Palladium-Catalyzed, N-(2-Aminophenyl)acetamide-Assisted Ortho-Arylation of Substituted Benzamides: Application to the Synthesis of Urolithins B, M6, and M7

Article abstract of DOI:10.1021/acs.joc.7b00256

Pd-catalyzed, selective, monoarylation of ortho-C-H bonds of various benzamides with aryl/heteroaryl iodides has been realized using N-(2-aminophenyl)acetamide (APA) as a new bidentate directing group for the first time. The reaction was tolerant of a wid

Full text of DOI:10.1021/acs.joc.7b00256

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Article
Palladium-Catalyzed, N-(2-aminophenyl)acetamide-
Assisted Ortho-Arylation of Substituted Benzamides—
Application to the Synthesis of Urolithins B, M6 and M7
M Damoder Reddy, Alexandra N. Blanton, and E. Blake Watkins
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Apr 2017
Downloaded from http://pubs.acs.org on April 21, 2017
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PalladiumꢀCatalyzed, Nꢀ(2ꢀAminophenyl)Acetamideꢀ
Assisted OrthoꢀArylation of Substituted Benzamides—
Application to the Synthesis of Urolithins B, M6 and M7
M. Damoder Reddy, Alexandra N. Blanton and E. Blake Watkins*
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Department of Pharmaceutical Sciences, School of Pharmacy, Union University, Jackson,
Tennessee, United States 38305
Eꢀmail: bwatkins@uu.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
ABSTRACT: Pdꢀcatalyzed, selective, monoarylation of orthoꢀCꢀH bonds of various benzamides
with aryl/heteroaryl iodides has been realized using Nꢀ(2ꢀaminophenyl)acetamide (APA) as a
new bidentate directing group for the first time. The reaction was tolerant of a wide range of
functional groups, and a variety of biaryl amide derivatives were successfully prepared in good
to moderate yield. The utilization of Nꢀ(2ꢀaminophenyl)acetamide as a novel directing group,
Mn(OAc) as a coꢀoxidant (silver free reaction conditions), and absolute orthoꢀmonoaryl
2
selectivity are notable features of this reaction. In addition, the obtained monoarylated products
could be further transformed into the bioactive natural products and human microflora
metabolites of dietary ellagic acid derivatives, urolithin B, urolithin M6 and urolithin M7.
INTRODUCTION
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Transition metalꢀcatalyzed carbonꢀcarbon (CꢀC) and carbonꢀheteroatom (CꢀX) bond formation
via CꢀH bond functionalization has emerged as a powerful and promising synthetic tool in
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organic synthesis in the past decade. Although various transition metal complexes involving
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Pd, Ru, Rh, Ni, Co and Cu for CꢀH bond functionalization have been investigated, Pdꢀcatalyzed
reactions to generate CꢀC and CꢀX bonds have recently seen tremendous advances due to broad
functional group tolerance and the unique reactivity of palladium. The number of reports
describing the utility of palladiumꢀcatalyzed CꢀC and CꢀX bond formation has dramatically
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increased in recent years. Regioselective CꢀH functionalization is one of the key challenges in
the development of synthetically useful reactions. In this line, substantial progress has been
realized using directing groupꢀassisted CꢀH activation/functionalization. Bidentate directing
groups have proven particularly instrumental in positionꢀselective CꢀH transformations under
metal catalysis. Bidentateꢀtype auxiliary groups have emerged as a new tool in metalꢀcatalyzed
CꢀH functionalizations due to their versatility and reliability. In addition, the bidentate directing
group strongly coordinates the metal with a double coordination strategy and facilitates the CꢀH
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functionalization process. In 2005, the pioneering discovery of 8ꢀaminoquinoline as a bidentate
directing group by Daugulis paved the way for siteꢀselective CꢀH functionalization reactions,
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particularly orthoꢀarylation of benzamide derivatives. Subsequently, various N,Nꢀ, N,Sꢀ and
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N,Oꢀbidentate directing groups such as 8ꢀaminoquinoline, picolinamide, pyridinꢀ2ꢀ
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ylmethanamine/(pyridineꢀ2ꢀyl)isopropyl amine (PIP), triazole, 2ꢀthiomethylaniline, peptide
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derivatives, 2ꢀaminopyridine 1ꢀoxide and others were reported and utilized for CꢀH
activation/CꢀC bond formation. In particular, Q, PA and PIP were shown to be highly active
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bidentate directing groups with diverse substrates.
More recently, tremendous progress has
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been made by Daugulis, Yu, Chatani,
Ackermann, Nakamura, Shi and others
in
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bidentate directing groupꢀassisted CꢀH orthoꢀarylation reactions. Despite great success in this
area, significant work remains to be done with respect to fully regioselective, orthoꢀ
monoarylation of benzamides using easily accessible bidentate assistance and further utilization
of these products for the synthesis of biologically important molecules. In continuation of our
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research on CꢀC bond forming reactions using the CꢀH functionalization strategy, herein, we
describe the Pdꢀcatalyzed, highly selective orthoꢀmonoarylation of benzamides using
commercially available Nꢀ(2ꢀaminophenyl)acetamide (APA) as a bidentate directing group for
the first time and apply this method to the preparation of several natural products of biological
interest.
RESULTS AND DISCUSSION
Our initial investigations commenced by exploring Nꢀ(2ꢀacetamidophenyl)benzamide (1a) and 4ꢀ
iodoanisole (2a) model substrates under palladiumꢀcatalyzed conditions (table 1). Initially, the
reaction of 1a and 2a was performed with 10 mol% Pd(OAc) and 1 equiv of AgOAc in toluene
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at 110 C for 24 h. To our delight, the expected monoarylated product (3a) could be isolated,
although in very low yield (table 1, entry 1). Introduction of Na CO as a base resulted in a
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modest increase to 14% of 3a (entry 2). Encouraged by these results, we further examined
various parameters for this reaction. Replacing toluene with other solvents such as tꢀAmOH or
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,4ꢀdioxane, led to formation of the desired product in 31% and 18% yields, respectively (entries
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and 4). Furthermore, the reaction of 1a with 2a using Mn(OAc) and Mn(OAc) ·H O was
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examined under palladiumꢀcatalyzed conditions (entries 5 and 6). Mn(OAc) proved to be far
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superior to AgOAc and Mn(OAc) . In the presence of Mn(OAc) with 10 mol% Pd(OAc) and
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equiv of Na CO in tꢀAmOH at 120 C for 36 h, the arylated product 3a was obtained in 82%
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yield (entry 5). Subsequently, the efficacy of other bases was also investigated under the
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palladium/manganese system. Cs CO and K CO promoted the reaction with equal efficacy
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(entries 7 and 8) although in slightly lower yield, but KOAc and NaOAc proved nonviable in this
transformation (entries 9 and 10). A variety of solvents were investigated, but all were inferior to
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tꢀAmOH (entries 11ꢀ14). Additionally, the influence of the coꢀoxidant was also investigated.
When the reaction was carried out in the absence of Mn(OAc) , only 42% of the expected
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product 3a was isolated (entry 15). With 0.5 equiv of Mn(OAc) , the desired product was
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isolated in 50% yield (entry 16), and with 2 equiv of Mn(OAc) , no significant improvement in
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the yield was effected (entry 17). Next, elevated temperature and longer reaction time provided
no additional improvement in the yield of 3a (entry 18). The arylation reaction proceeded
smoothly in the absence of base, although 3a was obtained in only 54% yield (entry 19).
Similarly, no arylated product was isolated in the absence of Pdꢀcatalyst (entry 20). Finally,
lower yields of arylated products were obtained when the reactions were carried out with 2 and 5
mol % of Pd(OAc) (entries 21 and 22). Therefore, the optimal conditions for the arylation
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reaction were identified as 10 mol% Pd(OAc) , 1 equiv of Mn(OAc) and 2 equiv of Na CO in
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tꢀAmOH at 120 C for 36 h.
a
Table 1. Optimization of reaction conditions.
