4-Amino-2,1,3-benzothiadiazole as a Removable Bidentate Directing Group for the Pd(II)-Catalyzed Arylation/Oxygenation of sp2/sp3 β-C-H Bonds of Carboxamides

Article abstract of DOI:10.1021/acs.joc.6b01831

In this paper, we report 4-amino-2,1,3-benzothiadiazole (ABTD) as a new bidentate directing group for the Pd(II)-catalyzed sp²/sp³ C-H activation/functionalization of various aliphatic/alicyclic/aromatic carboxamide systems. The Pd(II)-catalyzed, ABTD-directed sp³ C-H arylation/acetoxylation of aliphatic- and alicyclic carboxamides afforded the corresponding β-C-H arylated/acetoxylated carboxamides. The Pd(II)-catalyzed, ABTD-directed sp³ C-H arylation of cyclobutanecarboxamide with different aryl iodides afforded the corresponding bis β-C-H arylated cyclobutanecarboxamides having all-cis stereochemistry with a high degree of stereocontrol. The Pd(II)-catalyzed, ABTD-directed arylation/benzylation/acetoxylation/alkoxylation of ortho C(sp²)-H bonds of various benzamides afforded the corresponding ortho C-H arylated/benzylated/oxygenated benzamides. The observed regio- and stereoselectivity in the Pd(II)-catalyzed, ABTD-directed arylation/benzylation of aliphatic/alicyclic carboxamides and benzamides were ascertained from the X-ray structures of representative compounds 5g (bis-β-C(sp³)-H arylated cyclobutanecarboxamide) and 7f (ortho C(sp²)-H arylated benzamide). A brief description on the efficiency, scope, and limitations of bidentate directing group ABTD is reported.

Full text of DOI:10.1021/acs.joc.6b01831

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Article
4-Amino-2,1,3-Benzothiadiazole (ABTD) as a Removable
Bidentate Directing Group for the Pd(II)-Catalyzed Arylation/
Oxygenation of sp2/sp3 beta-C–H Bonds of Carboxamides
Chennakesava Reddy, Narendra Bisht, Ramarao Parella, and Srinivasarao Arulananda Babu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01831 • Publication Date (Web): 17 Nov 2016
Downloaded from http://pubs.acs.org on November 17, 2016
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4ꢀAminoꢀ2,1,3ꢀBenzothiadiazole (ABTD) as a Removable Bidentate Directing Group for
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the Pd(II)ꢀCatalyzed Arylation/Oxygenation of sp /sp βꢀC–H Bonds of Carboxamides
#
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Chennakesava Reddy, Narendra Bisht, Ramarao Parella, and Srinivasarao Arulananda
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Babu*
Department of Chemical Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab
140306, India
sababu@iisermohali.ac.in
#
Authors contributed equally.
ABSTRACT
In this paper, we report 4ꢀaminoꢀ2,1,3ꢀbenzothiadiazole (ABTD) as a new bidentate
2
3
directing group (BDG) for the Pd(II)ꢀcatalyzed sp /sp C–H activation/functionalization of
various aliphatic/alicyclic/aromatic carboxamide systems. The Pd(II)ꢀcatalyzed, ABTDꢀ
3
directed sp CꢀH arylation/acetoxylation of aliphaticꢀ and alicyclic carboxamides afforded the
corresponding βꢀCꢀH arylated/acetoxylated carboxamides. The Pd(II)ꢀcatalyzed, ABTDꢀ
3
directed sp CꢀH arylation of cyclobutanecarboxamide with different aryl iodides afforded the
corresponding bis βꢀC–H arylated cyclobutanecarboxamides having all cis stereochemistry
with
a
high degree of stereocontrol. The Pd(II)ꢀcatalyzed, ABTDꢀdirected
2
arylation/benzylation/acetoxylation/alkoxylation of ortho C(sp )–H bonds of various
benzamides afforded the corresponding
ortho CꢀH arylated/benzylated/oxygenated
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benzamides. The observed regioꢀ and stereoselectivity in the Pd(II)ꢀcatalyzed, ABTDꢀ
directed arylation/benzylation of aliphatic/alicyclic carboxamides and benzamides were
3
ascertained from the Xꢀray structures of representative compounds 5g (bis βꢀC(sp )–H
2
arylated cyclobutanecarboxamide) and 7f (ortho C(sp )–H arylated benzamide). A brief
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description on the efficiency, scope and limitations of bidentate directing group 4ꢀaminoꢀ
2,1,3ꢀbenzothiadiazole (ABTD) was reported.
INTRODUCTION
The transition metalꢀcatalyzed CꢀH activation followed by CꢀC bond forming process
1
ꢀ4
has emerged as one of the pivotal organic transformations. There exist numerous reports
dealing on the transition metalꢀcatalyzed, directing groupꢀaided or directing groupꢀfree C–H
1ꢀ4
2
activation/functionalization reactions. The functionalization of sp CꢀH bonds of organic
3
3
molecules, sp C–H bonds of benzylic systems, αꢀC(sp )ꢀH bonds next to a heteroatom (e.g.,
3
THF and pyrrolidine systems) and diazocarbonyl compoundꢀbased C(sp )ꢀH insertion
1
ꢀ4
reactions have been extensively studied.
Apart from these transformations, the
3
functionalization of unactivated sp C–H bonds of organic molecules was considered as an
arduous task in the past decades. However, in recent years various research groups have
3
shown that the functionalization of unactivated sp C–H bonds of organic molecules is an
1
ꢀ4
achievable task.
5
,6
The first paper by Daugulis dealing on the Pd(II)ꢀcatalyzed, bidentate directing
3
group 8ꢀaminoquinoline (DGꢀa)ꢀassisted arylation of unactivated sp C(β)–H bonds of
aliphatic and aromatic carboxamides has given an inspiring direction to the research area
3
1ꢀ4,7,8
pertaining to the sp C–H activation/functionalization reactions (Figure 1).
Concurrently,
9
a
Yu’s work dealing on the Pd(II)ꢀcatalyzed, monodentate directing group 2,3,5,6ꢀtetrafluoroꢀ
3
4
ꢀ(trifluoromethyl)aniline (DGꢀb)ꢀassisted functionalization of unactivated sp C–H bonds of
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organic molecules has provided a motivation to the synthetic organic chemists (Figure 1).
Consequently, while the directing groupꢀfree C–H activation/functionalization transformation
still remains as a challenging and less explored area; the directing groupꢀassisted C–H
activation/functionalization tactic has emerged as a dependable method to functionalize
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ꢀ4
organic molecules with high degree of siteꢀselectivity.
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Figure 1. Bidentate directing groups explored for sp /sp C–H activation/functionalization.
