The palladium(ii)-catalyzed regioselective ortho-C-H bromination/iodination of arylacetamides with in situ generated imidic acid as the directing group: Mechanistic exploration

Article abstract of DOI:10.1039/c9ob01082c

In the present study, we report the palladium(ii)-catalyzed regioselective ortho-C-H bromination/iodination of challenging arylacetamide derivatives using N-halosuccinimides as halogenating agents. Diverse arylacetamides underwent the regioselective ortho-bromination and iodination of aromatic C-H bonds in the presence of a reactive benzylic C(sp³)-H bond without installing any bulky auxiliaries via unfavorable six-membered metallacycles. Weak coordination, the use of ubiquitous primary amides for challenging C-H functionalization, the simple catalytic system and the wide substrate scope are the key features of this transformation. Further, the halogenated amide derivatives were transformed into a variety of valuable synthons. Detailed mechanistic studies revealed some interesting aspects concerning the reaction pathway. We present for the first time strong evidence for the formation of imidic acid (in situ) from primary amides under Br?nsted acid conditions that eventually aids in the stabilization of palladacycles of amide derivatives and drives regioselective C-X bond formation.

Full text of DOI:10.1039/c9ob01082c

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Palladium(II)-Catalyzed
Regioselective
Ortho-C_H
Bromination/Iodination of Arylacetamides via in situ Generated
Imidic Acid as Directing Group: Mechanistic Exploration
Yogesh Jaiswal, Yogesh Kumar and Amit Kumar*
Department of Chemistry, Indian Institute of Technology Patna, Bihta 801106, Bihar, India
ABSTRACT
In the present study, we report palladium(II)-catalyzed regioselective ortho-C-H
bromination/iodination of challenging arylacetamide derivatives using N-halo-succinimide as
halogenating agents. Diverse arylacetamides underwent regioselective ortho-bromination and
iodination of aromatic C-H bonds in the presence of reactive benzylic C(sp3)-H bond without
installing any bulky auxiliary via unfavorable six-membered metallacycle. Weak coordination,
usages of ubiquitous primary amide for challenging C-H functionalization, simple catalytic
system and wide substrate scope are the key features of this transformation. Further, the
halogenated amide derivatives were transformed into a variety of valuable synthons. Detailed
mechanistic studies revealed some interesting aspects concerning the reaction pathway. We
present first time the strong evidence for the formation of imidic acid (in situ) from primary
amide under Brønsted acid conditions that eventually aids in the stabilization of palladacycle of
amide derivatives and drives for regioselective C-X bonds formation.
INTRODUCTION
Halo-derivatives, in particularly aromatic halides, have attracted much attention from organic
chemists owing to their unique electronic features and ubiquitous presence in a large number of
biologically relevant natural products and active pharmaceutical ingredients.1 Moreover,

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aromatic halides (X = Cl, Br, I) serve as versatile synthetic intermediates for the synthesis of
functionalized heterocycles, functional materials, and nucleophilic substitution reactions.2 They
are also used as a key precursor for the preparation of organometallic reagents.3 Due to their
intriguing chemical and biological properties, organic chemists have given considerable attention
to the development of efficient and selective synthetic strategies for their synthesis.
Traditionally, these derivatives were synthesized by following the classical routes a) electrophilic
aromatic substitution (SEAr),4a-b b) directed-ortho-metallation (DoM),4c and c) Sandmeyer
reaction4d. However, these classical methods have their own limitation such as strong reaction
conditions, limited substrate scope, low yields, and poor regioselectivity.
The direct and regioselective installation of halo functional groups (X = Cl, Br, I) on aromatic
compounds via the activation of unfunctionalized C(sp2)-H bonds in the presence of transition
metal is an alternate and effective route to obtain the desired aromatic halides.5 Nevertheless,
these methods have severe limitations as they strongly depend on the nature of directing groups.
In general, directing groups has to be preinstalled on the desired substrate to activate the
proximal C-H bond followed by uninstallation of directing groups after the desired operation,
which eventually increases the cost and time of overall reactions.6 Amide groups are key
structural motifs in many physiologically active compounds and recent years, it has been
extensively employed as a directing group for direct C-H bond functionalization via favorable
five-membered cyclometallation.7 Despite the great achievements in transition-metal-catalyzed
C-H activation using aromatic amides as versatile directing groups,8 very limited reports are
available in the literature where aliphatic amides were used for distal C(sp2)-H bond
functionalization.9 Indeed, Yu and co-workers in 2013 reported a very effective method for the
regioselective ortho-iodination on challenging N-substituted arylacetamides using molecular

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iodine as a sole oxidant (Scheme 1a).10 However, the success of this strategy completely depends
on the nature of amide auxiliaries, where acidic N-H bond coordinates to the metal-salt to
minimize the entropic cost for C-H activation. Hence, there is a need to develop an efficient and
regioselective approach to introduce the halides on challenging arylacetamides by using diverse
primary amide as a directing group without installing the bulky and costly auxiliaries. However,
the primary amide group, in particular, aliphatic amide is considered as one of the least reactive
functional moiety owing to their high degree of nitrogen lone pair delocalization and eventually
responsible for the generation of unfavorable metallacycle during the C-H activation reaction via
weak coordination. With these limitation in mind and continuation of our own research
emphasis on the development of a step-economical approach for C-H functionalization via
weakly coordinating group,11 we herein disclose an efficient and simple catalytic system for the
regioselective introduction of bromide and iodide on aromatic ring of arylacetamides catalyzed
by palladium(II)-salt (Scheme 1b). Detailed experimental and theoretical investigation
highlighted some interesting aspects of primary amide directing abilities and a triple role of TFA
in this transformation. To the best of our knowledge, aliphatic primary amide directed ortho-C-H
bromination/iodination has not been reported till date.
(a) previous work : Iodination of N-substituted arylacetamides10
I
H
NH-Ar
NH-Ar
Pd(OAc)2, I2, CsOAc
t-AmylOH/DMF, 65 oC
O
O
I
H
Ar = (4-CF3)C6F4
(b) this work: Bromination and Iodination of primary amide derivatives of
arylacetamides
H
H
NH2
NH2
Pd(OAc)2, NXS
TFA: DCE, 50 oC
O
O
X
H
X = Br, I

