxalylamide substrate 11a was performed using 10 mol% of the catalyst
in 5 h, we observed the formation of the expected ε-C-H acetoxylated product 13 along with a
thiophene C5-acetoxylated product. Similarly, when the acetoxylation of the oxalylamide
substrate 11b was performed using 10 mol% of the catalyst in 5 h, we observed the formation of
the expected ε-C-H acetoxylated product 14 along with a thiophene C5-acetoxylated product.
However, we could not reproduce these results and our trials to get the corresponding thiophene
1
C5-acetoxylated products in pure form led to the decomposition of the products. The H NMR of
the fractions obtained after column chromatography indicated that the column fractions
contained a mixture of compounds and impurities.
It is to be noted that the C(2)-H and C(5)-H bonds of thiophene ring are susceptible for
the direct C-H functionalization (e.g. arylation) and the direct functionalization/arylation of the
C(2)-H and C(5)-H bonds of the thiophene/furan rings has been well documented in the
2
5
literature. In the present study comprising the ε-C-H acetoxylation of the thiophene-based
biaryls 4a-m/9a-d and furan-based biaryls 7a-c selectively afforded the corresponding ε-C-H
acetoxylated products 5a-m/10a-d and 8a-c. In these cases, the corresponding bidentate directing
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8
9
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
groups, such as, PA and PyrA have effectively directed the ε-C-H acetoxylation of 4a-m/9a-d
and 7a-c and we did not obtain any of the corresponding thiophene/furan C5-acetoxylated
products as the by-products in characterizable amounts.
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 5. Plausible Mechanism for the ε-C-H Acetoxylation of 4a.
While in the literature it is debated that the C-H acetoxylation might occur via an oxidative
8,12-18
radical mechanism when PhI(OAc) is used as an oxidant.
2
We have found that the reaction
of 4b with PhI(OAc) and TEMPO still afforded the product 5b in 60% yield. This observation
2
indicated that perhaps the ε-C-H acetoxylation of substrates investigated in this work does not
proceed via the single electron transfer (SET) or free radical pathway. Then, in concurrence with
8
,12-18
the literature reports,
a plausible mechanism is proposed for the chemoselective ε-C-H
acetoxylation of a typical compound 4a involving the plausible 7-membered palladacycle 16a,
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which is formed after an initial co-ordination followed by the ε-C-H activation. Then, an
oxidative addition of 16a with PhI(OAc) followed by the reductive elimination affords the
2
products 5a/6a (Scheme 5).
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
The regioselectivity/chemoselectivity of the process comprising the Pd(II)-catalyzed
acetoxylation of ε-C-H bonds of aryl rings of 4a-m / 7a-c / 9a-d / 11a,b and the regiochemistry
of the aryl rings of structures of the compounds 5a-m, 6a-i, 8a-c, 10a-d, and 12-14 were
1
assigned based on the similarity in their H NMR spectral pattern and coupling constant
values/splitting pattern of the corresponding aryl ring that is subjected to the mono/bis ε-C-H
acetoxylation. For example, the proton NMR of the compound 5j (or 8c or 10d) revealed the
presence of two singlet peaks for the respective para protons of the aryl ring after the ε-C-H
acetoxylation of 4j (or 7c or 9d). This observation confirmed that in the substrates 4j (or 7c or
n
m
9
d), the ε-C-H bond was selectively acetoxylated over the ε-C-H bond to afford the
corresponding mono ε-C-H acetoxylation products (5a-m, 8a-c, 10a-d, 12 and 14). Similarly, the
double ε-C-H acetoxylation products 6a-i/10aA/13 were assigned based on the similarity in their
1
H NMR spectral pattern and coupling constant values/splitting pattern of the corresponding aryl
ring that is subjected to ε-C-H acetoxylation. For example, the proton NMR of the compound 6a
revealed the presence of a doublet peak for the respective para protons of the aryl ring after the
double ε-C-H acetoxylation of 4a. This observation confirmed that in the substrate 4a, both the ε-
n
m
C-H and ε-C-H bonds were selectively acetoxylated. In an another example, the proton NMR
of the compound 6c revealed the presence of a singlet peak for the respective para protons of the
aryl ring after the double ε-C-H acetoxylation of 4c. This confirmed that in the substrate 4c, both
n
m
the ε-C-H and ε-C-H bonds were selectively acetoxylated. Additionally, the proton NMR of all
the thiophene-based products 5a-m / 6a-i / 10a-d / 12-14, revealed the presence of two doublets
1
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9
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
with a coupling constant (J) value in the range of 5.2 Hz (as usually reported in the literature) for
the thiophene C4 and C5 protons respectively. This indicated that the thiophene C4 and C5-
protons are intact in the cases of the products 5a-m / 6a-i / 10a-d / 12-14. Similarly, the proton
NMR of the furan-based products 8a-c, revealed the presence of two doublets with a coupling
constant (J) value in the range of 1.8 Hz (as usually reported in the literature) for the furan C4
and C5 protons respectively. This indicated that the furan C4 and C5-protons are intact in the
cases of the products 8a-c.