1ꢀ4,7,8
The bidentate directing group 8ꢀaminoquinoline (DGꢀa, Figure 1)
was found to
be efficient for the functionalization (e.g., arylation, alkylation, acetoxylation) of βꢀCꢀH
bonds of carboxylic acid and amino acid systems (substrate type 1, Figure 1). However,
considering the importance of the C–H activation/functionalization in organic synthesis and
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to pronounce the availability of other optional bidentate directing groups,
few other
auxiliaries were also identified for performing the C–H activation/functionalization of
carboxylic acid derivatives and amine systems (substrate type 2, Figure 1).
With regard to the substrate type 1, several research groups showed the
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functionalization of sp /sp C–H bonds of carboxylic acid derivatives using the directing
1
ꢀ4
5,6
6,10a
group DGꢀa (Figure 1). Apart from the popular directing group DGꢀa, the DGꢀc
was
found to be moderately efficient directing group for the CꢀH activation followed by CꢀC bond
1
ꢀ4
formation and the DGꢀc was not popularly used for the CꢀH oxygenation reactions. Yu’s
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,10a
group extensively exploited the DGꢀb
for the CꢀC bond formation and to the best of our
1
ꢀ4
knowledge, the DGꢀb was not popularly used for the CꢀH oxygenation reactions. The DGꢀ
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6,11a,b
d and DGꢀe
were less commonly used and it appears that the DGꢀd and DGꢀe are
relatively less efficient directing groups for the functionalization of βꢀCꢀH bonds of
carboxylic acid derivatives (substrate type 1, Figure 1).
12a
Chen et al. used the modified quinolineꢀtype bidentate directing group DGꢀf for the
3
13a
γꢀC(sp )ꢀH amination reactions. Shi used the DGꢀg for performing the palladiumꢀcatalyzed
13b
substitution/cyclization reactions of amine systems. Ackermann also used the DGꢀg for
performing the Feꢀcatalyzed, Grignard reagentꢀemployed arylation of βꢀCꢀH bonds of
1
2f,g
carboxylic acid derivatives. Recently, Niu and Song
used the pyridine Nꢀoxideꢀtype
3
directing group Dgꢀh for the Pd(II)ꢀcatalyzed arylation of βꢀC(sp )ꢀH bonds of aliphatic
12e
carboxylic acids. Concurrently, Zeng and Lu also used the pyridine Nꢀoxideꢀtype directing
3
group Dgꢀh for the Pd(II)ꢀcatalyzed selective arylation of βꢀC(sp )ꢀH bond of propionic acid
system.
11c
Recently, Chatani described the Pd(II)ꢀcatalyzed functionalization of ortho CꢀH
bonds in Nꢀbenzoyl αꢀamino ester derivatives, in which both the NHꢀamido and the ester
carbonyl groups of the DGꢀi reported to play a role in the CꢀH activation/functionalization
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2c
13c
formation process. Shi and Sahoo have respectively introduced the directing groups Dgꢀj
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and Dgꢀk for the oxidation/oxygenation of βꢀC(sp )ꢀH bonds of aliphatic carboxylic acids.
Furthermore, Shi revealed the utility of the directing group Dgꢀj for the Pd(II)ꢀcatalyzed
3
11e,f
selective arylation of sp CꢀH bonds of alanine and aliphatic carboxylic acid systems.
In
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general, the Pd(II)ꢀcatalyzed, bidentate directing groupꢀassisted
CꢀH
1
ꢀ4
arylation/functionalization reactions have been performed using silver salts as additives. It
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is to be noted that the Pd(II)ꢀcatalyzed, the Dgꢀjꢀdirected arylations of methylene sp CꢀH
1
1f
bonds aliphatic carboxylic acid systems were performed without using any silver salts.
With regard to the substrate type 2, several research groups showed the
2
3
functionalization of sp /sp C–H bonds of various amine systems using the bidentate directing
4
f,6,10a
10b
8a
group DGꢀm (picolinamide directing group, Figure 1).
Additionally, Baran and Shi
3
showed the utility of the directing group DGꢀm for the arylation of sp CꢀH bonds of
12b
amine/carboxylic acid systems. Carretero used the Nꢀ(2ꢀpyridyl)sulfonyl directing group
3
DGꢀl for the Pd(II)ꢀcatalyzed functionalization of sp CꢀH bonds of amino acid derivatives.
13d
Huang and Zhao used the oxalylamide directing group DGꢀn for the functionalization of Cꢀ
11d
H bonds of amine systems. Recently, Shi
revealed an oxazolineꢀcarboxylate directing
2
3
12d
group DGꢀo for the arylation of sp /sp CꢀH bonds of various amine systems. Ma reported
2ꢀmethoxyiminoacetyl directing group DGꢀp (MIA) for the Pd(II)ꢀcatalyzed functionalization
3
of sp CꢀH bonds of amine systems.
The reported bidentate directing groups were efficient and developed with an aim to
achieve high degree of siteꢀselectivity in the Pd(II)ꢀcatalyzed CꢀH activationꢀbased CꢀC/CꢀO
1ꢀ4,14ꢀ16
bond forming reactions involving the substrate type 1.
Nevertheless, some of the
seminal bidentate directing groups (e.g., DGꢀg, DGꢀh, DGꢀj and DGꢀk) are not
commercially available and need to be preꢀassembled by involving few synthetic
12c,eꢀg,13aꢀc
5,6
steps/transformations.
Additionally, Daugulis et al. revealed that the attempts on
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the Pd(II)ꢀcatalyzed CꢀH arylation of methyl group of propionic acid with the help of the
typically used bidentate directing groups (e.g., DGꢀa and DGꢀc) afforded the corresponding
mono arylation product (3ꢀarylated propionamide) and bis arylation product (3,3ꢀbis arylated
propionamide).
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Given that the research field pertaining to the bidentate directing groupꢀdirected siteꢀ
3
selective sp C–H activation/functionalization reactions is still emerging; the scope and
limitations of the bidentate directing groups yet to be clearly scrutinized. Furthermore, given
the importance of the C–H activation/functionalization tactics in organic synthesis, advancing
the research area pertaining to the directing groupꢀassisted C–H activation/functionalization
reactions by developing new directing groups might (a) ensure the availability of
commercially available other optional bidentate directing groups, and (b) enhance the
understanding with regard to the scope and limitations of bidentate directing groups while
executing the siteꢀselective CꢀH functionalization of suitable substrates. Hence, with an
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aspiration to bolster the sp /sp C–H activation/functionalization method,
we envisaged to
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report 4ꢀaminoꢀ2,1,3ꢀbenzothiadiazole (ABTD) as a new bidentate directing group for the
2
3
Pd(II)ꢀcatalyzed,
sp /sp
C–H
activation/functionalization
of
various
aliphatic/alicyclic/aromatic carboxamide systems. The results from our investigation on the
3
Pd(II)ꢀcatalyzed, ABTDꢀdirected arylation/acetoxylation of βꢀC(sp )ꢀH bonds of
aliphatic/alicyclic carboxamides and arylation/benzylation/acetoxylation/methoxylation of
2
ortho C(sp )ꢀH bonds of various benzamides are reported.