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O
AP
O
4
-iodoanisole (2a)
AP
N
Pd(OAc) (10 mol %)
2
H
N
H
NHAc
additive, base, solvent
temperature, time
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3a
OMe
yieldb
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temperature/time
oC/hours
entry
additive
base
solvent
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6
AgOAc
AgOAc
-
toluene
toluene
110/24
110/36
120/36
110/36
120/36
120/48
5 (79)
Na CO
14 (65)
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3
AgOAc
Na CO
t-AmOH
1,4-dioxane
t-AmOH
31 (55)
18 (70)
82 (12)c
22 (65)
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3
AgOAc
Na CO
2
Mn(OAc)2
Mn(OAc) .H O
Na CO
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3
Na CO
t-AmOH
3
2
2
3
7
8
9
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Cs CO
t-AmOH
t-AmOH
t-AmOH
120/36
120/36
120/36
76 (15)
75 (15)
12 (65)
2
3
K CO
2
3
KOAc
NaOAc
1
1
0
1
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
t-AmOH
1,4-dioxane
DMF
120/36
120/36
120/24
120/24
10 (60)
54 (26)
0 (24)
Na CO
2
3
3
3
3
12
Na CO
2
1
1
1
3
4
5
Na CO
DMSO
0 (20)
2
Mn(OAc)2
--
Na CO
CF CH OH
100/36
120/36
120/36
60 (15)
42 (40)
50 (35)
2
3
2
Na2CO3
Na2CO3
t-AmOH
t-AmOH
16d
7e
Mn(OAc)2
1
Mn(OAc)2
Na CO
t-AmOH
120/36
81 (10)
2
3
3
1
8
Mn(OAc)2
Mn(OAc)2
Na CO
t-AmOH
t-AmOH
150/48
120/36
65 (15)
54 (36)
2
19
0f
1g
22h
--
2
Mn(OAc)2
Na2CO3
Na CO
t-AmOH
120/48
0 (80)
2
Mn(OAc)2
Mn(OAc)2
t-AmOH
t-AmOH
120/36
120/36
32 (50)
60 (28)
2
3
Na CO
2
3
aReaction conditions: benzamide 1a (0.3 mmol), 4-iodoanisole (2a) (0.9 mmol),
b
Pd(OAc) (10 mol %), additive (0.3 mmol), base (0.6 mmol), solvent (5 mL); All the
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13
c
products were characterized by H, C NMR, IR and MS; 0.3 mmol of Ar-I gave 49%
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e
while 0.6 mmol gave 68% yield; 0.15 mmol of Mn(OAc) was used; 0.6 mmol of
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f
g
h
Mn(OAc) was used; no Pd(OAc) used; Pd(OAc) (2 mol %); Pd(OAc) (5 mol %);
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2
2
2
The values in the parentheses refer to starting material recovered.
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Having established the conditions for orthoꢀmonoarylation using 2ꢀAPA, we screened other
amide derivatives to differentiate reactivity and selectivity (scheme 1) to better understand the
influence of the Nꢀacetamide group. Monoarylated benzamide 5a was isolated in 76% yield after
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8 hours at 120 °C. The absence of the Nꢀacetamide group allowed us to examine the impact of a
pK change on reactivity and regioselectivity. Introduction of the electronꢀwithdrawing Nꢀ
a
trifluoroacetamide group gave the monoarylated compound 5b in 55% yield. In both instances,
no evidence of the presence of the diꢀarylated product was found. Next, we examined amides
prepared from other bidentate ligands such as 2ꢀ(methylthio)aniline and 8ꢀaminoquinoline under
the standard conditions for the arylation reaction to afford the corresponding mixture of mono
and diꢀorthoꢀarylated products in moderate yields (monoarylated products: 5c, 72% and 5d, 68%
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and diꢀarylated products: 5c′, 6% and 5d′, 9%). As expected, benzamides of 2ꢀaminopyridine
and aniline gave no product formation (5e or 5f) following treatment with aryl iodides after 48 h
ο
at 120 C.
Scheme 1. Screening of directing groups.
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Having established optimal reaction conditions, we next explored the scope of aryl iodides to test
the compatibility of the present protocol (scheme 2). Evaluation of substituted aryl iodides
established that the present method is viable with electron donating and withdrawing substituents
including methoxy, ester, ketone, nitroꢀ and chloroꢀ functional groups at various positions, with
all products being furnished in moderate to good yields (3aꢀh, 60ꢀ84%). Additionally, the
methodology was utilized to prepare 3a on a gramꢀscale to demonstrate its synthetic usefulness.
Benzamide 1a (4 mmol) and 2a (12 mmol) were heated under the standard reaction conditions to
furnish 3a in 70% yield (1.0 g). Disubstituted aryl iodides (2i and 2j) reacted smoothly with 1a
under standard conditions to give the corresponding arylated products 3i and 3j, respectively.
The bicyclic heteroaromatic iodide, 5ꢀiodoꢀ2,3ꢀdihydrobenzofuran (2k), was also transformed
into the corresponding arylheteroaryl biarene (3k) in 81% yield. Gratifyingly, other
heteroaromatic iodides 2l, 2m and 2n provided the expected biaryl derivatives in moderate yields
(3l in 62%, 3m in 54% and 3n in 63% yields, respectively). In contrast, orthoꢀsubstituted
iodoarenes, aryl bromides/chlorides and (4ꢀmethoxyphenyl)boronic acid were not viable under
the current catalytic conditions.
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Scheme 2. Reactivity of various aryl/heteroaryl iodides with 1a
Encouraged by these results, we next explored the versatility of substituted benzamides in the
selective CꢀH arylation protocol (scheme 3). Thus a range of amide derivatives (1) were prepared
starting from commercially available Nꢀ(2ꢀaminophenyl)acetamide (APA) and diverse benzoic
acids/acid chlorides as coupling partners. Interestingly, considerable structural diversity of the
benzamides was tolerated (scheme 3). Arylation of electron rich methyl and mono, di, triꢀ
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methoxyꢀsubstituted benzamides gave the corresponding products in 45ꢀ84% yields (4bꢀe).
Moreover, a variety of halogenated benzamides reacted well with 2a, giving the biaryl amides in
moderate to good yields (4fꢀk), thereby providing a complementary platform for further
synthetic manipulation through crossꢀcoupling reactions. Furthermore, CꢀH arylation of
benzamides bearing electronꢀwithdrawing groups (trifluoromethyl, 1l and nitro, 1m) proceeded
under optimal conditions to provide biaryl derivatives, 4l and 4m, although the yields were
somewhat lower (53% and 45%, respectively). In stark contrast, the heteroaromatic benzamide
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n, when treated with 2a under standard reaction conditions, failed to yield the corresponding
arylated product (4n).
Next, to determine whether regioselective Zꢀcinnamoyl derivatives could be obtained under the
current conditions, the alkenyl benzamide (1o) was prepared from methacryloyl chloride and 2ꢀ
APA. Treatment of 1o with 2a gave a mixture of E/Z isomers that proved difficult to separate
using column chromatography (65% yield of geometric isomers 4o). The CꢀH arylation reaction
of 1c, 1g, 1i and 1j revealed high position selectivity in favor of the sterically less crowded CꢀH
bond cleavage to furnish orthoꢀarylated products 4c, 4g, 4i and 4j. In each instance, only
monoarylated products were detected. Lower yields were observed and longer reaction times
needed for substrates with electronꢀwithdrawing substituents (4l and 4m) or with increased steric
hindrance (1d, and 1e). In these instances, the reactions failed to reach completion, with
unreacted benzamide remaining.
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a
Scheme 3. Scope of substituted benzamides in the arylation reaction.
