Acid-promoted palladium(II)-catalyzed ortho-halogenation of primary benzamides: En route to halo-arenes

Article abstract of DOI:10.1016/j.catcom.2019.105784

Br?nsted acid-promoted palladium(II)-catalyzed regioselective installation of halogens (Br, Cl, and I) to the aromatic ring of benzamide derivatives has been achieved using primary amides. A wide variety of benzamides were compatible under established conditions to afford the halogenated products without installing any external auxiliary. Mild reaction conditions, use of primary amide as a directing group, external additive-free conditions, and gram-scale reaction are some appealing features of this protocol. Detailed experimental results revealed that Br?nsted acid plays a critical role in this transformation.

Full text of DOI:10.1016/j.catcom.2019.105784

Accepted Manuscript
Acid-promoted palladium(II)-catalyzed ortho-halogenation of
primary benzamides: En route to halo-arenes
Yogesh Jaiswal, Amit Kumar
PII:
DOI:
Article Number:
Reference:
S1566-7367(19)30246-8
https://doi.org/10.1016/j.catcom.2019.105784
105784
CATCOM 105784
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Catalysis Communications
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9 August 2019
11 August 2019
Please cite this article as: Y. Jaiswal and A. Kumar, Acid-promoted palladium(II)-
catalyzed ortho-halogenation of primary benzamides: En route to halo-arenes, Catalysis
Communications, https://doi.org/10.1016/j.catcom.2019.105784
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ACCEPTED MANUSCRIPT
Acid-Promoted Palladium(II)-Catalyzed Ortho-Halogenation of Primary
Benzamides: En Route to Halo-Arenes
Yogesh Jaiswal and Amit Kumar* amitkt@iitp.ac.in or amitktiitk@gmail.com
Department of Chemistry, Indian Institute of Technology Patna, Bihta 801106, Bihar, India
*Corresponding author.

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Abstract
Brønsted acid-promoted palladium(II)-catalyzed regioselective installation of halogens (Br, Cl,
and I) to the aromatic ring of benzamide derivatives has been achieved using primary amides. A
wide variety of benzamides were compatible under established conditions to afford the
halogenated products without installing any external auxiliary. Mild reaction conditions, use of
primary amide as a directing group, external additive-free conditions, and gram-scale reaction
are some appealing features of this protocol. Detailed experimental results revealed that Brønsted
acid plays a critical role in this transformation.
Keywords: Amide, Brønsted acid, C-H activation, palladium, bromination, and chlorination.

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1. Introduction
Design and development of a sustainable strategy for the synthesis of high-value synthons are a
demanding and continuous task for contemporary organic chemists. Hence, to identify the
effective strategy that could satisfy the parameters of atom and cost-economy and avoid
excessive generation of chemical waste is well appreciated and in high demands worldwide.
Among the various functionalized organic molecules, aryl halides are considered as one of the
most valuable building blocks for organic, medicinal, materials, and industrial science [1-4].
Owing to their diverse electronic properties, the aryl halides are extensively employed for
various synthetic elaboration and serves as key precursors for the synthesis of numerous
organometallic reagents [5] and nucleophile substitution reactions [6]. Indeed, aryl halides are
the key structural motifs that are present in several important natural products, pharmaceuticals
(Figure 1), agrochemicals, solvents, and surfactants [7-9]. Classical methodologies for aryl
halides formation involve electrophilic aromatic substitution (SEAr) [10], directed-ortho-
metallation (DoM) [11], and Sandmeyer reaction [12] but are limited in application. Therefore,
the development of a new synthetic method for obtaining these valuable motifs from simple
synthetic precursors such as arenes under mild conditions is the long-standing interest of organic
chemists.
Figure 1. Selected examples of bioactive halogenated amide derivatives.

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The direct and site-specific C-H bond functionalization via either the presence of transition-
metals or metal-free conditions provides a viable and cost-economical route to obtain the desired
compounds [13-15]. However, the installation of desired functional groups to the robust and un-
polarized C-H bonds is a difficult task. In general, chemo- and regioselective C-H bond
functionalization occurred through conformationally rigid five- to seven-membered
metallacycles (in situ formation) in the presence of adjacent functional groups [16-17]. Several
functional groups, for instance, pyridine [18-19], azo [20], cyano [21], ester [22], keto [23], acid
[24], and amide [25-28], have been extensively employed as a directing group to complete the
transformations. However, the additional functional groups may have to be knocked-off after the
desired operation as per the requirements of final molecules, which eventually increases the cost
and steps of the overall reactions. Therefore, in recent times, the major focus has been shifted to
the use of either traceless directing groups or employ the omnipresent functional groups as
directing moiety for C-H functionalization and obviate the unnecessary steps [29].
Figure 1: Amide-directed ortho-halogenation of benzamides.
Amide groups, particularly secondary and tertiary amides, have been frequently employed by
various research groups (Rao, Ackermann, Glorius, Guan, and others) as a directing group for
regioselective installation of halo functional moiety to the aromatic system at ortho-positions in
the presence of different metal salts (Figure 1) [22, 25-28]. Interestingly, the free form of amide,