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Scheme 1. Acetamide directed catalytic ortho- C-H bromination/iodination of arylacetamides.
RESULT AND DISSCUSION
At the outset, we began our experiment by selecting phenylacetamide (1a) as designed substrate,
where the benzyl group is present adjacent to the amide functionality which makes the substrates
more receptive for further functionalization, commercially available NBS (N-bromo
succinimide) as the brominating reagents, Pd(OAc)2 as a choice of catalyst, DCE (1,2-
o
dichloroethane) as the desired solvent at 60 C (Table 1). The desired ortho-brominated
phenylacetamide (2a) was isolated in 5% yield only, and rest starting material (1a) was
recovered (entry 1). Previous observations from our laboratory revealed that the presence of
strong Brønsted acid is crucial for the primary amide directed palladium(II)-catalyzed activation
of C-H bond of arylacetamide derivatives. Therefore, we screened several Brønsted acids in
different proportions to get the optimal reaction conditions (entry 2-8), and we found that
addition of 10.0 equiv of trifluoroacetic acid (TFA) into the reaction mixture effectively
improved the yield of desired products (2a/2aa) in 60% and 25%, respectively (entry 3). The
enhanced efficiency of phenylacetamide can be attributed to the formation of imidic acid (OH-
C=NH) from amide (H2N-C=O) under acidic conditions.12 Indeed, it is well known that benzylic
C-H bond undergoes for C-Br bond formation under protic conditions.13 Interestingly, the
benzylic C-H bond remained unaltered under the given conditions, and that was quite
commendable achievements. Bromination in several other solvents was also investigated (entry
8-12), and we found that DCE was far superior to other solvents. On the other hand, we also
screened the various palladium salts (entry 13-15) and loading of the catalyst in the reaction
conditions and observed that 5 mol % of Pd(OAc)2 was best suited to promote the desired
transformation with good regioselectivity (entry 19). More importantly, when the reaction was

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carried out in the absence of Pd(II)-catalyst, the desired ortho-brominated 2a was isolated, albeit
in meager yield via classical electrophilic aromatic substitution reaction and rest starting
materials was recovered (entry 20). This result clearly demonstrates that the ortho-bromination
product is formed predominantly by the palladium(II)-catalyzed directed C-H activation via the
six-membered metallacycle transition state. Therefore, the reaction conditions described in entry
19 was selected as an optimal condition for the regioselective ortho-bromination/iodination of
arylacetamides.
Table 1. Optimization of the reaction conditions for ortho-C-H bromination of
phenylacetamidea
Br
NH2
NH2
NH2
NBS
cat.,
+
O
solvent, temp
O
O
Br
Br
1a
2aa
2a
entry
catalyst
solvent
acid additive
(equiv)
temp (oC)
yield (%)b
and time (h)
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
2a
2aa
1.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DCE
DCE
-
5
-
-
2.
TFA (5)
40
60
55
52
30
-
3.
DCE
TFA (10)
TFA (15)
TFA (25)
AcOH (10)
PivOH (10)
PTSA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
25
23
35
-
4.
DCE
5.
DCE
6.
DCE
7.
DCE
-
8.
DCE
36
18
-
-
9.
ACN
-
10.
11.
12.
Toluene
TFE
-
52
23
18
-
Ethyl acetate

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13.
14.
15.
16.
17.
18.
19.c
20.
Pd(TFA)2
PdCl2
DCE
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
60, 24
55
15
66
33
-
20
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
60, 24
50, 24
80, 24
r.t., 24
50, 12
50, 24
60, 24
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
15
30
-
42
66
20
5
15
-
aReaction conditions: 1a (0.25 mmol), Pd(OAc)2 (10 mol %), NBS (0.3 mmol), solvent (2.0 mL)
in sealed tube. bIsolated yield after column chromatography. c5 mol % of the Pd(OAc)2 was used.
PTSA = p-Toluenesulfonic acid, TFE = 2,2,2-Trifluoroethanol.
Scheme 2: Substrate scope with respect to N-bromo succinimide.a
NH2
NH2
Pd(OAc)2 (5 mol %)
NBS, TFA/ DCE
R
R
O
O
Br
1
2
NH2
Me
NH2
MeO
NH2
NH2
O
O
O
O
Me
Br
Br
2c, 75% (7%)
Br
2d, 74% (8%)
Br
2b, 63% (15%)
2a, 66% (15%)
NH2
NH2
NH2
O
O
O
O
O
Cl
Br
Br
Br
Br
2g, 52%b (9%)
2f, 45%b (8%)
2e, 78%
Cl
NH2
NH2
NH2
NH2
O
O
O
O
F
Br
O2N
Br
F3C
Br
2k, 50 (8)%d
Cl
Br
2h, , 75%b
2i, 58%c
2j, 62%c
aReaction conditions: 1a (0.25 mmol), Pd(OAc)2 (5 mol%), NBS (0.3 mmol), TFA (10 equiv),
o
b
c
DCE (2.0 mL) at 50 C for 24 h in sealed tube. 20 equiv of TFA was used. Reaction was

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performed in (4:1) of TFA : DCE at 100 oC. dReaction was performed in (1:3) of TFA : DCE at
80 oC. Yields of dihalogenated products are given in parenthesis.
Under the optimized condition, first we investigated the scope of arylacetamides with NBS and
results are summarized in Scheme 2. For instance, electron-rich substituents such as methyl,
methoxy, and dioxy attached at para and meta-positions of arylacetamides were successfully
tolerated and afforded the desired ortho-bromination products (2b-e) in good yields. The
structure of regioselective product (2e) was confirmed by single X-ray diffraction analysis.
Notably, arylacetamides containing moderate electron-withdrawing groups, such as halogen
functionality (X= Cl, Br, F) were also successfully employed to provide ortho-brominated
products (2f-i) in moderate to good yields. Indeed, these dihalogented derivatives provide a
strong platform for further synthetic manipulation. A substrate bearing a strong electron-
withdrawing group like -NO2 and -CF3 at para-position also reacted smoothly with NBS to
provide mono-brominated products (2j-k) in good yields.
Next, we explored the scope for this reaction with NIS (N-iodo succinimide), to obtain ortho-
iodination products. Delightfully, we observed that under the optimized reaction conditions the
iodinated product (3) was readily obtained using NIS as the source of iodine (Scheme 3).
Arylacetamides with electron-rich substituent could easily give the corresponding iodination
products (3b-e) in good yields with high regioselectivity. Structures of all synthesized products
were confirmed through the NMR analysis. Halogen substituent at para-position of aryl ring
reacted well to afford good yields of monoiodonation products (3f-g). When dicholrosubtituted
phenylacetamide was reacted under the optimized conditions, iodination occurred at a less
hindered site to give the product (3h) in 55% yield. However, arylacetamides attached with
electron-withdrawing groups (-F, -NO2, -CF3) at a different position of the aromatic ring, gave