2
After investigating the APꢀassisted Pdꢀcatalyzed, selective, monoarylation of C(sp )ꢀH bonds of
benzamides (3aꢀn and 4bꢀo), we further explored the arylation of benzamides using the benzeneꢀ
1
,2ꢀdiamine system as a bidentate auxiliary (scheme 4). In this line, we prepared benzamide 1p
2
from benzoyl chloride and benzeneꢀ1,2ꢀdiamine. The selective arylation of orthoꢀC(sp )ꢀH bonds
of benzamide 1p with a set of aryl/heteroaryl iodides in the presence of 10 mol% Pd(OAc)2,
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ο
Mn(OAc) and Na CO in tꢀAmOH at 120 C for 48 h gave the corresponding products (5a and
2
2
3
5
gꢀk). The reaction of 1p with 4ꢀ and 3ꢀmethoxy iodobenzene proceeded smoothly to furnish the
corresponding biaryl compounds (5a and 5g) in 76% and 72% yields, respectively. Furthermore,
aryl iodides with electronꢀwithdrawing groups (2d, e and 2h) were also tolerated in the present
conditions with 1p to afford the expected arylated aminobenzamide products (5hꢀj) although in
lower yields (22%ꢀ58%). Finally, 2ꢀiodoꢀ6ꢀmethoxypyrazine (2m) with 1p was found to undergo
orthoꢀarylation to give the corresponding aryl/heteroaryl substrate 5k in 55% yield.
Interestingly, in each of these reactions, less than 15% of unreacted starting material was
recovered. The remainder apparently decomposed to indistinguishable products as evidenced by
TLC. Based on these results, the Nꢀacetamide directing group is superior to the free amine under
the current reaction conditions.
1
1
1
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a
Scheme 4. Scope of arylation reaction with Nꢀ(2ꢀaminophenyl)benzamide.
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Additionally, to demonstrate the potential of the developed methodology, removal of the
directing group was attempted on various products. Orthoꢀarylated benzamides (3a, 4d and 4e)
24,26
were subjected to NaOH/EtOH under reflux conditions
to give biaryl acid derivatives (6aꢀc)
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in excellent yields (scheme 5). The obtained biaryl carboxylic acids were used as key structural
27,28
motifs for the synthesis of bioactive urolithin natural products (B, M6, and M7).
Urolithins
are human intestinal metabolites of ellagitannins, consisting of a benzopyranone core unit with
phenolic hydroxy groups at various positions. Urolithins have been reported to exhibit strong
28a
28b
28c,28d
28b
antioxidant properties, antiꢀcancer, antiꢀinflammatory
and antiglycation activities.
Additionally, these molecules also reduce triglyceride accumulation and increase the oxidation
2
8e
process of fatty acids in hepatocytes as well as adipocytes. Recent studies also suggest that
urolithins may hold potential for the treatment of Type 2 diabetes. The biological significance
and pharmacological potential of urolithins have made them attractive targets for both synthetic
and medicinal chemists to study their medicinal properties. To this end, Nꢀiodosuccinimideꢀ
2
29
mediated C(sp )ꢀH functionalization/CꢀO cyclization of 6aꢀc led to the formation of the
corresponding lactones (7aꢀc) in 80ꢀ92% yields. Alternatively, the cyclization could be
ο
conducted under palladium catalysis. To this end, 6b was heated to 80 C for 24 h in the
presence of Pd(OAc) (10 mol%) and Mn(OAc) (1 equiv.), and the cyclized product (7b) was
2
2
isolated in 63% yield. Finally, the phenolic natural products urolithin B (8a), urolithin M7 (8b)
and urolithin M6 (8c) were isolated in excellent yields following deprotection of the methyl
29
ethers in the presence of BBr /DCM (scheme 6).
3
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b, 63%
Pd(OAc)2,
Mn(OAc)2,
o
8
0 C, 24 h
O
O
NIS, (CH ) Cl
2
2
2
R1
R1
1
1
1
1
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o
NaOH, EtOH
reflux, 24 h
OH
75 C
O
3a/4d/4e
R2
R2
R3
R3
OMe
OMe
1
2
3
1
2
3
R , R , R = H; 6a; 92%
R , R , R = H; 7a; 92%
1
3
2
1
3
2
R , R = OMe, R = H; 6b; 85%
R , R = OMe, R = H; 7b; 86%
1
2
3
1
2
3
R , R , R = OMe; 6c; 79%
R , R , R = OMe; 7c; 80%
Scheme 5. Directing group removal and CꢀH functionalization/CꢀO cyclization.
Scheme 6. Synthesis of urolithins.
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Scheme 7. Deuterium labeling studies.
Deuteriumꢀlabeling experiments were performed to gain insight into the mechanism of the
monoarylation reaction (scheme 7). Heating 1aꢀd under the reaction conditions in the absence of
5
aryl iodide resulted in H/D exchange (26%, scheme 7c) at the ortho positions indicating that CꢀH
30
cleavage is reversible. Kinetic isotope effects (KIE) were determined from independent rates
and intermolecular competition of 1a and 1aꢀd (scheme 7b and c). Separate reactions of 1a and
5
1aꢀd resulted in a KIE of 1.95 (scheme 7b), while the competition reaction yielded a similar
5
KIE of 2.57 (scheme 7c).
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In all the reactions conducted using the AP directing group under the optimized conditions, only
monoarylated products were isolated. Analysis of 3aꢀd (scheme 7b) revealed no detectable
4
exchange at the ortho position of the benzamide, indicating that CꢀH activation does not occur,
providing evidence for the observed monoꢀselectivity. Further investigation is underway to
determine the precise barrier to CꢀH activation leading to diꢀarylation.
1
1
1
1
1
1
1
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1
1
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Based on the above observations and the known reports on bidentate directing groupꢀassisted Cꢀ
4
aꢀc,4e,4g, 5, 10b,10c, 11aꢀc
H activation under palladiumꢀcatalyzed conditions,
a tentative reaction
mechanism is proposed (scheme 8). Initially, the coordination of benzamide 1a with Pd(OAc)2
followed by ligand exchange provides bidentateꢀcoordinated intermediate A, which undergoes
rapid cyclometalation of the aryl group, resulting in the formation of B. Oxidative addition of the
aryl iodide to complex B provides complex C, with a subsequent increase in oxidation state to
IV
Pd . Finally, reductive elimination of C provides D followed by ligand exchange to give the
orthoꢀarylated product 3a and regeneration of Pd(OAc)2.
O
H
O
N
N
PdII NHAc
PdII NHAc
OAc
NaOAc
NaHCO3
A
Na CO
B
2
3
NaOAc
NaHCO3
coordination
C-H activation
2
Na CO3
oxidative
Ar-I
Pd(OAc)2
addition
O
O
3a
reductive
elimination
N
N
PdII NHAc
PdIV NHAc
Ar
I
OAc
D
Ar
Mn(OAc)2
C
Scheme 8. Plausible reaction mechanism.
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6
CONCLUSION
In conclusion, we have developed a facile method for the regioselective synthesis of
monoarylated benzamides under Pdꢀcatalyzed conditions, with Nꢀ(2ꢀaminophenyl)acetamide
(APA) as a new N,Nꢀbidentate directing group in a CꢀH functionalization reaction for the first
time. Preliminary screening of directing groups for the arylation reaction revealed that APA is
superior to the free amine (1p), trifluoroacetamide (1q) and other bidentate substrates under the
present reaction conditions. Furthermore, we demonstrated the synthetic usefulness of the
products by accomplishing the synthesis of natural products urolithin B, urolithin M6, and
urolithin M7. Further application of the APA directing group in CꢀH functionalization reactions
and the precise origin of its monoarylation selectivity are currently underway in our laboratory.