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
CONCLUSION
In conclusion, we have shown our successful attempts of the Pd(II)-catalyzed, bidentate directing
2
group-aided, chemoselective acetoxylation of remote ε-C(sp )-H bond over cyclization using
heteroaryl-aryl-based biaryl systems. Notably, the chemoselective acetoxylation of ε-C-H bond
was possible in the biaryl substrate 4/7/9/11 and not in the biaryl substrate 2a. Among the
bidentate directing groups used, picolinamide (PA) and pyrazine-2-carboxamide (PyrA) have
effectively directed the ε-C-H acetoxylation than the oxalylamide (OA). Given the importance of
2
0a,21
biaryl systems in medicinal chemistry research,
the present work comprising the
functionalization of remote ε-C-H bond in biaryl systems will be a contribution towards the
enrichment of the library of biaryl systems with the functionalized heteroaryl-aryl-based biaryl
systems prepared in this work. Our efforts to remove the bidentate directing group from the
biaryl systems after the ε-C-H acetoxylation reactions using the standard reaction conditions
were not fruitful at this stage. Nevertheless, we are trying to find a suitable condition for
removing of the bidentate directing group from the C-H acetoxylated biaryl systems.
2
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EXPERIMENTAL SECTION
1
13
General: IR spectra of compounds were recorded as neat or thin films or KBr pellets. H and C
NMR spectra of all compounds were recorded in 400 and 100 MHz spectrometers, respectively,
using TMS as an internal standard. The HRMS measurements were obtained from QTOF mass
analyzer using electrospray ionization (ESI) method. Column chromatography purification was
carried out on silica gel (100–200 mesh). Reactions were conducted in anhydrous solvents under
a nitrogen atmosphere wherever required. Organic layers obtained after work up were dried
using anhydrous Na SO . Reagents were added to the reaction flask using a syringe. Thin layer
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
2
4
chromatography (TLC) analysis was performed on alumina plates and components were
visualized by observation under iodine vapour. Isolated yields of all the products (Tables 1, 2
and 4 and Schemes 3 and 4) are reported and yields were not optimized. In all the cases, after the
Pd(II)-catalyzed acetoxylation reactions, the respective crude reaction mixtures were subjected to
column chromatographic purification method. Then, the fractions were collected according to the
TLC and in all the cases we focused to isolate the corresponding acetoxylation products reported
here to the best of our effort and the column chromatographic purification of the respective crude
reaction mixtures did not give and we could not detect any of the corresponding cyclized
products in characterizable amount. The starting materials 4a-m / 7a-c / 9a-d / 11a,b used in this
6
h
work are known compounds.
General procedure for assembling the biaryl starting materials 4a-m / 7a-c / 9a-d via the
Pd(II)-promoted DG-enabled C-H arylation of the C-3 position of the corresponding 2- or
6
-(aminoalkyl)-thiophene and furfurylamine derivatives. A mixture of appropriate 2- or 3-
h
3
(aminoalkyl)-thiophene and furfurylamine carboxamides (1 equiv, 0.25 mmol), Pd(OAc) (10-30
2
mol%, 5.5-16.7 mg), AgOAc (1-2.2 equiv, 41-82 mg) or Ag CO (2.2-4 equiv, 150-273 mg) and
2
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appropriate ArI (3-4 equiv, 0.75-1 mmol) in anhydrous toluene (2.5 mL) was heated at 110 °C
for 24–72 h under a nitrogen atm. Then, the reaction mixture was concentrated in vacuum and
purification of the reaction mixture by silica gel column chromatography (EtOAc:Hexanes =
0
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40:60) gave the corresponding C3-arylated compounds 4a-m / 7a-c / 9a-d.