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the desired iodination products (3i-k) in moderate yields. Gratifyingly, ortho-brominated
phenylacetamide was also compatible under the reaction condition to give ortho-dihalogenated
product (3l). Also, 2-napthylacetamide underwent the desired transformation smoothly to
produce monoiodinated-derivative (3m) in good yield and high regioselectivity. Crystal structure
of 3m further confirmed the absolute structure of the ortho-iodinated product. Next, we checked
the scope of α-methylphenylacetamide as a directing group for ortho-iodination under the
optimized reaction conditions and furnished the mono-iodinated product (3n) in 58% yield.
Scheme 3: Substrate scope with respect to N-iodosuccinimide.a
NH2
NH2
Pd(OAc)2 (5 mol %)
NIS, TFA/ DCE
R
R
O
O
I
1
3
NH2
NH2
Me
NH2 MeO
NH2
O
O
NH2
O
O
O
I
O
O
I
Me
I
I
I
3e, 70%
3d, 80%, (9%)
3a, 62% (18%)
3b, 66% (20%)
3c, 66% (8%)
NH2
NH2
NH2
NH2
Cl
Cl
NH2
O
O
O
O
O
Cl
I
Br
I
F
I
O2N
I
3j, 33%b
I
3f, 50% (8%)
3h, 55%b
I
3i, 35%b
3g, 60% (6%)
Br
CH3
NH2
NH2
NH2
NH2
O
O
I
O
F3C
I
O
I
3n, 58%
3k, 20%c
3l, 55%
3m, 78%
aReaction conditions: 1a (0.25 mmol), Pd(OAc)2 (5 mol %), NIS (0.3 mmol), TFA (10 equiv),
DCE (2.0 mL) at 50 oC for 24 h in sealed tube. b20.0 equiv of TFA was used. cReaction was
performed in (1:3) of TFA : DCE at 80 oC. Yields of dihalogenated products are given in the
parenthesis.

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Aware of the facts that aryl halides are the valuable synthons for organic chemists, we became
interested in showcasing the synthetic utility of ortho-bromo-phenylacetamide (2a) for various
organic transformation reactions (Scheme 4). The ortho-brominated phenylacetamide (2a) was
efficiently transformed to the halogenated benzyl nitrile (4a) and synthetically challenging
phenylacetic acid (4b) in good yields. Indeed, ortho-brominated phenylacetamide was further
employed as a key precursor for the cross-coupling reaction to form biarylacetamide (4c) via
Suzuki type cross-coupling reaction with para-methoxy-boronic acid.
Scheme 4: Synthetic utility of 2-bromo-phenylacetamide.
OH
NH2
2a
PdCl2 (10 mol %)
CN
20 % H2SO4/H2O
100 oC, 15h
O
O
CH3CN:H2O
60 oC, 12 h
Br
4a, 76%
Br
4b, 93%
Br
PdCl2 (5 mol %)
p-methoxy boronic acid
50 oC, 30 min
NH2
O
4c, 92%
OMe
Studies were performed to shed some light on mechanistic aspects (Scheme 5).
(1) A competition reaction between electron rich 4-methyl-phenylacetamide (1b) and electron
deficient 4-nitro-phenylacetamide (1j) was carried out under standard conditions and the desired
halogenated derivatives (2b) and (2j) were isolated in 57% and 4% yields, respectively. The
result concluded that reaction is strongly favored for the electron-rich amides over the electron-
deficient amide derivatives and highlighting that the desired transformation proceeds via base-

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assisted internal electrophilic type substitution (BIES) over the concerted metalation
deprotonation (CMD) pathway (Scheme 5a).
Scheme 5: Mechanism study
(a) Intermolecular Competition experiment
NH2
NH2
+
NH2
+
NH2
standard condition
O
O
O
O
O
O2N
Br
Me
Br
Me
O2N
1b
1j
2b, 57%
2j, 4%
(b) Directing group effect
NH2
NHCH2Ph
NHCH2Ph
standard condition
NH2
+
+
O
O
O
Br
Br
5a, 28%
1a
5
2a, 38%
(c) KIE experiment
Competition experiment
NH2
NH2
standard condition
2 h
NH2
H4/D4
D5
+
O
O
O
Br
1a-D5
1a
2a-D4 : 2a (1:1), 20%
Parallel experiment
NH2
NH2
+
NH2
standard condition
2 h
NH2
D4
D5
+
O
O
O
O
Br
Br
1a-D5
1a
2a-D4 (14%)
2a (18%)
(d) H/D exchange experiment
H/D (0% D)
NH2
NH2
standard condition
CF3COOD (10 equiv)
O
O
Br
1a
2a, 55%
H/D (14% D)
NH2
NH2
Pd(OAc)2
CF3COOD (10 equiv)
O
O
H/D
DCE
1a-d
1a

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(2) To examine the directing ability of primary amide group under the given conditions, we
further set a few competition experiments with differentially substituted amide, in particular to
secondary amide. Indeed, results clearly indicate that the challenging primary amide has a higher
priority as DG over the secondary amide under optimized reaction conditions (Scheme 5b).
(3) Next, intermolecular reaction (via parallel and competition) between (1a) and (1a-D5) were
carried out. Moderate values of the KIE were observed, both via competition and parallel
reactions, clearly suggests that C-H bond cleavage is not a rate-limiting step in this
transformation (Scheme 5c).
(4) Deuterium incorporation experiment with CF3COOD demonstrates the irreversibility of the
C-H activation step in this reaction, both in the presence of the halogenating agent and in the
absence of it (Scheme 5d).
Mechanistic investigation: To understand the origin of reactivity of the amide derivatives for
distal C-H bond activation under the established conditions, detailed control experiments were
further carried out (Figure 2 and 3). The amide has three possible coordinating sites under acidic
conditions: (a) carbonyl oxygen (-C=O), (b) imine nitrogen (-C=NH) and (c) electron-rich
nitrogen (-NH2) to form a six-membered palladacycle intermediate (Figure 1).
OH
NH
O
NH2
NH2
O
Pd
Pd
Pd
(A)
(A')
(A'')
Figure 1: Possible coordination sites of the primary amide with palladium(II) salt.

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Hence, we first decided to investigate how the primary amide group coordinates to the
electrophilic palladium(II) center under optimized conditions. It is well known that amide group
(H2N-C=O) undergoes tautomerism to form imidic acid (HO-C=NH) under certain physiological
conditions.12 Considering these facts, we anticipated that primary amide moiety under Brønsted
acid conditions might generate an imidic acid and imidic (-NH) coordinates to the palladium(II)
salt preferentially over the carbonyl oxygen (-C=O) site of amide moiety. To resolve the
ambiguity, we tried to obtain the crystal of the six-membered palladacycle intermediate, but
13
unfortunately, failed. Therefore, we decided to conduct several NMR (1H NMR, C NMR, and
15N NMR) and HRMS experiments along with preliminary DFT calculation. First, full quantum
chemical calculations were done with density functional theory (DFT) using the Gaussian 09
program package to understand the coordination site of the directing group under standard
conditions. The result demonstrates that the formation of complex A is more favored (ΔG = 3.6
kcal/mole) over the complex A′ with palladium (II) salt (for details, see SI). Hence, we believe
that under Brønsted acid conditions imidic acid (-NH) coordinates to the palladium(II) salt
preferentially over the carbonyl oxygen (-C=O) of phenylacetamide, which is considered to be
the starting point of the catalytic cycle.
1
The H NMR of phenylacetamide (1a) typically showed amide (-NH2) peaks around δ 5.46 and
5.91 ppm (Figure 2a). Interestingly, when phenylacetamide was mixed with 10.0 equiv of TFA, a
significant shift of amide and benzylic proton peaks were seen in the 1H NMR spectrum (Figure
2b). The new peak appeared at δ 8.31 ppm, which eventually correspond to the -NH of imidic
acid and peak at δ 6.59 ppm corresponds to OH of imidic acid. Indeed, we observed that benzylic
protons were also deshielded from δ 3.60 to 3.81 ppm.