0
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EXPERIMENTAL SECTION
General Methods. Unless otherwise noted, materials obtained from commercial suppliers were
used without further purification. All reactions were conducted in glassware that was dried in an
oven (120 °C), heated under reduced pressure, and cooled under a stream of argon before use.
Reactions were monitored by thinꢀlayer chromatography on silica gel plates using UV light (254
nm) and ceric sulfate or βꢀnaphthol for visualization. Column chromatography was performed on
a flash chromatography system with silica gel columns using nꢀhexane and ethyl acetate as
eluent. Evaporation of solvents was conducted under reduced pressure at 50 °C using rotary
−
1
evaporators. FTIR spectra were recorded neat, and wavenumbers are indicated in cm . NMR
1
13
spectra were recorded at 400 MHz ( H) and 100 MHz ( C). Deuterated chloroform was used as
the solvent, unless otherwise stated, and spectra were calibrated against the residual solvent peak
1
13
at 7.26 ppm for H and at 77.0 ppm for C or against TMS. Chemical shifts (δ) and coupling
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constants (J) are given in ppm (parts per million) and Hz (Hertz), respectively. The following
abbreviations are used to describe the multiplicities: s = singlet, d = doublet, t = triplet, m =
multiplet, bs = broad singlet. Lowꢀresolution mass spectra were obtained by electrospray
ionization (ESI). Highꢀresolution mass spectra (HRMS) were performed with an orbitrap mass
analyzer by electrospray ionization (ESI).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
2
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Starting materials (1rꢀu) were prepared using literature procedures: Nꢀ(2ꢀ
8
e
8e,12a
(methylthio)phenyl)benzamide (1r), Nꢀ(quinolinꢀ8ꢀyl)benzamide (1s),
Nꢀphenylbenzamide
1
2a
12a
(
1t), Nꢀ(pyridinꢀ2ꢀyl)benzamide (1u).
14a,24
General procedure for the synthesis of benzamides from acid chlorides (1aꢀc and 1fꢀo):
Nꢀ(2ꢀAminophenyl)acetamide (0.5 g, 3.33 mmol, 1 equiv) and triethylamine (0.7 mL, 4.99
mmol, 1.5 equiv) were dissolved in anhydrous CH Cl (30 mL) in a 100 mL roundꢀbottom flask,
2
2
followed by dropwise addition of the aroyl chloride (3.66 mmol, 1.1 equiv, dissolved in 10 mL
ο
of DCM) via syringe over a period of 15 min at 0 C. The reaction mixture was warmed to room
temperature and stirred overnight. After completion, the reaction was diluted with CH Cl (40
2
2
mL), washed with a saturated solution of NaHCO (40 mL), 1 N aqueous HCl (40 mL), brine (40
3
mL), and dried over MgSO . The organic solvent was removed by evaporation. The residue was
4
purified by flash column chromatography on silica gel (hexanes/EtOAc = 90:10 to 40:60) to
afford the corresponding amide.
3
0a
Nꢀ(2ꢀAcetamidophenyl)benzamide (1a): From benzoyl chloride (0.515 g, 0.425 mL, 3.66
mmol) using the above general procedure. The crude residue was purified by silica gel column
chromatography (hexanes/EtOAc = 80/20; R = 0.40 in hexanes/EtOAc = 3/1). The product was
f
1
obtained as a brown solid (0.753 g, 89%); H NMR (400 MHz, 8:2 CDCl :DMSOꢀd ): δ 9.49 (s,
3
6
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2
2
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2
2
2
2
2
3
3
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1
2
H), 8.71 (s, 1H), 7.98ꢀ7.93 (m, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.55ꢀ7.48 (m, 3H), 7.08ꢀ7.02 (m,
1
3
1
H), 6.92 (t, J = 7.1 Hz, 1H), 2.04 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ
3
6
170.3, 166.6, 133.5, 132.2, 130.8, 130.4, 128.8, 127.5, 126.3, 126.2, 126.0, 125.0, 23.6; FTIR
ꢀ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
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6
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3
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4
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8
9
0
(neat): 3231, 3091, 1646, 1512, 1431, 1329, 1292, 1155, 1090, 821 cm ; MS (ESI) m/z 255
+
+
[
M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H O N 255.1128; Found: 255.1134.
1
5
15
2
2
Nꢀ(2ꢀAcetamidophenyl)ꢀ4ꢀmethylbenzamide (1b): From 4ꢀmethylbenzoyl chloride (0.566 g,
3.66 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 80/20; R = 0.42 in hexanes/EtOAc = 3/1). The
f
ο
1
product was obtained as a brown solid (0.767 g, 86%); mp = 166ꢀ168 C; H NMR (400 MHz,
8:2 CDCl :DMSOꢀd ): δ 9.77 (s, 1H), 9.71 (s, 1H), 7.86 (dd, J = 8.1, 2.2 Hz, 2H), 7.78 (d, J =
3
6
7
.9 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.15 (t, J
1
3
1
=
7.6 Hz, 1H), 2.24 (s, 3H), 2.16 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ
3 6
170.1, 165.5, 142.2, 131.6, 131.4, 130.5, 129.2, 127.5, 125.8, 125.6, 125.3, 124.9, 23.7, 21.5;
ꢀ1
FTIR (neat): 3239, 3059, 1666, 1643, 1598, 1503, 1439, 1322, 1272, 1189, 1099, 822 cm ; MS
+
+
(ESI) m/z 269 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H O N 269.1285; Found:
16 17 2 2
2
69.1291.
Nꢀ(2ꢀAcetamidophenyl)ꢀ3ꢀmethoxybenzamide (1c): From 3ꢀmethoxybenzoyl chloride (0.625
g, 3.66 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 70/30; R = 0.25 in hexanes/EtOAc = 3/1). The
f
ο
1
product was obtained as a white solid (0.598 g, 63%); mp = 185ꢀ186 C; H NMR (400 MHz,
8
7
:2 CDCl :DMSOꢀd ): δ 9.82 (s, 1H), 9.64 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.59ꢀ7.52 (m, 2H),
3 6
.39 (t, J = 8.1 Hz, 1H), 7.35 (dd, J = 7.8, 1.0 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.7
1
3
1
Hz, 1H), 7.08 (dd, J = 8.2, 1.2 Hz, 1H), 3.88 (s, 3H), 2.19 (s, 3H); C{ H}NMR (100 MHz, 8:2
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CDCl :DMSOꢀd ): δ 170.1, 165.3, 159.6, 135.7, 131.2, 130.4, 129.5, 125.8, 125.5, 125.3, 124.8,
3
6
1
19.4, 117.9, 112.5, 55.3, 23.6; FTIR (neat): 3053, 1661, 1642, 1581, 1502, 1436, 1321, 1285,
ꢀ1
+
+
1187, 1090, 822 cm ; MS (ESI) m/z 285 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for
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
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 O N 285.1234; Found: 285.1238.
16
17
3
2
Nꢀ(2ꢀAcetamidophenyl)ꢀ4ꢀbromobenzamide (1f): From 4ꢀbromobenzoyl chloride (0.800 g,
.66 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 70/30; R = 0.40 in hexanes/EtOAc = 3/1). The
3
f
ο
1
product was obtained as a white solid (0.830 g, 75%); mp = 210ꢀ211 C; H NMR (400 MHz,
8
:2 CDCl :DMSOꢀd ): δ 9.96 (s, 1H), 9.76 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 7.9 Hz,
3
6
1H), 7.62 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.17 (t, J = 7.6
1
3
1
Hz, 1H), 2.18 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.3, 164.5, 133.4,
3
6
1
31.7, 131.0, 130.7, 129.3, 126.3, 125.8, 125.7, 125.5, 124.9, 23.7; FTIR (neat): 3308, 3128,
ꢀ1
+
2995, 1640, 1592, 1493, 1370, 1269, 1144, 1071, 822 cm ; MS (ESI) m/z 333 [M+H] ; HRMS
+
(
ESI) m/z: [M+H] Calcd for C H BrO N 333.0233; Found: 333.0241.
