Primary Amide Directed Regioselective ortho-C-H-Arylation of (Aryl)Acetamides

Article abstract of DOI:10.1021/acs.joc.6b02353

An efficient and regioselective palladium(II)-catalyzed primary acetamide assisted ortho arylation of arylacetamide has been discovered. This is the first report where functionalizable primary acetamide (?CH₂CONH₂) is used as a directing group for C(sp²)-H activation/cross-coupling reactions, circumventing the extra steps of installation and subsequent removal of the directing groups. The synthetic utility of this transformation is demonstrated through the scale-up synthesis. In addition, the primary acetamide can be manipulated into synthetically important derivatives such as nitriles and carboxylic acids.

Full text of DOI:10.1021/acs.joc.6b02353

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Note
Primary Amide Directed Regioselective
Ortho-C-H-Arylation of (Aryl)Acetamides
Yogesh Jaiswal, Yogesh Kumar, Rima Thakur, Jagannath Pal, Ranganathan Subramanian, and Amit Kumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02353 • Publication Date (Web): 10 Nov 2016
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Primary Amide Directed Regioselective Ortho-C-H-Arylation of
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(Aryl)Acetamides
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Yogesh Jaiswal,†Yogesh Kumar,† Rima Thakur‡ Jagannath Pal,† Ranga Subramanian† and Amit
Kumar*†
†Department of Chemistry, Indian Institute of Technology Patna, Bihta 801103, Bihar, India.
‡Department of Chemistry, National Institute of Technology Patna, Patna- 800005, Bihar, India.
*E-mail: amitkt@iitp.ac.in or amitktiitk@gmail.com
Table of Contents/Abstract Graphic
Abstract
An efficient and regioselective palladium(II)-catalyzed primary acetamide assisted ortho
arylation of arylacetamide has been discovered. This is the first report where functionalizable
primary acetamide (-CH2CONH2) is used as a directing group for C(sp2)-H activation/cross-
coupling reactions circumvent the extra steps of installation and subsequent removal of the
directing groups. The synthetic utility of this transformation is demonstrated through the scale-up
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synthesis. In addition, the primary acetamide can be manipulated into synthetically important
derivatives such as nitriles and carboxylic acids.
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Directing group assisted transition metal catalyzed selective C-H bond functionalization has
emerged as an efficient and robust synthetic tool for construction of C-C and C-X bonds for the
synthesis of complex target molecules from ubiquitous C-H bonds.1-2 In the past decade, a
variety of directing groups such as acetanilides,3 pyridyls4, oxazolyl,5 oximes,6 trizoles7 and N-
substituted secondary and tertiary amides8 have been introduced for the regioselective C-H
transformation. However, a major limitation of these strategies lie in requirements of pre-
installation of directing groups followed by their uninstallation, which demands two extra steps
and by virtue of which the atom and step economy of the complete transformation is eventually
reduced.9 Hence, to make direct C-H functionalization transformation more appealing and
attractive for the routine synthesis of organic compounds, developing new directing groups are
still highly desirable.
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Scheme1: Different synthetic routes toward the diverse product of arylacetamides.
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Biaryl and its derivatives are key structural motifs present in many natural and synthetic
products including light-emitting devices.10 Biarylacetamide displays a broad range of biological
activities.11 This key scaffold can be procured by cross coupling reaction on using N-substituted
amides as directing groups (Scheme 1).12 Wang and co-workers first reported a method for
ortho-arylation of benzamides and latter on Laha et al. attained chemo- and regioselective ortho-
benzylation of benzamides by using primary amide as a directing groups.13a,b In spite of these
significant progress, regioselective ortho-arylation under the mild conditions and further
utilization of the directing group is major challenge for organic chemists. 12a,14 Yu and coworker
first reported the application of phenylacetic acid and its derivatives as directing group for
regio- and chemoselective C-H functionalization.15,16 Inspired by the pioneer work of Yu et al.
and our interest in transition metal catalyzed reactions,17 we herein report a functionalizable
primary acetamide directed palladium (II)-catalyzed regioselective ortho-arylation of aryl-
acetamides. To the best of our knowledge, primary acetamide as a directing group to form
arylation products has never been reported earlier. The primary amides are widely available in
nature and can be easily manipulated into a range of other functional groups such as acids,
nitriles, and amines.18 Use of primary acetamide as a directing group for ortho C-H activation
will be an exciting addition to the literature.
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Table 1.Optimization of reaction conditionsa
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Entry
1.
Solvent
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
HFIP
Oxidant
Ag2CO3
AgO
Yieldb (%)
Ratio (3a:3aa)c
11
trace
11
n.d.
n.d
2.
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3.
AgOAc
AgSbF6
AgBF4
--
n.d
4.
90
1.3:1
6:1
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84
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0
n.d.
5.6:1
10:1
n.d.
n.d.
n.d.
7.
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
66
8.
TFA
30
9.
DMF
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10.
11.
DMSO
NMP
trace
trace
aReaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), Pd(OAc)2 (5 mol%), Oxidant (0.5
mmol), solvent (2.5 mL), at 50 oC for 8 h in pressure tube. bCombined yield of 3a and 4a. cRatio
of 3a and 4a was determined after isolation of product through column chromatography. n.d =
not determined.