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NH2
(a)
O
N-H protons of amide
(b)
OH
NH
NH2
CF3COOH
O
N-H proton of imine
O-H proton
(c) 1H NMR after basic work up
NH2
O
N-H proton of amide
(d)
NH2
O
carbonyl carbon of amide
(e)
OH
NH
iminyl carbon of imidic acid

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Figure 2. 1H NMR spectra in CDCl3 of (a) pure acetamide 1a, (b) 1a plus TFA (10.0 equiv) at rt,
(c) after following basic aqueous extraction, (d) 13C spectra of pure 2a (e) 13C spectra of 1a plus
TFA (10.0 equiv) at rt, (f) 1a in CF3COOD, and (g) HRMS spectrum of 1a in the presence of
CF3COOD (10.0 equiv) in acetonitrile.
Further, aqueous workup was carried out of the reaction mixture and 1H NMR of crude material
was again recorded. The peaks of phenylacetamide (-NH2) were again reemerged (Figure 2c).
Similarly, amide carbonyl carbon of phenylacetamide (1a) was observed at δ 173.6 ppm (Figure
2d), after addition of TFA, this peak shifted to δ 180.7 ppm which support the formation of
imidic carbon (Figure 2e). Additionally, both of amide protons were exchanged completely with
1
deuterium, when H NMR of (1a) was recorded in deuterated trifluoroacetic acid (Figure 2f).
The HRMS spectra of phenylacetamide (1a) was then recorded in deuterated trifluoroacetic acid,
and one small peak at m/z = 137.0793 was observed in HRMS spectrometry, which could be

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15
assigned to the corresponding deuterated imidic acid [C8H9DNO]+ (Figure 2g). The N NMR
spectrum of pure phenylacetamide in DMSO-d6 features four sharp peaks at δ 199.99, 111.11,
109.63 and 107.46 ppm (Figure 3a). These peaks were assigned to the nitrogen atom of amide
form which is present in the different state and peak corresponds to 199.99 may be attributed to
the N-O bond.12e Interestingly, in the presence of 10.0 euqiv of TFA in the reaction mixture,
15
only one peak retained at 199.99 (N-O bond) in N NMR spectrum (Figure 3b). These results
illustrate that the Brønsted acid promoted the tautomerization of amide to imidic acid, where
imidic acid N atom bonded with the O atom of DMSO-d6.
(a)
(b)
Figure 3. 15N NMR spectra in DMSO-d6 of (a) pure 1a, (b) 1a in the presence of CF3COOH at rt.

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O
NH2
N H
O
O
TFA
1
OH
NH
TFA
OCOCF3
Pd(TFA)2
O
Pd
O
N
NH2
NH2
OH
NH
Pd
TFA
(D)
O
O
X
Pd(OAc)2
Pd
2/3
F3COCO
F3COCO
OCOCF3
(A')
OCOCF3
(A)
OH
NH
Pd (IV)
(C)
OH
X
O
OCOCF3
O
N
NH
Pd
O
OH
H
OCOCF3
O
NH
Pd (II)
O
O H
CF3
TS-I
H+
(B)
OCOCF3
N X
N
X
CF3COOH
O
O
Scheme 6. The proposed reaction mechanism for Pd(II)-catalyzed distal activation of
arylacetamides.
Based on these detailed studies and previous reports,8,14 we propose a plausible reaction
mechanism for the ortho-bromination/iodination on challenging arylacetamides (Scheme 6). We
anticipate that reaction would have started with the generation of imidic acid from primary amide
1a under Brønsted acid conditions. Subsequently, in situ generated imidic acid species
coordinates with electrophilic palladium(II) salt to form the complex A via the imine moiety. A
regioselective C-H activation viz the base assisted internal electrophilic substitution (BIES)15
pathway leads to the formation of six-membered palladacycle B via transition state-I. Followed
by oxidative addition of NXS to the palladacycle B gave Pd(IV) species C. This species then
undergoes reductive elimination to afford the desired halogenated derivatives 2/3 and regenerate

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the electrophilic Pd(TFA)2 catalyst from species D in the presence of excess TFA. Based on the
outcome, we believe that TFA plays a triple role in this transformation. First, it activates N-
halosuccinimide viz the protonation of one of the two carbonyl groups and enhancing the
concentration of halogen cations (Br+, I+) and second, it facilitates the tautomerization of amide
to imidic acid and third, it increases the electrophilic character of Pd(II)-salt.
CONCLUSION
In summary, we have developed an efficient and practical strategy for regioselective ortho-C-H
bromination and iodination on the aromatic ring of challenging arylacetamide derivatives under
simple catalytic conditions. This protocol represents the first example of direct
bromination/iodination of ubiquitous arenes containing the primary amide group by using
palladium(II) salt without installing any bulky auxiliary. Detailed mechanistic studies
demonstrated that this reaction proceeds via generation of imidic acid (in situ) from primary
amide under Brønsted acidic conditions and possibly facilitate the formation of six-membered
metallacycle (-NH coordinated to palladium(II)) and drives C-X bond formation. The key roles
of TFA were determined as an activator of N-halosuccinimide through the protonation as well as
a facilitator for tautomerization process of amide to imidic acid. Indeed, we believe that these
detailed studies may help in better understanding the chemistry of amide and imidic acid in
catalytic C-H bond activation/functionalization.