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namely, primary amide functionality, which is ubiquitous in biologically active and industrial
useful molecules, has been rarely utilized as a directing group for the desired C-H bond
functionalization. Moreover, the use of primary amide as the directing group eventually
circumvents two troublesome steps (installation and removal of an external auxiliary), which in
general reduces the atom and step economy of the desired transformation. In addition, the
primary amide moiety can be easily manipulated into a range of other functional groups. Hence,
the use of a primary amide group as a desired directing moiety for the C-H bond
functionalization is the advantageous choice over other groups. In a rare example, Rao and co-
workers revealed primary amide-directed installation of chlorine moiety on the aromatic ring of
benzamide. However, the reported method has remained limited in terms of substrate scope; only
one example was reported [22]. Very recently, Cai and coworkers have developed a method for
the regioselective introduction of halo groups at electron-deficient arenes using Ni(II) as a
catalyst. Moreover, the developed strategy strongly required an expensive silver salt as an
additive to complete the catalytic system, thus limiting their broad scope [28]. With these
understanding and continuation of our own research emphasis on the development of a step-
economical approach for C-H functionalization [30-32], we report here palladium(II)-catalyzed
primary amide-directed regioselective ortho-C-H halogenation of benzamide derivatives under
external additive-free conditions (Figure 1).
2. Experimental section
2.1 General procedure for palladium(II)-catalyzed ortho-halogenation of benzamides:
To a clean oven-dried 15 mL sealed tube equipped with magnetic stir bar, benzamide (0.25
mmol, 1.0 equiv), Pd(OAc)2 (5.0 mol%, 2.8 mg), and NXS (0.3 mmol, 1.2 equiv.) were added

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sequentially. DCE (2.0 mL) was then added to the reaction mixture followed by trifluoroacetic
acid (475 µL). The tube was tightly closed and placed in a preheated oil bath of 60 oC and stirred
for 24 h. In each case, the reaction was monitored by TLC, and after completion, the reaction
mixture was cooled to room temperature. The solvent was evaporated under reduced pressure
and then diluted with ethyl acetate followed by neutralization with a saturated solution of sodium
bicarbonate. After extraction with ethyl acetate (15 mL x 3), the organic layer was washed with
brine solution and dried over sodium sulphate. After evaporation of the solvent, the crude
mixture was purified by column chromatography silica gel using ethyl acetate/hexanes as the
eluent.
3. Results and Discussion
We initiated our studies by selecting benzamide (1a) as a model substrate, commercially
available NBS as the brominating reagent, Pd(OAc)2 as the choice of catalyst, and DCE as the
o
solvent under acidic conditions at 80 C (Table 1, entry 1). Under the given conditions, the
desired product 2a was isolated in 45% yield. To increase the overall yield of ortho-bromo-
benzamide 2a, several reaction parameters were further screened. For instance, when the reaction
o
was performed with 25.0 equiv of TFA at 60 C, the desired mono-brominated product 2a was
isolated in 75% yield along with dibrominated product 2aa in 12% yield (entry 3). The
dibrominated product could be easily separated from the mono-brominated product through the
column chromatography. Interestingly, when the reaction was carried out with
trifluoromethanesulfonic acid (TfOH) under the similar conditions, (entry 9, table-1), the desired
product was obtained along with the meta-brominated product in 18% and 22% yields,
respectively. Thereafter, the effects of time and temperature were also examined, and the results
revealed that these factors play an important role in controlling the regioselectivity. Long