1
5
14
2
2
Nꢀ(2ꢀAcetamidophenyl)ꢀ3ꢀbromobenzamide (1g): From 3ꢀbromobenzoyl chloride (0.800 g,
.66 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 70/30; R = 0.40 in hexanes/EtOAc = 3/1). The
3
f
ο
1
product was obtained as a white solid (0.760 g, 69%); mp = 195ꢀ197 C; H NMR (400 MHz,
8
:2 CDCl :DMSOꢀd ): δ 9.93 (s, 1H), 9.56 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 7.0 Hz,
3
6
1H), 7.75 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.24 (t, J = 7.7
1
3
1
Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 2.19 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ):
3
6
δ 170.1, 164.0, 136.4, 134.5, 130.8, 130.9, 130.7, 130.5, 130.0, 125.5, 125.8, 125.6, 124.8, 122.5,
ꢀ1
23.6; FTIR (neat): 3241, 3058, 1646, 1598, 1513, 1443, 1375, 1283, 1162, 1063, 828 cm ; MS
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1
1
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1
1
1
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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
+
+
(
ESI) m/z 333 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H BrO N 333.0233; Found:
1
5
14
2
2
3
33.0241.
Nꢀ(2ꢀAcetamidophenyl)ꢀ4ꢀchlorobenzamide (1h): From 4ꢀchlorobenzoyl chloride (0.641 g,
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
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1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3.66 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 70/30; R = 0.40 in hexanes/EtOAc = 3/1). The
f
ο
1
product was obtained as a brown solid (0.817 g, 85%); mp = 189ꢀ190 C; H NMR (400 MHz,
8:2 CDCl :DMSOꢀd ): δ 9.95 (s, 1H), 9.75 (s, 1H), 7.95 (dd, J = 8.5, 2.3 Hz, 2H), 7.78 (d, J =
3
6
7
7
.9 Hz, 1H), 7.47 (dd, J = 8.6, 2.5 Hz, 2H), 7.37 (d, J = 6.3 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H),
13
1
.18 (t, J = 7.7 Hz, 1H), 2.18 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.2,
3
6
164.3, 137.7, 133.0, 131.0, 130.7, 129.1, 128.7, 125.8, 125.7, 125.5, 124.8, 23.7; FTIR (neat):
ꢀ1
3
301, 2935, 1702, 1645, 1580, 1495, 1332, 1275, 1151, 1030, 821 cm ; MS (ESI) m/z 289
+
+
[
M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H ClO N 289.0738; Found: 289.0745.
15 14 2 2
Nꢀ(2ꢀAcetamidophenyl)ꢀ3ꢀchlorobenzamide (1i): From 3ꢀchlorobenzoyl chloride (0.641 g,
3.66 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 70/30; R = 0.38 in hexanes/EtOAc = 3/1). The
f
ο
1
product was obtained as a brown solid (0.675 g, 70%); mp = 199ꢀ200 C; H NMR (400 MHz,
8:2 CDCl :DMSOꢀd ): δ 9.97 (s, 1H), 9.67 (s, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 6.8 Hz,
3
6
1
1
H), 7.76 (d, J = 7.8 Hz, 1H), 7.55ꢀ7.49 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.7 Hz,
1
3
1
H), 7.27ꢀ7.14 (m, 2H), 2.19 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.2,
3
6
164.2, 136.4, 134.5, 131.7, 130.9, 130.7, 130.0, 128.0, 125.8, 125.7, 125.7, 125.6, 124.9, 23.8;
ꢀ1
FTIR (neat): 3238, 3059, 2933, 1647, 1565, 1493, 1315, 1284, 1126, 1067, 826 cm ; MS (ESI)
+
+
m/z 289 [M+H] ; HRMS (ESI) m/z: [M+Na] Calcd for C H ClO N Na 311.0558; Found:
1
5
13
2
2
311.0565.
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Nꢀ(2ꢀAcetamidophenyl)ꢀ3,4ꢀdichlorobenzamide (1j): From 3,4ꢀdichlorobenzoyl chloride
(0.763 g, 3.66 mmol) using the above general procedure. The crude residue was purified by silica
gel column chromatography (hexanes/EtOAc = 70/30; R = 0.36 in hexanes/EtOAc = 3/1). The
f
ο
1
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
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
product was obtained as a white solid (0.910 g, 85%); mp = 164ꢀ165 C; H NMR (400 MHz,
8
:2 CDCl :DMSOꢀd ): δ 10.01 (s, 1H), 9.71 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73
3
6
(d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H),
13
1
7
.17 (t, J = 7.5 Hz, 1H), 2.19 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.2,
3 6
1
63.3, 135.6, 134.3, 132.6, 130.6, 130.5, 130.4, 129.9, 126.6, 125.8, 125.7, 125.6, 124.6, 23.6;
ꢀ1
FTIR (neat): 3253, 3059, 1639, 1598, 1467, 1366, 1239, 1115, 1032, 826 cm ; MS (ESI) m/z
+
+
3
3
23 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H Cl O N Na 345.0168; Found:
15 12 2 2 2
45.0175.
Nꢀ(2ꢀAcetamidophenyl)ꢀ4ꢀfluorobenzamide (1k): From 4ꢀfluorobenzoyl chloride (0.581 g,
3.66 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 70/30; R = 0.40 in hexanes/EtOAc = 3/1). The
f
ο
1
product was obtained as a brown solid (0.640 g, 70%); mp = 195ꢀ196 C; H NMR (400 MHz,
8:2 CDCl :DMSOꢀd ): δ 9.87 (s, 1H), 9.64 (s, 1H), 8.05ꢀ7.96 (m, 2H), 7.78 (d, J = 7.9 Hz, 1H),
3
6
1
3
1
7
.32 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.16 (m, 3H), 2.19 (s, 3H); C{ H}NMR (100
MHz, 8:2 CDCl :DMSOꢀd ): δ 170.1, 165.9, 164.3, 163.4, 131.0, 130.4, 130.3, 129.8, 125.8,
3
6
1
1
25.4, 124.7, 115.5, 23.5; FTIR (neat): 3244, 3057, 2933, 2838, 1665, 1574, 1502, 1437, 1315,
ꢀ1
+
+
280, 1180, 1026, 821 cm ; MS (ESI) m/z 273 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for
C H FO N Na 295.0853; Found: 295.0858.
15
13
2
2
Nꢀ(2ꢀAcetamidophenyl)ꢀ4ꢀ(trifluoromethyl)benzamide (1l): From 4ꢀ(trifluoromethyl)benzoyl
chloride (0.764 g, 3.66 mmol) using the above general procedure. The crude residue was purified
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by silica gel column chromatography (hexanes/EtOAc = 70/30; R = 0.25 in hexanes/EtOAc =
f
ο
1
3
/1). The product was obtained as a brown solid (0.792 g, 74%); mp = 182ꢀ183 C; H NMR
(400 MHz, 8:2 CDCl :DMSOꢀd ): δ 10.11 (s, 1H), 9.77 (s, 1H), 8.13 (d, J = 7.9 Hz, 2H), 7.81 (d,
3
6
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
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1
2
3
4
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8
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2
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7
8
9
0
J = 7.7 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.19
1
3
1
(
t, J = 7.4 Hz, 1H), 2.19 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.3,
3 6
164.0, 138.0, 132.7, 130.7, 130.11, 128.1, 125.9, 125.7, 125.5, 125.5, 125.1, 122.5, 23.7; FTIR
ꢀ1
(
neat): 3245, 3056, 2994, 1665, 1602, 1502, 1436, 1367, 1252, 1179, 1025, 822 cm ; MS (ESI)
+
+
m/z 323 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H F O N Na 345.0821; Found:
1
6
13
3
2
2
345.0827.