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Experimental Section
1. General Consideration. Unless otherwise noted, all reagents were purchased from a
commercial supplier and used without further purification. All arylacetamides derivatives were
prepared by following the reported procedure in literature.16 All the reactions were run in sealed
1
tubes, and the indicated temperature was that of an oil bath. H NMR spectra were recorded at
13
19
400 MHz, C{1H} NMR spectra were recorded at 100 MHz, F NMR were recorded at 376
15
MHz and N NMR were recorded at 40.5 MHz, CDCl3 and DMSO-d6 were used as solvents.
Chemical shifts are reported in δ (ppm) referenced to CDCl3 (δ 7.26), DMSO-d6 (δ 2.50) for 1H
NMR and CDCl3 (δ 77.0), DMSO-d6 (δ 39.5) for 13C NMR. The following abbreviations are
used to explain multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad
singlet; J, coupling constant (hertz). Infrared spectra were recorded with an FT-IR apparatus.
High-resolution mass spectra (HRMS) spectra were obtained on an ESI-TOF (electron spray
ionization-time-of-flight) spectrometer, methanol and acetonitrile were used to dissolve the
sample. Column chromatography was performed on silica gel (100−200) mesh using ethyl
acetate and hexanes as eluents in different ratios.
2. General procedure for palladium catalyzed ortho-bromination/iodination of
arylacetamides (GP): To a clean oven-dried 15 mL sealed tube equipped with magnetic stir bar
was sequentially added arylacetamide (0.25 mmol, 1 equiv), Pd(OAc)2 (5 mol %, 2.8 mg), NXS
(0.3 mmol, 1.2 equiv.) Then, DCE (2.0 mL) was added followed by trifluoroacetic acid (190 µL,
10.0 equiv) was added to the reaction mixture. The sealed tube was tightly closed and placed in
pre-heated oil bath and stirred for 24 h at 50 oC. The progress of reaction was monitored by TLC
and after completion, the reaction mixture was cooled to room temperature and solvent was
evaporated under reduced pressure and diluted with ethyl acetate followed by neutralization with

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saturated solution of sodium bicarbonate. After extraction with ethyl acetate (15 mL x 3) organic
layer was washed with brine solution and dried over sodium sulphate. After evaporation of
solvent, the crude mixture was purified by column chromatography silica gel and ethyl
acetate/hexanes as eluent or acetone/DCM as eluent.
2-(2-Bromo-phenyl)-acetamide (2a) Following GP isolated as white solid (35 mg, 66% yield);
Rf (6:4 Hexane/EtOAc) = 0.3; Mp 168-170 oC; IR(ATR) 3385, 3184, 1663, 1394 cm-1; 1H NMR
(400 MHz, DMSO-d6) δ 7.57 (d, J = 8.0, 1H), 7.46 (brs, 1H), 7.37 – 7.29 (m, 2H), 7.21 – 7.14
13
(m, 1H), 6.97 (brs, 1H), 3.57 (s, 2H). C NMR (100 MHz, DMSO-d6) δ 170.8, 136.1, 132.2,
132.0, 128.5, 127.7, 124.5, 42.1. HRMS (ESI-TOF) m/z Calcd for C8H9BrNO [M + H]+
213.9862, found 213.9857.
2-(2,6-Dibromo-phenyl)-acetamide (2aa) Following GP isolated as white solid (11 mg, 15%
yield); Rf (6:4 Hexane/EtOAc) = 0.5; Mp 168-170 oC; IR(ATR) 3304, 3181, 2925, 1656 cm-1; 1H
NMR (400 MHz, CDCl3 + DMSO-d6) δ 7.47 (d, J = 8.2 Hz, 2H), 6.94 (t, J = 8.0 Hz, 1H), 6.50
(brs, 1H), 6.24 (brs, 1H), 3.92 (s, 2H). 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 169.8, 134.7,
131.6, 129.1, 125.7, 43.0. HRMS (ESI-TOF) m/z Calcd for C8H9Br2NO [M + H]+ 291.8967
found 291.8966.
2-(2-Bromo-4-methyl-phenyl)-acetamide (2b) Following GP isolated as white solid (36 mg,
o
63% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 175-177 C; IR(ATR) 3355, 3174, 2922, 1656,
1
1410 cm-1; H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.38 (brs, 1H), 7.22 (d, J = 7.8 Hz,
13
1H), 7.12 (d, J = 7.7 Hz, 1H), 6.93 (brs, 1H), 3.50 (s, 2H), 2.27 (s, 3H). C NMR (100 MHz,
DMSO-d6) δ 170.9, 138.1, 132.9, 132.3, 131.9, 128.1, 124.2, 41.6, 20.0. HRMS (ESI-TOF) m/z
Calcd for C9H11BrNO [M + H]+ 228.0019 found 228.0009.

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2-(2,6-Dibromo-4-methyl-phenyl)-acetamide (2bb) Following GP isolated as white solid (12
o
mg, 15% yield); Rf (6:4 Hexane/EtOAc) = 0.5; Mp 228-230 C; IR(ATR) 3408, 3175, 1665,
1390 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.57 (s, 1H), 7.47 (brs, 1H), 6.99 (brs,
13
1H), 3.53 (s, 2H), 2.31 (s, 3H). C NMR (100 MHz, DMSO-d6) δ 170.5, 137.6, 135.7, 134.8,
133.9, 123.3, 122.8, 41.1, 21.5. HRMS (ESI-TOF) m/z Calcd for C9H11Br2NO [M + H]+
305.9125 found 305.9116.
2-(2-Bromo-5-methyl-phenyl)-acetamide (2c) Following GP isolated as white solid (43 mg,
o
75% yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 145-147 C; IR(ATR) 3385, 3194, 2922, 1653,
1401cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 8.1 Hz, 2H), 7.16 (s, 1H), 6.99 (d, J =
8.1 Hz, 1H), 6.95 (brs, 1H), 3.51 (s, 2H), 2.25 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 170.9,
136.9, 135.7, 132.6, 131.9, 129.2, 121.2, 42.0, 20.4. HRMS (ESI-TOF) m/z Calcd for
C9H11BrNO [M + H]+ 228.0019 found 228.0025.
2-(2-Bromo-5-methoxy-phenyl)-acetamide (2d) Following GP isolated as white solid (45 mg,
o
74% yield); Rf (1:1 Hexane/EtOAc) = 0.3; Mp 161-163 C; IR(ATR) 3375, 3194, 2928, 1659,
1397 cm-1;1H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.8 Hz, 1H), 7.40 (brs, 1H), 6.95 (d, J =
2.9 Hz, 2H), 6.78 (d, J = 8.8, 2.9 Hz, 1H), 3.73 (s, 3H), 3.52 (s, 2H). 13C NMR (100 MHz,
DMSO-d6) δ 170.8, 158.5, 137.0, 132.7, 117.8, 114.9, 114.1, 55.4, 42.2. HRMS (ESI-TOF) m/z
Calcd for C9H11BrNO2 [M + H]+ 243.9968 found 243.9969.
2-(6-Bromo-benzo[1,3]dioxol-5-yl)-acetamide (2e) Following GP isolated as white solid (50
o
mg, 78% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 145-147 C; IR(ATR) 3394, 3207, 2915,
1653 cm-1;1H NMR (400 MHz, DMSO-d6) δ 7.34 (brs, 1H), 7.16 (s, 1H), 6.94 (s, 2H), 6.04 (s,
13
2H), 3.46 (s, 2H). C NMR (100 MHz, DMSO-d6) δ 170.9, 146.9, 146.9, 129.1, 114.6, 111.9,