Phenylacetamide 1a and iodobenzene 2a were selected as the designed substrates to optimize the
reaction conditions and the results are summarized in Table 1.The reaction of 1a and 2a was
conducted in the presence of Pd(OAc)2 as a catalyst and Ag2CO3 as an oxidant in acetic acid at
50 oC. The desired monoarylated product 3awas obtained, albeit in a low yield of 11% (Table 1,
entry 1). Inspired by the initial result, we optimized various parameters of the reaction conditions
such as solvent and oxidants. The efficiency and regioselectivity of the reaction were
significantly improved by using AgBF4 as a suitable oxidant, the monoaryalted compound 3a
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was obtained as a major product in 72% yield with a high selectivity (6:1) (Table 1, entry 5).
Other sliver salts such as AgO, AgOAc, and AgSbF6 were less effective (entries 2-4). Although
the use of AgSbF6 allowed the formation of arylated product in 90% yield, regioselectivity was
compromised (1.3:1, entry 4). It is important to note that, a control experiment in the absence of
silver salt yielded no product and the starting material remained intact (entry 6).7f Furthermore,
the screening of the reaction solvent exposed that acetic acid is the best choice (entry 5) among
other solvents such as HFIP, TFA, DMF, and DMSO (entries 7-11). It is noteworthy that other
parameters such as the reaction time and temperature played a very important role in controlling
the regioselective outcome. It was observed that long reaction time and high temperature lead to
the formation of biarylated product as a major compound (for the details see the SI, Table 1).19
Additional experiments also revealed that the presence of a catalyst is essential for the progress
of reaction (see the SI, Table 2)19 and increase/decrease in the loading of catalyst gave inferior
yield. Finally, the reaction conditions described in entry 5 were selected as the standard condition
for further exploration.
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With an optimized catalytic system in hand, we next investigated the scope of palladium-
catalyzed primary acetamide directed ortho-arylation of phenylacetamides (Scheme 2). We noted
that various arylacetamides substituted with electron donating groups (EDG) such as methyl,
methoxy, and 3,4-dioxy at ortho, meta and para positions of the aryl ring underwent smooth
ortho-arylation reaction to afford the highly regio-controlled monoarylated products in 55-92%
yields (3b-3e). Interestingly, the substrate bearing methyl group at meta-position (1d), afforded
mono-arylated product 3d in 92% yield. Phenylacetamides containing halo groups such as
chloro, fluoro and bromo were also suitable substrates to yield the corresponding products,
which enabled a potential application for further functionalization (3f-3i).
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Scheme 2. Scope of ArylAcetamide Derivativesa
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aReaction condition see: entry 5, Table 1. Yield of diarylated product is shown in parentheses.
b75 oC. c15 h. d100 oC. e24 h.
However, the presence of strong electron withdrawing group such as nitro1j at para position of
phenyl ring of phenylacetamide reduced the reactivity and resulted in only 40% yield of 3j even
at a higher temperature (100 oC). Under the standard conditions, when 2-napthyl-acetamide was
subjected, we got the desired product 3k in 65% yield. In general, phenyl ring substituted with
electron donating groups afforded the arylation products in higher yields (3a-3e) in comparison
to the electron withdrawing substituted groups (3f-3j) with higher selectivity.
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Scheme 3.Substrate scope for the synthesis of various mono-arylated acetamide Productsa
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aFor reaction condition: see entry 5, Table 1. Yield of diarylated product is shown in parentheses.
b75oC. c15 h.
Subsequently, the scope of the optimized strategy was further extended with various aryl iodide
substrates (Scheme 3). Iodobenzene with electron donating groups (EDG) such as methyl and
methoxy at para and meta position, gave the required products in 55-75% yields (3l-3o).
Interestingly, when 4-iodoanisole was reacted with phenylacetamide 1a leads to monoarylated
product 3o in moderate yield (55%). This may be due to the self-coupling of 4-iodoanisole
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leading to the formation of 4,4’-dimethoxy biphenyl as a side product. Of note, the presence of a
stronger electron-withdrawing group (-CF3and -NO2) at the para-position of iodobenzene,
resulted in moderate yields (35-60%) of required products (3p-3q, Scheme 3). Similarly, when 1-
iodonaphthalene was used as the coupling partner, corresponding product 3r was obtained in
52% yield. In addition, when phenylacetamide bearing methyl group at the meta-position
coupled with iodobenzene substituted with methoxy, methyl and hydroxyl group under
optimized conditions, the corresponding products were isolated in moderate to good (58-90%)
yields with excellent selectivity (3s-3u).
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Next, we sought to evaluate the scalability of the reaction under established protocol (Scheme 4).
The reactions involving 10 mmol of phenylacetamides 1a and 15 mmol of the iodobenzene 2a
was subjected under standard conditions. Subsequently, the product 3a was procured in 1.35 g
(64%) and there was no substantial drop in the yield. This result further demonstrates the
robustness of the optimized strategy.
Scheme.4 Gram-Scale Reaction
Furthermore, a competition experiment between electron rich 4-methoxy phenylacetamides 1c
and electron deficient 4-bromophenylacetamide 1g revealed that catalytic ortho-arylation is
slightly favored for the electron rich arylacetamide over the electron deficient arylacetamide
(Scheme 5). Ratio of product was found in 3c:3g = 1.3:1 (for detail see SI).19
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Scheme 5: Competition Experiment
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After successfully establishing the protocol for regioselective ortho-arylation of
phenylacetamides, further transformation of mono-arylacetamide 3a was studied. Amides and
their derivative are ubiquitous in nature and supply crucial intermediates to pharmaceuticals,
dyes and pesticides based industry. The functionalizable primary amide group can be easily
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hydrolyzed to the corresponding carboxylic acid 4a by treating with 40% H2SO4 at 100 C
(Scheme 6a). Dehydration of amide 3a with PPh3/NCS lead to the formation of
biphenylacetonitrile 4b in 93% yield (Scheme 6b).