RESULSTS AND DISCUSSION
To explore 4ꢀaminoꢀ2,1,3ꢀbenzothiadiazole (ABTD) as a directing group for the
Pd(II)ꢀcatalyzed C–H activation and direct arylation of carboxamides, initially we assembled
carboxamide 1a from butanoyl chloride and ABTD. We then carried out the optimization
3
reactions using carboxamide 1a and Table 1 shows the results for the Pd(II)ꢀcatalyzed sp Cꢀ
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H arylation of 1a with 2a in the presence of various palladium catalysts and additives in
different solvents. The reaction of a mixture of 1a (1 equiv), PhI (2a, 4 equiv), Pd(OAc)
2
o
catalyst (5 or 10 mol%) and AgOAc additive in toluene at 110 C afforded the methylene
C(β)–H arylated product 3a in 85ꢀ95% yields (entries 1 and 2, Table 1). The Pd(II)ꢀcatalyzed
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sp C–H arylation of 1a with 2a using additional additives, such as Ag CO or KOAc
2
3
furnished the product 3a in 75 and <10% yields, respectively (entries 3 and 4, Table 1). The
usage of PhI(OAc) as an additive failed to give the product 3a (entry 5, Table 1). The
arylation of 1a with 2a in the presence of other palladium catalysts, such as, PdCl or
2
2
Pd(TFA) furnished the product 3a in 84 and 40% yields, respectively (entries 6 and 7, Table
2
3
1). The Pd(II)ꢀcatalyzed sp C–H arylation of 1a with 2a in other solvents, such as, tertꢀ
amylOH or 1,2ꢀDCE furnished the product 3a in 93 and 92% yields, respectively (entries 8
3
and 9, Table 1). The sp C–H arylation of 1a with 2 or 3 equiv of 2a afforded the product 3a
in 70 and 87% yields, respectively (entries 10 and 11, Table 1).
We then examined the generality of the Pd(II)ꢀcatalyzed, ABTDꢀdirected arylation of
methylene C(β)–H bonds of various aliphatic carboxamides (Table 2). Using the optimized
2
reaction conditions, we carried out the Pd(OAc) /AgOAc catalytic systemꢀbased, ABTDꢀ
directed C–H arylation of 1a with different aryl iodides that possessed electronꢀdonating or
electronꢀwithdrawing groups at the para/meta position of the aryl ring in the corresponding
aryl iodides. Accordingly, a variety of corresponding βꢀCꢀH arylated butanamides 3aꢀg were
obtained in 52ꢀ97% yields (Table 2). The βꢀCꢀH arylated butanamides 3h (63%) and 3i
(
86%) were obtained from the Pd(II)ꢀcatalyzed, ABTDꢀdirected arylation of methylene C(β)–
H bond of 1a with the corresponding disubstituted aryl iodides (Table 2).
Next, we performed the Pd(OAc) /AgOAc catalytic systemꢀbased, ABTDꢀdirected
2
arylation of methylene C(β)–H bonds of various aliphatic carboxamides 1bꢀf with different
aryl iodides, which furnished the corresponding βꢀCꢀH arylated carboxamides 3jꢀn in 62ꢀ90%
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yields (Table 2). Then, we performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected arylations of
methylene C(β)–H bonds of substrates 1a,d,g with a heteroaryl iodide (e.g., 2ꢀfluoroꢀ5ꢀ
iodopyridine), which afforded the corresponding βꢀCꢀH arylated carboxamides 3oꢀq in 57ꢀ
90% yields (Table 2). Subsequently, we performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected C–H
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arylation of mono βꢀarylated propionamide 1h with 1ꢀiodoꢀ4ꢀmethoxybenzene and 4ꢀiodoꢀ
1,2ꢀdimethylbenzene to afford the corresponding β′ꢀaryl βꢀaryl propionamides 3r,s in 52 and
53% yields, respectively (Table 2). We also performed the diastereoselective Pd(II)ꢀcatalyzed
βꢀCꢀH arylation reactions using branched carboxamides 1aaꢀ1ac to obtain the corresponding
βꢀCꢀH arylated products 3aaꢀ3ac, however, these reactions were not fruitful.
Table 1. Optimization of Reactions. Pd(II)ꢀCatalyzed, ABTDꢀDirected Direct Arylation
of Methylene C(β)–H Bond of 1a
a
b
2
Equiv of 2a was used. 3 Equiv of 2a was used.
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Table 2. Scope and Generality of the Pd(II)ꢀCatalyzed, ABTDꢀDirected Direct Arylation
a,14d
of Methylene C(β)–H Bonds of Various Aliphatic Carboxamides
10
11
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1
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2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
3
3
3
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6
a
The βꢀCꢀH arylated carboxamides 3aꢀs were obtained from their respective starting
b
materials 1aꢀi. The reactions were carried out using the corresponding starting materials 1aa
and 1ab and products 3aa and 3ab could not be isolated as the corresponding reactions gave
c
a complex mixture. The reaction was performed using the starting material 1ac and
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
negligible amount of product formation was observed.
Scheme 1. Pd(II)ꢀCatalyzed, ABTDꢀDirected βꢀCꢀH Arylation of 1i and
βꢀCꢀH Acetoxylation of 1i,h.
a
The reaction was performed using 0.15 mmol of 1ꢀiodoꢀ3ꢀnitrobenzene for 18 h.
We also performed the Pd(OAc)
arylation of methyl C(β)–H bond of propionamide 1i with 1ꢀiodoꢀ3ꢀnitrobenzene and 1ꢀiodoꢀ
ꢀnitrobenzene, which furnished the corresponding mono arylated propionamides 3t,u in 54ꢀ
2
/AgOAc catalytic systemꢀbased, ABTDꢀdirected
4
56% yield, (Scheme 1). In these reactions the corresponding bis arylated propionamides were
not obtained in characterizable amounts. Furthermore, we wished to attempt the acetoxylation
3
of sp C–H bond of aliphatic carboxamide system with the help of the ABTD bidentate
directing group. In this regard, we performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected CꢀH
2
acetoxylation of propionamides 1i,h with PhI(OAc) , which gave the corresponding βꢀC–H
acetoxylated propionamides 3v,w in 68 and 55% yields, respectively (Scheme 1).