General procedure for obtaining the biaryl scaffolds 11a,b via the Pd(II)-promoted DG-
enabled C-H arylation of the C-3 position of the corresponding 2-(aminoalkyl)-thiophene
6
derivatives. A mixture of appropriate 2-(aminoalkyl)-thiophene oxalylamide (1 equiv, 0.25
h
mmol), Pd(OAc) (10 mol%, 5.5 mg), AgOAc (1.2-2.2 equiv, 41-82 mg) and ArI (3-4 equiv,
2
0.75-1 mmol) in anhydrous toluene (1.5 mL) was heated at 110 °C for 2-8 h under a nitrogen
atm. Then, the reaction mixture was concentrated in vacuum and purification of the reaction
mixture by silica gel column chromatography (EtOAc:Hexanes = 40:60) gave the corresponding
C3-arylated compounds 11a,b.
2
General procedure for the Pd(II)-catalyzed acetoxylation of remote ε-C(sp )-H bond of
biaryl systems 4/7/9/11. A dry RB flask (10 mL capacity) containing a mixture of an appropriate
biaryl carboxamide 4/7/9/11 (0.15 mmol), Pd(OAc) (10 mol%, 3.4 mg) and PhI(OAc) (2 equiv,
2
2
o
96.3 mg) in anhydrous toluene (2-2.5 mL) was heated at 110 C for 24 h. After this period, the
reaction mixture was cooled to rt, and concentrated in vacuum. The resulting residue was
purified by silica gel flash chromatography (EtOAc:Hexanes = 30:70) to give the corresponding
ε-C-H acetoxylated products (See the corresponding Tables/Schemes for specific entries and
conditions).
(6-Methoxythieno[3,2-c]isoquinolin-4(5H)-yl)(pyridin-2-yl)methanone (3a). The compound
3a was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
35:65) as a dark brown colored solid; Yield: 50% (24 mg); R = 0.50 (EtOAc/Hexanes = 35:65);
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o
IR (KBr): νmax 2925, 1651, 1475 and 1266 cm ; H NMR (CD CN, 400 MHz, 70 C): δ 8.59 (br.
3
s, 1H), 7.93-7.89 (m, 1H), 7.64 (d, 1H, J = 7.7 Hz), 7.50-7.47 (m, 1H), 7.36-7.20 (m, 3H), 7.08
(
d, 1H, J = 7.3 Hz), 6.95 (d, 1H, J = 8.0 Hz), 5.04 (br. s, 1H), 3.85 (s, 3H); HRMS (ESI) calcd
10
11
12
13
14
15
16
17
18
19
20
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24
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28
29
30
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45
46
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49
50
51
52
53
54
55
56
57
58
59
60
+
for C H N O S [M+H] 323.0854 found 323.0861. This compound seems to exist as amide
1
8
15
2
2
o
rotomers and we tried to record the NMR for this compound at 70 C. We did not get all the
1
peaks in C NMR and a representable C NMR spectrum even after 1200 scans and hence, the
3
13
1
3
C NMR data is not provided. However, this compound was unambiguously characterized by
the X-ray structure analysis.