Scheme 6: Transformation of biarylacetamide
Although the reaction mechanism is not clear at this stage, we propose a plausible reaction
mechanism based on earlier literature reports (Scheme 7).12b,20 We believe that the reaction might
have followed Pd(II)/Pd(IV) catalytic pathway.20a The acetamide has two possible coordinating
sites: a) carbonyl oxygen b) electron-rich nitrogen (-NH2) to form six-membered palladacycle
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intermediate. To resolve the ambiguity, we tried to get the crystal of six-membered palladacycle
intermediate, but unfortunately, failed to obtain. Further, full quantum chemical calculations
were done with density functional theory (DFT) using Gaussian 09 program package in order to
understand the coordination site of directing group under standard conditions (for details, please
see the SI).19 The result revealed that the formation of complex A is more exothermic in
comparison to the complex A’ (Scheme 7). The exothermicity, H equals -7.30 kcal/mol at the
LANL2DZ level and is -6.51 kcal/mol using LANL2TZ (f) basis set. The relative free energy
change, G is -7.42 kcal/mol at the LANL2DZ level and -6.73 kcal/mol LANL2TZ (f) levels,
respectively. This implies that the formation of complex A is more favored under reaction
conditions (Equilibrium Constant = 3.6×104, ∆G=-6.73kcal/mol). Based on ab inito calculation,
we believe that the reaction would have started with coordination of the carbonyl oxygen20b,d,21 of
phenylacetamide with Pd(OAc)2 to produce species A and subsequently, C(sp2)−H bond
activation at ortho-position to form a six-membered palladacycle species B. Then, oxidative
addition22 of aryl iodide to Pd(II) species B would afford to give a Pd(IV) intermediates C,
followed by reductive elimination to afford the desired product 3a and regenerate the Pd(II)
catalyst. Silver salt may have acted as a halide scavenger to improve the efficacy of
transformation.23
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Scheme 7: Proposed Reaction Mechanism
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In conclusion, we have developed an efficient and robust strategy for Pd(II)-catalyzed regio-
selective ortho-arylation of arylacetamides by using functionalizable primary acetamide (-
CH2CONH2) as a directing group for the first time. The developed protocol has a series of
advantages, a) regio-selective ortho-arylation, b) simple catalytic system, c) step economy, d)
broad substrate scope, e) gram scale synthesis, and f) no additional requirement of installation
and removal of the directing group. These advantages make acetamide as a better directing group
in comparison to the other reported N-substituted amides. Detailed mechanistic studies are in
progress, and study of a new application of acetamide as a directing group in the construction of
C−C or C−heteroatom bonds is underway in our laboratory.
Experimental Section
General Information: All reagents were purchased from a commercial supplier and used
1
without further purification unless specified. H NMR spectra were recorded at 400 MHz and
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13C{1H} NMR spectra were recorded at 100 MHz, CDCl3 and DMSO-d6 were used as a solvent.
TMS was used for internal referencing. Chemical shift is reported in parts per million. Data were
reported as follows: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiple, br, broad singlet), coupling constant (Hertz), integration. Infrared spectra were recorded
by FT-IR apparatus. HRMS spectra were performed on ESI-TOF spectrometer and acetonitrile
was used to dissolve the sample. Column chromatography was performed on silica gel (100-200)
mesh using ethylacetate and hexanes as eluent in different ratio.
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Preparation of Starting Material: Phenylacetamide and its derivatives 1a-1k were synthesized
by following know reported precedure.24
General Procedure for Pd-catalyzed ortho-Arylation of Arylacetamides (GP-A):
In a oven dried 15 mL pressure tube, aryl acetamide (0.25mmol, 1 equiv.), Pd(OAc)2 (5mol %,
2.8 mg), aryliodide (0.375 mmol, 1.5 equiv) and acetic acid (2.5 mL) were added. Subsequently,
silver tetrafluoroborate (0.5mmol, 98.3 mg, 2.0 equiv) was added in the reaction mixture under
nitrogen atmosphere. The reaction mixture was further flushed with nitrogen and closed with
screw cap. The reaction mixture was stirred at 50 oC for 8-15 h. The progress of the reaction was
monitored by TLC analysis. After completion of reaction, solvent was evaporated under reduced
pressure and the organic layer was neutralized with saturated sodium bicarbonate solution and
extracted with ethyl acetate (15 mL x 3). Organic layer was washed with brine solution (10 mL)
and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude
residue was purified using silica gel column chromatography with hexanes and EtOAc (70:30) as
the eluent to afford the corresponding products.
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2-Biphenyl 2-yl acetamide (3a).11 Following GP-A, 3a was prepared in 8 h and isolated as white
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crystalline solid (37.9 mg, 72% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 169-171 C; IR
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(ATR)3371, 3185, 1656, 1396, 750 cm-1;1H NMR(400MHz,CDCl3) δ 7.36-7.25 (m, 6H), 7.25-
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7.18 (m, 3H), 5.74 (brs, 1H), 5.20 (brs, 1H),3.45(s, 2H); C{1H} NMR(100MHz,CDCl3) 173.8,
142.6, 140.8, 132.4, 130.6, 130.5, 129.0 (2C), 128.4 (2C), 128.0, 127.5, 127.4, 40.8.