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reaction time and high temperature lead to the formation of a dibrominated product (for details,
see supporting information). Similarly, the reaction was also tested in several other solvents
(entry 8-13), and we found that DCE was far superior to other solvents. Further, we screened
various palladium salts and loading of the catalyst and observed that 5 mol % of Pd(OAc)2 was
best suited to promote the desired transformation. A control reaction (in the absence of TFA and
Pd(II)-catalyst, entry 15 and 16) demonstrate the indispensable role of Brønsted acid and
palladium(II)-salt in this transformation.
Table 1. Optimization of the reaction conditions for ortho-C-H bromination of benzamidea
entry
solvent
acid additive temp ( oC) and
yield (%)b
(equiv)
TFA (5)
time (h)
80, 24
80, 16
60, 24
60, 24
80, 16
60, 24
80, 16
80, 16
60, 24
60, 24
60, 24
60, 24
60, 24
60, 24
80, 24
2a
45
63
75
66
25
15
48
22
18
38
40
70
22
60
15
2aa
trace
22
12
25
0
1.
2.
3.
4.
5.
6.
7.
8.
DCE
DCE
TFA (25)
TFA (25)
TFA (30)
PTSA (25)
BF3·OEt2 (1.5)
AcOH (25)
PivOH (25)
TfOH (3)
TFA (25)
TFA (25)
TFA (25)
TFA (25)
TFA (25)
-
DCE
DCE
DCE
DCE
0
DCE
12
0
DCE
9.c
DCE
-
10.
11.
12.
13.
14.
15.
ACN
0
EtOAc
CHCl3
Toluene
TFE
5
15
0
33
-
DCE

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16.d
17.e
18.e
19.
DCE
DCE
DCE
DCE
TFA (25)
TFA (25)
60, 24
60, 24
60, 24
60, 24
-
-
10
5
68
36
-
AcOH (25)
AgOTf (1.5)
-
Reaction conditions: 1a (0.25 mmol), Pd(OAc)2 (5 mol %), NBS (0.3 mmol), and solvent (2.0 mL) in a
sealed tube. bIsolated yield after column chromatography. c22% of meta-substituted product was
isolated. dReaction was carried out without a catalyst under similar conditions and yielded a meta-
substituted product. ePd(TFA)2 was used as a catalyst.
Once we optimized the reaction conditions, various benzamide derivatives bearing both electron-
donating and electron-withdrawing groups were evaluated (Scheme 1). The presence of electron- rich
groups such as methyl and methoxy at para and meta positions were well tolerated and afforded
desired products (2b, 2c, 2d) in good yields along with some dibrominated products. The resultant
products were characterized by NMR techniques (1H NMR and 13C NMR). A reaction of meta-methoxy-
benzamide with NBS produced the regioselective monobrominated product (2c) in moderate yield,
along with other isomers that could not be separated through column chromatography. The synthetic
versatility of this transformation was further demonstrated through the scale-up synthesis. The desired
ortho-brominated-benzamide (2a) was obtained without a substantial drop in the overall yield.
Substrates with halogen substituents worked well with NBS and afforded the important difunctionalized
benzamides (2e-h) in good yields, which can be further utilized for useful synthetic application.
Indeed, benzamide containing strong electron-withdrawing groups such as -NO2 and -CF3 at para
positions also afforded the desired products (2i-j) in moderate yields under slightly modified
reaction conditions.
Scheme 1: Substrate scope with respect to NBS.a

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aReaction conditions: 1 (0.25 mmol), Pd(OAc)2 (5 mol %), NBS (0.3 mmol), TFA (25.0 equiv),
and DCE (2.0 mL) at 60 oC for 24 h in a sealed tube. bReaction was performed at 2.0 mmol scale.
cReaction was performed in DCE:TFA (1:1). dReaction was performed in TFA as a solvent at 90
oC. Dibrominated products were separated by column chromatography and yields are given in
parentheses.
Scheme 2: Substrate scope with respect to NCS and NIS.a

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aReaction conditions: For chlorination 1 (0.25 mmol), Pd(OAc)2 (5 mol %), NCS (0.3 mmol),
o
b
and TFA:DCE (3:2) = 2.0 mL were reacted at 90 C for 24 h in a sealed tube. Reaction was
o
performed in TFA as a solvent at 90 C. For iodination 1 (0.25 mmol), Pd(OAc)2 (10 mol %),
NIS (0.3 mmol), TFA (25.0 equiv.), and DCE (2.0 mL) were reacted at 60 oC for 24 h in a sealed
tube. Dichlorinated products were separated by column chromatography, and yields are given in
parentheses.
To demonstrate the generality and scope of the developed catalytic system and high demands of
arene-chlorides, we further became interested in installing the chlorine moiety at the aromatic