Nꢀ(2ꢀAcetamidophenyl)ꢀ4ꢀnitrobenzamide (1m): From 4ꢀnitrobenzoyl chloride (0.680 g, 3.66
mmol) using the above general procedure. The crude residue was purified by silica gel column
chromatography (hexanes/EtOAc = 60/40; R = 0.30 in hexanes/EtOAc = 2/1). The product was
f
ο
1
obtained as a brown solid (0.796 g, 80%); mp = 157ꢀ158 C; H NMR (400 MHz, 8:2
CDCl :DMSOꢀd ): δ 10.29 (s, 1H), 9.93 (s, 1H), 8.33 (dd, J = 8.7, 3.6 Hz, 2H), 8.22 (dd, J = 5.2,
3
6
3
.4 Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.30ꢀ7.16 (m, 2H), 2.19 (s, 3H);
1
3
1
C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.3, 163.4, 149.5, 140.3, 130.9, 130.6,
3
6
1
1
29.0, 125.9, 125.8, 125.7, 124.9, 123.7, 23.8; FTIR (neat): 3308, 3056, 2997, 1655, 1601, 1523,
ꢀ1
+
+
436, 1345, 1239, 1188, 1035, 821 cm ; MS (ESI) m/z 300 [M+H] ; HRMS (ESI) m/z: [M+H]
Calcd for C H O N Na 322.0798; Found: 322.0804.
1
5
13
4
3
Nꢀ(2ꢀAcetamidophenyl)ꢀ5ꢀchlorothiopheneꢀ2ꢀcarboxamide (1n): From 5ꢀchlorothiopheneꢀ2ꢀ
carbonyl chloride (0.655 g, 3.66 mmol) using the above general procedure. The crude residue
was purified by silica gel column chromatography (hexanes/EtOAc = 70/30; R = 0.30 in
f
hexanes/EtOAc = 2/1). The product was obtained as a brown solid (0.850 g, 79%); mp = 186ꢀ
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ο
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88 C; H NMR (400 MHz, 8:2 CDCl :DMSOꢀd ): δ 9.97 (s, 1H), 9.74 (s, 1H), 7.75 (d, J = 7.9
3 6
Hz, 1H), 7.60ꢀ7.54 (M, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.26ꢀ7.14 (m, 2H), 6.99ꢀ6.94 (m, 1H), 2.21
1
3
1
(s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.4, 159.2, 138.6, 135.5, 130.5,
3
6
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
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
1
1
30.4, 128.1, 127.4, 125.9, 125.5, 125.4, 124.8, 23.8; FTIR (neat): 3300, 3056, 2977, 1652,
ꢀ1
+
623, 1525, 1436, 1361, 1239, 1188, 1034, 822 cm ; MS (ESI) m/z 295 [M+H] .
Nꢀ(2ꢀAcetamidophenyl)methacrylamide (1o): From methacryloyl chloride (0.380 g, 3.66
mmol) using the above general procedure. The crude residue was purified by silica gel column
chromatography (hexanes/EtOAc = 70/30; R = 0.45 in hexanes/EtOAc = 2/1). The product was
f
ο
1
obtained as a brown solid (0.574 g, 72%); mp = 157ꢀ159 C; H NMR (400 MHz, CDCl ): δ 8.94
3
(
s, 1H), 8.57 (s, 1H), 7.49 (dd, J = 6.8, 1.4 Hz, 1H), 7.14 (td, J = 7.4, 1.4 Hz, 1H), 7.07 (td, J =
8
3
.0, 1.4 Hz, 1H), 7.03 (td, J = 10.0, 1.4 Hz, 1H), 5.95 (s, 1H), 5.52 (t, J = 2.3 Hz, 1H), 2.03 (s,
1
3
1
H), 2.00 (s, 3H); C{ H}NMR (100 MHz, CDCl ): δ 170.3, 167.6, 139.2, 130.7, 130.4, 126.3,
3
126.0, 125.9, 124.9, 122.3, 23.4, 18.6; FTIR (neat): 3312, 3052, 2977, 1644, 1621, 1525, 1434,
ꢀ1
+
1
361, 1240, 1180, 1034, 821 cm ; MS (ESI) m/z 219 [M+H] .
21a
General procedure for the synthesis of benzamides (1d, 1e and 1aꢀd5): Thionyl chloride
(
0.490 g, 0.300 mL, 4.12 mmol) was added slowly to a stirred solution of the carboxylic acid
(0.50 g, 2.74 mmol) in toluene (15 mL) and DMF (0.05 mL) at room temperature. The mixture
was stirred for 4 h at 110 °C and the solvent evaporated in vacuo. The residue was then dissolved
in toluene (5 mL), evaporated in vacuo to give the crude acid chloride.
The acid chloride was dissolved in 10 mL of DCM and added dropwise to a solution of Nꢀ(2ꢀ
aminophenyl)acetamide (412 mg, 2.74 mmol) and Et N (0.575 mL, 4.12 mmol) in CH Cl (30
3
2
2
ο
mL) at ꢀ10 C over 15 min. The resulting solution was warmed to room temperature and stirred
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overnight. The mixture was diluted with CH Cl (40 mL) and washed successively with a
2
2
saturated solution of NaHCO (30 mL), 1 N aqueous HCl (30 mL), brine (30 mL), and dried over
3
MgSO . The organic layer was concentrated under reduced pressure. The residue was purified by
4
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
8
9
0
flash column chromatography on silica gel, eluting with EtOAc/hexane (10:90 to 50:50), to
afford the corresponding amide 1.
Nꢀ(2ꢀAcetamidophenyl)ꢀ3,5ꢀdimethoxybenzamide (1d): From 3,5ꢀdimethoxybenzoic acid
(0.500 g, 2.74 mmol) using the above general procedure. The crude residue was purified by silica
gel column chromatography (hexanes/EtOAc = 60/40; R = 0.25 in hexanes/EtOAc = 2/1). The
f
ο
1
product was obtained as a brown solid (0.783 g, 91%); mp = 186ꢀ187 C; H NMR (400 MHz,
8:2 CDCl :DMSOꢀd ): δ 9.83 (s, 1H), 9.65 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.41ꢀ7.34 (m, 1H),
3
6
1
3
1
7
.27ꢀ7.09 (m, 4H), 6.61 (d, J = 1.6 Hz, 1H), 3.85 (s, 6H), 2.17 (s, 3H); C{ H}NMR (100 MHz,
8
:2 CDCl :DMSOꢀd ): δ 170.0, 165.2, 160.8, 136.6, 131.2, 130.5, 125.8, 125.5, 125.4, 124.9,
3
6
105.3, 104.0, 55.6, 23.8; FTIR (neat): 3233, 3056, 1668, 1640, 1593, 1329, 1270, 1189, 1096,
ꢀ
1
+
+
8
3
21 cm ; MS (ESI) m/z 315 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H O N
17 19 4 2
15.1339; Found: 315.1343.
Nꢀ(2ꢀAcetamidophenyl)ꢀ3,4,5ꢀtrimethoxybenzamide (1e): From 3,4,5ꢀtrimethoxybenzoic acid
(0.581 g, 2.74 mmol) using the above general procedure. The crude residue was purified by silica
gel column chromatography (hexanes/EtOAc = 60/40; R = 0.25 in hexanes/EtOAc = 2/1). The
f
ο
1
product was obtained as a brown solid (0.801 g, 85%); mp = 204ꢀ205 C; H NMR (400 MHz,
8:2 CDCl :DMSOꢀd ): δ 9.94 (s, 1H), 9.71 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.9 Hz,
3
6
1
2
H), 7.29 (s, 2H), 7.24 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 3.94 (s, 6H), 3.88 (s, 3H),
1
3
1
.18 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 170.2, 164.9, 153.0, 140.8,
3
6
131.4, 130.5, 129.6, 125.9, 125.4, 125.3, 124.9, 104.9, 60.8, 56.2, 23.8; FTIR (neat): 3239, 3072,
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ꢀ1
+
1
658, 1642, 1599, 1431, 1324, 1272, 1185, 1098, 822 cm ; MS (ESI) m/z 345 [M+H] ; HRMS
+
(
ESI) m/z: [M+H] Calcd for C H O N 345.1445; Found: 345.1445.