2-[1,1ˈ3;1̎]Terphenyl-2ˈ-ylacetamide (3aa). Following GP-A, 3aa was prepared in 8 h and
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isolated as white solid (8.6 mg, 12% yield ); Rf (6:4 Hexane/EtOAc) = 0.5; Mp 222-224 C;IR
(ATR) 3384, 3194, 1657, 1626, 1397, 1280, 756 cm-1;1H NMR (400 MHz, CDCl3) δ 7.35-7.25
(m, 11H), 7.22-7.18 (m, 2H), 5.24 (brs, 1H), 4.94 (brs, 1H), 3.38 (s, 2H); C{1H} NMR (100
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MHz, CDCl3)173.7, 143.6 (2C), 141.5 (2C), 130.3, 129.7 (2C), 129.2 (4C), 128.3 (4C), 127.3
(2C), 127.0, 38.1.HRMS (ESI-TOF) m/z calcd for C20H18NO [M+H]+ 288.1383, Found
288.1384.
2-(3-Methoxy-Biphenyl-2-yl)-acetamide (3b). Following GP-A, 3b was prepared in 8 h and
isolated as white solid (44.5 mg, 74% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 213-215
oC;IR(ATR)3369, 3178, 1648, 1403, 697 cm-1; H NMR(400MHz, DMSO-d6 with CDCl3) δ
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13
7.4 Hz, 1H), 6.67 (brs, 1H), 3.81 (s, 3H), 3.33 (s, 2H); C{1H}NMR (100MHz, DMSO-d6with
CDCl3) δ 172.7, 157.8, 143.3, 140.9, 128.9 (2C), 127.9(2C), 127.1, 126.8, 122.3, 121.7, 109.2,
55.4, 34.1; HRMS (ESI-TOF) m/z calcd for C15H15NO2Na [M+Na]+ 264.0995, Found 264.1002.
2-(5-Methoxy-Biphenyl-2-yl)-acetamide (3c).Following GP-A, 3c was prepared in 8 h and
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isolated as white solid (36.1mg, 60% yield); Rf (6:4 Hexane/EtOAc) = 0.25; Mp 143-145 C;
IR(ATR) 3365, 3178, 1647, 1489, 705 cm-1; H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m,3H),
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7.31-7.26 (m,3H), 6.93-6.90 (m, 1H), 6.84 (d,J=2.8,1H), 5.63 (brs,1H), 5.28 (brs,1H), 3.82
(s,3H) 3.45 (s, 2H); 13C{1H} NMR (100MHz,CDCl3)174.1,158.7, 143.8, 140.8, 131.7, 128.9
(2C), 128.5 (2C), 127.5,124.5,115.7,113.8,55.4, 30.0; HRMS (ESI-TOF) m/z calcd for
C15H15NO2Na [M+Na]+ 264.0995, Found 264.1003.
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2-(5ˈ-Methoxy-[1,1ˈ3ˈ;1̎]Terphenyl-2ˈ-yl)-acetamide (3cc).Following GP-A, 3cc was prepared
in 8 h and isolated as white solid (19.8 mg, 25% yield); Rf (6:4 Hexane/EtOAc) = 0.55; Mp201-
203oC;IR (ATR) 3385, 3183, 1656, 1595, 1338, 1431 cm-1;1H NMR (400 MHz, CDCl3) δ 7.34-
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7.25 (m, 10H), 6.78 ( s, 2H), 5.25 (brs, 1H), 4.99 (brs, 1H), 3.75 (s, 3H), 3.29 (s, 2H); C{1H}
NMR (100 MHz, CDCl3) 174.2, 157.9, 144.8 (2C), 141.5 (2C), 129.0 (4C), 128.3 (4C), 127.3
(2C), 122.6, 115.2 (2C), 55.4, 37.4. HRMS (ESI-TOF) m/z calcd for C21H20NO2 [M+H]+
318.1489, Found 318.1487.
2-(4-Methyl-Biphenyl-2-yl)-acetamide(3d).11 Following GP-A, 3d was prepared in 8 h and
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isolated as white solid (52 mg, 92% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 160-162 C; IR
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(ATR) 3402,3201, 1651, 1485, 1396, 759cm-1; H NMR(400MHz,CDCl3) δ 7.43-7.39 (m, 2H),
7.37-7.33 (m,1H), 7.30-7.25 (m, 2H), 7.21-7.15 (m, 3H), 5.54 (brs,1H), 5.26 (brs,1H), 3.51 (s,
2H), 2.40 (s,3H); 13C{1H} NMR(100MHz, CDCl3)173.7, 140.8, 139.7, 137.8, 132.1, 131.2 (2C),
130.5 (2C), 129.1, 128.42, 128.36, 127.2, 41.3, 21.0.