-(2-(Picolinamidomethyl)thiophen-3-yl)phenyl acetate (5a). The compound 5a was obtained
2
after purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a yellow
coloured liquid; Yield: 45% (47 mg) ; R = 0.50 (EtOAc/Hexanes = 30:70); IR (CH Cl ): ν
f
2
2
max
-1
1
2
927, 1767, 1673, 1518, 1458 and 1189 cm ; H NMR (400 MHz, CDCl ): δ 8.55 (d, J = 4.6
3
Hz, 1H), 8.45 (br. s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.45-7.38 (m, 3H),
7.33 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 5.2 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 5.2 Hz,
13
1
H), 4.71 (d, J = 6.1 Hz, 2H), 2.10 (s, 3H); C NMR (100 MHz, CDCl ): δ 169.3, 164.1, 149.7,
3
148.6, 148.1, 137.7, 137.3, 135.3, 131.3, 129.5, 129.1, 129.0, 126.3, 126.3, 124.1, 122.7, 122.4,
+
6.8, 20.7; HRMS (ESI): m/z [M + Na] calcd for C H N NaO S: 375.0779; found 375.0769.
3
19
16
2
3
2-(2-(Picolinamidomethyl)thiophen-3-yl)-1,3-phenylene diacetate (6a). The compound 6a
was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
0:70) as a yellow coloured liquid; Yield: 16% (20 mg); R = 0.45 (EtOAc/Hexanes = 30:70); IR
3
f
-
1 1
(
CH Cl ): ν 2931, 1768, 1674, 1518, 1458 and 1190 cm ; H NMR (400 MHz, CDCl ): δ 8.55
2
2
max
3
(d, J = 4.78 Hz, 1H), 8.55 (br. s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.87 (td, J = 7.7 Hz, J = 1.6 Hz,
1 2
1H), 7.47-7.42 (m, 2H), 7.25 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 6.83 (d, J = 5.2 Hz,
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H), 4.62 (d, J = 6.3 Hz, 2H), 2.04 (s, 6H); C NMR (100 MHz, CDCl ): δ 169.0, 164.2, 149.9,
3
1
49.8, 148.1, 139.5, 137.3, 129.5, 129.4, 128.7, 126.2, 124.3, 124.0, 122.5, 120.4, 36.5, 20.5;
+
HRMS (ESI): m/z [M + H] calcd for C H N O S: 411.1015; found 411.1031.
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1
19
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1
2
3
4
5
6
7
8
9
0
4
-Methyl-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5b): The compound 5b
was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
0:70) as a yellow coloured liquid; Yield: 80% (311 mg); R = 0.50 (EtOAc/Hexanes = 30:70);
3
f
-1
1
IR (CH Cl ): ν 2923, 1761, 1675, 1517 and 1191 cm ; H NMR (400 MHz, CDCl ): δ 8.55-
2
2
max
3
8.53 (m, 1H), 8.45 (br. s, 1H), 8.24 (dt, J = 7.8 Hz, J = 0.9 Hz, 1H), 7.86 (td, J = 7.7 Hz, J =
1
2
1
2
1
.7 Hz, 1H), 7.45-7.42 (m, 1H), 7.25 (d, J = 5.2 Hz, 1H), 7.21 (dd, J = 8.1 Hz, J = 1.6 Hz, 1H),
1 2
7
.17 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 4.71 (d, J = 6.1 Hz,
1
3
2H), 2.39 (s, 3H), 2.09 (s, 3H); C NMR (100 MHz, CDCl ): δ 169.6, 164.1, 149.7, 148.1,
3
1
2
5
46.3, 137.5, 137.3, 136.0, 135.4, 131.8, 129.7, 129.1, 129.1, 126.2, 124.1, 122.4, 122.3, 36.8,
+
0.9, 20.7; HRMS (ESI): m/z [M + Na] calcd for C H N NaO S: 389.0936; found 389.0952.
20 18
2
3
-Methyl-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5c): The compound 5c was
obtained after purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as
a yellow coloured liquid; Yield: 47% (34 mg); R = 0.50 (EtOAc/Hexanes = 30:70); IR (CH Cl ):
f
2
2
-1
1
νmax 3055, 2923, 1766, 1675, 1517 and 1202 cm ; H NMR (400 MHz, CDCl ): δ 8.55-8.54 (m,
3
1
H), 8.44 (br. s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.86 (td, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.44 (dd,
1 2
J = 7.5 Hz, J = 4.7 Hz, 1H), 7.28-7.24 (m, 2H), 7.14 (d, J = 7.7 Hz, 1H), 6.99 (s, 1H), 6.92 (d,
1
2
13
J = 5.1 Hz, 1H), 4.71 (d, J = 6.1 Hz, 2H), 2.41 (s, 3H), 2.10 (s, 3H); C NMR (100 MHz,
CDCl ): δ 169.4, 164.1, 149.7, 148.4, 148.1, 139.5, 137.5, 137.3, 135.4, 131.0, 129.1, 127.1,
3
+
26.4, 126.2, 124.0, 123.2, 122.4, 36.8, 21.2, 20.7; HRMS (ESI): m/z [M + H] calcd for
1
C H N O S: 367.1116; found 367.1130.