1
8
21
5
2
Nꢀ(2ꢀAcetamidophenyl)benzamideꢀ2,3,4,5,6ꢀd (1aꢀd ): From benzoicꢀ2,3,4,5,6ꢀd acid (0.348
5
5
5
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
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
g, 2.74 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/EtOAc = 60/40; R = 0.25 in hexanes/EtOAc = 2/1). The
f
ο
1
product was obtained as a brown solid (0.589 g, 83%); mp = 256ꢀ257 C; H NMR (400 MHz,
CDCl ): δ 9.50 (s, 1H), 8.73 (s, 1H), 7.51 (dd, J = 8.0, 1.0 Hz, 1H), 7.09ꢀ7.00 (m, 2H), 6.95ꢀ6.88
3
13
1
(
m, 1H), 2.04 (s, 3H); C{ H}NMR (100 MHz, CDCl ): δ 170.3, 166.6, 133.4, 131.7, 130.8,
3
1
30.5, 128.3, 127.2, 126.3, 126.2, 126.0, 125.0, 23.6; FTIR (neat): 3231, 3091, 1646, 1512,
ꢀ1
+
1431, 1329, 1292, 1155, 1090, 821 cm ; MS (ESI) m/z 260 [M+H] .
3
1
Nꢀ(2ꢀAminophenyl)benzamide (1p): To a stirred solution of benzeneꢀ1,2ꢀdiamine (4.00 g, 37
mmol, 2 equiv) in DCM (100 mL) Et N (2.6 mL, 18 mmol, 1 equiv) was added dropwise at room
3
temperature. The solution was heated to reflux, and benzoyl chloride (2.15 mL, 18 mmol, 1
equiv) dissolved in DCM (80 mL) was added dropwise via dropping funnel over 90 min. The
solution was refluxed for 2 h and concentrated in vacuo. The residue was purified by flash
chromatography (hexanes: EtOAc 70:30) to afford the amide 1p (2.86 g, 75 %) as a brown solid.
1
H NMR (400 MHz, 8:2 CDCl :DMSOꢀd ): δ 9.40 (s, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.52 (d, J =
3
6
7
.0 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.27 (d, J = 7.7 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 7.81 (d, J
13
1
=
7.9 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 4.44 (bs, 2H); C{ H}NMR (100 MHz, 8:2
CDCl :DMSOꢀd ): δ 166.0, 142.2, 134.7, 131.5, 128.4, 127.9, 126.9, 126.4, 124.3, 118.0, 117.3;
3
6
ꢀ1
FTIR (neat): 3400, 3265, 3060, 1640, 1577, 1522, 1313, 1252, 1062, 746 cm ; MS (ESI) m/z
+
2
13 [M+H] .
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Nꢀ(2ꢀ(2,2,2ꢀTrifluoroacetamido)phenyl)benzamide (1q): Nꢀ(2ꢀaminophenyl)benzamide (1n,
2
12 mg, 1.0 mmol) was dissolved in CH Cl (15 mL) and cooled to 0 °C. Trifluoroacetic
2 2
anhydride (315 mg, 0.212 mL, 1.5 mmol) and Et N (152 mg, 0.210 mL, 1.5 mmol) were added
3
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
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7
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3
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0
sequentially. The mixture was stirred at room temperature for 2 h, washed with water (20 mL),
and dried over MgSO . The solvent was removed and the residue was purified by column
4
chromatography on silica gel (EtOAc/hexanes = 30/70) to afford the product 1q as a white solid
1
(
265 mg, 86%); H NMR (400 MHz, CDCl ): δ 9.98 (s, 1H), 8.61 (s, 1H), 7.92 (d, J = 8.1 Hz,
3
2
H), 7.62 (t, J = 7.4 Hz, 1H), 7.56ꢀ7.49 (m, 3H), 7.24ꢀ7.20 (m, 1H), 7.14ꢀ7.08 (m, 2H);
1
3
1
C{ H}NMR (100 MHz, CDCl ): δ 167.0, 156.2 (q), 132.7, 132.6, 130.1, 128.9, 128.4, 127.6,
3
127.5, 127.0, 125.8, 125.4, 117.3 (q); FTIR (neat): 3238, 3056, 1709, 1646, 1529, 1312, 1170,
ꢀ1
+
+
9
15, 754 cm ; MS (ESI) m/z 309 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H F O N
15 12 3 2 2
3
09.0845; Found: 309.0848.
General procedure for the synthesis of arylated benzamides (3aꢀn and 4bꢀo). To an ovenꢀ
dried 10 mL screwꢀcapped vial, containing a magnetic stir bar were added the benzamide (1, 0.3
mmol), iodoarene (2, 0.9 mmol), Pd(OAc) (6.7 mg, 0.03 mmol), Na CO (64 mg, 0.6 mmol),
2
2
3
Mn(OAc) (52 mg, 0.3 mmol) and tꢀAmOH (5 mL). The mixture was stirred for 36ꢀ40 h at 120
2
°C followed by cooling. The reaction mixture was diluted with EtOAc (10 mL) and filtered
through a pad of Celite and concentrated under reduced pressure. Water (10 mL) was added to
the crude residue and extracted with EtOAc (10 mL x 2). The combined organic layers were
washed with brine (20 mL), dried over MgSO , and evaporated in vacuo. The residue was
4
purified by column chromatography on silica gel (3:1 mixture of EtOAc: EtOH/hexanes = 10/90
to 50/50) to afford the desired arylated product (3aꢀn and 4bꢀo).
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Nꢀ(2ꢀAcetamidophenyl)ꢀ4'ꢀmethoxyꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide (3a): From Nꢀ(2ꢀ
acetamidophenyl)benzamide 1a (76 mg, 0.30 mmol) and 1ꢀiodoꢀ4ꢀmethoxybenzene 2a (211 mg,
0.90 mmol) using the above general procedure. The crude residue was purified by silica gel
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
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3
3
3
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4
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5
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5
5
5
5
5
5
6
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
column chromatography (hexanes/3:1 mixture of EtOAc: EtOH = 90/10 to 60/40; R = 0.30 in
f
hexanes/3:1 mixture of EtOAc:EtOH = 4/1). The product 3a was obtained as a brown solid (88
ο
1
mg, 82%; 9 mg of starting material 1a was recovered, 12%); mp = 197ꢀ198 C; H NMR (400
MHz, 8:2 CDCl :DMSOꢀd ): δ 9.44 (s, 1H), 9.23 (s, 1H), 7.65ꢀ7.56 (m, 2H), 7.55ꢀ7.50 (m, 1H),
3
6
7
.47ꢀ7.36 (m, 5H), 7.16ꢀ7.07 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 1.98 (s, 3H);
1
3
1
C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 168.0, 167.8, 158.3, 138.4, 136.0, 131.6,
3
6
1
29.7, 129.6, 129.3, 129.2, 129.1, 128.9, 127.4, 126.1, 124.4, 124.2, 124.0, 113.2, 54.5, 23.0;
ꢀ1
FTIR (neat): 3362, 3046, 2989, 1685, 1600, 1512, 1482, 1367, 1243, 1082, 822 cm ; MS (ESI)
+
+
m/z 361 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H O N 361.1547; Found: 361.1549.