2-(4-Phenyl-benzo (1,3)Dioxol-5-yl)-acetamide(3e.) Following GP-A, 3e was prepared in 8 h
and isolated as White solid (40.1 mg, 63% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 161-163 oC;
IR(ATR)3378, 3194, 1649, 1507, 1224, 767cm-1;1H NMR(400MHz,DMSO-d6with CDCl3) δ
7.39-7.30 (m, 5H), 6.83 (s, 2H), 6.67 (s, 1H), 6.56 (brs, 1H), 5.98 (s, 2H), 3.33 (s, 2H); 13C{1H}
NMR(100 MHz, DMSO-d6 with CDCl3)173.0, 146.4, 145.9, 140.6, 135.3, 129.0 (2C), 127.8
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(2C), 126.5, 126.2, 109.9, 109.4, 100.6, 39.3; HRMS (ESI-TOF) m/z calcd for C15H13NO3Na [M
+ Na]+ 278.0788, Found 278.0794.
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2-(5-Chloro-Biphenyl-2-yl)-acetamide(3f).11 Following GP-A, 3f was prepared in 15 h and
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isolated as White solid (43 mg, 68% yield); Rf (6:4 Hexane/EtOAc) = 0.35;Mp 176-178 C;
IR(ATR)3377, 3188, 1653, 1417, 1392, 1288 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.45-7.34 (m,
3H), 7.33 (s, 2H), 7.31-7.27 (m, 3H), 5.61 (brs, 1H), 5.22 (brs, 1H), 3.48 (s, 2H);13C{1H} NMR
(100 MHz, CDCl3) 173.0, 144.1, 139.6, 133.1, 131.9, 130.9, 130.3, 128.9 (2C), 128.6 (2C),
128.0, 127.9, 40.0.
2-(5-Bromo-Biphenyl-2-yl)-acetamide (3g). Following GP-A, 3g was prepared in 15 h and
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isolated as white solid (31.9mg, 44%yield); Rf (6:4 Hexane/EtOAc) = 0.27; Mp 186-188 C; IR
(ATR) 3390, 3196, 1653, 1417,844 cm-1; 1H NMR(400MHz, DMSO-d6with CDCl3 ) δ 7.46-7.35
(m, 7H), 7.27 (d, J=8.2 Hz, 1H), 7.19 (brs, 1H), 6.78 (brs, 1H), 3.36 (s, 2H); 13C{1H}
NMR(100MHz, DMSO-d6with CDCl3)172.2, 144.0, 139.4, 132.7, 132.3, 131.9, 129.7, 128.8
(2C), 128.0 (2C), 127.2, 119.4, 38.8;HRMS (ESI-TOF) m/z calcd for C14H12NBrONa [M + Na]+
311.9994, Found 311.9997.
2-(5ˈ-Bromo-[1,1ˈ3ˈ;1̎]Terphenyl-2ˈ-yl)-acetamide (3gg).Following GP-A, 3gg was prepared in
15 h and isolated as white solid (18.3 mg, 20% yield); Rf (6:4 Hexane/EtOAc) = 0.55; Mp 239-
241 oC; IR (ATR) 3393, 3194, 1654, 1400, 873 cm-1. 1H NMR (400 MHz,DMSO-d6with CDCl3)
δ 7.39-7.32 (m, 10H), 7.31 (s, 2H), 6.77 (brs, 1H), 6.46 (brs, 1H), 3.19 (s, 2H); C{1H} NMR
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(100 MHz,DMSO-d6with CDCl3) 172.8, 145.1 (2C), 140.0 (2C), 131.1 (2C), 130.6, 128.6 (4C),
127.9 (4C), 127.2 (2C), 119.1, 37.1; HRMS (ESI-TOF) m/z calcd for C20H17BrNO [M+H]+
366.0488, Found 366.0484.
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2-(4-Fluoro-Biphenyl-2-yl)-acetamide (3h).11 Following GP-A, 3h was prepared in 15 h and
isolated as White solid (38.3 mg, 67% yield); Rf (6:4 Hexane/EtOAc) = 0.35;Mp 146-148 oC; IR
(ATR) 3334, 3203, 1651, 1481, 759 cm-1; 1H NMR(400MHz, DMSO-d6with CDCl3) δ 7.42-7.38
(m, 2H), 7.35-7.32 (m, 3H), 7.23-7.20 (m, 1H), 7.17 (brs, 1H), 7.13-7.10 (m, 1H), 7.04-6.99 (m,
1H), 6.76 (brs, 1H), 3.41 (s, 2H); 13C{1H}NMR(100MHz, DMSO-d6with CDCl3)172.2, 162.4
and 160.0 (J(C-F) = 248 Hz), 139.8, 138.03 and 138.00, (J(C-F)= 3 Hz), 135.7 and 135.6 (J(C-F)= 8
Hz), 131.1 and 131.0 (J(C-F)= 8 Hz), 129.0, 127.9 (2C), 126.8 (2C), 116.7 and 116.4 (J(C-F)= 21
Hz), 113.2 and 113.0 (J(C-F)= 21 Hz), 39.4.
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2-(4,5-Dichloro-Biphenyl-2-yl)-acetamide(3i). Following GP-A, 3i was prepared in 15 h and
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isolated as white solid (44.2mg, 63% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 191-193 C; IR
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(ATR) 3403, 3208, 1652, 1465, 701 cm1. H NMR(400MHz,DMSO-d6with CDCl3) δ 7.54 (s,
1H), 7.44-7.33 (m, 7H), 6.89 (brs, 1H), 3.36 (s, 2H); 13C{1H}NMR (100MHz,DMSO-d6with
CDCl3) 171.7, 142.2, 138.4, 134.3, 132.2, 130.9, 129.8, 129.0, 128.8 (2C), 128.1 (2C), 127.6,
38.5; HRMS (ESI-TOF) m/z calcd for C14H11Cl2NONa [M +Na]+ 302.0110, Found 302.0124.