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ring of the benzamide derivatives (Scheme 2). We observed that with a slight modification of the
reaction conditions, the chlorinated product (3a) was readily obtained using NCS as the source of
chlorine (for details, see SI). Benzamides possessing electron-donating substituent at ortho,
meta, and para position could easily afford the corresponding chlorinated products (3b-f) in
good to excellent yields. The structure of the regioselective product (3c) was confirmed by a
single X-ray diffraction analysis. Dioxy-substituted benzamide was also reacted well under the
reaction conditions, and chlorination occurred at the less-hindered side (3g). Halogen substitutes
such as -Br and -Cl at para and meta position of benzamides also reacted smoothly to afford the
desired products (3h-j) in good yields. Electron-withdrawing substituents such as –F, -NO2, and
–CF3 were also compatible to give the corresponding chlorinated products (3k-m) in moderate to
good yields under slightly modified reaction conditions. Subsequently, we explored the scope of
the optimized reaction for the regioselective introduction of the iodo group at the aromatic ring
of benzamide derivatives. Fortunately, the reaction of benzamide and 4-methyl-benzamide with
NIS under given conditions afforded the desired products (4a and 4b) in moderate yields
(scheme 2).
To understand the electronic preference and mechanism pathway of this reaction, some
additional control experiments were performed (Scheme 3). For instance, an intermolecular
competition experiment between an electron-donating substrate (1b) and electron-withdrawing
substrate (1j) was treated under standard conditions. The reaction provided product (2b) in 62%
yield and (2j) was isolated in a trace. This result suggests that the reaction is strongly favored for
an electron-donating group over the electron-withdrawing group and it proceeds via the base-
assisted internal electrophilic type substitution (BIES) pathway [33-34] (Scheme 3a). Next, we
performed the intermolecular competition experiment with tertiary amide and ester of benzamide

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with primary amide under optimized conditions to understand the relative directing ability of
these functional groups. The outcome of these reactions certainly illustrates that primary amide
has a superior directing ability than the ester and tertiary amide in this reaction condition
(Scheme 3b). On the other hand, the deuterium exchange experiment with D2O in the presence
and absence of NBS revealed that the ortho-C-H bond activation is an irreversible process in this
reaction (Scheme 3c).
Scheme 3. Mechanism Study

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Based on this supportive evidence and literature precedence [26, 27, 35], a plausible reaction
mechanism is proposed for regioselective ortho-halogenation of benzamides (Scheme 4). The
coordination of imidic nitrogen (OH-C=NH) (in situ generated from amide under acidic
conditions) atom to the active palladium species provides intermediate A. A regioselective C-H
activation viz the base-assisted internal electrophilic substitution (BIES) pathway leads to the
formation of thermodynamically favored five-membered palladacycle B. Subsequently, oxidative
insertion of NXS to the palladacycle results in the formation of intermediate C. Then, the
reductive elimination of intermediate C afforded the desired products 2/3/4 and regenerated the
catalyst (Pd(TFA)2) in the presence of excess TFA. Indeed, we believe that TFA plays a triple
role in this reaction: a) facilitator for tautomerization process of the amide to imidic acid, b)
activator of N-halosuccinimide through the protonation, and c) regeneration of electrophilic
palladium salt.
Scheme 4. Mechanism for the formation of halo-arenes.

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4. Conclusion
In summary, we reported for the first time palladium(II)-catalyzed regioselective ortho-
halogenation of primary benzamides under mild and external additive-free conditions assisted
with a primary amide group. The developed catalytic systems allowed site-selective
bromination/chlorination/iodination on primary benzamides with ample scope and excellent
functional group tolerance and satisfied the parameters of sustainable chemistry. Preliminary
mechanistic studies support the formation of imidic acid in situ under Brønsted acid condition,
which coordinates with a palladium salt to achieve regioselective halogenation.
Acknowledgments
The authors gratefully acknowledge Indian Institute of Technology (IIT) Patna and CSIR, New
Delhi (02(0229)/15/EMR-II), for financial support. Y. Jaiswal thank IIT Patna for an Institute
Research Fellowship. The authors also acknowledge SAIF-IIT Patna for providing HRMS and
XRD facilities.
Conflict of interest
There is no conflict of interest.
Appendix A. Supplementary data
1
Experimental details, characterization of products, and H, 13C NMR, and XRD data are
provided.

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Highlights:
 Palladium-catalyzed ortho-halogenation of primary benzamides.
 Broad substrate scope with 24 examples and scale up synthesis.
 NMR study support the formation of imidic acid from primary amide with Brønsted acid.
 Reaction proceeds via the formation of five-membered metallacycle.
Graphical abstract