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Table 3. Diastereoselective Pd(II)ꢀCatalyzed, ABTDꢀDirected Arylation of Methylene
C(β)–H Bonds of Cyclopropane and Cyclobutane Systems
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
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2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
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4
4
4
4
4
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5
5
5
5
5
5
5
5
6
Next, we were interested to explore the diastereoselective Pd(II)ꢀcatalyzed CꢀH
arylation of alicyclic carboxamides with the help of the ABTD bidentate directing group. In
this regard, initially we performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected C–H arylation of
cyclopropanecarboxamide 1j with 1ꢀiodoꢀ3ꢀnitrobenzene. This reaction gave the mono βꢀCꢀH
arylated product 4a in 27% yield (cis isomer) and bis βꢀCꢀH arylated product 4aA in 14%
yield (all cis isomer, Table 3). Similarly, the Pd(II)ꢀcatalyzed, ABTDꢀdirected C–H arylation
of cyclopropanecarboxamide 1j with 4ꢀiodoacetophenone furnished the corresponding mono
βꢀCꢀH arylated product 4b in 28% yield (cis isomer) and bis βꢀCꢀH arylated product 4bB in
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
<
10% yield (all cis isomer, Table 3). Then, we envisaged to attempt the diastereoselective
Pd(II)ꢀcatalyzed C–H arylation/alkylation of cyclobutanecarboxamide 1k with the help of the
ABTD bidentate directing group. Initially, we performed the Pd(II)ꢀcatalyzed, ABTDꢀ
directed C–H alkylation of cyclobutanecarboxamide 1k with ethyl iodoacetate, which
furnished the substituted cyclobutanecarboxamide 4c in 44% yield (Table 3). Next, we
performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected C–H arylation of 1k with 1ꢀiodoꢀ3ꢀ
nitrobenzene, 3ꢀfluoroꢀ1ꢀiodobenzene and 1ꢀiodoꢀ2ꢀnitrobenzene. These reactions afforded
the corresponding bis βꢀC–H arylated cyclobutanecarboxamides 5aꢀc having the all cis
stereochemistry in 56ꢀ95% yields (Table 3). Similarly, the Pd(II)ꢀcatalyzed, ABTDꢀdirected
C–H arylation of 1k with various aryl iodides that possessed electronꢀdonating or electronꢀ
withdrawing groups at the para position of the aryl ring in the corresponding aryl iodides,
successfully furnished the corresponding bis βꢀC–H arylated cyclobutanecarboxamides 5dꢀi
having the all cis stereochemistry in 79ꢀ98% yields (Table 3).
Furthermore, the Pd(II)ꢀcatalyzed, ABTDꢀdirected C–H arylation of
cyclobutanecarboxamide 1k with disubstituted arylꢀ and heteroaryl iodides underwent
smoothly to afford the corresponding bis βꢀC–H arylated cyclobutanecarboxamides 5jꢀm
having all cis stereochemistry in 58ꢀ98% yields (Table 3). It is worth to mention that the CꢀH
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arylation of 1k selectively occurred at both the βꢀpositions of cyclobutanecarboxamide 1k
with the help of the ABTD bidentate directing group and the corresponding bis βꢀC–H
arylated/alkylated carboxamides 4/5 were obtained with high diastereoselectivity. Notably,
the double βꢀC–H arylations of cyclobutanecarboxamide 1k have led to the assembling of
various trisubstituted cyclobutanecarboxamide scaffolds having the all cis stereochemistry,
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
1
0a,c
which are analogous to the naturally occurring bioactive cyclobutanes.
stereochemistry and structure of the cyclopropanes 4a, 4b, 4aA and 4bB and cyclobutanes
aꢀm were assigned based on the similarity of the NMR spectral pattern of these compounds
with the previous works dealing on the bidentate directing groupꢀdirected diastereoselective
The observed cis
5
1
5a,e,f
10a,14c
cis CꢀH arylation of cyclopropanecarboxamides
and cyclobutanecarboxamides
systems, respectively. Additionally, the Xꢀray structure analysis of 5g (see the Supporting
Information for the Xꢀray structure of 5g) clearly revealed that the compound 5g has the cis
10a,14c
stereochemistry in accordance with the previous reports.
The stereochemistry of the
16d,e
compound 4c
was assigned based on the stereochemistry of compounds 5aꢀm.
3
Having explored the Pd(II)ꢀcatalyzed direct arylation of sp C(β)–H bonds of aliphatic
and alicyclic carboxamides using the ABTD directing group, next we wished to perform the
2
Pd(II)ꢀcatalyzed direct arylation of ortho C(sp )–H bonds of aromatic carboxamides using the
ABTD bidentate directing group. In this regard, we assembled benzamides 6a and 8a from
their corresponding benzoyl chlorides and ABTD. We then performed the optimization
reactions using benzamides 6a and 8a. Table 4 shows the results for the ABTDꢀdirected
2
2
mono arylation of ortho C(sp )–H bond of benzamide 6a and bis arylation of ortho C(sp )–H
bonds of benzamide 8a in the presence of various palladium catalysts and additives in
different solvents.
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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
Table 4. Optimization Reactions. Pd(II)ꢀCatalyzed, ABTDꢀDirected Arylation of Ortho
2
aꢀc
C(sp )–H Bonds of Benzamides 6a/8a
BTD
BTD
BTD
BTD
BTD
HN
O
HN
O
HN
O
BTD
HN
O
Ar
I
Et
HN
O
Ar
I
N
N
(
0.32 mmol)
Me
Ar
H
H
(
0.4 mmol)
Ar
S
Ar
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
Me
H
+
o
o
8
5-110 C, 24 h
85-110 C, 24 h
6
a
7a
Me
Me
Me
8
(
a
(0.08 mmol)
10a
9
a
0.1 mmol)
Ar = C H -(p)-Et
6
4
entry 6a (or) 8a
1 equiv)
PdL
2
solvent
(3 mL)
additive
t
7a (or) 9a:
yield (%)
7a: 0
o
(
(10 mol%)
nil
(2.2 equiv)
( C)
1
2
6a
8a
6a
8a
6a
8a
6a
8a
6a
8a
6a
8a
6a
8a
6a
8a
6a
8a
6a
8a
6a
8a
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
AgOAc
110
9a: 0
3
7a: 70
9a: 75
7a: 24
9a: 50
7a: <5
9a: <5
7a: <5
9a: <5
7a: 0
Pd(OAc)
PdCl2
2
AgOAc
AgOAc
AgOAc
AgOAc
110
110
110
110
110
110
110
100
110
85
4
5
6
7
Pd(PPh
3
)
4
2
2
8
9
Pd(TFA)
Pd(OAc)
10
1
1
2
2 3
Ag CO
1
9a: 0
13
7a: 0
Pd(OAc)2
PhI(OAc)2
KOAc
1
4
5
9a: 0
1
7a: <5
9a: <5
7a: 30
9a: <5
7a: 0
Pd(OAc)
Pd(OAc)
2
2
16
1
7
8
1,4ꢀdioxane AgOAc
1
19
t
Pd(OAc)2
amylOH
BuOH
AgOAc
AgOAc
2
0
1
9a: 0
2
7a: 0
t
Pd(OAc)
2
22
9a: 0
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a
The reaction conditions given in any row corresponds to the independent reactions carried
out with 6a and 8a.
b
The product 7a was obtained from the corresponding reactions involving substrate 6a.
c
The product 9a was obtained from the corresponding reactions involving substrate 8a. The
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product 10a was not observed in the reactions involving the substrate 8a.