2-(5-Nitro-Biphenyl-2-yl)-acetamide (3j).11Following GP-A, 3j was prepared in 24 h and
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isolated as White solid (25.8 mg, 40% yield); Rf (6:4 Hexane/EtOAc) = 0.25; Mp 216-218 C;
IR(ATR) 3302, 3201, 1658, 1517, 1342, 578 cm-1;1H NMR (400MHz, DMSO-d6with CDCl3) δ
8.16 (dd, J= 8.5, 2.5 Hz, 1H), 8.02 (d, J = 2.4 Hz,1H), 7.62 (d, J = 8.5 Hz, 1H), 7.48-7.41 (m,
6H), 6.95 (brs, 1H), 3.53 (s, 2H); 13C{1H}NMR (100 MHz, DMSO-d6 with CDCl3) 171.4, 145.9,
143.0, 141.5, 138.7, 131.9, 128.8 (2C), 128.2 (2C), 127.8, 124.0, 121.6, 39.2.
2-(3-Phenyl-naphtalen-2-yl)-acetamide(3k). Following GP-A, 3k was prepared in 15 h and
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isolated as White solid (42.5mg, 65%yield); Rf (6:4 Hexane/EtOAc) = 0.35; Mp 178-180 C;
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IR(ATR) 3387, 3201, 1651, 1396, 640 cm-1;1H NMR (400MHz, DMSO-d6with CDCl3) δ 7.86-
7.83 (m, 3H), 7.72 (s, 1H), 7.50-7.37 (m, 7H), 7.21 (brs, 1H), 6.84 (brs, 1H), 3.55 (s, 2H);
13C{1H}NMR (100MHz,DMSO-d6with CDCl3) 172.5, 140.7, 140.5, 132.1, 132.0, 131.8, 129.2,
128.9 (2C), 128.2 (2C), 127.9, 127.3, 126.93, 126.91, 125.9, 125.7, 39.82; HRMS (ESI-TOF)
m/z calcd for C18H15NONa [M + Na]+ 284.1046, found 284.1062.
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2-(4׳-Methyl-Biphenyl-2-yl)-acetamide (3l). Following GP-A, 3l was prepared in 8 h and
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isolated as White solid (42.1mg,75%yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 168-170 C;
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IR(ATR) 3382, 3191, 1655, 1396, 755 cm-1; H NMR(400MHz,CDCl3) δ 7.38-7.31 (m,3H),
7.29-7.25 (m, 1H), 7.23-7.17 (m, 4H), 5.69 (brs, 1H), 5.27 (brs,1H), 3.54 (s,2H),2.39(s, 3H);
13C{1H} NMR(100 MHz, CDCl3) 173.8,142.6,137.8,137.1,132.5,130.63,130.58,129.1
(2C),128.9 (2C),127.8,127.5,40.9,21.2; HRMS (ESI-TOF) m/z Calcd for C15H16NO [M+H]+
226.1226, Found 226.1230.
2-(3׳-Methoxy-Biphenyl-2-yl)-acetamide (3m).Following GP-A, 3m was prepared in 8 h and
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isolated as White solid (41mg, 68%yield); Rf (6:4 Hexane/EtOAc) = 0.35;Mp 142-144 C;
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5H), 6.92-6.86 (m, 3H), 6.71 (brs, 1H), 6.48 (brs, 1H), 3.80 (s, 3H), 3.46 (s, 2H); 13C{1H}
NMR(100MHz,CDCl3) 173.1, 158.7, 142.0, 141.7, 132.7, 130.1, 129.4, 128.7, 127.0, 126.3,
121.0, 114.2, 112.5, 54.7, 39.7; HRMS (ESI-TOF) m/z calcd for C15H15NO2Na[ M + Na]+
264.0995, Found 264.0997.
2-(3׳-Methyl-Biphenyl-2-yl)-acetamide (3n). Following GP-A, 3n was prepared in 8 h and
isolated as White solid (39.5 mg, 70%yield); Rf (6:4 Hexane/EtOAc) = 0.35; Mp 159-161 oC; IR
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5H), 7.17 (d, J = 7.64, 1H), 7.09 (d, J = 7.92, 2H), 5.77 (brs, 1H), 5.27 (brs, 1H), 3.53 (s, 2H),
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2.38(s, 3H); C{1H} NMR(100 MHz, CDCl3)173.8, 142.7, 140.8, 138.0, 132.4, 130.56, 130.50
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129.8, 128.3, 128.1, 127.9, 127.4, 126.1, 40.8, 21.4; HRMS (ESI-TOF) m/z calcd for
C15H15NONa [M + Na]+ 248.1046, Found 248.1049.