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-Methyl-2-(2-(picolinamidomethyl)thiophen-3-yl)-1,3-phenylene diacetate (6c): The
compound 6c was obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes = 30:70) as a yellow coloured liquid; Yield: 25% (21 mg); R = 0.45
f
10
11
12
13
14
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-1 1
(
EtOAc/Hexanes = 30:70); IR (CH Cl ): ν 2931, 1770, 1675, 1464 and 1192 cm ; H NMR
2
2
max
(400 MHz, CDCl ): δ 8.55-8.54 (m, 2H), 8.25 (d, J = 7.8 Hz, 1H), 7.86 (td, J = 7.7 Hz, J = 1.7
3
1
2
Hz, 1H), 7.44-7.41 (m, 1H), 7.24 (d, J = 5.2 Hz, 1H), 6.92 (d, J = 0.9 Hz, 2H), 6.81 (d, J = 5.2
1
3
Hz, 1H), 4.61 (d, J = 6.3 Hz, 2H), 2.42 (s, 3H), 2.02 (s, 6H); C NMR (100 MHz, CDCl ): δ
3
169.2, 164.1, 149.8, 149.5, 148.1, 140.0, 139.3, 137.3, 129.6, 128.9, 126.2, 124.2, 122.5, 121.0,
+
20.8, 36.5, 21.3, 20.5; HRMS (ESI): m/z [M + H] calcd for C H N O S: 425.1171; found
1
22
21
2
5
4
25.1188.
5-Ethyl-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5d): The compound 5d was
obtained after purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as
a yellow coloured liquid; Yield: 24% (18 mg); R = 0.50 (EtOAc/Hexanes = 30:70); IR (CH Cl ):
f
2
2
-1
1
νmax 2969, 1769, 1676, 1518 and 1192 cm ; H NMR (400 MHz, CDCl ): δ 8.55-8.53 (m, 1H),
3
8
.44 (br. s, 1H), 8.24 (dt, J = 7.8 Hz, J = 2 Hz, 1H), 7.86 (td, J = 7.7 Hz, J = 1.7 Hz, 1H),
1 2 1 2
7.45-7.44 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 5.1 Hz, 1H), 7.17 (dd, J = 7.8 Hz, J =
1
2
1
.7 Hz, 1H), 7.0 (d, J = 1.5 Hz, 1H), 6.93 (d, J = 5.1 Hz, 1H), 4.71 (d, J = 6.1 Hz, 2H), 2.72 (q, J
13
=
7.6 Hz, 2H), 2.10 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H); C NMR (100 MHz, CDCl ): δ 169.4,
3
164.1, 149.7, 148.5, 148.1, 145.7, 137.5, 137.3, 135.4, 131.0, 129.1, 126.6, 126.2, 125.9, 124.0,
+
22.4, 121.9, 36.8, 28.4, 20.7, 15.1; HRMS (ESI): m/z [M + H] calcd for C H N O S:
1
3
5
2
1
21
2
3
81.1273; found 381.1292.