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111.5, 101.8, 41.8. HRMS (ESI-TOF) m/z Calcd for C9H9BrNO3 [M + H]+ 257.9760 found
257.9764.
2-(2,4-Dibromo-phenyl)-acetamide (2f) Following GP isolated as white solid (33 mg, 45%
o
yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 148-150 C; IR(ATR) 3381, 3185, 2921, 1658, 1397
cm-1;1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.48
(brs, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.01 (brs, 1H), 3.55 (s, 2H). 13C NMR (100 MHz, DMSO-d6)
δ 170.4, 135.7, 133.9, 133.6, 130.4, 125.4, 120.1, 41.5. HRMS (ESI-TOF) m/z Calcd for
C8H8Br2NO [M + H]+ 291.8967 found 291.8971.
2-(2-Bromo-4-chloro-phenyl)-acetamide (2g) Following GP isolated as white solid (32 mg,
52% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 83-85 oC; IR(ATR) 3404, 3197, 2922, 1650 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.49 (brs, 1H), 7.44-7.37 (m, 2H), 7.02 (brs, 1H),
3.57 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 170.5, 135.3, 133.2, 131.9, 131.3, 127.5, 125.1,
41.4. HRMS (ESI-TOF) m/z Calcd for C8H8BrClNO [M + H]+ 247.9472 found 247.9481.
2-(2-bromo-4,5-dichlorophenyl)acetamide (2h) Following GP isolates as white solid (53 mg,
o
75% yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 175-177 C; IR(ATR) 3455, 3300, 3197, 1660,
1
1460. H NMR (400 MHz, DMSO) δ 7.85 (s, 1H), 7.58 (s, 1H), 7.56 (s, 1H), 7.01 (s, 1H), 3.57
(s, 2H). 13C NMR (100 MHz, DMSO) δ 171.03, 137.39, 133.51, 130.73, 130.67, 123.73, 41.59.
HRMS (ESI-TOF) m/z Calcd for C8H7BrCl2NO [M + H]+ 281.9083 found 281.9082
2-(2-Bromo-4-fluoro-phenyl)-acetamide (2i) Following GP isolated as white solid (34 mg,
o
58% yield); Rf (1:1 Hexane/EtOAc) = 0.4; Mp 120-122 C; IR(ATR) 3413, 3197, 2924, 1651
cm-1;1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.6 Hz, 1H), 7.44 (brs, 1H), 7.41 – 7.37 (m,
1H), 7.20 (td, J = 8.5, 2.5 Hz, 1H), 6.97 (brs, 1H), 3.55 (s, 2H). 13C NMR (100 MHz, DMSO-d6)
170.7, 161.79 and 159.34 (d, J = 245.0 Hz), 133.11 and 133.02 (d, J = 9.0 Hz), 132.5, 124.4,

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119.19 and 118.94 (d, J = 25 Hz), 114.54 and 114.33 (d, J = 21.0 Hz), 41.3. 19F NMR (376 MHz,
DMSO-d6): δ -114.4. HRMS (ESI-TOF) m/z Calcd for C8H8BrFNO [M + H]+ 231.9768 found
231.9770.
2-(2-Bromo-4-nitro-phenyl)-acetamide (2j) Following GP isolated as white solid (40 mg, 62%
o
yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 198-200 C; IR(ATR) 3407, 3201, 2927, 1655, 1339
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.19 (dd, J = 8.4, 2.0 Hz, 1H), 7.64 (d, J =
8.5 Hz, 1H), 7.59 (brs, 1H), 7.10 (brs, 1H), 3.73 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ
169.8, 146.8, 144.1, 133.0, 126.8, 124.7, 122.3, 42.0. HRMS (ESI-TOF) m/z Calcd for
C8H8BrN2O3 [M + H]+ 258.9713 found 258.9715.
2-(2-bromo-4-(trifluoromethyl)phenyl)acetamide (2k) Following GP isolated as white solid
(35 mg, 50% yield); Rf (1:1 Hexane/EtOAc) = 0.4; Mp 162-164 oC; IR(ATR) 3418, 3292, 1654,
1394 cm-1; 1H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61 – 7.52 (m,
2H), 7.07 (s, 1H), 3.68 (s, 2H). 13C NMR (100 MHz, DMSO) δ 170.1, 141.2, 132.9, 128.9 (q, J =
19
32.0 Hz), 128.7 (q, J = 3.0 Hz), 124.9, 124.3 (q, J = 4.0 Hz), 123.3 (q, J = 271.0 Hz), 41.9. F
NMR (376 MHz, DMSO-d6): -61.02. HRMS (ESI-TOF) m/z Calcd for C9H8BrF3NO [M + H]+
281.9736 found 281.9735.
2-(2-iodophenyl)acetamide (3a) Following GP isolated as white solid (40 mg, 61% yield); Rf
o
1
(6:4 Hexane/EtOAc) = 0.4; Mp 175-177 C; IR(ATR) 3391, 3188, 2921, 1658, 1390 cm-1; H
NMR (400 MHz, CDCl3 + DMSO-d6) δ 7.79-7.74 (m, 1H), 7.32 – 7.21 (m, 2H), 6.98 – 6.83 (m,
2H), 6.62 (brs, 1H). 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 171.2, 138.7, 130.3, 128.1,
127.9, 100.8, 46.8. HRMS (ESI-TOF) m/z Calcd for C8H9INO [M + H]+ 261.9723 found
261.9724.

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2-(2,6-Diiodo-phenyl)-acetamide (3aa) Following GP isolated as white solid (19 mg, 18%
yield); Rf (6:4 Hexane/EtOAc) = 0.6; Mp 238-240 oC; IR(ATR) 3401, 3182, 1649, 1038 cm-1;1H
NMR (400 MHz, CDCl3 + DMSO-d6) δ 7.79 – 7.76 (m, 2H), 7.01 (brs, 1H), 6.66 (brs, 1H), 6.58-
6.54 (m, 1H), 4.00 (s, 2H). 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 169.4, 140.7, 139.1,
129.8, 100.6, 52.7. HRMS (ESI-TOF) m/z Calcd for C8H9I2NO [M + H]+ 387.8690 found
387.8692.
2-(2-iodo-4-methylphenyl)acetamide (3b) Following GP isolated as white solid (44 mg, 66%
yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 192-194 oC; IR(ATR) 3384, 3198, 2904, 1648 cm-1;1H
NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.39 (brs, 1H), 7.18 (t, J = 8.0 Hz, 2H), 6.97 (brs,
13
1H), 3.51 (s, 2H), 2.25 (s, 3H). C NMR (100 MHz, DMSO-d6) δ 171.1, 139.0, 137.9, 136.5,
130.6, 128.8, 101.6, 46.1, 19.8. HRMS (ESI-TOF) m/z Calcd for C9H11INO [M + H]+ 275.9880
found 275.9889.
2-(2,6-Diiodo-4-methyl-phenyl)-acetamide (3bb) Following GP isolated as white solid (20 mg,
o
20% yield); Rf (6:4 Hexane/EtOAc) = 0.6; Mp 228-230 C; IR(ATR) 3380, 3166, 1653, 1040
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.72 (s, 1H), 7.44 (brs, 1H), 6.98 (brs, 1H),
13
3.50 (s, 2H), 2.30 (s, 3H). C NMR (100 MHz, DMSO-d6) δ 170.6, 141.1, 140.0, 139.1, 101.4,
100.8, 45.2, 26.2. HRMS (ESI-TOF) m/z Calcd for C9H11I2NO [M + H]+ 401.8846 found
401.8839.
2-(2-iodo-5-methylphenyl)acetamide (3c) Following GP isolated as white solid (45 mg, 66%
o
1
yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 183-185 C; IR(ATR) 3378, 3191, 1655, cm-1; H
NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.0 Hz, 1H), 7.38 (brs, 1H), 7.12 (s, 1H), 6.96 (brs,
1H), 6.81 (dd, J = 8.0, 1.7 Hz, 1H), 2.23 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 170.8,