2
The arylation reaction of ortho C(sp )–H bond of benzamide 6a with 1ꢀethylꢀ4ꢀ
2
iodobenzene in the presence of 10 mol% of the Pd(OAc) catalyst and AgOAc additive in
o
toluene at 110 C afforded the mono CꢀH arylated benzamide 7a in a maximum yield of 70%
2
(entry 2, Table 4). Similarly, the Pd(II)ꢀcatalyzed arylation of ortho C(sp )–H bonds of
benzamide 8a with 1ꢀethylꢀ4ꢀiodobenzene afforded the bis C–H arylated benzamide 9a in a
maximum yield of 75% (entry 2, Table 4). Apart from these reactions, the other optimization
2
reactions comprising the mono and bis arylation of ortho C(sp )–H bonds of the
corresponding benzamides 6a and 8a in the presence of other palladium catalysts or additives
or solvents were not fruitful (entries 1 and 3ꢀ11, Table 4). Next, to examine the generality of
2
this work we planned to perform the arylation of ortho C(sp )–H bonds of various 2/3ꢀ
substitutedꢀbenzamides 6aꢀe, which were prepared from the ABTD directing group (Table 5).
Using the optimized reaction conditions (entry 2, Table 4), we attempted the
2
Pd(OAc)
2
/AgOAcꢀcatalytic systemꢀbased, ABTDꢀdirected arylation of ortho C(sp )–H bonds
of 2/3ꢀsubstitutedꢀbenzamides 6aꢀd with different aryl iodides that possessed electronꢀ
donating or electronꢀwithdrawing groups at the para/meta position of the aryl ring in the
corresponding aryl iodides. These reactions afforded a wide range of the corresponding mono
CꢀH arylated benzamides 7aꢀn in 50ꢀ77% yields (Table 5). The arylation of the meta
substituted benzamide 6e with 1ꢀiodoꢀ4ꢀmethoxybenzene afforded the corresponding mono
and bis arylated benzamides 7o and 7o′ in 44 and <10% yields. Further, the arylation of 6e
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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
with 1ꢀiodoꢀ3ꢀnitrobenzene afforded the corresponding mono and bis arylated benzamides 7p
(<10%) and 7p′ (<20%) in low yields (Table 5).
Table 5. Substrate Scope and Generality of the Pd(II)ꢀCatalyzed, ABTDꢀDirected
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
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8
9
0
2
a,b
Arylation of Ortho C(sp )–H Bond of Benzamides 6aꢀe and 8aꢀd
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a
1
2
1
2
1
2
The substrates used are: 6a; R = Me, R = H. 6b; R = Me, R = Me . 6c; R = OMe, R =
1
2
1
2
b
3
3
H. 6d; R = Cl, R = H; 6e; R = H, R = Me. The substrates used are: 8a; R = Me. 8b; R =
3
3
Cl. 8c; R = OMe. 8d; R = 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
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41
42
43
44
45
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50
51
52
53
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56
57
58
59
60
After investigating the Pd(II)ꢀcatalyzed, ABTDꢀdirected mono arylation of ortho
2
C(sp )–H bonds benzamides 6aꢀe, we then planned to extend the substrate scope by
2
examining the bis arylation of ortho C(sp )–H bonds of benzamides 8aꢀd. Accordingly, using
2
the optimized reaction conditions (entry 2, Table 4), we attempted the Pd(OAc) /AgOAcꢀ
2
catalytic systemꢀbased, ABTDꢀdirected arylation of ortho C(sp )–H bonds of benzamides 8aꢀ
d with several aryl iodides that possessed electronꢀdonating or electronꢀwithdrawing groups
at the para/meta position of the aryl ring in the corresponding aryl iodides. These reactions
furnished a wide range of bis CꢀH arylated benzamides 9aꢀm in 42ꢀ75% yields, respectively
(
Table 5).
Next, we focused our attention to explore the Pd(II)ꢀcatalyzed direct benzylation of
2
ortho C(sp )–H bonds of benzamides with the help of the ABTD bidentate directing group. In
this regard, initially, we carried out the Pd(OAc) /AgOAcꢀcatalytic systemꢀbased, ABTDꢀ
2
directed ortho C–H benzylation of 6a/6c/6d with 1ꢀ(bromomethyl)ꢀ4ꢀnitrobenzene (10).
These reactions afforded the corresponding ortho C–H benzylated benzamides 11aꢀc in 47ꢀ
6
5% yields, respectively (Scheme 2). Having done the Pd(II)ꢀcatalyzed mono benzylation of
2
ortho C(sp )–H bond of 6a/6c/6d, we then performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected
2
bis benzylation of ortho C(sp )–H bonds of benzamides 8a/8c/8d/6e with 10. These reactions
furnished the corresponding bis orthoꢀC–H benzylated benzamides 12aꢀc and 12d′ in 30ꢀ58%
yields, respectively (Scheme 2).
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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
Scheme 2. The Pd(II)ꢀCatalyzed, ABTDꢀDirected Mono and Bis Benzylation of Ortho
2
a
C(sp )–H Bonds of Benzamides 6 and 8.
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
The benzylation of 6e afforded the bis benzylated product 12d′ along with the
corresponding mono benzylated product 12d in <10% yield. Our efforts to isolate the
compound 12d in pure form were not fruitful.