-Ethyl-2-(2-(picolinamidomethyl)thiophen-3-yl)-1,3-phenylene
diacetate
(6d):
The
compound 6d was obtained after purification by column chromatography on silica gel
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(
EtOAc:Hexanes = 30:70) as a yellow coloured liquid; Yield: 44% (38 mg); R = 0.45
f
-1
1
(EtOAc/Hexanes = 30:70); IR (CH Cl ): ν 2978, 1764, 1677, 1449 and 1200 cm ; H NMR
2
2
max
(400 MHz, CDCl ): δ 8.55-8.53 (m, 2H), 8.24 (dt, J = 7.8 Hz, J = 1.0 Hz, 1H), 7.86 (td, J =
3
1
2
1
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
7
.7 Hz, J = 1.7 Hz, 1H), 7.44-7.41 (m, 1H), 7.24 (d, J = 5.2 Hz, 1H), 6.94 (s, 2H), 6.82 (d, J =
2
5.1 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 2.73 (q, J = 7.6 Hz, 2H), 2.03 (s, 6H), 1.30 (t, J = 7.6 Hz,
1
3
3
H); C NMR (100 MHz, CDCl ): δ 169.1, 164.1, 149.8, 149.6, 148.1, 146.3, 139.3, 137.3,
3
1
29.7, 128.9, 126.2, 124.2, 122.4, 120.9, 119.7, 36.5, 28.4, 20.5, 14.7; HRMS (ESI): m/z [M +
+
H] calcd for C H N O S: 439.1328; found 439.1350.
2
3
23
2
5
5
-Isopropyl-2-(2-(picolinamidomethyl)thiophen-3-yl)-1,3-phenylene diacetate (6e): The
compound 6e was obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes = 30:70) as a yellow coloured liquid; Yield: 55% (52 mg); R = 0.45
f
-1
1
(EtOAc/Hexanes = 30:70); IR (CH Cl ): ν 2964, 1770, 1676, 1518 and 1192 cm ; H NMR
2
2
max
(400 MHz, CDCl ): δ 8.56-8.53 (m, 2H), 8.24 (dt, J = 7.8 Hz, J = 0.9 Hz, 1H), 7.86 (td, J =
3
1
2
1
7
.7 Hz, J = 1.7 Hz, 1H), 7.44-7.41 (m, 1H), 7.24 (d, J = 5.2 Hz, 1H), 6.96 (s, 2H), 6.82 (d, J =
2
5
.2 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 3.00-2.93 (m, 1H), 2.03 (s, 6H), 1.30 (d, J = 6.9 Hz, 6H);
1
3
C NMR (100 MHz, CDCl ): δ 169.1, 164.2, 151.0, 149.8, 149.6, 148.1, 139.3, 137.3, 129.8,
3
1
28.9, 126.2, 124.2, 122.5, 121.0, 118.4, 36.6, 33.8, 23.6, 20.5; HRMS (ESI): m/z [M +
+
Na] calcd for C H N NaO S: 475.1304; found 475.1290.
2
4
24
2
5
5-Methoxy-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5f): The compound 5f
was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
3
0:70) as a yellow coloured liquid; Yield: 35% (21 mg); R = 0.50 (EtOAc/Hexanes = 30:70); IR
f
-1
1
(CH Cl ): ν 2937, 1769, 1672, 1518 and 1191 cm ; H NMR (400 MHz, CDCl ): δ 8.54 (d, J
2
2
max
3
=
4.8 Hz, 1H), 8.43 (br. s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 5.2 Hz, 1H), 6.90-6.87 (m,
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H), 6.72 (d, J = 2.4 Hz, 1H), 4.70 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H), 2.09 (s, 3H); C NMR (100
1
MHz, CDCl ): δ 169.2, 164.1, 160.1, 149.7, 149.4, 148.1, 137.4, 137.3, 135.2, 131.7, 129.2,
3
+
26.2, 124.0, 122.4, 121.6, 112.1, 108.4, 55.6, 36.8, 20.7; HRMS (ESI): m/z [M + Na] calcd for
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
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44
45
46
47
48
49
50
51
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53
54
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59
60
C H N NaO S: 405.0885; found 405.0870.