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139.2, 138.4, 137.5, 131.7, 129.3, 97.6, 46.4, 20.4. HRMS (ESI-TOF) m/z Calcd for C9H11INO
[M + H]+ 275.9880 found 275.9889.
2-(2-Iodo-5-methoxy-phenyl)-acetamide (3d) Following GP isolated as white solid (58 mg,
80% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 178-180 oC; IR(ATR) 3365, 3178, 1655 cm-1; 1H
NMR (400 MHz, CDCl3 + DMSO-d6) δ 7.62-7.54 (m, 1H), 6.85 – 6.85 (m, 1H), 6.52 – 6.48 (m,
2H), 6.38 (brs, 1H), 3.69 (s, 3H), 3.54 (s, 2H). 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 171.3,
159.4, 139.1, 139.2, 116.2, 114.3, 89.0, 54.8, 47.1. HRMS (ESI-TOF) m/z Calcd for C9H11INO2
[M + H]+ 291.9829 found 291.9833.
2-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (3e) Following GP isolated as white solid (53 mg,
o
70% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 148-150 C; IR(ATR) 3400, 3194, 1655, 1474
cm-1;1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 2H), 6.96 (brs, 1H), 6.93 (s, 1H), 6.02 (s, 2H),
3.47 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 171.1, 147.8, 146.9, 132.8, 117.7, 111.0, 101.6,
89.6, 46.3. HRMS (ESI-TOF) m/z Calcd for C9H9INO3 [M + H]+ 305.9622 found 305.9636.
2-(4-bromo-2-iodophenyl)acetamide (3f) Following GP isolated as white solid (42 mg, 50%
yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 175-177 oC; IR(ATR) 3384, 3194, 1648, 1403 cm-1; 1H
NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.55 (dd, J = 8.2, 2.0 Hz, 1H), 7.48 (brs, 1H), 7.26
(d, J = 8.2 Hz, 1H), 7.03 (brs, 1H), 3.55 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 170.5, 140.0,
139.2, 132.5, 130.9, 120.0, 102.8, 45.8. HRMS (ESI-TOF) m/z Calcd for C8H8BrINO [M + H]+
339.8828 found 339.8841.
2-(4-chloro-2-iodophenyl)acetamide (3g) Following GP isolated as white solid (44 mg, 60%
o
yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 168-170 C; IR(ATR) 3384, 3200, 2924, 1648, 1404,
1
1024 cm-1; H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.48 (brs, 1H), 7.42 (d, J = 8.1 Hz,
13
1H), 7.31 (d, J = 8.2 Hz, 1H), 7.03 (brs, 1H), 3.57 (s, 2H). C NMR (100 MHz, DMSO-d6) δ

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170.6, 138.8, 137.4, 132.1, 131.6, 128.0, 102.2, 45.7. HRMS (ESI-TOF) m/z Calcd for
C8H8ClINO [M + H]+ 295.9334 found 295.9343.
2-(2-iodo-4,5-dichlorophenyl)acetamide (3h) Following GP isolated as white solid (44 mg,
o
55% yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 100-102 C; IR(ATR) 3394, 3200, 2923, 1650
1
cm-1. H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.04 (s, 1H), 3.58
13
(s, 2H). C NMR (100 MHz, DMSO) δ 170.0, 140.8, 139.1, 132.0, 130.7, 129.8, 100.1, 45.4.
HRMS (ESI-TOF) m/z Calcd for C8H7Cl2INO [M + H]+ 329.8944 found 329.8940.
2-(4-Fluoro-2-iodo-phenyl)-acetamide (3i) Following GP isolated as white solid (25 mg, 35%
o
yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 158-160 C; IR(ATR) 3381, 3191, 2924, 1651, 1477
cm-1;1H NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J = 8.4, 2.7 Hz, 1H), 7.44 (brs, 1H), 7.33 (dd, J
13
= 8.5, 6.2 Hz, 1H), 7.21 (td, J = 8.5, 2.7 Hz, 1H), 7.00 (brs, 1H), 3.55 (s, 2H). C NMR (100
MHz, DMSO-d6) δ 170.9, 161.42 and 158.96 (d, J = 246 Hz), 136.08 and 136.04 (d, J = 4.0 Hz),
19
131.95 and 131.87 (d, J = 8.0 Hz) 125.25, 125.01, 115.06, 114.85, 101.30, 101.22, 45.47. F
NMR (376 MHz, DMSO-d6): δ -115.4. HRMS (ESI-TOF) m/z Calcd for C8H8FINO [M + H]+
279.9629 found 279.9648.
2-(2-Iodo-4-nitro-phenyl)-acetamide (3j) Following GP isolated as white solid (26 mg, 33%
o
yield); Rf (6:4 Hexane/EtOAc) = 0.25; Mp 217-219 C; IR(ATR) 3426, 3291, 2921, 1661, 1342
cm-1;1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.19 (d, J = 8.4, 1H), 7.57 (d, J = 8.3 Hz,
2H), 7.11 (brs, 1H), 3.74 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 169.9, 147.6, 146.3, 132.9,
131.7, 122.8, 101.5, 46.3. HRMS (ESI-TOF) m/z Calcd for C8H8IN2O3 [M + H]+ 306.9574 found
306.9589.
2-(2-iodo-4-(trifluoromethyl)phenyl)acetamide (3k) Following GP isolated as white solid (16
o
mg, 20% yield); Rf (1:1 Hexane/EtOAc) = 0.3; Mp 166-168 C; IR(ATR) 3393, 3204, 1650,