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2-(3,3̎ dimethyl-[1,1ˈ3ˈ;1̎]Terphenyl-2ˈ-yl)acetamide (3nn). Following GP-A, 3nn was prepared
in 8 h and isolated as white solid (10.2 mg, 13% yield); Rf (6:4 Hexane/EtOAc) = 0.5; Mp 194-
196 oC; IR (ATR) 3399, 3175, 1651, 1415, 778 cm-1;1H NMR (400 MHz, CDCl3) 7.29-7.25 (m,
1H), 7.21-7.17 (m, 4H), 7.08 (s, 4H), 7.07 (s, 2H), 5.48 (brs, 1H), 5.97 (brs, 1H), 3.38 (s, 2H),
2.29 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) 174.0, 143.6 (2C), 141.4 (2C), 137.8 (2C),
130.2, 130.0 (2C), 129.6 (2C), 128.1 (2C), 128.0 (2C), 127.0, 126.2 (2C), 38.2, 21.5 (2C);
HRMS (ESI-TOF) m/z calcd for C22H22NO [M + H]+316.1696, Found 316.1698.
2-(4׳-Methoxy-Biphenyl-2-yl)-acetamide (3o).Following GP-A, 3o was prepared in 8 h and
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isolated as White solid (33.2mg, 55%yield); Rf (6:4 Hexane/EtOAc) = 0.35; Mp 148-150 C; IR
(ATR) 3382, 3191, 1655, 1396, 755 cm-1; 1H NMR(400 MHz,CDCl3) δ 7.38-7.28 (m, 4H), 7.22
(d, J = 8.0Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 5.65 (brs, 1H), 5.29 (brs, 1H), 3.85 (s, 3H), 3.55 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3) 174.0, 159.1, 142.2, 133.3, 132.8, 130.9, 130.8, 130.4
(2C), 127.9, 127.7, 114.0 (2C), 55.5, 41.0;HRMS (ESI-TOF) m/z calcd for C15H15NO2Na[M +
Na]+264.0995, Found264.0984.
2-(4׳-Trifluoromethyl-Biphenyl-2-yl)-acetamide (3p).Following GP-A, 3p was prepared in 15 h
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and isolated as white solid (24.3mg, 35% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 208-210 C;
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7.77(d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.38-7.31 (m, 4H), 7.24 (d, J = 6.8 Hz, 1H), 6.8
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(brs, 1H), 3.36 (s, 2H); 13C{1H} NMR(100MHz, DMSO-d6with CDCl3)172.2, 145.06, 140.3,
133.6, 130.6, 129.9, 129.5, 127.8 and 127.5 (J(C-F) = 31 Hz) 126.6, 125.7 and 122.9 (J(C-F) = 270
Hz), 124.93 (q, J(C-F) = 4 Hz), 124.89, 39.1; HRMS (ESI-TOF) m/z calcd for C15H12F3NONa [M
+ Na]+ 302.0763, Found 302.0740.
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2-(4׳-Nitro-Biphenyl-2-yl)-acetamide (3q). Following GP-A, 3q was prepared in 15 h and
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isolated as White solid (39 mg, 60%yield); Rf (6:4 Hexane/EtOAc) = 0.3;Mp 278-280 C;
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IR(ATR) 3383,3198, 1651, 1510, 1348, 854 cm-1; H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8
Hz, 2H), 7.52 (d, J = 12 Hz, 2H), 7.48-7.39 (m, 3H), 7.30-7.28 (m, 1H), 5.61 (brs, 1H), 5.35 (brs,
1H), 3.51 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3)172.8, 147.6, 147.2, 140.4, 132.0, 131.0,
130.15, 130.13(2C), 129.1, 127.9, 123.7 (2C), 40.5; HRMS (ESI-TOF) m/z calcd for
C14H13N2O3 [M+H]+ 257.0921, found 257.0923.
2-(2-Napthalane-1-yl-phenyl)-acetamide (3r).Following GP-A, 3r was prepared in 15 h and
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isolated as White solid (34 mg, 52%yield); Rf (6:4 Hexane/EtOAc) = 0.45;Mp 148-150 C;
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7.53-7.31 (m,9H), 5.37(brs,1H), 5.01 (brs,1H),3.34(d, J=15.8, 1H), 3.21(d, J=15.8,1H); 13C{1H}
NMR (100 MHz, CDCl3) 173.3,140.4,138.2, 133.8, 133.6,132.0,131.1,130.3,128.4,128.3, 128.1,
127.4,127.2,126.4,126.0,125.7,125.4,40.7; HRMS (ESI-TOF) m/z calcd for C18H15NONa [M
+Na]+ 284.1046, found 284.1052.
2-(4׳-Methoxy-4-Methyl-Biphenyl-2-yl)-acetamide (3s). Following GP-A, 3s was prepared in 8
h and isolated as white solid (37mg, 58%yield); Rf (6:4 Hexane/EtOAc) = 0.35; Mp 154-156 oC;
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6.95-6.93 (m,2H), 5.57(brs,1H), 5.28(brs,1H), 3.84 (s,3H), 3.52 (s,2H),2.38(s,3H); 13C{1H}
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NMR (100 MHz, CDCl3) 173.8, 158.8, 139.3, 137.5, 133.1, 132.3, 131.2 (2C),130.7, 130.2,
128.4, 113.9 (2C), 55.3, 40.9, 21.0; HRMS (ESI-TOF) m/z calcd for C16H17NO2Na [M + Na]+
278.1151, Found 278.1153.