18
20
2
4
5-Methoxy-2-(2-(picolinamidomethyl)thiophen-3-yl)-1,3-phenylene diacetate (6f): The
compound 6f was obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes = 30:70) as a yellow coloured liquid; Yield: 27% (18 mg); R = 0.45
f
-1
1
(EtOAc/Hexanes = 30:70); IR (CH Cl ): ν 2935, 1770, 1674, 1518 and 1190 cm ; H NMR
2
2
max
(
400 MHz, CDCl ): δ 8.56-8.54 (m, 2H), 8.26-8.24 (m, 1H), 7.86 (td, J = 7.7 Hz, J = 1.7 Hz,
3
1
2
1H), 7.45-7.41 (m, 1H), 7.23 (d, J = 5.2 Hz, 1H), 6.81 (d, J = 5.2 Hz, 1H), 6.66 (s, 2H), 4.62 (d,
1
3
J = 6.3 Hz, 2H), 3.84 (s, 3H), 2.02 (s, 6H); C NMR (100 MHz, CDCl ): δ 168.9, 164.2, 160.3,
3
1
2
5
50.4, 149.8, 148.1, 139.4, 137.3, 129.5, 129.1, 126.2, 124.1, 122.5, 116.0, 106.6, 55.7, 36.5,
+
0.5; HRMS (ESI): m/z [M + H] calcd for C H N O S: 441.1120; found 441.1142.
22 21
2
6
-Acetyl-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5g) and 5-acetyl-2-(2-
(picolinamidomethyl)thiophen-3-yl)-1,3-phenylene diacetate (6g): The compounds 5g/6g
were isolated as a mixture and yellow coloured liquid (41 mg, 50%). The column
chromatographic purification on silica gel (EtOAc:Hexanes = 35:65), gave the compound 5g/6g
as an inseparable mixture because both compounds have the same R values (0.50
f
(EtOAc/Hexanes = 35:65); repetitive column chromatographic purification of the mixture of
compounds 5g/6g failed to give the corresponding compounds pure compounds. Because of
mixture of compounds with similar structure, it was difficult to assign the number of protons;
hence, we could not provide the proton and carbon NMR data, however, copies of proton/carbon
spectra were included in the NMR spectra section. The NMR spectra of the pure sample
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containing the mixture of compounds 5g/6g showed the signature peaks corresponding to 5g/6g.
Further, the HRMS analysis of the pure sample containing the mixture of compounds 5g/6g
+
confirmed the presence of 5g and 6g in the mixture. 5g. HRMS (ESI): m/z [M + Na] calcd for
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
+
C H N NaO S: 417.0885; found 417.0908. 6g. HRMS (ESI): m/z [M + Na] calcd for
21
18
2
4
C H N NaO S: 475.0940; found 475.0922.
2
23
20
6
5-Chloro-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5h): The compound 5h
was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
30:70) as a yellow coloured liquid; Yield: 36% (41 mg); R = 0.50 (EtOAc/Hexanes = 30:70); IR
f
-1
1
(
CH Cl ): ν 2928, 1770, 1674, 1518 and 1188 cm ; H NMR (400 MHz, CDCl ): δ 8.55-8.53
2
2
max
3
(
m, 1H), 8.43 (s, 1H), 8.23 (dt, J = 7.8 Hz, J = 1.1 Hz, 1H), 7.87 (td, J = 7.7 Hz, J = 1.7 Hz,
2
1
2
1
1H), 7.46-7.43 (m, 1H), 7.32-7.31 (m, 2H), 7.27 (d, J = 5.2 Hz, 1H), 7.20 (dd, J = 1.6 Hz, J =
2
1
13
.7 Hz, 1H), 6.90 (d, J = 5.2 Hz, 1H), 4.69 (d, J = 6.1 Hz, 2H), 2.10 (s, 3H); C NMR (100
0
MHz, CDCl ): δ 168.9, 164.1, 149.6, 149.0, 148.1, 138.1, 137.4, 134.2, 134.1, 132.0, 128.8,
3
+
28.2, 126.6, 126.3, 124.4, 123.3, 122.4, 36.8, 20.6; HRMS (ESI): m/z [M + Na] calcd for
1
C H ClN NaO S: 409.0390; found 409.0388.