The CꢀH arylated/benzylated compounds 7aꢀp, 9aꢀm, 11aꢀc, 12aꢀc and 12d′ obtained
from the Pd(II)ꢀcatalyzed, ABTDꢀdirected arylation/benzylation of ortho C–H bonds of the
corresponding substrates 6aꢀe and 8aꢀd were characterized based on their NMR spectra and
1
HRMS analyses data. For example, a comparison the H NMR spectra of substrate 6b and
carboxamide 7g was performed. The corresponding distinct doublet peaks of the meta and
para protons of ortho CꢀH arylated carboxamide 7g revealed that the arylation occurred at the
1
ortho C–H bond of the 2,3ꢀdimethylbenzamide system 6b. Similarly, a comparison the H
NMR spectra of substrate 8a and carboxamides 9d/12a was performed. The corresponding
distinct singlet peak of the meta protons of the bis ortho CꢀH arylated/benzylated 4ꢀ
methylbenzamide systems 9d/12a revealed that the arylation/benzylation occurred at both the
ortho C–H bonds of the 4ꢀmethylbenzamide system 8a. Additionally, the observed
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regioselectivity in the reactions comprising the Pd(II)ꢀcatalyzed, ABTDꢀdirected ortho
2
C(sp )–H arylation/benzylation of benzamides 6aꢀe and 8aꢀd was unambiguously confirmed
from the Xꢀray structure of a representative ortho C–H arylated benzamide 7f (see the
Supporting Information for the Xꢀray structure of 7f).
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
Scheme 3. Comparison of ABTD with the Pivotal Bidentate Directing Groups Reported
1
4c
for the Pd(II)ꢀCatalyzed Arylation of Cyclobutanecarboxamide
Next, it was envisaged to carry out a brief comparison on the efficiency, scope and
limitations of the 4ꢀaminoꢀ2,1,3ꢀbenzothiadiazole (ABTD) bidentate directing group with the
other seminal bidentate directing groups used for performing the Pd(II)ꢀcatalyzed
arylation/acetoxylation of carboxylic acid derivatives. Accordingly, Schemes 3ꢀ6 reveal a
comparison of the propensity of the ABTD directing group with the typical bidentate
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6
directing groups reported for the Pd(II)ꢀcatalyzed arylation of cyclobutanecarboxamide
system 13 (Scheme 3). The expected bis CꢀH arylated cyclobutanecarboxamides 14ꢀ16 did
not form in the Pd(II)ꢀcatalyzed C−H arylation of their corresponding starting materials. The
reason for this may be that the respective bidentate directing groups linked with the
cyclobutanecarboxamides 13 have not assisted the arylation of C−H bond of the
corresponding cyclobutanecarboxamides 13.
0
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Typically, the Pd(II)ꢀcatalyzed CꢀH arylations of carboxylic acid derivatives have
1
1
been performed using the 8ꢀaminoquinoline, 2ꢀ(methylthio)aniline and N ,N ꢀdimethylethane
3
,5,6
bidentate directing groups.
Using these bidentate directing groups, our lab reported the
Pd(II)ꢀcatalyzed diastereoselective double βꢀCꢀH activation and arylation of
1
4c
cyclobutanecarboxamides. A comparison of the efficiencies of these bidentate directing
groups with the ABTD directing group with regard to the diastereoselective βꢀCꢀH arylation
of cyclobutane system was carried out. It was found that the ABTD bidentate directing group
1
1
is relatively more efficient than the 2ꢀ(methylthio)aniline and N ,N ꢀdimethylethaneꢀ1,2ꢀ
diamine directing groups and the efficiency of the 4ꢀaminoꢀ2,1,3ꢀbenzothiadiazole directing
group was comparable to the 8ꢀaminoquinoline bidentate directing group (Scheme 3).
Furthermore, the results shown in Scheme 4 provided additional inputs with regard to
the assistance provided by the ABTD bidentate directing group for the selective mono βꢀCꢀH
5
,6
arylation of the methyl group of propionamide. Daugulis et al. revealed that the attempts on
the Pd(II)ꢀcatalyzed CꢀH arylation of methyl group of propionamide with the help of the
typically used bidentate directing groups (e.g., 8ꢀaminoquinoline and 2ꢀ(methylthio)aniline)
afforded the corresponding 3ꢀarylated propionamide (mono arylation product) and 3,3ꢀbis
5,6
arylated propionamide (bis arylation product).
In the present investigation, the
Pd(OAc)/AgOAcꢀcatalytic systemꢀbased CꢀH arylation of butyramide 20a (assembled from
1
1
the 2ꢀaminopyridine directing group) and propionamide 20b (assembled from the N ,N ꢀ
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dimethylethaneꢀ1,2ꢀdiamine directing group) did not give the expected products 21a, 21b and
21b′ (Scheme 4).
Scheme 4. Comparison of ABTD with the Other Pivotal Directing Groups Used for the
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13
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6
,14d
Mono βꢀCꢀH Arylation of Popionic Acid.
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6
The Pd(II)ꢀcatalyzed CꢀH arylation of 20c, which was assembled from the 2ꢀ
methylthio)aniline bidentate directing group afforded the mono arylation product 21c in low
(
yield (30%. Scheme 4). However, the Pd(II)ꢀcatalyzed CꢀH arylation of 20d, which was
assembled from the 8ꢀaminoquinoline bidentate directing group afforded the corresponding
mono arylation products 21d/21e (21ꢀ40%) and bis arylation product 21d′/21e′ (17ꢀ18%,
Scheme 4). Nonetheless, the Pd(II)ꢀcatalyzed CꢀH arylation of 1i, which was assembled from
the ABTD bidentate directing group selectively afforded the mono arylation products 3t/3x in
good yields (up to 56%, Schemes 1 and 4). Furthermore, we observed that the ABTDꢀ
directed CꢀH arylation of 6a selectively afforded the mono arylation product 7a in 70% yield
(Scheme 5). On the other hand, the 8ꢀaminoquinolineꢀdirected CꢀH arylation of 20i afforded
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9
0
the bis arylation product 22a in 53% yield along with the compound 22b in 5ꢀ10% yield
16f
(Scheme 5).
Scheme 5. Typical Comparison of ABTD with the Other Pivotal Directing Groups Used
for the CꢀH Arylation Carboxamides.
Additionally, we performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected βꢀCꢀH acetoxylation
2
of substrate 1i with PhI(OAc) , which afforded the corresponding CꢀH acetoxylated products
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3v/3w in 55ꢀ68% yields (Scheme 6). However, the Pd(II)ꢀcatalyzed βꢀCꢀH acetoxylation of
the corresponding carboxamides 20aꢀc, directed by the respective bidentate directing groups
were not fruitful (Scheme 6). We also performed the Pd(II)ꢀcatalyzed, ABTDꢀdirected βꢀCꢀH
acetoxylation of substrates 6c,d, which afforded the corresponding CꢀH acetoxylated 25a,b in
86ꢀ89% yields, respectively (Scheme 6). Similarly, the Pd(II)ꢀcatalyzed, ABTDꢀdirected βꢀCꢀ
H methoxylation of 6b,d afforded the corresponding CꢀH methoxylated products 25c,d in 64ꢀ
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13
14
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20
21
22
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57
58
59
60
71% yields, respectively. A comparison of the Pd(II)ꢀcatalyzed ABTD directing groupꢀbased
8bꢀe
CꢀH acetoxylation/alkoxylation reactions with the seminal works
dealing on the CꢀH
acetoxylation/alkoxylation using typical bidentate directing groups was shown in Scheme 6.