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2-(4,3׳-Dimethyl-Biphenyl-2-yl)-acetamide (3t). Following GP-A, 3t was prepared in 8 h and
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isolated as white solid (48 mg, 82% yield); Rf (6:4 Hexane/EtOAc) = 0.3; Mp 147-149 C;
IR(ATR) 3382, 3182, 1651, 1406, 663 cm-1;1H NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 1H),
7.18-7.13b (m, 4H), 7.09-7.07 (m, 2H), 5.71 (brs, 1H), 5.27 (brs,1H), 3.51 (s, 2H), 2.39 (s, 3H),
13
2.37 (s, 3H); C{1H} NMR (100 MHz, CDCl3) 173.9, 140.7, 139.8, 138.0, 137.6, 132.1, 131.1,
130.4, 129.9, 128.2, 127.9 (2C), 126.1, 40.8, 21.5, 21.0; HRMS (ESI-TOF) m/z calcd for
C16H17NONa [M + Na]+ 262.1202, Found 262.1202.
2-(4׳-Hydroxy-4-Methyl-Biphenyl-2-yl)-acetamide (3u). Following GP-A, 3u was prepared in 8
h and isolated as white solid (54.5 mg, 90% yield); Rf (6:4 Hexane/EtOAc) = 0.25;Mp 157-159
oC; IR(ATR) 3469,3327, 1653, 1456, 788, 704 cm-1; 1H NMR (400 MHz, DMSO-d6with CDCl3)
δ 9.22 (s, 1H), 7.17-7.05 (m, 4H), 6.88 (brs, 1H), 6.75-6.73 (m, 3H), 6.63 (brs, 1H), 3.41 (s, 2H),
2.35 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6 with CDCl3) 173.0, 156.8, 142.0, 139.2,
136.0, 132.7, 130.6, 129.3, 128.7, 127.0, 119.8, 116.0, 113.7, 39.46, 20.7; HRMS (ESI-TOF) m/z
calcd for C15H15NO2Na [M +Na]+ 264.0995, Found 264.0993.
Procedure for synthesis of Biphenyl acetic acid (4a).
By following a reported literature method,25 the solution of 3a (53 mg, 0.25mmol) in 3 mL of
o
40% (v/v) sulphuric acid was heated at 100 C for 20 h. After completion of reaction, mixture
was diluted with water and extract with diethyl ether (15 mL x 3). The organic layer was dried
over sodium sulphate and concentrate under reduced pressure to give colorless solid.
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Biphenyl-2-yl acetic acid (4a)26.Colorless solid (50.5mg, 95%yield); Mp 118-120 oC; IR (ATR)
3009 (br), 1694, 1419, 934, 697 cm-1.1H NMR (400 MHz, CDCl3) δ 7.41-7.27 (m, 9H), 3.62 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3)178.3, 142.6, 140.9, 131.0, 130.4, 130.3, 129.2 (2C),
128.3 (2C), 127.6, 127.4, 127.2, 38.5.
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Procedure for synthesis of Biphenyl-2-yl acetonitrile (4b).
By following known literature procedure,27 a solution of triphenylphosphine (131.1 mg, 0.5
mmol) and N-chlorosuccinimide (66.7mg, 0.5 mmol) in dichloromethane (4 mL) was prepared.
Biphenyl acetamide (53 mg, 0.25 mmol) was added in the solution. The reaction mixture was
stirred at room temperature for 45 min. After completion of reaction solvent was dried in vacuum
and crude product was purified by column chromatography using ethyl acetate and hexanes as
eluent to give biphenyl-2-yl acetonitrile as colorless liquid.
Biphenyl-2-yl acetonitrile (4b)28.Colourless liquid (45 mg, 93% yeild); IR (ATR) 3050, 2255,
1460, 745 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57-7.53 (m, 1H), 7.48-7.42 (m, 2H), 7.41-7.37
(m, 3H), 7.30-7.25 (m, 3H), 3.63 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) 141.9, 139.9, 130.5,
128.9 (2C), 128.7 (2C), 128.24, 128.23, 127.8, 127.7, 118.3, 22.0.
Procedure for gram scale synthesis.
Ina oven dried 250 mL round bottom flask, phenylacetamide (10 mmol, 1.35 g, 1equiv),
Pd(OAc)2 (5mol %, 112 mg), iodobenzene (15 mmol, 3.06 g, 1.5 equiv) and acetic acid (100 mL)
were added. Subsequently, silvertetrafluoroborate (20 mmol, 3.9 g, 2.0 equiv) was added in
reaction mixture under nitrogen atmosphere. The reaction mixture was flush with nitrogen and
o
tightly closed with a rubber septum. The reaction mixture was stirred at 50 C for 8 h. After
completion of reaction, the solvent was evaporated under reduced pressure and the organic layer
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was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (200
mL x 3). The organic layer was washed with brine solution and dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The crude product was purified by column
chromatography using ethyl acetate and hexanes as eluent to give 64% (1.35 g) of
biarylacetamide.
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ACKNOWLEDGMENTS
This work was supported by CSIR (02(0229)/15/EMR-II), New Delhi and Indian Institute of
Technology (IIT) Patna. Y. Jaiswal and Y. Kumar thank IIT Patna for an Institute Research
Fellowship. The authors also acknowledge SAIF-Punjab University for providing NMR
analytical facilities and SAIF-IIT Patna for HRMS facilities.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.1H
NMR and 13C NMR spectra of products and optimization of reaction conditions, DFT
calculation.
AUTHOR INFORMATION
Corresponding Author
*E-mail:amitkt@iitp.ac.in or amitktiitk@gmail.com
Notes
The authors declare no competing financial interest.
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