3
19
15
2
5-Chloro-2-(2-(picolinamidomethyl)thiophen-3-yl)-1,3-phenylene diacetate (6h): The
compound 6h was obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes = 30:70) as a yellow coloured liquid; Yield: 19% (25 mg); R = 0.45
f
-
1
1
(EtOAc/Hexanes = 30:70); IR (CH Cl ): ν 2931, 1773, 1676, 1518 and 1184 cm ; H NMR
2
2
max
(
400 MHz, CDCl ): δ 8.55-8.54 (m, 2H), 8.24 (dt, J = 7.8 Hz, J = 1.1 Hz, 1H), 7.87 (td, J =
3
1
2
1
7.7 Hz, J = 1.7 Hz, 1H), 7.26 (d, J = 5.2 Hz, 1H), 7.13 (s, 2H), 6.80 (d, J = 5.2 Hz, 1H), 4.61 (d,
2
1
3
J = 6.3 Hz, 2H), 2.03 (s, 6H); C NMR (100 MHz, CDCl ): δ 168.6, 164.2, 150.1, 149.7, 148.1,
3
2
8
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2
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7
8
9
1
39.8, 137.3, 134.4, 128.6, 128.5, 126.3, 124.6, 122.9, 122.5, 121.1, 36.5, 20.4; HRMS (ESI):
+
m/z [M + H] calcd for C H ClN O S: 445.0625; found 445.0646.
21 18
2
5
5
-Bromo-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5i): The compound 5i was
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
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53
54
55
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60
obtained after purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as
a yellow coloured liquid; Yield: 37% (38 mg); R = 0.50 (EtOAc/Hexanes = 30:70); IR (CH Cl ):
2
f
2
-
1
1
νmax 2923, 1768, 1672, 1516 and 1011 cm ; H NMR (400 MHz, CDCl ): δ 8.55-8.53 (m, 1H),
3
8.43 (br. s, 1H), 8.23 (dt, J = 7.8 Hz, J = 1.1 Hz, 1H), 7.87 (td, J = 7.7 Hz, J = 1.7 Hz, 1H),
1 2 1 2
7.47-7.42 (m, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.28-7.25 (m, 2H), 6.90 (d, J = 5.2 Hz, 1H), 4.69 (d,
13
J = 6.1 Hz, 2H), 2.09 (s, 3H); C NMR (100 MHz, CDCl ): δ 168.8, 164.1, 149.6, 149.0, 148.1,
3
138.1, 137.4, 134.1, 132.3, 129.5, 128.8, 128.7, 126.3, 126.1, 124.4, 122.4, 121.8, 36.8, 20.6;
+
HRMS (ESI): m/z [M + H] calcd for C H BrN O S: 431.0065; found 431.0051.
1
9
16
2
3
5-Bromo-2-(2-(picolinamidomethyl)thiophen-3-yl)-1,3-phenylene diacetate (6i): The
compound 6i was obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes = 30:70) as a yellow coloured liquid; Yield: 25% (29 mg); R = 0.45
f
-1
1
(
EtOAc/Hexanes = 30:70); IR (CH Cl ): ν 1772, 1674, 1518, and 1183 cm ; H NMR (400
2
2
max
MHz, CDCl ): δ 8.55-8.54 (m, 2H), 8.24 (dt, J = 7.8 Hz, J = 1.0 Hz, 1H), 7.87 (td, J = 7.7 Hz,
3
1
2
1
J2 = 1.7 Hz, 1H), 7.46-7.42 (m, 1H), 7.28 (s, 2H) 7.25 (d, J = 5.2 Hz, 1H), 6.79 (d, J = 5.2 Hz,
1
3
1
H), 4.60 (d, J = 6.1 Hz, 2H), 2.03 (s, 6H); C NMR (100 MHz, CDCl ): δ 168.6, 164.2, 150.2,
3
149.7, 148.1, 139.8, 137.3, 128.6, 128.5, 126.3, 124.6, 124.0, 123.5, 122.5, 121.6, 36.5, 20.4;
+
HRMS (ESI): m/z [M + Na] calcd for C H BrN NaO S: 510.9939; found 510.9930.
2
1
17
2
5
4
,5-Dimethyl-2-(2-(picolinamidomethyl)thiophen-3-yl)phenyl acetate (5j): The compound 5j
was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
0:70) as a yellow coloured liquid; Yield: 60% (41 mg); R = 0.50 (EtOAc/Hexanes = 30:70); IR
3
f
2
9
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