The ABTD directing groupꢀbased CꢀH acetoxylation/alkoxylation of benzamides 6bꢀd
afforded the products 25aꢀd in good yields involving relatively simple reaction conditions.
Overall, the results presented in Schemes 3ꢀ6 have afforded a brief comparison on the
adeptness, scope and limitations of the ABTD bidentate directing group with regard to the
other seminal bidentate directing groups used for performing the Pd(II)ꢀcatalyzed CꢀH
arylation/benzylation/acetoxylation of carboxylic acid derivatives.
Finally, we also attempted the removal of the ABTD bidentate directing group after
the CꢀH arylation of reactions using representative CꢀH arylated carboxamides (Scheme 7).
2 4
Initially, we attempted the amide hydrolysis reaction of 9m with aq. H SO , which afforded
the 9ꢀfluorenone derivative 27 (Scheme 7) and in this reaction, the corresponding carboxylic
acid was not obtained in characterizable amount. After the removal of the directing group, the
corresponding carboxylic acid has undergone an intramolecular FriedelꢀCrafts acylation to
directly afford the compound 27 under the experimental condition. The baseꢀmediated amide
hydrolysis of 5g and 5h furnished the corresponding trisubstituted cyclobutanecarboxylic
acids 28a and 28b (Scheme 7). The stereochemistry of carboxylic acids 28a and 28b was
14c
assigned by comparing the NMR spectral data of 28a and 28b with the previous work,
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6
which also revealed the occurrence of epimerization at the carbonyl group containing
1
4c
stereocenter of 28a and 28b under the experimental condition. The removal of the ABTD
bidentate directing group from 3a and 3e under the baseꢀmediated hydrolysis reaction
conditions gave the corresponding βꢀarylbutyric acids 28c and 28d (Scheme 7).
Scheme 6. Comparison of ABTD with the Other Seminal Works on the CꢀH
Acetoxylation/Alkoxylation of Carboxamides.
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Scheme 7. Removal of the ABTD Directing Group After the βꢀCꢀH Arylation of
14e
Carboxamides.
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20
21
22
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60
CONCLUSION
In summary, we have shown 4ꢀaminoꢀ2,1,3ꢀbenzothiadiazole (ABTD) as a new
2
3
2
bidentate directing group for the Pd(OAc) /AgOAc catalytic systemꢀbased sp /sp C–H
activation/functionalization and CꢀC/CꢀO bond formation. The ABTD directing group
directed the Pd(II)ꢀcatalyzed C–H arylation/acetoxylation to occur at the βꢀposition of various
aliphatic/alicyclic carboxamides and benzamides. Various examples comprising the βꢀCꢀH
arylated/acetoxylated carboxamides and trisubstituted cyclobutanecarboxamide scaffolds
having the all cis stereochemistry were synthesized in good yields. Further, the Pd(II)ꢀ
2
catalyzed, ABTDꢀdirected arylation and benzylation of ortho C(sp )–H bonds of various
benzamides afforded the corresponding mono/bis βꢀCꢀH arylated/benzylated benzamides in
good yields. A brief description on the efficiency, scope and limitations of the ABTD
bidentate directing group was presented by comparing the efficiency of ABTD with other
seminal bidentate directing groups. Finally, we have also shown the removal of the ABTD
directing group from representative CꢀH arylated compounds. It is to be noted that the
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3
research field pertaining to the bidentate directing groupꢀdirected siteꢀselective sp C–H
activation/functionalization is still emerging. Hence, advancing the research area pertaining
2
3
to the directing groupꢀassisted sp /sp C–H activation/functionalization reactions by
developing new directing groups/substrates will enhance the understanding with regard to the
scope and limitations of the directing groups while exercising the siteꢀselective CꢀH
functionalization. Hence, we believe that ABTD might serve as an optional directing group
when the siteꢀselective C–H activation/functionalization of suitable carboxylic acid substrates
is explored.
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EXPERIMENTAL SECTION
1
General. IR spectra of compounds were recorded as thin films or KBr pellets. H and
1
3
1
C{ H} NMR spectra of all compounds were recorded on 400 MHz and 100 MHz
spectrometers, respectively (using TMS as an internal standard). HRMS measurements were
obtained from QTOF mass analyzer using electrospray ionization (ESI) method. Column
chromatography was carried out using silica gel 100ꢀ200 mesh. Reactions were performed in
anhydrous solvent under a nitrogen atmosphere. Isolated yields of all compounds were
reported and yields of all compounds reported here were not optimized. Compounds 3aꢀi and
3
o were obtained from substrate 1a. Compounds 3j, 3k, 3l, 3m and 3n were obtained from
the corresponding substrates 1b, 1c, 1d, 1e and 1f. Compounds 3p, 3q, 3r and 3s were
obtained from the corresponding substrates 1d, 1g and 1h. Compounds 4a/4aA and 4b/4bB
were obtained from substrate 1j. Compounds 5aꢀm were obtained from substrate 1k.
20a
14c
14c
19
19
20b
6
6
6
20c
Compounds 27, 28a, 28b, 28c, 28d, 20a, 20b, 20c, 20d and 21d were
reported in the literature. The reactions shown in Scheme 3 for comparing the efficiency of
14c
the ABTD with other popular bidentate directing groups are reported by our group.
General procedures for the preparation of required carboxamide starting materials and CꢀH
arylation/benzylation/oxygenation of carboxamides are given below. See the respective
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Schemes 1ꢀ7 and Tables 1ꢀ5 for exact reaction conditions and starting materials/reagents
used.
General procedure for the synthesis of carboxamides 1aꢀk and 1aaꢀ1ac. A dry RB flask
containing benzo[c][1,2,5]thiadiazolꢀ4ꢀamine (1 mmol), Et N (1.1 mmol) was stirred for
3
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5−10 min under a nitrogen atmosphere. Then, to the reaction flask was added anhydrous
DCM (4 mL) followed by dropwise addition of the corresponding acid chloride (1 mmol).
Then, the reaction mixture was stirred for 12 h. After this period, the reaction mixture was
diluted with dichloromethane (3ꢀ5 mL) and washed with water (5ꢀ7 mL) and twice with
saturated aqueous NaHCO solution (3ꢀ5 mL). The combined organic layers were dried over
3
anhydrous Na SO , concentrated in vacuum and purification of the resulting reaction mixture
2
4
by column chromatography (silica gel, 100−200 mesh, EtOAc/hexanes) furnished the
corresponding carboxamides 1aꢀk and 1aaꢀ1ac.