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1323 cm-1; 1H NMR (400 MHz, DMSO) δ 8.11 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 6.8
13
Hz, 2H), 7.07 (s, 1H), 3.67 (s, 2H). C NMR (100 MHz, DMSO) δ 170.2, 144.7, 134.9 (q, J =
4.0 Hz), 131.6, 128.6 (q, J = 32.0 Hz), 124.8 (q, J = 3.0 Hz), 123.1 (q, J = 271.0 Hz), 101.9,
46.4. 19F NMR (376 MHz, DMSO-d6): -61.0. HRMS (ESI-TOF) m/z Calcd for C9H8IF3NO [M +
H]+ 329.9597 found 329.9575.
2-(2-Bromo-6-iodo-phenyl)-acetamide (3l) Following GP isolated as white solid (45 mg, 55%
yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 224-226 oC; IR(ATR) 3392, 3194, 1648, 1424 cm-1; 1H
NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.47 (brs, 1H),
7.01 (brs, 1H), 6.90 (t, J = 7.9 Hz, 1H), 3.89 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 169.3,
138.6, 138.4, 132.6, 130.3, 124.5, 103.4, 47.7. HRMS (ESI-TOF) m/z Calcd for C9H11INO [M +
H]+ 339.8828 found 339.8852.
2-(1-Iodo-naphthalen-2-yl)-acetamide (3m) Following GP isolated as white solid (60 mg, 77%
yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 205-207 oC; IR(ATR) 3378, 3188, 1648, 1390 cm-1;1H
NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.1, 5.0 Hz, 2H), 7.62 (t, J
13
= 7.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.05 (brs, 1H), 3.89 (s, 2H). C
NMR (100 MHz, DMSO-d6) δ 171.0, 139.4, 134.4, 132.5, 132.0, 128.8, 128.3, 128.25, 128.0,
126.3, 106.6, 48.6. HRMS (ESI-TOF) m/z Calcd for C12H11INO [M + H]+ 311.9880 found
311.9891.
2-(2-Iodo-phenyl)-propionamide (3n) Following GP isolated as white solid (40 mg, 58%
yield); Rf (6:4 Hexane/EtOAc) = 0.4; Mp 55-57 oC; IR(ATR) 3388, 3188, 2984, 1649, 1413cm-1;
1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 7.9 Hz, 1H), 7.38-7.34 (m, 3H), 6.97 (d, J = 5.8
13
Hz, 2H), 3.77 (q, J = 7.0 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). C NMR (100 MHz, DMSO-d6) δ

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174.4, 144.6, 139.1, 128.6, 128.5, 127.9, 101.5, 49.3, 18.8. HRMS (ESI-TOF) m/z Calcd for
C9H11INO [M + H]+ 275.9880 found 275.9887.
Procedure for synthesis of (2-Bromo-phenyl)-acetonitrile (4a)13: By following a reported
procedure,17 2a (0.2 mmol, 42 mg) in CH3CN/H2O (1:1 = 2.0 mL) was treated with PdCl2 (10
mol %, 3.5 mg) at 60 °C for 12 h. After completion, the reaction mixture was quenched with
water and extracted with ethyl acetate (15 mL × 3). Solvent was removed in vacuum, and crude
product was purified by column chromatography.
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0, 1H), 7.39 (td, J = 7.6,
13
1.1 Hz, 1H), 7.29 – 7.22 (m, 1H), 3.86 (s, 2H). C NMR (100 MHz, CDCl3) δ 133.1, 129.9,
129.8, 129.6, 128.1, 123.6, 116.8, 24.8.
Procedure for the synthesis of (2-Bromo-phenyl)-acetic acid (4b)18a: By following a reported
literature method,18b the solution of 2a (0.25 mmol, 42 mg) in 3 mL of 20% (v/v) sulfuric acid
was heated at 100 °C for 15 h. After reaction completion, the mixture was diluted with water and
extracted with ethyl acetate (15 mL × 3). The organic layer was washed with brine solution and
dried over sodium sulfate and concentrated under reduced pressure to give a white solid.
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.20 – 7.13 (m,
1H), 3.85 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 176.6, 133.5, 132.9, 131.5, 129.1, 127.6,
125.1, 41.3.
Procedure for synthesis of 2-(4'-Methoxy-biphenyl-2-yl)-acetamide (4c)11a: By following a
reported literature method,19 in 25 mL round bottom flask equipped with magnetic bar was
sequently added 2a (0.25 mmol, 53.5 mg), PdCl2 (5 mol%, 2.5 mg), K2CO3 (1.5 equiv, 51.7 mg)
followed by 4-methoxy boronic acid (1.5 equiv, 57 mg). Then DMF/H2O (1:1 = 3.0 mL) was

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o
added to reaction mixture. The reaction was stirred at 50 C in open air for 30 minutes. After
completion, the mixture was added to brine (15 mL) and extracted four times with ethyl acetate
(4 X 15 mL). The solvent was concentrated under vacuum and the product was isolated by
chromatography on a silica gel column using acetone in DCM as eluent.
1H NMR (400 MHz, CDCl3) δ 7.42 – 7.22 (m, 8H), 7.00 – 6.94 (m, 2H), 5.67 (s, 1H), 5.32 (s,
1H), 3.87 (s, 3H), 3.58 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 173.7, 158.9, 142.2, 133.1, 132.5,
130.7, 130.6, 130.1, 129.4, 129.0, 127.7, 127.5, 113.8, 55.3, 40.9.
1
N-benzyl-2-(2-bromophenyl)acetamide (5a)20 : H NMR (400 MHz, CDCl3) δ 7.60 (dd, J =
8.0, 1.1 Hz, 1H), 7.38 (dd, J = 7.6, 1.7 Hz, 1H), 7.29 (m, 6H), 7.17 (td, J = 7.7, 1.8 Hz, 1H), 5.88
13
(s, 1H), 4.45 (d, J = 5.8 Hz, 2H), 3.77 (s, 2H). C NMR (100 MHz, CDCl3) δ 162.3, 130.8,
127.6, 125.9, 124.5, 122.0, 121.4, 120.8, 120.3, 120.2, 117.8, 70.1, 69.8, 69.5, 36.8, 36.5.
ASSOCIATED CONTENT
Supporting Information
Detailed information on experimental procedures, characterization data, spectra and
crystallographic data (PDF).
AUTHOR INFORMATION
Corresponding Author
*Email: amitkt@iitp.ac.in or amitktiitk@gmail.com
ORCID
Amit Kumar: 0000-0002-1683-7740
Notes

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DOI: 10.1039/C9OB01082C
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Authors gratefully acknowledge Indian Institute of Technology (IIT) Patna and CSIR, New
Delhi (02(0229)/15/EMR-II), for financial support. Y. Jaiswal and Y. Kumar thank IIT Patna for
an Institute Research Fellowship. The authors also acknowledge SAIF-IIT Patna for providing
HRMS and XRD facilities. This work is dedicated to Prof. H.Ila (Dept. of Chemistry, JNCASR)
on the occasion of 75th birthday.
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