22 21
3
2
Nꢀ(2ꢀAcetamidophenyl)ꢀ3'ꢀmethoxyꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide (3b): From Nꢀ(2ꢀ
acetamidophenyl)benzamide 1a (76 mg, 0.30 mmol) and 1ꢀiodoꢀ3ꢀmethoxybenzene 2b (211 mg,
0
.90 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/3:1 mixture of EtOAc: EtOH = 90/10 to 60/40; R = 0.30 in
f
hexanes/3:1 mixture of EtOAc:EtOH = 4/1). The product 3b was obtained as a brown solid (86
ο
1
mg, 80%); mp = 142ꢀ143 C; H NMR (400 MHz, 8:2 CDCl :DMSOꢀd ): δ 9.49 (s, 1H), 9.20 (s,
3
6
1
H), 7.64 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.51ꢀ7.44 (m, 3H), 7.28 (t, J = 7.8 Hz,
H), 7.14ꢀ7.07 (m, 2H), 7.06ꢀ7.00 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 3.75 (s, 3H), 1.99 (s, 3H);
1
13
1
C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 168.1, 167.7, 158.6, 140.8, 138.7, 136.2,
3
6
1
29.8, 129.5, 129.4, 129.3, 128.7, 127.3, 126.7, 124.5, 124.2, 124.0, 123.9, 120.1, 113.6, 112.2,
ꢀ1
54.4, 23.0; FTIR (neat): 3366, 3054, 2980, 1688, 1607, 1514, 1455, 1369, 1263, 1086, 821 cm ;
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2
2
2
2
2
2
2
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3
3
3
3
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3
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3
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4
4
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5
5
5
5
6
+
+
MS (ESI) m/z 361 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H O N 361.1547; Found:
2
2
21
3
2
3
61.1549.
Nꢀ(2ꢀAcetamidophenyl)ꢀ3',4',5'ꢀtrimethoxyꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide (3c): From Nꢀ(2ꢀ
acetamidophenyl)benzamide 1a (76 mg, 0.30 mmol) and 5ꢀiodoꢀ1,2,3ꢀtrimethoxybenzene 2c
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
(
265 mg, 0.90 mmol) using the above general procedure. The crude residue was purified by silica
gel column chromatography (hexanes/3:1 mixture of EtOAc: EtOH = 70/30 to 40/60; R = 0.20
f
in hexanes/3:1 mixture of EtOAc:EtOH = 2/1). The product 3c was obtained as a brown solid
ο
1
(
106 mg, 84%); mp = 149ꢀ150 C; H NMR (400 MHz, CDCl ): δ 8.24 (s, 1H), 7.82 (s, 1H),
3
7
.60 (d, J = 7.2 Hz, 1H), 7.50ꢀ7.43 (m, 1H), 7.42ꢀ7.35 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.05 (t,
J = 7.3 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.61 (s, 2H), 3.80 (s, 3H), 3.68
1
3
1
(
s, 6H), 1.93 (s, 3H); C{ H}NMR (100 MHz, CDCl ): δ 168.2, 152.4, 138.5, 136.6, 134.5,
3
1
34.1, 129.7, 129.6, 129.2, 129.1, 128.9, 127.8, 126.8, 125.5, 124.9, 124.5, 123.4, 104.9, 59.9,
55.1, 22.8; FTIR (neat): 3341, 3019, 2920, 1647, 1605, 1513, 1481, 1313, 1245, 1179, 1032, 822
ꢀ1
+
+
cm ; MS (ESI) m/z 421 [M+H] ; HRMS (ESI) m/z: [M+Na] Calcd for C H O N Na
2
4
24
5
2
4
43.1577; Found: 443.1585.
Nꢀ(2ꢀAcetamidophenyl)ꢀ4'ꢀacetylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide
(3d):
From
Nꢀ(2ꢀ
acetamidophenyl)benzamide 1a (76 mg, 0.30 mmol) and 1ꢀ(4ꢀiodophenyl)ethanꢀ1ꢀone 2d (221
mg, 0.90 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/3:1 mixture of EtOAc: EtOH = 80/20 to 50/50; R = 0.25 in
f
hexanes/3:1 mixture of EtOAc:EtOH = 4/1). The product 3d was obtained as a white solid (80
ο
1
mg, 72%; 12 mg of starting material 1a was recovered, 16%); mp = 187ꢀ189 C; H NMR (400
MHz, 8:2 CDCl :DMSOꢀd ): δ 9.64 (s, 1H), 9.35 (s, 1H), 7.98 (d, J = 7.7 Hz, 2H), 7.73 (d, J =
3
6
7.0 Hz, 1H), 7.67ꢀ7.50 (m, 6H), 7.42 (t, J = 4.7 Hz, 1H), 7.19ꢀ7.08 (m, 2H), 2.58 (s, 3H), 1.97 (s,
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7
8
9
13
1
3
H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀd ): δ 198.0, 169.1, 168.0, 145.1, 138.7, 137.2,
3 6
1
36.0, 130.9, 130.7, 130.5, 129.1, 129.0, 128.9, 128.8, 128.7, 128.5, 125.6, 125.3, 125.2, 27.2,
ꢀ1
24.0; FTIR (neat): 3109, 3026, 2991, 1684, 1669, 1513, 1454, 1356, 1256, 1039, 822 cm ; MS
+
+
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
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
(
ESI) m/z 373 [M+H] ; HRMS (ESI) m/z: [M+H] Calcd for C H O N 373.1547; Found:
23 21 3 2
3
73.1549.
Methyl 2'ꢀ((2ꢀacetamidophenyl)carbamoyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀcarboxylate (3e): From Nꢀ(2ꢀ
acetamidophenyl)benzamide 1a (76 mg, 0.30 mmol) and methyl 4ꢀiodobenzoate 2e (236 mg,
0
.90 mmol) using the above general procedure. The crude residue was purified by silica gel
column chromatography (hexanes/3:1 mixture of EtOAc:EtOH = 80/20 to 50/50; R = 0.35 in
f
hexanes/3:1 mixture of EtOAc:EtOH = 4/1). The product 3e was obtained as a white solid (80
ο
1
mg, 69%; 12 mg of starting material 1a was recovered, 16%); mp = 215ꢀ216 C; H NMR (400
MHz, 8:2 CDCl :DMSOꢀd ): δ 9.37 (s, 1H), 9.22 (s, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.70ꢀ7.32 (m,
3
6
13
1
8H), 7.18ꢀ7.06 (m, 2H), 3.90 (s, 3H), 2.02 (s, 3H); C{ H}NMR (100 MHz, 8:2 CDCl :DMSOꢀ
3
d6): δ 168.9, 167.9, 166.0, 144.4, 138.2, 136.0, 129.8, 129.7, 129.6, 129.0, 128.5, 128.2, 128.1,
1
1
28.0, 127.6, 127.5, 125.0, 124.3, 124.2, 51.6, 23.2; FTIR (neat): 3091, 2929, 1654, 1600, 1527,
ꢀ1
+
+
466, 1348, 1272, 1180, 1035, 821 cm ; MS (ESI) m/z 389 [M+H] ; HRMS (ESI) m/z: [M+H]
Calcd for C H O N 389.1496; Found: 389.1499.
2
3
21
4
2
Nꢀ(2ꢀAcetamidophenyl)ꢀ4'ꢀnitroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide
(3f):
From
Nꢀ(2ꢀ
acetamidophenyl)benzamide 1a (76 mg, 0.30 mmol) and 1ꢀiodoꢀ4ꢀnitrobenzene 2f (224 mg, 0.90
mmol) using the above general procedure. The crude residue was purified by silica gel column
chromatography (hexanes/3:1 mixture of EtOAc:EtOH = 70/30 to 50/50; R = 0.30 in
f
hexanes/3:1 mixture of EtOAc:EtOH = 3/1). The product 3f was obtained as a white solid (71
ο
1
mg, 63%; 13 mg of starting material 1a was recovered, 18%); mp = 195ꢀ196 C; H NMR (400
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