General procedure for the CꢀH functionalization of carboxamides 1aꢀk, 1aaꢀ1ac and
20aꢀh. An appropriate carboxamide (0.125 mmol, 1 equiv), Pd(OAc) (2.8 mg, 10 mol%), an
2
appropriate aryl iodide (0.5 mmol, 4 equiv) and AgOAc (45.9 mg, 0.275 mmol, 2.2 equiv) in
o
anhydrous toluene (3 mL) was heated at 110 C for 12ꢀ48 h under a nitrogen atmosphere.
After the reaction period, the reaction mixture was concentrated in vacuum and purification
of the resulting reaction mixture through column chromatography furnished the
corresponding CꢀH arylated carboxamides 3aꢀ3s, 4a, 4aA, 4b, 4bB, 5aꢀ5m and 21 (see the
corresponding Tables/Schemes for specific examples).
General procedure for the selective mono arylation of carboxamide 1i. An appropriate
2
amide (0.125 mmol, 1 equiv), Pd(OAc) (2.8 mg, 10 mol%), an appropriate aryl iodide (0.15
mmol, 1.2 equiv) and AgOAc (45.9 mg, 0.275 mmol, 2.2 equiv) in anhydrous toluene (3 mL)
o
was heated at 110 C for 18ꢀ24 h under nitrogen atmosphere. After the reaction period, the
reaction mixture was concentrated in vacuum and purification of the resulting reaction
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6
mixture through column chromatography furnished the corresponding CꢀH arylated amides
3t,u (see the corresponding Scheme for specific examples).
General procedure for the CꢀH acetoxylation of carboxamides 1h,i/20aꢀc. An appropriate
amide (0.125 mmol, 1 equiv), Pd(OAc) (2.8 mg, 10 mol%), PhI(OAc) (0.32 mmol, 2.5
2
2
0
1
2
3
4
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9
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4
5
6
7
8
9
0
o
equiv) and anhydrous toluene (3 mL) was heated at 110 C for 18ꢀ24 h under a nitrogen
atmosphere. After the reaction period, the reaction mixture was concentrated in vacuum and
purification of the resulting reaction mixture through column chromatography furnished the
corresponding βꢀacetoxylated amides 3v,w (see the corresponding Schemes for specific
examples).
Procedure for the alkylation of 1k and the preparation of 4c. Cyclobutanecarboxamide 1k
(0.125 mmol), Pd(OAc)
2
(2.8 mg, 10 mol%), ethyl iodoacetate (80 mg, 0.37 mmol), Ag
2 3
CO
(75 mg, 0.27 mmol), and (BnO)
2
PO H (7 mg, 20 mol%) in anhydrous tertꢀamyl alcohol (2
2
mL) was heated at 110 °C for 24 h under a nitrogen atmosphere. After the reaction period, the
mixture was concentrated in vacuum, purification of the crude residue by column
chromatography on silica gel furnished the corresponding βꢀalkylated carboxamide 4c.
General procedure for the hydrolysis of CꢀH arylated carboxamides 5g,h, and 3a,e. A
solution of corresponding carboxamide (0.1 mmol) and NaOH (10ꢀ15 equiv) in ethanol (3ꢀ4
mL) was heated at 85 °C for 18ꢀ24 h. After this period, the reaction mixture was diluted with
water (3ꢀ4 mL) and extracted with DCM (2 × 10 mL) and then, the aqueous layer was
acidified with 1 N HCl to get a pH ≈ 2. The resulted aqueous layers were extracted with
2 4
DCM (2 × 10 mL) and the combined organic layers were dried over Na SO followed by the
evaporation of the solvent in vacuum resulted the corresponding pure carboxylic acids 28aꢀd.
General procedure for the synthesis of benzamides/carboxamides 6d, 8a, 8b, 8d and
2
0aꢀd. A dry flask containing 4ꢀaminoꢀ2,1,3ꢀbenzothiadiazole (1 mmol, 151 mg), Et N (1.1
3
mmol, 115 mg) was stirred for 5−10 min under a nitrogen atmosphere. Then, to the reaction
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flask anhydrous DCM (4 mL) was added followed by dropwise addition of an appropriate
acid chloride (1 mmol). The resulting mixture was stirred at rt for 12 h. After this period, the
reaction mixture was diluted with dichloromethane and washed with water and twice with
saturated aqueous NaHCO solution. The combined organic layers were dried over anhydrous
3
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13
14
15
16
17
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19
20
21
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25
26
27
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Na SO , concentrated in vacuum and purification of the resulting reaction mixture by column
2
4
chromatography (silica gel, 100−200 mesh, EtOAc/hexanes = 1:4) furnished the
corresponding benzamides 6d, 8a, 8b, 8d and 20aꢀd.
General procedure for the synthesis of benzamides 6aꢀ6c, 6e and 8c. The corresponding
carboxylic acid (3 mmol) was dissolved in dry DCM (15 mL) by adding 2 to 3 drops of dry
o
DMF, to this reaction mixture oxalyl chloride (1.5 equiv, 190 mg) was added at 0 C and
then, the reaction mixture was stirred and allowed to attain rt over the period of 6ꢀ8 h under a
nitrogen atm. After this period, the reaction mixture was concentrated in vacuum to remove
excess oxalyl chloride and solvent. The resultant acid chloride was dissolved in DCM (15
mL). Then, this DCM solution was added to a separate flask containing 4ꢀaminoꢀ2,1,3ꢀ
o
benzothiadiazole (2 mmol, 302 mg) and Et N (1.5 equiv, 303 mg) in DCM (3 mL) at 0 C.
3
After this the resultant reaction mixture was stirred and allowed to attain rt over the period of
6
ꢀ8 h under a nitrogen atm. After this period, the reaction mixture was diluted with
dichloromethane and then washed with water followed by saturated aqueous NaHCO
solution. The combined organic layers were dried over anhydrous Na SO and concentrated
3
2
4
in vacuum. Purification of the resulting reaction mixture by column chromatography (silica
gel, 100−200 mesh, EtOAc/hexanes = 1:4) furnished benzamides 6aꢀ6c, 6e and 8c.
2
General procedure for the Pd(II)ꢀcatalyzed, ABTDꢀdirected ortho C(sp )–H arylation
and benzylation of benzamides 6aꢀe and 8aꢀd. An appropriate benzamide 6/8 (0.12 mmol,
1
equiv), Pd(OAc) (10 mol%, 2.7 mg), an appropriate aryl iodide or 1ꢀ(bromomethyl)ꢀ4ꢀ
2
nitrobenzene (0.36 mmolꢀ0.48 mmol, 4 equiv) and AgOAc (0.24ꢀ0.264 mmol, 2ꢀ2.2 equiv,
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